CN104592098B - For antineoplastic piperidones of 3,5 2 aryl methylene of N methyl 4 and its quaternary ammonium salt derivative - Google Patents
For antineoplastic piperidones of 3,5 2 aryl methylene of N methyl 4 and its quaternary ammonium salt derivative Download PDFInfo
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- CN104592098B CN104592098B CN201510051863.6A CN201510051863A CN104592098B CN 104592098 B CN104592098 B CN 104592098B CN 201510051863 A CN201510051863 A CN 201510051863A CN 104592098 B CN104592098 B CN 104592098B
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- methyl
- piperidones
- bis
- methylene
- quaternary ammonium
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- 125000000958 aryl methylene group Chemical group 0.000 title claims abstract description 33
- 150000003242 quaternary ammonium salts Chemical class 0.000 title claims abstract description 28
- 230000000118 anti-neoplastic effect Effects 0.000 title claims abstract description 23
- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical class O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 title claims abstract description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 title abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 49
- -1 aromatic formaldehyde derivative Chemical class 0.000 claims abstract description 42
- 238000002360 preparation method Methods 0.000 claims abstract description 17
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 42
- 239000000543 intermediate Substances 0.000 claims description 35
- 125000003118 aryl group Chemical group 0.000 claims description 32
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 22
- 239000002904 solvent Substances 0.000 claims description 22
- 238000003756 stirring Methods 0.000 claims description 19
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 17
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 17
- 238000001556 precipitation Methods 0.000 claims description 15
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 claims description 14
- 238000001953 recrystallisation Methods 0.000 claims description 14
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- 238000001514 detection method Methods 0.000 claims description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- XTEGARKTQYYJKE-UHFFFAOYSA-M chlorate Inorganic materials [O-]Cl(=O)=O XTEGARKTQYYJKE-UHFFFAOYSA-M 0.000 claims description 10
- HUUPVABNAQUEJW-UHFFFAOYSA-N 1-methylpiperidin-4-one Chemical class CN1CCC(=O)CC1 HUUPVABNAQUEJW-UHFFFAOYSA-N 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- 239000007789 gas Substances 0.000 claims description 8
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 8
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 8
- 125000001424 substituent group Chemical group 0.000 claims description 7
- ZRSNZINYAWTAHE-UHFFFAOYSA-N p-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C=C1 ZRSNZINYAWTAHE-UHFFFAOYSA-N 0.000 claims description 6
- 229960000583 acetic acid Drugs 0.000 claims description 5
- 229910052731 fluorine Inorganic materials 0.000 claims description 5
- 239000011737 fluorine Substances 0.000 claims description 5
- 150000002576 ketones Chemical class 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 5
- 239000002994 raw material Substances 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical class FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 claims description 4
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 4
- 239000012362 glacial acetic acid Substances 0.000 claims description 4
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- OVYTZAASVAZITK-UHFFFAOYSA-M sodium;ethanol;hydroxide Chemical compound [OH-].[Na+].CCO OVYTZAASVAZITK-UHFFFAOYSA-M 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- SUISZCALMBHJQX-UHFFFAOYSA-N 3-bromobenzaldehyde Chemical class BrC1=CC=CC(C=O)=C1 SUISZCALMBHJQX-UHFFFAOYSA-N 0.000 claims description 3
- KBTMGSMZIKLAHN-UHFFFAOYSA-N 4-bromo-1,2-dimethoxybenzene Chemical compound COC1=CC=C(Br)C=C1OC KBTMGSMZIKLAHN-UHFFFAOYSA-N 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 claims description 3
- NVNPLEPBDPJYRZ-UHFFFAOYSA-N 1-(bromomethyl)-4-fluorobenzene Chemical group FC1=CC=C(CBr)C=C1 NVNPLEPBDPJYRZ-UHFFFAOYSA-N 0.000 claims description 2
- 150000001299 aldehydes Chemical class 0.000 claims description 2
- 150000003935 benzaldehydes Chemical class 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 230000031709 bromination Effects 0.000 claims description 2
- 238000005893 bromination reaction Methods 0.000 claims description 2
- 125000003963 dichloro group Chemical group Cl* 0.000 claims description 2
- 239000002244 precipitate Substances 0.000 claims description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 claims 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims 1
- ATHHXGZTWNVVOU-UHFFFAOYSA-N N-methylformamide Chemical compound CNC=O ATHHXGZTWNVVOU-UHFFFAOYSA-N 0.000 claims 1
- MHABMANUFPZXEB-UHFFFAOYSA-N O-demethyl-aloesaponarin I Natural products O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(O)C(C(O)=O)=C2C MHABMANUFPZXEB-UHFFFAOYSA-N 0.000 claims 1
- 238000006555 catalytic reaction Methods 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 229940113088 dimethylacetamide Drugs 0.000 claims 1
- 239000000463 material Substances 0.000 claims 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 claims 1
- 150000003839 salts Chemical class 0.000 claims 1
- 210000004027 cell Anatomy 0.000 abstract description 13
- 210000004881 tumor cell Anatomy 0.000 abstract description 10
- 230000000259 anti-tumor effect Effects 0.000 abstract description 9
- 239000003814 drug Substances 0.000 abstract description 7
- 230000008901 benefit Effects 0.000 abstract description 4
- 231100000025 genetic toxicology Toxicity 0.000 abstract description 3
- 230000001738 genotoxic effect Effects 0.000 abstract description 3
- 230000010354 integration Effects 0.000 abstract description 3
- 230000002441 reversible effect Effects 0.000 abstract description 3
- 231100000419 toxicity Toxicity 0.000 abstract description 3
- 230000001988 toxicity Effects 0.000 abstract description 3
- 238000009833 condensation Methods 0.000 abstract 1
- 230000005494 condensation Effects 0.000 abstract 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 48
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
- 238000004809 thin layer chromatography Methods 0.000 description 21
- 238000000967 suction filtration Methods 0.000 description 15
- 230000015572 biosynthetic process Effects 0.000 description 13
- 150000001875 compounds Chemical class 0.000 description 13
- 238000003786 synthesis reaction Methods 0.000 description 12
- 238000000034 method Methods 0.000 description 11
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- 125000003968 arylidene group Chemical group [H]C(c)=* 0.000 description 8
- 235000019441 ethanol Nutrition 0.000 description 7
- 239000008188 pellet Substances 0.000 description 7
- 230000008569 process Effects 0.000 description 7
- 238000004458 analytical method Methods 0.000 description 5
- 230000001376 precipitating effect Effects 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 4
- 108010087230 Sincalide Proteins 0.000 description 3
- 125000000649 benzylidene group Chemical group [H]C(=[*])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 3
