CN106243042A - 咪唑脱氢枞胺希夫碱类化合物及其制备方法和应用 - Google Patents
咪唑脱氢枞胺希夫碱类化合物及其制备方法和应用 Download PDFInfo
- Publication number
- CN106243042A CN106243042A CN201610597465.9A CN201610597465A CN106243042A CN 106243042 A CN106243042 A CN 106243042A CN 201610597465 A CN201610597465 A CN 201610597465A CN 106243042 A CN106243042 A CN 106243042A
- Authority
- CN
- China
- Prior art keywords
- dehydroabietylamine
- imidazoles
- formaldehyde
- schiff base
- base compounds
- 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.)
- Granted
Links
- 239000002262 Schiff base Substances 0.000 title claims abstract description 60
- -1 Imidazoles dehydroabietylamine schiff base compounds Chemical class 0.000 title claims abstract description 33
- 238000002360 preparation method Methods 0.000 title abstract description 9
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Natural products O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims abstract description 20
- 238000000034 method Methods 0.000 claims abstract description 15
- JVVXZOOGOGPDRZ-SLFFLAALSA-N [(1R,4aS,10aR)-1,4a-dimethyl-7-propan-2-yl-2,3,4,9,10,10a-hexahydrophenanthren-1-yl]methanamine Chemical compound NC[C@]1(C)CCC[C@]2(C)C3=CC=C(C(C)C)C=C3CC[C@H]21 JVVXZOOGOGPDRZ-SLFFLAALSA-N 0.000 claims description 29
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 15
- 238000006243 chemical reaction Methods 0.000 claims description 14
- 229960000583 acetic acid Drugs 0.000 claims description 8
- 239000012362 glacial acetic acid Substances 0.000 claims description 7
- 239000000843 powder Substances 0.000 claims description 7
- 238000001556 precipitation Methods 0.000 claims description 7
- 238000001816 cooling Methods 0.000 claims description 6
- 239000002994 raw material Substances 0.000 claims description 4
- 239000002246 antineoplastic agent Substances 0.000 claims description 3
- 229940041181 antineoplastic drug Drugs 0.000 claims description 2
- 150000003851 azoles Chemical class 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 11
- 238000011160 research Methods 0.000 abstract description 10
- 230000001093 anti-cancer Effects 0.000 abstract description 7
- 239000003814 drug Substances 0.000 abstract description 7
- 229940079593 drug Drugs 0.000 abstract description 4
- 150000002460 imidazoles Chemical class 0.000 abstract description 3
- 229930014626 natural product Natural products 0.000 abstract description 3
- 206010006187 Breast cancer Diseases 0.000 abstract description 2
- 208000026310 Breast neoplasm Diseases 0.000 abstract description 2
- 206010008342 Cervix carcinoma Diseases 0.000 abstract description 2
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 abstract description 2
- 201000008275 breast carcinoma Diseases 0.000 abstract description 2
- 201000010881 cervical cancer Diseases 0.000 abstract description 2
- 231100000419 toxicity Toxicity 0.000 abstract description 2
- 230000001988 toxicity Effects 0.000 abstract description 2
