CN111100079B - 一类常山碱衍生物及其制备方法和应用 - Google Patents
一类常山碱衍生物及其制备方法和应用 Download PDFInfo
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- CN111100079B CN111100079B CN201911390549.5A CN201911390549A CN111100079B CN 111100079 B CN111100079 B CN 111100079B CN 201911390549 A CN201911390549 A CN 201911390549A CN 111100079 B CN111100079 B CN 111100079B
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- acetonyl
- carboxamide
- acid
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- 238000006243 chemical reaction Methods 0.000 claims abstract description 33
- -1 cyano, hydroxy, amino Chemical group 0.000 claims abstract description 19
- 239000001257 hydrogen Substances 0.000 claims abstract description 19
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Abstract
Description
技术领域
本发明属于医药技术领域,具体涉及一类常山碱衍生物及其制备方法和应用。
背景技术
刚地弓形虫(Toxoplasma gondii)是一种地域分布广、宿主多、生活史复杂、危害大的人兽共患专性寄生虫。猫科动物作为弓形虫的唯一终末宿主,是传播弓形虫病的主要传染源之一。近年来,随着宠物猫数量的增多,猫科动物感染弓形虫也因此愈发受到人们关注。经济动物中弓形虫感染最常见的是猪,地处西南地区的重庆市猪感染率高达75.95%。我国是世界上最大的养猪和猪肉消费国,猪的高弓形虫感染率通过对猪肉的大量食用而增加了人类感染的风险,威胁人们的身体健康。弓形虫是一种条件性致病原虫,主要受害群体是妊娠期及免疫力损失或低下的人和动物。免疫力低下的艾滋病病毒感染者/获得性免疫缺陷综合征(HIV/AIDS)患者、自身免疫性疾病患者以及干细胞移植治疗患者等人群在感染弓形虫后,其隐性感染可激活为急性活动感染并引发脑炎、肺炎和眼病等严重疾病,甚至可导致患者死亡。目前临床上一般采用乙胺嘧啶联合磺胺嘧啶、甲氧苄氨嘧啶联合磺胺甲恶唑、螺旋霉素等药物治疗弓形虫病,二线治疗药物有阿托伐醌、依匹普林。这些药物虽然对治疗弓形虫病有一定效果,但是副作用明显,对潜伏感染没有效果,而且不能穿过血脑屏障治疗因弓形虫引起的中枢神经系统疾病。因此,研发疗效好、毒副作用低的新型抗弓形虫药物,对人类公共卫生安全和畜牧业健康发展具有重大意义。
常山碱(febrifugine)是20世纪40年代从传统中药常山中分离得到的生物碱,展现出抗疟原虫活性。其衍生物常山酮具有很好的抗球虫活性,已在养殖场得到了广泛使用。同时,常山酮还显示具有很好的抗癌活性。未查询到常山碱及其衍生物抑制弓形虫的报道。
发明内容
发明人设计并合成一类常山碱衍生物,发现这类化合物对刚地弓形虫具有较好的体外抑制作用,具有开发成抗弓形虫药物的前景。
在第一方面,本发明涉及式(I)的化合物或其药学上可接受的盐:
其中,
Ar环选自苯基、吡啶基或噻吩基;
R1选自氢、C1-4烷基或苯基;
R2、R3、R4、R5各自独自选自氢、卤素、三氟甲基、氰基、羟基、氨基、C1-4烷基、C1-4烷氧基或硝基。
