CN111170923B - 一类dl-色氨酸类化合物、其制备方法及用途 - Google Patents
一类dl-色氨酸类化合物、其制备方法及用途 Download PDFInfo
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- CN111170923B CN111170923B CN201811347823.6A CN201811347823A CN111170923B CN 111170923 B CN111170923 B CN 111170923B CN 201811347823 A CN201811347823 A CN 201811347823A CN 111170923 B CN111170923 B CN 111170923B
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- -1 DL-tryptophan compound Chemical class 0.000 title claims abstract description 27
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- 238000002360 preparation method Methods 0.000 title claims abstract description 19
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- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 claims description 18
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- 238000006482 condensation reaction Methods 0.000 claims description 12
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- 150000002367 halogens Chemical class 0.000 claims description 8
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Abstract
本发明提供了一种通式I表示的DL‑色氨酸类化合物或其药学上可接受的盐,同时提供了其制备方法及用途,尤其是在制备RANKL抑制剂中的用途。本发明的DL‑色氨酸类化合物或其药学上可接受的盐可通过抑制RANKL‑RANK相互作用,对OPG‑RANKL‑RANK信号系统进行干预,调控破骨前体细胞中RANKL活性从而抑制破骨细胞的形成,减少骨吸收。本发明的DL‑色氨酸类化合物或其药学上可接受的盐有望起到防治骨代谢疾病的作用,为骨代谢疾病患者带来福音。
Description
技术领域
本发明涉及一类DL-色氨酸类化合物、其制备方法及用途,具体涉及其在制备RANKL-RANK相互作用小分子抑制剂中的用途。
背景技术
核因子κB受体活化因子配体(receptor activator of NF-κB ligand),简称RANKL,是TNF家族中的一员;RANKL为Ⅱ型跨膜蛋白,在T、B淋巴细胞、单核-巨噬细胞等多种免疫细胞均有表达。RANKL可与破骨前体细胞的细胞膜表面的RANK受体结合,将信号传递给TRAP6,通过NIK和IKK活化NF-κB,从而激活下游信号通路如nuclear factor of activatedT-cells,cytoplasmic 1(NFATc1)/c-fos,启动相应的靶基因的表达与转录,最终诱导破骨细胞的形成,发挥调节破骨细胞分化和成熟的功能。(Masashi Honma等,Nature,doi:10.1038/s41586-018-0482-7)
在正常骨代谢中,骨骼新陈代谢是由成骨细胞的成骨作用与破骨细胞的溶骨作用相互协调进行的。成骨作用和溶骨作用处于一个动态平衡,骨组织不断更新,从而维持了骨骼的硬度和弹性,破骨细胞的过度活跃打破这一平衡而导致多种疾病如癌症骨转移、骨质疏松症、类风湿性关节炎、牙周炎、牙齿脱落、Paget’s骨病、佝偻病、骨巨细胞瘤以及骨髓瘤骨病造成的骨破坏。(Chunhao Yang等,Eur.J.Med.Chem.2016,123:769-776)
破骨细胞是人体唯一的骨吸收细胞,其骨吸收功能在维持骨代谢平衡中具有关键作用,有助于维持骨骼系统的完整性和矿物质的稳态,并且与局部或全身性骨代谢疾病密切相关。破骨细胞起源于骨髓的单核髓性造血干细胞,是特异分化的巨噬细胞,由巨噬细胞克隆刺激因子(M-CSF)、核因子κB配体激活受体(RANKL)刺激分化产生。在破骨前体细胞,M-CSF结合到其受体c-Fos上,为破骨前体细胞的增殖提供必要的信号;RANKL则与RANK结合主要引发前体破骨细胞向成熟破骨细胞的分化。因此,RANK-RANKL信号传导在破骨细胞形成中起重要作用,RANKL被认为是破骨细胞增殖分化和活化所必须的关键调控因子。(XiangFan等,Cell.Physiol.Biochem.2018,48(5),2123-2133)OPG-RANKL-RANK信号系统是指成骨细胞分泌的骨保护素(OPG)和破骨细
胞前体上的核因子κB受体活化因子配体(RANK ligand,RANKL)竞争性结合破骨细胞前体上的核因子κB受体活化因子(RANK),因此调控OPG-RANKL-RANK信号系统中的不同信号分子可以调节骨吸收和骨形成。(Ryuichi Morishita等,Proceedings of the NationalAcademy of Sciences,2014,111(22),8191–8196)
研究发现,RANKL呈剂量依赖性激活破骨细胞分化。因此通过抑制RANKL-RANK相互作用可抑制破骨细胞的形成,最终可用于骨代谢类相关疾病的治疗。目前,RANKL的单克隆抗体denosumab(狄诺塞麦)已经运用于临床治疗,但其存在价格昂贵、使用不便以及停药后可能会引发高钙血症等缺点,因此寻找更高效的、特异的RANKL-RANK相互作用小分子抑制剂具有重要意义。
发明内容
本发明提供了一类通式I表示的DL-色氨酸类化合物或其药学上可用的盐,
其中,R1、R2各自独立地为H、卤素、C1-C4烷基、或C1-C4烷氧基;
X为NH、O或S;
R3为-Y-(C1-C6烷基)-取代或未取代芳基、-Y-(C1-C6烷基)-取代或未取代稠合芳基、-Y-(C1-C6烷基)-(含1-2个选自O、S、N的杂原子的C5-C6杂芳基)、-Y-(C1-C6烷基)-(C3-C6环烷基)、或-(C1-C6烷基)-取代或未取代芳基,Y为O、S、羰基(-C(O)-)、羧基(-C(O)O-)或硫代羰基;其中,所述取代芳基、取代稠合芳基是指被选自如下取代基中的一种或多种所取代:卤素、C1-C4烷氧基、C1-C4烷基;
R4、R5、R6各自独立地为H、卤素、C1-C4烷基、C1-C4烷氧基、三氟甲基、二氟甲基、五氟乙基、砜基、C1-C4烷基取代或未取代氨基、或吗啉基
优选地,
R1、R2各自独立地为H、卤素、或C1-C4烷氧基;
X为NH或O;
R3为-Y-(C1-C6烷基)-取代或未取代芳基、-Y-(C1-C6烷基)-(含1-2个选自O、S、N的杂原子的C5-C6杂芳基)、-Y-(C1-C6烷基)-(C3-C6环烷基)、-(C1-C6烷基)-取代或未取代芳基,Y为羰基或羧基;其中,所述取代芳基指被卤素或甲氧基所取代;
R4、R5、R6各自独立地为H、卤素、C1-C4烷基、C1-C4烷氧基、三氟甲基、砜基、C1-C4烷基取代或未取代氨基、或吗啉基;
进一步优选地,
R1为H、氟、或甲氧基,R2为H或氟;
X为NH;
R3为-CO-O-CH2苯基、-CO-(C1-C4烷基)-取代或未取代芳基、-CO-CH2CH2-(含1-2个选自O、S、N的杂原子的C5-C6杂芳基)、-CO-CH2CH2-(C3-C6环烷基)、或-(C2-C5烷基)-芳基;
R4、R5各自独立地为H、氟、甲基;R6为H、氟、甲基、甲氧基、甲砜基三氟甲基、-N(CH3)2、或吗啉基;
最优选地,所述通式I表示的DL-色氨酸类化合物选自具有如下述结构的化合物:
本发明的另一目的是提供通式I表示的DL-色氨酸类化合物的制备方法,其可通过如下两种制备方法得到:
制备方法一:
步骤a:化合物S与二碳酸二叔丁酯(Boc2O)发生氨基保护反应,得到化合物1a;
步骤b:化合物1a与胺发生缩合反应,反应得到化合物1b;
步骤c:包括两步反应:第一步反应是化合物1b发生脱保护基反应,得到脱Boc产物;第二步反应是脱Boc产物与氯甲酸苄酯或苯乙酰氯发生酰基化反应;或与相应的酸发生缩合反应;或与苯乙醛发生还原胺化反应;或与相应的甲磺酸酯/>(n为2,3或4)发生取代反应,得到通式I表示的DL-色氨酸类化合物;
其中,R1、R2、R4、R5、R6的定义如前所述,R3为-CO-(C1-C6烷基)-取代或未取代芳基、-CO-(C1-C6烷基)-取代或未取代稠合芳基、-CO-(C1-C6烷基)-(含1-2个选自O、S、N的杂原子的C5-C6杂芳基)、-CO-(C1-C6烷基)-(C3-C6环烷基);其中,所述取代芳基、取代稠合芳基是指被选自如下取代基中的一种或多种所取代:卤素、C1-C4烷氧基、C1-C4烷基;
制备方法二:
步骤d:化合物S在酸性条件下与乙醇发生酯化反应,得到化合物2a;
步骤e:将化合物2a与3-苯基丙酸发生缩合反应得到化合物2b;
步骤f:化合物2b在碱性条件下发生水解反应得到化合物2c;
步骤g:化合物2c与胺发生缩合反应,得到通式I’表示的DL-色氨酸类化合物;
其中,R1、R2、R4、R5、R6的定义如前所述。
优选地,在所述制备方法一中,
步骤a中,所述氨基保护反应在碱存在下进行,所述碱优选为碳酸钠水溶液;
步骤a中,先将化合物S溶于1,4-二氧六环中,再进行氨基保护反应;
