CN112724128A - 与孤儿核激素受体α具有高亲和力的化合物、制备方法及应用 - Google Patents
与孤儿核激素受体α具有高亲和力的化合物、制备方法及应用 Download PDFInfo
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Abstract
本发明提供了一种与孤儿核激素受体α具有高亲和力的化合物、制备方法及应用,属于有机合成领域。本发明提供的与孤儿核激素受体α具有高亲和力的化合物的结构式如式I所示:
Description
技术领域
本发明涉及有机合成领域,具体涉及一种与孤儿核激素受体α具有高亲和力的化合物、制备方法及应用。
背景技术
昼夜节律(例如睡眠-唤醒周期)是存在于24h内的内部节律,这些节律是由下丘脑的上视交叉神经核(SCN)产生的,以整合环境线索并调节多种生物过程。重要的是,这些节奏可能会因衰老或环境/遗传变化而中断,从而导致异常的睡眠方式以及其他生理和转录障碍。昼夜节律紊乱是许多神经和精神疾病的症状,包括AD。AD是众所周知的伴有淀粉样蛋白(amyloid-beta,Aβ)斑块和神经原纤维缠结在大脑中积累,认知障碍和记忆力丧失的神经退行性疾病。昼夜节律紊乱会加剧与AD相关的分子变化。确实,最近的研究表明,昼夜节律直接影响Aβ的动力学和病理学。尽管有昼夜节律系统在Aβ代谢中的作用的证据,但其参与AD的潜在分子机制仍然未知。
Rev-erbα是一种核受体和昼夜节律成分,是小胶质细胞激活和神经炎症的介体,在AD发病机制中起重要作用。Rev-erbα缺失导致海马自发性小胶质细胞活化,促炎转录本表达增加,继发星形胶质细胞增多症。小胶质细胞中失调的昼夜节律生物钟(Rev-erbα)机制可能会在Aβ清除的情况下影响小胶质细胞的行为。Reverbα-/-小鼠对周围LPS注射表现出增强的海马神经炎症反应,而小分子激动剂SR9009对Rev-erbs的药理激活抑制了LPS诱导的海马神经炎症。Rev-erbα缺失影响神经元的健康,因为缺乏Rev-erbα的原始神经胶质细胞培养的条件培养基会加剧培养的神经元的氧化损伤,Rev-erbα-/-小鼠还表现出显著改变的皮质静止状态功能连接性,类似于在神经退行性模型中观察到的。
发明内容
本发明是为了解决上述问题而进行的,目的在于提供一种与孤儿核激素受体α具有高亲和力的化合物、制备方法及应用。
本发明提供了一种与孤儿核激素受体α具有高亲和力的化合物,具有这样的特征,结构式如式I所示,
在本发明提供的与孤儿核激素受体α具有高亲和力的化合物中,还具有这样的特征,结构式如式II所示,
本发明提供了一种与孤儿核激素受体α具有高亲和力的化合物的中间体,用于制备与孤儿核激素受体α具有高亲和力的化合物,具有这样的特征,其中,中间体的结构式如式III所示,
本发明提供了一种与孤儿核激素受体α具有高亲和力的化合物的制备方法,用于制备上述与孤儿核激素受体α具有高亲和力的化合物,具有这样的特征,其合成路线如下:
在本发明提供的与孤儿核激素受体α具有高亲和力的化合物的制备方法中,还具有这样的特征,其中,式III中B为H时,其合成路线如下:
,X为F、Cl、Br、I中的任意一种。
在本发明提供的与孤儿核激素受体α具有高亲和力的化合物的制备方法中,还具有这样的特征,其中,卤代酰基化试剂优选为三光气。
在本发明提供的与孤儿核激素受体α具有高亲和力的化合物的制备方法中,还具有这样的特征,其中,式III中B为烷氧羰基、苄基或苄氧羰基中的任意一种时,其合成路线如下:
