Synergistic compositions for the protection of agrarian crops and the use thereof

Abstract

Synergistic compositions comprising: one component (A), consisting of the compound having formula (I) 3-difluoromethyl-N-(7-fluoro-1,1,3-trimethyl-4-indanyl)-1-methyl-4-pyrazolecarboxamide ##STR00001##
one or more components (B) having a fungicidal or insecticidal activity, and their use for the control of of harmful insects in agrarian crops.

Claims

1. A synergistic composition for the protection of agrarian crops comprising: at least one component consisting of a compound of formula (I), 3-difluoromethyl-N-(7-fluoro-1,1,3-trimethyl-4-indanyl)-1-methyl-4-pyrazolecarboxamide ##STR00008## wherein Me is a methyl group, and at least one component [B] having a fungicidal or insecticidal activity which is: ii) an amino derivate selected from the group consisting of aldimorph, dodine, dodemorph, fenpropimorph, fenpropidin, guazatine, iminoctadine, spiroxamine, and tridemorph; iii) a strobilurin selected from azoxystrobin, dimoxystrobin, fluoxastrobin, kresoxim-methyl, metominostrobin, orysastrobin, picoxystrobin, pyraclostrobin, pyrametostrobin, pyraoxostrobin, and trifloxystrobin; iii) specific anti oidium compounds; vi) a benzimidazole selected from the group consisting of benomyl, carbendazim, fuberidazole, thiabendazole, and thiophanate-methyl; vii) a dicarboxyimide selected from the group consisting of iprodione, and procymidone; viii) a polyhalogenated fungicide selected from the group consisting of chlorothalonil, captan, captafol, folpet, dichlofluanid, and tolylfluanid; ix) an inducer of acquired systemic resistance (SAR) selected from the group consisting of acibenzolar, probenazole, isotianil, and tiadinil; xi) an acylalanine selected from the group consisting of benalaxyl, benalaxyl-M, furalaxyl, metalaxyl, and metalaxyl-M; xii) an antiperonosporic compound selected from the group consisting of ametoctradin, amisulbrom, benthiavalicarb, cyazofamid, cymoxanil, dimethomorph, ethaboxam, famoxadone, fenamidone, flumetover, flumorph, fluopicolide, iprovalicarb, mandipropamid, and valifenalate; xiii) a dithiocarbamate selected from the group consisting of maneb, mancozeb, propineb, and zineb; xvi) a copper-based cupric fungicide selected from the group consisting of copper (II) hydroxide, copper oxychloride, copper (II) sulfate, Bordeaux mixture, copper salicylate C.sub.7H.sub.4O.sub.3.Math.Cu, and cuprous oxide Cu.sub.2O; xvii) a fungicidal amide carpropamid, fenhexamid, silthiofam, zoxamid, bixafen, boscalid, carboxin, fluopicolide, fluopyram, flutolanil, fluxapyroxad, furametpyr, isopyrazam, oxycarboxin, penflufen, penthiopyrad, sedaxane, and thifluzamide; xix) a neonicotinoid selected from the group consisting of acetamiprid, clothianidin, dinotefuran, flupyradifurone, imidacloprid, nitenpyram, thiacloprid, and thiamethoxam; and xxi) a pyrethroid selected from the group consisting of bifenthrin, beta-cyfluthrin, lambda-cyhalothrin, cypermethrin, deltamethrin, and tefluthrin.

2. The composition according to claim 1, wherein said at least one component [B] is selected from: ii) fenpropimorph, spiroxamine; iii) azoxystrobin, fluoxastrobin, kresoxim-methyl, picoxystrobin, pyraclostrobin, trifloxystrobin; vi) carbendazim, thiophanate-methyl; vii) iprodione, procymidone; viii) chlorothalonil; xi) benalaxyl, benalaxyl-M, metalaxyl-M; xii) benthiavalicarb, cyazofamid, cymoxanil, dimetomorph, mandipropamid, valifenalate; xvi) copper (II) hydroxide, copper oxychloride, copper salicylate C.sub.7H.sub.4O.sub.3.Math.Cu, cuprous oxide Cu.sub.2O; xix) clothianidin, imidacloprid, thiachloprid, thiamethoxam; and xxi) lambda-cyhalothrin, deltamethrin, tefluthrin.

3. The composition according to claim 1, wherein said compound having formula (I) is a racemic mixture ((I)-RS).

4. The composition according to claim 1, wherein said compound having formula (I) comprises: a mixture enriched with an enantiomer, of a compound of formulia (I) or an enantiomer R or S form.