步骤b中,所述缩合反应在2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐(HATU)、N,N-二异丙基乙胺(DIPEA)的N,N-二甲基甲酰胺(DMF)溶液的存在下进行;
步骤c中,第一步脱保护基反应在三氟乙酸(TFA)的二氯甲烷(DCM)溶液存在下进行;
步骤c中,第二步所述脱Boc产物与氯甲酸苄酯或苯乙酰氯发生的酰基化反应,在三乙胺(TEA)或4-二甲氨基吡啶(DMAP)的二氯甲烷(DCM)溶液下进行;与相应的酸发生的缩合反应,在HATU、DIPEA的DMF溶液存在下进行;与苯乙醛发生的还原胺化反应,在氰基硼氢化钠(NaBH3CN)的乙腈(MeCN)溶液存在下进行;与相应的甲磺酸酯/>发生的取代反应,在三乙胺(TEA)、碳酸钾(K2CO3)和碘化钠(NaI)的乙腈溶液存在下进行。
优选地,在所述制备方法二中,
步骤d中,所述酯化反应在二氯亚砜(SOCl2)存在下,在加热回流条件下进行;
步骤e中,所述缩合反应在HATU、DIPEA的DMF溶液存在下进行;
步骤f中,所述碱性条件为氢氧化钠(NaOH)水溶液条件下进行;
步骤g中,所述缩合反应在HATU、DIPEA的DMF溶液存在下进行;或在1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)、1-羟基苯并三唑(HOBT)、三乙胺(TEA)溶于乙腈(MeCN)和四氢呋喃(THF)的混合溶液存在下进行。
本发明的另一目的是提供上述通式I表示的DL-色氨酸类化合物或其药学上可接受的盐,在制备RANKL活性抑制剂中的用途。
本发明的另一目的是提供上述通式I表示的DL-色氨酸类化合物或其药学上可用的盐,在制备治疗和/或预防骨代谢疾病的药物中的用途。
其中,所述骨代谢疾病包括骨质疏松症、风湿性关节炎、银屑病性关节炎、实体瘤骨转移等以及肿瘤如乳腺癌等。
本发明的DL-色氨酸类化合物或其药学上可接受的盐可通过抑制RANKL-RANK相互作用,对OPG-RANKL-RANK信号系统进行干预,调控破骨前体细胞中RANKL活性抑制破骨细胞的形成,从而减少骨吸收。本发明的DL-色氨酸类化合物或其药学上可接受的盐有望起到防治骨代谢疾病的作用,为骨代谢疾病患者带来福音。
附图说明
图1为化合物P-34与蛋白的结合信号变化曲线图;
图2为化合物P-34对破骨细胞出泡的影响(100X)
具体实施方式
下面结合实施例对本发明作进一步阐述,但这些实施例绝对不是对本发明的任何限制。所有实施例中,BrukerAvance III 600型、BrukerAvance III 500型和Varian-Mercury Plus-400型核磁共振仪记录,化学位移以δ(ppm)表示;分离用硅胶为200-300目。
步骤a:化合物1a的制备
将化合物S-1(10.2g,50mmol)、10%Na2CO3溶液(120mL)、1,4-二氧六环(200mL)溶液混合,将Boc2O(11.35g,52mmol)溶于1,4-二氧六环(100mL)溶液中,经恒压滴液漏斗缓慢加入上述反应液,室温反应过夜,真空浓缩除去溶剂,加水(300mL)溶解,用2M盐酸溶液调pH至2-3,用乙酸乙酯(200mL)萃取两次,合并有机层,饱和食盐水(200mL)洗涤,无水硫酸钠干燥,真空浓缩除去溶剂,得浅黄色固体1a-1(13.8g,91%)。
1H NMR(500MHz,DMSO-d6)δ12.53(s,1H),10.82(s,1H),7.52(d,J=7.9Hz,1H),7.34(d,J=8.0Hz,1H),7.14(s,1H),7.06(t,J=7.5Hz,1H),6.98(t,J=7.4Hz,1H),6.94(d,J=7.8Hz,1H),4.16(td,J=8.6,5.1Hz,1H),3.14(dd,J=14.5,4.4Hz,1H),2.98(dd,J=14.5,9.4Hz,1H),1.33(s,9H).
化合物S-2(111mg,0.5mmol)、10%Na2CO3溶液(1.2mL)、1,4-二氧六环(3mL)、Boc2O(113mg,0.52mmol),操作过程同化合物1a-1的合成,得浅黄色固体1a-2(148mg,92%)。
1H NMR(500MHz,DMSO-d6)δ10.93(s,1H),7.32(dd,J=8.7,4.5Hz,1H),7.29–7.24(m,1H),7.22(s,1H),6.96(d,J=8.0Hz,1H),6.89(td,J=9.2,2.3Hz,1H),4.12(td,J=8.7,4.8Hz,1H),3.09(dd,J=14.5,4.5Hz,1H),2.95(dd,J=14.6,9.4Hz,1H),1.32(s,9H).
化合物S-3(117mg,0.5mmol)、10%Na2CO3溶液(1.2mL)、1,4-二氧六环(3mL)、Boc2O(113mg,0.52mmol),操作过程同化合物1a-1的合成,得黄色固体1a-3(150mg,90%)。
1H NMR(600MHz,DMSO-d6)δ10.67(s,1H),7.21(d,J=8.7Hz,1H),7.10(d,J=1.9Hz,1H),7.03(d,J=2.1Hz,1H),6.99(d,J=8.2Hz,1H),6.70(dd,J=8.7,2.3Hz,1H),4.13(td,J=9.0,4.6Hz,1H),3.76(s,3H),3.08(dd,J=14.6,4.5Hz,1H),2.94(dd,J=14.6,9.5Hz,1H),1.32(s,9H).
化合物S-4(111mg,0.5mmol)、10%Na2CO3溶液(1.2mL)、1,4-二氧六环(3mL)、Boc2O(113mg,0.52mmol),操作过程同化合物1a-1的合成,得浅黄色固体1a-4(152mg,94%)。
1H NMR(600MHz,DMSO-d6)δ12.56(s,1H),10.91(s,1H),7.50(dd,J=8.5,5.5Hz,1H),7.14(s,1H),7.11(dd,J=10.1,2.0Hz,1H),7.01(d,J=8.1Hz,1H),6.87–6.82(m,1H),4.12(td,J=8.9,4.8Hz,1H),3.10(dd,J=14.6,4.5Hz,1H),2.95(dd,J=14.6,9.6Hz,1H),1.32(s,9H).
步骤b:化合物1b的制备
将化合物1a-1(1.0g,3.29mmol)溶于N,N-二甲基甲酰胺(30mL)溶液中,依次加入HATU(1.63g,4.28mmol)、DIPEA(1.63mL,9.87mmol),室温反应30分钟,加入2,6-二甲基苯胺(0.44mL,3.62mmol),80摄氏度下反应过夜,将反应液倒入水(100mL)中,乙酸乙酯(100mL)萃取两次,有机层合并,水(100mL)洗两次,饱和食盐水(100mL)洗涤,无水硫酸钠干燥,真空浓缩除去溶剂,柱层析纯化(石油醚:乙酸乙酯=10:1至2:1梯度洗脱),得到白色固体1b-1(892mg,66%)。
1H NMR(400MHz,DMSO-d6)δ10.85(s,1H),9.38(s,1H),7.69(d,J=7.8Hz,1H),7.35(d,J=7.9Hz,1H),7.24(s,1H),7.11–6.98(m,6H),4.41(q,J=8.2Hz,1H),3.20(dd,J=14.3,4.9Hz,1H),3.01(dd,J=14.1,9.9Hz,1H),2.06(s,6H),1.35(s,9H).
化合物1a-2(100mg,0.31mmol)、DMF(3mL)、HATU(152mg,0.40mmol)、DIPEA(0.16mL,0.93mmol)、2,6-二甲基苯胺(42μL,0.34mmol),操作过程同化合物1b-1的合成,得黄色固体1b-2(63mg,48%)。
1H NMR(400MHz,DMSO-d6)δ10.95(s,1H),9.41(s,1H),7.47(dd,J=10.3,2.2Hz,1H),7.35–7.31(m,1H),7.31–7.29(m,1H),7.10–7.01(m,4H),6.91(td,J=9.2,2.3Hz,1H),4.37(td,J=9.6,5.0Hz,1H),3.13(dd,J=14.6,5.1Hz,1H),2.97(dd,J=14.3,9.7Hz,1H),1.33(s,9H).
化合物1a-3(117mg,0.35mmol)、DMF(3mL)、HATU(175mg,0.46mmol)、DIPEA(0.18mL,1.05mmol)、2,6-二甲基苯胺(48μL,0.39mmol),操作过程同化合物1b-1的合成,得黄色固体1b-3(70mg,46%)。
1H NMR(500MHz,DMSO-d6)δ10.66(s,1H),9.36(s,1H),7.23(d,J=8.7Hz,1H),7.19(d,J=2.2Hz,1H),7.16(d,J=1.9Hz,1H),7.09–6.99(m,4H),6.72(dd,J=8.7,2.3Hz,1H),4.38(td,J=9.4,5.2Hz,1H),3.78(s,3H),3.14(dd,J=14.6,5.2Hz,1H),2.98(dd,J=14.3,9.7Hz,1H),1.34(s,9H).
化合物1a-4(100mg,0.31mmol)、DMF(3mL)、HATU(152mg,0.40mmol)、DIPEA(0.16mL,0.93mmol)、2,6-二甲基苯胺(42μL,0.34mmol),操作过程同化合物1b-1的合成,得黄色固体1b-4(76mg,51%)。
1H NMR(400MHz,DMSO-d6)δ10.92(s,1H),9.38(s,1H),7.66(dd,J=8.7,5.5Hz,1H),7.23(d,J=2.3Hz,1H),7.11(dd,J=10.2,2.3Hz,1H),7.09–7.00(m,4H),6.86(t,J=9.3Hz,1H),4.39(q,J=8.0Hz,1H),3.16(dd,J=14.5,5.5Hz,1H),2.98(dd,J=14.4,9.5Hz,1H),2.04(s,6H),1.34(s,9H).
