CN107963978A - 一种苯甲酰胺衍生物的制备方法及其用途 - Google Patents

一种苯甲酰胺衍生物的制备方法及其用途 Download PDF

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CN107963978A
CN107963978A CN201711209697.3A CN201711209697A CN107963978A CN 107963978 A CN107963978 A CN 107963978A CN 201711209697 A CN201711209697 A CN 201711209697A CN 107963978 A CN107963978 A CN 107963978A
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carbamate derivatives
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贺殿
赵静思
魏堆堆
蔺瑞丽
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Lanzhou University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/81—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/82—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/83—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom of an acyclic saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/36—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

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Abstract

本发明公开一种如式(Ⅰ)示的苯甲酰胺衍生物的制备方法及其应用。本

Description

一种苯甲酰胺衍生物的制备方法及其用途
技术领域
本发明涉及一种苯甲酰胺衍生物的制备方法及其应用。
背景技术
恶性肿瘤是严重威胁人类健康的常见病、多发病，且随人类生活水平提高，其发病率日趋上升态势，为了治疗癌症，人们已经做了大量的努力来研制各种类型的抗肿瘤药。近年来人们对HDAC靶点的研究日益增多，其中比较典型的HDACIs上市药物有伏立诺他(SAHA)与贝利司他，在调查口服治疗或静脉注射治疗对晚期白血病和实体瘤的抗癌活性、药物动力学性质和药物稳定性的临床Ⅰ期试验中，SAHA表现出较为理想的抗癌活性，但也有相当的毒副作用，这可能与其异羟肟酸结构的不稳定性有关，同时其还存在亚型选择性低的缺点。寻找一种高效、低毒、化学结构稳定的新型HDACIs抗肿瘤药是当前的课题之一。
发明内容
本发明公开一种苯甲酰胺衍生物类化合物，同时公开这种化合物的制备方法及用途。
本发明的苯甲酰胺衍生物类化合物，其化学式如式Ⅰ所示：
其中，取代基R1为氢、氟、氯、溴、碘、甲基、三氟甲基、N,N-二甲氨基或苯基中的任何一个；取代基R2为氢或甲基中的任何一个。
本发明公开的苯甲酰胺衍生物类化合物通过反应式II所示方法制备：
本专利合成的苯甲酰胺衍生物HDACi旨在提高传统组蛋白去乙酰化酶锌离子的螯合稳定性，以期获得组蛋白去乙酰化酶抑制作用更强，选择性更强的HDACi，本发明的化合物可在抗肿瘤药物的制备中应用，可以增大HDACi对部分肿瘤细胞的选择性，同时减少细胞毒性。
具体实施方式
一、本发明化合物的制备及表征
本发明化合物的具体制备方法参见反应式Ⅲ：
由式Ⅲ可知，当先用不同的取代苯甲酸及不同的胺，可得到不同的15种目标化合物，这些化合物的制备如下所述：
Ⅰ.称取取代苯甲酸(6mmol)溶于1,4-二氧六环20mL中，后加入N-羟基丁二酰亚胺(NHS)0.83g(7.2mmol)，后称取N,N-二环己基碳二亚胺(DCC)1.50g(7.2mmol)溶于适量1,4-二氧六环，将此溶液缓慢滴加到上述反应液中常温条件下搅拌6h，期间产生浑浊的白色沉淀(DCU)，反应结束后抽滤除去白色沉淀，留取滤液待用，滤液为淡黄色澄清液体。
