CN101675056A - 杂环化合物及其作为杀虫剂的用途 - Google Patents
杂环化合物及其作为杀虫剂的用途 Download PDFInfo
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- CN101675056A CN101675056A CN200880014405A CN200880014405A CN101675056A CN 101675056 A CN101675056 A CN 101675056A CN 200880014405 A CN200880014405 A CN 200880014405A CN 200880014405 A CN200880014405 A CN 200880014405A CN 101675056 A CN101675056 A CN 101675056A
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- 150000004945 aromatic hydrocarbons Chemical group 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 159000000009 barium salts Chemical class 0.000 description 1
- 229910001038 basic metal oxide Inorganic materials 0.000 description 1
- 150000003818 basic metals Chemical group 0.000 description 1
- NDKBVBUGCNGSJJ-UHFFFAOYSA-M benzyltrimethylammonium hydroxide Chemical compound [OH-].C[N+](C)(C)CC1=CC=CC=C1 NDKBVBUGCNGSJJ-UHFFFAOYSA-M 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 239000003139 biocide Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- QLHULAHOXSSASE-UHFFFAOYSA-N butan-2-yl 2-(2-hydroxyethyl)piperidine-1-carboxylate Chemical compound CCC(C)OC(=O)N1CCCCC1CCO QLHULAHOXSSASE-UHFFFAOYSA-N 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 150000001244 carboxylic acid anhydrides Chemical class 0.000 description 1
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- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- YUAUPYJCVKNAEC-SEYXRHQNSA-N cymiazole Chemical compound CC1=CC(C)=CC=C1\N=C/1N(C)C=CS\1 YUAUPYJCVKNAEC-SEYXRHQNSA-N 0.000 description 1
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- SWXVUIWOUIDPGS-UHFFFAOYSA-N diacetone alcohol Chemical compound CC(=O)CC(C)(C)O SWXVUIWOUIDPGS-UHFFFAOYSA-N 0.000 description 1
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- SZXQTJUDPRGNJN-UHFFFAOYSA-N dipropylene glycol Chemical compound OCCCOCCCO SZXQTJUDPRGNJN-UHFFFAOYSA-N 0.000 description 1
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- 201000010099 disease Diseases 0.000 description 1
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- 208000006275 fascioliasis Diseases 0.000 description 1
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- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 239000003630 growth substance Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 150000005826 halohydrocarbons Chemical class 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- YVXHZKKCZYLQOP-UHFFFAOYSA-N hept-1-yne Chemical compound CCCCCC#C YVXHZKKCZYLQOP-UHFFFAOYSA-N 0.000 description 1
- 239000008241 heterogeneous mixture Substances 0.000 description 1
- 125000003707 hexyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 230000020245 homoiothermy Effects 0.000 description 1
- 230000003054 hormonal effect Effects 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 229950001891 iprotiazem Drugs 0.000 description 1
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- XUGNVMKQXJXZCD-UHFFFAOYSA-N isopropyl palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC(C)C XUGNVMKQXJXZCD-UHFFFAOYSA-N 0.000 description 1
- 230000001418 larval effect Effects 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- 230000033001 locomotion Effects 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 210000001365 lymphatic vessel Anatomy 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 235000013372 meat Nutrition 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 238000001465 metallisation Methods 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- OFXSXYCSPVKZPF-UHFFFAOYSA-N methoxyperoxymethane Chemical compound COOOC OFXSXYCSPVKZPF-UHFFFAOYSA-N 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 229920005615 natural polymer Polymers 0.000 description 1
- 230000001069 nematicidal effect Effects 0.000 description 1
- 239000005645 nematicide Substances 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229940055577 oleyl alcohol Drugs 0.000 description 1
- XMLQWXUVTXCDDL-UHFFFAOYSA-N oleyl alcohol Natural products CCCCCCC=CCCCCCCCCCCO XMLQWXUVTXCDDL-UHFFFAOYSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 210000004681 ovum Anatomy 0.000 description 1
- 206010033675 panniculitis Diseases 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 230000000590 parasiticidal effect Effects 0.000 description 1