5. The composition according to claim 1, wherein the weight ratio between said at least one component [A] and said at least one component [B] ranges from 1:20 to 20:1.

6. The composition according to claim 1, selected from: C10: (I)-RS +fenpropimorph; C11: (I)-RS +spiroxamine; C12: (I)-RS +azoxystrobin; C13: (I)-RS +fluoxastrobin; C14: (I)-RS +kresoxim-methyl; C15: (I)-RS +picoxystrobin; C16: (I)-RS +pyraclostrobin; C17: (I)-RS +trifloxystrobin; C22: (I)-RS +iprodione; C23: (I)-RS +procymidone; C24: (I)-RS +carbendazim; C25: (I)-RS +thiophanate-methyl; C26: (I)-RS +chlorothalonil; C28: (I)-RS +benalaxyl-M; C29: (I)-RS +metalaxyl-M; C30: (I)-RS +benthiavalicarb; C31: (I)-RS +cyazofamid; C32: (I)-RS +cymoxanil; C33: (I)-RS +dimethomorph; C34: (I)-RS +mandipropamid; C35: (I)-RS +valifenalate; C36: (I)-RS +copper salicylate C.sub.7H.sub.4O.sub.3.Math.Cu; C37: (I)-RS +cuprous oxide Cu.sub.2O; C38: (I)-RS +clothianidin; C39: (I)-RS +imidacloprid; C40: (I)-RS +thiacloprid; C41: (I)-RS +thiamethoxam; C44: (I)-RS +lambda-cyhalothrin; C45: (I)-RS +deltamethrin; C46: (I)-RS +tefluthrin; C67: (I)-RS +chlorothalonil +azoxystrobin; C68: (I)-RS +chlorothalonil +picoxystrobin; C69: (I)-RS +chlorothalonil +pyraclostrobin; C70: (I)-RS +chlorothalonil +kresoxim methyl; C71: (I)-RS +copper (II) hydroxide +copper oxychloride; C72: (I)-RS +copper (II) hydroxide +copper oxychloride +copper salicylate C.sub.7H.sub.4O.sub.3.Math.Cu; C74: (I)-R.sub.8S.sub.2 +azoxystrobin; C75: (I)-R.sub.8S.sub.2 +benalaxyl; C77: (I)-R.sub.9S.sub.1 +azoxystrobin; wherein: (I)-RS indicates a compound of formula (I) in the form of a racemic mixture, (I)-R.sub.8S.sub.2 indicates a compound of formula (I) containing the enantiomers R and S in a molar ratio R:S=8:2, (I)-R.sub.9S.sub.1 indicates the a compound of formula (I) containing the enantiomers R and S in a molar ratio R:S=9:1, (I)-R indicates the enantiomer R of formula (I) in substantially pure form (>99,99% by weight).

7. The composition according to claim 1, wherein said at least one component [A] and said at least one component [B], together or separately, are diluted with one or more solid or liquid diluents, optionally with the addition of one or more surfactants, dispersing agents, suspending agents, stabilizers, adjuvants, anti-freeze agents, or adhesion agents.

8. The composition according to claim 1, comprising at least a further active principle selected from the group consisting of phytoregulators, antibiotics, herbicides, fertilizers and mixtures thereof.

9. A method for the control of phytopathogenic fungi in agricultural crops comprising the application to agricultural crops of an effective amount of a composition according to claim 1.

10. A method for the control of phytopathogenic fungi in agricultural crops according to claim 9, where the fungi is selected from the following groups: Basidiomycetes, Ascomycetes, Deuteromycetes or imperfect fungi, Oomycetes: Puccinia spp., Ustilago spp., Tilletia spp., Uromyces spp., Phakopsora spp., Rhizoctonia spp., Erysiphe spp., Sphaerotheca spp., Podosphaera spp., Uncinula spp., Helminthosporium spp., Rhynchosporium spp., Pyrenophora spp., Monilinia spp., Sclerotinia spp., Septoria spp. (Mycosphaerella spp.), Venturia spp., Botrytis spp., Alternaria spp., Fusarium spp., Cercospora spp., Cercosporella herpotrichoides, Colletotrichum spp., Pyricularia oryzae, Sclerotium spp., Phytophtora spp., Pythium spp., Plasmopara viticola, Peronospora spp., Pseudoperonospora cubensis, Bremia lactucae.

11. A method for the control of phytopathogenic fungi in agricultural crops according to claim 9, wherein the agricultural crops are selected from: cereals, fruit trees, citrus fruits, legumes, horticultural crops, cucurbits, oleaginous plants, tobacco, coffee, tea, cocoa, sugar beet, sugar cane and cotton.