Ⅱ.称取碳酸氢钠1.00g(12mmol)溶于适量水中，称取6-氨基己酸0.79g(6mmol)溶于上述碳酸氢钠溶液，充分溶解后将此溶液缓慢滴加至Ⅰ步骤中留取待用的滤液中，50℃下搅拌24h。反应完成后产生少量白色不溶沉淀，抽滤除去沉淀留取滤液，滤液减压蒸除大部分溶剂，剩余物加入水40mL，超声下震摇均匀，用乙酸乙酯(30ml×2)洗滤液，水层用浓盐酸酸化至pH＝3，搅拌10分钟后溶液底部产生黄色油状物，后用乙酸乙酯(30ml×2)萃取，合并有机层，用无水硫酸钠干燥乙酸乙酯后抽滤，后将乙酸乙酯减压蒸除浓缩，得到粗产物中间体。
Ⅲ.将上述中间体约5mmol溶于25mL无水四氢呋喃(THF)中，称取0.58g(5mmol)NHS溶于上述溶液中冰浴条件下搅拌，随后称取1.14g(5.5mmol)的DCC加入反应液，0℃条件下搅拌5min，后于室温条件下搅拌反应6h，期间产生浑浊白色沉淀(DCU)，反应结束抽滤除去白色沉淀，滤液减压浓缩，剩余物为产生的活性酯，留取备用。
Ⅳ.上述活性酯溶于25mL无水THF中，置于冰浴中，向内滴加乙醇胺0.31g(5mmol)/2-羟基丙胺0.38g(5mmol)滴加完毕于常温下搅拌反应16h，有白色浑浊固体产生，减压除去四氢呋喃，剩余物用无水甲醇溶解，抽滤，不溶部分弃掉，留取滤液，进行柱层析纯化分离(展开剂：氯仿：乙酸乙酯：甲醇＝4:4:1～4:6:1)，最终可得到15种目标化合物，即化合物e1，化合物e2，……，化合物e15。
本发明的15种目标化合物的结构、产率、性状及谱图数据如下：
N-(6-((2-hydroxyethyl)amino)-6-oxohexyl)benzamide(e1):灰白色粉末；Yield:41％；mp：111.2-114.5℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ8.40(t,1H,J＝6.0Hz,-ArCONH-),7.80-7.77(m,2H,Ar-H2,Ar-H6),7.73(t,1H,J＝4.0Hz,-CONH-),7.49-7.39(m,3H,Ar-H3,Ar-H4,Ar-H5),4.60(t,1H,J＝4.0Hz,-OH),3.35-3.30(dd,2H,J1＝8.0Hz,J2＝12.0Hz,-CH2OH),3.22-3.17(dd,2H,J1＝8.0Hz,J2＝12.0Hz,-CH2NH-),3.07-3.03(dd,2H,J1＝4.0Hz,J2＝12.0Hz,-CH2NH-),2.03(t,2H,J＝6.0Hz,-CH2CO-),1.50-1.43(m,4H,-CH2-,-CH2-),1.27-1.19(m,2H,-CH2-).13C-NMR(100MHz,DMSO-d6,TMS,ppm):172.66,166.53,135.19,131.43,128.68,127.58,60.44,41.86,39.77,35.78,29.41,26.67,25.52.ESI-MS:Calcd for C15H22N2O3[M+H]+279.1630,found 279.1744.。
4-(dimethylamino)-N-(6-((2-hydroxyethyl)amino)-6-oxohexyl)benzamide(e2):淡黄色固体粉末；Yield:42％；mp：120.4-122.3℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ8.01(t,1H,J＝5.6Hz,-ArCONH-),7.70(t,1H,J＝5.6Hz,-CONH-),7.67-7.65(m,2H,Ar-H2,Ar-H6),6.66-6.63(m,2H,Ar-H3,Ar-H5),4.58(t,1H,J＝5.4Hz,-OH),3.35-3.31(dd,2H,J1＝6.0Hz,J2＝12.0Hz,-CH2OH),3.18-3.13(dd,2H,J1＝6.8Hz,J2＝12.8Hz,-CH2NH-),3.07-3.03(dd,2H,J1＝6.0Hz,J2＝12.0Hz,-CH2NH-),2.91(s,6H,-N(CH3)2),2.02(t,2H,J＝7.2Hz,-CH2CO-),1.50-1.40(m,4H,-CH2-,-CH2-),1.25-1.18(m,2H,-CH2-).13C-NMR(100MHz,DMSO-d6,TMS,ppm):172.68,167.70,154.51,130.23,123.71,111.29,60.29,41.56,41.43,41.73,39.78,36.45,29.61,25.56,25.41.ESI-MS:Calcd for C17H27N3O3[M+H]+322.2052,found 322.2136.。
