CN101161645B - 尿素类衍生物及其制备方法与用途 - Google Patents
尿素类衍生物及其制备方法与用途 Download PDFInfo
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- CN101161645B CN101161645B CN2007101906297A CN200710190629A CN101161645B CN 101161645 B CN101161645 B CN 101161645B CN 2007101906297 A CN2007101906297 A CN 2007101906297A CN 200710190629 A CN200710190629 A CN 200710190629A CN 101161645 B CN101161645 B CN 101161645B
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- Prior art keywords
- urea
- dimethyl
- nitrobenzyl
- hydroxybenzyl
- morpholine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 238000002360 preparation method Methods 0.000 title claims abstract description 58
- 150000003672 ureas Chemical class 0.000 title claims abstract description 22
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 3
- 229940041181 antineoplastic drug Drugs 0.000 claims abstract description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 38
- 239000004202 carbamide Substances 0.000 claims description 28
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 27
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 22
- -1 3-nitrobenzyl Chemical group 0.000 claims description 14
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 11
- 239000012074 organic phase Substances 0.000 claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- 238000003756 stirring Methods 0.000 claims description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 7
- 238000006243 chemical reaction Methods 0.000 claims description 5
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- ANDJOBJHEHVUKB-UHFFFAOYSA-N 1-(furan-2-ylmethyl)-1-[(2-hydroxy-5-nitrophenyl)methyl]-3,3-dimethylurea Chemical compound C=1C([N+]([O-])=O)=CC=C(O)C=1CN(C(=O)N(C)C)CC1=CC=CO1 ANDJOBJHEHVUKB-UHFFFAOYSA-N 0.000 claims 1
- GXJZGLXREOODLH-UHFFFAOYSA-N 1-(furan-2-ylmethyl)-1-[(4-hydroxyphenyl)methyl]-3,3-dimethylurea Chemical compound C=1C=C(O)C=CC=1CN(C(=O)N(C)C)CC1=CC=CO1 GXJZGLXREOODLH-UHFFFAOYSA-N 0.000 claims 1
- KLNOCAATAUQTIH-UHFFFAOYSA-N 1-(furan-2-ylmethyl)-3,3-dimethyl-1-[(3-nitrophenyl)methyl]urea Chemical compound C=1C=CC([N+]([O-])=O)=CC=1CN(C(=O)N(C)C)CC1=CC=CO1 KLNOCAATAUQTIH-UHFFFAOYSA-N 0.000 claims 1
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- FFFVUIKFTZTONI-UHFFFAOYSA-N ethyl 4-[dimethylcarbamoyl-[(4-nitrophenyl)methyl]amino]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OCC)CCC1N(C(=O)N(C)C)CC1=CC=C([N+]([O-])=O)C=C1 FFFVUIKFTZTONI-UHFFFAOYSA-N 0.000 claims 1
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Abstract
Description
技术领域
本发明涉及尿素类衍生物及其制备方法与用途。
背景技术
N-取代尿素类衍生物是一类用途广泛的化合物,由于结构中含有不同取代的酰胺键,且非对称单元是许多酶抑制剂和生物模拟肽的常见结构特征,故多数具有生物活性(参见:P.E.Sum,P.Petersen,Bioorg.Med.Chem.Lett.1999,9,1459.)。在农药上应用广泛,其中许多可用作除草剂、杀虫剂、杀菌剂和植物生长调节剂等,在医药、生物领域中也具有举足轻重的地位,有些是重要中间体,有些非对称取代化合物还可以在手性拆分色谱柱中用作CSP(手性固定相),在手性分析化学称为:尿素型固定相。这种优良的活性越来越引起广大化学家的重视。因此,取代尿素类化合物具有广泛的应用前景。
自60年前发现尿素类化合物具有一定的生物活性后,人们就将其作为一种具有开发潜力的生物靶标,开展合理分子设计以及从天然生物活性物质中寻找更高或更广谱的生物活性、更高的选择性、更低的毒性、更长或更短的残效期等,即开发出具有广阔前景且对人类、生态更安全的新型尿素类化合物(参见:刘长令.农药.1998,37,1)。
尿素类衍生物作为医药具有一定的活性,有很好的前景;同时由于其能抑制杂草种子的光合成,表现出极好的除草效果,且对温血动物完全无害,可将取代尿素类衍生物作为一个具有潜在活性的结构(先导结构)加以研究。对此进行深入研究具有一定的理论和实际价值,尤其是在合成系列新型取代尿素类衍生物的基础上对它们的生物活性进行系统的研究具有十分重要的意义。
发明内容
本发明的目的在于提供一类新尿素类衍生物以及它们的制备方法与用途。
本发明的技术方案如下:
一类尿素类衍生物,其特征是它有如下通式:
式中:R1为:
一种上述的尿素类衍生物的制法,它由下列步骤组成:
步骤1.于无水CH2Cl2溶液中,加入无水二甲基甲酰胺和SOCl2,二甲基甲酰胺与SOCl2的物质的量之比为1∶2~1∶2.5,搅拌加热至70-80℃,反应4-5个小时后冷却,减压蒸干,蒸去多余的SOCl2,得到ClCON(CH3)2,
步骤2.将吡啶和与二甲基甲酰胺等物质的量的R1NHR2溶于无水CH2Cl2中配成溶液,
步骤3.在步骤1得到的ClCON(CH3)2加入无水CH2Cl2,逐滴加入步骤2配制的溶液,搅拌加热至50-60℃,反应5-6小时后,将反应混合物倒入冰水中,分离出有机相,水相加乙酸乙酯萃取,合并有机相,用饱和碳酸氢钠和水分别洗涤有机相,用无水NaSO4干燥有机相,减压蒸去部分溶剂,得到粘稠油状浓缩液,
步骤4.将步骤3得到的粘稠油状浓缩液用丙酮或乙酸乙酯稀释,层析(石油醚∶乙酸乙酯=2∶1-1∶2)得到本发明的尿素类衍生物。
上述的制法,所述的步骤1中,CH2Cl2的用量为每摩尔二甲基甲酰胺加350-400ml。
上述的制法,所述的步骤2中,吡啶和CH2Cl2的用量为每摩尔二甲基甲酰胺加吡啶100-120ml,加CH2Cl2230-280ml。
上述的制法,所述的步骤3中,CH2Cl2的用量为每摩尔二甲基甲酰胺加350-400ml。
本发明的尿素类衍生物对人白血病细胞(K562)和人体口腔上表皮癌细胞(KB)有明显的抑制作用,因此本发明的尿素类衍生物可以应用于制备抗肿瘤药物。
具体实施方式
实施例一:N,N-二甲基-N’-(3-吗啉丙基)-N’-(3-硝基苄基)脲(化合物1)的制备
于50ml单口圆底烧瓶中加入25ml无水乙醇,选用间硝基苯甲醛(20mmol)和N-(3-氨基丙基)吗啉(20mmol)。搅拌反应约1个小时后在瓶中分批加入硼氢化钠(1.6g,0.05mol),搅拌加热至约50℃,反应2-3小时后,取下。减压蒸干,旋去多余的溶剂乙醇。加入30ml乙酸乙酯溶解瓶中油状物,水洗两次,每次约20ml,分离出有机相,合并,无水NaSO4干燥半小时,减压旋去溶剂,得到粘稠油状浓缩液。以丙酮稀释,板层析(石油醚∶乙酸乙酯=1∶1-1∶3)得到N-(3-硝基苄基)-3-吗啉基-丙胺。
于50ml单口圆底烧瓶中加入15ml无水CH2Cl2,1.5ml无水DMF(20mmol)和7mlSOCl2(0.10mol)。搅拌加热至70℃;回流反应约4个小时后冷却,减压蒸干,蒸去多余的SOCl2。继而在瓶中加入15ml无水CH2Cl2,将3ml吡啶和20mmol量的N-(3-吗啉)-N-(3-硝基苄基)丙胺溶于10ml无水CH2Cl2中的溶液逐滴加入。搅拌加热至50-60℃,反应5-6小时后,取下。将反应液倒入20ml的冰水中,分离出有机相,水相加乙酸乙酯萃取三次,合并有机相,用饱和碳酸氢钠和水分别洗两次,无水NaSO4干燥半小时,减压旋去部分溶剂,得到粘稠油状浓缩液。以丙酮或乙酸乙酯稀释,板层析(石油醚∶乙酸乙酯=2∶1-1∶2)得到黄色粉末状目标化合物。产率51%。Mp 121-122℃.1H-NMR(500MHz,DMSO-d6,δppm):1.77(m,2H);2.83(s,6H);3.20(t,J=5.2,2H);3.26(t,J=4.5,4H);3.44(t,J=4.3,2H);3.52(t,J=4.1,4H);4.23(s,2H);7.72(t,J=7.8,1H);8.14(d,J=7.5,1H);8.27(d,J=8.0,1H);8.48(s,1H).MS(ESI):350.2([M+H]+).Anal.calc.for C17H26N4O4:C 58.27,H 7.48,N 15.99%;found:C 58.34,H 7.35,N 15.30%.
实施例二:N,N-二甲基-N’-(2-吗啉乙基)-N’-(3-硝基苄基)脲(化合物2)的制备
制备方法同实施例一。以N-(3-氨基乙基)吗啉代替N-(3-氨基丙基)吗啉,得到黄色粉末状目标化合物。产率48%。Mp 124-126℃.1H-NMR(500MHz,DMSO-d6,δppm):2.61(s,6H);2.82(t,J=5.6,2H);3.21(t,J=4.2,4H);3.24(t,J=4.6,2H);3.50(t,J=4.7,4H);4.28(s,2H);7.73(t,J=7.9,1H);8.14(d,J=7.5,1H);8.28(d,J=7.0,1H);8.50(s,1H).MS(ESI):336.18([M+H]+).Anal.calc.for C16H24N4O4:C 57.13,H 7.19,N 16.66%;found:C 57.24,H 7.08,N 16.62%.
实施例三:N,N-二甲基-N’-(2-呋喃甲基)-N’-(3-硝基苄基)脲(化合物3)的制备
制备方法同实施例一。以糠胺代替N-(3-氨基丙基)吗啉,得到黄色粉末状目标化合物。产率48%。Mp 121-122℃.1H-NMR(500MHz,DMSO-d6,δppm):2.91(s,6H);4.25(s,2H);4.84(s,2H);6.27(d,J=2.4,1H);6.42(t,J=1.8,1H);7.51(d,J=2.6,1H);7.59(t,J=7.8,1H);8.11(d,J=7.6,1H);8.28(d,J=7.5,1H);8.39(s,1H).MS(ESI):303.1([M+H]+).Anal.calc.for C15H17N3O4:C 59.40,H 5.65,N 13.85%;found:C 59.60,H 5.82,N13.68%.
实施例四:N,N-二甲基-N’-(3-硝基苄基)-N’-(1-乙氧羰基-4-哌啶基)脲(化合物4)的制备
制备方法同实施例一。以(1-乙氧羰基-4-哌啶基)胺代替N-(3-氨基丙基)吗啉,得到黄色油状目标化合物。产率44%。1H-NMR(500MHz,DMSO-d6,δppm):1.26(t,J=3.7,3H);1.74(m,4H);2.85(s,6H);3.18(m,4H);3.49(m,1H);4.15(q,J=7.0,2H);4.26(s,2H);7.75(t,J=7.8,1H);8.12(d,J=7.8,1H);8.26(d,J=7.5,1H);8.52(s,1H).MS(ESI):378.2([M+H]+).Anal.calc.for C18H26N4O5:C 57.13,H 6.93,N 14.81%;found:C57.42,H 6.86,N 14.73%.
实施例五:N,N-二甲基-N’-(5-氯-2-羟基苄基)-N’-(2-呋喃甲基)-脲(化合物5)的制备
制备方法同实施例一。以5-氯水杨醛代替间硝基苯甲醛,糠胺代替N-(3-氨基丙基)吗啉,得到黄色油状目标化合物。产率57%。1H-NMR(500MHz,DMSO-d6,δppm):2.82(s,6H);4.27(s,2H);4.54(s,2H);6.27(d,J=2.3,1H);6.39(t,J=1.7,1H);6.73(d,J=2.4,1H);7.08(m,1H);7.10(d,J=7.8,1H);7.17(s,1H).MS(ESI):308.1([M+H]+).Anal.calc.for C15H17ClN2O3:C 58.35,H 5.55,N 9.07%;found:C 58.50,H 5.62,N 8.89%.
实施例六:N,N-二甲基-N’-(5-氯-2-羟基苄基)-N’-(2-吗啉乙基)脲(化合物6)的制备
制备方法同实施例一。以5-氯水杨醛代替间硝基苯甲醛,N-(2-氨基乙基)吗啉代替N-(3-氨基丙基)吗啉,得到黄色油状目标化合物。产率52%。1H-NMR(500MHz,DMSO-d6,δppm):2.62(t,J=5.2,2H);2.94(s,6H);3.16(t,J=4.8,4H);3.26(t,J=4.2,2H);3.52(t,J=4.2,4H);4.36(s,2H);6.88(d,J=8.8,1H);7.32(d,J=8.2,1H);7.52(s,1H)8.53(s,1H).MS(ESI):341.1([M+H]+).Anal.calc.for C16H24ClN3O3:C 56.22,H 7.08,N 12.29%;found:C 56.40,H 7.12,N 12.09%.
实施例七:N,N-二甲基-N’-(5-氯-2-羟基苄基)-N’-(3-吗啉丙基)脲(化合物7)的制备
制备方法同实施例一。以5-氯水杨醛代替间硝基苯甲醛,得到黄色油状目标化合物。产率45%。1H-NMR(500MHz,DMSO-d6,δppm):1.76(m,2H);2.83(s,6H);2.96(t,J=5.4,2H);3.22(t,J=4.6,4H);3.36(t,J=4.7,2H);3.54(t,J=4.0,4H);4.34(s,2H);6.87(d,J=7.8,1H);7.32(d,J=7.6,1H);7.53(s,1H)8.53(s,1H).MS(ESI):355.2([M+H]+).Anal.calc.for C17H26ClN3O3:C 57.38,H 7.36,N 11.81%;found:C 57.25,H 7.42,N 11.90%.
