CN114514224A - 甲硫氨酸代谢途径抑制剂 - Google Patents
甲硫氨酸代谢途径抑制剂 Download PDFInfo
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- CN114514224A CN114514224A CN202080046303.0A CN202080046303A CN114514224A CN 114514224 A CN114514224 A CN 114514224A CN 202080046303 A CN202080046303 A CN 202080046303A CN 114514224 A CN114514224 A CN 114514224A
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- alkyl
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- alkoxy
- hydrogen
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Abstract
本发明提供了新型胱硫醚γ合酶(CGS)抑制剂,它们作为选择性和非选择性除草剂、农业和非农业除草剂、病虫害综合治理中的除草剂、用于园艺、清理荒地、清理工业或建筑场所、清理铁路和铁路路堤的除草剂、杀虫剂、杀真菌剂、农业植物刺激剂或抗微生物剂的用途。还提供了一种用于控制不想要的植被或从区域清理不想要的植被的方法,其包括向所述不想要的植被的所在地、向不想要的植物或向其栖息地施用除草有效量的本发明的化合物。
Description
技术领域
本申请涉及甲硫氨酸代谢途径抑制领域。特别地,本申请涉及新型胱硫醚γ合酶(CGS)抑制剂、基于所获得的结构信息进行其分子设计和鉴定的方法,以及它们在各种农业和非农业应用中的用途。
背景技术
胱硫醚γ-合酶(CGS)是细菌和植物中反式硫化途径的第一种酶。在细菌中,硫化物源自硫酸盐的还原,并结合到L-半胱氨酸(L-Cys)中,后者随后转化为L-高半胱氨酸(L-Hcys),其为L-甲硫氨酸(L-Met)的直接前体。这与L-Hcys转化为L-Cys的哺乳动物逆向反式硫化途径形成对比。
CGS催化甲硫氨酸生物合成的关键步骤。由大肠杆菌(E.coli)中的metB基因编码的CGS催化磷酸吡哆醛依赖性α,γ-置换反应,其中L-Cys和O-琥珀酰-L-高丝氨酸缩合产生L-胱硫醚(L-Cth)和琥珀酸盐。对十一种高等植物(包括两种裸子植物和九种被子植物)的CGS活性的调查发表在Datko等人(1974)“Homocysteine biosynthesis in green plants”(绿色植物中同型半胱氨酸的生物合成),Journal of Biological Chemistry(生物化学杂志)249A,第1139-1155页中。该调查表明,植物的反式硫化途径与细菌的反式硫化途径相似,只是植物和细菌CGS的底物不同:分别为O-磷酸-L-高丝氨酸和O-琥珀酰-L-高丝氨酸。
最近的研究表明,对于CGS和反式硫化途径的相关酶的研究有大量的重要应用。该途径是微生物和植物独有的,使该酶成为开发抗微生物剂和除草剂的有吸引力的目标。考虑到CGS在植物中产生L-Met中所起的关键作用,据信将选择性结合CGS的小分子抑制剂有可能被开发成除草剂。此外,由于其在哺乳动物中的不存在,任何发现的基于CGS的除草剂都被认为对人类无毒。
Steegborn等人(1999)“The crystal structure of cystathionineγ-synthasefrom Nicotiana tabacum reveals its substrate and reaction specificity”(来自烟草的胱硫醚γ-合酶的晶体结构揭示其底物和反应特异性),Journal of MolecularBiology(分子生物学杂志),290(5),第983-996页将来自烟草(Nicotiana tabacum)的CGS的结构解析为令人满意的的分辨率。发现烟草的CGS活性位点比同一组一年前解析的大肠杆菌活性位点更受限制。与对大肠杆菌具有特异性的O-琥珀酰-L-高丝氨酸相比,它对应于更小的O-磷酸-L-高丝氨酸底物,并且其活性位点具有较少的由残基36*至45*所采用的扩展环结构(其中星号表示来自第二亚基的残基)。
Steegborn等人(2001)在“Crystal structures of cystathionine gamma-synthase inhibitor complexes rationalize the increased affinity of a novelinhibitor”(胱硫醚γ-合酶抑制剂复合物的晶体结构使新型抑制剂的亲和力增加合理化),Journal of Molecular Biology(分子生物学杂志),311,第789-801页中用不同化合物类别的抑制剂解析了来自烟草的CGS的几种复合物的晶体结构。与特异性底物类似物dl-E-2-氨基-5-膦酰基-3-戊烯酸的复合物证实了羧酸结合Arg423残基的作用并确定了活性位点的磷酸结合口袋。解析的结构证实了Lys165在特异性测定中的作用和Tyr163柔性侧链在催化中的作用。
Steegborn等人(2001)鉴定的CGS抑制剂5-羧甲硫基-3-(3'-氯苯基)-1,2,4-噁二唑显示出迄今为止报道的对CGS的最高亲和力,这是由于与生理底物不使用的另外的活性位点口袋结合。据推测,该抑制剂的紧密弯曲构象使其能够同时结合羧酸识别位点和Arg423与Ser388之间的另一结合口袋。
