CN104262240B - For antineoplastic 3,5-diphenylmethylene-4-derivative of piperidone and preparation method thereof - Google Patents
For antineoplastic 3,5-diphenylmethylene-4-derivative of piperidone and preparation method thereof Download PDFInfo
- Publication number
- CN104262240B CN104262240B CN201410371957.7A CN201410371957A CN104262240B CN 104262240 B CN104262240 B CN 104262240B CN 201410371957 A CN201410371957 A CN 201410371957A CN 104262240 B CN104262240 B CN 104262240B
- Authority
- CN
- China
- Prior art keywords
- piperidone
- derivative
- preparation
- diphenylmethylene
- antineoplastic
- 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.)
- Expired - Fee Related
Links
- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical class O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 title claims abstract description 26
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- 230000000118 anti-neoplastic effect Effects 0.000 title claims abstract description 20
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 12
- 230000006103 sulfonylation Effects 0.000 claims abstract description 12
- 238000005694 sulfonylation reaction Methods 0.000 claims abstract description 12
- GJQNVZVOTKFLIU-UHFFFAOYSA-N piperidin-1-ium-4-one;chloride Chemical compound Cl.O=C1CCNCC1 GJQNVZVOTKFLIU-UHFFFAOYSA-N 0.000 claims abstract description 5
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 27
- 238000006243 chemical reaction Methods 0.000 claims description 23
- 238000001953 recrystallisation Methods 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 12
- 239000003153 chemical reaction reagent Substances 0.000 claims description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- 238000001556 precipitation Methods 0.000 claims description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- -1 4-nitro benzoyl 4-Methyl benzenesulfonyl Chemical group 0.000 claims description 7
- 125000001424 substituent group Chemical group 0.000 claims description 7
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 6
- 229960001413 acetanilide Drugs 0.000 claims description 6
- 239000007789 gas Substances 0.000 claims description 6
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 6
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 6
- 239000002994 raw material Substances 0.000 claims description 6
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 claims description 6
- 229960000583 acetic acid Drugs 0.000 claims description 5
- 239000012362 glacial acetic acid Substances 0.000 claims description 5
- 239000003444 phase transfer catalyst Substances 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- YFLKVSOKVKZERQ-UHFFFAOYSA-N 4-acetyl-4-aminocyclohexa-1,5-diene-1-sulfonyl chloride Chemical compound CC(=O)C1(N)CC=C(S(Cl)(=O)=O)C=C1 YFLKVSOKVKZERQ-UHFFFAOYSA-N 0.000 claims description 3
- JXRGUPLJCCDGKG-UHFFFAOYSA-N 4-nitrobenzenesulfonyl chloride Chemical compound [O-][N+](=O)C1=CC=C(S(Cl)(=O)=O)C=C1 JXRGUPLJCCDGKG-UHFFFAOYSA-N 0.000 claims description 3
- SKDHHIUENRGTHK-UHFFFAOYSA-N 4-nitrobenzoyl chloride Chemical compound [O-][N+](=O)C1=CC=C(C(Cl)=O)C=C1 SKDHHIUENRGTHK-UHFFFAOYSA-N 0.000 claims description 3
- 150000003935 benzaldehydes Chemical class 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- DDXLVDQZPFLQMZ-UHFFFAOYSA-M dodecyl(trimethyl)azanium;chloride Chemical compound [Cl-].CCCCCCCCCCCC[N+](C)(C)C DDXLVDQZPFLQMZ-UHFFFAOYSA-M 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- XKBGEWXEAPTVCK-UHFFFAOYSA-M methyltrioctylammonium chloride Chemical compound [Cl-].CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC XKBGEWXEAPTVCK-UHFFFAOYSA-M 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 2
- 230000000259 anti-tumor effect Effects 0.000 abstract description 11
- 210000004881 tumor cell Anatomy 0.000 abstract description 10
- 210000004027 cell Anatomy 0.000 abstract description 9
- 239000003814 drug Substances 0.000 abstract description 8
- 239000002246 antineoplastic agent Substances 0.000 abstract description 5
- 229940041181 antineoplastic drug Drugs 0.000 abstract description 5
- 230000008901 benefit Effects 0.000 abstract description 4
- 230000010354 integration Effects 0.000 abstract description 4
- 231100000025 genetic toxicology Toxicity 0.000 abstract description 3
- 230000001738 genotoxic effect Effects 0.000 abstract description 3
- 231100000419 toxicity Toxicity 0.000 abstract description 3
- 230000001988 toxicity Effects 0.000 abstract description 3
- 238000005882 aldol condensation reaction Methods 0.000 abstract description 2
