CN105669536B - Derivative of piperidone with antitumor activity and preparation method thereof - Google Patents
Derivative of piperidone with antitumor activity and preparation method thereof Download PDFInfo
- Publication number
- CN105669536B CN105669536B CN201610134780.8A CN201610134780A CN105669536B CN 105669536 B CN105669536 B CN 105669536B CN 201610134780 A CN201610134780 A CN 201610134780A CN 105669536 B CN105669536 B CN 105669536B
- Authority
- CN
- China
- Prior art keywords
- methyl
- benzylidene
- amino
- derivative
- piperidones
- 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.)
- Active
Links
- 230000000259 anti-tumor effect Effects 0.000 title claims abstract description 29
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical class O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 title abstract description 7
- 125000000649 benzylidene group Chemical group [H]C(=[*])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims abstract description 38
- 238000006243 chemical reaction Methods 0.000 claims abstract description 17
- 230000000118 anti-neoplastic effect Effects 0.000 claims abstract description 7
- VBRMYHZDRGRBRD-UHFFFAOYSA-N 2-[(3-aminophenyl)methylidene]piperidin-4-one Chemical class NC=1C=C(C=C2NCCC(C2)=O)C=CC=1 VBRMYHZDRGRBRD-UHFFFAOYSA-N 0.000 claims abstract description 5
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 17
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 12
- 239000002994 raw material Substances 0.000 claims description 10
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 claims description 8
- 238000001556 precipitation Methods 0.000 claims description 8
- 238000003756 stirring Methods 0.000 claims description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 7
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical group COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- 235000019253 formic acid Nutrition 0.000 claims description 6
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 6
- SMQUZDBALVYZAC-UHFFFAOYSA-N salicylaldehyde Chemical class OC1=CC=CC=C1C=O SMQUZDBALVYZAC-UHFFFAOYSA-N 0.000 claims description 6
- 150000003935 benzaldehydes Chemical class 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 4
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 claims description 4
- CRPNQSVBEWWHIJ-UHFFFAOYSA-N 2,3,4-trihydroxybenzaldehyde Chemical class OC1=CC=C(C=O)C(O)=C1O CRPNQSVBEWWHIJ-UHFFFAOYSA-N 0.000 claims description 3
- AHIGQYAVHIZQQE-UHFFFAOYSA-N 3,5-bis[(3-aminophenyl)methylidene]-1-methylpiperidin-4-one Chemical class CN1CC(C(C(C1)=CC1=CC(=CC=C1)N)=O)=CC1=CC(=CC=C1)N AHIGQYAVHIZQQE-UHFFFAOYSA-N 0.000 claims description 3
- 238000005481 NMR spectroscopy Methods 0.000 claims description 2
- 238000002329 infrared spectrum Methods 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- WQGWDDDVZFFDIG-UHFFFAOYSA-N pyrogallol Chemical class OC1=CC=CC(O)=C1O WQGWDDDVZFFDIG-UHFFFAOYSA-N 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims 1
- 231100000025 genetic toxicology Toxicity 0.000 abstract description 3
- 230000001738 genotoxic effect Effects 0.000 abstract description 3
- -1 hydroxy benzaldehyde series compound Chemical class 0.000 abstract description 3
- 239000002262 Schiff base Substances 0.000 abstract description 2
- 150000004753 Schiff bases Chemical class 0.000 abstract description 2
- 230000009286 beneficial effect Effects 0.000 abstract description 2
- 238000006482 condensation reaction Methods 0.000 abstract description 2
- 230000008685 targeting Effects 0.000 abstract description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 abstract 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
- 210000004027 cell Anatomy 0.000 description 12
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- 238000004587 chromatography analysis Methods 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 5
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 238000011156 evaluation Methods 0.000 description 4
- 210000004881 tumor cell Anatomy 0.000 description 4
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000000921 elemental analysis Methods 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 241000234314 Zingiber Species 0.000 description 2
- 235000006886 Zingiber officinale Nutrition 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- 125000000958 aryl methylene group Chemical group 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 230000004900 autophagic degradation Effects 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- VFLDPWHFBUODDF-FCXRPNKRSA-N curcumin Chemical compound C1=C(O)C(OC)=CC(\C=C\C(=O)CC(=O)\C=C\C=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-FCXRPNKRSA-N 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 235000008397 ginger Nutrition 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect 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
- 239000000126 substance Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 239000003643 water by type Substances 0.000 description 2
- HUUPVABNAQUEJW-UHFFFAOYSA-N 1-methylpiperidin-4-one Chemical class CN1CCC(=O)CC1 HUUPVABNAQUEJW-UHFFFAOYSA-N 0.000 description 1
- OPKPFEWFKYKJCF-UHFFFAOYSA-N 2-benzylideneindene-1,3-dione Chemical class O=C1C2=CC=CC=C2C(=O)C1=CC1=CC=CC=C1 OPKPFEWFKYKJCF-UHFFFAOYSA-N 0.000 description 1
- KKAJSJJFBSOMGS-UHFFFAOYSA-N 3,6-diamino-10-methylacridinium chloride Chemical compound [Cl-].C1=C(N)C=C2[N+](C)=C(C=C(N)C=C3)C3=CC2=C1 KKAJSJJFBSOMGS-UHFFFAOYSA-N 0.000 description 1
- ZETIVVHRRQLWFW-UHFFFAOYSA-N 3-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC=CC(C=O)=C1 ZETIVVHRRQLWFW-UHFFFAOYSA-N 0.000 description 1
- 102000003952 Caspase 3 Human genes 0.000 description 1
- 108090000397 Caspase 3 Proteins 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- 101710112752 Cytotoxin Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 108010047956 Nucleosomes Proteins 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 229940009456 adriamycin Drugs 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 230000003712 anti-aging effect Effects 0.000 description 1
- 230000000879 anti-atherosclerotic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940034982 antineoplastic agent Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229940109262 curcumin Drugs 0.000 description 1
- 235000012754 curcumin Nutrition 0.000 description 1
- 239000004148 curcumin Substances 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 231100000599 cytotoxic agent Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 239000002619 cytotoxin Substances 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- VFLDPWHFBUODDF-UHFFFAOYSA-N diferuloylmethane Natural products C1=C(O)C(OC)=CC(C=CC(=O)CC(=O)C=CC=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002211 flavins Chemical class 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 210000003494 hepatocyte Anatomy 0.000 description 1
- 235000011167 hydrochloric acid Nutrition 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- 208000025113 myeloid leukemia Diseases 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 210000001623 nucleosome Anatomy 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- GHMLBKRAJCXXBS-UHFFFAOYSA-N resorcinol Chemical class OC1=CC=CC(O)=C1 GHMLBKRAJCXXBS-UHFFFAOYSA-N 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000814 tuberculostatic agent Substances 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)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
The present invention relates to four kinds of N methyl 3,5 two (3 (2 phenol methylene amino) benzylidene) 4 derivative of piperidone with antitumor activity and preparation method thereof, belong to antineoplastic and preparation method thereof technical field.Its preparation method is that (3 amino benzylidene) 4 piperidones of N methyl 3,5 2 obtain invention product A~D with hydroxy benzaldehyde series compound by Schiff base condensation reactions.The derivative antitumor activity is good, can avoid the genotoxicity of antineoplastic used now, and targeting is clear and definite.Preparation method is easy, and reaction condition is gentle, and synthetic yield is high, beneficial to its being widely popularized in antitumor field.
Description
Technical field
The present invention relates to (3- (2- phenol methylenes amino) benzene of N- methyl -3,5- two that four kinds have antitumor activity
Methylene) -4- derivative of piperidone and preparation method thereof, belong to antineoplastic and preparation method thereof technical field.
Background technology
Curcumin has anti-inflammatory, anti-oxidant, antitumor, the effect of antiatherosclerosis, anti-aging etc..But by
In poorly water-soluble, chemical constitution is unstable, bioavilability is low, limits its further applying clinically.And then to ginger
The structure of modification of flavine turns into the focus studied now.Aryl methylene -4- the derivative of piperidone of 3,5- bis- is the ginger studied now
One kind in flavin derivatives.Because it has two α, β-unsaturated unit, sulfydryl (being not present in nucleic acid) can be formed
Continuous alkylation twice, and affinity very little to amino and hydroxyl (in nucleic acid) or almost do not have, i.e., to tumour cell
Preferable selectivity is shown, or toxicity very little almost non-toxic to normal cell, so as to avoid present many antineoplastics
Genotoxicity.And after the nitrogen-atoms of piperidones is substituted, then it can form another auxiliary anchor position.Dimmock team one
Directly be engaged in the research of such compound, the team performs the derivatization on the nitrogen of piperidones, find such medicine not only have compared with
Good antitumor activity[1], also with antibiotic property[2].Such medicine can activate caspase 3 and induce DNA break between nucleosome
So as to cause Apoptosis or autophagy[3,4].This Subject Design has simultaneously synthesized a series of aryl methylene -4- piperazines of 3,5- bis-
Pyridine ketone compounds, and antitumor activity and Cytotoxic evaluation have been carried out to such compound by mtt assay.
The content of the invention
It is contemplated that find good, small to the normal cytotoxicity or nontoxic new antitumoral medicine of antitumor activity
Thing, therefore, the invention provides the (3- (2- phenol methylenes amino) of N- methyl -3,5- bis- that four have antitumor activity
Benzylidene) -4- derivative of piperidone；The present invention also provides the preparation method of aforementioned four derivative simultaneously.
The present invention is achieved by the following technical solutions：
N- methyl -3,5- two (3- (2- phenol methylenes amino) benzylidene) -4- piperidines with antitumor activity
Ketone derivatives, it is respectively designated as N- methyl -3,5- bis- (3- (2,3- dihydroxy benzenes methene amido) benzylidene) -4- piperidones
(A), N- methyl -3,5- two (3- (2,4- dihydroxy benzenes methene amido) benzylidene) -4- piperidones (B), N- methyl -3,5-
Two (3- (2,5- dihydroxy benzenes methene amido) benzylidene) -4- piperidones (C) and (3- (2,3,4- tri- of N- methyl -3,5- two
Phenol methylene amino) benzylidene) -4- piperidones (D)；
It is characterized in that, its structural formula is：
N- methyl -3,5- two (3- (2- phenol methylenes amino) benzylidene) -4- piperidines with antitumor activity
Ketone derivatives, its composition principle are：(3- amino the benzylidene) -4- piperidones of N- methyl -3,5- two and hydroxy benzaldehyde series
Compound obtains (3- (2- phenol methylenes amino) the benzene methylenes of N- methyl -3,5- two by Schiff-base condensation reactions
Base) -4- derivative of piperidone A~D.
Above-mentioned N- methyl -3,5- two (3- (2- phenol methylenes amino) benzylidene) -4- with antitumor activity
The preparation method of derivative of piperidone, it is characterized in that, specific preparation process is as follows：
With hydroxy benzaldehyde series raw material and N- methyl -3,5- bis- (3- amino benzylidene) -4- piperidones raw materials, in alcohol
Mixed in solution, add catalyst, stirring at normal temperature reaction a period of time, precipitation filters, and obtains invention product N- methyl -3,5- bis-
(3- (2- phenol methylenes amino) benzylidene) -4- derivative of piperidone A~D.
And pass through nuclear magnetic resonance, the correctness of infrared spectrum its structure.
Derive in invention product N- methyl -3,5- two (3- (2- phenol methylenes amino) benzylidene) -4- piperidones
In thing A~D preparation process, hydroxy benzaldehyde series raw material is using 2,3- 4-dihydroxy benzaldehydes, 2,4- dihydroxy benzenes first
Aldehyde, 2,5- 4-dihydroxy benzaldehydes or 2,3,4- tri hydroxybenzaldehydes；
Derive in invention product N- methyl -3,5- two (3- (2- phenol methylenes amino) benzylidene) -4- piperidones
In thing A~D preparation process, the alcohol of alcoholic solution is methanol, any one in ethanol, isopropanol；
Derive in invention product N- methyl -3,5- two (3- (2- phenol methylenes amino) benzylidene) -4- piperidones
In thing A~D preparation process, addition catalyst is any one in formic acid, acetic acid, and mass concentration is 0.1%~2%；
Derive in invention product N- methyl -3,5- two (3- (2- phenol methylenes amino) benzylidene) -4- piperidones
In thing A~D preparation process, to ensure that the reaction of N- methyl -3,5- bis- (3- amino benzylidene) -4- piperidones (B) is complete, this
Hydroxy benzaldehyde series raw material and the mol ratio of N- methyl -3,5- two (3- amino benzylidene) -4- piperidones raw materials in invention
For 2:1~5:1；
Derive in invention product N- methyl -3,5- two (3- (2- phenol methylenes amino) benzylidene) -4- piperidones
In thing A~D preparation process, refer to for a period of time 2~18 hours.
N- methyl -3,5- two (3- (2- phenol methylene amino) benzylidene) of the present invention with antitumor activity -
4- derivative of piperidone A~D, the genotoxicity of antineoplastic used now can be avoided, antitumor activity is good, and targeting is bright
Really.Meanwhile its preparation method is easy, reaction condition is gentle, and synthetic yield is high, beneficial to its being widely popularized in antitumor field.