Steegborn等人(2001)描述的CGS抑制剂结构建议对已知抑制剂进行改进,并为开发新的先导化合物提供指导。然而,由于与磷酸根和羧酸根识别位点相互作用的官能团的非最佳排列,该结构仍然具有相对较低的亲和力。为了开发作用机理是植物CGS抑制的新型除草剂,因此有必要找到更有效和更具特异性的化合物作为CGS抑制剂。为了以合理的方式使其成为可能,非常需要进一步研究植物CGS结构和研究潜在抑制剂与酶活性位点相互作用的精确方式。
发明内容
在一个方面,本申请涉及具有式(I)的甲硫氨酸代谢途径的抑制剂:
其中T为磺酰基基团或羰基基团:
R1为式(A)、(B)、(C)或(D)的基团:
其中R4为具有一至三个选自N、O和S的杂原子并且任选地被(C1-C3)-烷基、(C1-C3)-卤代烷基、(C1-C3)-烷氧基或羟基基团或卤素原子取代的五元杂芳环;
R5为氢或(C1-C3)-烷基、(C1-C3)-卤代烷基或(C1-C3)-烷氧基;
R6、R8和R9独立地选自氢、卤素、氨基、氰基、(C1-C3)-烷基、(C1-C3)-卤代烷基、羟基、(C1-C3)-烷氧基、(C1-C3)-卤代烷氧基、单-(C1-C3)-烷基氨基、二-(C1-C3)-烷基氨基、氨基-(C1-C3)-烷基、单-(C1-C3)-烷基氨基-(C1-C3)-烷基、二-(C1-C3)-烷基氨基-(C1-C3)-烷基和硝基;
R7为氢、卤素、氰基、(C1-C3)-烷基、(C1-C3)-卤代烷基、(C1-C3)-烷氧基、羟基、(C1-C3)-卤代烷氧基、氨基、单-(C1-C3)-烷基氨基、二-(C1-C3)-烷基氨基、氨基-(C1-C3)-烷基、单-(C1-C3)-烷基氨基-(C1-C3)-烷基、二-(C1-C3)-烷基氨基-(C1-C3)-烷基、硝基或3,5-二甲基-1H-吡唑-1-基;
R为CH或N;
式(D)中的两个虚线箭头指向苯环的两个碳原子,羰基能够连接至所述两个碳原子;
A为CH-R10或N-R11;
E为C-R12或N;
J为C-R13或N;并且
R10、R11、R12和R13独立地选自氢、(C1-C3)-烷基和(C1-C3)-卤代烷基;
X和Y独立地为CH或N;
Z为C-R14或N;
R14为氢、卤素、(C1-C3)-烷基、(C1-C3)-卤代烷基、羟基、(C1-C3)-烷氧基、羧酸根、(C1-C3)-烷基羧酸根、羧酸、(C1-C3)-烷基羧酸、羧酰胺、(C1-C3)-烷基羧酰胺、氰基、硝基、苯基、苄基、吡啶基或苯基氨基,其中所述苯基、苄基、吡啶基或苯基氨基任选地被一至三个相同或不同的独立地选自以下的取代基取代:卤素、(C1-C3)-烷基、(C3-C6)-环烷基、(C1-C3)-卤代烷基、羟基、(C1-C3)-烷氧基、氰基、氨基、羧酸和硝基;
L为N-R15、O或S;并且
R15为氢、(C1-C3)-烷基、(C1-C3)-卤代烷基、苄基、吡啶基或苯基,其中所述苄基、吡啶基或苯基任选地被一至三个相同或不同的独立地选自以下的取代基取代:卤素、(C1-C3)-烷基、(C1-C3)-卤代烷基、羟基、(C1-C3)-烷氧基、氰基、氨基和硝基;
(i)当T为磺酰基基团,并且R1为式(A)的基团时,则
R2为氢原子,并且
R3为任选地被一至三个相同或不同的独立地选自以下的取代基取代的苯基基团:卤素原子、(C1-C3)-烷基、(C1-C3)-卤代烷基、(C1-C3)-烷氧基、氨基、氰基、羟基、硝基、羧酸、(C1-C3)-烷基羧酸、羧酸根、羧酰胺、(C1-C3)-烷基羧酸根和(C1-C3)-烷基羧酰胺基团;以及
(ii)当R1为式(B)的基团时,则
R2为氢原子,并且
R3为苯基或吡啶基,所述苯基或吡啶基被式(E)的基团取代,并且苯基或吡啶基环的任何可用的碳原子任选地被以下基团取代:(C1-C3)-烷基、(C1-C3)-卤代烷基、(C1-C3)-烷氧基、羧酸、羧酸根、(C1-C3)-烷基羧酸、(C1-C3)-烷基羧酸根、(C1-C3)-烷基羧酰胺、羧酰胺、卤素、氰基、羟基或硝基;
(iii)当R1为式(C)的基团时,则
R2和R3一起在它们所连接的氮原子周围形成下式的吲哚啉基基团:
其中所述吲哚啉基基团的吡咯烷基环被一个R16基团取代,所述R16基团连接至任何可用的吡咯烷基环碳原子,R16基团选自以下取代基:氢、卤素、硝基、(C1-C3)-烷基、(C1-C3)-卤代烷基、(C1-C3)-烷氧基、羟基、氰基、羧酸、羧酸根、(C1-C3)-烷基羧酸根、羧酰胺、(C1-C3)-烷基羧酸、(C1-C3)-烷基羧酰胺或氨基;并且所述基团的苯基芳环任选地被一至三个R17取代,所述R17与任何可用的苯环碳原子连接并且独立地选自以下基团:卤素、硝基、(C1-C3)-烷基、(C1-C3)-卤代烷基、(C1-C3)-烷氧基、羟基、氰基、羧酸、羧酸根、(C1-C3)-烷基羧酸根、羧酰胺、(C1-C3)-烷基羧酸、(C1-C3)-烷基羧酰胺或氨基;以及
(iv)当T为羰基基团并且R1为式(D)的基团时,则
R2为氢或(C1-C3)-烷基,并且
R3为下式的基团:
其中R18为一至三个相同或不同的与所述苯环的任何可用的碳原子连接的取代基,所述R18独立地选自以下的取代基:氢、氨基、(C1-C3)-烷基、(C1-C3)-卤代烷基、(C1-C3)-烷氧基、(C1-C3)-烷基羧酸、羧酸、(C1-C3)-烷基羧酸根、羧酸根、(C1-C3)-烷基羧酰胺、羧酰胺、卤素、氰基、羟基、硝基和乙酰氨基;以及以下择其一:
能够抑制甲硫氨酸代谢途径的式(I)的化合物通常可用于抑制胱硫醚γ-合酶(CGS),特别是在植物、真菌和细菌中。这些化合物可用作除草剂、杀虫剂、杀真菌剂、农业植物刺激剂或抗微生物剂。本发明的化合物可用于种子处理。在一个具体的实施方案中,本发明的化合物用作选择性除草剂、非选择性除草剂、农业除草剂、非农业除草剂或除莠剂、病虫害综合治理中的除草剂、园艺中的除草剂、清理荒地中的除草剂、清理工业或建筑场所中的除草剂、或清理铁路和铁路路堤中的除草剂。
