CN103570672A - Benzoyl hydrazine compound containing thiophene ring, and preparation method and application of compound - Google Patents
Benzoyl hydrazine compound containing thiophene ring, and preparation method and application of compound Download PDFInfo
- Publication number
- CN103570672A CN103570672A CN201310574554.8A CN201310574554A CN103570672A CN 103570672 A CN103570672 A CN 103570672A CN 201310574554 A CN201310574554 A CN 201310574554A CN 103570672 A CN103570672 A CN 103570672A
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- Prior art keywords
- compound
- thiophene ring
- formula
- preparation
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 55
- -1 Benzoyl hydrazine compound Chemical class 0.000 title claims abstract description 41
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 title claims abstract description 24
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- 239000002253 acid Substances 0.000 claims abstract description 12
- 230000000259 anti-tumor effect Effects 0.000 claims abstract description 10
- 239000011230 binding agent Substances 0.000 claims abstract description 9
- 241000500437 Plutella xylostella Species 0.000 claims abstract description 8
- 241000256113 Culicidae Species 0.000 claims abstract description 7
- 239000002917 insecticide Substances 0.000 claims abstract description 6
- 241000607479 Yersinia pestis Species 0.000 claims abstract description 5
- 208000032839 leukemia Diseases 0.000 claims abstract description 4
- 206010017758 gastric cancer Diseases 0.000 claims abstract description 3
- 201000007270 liver cancer Diseases 0.000 claims abstract description 3
- 208000014018 liver neoplasm Diseases 0.000 claims abstract description 3
- 239000003085 diluting agent Substances 0.000 claims abstract 5
- DDPWVABNMBRBFI-UHFFFAOYSA-N tert-butylhydrazine;hydron;chloride Chemical compound Cl.CC(C)(C)NN DDPWVABNMBRBFI-UHFFFAOYSA-N 0.000 claims abstract 3
- 241001477931 Mythimna unipuncta Species 0.000 claims abstract 2
- 206010061306 Nasopharyngeal cancer Diseases 0.000 claims abstract 2
- 208000005718 Stomach Neoplasms Diseases 0.000 claims abstract 2
- 201000011549 stomach cancer Diseases 0.000 claims abstract 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 11
- 210000004027 cell Anatomy 0.000 claims description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- 210000004881 tumor cell Anatomy 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 239000003112 inhibitor Substances 0.000 claims description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims description 4
- LZDKZFUFMNSQCJ-UHFFFAOYSA-N 1,2-diethoxyethane Chemical compound CCOCCOCC LZDKZFUFMNSQCJ-UHFFFAOYSA-N 0.000 claims description 3
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 3
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 claims description 2
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 claims description 2
- IQHSSYROJYPFDV-UHFFFAOYSA-N 2-bromo-1,3-dichloro-5-(trifluoromethyl)benzene Chemical group FC(F)(F)C1=CC(Cl)=C(Br)C(Cl)=C1 IQHSSYROJYPFDV-UHFFFAOYSA-N 0.000 claims description 2
- ZNQVEEAIQZEUHB-UHFFFAOYSA-N 2-ethoxyethanol Chemical compound CCOCCO ZNQVEEAIQZEUHB-UHFFFAOYSA-N 0.000 claims description 2
- QDFXRVAOBHEBGJ-UHFFFAOYSA-N 3-(cyclononen-1-yl)-4,5,6,7,8,9-hexahydro-1h-diazonine Chemical compound C1CCCCCCC=C1C1=NNCCCCCC1 QDFXRVAOBHEBGJ-UHFFFAOYSA-N 0.000 claims description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 2
- KVNRLNFWIYMESJ-UHFFFAOYSA-N butyronitrile Chemical compound CCCC#N KVNRLNFWIYMESJ-UHFFFAOYSA-N 0.000 claims description 2
- 229940117389 dichlorobenzene Drugs 0.000 claims description 2
- XXJWXESWEXIICW-UHFFFAOYSA-N diethylene glycol monoethyl ether Chemical compound CCOCCOCCO XXJWXESWEXIICW-UHFFFAOYSA-N 0.000 claims description 2
- 229940075557 diethylene glycol monoethyl ether Drugs 0.000 claims description 2
