Phthalic diamide

Figure 9. Effect of caffeine and phthalic diamides on mouse muscle cell line C2C12. representative [Ca ] traces of a Fura2-AM-loaded C2C12 cell during application of caffeine, flubendiamide sulfoxide, and again caffeine.

Figure 2. Phthalic diamide-induced release in isolated Heliothis neurons,...

To further investigate the effect of phthalic diamides on the calcium regulation of RyR, ryanodine binding to the Heliothis RyR was measured as a function of [Ca (Figure 6). 

Hjflubendiamide was used as a radioligand in equilibrium binding experiments to characterize the phthalic diamide binding site pharmacologically. 

Phthalic Diamides Disrupted the Calcium Regulation of the Ryanodine Receptor... 

As an important feature, phthalic diamides seem to be specific for insect RyR no calcium release could be measured after application of flubendiamide to the mammalian skeletal muscle subtypes RyRl (and RyR3) present in differentiated mouse C2CI2 cells (16). In addition, flubendiamide had no effect on [ Hjryanodine binding to the mammalian cardiac muscle subtype RyR2 prepared from pig heart (unpublished results). 

A mixture of trifluoroacetic anhydride and triethylamine added to a soln. of N-phenylphthalamic acid in dry dioxane, and after 5 min. poured on ice N-phenylphthalisoimide (Y 92%) dissolved in ether and treated with an ethereal soln. of the equimolar amount of n-butylamine N-n-butyl-N -phenyl-phthalic diamide (Y 81%). F. e. s. E. G. Diaz de Toranzo and J. A. Brieux, J. Med. Ghem. 10, 982 (1967). 

The following example illustrates in detail the preparation of amino benzoic acids from the hot reaction product obtained by the oxidation of a xylene and containing a mixture of salt, amide salt and diamide of a phthalic acid. 

Flubendiamide is an example of a new chemical class of insecticides that have been termed phthalic acid diamides (Nauen 2006, Copping and Duke 2007). They are related to the alkaloid ryanodine, which is extracted from Ryania species. Ryanodine affects muscles by binding to calcium channels of the sarcoplasmic reticulum. Ca + ions act as intracellular messengers, and their flux is modulated by calcium channels of this type. The toxic action of ryanodine and synthetic insecticides related to it is due to the disturbance of calcium flux. 

The baking process has remained much the same until the present day at a stoichiometric ratio of 1 4, phthalic anhydride or phthalic acid reacts with an ammonia releasing compound. The reaction may also start from other suitable materials, such as phthalic acid derivatives, including phthalic acid esters, phthalic acid diamide, or phthalimide. Appropriate ammonia releasing agents include urea and its derivatives, such as biuret, guanidine, and dicyanodiamide. The fact that a certain amount of urea decomposes to form side products makes it necessary to use excess urea. Approximately 0.2 to 0.5, preferably 0.25 equivalents of copper salt should be added for each mole of phthalic anhydride. 0.1 to 0.4 moles of molybdenum salt per mole of phthalic anhydride is sufficient. The reaction temperature is between 200 and 300°C. 

Benzonitrile also can be prepared by this method in comparable yields, but a longer reaction time (7 hours) is required. The method was found to be unsatisfactory for the preparation of the nitriles of azelaic and phthalic acids from the corresponding diamides. 

Typical lubricants are fatty alcohols C]2-C22, fatty acids C14-Ci8, their esters with fatty alcohols, glycerol or pentaerythritol, amides (2) or diamides (3) and metallic soaps (see Heat stabilizers ), acids C28-C31 from montan wax and their esters, diesters of phthalic acid (4b), paraffin wax C2o-C70, PE waxes Ci25-C70o or their oxidized (polar) grades containing hydroxyl and carbonyl groups. 

Ebbinghaus-Kintscher, U., Luemmen, P, Lobitz, N., Schsulte, T., Funke, C., Fischer, R., Masaki, T., Yasokawa, N., and Tohnishi, M., Phthalic acid diamides activate ryanodine-sensitive Ca2+ release channels in insects, Cell Calcium, 39, 21, 2006. 

Except for the diamide derived from phthalic acid (19.2) which is a viscous liquid at room temperature, the diamides of isophthalic and terephthalic acids are solid, with convenient melting points. Because these diamides have a relatively high hydroxyl number of around 650 mg KOH/g, a propoxylation reaction (reaction 19.6) was developed. The... 

Flubendiamide is a promising new insecticide which is particularly active against lepidopteran pest species and is currently being co-developed by Nihon Nohyaku and Bayer CropScience. It is the first member ofa new chemical class of insecticides named phthalic acid diamides (Figure 5) to be developed. It has been shown to be extremely potent against lepidopterous pests including those resistant... 

Figure 5. Structures of the phthalic acid diamides used in the MoA study.

Phthalic acid diamides Mode of action and target selectivity (U. Ebbinghaus-Kintscher, Bayer CropScience, Germany)... 

This ranking of halogen atoms can be exemplified by the recently described SAR of halogenated phthalic acid diamides (F < Cl < Br < I) in the development product fiubendiamide (54 ISO-proposed, Hal = I Nihon Nohyaku Co., Ltd./ Bayer Crop Science) [24], which activates selective ryanodine-sensitive intracellular Ca + release channels in insects as novel mode of action [25]. Introduction of a bulky and moderate lipophilic halogen such as iodine into 3-position of the phthalic acid aryl moiety increased the insecticidal activity considerably (Fig. 35.4) (for more details see Chapter 34). 

Fig. 35.4. SAR of halogen-containing phthalic acid diamides, flubendiamide (54 Hal = I).

Fig. 35.13. Phthalic acid and anthranilic acid diamides such as flubendiamide (54) and DP-23 (55).

Carbonylbis 1,3-isobenzofurandione 4,4 -Carbonylbis (phthalic anhydride). See 3,3, 4,4-Benzophenone tetracarboxylic dianhydride Carbonyl diamide Carbonyidiamine. See Urea 1,3-Carbonyi dioxypropane. See Propylene carbonate 4,4 -Carbonyidiphtnaiic acid anhydride 4,4 -Carbonyldiphthalk anhydride. See 3,3, 4,4-Benzophenone tetracarboxylic dianhydride Carborundeum Carborundum. See Silicon carbide Carbothialdine. See3,5-Dimethyl tetrahydro-2-H,1,3,5-thiadiazone-2-thione Carboxyaniline 2-Carboxyaniline o-Carboxyaniline. SeeAnthranilic acid Carboxybenzene. See Benzoic acid Carboxyethane. See Propionic acid... 

Phthalic Acid Diamides Activate Insect Ryanodine... 

In this communication, we present evidence that the phthalic acid diamides, a novel chemical class of highly potent insecticides discovered by Nihon Nohyaku Co., Ltd. (14), act on ryanodine-sensitive calcium release channels in insects by a mechanism distinct from that of ryanodine. 

The phthalic acid diamides flubendiamide and the corresponding sulfoxide were synthesized by Nihon Nohyaku Co., Ltd., and Bayer CropScience AG. Ryanodine, Fura-2 acetoxymethyl ester (Fura-2 AM) and Fura-2 were obtained from Sigma and stored frozen as aliquots (stock solution ImM in DMSO). 

Phthalic Acid Diamides Elicited Intracellular Calcium Transients in Heliothis Neurons... 

Figure I. Structures of the Phthalic Acid Diamides Employed in the Current Study (I, flubendiamide II, flubendiamide-sulfoxide)...

In sununary, phthalic acid diamides increased the ryanodine affinity of the Heliothis ryanodine receptor. At low [Ca ] the compounds offset the cooperativity between the ryanodine sites. 

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