CN116693595A - 一种雷公藤甲素衍生物及其制备方法和应用 - Google Patents
一种雷公藤甲素衍生物及其制备方法和应用 Download PDFInfo
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- CN116693595A CN116693595A CN202310675273.5A CN202310675273A CN116693595A CN 116693595 A CN116693595 A CN 116693595A CN 202310675273 A CN202310675273 A CN 202310675273A CN 116693595 A CN116693595 A CN 116693595A
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- triptolide
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- compound
- triptolide derivative
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- DFBIRQPKNDILPW-CIVMWXNOSA-N Triptolide Chemical class O=C1OCC([C@@H]2C3)=C1CC[C@]2(C)[C@]12O[C@H]1[C@@H]1O[C@]1(C(C)C)[C@@H](O)[C@]21[C@H]3O1 DFBIRQPKNDILPW-CIVMWXNOSA-N 0.000 title claims abstract description 67
- 238000002360 preparation method Methods 0.000 title claims abstract description 37
- 239000002243 precursor Substances 0.000 claims abstract description 24
- 150000003839 salts Chemical class 0.000 claims abstract description 24
- 239000004480 active ingredient Substances 0.000 claims abstract description 12
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- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 7
- 239000003937 drug carrier Substances 0.000 claims abstract description 6
- 238000004519 manufacturing process Methods 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 37
- -1 hydroxy, amino Chemical group 0.000 claims description 29
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 21
- 229910052739 hydrogen Inorganic materials 0.000 claims description 15
- YKUJZZHGTWVWHA-UHFFFAOYSA-N triptolide Natural products COC12CC3OC3(C(C)C)C(O)C14OC4CC5C6=C(CCC25C)C(=O)OC6 YKUJZZHGTWVWHA-UHFFFAOYSA-N 0.000 claims description 14
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
- 229910052799 carbon Inorganic materials 0.000 claims description 12
- 238000005917 acylation reaction Methods 0.000 claims description 11
- 238000006467 substitution reaction Methods 0.000 claims description 11
- 229910052736 halogen Inorganic materials 0.000 claims description 10
- 150000002367 halogens Chemical class 0.000 claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 7
- 238000006482 condensation reaction Methods 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
- 125000001424 substituent group Chemical group 0.000 claims description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
- NXLNNXIXOYSCMB-UHFFFAOYSA-N (4-nitrophenyl) carbonochloridate Chemical compound [O-][N+](=O)C1=CC=C(OC(Cl)=O)C=C1 NXLNNXIXOYSCMB-UHFFFAOYSA-N 0.000 claims description 5
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Abstract
本发明提供了一种雷公藤甲素衍生物及其制备方法和应用,属于医药化学技术领域。本发明提供的雷公藤甲素衍生物具有式(I)所示结构。药理活性实验表明,本发明提供的雷公藤甲素衍生物及其药学上可接受的盐或前体物对HIV‑1蛋白酶具有良好的抑制活性,可作为抗艾滋病药物活性成分。本发明提供了上述雷公藤甲素衍生物的制备方法,此法操作简单,易于实现工业化批量生产。进一步的,本发明提供了一种抗艾滋病药物组合物,包括活性成分和药物载体,所述活性成分为上述雷公藤甲素衍生物及其药学上可接受的盐或前体物。此药物组合物可用作HIV‑1蛋白酶抑制剂。