4-chloro-N-(6-((2-hydroxyethyl)amino)-6-oxohexyl)benzamide(e3):灰白色粉末；Yield:43％；mp：112.4-115.9℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ8.52(t,1H,J＝5.6Hz,-ArCONH-),7.85(d,2H,J＝8.0Hz,Ar-H2,Ar-H6),7.77(t,1H,J＝5.2Hz,-CONH-),7.53(d,2H,J＝8.0Hz,Ar-H3,Ar-H5),4.64(s,1H,-OH),3.38-3.33(dd,2H,J1＝8.0Hz,J2＝12.0Hz,-CH2OH),3.25-3.20(dd,2H,J1＝7.2Hz,J2＝12.0Hz,-CH2NH-),3.11-3.06(dd,2H,J1＝8.0Hz,J2＝12.0Hz,-CH2NH-),2.06(t,2H,J＝8.0Hz,-CH2CO-),1.54-1.47(m,4H,-CH2-,-CH2-),1.30-1.24(m,2H,-CH2-).13C-NMR(100MHz,DMSO-d6,TMS,ppm):172.65,165.46,136.27,133.88,129.53,128.77,60.44,41.85,39.63,35.76,29.32,26.65,25.69.ESI-MS:Calcd for C15H21N2O3[M+H]+313.1241,found 313.1317.。
N-(6-((2-hydroxyethyl)amino)-6-oxohexyl)-4-(trifluoromethyl)benzamide(e4):白色固体粉末；Yield:45％；mp：105.0-106.3℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ8.65(t,1H,J＝5.6Hz,-ArCONH-),7.99(d,2H,J＝8.0Hz,Ar-H2,Ar-H6),7.81(d,2H,J＝8.0Hz,Ar-H3,Ar-H5),7.73(t,1H,J＝5.8Hz,-CONH-),4.61(s,1H,-OH),3.34-3.29(dd,2H,J1＝6.4Hz,J2＝12.8Hz,-CH2OH),3.24-3.19(dd,2H,J1＝7.2Hz,J2＝12.8Hz,-CH2NH-),3.07-3.02(dd,2H,J1＝6.0Hz,J2＝11.6Hz,-CH2NH-),2.03(t,2H,J＝7.2Hz,-CH2CO-),1.52-1.43(m,4H,-CH2-,-CH2-),1.27-1.19(m,2H,-CH2-).13C-NMR(100MHz,DMSO-d6,TMS,ppm):172.63,165.37,138.92,131.57,128.51,125.76,125.73,60.44,41.85,39.8,35.75,29.25,26.63.25.48.ESI-MS:Calcd for C16H21F3N2O3[M+H]+347.1504,found 347.1583.。
4-bromo-N-(6-((2-hydroxyethyl)amino)-6-oxohexyl)benzamide(e5):白色粉末；Yield:35％；mp：115.7-118.7℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ8.49(t,1H,J＝5.6Hz,-ArCONH-),7.74(t,1H,J＝5.4Hz,-CONH-),7.73-7.72(m,2H,Ar-H2,Ar-H6),7.64-7.62(m,2H,Ar-H3,Ar-H5),4.62-4.59(m,1H,-OH),3.35-3.21(dd,2H,J1＝5.6Hz,J2＝12.8Hz,-CH2OH),3.19-3.14(dd,2H,J1＝6.4Hz,J2＝12.4Hz,-CH2NH-),3.01-2.97(dd,2H,J1＝5.6Hz,J2＝11.2Hz,-CH2NH-),2.02(t,2H,J＝7.2Hz,-CH2CO-),1.49-1.42(m,4H,-CH2-,-CH2-),1.24-1.19(m,2H,-CH2-).13C-NMR(100MHz,DMSO-d6,TMS,ppm):172.62,165.41,133.25,131.27,129.67,126.85,60.43,40.61,39.72,36.45,29.61,25.66,25.21.ESI-MS:Calcd for C15H21BrN2O3[M+H]+357.0736,found 357.0806and359.0825.。
