CN108250092B - 对环芳烷-氨基酸衍生物及其制备方法 - Google Patents

对环芳烷-氨基酸衍生物及其制备方法 Download PDF

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CN108250092B
CN108250092B CN201810192298.9A CN201810192298A CN108250092B CN 108250092 B CN108250092 B CN 108250092B CN 201810192298 A CN201810192298 A CN 201810192298A CN 108250092 B CN108250092 B CN 108250092B
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孙彬皓
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Shanghai Xianglihe Pharmaceutical Co ltd
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Abstract

本发明涉及一种对环芳烷‑氨基酸衍生物，它是以从蓝藻中分离、纯化得到的化合物MerocyclophanesA为先导化合物与氨基酸偶联反应制备得到的，经活性测试所述的对环芳烷‑氨基酸衍生物均具备一定的抗小RNA病毒肠道病毒71的活性，具有开发成为抗小RNA病毒药物的潜力。本发明还提供该化合物的制备方法。

Description

对环芳烷-氨基酸衍生物及其制备方法
技术领域
本发明属于药物化学领域，具体涉及一种可作为抗小RNA病毒的药物的对环芳烷-氨基酸衍生物或其药学上可接受的盐或其旋光异构体或其前药或其溶剂合物或其晶体。本发明还涉及这一类衍生物的制备方法。
技术背景
天然产物化学是植物化学、药物化学、生物化学、农业化学的基础，它与生物学、药物学、农艺学等学科密切相关，它的成果可广泛应用于医药、食品、轻工、化工等领域。天然产物化学是以各类生物为研究对象，以有机化学为基础，以化学和物理方法为手段，研究生物二次代谢产物的提取、分离、结构、功能、生物合成、化学合成与修饰及其用途的一门科学，是生物资源开发利用的基础研究。目的是希望从中获得医治严重危害人类健康疾病的防治药物、医用及农用抗菌素、开发高效低毒农药以及植物生长激素和其他具有经济价值的物质。天然产物是自然界的生物历经千百万年的进化过程通过自然选择保留下来的二次代谢产物，具有化学多样性、生物多样性和类药性。临床上应用的许多药物都直接来源于天然产物，同时以天然产物作为先导化合物，综合理性药物分子设计、活性筛选、分子优化等手段为新药的发现提供了新的思路。
对环芳烷衍生物是从蓝藻中分离、纯化得到的一系列化合物，具体可参见DanielS.May等在J.Nat.Prod.2017，80，73-1080发表的文章和Hahk-Soo Kang等在Phytochemistry 2012，79，109–115发表的文章，这一类化合物主要包括MerocyclophanesA，B，C，D等。这一
Figure BDA0001592461340000011
类化合物具有一定的抗肿瘤活性，尤其是抗多药耐药肿瘤活性；本发明专利的发明人为了进一步研究这一类化合物的生物活性，在多种生物模型上进行筛选，偶然发现化合物Merocyclophanes A-D均具有微弱的抗小RNA病毒(肠道病毒71)活性，提示这一类化合物可作为制备抗小RNA病毒(肠道病毒71，EV71)活性的先导化合物。
人类肠病毒71型属于小核糖核酸病毒科，于1969年首次从加利福尼亚患有中枢神经系统疾病的婴儿粪便标本中分离出来的，这些病毒可被培养在恒河猴肾脏细胞(rhesusmonkey kidney cell；RhMK)及人胚二倍体细胞(human fetal diploid cell)中。若检体取自病人粪便及组织即以人胚肾二倍体细胞(diploid strain of human fetal kidneycell；HFDK)培养；若为咽喉拭子检体则选用人胚肺二倍体细胞(diploid strain of humanfetal lung cell)培养。EV 71为目前肠病毒群中最晚发现的病毒，其感染性强且致病率高，尤其是神经系统方面的并发症。其它同属于肠病毒群之病毒尚包括小儿麻痹病毒(Polioviruses；具3种型别)、柯萨奇病毒(Coxsackieviruses；A型具23种型别、B型具6种型别)、伊科病毒(Echoviruses；具31种型别)及肠病毒(Enteroviruses 68～72型)。
目前具备抗小RNA病毒(肠道病毒71，EV71)的小分子化合物很少，发现具备抗小RNA病毒活性的先导化合物无疑对于进一步寻找和发现具有更好活性的抗小RNA病毒药物具有重要的意义。
发明内容
本发明的目的是提供一种具备小RNA病毒(肠道病毒71，EV71)抑制活性的对环芳烷-氨基酸衍生物或其药学上可接受的盐或其旋光异构体或其前药或其溶剂合物或其晶体；本发明的另外一个目的在于提供上述对环芳烷-氨基酸衍生物的制备方法。
本发明的上述目的是通过下面的技术方案得以实现的：
一种对环芳烷-氨基酸衍生物或其药学上可接受的盐或其旋光异构体或其前药或其溶剂合物或其晶体，它具有下述式(Ⅰ)所述的结构，
Figure BDA0001592461340000021
其中R1，R2，R3，R4相同或不同，各自独立的选自下述基团之一：
Figure BDA0001592461340000031
其中
Figure BDA0001592461340000032
表示基团的连接位置，优选的所述的R1，R2，R3，R4相同。
式(Ⅰ)所述的化合物可以通过Scheme 1或Scheme 2所述的方法制备：
Figure BDA0001592461340000033
其中R为氨基酸除羧基和被保护的胺基之外的残基或基团，具体可以为本发明对R1-R4的定义除胺基和羰基之外的残基或基团；所述的氨基酸优选为天然L型氨基酸；P为胺基保护基，所述胺基上的保护基可以但不限于BOC(叔丁氧羰基)、CBZ(苄氧羰基)或Fmoc(芴甲氧羰基)；X为卤素，优选为氯，溴或碘中的一种或几种；在Scheme 1中第一步表示化合物Merocyclophanes A与氨基保护的氨基酸的缩合反应，第二步表示脱除保护基的步骤，所述缩合反应优选在缩合剂的存在下进行，所述的缩合剂优选为碳二亚胺类缩合剂，包括但不限于DCC，DIC,EDCI；所述脱除胺基保护基的方法也是本领域的技术人员所公知的，如三氟乙酸，Pd/C，有机碱(如哌啶等)等；
在Scheme 2中第一步表示化合物Merocyclophanes A与氨基保护的氨基酸酰卤的缩合反应，第二步表示脱除保护基的步骤，所述缩合反应优选在缚酸剂的催化下进行，所述的缚酸剂优选为有机碱或无机碱，包括但不限于碳酸钠，碳酸钾，碳酸氢钠，碳酸氢钾，三乙胺，DMAP等；所述脱除胺基保护基的方法也是本领域的技术人员所公知的，如三氟乙酸，催化氢解，有机碱(如哌啶等)等。
本发明的活性化合物用作药物时，可以直接使用，或者以药物组合物的形式使用。该药物组合物含有治疗有效量的本发明化合物(Ⅰ)，其余为药物学上可接受的、对人和动物无毒和惰性的可药用载体和/或赋形剂。所述的可药用载体或赋形剂是一种或多种选自固体、半固体和液体稀释剂、填料以及药物制品辅剂。将本发明的药物组合物以单位体重服用量的形式使用。本发明药物可通过口服或注射的形式施用于需要治疗的患者。用于口服时，可将其制成片剂、缓释片、控释片、胶囊、滴丸、微丸、混悬剂、乳剂、散剂或颗粒剂、口服液等；用于注射时，可制成灭菌的水性或油性溶液、无菌粉针、脂质体或乳剂等。
本发明的另外一方面提供了式(I)所述化合物、其旋光异构体、药学可接受的盐、溶剂合物或者晶体或者本发明药物组合物在制备用于治疗/或预防与病毒感染有关的疾病或病症的药物中的用途。所述病毒是小RNA病毒，所述小RNA病毒选自：鼻病毒、肠道病毒(优选为肠道病毒71)、口疾病毒、心脏病毒、肝病毒和双艾柯病毒，所述与病毒感染有关的疾病或病症选自：呼吸疾病(包括但不限于：普通感冒(例如夏季感冒)、咽炎、扁桃腺炎和义膜性喉炎)、手足口疾病、脑膜炎/脑炎、急性骨髓。
本发明所述的药学上可接受的盐优选为有机酸盐或无机酸盐，更优选为乙酸盐、丙酸盐、丁酸盐、草酸盐、三甲基乙酸盐、己二酸盐、藻酸盐、乳酸盐、柠檬酸盐、酒石酸盐、琥珀酸盐、马来酸盐、富马酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、硝酸盐、硫酸盐、硫酸氢盐、磷酸盐、磷酸氢盐等。
具体实施例
实施例1：化合物1
Figure BDA0001592461340000041
的制备：
将化合物Merocyclophanes A(
Figure BDA0001592461340000051
55.3mg，0.1mmol)溶于10ml二氯甲烷，加入N-苄氧羰基-丙氨酸(111.6mg，0.5mmol)、DCC(103.2mg，0.5mmol)和DMAP(12.2mg，0.1mmol)，加毕室温反应8小时，HPLC-MS监测反应物反应完全，主要产生一个新物质。过滤，用5ml乙醚洗涤滤饼，旋干溶剂，用硅胶柱色谱纯化，收集并合并所含物质相同的紫外吸收最强的洗脱液，旋干溶剂，加入10ml乙醇和10mg10％的Pd/C，常压氢化反应5小时，HPLC-MS监测反应物反应完全，过滤，旋干溶剂，硅胶柱色谱纯化，制备得到白色固体70.0mg，两步总体收率83.7％，ESI-MS(m/z):[M+H]+837.6。
实施例2：化合物1
Figure BDA0001592461340000052
的制备：
将化合物Merocyclophanes A(
Figure BDA0001592461340000053
55.3mg，0.1mmol)溶于10ml二氯甲烷，加入N-苄氧羰基-丙胺酰氯(120.5mg，0.5mmol)和三乙胺(50.5mg，0.5mmol)，加毕室温反应4小时，HPLC-MS监测反应物反应完全，主要产生一个新物质。加入10ml饱和碳酸氢钠溶液，用10ml二氯甲烷萃取3次，合并有机相，用5ml饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，旋干溶剂。用硅胶柱色谱纯化，收集并合并所含物质相同的紫外吸收最强的洗脱液，旋干溶剂，加入10ml乙醇和10mg10％的Pd/C，常压氢化反应5小时，过滤，旋干溶剂，HPLC-MS监测反应物反应完全，硅胶柱色谱纯化，制备得到白色固体65.0mg，两步总体收率77.7％，ESI-MS(m/z):[M+H]+837.6。
实施例3：化合物2
Figure BDA0001592461340000054
的制备，其中R1-R4均为
Figure BDA0001592461340000055
参考实施例1的制备方法，将N-苄氧羰基-丙氨酸替换为N-苄氧羰基天冬酰胺，得到白色固体79.6mg，两步总体收率78.9％，ESI-MS(m/z):[M+H]+1009.6。
实施例4：化合物3
Figure BDA0001592461340000061
的制备，其中R1-R4均为
Figure BDA0001592461340000062
参考实施例1的制备方法，将N-苄氧羰基-丙氨酸替换为N-苄氧羰基谷氨酰胺，得到白色固体88.5mg，两步总体收率83.2％，ESI-MS(m/z):[M+H]+1065.6。
实施例5：化合物4
Figure BDA0001592461340000063
的制备，其中R1-R4均为
Figure BDA0001592461340000064
参考实施例1的制备方法，将N-苄氧羰基-丙氨酸替换为
Figure BDA0001592461340000065
得到白色固体67.4mg，两步总体收率63.1％，ESI-MS(m/z):[M+H]+1069.6。
实施例6：化合物5
Figure BDA0001592461340000066
的制备，其中R1-R4均为
Figure BDA0001592461340000067
参考实施例1的制备方法，将N-苄氧羰基-丙氨酸替换为
Figure BDA0001592461340000068
得到白色固体84.3mg，两步总体收率76.6％，ESI-MS(m/z):[M+H]+1101.7。
实施例7：化合物6
Figure BDA0001592461340000071
的制备，其中R1-R4均为
Figure BDA0001592461340000072
参考实施例1的制备方法，将N-苄氧羰基-丙氨酸替换为N-苄氧羰基-异亮胺酸，得到白色固体72.0mg，两步总体收率71.6％，ESI-MS(m/z):[M+H]+1005.7。
实施例8：化合物7
Figure BDA0001592461340000073
的制备，其中R1-R4均为
Figure BDA0001592461340000074
参考实施例1的制备方法，将N-苄氧羰基-丙氨酸替换为N-苄氧羰基-甘胺酸，得到白色固体69.9mg，两步总体收率89.5％，ESI-MS(m/z):[M+H]+781.5。
实施例9：化合物8
Figure BDA0001592461340000075
的制备，其中R1-R4均为
Figure BDA0001592461340000076
参考实施例1的制备方法，将N-苄氧羰基-丙氨酸替换为N-苄氧羰基-亮胺酸，得到白色固体81.0mg，两步总体收率80.6％，ESI-MS(m/z):[M+H]+1005.8。
实施例10：化合物9
Figure BDA0001592461340000077
的制备，其中R1-R4均为
Figure BDA0001592461340000078
参考实施例1的制备方法，将N-苄氧羰基-丙氨酸替换为N-苄氧羰基-蛋胺酸，得到白色固体93.9mg，两步总体收率87.2％，ESI-MS(m/z):[M+H]+1077.6。
实施例11：化合物10
Figure BDA0001592461340000081
的制备，其中R1-R4均为
Figure BDA0001592461340000082
参考实施例1的制备方法，将N-苄氧羰基-丙氨酸替换为N，N-双苄氧羰基-赖氨酸，得到白色固体85.0mg，两步总体收率79.9％，ESI-MS(m/z):[M+H]+1065.8。
实施例12：化合物11
Figure BDA0001592461340000083
的制备，其中R1-R4均为
Figure BDA0001592461340000084
参考实施例1的制备方法，将N-苄氧羰基-丙氨酸替换为N-苄氧羰基-苯丙氨酸，得到白色固体96.0mg，两步总体收率84.1％，ESI-MS(m/z):[M+H]+1141.7。
实施例13：化合物12
Figure BDA0001592461340000085
的制备，其中R1-R4均为
Figure BDA0001592461340000086
参考实施例1的制备方法，将N-苄氧羰基-丙氨酸替换为N-苄氧羰基-脯氨酸，得到白色固体73.3mg，两步总体收率77.9％，ESI-MS(m/z):[M+H]+941.6。
实施例14：化合物13
Figure BDA0001592461340000091
的制备，其中R1-R4均为
Figure BDA0001592461340000092
参考实施例1的制备方法，将N-苄氧羰基-丙氨酸替换为N，O-双苄氧羰基-丝氨酸，得到白色固体72.7mg，两步总体收率80.7％，ESI-MS(m/z):[M+H]+901.5。
实施例15：化合物14
Figure BDA0001592461340000093
的制备，其中R1-R4均为
Figure BDA0001592461340000094
参考实施例1的制备方法，将N-苄氧羰基-丙氨酸替换为N，O-双苄氧羰基-苏氨酸，得到白色固体72.0mg，两步总体收率75.3％，ESI-MS(m/z):[M+H]+957.6。
实施例16：化合物15
Figure BDA0001592461340000095
的制备，其中R1-R4均为
Figure BDA0001592461340000096
参考实施例1的制备方法，将N-苄氧羰基-丙氨酸替换为N-苄氧羰基-色氨酸，得到白色固体111.0mg，两步总体收率85.6％，ESI-MS(m/z):[M+H]+1297.7。
实施例17：化合物16
Figure BDA0001592461340000097
的制备，其中R1-R4均为
Figure BDA0001592461340000098
参考实施例1的制备方法，将N-苄氧羰基-丙氨酸替换为N，O-双苄氧羰基-酪氨酸，得到白色固体98.8mg，两步总体收率82.0％，ESI-MS(m/z):[M+H]+1205.7。
实施例18：化合物17
Figure BDA0001592461340000101
的制备，其中R1-R4均为
Figure BDA0001592461340000102
参考实施例1的制备方法，将N-苄氧羰基-丙氨酸替换为N-苄氧羰基-缬氨酸，得到白色固体77.3mg，两步总体收率81.4％，ESI-MS(m/z):[M+H]+949.7。
实施例19：化合物活性测试
以Vero细胞为病毒宿主细胞，测定样品抑制肠道病毒EV71引起Vero细胞病变的程度。其中病毒株肠道病毒EV71由实验室传代保存，Vero细胞由实验室自行传代培养保存。
样品预处理：DMSO配成母液，-20℃冰箱保存，临用前培养液稀释成所需浓度。
测试方法：Vero细胞种96孔培养板，24小时后感染病毒，吸附2小时，弃病毒液，加入含不同浓度样品的维持液，同时设细胞对照孔和病毒对照孔，待病毒对照组病变程度(CPE)达4+时观察各组细胞病变程度(CPE)，完全病变为4，75％病变为3，50％病变为2，25％病变为1，无病变为0。用Reed-Muench法分别计算样品对肠道病毒EV71半数抑制浓度(EC50)，其活性结果如下表所示：
化合物 Merocyclophanes A 1 2 3 4 5 6 7 8
EC50(ng/ml) ＞600 51 78 69 27 89 ＞210 5.3 ＞370
化合物 9 10 11 12 13 14 15 16 17
EC50(μg/ml) ＞230 6.7 29 36 7.6 2.4 98 56 117
以上数据表明本申请制备得到的化合物均具备一定的抗肠道病毒71(EV71)活性，部分化合物的活性显著优于Merocyclophanes A。
应该说明的是，以上实施例仅用于说明本发明的技术方案而非限制，尽管参照较佳的实施例对本发明进行了详细的说明，本领域的普通技术人员应当理解，可以对本发明的技术方案进行修改或者等同替换，而不脱离本发明技术方案的精神和范围，其均涵盖在本发明的权利要求范围内。

Claims (9)

1.式Ⅰ所述结构的具备抗小RNA病毒活性的化合物或其药学上可接受的盐：
Figure FDA0002691799800000011
其特征在于所述的R1，R2，R3，R4相同，选自下述基团之一：
Figure FDA0002691799800000012
2.根据权利要求1所述化合物的药学上可接受的盐，其特征在于所述的盐为药学上可接受的有机酸盐或无机酸盐。
3.一种组合物，其特征在于包含治疗有效量的权利要求1所述的化合物或其药学上可接受的盐。
4.权利要求1所述化合物的制备方法，通过Scheme 1所述的方法制备：
Figure FDA0002691799800000021
1)化合物Merocyclophanes A与氨基保护的氨基酸的缩合反应，所述缩合反应在缩合剂的存在下进行；
2)脱除胺基保护基，其中所述的P为胺基保护基。
5.根据权利要求4所述的方法，其特征在于所述的缩合剂为碳二亚胺类缩合剂。
6.根据权利要求5所述的方法，其特征在于所述的缩合剂为DCC，DIC或EDCI。
7.根据权利要求4所述的方法，其特征在于在三氟乙酸，Pd/C或哌啶的作用下脱除保护基。
8.权利要求1所述化合物的制备方法，通过Scheme 2所述的方法制备：
Figure FDA0002691799800000022
1)化合物Merocyclophanes A与氨基保护的氨基酸酰卤的缩合反应：所述缩合反应在缚酸剂的催化下进行，所述的缚酸剂为有机碱或无机碱；
2)脱除胺基保护基，其中所述的P为胺基保护基。
9.根据权利要求8所述的方法，其特征在于所述的缚酸剂为碳酸钠，碳酸钾，碳酸氢钠，碳酸氢钾，三乙胺或DMAP；在三氟乙酸，Pd/C或哌啶的作用下脱除保护基。
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