其中,X为F、Cl、Br、I中的任意一种,具体地,上述合成路线的具体方法如下:步骤1.1,将式III化合物溶于溶剂B,加酸反应,反应完成后,调节pH、萃取、干燥、浓缩、纯化,得式IV化合物;步骤1.2,将卤代酰基化试剂溶解在溶剂C中,加入式IV化合物及碱D,反应完成后,萃取、干燥、浓缩,得式V化合物;步骤1.3,将OHR1OH、碱D加入反应瓶中,再加入式IV化合物的乙腈溶液进行反应,反应完成后,调节pH、萃取、干燥、浓缩、纯化,得式VI化合物;步骤2,将对甲苯磺酸酐、式VI化合物溶于溶剂C,再加碱D进行反应,萃取、干燥、浓缩、纯化,得目标化合物GSKS。
在本发明提供的与孤儿核激素受体α具有高亲和力的化合物的制备方法中,还具有这样的特征,其中,步骤1.1中的溶剂B选自C1~C4的脂肪醇,优选为甲醇。
在本发明提供的与孤儿核激素受体α具有高亲和力的化合物的制备方法中,还具有这样的特征,其中,步骤1.2、步骤2中的溶剂C选自二氯甲烷、二氯乙烷、三氯甲烷中的任意一种,优选为二氯甲烷。
在本发明提供的与孤儿核激素受体α具有高亲和力的化合物的制备方法中,还具有这样的特征,其中,步骤1.1中的酸选自盐酸、硫酸、三氟乙酸、对甲苯磺酸中的任意一种,优选为盐酸。
在本发明提供的与孤儿核激素受体α具有高亲和力的化合物的制备方法中,还具有这样的特征,其中,步骤1.1中式III化合物中B为烷氧羰基,还原试剂为盐酸。
在本发明提供的与孤儿核激素受体α具有高亲和力的化合物的制备方法中,还具有这样的特征,其中,步骤1.1中式III化合物中B为苄基或苄氧羰基时,还原试剂为钯碳/氢气。
在本发明提供的与孤儿核激素受体α具有高亲和力的化合物的制备方法中,还具有这样的特征,其中,步骤1.2、步骤1.3、步骤2中的碱D选自三乙胺、DBU、DMAP、吡啶、N-甲基吗啉或四甲基乙二胺中的任意一种,优选为三乙胺。
在本发明提供的与孤儿核激素受体α具有高亲和力的化合物的制备方法中,还具有这样的特征,其中,当式III中B为卤代酰基时,其合成路线如下:
,X为F、Cl、Br、I中的任意一种。
在本发明提供的与孤儿核激素受体α具有高亲和力的化合物的制备方法中,还具有这样的特征,其中,步骤1中HOR1OH优选为乙二醇。
本发明提供了与孤儿核激素受体α具有高亲和力的化合物在治疗与孤儿核激素受体α相关疾病的药物中的应用,具有这样的特征,其中,与孤儿核激素受体α相关的疾病包括阿尔茨海默病、淀粉样脑血管病、血管炎症、动脉粥样硬化、心血管系统疾病、纤溶酶系统疾病。
发明的作用与效果
根据本发明所涉及的一种与孤儿核激素受体α具有高亲和力的化合物、制备方法及应用,因为该与孤儿核激素受体α具有高亲和力的化合物不仅与孤儿核激素受体α具有高亲和力,还能够降低细胞活力,改变细胞代谢,改变缺乏REV-ERBα的肝细胞和胚胎干细胞中的基因转录,而且该与孤儿核激素受体α具有高亲和力的化合物制备方法简单,原料易得,所以本发明提供的与孤儿核激素受体α具有高亲和力的化合物可用于治疗与孤儿核激素受体α相关的各种疾病,具有广泛的应用前景。
附图说明
图1为本发明的测试例中标准品的亲和力实验结果图。
具体实施方式
为了使本发明实现的技术手段、创作特征、达成目的与功效易于明白了解,以下结合实施例及附图对本发明作具体阐述。
<实施例1>
一种与孤儿核激素受体α具有高亲和力的化合物
本实施例提供了一种与孤儿核激素受体α具有高亲和力的化合物,其制备步骤如下:
步骤1,化合物GSKS-1的制备方法如下:
在氮气保护下将2.0g(12.7mmol)5-硝基噻酚-2-甲醛和2.0g(14.0mmol)对氯苯甲醛以及1.5g(25.4mmol)乙酸溶于40mL二氯甲烷加入到反应瓶中,降温到0℃,将6.7g(31.7mmol)三乙酰氧基硼氢化钠的二氯甲烷溶液40mL滴加到反应体系中,20分钟内滴完,在此温度下再搅拌10分钟,升温到25℃反应3h,反应结束后,将反应液倒入到100mL的饱和氯化钠溶液中,用浓氨水调节pH=10,二氯甲烷萃取,有机相干燥后,以(乙酸乙酯:二氯甲烷:正己烷=1:1:3)柱层析分离后,得GSKS-1(N-(4-氯苄基)-1-(5-硝基噻吩-2-基)甲胺)的质量为3.1g,产率为87.1%。
化合物GSKS-1的核磁数据和表征数据如下:
1HNMR(CDCl3,300MHz)δ7.796-7.782(d,2H,J=4.2Hz),7.330-7.262(m,4H),6.870-6.856(d,1H,J=4.2Hz),3.982(s,2H),3.828(s,2H).
HRMS(EI):calcd for C12H12ClN2O2S[M+H]+283.0,found 283.
步骤2,化合物GSKS-2的制备方法如下:
在氮气保护下将2.0g(7.1mmol)GSKS-1和1.6g(7.8mmol)1-Boc-3-吡咯烷甲醛以及0.8g(14.2mmol)乙酸,溶于40mL二氯甲烷加入到反应瓶中,降温到0℃,将3.8g(17.7mmol)三乙酰氧基硼氢化钠的二氯甲烷40mL溶液滴加到反应体系中,20分钟内滴完,在此温度下再搅拌10分钟,升温到25℃反应3h,反应结束,将反应液倒入到100mL的饱和氯化钠溶液中,用浓氨水调节pH=10,二氯甲烷萃取,有机相干燥后,以(乙酸乙酯:二氯甲烷:正己烷=1:1:2)柱层析分离后,得化合物GSKS-2(叔丁基-3-(((4-氯苄基)((5-硝基噻吩-2-基)甲基)氨基)甲基)吡咯烷-1-羰基)的质量为2.6g,产率为77.9%。
化合物GSKS-2的核磁数据和表征数据如下:
1HNMR(CDCl3,300MHz)δ7.793-7.779(d,2H,J=4.2Hz),7.340-7.275(m,4H),6.859-6.845(d,1H,J=4.2Hz),3.714(s,2H),3.600-3.479(m,3H),3.363-3.242(m,2H),2.455(s,3H),2.027-1.985(m,1H),1.612(s,1H),1.454-1.439(d,9H,J=4.5Hz).
HRMS(ESI):calcd for C22H29ClN3O4S[M+H]+446.1,found446.1.
步骤3,化合物GSKS-3的制备方法如下:
氮气保护下将2.0g(4.3mmol)GSKS-2和HCl/MeOH(4mol/L)加入到反应瓶中,升温到25℃反应3h,反应结束,将反应液旋干得到3.1g的粗品,将粗品用100mL二氯甲烷溶解,再倒入100mL的饱和氯化钠溶液中,用浓氨水调节pH=10,二氯甲烷萃取,有机相干燥后,以二氯甲烷:甲醇=1:20)柱层析分离,得到化合物GSKS-3(N-(4-氯苄基)-1-(5-硝基噻吩-2-基)-N-(吡咯烷-3-亚甲基)甲胺)的质量为1.3g,产率为80.9%。
化合物GSKS-3的核磁数据和表征数据如下:
1HNMR(CDCl3,300MHz)δ7.793-7.779(d,2H,J=4.2Hz),7.340-7.275(m,4H),6.589-6.845(d,1H,J=4.2Hz),3.714(s,2H),3.600-3.479(m,3H),3.363-3.242(m,2H),2.455(s,3H),2.027-1.985(m,1H),1.612(s,1H).
HRMS(ESI):calcd for C17H21ClN3O2S[M+H]+366.1,found 336.1
步骤4,化合物GSKS-4的制备方法如下:
氮气保护下将3.2g(10.8mmol)三光气和30mL二氯甲烷加入到反应瓶中,降温到-50℃,在此温度下缓慢的滴加2.0g(5.4mmol)GSKS-3和3.2g(32.4mmol)三乙胺于20mL二氯甲烷溶液,反应1.5h,升温到25℃搅拌2h,反应结束后,将反应液在25℃下减压除去溶剂,将粗品用100mL二氯甲烷溶解,减压带旋2次,加入硅胶拌样,以(乙酸乙酯:正己烷=1:3)柱层析分离,得到化合物GSKS-4(3-(((4-氯苄基)((5-硝基噻吩-2-基)甲基)氨基)甲基)吡咯烷-1-碳酰氯)的质量为5.0g,直接进行下一步反应。
化合物GSKS-4的表征数据如下:
HRMS(ESI):calcd for C18H20Cl2N3O3S[M+H]+428.1,found 428.1.
步骤5,化合物GSKS-5的制备方法如下:
氮气保护下将10mL乙二醇和1.4g(13.8mmol)三乙胺加入到反应瓶中,降温到0℃,在此温度下缓慢的滴加1.0g(2.3mmol)GSKS-4的10mL乙腈溶液,20分钟内滴完,反应1.5小时,升温到25℃再反应7小时,反应结束后,将反应液倒入到100mL的饱和氯化钠溶液中,用浓氨水调节pH=10,用二氯甲烷萃取,有机相干燥后,以(乙酸乙酯:正己烷=1:1)柱层析分离,得到化合物GSKS-5(2-羟乙基3-(((4-氯苄基)((5-硝基噻吩-2-基)甲基)氨基)甲基)吡咯烷-1-羰基)的质量为0.6g,产率为53.5%。
化合物GSKS-5的核磁数据和表征数据如下:
1HNMR(CDCl3,300MHz)δ7.799-7.785(d,2H,J=4.2Hz),7.347-7.278(m,4H),6.867-6.853(d,1H,J=4.2Hz),4.284-4.227(m,2H),3.816(s,2H),3.744(s,2H),3.612-3.534(m,2H),3.391-3.304(m,2H),3.056-3.035(m,1H),2.474(s,3H),2.039(s,1H),1.632(s,2H).
HRMS(ESI):calcd for C20H25ClN3O5S[M+H]+454.2,found 454.2.
步骤6,化合物GSKS的制备方法如下:
氮气保护下将0.4g(1.2mmol)对甲苯磺酸酐和二氯甲烷加入到反应瓶中,降温到0℃,在此温度下缓慢的滴加0.2g(0.4mmol)GSKS-5的10mL二氯甲烷溶液,10分钟内滴完,然后再滴加0.2g(2.4mmol)三乙胺的15mL二氯甲烷的溶液,反应0.5h,升温到25℃搅拌反应7h,反应结束后,将反应液倒入到100mL的饱和氯化钠溶液中,用浓氨水调节pH=10,二氯甲烷萃取,有机相干燥后,以(乙酸乙酯:正己烷=1:2)柱层析分离,得到化合物GSKS(2-(对甲苯磺酰基)乙基3-(((4-氯苄基)((5-硝基噻吩-2-基)甲基)氨基)甲基)吡咯烷-1-羰基)的质量为0.2g,产率为72.7%。
化合物GSKS的核磁数据和表征数据如下:
1HNMR(CDCl3,300MHz)δ7.799-7.782(m,1H),7.347-7.278(m,4H),6.861-6.848(m,1H),4.538-4.492(m,1H),4.492-4.451(m,1H),4.370(s,1H),4.274(s,1H),3.746(s.2H),3.601-3.553(m,3H),3.361-3.324(m,2H),3.078-3.023(m,1H),2.472(s,3H),2.049(s,2H),1.573(s,1H).