附图说明
根据以下结合附图的详细描述,将更全面地理解和领会所公开的实施方案。
图1示出了从镍柱洗脱的蛋白质的考马斯染色的12%SDS凝胶电泳:
泳道1是标志带,
泳道2和泳道3—在添加IPTG之前第一菌落和第二菌落的不可溶物,
泳道4和泳道5—在添加1mM IPTG之后4小时第一菌落和第二菌落的不可溶物,
泳道6和泳道7—在添加IPTG之前第一菌落和第二菌落的可溶物,
泳道8和泳道9—在添加1mM IPTG之后4小时第一菌落和第二菌落的可溶物,以及
泳道10—示出在从镍柱洗脱之后第一菌落表达的蛋白质的条带。
图2a至图2b示出了用于监测CGS活性的测定开发。图2a中的条形图示出了CGS、半胱氨酸和磷酸-丝氨酸酯与7-甲基-6-硫代鸟苷(MESG)和嘌呤核苷磷酸化酶(PNP)一起温育后在360nm处的吸光度。MESG是用于在PNP测定中定量无机磷酸盐的发色底物。增加的吸光度表明磷酸盐释放。图2b提供了示出反应中使用的对应初始组分的表格。
具体实施方式
根据以下结合附图的详细描述,将更全面地理解和领会所公开的实施方案。本文所包括和描述的附图是示意性的并且不限制本公开的范围。还应当注意,在附图中,一些元件的尺寸可能被放大,因此为了说明的目的没有按比例绘制。尺寸和相对尺寸不一定对应于本公开的实践的实际缩减。
在以下具体实施方式中,将描述本申请的各个方面。出于解释的目的,阐述了具体配置和细节以便提供对本申请的透彻理解。然而,对于本领域技术人员来说显而易见的是,本申请可以在没有本文给出的具体细节的情况下被实践。此外,可以省略或简化公知的特征,以免模糊本申请。
权利要求中使用的术语“包括”是“开放式的”,并且是指所列举的要素,或它们在结构或功能上的等同物,加上未列举的任何其他一个或多个同物。它不应被解释为仅限于其后列出的方式;它不排除其他要素或步骤。需要被解释为指定所提及的所述特征、整体、步骤或部件的存在,但不排除一个或多个其他特征、整体、步骤或部件或其组的存在或添加。因此,例如,表述“包含x和z的组合物”的范围不应受限于仅由成分x和z组成的组合物。同样,表述“包括步骤x和z的方法”的范围不应受限于仅由这些步骤组成的方法。
除非明确说明,否则如本文所用,术语“约”应被理解为在本领域的正常公差范围内,例如在平均值的两个标准偏差内。在一个实施方案中,术语“约”是指在其所使用的数字的报告数值的10%内,优选在报告数值的5%内。例如,术语“约”可立即理解为在所述值的10%、9%、8%、7%、6%、5%、4%、3%、2%、1%、0.5%、0.1%、0.05%或0.01%内。在其他实施方案中,术语“约”可意指更高的变化容限,这取决于例如所使用的实验技术。特定值的所述变化是本领域技术人员所理解的,并且在本发明的上下文内。作为说明,“约1至约5”的数值范围应被解释为不仅包括明确列举的约1至约5的值,而且还包括在所示范围内的单个值和子范围。因此,包括在该数值范围内的是单个值,例如2、3和4和子范围,例如1-3、2-4和3-5,以及单独地1、2、3、4、5或6。这个相同的原则适用于仅引用一个数值作为最小值或最大值的范围。除非上下文另有明确说明,否则本文提供的所有数值均由术语“约”修饰。其他类似的术语,例如“基本上”、“一般地”、“至多”等应被解释为修饰术语或值,使得它不是绝对的。这些术语将由它们所修饰的环境和术语来定义,因为这些术语是本领域技术人员所理解的。这至少包括用于测量值的给定实验、技术或仪器的预期实验误差、技术误差和仪器误差的程度。
如本文所用,术语“和/或”包括一个或多个相关联的所列项目的任何和所有组合。除非另外定义,否则本文所用的所有术语(包括技术和科学术语)具有与本发明所属领域的普通技术人员通常理解的含义相同的含义。还应理解,诸如常用词典中定义的那些的术语应被解释为具有与其在说明书和相关领域的背景中的含义一致的含义,并且不应被解释为理想化或过于正式的含义,除非本文中明确如此定义。为简洁和/或清楚起见,可能未详细描述众所周知的功能或构造。
考虑到胱硫醚γ-合酶(CGS)在植物中产生甲硫氨酸中所起的关键作用,本实施方案涉及能够结合并因此选择性抑制胱硫醚γ-合酶(CGS)的小有机化合物。这些有机化合物有可能被开发成基于CGS的除草剂,其将对人类无毒,因为CGS在哺乳动物中不存在。
术语“烷基”是指饱和一价烃基基团。示例性烷基基团包括甲基、乙基和丙基。术语“(C1-C3)-烷基”是指含有一至三个碳原子的烷基。当烷基用作另一个命名的基团如“卤代烷基”之后的后缀时,其意在指在烷基的直链或支链上的任何连接点处键合有一个、两个或三个其他具体命名的基团例如卤素的烷基。
术语“芳基”是指具有单个环或多个稠环的六至十八个环原子的一价不饱和芳烃基团。示例性芳基为苯基、联苯基、苄基、萘基、蒽基、芘基等。当术语“取代的”与此类基团一起使用时,如在“任选地被一至三个独立地选自以下的取代基取代”中,应当理解,芳基部分可以任选地被相同或不同的基团取代,这些基团独立地选自上文和下文中所述的那些,视情况而定。
术语“环烷基”是指在环中具有三至六个碳原子的完全饱和和部分不饱和的环状一价烃基。示例性环烷基为环丙基、环丁基、环戊基和环己基。