12. A method for controlling phytopathogenic fungi in agrarian crops, which comprises applying an effective dose of at least one synergistic composition according to claim 1, on one or more parts of the plants to be protected and/or on the seeds of said plants before sowing and/or on the ground in which said plants grow.

13. (withdrawn/currently amended): A method for controlling harmful insects in agrarian crops, which comprises applying an effective dose of at least one synergistic composition as defined in claim 1, on one or more parts of the plants to be protected and/or on the seeds of said plants before sowing and/or on the ground in which said plants grow.

14. The composition according to claim 4, wherein said mixture is a mixture enriched with enantiomer R.

15. The composition according to claim 4, wherein said mixture is a mixture enriched in enantiomer R having a purity of >99.99% by weight.

Description

EXAMPLE 1

Preparation of the 3-difluoromethyl-N-(7-fluoro-1,1,3-trimethyl-4-indanyl)-1-methyl-4-pyrazolecarboxamide (I)

(1) A solution of 40 g of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbonyl chloride [compound of formula (III); MW 194,5] in 40 ml of dichloroethane, is dropped at room temperature in a solution of 34 g of 6-fluoro-2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline [compound of formula (V); MW 193] and 30 ml of triethylamine in 200 ml of dichloroethane.

(2) After stirring for 3 hours at reflux, the reaction mixture is poured in water (1,2 1) and extracted with dichloroethane. The organic layer is washed with 10% aqueous hydrochloric acid, anhydrified with sodium sulfate, concentrated under vacuum to afford 58 g of a crude solid product corresponding to N-(3-difluoromethyl-1-methyl-1H-4-pyrazolecarbonyl)-6-fluoro-2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline [compound of formula (II); GC-mass: M.sup.+=351].

(3) To this crude product, 165 ml of 85% aqueous sulfuric acid are added and the mixture is then heated under stirring at 60° C. for 30 minutes. After cooling the mixture is poured into water and ice, and extracted with dichloromethane. The organic layer is then washed with water, with a saturated solution of sodium bicarbonate in water, and with a saturated solution of sodium chloride in water. The organic layer is anhydrified with sodium sulfate and concentrated under vacuum: the residue is purified by chromatography on silica gel (eluent heptane/EtOAc 6:4) to give 48 g of a white solid with melting point 147° C., corresponding to the desired product in racemic form, (I)-RS. GC-mass: M.sup.+=351.

(4) .sup.1H NMR (200 Mhz, CDCl.sub.3) δ at: 1,43 (3H,d), 1,38 (3H,s), 1,44 (3H,s), 1,66 (1H,dd), 2,21 (1H,dd), 3,38 (1H m), 3,98(3H,s),6,81 (1H, bs), 6,95 (1H,t), 6,70.(1H, m), 7,81 (1H,bs), 8,03 (1H,bs)

EXAMPLE 2

Preparation of Separated enantiomers of Compound (I)

(5) 36.8 g (1 eq) of racemic 7-fluoro-1,1,3-trimethyl-4-aminoindane [compound (IV)] and 14.3 g (0.5 eq) of D-(2S,3S)-(−)-tartaric acid in methanol (30 ml) were mixed and heated at 70° C. for 1 hour.

(6) The mixture was left to cool to room temperature; a precipitate was formed and the mixture kept for one night at 4° C. The formed solid was filtered off, washed with a small amount of methanol and re-crystallized from methanol for six times to afford 14.8 g of an off white solid, corresponding to the 7-fluoro-1,1,3-trimethyl-4-aminoindane D-tartarate.

(7) To the salt, a 5% sodium hydroxide aqueous solution was added until pH≥10, and the mixture extracted three times with diethyl ether. The reunited organic layers were washed with water and brine. Then, dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to obtain 6.38 g of (−)-4-amino-7-fluoro-1,1,3-trimethylindane as a white powder (yield 17%); e.e. >99% (HPLC).

(8) To a solution of 600 mg of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid [compound (III)] and a catalytic amount of N,N-dimethylformamide in dichloromethane (7 mL), 450 mg of thionyl chloride were added dropwise. The mixture was refluxed for 2 h. The reaction was monitored by GC/MS. The solvent was evaporated in vacuo. The crude acid chloride obtained was used in the following step.

(9) A solution of the crude 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride in dichloroethane (6 mL) was added dropwise over a period of 10 minutes, under nitrogen atmosphere, to a solution of 660 mg of (−)-4-amino-7-fluoro-1,1,3-trimethylindane, a catalytic amount of 4-dimethylaminopyridine and 420 mg of triethylamine in dichloroethane (5 mL).

(10) The mixture was stirred at room temperature overnight. At completion of the reaction (monitored through GC-MS) the mixture was diluted with dichloro-methane (20 mL) and cooled at 0° C.; a solution (20 mL) of 5% HCl was added.

(11) The layers were separated and the organic phase washed with 5% HCl solution (2×20 mL), water (2×20 mL) and brine, then dried over Na.sub.2SO.sub.4. The solvent was evaporated under reduced pressure to give 1.3 g of a pale yellow solid.

(12) The crude product was purified by column chromatograpy (eluent: heptane/EtOAc 6:4) to give 1.1 g (yield 92%) of 99.5% pure enantiomer (−) (e.e. >99% determined by HPLC with chiral column) as a white solid with m.p. =129-130° C. GC-MS: M.sup.+=351; [α].sub.D.sup.20=−59.50°(CHCl.sub.3, 1g/100 ml).

(13) In analogous manner, starting from racemic 7-fluoro-1,1,3-trimethyl-4-aminoindane [compound (IV)] and L-(2R,3R)-(+)-tartaric acid, the 99.3%pure enantiomer (+) was prepared (e.e. >99% determined by HPLC with chiral column): white solid with m.p. =131-132° C.

(14) GC-MS: M.sup.+=351; [α].sub.D.sup.20=+60.1° (CHCl.sub.3, 1g/100 ml).

EXAMPLE 3

Determination of “in vitro” activities of racemic (I) and enantiomers against phytopathogenic microorganisms.

(15) Under sterile conditions, the technical racemic (I), the (−) and (+) enantiomers (prepared in Example 2) under testing, were dissolved in dimethylsulfoxide and serially diluted 3-fold to obtain a growth inhibition curve. Aqueous treatment solutions were prepared by adding DMSO stocks to water and mixing by pipet resulting in 2× final treatment concentration and 2× final DMSO concentration of 1.6%.

(16) Sporulating plates of phytopathogenic micro-organisms were harvested under sterile conditions in strength Potato Dextrose Broth. Spores were filtered with cheesecloth and diluted to about 40000 spores per ml. Spores were aliquotted into 96 well microtiter plates at 150 microliters of spore suspension per well.

(17) Pathogenic spore suspensions were then treated with the 2× aqueous treatment solution or 1.6% DMSO for controls to give 1× final concentration or 0.8% DMSO. Plates were then held for 43 hours at room temperature.

(18) After 43 hours at room temperature, plates were visually assessed microscopically for spore germination and growth inhibition. Plates were also quantitatively measured for growth inhibition by measuring optical density on a spectrophotometric plate reader at 405 nanometer wavelength. Optical density was corrected for absorbance of the media and active ingredient by subtracting the 405 nm readings for the 2× aqueous treatment solution or DMSO solution diluted with 1/2 strength POTATO DEXTROSE BROTH and no spores.

(19) The % growth inhibition of the pathogen obtained for the technical racemic (I), (−) and (+) enantiomers was calculated according to the formula: Percent Inhibition =((1−(OD trt−OD trt blank)/(OD untreated−OD untreated blank))×100) wherein OD trt is the optical density at 405 nm for the spore suspension plus aqueous treatment solution and OD trt blank is the optical density at 405 nm for the 2× aqueous treatment solution plus ½ strength POTATO DEXTROSE BROTH and no spores and OD untreated is the optical density at 405 nm for the spores plus 1.6% DMSO and OD untreated blank is the optical density at 405nm for the 1.6% DMSO plus ½ strength POTATO DEXTROSE BROTH and no spores. Values are the average of three replicates. Concentrations of the racemic, (−) and (+) enantiomers giving 50% growth inhibition (pI50) were calculated using GraphPad Prism software Percent inhibition values were calculated using GraphPad Prism software Version 4.

(20) Microorganisms tested were Botrytis cinerea (BC), Stagonospora nodorum (SN) and Magnaporthe griseae (MG).

(21) The results are reported in Table 1.

(22) TABLE-US-00001 TABLE 1 BC pI50 SN pI50 MG pI50 Compound (ppm) (ppm) (ppm) Racemic (I) 0.32 1.1 0.72 (−)-(I) 0.17 0.42 0.46 (+)-(I) n.i. 72 4.6 n.i. = no inhibition

EXAMPLE 4

Determination of the fungicidal Activity in Preventive Application (5 Days) Against Puccinia recondita on Wheat

(23) Leaves of wheat plants of the Salgemma variety, grown in pots in a conditioned environment kept at 20° C. and 70% of relative humidity (R.H.), were treated by spraying both sides of the leaves with the compounds and the compositions under testing, dispersed in hydroacetonic solutions at 20% by volume of acetone.

