CN111187220B - 含席夫碱结构单元的三氟甲基嘧啶类衍生物及其制备方法和用途 - Google Patents
含席夫碱结构单元的三氟甲基嘧啶类衍生物及其制备方法和用途 Download PDFInfo
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- CN111187220B CN111187220B CN202010057671.7A CN202010057671A CN111187220B CN 111187220 B CN111187220 B CN 111187220B CN 202010057671 A CN202010057671 A CN 202010057671A CN 111187220 B CN111187220 B CN 111187220B
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- Prior art keywords
- trifluoromethyl
- pyrimidine
- prop
- hydrazino
- ylthio
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- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- 239000002262 Schiff base Substances 0.000 title claims abstract description 16
- 150000004753 Schiff bases Chemical class 0.000 title claims abstract description 16
- BQDJLAWUTBCDHK-UHFFFAOYSA-N 2-(trifluoromethyl)pyrimidine Chemical class FC(F)(F)C1=NC=CC=N1 BQDJLAWUTBCDHK-UHFFFAOYSA-N 0.000 title claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 16
- 239000003814 drug Substances 0.000 claims abstract description 11
- 229940079593 drug Drugs 0.000 claims abstract description 9
- 230000000259 anti-tumor effect Effects 0.000 claims abstract description 7
- PIKNVEVCWAAOMJ-UHFFFAOYSA-N 3-fluorobenzaldehyde Chemical compound FC1=CC=CC(C=O)=C1 PIKNVEVCWAAOMJ-UHFFFAOYSA-N 0.000 claims description 24
- -1 3, 4-difluorophenyl Chemical group 0.000 claims description 22
- 238000000034 method Methods 0.000 claims description 11
- 239000001431 2-methylbenzaldehyde Substances 0.000 claims description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 9
- BTFQKIATRPGRBS-UHFFFAOYSA-N o-tolualdehyde Chemical compound CC1=CC=CC=C1C=O BTFQKIATRPGRBS-UHFFFAOYSA-N 0.000 claims description 8
- FXLOVSHXALFLKQ-UHFFFAOYSA-N p-tolualdehyde Chemical compound CC1=CC=C(C=O)C=C1 FXLOVSHXALFLKQ-UHFFFAOYSA-N 0.000 claims description 8
- RGHHSNMVTDWUBI-UHFFFAOYSA-N 4-hydroxybenzaldehyde Chemical compound OC1=CC=C(C=O)C=C1 RGHHSNMVTDWUBI-UHFFFAOYSA-N 0.000 claims description 7
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 claims description 7
- 238000006243 chemical reaction Methods 0.000 claims description 6
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 5
- XXFUZSHTIOFGNV-UHFFFAOYSA-N 1-bromoprop-1-yne Chemical compound CC#CBr XXFUZSHTIOFGNV-UHFFFAOYSA-N 0.000 claims description 4
- FPYUJUBAXZAQNL-UHFFFAOYSA-N 2-chlorobenzaldehyde Chemical compound ClC1=CC=CC=C1C=O FPYUJUBAXZAQNL-UHFFFAOYSA-N 0.000 claims description 4
- JPHKMYXKNKLNDF-UHFFFAOYSA-N 3,4-difluorobenzaldehyde Chemical compound FC1=CC=C(C=O)C=C1F JPHKMYXKNKLNDF-UHFFFAOYSA-N 0.000 claims description 4
- SRWILAKSARHZPR-UHFFFAOYSA-N 3-chlorobenzaldehyde Chemical compound ClC1=CC=CC(C=O)=C1 SRWILAKSARHZPR-UHFFFAOYSA-N 0.000 claims description 4
- IAVREABSGIHHMO-UHFFFAOYSA-N 3-hydroxybenzaldehyde Chemical compound OC1=CC=CC(C=O)=C1 IAVREABSGIHHMO-UHFFFAOYSA-N 0.000 claims description 4
- AVPYQKSLYISFPO-UHFFFAOYSA-N 4-chlorobenzaldehyde Chemical compound ClC1=CC=C(C=O)C=C1 AVPYQKSLYISFPO-UHFFFAOYSA-N 0.000 claims description 4
- UOQXIWFBQSVDPP-UHFFFAOYSA-N 4-fluorobenzaldehyde Chemical compound FC1=CC=C(C=O)C=C1 UOQXIWFBQSVDPP-UHFFFAOYSA-N 0.000 claims description 4
- 206010006187 Breast cancer Diseases 0.000 claims description 4
- 208000026310 Breast neoplasm Diseases 0.000 claims description 4
- QPHZAQKLSMXZLE-AWQFTUOYSA-N N-[(E)-(3-fluorophenyl)methylideneamino]-2-prop-2-ynylsulfanyl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound C#CCSC1=NC(=CC(=N1)N/N=C/C2=CC(=CC=C2)F)C(F)(F)F QPHZAQKLSMXZLE-AWQFTUOYSA-N 0.000 claims description 4