实施例把八:N,N-二甲基-N’-(5-氯-2-羟基苄基)-N’-(1-乙氧羰基-4-哌啶基)脲(化合物8)的制备
制备方法同实施例一。以5-氯水杨醛代替间硝基苯甲醛,(1-乙氧羰基-4-哌啶基)胺代替N-(3-氨基丙基)吗啉得到黄色油状目标化合物。产率42%。1H-NMR(500MHz,DMSO-d6,δppm):1.28(t,J=3.8,3H);1.72(m,4H);2.80(s,6H);3.13(m,4H);3.46(m,1H);4.17(q,J=7.0,2H);4.29(s,2H);6.92(d,J=8.3,1H);7.28(d,J=7.8,1H);7.43(s,1H)8.36(s,1H).MS(ESI):383.2([M+H]+).Anal.calc.for C18H26ClN3O4:C 56.32,H 6.83,N 10.95%;found:C 56.46,H 6.56,N 11.23%.
实施例九:N,N-二甲基-N’-(4-羟基苄基)-N’-(2-吗啉乙基)脲(化合物9)的制备
制备方法同实施例一。以对羟基苯甲醛代替间硝基苯甲醛,N-(2-氨基乙基)吗啉代替N-(3-氨基丙基)吗啉得到黄色粉末状目标化合物。产率55%。Mp 144-146℃.1H-NMR(500MHz,DMSO-d6,δppm):2.55(t,J=5.0,4H);2.94(s,6H);3.08(t,J=5.2,2H);3.26(t,J=4.6,2H);3.61(t,J=4.0,4H);4.49(s,2H);6.75(d,J=8.5,2H);7.52(d,J=8.5,2H)8.16(s,1H).MS(ESI):307.2([M+H]+).Anal.calc.for C16H25N3O3:C 62.52,H8.20,N 13.67%;found:C 62.46,H 8.36,N 13.53%.
实施例十:N,N-二甲基-N’-(4-羟基苄基)-N’-(3-吗啉丙基)脲(化合物10)的制备
制备方法同实施例一。以对羟基苯甲醛代替间硝基苯甲醛,得到黄色油状目标化合物。产率41%。1H-NMR(500MHz,DMSO-d6,δppm):1.67(m,2H);2.76(t,J=5.4,2H);2.81(s,6H);3.02(t,J=4.6,4H);3.26(t,J=4.7,2H);3.44(t,J=4.0,4H);4.28(s,2H);6.73(d,J=8.4,2H);7.52(d,J=8.8,2H)8.15(s,1H).MS(ESI):321.2([M+H]+).Anal.calc.for C17H27N3O3:C 63.53,H 8.47,N 13.07%;found:C 63.67,H 8.42,N 12.90%.
实施例十一:N,N-二甲基-N’-(2-呋喃甲基)-N’-(4-羟基苄基)-脲(化合物11)的制备
制备方法同实施例一。以对羟基苯甲醛代替间硝基苯甲醛,糠胺代替N-(3-氨基丙基)吗啉得到黄色油状目标化合物。产率51%。1H-NMR(500MHz,DMSO-d6,δppm):2.84(s,6H);4.26(s,2H);4.57(s,2H);6.26(d,J=2.2,1H);6.35(t,J=1.9,1H);6.72(d,J=2.4,1H);6.85(d,J=8.4,2H);7.55(d,J=8.8,2H)8.05(s,1H).MS(ESI):274.1([M+H]+).Anal.calc.for C15H18N2O3:C 65.68,H 6.61,N 10.21%;found:C 65.50,H 6.72,N10.29%.
实施例十二:N,N-二甲基-N’-(4-羟基苄基)-N’-(1-乙氧羰基-4-哌啶基)脲(化合物12)的制备
制备方法同实施例一。以对羟基苯甲醛代替间硝基苯甲醛,(1-乙氧羰基4-哌啶基)胺代替N-(3-氨基丙基)吗啉得到黄色油状目标化合物。产率40%。1H-NMR(500MHz,DMSO-d6,δppm):1.26(t,J=3.7,3H);1.74(m,4H);2.85(s,6H);3.15(m,4H);3.43(m,1H);4.18(q,J=5.2,2H);4.33(s,2H);6.83(d,J=8.5,2H);7.56(d,J=8.9,2H)8.16(s,1H).MS(ESI):349.2([M+H]+).Anal.calc.for C18H27N3O4:C 61.87,H 7.79,N 12.03%;found:C 61.95,H 7.86,N 11.68%.
实施例十三:N,N-二甲基-N’-(2-吗啉乙基)-N’-(4-硝基苄基)脲(化合物13)的制备
制备方法同实施例一。以对硝基苯甲醛代替间硝基苯甲醛,N-(2-氨基乙基)吗啉代替N-(3-氨基丙基)吗啉得到黄色油状目标化合物。产率47%。1H-NMR(500MHz,DMSO-d6,δppm):2.43(t,J=5.2,4H);2.61(t,J=6.5,2H);2.84(s,6H);3.55(t,J=4.9,2H);3.76(t,J=6.5,4H);4.42(s,2H);7.98(d,J=9.0,2H);8.29(d,J=9.0,2H).MS(ESI):336.2([M+H]+).Anal.calc.for C16H24N4O4:C 57.13,H 7.19,N 16.66%;found:C 57.42,H7.06,N 16.53%.