- 230000024241 parasitism Effects 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 230000007918 pathogenicity Effects 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 125000004115 pentoxy group Chemical group [*]OC([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 239000011297 pine tar Substances 0.000 description 1
- 229940068124 pine tar Drugs 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 125000001844 prenyl group Chemical group [H]C([*])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 150000003233 pyrroles Chemical class 0.000 description 1
- 239000010499 rapseed oil Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000005932 reductive alkylation reaction Methods 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 239000004576 sand Substances 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- CQLFBEKRDQMJLZ-UHFFFAOYSA-M silver acetate Chemical compound [Ag+].CC([O-])=O CQLFBEKRDQMJLZ-UHFFFAOYSA-M 0.000 description 1
- 229940071536 silver acetate Drugs 0.000 description 1
- HKZLPVFGJNLROG-UHFFFAOYSA-M silver monochloride Chemical compound [Cl-].[Ag+] HKZLPVFGJNLROG-UHFFFAOYSA-M 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- GGCZERPQGJTIQP-UHFFFAOYSA-N sodium;9,10-dioxoanthracene-2-sulfonic acid Chemical compound [Na+].C1=CC=C2C(=O)C3=CC(S(=O)(=O)O)=CC=C3C(=O)C2=C1 GGCZERPQGJTIQP-UHFFFAOYSA-N 0.000 description 1
- 239000002594 sorbent Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 239000012622 synthetic inhibitor Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 239000008399 tap water Substances 0.000 description 1
- 235000020679 tap water Nutrition 0.000 description 1
- 125000002769 thiazolinyl group Chemical group 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000005019 zein Substances 0.000 description 1
- 229940093612 zein Drugs 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
- C07D209/12—Radicals substituted by oxygen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/10—Anthelmintics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/14—Ectoparasiticides, e.g. scabicides
-
- 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
- C07D209/52—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 condensed with a ring other than six-membered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
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- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Tropical Medicine & Parasitology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Indole Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
本发明涉及通式(I)的化合物以及任选其对映体,其中R1、Q、Z和m具有权利要求书中所给含义。这些活性成分具有有利的杀虫性能。它们尤其适合在温血动物和植物中或在温血动物和植物上控制寄生虫。
Description
本发明涉及新型N-芳基取代的杂吲哚,其制备方法,包含所述化合物的兽用组合物及其在温血繁殖牲畜和家畜上控制体外寄生虫,尤其是蜱和蚤中的用途。
持续需要具有改进杀虫性能的新型活性成分,例如因为现在使用的产品不能满足与效力和活性谱有关的所有要求。此外,体外寄生虫对一些已知杀虫剂逐步形成抗药性产生了问题。现在惊人的是已经发现新型特定N-芳基取代的杂吲哚具有优异的杀虫性能,尤其是针对体外寄生虫。
因此,本发明一方面涉及下式化合物:
其中
Z为稠合碳环或杂环,苯环除外;
R1为卤素、氰基、硝基、C1-C6烷基、C3-C6环烷基、C2-C6链烯基、C2-C6炔基、羟基-C1-C6烷基、卤代-C1-C6烷基、羟基、C1-C6烷氧基、卤代-C1-C6烷氧基、SH、C1-C6烷硫基、卤代-C1-C6烷硫基、C1-C6烷基亚磺酰基、卤代-C1-C6烷基亚磺酰基、C1-C6烷基磺酰基、卤代-C1-C6烷基磺酰基、S03R3、SO2NR3R4、NR3R4、COR3、COOR3或CONR3R4,其中若m大于1,则R1的含义可以相同或不同;
T为下式基团:
R2为卤素、氰基、硝基、C1-C6烷基、卤代-C1-C6烷基、C3-C6环烷基、C2-C6链烯基、C2-C6炔基、羟基、C1-C6烷氧基、卤代-C1-C6烷氧基、SH、C1-C6烷硫基、卤代-C1-C6烷硫基、C1-C6烷基亚磺酰基、卤代-C1-C6烷基亚磺酰基、C1-C6烷基磺酰基、卤代-C1-C6烷基磺酰基、SO3R3、SO2NR3R4、NR3R4、COR3、COOR3、CONR3R4或SF5,其中若n大于1,则R2的含义可以相同或不同;
R3和R4相互独立地为氢,未被取代或被卤素、氰基、NO2、C1-C4烷氧基、C1-C4烷基羰基、C1-C4烷基羰氧基或C1-C4烷氧羰基取代的C1-C6烷基,或者为C1-C2烷氧基-C1-C2烷基;
m表示0、1、2或3;
n表示1、2、3或4;
X为N或C(R2’),其中R2’为氢或独立地具有R2的含义;条件是若n为1,则R2’不为氢;
Q为下式基团:
A为O、S、S(O)或S(O2);
R6为氢,C1-C6烷基,C1-C6羟烷基,C3-C6环烷基,C3-C6环烷基甲基,C1-C4烷氧基甲基,C1-C2烷氧基-C1-C2烷氧基甲基,苯基结构部分中未被取代或被卤素、C1-C2烷基、卤代-C1-C2烷基或C1-C2烷氧基取代的苯氧基甲基,苄氧基甲基,C2-C6链烯基,C2-C6炔基,卤代-C1-C6烷基,卤代-C3-C6环烷基,卤代-C1-C6环烷基甲基,卤代-C2-C6链烯基,卤代-C2-C6炔基,COR3,COOR3,CONR3R4,CSNR3R4,C1-C4烷基甲硅烷基,苯基或苯基-C1-C2烷基,其中苯基各自未被取代或被卤素、硝基、氰基、羟基、C1-C4烷基、卤代-C1-C4烷基、C1-C4烷氧基、卤代-C1-C4烷氧基、NH2、N-C1-C4烷基氨基、N,N-二-C1-C4烷基氨基、C1-C4烷硫基、COR3、COOR3或CONR3R4取代;
R7为C1-C6烷基、C2-C6链烯基、C2-C6炔基、卤代-C1-C6烷基、卤代-C2-C6链烯基、卤代-C2-C6炔基、C3-C8环烷基、卤代-C3-C8环烷基、羟基-C1-C6烷基、COR3或COOR3;以及
R8为氢;未被取代或被卤素、C1-C4烷硫基、羟基、C1-C4烷氧基、氨基或N-单-或N,N-二-C1-C4烷基氨基取代的C1-C6烷基;未被取代或卤素取代的C2-C6链烯基;未被取代或卤素取代的C2-C6炔基;未被取代或卤素取代的C3-C8环烷基;C5-C6环烷基甲基,其中该环烷基的1-3个碳原子可以被选自NH、N(C1-C4烷基)、O和S的杂原子替代;苄基;未被取代或被卤素、卤代-C1-C2烷基或卤代-C1-C2烷氧基取代的苯基;氰基、COR3或COOR3;