术语“杂环的”和“杂环基”是指每个环中具有三至八个环原子的完全饱和或部分不饱和的非芳族环状基团(在每个单环基团中,在双环基团中具有六至十二个原子,在三环基团中具有十至十八个原子),其在环中具有至少一个杂原子(氮、氧或硫)和至少一个碳原子。含有杂原子的杂环基团的每个环可以具有一至三个杂原子,其中氮和/或硫杂原子可以任选地被氧化,并且氮杂原子可以任选地被季铵化。杂环基基团可具有被羰基基团取代的碳环原子。杂环基基团可在环或环体系的任何氮原子或碳原子处连接至分子的其余部分。另外,杂环基团可具有以螺或稠合方式与其连接的第二或第三环,条件是连接点连接到杂环基基团。连接的螺环可以是碳环或杂环,并且第二和/或第三稠环可以是环烷基、芳基或杂芳基环。示例性单环杂环基团包括氮杂环丁烷基、环氧乙烷基、吡咯烷基、吡唑啉基、咪唑烷基、二氧杂环己烷基、二氧戊环基、噁唑烷基、哌啶基、哌嗪基、吗啉基、四氢呋喃基、四氢吡喃基、硫代吗啉基等。示例性双环杂环基团包括吲哚啉基、异吲哚啉基、奎宁环基、苯并吡咯烷基、苯并吡唑啉基、苯并咪唑烷基、苯并哌啶基、四氢异喹啉基、四氢喹啉基、二氢异吲哚基等。
术语“杂芳基”是指每个环中具有三至八个环原子的芳族单环、双环或三环基团(例如,在单环基团中具有三至八个原子,在双环基团中具有六至十二个原子,在三环基团中具有至十八个原子),其在环中具有至少一个杂原子(氮、氧或硫)和至少一个碳原子。杂芳基基团的每个环可以具有一至四个杂原子,其中氮和/或硫可以任选地被氧化,并且氮杂原子可以任选地被季铵化。杂芳基基团可在环或环体系的任何氮原子或碳原子处连接至分子的其余部分。另外,杂芳基基团可具有与其稠合的第二或第三碳环(环烷基或芳基)或杂环,条件是连接点连接到杂芳基基团。示例性杂芳基基团是吡咯基、噻吩基、噻唑基、咪唑基、呋喃基、吲哚基、异吲哚基、噁唑基、异噁唑基、苯并噻唑基、苯并噁唑基、喹啉基、异喹啉基、吡啶基、嘧啶基、吡嗪基、哒嗪基、三唑基、四唑基等。示例性双环杂芳基基团包括苯并噻唑基、苯并噁唑基、喹啉基、苯并噁二唑基、苯并噻吩基、色烯基、吲哚基、吲唑基、异喹啉基、苯并咪唑基、苯并吡喃基、苯并呋喃基、苯并呋呫基、苯并吡喃基、噌啉基、喹喔啉基、吡咯并吡啶基、呋喃并吡啶基(例如呋喃并[2,3-c]吡啶基、呋喃并[3,2-b]吡啶基]或呋喃并[2,3-b]吡啶基)、三嗪基氮杂基等。
杂环基环可以任选地稠合至如本文所定义的(一个)芳基或杂芳基环,条件是芳基和杂芳基环是单环的。另外,杂环基环中的一个或两个环碳原子可任选地被羰基基团取代。当杂环基环部分饱和时,其可含有一至三个环双键,条件是该环不是芳族的。
术语“烷氧基”是指结构-OR的基团,其中基团R独立地选自上文和下文适当定义和列举的烷基或环烷基基团。
术语“烷基氨基”或“二烷基氨基”是指其中一个或两个氢原子被选自上文和下文适当定义和列举的烷基或环烷基基团的基团取代的氨基基团。
术语“卤代”和“卤素”相对地是指氟代/氟、氯代/氯、溴代/溴或碘代/碘基团/原子。术语“卤代烷基”是指被一个或多个卤素原子取代的如上定义的烷基和环烷基基团,包括被不同卤素取代的那些。示例性基团是氯甲基、三氟甲基、全氟丙基、三氯乙烯基、氯乙炔基等。
本发明提供了具有下式(I)的甲硫氨酸代谢途径的抑制剂:
其中T为磺酰基基团或羰基基团:
R1为式(A)、(B)、(C)或(D)的基团:
其中R4为具有一至三个选自N、O和S的杂原子并且任选地被(C1-C3)-烷基、(C1-C3)-卤代烷基、(C1-C3)-烷氧基或羟基或卤素原子取代的五元杂芳环;
R5为氢或(C1-C3)-烷基、(C1-C3)-卤代烷基或(C1-C3)-烷氧基;
R6、R8和R9独立地选自氢、卤素、氨基、氰基、(C1-C3)-烷基、(C1-C3)-卤代烷基、羟基、(C1-C3)-烷氧基、(C1-C3)-卤代烷氧基、单-(C1-C3)-烷基氨基、二-(C1-C3)-烷基氨基、氨基-(C1-C3)-烷基、单-(C1-C3)-烷基氨基-(C1-C3)-烷基、二-(C1-C3)-烷基氨基-(C1-C3)-烷基和硝基;
R7为氢、卤素、氰基、(C1-C3)-烷基、(C1-C3)-卤代烷基、(C1-C3)-烷氧基、羟基、(C1-C3)-卤代烷氧基、氨基、单-(C1-C3)-烷基氨基、二-(C1-C3)-烷基氨基、氨基-(C1-C3)-烷基、单-(C1-C3)-烷基氨基-(C1-C3)-烷基、二-(C1-C3)-烷基氨基-(C1-C3)-烷基、硝基或3,5-二甲基-1H-吡唑-1-基基团;
R为CH或N;
式(D)中的两个虚线箭头指向苯环的两个碳原子,羰基能够连接至所述两个碳原子;
A为CH-R10或N-R11;
E为C-R12或N;
J为C-R13或N;并且
R10、R11、R12和R13独立地选自氢、(C1-C3)-烷基和(C1-C3)-卤代烷基;
X和Y独立地为CH或N;
Z为C-R14或N;
R14为氢、卤素、(C1-C3)-烷基、(C1-C3)-卤代烷基、羟基、(C1-C3)-烷氧基、羧酸根、(C1-C3)-烷基羧酸根、羧酸、(C1-C3)-烷基羧酸、羧酰胺、(C1-C3)-烷基羧酰胺、氰基、硝基、苯基、苄基、吡啶基或苯基氨基,其中所述苯基、苄基、吡啶基或苯基氨基任选地被一至三个相同或不同的独立地选自以下的取代基取代:卤素、(C1-C3)-烷基、(C3-C6)-环烷基、(C1-C3)-卤代烷基、羟基、(C1-C3)-烷氧基、氰基、氨基、羧酸和硝基基团;
L为N-R15、O或S;并且
R15为氢、(C1-C3)-烷基、(C1-C3)-卤代烷基、苄基、吡啶基或苯基,其中所述苄基、吡啶基或苯基任选地被一至三个相同或不同的独立地选自以下的取代基取代:卤素、(C1-C3)-烷基、(C1-C3)-卤代烷基、羟基、(C1-C3)-烷氧基、氰基、氨基和硝基基团;
(i)当T为磺酰基基团,并且R1为式(A)的基团时,则
R2为氢原子,并且
R3为任选地被一至三个相同或不同的独立地选自以下的取代基取代的苯基基团:卤素原子、(C1-C3)-烷基、(C1-C3)-卤代烷基、(C1-C3)-烷氧基、氨基、氰基、羟基、硝基、羧酸、(C1-C3)-烷基羧酸、羧酸根、羧酰胺、(C1-C3)-烷基羧酸根和(C1-C3)-烷基羧酰胺基团;以及
(ii)条件是当R1为式(B)的基团时,则
R2为氢原子,并且
