CN105960401B - 吡啶基或嘧啶基化合物 - Google Patents
吡啶基或嘧啶基化合物 Download PDFInfo
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- CN105960401B CN105960401B CN201480062769.4A CN201480062769A CN105960401B CN 105960401 B CN105960401 B CN 105960401B CN 201480062769 A CN201480062769 A CN 201480062769A CN 105960401 B CN105960401 B CN 105960401B
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Classifications
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- 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
- A01N43/80—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 one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,2
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D—HETEROCYCLIC COMPOUNDS
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- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
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- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
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- 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
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Abstract
本发明涉及通式(I)的化合物,或其生理上可接受的盐
Description
发明领域
本发明涉及新型吡啶基或嘧啶基化合物,它们的制备方法,它们在防治动物、特别是生产性家畜和家养动物中及其上的体内寄生虫中的用途,和含有这些化合物中的一种或多种的杀虫组合物。
发明概述
本发明涉及下式的新化合物,或其生理上可接受的盐
其中Z1和Z2各自独立地是N或CR1’;
R1和R1’彼此独立地是H、卤素、氰基、硝基、C1-C4-烷基、C1-C4-卤代烷基、C1-C4-烷氧基、C1-C3-卤代烷氧基、C1-C4-烷基硫基、卤代-C1-C4-烷基硫基、SF5、氨基、N-单-或N,N-二-C1-C4-烷基氨基、氨基磺酰基、N-单-或N,N-二-C1-C4-烷基氨基磺酰基、N-单-或N,N-二-卤代-C1-C4-烷基氨基磺酰基、C1-C4-烷基磺酰基、C1-C4-烷基亚磺酰基、C1-C4-烷基磺酰基氨基、卤代-C1-C4-烷基磺酰基、卤代-C1-C4-烷基亚磺酰基、卤代-C1-C4-烷基磺酰基氨基或苄基磺酰基氨基;
Q是Ar1或-C(O)-(O)m-R2,
m是0或1;R2是C1-C6-烷基或C3-C8-环烷基;
Ar1是(i) 被1个或2个相同或不同的选自以下的取代基取代的苯基:卤素、氰基、硝基、C1-C4-烷基、C1-C4-卤代烷基、C1-C4-烷氧基、C1-C4-卤代烷氧基、C1-C4-烷基硫基、卤代-C1-C4-烷基硫基、SF5、氨基、N-单-或N,N-二-C1-C4-烷基氨基、氨基磺酰基、N-单-或N,N-二-C1-C4-烷基氨基磺酰基、N-单-或N,N-二-卤代-C1-C4-烷基氨基磺酰基、C1-C4-烷基磺酰基、C1-C4-烷基亚磺酰基、C1-C4-烷基磺酰基氨基、苄基磺酰基氨基、卤代-C1-C4-烷基磺酰基、卤代-C1-C4-烷基亚磺酰基和卤代二氧杂环戊烯基;或是(ii) 杂芳基,其选自2-、3-或4-吡啶基和2-或3-噻吩基,其各自未被取代或例如被甲基、乙基、卤素、CF3或羧基取代;
Ar2是被1至3个相同或不同的选自以下的取代基取代的苯基:卤素、氰基、硝基、C1-C4-烷基、C1-C4-卤代烷基、C1-C4-烷氧基、C1-C4-卤代烷氧基、C1-C4-烷基硫基、卤代-C1-C4-烷基硫基、SF5、氨基、N-单-或N,N-二-C1-C4-烷基氨基、氨基磺酰基、N-单-或N,N-二-C1-C4-烷基氨基磺酰基、N-单-或N,N-二-卤代-C1-C4-烷基氨基磺酰基、C1-C4-烷基磺酰基、C1-C4-烷基亚磺酰基、C1-C4-烷基磺酰基氨基、苄基磺酰基氨基、卤代-C1-C4-烷基磺酰基、卤代-C1-C4-烷基亚磺酰基和卤代二氧杂环戊烯基;
L1是下式的双官能连接基基团
L2是下式的双官能连接基基团