- 230000002441 reversible effect Effects 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 20
- 150000001875 compounds Chemical class 0.000 description 16
- 230000015572 biosynthetic process Effects 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- 238000003756 stirring Methods 0.000 description 7
- 238000004458 analytical method Methods 0.000 description 5
- 239000012046 mixed solvent Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 108010087230 Sincalide Proteins 0.000 description 3
- 238000010609 cell counting kit-8 assay Methods 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- 238000000034 method Methods 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
- 238000000967 suction filtration Methods 0.000 description 3
- KPVTZSGWKGUMLH-UHFFFAOYSA-N 3,5-dibenzylidenepiperidin-4-one Chemical compound O=C1C(=CC=2C=CC=CC=2)CNCC1=CC1=CC=CC=C1 KPVTZSGWKGUMLH-UHFFFAOYSA-N 0.000 description 2
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 2
- UXTMROKLAAOEQO-UHFFFAOYSA-N chloroform;ethanol Chemical compound CCO.ClC(Cl)Cl UXTMROKLAAOEQO-UHFFFAOYSA-N 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000036457 multidrug resistance Effects 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
- 125000003232 p-nitrobenzoyl group Chemical group [N+](=O)([O-])C1=CC=C(C(=O)*)C=C1 0.000 description 2
- 201000002528 pancreatic cancer Diseases 0.000 description 2
- 208000008443 pancreatic carcinoma Diseases 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000012313 reversal agent Substances 0.000 description 2
- 102100033350 ATP-dependent translocase ABCB1 Human genes 0.000 description 1
- 108010047230 Member 1 Subfamily B ATP Binding Cassette Transporter Proteins 0.000 description 1
- CVMOPKROILOZFI-UHFFFAOYSA-N O=S(=O)=Cl Chemical compound O=S(=O)=Cl CVMOPKROILOZFI-UHFFFAOYSA-N 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- ODJZWVFLHZHURI-UHFFFAOYSA-M [Br-].C(CCC)[P+](CCCC)(CCCC)CCCC.[NH4+].[Br-] Chemical compound [Br-].C(CCC)[P+](CCCC)(CCCC)CCCC.[NH4+].[Br-] ODJZWVFLHZHURI-UHFFFAOYSA-M 0.000 description 1
- 239000003929 acidic solution Substances 0.000 description 1
- 230000009471 action Effects 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
- 239000003005 anticarcinogenic agent Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 244000309466 calf Species 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000035572 chemosensitivity Effects 0.000 description 1
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 201000000014 lung giant cell carcinoma Diseases 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Substances [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- ODUCDPQEXGNKDN-UHFFFAOYSA-N nitroxyl Chemical compound O=N ODUCDPQEXGNKDN-UHFFFAOYSA-N 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000000452 restraining effect Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 210000002966 serum Anatomy 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
- 238000012546 transfer Methods 0.000 description 1
- 238000005406 washing Methods 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
-
- 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
- C07D213/89—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 with hetero atoms directly attached to the ring nitrogen atom
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 3,5-diphenylmethylene-4-derivative of piperidone with anti-tumor activity and preparation method thereof, belong to antitumor drug and preparation method thereof technical field.Its preparation method is the 4-derivative of piperidone with anti-tumor activity is carry out Claisen-Schmidt condensation by 4-piperidone hydrochloride and 4-trifluoromethyl to be obtained by reacting intermediate a; and then react and obtain N-R-3 by intermediate a and acidylate or sulfonylation agent, 5-bis-(4-trifluoromethyl α-tolylene)-4-piperidone b-e.This 3,5-diphenylmethylene-4-derivative of piperidone novel structure, can avoid the genotoxicity that the antitumor drug used now has, and have the advantage of polymolecular targeted integration, have multi-medicine tolerant reversal activity simultaneously.Its anti-tumor activity had and normal cell compare tumour cell and have larger toxicity, thus have great application prospect in field of antineoplastic medicaments.
Description
Technical field
The present invention relates to a kind of for antineoplastic 3,5-diphenylmethylene-4-derivative of piperidone and preparation method thereof, belong to antitumor drug and preparation method thereof technical field.