- XXBDWLFCJWSEKW-UHFFFAOYSA-N dimethylbenzylamine Chemical compound CN(C)CC1=CC=CC=C1 XXBDWLFCJWSEKW-UHFFFAOYSA-N 0.000 claims description 2
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 claims description 2
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 claims description 2
- JIKUXBYRTXDNIY-UHFFFAOYSA-N n-methyl-n-phenylformamide Chemical compound O=CN(C)C1=CC=CC=C1 JIKUXBYRTXDNIY-UHFFFAOYSA-N 0.000 claims description 2
- 239000000575 pesticide Substances 0.000 claims description 2
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- XMVJITFPVVRMHC-UHFFFAOYSA-N roxarsone Chemical group OC1=CC=C([As](O)(O)=O)C=C1[N+]([O-])=O XMVJITFPVVRMHC-UHFFFAOYSA-N 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 3
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 claims 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims 2
- WADSJYLPJPTMLN-UHFFFAOYSA-N 3-(cycloundecen-1-yl)-1,2-diazacycloundec-2-ene Chemical compound C1CCCCCCCCC=C1C1=NNCCCCCCCC1 WADSJYLPJPTMLN-UHFFFAOYSA-N 0.000 claims 1
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims 1
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims 1
- 208000001894 Nasopharyngeal Neoplasms Diseases 0.000 claims 1
- WSGCRAOTEDLMFQ-UHFFFAOYSA-N nonan-5-one Chemical compound CCCCC(=O)CCCC WSGCRAOTEDLMFQ-UHFFFAOYSA-N 0.000 claims 1
- 239000003208 petroleum Substances 0.000 claims 1
- 229910000027 potassium carbonate Inorganic materials 0.000 claims 1
- 239000008096 xylene Substances 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 8
- 230000002401 inhibitory effect Effects 0.000 abstract description 4
- 208000002454 Nasopharyngeal Carcinoma Diseases 0.000 abstract 1
- 201000011216 nasopharynx carcinoma Diseases 0.000 abstract 1
- 238000000034 method Methods 0.000 description 13
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 11
- 229910052731 fluorine Inorganic materials 0.000 description 11
- 239000011737 fluorine Substances 0.000 description 11
- 229930192474 thiophene Natural products 0.000 description 8
- GXXOBXPRDUPYEJ-UHFFFAOYSA-N butylhydrazine;hydron;chloride Chemical group Cl.CCCCNN GXXOBXPRDUPYEJ-UHFFFAOYSA-N 0.000 description 7
- 238000002474 experimental method Methods 0.000 description 7
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- KENNKQXJFVDKAB-UHFFFAOYSA-N formohydrazide;thiophene Chemical compound NNC=O.C=1C=CSC=1 KENNKQXJFVDKAB-UHFFFAOYSA-N 0.000 description 5
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- WHLUQAYNVOGZST-UHFFFAOYSA-N tifenamil Chemical group C=1C=CC=CC=1C(C(=O)SCCN(CC)CC)C1=CC=CC=C1 WHLUQAYNVOGZST-UHFFFAOYSA-N 0.000 description 4
- JLYFCTQDENRSOL-UHFFFAOYSA-N 2-chloro-N-(2,4-dimethylthiophen-3-yl)-N-(1-methoxypropan-2-yl)acetamide Chemical compound COCC(C)N(C(=O)CCl)C=1C(C)=CSC=1C JLYFCTQDENRSOL-UHFFFAOYSA-N 0.000 description 3
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- 238000004519 manufacturing process Methods 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000003020 moisturizing effect Effects 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 210000004681 ovum Anatomy 0.000 description 1
- 238000005554 pickling Methods 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 229940043267 rhodamine b Drugs 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229960001866 silicon dioxide Drugs 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
- 201000000498 stomach carcinoma Diseases 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- GGCSSNBKKAUURC-UHFFFAOYSA-N sufentanil Chemical compound C1CN(CCC=2SC=CC=2)CCC1(COC)N(C(=O)CC)C1=CC=CC=C1 GGCSSNBKKAUURC-UHFFFAOYSA-N 0.000 description 1
- 229960004739 sufentanil Drugs 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- MDKGKXOCJGEUJW-UHFFFAOYSA-N suprofen Chemical compound C1=CC(C(C(O)=O)C)=CC=C1C(=O)C1=CC=CS1 MDKGKXOCJGEUJW-UHFFFAOYSA-N 0.000 description 1
- 229960004492 suprofen Drugs 0.000 description 1
- LOQQVLXUKHKNIA-UHFFFAOYSA-N thifensulfuron Chemical compound COC1=NC(C)=NC(NC(=O)NS(=O)(=O)C2=C(SC=C2)C(O)=O)=N1 LOQQVLXUKHKNIA-UHFFFAOYSA-N 0.000 description 1
- AHTPATJNIAFOLR-UHFFFAOYSA-N thifensulfuron-methyl Chemical group S1C=CC(S(=O)(=O)NC(=O)NC=2N=C(OC)N=C(C)N=2)=C1C(=O)OC AHTPATJNIAFOLR-UHFFFAOYSA-N 0.000 description 1
- 229960001312 tiaprofenic acid Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur 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
- C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/02—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms
- A01N43/04—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom
- A01N43/06—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom five-membered rings
- A01N43/10—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom five-membered rings with sulfur as the ring hetero atom
Landscapes
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Dentistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Plant Pathology (AREA)
- General Health & Medical Sciences (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- Environmental Sciences (AREA)
- Pest Control & Pesticides (AREA)
- Agronomy & Crop Science (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种含噻吩环苯甲酰肼类化合物及其制备方法和应用。该类化合物的结构通式如式Ⅰ或式Ⅱ所示。所述含噻吩环苯甲酰肼类化合物制备方法包括：在稀释剂和缚酸剂存在下，由式Ⅳ化合物与叔丁基肼盐酸盐进行反应而得。所述含噻吩环苯甲酰肼类化合物对粘虫、小菜蛾和蚊幼虫有明显防治效果，可以作为农用杀虫剂应用于植物虫害的防治；同时所述含噻吩环苯甲酰肼类化合物对HL-60人白血病细胞，BGC-823人胃癌细胞，Bel-7402人肝癌细胞，KB人鼻咽癌细胞有抑制效果，在抗肿瘤活性方面有应用前景。 The invention discloses a benzohydrazide compound containing a thiophene ring, a preparation method and application thereof. The general structural formula of this type of compound is shown in formula I or formula II. The preparation method of the thiophene ring-containing benzohydrazine compound comprises: reacting the compound of formula IV with tert-butylhydrazine hydrochloride in the presence of a diluent and an acid-binding agent. The thiophene ring-containing benzohydrazide compound has obvious control effects on armyworm, diamondback moth and mosquito larvae, and can be used as an agricultural insecticide for the control of plant pests; at the same time, the thiophene ring-containing benzohydrazide compound It has inhibitory effects on HL-60 human leukemia cells, BGC-823 human gastric cancer cells, Bel-7402 human liver cancer cells, and KB human nasopharyngeal carcinoma cells, and has application prospects in anti-tumor activity.
Description
Technical field
The invention belongs to the synthetic field of heterogeneous ring compound, particularly a kind of containing thiphene ring benzoyl hydrazine compounds and its preparation method and application.
Background technology
In recent years, heterogeneous ring compound occupies very consequence in novel ultra-high efficiency agricultural chemicals initiative, when searching novel structure has bioactive compound, design and synthetic various heterogeneous ring compounds are one of very important approach, already become quite active field ((a) new heterocyclic pesticide-sterilant, Song Baoan chief editor, Chemical Industry Press, 2009; (b) new heterocyclic pesticide-sterilant, Song Baoan, Jin Linjiang chief editor, Chemical Industry Press, 2010; (c) new heterocyclic pesticide-weedicide, Song Baoan, Wu Jian chief editor, Chemical Industry Press, 2011).In heterogeneous ring compound, sulfur heterocyclic compound more and more receives investigator's concern, thiophenes is wherein efficient because having, low toxicity, good biological activity and the various feature of structural changes, agricultural chemicals and medical aspect have a wide range of applications, be the focus and emphasis of organic chemistry research always.
Aspect medical, the microbiotic that contains thiphene ring often has better curative effect than the microbiotic that contains phenyl ring.Some anti-inflammation and analgesic drugs evident in efficacy as: sutoprofen (1), sufentanil (2), tiaprofenic acid (3) etc. are the derivative of thiophene.