或者R7和R8与它们所连接的碳原子一起形成3-6个原子的脂族环,该环任选包括一个选自氮、硫或氧的额外杂原子或一个羰基,任选被1-4个相互独立地选自卤素、CN、NO2、羟基、C1-C4烷基和C1-C4烷氧基的取代基取代。
除非另有指明,上文和下文所用通用术语具有下列含义。
烷基-本身作为基团以及作为其他基团和化合物如卤代烷基、烷氧基和烷硫基的结构单元-在适当考虑所述基团或化合物中的特定碳原子数的各种情况下为直链的,即甲基、乙基、丙基、丁基、戊基或己基,或为支化的,例如异丙基、异丁基、仲丁基、叔丁基、异戊基、新戊基或异己基,优选直链或支化的C1-C4烷基,尤其是C1-C2烷基。
链烯基-本身作为基团以及作为其他基团和化合物的结构单元-在适当考虑所述基团或化合物中的特定碳原子数和共轭或分离双键的各种情况下为直链的,例如乙烯基、烯丙基、2-丁烯基、3-戊烯基、1-己烯基或1,3-己二烯基,或为支化的,例如异丙烯基、异丁烯基、异戊二烯基、叔戊烯基或异己烯基,优选C2-C4链烯基,尤其是乙烯基或烯丙基。
炔基-本身作为基团以及作为其他基团和化合物的结构单元-在适当考虑所述基团或化合物中的特定碳原子数和共轭或分离双键的各种情况下为直链的,例如乙炔基、炔丙基、2-丁炔基、3-戊炔基、1-己炔基、1-庚炔基或3-己烯-1-炔基,或为支化的,例如3-甲基丁-1-炔基、4-乙基戊-1-炔基或4-甲基己-2-炔基,优选C2-C4炔基,尤其是乙炔基。
环烷基-本身作为基团以及作为其他基团和化合物的结构单元-在适当考虑所述基团或化合物中的特定碳原子数的各种情况下例如为环丙基、环丁基、环戊基或环己基,尤其是环戊基或环己基。
卤素-本身作为基团以及作为其他基团和化合物如卤代烷基、卤代烷氧基和卤代烷硫基的结构单元-例如为氟、氯、溴或碘,尤其是氟、氯或溴,特别是氟或氯。
卤素取代的含碳基团和化合物如卤代烷基、卤代烷氧基或卤代烷硫基可以是部分卤代的或全卤代的,其中在多重卤代的情况下,卤素取代基可以相同或不同。卤代烷基-本身作为基团以及作为其他基团和化合物如卤代烷氧基或卤代烷硫基的结构单元-的实例是被氟、氯和/或溴取代1-3次的甲基,如CHF2或尤其是CF3;被氟、氯和/或溴取代1-5次的乙基,如CH2CF3、CF2CF3、CF2CCl3、CF2CHCl2、CF2CHF2、CF2CFCl2、CF2CHBr2、CF2CHClF、CF2CHBrF或CClFCHClF;被氟、氯和/或溴取代1-7次的丙基或异丙基,如CH2CHBrCH2Br、CF2CHFCF3、CH2CF2CF3或CH(CF3)2;被氟、氯和/或溴取代1-9次的丁基或其异构体之一,如CF(CF3)CHFCF3或CH2(CF2)2CF3;被氟、氯和/或溴取代1-11次的戊基或其异构体之一,如CF(CF3)(CHF)2CF3或CH2(CF2)3CF3;被氟、氯和/或溴取代1-13次的己基或其异构体之一,如(CH2)4CHBrCH2Br、CF2(CHF)4CF3、CH2(CF2)4CF3或C(CF3)2(CHF)2CF3。
烷氧基的链长例如为1-6个碳原子,更优选1-4个碳原子,尤其是一个或两个碳原子。烷氧基例如为甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基和叔丁氧基,以及异构体戊氧基和己氧基;优选甲氧基或乙氧基。卤代烷氧基的链长优选为1-6个碳原子。卤代烷氧基例如为氟代甲氧基、二氟甲氧基、三氟甲氧基、2,2,2-三氟乙氧基、1,1,2,2-四氟乙氧基、2-氟乙氧基、2-氯乙氧基、2,2-二氟乙氧基和2,2,2-三氯乙氧基;优选二氟甲氧基、2-氯乙氧基或尤其是三氟甲氧基。
烷硫基的链长优选为1-6个碳原子。烷硫基例如为甲硫基、乙硫基、丙硫基、异丙硫基、正丁硫基、异丁硫基、仲丁硫基或叔丁硫基,优选乙硫基或尤其是甲硫基。
Z例如为在吡咯的4和5位稠合的5-7员,优选5或6员碳环或杂环。
合适的碳环Z例如为5-7员,优选5或6员脂环族环,其可以被1-3个上述基团R1取代。Z尤其为5或6员脂环族环,其进一步是未取代的或被单一基团R1取代,即m优选为0或1。
合适的杂环Z例如为具有1-3个,优选一个或两个相同或不同的选自N、O和S的杂原子的5或6员环,该环可以被1-3个上述基团R1取代。杂环Z尤其为具有一个选自N、O和S的杂原子的5或6员杂芳族环,该环进一步是未取代的或被单一取代基R1取代,即m优选为0或1。
因此,本发明的一类特别优选化合物是下式的那些:
其中k为数字3、4或5,尤其是3或4,以及R1、Q、T和m如上所定义,包括所给优选情形。
因此,本发明的另一类特别优选化合物是下式的那些:
其中基团Y1、Y2、Y3和Y4中的一个或两个独立地为选自N、O和S的杂原子,而其余的为CH,r为数字0或1,以及R1、Q、T和m如上所定义,包括所给优选情形。在式Ib化合物的一个实施方案中,r为0,并且基团Y1、Y2和Y3中的一个或两个,尤其是一个为选自N、O和S的杂原子,其余的为CH。在式Ib化合物的另一实施方案中,r为1,以及基团Y1、Y2、Y3和Y4中的一个或两个,尤其是一个为选自N、O和S的杂原子,尤其是N,其余的为CH。
R1优选为卤素、氰基、硝基、C1-C4烷基、羟基-C1-C4烷基、卤代-C1-C4烷基、羟基、C1-C4烷氧基、卤代-C1-C4烷氧基、SH、C1-C4烷硫基、卤代-C1-C4烷硫基、C1-C4烷基亚磺酰基、卤代-C1-C4烷基亚磺酰基、C1-C4烷基磺酰基或卤代-C1-C4烷基磺酰基;更优选卤素、C1-C2烷基、卤代-C1-C2烷基、C1-C2烷氧基、卤代-C1-C2烷氧基、C1-C2烷硫基或卤代-C1-C2烷硫基;甚至更优选卤素、C1-C2烷基或CF3。在m大于1的情况下,R1的含义在每种情况下可以相同或不同。
式I、Ia或Ib化合物中的变量m优选为0、1或2,更优选0或1,尤其是0。
在式II中,R2优选为卤素、氰基、硝基、C1-C4烷基、卤代-C1-C4烷基、C2-C4链烯基、C2-C4炔基、羟基、C1-C4烷氧基、卤代-C1-C4烷氧基、SH、C1-C4烷硫基、卤代-C1-C4烷硫基或SF5,更优选卤素、氰基、硝基、卤代-C1-C2烷基、C2-C4链烯基、C2-C4炔基、卤代-C1-C2烷氧基、卤代-C1-C2烷硫基或SF5,最优选卤素或卤代-C1-C2烷基。当n大于1时,R2的含义在每种情况下可以相同或不同,优选不同。
式II化合物中的变量n优选为1或2,最优选2。
在式II中,X优选为N或C(R2’),其中对于R2’,上面对R2所给的含义和优选情形独立地适用。X优选为基团C(R2’),其中R2’为卤素,尤其是氯。
特别优选的基团T具有下式:
其中R2’和R2”各自为卤素,尤其是氯,并且R2为卤代-C1-C2烷基,尤其是CF3。
在式III中,A优选为O。
R6优选为氢、C1-C4烷基、卤代-C1-C4烷基、羟基-C1-C4烷基、C1-C4烷氧基甲基、苯氧基甲基、苄氧基甲基、苯基、苄基或COC1-C4烷基;更优选氢、C1-C2烷基、 羟基-C1-C2烷基、C1-C2烷氧基甲基或COC1-C2烷基;尤其是氢、C1-C2烷基或CO-C1-C2烷基。
R7优选为C1-C4烷基、卤代-C1-C4烷基或羟基-C1-C4烷基;更优选C1-C4烷基或卤代-C1-C4烷基;甚至更优选C1-C2烷基或卤代-C1-C2烷基;尤其是CF3。
R8优选为氢,未被取代或被卤素、羟基或C1-C2烷氧基取代的C1-C4烷基,C2-C4链烯基,C2-C4炔基,苄基,或未被取代或被卤素、卤代-C1-C2烷基或卤代-C1-C2烷氧基取代的苯基;更优选氢、C1-C4烷基、卤代-C1-C4烷基、C2-C4链烯基或C2-C4炔基;尤其是氢、C1-C2烷基、CF3、乙烯基或乙炔基。
若R7和R8与它们所连接的碳原子一起形成脂族环,则这优选为哌啶环或N-C1-C2烷基哌啶环。
优选的基团Q具有上式III,其中A为O,R6为氢,R7为CF3,并且对于R8,上面所给含义和优选情形适用。
本发明的优选实施方案涉及上式I的化合物,其中R1为卤素或C1-C4烷基;
m表示0、1或2;
T为式II的基团,其中X为N或C(R2’),n为1或2,以及R2和R2’各自独立地为卤素、氰基、硝基、C2-C4炔基、卤代-C1-C4烷基、卤代-C1-C4烷氧基或SF5,其中若n为2,则R2的含义可以相同或不同;
Q为式III的基团,其中A为O,R6为氢、C1-C4烷基或C(O)-C1-C2烷基,R7为C1-C4烷基或卤代-C1-C4烷基并且R8为氢、C1-C4烷基、卤代-C1-C4烷基、C2-C4链烯基或C2-C4炔基;以及
对于环Z,上面所给含义和优选情形适用。
本发明的另一优选实施方案涉及下式化合物:
其中对于环Z、R1、R2、R2’、R8和m,上面所给含义和优选情形各自适用,并且R2”独立地具有R2的含义。式Ic中的R2’优选为卤素,尤其是氯。式Ic中的R2’和R2”最优选各自为卤素,尤其是氯,并且R2为卤代-C1-C2烷基,尤其是CF3。
特别优选的实施方案涉及上式Ic的化合物,其中
R1为卤素或C1-C2烷基;
m为0或1,尤其是0;
R2为三氟甲基,并且R2’和R2”各自为氯;
R8为C1-C2烷基、卤代-C1-C2烷基、C2-C4链烯基或C2-C4炔基;以及
环Z为具有一个选自N、O和S的杂原子的5或6员脂环族环或5或6员杂芳族环。
本发明的式I化合物例如可以通过包括如下步骤的方法制备:
(i)卤化下式化合物:
其中R1、Z和m如上所定义,得到下式化合物:
其中Hal为卤素,例如溴,并且R1、Z和m如上所定义;
(ii)使根据步骤(i)得到的式IVa化合物与下式化合物任选在碱性催化剂存在下反应:
L-T V,
其中T如上所定义且L为离去基团,得到下式化合物:
其中Hal为卤素,例如溴,并且R1、T、Z和m如上所定义;和
(iii)使式IVb化合物与锂-有机化合物如正丁基锂反应,然后使所得锂-有机化合物与下式的酮反应:
其中A、R7和R8如上所定义,得到式I化合物。
式IV化合物可以在步骤(i)中以本身由有机教科书已知的方式卤化。例如可以使用溴或N-溴代琥珀酰亚胺(NBS)进行式IV化合物的溴化。
