CN105732468A - N'-(2-(1H-indole-3-yl)acetyl)arylhydrazide compound and preparation method and application thereof - Google Patents
N'-(2-(1H-indole-3-yl)acetyl)arylhydrazide compound and preparation method and application thereof Download PDFInfo
- Publication number
- CN105732468A CN105732468A CN201610213100.1A CN201610213100A CN105732468A CN 105732468 A CN105732468 A CN 105732468A CN 201610213100 A CN201610213100 A CN 201610213100A CN 105732468 A CN105732468 A CN 105732468A
- Authority
- CN
- China
- Prior art keywords
- indole
- indol
- acetyl group
- reaction
- formula
- 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
- 150000001875 compounds Chemical class 0.000 title claims abstract description 39
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 238000006243 chemical reaction Methods 0.000 claims description 47
- -1 2-(1H-indol-3-yl) acetyl Chemical group 0.000 claims description 31
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- 125000003118 aryl group Chemical group 0.000 claims description 17
- 239000003153 chemical reaction reagent Substances 0.000 claims description 12
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 12
- IHAHDDFBNJYSMV-UHFFFAOYSA-N acetohydrazide 1H-indole Chemical compound C(C)(=O)NN.N1C=CC2=CC=CC=C12 IHAHDDFBNJYSMV-UHFFFAOYSA-N 0.000 claims description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 8
- 125000005251 aryl acyl group Chemical group 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 6
- 238000005660 chlorination reaction Methods 0.000 claims description 6
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 235000011149 sulphuric acid Nutrition 0.000 claims description 5
- 239000001117 sulphuric acid Substances 0.000 claims description 5
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 150000001454 anthracenes Chemical class 0.000 claims description 4
- 150000002240 furans Chemical class 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- 150000002790 naphthalenes Chemical class 0.000 claims description 4
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical group COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 claims description 3
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 claims description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 3
- 230000032050 esterification Effects 0.000 claims description 3
- 238000005886 esterification reaction Methods 0.000 claims description 3
- 125000001424 substituent group Chemical group 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 229940124404 anti-hepatitis c virus drug Drugs 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims description 2
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims description 2
- 150000007984 tetrahydrofuranes Chemical group 0.000 claims 1
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 abstract description 11
- 229960000329 ribavirin Drugs 0.000 abstract description 11
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 abstract description 11
- 241000700605 Viruses Species 0.000 abstract description 9
- 230000002401 inhibitory effect Effects 0.000 abstract description 2
- 102000014150 Interferons Human genes 0.000 abstract 1
- 108010050904 Interferons Proteins 0.000 abstract 1
- 229940121657 clinical drug Drugs 0.000 abstract 1
- 229940000406 drug candidate Drugs 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- 229940079322 interferon Drugs 0.000 abstract 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 68
- 239000007787 solid Substances 0.000 description 38
- 238000005160 1H NMR spectroscopy Methods 0.000 description 35
- 239000003814 drug Substances 0.000 description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- 230000000694 effects Effects 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 9
- 229940079593 drug Drugs 0.000 description 8
- 229940042795 hydrazides for tuberculosis treatment Drugs 0.000 description 8
- 239000003112 inhibitor Substances 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical class C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 6
- 238000010790 dilution Methods 0.000 description 6
- 239000012895 dilution Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 5
- 238000004809 thin layer chromatography Methods 0.000 description 5
- 101000959820 Homo sapiens Interferon alpha-1/13 Proteins 0.000 description 4
- 102100040019 Interferon alpha-1/13 Human genes 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 235000019441 ethanol Nutrition 0.000 description 4
- XZBIXDPGRMLSTC-UHFFFAOYSA-N formohydrazide Chemical compound NNC=O XZBIXDPGRMLSTC-UHFFFAOYSA-N 0.000 description 4
- 150000004702 methyl esters Chemical class 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 208000005176 Hepatitis C Diseases 0.000 description 3
- OFLXLNCGODUUOT-UHFFFAOYSA-N acetohydrazide Chemical compound C\C(O)=N\N OFLXLNCGODUUOT-UHFFFAOYSA-N 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 230000007524 negative regulation of DNA replication Effects 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 231100001274 therapeutic index Toxicity 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- 208000035126 Facies Diseases 0.000 description 2
- 229940122604 HCV protease inhibitor Drugs 0.000 description 2
- 241000711549 Hepacivirus C Species 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 101800001020 Non-structural protein 4A Proteins 0.000 description 2
- 108091005804 Peptidases Proteins 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 2
- 102000012479 Serine Proteases Human genes 0.000 description 2
- 108010022999 Serine Proteases Proteins 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 230000001464 adherent effect Effects 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000010276 construction Methods 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000002532 enzyme inhibitor Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 208000006454 hepatitis Diseases 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine Substances NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 2
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 125000006237 oxymethylenoxy group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 2
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 230000003612 virological effect Effects 0.000 description 2
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 description 1
- WHXCJMXFWARVBE-UHFFFAOYSA-N 1,3-oxazolidine;thiophene Chemical class C1COCN1.C=1C=CSC=1 WHXCJMXFWARVBE-UHFFFAOYSA-N 0.000 description 1
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 1
- JFBXNQGAIGCUKF-UHFFFAOYSA-N 2-cyclohexylacetohydrazide Chemical compound NNC(=O)CC1CCCCC1 JFBXNQGAIGCUKF-UHFFFAOYSA-N 0.000 description 1
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- FPTCVTJCJMVIDV-UHFFFAOYSA-N 2-phenylacetohydrazide Chemical compound NNC(=O)CC1=CC=CC=C1 FPTCVTJCJMVIDV-UHFFFAOYSA-N 0.000 description 1
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 101100004286 Caenorhabditis elegans best-5 gene Proteins 0.000 description 1
- 206010008909 Chronic Hepatitis Diseases 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- NYHBQMYGNKIUIF-UUOKFMHZSA-N Guanosine Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O NYHBQMYGNKIUIF-UUOKFMHZSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 108010047761 Interferon-alpha Proteins 0.000 description 1
- 102000006992 Interferon-alpha Human genes 0.000 description 1
- JVXXKQIRGQDWOJ-UHFFFAOYSA-N NC(c1cc2ccccc2cc1)=O Chemical compound NC(c1cc2ccccc2cc1)=O JVXXKQIRGQDWOJ-UHFFFAOYSA-N 0.000 description 1
- RMHJJUOPOWPRBP-UHFFFAOYSA-N NC(c1cccc2ccccc12)=O Chemical compound NC(c1cccc2ccccc12)=O RMHJJUOPOWPRBP-UHFFFAOYSA-N 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 108010076039 Polyproteins Proteins 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 101800001554 RNA-directed RNA polymerase Proteins 0.000 description 1
- 101710118046 RNA-directed RNA polymerase Proteins 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- 101800001838 Serine protease/helicase NS3 Proteins 0.000 description 1
- 108050000761 Serpin Proteins 0.000 description 1
- 102000008847 Serpin Human genes 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 125000004442 acylamino group Chemical group 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 150000001556 benzimidazoles Chemical class 0.000 description 1
- 125000005605 benzo group Chemical group 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009395 breeding Methods 0.000 description 1
- 230000001488 breeding effect Effects 0.000 description 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 239000002254 cytotoxic agent Substances 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 229940125532 enzyme inhibitor Drugs 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- OPOLXKNJPIOEQA-UHFFFAOYSA-N formohydrazide;furan Chemical compound NNC=O.C=1C=COC=1 OPOLXKNJPIOEQA-UHFFFAOYSA-N 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000002429 hydrazines Chemical class 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- OHDXDNUPVVYWOV-UHFFFAOYSA-N n-methyl-1-(2-naphthalen-1-ylsulfanylphenyl)methanamine Chemical compound CNCC1=CC=CC=C1SC1=CC=CC2=CC=CC=C12 OHDXDNUPVVYWOV-UHFFFAOYSA-N 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- KJASTBCNGFYKSR-UHFFFAOYSA-N prop-2-enehydrazide Chemical compound NNC(=O)C=C KJASTBCNGFYKSR-UHFFFAOYSA-N 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- DXGIRFAFSFKYCF-UHFFFAOYSA-N propanehydrazide Chemical compound CCC(=O)NN DXGIRFAFSFKYCF-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000019833 protease Nutrition 0.000 description 1
- 235000019419 proteases Nutrition 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000002342 ribonucleoside Substances 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000003001 serine protease inhibitor Substances 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000012916 structural analysis Methods 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Indole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a N'-(2-(1H-indole-3-yl)acetyl)arylhydrazide compound and a preparation method and application thereof.The N'-(2-(1H-indole-3-yl)acetyl)arylhydrazide compound has a structure shown as a formula I (please see the formula in the description) and has the obvious inhibiting effect on an HCV virus, the anti-HCV virus treatment index is higher than that of existing clinical drugs including alpha-1b(IFNalpha-1b) interferon and ribavirin, and the N'-(2-(1H-indole-3-yl)acetyl)arylhydrazide compound can serve as an anti-HCV drug candidate; in addition, the preparation method is simple, high in yield and suitable for industrial production.