- 239000000047 product Substances 0.000 description 26
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- 150000001875 compounds Chemical class 0.000 description 8
- 230000002401 inhibitory effect Effects 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 7
- 238000010521 absorption reaction Methods 0.000 description 6
- 239000012141 concentrate Substances 0.000 description 6
- 239000000523 sample Substances 0.000 description 6
- 230000001629 suppression Effects 0.000 description 6
- 206010028980 Neoplasm Diseases 0.000 description 5
- 150000004753 Schiff bases Chemical group 0.000 description 5
- 230000000259 anti-tumor effect Effects 0.000 description 5
- 238000003556 assay Methods 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 238000006356 dehydrogenation reaction Methods 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- 241001597008 Nomeidae Species 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 4
- 201000009030 Carcinoma Diseases 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 230000000844 anti-bacterial effect Effects 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 150000001735 carboxylic acids Chemical class 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- KYWMCFOWDYFYLV-UHFFFAOYSA-N 1h-imidazole-2-carboxylic acid Chemical compound OC(=O)C1=NC=CN1 KYWMCFOWDYFYLV-UHFFFAOYSA-N 0.000 description 2
- RSWGJHLUYNHPMX-UHFFFAOYSA-N Abietic-Saeure Natural products C12CCC(C(C)C)=CC2=CCC2C1(C)CCCC2(C)C(O)=O RSWGJHLUYNHPMX-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- KHPCPRHQVVSZAH-HUOMCSJISA-N Rosin Natural products O(C/C=C/c1ccccc1)[C@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 KHPCPRHQVVSZAH-HUOMCSJISA-N 0.000 description 2
- 241000191967 Staphylococcus aureus Species 0.000 description 2
- 208000007107 Stomach Ulcer Diseases 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- RSWGJHLUYNHPMX-ONCXSQPRSA-N abietic acid Chemical compound C([C@@H]12)CC(C(C)C)=CC1=CC[C@@H]1[C@]2(C)CCC[C@@]1(C)C(O)=O RSWGJHLUYNHPMX-ONCXSQPRSA-N 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 238000004043 dyeing Methods 0.000 description 2
- 238000005194 fractionation Methods 0.000 description 2
- 201000005917 gastric ulcer Diseases 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 239000002917 insecticide Substances 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000002547 new drug Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 150000003141 primary amines Chemical class 0.000 description 2
- 230000001954 sterilising effect Effects 0.000 description 2
- 238000004659 sterilization and disinfection Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- KHPCPRHQVVSZAH-UHFFFAOYSA-N trans-cinnamyl beta-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OCC=CC1=CC=CC=C1 KHPCPRHQVVSZAH-UHFFFAOYSA-N 0.000 description 2
- HBXGSIZEPYWAOK-UHFFFAOYSA-N 2-benzylpiperidin-4-one Chemical class C1C(=O)CCNC1CC1=CC=CC=C1 HBXGSIZEPYWAOK-UHFFFAOYSA-N 0.000 description 1