Embodiment
Embodiment of the invention given below, for the present invention is further described.
Embodiment 1
The synthesis of N- methyl -3,5- two (3- amino benzylidene) -4- piperidones
The m-nitrobenzaldehyde of 0.01mol N- methyl -4- piperidones and 0.022mol is mixed in 20mL first alcohol and waters
Solution in, at room temperature add the sodium hydroxide solutions of 20mL 20%, stirring at normal temperature reaction 12h, pass through thin-layered chromatography (TLC)
Tlc analysis determines reaction end.Precipitation filter intermediate is buff powder.By intermediate and 0.065mol stannous chlorides
6~8h of stirring reaction in 25mL concentrated hydrochloric acids is added to, is analyzed by thin-layered chromatography (TLC) and determines reaction end, precipitation filters,
10% sodium carbonate liquor lotion, 15mL ethanol/waters (volume ratio 1:1) yellow powder, i.e. N- methyl -3,5- bis- are recrystallized to give
(3- amino benzylidene) -4- piperidones.
Embodiment 2
N- methyl -3,5- two (3- (2,3- dihydroxy benzenes methene amido) benzylidene) -4- piperidones (A)
By (3- amino the benzylidene) -4- piperidones of 0.001mol N- methyl -3,5- two and 0.003mol 2,3- dihydroxies
Benzaldehyde is dissolved in 40mL methanol, and 3 drop formic acid are added dropwise, stirring at normal temperature reaction 8h, is analyzed and determined by thin-layered chromatography (TLC)
Reaction end.Precipitation filters, and is washed with methanol, is dried in vacuo to obtain (3- (2, the 3- dihydroxy benzenes of red powder N- methyl -3,5- bis-
Methene amido) benzylidene) -4- piperidones (A) 0.3133g, yield 56%.
IR(cm-1):3253(br),1614(s),1573(s),1460(m),1363(m),1273(s),1209(s),1183
(m),1028(w),939(w),850(w),789(m),734(s),684(s),540(w).1H NMR(400MHz,DMSO,25
℃,TMS,ppm):δ13.03(s,2H),9.26(s,2H),8.97(s,2H),7.69(s,2H),7.62-7.50(m,4H),
7.50-7.40 (m, 4H), 7.13 (d, J=8Hz, 2H), 6.98 (d, J=8Hz, 2H), 6.81 (t, J=8Hz, 2H), 3.82 (s,
4H),2.42(s,3H).13C NMR(100MHz,CDCl3):186.27,164.75,149.25,148.42,145.63,
135.85,134.47,134.04,129.86,128.46,123.32,122.85,122.25,119.38,119.14,118.87,
56.17,45.15.Elemental analysis (%) caled.for C34H29N3O5:C 72.97,H 5.22,N 7.51；
Found:C 73.01,H 5.25, N 7.49.
Embodiment 3
N- methyl -3,5- two (3- (2,4- dihydroxy benzenes methene amido) benzylidene) -4- piperidones (B)
By (3- amino the benzylidene) -4- piperidones of 0.001mol N- methyl -3,5- two and 0.0035mol 2,4- dihydroxies
Benzaldehyde is dissolved in 45mL methanol, and 6 drop formic acid are added dropwise, stirring at normal temperature reaction 9h, is analyzed and determined by thin-layered chromatography (TLC)
Reaction end.Precipitation filters, and is washed with methanol, is dried in vacuo to obtain (3- (2, the 4- dihydroxy benzenes of yellow powder N- methyl -3,5- bis-
Methene amido) benzylidene) -4- piperidones (B) 0.3025g, yield 54%.
IR(cm-1):3144(br),1672(w),1607(s),1568(s),1509(w),1455(w),1329(w),1281
(w),1208(s),1176(m),1127(m),977(m),850(m),788(s),691(s),651(w),538(w).1H NMR
(400MHz,DMSO,25℃,TMS,ppm):δ13.38(s,2H),10.50(s,2H),8.84(s,2H),7.66(s,2H),
7.53 (t, J=8Hz, 2H), 7.46 (d, J=8Hz, 4H), 7.38 (t, J=8Hz, 4H), 6.43 (d, J=8Hz, 2H), 6.31
(s,2H),3.78(s,4H),2.40(s,3H).13C NMR(100MHz,CDCl3):δ186.38,163.44,162.95,
162.66,148.70,135.83,134.56,134.46,134.12,129.78,127.77,123.03,122.09,112.06,
107.99,102.36,56.26,45.23.Elemental analysis (%) caled.for C34H29N3O5:C 72.97,H
5.22,N 7.51；Found:C73.00,H 5.26,N 7.53.
Embodiment 4
N- methyl -3,5- two (3- (2,5- dihydroxy benzenes methene amido) benzylidene) -4- piperidones (C)
By (3- amino the benzylidene) -4- piperidones of 0.001mol N- methyl -3,5- two and 0.0032mol 2,5- dihydroxies
Benzaldehyde is dissolved in 60mL ethanol, and 5 drop formic acid are added dropwise, stirring at normal temperature reaction 12h, are analyzed by thin-layered chromatography (TLC) true
Determine reaction end.Precipitation filters, and is washed with ethanol, is dried in vacuo to obtain (3- (2, the 5- dihydroxies of buff powder N- methyl -3,5- bis-
Base benzylideneamino) benzylidene) -4- piperidones (C) 0.3216g, yield 57%.
IR(cm-1):3173(br),1674(w),1615(s),1568(s),1485(s),1433(w),1373(w),1349
(w),1292(s),1217(s),1148(s),874(m),824(m),787(s),727(w),681(s),642(w),615(w),
530(m).1H NMR(400MHz,DMSO,25℃,TMS,ppm):δ12.10(s,2H),8.89(s,2H),7.68(s,2H),
7.55 (t, J=8Hz, 2H), 7.50 (s, 2H), 7.43 (t, J=8Hz, 4H), 7.07 (d, J=4Hz, 2H), 6.90 (dd, J=
8,8HZ2H), 6.82 (d, J=8Hz, 2H), 3.79 (s, 4H), 2.41 (s, 3H)13C NMR(100MHz,CDCl3):δ
186.46,163.90,153.05,149.67,149.03,135.85,134.35,134.23,129.79,128.30,123.19,
122.35,121.35,119.30,117.23,116.85,56.28,45.25.Elemental analysis (%)
caled.for C34H29N3O5:C 72.97,H5.22,N 7.51；Found:C 72.95,H 5.20,N 7.50.
Embodiment 5
N- methyl -3,5- two (3- (2,3,4- trihydroxy benzenes methene amido) benzylidene) -4- piperidones (D)
By (3- amino the benzylidene) -4- piperidones of 0.001mol N- methyl -3,5- two and 0.004mol 2,3,4- tri-
Hydroxy benzaldehyde is dissolved in 35mL isopropanols, and 2 drop formic acid are added dropwise, stirring at normal temperature reaction 6h, are analyzed by thin-layered chromatography (TLC)
Determine reaction end.Precipitation filters, and is washed with isopropanol, is dried in vacuo to obtain (the 3- (2,3,4- of red powder N- methyl -3,5- bis-
Trihydroxy benzene methene amido) benzylidene) -4- piperidones (D) 0.3576g, yield 64%.
IR(cm-1):3061(br),1613(m),1578(m),1516(w),1452(w),1276(w),1207(m),1169
(m),1082(m),1057(w),979(m),935(w),875(w),771(w),681(w),606(w),592(w),573(m),
564(m),553(m),538(w),532(w).1H NMR(400MHz,DMSO,25℃,TMS,ppm):δδ13.47(s,2H),
9.79 (s, 2H), 8.83 (s, 2H), 8.54 (s, 2H), 7.68 (s, 2H), 7.54 (t, J=8Hz, 2H), 7.48 (s, 2H),
7.45-7.35 (m, 4H), 6.98 (d, J=8Hz, 2H), 6.46 (d, J=8Hz, 2H), 3.82 (s, 4H), 2.43 (s, 3H)13C
NMR(100MHz,CDCl3):193.04,163.97,151.30,150.54,148.33,135.81,132.39,129.83,
127.83,124.26,123.04,121.98,112.33,107.89,56.17,45.14.El emental analysis (%)
caled.for C34H29N3O7:C69.03,H 4.94,N 7.10；Found:C 69.00,H 4.95,N 7.12.
Antitumor activity evaluation
The antitumor work of 3,5- bis- (3- (2- oxybenzenes methene amido) benzylidene) -4- derivative of piperidone of the present invention
Property evaluation.
Antitumor activity evaluation uses mtt assay in the present invention.
5 kinds of cell lines are used in the present invention altogether, are Human normal hepatocyte cell line LO2, Human cervical cancer cell lines respectively
Hela, human hepatoma cell line HepG2, human leukemia cell line K562 and people's monokaryon myeloid leukemia cell line THP-1, one
Four tumor cell lines of normal cell system, all from China Concord Medical Science University.The RPMI- of 10% hyclone of cell
1640 culture medium is in 37 DEG C, 5%CO2, saturated humidity incubator in cultivate.
The cell in growth period of taking the logarithm is configured to 4 × 104Individual/mL cell suspension, it is inoculated in 96 well culture plates, per hole
Add 200 μ L, culture adds the synthesis compound of 20 μ L various concentrations after 24 hours, after continuing culture 24 hours, added to every hole
20 μ L MTT reagents, after 37 DEG C are incubated 4 hours, supernatant is abandoned, add 150 μ L DMSO, vibration 10min fully to dissolve knot per hole
Crystalline substance, the absorbance at 570nm is determined with ELIASA, calculates IC50.The concentration of compound used therefor is 10 μ g/mL, 6 μ g/ respectively
ML, 5 μ g/mL, 3 μ g/mL, 2 μ g/mL, 1.5 μ g/mL, 1 μ g/mL, 0.5 μ g/mL, 0.1 μ g/mL, the positive is done with adriamycin (DOX)
Control, concentration used is 8 μ g/mL, 6 μ g/mL, 5 μ g/mL, 3 μ g/mL, 1.5 μ g/mL, 1 μ g/mL, 0.8 μ g/mL, 0.5 respectively
μ g/mL, 0.1 μ g/mL, each concentration set 6 multiple holes.
The half-inhibition concentration IC of tetra- medicines of table 1.A, B, C, D50
IC of tetra- compounds of A, B, C, D to 4 tumor cell lines as can be seen from the table50Value is below 5 μM, and aligns
The toxicity of normal cell is small compared with tumour cell, and particularly D antitumor activity is preferable.
Bibliography：
[1]Pati H N,Das U,Sakagami H,et al.1,3-diaryl-2-propenones and 2-
benzylidene-1,3-indandiones:a quest for compounds displaying greater toxicity
to neoplasms than normal cells.[J].Archiv Der Pharmazie,2010,343(9):535–541.
[2]Das U,Lorand T,Dimmock S G,et al.3-Benzylidene-4-chromanones:a
novel cluster of anti-tubercular agents[J].Journal of Enzyme Inhibition&
Medicinal Chemistry,2015,30:1-5.
[3]Pati H N,Das U,Kawase M,et al.1-Aryl-2-dimethylaminomethyl-2-
propen-1-one hydrochlorides and related adducts:A quest for selective
cytotoxicity for malignant cells[J].Bioorganic&Medicinal Chemistry,2008,16
(10):5747-5753.
[4]Das U,Sakagami H,Chu Q,et al.3,5-Bis(benzylidene)-1-[4-2-
(morpholin-4-yl)ethoxyphenylcarbonyl]-4-piperidone hydrochloride:A lead
tumor-specific cytotoxin which induces apoptosis and autophagy[J].Bioorganic&
Medicinal Chemistry Letters,2010,20(3):912-917。
Claims (9)
1. N- methyl -3,5- two (3- (2- phenol methylenes amino) benzylidene) -4- piperidones with antitumor activity
Derivative, be respectively designated as N- methyl -3,5- bis- (3- (2,3- dihydroxy benzenes methene amido) benzylidene) -4- piperidones A,
(the 3- of N- methyl -3,5- two (3- (2,4- dihydroxy benzenes methene amido) benzylidene) -4- piperidones B, N- methyl -3,5- two
(2,5- dihydroxy benzenes methene amido) benzylidene) two (3- (2,3,4- trihydroxy benzenes of -4- piperidones C and N- methyl -3,5-
Methene amido) benzylidene) -4- piperidones D；It is characterised by, its structural formula is as follows：
2. there is (3- (2- phenol methylenes amino) benzene methylenes of N- methyl -3,5- two of antitumor activity described in claim 1
Base) -4- derivative of piperidone preparation method, be characterised by, comprise the following steps：
It is water-soluble in alcohol with hydroxy benzaldehyde series raw material and N- methyl -3,5- bis- (3- amino benzylidene) -4- piperidones raw materials
Mixed in liquid, add catalyst, stirring at normal temperature reaction a period of time, precipitation filters, and obtains invention product N- methyl -3,5- bis-
(3- (2- phenol methylenes amino) benzylidene) -4- derivative of piperidone A~D；And tested by nuclear magnetic resonance, infrared spectrum
Demonstrate,prove the correctness of its structure.
3. there is (3- (2- phenol methylenes amino) benzene of N- methyl -3,5- two of antitumor activity as claimed in claim 2
Methylene) -4- derivative of piperidone preparation method, be characterised by
The hydroxy benzaldehyde series raw material is using 2,3- 4-dihydroxy benzaldehydes, 2,4- 4-dihydroxy benzaldehydes, 2,5- dihydroxies
Benzaldehyde or 2,3,4- tri hydroxybenzaldehydes.
4. there is (3- (2- phenol methylenes amino) benzene of N- methyl -3,5- two of antitumor activity as claimed in claim 2
Methylene) -4- derivative of piperidone preparation method, be characterised by
The alcohol of the alcohol solution is any one in methanol, ethanol, isopropanol.
5. there is (3- (2- phenol methylenes amino) benzene of N- methyl -3,5- two of antitumor activity as claimed in claim 2
Methylene) -4- derivative of piperidone preparation method, be characterised by
The catalyst is formic acid, any one in acetic acid, and mass concentration is 0.1%~2%.
6. there is (3- (2- phenol methylenes amino) benzene of N- methyl -3,5- two of antitumor activity as claimed in claim 2
Methylene) -4- derivative of piperidone preparation method, be characterised by
The hydroxy benzaldehyde series raw material and mole of N- methyl -3,5- two (3- amino benzylidene) -4- piperidones raw materials
Than for 2:1~5:1.
7. there is (3- (2- phenol methylenes amino) benzene of N- methyl -3,5- two of antitumor activity as claimed in claim 2
Methylene) -4- derivative of piperidone preparation method, be characterised by
A period of time refers to 2~18 hours.
8. N- methyl -3,5- two (3- (2- phenol methylenes amino) benzylidene) -4- piperidones described in claim 1 spreads out
Applications of the biological A~D in antineoplastic is prepared.
9. (3- (the 2- phenol methylenes of N- methyl -3,5- two obtained according to preparation method described in any rights of claim 2-7
Amino) benzylidene) the applications of -4- derivative of piperidone A~D in antineoplastic is prepared.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610134780.8A CN105669536B (en) | 2016-03-10 | 2016-03-10 | Derivative of piperidone with antitumor activity and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610134780.8A CN105669536B (en) | 2016-03-10 | 2016-03-10 | Derivative of piperidone with antitumor activity and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105669536A CN105669536A (en) | 2016-06-15 |
| CN105669536B true CN105669536B (en) | 2018-04-10 |
Family
ID=56308083
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610134780.8A Active CN105669536B (en) | 2016-03-10 | 2016-03-10 | Derivative of piperidone with antitumor activity and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105669536B (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104230796A (en) * | 2014-07-31 | 2014-12-24 | 滨州医学院 | Anti-tumor 3, 5-di(2-bromo-4, 5-dimethoxyl benzylidene)-4-piperidone derivatives and preparation method thereof |
| CN104262240A (en) * | 2014-07-31 | 2015-01-07 | 滨州医学院 | Antitumor 3,5-diphenylmethylene-4-piperidone derivative and preparation method thereof |
| CN104592098A (en) * | 2015-01-31 | 2015-05-06 | 滨州医学院 | Antitumor N-methyl-3,5-diarylmethylene-4-piperidone and quaternary ammonium derivatives thereof |
-
2016
- 2016-03-10 CN CN201610134780.8A patent/CN105669536B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104230796A (en) * | 2014-07-31 | 2014-12-24 | 滨州医学院 | Anti-tumor 3, 5-di(2-bromo-4, 5-dimethoxyl benzylidene)-4-piperidone derivatives and preparation method thereof |
| CN104262240A (en) * | 2014-07-31 | 2015-01-07 | 滨州医学院 | Antitumor 3,5-diphenylmethylene-4-piperidone derivative and preparation method thereof |
| CN104592098A (en) * | 2015-01-31 | 2015-05-06 | 滨州医学院 | Antitumor N-methyl-3,5-diarylmethylene-4-piperidone and quaternary ammonium derivatives thereof |
Non-Patent Citations (4)
| Title |
|---|