- 238000010609 cell counting kit-8 assay Methods 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 231100000135 cytotoxicity Toxicity 0.000 description 3
- 230000003013 cytotoxicity Effects 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
- 230000036457 multidrug resistance Effects 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 3
- UQQROBHFUDBOOK-UHFFFAOYSA-N 2-bromo-4,5-dimethoxybenzaldehyde Chemical class COC1=CC(Br)=C(C=O)C=C1OC UQQROBHFUDBOOK-UHFFFAOYSA-N 0.000 description 2
- UOQXIWFBQSVDPP-UHFFFAOYSA-N 4-fluorobenzaldehyde Chemical class FC1=CC=C(C=O)C=C1 UOQXIWFBQSVDPP-UHFFFAOYSA-N 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 2
- 229940073608 benzyl chloride Drugs 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- QBKSWRVVCFFDOT-UHFFFAOYSA-N gossypol Chemical compound CC(C)C1=C(O)C(O)=C(C=O)C2=C(O)C(C=3C(O)=C4C(C=O)=C(O)C(O)=C(C4=CC=3C)C(C)C)=C(C)C=C21 QBKSWRVVCFFDOT-UHFFFAOYSA-N 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- NBVXSUQYWXRMNV-UHFFFAOYSA-N monofluoromethane Natural products FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 description 2
- 150000007523 nucleic acids Chemical class 0.000 description 2
- 102000039446 nucleic acids Human genes 0.000 description 2
- 108020004707 nucleic acids Proteins 0.000 description 2
- GTLWADFFABIGAE-UHFFFAOYSA-N 1-chloroethylbenzene Chemical compound CC(Cl)C1=CC=CC=C1 GTLWADFFABIGAE-UHFFFAOYSA-N 0.000 description 1
- 102100033350 ATP-dependent translocase ABCB1 Human genes 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
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- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 241001175904 Labeo bata Species 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 108010047230 Member 1 Subfamily B ATP Binding Cassette Transporter Proteins 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- QHOPXUFELLHKAS-UHFFFAOYSA-N Thespesin Natural products CC(C)c1c(O)c(O)c2C(O)Oc3c(c(C)cc1c23)-c1c2OC(O)c3c(O)c(O)c(C(C)C)c(cc1C)c23 QHOPXUFELLHKAS-UHFFFAOYSA-N 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 238000005882 aldol condensation reaction Methods 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- WRUAHXANJKHFIL-UHFFFAOYSA-N benzene-1,3-disulfonic acid Chemical class OS(=O)(=O)C1=CC=CC(S(O)(=O)=O)=C1 WRUAHXANJKHFIL-UHFFFAOYSA-N 0.000 description 1
- JFKWZVQEMSKSBU-UHFFFAOYSA-N benzyl 2-hydroxy-2-phenylacetate Chemical compound C=1C=CC=CC=1C(O)C(=O)OCC1=CC=CC=C1 JFKWZVQEMSKSBU-UHFFFAOYSA-N 0.000 description 1
- 201000008275 breast carcinoma Diseases 0.000 description 1
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical class BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 1
- 210000003850 cellular structure Anatomy 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000035572 chemosensitivity Effects 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 125000005909 ethyl alcohol group Chemical group 0.000 description 1
- 229930000755 gossypol Natural products 0.000 description 1
- 229950005277 gossypol Drugs 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000012313 reversal agent Substances 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- VSIVTUIKYVGDCX-UHFFFAOYSA-M sodium;4-[2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)tetrazol-2-ium-5-yl]benzene-1,3-disulfonate Chemical compound [Na+].COC1=CC([N+]([O-])=O)=CC=C1[N+]1=NC(C=2C(=CC(=CC=2)S([O-])(=O)=O)S([O-])(=O)=O)=NN1C1=CC=C([N+]([O-])=O)C=C1 VSIVTUIKYVGDCX-UHFFFAOYSA-M 0.000 description 1
- 235000013599 spices Nutrition 0.000 description 1
- 239000000052 vinegar Substances 0.000 description 1
- 235000021419 vinegar Nutrition 0.000 description 1
Classifications
-
- 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
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/68—One oxygen atom attached in position 4
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a kind of antineoplastic, and in particular to one kind is used for antineoplastic piperidones of 3,5 two aryl methylene of N methyl 4 and its quaternary ammonium salt derivative.Its preparation method is to carry out the reaction of Clarkson Schmidt condensation by the piperidones of N methyl 4 and aromatic formaldehyde derivative to obtain intermediate, and then quaterisation is carried out by intermediate and benzyl halogen and N methyl Ns R 3 is obtained, the piperidones quaternary ammonium salt derivative of 5 two aryl methylene 4.The piperidones of 3,5 two aryl methylene of N methyl 4 and its quaternary ammonium salt derivative structure are novel, the genotoxicity that the antineoplastic used now can be avoided to have, and the advantage with polymolecular targeted integration, while having multi-medicine tolerant reversal activity.Its antitumor activity having has bigger toxicity compared with normal cell to tumour cell, thus has great application prospect in field of antineoplastic medicaments.
Description
Technical field
The present invention relates to a kind of antineoplastic, and in particular to one kind is used for the fragrant methylene of antineoplastic N- methyl -3,5- bis-
Base -4- piperidones and its quaternary ammonium salt derivative.
Background technology
Aryl methylene -4- the derivative of piperidone of 3,5- bis- is the change that a class cyclic, bata beta-unsaturated ketone is combined with β amino ketones
Compound.α, beta unsaturated ketone class compound numbers are numerous, are the very important organic synthesis intermediates of a class, are widely used in doctor
The fields such as medicine, chemical industry and spices.The research such as Dimmock shows that many α, beta unsaturated ketone show cytotoxicity and antitumor work
Property, the mode of action of this kind of compound is unique, and they have significant affinity to non-existent sulfydryl in nucleic acid, and right
It is present in amino and hydroxyl affinity very little or almost no affinity, therefore many anticancers used now can be avoided in nucleic acid
The genotoxicity of medicine；Further, since many cell components all contain sulfydryl, so such compound also has and polymolecular target spot
With reference to advantage.Because it has the advantage with polymolecular targeted integration, therefore such compound is the antitumor of class formation novelty
Reactive compound.In addition research is it has also been found that such compound can avoid multidrug resistance by reversing P- glycoprotein, therefore
It is possible to therefrom find effective MDR reversal agentses.
The drug effect center of such compound is 1,5- diaryl -3- oxygen-Isosorbide-5-Nitrae-pentadienyl, can after being combined with piperidones ring
With to sulfydryl formation continuous alkylation twice, as shown in figure 1, this is a main knot of such compound and tumour cell
Site is closed, and after the nitrogen-atoms in piperidones is substituted, then can form the binding site of another auxiliary, so as to be converted into one
The alkylating agent of individual three functions base, as shown in Fig. 2 so much such compound antitumor effect are significant.In many cases, with
Normal cell is stronger compared to the chemosensitivity of tumour cell, and this continuous chemical bond makes tumour cell be easier to be hindered
Evil, therefore there is bigger toxicity to tumour cell, it, which is studied, is expected to therefrom search out to the new anti-of normal cytotoxic
Tumour medicine.
