CN116332917A - 吡啶氰基胍衍生物及其应用 - Google Patents
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Abstract
本发明公开了一类吡啶氰基胍衍生物或其可药用盐,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。其以腈基胍结合哌嗪或者四氢吡咯为主体,中间以脂肪链相连,侧面辅助以芳香环甲酰基(或杂环甲酰基)和吡啶基(或取代吡啶基);此结构来源于对高效NAMPT抑制剂FK866的结构优化,其中取代甲酰基哌嗪和取代甲酰基四氢吡咯是在FK866基础上进一步优化,加强了和NAMPT的相互作用,而腈基胍结构的引进不仅进一步增强了和NAMPT的亲和力,同时也改善了FK866的水溶性不好的缺点,更加有利于后续的药物试验。
Description
技术领域
本发明涉及胍类化合物及其应用,具体涉及吡啶氰基胍衍生物及其应用。
背景技术
肿瘤细胞和正常细胞的代谢有着明显不同,肿瘤细胞为了自身快速分裂,增殖和侵袭,具有很高的糖酵解能力和能量消耗,在这个过程中肿瘤细胞对于NAD+有很大的需求,而肿瘤细胞NAD+的主要来源要通过NAD+补救途径来达成,其中NAMPT是补救途径中的关键限速酶。所以抑制NAMPT能够降低肿瘤细胞中NAD+的水平,从而最后诱导肿瘤细胞死亡。
最近的研究已经证实通过NAMPT抑制剂抑制NAMPT的活性能够明显抑制体外肿瘤细胞的增殖和体内肿瘤的生长;在原发急性髓系白血病细胞中NAMPT及Sirt2的表达显著升高,而特异性抑制NAMPT或者Sirt2的表达后可抑制细胞增殖并诱发急性髓细胞性白血病细胞及原始细胞的凋亡。从上述研究可以看出,NAMPT作为抗肿瘤的新靶点越来越受到研究人员的重视,NAMPT抑制剂也作为新一代潜在广谱抗肿瘤药物成为抗癌药物的热点。
发明内容
本发明的目的是提供一种吡啶氰基胍衍生物及其应用,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)或式(II)所示的吡啶氰基胍衍生物或其可药用盐:
R1是芳香环甲酰基或杂环甲酰基,其中芳香环或杂环也可以是一取代或多取代衍生物;
X1是氢、氟、氯、溴、碘或羟基;
X2是氢、氟、氯、溴、碘或羟基;
A1是碳或氮;
A2是碳或氮。
本发明提供了式(III)或式(IV)或式(V)或式(VI)所示的吡啶氰基胍衍生物或其可药用盐:
R1是芳香环甲酰基或杂环甲酰基,其中芳香环或杂环也可以是一取代或多取代衍生物;
X1是氢、氟、氯、溴、碘或羟基;
X2是氢、氟、氯、溴、碘或羟基;
A1是碳或氮;
A2是碳或氮。
本发明提供了式(VII)或式(VIII)或式(IX)或式(X)所示的吡啶氰基胍衍生物或其可药用盐:
X1是氢、氟、氯、溴、碘或羟基;
X2是氢、氟、氯、溴、碘或羟基;
A1是碳或氮;
A2是碳或氮;
Ar1是环状含杂原子烷基或芳香环体系,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。
本发明提供了式(XI)或式(XII)或式(XIII)或式(XIV)所示的吡啶氰基胍衍生物或其可药用盐:
X1是氢、氟、氯、溴、碘或羟基;
X2是氢、氟、氯、溴、碘或羟基;
Ar1是环状含杂原子烷基或芳香环体系,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。
本发明提供了式(XV)或式(XVI)或式(XVII)或式(XVIII)所示的吡啶氰基胍衍生物或其可药用盐:
X1是氢、氟、氯、溴、碘或羟基;
X2是氢、氟、氯、溴、碘或羟基;
X3是氢、羟基、C1-C3烷基或C1-C3烷氧基;
X4是氢、羟基、C1-C3烷基或C1-C3烷氧基;
X5是氢、羟基、C1-C3烷基或C1-C3烷氧基。
本发明提供了式(XIX)或式(XX)或式(XXI)或式(XXII)所示的吡啶氰基胍衍生物或其可药用盐:
X1是氢、氟、氯、溴、碘或羟基;
X2是氢、氟、氯、溴、碘或羟基;
X3是氢、氟、氯、溴、碘或羟基;
Y为杂原子,包括氮、氧或硫。
本发明提供了式(XXIII)或式(XXIV)或式(XXV)或式(XXVI)所示的吡啶氰基胍衍生物或其可药用盐:
X1是氢、氟、氯、溴、碘或羟基;
X2是氢、氟、氯、溴、碘或羟基;
Y为杂原子,包括氮、氧或硫。
本发明提供了式(XXVII)或式(XXVIII)或式(XXIX)或式(XXX)所示的吡啶氰基胍衍生物或其可药用盐:
X1是氢、氟、氯、溴、碘或羟基;
X2是氢、氟、氯、溴、碘或羟基;
X3是氢、羟基、C1-C3烷基或C1-C3烷氧基;
X4是氢、羟基、C1-C3烷基或C1-C3烷氧基;
X5是氢、羟基、C1-C3烷基或C1-C3烷氧基。
本发明提供了式(XXXI)或式(XXXII)或式(XXXIII)或式(XXXIV)所示的吡啶氰基胍衍生物或其可药用盐:
X1是氢、氟、氯、溴、碘或羟基;
X2是氢、氟、氯、溴、碘或羟基;
Y为杂原子,包括氮、氧或硫。
本发明提供了式(XXXV)或式(XXXVI)或式(XXXVII)或式(XXXVIII)所示的吡啶氰基胍衍生物或其可药用盐:
X1是氢、氟、氯、溴、碘或羟基;
X2是氢、氟、氯、溴、碘或羟基;
Y为杂原子,包括氮、氧或硫。
在一些实施例中所述的吡啶氰基胍衍生物或其可药用盐,选自下列吡啶氰基胍衍生物或其可药用盐:
