Structure benzenedicarboxamides

Resistance has often been a problem or a potential problem for insecticides and this is one of the most important reasons why the insecticides with a new mode of action have been always desired, though it is quite a difficult task to find such molecules. Flubendiamide, discovered by Nihon Nohyaku (NNC), is a novel insecticide belonging to the new chemical class of 1,2-benzenedicarboxamides or phfhalic diamides, having a unique chemical structure (Figure 1) [1-3], Flubendiamide is co-developed by NNC and Bayer CropScience globally [4], The structure-activity relationships, the chemistry, including topics in process research, the mode of action and the biological profiles are described. 

Figure 2 shows the early phase of research for flubendiamide. In 1989, Dr. T. Tsuda, at Osaka Prefecture University in Japan, reported that some pyrazinedicarbox-amide derivatives showed moderate herbicidal activity [5]. From 1990, the research for herbicide discovery was conducted at NNC Research Center. In the course of this research, a lead compound for an insecticide was discovered in 1993 from the class of benzenedicarboxamides as shown in Figure 2. This compound provided insecticidal activity on lepidoptera at the relatively high dose of 50-500 mg a.i./L. Moreover, it did not show activity against other species such as Hemiptera or Aca-rina. Although the level of activity was not satisfactory, this compound attracted the attention of researchers for both the novelty of its chemical structure and the characteristic insecticidal symptoms such as gradual contractions of the insect body. We therefore started the study for further optimization of this lead compound.

The chemical structure of benzenedicarboxamides can be divided into three parts as shown in Figure 3. These are characterized by (A) the phthaloyl moiety, (B) the aliphatic amide moiety and (C) the aromatic amide moiety. A brief description of the structure-activity relationships for each part is described below. 

Benzenedicarboxamide compounds, including flubendiamide, were found through original research at NNC. However, notably, anthranilic diamides, structurally very different from benzenedicarboxamides, were discovered by DuPont [20] to have the same mode of action [21] and a couple of companies are following with patent applications Nissan Chemical [41] and Takeda Pharmaceutical Company [42] have applied for patents of the related compounds of benzenedicarboxamides, and Ishihara Sangyo Kaisha [43] has applied for patent of the related compounds of anthranilic diamides. The market entry of insecticides from this new generation could intensify competition with conventional insecticides in the future. 

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