- KVTHMAAGKKCLIH-UHFFFAOYSA-N 2-methyl-4-phenyl-4-sulfanylidenebutanoic acid Chemical compound OC(=O)C(C)CC(=S)C1=CC=CC=C1 KVTHMAAGKKCLIH-UHFFFAOYSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- 241000193830 Bacillus <bacterium> Species 0.000 description 1
- 206010006002 Bone pain Diseases 0.000 description 1
- 240000007124 Brassica oleracea Species 0.000 description 1
- 241000195493 Cryptophyta Species 0.000 description 1
- JPVYNHNXODAKFH-UHFFFAOYSA-N Cu2+ Chemical compound [Cu+2] JPVYNHNXODAKFH-UHFFFAOYSA-N 0.000 description 1
- SBJKKFFYIZUCET-JLAZNSOCSA-N Dehydro-L-ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(=O)C1=O SBJKKFFYIZUCET-JLAZNSOCSA-N 0.000 description 1
- KRHAHEQEKNJCSD-UHFFFAOYSA-N Dihydroasparagusic acid Natural products OC(=O)C(CS)CS KRHAHEQEKNJCSD-UHFFFAOYSA-N 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 241000305071 Enterobacterales Species 0.000 description 1
- 239000004593 Epoxy Substances 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 208000037147 Hypercalcaemia Diseases 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- VEQPNABPJHWNSG-UHFFFAOYSA-N Nickel(2+) Chemical compound [Ni+2] VEQPNABPJHWNSG-UHFFFAOYSA-N 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 241000228143 Penicillium Species 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 241000222481 Schizophyllum commune Species 0.000 description 1
- 241000588902 Zymomonas mobilis Species 0.000 description 1
- WREBNDYJJMUWAO-LWYYNNOASA-N [(1r,4ar,4br,10ar)-1,4a-dimethyl-7-propan-2-yl-2,3,4,4b,5,6,10,10a-octahydrophenanthren-1-yl]methanamine Chemical compound NC[C@]1(C)CCC[C@]2(C)[C@@H](CCC(C(C)C)=C3)C3=CC[C@H]21 WREBNDYJJMUWAO-LWYYNNOASA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 102000001307 androgen receptors Human genes 0.000 description 1
- 108010080146 androgen receptors Proteins 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000002467 anti-pepsin effect Effects 0.000 description 1
- 230000002155 anti-virotic effect Effects 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000003093 cationic surfactant Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000005068 cooling lubricant Substances 0.000 description 1
- 150000004696 coordination complex Chemical class 0.000 description 1
- 230000007797 corrosion Effects 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- 239000010779 crude oil Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 239000012531 culture fluid Substances 0.000 description 1
- 229940011405 cupric glycinate Drugs 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- QGBSISYHAICWAH-UHFFFAOYSA-N dicyandiamide Chemical group NC(N)=NC#N QGBSISYHAICWAH-UHFFFAOYSA-N 0.000 description 1
- JYGAZEJXUVDYHI-UHFFFAOYSA-N dihydroartemisininic acid Natural products C1CC(C)=CC2C(C(C)C(O)=O)CCC(C)C21 JYGAZEJXUVDYHI-UHFFFAOYSA-N 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000008396 flotation agent Substances 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- RBZVCMKUEIDTSC-UHFFFAOYSA-N formaldehyde;1h-imidazole Chemical compound O=C.C1=CNC=N1 RBZVCMKUEIDTSC-UHFFFAOYSA-N 0.000 description 1