The content of the invention
It is an object of the invention to find small to normal cytotoxicity or avirulent new type antineoplastic medicine, and can
Reverse the reversal agent of existing antineoplastic multidrug resistance there is provided one kind be used for antineoplastic aryl methylene of N- methyl -3,5- bis- -
4- piperidones and its quaternary ammonium salt derivative, its structure are novel, and with antitumor activity and multi-medicine tolerant reversal activity；The present invention
The preparation method of the antineoplastic is also provided simultaneously.
The present invention is achieved by the following technical solutions：
For antineoplastic aryl methylene -4- piperidones of N- methyl -3,5- bis- and its quaternary ammonium salt derivative, special character exists
It is in its structural formula
The R1Substituent is the bromo- 4,5- dimethoxybenzylidens of 2-4- fluorobenzylidenes4- trifluoromethyl benzylidenes3- bromobenzene methylene4- methoxybenzene methylenes
BaseAny of；The R2Substituent is hydrogen atom H, 4- luorobenzylBenzyl4- methoxies
Base benzylIn any one.
The X-For Br-Or Cl-。
R2When substituent is hydrogen atom, derivative is respectively designated as (the 2- bromo-4,5-dimethoxy benzene of N- methyl -3,5- bis-
Methylene) bis- (4- tri- of -4- piperidones 1a, N- methyl -3,5- bis- (4- fluorobenzylidenes) -4- piperidones 2a, N- methyl -3,5-
Methyl fluoride benzylidene) -4- piperidones Bromide 3a, N- methyl -3,5- bis- (3- bromobenzenes methylene) -4- piperidones 4a, N- first
Base -3,5- two (4- methoxybenzylidenes) -4- piperidones Bromides 5a；
R2When substituent is 4- luorobenzyls, derivative is respectively designated as N- methyl-N- (4- luorobenzyls), and (2- is bromo- by -3,5- bis-
4,5- dimethoxybenzylidens) -4- piperidones Bromide 1b, N- methyl-N- (4- luorobenzyls) (4- fluorobenzene methylenes of -3,5- bis-
Base) -4- piperidones 2b, N- methyl-N- (4- luorobenzyls) -3,5- bis- (4- trifluoromethyls benzylidene) -4- piperidones Bromides
3b, N- methyl-N- (4- luorobenzyls) (3- bromobenzenes methylene) -4- piperidones 4b, the N- methyl-N- of -3,5- bis- (4- luorobenzyls) -3,
5- bis- (4- methoxybenzylidenes) -4- piperidones Bromides 5b；
R2When substituent is benzyl, derivative is respectively designated as (bromo- 4, the 5- dimethoxies of 2- of N- methyl-N-benzyls -3,5- bis-
Base benzylidene) -4- piperidones Bromide 1c, N- methyl-N-benzyl -3,5- bis- (4- fluorobenzylidenes) -4- piperidones 2c, N-
Methyl-N-benzyl -3,5- bis- (4- trifluoromethyls benzylidene) -4- piperidones Bromide 3c, N- methyl-N-benzyl -3,5- bis-
(4- the methoxybenzylidenes) -4- piperidones brominations of (3- bromobenzenes methylene) -4- piperidones 4c, N- methyl-N-benzyl -3,5- bis-
Salt 5c；
R2When substituent is (4- methoxy-benzyls), derivative is respectively designated as N- methyl-N- (4- methoxy-benzyls) -3,
(2- bromo-4,5-dimethoxies benzylidene) -4- piperidones chlorate 1d, the N- methyl-N- of 5- bis- (4- methoxy-benzyls) -3,5-
Two (4- fluorobenzylidenes) -4- piperidones chlorate 2d, N- methyl-N- (4- methoxy-benzyls) (4- trifluoromethylbenzenes of -3,5- bis-
Methylene) -4- piperidones chlorate 3d, N- methyl-N- (4- methoxy-benzyls) -3,5- bis- (3- bromobenzenes methylene) -4- piperidines
Ketone chlorate 4d, N- methyl-N- (4- methoxy-benzyls) -3,5- bis- (4- methoxybenzylidenes) -4- piperidones chlorates 5d.
The preparation method of the above-mentioned aryl methylene -4- piperidones of N- methyl -3,5- bis- and its quaternary ammonium salt derivative, its principle
For：It is by N- methyl -4- for antineoplastic aryl methylene -4- piperidones of N- methyl -3,5- two and its quaternary ammonium salt derivative
Piperidones and aromatic formaldehyde derivative carry out Claisen-Schmidt condensation reaction obtain the aryl methylenes of intermediate N methyl -3,5- two -
4- piperidones 1a-5a, and then quaterisation is carried out by intermediate 1a-5a and benzyl halogen and N- methyl-N-R-3 are obtained, 5- bis-
Aryl methylene -4- piperidones quaternary ammonium salt derivatives 1b-1d, 2b-2d, 3b-3d, 4b-4d, 5b-5d.
The preparation method is characterized in that it comprises the following steps：
(1), the aryl methylene -4- piperidones intermediates 1a-5a of N- methyl -3,5- two preparation
Aromatic formaldehyde derivative and N- methyl -4- piperidones are raw material, are mixed in alcohol solvent or glacial acetic acid solvent, addition
Catalyst, reaction is finished, and collects precipitation, and the aryl methylene -4- piperidones intermediates of N- methyl -3,5- bis- are made in recrystallization operation
1a-5a；
(2), N- methyl-N-R-3,5- bis- aryl methylene -4- piperidones quaternary ammonium salt derivative 1b-1d, 2b-2d, 3b-3d,
4b-4d, 5b-5d preparation
Using replace benzyl halogen and the aryl methylene -4- piperidones intermediate 1a-5a of gained N- methyl -3,5- two in step (1) as
Raw material, the two mol ratio is 1.2:1-1.8:1；
Intermediate 1a-5a dissolves in organic solvent, and the heating stirring in oil bath is until intermediate all dissolvings, rear to add
Replace benzyl halogen, continue oil bath stirring, and reaction process is detected with TCL, addition ether is complete to precipitating after completion of the reaction, collects and sinks
Form sediment, N- methyl-N-R-3,5- bis- aryl methylene -4- piperidones quaternary ammonium salt derivative 1b-1d, 2b-2d is made in recrystallization operation,
3b-3d, 4b-4d, 5b-5d.
Because substitution benzyl halogen is unstable, therefore the present invention replaces the mol ratio of benzyl halogen and intermediate 1a-5a to be more than 1 in preparing, with
Ensure that reaction is complete, improve yield.
A modification of the present invention scheme is, per in 0.01mol N- methyl -4- piperidones raw materials in the step (1)
Add N- methyl -3,5- bis- per 0.001mol in 23-27mL glacial acetic acid solvents or 48-52mL alcohol solvent, step (2)
Aryl methylene -4- piperidones intermediates 1a-5a adds 1.8-2.2mL solvent.
Second of improvement project of the present invention is that low-temp reaction bathes controlling reaction temperature in 15-25 in the step (1)
DEG C, the control reaction time was at 7-24 hours；Oil bath controlling reaction temperature is at 75-95 DEG C in step (2), and the control reaction time exists
0.5-5 hours, to carry out reaction synthesis under preferably reaction condition.
The third improvement project of the present invention is that catalyst is the hydroxide that mass fraction is 10% in the step (1)
Sodium ethoxide solution or the hydrogen chloride gas of drying, hydrogen chloride gas are passed through the time for 45min-1.5h, using sodium hydroxide ethanol
Intermediate 1a-5a is directly made during solution, when making catalyst using dry hydrogen chloride gas, reaction, which is finished, need to use quality point
Number washs for 10% sodium hydroxide solution, and to neutralize acid solution, intermediate 1a-5a is made in recrystallization operation.
Organic solvent used in intermediate in recrystallization solvent for use and step (2) is made in preparation method of the present invention
Limitation selection, to coordinate invention course of reaction and product characteristicses, does not influence the derivative product property of generation, thus, it is described
Recrystallization operation solvent for use is acetone, ether, water, alcohol, chloroform, dichloromethane, N,N-dimethylformamide, N, N- dimethyl
At least one of acetamide；Organic solvent is in N,N-dimethylformamide, tetrahydrofuran, acetone, alcohol in step (2)
Any one.
Aryl methylene -4- piperidones intermediate the 1a-5a of N- methyl -3,5- bis- of complex reaction generation, the step (1)
Middle aromatic formaldehyde derivative is from the adaptable bromo- 4,5- dimethoxy benzaldehydes of 2-, 4- fluorobenzaldehydes, 4- trifluoromethylbenzene first
Any one in aldehyde, 3- bromobenzaldehydes, 4-methoxybenzaldehyde, so as to react obtained above intermediate.
N- methyl-N-R-3,5- bis- aryl methylene -4- piperidones the quaternary ammonium salts 1b-1d, 2b-2d, 3b- of complex reaction generation
Replace benzyl halogen in 15 kinds of derivatives of 3d, 4b-4d, 5b-5d, the step (2) from adaptable 4- fluorobenzyl bromides, benzyl bromine, 4-
Any one in methoxyl group benzyl chloride, thus react be made more than 15 kinds of derivatives.
Further, TCL detections solvent chloroform used in the step (2)：Methanol ratio is 10:1、15:1、20:
1、30:Any one in 1.
Aryl methylene -4- the piperidones of N- methyl -3,5- bis- and its quaternary ammonium salt derivative structure are novel, can avoid making now
The genotoxicity that antineoplastic has, and the advantage with polymolecular targeted integration, while having multidrug resistance inverse
Turning a work property.Its antitumor activity having has bigger toxicity compared with normal cell to tumour cell, thus antitumor
Drug field has great application prospect.
Brief description of the drawings
Fig. 1：The continuous knot of the aryl methylene -4- piperidones of N- methyl-N-R-3,5- two and its quaternary ammonium salt derivative and sulfydryl
Conjunction mode and binding site A and B figure；
Fig. 2：Aryl methylene -4- the piperidones of N- methyl-N-R-3,5- two and its quaternary ammonium salt derivative chemical reactive synthesis road
Line chart.
Embodiment
Embodiment of the invention given below, for the present invention is further described.
Embodiment 1
(4- trifluoromethyls the benzylidene) -4- piperidones intermediates of N- methyl -3,5- two 3a synthesis
The 4- trifluoromethylated benzaldehydes of 0.005mol N- methyl -4- piperidones and 0.01mol are mixed in 12.5mL ice
In acetic acid, dry HCl gas 45min, stirring reaction 7-24h are passed through at room temperature, it is true by TLC thin-layered chromatography tlc analysis
Determine reaction end.Suction filtration after completion of the reaction, gained precipitation adds the sodium hydroxide solution that 12.5mL mass fractions are 10%, room temperature
Lower stirring 0.5h, suction filtration, with recrystallizing methanol, obtains N- methyl -3,5- bis- (4- trifluoromethyls benzylidene) -4- piperidones
2.82g, yield is 48%, 122-126 DEG C of fusing point.
UVλmax(logε)316(0.848),214(2.102)nm.IR(KBr Pellet cm-1):2785(w),1415
(m),3347(m),696(m),1614(s),1583(m),2360(m),2332(m),1325(s),1277(s),1171(s),
825(m),924(m),1117(s),1070(s).1H NMR(400MHz,DMSO,25℃,TMS,ppm):δ=3.01 (s, 3H,
NCH3), 3.69 (s, 3H, aryl OCH3), 4.65 (s, 2H, C6H5CH2), 4.83-4.88 (d, J=14.3Hz, 4H,
), CH2NCH2 7.13-7.17 (t, 2H, aryl H), 7.41-7.44 (t, 2H, aryl H), 7.73-7.75 (d, 4H, J=
8.0Hz, aryl H), 7.91-7.93 (d, 4H, J=8.0Hz, aryl H), 8.18 (s, 2H, arylidene H) .13C NMR
(100MHz,DMSO)δ(ppm):48.46(NCH3),55.11(OCH3),58.65(2NCH2),64.76(CH2),114.07,
(q, J=270.69Hz, CF3), 118.76,123.94 125.69 (125.72), 127.13,129.93 (q, J=31.83Hz,
aryl C),131.21,134.21,137.13,140.91,160.63,180.60(CO).
Embodiment 2
N- methyl-N- (4- luorobenzyls) -3,5- two (4- trifluoromethyls benzylidene) -4- piperidones Bromides 3b synthesis
0.001mol intermediates 3a and 1.5mL DMF solution are mixed in 25ml two-mouth bottles, 80 DEG C
Under be heated with stirring to intermediate 3a dissolvings, the rear 0.0015mol that is added dropwise detects the process of reaction, TLC with TLC to fluorine bromobenzyl solution
Solvent dichloromethane in detection：Methanol is 15:1, reaction is finished, and is washed 2-3 times with ether, complete to precipitating, and passes through suction filtration
Operation collect precipitation, after carry out recrystallization operation with methanol, obtain N- methyl-N- (4- luorobenzyls) (4- trifluoromethylbenzenes of -3,5- bis-
Methylene) -4- piperidones Bromide 0.315g, yield is 59.0%, 184-189 DEG C of fusing point.
