CN114656372A - 对苯二胺桥连化合物及其在制备治疗糖代谢紊乱疾病的药物中的应用 - Google Patents
对苯二胺桥连化合物及其在制备治疗糖代谢紊乱疾病的药物中的应用 Download PDFInfo
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- CN114656372A CN114656372A CN202210225352.1A CN202210225352A CN114656372A CN 114656372 A CN114656372 A CN 114656372A CN 202210225352 A CN202210225352 A CN 202210225352A CN 114656372 A CN114656372 A CN 114656372A
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Abstract
Description
本申请是申请号为“202010959328.1”的中国专利申请的分案申请,原申请的申请日为“2020年9月14日”、发明名称为“一种化合物及其制法和在制备治疗糖代谢紊乱疾病的药物中的应用”。
技术领域
本发明属于药物化学领域,具体涉及一种对苯二胺桥连化合物及其制法和在制备治疗糖代谢紊乱疾病的药物中的应用。
背景技术
糖尿病(Diabetes Mellitus,DM)是由于机体胰岛素分泌不足或胰岛素抵抗而引起的以高血糖和糖尿为主要特征的内分泌代谢综合征。糖尿病患者长期处于高血糖状态容易诱发糖尿病并发症,主要有三大类:视网膜病变,如:青光眼、白内障等;周围神经病变,如:末梢神经炎,足部溃疡等;肾脏病变,如:肾微血管病变,严重时会导致肾衰竭、尿毒症等。
此外也可能并发心脑血管病变,可能导致中风、心肌肥厚、充血性心力衰竭等。这些并发症都是机体长期高血糖导致的,高血糖损伤了血管壁及外周神经,大大增加了心血管疾病的风险。
尽管糖尿病一直困扰着患者健康,但是真正威胁患者生命安全的却是由于体内持续高血糖所导致的一系列并发症。这些并发症的发生与醛糖还原酶(Aldose Reductase,AR)在高糖环境下被过分激活有关。
对AR的抑制已经被证明是糖尿病并发症治疗的一条有效途径。据文献调研,虽然已有许多AR抑制剂被研发,但可供临床使用的、效果较好而不良反应又较小的醛糖还原酶抑制剂却很少。已上市的、化学合成的醛糖还原酶抑制剂有依帕司他(epalrestat)、阿司他丁(alrestatin)、泊那司他(ponalrestat)、索比尼尔(sorbinil)和托瑞司他(tolrestat)。这些药物也不甚理想。开发疗效确切、安全的醛糖还原酶抑制剂存在迫切性。
中国授权发明专利ZL201410723116.8和ZL201710372369.9都公开了一种具有醛糖还原酶抑制活性的化合物,但是专利ZL201410723116.8中的化合物,其对AR的抑制活性均弱于阳性对照药依帕斯他,而且抗氧化活性低于Trolox;而发明专利ZL201710372369.9虽然发现了AR抑制活性及抗氧化活性俱佳的候选化合物,然而其稳定性及生物利用度存在缺陷,需要进一步完善。
发明内容
有鉴于此,本发明的首要目的在于提供一种新型醛糖还原酶抑制活性兼具抗氧化活性的对苯二胺桥连化合物。
本发明的另一目的在于提供上述化合物的制备方法。
本发明的再一目的在于提供上述化合物在制备治疗糖代谢紊乱疾病药物中的应用,尤其是在制备治疗糖尿病并发症药物中的应用。
本发明的目的通过下述技术方案实现:
一种对苯二胺桥连化合物,具有如式I所示的结构:
式I结构中,X基团具有如式II-1或式II-2所示的结构:
式II-1、式II-2所示的结构中,R为单羟基取代、双羟基取代,或羟基和羟甲基双取代;
优选地,所述的R为单羟基时,在式II-1中其取代位置可以是2-,3-,4-,优选4-;在式II-2中其取代位置可以是5-,6-,7-,8-,优选6-。
优选地,R为双羟基取代,或羟基和羟甲基双取代时,是邻位取代;
进一步优选地,所述的R为双羟基时,在式II-1中其取代位置可以是2,3-或3,4-;在式II-2中其取代位置可以是5,6-、6,7-或7,8-。
进一步优选地,所述的R为羟基和羟甲基双取代时,在式II-1中其取代位置优选3-羟甲基-4-羟基;在式II-2中其取代位置优选6-羟基-7-羟甲基。
式I所示的结构中,q为0-4。
Z基团为甲基、异丙基或环丙基。
优选地,本发明所述的化合物是如表1所示的具体化合物:
表1
本发明还请求保护式I所示结构的化合物和表1所示的具体化合物在药学上可以接受的盐。
本发明还请求保护式I所示结构的化合物和表1所示的具体化合物的合成中间体(或称前体药物)。
式I所示结构的化合物的制备方法,包括以下步骤:
(1)N-叔丁氧酰基保护的取代酰二胺的制备:将羧酸溶于溶剂,加入羧酸1.0~3.0倍摩尔量的偶合试剂,-20~0℃下搅拌反应10~40min,随后加入羧酸1.0~3.0倍摩尔量的一端N-叔丁氧酰基保护的首尾二胺和有机碱,-20~0℃下搅拌反应30~60min,升温至30~60℃,继续搅拌反应24~36h;反应结束,旋蒸除去溶剂,浓缩物用硅胶柱层析纯化,得一端N-叔丁氧酰基保护的酰首尾二胺;
所述的羧酸具有如式II-1’或式II-2’所示的结构:
所述的一端N-叔丁氧酰基保护的首尾二胺具有如式III-2’所示的结构:
(2)一端单酰首尾二胺:取一端N-叔丁氧酰基保护的酰首尾二胺溶于溶剂,缓慢加入一端N-叔丁氧酰基保护的酰首尾二胺5~20倍摩尔量的4M盐酸溶液,0~40℃下搅拌反应3~6h;反应结束,旋蒸除去溶剂,冻干,得一端单酰首尾二胺;
(3)N-酰化-O-苄基-D-丝氨酸的制备:取O-苄基-D-丝氨酸,加入O-苄基-D-丝氨酸1.0~5.0倍摩尔量的酰化试剂,50~100℃下搅拌反应4~9h,旋蒸除去溶剂,浓缩物用高效液相色谱分离纯化,得N-酰化-O-苄基-D-丝氨酸;
(4)式I结构化合物的制备:取N-酰化-O-苄基-D-丝氨酸溶于溶剂,加入N-酰化-O-苄基-D-丝氨酸1.0~3.0倍摩尔量的偶合试剂,-20~0℃下搅拌反应10~40min,得A液;另取步骤(2)制备的一端单酰首尾二胺溶于溶剂,加入一端单酰首尾二胺3.0~5.0倍摩尔量有机碱,冷却至-30℃以下,搅拌下滴加A液,滴加完毕,保持该温度,搅拌1~3h;升至室温,继续反应20~40h;反应结束,旋蒸去除溶剂;浓缩物用硅胶柱层析纯化,得到式I所示结构的化合物;
步骤(1)和(4)所用的溶剂为N,N-二甲基甲酰胺(DMF)或体积比为10:1的二氯甲烷(DCM)/DMF混合液。
步骤(1)和(4)所用的偶合试剂可以是氯甲酸乙酯、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(EDC·HCl)、N,N-二异丙基碳二亚胺(DIC)、六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷(PyBOP)中的一种与N-羟基苯骈三氮唑(HOBt)按1:1摩尔比混合而成。
步骤(1)和(4)所用的有机碱为三乙基胺或二异丙基乙胺(DIPEA)。
步骤(2)所用的溶剂为甲醇、乙醇、DMF中的一种。
步骤(3)所用的酰化试剂为酸酐或酰氯。
步骤(4)中,N-酰化-O-苄基-D-丝氨酸与一端单酰首尾二胺的摩尔比为1:(1-3),优选1.0:1.1。
再一方面,本发明还提供上述化合物(式I结构化合物和表1所列的化合物)在制备治疗糖代谢紊乱疾病药物中的应用,尤其是在制备治疗糖尿病并发症药物中的应用。这些糖尿病并发症包括糖尿病视网膜病、糖尿病神经末梢障碍病、糖尿病老年痴呆症。
