CN111116464B - (e)-4-(吡啶甲酰基亚肼基)-n-苯基苯甲酰胺类抗肿瘤化合物 - Google Patents
(e)-4-(吡啶甲酰基亚肼基)-n-苯基苯甲酰胺类抗肿瘤化合物 Download PDFInfo
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- CN111116464B CN111116464B CN202010004480.4A CN202010004480A CN111116464B CN 111116464 B CN111116464 B CN 111116464B CN 202010004480 A CN202010004480 A CN 202010004480A CN 111116464 B CN111116464 B CN 111116464B
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- methyl
- benzamide
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- hydrazono
- nicotinoylhydrazono
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Images
Classifications
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- C—CHEMISTRY; METALLURGY
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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 ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/88—Nicotinoylhydrazones
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
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- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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 ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/86—Hydrazides; Thio or imino analogues thereof
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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 ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/86—Hydrazides; Thio or imino analogues thereof
- C07D213/87—Hydrazides; Thio or imino analogues thereof in position 3
Abstract
Description
技术领域
本发明属于医药技术领域,涉及一类具有抗肿瘤活性的特定化学结构的化合物,具体为具有(E)-4-(吡啶甲酰基亚肼基)-N-苯基苯甲酰胺类抗肿瘤化合物及其制备方法和应用。
背景技术
目前,癌症仍然是对人类健康的严重威胁。癌症的常规治疗方法包括手术,化疗和放疗。其中,化疗作为癌症治疗的主要手段,可以有效地破坏癌细胞,控制肿瘤的扩散和转移,但是由于大多数临床上使用的化疗药物无法准确区分癌细胞和快速分裂的健康细胞,所以仍存在着一些不良反应,如严重的毒副作用和耐药性等。因此,开发具有高选择性、低毒性和克服耐药性的新型抗肿瘤药物仍然是一项重大挑战。
受体酪氨酸激酶(RTKs)在控制细胞生长,分化,迁移和凋亡等途径中起关键作用,通过与其同源配体结合而被激活,导致受体上的酪氨酸残基和下游信号蛋白的磷酸化。在癌细胞中可以发现RTKs过度表达或过度活化。因此,通过抑制多种RTKs的抗肿瘤药物的开发已成为癌症化疗中有效且有前途的方法。到目前为止,许多结构多样的RTKs抑制剂已经通过临床试验得到验证,例如伊马替尼(Imatinib)用于治疗恶性胃肠道间质肿瘤,索拉非尼(Sorafenib)用于治疗胃肠道基质肿瘤和转移性肾细胞癌。根据结构分析,这些药物显示出相似的结构,它们都具有吡啶结构和二苯基酰胺或二苯基脲骨架,如图1所示。此外,N-酰腙支架(-CO-NH-N=CH-)作为一类重要的生物学特性结构在药物化学中得到了广泛的应用,一些N-酰腙衍生物已被强调为潜在的抗癌剂。
本发明根据这两种小分子酪氨酸激酶抑制剂的结构特点,创新性的以N-酰腙支架作为连接片段连接吡啶环与N-苯基苯甲酰胺结构,以期得到抗肿瘤活性更好的全新化合物,现有技术并未见到相关结构的报道。
发明内容
针对上述问题,本发明的目的是提供一种(E)-4-(吡啶甲酰基亚肼基)-N-苯基苯甲酰胺类化合物及其制备方法和应用,此类化合物具有良好抗肿瘤活性,可用于制备抗肿瘤药物。
为实现上述目的,本发明采用以下技术方案。
一种(E)-4-(吡啶甲酰基亚肼基)-N-苯基苯甲酰胺类抗肿瘤化合物,其结构通式I如下:
其中:
X为氮原子时,Y和Z均为碳原子;
Y为氮原子时,X和Z均为碳原子;
Z为氮原子时,X和Y均为碳原子;
苯环上R取代基团可以为氢原子、甲基、甲氧基、氟原子、氯原子、溴原子或4-氯-3-三氟甲基。
所述的(E)-4-(吡啶甲酰基亚肼基)-N-苯基苯甲酰胺类抗肿瘤化合物,其特征在于,所述的通式Ⅰ的化合物为下述任意一种:
(E)-4-((2-异烟酰基亚肼基)甲基)-N-苯基苯甲酰胺(A1);
(E)-4-((2-异烟酰基亚肼基)甲基)-N-(对甲苯基)苯甲酰胺(A2);
(E)-4-((2-异烟酰基亚肼基)甲基)-N-(4-甲氧基苯基)苯甲酰胺(A3);
(E)-N-(4-氟苯基)-4-((2-异烟酰基亚肼基)甲基)苯甲酰胺(A4);
(E)-N-(4-氯苯基)-4-((2-异烟酰基亚肼基)甲基)苯甲酰胺(A5);
(E)-N-(4-溴苯基)-4-((2-异烟酰基亚肼基)甲基)苯甲酰胺(A6);
(E)-N-(4-氯-3-(三氟甲基)苯基)-4-((2-异烟酰基亚肼基)甲基)苯甲酰胺(A7);
(E)-4-((2-烟酰基亚肼基)甲基)-N-苯基苯甲酰胺(B1);
(E)-4-((2-烟酰基亚肼基)甲基)-N-(对甲苯基)苯甲酰胺(B2);
(E)-4-((2-烟酰基亚肼基)甲基)-N-(4-甲氧基苯基)苯甲酰胺(B3);
(E)-N-(4-氟苯基)-4-((2-烟酰基亚肼基)甲基)苯甲酰胺(B4);
(E)-N-(4-氯苯基)-4-((2-烟酰基亚肼基)甲基)苯甲酰胺(B5);
(E)-N-(4-溴苯基)-4-((2-烟酰基亚肼基)甲基)苯甲酰胺(B6);
(E)-N-(4-氯-3-(三氟甲基)苯基)-4-((2-烟酰基亚肼基)甲基)苯甲酰胺(B7);
(E)-N-苯基-4-((2-吡啶甲酰基亚肼基)甲基)苯甲酰胺(C1);
(E)-4-((2-吡啶甲酰基亚肼基)甲基)-N-(对甲苯基)苯甲酰胺(C2);
(E)-N-(4-甲氧基苯基)-4-((2-吡啶甲酰基亚肼基)甲基)苯甲酰胺(C3);
(E)-N-(4-氟苯基)-4-((2-吡啶甲酰基亚肼基)甲基)苯甲酰胺(C4);
(E)-N-(4-氯苯基)-4-((2-吡啶甲酰基亚肼基)甲基)苯甲酰胺(C5);
(E)-N-(4-溴苯基)-4-((2-吡啶甲酰基亚肼基)甲基)苯甲酰胺(C6);
(E)-N-(4-氯-3-(三氟甲基)苯基)-4-((2-吡啶甲酰基亚肼基)甲基)苯甲酰胺(C7);
但不仅限于以上化合物,只要化合物结构满足结构通式,均为本发明的限定范围。
一种(E)-4-(吡啶甲酰基亚肼基)-N-苯基苯甲酰胺类抗肿瘤化合物的制备方法,包括以下步骤。
(1)以对醛基苯甲酸为起始原料,氯仿作溶剂,经氯化亚砜氯化制得4-甲酰基苯甲酰氯。
(2)R取代苯胺与4-甲酰基苯甲酰氯在二氯甲烷作溶剂,三乙胺作缚酸剂条件下反应制得重要中间体4-甲酰基-N-(R取代苯基)苯甲酰胺。
(3)4-甲酰基-N-(R取代苯基)苯甲酰胺与相应的吡啶甲酰肼在乙醇作溶剂,冰醋酸作催化剂条件下回流反应,制得通式I所示的目标化合物。
一种药物组合物包括任一所述的(E)-4-(吡啶甲酰基亚肼基)-N-苯基苯甲酰胺类抗肿瘤化合物、其药学上可接受的盐、水合物或溶剂化物和药学上可接受的载体。
所述的(E)-4-(吡啶甲酰基亚肼基)-N-苯基苯甲酰胺类抗肿瘤化合物或其药学上可接受的盐或其药物组合物在制备治疗抗肿瘤药物中的应用。
所述的抗肿瘤药物为抑制人早幼粒急性白血病细胞HL-60的药物。
本发明还包括本发明化合物的前药。本发明化合物的前药是通式I的衍生物,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。本发明的药用组合物可配制成若干种剂型,所述剂型包括但不限于注射剂、片剂、胶囊剂、散剂等。
与现有技术比,本发明的有益效果如下。
本发明的化合物在体外抗肿瘤活性试验中具有显著效果。为今后的肿瘤药物的深入研究和开发,开辟了新的途径。在合成过程中,简化了合成步骤,优化了反应条件,对未来工业生产提供可能。
附图说明
图1是具有吡啶结构和二苯基酰胺或二苯基脲骨架RTKs抑制剂的化学结构式。
具体实施方式
下面结合附图和实施例,对本发明的具体实施方式作进一步详细描述。以下实施例用于说明本发明,但这些实施例仅为了对本发明加以说明,本发明并不限于这些内容。
实施例1(E)-4-((2-异烟酰基亚肼基)甲基)-N-苯基苯甲酰胺(A1)的制备。
a.4-甲酰基苯甲酰氯的制备。
于250mL反应瓶中加入对醛基苯甲酸(2g,13.32mmol),氯仿(CHCl3)80mL作溶剂,再加入氯化亚砜(SOCl2)(2.38g,19.98mmol)和催化量DMF 5滴,于55℃搅拌反应5小时,薄层色谱监控反应进程。反应完毕后,减压旋蒸除去溶剂得淡黄色油状液体,备用。
b.4-甲酰基-N-苯基苯甲酰胺的制备。
于250mL反应瓶中加入苯胺(1.52g,16.36mmol),二氯甲烷(80mL)作溶剂,再加入三乙胺(2.48g,24.54mmol),于冰浴条件下缓慢滴加上一步骤制得的4-甲酰基苯甲酰氯的二氯甲烷(25mL)溶液,滴加完毕后,室温反应过夜,薄层色谱监控反应进程。反应完毕后,减压旋蒸除去溶剂,加入甲醇(50mL)溶解分散,然后将混合物倾倒入150mL水中并不断搅拌,用37%浓盐酸调节pH至5-7,然后用乙酸乙酯萃取得有机层,无水硫酸钠干燥,减压旋蒸得粗产物,经乙酸乙酯/石油醚重结晶制得4-甲酰基-N-苯基苯甲酰胺,为白色固体。