UVλmax(logε)308(0.436),220(0.360)nm.IR(KBr Pellet cm-1):3400(w),1415
(m),1514(m),600.99(m),696(m),854(m),1612(s),1327(s),1174(s),1070(s),1119(s)
.1H NMR(400MHz,DMSO,25℃,TMS,ppm):δ=3.03 (s, 3H, NCH3), 4.72 (s, 2H, C6H5CH2), 4.81-
4.85 (d, J=15.0Hz, 2H, CH2NCH2), 4.91-4.95 (d, J=15.0Hz, 2H, CH2NCH2), 7.13-7.17 (t,
2H, aryl H), 7.41-7.44 (t, 2H, aryl H), 7.73-7.75 (d, 4H, J=8.0Hz, aryl H), 7.91-7.93
(d, 4H, J=8.0Hz, aryl H), 8.18 (s, 2H, arylidene H) .13C NMR (100MHz, DMSO) δ (ppm):
48.49 (NCH3), 58.91 (2NCH2), 64.56 (CH2), 115.71 (115.93), 123.92 (q, J=270.95Hz, CF3),
123.43 (123.46), 125.68 (125.71), 126.95,129.95 (q, J=31.85Hz, aryl C), 131.06
(131.20),135.17(135.25),137.05,140.99,161.96,180.44(CO).
Embodiment 3
(4- trifluoromethyls the benzylidene) -4- piperidones Bromides of N- methyl-N-benzyls -3,5- two 3c synthesis
1.5mL DMF solution is added in 0.001mol intermediate 3a, heats and stirs at 80 DEG C of oil bath
Mix to intermediate 3a dissolvings, it is rear that 0.0015mol benzyl bromines are added dropwise, the process of reaction, solvent dichloro in TLC detections are detected with TLC
Methane：Methanol is 20:1, reaction is finished, and is washed 2-3 times with ether, complete to precipitating, and collects precipitation by suction filtration operation, third is used afterwards
Ketone carries out recrystallization operation, and 30 DEG C are dried in vacuo two hours, obtain (the 4- trifluoromethylbenzene methylenes of N- methyl-N-benzyls -3,5- bis-
Base) -4- piperidones Bromide 0.39g, yield is 75.6%, 194-196 DEG C of fusing point.
UVλmax(logε)423(0.001),306(0.278),220(0.251),208(0.183)nm.IR(KBr
Pellet cm-1):2995(w),1415(m),1475(m),3429(m),611(m),708(m),854(m),1614(s),
1329(s),1167(s),1070(s).1HNMR(400MHz,DMSO,25℃,TMS,ppm):δ=3.03 (s, 3H, NCH3),
4.68 (s, 2H, C6H5CH2), 4.80-4.84 (d, J=15.1Hz, 2H, CH2NCH2), 4.94-4.98 (d, J=15.1Hz,
2H, CH2NCH2), 7.26-7.32 (m, 4H, aryl H), 7.41-7.43 (m, 1H, aryl H), 7.74-7.76 (d, 4H, J=
8.0Hz, aryl H), 7.91-7.93 (d, 4H, J=8.0Hz, aryl H), 8.19 (s, 2H, arylidene H) .13CNMR
(100MHz,DMSO)δ(ppm):48.49(NCH3),58.91(2NCH2),64.56(CH2),125.69(125.72),123.92
(q, J=270.91Hz, CF3), 126.99,127.02,128.78,129.96 (q, J=31.79Hz, aryl C), 130.48,
131.20,132.75,137.09,141.04,180.47(CO).
Embodiment 4
N- methyl-N- (4- methoxy-benzyls) -3,5- two (4- trifluoromethyls benzylidene) -4- piperidones chlorates 3d's
Synthesis
0.001mol intermediates 3a is mixed with 1.5mL tetrahydrofuran solution, heating stirring is to centre under 80 DEG C of oil baths
Body 3a is dissolved, rear that 0.0015mol 4- methoxyl group benzyl chloride solution is added dropwise, and the process of reaction, solvent in TLC detections are detected with TLC
Dichloromethane：Methanol is 10:1, reaction is finished, and is washed 2-3 times with ether, complete to precipitating, and precipitation is collected by suction filtration operation, after
Recrystallization operation is carried out with acetone, 30 DEG C are dried in vacuo two hours, obtain N- methyl-N- (4- methoxy-benzyls) -3,5- bis- (4- tri-
Methyl fluoride benzylidene) -4- piperidones chlorate 0.38g, yield is 69.0%, 185-188 DEG C of fusing point.
UVλmax(logε)305(0.677),232(0.959).IR(KBr Pellet cm-1):2845(w),2943
(m),3008(m),1516(m),791(m),837(m),1014(m),1612(s),1328(s),1169(s),1122(s),
1068(s).1H NMR(400MHz,DMSO,25℃,TMS,ppm):δ=3.01 (s, 3H, NCH3), 3.69 (s, 3H,
ArylOCH3), 4.65 (s, 2H, C6H5CH2), 4.83-4.88 (d, J=14.3Hz, 4H, CH2NCH2), 7.13-7.17 (t,
2H, aryl H), 7.41-7.44 (t, 2H, aryl H), 7.73-7.75 (d, 4H, J=8.0Hz, aryl H), 7.91-7.93
(d, 4H, J=8.0Hz, arylH), 8.18 (s, 2H, arylidene H) .13C NMR (100MHz, DMSO) δ (ppm):48.46
(NCH3), 55.11 (OCH3), 58.65 (2NCH2), 64.76 (CH2), 114.07,118.76,123.94 (q, J=
270.69Hz, CF3), 125.69 (125.72), 127.13,129.93 (q, J=31.83Hz, aryl C), 131.21,
134.21,137.13,140.91,160.63,180.60(CO).
Embodiment 5
N- methyl-N- (4- luorobenzyls) -3,5- two (the bromo- 4,5- dimethoxybenzylidens of 2-) -4- piperidones Bromides
1b synthesis
(1), the bromo- 4,5- dimethoxy benzaldehydes of the 0.005mol 2- of N- methyl -4- piperidones and 0.01mol are mixed
Together in dry HCl gas 55min, stirring reaction 7-24h in 25mL absolute ethyl alcohols, is passed through at room temperature, pass through TLC thin-layer chromatographys
Method tlc analysis determines reaction end.Suction filtration after completion of the reaction, gained precipitation adds the hydrogen-oxygen that 12.5mL mass fractions are 10%
Change sodium solution, 0.5h is stirred at room temperature, suction filtration, with Gossypol recrystallized from chloroform, obtains (the 2- bromo-4,5-dimethoxy benzene of N- methyl -3,5- bis-
Methylene) -4- piperidones 1a.