A和B各自独立地是分别包含两个N-原子的C3-C8-杂-亚环烷基(hetero-cycloalkylene)或C5-C10-杂-亚双环烷基(hetero-bicycloalkylene),其各自未被取代或被C1-C2-烷基取代;
A1、A2、B1和B2各自独立地是分别包含N-原子的C3-C8-杂-亚环烷基;
R和R’彼此独立地是H或C1-C4-烷基。
本发明还提供包含式(I)的化合物或其盐和至少一种选自表面活性剂、固体稀释剂和液体稀释剂的额外组分的组合物。
在一个实施方案中,本发明还提供用于防治寄生虫、特别是体内寄生虫的组合物,所述组合物包含生物有效量的式(I)的化合物或其盐,以及至少一种选自表面活性剂、固体稀释剂和液体稀释剂的额外组分,所述组合物任选进一步包含生物有效量的至少一种额外的生物活性化合物或试剂。
发明详述
在上文描述中,单独使用或在复合词诸如“烷基硫基”或“卤代烷基”中使用的术语“烷基”包括直链或支链烷基,诸如甲基、乙基、正丙基、异丙基或不同的丁基、戊基或己基异构体。
“烷氧基”包括例如甲氧基、乙氧基、正丙氧基、异丙氧基和不同的丁氧基、戊氧基和己氧基异构体。“烷基硫基”包括支链或直链烷基硫基基团,诸如甲基硫基、乙基硫基和不同的丙基硫基、丁基硫基、戊基硫基和己基硫基异构体。
“烷基亚磺酰基”包括烷基亚磺酰基的两种对映异构体。“烷基亚磺酰基”的实例包括CH3S(O)-、CH3CH2S(O)-、CH3CH2CH2S(O)-、(CH3)2CHS(O)-和不同的丁基亚磺酰基异构体。
“烷基磺酰基”的实例包括CH3S(O)2-、CH3CH2S(O)2-、CH3CH2CH2S(O)2-、(CH3)2CHS(O)2-和不同的丁基磺酰基异构体。
“N-烷基氨基”、“N,N-二-烷基氨基”等类似于上文实例进行定义。
“亚环烷基”包括,例如,亚环丙基、亚环丁基、亚环戊基、亚环己基、亚环庚基或亚环辛基,优选亚环丙基、亚环丁基、亚环戊基、亚环己基,且特别是亚环戊基、亚环己基。
包含1个或2个杂原子的杂-亚双环烷基基团的实例是下式的基团
其中r和s彼此独立地是整数0、1或2。优选的杂亚双环烷基基团的实例是螺-二氮杂-C5-C10-亚烷基,诸如1,6-或2,6-二氮杂螺-[3.3]亚庚基,1,6-或2,6-二氮杂螺-[3.4]亚辛基或1,7-或2,7-二氮杂螺-[4.4]亚壬基。
单独使用或在复合词诸如“卤代烷基”中使用的术语“卤素”包括氟、氯、溴或碘。此外,当在复合词诸如“卤代烷基”中使用时,所述烷基可以被可相同或不同的卤素原子部分或全部取代。“卤代烷基”的实例包括F3C-、ClCH2-、CF3CH2-和CF3CCl2-。术语“卤代环烷基”、“卤代烷氧基”、“卤代烷基硫基”等类似于术语“卤代烷基”进行定义。“卤代烷氧基”的实例包括CF3O-、CCl3CH2O-、HCF2CH2CH2O-和CF3CH2O-。“卤代烷基硫基”的实例包括CCl3S-、CF3S-、CCl3CH2S-和ClCH2CH2CH2S-。“卤代烷基亚磺酰基”的实例包括CF3S(O)-、CCl3S(O)-、CF3CH2S(O)-和CF3CF2S(O)-。“卤代烷基磺酰基”的实例包括CF3S(O)2-、CCl3S(O)2-、CF3CH2S(O)2-和CF3CF2S(O)2-。
取代基中碳原子的总数以“Ci-Cj”前缀表示,其中i和j是整数。例如,C1-C4烷基磺酰基表示甲基磺酰基至丁基磺酰基;C2-烷氧基烷基表示CH3OCH2;C3-烷氧基烷基表示例如CH3CH(OCH3)、CH3OCH2CH2或CH3CH2OCH2;且C4-烷氧基烷基表示被总共含有四个碳原子的烷氧基取代的烷基的各种异构体,实例包括CH3CH2CH2OCH2和CH3CH2OCH2CH2-。
当化合物被具有表明所述取代基的数目可以超过1的下标的取代基取代时,所述取代基(当它们超过1时)独立地选自定义的取代基的组,例如(R2)n,n为1或2。
“芳香族的”表明各环原子基本上在相同平面并且具有垂直于环平面的p-轨道,并且其中(4n+2)π电子(其中n是正整数)与环相关,以符合Hϋckel氏规则。
在式(I)的化合物中,R1和R1’各自独立地优选为H、卤素、氰基、C1-C2-烷基、C1-C2-卤代烷基、C1-C2-烷氧基、C1-C2-卤代烷氧基、C1-C2-烷基硫基、氨基或N-单-或N,N-二- C1-C2-烷基氨基,更优选H、卤素、氰基、C1-C2-烷基、C1-C2-烷氧基、C1-C2-烷基硫基或N,N-二-C1-C2-烷基氨基,且特别是H、氰基、甲基或甲氧基。R1优选为H、氰基、甲基或甲氧基,更优选H或氰基,且特别是H。R1’优选为H、氰基、甲基或甲氧基,更优选H、氰基或甲氧基,且特别是H。
根据一个实施方案,Z1是N且Z2是CR1', 其中对于R1’,上面给出的含义和优选方案适用。最优选地,Z1是N且Z2是CH。
根据另一个实施方案,Z1和Z2均为N。
根据又一个实施方案,Z1是CR1’且Z2是N, 其中对于R1’,上面给出的含义和优选方案适用。最优选地,Z1是CH且Z2是N。
根据又一个实施方案,Z1和Z2各自独立地是CR1’,其中对于R1’,适用上面给出的含义和优选方案,特别是均为CH。
Ar1作为苯基优选为被1个或2个相同或不同的选自以下的取代基取代的苯基:卤素、氰基、硝基、C1-C2-烷基、C1-C2-卤代烷基、C1-C2-烷氧基或C1-C2-卤代烷氧基。尤其优选的苯基基团Ar1是被1个或2个相同或不同的选自以下的基团取代的苯基:卤素、氰基和C1-C2-卤代烷基,特别是氯、氟、氰基或CF3。特别优选的苯基基团 Ar1是被CF3单取代的苯基,尤其是4-CF3-苯基。