Aspect agricultural chemicals, up to the present, there have been 3 compounds that contain thiphene ring successfully to be developed and become sterilant, they are respectively: the Guardian (ethaboxam of Korea S LG chemical company exploitation in 1994,4), the Silthiopham (silthiopham, 5) of Monsanto Company's exploitation in 1994, the pyrrole metsulfovax (penthiopyrad, 6) of 1996 Nian You Mitsui chemical companies exploitation.
3 compounds containing thiophene-based are successfully developed as weedicide, they are respectively: the thifensulfuron methyl (thifensulfuron of 1979 Nian You du pont company (Du Pont) exploitation, 7), the dimethenamid (dimethenamid of nineteen eighty-two Switzerland Shandeshi company (Sandoz Ltd.) exploitation, 8) and the thenylchlor (thenylchlor, 9) of day nineteen eighty-three Bender mountain (Tokuyama) Co., Ltd. exploitation.
Application aspect sterilant, can trace back to French Russell in 1974---You Ke good fortune company Development and Production containing the thiophene chrysanthemum ester derivative chrysanthemum ester (kadathrin, 10) that overcomes the enemy.Early 1980s, carried out the research of thiophenes insecticidal activity abroad, find that these compounds have significant photoactivation toxic action to mosquitos and flies ovum, larva.Lepidoptera pest is also shown obvious photoactivation toxicity and growing of its larva played to restraining effect.1987, the Philips-Duphar B.V. company of Holland developed sterilant thicyofen (thicyofen, 11), has mechanism of action novelty, and to features such as people and animals' low toxicities, this compound also has good fungicidal activity simultaneously.Thereby caused scientific research personnel to thiophene derivants the extensive concern as sterilant.
Because thiphene ring itself has good biological activity, and thiphene ring has aromaticity, and in its sulphur atom, sp2 track exists a pair of lone-pair electron, can participate in the formation of hydrogen bond in organism, increases the interaction between giving and accepting, and contributes to improve biological activity.Thiophene-based structure is started late on pesticide research, and therefore, the thiophenes of practical application is fewer.
Summary of the invention
The object of the present invention is to provide a kind of thiphene ring benzoyl hydrazine compounds that contains, this compound has good biological activity, can be for agricultural insecticide or anti-tumor activity inhibitor.
Another object of the present invention is to provide the described preparation method containing thiphene ring benzoyl hydrazine compounds.
Another object of the present invention is to provide the described application containing thiphene ring benzoyl hydrazine compounds.
Above-mentioned purpose of the present invention is achieved by following technical solution:
A thiphene ring benzoyl hydrazine compounds, described have suc as formula structure shown in I or formula II containing thiphene ring benzoyl hydrazine compounds:
Described R base is one or more, and described R base is alkyl or the alkoxyl group that hydrogen, halogen, nitro, hydroxyl, carbonatoms are 1～4.
As a kind of preferred version, described R base is preferably hydrogen, 4-methoxyl group, 2-chloro, 3-chloro, 4-chloro, 4-bromo, 4-methyl, 2-is fluorine-based, 3-is fluorine-based, 4-is fluorine-based, 2, and 4-bis-is fluorine-based, 2, and 6-bis-is fluorine-based, 2-nitro, 3-nitro or 4-nitro.
As a kind of more preferably scheme, described R base more preferably 2-chloro, 3-chloro, 4-chloro, 2-is fluorine-based, 3-is fluorine-based, 4-is fluorine-based, 2,4-bis-is fluorine-based or 2,6-bis-is fluorine-based.
A described preparation method containing thiphene ring benzoyl hydrazine compounds, comprises the steps:
S1. under thinner exists, compound and SOCl shown in formula III
2reaction, preparation formula IV compound;
S2. under thinner and acid binding agent existence, formula IV compound reacts with tertiary butyl hydrazine hydrochloride, and separation obtains formula I and formula II compound;
Described R base is one or more, and described R base is alkyl or the alkoxyl group that hydrogen, halogen, nitro, hydroxyl, carbonatoms are 1～4.