根据本发明的一个实施方案,本发明式(I)的化合物或其药学上可接受的盐选自化合物(I-a)、(I-b)或(I-c)。
其中,
R1选自氢、C1-4烷基或苯基;
R2选自氢、卤素、三氟甲基、氰基、羟基、氨基、C1-4烷基、C1-4烷氧基或硝基;
R4选自氢、卤素、三氟甲基、氰基、羟基、氨基、C1-4烷基、C1-4烷氧基或硝基;
R5选自氢、卤素、三氟甲基、氰基、羟基、氨基、C1-4烷基、C1-4烷氧基或硝基。
本发明所用的术语“卤素”是指氟、氯、溴或碘。
本发明所用的术语“C1-4烷基”是指具有1-4个碳原子的饱和的直链或支链烃基,例如甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基,优选甲基、乙基、丙基、异丙基、丁基或异丁基,更优选甲基、乙基或丙基。
本发明所用的术语“C1-4烷氧基”是指总共具有1-4个碳原子通过氧原子与分子的其余部分相连的烷氧基,例如甲氧基、乙氧基、丙氧基、叔丁氧基。
式(I)的化合物具体选自化合物(I-1)-(I-16)。
表1化合物(I-1)-(I-16)
本发明药学上可接受的盐为酸与化合物(I)中的含孤对电子的氮形成的盐,例如与以下酸形成的盐:盐酸,氢溴酸,硫酸,甲磺酸,三氟乙酸,酒石酸,乳酸,马来酸,富马酸,苹果酸等。
在第二方面,本发明涉及式(I)的化合物或其药学上可接受的盐的制备方法。
式(I)的化合物或其药学上可接受的盐的制备方法,反应路线如下:
式(II)化合物与式(III)化合物反应,得到化合物(V);化合物(V)与式(IV)化合物反应得到本发明式(I)化合物。
上述式(I)化合物或其药学上可接受的盐的制备方法,包括以下步骤:将如式(II)所示的化合物与如式(III)所示的化合物在有机溶剂中在碱的作用下反应,反应完成后,加水后用乙酸乙酯萃取,干燥浓缩,经柱层析纯化得到化合物(V);接着将中间体(V)与如式(IV)所示的苯甲酰氯衍生物在吡啶中回流,反应完成后,加入乙酸乙酯稀释,后用水和饱和食盐水洗涤有机相,干燥浓缩有机相,经柱层析纯化或者通过重结晶得到如式(I)化合物。
式(II)化合物中,Ar环选自苯基、吡啶基、噻吩基中的一种;式(III)化合物中R1选自氢、甲基、苯基、甲酸叔丁酯基的一种;式(IV)化合物中R2~R5分别选自氢、卤素、三氟甲基、氰基、带保护的羟基、带保护的氨基、烷基、烷氧基或硝基中的一种。
为了节约溶剂并让反应底物充分溶解,所述反应使用的有机溶剂为乙腈、四氢呋喃、1,4-二氧六环、N,N-二甲基酰胺中的至少一种。
为提高反应收率,所述反应使用的碱为碳酸钾、碳酸铯和钠氢中的一种。
为节约能源及方便操作,所述反应的温度为25~90℃。
为提高产物收率,所述重结晶步骤的溶剂乙醇、甲醇、乙酸乙酯、二氯甲烷、乙醚中的一种或者其中两种的任一组合。
在第三方面,本发明涉及式(I)的化合物或其药学上可接受的盐在抗弓形虫方面的应用。
在第四方面,本发明涉及式(V)的化合物:
其中,
Ar环选自苯基、吡啶基或噻吩基;
R1选自氢、C1-4烷基或苯基。
本发明化合物(V)具体选自化合物(V-1)-(V-5)。
表2化合物(V-1)-(V-5)
在第五方面,化合物(V)作为化合物(I)的制药中间体或药物检测中杂质对照品的新用途。
有益效果:
本发明提供一类常山碱衍生物化合物(I),发现这类化合物对刚地弓形虫具有较好的体外抑制作用,对宿主细胞毒性较小,具有开发成抗弓形虫药物的前景。本发明的制备过程在空气条件下进行,反应条件温和,易于控制,所用原料易得,底物适用范围广。本发明反应转化率高,在较短时间内可以得到较高的选择性和收率,反应产物稳定性好且后处理简便、绿色环保。
具体实施方式
为了使本发明的目的和技术方案更加清楚,下面对本发明的优选实施例进行详细的描述。要说明的是:以下实施例只用于对本发明进行进一步的说明,而不能理解为对本发明保护范围的限制。本领域的技术人员根据本发明的上述内容做出的一些非本质的改进和调整均属于本发明的保护范围。