| Jufeng Sun，等.Design, Synthesis and Bioevaluation of Novel N-Substituted-3,5-Bis(Arylidene)-4-piperidone Derivatives as Cytotoxic and Antitumor Agents with Fluorescent Properties.《Chem Biol Drug Des》.2013,第83卷p392-400. * |
| Umashankar Das，等.Umashankar Das，等 Design, synthesis and cytotoxic properties of novel 1-[4-(2-alkylaminoethoxy)phenylcarbonyl]-3,5-bis(arylidene)-4-piperidones and related compounds.《European Journal of Medicinal Chemistry》.2006,第42卷71-80. * |
| 刘文帅，等.两个α，β-不饱和酮药物的合成及抗肿瘤活性研究.《分析测试学报》.2015,第34卷(第8期),p900-904. * |
| 孙居锋，等.N-甲基-3, 5-二芳亚甲基-4-哌啶酮衍生物的合成与表征.《精细石油化工》.2010,第27卷(第5期),22-24. * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105669536A (en) | 2016-06-15 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Yee et al. | Synthesis of novel isoflavene–propranolol hybrids as anti-tumor agents | |
| CN111072610B (en) | Preparation and application of substituted benzofuran 2-formyl hydrazone LSD1 inhibitor | |
| CN109467549A (en) | Quinoline replaces chalcone compounds, preparation method and the usage | |
| Chen et al. | Design, synthesis, anticancer activity and cytotoxicity of novel 4-piperidone/cyclohexanone derivatives | |
| CN101434525B (en) | 4-(4-hydroxy3-methoxybenzene methyl) curcumin and use thereof in preparing anti-tumor medicament | |
| CN101332198B (en) | Pharmaceutical use of 6-aryl-3-substituted carbonyl pyridine compound | |
| CN105669536B (en) | Derivative of piperidone with antitumor activity and preparation method thereof | |
| CN111303026A (en) | Propenone derivative of enrofloxacin and preparation method and application thereof | |
| CN103833623B (en) | One seed amino acid-amine conjugate and its preparation method and application | |
| CN101691353A (en) | N-Boc-3,5-(E)-diarylidene-4-piperidone and application thereof in preparation of anti-tumor drugs | |
| CN103130632B (en) | 1-substituted benzylidene-2-naphthalenone derivative, preparation method thereof and use thereof | |
| Kurnia et al. | Synthesis and anticancer potential of aminomethyl derivatives of methyl-substituted asymmetrical curcumin mono-carbonyl | |
| CN105601528A (en) | Molecular tweezer compound with ent-beyerane diterpene as chiral arm, and preparation method and application thereof | |
| Zou et al. | Synthesis, biological evaluation, and structure–activity relationship study of novel cytotoxic aza-caffeic acid derivatives | |
| CN105669537A (en) | 3,5-bis(3-aminobenzylidene)-4-piperidone derivatives with antitumor activity and preparation method thereof | |
| CN111647004B (en) | Propenone derivative for removing N-methylofloxacin and preparation method and application thereof | |
| CN107540680A (en) | A kind of lappaconitine acetal analog derivative and its synthetic method with antitumor activity | |
| Usifoh et al. | Synthesis, Characterization and Antimicrobial Assessment of 3, 4, 5-Trimethoxy-3’, 4’-Dimethoxychalcone and 2, 4, 6-Trimethoxy-3’, 4’-Dimethoxychalcone | |
| Yuan et al. | Synthesis and biological evaluation of novel 1-aryl, 5-(phenoxy-substituted) aryl-1, 4-pentadien-3-one derivatives | |
| CN108191751A (en) | Bis- aryl methylene -4- piperidines ketone compounds of 3,5- of 4- fluorophenylsulphonyls substitution and preparation method thereof | |
| Chen et al. | Novel rotundic acid derivatives: Synthesis, structural characterization and in vitro antitumor activity | |
| CN105601561B (en) | Piperidones Schiff base derivatives of 3,5 2 aryl methylene 4 with antitumor activity and preparation method thereof | |
| Nigam et al. | Investigating the potential of tetrahydropyridinyl chalcones as useful agents against breast carcinoma: An in vitro and in vivo study | |
| CN108997310B (en) | Asymmetric 3-pyridine substituted 3, 5-diarylmethylene-4-piperidone and preparation method thereof | |
| CN105985287B (en) | A kind of Rui Gefeini novel crystal forms |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| OL01 | Intention to license declared | ||
| OL01 | Intention to license declared |