- ZDNYZHIOJDALOJ-AWQFTUOYSA-N N-[(E)-(4-fluorophenyl)methylideneamino]-2-prop-2-ynylsulfanyl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound C#CCSC1=NC(=CC(=N1)N/N=C/C2=CC=C(C=C2)F)C(F)(F)F ZDNYZHIOJDALOJ-AWQFTUOYSA-N 0.000 claims description 4
- 206010060862 Prostate cancer Diseases 0.000 claims description 4
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 4
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 4
- YMNKUHIVVMFOFO-UHFFFAOYSA-N anthracene-9-carbaldehyde Chemical compound C1=CC=C2C(C=O)=C(C=CC=C3)C3=CC2=C1 YMNKUHIVVMFOFO-UHFFFAOYSA-N 0.000 claims description 4
- CNUDBTRUORMMPA-UHFFFAOYSA-N formylthiophene Chemical compound O=CC1=CC=CS1 CNUDBTRUORMMPA-UHFFFAOYSA-N 0.000 claims description 4
- 206010017758 gastric cancer Diseases 0.000 claims description 4
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 claims description 4
- 201000011549 stomach cancer Diseases 0.000 claims description 4
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 3
- CSDSSGBPEUDDEE-UHFFFAOYSA-N 2-formylpyridine Chemical compound O=CC1=CC=CC=N1 CSDSSGBPEUDDEE-UHFFFAOYSA-N 0.000 claims description 3
- ISDBWOPVZKNQDW-UHFFFAOYSA-N 4-phenylbenzaldehyde Chemical compound C1=CC(C=O)=CC=C1C1=CC=CC=C1 ISDBWOPVZKNQDW-UHFFFAOYSA-N 0.000 claims description 3
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 3
- OLNJUISKUQQNIM-UHFFFAOYSA-N indole-3-carbaldehyde Chemical compound C1=CC=C2C(C=O)=CNC2=C1 OLNJUISKUQQNIM-UHFFFAOYSA-N 0.000 claims description 3
- QJZUKDFHGGYHMC-UHFFFAOYSA-N pyridine-3-carbaldehyde Chemical compound O=CC1=CC=CN=C1 QJZUKDFHGGYHMC-UHFFFAOYSA-N 0.000 claims description 3
- BGUWFUQJCDRPTL-UHFFFAOYSA-N pyridine-4-carbaldehyde Chemical compound O=CC1=CC=NC=C1 BGUWFUQJCDRPTL-UHFFFAOYSA-N 0.000 claims description 3
- KTMNPWCZNGBVNO-DJKKODMXSA-N 2-prop-2-ynylsulfanyl-N-[(E)-pyridin-2-ylmethylideneamino]-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound C#CCSC1=NC(=CC(=N1)N/N=C/C2=CC=CC=N2)C(F)(F)F KTMNPWCZNGBVNO-DJKKODMXSA-N 0.000 claims description 2
- JWGQPPIGVDQKBJ-DJKKODMXSA-N 2-prop-2-ynylsulfanyl-N-[(E)-pyridin-3-ylmethylideneamino]-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound C#CCSC1=NC(=CC(=N1)N/N=C/C2=CN=CC=C2)C(F)(F)F JWGQPPIGVDQKBJ-DJKKODMXSA-N 0.000 claims description 2
- JKLQGBHBGWKLDN-DJKKODMXSA-N 2-prop-2-ynylsulfanyl-N-[(E)-pyridin-4-ylmethylideneamino]-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound C#CCSC1=NC(=CC(=N1)N/N=C/C2=CC=NC=C2)C(F)(F)F JKLQGBHBGWKLDN-DJKKODMXSA-N 0.000 claims description 2
- JNXKGRJQGPOPKA-DJKKODMXSA-N 3-[(E)-[[2-prop-2-ynylsulfanyl-6-(trifluoromethyl)pyrimidin-4-yl]hydrazinylidene]methyl]phenol Chemical compound C#CCSC1=NC(=CC(=N1)N/N=C/C2=CC(=CC=C2)O)C(F)(F)F JNXKGRJQGPOPKA-DJKKODMXSA-N 0.000 claims description 2
- YGPHOVHTKMEVRY-AWQFTUOYSA-N N-[(E)-(2-chlorophenyl)methylideneamino]-2-prop-2-ynylsulfanyl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound C#CCSC1=NC(=CC(=N1)N/N=C/C2=CC=CC=C2Cl)C(F)(F)F YGPHOVHTKMEVRY-AWQFTUOYSA-N 0.000 claims description 2
- NUKIWCLHCLEMGT-KEBDBYFISA-N N-[(E)-(2-methylphenyl)methylideneamino]-2-prop-2-ynylsulfanyl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound CC1=CC=CC=C1/C=N/NC2=NC(=NC(=C2)C(F)(F)F)SCC#C NUKIWCLHCLEMGT-KEBDBYFISA-N 0.000 claims description 2
- UBQJZCGPNRQTMC-ODCIPOBUSA-N N-[(E)-(3,4-difluorophenyl)methylideneamino]-2-prop-2-ynylsulfanyl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound C#CCSC1=NC(=CC(=N1)N/N=C/C2=CC(=C(C=C2)F)F)C(F)(F)F UBQJZCGPNRQTMC-ODCIPOBUSA-N 0.000 claims description 2
- HQQMTEMKGPHHCE-AWQFTUOYSA-N N-[(E)-(3-chlorophenyl)methylideneamino]-2-prop-2-ynylsulfanyl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound C#CCSC1=NC(=CC(=N1)N/N=C/C2=CC(=CC=C2)Cl)C(F)(F)F HQQMTEMKGPHHCE-AWQFTUOYSA-N 0.000 claims description 2