实施例1
3-((4-苯基哌嗪-1-基)丙酮基)-3,4-二氢喹唑啉-4-酮(3H)-2-甲酰胺(V-1)的制备。
将3,4-二氢喹唑啉-4-酮(3H)-2-甲酰胺(10mmol)加入装有磁力搅拌子和N,N-二甲基酰胺(100mL)的250mL三通圆底烧瓶中,0℃冰浴下,氮气保护下快速加入钠氢(120mmol)。混合液在0℃搅拌1小时,接着加入1-溴-3-(4-苯基哌嗪-1-基)丙酮(10mmol),反应液升温至室温反应。TLC点板显示原料消失,加入水(100mL)猝灭反应。用乙酸乙酯(75mL×3)萃取三次,合并有机相。有机相用饱和食盐水(50mL×3)洗涤三次,无水硫酸钠干燥,抽滤,滤液真空浓缩。浓缩物上硅胶柱进行柱层析,用二氯甲烷/甲醇(v/v=50/1~25/1)作流动相冲洗,得如式(V-1)所示的中间体。(V-1)化合物的核磁为:1H NMR(DMSO-d6,400MHz):δ12.62-11.89(2H,brs),8.14(1H,d,J=7.6Hz),7.79-7.65(4H,m),7.46-7.41(1H,m),7.39(2H,d,J=7.6Hz),7.15-7.12(1H,m),4.99(2H,s),4.00(2H,s),3.21-3.19(4H,m),2.74-2.72(4H,m).ESI-MS m/z:406.2[M+H]+.
实施例2
3-((4-甲基哌嗪-1-基)丙酮基)-3,4-二氢喹唑啉-4-酮(3H)-2-甲酰胺(V-2)的制备。实施步骤和反应条件同实施例1。(V-2)化合物的核磁为:1H NMR(DMSO-d6,400MHz):δ12.22-11.96(2H,brs),7.84(1H,d,J=7.6Hz),7.69-7.58(4H,m),7.36-7.29(1H,m),7.19(2H,t,J=7.6Hz),7.12-7.06(1H,m),5.01(2H,s),3.86(2H,m),3.38-3.29(4H,m),2.94-2.82(4H,m).ESI-MS m/z:344.2[M+H]+.
实施例3
3-((哌嗪-1-基)-丙酮基)-3,4-二氢喹唑啉-4-酮(3H)-2-甲酰胺(V-3)的制备。实施步骤和反应条件同实施例1。(V-3)化合物的核磁为:1H NMR(DMSO-d6,400MHz):δ11.38-10.96(2H,brs),8.03-7.68(4H,m),4.91(2H,s),3.93(2H,m),3.28-3.09(4H,m),2.74-2.52(4H,m),1.38(9H,s).ESI-MS m/z:430.3[M+H]+.
实施例4
3-((4-苯基哌嗪-1-基)丙酮基)-3,4-二氢吡啶并[2,3-d]嘧啶-4-酮(3H)-2-甲酰胺(V-4)的制备。
将3,4-二氢吡啶并[2,3-d]嘧啶-4-酮(3H)-2-甲酰胺(10mmol)加入装有磁力搅拌子和1,4-二氧六环(100mL)的250mL圆底烧瓶中,然后加入碳酸铯(120mmol)和1-溴-3-(4-苯基哌嗪-1-基)丙酮(10mmol),反应液升温至90℃反应16个小时。TLC点板显示原料消失,加水(100mL)猝灭反应。用乙酸乙酯(75mL×3)萃取三次,合并有机相。有机相用饱和食盐水(50mL×3)洗涤三次,无水硫酸钠干燥,抽滤,滤液真空浓缩。浓缩物上硅胶柱进行柱层析,用二氯甲烷/甲醇(v/v=40/1~15/1)作流动相冲洗,得如式(V-4)所示的中间体。(V-4)化合物的核磁为:1H NMR(DMSO-d6,400MHz):δ12.62-11.89(2H,brs),8.14(1H,d,J=7.6Hz),7.79-7.65(4H,m),7.46-7.41(1H,m),7.39(2H,t,J=7.6Hz),7.15-7.12(1H,m),4.99(2H,s),4.00(2H,s),3.21-3.19(4H,m),2.74-2.72(4H,m).ESI-MS m/z:406.2[M+H]+.