Background technology
3,5-diphenylmethylene-4-derivative of piperidone is a class ring-type α, the compound that beta unsaturated ketone combines with β keto-amine.α, beta unsaturated ketone compounds Numerous, is the very important organic synthesis intermediate of a class, is widely used in the fields such as medicine, chemical industry and spices.The research such as Dimmock shows many α, beta unsaturated ketone demonstrates cytotoxicity and anti-tumor activity, the mode of action of this compounds is unique, they have significant avidity to sulfydryl non-existent in nucleic acid, and to the amino be present in nucleic acid and hydroxyl avidity very little or almost there is no avidity, therefore can avoid the genotoxicity of present many anticarcinogens used; In addition, because many cellular constituents all contain sulfydryl, so this compounds also has the advantage with polymolecular targeted integration.Because it has the advantage with polymolecular targeted integration, so compounds is the active compound for anti tumor of a class formation novelty.In addition study and also find that this compounds can avoid multidrug resistance by reversing P-glycoprotein, therefore likely therefrom find effective MDR reversal agents.
The drug effect center of this compounds is 1,5-diaryl-3-oxygen-1,4-pentadienyl, can form twice continuous print alkylation to sulfydryl after closing, as shown in Figure 1 with piperidone loops, this is the main binding site of this compounds and tumour cell one, and after the nitrogen-atoms in piperidone is substituted, then can form the binding site that another is auxiliary, thus be converted into the alkylating agent of three function bases, as shown in Figure 2, so this type of compound antitumor effect much shows.In many cases, the chemosensitivity of tumour cell is stronger compared with normal cell, this continuous print Chemical bond makes tumour cell more easily come to harm, and therefore has larger toxicity to tumour cell, and its research is expected to therefrom search out the new type antineoplastic medicine to not normal cells.
Summary of the invention
The object of the invention is to find to normal cytotoxicity little or avirulent new type antineoplastic medicine, and the reversal agent of existing antitumor drug multidrug resistance can be reversed, there is provided a kind of for antineoplastic 3,5-diphenylmethylene-4-derivative of piperidone, it has anti-tumor activity and multi-medicine tolerant reversal is active; The present invention provides the preparation method of this derivative simultaneously.
The present invention is achieved by the following technical solutions:
For antineoplastic 3,5-diphenylmethylene-4-derivative of piperidone, special character is that its structural formula is
Described R substituent is hydrogen atom
, 4-nitro benzoyl
, 4-Methyl benzenesulfonyl base
, 4-P-acetamido benzene sulfonyl base
, 4-nitrobenzenesulfonyl
in one.
When R substituent is hydrogen atom, derivative called after 3,5-bis-(4-trifluoromethyl α-tolylene)-4-piperidone a; When R substituent is 4-nitro benzoyl, derivative called after N-(4-nitro benzoyl)-3,5-bis-(4-trifluoromethyl α-tolylene)-4-piperidone b; When R substituent is 4-Methyl benzenesulfonyl base, derivative called after N-(4-Methyl benzenesulfonyl base)-3,5-bis-(4-trifluoromethyl α-tolylene)-4-piperidone c; When R substituent is 4-P-acetamido benzene sulfonyl base, derivative called after N-(4-P-acetamido benzene sulfonyl base)-3,5-bis-(4-trifluoromethyl α-tolylene)-4-piperidone d; When R substituent is 4-nitrobenzenesulfonyl, derivative called after N-(4-nitrobenzenesulfonyl)-3,5-bis-(4-trifluoromethyl α-tolylene)-4-piperidone e.
Above-mentioned 3; the preparation method of 5-diphenylmethylene-4-derivative of piperidone; its principle is: be carry out Claisen-Schmidt condensation by 4-piperidone hydrochloride and 4-trifluoromethyl to be obtained by reacting intermediate a for antineoplastic 4-derivative of piperidone; and then react and obtain N-R-3 by intermediate a and acidylate or sulfonylation agent, 5-bis-(4-trifluoromethyl α-tolylene)-4-piperidone b-e.
This preparation method's special character is, it comprises the steps:
(1), the preparation of 3,5-bis-(4-trifluoromethyl α-tolylene)-4-piperidone intermediate a
4-trifluoromethylated benzaldehyde and 4-piperidone hydrochloride are raw material, mix in alcohol solvent or glacial acetic acid solvent, and add catalyzer, react complete, collecting precipitation, recrystallization operation obtains 3,5-bis-(4-trifluoromethyl α-tolylene)-4-piperidone intermediate a;
(2), the preparation of N-R-3,5-bis-(4-trifluoromethyl α-tolylene)-4-piperidone b-e
So that in acylating reagent or sulfonylation agent and step (), gained 3,5-bis-(4-trifluoromethyl α-tolylene)-4-piperidone intermediate a is for raw material, the two mol ratio is 1.2:1-1.8:1;
Intermediate a dissolves in organic solvent, mixes with sodium hydroxide solution, and drip phase-transfer catalyst, rear interpolation acylating reagent or sulfonylation agent, react complete, is solution of potassium carbonate or the 2molL of 10% with massfraction
-1hCl treatment, collecting precipitation, recrystallization operation obtains N-R-3,5-bis-(4-trifluoromethyl α-tolylene)-4-piperidone b-e.