(2), by the ethanol solution of 0.001mol the intermediates 1a and 1.5mL of gained in step (1), it is mixed in
In 25ml two-mouth bottles, intermediate 1a dissolvings are heated with stirring under 80 DEG C of oil baths, it is rear that 0.0015mol 4- fluorine bromobenzyl solution is added dropwise, use
The process of TLC detection reactions, solvent dichloromethane in TLC detections：Methanol is 15:1, reaction is finished, and 2-3 is washed with ether
It is secondary, it is complete to precipitating, precipitation is collected by suction filtration operation, after carry out recrystallization operation with methanol, obtain N- methyl-N- (4- fluorine benzyls
Base) -3,5- bis- (2- bromo-4,5-dimethoxies benzylidene) -4- piperidones Bromide 0.39g, yield is 51.0%, fusing point
170-173℃。
UVλmax(logε)385(0.551),319(0.572)nm.1H NMR(400MHz,DMSO,25℃,TMS,ppm):
δ=3.06 (s, 3H, NCH3),3.86(s,6H,arylOCH3),3.88(s,6H,aryl OCH3),4.71(s,2H,C6H5CH2),
4.71-4.75(d,4H,CH2NCH2),4.87-4.90(d,Hz,2H,CH2NCH2),6.84(s,2H,aryl H),7.20-7.26
(m,2H,aryl H),7.43-7.47(m,2H,aryl H),8.09(s,2H,arylidene H).13C NMR(100MHz,
DMSO)δ(ppm):48.49(NCH3),56.04(2OCH3),56.29(2OCH3),58.78(2NCH2),64.44(CH2),
113.65,115.74(115.96),116.09,116.56,123.68,124.60,125.19,135.16,141.70,
147.96,151.23,162.03,180.42(CO).
Embodiment 6
N- methyl-N-benzyls -3,5- two (4- fluorobenzylidenes) -4- piperidones Bromides 2c synthesis
(1) the 4- fluorobenzaldehydes of 0.005mol N- methyl -4- piperidones and 0.01mol, are mixed in 13.5mL ice vinegar
In acid, dry HCl gas 50min, stirring reaction 7-24h is passed through at room temperature, is determined by TLC thin-layered chromatography tlc analysis
Reaction end.Suction filtration, the sodium hydroxide solution that gained precipitation addition 13mL mass fractions are 10%, are stirred at room temperature after completion of the reaction
0.5h is mixed, suction filtration, with recrystallize with dichloromethane, obtains N- methyl -3,5- bis- (2- bromo-4,5-dimethoxies benzylidene) -4- piperazines
Pyridine ketone 2a.
(2), by 0.001mol intermediates 2a and 1.5mL tetrahydrofuran solution, it is mixed in 25ml two-mouth bottles, 85 DEG C
Intermediate 2a dissolvings are heated with stirring under oil bath.0.0015mol benzyl bromines are added dropwise in backward two-mouth bottle, drop finishes, and is detected and reacted with TLC
Process, TLC detection in solvent dichloromethane：Methanol is 10:1, reaction is finished, and is washed 2-3 times with ether, completely precipitation,
By suction filtration operation collect precipitation, after carry out recrystallization operation with chloroform, obtain (the 4- fluorobenzene of N- methyl-N-benzyls -3,5- bis-
Methylene) -4- piperidones Bromide 0.24g, yield 47.1%.137-142 DEG C of fusing point.
UVλmax(logε)328(0.684)nm.IR(KBr Pellet cm-1):3404.19(w),3437.19(w),
3404.19(w),1678.15(m),1612.23(s),1599.16(s),1508.13(s),1478.57(w),1417.57(w),
12996.55(w),1275.47(m),1234.21(s),1105.58(w),994.47(m),837.44(m),538.40(w),
498.32(m).1H NMR(400MHz,DMSO,25℃,TMS,ppm):δ=3.03 (s, 3H, NCH3),4.71(s,2H,
C6H5CH2),4.84-4.88(d,2H,CH2NCH2),4.93-4.97(d,2H,CH2NCH2),7.27-7.34(m,4H,aryl
H),7.36-7.42(m,6H,aryl H),7.61-7.64(t,3H,aryl H),8.12(s,2H,arylidene H).13C
NMR(100MHz,DMSO)δ(ppm):48.60(NCH3),59.20(2NCH2),64.80(CH2),116.03(116.24),
124.74,127.31,128.80,129.74,130.51,132.76,133.34,141.41,161.92,180.52(CO).
Embodiment 7
(3- bromobenzenes the methylene) -4- piperidones chlorates 4d of N- methyl-N-4- methoxy-benzyls -3,5- two synthesis
(1) the 3- bromobenzaldehydes of 0.005mol N- methyl -4- piperidones and 0.01mol, are mixed in the anhydrous second of 24mL
In alcohol, the sodium hydroxide ethanol solution that mass fraction is 10% is passed through at room temperature, and stirring reaction 7-24h passes through TLC thin-layer chromatographys
Method tlc analysis determines reaction end.Suction filtration, with recrystallizing methanol, obtains (the 3- bromobenzene methylenes of N- methyl -3,5- bis- after completion of the reaction
Base) -4- piperidones 4a.
(2), by 0.001mol intermediates 4a and 1.5mL DMF solution, 25ml two-mouth bottles are mixed in
In, intermediate 4a dissolvings are heated with stirring under 90 DEG C of oil baths, 1.5mmol are then added to methyl benzyl chloride.Continue oil bath stirring anti-
Should, the process of reaction, solvent dichloromethane in TLC detections are detected with TLC：Methanol is 15:1, reaction is finished, and is washed with ether
2-3 times, precipitation completely goes the removal of impurity as far as possible, and precipitation is collected by suction filtration operation, after carry out recrystallization operation with dichloromethane and obtain
To N- methyl-N-4- methoxy-benzyls -3,5- bis- (3- bromobenzenes methylene) -4- piperidones chlorate 0.36g, yield 58.9%.
125-128 DEG C of fusing point.
