CN116332818B - 四氢吡咯衍生物及其应用 - Google Patents

四氢吡咯衍生物及其应用 Download PDF

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CN116332818B
CN116332818B CN202111595168.8A CN202111595168A CN116332818B CN 116332818 B CN116332818 B CN 116332818B CN 202111595168 A CN202111595168 A CN 202111595168A CN 116332818 B CN116332818 B CN 116332818B
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CN116332818A (zh
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王喆明
谭昊
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Hangzhou Rushi Biotechnology Co ltd
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Abstract

本发明公开一种四氢吡咯衍生物或其光学活性体或其可药用盐，可以作为NAMPT抑制剂，并可用作多种NAD+表达异常相关疾病的化学治疗的潜在药物。其以四氢吡咯为主体，中间以脂肪链与吡啶基脲(或取代吡啶基脲)相连，侧面辅助以芳香环甲酰基(或杂环甲酰基)。此结构是对NAMPT抑制剂FK866的结构优化，用脲结构取代了丙烯酰胺基团，加强了化合物的水溶性，同时对于合成上的难度也相应下降，利于后续的工业化生产。

Description

四氢吡咯衍生物及其应用
技术领域
本发明涉及四氢吡咯类化合物，具体涉及四氢吡咯衍生物及其应用。
背景技术
NAD+是细胞氧化还原的关键辅酶和NAD+依赖酶的关键底物，它参与了广泛的生理过程，例如生物体内氧化还原，DNA修复，基因表达，RNA加工，免疫系统和炎症以及生物钟调控等等。NAD+的水平异常会带来一系列的代谢疾病和机体老化，而保持NAD+在体内的正常水平需要通过补救途径来达成，其中NAMPT是两种补救途径之一中的关键限速酶。
肿瘤细胞具有很高的葡萄糖摄取能力和高糖酵解速率，这种异常的代谢改变需要大量的氧化还原辅酶NAD+，而NAMPT对于细胞内NAD+的补充是必不可少的，因此多种癌症的发展都与NAMPT的表达增加相关。
通过对NAMPT的研究，发现减少NAMPT的表达与癌症信号通路失调密切相关并且肿瘤细胞比正常细胞更容易受到NAMPT抑制，NAMPT可以作为癌症治疗的新靶点。并且越来越多证据表明，NAMPT抑制剂具有作为抗癌药物的潜力。NMAPT的小分子抑制剂可以抑制细胞内NAD+的补救途径，降低NAD+水平从而最后诱导肿瘤细胞死亡。
发明内容
本发明的目的是提供一种四氢吡咯衍生物及其应用，以解决现有技术的不足。
本发明采用以下技术方案：
本发明提供了式(I)所示的四氢吡咯衍生物或式(II)所示的其光学活性体或式(III) 所示的其光学活性体或其可药用盐：
R1是环状含杂原子烷基或者芳香环体系，包括杂原子五环烷基、杂原子六环烷基、苯基、杂环芳基或苯并杂环基，也可以是一取代、二取代或三取代衍生物，取代基团包括C1-C3烷基、C1-C3烷氧基或羟基；
Ar1是芳香环体系，包括苯基或杂环芳基，也可以是一取代、二取代或三取代衍生物，取代基团包括卤代物或羟基。
本发明提供了式(IV)所示的四氢吡咯衍生物或其可药用盐：
A1是氢、羟基、C1-C3烷基或C1-C3烷氧基；
A2是氢、羟基、C1-C3烷基或C1-C3烷氧基；
A3是氢、羟基、C1-C3烷基或C1-C3烷氧基；
Ar1是芳香环体系，包括苯基或杂环芳基，也可以是一取代、二取代或三取代衍生物，取代基团包括卤代物或羟基。
本发明提供了式(V)所示的四氢吡咯衍生物或其可药用盐：
X为杂原子，包括氮、氧或硫；
Y1是氢、氟、氯、溴、碘或羟基；
Ar1是芳香环体系，包括苯基或杂环芳基，也可以是一取代、二取代或三取代衍生物，取代基团包括卤代物或羟基。
本发明提供了式(VI)所示的四氢吡咯衍生物或其可药用盐：
X为杂原子，包括氮、氧或硫；
Ar1是芳香环体系，包括苯基或杂环芳基，也可以是一取代、二取代或三取代衍生物，取代基团包括卤代物或者羟基。
本发明提供了式(VII)所示的四氢吡咯衍生物或其可药用盐：
X为杂原子，包括氮、氧或硫；
Ar1是芳香环体系，包括苯基或杂环芳基，也可以是一取代、二取代或三取代衍生物，取代基团包括卤代物或羟基。
本发明提供了式(VIII)或式(IX)所示的四氢吡咯衍生物或其可药用盐：
A1是氢、羟基、C1-C3烷基或C1-C3烷氧基；
A2是氢、羟基、C1-C3烷基或C1-C3烷氧基；
A3是氢、羟基、C1-C3烷基或C1-C3烷氧基；
Ar1是芳香环体系，包括苯基或杂环芳基，也可以是一取代、二取代或三取代衍生物，取代基团包括卤代物或羟基。
本发明提供了式(X)或式(XI)所示的四氢吡咯衍生物或其可药用盐：
X为杂原子，包括氮、氧或硫；
Y1是氢、氟、氯、溴、碘或羟基；
Ar1是芳香环体系，包括苯基或杂环芳基，也可以是一取代、二取代或三取代衍生物，取代基团包括卤代物或羟基。
本发明提供了式(XII)或式(XIII)所示的四氢吡咯衍生物或其可药用盐：
X为杂原子，包括氮、氧或硫；
Ar1是芳香环体系，包括苯基或杂环芳基，也可以是一取代、二取代或三取代衍生物，取代基团包括卤代物或羟基。
本发明提供了式(XIV)或式(XV)所示的四氢吡咯衍生物或其可药用盐：
X为杂原子，包括氮、氧或硫；
Ar1是芳香环体系，包括苯基或杂环芳基，也可以是一取代、二取代或三取代衍生物，取代基团包括卤代物或羟基。
本发明提供了式(XVI)或式(XVII)或式(XVIII)或式(XIX)所示的四氢吡咯衍生物或其可药用盐：
A1是氢、羟基、C1-C3烷基或C1-C3烷氧基；
A2是氢、羟基、C1-C3烷基或C1-C3烷氧基；
A3是氢、羟基、C1-C3烷基或C1-C3烷氧基；
A4是氢、氟、氯、溴、碘或羟基；
A5是氢、氟、氯、溴、碘或羟基。
本发明提供了式(XX)或式(XXI)或式(XXII)或式(XXIII)所示的四氢吡咯衍生物或其可药用盐：
X为杂原子，包括氮、氧或硫；
Y1是氢、氟、氯、溴、碘或羟基；
A4是氢、氟、氯、溴、碘或羟基；
A5是氢、氟、氯、溴、碘或羟基。
本发明提供了式(XXIV)或式(XXV)或式(XXVI)或式(XXVII)所示的四氢吡咯衍生物或其可药用盐：
X为杂原子，包括氮、氧或硫；
A4是氢、氟、氯、溴、碘或羟基；
A5是氢、氟、氯、溴、碘或羟基。
本发明提供了式(XXVIII)或式(XXIX)或式(XXX)或式(XXXI)所示的四氢吡咯衍生物或其可药用盐：
X为杂原子，包括氮、氧或硫；
A4是氢、氟、氯、溴、碘或羟基；
A5是氢、氟、氯、溴、碘或羟基。
在一些实施例中所述的四氢吡咯衍生物或其可药用盐，选自下列四氢吡咯衍生物或其可药用盐：