Because of acylating reagent or sulfonylation agent facile hydrolysis, therefore in the present invention's preparation, the mol ratio of acylating reagent or sulfonylation agent and intermediate a is greater than 1, to ensure to react completely, improves yield.
A modification of the present invention scheme is, the alcohol solvent of 23-27mL glacial acetic acid solvent or 48-52mL is added in every 0.01mol4-piperidone hydrochloride raw material in described step (), in step (two), 3,5-bis-(4-trifluoromethyl α-tolylene)-4-piperidone intermediate a of every 0.001mol adds the solvent of 4.8-5.2mL.
The second improvement project of the present invention is, in described step (), low-temp reaction bath controls temperature of reaction at 15-25 DEG C, controls the reaction times at 7-24 hour; Low-temp reaction bath controls temperature of reaction at 0-5 DEG C in step (two), controls the reaction times at 1-10 hour, to carry out Reactive Synthesis under preferably reaction conditions.
The third improvement project of the present invention is, in described step (), catalyzer is massfraction is the sodium hydroxide ethanolic soln of 10% or the hydrogen chloride gas of drying, it is 45min-1.5h that hydrogen chloride gas passes into the time, adopt during sodium hydroxide ethanolic soln and directly obtain intermediate a, when adopting dry hydrogen chloride gas to make catalyzer, react complete need with massfraction be 25% solution of potassium carbonate and acetone mixed solution washing, with in and acidic solution, recrystallization operation obtains intermediate a.
In the present invention, in step (two), solvent for use, phase-transfer catalyst and recrystallization solvent for use have all made restriction selection, to coordinate invention reaction process and product characteristics, do not affect the derivative product property of generation, thus, in step (two), organic solvent selects any one in 1,2-ethylene dichloride, tetrahydrofuran (THF), acetone, alcohol; In step (two), phase-transfer catalyst is any one in Tetrabutyl amonium bromide, benzyltriethylammoinium chloride, tri-n-octyl methyl ammonium chloride, tetrabutylammonium chloride, Dodecyl trimethyl ammonium chloride; Described recrystallization operation solvent for use is at least one in acetone, ether, water, alcohol, chloroform, methylene dichloride, DMF, N,N-dimethylacetamide.
The N-R-3 that complex reaction generates; 5-bis-(4-trifluoromethyl α-tolylene)-4-piperidone b-e five kinds of derivatives; acylating reagent or sulfonylation agent select the 4-nitrobenzoyl chloride, 4-toluene sulfonyl chloride, 4-acetylsulphanilyl chloride, any one in 4-nitrobenzene sulfonyl chloride that adapt in described step (two), thus the obtained above five kinds of derivatives of reaction.Adopt wherein acylating reagent time, need the solution of potassium carbonate with massfraction is 10% to process after completion of the reaction, obtain derivative b with further recrystallization operation; Adopt wherein sulfonylation agent time, need after completion of the reaction to use 2molL
-1hCl treatment, then recrystallization operation obtains derivative c-e.
This 3,5-diphenylmethylene-4-derivative of piperidone novel structure, can avoid the genotoxicity that the antitumor drug used now has, and have the advantage of polymolecular targeted integration, have multi-medicine tolerant reversal activity simultaneously.Its anti-tumor activity had and normal cell compare tumour cell and have larger toxicity, thus have great application prospect in field of antineoplastic medicaments.
Accompanying drawing explanation
The continuous combination figure of Fig. 1: 3,5-diphenylmethylene-4-piperidone and sulfydryl;
The binding site A of Fig. 2: 3,5-diphenylmethylene-4-piperidone and B schematic diagram;
Fig. 3: 3,5-diphenylmethylene-4-derivative of piperidone chemical reactive synthesis route map.
Embodiment
Below provide the specific embodiment of the present invention, be used for being further described the present invention.
Embodiment 1
The synthesis of 3,5-bis-(4-trifluoromethyl α-tolylene)-4-piperidone a
Be mixed in 12.5mL Glacial acetic acid by the 4-piperidone hydrochloride of 0.005mol and the 4-trifluoromethylated benzaldehyde of 0.01mol, pass into dry HCl gas 60min under room temperature, stirring reaction 8h, by tlc (TLC) tlc analysis determination reaction end.Suction filtration after completion of the reaction, it is the solution of potassium carbonate of 25% and the mixed solution of 12.5mL acetone soln that gained precipitation adds 12.5mL massfraction, stirred at ambient temperature 0.5h, suction filtration, with methyl alcohol, chloroform mixed solvent recrystallization, obtain 3,5-bis-(4-trifluoromethyl α-tolylene)-4-piperidone 1.21g, yield is 59%.