将化合物1a-1(152mg,0.50mmol)溶于N,N-二甲基甲酰胺(5mL)溶液中,依次加入HATU(247mg,0.65mmol)、DIPEA(0.25mL,1.50mmol),室温反应30分钟,加入4-三氟甲基苯胺(69μL,0.55mmol),室温反应过夜,将反应液倒入水(15mL)中,乙酸乙酯(15mL)萃取两次,有机层合并,水(15mL)洗两次,饱和食盐水(15mL)洗涤,无水硫酸钠干燥,真空浓缩除去溶剂,柱层析纯化(石油醚:乙酸乙酯(v:v)=10:1至2:1梯度洗脱),得到黄色固体1b-5(96mg,43%)。
1H NMR(500MHz,DMSO-d6)δ10.82(s,1H),10.40(s,1H),7.82(d,J=8.5Hz,2H),7.71–7.62(m,3H),7.32(d,J=8.0Hz,1H),7.18(d,J=2.3Hz,1H),7.08–7.00(m,2H),6.97(t,J=7.4Hz,1H),4.40(td,J=8.3,5.4Hz,1H),3.14(dd,J=14.5,5.5Hz,1H),3.02(dd,J=14.6,9.0Hz,1H),1.34(s,9H).
化合物1a-1(152mg,0.50mmol)、DMF(5mL)、HATU(247mg,0.65mmol)、DIPEA(0.25mL,1.50mmol)、4-甲砜基苯胺(94mg,0.55mmol),操作过程同化合物1b-5的合成,得到黄色固体1b-6(66mg,29%)。
1H NMR(600MHz,DMSO-d6)δ10.83(s,1H),10.51(s,1H),7.88–7.82(m,4H),7.65(d,J=8.0Hz,1H),7.32(d,J=8.0Hz,1H),7.18(d,J=2.3Hz,1H),7.10–7.04(m,2H),6.97(t,J=7.4Hz,1H),4.39(q,J=8.0Hz,1H),3.16(s,3H),3.13(dd,J=14.4,5.4Hz,1H),3.01(dd,J=14.5,9.0Hz,1H),1.33(s,9H).
步骤c:化合物P-1~化合物P-19,化合物P-27,化合物P-29~化合物P-36的合成
将化合物1b-1(94mg,0.23mmol)溶于二氯甲烷(0.85mL,VDCM:VTFA=5:1)溶液中,加入三氟乙酸(0.17mL,2.3mmol),室温反应2h,TLC监测反应完全,真空浓缩除去溶剂,得到脱Boc产物备用。将上述脱Boc产物溶于二氯甲烷(3mL)溶液中,加入三乙胺(64μL,0.46mmol),置于冰浴下反应,缓慢滴加氯甲酸苄酯(49μL,0.35mmol),将反应液移至室温反应过夜,加水(10mL)淬灭,二氯甲烷(10mL)萃取,有机层用饱和食盐水(10mL)洗涤一次,无水硫酸钠干燥,柱层析纯化(石油醚:乙酸乙酯(v:v)=10:1至2:1梯度洗脱),得白色固体P-1(41mg,40%)。
1H NMR(500MHz,DMSO-d6)δ10.84(s,1H),9.46(s,1H),7.71(d,J=7.9Hz,1H),7.59(d,J=8.1Hz,1H),7.38–7.33(m,2H),7.33–7.25(m,4H),7.25(d,J=2.3Hz,1H),7.09(t,J=7.6Hz,1H),7.07–7.02(m,3H),7.00(t,J=7.4Hz,1H),5.04(d,J=12.7Hz,1H),4.94(d,J=12.7Hz,1H),4.52(ddd,J=9.9,8.1,5.0Hz,1H),3.25(dd,J=14.6,5.2Hz,1H),3.04(dd,J=14.4,9.7Hz,1H),2.06(s,6H).
将化合物1b-1(70mg,0.17mmol)溶于二氯甲烷(0.65mL,VDCM:VTFA=5:1)溶液中,加入三氟乙酸(0.13mL,1.7mmol),室温反应2h,TLC监测反应完全,真空浓缩除去溶剂,得到脱Boc产物备用。将3-苯基丙酸(23mg,0.15mmol)溶于N,N-二甲基甲酰胺(2mL)溶液中,依次加入HATU(76mg,0.20mmol)、DIPEA(74μL,0.45mmol),室温反应30分钟,将上述所得脱Boc产物溶于N,N-二甲基甲酰胺(1mL)溶液中,加入反应液混合,室温反应2h,TLC监测反应完全,将反应液倒入水(10mL)中,用乙酸乙酯(10mL)萃取两次,合并有机层,水(10mL)洗两次,饱和食盐水(10mL)洗涤一次,无水硫酸钠干燥,真空浓缩除去溶剂,柱层析纯化(石油醚:乙酸乙酯(v:v)=5:1至2:1梯度洗脱),得黄色固体P-2(48mg,64%)。
1H NMR(600MHz,DMSO-d6)δ10.84(d,J=2.3Hz,1H),9.40(s,1H),8.27(d,J=8.0Hz,1H),7.67(d,J=7.9Hz,1H),7.34(d,J=8.1Hz,1H),7.23–7.18(m,3H),7.16–7.12(m,3H),7.08(t,J=7.2Hz,1H),7.06–7.01(m,3H),7.00(t,J=7.9Hz,1H),4.78(td,J=8.5,5.9Hz,1H),3.23(dd,J=14.5,5.7Hz,1H),2.99(dd,J=14.5,9.1Hz,1H),2.80–2.70(m,2H),2.47–2.37(m,2H),2.02(s,6H).
将化合物1b-1(94mg,0.23mmol)溶于二氯甲烷(0.85mL,VDCM:VTFA=5:1)溶液中,加入三氟乙酸(0.17mL,2.3mmol),室温反应2h,TLC监测反应完全,真空浓缩除去溶剂,得到脱Boc产物备用。将上述脱Boc产物溶于二氯甲烷(3mL)溶液中,加入三乙胺(64μL,0.46mmol)、4-二甲氨基吡啶(2mg,0.012mmol),置于冰浴下反应,缓慢滴加苯乙酰氯(49μL,0.37mmol),将反应液移至室温反应1h,TLC监测反应完全,加水(10mL)淬灭,二氯甲烷(10mL)萃取,有机层用饱和食盐水(10mL)洗涤一次,无水硫酸钠干燥,柱层析纯化(石油醚:乙酸乙酯(v:v)=10:1至1:1梯度洗脱),得黄色固体P-3(37mg,38%)。
1H NMR(600MHz,DMSO-d6)δ10.86(d,J=2.4Hz,1H),9.45(s,1H),8.50(d,J=8.1Hz,1H),7.67(d,J=7.8Hz,1H),7.35(d,J=8.1Hz,1H),7.25–7.20(m,3H),7.18(d,J=7.1Hz,1H),7.16–7.13(m,2H),7.07(t,J=7.8Hz,1H),7.05–7.00(m,3H),6.99(t,J=7.5Hz,1H),4.78(q,J=8.4Hz,1H),3.46(d,J=2.5Hz,2H),3.27(dd,J=14.3,5.9Hz,1H),3.03(dd,J=14.4,9.0Hz,1H),1.98(s,6H).
化合物1b-1(50mg,0.12mmol)、DCM(0.5mL)、TFA(0.1mL,1.3mmol);4-苯基丁酸(18mg,0.11mmol)、HATU(53mg,0.14mmol)、DIPEA(55μL,0.33mmol)、DMF(3mL),操作过程同化合物P-2的合成,得白色固体P-4(23mg,46%)。
1H NMR(500MHz,DMSO-d6)δ10.82(d,J=2.2Hz,1H),9.40(s,1H),8.18(d,J=8.0Hz,1H),7.67(d,J=7.8Hz,1H),7.33(d,J=8.1Hz,1H),7.28–7.23(m,2H),7.22(d,J=2.0Hz,1H),7.16(t,J=7.4Hz,1H),7.13–7.09(m,2H),7.09–7.05(m,1H),7.05–7.01(m,3H),7.01–6.97(m,1H),4.79(td,J=8.6,5.8Hz,1H),3.24(dd,J=14.4,5.6Hz,1H),3.01(dd,J=14.5,9.3Hz,1H),2.49–2.44(m,2H),2.20–2.07(m,2H),2.03(s,6H),1.78–1.68(m,2H).
化合物1b-1(40mg,0.10mmol)、DCM(0.5mL)、TFA(0.1mL,1.3mmol);5-苯基戊酸(16mg,0.09mmol)、HATU(46mg,0.12mmol)、DIPEA(45μL,0.27mmol)、DMF(3mL),操作过程同化合物P-2的合成,得白色固体P-5(25mg,59%)。
1H NMR(500MHz,DMSO-d6)δ10.81(d,J=2.4Hz,1H),9.38(s,1H),8.16(d,J=8.0Hz,1H),7.66(d,J=7.8Hz,1H),7.33(d,J=8.1Hz,1H),7.26–7.20(m,3H),7.17–7.10(m,3H),7.07(t,J=6.1Hz,1H),7.05–7.00(m,3H),7.00–6.96(m,1H),4.77(q,J=8.4Hz,1H),3.23(dd,J=14.4,5.7Hz,1H),3.00(dd,J=14.4,9.1Hz,1H),2.55–2.51(m,2H),2.19–2.07(m,2H),2.00(s,6H),1.51–1.40(m,4H).