优选的杂芳基基团Ar1是2-、3-或4-吡啶基,其未被取代或例如被甲基、乙基、卤素、CF3或羧基取代。特别优选的杂芳基基团Ar1是2-或3-吡啶基,其未被取代或被卤素或CF3取代,尤其是5-CF3-吡啶-2-基或6-CF3-吡啶-3-基。
R2优选为C1-C4-烷基或C3-C6-环烷基,特别是叔丁基、环丙基、环丁基、环戊基或环己基,特别是叔丁基或环丙基,尤其是叔丁基。
优选的基团 Q是被1个或2个相同或不同的选自氯、氟、氰基或CF3的基团取代的苯基:未被取代或被卤素或CF3取代的2-或3-吡啶基;或者是–C(O)-(O)0-1-R2,其中R2是C1-C4-烷基或C3-C6-环烷基。特别优选的基团 Q是4-CF3-苯基、5-CF3-吡啶-2-基、6-CF3-吡啶-3-基、-C(O)-O-叔丁基或-C(O)-环丙基。
Ar2作为苯基优选为被1个或2个相同或不同的选自以下的取代基取代的苯基:卤素、氰基、硝基、C1-C4-烷基、C1-C2-卤代烷基、C1-C2-烷氧基、C1-C2-卤代烷氧基、C1-C2-烷基硫基、C1-C2-卤代烷基硫基、C1-C2-烷基磺酰基、卤代-C1-C2-烷基磺酰基、氨基、N-单-和N,N-二-C1-C4-烷基氨基、氨基磺酰基和C1-C2-烷基氨基磺酰基。甚至更优选的苯基基团 Ar2是被1个或2个相同或不同的选自以下的基团取代的苯基:卤素、氰基、硝基、C1-C4-烷基、C1-C2-卤代烷基、C1-C2-烷氧基、C1-C2-卤代烷氧基、C1-C2-卤代烷基硫基、C1-C2-烷基磺酰基、卤代-C1-C2-烷基磺酰基、氨基和C1-C2-烷基氨基磺酰基。特别优选的苯基基团 Ar2是被1个或2个相同或不同的选自以下的基团取代的苯基:卤素、氰基、硝基、C1-C2-卤代烷基、C1-C2-卤代烷氧基或C1-C2-卤代烷基硫基。尤其优选的苯基基团 Ar2是被2个相同或不同的选自以下的基团取代的苯基:氟、氰基、硝基和CF3。特别优选的基团 Ar2的实例是4-硝基-3-CF3-苯基、4-氰基-2-CF3-苯基、4-氰基-3-CF3-苯基、3,4-二-CF3-苯基、4-CF3-3-氟苯基、3-CF3-4-氟苯基,特别是4-氰基-3-CF3-苯基。
基团 L1和L2可以是相同或不同的,特别是不同的。
关于基团L1,适用以下优选方案:
变量A优选为分别包含两个N-原子的未取代的杂-亚环烷基或杂-亚双环烷基基团,尤其是C3-C6-杂-亚环烷基或C5-C8-杂-亚双环烷基。
式(IIa)的优选连接基L1是基团
其中s和r各自独立地是整数1或2,且r'是整数0、1或2;在上式中,s和r之一优选为1,且另一个为1或2,且r'优选为1或2,特别是为1。
式(IIa)的双官能连接基的实例是
。
式(IIb)的优选的双官能连接基是基团
其中s'是整数0、1或2,且R是H或甲基,特别是H。
式(IIb)的双官能连接基的实例是
。
式(IIc)的优选的双官能连接基是基团
其中s'是整数0、1或2,特别是1或2,且R是H或甲基。
式(IIc)的合适的双官能连接基的实例是基团
。
特别优选的基团 L1是基团。
关于基团L2,适用以下优选方案:
B优选为包含两个N-原子的未取代的杂-亚环烷基或杂-亚双环烷基基团,尤其是C3-C6-杂-亚环烷基,特别是C3-C4-杂-亚环烷基。
式(IIIa)的优选的双官能连接基L2是下式的基团
其中r''是0或1,特别是基团。
式(IIIb)的优选的双官能连接基L2是下式的基团
其中s''是整数0、1或2,且R'是H或甲基,特别是H;尤其是
基团。
式(IIIc)的优选的双官能连接基L2是下式的基团
其中s'是整数0、1或2,特别是1或2,且R'是H或甲基,特别是H。实例是基团。
特别优选的基团L2的实例是基团
。
根据本发明的一组优选化合物具有下式
其中对于R1、R2、m、L1、L2、Z1、Z2和Ar2,各自适用上面给出的含义和优选方案。
根据本发明的另一组优选化合物具有下式
其中对于R1、Ar1、Ar2、L1、L2、Z1和Z2,各自适用上面给出的含义和优选方案,或是其生理上可接受的盐。
本发明的一个优选的实施方案涉及上式(I)的化合物,或其生理上可接受的盐,其中Z1和Z2各自独立地是N或CR1’;
R1和R1’彼此独立地是H、氰基、甲基或甲氧基,特别是H;
Q是被1个或2个相同或不同的选自氯、氟、氰基或CF3的基团取代的苯基:未被取代或被卤素或CF3取代的2-或3-吡啶基;或是–C(O)-(O)0-1-R2,其中R2是C1-C4-烷基或C3-C6-环烷基;
Ar2是被2个相同或不同的选自氟、氰基、硝基和CF3的基团取代的苯基;
L1是基团
L2是基团。
本发明的另一个优选的实施方案涉及下式的化合物,或其生理上可接受的盐,
其中Q是4-CF3-苯基、5-CF3-吡啶-2-基、6-CF3-吡啶-3-基、-C(O)-O-叔丁基或-C(O)-环丙基;
Z1是N或CH,特别是N;
Z2是N或CH,特别是CH;
L1是基团
L2是基团
R3是CF3;且R3’是氰基或硝基,特别是氰基。
式(I)的化合物可以例如通过以下来制备:使下式的化合物
其中R1、Z1和Z2各自如上所定义,且X1和X2各自独立地是离去基团,例如卤素,特别是氯;
相继与下式各化合物
其中Q、Ar2、L1和L2各自如上所定义;
以本身已知的方式,特别是在适合于上式(IV)的吡啶或嘧啶的芳香族亲核取代的介质中,进行反应。反应条件根据所用的式(Va)或(Vb)的化合物的反应性而变化。与具有末端伯氨基或仲氨基的式(Va)或(Vb)的化合物相比,具有末端羟基或巯基的式(Va)或(Vb)的化合物与式(IV)的化合物更容易反应,例如在非质子偶极溶剂中在室温下,其优选在偶极非质子溶剂中在较高温度诸如70至120℃下,任选地在催化剂诸如Pd(OAc)2、RuPhos等存在的情况下反应。卤代吡啶类和卤代嘧啶类的这些芳香族亲核取代反应的具体实例是已知的,例如,从J.Med.Chem. 2011, Vol 54, p.6563-6585、J.Med.Chem. 2009, Vol 52,p.5999-6011或Chem.Science 2011, Vol.2, p.57-68已知。
式(IV)的化合物是已知的或可以通过本身已知的方法获得。式(Va)和(Vb)的化合物同样可以通过本身已知的方法获得,例如通过卤代化合物Ar1或Ar2与化合物H-L1-H或H-L2H的芳香族亲核取代来获得。
化合物I的盐可以以已知方式产生。化合物I的酸加成盐,例如,可通过用合适的酸或合适的离子交换试剂处理而获得,且与碱的盐可通过用合适的碱或合适的离子交换试剂处理而获得。
化合物I的盐可以通过常规方式转化为游离的化合物I,酸加成盐例如通过用合适的碱性组合物或用合适的离子交换试剂处理,且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的盐可以以已知方式转化为化合物I的其它盐;酸加成盐可以转化为例如其它酸加成盐,例如通过在合适的溶剂中用合适的金属盐(诸如酸的钠、钡或银盐,例如用乙酸银)处理无机酸的盐(诸如盐酸盐),在所述合适的溶剂中,所得无机盐,例如氯化银,是不可溶的且因此从反应混合物中沉淀出来。
取决于方法和/或反应条件,具有成盐特征的化合物I可以以游离形式或以盐的形式获得。
化合物I也可以以它们的水合物的形式获得,和/或也可以包括其它溶剂,其例如在必要时用于以固体形式存在的化合物的结晶。
式I的化合物可以任选地作为光学和/或几何异构体或作为其混合物存在。本发明涉及纯异构体和所有可能的异构混合物两者,并且上文和下文应如此理解,即使在每种情况下没有特别提到立体化学细节。
可通过所述方法或以另一种方式获得的式(I)化合物的非对映异构的混合物可以以已知方式基于它们的组分的物理-化学差异分离为纯非对映异构体,例如通过分级结晶、蒸馏和/或层析。
将可相应获得的对映异构体的混合物拆分为纯异构体可以通过已知的方法实现,例如通过从光学活性溶剂中重结晶,通过手性吸附剂上的层析,例如通过乙酰纤维素上的高压液相层析(HPLC),在适当的微生物的帮助下,通过用特定的固定化酶裂解,通过形成包合化合物,例如使用手性冠醚,由此络合仅一种对映异构体。
根据本发明的化合物(I)具有显著的宽活性谱,并且是用于温血动物、尤其是家畜和家养动物中及其上的害虫防治,包括特别是体内寄生虫和体外寄生虫、尤其是蠕虫的防治的有价值的活性成分,同时被温血动物和鱼良好耐受。
在本发明的上下文中,体外寄生虫应理解为特别是昆虫、螨虫和蜱虫。这些包括以下目的昆虫:鳞翅目(Lepidoptera)、鞘翅目(Coleoptera)、同翅目(Homoptera)、异翅目(Heteroptera)、双翅目(Diptera)、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,可以特别提及的体外寄生虫是困扰人和动物并且携带病原体的那些,例如蝇类诸如家蝇(Musca domestica)、灌木丛蝇(Musca vetustissima)、秋蝇(Musca autumnalis)、黄腹厕蝇(Fannia canicularis)、尸食性麻蝇(Sarcophaga carnaria)、铜绿蝇(Lucilia cuprina)、牛皮蝇(Hypoderma bovis)、纹皮蝇(Hypoderma lineatum)、绿藻金蝇(Chrysomyia chloropyga)、人皮蝇(Dermatobia hominis)、嗜人锥蝇 (Cochliomyia hominivorax)、肠胃蝇(Gasterophilus intestinalis)、羊狂蝇(Oestrus ovis)、厩螫蝇(Stomoxys calcitrans)、扰血蝇(Haematobia irritans),和蚊类(长角亚目(Nematocera)),诸如蚊科(Culicidae)、蚋科(Simuliidae)、毛蠓科(Psychodidae),以及吸血寄生虫,例如蚤类,诸如猫栉头蚤(Ctenocephalides felis)和犬栉头蚤(Ctenocephalides canis)(猫和狗蚤类)、印鼠客蚤(Xenopsylla cheopis)、致痒人蚤(Pulex irritans)、穿皮潜蚤(Dermatophilus penetrans),虱类,诸如Damalina ovis、人虱(Pediculus humanis),咬蝇和马蝇(虻科(Tabanidae)),麻虻属(Haematopota spp.),诸如鸻麻虻(Haematopota pluvialis),Tabanidea属(Tabanidea spp.),诸如Tabanus nigrovittatus,斑虻属(Chrysopsinaespp.),诸如盲斑虻(Chrysops caecutiens),采采蝇(tsetse flies),诸如舌蝇属(speciesof Glossinia),咬虫,特别是蜚蠊,诸如德国蜚蠊(Blatella germanica)、东方蜚蠊(Blatta orientalis)、美洲大蠊(Periplaneta americana),螨类,诸如鸡皮刺螨(Dermanyssus gallinae),疥螨(Sarcoptes scabiei)、羊痒螨(Psoroptes ovis)和疮螨属(Psorergates spp.)和最后但并非最不重要的蜱类。后者属于蜱螨目。已知的蜱类的代表是例如牛蜱属(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)、牛壁虱属(Margaropus)、扇头蜱属(Rhipicephalus)、锐缘蜱属(Argas)、耳蜱属(Otobius)和钝缘蜱属(Ornithodoros)等,其优选侵扰温血动物,包括农场动物,诸如牛、猪、绵羊和山羊,家禽诸如小鸡、火鸡和鹅,毛皮动物诸如貂、狐狸、毛丝鼠、兔等,以及家养动物诸如猫和狗,还有人。
根据本发明的式(I)的化合物对显示正常敏感性的动物害虫以及显示耐受性的那些害虫(诸如昆虫和蜱螨目的成员)的所有或各个发育阶段也是有效的。本发明的活性物质的杀昆虫、杀卵和/或杀螨效果可以自身直接显现,即立即或在经过一段时间之后杀死害虫,例如当蜕皮发生时,或通过破坏它们的卵,或者间接显现,例如降低产卵的数目和/或孵化速率,其具有对应于至少50至60%的杀虫率(死亡率)的良好效力。
化合物(I)还可以用于抗卫生害虫,尤其是双翅目(Diptera)的麻蝇科(Sarcophagidae)、Anophilidae和蚊科(Culicidae);直翅目(Orthoptera)、网翅目(Dictyoptera)(例如蜚蠊科(Blattidae))和膜翅目(Hymenoptera)(例如,蚁科(Formicidae))。
特别是,所述化合物对蠕虫有效,其中体内寄生的线虫类和吸虫类可引起哺乳动物和家禽的严重疾病,所述哺乳动物和家禽例如绵羊、猪、山羊、牛、马、驴、狗、猫、豚鼠或外来禽类,特别是绵羊或尤其是牛。该适应症的典型线虫是:血矛线虫属(Haemonchus)、毛圆线虫属(Trichostrongylus)、奥斯特线虫属(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)、毛线线虫属(Trichonema)、网尾线虫属(Dictyocaulus)、毛细线虫属(Capillaria)、异刺线虫属(Heterakis)、弓蛔虫属(Toxocara)、禽蛔虫属(Ascaridia)、尖尾线虫属(Oxyuris)、钩口线虫属(Ancylostoma)、钩虫属(Uncinaria)、弓蛔线虫属(Toxascaris)、恶丝虫属(Dirofilaria)、棘唇线虫属(Acanthocheilonema)和副蛔虫属(Parascaris)。吸虫类特别包括拟片吸虫属(Fasciolideae),尤其是肝片形吸虫(Fasciola hepatica)。
还可以令人惊讶和出乎意料地显示,式(I)的化合物对于对许多活性物质耐受的线虫具有异常高效力。这可以在体外通过LDA测试和在体内例如在蒙古沙鼠中得到证明。显示杀死捻转血矛线虫(Haemonchus contortus)或蛇形毛圆线虫(Trichostrongylus colubriformis)的敏感株的活性物质的量在防治对苯并咪唑类或左旋咪唑耐受的对应株中也是足够有效的。
细颈线虫属(Nematodirus)、古柏线虫属(Cooperia)和结节线虫属(Oesophagostonum)的某些害虫侵扰宿主动物的肠道,而血矛线虫属(Haemonchus)和奥斯特线虫属(Ostertagia)的其它害虫在胃中寄生,网尾线虫属(Dictyocaulua)的那些害虫在肺组织中寄生。丝虫科(Filariidae)和丝状科(Setariidae)的寄生虫可见于内部细胞组织和器官(例如心脏、血管、淋巴管和皮下组织)中。特别值得注意的寄生虫是狗的心丝虫—犬恶丝虫(Dirofilaria immitis)。式(I)的化合物对这些寄生虫是非常有效的。
可以通过式I的化合物防治的害虫还包括来自绦虫纲(Cestoda)(绦虫)的那些,例如中殖孔科(Mesocestoidae),尤其是中殖孔绦虫属 (Mesocestoides),特别是线中殖孔绦虫(M. lineatus);复孔绦虫科(Dilepidide),尤其是犬复孔绦虫(Dipylidium caninum)、约优克斯绦虫属(Joyeuxiella spp.),特别是Joyeuxiella pasquali和复孔绦虫属(Diplopylidium spp.),以及带绦虫科(Taeniidae),尤其是豆状绦虫(Taenia pisiformis)、獐绦虫(Taenia cervi)、羊绦虫(Taenia ovis)、水泡绦虫(Taneia hydatigena)、多头绦虫 (Taenia multiceps)、巨颈绦虫(Taenia taeniaeformis)、锯齿状绦虫(Taenia serialis)和棘球绦虫属(Echinocuccus spp.),最优选水泡绦虫(Taneia hydatigena)、羊绦虫(Taenia ovis)、多头绦虫(Taenia multiceps)、锯齿状绦虫(Taenia serialis);细粒棘球绦虫(Echinocuccus granulosus)和细粒棘球绦虫(Echinococcus granulosus)和多房棘球绦虫(Echinococcus multilocularis)以及多头绦虫(Multiceps multiceps)。
最特别地,水泡绦虫(Taenia hydatigena)、豆状绦虫(T. pisiformis)、羊绦虫(T. ovis)、巨颈绦虫(T. taeniaeformis)、多头绦虫(Multiceps multiceps)、Joyeuxiella pasquali、犬复孔绦虫(Dipylidium caninum)、中殖孔绦虫属(Mesocestoides spp.)、细粒棘球绦虫(Echinococcus granulosus)和多房棘球绦虫(E. multilocularis)与恶丝虫属(Dirofilaria ssp.)、钩虫属(Ancylostoma ssp.)、弓蛔虫属(Toxocara ssp.)和/或狐毛尾线虫(Trichuris vulpis)在狗和猫上或其内同时得到防治。同样优选地,猫栉头蚤(Ctenocephalides felis)和/或犬栉头蚤(C.canis)与上面提及的线虫类和绦虫类同时得到防治。
此外,式(I)的化合物适合于防治人致病寄生虫。这些中,出现于消化道中的典型代表是钩虫属(Ancylostoma)、板口线虫属(Necator)、蛔虫属(Ascaris)、类圆线虫属(Strongyloides)、旋毛线虫属(Trichinella)、毛细线虫属(Capillaria)、鞭虫属(Trichuris)和蛲虫属(Enterobius)的那些。本发明的化合物对出现于血液中、组织中和各种器官中的来自丝虫科(Filariidae)的吴策丝虫属(Wuchereria)、布鲁格丝虫属(Brugia)、盘尾丝虫属(Onchocerca)和洛阿丝虫属(Loa)以及对特别侵扰胃肠道的龙线虫属(Dracunculus)及类圆线虫属(Strongyloides)和旋毛线虫属(Trichinella)的寄生虫也是有效的。
根据本发明的式(I)的化合物的良好杀虫活性对应于所提及的害虫的至少 50-60%的死亡率。特别是,式(I)的化合物具有突出的的异常长的效力持续时间。
式(I)的化合物优选以未修饰的形式或优选与制剂领域中常规使用的辅助剂一起应用,因此可以以已知的方式处理,以得到例如乳油(emulsifiable concentrates)、可直接稀释的溶液、稀乳液、可溶粉末、颗粒或聚合物质中的微胶囊。与所述组合物一样,施用方法根据预期目标和流行情况进行选择。
制剂,即,含有式(I)的活性成分或这些活性成分与其它活性成分和任选固体或液体辅助剂的组合的药剂、制品或组合物,以本身已知的方式制备,例如通过将活性成分与展着组合物,例如与溶剂、固体载体和任选表面活性化合物(表面活性剂) 密切混合和/或研磨而制备。
所述溶剂可以是:醇类,诸如乙醇、丙醇或丁醇,以及二醇类和它们的醚和酯,诸如丙二醇、二丙二醇醚、乙二醇、乙二醇单甲基或-乙基醚,酮类,诸如环己酮、异佛尔酮或双丙酮醇(diacetanol alcohol),强极性溶剂,诸如N-甲基-2-吡咯烷酮、二甲亚砜或二甲基甲酰胺,或水,植物油类,诸如菜油、蓖麻油、椰子油或大豆油,以及(如果合适)硅油。
在蠕虫的防治中在温血动物上使用的优选施用形式包括溶液、乳液、悬浮液(顿服剂(drenches))、食物添加剂、粉末、片剂(包括泡腾片剂)、大丸剂、胶囊、微胶囊和浇泼(pour-on)制剂,由此必须考虑制剂赋形剂的生理相容性。
用于片剂和大丸剂(boli)的粘合剂可以是化学改性的聚合的天然物质,其可溶于水或醇,诸如淀粉、纤维素或蛋白衍生物(例如甲基纤维素、羧甲基纤维素、乙基羟基乙基纤维素、蛋白诸如玉米醇溶蛋白、明胶等)以及合成的聚合物,诸如聚乙烯醇、聚乙烯吡咯烷酮等。所述片剂还含有填充剂(例如,淀粉、微晶纤维素、糖、乳糖等)、助流剂和崩解剂。
如果抗蠕虫剂以饲料浓缩物的形式存在,则所使用的载体是例如性能饲料、饲料谷物或蛋白浓缩物。除了活性成分以外,此类饲料浓缩物或组合物还可以含有添加剂、维生素、抗生素、化疗剂或其它杀虫剂,主要是抑细菌剂、抑真菌剂、抑球虫剂或者甚至激素制剂、具有合成代谢作用的物质或促进生长、影响屠宰动物的肉质或以另一种方式对生物体有利的物质。如果将所述组合物或其中含有的式I的活性成分直接添加至饲料或饮用水槽,则配制的饲料或饮品含有优选约0.0005至0.02重量%(5-200 ppm)的浓度的活性成分。
根据本发明的式(I)的化合物可以单独使用或与其它杀生物剂组合使用。它们可以与具有相同范围活性的杀虫剂组合,例如以增加活性,或与具有另一范围活性的物质组合,例如以拓宽活性范围。也可以合理添加所谓的驱虫剂。如果要将活性范围延伸至体内寄生虫,例如蠕虫,则将式I的化合物合适地与具有体内寄生特性的物质组合。当然,它们也可以与抗细菌组合物组合使用。由于式I的化合物是杀成虫剂,即由于它们特别是对成年期的目标寄生虫有效,所以添加反而攻击幼年期的寄生虫的杀虫剂可能是非常有利的。以该方式,将覆盖最大部分的那些产生很大经济损失的寄生虫。而且,该作用将实质上有助于避免耐受性的形成。许多组合也可以导致协同作用,即可以降低活性成分的总量,这从生态学观点来看是期望的。下面命名组合伴侣的优选组和尤其优选的组合伴侣,由此除了式(I)的化合物之外,组合还可以含有这些伴侣中的一种或多种。