N-(6-((2-hydroxyethyl)amino)-6-oxohexyl)-4-iodobenzamide(e6):白色粉末；Yield:33％；mp：150.4-150.9℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ8.47(t,1H,J＝5.6Hz,-ArCONH-),7.80(d,2H,J＝8.4Hz,Ar-H2,Ar-H6),7.73(t,1H,J＝5.2Hz,-CONH-),7.57(d,2H,J＝8.8Hz,Ar-H3,Ar-H5),4.62-4.59(m,1H,-OH),3.34-3.21(dd,2H,J1＝6.0Hz,J2＝12.0Hz,-CH2OH),3.20-3.16(dd,2H,J1＝7.2Hz,J2＝12.8Hz,-CH2NH-),3.07-3.02(dd,2H,J1＝6.0Hz,J2＝12.0Hz,-CH2NH-),2.02(t,2H,J＝7.2Hz,-CH2CO-),1.49-1.42(m,4H,-CH2-,-CH2-),1.24-1.18(m,2H,-CH2-).13C-NMR(100MHz,DMSO-d6,TMS,ppm):172.61,166.67,137.57,133.21,129.19,97.75,60.41,41.65,39.46,36.23,29.20,25.89,25.30.ESI-MS:Calcd for C15H21IN2O3[M+H]+405.0597,found 405.0692.。
N-(6-((2-hydroxyethyl)amino)-6-oxohexyl)benzo[d][1,3]dioxole-5-carboxamide(e7):白色粉末；Yield:37％；mp：94.5-96.7℃；1HNMR(400MHz,DMSO-d6,TMS,ppm):δ8.24(t,1H,J＝5.6Hz,-ArCONH-),7.73(t,1H,J＝5.6Hz,-CONH-),7.39-7.37(m,1H,Ar-H6),7.33(d,1H,J＝2.0Hz,Ar-H2),6.93(d,1H,J＝8.4Hz,Ar-H5),6.04(s,2H,-OCH2O-),4.61-4.59(m,1H,-OH),3.35-3.30(dd,2H,J1＝6.0Hz,J2＝12.0Hz,-CH2OH),3.18-3.15(dd,2H,J1＝6.8Hz,J2＝12.8Hz,-CH2NH-),3.07-3.02(dd,2H,J1＝6.0Hz,J2＝12.0Hz,-CH2NH-),2.02(t,2H,J＝7.6Hz,-CH2CO-),1.50-1.41(m,4H,-CH2-,-CH2-),1.25-1.17(m,2H,-CH2-).13C-NMR(100MHz,DMSO-d6,TMS,ppm):172.65,166.63,152.32,148.19,128.46,120.82,114.73,111.92,101.42,60.34,41.55,39.54,36.35,29.38,25.48,25.16.ESI-MS:Calcdfor C16H22N2O5[M+H]+322.1529,found 322.1546.。
N-(6-((2-hydroxyethyl)amino)-6-oxohexyl)-[1,1'-biphenyl]-4-carboxamide(e8):白色粉末；Yield:36％；mp：147.6-148.5℃；1HNMR(400MHz,DMSO-d6,TMS,ppm):δ8.46(t,1H,J＝5.6Hz,-ArCONH-),7.89-7.87(m,2H,Ar1-H2,Ar1-H6),7.73-7.71(m,3H,-CONH-,Ar1-H3,Ar1-H5),7.70-7.67(m,2H,Ar2-H2,Ar2-H6),7.47-7.43(m,2H,Ar2-H3,Ar2-H5),7.38-7.36(m,1H,Ar2-H4),4.60(t,1H,J＝5.2Hz,-OH),3.35-3.31(dd,2H,J1＝5.6Hz,J2＝12.0Hz,-CH2OH),3.19-3.14(dd,2H,J1＝7.2Hz,J2＝12.0Hz,-CH2NH-),3.01-2.96(dd,2H,J1＝5.6Hz,J2＝11.6Hz,-CH2NH-),2.03(t,2H,J＝7.6Hz,-CH2CO-),1.51-1.42(m,4H,-CH2-,-CH2-),1.26-1.15(m,2H,-CH2-).13C-NMR(100MHz,DMSO-d6,TMS,ppm):172.65,166.16,144.03,139.71,133.98,129.48,128.46,128.28,127.32,126.92,60.45,41.86,35.79,29.43,25.42,24.93.ESI-MS:Calcd for C21H26N2O3[M+H]+355.1943,found355.2025.。