R3为苯基或吡啶基,所述苯基或吡啶基被式(E)的基团取代,并且苯基或吡啶基环的任何可用的碳原子处任选地被以下基团取代:(C1-C3)-烷基、(C1-C3)-卤代烷基、(C1-C3)-烷氧基、羧酸、羧酸根、(C1-C3)-烷基羧酸、(C1-C3)-烷基羧酸根、(C1-C3)-烷基羧酰胺、羧酰胺、卤素、氰基、羟基或硝基;
(iii)当R1为式(C)的基团时,则
R2和R3一起在它们所连接的氮原子周围形成下式的吲哚啉基基团:
其中所述吲哚啉基基团的吡咯烷基环被一个R16基团取代,所述R16基团连接至任何可用的吡咯烷基环碳原子,R16基团选自以下基团:氢、卤素、硝基、(C1-C3)-烷基、(C1-C3)-卤代烷基、(C1-C3)-烷氧基、羟基、氰基、羧酸、羧酸根、(C1-C3)-烷基羧酸根、羧酰胺、(C1-C3)-烷基羧酸、(C1-C3)-烷基羧酰胺或氨基;并且所述基团的苯基芳环任选地被一至三个R17取代,所述R17与任何可用的苯环碳原子连接并且独立地选自以下基团:卤素、硝基、(C1-C3)-烷基、(C1-C3)-卤代烷基、(C1-C3)-烷氧基、羟基、氰基、羧酸、羧酸根、(C1-C3)-烷基羧酸根、羧酰胺、(C1-C3)-烷基羧酸、(C1-C3)-烷基羧酰胺或氨基;以及
(iv)当T为羰基基团并且R1为式(D)的基团时,则
R2为氢或(C1-C3)-烷基,并且
R3为下式的基团:
其中R18为一至三个相同或不同的与所述苯环的任何可用的碳原子连接的取代基,所述R18独立地选自以下的取代基:氢、氨基、(C1-C3)-烷基、(C1-C3)-卤代烷基、(C1-C3)-烷氧基、(C1-C3)-烷基羧酸、羧酸、(C1-C3)-烷基羧酸根、羧酸根、(C1-C3)-烷基羧酰胺、羧酰胺、卤素、氰基、羟基、硝基和乙酰氨基;以及以下择其一:
在一个实施方案中,本发明提供了式(IA)的化合物:
其中R2为任选地被一至三个相同或不同的独立地选自以下的取代基取代的苯基基团:卤素原子、(C1-C3)-烷基、(C1-C3)-卤代烷基、(C1-C3)-烷氧基、氨基、氰基、羟基、硝基、羧酸、(C1-C3)-烷基羧酸、羧酸根、羧酰胺、(C1-C3)-烷基羧酸根和(C1-C3)-烷基羧酰胺;
R3为选自以下的五元杂芳环基团:
所述五元杂芳环任选地被卤素原子或羟基、(C1-C3)-烷基、(C1-C3)-卤代烷基或(C1-C3)-烷氧基取代;并且
R4为氢、(C1-C3)-烷基、(C1-C3)-卤代烷基或(C1-C3)-烷氧基。
在一个具体的实施方案中,式(IA)的化合物具有R2,其被定义为任选地被一至三个相同或不同的独立地选自以下的取代基取代的苯基:卤素原子、(C1-C3)-烷基、羧酸、羧酸根、羧酰胺、(C1-C3)-烷基羧酸和(C1-C3)-烷基羧酸根;
R3为任选地被卤素原子或羟基、(C1-C3)-烷基、(C1-C3)-卤代烷基或(C1-C3)-烷氧基取代的1,3-噻唑基;并且
R4为氢、(C1-C3)-烷基、(C1-C3)-卤代烷基或(C1-C3)-烷氧基基团。
在另一个具体的实施方案中,式(IA)的化合物具有R2,其被定义为任选地被一个选自卤素原子、(C1-C3)-烷基和羧酸基团的取代基取代的苯基基团。式(IA)的示例性化合物如下所列:
在另一个实施方案中,本发明提供了具有式(IB-1)或(IB-2)的化合物:
其中R6、R7、R8和R9独立地选自氢、卤素、(C1-C3)-烷基、(C1-C3)-烷氧基和(C1-C3)-卤代烷基。
X和Y独立地为CH或N;
Z为C-R19或N;
R19为氢、乙基、环戊基、三氟甲基、羟基、苄基或苯基氨基,其中所述苄基或苯基氨基任选地被一至三个相同或不同的独立地选自卤素、甲基、三氟甲基、羟基、甲氧基或羧酸基团的取代基取代;
L为N-R20、O或S;
R20为氢、甲基或苄基;
Q为C-R21或N;并且
R21为羧酸、羧酸根、(C1-C3)-烷基羧酸或(C1-C3)-烷基羧酸根基团。
式(IB-1)和(IB-2)的示例性化合物如下所示:
在另一个实施方案中,本发明提供了式(IC-1)或(IC-2)的化合物:
其中所述化合物的吡咯烷基环被一个R16基团取代,所述R16基团与任何可用的吡咯烷基环碳原子连接并且选自甲基、羧酰胺、羧酸根、羧酸或乙酸基团;并且任选地被一至三个R17基团取代,所述R17基团取代与任何可用的苯环碳原子连接并且独立地选自(C1-C3)-烷基、(C1-C3)-烷氧基或卤素原子的取代基。
式(IC-1)和(IC-2)的示例性化合物如下所示:
在另一个实施方案中,本发明提供了式(ID)的化合物:
其中R18为一个与苯环的任何可用的碳原子连接并且选自氢、(C1-C3)-烷基和乙酰氨基的取代基;
R10、R11、R12和R13独立地选自氢和(C1-C3)-烷基;
式(ID)的示例性化合物如下所示:
如下文将证明的,本发明的化合物确实具有除草活性,而且当以除草有效量在杂草出苗前或杂草出苗后施用于生长培养基时,能有效调节多种不想要的植物即杂草的生长。术语“除草有效量”是本发明的化合物或化合物的混合物如此伤害或损害杂草使得杂草在施用后不能恢复所需的量。为了表现出令人满意的除草效果而施用的本发明的化合物或化合物的混合物的量可以在宽范围内变化,并且取决于多种因素,例如特定杂草物种的难治性、杂草侵染程度、气候条件、土壤条件、施用方法等。当然,特定化合物对特定杂草物种的效力可以容易地通过常规实验室或田间试验以本领域公知的方式测定。
本发明的一种或多种化合物可以与农业上可接受的助剂、惰性载体、其他除草剂或其他常用的农业化合物例如杀虫剂、杀真菌剂、农药、稳定剂、安全剂、肥料等一起用于各种配制剂中。本发明的化合物单独或与其他农业上使用的材料一起配制,通常以粉剂、颗粒剂、可湿性粉剂、溶液、悬浮液、气雾剂、乳剂、分散剂等形式以本领域公知的方式施用。当与其他通常使用的农学上可接受的材料一起配制时,本发明的一种或多种化合物的量可以在宽范围内变化,例如,基于制剂的重量,约0.05重量%至约95重量%。通常,此类制剂将含有约5重量%至75重量%的本发明的一种或多种化合物。