- GHDOPKDRWOVZNF-AWQFTUOYSA-N N-[(E)-(4-chlorophenyl)methylideneamino]-2-prop-2-ynylsulfanyl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound C#CCSC1=NC(=CC(=N1)N/N=C/C2=CC=C(C=C2)Cl)C(F)(F)F GHDOPKDRWOVZNF-AWQFTUOYSA-N 0.000 claims description 2
- YLSYSMZPKLCUAF-KEBDBYFISA-N N-[(E)-(4-methylphenyl)methylideneamino]-2-prop-2-ynylsulfanyl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound CC1=CC=C(C=C1)/C=N/NC2=NC(=NC(=C2)C(F)(F)F)SCC#C YLSYSMZPKLCUAF-KEBDBYFISA-N 0.000 claims description 2
- GFKHAWLXCLNRGX-AFUMVMLFSA-N N-[(E)-(4-phenylphenyl)methylideneamino]-2-prop-2-ynylsulfanyl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound C#CCSC1=NC(=CC(=N1)N/N=C/C2=CC=C(C=C2)C3=CC=CC=C3)C(F)(F)F GFKHAWLXCLNRGX-AFUMVMLFSA-N 0.000 claims description 2
- BUYUXVBVESAVBH-MZJWZYIUSA-N N-[(E)-anthracen-9-ylmethylideneamino]-2-prop-2-ynylsulfanyl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound C#CCSC1=NC(=CC(=N1)N/N=C/C2=C3C=CC=CC3=CC4=CC=CC=C42)C(F)(F)F BUYUXVBVESAVBH-MZJWZYIUSA-N 0.000 claims description 2
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- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims 1
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims 1
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims 1
- 125000004208 3-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C([H])C(*)=C1[H] 0.000 claims 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims 1
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims 1
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 claims 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 1
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- 239000002246 antineoplastic agent Substances 0.000 description 4
- 229940041181 antineoplastic drug Drugs 0.000 description 4
- ZRSNZINYAWTAHE-UHFFFAOYSA-N p-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C=C1 ZRSNZINYAWTAHE-UHFFFAOYSA-N 0.000 description 4
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- FXPVWFBGUQUFEE-UHFFFAOYSA-N 2-pyridin-2-ylbenzaldehyde Chemical compound O=CC1=CC=CC=C1C1=CC=CC=N1 FXPVWFBGUQUFEE-UHFFFAOYSA-N 0.000 description 1
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- ZRSNZINYAWTAHE-PTQBSOBMSA-N 4-methoxybenzaldehyde Chemical group COC1=CC=C([13CH]=O)C=C1 ZRSNZINYAWTAHE-PTQBSOBMSA-N 0.000 description 1
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- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
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Abstract
本发明属于药物化学领域,公开了具有抗肿瘤活性的含席夫碱结构单元的三氟甲基嘧啶类衍生物及其制备方法和用途。本发明化合物具有通式Ⅰ结构。体外抗肿瘤活性评价发现该系列化合物对多种肿瘤细胞具有明显的抑制和杀伤作用。可以将其应用于制备临床预防、治疗癌症药物。
Description
技术领域
本发明属于药物化学领域,涉及嘧啶类衍生物,具体涉及抗肿瘤活性的基于含席夫碱结构单元的三氟甲基嘧啶类衍生物及其制备方法和用途。
背景技术
肿瘤是当今世界危及人类生命健康的最常见、最严重的疾病之一。目前已上市的抗肿瘤药物有很多,嘧啶类化合物表现出了广泛的生物活性,例如:抗癌、抗菌、抗炎和抗惊厥等。其抗肿瘤活性的优秀代表为:厄洛替尼(Erlotinib)、拉帕替尼(Lapatinib)等。但已开发的药物远不能满足患者的需求,因此,研究与开发具有高效、低毒的抗肿瘤药物具有深远的意义。席夫碱具有抑菌、杀菌、抗肿瘤、抗病毒的生物活性等特殊的生理活性,近年来,越来越引起医药界的重视。三氟甲基可增强化合物的生物活性、亲油性、代谢稳定性和选择性,将其引入到嘧啶类化合物,有可能有效地改变嘧啶类化合物的极性、亲脂性、代谢稳定性。因此,在嘧啶的四位,引入三氟甲基,以其作为基本母核,再对其进行结构修饰,引入席夫碱合成基于含席夫碱结构单元的三氟甲基嘧啶类衍生物,对其进行活性研究具有非常重要的研究价值,有利于我国自主产权药物的开发。
发明内容
为开发利用现有的临床药物资源,本发明目的在于提供一类基于含席夫碱结构单元的三氟甲基取代的嘧啶类衍生物,为寻找新的抗肿瘤活性化合物开辟一条新途径;本发明另一目的在于提供其在制备抗肿瘤药物中的应用。
本发明所述基于三氟甲基取代的嘧啶类衍生物的结构通式如下:
通式Ⅰ中:R为苯甲醛基、3-氟苯甲醛基、4-氟苯甲醛基、2-氯苯甲醛基、3-氯苯甲醛基、4-氯苯甲醛基、3,4-二氟苯甲醛基、2-甲基苯甲醛基、3-甲基苯甲醛基、4-甲基苯甲醛基、2-甲氧基苯甲醛基、3-甲氧基苯甲醛基、4-甲氧基苯甲醛基、2,3-二甲氧基苯甲醛基、2-噻吩苯甲醛基、3-吲哚苯甲醛基、2-吡啶苯甲醛基、3-吡啶苯甲醛基、4-吡啶苯甲醛基、9-蒽醛基、4-苯基苯甲醛基、4-羟基苯甲醛基、3-羟基苯甲醛基、3-吲哚甲醛基。
优选以下化合物:
5a:(E)-4-(2-苯基烯二肼)-2-(丙-2-炔-1-基硫代)-6-(三氟甲基)嘧啶;