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本发明还提供了上述四氢吡咯衍生物或其可药用盐在制备用于治疗NAD+表达异常相关疾病药物中的应用，所述NAD+表达异常相关疾病包括炎症、自身免疫疾病、心血管疾病或癌症；炎症包括骨关节炎、肾炎或特应性皮炎；自身免疫性疾病包括系统红斑狼疮、多发性硬化或类风湿关节炎；心血管疾病包括动脉粥样硬化或中风；癌症包括乳腺癌、前列腺癌、肺癌、肝癌、食管癌、胃癌、结肠癌、胰腺癌或多发性骨髓瘤。
以上“可药用盐”是指本发明化合物保持游离酸或游离碱的生物有效性和特性，且所述的游离酸通过与无毒的无机碱或有机碱，所述的游离碱通过与无毒的无机酸或有机酸反应获得的盐。
以上“光学活性体”是指由分子中原子在空间排列方式不同所产生的异构体，包括顺反异构体，对映异构体，非对映异构体和构象异构体。
本发明的有益效果：
本发明涉及一类四氢吡咯衍生物或其光学活性体或其可药用盐，可以作为NAMPT抑制剂，并可用作多种NAD+表达异常相关疾病的化学治疗的潜在药物。其以四氢吡咯为主体，中间以脂肪链与吡啶基脲(或取代吡啶基脲)相连，侧面辅助以芳香环甲酰基(或杂环甲酰基)。此结构是对NAMPT抑制剂FK866的结构优化，用脲结构取代了丙烯酰胺基团，加强了化合物的水溶性，同时对于合成上的难度也相应下降，利于后续的工业化生产。
FK866结构如下：
具体实施方式
下面结合实施例对本发明做更进一步地解释。下列实施例仅用于说明本发明，但并不用来限定本发明的实施范围。
实施例1
将2.1克三苯基膦溶于20ml四氢呋喃中，加入2.5克4-溴-1-丁醇，氮气保护下回流过夜，大量固体析出，静置，将液体倒出后用10ml无水四氢呋喃清洗白色固体两次，加入20ml 无水四氢呋喃，冷却至-10℃，氮气保护下缓慢滴加正丁基锂溶液(2.5M)5.6ml，控制温度低于-5℃，滴加完毕后，继续搅拌保温反应2小时，冷却至-10℃下，将2克1-Boc-3-吡咯烷甲醛溶于20ml无水四氢呋喃的溶液，滴加入上述反应液中，保温反应2小时后，升至室温搅拌过夜。反应液冷却至0℃，滴加饱和氯化铵溶液10ml，加入水20ml，分液，水层用30ml 乙酸乙酯萃取2遍，合并有机层，依次饱和氯化钠溶液、水洗，有机层用无水硫酸镁干燥，减压浓缩，柱分离(乙酸乙酯EA/石油醚PE体积比＝1:10-1:1，梯度洗脱)得到2.3克油状物1-Boc-3-(5’-羟基-1’-烯-戊基)吡咯烷(1)。
实施例2
将0.5克1-Boc-3-(5’-羟基-1’-烯-戊基)吡咯烷(1)溶于10ml甲醇中，加入0.025克 Pd/C(5％)，升温至40℃，加氢气(4个大气压)下反应48小时后，过滤，滤液减压浓缩后，过柱分离(EA/PE体积比＝1:1-10:1，梯度洗脱)得到0.45克油状物1-Boc-3-(5’-羟基 -1’-戊基)吡咯烷(2)。
实施例3
将1-Boc-3-(5’-羟基-1’-戊基)吡咯烷(2)0.45克溶于10ml二氯甲烷中，冷却至0℃，加入1.5ml三乙胺，氮气保护下滴加1.2克对甲苯磺酰氯溶于6ml二氯甲烷的溶液，搅拌反应过夜，加入饱和氯化铵溶液，分液，水层用10ml二氯甲烷萃取，合并有机层用无水硫酸镁干燥，过滤，滤液减压浓缩后，过柱分离(EA/PE体积比＝1:4)，得到油状物1-Boc-3-(5’-对甲苯磺酰基-1’-戊基)吡咯烷(3)0.51克。
实施例4
将1-Boc-3-(5’-对甲苯磺酰基-1’-戊基)吡咯烷(3)0.5克溶于10ml二氯甲烷中，加入2ml三氟乙酸，室温搅拌过夜后减压浓缩，加入10ml二氯甲烷，滴加入1ml三乙胺，冷却至0℃，在氮气保护下，加入1.2克苯甲酰氯，搅拌反应过夜，加入饱和氯化铵溶液，分液，水层用10ml二氯甲烷萃取，合并有机层用无水硫酸镁干燥，过滤，滤液减压浓缩后，过柱分离(EA/P体积比＝1:2-2:1，梯度洗脱)，得到油状物1-苯甲酰基-3-(5’-对甲苯磺酰基 -1’-戊基)吡咯烷(4)0.43克。
实施例5
将1-苯甲酰基-3-(5’-对甲苯磺酰基-1’-戊基)吡咯烷(4)0.39克溶于4ml N,N-二甲基甲酰胺DMF中，加入叠氮化钠0.15克，加热至70℃反应过夜，减压浓缩后加入二氯甲烷10ml，依次用水和饱和氯化钠溶液洗涤，减压浓缩后，过柱分离(EA/PE体积比＝1:4-1:1，梯度洗脱)，得到油状物1-苯甲酰基-3-(5’-叠氮基-1’-戊基)吡咯烷(5)0.24克。
实施例6
将1-苯甲酰基-3-(5’-叠氮基-1’-戊基)吡咯烷(5)0.18克溶于5ml四氢呋喃，加入0.15 克三苯基膦和2滴水，回流过夜，减压浓缩后加入二氯甲烷10ml，依次用水和饱和氯化钠溶液洗涤，减压浓缩后，过柱分离(二氯甲烷/甲醇/氨水体积比＝10:1:0.1)，得到油状物1- 苯甲酰基-3-(5’-胺基-1’-戊基)吡咯烷(6)0.16克，LCMS:261[M+H]。
实施例7
将1-Boc-3-(5’-对甲苯磺酰基-1’-戊基)吡咯烷(3)0.5克溶于10ml二氯甲烷中，加入2ml三氟乙酸，室温搅拌过夜后减压浓缩，加入10ml二氯甲烷，滴加入1ml三乙胺，冷却至0℃，在氮气保护下，加入1.5克2-噻吩甲酰氯，搅拌反应过夜，加入饱和氯化铵溶液，分液，水层用10ml二氯甲烷萃取，合并有机层用无水硫酸镁干燥，过滤，滤液减压浓缩后，过柱分离(EA/PE体积比＝1:2-2:1，梯度洗脱)，得到油状物1-(2-噻吩甲酰基)-3-(5’-对甲苯磺酰基-1’-戊基)吡咯烷(7)0.41克。
实施例8
将1-(2-噻吩甲酰基)-3-(5’-对甲苯磺酰基-1’-戊基)吡咯烷(7)0.41克溶于4mlDMF 中，加入叠氮化钠0.15克，加热至70℃反应过夜，减压浓缩后加入二氯甲烷10ml，依次用水和饱和氯化钠溶液洗涤，减压浓缩后，过柱分离(EA/PE体积比＝1:4-1:1，梯度洗脱)，得到油状物1-(2-噻吩甲酰基)-3-(5’-叠氮基-1’-戊基)吡咯烷(8)0.25克。
实施例9
将1-(2-噻吩甲酰基)-3-(5’-叠氮基-1’-戊基)吡咯烷(8)0.21克溶于5ml四氢呋喃，加入0.15克三苯基膦和2滴水，回流过夜，减压浓缩后加入二氯甲烷10ml，依次用水和饱和氯化钠溶液洗涤，减压浓缩后，过柱分离(二氯甲烷/甲醇/氨水体积比＝10:1:0.1)，得到油状物1-(2-噻吩甲酰基)-3-(5’-胺基-1’-戊基)吡咯烷(9)0.18克，LCMS:267[M+H]。
按照上述从化合物3作为起始原料制备化合物6和化合物9的方法可以制备得到下列化合物：
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实施例11
在冰水浴下，将4-氨基吡啶(0.96g，10.24mmol)分批加入到氯甲酸苯酯(1.75g，11.2mmol) 和三乙胺(1.46g，14.4mmol)的二氯甲烷(30ml)溶液中，逐渐升至室温搅拌16小时后，加入饱和NaHCO3水溶液(50ml)洗涤，分液，水层用CH2CI2(20mlX3)萃取。合并有机层，用盐水(50ml)洗涤，干燥(Na2SO4)过滤并减压浓缩，得到白色固体粉末状的4-吡啶氨基甲酸苯酯(18)(1.95mg，90％)，1H NMR(CDCl3)δ7.22-7.18(d,2H),7.26-7.31(m, IH),7.36(brs,IH),7.36-7.47(m,4H),8.49-8.55(d,2H)，LCMS:215[M+H]。