化合物1b-1(94mg,0.23mmol)、DCM(0.85mL)、TFA(0.17mL,2.3mmol);3-(4-氟苯基)丙酸(42mg,0.25mmol)、HATU(114mg,0.30mmol)、DIPEA(115μL,0.69mmol)、DMF(3mL),操作过程同化合物P-2的合成,得白色固体P-6(45mg,43%)。
1H NMR(600MHz,DMSO-d6)δ10.85(s,1H),9.42(s,1H),8.27(d,J=7.9Hz,1H),7.68(d,J=7.8Hz,1H),7.35(d,J=8.0Hz,1H),7.22(s,1H),7.15–7.11(m,2H),7.08(t,J=7.5Hz,1H),7.06–7.00(m,4H),7.00–6.95(m,2H),4.77(q,J=8.3Hz,1H),3.23(dd,J=14.4,5.5Hz,1H),2.99(dd,J=14.4,9.2Hz,1H),2.74(t,J=7.3Hz,2H),2.40(t,J=7.6Hz,2H),2.01(s,6H).
化合物1b-1(80mg,0.20mmol)、DCM(0.75mL)、TFA(0.15mL,2.0mmol);3-(3-氟苯基)丙酸(37mg,0.22mmol)、HATU(99mg,0.26mmol)、DIPEA(99μL,0.60mmol)、DMF(3mL),操作过程同化合物P-2的合成,得黄色固体P-7(45mg,49%)。
1H NMR(600MHz,DMSO-d6)δ10.84(d,J=2.4Hz,1H),9.41(s,1H),8.29(d,J=8.0Hz,1H),7.66(d,J=7.9Hz,1H),7.34(d,J=8.1Hz,1H),7.25–7.21(m,1H),7.20(d,J=2.2Hz,1H),7.09–7.06(m,1H),7.06–7.00(m,4H),7.00–6.98(m,1H),6.98–6.94(m,2H),4.78(td,J=8.5,6.0Hz,1H),3.23(dd,J=14.4,5.8Hz,1H),2.98(dd,J=14.5,9.0Hz,1H),2.82–2.72(m,2H),2.49–2.39(m,2H),2.00(s,6H).
化合物1b-1(94mg,0.23mmol)、DCM(0.85mL)、TFA(0.17mL,2.3mmol);3-(4-甲氧基苯基)丙酸(42mg,0.25mmol)、HATU(114mg,0.30mmol)、DIPEA(115μL,0.69mmol)、DMF(3mL),操作过程同化合物P-2的合成,得黄色固体P-8(35mg,32%)。
1H NMR(600MHz,DMSO-d6)δ10.85(d,J=2.4Hz,1H),9.38(s,1H),8.25(d,J=8.0Hz,1H),7.67(d,J=7.9Hz,1H),7.35(d,J=8.1Hz,1H),7.23(d,J=2.1Hz,1H),7.08(t,J=7.9Hz,1H),7.06–7.02(m,4H),7.02–6.98(m,2H),6.76–6.71(m,2H),4.77(td,J=8.5,5.9Hz,1H),3.68(s,3H),3.24(dd,J=14.4,5.7Hz,1H),3.00(dd,J=14.5,9.1Hz,1H),2.73–2.64(m,2H),2.42–2.33(m,2H),2.02(s,6H).
化合物1b-1(94mg,0.23mmol)、DCM(0.85mL)、TFA(0.17mL,2.3mmol);3-(3-甲氧基苯基)丙酸(42mg,0.25mmol)、HATU(114mg,0.30mmol)、DIPEA(115μL,0.69mmol)、DMF(3mL),操作过程同化合物P-2的合成,得黄色固体P-9(47mg,44%)。
1H NMR(600MHz,DMSO-d6)δ10.84(d,J=2.4Hz,1H),9.39(s,1H),8.27(d,J=8.0Hz,1H),7.67(d,J=7.9Hz,1H),7.34(d,J=8.1Hz,1H),7.21(d,J=2.1Hz,1H),7.12(t,J=7.8Hz,1H),7.08(t,J=7.6Hz,1H),7.05–7.01(m,3H),7.01–6.98(m,1H),6.77–6.74(m,1H),6.73–6.69(m,2H),4.78(td,J=8.4,6.0Hz,1H),3.69(s,3H),3.24(dd,J=14.5,5.8Hz,1H),3.00(dd,J=14.5,9.0Hz,1H),2.78–2.68(m,2H),2.47–2.37(m,2H),2.01(s,6H).
化合物1b-1(70mg,0.17mmol)、DCM(0.65mL)、TFA(0.13mL,1.7mmol);3-(4-氯苯基)丙酸(28mg,0.15mmol)、HATU(76mg,0.20mmol)、DIPEA(74μL,0.45mmol)、DMF(3mL),操作过程同化合物P-2的合成,得白色固体P-10(36mg,51%)。
1H NMR(500MHz,DMSO-d6)δ10.83(d,J=2.3Hz,1H),9.38(s,1H),8.25(d,J=8.0Hz,1H),7.67(d,J=7.9Hz,1H),7.35(d,J=8.1Hz,1H),7.22(d,J=2.0Hz,1H),7.22–7.19(m,2H),7.14–7.10(m,2H),7.10–7.07(m,1H),7.06–7.02(m,3H),7.02–6.98(m,1H),4.77(td,J=8.6,5.8Hz,1H),3.23(dd,J=14.4,5.6Hz,1H),2.99(dd,J=14.4,9.1Hz,1H),2.79–2.69(m,2H),2.41(t,J=7.6Hz,2H),2.01(s,6H).
化合物1b-1(70mg,0.17mmol)、DCM(0.65mL)、TFA(0.13mL,1.7mmol);3-(3-氯苯基)丙酸(28mg,0.15mmol)、HATU(76mg,0.20mmol)、DIPEA(74μL,0.45mmol)、DMF(3mL),操作过程同化合物P-2的合成,得黄色固体P-11(35mg,49%)。
1H NMR(500MHz,DMSO-d6)δ10.82(d,J=2.4Hz,1H),9.38(s,1H),8.26(d,J=8.0Hz,1H),7.66(d,J=7.8Hz,1H),7.34(d,J=8.1Hz,1H),7.25(d,J=2.0Hz,1H),7.24–7.19(m,3H),7.12–7.06(m,2H),7.06–7.01(m,3H),6.99(t,J=6.0Hz,1H),4.77(td,J=8.5,5.9Hz,1H),3.23(dd,J=14.4,5.9Hz,1H),2.98(dd,J=14.5,8.9Hz,1H),2.82–2.71(m,2H),2.49–2.38(m,2H),2.00(s,6H).
化合物1b-1(80mg,0.20mmol)、DCM(0.75mL)、TFA(0.15mL,2.0mmol);3-(4-吡啶基)丙酸(33mg,0.22mmol)、HATU(99mg,0.26mmol)、DIPEA(99μL,0.60mmol)、DMF(3mL),操作过程同化合物P-2的合成,得黄色固体P-12(43mg,49%)。
1H NMR(600MHz,DMSO-d6)δ10.86(s,1H),9.44(s,1H),8.38–8.31(m,3H),7.68(d,J=7.9Hz,1H),7.35(d,J=8.1Hz,1H),7.22(s,1H),7.11(d,J=5.0Hz,2H),7.08(t,J=7.7Hz,1H),7.06–6.98(m,4H),4.78(q,J=7.8Hz,1H),3.24(dd,J=14.5,5.6Hz,1H),3.00(dd,J=14.5,9.2Hz,1H),2.77(t,J=7.7Hz,2H),2.46(t,J=7.6Hz,2H),2.01(s,6H).
化合物1b-1(80mg,0.20mmol)、DCM(0.75mL)、TFA(0.15mL,2.0mmol);3-(3-吡啶基)丙酸(33mg,0.22mmol)、HATU(99mg,0.26mmol)、DIPEA(99μL,0.60mmol)、DMF(3mL),操作过程同化合物P-2的合成,得黄色固体P-13(41mg,47%)。
1H NMR(600MHz,DMSO-d6)δ10.84(d,J=2.3Hz,1H),9.43(s,1H),8.41(s,1H),8.36(d,J=4.8Hz,1H),8.30(d,J=8.0Hz,1H),7.67(d,J=7.9Hz,1H),7.51(dd,J=7.9,2.0Hz,1H),7.35(d,J=8.0Hz,1H),7.22–7.17(m,2H),7.08(t,J=7.5Hz,1H),7.06–6.98(m,4H),4.78(td,J=8.5,5.8Hz,1H),3.23(dd,J=14.4,5.8Hz,1H),2.98(dd,J=14.5,9.0Hz,1H),2.82–2.73(m,2H),2.49–2.41(m,2H),2.00(s,6H).
化合物1b-1(94mg,0.23mmol)、DCM(0.85mL)、TFA(0.17mL,2.3mmol);3-(3-噻吩)丙酸(39mg,0.25mmol)、HATU(114mg,0.30mmol)、DIPEA(115μL,0.69mmol)、DMF(3mL),操作过程同化合物P-2的合成,得黄色固体P-14(43mg,42%)。
1H NMR(600MHz,DMSO-d6)δ10.84(s,1H),9.42(s,1H),8.28(d,J=8.0Hz,1H),7.67(d,J=7.9Hz,1H),7.37(dd,J=4.9,3.0Hz,1H),7.35(d,J=8.1Hz,1H),7.21(d,J=2.3Hz,1H),7.09–7.06(m,1H),7.06–7.01(m,4H),7.01–6.98(m,1H),6.92(dd,J=4.9,1.2Hz,1H),4.79(td,J=8.6,5.8Hz,1H),3.24(dd,J=14.4,5.7Hz,1H),3.00(dd,J=14.5,9.2Hz,1H),2.81–2.72(m,2H),2.48–2.37(m,2H),2.02(s,6H).
化合物1b-1(94mg,0.23mmol)、DCM(0.85mL)、TFA(0.17mL,2.3mmol);3-(2-噻吩)丙酸(39mg,0.25mmol)、HATU(114mg,0.30mmol)、DIPEA(115μL,0.69mmol)、DMF(3mL),操作过程同化合物P-2的合成,得黄色固体P-15(38mg,37%)。
1H NMR(600MHz,DMSO-d6)δ10.84(s,1H),9.41(s,1H),8.33(d,J=8.0Hz,1H),7.66(d,J=7.9Hz,1H),7.34(d,J=8.1Hz,1H),7.25(dd,J=5.1,1.3Hz,1H),7.20(s,1H),7.07(t,J=7.4Hz,1H),7.06–7.01(m,3H),6.99(t,J=7.5Hz,1H),6.87–6.84(m,1H),6.76(d,J=3.4Hz,1H),4.78(td,J=8.4,5.7Hz,1H),3.24(dd,J=14.5,5.7Hz,1H),3.00(dd,J=14.5,9.2Hz,1H),2.98–2.91(m,2H),2.53–2.42(m,2H),2.01(s,6H).
化合物1b-1(50mg,0.12mmol)、DCM(0.5mL)、TFA(0.1mL,1.3mmol);3-(2-噻唑基)丙酸(17mg,0.11mmol)、HATU(53mg,0.14mmol)、DIPEA(55μL,0.33mmol)、DMF(3mL),操作过程同化合物P-2的合成,得黄色固体P-16(15mg,31%)。
1H NMR(600MHz,DMSO-d6)δ10.83(d,J=2.4Hz,1H),9.40(s,1H),8.40(d,J=7.9Hz,1H),7.65(d,J=7.9Hz,1H),7.58(d,J=3.3Hz,1H),7.50(d,J=3.3Hz,1H),7.34(d,J=8.1Hz,1H),7.21(d,J=2.3Hz,1H),7.09–7.06(m,1H),7.06–7.01(m,3H),6.99(t,J=7.4Hz,1H),4.76(td,J=8.5,5.5Hz,1H),3.26(dd,J=14.5,5.5Hz,1H),3.15(td,J=7.5,3.5Hz,2H),3.00(dd,J=14.5,9.2Hz,1H),2.64(dt,J=15.0,7.5Hz,1H),2.56(dt,J=15.0,7.4Hz,1H),2.01(s,6H).
化合物1b-1(80mg,0.20mmol)、DCM(0.75mL)、TFA(0.15mL,2.0mmol);3-环己基丙酸(37μL,0.22mmol)、HATU(99mg,0.26mmol)、DIPEA(99μL,0.60mmol)、DMF(3mL),操作过程同化合物P-2的合成,得黄色固体P-17(27mg,30%)。
1H NMR(600MHz,DMSO-d6)δ10.84(d,J=2.4Hz,1H),9.40(s,1H),8.16(d,J=8.1Hz,1H),7.66(d,J=7.9Hz,1H),7.33(d,J=8.1Hz,1H),7.21(d,J=2.3Hz,1H),7.09–7.05(m,1H),7.05–7.01(m,3H),7.00–6.97(m,1H),4.77(td,J=8.7,5.9Hz,1H),3.22(dd,J=14.4,5.8Hz,1H),2.99(dd,J=14.5,9.1Hz,1H),2.17–2.05(m,2H),2.02(s,6H),1.66–1.55(m,5H),1.39–1.27(m,2H),1.16–1.04(m,4H),0.84–0.74(m,2H).
化合物1b-1(80mg,0.20mmol)、DCM(0.75mL)、TFA(0.15mL,2.0mmol);3-环戊基丙酸(31μL,0.22mmol)、HATU(99mg,0.26mmol)、DIPEA(99μL,0.60mmol)、DMF(3mL),操作过程同化合物P-2的合成,得白色固体P-18(31mg,36%)。
1H NMR(600MHz,DMSO-d6)δ10.84(d,J=2.5Hz,1H),9.41(s,1H),8.16(d,J=8.1Hz,1H),7.66(d,J=7.9Hz,1H),7.33(d,J=8.0Hz,1H),7.21(d,J=2.3Hz,1H),7.09–7.01(m,4H),6.99(t,J=7.4Hz,1H),4.77(td,J=8.8,5.8Hz,1H),3.23(dd,J=14.4,5.7Hz,1H),3.00(dd,J=14.4,9.2Hz,1H),2.16–2.05(m,2H),2.02(s,6H),1.67–1.57(m,3H),1.56–1.47(m,2H),1.47–1.38(m,4H),1.03–0.95(m,2H).
化合物1b-1(80mg,0.20mmol)、DCM(0.75mL)、TFA(0.15mL,2.0mmol);3-环丙基丙酸(22μL,0.22mmol)、HATU(99mg,0.26mmol)、DIPEA(99μL,0.60mmol)、DMF(3mL),操作过程同化合物P-2的合成,得白色固体P-19(38mg,47%)。
1H NMR(500MHz,DMSO-d6)δ10.81(s,1H),9.38(s,1H),8.14(d,J=8.0Hz,1H),7.66(d,J=7.8Hz,1H),7.33(d,J=8.1Hz,1H),7.21(d,J=2.3Hz,1H),7.08–7.05(m,1H),7.05–6.96(m,4H),4.76(td,J=8.7,5.8Hz,1H),3.23(dd,J=14.4,5.7Hz,1H),3.00(dd,J=14.5,9.1Hz,1H),2.25–2.12(m,2H),2.02(s,6H),1.39–1.27(m,2H),0.61–0.52(m,1H),0.34–0.23(m,2H),-0.01–-0.08(m,2H).
化合物1b-6(50mg,0.11mmol)、DCM(0.50mL)、TFA(0.10mL,1.3mmol);3-苯基丙酸(15mg,0.10mmol)、HATU(49mg,0.13mmol)、DIPEA(50μL,0.30mmol)、DMF(3mL),操作过程同化合物P-2的合成,得黄色固体P-27(16mg,33%)。
1H NMR(400MHz,DMSO-d6)δ10.82(d,J=2.4Hz,1H),10.57(s,1H),8.31(d,J=7.7Hz,1H),7.89–7.81(m,4H),7.64(d,J=7.9Hz,1H),7.32(d,J=8.0Hz,1H),7.24–7.18(m,2H),7.17–7.10(m,4H),7.06(t,J=7.5Hz,1H),6.97(t,J=7.4Hz,1H),4.74(q,J=7.5Hz,1H),3.17(dd,J=14.4,5.7Hz 1H),3.16(s,3H),3.00(dd,J=14.6,8.4Hz,1H),2.74(t,J=7.8Hz,2H),2.42(t,J=7.8Hz,2H).
化合物1b-5(48mg,0.11mmol)、DCM(0.50mL)、TFA(0.10mL,1.3mmol);3-苯基丙酸(15mg,0.10mmol)、HATU(49mg,0.13mmol)、DIPEA(50μL,0.30mmol)、DMF(3mL),操作过程同化合物P-2的合成,得黄色固体P-29(14mg,29%)。
1H NMR(500MHz,DMSO-d6)δ10.81(d,J=2.5Hz,1H),10.47(s,1H),8.29(d,J=7.8Hz,1H),7.82(d,J=8.5Hz,2H),7.67(d,J=8.6Hz,2H),7.64(d,J=8.0Hz,1H),7.33(d,J=8.1Hz,1H),7.23–7.18(m,2H),7.16–7.12(m,4H),7.06(ddd,J=8.1,6.9,1.2Hz,1H),6.97(ddd,J=8.0,7.0,1.0Hz,1H),4.75(td,J=8.1,5.9Hz,1H),3.17(dd,J=14.6,5.8Hz,1H),3.02(dd,J=14.6,8.5Hz,1H),2.75(t,J=7.8Hz,2H),2.43(dd,J=8.8,6.8Hz,2H).
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化合物1b-2(50mg,0.12mmol)、DCM(0.5mL)、TFA(0.1mL,1.3mmol);3-苯基丙酸(20mg,0.13mmol)、HATU(61mg,0.16mmol)、DIPEA(60μL,0.36mmol)、DMF(3mL),操作过程同化合物P-2的合成,得白色固体P-30(30mg,55%)。
1H NMR(500MHz,DMSO-d6)δ10.93(d,J=2.5Hz,1H),9.41(s,1H),8.25(d,J=8.0Hz,1H),7.46(dd,J=10.2,2.5Hz,1H),7.33(dd,J=8.8,4.5Hz,1H),7.28(d,J=2.4Hz,1H),7.22–7.17(m,2H),7.16–7.10(m,3H),7.07–7.01(m,3H),6.91(td,J=9.1,2.5Hz,1H),4.76(td,J=8.7,5.8Hz,1H),3.18(dd,J=14.4,5.7Hz,1H),2.96(dd,J=14.4,9.2Hz,1H),2.79–2.68(m,2H),2.46–2.35(m,2H),2.01(s,6H).
化合物1b-3(53mg,0.12mmol)、DCM(0.5mL)、TFA(0.1mL,1.3mmol);3-苯基丙酸(20mg,0.13mmol)、HATU(61mg,0.16mmol)、DIPEA(60μL,0.36mmol)、DMF(3mL),操作过程同化合物P-2的合成,得白色固体P-31(28mg,50%)。
1H NMR(500MHz,DMSO-d6)δ10.68(d,J=2.5Hz,1H),9.40(s,1H),8.28(d,J=8.1Hz,1H),7.27–7.20(m,3H),7.19–7.17(m,2H),7.17–7.12(m,3H),7.09–7.01(m,3H),6.74(dd,J=8.7,2.4Hz,1H),4.77(td,J=8.6,5.6Hz,1H),3.79(s,3H),3.21(dd,J=14.3,5.5Hz,1H),2.98(dd,J=14.5,9.1Hz,1H),2.82–2.70(m,2H),2.49–2.38(m,2H),2.04(s,6H).