实施例十四:N,N-二甲基-N’-(3-吗啉丙基)-N’-(4-硝基苄基)脲(化合物14)的制备
制备方法同实施例一。以对硝基苯甲醛代替间硝基苯甲醛,得到黄色油状目标化合物。产率53%。1H-NMR(500MHz,DMSO-d6,δppm):1.70(m,2H);2.38(t,J=7.5,2H);2.67(t,J=6.6,4H);2.88(s,6H);3.28(t,J=5.6,2H);3.64(t,J=4.8,4H);4.32(s,2H);7.49(d,J=8.1,2H);8.16(d,J=7.8,2H).MS(ESI):350.2([M+H]+).Anal.calc.forC17H26N4O4:C 58.27,H 7.48,N 15.99%;found:C 58.33,H 7.28,N 15.87%.
实施例十五:N,N-二甲基-N’-(2-呋喃甲基)-N’-(4-硝基苄基)脲(化合物15)的制备
制备方法同实施例一。以对硝基苯甲醛代替间硝基苯甲醛,糠胺代替N-(3-氨基丙基)吗啉,得到棕色粉末状目标化合物。产率48%。Mp 121-122℃.1H-NMR(500MHz,DMSO-d6,δppm):2.88(s,6H);4.28(s,2H);4.85(s,2H);6.35(q,J=2.5,1H);6.46(t,J=1.9,1H);7.41(q,J=2.5,1H);7.94(q,J=7.8,2H);8.27(d,J=8.2,2H).MS(ESI):303.1([M+H]+).Anal.calc.for C15H17N3O4:C 59.40,H 5.65,N 13.85%;found:C 59.23,H 5.87,N13.89%.
实施例十六:N,N-二甲基-N’-(4-硝基苄基)-N’-(1-乙氧羰基-4-哌啶基)脲(化合物16)的制备
制备方法同实施例一。以对硝基苯甲醛代替间硝基苯甲醛,(1-乙氧羰基4-哌啶基)胺代替N-(3-氨基丙基)吗啉,得到黄色油状目标化合物。产率42%。1H-NMR(500MHz,DMSO-d6,δppm):1.24(t,J=3.6,3H);1.72(m,4H);2.89(s,6H);3.13(m,4H);3.44(m,1H);4.16(q,J=5.6,2H);4.35(s,2H);7.48(d,J=8.0,2H);8.15(d,J=7.9,2H).MS(ESI):378.2([M+H]+).Anal.calc.for C18H26N4O5:C 57.13,H 6.93,N 14.81%;found:C 57.55,H7.06,N 14.68%.
实施例十七:N,N-二甲基-N’-(2-呋喃甲基)-N’-(2-羟基-5-硝基苄基)-脲(化合物17)的制备
制备方法同实施例一。以5-硝基水杨醛代替间硝基苯甲醛,糠胺代替N-(3-氨基丙基)吗啉,得到黄色油状目标化合物。产率51%。1H-NMR(500MHz,DMSO-d6,δppm):2.86(s,6H);4.26(s,2H);4.56(s,2H);6.28(d,J=2.2,1H);6.41(t,J=1.9,1H);6.75(d,J=2.1,1H);7.02(m,1H);7.13(d,J=7.8,1H);7.27(s,1H),8.24(s,1H).MS(ESI):319.1([M+H]+).Anal.calc.for C15H17N3O5:C 56.42,H 5.37,N 13.16%;found:C 56.57,H5.42,N 13.02%.
实施例十八:N,N-二甲基-N’-(2-羟基-5-硝基苄基)-N’-(2-吗啉乙基)脲(化合物18)的制备
制备方法同实施例一。以5-硝基水杨醛代替间硝基苯甲醛,N-(2-氨基乙基)吗啉代替N-(3-氨基丙基)吗啉,得到黄色油状目标化合物。产率53%。1H-NMR(500MHz,DMSO-d6,δppm):2.60(t,J=4.2,2H);2.96(s,6H);3.06(t,J=4.9,4H);3.24(t,J=4.8,2H);3.54(t,J=4.6,4H);4.37(s,2H);6.98(d,J=8.9,1H);7.42(d,J=8.0,1H);7.62(s,1H)8.58(s,1H).MS(ESI):352.2([M+H]+).Anal.calc.for C16H24N4O5:C 54.53,H 6.86,N15.90%;found:C 54.40,H 6.98,N 15.92%.