5b:(E)-4-(2-(3-氟苯亚甲基)肼基)-2-(丙-2-炔-1-基硫代)-6-(三氟甲基)嘧啶;
5c:(E)-4-(2-(4-氟苯亚甲基)肼基)-2-(丙-2-炔-1-基硫代)-6-(三氟甲基)嘧啶;
5d:(E)-4-(2-(2-氯苯亚甲基)肼基)-2-(丙-2-炔-1-基硫代)-6-(三氟甲基)嘧啶;
5e:(E)-4-(2-(3-氯苯亚甲基)肼基)-2-(丙-2-炔-1-基硫代)-6-(三氟甲基)嘧啶;
5f:(E)-4-(2-(4-氯苯亚甲基)肼基)-2-(丙-2-炔-1-基硫代)-6-(三氟甲基)嘧啶;
5g:(E)-4-(2-(3,4-二氟苯亚甲基)肼基)-2-(丙-2-炔-1-基硫代)-6-(三氟甲基)嘧啶;
5h:(E)-4-(2-(2-甲基亚苄基)肼基)-2-(丙-2-炔-1-基硫代)-6-(三氟甲基)嘧啶;
5i:(E)-4-(2-(4-甲基亚苄基)肼基)-2-(丙-2-炔-1-基硫代)-6-(三氟甲基)嘧啶;
5n:(E)-4-(2-(苯并[c]噻吩-1-基亚甲基)肼基)-2-(丙-2-炔-1-基硫代)-6-(三氟甲基)嘧啶;
5o:(E)-2-(丙-2-炔-1-基硫基)-4-(2-(吡啶-2-基亚甲基)肼基)-6-(三氟甲基)嘧啶;
5p:(E)-2-(丙-2-炔-1-基硫基)-4-(2-(吡啶-3-基亚甲基)肼基)-6-(三氟甲基)嘧啶;
5q:(E)-2-(丙-2-炔-1-基硫基)-4-(2-(吡啶-4-基亚甲基)肼基)-6-(三氟甲基)嘧啶;
5s:(E)-4-(2-(蒽-9-基亚甲基)肼基)-2-(丙-2-炔-1-基硫代)-6-(三氟甲基)嘧啶;
5w:(E)-4-(2-([1,1'-联苯]-4-基亚甲基)肼基)-2-(丙-2-炔-1-基硫代)-6-(三氟甲基)嘧啶;
5t:(E)-3-((2-(2-(丙-2-炔-1-基硫代)-6-(三氟甲基)嘧啶-4-基)亚肼基)甲基)苯酚;
5v:(E)-1-((2-(2-(丙-2-炔-1-基硫代)-6-(三氟甲基)嘧啶-4-基)亚肼基)甲基)-2H-异吲哚。
本发明所述基于三氟甲基取代的嘧啶类衍生物的制备方法包含以下合成步骤:a.将2-巯基-6-(三氟甲基)嘧啶-4-醇和溴代丙炔、氢氧化钾水溶液加入反应器中发生取代反应,生成4位为羟基的溴丙炔的嘧啶类生物2;b.4位为羟基的溴丙炔的嘧啶类生物2与三氯氧磷反应,生成4位为氯原子的含溴丙炔的嘧啶类生物3;c.4位为氯原子的含溴丙炔的嘧啶类生物3与水合肼在无水乙醇中反应生成化合物4;d.化合物4与不同的醛反应得到目标化合物5a-5y。
合成路线如下:
所述的醛类化合物为:苯甲醛、3-氟苯甲醛、4-氟苯甲醛、2-氯苯甲醛、3-氯苯甲醛、4-氯苯甲醛、3,4-二氟苯甲醛、2-甲基苯甲醛、3-甲基苯甲醛、4-甲基苯甲醛、2-甲氧基苯甲醛、3-甲氧基苯甲醛、4-甲氧基苯甲醛、2,3-二甲氧基苯甲醛、2-噻吩苯甲醛、3-吲哚苯甲醛、2-吡啶苯甲醛、3-吡啶苯甲醛、4-吡啶苯甲醛、9-蒽醛、4-苯基苯甲醛、4-羟基苯甲醛、3-羟基苯甲醛、3-吲哚甲醛。经体外抗肿瘤活性测试,本发明所述含席夫碱结构单元的基于三氟甲基取代的嘧啶类衍生物对人乳腺癌细胞(MCF-7)、人胃癌细胞(MGC-803)、人前列腺癌细胞(PC-3)有很好的抑制作用。其中有些化合物对乳腺癌细胞(MCF-7)、胃癌细胞(MGC-803)、前列腺癌细胞(PC-3)的IC50值小于10(μmol/L),与临床上已使用的抗肿瘤药物5-氟尿嘧啶做对照,优于其活性。因此,本发明提供的此类含席夫碱结构单元的基于三氟甲基取代的嘧啶类衍生物为开发新型抗肿瘤药物和药物的联合用药开辟了新途径。
具体实施方式
下面结合具体实施例,进一步阐述本发明。这些实施例仅用于说明本发明而不用于限制本发明要求保护的范围。
合成化合物表征使用的仪器:NMR谱使用瑞典Bruker DPX-400型超导核磁共振仪测定,TMS为内标;高分辨质谱使用Waters-Micromass公司Q-Tof质谱仪测定。
实施例1(E)-4-(2-苯基烯二肼)-2-(丙-2-炔-1-基硫代)-6-(三氟甲基)嘧啶的制备(5a)
室温条件下,将2-巯基-6-(三氟甲基)嘧啶-4-醇(1.95g,10mmol)溶于氢氧化钾(0.67g,12.05mmol)的N,N-二甲基甲酰(20ml)胺溶液中,缓慢滴入溴丙炔(940ul,12.05mmol),升温至80℃发生取代反应,TLC检测反应完成,将反应液冷至室温,加入冰水混合物中搅拌,有大量淡黄色固体析出,抽滤,水洗3-4次,干燥,得到化合物3-(丙-2-炔-1-基硫基)-5-(三氟甲基)苯酚。
淡黄色固体,收率83.5%;1H NMR(400MHz,DMSO-d6)δ7.29(s,1H),5.19(d,J=2.3Hz,2H),4.82(d,J=2.3Hz,1H).13C NMR(101MHz,DMSO-d6)δ170.89,168.65,163.40,159.39,155.72,155.37,155.02,154.66,73.40,55.37,20.59,19.17.HR-MS(ESI):Calcdfor C10H8F3OS[M+H]+:233.0248,found:233.0247.
0℃条件下,将10ml三氯氧磷缓慢滴加到上述合成的3-(丙-2-炔-1-基硫基)-5-(三氟甲基)苯酚(1.15g,5mmol)中,缓慢梯度升温至90℃,继续反应3h,然后停止反应,将反应液冷至室温,逐滴加入到碎冰中,边滴加边搅拌,析出棕色固体,抽滤,水洗至中性,室温干燥,得到棕色固体(3-氯-5-(三氟甲基)苯基)(丙-2-炔-1-基)硫烷。
棕色固体,收率74.2%;1H NMR(400MHz,DMSO-d6)δ7.22(s,1H),5.20(d,J=2.4Hz,2H),3.62–3.58(m,1H).13C NMR(101MHz,DMSO-d6)δ171.70,167.89,164.06,159.39,155.72,155.37,155.02,154.66,77.30,55.53,34.27,20.83.HR-MS(ESI):Calcd forC10H7ClF3S[M+H]+:250.9909,found:250.9908.
室温条件下,将(3-氯-5-(三氟甲基)苯基)(丙-2-炔-1-基)硫烷(2.11g,8.42mmol)加入20ml无水乙醇中,升温至80℃,缓慢加入水合肼(821ul,16.84mmol),TLC检测反应完成,将反应液冷至室温,抽滤,得到白色固体(3-(丙-2-炔-1-基硫基)-5-(三氟甲基)苯基)肼。
白色固体,81.7%;1H NMR(400MHz,DMSO-d6)δ9.30(s,1H),6.93(s,1H),4.68(s,2H),3.94(dd,J=24.2,8.6Hz,2H),3.12(s,1H).13C NMR(101MHz,DMSO-d6)δ170.89,168.65,163.40,159.39,155.72,155.46,154.89,154.74,149.04,74.21,73.21,55.37,33.52.HR-MS(ESI):Calcd for C10H10F3N2S[M+H]+:247.0517,found:247.0518.
室温条件下,将(3-(丙-2-炔-1-基硫基)-5-(三氟甲基)苯基)(0.15g,0.609mmol)肼加入6ml无水乙醇中,升温至80℃,缓慢加入苯甲醛(70.44ul,0.609mmol),TLC检测反应完成,将反应液冷至室温,进行柱层析(V石油醚:V乙酸乙酯=6:1),浓缩洗脱剂得产物(E)-4-(2-苯基烯二肼)-2-(丙-2-炔-1-基硫代)-6-(三氟甲基)嘧啶。
白色固体粉末,收率52.5%;1H NMR(400MHz,DMSO-d6)δ12.19(s,1H),8.23(s,1H),7.97(d,J=7.3Hz,1H),7.80–7.74(m,2H),7.46(d,J=6.4Hz,2H),7.27(s,1H),4.00(d,J=2.4Hz,2H),3.19(t,J=2.4Hz,1H).13C NMR(101MHz,DMSO-d6)δ192.55,169.80,161.88,145.30,141.43,139.13,132.63,130.27,128.86,127.53,126.89,126.50,119.28,95.80,79.76,73.31,18.44.HR-MS(ESI):Calcd forC15H12F3N4S[M+H]+:337.0735,found:337.0734.