Description
Technical field
The invention belongs to field of medicine preparing technology, relate to a kind of N'-(2-(1H-indol-3-yl) acetyl group) virtue
Hydrazide kind compound and its production and use.
Background technology
Hepatitis C is a kind of serious threat mankind caused by hepatitis C virus (hepatitis C virus, HCV)
Healthy hepatic disease, about 1.7 hundred million people's HCV infection in world wide, wherein nearly 60%-80% would develop into chronic hepatitis, portion
Divide and be further development of liver cirrhosis and hepatocarcinoma.HCV still lacks effective vaccine, and the Therapeutic Method over nearly 20 years is the most dry
Disturb element (IFN)-α or the use in conjunction of long-acting IFN that Polyethylene Glycol (PEG) is modified and broad-spectrum antiviral medicament ribavirin, should
Therapy is evident in efficacy for II type and III type patient, but only effective to the I type patient of about 40%, and erythra etc. are serious not
Good reaction also have impact on it and uses.In recent years have developed a series of HCV protease inhibitor, such as NS3/4A serine stretch protein enzyme level
Agent, NS5B RdRp AG14361, NS3 unwindase/ribonucleoside triphosphote enzyme inhibitor etc., wherein NS3 serine protease exists
Polyprotein is transcribed and plays a decisive role in hydrolytic process, suppresses its proteinase activity, can hinder the growth of HCV, breeding, because of
This is considered one of best target spot of Effect of Anti hepatitis C medicine.Along with the inhibitor VX-960 with HCV NS3/4A as target
(telarevir) with IFN-α and ribavirin use in conjunction clinically, HCV Ns3/4A inhibitor has become as research heat
Point.For the inhibitor of NS3/NS4A serine protease mainly from substrate structure design molecule, these inhibitor are from change
Learn and be broadly divided into peptides and non-peptide inhibitor in structure.Now report the compound of some non-peptide albuminoid enzyme inhibitors, such as thiophene
Oxazolidine analog derivative, phenanthrenequione compounds, benzimidazoles derivative etc., they have good NS 3 protease to suppress in vitro
Activity, we are found by structural analysis, although these inhibitor structures are different, but typically all contain virtue in they molecules
Fragrant female ring, rich in amido link, and these inhibitor molecules present more calm linear structure mostly, thus with NS3 protease with
Substrate binding site is suitable compared with shallow trench.
Benzazole compounds has a series of biological activity, and its many derivants have significant pharmacologically active.In clinic
Pharmaceutically, some indole derivativeses have been used for treating multiple disease, such as cancer, tumor, anti-inflammatory analgesic and viral disease and
Infectious disease.
CN1752085A discloses a kind of aromatic hydrazide kind compound, and it has a following structure:
In the structure shown here, R1 is hydrogen atom or C1-C6 alkyl；Ar1 and Ar2 is each
Independently selected from: 3-indyl, 5-indyl, 2-quinolyl, 4-quinolyl, 2-pyridine radicals, 3-pyridine radicals, 2-pyrrole radicals, 3-
Pyrrole radicals, 2-thienyl, 3-thienyl, pyrazolyl, 2-furyl, 3-furyl；Above-mentioned group is unsubstituted or by 1 or 2
Individual selected from following substituent group replacement: halogen, nitro, hydroxyl, trifluoromethyl, C1-C6 alkyl, C1-C6 alkoxyl, C1-C6 alkane
Oxygen acyl group, amino, carboxyl, phenyl, benzyl, benzenesulfonyl.This compound may be used for prevention and/or treats some autoimmune
Property disease.
In the art, it is desirable to the biological activity combining Benzazole compounds has anti-hepatitis c virus to prepare one
The medicine of effect.
Summary of the invention
For the deficiencies in the prior art, it is an object of the invention to provide a kind of N'-(2-(1H-indol-3-yl) acetyl
Base) aromatic hydrazide kind compound and its production and use.
For reaching this purpose, the present invention by the following technical solutions:
On the one hand, the present invention provides a kind of N'-(2-(1H-indol-3-yl) acetyl group) aromatic hydrazide kind compound, and it has
Structure shown in Formulas I:
In Formulas I, n=0,1 or 2, R be substituted or unsubstituted phenyl ring, substituted or unsubstituted naphthalene nucleus, substituted or
Unsubstituted anthracene nucleus, substituted or unsubstituted furan nucleus, substituted or unsubstituted xenyl,In any one, described
The substituent group of phenyl ring, naphthalene nucleus, anthracene nucleus, furan nucleus and xenyl is independently selected from halogen, hydroxyl, nitro, trifluoromethyl, C1-C10
Any one or the combination of at least two in alkyl or C1-C10 alkoxyl.
The present invention combines NS3/NS4A serpin construction features analysis, and this construction unit of indole is drawn
Enter in the design of HCV protease inhibitor, and import the acylamino-group that can combine with serine, synthesized serial chain type
N '-(2-(1H-indol-3-yl) acetyl group) virtue hydrazide compound, experiment in vitro proves that this compounds has obvious HCV-Ab IgG
Activity.
In the present invention, any one or the combination of at least two during described halogen is F, Cl, Br or I.
In the present invention, described C1-C10 alkyl can be C1, C2, C3, C4, C5, C6, C7, C8, C9 or C10 alkyl, example
It is not limited to methyl, ethyl, propyl group, butyl or amyl group as being.
In the present invention, described C1-C10 alkoxyl can be C1, C2, C3, C4, C5, C6, C7, C8, C9 or C10 alcoxyl
Base, such as, can be but be not limited to methoxyl group, ethyoxyl, propoxyl group or butoxy.
Preferably, N'-of the present invention (2-(1H-indol-3-yl) acetyl group) aromatic hydrazide kind compound is for having table 1 institute
Show any one or the combination of at least two in the compound of structure.
Table 1
On the other hand, the invention provides N'-(2-(1H-indol-3-yl) acetyl group) virtue acyl as described in relation to the first aspect
The preparation method of hydrazine class compound, said method comprising the steps of:
(1) heteroauxing and C1-C5 alcohol generation esterification obtain ethychlozate ester shown in Formula II, and reaction equation is as follows:
Wherein R1For C1-C5 alkyl；
(2) ethychlozate ester shown in Formula II and hydrazine hydrate react and obtain indole acethydrazide shown in formula III, and reaction equation is as follows:
(3) being reacted by aromatic carboxylic acids shown in formula IV and chlorination reagent and prepare aryl-acyl chlorides shown in Formula V, reaction equation is such as
Under:
(4) reacted by indole acethydrazide shown in formula III and aryl-acyl chlorides shown in Formula V and obtain (2-(the 1H-Yin of N'-shown in Formulas I
Diindyl-3-base) acetyl group) aromatic hydrazide kind compound, reaction equation is as follows:
In the preparation process in accordance with the present invention, step (1) described C1-C5 alcohol can be C1, C2, C3, C4 or C5 alcohol, is preferably
Any one in methanol, ethanol, propanol, butanol or amylalcohol, more preferably methanol, i.e. R1It can be C1 alkyl (i.e. first
Base), C2 alkyl, C3 alkyl, C4 alkyl or C5 alkyl, preferably methyl.
Preferably, the mol ratio of step (1) described heteroauxing and C1-C5 alcohol is 1:(5-40), such as 1:6,1:8,1:
10,1:12,1:15,1:18,1:20,1:22,1:24,1:28,1:30,1:32,1:35 or 1:38.In the present invention, alcohol is both made
Reaction dissolvent is also served as, it is therefore desirable to more alcohol for reaction raw materials.