N-(6-((2-hydroxyethyl)amino)-6-oxohexyl)-2-naphthamide(e9):白色粉末；Yield:50％；mp：115.1-117.8℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ8.45(t,1H,J＝5.4Hz,-ArCONH-),8.38(s,1H,Ar-H1),7.98-7.87(m,4H,Ar-H3,Ar-H4,Ar-H5,Ar-H8),7.59(t,1H,J＝5.6Hz,-CONH-),7.58-7.54(m,2H,Ar-H6,Ar-H7),4.47(t,1H,J＝5.6Hz,-OH),3.37-3.33(dd,2H,J1＝6.0Hz,J2＝12.0Hz,-CH2OH),3.30-3.25(dd,2H,J1＝7.2Hz,J2＝9.2Hz,-CH2NH-),3.09-3.05(dd,2H,J1＝6.0Hz,J2＝12.0Hz,-CH2NH-),2.05(t,2H,J＝7.0Hz,-CH2CO-),1.55-1.47(m,4H,-CH2-,-CH2-),1.33-1.26(m,2H,-CH2-).13C-NMR(100MHz,DMSO-d6,TMS,ppm):172.63,166.46,135.62,134.12,132.45,129.55,128.36,128.85,128.43,127.27,126.89,124.42,61.62,41.43,39.31,36.84,29.21,25.49,25.06.ESI-MS:Calcd for C19H24N2O3[M+H]+329.1787,found 329.1828.。
N-(6-((2-hydroxyethyl)amino)-6-oxohexyl)-3,5-dimethylbenzamide(e10):白色粉末；Yield:52％；mp：110.1-111.8℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ8.27(t,1H,J＝5.6Hz,-ArCONH-),7.72(t,1H,J＝5.6Hz,-CONH-),7.39(s,2H,Ar-H2,Ar-H6),7.10(s,1H,Ar-H4),4.59(s,1H,-OH),3.34-3.29(dd,2H,J1＝6.4Hz,J2＝12.0Hz,-CH2OH),3.20-3.14(dd,2H,J1＝7.0Hz,J2＝13.0Hz,-CH2NH-),3.07-3.02(dd,2H,J1＝5.8Hz,J2＝12.2Hz,-CH2NH-),2.26(s,6H,-CH3,-CH3),2.02(t,2H,J＝7.6Hz,-CH2CO-),1.48-1.42(m,4H,-CH2-,-CH2-),1.25-1.19(m,2H,-CH2-).13C-NMR(100MHz,DMSO-d6,TMS,ppm):172.65,166.33,138.54,137.47,134.32,128.14,61.23,41.93,39.55,36.17,29.54,25.85,25.43,21.02.ESI-MS:Calcd for C17H26N2O3[M+H]+307.1943,found 307.2024.。
N-(6-((2-hydroxyethyl)amino)-6-oxohexyl)-4-methylbenzamide(e11):白色粉末；Yield:45％；mp：116.5-118.5℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ8.31(t,1H,J＝5.6Hz,-ArCONH-),7.72(t,1H,J＝5.2Hz,-CONH-),7.69(d,2H,J＝8.0Hz,Ar-H2,Ar-H6),7.21(d,2H,J＝8.0Hz,Ar-H3,Ar-H5),4.59(s,1H,-OH),3.34-3.21(dd,2H,J1＝6.0Hz,J2＝12.4Hz,-CH2OH),3.20-3.15(dd,2H,J1＝7.2Hz,J2＝13.0Hz,-CH2NH-),3.07-3.03(dd,2H,J1＝6.0Hz,J2＝11.8Hz,-CH2NH-),2.30(s,3H,-CH3),2.02(t,2H,J＝7.0Hz,-CH2CO-),1.50-1.43(m,4H,-CH2-,-CH2-),1.26-1.19(m,2H,-CH2-).13C-NMR(100MHz,DMSO-d6,TMS,ppm):172.52,165.65,134.31,131.75,129.79,125.22,61.29,51.79,35.27,29.36,26.70,25.55,21.43.ESI-MS:Calcd for C16H24N2O3[M+H]+293.1787,found 293.1868.。
4-fluoro-N-(6-((2-hydroxyethyl)amino)-6-oxohexyl)benzamide(e12):淡黄色粉末；Yield:51％；mp:131.2-132.9℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ8.43(t,1H,J＝5.6Hz,-ArCONH-),7.88-7.83(m,2H,Ar-H2,Ar-H6),7.73(t,1H,J＝6.0Hz,-CONH-),7.28-7.22(m,2H,Ar-H3,Ar-H5),4.60(t,1H,J＝5.6Hz,-OH),3.35-3.30(dd,2H,J1＝6.0Hz,J2＝12.0Hz,-CH2OH),3.20-3.16(dd,2H,J1＝6.8Hz,J2＝12.8Hz,-CH2NH-),3.07-3.02(dd,2H,J1＝6.0Hz,J2＝12.0Hz,-CH2NH-),2.02(t,2H,J＝7.6Hz,-CH2CO-),1.50-1.43(m,4H,-CH2-,-CH2-),1.26-1.19(m,2H,-CH2-).13C-NMR(100MHz,DMSO-d6,TMS,ppm):172.64,165.46,162.97,130.23,130.14,115.68,60.44,41.85,35.77,29.37,26.65,25.50.ESI-MS:Calcdfor C15H21FN2O3[M+H]+297.1536,found 297.1622.。
4-fluoro-N-(6-((2-hydroxypropyl)amino)-6-oxohexyl)benzamide(e13):淡黄色粉末；Yield:41％；mp:99.3-100.8℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ8.33(t,1H,J＝5.2Hz,-ArCONH-),7.88-7.84(m,2H,Ar-H2,Ar-H6),7.58(t,1H,J＝5.2Hz,-CONH-),7.25-7.20(m,2H,Ar-H3,Ar-H5),4.53-4.49(m,1H,-OH),3.56(s,3H,-CH3),3.29-3.25(dd,2H,J1＝6.8Hz,J2＝12.4Hz,-CH2OH),3.20-3.16(dd,2H,J1＝6.4Hz,J2＝12.0Hz,-CH2NH-),2.96-2.91(dd,2H,J1＝6.0Hz,J2＝12.4Hz,-CH2NH-),2.05(t,2H,J＝6.4Hz,-CH2CO-),1.52-1.45(m,4H,-CH2-,-CH2-),1.27-1.20(m,2H,-CH2-).13C-NMR(100MHz,DMSO-d6,TMS,ppm):172.65,167.34,166.12,129.37,129.82,115.66,68.27,49.30,39.54,36.35,29.81,25.57,25.31,21.01.ESI-MS:Calcd for C16H23FN2O3[M+H]+311.1693,found 311.1736.。
N-(6-((2-hydroxypropyl)amino)-6-oxohexyl)-3-(trifluoromethyl)benzamide(e14):白色粉末；Yield:43％；mp：106.3-108.1℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ8.64(t,1H,J＝5.6Hz,-ArCONH-),7.98(d,2H,J＝8.4Hz,Ar-H4,Ar-H6),7.81(d,2H,J＝8.4Hz,Ar-H2,Ar-H3),7.69(t,1H,J＝6.0Hz,-CONH-),4.63-4.59(t,1H,-OH),3.55(s,3H,-CH3),3.22-3.14(m,4H,-CH2OH,-CH2NH-),2.94-2.89(dd,2H,J1＝6.0Hz,J2＝12.0Hz,-CH2NH-),2.04(t,2H,J＝7.4Hz,-CH2CO-),1.48-1.44(m,4H,-CH2-,-CH2-),1.23-1.16(m,2H,-CH2-).13C-NMR(100MHz,DMSO-d6,TMS,ppm):172.63,167.42,134.53,131.81,130.82,129.32,128.45,123.28,123.37,68.21,49.28,39.50,36.42,29.45,25.36,25.13,21.13.ESI-MS:Calcd for C17H23F3N2O3[M+H]+361.1661,found 361.1696.。
4-bromo-N-(6-((2-hydroxypropyl)amino)-6-oxohexyl)benzamide(e15):淡黄色粉末；Yield:39％；mp:123.5-125.6℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ8.48(t,1H,J＝5.4Hz,-ArCONH-),7.73(d,2H,J＝8.8Hz,Ar-H2,Ar-H6),7.68(t,1H,J＝6.4Hz,-CONH-),7.64-7.62(d,2H,J＝8.8Hz,Ar-H3,Ar-H5),4.62(s,1H,-OH),3.55(s,3H,-CH3),3.19-3.14(dd,2H,J1＝6.4Hz,J2＝12.4Hz,-CH2OH),2.94-2.89(dd,2H,J1＝5.2Hz,J2＝12.0Hz,-CH2NH-),2.84-2.79(dd,2H,J1＝6.4Hz,J2＝12.4Hz,-CH2NH-),2.04(t,2H,J＝7.6Hz,-CH2CO-),1.48-1.44(m,4H,-CH2-,-CH2-),1.25-1.16(m,2H,-CH2-).13C-NMR(100MHz,DMSO-d6,TMS,ppm):172.56,167.35,133.41,131.56,129.76,126.53,68.12,49.42,39.448,36.51,29.81,25.38,25.72,21.01.ESI-MS:Calcd for C16H23BrN2O3[M+H]+371.0892,found371.0926.。
二、体外细胞试验
1)实验材料
细胞株：3种肿瘤细胞株均由兰州大学基础医学院实验中心提供，包括：HeLa(人宫颈癌细胞株)，A549(人非小细胞肺癌细胞株)和Hep-G2(人肝癌细胞株)，WI-38细胞(正常人胚肺成纤维细胞，ATCC细胞库)，所有细胞株均冻存于液氮中。
仪器：超声波清洗器(昆山市超声仪器有限公司)，二氧化碳培养箱(北京五洲东方科技发展有限公司)，无菌过滤器(0.22μm，兰州科恒化玻公司)，96孔板(美国Corning公司)，分析天平(兰州金昱电子衡器)，高压灭菌锅(厦门致微仪器有限公司)，超净工作台(VS-840U，沪净净化)，SIGMA冷冻离心机(北京五洲东方科技发展有限公司)，i-MARK酶标仪(上海拜力科技有限公司)，多种规格移液枪(甘肃瑞德生物有限公司)。
试剂：1640培养基(天津灏洋生物制品)，胎牛血清(Gibco公司)，DMEM高糖培养基，PBS缓冲盐，胰蛋白酶(SIGMA公司产品)，青霉素与链霉素双抗(甘肃RED生物有限公司)，MTT(噻唑蓝，Amresco公司)，二甲基亚砜(SIGMA公司产品)，SAHA(纯度99％，百灵威化学试剂公司)。
2)实验方法及操作步骤
(1)取处于对数期生长的HeLa、A549和Hep-G2肿瘤细胞接种在96孔板中，用细胞计数板计数，调整细胞悬浮液浓度，按照5×103个/mL的浓度每孔加入100μL细胞悬浮液；
(2)空白组只加入100μL不含细胞的培养液，培养箱中37℃培养1-2h至细胞贴壁；
(3)实验组加入按浓度梯度稀释(500、100、20、4、0.8μmol/L)的待测化合物，每个浓度设置三个平行孔，空白对照组不加入化合物，阳性对照组加入相同浓度梯度的SAHA，置于培养箱中37℃培养；
(4)培养48h后每孔加入10μL浓度为5mg/mL的MTT溶液，放置在培养箱37℃中继续培养4h，小心弃去上清液，每孔中加入DMSO 150μL，并充分震荡使甲瓒溶解；
(5)将上述溶液在酶标仪570nm下测定吸光度(OD值)，收集数据后计算出抑制率，最后用SPSS软件计算出IC50的值。
3)实验结果
表1目标化合物对不同细胞株的抑制作用
从表1可以看出，新合成的15种化合物对正常细胞的毒性均小于阳性对照物SAHA，显示出了本发明的化合物对肿瘤细胞一定的选择性；相比于Hep-G2与HeLa，化合物对A549(IC50＝1.68～33.42μM)细胞株有着较强的敏感性，尤其当化合物苯环4位被苯基取代时的e8活性最佳(IC50＝1.68μM)，显示出优于阳性对照物SAHA(IC50＝4.85μM)的抑制活性，同时化合物e2(4-二甲氨基)、e9(萘酸)、e10(3,5-二甲基)、e11(4-甲基)对3种细胞株展示出均衡且较好的活性，当化合物ZBG端羟基的邻位添加甲基集团时(e13、e14、e15)，其化合物的活性并未有多大改变(对比化合物e12与e13、e5与e15)，当帽端基团的体积较大时(e2、e8、e9、e10)，化合物活性总体偏好，由于此类化合物大部分为4位取代，因此不能判别苯环的几位取代活性较好。
由以上内容可知本发明合成的15种苯甲酰胺衍生物均为首次被设计与合成，它们的结构均经过氢谱、碳谱和质谱的确证；本发明的化合物对体外肿瘤增殖抑制实验结果显示：此类化合物对正常细胞的毒性均较SAHA小，显示对肿瘤细胞一定的选择性，特别是对人非小细胞肺癌细胞株A549有着较强的敏感性，为HDACIs的临床前研究提供了一定基础。

Claims (8)

1.一种如式Ⅰ所示苯甲酰胺衍生物类化合物，其中，取代基R1为氢、氟、
氯、溴、碘、甲基、三氟甲基、N,N-二甲氨基或苯基；取代基R2为氢或甲基。
2.权利要求1所述的苯甲酰胺衍生物类化合物的制备方法，其特征在于所述的苯甲酰胺衍生物类化合物通过反应式II所示方法制备：
3.如权利要求2所述的制备方法，其特征在于：所述的合成方法如下：
1)称取6mmol的取代苯甲酸溶于20mL的1,4-二氧六环中，然后加入7.2mmol N-羟基丁二酰亚胺，称取N,N-二环己基碳二亚胺7.2mmol溶于适量1,4-二氧六环，将此溶液缓慢滴加到前述反应液中常温条件下搅拌6h，期间产生浑浊的白色沉淀的二环己基脲，反应结束后抽滤除去白色沉淀，留取滤液待用；
2)称取12mmol的碳酸氢钠溶于适量水中，称取6mmol的6-氨基己酸溶于前述碳酸氢钠溶液中，再在前述的碳酸氢钠溶液中缓慢滴加至Ⅰ步骤中留取的滤液中，50℃下搅拌24h。反应完成后产生少量白色不溶沉淀，抽滤除去沉淀留取滤液，滤液减压蒸除大部分溶剂，剩余物加入水40mL，超声下震摇均匀，用乙酸乙酯洗滤液，水层用浓盐酸酸化至pH＝3，搅拌10分钟后溶液底部产生黄色油状物，后用乙酸乙酯萃取，合并有机层，用无水硫酸钠干燥乙酸乙酯后抽滤，后将乙酸乙酯减压蒸除浓缩，得到粗产物中间体；
3)将上述中间体约5mmol溶于25mL无水四氢呋喃中，称取5mmolNHS溶于前述溶液中，在冰浴条件下搅拌，随后称取5.5mmol的DCC加入反应液，0℃条件下搅拌5min，后于室温条件下搅拌反应6h，期间产生浑浊白色沉淀的DCU，反应结束抽滤除去白色沉淀，滤液减压浓缩，剩余物为产生的活性酯，留取备用；
4)将上一步骤得到的活性酯溶于25mL无水THF中，置于冰浴中，向内滴加5mmol的乙醇胺和5mmol的2-羟基丙胺，滴加完毕于常温下搅拌反应16h，有白色浑浊固体产生，减压除去四氢呋喃，剩余物用无水甲醇溶解，抽滤，不溶部分弃掉，留取滤液，进行柱层析纯化分离得到目标化合物。
4.权利要求1所述的苯甲酰胺衍生物类化合物在制备组蛋白去乙酰化酶抑制药物中的应用。
5.权利要求1所述的苯甲酰胺衍生物类化合物在制备抗肿瘤药物中的应用。
6.权利要求1所述的苯甲酰胺衍生物类化合物在制备抗人非小细胞肺癌药物中的应用。
7.权利要求1所述的苯甲酰胺衍生物类化合物在制备抗人宫颈癌药物中的应用。
8.权利要求1所述的苯甲酰胺衍生物类化合物在制备抗人肝癌药物中的应用。
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2001139534A (ja) * 1999-11-16 2001-05-22 Yoshimitsu Nagao バリン誘導体およびその用途
CN106963752A (zh) * 2017-04-13 2017-07-21 广州赛加生物科技有限公司 一种含有组氨酸去乙酰化酶抑制剂衍生物的抗肿瘤药物

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2001139534A (ja) * 1999-11-16 2001-05-22 Yoshimitsu Nagao バリン誘導体およびその用途
CN106963752A (zh) * 2017-04-13 2017-07-21 广州赛加生物科技有限公司 一种含有组氨酸去乙酰化酶抑制剂衍生物的抗肿瘤药物

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Application publication date: 20180427