(24) After remaining 5 days in a conditioned environment, the plants were sprayed on both sides of the leaves with an aqueous suspension of conidia of Puccinia recondita (2 mg of inoculum per 1 ml of solution for infection).

(25) After being sprayed, the plants were kept in a humidity-saturated environment at a temperature ranging from 18 to 24° C. for the incubation period of the fungus (1 day).

(26) After this period, the plants were put in a greenhouse with R.H. of 70% and at a temperature of 18-24° C. for 14 days.

(27) At the end of this period the external symptoms of the pathogen appeared and it was therefore possible to proceed with the visual assessment of the intensity of the infection. The fungicidal activity was expressed as percentage of reduction of affected leaves areas with respect to those of untreated plants used as control: the scale comprised, as extremes, the value 100 (full activity; healthy plant) and the value 0 (no activity; completely infected plant).

(28) At the same time, the phytotoxicity (percentage of leaf necrosis) induced on the wheat plants by the application of the products and compositions was evaluated: in this case, the scale ranged from 0 (no phytotoxicity) to 100 (completely necrotized plant).

(29) In Table 2, the activities of racemic (I) and pure enantiomers of compound (I), prepared in Example 2, are reported.

(30) TABLE-US-00002 TABLE 2 Compound Rate (ppm) % Activity % Phytotoxicity Racemic (I) 125 98 0 62.5 96 0 (−)-(I) 125 100 0 62.5 96 0 (+)-(I) 125 45 0 62.5 20 0

(31) The synergism of the compositions (A+B) under testing was evaluated according to the Colby's formula:
E.sub.t=E.sub.A+E.sub.B−(E.sub.A×E.sub.B/100)
wherein E.sub.t is the expected efficacy percentage for the composition containing the compounds A and B at the dosages d.sub.A+d.sub.B, E.sub.A is the efficacy percentage observed for the component A at the dosage d.sub.A, E.sub.B is the efficacy percentage observed for the component B at the dosage d.sub.B.

(32) When the efficacy observed for the composition A+B (E.sub.A+B) is higher than the efficacy expected according to the Colby's formula (E.sub.A+B/E.sub.L>1), a synergistic effect is confirmed.

EXAMPLE 5

Determination of Synergistic Effects “In Vitro” Against Phytopathogenic Microorganisms

(33) Under sterile conditions, the products and the compositions under testing were dissolved in dimethylsulfoxide, diluted with water and added under vigorous stirring to POTATO DEXTROSE AGAR, kept in a thermostatic bath at 55° C. The AGAR preparations, containing the compounds and the compositions under testing at the desired rates, were poured into 60 mm diameter Petri dishes (three for each product and composition) and left to cool to ambient temperature.

(34) After solidification of the agarized medium, AGAR disks having 6 mm of diameter and supporting the micelyum of the microorganism, were placed in the centre of the Petri dishes; Petri dishes containing untreated POTATO DEXTROSE AGAR were also inoculated with the microorganism and used as control.

(35) After incubation at 28° C., when control colonies had grown over 30 mm in diameter, but without reaching the edge of the dishes, the diameters of the developed colonies in treated and untreated dishes were measured; the percentage growth inhibition of the microorganism obtained with products and compositions was calculated according to the formula:
I=(1−z.sub.1/z.sub.0)×100
wherein z.sub.1 is the diameter (average of three replicates) of the colonies treated with compounds and mixtures and z.sub.0 is the diameter (average of three replicates) of untreated colonies.

(36) Microorganisms tested were Botrytis cinerea, Fusarium culmorum, Helminthosporium teres, Pyricularia oryzae, Septoria nodorum, Venturia inaequalis.

(37) The synergism of a binary mixture (A+B) at the dose (d.sub.A+d.sub.B) was evaluated according to the Colby's formula:
I.sub.L=I.sub.A+I.sub.B −(I.sub.A×I.sub.B/100)
wherein:

(38) I.sub.t is the % growth inhibition expected for the mixture;

(39) I.sub.A is the % growth inhibition observed for compound A at the dose d.sub.A; 1.sub.B is the % growth inhibition observed for compound B at the dose d.sub.B.

(40) When the % growth inhibition observed for the composition (A+B) is higher than that calculated by the Colby's formula (I.sub.A+B>I.sub.t; >1), a synergistic effect is confirmed.