Preferably, step (1) described reaction using strong acid as catalyst, preferably concentrated sulphuric acid, described concentrated sulphuric acid preferably 98%
Concentrated sulphuric acid.
Preferably, the temperature of step (1) described reaction is 50-80 DEG C, such as 50 DEG C, 53 DEG C, 55 DEG C, 58 DEG C, 60 DEG C, 63
DEG C, 65 DEG C, 68 DEG C, 70 DEG C, 73 DEG C, 75 DEG C, 78 DEG C or 80 DEG C.
Preferably, the time of step (1) described reaction is 1-8 hour, such as 1 hour, 1.5 hours, 2 hours, 2.5 little
Time, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 5.5 hours, 6 hours, 6.5 hours, 7 hours, 7.5 time or 8 little
Time.
Preferably, ethychlozate ester shown in step (2) described Formula II is 1:(1-4 with the mol ratio of hydrazine hydrate), such as 1:
1,1:1.5,1:1.8,1:2,1:2.2,1:2.5,1:2.8,1:3,1:3.3,1:3.5,1:3.8 or 1:4.
Preferably, in step (2) described reaction, solvent for use is ethylene glycol monomethyl ether.
Preferably, the temperature of step (2) described reaction is 110-130 DEG C, such as 110 DEG C, 115 DEG C, 120 DEG C, 125 DEG C or
130℃。
Preferably, the time of step (2) described reaction is 5-24 hour, such as 6 hours, 7 hours, 8 hours, 9 hours, 10
Hour, 12 hours, 14 hours, 15 hours, 17 hours, 19 hours, 20 hours, 21 hours, 22 hours or 23 hours.
Preferably, step (3) described chlorination reagent be in thionyl chloride, Phosphorous chloride. or phosphorus pentachloride any one or
The combination of at least two, preferably thionyl chloride.
Preferably, step (3) described aromatic carboxylic acids is 1:(2-6 with the mol ratio of chlorination reagent), such as 1:2,1:2.2,
1:2.5,1:2.8,1:3,1:3.5,1:4,1:4.3,1:4.5,1:4.8,1:5,1:5.5,1:5.8 or 1:6.
Preferably, in step (3) described reaction, solvent for use is oxolane, preferably adds 1-3 in oxolane
Drip DMF.
Preferably, the temperature of step (3) described reaction is 60-90 DEG C, such as 60 DEG C, 65 DEG C, 70 DEG C, 75 DEG C, 80 DEG C, 85
DEG C or 90 DEG C.
Preferably, the time of step (3) described reaction is 5-20 hour, such as 5 hours, 6 hours, 7 hours, 8 hours, 9
Hour, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours or 20 hours.
Preferably, the mol ratio of step (4) described indole acethydrazide and aryl-acyl chlorides is 1:(1-1.5), such as 1:1,1:
1.1,1:1.2,1:1.3,1:1.4 or 1:1.5.
Preferably, step (4) described reaction is carried out in the presence of alkaline reagent.
Preferably, described alkaline reagent is triethylamine.
Preferably, the mol ratio of described alkaline reagent and indole acethydrazide is 1:(1-3), such as 1:1,1:1.3,1:1.5,
1:1.8,1:2,1:2.2,1:2.5,1:2.8 or 1:3.
Preferably, in step (4) described reaction, solvent for use is oxolane.
Preferably, the temperature of step (4) described reaction is 0-30 DEG C, such as 0 DEG C, 5 DEG C, 10 DEG C, 12 DEG C, 15 DEG C, 18 DEG C,
20 DEG C, 23 DEG C, 25 DEG C, 28 DEG C or 30 DEG C.
Preferably, the time of step (4) described reaction is 5-24 hour, such as 5 hours, 8 hours, 10 hours, 12 hours,
14 hours, 16 hours, 18 hours, 20 hours, 21 hours, 22 hours, 23 hours or 24 hours.
As the preferred technical solution of the present invention, N'-of the present invention (2-(1H-indol-3-yl) acetyl group) virtue hydrazides
The preparation method of compounds comprises the following steps:
(1) heteroauxing and methanol generation esterification obtain heteroauxing methyl ester, and reaction equation is as follows:
(2) heteroauxing methyl ester and hydrazine hydrate react and obtain indole acethydrazide, and reaction equation is as follows:
(3) being reacted by aromatic carboxylic acids shown in formula IV and thionyl chloride and prepare aryl-acyl chlorides shown in Formula V, reaction equation is such as
Under:
(4) reacted by indole acethydrazide shown in formula III and aryl-acyl chlorides shown in Formula V and obtain (2-(the 1H-Yin of N'-shown in Formulas I
Diindyl-3-base) acetyl group) aromatic hydrazide kind compound, reaction equation is as follows:
On the other hand, the invention provides N'-(2-(1H-indol-3-yl) acetyl group) virtue acyl as described in relation to the first aspect
Hydrazine class compound purposes in preparing anti hepatitis C virus drug.
Aromatic hydrazide kind compound can be as anti-hepatitis C virus for N'-of the present invention (2-(1H-indol-3-yl) acetyl group)
The active component material standed for of cytotoxic drug, has obvious anti-HCV activity.
Relative to prior art, the method have the advantages that
HCV virus is had bright by N'-(2-(1H-indol-3-yl) acetyl group) aromatic hydrazide kind compound prepared by the present invention
Aobvious inhibitory action, HCV-Ab IgG viral therapy index is higher than existing clinical medicine interferon α-1b (IFN α-1b) and ribavirin
(Ribavirin), can be as anti-HCV medicament material standed for, and the preparation method of the present invention is simple, productivity is high, it is adaptable to industry
Produce.
Detailed description of the invention
Technical scheme is further illustrated below by detailed description of the invention.Those skilled in the art should be bright
, the only help of described embodiment understands the present invention, is not construed as the concrete restriction to the present invention.
Embodiment 1
In the present embodiment, it is prepared by the following method Formulas I-1 compound, specifically includes following steps:
(1) in 500 milliliters of round-bottomed flasks, heteroauxing 8.8g (50mmol), methanol (60mL), concentrated sulphuric acid are added
(3mL), 70 DEG C are reacted 1-3 hour, and TLC detects after completion of the reaction, steam methanol, add water (50mL), separate organic facies, aqueous phase
Extract by ethyl acetate (3 × 20mL), merge organic facies, successively with saturated sodium bicarbonate solution and water washing, anhydrous sodium sulfate
Being dried, obtain heteroauxing methyl ester crude product after concentrating under reduced pressure, this product is directly used in next step reaction without purification.
(2) in 500 milliliters of round-bottomed flasks, heteroauxing methyl ester 9.46g (48mmol) is added, ethylene glycol monomethyl ether (40mL),
Hydrazine hydrate 5mL, 115 DEG C of heating reflux reactions about 20 hours, thin layer chromatography (TLC) detection raw material point disappears, stopped reaction, cooling
To room temperature, adding water (50mL), stand and separate out white solid, sucking filtration obtains crude product, obtains indole acethydrazide with ethyl alcohol recrystallization
White solid 9.2 grams.
(3) in 100 milliliters of round-bottomed flasks, add various aromatic carboxylic acids 1.6mmol, anhydrous tetrahydro furan 10mL, drip one
Dripping DMF, add 0.5mL thionyl chloride, oil bath, 70 DEG C of reacting by heating about 10 hours, TLC detects after completion of the reaction, steams solvent,
Obtain aroyl chloride crude product and be directly used in next step reaction.
(4) in 100 milliliters of round-bottomed flasks, 3-indole acethydrazide (300mg, 1.59mmol), anhydrous tetrahydro furan 10 are added
Milliliter, Et3N (3mL, 1.59mmol), the tetrahydrofuran solution of dropping Benzenecarbonyl chloride. (1.59mmol), produce precipitation, continue room
Temperature (25 DEG C) stir 12 hours, TLC detect after completion of the reaction, removal of solvent under reduced pressure obtains orange/yellow solid, respectively with ethyl acetate,
Water washs, and sucking filtration obtains faint yellow crude product, obtains white solid sterling with appropriate solvent recrystallization, productivity: 92%.Mp:
180.0-181.0℃。
The product obtained is carried out nucleus magnetic hydrogen spectrum and mass spectral characteristi, and result is as follows:
1H-NMR(500MHz,DMSO-d6),δ(ppm):3.78(s,2H,CH2),7.02(s,1H,Ar-H),7.09-7.34
(m,4H,Ar-H),7.43-7.54(m,2H,Ar-H),7.63-7.65(m,1H,Ar-H),7.84-7.86(m,2H,Ar-H),
10.18 (s, 1H, NH), 10.36 (s, 1H, NH), 10.91 (s, 1H, indole-NH)；m/z 294.1[M++1]。
Embodiment 2
In the present embodiment, the compound of formula I-2 to Formulas I-35, preparation method and embodiment 1 Formulas I-1 compound
Preparation the difference is that only, the aroyl chloride used in step (4) is respectively In addition, preparation method is changed with the Formulas I-1 of embodiment 1
The preparation method of compound is identical.