实施例5
3-((4-苯基哌嗪-1-基)丙酮基)-3,4-二氢噻吩并[2,3-d]嘧啶-4-酮(3H)-2-甲酰胺(V-5)的制备。
将2-氨基噻吩3-甲酰胺(10mmol)加入装有磁力搅拌子和乙腈(100mL)的250mL圆底烧瓶中,氮气保护下快速加入碳酸钾(110mmol)。混合液25℃搅拌1小时,然后加入1-溴-3-(4-苯基哌嗪-1-基)丙酮(10mmol),反应液升温至室温反应。TLC点板显示原料消失,加入水(100mL)猝灭反应。用乙酸乙酯(75mL×3)萃取三次,合并有机相。有机相用饱和食盐水(50mL×3)洗涤三次,无水硫酸钠干燥,抽滤,滤液真空浓缩。浓缩物上硅胶柱进行柱层析,用二氯甲烷/甲醇(v/v=50/1~35/1)作流动相冲洗,得如式(V-5)所示的中间体。(V-5)化合物的核磁为:1H NMR(DMSO-d6,400MHz):δ12.41-11.83(2H,brs),8.04(1H,d,J=7.6Hz),7.31(2H,t,J=7.6Hz),7.22-6.84(4H,m),6.79-6.68(1H,m),4.75(2H,s),3.68(2H,s),3.34-3.25(4H,m),2.38-2.44(4H,m).ESI-MS m/z:412.1[M+H]+.
实施例6
N-苯甲酰基-3-(3-(4-苯基哌嗪-1-基)丙酮基)-3,4-二氢喹唑啉-2-甲酰胺(I-1)的制备。
将中间体(V-1)(2mmol),吡啶(20mL)和苯甲酰氯(2.2mmol)加入洁净干燥的100mL梨形烧瓶。反应液在115℃回流,2小时后,加水20mL,用乙酸乙酯(25mL×3)萃取三次,合并有机相。有机相用饱和食盐水(20mL×3)洗涤三次,无水硫酸钠干燥,抽滤,滤液真空浓缩。浓缩残留物上硅胶柱进行柱层析,用二氯甲烷/甲醇(v/v=50/1~25/1)作流动相冲洗,得如式(I-1)所示的产物。(I-1)化合物的核磁为:1H NMR(DMSO-d6,400MHz):δ12.33(1H,s),7.88-7.72(4H,m),7.42-7.28(4H,m),7.15-7.12(3H,m),6.98-6.88(2H,m),4.95(2H,s),3.86(2H,m),3.44-3.28(4H,m),2.69-2.48(4H,m).ESI-MS m/z:510.3[M+H]+.
实施例7
N-苯甲酰基-3-(3-(4-甲基哌嗪-1-基)丙酮基)-3,4-二氢喹唑啉-2-甲酰胺(I-2)的制备。操作步骤和反应条件同实施例6。(I-2)化合物的核磁为:1H NMR(DMSO-d6,400MHz):δ12.18(1H,s),7.76-7.59(3H,m),7.39-7.25(3H,m),6.78-6.68(2H,m),4.74(2H,s),3.69(2H,m),2.87-2.68(4H,m),2.35-2.28(4H,m),2.19(3H,s).ESI-MS m/z:448.2[M+H]+.