实施例2(E)-4-(2-(3-氟苯亚甲基)肼基)-2-(丙-2-炔-1-基硫代)-6-(三氟甲基)嘧啶的制备(5b)
室温条件下,将(3-(丙-2-炔-1-基硫基)-5-(三氟甲基)苯基)(0.15g,0.609mmol)肼加入6ml无水乙醇中,升温至80℃,缓慢加入3-氟苯甲醛(60.97ul,0.609mmol),TLC检测反应完成,将反应液冷至室温,进行柱层析(V石油醚:V乙酸乙酯=6:1),浓缩洗脱剂得产物。
白色固体,收率74.0%;1H NMR(400MHz,DMSO-d6)δ1H NMR(400MHz,DMSO)δ12.26(s,1H),8.21(s,1H),7.67(d,J=9.8Hz,1H),7.59(d,J=7.8Hz,1H),7.49(dt,J=13.8,6.9Hz,1H),7.34(s,1H),7.30–7.23(m,1H),3.99(d,J=2.6Hz,2H),3.18(t,J=2.6Hz,1H).13C NMR(101MHz,DMSO-d6)δ169.92,163.66,162.15,161.23,144.41,136.43,130.88,130.79,123.59,116.89,116.68,113.10,112.88,96.17,79.88,73.44,18.57.HR-MS(ESI):Calcd for C15H11F4N4S[M+H]+:355.0641,found:355.0640.
实施例3(E)-4-(2-(4-氟苯亚甲基)肼基)-2-(丙-2-炔-1-基硫代)-6-(三氟甲基)嘧啶的制备(5c)
用4-氟苯甲醛替代3-氟苯甲醛,制备方法同实施例2。
白色固体粉末,收率62.4%;1H NMR(400MHz,DMSO-d6)δ12.19(s,1H),8.22(s,1H),8.05–8.00(m,4H),7.33(s,1H),4.00(d,J=2.5Hz,2H),3.19(t,J=2.6Hz,1H).13C NMR(101MHz,DMSO-d6)δ170.09,161.97,152.63,147.84,141.66,127.28,124.40,122.01,119.16,117.08,114.31,95.70,79.91,73.40,61.18,55.75,18.57.HR-MS(ESI):Calcd forC15H11F4N4S[M+H]+:355.0641,found:355.0642.
实施例4(E)-4-(2-(2-氯苯亚甲基)肼基)-2-(丙-2-炔-1-基硫代)-6-(三氟甲基)嘧啶(5d)
用2-氯苯甲醛替代3-氟苯甲醛,制备方法同实施例2。
白色固体粉末,收率62.7%;1H NMR(400MHz,DMSO-d6)δ12.33(s,1H),8.62(s,1H),8.13–8.05(m,1H),7.52–7.46(m,1H),7.46–7.39(m,2H),7.27(s,1H),4.00(d,J=2.5Hz,2H),3.19(t,J=2.5Hz,1H).13C NMR(101MHz,DMSO-d6)δ192.55,169.80,161.88,145.30,141.43,139.13,132.63,130.27,128.86,127.53,126.89,126.50,119.28,95.80,79.76,73.31,18.44.HR-MS(ESI):Calcd for.C15H11Cl F3N4S[M+H]+:371.0345,found:371.0344.
实施例5(E)-4-(2-(3-氯苯亚甲基)肼基)-2-(丙-2-炔-1-基硫代)-6-(三氟甲基)嘧啶(5e)
用3-氯苯甲醛替代3-氟苯甲醛,制备方法同实施例2。
白色固体粉末,收率59.8%;1H NMR(400MHz,DMSO-d6)δ12.28(s,1H),8.19(s,1H),7.86(s,1H),7.74(s,1H),7.48(d,J=4.7Hz,2H),7.34(s,1H),3.99(d,J=2.5Hz,2H),3.18(t,J=2.5Hz,1H).13C NMR(101MHz,DMSO-d6)δ169.94,162.12,153.79,144.21,136.05,133.69,130.65,129.68,126.38,125.72,121.93,119.20,96.15,79.87,73.44,18.58.HR-MS(ESI):Calcd for.C15H11Cl F3N4S[M+H]+:371.0345,found:371.0344.
实施例6(E)-4-(2-(4-氯苯亚甲基)肼基)-2-(丙-2-炔-1-基硫代)-6-(三氟甲基)嘧啶(5f)
用4-氯苯甲醛替代3-氟苯甲醛,制备方法同实施例2。
白色固体粉末,收率60.3%;1H NMR(400MHz,DMSO-d6)δ12.11(s,1H),8.51(s,1H),7.86(d,J=7.6Hz,1H),7.31–7.25(m,3H),7.20(s,1H),3.99(d,J=2.5Hz,2H),3.19(t,J=2.5Hz,1H).13C NMR(101MHz,DMSO-d6)δ169.84,161.69,144.75,136.84,131.74,130.80,129.66,129.43,126.10,121.77,119.19,95.76,79.90,73.39,19.20,18.57.HR-MS(ESI):Calcd for.C15H11Cl F3N4S[M+H]+:371.0345,found:371.0344.
实施例7(E)-4-(2-(3,4-二氟苯亚甲基)肼基)-2-(丙-2-炔-1-基硫代)-6-(三氟甲基)嘧啶(5g)
用3,4-二氟苯甲醛替代3-氟苯甲醛,制备方法同实施例2。
白色固体粉末,收率33.1%;1H NMR(400MHz,DMSO-d6)δ12.26(s,1H),8.16(s,1H),7.94(d,J=8.3Hz,1H),7.64–7.57(m,1H),7.51(dd,J=10.3,8.4Hz,1H),7.36(s,1H),3.98(d,J=2.6Hz,2H),3.18(t,J=2.6Hz,1H).13C NMR(101MHz,DMSO-d6)δ169.86,161.93,159.82,143.02,132.04,124.39,121.52,119.14,117.99,117.70,116.50,115.40,115.22,96.20,80.14,73.71,18.49.HR-MS(ESI)calcd for C15H10F5N4S[M+H]+:373.0546,found:373.0547.
实施例8(E)-4-(2-(2-甲基亚苄基)肼基)-2-(丙-2-炔-1-基硫代)-6-(三氟甲基)嘧啶(5h)
用2-甲基苯甲醛替代3-氟苯甲醛,制备方法同实施例2。
白色固体粉末,收率59.0%;1H NMR(400MHz,DMSO-d6)δ12.14(s,1H),8.57(s,1H),7.94(dd,J=7.7,1.4Hz,1H),7.46–7.39(m,1H),7.25(s,1H),7.10(d,J=8.2Hz,1H),7.02(t,J=7.5Hz,1H),3.98(d,J=2.6Hz,2H),3.87(s,3H),3.18(t,J=2.6Hz,1H).13C NMR(101MHz,DMSO-d6)δ192.55,169.80,161.88,145.30,141.43,139.13,132.63,130.27,128.86,127.53,126.89,126.50,119.28,95.80,79.76,73.31,18.44.HR-MS(ESI)calcdfor C16H15F3N4OS[M+OH]-:367.0840,found:367.0800.