化合物1b-4(50mg,0.12mmol)、DCM(0.5mL)、TFA(0.1mL,1.3mmol);3-苯基丙酸(20mg,0.13mmol)、HATU(61mg,0.16mmol)、DIPEA(60μL,0.36mmol)、DMF(3mL),操作过程同化合物P-2的合成,得白色固体P-32(28mg,51%)。
1H NMR(500MHz,DMSO-d6)δ10.90(s,1H),9.38(s,1H),8.25(d,J=8.0Hz,1H),7.65(dd,J=8.7,5.4Hz,1H),7.23–7.18(m,3H),7.17–7.10(m,4H),7.07–7.00(m,3H),6.89–6.83(m,1H),4.77(td,J=8.5,5.8Hz,1H),3.21(dd,J=14.5,5.8Hz,1H),2.98(dd,J=14.5,9.0Hz,1H),2.81–2.68(m,2H),2.48–2.36(m,2H),2.01(s,6H).
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将化合物1b-1(408mg,1mmol)溶于二氯甲烷(3.75mL,VDCM:VTFA=5:1)溶液中,加入三氟乙酸(0.75mL,10mmol),室温反应2h,TLC监测反应完全,真空浓缩除去溶剂,得到脱Boc产物备用。将上述脱Boc产物溶于乙腈(10mL)溶液中,加入苯乙醛(170μL,1.5mmol),反应15分钟,加入氰基硼氢化钠(377mg,6mmol),室温反应过夜,真空浓缩除去溶剂,加水(50mL),乙酸乙酯(30mL)萃取,有机层用饱和食盐水(20mL)洗涤一次,无水硫酸钠干燥,柱层析纯化(石油醚:乙酸乙酯(v:v)=10:1至4:1梯度洗脱),得白色固体P-33(80mg,19%)。
1H NMR(400MHz,Chloroform-d)δ8.76(s,1H),8.14(s,1H),7.69(dd,J=7.9,1.1Hz,1H),7.37(dt,J=8.2,0.9Hz,1H),7.22(ddd,J=8.1,7.0,1.2Hz,1H),7.16–7.09(m,4H),7.08–7.04(m,3H),6.95–6.90(m,3H),3.60(dd,J=10.2,3.6Hz,1H),3.48(dd,J=14.3,3.3Hz,1H),3.01–2.90(m,2H),2.83(dt,J=11.7,6.5Hz,1H),2.62(td,J=6.7,1.9Hz,2H),2.17(s,6H).
将化合物1b-1(102mg,0.25mmol)溶于二氯甲烷(0.9mL,VDCM:VTFA=5:1)溶液中,加入三氟乙酸(0.18mL,2.5mmol),室温反应2h,TLC监测反应完全,真空浓缩除去溶剂,得到脱Boc产物备用。将上述脱Boc产物溶于乙腈(5mL)溶液中,加入三乙胺(175μL,1.25mmol)、甲磺酸-3-苯基丙酯(合成参考WO 2003080631(A2),64mg,0.3mmol)、碳酸钾(69mg,0.5mmol)、碘化钠(75mg,0.5mmol),80摄氏度下回流过夜,真空浓缩除去溶剂,加水(20mL),乙酸乙酯(20mL)萃取,有机层用饱和食盐水(20mL)洗涤一次,无水硫酸钠干燥,柱层析纯化(石油醚:乙酸乙酯(v:v)=10:1至3:1梯度洗脱),得黄色固体P-34(23mg,22%)。
1H NMR(400MHz,Chloroform-d)δ8.84(s,1H),8.19(s,1H),7.74(d,J=7.9Hz,1H),7.39(d,J=8.1Hz,1H),7.23(d,J=7.9Hz,1H),7.19–7.13(m,3H),7.13–7.05(m,5H),6.91(d,J=7.2Hz,2H),3.58(dd,J=10.2,3.5Hz,1H),3.52(dd,J=14.3,3.6Hz,1H),3.01(dd,J=14.4,10.2Hz,1H),2.68(dt,J=13.5,7.2Hz,1H),2.54(dt,J=12.3,6.7Hz,1H),2.50–2.35(m,2H),2.17(s,6H),1.66(tt,J=7.9,7.6Hz,2H).
化合物1b-1(204mg,0.50mmol)、DCM(1.85mL)、TFA(0.37mL,5.0mmol);三乙胺(350μL,2.5mmol)、甲磺酸-4-苯基丁酯(合成参考WO 2003080631(A2),228mg,1mmol)、碳酸钾(207mg,1.5mmol)、碘化钠(225mg,1.5mmol)、乙腈(10mL),操作过程同化合物P-34的合成,得白色固体P-35(49mg,22%)。
1H NMR(400MHz,Chloroform-d)δ8.91(s,1H),8.13(s,1H),7.74(d,J=7.9Hz,1H),7.38(dt,J=8.1,0.9Hz,1H),7.25–7.20(m,3H),7.18–7.12(m,2H),7.12–7.06(m,4H),7.05–7.00(m,2H),3.59(dd,J=10.1,3.6Hz,1H),3.51(dd,J=14.5,3.6Hz,1H),3.00(dd,J=14.4,10.2Hz,1H),2.69(dt,J=13.0,6.8Hz,1H),2.56(dt,J=12.0,6.4Hz,1H),2.44(t,J=7.3Hz,2H),2.21(s,6H),1.47–1.33(m,4H).
化合物1b-1(204mg,0.50mmol)、DCM(1.85mL)、TFA(0.37mL,5.0mmol);三乙胺(350μL,2.5mmol)、甲磺酸-5-苯基戊酯(合成参考WO 2003080631(A2),242mg,1mmol)、碳酸钾(207mg,1.5mmol)、碘化钠(225mg,1.5mmol)、乙腈(10mL),操作过程同化合物P-34的合成,得黄色固体P-36(44mg,19%)。
1H NMR(400MHz,Chloroform-d)δ8.94(s,1H),8.23(s,1H),7.72(d,J=7.9Hz,1H),7.36(d,J=8.1Hz,1H),7.27–7.20(m,2H),7.20–7.11(m,3H),7.11–7.06(m,5H),7.04(d,J=2.3Hz,1H),3.57(dd,J=10.1,3.6Hz,1H),3.51(dd,J=14.5,3.6Hz,1H),2.99(dd,J=14.4,10.2Hz,1H),2.65(dt,J=11.7,7.2Hz,1H),2.52(dt,J=11.7,6.7Hz,1H),2.45(t,J=7.7Hz,2H),2.22(s,6H),1.50–1.38(m,2H),1.36–1.28(m,2H),1.17–1.05(m,2H).
步骤d:化合物2a的合成
将化合物S-1(2.04g,10mmol)溶于乙醇(37.5mL)溶液中,冰浴下,向反应液中缓慢滴加SOCl2(2.2mL,30mmol),滴加完毕,反应液移至80摄氏度下回流过夜,真空浓缩除去溶剂,浓缩物用乙酸乙酯(80mL)溶解,饱和NaHCO3溶液(50mL)洗涤两次,水(50mL)洗涤一次,饱和食盐水(50mL)洗涤一次,无水硫酸钠干燥,真空浓缩除去溶剂,得黄色油状液体2a(2.11g,91%)。
1H NMR(500MHz,DMSO-d6)δ10.83(s,1H),7.49(d,J=7.8Hz,1H),7.33(d,J=8.1Hz,1H),7.11(d,J=2.4Hz,1H),7.05(t,J=7.5Hz,1H),6.96(t,J=7.4Hz,1H),3.99(q,J=7.1Hz,2H),3.60(t,J=6.4Hz,1H),3.01(dd,J=14.2,6.3Hz,1H),2.93(dd,J=14.2,6.5Hz,1H),1.82(s,2H),1.09(t,J=7.1Hz,3H).
步骤e:化合物2b的合成
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将3-苯基丙酸(1.35g,9mmol)溶于N,N-二甲基甲酰胺(90mL)溶液中,依次加入HATU(4.45g,11.7mmol)、DIPEA(4.46mL,27mmol),室温反应30分钟,将化合物2a溶于N,N-二甲基甲酰胺(10mL)溶液中,加入上述反应液,室温反应过夜,将反应液倒入水(200mL)中,乙酸乙酯(200mL)萃取两次,合并有机层,水(200mL)洗三次,饱和食盐水(200mL)洗涤一次,无水硫酸钠干燥,柱层析纯化(石油醚:乙酸乙酯(v:v)=5:1至1:1梯度洗脱),得黄色固体2b(2.60g,79%)。
1H NMR(600MHz,DMSO-d6)δ10.86(s,1H),8.31(d,J=7.5Hz,1H),7.49(d,J=7.9Hz,1H),7.34(d,J=8.1Hz,1H),7.24(t,J=7.6Hz,2H),7.18–7.14(m,3H),7.11(d,J=2.1Hz,1H),7.07(t,J=7.2Hz,1H),6.99(t,J=7.2Hz,1H),4.50(q,J=7.9Hz,1H),4.01(q,J=7.1Hz,2H),3.12(dd,J=14.5,5.9Hz,1H),3.01(dd,J=14.6,8.4Hz,1H),2.80–2.70(m,2H),2.40(t,J=7.8Hz,2H),1.07(t,J=7.1Hz,3H).
步骤f:化合物2c的合成
将化合物2b(1.0g,2.74mmol)溶于乙醇(20mL)溶液中,将氢氧化钠(549mg,13.72mmol)溶于水(2mL)并加入上述反应液中,室温反应过夜,真空浓缩除去溶剂,加入水(40mL),用2M盐酸溶液调pH至2-3,析出白色固体,抽滤,滤饼烘干,得白色固体2c(856mg,93%)。
1H NMR(600MHz,DMSO-d6)δ12.64(s,1H),10.83(s,1H),8.16(d,J=7.9Hz,1H),7.53(d,J=7.9Hz,1H),7.33(d,J=8.1Hz,1H),7.23(t,J=7.4Hz,2H),7.18–7.12(m,3H),7.09(d,J=2.0Hz,1H),7.06(t,J=7.5Hz,1H),6.98(t,J=7.4Hz,1H),4.48(td,J=8.3,5.2Hz,1H),3.15(dd,J=14.6,5.0Hz,1H),2.99(dd,J=14.6,8.7Hz,1H),2.78–2.68(m,2H),2.38(t,J=7.9Hz,2H).
步骤g:化合物P-(20-26),28的合成
将化合物2c(67mg,0.20mmol)溶于N,N-二甲基甲酰胺(3mL)溶液中,依次加入HATU(99mg,0.26mmol)、DIPEA(99μL,0.60mmol),室温反应30分钟,加入邻甲苯胺(23μL,0.22mmol),室温反应过夜,将反应液倒入水(10mL)中,用乙酸乙酯(10mL)萃取两次,合并有机层,水(10mL)洗两次,饱和食盐水(10mL)洗涤一次,无水硫酸钠干燥,真空浓缩除去溶剂,柱层析纯化(石油醚:乙酸乙酯(v:v)=5:1至1:1梯度洗脱),得白色固体P-20(52mg,61%)。
1H NMR(500MHz,DMSO-d6)δ10.82(d,J=2.3Hz,1H),9.35(s,1H),8.23(d,J=7.9Hz,1H),7.64(d,J=7.9Hz,1H),7.34(d,J=8.1Hz,1H),7.31(d,J=7.8Hz,1H),7.23–7.16(m,4H),7.16–7.11(m,4H),7.10–7.04(m,2H),6.99(t,J=7.4Hz,1H),4.78(td,J=8.1,6.0Hz,1H),3.21(dd,J=14.5,6.1Hz,1H),3.02(dd,J=14.5,8.4Hz,1H),2.76(td,J=7.5,2.4Hz,2H),2.44(t,J=7.8Hz,2H),2.07(s,3H).
将化合物2c(67mg,0.20mmol)、EDCI(58mg,0.3mmol)、HOBT(41mg,0.3mmol)溶于乙腈/四氢呋喃(1mL/1mL)混合溶液中,加入邻氟苯胺(20μL,0.21mmol)和三乙胺(56μL,0.4mmol),室温反应过夜,真空浓缩除去溶剂,加水(10mL),乙酸乙酯(10mL)萃取一次,有机层用水(10mL)洗涤两次,饱和食盐水(10mL)洗涤一次,无水硫酸钠干燥,柱层析纯化(石油醚:乙酸乙酯(v:v)=5:1至1:1梯度洗脱),得黄色固体P-21(22mg,26%)。
1H NMR(500MHz,DMSO-d6)δ10.81(s,1H),9.82(s,1H),8.23(d,J=8.0Hz,1H),7.80–7.74(m,1H),7.64(d,J=7.9Hz,1H),7.33(d,J=8.0Hz,1H),7.27–7.22(m,1H),7.22–7.17(m,2H),7.17–7.14(m,3H),7.14–7.10(m,3H),7.06(t,J=7.5Hz,1H),6.97(t,J=7.4Hz,1H),4.84(td,J=8.4,5.5Hz,1H),3.18(dd,J=14.6,5.4Hz,1H),3.01(dd,J=14.6,8.8Hz,1H),2.73(td,J=7.5,2.6Hz,2H),2.40(t,J=7.8Hz,2H).
化合物2c(67mg,0.20mmol),DMF(3mL),HATU(99mg,0.26mmol),DIPEA(99μL,0.60mmol),苯胺(20μL,0.22mmol),操作过程同化合物P-20的合成,得白色固体P-22(66mg,80%)。
1H NMR(500MHz,DMSO-d6)δ10.79(d,J=2.3Hz,1H),10.09(s,1H),8.22(d,J=7.9Hz,1H),7.65(d,J=7.9Hz,1H),7.62–7.58(m,2H),7.34–7.27(m,3H),7.23–7.18(m,2H),7.17–7.11(m,4H),7.08–7.03(m,2H),6.97(t,J=7.4Hz,1H),4.74(td,J=8.2,5.9Hz,1H),3.15(dd,J=14.6,5.8Hz,1H),2.99(dd,J=14.6,8.5Hz,1H),2.74(dd,J=8.9,6.8Hz,2H),2.42(dd,J=8.8,6.9Hz,2H).
化合物2c(67mg,0.20mmol),DMF(3mL),HATU(99mg,0.26mmol),DIPEA(99μL,0.60mmol),对甲苯胺(24mg,0.22mmol),操作过程同化合物P-20的合成,得黄色固体P-23(53mg,62%)。
1H NMR(500MHz,DMSO-d6)δ10.79(d,J=2.4Hz,1H),9.98(s,1H),8.19(d,J=8.0Hz,1H),7.64(d,J=7.9Hz,1H),7.50–7.45(m,2H),7.32(d,J=8.1Hz,1H),7.23–7.18(m,2H),7.16–7.13(m,2H),7.13–7.11(m,2H),7.11–7.08(m,2H),7.06(t,J=7.5Hz,1H),6.97(t,J=7.0Hz,1H),4.72(td,J=8.2,5.8Hz,1H),3.14(dd,J=14.5,5.8Hz,1H),2.98(dd,J=14.6,8.4Hz,1H),2.74(dd,J=8.8,6.8Hz,2H),2.41(t,J=7.9Hz,2H),2.25(s,3H).
化合物2c(67mg,0.20mmol),DMF(3mL),HATU(99mg,0.26mmol),DIPEA(99μL,0.60mmol),对甲氧基苯胺(27mg,0.22mmol),操作过程同化合物P-20的合成,得黄色固体P-24(61mg,69%)。
1H NMR(400MHz,DMSO-d6)δ10.80(d,J=2.4Hz,1H),9.96(s,1H),8.21(d,J=8.0Hz,1H),7.64(d,J=7.9Hz,1H),7.53–7.47(m,2H),7.32(dt,J=8.0,0.9Hz,1H),7.24–7.18(m,2H),7.17–7.10(m,4H),7.06(ddd,J=8.1,6.9,1.2Hz,1H),6.97(ddd,J=8.0,7.0,1.1Hz,1H),6.91–6.84(m,2H),4.70(td,J=8.2,5.9Hz,1H),3.71(s,3H),3.14(dd,J=14.6,5.8Hz,1H),2.98(dd,J=14.5,8.4Hz,1H),2.77–2.69(m,2H),2.44–2.37(m,2H).
化合物2c(100mg,0.30mmol),DMF(3mL),HATU(148mg,0.39mmol),DIPEA(149μL,0.90mmol),4-氨基-N,N-二甲基苯胺(45mg,0.33mmol),操作过程同化合物P-20的合成,得灰色固体P-25(18mg,13%)。
1H NMR(500MHz,DMSO-d6)δ10.78(d,J=2.4Hz,1H),9.75(s,1H),8.14(d,J=8.2Hz,1H),7.64(d,J=7.9Hz,1H),7.41–7.36(m,2H),7.31(d,J=8.1Hz,1H),7.23–7.18(m,2H),7.16–7.12(m,3H),7.11(d,J=2.3Hz,1H),7.05(ddd,J=8.1,6.9,1.2Hz,1H),6.99–6.95(m,1H),6.70–6.65(m,2H),4.69(td,J=8.1,5.9Hz,1H),3.13(dd,J=14.5,5.9Hz,1H),2.97(dd,J=14.5,8.3Hz,1H),2.84(s,6H),2.73(dd,J=9.0,6.7Hz,2H),2.40(dd,J=8.8,7.0Hz,2H).
化合物2c(67mg,0.20mmol),DMF(3mL),HATU(99mg,0.26mmol),DIPEA(99μL,0.60mmol),4-(4-吗啉基)苯胺(39mg,0.22mmol),操作过程同化合物P-20的合成,得黄色固体P-26(48mg,48%)。
1H NMR(500MHz,DMSO-d6)δ10.78(d,J=2.4Hz,1H),9.86(s,1H),8.17(d,J=8.1Hz,1H),7.64(d,J=7.9Hz,1H),7.48–7.42(m,2H),7.32(d,J=8.1Hz,1H),7.24–7.18(m,2H),7.17–7.12(m,3H),7.11(d,J=2.2Hz,1H),7.06(ddd,J=8.1,7.0,1.2Hz,1H),6.97(td,J=7.4,1.0Hz,1H),6.91–6.86(m,2H),4.70(td,J=8.2,5.9Hz,1H),3.72(t,J=4.8Hz,4H),3.13(dd,J=14.6,5.9Hz,1H),3.03(dd,J=5.7,3.9Hz,4H),2.98(dd,J=14.6,8.3Hz,1H),2.73(dd,J=8.9,6.8Hz,2H),2.41(dd,J=8.9,6.9Hz,2H).
化合物2c(67mg,0.20mmol),DMF(3mL),HATU(99mg,0.26mmol),DIPEA(99μL,0.60mmol),4-氟苯胺(21μL,0.22mmol),操作过程同化合物P-20的合成,得黄色固体P-28(60mg,70%)。
1H NMR(600MHz,DMSO-d6)δ10.80(s,1H),10.16(s,1H),8.25(d,J=7.9Hz,1H),7.63(d,J=7.9Hz,1H),7.62–7.58(m,2H),7.32(d,J=8.1Hz,1H),7.23–7.18(m,2H),7.16–7.11(m,6H),7.05(ddd,J=8.0,6.9,1.2Hz,1H),6.97(ddd,J=7.9,6.9,1.0Hz,1H),4.70(td,J=8.2,5.9Hz,1H),3.14(dd,J=14.6,5.9Hz,1H),2.98(dd,J=14.6,8.5Hz,1H),2.77–2.69(m,2H),2.41(dd,J=9.0,6.8Hz,2H).