- 210000004211 gastric acid Anatomy 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 210000001156 gastric mucosa Anatomy 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000000148 hypercalcaemia Effects 0.000 description 1
- 208000030915 hypercalcemia disease Diseases 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 230000003405 preventing effect Effects 0.000 description 1
- 238000007639 printing Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 201000001514 prostate carcinoma Diseases 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 208000028172 protozoa infectious disease Diseases 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 230000003439 radiotherapeutic effect Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000005556 structure-activity relationship Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000004753 textile Substances 0.000 description 1
- 239000012745 toughening agent Substances 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- XRASPMIURGNCCH-UHFFFAOYSA-N zoledronic acid Chemical compound OP(=O)(O)C(P(O)(O)=O)(O)CN1C=CN=C1 XRASPMIURGNCCH-UHFFFAOYSA-N 0.000 description 1
- 229960004276 zoledronic acid Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
Abstract
本发明公开了咪唑脱氢枞胺希夫碱类化合物及其制备方法和应用，该咪唑脱氢枞胺希夫碱类化合物为咪唑‑2‑甲醛‑脱氢枞胺希夫碱或咪唑‑4‑甲醛‑脱氢枞胺希夫碱。本发明的咪唑脱氢枞胺希夫碱类化合物拓展了脱氢枞胺基希夫碱化合物种类，为研究脱氢枞胺基希夫碱化合物结构与性能之间的关系创造条件。同时，该咪唑脱氢枞胺希夫碱类化合物表现出良好的抗癌活性，并对正常细胞毒副作用小，为抗宫颈癌、乳腺癌新药物的开发提供依据。该咪唑脱氢枞胺希夫碱类化合物的制备方法易操作，方法中所需物品毒性小，结合天然产物，具有很好的实用性。
Description
技术领域
本发明涉及脱氢枞胺基化合物，具体涉及咪唑脱氢枞胺希夫碱类化合物及其制备方法和应用。
背景技术
天然产物是在自然界中由活生物产生的那些通常具有药理学或生物学活性的化学物质，可被用于药学上的药物研发与药物设计。树木中提取出的松香是我国重要的林产化工产品之一，也是重要的出口产品，更是我国特色的资源产品。松香的重要改性产品——脱氢枞胺(dehydroabietylamine，DHAA)又叫去氢枞胺(如式I所示)，是歧化松香胺的主要成分，是一种有光学活性的胺，具有性质稳定、比旋光度大等其它松香衍生物所不具备的一些独特理化性质。近年来，脱氢枞胺的提取和纯化技术取得了飞速进展，王道林等将脱氢枞胺的产品含量从原来的40％～60％提高到98％以上，为进一步拓展脱氢枞胺的应用奠定了基础。
脱氢枞胺衍生物被广泛用于生产各种工业助剂，如杀虫剂、杀菌剂、抗癌、抗炎、除藻剂、缓蚀剂、金属切削加工冷却润滑剂、浮选剂、原油破乳剂、塑料增韧剂和各种用途的表面活性剂。在光化学拆分、造纸、选矿、纺织印染、涂料、石油开采、医药、农药等领域有着广泛的应用前景。早期Cannon L C将脱氢枞胺成功运用于抗生素盘尼西林生产，BuzbyJrGeorge C报道用来拆分3-硫代苯甲酰-2-甲基丙酸，Kohl等报道用来拆分光学活性的医药中间体2-(X-苯氧基烷基)环氧羧酸，Chiu CharlesK等用来拆分2-苄基-4-哌啶酮丁二酸。黄春林等以手性脱氢枞胺为拆分剂，乙醇水溶液为溶剂体系，用结晶法拆分手段，实现了脱氢枞胺对外消旋联萘酚的拆分。
脱氢枞胺的许多衍生物都具有一定的生物活性，如局部抗炎，抗胃蛋白酶并抑制分泌，保护胃黏膜不受酒精胃酸损害，抵抗对肺成纤维细胞和胃上皮细胞的细胞毒作用，降血脂，防止动脉硬化，抗肿瘤和抗病毒作用等。也可以用来制备特效的杀虫剂、杀菌剂和防霉剂。李海涛等以脱氢枞胺钾盐为研究对象，研究其对各种胃溃疡动物模型的保护作用，发现其对多种类型胃溃疡有抑制和治疗的作用。张曙光等发现12-硝基脱氢枞胺和12,14-二硝基脱氢枞胺对皱褶青霉、裂褶菌有一定的抑制效果，对金黄色葡萄球菌、荧光单胞菌、大肠杆菌具有显著的抑制活性。梁梦兰等[13]以脱氢松香胺为原料合成的N,N-二甲基-N-脱氢松香基氯化铵和N,N,N-三甲基-N-脱氢松香基单甲酯胺,具有良好的表面活性,并且与直链季胺盐类阳离子表面活性剂一样具有良好的杀菌和抑菌性能。
在脱氢枞胺基N-C衍生物中，希夫碱结构的研究引起了广泛关注。众所周知，癌症能够危害人类的健康和生命，具有极高的死亡率，而化学治疗则一直被看作是治疗癌症的十分重要的手段之一，多年的研究表明，大部分希夫碱及其衍生物具有非常良好的杀菌抗癌活性。例如，在唐慧安[唐慧安,王哲民,朱巧军等.主族元素Sn的含硫希夫碱配合物的合成、表征、抗肿瘤活性[J].兰州大学学报(自然科学版),2001,37(1):121-122.]等的研究报道中，指出了某些希夫碱类配合物因含有硫原子而具有非常良好的抗肿瘤效果。这些年来人们均广泛关注由α-氨基酸所形成的希夫碱及其过渡金属配合物的抗癌活性。研究结果表明：水杨醛-甘氨酸铜(II)配合物对小鼠艾氏腹水癌的抑制率可达到100％，而2,4-二羟基苯甲醛-L精氨酸与铜(II)、镍(II)的配合物对小鼠艾氏腹水癌的抑制率也能达到53％及51％，这一研究表明了氨基酸希夫碱与金属离子生成的配合物是一类具有优良前景的抗癌剂。
咪唑羧酸及其衍生物是一类重要的医药中间体,同时本身就具有显著的生物活性，如2-[1-咪唑基]乙酸可用于体外1H-NMR探针来测定体内血红细胞的pH及细胞空间大小。而其C取代衍生物广泛地用作化学疗法试剂,如[1-(4-硝基咪唑)]羧酸是一类很好的免疫抑制剂、放射疗法的协助剂，[1-(5-硝基咪唑)]羧酸系列化合物可治疗原生虫传染病。并且由它合成的双膦酸类新药如唑来膦酸等,在临床上已用于治疗高钙血症和骨痛症等疾病,均取得了显著疗效。
肿瘤严重危害人类的生命健康。天然药物毒副作用小，越来越受到人们的重视。脱氢枞胺类化合物可以抑制肿瘤增殖，表现出一定的抗肿瘤活性。陈泳将所合成的脱氢枞胺衍生物进行筛选,测试其抗癌活性、抗菌活性等,并对构效关系进行分析,发现脱氢枞胺衍生物对前列腺癌细胞、卵巢癌细胞、肝癌细胞有抑制作用；脱氢枞胺衍生物的雄激素受体结合活性为前列腺癌的治疗提供新的思路和参考；对金黄色葡萄球菌、大肠杆菌以及枯草芽孢杆菌具有显著的抑制活性。脱氢枞胺和咪唑羧酸都具有良好的生物活性，将二者结合起来，合成一系列新的脱氢枞胺咪唑希夫碱类化合物，有望设计开发出具有独特抗氧化活性或抗肿瘤活性的新化合物，为新药开发奠定基础。
发明内容
发明目的：针对现有技术中存在的不足，本发明的目的是提供一种咪唑脱氢枞胺希夫碱类化合物，该化合物具有良好的抗癌活性。本发明的另一目的是提供一种上述咪唑脱氢枞胺希夫碱类化合物的制备方法。本发明还有一目的是提供上述咪唑脱氢枞胺希夫碱类化合物的应用。
技术方案：为了实现上述发明目的，本发明采用的技术方案为：
咪唑脱氢枞胺希夫碱类化合物，为咪唑-2-甲醛-脱氢枞胺希夫碱或咪唑-4-甲醛-脱氢枞胺希夫碱，结构式如下：
一种制备所述的咪唑脱氢枞胺希夫碱类化合物的方法：以咪唑-2-甲醛和脱氢枞胺为原料，在冰醋酸和EtOH体系中，回流反应；反应停止后静置自然冷却，无沉淀，浓缩，产物为橙色粉末，烘干，得产物咪唑-2-甲醛-脱氢枞胺希夫碱。
一种制备所述的咪唑脱氢枞胺希夫碱类化合物的方法：以4-咪唑甲醛和脱氢枞胺为原料，在冰醋酸和EtOH体系中，回流反应；反应停止，静置自然冷却，无沉淀，完全浓缩，产物为橙色粉末，烘干，得产物咪唑-4-甲醛-脱氢枞胺希夫碱。
所述的咪唑脱氢枞胺希夫碱类化合物在制备抗肿瘤药物中的应用。
有益效果：与现有技术相比，本发明的咪唑脱氢枞胺希夫碱类化合物拓展了脱氢枞胺基希夫碱化合物种类，为研究脱氢枞胺基希夫碱化合物结构与性能之间的关系创造条件。同时，该咪唑脱氢枞胺希夫碱类化合物表现出良好的抗癌活性，并对正常细胞毒副作用小，为抗宫颈癌、乳腺癌新药物的开发提供依据。该咪唑脱氢枞胺希夫碱类化合物的制备方法易操作，方法中所需物品毒性小，结合天然产物，具有很好的实用性。
附图说明：
图1是咪唑-2-甲醛-脱氢枞胺希夫碱的红外光谱图；
图2是咪唑-4-甲醛-脱氢枞胺希夫碱的红外光谱图。
具体实施方式
下面结合具体实施例对本发明做进一步的说明。
在以下实施例中产物的表征中，红外光谱是在德国布鲁克公司VERTEX-80上采用KBr压片法测得的。MS谱在美国热电公司LTQ Orbitrap XL液相质谱联用仪上测得。1H-NMR、13C-NMR光谱在瑞士布鲁克拜厄斯宾公司AVANCEⅢ600MHz型核磁共振光谱仪上测定。
实施例1
咪唑-2-甲醛-脱氢枞胺希夫碱(L1)的制备：在250mL的圆底烧瓶中加入15mmol咪唑-2-甲醛，15mmol脱氢枞胺，86滴冰醋酸，溶于120mL EtOH，回流反应24h，反应停止，静置自然冷却，无沉淀，完全浓缩，产物为橙色粉末，烘干，共得4.1012g产物，产率75.3％。
产物的IR谱图如图1所示：与脱氢枞胺对比，产物中3410cm-1处的的峰为单峰，证明伯胺已反应；2950cm-1处的峰为苯环上的C-H伸缩振动峰，2865cm-1处的的峰为为CH3-和-CH2-中的C-H伸缩振动峰，1450cm-1处的峰为H-C-H面内摇摆振动峰，1385cm-1处的峰为H-C-H对称的剪式振动单峰。与2-咪唑甲醛的红外相比较，1612cm-1处的-HC＝O特征吸收峰消失，1645cm-1处的峰是新的红外吸收峰，为-HC＝N-的特征吸收峰。表明了有-HC＝N-的生成。
产物的1H-NMR(CDCl3，δ/ppm，600MHz)：1.00(3H，s，H-23)；1.21～1.23(9H，s，H-21，22，24)；1.37～1.39(9H，m，H-7)；1.48～1.53(1H，m，H-9α)；1.64(2H，d，J＝10.8Hz，H-8)；1.72～1.77(2H，m，H-12)；1.83～1.87(1H，m，H-9β)；2.79～2.82(2H，m，H-13)；2.86～2.90(1H，m，H-20)；3.29，3.56(2H，dd，J＝150.6Hz，H-5)；6.87(1H，d，H-19)；6.98，7.00(1H，dd，J＝7.8Hz，H-17)；7.05(1H，d，H-16)；7.17(1H，d，J＝8.4Hz，H-1、2)；8.18(1H，s，H-4)。
产物的13C-NMR(CDCl3，δ/ppm，151MHz)：19.38，19.51，19.85，22.23，23.92，25.15，27.20，29.92，30.08，32.56，33.36，35.35，36.52，37.49，38.07，38.32，45.41，45.57，52.70，72.38，123.79，123.95，124.17，124.50，124.61，124.78，125.06，126.82，134.72，144.75，145.67，147.28，152.26。
产物的质谱：m/z：364.33[1+H]+。
可见产物为：咪唑-2-甲醛-脱氢枞胺希夫碱，结构式如下：
实施例2
咪唑-4-甲醛-脱氢枞胺希夫碱(L2)的制备：在250mL的圆底烧瓶中加入15mmol 4-咪唑甲醛，15mmol脱氢枞胺，6滴冰醋酸，溶于120mLEtOH，回流反应24h，反应停止，静置自然冷却，无沉淀，完全浓缩，产物为橙色粉末，烘干，共得5.374g产物，产率98.6％。
产物的IR谱图如图2所示：与脱氢枞胺对比，产物中3410cm-1处的的峰为单峰，证明伯胺已反应；2950cm-1处的峰为苯环上的C-H伸缩振动峰，2865cm-1处的的峰为为CH3-和-CH2-中的C-H伸缩振动峰，1450cm-1处的峰为H-C-H面内摇摆振动峰，1385cm-1处的峰为H-C-H对称的剪式振动单峰。与2-咪唑甲醛的红外相比较，1665cm-1处的-HC＝O特征吸收峰消失，1650cm-1处的峰是新的红外吸收峰，为-HC＝N-的特征吸收峰。表明了有-HC＝N-的生成。