实施例9(E)-4-(2-(4-甲基亚苄基)肼基)-2-(丙-2-炔-1-基硫代)-6-(三氟甲基)嘧啶(5i)
用4-甲基苯甲醛替代3-氟苯甲醛,制备方法同实施例2。
白色固体粉末,收率48.0%;1H NMR(400MHz,DMSO-d6)δ12.12(s,1H),8.18(s,1H),7.65(d,J=8.1Hz,2H),7.28(d,J=6.7Hz,1H),7.25(d,J=4.0Hz,2H),3.98(d,J=2.5Hz,2H),3.35(s,3H),3.18(t,J=2.6Hz,1H).13C NMR(101MHz,DMSO-d6)δ169.88,161.94,153.55,145.96,139.96,131.11,129.42,129.28,129.06,127.03,121.96,95.84,79.90,73.43,21.01,18.55.HR-MS(ESI)calcd forC16H15F3N4OS[M+OH]-:367.0840,found:367.0841.
实施例10(E)-4-(2-(2-甲氧基亚苄基)肼基)-2-(丙-2-炔-1-基硫代)-6-(三氟甲基)嘧啶(5j)
用2-甲氧基苯甲醛替代3-氟苯甲醛,制备方法同实施例2。
白色固体粉末,收率47.3%;1H NMR(400MHz,DMSO-d6)δ12.15(s,1H),8.57(s,1H),7.95(dd,J=7.7,1.3Hz,1H),7.45–7.39(m,1H),7.25(s,1H),7.11(d,J=8.2Hz,1H),7.02(t,J=7.5Hz,1H),3.98(d,J=2.6Hz,2H),3.86(s,3H),3.18(t,J=2.6Hz,1H).13C NMR(101MHz,DMSO-d6)δ169.88,161.93,157.58,153.54,141.45,131.63,125.65,121.85,120.78,119.22,111.81,95.89,79.91,73.41,55.71,18.55.HR-MS(ESI)calcd forC16H14F3N4OS[M+H]+:367.0840,found:367.0841.
实施例11(E)-4-(2-(3-甲氧基亚苄基)肼基)-2-(丙-2-炔-1-基硫代)-6-(三氟甲基)嘧啶(5k)
用3-甲氧基苯甲醛替代3-氟苯甲醛,制备方法同实施例2。
白色固体粉末,收率47.5%;1H NMR(400MHz,DMSO-d6)δ12.18(s,1H),8.18(s,1H),7.37(s,1H),7.35(d,J=2.5Hz,1H),7.30(s,1H),7.27(s,1H),7.01(ddd,J=7.7,2.5,1.6Hz,1H),3.99(d,J=2.5Hz,2H),3.85–3.80(m,3H),3.18(t,J=2.6Hz,1H).13C NMR(101MHz,DMSO-d6)δ170.08,161.93,159.53,145.70,135.21,129.90,129.63,121.90,119.57,115.95,111.83,95.95,79.87,73.42,55.14,18.56.HR-MS(ESI)calcd forC16H14F3N4OS[M+H]+:367.0840,found:367.0842.
实施例12(E)-4-(2-(4-甲氧基亚苄基)肼基)-2-(丙-2-炔-1-基硫代)-6-(三氟甲基)嘧啶(5l)
用4-甲氧基苯甲醛替代3-氟苯甲醛,制备方法同实施例2。
白色固体粉末,收率72.1%;1H NMR(400MHz,DMSO-d6)δ12.07(s,1H),8.16(s,1H),7.71(d,J=8.8Hz,2H),7.23(s,1H),7.01(d,J=8.8Hz,2H),3.98(d,J=2.5Hz,2H),3.18(t,J=2.6Hz,1H).13C NMR(101MHz,DMSO-d6)δ192.55,169.80,161.88,145.30,141.43,139.13,132.63,130.27,128.86,127.53,126.89,126.50,119.28,95.80,79.76,73.31,18.44.HR-MS(ESI)calcd for C16H14F3N4OS[M+H]+:367.0840,found:367.0839.
实施例13(E)-4-(2-(2,3-二甲氧基亚苄基)肼基)-2-(丙-2-炔-1-基硫代)-6-(三氟甲基)嘧啶(5m)
用2,3-二甲氧基苯甲醛替代3-氟苯甲醛,制备方法同实施例2。
白色固体粉末,收率67.2%;1H NMR(400MHz,DMSO-d6)δ12.15(s,1H),8.52(s,1H),7.54(dd,J=6.7,2.5Hz,1H),7.24(s,1H),7.18–7.10(m,2H),3.99(t,J=7.9Hz,2H),3.84(s,3H),3.79(s,3H),3.17(t,J=2.5Hz,1H).13C NMR(101MHz,DMSO-d6)δ192.55,169.80,161.88,145.30,141.43,139.13,132.63,130.27,128.86,127.53,126.89,126.50,119.28,95.80,79.76,73.31,18.44.HR-MS(ESI)calcd for C17H18F3N4O3S[M+H3O]+:415.1052,found:415.2080.
实施例14(E)-4-(2-(苯并[c]噻吩-1-基亚甲基)肼基)-2-(丙-2-炔-1-基硫代)-6-(三氟甲基)嘧啶(5n)
用2-噻吩甲醛替代3-氟苯甲醛,制备方法同实施例2。
白色固体粉末,收率70.2%;1H NMR(400MHz,DMSO-d6)δ12.19(s,1H),8.86(s,1H),8.40(s,1H),7.68(d,J=5.0Hz,1H),7.49(d,J=2.9Hz,1H),7.06(s,1H),3.98(d,J=2.5Hz,2H),3.18(t,J=2.6Hz,1H).13C NMR(101MHz,DMSO-d6)δ170.00,161.64,155.72,140.87,138.50,133.75,130.96,130.83,128.96,128.01,79.89,73.46,18.46.HR-MS(ESI)calcd for C13H10F3N4S 2[M+H]+:343.0299,found:343.0300.
实施例15(E)-2-(丙-2-炔-1-基硫基)-4-(2-(吡啶-2-基亚甲基)肼基)-6-(三氟甲基)嘧啶(5o)
用2-吡啶甲醛替代3-氟苯甲醛,制备方法同实施例2。
白色固体粉末,收率58.6%;1H NMR(400MHz,DMSO-d6)δ12.37(s,1H),8.61(d,J=4.7Hz,1H),8.25(s,1H),8.11(d,J=7.9Hz,1H),7.88(dd,J=10.9,4.5Hz,1H),7.46–7.39(m,1H),7.35(s,1H),4.00(d,J=2.5Hz,2H),3.19(t,J=2.5Hz,1H).13C NMR(101MHz,DMSO-d6)δ170.07,162.17,159.73,152.70,149.47,146.42,146.11,136.82,124.34,120.18,96.18,79.85,73.46,20.18,18.61.HR-MS(ESI)calcd for C14H11F3N5S[M+H]+:338.0687,found:338.0686.
实施例16(E)-2-(丙-2-炔-1-基硫基)-4-(2-(吡啶-3-基亚甲基)肼基)-6-(三氟甲基)嘧啶(5p)
用3-吡啶甲醛替代3-氟苯甲醛,制备方法同实施例2。
白色固体粉末,收率59.4%;1H NMR(400MHz,DMSO-d6)δ12.34(s,1H),8.92(s,1H),8.61(d,J=4.6Hz,1H),8.24(d,J=8.3Hz,2H),7.48(dd,J=7.8,4.6Hz,1H),7.36(s,1H),3.99(d,J=2.4Hz,2H),3.19(d,J=2.6Hz,1H).13C NMR(101MHz,DMSO-d6)δ192.55,169.80,161.88,145.30,141.43,139.13,132.63,130.27,128.86,127.53,126.89,126.50,119.28,95.80,79.76,73.31,18.44.HR-MS(ESI)calcd for C14H11F3N5S[M+H]+:338.0687,found:338.0685.
实施例17(E)-2-(丙-2-炔-1-基硫基)-4-(2-(吡啶-4-基亚甲基)肼基)-6-(三氟甲基)嘧啶(5q)
用4-吡啶甲醛替代3-氟苯甲醛,制备方法同实施例2。
白色固体粉末,收率72.1%;1H NMR(400MHz,DMSO-d6)δ12.44(s,1H),8.65(d,J=5.4Hz,2H),8.19(s,1H),7.74(d,J=5.9Hz,2H),7.37(s,1H),4.00(d,J=2.5Hz,2H),3.19(t,J=2.6Hz,1H).13C NMR(101MHz,DMSO-d6)δ192.55,169.80,161.88,145.30,141.43,139.13,132.63,130.27,128.86,127.53,126.89,126.50,119.28,95.80,79.76,73.31,18.44.HR-MS(ESI)calcd for C14H11F3N5S[M+H]+:338.0687,found:338.0688.
实施例18(E)-4-(2-(蒽-9-基亚甲基)肼基)-2-(丙-2-炔-1-基硫代)-6-(三氟甲基)嘧啶(5s)
用9-蒽甲醛替代3-氟苯甲醛,制备方法同实施例2。
白色固体粉末,收率58.4%;1H NMR(400MHz,DMSO-d6)δ12.40(s,1H),9.46(s,1H),8.75(s,1H),8.62(d,J=8.7Hz,2H),8.18(d,J=8.3Hz,2H),7.71–7.64(m,2H),7.63–7.57(m,2H),7.16(s,1H),4.04(s,2H),3.22(t,J=2.5Hz,1H).13C NMR(101MHz,DMSO-d6)δ159.72,149.63,146.39,145.01,143.94,130.99,130.88,129.51,129.05,128.99,128.46,127.29,126.94,125.54,124.65,124.42,119.14,101.69,95.64,79.95,73.44,20.18,18.66.HR-MS(ESI)calcd forC23H16F3N4S[M+H]+:437.1048,found:437.1234.
实施例19(E)-4-(2-([1,1'-联苯]-4-基亚甲基)肼基)-2-(丙-2-炔-1-基硫代)-6-(三氟甲基)嘧啶(5w)
用4-苯基苯甲醛替代3-氟苯甲醛,制备方法同实施例2。
白色固体粉末,收率72.3%;1H NMR(400MHz,DMSO-d6)δ12.23(s,1H),8.26(s,1H),7.86(d,J=8.3Hz,2H),7.76(d,J=8.3Hz,2H),7.72(d,J=7.5Hz,2H),7.50(t,J=7.6Hz,3H),7.40(t,J=7.3Hz,1H),7.30(s,1H),3.99(d,J=2.4Hz,2H),3.18(t,J=2.5Hz,1H).13CNMR(101MHz,DMSO-d6)δ192.55,169.80,161.88,145.30,141.43,139.13,132.63,130.27,128.86,127.53,126.89,126.50,119.28,95.80,79.76,73.31,18.44.HR-MS(ESI)calcdfor C23H16F3N4S[M+H]+:437.1048,found:437.1234.
实施例20(E)-3-((2-(2-(丙-2-炔-1-基硫代)-6-(三氟甲基)嘧啶-4-基)亚肼基)甲基)苯酚(5t)
用3-羟基苯甲醛替代3-氟苯甲醛,制备方法同实施例2。
白色固体粉末,收率47.5%;1H NMR(400MHz,DMSO-d6)δ12.15(s,1H),9.64(s,1H),8.14(s,1H),7.26(t,J=7.8Hz,1H),7.21(d,J=7.1Hz,2H),7.14(d,J=7.6Hz,1H),6.89–6.80(m,1H),3.99(d,J=2.5Hz,2H),3.18(t,J=2.6Hz,1H).13C NMR(101MHz,DMSO-d6)δ169.97,161.98,157.65,154.04,146.03,135.03,129.90,121.94,119.21,118.65,117.49,112.58,95.76,79.90,73.42,18.57.HR-MS(ESI)calcd for C15H12F3N4OS[M+H]+:353.0684,found:353.0683.
实施例21(E)-4-((2-(2-(丙-2-炔-1-基硫代)-6-(三氟甲基)嘧啶-4-基)亚肼基)甲基)苯酚(5u)
用4-羟基苯甲醛替代3-氟苯甲醛,制备方法同实施例2。
白色固体粉末,收率48.4%;1H NMR(400MHz,DMSO-d6)δ11.34(s,1H),9.96(s,1H),8.12(s,1H),7.60(d,J=8.6Hz,2H),7.20(s,1H),6.84(d,J=8.6Hz,2H),3.97(d,J=2.5Hz,2H),3.17(t,J=2.6Hz,1H).13C NMR(101MHz,DMSO-d6)δ159.74,159.50,151.63,151.29,149.66,146.45,146.24,128.86,124.83,122.06,119.33,115.73,101.70,73.40,20.18,18.51.HR-MS(ESI)calcd for C15H12F3N4OS[M+H]+:353.0684,found:353.0683.
