CN106986874B - (1H-吡唑[3,4-d]嘧啶)-4-氨基衍生物及其作为IDO抑制剂在药物制备中的用途 - Google Patents
(1H-吡唑[3,4-d]嘧啶)-4-氨基衍生物及其作为IDO抑制剂在药物制备中的用途 Download PDFInfo
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- 239000003814 drug Substances 0.000 title claims description 10
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- 238000004519 manufacturing process Methods 0.000 title 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一类(1H‑吡唑[3,4‑d]嘧啶)‑4‑氨基衍生物,还公开了所述化合物的制备方法和作为IDO抑制剂的用途。本发明的化合物可以用于预防和/或治疗多种疾病,如阿尔茨海默病、白内障、细胞免疫激活相关的感染、自身免疫性疾病、艾滋病、癌症、抑郁症或色氨酸代谢异常等。
Description
技术领域
本发明涉及1H-吡唑[3,4-d]嘧啶)-4-氨基衍生物,还涉及其制备方法和作为IDO抑制剂的用途。
背景技术
吲哚胺2,3-双加氧酶(Indoleamine 2,3-dioxygenase,IDO)是催化色氨酸等吲哚胺类分子中吲哚环氧化裂解,使其按犬尿酸途径分解代谢的限速酶。
IDO在肿瘤免疫豁免及肿瘤发生过程中起着重要作用。正常情况下,IDO在体内呈低水平表达,而大多数肿瘤细胞则会组成的高表达IDO,将L-色氨酸转化为N-甲酰犬尿氨酸,降低了细胞微环境中的色氨酸浓度,使得色氨酸依赖的T细胞合成停滞于G1期,T细胞增殖受到抑制,从而抑制了机体免疫***对肿瘤组织的杀伤作用。同时,IDO作用下色氨酸的代谢产物存在细胞毒性,可对T细胞产生直接溶解作用。
因此,抑制IDO的活性可以有效地阻止肿瘤细胞周围色氨酸的降解,促进T细胞的增殖,从而增强机体对肿瘤细胞的攻击能力。并且,IDO抑制剂还可以与化疗药物合用,降低肿瘤细胞的耐药性,从而增强常规细胞毒疗法的抗肿瘤活性。同时服用IDO抑制剂也可提高癌症病人的治疗性疫苗的疗效。
除了在肿瘤细胞耐药性方面发挥着重要作用,IDO还与多种与细胞免疫激活相关的疾病的发病机制密切相关。IDO已被证实是与细胞免疫激活相关的感染、恶性肿瘤、自身免疫性疾病、艾滋病等重大疾病的靶标。同时,抑制IDO还是对于患有神经***疾病如抑郁症,阿尔茨海默病的病人的重要治疗策略。因此,IDO抑制剂具有广阔的临床应用前景。
发明内容
为解决上述问题,本发明主要提供了一类新型的IDO抑制剂类药物,它们均是(1H-吡唑[3,4-d]嘧啶)-4-氨基衍生物,均是氨基氮上的取代。
本发明提供了一种化合物或其药学上可接受的盐或其溶剂合物,所所述化合物的结构如式(Ⅰ)所示:
其中,R1选自H、卤素或C1~C4的烷基;
R2选自取代的或非取代的芳基、环烷基、杂芳基或杂环基,所述取代的芳基、环烷基、杂芳基或杂环基分别独立地被一个或多个选自-(CH2)mCOOH、卤素、羟基、氨基、硝基、烷基的取代基所取代;
n=1、2或3;
m=0、1、2或3。
进一步地,所述R2选自苯基或取代的苯基,所述取代的苯基被一个或多个选自-(CH2)mCOOH、卤素、羟基、氨基、硝基、烷基的取代基所取代;m=0或1。
更进一步地,所述R2选自下述基团之一:
进一步地,R1选自H或甲基。
进一步地,所述化合物的结构如下所示:
本发明还提供了一种制备所述式(Ⅰ)化合物的方法,包括以下步骤:
以化合物9和化合物10为原料,溶于有机溶剂中,在惰性气体环境和碱的存在下反应,纯化得到式(Ⅰ)化合物。
作为一种具体的实施方式,反应时,化合物9稍过量。化合物9可按照本发明具体实施方式中的方法合成也可以按照现有技术中的方法合成。
进一步地,所述碱选自有机碱或无机碱,所述有机碱选自三乙胺或吡啶,所述无机碱选择碳酸氢钠、碳酸钠或氢氧化钠。
进一步地,所述有机溶剂选自二甲基甲酰胺、四氢呋喃、乙酸乙酯、丙酮或二氯甲烷。
例如,在本发明具体的实施方式中,上述化合物1a、1b、1c和1d通过下述路线制备得到:
本发明还提供了所述化合物、或其药学上可接受的盐、或其前药、或其溶剂合物在制备IDO抑制剂类药物上的用途。
进一步地,所述药物是预防和/或治疗阿尔茨海默病、白内障、细胞免疫激活相关的感染、自身免疫性疾病、艾滋病、癌症、抑郁症或色氨酸代谢异常的药物。
本发明还提供了一种药物组合物,它是所述的化合物或其药学上可接受的盐为活性成分,加上药学上可接受的辅料制备而成的制剂。
其中,所述组合物是治疗或预防和/或治疗阿尔茨海默病、白内障、细胞免疫激活相关的感染、自身免疫性疾病、艾滋病、癌症、抑郁症或色氨酸代谢异常的药物
本发明所述C1~C4的烷基指的是具有1~4个碳原子的直链或支链的烷基,包括甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、仲丁基等。
所述前药是前述化合物的衍生物,它们自身可能具有较弱的活性或甚至没有活性,但是在给药后,在生理条件下(例如通过代谢、溶剂分解或另外的方式)被转化成相应的生物活性形式。
所述的制剂可以包括注射剂或口服制剂。
本发明中的关键中间体和化合物进行分离和纯化,所使用的方式是有机化学中常用的分离和纯化方法。
本发明的一种或多种化合物可以彼此联合使用,也可选择将本发明的化合物与任何其它的活性试剂结合使用,用于制备IDO抑制剂。如果使用的是一组化合物,则可将这些化合物同时、分别或有序地对受试对象进行给药。
本发明所述药学上可接受的辅料,是指除活性成分以外包含在剂型中的物质。
经试验证明,本发明提供的9-位取代的吡啶并[3,4-b]吲哚衍生物对IDO具有优异的抑制作用,可以用于预防和/或治疗多种疾病,如阿尔茨海默病、白内障、细胞免疫激活相关的感染、自身免疫性疾病、艾滋病、癌症、抑郁症或色氨酸代谢异常等。
显然,根据本发明的上述内容,按照本领域的普通技术知识和惯用手段,在不脱离本发明上述基本技术思想前提下,还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式,对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
具体实施方式
原料和试剂均为分析纯:所用原料购于成都瑞欧克科技有限公司,试剂购于成都科龙试剂公司。
实施例1本发明中间体6-甲基-1H-吡唑[3,4-d]嘧啶-4(7H)-酮(8b)的合成
合成路线如下所示:
将化合物(7)(CAS:5334-31-6,1.0g,7.94mmol)加入冰醋酸(6mL)和多聚磷酸(6mL)的混合溶液中,于120℃下反应7小时。反应液冷却至室温,倒入70mL水中,用50%的NaOH水溶液调节pH为5,有白色固体析出,过滤,滤饼用大量水冲洗。将滤饼悬浮在甲醇中,搅拌10分钟,过滤,滤饼用50mL乙酸乙酯洗涤。滤饼减压真空干燥得白色固体887.5mg,收率76%。
实施例2本发明化合物1a的制备
合成路线如下所示:
8a(CAS:315-30-0)可直接购买。
1、化合物9a的合成
将化合物8a(0.5g,3.68mmol)于氩气保护下滴入二氯亚砜(15ml)和DMF(1.5mL),滴加完毕后升温至80℃回流反应2小时。反应液冷却至室温,缓慢倒入剧烈搅拌的150mL冰水中,用100mL乙酸乙酯萃取三次,合并有机相,用饱和食盐水洗,无水硫酸镁干燥,旋干得黄色粉末9a 367mg,收率64%。
2、化合物1a的合成
将化合物9a(0.32mmol)和化合物10a(40.6mg,0.27mmol)溶于DMF(1.5mL)中,加入三乙胺(66.8μL,0.484mmol),氩气保护下于80℃反应4小时。减压旋尽溶剂,残留物加入8mL乙酸乙酯,用4mL水洗涤三次。有机相经无水硫酸镁干燥,旋干过柱(DCM:MeOH=10:1),得淡黄色固体31.1mg,收率43%。
3-((1H-吡唑[3,4-d]嘧啶-4-氨基)甲基)苯甲酸(1a).1H-NMR(400MHz,d6-DMSO,ppm):δ13.44(br,2H,COOH and pyrazole NH),8.81(m,1H,amino),8.23(s,1H,pyrimidine-CH),8.17(s,1H,pyrazole-CH),7.94(s,1H,Ar-H2),7.83(d,1H,J=7.6Hz,Ar-H6),7.46(d,1H,J=7.6Hz,Ar-H4),7.46(t,1H,J=7.6Hz,Ar-H5),4.80(d,2H,J=6.0Hz,benzyl-CH2).ESI-MS:270.09[M+H].
实施例3本发明化合物1b的制备
按照实施例2中类似的方法合成化合物1b,区别在于以化合物9b替代化合物9a,得黄色固体1b,收率41%。
4-((1H-吡唑[3,4-d]嘧啶-4-氨基)甲基)苯甲酸(1b).1H-NMR(400MHz,d6-DMSO,ppm):δ14.50(s,1H,br,COOH),13.41(s,1H,pyrazole NH),8.79(m,1H,amino),8.23(s,1H,pyrimidine CH),8.17(s,1H,pyrazole CH),7.91(d,2H,J=7.6Hz,Ar-H2 and Ar-H6),7.46(d,2H,J=7.6Hz,Ar-H3 and Ar-H5),4.82(d,2H,J=5.2Hz,benzyl-CH2).ESI-MS:270.09[M+H].
实施例4本发明化合物1c的制备
按照实施例2中类似的方法合成化合物1c,区别在于以化合物9b替代化合物9a,以化合物10b替代化合物10a,得黄色固体1c,收率36%
3-((6-甲基1H-吡唑[3,4-d]嘧啶-4-氨基)甲基)苯甲酸(1c).1H-NMR(400MHz,d6-DMSO,ppm):δ14.58(s,1H,pyrazole-NH),12.92(br,1H,COOH),11.43(t,1H,J=6.0Hz,amino),8.52(s,1H,pyrazole-CH),8.02(s,1H,Ar-H2),7.98(d,1H,J=7.6Hz,Ar-H6),7.56(d,1H,J=7.6Hz,Ar-H4),7.50(t,1H,J=7.6Hz,Ar-H5),5.02(d,2H,J=6.0Hz,benzyl-CH2),2.33(s,1H,CH3).ESI-MS:284.11[M+H].
实施例5本发明化合物1d-k的制备
按照实施例2中类似的方法合成化合物1d,区别在于以化合物9b替代化合物9a,以化合物10b替代化合物10a,得黄色固体1d,收率39%。
4-((6-甲基-1H-吡唑[3,4-d]嘧啶-4-氨基)甲基)苯甲酸(1d).1H-NMR(400MHz,d6-DMSO,ppm):δ14.74(s,1H,pyrazole-NH),12.94(br,1H,COOH),11.39(t,1H,J=6.0Hz,amino),8.55(s,1H,pyrazole-CH),7.93(d,2H,J=8.3Hz,Ar-H2 and Ar-H6),7.46(d,2H,J=8.3Hz,Ar-H3 and Ar-H5),5.08(d,2H,J=6.0Hz,benzyl-CH2),2.34(s,1H,CH3).ESI-MS:284.11[M+H].
选择相应的原料,按照类似的方法制备得到化合物1e-k,结果和表征如下:
黄色固体,收率41%。1H-NMR(400MHz,d6-DMSO,ppm):δ13.52(s,1H,pyrazole NH),8.64(m,1H,amino),8.17(s,1H,pyrimidine CH),8.11(s,1H,pyrazole CH),7.45-6.67(m,5H,Ar-H),4.12(d,2H,J=5.2Hz,benzyl-CH2).ESI-MS:226.09[M+H].
黄色固体,收率49%。1H-NMR(400MHz,d6-DMSO,ppm):δ13.52(s,1H,pyrazole NH),8.64(m,1H,amino),8.19(s,1H,pyrimidine CH),8.12(s,1H,pyrazole CH),7.45(d,2H,J=7.6Hz,Ar-H2 and Ar-H6),7.12(d,2H,J=7.6Hz,Ar-H3 and Ar-H5),4.01(d,2H,J=5.2Hz,benzyl-CH2),2.33(s,3H,CH3).ESI-MS:240.12[M+H].
黄色固体,收率46%。1H-NMR(400MHz,d6-DMSO,ppm):δ13.44(s,1H,pyrazole NH),8.80(m,1H,amino),8.25(s,1H,pyrimidine CH),8.19(s,1H,pyrazole CH),7.98(d,2H,J=7.6Hz,Ar-H2 and Ar-H6),7.42(d,2H,J=7.6Hz,Ar-H3 and Ar-H5),4.85(d,2H,J=5.2Hz,benzyl-CH2).ESI-MS:260.06[M+H].
黄色固体,收率52%。1H-NMR(400MHz,d6-DMSO,ppm):δ13.52(s,1H,pyrazole NH),8.45(m,1H,amino),8.07(s,1H,pyrimidine CH),8.01(s,1H,pyrazole CH),7.23(d,2H,J=7.6Hz,Ar-H2 and Ar-H6),7.07(d,2H,J=7.6Hz,Ar-H3 and Ar-H5),4.03(d,2H,J=5.2Hz,benzyl-CH2).ESI-MS:242.12[M+H].
黄色固体,收率55%。1H-NMR(400MHz,d6-DMSO,ppm):δ14.59(s,1H,pyrazole-NH),12.93(br,1H,COOH),11.41(t,1H,J=6.0Hz,amino),8.51(s,1H,pyrazole-CH),8.00(s,1H,Ar-H2),7.87(d,1H,J=7.6Hz,Ar-H6),7.34(d,1H,J=7.6Hz,Ar-H5),4,98(d,2H,J=6.0Hz,benzyl-CH2).ESI-MS:286.10[M+H].
黄色固体,收率46%。1H-NMR(400MHz,d6-DMSO,ppm):δ14.74(s,1H,pyrazole-NH),12.94(br,1H,COOH),11.23(t,1H,J=6.0Hz,amino),8.51(s,1H,pyrazole-CH),7.86(d,2H,J=8.3Hz,Ar-H2 and Ar-H6),7.23(d,2H,J=8.3Hz,Ar-H3 and Ar-H5),4.89(d,2H,J=6.0Hz,CH2NH),3.68(s,2H,CH2COOH),2.34(s,1H,CH3).ESI-MS:298.11[M+H].
黄色固体,收率41%。1H-NMR(400MHz,d6-DMSO,ppm):δ14.51(s,1H,pyrazole-NH),12.93(br,1H,COOH),11.41(t,1H,J=6.0Hz,amino),8.53(s,1H,pyrazole-CH),8.02(s,1H,Ar-H2),7.95(d,1H,J=7.6Hz,Ar-H6),7.52(d,1H,J=7.6Hz,Ar-H4),7.54(t,1H,J=7.6Hz,Ar-H5),4.23(m,2H,CH2),2.94(m,2H,CH2).ESI-MS:284.11[M+H].
实施例6本发明化合物对IDO蛋白的抑制活性
重组人IDO蛋白经大肠杆菌表达,镍亲合层析纯化而得。化合物对IDO抑制活性实验采用L-色氨酸作为底物。待测化合物溶解在10%DMSO溶液中配制成稀释液。取5uL稀释液加入到100μL反应体系中。100μL反应体系中含有0.5%DMSO,40nmol/L IDO,900μmol/L L-色氨酸,以及其他反应共存物(磷酸钾缓冲液、抗坏血酸、过氧化氢酶,亚甲基蓝)。反应混合物于37度下培育180分钟,再加入三氯乙酸终止反应。使用Tecan Infinite M1000酶标仪在321nm处测定产生的N-甲酰基犬尿氨酸的浓度,从而评价化合物对IDO的抑制活性。阴性对照物是以5μL的缓冲液代替IDO。临床III期的IDO抑制剂INCB024360作为阳性对照,验证本实验建立的IDO活性检测体系是否有效。
每个浓度设立三复孔。使用软件Graphpad Prism进行数据分析。在不含待测化合物的反应液中,吸光度(At)定义为100%活性。在不含IDO的反应液中,吸光度(Ab)定义为0%活性。对于待测化合物,活性的计算公式为:%activity=[(A-Ab)/(At-Ab)]×100,其中A为含待测化合物的反应液的吸光度。抑制率的计算公式为:%inhibition=100-%activity.
通过以上实验方法,测试了本发明中的部分化合物针对IDO的抑制活性。具体部化合物在1μM、10μM、100μM浓度下的抑制活性见表1。
其中A表示抑制率大于30%、B表示抑制率20%-30%,C表示抑制率为10%-20%;D表示抑制率为小于10%;阳性对照物在浓度为0.05μM时的抑制率为46%。
表1 本发明化合物对IDO的抑制活性
结果显示,本发明的化合物均对IDO具有一定的抑制活性。其中R2选自时,效果较佳。
综上所述,本发明提供的(1H-吡唑[3,4-d]嘧啶)-4-氨基衍生物,对IDO具有优异的抑制作用,可以用于预防和/或治疗多种疾病,如阿尔茨海默病、白内障、细胞免疫激活相关的感染、自身免疫性疾病、艾滋病、癌症、抑郁症或色氨酸代谢异常等。
Claims (8)
1.一种化合物或其药学上可接受的盐,所述化合物的结构如下所示:
2.制备权利要求1所述化合物的方法,其特征在于:包括以下步骤:
以化合物9和化合物10为原料,溶于有机溶剂中,在惰性气体环境和碱的存在下反应,纯化得到权利要求1所述化合物;
其中,化合物9为化合物10为
3.根据权利要求2所述的方法,其特征在于:所述碱选自有机碱或无机碱,所述有机碱选自三乙胺或吡啶,所述无机碱选择碳酸氢钠、碳酸钠或氢氧化钠。
4.根据权利要求2或3所述的方法,其特征在于:所述有机溶剂选自二甲基甲酰胺、四氢呋喃、乙酸乙酯、丙酮或二氯甲烷。
5.根据权利要求2所述的方法,其特征在于:所述反应的温度是25℃-100℃。
6.权利要求1所述化合物、或其药学上可接受的盐在制备IDO抑制剂类药物上的用途。
7.根据权利要求6所述的用途,其特征在于:所述药物是预防和/或治疗阿尔茨海默病、白内障、细胞免疫激活相关的感染、自身免疫性疾病、艾滋病、抑郁症或色氨酸代谢异常的药物。
8.一种药物组合物,其特征在于:它是以权利要求1所述的化合物或其药学上可接受的盐为活性成分,加上药学上可接受的辅料制备而成的制剂。
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