步骤(ii)中的反应参与物可以直接相互反应,即不加入溶剂或稀释剂,例如在熔体中相互反应。然而在大多数情况下加入惰性溶剂或稀释剂或其混合物是有利的。该类溶剂或稀释剂的实例是芳烃、脂族烃和脂环烃以及卤代烃,如苯、甲苯、二甲苯、1,3,5-三甲基苯、1,2,3,4-四氢化萘、氯苯、二氯苯、溴苯、石油醚、己烷、环己烷、二氯甲烷、三氯甲烷、四氯甲烷、二氯乙烷、三氯乙烯或四氯乙烯;醚类,如乙醚、二丙基醚、二异丙基醚、二丁基醚、叔丁基甲基醚、乙二醇单甲醚、乙二醇单乙醚、乙二醇二甲醚、二甲氧基二乙醚、四氢呋喃或二噁烷;酮类,如丙酮、甲基乙基酮或甲基异丁基酮;酰胺类,如N,N-二甲基甲酰胺、N,N-二乙基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷酮或六甲基磷酸三酰胺;腈类,如乙腈或丙腈;以及亚砜类,如二甲亚砜。
适合促进反应的碱例如为碱金属或碱土金属氢氧化物、氢化物、氨化物、链烷醇盐、乙酸盐、碳酸盐、二烷基氨化物或烷基甲硅烷基氨化物;烷基胺,亚烷基二胺,任选N-烷基化、任选不饱和的环烷基胺,碱性杂环,氢氧化铵,以及碳环胺。可以作为举例提到的那些是氢氧化钠、氢化钠、氨化钠、甲醇钠、乙酸钠、碳酸钠、叔丁醇钾、氢氧化钾、碳酸钾、氢化钾、二异丙基氨化锂、二(三甲基甲硅烷基)氨化钾、氢化钙、三乙胺、二异丙基乙基胺、三亚乙基二胺、环己基胺、N-环己基-N,N-二甲基胺、N,N-二乙基苯胺、吡啶、4-(N,N-二甲基氨基)吡啶、奎宁环、N-甲基吗啉、苄基三甲基氢氧化铵以及1,5-二氮杂双环[5.4.0]十一碳-5-烯(DBU)。
优选的离去基团L为卤素,尤其是氟或氯。
该反应有利地在约0-150℃,优选约50-120℃的温度下进行。
在优选方法中,使式IVa化合物在90℃下在酰胺,优选N,N-二甲基甲酰胺中与式V化合物在碱,优选碳酸钾存在下反应。
式IVa和V化合物是已知且可市购的,或者可以根据本领域熟知的方法制备,例如由有机化学教科书已知的方法制备。
在步骤(iii)中,金属化和与式VI化合物的进一步反应全部可以以本身由有机化学教科书已知的方式进行。
制备式I化合物的另一方法包括如下步骤:
(i)使上面所给式IV化合物与下式的羧酰卤或羧酸酐反应:
R7-C(O)-Hal VIa或R7-C(O)-O-C(O)-R7 VIb
得到下式化合物:
其中Z、R1、R7和m如上所定义,
(ii)使根据步骤(i)得到的式VII化合物与下式化合物任选在碱性催化剂存在下反应:
L-T V,
其中T如上所定义且L为离去基团,得到下式化合物:
(iii)使根据步骤(ii)得到的式VIIa化合物与下式化合物反应:
R8-L1 VIII,
其中L1为离去基团且R8如上所定义,得到式I化合物。
在步骤(iii)中,反应参与物可以直接相互反应,即不加入溶剂或稀释剂,例如在熔体中反应。然而,在大多数情况下加入惰性溶剂或稀释剂或其混合物是有利的。该类溶剂或稀释剂的实例是芳族、脂族和脂环族烃类以及卤代烃类,如苯、甲苯、二甲苯、1,3,5-三甲基苯、1,2,3,4-四氢化萘、氯苯、二氯苯、溴苯、石油醚、己烷、环己烷、二氯甲烷、三氯甲烷、四氯甲烷、二氯乙烷、三氯乙烯或四氯乙烯;醚类,如乙醚、二丙醚、二异丙醚、二丁醚、叔丁基甲基醚、乙二醇单甲醚、乙二醇单乙醚、乙二醇二甲醚、二甲氧基乙醚、四氢呋喃或二噁烷;酰胺类,如N,N-二甲基甲酰胺、N,N-二乙基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷酮或六甲基磷酸三酰胺;腈类,如乙腈或丙腈;以及亚砜类,如二甲亚砜。
优选的离去基团L1是MgBr、MgCl、MgI或Li,尤其是MgBr。
该反应有利地在约-20℃至约100℃,优选约0-30℃的温度下进行。
在优选方法中,使式VIIa化合物在室温下在醚,优选乙醚中与式VIII化合物反应。
由上述方法得到的式I化合物还可以通过本身由有机化学教科书已知的反应转化成另一式I化合物。例如,可以通过合适的酰化或醚化反应将其中Q为基团-C(OH)(R7)(R8)的式I化合物容易地转化成具有不同基团-C(OR6)(R7)(R8)的式I化合物;或者可以通过还原性烷基化将其中Q为基团-C(O)-R5的式I化合物转化成其中Q为基团-C(OH)(R7)(R8)的化合物。
化合物I的盐可以由已知方式生产。酸加成盐例如可以通过用合适的酸或合适的离子交换试剂处理而由化合物I得到,而与碱的盐可以通过用合适的碱或合适的离子交换试剂处理而得到。
化合物I的盐可以通过常规方法转化成游离化合物I,对于酸加成盐例如通过用合适的碱性组合物或合适的离子交换试剂处理,而对于与碱的盐例如通过用合适的酸或合适的离子交换试剂处理。
化合物I的盐可以已知方式转化成化合物I的其他盐;酸加成盐例如可以通过用合适的金属盐(如酸的钠盐、钡盐或银盐,例如乙酸银)在合适的溶剂中处理无机酸的盐如盐酸盐而转化成例如其他酸加成盐,所得无机盐如氯化银在该溶剂中不溶且因此由反应混合物沉淀出来。
取决于方法和/或反应条件,具有成盐特性的式I化合物可以游离形式或盐形式得到。
式I化合物还可以以其水合物形式得到和/或还可以包括例如必要的话用于以固体形式存在的化合物的结晶的其他溶剂。
式I或Ia化合物可以任选以光学和/或几何异构体或以其混合物存在。本发明涉及纯的异构体和所有可能的异构混合物,并且在上文和下文中按此理解,即使在每种情况下没有具体提到立体化学细节。
可以通过该方法或以另一方式得到的式I和Ia化合物的非对映异构混合物可以基于其组分的物理化学差异的已知方式分离成纯非对映异构体,例如通过分级结晶、蒸馏和/或层析分离。
将可相应地得到的对映体混合物分离成纯异构体可以通过已知方法实现,例如通过由光学活性溶剂中重结晶,通过在手性吸附剂上层析,例如在乙酰纤维素上的高压液相色谱法(HPLC),借助合适的微生物,通过用特殊的固定化酶裂解,通过形成包合物,例如使用手性冠醚,由此仅络合一种对映体。
根据本发明,除了对应异构体混合物的分离外,还可以使用通常已知的非对映选择性或对映选择性合成方法来得到纯非对映异构体或对映体,例如通过使用具有相应地合适的立体化学的离析物进行本发明方法。
有利的是分离或合成更具生物活性的异构体如对映体,条件是各组分具有不同的生物效力。
在本发明方法中,所用原料和中间体优选为导致开头所述的化合物I尤其有用的那些。
本发明尤其涉及实施例中所述的制备方法。为新颖的且根据本发明用于制备式I化合物的原料和中间体以及它们的用途及其制备方法类似地构成本发明目的。
本发明的式I或Ia化合物的特征在于它们的宽活性谱且对于害虫控制(尤其包括在动物中和在动物上控制体内和体外寄生虫)应用而言是有价值的活性成分,同时被温血动物、鱼和植物良好耐受。
在本发明上下文中,体外寄生虫应理解为尤其是昆虫、螨虫(螨和蜱)和甲壳动物(海虱)。这些包括下列目的昆虫:鳞翅目(Lepidoptera)、鞘翅目(Coleoptera)、同翅目(Homoptera)、半翅目(Hemiptera)、异翅目(Heteroptera)、双翅目(Diptera)、网翅目(Dictyoptera)、缨翅目(Thysanoptera)、直翅目(Orthoptera)、虱目(Anoplura)、蚤目(Siphonaptera)、食毛目(Mallophaga)、缨尾目(Thysanura)、等翅目(Isoptera)、啮虫目(Psocoptera)和膜翅目(Hymenoptera)。然而,尤其可以提到的体外寄生虫是烦扰人类或动物且携带病原体的那些,例如蝇类如家蝇(Musca domestica)、市蝇(Musca vetustissima)、秋家蝇(Muscaautumnalis)、黄腹厕蝇(Fannia canicularis)、麻蝇(Sarcophaga carnaria)、铜绿蝇(Lucilia cuprina)、丝光绿蝇(Lucilia sericata)、牛皮下蝇(Hypodermabovis)、纹皮下蝇(Hypoderma lineatum)、金蝇(Chrysomyia chloropyga)、人皮蝇(Dermatobia hominis)、嗜人锥蝇(Cochliomyia hominivorax)、肠胃蝇(Gasterophilus intestinalis)、羊狂蝇(Oestrus ovis),叮咬蝇如西方角蝇(Haematobia irritans irritans)、东方角蝇(Haematobia irritans exigua)、厩螫蝇(Stomoxys calcitrans),虻(Tabanidae)亚科马蝇(虻科昆虫(Tabanids))如麻虻属(Haematopota)如麻虻(Haematopota pluvialis)和虻属(Tabanus)如黑纹虻(Tabanus nigrovittatus)以及斑虻(Chrysopsinae)亚科马蝇如斑虻属(Chrysops spp.)(例如斑虻蝇(Chrysops caecutiens));虱蝇科昆虫(Hippoboscids)如羊蜱蝇(Melophagus ovinus(羊虱蝇));舌蝇类如采采蝇属(Glossinia);其他叮咬昆虫如蠓,如蠓科(Ceratopogonidae(叮咬蠓)),Simuliidae(黑蝇),毛蠓科(Psychodidae(蚋);还有吸血昆虫,例如蚊子,如按蚊属(Anopheles)、伊蚊属(Aedes)和库蚊属(Culex),蚤,如猫跳蚤(Ctenocephalides felis)和狗跳蚤(Ctenocephalides canis)(猫蚤和狗蚤),印鼠客蚤(Xenopsylla cheopis),致痒蚤(Pulex irritans),禽角叶蚤(Ceratophylllusgallinae),沙蚤(Dermatophilus penetrans),吸血虱(虱目),如颚虱属(Linognathus),血虱属(Haematopinus),管虱属(Solenopotes),人虱(Pediculus humanis);还有羽虱(食毛目),如绵羊虱(Bovicola(Damalinia)ovis),牛虱(Bovicola(Damalinia)bovis)和其他Bovicola spp.。体外寄生虫还包括蜱螨目(Acarina)成员,如螨(例如牛足螨(Chorioptes bovis),姬螯螨属(Cheyletiella spp.),鸡皮刺螨(Dermanyssus gallinae),犬蠕螨(Demodexcanis),人疥螨(Sarcoptes scabiei),绵羊疥螨(Psoroptes ovis)和Psorergatesspp.以及蜱。蜱的已知代表例如为牛蜱属(Boophilus)、花蜱属(Amblyomma)、暗眼蜱属(Anocentor)、革蜱属(Dermacentor)、血蜱属(Haemaphysalis)、璃眼蜱属(Hyalomma)、硬蜱属(Ixodes)、扇革蜱属(Rhipicentor)、巨肢蜱属(Margaropus)、扇头蜱属(Rhipicephalus)、锐缘蜱属(Argas)、耳蜱属(Otobius)和钝缘蜱属(Ornithodoros)等,它们优选侵袭包括农场动物如牛、马、猪、绵羊和山羊,家禽如鸡、火鸡、珍珠鸡和鹅,产皮动物如水貂、狐狸、龙猫、兔等,以及家畜如猫和狗在内的温血动物,还有人类。