实施例8
N-苯甲酰基-3-((4-苯基哌嗪-1-基)丙酮基)-3,4-二氢喹唑啉-2-甲酰胺(I-3)的制备。操作步骤和反应条件同实施例6。(I-3)化合物的核磁为:1H NMR(DMSO-d6,400MHz):δ11.90(1H,s),7.65-7.49(4H,m),7.34-7.22(4H,m),4.63(2H,s),3.88(1H,brs),3.52(2H,m),2.65-2.48(4H,m),2.37-2.29(4H,m).ESI-MS m/z:448.2[M+H]+.
实施例9
N-苯甲酰基-3-((4-苯基哌嗪-1-基)丙酮基)-3,4-二氢吡啶并[2,3-d]嘧啶-4-酮(3H)-2-甲酰胺(I-4)的制备。操作步骤和反应条件同实施例6。(I-4)化合物的核磁为:1HNMR(DMSO-d6,400MHz):δ12.39(1H,s),7.45-7.37(m,1H),7.37-7.27(m,6H),7.17(q,J=8.4Hz,4H),7.13-7.07(m,2H),5.04(2H,s),4.15(2H,m),3.36-3.29(4H,m),2.84-2.76(4H,m).ESI-MS m/z:511.3[M+H]+.
实施例10
N-苯甲酰基-3-((4-苯基哌嗪-1-基)丙酮基)-3,4-二氢噻吩并[2,3-d]嘧啶-4-酮(3H)-2-甲酰胺(I-5)的制备。操作步骤和反应条件同实施例6。(I-5)化合物的核磁为:1HNMR(DMSO-d6,400MHz):δ12.18(1H,s),8.19(1H,d,J=5.4Hz),7.41(1H,d,J=5.3Hz),8.03-7.70(5H,m),7.27-6.94(4H,m),6.79-6.71(1H,m),5.21(2H,s),4.33(2H,m),3.44-3.34(4H,m),2.94-2.82(4H,m).ESI-MS m/z:516.2[M+H]+.
实施例11
N-(2-甲基苯甲酰基)-3-((哌嗪-1-基)丙酮基)-3,4-二氢喹唑啉-4-酮(3H)-2-甲酰胺(I-6)的制备。
将中间体(V-3)(2mmol),吡啶(20mL)和邻甲基苯甲酰氯(2.2mmol)加入洁净干燥的100mL梨形烧瓶。反应液在115℃回流,2小时后,加水20mL,用乙酸乙酯(25mL×3)萃取三次,合并有机相。有机相用饱和食盐水(20mL×3)洗涤三次,无水硫酸钠干燥,抽滤,滤液真空浓缩。浓缩物上硅胶柱进行柱层析,用二氯甲烷/甲醇(v/v=50/1~25/1)作流动相冲洗。纯化所得产物溶解在干燥二氯甲烷(10mL),然后加入三氟乙酸(1mL)。反应混合液室温反应过夜。减压浓缩反应液,浓缩产物溶于纯水(10mL),用饱和碳酸氢钠调pH至7~8,然后用乙酸乙酯(5mL×3)萃取三次,无水硫酸钠干燥,抽滤,滤液真空浓缩。浓缩物用无水乙醇进行重结晶,收率68%。(I-6)化合物的核磁为:1H NMR(DMSO-d6,400MHz):δ11.88(1H,s),7.88(1H,dd,J=8.0,2.0Hz),7.82(2H,d,J=8.0Hz),7.46(1H,dt,J=8.0,2.0Hz),7.37(2H,d,J=8.0Hz),6.96-7.08(m,2H),4.63(2H,s),3.88(1H,brs),3.52(2H,m),2.65-2.48(4H,m),2.40-2.31(4H,m),2.36(3H,s).ESI-MS m/z:448.2[M+H]+.