产物的1H-NMR(CDCl3，δ/ppm，600MHz)：0.98(3H，s，H-23)；1.20(9H，t，H-21，22，24)；1.33～1.56(4H，m，H-8、7)；1.61～1.63(1H，m，H-9α)；1.71～1.75(2H，m，H-12)；1.81～1.82(1H，m，H-9β)；2.75～2.81(2H，m，H-13)；2.23～2.26(2H，m，H-11)；2.85～2.88(1H，m，H-20)；3.34，3.43(2H，dd，J＝51Hz，H-5)；6.85(1H，d，H-19)；6.97(1H，d，J＝7.8Hz，H-17)；7.15(1H，d，J＝7.2Hz，H-16)；7.41(1H，s，H-3)；7.67(1H，s，H-1)；8.08(1H，s，H-4)；8.64(1H，s，-NH)。
产物的13C-NMR(CDCl3，δ/ppm，151MHz)：18.73，19.31，23.94，25.44，30.12，33.36，36.58，37.50，38.05，38.32，45.51，72.76，123.79，124.24，126.79，130.43，130.48，134.70，137.54，145.46，147.33，151.32。
产物的质谱：m/z：364.42[1+H]+。
可见产物为：咪唑-4-甲醛-脱氢枞胺希夫碱，结构式如下：
实施例3
1)采用MTT法研究咪唑-2-甲醛-脱氢枞胺希夫碱、咪唑-4-甲醛-脱氢枞胺希夫碱对Hela的抑制作用，结果IC50分别为5.15μmol/L、6.97μmol/L。
MTT法具体操作如下：取对数生长期的待测试细胞，配制成105个/mL的单细胞悬液，在96孔培养板上接种，每孔100μL，于体积分数为5％的二氧化碳、饱和湿度、37℃培养箱中培养一天；之后，将100μL不同浓度的待测样品加入到培养板上，每种浓度均为2个复孔；继续培养24h后，每孔加20μL的MTT染色液，在培养箱中继续培养4h，小心去除上层清液，然后每孔加200μL THF，充分震荡半小时后，在酶标仪上595nm波长处测定OD样值，实验的空白组是用100μL无血清的DMEM培养液代替样品的，这时的吸光度值为OD空白值，通过以下公式计算样品对Hela细胞抑制率：
m＝1-n＝1-OD样/OD空白。式中，m：抑制率，n：细胞存活率。
然后通过以下公式算出IC50：
lgIC50＝a-b(c-(3-d-e)/4)。式中，a：lg最大浓度；b：lg(最大浓度/相邻浓度)；c：抑制率总和；d：最大抑制率；e：最小抑制率。
2)采用MTT法研究咪唑-2-甲醛-脱氢枞胺希夫碱、咪唑-4-甲醛-脱氢枞胺希夫碱对HepG2的抑制作用，方法同上，结果IC50分别为5.18μmol/L、5.38μmol/L。
3)采用MTT法研究咪唑-2-甲醛-脱氢枞胺希夫碱、咪唑-4-甲醛-脱氢枞胺希夫碱对Mcf-7的抑制作用，方法同上，结果IC50分别为5.85μmol/L、5.03μmol/L。
4)采用MTT法研究咪唑-2-甲醛-脱氢枞胺希夫碱、咪唑-4-甲醛-脱氢枞胺希夫碱对Huvec的抑制作用，方法同上，结果IC50分别为10.42μmol/L、18.16μmol/L，咪唑-2-甲醛-脱氢枞胺希夫碱、咪唑-4-甲醛-脱氢枞胺希夫碱的毒副作用较低。
实施例3
在250mL的圆底烧瓶中加入12mmol咪唑-2-甲醛，10mmol脱氢枞胺，8滴冰醋酸，溶于150mL EtOH，回流反应24h反应停止，静置自然冷却，无沉淀，完全浓缩，产物为橙色泡沫状和褐色粘稠状混合物，用正己烷洗，过滤，得乳白色固体，滤液浓缩，得橙色粉末，烘干，共得2.6318g产物，产率72.4％。
改用甲醇作溶剂，设置回流温度为70℃，其他条件不变，得相同产物，产率为71.9％。
Claims (6)
1.咪唑脱氢枞胺希夫碱类化合物，其特征在于：为咪唑-2-甲醛-脱氢枞胺希夫碱或咪唑-4-甲醛-脱氢枞胺希夫碱，结构式如下：
2.一种制备权利要求1所述的咪唑脱氢枞胺希夫碱类化合物的方法，其特征在于：以咪唑-2-甲醛和脱氢枞胺为原料，在冰醋酸和EtOH体系中，回流反应；反应停止后静置自然冷却，无沉淀，浓缩，产物为橙色粉末，烘干，得产物咪唑-2-甲醛-脱氢枞胺希夫碱。
3.根据权利要求2所述的制备咪唑脱氢枞胺希夫碱类化合物的方法，其特征在于：咪唑-2-甲醛与脱氢枞胺的用量比例为1～1.2:1。
4.一种制备权利要求1所述的咪唑脱氢枞胺希夫碱类化合物的方法，其特征在于：以4-咪唑甲醛和脱氢枞胺为原料，在冰醋酸和EtOH体系中，回流反应；反应停止，静置自然冷却，无沉淀，完全浓缩，产物为橙色粉末，烘干，得产物咪唑-4-甲醛-脱氢枞胺希夫碱。
5.根据权利要求4所述的制备咪唑脱氢枞胺希夫碱类化合物的方法，其特征在于：4-咪唑甲醛与脱氢枞胺的用量比例为1～1.2:1。
6.权利要求1所述的咪唑脱氢枞胺希夫碱类化合物在制备抗肿瘤药物中的应用。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610597465.9A CN106243042B (zh) | 2016-07-26 | 2016-07-26 | 咪唑脱氢枞胺希夫碱类化合物及其制备方法和应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610597465.9A CN106243042B (zh) | 2016-07-26 | 2016-07-26 | 咪唑脱氢枞胺希夫碱类化合物及其制备方法和应用 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106243042A true CN106243042A (zh) | 2016-12-21 |
| CN106243042B CN106243042B (zh) | 2019-07-30 |
Family
ID=57604734
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610597465.9A Expired - Fee Related CN106243042B (zh) | 2016-07-26 | 2016-07-26 | 咪唑脱氢枞胺希夫碱类化合物及其制备方法和应用 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106243042B (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107759475A (zh) * | 2017-11-09 | 2018-03-06 | 嘉兴学院 | 脱氢枞胺衍生物及其制备方法和应用 |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101003548A (zh) * | 2006-12-12 | 2007-07-25 | 中国林业科学研究院林产化学工业研究所 | 松香基二萜改性α－氨基磷酸酯、制备方法及抗肿瘤应用 |