本发明利用以下实验证明上述的化合物(式I结构化合物和表1所列的化合物)对醛糖还原酶具有优良的抑制活性:以D,L-甘油醛为底物测定α-氰基-3,4-二羟基肉桂酸衍生物(即本发明的化合物)对醛糖还原酶酶解活性的抑制率,以临床药物依帕司他(Epalrestat)作为阳性对照。结果表明,(E)-4-(N-乙酰-O-苄基-D-丝氨酰)-1-(α-氰基-3-(3,4-二羟基苯基)丙烯酰)哌嗪(CHR-5N-G)对人源醛糖还原酶的抑制活性最好,IC50值为12.26±0.85nmol/L,强于依帕司他的水平(IC50=75.64±4.22nmol/L),强于专利CN201410723116.8所报道的CHR-532R(IC50=89.71±3.51nmol/L),强于专利CN201710372369.9所报道的CHR-5N-D(IC50=41.02±2.83nmol/L)。本发明的其它化合物对醛糖还原酶也体现出一定的体外抑制活性。
考察上述化合物(式I结构化合物和表1所列的化合物)对1,1-二苯基-2-三硝基苯肼(DPPH)所产生自由基的清除效果,发现CHR-5N-F表明出优良的抗氧化作用,其半数清除浓度EC50=8.81±0.51μM,明显强于阳性对照药Trolox(EC50=14.39±0.23μM)。本发明的其它化合物也体现出一定的自由基清除能力。
参照文献(Zhang L,Li YF,Yuan S,et al.Scientific Reports,2016,6:24942)所报道的实验方法,考察高糖环境下(0.4mmol/egg)待试药CHR-5N-G和阳性对照药依帕司他(Epalrestat)、抗氧化剂依达拉奉(Edaravone)对鸡胚生存率、死亡率、神经管畸形率及鸡胚形态和体重的影响。结果表明,在500nM浓度下,经CHR-5N-G处理的鸡胚生存率、死亡率、总体畸形率、体重分别为78.8%、20.7%、11.3%、243.2mg;经依帕司他处理的鸡胚生存率、死亡率、总体畸形率、体重则分别为69.6%、29.8%、27.9.0%、231.4mg;经依达拉奉处理的鸡胚生存率、死亡率、总体畸形率、体重则分别为71.2%、30.4%、22.3%、228.5mg。结果表明,待试药CHR-5N-G的效果总体优于依帕司他和依达拉奉。
同时又发现本发明化合物对AR有专一性地抑制活性,发现对ALR2表现出显著的酶抑制活性,优于阳性对照药,与体外活性结果一致;而对于其同工酶ALR1并没有表现出明显的抑制活性,因此目标化合物对AR的抑制是有高度选择性的。化合物通过抑制AR的活性,从而显著抑制葡萄糖代谢的多元醇途径,阻止该途径的代谢产物山梨醇的产生。其体内抗氧化实验也表明,该化合物能显著抑制胚胎体内氧化产物MDA的形成,同时ORAC水平显示具有良好的自由基清除能力。以上实验均有力地证明了化合物CHR-5N-G能对高糖诱导的鸡胚神经管畸形起到很好的保护作用,其次其体内酶抑制活性及体内抗氧化活性突出,与体外实验一致,同时还能显著提高调控蛋白Pax 3的表达。
参照文献(Neural Regeneration Research 2016,11(2),345-351)建立糖尿病周边神经病大鼠模型,显示CHR-5N-G对高糖诱导的周边神经病变有明显的治疗作用。
因此,本发明上述的化合物(式I结构化合物和表1所列的化合物,以及它们在药学上可接受的盐和合成中间体)可用于制备治疗糖代谢紊乱疾病的药物,尤其可用于制备治疗糖尿病并发症如糖尿病视网膜病、糖尿病老年痴呆、神经末梢障碍等疾病的药物;上述的化合物可用于制备治疗由氧化应激所引起的疾病的药物,尤其糖尿病并发症。
本发明相对于现有技术具有如下的优点及效果:
本发明的化合物对醛糖还原酶的抑制活性以及在制备治疗糖代谢紊乱疾病的药物、治疗糖尿病并发症药物以及治疗由氧化应激所引起疾病中的应用为首次报道。相比于其它现有技术,本发明的化合物结构新颖、制备工艺简单、疗效优于阳性对照药依帕司他。
附图说明
图1为(E)-4-(N-乙酰-O-苄基-D-丝氨酰)-1-(α-氰基-3-(3,4-二羟基苯基)丙烯酰)哌嗪(CHR-5N-G)的1H NMR图谱。
图2为(E)-4-(N-乙酰-O-苄基-D-丝氨酰)-1-(α-氰基-3-(3,4-二羟基苯基)丙烯酰)哌嗪(CHR-5N-G)的13C MRC图谱。
图3为(E)-4-(N-乙酰-O-苄基-D-丝氨酰)-1-(α-氰基-3-(3,4-二羟基苯基)丙烯酰)哌嗪(CHR-5N-G)的HR-ESI-MS谱。
图4为部分化合物的体外ALR2酶抑制率柱状图。
图5为Trolox、CHR-5N-G、CHR-5N-F不同浓度的自由基清除率柱状图。
具体实施方式
下面结合实施例及附图对本发明作进一步详细的描述,但本发明的实施方式不限于此。
实施例1
(E)-N-(4-(N-乙酰-O-苄基-D-丝氨酰)氨苯基)-α-氰基-3-(4-羟基苯基)丙烯酰胺(CHR-5F-B)的制备,包括以下五个步骤:
(1)(E)-α-氰基-4-羟基肉桂酸的合成:称取4-羟基苯甲醛122.1mg(1.0mmol)于干燥的50mL圆底烧瓶中,加入氰基乙酸85mg(1.0mmol),醋酸铵15.4mg(0.2mmol),注射器称取冰醋酸48mg(0.8mmol)加入反应体系,再加入10mL甲苯作溶剂,反应瓶上接小型分水器、冷凝管、干燥管。于120℃油浴锅中搅拌回流反应18h。反应毕,降至室温,然后低温下静置,过滤,滤饼用二氯甲烷(DCM)洗涤三次,得黄色固体,收率92.8%。1H NMR(300MHz,CD3OD)δ:9.66(s,1H,Ar-OH),8.21(s,1H,=CH-),7.46(d,2H,J=8.3Hz,Ar-H),6.88(d,J=8.3Hz,2H,Ar-H);ESI-MS(m/z):188.3[M-H]-。
(2)(E)-N-(N-Boc-4-氨苯基)-α-氰基-4-羟基肉桂酰胺的制备:在100mL圆底烧瓶中加入α-氰基-4-羟基肉桂酸1.89g(10.0mmol),加入30mL DCM/DMF=10:1(V/V)搅拌溶解,烧瓶中加入已称好的EDC·HCl 1.15g(11.0mmol),0℃搅拌反应10min,然后将已称好的HOBt 0.82g(11.0mmol)加入反应烧瓶,0℃搅拌反应10min,充分活化游离羧基。待羧基充分活化后,注射器分别量取4-N-Boc-氨基苯胺2.29g(11.0mmol)和DIPEA 4.6mL(26.4mmol)依次注入反应烧瓶,0℃搅拌反应约30min后缓慢升至室温,继续反应24h。反应结束,除去溶剂,硅胶柱层析(氯仿:甲醇=40:1)分离纯化,得黄色固体3.29g,收率86.7%。1H NMR(400MHz,DMSO-d6)δ:10.03(s,Ar-NH),9.34(s,Ar-NH),8.75(s,Ar-OH),8.45(s,=CH),7.75(m,4H,Ar),7.45(d,J=8.3Hz,2H,Ar-H),6.46(d,J=8.3Hz,2H,Ar-H),1.48(CH3,9H);13C NMR(101MHz,DMSO-d6)δ:163.8,157.7,152.5,150.4,143.2,133.6,133.2,124.7,121.8,115.8,106.9,79.5,28.4。
(3)(E)-N-(4-氨苯基)-α-氰基-4-羟基肉桂酰胺的制备:将(E)-N-(N-Boc-4-氨苯基)-α-氰基-4-羟基肉桂酰胺1.14g(3.0mmol)用30mL干燥的甲醇溶解,转移至50mL圆底烧瓶,缓慢滴加7.5mL的4mol/L HCl溶液(30mmol),室温条件下搅拌反应4h。除去溶剂得浅黄色固体,收率97.3%。1H NMR(400MHz,DMSO-d6)δ:10.03(s,1H,Ar-NH),8.75(s,1H,Ar-OH),8.45(s,1H,=CH),7.45(d,J=8.3Hz,2H,Ar-H),7.38(d,J=8.1Hz,2H,Ar-H),6.58(d,J=8.3Hz,2H,Ar-H),6.32(d,J=8.1Hz,2H,Ar-H),4.53(br,2H,Ar-NH2);13C NMR(101MHz,DMSO-d6)δ:163.8,157.7,152.5,150.4,143.2,133.6,133.2,124.7,121.8,115.8,106.9。