实施例12
N-(2-甲氧基苯甲酰基)-3-((哌嗪-1-基)丙酮基)-3,4-二氢喹唑啉-4-酮(3H)-2-甲酰胺(I-7)的制备。操作步骤和反应条件同实施例11。(I-7)化合物的核磁为:1H NMR(DMSO-d6,400MHz):δ11.56(1H,s),7.62(1H,d,J=7.3Hz),7.43-7.39(1H,m),7.35-7.26(4H,m),7.04(2H,t,J=7.8Hz),4.68(2H,s),3.94(1H,brs),3.63(2H,m),3.57(3H,s),2.55-2.38(4H,m),2.30-2.19(4H,m).ESI-MS m/z:464.2[M+H]+.
实施例13
N-(3-氟苯甲酰基)-3-((哌嗪-1-基)丙酮基)-3,4-二氢喹唑啉-4-酮(3H)-2-甲酰胺(I-8)的制备。操作步骤和反应条件同实施例11。(I-8)化合物的核磁为:1H NMR(DMSO-d6,400MHz):δ11.75(1H,s),7.49-7.31(6H,m),7.23-7.11(2H,m),4.87(2H,s),4.05(1H,brs),3.78(2H,m),2.65-2.48(4H,m),2.40-2.29(4H,m).ESI-MS m/z:452.2[M+H]+.
实施例14
N-(4-氯苯甲酰基)-3-((哌嗪-1-基)丙酮基)-3,4-二氢喹唑啉-4-酮(3H)-2-甲酰胺(I-9)的制备。操作步骤和反应条件同实施例11。(I-9)化合物的核磁为:1H NMR(DMSO-d6,400MHz):δ12.05(1H,s),7.48-7.42(5H,m),7.38-7.31(3H,m),4.77(2H,s),3.63(2H,m),3.45(1H,brs),2.55-2.48(4H,m),2.38-2.29(4H,m).ESI-MS m/z:438.1[M+H]+.
实施例15
N-(4-溴苯甲酰基)-3-((哌嗪-1-基)丙酮基)-3,4-二氢喹唑啉-4-酮(3H)-2-甲酰胺(I-10)的制备。操作步骤和反应条件同实施例11。(I-10)化合物的核磁为:1H NMR(DMSO-d6,400MHz):δ11.92(1H,s),7.46-7.28(6H,m),7.21(1H,d,J=8.2Hz),7.14(1H,d,J=8.1Hz),4.97(2H,s),3.73(2H,m),3.25(1H,brs),2.75-2.68(4H,m),2.48-2.39(4H,m).ESI-MS m/z:512.1[M+H]+.
实施例16
N-(3-硝基苯甲酰基)-3-((哌嗪-1-基)丙酮基)-3,4-二氢喹唑啉-4-酮(3H)-2-甲酰胺(I-11)的制备。操作步骤和反应条件同实施例11。(I-11)化合物的核磁为:1H NMR(DMSO-d6,400MHz):δ12.12(1H,s),7.56-7.48(4H,m),7.35-7.27(3H,m),7.21(1H,d,J=1.8Hz),4.88(2H,s),3.65(2H,m),3.32(1H,brs),2.65-2.58(4H,m),2.28-2.19(4H,m).ESI-MS m/z:479.1[M+H]+.
实施例17
N-(3-氰基苯甲酰基)-3-((哌嗪-1-基)丙酮基)-3,4-二氢喹唑啉-4-酮(3H)-2-甲酰胺(I-12)的制备。操作步骤和反应条件同实施例11。(I-12)化合物的核磁为:1H NMR(DMSO-d6,400MHz):δ11.42(1H,s),7.46-7.38(4H,m),7.33-7.25(3H,m),7.08(1H,d,J=2.0Hz),4.96(2H,s),3.75(2H,m),3.12(1H,brs),2.75-2.68(4H,m),2.48-2.29(4H,m).ESI-MS m/z:459.2[M+H]+.
实施例18
N-(3,5-二氯苯甲酰基)-3-((哌嗪-1-基)丙酮基)-3,4-二氢喹唑啉-4-酮(3H)-2-甲酰胺(I-13)的制备。操作步骤和反应条件同实施例11。(I-13)化合物的核磁为:1H NMR(DMSO-d6,400MHz):δ11.62(1H,s),7.65-7.58(4H,m),7.25(1H,d,J=6.8Hz),7.08(2H,d,J=6.5Hz),4.66(2H,s),3.65(2H,m),3.42(1H,brs),2.85-2.78(4H,m),2.43-2.26(4H,m).ESI-MS m/z:502.2[M+H]+.
实施例19
N-(3-三氟甲基苯甲酰基)-3-((哌嗪-1-基)丙酮基)-3,4-二氢喹唑啉-4-酮(3H)-2-甲酰胺(I-14)的制备。操作步骤和反应条件同实施例11。(I-14)化合物的核磁为:1H NMR(DMSO-d6,400MHz):δ11.82(1H,s),7.67-7.61(3H,m),7.51-7.45(4H,m),7.40-7.36(1H,m),4.96(2H,s),3.75(2H,m),3.22(1H,brs),2.95-2.89(4H,m),2.33-2.20(4H,m).ESI-MSm/z:502.1[M+H]+.
实施例20
N-(3-三氟甲基苯甲酰基)-8-硝基-3-((哌嗪-1-基)丙酮基)-3,4-二氢喹唑啉-4-酮(3H)-2-甲酰胺(I-15)的制备。操作步骤和反应条件同实施例11。(I-15)化合物的核磁为:1H NMR(DMSO-d6,400MHz):δ12.60(1H,s),8.30-7.66(3H,m),7.55-7.48(4H,m),5.10(2H,s),4.05(2H,m),3.43(1H,brs),3.07-2.94(4H,m),2.42-2.29(4H,m).ESI-MS m/z:479.1[M+H]+.
实施例21
N-苯甲酰基-3-((哌嗪-1-基)丙酮基)-5-硝基-3,4-二氢噻吩并[2,3-d]嘧啶-4-酮(3H)-2-甲酰胺(I-16)的制备。操作步骤和反应条件同实施例11。(I-16)化合物的核磁为:1H NMR(DMSO-d6,400MHz):δ12.91(1H,s),9.34(1H,s),7.71-7.58(4H,m),4.89(2H,s),3.88(2H,m),3.21(1H,brs),2.98-2.84(4H,m),2.36-2.20(4H,m).ESI-MS m/z:485.1[M+H]+.
实施例22
利用MTT法对实施例6~21所制备的常山碱衍生物(化合物(I-1)-化合物(I-16))进行抑制刚地弓形虫(T.gondii)和人包皮成纤维细胞(HFF)的活性测试,然后利用酶标仪迅速测定490nm的吸光值,运用SPSS软件计算其IC50值,具体结果见下表3。
表3化合物抗弓形虫活性
由表3可以看出,本发明的常山碱衍生物对弓形虫具有较好的抑制活性,对宿主细胞毒性较小,具有潜在的开发价值。
以上所述实施例仅表达了本发明的几种实施方式,其描述较为具体和详细,但并不能因此而理解为对发明专利范围的限制。应当指出的是,对于本领域的普通技术人员来说,在不脱离本发明构思的前提下,还可以做出若干变形和改进,这些都属于本发明的保护范围。因此,本发明专利的保护范围应以所附权利要求为准。
Claims (11)
3.如权利要求1或2所述的式(I)化合物或其药学上可接受的盐,其特征在于:所述C1-4烷基选自甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基;所述C1-4烷氧基选自甲氧基、乙氧基、丙氧基或叔丁氧基。
4.如权利要求3所述的式(I)化合物或其药学上可接受的盐,其特征在于:所述C1-4烷基选自甲基、乙基、丙基、异丙基、正丁基或异丁基。
5.式(I)化合物或其药学上可接受的盐,其特征在于,式(I)化合物选自:
N-苯甲酰基-3-(3-(4-苯基哌嗪-1-基)丙酮基)-3,4-二氢喹唑啉-4-酮(3H)-2-甲酰胺;
N-苯甲酰基-3-(3-(4-甲基哌嗪-1-基)丙酮基)-3,4-二氢喹唑啉-4-酮(3H)-2-甲酰胺;
N-苯甲酰基-3-((哌嗪-1-基)丙酮基)-3,4-二氢喹唑啉-4-酮(3H)-2-甲酰胺;
N-苯甲酰基-3-((4-苯基哌嗪-1-基)丙酮基)-3,4-二氢吡啶并[2,3-d]嘧啶-4-酮(3H)-2-甲酰胺;
N-(2-甲基苯甲酰基)-3-((哌嗪-1-基)丙酮基)-3,4-二氢喹唑啉-4-酮(3H)-2-甲酰胺;
N-(2-甲氧基苯甲酰基)-3-((哌嗪-1-基)丙酮基)-3,4-二氢喹唑啉-4-酮(3H)-2-甲酰胺;
N-(3-氟苯甲酰基)-3-((哌嗪-1-基)丙酮基)-3,4-二氢喹唑啉-4-酮(3H)-2-甲酰胺;
N-(4-氯苯甲酰基)-3-((哌嗪-1-基)丙酮基)-3,4-二氢喹唑啉-4-酮(3H)-2-甲酰胺;
N-(4-溴苯甲酰基)-3-((哌嗪-1-基)丙酮基)-3,4-二氢喹唑啉-4-酮(3H)-2-甲酰胺;
N-(3-硝基苯甲酰基)-3-((哌嗪-1-基)丙酮基)-3,4-二氢喹唑啉-4-酮(3H)-2-甲酰胺;
N-(3-氰基苯甲酰基)-3-((哌嗪-1-基)丙酮基)-3,4-二氢喹唑啉-4-酮(3H)-2-甲酰胺;
N-(3,5-二氯苯甲酰基)-3-((哌嗪-1-基)丙酮基)-3,4-二氢喹唑啉-4-酮(3H)-2-甲酰胺;
N-(3-三氟甲基苯甲酰基)-3-((哌嗪-1-基)丙酮基)-3,4-二氢喹唑啉-4-酮(3H)-2-甲酰胺;
N-(3-三氟甲基苯甲酰基)-8-硝基-3-((哌嗪-1-基)丙酮基)-3,4-二氢喹唑啉-4-酮(3H)-2-甲酰胺;
N-苯甲酰基-3-((哌嗪-1-基)丙酮基)-5-硝基-3,4-二氢噻吩并[2,3-d]嘧啶-4-酮(3H)-2-甲酰胺。
6.如权利要求1、2、4或5所述的式(I)化合物或其药学上可接受的盐,其特征在于:所述药学上可接受的盐为酸与化合物(I)中的含孤对电子的氮形成的盐;所述酸选自盐酸,氢溴酸,硫酸,甲磺酸,三氟乙酸,酒石酸,乳酸,马来酸,富马酸或苹果酸。
7.如权利要求3所述的式(I)化合物或其药学上可接受的盐,其特征在于:所述药学上可接受的盐为酸与化合物(I)中的含孤对电子的氮形成的盐;所述酸选自盐酸,氢溴酸,硫酸,甲磺酸,三氟乙酸,酒石酸,乳酸,马来酸,富马酸或苹果酸。
9.如权利要求1-7任一项所述式(I)化合物或其药学上可接受的盐在制备抗弓形虫药物中的应用。
11.如权利要求10所述的式(V)化合物,所述式(V)化合物选自:
3-((4-苯基哌嗪-1-基)丙酮基)-3,4-二氢喹唑啉-4-酮(3H)-2-甲酰胺;
3-((4-甲基哌嗪-1-基)丙酮基)-3,4-二氢喹唑啉-4-酮(3H)-2-甲酰胺;
4-(3-(2-氨基甲酰基-4-氧代喹唑啉-3(4H)-基)-丙酮基)哌嗪-1-甲酸叔丁酯;
3-((4-苯基哌嗪-1-基)丙酮基)-3,4-二氢吡啶并[2,3-d]嘧啶-4-酮(3H)-2-甲酰胺。
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