通过施用本发明的化合物可以有效控制的杂草是例如稗草(Echinochloacrusgalli)、马唐草(Digitaria sauguinalis)、拟南芥(Arabidopsis thaliana)、咖啡草(Daubentonia punices)、蔓陀罗(Datura stamonium)、约翰逊草(Sorghum halepense)、圆叶牵牛(Ipomoea purpurea)、野芥菜(Brassica caber)、茶树(Sida Spinosa)、苘麻(Abutilin Theophrasti)、野燕麦(Avena fatua)、黄狗尾(Setaria glauca)、油莎草(Cyperus esculentus)等。
如上所述,本发明的化合物以包含除草有效量的一种或多种化合物的除草组合物的形式施用于不想要的植被的所在地、不想要的植物或其栖息地。在出苗后,本发明的除草剂可以纯的或作为乳液或溶液施用于不想要的植被的所在地。在其中除草剂可溶解或可被乳化的任何溶剂可用作稀释剂。合适的溶剂包括水或水溶性醇例如甲醇、乙醇和异丙醇,或酮例如丙酮或甲基乙基酮。此类化合物进一步与水形成乳液。
在本发明的另一个实施方案中,用于控制不想要的植被或从区域清理不想要的植被的方法包括向不想要的植被的所在地施用除草有效量的本发明的一种或多种化合物。本发明的方法可用于通过使不想要的植被的叶子与除草组合物接触来控制播种作物附近或杂草集中区域中的已生长植被。此类除草组合物的除草活性在接触时迅速消散在不想要的植被中。用本发明的化合物处理的不想要的植物的所在地可以是农业区域、作物田地、花园、荒地、工业或建筑场所、铁路或铁路路堤。
式(I)的化合物已通过计算机筛选方法发现。进行CGS蛋白结构的全面结构分析(基于公开的X-射线结构)和鉴定小分子抑制剂的潜在结合位点。基于小分子的除草剂样图谱文库进行虚拟筛选。根据从各种商业来源获得的约3千万个小有机化合物的内部数据库产生图谱文库。基于所有可获得的除草剂的列表,定义了植物内活性化合物的化学空间。基于这组独特性质过滤数据库,例如图谱分析以产生可能在植物中有活性的初始化合物组。这些用于虚拟和体外筛选。
在生物分子数据库例如PDB(蛋白质数据库)中可获得的具有抑制剂的复合物中存在两种类型的CGS晶体结构。这两种结构结合了磷酸吡哆醛辅因子(PLP):
1)具有PDB代码1I41的结构,其具有共价粘结剂,例如天然代谢物胱硫醚;以及
2)具有PDB代码1I48和1QGN的结构,其具有非共价粘结剂,其包括蛋白质活性位点的两个晶体结构。
因此,使用两种类型的分子对接和三种结构的酶进行计算机筛选。一种类型的分子对接针对潜在的共价(不可逆)粘结剂,另一种针对可逆粘结剂。
后者用考马斯染色的12%十二烷基硫酸钠(SDS)凝胶的表达测试清楚地证明了在诱导含有CGS基因的质粒的BL21-plys细胞后条带的积累。条带分子量符合预期的蛋白质大小。
为了在各种测定中测试CGS酶,克隆了来自烟草的MetB基因的DNA序列,其被翻译为CGS酶。将该基因克隆到修饰的pET11载体中,其含有N-末端6xHIS和GB1可溶性标签,其后是TEV切割位点。为了证实CGS表达为可溶性蛋白,进行以下表达和纯化。
对于蛋白质表达测试和建立初步筛选测定,使用以下构建体:
1.CGS(烟草)-his'(pet载体)
2.GST-CGS(烟草)-his'(pgex载体)
3.CGS(拟南芥)-his'(pet载体)
4.GST-CGS(拟南芥)-his'(pgex载体)
用两种不同类型的大肠杆菌测试上述质粒中的每一种的可溶性蛋白质的表达:BL-21和BL-21plys。用含有CGS的载体转化的BL21细胞的这两个代表性菌落在37℃下培养,直到600nm处的光密度(OD)达到0.8。此时,添加1mM IPTG并将细胞再培养四小时。所有CGS构建体的初步表达测试均为阳性。
为了从细胞裂解物中纯化CGS蛋白,使用两种连续的纯化方法:镍柱和S75尺寸排阻色谱。镍柱将HISx6标签表达的C-末端结合至CGS。将第一菌落的可溶性级分的内容物通过镍柱,并将洗脱的级分在考马斯染色的12%十二烷基硫酸钠(SDS)凝胶电泳上运行。图1示出了从镍柱洗脱的蛋白质的考马斯染色的12%SDS凝胶电泳。在泳道8和泳道9中可以观察到可溶性CGS的积累,并且纯化的蛋白质通过其在泳道10中作为单一条带的清晰外观为标志。
为了证实纯化的酶是活性的,本发明人目前开发了一种新的生化体外活性测定法。该测定利用由CGS酶催化的化学反应,其是根据以下反应方案将半胱氨酸和磷酸-丝氨酸酯转化成胱硫醚:
然后,在该反应中作为副产物释放的磷酸盐可以通过其在另外的选择性化学反应中的缀合、通过嘌呤核苷磷酸化酶(PNP)将2-氨基-6-巯基-7-甲基嘌呤核苷(MESG)转化成1-磷酸核糖和2-氨基-6-巯基-7-甲基嘌呤来监测。后一种产物在360nm的UV光谱中具有独特的吸光度。
现在参考图2a至图2b,它们示出了用于监测CGS活性的测定开发。图2a中的条形图示出了在测定中CGS、半胱氨酸和磷酸-丝氨酸酯与7-甲基-6-硫代鸟苷(MESG)和嘌呤核苷磷酸化酶(PNP)一起温育后在360nm处的吸光度。这是由M.R.Webb,1992,Proc.Natl.Acad.Sci.USA(美国国家科学院院刊)89,4884-4887开发的用于测定蛋白磷酸酶活性的连续分光光度测定法。该测定法将偶联酶体系与嘌呤核苷磷酸化酶和用于定量无机磷酸盐的发色底物7-甲基-6-硫代鸟苷(MESG)合并。图2a示出了所获得的测定的初步结果,其测量反应混合物在360nm处的吸光度(第1列)。增加的吸光度清楚地表明磷酸盐的释放。从混合物中除去各初始组分的结果示于第2-4列。添加外部游离磷酸盐的结果示于第5列。图2b提供了示出反应中使用的对应初始组分的表格。