实施例22(E)-1-((2-(2-(丙-2-炔-1-基硫代)-6-(三氟甲基)嘧啶-4-基)亚肼基)甲基)-3H-异吲哚(5v)
用3-吲哚甲醛替代3-氟苯甲醛,制备方法同实施例2。
白色固体粉末,收率53.5%;1H NMR(400MHz,DMSO-d6)δ11.69(s,1H),9.94(s,1H),8.44(s,1H),8.29(d,J=3.1Hz,1H),8.10(d,J=7.4Hz,2H),7.89(d,J=2.6Hz,1H),7.52(d,J=8.0Hz,1H),7.16(s,1H),4.00(t,J=6.5Hz,2H),3.19(t,J=2.6Hz,1H).13C NMR(101MHz,DMSO-d6)δ184.91,169.60,161.24,143.65,138.38,137.12,137.02,130.81,124.09,123.41,122.07,120.78,118.14,112.37,111.02,80.02,73.42,18.49.HR-MS(ESI)calcd for C17H13F3N5S[M+H]+:376.0844,found:376.4000.
应用实例
体外抗肿瘤活性测试:以MTT法采用三种细胞系,分别为人乳腺癌细胞(MCF-7)、胃癌细胞(MGC-803)、前列腺癌细胞(PC-3)。
收集对数期细胞,调整细胞悬液浓度,每孔加入100μl,铺板调整待测细胞密度,(边缘孔用PBS填充)。体积百分比5%CO2下37℃孵育24h,至细胞单层铺满孔底(96孔平地板),加入浓度梯度本发明合成的药物,设9个浓度,每孔200μl,设3个复孔。体积百分比5%CO2下37℃孵育72h,倒置显微镜下观察,每孔加入20μl MTT溶液(5mg/ml,即0.5%MTT),继续培养4h后终止培养,吸去孔内培养液,每孔加入150μl二甲基亚砜,置摇床上低速振荡10min,使结晶物充分溶解。在酶联免疫检测仪OD490 nm处测量各孔的吸光值。用SPSS软件对实验结果进行统计并计算IC50(μmol/L)值,结果如下表1。
表1体外抗肿瘤活性测试表
Claims (5)
2.如权利要求1所述的含席夫碱结构单元的三氟甲基嘧啶类衍生物,其特征在于:选自以下化合物之一:
5a:(E)-4-(2-苯亚甲基)肼基)-2-(丙-2-炔-1-基硫代)-6-(三氟甲基)嘧啶;
5b:(E)-4-(2-(3-氟苯亚甲基)肼基)-2-(丙-2-炔-1-基硫代)-6-(三氟甲基)嘧啶;
5c:(E)-4-(2-(4-氟苯亚甲基)肼基)-2-(丙-2-炔-1-基硫代)-6-(三氟甲基)嘧啶;
5d:(E)-4-(2-(2-氯苯亚甲基)肼基)-2-(丙-2-炔-1-基硫代)-6-(三氟甲基)嘧啶;
5e:(E)-4-(2-(3-氯苯亚甲基)肼基)-2-(丙-2-炔-1-基硫代)-6-(三氟甲基)嘧啶;
5f:(E)-4-(2-(4-氯苯亚甲基)肼基)-2-(丙-2-炔-1-基硫代)-6-(三氟甲基)嘧啶;
5g:(E)-4-(2-(3,4-二氟苯亚甲基)肼基)-2-(丙-2-炔-1-基硫代)-6-(三氟甲基)嘧啶;
5h:(E)-4-(2-(2-甲基亚苄基)肼基)-2-(丙-2-炔-1-基硫代)-6-(三氟甲基)嘧啶;
5i:(E)-4-(2-(4-甲基亚苄基)肼基)-2-(丙-2-炔-1-基硫代)-6-(三氟甲基)嘧啶;
5n:(E)-4-(2-(噻吩-1-基亚甲基)肼基)-2-(丙-2-炔-1-基硫代)-6-(三氟甲基)嘧啶;
5o:(E)-2-(丙-2-炔-1-基硫基)-4-(2-(吡啶-2-基亚甲基)肼基)-6-(三氟甲基)嘧啶;
5p:(E)-2-(丙-2-炔-1-基硫基)-4-(2-(吡啶-3-基亚甲基)肼基)-6-(三氟甲基)嘧啶;
5q:(E)-2-(丙-2-炔-1-基硫基)-4-(2-(吡啶-4-基亚甲基)肼基)-6-(三氟甲基)嘧啶;
5s:(E)-4-(2-(蒽-9-基亚甲基)肼基)-2-(丙-2-炔-1-基硫代)-6-(三氟甲基)嘧啶;
5w:(E)-4-(2-([1,1'-联苯]-4-基亚甲基)肼基)-2-(丙-2-炔-1-基硫代)-6-(三氟甲基)嘧啶;
5t:(E)-3-((2-(2-(丙-2-炔-1-基硫代)-6-(三氟甲基)嘧啶-4-基)亚肼基)甲基)苯酚;
5v:(E)-1-((2-(2-(丙-2-炔-1-基硫代)-6-(三氟甲基)嘧啶-4-基)亚肼基)甲基)-2H-吲哚。
3.制备如权利要求1所述的含席夫碱结构单元的三氟甲基嘧啶类衍生物的方法,其特征在于,通过如下合成步骤实现:
a.将2-巯基-6-(三氟甲基)嘧啶-4-醇和溴代丙炔、氢氧化钾水溶液加入反应器中进行反应,得到化合物2;b.化合物2与三氯氧磷反应,生成化合物3;c.化合物3与水合肼在无水乙醇中反应生成化合物4;d.化合物4与不同的醛类化合物反应得到目标化合物;
所述的醛类化合物为:苯甲醛、3-氟苯甲醛、4-氟苯甲醛、2-氯苯甲醛、3-氯苯甲醛、4-氯苯甲醛、3,4-二氟苯甲醛、2-甲基苯甲醛、4-甲基苯甲醛、2-噻吩甲醛、2-吡啶甲醛、3-吡啶甲醛、4-吡啶甲醛、9-蒽醛、4-苯基苯甲醛、4-羟基苯甲醛、3-羟基苯甲醛或3-吲哚甲醛。
4.如权利要求1-2其中之一所述的含席夫碱结构单元的三氟甲基嘧啶类衍生物在药物制备中的应用,其特征在于,作为活性成分用于制备抗肿瘤药物。
5.如权利要求4所述的含席夫碱结构单元的三氟甲基嘧啶类衍生物在药物制备中的应用,其特征在于,作为活性成分用于制备抗乳腺癌细胞、胃癌细胞或前列腺癌细胞药物。
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