Embodiment 2
The synthesis of N-(4-nitro benzoyl)-3,5-bis-(4-trifluoromethyl α-tolylene)-4-piperidone b
Be the NaOH solution of 25% by 2mL massfraction, with 1mmol3, 5-bis-(4-trifluoromethyl α-tolylene)-4-piperidone mixes in the tetrahydrofuran solution of 5mL, adding 0.02g massfraction is the Tetrabutyl amonium bromide of 5%, 15min is stirred at 0-5 DEG C of temperature, drip 1.5mmol4-nitrobenzoyl chloride solution, continue to stir 2h, by tlc (TLC) tlc analysis determination reaction end, suction filtration, resistates adds the solution of potassium carbonate that 10mL massfraction is 10%, stirring at room temperature 2h, collecting precipitation, with methanol-chloroform mixed solvent recrystallization, obtain N-(4-nitro benzoyl)-3, 5-bis-(4-trifluoromethyl α-tolylene)-4-piperidone 0.44g, yield is 78%.
Embodiment 3
The synthesis of N-(4-Methyl benzenesulfonyl base)-3,5-bis-(4-trifluoromethyl α-tolylene)-4-piperidone c
Be NaOH solution and the 1mmol3 of 25% by 2mL massfraction, 5-bis-(4-trifluoromethyl α-tolylene)-4-piperidone is at 1 of 5mL, mix in 2-dichloroethane solution, adding 0.01g massfraction is the tetrabutylammonium chloride of 5%, at 0-5 DEG C of temperature, stir 15min, drip 1.5mmol4-Methyl benzenesulfonyl chlorine solution, continue to stir 5h, by tlc (TLC) tlc analysis determination reaction end, use 2molL
-1hydrochloric acid adjust pH be 1-4, collecting precipitation, uses chloroform solvent recrystallization, and obtain N-(4-Methyl benzenesulfonyl base)-3,5-bis-(4-trifluoromethyl α-tolylene)-4-piperidone 0.45g, yield is 79%.
Embodiment 4
The synthesis of N-(4-P-acetamido benzene sulfonyl base)-3,5-bis-(4-trifluoromethyl α-tolylene)-4-piperidone d
Be NaOH solution, the 1mmol3 of 25% by 2mL massfraction, 5-bis-(4-trifluoromethyl α-tolylene)-4-piperidone mixes in 5mL aqueous isopropanol, add the tetrabutyl phosphonium bromide ammonium solution that 0.02g massfraction is 5%, 15min is stirred at 0-5 DEG C of temperature, drip 1.5mmol4-acetylsulphanilyl chloride solution, continue to stir 8h, by tlc (TLC) tlc analysis determination reaction end, use 2molL after completion of the reaction
-1hydrochloric acid adjust pH be 5-6, collecting precipitation, with chloroform-ethanol mixed solvent recrystallization, obtain N-(4-P-acetamido benzene sulfonyl base)-3,5-bis-(4-trifluoromethyl α-tolylene)-4-piperidone 0.27g, yield is 45%.
Embodiment 5
The synthesis of N-(4-nitrobenzenesulfonyl)-3,5-bis-(4-trifluoromethyl α-tolylene)-4-piperidone e
Get NaOH solution and 1mmol3 that 2mL massfraction is 25%, 5-bis-(4-trifluoromethyl α-tolylene)-4-piperidone mixes in 5mL acetone soln, add the benzyltriethylammoinium chloride solution that 0.01g massfraction is 5%, 15min is stirred at 0-5 DEG C of temperature, drip 1.5mmol4-nitrobenzene sulphonyl chlorine solution, continue to stir 7h, by tlc (TLC) tlc analysis determination reaction end, use 2molL after completion of the reaction
-1hydrochloric acid adjust pH be 1-4, collecting precipitation, with chloroform-ethanol mixed solvent recrystallization, obtain N-(4-nitrobenzenesulfonyl)-3,5-bis-(4-trifluoromethyl α-tolylene)-4-piperidone 0.43g, yield is 74%.
Diphenylmethylene-4-derivative of piperidone antitumor activity evaluation.
In the present invention, antitumor activity evaluation adopts CCK-8 method, CCK-8 is owned by France in the upgrade method of mtt assay, a kind of based on WST-8(chemical name: 2-(2-methoxyl group-4-nitre phenyl)-3-(4-nitre phenyl)-5-(2,4-disulfobenzene)-2H-tetrazolium monosodium salt) be widely used in cell proliferation and Cytotoxic fast high-sensitive degree detection method.