Description
技术领域
本发明涉及医药化学技术领域,特别涉及一种雷公藤甲素衍生物及其制备方法和应用。
背景技术
获得性免疫缺陷综合征,是人类因感染免疫缺陷病毒(Human ImmunodeficiencyVirus,HIV)而导致免疫缺陷,并引发一系列机会性感染及肿瘤的综合征。虽然目前已有多种防治HIV的途径,但研发新型的抗HIV药物仍是治疗艾滋病的最有效的方式。
在艾滋病治疗的最初阶段,临床上仅使用核苷类逆转录酶抑制剂如拉夫米定、齐多夫定等单一药物。1995年第一个HIV蛋白酶抑制剂沙奎那韦(Saquinavir)的上市意味着高效抗逆转录病毒联合疗法(HAART)的开端,HAART可最大限度地抑制病毒的复制,延缓病程进展,极大地延长了患者的生命,提高了生活质量。
日益增加的HIV/AIDS患者给社会带来了巨大负担,危害了社会经济发展及稳定。目前,HIV/AIDS的治疗仍采用药物治疗。但是,随着各种抗HIV药物的频繁使用,越来越多的药物产生了耐药性,从而限制了其临床应用。HIV-1PR是由HIV基因编码的一种特异性天冬氨酰蛋白酶,抑制蛋白酶的活性可使被感染的细胞只能产生不成熟、不具有感染性的病毒。因此,HIV-1PR是研发抗HIV药物的重要靶点。
发明内容
有鉴于此,本发明目的在于提供一种雷公藤甲素衍生物及其制备方法和应用。本发明提供的雷公藤甲素衍生物及其药学上可接受的盐或前体物具有良好的HIV-1蛋白激酶抑制活性。
为了实现上述发明目的,本发明提供以下技术方案:
本发明提供了雷公藤甲素衍生物及其药学上可接受的盐或前体物,其特征在于,所述雷公藤甲素衍生物具有式(I)所示结构:
式(I)中,R1为H、取代或非取代的C1~C4烷基、取代或非取代的C3~C6环烷基,取代或非取代的6~10元芳基或取代或非取代的5~10元杂芳基;
R2为H、卤素、-CN、-CF3、-OCF3、-OR21、-CH2OR21、-SR21、-CH2SR21、-NR21R22、C1~C4烷基或C3~C6环烷基;其中R21、R22独立地为H或C1~C4烷基;
R3为R或S型;R3选自H、C1~C4烷基、C3~C6环烷基、-CH2OR31、-CH2SR31或-CH2CONR31R32;其中R31、R32独立地为H或C1~C4烷基。
优选的,所述取代的C1~C4烷基、取代的C3~C6环烷基,取代的6~10元芳基或取代的5~10元杂芳基中,取代基的数量为1~3个;所述取代基独立地为氢、卤素、羟基、氨基、三氟甲基、三氟甲氧基、巯基、C1~C4烷基、C1~C4烷硫基或C1~C4烷氧基。
优选的,R1为H、
R2为H、卤素、-CN、-CF3、-OCF3、-OR21、-SR21或-NR21R22;其中R21、R22独立地为H或C1~C4烷基。
优选的,R3为H、-CH3或-CH2CONH2。
优选的,具有式1~31任意一项所示结构:
本发明提供了雷公藤甲素衍生物及其药学上可接受的盐或前体物的制备方法,所述雷公藤甲素衍生物的制备方法,包括以下步骤:
在吡啶的作用下,具有式A所示结构的雷公藤甲素与具有式B所示结构的氯甲酸对硝基苯酯进行取代反应,得到具有式C所示结构的化合物;
具有式D所示结构的化合物与具有式E所示结构的化合物进行缩合反应,经脱Boc保护后得到具有式F所示结构的化合物;
在三乙胺的作用下,具有式C所示结构的化合物与具有式F所示结构的化合物进行酰化反应,得到雷公藤甲素衍生物。
优选的,所述取代反应的温度为0~25℃,时间为2~4h;
所述缩合反应的温度为0~25℃,时间为2~5h;
所述脱Boc保护的温度为25℃,时间为2~5h。
优选的,所述具有式C所示结构的化合物与三乙胺的摩尔比为1:2~3;
所述酰化反应的温度为25℃,时间为2~5h。
本发明提供了上述雷公藤甲素衍生物及其药学上可接受的盐或前体物在制备抗艾滋病药物中的应用。
本发明提供了一种抗艾滋病药物组合物,包括活性成分和药物载体,其特征在于,所述活性成分包括上述雷公藤甲素衍生物及其药学上可接受的盐或前体物。
本发明提供了雷公藤甲素衍生物及其药学上可接受的盐或前体物,所述雷公藤甲素衍生物具有式(I)所示结构。药理活性实验表明,本发明提供的雷公藤甲素衍生物及其药学上可接受的盐或前体物对HIV-1蛋白酶具有良好的抑制活性,可作为抗艾滋病药物活性成分。
本发明提供了上述雷公藤甲素衍生物的制备方法,此法操作简单,易于实现工业化批量生产。
进一步的,本发明提供了一种抗艾滋病药物组合物,包括活性成分和药物载体,所述活性成分为上述雷公藤甲素衍生物及其药学上可接受的盐或前体物。此药物组合物可用作HIV-1蛋白酶抑制剂。
附图说明
图1为雷公藤甲素衍生物的合成路线图。
具体实施方式
本发明提供了雷公藤甲素衍生物及其药学上可接受的盐或前体物,所述雷公藤甲素衍生物具有式(I)所示结构:
式(I)中,R1为H、取代或非取代的C1~C4烷基、取代或非取代的C3~C6环烷基,取代或非取代的6~10元芳基或取代或非取代的5~10元杂芳基。在本发明中,所述取代或非取代的6~10元芳基或取代或非取代的5~10元杂芳基中,杂原子独立为为O、N或S;所述杂原子的数量独立优选为1~3个。
在本发明中,所述取代的C1~C4烷基、取代的C3~C6环烷基,取代的6~10元芳基或取代的5~10元杂芳基中,取代基记为R11,所述取代基的数量优选为1~3个;所述取代基独立地优选为氢、卤素、羟基、氨基、三氟甲基、三氟甲氧基、巯基、C1~C4烷基、C1~C4烷硫基或C1~C4烷氧基。
在本发明中,R1优选为H、
在本发明中,R2为H、卤素、-CN、-CF3、-OCF3、-OR21、-CH2OR21、-SR21、-CH2SR21、-NR21R22、C1~C4烷基或C3~C6环烷基;其中R21、R22独立地为H或C1~C4烷基;在本发明中,R21、R22相同或不同,R21、R22独立地为H或C1~C4烷基。进一步的,R2优选为H、卤素、-CN、-CF3、-OCF3、-OR21、-SR21、-NR21R22。
在本发明中,R3为R或S型;R3选自H、C1~C4烷基、C3~C6环烷基、-CH2OR31、-CH2SR31或-CH2CONR31R32;在本发明中,R31、R32相同或不同,R31、R32独立地为H或C1~C4烷基。
在本发明中,R3优选为H、-CH3或-CH2CONH2。
在本发明中,上述C1~C4烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基;C3~C6环烷基为环丙基、环丁基、环戊基或环己基。
在本发明中,上述卤素为氟、氯、溴或碘;上述芳基为单环或多环的环状芳香体系,杂芳基为含有一个或多个选自N、O、S杂原子的单环或多环的环状体系。
在本发明中,所述雷公藤甲素衍生物优选具有表1所示结构。
表1雷公藤甲素衍生物的结构和名称
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在本发明中,所述雷公藤甲素衍生物及其药学上可接受的盐或前体物中,所述药学上可接受的盐为与雷公藤甲素衍生物与酸加成得到的盐。在本发明中,所述酸为无机酸和/或有机酸,具体优选为盐酸、氢溴酸、硫酸、磷酸、甲磺酸、乙磺酸、对甲苯磺酸、苯磺酸、萘二磺酸、乙酸、丙酸、乳酸、三氟乙酸、马来酸、柠檬酸、富马酸、草酸、酒石酸和苯甲酸中的一种或几种。
本发明还提供了雷公藤甲素类衍生物的前体物,即前药。本发明雷公藤甲素类衍生物衍生物的前药是式(I)的衍生物,它们自身可能具有较弱的活性甚至没有活性,但是给药后,在生理条件下(例如通过代谢、溶剂分解或另外的方式)被转化成相应的生物活性形式。
本发明提供了上述雷公藤甲素衍生物及其药学上可接受的盐或前体物的制备方法,所述雷公藤甲素衍生物的制备方法,包括以下步骤:
在吡啶的作用下,具有式A所示结构的雷公藤甲素与具有式B所示结构的氯甲酸对硝基苯酯进行取代反应,得到具有式C所示结构的化合物;
具有式D所示结构的化合物与具有式E所示结构的化合物进行缩合反应,经脱Boc保护后得到具有式F所示结构的化合物;
在三乙胺的作用下,具有式C所示结构的化合物与具有式F所示结构的化合物进行酰化反应,得到雷公藤甲素衍生物。
在本发明中,在吡啶的作用下,具有式A所示结构的雷公藤甲素与具有式B所示结构的氯甲酸对硝基苯酯进行取代反应,得到具有式C所示结构的化合物。在本发明中,具有式A所示结构的雷公藤甲素与吡啶的摩尔比优选为1:2。在本发明中,所述取代反应优选在有机溶剂中进行,所述有机溶剂优选为二氯甲烷。
在本发明中,所述取代反应的温度优选为0~25℃,时间优选为2~4h,更优选为3h。
所述取代反应后,本发明优选对所得取代反应液进行后处理。在本发明中,所述后处理优选包括以下步骤:
将所述取代反应液与水混合,合并有机相,去除有机溶剂,进行柱层析分离,得到具有式C所示结构的化合物纯品。
在本发明中,所述去除有机溶剂的方式优选为减压浓缩;所述柱层析分离的流动相为环己烷和乙酸乙酯,所述环己烷和乙酸乙酯的体积比为1:1。
在本发明中,具有式D所示结构的化合物与具有式E所示结构的化合物进行缩合反应,经脱Boc保护后得到具有式F所示结构的化合物。在本发明中,所述缩合反应的温度优选为0~25℃,时间优选为2~5h,更优选为3~4h;所述脱Boc保护的温度优选为25℃,时间优选为2~5h,更优选为3~4h。
在本发明中,所述具有式F所示结构的化合物的制备方法参考BioorganicMedicinal Chemistry Letters 25(2015)1880–1883;European Journal of MedicinalChemistry 137(2017)30-44;Bioorganic&Medicinal Chemistry 28(2020)115623。
在本发明中,在三乙胺的作用下,具有式C所示结构的化合物与具有式F所示结构的化合物进行酰化反应,得到雷公藤甲素衍生物。在本发明中,所述具有式C所示结构的化合物与三乙胺的摩尔比优选为1:2~3,更优选为1:2.29。在本发明中,所述酰化反应优选在有机溶剂中进行,所述有机溶剂优选为乙腈。
在本发明中,所述酰化反应的温度优选为25℃,时间优选为2~5h,更优选为3~4h。
所述酰化反应后,本发明优选对所得酰化反应液进行后处理。在本发明中,所述后处理优选包括以下步骤:
去除所述酰化反应液的有机溶剂,萃取有机相,进行干燥和柱层析分离,得到雷公藤甲素衍生物纯品。
在本发明中,去除有机溶剂的方式优选为减压浓缩。在本发明中,所述萃取使用的萃取剂优选为乙酸乙酯,干燥使用的干燥剂优选为无水硫酸钠。在本发明中,所述柱层析分离优选使用硅胶柱,所述柱层析的流动相优选为二氯甲烷和甲醇,所述二氯甲烷和甲醇的体积比优选为50:1。
在本发明中,所述雷公藤甲素衍生物的合成路线如图1所示。
本发明提供了上述雷公藤甲素衍生物及其药学上可接受的盐或前体物在制备抗艾滋病药物中的应用。
本发明提供了一种抗艾滋病药物组合物,包括活性成分和药物载体,其特征在于,所述活性成分包括上述雷公藤甲素衍生物及其药学上可接受的盐或前体物。
在本发明中,所述药物载体优选为微囊、微球、纳米粒和脂质体中的一种或几种。
下面结合实施例对本发明提供的雷公藤甲素衍生物及其制备方法和应用进行详细的说明,但是不能把它们理解为对本发明保护范围的限定。
以下实施例在合成方法上具有代表性,本发明式(I)所示结构雷公藤甲素衍生物(尤其是表一中的化合物1至31)均可参照合成路线以及实施例的制备方法合成得到。
实施例1化合物1的制备:雷公藤甲素-(2-(((2S,3R)-3-羟基-4-((N-异丁基-4-甲氧基苯基)磺酰胺基)-1-苯基丁烷-2-基)胺基)-2-氧代乙基)氨基酸甲酯
步骤A:雷公藤甲素-(4-硝基苯基)甲酸酯的制备(C)
将雷公藤甲素(0.30g,0.83mmol)加入含有15mL二氯甲烷的50mL茄型瓶中,冰浴下缓慢滴加氯甲酸对硝基苯酯(0.25g,1.25mmol),随后缓慢加入吡啶(0.13mL,1.66mmol),加毕后转移至室温反应2小时,TLC检测反应完毕,分3次加入45mL水,有机相合并,减压浓缩除去二氯甲烷,粗品经柱层析(流动相正己烷:乙酸乙酯=1:1)后得到目标产品,白色固体0.32g(73.4%)。
1H NMR(400MHz,Chloroform-d)δ8.29(d,J=9.0Hz,2H),7.44(d,J=9.0Hz,2H),4.91(s,1H),4.75–4.66(m,2H),3.88(d,J=3.0Hz,1H),3.61(d,J=3.0Hz,1H),3.56(d,J=5.4Hz,1H),2.73(d,J=12.8Hz,1H),2.37–2.32(m,1H),2.26–2.16(m,2H),2.07–1.93(m,2H),1.68(s,1H),1.63–1.59(m,1H),1.11(s,3H),1.03(d,J=7.0Hz,3H),0.91(d,J=7.0Hz,3H);
13C NMR(101MHz,Chloroform-d)δ173.17,159.70,155.45,152.50,145.41,125.71,125.27,121.72,69.98,63.39,62.78,61.53,59.61,55.33,55.18,40.30,35.66,29.83,28.25,23.36,17.52,17.05,16.67,13.82;
LC-MS(ESI)[M+H]+m/z 525.2.
步骤B:化合物1的制备
将中间体C(0.20g,0.38mmol),Et3N(0.12ml,0.87mmol),2-胺基-N-((2S,3R)-3-羟基-4-((N-异丁基-4-甲氧基苯基)磺酰胺)-1-苯基丁烷-2-基)乙酰胺(0.16g,0.34mmol)加入到含有10mL乙腈的50mL茄形瓶中,室温反应2.5小时,TLC检测反应完毕,反应体系减压浓缩除去多余的乙腈后用30mL(3×10mL)乙酸乙酯萃取,有机相用无水硫酸钠干燥,选用CH2Cl2:MeOH=50:1的流动相硅胶柱层析,得到白色固体化合物10.17g(53.1%)。
1HNMR(400MHz,MeOD)δ7.77(d,J=8.8Hz,2H),7.24–7.19(m,4H),7.15–7.11(m,1H),7.05(d,J=8.8Hz,2H),4.90(s,1H),4.79–4.72(m,2H),4.01(ddd,J=10.6,6.8,3.6Hz,1H),3.96(d,J=3.2Hz,1H),3.84(s,3H),3.82–3.80(m,1H),3.60–3.58(m,2H),3.51(d,J=5.6Hz,1H),3.39(dd,J=15.0,3.2Hz,1H),3.18(dd,J=14.0,3.6Hz,1H),3.00(dd,J=13.6,8.4Hz,1H),2.85(dd,J=15.0,8.8Hz,1H),2.77(dd,J=13.6,6.6Hz,2H),2.61(dd,J=14.0,10.8Hz,1H),2.28–2.19(m,2H),2.06(d,J=8.8Hz,1H),2.00–1.88(m,3H),1.48(dd,J=12.4,4.8Hz,1H),1.38–1.27(m,2H),1.05(s,3H),0.92(d,J=7.0Hz,3H),0.88(d,J=7.0Hz,3H),0.82(d,J=4.8Hz,3H),0.80(d,J=4.8Hz,3H).
13C NMR(101MHz,MeOD)δ174.6,170.2,163.1,162.3,157.1,138.4,130.6,129.3,128.9,127.9,125.9,124.1,113.9,72.7,72.6,70.5,63.5,62.9,61.9,60.5,57.9,55.7,54.8,54.3,52.7,43.6,40.0,35.6,35.4,29.4,28.2,26.5,22.8,19.1,19.0,16.6,16.5,15.7,13.0.
HRMS(ESI)m/z calcd.for C44H55N3O12S([M+Na]+):872.3404,found872.3391.
实施例2化合物2的制备:雷公藤甲素-(2-(((2S,3R)-3-羟基-4-((N-异丁基-4-胺基苯基)磺酰胺基)-1-苯基丁烷-2-基)胺基)-2-氧代乙基)氨基酸甲酯
制备方法参照实施例1,其中,步骤B中将2-胺基-N-((2S,3R)-3-羟基-4-((N-异丁基-4-甲氧基苯基)磺酰胺)-1-苯基丁烷-2-基)乙酰胺替换为2-胺基-N-((2S,3R)-3-羟基-4-((N-异丁基-4-甲氧基苯基)磺酰胺)-1-苯基丁烷-2-基)乙酰胺。
1H NMR(400MHz,MeOD)δ7.50(d,J=8.8Hz,2H),7.24–7.19(m,4H),7.15–7.11(m,1H),6.67(d,J=8.8Hz,2H),4.90(s,1H),4.80–4.72(m,2H),4.03(ddd,J=10.4,6.4,3.6Hz,1H),3.95(d,J=3.2Hz,1H),3.83–3.79(m,1H),3.62(d,J=17.0Hz,1H),3.58(d,J=2.8Hz,1H),3.52(d,J=17.0Hz,1H),3.49(d,J=5.6Hz,1H),3.37–3.32(m,1H),3.16(dd,J=14.0,3.6Hz,1H),2.93(dd,J=13.6,8.0Hz,1H),2.84(dd,J=15.0,8.4Hz,1H),2.73(dd,J=13.6,6.8Hz,2H),2.62(dd,J=14.0,10.8Hz,1H),2.27–2.22(m,1H),2.20(d,J=5.4Hz,1H),2.06(d,J=8.8Hz,1H),1.98–1.87(m,3H),1.47(dd,J=12.4,4.8Hz,1H),1.30(td,J=11.8,5.6Hz,1H),1.04(s,3H),0.92(d,J=7.0Hz,3H),0.88(d,J=6.8Hz,3H),0.82(t,J=6.8Hz,6H).
13C NMR(101MHz,MeOD)δ174.6,170.2,162.4,157.0,152.8,138.5,129.2,128.9,127.9,125.8,124.5,124.1,113.1,72.7,70.6,63.5,63.0,61.9,60.4,58.1,55.7,54.7,54.3,52.8,43.6,40.0,35.4,29.4,28.2,26.6,22.8,19.2,19.1,16.6,16.5,15.7,13.0.
HRMS(ESI)m/z calcd.for C43H54N4O11S([M+Na]+):857.3407,857.3440.
实施例3化合物3的制备:雷公藤甲素-(2-(((2S,3R)-3-羟基-4-((N-异丁基-4-甲硫基苯基)磺酰胺基)-1-苯基丁烷-2-基)胺基)-2-氧代乙基)氨基酸甲酯
制备方法参照实施例1,其中,步骤B中将2-胺基-N-((2S,3R)-3-羟基-4-((N-异丁基-4-甲氧基苯基)磺酰胺)-1-苯基丁烷-2-基)乙酰胺替换为2-胺基-N-((2S,3R)-3-羟基-4-((N-异丁基-4-甲硫基苯基)磺酰胺)-1-苯基丁烷-2-基)乙酰胺。
1H NMR(400MHz,MeOD)δ7.73(d,J=8.6Hz,2H),7.36(d,J=8.6Hz,2H),7.24–7.18(m,4H),7.15–7.11(m,1H),4.90(s,1H),4.79–4.72(m,2H),4.03–4.00(m,1H),3.95(d,J=3.2Hz,1H),3.84–3.79(m,1H),3.59–3.58(m,2H),3.55(s,1H),3.51–3.50(m,1H),3.41(dd,J=15.0,3.2Hz,1H),3.18(dd,J=14.0,3.6Hz,1H),3.02(dd,J=13.6,8.4Hz,1H),2.87(dd,J=15.0,9.0Hz,1H),2.80–2.73(m,2H),2.60(dd,J=14.0,10.8Hz,1H),2.50(s,3H),2.28–2.19(m,2H),2.06(dd,J=14.8,5.6Hz,1H),1.99(dd,J=14.0,7.2Hz,1H),1.94–1.87(m,2H),1.48(dd,J=12.4,4.8Hz,1H),1.35–1.27(m,1H),1.04(s,3H),0.92(d,J=7.0Hz,3H),0.89(d,J=7.0Hz,3H),0.81(t,J=7.0Hz,6H).
13C NMR(101MHz,MeOD)δ174.6,170.2,162.3,157.1,145.8,138.4,134.7,128.9,127.9,127.6,125.9,125.1,124.1,72.7,72.6,70.5,63.5,62.9,61.9,60.5,57.8,55.7,54.7,54.4,52.7,43.6,40.0,35.7,35.4,29.4,28.2,26.5,22.8,19.1,19.0,16.6,16.5,15.7,13.2,13.1.
HRMS(ESI)m/z calcd.for C44H55N3O11S2([M+Na]+):888.3176,found888.3210.
实施例4化合物6的制备:雷公藤甲素-(2-(((2S,3R)-3-羟基-4-((N-环丙基-4-甲氧基苯基)磺酰胺基)-1-苯基丁烷-2-基)胺基)-2-氧代乙基)氨基酸甲酯
制备方法参照实施例1,其中,步骤B中将2-胺基-N-((2S,3R)-3-羟基-4-((N-异丁基-4-甲氧基苯基)磺酰胺)-1-苯基丁烷-2-基)乙酰胺替换为2-胺基-N-((2S,3R)-3-羟基-4-((N-环丙基-4-甲氧基苯基)磺酰胺)-1-苯基丁烷-2-基)乙酰胺。
1H NMR(400MHz,CDCl3)δ7.85(d,J=8.8Hz,2H),7.35–7.32(m,2H),7.29–7.23(m,3H),7.04(d,J=8.8Hz,2H),5.00(s,1H),4.79–4.69(m,2H),4.18(tt,J=9.6,4.8Hz,1H),4.03(dd,J=8.4,4.4Hz,1H),3.99–3.96(m,1H),3.91(d,J=5.6Hz,4H),3.61–3.55(m,2H),3.52(d,J=5.6Hz,1H),3.47(dd,J=14.4,4.4Hz,1H),3.24(dd,J=14.0,4.0Hz,1H),3.04(dd,J=14.4,8.4Hz,1H),2.82(dd,J=14.0,10.4Hz,1H),2.71(d,J=12.8Hz,1H),2.37(d,J=16.0Hz,1H),2.21(dt,J=14.8,5.6Hz,2H),2.07–1.99(m,3H),1.61(dd,J=12.0,4.8Hz,1H),1.30–1.26(m,1H),1.14(s,3H),1.04(d,J=7.0Hz,3H),0.99(d,J=6.4Hz,1H),0.91(d,J=7.0Hz,3H),0.88–0.81(m,1H),0.79–0.74(m,1H),0.71–0.64(m,1H).
13C NMR(101MHz,CDCl3)δ173.3,169.3,163.3,160.1,156.3,138.2,130.1,129.4,128.5,128.4,126.5,125.5,114.3,72.9,72.6,70.2,63.5,63.3,62.6,60.9,56.0,55.7,55.2,54.9,54.3,44.6,40.3,35.7,35.5,32.9,30.0,28.5,23.4,17.6,17.1,16.7,14.1,8.12,7.15.
HRMS(ESI)m/z calcd.for C43H51N3O12S([M+Na]+):856.3091,found856.3115.
实施例5化合物11的制备:雷公藤甲素((S)-1-(((2S,3R)-3-羟基-4-((N-异丁基-4-甲氧基苯基)磺酰胺基)-1-苯基丁烷-2-基)胺基)-1-氧代丙烷-2-基)氨基酸甲酯
制备方法参照实施例1,其中,步骤B中将2-胺基-N-((2S,3R)-3-羟基-4-((N-异丁基-4-甲氧基苯基)磺酰胺)-1-苯基丁烷-2-基)乙酰胺替换为(S)-2-胺基-N-((2S,3R)-3-羟基-4-((N-异丁基-4-甲氧基苯基)磺酰胺)-1-苯基丁烷-2-基)丙酰胺。
1H NMR(400MHz,MeOD)δ7.81(d,J=8.8Hz,2H),7.25–7.19(m,4H),7.13(t,J=7.0Hz,1H),7.03(d,J=8.8Hz,2H),4.93(s,1H),4.81–4.73(m,2H),3.99(d,J=3.2Hz,1H),3.95(dd,J=7.2,3.6Hz,1H),3.90(d,J=7.2Hz,1H),3.84(d,J=11.2Hz,4H),3.61–3.60(m,2H),3.41(dd,J=15.0,3.0Hz,1H),3.23(d,J=3.6Hz,1H),3.00(dd,J=13.6,8.8Hz,1H),2.84(dd,J=15.0,9.2Hz,1H),2.75(dd,J=13.6,6.4Hz,2H),2.60(dd,J=13.8,11.2Hz,1H),2.30–2.20(m,2H),1.99–1.87(m,3H),1.50(dd,J=12.4,4.8Hz,1H),1.35(dd,J=12.0,6.0Hz,1H),1.31–1.27(m,1H),1.10(s,3H),0.99(d,J=7.2Hz,3H),0.96(d,J=7.2Hz,3H),0.89(d,J=6.8Hz,3H),0.85(d,J=6.8Hz,3H),0.80(d,J=6.8Hz,3H).
13C NMR(101MHz,MeOD)δ174.6,173.5,163.0,162.3,156.3,138.4,130.7,129.4,129.0,127.9,125.9,124.1,113.9,72.8,72.7,70.5,63.5,62.9,62.5,60.9,58.1,56.0,54.8,54.7,54.5,52.9,51.1,39.9,36.1,35.4,29.5,28.6,26.5,22.8,19.1,16.6,16.5,16.2,15.7,13.2.
HRMS(ESI)m/z calcd.for C45H57N3O12S([M+Na]+):886.3561,found886.3564.
实施例6化合物12的制备:雷公藤甲素((S)-1-(((2S,3R)-3-羟基-4-((N-异丁基-4-胺基苯基)磺酰胺基)-1-苯基丁烷-2-基)胺基)-1-氧代丙烷-2-基)氨基酸甲酯
制备方法参照实施例1,其中,步骤B中将2-胺基-N-((2S,3R)-3-羟基-4-((N-异丁基-4-甲氧基苯基)磺酰胺)-1-苯基丁烷-2-基)乙酰胺替换为(S)-2-胺基-N-((2S,3R)-3-羟基-4-((N-异丁基-4-胺基苯基)磺酰胺)-1-苯基丁烷-2-基)丙酰胺。
1H NMR(400MHz,MeOD)δ7.53(d,J=8.8Hz,2H),7.25–7.19(m,4H),7.14–7.11(m,1H),6.66(d,J=8.8Hz,2H),4.92(s,1H),4.80–4.73(m,2H),3.98(d,J=3.2Hz,1H),3.97–3.93(m,1H),3.91(d,J=7.2Hz,1H),3.85–3.80(m,1H),3.60(d,J=2.8Hz,1H),3.58(d,J=5.6Hz,1H),3.36(dd,J=15.0,3.2Hz,1H),3.23(dd,J=14.0,3.2Hz,1H),2.94(dd,J=13.6,8.4Hz,1H),2.82(dd,J=15.0,9.2Hz,1H),2.71(dd,J=13.6,6.4Hz,2H),2.61(dd,J=13.8,11.2Hz,1H),2.28–2.22(m,1H),2.20(s,1H),2.07(d,J=8.8Hz,1H),1.98–1.86(m,3H),1.49(dd,J=12.4,4.8Hz,1H),1.33(dd,J=12.0,5.6Hz,1H),1.08(s,3H),1.01(d,J=7.2Hz,3H),0.95(d,J=7.0Hz,3H),0.88(d,J=6.8Hz,3H),0.85(d,J=6.8Hz,3H),0.82(d,J=6.8Hz,3H).
13C NMR(101MHz,MeOD)δ174.6,173.4,162.3,156.2,152.8,138.4,129.2,129.0,127.9,125.9,124.7,124.1,113.1,72.7,70.6,63.5,62.9,62.4,60.9,58.2,56.0,54.8,54.4,53.0,51.0,39.9,35.9,35.4,29.5,28.6,26.6,22.8,19.2,19.1,16.6,16.5,16.3,15.7,13.2.
HRMS(ESI)m/z calcd.for C44H56N4O11S([M+Na]+):871.3564,found871.3589.
实施例7化合物13的制备:雷公藤甲素((S)-1-(((2S,3R)-3-羟基-4-((N-异丁基-4-甲硫基苯基)磺酰胺基)-1-苯基丁烷-2-基)胺基)-1-氧代丙烷-2-基)氨基酸甲酯
制备方法参照实施例1,其中,步骤B中将2-胺基-N-((2S,3R)-3-羟基-4-((N-异丁基-4-甲氧基苯基)磺酰胺)-1-苯基丁烷-2-基)乙酰胺替换为(S)-2-胺基-N-((2S,3R)-3-羟基-4-((N-异丁基-4-甲硫苯基)磺酰胺)-1-苯基丁烷-2-基)丙酰胺。
1H NMR(400MHz,MeOD)δ7.77(d,J=8.6Hz,2H),7.35(d,J=8.6Hz,2H),7.25–7.22(m,2H),7.20–7.18(m,2H),7.15–7.11(m,1H),4.93(s,1H),4.81–4.73(m,2H),3.99(d,J=3.2Hz,1H),3.93–3.89(m,2H),3.87–3.81(m,1H),3.61–3.59(m,2H),3.42(dd,J=15.0,3.0Hz,1H),3.23(d,J=3.6Hz,1H),3.02(dd,J=13.6,8.8Hz,1H),2.86(dd,J=15.0,9.6Hz,1H),2.79–2.75(m,2H),2.60(dd,J=14.0,11.2Hz,1H),2.49(s,3H),2.28–2.21(m,2H),2.00–1.87(m,3H),1.50(dd,J=12.4,4.8Hz,1H),1.37–1.26(m,2H),1.09(s,3H),0.99(d,J=7.2Hz,3H),0.96(d,J=7.2Hz,3H),0.89(d,J=6.8Hz,3H),0.85(d,J=6.8Hz,3H),0.81(d,J=6.8Hz,3H).
13C NMR(101MHz,MeOD)δ174.6,173.6,162.3,156.3,145.7,138.4,134.8,128.9,128.0,127.6,125.9,125.0,124.1,72.8,72.7,70.5,63.5,62.9,62.5,61.0,58.0,56.0,54.8,54.5,52.9,51.1,39.9,36.1,35.4,29.5,28.6,26.5,22.8,19.1,16.6,16.5,16.2,15.7,13.3,13.2.
HRMS(ESI)m/z calcd.for C45H57N3O11S2([M+Na]+):902.3332,found902.3340.
实施例8化合物21的制备:雷公藤甲素((R)-1-(((2S,3R)-3-羟基-4-((N-异丁基-4-甲氧基苯基)磺酰胺基)-1-苯基丁烷-2-基)胺基)-1-氧代丙烷-2-基)氨基酸甲酯
制备方法参照实施例1,其中,步骤B中将2-胺基-N-((2S,3R)-3-羟基-4-((N-异丁基-4-甲氧基苯基)磺酰胺)-1-苯基丁烷-2-基)乙酰胺替换为(R)-2-胺基-N-((2S,3R)-3-羟基-4-((N-异丁基-4-甲氧基苯基)磺酰胺)-1-苯基丁烷-2-基)丙酰胺。
1H NMR(400MHz,MeOD)δ7.74(d,J=8.8Hz,2H),7.22–7.18(m,4H),7.14–7.10(m,1H),7.05(d,J=8.8Hz,2H),4.78–4.71(m,3H),3.98(ddd,J=11.2,7.6,3.6Hz,1H),3.91(d,J=3.2Hz,1H),3.88(d,J=7.2Hz,1H),3.85(s,3H),3.72(td,J=8.8,2.8Hz,1H),3.51(d,J=2.8Hz,1H),3.42–3.35(m,2H),3.23(dd,J=14.0,3.6Hz,1H),2.98–2.92(m,2H),2.83(dd,J=13.2,7.2Hz,1H),2.74–2.71(m,1H),2.54(dd,J=14.0,11.2Hz,1H),2.25–2.19(m,2H),2.06–1.93(m,2H),1.84(dt,J=13.6,10.0Hz,2H),1.45(dd,J=12.4,4.4Hz,1H),1.32–1.27(m,1H),0.99(s,3H),0.88(t,J=6.8Hz,6H),0.84(d,J=6.8Hz,3H),0.74(d,J=6.8Hz,3H),0.64(d,J=6.8Hz,3H).
13C NMR(101MHz,MeOD)δ174.6,173.7,163.0,162.4,155.8,138.6,130.7,129.3,128.9,127.8,125.8,124.1,114.0,73.3,72.0,70.5,63.6,63.1,61.0,59.7,57.8,55.5,54.8,54.6,53.6,52.8,50.7,40.0,35.8,35.4,29.3,27.6,26.5,22.7,19.1,19.0,16.7,16.6,16.4,15.6,12.7.
HRMS(ESI)m/z calcd.for C45H57N3O12S([M+Na]+):886.3561,found886.3572.
实施例9化合物26的制备:雷公藤甲素((R)-1-(((2S,3R)-3-羟基-4-((N-((S)-2-羟丙基)-4-甲氧基苯基)磺酰胺基)-1-苯基丁烷-2-基)胺基)-1-氧代丙烷-2-基)氨基酸甲酯
制备方法参照实施例1,其中,步骤B中将2-胺基-N-((2S,3R)-3-羟基-4-((N-异丁基-4-甲氧基苯基)磺酰胺)-1-苯基丁烷-2-基)乙酰胺替换为(R)-2-胺基-N-((2S,3R)-3-羟基-4-((N-((S)-2-羟丙基)-4-甲氧基苯基)磺酰胺基)-1-苯基丁烷-2-基)丙酰胺。
1H NMR(600MHz,CDCl3)δ7.73(d,J=8.8Hz,2H),7.27–7.25(m,2H),7.22–7.18(m,3H),6.99(d,J=8.8Hz,2H),4.83(s,1H),4.69–4.63(m,2H),4.26–4.21(m,1H),4.11–4.09(m,1H),3.95(t,J=7.0Hz,2H),3.87(s,3H),3.82(d,J=2.8Hz,1H),3.49(d,J=2.4Hz,1H),3.45(d,J=5.6Hz,1H),3.21(dd,J=15.0,7.2Hz,1H),3.14–3.08(m,3H),2.90(dd,J=14.0,9.0Hz,1H),2.86–2.81(m,1H),2.67(d,J=12.6Hz,1H),2.31(d,J=16.4Hz,1H),2.17–2.13(m,2H),1.93–1.89(m,2H),1.55(dd,J=12.0,5.0Hz,1H),1.23–1.19(m,1H),1.17(d,J=7.2Hz,3H),1.13(d,J=7.2Hz,3H),1.05(s,3H),0.86(d,J=6.8Hz,3H),0.77(d,J=6.8Hz,3H).
13C NMR(101MHz,CDCl3)δ173.3,172.2,163.2,160.1,155.8,137.8,129.6,129.3,129.2,128.5,126.5,125.6,114.5,73.0,72.3,70.1,67.0,63.7,63.5,61.2,59.9,58.5,55.7,55.6,54.9,54.2,53.6,51.1,40.4,36.0,35.7,29.9,28.0,23.4,20.8,18.0,17.5,17.1,16.6,13.8.
HRMS(ESI)m/z calcd.for C44H55N3O13S([M+Na]+):888.3353,found888.3380.
实施例10化合物28的制备:雷公藤甲素((R)-1-(((2S,3R)-3-羟基-4-((N-((R)-2-羟丙基)-4-甲氧基苯基)磺酰胺基)-1-苯基丁烷-2-基)胺基)-1-氧代丙烷-2-基)氨基酸甲酯
制备方法参照实施例1,其中,步骤B中将2-胺基-N-((2S,3R)-3-羟基-4-((N-异丁基-4-甲氧基苯基)磺酰胺)-1-苯基丁烷-2-基)乙酰胺替换为(R)-2-胺基-N-((2S,3R)-3-羟基-4-((N-((R)-2-羟丙基)-4-甲氧基苯基)磺酰胺基)-1-苯基丁烷-2-基)丙酰胺。
1H NMR(600MHz,CDCl3)δ7.72(d,J=8.8Hz,2H),7.25(d,J=7.2Hz,2H),7.21–7.17(m,3H),6.99(d,J=8.8Hz,2H),4.84(s,1H),4.70–4.64(m,2H),4.22–4.14(m,2H),4.04(t,J=6.0Hz,1H),3.94–3.92(m,1H),3.87(s,3H),3.82(d,J=2.4Hz,1H),3.46(dd,J=17.4,12.6Hz,3H),3.24(d,J=16.2Hz,1H),3.12(dd,J=14.4,4.8Hz,1H),2.93–2.85(m,2H),2.76(dd,J=12.6,11.4Hz,1H),2.68–2.66(m,1H),2.31(d,J=18.0Hz,1H),2.17–2.10(m,2H),1.90(t,J=15.6Hz,2H),1.56(dd,J=12.6,5.4Hz,1H),1.23–1.19(m,1H),1.16(d,J=6.6Hz,3H),1.13(d,J=7.0Hz,3H),1.06(s,3H),0.88(d,J=6.6Hz,3H),0.76(d,J=6.6Hz,3H).
13C NMR(101MHz,CDCl3)δ173.3,172.2,163.2,160.1,155.6,137.8,129.6,129.5,129.3,128.5,126.5,125.6,114.5,74.1,72.3,70.0,68.1,63.7,63.5,61.2,59.9,59.5,55.8,55.7,54.9,52.9,51.0,40.4,35.7,35.4,29.9,28.0,23.4,20.5,18.0,17.5,17.1,16.6,13.9.
HRMS(ESI)m/z calcd.for C44H55N3O13S([M+Na]+):888.3353,found888.3376.
测试例药理活性测试
本发明所述化合物采用的底物为(Arg-Glu(EDANS)-Ser-Gln-Asn-Tyr-Pro-Ile-Val-Gln-Lys(DABCYL)-Arg)(AnaSpec),底物切点两侧分别标记Edans和Dabcyl发色团。Edans的荧光发色光谱与Dabcyl的吸收光谱重叠,在足够近的距离内通过荧光共振能量转移产生荧光淬灭,使完整的底物几乎没有荧光。当荧光底物经HIV蛋白酶切后,Edans发色团远离了Dabcyl基团,荧光淬灭条件小时,这时Edans就在340nm的激发光下于490nm处产生荧光,加入待测化合物后,化合物对酶抑制活性强时则底物产物减少,荧光强度降低,反之荧光强度增加。
HIV-1蛋白酶在大肠杆菌中表达并纯化,蛋白酶使用PD-10柱脱盐。活性测定在PH4.7的缓冲溶液中进行,缓冲溶液用0.1M醋酸钠、1M氯化钠、1mM EDTA、1mM DTT,2%DMSO和1mg/mL牛血清白蛋白配置。
用96孔板对样品进行HIV-1蛋白酶抑制活性的测定,每孔加入底物(5μM)和缓冲液185μL,加入5μL样品溶液,测定空白吸收,加入10μL HIV-1蛋白酶,孵育5min后测定490nm波长的吸光度,计算出各个浓度下样品的抑制率,用Graphpad软件计算得到IC50值,所得结果如表2所示。
表2化合物1~31HIV-1蛋白酶抑制药理活性测试结果
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表2中的初步药理活性结果显示:本发明提供了雷公藤甲素衍生物具有较好的HIV-1蛋白酶抑制活性,其中化合物30的IC50值为0.16nM,优于阳性对照Darunavir 0.82nM。鉴于目前尚未见将雷公藤甲素引入HIV-1蛋白酶的设计中的研究报道,因此具有式(I)所示结构的了雷公藤甲素衍生物具有良好的进一步研发前景。
以上所述仅是本发明的优选实施方式,应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以做出若干改进和润饰,这些改进和润饰也应视为本发明的保护范围。
Claims (10)
1.雷公藤甲素衍生物及其药学上可接受的盐或前体物,其特征在于,所述雷公藤甲素衍生物具有式(I)所示结构:
式(I)中,R1为H、取代或非取代的C1~C4烷基、取代或非取代的C3~C6环烷基,取代或非取代的6~10元芳基、取代或非取代的5~10元杂芳基中的一种;
R2为H、卤素、-CN、-CF3、-OCF3、-OR21、-CH2OR21、-SR21、-CH2SR21、-NR21R22、C1~C4烷基或C3~C6环烷基;其中R21、R22独立地为H或C1~C4烷基;
R3为R或S型;R3选自H、C1~C4烷基、C3~C6环烷基、-CH2OR31、-CH2SR31或-CH2CONR31R32;其中R31、R32独立地为H或C1~C4烷基。
2.根据权利要求1所述的雷公藤甲素衍生物及其药学上可接受的盐或前体物,其特征在于,所述取代的C1~C4烷基、取代的C3~C6环烷基,取代的6~10元芳基或取代的5~10元杂芳基中,取代基的数量为1~3个;所述取代基独立地为氢、卤素、羟基、氨基、三氟甲基、三氟甲氧基、巯基、C1~C4烷基、C1~C4烷硫基或C1~C4烷氧基。
3.根据权利要求1或2所述的雷公藤甲素衍生物及其药学上可接受的盐或前体物,其特征在于,R1为H、
R2为H、卤素、-CN、-CF3、-OCF3、-OR21、-SR21或-NR21R22;其中R21、R22独立地为H或C1~C4烷基。
4.根据权利要求3所述的雷公藤甲素衍生物及其药学上可接受的盐或前体物,其特征在于,R3为H、-CH3或-CH2CONH2。
5.根据权利要求1所述的雷公藤甲素衍生物及其药学上可接受的盐或前体物,其特征在于,具有式1~31任意一项所示结构:
6.权利要求1~5任意一项所述雷公藤甲素衍生物及其药学上可接受的盐或前体物的制备方法,其特征在于,所述雷公藤甲素衍生物的制备方法,包括以下步骤:
在吡啶的作用下,具有式A所示结构的雷公藤甲素与具有式B所示结构的氯甲酸对硝基苯酯进行取代反应,得到具有式C所示结构的化合物;
具有式D所示结构的化合物与具有式E所示结构的化合物进行缩合反应,经脱Boc保护后得到具有式F所示结构的化合物;
在三乙胺的作用下,具有式C所示结构的化合物与具有式F所示结构的化合物进行酰化反应,得到雷公藤甲素衍生物。
7.根据权利要求6所述的制备方法,其特征在于,所述取代反应的温度为0~25℃,时间为2~4h;
所述缩合反应的温度为0~25℃,时间为2~5h;
所述脱Boc保护的温度为25℃,时间为2~5h。
8.根据权利要求6或7所述的制备方法,其特征在于,所述具有式C所示结构的化合物与三乙胺的摩尔比为1:2~3;
所述酰化反应的温度为25℃,时间为2~5h。
9.权利要求1~5任意一项所述的雷公藤甲素衍生物及其药学上可接受的盐或前体物或权利要求6~8任意一项所述制备方法制备得到的雷公藤甲素衍生物及其药学上可接受的盐或前体物在制备抗艾滋病药物中的应用。
10.一种抗艾滋病药物组合物,包括活性成分和药物载体,其特征在于,所述活性成分包括权利要求1~5任意一项所述的雷公藤甲素衍生物及其药学上可接受的盐或前体物或权利要求6~8任意一项所述制备方法制备得到的雷公藤甲素衍生物及其药学上可接受的盐或前体物。
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