CN114957160A - 一种2,4,5-三取代噻唑化合物、制备方法及其应用 - Google Patents
一种2,4,5-三取代噻唑化合物、制备方法及其应用 Download PDFInfo
- Publication number
- CN114957160A CN114957160A CN202210310615.9A CN202210310615A CN114957160A CN 114957160 A CN114957160 A CN 114957160A CN 202210310615 A CN202210310615 A CN 202210310615A CN 114957160 A CN114957160 A CN 114957160A
- Authority
- CN
- China
- Prior art keywords
- naphthyl
- phenyl
- thiocyano
- methoxy
- reaction
- 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.)
- Pending
Links
- -1 2,4, 5-trisubstituted thiazole compound Chemical class 0.000 title claims abstract description 26
- 238000002360 preparation method Methods 0.000 title abstract description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 60
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 40
- 238000006243 chemical reaction Methods 0.000 claims abstract description 39
- 239000002904 solvent Substances 0.000 claims abstract description 28
- CIOAUMWLWLNGTF-UHFFFAOYSA-N COC(C1=C(C2=CC=CC=C2)N=C(NC2=CC=CC=C2)S1)C1=CC=CC2=CC=CC=C12 Chemical compound COC(C1=C(C2=CC=CC=C2)N=C(NC2=CC=CC=C2)S1)C1=CC=CC2=CC=CC=C12 CIOAUMWLWLNGTF-UHFFFAOYSA-N 0.000 claims abstract description 19
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 18
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims abstract description 16
- 206010006187 Breast cancer Diseases 0.000 claims abstract description 13
- 208000026310 Breast neoplasm Diseases 0.000 claims abstract description 13
- 239000007787 solid Substances 0.000 claims abstract description 11
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Natural products CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000012670 alkaline solution Substances 0.000 claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 8
- 125000005031 thiocyano group Chemical group S(C#N)* 0.000 claims abstract description 8
- 239000012074 organic phase Substances 0.000 claims abstract description 7
- SQAINHDHICKHLX-UHFFFAOYSA-N 1-naphthaldehyde Chemical compound C1=CC=C2C(C=O)=CC=CC2=C1 SQAINHDHICKHLX-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000011968 lewis acid catalyst Substances 0.000 claims abstract description 6
- 238000010992 reflux Methods 0.000 claims abstract description 5
- 238000001035 drying Methods 0.000 claims abstract description 4
- 238000010438 heat treatment Methods 0.000 claims abstract description 4
- 238000006482 condensation reaction Methods 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- DUXOKTVNGKSFTK-BUHFOSPRSA-N (e)-3-naphthalen-1-yl-1-phenylprop-2-en-1-one Chemical compound C=1C=CC2=CC=CC=C2C=1/C=C/C(=O)C1=CC=CC=C1 DUXOKTVNGKSFTK-BUHFOSPRSA-N 0.000 claims description 16
- 239000003814 drug Substances 0.000 claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical group FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 claims description 7