实施例十九:N,N-二甲基-N’-(2-羟基-5-硝基苄基)-N’-(3-吗啉丙基)脲(化合物19)的制备
制备方法同实施例一。以5-硝基水杨醛代替间硝基苯甲醛,得到黄色油状目标化合物。产率45%。1H-NMR(500MHz,DMSO-d6,δppm):1.74(m,2H);2.82(s,6H);2.98(t,J=5.2,2H);3.24(t,J=4.8,4H);3.38(t,J=4.8,2H);3.56(t,J=4.4,4H);4.36(s,2H);6.92(d,J=7.8,1H);7.46(d,J=7.6,1H);7.67(s,1H)8.50(s,1H).MS(ESI):366.2([M+H]+).Anal.calc.for C17H26N4O5:C 55.72,H 7.15,N 15.29%;found:C 55.65,H 7.23,N15.36%.
实施例二十:N,N-二甲基-N’-(2-羟基-5-硝基苄基)-N’-(1-乙氧羰基-4-哌啶基)脲(化合物20)的制备
制备方法同实施例一。以5-硝基水杨醛代替间硝基苯甲醛,(1-乙氧羰基4-哌啶基)胺代替N(3-氨基丙基)吗啉得到黄色油状目标化合物。产率41%。1H-NMR(500MHz,DMSO-d6,δppm):1.26(t,J=3.7,3H);1.74(m,4H);2.82(s,6H);3.14(m,4H);3.48(m,1H);4.18(q,J=4.0,2H);4.32(s,2H);6.94(d,J=7.9,1H);7.56(d,J=7.8,1H);7.89(s,1H)8.52(s,1H).MS(ESI):394.2([M+H]+).Anal.calc.for C18H26N4O6:C 54.81,H 6.64,N14.20%;found:C 54.56,H 6.78,N 14.23%.
实施例二十一:N,N-二甲基-N’-(5-溴-2-羟基苄基)-N’-(2-呋喃甲基)-脲(化合物21)的制备
制备方法同实施例一。以5-溴水杨醛代替间硝基苯甲醛,糠胺代替N-(3-氨基丙基)吗啉,得到黄色油状目标化合物。产率55%。1H-NMR(500MHz,DMSO-d6,δppm):2.87(s,6H);4.15(s,2H);4.41(s,2H);6.18(d,J=2.5,1H);6.38(t,J=1.9,1H);6.93(d,J=2.2,1H);7.18(d,J=7.8,1H);7.40(d,J=7.8,1H);7.62(s,1H);8.82(s,1H).MS(ESI):352.0([M+H]+).Anal.calc.for C15H17BrN2O3:C 51.01,H 4.85,N 7.93%;found:C51.23,H 4.72,N 7.80%.
实施例二十二:N,N-二甲基-N’-(5-溴-2-羟基苄基)-N’-(2-吗啉乙基)脲(化合物22)的制备
制备方法同实施例一。以5-溴水杨醛代替间硝基苯甲醛,N-(2-氨基乙基)吗啉代替N-(3-氨基丙基)吗啉,得到黄色油状目标化合物。产率51%。1H-NMR(500MHz,DMSO-d6,δppm):2.57(t,J=5.2,2H);2.92(s,6H);3.12(t,J=4.6,4H);3.28(t,J=4.8,2H);3.56(t,J=4.3,4H);4.42(s,2H);7.06(d,J=7.5,1H);7.42(d,J=7.6,1H);7.70(s,1H);8.67(s,1H).MS(ESI):385.1([M+H]+).Anal.calc.for C16H24BrN3O3:C49.75,H 6.26,N 10.88%;found:C 49.49,H 6.38,N 10.96%.
实施例二十三:N,N-二甲基-N’-(5-溴-2-羟基苄基)-N’-(3-吗啉丙基)脲(化合物23)的制备
制备方法同实施例一。以5-溴水杨醛代替间硝基苯甲醛,得到黄色油状目标化合物。产率41%。1H-NMR(500MHz,DMSO-d6,δppm):1.68(m,2H);2.86(s,6H);2.89(t,J=4.8,2H);3.01(t,J=4.4,4H);3.23(t,J=4.6,2H);3.52(t,J=4.2,4H);4.38(s,2H);7.08(d,J=7.6,1H);7.44(d,J=7.6,1H);7.72(s,1H);8.66(s,1H).MS(ESI):399.2([M+H]+).Anal.calc.for C17H26BrN3O3:C 51.01,H 6.55,N 10.50%;found:C 51.29,H 6.41,N 10.32%.
实施例二十四:N,N-二甲基-N’-(5-溴-2-羟基苄基)-N’(1-乙氧羰基-4-哌啶基)脲(化合物24)的制备
制备方法同实施例一。以5-溴水杨醛代替间硝基苯甲醛,(1-乙氧羰基-4-哌啶基)胺得到黄色油状目标化合物。产率40%。1H-NMR(500MHz,DMSO-d6,δppm):1.32(t,J=3.6,3H);1.74(m,4H);2.82(s,6H);3.15(m,4H);3.48(m,1H);4.19(q,J=4.0,2H);4.32(s,2H);7.06(d,J=7.6,1H);7.42(d,J=7.6,1H);7.67(s,1H);8.56(s,1H).MS(ESI):427.1([M+H]+).Anal.calc.for C18H26BrN3O4:C 50.47,H 6.12,N 9.81%;found:C50.78,H 5.69,N 9.77%.
实施例二十五:尿素类衍生物体外抗肿瘤活性研究
采用MTT[3-(4,5)-双甲基-2-噻唑-(2,5)-苯基溴化四氮唑蓝]法来测定尿素类衍生物对人体口腔上表皮癌细胞株(KB)和人白血病细胞株(K562)的最低抑菌浓度(minimalinhibitory concentration,MIC)。
(1)培养液(每升)的配制:①悬浮细胞:RPMI-1640培养粉一袋(10.4g),新生牛血清100ml,青霉素溶液(20万U/ml)0.5ml,链霉素溶液(20万U/ml)0.5ml,加三蒸水溶解后,用5.6%的NaHCO3溶液调PH值至7.2-7.4,最后定容至1000ml。过滤灭菌。②贴壁细胞:同上,再加入NaHCO32.00g,HEPES 2.38g。
(2)D-Hanks缓冲液(每升)的配制:NaCl 8.00g,KCl 0.40g,Na2HPO4·12H2O 0.06g,KH2PO40.06g,NaHCO30.35g。高压灭菌。
(3)胰蛋白酶液的配制:利用D-Hanks缓冲液配成浓度为0.5%胰蛋白酶液。过滤除菌。
(4)实验药液的配制:将测试样品用少量的三蒸水溶解配成储备液,一般按实验最高浓度的10倍配制储备液。根据化合物溶解性不同,可用三蒸水直接溶解,或用少量DMSO助溶,再加三蒸水溶解。DMSO在培养液中的浓度不宜过大,加药后的每孔细胞悬液中DMSO的终浓度一般不超过0.05%-0.1%。储备液保存于-20℃冰箱中备用。
(5)人白血病细胞K562的培养:为悬浮生长细胞,常规培养于RPMI-1640培养液内(含10%小牛血清、100U/ml链霉素),置于37℃、5%CO2培养箱中培养,每隔3-4天传代一次。传代时将原瓶中培养液转移至离心管中,1000rpm离心5min,弃去原培养液,加入等量新鲜培养液,吹打均匀,移取适量至新鲜培养瓶中,再补充新鲜培养液至原体积(培养液体积约为培养瓶容量的1/10)。
(6)人体口腔上表皮癌细胞KB的培养:为贴壁生长细胞,常规培养于RPMI-1640培养液内(含10%小牛血清、100U/ml链霉素),置37℃、5%CO2培养箱中培养,每隔3-4天传代一次。传代时先弃去原培养液,再用D-Hanks缓冲液洗涤;然后用0.5%胰蛋白酶消化30秒左右,加入少量新鲜培养液终止消化;吹打,使贴壁细胞从培养瓶壁上脱落下来;移取适量至新鲜培养瓶中,再补充新鲜培养液至原体积(培养液体积约为培养瓶容量的1/10)。
(7)细胞孵育:取对数生长期的2种肿瘤细胞,调细胞悬液浓度为1-1.5×105个ml-1。在96孔培养板中每孔加细胞悬液100μl,置37℃,5%CO2培养箱中培养24h。培养24h后,分别按设计加入药液。
(8)加药:将测试药液按照最终浓度的浓度梯度分别加入到各个孔中,每个浓度设6个平行孔。实验分为药物试验组(分别加入不同浓度的测试药)、对照组(只加培养液和细胞,不加测试药)和空白组(只加培养液,不加细胞和测试药)。将加药后的96孔板置于37℃,5%CO2培养箱中培养48h。阳性对照药物的活性按照测试样品的方法测定。
(9)存活细胞的测定:在培养了48h后的96孔板中,每孔加MTT 40μl(用D-Hanks缓冲液配成4mg/ml)。在37℃放置4h后,移去上清液。每孔加150μl DMSO,振荡5min,使formazan结晶溶解。最后,利用自动酶标仪在570nm波长处检测各孔的光密度(OD值)。
抑制率的计算:细胞生长的抑制率按照下列公式计算:
生长抑制率=(1-存活率)×100%=[1-(OD实验-OD空间)/(OD对照-OD空白)]×100%(OD实验表示测试药物组的平均光密度,OD对照表示对照组的平均光密度,OD空白表示对照组的平均光密度)。
半数抑制浓度(IC50)定义为当50%的肿瘤细胞存活时的药物浓度。根据测定的光密度(OD值),制作细胞生长抑制率的标准曲线,在标准曲线上求得其对应的药物浓度。测得的IC50见表1所示
表1本发明所列尿素类化合物的对肿瘤细胞的抑制IC50值(μM)
Claims (7)