UVλmax(logε)217(0.833),319(0.540)nm.IR(KBr Pellet cm-1):3958(w),2935
(w),2835(w),1678(s),1608(s),1558(s),1516(s),1473(s),1257(s),1188(s),1018(w),
995(w),899(m),841(m),787(m),683(s),579(m).1H NMR(400MHz,DMSO,25℃,TMS,ppm):δ
=2.95 (s, 3H, NCH3),3.74(s,3H,aryl OCH3),4.68(s,2H,C6H5CH2),4.81-4.85(d,2H,
CH2NCH2),4.87-4.91(d,2H,CH2NCH2), 6.88-6.90 (d, 2H, J=8.3Hz, aryl H), 7.35-7.37 (d,
2H, J=8.3Hz, aryl H), 7.45-7.52 (m, 4H, arylH), 7.73-7.76 (m, 4H, aryl H), 8.15 (s, 2H,
arylidene H).13C NMR(100MHz,DMSO)δ(ppm):47.48(NCH3),55.24(OCH3),58.81(2NCH2),
65.77(CH2),114.19,118.85,122.20 126.14,129.60,130.98,132.83,134.31,135.43,
140.96,160.68,180.45(CO).
Embodiment 8
N- methyl-N- (4- luorobenzyls) -3,5- two (4- methoxybenzylidenes) -4- piperidones Bromides 5b synthesis
(1), by the 4-methoxybenzaldehyde of 0.005mol N- methyl -4- piperidones and 0.01mol be mixed in 26mL without
In water-ethanol, the sodium hydroxide ethanol solution that mass fraction is 10% is passed through at room temperature, and stirring reaction 7-24h passes through TLC thin layers
Chromatography tlc analysis determines reaction end.Suction filtration, is recrystallized with DMF after completion of the reaction, obtain N- methyl-
3,5- bis- (4- methoxybenzylidenes) -4- piperidones Bromides 5a.
(2), by 0.001mol intermediates 5a and 1.5mL tetrahydrofuran solution, it is mixed in 25ml two-mouth bottles, 80 DEG C
Intermediate 5a dissolvings are heated with stirring under oil bath, 0.0015mol 4- fluorine bromobenzyls are then added, proceed oil bath stirring anti-
Should, the process of reaction, solvent dichloromethane in TLC detections are detected with TLC：Methanol is 30:1, determine the reaction time.React
Finish, wash 2-3 time with ether, completely precipitation as far as possible goes the removal of impurity, by suction filtration operation collection precipitate, after tied again with methanol
Crystalline substance operation obtains product N- methyl-N- (4- luorobenzyls) -3,5- two (4- methoxybenzylidenes) -4- piperidones Bromides
0.28g, yield 52.0%.158-160 DEG C of fusing point.
UVλmax(logε)374(0.892),249(0.648)nm.IR(KBr Pellet cm-1):3005(w),2950
(m),2929(m),2848(m),1672(w),1593(s),1512(s),1460(w),1308(m),1255(s),1163(s),
1034(m),837(m),569(w),534(m).1H NMR(400MHz,DMSO,25℃,TMS,ppm):δ=3.02 (s, 3H,
NCH3),3.86(s,3H,aryl OCH3),4.75(s,2H,C6H5CH2),4.89(s,4H,CH2NCH2),7.11-7.13(d,J
=8.4Hz, 4H, aryl H), 7.17-7.21 (t, 2H, arylH), 7.45-7.48 (t, 2H, aryl H), 7.52-7.54 (d, J
=8.4Hz, 4H, aryl H), 8.06 (s, 2H, arylidene H)13C NMR(100MHz,DMSO)δ(ppm):48.05
(NCH3),55.56(2OCH3),59.32(2NCH2),64.43(CH2),114.61,115.99,122.51,125.67,
132.13,135.25,142.01,161.22,164.42,180.28(CO).
Aryl methylene -4- the piperidones of N- methyl -3,5- two and its quaternary ammonium salt derivative antitumor activity evaluation.
Antitumor activity evaluation uses CCK-8 methods in the present invention, and the CCK-8 upgrade methods owned by France in mtt assay are a kind of bases
In WST-8 (chemical names：2- (2- methoxyl group -4- nitre phenyl) -3- (4- nitre phenyl) -5- (2,4- disulfobenzenes) -2H- tetrazolium lists
Sodium salt) be widely used in cell propagation and cytotoxicity fast high-sensitive degree detection method.
It is Human cervical cancer cell lines Hela, people's knot respectively altogether using 7 human tumor cell lines in the antitumor activity evaluation
Colon-cancer cell system HT-29, human leukemia cell line K562, human breast carcinoma cell lines MCF-7, human lymphoma cell system U937, people
Glioma cell line U87, human hepatoma cell line HepG2, both from Binzhou Medical College.Cell is in 37 DEG C, 5%CO2, saturation it is wet
Cultivated in the incubator of degree, with the RPMI-1640 nutrient solutions of 10% NBCS.
Take 1 × 104/ 100 μ L cell, is inoculated in 96 well culture plates, and culture adds 20 μ L various concentrations after 24 hours
Synthesis compound, continue cultivate 48 hours after, to every hole add 10 μ L CCK-8 reagents, 37 DEG C be incubated 4 hours after, use enzyme
Absorbance of the instrument measure at 450nm is marked, IC is calculated50.The concentration of compound used therefor is 200,100,10,1,0.1,0.01 respectively
μ g/mL, positive control is made of cis-platinum, and concentration used is 250,25,2.5,0.25,0.025 μ g/mL respectively.
Aryl methylene -4- the piperidones of N- methyl -3,5- bis- and its quaternary ammonium salt derivative 1a-1d, 2a-2d, 3a-3d, 4a-
The IC of 4d, 5a-5d to 7 tumor cell line HepG250(μM) value, specifically see the table below.
IC of 20 compounds to 7 human tumor cell lines as can be seen from the table50Value 78% is below 5 μM, this explanation
This 20 compounds have significant inhibitory action to each tumor cell line.