| CN101580477A (zh) * | 2009-06-18 | 2009-11-18 | 南京林业大学 | 脱氢枞胺衍生物及其在杀菌抗肿瘤药物中的应用 |
| WO2012078667A2 (en) * | 2010-12-06 | 2012-06-14 | The Penn State Research Foundation | Compositions and methods relating to proliferative diseases |
| CN104961673A (zh) * | 2015-06-26 | 2015-10-07 | 南京林业大学 | 一种联吡啶脱氢枞胺希夫碱化合物及其制备方法 |
-
2016
- 2016-07-26 CN CN201610597465.9A patent/CN106243042B/zh not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101003548A (zh) * | 2006-12-12 | 2007-07-25 | 中国林业科学研究院林产化学工业研究所 | 松香基二萜改性α－氨基磷酸酯、制备方法及抗肿瘤应用 |
| CN101580477A (zh) * | 2009-06-18 | 2009-11-18 | 南京林业大学 | 脱氢枞胺衍生物及其在杀菌抗肿瘤药物中的应用 |
| WO2012078667A2 (en) * | 2010-12-06 | 2012-06-14 | The Penn State Research Foundation | Compositions and methods relating to proliferative diseases |
| CN104961673A (zh) * | 2015-06-26 | 2015-10-07 | 南京林业大学 | 一种联吡啶脱氢枞胺希夫碱化合物及其制备方法 |
Non-Patent Citations (7)
| Title |
|---|
| LING-YING LIN等: "N-Benzoyl-12-nitrodehydroabietylamine-7-one, a novel dehydroabietylamine derivative, induces apoptosis and inhibits proliferation in HepG2 cells", 《CHEMICO-BIOLOGICAL INTERACTIONS》 * |
| XIAOPING RAO等: "Antitumor activity and structure-activity relationship of diterpenoids with a dehydroabietyl skeleton", 《COMBINATORIAL CHEMISTRY & HIGH THROUGHPUT SCREENING》 * |
| 刘玲，等: "脱氢枞胺对氟苯甲醛对人肝癌细胞的抑制作用", 《中国药学杂志》 * |
| 刘超祥，等: "脱氢枞胺衍生物及功能性研究", 《安徽农业科学》 * |
| 叶发青: "《药物化学》", 28 June 2012 * |
| 姜大炜，等: "脱氢枞胺Schiff碱的合成及其表征", 《江苏教育学院学报( 自然科学)》 * |
| 张曙光,等: "脱氢枞胺衍生物 Schiff 碱的合成及其抗肿瘤活性", 《中国医药工业杂志》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107759475A (zh) * | 2017-11-09 | 2018-03-06 | 嘉兴学院 | 脱氢枞胺衍生物及其制备方法和应用 |
| CN107759475B (zh) * | 2017-11-09 | 2020-09-22 | 嘉兴学院 | 脱氢枞胺衍生物及其制备方法和应用 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106243042B (zh) | 2019-07-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Liu et al. | Synthesis, characterization, and in vitro studies of bis [1, 3-diethyl-4, 5-diarylimidazol-2-ylidene] gold (I/III) complexes | |
| Siddiqui et al. | Synthesis, characterization and anticancer studies of new steroidal oxadiazole, pyrrole and pyrazole derivatives | |
| Yan et al. | Design, synthesis and fungicidal activity evaluation of novel pyrimidinamine derivatives containing phenyl-thiazole/oxazole moiety | |
| Haribabu et al. | Synthesis, crystal structure, and in vitro and in silico molecular docking of novel acyl thiourea derivatives | |
| Jarrahpour et al. | Synthesis of novel β-lactams bearing an anthraquinone moiety, and evaluation of their antimalarial activities | |
| Wang et al. | Novel NIR fluorescent probe with dual models for sensitively and selectively monitoring and imaging Cys in living cells and mice | |
| CN101580477A (zh) | 脱氢枞胺衍生物及其在杀菌抗肿瘤药物中的应用 | |
| CN108610348A (zh) | 一种含咪唑取代基的5H-色烯并[2,3-b]吡啶-3-腈衍生物及其制备与应用 | |