The Formulas I-2 prepared is as follows to the character of Formulas I-35 compound, productivity and structural characterization result:
N'-(2-(1H-indol-3-yl) acetyl group)-2-iodobenzene formylhydrazine (Formulas I-2): white solid, productivity: 94%,
mp:188.1-189.0℃；1H-NMR(500MHz,DMSO-d6),δ(ppm):3.68(s,2H,CH2),6.92-6.93(s,1H,
Ar-H),6.98-7.24(m,4H,Ar-H),7.32-7.35(m,1H,Ar-H),7.43-7.44(m,1H,Ar-H),7.53-
7.55(m,1H,Ar-H),7.80-7.82(m,1H,Ar-H),10.23(s,1H,NH),10.29(s,1H,NH),10.97(s,
1H, indole-NH)；m/z 418.0[M+-1]。
N'-(2-(1H-indol-3-yl) acetyl group) phenylacetyl hydrazine (Formulas I-3): white solid, productivity: 92%, mp:
96.4-197.4℃；1H-NMR(500MHz,DMSO-d6),δ(ppm):3.58(s,2H,CH2),3.73(s,2H,CH2),7.23
(s,1H,Ar-H),7.31(m,2H,Ar-H),7.32(m,1H,Ph-H),7.33(m,2H,Ar-H),7.35-7.36(m,4H,
Ar-H), 10.01 (2H, 2NH), 10.42 (1H, NH-indole)；m/z 307.1[M+]。
N'-(2-(1H-indol-3-yl) acetyl group)-4-methoxybenzene acethydrazide (Formulas I-4), faint yellow solid, productivity:
88%, mp:181.2-182.2 DEG C；1H-NMR(500MHz,DMSO-d6),δ(ppm):3.34(s,2H,CH2),3.60(s,3H,
OCH3),3.46(s,2H,CH2),7.16(m,2H,Ar-H),7.21(s,1H,Ar-H),7.23(m,2H,Ar-H),7.24-7.25
(m, 4H, Ar-H), 10.03 (2H, 2NH), 10.88 (1H, NH-indole)；m/z 338.1[M++1]。
N'-(2-(1H-indol-3-yl) acetyl group)-3-(3,4-Dimethoxyphenyl) propionyl hydrazine (Formulas I-5): orange-yellow
Solid, productivity: 95%, 137.2-138.2 DEG C；1H-NMR(500MHz,DMSO-d6),δ(ppm):2.53(t,2H,CH2),2.89
(t,2H,CH2),3.73(s,2H,CH2),3.79(6H,s,2OCH3),6.77(s,1H,Ar-H),6.83(s,1H,Ar-H),
6.85(m,1H,Ar-H),7.03(s,1H,Ar-H),7.11-7.61(m,4H,Ar-H),9.88(s,1H,NH),10.12(s,
1H, NH), 10.93 (s, 1H, indole-NH)；m/z382.1[M++1]。
N'-(2-(1H-indol-3-yl) acetyl group)-2-hydroxybenzoyl hydrazine (Formulas I-6), white solid, productivity: 75%,
mp:189.2-190.0℃；1H-NMR(500MHz,DMSO-d6),δ(ppm):3.82(s,2H,C H2),6.92(s,1H,Ar-
H),7.04-7.07(m,1H,Ar-H),7.11-7.14(m,1H,Ar-H),7.29-7.42(m,4H,Ar-H),7.66-7.67
(m, 1H, Ar-H), 7.82-7.84 (m, 1H, Ar-H), 10.13 (1H, NH), 10.41 (s, 1H, NH)；10.88 (1H, NH-Yin
Diindyl)；m/z 308.1[M+-1]。
N'-(2-(1H-indol-3-yl) acetyl group)-4-methylbenzene acethydrazide (Formulas I-7), faint yellow solid, productivity:
89%, mp:188.2-189.2 DEG C；1H-NMR(500MHz,DMSO-d6),δ(ppm):2.26(s,3H,CH3),3.41(s,2H,
CH2),3.62(s,2H,CH2),6.97(s,1H,Ar-H),7.05-7.17(m,4H,Ar-H),7.18-7.60(m,4H,Ar-H),
10.01 (s, 1H, NH), 10.03 (s, 1H, NH), 10.86 (s, 1H, NH-indole)；m/z 322.1[M++1]。
N'-(2-(1H-indol-3-yl) acetyl group)-1-naphthalene acethydrazide (Formulas I-8), orange/yellow solid, productivity: 85%,
mp:197.5-198.5℃；1H-NMR(500MHz,DMSO-d6),δ(ppm):3.56(s,2H,CH2),
3.96(s,2H,CH2),6.96(s,1H,Ar-H),7.05-7.23(m,1H,Ar-H),7.33-7.51(m,4H,
Ar-H),7.51-7.55(m,3H,Ar-H),7.57-7.59(m,1H,Ar-H),7.82-7.83(m,1H,Ar-H),8.12-
8.13 (m, 1H, Ar-H), 10.03 (s, 1H, NH), 10.20 (s, 1H, NH), 10.85 (s, 1H, NH-indole)；m/z 357.1[M+]。
N'-(2-(1H-indol-3-yl) acetyl group) cyclohexyl acethydrazide (Formulas I-9), white solid, productivity: 76%, mp:
187.5-188.5；1H-NMR(500MHz,DMSO-d6),δ(ppm):0.87-1.87(m,11H,cyclohexyl),2.04(s,
2H,CH2),3.60(s,2H,CH2),6.90(s,1H,Ar-H),6.92-7.49(m,4H,Ar-H),10.06(2H,2NH),
10.65 (1H, NH-indole)；m/z 315.3[M++2]。
N'-(2-(1H-indol-3-yl) acetyl group)-3-(3,4,5-trimethoxyphenyl) propylene hydrazides (Formulas I-10), in vain
Color solid, productivity: 93%, mp:99.2-100.2 DEG C；1H-NMR(500MHz,DMSO-d6),δ(pp m):3.37(s,2H,
CH2),3.86(s,9H,3OCH3), 6.88 (s, 2H, Ar-H), 6.93 (s, 1H, Ar-H), 7.05-7.02 (d, 1H, CH=CH),
7.59-7.10 (m, 4H, Ar-H), 7.65-7.63 (d, 1H, CH=CH), 10.09 (s, 1H, NH), 10.28 (s, 1H, NH),
10.51 (s, 1H, indole-NH)；m/z410.1[M++1]。
N'-(2-(1H-indol-3-yl) acetyl group) furan-2-formylhydrazine (6-11), white solid, productivity: 77%, mp:
89.5-89.9℃；1H-NMR(500MHz,DMSO-d6),δ(ppm):3.61(s,2H,CH2),6.65(m,1H,Ar-H),6.98
(s,1H,Ar-H),7.07-7.35(m,4H,Ar-H),7.61-7.63(d,1H,Ar-H),7.88(d,1H,Ar-H),10.05
(s, 1H, NH), 10.23 (s, 1H, NH), 10.88 (s, 1H, NH-indole)；m/z 284.1[M++1]。
N'-(2-(1H-indol-3-yl) acetyl group)-4-nitrobenzoyl hydrazides, yellow solid (Formulas I-12), productivity:
91%, mp:196.8-197.8 DEG C；1H-NMR(500MHz,DMSO-d6),δ(ppm):3.66(s,2H,C H2),7.00(s,1H,
Ar-H),7.07-7.66(m,4H,Ar-H),8.09-8.11(m,2H,Ar-H),8.33-8.35(m,2H,Ar-H),10.25(s,
1H, NH), 10.71 (s, 1H, NH), 10.90 (s, 1H, NH-indole)；m/z 339.1[M++1]。
N'-(2-(1H-indol-3-yl) acetyl group) Cortex Cinnamomi hydrazides (Formulas I-13), white solid, productivity: 85%, mp:
226.5-227.5℃；1H-NMR(500MHz,DMSO-d6),δ(ppm):3.62(s,2H,CH2),6.70(s,1H,Ar-H),
6.94-7.00 (d, 1H, CH=CH), 7.06-7.08 (m, 1H, Ar-H), 7.27-7.43 (m, 4H, Ar-H), 7.52-7.55 (m,
2H, Ar-H), 7.59-7.60 (m, 2H, Ar-H), 7.61-7.63 (d, 1H, CH=CH), 10.16 (s, 1H, NH), 10.24 (s,
1H, NH), 10.89 (s, 1H, NH-indole)；m/z 320.1[M++1].
N'-(2-(1H-indol-3-yl) acetyl group)-4-hydroxybenzoyl hydrazine (Formulas I-14), white solid, productivity:
68%, mp:220.1-221.1 DEG C；1H-NMR(500MHz,DMSO-d6),δ(ppm):3.61(s,2H,CH2),6.85(s,1H,
Ar-H),7.07-7.10(m,2H,Ar-H),7.26-7.79(m,4H,Ar-H),7.82-7.84(m,2H,Ar-H),10.02(s,
2H,NH),10.90(s,1H,Ar-H)；m/z 310.1[M++1]。
N'-(2-(1H-indol-3-yl) acetyl group)-3,5-dinitro benzoyl hydrazine (6-15), faint yellow solid, productivity:
93%, mp:215.5-216.5 DEG C；1H-NMR(500MHz,DMSO-d6),δ(ppm):3.69(s,2H,CH2),7.00(s,1H,
Ar-H),7.07-7.65(m,4H,Ar-H),8.95(s,1H,Ar-H),9.06(s,2H,Ar-H),10.43(s,1H,NH),
10.90 (s, 1H, NH), 11.17 (s, 1H, NH-indole)；m/z 384.1[M++1]。
N'-(2-(1H-indol-3-yl) acetyl group)-2,4,5-trimethoxybenzoyl hydrazines (Formulas I-16), white solid,
Productivity: 79%, mp:224.5-225.5 DEG C；1H-NMR(500MHz,DMSO-d6),δ(ppm):3.66(s,2H,CH2),3.75-
3.93(s,9H,3OCH3),6.77(s,1H,Ar-H),7.01(s,1H,Ar-H),7.08-7.65(m,4H,Ar-H),7.66(s,
1H, Ar-H), 9.90 (s, 1H, NH), 10.53 (s, 1H, NH), 10.92 (s, 1H, NH-indole)；m/z 384.1[M++1]。
N'-(2-(1H-indol-3-yl) acetyl group)-4-iodobenzene formylhydrazine (Formulas I-17), white solid, productivity: 86%,
mp:224.0-245.0℃；1H-NMR(500MHz,DMSO-d6),δ(ppm):3.65(s,2H,CH2),
7.01(s,1H,Ar-H),7.08-7.65(m,4H,Ar-H),7.66-7.67(m,2H,Ph-H),7.88-7.90
(m, 2H, Ar-H), 10.17 (s, 1H, NH), 10.45 (s, 1H, NH), 10.91 (s, 1H, NH-indole)；m/z 420.0[M++
1]。
N'-(2-(1H-indol-3-yl) acetyl group)-4-bromobenzoylhydrazine (Formulas I-18), white solid, productivity: 84%,
mp:221.2-222.2℃；1H-NMR(500MHz,DMSO-d6),δ(ppm):3.64(s,2H,CH2),7.00-7.02(d,1H,
Ar-H),7.07-7.10(d,1H,Ar-H),7.24(s,1H,Ar-H),7.34-7.36(d,2H,Ar-H),7.59-7.64(d,
2H, Ar-H), 7.68-7.70 (d, 2H, Ar-H), 10.13 (s, 1H, NH), 10.41 (s, 1H, NH), 10.59 (s, 1H, NH-Yin
Diindyl)；m/z 374.3[M++2]。
N'-(2-(1H-indol-3-yl) acetyl group)-2-nitrobenzoyl hydrazides, faint yellow solid (Formulas I-19), productivity:
86%, mp:189.5-199.5 DEG C；1H-NMR(500MHz,DMSO-d6),δ(ppm):3.67(s,2H,CH2),6.88(s,1H,
Ar-H),7.00-7.68(m,4H,Ar-H),7.70-7.73(m,1H,Ar-H),7.75-7.78(m,1H,Ar-H),7.82-
7.85(m,1H,Ar-H),8.08-8.10(m,1H,Ar-H),10.43(s,1H,NH),10.62(s,1H,NH),10.93(s,
1H, NH-indole)；m/z 339.1[M++1]。
N'-(2-(1H-indol-3-yl) acetyl group)-3-phenylpropyl alcohol hydrazides (Formulas I-20), white solid, productivity: 81%, mp:
200.0-201.0℃；1H-NMR(500MHz,DMSO-d6),δ(ppm):2.44-2.47(t,2H,C H2),2.84-2.87(t,
2H,CH2),3.60(s,2H,CH2),7.01(s,1H,Ar-H),7.07-7.10(m,1H,Ar-H),7.18-7.28(m,4H,Ar-
H), 7.29-7.63 (m, 4H, Ar-H), 9.86 (s, 1H, NH), 10.89 (s, 1H, indole-NH), 10.02 (s, 1H, NH)；m/z
322.3[M+1]。
N'-(2-(1H-indol-3-yl) acetyl group)-2-chloro-4-nitrobenzoyl hydrazides (Formulas I-21), yellow solid, produces
Rate: 92%, mp:187.0-188.0 DEG C；1H-NMR(500MHz,DMSO-d6),δ(ppm):3.64(s,2H,CH2),6.89-
6.94(m,1H,Ar-H),6.97-7.00(m,1H,Ar-H),7.26(s,1H,Ar-H),7.35-7.43(m,1H,Ar-H),
7.61-7.62(d,1H,Ar-H),7.72-7.75(d,1H,Ar-H),8.23-8.24(d,1H,Ar-H),8.33(s,1H,Ar-
H), 10.30 (s, 1H, NH), 10.62 (s, 1H, NH), 10.85 (s, 1H, indole-NH)；m/z 374.1[M++2]。
N'-(2-(1H-indol-3-yl) acetyl group)-4-methoxybenzoyl hydrazine (Formulas I-22), white solid, productivity:
93%, mp:165.2-166.2 DEG C；1H-NMR(500MHz,DMSO-d6),δ(ppm):3.66(s,2H,CH2),3.81(s,3H,
OCH3),7.09-7.12(s,1H,Ar-H),7.04-7.12(d,2H,Ar-H),7.32-7.69(m,4H,Ar-H),7.89-
7.90(d,2H,Ar-H),10.11(s,1H,NH),10.25(s,1H,
NH), 10.93 (s, 1H, indole-NH)；m/z 324.1[M++1]。
N'-(2-(1H-indol-3-yl) acetyl group)-3-iodobenzene formylhydrazine (Formulas I-23), white solid, productivity: 90%,
mp:193.5-194.5℃；1H-NMR(MHz,DMSO-d6),δ(ppm):3.64(s,2H,CH2),7.0(s,1H,Ar-H),
7.09-7.37(m,4H,Ar-H),7.64-7.65(d,1H,Ar-H),7.88-7.89(d,1H,Ar-H),7.92-7.94(d,
1H, Ar-H), 8.22 (s, 1H, Ar-H), 10.20 (s, 1H, NH), 10.48 (s, 1H, NH), 10.91 (s, 1H, indole-NH)；m/
z 420.0[M++1]。
N'-(2-(1H-indol-3-yl) acetyl group)-3-(3-chlorphenyl) propylene hydrazides (Formulas I-24), white solid, produces
Rate: 91%, mp:232.5-233.5 DEG C；1H-NMR(500MHz,DMSO-d6),δ(ppm):3.65(s,
2H,CH2), 6.74-6.77 (d, 1H, Ar-H), 6.99-7.00 (d, 1H, CH=CH), 7.02-7.38 (m, 4H,
Ar-H),7.43-7.44(d,1H,Ar-H),7.52(s,1H,Ar-H),7.56-7.57(m,1H,Ar-H),7.57-7.64(m,
1H, Ar-H), 7.65-7.67 (d, 1H, CH=CH), 10.24 (s, 1H, NH), 10.32 (s, 1H, NH), 10.91 (s, 1H, Yin
Diindyl-NH)；m/z 354.5[M++1]。
N'-(2-(1H-indol-3-yl) acetyl group)-3,5-dimethylbenzohydrazide (Formulas I-25), white solid, productivity:
92%, mp:193.5-194.5 DEG C；1H-NMR(500MHz,DMSO-d6),δ(ppm):2.31(s,6H,2CH3),3.64(s,2H,
CH2),7.00-7.02(d,1H,Ar-H),7.19(s,1H,Ar-H),7.30(s,1H,Ar-H),7.36-7.38(d,1H,Ar-
H),7.08-7.09(d,1H,Ar-H),7.50(s,2H,Ar-H),7.65-7.66(d,1H,Ar-H),10.12(s,1H,NH),
10.25 (s, 1H, NH), 10.90 (s, 1H, indole-NH)；m/z 322.3[M++1]。
N'-(2-(1H-indol-3-yl) acetyl group)-4-chlorobenzoyl hydrazine (Formulas I-26), white solid, productivity: 86%,
mp:207.0-208.0℃；1H-NMR(500MHz,DMSO-d6),δ(ppm):4.02(s,2H,CH2),6.98-7.01(t,1H,
Ar-H),7.07-7.10(t,1H,Ar-H),7.29(s,1H,Ar-H),7.35-7.37(d,1H,Ar-H),7.55-7.57(d,
1H,Ar-H),7.63-7.65(d,2H,Ar-H),7.87-7.89(d,2H,Ar-H),10.17(s,1H,NH),10.45(s,1H,
NH), 10.88 (s, 1H, indole-NH)；m/z329.1[M++2]。
N'-(2-(1H-indol-3-yl) acetyl group) anthracene-10-formylhydrazine (Formulas I-27), faint yellow solid, productivity: 88%,
mp:258.0-259.0℃；1H-NMR(500MHz,DMSO-d6),δ(ppm):3.82(s,2H,CH2),7.07(s,1H,),
7.51-7.58(m,4H,Ar-H),7.59-7.62(m,2H,Ar-H),7.75-7.77(d,2H,Ar-H),8.13-8.15(d,
2H,Ar-H),8.39-8.40(d,1H,Ar-H),8.69(s,2H,Ar-H),10.39(s,1H,NH),10.61(s,1H,NH),
11.01 (s, 1H, indole-NH)；m/z 391.2[M+-2]。
N'-(2-(1H-indol-3-yl) acetyl group)-4-ethoxybenzene formylhydrazine (Formulas I-28), white solid, productivity:
93%, mp:170.1-171.1 DEG C；1H-NMR(500MHz,DMSO-d6),δ(ppm):1.32-1.34(t,3H,CH3),3.67
(s,2H,CH2),4.04-4.08(q,2H,CH2),6.99(s,1H,Ar-H),7.01-7.33(d,1H,Ar-H),7.38-7.69
(m, 4H, Ar-H), 7.87-7.89 (d, 2H, Ar-H), 10.10 (s, 1H, NH), 10.24 (s, 1H, NH), 10.92 (s, 1H, Yin
Diindyl-NH)；m/z 338.1[M++1]。
N'-(2-(1H-indol-3-yl) acetyl group) benzo [d] [1,3] dioxa amylene-5-carbohydrazide (Formulas I-29), in vain
Color solid, productivity: 92%, mp:106.5-107.5 DEG C；1H-NMR(500MHz,DMSO-d6),δ(p pm):3.67(s,2H,
CH2),6.10(s,2H,OCH2O),7.01(s,1H,Ar-H),7.02(d,1H,A r-H),7.11-7.44(m,4H,Ar-H),
7.52-7.53(d,1H,Ar-H),7.67-7.69(d,1H,Ar-H),10.13(s,1H,NH),10.25(s,1H,NH),10.92
(s, 1H, indole-NH)；m/z 338.1[M++1]。
N'-(2-(1H-indol-3-yl) acetyl group)-3-6-bromobenzene also [d] [1,3] dioxa amylene-5-base) acryloyl
Hydrazine (Formulas I-30), white solid, productivity: 89%, mp:242.7-243.7 DEG C；1H-NMR(500MHz,DMS O-d6),δ(ppm):
3.66(s,2H,CH2),6.12(s,2H,OCH2O), 6.57 (s, 1H, Ar-H), 6.60 (s, 1H, CH=CH), 7.01 (s, 1H,
Ar-H), 7.11 (s, 1H, Ar-H), 7.25-7.66 (d, 4H, Ar-H), 7.73-7.76 (d, 1H, CH=CH), 10.21 (s, 1H,
NH), 10.30 (s, 1H, NH), 10.97 (s, 1H, indole-NH)；m/z 443.0[M++2]。
N'-(2-(1H-indol-3-yl) acetyl group)-2-fluorobenzoyl hydrazine (Formulas I-31), white solid, productivity: 91%,
mp:153.0-154.0℃；1H-NMR(500MHz,DMSO-d6),δ(ppm):3.66(s,2H,CH2),7.00-7.02(s,1H,
Ar-H),7.09-7.12(m,1H,Ar-H),7.29-7.32(m,1H,Ar-H),7.38-7.39(d,4H,Ar-H),7.54-
7.63(m,1H,Ar-H),7.64-7.68(m,2H,Ar-H),10.26(s,1H,NH),10.27(s,1H,NH),10.92(s,
1H, indole-NH)；m/z 312.1[M++1]。
N'-(2-(1H-indol-3-yl) acetyl group)-2,3-dichloro-benzoyl hydrazine (Formulas I-32), white solid, productivity:
89%, mp:214.5-215.5 DEG C；1H-NMR(500MHz,DMSO-d6),δ(ppm):3.67(s,2H,CH2),7.00-7.03
(s,1H,Ar-H),7.09-7.46(m,4H,Ar-H),7.46(d,1H,Ar-H),7.73-7.75(d,1H,Ar-H),7.66-
7.67 (d, 1H, Ar-H), 10.35 (s, 1H, NH), 10.44 (s, 1H, NH), 10.93 (s, 1H, indole-NH)；m/z 363.0(M++2)。
N'-(2-(1H-indol-3-yl) acetyl group)-4-phenylbenzohydrazide (Formulas I-33), white solid, productivity:
92%, mp:221.0-222.0 DEG C；1H-NMR(500MHz,DMSO-d6),δ(ppm):3.74(s,2H,CH2),7.04(s,1H,
Ar-H),7.12(s,1H,Ar-H),7.37-7.48(m,4H,Ar-H),7.65-7.67(m,4H,Ar-H),7.72-7.75(t,
3H, Ar-H), 8.00-8.02 (d, 2H, Ar-H), 10.28 (s, 1H, NH), 10.52 (s, 1H, NH), 10.91 (s, 1H, indole-
NH)；m/z 370.2[M++1]。
N'-(2-(1H-indol-3-yl) acetyl group)-1-naphthoyl hydrazine (Formulas I-34), white solid, productivity: 93%, mp:
203.0-204.0℃；1H-NMR(500MHz,DMSO-d6),δ(ppm):3.67(s,2H,CH2),7.08(s,1H,Ar-H),
7.16-7.19(m,1H,Ar-H),7.44-7.48(m,2H,Ar-H),7.58-7.64(m,4H,Ar-H),7.74-7.80(m,
2H,Ar-H),8.00-8.01(d,1H,Ar-H),8.06-8.07(d,1H,Ar-H),8.48-8.50(d,1H,Ar-H),10.38
(s, 1H, NH), 10.46 (s, 1H, NH), 11.03 (s, 1H, indole-NH)；m/z 344.1[M++1]。
N'-(2-(1H-indol-3-yl) acetyl group)-2-naphthoyl hydrazine (Formulas I-35), white solid, productivity: 89%, mp:
214.0-215.0℃；1H-NMR(500MHz,DMSO-d6),δ(ppm):3.74(s,2H,CH2),7.04-7.06(s,1H,Ar-
H),7.11-7.14(m,1H,Ar-H),7.38-7.42(m,2H,Ar-H),7.59-7.65(m,2H,Ar-H),7.73-7.74
(d,1H,Ar-H),7.98-8.05(m,4H,Ar-H),8.56(s,1H,Ar-H),10.29(s,1H,NH),10.61(s,1H,
NH), 10.97 (s, 1H, indole-NH)；m/z344.2[M++1]。
Embodiment 3
In the present embodiment, Formulas I-1 is evaluated to the external anti-HCV activity of Formulas I-35 compound, uses people's hepatocarcinoma
Cell strain Huh 7.5.1 carries out cell in vitro horizontal anti-HCV activity evaluation, and method is described as follows:
Mtt assay detection drug cytotoxicity: the Huh 7.5.1 cell of trophophase of taking the logarithm, with 9 × 103Individual cells/well spreads
In 96 orifice plates, after adherent 5 hours, adding 2 μ L DMSO gradient dilution medicines, 5 times of dilutions, 5 dilution factors, each gradient is provided with
Three repeating holes, arrange blank (containing only culture medium), cell controls, DMSO comparison and HCV-Ab IgG positive drug profit bar simultaneously
Wei Lin (Ribavirin) compares, final volume 200 μ L/ hole.Culture plate is placed in 37 DEG C, 5%CO2Incubator is cultivated.3rd
It adds the 5mg/mL MTT solution of 20 μ L, 37 DEG C, 5%CO in experimental port2Hatch 4 hours.Supernatant discarded, adds 150 μ L/
The DMSO of well, after vibration is dissolved 10 minutes, measures the value of OD490 in microplate reader, and calculates with Graphad Prism 5.0
Medicine IC50 (IC50: half-inhibition concentration, the concentration by needed for cell growth inhibition 50%) value.Computing formula: cell grows
Suppression ratio (%)=(1 test hole OD value/control wells OD value) × 100%.
HCV inhibition of DNA replication is tested: the Huh 7.5.1 cell of trophophase of taking the logarithm, with 9 × 103Cells/well cell spreads
In 96 orifice plates, after adherent 5 hours, adding 2 μ LDMSO gradient dilution medicines, 5 times of dilutions, 5 dilution factors, each gradient is provided with three
Individual repeating hole, is simultaneously introduced virus, if cell controls, virus control, HCV-Ab IgG positive control (ribavirin), DMSO comparison, eventually
Volume 200 μ L/ hole.Culture plate is placed in 37 DEG C, 5%CO2Incubator is cultivated, after 3 days collect supernatant 3000rpm/min from
Heart 10min, takes clarified supernatant and carries out RNA carrying capacity detection.HCV inhibition of DNA replication rate and EC50 is calculated with Graphad Prism 5.0
(EC50: half effective concentration causes the individual drug dose producing a kind of specific effect of study subject 50%).Computing formula:
HCV inhibition of DNA replication rate (%)=(1-test hole HCV RNA carrying capacity/control wells HCV RNA carrying capacity) × 100%
HCV-Ab IgG evaluating drug effect: therapeutic index (Therapeutic index, TI) is that the half of cell is suppressed dense by medicine
Degree IC50With the ratio of the half effective concentration to virus, representing Drug safety, this numerical value is the biggest more safe.
Using HCV-Ab IgG clinical treatment agents Ribavirin (Ribavirin) as positive control.As stated above to synthesis
35 compounds have carried out drug cytotoxicity and the screening of HCV-Ab IgG virus activity, specifically test data (IC50、EC50And SI value)
See table 2, as seen from the table, 35 compounds surveyed have 10 compounds for treating indexes higher than Ribavirin, wherein live
Best 5 Formula I-4, Formulas I-5, Formulas I-6, Formulas I-9 and Formulas I-14 therapeutic index of property is higher 7-75 times than ribavirin, can
Primer as HCV-Ab IgG is used.
Table 2
Applicant states, the present invention illustrates the N'-of the present invention (2-(1H-indol-3-yl) acetyl by above-described embodiment
Base) aromatic hydrazide kind compound and its production and use, but the invention is not limited in above-described embodiment, i.e. do not mean that this
Invention has to rely on above-described embodiment and could implement.Person of ordinary skill in the field is it will be clearly understood that any to the present invention
Improving, the equivalence of raw material each to product of the present invention is replaced and the interpolation of auxiliary element, concrete way choice etc., all falls within this
Within the scope of bright protection domain and disclosure.
Claims (10)
1. N'-(2-(1H-indol-3-yl) acetyl group) aromatic hydrazide kind compound, it is characterised in that it has shown in Formulas I
Structure:
In Formulas I, n=0,1 or 2；R is substituted or unsubstituted phenyl ring, substituted or unsubstituted naphthalene nucleus, substituted or do not take
The anthracene nucleus in generation, substituted or unsubstituted furan nucleus, substituted or unsubstituted xenyl,In any one, described
The substituent group of phenyl ring, naphthalene nucleus, anthracene nucleus, furan nucleus and xenyl is independently selected from halogen, hydroxyl, nitro, trifluoromethyl, C1-C10
Any one or the combination of at least two in alkyl or C1-C10 alkoxyl.
N'-the most according to claim 1 (2-(1H-indol-3-yl) acetyl group) aromatic hydrazide kind compound, its feature exists
It is any one or the combination of at least two in F, Cl, Br or I in, described halogen.
N'-the most according to claim 1 and 2 (2-(1H-indol-3-yl) acetyl group) aromatic hydrazide kind compound, its feature
Being, described N'-(2-(1H-indol-3-yl) acetyl group) aromatic hydrazide kind compound is to have in the compound of following structure
Any one or the combination of at least two:
4. according to N'-(2-(1H-indol-3-yl) acetyl group) aromatic hydrazide kind compound according to any one of claim 1-3
Preparation method, it is characterised in that said method comprising the steps of:
(1) heteroauxing and C1-C5 alcohol generation esterification obtain ethychlozate ester shown in Formula II, and reaction equation is as follows:
Wherein R1For C1-C5 alkyl；
(2) ethychlozate ester shown in Formula II and hydrazine hydrate react and obtain indole acethydrazide shown in formula III, and reaction equation is as follows:
(3) being reacted by aromatic carboxylic acids shown in formula IV and chlorination reagent and prepare aryl-acyl chlorides shown in Formula V, reaction equation is as follows:
(4) reacted by indole acethydrazide shown in formula III and aryl-acyl chlorides shown in Formula V and obtain (2-(1H-indole-the 3-of N'-shown in Formulas I
Base) acetyl group) aromatic hydrazide kind compound, reaction equation is as follows:
Preparation method the most according to claim 4, it is characterised in that step (1) described C1-C5 alcohol be methanol, ethanol, third
Any one in alcohol, butanol or amylalcohol, preferably methanol；
Preferably, step (1) described heteroauxing is 1:(5-40 with the mol ratio of C1-C5 alcohol)；
Preferably, step (1) described reaction using strong acid as catalyst, preferably concentrated sulphuric acid；
Preferably, the temperature of step (1) described reaction is 50-80 DEG C；
Preferably, the time of step (1) described reaction is 1-8 hour.
6. according to the preparation method described in claim 4 or 5, it is characterised in that ethychlozate ester shown in step (2) described Formula II
It is 1:(1-4 with the mol ratio of hydrazine hydrate)；
Preferably, in step (2) described reaction, solvent for use is ethylene glycol monomethyl ether；
Preferably, the temperature of step (2) described reaction is 110-130 DEG C；
Preferably, the time of step (2) described reaction is 5-24 hour.
7. according to the preparation method according to any one of claim 4-6, it is characterised in that step (3) described chlorination reagent is
Any one or the combination of at least two, preferably thionyl chloride in thionyl chloride, Phosphorous chloride. or phosphorus pentachloride；
Preferably, step (3) described aromatic carboxylic acids is 1:(2-6 with the mol ratio of chlorination reagent)；
Preferably, in step (3) described reaction, solvent for use is oxolane；
Preferably, the temperature of step (3) described reaction is 60-90 DEG C；
Preferably, the time of step (3) described reaction is 5-20 hour.
8. according to the preparation method according to any one of claim 4-7, it is characterised in that step (4) described indole acethydrazide
It is 1:(1-1.5 with the mol ratio of aryl-acyl chlorides).
9. according to the preparation method according to any one of claim 4-7, it is characterised in that step (4) described reaction is in alkalescence
Carry out in the presence of reagent；
Preferably, described alkaline reagent is triethylamine；
Preferably, described alkaline reagent is 1:(1-3 with the mol ratio of indole acethydrazide)；
Preferably, the temperature of step (4) described reaction is 0-30 DEG C；
Preferably, the time of step (4) described reaction is 5-24 hour.