本发明还提供了上述吡啶氰基胍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。
本发明的有益效果:
本发明涉及一类吡啶氰基胍衍生物或其可药用盐,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。其以腈基胍结合哌嗪或者四氢吡咯为主体,中间以脂肪链相连,侧面辅助以芳香环甲酰基(或杂环甲酰基)和吡啶基(或取代吡啶基);此结构来源于对高效NAMPT抑制剂FK866的结构优化,其中取代甲酰基哌嗪和取代甲酰基四氢吡咯是在FK866基础上进一步优化,加强了和NAMPT的相互作用,而腈基胍结构的引进不仅进一步增强了和NAMPT的亲和力,同时也改善了FK866的水溶性不好的缺点,更加有利于后续的药物试验。
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
5-氨基戊酸11.7g加到130ml二氯乙烷中,加入苯甲醛26.5g,加入三乙胺13.3g,升温至回流2小时,冷却至室温,加入氰基硼氢化钠15.75g,回流过夜,减压浓缩后,柱分离(二氯甲烷:甲醇体积比10:1),得到11.3g粘稠物N,N-二苄基-5-氨基戊酸(1),1HNMR(400MHz,CDCl3):δ=7.45-7.26(m,10H),4.71(s,4H),3.43-3.35(m,2H),2.41-2.30(m,2H),2.11-1.95(m,2H),1.27-1.19(m,2H);[M+H]:298.3。
实施例2
N,N-二苄基-5-氨基戊酸(1)2.97g溶于二氯甲烷中,分批加入N,N'-羰基二咪唑(CDI)1.4g,室温搅拌半小时后,滴加加入Boc-哌嗪1.863g溶于10ml二氯甲烷溶液,搅拌过夜,减压浓缩后,柱分离(乙酸乙酯:石油醚体积比3:1),得到3.1g粘稠产物(2),1HNMR(400MHz,CDCl3):δ=7.49-7.24(m,10H),3.55(s,4H),3.49-3.25(m,8H),2.49-2.39(m,2H),2.21-2.15(m,2H),1.78-1.54(m,4H),1.50(s,9H);[M+H]:466.6。
实施例3
将上一步得到化合物(2)3g溶于30ml四氢呋喃中,冷却至0℃,分批加入氢化锂铝2.5g,升至室温搅拌3小时后,加入50wt%氢氧化钠溶液10ml,加入二氯甲烷30ml,分液,有机层用水洗涤,无水硫酸钠干燥后,减压浓缩后,过柱分离(二氯甲烷:甲醇:氨水体积比20:1:0.01),得到黄色粘稠产物(3)2.12g,1HNMR(400MHz,CDCl3):δ=7.45-7.21(m,10H),3.56(s,4H),3.48-3.39(m,2H),2.49-2.35(m,4H),2.34-2.30(m,2H),2.29-2.26(m,4H),1.61-1.55(m,2H),1.41-1.35(m,2H),1.34-1.25(m,2H);[M+H]:352.5。
实施例4
将上一步得到化合物(3)2g溶于20ml二氯甲烷中,加入1.8g三乙胺,冷却至0℃,滴加入糠酰氯1.58g,升至室温搅拌过夜后,减压浓缩后,过柱分离(乙酸乙酯:石油醚体积比5:1),得到粘稠产物(4)2.12g,1HNMR(400MHz,CDCl3):δ=7.50-7.47(d,1H),7.38-7.20(m,10H),7.09-7.07(d,1H),6.47-6.44(m,1H),3.70(s,4H),3.17-3.11(m,4H),2.91-2.80(m,2H),2.63-2.55(m,2H),2.52-2.48(m,2H),2.60-2.46(m,4H),1.52-1.36(m,4H);[M+H]:446.6。
实施例5
将上一步得到化合物(4)2g溶于20ml甲醇中,加入0.2gPd/C(5%),4atm室温反应10小时后,过滤,滤液减压浓缩后得到1.2g产物1-糠酰基-4-(5’-胺基-1’-戊基)哌嗪(5)MS(m/z),266(M+1),直接用于下一步。
按照上述从5-氨基戊酸作为起始原料制备化合物5的方法可以制备得到下列化合物:
实施例6
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后减压浓缩后,柱分离(EA/PE体积比=1:10-1:1,梯度洗脱,EA为乙酸乙酯,PE为石油醚)得到2.3克油状物1-Boc-3-(5’-羟基-1’-烯-戊基)吡咯烷(10)。
实施例7
将0.5克1-Boc-3-(5’-羟基-1’-烯-戊基)吡咯烷(10)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(11)。
实施例8
将1-Boc-3-(5’-羟基-1’-戊基)吡咯烷(11)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二氯甲烷的溶液中,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(12)0.51克。
实施例9
将1-Boc-3-(5’-对甲苯磺酰基-1’-戊基)吡咯烷(12)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后,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/PE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(13)0.43克。
实施例10
将1-苯甲酰基-3-(5’-对甲苯磺酰基-1’-戊基)吡咯烷(13)0.39克溶于4mlN,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(14)0.24克。
实施例11
将1-苯甲酰基-3-(5’-叠氮基-1’-戊基)吡咯烷(14)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(15)0.16克,LCMS:261[M+H]。
按照上述从化合物12作为起始原料制备化合物15的方法可以制备得到下列化合物:
实施例12
将4-氨基吡啶(0.612g)、N-氰基羰亚胺二苯基酯(1.540g)和三乙胺(1.0mL)在乙腈(15ml)中的溶液在80℃下搅拌2h,在室温下搅拌12h。反应混合物在减压下浓缩,得到残渣。残渣用乙酸乙酯(20ml)稀释,用水(20ml)洗涤2遍,有机层在无水硫酸钠干燥,并在减压下浓缩以得到固体。异丙醇(5ml)搅拌洗涤,过滤、干燥得固体1-氰基-2-苯基-3-(吡啶-4-基)异脲(28)1.2g,LCMS:239.10[M+H]。
按照实施例12的方法可以制备得到下列化合物
实施例13
将1-氰基-2-苯基-3-(吡啶-4-基)异脲(28)35mg和1-苯甲酰基-4-(5’-胺基-1’-戊基)哌嗪(6)50mg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(乙酸乙酯/甲醇体积比=10:1-5:1,梯度洗脱),得到约60mg粘稠物目标化合物2-氰基-1-(5-((1-(苯甲酰基)哌嗪-4-基)戊基)-3-(4-吡啶基)胍(BSS-PC003),1HNMR(400MHz,CDCl3):δ=8.47-8.29(m,2H),7.41-7.36(d,3H),7.31-7.27(m,2H),7.17-7.03(m,2H),6.02-5.92(m,1H,N-H),3.09-3.03(m,4H),2.89-2.71(m,2H),2.57-2.48(m,2H),2.48-2.43(m,2H),2.41-2.32(m,4H),1.57-1.41(m,4H);[M+H]:420.3。
实施例14
将1-氰基-2-苯基-3-(吡啶-4-基)异脲(28)37mg和1-糠酰基-4(5’-胺基-1’-戊基)哌嗪(5)53mg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(乙酸乙酯/甲醇体积比=10:1-5:1,梯度洗脱),得到约72mg粘稠物目标化合物2-氰基-1-(5-((1-糠酰基)哌嗪-4-基)戊基)-3-(4-吡啶基)胍(BSS-PC007),1HNMR(400MHz,CDCl3):δ=8.55-8.47(m,2H),7.50-7.47(d,1H),7.35-7.28(m,2H),7.09-7.03(d,1H),6.47-6.44(m,1H),6.07-5.90(m,1H,N-H),3.12-3.05(m,4H),2.92-2.77(m,2H),2.59-2.50(m,2H),2.49-2.45(m,2H),2.44-2.35(m,4H),1.55-1.39(m,4H);[M+H]:410.5。
实施例15
将1-氰基-2-苯基-3-(吡啶-4-基)异脲(28)36mg和1-苯甲酰基-3-(5’-胺基-1’-戊基)吡咯烷(15)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63mg粘稠物目标化合物2-氰基-1-(5-((1-苯甲酰基)吡咯烷-3-基)戊基)-3-(4-吡啶基)胍(BSS-PC028),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:405[M+H]。
实施例16
将1-氰基-2-苯基-3-(吡啶-4-基)异脲(28)34mg和1-(2-噻吩甲酰基)-3-(5’-胺基-1’-戊基)吡咯烷(20)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2-氰基-1-(5-(1-(2-噻吩甲酰基)吡咯烷-3-基)戊基)-3-(4-吡啶基)胍(BSS-PC029),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:411[M+H]。
按照上述从化合物6和28制备化合物BSS-PC003的方法可以制备得到下列化合物:
实施例17
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;
1)每孔加入10μlCCK-8,在培养箱继续培养2-3小时;
2)摇床10分钟轻轻地混匀,去除96孔板中气泡;
3)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
Claims (12)
12.权利要求11所述的吡啶氰基胍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。
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