- 239000007788 liquid Substances 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 238000010791 quenching Methods 0.000 claims description 6
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 6
- 230000002401 inhibitory effect Effects 0.000 claims description 5
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 4
- KVRSDIJOUNNFMZ-UHFFFAOYSA-L nickel(2+);trifluoromethanesulfonate Chemical compound [Ni+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F KVRSDIJOUNNFMZ-UHFFFAOYSA-L 0.000 claims description 4
- 238000000926 separation method Methods 0.000 claims description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 3
- 239000011592 zinc chloride Substances 0.000 claims description 3
- 235000005074 zinc chloride Nutrition 0.000 claims description 3
- 239000008367 deionised water Substances 0.000 claims description 2
- 229910021641 deionized water Inorganic materials 0.000 claims description 2
- 229940081974 saccharin Drugs 0.000 claims description 2
- 235000019204 saccharin Nutrition 0.000 claims description 2
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 claims description 2
- 125000000858 thiocyanato group Chemical group *SC#N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 6
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 230000000171 quenching effect Effects 0.000 claims 1
- 230000005764 inhibitory process Effects 0.000 abstract description 4
- 230000003013 cytotoxicity Effects 0.000 abstract description 2
- 231100000135 cytotoxicity Toxicity 0.000 abstract description 2
- 239000012434 nucleophilic reagent Substances 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 230000009982 effect on human Effects 0.000 abstract 1
- 238000001228 spectrum Methods 0.000 description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- 238000005481 NMR spectroscopy Methods 0.000 description 11
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 229910052739 hydrogen Inorganic materials 0.000 description 8
- 239000001257 hydrogen Substances 0.000 description 8
- 238000001819 mass spectrum Methods 0.000 description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 7
- 229910052799 carbon Inorganic materials 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- WHIBSDNTONPLBC-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) thiocyanate Chemical compound O=C1CCC(=O)N1SC#N WHIBSDNTONPLBC-UHFFFAOYSA-N 0.000 description 5
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000002246 antineoplastic agent Substances 0.000 description 4
- 229940041181 antineoplastic drug Drugs 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- 239000005457 ice water Substances 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- 239000008213 purified water Substances 0.000 description 4
- 238000002390 rotary evaporation Methods 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- 238000000967 suction filtration Methods 0.000 description 4
- GAEBZVNMZPHKQD-UHFFFAOYSA-N COC(C1=C(C2=CC=CC=C2)N=C(NC2=CC=CC=C2)S1)C1=CC=CC=C1 Chemical compound COC(C1=C(C2=CC=CC=C2)N=C(NC2=CC=CC=C2)S1)C1=CC=CC=C1 GAEBZVNMZPHKQD-UHFFFAOYSA-N 0.000 description 3
- 229930012538 Paclitaxel Natural products 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 3
- 229960001592 paclitaxel Drugs 0.000 description 3
- 239000002953 phosphate buffered saline Substances 0.000 description 3
- 239000013641 positive control Substances 0.000 description 3
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 3
- 150000003557 thiazoles Chemical class 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 102000004142 Trypsin Human genes 0.000 description 2
- 108090000631 Trypsin Proteins 0.000 description 2
- 229910002091 carbon monoxide Inorganic materials 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 230000029087 digestion Effects 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- HPJKCIUCZWXJDR-UHFFFAOYSA-N letrozole Chemical compound C1=CC(C#N)=CC=C1C(N1N=CN=C1)C1=CC=C(C#N)C=C1 HPJKCIUCZWXJDR-UHFFFAOYSA-N 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000012827 research and development Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- FVRDYQYEVDDKCR-DBRKOABJSA-N tiazofurine Chemical compound NC(=O)C1=CSC([C@H]2[C@@H]([C@H](O)[C@@H](CO)O2)O)=N1 FVRDYQYEVDDKCR-DBRKOABJSA-N 0.000 description 2
- 229960003723 tiazofurine Drugs 0.000 description 2
- 239000012588 trypsin Substances 0.000 description 2
- FSZLHEOJSFBKTB-UHFFFAOYSA-N (1,1,3-trioxo-1,2-benzothiazol-2-yl) thiocyanate Chemical compound S(C#N)N1S(=O)(=O)C2=CC=CC=C2C1=O FSZLHEOJSFBKTB-UHFFFAOYSA-N 0.000 description 1
- OGYGFUAIIOPWQD-UHFFFAOYSA-N 1,3-thiazolidine Chemical compound C1CSCN1 OGYGFUAIIOPWQD-UHFFFAOYSA-N 0.000 description 1
- NBWRJAOOMGASJP-UHFFFAOYSA-N 2-(3,5-diphenyl-1h-tetrazol-1-ium-2-yl)-4,5-dimethyl-1,3-thiazole;bromide Chemical compound [Br-].S1C(C)=C(C)N=C1N1N(C=2C=CC=CC=2)N=C(C=2C=CC=CC=2)[NH2+]1 NBWRJAOOMGASJP-UHFFFAOYSA-N 0.000 description 1
- BFYIZQONLCFLEV-DAELLWKTSA-N Aromasine Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC(=C)C2=C1 BFYIZQONLCFLEV-DAELLWKTSA-N 0.000 description 1
- 102000018832 Cytochromes Human genes 0.000 description 1
- 108010052832 Cytochromes Proteins 0.000 description 1
- 238000006846 Hantzsch Thiazole synthesis reaction Methods 0.000 description 1
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 1
- 102000034570 NR1 subfamily Human genes 0.000 description 1
- 108020001305 NR1 subfamily Proteins 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 229960002932 anastrozole Drugs 0.000 description 1
- YBBLVLTVTVSKRW-UHFFFAOYSA-N anastrozole Chemical compound N#CC(C)(C)C1=CC(C(C)(C#N)C)=CC(CN2N=CN=C2)=C1 YBBLVLTVTVSKRW-UHFFFAOYSA-N 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- HUMNYLRZRPPJDN-KWCOIAHCSA-N benzaldehyde Chemical group O=[11CH]C1=CC=CC=C1 HUMNYLRZRPPJDN-KWCOIAHCSA-N 0.000 description 1
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzenecarboxaldehyde Natural products O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229960003668 docetaxel Drugs 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 102000015694 estrogen receptors Human genes 0.000 description 1
- 108010038795 estrogen receptors Proteins 0.000 description 1
- 229960000255 exemestane Drugs 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 239000003547 immunosorbent Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 229960003881 letrozole Drugs 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
- 229940126586 small molecule drug Drugs 0.000 description 1
- 238000009987 spinning Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- JNMRHUJNCSQMMB-UHFFFAOYSA-N sulfathiazole Chemical compound C1=CC(N)=CC=C1S(=O)(=O)NC1=NC=CS1 JNMRHUJNCSQMMB-UHFFFAOYSA-N 0.000 description 1
- 229960001544 sulfathiazole Drugs 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 150000007979 thiazole derivatives Chemical class 0.000 description 1
- 229960005026 toremifene Drugs 0.000 description 1
- XFCLJVABOIYOMF-QPLCGJKRSA-N toremifene Chemical compound C1=CC(OCCN(C)C)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 XFCLJVABOIYOMF-QPLCGJKRSA-N 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
- C07D277/38—Nitrogen atoms
- C07D277/42—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/14—Drugs for genital or sexual disorders; Contraceptives for lactation disorders, e.g. galactorrhoea
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Reproductive Health (AREA)
- Endocrinology (AREA)
- Gynecology & Obstetrics (AREA)
- Pregnancy & Childbirth (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Thiazole And Isothizaole Compounds (AREA)
Abstract
本发明涉及一种2,4,5‑三取代噻唑化合物、制备方法及其应用,属于有机合成技术领域。所述化合物为N,4‑二苯基‑5‑(甲氧基(1‑萘基)甲基)噻唑‑2‑胺。通过将α‑萘甲醛和苯乙酮溶于醇类溶剂Ⅰ中,加入碱性溶液进行缩合反应,得到的固体溶于低极性溶剂中,加入亲电硫氰基试剂、亲核试剂甲醇和Lewis酸催化剂,进行反应,有机相干燥纯化后溶于醇类溶剂Ⅱ中,加入苯胺,加热回流反应,得到所述化合物。所述化合物对人乳腺癌细胞表现出较好的细胞毒性和抑制作用。
Description
技术领域
本发明涉及一种2,4,5-三取代噻唑化合物、制备方法及其应用,属于有机合成技术领域。
背景技术
噻唑是一种含硫、氮的五元杂环化合物,噻唑环上杂原子的存在,使其容易与多类作用位点形成氢键、配位作用、堆积作用以及静电作用等非化学键作用,给予该结构多种特殊的性能,因此在众多领域有着潜在的应用,特别是在医药领域。目前已知噻唑类化合物可与生物体内多种酶和受体等靶点结合从而表现出多种生物活性,如磺胺噻唑(sulfathiazole)就是含有噻唑母环的药物分子,青霉素分子中也含有噻唑烷结构单元。
癌症是人类健康的严重威胁之一,抗癌药物的研发也是医药研究最多的领域之一,噻唑类药物是抗肿瘤药物研发的一个重要方向。但是噻唑本身并无直接的药物活性,必须在其骨架上进行适当的衍生才能发挥作用。以噻唑为母环骨架的衍生物,如噻唑呋林(Tiazofurine)等已经作为抗肿瘤药物在临床上得到应用。将多种官能团与噻唑进行组装,开发新型的多取代噻唑衍生物,以此来探索具有良好活性的先导化合物是开发新药物的有效手段。
噻唑环具有芳香性,化学性质稳定,直接在噻唑上进行取代反应非常困难。现有的多取代噻唑类化合物的合成方法大多基于传统的Hantzsch噻唑合成法,如中国专利申请CN103159695A中所公开的方法,该法反应步骤长,且必须要有卤素作为定位基,通常还需要使用过渡金属;此方法虽然能引入较多的官能团,但必须增加额外的反应步骤,在合成多取代噻唑化合物方面仍存在较大的局限性。
目前,抗乳腺癌细胞的小分子药物主要有三类:(1)作用于雌激素受体的药物,有雷诺昔芬、托瑞米芬、他莫昔芬;(2)作用于细胞色素P450 19A1的药物,有阿那曲唑、依西美坦、来曲唑;(3)作用于核受体亚家族1组I分子2的药物,有紫杉醇、多西紫杉醇。
发明内容
有鉴于此,本发明的目的在于提供一种2,4,5-三取代噻唑化合物、制备方法及其应用。
为实现上述目的,本发明的技术方案如下:
一种2,4,5-三取代噻唑化合物,所述化合物为N,4-二苯基-5-(甲氧基(1-萘基)甲基)噻唑-2-胺,结构式如下:
一种本发明所述的2,4,5-三取代噻唑化合物的制备方法,所述方法步骤如下:
(1)将α-萘甲醛和苯乙酮溶于醇类溶剂Ⅰ中,加入碱性溶液进行缩合反应,反应结束后,固液分离,收集固体,得到(E)-1-苯基-3-(1-萘基)丙-2-烯-1-酮;
(2)将所述(E)-1-苯基-3-(1-萘基)丙-2-烯-1-酮溶于低极性溶剂中,加入亲电硫氰基试剂([SCN]+试剂)、亲核试剂甲醇和Lewis酸催化剂,反应6h~24h,反应结束后加入去离子水纯度以上的水淬灭反应,收集有机相,干燥纯化,得到1-苯基-2-硫氰基-3-甲氧基-3-(1-萘基)丙酮;
(3)将1-苯基-2-硫氰基-3-甲氧基-3-(1-萘基)丙酮溶于醇类溶剂Ⅱ中,加入苯胺,加热回流反应,薄层色谱(TLC)检测1-苯基-2-硫氰基-3-甲氧基-3-(1-萘基)丙酮反应完全,固液分离,收集固体,得到一种2,4,5-三取代噻唑化合物。
优选的,步骤(1)中,所述醇类溶剂Ⅰ为甲醇或乙醇。
优选的,步骤(1)中,所述碱性溶液浓度为0.5~2mol/L,所述醇类溶剂与碱性溶液的体积比为0.5:1~2:1。
优选的,步骤(2)中,所述低极性溶剂为卤代溶剂或甲苯;更优选的,所述低极性溶剂为二氯甲烷、氯仿、1,2-二氯乙烷、四氯化碳或甲苯。
优选的,步骤(2)中,所述Lewis酸催化剂为三氟化硼乙醚、氯化锌、三甲基硅基三氟甲磺酸酯或三氟甲磺酸镍。
优选的,步骤(2)中,所述(E)-1-苯基-3-(1-萘基)丙-2-烯-1-酮、亲电硫氰基试剂和甲醇的摩尔比为1:1~2:3~20。
优选的,步骤(2)中,催化剂用量为(E)-1-苯基-3-(1-萘基)丙-2-烯-1-酮的5~50mol%,更优选为10~20mol%。
优选的,步骤(3)中,所述1-苯基-2-硫氰基-3-甲氧基-3-(1-萘基)丙酮与苯胺的摩尔比为1:1~1:3。
优选的,步骤(3)中,所述醇类溶剂Ⅱ为甲醇或乙醇。
一种本发明所述的2,4,5-三取代噻唑化合物在制备抑制人乳腺癌药物中的应用。
一种本发明所述的2,4,5-三取代噻唑化合物在制备抑制人乳腺癌细胞药物中的应用。
优选的,所述2,4,5-三取代噻唑化合物的浓度为10μM~30μM。
优选的,所述人乳腺癌细胞为人乳腺癌细胞MCF-7。
有益效果
本发明提供了一种2,4,5-三取代噻唑化合物,结构新颖,具有开发抗肿瘤药物的潜在价值。
本发明提供了一种2,4,5-三取代噻唑化合物的制备方法,所述方法不使用金属催化,也不使用卤素作为定位基团,合成路线简便,原子经济性和环保性优势明显。
本发明提供了一种2,4,5-三取代噻唑化合物的应用,所述化合物对人乳腺癌细胞表现出较好的细胞毒性,对人乳腺癌细胞有较好的抑制作用,在医药领域具有良好的应用前景。
附图说明
图1为实施例1中所述N,4-二苯基-5-(甲氧基(1-萘基)甲基)噻唑-2-胺的核磁共振氢谱图。
图2为实施例1中所述N,4-二苯基-5-(甲氧基(1-萘基)甲基)噻唑-2-胺的核磁共振碳谱图。
图3为实施例1中所述N,4-二苯基-5-(甲氧基(1-萘基)甲基)噻唑-2-胺的高分辨质谱图。
具体实施方式
下面结合具体实施例对本发明作进一步详细的说明。
实施例1
N,4-二苯基-5-(甲氧基(1-萘基)甲基)噻唑-2-胺的具体制备步骤如下:
(1)于100mL烧瓶中加入1.7g(10.0mmol)α-萘甲醛(式I)、1.1g(10.0mmol)苯乙酮(式II)和25mL乙醇,在冰水浴条件下搅拌溶解,向反应液中滴加入25mL浓度为1mol/L的NaOH溶液,保持冰水浴反应6h,反应液抽滤,冰乙醇洗涤,并以乙醇重结晶,得2.3g黄色晶体(E)-1-苯基-3-(1-萘基)丙-2-烯-1-酮(式III),收率为89%;
反应方程式如下:
(2)将1.29g(5.0mmol)所述(E)-1-苯基-3-(1-萘基)丙-2-烯-1-酮(式III)加入100mL反应瓶中,加入25mL二氯甲烷溶解,然后依次加入1.00g(6.5mmol)N-硫氰基琥珀酰亚胺试剂(式IV)、2mL(50mmol)甲醇和0.4mL(2.0mmol)三甲基硅基三氟甲磺酸酯;室温(25℃)下搅拌反应12h,反应完毕后加10mL纯化水淬灭反应,用10mL二氯甲烷萃取三次,收集有机相,旋转蒸发除去溶剂,使用快速硅胶柱色谱(洗脱剂是体积比为10:1的石油醚与乙酸乙酯)纯化产物,得到1.02g黄色油状产物1-苯基-2-硫氰基-3-甲氧基-3-(1-萘基)丙酮(式V),收率为59%;
反应方程式如下:
(3)在10mL反应管中加入173mg(0.5mmol)所述1-苯基-2-硫氰基-3-甲氧基-3-(1-萘基)丙酮(式V),加入2mL甲醇溶解,滴加50μL(0.6mmol)苯胺,反应液加热至65℃回流反应8h,将反应液静置并缓慢降温至0℃,抽滤得浅黄色固体,使用20mL冰甲醇洗涤,洗涤液及滤液收集并旋干,残余产物使用甲醇再次重结晶,合并,得到120mg浅黄色固体N,4-二苯基-5-(甲氧基(1-萘基)甲基)噻唑-2-胺(式VI),收率为57%;
反应方程式如下:
对所述N,4-二苯基-5-(甲氧基(1-萘基)甲基)噻唑-2-胺进行核磁共振氢谱、碳谱及高分辨质谱表征,表征结果如下:
1H NMR(400MHz,CDCl3):δ7.85(d,J=8.0Hz,1H),7.82(d,J=8.0Hz,1H),7.79(d,J=8.0Hz,1H),7.70(d,J=8.0Hz,2H),7.57–7.42(m,7H),7.37–7.28(m,2H),7.25–7.18(m,2H),7.05–7.00(m,1H),6.12(s,1H),3.52(s,3H);核磁共振氢谱图如图1所示。
13C NMR(101MHz,CDCl3):δ164.3,148.2,139.7,136.5,134.2,133.9,130.8,129.4,128.9,128.8,128.8,128.7,128.6,126.3,125.8,125.4,123.4,123.4,123.2,122.9,118.6,75.8,56.9;核磁共振碳谱图如图2所示。
HRMS(ESI)m/z计算值C27H23N2OS+([M+H]+)423.1526,实际测量值423.1514;高分辨质谱图如图3所示。
实施例2
(1)于100mL烧瓶中加入1.7g(10.0mmol)α-萘甲醛、1.1g(10.0mmol)苯乙酮和50mL乙醇,在冰水浴条件下搅拌溶解,向反应液中滴加入25mL浓度为2mol/L的NaOH溶液,保持冰水浴反应3h,反应液抽滤,冰乙醇洗涤,并以乙醇重结晶,得到2.4g黄色晶体(E)-1-苯基-3-(1-萘基)丙-2-烯-1-酮,收率为93%;
步骤(2)-(3)与实施例1相同。
对所述N,4-二苯基-5-(甲氧基(1-萘基)甲基)噻唑-2-胺进行核磁共振氢谱、碳谱及高分辨质谱表征,结果如实施例1类似。
实施例3
步骤(1)与实施例1相同;
(2)将1.29g(5.0mmol)所述(E)-1-苯基-3-(1-萘基)丙-2-烯-1-酮加入100mL反应瓶中,加入25mL二氯甲烷溶解,然后依次加入1.80g(7.5mmol)N-硫氰基糖精试剂、2mL(50mmol)甲醇和0.2mL(0.8mmol)三氟化硼乙醚;室温(25℃)下搅拌反应6h,反应完毕后加10mL纯化水淬灭反应,用10mL二氯甲烷萃取三次,收集有机相,旋转蒸发除去溶剂,使用快速硅胶柱色谱(洗脱剂是体积比为10:1的石油醚与乙酸乙酯)纯化产物,得到1.17g黄色油状产物1-苯基-2-硫氰基-3-甲氧基-3-(1-萘基)丙酮,收率为68%;
步骤(3)与实施例1相同。
对所述N,4-二苯基-5-(甲氧基(1-萘基)甲基)噻唑-2-胺进行核磁共振氢谱、碳谱及高分辨质谱表征,结果如实施例1类似。
实施例4
步骤(1)与实施例1相同;
(2)将1.29g(5.0mmol)所述(E)-1-苯基-3-(1-萘基)丙-2-烯-1-酮加入100mL反应瓶中,加入25mL 1,2-二氯乙烷溶解,然后依次加入1.00g(6.5mmol)N-硫氰基琥珀酰亚胺试剂、2mL(50mmol)甲醇和0.10g(0.5mmol)三氟甲磺酸镍;50℃下搅拌反应24h,反应完毕后加10mL纯化水淬灭反应,用10mL二氯甲烷萃取三次,收集有机相,旋转蒸发除去溶剂,使用快速硅胶柱色谱(洗脱剂是体积比为10:1的石油醚与乙酸乙酯)纯化产物,得到0.87g黄色油状产物1-苯基-2-硫氰基-3-甲氧基-3-(1-萘基)丙酮,收率为50%;
步骤(3)与实施例1相同。
对所述N,4-二苯基-5-(甲氧基(1-萘基)甲基)噻唑-2-胺进行核磁共振氢谱、碳谱及高分辨质谱表征,结果如实施例1类似。
实施例5
步骤(1)与实施例1相同;
(2)将1.29g(5.0mmol)所述(E)-1-苯基-3-(1-萘基)丙-2-烯-1-酮加入100mL反应瓶中,加入25mL甲苯溶解,然后依次加入1.00g(6.5mmol)N-硫氰基琥珀酰亚胺试剂、2mL(50mmol)甲醇和0.2mL(1.0mmol)三甲基硅基三氟甲磺酸酯;50℃下搅拌反应6h,反应完毕后加10mL纯化水淬灭反应,用10mL甲苯萃取三次,收集有机相,旋转蒸发除去溶剂,使用快速硅胶柱色谱(洗脱剂是体积比为10:1的石油醚与乙酸乙酯)纯化产物,得到1.45g黄色油状产物1-苯基-2-硫氰基-3-甲氧基-3-(1-萘基)丙酮,收率为84%;
步骤(3)与实施例1相同。
对所述N,4-二苯基-5-(甲氧基(1-萘基)甲基)噻唑-2-胺进行核磁共振氢谱、碳谱及高分辨质谱表征,结果如实施例1类似。
实施例6
步骤(1)、(2)与实施例1相同;
(3)在10mL反应管中加入173mg(0.5mmol)所述1-苯基-2-硫氰基-3-甲氧基-3-(1-萘基)丙酮,加入1mL乙醇溶解,滴加42μL(0.5mmol)苯胺,反应液加热至80℃回流反应10h,将反应液静置并缓慢降温至0℃,抽滤得浅黄色固体,使用20mL冰乙醇洗涤,收集固体,洗涤液及滤液旋干后加入甲醇重结晶,合并固体,得到150mg浅黄色固体N,4-二苯基-5-(甲氧基(1-萘基)甲基)噻唑-2-胺,收率为71%。
对所述N,4-二苯基-5-(甲氧基(1-萘基)甲基)噻唑-2-胺进行核磁共振氢谱、碳谱及高分辨质谱表征,结果如实施例1类似。
实施例7
以紫杉醇为阳性对照(IC50<0.008μM),用(3-(4,5-二甲基-2-噻唑基)-2,5-二苯基四氮唑溴盐)(MTT)法测定N,4-二苯基-5-(甲氧基(1-萘基)甲基)噻唑-2-胺对乳腺癌细胞(MCF-7)的体外抑制活性。
选用实验室培养至3~4代的MCF-7细胞,用磷酸缓冲盐溶液(PBS)3mL清洗1~2遍后弃去,加入1mL胰蛋白酶消化一分钟后,弃去胰蛋白酶,加入完全培养基终止消化,将细胞吹打均匀后使细胞重悬,计数后,将MCF-7细胞以5×104个/mL的密度接种于96孔板内,每孔加入200μL细胞悬液,孔板边缘用200μL/孔的PBS进行填充,然后置于培养箱(37℃,5%CO2)中,待细胞贴壁后给药。同时设置空白组、阳性对照组、阴性对照组和实验组。空白组不做处理;阳性对照组每孔加入0.5μL浓度为8mM的紫杉醇;阴性对照组加入0.5μL的DMSO;实验组加入0.5μL浓度为8mM的N,4-二苯基-5-(甲氧基(1-萘基)甲基)噻唑-2-胺溶液。置于培养箱(37℃,5%CO2)中培养24h后,在避光条件下,每孔加入20μL MTT溶液(5mg/mL),然后放置于培养箱中反应4h后,弃去上清,每孔加入150μL的DMSO,将96孔板置于摇床或微孔振荡器上震荡10min左右,待甲瓒结晶充分溶解后,用酶联免疫仪在490nm波长下检测吸光度(OD)值,并根据下面公式计算抑制率。
结果表明,当N,4-二苯基-5-(甲氧基(1-萘基)甲基)噻唑-2-胺工作浓度为20μM时,对MCF-7细胞的抑制率为41.79%。
对比例1
将实施例1中的α-萘甲醛替换为苯甲醛,其余同实施例1,制备得到N,4-二苯基-5-(甲氧基苯基甲基)噻唑-2-胺。
将实施例7中的N,4-二苯基-5-(甲氧基(1-萘基)甲基)噻唑-2-胺替换为本对比例中的N,4-二苯基-5-(甲氧基苯基甲基)噻唑-2-胺,按照实施例7中的条件进行活性测试,结果表明,N,4-二苯基-5-(甲氧基苯基甲基)噻唑-2-胺对MCF-7细胞无抑制作用。
综上所述,发明包括但不限于以上实施例,凡是在本发明的精神和原则之下进行的任何等同替换或局部改进,都将视为在本发明的保护范围之内。
Claims (10)
2.一种如权利要求1所述的2,4,5-三取代噻唑化合物的制备方法,其特征在于:所述方法步骤如下:
(1)将α-萘甲醛和苯乙酮溶于醇类溶剂Ⅰ中,加入碱性溶液进行缩合反应,反应结束后,固液分离,收集固体,得到(E)-1-苯基-3-(1-萘基)丙-2-烯-1-酮;
(2)将所述(E)-1-苯基-3-(1-萘基)丙-2-烯-1-酮溶于低极性溶剂中,加入亲电硫氰基试剂、甲醇和Lewis酸催化剂,反应6h~24h,反应结束后加入去离子水纯度以上的水淬灭反应,收集有机相,干燥纯化,得到1-苯基-2-硫氰基-3-甲氧基-3-(1-萘基)丙酮;
(3)将1-苯基-2-硫氰基-3-甲氧基-3-(1-萘基)丙酮溶于醇类溶剂Ⅱ中,加入苯胺,加热回流反应,1-苯基-2-硫氰基-3-甲氧基-3-(1-萘基)丙酮反应完全,固液分离,收集固体,得到一种2,4,5-三取代噻唑化合物。
5.如权利要求2所述的一种2,4,5-三取代噻唑化合物的制备方法,其特征在于:步骤(1)中,所述碱性溶液浓度为0.5~2mol/L,所述醇类溶剂与碱性溶液的体积比为0.5:1~2:1;
步骤(2)中,所述(E)-1-苯基-3-(1-萘基)丙-2-烯-1-酮、亲电硫氰基试剂和甲醇的摩尔比为1:1~2:3~20;催化剂用量为(E)-1-苯基-3-(1-萘基)丙-2-烯-1-酮的5~50mol%;
步骤(3)中,所述1-苯基-2-硫氰基-3-甲氧基-3-(1-萘基)丙酮与苯胺的摩尔比为1:1~1:3。
6.如权利要求5所述的一种2,4,5-三取代噻唑化合物的制备方法,其特征在于:步骤(2)中,催化剂用量为(E)-1-苯基-3-(1-萘基)丙-2-烯-1-酮的10~20mol%。
7.如权利要求2所述的一种2,4,5-三取代噻唑化合物的制备方法,其特征在于:步骤(1)中,所述醇类溶剂Ⅰ为甲醇或乙醇;所述碱性溶液浓度为0.5~2mol/L,所述醇类溶剂与碱性溶液的体积比为0.5:1~2:1;
步骤(2)中,所述低极性溶剂为二氯甲烷、氯仿、1,2-二氯乙烷、四氯化碳或甲苯;所述Lewis酸催化剂为三氟化硼乙醚、氯化锌、三甲基硅基三氟甲磺酸酯或三氟甲磺酸镍;所述亲电硫氰基试剂所述(E)-1-苯基-3-(1-萘基)丙-2-烯-1-酮、亲电硫氰基试剂和甲醇的摩尔比为1:1~2:3~20;催化剂用量为(E)-1-苯基-3-(1-萘基)丙-2-烯-1-酮的10~20mol%;
步骤(3)中,所述醇类溶剂Ⅱ为甲醇或乙醇;所述1-苯基-2-硫氰基-3-甲氧基-3-(1-萘基)丙酮与苯胺的摩尔比为1:1~1:3。
8.一种如权利要求1所述的2,4,5-三取代噻唑化合物的应用,其特征在于:所述化合物在制备治疗乳腺癌药物中的应用。
9.如权利要求8所述的一种2,4,5-三取代噻唑化合物的应用,其特征在于:所述化合物在制备抑制人乳腺癌细胞药物中的应用。
10.如权利要求9所述的一种2,4,5-三取代噻唑化合物的应用,其特征在于:所述化合物的浓度为10μM~30μM;所述人乳腺癌细胞为人乳腺癌细胞MCF-7。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202210310615.9A CN114957160A (zh) | 2022-03-28 | 2022-03-28 | 一种2,4,5-三取代噻唑化合物、制备方法及其应用 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202210310615.9A CN114957160A (zh) | 2022-03-28 | 2022-03-28 | 一种2,4,5-三取代噻唑化合物、制备方法及其应用 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN114957160A true CN114957160A (zh) | 2022-08-30 |
Family
ID=82975810
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202210310615.9A Pending CN114957160A (zh) | 2022-03-28 | 2022-03-28 | 一种2,4,5-三取代噻唑化合物、制备方法及其应用 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN114957160A (zh) |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH06256326A (ja) * | 1993-03-09 | 1994-09-13 | Sumitomo Chem Co Ltd | 2−アミノチアゾール誘導体の製造法 |
WO1995023790A1 (en) * | 1994-03-03 | 1995-09-08 | Smithkline Beecham Corporation | Cytokine inhibiting imidazole substituted hydroxamic acid derivatives |
WO2004071509A1 (ja) * | 2003-02-12 | 2004-08-26 | Nippon Chemiphar Co., Ltd. | オリゴデンドロサイト分化促進剤 |
CN1980906A (zh) * | 2004-05-24 | 2007-06-13 | Irm责任有限公司 | 作为ppar调节剂的化合物和组合物 |
CN103159695A (zh) * | 2011-12-08 | 2013-06-19 | 首都师范大学 | 可抑制hiv复制并对耐药hiv病毒株有效的噻唑类化合物及其制备方法和用途 |
KR20150136294A (ko) * | 2014-05-27 | 2015-12-07 | 주식회사 레고켐 바이오사이언스 | 인자 XIa 억제 활성을 가지는 신규한 화합물 |
WO2019154859A1 (en) * | 2018-02-06 | 2019-08-15 | Universität Heidelberg | Fap inhibitor |
-
2022
- 2022-03-28 CN CN202210310615.9A patent/CN114957160A/zh active Pending
Patent Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH06256326A (ja) * | 1993-03-09 | 1994-09-13 | Sumitomo Chem Co Ltd | 2−アミノチアゾール誘導体の製造法 |
WO1995023790A1 (en) * | 1994-03-03 | 1995-09-08 | Smithkline Beecham Corporation | Cytokine inhibiting imidazole substituted hydroxamic acid derivatives |
WO2004071509A1 (ja) * | 2003-02-12 | 2004-08-26 | Nippon Chemiphar Co., Ltd. | オリゴデンドロサイト分化促進剤 |
CN1980906A (zh) * | 2004-05-24 | 2007-06-13 | Irm责任有限公司 | 作为ppar调节剂的化合物和组合物 |
CN1980919A (zh) * | 2004-05-24 | 2007-06-13 | Irm责任有限公司 | 作为ppar调节剂的化合物和组合物 |
CN103159695A (zh) * | 2011-12-08 | 2013-06-19 | 首都师范大学 | 可抑制hiv复制并对耐药hiv病毒株有效的噻唑类化合物及其制备方法和用途 |
KR20150136294A (ko) * | 2014-05-27 | 2015-12-07 | 주식회사 레고켐 바이오사이언스 | 인자 XIa 억제 활성을 가지는 신규한 화합물 |
WO2019154859A1 (en) * | 2018-02-06 | 2019-08-15 | Universität Heidelberg | Fap inhibitor |
Non-Patent Citations (2)
Title |
---|
LUIS M.G. ABEGÃO等: "Chalcone-based molecules: Experimental and theoretical studies on the two-photon absorption and molecular first hyperpolarizability", 《SPECTROCHIMICA ACTA PART A: MOLECULAR AND BIOMOLECULAR SPECTROSCOPY》, vol. 227, pages 1 - 10 * |
ZHENDA FU等: "Electrophilic Thiocyanato Reagent Assisted Oxa-Michael/Thiocyanation of α, β-Unsaturated Ketones", 《J. ORG. CHEM.》, vol. 86, pages 17418 * |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN113045399B (zh) | 查尔酮衍生物及其用途 | |
CN108863969A (zh) | 一种4-烯丙基-3,5-二取代异噁唑的合成方法 | |
CN113666824A (zh) | 一种大麻二酚-2-丙酸酯及其应用 | |
CN113735709A (zh) | 一种大麻二酚-2-丁酸酯及其应用 | |
CN112250686A (zh) | 一类口字型格空穴传输材料及其制备方法与应用 | |
CN114957160A (zh) | 一种2,4,5-三取代噻唑化合物、制备方法及其应用 | |
CN110642740B (zh) | 异斯特维醇酰胺衍生物及其制备方法 | |
CN111253411A (zh) | 一种小檗碱亚油酸缀合物及其制备方法和用途 | |
CN111471080A (zh) | ocotillol型人参皂苷元A环并氨基噻唑环衍生物及制备方法 | |
CN111362962B (zh) | 去甲斑蝥素羧酸四氟苄酯及其合成方法 | |
CN110790707A (zh) | 一种二硫代1,8-萘二酰亚胺类化合物及其制备方法和应用 | |
Pettit et al. | Antineoplastic agents. 200. Absolute configuration of the bryostatins | |
CN113045527B (zh) | 二氢色原酮衍生物及其合成方法和用途 | |
CN111233843B (zh) | 一种γ-丁烯酸内酯类衍生物及其制备方法和应用 | |
CN113173965A (zh) | 一种抗肿瘤的白桦酸衍生物及其制备方法 | |
CN111269242A (zh) | 去甲斑蝥素羧酸单氟苄酯及其合成方法和抗肿瘤应用 | |
CN113651822B (zh) | 一种8-h取代的五环螺吲哚啉化合物及其制备方法和应用 | |
CN108586495B (zh) | 一种二氟代c2-螺环吲哚啉类化合物及其制备方法 | |
CN107954966B (zh) | 一种Sc(III)催化合成2,3-二取代-4H-苯并吡喃的制备方法 | |
JPS6183163A (ja) | 抗腫瘍剤 | |
CN111303179B (zh) | 一类去甲斑蝥素羧酸二氟苄酯的合成及其抗肿瘤应用 | |
CN114191439B (zh) | A环并异噁唑环常春藤皂苷元c-23位含氮杂环衍生物的应用 | |
CN116217611B (zh) | 一种环丁酮衍生物及制备方法、用途 | |
CN109912510A (zh) | 一种替硝唑-香草酸药物共晶及其制备方法 | |
CN113563330B (zh) | 一类β-卡波林的3位衍生物及其制备方法和用途 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination |