CN106470972A - 新的磺酰基氨基苯甲酰胺化合物 - Google Patents
新的磺酰基氨基苯甲酰胺化合物 Download PDFInfo
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- CN106470972A CN106470972A CN201580032901.1A CN201580032901A CN106470972A CN 106470972 A CN106470972 A CN 106470972A CN 201580032901 A CN201580032901 A CN 201580032901A CN 106470972 A CN106470972 A CN 106470972A
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- Prior art keywords
- alkyl
- amino
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- formula
- bis
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 109
- -1 sulfuryl amino Chemical group 0.000 title claims description 73
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- 150000003839 salts Chemical class 0.000 claims abstract description 26
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- 238000000034 method Methods 0.000 claims description 49
- 229910052736 halogen Inorganic materials 0.000 claims description 46
- 150000002367 halogens Chemical group 0.000 claims description 45
- 229910052757 nitrogen Inorganic materials 0.000 claims description 37
- 239000000203 mixture Substances 0.000 claims description 31
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 25
- 241001465754 Metazoa Species 0.000 claims description 22
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 20
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 15
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 15
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 claims description 13
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 12
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 12
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 10
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- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 7
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- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 6
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- 125000006771 (C1-C6) haloalkylthio group Chemical group 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- ZHXTWWCDMUWMDI-UHFFFAOYSA-N dihydroxyboron Chemical compound O[B]O ZHXTWWCDMUWMDI-UHFFFAOYSA-N 0.000 claims description 4
- 239000011737 fluorine Substances 0.000 claims description 4
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- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
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- 125000002252 acyl group Chemical group 0.000 claims description 2
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- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 2
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- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 description 3
- 241000244037 Acanthocheilonema viteae Species 0.000 description 3
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- 239000004034 viscosity adjusting agent Substances 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
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Abstract
本发明涉及新的式(I)化合物,其中变量具有在权利要求中指明的含义;或其对映异构体或盐。式(I)化合物可用于防治脊椎动物体内或体表的寄生虫,特别是体内寄生虫。
Description
本发明涉及新的磺酰基氨基苯甲酰胺化合物及其在防治温血动物体内的体内寄生虫,例如心丝虫中的用途。
心丝虫(Dirofilaria immitis)是一种寄生的线虫动物,其通过蚊子叮咬在宿主之间传播。其终宿主是狗,但是其也可以感染猫和其它温血动物。尽管通常被称为心丝虫,但是成虫通常多半存在于肺动脉系统(肺动脉),并且对动物健康的主要影响是对肺血管和组织的损伤。偶然地,在严重感染者中,成年心丝虫会迁移至右心并且甚至是大静脉。心丝虫感染可以导致宿主的严重疾病。
心丝虫感染可以用基于砷的化合物来对抗;所述治疗是耗时的、麻烦的,并且经常仅仅是部分成功的。因此,主要的焦点是预防心丝虫感染。心丝虫预防目前唯一地通过全年定期给狗、猫或其它温血动物施用大环内酯诸如伊维菌素、莫昔克丁或米尔贝肟而进行。不幸的是,已经在美国部分地区观察到心丝虫对大环内酯类的即将出现的抗性。因此,强烈需要发现新类型的化合物,其通过预防或直接杀死不同阶段的心丝虫而有效地防治心丝虫感染。现在已经令人惊讶地发现一组新的磺酰基氨基苯甲酰胺化合物,其有效地防治温血动物体表的体内寄生虫,包括心丝虫。
因此,根据一个实施方案,本发明涉及下式化合物
或其盐或对映异构体,其中X是O、S、NR2C(O)、C(CN)或CH=CH,
R0是H、C1-C4-烷基或羟基;
n是0或1,
每个R独立地是卤素;C1-C6-烷基;C1-C6-卤代烷基;C3-C6-环烷基;C3-C6-卤代环烷基;氨基;N-单-或N,N-二-C1-C4-烷基氨基;羟基;C1-C6-烷氧基;C1-C6-卤代烷氧基;C1-C6-烷基硫基;C1-C6-卤代烷基硫基;C1-C6-烷基-亚磺酰基;C1-C6-卤代烷基亚磺酰基;C1-C6-烷基磺酰基;C1-C6-卤代烷基磺酰基;SF5;三-C1-C4-烷基甲硅烷基;C1-C6-烷氧基羰基;氨基羰基;N-单-或N,N-二-C1-C6-烷基氨基羰基;氨基磺酰基;N-单-或N,N-二-C1-C6-烷基氨基磺酰基;N-C1-C6-烷基磺酰基氨基;C1-C6-烷氧基羰基氨基;N-C1-C4-烷基-N-C1-C6-烷氧基羰基氨基;氰基;硝基;或未取代的或被卤素、C1-C4-烷基、C1-C4-卤代烷基、C3-C6-环烷基、C1-C4-烷氧基、C1-C4-卤代烷氧基、氨基、氰基或硝基取代的C3-C6-杂环基;
m是0-4的整数;
每个R1独立地是卤素;C1-C6-烷基;C1-C6-卤代烷基;C3-C6-环烷基;C3-C6-卤代环烷基;C1-C6-烷氧基;C1-C6-卤代烷氧基;C1-C6-烷基硫基;C1-C6-卤代烷基硫基;C1-C6-烷基-亚磺酰基;C1-C6-卤代烷基亚磺酰基;C1-C6-烷基磺酰基;C1-C6-卤代烷基磺酰基;SF5;氨基;
N-单-或N,N-二-C1-C6-烷基氨基;三-C1-C4-烷基甲硅烷基;C1-C6-烷氧基羰基;氨基羰基;N-单-或N,N-二-C1-C6-烷基氨基羰基;N,N-二-C1-C4-烷基氨基-C1-C4-烷基氨基羰基;氨基磺酰基;N-单-或N,N-二-C1-C6-烷基氨基磺酰基;N-C1-C6-烷基磺酰基氨基;C1-C6-烷氧基羰基氨基;N-C1-C4-烷基-N-C1-C6-烷氧基羰基氨基;氰基;硝基;羟基;B(OH)2;或苯基、苯甲酰基、C3-C6-杂环基、C3-C6-杂环基氧基或C6-C8-苯并杂环基,其各自是未取代的或被卤素、C1-C4-烷基、C1-C4-卤代烷基、C3-C6-环烷基、C1-C4-烷氧基、C1-C4-卤代烷氧基、氨基、氰基或硝基取代;和
r是1-4的整数。
本发明也提供了一种组合物,其包含式(I)化合物、或其盐或对映异构体,和至少一种载体,例如表面活性剂、固体稀释剂和/或液体稀释剂。
在一个实施方案中,本发明也提供了一种用于防治寄生虫,特别是体内寄生虫的组合物,其包含生物学有效量的式(I)化合物、或其盐,和选自表面活性剂、固体稀释剂和液体稀释剂的至少一种额外的组分,所述组合物任选地进一步包含生物学有效量的至少一种额外的药学或兽医学活性化合物或试剂。
本发明也提供了一种用于防治寄生虫的方法,其包含使寄生虫或其环境与药学或兽医学有效量的式(I)化合物、其对映异构体或盐(例如,作为本文所述的组合物)接触。本发明也涉及这样的方法,其中使寄生虫或其环境与一种组合物接触,所述组合物包含药学或兽医学有效量的式(I)化合物、其对映异构体或盐,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的组分,所述组合物任选地进一步包含药学或兽医学有效量的至少一种额外的药学或兽医学活性化合物或试剂。
本发明也提供了一种保护动物免于寄生害虫侵害的方法,其包括给动物施用杀寄生虫有效量的式(I)化合物、其对映异构体或盐。
发明详述
在上面的描述中,单独或在复合词诸如“烷基硫基”、“卤代烷基硫基”、“卤代烷基”、“N-烷基氨基”、“N,N-二烷基氨基”等中使用的术语“烷基”包括直链或支链烷基,诸如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基或不同的戊基或己基异构体。
单独或在复合词诸如“卤代烷氧基”、“烷氧基羰基”中使用的术语“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”包括烷基亚磺酰基基团的两种对映异构体。“烷基亚磺酰基”的例子包括CH3S(O)-、CH3CH2S(O)-、CH3CH2CH2S(O)-、(CH3)2CHS(O)-和不同的丁基亚磺酰基、戊基亚磺酰基和己基亚磺酰基异构体。
“烷基羰基”表示键合至C(=O)基团的直链或支链烷基基团。“烷基羰基”的例子包括CH3C(=O)-、CH3CH2CH2C(=O)-和(CH3)2CHC(=O)-。“烷氧基羰基”的例子包括CH3OC(=O)-、CH3CH2OC(=O)、CH3CH2CH2OC(=O)-、(CH3)2CHOC(=O)-和不同的丁氧基-或戊氧基羰基异构体,例如叔-丁氧基羰基 (Boc)。“烷氧基羰基氨基”或N-烷氧基羰基、N-烷基氨基的例子包括叔-丁氧基羰基氨基和N-叔-丁氧基羰基、N-甲基氨基。“N-单-或N,N-二-烷基氨基羰基”的例子包括“N-甲基氨基羰基”、“N-乙基氨基羰基、N-甲基-N-乙基氨基羰基、N,N-二-甲基氨基羰基或N,N-二-乙基氨基羰基。“烷基羰基氨基”的例子包括”、“甲基羰基氨基”或“乙基羰基氨基”。
“烷基磺酰基”的例子包括CH3S(O)2-、CH3CH2S(O)2-、CH3CH2CH2S(O)2-、(CH3)2CHS(O)2-和不同的丁基磺酰基、戊基磺酰基和己基磺酰基异构体。“N-单-或N,N-二-烷基氨基磺酰基”的例子包括“N-甲基氨基磺酰基”、“N-乙基氨基磺酰基、N-甲基-N-乙基氨基磺酰基、N,N-二-甲基氨基磺酰基或N,N-二-乙基氨基磺酰基。“烷基磺酰基氨基”的例子包括”、“甲基磺酰基氨基”或“乙基磺酰基氨基”。
“环烷基”包括,例如,环丙基、环丁基、环戊基和环己基。术语“烷基环烷基”表示环烷基基团上的烷基取代,并包括,例如,乙基环丙基、异丙基环丁基、3-甲基环戊基和4-甲基环己基。
单独或在复合词诸如“卤代烷基”中的术语“卤素”包括氟、氯、溴或碘。此外,当用在复合词诸如“卤代烷基”中时,所述烷基可以部分地或完全地被卤素原子取代,所述卤素原子可以相同或不同。“卤代烷基”的例子包括F3C-、ClCH2-、CF3CH2-和CF3CCl2-。术语“卤代环烷基”、“卤代烷氧基”、“卤代烷基硫基”等,与术语“卤代烷基”类似地定义。“卤代烷氧基”的例子包括CF3O-、CF3CF2-O-、CF3CH2O-、CCl3CH2O-、CF3CHFCF2O-和HCF2CH2CH2O-;和“卤代烷基硫基”的例子包括CCl3S-、CF3S-、CCl3CH2S-和ClCH2CH2CH2S-。“卤代烷基亚磺酰基”的例子包括CF3S(O)-、CCl3S(O)-、CF3CH2S(O)-和CF3CF2S(O)-。“卤代烷基磺酰基”的例子包括CF3S(O)2-、CCl3S(O)2-、CF3CH2S(O)2-和CF3CF2S(O)2-。
取代基中的碳原子的总数由前缀“Ci-Cj”来指示,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。
当某化合物被携带指示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)独立地选自限定的取代基,例如,(R2)n,n是1或2。“芳族”指示每个环原子基本上是在相同平面,并且具有与环平面垂直的ap-轨道,并且其中(4n + 2) π电子(其中n是正整数)与该环相关联以符合Hϋckel规则。
术语“杂环基”、“杂环(heterocyclic ring)”或“杂环(heterocycle)”表示这样的环,其中形成环骨架的至少一个原子不是碳,例如,氮、氧、硫或基团S(O)或S(O2)。通常,杂环含有不超过4个氮,不超过2个氧和不超过2个硫。此外,杂环可以含有基团–C(O)-、-S(O)-或–S(O2)-。除非另外指明,否则杂环可以是饱和的、部分不饱和的或完全不饱和的环。当完全不饱和的杂环满足Hϋckel规则时,则所述环也被称为“杂芳环”或“杂芳基”取代基。除非另外指明,否则杂环和环系统可以通过任何可利用的碳或氮连接(通过代替所述碳或氮上的氢)。
单独或在复合词诸如杂环基氧基中的术语杂环基可以是例如5-或6-元杂环基团,其具有1-4个、优选1-3个相同或不同的选自N、O和S的杂原子,所述杂环基团是进一步未取代的或被取代的。
术语杂环基可以表示例如5-或6元杂芳基基团,其具有1-4个、优选1-3个相同或不同的选自N、O和S的杂原子,所述杂芳基基团是进一步未取代的或被一个或多个如下面所述的取代基取代的。杂芳基基团优选被 0-3个,特别是0、1或2个来自下面所定义的组的取代基取代。
杂芳基的合适的取代基的例子是卤素、羟基、C1-C6-烷基、C2-C6-烯基、C2-C6-炔基、C3-C6-环烷基、C1-C6-卤代烷基、C1-C6-烷氧基、C1-C6-卤代烷氧基、C1-C6-烷基硫基、C1-C6-烷基亚磺酰基、C1-C6-烷基磺酰基、氰基、硝基、氨基、N-单-或N,N-二-C1-C6-烷基氨基、C3-C6-环烷基氨基、COOH、C1-C6-烷氧基羰基、C2-C6-烷基羰基、C1-C6-烷基羰基氨基、氨基羰基、N-单-或N,N-二-C1C6-烷基氨基羰基、氨基磺酰基或N-单-或N,N-二-C1-C4-烷基氨基磺酰基。
5-或6-元杂芳基基团的例子包括噻吩基、吡咯基、呋喃基、噁唑基、噻唑基、吡啶基或嘧啶基,其各自是未取代的或取代的,例如被卤素、C1-C2-烷基、C1-C2-卤代烷基、C3-C6-环烷基或C1-C4-烷氧基羰基取代。
术语杂环基可以进一步表示3-6-元杂环烷基基团,其具有1-3个相同或不同的选自 N、O和S的杂原子,所述杂环烷基基团是进一步未取代的或被一个或多个如上面针对杂环基所定义的取代基取代。亚杂环烷基基团优选地被 0-3个,特别是0、1或2个来自上面所定义的组的取代基取代。例子是四氢呋喃基、吡咯烷基、吗啉基、哌啶基或哌嗪基,其各自是未取代的或被卤素、C1-C2-烷基、C1-C2-卤代烷基或C1-C2-烷氧基取代。
杂环基氧基的例子是2-, 3-或4-吡啶基氧基或嘧啶-4-基氧基,其各自是未取代的或被卤素、C1-C2-烷基、C3-C6-环烷基、C1-C2-卤代烷基或C1-C2-烷氧基取代。
C6-C8-苯并杂环基的例子是苯并噁唑基、苯并噻唑基或吲哚基,其各自可以是未取代的或被例如卤素、C1-C2-烷基、C1-C2-卤代烷基或C1-C2-烷氧基取代。
关于式(I)化合物中所含有的变量,下述含义和优选方案适用。
变量m优选是1-4的整数,更优选地是整数1、2或3,甚至更优选地是整数1或2且特别是1。
每个R独立地优选地是卤素;C1-C4-烷基;C1-C4-卤代烷基;氨基;C1-C4-烷氧基;C1-C4-卤代烷氧基;C1-C4-卤代烷基硫基;C1-C4-烷基磺酰基;C1-C4-卤代烷基磺酰基;三-C1-C2-烷基甲硅烷基;C1-C4-烷氧基羰基;N-单-或N,N-二-C1-C4-烷基氨基羰基;氨基磺酰基;N-单-或N,N-二-C1-C4-烷基氨基磺酰基;N-C1-C2-烷基-N-C1-C4-烷氧基羰基氨基;氰基;硝基;或包含1或2个相同或不同的选自O、S和N的杂原子的5-或6-元杂环烷基,其是未取代的或被卤素、C1-C2-烷基、C1-C2-卤代烷基或C1-C2-烷氧基取代。
每个R独立地更优选地是卤素;C1-C2-烷基;C1-C4-卤代烷基;氨基;C1-C4-烷氧基;C1-C4-卤代烷氧基;C1-C4-烷基磺酰基;C1-C4-卤代烷基磺酰基;三甲基甲硅烷基;C1-C4-烷氧基羰基;N,N-二-C1-C2-烷基氨基羰基;氨基磺酰基;N,N-二-C1-C2-烷基氨基磺酰基;N-C1-C2-烷基-N-C1-C4-烷氧基羰基氨基;氰基;硝基;或选自四氢呋喃基、吡咯烷基、吗啉基和哌啶基的杂环烷基基团。
每个R独立地特别优选地是卤素、C1-C2-烷基、C1-C2-卤代烷基、C1-C2-烷氧基、C1-C2-卤代烷氧基或氰基,并且尤其是氯、氟或CF3。具体的优选的取代基(R)m是2-, 3-或4-Cl、4-CF3、3,5-二-Cl、3,5-二-CF3、2,4,6-三-Cl、3,4,5-三-Cl、2-Cl-4-CF3、2-CF3-4-Cl、2,6-二-Cl-4-CF3,特别是4-Cl。
变量r优选地是整数1、2或3且更优选地是2或3。
每个R1独立地优选地是卤素;C1-C4-烷基;C1-C4-卤代烷基;C3-C6-环烷基;C1-C4-烷氧基;C1-C4-卤代烷氧基;C1-C4-卤代烷基硫基;SF5;N,N-二-C1-C4-烷基氨基-C1-C4-烷基氨基羰基;N-C1-C4-烷基磺酰基氨基;氰基;硝基;羟基;B(OH)2、吗啉代;或苯基、苯甲酰基、吡啶基氧基、嘧啶基氧基或苯并噻唑基,其各自是未取代的或被卤素、C1-C4-烷基、C1-C4-卤代烷基、C3-C6-环烷基或C1-C4-烷氧基取代。
每个R1独立地更优选地是卤素;C1-C2-烷基;C1-C3-卤代烷基;C1-C2-烷氧基;C1-C3-卤代烷氧基;C1-C2-卤代烷基硫基;SF5;硝基或羟基。
每个R1独立地特别优选地是卤素、甲基、C1-C3-卤代烷基、甲氧基、C1-C3-卤代烷氧基、SCF3、SF5、硝基或羟基并且尤其是卤素或CF3。具体的优选的取代基(R)m是3,4,5-三-Cl、3,5-二-CF3-4-Cl、3,5-二-CF3。
根据本发明的一个优选实施方案,r是整数1、2或3,且每个R1独立地是卤素;C1-C2-烷基;C1-C3-卤代烷基;C1-C2-烷氧基;C1-C3-卤代烷氧基;C1-C2-卤代烷基硫基;SF5;硝基或羟基。根据本发明的一个特别优选的实施方案,r是整数2或3,且每个R1独立地是卤素;或C1-C3-卤代烷基。
变量X 优选地表示O。
R0优选地是H或甲基,特别是H。
本发明的一个实施方案涉及下式化合物
其中R、R0、R1、m和r 各自具有上面给出的含义,包括优选方案。优选的实施方案涉及式(Ia)化合物,其中R0是H,m是1、2或3,尤其是1或2,r是2或3,尤其是2,且对于R和R1,每个上面给出的含义和优选方案均适用。特别优选的实施方案涉及式(Ia)化合物,其中R0是H,m是1或2,r是2或3,每个R独立地是卤素、C1-C2-烷基、C1-C4-卤代烷基、C1-C4-烷氧基、C1-C4-卤代烷氧基、C1-C4-烷基磺酰基、三甲基甲硅烷基、N,N-二-C1-C2-烷基氨基磺酰基、N-C1-C2-烷基-N-C1-C4-烷氧基羰基氨基、氰基、硝基或吡咯烷基,且每个R1独立地是C1-C4-卤代烷基。一个尤其优选的实施方案涉及式(Ia)化合物,其中R0是H,m是1或2,r是2,每个R独立地是卤素或CF3,且R1是CF3。
本发明的优选的实施方案涉及下式化合物
其中对于R和m,每个上面给出的含义和优选方案都适用。
本发明的另一个实施方案涉及下式化合物
其中对于R、R1、m和r,每个上面给出的含义和优选方案都适用。
优选的实施方案涉及式(Ib)化合物,其中m是1或2,尤其是1,r是2或3,并且对于R和R1,每个上面给出的含义和优选方案均适用。特别优选的实施方案涉及式(Ia)化合物,其中m是1,r是2或3,每个R是卤素、C1-C3-卤代烷基、C1-C2-烷氧基或氰基,且每个R1独立地是卤素、C1-C2-烷基、C1-C3-卤代烷基、C1-C2-烷氧基、C1-C3-卤代烷氧基、C1-C2-卤代烷基硫基、SF5、硝基或羟基。一个尤其优选的实施方案涉及式(Ib)化合物,其中m是1,r是2或3,R是卤素或CF3,特别是氯,且每个R1是卤素或CF3。
本发明的另一个优选的实施方案涉及下式化合物
其中变量a和b各自独立地是0或1,(Hal)是卤素,且R是卤素或CF3,特别是卤素。在上式(Ib')中,变量a和b中的一个优选地是1,且另一个是0或1。
式(I)化合物的盐可以以已知方式生产。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来获得,并且与碱形成的盐可通过用合适的碱或合适的离子交换试剂处理来获得。
式(I)化合物的盐可以通过常用手段转化成游离化合物、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)和与碱形成的盐(例如通过用合适的酸或合适的离子交换试剂处理)。
可以以已知的方式将式(I)化合物的盐转化成式(I)化合物的其它盐;酸加成盐可以被转化成例如其它酸加成盐,例如,通过在合适的溶剂中用酸的合适的金属盐,诸如钠盐、钡盐或银盐,例如用乙酸银处理无机酸的盐,诸如盐酸盐,其中所得无机盐,例如氯化银是不溶性的,并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,具有成盐特征的式(I)化合物可以以游离形式或以盐的形式获得。
式(I)化合物也可以以其水合物的形式获得和/或也可以包括其它溶剂化物,其例如在必要时用于结晶以固体形式存在的化合物。
如前所述,式(I)化合物可以任选地以光学和/或几何异构体或其混合物的形式存在。本发明涉及纯的异构体和所有可能的异构体混合物,并且在上文和下文中都如此理解,即使在每种情况下没有具体提及立体化学细节。
基于其组分的立体化学差异,式(I)化合物的非对映异构体混合物(其可以通过所述方法或以另一种方式获得)可以以已知的方式分离成纯的非对映异构体,例如通过分步结晶、蒸馏和/或色谱法。
可以通过已知方法,例如通过从光学活性溶剂中重结晶,通过在手性吸附剂上的色谱法,例如在乙酰纤维素上的高压液相色谱法(HPLC),在合适的微生物的辅助下,通过用特异的固定酶裂解,通过形成包合物,例如使用手性冠醚(由此仅络合一种对映异构体),可以实现将可以相应地获得的对映异构体的混合物拆分成纯的异构体。
式(I)化合物(其中 n是0)可以例如如下进行制备:在钯催化剂存在下,使下式化合物
其中R0、R1和r各自如前面所定义且LG是离去基团,例如卤素诸如溴,与下式化合物反应
其中R和m各自如上面所定义。该钯催化的碳-碳键形成反应(称为Suzuki反应)的细节是从有机化学的教科书中已知的。
式(II)化合物是已知的或可以根据已知方法来制备,例如,通过使下式化合物
与下式化合物反应
其中LG'是离去基团,例如卤素、C1-C2-烷氧基或羟基,且其它变量各自具有上述含义。羧酸或其衍生物与胺形成酰胺是从有机化学的教科书中已知的。式(IV)化合物是已知的或可以根据已知方法来制备,例如通过使相应的胺与甲磺酰氯以已知的方式反应。式(III)和(V)的化合物是商购可得的已知化合物。
式(I)化合物(其中n是1且X是O)可以例如如下制备:使下式化合物
与下式化合物反应
其中变量如前面所定义,随后还原硝基并进一步使所得到的胺与甲磺酰氯反应。这些反应的细节是从有机化学教科书中已知的。式(VI)化合物可以以类似于式(II)化合物的方式制备。式(VII)化合物是本身已知的并且是商购可获得的。
式(I)化合物(其中n是1)也可以如下制备:使下式化合物
与下式化合物反应
其中变量各自具有上面给出的含义,随后还原硝基并进一步使所得到的胺与甲磺酰氯反应。可替换地,式(VIII)化合物的硝基可以首先被还原,并且所得氨基可以与甲磺酰氯反应,然后进行与式(V)化合物的反应。
式(VIII)化合物可以以本身已知的方式制备,例如通过使下式化合物
与下式化合物 反应,得到下式化合物
其可以例如通过在水性介质中与强碱诸如氢氧化锂作用被进一步转化成下式化合物
。
实施例进一步例示了不同的合成方法。
根据本发明的式(I)化合物由于其广的活性谱而值得关注,并且是用于害虫防治(特别包括在温血动物,尤其是产出性的家畜和宠物体内及体表防治体内寄生虫,尤其是蠕虫)的有价值的活性成分,同时还被温血动物和鱼所良好耐受。
产出性的家畜包括哺乳动物诸如,例如,牛、马、绵羊、猪、山羊、驴、兔、鹿以及鸟类,例如鸡、鹅、火鸡、鸭和外来鸟类。
宠物包括,例如,狗、猫和仓鼠,特别是狗和猫。
本发明的式(I)化合物对蠕虫有效,其中内寄生性的线虫和吸虫可以是哺乳动物和家禽的严重疾病的病因。该适应症的典型线虫是:丝虫科(Filariidae)、丝状科(Setariidae)、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)、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)。吸虫特别包括拟片吸虫科(Fasciolideae),尤其是肝片吸虫(Fasciola hepatica)。
也可以令人惊讶地和预料不到地证实,本发明的组合物具有对抗对许多活性物质耐受的线虫的特别高的效力。这可以例如通过LDA测试在体外证实。
细颈线虫属(Nematodirus)、古柏线虫属(Cooperia)和结节线虫属(Oesophagostonum)的某些害虫侵染宿主动物的肠道,而血矛线虫属(Haemonchus)和胃线虫属(Ostertagia)的其它害虫寄生在胃中,且网尾线虫属(Dictyocaulus)的那些害虫寄生在肺组织中。多个科的寄生虫可以在内部细胞组织和在器官中找到,例如心脏、血管、淋巴管和皮下组织。特别值得注意的寄生虫是犬心丝虫 (Dirofilaria immitis)。
根据本发明的式(I)化合物对这些寄生虫是高度有效的。
本发明的式(I)化合物可以防治的害虫也包括来自绦虫纲(Cestoda)(绦虫)的那些,例如中孔绦虫科(Mesocestoidae),尤其是中殖孔绦虫属(Mesocestoides),特别是线中殖孔绦虫(M. lineatus);复孔科(Dipylidiidae),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.),和带绦虫科(Taeniidae),尤其是豆状带绦虫(Taenia pisiformis)、獐绦虫(Taenia cervi)、羊绦虫(Taenia ovis)、水泡绦虫(Taeneia hydatigena)、多头绦虫(Taenia multiceps)、巨颈绦虫(Taenia taeniaeformis)、连续涤虫(Taenia serialis)和棘球属(Echinococcus spp.),最优选水泡绦虫、羊绦虫、多头绦虫、连续涤虫;细粒棘状绦虫(Echinococcus granulosus)和多房棘球绦虫(Echinococcus multilocularis)。
此外,式(I)化合物适合于防治人类病原性寄生虫。在这些中,出现在消化道中的典型代表是钩口线虫属(Ancylostoma)、板口线虫属(Necator)、蛔虫属(Ascaris)、类圆线虫属(Strongyloides)、毛线虫属(Trichinella)、毛细线虫属(Capillaria)、鞭虫属(Trichuris)和蛲虫属(Enterobius)的那些。本发明的化合物也对来自龙线虫属(Dracunculus)家族的吴策线虫属(Wuchereria)、布鲁丝虫属(Brugia)、盘尾丝虫属(Onchocerca)和罗阿线虫属(Loa)的寄生虫以及类圆线虫属(Strongyloides)和毛线虫属(Trichinella)的寄生虫(其特别感染胃肠道)有效。
式(I)化合物的良好的杀内寄生虫活性对应于至少50-60%,特别是至少80%并且尤其是至少90%的所提及的体内寄生虫的死亡率。
根据本发明的式(I)化合物的施用可以治疗性地或优选预防性地进行。
根据本发明的式(I)化合物向待治疗的动物的应用可以如下进行:例如,局部地、口服地、胃肠外地或皮下地。本发明的优选的实施方案涉及胃肠外使用的,或者特别是口服使用的式(I)化合物。
在线虫/蠕虫的防治中,用于温血动物的优选的应用形式包括:溶液;乳液,包括经典乳液、微乳和自乳化组合物,所述自乳化组合物为无水有机的、优选油性的组合物,在加入到动物体后与体液一起形成乳液;混悬液(兽用顿服药);浇注制剂(pour-onformulations);食品添加剂;粉剂;片剂,包括泡腾片;大丸药;胶囊,包括微囊;和可咀嚼的零食(chewable treats);其中制剂赋形剂的生理相容性必须予以考虑。特别优选的应用形式是片剂、胶囊、食品添加剂或可咀嚼的零食。
本发明的式(I)化合物以未改性的形式使用,或优选地与常规用于制剂领域中的辅助剂一起使用,并且可以因而以已知的方式加工以得到,例如,乳油、可直接稀释的溶液、稀乳液、可溶性粉末、粉末混合物、颗粒或在聚合物质中的微囊。对于组合物而言,根据预期的目的和一般情况选择应用方法。
所述制剂,即含有一种或多种活性成分并任选含有固体或液体辅助剂的试剂、制品或组合物以本身已知的方式生产,例如通过紧密地混合和/或研磨活性成分与辅助剂,例如溶剂、固体载体和/或表面活性化合物 (表面活性剂)。
所述溶剂可以是:醇,诸如乙醇、丙醇或丁醇,以及二醇及其醚和酯,诸如丙二醇、二丙二醇醚、乙二醇、乙二醇单甲基或-乙基醚,酮,诸如环己酮、异佛尔酮或双醋他洛醇(diacetanol alcohol),强极性溶剂,诸如N-甲基-2-吡咯烷酮、二甲基亚砜或二甲基甲酰胺,或水、植物油,诸如菜籽油、蓖麻油、椰子油或大豆油,并且如果适当的话,还可以是硅酮油。
合适的表面活性剂为,例如,非离子型表面活性剂,诸如,例如,壬基苯酚聚乙氧基乙醇;蓖麻油聚乙二醇醚,例如聚乙二醇甘油羟基硬脂酸酯40;聚乙二醇;聚丙烯/聚氧乙烯加成化合物;或聚氧乙烯脱水山梨糖醇的脂肪酸酯,例如聚氧乙烯脱水山梨糖醇单油酸酯。
固体载体,例如片剂和大丸药的固体载体,可以是可溶于水或醇的化学改性的聚合的天然物质,诸如淀粉、纤维素或蛋白质衍生物(例如甲基纤维素、羧甲基纤维素、乙基羟基乙基纤维素、蛋白质诸如玉米醇溶蛋白、明胶等),以及合成聚合物,诸如聚乙烯醇、聚乙烯吡咯烷酮等。片剂也含有填充剂(例如淀粉、微晶纤维素、糖、乳糖等)、助流剂和崩解剂。
如果驱蠕虫药以浓缩饲料的形式存在,则所使用的载体是例如性能饲料、饲料谷物或蛋白质浓缩物。除了活性成分之外,这样的浓缩饲料或组合物还可以含有添加剂、维生素、抗生素、化学治疗剂或其它农药,主要是抑菌剂、抑真菌剂、抗球虫药,或甚至激素制品、具有合成代谢作用的物质或促进生长、影响用于屠宰的动物的肉的质量或以其它方式有益于生物体的物质。
式(I)化合物的合适的组合物也可以含有其它添加剂,诸如稳定剂、抗氧化剂例如生育酚如α-生育酚、消泡剂、粘度调节剂、粘合剂、颜料或增粘剂,以及其它活性成分,以便实现特定的效果。优选地,所述组合物包含0.001-1 % w/v的一种或多种抗氧化剂。如果需要,本发明的制剂可以包含颜料,例如以0.001-1 % w/v的量。
作为一项规则,根据本发明的驱蠕虫组合物含有0.1-99 重量%,尤其是0.1-95 重量%的式(I)化合物、99.9-1 重量%,尤其是99.8-5 重量%的固体或液体混合物,包括 0-25重量%,尤其是0.1-25 重量%的表面活性剂。
在根据本发明的用于害虫防治的每种方法中,或在根据本发明的每种害虫防治组合物中,式(I)化合物都可以以其所有立体构型或其混合物的形式使用。
本发明也包括预防性地保护温血动物,尤其是产出性的家畜和宠物,特别是狗或猫免遭寄生性蠕虫侵害的方法,其特征在于将式(I)化合物或由其制备的活性成分制剂作为饲料或饮品的添加剂或以固体或液体形式口服或通过注射或胃肠外地施用给温血动物。本发明也包括用于上述方法之一的根据本发明的式(I)化合物。
根据本发明的式(I)化合物可以单独使用或与其它杀虫剂联合使用。它们可以与具有相同活性谱的农药组合,以例如增加活性,或与具有另一种活性谱的物质组合,例如以扩大活性范围。也可以合理地加入所谓的防护剂。
下述实施例进一步说明了本发明。
在每一情况下,使用具有反相柱(使用下述方法B)的Waters自净化(HPLC/MS)系统进行纯化的样品的分析。样品用m/z和保留时间来表征。在每一情况下,上面给出的保留时间涉及使用包含两种不同溶剂的溶剂系统,溶剂 A: H2O + 0.01% HCOOH,且溶剂 B: CH3CN+ 0.01% HCOOH)。
- 方法B: 柱Waters XTerra MS C18 5μm, 50X4.6mm (Waters),流速3.00 mL/min,具有在下表中给出的时间依赖性的梯度:
时间[min] | A [%] | B [%] |
0 | 90 | 10 |
0.5 | 90 | 10 |
2.5 | 5 | 95 |
2.8 | 5 | 95 |
2.9 | 90 | 10 |
3.0 | 90 | 10 |
实施例1: N-(3,5-二(三氟甲基)苯基)-2'-氯-4-(甲基-磺酰氨基)-4'-(三氟甲基)-[1,1'-联苯]-3-甲酰胺(表1中的实施例1.13 )的合成
步骤A: 5-溴-2-(甲基磺酰氨基)苯甲酸甲酯.
将2-氨基-5-溴苯甲酸甲酯(2.8 g)在10 mL 1 吡啶中的N2脱气的溶液冷却至0℃,然后滴加甲磺酰氯(0.9 mL)。将反应混合物在室温搅拌过夜,然后用50 mL乙酸乙酯稀释。将有机层用Na2CO3饱和溶液、用盐水洗涤,然后经MgSO4干燥并蒸发至干(收率:82%)。LCMS (方法B): 305.6 (M-H)-,在1.55 min。
步骤B: 5-溴-2-(甲基磺酰氨基)苯甲酸
将5-溴-2-(甲基磺酰氨基)苯甲酸甲酯(3.15 g)悬浮于THF (20 mL, 1/1)中。加入NaOH 4 N (6.9 mL)并将反应混合物在回流下搅拌4h。完成后,将反应混合物用2N HCl(1mL)处理并用乙酸乙酯萃取两次。将合并的有机层用H2O、盐水洗涤,经Na2SO4干燥,过滤并蒸发至干。通过LCMS确定所述标题产物是足够纯净的,从而能够不经进一步纯化地用于下一步。(收率:66%)。
LCMS (方法B): 291.64 (M-H)-,在1.2 min。
步骤C: N-(3,5-二(三氟甲基)苯基)-5-溴-2-(甲基磺酰氨基)苯甲酰胺.
将5-溴-2-(甲基磺酰氨基)苯甲酸(2.4 g)用亚硫酰氯(23 mL)在回流下处理4h。在真空下除去过量的SOCl2。将CH2Cl2 (20 mL)加入到酰氯中。在0℃,缓慢地加入3,5-二(三氟甲基)苯胺(1.4 mL)和NEt3 (5.68 mL)在10 mL CH2Cl2中的溶液。使反应混合物温热并将其在室温搅拌过夜。将反应混合物用30 mL CH2Cl2稀释。加入20 mL HCl 2 N 和20 mL H2O,并搅拌混合物,直到形成黄色沉淀。将沉淀滤出并在分析前在高真空下干燥(收率:67%)。
LCMS (方法B): 502.93 (M-H)-,在1.99 min。
步骤D: N-(3,5-二(三氟甲基)苯基)-2'-氯-4-(甲基-磺酰氨基)-4'-(三氟甲基)-[1,1'-联苯]-3-甲酰胺的合成。
在N2下向N-(3,5-二(三氟甲基)苯基)-5-溴-2-(甲基磺酰氨基)苯甲酰胺 (0.5g)和2-氯-4-(三氟甲基)苯硼酸(286 mg)在二噁烷/H2O (4 mL, 1/1)中的溶液中加入Na2CO3 (636 mg)和(1,1’-二-二苯基膦基-二茂铁)钯-II-二氯化物(Pd(dppf)Cl2.CH2Cl2,366 mg)。将反应混合物在85℃搅拌1h。将其用乙酸乙酯稀释,经硅藻土过滤。将滤液用H2O、盐水洗涤,经Na2SO4干燥,过滤并蒸发至干。
将粗制的混合物通过快速色谱法纯化,用100% 庚烷至60% 庚烷/40%乙酸乙酯的梯度洗脱,以37% 收率得到标题化合物。
LCMS (方法C): 604.7 (M+H)+,在2.32 min。
与上述方法类似地制备下表1中命名的物质。所述化合物为下式
其中(R)m的含义在表1中给出。
根据上述HPLC/MS表征方法获得下述物理学数据。
表1:
实施例编号 | (R)m | m/z: [M+H+] | Rt [min] (方法) | 物理状态 |
1.1 | 4-CF3 | 570.7 | 2.27 (B) | 粉末 |
1.2 | 2,5-二-Cl | 570.6 | 2.34 (B) | 粉末 |
1.3 | 3-(吡咯烷-1-基) | 571.8 | 2.40 (B) | 粉末 |
1.4 | 4-N-叔丁氧基羰基,N-甲基氨基 | 631.7 | 2.32 (B) | 粉末 |
1.5 | 3,5-二-Cl | 570.8 | 2.40 (B) | 粉末 |
1.6 | 2-F-3-Cl | 554.7 | 2.25 (B) | 粉末 |
1.7 | 3-NO2-4-甲基 | 561.7 | 2.17 (B) | 粉末 |
1.8 | 3-Si(CH3)3 | 574.7 | 2.53 (B) | 固体 |
1.9 | 3,5-二-CH3 | 530.8 | 2.33 (B) | 粉末 |
1.10 | 2,3,4,5-四-F | 574.8 | 2.20 (B) | 粉末 |
1.11 | 4-CN | 527.7 | 2.01 (B) | 粉末 |
1.12 | 3-CF3-4-Cl | 604.7 | 2.34 (B) | 泡沫 |
1.13 | 2-Cl-4-CF3 | 604.7 | 2.32 (B) | 粉末 |
1.14 | 3,5-二-CF3 | 638.7 | 2.38 (B) | 粉末 |
1.15 | 4-异丙基磺酰基 | 608.7 | 1.98 (B) | 粉末 |
1.16 | 3-N,N-二乙基氨基羰基 | 601.8 | 2.00 (B) | 粉末 |
1.17 | 3-N,N-二甲基氨基磺酰基 | 609.9 | 1.97 (B) | 泡沫 |
1.18 | 3-三氟甲氧基-5-氨基 | 601.9 | 2.10 (B) | 粉末 |
1.19 | 3,4,5-三-Cl | 604.7 | 2.52 (B) | 粉末 |
1.20 | 4-五氟乙氧基 | 636.9 | 2.43 (B) | 粉末 |
1.21 | 3,4,5-三-F | 556.9 | 2.20 (B) | 粉末 |
1.22 | 2,4,6-三-Cl | 604.8 | 2.36 (B) | 粉末 |
1.23 | 2,6-二-Cl-4-CF3 | 638.8 | 2.34 (B) | 粉末 |
1.24 | 3-CF3-4-Br | 614.8 | 2.30 (B) | 粉末 |
1.25 | 2-Cl-4-CF3 | 682.7 | 2.42 (B) | 固体 |
1.26 | 2,4,6-三-CH3 | 543.01(M-H)- | 2.36 (B) | 泡沫 |
实施例2: 5-(4-氯苯氧基)-2-(甲基磺酰氨基)-N-(3,4,5-三氯苯基)苯甲酰胺(表2中的实施例2.1)
步骤A: 5-氯-2-硝基-N-(3,4,5-三氯苯基)苯甲酰胺。将5-氯-2-硝基苯甲酸(10 g)用亚硫酰氯(7.2 mL)在回流下处理4h。在真空下除去过量的SOCl2。将CH2Cl2 (100 mL)加入至酰氯中。在0℃,缓慢地加入3,4,5-三氯苯胺(9.7 g)和NEt3 (13.8 mL)在100 mL CH2Cl2中的溶液。使反应混合物温热并将其在室温(RT)搅拌过夜。
将反应混合物用200 mL乙醚稀释。加入10 mL HCl 2 N和200 mL H2O,并搅拌混合物,直到形成黄色沉淀。将沉淀滤出并在分析前在高真空下干燥(收率:66%)。
LCMS (方法B): 380.59 (M+H)+,在1.97 min。
步骤B: 5-(4-氯苯氧基)-2-硝基-N-(3,4,5-三氯苯基)苯甲酰胺.
将5-氯-2-硝基-N-(3,4,5-三氯苯基)苯甲酰胺(8.77 g)、K2CO3(6.7 g)和4-氯苯酚(3.26 g)在DMA中的溶液在140℃加热14h。将反应混合物倒入H2O (100 mL)中,将沉淀滤出,在高真空下干燥,得到棕色固体 (收率:55%)。
LCMS (方法B): 468.45 (M-H)-,在2.25 min。
步骤C: 2-氨基-5-(4-氯苯氧基)-N-(3,4,5-三氯苯基)苯甲酰胺.
在N2下,将5-(4-氯苯氧基)-2-硝基-N-(3,4,5-三氯苯基)苯甲酰胺(13.2 g)在80 mLEtOH/H2O (3/1)中的溶液用Fe (10.9 g)和HCl 25% (0.6 mL)处理并将反应混合物在RT搅拌4 h。当还原完成时,将反应混合物在硅藻土塞子上过滤并用乙酸乙酯洗涤。将滤液在真空下蒸发。加入乙酸乙酯,并将有机层用盐水洗涤,经MgSO4干燥,并蒸发至干(收率:89%)。
LCMS (方法B): 442.54 (M+H)+,在2.41 min。
步骤D: 5-(4-氯苯氧基)-2-(甲基磺酰氨基)-N-(3,4,5-三氯苯基)苯甲酰胺
向2-氨基-5-(4-氯苯氧基)-N-(3,4,5-三氯苯基)苯甲酰胺(9 g)在50 mL CH2Cl2中的N2脱气的溶液中加入吡啶(8.2 mL)。将混合物冷却至0℃,然后滴加甲磺酰氯(1.6 mL)。将反应混合物在室温搅拌过夜,然后用额外的50 mL CH2Cl2稀释。将有机层用Na2CO3饱和溶液、用盐水洗涤,然后经MgSO4干燥并蒸发至干(收率:81%)。
LCMS (方法B): 518.5 (M+H)+,在2.27 min。
实施例3: 5-((4-氯苯基)(氰基)甲基)-2-(甲基磺酰氨基)-N-(3,4,5-三氯苯基)苯甲酰胺(表2中的实施例2.7)
步骤A: 5-((4-氯苯基)(氰基)甲基)-2-硝基苯甲酸甲酯.
将NaH (140 mg)悬浮于10 mL DMF中。在0℃将2-(4-氯苯基)乙腈(600 mg)在2 mL DMF中的溶液滴加至反应混合物中,然后在室温搅拌2h。将混合物冷却至0℃,然后滴加溶解在1.5 mL DMF中的5-氯-2-硝基苯甲酸甲酯 (1.024 g)。将反应在0℃搅拌2h,然后在RT搅拌过夜。加入二异丙基醚,并将混合物用H2O、盐水洗涤,经Na2SO4干燥,过滤并蒸发至干。将粗产物在半制备型HPLC上纯化,以12% 收率得到标题化合物。
LCMS (方法B): 328.84 (M-H)-,在1.75 min。
步骤B: 2-氨基-5-((4-氯苯基)(氰基)甲基)苯甲酸甲酯
以与实施例2的步骤C类似的方式还原5-((4-氯苯基)(氰基)甲基)-2-硝基苯甲酸甲酯(收率:96%)。
LCMS (方法B): 300.88 (M+H)+,在1.72 min。
步骤C: 5-((4-氯苯基)(氰基)甲基)-2-(甲基磺酰氨基)苯甲酸甲酯
以与实施例2的步骤D 类似的方式磺酰化2-氨基-5-((4-氯苯基)(氰基)甲基)苯甲酸甲酯(收率:55%)。
LCMS (方法B): 376.76 (M-H)-,在1.71 min。
步骤D: 5-((4-氯苯基)(氰基)甲基)-2-(甲基磺酰氨基)苯甲酸
将5-((4-氯苯基)(氰基)甲基)-2-(甲基磺酰氨基)苯甲酸甲酯(50 mg)悬浮于MeOH/H2O (1 mL, 1/1)中。加入 NaOH (6 mg)并将反应混合物在室温搅拌过夜。完成后,将反应混合物用2N HCl (1mL)处理并用乙酸乙酯萃取两次。将合并的有机层用H2O、盐水洗涤,经Na2SO4干燥,过滤并蒸发至干。通过LCMS确定所述标题产物是足够纯净的,从而能够不经进一步纯化地用于下一步。
LCMS (方法B): 362.71 (M-H)-,在1.52 min。
步骤E: 5-((4-氯苯基)(氰基)甲基)-2-(甲基磺酰氨基)-N-(3,4,5-三氯-苯基)苯甲酰胺
将5-((4-氯苯基)(氰基)甲基)-2-(甲基磺酰氨基)苯甲酸(48 mg)溶解在CH2Cl2 (1.5mL)中。加入3,4,5-三氯苯胺(31 mg)、苯并三唑-1-基-氧基三吡咯烷子基鏻六氟磷酸盐(Pybop, 75 mg)和二异丙基乙胺(DIPEA, 69 L)。将反应混合物在RT搅拌过夜。加入H2O并将混合物用CH2Cl2萃取。将合并的有机层用Na2CO3饱和溶液、盐水洗涤,过滤并蒸发至干。将粗产物在半制备型HPLC上纯化,以46% 收率得到标题化合物。
LCMS (方法B): 539.58 (M-H)-,在2.15 min。
实施例4: 5-(4-氯苯甲酰基)-2-(甲基磺酰氨基)-N-(3,4,5-三氯苯基)苯甲酰胺(表2中的实施例2.6)
步骤A: 5-(4-氯苯甲酰基)-2-硝基苯甲酸.
将5-((4-氯苯基)(氰基)甲基)-2-硝基苯甲酸甲酯(150 mg,参见实施例3步骤A)用LiOH (6当量)在THF/H2O (4/1, 5 mL)中的溶液在室温处理过夜。加入额外的6当量的LiOH。72h后反应完全。加入HCl 2N,直到达到pH 1-2,然后将反应混合物用乙酸乙酯萃取两次。将合并的有机层用H2O、盐水洗涤,经Na2SO4干燥,过滤并蒸发至干。标题化合物对于用于步骤B而言是足够纯净的。
LCMS (方法B): 303.85 (M-H)-,在1.54 min。
步骤B: 5-(4-氯苯甲酰基)-2-硝基-N-(3,4,5-三氯苯基)苯甲酰胺.
以与实施例3步骤E所述类似的方式处理5-(4-氯苯甲酰基)-2-硝基苯甲酸(收率:71%)。
LCMS (方法B): 480.57 (M-H)-,在2.20 min。
步骤C: 2-氨基-5-(4-氯苯甲酰基)-N-(3,4,5-三氯苯基)苯甲酰胺.
以与实施例3步骤B所述类似的方式处理5-(4-氯苯甲酰基)-2-硝基-N-(3,4,5-三氯苯基)苯甲酰胺(收率:93%)。
LCMS (方法B): 450.61 (M-H)-,在2.31 min。
步骤D: 5-(4-氯苯甲酰基)-2-(甲基磺酰氨基)-N-(3,4,5-三氯苯基)苯甲酰胺.
以与实施例2步骤D所述类似的方式处理2-氨基-5-(4-氯苯甲酰基)-N-(3,4,5-三氯苯基)苯甲酰胺(收率:18%)。
LCMS (方法B): 530.5 (M+H)+,在2.23 min。
与上述方法类似地制备下表2中命名的物质。所述化合物为下式
其中(R1)r、(R)m和X的含义在表2中给出
根据上述HPLC/MS表征方法获得下述物理学数据。
表2:
实施例编号 | (R)m | (R1)r | X | m/z: [M+H+] | Rt [min] (方法) | Rt [min] (方法) |
2.1 | 4-Cl | 3,4,5-三-Cl | O | 518.5 | 2.27 (B) | 固体 |
2.2 | H | 3,4,5-三-Cl | O | 484.6 | 2.16 (B) | 粉末 |
2.3 | 4-Cl | 3,4,5-三-Cl | NH | 517.5 | 2.13 (B) | 粉末 |
2.4 | 4-Cl | 3,4,5-三-Cl | S | 534.5 | 2.38 (B) | 固体 |
2.5 | H | 3,4,5-三-Cl | NH | 483.7 | 1.98 (B) | 固体 |
2.6 | 4-Cl | 3,4,5-三-Cl | C(O) | 530.6 | 2.23 (B) | 固体 |
2.7 | 4-Cl | 3,4,5-三-Cl | C(CN) | 541.5 | 2.15 (B) | 泡沫 |
2.8 | 4-Br | 3,5-二-CF3 | O | 596.9 | 2.23 (B) | 泡沫 |
2.9 | 4-CN | 3,5-二-CF3 | O | 543.9 | 1.98 (B) | 胶状物 |
2.10 | 3,5-二-CF3 | 3,5-二-CF3 | O | 654.9 | 2.31 (B) | 固体 |
2.11 | 2-Cl | 3,5-二-CF3 | O | 552.9 | 2.19 (B) | 胶状物 |
2.12 | 3-Cl | 3,5-二-CF3 | O | 552.9 | 2.14 (B) | 固体 |
2.13 | 4-CF3 | 3,5-二-CF3 | O | 586.9 | 2.22 (B) | 油状物 |
2.14 | 3-OCH3 | 3,5-二-CF3 | CH=CH | 558,8 | 2.21(B) | 固体 |
2.15 | 4-Cl | 3,4-二-Cl | O | 484 [M−H]− | 2.11 (B) | 固体 |
2.16 | 4-Cl | 4-OCF3 | O | 500.7 | 2.03 (B) | 粉末 |
2.17 | 4-Cl | 3-CF3-4-OCH3 | O | 514.6 | 1.94 (B) | 粉末 |
2.18 | 4-Cl | 4-SF5 | O | 542.5 | 2.04 (B) | 固体 |
2.19 | 4-Cl | 3,4,5-三-F | O | 470.6 | 1.96 (B) | 固体 |
2.20 | 4-Cl | 3-B(OH)2 | O | 460.7 | 2.01 (B) | 油状物 |
2.21 | 4-Cl | 3-CF3-4-Br | O | 562.5 | 2.10 (B) | 油状物 |
2.22 | 4-Cl | 4-CF(CF3)2-2,6-二-CH3 | O | 612.7 | 2.18 (B) | 油状物 |
2.23 | 4-Cl | 2,3,4-三-Cl | O | 518.6 | 2.12 (B) | 油状物 |
2.24 | 4-Cl | 4-环己基 | O | 498.8 | 2.35 (B) | 油状物 |
2.25 | 4-Cl | 4-OCF2CHFCF3-2,5-二-Cl | O | 650.6 | 2.19 (B) | 固体 |
2.26 | 4-Cl | 3,5-二-CF3 | O | 552.6 | 2.14 (B) | 固体 |
2.27 | 4-Cl | 3-CF3-4-Cl | O | 518.6 | 2.09 (B) | 固体 |
2.28 | 4-Cl | 4-NO2-2-Cl | O | 495.6 | 1.93 (B) | 油状物 |
2.29 | 4-Cl | 4-SCF3 | O | 516.7 | 2.17 (B) | 油状物 |
2.30 | 4-Cl | 2,4,5-三-F | O | 470.7 | 1.93 (B) | 油状物 |
2.31 | 4-Cl | 3,5-二-F-4-Cl | O | 486.7 | 2.10 (B) | 油状物 |
2.32 | 4-Cl | 2-(N-吗啉代) | O | 501.8 | 1.97 (B) | 油状物 |
2.33 | 4-Cl | 2,3,4-三-F | O | 470.8 | 1.96 (B) | 油状物 |
2.34 | 4-Cl | 3,4-二-F | O | 452.8 | 2.00 (B) | 油状物 |
2.35 | 4-Cl | 3,5-二-F | O | 452.8 | 2.02(B) | 泡沫 |
2.36 | 4-Cl | 2,3,5-三-F | O | 470.8 | 1.99 (B) | 泡沫 |
2.37 | 4-Cl | 3,5-二-Cl-4-F | O | 502.7 | 2.21 (B) | 油状物 |
2.38 | 4-Cl | 3,5-二-Cl | O | 484.7 | 2.23 (B) | 油状物 |
2.39 | 4-Cl | 4-NO2 | O | 461.8 | 2.42 (B) | 粉末 |
2.40 | 4-Cl | 3-Cl-4-Br | O | 528.7 | 2.15 (B) | 固体 |
2.41 | 4-Cl | 2-(N,N-二乙基氨基)乙基-氨基羰基 | O | 559.0 | 1.21 (B) | 油状物 |
2.42 | 4-Cl | 3-Cl-4-J | O | 576.6 | 2.17 (B) | 油状物 |
2.43 | 4-Cl | 2-F-4-Br | O | 512.7 | 2.00 (B) | 晶体 |
2.44 | 4-Cl | 3,4-二-Br | O | 572.6 | 2.14 (B) | 固体 |
2.45 | 4-Cl | 3,5-二-Cl-4-Br | O | 562.6 | 2.19 (B) | 油状物 |
2.46 | 4-Cl | 3,5-二-Cl-4-CH3 | O | 498.8 | 2.30 (B) | 油状物 |
2.47 | 4-Cl | 3,5-二-Cl-4-OH | O | 500.6 | 1.83 (B) | 油状物 |
2.48 | 4-Cl | 3,5-二-CF3-4-Br | O | 630.5 | 2.30 (B) | 固体 |
2.49 | 4-Cl | 3,5-二-Cl-4-OCH3 | O | 514.6 | 2.12 (B) | 泡沫 |
2.50 | 4-Cl | 4-CF(CF3)2 | O | 584.8 | 2.23 (B) | 泡沫 |
2.51 | 4-Cl | 3-CF3 | O | 484.9 | 2.03 (B) | 泡沫 |
2.52 | 4-Cl | 3-OCF3 | O | 500.8 | 2.06 (B) | 泡沫 |
2.53 | 4-Cl | 3-CHF2 | O | 466.8 | 1.90 (B) | 泡沫 |
2.54 | 4-Cl | 3-SF5 | O | 542.9 | 1.97 (B) | 粉末 |
2.55 | 4-Cl | 4-CF3 | O | 484.8 | 2.04 (B) | 粉末 |
2.56 | 4-Cl | 3,5-二-CF3-4-Cl | O | 586.8 | 2.28 (B) | 粉末 |
2.57 | 4-Cl | 3,5-二-Cl-2-OH | O | 500.6 | 1.94 (B) | 油状物 |
2.58 | 4-Cl | 2-CH3SO2NH-4,5-二-Cl | O | 577.7 | 1.89(B) | 粉末 |
与上述方法类似地制备下表3中命名的物质。所述化合物为下式
其中含义Y在表3中给出。根据上述HPLC/MS表征方法获得下述物理学数据。
表3:
实施例编号 | Y | m/z: [M+H+] | Rt [min] (方法) | Rt [min] (方法) |
3.1 | 577.7 | 2.09 (B) | 粉末 | |
3.2 | 711.6 | 2.34 (B) | 粉末 | |
3.3 | 618.8 | 2.22 (B) | 粉末 | |
3.4 | 584.7 | 2.19 (B) | 固体 | |
3.5 | 563.8 | 2.38 (B) | 固体 | |
3.6 | 492.9 | 2.18 (B) | 固体 | |
3.7 | 481.8 | 1.91 (B) | 固体 | |
3.8 | 492.8 | 1.98 (B) | 固体 | |
3.9 | 492.8 | 2.10 (B) | 固体 | |
3.10 | 522.8 | 2.14 (B) | 固体 |
生物学实施例:
胃肠幼虫发育测定
将新鲜收获并净化的线虫卵用于接种具有适当格式的孔板,所述孔板含有待评估抗寄生虫活性的测试物质和允许卵完全发育至第三龄幼虫的媒介物。将板在25℃和60%相对湿度下温育6天。记录卵的孵化和随后的幼虫发育,以鉴别可能的杀线虫活性。效力如下表示:降低的卵孵化、降低的L3发育或在任何阶段下的幼虫的麻痹和死亡的百分比。化合物编号1.9-1.13、1.21-1.23、1.25、1.26、2.13、2.50、2.51和2.54在10ppm时达到≥ 60%效力,并且因此被认为是有活性的。
心丝虫微丝测定
从供体动物狗的血液制备新鲜收获并净化的心丝虫微丝。然后将微丝分配到格式化的微量培养板中,所述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)下温育48小时。然后记录微丝的运动性以确定效力。效力如下表示:与对照和标准相比的降低的运动性的百分比。化合物编号1.1-1.25、2.1-2.58和3.1-3.10 在10ppm时显示高于50%的效力,并且因此被认为是有活性的。
沙鼠中的魏氏棘唇线虫(Acanthocheilonema viteae)
通过皮下注射使沙鼠人工感染80个魏氏棘唇线虫的L3幼虫。在注射后第5天到第9天用配制的测试化合物通过灌胃法进行连续治疗。感染后84天,取沙鼠的血以计数循环中的微丝(使用Fuchs-Rosenthal计数槽和显微镜)。仅将循环中的微丝的平均值比安慰剂治疗组低至少50%的测试组完全分割以复原成虫。效力如下表示:与安慰剂治疗组相比的蠕虫数目减少的%(使用Abbot公式)。化合物编号 1.5、1.10、1.13、1.17、2.1、2.21、2.26和2.51在10mg/kg时显示出高于80%的效力。
成熟肝吸虫体外测定
将来自牛或绵羊肝脏的新鲜收获的成熟肝片吸虫分配在具有4 mL RPMI完全培养基的12-孔板(1只吸虫/孔)中并在37℃培养箱中保持大约12小时。在更新培养基后,通过视频记录每只吸虫的活动(预定值)确定吸虫的活力。以100 µg/mL的浓度加入测试化合物,并在6和24小时后测量吸虫的活动。效力表示为:基于预定值和未治疗的对照,降低的运动的百分比。在该测试中,在6h后显示出超过>90%的效力并且在24h后显示出>95%的效力的下述实施例被认为是阳性的:1.5、1.10、1.13、2.19、2.21、2.26和2.48。
Claims (15)
1.下式化合物
或其盐或对映异构体,其中X是O、S、NR2C(O)、C(CN)或CH=CH,
R0是H、C1-C4-烷基或羟基;
n是0或1,
每个R独立地是卤素;C1-C6-烷基;C1-C6-卤代烷基;C3-C6-环烷基;C3-C6-卤代环烷基;氨基;N-单-或N,N-二-C1-C4-烷基氨基;羟基;C1-C6-烷氧基;C1-C6-卤代烷氧基;C1-C6-烷基硫基;C1-C6-卤代烷基硫基;C1-C6-烷基-亚磺酰基;C1-C6-卤代烷基亚磺酰基;C1-C6-烷基磺酰基;C1-C6-卤代烷基磺酰基;SF5;三-C1-C4-烷基甲硅烷基;C1-C6-烷氧基羰基;氨基羰基;N-单-或N,N-二-C1-C6-烷基氨基羰基;氨基磺酰基;N-单-或N,N-二-C1-C6-烷基氨基磺酰基;N-C1-C6-烷基磺酰基氨基;C1-C6-烷氧基羰基氨基;N-C1-C4-烷基-N-C1-C6-烷氧基羰基氨基;氰基;硝基;或未取代的或被卤素、C1-C4-烷基、C1-C4-卤代烷基、C3-C6-环烷基、C1-C4-烷氧基、C1-C4-卤代烷氧基、氨基、氰基或硝基取代的C3-C6-杂环基;
m是0-4的整数;
每个R1独立地是卤素;C1-C6-烷基;C1-C6-卤代烷基;C3-C6-环烷基;C3-C6-卤代环烷基;C1-C6-烷氧基;C1-C6-卤代烷氧基;C1-C6-烷基硫基;C1-C6-卤代烷基硫基;C1-C6-烷基-亚磺酰基;C1-C6-卤代烷基亚磺酰基;C1-C6-烷基磺酰基;C1-C6-卤代烷基磺酰基;SF5;氨基;
N-单-或N,N-二-C1-C6-烷基氨基;三-C1-C4-烷基甲硅烷基;C1-C6-烷氧基羰基;氨基羰基;N-单-或N,N-二-C1-C6-烷基氨基羰基;N,N-二-C1-C4-烷基氨基-C1-C4-烷基氨基羰基;氨基磺酰基;N-单-或N,N-二-C1-C6-烷基氨基磺酰基;N-C1-C6-烷基磺酰基氨基;C1-C6-烷氧基羰基氨基;N-C1-C4-烷基-N-C1-C6-烷氧基羰基氨基;氰基;硝基;羟基;B(OH)2;或苯基、苯甲酰基、C3-C6-杂环基、C3-C6-杂环基氧基或C6-C8-苯并杂环基,其各自是未取代的或被卤素、C1-C4-烷基、C1-C4-卤代烷基、C3-C6-环烷基、C1-C4-烷氧基、C1-C4-卤代烷氧基、氨基、氰基或硝基取代;和
r是1-4的整数。
2.根据权利要求1所述的式(I)化合物,其中每个R独立地是卤素;C1-C4-烷基;C1-C4-卤代烷基;氨基;C1-C4-烷氧基;C1-C4-卤代烷氧基;C1-C4-卤代烷基硫基;C1-C4-烷基磺酰基;C1-C4-卤代烷基磺酰基;三-C1-C2-烷基甲硅烷基;C1-C4-烷氧基羰基;N-单-或N,N-二-C1-C4-烷基氨基羰基;氨基磺酰基;N-单-或N,N-二-C1-C4-烷基氨基磺酰基;N-C1-C2-烷基-N-C1-C4-烷氧基羰基氨基;氰基;硝基;或包含1或2个相同或不同的选自O、S和N的杂原子的5-或6-元杂环烷基,其是未取代的或被卤素、C1-C2-烷基、C1-C2-卤代烷基或C1-C2-烷氧基取代。
3.根据权利要求1所述的式(I)化合物,其中每个R是卤素、C1-C2-烷基、C1-C2-卤代烷基、C1-C2-烷氧基、C1-C2-卤代烷氧基或氰基,特别是氯、氟或CF3。
4.根据权利要求1-3中任一项所述的式(I)化合物,其中m是整数1、2或3,优选地是1或2,特别是1。
5.根据权利要求1-4中任一项所述的式(I)化合物,其中每个R1独立地是卤素;C1-C4-烷基;C1-C4-卤代烷基;C3-C6-环烷基;C1-C4-烷氧基;C1-C4-卤代烷氧基;C1-C4-卤代烷基硫基;SF5;N,N-二-C1-C4-烷基氨基-C1-C4-烷基氨基羰基;N-C1-C4-烷基磺酰基氨基;氰基;硝基;羟基;B(OH)2, 吗啉代;或苯基、苯甲酰基、吡啶基氧基、嘧啶基氧基或苯并噻唑基,其各自是未取代的或被卤素、C1-C4-烷基、C1-C4-卤代烷基、C3-C6-环烷基或C1-C4-烷氧基取代。
6.根据权利要求1-4中任一项所述的式(I)化合物,其中每个R1独立地是卤素;C1-C2-烷基;C1-C3-卤代烷基;C1-C2-烷氧基;C1-C3-卤代烷氧基;C1-C2-卤代烷基硫基;SF5;硝基;或羟基;且特别是卤素或CF3。
7.根据权利要求1-6中任一项所述的式(I)化合物,其中r是整数1、2或3,特别是2或3。
8.根据权利要求1-7中任一项所述的式(I)化合物,其中R0是H,m是0或1且X是O。
9.根据权利要求1所述的化合物,其为下式
其中R和m 各自如权利要求1中所定义。
10.根据权利要求1所述的化合物,其为下式
其中R、R1、m和r 各自如权利要求1中所定义。
11.根据权利要求10所述的式(Ib)化合物,其中m是整数1或2,r是整数2或3,每个R独立地是卤素或CF3,且每个R1独立地是卤素或CF3。
12.用于防治寄生虫的组合物,其含有作为活性成分的至少一种根据权利要求1-11中任一项所述的式(I)化合物,以及载体和/或分散剂。
13.根据权利要求1-11中任一项所述的式(I)化合物,其用于防治温血动物体内或体表的体内寄生虫。
14.防治温血动物体表的体内寄生虫的方法,其包括给温血动物施用兽医学上有效量的至少一种根据权利要求1-11中任一项所述的式(I)化合物。
15.根据权利要求1-11中任一项所述的式(I)化合物在制备对抗温血动物体内或体表的体内寄生虫的兽用组合物或药物组合物中的用途。
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