The i.e. following reaction of experience:
The preparation method of formula III compound can carry out with reference to prior art; for example; R is that the phenyl substituted thiophene formic acid of hydrogen can be starting raw material from thiophenic acid; through Meerwein arylation reaction make (referring to: for example; (a) J.Agric.Food Chem.; 2012,60 (47), 11649-11656; (b) Eur.J.Med.Chem., 2010,45 (12), 5576-5584; (c) Collection Czechoslov Chemical Communication, 1974,39 (3), 767-771).The thiophenic acid that the phenyl that all the other R make for other substituting group replaces also can prepare with reference to aforesaid method.
Tertiary butyl hydrazine generally exists with the form of hydrochlorate.As a kind of preferred version, the described preparation method containing thiphene ring benzoyl hydrazine compounds is preferably, first thinner is mixed with tertiary butyl hydrazine hydrochloride, slowly add part acid binding agent, tertiary butyl hydrazine is discharged, slowly add again compound shown in formula IV and remaining acid binding agent, temperature reaction.
Described thinner is inert organic solvents, as a kind of preferred version, described thinner is selected from benzene, toluene, dimethylbenzene, chlorobenzene, dichlorobenzene, sherwood oil, hexane, hexanaphthene, methylene dichloride, chloroform, tetracol phenixin, ether, diisopropyl ether, dioxan, tetrahydrofuran (THF), glycol dimethyl ether, ethylene glycol diethyl ether, acetone, butanone, mibk, acetonitrile, propionitrile, butyronitrile, N, dinethylformamide, N, N-N,N-DIMETHYLACETAMIDE, N-methyl-formylaniline, N-Methyl pyrrolidone, HMPA, methyl acetate, ethyl acetate, dimethyl sulfoxide (DMSO), methyl alcohol, ethanol, n-propyl alcohol, Virahol, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, diethylene glycol monomethyl ether or diethylene glycol monoethyl ether.
As a kind of more preferably scheme, described thinner is selected from benzene, toluene or tetrahydrofuran (THF).
The carrying out that is conducive to reaction under the existence of acid binding agent.As a kind of preferred version, described acid binding agent is preferably sodium hydroxide, salt of wormwood, sodium ethylate, triethylamine, Trimethylamine 99, Tributylamine, pyridine, N, accelerine, N, N-dimethyl benzylamine, N-methyl piperidine, N-methylmorpholine, N, N-dimethyl aminopyridine, diazabicyclooctane, Diazabicyclononene or diazabicylo undecylene.
As a kind of most preferably scheme, described acid binding agent most preferably is sodium hydroxide.
S2. in, the temperature of reaction that formula IV compound reacts with tertiary butyl hydrazine hydrochloride can be carried out according to the selection of thinner under wider scope, is preferably 0～160 ℃.As a kind of more preferably scheme, more preferably 0～30 ℃.
S2., in, the reaction times that compound shown in formula IV reacts with tertiary butyl hydrazine hydrochloride is 3～15 hours.More preferably 10 hours.
As a kind of preferred version, in S1., the mol ratio of compound shown in thinner, formula III and SOCl2 is preferably: 40～80:1～1.5:1～3.
As a kind of more preferably scheme, in S1., the mol ratio of compound shown in thinner, formula III and SOCl2 more preferably: 60:1:1.5.
As a kind of preferred version, in S2., the mol ratio of compound shown in thinner, formula IV and tertiary butyl hydrazine hydrochloride is preferably: 40～80:1～1.5:1～5.
As a kind of more preferably scheme, in S2., the mol ratio of compound shown in thinner, formula IV and tertiary butyl hydrazine hydrochloride more preferably: 60:1:2.5.
Described containing the application of thiphene ring benzoyl hydrazine compounds in preparing agricultural insecticide or anti-tumor activity inhibitor.
The preparation method of compound of the present invention is simple, and productive rate is high, the experiment proved that, it has good preventive effect to lepidopteran and Diptera pest.This compounds has good restraining effect to the growth of tumour cell simultaneously.As a kind of preferred version, described agricultural insecticide for insect be mythimna separata, small cabbage moth or mosquito larvae; Described anti-tumor activity inhibitor for tumor cell line be human leukemia cell line (HL-60), SGC-7901 (BGC-823), Bel7402 (Bel-7402) or CNE cell line (KB).
