CN108484494B - 2-氧代-1,2-二氢吡啶-4-甲酸类化合物 - Google Patents

2-氧代-1,2-二氢吡啶-4-甲酸类化合物 Download PDF

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CN108484494B
CN108484494B CN201810618313.1A CN201810618313A CN108484494B CN 108484494 B CN108484494 B CN 108484494B CN 201810618313 A CN201810618313 A CN 201810618313A CN 108484494 B CN108484494 B CN 108484494B
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张为革
石爱龙
包凯
关奇
张利超
杨明正
王思博
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Shenyang Pharmaceutical University
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Abstract

本发明属于医药技术领域，涉及具有黄嘌呤氧化酶抑制活性的通式I的3‑氰基/氨甲酰基‑6‑取代苯基‑2‑氧代‑1,2‑二氢吡啶‑4‑甲酸类化合物、可药用的盐、可药用的溶剂化物及其制备方法，本发明还涉及这些化合物在治疗高尿酸血症、痛风中的用途以及与黄嘌呤氧化酶相关疾病诊断中的用途。

Description

2-氧代-1,2-二氢吡啶-4-甲酸类化合物
技术领域
本发明属于医药技术领域，涉及3-氰基/氨甲酰基-6-取代苯基-2- 氧代-1,2-二氢吡啶-4-甲酸类化合物和制备方法，具体涉及3-氰基/氨甲酰基-6-取代苯基-2-氧代-1,2-二氢吡啶-4-甲酸类化合物、可药用的盐、可药用的溶剂化物及其制备方法，同时还涉及这些化合物在高尿酸血症、痛风中的治疗用途以及与黄嘌呤氧化酶相关疾病诊断中的用途。
背景技术
痛风(gout)是由尿酸盐在关节及其他组织沉积所引发的炎症性疾病，可引发多种并发症，在多数发达国家及部分发展中国家中，其发病率呈逐年上升趋势。持续性高尿酸血症(hyperuricemia)是引发痛风的重要病因之一。据现有资料显示，欧美地区高尿酸血症患病率约为2％～18％，痛风的患病率为0.2％～1.7％。目前我国高尿酸血症和痛风的发病率分别为5.5％—19.3％与0.86％—3.58％。痛风增加了患者的生存负担，降低了生活质量，如不及时治疗可导致残疾甚至死亡。随着社会不断发展以及全球人口日益老龄化，痛风的治疗和管理显得尤为重要。
目前治疗痛风的主要策略是使用能够促使尿酸钠晶体溶解的降尿酸药物。降尿酸药物主要包括减少尿酸生成的药物、促进尿酸排泄药物和尿酸酶类药物。减少尿酸生成的药物是通过抑制黄嘌呤氧化酶 (XO)活性来减少尿酸的生物合成来达到降尿酸的目的。别嘌吟醇是临床上使用的第一个黄嘌呤氧化酶抑制剂用于痛风和高尿酸血症的治疗。临床数据表明，部分患者服用该药后容易引发别嘌呤醇过敏综合征(AHS)等一系列毒性反应。非布索坦(febuxostat)最早公开于WO9209279A1中，为新一代黄嘌呤氧化酶抑制剂。