10. according to N'-(2-(1H-indol-3-yl) acetyl group) aromatic hydrazide kind compound according to any one of claim 1-3
Purposes in preparing anti hepatitis C virus drug.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610213100.1A CN105732468B (en) | 2016-04-07 | 2016-04-07 | A kind of N '-(2- (1H- indol-3-yls) acetyl group) aromatic hydrazide kind compound and its preparation method and application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610213100.1A CN105732468B (en) | 2016-04-07 | 2016-04-07 | A kind of N '-(2- (1H- indol-3-yls) acetyl group) aromatic hydrazide kind compound and its preparation method and application |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105732468A true CN105732468A (en) | 2016-07-06 |
| CN105732468B CN105732468B (en) | 2018-10-19 |
Family
ID=56252928
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610213100.1A Expired - Fee Related CN105732468B (en) | 2016-04-07 | 2016-04-07 | A kind of N '-(2- (1H- indol-3-yls) acetyl group) aromatic hydrazide kind compound and its preparation method and application |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105732468B (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106377526A (en) * | 2016-08-30 | 2017-02-08 | 白强 | Pharmaceutical composition for promoting stroke patient nerve regeneration and use thereof |
| CN106389419A (en) * | 2016-08-31 | 2017-02-15 | 段占娥 | Application of arylhydrazide compound in treatment of acute myocardial ischemic coronary heart disease |
| CN106474112A (en) * | 2016-08-31 | 2017-03-08 | 段占娥 | A kind of pharmaceutical composition of anti-acute myocardial ischemia coronary heart disease and its application |
| CN106474113A (en) * | 2016-08-30 | 2017-03-08 | 白强 | A kind of pharmaceutical composition for neuranagenesis after cerebral infarction and its application |
| CN107602662A (en) * | 2017-08-17 | 2018-01-19 | 河南师范大学 | A kind of preparation method of fragrant hydrazides macrocyclic compounds |
| CN112624938A (en) * | 2020-07-20 | 2021-04-09 | 南开大学 | Novel method for synthesizing ethyl hydrazine dihydrochloride |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1260345A (en) * | 1998-12-17 | 2000-07-19 | 阿迪尔公司 | Hydrazide compound, its preparing method and medicine compositions thereof |
| WO2009086303A2 (en) * | 2007-12-21 | 2009-07-09 | University Of Rochester | Method for altering the lifespan of eukaryotic organisms |
-
2016
- 2016-04-07 CN CN201610213100.1A patent/CN105732468B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1260345A (en) * | 1998-12-17 | 2000-07-19 | 阿迪尔公司 | Hydrazide compound, its preparing method and medicine compositions thereof |
| WO2009086303A2 (en) * | 2007-12-21 | 2009-07-09 | University Of Rochester | Method for altering the lifespan of eukaryotic organisms |
Non-Patent Citations (4)
| Title |
|---|
| PATRICK MARKT，等: "Discovery of Novel Cathepsin S Inhibitors by Pharmacophore-Based Virtual High-Throughput Screening", 《J. CHEM. INF. MODEL》 * |
| STEFANIE SCHMIDT，等: "Dual IGF-1R/SRC inhibitors based on a N0-aroyl-2-(1H-indol-3-yl)-2-oxoacetohydrazide structure", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 * |
| 王沙沙: "《STN检索报告》", 23 January 2018 * |
| 范孟然: "新型HCV丝氨酸蛋白酶抑制剂的设计与合成及抗HCV活性研究(I)", 《云南大学硕士学位论文》 * |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106377526A (en) * | 2016-08-30 | 2017-02-08 | 白强 | Pharmaceutical composition for promoting stroke patient nerve regeneration and use thereof |
| CN106474113A (en) * | 2016-08-30 | 2017-03-08 | 白强 | A kind of pharmaceutical composition for neuranagenesis after cerebral infarction and its application |
| CN106474113B (en) * | 2016-08-30 | 2019-02-26 | 徐州医科大学 | A kind of pharmaceutical composition and its application for nerve regneration after cerebral arterial thrombosis |
| CN106389419A (en) * | 2016-08-31 | 2017-02-15 | 段占娥 | Application of arylhydrazide compound in treatment of acute myocardial ischemic coronary heart disease |
| CN106474112A (en) * | 2016-08-31 | 2017-03-08 | 段占娥 | A kind of pharmaceutical composition of anti-acute myocardial ischemia coronary heart disease and its application |
| CN107602662A (en) * | 2017-08-17 | 2018-01-19 | 河南师范大学 | A kind of preparation method of fragrant hydrazides macrocyclic compounds |
| CN112624938A (en) * | 2020-07-20 | 2021-04-09 | 南开大学 | Novel method for synthesizing ethyl hydrazine dihydrochloride |
| CN112624938B (en) * | 2020-07-20 | 2022-12-30 | 南开大学 | Novel method for synthesizing ethyl hydrazine dihydrochloride |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105732468B (en) | 2018-10-19 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105732468B (en) | A kind of N '-(2- (1H- indol-3-yls) acetyl group) aromatic hydrazide kind compound and its preparation method and application | |
| JP6506836B2 (en) | Novel pyridazones and triazinones for the treatment and prevention of hepatitis B virus infection | |
| JP4939527B2 (en) | Biheterocyclic linking compound having antiviral function, application thereof and composition containing the compound | |
| CA2513436A1 (en) | Hydroxamid acid derivatives as histone deacetylase (hdac) inhibitors | |
| CA2838703C (en) | Indanone derivatives, pharmaceutically acceptable salts or optical isomers thereof, preparation method for same, and pharmaceutical compositions containing same as active ingredient for preventing or treating viral diseases | |
| WO2007036131A1 (en) | Carzole sulphamide derivatives and their preparation method | |
| CN102898408B (en) | Benzopyran compounds, preparation method and applications thereof | |
| CA2871324A1 (en) | Substituted acyloxyamidines as hcv ns3/4a inhibitors | |
| WO2004024694A1 (en) | 4-(substituted aryl)-5-hydroxyisoquinolinone derivative | |
| WO2019206120A1 (en) | Formamide compound, preparation method therefor and application thereof | |
| Hayallah et al. | Design and synthesis of new pyrido [2, 3-d] pyrimidine-1, 4-dione derivatives as anti-inflammatory agents | |
| CN101973935B (en) | Preparation method and application of N-substituted-3,5-dibenzal piperidine-4-one | |
| CN108997226B (en) | Synthesis process of cardiovascular drug Apabetalone | |
| EA009519B1 (en) | 3-NITROPYRAZOLO [1,5a]PYRIMIDINE DERIVATIVES, A PROCESS FOR PREPARING THEREOF, INTERMEDIATES USED THEREFOR, A MEDICAMENT (EMBODIMENT) AND A METHOD FOR TREATING AND PREVENTING DISEASES ASSOCIATED WITH GABARECEPTOR MODULATION | |
| CN114621194B (en) | 4-methylene-N-hydroxybenzoamide compound and application thereof | |
| WO2016184361A1 (en) | Anti-hepatitis c virus nucleoside compound and use thereof | |
| CN103396351B (en) | Pyrrolidines Bcl-2 protein micromolecular inhibitor compound and preparation, pharmaceutical composition and pharmaceutical applications | |
| CN104016898A (en) | 3,4-disubstituted pyrrole compound as well as preparation method and application thereof | |
| CN111978312B (en) | 5-aryl-1, 3, 4-thiadiazole/1, 3, 4-oxadiazole-2-amine compound, and preparation method and application thereof | |
| WO2017173960A1 (en) | Macro-heterocycle for suppressing hepatitis c virus, and preparation and application thereof | |
| CN110041349A (en) | One kind dihydropyrimidine derivatives containing spiral shell and its preparation method and application | |
| CN107011206B (en) | Acrylamide compound, preparation method and medical application thereof | |
| CN105859633B (en) | A kind of 2- thiacetamides benzimidazoles compound and its preparation method and application | |
| CN114174283B (en) | Compounds as NMT inhibitors and uses thereof | |
| CN108610332A (en) | Induce MDM2 self degradation E3 ubiquitin ligase dimer ester micromoleculars PROTACs |
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 | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20181019 Termination date: 20200407 |