所述混合物中的合适伴侣可以是杀生物剂,例如具有不同活性机制的杀昆虫剂和杀螨剂,这是本领域技术人员已知的,例如壳多糖合成抑制剂、生长调节剂;用作保幼激素的活性成分;用作杀成虫剂的活性成分;广谱杀昆虫剂、广谱杀螨剂和杀线虫剂;还有众所周知的抗蠕虫剂和阻止昆虫和/或蜱螨的物质,驱虫剂,脱附剂(detacher)和增效剂。
合适的杀昆虫剂和杀螨剂的非限制性实例于WO 2009/071500的第18-21页的化合物1-284中所提及。
合适的抗蠕虫剂的非限制性实例于WO 2009/071500的第21页的化合物(A1)-(A31)中所提及。
合适的驱虫剂和脱附剂的非限制性实例于WO 2009/071500的第 21和22页的化合物(R1)-(R3)中所提及。
合适的增效剂的非限制性实例于WO 2009/071500的第22页的化合物(S1)-(S3)中所提及。
因此,本发明的另一个重要方面涉及用于防治温血动物上的寄生虫的组合制品,其特征在于除了式(I)的化合物之外,它们还含有至少一种具有相同或不同范围活性的其它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。
在本发明的一个实施方案中,式(I)的化合物与一种或多种其它抗蠕虫剂组合使用。此类组合可以进一步降低耐受性产生的可能性。合适的其它抗蠕虫剂包括。
实施例进一步说明本发明。其后在表1和2的最后一列中报道的表征数据使用具有反相柱(XTerra®, MS C18 5 µm, 50x4.6mm)的Waters Autopurification (HPLC/MS)系统获得。所述样品通过m/z和保留时间来表征。保留时间在各情况下涉及使用包含两种不同溶剂(溶剂A:H2O + 0.01% HCOOH,和溶剂B:CH3CN + 0.01% HCOOH)的溶剂系统。以2.00 ml/min的流速用如下表中给出的时间依赖性梯度利用所述两种溶剂A和B:
实施例1(下表2中的No. 32)
在0℃在氮气下,将溶解于2ml 二氯甲烷中的366mg商业可得的2-氯吡啶-4-碳酰氯逐滴添加至530mg商业可得的4-(1-哌嗪基)-2-三氟甲基苄腈于5ml二氯甲烷和630mgEt3N中的溶液。将反应混合物在室温下搅拌过夜,倒到100ml EtOAc和40ml 水的搅拌混合物上。用EtOAc萃取水层。将合并的有机层用盐水洗涤,经MgSO4干燥,过滤,在真空下浓缩并通过硅胶上的柱层析纯化以分离620mg 4-{4-[(2-氯吡啶-4-基)羰基]哌嗪-1-基}-2-(三氟甲基)苄腈。然后将99mg该物质添加至85mg商业可得的1-(4-三氟甲基苯基)哌嗪、6mg Pd(OAc)2、23mg RuPhos、163mg Cs2CO3和1.5ml 叔丁醇的脱气混合物,然后加热至85℃过夜。然后将反应混合物在室温下倒到50ml EtOAc和10ml 水的搅拌混合物上。用10ml EtOAc萃取水层。将合并的有机层用盐水洗涤,经MgSO4干燥,过滤,在真空下浓缩并通过柱层析纯化以分离60mg表2中的化合物No. 32。
与上述方法类似地制备如下表1和2中所示的物质。
表 1
表 2
以类似方式制备以下分子:
在以下测试中评价新型化合物的抗蠕虫潜能:
胃-肠幼体发育测定
新鲜收获和清洗的线虫卵用于接种合适格式化的孔板,所述孔板含有待评估抗寄生虫活性的测试物质和允许卵充分发育至第3龄幼虫的介质。将板在25℃和60%相对湿度下孵育6天。记录卵孵化和随后的幼虫发育以鉴定可能的杀线虫活性。效力以卵孵化降低、L3发育降低或幼虫在任何阶段的麻痹和死亡的百分比表示。化合物No. 1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、17、18、23、24、25、26、27、29、31、32、34、35、36、37、38、39、40、41、42、43、44 和46在10ppm下达到≥60%效力,且因此被认为是有效的。
沙鼠中的胃-肠蠕虫
在治疗之前7或6天,用蛇形毛圆线虫(T. colubriformis (Tc))和捻转血矛线虫(H. contortus (Hc))各自的约2000个第3龄幼虫通过管饲法人工感染沙鼠。用配制的测试化合物经口(p.o.)进行治疗。治疗之后3天,使沙鼠安乐死并解剖,以便从胃回收捻转血矛线虫并从中肠的上部回收蛇形毛圆线虫。
效力表示为使用Abbot的公式计算的相比于安慰剂治疗组的蠕虫数目的百分数降低。化合物No. 1、2、4、5、6、8、11、12、13、15、23、25、31、32、34、42、43和44至少在10mg/kgp.o.下在沙鼠中显示对Hc的高于80%的效力,且化合物No. 2、11、13、43和44至少在10mg/kg p.o.下在沙鼠中显示对Tc的高于80%的效力,因此被认为是有效的。
犬恶丝虫微丝蚴测定
从来自供体动物狗的血液制备新鲜收获和清洗的犬恶丝虫微丝蚴。然后将微丝蚴分配在格式化微孔板中,所述格式化微孔板含有待评估抗寄生虫活性的测试物质。将板在25℃和60%相对湿度(RH)下孵育48小时。然后记录微丝蚴的运动性以测定效力。效力以与对照和标准品相比的运动性降低百分比表示。化合物No. 1-46各自在10ppm下显示高于50%的效力,因此被认为是有效的。
沙鼠中的魏氏棘唇线虫(Acanthocheilonema viteae)。
用80个魏氏棘唇线虫(A. viteae)的L3幼虫通过皮下注射人工感染沙鼠。在感染之后第5天至第9天连续进行用配制的测试化合物通过管饲法的治疗。感染之后八十四天,将沙鼠采血,用于使用Fuchs-Rosenthal计数室和显微镜计数循环微丝蚴。仅测试组(其循环微丝蚴的平均值比安慰剂治疗组低至少50%)被充分解剖以回收成体蠕虫。效力表示为使用Abbot的公式计算的相比于安慰剂治疗组的蠕虫数目的%降低。化合物No. 1在3mg/kg下显示高于80%的效力。
Claims (14)
1.下式的化合物,或其生理上可接受的盐
其中Z1和Z2各自独立地是N或CR1’;
R1和R1’彼此独立地是H、卤素、氰基、硝基、C1-C4-烷基、C1-C4-卤代烷基、C1-C4-烷氧基、C1-C3-卤代烷氧基、C1-C4-烷基硫基、卤代-C1-C4-烷基硫基、SF5、氨基、N-单-或N,N-二-C1-C4-烷基氨基、氨基磺酰基、N-单-或N,N-二-C1-C4-烷基氨基磺酰基、N-单-或N,N-二-卤代-C1-C4-烷基氨基磺酰基、C1-C4-烷基磺酰基、C1-C4-烷基亚磺酰基、C1-C4-烷基磺酰基氨基、卤代-C1-C4-烷基磺酰基、卤代-C1-C4-烷基亚磺酰基、卤代-C1-C4-烷基磺酰基氨基或苄基磺酰基氨基;
Q是Ar1或-C(O)-(O)m-R2;
m是0或1;R2是C1-C6-烷基或C3-C8-环烷基;
Ar1是(i) 被1个或2个相同或不同的选自以下的取代基取代的苯基:卤素、氰基、硝基、C1-C4-烷基、C1-C4-卤代烷基、C1-C4-烷氧基、C1-C4-卤代烷氧基、C1-C4-烷基硫基、卤代-C1-C4-烷基硫基、SF5、氨基、N-单-或N,N-二-C1-C4-烷基氨基、氨基磺酰基、N-单-或N,N-二-C1-C4-烷基氨基磺酰基、N-单-或N,N-二-卤代-C1-C4-烷基氨基磺酰基、C1-C4-烷基磺酰基、C1-C4-烷基亚磺酰基、C1-C4-烷基磺酰基氨基、苄基磺酰基氨基、卤代-C1-C4-烷基磺酰基、卤代-C1-C4-烷基亚磺酰基和卤代二氧杂环戊烯基;或是(ii) 杂芳基,其选自2-、3-或4-吡啶基和2-或3-噻吩基,其各自未被取代或被甲基、乙基、卤素、CF3 或羧基取代;
Ar2是被1至3个相同或不同的选自以下的取代基取代的苯基:卤素、氰基、硝基、C1-C4-烷基、C1-C4-卤代烷基、C1-C4-烷氧基、C1-C4-卤代烷氧基、C1-C4-烷基硫基、卤代-C1-C4-烷基硫基、SF5、氨基、N-单-或N,N-二-C1-C4-烷基氨基、氨基磺酰基、N-单-或N,N-二-C1-C4-烷基氨基磺酰基、N-单-或N,N-二-卤代-C1-C4-烷基氨基磺酰基、C1-C4-烷基磺酰基、C1-C4-烷基亚磺酰基、C1-C4-烷基磺酰基氨基、苄基磺酰基氨基、卤代-C1-C4-烷基磺酰基、卤代-C1-C4-烷基亚磺酰基和卤代二氧杂环戊烯基;
L1是下式的双官能连接基基团
L2是下式的双官能连接基基团
A和B各自独立地是分别包含两个N-原子的C3-C8-杂-亚环烷基或C5-C10-杂-亚双环烷基,其各自未被取代或被C1-C2-烷基取代;
A1、A2、B1和B2各自独立地是分别包含N-原子的C3-C8-杂-亚环烷基;
R和R'彼此独立地是H或C1-C4-烷基。
2.根据权利要求1的化合物,其中R1和R1’彼此独立地是H、氰基、甲基或甲氧基。
3.根据权利要求1的化合物,其中Z1是N且Z2是CR1’。
4.根据权利要求1至3中任一项的化合物,其中Q是Ar1且Ar1是被1个或2个相同或不同的选自卤素、氰基和C1-C2-卤代烷基的基团取代的苯基。
5.根据权利要求1至3中任一项的化合物,其中Q是基团-C(O)-(O)m-R2,其中R2是C1-C4-烷基或C3-C6-环烷基。
6.根据权利要求1至3中任一项的化合物,其中Ar2是被1个或2个相同或不同的选自卤素、氰基、硝基、C1-C2-卤代烷基、C1-C2-卤代烷氧基或C1-C2-卤代烷基硫基的基团取代的苯基。
7.根据权利要求1至3中任一项的化合物,其中所述连接基L1具有下式
其中s和r各自独立地是整数1或2,r'是整数0、1或2,s'是整数0、1或2且R是H或甲基。
8.根据权利要求1至3中任一项的化合物,其中所述连接基L2是下式的基团:
其中r''是0或1,s'是整数1或2且R'是H或甲基。
9.根据权利要求1至3中任一项的化合物,其中L1是基团,且L2是基团。
10.根据权利要求1的化合物,其具有下式
其中R1、R2、m、L1、L2、Z1、Z2和Ar2各自如权利要求1中所定义。
11.根据权利要求1的化合物,其具有下式
其中R1、Ar1、Ar2、L1、L2、Z1和Z2各自如权利要求1中所定义。
12.根据权利要求1的化合物,或其生理上可接受的盐,所述化合物具有下式
其中Q是4-CF3-苯基、5-CF3-吡啶-2-基、6-CF3-吡啶-3-基、-C(O)-O-叔丁基或-C(O)-环丙基;
Z1是N或CH;
Z2是N或CH;
L1是基团;
L2是基团
R3是CF3;且R3’是氰基或硝基。
13.用于防治寄生虫的组合物,所述组合物除了载体和/或分散剂以外,还含有作为活性成分的至少一种根据权利要求1至12中任一项的化合物。
14.根据权利要求1至12中任一项的化合物用于制备抗温血动物中的体内寄生虫的兽用组合物或药物组合物的用途。
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