式I化合物还可以用于对抗卫生害虫,尤其是双翅目家蝇科(Muscidae)、麻蝇科(Sarcophagidae)、Anophilidae和蚊科(Culicidae);直翅目、网翅目(例如蜚蠊科(Blattidae(蟑螂)),如德国小蠊(Blatellagermanica)、东方蜚蠊(Blatta orientalis)、美洲蟑螂(Periplaneta americana))和膜翅目(例如蚁科(Formicidae)(蚂蚁)和胡蜂科(Vespidae)(胡蜂)。
式I化合物还对寄生螨和植物昆虫具有持续效力。在蜱螨目叶螨的情况下,它们对叶螨科(Tetranychidae)(叶螨属(Tetranychus)和全爪螨属(Panonychus))的虫卵、蛹和成虫有效。
它们对同翅目吸虫,尤其是蚜科(Aphididae)、飞虱科(Delphacidae)、大叶蝉科(Cicadellidae)、木虱科(Psyllidae)、Loccidae、盾阶科(Diaspididae)和Eriophydidae害虫(例如柑橘类的水果上的锈螨);半翅目、异翅目和缨翅目以及鳞翅目、鞘翅目、双翅目和直翅目植食性昆虫具有高活性。
它们类似地适合作为对抗土壤害虫的土壤杀虫剂。
因此,式I化合物对作物如禾谷类、棉花、稻、玉米、大豆、土豆、蔬菜、果实、烟草、啤酒花、柑橘、鳄梨和其他作物上的吸虫和咬食昆虫的所有发育阶段有效。
式I化合物还对根结线虫属(Meloidogyne)、异皮线虫属(Heterodera)、根腐线虫属(Pratylenchus)、茎线虫属(Ditylenchus)、穿孔线虫属(Radopholus)、盘旋线虫属(Rizoglyphus)等植物线虫有效。
具体而言,这些化合物对蠕虫有效,其中体内寄生线虫和吸虫可能是哺乳动物和禽类如绵羊、猪、山羊、牛、马、驴、狗、猫、天竺鼠和外来鸟类发生严重疾病的诱因。该适应症的典型线虫是:血矛线虫属(Haemonchus)、毛圆线虫属(Trichostrongylus)、胃线虫属(Ostertagia)、细颈线虫属(Nematodirus)、古柏线虫属(Cooperia)、蛔虫属(Ascaris)、仰口线虫属(Bunostonum)、结节线虫属(Oesophagostonum)、夏柏特线虫属(Charbertia)、鞭虫属(Trichuris)、圆线虫属(Strongylus)、毛线属(Trichonema)、网尾属(Dictyocaulus)、毛细线虫属(Capillaria)、异刺属(Heterakis)、弓蛔虫属(Toxocara)、鸡蛔虫属(Ascaridia)、尖尾线虫属(Oxyuris)、钩口线虫属(Ancylostoma)、钩虫属(Uncinaria)、弓蛔线虫属(Toxascaris)和副蛔虫属(Parascaris)。吸虫包括支睾吸虫属(Clonorchis)、双腔吸虫属(Dicrocoelium)、棘口吸虫属(Echinostoma)以及特别是拟片吸虫属(Fasciolideae),尤其是肝片吸虫(Fasciola hepatica)。式I化合物的特殊优点是它们对耐受基于苯并咪唑的活性成分的那些寄生虫有效。
某些细颈线虫属、古柏线虫属和结节线虫属(Oesophagostonum)害虫侵袭宿主动物的肠道,而血矛线虫属和胃线虫属中的其他寄生在胃中且网尾属的那些寄生在肺组织中。丝虫科(Filariidae)和鬃丝虫科(Setariidae)寄生虫可能在内室组织以及器官如心脏、血管、淋巴管和皮下组织中发现。特别应注意的寄生虫是犬恶丝虫(Dirofilaria immitis)。式I化合物对这些寄生虫高度有效。
此外,式I化合物适于控制人病原性寄生虫。其中出现在消化道的典型代表是钩口线虫属、板口线虫属(Necator)、蛔虫属、类圆线虫属(Strongyloides)、旋毛虫属(Trichinella)、毛细线虫属、鞭虫属和蛲虫属(Enterobius)的那些。本发明化合物还对出现在血液、组织和各种器官中的吴策线虫属(Wuchereria)、布鲁格氏丝虫属(Brugia)、盘尾属(Onchocerca)和罗阿丝虫属(Loa)的丝虫科寄生虫以及尤其影响胃肠道的龙线虫属(Dracunculus)、类圆线虫属和旋毛虫属寄生虫有效。
本发明式I化合物的良好杀虫活性对应于所述害虫的死亡率为至少50-60%。具体而言,式I化合物的特征在于特别长的效力持续期。
式I化合物优选以未改性形式使用或优选与常用于配制剂领域的助剂一起使用并且因此可以以已知方式加工而得到例如可乳化的浓缩物、可直接稀释溶液、稀乳液、可溶性粉末、颗粒或在聚合物中的微囊包封剂。与组合物一样,施用方法按照意欲的目标和盛行的情形选择。
配制剂,即含有式I的活性成分或这些活性成分与其他活性成分的组合和任选含有固体或液体助剂的试剂、制剂或组合物,以本身已知的方式生产,例如通过紧密混合和/或研磨活性成分和分散组合物,例如溶剂、固体载体和任选的表面活性化合物(表面活性剂)。
所述溶剂可以是醇类,如乙醇、丙醇或丁醇,以及二醇及其醚和酯,如丙二醇、二丙二醇醚、乙二醇、乙二醇单甲醚或乙二醇单乙醚,酮类,如环己酮、异佛尔酮或双丙酮醇,强极性溶剂,如N-甲基-2-吡咯烷酮、二甲亚砜或N,N-二甲基甲酰胺,或水,植物油,如菜油、蓖麻油、椰子油或大豆油以及合适的话还有硅油。
对于在控制蠕虫时在温血动物上的使用优选的施用形式包括溶液、乳液、悬浮液(浸液)、食品添加剂、散剂、包括泡腾片在内的片剂、大丸剂、胶囊、微胶囊和浇泼配制剂,其中必须考虑配制赋形剂的生理相容性。
片剂和大丸剂的粘结剂可以是可溶于水或醇中的化学改性的天然聚合物,如淀粉、纤维素或蛋白质衍生物(例如甲基纤维素、羧甲基纤维素、乙基羟乙基纤维素,蛋白质如玉米蛋白、明胶等),以及合成聚合物,如聚乙烯醇、聚乙烯基吡咯烷酮等。片剂还含有填料(例如淀粉、微晶纤维素、蔗糖、乳糖等)、助流剂和崩解剂。
若驱肠虫药以饲料浓缩物形式存在,则所用载体例如为功能饲料、饲料谷物或蛋白浓缩物。该类饲料浓缩物或组合物除了活性成分外还可以含有添加剂、维生素、抗生素、化疗药或其他杀虫剂,主要是抑菌剂、抑真菌剂、球虫抑制药,或者甚至激素制剂,具有促代谢作用的物质或促进生长、影响屠宰动物的肉质量或以另一方式对该有机体有益的物质。若组合物或其中所含式I的活性成分直接加入饲料或饮水槽中,则配制的饲料或饮用水优选以约0.0005-0.02重量%(5-200ppm)的浓度含有活性成分。
本发明的式I化合物可以单独使用或与其他生物杀伤剂组合使用。它们可以与具有相同活性范围的杀虫剂组合,以例如提高活性,或与具有另一活性范围的物质组合,以例如拓宽活性范围。也可能有意义的是加入所谓的驱避剂。若要将活性范围扩展到体内寄生虫,例如蠕虫,则适当的是将式I化合物与具有杀体内寄生虫性能的物质组合。当然,它们还可以与抗菌组合物结合使用。因为式I化合物是杀成虫药,即因为它们尤其对目标寄生虫的成虫阶段有效,因此加入攻击寄生虫的幼虫阶段的杀虫剂是非常有利的。由此可以覆盖绝大部分产生大的经济损害的那些寄生虫。此外,该作用明显有助于避免形成抗药性。许多组合还可能导致协同增效作用,即活性成分的总量可以降低,这从生态学观点来看是希望的。组合参与物的优选组和尤其优选的组合参与物在下文中提到,其中各组合除式I化合物外可以含有这些参与物中的一种或多种。
混合物中的合适配对可以是生物杀伤剂,例如活性机理可变的杀虫剂和杀螨剂,它们在下文提到且本领域熟练技术人员长时间就已知,例如甲壳质合成抑制剂、生长调节剂;起幼虫激素作用的活性成分;起杀成虫药作用的活性成分;广谱杀虫剂、广谱杀螨剂和杀线虫剂;以及众所周知的驱肠虫药和昆虫-和/或螨虫抑制物质,所述驱避剂或脱除剂。
合适杀虫剂和杀螨剂的非限制性实例例如公开于WO 2005/058802第13-15页第1-185号中。合适驱肠虫药的非限制性实例例如在WO2005/058802第16页第(A1)-(A12)号提到。合适驱避剂和脱除剂的非限制性实例是(i)DEET(N,N-二乙基间甲苯甲酰胺),(ii)KBR 3023 N-丁基-2-氧基羰基-(2-羟基)哌啶,以及(iii)噻螨胺(Cymiazole)=N,-2,3-二氢-3-甲基-1,3-噻唑-2-亚基-2,4-二甲苯胺。
该混合物中的所述参与物对本领域专家而言是熟知的。大多数描述于the Pesticide Manual,The British Crop Protection Council,London的各种版本中,而其他的描述于The Merck Index,Merck & Co.,Inc.,Rahway,New Jersey,USA的各种版本或专利文献中。包括基准物的合适参与物的列表公开于WO 2005/058802第16-21页第(I)-(CLXXXIII)号中。
由于上述详情,本发明的另一基本方面涉及用于在温血动物上控制寄生虫的组合制剂,其特征在于它们除了式I化合物外还含有至少一种具有相同或不同活性范围的其他活性成分和至少一种生理上可接受的载体。本发明不限于双重组合。
本发明组合物通常含有0.1-99重量%,尤其是0.1-95重量%式I、Ia的活性成分或其混合物,99.9-1重量%,尤其是99.8-5重量%固体或液体混合物,包括0-25重量%,尤其是0.1-25重量%表面活性剂。
将本发明组合物施用于待处理动物上可以局部、经口、胃肠外或皮下进行,其中该组合物以溶液、乳液、悬浮液(浸液)、散剂、片剂、大丸剂、胶囊和浇泼配制剂形式存在。
浇泼或蘸点方法包括将式I化合物施用于皮肤或表皮的特定位置,有利的是动物的颈或脊椎上。这例如通过将擦拭或喷雾的浇泼或蘸点配制剂施用于较小的表皮区域而进行,由于配制剂中各组分的扩散性质并由动物运动所辅助,活性物质从该区域几乎自动分散在宽范围的毛皮区域。
浇泼或蘸点配制剂适当地含有载体,后者促进在皮肤表面上或在宿主动物的表皮中快速分散并且通常被认为是扩散油。合适的载体例如为油溶液;醇溶液和异丙醇溶液,例如2-辛基十二烷醇或油醇的溶液;在单羧酸酯如肉豆蔻酸异丙酯、棕榈酸异丙酯、月桂酸草酸酯、油酸油酯、油酸癸酯、月桂酸己酯、油酸油酯、油酸癸酯、链长为C12-C18的饱和脂肪醇的癸酸酯中的溶液;二羧酸酯如邻苯二甲酸二丁酯、间苯二甲酸二异丙酯、己二酸二异丙酯、己二酸二正丁酯的溶液或脂族酸酯如脂族酸二醇酯的溶液。可能有利的是额外存在分散剂,如由药物或化妆品工业已知的分散剂。实例是2-吡咯烷酮、2-(N-烷基)吡咯烷酮、丙酮、聚乙二醇及其醚和酯、丙二醇或合成甘油三酯。
油溶液例如包括植物油如橄榄油、花生油、芝麻油、松油、亚麻子油或蓖麻油。植物油还可以以环氧化形式存在。还可以使用石蜡和硅油。
浇泼或蘸点配制剂通常含有1-20重量%式I化合物,0.1-50重量%分散剂和45-98.9重量%溶剂。
浇泼或蘸点方法对于在成群动物如牛、马、绵羊或猪上使用尤其有利的,其中经口或通过注射处理所有动物是困难或耗时的。由于其简单性,该方法当然还可以用于所有其他动物,包括单个家畜或宠物,并且对动物饲养员大为有利,因为通常可以在兽医专家不在场下进行。
然而,优选将市售产品配制成浓缩物,最终用户通常使用稀配制剂。
该类组合物还可以含有其他添加剂,如稳定剂、消泡剂、粘度调节剂、粘结剂或增粘剂,以及其他活性成分,以实现特殊功效。
由最终用户使用的这类组合物同样形成本发明的组成部分。
在本发明的各害虫控制方法中或在本发明的各害虫控制组合物中,式I的活性成分可以以其所有立体构型或其混合物使用。
本发明还包括一种预防保护温血动物,尤其是繁殖牲畜、家畜和宠物以防寄生害虫的方法,其特征在于将式I的活性成分或由其制备的活性成分配制剂作为饲料或饮用水添加剂或以固体或液体形式经口或通过注射或胃肠外方式给药于动物。本发明还包括用于所述方法之一的本发明式I化合物。
本发明化合物的优选配制剂按如下配制:
(%=重量百分数)
配制剂实施例
1.颗粒剂 a) b)
活性成分 5% 10%
高岭土 94% -
高度分散的硅酸 1% -
硅镁土 - 90%
将活性成分溶于二氯甲烷中,喷雾于载体上并随后通过真空蒸发浓缩溶剂。这类颗粒剂可以与动物饲料混合。
2.颗粒剂
活性成分 3%
聚乙二醇(Mw 200) 3%
高岭土 94%
(Mw=分子量)
在混合器中将细碎的活性成分均匀施用于已经用聚乙二醇润湿的高岭土上。以此方式得到无尘的涂敷颗粒。
3.片剂或大丸剂
I活性成分 33.00%
甲基纤维素 0.80%
高度分散的硅酸 0.80%
玉米淀粉 8.40%
II结晶乳糖 22.50%
玉米淀粉 17.00%
微晶纤维素 16.50%
硬脂酸镁 1.00%
I将甲基纤维素搅拌到水中。在材料溶胀之后,搅入硅酸并将该混合物均匀悬浮。混合活性成分和玉米淀粉。将含水悬浮液加入该混合物中并捏合成团。所得物质通过12M筛造粒并干燥。
II将所有4种赋形剂彻底混合。
III将根据I和II得到的初步混合物混合并压制成片剂或大丸剂。
4.注射剂
A.油性赋形剂(缓释)
1.活性成分 0.1-1.0g
花生油 加至100ml
2.活性成分 0.1-1.0g
芝麻油 加至100ml
制备:在搅拌和需要的话温和加热下将活性成分溶于部分油中,然后在冷却后配成所需体积并无菌滤过孔度为0.22mm的合适膜滤器。
B.水溶混性溶剂(平均释放速率)
活性成分 0.1-1.0g
4-羟甲基-1,3-二氧戊环(甘油缩甲醛) 40g
1,2-丙二醇 加至100ml
活性成分 0.1-1.0g
甘油二甲基缩酮 40g
1,2-丙二醇 加至100ml
制备:在搅拌下将活性成分溶于部分溶剂中,配成所需体积并无菌滤过孔度为0.22mm的合适膜滤器。
C.含水增溶物(快速释放)
1.活性成分 0.1-1.0g
聚乙氧基化蓖麻油(40个氧化乙烯单元) 10g
1,2-丙二醇 20g
苄醇 1g
注射用水 加至100ml
2.活性成分
0.1-1.0g
聚乙氧基化脱水山梨醇单油酸酯(20个氧化乙烯单元) 8g
4-羟甲基-1,3-二氧戊环(甘油缩甲醛) 20g
苄醇 1g
注射用水 加至100ml
制备:将活性成分溶于溶剂和表面活性剂中并用水配成所需体积。无菌滤过0.22mm孔度的合适膜滤器。
5.浇泼剂
A.
活性成分 5g
肉豆蔻酸异丙酯 10g
异丙醇 加至100ml
B.
活性成分 2g
月桂酸己酯 5g
中链甘油三酯 15g
乙醇 加至100ml
C.
活性成分 2g
油酸油酯 5g
N-甲基吡咯烷酮 40g
异丙醇 加至100ml
含水体系还可以优选用于口服和/或腔内给药。
组合物还可含有其他添加剂如稳定剂,例如合适的话环氧化的植物油(环氧化椰子油、油菜籽油或大豆油);消泡剂如硅油,防腐剂,粘度调节剂,粘结剂,增粘剂,以及肥料或其他活性成分以实现特殊功效。
还可将对式I化合物呈中性且对待治疗宿主动物没有有害作用的其他生物活性物质或添加剂以及无机盐或微生物加入所述组合物中。
下列实施例仅用于说明本发明而不限制本发明,术语活性成分表示实施例或表1、2或3中所列物质。
实施例1:2-[1-(2,6-二氯-4-三氟甲基苯基)-1H-吡咯并[3,2-b]吡啶-3-
基]-1,1,1-三氟丙-2-醇
a)向4-氮杂吲哚(400mg)在冷却到-78℃的干燥THF(10mL)中的溶液中一次加入N-溴琥珀酰亚胺(783mg)。将反应混合物在-78℃下搅拌2小时并温热至室温。然后倾倒于含有7gHM-N吸着剂的50mL卡盒(硅藻土载体填充的柱)上并用CH2Cl2洗脱,随后用丙酮洗脱。真空蒸发丙酮级分得到白色固体状4-氮杂-3-溴吲哚。
b)向4-氮杂-3-溴吲哚(680mg)在干燥DMF(7mL)中的溶液中加入碳酸钾(575mg)和3,5-二氯-4-氟三氟甲苯(630μL)。将反应混合物室温搅拌22小时,然后倾于含有7gHM-N吸着剂的50mL卡盒上。用CH2Cl2洗脱,在除去溶剂之后得到黄色固体状3-溴-1-(2,6-二氯-4-三氟甲基苯基)-1H-吡咯并[3,2-b]吡啶。
c)向3-溴-1-(2,6-二氯-4-三氟甲基苯基)-1H-吡咯并[3,2-b]吡啶(400mg)在冷却到-78℃的干燥THF(5mL)中的溶液中加入正丁基锂(n-BuLi,1.40mL,1.6M,在己烷中)。将反应混合物在-78℃下搅拌15分钟,然后滴加三氟丙酮(0.24mL)并再继续在-78℃下搅拌30分钟。小心加入饱和NaHCO3溶液并将该混合物用CH2Cl2萃取。合并的有机相用盐水洗涤,在MgSO4上干燥并过滤。在除去溶剂之后将残余物通过柱层析使用乙酸乙酯/己烷梯度提纯,在真空下蒸发后以白色固体得到标题化合物。
实施例2:乙酸1-[1-(2,6-二氯-4-三氟甲基苯基)-1H-吡咯并[3,2-b]吡啶-3-
基]-2,2,2-三氟-1-甲基乙基酯
向2-[1-(2,6-二氯-4-三氟甲基苯基)-1H-吡咯并[3,2-b]吡啶-3-基]-1,1,1-三氟丙-2-醇(100mg,根据实施例1合成)在氮气下的0℃干燥DMF(1mL)中的溶液中加入氢化钠(7mg,95%)。将反应混合物在0℃下搅拌15分钟并加入乙酰氯(25μL)。将该混合物室温搅拌20小时。在用饱和NaHCO3溶液和二氯甲烷终止之后,将该混合物在含有硅胶和HM-N的卡盒上过滤。将含有HM-N的卡盒用二氯甲烷洗涤。在除去溶剂之后将残余物通过在柱Daisogel C18-ODS AP上的制备型反相层析使用水/甲酸(10’000∶1)至乙腈/甲酸(10’000∶1)梯度提纯,在除去溶剂之后得到标题化合物。
实施例3:2-[6-(2,6-二氯-4-三氟甲基苯基)-6H-噻吩并[2,3-b]吡咯-4-
基]-1,1,1-三氟丙-2-醇
a)向6H-噻吩并[2,3-b]吡咯(250mg)在冷却到0℃的干燥THF(5mL)中的溶液中加入三氟乙酸酐(0.37mL)。将该混合物温热到室温并搅拌18小时。真空除去挥发物并将残余物通过柱层析使用乙酸乙酯/己烷梯度提纯,以米色固体得到2,2,2-三氟-1-(6H-噻吩并[2,3-b]吡咯-4-基)乙酮。
b)向2,2,2-三氟-1-(6H-噻吩并[2,3-b]吡咯-4-基)乙酮(252mg)在干燥DMF(5mL)中的溶液中加入干燥碳酸钾(158mg),然后加入3,5-二氯-4-氟三氟甲苯(266mg)。将所得悬浮液在90℃下搅拌24小时。在真空除去溶剂之后,将残余物分配在乙醚和水之间并将水相用乙醚萃取。合并的有机相在MgSO4上干燥,过滤并真空蒸发。残余物通过使用乙酸乙酯/己烷梯度的柱层析提纯,得到1-[6-(2,6-二氯-4-三氟甲基苯基)-6H-噻吩并[2,3-b]吡咯-4-基]-2,2,2-三氟乙酮。
c)向1-[6-(2,6-二氯-4-三氟甲基苯基)-6H-噻吩并[2,3-b]吡咯-4-基]-2,2,2-三氟乙酮(115mg)在冷却到0℃的干燥乙醚(5mL)中的溶液中缓慢加入甲基溴化镁(0.18mL,3M,在乙醚中)。将该混合物在5℃下搅拌2小时并温热至室温。然后将反应混合物用饱和氯化铵溶液处理并分离有机层。水相用乙醚萃取,合并的有机相在硫酸镁上干燥并过滤。在蒸发溶剂之后,将残余物通过在Daisogel C18-ODS AP柱上的制备型反相层析使用水/甲酸(10’000∶1)至乙腈/甲酸(10’000∶1)梯度提纯。通过除去溶剂分离出标题化合物。
使用实施例1-3中所述方法得到表1和2中所列出的下列化合物(MP=熔点)。在这些表中的变量Z-1至Z-12具有下列含义:
Z-1 Z-2 Z-3 Z-4
Z-5 Z-6 Z-7 Z-8
Z-9 Z-10 Z-11 Z-12。
表1
实施例 | X | Z | R | R6 | MP |
1.1 | CCl | Z-1 | Me | H | 蜡 |
1.2 | CCl | Z-1 | CH=CH2 | H | |
1.3 | CCl | Z-1 | C≡CH | H | |
1.4 | N | Z-1 | Me | H | |
1.5 | N | Z-1 | CH=CH2 | H | |
1.6 | N | Z-1 | C≡CH | H | |
1.7 | CCl | Z-2 | Me | H |
1.8 | CCl | Z-2 | CH=CH2 | H | |
1.9 | CCl | Z-2 | C≡CH | H | |
1.10 | N | Z-2 | Me | H | |
1.11 | N | Z-2 | CH=CH2 | H | |
1.12 | N | Z-2 | C≡CH | H | |
1.13 | CCl | Z-3 | Me | H | |
1.14 | CCl | Z-3 | CH=CH2 | H | |
1.15 | CCl | Z-3 | C≡CH | H | |
1.16 | N | Z-3 | Me | H | |
1.17 | N | Z-3 | CH=CH2 | H | |
1.18 | N | Z-3 | C≡CH | H | |
1.19 | CCl | Z-4 | Me | H | |
1.20 | CCl | Z-4 | CH=CH2 | H | |
1.21 | CCl | Z-4 | C≡CH | H | |
1.22 | N | Z-4 | Me | H | |
1.23 | N | Z-4 | CH=CH2 | H | |
1.24 | N | Z-4 | C≡CH | H | |
1.25 | CCl | Z-5 | Me | H | 189-190 |
1.26 | CCl | Z-5 | CH=CH2 | H | |
1.27 | CCl | Z-5 | C≡CH | H | |
1.28 | N | Z-5 | Me | H | |
1.29 | N | Z-5 | CH=CH2 | H | |
1.30 | N | Z-5 | C≡CH | H | |
1.31 | CCl | Z-6 | Me | H | |
1.32 | CCl | Z-6 | CH=CH2 | H | |
1.33 | CCl | Z-6 | C≡CH | H | |
1.34 | N | Z-6 | Me | H | |
1.35 | N | Z-6 | CH=CH2 | H | |
1.36 | N | Z-6 | C≡CH | H | |
1.37 | CCl | Z-7 | Me | H | 244-246 |
1.38 | CCl | Z-7 | CH=CH2 | H | |
1.39 | CCl | Z-7 | C≡CH | H | |
1.40 | N | Z-7 | Me | H | |
1.41 | N | Z-7 | CH=CH2 | H | |
1.42 | N | Z-7 | C≡CH | H | |
1.43 | CCl | Z-8 | Me | H | 187-190 |
1.44 | CCl | Z-8 | Et | H | |
1.45 | CCl | Z-8 | Me | COCH3 | |
1.46 | CCl | Z-8 | Me | CO2CH3 |
1.47 | CCl | Z-8 | Me | Me | |
1.48 | CCl | Z-8 | CH=CH2 | H | |
1.49 | CCl | Z-8 | C≡CH | H | |
1.50 | N | Z-8 | Me | H | |
1.51 | N | Z-8 | CH=CH2 | H | |
1.52 | N | Z-8 | C≡CH | H | |
1.53 | CCl | Z-9 | Me | H | |
1.54 | CCl | Z-9 | CH=CH2 | H | |
1.55 | CCl | Z-9 | C≡CH | H | |
1.56 | N | Z-9 | Me | H | |
1.57 | N | Z-9 | CH=CH2 | H | |
1.58 | N | Z-9 | C≡CH | H | |
1.59 | CCl | Z-10 | Me | H | |
1.60 | CCl | Z-10 | CH=CH2 | H | |
1.61 | CCl | Z-10 | C≡CH | H | |
1.62 | N | Z-10 | Me | H | |
1.63 | N | Z-10 | CH=CH2 | H | |
1.64 | N | Z-10 | C≡CH | H | |
1.65 | CCl | Z-11 | Me | H | 114-116 |
1.66 | CCl | Z-11 | CH=CH2 | H | |
1.67 | CCl | Z-11 | C≡CH | H | |
1.68 | N | Z-11 | Me | H | |
1.69 | N | Z-11 | CH=CH2 | H | |
1.70 | N | Z-11 | C≡CH | H | |
1.71 | CCl | Z-12 | Me | H | |
1.72 | CCl | Z-12 | CH=CH2 | H | |
1.73 | CCl | Z-12 | C≡CH | H | |
1.74 | N | Z-12 | Me | H | |
1.75 | N | Z-12 | CH=CH2 | H | |
1.76 | N | Z-12 | C≡CH | H |
表2
实施例 | Z | R | (R2)n | MP |
2.1 | Z-1 | Me | 4-NO2,6-Cl | |
2.2 | Z-1 | Me | 4-OCF3,6-Cl | |
2.3 | Z-1 | Me | 4-Cl,6-Cl | |
2.4 | Z-1 | Me | 4-Br,6-Cl | |
2.5 | Z-1 | Me | 4-C≡CH,6-Cl | |
2.6 | Z-1 | Me | 4-CN,6-Cl | |
2.7 | Z-1 | Me | 4-CF3,6-NO2 | |
2.8 | Z-1 | Me | 4-CF3,6-Br | |
2.9 | Z-1 | Me | 4-CF3,6-C≡CH | |
2.10 | Z-1 | Me | 4-CF3,6-CN | |
2.11 | Z-1 | Me | 4-SF5,6-Cl | |
2.12 | Z-8 | Me | 4-NO2,6-Cl | |
2.13 | Z-8 | Me | 4-OCF3,6-Cl | |
2.14 | Z-8 | Me | 4-Cl,6-Cl | |
2.15 | Z-8 | Me | 4-Br,6-Cl | |
2.16 | Z-8 | Me | 4-C≡CH,6-Cl | |
2.17 | Z-8 | Me | 4-CN,6-Cl | |
2.18 | Z-8 | Me | 4-CF3,6-NO2 | |
2.19 | Z-8 | Me | 4-CF3,6-Br | |
2.20 | Z-8 | Me | 4-CF3,6-C≡CH | |
2.21 | Z-8 | Me | 4-CF3,6-CN | |
2.22 | Z-8 | Me | 4-SF5,6-Cl | |
2.23 | Z-8 | CH=CH2 | 4-NO2,6-Cl | |
2.24 | Z-8 | CH=CH2 | 4-OCF3,6-Cl | |
2.25 | Z-8 | CH=CH2 | 4-Cl,6-Cl | |
2.26 | Z-8 | CH=CH2 | 4-Br,6-Cl | |
2.27 | Z-8 | CH=CH2 | 4-C≡CH,6-Cl | |
2.28 | Z-8 | CH=CH2 | 4-CN,6-Cl | |
2.29 | Z-8 | CH=CH2 | 4-CF3,6-NO2 | |
2.30 | Z-8 | CH=CH2 | 4-CF3,6-Br |
2.31 | Z-8 | CH=CH2 | 4-CF3,6-C≡CH | |
2.32 | Z-8 | CH=CH2 | 4-CF3,6-CN | |
2.33 | Z-8 | CH=CH2 | 4-SF5,6-Cl | |
2.34 | Z-8 | C≡CH | 4-NO2,6-Cl | |
2.35 | Z-8 | C≡CH | 4-OCF3,6-Cl | |
2.36 | Z-8 | C≡DH | 4-Cl,6-Cl | |
2.37 | Z-8 | C≡CH | 4-Br,6-Cl | |
2.38 | Z-8 | C≡CH | 4-C≡CH,6-Cl | |
2.39 | Z-8 | C≡CH | 4-CN,6-Cl | |
2.40 | Z-8 | C≡CH | 4-CF3,6-NO2 | |
2.41 | Z-8 | C≡CH | 4-CF3,6-Br | |
2.42 | Z-8 | C≡CH | 4-CF3,6-C≡CH | |
2.43 | Z-8 | C≡CH | 4-CF3,6-CN | |
2.44 | Z-8 | C≡CH | 4-SF5,6-Cl | |
2.45 | Z-11 | Me | 4-NO2,6-Cl | |
2.46 | Z-11 | Me | 4-OCF3,6-Cl | |
2.47 | Z-11 | Me | 4-Cl,6-Cl | |
2.48 | Z-11 | Me | 4-Br,6-Cl | |
2.49 | Z-11 | Me | 4-C≡CH,6-Cl | |
2.50 | Z-11 | Me | 4-CN,6-Cl | |
2.51 | Z-11 | Me | 4-CF3,6-NO2 | |
2.52 | Z-11 | Me | 4-CF3,6-Br | |
2.53 | Z-11 | Me | 4-CF3,6-C≡CH | |
2.54 | Z-11 | Me | 4-CF3,6-CN | |
2.55 | Z-11 | Me | 4-SF5,6-Cl |
生物学实施例:
1.体外抗血红扇头蜱(Rhipicephalus sanguineus)(犬蜱)的活性
将新鲜的成虫蜱种群用于接种含有待评价杀寄生虫活性的测试物质的适当配置的96孔板。各化合物通过系列稀释进行测试以测定其最小有效剂量(MED)。使蜱与测试化合物接触10分钟,然后在28℃和80%相对湿度下孵育7天,期间监测测试化合物的功效。若成虫蜱死亡则证实有杀螨活性。
在该测试中,第1.43号化合物在640ppm下显示出大于80%的功效。
2.体外抗猫跳蚤(Ctenocephalides felis(猫蚤))的活性
将混合的成虫蚤种群置于适当配置的96孔板中,允许蚤经由人工进食系统接近并进食处理过的血液。各化合物通过系列稀释进行测试以测定其MED。蚤进食处理过的血液24小时,然后记录化合物的功效。基于由进食系统回收的死亡蚤数目确定杀虫活性。
在该测试中,第1.43号化合物在100ppm下显示出大于80%的功效。
Claims (12)
1.下式化合物:
其中
Z为稠合碳环或杂环,苯环除外;
R1为卤素、氰基、硝基、C1-C6烷基、C3-C6环烷基、C2-C6链烯基、C2-C6炔基、羟基-C1-C6烷基、卤代-C1-C6烷基、羟基、C1-C6烷氧基、卤代-C1-C6烷氧基、SH、C1-C6烷硫基、卤代-C1-C6烷硫基、C1-C6烷基亚磺酰基、卤代-C1-C6烷基亚磺酰基、C1-C6烷基磺酰基、卤代-C1-C6烷基磺酰基、SO3R3、SO2NR3R4、NR3R4、COR3、COOR3或CONR3R4,其中若m大于1,则R1的含义可以相同或不同;
T为下式基团:
R2为卤素、氰基、硝基、C1-C6烷基、卤代-C1-C6烷基、C3-C6环烷基、C2-C6链烯基、C2-C6炔基、羟基、C1-C6烷氧基、卤代-C1-C6烷氧基、SH、C1-C6烷硫基、卤代-C1-C6烷硫基、C1-C6烷基亚磺酰基、卤代-C1-C6烷基亚磺酰基、C1-C6烷基磺酰基、卤代-C1-C6烷基磺酰基、SO3R3、SO2NR3R4、NR3R4、COR3、COOR3、CONR3R4或SF5,其中若n大于1,则R2的含义可以相同或不同;
R3和R4相互独立地为氢,未被取代或被卤素、氰基、NO2、C1-C4烷氧基、C1-C4烷基羰基、C1-C4烷基羰氧基或C1-C4烷氧羰基取代的C1-C6烷基,或者为C1-C2烷氧基-C1-C2烷基;
m表示0、1、2或3;
n表示1、2、3或4;
X为N或C(R2’),其中R2’为氢或独立地具有R2的含义;条件是若n为1,
则R2’不为氢;
Q为下式基团:
A为O、S、S(O)或S(O2);
R6为氢,C1-C6烷基,C1-C6羟烷基,C3-C6环烷基,C3-C6环烷基甲基,C1-C4烷氧基甲基,C1-C2烷氧基-C1-C2烷氧基甲基,苯基结构部分中未被取代或被卤素、C1-C2烷基、卤代-C1-C2烷基或C1-C2烷氧基取代的苯氧基甲基,苄氧基甲基,C2-C6链烯基,C2-C6炔基,卤代-C1-C6烷基,卤代-C3-C6环烷基,卤代-C1-C6环烷基甲基,卤代-C2-C6链烯基,卤代-C2-C6炔基,COR3,COOR3,CONR3R4,CSNR3R4,C1-C4烷基甲硅烷基,苯基或苯基-C1-C2烷基,其中苯基各自未被取代或被卤素、硝基、氰基、羟基、C1-C4烷基、卤代-C1-C4烷基、C1-C4烷氧基、卤代-C1-C4烷氧基、NH2、N-C1-C4烷基氨基、N,N-二-C1-C4烷基氨基、C1-C4烷硫基、COR3、COOR3或CONR3R4取代;
R7为C1-C6烷基、C2-C6链烯基、C2-C6炔基、卤代-C1-C6烷基、卤代-C2-C6链烯基、卤代-C2-C6炔基、C3-C8环烷基、卤代-C3-C8环烷基、羟基-C1-C6烷基、COR3或COOR3;以及
R8为氢;未被取代或被卤素、C1-C4烷硫基、羟基、C1-C4烷氧基、氨基或N-单-或N,N-二-C1-C4烷基氨基取代的C1-C6烷基;未被取代或卤素取代的C2-C6链烯基;未被取代或卤素取代的C2-C6炔基;未被取代或卤素取代的C3-C8环烷基;C5-C6环烷基甲基,其中该环烷基的1-3个碳原子可以被选自NH、N(C1-C4烷基)、O和S的杂原子替代;苄基;未被取代或被卤素、卤代-C1-C2烷基或卤代-C1-C2烷氧基取代的苯基;氰基、COR3或COOR3;
或者R7和R8与它们所连接的碳原子一起形成3-6个原子的脂族环,该环任选包括一个选自氮、硫或氧的额外杂原子或一个羰基,任选被1-4个相互独立地选自卤素、CN、NO2、羟基、C1-C4烷基和C1-C4烷氧基的取代基取代。
5.根据权利要求1-4中任一项的式I化合物,其中Q为上式III的基团,其中A为O,R6为氢,R7为CF3,并且R8为氢,未被取代或被卤素、羟基或C1-C2烷氧基取代的C1-C4烷基,C2-C4链烯基,C2-C4炔基,苄基,或未被取代或被卤素、卤代-C1-C2烷基或卤代-C1-C2烷氧基取代的苯基,优选氢、C1-C4烷基、卤代-C1-C4烷基、C2-C4链烯基或C2-C4炔基,尤其是氢、C1-C2烷基、CF3、乙烯基或乙炔基。
6.根据权利要求1的式I化合物,其中R1为卤素或C1-C4烷基;
m表示0、1或2;
T为式II的基团,其中X为N或C(R2’),n为1或2,以及R2和R2’各自独立地为卤素、氰基、硝基、C2-C4炔基、卤代-C1-C4烷基、卤代-C1-C4烷氧基或SF5,其中若n为2,则R2的含义可以相同或不同,
Q为式III的基团,其中A为O,R6为氢、C1-C4烷基或C(O)-C1-C2烷基,R7为C1-C4烷基或卤代-C1-C4烷基,R8为氢、C1-C4烷基、卤代-C1-C4烷基、C2-C4链烯基或C2-C4炔基,并且Z如前所定义。
9.根据权利要求1-7中任一项的式I化合物在除人以外的温血动物中或在除人以外的温血动物上以及在植物上控制体外寄生虫的用途。
10.一种在除人以外的温血动物中或在除人以外的温血动物上控制寄生虫的组合物,其除了生理上可接受的载体和/或分散剂外还含有有效量的根据权利要求1-7中任一项的式I化合物作为活性成分。
11.在除人以外的温血动物中或在除人以外的温血动物上以及在植物上控制寄生虫的方法,其中在寄生虫或其场所上使用有效量的根据权利要求1-7中任一项的式I化合物。
12.根据权利要求1-7中任一项的式I化合物在制备在温血动物中或在温血动物上或在植物上抵抗寄生虫的药物组合物中的用途。
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CN112321481A (zh) * | 2020-09-30 | 2021-02-05 | 杭州师范大学 | 一种手性吲哚类化合物及其制备方法 |
CN114206860A (zh) * | 2019-06-07 | 2022-03-18 | 礼蓝动物保健有限公司 | 用于治疗体内寄生虫的双环衍生物 |
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GB201004311D0 (en) | 2010-03-15 | 2010-04-28 | Proximagen Ltd | New enzyme inhibitor compounds |
EP2755974A1 (en) | 2011-09-14 | 2014-07-23 | Proximagen Limited | New enzyme inhibitor compounds |
JP5765371B2 (ja) * | 2013-06-14 | 2015-08-19 | 宇部興産株式会社 | ペンタフルオロスルファニル基を有する複素環オリゴマー化合物 |
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US5451566A (en) * | 1993-11-17 | 1995-09-19 | Zeneca Limited | Herbicidal pyrrolopyridine compounds |
JPH08311036A (ja) * | 1995-03-14 | 1996-11-26 | Takeda Chem Ind Ltd | ピラゾール誘導体、その用途 |
GB9810354D0 (en) * | 1998-05-14 | 1998-07-15 | Pfizer Ltd | Heterocycles |
JP2003040866A (ja) * | 2001-07-31 | 2003-02-13 | Nippon Kayaku Co Ltd | N置換インドール誘導体、その製造法及びそれを有効成分とする害虫防除剤 |
EP1783114A1 (en) * | 2005-11-03 | 2007-05-09 | Novartis AG | N-(hetero)aryl indole derivatives as pesticides |
CN101687789A (zh) * | 2007-02-12 | 2010-03-31 | 因特蒙公司 | C型肝炎病毒复制的新颖抑制剂 |
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CN114206860A (zh) * | 2019-06-07 | 2022-03-18 | 礼蓝动物保健有限公司 | 用于治疗体内寄生虫的双环衍生物 |
CN112321481A (zh) * | 2020-09-30 | 2021-02-05 | 杭州师范大学 | 一种手性吲哚类化合物及其制备方法 |
CN112321481B (zh) * | 2020-09-30 | 2022-06-10 | 杭州师范大学 | 一种手性吲哚类化合物及其制备方法 |
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