R is that the fluorine-based formula I compound of 2,4-bis-all has obvious prevention effect to mythimna separata, small cabbage moth or mosquito larvae especially; R is that the formula I compound of 4-chloro all has obvious inhibition to Bel7402 (Bel-7402) or CNE cell line (KB).
Compared with prior art, the present invention has following beneficial effect:
The present invention discloses a kind of containing thiphene ring benzoyl hydrazine compounds, and described have good biological activity containing thiphene ring benzoyl hydrazine compounds novel structure, can be for agricultural insecticide or anti-tumor activity inhibitor.The described preparation method containing thiphene ring benzoyl hydrazine compounds is simple, and productive rate is high.Expanded the application prospect of thiophene-based structure aspect agricultural chemicals or antitumor drug.
Embodiment
Below in conjunction with specific embodiment, the present invention is further explained, but embodiments of the present invention is not limited in any way.Unless stated otherwise, in embodiment, related reagent, method is the conventional reagent in this area and method.
The embodiment 1:N-tertiary butyl-3-(2 '-chloro-phenyl-) thiophene-2-formyl hydrazine (I-1) and N '-tertiary butyl-3-(2 '-chloro-phenyl-) preparation of thiophene-2-formyl hydrazine (II-11)
In being housed, the 50ml there-necked flask of thermometer adds 15mmol tertiary butyl hydrazine hydrochloride and 10ml methylene dichloride, stirring is cooled to 0 ℃, drip 10% (wt.) aqueous sodium hydroxide solution containing 15mmol sodium hydroxide, control rate of addition, make temperature remain on 0 ℃ of left and right.Dropwise rear stirring 30min.Maintenance system temperature, at 0 ℃, drips the dichloromethane solution that contains 7.5mmol2-chloro-phenyl-thiophene chloride and 10% (wt.) aqueous sodium hydroxide solution that contains 7.5mmol sodium hydroxide simultaneously.Control rate of addition, both are added simultaneously.Dropwise, slowly rise to room temperature, at 25 ℃ of reaction 9.5～10h.Filter, after organic layer washing, by dried over mgso, spend the night.After leaching siccative, steam solvent, obtain faint yellow solid.With silicagel column (eluent is V sherwood oil/V ethyl acetate=3/1) separation, obtain I-1 and II-1 compound, yield: 58%(I-1), 25.8% (II-1) fusing point: 187～188 ℃ (I-1), 201～202 ℃ (II-1).
According to the similar method of embodiment 1, only by the R in compound shown in formula I and II according to replacing shown in table 1, obtain product shown in corresponding formula I and II.The outward appearance of above-claimed cpd, productive rate and ultimate analysis value are all listed in table 1, and nucleus magnetic hydrogen spectrum detected result is all listed in table 2.As from the foregoing, above-claimed cpd structure is correct, is compound shown in formula I and II.
The physicochemical constant of compound shown in table 1 formula I and II and ultimate analysis data
Infrared and the proton nmr spectra data of compound shown in table 2 formula I and II
Shown in embodiment 2 formula I and II, contain the insecticidal activity of thiphene ring benzoyl hydrazine compounds to small cabbage moth
Experiment examination worm: small cabbage moth (Plutella xylostella Linnaeus), at indoor brassicaceous vegetable blade, to raise, raising condition is room temperature (27 ± 1) ℃, and humidity is 80%, and intensity of illumination is 2000lux, and light application time is 12h every day.Under indoor feeding condition, with worm age, body weight and 2 consistent instar larvaes of physiological situation, carry out the test of medicament screening active ingredients.
Proved recipe method: adopt pickling process, carry out the indoor general sieve activity test of compound.With punch tool device, clean cabbage leaves is broken into diameter 2cm leaf dish, in liquid, flood 5s, dry posterior lobe and put into the diameter 6cm culture dish that is added with moisturizing filter paper on dorsad, 10 of access small cabbage moth 2 instar larvaes, put into (27 ± 1) ℃ illumination box after adding a cover.Check result after 72h.Dead judging criterion is: touch polypide, the insect individuality that can not normally creep is considered as dead individual.
