CN113636984A - 一类含吗啉基团的1,3,4-噁二唑类化合物及其制备方法和用途 - Google Patents
一类含吗啉基团的1,3,4-噁二唑类化合物及其制备方法和用途 Download PDFInfo
- Publication number
- CN113636984A CN113636984A CN202110951977.1A CN202110951977A CN113636984A CN 113636984 A CN113636984 A CN 113636984A CN 202110951977 A CN202110951977 A CN 202110951977A CN 113636984 A CN113636984 A CN 113636984A
- Authority
- CN
- China
- Prior art keywords
- compound
- canker
- optionally substituted
- salt
- unsubstituted
- 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
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 title claims abstract description 21
- 238000002360 preparation method Methods 0.000 title abstract description 10
- 150000005072 1,3,4-oxadiazoles Chemical class 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 60
- 230000001580 bacterial effect Effects 0.000 claims abstract description 41
- -1 1,3, 4-oxadiazole compound Chemical class 0.000 claims abstract description 37
- 240000007594 Oryza sativa Species 0.000 claims abstract description 26
- 235000007164 Oryza sativa Nutrition 0.000 claims abstract description 26
- 235000009566 rice Nutrition 0.000 claims abstract description 26
- 244000052616 bacterial pathogen Species 0.000 claims abstract description 17
- 241000207199 Citrus Species 0.000 claims abstract description 14
- 235000020971 citrus fruits Nutrition 0.000 claims abstract description 14
- 235000002566 Capsicum Nutrition 0.000 claims abstract description 7
- 239000006002 Pepper Substances 0.000 claims abstract description 6
- 235000016761 Piper aduncum Nutrition 0.000 claims abstract description 6
- 235000017804 Piper guineense Nutrition 0.000 claims abstract description 6
- 235000008184 Piper nigrum Nutrition 0.000 claims abstract description 6
- 244000203593 Piper nigrum Species 0.000 claims abstract 3
- 150000003839 salts Chemical class 0.000 claims description 27
- 239000012453 solvate Substances 0.000 claims description 19
- 241000607479 Yersinia pestis Species 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 16
- 239000000203 mixture Substances 0.000 claims description 16
- 241000196324 Embryophyta Species 0.000 claims description 15
- 239000004495 emulsifiable concentrate Substances 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 11
- 201000010099 disease Diseases 0.000 claims description 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 11
- 125000003118 aryl group Chemical group 0.000 claims description 9
- 240000008067 Cucumis sativus Species 0.000 claims description 8
- 235000010799 Cucumis sativus var sativus Nutrition 0.000 claims description 8
- 241000223218 Fusarium Species 0.000 claims description 8
- 125000003342 alkenyl group Chemical group 0.000 claims description 8
- 125000001072 heteroaryl group Chemical group 0.000 claims description 8
- 241000209140 Triticum Species 0.000 claims description 7
- 235000021307 Triticum Nutrition 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 6
- UHPMCKVQTMMPCG-UHFFFAOYSA-N 5,8-dihydroxy-2-methoxy-6-methyl-7-(2-oxopropyl)naphthalene-1,4-dione Chemical compound CC1=C(CC(C)=O)C(O)=C2C(=O)C(OC)=CC(=O)C2=C1O UHPMCKVQTMMPCG-UHFFFAOYSA-N 0.000 claims description 5
- 208000035143 Bacterial infection Diseases 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
- 229910052717 sulfur Chemical group 0.000 claims description 5
- 235000009434 Actinidia chinensis Nutrition 0.000 claims description 4
- 244000298697 Actinidia deliciosa Species 0.000 claims description 4
- 235000009436 Actinidia deliciosa Nutrition 0.000 claims description 4
- 241000123650 Botrytis cinerea Species 0.000 claims description 4
- 229920002752 Konjac Polymers 0.000 claims description 4
- 235000007688 Lycopersicon esculentum Nutrition 0.000 claims description 4
- 208000031888 Mycoses Diseases 0.000 claims description 4
- 241000233622 Phytophthora infestans Species 0.000 claims description 4
- 241000221662 Sclerotinia Species 0.000 claims description 4
- 240000003768 Solanum lycopersicum Species 0.000 claims description 4
- 235000009754 Vitis X bourquina Nutrition 0.000 claims description 4
- 235000012333 Vitis X labruscana Nutrition 0.000 claims description 4
- 240000006365 Vitis vinifera Species 0.000 claims description 4
- 235000014787 Vitis vinifera Nutrition 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 239000000417 fungicide Substances 0.000 claims description 4
- 239000008187 granular material Substances 0.000 claims description 4
- 235000010485 konjac Nutrition 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 239000003094 microcapsule Substances 0.000 claims description 4
- 239000000843 powder Substances 0.000 claims description 4
- 125000004434 sulfur atom Chemical group 0.000 claims description 4
- 239000004546 suspension concentrate Substances 0.000 claims description 4
- 239000004562 water dispersible granule Substances 0.000 claims description 4
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 208000022362 bacterial infectious disease Diseases 0.000 claims description 3
- 230000000855 fungicidal effect Effects 0.000 claims description 3
- 239000002917 insecticide Substances 0.000 claims description 3
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 3
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 3
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 3
- 125000006276 2-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 2
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 2
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 2
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 2
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 2
- 244000247812 Amorphophallus rivieri Species 0.000 claims description 2
- 235000001206 Amorphophallus rivieri Nutrition 0.000 claims description 2
- 240000002791 Brassica napus Species 0.000 claims description 2
- 235000006008 Brassica napus var napus Nutrition 0.000 claims description 2
- 241000223195 Fusarium graminearum Species 0.000 claims description 2
- 244000061176 Nicotiana tabacum Species 0.000 claims description 2
- 235000002637 Nicotiana tabacum Nutrition 0.000 claims description 2
- 206010039509 Scab Diseases 0.000 claims description 2
- 239000002671 adjuvant Substances 0.000 claims description 2
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 claims description 2
- 239000000839 emulsion Substances 0.000 claims description 2
- 238000009472 formulation Methods 0.000 claims description 2
- 230000002363 herbicidal effect Effects 0.000 claims description 2
- 239000004009 herbicide Substances 0.000 claims description 2
- 125000002883 imidazolyl group Chemical group 0.000 claims description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 239000000252 konjac Substances 0.000 claims description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 125000001209 o-nitrophenyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])[N+]([O-])=O 0.000 claims description 2
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 claims description 2
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 claims description 2
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 230000000391 smoking effect Effects 0.000 claims description 2
- 239000007921 spray Substances 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims 3
- 229910052805 deuterium Inorganic materials 0.000 claims 3
- 229910052736 halogen Inorganic materials 0.000 claims 3
- 150000002367 halogens Chemical class 0.000 claims 3
- 150000002431 hydrogen Chemical class 0.000 claims 3
- 125000002541 furyl group Chemical group 0.000 claims 1
- 125000006038 hexenyl group Chemical group 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims 1
- 230000001473 noxious effect Effects 0.000 claims 1
- 125000002971 oxazolyl group Chemical group 0.000 claims 1
- 125000003226 pyrazolyl group Chemical group 0.000 claims 1
- 125000000168 pyrrolyl group Chemical group 0.000 claims 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims 1
- 239000000126 substance Substances 0.000 claims 1
- 125000000335 thiazolyl group Chemical group 0.000 claims 1
- 125000001544 thienyl group Chemical group 0.000 claims 1
- 229920002554 vinyl polymer Polymers 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 17
- 230000005764 inhibitory process Effects 0.000 abstract description 11
- 230000004071 biological effect Effects 0.000 abstract description 5
- 240000000851 Vaccinium corymbosum Species 0.000 abstract description 3
- 235000003095 Vaccinium corymbosum Nutrition 0.000 abstract description 3
- 235000017537 Vaccinium myrtillus Nutrition 0.000 abstract description 3
- 235000021014 blueberries Nutrition 0.000 abstract description 3
- FKASFBLJDCHBNZ-UHFFFAOYSA-N 1,3,4-oxadiazole Chemical group C1=NN=CO1 FKASFBLJDCHBNZ-UHFFFAOYSA-N 0.000 abstract description 2
- 244000053095 fungal pathogen Species 0.000 abstract 1
- 239000003814 drug Substances 0.000 description 19
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
- 239000007788 liquid Substances 0.000 description 14
- 239000002609 medium Substances 0.000 description 12
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 11
- 230000000844 anti-bacterial effect Effects 0.000 description 11
- 229940125797 compound 12 Drugs 0.000 description 11
- 229940079593 drug Drugs 0.000 description 11
- 239000000243 solution Substances 0.000 description 9
- 125000001424 substituent group Chemical group 0.000 description 9
- 239000000543 intermediate Substances 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- 241000894006 Bacteria Species 0.000 description 6
- 244000000005 bacterial plant pathogen Species 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- 230000003902 lesion Effects 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 241000233866 Fungi Species 0.000 description 5
- 241001272684 Xanthomonas campestris pv. oryzae Species 0.000 description 5
- 239000001963 growth medium Substances 0.000 description 5
- 125000005842 heteroatom Chemical group 0.000 description 5
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 5
- 238000011160 research Methods 0.000 description 5
- 230000001988 toxicity Effects 0.000 description 5
- 231100000419 toxicity Toxicity 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 241000191967 Staphylococcus aureus Species 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 239000000575 pesticide Substances 0.000 description 4
- 230000000144 pharmacologic effect Effects 0.000 description 4
- 230000001681 protective effect Effects 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- HVCNXQOWACZAFN-UHFFFAOYSA-N 4-ethylmorpholine Chemical compound CCN1CCOCC1 HVCNXQOWACZAFN-UHFFFAOYSA-N 0.000 description 3
- FOHWXVBZGSVUGO-UHFFFAOYSA-N 5-phenyl-3h-1,3,4-oxadiazole-2-thione Chemical compound O1C(S)=NN=C1C1=CC=CC=C1 FOHWXVBZGSVUGO-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 244000068988 Glycine max Species 0.000 description 3
- 235000010469 Glycine max Nutrition 0.000 description 3
- 231100000674 Phytotoxicity Toxicity 0.000 description 3
- 240000003889 Piper guineense Species 0.000 description 3
- 229920001213 Polysorbate 20 Polymers 0.000 description 3
- IKGXLCMLVINENI-QOXGANSBSA-M [Br-].COc1cc(Br)c(C[N+]2(CCOCC[C@@H]3CC[C@H]4C[C@@H]3C4(C)C)CCOCC2)cc1OC Chemical compound [Br-].COc1cc(Br)c(C[N+]2(CCOCC[C@@H]3CC[C@H]4C[C@@H]3C4(C)C)CCOCC2)cc1OC IKGXLCMLVINENI-QOXGANSBSA-M 0.000 description 3
- 125000002619 bicyclic group Chemical group 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 230000001276 controlling effect Effects 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 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 3
- 230000000749 insecticidal effect Effects 0.000 description 3
- 150000002780 morpholines Chemical class 0.000 description 3
- 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 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 230000001717 pathogenic effect Effects 0.000 description 3
- 229960002088 pinaverium bromide Drugs 0.000 description 3
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 3
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 3
- 230000002265 prevention Effects 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000005507 spraying Methods 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- DKEGCUDAFWNSSO-UHFFFAOYSA-N 1,8-dibromooctane Chemical compound BrCCCCCCCCBr DKEGCUDAFWNSSO-UHFFFAOYSA-N 0.000 description 2
- RSNWORHVUOZYLT-UHFFFAOYSA-N 5-[[(2-sulfanylidene-3h-1,3,4-thiadiazol-5-yl)amino]methylamino]-3h-1,3,4-thiadiazole-2-thione Chemical compound S1C(=S)NN=C1NCNC1=NNC(=S)S1 RSNWORHVUOZYLT-UHFFFAOYSA-N 0.000 description 2
- 241001124076 Aphididae Species 0.000 description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 2
- 239000005794 Hymexazol Substances 0.000 description 2
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 206010052428 Wound Diseases 0.000 description 2
- 208000027418 Wounds and injury Diseases 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 239000003899 bactericide agent Substances 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 238000004364 calculation method Methods 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 229910052802 copper Inorganic materials 0.000 description 2
- 239000010949 copper Substances 0.000 description 2
- 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 2
- 238000011161 development Methods 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 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 2
- 125000001183 hydrocarbyl group Chemical group 0.000 description 2
- KGVPNLBXJKTABS-UHFFFAOYSA-N hymexazol Chemical compound CC1=CC(O)=NO1 KGVPNLBXJKTABS-UHFFFAOYSA-N 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- 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 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- 244000052769 pathogen Species 0.000 description 2
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 230000003032 phytopathogenic effect Effects 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000004382 potting Methods 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 238000010008 shearing Methods 0.000 description 2
- 238000002791 soaking Methods 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 125000006168 tricyclic group Chemical group 0.000 description 2
- WCXDHFDTOYPNIE-RIYZIHGNSA-N (E)-acetamiprid Chemical compound N#C/N=C(\C)N(C)CC1=CC=C(Cl)N=C1 WCXDHFDTOYPNIE-RIYZIHGNSA-N 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- 125000006040 2-hexenyl group Chemical group 0.000 description 1
- 125000006022 2-methyl-2-propenyl group Chemical group 0.000 description 1
- 125000006024 2-pentenyl group Chemical group 0.000 description 1
- 125000006512 3,4-dichlorobenzyl group Chemical group [H]C1=C(Cl)C(Cl)=C([H])C(=C1[H])C([H])([H])* 0.000 description 1
- 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 description 1
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 1
- 125000006041 3-hexenyl group Chemical group 0.000 description 1
- 125000006042 4-hexenyl group Chemical group 0.000 description 1
- 125000003119 4-methyl-3-pentenyl group Chemical group [H]\C(=C(/C([H])([H])[H])C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000006043 5-hexenyl group Chemical group 0.000 description 1
- HRJRKWIXCKJRIM-UHFFFAOYSA-N 8-bromooctane-1-thiol Chemical compound SCCCCCCCCBr HRJRKWIXCKJRIM-UHFFFAOYSA-N 0.000 description 1
- 239000005875 Acetamiprid Substances 0.000 description 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 1
- 241000952611 Aphis craccivora Species 0.000 description 1
- 241000235349 Ascomycota Species 0.000 description 1
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 1
- 240000008574 Capsicum frutescens Species 0.000 description 1
- KIWBPDUYBMNFTB-UHFFFAOYSA-N Ethyl hydrogen sulfate Chemical compound CCOS(O)(=O)=O KIWBPDUYBMNFTB-UHFFFAOYSA-N 0.000 description 1
- 241000223221 Fusarium oxysporum Species 0.000 description 1
- 241000427940 Fusarium solani Species 0.000 description 1
- 241000258937 Hemiptera Species 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 1
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- 241000233629 Phytophthora parasitica Species 0.000 description 1
- 241000235545 Rhizopus niveus Species 0.000 description 1
- 241000589634 Xanthomonas Species 0.000 description 1
- 241000589655 Xanthomonas citri Species 0.000 description 1
- 241000589652 Xanthomonas oryzae Species 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 238000012271 agricultural production Methods 0.000 description 1
- 125000004450 alkenylene group Chemical group 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 230000003385 bacteriostatic effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- HOZOZZFCZRXYEK-GSWUYBTGSA-M butylscopolamine bromide Chemical compound [Br-].C1([C@@H](CO)C(=O)O[C@H]2C[C@@H]3[N+]([C@H](C2)[C@@H]2[C@H]3O2)(C)CCCC)=CC=CC=C1 HOZOZZFCZRXYEK-GSWUYBTGSA-M 0.000 description 1
- 239000001390 capsicum minimum Substances 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 125000003636 chemical group Chemical group 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 125000004803 chlorobenzyl group Chemical group 0.000 description 1
- 238000002052 colonoscopy Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 125000006286 dichlorobenzyl group Chemical group 0.000 description 1
- 238000003113 dilution method Methods 0.000 description 1
- 235000021186 dishes Nutrition 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 229940096118 ella Drugs 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 244000000004 fungal plant pathogen Species 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000005462 in vivo assay Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000012212 insulator Substances 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene chloride Substances ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 1
- 229960003085 meticillin Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- BVJOXYJFOYNQRB-UHFFFAOYSA-N morpholine;hydrobromide Chemical compound Br.C1COCCN1 BVJOXYJFOYNQRB-UHFFFAOYSA-N 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 230000008635 plant growth Effects 0.000 description 1
- 244000000003 plant pathogen Species 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- GWKKVWOEQGDUSY-UHFFFAOYSA-N pyridine;sodium Chemical class [Na].C1=CC=NC=C1 GWKKVWOEQGDUSY-UHFFFAOYSA-N 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical class C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 229950009846 scopolamine butylbromide Drugs 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- SRVJKTDHMYAMHA-WUXMJOGZSA-N thioacetazone Chemical compound CC(=O)NC1=CC=C(\C=N\NC(N)=S)C=C1 SRVJKTDHMYAMHA-WUXMJOGZSA-N 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 231100000820 toxicity test Toxicity 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 230000002087 whitening effect Effects 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
- C07D271/113—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
- A01N43/82—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with three ring hetero atoms
-
- 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
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Dentistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Plant Pathology (AREA)
- General Health & Medical Sciences (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- Environmental Sciences (AREA)
- Pest Control & Pesticides (AREA)
- Agronomy & Crop Science (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本申请涉及一类含吗啉基团的1,3,4‑噁二唑类化合物及其制备方法和用途。该化合物具有如通式(I)所示的结构:
Description
技术领域
本申请涉及药物化学技术领域,尤其是一种含吗啉基团的1,3,4-噁二唑类化合物及其制备方法与应用。
背景技术
植物病原体是一组侵袭性微生物并且在世界范围内广泛分布,可以侵入各种植物进行营养竞争并自我繁殖,并且导致重要作物发生严重疾病,严重威胁农产品的质量和产量。例如,小麦赤霉病菌(Gibberella saubinetii)是丝状的子囊菌,是由多种镰刀菌侵染所引起的、发生在小麦上的病害。该病菌能引起小麦苗腐、茎基腐、秆腐和穗腐,它每年给小麦种植的国家带来至少10-20%的减产。此外,水稻白叶枯病菌(Xanthomonasoryzaepv.Oryzae)是杆状的革兰氏阴性菌,该病菌能使水稻的叶片枯萎、变白,它每年给水稻种植的国家带来至少10-50%的减产。柑橘溃疡病菌(Xanthomonas axonopodispv.Citri)会导致柑橘腐烂,在全球范围内影响着柑橘的产量。目前,在农业生产过程中,由于传统杀菌剂的长期滥用,使得植物病原菌对其产生了一定的抗性。因此,创制新型高效、低毒、安全的绿色农药具有十分重要的意义。
季铵盐类化合物类因为具有多种生物活性,特别是在抗细菌和真菌方面优异的杀菌活性,在杀菌剂的研发中得到了研究者的特别关注。作为季铵盐家族的一员的吗啉盐据文献报道,其衍生物展示出了广谱生物活性,比如;抗菌、杀虫、及调节植物生长、抗肿瘤、抗炎等。在我们之前的工作中,我们开发并评估了一系列吡啶鎓定制化合物的抗菌功能,发现它们具有优异的抗菌活性,但对水稻叶片具有较高的植物毒性。
为开发出一种安全的可应用于农业防治植物细菌病害的安全季铵化合物,本文采用吗啉支架取代平面结构的吡啶基,制备了一种含1,3,4-噁二唑基团类化合物,测试其生物活性,为新农药的研发和创制提供重要的科学基础。
吗啉类化合物的生物活性研究进展如下:
2017年Wang等[Wang,X.L.;Zhou,J.N.;Li,R.;Pan,X.L.;Ren,H.Y.;Jun,L.Improvement of Quality of Nonanesthetic Colonoscopy by Preoperative Administration of Pinaverium Bromide[J].Chinese Medical Journal,2017,130:631-635]探讨结肠镜检查前预防性给予吗啉盐类医用药物匹维溴铵的效果以及单独使用匹维溴铵在不同时间点或与东莨菪碱丁基溴联用的效果。
2014年Bakhite等[Bakhite,E.A.;Abd-Ella,A.A.;El-Sayed,M.E.A.;Abdel-Raheem,S.A.A.Pyridine Derivatives as Insecticides.Part 1:Synthesis andToxicity of Some Pyridine Derivatives Against Cowpea Aphid,Aphis craccivoraKoch(Homoptera:Aphididae)[J].J.Agric.Food Chem,2014,62,9982-9986]测定了一系列化合物的杀虫活性,生物测定结果表明,含有吗啉盐结构的化合物1的杀虫活性是啶虫脒杀虫剂的4倍左右。
2016年Yang等[Yang,S.C.;Aljuffali,I.;Sung,C.T.;Lin,C.F.;Fang,J.Y.Antimicrobial activity of topically-applied soyaethyl morpholiniumethosulfate micelles against Staphylococcus species[J].Nanomedicine,2016,11(6):657-671]评估了大豆乙基吗啉对金黄色葡萄球菌和耐甲氧西林金黄色葡萄球菌(MRSA)的抗菌功效乙基硫酸盐(SME)。结果表明大豆乙基吗啉对金黄色葡萄球菌和MRSA的最低抑菌浓度和最低杀菌浓度分别为1.71-3.42和1.71-6.84微克/毫升,同时其具有对哺乳动物细胞毒性低。
发明内容
本申请的目的之一提供了一种含吗啉基团的1,3,4-噁二唑类化合物或其立体异构体、或其盐或其溶剂化物。
本申请的另一目的是提供了制备上述化合物或其立体异构体、或其盐或其溶剂化物的中间体化合物及其制备方法。
本申请还有一目的是提供了一种含有上述化合物或其立体异构体、或其盐或其溶剂化物的组合物。
本申请还有一目的是提供了上述化合物或其立体异构体、或其盐或其溶剂化物,或所述组合物的用途。
本申请另一目的是提供了利用上述化合物或其立体异构体、或其盐或其溶剂化物,或所述组合物防治农业病虫害的方法。
为实现上述目的,本申请采用了下述技术方案:
一种含吗啉基团的1,3,4-噁二唑类化合物或其立体异构体、或其盐或其溶剂化物,该化合物具有如通式(I)所示的结构:
R独立的选自氢、任意取代或未取代的烷基、氨基、任意取代或未取代的烯基、任意取代或未取代的烷氧基、任意取代或未取代的环烷基、任意取代或未取代的芳基、任意取代或未取代的杂芳基中的一个或多个、任意取代或未取代的苄基、任意取代或未取代的α-甲基-苄基、任意取代或未取代的苯磺酰基;X为氧原子或硫原子;n1为0,1,2或3;n2为大于1的自然数,优选地,n为1~20,更优选地,n为2~18,更优选地,n为2~15。
优选地,R选自氢、甲基、乙基、己基、苯基、邻氟苯基、间氟苯基、对氟苯基、邻氯苯基、间氯苯基、对氯苯基、邻溴苯基、间溴苯基、对溴苯基、邻甲基苯基、间甲基苯基、对甲基苯基、邻硝基苯基、间硝基苯基、对硝基苯基;
最优选地,所述的含吗啉基团的1,3,4-噁二唑类化合物选自下述化合物:
本申请还提供了一种中间体化合物:
本申请还提供了所述的含吗啉基团的1,3,4-噁二唑类化合物的制备方法,包括下述步骤:
优选地,进一步包括下述步骤:
最优选地,进一步包括下述步骤:
其中,R选自氢、任意取代或未取代的烷基、氨基、任意取代或未取代的烯基、任意取代或未取代的烷氧基、任意取代或未取代的环烷基、任意取代或未取代的芳基、任意取代或未取代的杂芳基中的一个或多个、任意取代或未取代的苄基、任意取代或未取代的α-甲基-苄基、任意取代或未取代的苯磺酰基;X为氧原子或硫原子;n1为0,1,2或3;n为大于1的自然数。
本申请还提供了一种组合物,其含有所述的化合物或其立体异构体、或其盐或其溶剂化物,以及农业上可用的助剂或杀菌剂、杀虫剂或除草剂;优选地,所述组合物的剂型选自乳油(EC)、粉剂(DP)、可湿性粉剂(WP)、颗粒剂(GR)、水剂(AS)、悬浮剂(SC)、超低容量喷雾剂(ULV)、可溶性粉剂(SP)、微胶囊剂(MC)、烟剂(FU)、水乳剂(EW)、水分散性粒剂(WG)。
所述的化合物或其立体异构体、或其盐或其溶剂化物,或所述的组合物可用于防治农业病虫害,优选地,所述农业病虫害为植物细菌性或真菌性病害;更优选地,所述农业病虫害为植物叶枯病和植物溃疡病;最优选地,所述农业病虫害为水稻白叶枯病、黄瓜白叶枯病、魔芋白叶枯病、柑橘溃疡病、葡萄溃疡病、番茄溃疡病、猕猴桃溃疡病、苹果溃疡病、黄瓜灰霉病菌、辣椒枯萎病原菌、油菜菌核病菌、小麦赤霉病菌、马铃薯晚疫病菌。
本申请还提供了一种防治农业病虫害的方法,使所述的化合物或其立体异构体、或其盐或其溶剂化物,或所述的组合物作用于有害物或其生活环境;优选地,所述农业病虫害为植物细菌性或真菌性病害;更优选地,所述农业病虫害为水稻白叶枯病、烟草青枯病菌、黄瓜白叶枯病、魔芋白叶枯病、柑橘溃疡病、葡萄溃疡病、番茄溃疡病、猕猴桃溃疡病、苹果溃疡病、黄瓜灰霉病菌、辣椒枯萎病原菌、油菜菌核病菌、小麦赤霉病菌、马铃薯晚疫病菌。
本申请还提供了一种用于保护植物免受农业病虫害侵害的方法,其包括其中使植物与所述的化合物或其立体异构体、或其盐或其溶剂化物,或所述的组合物接触的方法步骤。
此处用到的术语“烷基”是包括具有特定数目碳原子的支链和直链饱和烃基。例如“C1-10烷基”(或亚烷基)目的是C1、C2、C3、C4、C5、C6、C7、C8、C9和C10烷基。另外,例如“C1-6烷基”表示具有1到6个碳原子的烷基。烷基可为非取代或取代的,以使一个或多个其氢原子被其它化学基团取代。烷基的实施例包括但不限于甲基(Me)、乙基(Et)、丙基(如正丙基和异丙基)、丁基(如正丁基、异丁基、叔丁基)、戊基(如正戊基、异戊基、新戊基)及其类似物。
“烯基”是既包括直链或支链结构的烃,且具有一个或多个出现在链中任何稳定点的碳-碳双键。例如“C2-6烯基”(或亚烯基)目的是包括C2、C3、C4、C5和C6烯基。烯基的实例包括但不限于乙烯基、1-丙烯基,2-丙烯基、2-丁烯基、3-丁烯基、2-戊烯基、3-戊烯基、4-戊烯基、2-己烯基、3-己烯基、4-己烯基、5-己烯基、2-甲基-2-丙烯基、4-甲基-3-戊烯基及其类似物。
此处用到的术语“取代的”指的是在指定原子或基团上的任意一个或多个氢原子以选择的指定基团取代,前提是不超过指定原子的一般化合价。如果没有其它说明,取代基命名至中心结构。例如,可以理解的是当(环烷基)烷基是可能的取代基,该取代基至中心结构的连接点是在烷基部分中。此处使用的环双键是形成于两个临近环原子之间的双键(如C=C、C=N或N=N)。当提到取代时,特别是多取代时,指的是多个取代基在指定基团上的各个位置上取代,如二氯苄基指的是2,3-二氯苄基、2,4-二氯苄基、2,5-二氯苄基、2,6-二氯苄基、3,4-二氯苄基和3,5-二氯苄基。
取代基和变量的组合是允许的,仅当这些组合产生稳定的化合物或有用的合成中间体。稳定的化合物或稳定结构暗示所述化合物以有用的纯度从反应混合物分离出来时是足够稳定的,随之配制形成有效的治疗试剂。
术语“杂芳基”指的是取代和非取代芳香5或6元单环基团,9-或10-元双环基团,和11到14元三环基团,在至少一个环中具有至少一个杂原子(O,S或N),所述含杂原子的环优选具有1、2或3个选自O、S和N中的杂原子。含杂原子的杂芳基的每个环可含一个或两个氧或硫原子和/或由1到4个氮原子,前提是每个环中杂原子的总数是4或更少,且每个环具有至少一个碳原子。完成双环和三环基团的稠合环可仅含有碳原子,并可以是饱和、部分饱和或不饱和。氮可任选被氧化及被季铵化。双环或三环的杂芳基必须包括至少一个全芳香环,氮其它稠合环可为芳香性或非芳香性的。杂芳基可在任何环的任何可利用氮或碳原子上连接。
如果没有其它说明,本申请的化合物理解为包括游离态和其盐。术语“盐”表示以无机和/或有机酸和碱形成酸式和/或碱式盐。另外,术语“盐可包括两性离子(内盐),如当式I化合物含有碱性片段如胺或吡啶或咪唑环,和酸式片段如羧酸。药物上可接受的(即非毒性、生理学上可接受的)盐是优选的,如可接受的金属和胺盐,其中阳离子没有显著贡献毒性或盐的生物活性。然而,其它盐可是有用的,如在制备过程中采用分离或纯化步骤,因此也包含于本申请范围中。
优选地,C1-C10烷基指的是甲基、乙基、丙基、丁基、戊基、己基、庚基、辛基、壬基、癸基及其同分异构体;C2-C5烯基指的是乙烯基、丙烯基、烯丙基、丁烯基、戊烯基及其同分异构体。
当提到取代基为烯基、烷基、芳基、苄基、环烷基时,或这些取代基具体的为某个具体的烯基、烷基、芳基、苄基、环烷基时,指的是一个到三个上述取代基。如氯苄基指的是一个到三个氯取代的苄基。
通过采用上述技术方案,本申请以5-苯基-1,3,4-噁二唑-2-硫醇为起始原料,合成一系列含吗啉基团的1,3,4-噁二唑类化合物,且发现该化合物对致病植物病原细菌具有良好的抑制作用,针对病原细菌[如水稻白叶枯病菌(Xanthomonas oryzae pv.oryzae,Xoo)、柑橘溃疡病菌(Xanthomonas axonopodis pv.citri,Xac)均具有良好的抑制效果,为新农药的研发和创制提供重要的科学基础。
附图说明
图1为与不同浓度的化合物12孵育后的植物毒性图片(处理7天):(a)0μg/mL,(b)200μg/mL。
实施例
下面通过实施例对本申请作进一步说明。应该理解的是,本申请实施例所述方法仅仅是用于说明本申请,而不是对本申请的限制,在本申请的构思前提下对本申请制备方法的简单改进都属于本申请要求保护的范围。实施例中用到的所有原料和溶剂均为市售相应纯度产品。
实施例1:中间体2-((8-溴辛基)硫醇)-5-苯基-1,3,4-噁二唑的制备
将5-苯基-1,3,4-噁二唑-2-硫醇(1mmol),K2CO3(1.3mmol)及8mL DMF加入到25mL圆底烧瓶中,然后加入1,8-二溴辛烷(1.3mmol)常温搅拌2小时后结束反应。脱溶,柱层析(洗脱剂石油醚『乙酸乙酯=10『1,V/V)得中间体。同时,其它链长的中间体,除将1,8-二溴辛烷换成不同链长之外,其余中间体实验步骤及投料比例与实施例1一致。
实施例2:4-甲基-4-(8-((5-苯基-2-1,3,4-噁二唑基)硫醇)辛基)吗啉-4-鎓溴化物
将2-((8-溴辛基)硫醇)-5-苯基-1,3,4-噁二唑(0.4mmol)和4-甲基吗啉(4.55mmol)溶于4mL CH3CN中并投入到15mL反应瓶中,在85℃下回流8h。TLC追踪反应完成。加入水(3×20mL)和乙酸乙酯(50mL)进行萃取。有机相经无水Na2SO4干燥,抽滤,减压浓缩。粗残余物通过硅胶柱色谱法进一步纯化,使用CH2Cl2和CH3OH(20∶1,v/V)作为洗脱剂,得淡黄色固体,收率63.2%,其余实验步骤及投料比例与实施例2一致。
其余的含吗啉基团的1,3,4-噁二唑类化合物,采用相应的原料或取代基,参照实施例1和2的步骤合成。
表1 化合物的核磁其振氢谱和碳谱数据
表2 化合物的理化性质
药理实施例1:
EC50(median effective concentration)是评价植物病原菌对化合物敏感性的重要指标,同时也是对目标化合物作用机制研究时,化合物浓度设置的重要参数。在浓度梯度实验中,采用二倍稀释法设定合适的5个浓度,最后将药剂对植物病原菌的抑制率、药剂浓度换算成对数值,通过SPSS软件回归分析得到毒力曲线,计算出EC50。
采用浊度法测试目标化合物对植物病原菌的有效中浓度EC50,试验对象为水稻白叶枯病菌(Xoo)、柑橘溃疡病菌(Xac)。DMSO溶解在培养基中作为空白对照。将水稻白叶枯病菌(水稻白叶枯病原菌在M210固体培养基)放到NB培养基中,在28℃、180rpm恒温摇床中振荡培养到对数生长期备用;将柑橘溃疡病菌(在M210固体培养基上)放到NB培养基中,在28℃、180rpm恒温摇床中振荡培养到对数生长期备用。将药剂(化合物)配置成不同浓度(例:100,50,25,12.5,6.25μg/mL)的含毒NB液体培养基5mL加入到试管中,分别加入40μL含有植病细菌的NB液体培养基,在28℃、180rpm恒温摇床中振荡,其水稻白叶枯病原菌培养36h,柑橘溃疡病菌培养48h。将各个浓度的菌液在分光光度计上测定OD595值,并且另外测定对应浓度的含毒无菌NB液体培养基的OD595值。
校正OD值=含菌培养基OD值-无菌培养基OD值
抑制率%=[(校正后对照培养基菌液OD值-校正含毒培养基OD值)/校正后对照培养基菌液OD值]×100
本申请实施例辅以说明本申请的技术方案,但实施例的内容并不局限于此,目标化合物实验结果如表3所示。
表3 化合物对植物病原细菌的EC50
从表3中可以看出,在离体试验中,目标化合物对植物致病病原菌(如水稻白叶枯病菌、柑橘溃疡病菌)表现出了良好的抑制活性。从结构与活性的角度分析,可以看出所有化合物的抑菌活性都会随着碳链的延长而明显提升。比如结构中含有10或者12个碳链的所有化合物对水稻白叶枯病菌、柑橘溃疡病菌的EC50都在10以内,并且编号为3、6、8、9、12、15、18这7个化合物对水稻白叶枯病菌具有极为优异的活性,EC50分别为1.70、1.69、1.90、1.80、2.8、1.40和1.78μg/mL;编号为3、6、9、12、15、18这6个化合物对柑橘溃疡病菌表现出了极为显著的活性,EC50分别为1.61、2.89、1.61、0.90、1.45和1.69μg/mL。同时,大部分化合物与对照药(叶枯唑、噻菌铜)相比,都具有极好的抗菌活性,抗水稻百叶枯菌的最小EC50为1.40μg/mL,与对照药噻菌铜相比,活性提升了48倍;抗柑橘溃疡病菌的最小EC50为0.90μg/mL,与对照药叶枯唑相比,活性提升了105倍。由此,可知此类化合物极具研究前景,可用于制备抗植物致病病原细菌农药。
药理实施例2:
基于化合物12对水稻白叶枯病菌显示出最好的活性(EC50为1.40μg/mL),进行了化合物12对水稻白叶枯病的毒性盆栽实验。具体实验步骤如下:
将化合物12用小于1%的Tween20溶液配成200μg/mL的含药溶液;将配置好的药液分别喷在已经生长4周的水稻叶片表面,直到有液滴滴下为止;设不加药剂的等量DMSO对照,每个处理均有三个重复,7天后检查毒性情况。
本申请实施例辅以说明本申请的技术方案,但实施例的内容并不局限于此,目标化合物实验结果如附图1所示。
从图1中可以看出,在毒性测试试验中,浓度为200μg/mL的化合物12对水稻叶片的毒性基本与空白对照组一致,表现出基本无毒,表明含吗啉基团的1,3,4-噁二唑类化合物具有较好的生物友好性,降低了高活性盐类化合物的植物毒性,具有一定的研究前景。
药理实施例3:
基于化合物12对水稻白叶枯病菌显示出最好的活性(EC50为1.40μg/mL),进行了化合物12对水稻白叶枯病的活体盆栽实验。具体实验步骤如下:
保护活性:将化合物12,对照药噻菌酮(20%含量制剂)用小于1%的Tween20溶液配成200μg/mL的含药溶液,再多配制两份浓度为200μg/mL的化合物12溶液;将配置好的药液分别喷在已经生长8周的水稻叶片表面,直到有液滴滴下为止;24h后,在叶片距离叶尖2cm处用沾有OD595=0.6-0.8范围内的水稻白叶枯病菌的剪刀把叶尖剪掉,并将伤口在菌液中侵泡10s左右,设不加药剂的等量DMSO及菌叶对照,每个处理均有三个重复,14天后检查发病情况,记录水稻叶片的病斑长度及总长度,并计算其病情指数和防效。
首先测量每片叶子的斑点面积和整个叶子面积,然后测量整个斑点面积的百分比计算叶面积。其次,按照以下等级标准对这些叶子进行分类:1级,病斑面积不到整个叶子面积的5%。3级,病斑面积占全叶面积的6-10%;5级,病斑面积5占全叶面积的11-20%;7级,病斑面积占全叶面积的21-50%;9级,病斑面积占整个叶片面积的50%以上;病情指数的计算方法如下:
病情指数=∑(每个等级的叶片数×相应等级)/(叶片总数×最高级)
防效计算方法如下:
防效%=(对照组病情指数-处理组病情指数)/对照组病情指数×100%
治疗活性:在叶片距离叶尖2cm处用沾有OD595=0.6-0.8范围内的水稻白叶枯病菌的剪刀把叶尖剪掉,并将伤口在菌液中侵泡10s左右;24h后,将配好的上述药液以及添加助剂的药液分别喷在已经生长8周的水稻叶片表面,直到有液滴滴下为止,设不加药剂的等量DMSO及菌叶对照,每个处理均有三个重复,14天后检查发病情况,记录水稻叶片的病斑长度及总长度,并计算其病情指数和防效,计算方法同上。
本申请实施例辅以说明本申请的技术方案,但实施例的内容并不局限于此,目标化合物实验结果如表4所示。
表4 化合物12对水稻白叶枯病菌的保护和治疗活性
从表4中可以看出,在活体试验中,化合物12对水稻白叶枯病菌表现出了良好的治疗活性(55.95%)和保护活性(53.09%)。优于对照药噻菌酮(治疗活性37.53%;保护活性36.68%)。由此,可知此类化合物极具研究前景。
药理实施例4:
采用菌丝体生长速率抑制法在PDA培养基上测定了化合物对辣椒枯萎病菌(Fusarium oxysporum,F.o.),蓝莓根腐病菌(Phytophthora cinnamomi,P.c.)等植物病原真菌的抗菌活性,菌种均提前活化。用万分之一天平称取待测化合物加入1mL DMSO溶解后在无菌操作台中转移至15m L灭菌的离心管中,加入9mL吐温水(Tween-20)定溶10mL,倒入培养基中,混匀后平均分装至9个培养皿中冷却备用;在无菌操作台内,以灭菌的打孔器(5mm)将生长正常的菌落制成菌饼,用接菌环将菌饼倒扣于培养基中央,于28℃条件下培养3~5天,待对照菌落生长至整个平板直径的2/3时用直尺按十字交叉法测量2次,以平均值计算菌落直径大小。初期我们选择25μg/m L为初筛浓度,化合物在此浓度下对相应的病菌抑制率大于50%时再对其进行EC50测试,根据下列公式求出菌丝生长抑制率。将噁霉灵作为对照药剂一起参与测试。
计算公式如下:
抑制率(%)=(C1-C2)/(C1-0.4)×100公式中:
C1——对照菌落直径即DMSO处理的菌落直径;
C2——处理菌落直径即加药处理的菌落直径;
0.5——为母菌菌饼的直径。
本申请实施例辅以说明本申请的技术方案,但实施例的内容并不局限于此,部分目标化合物实验结果如表5所示。
表5 化合物对植物病原真菌的抑制率(25μg/mL)
从表5中可以看出,在离体试验中,部分目标化合物在25.0μg/mL时对植物致病病原菌(如辣椒枯萎病菌、蓝莓根腐病菌)表现出了良好的抑制活性。其中,化合物2、3、6、8、9、15对辣椒枯萎病菌的抑制率为43.45-59.52%,优于对照药噁霉灵(39.22%)。对于蓝莓根腐病菌来说,
化合物5和6的抑制作用分别为50.16%和44.98%。这一结果表明,本申请化合物也可以作为未来新型杀菌剂设计的抗真菌先导物。
Claims (10)
2.根据权利要求1所述的含吗啉基团的1,3,4-噁二唑类化合物或其立体异构体、或其盐或其溶剂化物,其特征在于:R各自独立的选自氢、氘、氨基、卤素、硝基、苄基、α-甲基-苄基、C1-10烷基、C2-8烯基、C1-10烷氧基、C3-10环烷基、C6-8芳基、C5-6杂芳基中的一个或多个;n为2~18。
3.根据权利要求1所述的含吗啉基团的1,3,4-噁二唑类化合物或其立体异构体、或其盐或其溶剂化物,其特征在于:R各自独立的选自氢、氘、氨基、卤素、硝基、苄基、α-甲基-苄基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基、乙烯基、丙烯基、烯丙基、丁烯基、戊烯基、己烯基、甲氧基、乙氧基、丙氧基、丁氧基、苯基、呋喃基、噻吩基、吡咯基、吡唑基、咪唑基、噁唑基、噻唑基、吡啶基、邻氟苯基、间氟苯基、对氟苯基、邻氯苯基、间氯苯基、对氯苯基、邻溴苯基、间溴苯基、对溴苯基、邻甲基苯基、间甲基苯基、对甲基苯基、邻硝基苯基、间硝基苯基、对硝基苯基中的一个或多个;n为2、3、4、5、6、7、8、9、10、11、12、13、14、15。
7.一种组合物,其特征在于含有权利要求1-4任一所述的化合物或其立体异构体、或其盐或其溶剂化物,以及农业上可用的助剂或杀菌剂、杀虫剂或除草剂;优选地,所述组合物的剂型选自乳油(EC)、粉剂(DP)、可湿性粉剂(WP)、颗粒剂(GR)、水剂(AS)、悬浮剂(SC)、超低容量喷雾剂(ULV)、可溶性粉剂(SP)、微胶囊剂(MC)、烟剂(FU)、水乳剂(EW)、水分散性粒剂(WG)。
8.权利要求1-3任一所述的化合物或其立体异构体、或其盐或其溶剂化物,或权利要求7所述的组合物在防治农业病虫害方面的用途,优选地,所述农业病虫害为植物细菌性或真菌性病害;更优选地,所述农业病虫害为植物叶枯病和植物溃疡病;最优选地,所述农业病虫害为水稻白叶枯病、黄瓜白叶枯病、魔芋白叶枯病、柑橘溃疡病、猕猴桃溃疡病、葡萄溃疡病、番茄溃疡病、苹果溃疡病、黄瓜灰霉病菌、辣椒枯萎病原菌、油菜菌核病菌、小麦赤霉病菌、马铃薯晚疫病菌。
9.一种防治农业病虫害的方法,其特征在于:使权利要求1-4任一所述的化合物或其立体异构体、或其盐或其溶剂化物,或权利要求7所述的组合物作用于有害物或其生活环境;优选地,所述农业病虫害为植物细菌性或真菌性病害;更优选地,所述农业病虫害为水稻白叶枯病、烟草青枯病菌、黄瓜白叶枯病、魔芋白叶枯病、柑橘溃疡病、猕猴桃溃疡病、葡萄溃疡病、番茄溃疡病、苹果溃疡病、黄瓜灰霉病菌、辣椒枯萎病原菌、油菜菌核病菌、小麦赤霉病菌、马铃薯晚疫病菌。
10.用于保护植物免受农业病虫害侵害的方法,其包括其中使植物与权利要求1-4任一所述的化合物或其立体异构体、或其盐或其溶剂化物,或权利要求7所述的组合物接触的方法步骤。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202110951977.1A CN113636984B (zh) | 2021-08-18 | 2021-08-18 | 一类含吗啉基团的1,3,4-噁二唑类化合物及其制备方法和用途 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202110951977.1A CN113636984B (zh) | 2021-08-18 | 2021-08-18 | 一类含吗啉基团的1,3,4-噁二唑类化合物及其制备方法和用途 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN113636984A true CN113636984A (zh) | 2021-11-12 |
CN113636984B CN113636984B (zh) | 2023-11-17 |
Family
ID=78422841
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202110951977.1A Active CN113636984B (zh) | 2021-08-18 | 2021-08-18 | 一类含吗啉基团的1,3,4-噁二唑类化合物及其制备方法和用途 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN113636984B (zh) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113999222A (zh) * | 2021-11-19 | 2022-02-01 | 贵州大学 | 一类含金刚烷基噁二唑类化合物及其制备方法和应用 |
CN114773328A (zh) * | 2022-05-31 | 2022-07-22 | 贵州大学 | 含噁二唑硫醚和砜类化合物、其立体异构体、其盐或其溶剂化物,制备方法,组合物及用途 |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4217365A (en) * | 1977-03-11 | 1980-08-12 | Edmund Bakuniak | Fungicidal quaternary ammonium composition |
US4328226A (en) * | 1977-11-16 | 1982-05-04 | Instytut Przemyslu Organicznego & Politechnika Wroclawska | Quaternary benzylmorpholine salts having formyl or nitrile substituents in a ring and fungicidal compositions |
WO2007012724A1 (fr) * | 2005-07-27 | 2007-02-01 | Cytomics Systems | Derives de 1 , 2 , 4-thiadiazole utiles comme antifongiques , compositions contenant ces composes et leurs utilisations |
CN105541822A (zh) * | 2016-01-05 | 2016-05-04 | 贵州大学 | 含1,3,4-噁(噻)二唑基的吡啶盐类化合物及其制备方法及应用 |
CN107089975A (zh) * | 2017-05-03 | 2017-08-25 | 贵州大学 | 含1,3,4‑噁二唑基的噻唑盐类化合物及其制备方法及应用 |
CN109535145A (zh) * | 2019-01-11 | 2019-03-29 | 贵州大学 | 一种1,3,4-噁(噻)二唑基的咪唑类化合物及其制备方法和用途 |
-
2021
- 2021-08-18 CN CN202110951977.1A patent/CN113636984B/zh active Active
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4217365A (en) * | 1977-03-11 | 1980-08-12 | Edmund Bakuniak | Fungicidal quaternary ammonium composition |
US4328226A (en) * | 1977-11-16 | 1982-05-04 | Instytut Przemyslu Organicznego & Politechnika Wroclawska | Quaternary benzylmorpholine salts having formyl or nitrile substituents in a ring and fungicidal compositions |
WO2007012724A1 (fr) * | 2005-07-27 | 2007-02-01 | Cytomics Systems | Derives de 1 , 2 , 4-thiadiazole utiles comme antifongiques , compositions contenant ces composes et leurs utilisations |
CN105541822A (zh) * | 2016-01-05 | 2016-05-04 | 贵州大学 | 含1,3,4-噁(噻)二唑基的吡啶盐类化合物及其制备方法及应用 |
CN107089975A (zh) * | 2017-05-03 | 2017-08-25 | 贵州大学 | 含1,3,4‑噁二唑基的噻唑盐类化合物及其制备方法及应用 |
CN109535145A (zh) * | 2019-01-11 | 2019-03-29 | 贵州大学 | 一种1,3,4-噁(噻)二唑基的咪唑类化合物及其制备方法和用途 |
Non-Patent Citations (4)
Title |
---|
ETIFY A. BAKHITE 等: "Pyridine Derivatives as Insecticides. Part 1: Synthesis and Toxicity of Some Pyridine Derivatives Against Cowpea Aphid, Aphis craccivora Koch (Homoptera: Aphididae)", 《J. AGRIC. FOOD CHEM.》, vol. 62, pages 9982 * |
SHIH-CHUN YANG 等: "Antimicrobial activity of topically-applied soyaethyl morpholinium ethosulfate micelles against Staphylococcus species", 《NANOMEDICINE》, pages 1 - 15 * |
XINXIN TUO 等: "Synthesis of N-Methylmorpholinium Derivatives Possessing a 1,3,4-Oxadiazole Core as Feasible Antibacterial Agents against Plant Bacterial Diseases", 《JOURNAL OF CHEMISTRY》, vol. 2021, pages 1 - 10 * |
董卫莉 等: "1,2,3-噻二唑-4-乙酰胺(吗啉)类衍生物的合成与生物活性", 《高等学校化学学报》, vol. 28, no. 09, pages 1671 - 1676 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113999222A (zh) * | 2021-11-19 | 2022-02-01 | 贵州大学 | 一类含金刚烷基噁二唑类化合物及其制备方法和应用 |
CN114773328A (zh) * | 2022-05-31 | 2022-07-22 | 贵州大学 | 含噁二唑硫醚和砜类化合物、其立体异构体、其盐或其溶剂化物,制备方法,组合物及用途 |
Also Published As
Publication number | Publication date |
---|---|
CN113636984B (zh) | 2023-11-17 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US4229465A (en) | Cyanopyrrole derivatives | |
CN109651350B (zh) | 一类杂环取代的1,3,4-噁(噻)二唑类化合物及其制备方法和用途 | |
JPS6344571A (ja) | アクリル酸誘導体、その製造方法及びこれを有効成分とする農薬組成物 | |
CN109627206B (zh) | 一类具有手性中心的咔唑基异丙醇胺衍生物的制备方法和应用 | |
EP0105548B1 (en) | Propynylaminoisoxazole derivatives | |
CN113636984B (zh) | 一类含吗啉基团的1,3,4-噁二唑类化合物及其制备方法和用途 | |
JPS609748B2 (ja) | 1、2−ジクロロシアノビニル化合物及び微生物抑制剤としての利用 | |
CN112608307A (zh) | 一类杂环取代1,3,4-噁二唑酰肼类化合物及其制备方法和应用 | |
CN112592335A (zh) | 一类含1,2,3-三氮唑的咔唑异丙醇二胺类化合物及其制备方法和应用 | |
CN110713512A (zh) | 一类含异丙醇胺亚结构的甘草次酸哌嗪类化合物及其制备方法和应用 | |
CN113278020B (zh) | 含酰基硫脲结构的pityriacitrin生物碱衍生物及其制备方法和用途 | |
CN113461634A (zh) | 一类噻唑酰肼类化合物及其制备方法和应用 | |
CN115260046B (zh) | 一种松香酸酯类化合物及其制备方法和应用 | |
CN110776548B (zh) | 一类含异丙醇胺亚结构的乙酰氧基熊果酸哌嗪类化合物及其制备方法和应用 | |
CN112624931A (zh) | 一类含异丙醇芳香醚类结构的紫檀芪胺类化合物及其制备方法和应用 | |
KR880001049B1 (ko) | 프로피닐 아미노티아졸 유도체의 제조방법 | |
KR950007593B1 (ko) | 이속사졸릴에탄올 유도체의 제조방법 | |
CN113563281B (zh) | 一类含1,3,4-噻二唑硫醚结构的苯甲酮类化合物及其应用 | |
CN115536543B (zh) | 一种含异丙醇胺结构的三氯生类化合物及其制备方法和应用 | |
CN107033134B (zh) | 含吡啶盐和1,3,4-噁二唑基的双酰胺类化合物及其制备方法及应用 | |
CN114380802B (zh) | 一类含咔唑基咪唑盐类化合物及其制备方法和应用 | |
CN114773328A (zh) | 含噁二唑硫醚和砜类化合物、其立体异构体、其盐或其溶剂化物,制备方法,组合物及用途 | |
CN118164872A (zh) | 一类含席夫碱核心骨架的丁香酚类化合物及其制备方法和应用 | |
KR930009820B1 (ko) | 2-퀴놀린온 유도체 | |
CN114409611A (zh) | 一类噁二唑酰肼类化合物及其制备方法和应用 |
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 | ||
GR01 | Patent grant | ||
GR01 | Patent grant |