测试实施例
1、主要实验材料与仪器
材料:胎牛血清、ɑ-MEM培养基、青霉素/链霉素购自Gibco,DMSO、MTT、TRAP染色试剂盒购自sigma,细胞因子如mM-CSF、mRANKL、hRNAK和hRNAKL购自peprotech,细胞裂解液购自promega,PBS购自WISENT公司,4周龄C57BL/6小鼠购自斯莱克。
细胞:骨髓破骨前体细胞,取自C57BL/6小鼠股骨与胫骨髓腔细胞正常培养,培养时采用完全α-MEM培养基,即α-MEM+10%胎牛血清+1%青霉素/链霉素。
仪器:Thermo scientific公司CO2培养箱,Olympus倒置显微镜,Tecan公司酶标仪,GE公司Biacore T200。
2、实验方法:
1)受试细胞的制备:
C57BL/6小鼠断颈处死,75%酒精浸泡消毒,无菌条件下剥离后肢长骨(股骨、胫骨),去除附着的软组织,用完全培养基反复冲洗骨髓腔内表面,将骨髓腔内细胞彻底冲出,细胞悬液用细胞筛过滤,细胞定量后接种于10cm细胞培养皿内,于5%CO2和饱和湿度条件下培养过夜,次日离心取上清未贴壁细胞,换新鲜完全的增殖培养基(完全培养基加入30ng/mL M-CSF)继续培养两天得到骨髓破骨前体细胞。两天后,取骨髓破骨前体细胞按一定浓度种入孔板中,并加入诱导培养基(完全培养基加入30ng/mL M-CSF和50ng/mL RANKL)培养5-6天得到成熟破骨细胞。
2)TRAP活性测试检测化合物抑制破骨细胞形成:
骨髓破骨细胞前体细胞以每孔5000个的浓度接种到96孔板,每孔100μL培养液,培养过夜。第二天,对细胞进行不同处理。实验组细胞处理方式为:将吲哚类化合物(化合物P-1至P-36)分别用诱导培养基配制成终浓度为5μM的溶液加入实验组孔板中,而阴性对照组内加入与实验组相同浓度DMSO的诱导培养基,空白对照组加入相同浓度DMSO的增殖培养基。处理3天后弃培养液,PBS轻洗3次,然后按照TRAP酶活性检测试剂盒说明书进行操作,在405nm处测定吸光度值,最后换算出酶活力。以96孔培养板的1孔细胞在37℃与底物作用,1min产生1nmol的游离酚表示1个酶活力单位。抑制率计算方式如下:
3)MTT法检测化合物对骨髓破骨前体细胞存活率的影响:
基于TRAP活性实验的结果,我们选取对TRAP活性抑制作用比较好的五个化合物(化合物P-2,P-10,P-32,P-34,P-36)进行MTT测试,用来评价化合物对骨髓破骨前体细胞存活的影响。将骨髓破骨细胞前体细胞以每孔5000个的浓度接种到96孔板,每孔100μL,培养过夜。本实验设置实验组和阴性对照组。实验组:将吲哚类化合物用增殖培养基配制成终浓度为10μM的溶液,加入实验组孔板中;阴性对照组:加入与实验组相同浓度DMSO的增殖培养基。培养48h后,每孔加入MTT(5g·L-1)20μL,反应2h后,小心吸去培养液。再向孔中加入DMSO(100μL/孔),震荡10分钟使结晶充分溶解。用酶标仪检测560nm波长处的吸光度值,计算细胞存活率。抑制率计算方式如下:
4)表面等离子共振实验检测化合物与生物蛋白之间的结合能力:
基于TRAP活性的结果,我们选取了对TRAP活性抑制作用比较好的五个化合物(化合物P-2,P-10,P-32,P-34,P-36)进一步做与RANKL的结合活性以及抑制RANKL/RANK相互作用的活性研究。本发明中我们利用基于Biacore T200的SPR技术,检测化合物与RANKL的结合并得到其对RANKL亲和力的相关数据。将新鲜制备的hRANKL蛋白(纯度达95%以上)通过标准氨基偶联的方法偶联在CM5芯片上,用hRANK验证芯片上的hRANKL蛋白具有配体结合活性。接着将不同浓度的化合物流经芯片表面,检测化合物与蛋白的结合信号,并通过软件对其进行拟合,得到平衡解离常数(KD)。亲和力一般通过KD进行测量和报告,此常数用于评估双分子相互作用的强度以及对此类强度进行排序。KD值越小,配体对于其目标的结合亲和力就越大。
3、结果:
(1)本发明的吲哚类化合物对破骨细胞分化的TRAP活性的抑制作用研究
我们选取5μM本发明的化合物进行实验,并通过M-CSF和RANKL对骨髓破骨前体细胞进行破骨分化的诱导,检测吲哚类化合物对分化过程中TRAP活性的影响,如表1所示。结果表明:本发明的吲哚类化合物P-1至P-36对骨髓破骨细胞分化过程中的TRAP活性有非常好的抑制作用,其中化合物P-2,P-10,P-32,P-34,P-36的抑制活性最好,对破骨细胞的形成抑制率分别达到90.3%,89%,89.4%,92.9%,89.2%,如表1所示。
表1.吲哚类化合物对骨髓破骨前体细胞分化TRAP活性的抑制作用
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(2)本发明的吲哚类化合物对骨髓破骨前体细胞的存活作用研究
选择10μM的本发明化合物P-2,P-10,P-32,P-34与骨髓破骨前体细胞进行共孵育,并通过MTT对细胞存活率进行检测,结果如表2所示。试验结果表明:本发明的吲哚类化合物P-2,P-10,P-32,P-34对骨髓破骨前体细胞无明显毒性。
表2.吲哚类化合物对骨髓破骨前体细胞的存活的影响
(3)本发明的吲哚类化合物和Rankl蛋白质相互结合的强度
选取不同浓度的化合物(化合物P-2,P-10,P-32,P-34)进一步做与RANKL结合能力研究。将不同浓度的化合物(化合物P-2,P-10,P-32,P-34)流经芯片表面,检测化合物与蛋白的结合信号。如图1所示,随着化合物浓度的增加,它们与RANKL的结合能力也相应增加,我们通过软件拟合得出其结合解离平衡常数KD如表3所示。其中化合物P-34与蛋白的结合中,结合常数KD值最小,说明化合物P-34为潜在的RANKL配体。P-34与RANKL的结合图如图1所示。
表3.吲哚类化合物对RANKL的结合解离平衡常数(KD)
(4)本发明的化合物P-34对破骨细胞形成的影响
选取不同浓度的化合物P-34干预骨髓破骨前体细胞破骨分化,分化结束后对破骨细胞进行TRAP染色,并以≧3个细胞核为破骨细胞样细胞计数。如图2和表4所示,本发明的吲哚类化合物P-34能有效的浓度依赖性地抑制破骨细胞的形成。
表4.化合物P-34对破骨细胞形成数量的影响
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Claims (6)
1.一类通式I表示的DL-色氨酸类化合物或其药学上可用的盐,
其中,
R1为H、氟、或甲氧基,R2为H或氟;
X为NH;
R3为-CO-C1-C4烷基-取代或未取代苯基、-CO-CH2CH2-含1-2个选自O、S、N的杂原子的C5-C6杂芳基、-CO-CH2CH2-C3-C6环烷基、或-C2-C5烷基-苯基;其中,所述取代苯基是指被选自如下取代基中的一种或多种所取代:卤素、C1-C4烷氧基、C1-C4烷基;
R4、R5各自独立地为H、氟、甲基;R6为H、氟、甲基、甲氧基、甲砜基、三氟甲基、-N(CH3)2、或吗啉基,其中R4、R5和R6不同时为H。
2.一类DL-色氨酸类化合物或其药学上可用的盐,其特征在于,所述DL-色氨酸类化合物选自具有如下述结构的化合物:
3.如权利要求1所述的DL-色氨酸类化合物的制备方法,其特征在于,选自如下两种制备方法:
制备方法一:
步骤a:化合物S与Boc2O发生氨基保护反应,得到化合物1a;
步骤b:化合物1a与胺发生缩合反应,反应得到化合物1b;
步骤c:包括两步反应:第一步反应是化合物1b发生脱保护基反应,得到脱Boc产物;第二步反应是脱Boc产物与苯乙酰氯发生酰基化反应;或与相应的酸发生缩合反应;或与苯乙醛发生还原胺化反应;或与相应的甲磺酸酯/>发生取代反应,得到通式I表示的DL-色氨酸类化合物,
其中,R1、R2、R3、R4、R5、R6的定义与权利要求1中相同;n为2,3或4;
制备方法二:
步骤d:化合物S在酸性条件下与乙醇发生酯化反应,得到化合物2a;
步骤e:将化合物2a与3-苯基丙酸发生缩合反应得到化合物2b;
步骤f:化合物2b在碱性条件下发生水解反应得到化合物2c;
步骤g:化合物2c与胺发生缩合反应,得到通式I’表示的DL-色氨酸类化合物;
其中,R1、R2、R4、R5、R6的定义与权利要求1中相同。
4.权利要求1或2所述的DL-色氨酸类化合物或其药学上可用的盐在制备RANKL抑制剂中的用途。
5.权利要求1或2所述的DL-色氨酸类化合物或其药学上可用的盐在制备治疗和/或预防骨代谢疾病的药物中的用途。
6.如权利要求5所述的用途,所述骨代谢疾病为骨质疏松症、风湿性关节炎、银屑病性关节炎、实体瘤骨转移以及肿瘤。
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