Five human tumor cell lines are used altogether in this antitumor activity evaluation, be people's giant cell carcinoma of lung high-transfer cell strain PG-BE1, MCF-7 SK-BR-3, human pancreatic cancer cell SW1990, human pancreatic cancer cell MIAPaCa-2 and Non-small cell lung carcinoma NCI-H460 respectively, it all comes from China Concord Medical Science University.Cell is at 37 DEG C, 5%CO
2, saturated humidity incubator in cultivate, with the RPMI-1640 nutrient solution of 10% new-born calf serum.
Get 1 × 10
4the cell of/100 μ L, is inoculated in 96 well culture plates, cultivates the synthetic compound adding 20 μ L different concns after 24 hours, continue cultivation after 48 hours, add the CCK-8 reagent of 10 μ L to every hole, 37 DEG C hatch 4 hours after, be determined at the absorbancy at 450nm place by microplate reader, calculate IC
50.The concentration of compound used therefor is 200,100,10,1,0.1,0.01 μ g/mL respectively, does positive control with 5 FU 5 fluorouracil, and concentration used is 250,25,2.5,0.25,0.025 μ g/mL respectively.
5 N-R-3,5-bis-(4-trifluoromethyl α-tolylene)-4-derivative of piperidone to 5 human tumor cell line SW1990, the half-inhibition concentration IC of MIAPaCa-2, PG-BE1, NCI-H460, SK-BR-3
50, as shown in the table.
A-e5 compound is to the IC of 5 human tumor cell lines as can be seen from the table
50value 100% is lower than 5 μMs, and wherein have 60% to be Ya Moer level, this illustrates that these 5 compounds have potent restraining effect to each tumor cell line, and especially compound a, d, e mean titre value to 5 clones are 0.98,0.68,0.32 μM respectively.From table, it can also be seen that 5 compounds are to the IC of MIAPaCa-2 in addition
50value all belongs to Ya Moer level, shows 5 compounds the most responsive to MIAPaCa-2.
Claims (10)
1., for antineoplastic 3,5-diphenylmethylene-4-derivative of piperidone, it is characterized in that its structural formula is:
Described R substituent is hydrogen atom H, 4-nitro benzoyl
4-Methyl benzenesulfonyl base
4-P-acetamido benzene sulfonyl base
4-nitrobenzenesulfonyl
in one.
2., as claimed in claim 1 for the preparation method of antineoplastic 3,5-diphenylmethylene-4-derivative of piperidone, it is characterized in that it comprises the steps:
(1), the preparation of 3,5-bis-(4-trifluoromethyl α-tolylene)-4-piperidone intermediate a
With 4-trifluoromethylated benzaldehyde and 4-piperidone hydrochloride for raw material, mix in alcohol solvent or glacial acetic acid solvent, add catalyzer, react complete, collecting precipitation, recrystallization operation obtains 3,5-bis-(4-trifluoromethyl α-tolylene)-4-piperidone intermediate a;
(2), the preparation of N-R-3,5-bis-(4-trifluoromethyl α-tolylene)-4-piperidone b-e
So that in acylating reagent or sulfonylation agent and step (), gained 3,5-bis-(4-trifluoromethyl α-tolylene)-4-piperidone intermediate a is for raw material, the two mol ratio is 1.2:1-1.8:1;
Intermediate a dissolves in organic solvent, mixes with sodium hydroxide solution, and drip phase-transfer catalyst, rear interpolation acylating reagent or sulfonylation agent, react complete, is solution of potassium carbonate or the 2molL of 10% with massfraction
-1hCl treatment, collecting precipitation, recrystallization operation obtains N-R-3,5-bis-(4-trifluoromethyl α-tolylene)-4-piperidone b-e.
3. as claimed in claim 2 for antineoplastic 3, the preparation method of 5-diphenylmethylene-4-derivative of piperidone, it is characterized in that the alcohol solvent adding 23-27mL glacial acetic acid solvent or 48-52mL in described step () in every 0.01mol4-piperidone hydrochloride raw material, in step (two), 3,5-bis-(4-trifluoromethyl α-tolylene)-4-piperidone intermediate a of every 0.001mol adds the solvent of 4.8-5.2mL.
4. as claimed in claim 2 for antineoplastic 3, the preparation method of 5-diphenylmethylene-4-derivative of piperidone, it is characterized in that in described step (), low-temp reaction bath controls temperature of reaction at 15-25 DEG C, controls the reaction times at 7-24 hour; In step (two), low-temp reaction bath controls temperature of reaction at 0-5 DEG C, controls the reaction times at 1-10 hour.
5. as described in claim 2,3 or 4 for antineoplastic 3, the preparation method of 5-diphenylmethylene-4-derivative of piperidone, it is characterized in that in described step () that catalyzer is massfraction is the sodium hydroxide ethanolic soln of 10% or the hydrogen chloride gas of drying, and it is 45min-1.5h that hydrogen chloride gas passes into the time.
6. as described in claim 2,3 or 4 for antineoplastic 3, the preparation method of 5-diphenylmethylene-4-derivative of piperidone, it is characterized in that organic solvent in described step (two) is any one in 1,2-ethylene dichloride, tetrahydrofuran (THF), acetone, alcohol.
7. as described in claim 2,3 or 4 for antineoplastic 3, the preparation method of 5-diphenylmethylene-4-derivative of piperidone, is characterized in that phase-transfer catalyst in described step (two) is any one in Tetrabutyl amonium bromide, benzyltriethylammoinium chloride, tri-n-octyl methyl ammonium chloride, tetrabutylammonium chloride, Dodecyl trimethyl ammonium chloride.
8. as described in claim 2,3 or 4 for antineoplastic 3; the preparation method of 5-diphenylmethylene-4-derivative of piperidone, is characterized in that acylating reagent or sulfonylation agent in described step (two) are any one in 4-nitrobenzoyl chloride, 4-toluene sulfonyl chloride, 4-acetylsulphanilyl chloride, 4-nitrobenzene sulfonyl chloride.
9. as claimed in claim 5 for antineoplastic 3; the preparation method of 5-diphenylmethylene-4-derivative of piperidone, is characterized in that acylating reagent or sulfonylation agent in described step (two) are any one in 4-nitrobenzoyl chloride, 4-toluene sulfonyl chloride, 4-acetylsulphanilyl chloride, 4-nitrobenzene sulfonyl chloride.
10. as described in claim 2,3 or 4 for antineoplastic 3, the preparation method of 5-diphenylmethylene-4-derivative of piperidone, it is characterized in that in described step (two), recrystallization operation solvent for use is acetone, ether, water, alcohol, chloroform, methylene dichloride, N, at least one in dinethylformamide, N,N-dimethylacetamide.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410371957.7A CN104262240B (en) | 2014-07-31 | 2014-07-31 | For antineoplastic 3,5-diphenylmethylene-4-derivative of piperidone and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410371957.7A CN104262240B (en) | 2014-07-31 | 2014-07-31 | For antineoplastic 3,5-diphenylmethylene-4-derivative of piperidone and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104262240A CN104262240A (en) | 2015-01-07 |
| CN104262240B true CN104262240B (en) | 2016-04-20 |
Family
ID=52153859
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410371957.7A Expired - Fee Related CN104262240B (en) | 2014-07-31 | 2014-07-31 | For antineoplastic 3,5-diphenylmethylene-4-derivative of piperidone and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104262240B (en) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104592098B (en) * | 2015-01-31 | 2017-08-25 | 滨州医学院 | For antineoplastic piperidones of 3,5 2 aryl methylene of N methyl 4 and its quaternary ammonium salt derivative |
| CN105601561B (en) * | 2016-03-10 | 2018-04-10 | 滨州医学院 | Piperidones Schiff base derivatives of 3,5 2 aryl methylene 4 with antitumor activity and preparation method thereof |
| CN105669537A (en) * | 2016-03-10 | 2016-06-15 | 滨州医学院 | 3,5-bis(3-aminobenzylidene)-4-piperidone derivatives with antitumor activity and preparation method thereof |
| CN105669536B (en) * | 2016-03-10 | 2018-04-10 | 滨州医学院 | Derivative of piperidone with antitumor activity and preparation method thereof |
| US9486444B1 (en) | 2016-03-21 | 2016-11-08 | King Saud University | Anti-cancer compound |
| CN108191750B (en) * | 2018-01-08 | 2023-06-27 | 滨州医学院 | 3, 5-diarylmethylene-N-benzenesulfonyl-4-piperidone compound and preparation method thereof |
| CN108191751B (en) * | 2018-01-08 | 2023-06-27 | 滨州医学院 | 4-fluorobenzenesulfonyl substituted 3, 5-diarylmethylene-4-piperidone compound and preparation method thereof |
| CN108191742B (en) * | 2018-01-08 | 2023-06-27 | 滨州医学院 | 4-acetamidobenzenesulfonyl-substituted 3, 5-diarylmethylene-4-piperidone compound and preparation method thereof |
| CN109078014A (en) * | 2018-03-26 | 2018-12-25 | 温州医科大学 | 3,4- dimethoxybenzyliden piperidines keto analog is preparing the application in anti-lung-cancer medicament |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102863376A (en) * | 2012-09-27 | 2013-01-09 | 上海师范大学 | N-substituted methyl-3,5-disubstituted benzylidene base-4-piperidone and preparation method and application thereof |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2009516656A (en) * | 2005-11-22 | 2009-04-23 | ユニバーシティ オブ サスカチュワン | Antitumor active compound |
-
2014
- 2014-07-31 CN CN201410371957.7A patent/CN104262240B/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102863376A (en) * | 2012-09-27 | 2013-01-09 | 上海师范大学 | N-substituted methyl-3,5-disubstituted benzylidene base-4-piperidone and preparation method and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| Design, synthesis and cytotoxic properties of novel 1-[4-(2-alkylaminoethoxy)phenylcarbonyl]-3,5-bis(arylidene)-4-piperidones and related compounds;Umashankar Das et al;《European Journal of Medicinal Chemistry》;20060922;第42卷;71-80，第71页摘要，第72页Figure 1、2，第73页Scheme 1，第76页6.1.2 2a、b的一般制备方法，引用文献8第591页系列1的合成 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104262240A (en) | 2015-01-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104262240B (en) | For antineoplastic 3,5-diphenylmethylene-4-derivative of piperidone and preparation method thereof | |
| CN104230796A (en) | Anti-tumor 3, 5-di(2-bromo-4, 5-dimethoxyl benzylidene)-4-piperidone derivatives and preparation method thereof | |
| CN103313992B (en) | There is the inhibiting camptothecin derivative of HDAC | |
| Leung et al. | Identification, design and biological evaluation of heterocyclic quinolones targeting Plasmodium falciparum type II NADH: quinone oxidoreductase (PfNDH2) | |
| CN101628912B (en) | Anti-tumor compound containing triazole heterocyclic structure and application thereof | |
| JP2018520109A (en) | Pyrido-azaheterocyclic compound and production method and use thereof | |
| CN102153535A (en) | Benzopyranyl-3-alcohol esterified derivative serving as antineoplastic multidrug resistance inhibitor and preparation method and application of benzopyranyl-3-alcohol esterified derivative | |
| CN105399757A (en) | Acid-sensitive camptothecin-site 20 norcantharidate derivative and antineoplastic application thereof | |
| CN102153519A (en) | Preparation method of quinazoline derivative | |
| CN104803925A (en) | 2,4,5-trisubstituted pyrimidine compounds taking FGFRs (fibroblast growth factor receptors) as targets as well as preparation methods and application of 2,4,5-trisubstituted pyrimidine compounds | |
| CN102321032A (en) | Preparation method of quinazoline derivate | |
| Abdel-Maksoud et al. | Discovery of new imidazo [2, 1-b] thiazole derivatives as potent Pan-RAF inhibitors with promising in vitro and in vivo anti-melanoma activity | |
| CN101027309B (en) | Enantiomers of selected fused pyrimidones and uses in the treatment and prevention of cancer | |
| CN105745198B (en) | Carboxymethyl piperidine derivative | |
| CN104592098A (en) | Antitumor N-methyl-3,5-diarylmethylene-4-piperidone and quaternary ammonium derivatives thereof | |
| CN104761460A (en) | Glaucocalyxin A derivative and preparation method and application thereof | |
| CN104530056B (en) | The heterozygote of a kind of adjacent naphthoquinones and tetrazolo pyrimidine and synthetic method thereof | |
| Liu et al. | Mithramycin 2′-oximes with improved selectivity, pharmacokinetics, and Ewing sarcoma antitumor efficacy | |
| CN103450096A (en) | Two nitrogen mustard derivatives, as well as preparation method and application therefore in tumor treatment | |
| CN102558058B (en) | 1-aryl-3-substituent-5-substituted amino-4-pyrazole formamide compound and application thereof | |
| CN105646546B (en) | The position 20 of camptothecins ester derivant and its antitumor application thereof of acid-sensitive type | |
| CN103214422B (en) | Preparation methods and anti-cancer effect of novel substituted amido imidazolone derivatives | |
| CN103435560B (en) | Synthesis and application of aceanthrylene [1,2-b] quinoxaline derivative with flexible side chain | |
| CN106397407B (en) | The preparation method of antitumor drug AZD9291 derivatives | |
| CN103483414A (en) | 4-azasteroid purine nucleoside analog, and preparation and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20160420 |