HRMS(ESI):calcd for C20H24ClN3O5SF[M+H]+455.1,found 455.8.
步骤7,标准品(化合物GSKF)的制备方法如下:
氮气保护下将氟乙醇(50ml)和三乙胺(0.71g)加入三口瓶中,冰盐降温至0℃,缓慢滴加GSKS-4(0.5g)的10ml乙睛溶液,约20分钟内滴完。滴完保温反应1.5h,自然升至室温反应7h。反应毕,倒入100ml饱和盐水,用浓氨水调节PH=10,二氯甲烷萃取(3*100ml),有机相干燥后,以(乙酸乙酯:正己烷=1:1)柱层析分离,得到化合物GSKF的质量为0.2g,产率为37.9%。
标准品(化合物GSKF)的核磁数据和表征数据如下:
1HNMR(CDCl3,300MHz)δ7.799-7.782(m,1H),7.347-7.278(m,4H),6.861-6.848(m,1H),4.538-4.492(m,1H),4.492-4.451(m,1H),4.370(s,1H),4.274(s,1H),3.746(s.2H),3.601-3.553(m,3H),3.361-3.324(m,2H),3.078-3.023(m,1H),2.472(s,3H),2.049(s,2H),1.573(s,1H).
HRMS(ESI):calcd for C20H24ClN3O5SF[M+H]+455.1,found 455.8.
<实施例2>
一种与孤儿核激素受体α具有高亲和力的化合物
本实施例提供了一种与孤儿核激素受体α具有高亲和力的化合物,其制备步骤如下:
步骤1,化合物GSKS-1的制备方法如下:
制备方法和实施例1中化合物GSKS-1的制备方法相同,区别仅在于将反应试剂三乙酰氧基硼氢化钠换成氰基硼氢化钠,收率为86%。
化合物GSKS-1 | 反应试剂 | 收率:% |
实施例1 | 三乙酰氧基硼氢化钠 | 87.1 |
实施例2 | 氰基硼氢化钠 | 86 |
步骤2,化合物GSKS-2的制备方法如下:
制备方法和实施例1中化合物GSKS-2的制备方法相同,区别仅在于将反应试剂三乙酰氧基硼氢化钠换成硼氢化钠,溶剂二氯甲烷换成三氯甲烷,收率为73%。
化合物GSKS-2 | 反应试剂 | 溶剂 | 收率:% |
实施例1 | 三乙酰氧基硼氢化钠 | 二氯甲烷 | 77.9 |
实施例2 | 硼氢化钠 | 三氯甲烷 | 73 |
步骤3,化合物GSKS-3的制备方法如下:
制备方法和实施例1中化合物GSKS-3的制备方法相同,区别仅在于将反应试剂HCl/MeOH换为三氟乙酸/乙醇,化合物GSKS-3的质量为1.2g,产率为76.8%。
化合物GSKS-3 | 反应试剂 | 收率:% |
实施例1 | HCl/MeOH | 80.9 |
实施例2 | 三氟乙酸/乙醇 | 76.8 |
步骤4,化合物GSKS-4的制备方法如下:
制备方法和实施例1中化合物GSKS-4的制备方法相同,区别仅在于将反应试剂三乙胺换成N-甲基吗啉,产率为50.2%。
步骤5,化合物GSKS-5的制备方法如下:
制备方法和实施例1中化合物GSKS-5的制备方法相同,区别仅在于将反应试剂三乙胺换成DMAP,产率为52.0%。
化合物GSKS-5 | 碱 | 收率:% |
实施例1 | 三乙胺 | 53.5 |
实施例2 | DMAP | 52.0 |
步骤6,化合物GSKS的制备方法如下:
制备方法和实施例1中化合物GSKS的制备方法相同,区别仅在于将反应试剂三乙胺换成DBU,产率为72.0%。
化合物GSKS | 碱 | 收率:% |
实施例1 | 三乙胺 | 72.7 |
实施例2 | DBU | 72.0 |
<测试例>
标准品的亲和力测试实验
实验原料来源:Rev-erbα蛋白购置于葛兰素史克公司。生物素化的核受体辅抑制因子1(NCoR1,Nuclear receptor co-repressor 1)购置于CPC Scientific Inc。APC标记的Streptavidin链霉亲和素和Eu-W1024标记的链霉亲和素购置于珀金埃尔默公司。
实验方法:使用标准方法对蛋白质进行化学生物素化。
具体实验方法包括以下步骤:
步骤1,将实施例1制得的标准品(化合物GSKF)加DMSO稀释到10mM,得测试物稀释液,放置于中间板中,取100nL的测试药物稀释液备用;
步骤2,将103g的3-吗啉丙磺酸溶解于800mL水中并添加适量的氢氧化钠以配制成缓冲液原液(pH为7.5,浓度为0.5M);将NaF(2.09g),CHAPS(0.03g),和BSA(0.1g)溶于100mL的缓冲液原液中得分析缓冲液,并在量筒中加入水扩增至1L以备后用;
步骤3,配制混合溶液,包括以下子步骤:
步骤3-1,将DTT(二硫苏糖醇)加入到分析缓冲液中并配制成10mM的溶液A;
步骤3-2,在锥形离心管加入适量的分析缓冲液和生物素化的核受体辅抑制因子1(NCoR1),配制成浓度为20nM的溶液B;
步骤3-3,将Eu-W1024标记的链霉亲和素加入到混合液B中配制成浓度为10nM的溶液C,在室温下孵育15分钟;
步骤3-4,在另一离心管中加入生物素化的Rev-erbα蛋白和缓冲液原液以配制成20nM的溶液D;
步骤3-5,在装有蛋白的混合液D中加入APC标记的链霉亲和素以配制成10nM的溶液E,室温下孵育15分钟后,将20倍当量的生物素加入到溶液E中,室温下孵育10分钟,然后将上述五种溶液混合配制成10nM DTT,20nM Rev-erbα蛋白,10nM APC,20nM NCoR1和10nMEu-W1024的混合液并孵育5分钟;
步骤4,将10μL的上述混合液和100nL的测试药物稀释液加入到微孔板中并共同孵育1小时后通过酶标仪读取数据,并将测得的数据通过GraphPad Prism 9进行标准化分析。
实验结果如图1所示。图1为本发明的测试例中标准品的亲和力的实验结果图。根据图1可知,EC50=615nm,19F标记的标准品具有亲和力,所以,本实施例提供的与孤儿核激素受体α具有高亲和力的化合物在进行18F标记后也具有亲和力。
实施例的作用与效果
根据本实施例所涉及的一种与孤儿核激素受体α具有高亲和力的化合物、制备方法及应用,因为该与孤儿核激素受体α具有高亲和力的化合物不仅与孤儿核激素受体α具有高亲和力,还能够降低细胞活力,改变细胞代谢,改变缺乏REV-ERBα的肝细胞和胚胎干细胞中的基因转录,而且该与孤儿核激素受体α具有高亲和力的化合物制备方法简单,原料易得,所以本实施例提供的与孤儿核激素受体α具有高亲和力的化合物可用于治疗与孤儿核激素受体α相关的各种疾病,具有广泛的应用前景。
上述实施方式为本发明的优选案例,并不用来限制本发明的保护范围。
Claims (9)
9.与孤儿核激素受体α具有高亲和力的化合物在治疗与孤儿核激素受体α相关疾病的药物中的应用,其特征在于:
其中,所述与孤儿核激素受体α相关的疾病包括阿尔茨海默病、淀粉样脑血管病、血管炎症、动脉粥样硬化、心血管系统疾病、纤溶酶系统疾病。
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