c.(E)-4-((2-异烟酰基亚肼基)甲基)-N-苯基苯甲酰胺(A1)的制备。
于100mL反应瓶中加入4-吡啶甲酰肼(0.5g,3.65mmol),20mL乙醇作溶剂,再加入4-甲酰基-N-苯基苯甲酰胺(0.82g,3.65mmol)和催化量冰醋酸5滴,于80℃回流反应过夜。反应完毕后,将反应液静置冷却至室温,抽滤得滤饼,用适量乙醇洗涤,干燥得目标化合物,为白色固体,收率:78%。
1H NMR(600MHz,DMSO-d6)δ12.21(s,1H),10.34(s,1H),8.81(dd,J=4.5,1.4Hz,2H),8.55(s,1H),8.06(d,J=8.3Hz,2H),7.91(d,J=8.3Hz,2H),7.85(dd,J=4.5,1.4Hz,2H),7.80(d,J=7.8Hz,2H),7.36(t,J=7.9Hz,2H),7.11(t,J=7.4Hz,1H).13C NMR(150MHz,DMSO-d6)δ165.41,162.30,150.86(2C),148.46,140.84,139.53,137.34,136.69,129.11(2C),128.74(2C),127.61(2C),124.27,122.03(2C),120.92(2C)。
实施例2(E)-4-((2-异烟酰基亚肼基)甲基)-N-(对甲苯基)苯甲酰胺(A2)的制备。
以对醛基苯甲酸为原料,按照实施例1a步骤制得4-甲酰基苯甲酰氯,以对甲基苯胺为原料,按照实施例1b步骤制得4-甲酰基-N-(对甲苯基)苯甲酰胺,以4-吡啶甲酰肼为原料,按照实施例1c步骤制得(E)-4-((2-异烟酰基亚肼基)甲基)-N-(对甲苯基)苯甲酰胺(A2),白色固体,收率:75%。
1H NMR(600MHz,DMSO-d6)δ12.20(s,1H),10.26(s,1H),8.80(dd,J=4.5,1.5Hz,2H),8.54(s,1H),8.04(d,J=8.3Hz,2H),7.90(d,J=8.3Hz,2H),7.84(dd,J=4.5,1.5Hz,2H),7.67(d,J=8.3Hz,2H),7.16(d,J=8.3Hz,2H),2.28(s,3H).13C NMR(150MHz,DMSO-d6)δ165.18,162.29,150.85(2C),148.48,140.84,137.24,137.00,136.77,133.24,129.49(2C),128.68(2C),127.60(2C),122.03(2C),120.94(2C),20.98。
实施例3(E)-4-((2-异烟酰基亚肼基)甲基)-N-(4-甲氧基苯基)苯甲酰胺(A3)的制备。
以对醛基苯甲酸为原料,按照实施例1a步骤制得4-甲酰基苯甲酰氯,以对甲氧基苯胺为原料,按照实施例1b步骤制得4-甲酰基-N-(4-甲氧基苯基)苯甲酰胺,以4-吡啶甲酰肼为原料,按照实施例1c步骤制得((E)-4-((2-异烟酰基亚肼基)甲基)-N-(4-甲氧基苯基)苯甲酰胺(A3),浅黄色固体,收率:84%。
1H NMR(600MHz,DMSO-d6)δ12.20(s,1H),10.22(s,1H),8.80(dd,J=4.5,1.5Hz,2H),8.54(s,1H),8.05(d,J=8.2Hz,2H),7.89(d,J=8.3Hz,2H),7.84(dd,J=4.5,1.5Hz,2H),7.69(d,J=8.9Hz,2H),6.94(d,J=9.0Hz,2H),3.75(s,3H).13C NMR(150MHz,DMSO-d6)δ164.94,162.29,156.12,150.85(2C),148.50,140.85,137.18,136.78,132.58,128.62(2C),127.59(2C),122.53(2C),122.03(2C),114.24(2C),55.66。
实施例4(E)-N-(4-氟苯基)-4-((2-异烟酰基亚肼基)甲基)苯甲酰胺(A4)的制备。
以对醛基苯甲酸为原料,按照实施例1a步骤制得4-甲酰基苯甲酰氯,以4-氟苯胺为原料,按照实施例1b步骤制得N-(4-氟苯基)-4-甲酰基苯甲酰胺,以4-吡啶甲酰肼为原料,按照实施例1c步骤制得((E)-N-(4-氟苯基)-4-((2-异烟酰基亚肼基)甲基)苯甲酰胺(A4),白色固体,收率:82%。
1H NMR(600MHz,DMSO-d6)δ12.21(s,1H),10.40(s,1H),8.80(d,J=5.5Hz,2H),8.54(s,1H),8.05(d,J=8.1Hz,2H),7.90(d,J=8.1Hz,2H),7.85(d,J=5.6Hz,2H),7.81(dd,J=8.7,5.1Hz,2H),7.20(t,J=8.8Hz,2H).13C NMR(150MHz,DMSO-d6)δ165.31,162.31,159.64,158.05,150.84(2C),148.45,140.83,137.39,136.49,135.88(d,J=1.9Hz),128.70(2C),127.62(2C),122.76(d,J=8.0Hz)(2C),122.04(2C),115.67(d,J=22.0Hz)(2C)。
实施例5(E)-N-(4-氯苯基)-4-((2-异烟酰基亚肼基)甲基)苯甲酰胺(A5)的制备。
以对醛基苯甲酸为原料,按照实施例1a步骤制得4-甲酰基苯甲酰氯,以4-氯苯胺为原料,按照实施例1b步骤制得N-(4-氯苯基)-4-甲酰基苯甲酰胺,以4-吡啶甲酰肼为原料,按照实施例1c步骤制得(E)-N-(4-氯苯基)-4-((2-异烟酰基亚肼基)甲基)苯甲酰胺(A5),白色固体,收率:77%。
1H NMR(600MHz,DMSO-d6)δ12.21(s,1H),10.46(s,1H),8.80(dd,J=4.5,1.5Hz,2H),8.54(s,1H),8.05(d,J=8.3Hz,2H),7.91(d,J=8.3Hz,2H),7.85–7.82(m,4H),7.42(d,J=8.8Hz,2H).13C NMR(150MHz,DMSO-d6)δ165.50,162.30,150.85(2C),148.40,140.83,138.51,137.49,136.38,129.03(2C),128.77(2C),127.88,127.64(2C),122.40(2C),122.03(2C)。
实施例6(E)-N-(4-溴苯基)-4-((2-异烟酰基亚肼基)甲基)苯甲酰胺(A6)的制备。
以对醛基苯甲酸为原料,按照实施例1a步骤制得4-甲酰基苯甲酰氯,以4-溴苯胺为原料,按照实施例1b步骤制得N-(4-溴苯基)-4-甲酰基苯甲酰胺,以4-吡啶甲酰肼为原料,按照实施例1c步骤制得(E)-N-(4-溴苯基)-4-((2-异烟酰基亚肼基)甲基)苯甲酰胺(A6),白色固体,收率:83%。
1H NMR(600MHz,DMSO-d6)δ12.21(s,1H),10.46(s,1H),8.80(d,J=5.4Hz,2H),8.54(s,1H),8.05(d,J=8.1Hz,2H),7.90(d,J=8.1Hz,2H),7.84(d,J=5.4Hz,2H),7.78(d,J=8.7Hz,2H),7.55(d,J=8.6Hz,2H).13C NMR(150MHz,DMSO-d6)δ165.51,162.31,150.85(2C),148.41,140.83,138.94,137.50,136.37,131.94(2C),128.77(2C),127.64(2C),122.77(2C),122.03(2C),115.97。
实施例7(E)-N-(4-氯-3-(三氟甲基)苯基)-4-((2-异烟酰基亚肼基)甲基)苯甲酰胺(A7)的制备。
以对醛基苯甲酸为原料,按照实施例1a步骤制得4-甲酰基苯甲酰氯,以4-氯-3-(三氟甲基)苯胺为原料,按照实施例1b步骤制得N-(4-氯-3-(三氟甲基)苯基)-4-甲酰基苯甲酰胺,以4-吡啶甲酰肼为原料,按照实施例1c步骤制得(E)-N-(4-氯-3-(三氟甲基)苯基)-4-((2-异烟酰基亚肼基)甲基)苯甲酰胺(A7),白色固体,收率:76%。
1H NMR(600MHz,DMSO-d6)δ12.22(s,1H),10.71(s,1H),8.80(d,J=5.8Hz,2H),8.54(s,1H),8.37(d,J=2.3Hz,1H),8.12(dd,J=8.7,2.2Hz,1H),8.07(d,J=8.3Hz,2H),7.92(d,J=8.3Hz,2H),7.84(d,J=5.9Hz,2H),7.70(d,J=8.8Hz,1H).13C NMR(150MHz,DMSO-d6)δ165.77,162.30,150.83(2C),148.30,140.79,139.06,137.80,135.78,132.47,128.81(2C),127.68(2C),127.12(d,J=30.7Hz),125.42,124.88,124.15,122.02(2C),119.46(d,J=5.4Hz)。
实施例8(E)-4-((2-烟酰基亚肼基)甲基)-N-苯基苯甲酰胺(B1)的制备。
以对醛基苯甲酸为原料,按照实施例1a步骤制得4-甲酰基苯甲酰氯,以苯胺为原料,按照实施例1b步骤制得4-甲酰基-N-苯基苯甲酰胺,以3-吡啶甲酰肼为原料,按照实施例1c步骤制得(E)-4-((2-烟酰基亚肼基)甲基)-N-苯基苯甲酰胺(B1),白色固体,收率:73%。
1H NMR(600MHz,DMSO-d6)δ12.16(s,1H),10.34(s,1H),9.10(s,1H),8.78(d,J=3.8Hz,1H),8.53(s,1H),8.28(d,J=7.9Hz,1H),8.06(d,J=8.1Hz,2H),7.90(d,J=8.1Hz,2H),7.80(d,J=7.9Hz,2H),7.59(dd,J=7.7,4.9Hz,1H),7.36(t,J=7.8Hz,2H),7.11(t,J=7.3Hz,1H).13C NMR(150MHz,DMSO-d6)δ165.42,162.38,152.87,149.11,147.87,139.54,137.45,136.59,136.00,129.57,129.10(2C),128.72(2C),127.54(2C),124.26,124.12,120.93(2C)。
实施例9(E)-4-((2-烟酰基亚肼基)甲基)-N-(对甲苯基)苯甲酰胺(B2)的制备。