美国食品药品监督管理局(FDA)和欧洲药品监督管理局(EMA)均批准非布索坦用于治疗痛风及高尿酸血症。与别嘌呤醇相比非布索坦具有更好的疗效和更小的毒副作用。新型非嘌呤类XO抑制剂非布索坦的上市在很大程度上弥补了别嘌呤醇临床上的缺陷，但随着痛风及高尿酸血症的发病率逐年升高，仍需要Me-too或Me-better的后续药物来缓解市场对降尿酸药物的需求。目前，非布索坦类似物的研究主要集中于用其他五元杂环替换非布索坦的噻唑环，所用的五元杂环包括吡唑、噻吩、硒唑、噁唑、异噁唑、咪唑、三氮唑等。然而，采用六员杂环替换非布索坦噻唑环的例子却很少。
黄嘌呤氧化酶(XO)不仅是治疗痛风及高尿酸血症的重要靶标，还与许多疾病有紧密的联系。因此检测体内生物样品中XO水平对于某些疾病的早期诊断具有重要意义。
3-氰基/氨甲酰基-6-取代苯基-2-氧代-1,2-二氢吡啶-4-甲酸类化合物是一类结构新颖的小分子化合物，其合成和应用研究较少见。3- 氰基/氨甲酰基-6-取代苯基-2-氧代-1,2-二氢吡啶-4-甲酸类化合物作为XO抑制剂及XO荧光探针的研究目前尚未见报道。
发明内容
本发明的目的在于设计、合成具有良好XO抑制活性和XO荧光检测功能的3-氰基/氨甲酰基-6-取代苯基-2-氧代-1,2-二氢吡啶-4-类化合物；所制备的化合物在体外表现出良好的黄嘌呤氧化酶抑制作用，可用于高尿酸血症和痛风的治疗和体外生物样品中XO含量的检测。
本发明的目标物的结构通式如下：
Figure BDA0001697446310000021
其中：R为直链或支链的C1-C10烷基、C3-C10烯烷基、C3-C10炔烷基、C4-C7环烷基烷基、C7-C10芳基烷基；X为氢、卤素、氰基或硝基；Y为氰基或胺甲酰基。
优选地，R为直链或支链的C1-C8烷基、C3-C8烯烷基、C3-C8炔烷基、C4-C6环烷基烷基、C7-C9芳基烷基；X为碘、氰基；Y为氰基或胺甲酰基。
更优选地，R为直链或支链的C1-C6烷基、C3-C6烯烷基、C3-C6炔烷基、C4-C6环烷基烷基、C7-C9芳基烷基；X为碘、氰基；Y为氰基或胺甲酰基。
最优选，R为正丙基、异丙基、正丁基、异丁基、正戊基、异戊基、苄基、烯丙基；X为碘、氰基；Y为氰基或胺甲酰基。
本发明的化合物还包括上述结构式所示衍生物所形成的在药学上可接受的无毒盐及其水合物或者其他前药形式，这些药学上可接受的无毒盐包括该衍生物与碱所形成的盐。例如：碱金属盐如Li、Na 和K盐；碱土金属盐如Ca和Mg盐；有机碱盐，如赖氨酸、精氨酸、胍、二乙醇胺、胆碱、氨丁三醇等等；铵或取代的铵盐和铝盐。所述水合物的结晶水数目为0～16中的任意实数。这些盐和前药形式可以各自游离出上述结构式化合物。
本发明优选的部分化合物结构及命名如下：
化合物1
Figure BDA0001697446310000031
3-氰基-6-(3-氰基-4-异丁氧基苯基)-2-氧代-1,2-二氢吡啶-4-甲酸化合物2
Figure BDA0001697446310000032
3-氨甲酰基-6-(3-氰基-4-异丁氧基苯基)-2-氧代-1,2-二氢吡啶-4-甲酸化合物3
Figure BDA0001697446310000033
3-氨甲酰基-6-(3-氰基-4-异丙氧基苯基)-2-氧代-1,2-二氢吡啶-4-甲酸化合物4
Figure BDA0001697446310000034
3-氨甲酰基-6-(3-氰基-4-异戊氧基苯基)-2-氧代-1,2-二氢吡啶-4- 甲酸
化合物5
Figure BDA0001697446310000041
3-氨甲酰基-6-(3-碘-4-异丁氧基苯基)-2-氧代-1,2-二氢吡啶-4-甲酸
本发明的3-氰基/氨甲酰基-6-取代苯基-2-氧代-1,2-二氢吡啶-4-甲酸按照如下路线合成得到：
Figure BDA0001697446310000042
以(Z)-4-(3,4-取代苯基)-2-羟基-4-氧代丁-2-烯酸甲脂为原料(合成方法参见US8822467,2014.；European Journal of Medicinal Chemistry,2010,45(6):2663)，经环合及水解反应，得到3-氰基-6-取代苯基-2-氧代-1,2-二氢吡啶-4-甲酸类化合物；再经水解得到3-氨甲酰基-6-取代苯基-2-氧代-1,2-二氢吡啶-4-甲酸类化合物。
本发明所提供的3-氰基/氨甲酰基-6-取代苯基-2-氧代-1,2-二氢吡啶-4-甲酸类化合物的制备方法简单可行，收率较好。
3-氰基/氨甲酰基-6-取代苯基-2-氧代-1,2-二氢吡啶-4-甲酸类化合物具有较好的黄嘌呤氧化酶抑制作用，可用于制备抗痛风、高尿酸血症药物。此外。3-氰基/氨甲酰基-6-取代苯基-2-氧代-1,2-二氢吡啶-4- 甲酸类化合物还具有一定的XO检测功能，可作为XO的体外荧光探针。
附图说明
图1为在不同浓度XO的PBS缓冲液(pH8.1)中化合物5(5μM) 荧光光谱
图2为基于I375/I485与XO浓度比较的线性回归
具体实施方式
通过下述实例将有助于理解本发明，但本发明的内容并不限于所举实例。
本发明所用试剂均为市售，核磁共振谱由AVANCE-400/600、 Bruker ARX-300傅立叶变换核磁共振波谱仪测定，质谱由Brukee Esqure 2000、Shimadzu GCMS-QP5050A型质谱仪测定。
实施例1：
(1)环合反应：
将(Z)-4-(3-氰基-4-异丁氧基苯基)-2-羟基-4-氧代丁-2-烯酸甲脂 (1.52g,5mmol)，氰基乙酰胺(0.42g,5mmol)，无水碳酸钾(1.38g, 10mmol)，加入至25mLDMF中，升温至57℃反应10h。将反应液倾入50mL水中，用乙酸乙酯(30mL×2)萃取。合并有机相，并用无水硫酸镁干燥。旋蒸除去溶剂。粗品经乙醇重结晶得3-氰基-6-(3- 氰基-4-异丁氧基苯基)-2-氧代-1,2-二氢吡啶-4-甲酸甲脂，收率73％。
(2)水解反应：
将3-氰基-6-(3-氰基-4-异丁氧基苯基)-2-吡啶酮-4-甲酸甲脂 (1.05g,3mmol)，20mL 1M NaOH溶液，5mL乙醇。室温反应1.5h。向体系中滴加1M HCl溶液将体系pH调至5，析出固体。抽滤，用水洗涤滤饼，粗品经过乙醇重结晶得到3-氰基-6-(3-氰基-4-异丁氧基苯基)-2-氧代-1,2-二氢吡啶-4-甲酸，收率85％。
3-氰基-6-(3-氰基-4-异丁氧基苯基)-2-吡啶酮-4-甲酸(化合物1) 的总收率为62％(以原料(Z)-4-(3-氰基-4-异丁氧基苯基)-2-羟基-4-氧代丁-2-烯酸甲脂计)，其结构式、1H-NMR和MS数据列于表-1中。
实施例2：3-氨甲酰基-6-(3-氰基-4-异丁氧基苯基)-2-氧代-1,2-二氢吡啶-4-甲酸(化合物2)的制备
以实施例1制得的3-氰基-6-(3-氰基-4-异丁氧基苯基)-2-氧代 -1,2-二氢吡啶-4-甲酸(化合物1)为原料，再经水解反应得3-氨甲酰基-6-(3-氰基-4-异丁氧基苯基)-2-氧代-1,2-二氢吡啶-4-甲酸(化合物 2)。
水解反应：
将3-氰基-6-(3-氰基-4-异丁氧基苯基)-2-吡啶酮-4-甲酸(化合物 1)(0.34g,1mmol)，20mL 1M HCl溶液，5mL甲醇。升温至55℃反应15h。旋蒸除去部分溶剂，冷却析出固体。抽滤，用水洗涤滤饼，粗品经过乙醇重结晶得到3-氨甲酰基-6-(3-氰基-4-异丁氧基苯基)-2- 吡啶酮-4-甲酸(化合物2)。总收率为49％(以原料(Z)-4-(3-氰基-4- 异丁氧基苯基)-2-羟基-4-氧代丁-2-烯酸甲脂计)，其结构式、1H-NMR 和MS数据列于表-1中。
实施例3：3-氨甲酰基-6-(3-氰基-4-异丙氧基苯基)-2-氧代-1,2-二氢吡啶-4-甲酸(化合物3)的制备
以(Z)-4-(3-氰基-4-异丙氧基苯基)-2-羟基-4-氧代丁-2-烯酸甲脂为原料，经与实施例2相同的方法得到3-氨甲酰基-6-(3-氰基-4-异丙氧基苯基)-2-氧代-1,2-二氢吡啶-4-甲酸(化合物3)，总收率为45％(以原料(Z)-4-(3-氰基-4-异丙氧基苯基)-2-羟基-4-氧代丁-2-烯酸甲脂计)，其结构式、1H-NMR和MS数据列于表-1中。
实施例4：3-氨甲酰基-6-(3-氰基-4-异戊氧基苯基)-2-吡啶酮-4-甲酸 (化合物4)的制备
以(Z)-4-(3-氰基-4-异戊氧基苯基)-2-羟基-4-氧代丁-2-烯酸甲脂为原料，经与实施例2相同的方法得到3-氨甲酰基-6-(3-氰基-4-异戊氧基苯基)-2-氧代-1,2-二氢吡啶-4-甲酸(化合物4)，总收率为40％(以原料(Z)-4-(3-氰基-4-异丙氧基苯基)-2-羟基-4-氧代丁-2-烯酸甲脂计)，其结构式、1H-NMR和MS数据列于表-1中。
实施例5：3-氨甲酰基-6-(3-碘-4-异戊氧基苯基)-2-吡啶酮-4-甲酸(化合物5)的制备
以(Z)-4-(3-碘-4-异戊氧基苯基)-2-羟基-4-氧代丁-2-烯酸甲脂为原料，经与实施例2相同的方法得到3-氨甲酰基-6-(3-碘-4-异戊氧基苯基)-2-氧代-1,2-二氢吡啶-4-甲酸(化合物5)，总收率为50％(以原料 (Z)-4-(3-碘-4-异丙氧基苯基)-2-羟基-4-氧代丁-2-烯酸甲脂计)，其结构式、1H-NMR和MS数据列于表-1中。
实施例6：本发明的化合物的体外药理学测试
(1)实验原理：以黄嘌呤(购自SIGMA)为底物检测XO(购自SIGMA)活性。观察样品对酶的活性抑制，以评价样品的抑制效果。采用的阳性参照化合物为别嘌呤醇(allopurinol)。
(2)体外活性测试方法和结果：200μL反应体系中含适量XO、 pH 8.0磷酸缓冲液、黄嘌呤(购自SIGMA)和祥品，同时设立空白对照(不含酶和样品)和阴性对照(不含样品)，样品浓度为1μmol·L-1， 30℃反应20min，295nM测定OD值、根据如下公式计算抑制率, 各化合物的抑制率值见表-2。
Figure BDA0001697446310000061
实施例6：本发明的化合物基于XO的荧光性质测试