按照实施例11的方法可以制备得到下列化合物：
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实施例12
将4-吡啶氨基甲酸苯酯(18)36mg和1-苯甲酰基-3-(5’-胺基-1’-戊基)吡咯烷(6)51mg 溶于5ml乙腈中，加入三乙胺20.8μl，30℃搅拌过夜(30h)，减压浓缩后，直接过柱分离(二氯甲烷/甲醇体积比＝10:1-5:1，梯度洗脱)，得到约45mg粘稠物目标化合物BSS-TP0071-(5- (1-(苯甲酰基)吡咯烷-3-基)戊基)-2-(4-吡啶基)脲
1HNMR(400MHz,CDCl3):δ＝8.42-8.21(m,2H),7.37-7.30(m,3H),7.29-7.26(m,2H),7.16-7.04(m,2H),6.04-5.83(m,1H,N-H),4.11-3.95(m,2H),3.89-3.74(m,2H),3.65-3.11(m,3H),2.29-1.92(m,2H),1.70-1.53(m,2H),1.47-1.32(m,4H),1.32-1.19(m, 2H)；LC-MS:381[M+H]。
实施例13
将4-吡啶氨基甲酸苯酯(18)34mg和1-(2-噻吩甲酰基)-3-(5’-胺基-1’-戊基)吡咯烷(9)50mg溶于5ml乙腈中，加入三乙胺22μl，30℃搅拌过夜(30h)，减压浓缩后，直接过柱分离(二氯甲烷/甲醇体积比＝10:1-5:1，梯度洗脱)，得到约40mg粘稠物目标化合物 BSS-TP008 1-(5-(1-(2-噻吩甲酰基)吡咯烷-3-基)戊基)-2-(4-吡啶基)脲
1HNMR(400MHz,CDCl3):δ＝8.60-8.31(m,2H),7.46-7.42(1H),7.30-7.18(m,3H),7.07-7.01(m,1H),6.09-5.99(m,1H,N-H),4.09-3.92(m,2H),3.88-3.73(m,2H),3.60-3.15(m,3H),2.32-1.95(m,2H),1.67-1.51(m,2H),1.49-1.29(m,4H),1.33-1.18(m, 2H)；LC-MS:387[M+H]。
实施例14
化合物BSS-TP007通过手性液相柱拆分得到化合物BSS-TP037(ee％>99％，手性HPLC，流动相：正己烷/乙醇体积比＝90/10，柱温：35℃；流速：0.8mL/min，检测波长：227nm，保留时间：14.32min)和BSS-TP038(ee％>99％，手性HPLC，流动相：正己烷/乙醇＝体积比90/10，柱温：35℃；流速：0.8mL/min，检测波长：227nm，保留时间：18.76min)；
BSS-TP037：1HNMR(400MHz,CDCl3):δ＝8.42-8.21(m,2H),7.37-7.30(m,3H),7.29-7.26(m,2H),7.16-7.04(m,2H),6.04-5.83(m,1H,N-H),4.11-3.95(m,2H),3.89-3.74(m,2H),3.65-3.11(m,3H),2.29-1.92(m,2H),1.70-1.53(m,2H),1.47-1.32(m, 4H),1.32-1.19(m,2H)；LC-MS:381[M+H]；
BSS-TP038：1HNMR(400MHz,CDCl3):δ＝8.42-8.21(m,2H),7.37-7.30(m,3H),7.29-7.26(m,2H),7.16-7.04(m,2H),6.04-5.83(m,1H,N-H),4.11-3.95(m,2H),3.89-3.74(m,2H),3.65-3.11(m,3H),2.29-1.92(m,2H),1.70-1.53(m,2H),1.47-1.32(m, 4H),1.32-1.19(m,2H)；LC-MS:381[M+H]。
按照上述从化合物6和18制备化合物BSS-TP007的方法可以制备得到下列化合物：
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实施例15
应用CCK-8细胞增殖检测法测定样品对人肿瘤细胞体外增殖的影响。
表1细胞株及培养条件
细胞实验方法包括如下步骤：
1)将细胞消化、计数，利用对应培养基(表1)配制细胞悬液(CFPAC-1，RPMI 8226为5×104个/ml，其余细胞为3.5×104个/ml)，96孔细胞培养板中每孔加入100μl细胞悬液；
2)96孔细胞培养板置于37℃，5％CO2培养箱中培养24小时；
3)用培养基稀释药物至所需工作液浓度，每孔加入100μl相应的含药培养基，同时设立阴性对照组(加入不含药的培养基)；
4)96孔细胞培养板置于37℃，5％CO2培养箱中培养72小时；
5)将96孔细胞培养板进行CCK-8染色，λ＝450nm，测定OD值；
a)每孔加入10μl CCK-8，在培养箱继续培养2-3小时；
b)摇床10分钟轻轻地混匀，去除96孔板中气泡；
c)λ＝450nm，酶标仪读出每孔的OD值，计算抑制率。
6)计算各组抑制率。
细胞实验数据如下表所示(IC50：单位μM)：
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Claims (11)

1.式(XVI)或式(XVII)或式(XVIII)或式(XIX)所示的四氢吡咯衍生物或其可药用盐：
A1是氢、羟基、C1-C3烷基或C1-C3烷氧基；
A2是氢、羟基、C1-C3烷基或C1-C3烷氧基；
A3是氢、羟基、C1-C3烷基或C1-C3烷氧基；
A4是氢、氟、氯、溴、碘或羟基；
A5是氢、氟、氯、溴、碘或羟基。
2.式(XX)或式(XXI)或式(XXII)或式(XXIII)所示的四氢吡咯衍生物或其可药用盐：
X为杂原子，包括氮、氧或硫；
Y1是氢、氟、氯、溴、碘或羟基；
A4是氢、氟、氯、溴、碘或羟基；
A5是氢、氟、氯、溴、碘或羟基。
3.式(XXIV)或式(XXV)或式(XXVI)或式(XXVII)所示的四氢吡咯衍生物或其可药用盐：
X为杂原子，包括氮、氧或硫；
A4是氢、氟、氯、溴、碘或羟基；
A5是氢、氟、氯、溴、碘或羟基。
4.式(XXVIII)或式(XXIX)或式(XXX)或式(XXXI)所示的四氢吡咯衍生物或其可药用盐：
X为杂原子，包括氮、氧或硫；
A4是氢、氟、氯、溴、碘或羟基；
A5是氢、氟、氯、溴、碘或羟基。
5.四氢吡咯衍生物或其可药用盐，选自下列四氢吡咯衍生物或其可药用盐：
6.权利要求5所述的四氢吡咯衍生物或其可药用盐在制备用于治疗NAD+表达异常相关疾病药物中的应用。
7.根据权利要求6所述的应用，其特征在于，所述NAD+表达异常相关疾病包括炎症、自身免疫疾病、心血管疾病或癌症。
8.根据权利要求7所述的应用，其特征在于，所述炎症包括骨关节炎、肾炎或特应性皮炎。
9.根据权利要求7所述的应用，其特征在于，所述自身免疫性疾病包括系统红斑狼疮、多发性硬化或类风湿关节炎。
10.根据权利要求7所述的应用，其特征在于，心血管疾病包括动脉粥样硬化或中风。
11.根据权利要求7所述的应用，其特征在于，癌症包括乳腺癌、前列腺癌、肺癌、肝癌、食管癌、胃癌、结肠癌、胰腺癌或多发性骨髓瘤。
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