以对醛基苯甲酸为原料,按照实施例1a步骤制得4-甲酰基苯甲酰氯,以对甲基苯胺为原料,按照实施例1b步骤制得4-甲酰基-N-(对甲苯基)苯甲酰胺,以3-吡啶甲酰肼为原料,按照实施例1c步骤制得(E)-4-((2-烟酰基亚肼基)甲基)-N-(对甲苯基)苯甲酰胺(B2),白色固体,收率:71%。
1H NMR(600MHz,DMSO-d6)δ12.16(s,1H),10.26(s,1H),9.09(d,J=1.4Hz,1H),8.78(dd,J=4.7,1.1Hz,1H),8.52(s,1H),8.28(d,J=7.9Hz,1H),8.04(d,J=8.2Hz,2H),7.89(d,J=8.2Hz,2H),7.67(d,J=8.2Hz,2H),7.59(dd,J=7.7,4.9Hz,1H),7.16(d,J=8.2Hz,2H),2.28(s,3H).13C NMR(150MHz,DMSO-d6)δ165.19,162.35,152.87,149.11,147.88,137.36,137.01,136.66,135.99,133.22,129.58,129.49(2C),128.67(2C),127.52(2C),124.12,120.93(2C),20.98。
实施例10(E)-4-((2-烟酰基亚肼基)甲基)-N-(4-甲氧基苯基)苯甲酰胺(B3)的制备。
以对醛基苯甲酸为原料,按照实施例1a步骤制得4-甲酰基苯甲酰氯,以对甲氧基苯胺为原料,按照实施例1b步骤制得4-甲酰基-N-(对甲氧苯基)苯甲酰胺,以3-吡啶甲酰肼为原料,按照实施例1c步骤制得(E)-4-((2-烟酰基亚肼基)甲基)-N-(4-甲氧基苯基)苯甲酰胺(B3),浅黄色固体,收率:79%。
1H NMR(600MHz,DMSO-d6)δ12.15(s,1H),10.23(s,1H),9.10(s,1H),8.78(d,J=3.8Hz,1H),8.52(s,1H),8.28(d,J=7.9Hz,1H),8.05(d,J=8.1Hz,2H),7.89(d,J=8.1Hz,2H),7.70(d,J=8.8Hz,2H),7.58(dd,J=7.7,4.9Hz,1H),6.94(d,J=8.9Hz,2H),3.75(s,3H).13C NMR(150MHz,DMSO-d6)δ164.96,162.37,156.12,152.86,149.12,147.91,137.30,136.68,135.99,132.59,129.58,128.61(2C),127.52(2C),124.10,122.54(2C),114.24(2C),55.65。
实施例11(E)-N-(4-氟苯基)-4-((2-烟酰基亚肼基)甲基)苯甲酰胺(B4)的制备。
以对醛基苯甲酸为原料,按照实施例1a步骤制得4-甲酰基苯甲酰氯,以4-氟苯胺为原料,按照实施例1b步骤制得N-(4-氟苯基)-4-甲酰基苯甲酰胺,以3-吡啶甲酰肼为原料,按照实施例1c步骤制得(E)-N-(4-氟苯基)-4-((2-烟酰基亚肼基)甲基)苯甲酰胺(B4),白色固体,收率:84%。
1H NMR(600MHz,DMSO-d6)δ12.16(s,1H),10.40(s,1H),9.10(d,J=1.5Hz,1H),8.78(dd,J=4.7,1.2Hz,1H),8.52(s,1H),8.28(d,J=7.9Hz,1H),8.05(d,J=8.2Hz,2H),7.90(d,J=8.2Hz,2H),7.81(dd,J=8.9,5.0Hz,2H),7.58(dd,J=7.7,4.9Hz,1H),7.20(t,J=8.8Hz,2H).13C NMR(150MHz,DMSO-d6)δ165.32,162.37,159.63,158.04,152.87,149.12,147.84,137.51,136.39,135.99,135.90,129.57,128.69(2C),127.55(2C),124.10,122.75(d,J=7.8Hz),115.68(d,J=22.4Hz)(2C)。
实施例12(E)-N-(4-氯苯基)-4-((2-烟酰基亚肼基)甲基)苯甲酰胺(B5)的制备。
以对醛基苯甲酸为原料,按照实施例1a步骤制得4-甲酰基苯甲酰氯,以4-氯苯胺为原料,按照实施例1b步骤制得N-(4-氯苯基)-4-甲酰基苯甲酰胺,以3-吡啶甲酰肼为原料,按照实施例1c步骤制得(E)-N-(4-氯苯基)-4-((2-烟酰基亚肼基)甲基)苯甲酰胺(B5),白色固体,收率:78%。
1H NMR(600MHz,DMSO-d6)δ12.17(s,1H),10.46(s,1H),9.10(d,J=1.2Hz,1H),8.78(d,J=3.7Hz,1H),8.52(s,1H),8.28(d,J=7.9Hz,1H),8.05(d,J=8.2Hz,2H),7.90(d,J=8.2Hz,2H),7.84(d,J=8.8Hz,2H),7.58(dd,J=7.7,4.9Hz,1H),7.42(d,J=8.7Hz,2H).13C NMR(150MHz,DMSO-d6)δ165.50,162.37,152.87,149.12,147.81,138.53,137.60,136.27,135.99,129.56,129.01(2C),128.75(2C),127.87,127.56(2C),124.10,122.40(2C)。
实施例13(E)-N-(4-溴苯基)-4-((2-烟酰基亚肼基)甲基)苯甲酰胺(B6)的制备。