通过微量热泳(MST)测试实施方案的化合物与CGS的直接结合。在MST测定中,用荧光团标记CGS蛋白,加热样品,并且随配体浓度的变化测量荧光的变化。在MST测定中,类似于上述表达和纯化,将重组烟草CGS蛋白在大肠杆菌BL21细胞中表达并纯化至均质。为了该特定目的,克隆含有烟草CGS的DNA序列的pET-11载体,并将其转化到细菌细胞中,该DNA序列具有N-末端6xHIS标签,其后是TEV-可切割的GB1可溶性标签。将细胞培养至OD=0.8,并且添加1mM IPTG诱导蛋白表达。将细胞在25℃再培养16小时。
细胞裂解后,将可溶性级分通过镍柱,用300mM咪唑洗脱结合的带HIS标签的蛋白。然后,标签6xHIS和GB1在o/n透析中切割,混合物再次通过镍柱以从TEV和HIS-GB1构建体中分离CGS。作为最后一步,CGS在S75尺寸排阻层析上运行。
因此,进行MST测定以测量化合物与CGS蛋白的结合。为此目的,根据制造说明用可商购获得的胺反应性荧光团(目录号MO-L001,NanoTemper)标记CGS。然后使用MonolithNT.115装置通过将标记的蛋白质与指定化合物以剂量-响应方式一起温育来测量MST结合曲线。下表1总结了本发明的示例性化合物与MST全曲线验证的剂量-响应。表1示出了使用MST实验对与烟草CGS的结合的评价,其中活性等级为0至5(这些值定性地描述了表观效果的显著性,0表示没有效果,5表示最显著的效果):
表1.对烟草CGS进行MST(0至5的值)。
对于本发明实施方案的许多化合物,施用本发明的化合物后拟南芥根长度生长的结果总结于下表2中。这些实验如下进行。将种子用70%乙醇洗涤一分钟,然后用无菌水洗涤。用50%漂白溶液(3%)和0.2%Triton x-100灭菌十分钟,然后用无菌水洗涤五次。将种子置于六个含有半Murashige and Skoog培养基(MS;Duchefa,Haarlem,Netherlands)的孔板中,该培养基含有1%蔗糖(w/v),pH 5.8。将具有拟南芥种子的平板在4℃放置两天,然后以16/8h的日/光循环转移至生长室(22±2℃)七天。将板竖直放置。在每个板中,添加在培养基中包含0.1%DMSO的对照。通过用0.1%DMSO将50mM储备液稀释1000倍,得到50μM的最终浓度来测试本发明化合物的除草效率。
表2.与阴性对照(DMSO)处理相比,添加50μM化合物后的拟南芥根长度。长度值表示未处理的板(仅5%DMSO)与添加50uM各化合物后的长度之比。较低的值表示较短的根长度,并因此表示较大的效果。
表3示出了BY-2生存力测定的结果。在该测定中,在用本发明的化合物处理后测试BY2烟草细胞的生存力。为此目的,将细胞培养在补充有2,4-二氯-苯氧基乙酸(0.2mg/L)和蔗糖(3%)的Murashige and Skoog基础培养基(Sigma-Aldrich,目录号M0404)中,并在25℃下在暗处温育,然后每7天在新鲜培养基中以1:15稀释度进行传代培养。
在处理之前,将细胞悬浮液调节至OD=0.4(在600nm处)并以每个细胞3ml的体积接种在6孔板中。然后将示例性化合物以25μM(0.05%DMSO)的最终浓度添加到孔中,并温育48小时。使用可商购获得的PrestoBlueTM测定剂(ThermoFisher Scientific,PrestoBlueTM细胞生存力试剂目录号A13261)测量细胞生存力。PrestoBlueTM试剂是细胞渗透性非荧光化合物,其被代谢活性细胞还原并提供定量荧光信号。在测定中,将10μL PrestoBlueTM试剂添加到90μL经处理的细胞中,并在Tecan M200平板读数器中用560/590nm的激发/发射波长进行荧光测量。结果显示相对于仅用0.05%DMSO处理的细胞的细胞生存力。
表3.BY-2生存力测定。
如上所述,植物中甲硫氨酸生物合成的第一反应由CGS酶催化。在该反应中,胱硫醚的形成通过半胱氨酸对O-磷酸-高丝氨酸的磷酰基取代基的γ-取代和正磷酸基团的连续释放来进行。以下实验证明了许多本发明的化合物对CGS活性的直接抑制的评价。
通过将含有具有6xHIS标签、GB1可溶性标签和是TEV切割位点的烟草CGS的DNA序列的pET-11载体转化到BL-21细胞中,进行重组CGS的表达。这些细胞在37℃并且在600nm处光密度(OD)=0.8蛋白质下培养,并且通过添加1mM IPTG在25℃诱导表达16小时。将蛋白质在镍柱上纯化至均质,并通过用TEV蛋白酶进行o/n透析来切割。第二镍柱用于将切割的CGS与TEV和GB1可溶性标签分离。表4示出了TEV相对于DMSO所有实验的结果。
表4.TEV相对于DMSO的所有实验。
表5示出了本发明几种化合物的大肠杆菌测定LE395和大肠杆菌特异性(MOA)的结果,
表5.大肠杆菌测定LE395和大肠杆菌特异性。
Claims (15)
1.一种化合物,其特征在于,所述化合物具有式(I):
其中T为磺酰基或羰基:
R1为式(A)、(B)、(C)或(D)的基团:
其中R4为具有一至三个选自N、O和S的杂原子并且任选地被(C1-C3)-烷基、(C1-C3)-卤代烷基、(C1-C3)-烷氧基或羟基或卤素原子取代的五元杂芳环;
R5为氢或(C1-C3)-烷基、(C1-C3)-卤代烷基或(C1-C3)-烷氧基;
R6、R8和R9独立地选自氢、卤素、氨基、氰基、(C1-C3)-烷基、(C1-C3)-卤代烷基、羟基、(C1-C3)-烷氧基、(C1-C3)-卤代烷氧基、单-(C1-C3)-烷基氨基、二-(C1-C3)-烷基氨基、氨基-(C1-C3)-烷基、单-(C1-C3)-烷基氨基-(C1-C3)-烷基、二-(C1-C3)-烷基氨基-(C1-C3)-烷基和硝基;