Shown in embodiment 3 formula I and II, contain the insecticidal activity of thiphene ring benzoyl hydrazine compounds to mythimna separata
Experiment examination worm: mythimna separata (Mythimna separata) 3 instar larvaes (being indoor with fresh corn leaf raising sensitive strain for many years)
Experimental technique: adopt Potter spray method, carry out the indoor general sieve activity test of compound.Take appropriate reagent agent, dissolve, then add a small amount of tween 80 emulsifying agent with dimethyl formamide, stir, add quantitative clear water, being mixed with concentration is the confession reagent liquid of 200mg/L.Test method adopts Potter spray method (seeing SCBZ/CH-HN-2000-001 bar), observes examination worm every day and grows and death condition, checks and record death condition after 6d.
Shown in embodiment 4 formula I and II, contain the insecticidal activity of thiphene ring benzoyl hydrazine compounds to mosquito larvae
Experiment examination worm: culex pipiens pallens (Culex pipiens pallens) four-age larva
Experimental technique: employing immersion method, carry out the indoor general sieve activity test of compound.By (waist chap) in 4 ages 10 larvas, put into the beaker of the standing tap water of 99.5mL (tap water is placed more than 1 month), active compound experiment repeats 4 times.Every glass of acetone liquid of putting into 0.5mL2000mg/L (2000mg/L) concentration, and do blank with 0.5mL acetone soln, add a small amount of mosquito feed and sucking-off mosquito pupa every day, and the moisture evaporating in supplementary beaker (5mL/ days), until mosquito larvae is all dead or pupate.
The compounds of this invention is prevented and treated the selection result in Table 3 to confession examination insect.
Compound shown in table 3 formula I and II is to supplying examination pest control the selection result
As can be seen from Table 3, shown in formula I and II, compound generally has good insecticidal activity, and wherein I-No. 7 compound has obvious insecticidal activity to the insect of test, approaches or surpass the preventive effect of contrast sterilant RH-5849.
Embodiment 5: the antitumor cytolytic activity of compound shown in formula I and II
For trying tumour cell: HL-60 human leukemia cell, BGC-823 gastric carcinoma cells, Bel-7402 human liver cancer cell, KB KB cell.
Sample test concentration: 10 μ M.
Test method: adopt MTT (tetramethyl-azo azoles salt) method or SRB (sulphonyl rhodamine B) method, carry out the anti-tumor activity test of compound.
Adopt MTT(J.Immunol.Methods1986,89 (2): 271-277) method, the vegetative period tumor cell line of taking the logarithm is seeded on 96 well culture plates and cultivates.After adherent, add test-compound, cultivate 72h, add MTT.After 4h, remove nutrient solution, add acidifying Virahol, after vibration, under microplate reader 570nm wavelength, measure absorbancy (OD).According to following formula, calculate inhibiting rate:
Inhibiting rate=(experimental group OD value/control group OD value) * 100%
Adopt SRB(J.Natl.Cancer Inst.1991,83 (11): 757-766) method, the vegetative period tumor cell line of taking the logarithm is seeded on 96 well culture plates, adds the test-compound of design flow after 24h.After cultivating 48h, add Tricholroacetic Acid, place 1h for 4 ℃.Then water rinses precipitation, and room temperature control is dry, adds SRB.After 10min, with 1% acetic acid, rinse, finally add 10mmol/L Tris solution, vibration is measured OD under microplate reader 540nm wavelength.According to above formula, calculate inhibiting rate.
The compounds of this invention is prevented and treated the selection result in Table 4 to confession examination tumor cell line.
Compound shown in table 4 formula I and II is to the selection result of preventing and treating for examination tumor cell line
As can be seen from Table 4, shown in formula I and II, compound generally has good anti-tumor activity, wherein I-No. 3 compound has obvious inhibition activity to Bel-7402 and KB, approach or be better than contrasting the preventive effect of Doxorubicin, the inhibition activity of chemical compounds I-2 and I-6 couple KB is better than contrasting Doxorubicin, has good application prospect.
Claims (10)
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| CN105918332A (en) * | 2016-05-06 | 2016-09-07 | 烟台图文马克化工科技有限公司 | Pesticide for preventing and treating flattened eucleid |
| CN113975271A (en) * | 2021-09-02 | 2022-01-28 | 苏州大学附属第一医院 | Application of small molecular compound in preparing medicine for treating tumor |
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