(4)N-乙酰-O-苄基-D-丝氨酸的制备:称取O-苄基-D-丝氨酸195.2mg(1.0mmol)于50mL圆底烧瓶,溶于10mL重蒸甲醇,注射器量取乙酸酐0.3mL(约3mmol)、DIEA0.5mL(约3mmol)加入反应体系中,70℃回流反应7h。反应毕,减压除去反应液中的甲醇,冷冻干燥除去未反应的乙酸酐。经HPLC制备(流动相为甲醇:水=50:50,含0.05%TFA,紫外波长254nm)得无色油状物,收率74.5%。1H NMR(400MHz,CDCl3)δ:11.63(s,1H,-COOH),7.26(m,5H,Ar-H),7.04(d,J=7.8Hz,1H,-CO-NH-),4.79-4.67(m,1H,-N-CH-),4.47(s,2H,Ar-CH2-O-),3.82-3.78(m,2H,-CH2-O-),2.01(s,3H,-CO-CH3);13C NMR(75MHz,CDCl3)δ172.98,171.69,137.45,128.61,128.09,127.90,73.53,69.66,52.91,22.92.ESI-MS(m/z):236.7[M-H]-。
(5)(E)-N-(4-(N-乙酰-O-苄基-D-丝氨酰)氨苯基)-α-氰基-3-(4-羟基苯基)丙烯酰胺的制备:称取N-乙酰-O-苄基-D-丝氨酸118.7mg(0.5mmol)于西林瓶,依次加入HOBt101.5mg(0.75mmol)和EDC·HCl 144mg(0.75mmol),3~10mL DCM/DMF(10:1,V/V)作为溶剂,搅拌反应10min,得A液。另称取(E)-N-(4-氨苯基)-α-氰基-4-羟基肉桂酰胺153.6mg(0.55mmol)溶于3~10mL的DCM/DMF中,加入DIPEA0.4mL(2.2mmol),冷却至-30℃,搅拌下滴加A液,滴加完毕,保持该温度搅拌1h。随后升至室温,继续反应23h。反应结束,旋蒸去除溶剂。经硅胶柱层析(氯仿:甲醇=40:1,V:V),梯度洗脱分离纯化,得淡黄色固体181.1mg,收率66.1%。1H NMR(300MHz,DMSO-d6)δ:9.67(s,1H),8.17(d,J=8.0Hz,3H),7.37–7.23(m,11H,=CH,Ar-H),6.52(d,J=8.7Hz,2H),4.65(d,J=7.9Hz,1H),4.50(d,J=3.8Hz,2H),3.61(s,1H),3.12(s,1H),1.88(s,3H,CH3);13C NMR(101MHz,DMSO-d6)δ:171.80,169.49,167.79,144.76,138.32,138.21,128.37,128.36,127.67,127.65,127.62,127.59,121.25,114.12,72.19,70.13,69.75,53.79,53.34,52.44,42.02,22.68,22.51,18.27,16.92,12.63.ESI-MS(m/z):499.2for C28H26N4O5([M+H]+);
上述数据证实该化合物为(E)-N-(4-(N-乙酰-O-苄基-D-丝氨酰)氨苯基)-α-氰基-3-(4-羟基苯基)丙烯酰胺(CHR-5F-B),结构如下所示。
实施例2
(E)-N-(4-(N-乙酰-O-苄基-D-丝氨酰)氨环己基)-α-氰基-3-(4-羟基苯基)丙烯酰胺(CHR-5F-E)的制备,包括以下五个步骤。
(1)(E)-α-氰基-4-羟基肉桂酸的制备。步骤同实施例1步骤(1)
(2)(E)-N-(N-Boc-4-氨基环己基)-α-氰基-4-羟基肉桂酰胺的制备:步骤同实施例1步骤(2)。将4-N-Boc-氨基苯胺2.29g(11.0mmol)改为4-N-Boc-氨基环己胺2.36g(11.0mmol),得淡黄色固体2.29g,收率59.5%。1H NMR(300MHz,DMSO-d6)δ:10.50(s,1H,Ar-OH),8.31(s,1H),8.15(s,1H),7.85(s,1H),7.77(d,J=8.2Hz,2H),6.94(d,J=8.2Hz,2H),3.70(m,1H),3.43(m,1H),1.66(m,4H),1.51(m,4H),1.38(s,9H);13C NMR(75MHz,DMSO-d6)δ:161.64,160.97,154.91,150.00,132.72,122.95,117.31,116.18,101.68,77.46,46.97,28.29,28.08,26.84。
(3)(E)-N-(4-氨基环己基)-α-氰基-4-羟基肉桂酰胺的制备:步骤同实施例1步骤(3)。投入上步所得的(E)-N-(N-Boc-4-氨基环己基)-α-氰基-4-羟基肉桂酰胺,得浅棕色固体1.67g,收率89.6%。1H NMR(300MHz,DMSO-d6)δ:10.50(s,1H,Ar-OH),8.33(s,1H),8.17(s,1H),7.52(d,J=8.1Hz,2H),6.63(d,J=8.1Hz,2H),3.65(m,1H),2.58(m,1H),1.73(m,4H),1.52(br,2H),1.47(m,4H);13C NMR(75MHz,DMSO-d6)δ:161.65,160.96,150.01,132.73,122.97,117.33,116.17,101.69,46.98,28.32,28.10。
(4)N-乙酰-O-苄基-D-丝氨酸的制备:步骤同实施例1步骤(4)。
(5)(E)-N-(4-(N-乙酰-O-苄基-D-丝氨酰)氨环己基)-α-氰基-3-(4-羟基苯基)丙烯酰胺的制备:步骤同实施例1步骤(5)。将(E)-N-(4-氨苯基)-α-氰基-4-羟基肉桂酰胺153.6mg(0.55mmol)替换为(E)-N-(4-氨基环己基)-α-氰基-4-羟基肉桂酰胺156.9mg(0.55mmol)。经硅胶柱层析(氯仿:甲醇=40:1,V:V),梯度洗脱分离纯化,得淡黄色固体174.3mg,收率62.8%。1H NMR(300MHz,CDCl3)δ:9.72(s,1H,Ar-OH),8.32(br,2H),8.16(s,1H),8.13(br,1H),7.89(d,J=8.7Hz,2H,Ar-H),7.40-7.28(m,5H,Ar-H),6.98(d,J=8.7Hz,2H,Ar-H),4.75(m,1H),4.63(s,2H),4.03-3.84(m,3H),3.64-3.46(m,2H),2.05(s,3H,CH3),1.74(m,4H),1.51(m,4H);13C NMR(75MHz,CDCl3)δ:161.4,160.7,154.9,150.7,149.4,143.2,137.5,132.8,128.6,122.4,117.7,116.8,101.8,77.3,69.7,57.3,50.6,46.9,28.7,26.9.ESI-MS(m/z):503.6for C28H32N4O5([M-H]+);
上述数据证实该化合物为(E)-N-(4-(N-乙酰-O-苄基-D-丝氨酰)氨环己基)-α-氰基-3-(4-羟基苯基)丙烯酰胺(CHR-5F-E),结构如下所示。
实施例3
(E)-4-(N-乙酰-O-苄基-D-丝氨酰基)-1-(α-氰基-3-(4-羟基苯基)丙烯酰)哌嗪(CHR-5F-G)的制备,包括以下五个步骤:
(1)(E)-α-氰基-4-羟基肉桂酸的制备。步骤同实施例1步骤(1)
(2)(E)-4-Boc-1-(α-氰基-4-羟基肉桂酰基)哌嗪的制备:步骤同实施例1步骤(2)。将4-N-Boc-氨基苯胺2.29g(11.0mmol)改为N-Boc-哌嗪2.05g(11.0mmol)。得淡黄色固体1.89g,收率52.9%。1H NMR(400MHz,CDCl3)δ:9.68(s,1H),8.12(s,1H),7.83(d,J=8.7Hz,2H),6.97(d,J=8.7Hz,2H),3.55-3.51(m,8H),1.48(s,9H);13C NMR(101MHz,CDCl3)δ:163.97,160.14,154.43,152.81,132.69,124.48,116.60,116.15,101.31,80.56,50.91,48.82,28.21。
(3)(E)-α-氰基-4-羟基肉桂酰哌嗪的制备:步骤同实施例1步骤(3)。投入上步所得的(E)-4-Boc-1-(α-氰基-4-羟基肉桂酰基)哌嗪,得浅棕色固体1.23g,收率90.5%。1HNMR(400MHz,CDCl3)δ:9.69(s,1H),8.13(s,1H),7.82(d,J=8.7Hz,2H),6.96(d,J=8.7Hz,2H),3.36(m,4H),2.87(m,4H),1.23(br,1H);13C NMR(101MHz,CDCl3)δ:164.12,154.45,152.83,133.21,124.53,116.62,116.17,101.35,80.56,51.62,47.13。
(4)N-乙酰-O-苄基-D-丝氨酸的制备:步骤同实施例1步骤(4)。
(5)(E)-4-(N-乙酰-O-苄基-D-丝氨酰基)-1-(α-氰基-3-(4-羟基苯基)丙烯酰)哌嗪的制备:步骤同实施例1步骤(5)。将(E)-N-(4-氨苯基)-α-氰基-4-羟基肉桂酰胺153.6mg(0.55mmol)替换为(E)-α-氰基-4-羟基肉桂酰哌嗪141.5mg(0.55mmol)。经硅胶柱层析(氯仿:甲醇=40:1,V:V),梯度洗脱分离纯化,得淡黄色固体132.6mg,收率50.6%。1H NMR(400MHz,DMSO-d6)δ:9.72(s,1H,Ar-OH),8.56(s,1H),8.15(s,1H),7.52(d,J=8.7Hz,2H),7.42(m,5H,Ar-H),6.69(d,J=8.7Hz,2H),4.76(m,1H),4.63(s,2H),3.62(m,1H),3.53(m,4H),3.41(m,4H),3.32(m,2H),2.04(s,3H,CH3);13C NMR(101MHz,DMSO-d6)δ:171.73,169.75,168.12,157.87,151.43,144.25,138.52,129.61,128.82,127.40,124.70,115.80,115.60,106.90,72.30,70.0,54.80,49.40,48.90,22.90;ESI-MS(m/z):499.5forC26H28N4O5([M+Na]+);
以上数据证明该化合物为(E)-4-(N-乙酰-O-苄基-D-丝氨酰基)-1-(α-氰基-3-(4-羟基苯基)丙烯酰)哌嗪(CHR-5F-G),结构如下:
实施例4
(E)-N-(4-(N-乙酰-O-苄基-D-丝氨酰)氨苯基)-α-氰基-3-(3,4-二羟基苯基)丙烯酰胺(CHR-5N-B)的制备,包括以下五个步骤:
(1)(E)-α-氰基-3,4-二羟基肉桂酸的合成:称取3,4-二羟基苯甲醛138mg(1.0mmol)于干燥的50mL圆底烧瓶中,加入氰基乙酸85mg(1.0mmol),醋酸铵15.4mg(0.2mmol),注射器称取冰醋酸48mg(0.8mmol)加入反应体系,再加入10mL甲苯作溶剂,反应瓶上接小型分水器、冷凝管、干燥管。于120℃油浴锅中搅拌回流反应18h。反应毕,降至室温,然后低温下静置,过滤,滤饼用二氯甲烷(DCM)洗涤三次,得黄色固体196.3mg,收率95.7%。1H NMR(300MHz,CD3OD)δ:9.52(s,2H,Ar-OH),8.21(s,1H,=CH-),7.64(d,J=8.3Hz,1H),7.36(s,1H,Ar-H),6.88(d,J=8.3Hz,1H,Ar-H);ESI-MS(m/z):204.3forC10H6NO4([M-H]-)。
(2)(E)-N-(N-Boc-4-氨苯基)-α-氰基-3,4-二羟基肉桂酰胺的制备:将α-氰基-4-羟基肉桂酸1.89g(10.0mmol)替换为α-氰基-3,4-二羟基肉桂酸2.05g(10.0mmol),步骤同实施例1步骤(2)。得黄色固体2.82g,收率71.3%。1H NMR(400MHz,DMSO-d6)δ:10.03(s,1H),9.34(s,1H,Ar-NH),8.75(s,2H,2×Ar-OH),8.45(s,1H,=CH),7.75(m,4H,Ar),7.66(d,J=8.3Hz,1H),7.38(s,1H,Ar-H),6.89(d,J=8.3Hz,1H,Ar-H),1.49(s,9H,3×CH3);13C NMR(101MHz,DMSO-d6)δ:163.8,157.7,152.5,150.4,143.2,133.6,133.2,124.7,121.8,115.8,106.9,79.5,28.4。
(3)(E)-N-(4-氨苯基)-α-氰基-3,4-二羟基肉桂酰胺的制备:将(E)-N-(N-Boc-4-氨苯基)-α-氰基-4-羟基肉桂酰胺1.14g(3.0mmol)替换为(E)-N-(N-Boc-4-氨苯基)-α-氰基-3,4-二羟基肉桂酰胺1.19g(3.0mmol),步骤同实施例1步骤(3)。得浅黄色固体,收率96.4%。1H NMR(400MHz,DMSO-d6)δ:10.05(s,1H,Ar-NH-),8.77(s,2H,2×Ar-OH),8.46(s,1H,=CH),7.76(d,J=7.6Hz,2H,Ar-H),7.65(d,J=8.3Hz,1H),7.36(s,1H,Ar-H),6.87(d,J=8.3Hz,1H,Ar-H),6.53(d,J=7.6Hz,2H,Ar-H),4.56(br,2H);13C NMR(101MHz,DMSO-d6)δ:163.9,151.8,150.2,142.6,133.4,132.8,124.6,121.7,115.6,106.8。
(4)N-乙酰-O-苄基-D-丝氨酸的制备:步骤同实施例1步骤(4)。
(5)(E)-N-(4-(N-乙酰-O-苄基-D-丝氨酰)氨苯基)-α-氰基-3-(3,4-二羟基苯基)丙烯酰胺的制备:将(E)-N-(4-氨苯基)-α-氰基-4-羟基肉桂酰胺153.6mg(0.55mmol)替换为(E)-N-(4-氨苯基)-α-氰基-3,4-二羟基肉桂酰胺162.4mg(0.55mmol),步骤同实施例1步骤(5)。经硅胶柱层析(氯仿:甲醇=40:1,V:V),梯度洗脱分离纯化,得淡黄色固体152.2mg,收率53.8%。1H NMR(300MHz,DMSO-d6)δ:10.18(s,1H,-CONH-Ar),9.62(s,1H,Ar-NHCO-),9.47(s,2H,2×Ar-OH),8.34(d,J=18.2Hz,1H),7.96(s,1H,=CH),7.65(d,J=6.2Hz,2H),7.59(d,J=6.2Hz,2H),7.51(d,J=8.5Hz,1H),7.25(m,5H,Ar-H),7.11(s,1H),6.85(d,J=8.5Hz,1H),5.05(d,J=13.1Hz,1H,CO-CH-N),4.65(s,2H,Ar-CH2-O),3.55(s,1H,O-CH2),3.07(s,1H,O-CH2),1.80(s,3H,CH3);13C NMR(75MHz,DMSO-d6)δ:172.81,171.23,163.92,150.56,146.92,144.76,137.53,134.31,133.42,129.33,128.62(2),127.87,127.65,127.62,123.20,121.25(4),117.29,115.76,115.32,109.51,72.29,69.75,56.63,22.92.ESI-MS(m/z):545.7for C28H26N4O6([M+Na]+).
以上数据证明该化合物为(E)-N-(4-(N-乙酰-O-苄基-D-丝氨酰)氨苯基)-α-氰基-3-(3,4-二羟基苯基)丙烯酰胺(CHR-5N-B),结构如下:
实施例5
(E)-N-(4-(N-乙酰-O-苄基-D-丝氨酰)氨苯基)-α-氰基-3-(3-羟甲基-4-羟基苯基)丙烯酰胺(CHR-5N-C)的制备,包括以下五个步骤:
(1)(E)-α-氰基-3-羟甲基-4-羟基肉桂酸的合成:将3,4-二羟基苯甲醛138mg(1.0mmol)替换为3-羟甲基-4-羟基苯甲醛152.1mg(1.0mmol),步骤同实施例4步骤(1)。得黄色固体204.9mg,收率93.5%。1H NMR(300MHz,CD3OD)δ:9.62(s,H,Ar-OH),8.26(s,1H,=CH-),7.54(d,J=8.3Hz,1H),7.32(d,J=8.3Hz,1H,Ar-H),7.14(s,1H,Ar-H),7.02(br,1H),4.63(s,2H);ESI-MS(m/z):218.4for C11H8NO4([M-H]-)。
(2)(E)-N-(N-Boc-4-氨苯基)-α-氰基-3-羟甲基-4-羟基肉桂酰胺的制备:将α-氰基-4-羟基肉桂酸1.89g(10.0mmol)替换为α-氰基-3-羟甲基-4-羟基肉桂酸2.19g(10.0mmol),步骤同实施例1步骤(2)。得黄色固体3.01g,收率73.2%。1H NMR(400MHz,DMSO-d6)δ:10.13(s,1H,-CO-NH-Ar),9.84(s,1H,Ar-NH-Boc-),9.72(s,1H,Ar-OH),8.45(s,1H,=CH),7.75(m,4H,Ar),7.66(d,J=8.3Hz,1H),7.38(d,J=8.3Hz,1H,Ar-H),7.14(s,1H,Ar-H),7.06(br,1H),4.63(s,2H,Ar-CH2-O),1.51(s,9H,3×CH3);13C NMR(101MHz,DMSO-d6)δ:163.8,156.13,153.06,150.51,133.62,133.25,129.60,128.83,128.18,126.20,121.76(4),115.84,107.11,79.53,61.12,29.05(3)。
(3)(E)-N-(4-氨苯基)-α-氰基-3-羟甲基-4-羟基肉桂酰胺的制备:将(E)-N-(N-Boc-4-氨苯基)-α-氰基-4-羟基肉桂酰胺1.14g(3.0mmol)替换为(E)-N-(N-Boc-4-氨苯基)-α-氰基-3-羟甲基-4-羟基肉桂酰胺1.23g(3.0mmol),步骤同实施例1步骤(2)。得浅黄色固体88.7mg,收率95.6%。1H NMR(400MHz,DMSO-d6)δ:10.15(s,1H,Ar-NH-),9.77(s,1H,Ar-OH),8.21(s,1H,=CH),7.52(d,J=7.6Hz,1H,Ar-H),7.43(d,J=8.3Hz,2H),7.37(d,J=7.6Hz,1H,Ar-H),7.21(s,1H,Ar-H),6.33(d,J=8.3Hz,2H,Ar-H),4.56(br,2H);13C NMR(101MHz,DMSO-d6)δ:163.9,156.14,150.52,133.63,133.26,129.63,128.85,128.17,126.22,121.78(4),115.85,107.12,61.13。
(4)N-乙酰-O-苄基-D-丝氨酸的制备:步骤同实施例1步骤(4)。
(5)(E)-N-(4-(N-乙酰-O-苄基-D-丝氨酰)氨苯基)-α-氰基-3-(3-羟甲基-4-羟基苯基)丙烯酰胺的制备:将(E)-N-(4-氨苯基)-α-氰基-4-羟基肉桂酰胺153.6mg(0.55mmol)替换为(E)-N-(4-氨苯基)-α-氰基-3-羟甲基-4-羟基肉桂酰胺170.1mg(0.55mmol),步骤同实施例1步骤(5)。经硅胶柱层析(氯仿:甲醇=40:1,V:V),梯度洗脱分离纯化,得淡黄色固体157.8mg,收率54.3%。1H NMR(300MHz,DMSO-d6)δ:10.13(s,1H,-CONH-Ar),9.71(s,1H,Ar-NHCO-),9.57(s,1H,Ar-OH),8.33(d,J=18.2Hz,1H),8.16(s,1H,=CH),7.66(d,J=6.2Hz,2H),7.57(d,J=6.2Hz,2H),7.53(d,J=8.5Hz,1H),7.25(m,5H,Ar-H),7.14(s,1H),7.05(br,1H,Bn-OH),6.86(d,J=8.5Hz,1H),5.07(d,J=13.1Hz,1H,CO-CH-N),4.68(s,2H,Ar-CH2-O-),4.63(s,2H,Ar-CH2-O),3.56(s,1H,O-CH2),3.08(s,1H,O-CH2),1.82(s,3H,CH3);13C NMR(75MHz,DMSO-d6)δ:172.83,171.23,164.01,154.87,138.02,134.21,133.34,129.56,128.74,128.63(2),128.06,127.82,127.45(2),126.14,121.85(4),115.12,107.11,72.32,69.11,61.25,57.14,53.34,22.93.ESI-MS(m/z):551.8for C29H28N4O6Na([M+Na]+).
以上数据证明该化合物为(E)-N-(4-(N-乙酰-O-苄基-D-丝氨酰)氨苯基)-α-氰基-3-(3-羟甲基-4-羟基苯基)丙烯酰胺(CHR-5N-C),结构如下:
实施例6
(E)-4-(N-乙酰-O-苄基-D-丝氨酰)-1-(α-氰基-3-(3,4-二羟基苯基)丙烯酰)哌嗪(CHR-5N-G)的制备,包括以下五个步骤:
(1)步骤同实施例4步骤(1)。
(2)(E)-4-Boc-1-(α-氰基-3,4-二羟基肉桂酰基)哌嗪的制备:步骤同实施例4步骤(2)。将4-N-Boc-氨基苯胺2.29g(11.0mmol)改为N-Boc-哌嗪2.05g(11.0mmol)。得淡黄色固体2.34g,收率62.7%。1H NMR(400MHz,CDCl3)δ:9.57(s,2H,2×OH),8.15(s,1H,=CH),7.52(d,J=8.3Hz,1H,Ar-H),7.03(s,1H,Ar-H),6.86(d,J=8.3Hz,1H,Ar-H),3.55-3.52(m,4H,CH2),3.39(m,4H,CH2),1.40(s,9H,3×CH3);13C NMR(101MHz,DMSO-d6)δ:163.59,153.98,150.95,146.56,145.84,128.85,124.72,123.81,117.22,116.00,106.17,79.47,51.21(2),49.03(2),28.22(3)。
(3)(E)-α-氰基-3,4-二羟基肉桂酰哌嗪的制备:步骤同实施例1步骤(3)。投入上步所得的(E)-4-Boc-1-(α-氰基-3,4-二羟基肉桂酰基)哌嗪,得浅棕色固体1.60g,收率93.4%。1HNMR(400MHz,CDCl3)δ:9.63(s,2H,2×OH),8.16(s,1H),7.61(d,J=8.7Hz,1H),7.03(s,1H,Ar-H),6.93(d,J=8.7Hz,1H),3.36(m,4H),2.87(m,4H),1.23(br,1H);13C NMR(101MHz,CDCl3)δ:166.52,150.93,146.55,145.83,128.84,124.73,123.82,117.23,116.00,106.17,51.21(2),47.03(2)。
(4)N-乙酰-O-苄基-D-丝氨酸的制备:步骤同实施例1步骤(4)。
(5)(E)-4-(N-乙酰-O-苄基-D-丝氨酰基)-1-(α-氰基-3-(3,4-二羟基苯基)丙烯酰)哌嗪的制备:步骤同实施例1步骤(5)。将(E)-N-(4-氨苯基)-α-氰基-4-羟基肉桂酰胺153.6mg(0.55mmol)替换为(E)-α-氰基-3,4-二羟基肉桂酰哌嗪150.3mg(0.55mmol)。经硅胶柱层析(氯仿:甲醇=40:1,V:V),梯度洗脱分离纯化,得淡黄色固体145.7mg,收率53.8%。1H NMR(400MHz,DMSO-d6)δ:9.52(s,2H,2×Ar-OH),8.36(s,1H,Ac-NH-),8.13(s,1H,Ar-CH=),7.53(d,J=8.1Hz,1H),7.33(m,5H,Ar-H),7.08(s,1H,Ar-H),6.95(d,J=8.1Hz,1H),4.75(m,1H,-CO-CH-N-),4.67(s,2H,Ar-CH2 O-),3.62(m,1H),3.53(m,4H),3.39(m,4H),3.33(m,1H),1.86(s,3H,CH3-CO-)(见图1);13C NMR(101MHz,DMSO-d6)δ:172.61,170.13,168.04,151.22,146.63,145.92,138.05,129.31,128.64(2),127.81,127.47(2),123.18,116.97,115.92,115.17,107.15,72.33,69.98,54.91,49.53(2),48.95(2),22.94.ESI-MS(m/z):493.4C26H29N4O6([M+H]+)(见图2);HR-ESI-MS(m/z):493.2087(见图3);
以上数据证明该化合物为(E)-4-(N-乙酰-O-苄基-D-丝氨酰基)-1-(α-氰基-3-(3,4-二羟基苯基)丙烯酰)哌嗪(CHR-5N-G),结构如下:
实施例7
(E)-4-(N-乙酰-O-苄基-D-丝氨酰)-1-(α-氰基-3-(3-羟甲基-4-羟基苯基)丙烯酰)哌嗪(CHR-5N-H)的制备,包括以下五个步骤:
(1)步骤同实施例5步骤(1)。
(2)(E)-4-Boc-1-(α-氰基-3-羟甲基-4-羟基肉桂酰基)哌嗪的制备:步骤同实施例5步骤(2)。将4-N-Boc-氨基苯胺2.29g(11.0mmol)改为N-Boc-哌嗪2.05g(11.0mmol)。得淡黄色固体2.55g,收率65.8%。1H NMR(400MHz,CDCl3)δ:9.63(s,1H,Ar-OH),8.13(s,1H,=CH),7.48(d,J=8.2Hz,1H,Ar-H),7.31(d,J=8.2Hz,1H,Ar-H),7.13(s,1H,Ar-H),7.05(s,1H,Ar-H),4.65(s,2H,O-CH2-Ar),3.36(m,4H,CH2),3.32(m,4H,CH2),1.43(s,9H,3×CH3);13C NMR(101MHz,DMSO-d6)δ:167.52,155.46,154.81,150.65,129.85,128.73,128.15,126.32,117.22,116.07,115.85,106.94,79.86,51.03(2),48.81(2),28.52(3)。
(3)(E)-α-氰基-3-羟甲基-4-羟基肉桂酰哌嗪的制备:步骤同实施例1步骤(3)。投入上步所得的(E)-4-Boc-1-(α-氰基-3-羟甲基-4-羟基肉桂酰基)哌嗪,得浅棕色固体1.75g,收率92.5%。1H NMR(400MHz,CDCl3)δ:9.65(s,1H,Ar-OH),8.16(s,1H,=CH),7.45(d,J=8.2Hz,1H,Ar-H),7.29(d,J=8.2Hz,1H,Ar-H),7.12(s,1H,Ar-H),7.04(s,1H,Ar-H),4.62(s,2H,O-CH2-Ar),3.25(m,4H,CH2),2.82(m,4H,CH2),1.08(br,1H);13C NMR(101MHz,DMSO-d6)δ:167.71,155.47,150.58,129.93,128.81,128.09,126.26,116.05,115.83,106.96,51.62(2),47.33(2)。
(4)N-乙酰-O-苄基-D-丝氨酸的制备:步骤同实施例1步骤(4)。
(5)(E)-4-(N-乙酰-O-苄基-D-丝氨酰基)-1-(α-氰基-3-(3-羟甲基-4-羟基苯基)丙烯酰)哌嗪的制备:步骤同实施例1步骤(5)。将(E)-N-(4-氨苯基)-α-氰基-4-羟基肉桂酰胺153.6mg(0.55mmol)替换为(E)-α-氰基-3-羟甲基-4-羟基肉桂酰哌嗪158.1mg(0.55mmol)。经硅胶柱层析(氯仿:甲醇=40:1,V:V),梯度洗脱分离纯化,得淡黄色固体153.8mg,收率55.2%。1H NMR(400MHz,DMSO-d6)δ:9.63(s,1H,Ar-OH),8.33(s,1H,Ac-NH-),8.12(s,1H,Ar-CH=),7.49(d,J=8.2Hz,1H),7.33(m,5H,Ar-H),7.29(d,J=8.2Hz,1H),7.05(s,1H,Bn-OH),4.76(m,1H,-CO-CH-N-),4.66(s,2H,Ph-CH2O-),4.63(s,2H,Ar-CH2O-),3.59(m,1H),3.48(m,4H),3.36(m,4H),3.32(m,1H),1.87(s,3H,CH3-CO-);13C NMR(101MHz,DMSO-d6)δ:170.73,169.84,167.23,155.45,150.56,137.52,129.61,128.75,128.62(2),128.03,127.83,127.52(2),126.18,116.06,115.83,107.13,72.35,70.02,60.51,54.93,49.46(2),48.94(2),22.95.ESI-MS(m/z):507.6C27H31N4O6([M+H]+);
以上数据证明该化合物为(E)-4-(N-乙酰-O-苄基-D-丝氨酰基)-1-(α-氰基-3-(3-羟甲基-4-羟基苯基)丙烯酰)哌嗪(CHR-5N-H),结构如下:
实施例8
N-(4-(N-乙酰-O-苄基-D-丝氨酰)氨环己基)-6-羟基-β-萘甲酰胺(CHR-5Y-E1)的制备,包括以下四个步骤:
(1)N-(N-Boc-4-氨基环己基)-6-羟基-β-萘酰胺的制备:步骤同实施例2步骤(2)。将4-羟基-α-氰基肉桂酸1.89g(10.0mmol)改为6-羟基-β-萘甲酸1.88g(10.0mmol),得淡黄色固体3.63g,收率94.5%。1H NMR(300MHz,DMSO-d6)δ:9.99(s,1H,OH),8.33(s,1H,=CH-CO),8.07(m,1H,Ar-H),7.85(m,2H,Ar-H),7.72(m,2H),7.46(m,1H),7.26(m,1H),3.88(m,1H),3.46(m,1H),1.78(s,4H,CH2),1.59(s,4H,CH2),1.39(s,9H,3×CH3);13C NMR(101MHz,DMSO-d6)δ:166.95,157.73,154.99,134.94,131.48(2),130.92,129.09,127.41,126.65,125.75,124.70,119.32,108.62,77.44,53.76,51.61,28.71(2),28.63(2),28.41(3)。
(2)N-(4-氨基环己基)-6-羟基-β-萘酰胺的制备:步骤同实施例1步骤(3)。投入上步所得的N-(N-Boc-4-氨基环己基)-6-羟基-β-萘酰胺,得浅棕色固体2.45g,收率91.2%。1H NMR(300MHz,DMSO-d6)δ:9.28(s,1H,OH),8.31(s,1H),8.08(m,1H,Ar-H),7.83(m,2H,Ar-H),7.72(m,1H),7.46(s,1H),7.28(m,1H),3.88(m,1H),3.55(m,1H),2.58(m,1H),1.78(m,2H,CH2),1.73(m,2H),1.54(m,2H),1.51(m,2H);13C NMR(101MHz,DMSO-d6)δ:167.23,158.13,133.54,131.81,131.32,130.93,128.29,126.67,124.73,118.35,109.14,51.65,50.32,31.41(2),28.73(2)。
(3)N-乙酰-O-苄基-D-丝氨酸的制备:步骤同实施例1步骤(4)。
(4)N-(4-(N-乙酰-O-苄基-D-丝氨酰)氨环己基)-6-羟基-β-萘酰胺的制备:步骤同实施例1步骤(5)。将(E)-N-(4-氨苯基)-α-氰基-4-羟基肉桂酰胺153.6mg(0.55mmol)替换为N-(4-氨基环己基)-6-羟基-β-萘酰胺156.4mg(0.55mmol)。经硅胶柱层析(氯仿:甲醇=40:1,V:V),梯度洗脱分离纯化,得淡黄色固体181.4mg,收率65.5%。1H NMR(300MHz,CDCl3)δ:10.06(s,1H,OH),8.34(s,1H,Ac-NH-),8.31(s,1H,Ar-H),8.14(d,J=7.4Hz,1H,-NH-CO-),8.08(d,J=8.7Hz,1H,Ar-H),7.81(m,2H,Ar-H),7.72(d,J=8.7Hz,1H,Ar-H),7.45(s,1H,Ar-H),7.34(m,5H,Ar-H),7.26(m,1H,Ar-H),4.67(m,1H,CO-CH-NH),4.62(s,2H,Ar-O-CH2-),3.58(m,1H),3.53(m,2H),3.34(m,1H),1.88(s,3H,CH3-CO-),1.81(m,2H),1.76(m,2H),1.53(m,2H),1.49(m,2H);13C NMR(101MHz,DMSO-d6)δ:171.42,170.69,167.18,158.14,138.25,135.95,130.49,129.07,128.20,127.45,126.62,125.75,124.76,119.36,108.63,72.03,70.29,52.49,46.84,45.22,28.01,27.47,22.56.ESI-MS(m/z):526.7C29H33N3O5([M+Na]+);
上述数据证实该化合物为N-(4-(N-乙酰-O-苄基-D-丝氨酰)氨环己基)-6-羟基-β-萘甲酰胺(CHR-5Y-E1),结构如下所示。
实施例9
4-(N-乙酰-O-苄基-D-丝氨酰基)-1-(6-羟基-β-萘甲酰)哌嗪(CHR-5Y-G)的制备,包括以下四个步骤:
(1)4-Boc-1-(6-羟基-β-萘甲酰基)哌嗪的制备:步骤同实施例3步骤(2)。将4-羟基-α-氰基肉桂酸1.89g(10.0mmol)替换为6-羟基-β-萘甲酸1.88g(10.0mmol),得淡黄色固体2.34g,收率65.8%。1H NMR(400MHz,CD3OD)δ:9.23(s,1H,OH),8.31(s,1H,Ar-H),8.08(d,J=8.5Hz,1H,Ar-H),7.77(d,J=9.7Hz,1H,Ar-H),7.69(d,J=8.5Hz,1H,Ar-H),7.41(s,1H,Ar-H),7.26(d,J=9.7Hz,1H,Ar-H),3.61(m,4H,CH2),3.35(m,4H),1.47(s,9H,3×CH3);13CNMR(101MHz,CD3OD)δ:172.87,157.82,155.95,136.89,131.81,131.32,130.89,128.47,126.59,125.12,120.26,118.33,109.70,81.39,50.92(2),49.81(2),28.39。
(2)6-羟基-β-萘甲酰哌嗪的制备:步骤同实施例1步骤(3)。投入上步所得的4-Boc-1-(6-羟基-β-萘甲酰基)哌嗪,得浅棕色固体1.55g,收率91.8%。1H NMR(400MHz,CD3OD)δ:9.21(s,1H,OH),8.29(s,1H,Ar-H),8.10(d,J=8.3Hz,1H,Ar-H),7.79(d,J=9.5Hz,1H,Ar-H),7.68(d,J=8.3Hz,1H,Ar-H),7.43(s,1H,Ar-H),7.28(d,J=9.5Hz,1H,Ar-H),3.48(m,4H,CH2),2.92(m,4H);13C NMR(101MHz,CD3OD)δ:169.02,158.23,134.04,131.78,131.29,130.89,128.36,126.65,124.80,118.33,109.20,52.67(2),47.11(2)。
(3)N-乙酰-O-苄基-D-丝氨酸的制备:步骤同实施例1步骤(4)。
(5)4-(N-乙酰-O-苄基-D-丝氨酰基)-1-(6-羟基-β-萘甲酰基)哌嗪的制备:步骤同实施例1步骤(5)。将(E)-N-(4-氨苯基)-α-氰基-4-羟基肉桂酰胺153.6mg(0.55mmol)替换为6-羟基-β-萘甲酰哌嗪141.0mg(0.55mmol)。经硅胶柱层析(氯仿:甲醇=40:1,V:V),梯度洗脱分离纯化,得淡黄色固体136.8mg,收率52.3%。1H NMR(400MHz,DMSO-d6)δ:9.98(s,1H,Ar-OH),8.35(d,J=8.1Hz,1H,Ar-H),8.30(s,1H,Ar-H),8.25(d,J=8.2Hz,1H,Ar-H),7.84(d,J=8.6Hz,1H,Ar-H),7.68(d,J=8.2Hz,1H),7.32(m,5H,Ar-H),7.28(d,J=8.6Hz,1H,Ar-H),4.75(m,1H,-CO-CH-N-),4.62(s,2H,Ar-CH2-O),3.58(m,1H),3.61(m,4H),3.52(m,4H),3.35(m,1H),1.85(s,3H,CH3CO-);13C NMR(101MHz,DMSO-d6)δ:170.59,169.72,168.85,158.19,137.56,134.07,131.18,130.93,128.65(2),128.27,127.61,127.53,127.46,126.90,126.71,126.13,124.87,119.43,108.66,72.19,69.64,50.02(2),49.42(2),22.93.ESI-MS(m/z):474.5C27H29N3O5([M-H]+);
以上数据证明该化合物为4-(N-乙酰-O-苄基-D-丝氨酰基)-1-(6-羟基-β-萘甲酰)哌嗪(CHR-5Y-G),结构如下:
实施例10
3-N-(N-乙酰-O-苄基-D-丝氨酰)-7-羟基-3-喹啉甲酰丙二胺(CHR-5H)的制备,包括以下四个步骤:
(1)N-(3-N-Boc-氨丙基)-7-羟基-3-喹啉甲酰胺的制备:步骤同实施例1步骤(2)。将4-羟基-α-氰基肉桂酸1.89g(10.0mmol)替换为7-羟基-3-喹啉甲酸1.89g(10.0mmol);4-N-Boc-氨基苯胺2.29g(11.0mmol)替换为N-Boc-1,3-丙二胺1.92g(11.0mmol)得淡黄色固体2.51g,收率72.7%。1H NMR(400MHz,DMSO-d6)δ:9.42(s,1H,Ar-OH),8.83(s,1H,-C-CH=C-),8.63(s,1H,-N=CH-),8.35(m,1H,ArCO-NH-),7.90(d,J=8.9Hz,1H,NH),7.47(m,2H,Ar-H),6.80(m,1H,-NH-Boc),3.21(m,4H),1.78(m,2H),1.37(s,9H,3×CH3);13C NMR(101MHz,DMSO-d6)δ:166.1,160.5,156.1,149.7,146.5,136.3,131.6,125.9,124.6,119.1,110.5,79.7,39.6,37.3,28.8,28.5(3)。
(2)N-(3-氨丙基)-7-羟基-3-喹啉甲酰胺的制备:步骤同实施例1步骤(3)。投入上步所得的N-(3-N-Boc-氨丙基)-7-羟基-3-喹啉甲酰胺,得浅棕色固体1.54g,收率95.3%。1H NMR(400MHz,DMSO-d6)δ:9.39(s,1H,Ar-OH),8.81(s,1H,-C-CH=C-),8.64(s,1H,-N=CH-),8.34(m,1H,ArCO-NH-),7.87(d,J=8.9Hz,1H,NH),7.45(m,2H,Ar-H),3.19(m,2H),2.69(m,2H),1.89(m,2H);13C NMR(101MHz,DMSO-d6)δ:165.8,160.3,149.6,146.4,136.1,131.7,125.8,124.5,119.2,110.6,39.2,35.8,28.6。
(3)N-乙酰-O-苄基-D-丝氨酸的制备:步骤同实施例1步骤(4)。
(4)3-N-(N-乙酰-O-苄基-D-丝氨酰)-7-羟基-3-喹啉甲酰丙二胺的制备:步骤同实施例1步骤(5)。将(E)-N-(4-氨苯基)-α-氰基-4-羟基肉桂酰胺153.6mg(0.55mmol)替换为N-(3-氨丙基)-7-羟基-3-喹啉甲酰胺134.9mg(0.55mmol)。经硅胶柱层析(氯仿:甲醇=40:1,V:V),梯度洗脱分离纯化,得淡黄色固体167.8mg,收率65.7%。1H NMR(400MHz,DMSO-d6)δ:10.49(s,1H,OH),9.13(s,1H,=CH-CO),8.65(s,1H,-N=CH-),8.43(s,1H,ArCO-NH-),8.33(m,1H,Ac-NH-),8.03(m,1H,-NH-CO),7.90(d,J=8.8Hz,1H,Ar-H),7.47(m,2H,Ar-H),7.32(m,5H),4.74(m,1H,CO-CH-N),4.61(s,2H,-CH2-OAr),3.61(m,1H),3.32(m,1H),3.17(m,4H),2.36(m,2H),1.85(s,3H,CH3CO-);13C NMR(101MHz,DMSO-d6)δ:173.32,170.91,165.73,160.22,150.65,149.16,137.90,136.15,131.64,128.56(2),127.69,127.42(2),125.48,124.38,120.88,119.06,110.11,73.00,70.11,57.44,39.52,37.35,28.67,22.25.ESI-MS(m/z):465.6C25H28N4O5([M+H]+);
以上数据证明该化合物为3-N-(N-乙酰-O-苄基-D-丝氨酰)-7-羟基-3-喹啉甲酰丙二胺(CHR-5H),结构如下:
按照本申请公开的式I化合物的合成路线和方法,以及结合实施例1-10的具体化合物的合成方法,本领域技术人员可以根据目标产物的结构,调整合成方法中涉及的原料,从而合成表1中所记载的其他化合物,在此不再一一列举。
实施例11
表1中的化合物对醛糖还原酶的抑制活性
本发明中,醛糖还原酶(AR)、还原型辅酶Ⅱ(NADPH)、DL-甘油醛均购自Sigma公司;依帕司他(Epalrestat)购自东京化成工业株式会社。
实验步骤:酶反应体系在96孔板上进行,反应体系包括:PBS缓冲液(pH=6.2)100μL,1.5mmol/L NADPH 20μL,100mmol/L DL-甘油醛20μL,不同浓度(Epalrestat或者受试样品)溶液20μL,AR稀释液20μL,蒸馏水20μL。实验设置空白照组、标准对照组、酶代谢组如表格2-1。
表2-1.分组及给药情况表
注:以上所有体积单位均为μL。
上述液体于37℃孵育5min后,除空白溶媒组外,每组加20μL AR启动反应,迅速将96孔板放入荧光酶标仪内,温度37℃,检测波长340nm,连续检测NADPH吸光度的变化情况,每30s检测一次,共检测30min。
根据实验测得的结果,分别求出空白组NADPH吸光度的下降值A0,酶活力组(未加样品)NADPH吸光度的下降值A1,Epalrestat组及受试样品组NADPH吸光度的下降值AEPS、A2。利用各组NADPH吸光度变化值求出其抑制率:
样品对AR抑制率/%=[1-(A2-A0)/(A1-A0)]×100%。
根据酶反应实验结果,以样品终浓度为横坐标,抑制率为纵坐标,绘制抑制曲线,依据动力学曲线求出不同样品的IC50。所有数据均用表示,数据统计由SPSS10.0软件处理,组间比较用t检验。求得阳性对照品Epalrestat的IC50为75.64±4.22。用以上方法求得目标终产物的IC50值,结果如表2-2所示:
表2-2.目标化合物的IC50值
从表2-2及图4可以看出,化合物CHR-5N-G对醛糖还原酶的体外抑制活性最佳,明显强于阳性对照药依帕司他,也明显强于专利CN 201410723116.8所报道的化合物CHR-532R和专利CN201710372369.9所报道的化合物CHR-5N-D;
除化合物CHR-5N-E、CHR-5Y-1、CHR-5H-E、CHR-5H-G、CHR-5H-H表现出比阳性药依帕司他弱的酶抑制活性外,其它化合物对醛糖还原酶的体外抑制活性均比阳性对照药强。
实施例12
表1中的化合物的体外抗氧化活性
本实施例中,Trolox(6-Hydroxy-2,5,7,8-tetramethylchroman-2-carboxylicacid);1,1-diphenyl-2-picrylhydrazyl(DPPH)购自Sigma公司。
实验步骤:反应体系在96孔板上进行,将每种供试品溶液取40μL加入96孔板中,然后,每个孔中平行加入DPPH溶液160μL。同时设置对照组(40μL甲醇+160μL DPPH),空白组(40μL供试品+160μL甲醇)。振摇1min,使其混合均匀,将96孔板置于避光条件下静置反应0.5h,迅速将板放入酶标仪中,检测波长517nm。测得最终吸光度(A)值,每个样品平行检测三次,取平均值。清除率的计算公式如下:
自由基清除率(%)=(A对照-(A样品-A空白))/A对照×100%
A对照为未加样品的对照组吸光度;
A样品为加入测试样品后反应液的吸光度;
A空白为空白组的吸光度。
表3-1.目标化合物在100μM浓度时对DPPH的抑制率
所考察化合物在100μM时对DPPH的抑制率如表3-1所示。从表3-1可以看出,所考察的化合物均体现出一定程度的自由基清除率,其中CHR-5Y-2、CHR-5Y-3和CHR-5Y-E2的体外抗氧化活性强于阳性对照品Trolox。
对于抑制活性突出的化合物和阳性对照,为方便比较其抑制活性,作出其25μM、12.5μM、6.25μM三个浓度的浓度-抑制率柱状图5所示:
通过对化合物的浓度对数与抑制率的线性回归分析得到Trolox、CHR-5Y-2、CHR-5Y-3的半数清除浓度,即EC50值,结果列于表3-2。
表3-2.化合物对应EC50值
从表3-2结果分析可见,化合物CHR-5Y-2和CHR-5Y-3的抗氧化能力优良,强于阳性药Trolox。
上述实施例为本发明较佳的实施方式,但本发明的实施方式并不受上述实施例的限制,其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化,均应为等效的置换方式,都包含在本发明的保护范围之内。
Claims (10)
2.根据权利要求1所述的化合物,其特征在于:R为双羟基取代,或羟基和羟甲基双取代时,是邻位取代。
3.根据权利要求1所述的化合物,其特征在于:式I所示的结构中,q为0-4。
5.权利要求1-4任一项所述的化合物在药学上可以接受的盐。
6.权利要求1-3所述化合物的制备方法,其特征在于包括以下步骤:
(1)N-叔丁氧酰基保护的取代酰二胺的制备:将羧酸溶于溶剂,加入羧酸1.0~3.0倍摩尔量的偶合试剂,-20~0℃下搅拌反应10~40min,随后加入羧酸1.0~3.0倍摩尔量的一端N-叔丁氧酰基保护的首尾二胺和有机碱,-20~0℃下搅拌反应30~60min,升温至30~60℃,继续搅拌反应24~36h;反应结束,旋蒸除去溶剂,浓缩物用硅胶柱层析纯化,得一端N-叔丁氧酰基保护的酰首尾二胺;
所述的羧酸具有如式II-1’或式II-2’所示的结构:
所述的一端N-叔丁氧酰基保护的首尾二胺具有如式III-2’所示的结构:
(2)一端单酰首尾二胺:取一端N-叔丁氧酰基保护的酰首尾二胺溶于溶剂,缓慢加入一端N-叔丁氧酰基保护的酰首尾二胺5~20倍摩尔量的4M盐酸溶液,0~40℃下搅拌反应3~6h;反应结束,旋蒸除去溶剂,冻干,得一端单酰首尾二胺;
(3)N-酰化-O-苄基-D-丝氨酸的制备:取O-苄基-D-丝氨酸,加入O-苄基-D-丝氨酸1.0~5.0倍摩尔量的酰化试剂,50~100℃下搅拌反应4~9h,旋蒸除去溶剂,浓缩物用高效液相色谱分离纯化,得N-酰化-O-苄基-D-丝氨酸;
(4)式I结构化合物的制备:取N-酰化-O-苄基-D-丝氨酸溶于溶剂,加入N-酰化-O-苄基-D-丝氨酸1.0~3.0倍摩尔量的偶合试剂,-20~0℃下搅拌反应10~40min,得A液;另取步骤(2)制备的一端单酰首尾二胺溶于溶剂,加入一端单酰首尾二胺3.0~5.0倍摩尔量有机碱,冷却至-30℃以下,搅拌下滴加A液,滴加完毕,保持该温度,搅拌1~3h;升至室温,继续反应20~40h;反应结束,旋蒸去除溶剂;浓缩物用硅胶柱层析纯化,得到式I所示结构的化合物;
步骤(3)所用的酰化试剂为酸酐或酰氯。
7.权利要求1-4任一项所述的化合物或权利要求5所述的盐在制备治疗糖代谢紊乱疾病的药物中的应用。
8.权利要求1-4任一项所述的化合物或权利要求5所述的盐在制备治疗由氧化应激所引起的疾病的药物中的应用。
9.权利要求1-4任一项所述的化合物或权利要求5所述的盐在制备治疗糖尿病并发症的药物中的应用。
10.根据权利要求9所述的应用,其特征在于:所述的糖尿病并发症包括糖尿病视网膜病、糖尿病神经末梢障碍病、糖尿病老年痴呆症。
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