1.一类尿素类衍生物,其特征是它们是:N,N-二甲基-N’-(3-吗啉丙基)-N’-(3-硝基苄基)脲、N,N-二甲基-N’-(2-吗啉乙基)-N’-(3-硝基苄基)脲、N,N-二甲基-N’-(2-呋喃甲基)-N’-(3-硝基苄基)脲、N,N-二甲基-N’-(3-硝基苄基)-N’-(1-乙氧羰基-4-哌啶基)脲、N,N-二甲基-N’-(5-氯-2-羟基苄基)-N’-(2-呋喃甲基)-脲、N,N-二甲基-N’-(5-氯-2-羟基苄基)-N’-(2-吗啉乙基)脲、N,N-二甲基-N’-(5-氯-2-羟基苄基)-N’-(3-吗啉丙基)脲、N,N-二甲基-N’-(5-氯-2-羟基苄基)-N’-(1-乙氧羰基-4-哌啶基)脲、N,N-二甲基-N’-(4-羟基苄基)-N’-(2-吗啉乙基)脲、N,N-二甲基-N’-(4-羟基苄基)-N’-(3-吗啉丙基)脲、N,N-二甲基-N’-(2-呋喃甲基)-N’-(4-羟基苄基)-脲、N,N-二甲基-N’-(4-羟基苄基)-N’-(1-乙氧羰基-4-哌啶基)脲、N,N-二甲基-N’-(2-吗啉乙基)-N’-(4-硝基苄基)脲、N,N-二甲基-N’-(3-吗啉丙基)-N’-(4-硝基苄基)脲、N,N-二甲基-N’-(2-呋喃甲基)-N’-(4-硝基苄基)脲、N,N-二甲基-N’-(4-硝基苄基)-N’-(1-乙氧羰基-4-哌啶基)脲、N,N-二甲基-N’-(2-呋喃甲基)-N’-(2-羟基-5-硝基苄基)-脲、N,N-二甲基-N’-(2-羟基-5-硝基苄基)-N’-(2-吗啉乙基)脲、N,N-二甲基-N’-(2-羟基-5-硝基苄基)-N’-(3-吗啉丙基)脲、N,N-二甲基-N’-(2-羟基-5-硝基苄基)-N’-(1-乙氧羰基-4-哌啶基)脲、N,N-二甲基-N’-(5-溴-2-羟基苄基)-N’-(2-呋喃甲基)-脲、N,N-二甲基-N’-(5-溴-2-羟基苄基)-N’-(2-吗啉乙基)脲、N,N-二甲基-N’-(5-溴-2-羟基苄基)-N’-(3-吗啉丙基)脲或N,N-二甲基-N’-(5-溴-2-羟基苄基)-N’(1-乙氧羰基-4-哌啶基)脲。
2.一种权利要求1所述的尿素类衍生物的制法,其特征是它由下列步骤组成:
步骤1.于无水CH2Cl2溶液中,加入无水二甲基甲酰胺和SOCl2,二甲基甲酰胺与SOCl2的物质的量之比为1∶2~1∶2.5,搅拌加热至70-80℃,反应4-5个小时后冷却,减压蒸干,蒸去多余的SOCl2,得到ClCON(CH3)2,
步骤2.将吡啶和与二甲基甲酰胺等物质的量的R1NHR2溶于无水CH2Cl2中配成溶液,其中R1为3-硝基苄基、4-硝基苄基、4-羟基苄基、5-氯-2-羟基苄基、5-溴-2-羟基苄基或2-羟基-5-硝基苄基;R2为2-吗啉乙基、3-吗啉丙基、2-呋喃甲基或1-乙氧羰基-4-哌啶基,
步骤3.在步骤1得到的ClCON(CH3)2加入无水CH2Cl2,逐滴加入步骤2配制的溶液,搅拌加热至50-60℃,反应5-6小时后,将反应混合物倒入冰水中,分离出有机相,水相加乙酸乙酯萃取,合并有机相,用饱和碳酸氢钠和水分别洗涤有机相,用无水NaSO4干燥有机相,减压蒸去部分溶剂,得到粘稠油状浓缩液,
步骤4.将步骤3得到的粘稠油状浓缩液用丙酮或乙酸乙酯稀释,层析得到本发明的尿素类衍生物。
3.根据权利要求2所述的制法,其特征是:所述的步骤1中,CH2Cl2的用量为每摩尔二甲基甲酰胺加350-400ml。
4.根据权利要求2所述的制法,其特征是:所述的步骤2中,吡啶和CH2Cl2的用量为每摩尔二甲基甲酰胺加吡啶100-120ml,加CH2Cl2230-280ml。
5.根据权利要求2所述的制法,其特征是:所述的步骤3中,CH2Cl2的用量为每摩尔二甲基甲酰胺加350-400ml。
6.根据权利要求2所述的制法,其特征是:层析的洗脱液为石油醚∶乙酸乙酯=2∶1-1∶2的溶液。
7.根据权利要求1所述的尿素类衍生物在制备抗肿瘤药物中的应用。
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