Claims (9)
1. for antineoplastic aryl methylene -4- piperidones quaternary ammonium salt derivatives of N- methyl -3,5- bis-, it is characterised in that its structure
Formula is
The R1Substituent is the bromo- 4,5- dimethoxybenzylidens of 2-4- fluorobenzylidenes
4- trifluoromethyl benzylidenes3- bromobenzene methylene4- methoxybenzylidenesAny of；
The R2Substituent is 4- luorobenzylsBenzyl4- methoxy-benzylsIn any one；
The X-For Br-Or Cl-；
R2When substituent is 4- luorobenzyls, derivative is respectively designated as N- methyl-N- (4- luorobenzyls) -3,5- bis- (2- bromo- 4,5-
Dimethoxybenzyliden) -4- piperidones Bromide 1b, N- methyl-N- (4- luorobenzyls) -3,5- bis- (4- fluorobenzylidenes) -
4- piperidones Bromide 2b, N- methyl-N- (4- luorobenzyls) -3,5- bis- (4- trifluoromethyls benzylidene) -4- piperidones brominations
Salt 3b, N- methyl-N- (4- luorobenzyls) -3,5- bis- (3- bromobenzenes methylene) -4- piperidones Bromide 4b, N- methyl-N- (4- fluorine
Benzyl) -3,5- two (4- methoxybenzylidenes) -4- piperidones Bromides 5b；
R2When substituent is benzyl, derivative is respectively designated as (the 2- bromo-4,5-dimethoxy benzene of N- methyl-N-benzyls -3,5- bis-
Methylene) bis- (4- fluorobenzylidenes) -4- piperidones Bromide 2c of -4- piperidones Bromide 1c, N- methyl-N-benzyl -3,5-,
N- methyl-N-benzyls -3,5- bis- (4- trifluoromethyls benzylidene) -4- piperidones Bromide 3c, N- methyl-N-benzyls -3,5-
(4- the methoxybenzylidenes) -4- piperazines of two (3- bromobenzenes methylene) -4- piperidones Bromide 4c, N- methyl-N-benzyls -3,5- bis-
Pyridine ketone Bromide 5c；
R2When substituent is (4- methoxy-benzyls), derivative is respectively designated as N- methyl-N- (4- methoxy-benzyls) -3,5- bis-
(2- bromo-4,5-dimethoxies benzylidene) -4- piperidones chlorate 1d, N- methyl-N- (4- methoxy-benzyls) -3,5- bis-
(4- trifluoromethylbenzenes are sub- by (4- fluorobenzylidenes) -4- piperidones chlorate 2d, N- methyl-N- (4- methoxy-benzyls) -3,5- bis-
Methyl) -4- piperidones chlorate 3d, N- methyl-N- (4- methoxy-benzyls) -3,5- bis- (3- bromobenzenes methylene) -4- piperidones
Chlorate 4d, N- methyl-N- (4- methoxy-benzyls) -3,5- bis- (4- methoxybenzylidenes) -4- piperidones chlorates 5d.
2. the preparation method of the aryl methylene -4- piperidones quaternary ammonium salt derivatives of methyl -3,5- bis- as claimed in claim 1, it is special
Levy and be that it comprises the following steps：
One), the aryl methylene -4- piperidones intermediates 1a-5a of N- methyl -3,5- two preparation
Aromatic formaldehyde derivative and N- methyl -4- piperidones are raw material, are mixed in alcohol solvent or glacial acetic acid solvent, addition catalysis
Agent, reaction is finished, and collects precipitation, and the aryl methylene -4- piperidones intermediate 1a-5a of N- methyl -3,5- bis- are made in recrystallization operation,
I.e. (4- fluorobenzene is sub- for N- methyl -3,5- bis- (2- bromo-4,5-dimethoxies benzylidene) -4- piperidones 1a, N- methyl -3,5- bis-
Methyl) -4- piperidones 2a, N- methyl -3,5- bis- (4- trifluoromethyls benzylidene) -4- piperidones Bromide 3a, N- methyl -3,
(4- the methoxybenzylidenes) -4- piperidones Bromides of 5- bis- (3- bromobenzenes methylene) -4- piperidones 4a, N- methyl -3,5- bis-
5a；
(2), N- methyl-N-R-3,5- bis- aryl methylene -4- piperidones quaternary ammonium salt derivatives 1b-1d, 2b-2d, 3b-3d, 4b-
4d, 5b-5d preparation
To replace benzyl halogen with the aryl methylene -4- piperidones intermediate 1a-5a of gained N- methyl -3,5- two in step (1) as original
Material, the two mol ratio is 1.2:1-1.8:1；
Intermediate 1a-5a dissolves in organic solvent, and the heating stirring in oil bath is until intermediate all dissolvings, rear to add substitution
Benzyl halogen, continues oil bath stirring, and detects reaction process with TCL, and ether is added after completion of the reaction and extremely precipitates complete, precipitation is collected,
N- methyl-N-R-3,5- bis- aryl methylene -4- piperidones quaternary ammonium salt derivatives 1b-1d, 2b-2d, 3b- is made in recrystallization operation
3d, 4b-4d, 5b-5d.
3. it is used for antineoplastic aryl methylene -4- piperidones quaternary ammonium salt derivatives of N- methyl -3,5- two as claimed in claim 2
Preparation method, it is characterised in that in the step (1) per 0.01mol N- methyl -4- piperidones raw materials in add 23-27mL
Aryl methylene-the 4- of N- methyl -3,5- bis- in the alcohol solvent of glacial acetic acid solvent or 48-52mL, step (2) per 0.001mol
Piperidones intermediate 1a-5a adds 1.8-2.2mL solvent.
4. it is used for antineoplastic aryl methylene -4- piperidones quaternary ammonium salt derivatives of N- methyl -3,5- two as claimed in claim 2
Preparation method, it is characterised in that in the step (1) low-temp reaction bathe controlling reaction temperature at 15-25 DEG C, control reaction when
Between at 7-24 hours；Oil bath controlling reaction temperature is at 75-95 DEG C in step (2), and the control reaction time was at 0.5-5 hours.
5. it is used for antineoplastic aryl methylene -4- piperidones quaternary ammonium salt derivatives of N- methyl -3,5- two as claimed in claim 2
Preparation method, it is characterised in that in the step (1) catalyst be sodium hydroxide ethanol solution that mass fraction is 10% or
Dry hydrogen chloride gas, hydrogen chloride gas is passed through the time for 45min-1.5h.
6. it is used for antineoplastic aryl methylene -4- piperidones quaternary ammonium salts of N- methyl -3,5- two as described in claim 3 or 4 or 5
The preparation method of derivative, it is characterised in that the recrystallization operation solvent for use is acetone, ether, water, alcohol, chloroform, dichloro
At least one of methane, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide；Organic solvent is N, N- bis- in step (2)
Any one in NMF, tetrahydrofuran, acetone, alcohol.
7. it is used for antineoplastic aryl methylene -4- piperidones quaternary ammonium salts of N- methyl -3,5- two as described in claim 3 or 4 or 5
The preparation method of derivative, it is characterised in that the aromatic formaldehyde derivative is 2- bromo-4,5-dimethoxies benzaldehyde, 4- fluorobenzene first
Any one in aldehyde, 4- trifluoromethylated benzaldehydes, 3- bromobenzaldehydes, 4-methoxybenzaldehyde.
8. it is used for antineoplastic aryl methylene -4- piperidones quaternary ammonium salts of N- methyl -3,5- two as described in claim 3 or 4 or 5
The preparation method of derivative, it is characterised in that it is 4- fluorobenzyl bromides, benzyl bromine, 4- methoxyl group benzyl chlorides to replace benzyl halogen in the step (2)
In any one.
9. it is used for antineoplastic aryl methylene -4- piperidones quaternary ammonium salt derivatives of N- methyl -3,5- two as claimed in claim 2
Preparation method, it is characterised in that TCL detections solvent chloroform used in the step (2)：Methanol ratio is 10:1、15:1、
20:1、30:Any one in 1.
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