以3-氨甲酰基-6-(3-碘-4-异丁氧基苯基)-2-氧代-1,2-二氢吡啶-4- 甲酸(化合物5)为荧光检测探针，将其溶解于DMF溶液中得到5.0 ML标准溶液。用pH 7.8的PBS缓冲溶液将样品标准稀释后与不同浓度酶(0-2.4μL/mL)的PBS溶液混合，样品最终浓度为5μML，测试温度为30℃，孵育时间为20min。以365nm为激发波长，测定样品的荧光曲线见图1，随着XO浓度的不断增大，最大波长在485nm 的荧光峰缓慢降低，最大波长在375nm的荧光峰显著提高。以375nm 与485nm的荧光强度的比值作为纵坐标，以酶的浓度作为横坐标得到图2，在0.4-2.4μL范围内，I375/I485与酶浓度显示出了一种线性关系，线性方程为y＝0.8424x-0.056，R2＝0.994。该方法适用于对各种生物样品中XO含量的检测。
表-1
Figure BDA0001697446310000071
Figure BDA0001697446310000081
表-2
Figure BDA0001697446310000082

Claims (10)

1.一种如通式I的化合物，其药学上可接受的盐：
Figure DEST_PATH_IMAGE002
其中：R为直链或支链的C1-C10烷基；X为卤素、氰基；Y为氰基或氨基甲酰基。
2.根据权利要求1所述的化合物，其药学上可接受的盐，其特征在于：R为直链或支链的C1-C8烷基；X为碘、氰基；Y为氰基或氨基甲酰基。
3.根据权利要求1所述的化合物，其药学上可接受的盐，其特征在于：R为直链或支链的C1-C6烷基；X为碘、氰基；Y为氰基或氨基甲酰基。
4.根据权利要求1所述的化合物，其药学上可接受的盐，其特征在于：R为正丙基、异丙基、正丁基、异丁基、正戊基、异戊基；X为碘、氰基；Y为氰基或氨基甲酰基。
5.根据权利要求1-4任何一项所述的化合物，其药学上可接受的盐，其特征在于：其中所述的盐为碱金属盐、碱土金属盐或有机碱盐，所述的碱金属盐为Li、Na或K盐，所述的碱土金属盐为Ca或Mg盐，所述的有机碱盐为赖氨酸、精氨酸、胍、二乙醇胺、胆碱或氨丁三醇的盐，铵或取代的铵盐或铝盐。
6.权利要求1所述的化合物，药学上可接受的盐，选自：
3-氰基-6-(3-氰基-4-异丁氧基苯基)-2-氧代-1,2-二氢吡啶-4-甲酸；
3-氨甲酰基-6-(3-氰基-4-异丁氧基苯基)-2-氧代-1,2-二氢吡啶-4-甲酸；
3-氨甲酰基-6-(3-氰基-4-异丙氧基苯基)-2-氧代-1,2-二氢吡啶-4-甲酸；
3-氨甲酰基-6-(3-氰基-4-异戊氧基苯基) -2-氧代-1,2-二氢吡啶-4-甲酸；
3-氨甲酰基-6-(3-碘-4-异丁氧基苯基)-2-氧代-1,2-二氢吡啶-4-甲酸。
7.一种药物组合物，包含权利要求1-6任何一项所述的化合物，其药学上可接受的盐和药学上可接受的载体。
8.一种如权利要求1所述的化合物的制备方法，其特征在于：
以 (Z)-4-(3,4-取代苯基)-2-羟基-4-氧代丁-2-烯酸甲脂为原料，经环合及水解反应，得到3-氰基-6-取代苯基-2-氧代-1,2-二氢吡啶-4-甲酸类化合物；再经水解得到3-氨甲酰基-6-取代苯基-2-氧代-1,2-二氢吡啶-4-甲酸类化合物。
9.权利要求1-6任何一项所述的化合物、其药学上可接受的盐或权利要求7所述的组合物在制备治疗痛风、高尿酸血症药物中的应用。
10.权利要求1-6任何一项所述的化合物、其药学上可接受的盐或权利要求7所述的组合物在制备黄嘌呤氧化酶含量测定的药物中的应用。
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