R7为氢、卤素、氰基、(C1-C3)-烷基、(C1-C3)-卤代烷基、(C1-C3)-烷氧基、羟基、(C1-C3)-卤代烷氧基、氨基、单-(C1-C3)-烷基氨基、二-(C1-C3)-烷基氨基、氨基-(C1-C3)-烷基、单-(C1-C3)-烷基氨基-(C1-C3)-烷基、二-(C1-C3)-烷基氨基-(C1-C3)-烷基、硝基或3,5-二甲基-1H-吡唑-1-基基团;
R为CH或N;
式(D)中的两个虚线箭头指向苯环的两个碳原子,羰基能够连接至所述两个碳原子;
A为CH-R10或N-R11;
E为C-R12或N;
J为C-R13或N;并且
R10、R11、R12和R13独立地选自氢、(C1-C3)-烷基和(C1-C3)-卤代烷基;
X和Y独立地为CH或N;
Z为C-R14或N;
R14为氢、卤素、(C1-C3)-烷基、(C1-C3)-卤代烷基、羟基、(C1-C3)-烷氧基、羧酸根、(C1-C3)-烷基羧酸根、羧酸、(C1-C3)-烷基羧酸、羧酰胺、(C1-C3)-烷基羧酰胺、氰基、硝基、苯基、苄基、吡啶基或苯基氨基,其中所述苯基、苄基、吡啶基或苯基氨基任选地被一至三个相同或不同的独立地选自以下的取代基取代:卤素、(C1-C3)-烷基、(C3-C6)-环烷基、(C1-C3)-卤代烷基、羟基、(C1-C3)-烷氧基、氰基、氨基、羧酸和硝基基团;
L为N-R15、O或S;并且
R15为氢、(C1-C3)-烷基、(C1-C3)-卤代烷基、苄基、吡啶基或苯基,其中所述苄基、吡啶基或苯基任选地被一至三个相同或不同的独立地选自以下的取代基取代:卤素、(C1-C3)-烷基、(C1-C3)-卤代烷基、羟基、(C1-C3)-烷氧基、氰基、氨基和硝基基团;
(i)当T为磺酰基基团,并且R1为式(A)的基团时,则
R2为氢原子,并且
R3为任选地被一至三个相同或不同的独立地选自以下的取代基取代的苯基基团:卤素原子、(C1-C3)-烷基、(C1-C3)-卤代烷基、(C1-C3)-烷氧基、氨基、氰基、羟基、硝基、羧酸、(C1-C3)-烷基羧酸、羧酸根、羧酰胺、(C1-C3)-烷基羧酸根和(C1-C3)-烷基羧酰胺基团;以及
(ii)当R1为式(B)的基团时,则
R2为氢原子,并且
R3为苯基或吡啶基,所述苯基或吡啶基被式(E)的基团取代,并且苯基或吡啶基环的任何可用的碳原子处任选地被以下基团取代:(C1-C3)-烷基、(C1-C3)-卤代烷基、(C1-C3)-烷氧基、羧酸、羧酸根、(C1-C3)-烷基羧酸、(C1-C3)-烷基羧酸根、(C1-C3)-烷基羧酰胺、羧酰胺、卤素、氰基、羟基或硝基;
(iii)当R1为式(C)的基团时,则
R2和R3一起在它们所连接的氮原子周围形成下式的吲哚啉基基团:
其中所述吲哚啉基基团的吡咯烷基环被一个R16基团取代,所述R16基团连接至任何可用的吡咯烷基环碳原子,R16基团选自以下基团:氢、卤素、硝基、(C1-C3)-烷基、(C1-C3)-卤代烷基、(C1-C3)-烷氧基、羟基、氰基、羧酸、羧酸根、(C1-C3)-烷基羧酸根、羧酰胺、(C1-C3)-烷基羧酸、(C1-C3)-烷基羧酰胺或氨基;并且所述基团的苯基芳环任选地被一至三个R17取代,所述R17与任何可用的苯环碳原子连接并且独立地选自以下基团:卤素、硝基、(C1-C3)-烷基、(C1-C3)-卤代烷基、(C1-C3)-烷氧基、羟基、氰基、羧酸、羧酸根、(C1-C3)-烷基羧酸根、羧酰胺、(C1-C3)-烷基羧酸、(C1-C3)-烷基羧酰胺或氨基;以及
(iv)当T为羰基基团并且R1为式(D)的基团时,则
R2为氢或(C1-C3)-烷基,并且
R3为下式的基团:
其中R18为一至三个相同或不同的与苯环的任何可用的碳原子连接的取代基,所述R18独立地选自以下的取代基:氢、氨基、(C1-C3)-烷基、(C1-C3)-卤代烷基、(C1-C3)-烷氧基、(C1-C3)-烷基羧酸、羧酸、(C1-C3)-烷基羧酸根、羧酸根、(C1-C3)-烷基羧酰胺、羧酰胺、卤素、氰基、羟基、硝基和乙酰氨基;以及以下择其一:
3.如权利要求2所述的化合物,其特征在于,
其中R2为任选地被一至三个相同或不同的独立地选自以下的取代基取代的苯基:卤素原子、(C1-C3)-烷基、羧酸、羧酸根、羧酰胺、(C1-C3)-烷基羧酸和(C1-C3)-烷基羧酸根;
R3为任选地被卤素原子或羟基、(C1-C3)-烷基、(C1-C3)-卤代烷基或(C1-C3)-烷氧基取代的1,3-噻唑基;并且
R4为氢、(C1-C3)-烷基、(C1-C3)-卤代烷基或(C1-C3)-烷氧基。
4.如权利要求3所述的化合物,其特征在于,其中R2为任选地被一个选自卤素原子、(C1-C3)-烷基和羧酸基团的取代基取代的苯基基团。
12.如权利要求1-11中任一项所述的化合物,其特征在于,其用作除草剂、杀虫剂、杀真菌剂、农业植物刺激剂或抗微生物剂。
13.如权利要求1-11中任一项所述的化合物,其特征在于,其用作选择性除草剂、非选择性除草剂、农业除草剂、非农业除草剂、病虫害综合治理中的除草剂、园艺中的除草剂、清理荒地中的除草剂、清理工业或建筑场所中的除草剂、或清理铁路和铁路路堤中的除草剂。
14.一种用于控制不想要的植被或从区域清理不想要的植被的方法,其特征在于,其包括向所述不想要的植被的所在地、向不想要的植物或向其栖息地施用除草有效量的如权利要求1-11中任一项所述的化合物。
15.如权利要求14所述的方法,其特征在于,所述所在地是农业区域、作物田地、花园、荒地、工业或建筑场所、铁路或铁路路堤。
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