以对醛基苯甲酸为原料,按照实施例1a步骤制得4-甲酰基苯甲酰氯,以4-溴苯胺为原料,按照实施例1b步骤制得N-(4-溴氯苯基)-4-甲酰基苯甲酰胺,以3-吡啶甲酰肼为原料,按照实施例1c步骤制得(E)-N-(4-溴苯基)-4-((2-烟酰基亚肼基)甲基)苯甲酰胺(B6),白色固体,收率:81%。
1H NMR(600MHz,DMSO-d6)δ12.15(s,1H),10.46(s,1H),9.09(d,J=1.4Hz,1H),8.78(dd,J=4.6,1.1Hz,1H),8.52(s,1H),8.28(d,J=7.9Hz,1H),8.04(d,J=8.2Hz,2H),7.90(d,J=8.2Hz,2H),7.78(d,J=8.8Hz,2H),7.58(dd,J=7.7,4.9Hz,1H),7.55(d,J=8.7Hz,2H).13C NMR(150MHz,DMSO-d6)δ165.52,162.38,152.88,149.11,147.82,138.94,137.61,136.26,136.00,131.93(2C),129.56,128.75(2C),127.56(2C),124.11,122.77(2C),115.96。
实施例14(E)-N-(4-氯-3-(三氟甲基)苯基)-4-((2-烟酰基亚肼基)甲基)苯甲酰胺(B7)的制备。
以对醛基苯甲酸为原料,按照实施例1a步骤制得4-甲酰基苯甲酰氯,以4-氯-3-(三氟甲基)苯胺为原料,按照实施例1b步骤制得N-(4-氯-3-(三氟甲基)苯基)-4-甲酰基苯甲酰胺,以3-吡啶甲酰肼为原料,按照实施例1c步骤制得(E)-N-(4-氯-3-(三氟甲基)苯基)-4-((2-烟酰基亚肼基)甲基)苯甲酰胺(B7),白色固体,收率:70%。
1H NMR(600MHz,DMSO-d6)δ12.17(s,1H),10.71(s,1H),9.09(d,J=1.2Hz,1H),8.78(d,J=3.7Hz,1H),8.52(s,1H),8.37(d,J=2.0Hz,1H),8.28(d,J=7.9Hz,1H),8.13(dd,J=8.7,1.8Hz,1H),8.07(d,J=8.2Hz,2H),7.92(d,J=8.2Hz,2H),7.71(d,J=8.8Hz,1H),7.58(dd,J=7.7,4.9Hz,1H).13C NMR(150MHz,DMSO-d6)δ165.80,162.37,152.88,149.11,147.71,139.07,137.92,135.99,135.69,132.49,129.54,128.81(2C),127.61(2C),127.12(d,J=30.6Hz),125.44,124.87,124.10,122.35,119.47(d,J=5.3Hz)。
实施例15(E)-N-苯基-4-((2-吡啶甲酰基亚肼基)甲基)苯甲酰胺(C1)的制备。
以对醛基苯甲酸为原料,按照实施例1a步骤制得4-甲酰基苯甲酰氯,以苯胺为原料,按照实施例1b步骤制得4-甲酰基-N-苯基苯甲酰胺,以2-吡啶甲酰肼为原料,按照实施例1c步骤制得(E)-N-苯基-4-((2-吡啶甲酰基亚肼基)甲基)苯甲酰胺(C1),白色固体,收率:86%。
1H NMR(600MHz,DMSO-d6)δ12.30(s,1H),10.34(s,1H),8.74(s,1H),8.72(d,J=4.4Hz,1H),8.16(d,J=7.8Hz,1H),8.08–8.04(m,3H),7.87(d,J=8.2Hz,2H),7.80(d,J=7.9Hz,2H),7.67(dd,J=6.9,5.2Hz,1H),7.36(t,J=7.8Hz,2H),7.11(t,J=7.3Hz,1H).13CNMR(150MHz,DMSO-d6)δ165.42,161.08,149.92,149.00,148.65,139.55,138.52,137.69,136.48,129.09(2C),128.73(2C),127.58,127.50(2C),124.25,123.26,120.95(2C)。
实施例16(E)-4-((2-吡啶甲酰基亚肼基)甲基)-N-(对甲苯基)苯甲酰胺(C2)的制备。
以对醛基苯甲酸为原料,按照实施例1a步骤制得4-甲酰基苯甲酰氯,以对甲基苯胺为原料,按照实施例1b步骤制得4-甲酰基-N-(对甲苯基)苯甲酰胺,以2-吡啶甲酰肼为原料,按照实施例1c步骤制得(E)-4-((2-吡啶甲酰基亚肼基)甲基)-N-(对甲苯基)苯甲酰胺(C2),白色固体,收率:76%。
1H NMR(600MHz,DMSO-d6)δ12.29(s,1H),10.26(s,1H),8.73(d,J=6.1Hz,2H),8.16(d,J=7.7Hz,1H),8.06(dd,J=18.8,4.7Hz,3H),7.86(d,J=8.2Hz,2H),7.68(t,J=6.7Hz,3H),7.16(d,J=8.2Hz,2H),2.28(s,3H).13C NMR(150MHz,DMSO-d6)δ165.19,161.06,149.94,149.00,148.65,138.53,137.59,137.02,136.55,133.21,129.49(2C),128.67(2C),127.58,127.48(2C),123.26,120.95(2C),20.98。
实施例17(E)-N-(4-甲氧基苯基)-4-((2-吡啶甲酰基亚肼基)甲基)苯甲酰胺(C3)的制备。
以对醛基苯甲酸为原料,按照实施例1a步骤制得4-甲酰基苯甲酰氯,以对甲氧基苯胺为原料,按照实施例1b步骤制得4-甲酰基-N-(4-甲氧基苯基)苯甲酰胺,以2-吡啶甲酰肼为原料,按照实施例1c步骤制得(E)-N-(4-甲氧基苯基)-4-((2-吡啶甲酰基亚肼基)甲基)苯甲酰胺(C3),浅黄色固体,收率:71%。
1H NMR(600MHz,DMSO-d6)δ12.29(s,1H),10.22(s,1H),8.73(dt,J=4.6,1.8Hz,2H),8.15(dt,J=7.9,1.0Hz,1H),8.06(ddd,J=12.8,9.4,5.0Hz,3H),7.85(d,J=8.4Hz,2H),7.71–7.67(m,3H),6.96–6.94(m,1H),6.94–6.92(m,1H),3.75(s,3H).13C NMR(150MHz,DMSO-d6)δ164.95,161.05,156.11,149.94,149.01,148.66,138.54,137.52,136.56,132.60,128.62(2C),127.59,127.47(2C),123.26,122.53(2C),114.24(2C),55.66。
实施例18(E)-N-(4-氟苯基)-4-((2-吡啶甲酰基亚肼基)甲基)苯甲酰胺(C4)的制备。
以对醛基苯甲酸为原料,按照实施例1a步骤制得4-甲酰基苯甲酰氯,以4-氟苯胺为原料,按照实施例1b步骤制得N-(4-氟苯基)-4-甲酰基苯甲酰胺,以2-吡啶甲酰肼为原料,按照实施例1c步骤制得(E)-N-(4-氟苯基)-4-((2-吡啶甲酰基亚肼基)甲基)苯甲酰胺(C4),白色固体,收率:85%。
1H NMR(600MHz,DMSO-d6)δ12.29(s,1H),10.39(s,1H),8.75–8.71(m,2H),8.16(d,J=7.8Hz,1H),8.08–8.04(m,3H),7.87(d,J=8.3Hz,2H),7.83–7.80(m,2H),7.70–7.66(m,1H),7.20(t,J=8.9Hz,2H).13C NMR(150MHz,DMSO-d6)δ165.32,161.07,159.63,158.04,149.92,149.00,148.62,138.52,137.74,136.28,135.90(d,J=2.4Hz),128.70(2C),127.54(d,J=10.7Hz)(2C),123.26,122.76(d,J=7.8Hz)(2C),115.67(d,J=22.0Hz)(2C)。
实施例19(E)-N-(4-氯苯基)-4-((2-吡啶甲酰基亚肼基)甲基)苯甲酰胺(C5)的制备。
以对醛基苯甲酸为原料,按照实施例1a步骤制得4-甲酰基苯甲酰氯,以4-氯苯胺为原料,按照实施例1b步骤制得N-(4-氯苯基)-4-甲酰基苯甲酰胺,以2-吡啶甲酰肼为原料,按照实施例1c步骤制得(E)-N-(4-氯苯基)-4-((2-吡啶甲酰基亚肼基)甲基)苯甲酰胺(C5),白色固体,收率:81%。
1H NMR(600MHz,DMSO-d6)δ12.30(s,1H),10.46(s,1H),8.73(d,J=5.8Hz,2H),8.15(d,J=7.8Hz,1H),8.09–8.03(m,3H),7.87(d,J=8.3Hz,2H),7.84(d,J=8.8Hz,2H),7.68(dd,J=7.1,5.1Hz,1H),7.42(d,J=8.8Hz,2H).13C NMR(150MHz,DMSO-d6)δ165.50,161.07,149.92,149.01,148.57,138.53,137.84,136.16,129.02(2C),128.76(2C),127.86,127.59,127.52(2C),123.27,122.41(2C)。
实施例20(E)-N-(4-溴苯基)-4-((2-吡啶甲酰基亚肼基)甲基)苯甲酰胺(C6)的制备。
以对醛基苯甲酸为原料,按照实施例1a步骤制得4-甲酰基苯甲酰氯,以4-溴苯胺为原料,按照实施例1b步骤制得N-(4-溴苯基)-4-甲酰基苯甲酰胺,以2-吡啶甲酰肼为原料,按照实施例1c步骤制得(E)-N-(4-溴苯基)-4-((2-吡啶甲酰基亚肼基)甲基)苯甲酰胺(C6),白色固体,收率:79%。
1H NMR(600MHz,DMSO)δ12.30(s,1H),10.45(s,1H),8.74–8.72(m,2H),8.15(d,J=7.8Hz,1H),8.08–8.04(m,3H),7.87(d,J=8.3Hz,2H),7.78(d,J=8.9Hz,2H),7.68(ddd,J=7.5,4.7,1.1Hz,1H),7.55(d,J=8.8Hz,2H).13C NMR(150MHz,DMSO-d6)δ165.52,161.07,149.92,149.01,148.57,138.96,138.54,137.85,136.15,131.94(2C),128.77(2C),127.60,127.52(2C),123.27,122.78(2C),115.95。
实施例21(E)-N-(4-氯-3-(三氟甲基)苯基)-4-((2-吡啶甲酰基亚肼基)甲基)苯甲酰胺(C7)的制备。
以对醛基苯甲酸为原料,按照实施例1a步骤制得4-甲酰基苯甲酰氯,以4-氯-3-(三氟甲基)苯胺为原料,按照实施例1b步骤制得N-(4-氯-3-(三氟甲基)苯基)-4-甲酰基苯甲酰胺,以2-吡啶甲酰肼为原料,按照实施例1c步骤制得(E)-N-(4-氯-3-(三氟甲基)苯基)-4-((2-吡啶甲酰基亚肼基)甲基)苯甲酰胺(C7),白色固体,收率:72%。
1H NMR(600MHz,DMSO-d6)δ12.30(s,1H),10.71(s,1H),8.75–8.71(m,2H),8.37(d,J=2.4Hz,1H),8.16–8.11(m,2H),8.08–8.04(m,3H),7.88(d,J=8.4Hz,2H),7.72–7.66(m,2H).13C NMR(150MHz,DMSO-d6)δ165.78,161.07,149.90,148.98,148.48,139.08,138.50,138.15,135.56,132.46,128.81(2C),127.56(2C),127.11(d,J=30.6Hz),125.43,124.86,124.15,123.26,122.34,119.48(q,J=5.4Hz)。
实施例22抑制肿瘤细胞增殖实验。
对本发明的化合物进行了肿瘤细胞增殖抑制实验,试验方法采用常规的MTT法。
肿瘤细胞的培养:细胞株选用HL-60(人早幼粒急性白血病细胞)以RPMI1640+10%FBS+双抗(青霉素100单位/mL,链霉素100μg/mL)的培养液培养。
样品配制:用DMSO(Merck)溶解后,加入PBS(-)配成1000μg/mL的溶液或均匀的混悬液,然后用含DMSO的PBS(-)稀释。最终浓度分别为:5μM、1μM、0.5μM、0.25μM、0.05μM。以伊马替尼(Imatinib)作为对照。
细胞增殖抑制的测试方法:96孔板每孔加入浓度为4~5×104个/mL的细胞悬液100μL,置37℃,5%CO2培养箱内。24小时后,分别加入样品液和对照品液,10μL/孔,设双复孔,37℃,5%CO2作用24小时。每孔加入5mg/mL的MTT(3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四唑翁溴化物)溶液15μL,作用4小时后加入溶解液DMSO,100μL/孔,置培养箱内,溶解后用MK-2全自动酶标仪测490nm OD值,计算抑制率。
实验结果见表1。
表1.样品对人体肿瘤细胞的体外增殖抑制活性IC50值
以上实验数据显示,本发明中(E)-4-(吡啶甲酰基亚肼基)-N-苯基苯甲酰胺类抗肿瘤化合物具有较好的体外抗肿瘤活性,对人早幼粒急性白血病细胞HL-60的增殖抑制活性明显,因而为深入研究和开发新的抗肿瘤药物开辟了新的途径。
Claims (5)
1.一种(E)-4 - (吡啶甲酰基亚肼基)甲基)-N-取代苯基苯甲酰胺类抗肿瘤化合物,其特征在于,所述的化合物为下述任意一种:
(E)-4 - ((2-异烟酰基亚肼基)甲基)-N-苯基苯甲酰胺;
(E)-4 - ((2-异烟酰基亚肼基)甲基)-N-(对甲苯基)苯甲酰胺;
(E)-4 - ((2-异烟酰基亚肼基)甲基)-N-(4-甲氧基苯基)苯甲酰胺;
(E)-N-(4-氟苯基)-4 - ((2-异烟酰基亚肼基)甲基)苯甲酰胺;
(E)-N-(4-氯苯基)-4 - ((2-异烟酰基亚肼基)甲基)苯甲酰胺;
(E)-N-(4-溴苯基)-4 - ((2-异烟酰基亚肼基)甲基)苯甲酰胺;
(E)-N-(4-氯-3-(三氟甲基)苯基)-4 - ((2-异烟酰基亚肼基)甲基)苯甲酰胺;
(E)-4 - ((2-烟酰基亚肼基)甲基)-N-苯基苯甲酰胺;
(E)-4 - ((2-烟酰基亚肼基)甲基)-N-(对甲苯基)苯甲酰胺;
(E)-4 - ((2-烟酰基亚肼基)甲基)-N-(4-甲氧基苯基)苯甲酰胺;
(E)-N-(4-氟苯基)-4 - ((2-烟酰基亚肼基)甲基)苯甲酰胺;
(E)-N-(4-氯苯基)-4 - ((2-烟酰基亚肼基)甲基)苯甲酰胺;
(E)-N-(4-溴苯基)-4 - ((2-烟酰基亚肼基)甲基)苯甲酰胺;
(E)-N-(4-氯-3-(三氟甲基)苯基)-4 - ((2-烟酰基亚肼基)甲基)苯甲酰胺;
(E)-4 - ((2-吡啶甲酰基亚肼基)甲基)-N-(对甲苯基)苯甲酰胺;
(E)-N-(4-氯苯基)-4 - ((2-吡啶甲酰基亚肼基)甲基)苯甲酰胺;
(E)-N-(4-溴苯基)-4 - ((2-吡啶甲酰基亚肼基)甲基)苯甲酰胺;
(E)-N-(4-氯-3-(三氟甲基)苯基)-4 - ((2-吡啶甲酰基亚肼基)甲基)苯甲酰胺。
2.如权利要求1所述的抗肿瘤化合物的制备方法,其特征在于,所述化合物的制备方法具体包括以下步骤:
(1)以对醛基苯甲酸为起始原料,氯仿作溶剂,经氯化亚砜氯化制得4-甲酰基苯甲酰氯;
(2)取代苯胺与4-甲酰基苯甲酰氯在二氯甲烷作溶剂,三乙胺作缚酸剂条件下反应制得中间体4-甲酰基-N-(取代苯基)苯甲酰胺;
(3)4-甲酰基-N-(取代苯基)苯甲酰胺与相应的吡啶甲酰肼在乙醇作溶剂,冰醋酸催化条件下回流反应,制得如权利要求1所述的抗肿瘤化合物。
3.一种药物组合物,其特征在于,包括权利要求1中所述任意一种抗肿瘤化合物、其药学上可接受的盐及药学上可接受的载体。
4.如权利要求1所述的抗肿瘤化合物、其药学上可接受的盐或权利要求3所述的药物组合物在制备抗肿瘤药物中的应用。
5.如权利要求4所述的应用,其特征在于,所述的抗肿瘤药物为抑制人早幼粒急性白血病细胞HL-60的药物。
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