| Hua et al. | Synthesis, fungicidal activity, and mechanism of action of pyrazole amide and ester derivatives based on natural products l-serine and waltherione alkaloids | |
| Fadda et al. | Utility of quaternary ammonium salts in synthesis of some novel cyanine dyes as potential antibacterial and antitumor agents | |
| CN103951566B (zh) | 一种N-烃基-1,2,3,4,5,6-六氢-1,1,5,5-四甲基-7H-2,4α-桥亚甲基萘-7-胺类化合物及其合成方法和应用 | |
| CN106588945B (zh) | 阿司匹林抗癌药物偶联物、合成方法及其应用 | |
| Elnagar et al. | Synthesis, characterization, and evaluation of biological activities of new 4′‐substituted ruthenium (II) terpyridine complexes: Prospective anti‐inflammatory properties | |
| Yamaguchi et al. | Design, Synthesis, and Anticancer Activity of Triptycene–Peptide Hybrids that Induce Paraptotic Cell Death in Cancer Cells | |
| CN106243042B (zh) | 咪唑脱氢枞胺希夫碱类化合物及其制备方法和应用 | |
| CN107573318A (zh) | 一种具抗肿瘤活性的新型棉酚席夫碱类衍生物及其合成方法 | |
| CN106588826B (zh) | 阿司匹林紫杉醇抗癌药物偶联物、合成方法及其应用 | |
| Li et al. | Synthesis and insecticidal activities of N-(5-dehydroabietyl-1, 3, 4-thiadiazol-2-yl)-benzenesulfonamides | |
| Knyazev et al. | Synthesis and antioxidant and cytotoxic activity of new dihydroquercetin derivatives | |
| CN102746226B (zh) | 吖啶衍生物及其制备方法和应用 | |
| CN105663112B (zh) | 一种Morusignin L及其衍生物的应用与制备方法 | |
| CN107253949A (zh) | 一类硫杂吴茱萸次碱化合物及其在抗肿瘤药物中的应用 | |
| CN103772397A (zh) | 一类哌嗪修饰的酞菁配合物及其制备方法 | |
| CN106146341A (zh) | 一种水杨醛脱氢枞胺希夫碱化合物及其制备方法和应用 | |
| CN110483405B (zh) | Kealiinine类衍生物及其制备和在抗植物病毒和病菌中的应用 |
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 | ||
| EE01 | Entry into force of recordation of patent licensing contract | ||
| EE01 | Entry into force of recordation of patent licensing contract |
Application publication date: 20161221 Assignee: SPECTRUM DETECTION (SUZHOU) Co.,Ltd. Assignor: Nanjing Forestry University Contract record no.: X2019320000186 Denomination of invention: Imidazole dehydroabietylamine Schiff base compound and preparation method and application thereof Granted publication date: 20190730 License type: Common License Record date: 20191029 |
|
| EC01 | Cancellation of recordation of patent licensing contract |
Assignee: SPECTRUM DETECTION (SUZHOU) Co.,Ltd. Assignor: NANJING FORESTRY University Contract record no.: X2019320000186 Date of cancellation: 20201223 |
|
| EC01 | Cancellation of recordation of patent licensing contract | ||
| EE01 | Entry into force of recordation of patent licensing contract |
Application publication date: 20161221 Assignee: SPECTRUM DETECTION (SUZHOU) Co.,Ltd. Assignor: NANJING FORESTRY University Contract record no.: X2020320000405 Denomination of invention: Imidazole dehydroabietylamine Schiff bases and their preparation and Application Granted publication date: 20190730 License type: Common License Record date: 20201228 |
|
| EE01 | Entry into force of recordation of patent licensing contract | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20190730 Termination date: 20210726 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |