PESTICIDALLY ACTIVE POLYCYCLIC DERIVATIVES WITH SULFUR CONTAINING SUBSTITUENTS
20170362224 · 2017-12-21
Assignee
Inventors
- Andrew Edmunds (Stein, CH)
- Michel Muehlebach (Stein, CH)
- Pierre Joseph Marcel Jung (Stein, CH)
- Andre Jeanguenat (Stein, CH)
Cpc classification
A01N2300/00
HUMAN NECESSITIES
A01N43/90
HUMAN NECESSITIES
A01N2300/00
HUMAN NECESSITIES
A01N43/90
HUMAN NECESSITIES
International classification
A01N43/90
HUMAN NECESSITIES
Abstract
Polycyclic derivatives of formula (I), wherein the substituents are as defined in claim 1, and the agrochemically acceptable salts salts, stereoisomers, enantiomers, tautomers and N-oxides of those compounds, can be used as insecticides and can be prepared in a manner known per se.
##STR00001##
Claims
1. A compound of formula I, ##STR00189## wherein A represents CH, N or the N-oxide; A.sub.1 is CH, N or the N-oxide; Q is phenyl which can be mono- or polysubstituted by substituents selected from the group consisting of halogen, cyano, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4haloalkyl, C.sub.1-C.sub.4haloalkoxy, C.sub.1-C.sub.4alkoxy, C.sub.1-C.sub.4haloalkylsulfanyl, C.sub.1-C.sub.4haloalkylsulfinyl, C.sub.1-C.sub.4haloalkylsulfonyl and —C(O)C.sub.1-C.sub.4haloalkyl; or Q is a five- to ten-membered monocyclic or fused bicyclic ring system linked via a carbon atom to the ring which contains the group A, said ring system can be aromatic, partially saturated or fully saturated and contains 1 to 4 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur, with the proviso that each ring system cannot contain more than 2 oxygen atoms and more than 2 sulfur atoms, said five- to ten-membered ring system can be mono- to polysubstituted by substituents independently selected from the group consisting of halogen, cyano, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4haloalkyl, C.sub.1-C.sub.4haloalkoxy, C.sub.1-C.sub.4alkoxy, C.sub.1-C.sub.4alkylsulfanyl, C.sub.1-C.sub.4alkylsulfinyl, C.sub.1-C.sub.4alkylsulfonyl, —C(O)C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4haloalkylsulfanyl, C.sub.1-C.sub.4haloalkylsulfinyl, C.sub.1-C.sub.4haloalkylsulfonyl and —C(O)C.sub.1-C.sub.4haloalkyl; or Q is a five- to six-membered, aromatic, partially saturated or fully saturated ring system linked via a nitrogen atom to the ring which contains the group A, said ring system can be mono- or polysubstituted by substituents selected from the group consisting of halogen, cyano, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4haloalkyl, C.sub.1-C.sub.4haloalkoxy, C.sub.1-C.sub.4alkoxy, C.sub.1-C.sub.4alkylsulfanyl, C.sub.1-C.sub.4alkylsulfinyl, C.sub.1-C.sub.4alkylsulfonyl, —C(O)C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4haloalkylsulfanyl, C.sub.1-C.sub.4haloalkylsulfinyl, C.sub.1-C.sub.4haloalkylsulfonyl and —C(O)C.sub.1-C.sub.4haloalkyl; and said ring system contains 1, 2 or 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulphur, with the proviso that said ring system cannot contain more than one oxygen atom and more than one sulfur atom; or Q is C.sub.3-C.sub.6cycloalkyl, or C.sub.3-C.sub.6cycloalkyl mono- or polysubstituted by substituents selected from the group consisting of halogen, cyano, CONH.sub.2, carboxyl, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4haloalkyl, C.sub.3-C.sub.6cycloalkyl and phenyl, wherein said phenyl can be mono- or polysubstituted by substituents selected from the group consisting of halogen, cyano, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4haloalkyl, C.sub.1-C.sub.4haloalkoxy, C.sub.1-C.sub.4alkoxy, C.sub.1-C.sub.4haloalkylsulfanyl, C.sub.1-C.sub.4halo-alkylsulfinyl, C.sub.1-C.sub.4haloalkylsulfonyl and —C(O)C.sub.1-C.sub.4haloalkyl; or Q is C.sub.2-C.sub.6alkenyl, or C.sub.2-C.sub.6alkenyl mono- or polysubstituted by substituents selected from the group consisting of halogen, cyano, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4haloalkyl, C.sub.3-C.sub.6cycloalkyl and phenyl, wherein said phenyl can be mono- or polysubstituted by substituents selected from the group consisting of halogen, cyano, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4haloalkyl, C.sub.1-C.sub.4haloalkoxy, C.sub.1-C.sub.4alkoxy, C.sub.1-C.sub.4haloalkylsulfanyl, C.sub.1-C.sub.4haloalkylsulfinyl, C.sub.1-C.sub.4haloalkylsulfonyl and —C(O)C.sub.1-C.sub.4haloalkyl; or Q is C.sub.2-C.sub.6alkynyl, or C.sub.2-C.sub.6alkynyl mono- or polysubstituted by substituents selected from the group consisting of halogen, cyano, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4haloalkyl, C.sub.3-C.sub.6cycloalkyl, tri(C.sub.1-C.sub.4alkyl)silyl and phenyl, wherein said phenyl can be mono- or polysubstituted by substituents selected from the group consisting of halogen, cyano, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4haloalkyl, C.sub.1-C.sub.4haloalkoxy, C.sub.1-C.sub.4alkoxy, C.sub.1-C.sub.4halo-alkylsulfanyl, C.sub.1-C.sub.4haloalkylsulfinyl, C.sub.1-C.sub.4haloalkylsulfonyl and —C(O)C.sub.1-C.sub.4haloalkyl; or Q is C.sub.1-C.sub.6alkyl, or C.sub.1-C.sub.6alkyl mono- or polysubstituted by substituents selected from the group consisting of halogen, cyano, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4haloalkyl, C.sub.3-C.sub.6cycloalkyl, tri(C.sub.1-C.sub.4alkyl)silyl and phenyl, wherein said phenyl can be mono- or polysubstituted by substituents selected from the group consisting of halogen, cyano, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4haloalkyl, C.sub.1-C.sub.4haloalkoxy, C.sub.1-C.sub.4alkoxy, C.sub.1-C.sub.4halo-alkylsulfanyl, C.sub.1-C.sub.4haloalkylsulfinyl, C.sub.1-C.sub.4haloalkylsulfonyl and —C(O)C.sub.1-C.sub.4haloalkyl; X is S, SO or SO.sub.2; R.sub.1 is C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4haloalkyl, C.sub.3-C.sub.6cycloalkyl, C.sub.3-C.sub.6cycloalkyl-C.sub.1-C.sub.4alkyl; or R.sub.1 is C.sub.3-C.sub.6cycloalkyl-C.sub.1-C.sub.4alkyl mono- or polysubstituted by substituents selected from the group consisting of halogen, cyano and C.sub.1-C.sub.4alkyl; or R.sub.1 is C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6haloalkenyl or C.sub.2-C.sub.6alkynyl; R.sub.2 is halogen, cyano, C.sub.1-C.sub.6haloalkyl or C.sub.1-C.sub.6haloalkyl substituted by one or two substituents selected from the group consisting of hydroxyl, methoxy and cyano; or R.sub.2 is C.sub.1-C.sub.4haloalkylsulfanyl, C.sub.1-C.sub.4haloalkylsulfinyl, C.sub.1-C.sub.4haloalkylsulfonyl, O(C.sub.1-C.sub.4haloalkyl), or —C(O)C.sub.1-C.sub.4haloalkyl; or R.sub.2 is C.sub.3-C.sub.6cycloalkyl which can be mono- or polysubstituted by substituents selected from the group consisting of halogen, cyano and C.sub.1-C.sub.4alkyl; X.sub.1 is NR.sub.5, wherein R.sub.5 is hydrogen, C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.4alkoxy-C.sub.1-C.sub.4alkyl or C.sub.3-C.sub.6cycloalkyl; or X.sub.1 is oxygen or sulfur; R.sub.3 is hydrogen or C.sub.1-C.sub.2-alkyl; R.sub.4 is hydrogen, halogen or C.sub.1-C.sub.3haloalkyl; or an agrochemically acceptable salt, a stereoisomer, an enantiomer, or a tautomer of one of those compounds.
2. A compound of formula I according to claim 1, wherein is selected from the group consisting of the following heterocyclic groups: pyrrolyl; pyrazolyl; isoxazolyl; furanyl; thienyl; imidazolyl; oxazolyl; thiazolyl; isothiazolyl; triazolyl; oxadiazolyl; thiadiazolyl; tetrazolyl; furyl; pyridyl; pyrimidyl; pyrazinyl; pyridazinyl; triazinyl, pyranyl; quinazolinyl; isoquinolinyl; indolizinyl; isobenzofuranylnaphthyridinyl; quinoxalinyl; cinnolinyl; phthalazinyl; benzothiazolyl; benzoxazolyl; benzotriazolyl; indazolyl; indolyl; (1H-pyrrol-1-yl)-; (1H-pyrrol-2-yl)-; (1H-pyrrol-3-yl)-; (1H-pyrazol-1-yl)-; (1H-pyrazol-3-yl)-; (3H-pyrazol-3-yl)-; (1H-pyrazol-4-yl)-; (3-isoxazolyl)-; (5-isoxazolyl)-; (2-furanyl)-; (3-furanyl)-; (2-thienyl)-; (3-thienyl)-; (1H-imidazol-2-yl)-; (1H-imidazol-4-yl)-; (1H-imidazol-5-yl)-; (2-oxazol-2-yl)-; (oxazol-4-yl)-; (oxazol-5-yl)-; (thiazol-2-yl)-; (thiazol-4-yl)-; (thiazol-5-yl)-; (isothiazol-3-yl)-; (isothiazol-5-yl)-; (1H-1,2,3-triazol-1-yl)-; (1H-1,2,4-triazol-3-yl)-; (4H-1,2,4-triazol-4-yl)-; (1H-1,2,4-triazol-1-yl)-(1,2,3-oxadiazol-2-yl)-; (1,2,4-oxadiazol-3-yl)-; (1,2,4-oxadiazol-4-yl)-; (1,2,4-oxadiazol-5-yl)-; (1,2,3-thiadiazol-2-yl)-; (1,2,4-thiadiazol-3-yl)-; (1,2,4-thiadiazol-4-yl)-; (1,3,4-thiadiazol-5-yl)-; (1H-tetrazol-1-yl)-; (1H-tetrazol-5-yl)-; (2H-tetrazol-5-yl)-; (2-pyridyl)-; (3-pyridyl)-; (4-pyridyl)-; (2-pyrimidinyl)-; (4-pyrimidinyl)-; (5-pyrimidinyl)-; (2-pyrazinyl)-; (3-pyridazinyl)-; (4-pyridazinyl)-; (1,3,5-triazin-2-yl)-; (1,2,4-triazin-5-yl)-; (1,2,4-triazin-6-yl)-; (1,2,4-triazin-3-yl)-; (furazan-3-yl)-; (2-quinolinyl)-; (3-quinolinyl)-; (4-quinolinyl)-; (5-quinolinyl)-; (6-quinolinyl)-; (3-isoquinolnyl)-; (4-isoquinolnyl)-; (2-quinozolinyl)-; (2-quinoxalinyl)-; (5-quinoxalinyl)-; (pyrido[2,3-b]pyrazin-7-yl)-; (benzoxazol-5-yl)-; (benzothiazol-5-yl)-; (benzo[b]thien-2-yl)- and (benzo[1,2,5]oxadiazol-5-yl)-; indolinyl and tetrahydroquinolynyl.
3. A compound of formula I according to claim 1, wherein Q is selected from the group consisting of J-0 to J-50: ##STR00190## ##STR00191## ##STR00192## ##STR00193## ##STR00194## wherein each group J-0 to J-50 is mono- di- or trisubstituted with Rx, wherein each Rx is, independently from each other, selected from hydrogen, halogen, cyano, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4haloalkyl, C.sub.1-C.sub.4haloalkoxy, C.sub.1-C.sub.4alkoxy, C.sub.1-C.sub.4alkylsulfanyl, C.sub.1-C.sub.4alkylsulfinyl, C.sub.1-C.sub.4alkylsulfonyl, —C(O)C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4haloalkylsulfanyl, C.sub.1-C.sub.4haloalkylsulfinyl, C.sub.1-C.sub.4haloalkylsulfonyl and —C(O)C.sub.1-C.sub.4haloalkyl.
4. A compound of formula I according to claim 1 represented by the compounds of formula I-1 ##STR00195## wherein R.sub.2, R.sub.4, A, X and Q are as defined under formula I in claim 1; and wherein R.sub.1 is methyl, ethyl, n-propyl, i-propyl or cyclopropylmethyl; R.sub.4 is hydrogen, halogen or C.sub.1-C.sub.3haloalkyl, and X.sub.1 is N-methyl, oxygen or sulfur; or an agrochemically acceptable salt, a stereoisomer, an enantiomer, or a tautomer of one of the compounds of formula I-1.
5. A compound of formula I according to claim 1 represented by the compounds of formula I-2; ##STR00196## wherein R.sub.2, R.sub.4, A, X and Q are as defined under formula I in claim 1; and wherein R.sub.1 is methyl, ethyl, n-propyl, i-propyl or cyclopropylmethyl; R.sub.4 is hydrogen, halogen or C.sub.1-C.sub.3haloalkyl; and X.sub.1 is N-methyl, oxygen or sulfur, or an agrochemically acceptable salt, a stereoisomer, an enantiomer, or a tautomer of one of the compounds of formula I-2.
6. A compound of formula I-1 according to claim 4 represented by the compounds of formula I-1a ##STR00197## wherein A is N or CH; X is S or SO.sub.2; R.sub.1 is C.sub.1-C.sub.4alkyl; R.sub.2 is C.sub.1-C.sub.4haloalkyl, C.sub.1-C.sub.4haloalkylsulfanyl, C.sub.1-C.sub.4haloalkylsulfinyl or C.sub.1-C.sub.4haloalkylsulfonyl; R.sub.4 is hydrogen or C.sub.1-C.sub.2haloalkyl; Q.sub.a1 is selected from the group consisting of the substituents ##STR00198## ##STR00199## wherein each Rx is, independently selected from the group consisting of hydrogen, halogen, cyano, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4haloalkyl, C.sub.1-C.sub.4haloalkoxy, C.sub.1-C.sub.4alkoxy, C.sub.1-C.sub.4alkylsulfanyl, C.sub.1-C.sub.4alkylsulfinyl, C.sub.1-C.sub.4alkylsulfonyl, —C(O)C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4haloalkylsulfanyl, C.sub.1-C.sub.4haloalkylsulfinyl, C.sub.1-C.sub.4haloalkylsulfonyl and —C(O)C.sub.1-C.sub.4haloalkyl.
7. A compound of formula I-1a according to claim 6 represented by the compounds of formula I-1a2 ##STR00200## wherein A is N or CH; R.sub.2 is C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkylsulfanyl, C.sub.1-C.sub.2haloalkylsulfinyl or C.sub.1-C.sub.2haloalkylsulfonyl; R.sub.4 is hydrogen or C.sub.1-C.sub.2haloalkyl; and Q.sub.a1 is selected from the group consisting of the substituents ##STR00201## wherein Rx is hydrogen, halogen, C.sub.1-C.sub.4alkyl, and C.sub.1-C.sub.4haloalkyl.
8. A compound of formula I-2 according to claim 5 represented by the compounds of formula I-2a ##STR00202## A is N or CH; X is S or SO.sub.2; R.sub.1 is C.sub.1-C.sub.4alkyl R.sub.2 is C.sub.1-C.sub.4haloalkyl, C.sub.1-C.sub.4haloalkylsulfanyl, C.sub.1-C.sub.4haloalkylsulfinyl or C.sub.1-C.sub.4haloalkylsulfonyl; R.sub.4 is hydrogen or C.sub.1-C.sub.1-C.sub.2haloalkyl; Q.sub.a1 is selected from the group consisting of the substituents ##STR00203## ##STR00204## wherein each Rx is, independently selected from hydrogen, halogen, cyano, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4haloalkyl, C.sub.1-C.sub.4haloalkoxy, C.sub.1-C.sub.4alkoxy, C.sub.1-C.sub.4alkylsulfanyl, C.sub.1-C.sub.4alkylsulfinyl, C.sub.1-C.sub.4alkylsulfonyl, —C(O)C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4haloalkylsulfanyl, C.sub.1-C.sub.4haloalkylsulfinyl, C.sub.1-C.sub.4haloalkylsulfonyl and —C(O)C.sub.1-C.sub.4haloalkyl.
9. A compound of formula I-2a according to claim 8 represented by the compounds of formula I-2a2 ##STR00205## wherein A is N or CH; R.sub.2 is C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkylsulfanyl, C.sub.1-C.sub.2haloalkylsulfinyl or C.sub.1-C.sub.2haloalkylsulfonyl; R.sub.4 is hydrogen or C.sub.1-C.sub.2haloalkyl; and Q.sub.a1 is selected from the group consisting of the substituents ##STR00206## wherein each Rx, independently from each other, is hydrogen, halogen, C.sub.1-C.sub.4alkyl or C.sub.1-C.sub.4haloalkyl.
10. A compound of formula I according to claim 1, wherein R.sub.1 is C.sub.1-C.sub.4alkyl; R.sub.2 is C.sub.1-C.sub.4haloalkyl or C.sub.1-C.sub.4haloalkylsulfanyl; R.sub.3 is hydrogen; R.sub.4 is hydrogen or C.sub.1-C.sub.4haloalkyl; Q is phenyl, which can be mono-, di- or trisubstituted by substituents selected from the group consisting of halogen and C.sub.1-C.sub.4haloalkyl; or Q is C.sub.2-C.sub.6alkenyl which can be mono-substituted by phenyl, which phenyl itself can be mono-substituted by C.sub.1-C.sub.4haloalkyl; or Q is pyrazolyl which can be mono-substituted by C.sub.1-C.sub.4haloalkyl or halogen; or Q is pyrimidinyl or C.sub.3-C.sub.6cycloalkyl, said cycloalkyl can be substituted by cyano; or Q is triazolyl which can be substituted by halogen; or Q is C.sub.1-C.sub.4alkyl which can be substituted by cyano; or Q is C.sub.2-C.sub.6alkynyl which can be mono-substituted by phenyl, which phenyl itself can be mono- or di-substituted by halogen; X is S or SO.sub.2; X.sub.1 is N—C.sub.1-C.sub.4alkyl; A is CH or N; and A.sub.1 is CH or N.
11. A pesticidal composition, which comprises at least one compound of formula I according to claim 1 or a tautomer thereof, in each case in free form or in agrochemically utilizable salt form, as active ingredient and at least one auxiliary.
12. A method for controlling pests, which comprises applying a composition according to claim 11 to the pests or their environment with the exception of a method for treatment of the human or animal body by surgery or therapy and diagnostic methods practised on the human or animal body.
13. A method for the protection of seeds from the attack by pests, which comprises treating the seeds or the site, where the seeds are planted, with a composition according to claim 11.
Description
PREPARATORY EXAMPLES
[0257] “Mpt.” means melting point in ° C. Free radicals represent methyl groups. .sup.1H NMR measurements were recorded on a Brucker 400 MHz spectrometer, chemical shifts are given in ppm relevant to a TMS standard. Spectra measured in deuterated solvents as indicated.
LCMS Methods:
Method 1:
[0258] Spectra were recorded on a Mass Spectrometer from Waters (SQD, SQDII or ZQ Single quadrupole mass spectrometer) equipped with an electrospray source (Polarity: positive or negative ions, Capillary: 3.00 kV, Cone range: 30-60 V, Extractor: 2.00 V, Source Temperature: 150° C., Desolvation Temperature: 350° C., Cone Gas Flow: 0 L/Hr, Desolvation Gas Flow: 650 L/Hr, Mass range: 100 to 900 Da) and an Acquity UPLC from Waters: Binary pump, heated column compartment and diode-array detector. Solvent degasser, binary pump, heated column compartment and diode-array detector. Column: Waters UPLC HSS T3, 1.8 mm, 30×2.1 mm, Temp: 60° C., DAD Wavelength range (nm): 210 to 500, Solvent Gradient: A=water+5% MeOH+0.05% HCOOH, B=Acetonitrile+0.05% HCOOH, gradient: 10-100% B in 1.2 min; Flow (mL/min) 0.85
Example H1: 2-[3-ethylsulfonyl-6-[3-(trifluoromethyl)pyrazol-1-yl]-2-pyridyl]-3-methyl-6-(trifluoromethyl)imidazo[4,5-c]pyridine (Compound P3, Table P)
[0259] ##STR00095##
Step A: tert-butyl N-[4-amino-6-(trifluoromethyl)-3-pyridyl]carbamate
[0260] ##STR00096##
[0261] To a solution of 6-(trifluoromethyl)pyridine-3,4-diamine (3.14 g, 17.73 mmol, prepared as described in U.S. Pat. No. 7,767,687) in tetrahydrofurane (50 ml) was added tert-butoxycarbonyl tert-butyl carbonate (4.64 g, 21.27 mmol) and the mixture was stirred at 50° C. After 8 hours, a further 1.1 g (5.0 mmol) of tert-butoxycarbonyl tert-butyl carbonate was added, and stirring at 50° C. continued for a further 4 hours. The reaction mixture was then concentrated in vacuo, and the brown residue was suspended in dichloromethane, filtered and dried in vacuo to give the title compound as white crystals. LCMS (method A): retention time: 0.79 min; 278 (M+H).
Step B: tert-butyl N-[4-amino-6-(trifluoromethyl)-3-pyridyl]-N-methyl-carbamate
[0262] ##STR00097##
[0263] To a stirred suspension of sodium hydride (0.648 g, 14.85 mmol) in 30 ml N,N-dimethylformamide, tert-butyl N-[4-amino-6-(trifluoromethyl)-3-pyridyl]carbamate (3.92 g, 14.14 mmol) dissolved in 20 ml N,N-dimethylformamide was added dropwise over a period of 20 min at 20-25° C. After 15 min stirring at ambient temperature, iodomethane (2.21 g, 15.55 mmol) was added. After 30 min at ambient temperature the mixture was poured onto 200 ml water, extracted twice with ethyl acetate, and the combined organic fractions washed successively with water and brine, dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The crude product was recrystallized from ethyl acetate/heptane to give the title compound (3.18 g) as white crystals. LCMS (method A): retention time: 0.85 min; 292 (M+H).
Step C: N3-methyl-6-(trifluoromethyl)pyridine-3,4-diamine
[0264] ##STR00098##
[0265] To a clear, colorless solution of tert-butyl N-[4-amino-6-(trifluoromethyl)-3-pyridyl]-N-methyl-carbamate (3.53 g, 12.119 mmol) in dioxane, hydrogen chloride (18 mL of a 2M solution in water, 36.36 mmol) was added and the mixture was heated to reflux. After gas evolution had ceased, the reaction mixture was cooled to room temperature, and treated with solid sodium hydrogen carbonate (3.1 g, 36.9 mmol). The slurry was diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed successively with water and brine, dried over Na.sub.2SO.sub.4 and concentrated in vacuo to give 2.25 g of the title compound as colorless crystals, Mpt 138-140° C. LCMS (method A): retention time 0.24 min, 192 (M+H).
[0266] Alternatively, N3-methyl-6-(trifluoromethyl)pyridine-3,4-diamine can be obtained by the following procedure:
[0267] To a solution of 6-(trifluoromethyl)pyridine-3,4-diamine (2.0 g, 12.2 mmol) and potassium carbonate (3.2 g, 23.1 mmol) in acetonitrile (10 mL) was added iodomethane (0.8 mL). The reaction mixture was stirred at 30° C. for 18 hours. Potassium carbonate was filtered off, the filtrate was dried in vacuo and purified with chromatography column on silica gel eluting with (petroleum:ethyl acetate=4:3) to afford the title compound as a light yellow solid (0.32 g). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ (ppm) 7.57 (s, 1H), 6.83 (s, 1H), 5.82 (s, 2H), 5.23 (d, J=4.8 Hz, 1H), 2.80 (d, J=4.8 Hz, 3H). .sup.19F NMR (300 MHz, DMSO-d6): δ (ppm) −60.12 (s, 3F).
Step D: N-[4-amino-6-(trifluoromethyl)-3-pyridyl]-3-ethylsulfonyl-N-methyl-pyridine-2-carboxamide and 3-ethylsulfonyl-N-[5-(methylamino)-2-(trifluoromethyl)-4-pyridyl]pyridine-2-carboxamide
[0268] ##STR00099##
[0269] To a solution of N3-methyl-6-(trifluoromethyl)pyridine-3,4-diamine (16.70 g, 87.37 mmol) in THF (167.0 mL) was added Et.sub.3N (22.32 g, 218.4 mmol). The reaction mixture cooled to 0° C. and 3-ethylsulfonylpyridine-2-carbonyl chloride (18.37 g, 78.63 mmol, prepared as described in WO 2013 018928) dissolved in dichloromethane (170 mL) was added dropwise at 0-10° C. to the mixture over 1 hour. After 1.5 hours LC/MS detected desired product at Rt=0.74. The ice-bath was removed and the reaction mixture was allowed to warm up to ambient temperature and stirred for 12 hours. The reaction mixture was then diluted with saturated NH.sub.4Cl, the organic phase separated, and the aqueous phase back extracted with dichloromethane. The combined organic phases were washed with water, brine, dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the crude product. The crude product was dissolved in dichloromethane and adsorbed on teflon bulk sorbents, and purified over a silica gel cartridge (Rf200) eluting with cyclohexane/ethyl acetate. This gave the crude title product as a mixture of amide region isomers that was used in the next step without further purification.
[0270] LCMS (method 1); Rt=0.73 min, [M+H] 389 and 0.8 min [M+H] 389.
Step E: 2-(3-ethylsulfonyl-2-pyridyl)-3-methyl-6-(trifluoromethyl)imidazo[4,5-c]pyridine
[0271] ##STR00100##
[0272] A yellow solution of the crude product mixture from step D (26.72 g, 68.80 mmol) in acetic 270 mL, was stirred at 120° C. over night. After cooling, the mixture was diluted with toluene and concentrated in vacuo.
[0273] The crude product was dissolved in dichloromethane and adsorbed on teflon bulk sorbents, and purified over a silica gel cartridge (TORENT) eluting with heptane:EtOAc to give the title product as beige solid.
[0274] LCMS (method 1): retention time 0.78 minutes, (M+H)=371. .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm: 1.36 (t, J=7.3 Hz, 3H); 3.77 (q, J=7.3 Hz, 2H); 3.90 (s, 3H); 7.77 (dd, J=8.1, 4.8 Hz, 1H); 8.12 (s, 1H); 8.55 (dd, J=8.1, 1.8 Hz, 1H); 9.00 (s, 1H); 9.02 (dd, J=4.8, 1.8 Hz, 1H).
Step F: 2-(3-ethylsulfonyl-1-oxido-pyridin-1-ium-2-yl)-3-methyl-6-(trifluoromethyl)imidazo[4,5-c]pyridine (A)
[0275] ##STR00101##
Method A:
[0276] To a solution of 2-(3-ethylsulfonyl-2-pyridyl)-3-methyl-6-(trifluoromethyl)imidazo[4,5-c]pyridine (18.70 g, 50.49 mmol) in dichloromethane (187.0 mL) was added meta-chloroperbenzoic acid (13.69 g, 55.53 mmol). The yellow solution was stirred at ambient temperature for 18 hours. After this time, the reaction mixture was cooled to ambient temperature, and diluted with aqueous sodium thiosulfate solution. The reaction mixture was extracted with dichloromethane, the combined organic fractions washed with
Na.sub.2CO.sub.3, dried over MgSO.sub.4, and concentrated in vacuo. The crude product was dissolved in dichloromethane and adsorbed on teflon bulk sorbents, and purified over a silica gel cartridge (TORENT) eluting with heptane/ethyl acetate and then dichloromethane:methanol. This gave the title product as the first eluting product.
[0277] LCMS (method 1): retention time 0.72 min, (M+H)=387. .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm; 1.35 (t, J=7.5 Hz, 3H); 3.39-3.52 (m, 1H); 3.66-3.82 (m, 1H); 3.87 (s, 3H); 7.71 (dd, J=8.1, 6.6 Hz, 1H); 8.00 (dd, J=8.1, 0.7 Hz, 1H); 8.13 (d, J=0.7 Hz, 1H); 8.55 (dd, J=6.6, 0.7 Hz, 1H) 9.03 (s, 1H).
[0278] As second eluting product was
2-(3-ethylsulfonyl-2-pyridyl)-3-methyl-5-oxido-6-(trifluoromethyl)imidazo[4,5-c]pyridin-5-ium (B)
[0279] ##STR00102##
[0280] LCMS (method 1): retention time 0.64 min, (M+H)=387. .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm: 1.37 (t, J=7.5 Hz, 3H); 3.76 (q, J=7.5 Hz, 2H); 3.77 (s, 3H); 7.77 (dd, J=8.1, 4.8 Hz, 1H); 8.09 (s, 1H); 8.55 (dd, J=8.1, 1.5 Hz, 1H); 8.71 (s, 1H); 9.01 (dd, J=4.8, 1.5 Hz, 1H).
[0281] As third eluting product was isolated
2-(3-ethylsulfonyl-1-oxido-pyridin-1-ium-2-yl)-3-methyl-5-oxido-6-(trifluoromethyl)imidazo[4,5-c]pyridin-5-ium (C)
[0282] ##STR00103##
[0283] LCMS (method 1): retention time 0.55 min, (M+H)=403. .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm: 1.36 (t, J=7.3 Hz, 3H); 3.33-3.54 (m, 1H); 3.60-3.80 (m, 1H); 7.72 (dd, J=8.1, 6.6 Hz, 1H); 7.99 (dd, J=8.1, 0.7 Hz, 1H); 8.10 (s, 1H); 8.54 (dd, J=6.6, 0.7 Hz, 1H); 8.68 (s, 1H).
[0284] The ratio of the products was (A):(B):(C) 9:15:1.
Method B:
[0285] To a solution of 2-(3-ethylsulfonyl-2-pyridyl)-3-methyl-6-(trifluoromethyl)imidazo[4,5-c]pyridine (1.00 g, 2.70 mmol) and urea hydrogen peroxide (0.288 g, 1.10 eq, 2.97 mmol) in dichloromethane (10.0 mL) was slowly added trifluoroacetic acid anhydride (1.15 g, 0.759 mL, 5.40 mmol) at 0° C. After 30 min the ice-bath was removed and the reaction mixture was allowed to warm to ambient temperature. LC/MS after 3 hours detected desired product at Rt=0.72, product B at Rt=0.64, and product D at Rt=0.55 It was stirred over the weekend at ambient temperature. Work-up and purification according to method A gave the same three products (A):(B):(C) in a ratio of 9:3:1.
Step G: 2-(6-chloro-3-ethylsulfonyl-2-pyridyl)-3-methyl-6-(trifluoromethyl)imidazo[4,5-c]pyridine
[0286] ##STR00104##
[0287] 2-(3-ethylsulfonyl-1-oxido-pyridin-1-ium-2-yl)-3-methyl-6-(trifluoromethyl)imidazo[4,5-c]pyridine (1.38 g, 1.00 eq, 3.57 mmol) and phosphoryl chloride (29.61 g, 18 mL, 53.5 eq, 191.2 mmol) were mixed in micro wave vial and heated at 130° C. for 6 hours in the microwave. LC/MS after this time showed reaction completion. The reaction mixture was concentrated in vacuo and purified over silica gel cartridge (Rf200), eluting with cyclohexane:ethyl acetate to give the title compound as a white solid: LCMS (method 1): retention time 0.95 minutes, (M+H)=405/407. .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm: 1.41 (t, J=7.5 Hz, 3H); 3.64 (q, J=7.5 Hz, 2H); 4.11 (s, 3H); 7.89 (d, J=8.4 Hz, 1H); 8.49 (d, J=8.4 Hz, 1H); 9.65 (s, 1H).
Step H: 2-[3-ethylsulfonyl-6-[3-(trifluoromethyl)pyrazol-1-yl]-2-pyridyl]-3-methyl-6-(trifluoromethyl)imidazo[4,5-c]pyridine (Compound P3, Table P)
[0288] ##STR00105##
[0289] A solution of 3-(trifluoromethyl)-1H-pyrazole (0.034 g, 0.25 mmol) in DMF (2.0 mL, 26 mmol) was cooled to 0° C. and treated with sodium hydride (60% in oil, 0.013 g, 0.32 mmol). The reaction was stirred 20 min at 0° C. and then treated with 2-(6-chloro-3-ethylsulfonyl-2-pyridyl)-3-methyl-6-(trifluoromethyl)imidazo[4,5-c]pyridine (0.10 g, 0.25 mmol) and the reaction allowed to warm and stirred at ambient temperature. LCMS showed reaction completion after 30 min. The reaction was diluted with tert-butyl dimethyl ether, and then quenched with sat. NaHCO.sub.3 sol. The organic layer was separated, washed 2× with water and brine, dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude product was dissolved in dichloromethane, adsorbed onto teflon bulk sorbents, and then purified over a silica gel cartridge (Rf200), eluting with cyclohexane/ethyl acetate, to give the title compound as a white solid. Mpt 261-263° C.
[0290] LCMS (method 1): retention time 1.07 min, (M+H)=505. .sup.1H NMR (400 MHz, CHLOROFORM-d) ppm: 1.38 (t, J=7.5 Hz, 3H); 3.73 (q, J=7.5 Hz, 2H); 3.93 (s, 3H); 6.80 (d, J=2.6 Hz, 1H); 8.15 (d, J=0.7 Hz, 1H); 8.45 (d, J=8.8 Hz, 1H); 8.59 (dd, J=2.6, 0.92 Hz, 1H) 8.68 (d, J=8.8 Hz, 1H) 9.04 (s, 1H).
Example H2: 2-[6-(4-chlorophenyl)-3-ethylsulfonyl-2-pyridyl]-3-methyl-6-(trifluoromethyl)imidazo[4,5-c]pyridine (Compound P1, Table P)
[0291] ##STR00106##
[0292] In a supelco vial, 2-(6-chloro-3-ethylsulfonyl-2-pyridyl)-3-methyl-6-(trifluoromethyl)imidazo[4,5-c]pyridine (Step G, example P1, 0.04 g, 0.1 mmol) dissolved in 1,4-dioxane (1 mL) was treated with (4-chlorophenyl)boronic acid (0.02 g, 0.1 mmol) and anhydrous K.sub.2CO.sub.3 (0.04 g, 0.3 mmol) and the mixture purged with argon for 10 min. Then, palladium-tris-triphenylphosphine (0.01 g, 0.01 mmol) was added and the solution heated at 100° C. LCMS analysis after 4 hours showed reaction completion. The reaction mixture was diluted with water and ethyl acetate, the organic layer was separated, washed with brine, dried over Na.sub.2SO.sub.4, filtered and evaporated and concentrated in vacuo. The crude product was dissolved in dichloromethane, adsorbed onto teflon bulk sorbents, and then purified over a silica gel cartridge (Rf200), eluting with cyclohexane/ethyl acetate, to give the title compound as a yellow solid. Mpt 255-256° C.
[0293] LCMS (method 1): retention time 1.11 min, (M+H)=481/483. .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm: 1.39 (t, J=7.5 Hz, 3H); 3.79 (q, J=7.5 Hz, 2H); 3.95 (s, 3H); 7.51 (d, J=8.8 Hz, 2H); 8.06 (d, J=8.8 Hz, 2H); 8.11 (d, J=8.4 Hz, 1H) 8.15 (s, 1H); 8.57 (d, J=8.4 Hz, 1H); 9.02 (s, 1H).
Example H3: 2-[3-ethylsulfonyl-6-[(E)-2-[2-(trifluoromethyl)phenyl]vinyl]-2-pyridyl]-3-methyl-6-(trifluoromethyl)imidazo[4,5-c]pyridine (Compound P2, Table P)
[0294] ##STR00107##
[0295] In a microwave vial, 2-(6-chloro-3-ethylsulfonyl-2-pyridyl)-3-methyl-6-(trifluoromethyl)imidazo[4,5-c]pyridine (Step G, example P1, 0.10 g, 0.25 mmol), anhydrous K.sub.2CO.sub.3 (0.068 g, 0.49 mmol), 2-(trifluoromethyl)styrene (0.043 g, 0.037 mL, 0.25 mmol) dissolved in acetonitrile were degassed with argon. To this mixture was added palladium(II)acetate (0.0051 g, 0.022 mmol) and the mixture then heated for 45 min at 140° C. after this time, a further portion of 2-(trifluoromethyl)styrene (0.074 mL) and palladium (II)acetate (0.0028 g, 0.050 eq, 0.012 mmol) were added and the mixture heated in the microwave 1 hour at 140° C. After this time, the reaction mixture was filtered over hyflo, and the filtrate diluted with ethyl acetate and washed successively with 1N HCl, water and brine, dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude product was dissolved in dichloromethane, adsorbed onto teflon bulk sorbents, and then purified over a silica gel cartridge (Rf200), eluting with cyclohexane/ethyl acetate. Further purification by reversed phase HPLC gave the title compound as white foam.
[0296] LCMS (method 1): retention time 1.14 min, (M+H)=541. .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm: 1.40 (t, J=7.3 Hz, 3H); 3.86 (q, J=7.34 Hz, 2H); 4.00 (s, 3H); 7.24 (d, J=15.7 Hz, 1H); 7.46-7.52 (m, 1H); 7.62 (t, J=7.5 Hz, 1H); 7.71-7.77 (m, 2H) 7.85 (d, J=7.75 Hz, 1H) 8.14 (s, 1H) 8.25 (dd, J=15.7, 2.20 Hz, 1H) 8.51 (d, J=8.4 Hz, 1H) 9.03 (s, 1H).
Example H4: 2-[3-ethylsulfonyl-5-(trifluoromethyl)-6-[4-(trifluoromethyl)phenyl]-2-pyridyl]-3-methyl-6-(trifluoromethyl)imidazo[4,5-c]pyridine (Compound P4, Table P))
[0297] ##STR00108##
Step A: Methyl 3-ethylsulfanyl-5-(trifluoromethyl)pyridine-2-carboxylate
[0298] ##STR00109##
[0299] A solution of methyl 3-chloro-5-(trifluoromethyl)pyridine-2-carboxylate (30 g, 125 mmol, CAS Registry Number [655235-65-7]) was dissolved in DMF (630 mL), Sodium ethanethiolate (12.87 g, 138 mmol) was added in portions keeping the temperature below 20° C. The reaction mixture was allowed to stir overnight after which LCMS analysis showed reaction completion. The mixture was diluted with water, extracted with AcOEt (3 times), and the combined organic phases washed successively with saturated aqueous NH.sub.4Cl and brine, dried over MgSO.sub.4 and concentrated in vacuo. The crude title compound was used for the next step without further purification.
[0300] LCMS (method 1); Rt=0.96 min, [M+H] 266. .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm: 1.43 (t, J=7.5 Hz, 3H); 3.00 (q, J=7.5 Hz, 2H); 4.04 (s, 3H); 7.87 (d, J=1.1 Hz, 1H); 8.66 (d, J=1.1 Hz, 1H).
Step B: methyl 3-ethylsulfonyl-5-(trifluoromethyl)pyridine-2-carboxylate
[0301] ##STR00110##
[0302] A solution of methyl 3-ethylsulfanyl-5-(trifluoromethyl)pyridine-2-carboxylate (5.94 g, 22.4 mmol) in dichloromethane (200 mL) was cooled to 0° C. To this solution was added m-CPBA (11.0 g, 44.8 mmol) in small portions at 0°. After 2 hours, the solution is allowed to warm to ambient and stirred for 3 hours at ambient temperature after which time LCMS showed reaction completion. The reaction mixture was poured onto NaHCO.sub.3 aq. and saturated sodium thiosulfate aqueous solution. The mixture was then extracted with dichloromethane (3×), washed with brine, dried over MgSO.sub.4 and concentrated in vacuo. The crude product was purified by Combi flash chromatography eluting with a gradient of cyclohexane+0-30% ethyl acetate. This gave the title compound as a white solid.
[0303] LCMS (method 1); Rt=0.76 min, [M+H] 298. .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm: 1.39 (t, J=7.5 Hz, 3H); 3.57 (q, J=7.5 Hz, 2H); 4.08 (s, 3H); 8.61 (d, J=1.8 Hz, 1H); 9.11 (d, J=1.8 Hz, 1H).
Step C: Methyl 3-ethylsulfonyl-1-oxido-5-(trifluoromethyl)pyridin-1-ium-2-carboxylate
[0304] ##STR00111##
[0305] A solution of methyl 3-ethylsulfonyl-5-(trifluoromethyl)pyridine-2-carboxylate (7.5 g, 25 mmol, prepared as described in) in dichloromethane (80 mL) was cooled to 0° C. and urea hydrogen peroxide complex (5.1 g, 53 mmol) added in small portions. To this mixture was added trifluoroacetic anhydride (11 g, 7.2 mL, 50.0 mmol) keeping the reaction temperature at 0° C. The reaction mixture was allowed to warm to rt and stirred overnight. After this time, the reaction was quenched with aqueous sodium hydrogen sulfite solution, and stirred for 15 min. The resulting mixture was poured onto 0.5 M HCl and extracted 3 times with dichloromethane. The combined organic extracts were washed with NaHCO.sub.3 aqueous solution, dried over Na.sub.2SO4, filtered and concentrated in vacuo. The crude product was purified by Combi flash chromatography, eluting with a gradient of cyclohexane+0-100% ethyl acetate, to give the title compound as a white solid.
[0306] LCMS (method 1); Rt=0.70 min, [M+H] 314. .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm: 1.39 (t, J=7.5 Hz, 3H); 3.38 (q, J=7.5 Hz, 2H); 4.08 (s, 3H); 7.93 (d, J=0.7 Hz, 1H); 8.62 (d, J=0.7 Hz, 1H).
Step D: Methyl 6-chloro-3-ethylsulfonyl-5-(trifluoromethyl)pyridine-2-carboxylate
[0307] ##STR00112##
[0308] A sample of methyl 3-ethylsulfonyl-1-oxido-5-(trifluoromethyl)pyridin-1-ium-2-carboxylate (1.43 g, 4.57 mmol) and phosphoryl chloride (24.3 mL) were placed in two microwave vials and the vials stirred at 130° C. for 6 hours in the microwave. After this time, the contents of the vials were combined and concentrated in vacuo. The crude product was purified over silica gel cartridge (Rf200) eluting with cyclohexane/ethyl acetate to give the title product as white crystals.
[0309] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm: 1.39 (t, J=7.5 Hz, 3H); 3.55 (q, J=7.5 Hz, 2H); 4.07 (s, 3H); 8.61 (s, 1H).
Step E: Methyl 3-ethylsulfonyl-5-(trifluoromethyl)-6-[4-(trifluoromethyl)phenyl]pyridine-2-carboxylate
[0310] ##STR00113##
[0311] A solution of methyl 6-chloro-3-ethylsulfonyl-5-(trifluoromethyl)pyridine-2-carboxylate (0.285 g, 0.86 mmol) in 1,4-dioxane (7 mL) was treated with [4-(trifluoromethyl)phenyl]boronic acid (0.212 g, 1.12 mmol) and anhydrous K.sub.2CO.sub.3 (0.356 g, 3.00 eq, 2.58 mmol) and the mixture purged with argon for 10 min. To this mixture was added tetrakis(triphenylphosphine)palladium(0) (0.0993 g, 0.100 eq, 0.0859 mmol) and the solution heated at 100° C. for 3 hr after which time LCMS showed good reaction conversion. The reaction mixture was diluted with NH.sub.4Cl sat sol, water and ethyl acetate. The organic phase was separated, washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude product was dissolved in dichloromethane and adsorbed on teflon bulk sorbents. Purification over a silica gel cartridge (Rf200), eluting with cyclohexane/ethyl acetate gave the title compound as a white solid.
[0312] LCMS (method 1); Rt=1.09 min, [M+H] 442. .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm: 1.44 (t, J=7.5 Hz, 3H); 3.59 (q, J=7.5 Hz, 2H); 4.06 (s, 3H); 7.70 (d, J=8.0 Hz, 2H); 7.78 (d, J=8.0 Hz, 2H); 8.73 (s, 1H).
Step F: 3-ethylsulfonyl-5-(trifluoromethyl)-6-[4-(trifluoromethyl)phenyl]pyridine-2-carboxylic Acid
[0313] ##STR00114##
[0314] Methyl 3-ethylsulfonyl-5-(trifluoromethyl)-6-[4-(trifluoromethyl)phenyl]pyridine-2-carboxylate (0.28 g, 0.63 mmol) was dissolved in tetrahydrofuran/H.sub.2O 3:1 (10 mL) and treated with lithium hydroxide hydrate (0.028 g, 0.67 mmol) at ambient temperature. LCMS analysis after stirring for 3 hours showed reaction. The reaction mixture was concentrated in vacuo and taken up in ethyl acetate and 10% aqueous HCl. The organic layer was separated and washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the title compound as beige solid that was used in the next step without further purification.
[0315] LCMS (method 1); Rt=0.88 min, [M+H] 428. .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.42 (t, J=7.3 Hz, 3H): 3.75 (q, J=7.3 Hz, 2H): 4.98 (br. s., 1H); 7.70 (d, J=7.8 Hz, 2H); 7.79 (d, J=7.8 Hz, 2H): 8.86 (s, 1H).
Step G: 3-ethylsulfonyl-N-[5-(methylamino)-2-(trifluoromethyl)-4-pyridyl]-5-(trifluoromethyl)-6-[4-(trifluoromethyl)phenyl]pyridine-2-carboxamide and N-[4-amino-6-(trifluoromethyl)-3-pyridyl]-3-ethylsulfonyl-N-methyl-5-(trifluoromethyl)-6-[4-(trifluoromethyl)phenyl]pyridine-2-carboxamide
[0316] ##STR00115##
[0317] A solution of 3-ethylsulfonyl-5-(trifluoromethyl)-6-[4-(trifluoromethyl)phenyl]pyridine-2-carboxylic acid (0.10 g, 0.23 mmol), EDCI (0.049 g, 0.26 mmol) and N3-methyl-6-(trifluoromethyl)pyridine-3,4-diamine (0.049 g, 0.26 mmol, step C, example P1) in pyridine (3.0 mL) was stirred at 120° C. After 2 hours LC/MS showed sufficient reaction progress for work-up. The reaction mixture was poured onto water, and extracted with ethyl acetate (×3). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The crude product was dissolved in dichloromethane and adsorbed on teflon bulk sorbents. Purification over a silica gel cartridge (Rf200), eluting with cyclohexane/ethyl acetate
[0318] Gradient gave a mixture of the title compounds as a yellow solid.
[0319] LCMS (method 1); Rt=1.10 min, [M+H] 601; Rt=1.14 min, [M+H] 601.
Step H: 2-[3-ethylsulfonyl-5-(trifluoromethyl)-6-[4-(trifluoromethyl)phenyl]-2-pyridyl]-3-methyl-6-(trifluoromethyl)imidazo[4,5-c]pyridine (Compound P4, Table P)
[0320] ##STR00116##
[0321] A yellow solution of 3-ethylsulfonyl-N-[5-(methylamino)-2-(trifluoromethyl)-4-pyridyl]-5-(trifluoromethyl)-6-[4-(trifluoromethyl)phenyl]pyridine-2-carboxamide and N-[4-amino-6-(trifluoromethyl)-3-pyridyl]-3-ethylsulfonyl-N-methyl-5-(trifluoromethyl)-6-[4-(trifluoromethyl)phenyl]pyridine-2-carboxamide: (0.055 g, 0.092 mmol) in acetic acid (1 mL) was stirred at 120° C. for 18 hours. LCMS analysis after this time showed reaction completion. The reaction mixture was cooled to ambient temperature, diluted with toluene and concentrated in vacuo. The crude product was dissolved in dichloromethane and adsorbed on teflon bulk sorbents. Purification over a silica gel cartridge (Rf200), eluting with a cyclohexane/ethyl acetate gradient gave a mixture of the title compounds as a white solid. Mpt. 140-142° C.
[0322] LCMS (method 1); Rt=1.17 min, [M+H] 583. .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.47 (t, J=7.5 Hz, 3H); 3.94 (q, J=7.5 Hz, 2H); 7.72-7.76 (m, 2H); 7.78-7.82 (m, 2H); 3.94 (q, J=7.34 Hz, 2H); 3.96 (s, 3H); 8.92 (s, 1H); 9.01 (s, 1H).
Example H5: 2-(6-cyclopropyl-3-ethylsulfonyl-2-pyridyl)-3-methyl-6-(trifluoromethyl)imidazo[4,5-c]pyridine (Compound P15, Table P)
[0323] ##STR00117##
Step A: 3,6-dichloropyridine-2-carbonyl Chloride
[0324] ##STR00118##
[0325] A sample of 3,6-dichloropyridine-2-carboxylic acid (5.00 g, 24.7 mmol) was diluted in dichloromethane (200 mL) and dimethylformamide (0.124 mL, 1.6 mmol) was added. To this solution was added oxalyl chloride (3.15 mL, 34.6 mmol) dropwise at room temperature over 10 min (gas evolution). The reaction mixture was stirred at room temperature, and after 2.5 h, a further 1 ml oxalyl chloride was added and stirring continued for 1 hr. After this time, the reaction mixture was concentrated in vacuo and used in the next step without further purification.
Step B: 3,6-dichloro-N-[5-(methylamino)-2-(trifluoromethyl)-4-pyridyl]pyridine-2-carboxamide
[0326] ##STR00119##
[0327] To a solution of N3-methyl-6-(trifluoromethyl)pyridine-3,4-diamine (52.0 g, 272 mmol) in tetrahydrofurane (260 mL) was added triethylamine (95.8 mL, 680 mmol). The red solution was cooled to 0° C. and 3,6-dichloropyridine-2-carbonyl chloride (51.5 g, 245 mmol) in dichloromethane (156 mL) was added dropwise at 0-10° C. over 90 min. The ice-bath was removed after 1 h and the mixture was stirred at room temperature. LC-MS analysis showed mainly desired mass after 2 hours. The reaction mixture was stirred overnight and then washed with NH.sub.4Cl sat sol and the mixture was concentrated in vacuo to remove tetrahydrofurane. The residue was then extracted with 1.2 L dichloromethane (800 ml) ethylacetate and again 1 L dichloromethane. The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the title compound as a brown solid. LCMS (method 1): 366 (M+H.sup.+); retention time: 0.83 min.
Step C: 2-(3,6-dichloro-2-pyridyl)-3-methyl-6-(trifluoromethyl)imidazo[4,5-c]pyridine
[0328] ##STR00120##
[0329] A yellow solution of 3,6-dichloro-N-[5-(methylamino)-2-(trifluoromethyl)-4-pyridyl]pyridine-2-carboxamide (99.3 g, 272 mmol) in acetic acid (298 mL) was stirred at 110° C. bath temperature for 16 hours. The reaction mixture was allowed to room temperature after which time LC-MS analysis showed desired mass. Toluene was added and the mixture was concentrated in vacuo. To the residue was added cyclohexane and dichloromethane and the mixture obtained was stirred under vacuum at 50° C. at 800 mbar. The slurry was further diluted with cyclohexane and the solid filtered at the pump. The cake was washed with cyclohexane (mixed with small amounts of DCM) and dried under vacuum. Toluene was added the mixture was evaporated and dried under vacuum at 60° C. and 20 mbar to remove traces of acetic acid, giving the title compound as a brown solid.
[0330] LCMS (method 1): 348 (M+H.sup.+); retention time: 0.95 min.
[0331] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.04 (s, 3H) 7.51 (d, J=8.44 Hz, 1H) 7.93 (d, J=8.44 Hz, 1H) 8.19 (s, 1H) 8.99 (s, 1H)
Step D: 2-(6-chloro-3-ethylsulfanyl-2-pyridyl)-3-methyl-6-(trifluoromethyl)imidazo[4,5-c]pyridine
[0332] ##STR00121##
[0333] A sample of 2-(3,6-dichloro-2-pyridyl)-3-methyl-6-(trifluoromethyl)imidazo[4,5-c]pyridine (1.14 g, 3.28 mmol) was dissolved in tetrahydrofurane under argon. Sodium ethanethiol (0.311 g, 3.28 mmol) was added portionwise at room temperature. The brown reaction mixture was stirred at room temperature for 2 hours by which time LC-MS analysis showed reaction completion with formation of the desired product. The reaction mixture was treated with NH.sub.4Cl followed by water and ethyl acetate. The organic layer was separated, washed with water and brine, dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude was purified by flash chromatography over silicagel to give the title compound as a beige solid.
[0334] LCMS (method 1): 373 (M+H+); retention time: 1.02 min.
[0335] 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.35 (t, J=7.34 Hz, 3H) 2.97 (q, J=7.34 Hz, 2H) 4.11 (s, 3H) 7.44 (d, J=8.44 Hz, 1H) 7.76 (d, J=8.44 Hz, 1H) 8.20 (d, J=0.73 Hz, 1H) 8.97 (s, 1H)
Step E: 2-(6-chloro-3-ethylsulfonyl-2-pyridyl)-3-methyl-6-(trifluoromethyl)imidazo[4,5-c]pyridine
[0336] ##STR00122##
[0337] At 0° C. m-CPBA (2.35 g, 10.5 mmol) was added to a solution of 2-(6-chloro-3-ethylsulfanyl-2-pyridyl)-3-methyl-6-(trifluoromethyl)imidazo[4,5-c]pyridine (1.86 g, 4.99 mmol) in chloroform (46.5 mL). After the addition the ice-bath was kept for 10 min and then the milky solution was allowed to warm to rt. The reaction mixture was stirred one night at room temperature. After this time a further portion of M-CPBA (1.12 g, 4.99 mmol) was added the mixture was stirred 2 hours at room temperature. LC-MS analysis showed the complexion of the reaction. Saturated sodium thiosulfate aqueous solution and sat NaHCO.sub.3aq were added and the mixture stirred 1 hour. The organic layer was separated, extracted with NaHCO.sub.3, dried over Na.sub.2SO.sub.4 and evaporated. The crude product was purified by flash chromatography over silicagel to give the title compound as a white solid.
[0338] LCMS (method 1): 406 (M+H+); retention time: 0.95 min.
[0339] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.37 (t, J=7.34 Hz, 3H) 3.79 (q, J=7.46 Hz, 2H) 3.94 (s, 3H) 7.75 (d, J=8.44 Hz, 1H) 8.11 (s, 1H) 8.47 (d, J=8.44 Hz, 1H) 9.00 (s, 1H)
Step F: 2-(6-cyclopropyl-3-ethylsulfonyl-2-pyridyl)-3-methyl-6-(trifluoromethyl)imidazo[4,5-c]pyridine (Compound P15, Table P)
[0340] ##STR00123##
[0341] In a supelco vial 2-(6-chloro-3-ethylsulfonyl-2-pyridyl)-3-methyl-6-(trifluoromethyl)imidazo[4,5-c]pyridine (0.40 g, 0.99 mmol) was dissolved in 1,4-dioxane (10 mL, 120 mmol). Cyclopropylboronic acid (0.18 g, 2.0 mmol) and potassium carbonate (0.41 g, 3.0 mmol) were added and the mixture was purged with argon. Then tetrakis(triphenylphosphine) palladium (0.11 g, 0.099 mmol) was added, the vial was capped and the brown solution was heated at 100° C. for 19 hours. LC-MS analysis showed the formation of desired product. Water and ethyl acetate were added, the organic layer was separated, washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude obtained was purified by flash chromatography on silica gel. The mixture obtained was dissolved in ethylacetate and washed again with NaHCO.sub.3. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, filtered and evaporated. The solid obtained was purified again by reverse phase to give the title compound as a white solid.
[0342] LCMS (method 1): 411 (M+H.sup.+); retention time: 1.01 min.
[0343] 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.11-1.13 (m, 1H) 1.11-1.23 (m, 4H) 1.33 (t, J=7.34 Hz, 3H) 2.22 (ddd, J=7.70, 4.77, 2.93 Hz, 1H) 3.70 (q, J=7.34 Hz, 2H) 3.84 (s, 3H) 7.54 (d, J=8.44 Hz, 1H) 8.09 (s, 1H) 8.30 (d, J=8.44 Hz, 1H) 8.97 (s, 1H)
Example H6: 2-[6-(3,5-difluorophenyl)-3-ethylsulfonyl-2-pyridyl]-3-methyl-6-(trifluoromethyl)imidazo[4,5-c]pyridine (Compound P8, Table P)
[0344] ##STR00124##
[0345] In a supelco vial, 2-(6-chloro-3-ethylsulfonyl-2-pyridyl)-3-methyl-6-(trifluoromethyl)imidazo[4,5-c]pyridine (100 mg, 0.2470 mmol), (3,5-difluorophenyl)boronic acid (46 mg, 0.2964 mmol) and potassium carbonate (102 mg, 0.7411 mmol) were dissolved in 1,4-dioxane (2.5 mL). The resulting mixture was flushed with argon over 5 minutes. After this time, tetrakis(triphenylphosphine) palladium (28 mg, 0.02470 mmol) was added and the vial was closed and heated at 95° C. for 16 hours. LC-MS analysis showed completion of the reaction. The reaction mixture was cooled to room temperature and quenched with water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated solution of NaHCO.sub.3 and saturated NaCl solution, dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude was purified by flash chromatography on silica gel to give the title compound as a yellow solid.
[0346] LCMS (method 1): 483 (M+H.sup.+); retention time: 1.09 min.
[0347] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.42 (t, J=7.34 Hz, 3H) 3.84 (q, J=7.34 Hz, 2H) 3.99 (s, 3H) 7.00-7.05 (m, 1H) 7.68 (d, J=5.87 Hz, 2H) 8.12 (d, J=8.44 Hz, 1H) 8.17 (s, 1H) 8.64 (d, J=8.44 Hz, 1H) 9.06 (s, 1H)
Example H7: 2-[3-ethylsulfonyl-6-[3-(trifluoromethyl)pyrazol-1-yl]-2-pyridyl]-3-methyl-6-(trifluoromethylsulfanyl)imidazo[4,5-c]pyridine (Compound P9, Table P)
[0348] ##STR00125##
Step A: Methyl 3-ethylsulfonyl-6-[3-(trifluoromethyl)pyrazol-1-yl]pyridine-2-carboxylate
[0349] ##STR00126##
[0350] To a stirred solution of methyl 6-chloro-3-ethylsulfonyl-pyridine-2-carboxylate (526 mg, 2 mmol), 3-(trifluoromethyl)-1H-pyrazole (1.361 g, 10 mmol) in dioxane (25 mL) was added CuI (38 mg, 0.2 mmol) N,N′-Dimethylethanediamine (880 mg, 1 mmol) and potassium carbonate (1.38 g, 10 mmol). The reaction system was refluxed under a nitrogen atmosphere at 120° C. for 4 h. After cooling to room temperature, the reaction mixture was filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel to give the title compound.
[0351] 1HNMR (400 MHz, CDCl3): δppm 1.36 (t, 3H), 3.49 (q, 2H), 4.06 (s, 3H), 6.69 (s, 1H), 8.26 (d, J=8.4 Hz, 1H), 8.44 (d, J=8.4 Hz, 1H), 8.68 (s, 1H); ESI-MS (+): 386 (M+Na)+
Step B: 3-ethylsulfonyl-6-[3-(trifluoromethyl)pyrazol-1-yl]pyridine-2-carboxylic Acid
[0352] ##STR00127##
[0353] To a stirred solution of methyl 3-ethylsulfonyl-6-[3-(trifluoromethyl)pyrazol-1-yl]pyridine-2-carboxylate (218 mg, 0.6 mmol) in THF (10 mL) was added NaOH (120 mg, 3 mmol), and H.sub.2O (30 ml). The reaction system was stirred at room temperature for 2 h. After this time, the pH value was adjusted to 2 with HCl and the reaction mixture extracted with ethyl acetate three times. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound.
[0354] 1HNMR (400 MHz, DMSO-d6): δppm 1.18 (t, 3H), 3.54 (q, 2H), 7.12 (s, 1H), 8.21 (d, J=8.8 Hz, 1H), 8.53 (d, J=8.4 Hz, 1H), 8.86 (s, 1H); ESI-MS (+): 348 (M−H)−
Step C: 2-[3-ethylsulfonyl-6-[3-(trifluoromethyl)pyrazol-1-yl]-2-pyridyl]-3-methyl-6-(trifluoromethylsulfanyl)imidazo[4,5-c]pyridine (Compound P9, Table P)
[0355] ##STR00128##
[0356] To a stirred solution of 3-ethylsulfonyl-6-[3-(trifluoromethyl)pyrazol-1-yl]pyridine-2-carboxylic acid (180 mg, 0.52 mmol), N3-methyl-6-(trifluoromethylsulfanyl)pyridine-3,4-diamine (250 mg, 1.11 mmol) and HATU (0.78 g, 2 mmol) in DMF (30 mL) was added DIPEA (2 ml, 10 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was then diluted with ethyl acetate and H.sub.2O, the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was used for the next step without further purification. The solution of the crude product in acetic acid (20 mL) was refluxed at 120° C. for 24 h. The reaction mixture was then evaporated to dryness. The residue was purified by chromatography on silica gel (petroleum:EtOAc=4:1) to afford the title compound as white solid.
[0357] LCMS (method 1): 537 (M+H.sup.+); retention time: 1.17 min.
[0358] 1HNMR (400 MHz, CDCl3): δ (ppm) 1.37 (t, 3H), 3.73 (q, 2H), 3.90 (s, 3H), 6.79 (s, 1H), 8.14 (s, 1H), 8.45 (d, J=4.8 Hz, 1H), 8.65 (s, 1H), 8.67 (d, J=4.8 Hz, 1H), 8.98 (s, 1H); 19FNMR (376 MHz, CDCl3): δ (ppm) −46.40 (s, 3F), −68.19 (s, 3F)
Example 2-(3-ethylsulfonyl-6-pyrimidin-2-yl-2-pyridyl)-3-methyl-6-(trifluoromethylsulfanyl)imidazo[4,5-c]pyridine (Compound P10, Table P)
[0359] ##STR00129##
Step A: N-methyl-4-nitro-6-(trifluoromethylsulfanyl)pyridin-3-amine
[0360] ##STR00130##
[0361] A sample of (bpy)CuSCF.sub.3 (14.4 g, 45 mmol) and 6-bromo-N-methyl-4-nitro-pyridin-3-amine (6.96 g, 30 mmol) in 120 ml of CH3CN was refluxed for 48 h under nitrogen. The reaction mixture was removed from the oil bath and allowed to cool to room temperature, and then filtered through SiO2. The silica gel was eluted with diethyl ether, and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the title compound.
[0362] 1HNMR (400 MHz, DMSO-d6): δ (ppm) 3.10 (d, J=5.2 Hz, 3H), 8.21 (s, 1H) 8.49 (q, 1H), 8.67 (s, 1H); 19FNMR (376 MHz, DMSO-d6): δ (ppm) −36.79 (s, 3F); ESI-MS: 252 (M−H)−.
Step B: N3-methyl-6-(trifluoromethylsulfanyl)pyridine-3,4-diamine
[0363] ##STR00131##
[0364] To a solution of N-methyl-4-nitro-6-(trifluoromethylsulfanyl)pyridin-3-amine (3.42 g, 13.5 mmol) in methanol (50 mL) was added Raney Ni (20% wt). To this mixtures was added hydrazine hydrate (10 mL) dropwise at room temperature. The reaction mixture was stirred at room temperature for 30 minutes. Raney Ni was filtered off through celite; the filtrate was dried in vacuo and purified with chromatography column on silica gel to afford the title compound as white solid.
[0365] 1HNMR (400 MHz, DMSO-d6): δppm 2.78 (d, J=5.2 Hz, 3H), 5.20 (q, 1H), 5.77 (s, 2H), 6.82 (s, 1H), 7.53 (s, 1H); 19FNMR (376 MHz, DMSO-d6): δppm −45.49 (s, 3F); ESI-MS (+): 224 (M+H)+.
Step C: Methyl 3,6-dichloropyridine-2-carboxylate
[0366] ##STR00132##
[0367] To a solution of 3,6-dichloropyridine-2-carboxylic acid (76.8 g, 0.4 mol) in methanol (500 mL) was added SOCl2 (150 ml) dropwise at room temperature. The reaction mixture was stirred at room temperature for 3 hours. After this time, the reaction mixture was poured into water and extracted with ethyl acetate three times. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound.
[0368] 1HNMR (400 MHz, DMSO-d6): δppm 3.90 (s, 3H), 7.80 (d, J=8.8 Hz, 1H), 8.20 (d, J=8.8 Hz, 1H); ESI-MS (+): 228 (M+Na)+.
Step D: Methyl 6-chloro-3-ethylsulfanyl-pyridine-2-carboxylate
[0369] ##STR00133##
[0370] To a solution of methyl 3,6-dichloropyridine-2-carboxylate (16 g, 77.6 mmol) in DMF (150 mL) was added sodium ethanethiolate (7.2 g, 85.8 mmol) at 0° C. After the addition, the reaction mixture was stirred at room temperature for 30 min. LCMS analysis after this time showed reaction completion. The reaction mixture was poured into water, and precipitate formed filtered and dried under an infrared oven to afford the title compound as white solid.
[0371] 1HNMR (400 MHz, CDCl3): δppm 1.38 (t, 3H), 2.92 (q, 2H), 3.98 (s, 3H), 7.40 (d, J=8.8 Hz, 1H), 7.66 (d, J=8.8 Hz, 1H); ESI-MS (+): 254 (M+Na)+.
Step E: Methyl 6-chloro-3-ethylsulfonyl-pyridine-2-carboxylate
[0372] ##STR00134##
[0373] A solution of methyl 6-chloro-3-ethylsulfanyl-pyridine-2-carboxylate (11.55 g, 50 mmol) and m-CPBA (25.8 g, 150 mmol) in 200 ml of dichloromethane was stirred at room temperature for 2 hours. After this time, the mixture was poured into a saturated solution of NaHCO.sub.3 and Na.sub.2SO.sub.3, and extracted with DCM three times. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo The crude product was purified by column chromatography on silica gel to give the title compound.
[0374] 1HNMR (400 MHz, CDCl3): δppm 1.33 (t, 3H), 3.51 (q, 2H), 4.02 (s, 3H), 7.63 (d, J=8 Hz, 1H), 8.29 (d, J=8 Hz, 1H); ESI-MS (+): 286 (M+Na)+.
Step F: Methyl 3-ethylsulfonyl-6-pyrimidin-2-yl-pyridine-2-carboxylate
[0375] ##STR00135##
[0376] To a stirred solution of methyl 6-chloro-3-ethylsulfonyl-pyridine-2-carboxylate (526 mg, 2 mmol) and tributyl(pyrimidin-2-yl)stannane (1.107 g, 3 mmol) in dioxane (25 mL) were added CuI (76 mg, 0.4 mmol) and PdCl2(PPh3)2 (140 mg, 0.2 mmol). The reaction mixture was refluxed under an nitrogen atmosphere at 120° C. for 4 hours. After cooling to room temperature, the reaction mixture was filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel to give the title compound.
[0377] 1HNMR (400 MHz, CDCl3): δppm 1.36 (t, 3H), 3.58 (q, 2H), 4.05 (s, 3H), 7.42 (t, 1H), 8.53 (d, J=8.4 Hz, 1H), 8.81 (d, J=8.4 Hz, 1H), 9.00 (d, J=4.8 Hz, 2H); ESI-MS (+): 330 (M+Na)+
Step G: 3-ethylsulfonyl-6-pyrimidin-2-yl-pyridine-2-carboxylic Acid
[0378] ##STR00136##
[0379] To a stirred solution of methyl 3-ethylsulfonyl-6-pyrimidin-2-yl-pyridine-2-carboxylate (522 mg, 1.7 mmol) in tetrahydrofurane (10 mL) was added NaOH (340 mg, 8.5 mmol) and water (30 ml). The reaction system was stirred at room temperature for 2 hours, by which time LCMS analysis showed reaction completion. The pH value was adjusted to 2 with HCl, and the reaction mixture was extracted with ethyl acetate three times. The organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound.
[0380] 1HNMR (400 MHz, DMSO-d6): δppm 1.22 (t, 3H), 3.57 (q, 2H), 7.66 (m, 1H), 7.68 (d J=4.8 Hz, 1H), 8.55 (d, J=8.4 Hz, 1H), 8.70 (d, J=8.4 Hz, 1H), 9.07 (d, J=4.8 Hz, 2H).
Step H: 2-(3-ethylsulfonyl-6-pyrimidin-2-yl-2-pyridyl)-3-methyl-6-(trifluoromethylsulfanyl)imidazo[4,5-c]pyridine (Compound P10, Table P)
[0381] ##STR00137##
[0382] To a stirred solution of 3-ethylsulfonyl-6-pyrimidin-2-yl-pyridine-2-carboxylic acid (470 mg, 1.6 mmol), N3-methyl-6-(trifluoromethylsulfanyl)pyridine-3,4-diamine (430 mg, 1.92 mmol) and HATU (1.216 g, 3.2 mmol) in DMF (30 mL) was added DIPEA (2.8 ml, 16 mmol). The reaction system was stirred at room temperature overnight. After this time the reaction mixture was diluted with ethyl acetate and H.sub.2O, and the organic layer washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was used for the next step without further purification.
[0383] A solution of the crude product in acetic acid (20 mL) was refluxed at 120° C. for 24 h. The reaction mixture was evaporated to dryness and the residue purified by chromatography on silica gel to afford the title compound as white solid.
[0384] LCMS (method 1): 481 (M+H+); retention time: 0.93 min
[0385] 1HNMR (400 MHz, CDCl3): δ (ppm) 1.38 (t, 3H), 3.80 (q, 2H), 3.93 (s, 3H), 7.44 (t, 1H), 8.10 (s, 1H), 8.70 (d, J=8.4 Hz, 1H), 8.96 (m, 2H), 9.0 (d, J=4.8 Hz, 2H); 19FNMR (376 MHz, CDCl3): δ (ppm) −45.77 (s, 3F);
Example H8: 2-(6-cyclopropyl-3-ethylsulfonyl-2-pyridyl)-3-methyl-6-(trifluoromethylsulfanyl)imidazo[4,5-c]pyridine (Compound P13, Table P)
[0386] ##STR00138##
Step A: Methyl 6-cyclopropyl-3-ethylsulfanyl-pyridine-2-carboxylate
[0387] ##STR00139##
[0388] To a stirred solution of methyl 6-chloro-3-ethylsulfanyl-pyridine-2-carboxylate (462 mg, 2 mmol), cyclopropylboronic acid (344 mg, 4 mmol) in dioxane (25 mL) was added potassium carbonate (552 mg, 4 mmol) and Pd(PPh3)4 (230 mg, 0.2 mmol). The reaction system was refluxed under an nitrogen atmosphere at 120° C. for 24 hours. After cooling to room temperature, the reaction mixture was filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel to give the title compound.
[0389] 1HNMR (400 MHz, CDCl3): δ (ppm) 0.98 (m, 4H), 1.32 (t, 3H), 2.08 (m, 1H), 2.88 (q, 2H), 3.95 (s, 3H), 7.08 (d, J=8.4 Hz, 1H), 7.57 (d, J=8 Hz, 1H); ESI-MS (+): 260 (M+Na)+.
Step B: 6-cyclopropyl-3-ethylsulfanyl-pyridine-2-carboxylic Acid
[0390] ##STR00140##
[0391] To a stirred solution of methyl 6-cyclopropyl-3-ethylsulfanyl-pyridine-2-carboxylate (320 mg, 1.35 mmol) in THF (10 mL) was added NaOH (280 mg, 7 mmol) and H.sub.2O (30 ml). The reaction system was stirred at room temperature for 4 hours. The pH value was adjusted to 2 with HCl., and the reaction mixture extracted with ethyl acetate three times. The combined organic layers dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound.
[0392] 1HNMR (400 MHz, DMSO-d6): δppm 0.93 (m, 4H), 1.18 (t, 3H), 2.07 (m, 1H), 2.91 (q, 2H), 7.36 (d, J=8.0 Hz, 1H), 7.73 (d, J=8.4 Hz, 1H), 12.93 (bs, 1H); ESI-MS (−): 222 (M−H)−.
Step C: 6-bromo-2-(6-cyclopropyl-3-ethylsulfanyl-2-pyridyl)-3-methyl-imidazo[4,5-c]pyridine
[0393] ##STR00141##
[0394] To a stirred solution of 6-cyclopropyl-3-ethylsulfanyl-pyridine-2-carboxylic acid (280 mg, 1.25 mmol), 6-bromo-N3-methyl-pyridine-3,4-diamine (303 mg, 1.5 mmol) and HATU (0.78 g, 2 mmol) in DMF (30 mL) was added DIPEA (2 ml, 10 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was then diluted with ethyl acetate and H.sub.2O, and the organic layer washed with brine, dried over anhydrous sodium sulfate, filtered and concentration in vacuo. The crude product was used for the next step without further purification. A solution of the crude product in acetic acid (20 mL) was refluxed at 120° C. for 24 h. The reaction mixture was concentrated, and purified by column chromatography on silica gel and purified to afford the title compound as white solid.
[0395] 1HNMR (400 MHz, CDCl3): δ (ppm) 1.04 (m, 4H), 1.31 (t, 3H), 2.1 (m, 1H), 2.91 (q, 2H), 3.92 (s, 3H), 7.25 (d, J=8.4 Hz, 1H), 7.66 (d, J=8 Hz, 1H), 7.94 (s, 1H), 8.62 (s, 1H); ESI-MS (+): 413 (M+Na)+.
Step D: 6-bromo-2-(6-cyclopropyl-3-ethylsulfonyl-2-pyridyl)-3-methyl-imidazo[4,5-c]pyridine (Compound P12, Table P)
[0396] ##STR00142##
[0397] A sample of 6-bromo-2-(6-cyclopropyl-3-ethylsulfanyl-2-pyridyl)-3-methyl-imidazo[4,5-c]pyridine (285 mg, 0.73 mmol) and m-CPBA (630 mg, 3.66 mmol) in 40 ml of DCM was stirred at room temperature for 2 hours. Then the mixture was poured into a saturated solution of NaHCO.sub.3 and Na.sub.2SO.sub.3 in water, and extracted with dichloromethane three times. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel to give the title compound.
[0398] LCMS (method 1): 421/423 (M+H.sup.+); retention time: 0.97 min
[0399] 1HNMR (400 MHz, CDCl3): δ (ppm) 1.16 (m, 4H), 1.34 (t, 3H), 2.05 (m, 1H), 3.69 (q, 2H), 3.76 (s, 3H), 7.53 (d, J=8.0 Hz, 1H), 7.86 (s, 1H), 8.30 (d, J=8.4 Hz, 1H), 8.66 (s, 1H);
Step E: 2-(6-cyclopropyl-3-ethylsulfonyl-2-pyridyl)-3-methyl-6-(trifluoromethylsulfanyl)imidazo[4,5-c]pyridine (Compound P13, Table P)
[0400] ##STR00143##
[0401] A sample of (bpy)CuSCF3 (410 mg, 1.28 mmol) and 6-bromo-2-(6-cyclopropyl-3-ethylsulfonyl-2-pyridyl)-3-methyl-imidazo[4,5-c]pyridine (270 mg, 0.64 mmol) in 20 ml of CH3CN was refluxed for 48 hours under nitrogen. The reaction mixture was removed from the oil bath and allowed to cool, and filtered through SiO2, eluting with diethyl ether. The filtrate was washed with brine, and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the title compound.
[0402] LCMS (method 1): 444 (M+H.sup.+); retention time: 1.07 min
[0403] 1HNMR (400 MHz, CDCl3): δ (ppm) 1.19 (m, 4H), 1.34 (t, 3H), 2.12 (m, 1H), 3.71 (q, 2H), 3.81 (s, 3H), 7.54 (d, J=8.4 Hz, 1H), 8.10 (s, 1H), 8.31 (d, J=8.8 Hz, 1H), 8.92 (s, 1H)
Example H9: 6-(6-cyclopropyl-3-ethylsulfanyl-2-pyridyl)-7-methyl-3-(trifluoromethyl)imidazo[4,5-c]pyridazine (Compound P22, Table P)
[0404] ##STR00144##
Step A: 3-chloro-6-iodopyridazine
[0405] ##STR00145##
[0406] Hydriodic acid (250 mL) was added to a mixture of 3, 6-dichloropyridazine (149 g, 1 mol) and NaI (180 g, 1.2 mol) in 500 mL of CHCl.sub.3. After the addition, the mixture was stirred at ambient temperature for 24 h, and poured into water and extracted with dichloromethane three times. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound.
[0407] .sup.1H-NMR (400 Mz, DMSO-d.sub.6) δ: 7.63 (d, 1H), 8.16 (d, 1H).
Step B: 3-chloro-6-(trifluoromethyl)pyridazine
[0408] ##STR00146##
[0409] TMSCF.sub.3 (198.8 g, 1.4 mol) was added to a mixture of 3-chloro-6-iodopyridazine (240 g, 1 mol), KF (81 g, 1.4 mol) and CuI (228 g, 1.2 mol) in 1 L of DMF under nitrogen. After the addition, the mixture was stirred at 50° C. for 2 h. The mixture was then poured into water and extracted with ether (three times). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel to give the title compound.
[0410] .sup.1H-NMR (400 Mz, DMSO-d.sub.6) δ: 8.30 (d, 1H), 8.38 (d, 1H); .sup.19F-NMR (400 Mz, DMSO-d.sub.6) δ: −64.93 (s, 3F).
Step C: N-methyl-6-(trifluoromethyl)pyridazin-3-amine
[0411] ##STR00147##
[0412] A solution of MeNH.sub.2 (100 g, 30% in EtOH) was added to a mixture of 3-chloro-6-(trifluoromethyl) pyridazine (91 g, 0.5 mol) in 100 ml of EtOH. After the addition, the mixture was stirred at 50° C. for 2 hours and then poured into water. The precipitated solid was filtered and dried in vacuum to give the title compound
[0413] .sup.1H-NMR (400 Mz, DMSO-d.sub.6) δ: 2.93 (d, 3H), 6.95 (d, 1H), 7.58 (q, 1H), 7.63 (d, 1H); .sup.19F-NMR (400 Mz, DMSO-d.sub.6) δ: −59.88 (s, 3F); ESI-MS (+): 178 (M+H).sup.+.
Step D: 4-bromo-N-methyl-6-(trifluoromethyl)pyridazin-3-amine
[0414] ##STR00148##
[0415] Bromine (32 g, 0.2 mol) was added to a mixture of N-methyl-6-(trifluoromethyl) pyridazin-3-amine (17.7 g, 0.1 mol) in 100 mL of MeCN. After the addition, the mixture was stirred at ambient temperature for 48 hours. After this time, the mixture was poured into ammonium hydroxide (10% solution) and extracted with ethyl acetate (three times). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel to give the title compound.
[0416] .sup.1H-NMR (400 Mz, DMSO-d.sub.6) δ: 3.03 (d, 3H), 7.45 (q, 1H), 8.23 (s, 1H); .sup.19F-NMR (400 Mz, DMSO-d.sub.6) δ: −59.47 (s, 3F); ESI-MS (+): 256/258 (M+H).sup.+.
Step E: N.SUP.3.-methyl-6-(trifluoromethyl)pyridazine-3,4-diamine
[0417] ##STR00149##
[0418] 4-Bromo-N-methyl-6-(trifluoromethyl)pyridazin-3-amine (3 g, 11.8 mmol) and 120 mL of ammonium hydroxide was placed in a 250 mL autoclave. Then, nitrogen gas was introduced to the autoclave and pressure was increased to 2 MPa. The mixture was stirred at 130° C. for 48 h, poured into water and extracted with ethyl acetate (three times). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give the title compound
[0419] .sup.1H-NMR (400 Mz, DMSO-d.sub.6) δ: 2.97 (d, 3H), 6.27 (s, 2H), 6.50 (q, 1H), 6.67 (s, 1H); .sup.19F-NMR (400 Mz, DMSO-d.sub.6) δ: −61.96 (s, 3F); ESI-MS (+): 193 (M+H).sup.+.
Step F: 6-cyclopropyl-3-ethylsulfanyl-pyridine-2-carbonyl Chloride
[0420] ##STR00150##
[0421] Oxalyl chloride (380 mg, 3 mmol) was added to a mixture of 6-cyclopropyl-3-ethylsulfanyl-pyridine-2-carboxylic acid (223 mg, 1 mmol) in 10 mL of dichloromethane and stirred at room temperature for 30 min. The excess oxalyl chloride and dichloromethane was removed under reduced pressure to give the title compound in almost quantitative yield (241 mg). The crude title compound was directly used for the next step without further purification.
Step G: 6-(6-cyclopropyl-3-ethylsulfanyl-2-pyridyl)-7-methyl-3-(trifluoromethyl)imidazo[4,5-c]pyridazine (Compound P22, Table P)
[0422] ##STR00151##
[0423] A sample of 6-cyclopropyl-3-ethylsulfanyl-pyridine-2-carbonyl chloride (241 mg, 1 mmol) was added to a mixture of N3-methyl-6-(trifluoromethyl) pyridazine-3,4-diamine (211 mg, 1.1 mmol) in 20 mL of THF and the mixture was reflux for 48 hours. After this time, the mixture was poured into water and extracted with ethyl acetate three times. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel to give the title compound.
[0424] 1H NMR (400 MHz, DMSO) δ 0.97-1.00 (m, 2H), 1.02-1.07 (m, 2H), 1.19 (t, 3H), 2.22-2.28 (m, 1H), 2.98 (q, 2H), 4.08 (s, 3H), 7.58 (d, 1H), 7.98 (d, 1H), 8.71 (s, 1H); 19F NMR (400 MHz, DMSO) δ −62.23 (s, 3F); ESI-MS (+): 380 (M+H)+, 434 (M+Na+MeOH)+.
Example H10: 6-(6-cyclopropyl-3-ethylsulfonyl-2-pyridyl)-7-methyl-3-(trifluoromethyl)imidazo[4,5-c]pyridazine (Compound P14, Table P)
[0425] ##STR00152##
[0426] A solution of 6-(6-cyclopropyl-3-ethylsulfanyl-2-pyridyl)-7-methyl-3-(trifluoromethyl)imidazo[4,5-c]pyridazine (70 mg, 0.18 mmol) and m-CPBA (93 mg, 0.54 mmol) in 10 ml of dichloromethane was stirred at room temperature for 2 hours. The mixture was then poured into a saturated solution of NaHCO.sub.3 and Na.sub.2SO.sub.3 in water, and extracted with ethyl acetate three times. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel to give the title compound.
[0427] LCMS (method 1): 413 (M+H.sup.+); retention time: 1.01 min.
[0428] 1H NMR (400 MHz, DMSO-d6) δ 1.05-1.07 (m, 2H), 1.13-1.18 (m, 2H), 1.15 (t, 3H), 2.38-2.42 (m, 1H), 3.63 (q, 2H), 3.88 (s, 3H), 7.88 (d, 1H), 8.34 (d, 1H), 8.72 (s, 1H); 19F-NMR (400 Mz, DMSO-d6) δ: −64.55 (s, 3F);
Example H11: 2-[5-ethylsulfonyl-6-[3-methyl-6-(trifluoromethyl)imidazo[4,5-c]pyridin-2-yl]-2-pyridyl]acetonitrile (Compound P23, Table P)
[0429] ##STR00153##
[0430] In a microwave vial 2-(6-chloro-3-ethylsulfonyl-2-pyridyl)-3-methyl-6-(trifluoromethyl)imidazo[4,5-c]pyridine (0.20 g, 0.49 mmol) was dissolved in DMF (1.0 mL). The vial was flushed with argon and TMSCN (0.10 mL, 0.74 mmol), difluorozinc (0.031 g, 0.30 mmol), Pd.sub.2(dba).sub.3 (0.0091 g, 0.0099 mmol) and XANTPHOS (0.012 g, 0.020 mmol) were added. The vial was capped and heated in the microwave at 140° C. for 30 min. The reaction mixture was diluted with ethyl acetate and filtered over hyflo. The filtrate was extracted with water and brine, dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel to give the title compound.
[0431] LCMS (method 1): 410 (M+H+); retention time: 0.84 min.
[0432] 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.40 (t, J=7.52 Hz, 3H) 3.83 (q, J=7.34 Hz, 2H) 3.97 (s, 3H) 4.17 (s, 2H) 7.89 (d, J=8.44 Hz, 1H) 8.15 (s, 1H) 8.63 (d, J=8.07 Hz, 1H) 9.04 (s, 1H)
Example H12: 1-[5-ethylsulfonyl-6-[3-methyl-6-(trifluoromethyl)imidazo[4,5-c]pyridin-2-yl]-2-pyridyl]cyclopropanecarbonitrile (Compound P17, Table P)
[0433] ##STR00154##
[0434] A sample of 2-[5-ethylsulfonyl-6-[3-methyl-6-(trifluoromethyl)imidazo[4,5-c]pyridin-2-yl]-2-pyridyl]acetonitrile (0.11 g, 0.27 mmol) was dissolved in acetonitrile (2.8 mL). Cesium carbonate (0.27 g, 0.81 mmol) was added followed by adding 1,2-dibromoethane (0.047 mL, 0.54 mmol). The mixture was stirred at 80° C. for 1 hour. LC-MS analysis showed consumption of the starting material and mass of desired product. The reaction was quenched with water and acetonitrile and the evaporated. The residue was diluted with ethyl acetate washed with water and brine, dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel to give the title compound
[0435] LCMS (method 1): 436 (M+H+); retention time: 0.94 min.
[0436] 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.38 (t, J=7.52 Hz, 3H) 1.88-2.02 (m, 4H) 3.73 (d, J=7.70 Hz, 2H) 3.86 (s, 3H) 8.12-8.19 (m, 2H) 8.54 (d, J=8.44 Hz, 1H) 9.02 (s, 1H)
Example H13: 2-[3-ethylsulfonyl-6-[2-(3-fluorophenyl)ethynyl]-2-pyridyl]-3-methyl-6-(trifluoromethyl)imidazo[4,5-c]pyridine (Compound P20, Table P)
[0437] ##STR00155##
[0438] A sample of 2-(6-chloro-3-ethylsulfonyl-2-pyridyl)-3-methyl-6-(trifluoromethyl)imidazo[4,5-c]pyridine (0.10 g, 0.25 mmol), 1-ethynyl-3-fluoro-benzene (0.044 mL, 0.37 mmol), DIPEA (0.086 mL, 0.49 mmol), copper(I)iodide (0.0024 g, 0.012 mmol) in tetrahydrofurane (4.0 mL) were mixed in a vial and the clear, pale yellow solution was flushed with argon. PdCl.sub.2(PPH.sub.3).sub.2 (0.0088 g, 0.012 mmol) was added and the mixture was stirred at room temperature overnight. Reaction after this time showed completion. The crude mixture was purified by flash chromatography to give the title compound as a beige solid.
[0439] LCMS (method 1): 489 (M+H.sup.+); retention time: 1.11 min.
[0440] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.39 (t, J=7.34 Hz, 3H) 3.78 (q, J=7.46 Hz, 2H) 3.96 (s, 3H) 7.14-7.24 (m, 1H) 7.32-7.38 (m, 1H) 7.37-7.48 (m, 2H) 7.92 (d, J=8.44 Hz, 1H) 8.14 (s, 1H) 8.54 (d, J=8.44 Hz, 1H) 9.02 (s, 1H)
[0441] Compounds in tables 1-88 can be prepared analogously to the methods described above.
TABLE-US-00012 TABLE P Examples of compounds of formula (I) Compound Melting No. Compound Point MS/NMR P1
[0442] The activity of the compositions according to the invention can be broadened considerably, and adapted to prevailing circumstances, by adding other insecticidally, acaricidally and/or fungicidally active ingredients. The mixtures of the compounds of formula I with other insecticidally, acaricidally and/or fungicidally active ingredients may also have further surprising advantages which can also be described, in a wider sense, as synergistic activity. For example, better tolerance by plants, reduced phytotoxicity, insects can be controlled in their different development stages or better behaviour during their production, for example during grinding or mixing, during their storage or during their use. Suitable additions to active ingredients here are, for example, representatives of the following classes of active ingredients: organophosphorus compounds, nitrophenol derivatives, thioureas, juvenile hormones, formamidines, benzophenone derivatives, ureas, pyrrole derivatives, carbamates, pyrethroids, chlorinated hydrocarbons, acylureas, pyridylmethyleneamino derivatives, macrolides, neonicotinoids and Bacillus thuringiensis preparations.
[0443] The following mixtures of the compounds of formula I with active ingredients are preferred (the abbreviation “TX” means “one compound selected from the group consisting of the compounds described in Tables 1 to 88 and P of the present invention”):
an adjuvant selected from the group of substances consisting of petroleum oils (628)+TX, an acaricide selected from the group of substances consisting of 1,1-bis(4-chlorophenyl)-2-ethoxyethanol (IUPAC name) (910)+TX, 2,4-dichlorophenyl benzenesulfonate (IUPAC/Chemical Abstracts name) (1059)+TX, 2-fluoro-N-methyl-N-1-naphthylacetamide (IUPAC name) (1295)+TX, 4-chlorophenyl phenyl sulfone (IUPAC name) (981)+TX, abamectin (1)+TX, acequinocyl (3)+TX, acetoprole [CCN]+TX, acrinathrin (9)+TX, aldicarb (16)+TX, aldoxycarb (863)+TX, alpha-cypermethrin (202)+TX, amidithion (870)+TX, amidoflumet [CCN]+TX, amidothioate (872)+TX, amiton (875)+TX, amiton hydrogen oxalate (875)+TX, amitraz (24)+TX, aramite (881)+TX, arsenous oxide (882)+TX, AVI 382 (compound code)+TX, AZ 60541 (compound code)+TX, azinphos-ethyl (44)+TX, azinphos-methyl (45)+TX, azobenzene (IUPAC name) (888)+TX, azocyclotin (46)+TX, azothoate (889)+TX, benomyl (62)+TX, benoxafos [CCN]+TX, benzoximate (71)+TX, benzyl benzoate (IUPAC name) [CCN]+TX, bifenazate (74)+TX, bifenthrin (76)+TX, binapacryl (907)+TX, brofenvalerate+TX, bromocyclen (918)+TX, bromophos (920)+TX, bromophos-ethyl (921)+TX, bromopropylate (94)+TX, buprofezin (99)+TX, butocarboxim (103)+TX, butoxycarboxim (104)+TX, butylpyridaben+TX, calcium polysulfide (IUPAC name) (111)+TX, camphechlor (941)+TX, carbanolate (943)+TX, carbaryl (115)+TX, carbofuran (118)+TX, carbophenothion (947)+TX, CGA 50'439 (development code) (125)+TX, chinomethionat (126)+TX, chlorbenside (959)+TX, chlordimeform (964)+TX, chlordimeform hydrochloride (964)+TX, chlorfenapyr (130)+TX, chlorfenethol (968)+TX, chlorfenson (970)+TX, chlorfensulfide (971)+TX, chlorfenvinphos (131)+TX, chlorobenzilate (975)+TX, chloromebuform (977)+TX, chloromethiuron (978)+TX, chloropropylate (983)+TX, chlorpyrifos (145)+TX, chlorpyrifos-methyl (146)+TX, chlorthiophos (994)+TX, cinerin I (696)+TX, cinerin II (696)+TX, cinerins (696)+TX, clofentezine (158)+TX, closantel [CCN]+TX, coumaphos (174)+TX, crotamiton [CCN]+TX, crotoxyphos (1010)+TX, cufraneb (1013)+TX, cyanthoate (1020)+TX, cyflumetofen (CAS Reg. No.: 400882-07-7)+TX, cyhalothrin (196)+TX, cyhexatin (199)+TX, cypermethrin (201)+TX, DCPM (1032)+TX, DDT (219)+TX, demephion (1037)+TX, demephion-O (1037)+TX, demephion-S (1037)+TX, demeton (1038)+TX, demeton-methyl (224)+TX, demeton-O (1038)+TX, demeton-O-methyl (224)+TX, demeton-S (1038)+TX, demeton-S-methyl (224)+TX, demeton-S-methylsulfon (1039)+TX, diafenthiuron (226)+TX, dialifos (1042)+TX, diazinon (227)+TX, dichlofluanid (230)+TX, dichlorvos (236)+TX, dicliphos+TX, dicofol (242)+TX, dicrotophos (243)+TX, dienochlor (1071)+TX, dimefox (1081)+TX, dimethoate (262)+TX, dinactin (653)+TX, dinex (1089)+TX, dinex-diclexine (1089)+TX, dinobuton (269)+TX, dinocap (270)+TX, dinocap-4 [CCN]+TX, dinocap-6 [CCN]+TX, dinocton (1090)+TX, dinopenton (1092)+TX, dinosulfon (1097)+TX, dinoterbon (1098)+TX, dioxathion (1102)+TX, diphenyl sulfone (IUPAC name) (1103)+TX, disulfiram [CCN]+TX, disulfoton (278)+TX, DNOC (282)+TX, dofenapyn (1113)+TX, doramectin [CCN]+TX, endosulfan (294)+TX, endothion (1121)+TX, EPN (297)+TX, eprinomectin [CCN]+TX, ethion (309)+TX, ethoate-methyl (1134)+TX, etoxazole (320)+TX, etrimfos (1142)+TX, fenazaflor (1147)+TX, fenazaquin (328)+TX, fenbutatin oxide (330)+TX, fenothiocarb (337)+TX, fenpropathrin (342)+TX, fenpyrad+TX, fenpyroximate (345)+TX, fenson (1157)+TX, fentrifanil (1161)+TX, fenvalerate (349)+TX, fipronil (354)+TX, fluacrypyrim (360)+TX, fluazuron (1166)+TX, flubenzimine (1167)+TX, flucycloxuron (366)+TX, flucythrinate (367)+TX, fluenetil (1169)+TX, flufenoxuron (370)+TX, flumethrin (372)+TX, fluorbenside (1174)+TX, fluvalinate (1184)+TX, FMC 1137 (development code) (1185)+TX, formetanate (405)+TX, formetanate hydrochloride (405)+TX, formothion (1192)+TX, formparanate (1193)+TX, gamma-HCH (430)+TX, glyodin (1205)+TX, halfenprox (424)+TX, heptenophos (432)+TX, hexadecyl cyclopropanecarboxylate (IUPAC/Chemical Abstracts name) (1216)+TX, hexythiazox (441)+TX, iodomethane (IUPAC name) (542)+TX, isocarbophos (473)+TX, isopropyl O-(methoxyaminothiophosphoryl)salicylate (IUPAC name) (473)+TX, ivermectin [CCN]+TX, jasmolin I (696)+TX, jasmolin II (696)+TX, jodfenphos (1248)+TX, lindane (430)+TX, lufenuron (490)+TX, malathion (492)+TX, malonoben (1254)+TX, mecarbam (502)+TX, mephosfolan (1261)+TX, mesulfen [CCN]+TX, methacrifos (1266)+TX, methamidophos (527)+TX, methidathion (529)+TX, methiocarb (530)+TX, methomyl (531)+TX, methyl bromide (537)+TX, metolcarb (550)+TX, mevinphos (556)+TX, mexacarbate (1290)+TX, milbemectin (557)+TX, milbemycin oxime [CCN]+TX, mipafox (1293)+TX, monocrotophos (561)+TX, morphothion (1300)+TX, moxidectin [CCN]+TX, naled (567)+TX, NC-184 (compound code)+TX, NC-512 (compound code)+TX, nifluridide (1309)+TX, nikkomycins [CCN]+TX, nitrilacarb (1313)+TX, nitrilacarb 1:1 zinc chloride complex (1313)+TX, NNI-0101 (compound code)+TX, NNI-0250 (compound code)+TX, omethoate (594)+TX, oxamyl (602)+TX, oxydeprofos (1324)+TX, oxydisulfoton (1325)+TX, pp′-DDT (219)+TX, parathion (615)+TX, permethrin (626)+TX, petroleum oils (628)+TX, phenkapton (1330)+TX, phenthoate (631)+TX, phorate (636)+TX, phosalone (637)+TX, phosfolan (1338)+TX, phosmet (638)+TX, phosphamidon (639)+TX, phoxim (642)+TX, pirimiphos-methyl (652)+TX, polychloroterpenes (traditional name) (1347)+TX, polynactins (653)+TX, proclonol (1350)+TX, profenofos (662)+TX, promacyl (1354)+TX, propargite (671)+TX, propetamphos (673)+TX, propoxur (678)+TX, prothidathion (1360)+TX, prothoate (1362)+TX, pyrethrin I (696)+TX, pyrethrin II (696)+TX, pyrethrins (696)+TX, pyridaben (699)+TX, pyridaphenthion (701)+TX, pyrimidifen (706)+TX, pyrimitate (1370)+TX, quinalphos (711)+TX, quintiofos (1381)+TX, R-1492 (development code) (1382)+TX, RA-17 (development code) (1383)+TX, rotenone (722)+TX, schradan (1389)+TX, sebufos+TX, selamectin [CCN]+TX, SI-0009 (compound code)+TX, sophamide (1402)+TX, spirodiclofen (738)+TX, spiromesifen (739)+TX, SSI-121 (development code) (1404)+TX, sulfiram [CCN]+TX, sulfluramid (750)+TX, sulfotep (753)+TX, sulfur (754)+TX, SZI-121 (development code) (757)+TX, tau-fluvalinate (398)+TX, tebufenpyrad (763)+TX, TEPP (1417)+TX, terbam+TX, tetrachlorvinphos (777)+TX, tetradifon (786)+TX, tetranactin (653)+TX, tetrasul (1425)+TX, thiafenox+TX, thiocarboxime (1431)+TX, thiofanox (800)+TX, thiometon (801)+TX, thioquinox (1436)+TX, thuringiensin [CCN]+TX, triamiphos (1441)+TX, triarathene (1443)+TX, triazophos (820)+TX, triazuron+TX, trichlorfon (824)+TX, trifenofos (1455)+TX, trinactin (653)+TX, vamidothion (847)+TX, vaniliprole [CCN] and YI-5302 (compound code)+TX,
an algicide selected from the group of substances consisting of bethoxazin [CCN]+TX, copper dioctanoate (IUPAC name) (170)+TX, copper sulfate (172)+TX, cybutryne [CCN]+TX, dichlone (1052)+TX, dichlorophen (232)+TX, endothal (295)+TX, fentin (347)+TX, hydrated lime [CCN]+TX, nabam (566)+TX, quinoclamine (714)+TX, quinonamid (1379)+TX, simazine (730)+TX, triphenyltin acetate (IUPAC name) (347) and triphenyltin hydroxide (IUPAC name) (347)+TX,
an anthelmintic selected from the group of substances consisting of abamectin (1)+TX, crufomate (1011)+TX, doramectin [CCN]+TX, emamectin (291)+TX, emamectin benzoate (291)+TX, eprinomectin [CCN]+TX, ivermectin [CCN]+TX, milbemycin oxime [CCN]+TX, moxidectin [CCN]+TX, piperazine [CCN]+TX, selamectin [CCN]+TX, spinosad (737) and thiophanate (1435)+TX,
an avicide selected from the group of substances consisting of chloralose (127)+TX, endrin (1122)+TX, fenthion (346)+TX, pyridin-4-amine (IUPAC name) (23) and strychnine (745)+TX,
a bactericide selected from the group of substances consisting of 1-hydroxy-1H-pyridine-2-thione (IUPAC name) (1222)+TX, 4-(quinoxalin-2-ylamino)benzenesulfonamide (IUPAC name) (748)+TX, 8-hydroxyquinoline sulfate (446)+TX, bronopol (97)+TX, copper dioctanoate (IUPAC name) (170)+TX, copper hydroxide (IUPAC name) (169)+TX, cresol [CCN]+TX, dichlorophen (232)+TX, dipyrithione (1105)+TX, dodicin (1112)+TX, fenaminosulf (1144)+TX, formaldehyde (404)+TX, hydrargaphen [CCN]+TX, kasugamycin (483)+TX, kasugamycin hydrochloride hydrate (483)+TX, nickel bis(dimethyldithiocarbamate) (IUPAC name) (1308)+TX, nitrapyrin (580)+TX, octhilinone (590)+TX, oxolinic acid (606)+TX, oxytetracycline (611)+TX, potassium hydroxyquinoline sulfate (446)+TX, probenazole (658)+TX, streptomycin (744)+TX, streptomycin sesquisulfate (744)+TX, tecloftalam (766)+TX, and thiomersal [CCN]+TX,
a biological agent selected from the group of substances consisting of Adoxophyes orana GV (12)+TX, Agrobacterium radiobacter (13)+TX, Amblyseius spp. (19)+TX, Anagrapha falcifera NPV (28)+TX, Anagrus atomus (29)+TX, Aphelinus abdominalis (33)+TX, Aphidius colemani (34)+TX, Aphidoletes aphidimyza (35)+TX, Autographa californica NPV (38)+TX, Bacillus firmus (48)+TX, Bacillus sphaericus Neide (scientific name) (49)+TX, Bacillus thuringiensis Berliner (scientific name) (51)+TX, Bacillus thuringiensis subsp. aizawai (scientific name) (51)+TX, Bacillus thuringiensis subsp. israelensis (scientific name) (51)+TX, Bacillus thuringiensis subsp. japonensis (scientific name) (51)+TX, Bacillus thuringiensis subsp. kurstaki (scientific name) (51)+TX, Bacillus thuringiensis subsp. tenebrionis (scientific name) (51)+TX, Beauveria bassiana (53)+TX, Beauveria brongniartii (54)+TX, Chrysoperla carnea (151)+TX, Cryptolaemus montrouzieri (178)+TX, Cydia pomonella GV (191)+TX, Dacnusa sibirica (212)+TX, Diglyphus isaea (254)+TX, Encarsia formosa (scientific name) (293)+TX, Eretmocerus eremicus (300)+TX, Helicoverpa zea NPV (431)+TX, Heterorhabditis bacteriophora and H. megidis (433)+TX, Hippodamia convergens (442)+TX, Leptomastix dactylopii (488)+TX, Macrolophus caliginosus (491)+TX, Mamestra brassicae NPV (494)+TX, Metaphycus helvolus (522)+TX, Metarhizium anisopliae var. acridum (scientific name) (523)+TX, Metarhizium anisopliae var. anisopliae (scientific name) (523)+TX, Neodiprion sertifer NPV and N. lecontei NPV (575)+TX, Orius spp. (596)+TX, Paecilomyces fumosoroseus (613)+TX, Phytoseiulus persimilis (644)+TX, Spodoptera exigua multicapsid nuclear polyhedrosis virus (scientific name) (741)+TX, Steinernema bibionis (742)+TX, Steinernema carpocapsae (742)+TX, Steinernema feltiae (742)+TX, Steinernema glaseri (742)+TX, Steinernema riobrave (742)+TX, Steinernema riobravis (742)+TX, Steinernema scapterisci (742)+TX, Steinernema spp. (742)+TX, Trichogramma spp. (826)+TX, Typhlodromus occidentalis (844) and Verticillium lecanii (848)+TX,
a soil sterilant selected from the group of substances consisting of iodomethane (IUPAC name) (542) and methyl bromide (537)+TX,
a chemosterilant selected from the group of substances consisting of apholate [CCN]+TX, bisazir [CCN]+TX, busulfan [CCN]+TX, diflubenzuron (250)+TX, dimatif [CCN]+TX, hemel [CCN]+TX, hempa [CCN]+TX, metepa [CCN]+TX, methiotepa [CCN]+TX, methyl apholate [CCN]+TX, morzid [CCN]+TX, penfluron [CCN]+TX, tepa [CCN]+TX, thiohempa [CCN]+TX, thiotepa [CCN]+TX, tretamine [CCN] and uredepa [CCN]+TX,
an insect pheromone selected from the group of substances consisting of (E)-dec-5-en-1-yl acetate with (E)-dec-5-en-1-ol (IUPAC name) (222)+TX, (E)-tridec-4-en-1-yl acetate (IUPAC name) (829)+TX, (E)-6-methylhept-2-en-4-ol (IUPAC name) (541)+TX, (E,Z)-tetradeca-4,10-dien-1-yl acetate (IUPAC name) (779)+TX, (Z)-dodec-7-en-1-yl acetate (IUPAC name) (285)+TX, (Z)-hexadec-11-enal (IUPAC name) (436)+TX, (Z)-hexadec-11-en-1-yl acetate (IUPAC name) (437)+TX, (Z)-hexadec-13-en-11-yn-1-yl acetate (IUPAC name) (438)+TX, (Z)-icos-13-en-10-one (IUPAC name) (448)+TX, (Z)-tetradec-7-en-1-al (IUPAC name) (782)+TX, (Z)-tetradec-9-en-1-ol (IUPAC name) (783)+TX, (Z)-tetradec-9-en-1-yl acetate (IUPAC name) (784)+TX, (7E,9Z)-dodeca-7,9-dien-1-yl acetate (IUPAC name) (283)+TX, (9Z,11E)-tetradeca-9,11-dien-1-yl acetate (IUPAC name) (780)+TX, (9Z,12E)-tetradeca-9,12-dien-1-yl acetate (IUPAC name) (781)+TX, 14-methyloctadec-1-ene (IUPAC name) (545)+TX, 4-methylnonan-5-ol with 4-methylnonan-5-one (IUPAC name) (544)+TX, alpha-multistriatin [CCN]+TX, brevicomin [CCN]+TX, codlelure [CCN]+TX, codlemone (167)+TX, cuelure (179)+TX, disparlure (277)+TX, dodec-8-en-1-yl acetate (IUPAC name) (286)+TX, dodec-9-en-1-yl acetate (IUPAC name) (287)+TX, dodeca-8+TX, 10-dien-1-yl acetate (IUPAC name) (284)+TX, dominicalure [CCN]+TX, ethyl 4-methyloctanoate (IUPAC name) (317)+TX, eugenol [CCN]+TX, frontalin [CCN]+TX, gossyplure (420)+TX, grandlure (421)+TX, grandlure I (421)+TX, grandlure II (421)+TX, grandlure III (421)+TX, grandlure IV (421)+TX, hexalure [CCN]+TX, ipsdienol [CCN]+TX, ipsenol [CCN]+TX, japonilure (481)+TX, lineatin [CCN]+TX, litlure [CCN]+TX, looplure [CCN]+TX, medlure [CCN]+TX, megatomoic acid [CCN]+TX, methyl eugenol (540)+TX, muscalure (563)+TX, octadeca-2,13-dien-1-yl acetate (IUPAC name) (588)+TX, octadeca-3,13-dien-1-yl acetate (IUPAC name) (589)+TX, orfralure [CCN]+TX, oryctalure (317)+TX, ostramone [CCN]+TX, siglure [CCN]+TX, sordidin (736)+TX, sulcatol [CCN]+TX, tetradec-11-en-1-yl acetate (IUPAC name) (785)+TX, trimedlure (839)+TX, trimedlure A (839)+TX, trimedlure B.sub.1 (839)+TX, trimedlure B.sub.2 (839)+TX, trimedlure C (839) and trunc-call [CCN]+TX,
an insect repellent selected from the group of substances consisting of 2-(octylthio)ethanol (IUPAC name) (591)+TX, butopyronoxyl (933)+TX, butoxy(polypropylene glycol) (936)+TX, dibutyl adipate (IUPAC name) (1046)+TX, dibutyl phthalate (1047)+TX, dibutyl succinate (IUPAC name) (1048)+TX, diethyltoluamide [CCN]+TX, dimethyl carbate [CCN]+TX, dimethyl phthalate [CCN]+TX, ethyl hexanediol (1137)+TX, hexamide [CCN]+TX, methoquin-butyl (1276)+TX, methylneodecanamide [CCN]+TX, oxamate [CCN] and picaridin [CCN]+TX,
an insecticide selected from the group of substances consisting of 1-dichloro-1-nitroethane (IUPAC/Chemical Abstracts name) (1058)+TX, 1,1-dichloro-2,2-bis(4-ethylphenyl)ethane (IUPAC name) (1056), +TX, 1,2-dichloropropane (IUPAC/Chemical Abstracts name) (1062)+TX, 1,2-dichloropropane with 1,3-dichloropropene (IUPAC name) (1063)+TX, 1-bromo-2-chloroethane (IUPAC/Chemical Abstracts name) (916)+TX, 2,2,2-trichloro-1-(3,4-dichlorophenyl)ethyl acetate (IUPAC name) (1451)+TX, 2,2-dichlorovinyl 2-ethylsulfinylethyl methyl phosphate (IUPAC name) (1066)+TX, 2-(1,3-dithiolan-2-yl)phenyl dimethylcarbamate (IUPAC/Chemical Abstracts name) (1109)+TX, 2-(2-butoxyethoxy)ethyl thiocyanate (IUPAC/Chemical Abstracts name) (935)+TX, 2-(4,5-dimethyl-1,3-dioxolan-2-yl)phenyl methylcarbamate (IUPAC/Chemical Abstracts name) (1084)+TX, 2-(4-chloro-3,5-xylyloxy)ethanol (IUPAC name) (986)+TX, 2-chlorovinyl diethyl phosphate (IUPAC name) (984)+TX, 2-imidazolidone (IUPAC name) (1225)+TX, 2-isovalerylindan-1,3-dione (IUPAC name) (1246)+TX, 2-methyl(prop-2-ynyl)aminophenyl methylcarbamate (IUPAC name) (1284)+TX, 2-thiocyanatoethyl laurate (IUPAC name) (1433)+TX, 3-bromo-1-chloroprop-1-ene (IUPAC name) (917)+TX, 3-methyl-1-phenylpyrazol-5-yl dimethylcarbamate (IUPAC name) (1283)+TX, 4-methyl(prop-2-ynyl)amino-3,5-xylyl methylcarbamate (IUPAC name) (1285)+TX, 5,5-dimethyl-3-oxocyclohex-1-enyl dimethylcarbamate (IUPAC name) (1085)+TX, abamectin (1)+TX, acephate (2)+TX, acetamiprid (4)+TX, acethion [CCN]+TX, acetoprole [CCN]+TX, acrinathrin (9)+TX, acrylonitrile (IUPAC name) (861)+TX, alanycarb (15)+TX, aldicarb (16)+TX, aldoxycarb (863)+TX, aldrin (864)+TX, allethrin (17)+TX, allosamidin [CCN]+TX, allyxycarb (866)+TX, alpha-cypermethrin (202)+TX, alpha-ecdysone [CCN]+TX, aluminium phosphide (640)+TX, amidithion (870)+TX, amidothioate (872)+TX, aminocarb (873)+TX, amiton (875)+TX, amiton hydrogen oxalate (875)+TX, amitraz (24)+TX, anabasine (877)+TX, athidathion (883)+TX, AVI 382 (compound code)+TX, AZ 60541 (compound code)+TX, azadirachtin (41)+TX, azamethiphos (42)+TX, azinphos-ethyl (44)+TX, azinphos-methyl (45)+TX, azothoate (889)+TX, Bacillus thuringiensis delta endotoxins (52)+TX, barium hexafluorosilicate [CCN]+TX, barium polysulfide (IUPAC/Chemical Abstracts name) (892)+TX, barthrin [CCN]+TX, Bayer 22/190 (development code) (893)+TX, Bayer 22408 (development code) (894)+TX, bendiocarb (58)+TX, benfuracarb (60)+TX, bensultap (66)+TX, beta-cyfluthrin (194)+TX, beta-cypermethrin (203)+TX, bifenthrin (76)+TX, bioallethrin (78)+TX, bioallethrin S-cyclopentenyl isomer (79)+TX, bioethanomethrin [CCN]+TX, biopermethrin (908)+TX, bioresmethrin (80)+TX, bis(2-chloroethyl) ether (IUPAC name) (909)+TX, bistrifluron (83)+TX, borax (86)+TX, brofenvalerate+TX, bromfenvinfos (914)+TX, bromocyclen (918)+TX, bromo-DDT [CCN]+TX, bromophos (920)+TX, bromophos-ethyl (921)+TX, bufencarb (924)+TX, buprofezin (99)+TX, butacarb (926)+TX, butathiofos (927)+TX, butocarboxim (103)+TX, butonate (932)+TX, butoxycarboxim (104)+TX, butylpyridaben+TX, cadusafos (109)+TX, calcium arsenate [CCN]+TX, calcium cyanide (444)+TX, calcium polysulfide (IUPAC name) (111)+TX, camphechlor (941)+TX, carbanolate (943)+TX, carbaryl (115)+TX, carbofuran (118)+TX, carbon disulfide (IUPAC/Chemical Abstracts name) (945)+TX, carbon tetrachloride (IUPAC name) (946)+TX, carbophenothion (947)+TX, carbosulfan (119)+TX, cartap (123)+TX, cartap hydrochloride (123)+TX, cevadine (725)+TX, chlorbicyclen (960)+TX, chlordane (128)+TX, chlordecone (963)+TX, chlordimeform (964)+TX, chlordimeform hydrochloride (964)+TX, chlorethoxyfos (129)+TX, chlorfenapyr (130)+TX, chlorfenvinphos (131)+TX, chlorfluazuron (132)+TX, chlormephos (136)+TX, chloroform [CCN]+TX, chloropicrin (141)+TX, chlorphoxim (989)+TX, chlorprazophos (990)+TX, chlorpyrifos (145)+TX, chlorpyrifos-methyl (146)+TX, chlorthiophos (994)+TX, chromafenozide (150)+TX, cinerin I (696)+TX, cinerin II (696)+TX, cinerins (696)+TX, cis-resmethrin+TX, cismethrin (80)+TX, clocythrin+TX, cloethocarb (999)+TX, closantel [CCN]+TX, clothianidin (165)+TX, copper acetoarsenite [CCN]+TX, copper arsenate [CCN]+TX, copper oleate [CCN]+TX, coumaphos (174)+TX, coumithoate (1006)+TX, crotamiton [CCN]+TX, crotoxyphos (1010)+TX, crufomate (1011)+TX, cryolite (177)+TX, CS 708 (development code) (1012)+TX, cyanofenphos (1019)+TX, cyanophos (184)+TX, cyanthoate (1020)+TX, cyclethrin [CCN]+TX, cycloprothrin (188)+TX, cyfluthrin (193)+TX, cyhalothrin (196)+TX, cypermethrin (201)+TX, cyphenothrin (206)+TX, cyromazine (209)+TX, cythioate [CCN]+TX, d-limonene [CCN]+TX, d-tetramethrin (788)+TX, DAEP (1031)+TX, dazomet (216)+TX, DDT (219)+TX, decarbofuran (1034)+TX, deltamethrin (223)+TX, demephion (1037)+TX, demephion-O (1037)+TX, demephion-S (1037)+TX, demeton (1038)+TX, demeton-methyl (224)+TX, demeton-O (1038)+TX, demeton-O-methyl (224)+TX, demeton-S (1038)+TX, demeton-S-methyl (224)+TX, demeton-S-methylsulphon (1039)+TX, diafenthiuron (226)+TX, dialifos (1042)+TX, diamidafos (1044)+TX, diazinon (227)+TX, dicapthon (1050)+TX, dichlofenthion (1051)+TX, dichlorvos (236)+TX, dicliphos+TX, dicresyl [CCN]+TX, dicrotophos (243)+TX, dicyclanil (244)+TX, dieldrin (1070)+TX, diethyl 5-methylpyrazol-3-yl phosphate (IUPAC name) (1076)+TX, diflubenzuron (250)+TX, dilor [CCN]+TX, dimefluthrin [CCN]+TX, dimefox (1081)+TX, dimetan (1085)+TX, dimethoate (262)+TX, dimethrin (1083)+TX, dimethylvinphos (265)+TX, dimetilan (1086)+TX, dinex (1089)+TX, dinex-diclexine (1089)+TX, dinoprop (1093)+TX, dinosam (1094)+TX, dinoseb (1095)+TX, dinotefuran (271)+TX, diofenolan (1099)+TX, dioxabenzofos (1100)+TX, dioxacarb (1101)+TX, dioxathion (1102)+TX, disulfoton (278)+TX, dithicrofos (1108)+TX, DNOC (282)+TX, doramectin [CCN]+TX, DSP (1115)+TX, ecdysterone [CCN]+TX, EI 1642 (development code) (1118)+TX, emamectin (291)+TX, emamectin benzoate (291)+TX, EMPC (1120)+TX, empenthrin (292)+TX, endosulfan (294)+TX, endothion (1121)+TX, endrin (1122)+TX, EPBP (1123)+TX, EPN (297)+TX, epofenonane (1124)+TX, eprinomectin [CCN]+TX, esfenvalerate (302)+TX, etaphos [CCN]+TX, ethiofencarb (308)+TX, ethion (309)+TX, ethiprole (310)+TX, ethoate-methyl (1134)+TX, ethoprophos (312)+TX, ethyl formate (IUPAC name) [CCN]+TX, ethyl-DDD (1056)+TX, ethylene dibromide (316)+TX, ethylene dichloride (chemical name) (1136)+TX, ethylene oxide [CCN]+TX, etofenprox (319)+TX, etrimfos (1142)+TX, EXD (1143)+TX, famphur (323)+TX, fenamiphos (326)+TX, fenazaflor (1147)+TX, fenchlorphos (1148)+TX, fenethacarb (1149)+TX, fenfluthrin (1150)+TX, fenitrothion (335)+TX, fenobucarb (336)+TX, fenoxacrim (1153)+TX, fenoxycarb (340)+TX, fenpirithrin (1155)+TX, fenpropathrin (342)+TX, fenpyrad+TX, fensulfothion (1158)+TX, fenthion (346)+TX, fenthion-ethyl [CCN]+TX, fenvalerate (349)+TX, fipronil (354)+TX, flonicamid (358)+TX, flubendiamide (CAS. Reg. No.: 272451-65-7)+TX, flucofuron (1168)+TX, flucycloxuron (366)+TX, flucythrinate (367)+TX, fluenetil (1169)+TX, flufenerim [CCN]+TX, flufenoxuron (370)+TX, flufenprox (1171)+TX, flumethrin (372)+TX, fluvalinate (1184)+TX, FMC 1137 (development code) (1185)+TX, fonofos (1191)+TX, formetanate (405)+TX, formetanate hydrochloride (405)+TX, formothion (1192)+TX, formparanate (1193)+TX, fosmethilan (1194)+TX, fospirate (1195)+TX, fosthiazate (408)+TX, fosthietan (1196)+TX, furathiocarb (412)+TX, furethrin (1200)+TX, gamma-cyhalothrin (197)+TX, gamma-HCH (430)+TX, guazatine (422)+TX, guazatine acetates (422)+TX, GY-81 (development code) (423)+TX, halfenprox (424)+TX, halofenozide (425)+TX, HCH (430)+TX, HEOD (1070)+TX, heptachlor (1211)+TX, heptenophos (432)+TX, heterophos [CCN]+TX, hexaflumuron (439)+TX, HHDN (864)+TX, hydramethylnon (443)+TX, hydrogen cyanide (444)+TX, hydroprene (445)+TX, hyquincarb (1223)+TX, imidacloprid (458)+TX, imiprothrin (460)+TX, indoxacarb (465)+TX, iodomethane (IUPAC name) (542)+TX, IPSP (1229)+TX, isazofos (1231)+TX, isobenzan (1232)+TX, isocarbophos (473)+TX, isodrin (1235)+TX, isofenphos (1236)+TX, isolane (1237)+TX, isoprocarb (472)+TX, isopropyl O-(methoxyaminothiophosphoryl)salicylate (IUPAC name) (473)+TX, isoprothiolane (474)+TX, isothioate (1244)+TX, isoxathion (480)+TX, ivermectin [CCN]+TX, jasmolin I (696)+TX, jasmolin II (696)+TX, jodfenphos (1248)+TX, juvenile hormone I [CCN]+TX, juvenile hormone II [CCN]+TX, juvenile hormone III [CCN]+TX, kelevan (1249)+TX, kinoprene (484)+TX, lambda-cyhalothrin (198)+TX, lead arsenate [CCN]+TX, lepimectin (CCN)+TX, leptophos (1250)+TX, lindane (430)+TX, lirimfos (1251)+TX, lufenuron (490)+TX, lythidathion (1253)+TX, m-cumenyl methylcarbamate (IUPAC name) (1014)+TX, magnesium phosphide (IUPAC name) (640)+TX, malathion (492)+TX, malonoben (1254)+TX, mazidox (1255)+TX, mecarbam (502)+TX, mecarphon (1258)+TX, menazon (1260)+TX, mephosfolan (1261)+TX, mercurous chloride (513)+TX, mesulfenfos (1263)+TX, metaflumizone (CCN)+TX, metam (519)+TX, metam-potassium (519)+TX, metam-sodium (519)+TX, methacrifos (1266)+TX, methamidophos (527)+TX, methanesulfonyl fluoride (IUPAC/Chemical Abstracts name) (1268)+TX, methidathion (529)+TX, methiocarb (530)+TX, methocrotophos (1273)+TX, methomyl (531)+TX, methoprene (532)+TX, methoquin-butyl (1276)+TX, methothrin (533)+TX, methoxychlor (534)+TX, methoxyfenozide (535)+TX, methyl bromide (537)+TX, methyl isothiocyanate (543)+TX, methylchloroform [CCN]+TX, methylene chloride [CCN]+TX, metofluthrin [CCN]+TX, metolcarb (550)+TX, metoxadiazone (1288)+TX, mevinphos (556)+TX, mexacarbate (1290)+TX, milbemectin (557)+TX, milbemycin oxime [CCN]+TX, mipafox (1293)+TX, mirex (1294)+TX, monocrotophos (561)+TX, morphothion (1300)+TX, moxidectin [CCN]+TX, naftalofos [CCN]+TX, naled (567)+TX, naphthalene (IUPAC/Chemical Abstracts name) (1303)+TX, NC-170 (development code) (1306)+TX, NC-184 (compound code)+TX, nicotine (578)+TX, nicotine sulfate (578)+TX, nifluridide (1309)+TX, nitenpyram (579)+TX, nithiazine (1311)+TX, nitrilacarb (1313)+TX, nitrilacarb 1:1 zinc chloride complex (1313)+TX, NNI-0101 (compound code)+TX, NNI-0250 (compound code)+TX, nornicotine (traditional name) (1319)+TX, novaluron (585)+TX, noviflumuron (586)+TX, O-5-dichloro-4-iodophenyl O-ethyl ethylphosphonothioate (IUPAC name) (1057)+TX, O,O-diethyl O-4-methyl-2-oxo-2H-chromen-7-yl phosphorothioate (IUPAC name) (1074)+TX, O,O-diethyl O-6-methyl-2-propylpyrimidin-4-yl phosphorothioate (IUPAC name) (1075)+TX, O,O,O′,O′-tetrapropyl dithiopyrophosphate (IUPAC name) (1424)+TX, oleic acid (IUPAC name) (593)+TX, omethoate (594)+TX, oxamyl (602)+TX, oxydemeton-methyl (609)+TX, oxydeprofos (1324)+TX, oxydisulfoton (1325)+TX, pp′-DDT (219)+TX, para-dichlorobenzene [CCN]+TX, parathion (615)+TX, parathion-methyl (616)+TX, penfluron [CCN]+TX, pentachlorophenol (623)+TX, pentachlorophenyl laurate (IUPAC name) (623)+TX, permethrin (626)+TX, petroleum oils (628)+TX, PH 60-38 (development code) (1328)+TX, phenkapton (1330)+TX, phenothrin (630)+TX, phenthoate (631)+TX, phorate (636)+TX, phosalone (637)+TX, phosfolan (1338)+TX, phosmet (638)+TX, phosnichlor (1339)+TX, phosphamidon (639)+TX, phosphine (IUPAC name) (640)+TX, phoxim (642)+TX, phoxim-methyl (1340)+TX, pirimetaphos (1344)+TX, pirimicarb (651)+TX, pirimiphos-ethyl (1345)+TX, pirimiphos-methyl (652)+TX, polychlorodicyclopentadiene isomers (IUPAC name) (1346)+TX, polychloroterpenes (traditional name) (1347)+TX, potassium arsenite [CCN]+TX, potassium thiocyanate [CCN]+TX, prallethrin (655)+TX, precocene I [CCN]+TX, precocene II [CCN]+TX, precocene III [CCN]+TX, primidophos (1349)+TX, profenofos (662)+TX, profluthrin [CCN]+TX, promacyl (1354)+TX, promecarb (1355)+TX, propaphos (1356)+TX, propetamphos (673)+TX, propoxur (678)+TX, prothidathion (1360)+TX, prothiofos (686)+TX, prothoate (1362)+TX, protrifenbute [CCN]+TX, pymetrozine (688)+TX, pyraclofos (689)+TX, pyrazophos (693)+TX, pyresmethrin (1367)+TX, pyrethrin I (696)+TX, pyrethrin II (696)+TX, pyrethrins (696)+TX, pyridaben (699)+TX, pyridalyl (700)+TX, pyridaphenthion (701)+TX, pyrimidifen (706)+TX, pyrimitate (1370)+TX, pyriproxyfen (708)+TX, quassia [CCN]+TX, quinalphos (711)+TX, quinalphos-methyl (1376)+TX, quinothion (1380)+TX, quintiofos (1381)+TX, R-1492 (development code) (1382)+TX, rafoxanide [CCN]+TX, resmethrin (719)+TX, rotenone (722)+TX, RU 15525 (development code) (723)+TX, RU 25475 (development code) (1386)+TX, ryania (1387)+TX, ryanodine (traditional name) (1387)+TX, sabadilla (725)+TX, schradan (1389)+TX, sebufos+TX, selamectin [CCN]+TX, SI-0009 (compound code)+TX, SI-0205 (compound code)+TX, SI-0404 (compound code)+TX, SI-0405 (compound code)+TX, silafluofen (728)+TX, SN 72129 (development code) (1397)+TX, sodium arsenite [CCN]+TX, sodium cyanide (444)+TX, sodium fluoride (IUPAC/Chemical Abstracts name) (1399)+TX, sodium hexafluorosilicate (1400)+TX, sodium pentachlorophenoxide (623)+TX, sodium selenate (IUPAC name) (1401)+TX, sodium thiocyanate [CCN]+TX, sophamide (1402)+TX, spinosad (737)+TX, spiromesifen (739)+TX, spirotetrmat (CCN)+TX, sulcofuron (746)+TX, sulcofuron-sodium (746)+TX, sulfluramid (750)+TX, sulfotep (753)+TX, sulfuryl fluoride (756)+TX, sulprofos (1408)+TX, tar oils (758)+TX, tau-fluvalinate (398)+TX, tazimcarb (1412)+TX, TDE (1414)+TX, tebufenozide (762)+TX, tebufenpyrad (763)+TX, tebupirimfos (764)+TX, teflubenzuron (768)+TX, tefluthrin (769)+TX, temephos (770)+TX, TEPP (1417)+TX, terallethrin (1418)+TX, terbam+TX, terbufos (773)+TX, tetrachloroethane [CCN]+TX, tetrachlorvinphos (777)+TX, tetramethrin (787)+TX, theta-cypermethrin (204)+TX, thiacloprid (791)+TX, thiafenox+TX, thiamethoxam (792)+TX, thicrofos (1428)+TX, thiocarboxime (1431)+TX, thiocyclam (798)+TX, thiocyclam hydrogen oxalate (798)+TX, thiodicarb (799)+TX, thiofanox (800)+TX, thiometon (801)+TX, thionazin (1434)+TX, thiosultap (803)+TX, thiosultap-sodium (803)+TX, thuringiensin [CCN]+TX, tolfenpyrad (809)+TX, tralomethrin (812)+TX, transfluthrin (813)+TX, transpermethrin (1440)+TX, triamiphos (1441)+TX, triazamate (818)+TX, triazophos (820)+TX, triazuron+TX, trichlorfon (824)+TX, trichlormetaphos-3 [CCN]+TX, trichloronat (1452)+TX, trifenofos (1455)+TX, triflumuron (835)+TX, trimethacarb (840)+TX, triprene (1459)+TX, vamidothion (847)+TX, vaniliprole [CCN]+TX, veratridine (725)+TX, veratrine (725)+TX, XMC (853)+TX, xylylcarb (854)+TX, YI-5302 (compound code)+TX, zeta-cypermethrin (205)+TX, zetamethrin+TX, zinc phosphide (640)+TX, zolaprofos (1469) and ZXI 8901 (development code) (858)+TX, cyantraniliprole [736994-63-19+TX, chlorantraniliprole [500008-45-7]+TX, cyenopyrafen [560121-52-0]+TX, cyflumetofen [400882-07-7]+TX, pyrifluquinazon [337458-27-2]+TX, spinetoram [187166-40-1+187166-15-0]+TX, spirotetramat [203313-25-1]+TX, sulfoxaflor [946578-00-3]+TX, flufiprole [704886-18-0]+TX, meperfluthrin [915288-13-0]+TX, tetramethylfluthrin [84937-88-2]+TX, triflumezopyrim (disclosed in WO 2012/092115)+TX, fluxametamide (WO 2007/026965)+TX, epsilon-metofluthrin [240494-71-7]+TX, epsilon-momfluorothrin [1065124-65-3]+TX, fluazaindolizine [1254304-22-7]+TX, chloroprallethrin [399572-87-3]+TX, fluxametamide [928783-29-3]+TX, cyhalodiamide [1262605-53-7]+TX, tioxazafen [330459-31-9]+TX, broflanilide [1207727-04-5]+TX, flufiprole [704886-18-0]+TX, cyclaniliprole [1031756-98-5]+TX, tetraniliprole [1229654-66-3]+TX, guadipyr (described in WO2010/060231)+TX, cycloxaprid (described in WO2005/077934)+TX,
a molluscicide selected from the group of substances consisting of bis(tributyltin) oxide (IUPAC name) (913)+TX, bromoacetamide [CCN]+TX, calcium arsenate [CCN]+TX, cloethocarb (999)+TX, copper acetoarsenite [CCN]+TX, copper sulfate (172)+TX, fentin (347)+TX, ferric phosphate (IUPAC name) (352)+TX, metaldehyde (518)+TX, methiocarb (530)+TX, niclosamide (576)+TX, niclosamide-olamine (576)+TX, pentachlorophenol (623)+TX, sodium pentachlorophenoxide (623)+TX, tazimcarb (1412)+TX, thiodicarb (799)+TX, tributyltin oxide (913)+TX, trifenmorph (1454)+TX, trimethacarb (840)+TX, triphenyltin acetate (IUPAC name) (347) and triphenyltin hydroxide (IUPAC name) (347)+TX, pyriprole [394730-71-3]+TX,
a nematicide selected from the group of substances consisting of AKD-3088 (compound code)+TX, 1,2-dibromo-3-chloropropane (IUPAC/Chemical Abstracts name) (1045)+TX, 1,2-dichloropropane (IUPAC/Chemical Abstracts name) (1062)+TX, 1,2-dichloropropane with 1,3-dichloropropene (IUPAC name) (1063)+TX, 1,3-dichloropropene (233)+TX, 3,4-dichlorotetrahydrothiophene 1,1-dioxide (IUPAC/Chemical Abstracts name) (1065)+TX, 3-(4-chlorophenyl)-5-methylrhodanine (IUPAC name) (980)+TX, 5-methyl-6-thioxo-1,3,5-thiadiazinan-3-ylacetic acid (IUPAC name) (1286)+TX, 6-isopentenylaminopurine (210)+TX, abamectin (1)+TX, acetoprole [CCN]+TX, alanycarb (15)+TX, aldicarb (16)+TX, aldoxycarb (863)+TX, AZ 60541 (compound code)+TX, benclothiaz [CCN]+TX, benomyl (62)+TX, butylpyridaben+TX, cadusafos (109)+TX, carbofuran (118)+TX, carbon disulfide (945)+TX, carbosulfan (119)+TX, chloropicrin (141)+TX, chlorpyrifos (145)+TX, cloethocarb (999)+TX, cytokinins (210)+TX, dazomet (216)+TX, DBCP (1045)+TX, DCIP (218)+TX, diamidafos (1044)+TX, dichlofenthion (1051)+TX, dicliphos+TX, dimethoate (262)+TX, doramectin [CCN]+TX, emamectin (291)+TX, emamectin benzoate (291)+TX, eprinomectin [CCN]+TX, ethoprophos (312)+TX, ethylene dibromide (316)+TX, fenamiphos (326)+TX, fenpyrad+TX, fensulfothion (1158)+TX, fosthiazate (408)+TX, fosthietan (1196)+TX, furfural [CCN]+TX, GY-81 (development code) (423)+TX, heterophos [CCN]+TX, iodomethane (IUPAC name) (542)+TX, isamidofos (1230)+TX, isazofos (1231)+TX, ivermectin [CCN]+TX, kinetin (210)+TX, mecarphon (1258)+TX, metam (519)+TX, metam-potassium (519)+TX, metam-sodium (519)+TX, methyl bromide (537)+TX, methyl isothiocyanate (543)+TX, milbemycin oxime [CCN]+TX, moxidectin [CCN]+TX, Myrothecium verrucaria composition (565)+TX, NC-184 (compound code)+TX, oxamyl (602)+TX, phorate (636)+TX, phosphamidon (639)+TX, phosphocarb [CCN]+TX, sebufos+TX, selamectin [CCN]+TX, spinosad (737)+TX, terbam+TX, terbufos (773)+TX, tetrachlorothiophene (IUPAC/Chemical Abstracts name) (1422)+TX, thiafenox+TX, thionazin (1434)+TX, triazophos (820)+TX, triazuron+TX, xylenols [CCN]+TX, YI-5302 (compound code) and zeatin (210)+TX, fluensulfone [318290-98-1]+TX,
a nitrification inhibitor selected from the group of substances consisting of potassium ethylxanthate [CCN] and nitrapyrin (580)+TX,
a plant activator selected from the group of substances consisting of acibenzolar (6)+TX, acibenzolar-S-methyl (6)+TX, probenazole (658) and Reynoutria sachalinensis extract (720)+TX,
a rodenticide selected from the group of substances consisting of 2-isovalerylindan-1,3-dione (IUPAC name) (1246)+TX, 4-(quinoxalin-2-ylamino)benzenesulfonamide (IUPAC name) (748)+TX, alpha-chlorohydrin [CCN]+TX, aluminium phosphide (640)+TX, antu (880)+TX, arsenous oxide (882)+TX, barium carbonate (891)+TX, bisthiosemi (912)+TX, brodifacoum (89)+TX, bromadiolone (91)+TX, bromethalin (92)+TX, calcium cyanide (444)+TX, chloralose (127)+TX, chlorophacinone (140)+TX, cholecalciferol (850)+TX, coumachlor (1004)+TX, coumafuryl (1005)+TX, coumatetralyl (175)+TX, crimidine (1009)+TX, difenacoum (246)+TX, difethialone (249)+TX, diphacinone (273)+TX, ergocalciferol (301)+TX, flocoumafen (357)+TX, fluoroacetamide (379)+TX, flupropadine (1183)+TX, flupropadine hydrochloride (1183)+TX, gamma-HCH (430)+TX, HCH (430)+TX, hydrogen cyanide (444)+TX, iodomethane (IUPAC name) (542)+TX, lindane (430)+TX, magnesium phosphide (IUPAC name) (640)+TX, methyl bromide (537)+TX, norbormide (1318)+TX, phosacetim (1336)+TX, phosphine (IUPAC name) (640)+TX, phosphorus [CCN]+TX, pindone (1341)+TX, potassium arsenite [CCN]+TX, pyrinuron (1371)+TX, scilliroside (1390)+TX, sodium arsenite [CCN]+TX, sodium cyanide (444)+TX, sodium fluoroacetate (735)+TX, strychnine (745)+TX, thallium sulfate [CCN]+TX, warfarin (851) and zinc phosphide (640)+TX,
a synergist selected from the group of substances consisting of 2-(2-butoxyethoxy)ethyl piperonylate (IUPAC name) (934)+TX, 5-(1,3-benzodioxol-5-yl)-3-hexylcyclohex-2-enone (IUPAC name) (903)+TX, farnesol with nerolidol (324)+TX, MB-599 (development code) (498)+TX, MGK 264 (development code) (296)+TX, piperonyl butoxide (649)+TX, piprotal (1343)+TX, propyl isomer (1358)+TX, S421 (development code) (724)+TX, sesamex (1393)+TX, sesasmolin (1394) and sulfoxide (1406)+TX,
an animal repellent selected from the group of substances consisting of anthraquinone (32)+TX, chloralose (127)+TX, copper naphthenate [CCN]+TX, copper oxychloride (171)+TX, diazinon (227)+TX, dicyclopentadiene (chemical name) (1069)+TX, guazatine (422)+TX, guazatine acetates (422)+TX, methiocarb (530)+TX, pyridin-4-amine (IUPAC name) (23)+TX, thiram (804)+TX, trimethacarb (840)+TX, zinc naphthenate [CCN] and ziram (856)+TX,
a virucide selected from the group of substances consisting of imanin [CCN] and ribavirin [CCN]+TX,
a wound protectant selected from the group of substances consisting of mercuric oxide (512)+TX, octhilinone (590) and thiophanate-methyl (802)+TX,
and biologically active compounds selected from the group consisting of azaconazole (60207-31-0]+TX, bitertanol [70585-36-3]+TX, bromuconazole [116255-48-2]+TX, cyproconazole [94361-06-5]+TX, difenoconazole [119446-68-3]+TX, diniconazole [83657-24-3]+TX, epoxiconazole [106325-08-0]+TX, fenbuconazole [114369-43-6]+TX, fluquinconazole [136426-54-5]+TX, flusilazole [85509-19-9]+TX, flutriafol [76674-21-0]+TX, hexaconazole [79983-71-4]+TX, imazalil [35554-44-0]+TX, imibenconazole [86598-92-7]+TX, ipconazole [125225-28-7]+TX, metconazole [125116-23-6]+TX, myclobutanil [88671-89-0]+TX, pefurazoate [101903-30-4]+TX, penconazole [66246-88-6]+TX, prothioconazole [178928-70-6]+TX, pyrifenox [88283-41-4]+TX, prochloraz [67747-09-5]+TX, propiconazole [60207-90-1]+TX, simeconazole [149508-90-7]+TX, tebuconazole [107534-96-3]+TX, tetraconazole [112281-77-3]+TX, triadimefon [43121-43-3]+TX, triadimenol [55219-65-3]+TX, triflumizole [99387-89-0]+TX, triticonazole [131983-72-7]+TX, ancymidol [12771-68-5]+TX, fenarimol [60168-88-9]+TX, nuarimol [63284-71-9]+TX, bupirimate [41483-43-6]+TX, dimethirimol [5221-53-4]+TX, ethirimol [23947-60-6]+TX, dodemorph [1593-77-7]+TX, fenpropidine [67306-00-7]+TX, fenpropimorph [67564-91-4]+TX, spiroxamine [118134-30-8]+TX, tridemorph [81412-43-3]+TX, cyprodinil [121552-61-2]+TX, mepanipyrim [110235-47-7]+TX, pyrimethanil [53112-28-0]+TX, fenpiclonil [74738-17-3]+TX, fludioxonil [131341-86-1]+TX, benalaxyl [71626-11-4]+TX, furalaxyl [57646-30-7]+TX, metalaxyl [57837-19-1]+TX, R-metalaxyl [70630-17-0]+TX, ofurace [58810-48-3]+TX, oxadixyl [77732-09-3]+TX, benomyl [17804-35-2]+TX, carbendazim [10605-21-7]+TX, debacarb [62732-91-6]+TX, fuberidazole [3878-19-1]+TX, thiabendazole [148-79-8]+TX, chlozolinate [84332-86-5]+TX, dichlozoline [24201-58-9]+TX, iprodione [36734-19-7]+TX, myclozoline [54864-61-8]+TX, procymidone [32809-16-8]+TX, vinclozoline [50471-44-8]+TX, boscalid [188425-85-6]+TX, carboxin [5234-68-4]+TX, fenfuram [24691-80-3]+TX, flutolanil [66332-96-5]+TX, mepronil [55814-41-0]+TX, oxycarboxin [5259-88-1]+TX, penthiopyrad [183675-82-3]+TX, thifluzamide [130000-40-7]+TX, guazatine [108173-90-6]+TX, dodine [2439-10-3] [112-65-2] (free base)+TX, iminoctadine [13516-27-3]+TX, azoxystrobin [131860-33-8]+TX, dimoxystrobin [149961-52-4]+TX, enestroburin {Proc. BCPC, Int. Congr., Glasgow, 2003, 1, 93}+TX, fluoxastrobin [361377-29-9]+TX, kresoxim-methyl [143390-89-0]+TX, metominostrobin [133408-50-1]+TX, trifloxystrobin [141517-21-7]+TX, orysastrobin [248593-16-0]+TX, picoxystrobin [117428-22-5]+TX, pyraclostrobin [175013-18-0]+TX, ferbam [14484-64-1]+TX, mancozeb [8018-01-7]+TX, maneb [12427-38-2]+TX, metiram [9006-42-2]+TX, propineb [12071-83-9]+TX, thiram [137-26-8]+TX, zineb [12122-67-7]+TX, ziram [137-30-4]+TX, captafol [2425-06-1]+TX, captan [133-06-2]+TX, dichlofluanid [1085-98-9]+TX, fluoroimide [41205-21-4]+TX, folpet [133-07-3]+TX, tolylfluanid [731-27-1]+TX, bordeaux mixture [8011-63-0]+TX, copperhydroxid [20427-59-2]+TX, copperoxychlorid [1332-40-7]+TX, coppersulfat [7758-98-7]+TX, copperoxid [1317-39-1]+TX, mancopper [53988-93-5]+TX, oxine-copper [10380-28-6]+TX, dinocap [131-72-6]+TX, nitrothal-isopropyl [10552-74-6]+TX, edifenphos [17109-49-8]+TX, iprobenphos [26087-47-8]+TX, isoprothiolane [50512-35-1]+TX, phosdiphen [36519-00-3]+TX, pyrazophos [13457-18-6]+TX, tolclofos-methyl [57018-04-9]+TX, acibenzolar-S-methyl [135158-54-2]+TX, anilazine [101-05-3]+TX, benthiavalicarb [413615-35-7]+TX, blasticidin-S [2079-00-7]+TX, chinomethionat [2439-01-2]+TX, chloroneb [2675-77-6]+TX, chlorothalonil [1897-45-6]+TX, cyflufenamid [180409-60-3]+TX, cymoxanil [57966-95-7]+TX, dichlone [117-80-6]+TX, diclocymet [139920-32-4]+TX, diclomezine [62865-36-5]+TX, dicloran [99-30-9]+TX, diethofencarb [87130-20-9]+TX, dimethomorph [110488-70-5]+TX, SYP-LI90 (Flumorph) [211867-47-9]+TX, dithianon [3347-22-6]+TX, ethaboxam [162650-77-3]+TX, etridiazole [2593-15-9]+TX, famoxadone [131807-57-3]+TX, fenamidone [161326-34-7]+TX, fenoxanil [115852-48-7]+TX, fentin [668-34-8]+TX, ferimzone [89269-64-7]+TX, fluazinam [79622-59-6]+TX, fluopicolide [239110-15-7]+TX, flusulfamide [106917-52-6]+TX, fenhexamid [126833-17-8]+TX, fosetyl-aluminium [39148-24-8]+TX, hymexazol [10004-44-1]+TX, iprovalicarb [140923-17-7]+TX, IKF-916 (Cyazofamid) [120116-88-3]+TX, kasugamycin [6980-18-3]+TX, methasulfocarb [66952-49-6]+TX, metrafenone [220899-03-6]+TX, pencycuron [66063-05-6]+TX, phthalide [27355-22-2]+TX, polyoxins [11113-80-7]+TX, probenazole [27605-76-1]+TX, propamocarb [25606-41-1]+TX, proquinazid [189278-12-4]+TX, pyroquilon [57369-32-1]+TX, quinoxyfen [124495-18-7]+TX, quintozene [82-68-8]+TX, sulfur [7704-34-9]+TX, tiadinil [223580-51-6]+TX, triazoxide [72459-58-6]+TX, tricyclazole [41814-78-2]+TX, triforine [26644-46-2]+TX, validamycin [37248-47-8]+TX, zoxamide (RH7281) [156052-68-5]+TX, mandipropamid [374726-62-2]+TX, isopyrazam [881685-58-1]+TX, sedaxane [874967-67-6]+TX, 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid (9-dichloromethylene-1,2,3,4-tetrahydro-1,4-methano-naphthalen-5-yl)-amide (dislosed in WO 2007/048556)+TX, 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid (3′,4′,5′-trifluoro-biphenyl-2-yl)-amide (disclosed in WO 2006/087343)+TX, [(3S,4R,4aR,6S,6aS,12R,12aS,12bS)-3-[(cyclopropylcarbonyl)oxy]-1,3,4,4a,5,6,6a,12,12a,12b-decahydro-6,12-dihydroxy-4,6a,12b-trimethyl-11-oxo-9-(3-pyridinyl)-2H,11Hnaphtho[2,1-b]pyrano[3,4-e]pyran-4-yl]methyl-cyclopropanecarboxylate [915972-17-7]+TX and 1,3,5-trimethyl-N-(2-methyl-1-oxopropyl)-N-[3-(2-methylpropyl)-4-[2,2,2-trifluoro-1-methoxy-1-(trifluoromethyl)ethyl]phenyl]-1H-pyrazole-4-carboxamide [926914-55-8]+TX; and
microbials including: Acinetobacter lwoffii+TX, Acremonium alternatum+TX+TX, Acremonium cephalosporium+TX+TX, Acremonium diospyri+TX, Acremonium obclavatum+TX, Adoxophyes orana granulovirus (AdoxGV) (Capex®)+TX, Agrobacterium radiobacter strain K84 (Galltrol-A®)+TX, Alternaria alternate+TX, Alternaria cassia+TX, Alternaria destruens (Smolder®)+TX, Ampelomyces quisqualis (AQ10®)+TX, Aspergillus flavus AF36 (AF36®)+TX, Aspergillus flavus NRRL 21882 (Aflaguard®)+TX, Aspergillus spp.+TX, Aureobasidium pullulans+TX, Azospirillum+TX, (MicroAZ®+TX, TAZO B®)+TX, Azotobacter+TX, Azotobacter chroocuccum (Azotomeal®)+TX, Azotobacter cysts (Bionatural Blooming Blossoms®)+TX, Bacillus amyloliquefaciens+TX, Bacillus cereus+TX, Bacillus chitinosporus strain CM-1+TX, Bacillus chitinosporus strain AQ746+TX, Bacillus licheniformis strain HB-2 (Biostart™ Rhizoboost®)+TX, Bacillus licheniformis strain 3086 (EcoGuard®+TX, Green Releaf®)+TX, Bacillus circulans+TX, Bacillus firmus (BioSafe®+TX, BioNem-WP®+TX, VOTiVO®)+TX, Bacillus firmus strain I-1582+TX, Bacillus macerans+TX, Bacillus marismortui+TX, Bacillus megaterium+TX, Bacillus mycoides strain AQ726+TX, Bacillus papillae (Milky Spore Powder®)+TX, Bacillus pumilus spp.+TX, Bacillus pumilus strain GB34 (Yield Shield®)+TX, Bacillus pumilus strain AQ717+TX, Bacillus pumilus strain QST 2808 (Sonata®+TX, Ballad Plus®)+TX, Bacillus spahericus (VectoLex®)+TX, Bacillus spp.+TX, Bacillus spp. strain AQ175+TX, Bacillus spp. strain AQ177+TX, Bacillus spp. strain AQ178+TX, Bacillus subtilis strain QST 713 (CEASE®+TX, Serenade®+TX, Rhapsody®)+TX, Bacillus subtilis strain QST 714 (JAZZ®)+TX, Bacillus subtilis strain AQ153+TX, Bacillus subtilis strain AQ743+TX, Bacillus subtilis strain QST3002+TX, Bacillus subtilis strain QST3004+TX, Bacillus subtilis var. amyloliquefaciens strain FZB24 (Taegro®+TX, Rhizopro®)+TX, Bacillus thuringiensis Cry2Ae+TX, Bacillus thuringiensis Cry1Ab+TX, Bacillus thuringiensis aizawai GC 91 (Agree®)+TX, Bacillus thuringiensis israelensis (BMP123®+TX, Aquabac®+TX, VectoBac®)+TX, Bacillus thuringiensis kurstaki (Javelin®+TX, Deliver®+TX, CryMax®+TX, Bonide®+TX, Scutella WP®+TX, Turilav WP®+TX, Astuto®+TX, Dipel WP®+TX, Biobit®+TX, Foray®)+TX, Bacillus thuringiensis kurstaki BMP 123 (Baritone®)+TX, Bacillus thuringiensis kurstaki HD-1 (Bioprotec-CAF/3P®)+TX, Bacillus thuringiensis strain BD#32+TX, Bacillus thuringiensis strain AQ52+TX, Bacillus thuringiensis var. aizawai (XenTari®+TX, DiPel®)+TX, bacteria spp. (GROWMEND®+TX, GROWSWEET®+TX, Shootup®)+TX, bacteriophage of Clavipacter michiganensis (AgriPhage®)+TX, Bakflor®+TX, Beauveria bassiana (Beaugenic®+TX, Brocaril WP®)+TX, Beauveria bassiana GHA (Mycotrol ES®+TX, Mycotrol O®+TX, BotaniGuard®)+TX, Beauveria brongniartii (Engerlingspilz®+TX, Schweizer Beauveria®+TX, Melocont®)+TX, Beauveria spp.+TX, Botrytis cineria+TX, Bradyrhizobium japonicum (TerraMax®)+TX, Brevibacillus brevis+TX, Bacillus thuringiensis tenebrionis (Novodor®)+TX, BtBooster+TX, Burkholderia cepacia (Deny®+TX, Intercept®+TX, Blue Circle®)+TX, Burkholderia gladii+TX, Burkholderia gladioli+TX, Burkholderia spp.+TX, Canadian thistle fungus (CBH Canadian Bioherbicide®)+TX, Candida butyri+TX, Candida famata+TX, Candida fructus+TX, Candida glabrata+TX, Candida guilliermondii+TX, Candida melibiosica+TX, Candida oleophila strain 0+TX, Candida parapsilosis+TX, Candida pelliculosa+TX, Candida pulcherrima+TX, Candida reukaufii+TX, Candida saitoana (Bio-Coat®+TX, Biocure®)+TX, Candida sake+TX, Candida spp.+TX, Candida tenius+TX, Cedecea dravisae+TX, Cellulomonas flavigena+TX, Chaetomium cochliodes (Nova-Cide®)+TX, Chaetomium globosum (Nova-Cide®)+TX, Chromobacterium subtsugae strain PRAA4-1T (Grandevo®)+TX, Cladosporium cladosporioides+TX, Cladosporium oxysporum+TX, Cladosporium chlorocephalum+TX, Cladosporium spp.+TX, Cladosporium tenuissimum+TX, Clonostachys rosea (EndoFine®)+TX, Colletotrichum acutatum+TX, Coniothyrium minitans (Cotans WG®)+TX, Coniothyrium spp.+TX, Cryptococcus albidus (YIELDPLUS®)+TX, Cryptococcus humicola+TX, Cryptococcus infirmo-miniatus+TX, Cryptococcus laurentii+TX, Cryptophlebia leucotreta granulovirus (Cryptex®)+TX, Cupriavidus campinensis+TX, Cydia pomonella granulovirus (CYD-X®)+TX, Cydia pomonella granulovirus (Madex®+TX, Madex Plus®+TX, Madex Max/Carpovirusine®)+TX, Cylindrobasidium laeve (Stumpout®)+TX, Cylindrocladium+TX, Debaryomyces hansenii+TX, Drechslera hawaiinensis+TX, Enterobacter cloacae+TX, Enterobacteriaceae+TX, Entomophtora virulenta (Vektor®)+TX, Epicoccum nigrum+TX, Epicoccum purpurascens+TX, Epicoccum spp.+TX, Filobasidium floriforme+TX, Fusarium acuminatum+TX, Fusarium chlamydosporum+TX, Fusarium oxysporum (Fusaclean®/Biofox C®)+TX, Fusarium proliferatum+TX, Fusarium spp.+TX, Galactomyces geotrichum+TX, Gliocladium catenulatum (Primastop®+TX, Prestop®)+TX, Gliocladium roseum+TX, Gliocladium spp. (SoilGard®)+TX, Gliocladium virens (Soilgard®)+TX, Granulovirus (Granupom®)+TX, Halobacillus halophilus+TX, Halobacillus litoralis+TX, Halobacillus trueperi+TX, Halomonas spp.+TX, Halomonas subglaciescola+TX, Halovibrio variabilis+TX, Hanseniaspora uvarum+TX, Helicoverpa armigera nucleopolyhedrovirus (Helicovex®)+TX, Helicoverpa zea nuclear polyhedrosis virus (Gemstar®)+TX, Isoflavone-formononetin (Myconate®)+TX, Kloeckera apiculata+TX, Kloeckera spp.+TX, Lagenidium giganteum (Laginex®)+TX, Lecanicillium longisporum (Vertiblast®)+TX, Lecanicillium muscarium (Vertikil®)+TX, Lymantria Dispar nucleopolyhedrosis virus (Disparvirus®)+TX, Marinococcus halophilus+TX, Meira geulakonigii+TX, Metarhizium anisopliae (Met52®)+TX, Metarhizium anisopliae (Destruxin WP®)+TX, Metschnikowia fruticola (Shemer®)+TX, Metschnikowia pulcherrima+TX, Microdochium dimerum (Antibot®)+TX, Micromonospora coerulea+TX, Microsphaeropsis ochracea+TX, Muscodor albus 620 (Muscudor®)+TX, Muscodor roseus strain A3-5+TX, Mycorrhizae spp. (AMykor®+TX, Root Maximizer®)+TX, Myrothecium verrucaria strain AARC-0255 (DiTera®)+TX, BROS PLUS®+TX, Ophiostoma piliferum strain D97 (Sylvanex®)+TX, Paecilomyces farinosus+TX, Paecilomyces fumosoroseus (PFR-97®+TX, PreFeRal®)+TX, Paecilomyces linacinus (Biostat WP®)+TX, Paecilomyces lilacinus strain 251 (MeloCon WG®)+TX, Paenibacillus polymyxa+TX, Pantoea agglomerans (BlightBan C9-1®)+TX, Pantoea spp.+TX, Pasteuria spp. (Econem®)+TX, Pasteuria nishizawae+TX, Penicillium aurantiogriseum+TX, Penicillium billai (Jumpstart®+TX, TagTeam®)+TX, Penicillium brevicompactum+TX, Penicillium frequentans+TX, Penicillium griseofulvum+TX, Penicillium purpurogenum+TX, Penicillium spp.+TX, Penicillium viridicatum+TX, Phlebiopsis gigantean (Rotstop®)+TX, phosphate solubilizing bacteria (Phosphomeal®)+TX, Phytophthora cryptogea+TX, Phytophthora palmivora (Devine®)+TX, Pichia anomala+TX, Pichia guilermondii+TX, Pichia membranaefaciens+TX, Pichia onychis+TX, Pichia stipites+TX, Pseudomonas aeruginosa+TX, Pseudomonas aureofasciens (Spot-Less Biofungicide®)+TX, Pseudomonas cepacia+TX, Pseudomonas chlororaphis (AtEze®)+TX, Pseudomonas corrugate+TX, Pseudomonas fluorescens strain A506 (BlightBan A506®)+TX, Pseudomonas putida+TX, Pseudomonas reactans+TX, Pseudomonas spp.+TX, Pseudomonas syringae (Bio-Save®)+TX, Pseudomonas viridiflava+TX, Pseudomons fluorescens (Zequanox®)+TX, Pseudozyma flocculosa strain PF-A22 UL (Sporodex L®)+TX, Puccinia canaliculata+TX, Puccinia thlaspeos (Wood Warrior®)+TX, Pythium paroecandrum+TX, Pythium oligandrum (Polygandron®+TX, Polyversum®)+TX, Pythium periplocum+TX, Rhanella aquatilis+TX, Rhanella spp.+TX, Rhizobia (Dormal®+TX, Vault®)+TX, Rhizoctonia+TX, Rhodococcus globerulus strain AQ719+TX, Rhodosporidium diobovatum+TX, Rhodosporidium toruloides+TX, Rhodotorula spp.+TX, Rhodotorula glutinis+TX, Rhodotorula graminis+TX, Rhodotorula mucilagnosa+TX, Rhodotorula rubra+TX, Saccharomyces cerevisiae+TX, Salinococcus roseus+TX, Sclerotinia minor+TX, Sclerotinia minor (SARRITOR®)+TX, Scytalidium spp.+TX, Scytalidium uredinicola+TX, Spodoptera exigua nuclear polyhedrosis virus (Spod-X®+TX, Spexit®)+TX, Serratia marcescens+TX, Serratia plymuthica+TX, Serratia spp.+TX, Sordaria fimicola+TX, Spodoptera littoralis nucleopolyhedrovirus (Littovir®)+TX, Sporobolomyces roseus+TX, Stenotrophomonas maltophilia+TX, Streptomyces ahygroscopicus+TX, Streptomyces albaduncus+TX, Streptomyces exfoliates+TX, Streptomyces galbus+TX, Streptomyces griseoplanus+TX, Streptomyces griseoviridis (Mycostop®)+TX, Streptomyces lydicus (Actinovate®)+TX, Streptomyces lydicus WYEC-108 (ActinoGrow®)+TX, Streptomyces violaceus+TX, Tilletiopsis minor+TX, Tilletiopsis spp.+TX, Trichoderma asperellum (T34 Biocontrol®)+TX, Trichoderma gamsii (Tenet®)+TX, Trichoderma atroviride (Plantmate®)+TX, Trichoderma hamatum TH 382+TX, Trichoderma harzianum rifai (Mycostar®)+TX, Trichoderma harzianum T-22 (Trianum-P®+TX, PlantShield HC®+TX, RootShield®+TX, Trianum-G®)+TX, Trichoderma harzianum T-39 (Trichodex®)+TX, Trichoderma inhamatum+TX, Trichoderma koningii+TX, Trichoderma spp. LC 52 (Sentinel®)+TX, Trichoderma lignorum+TX, Trichoderma longibrachiatum+TX, Trichoderma polysporum (Binab T®)+TX, Trichoderma taxi+TX, Trichoderma virens+TX, Trichoderma virens (formerly Gliocladium virens GL-21) (SoilGuard®)+TX, Trichoderma viride+TX, Trichoderma viride strain ICC 080 (Remedier®)+TX, Trichosporon pullulans+TX, Trichosporon spp.+TX, Trichothecium spp.+TX, Trichothecium roseum+TX, Typhula phacorrhiza strain 94670+TX, Typhula phacorrhiza strain 94671+TX, Ulocladium atrum+TX, Ulocladium oudemansii (Botry-Zen®)+TX, Ustilago maydis+TX, various bacteria and supplementary micronutrients (Natural II®)+TX, various fungi (Millennium Microbes®)+TX, Verticillium chlamydosporium+TX, Verticillium lecanii (Mycotal®+TX, Vertalec®)+TX, Vip3Aa20 (VIPtera®)+TX, Virgibaclillus marismortui+TX, Xanthomonas campestris pv. Poae (Camperico®)+TX, Xenorhabdus bovienii+TX, Xenorhabdus nematophilus; and
Plant extracts including: pine oil (Retenol®)+TX, azadirachtin (Plasma Neem Oil®+TX, AzaGuard®+TX, MeemAzal®+TX, Molt-X®+TX, Botanical IGR (Neemazad®+TX, Neemix®)+TX, canola oil (Lilly Miller Vegol®)+TX, Chenopodium ambrosioides near ambrosioides (Requiem®)+TX, Chrysanthemum extract (Crisant®)+TX, extract of neem oil (Trilogy®)+TX, essentials oils of Labiatae (Botania®)+TX, extracts of clove rosemary peppermint and thyme oil (Garden insect Killer®)+TX, Glycinebetaine (Greenstim®)+TX, Garlic+TX, lemongrass oil (GreenMatch®)+TX, neem oil+TX, Nepeta cataria (Catnip oil)+TX, Nepeta catarina+TX, nicotine+TX, oregano oil (MossBuster®)+TX, Pedaliaceae oil (Nematon®)+TX, pyrethrum+TX, Quillaja saponaria (NemaQ®)+TX, Reynoutria sachalinensis (Regalia®+TX, Sakalia®)+TX, rotenone (Eco Roten®)+TX, Rutaceae plant extract (Soleo®)+TX, soybean oil (Ortho Ecosense®)+TX, tea tree oil (Timorex Gold®)+TX, thymus oil+TX, AGNIQUE® MMF+TX, BugOil®+TX, mixture of rosemary sesame peppermint thyme and cinnamon extracts (EF 300®)+TX, mixture of clove rosemary and peppermint extract (EF 400®)+TX, mixture of clove peppermint garlic oil and mint (Soil Shot®)+TX, kaolin (Screen®)+TX, storage glucam of brown algae (Laminarin®); and
pheromones including: blackheaded fireworm pheromone (3M Sprayable Blackheaded Fireworm Pheromone®)+TX, Codling Moth Pheromone (Paramount dispenser-(CM)/Isomata C-Plus®)+TX, Grape Berry Moth Pheromone (3M MEC-GBM Sprayable Pheromone®)+TX, Leafroller pheromone (3M MEC-LR Sprayable Pheromone®)+TX, Muscamone (Snip7 Fly Bait®+TX, Starbar Premium Fly Bait®)+TX, Oriental Fruit Moth Pheromone (3M oriental fruit moth sprayable Pheromone®)+TX, Peachtree Borer Pheromone (Isomata-P®)+TX, Tomato Pinworm Pheromone (3M Sprayable Pheromone®)+TX, Entostat powder (extract from palm tree) (Exosex CM®)+TX, (E+TX,Z+TX,Z)-3+TX,8+TX,11 Tetradecatrienyl acetate+TX, (Z+TX,Z+TX,E)-7+TX,11+TX,13-Hexadecatrienal+TX, (E+TX,Z)-7+TX,9-Dodecadien-1-yl acetate+TX, 2-Methyl-1-butanol+TX, Calcium acetate+TX, Scenturion®+TX, Biolure®+TX, Check-Mate®+TX, Lavandulyl senecioate; and
Macrobials including: Aphelinus abdominalis+TX, Aphidius ervi (Aphelinus-System®)+TX, Acerophagus papaya+TX, Adalia bipunctata (Adalia-System®)+TX, Adalia bipunctata (Adaline®)+TX, Adalia bipunctata (Aphidalia®)+TX, Ageniaspis citricola+TX, Ageniaspis fuscicollis+TX, Amblyseius andersoni (Anderline®+TX, Andersoni-System®)+TX, Amblyseius californicus (Amblyline®+TX, Spical®)+TX, Amblyseius cucumeris (Thripex®+TX, Bugline cucumeris®)+TX, Amblyseius fallacis (Fallacis®)+TX, Amblyseius swirskii (Bugline Swirskii®+TX, Swirskii-Mite®)+TX, Amblyseius womersleyi (WomerMite®)+TX, Amitus hesperidum+TX, Anagrus atomus+TX, Anagyrus fusciventris+TX, Anagyrus kamali+TX, Anagyrus loecki+TX, Anagyrus pseudococci (Citripar®)+TX, Anicetus benefices+TX, Anisopteromalus calandrae+TX, Anthocoris nemoralis (Anthocoris-System®)+TX, Aphelinus abdominalis (Apheline®+TX, Aphiline®)+TX, Aphelinus asychis+TX, Aphidius colemani (Aphipar®)+TX, Aphidius ervi (Ervipar®)+TX, Aphidius gifuensis+TX, Aphidius matricariae (Aphipar-M®)+TX, Aphidoletes aphidimyza (Aphidend®)+TX, Aphidoletes aphidimyza (Aphidoline®)+TX, Aphytis lingnanensis+TX, Aphytis melinus+TX, Aprostocetus hagenowii+TX, Atheta coriaria (Staphyline®)+TX, Bombus spp.+TX, Bombus terrestris (Natupol Beehive®)+TX, Bombus terrestris (Beeline®+TX, Tripol®)+TX, Cephalonomia stephanoderis+TX, Chilocorus nigritus+TX, Chrysoperla carnea (Chrysoline®)+TX, Chrysoperla carnea (Chrysopa®)+TX, Chrysoperla rufilabris+TX, Cirrospilus ingenuus+TX, Cirrospilus quadristriatus+TX, Citrostichus phyllocnistoides+TX, Closterocerus chamaeleon+TX, Closterocerus spp.+TX, Coccidoxenoides perminutus (Planopar®)+TX, Coccophagus cowperi+TX, Coccophagus lycimnia+TX, Cotesia flavipes+TX, Cotesia plutellae+TX, Cryptolaemus montrouzieri (Cryptobug®+TX, Cryptoline®)+TX, Cybocephalus nipponicus+TX, Dacnusa sibirica+TX, Dacnusa sibirica (Minusa®)+TX, Diglyphus isaea (Diminex®)+TX, Delphastus catalinae (Delphastus®)+TX, Delphastus pusillus+TX, Diachasmimorpha krausii+TX, Diachasmimorpha longicaudata+TX, Diaparsis jucunda+TX, Diaphorencyrtus aligarhensis+TX, Diglyphus isaea+TX, Diglyphus isaea (Miglyphus®+TX, Digline®)+TX, Dacnusa sibirica (DacDigline®+TX, Minex®)+TX, Diversinervus spp.+TX, Encarsia citrina+TX, Encarsia formosa (Encarsia Max®+TX, Encarline®+TX, En-Strip®)+TX, Eretmocerus eremicus (Enermix®)+TX, Encarsia quadeloupae+TX, Encarsia haitiensis+TX, Episyrphus balteatus (Syrphidend®)+TX, Eretmoceris siphonini+TX, Eretmocerus californicus+TX, Eretmocerus eremicus (Ercal®+TX, Eretline E®)+TX, Eretmocerus eremicus (Bemimix®)+TX, Eretmocerus hayati+TX, Eretmocerus mundus (Bemipar®+TX, Eretline M®)+TX, Eretmocerus siphonini+TX, Exochomus quadripustulatus+TX, Feltiella acarisuga (Spidend®)+TX, Feltiella acarisuga (Feltiline®)+TX, Fopius arisanus+TX, Fopius ceratitivorus+TX, Formononetin (Wirless Beehome®)+TX, Franklinothrips vespiformis (Vespop®)+TX, Galendromus occidentalis+TX, Goniozus legneri+TX, Habrobracon hebetor+TX, Harmonia axyridis (HarmoBeetle®)+TX, Heterorhabditis spp. (Lawn Patrol®)+TX, Heterorhabditis bacteriophora (NemaShield HB®+TX, Nemaseek®+TX, Terranem-Nam®+TX, Terranem®+TX, Larvanem®+TX, B-Green®+TX, NemAttack®+TX, Nematop®)+TX, Heterorhabditis megidis (Nemasys H®+TX, BioNem H®+TX, Exhibitline Hm®+TX, Larvanem-M®)+TX, Hippodamia convergens+TX, Hypoaspis aculeifer (Aculeifer-System®+TX, Entomite-A®)+TX, Hypoaspis miles (Hypoline M®+TX, Entomite-M®)+TX, Lbalia leucospoides+TX, Lecanoideus floccissimus+TX, Lemophagus errabundus+TX, Leptomastidea abnormis+TX, Leptomastix dactylopii (Leptopar®)+TX, Leptomastix epona+TX, Lindorus lophanthae+TX, Lipolexis oregmae+TX, Lucilia caesar (Natufly®)+TX, Lysiphlebus testaceipes+TX, Macrolophus caliginosus (Mirical-N®+TX, Macroline C®+TX, Mirical®)+TX, Mesoseiulus longipes+TX, Metaphycus flavus+TX, Metaphycus lounsburyi+TX, Micromus angulatus (Milacewing®)+TX, Microterys flavus+TX, Muscidifurax raptorellus and Spalangia cameroni (Biopar®)+TX, Neodryinus typhlocybae+TX, Neoseiulus californicus+TX, Neoseiulus cucumeris (THRYPEX®)+TX, Neoseiulus fallacis+TX, Nesideocoris tenuis (NesidioBug®+TX, Nesibug®)+TX, Ophyra aenescens (Biofly®)+TX, Orius insidiosus (Thripor-I®+TX, Oriline I®)+TX, Orius laevigatus (Thripor-L®+TX, Oriline I®)+TX, Orius majusculus (Oriline M®)+TX, Orius strigicollis (Thripor-S®)+TX, Pauesia juniperorum+TX, Pediobius foveolatus+TX, Phasmarhabditis hermaphrodita (Nemaslug®)+TX, Phymastichus coffea+TX, Phytoseiulus macropilus+TX, Phytoseiulus persimilis (Spidex®+TX, Phytoline P®)+TX, Podisus maculiventris (Podisus®)+TX, Pseudacteon curvatus+TX, Pseudacteon obtusus+TX, Pseudacteon tricuspis+TX, Pseudaphycus maculipennis+TX, Pseudleptomastix mexicana+TX, Psyllaephagus pilosus+TX, Psyttalia concolor (complex)+TX, Quadrastichus spp.+TX, Rhyzobius lophanthae+TX, Rodolia cardinalis+TX, Rumina decollate+TX, Semielacher petiolatus+TX, Sitobion avenae (Ervibank®)+TX, Steinemema carpocapsae (Nematac C®+TX, Millenium®+TX, BioNem C®+TX, NemAttack®+TX, Nemastar®+TX, Capsanem®)+TX, Steinemema feltiae (NemaShield®+TX, Nemasys F®+TX, BioNem F®+TX, Steinernema-System®+TX, NemAttack®+TX, Nemaplus®+TX, Exhibitline Sf®+TX, Scia-Rid®+TX, Entonem®)+TX, Steinemema kraussei (Nemasys L®+TX, BioNem L®+TX, Exhibitline Srb®)+TX, Steinemema riobrave (BioVector®+TX, BioVektor®)+TX, Steinemema scapterisci (Nematac S®)+TX, Steinemema spp.+TX, Steinemematid spp. (Guardian Nematodes®)+TX, Stethorus punctillum (Stethorus®)+TX, Tamarixia radiate+TX, Tetrastichus setifer+TX, Thripobius semiluteus+TX, Torymus sinensis+TX, Trichogramma brassicae (Tricholine B®)+TX, Trichogramma brassicae (Tricho-Strip®)+TX, Trichogramma evanescens+TX, Trichogramma minutum+TX, Trichogramma ostriniae+TX, Trichogramma platneri+TX, Trichogramma pretiosum+TX, Xanthopimpla stemmator; and
other biologicals including: abscisic acid+TX, bioSea®+TX, Chondrostereum purpureum (Chontrol Paste®)+TX, Colletotrichum gloeosporioides (Collego®)+TX, Copper Octanoate (Cueva®)+TX, Delta traps (Trapline D®)+TX, Erwinia amylovora (Harpin) (ProAct®+TX, Ni-HIBIT Gold CST®)+TX, Ferri-phosphate (Ferramol®)+TX, Funnel traps (Trapline Y®)+TX, Gallex®+TX, Grower's Secret®+TX, Homo-brassonolide+TX, Iron Phosphate (Lilly Miller Worry Free Ferramol Slug & Snail Bait®)+TX, MCP hail trap (Trapline F®)+TX, Microctonus hyperodae+TX, Mycoleptodiscus terrestris (Des-X®)+TX, BioGain®+TX, Aminomite®+TX, Zenox®+TX, Pheromone trap (Thripline Ams®)+TX, potassium bicarbonate (MilStop®)+TX, potassium salts of fatty acids (Sanova®)+TX, potassium silicate solution (SD-Matrix®)+TX, potassium iodide+potassiumthiocyanate (Enzicur®)+TX, SuffOil-X®+TX, Spider venom+TX, Nosema locustae (Semaspore Organic Grasshopper Control®)+TX, Sticky traps (Trapline YF®+TX, Rebell Amarillo®)+TX and Traps (Takitrapline Y+b®)+TX.
[0444] The references in brackets behind the active ingredients, e.g. [3878-19-1] refer to the Chemical Abstracts Registry number. The above described mixing partners are known. Where the active ingredients are included in “The Pesticide Manual” [The Pesticide Manual—A World Compendium; Thirteenth Edition; Editor: C. D. S. TomLin; The British Crop Protection Council], they are described therein under the entry number given in round brackets hereinabove for the particular compound; for example, the compound “abamectin” is described under entry number (1). Where “[CCN]” is added hereinabove to the particular compound, the compound in question is included in the “Compendium of Pesticide Common Names”, which is accessible on the internet [A. Wood; Compendium of Pesticide Common Names, Copyright© 1995-2004]; for example, the compound “acetoprole” is described under the internet address http://www.alanwood.net/pesticides/acetoprole.html.
[0445] Most of the active ingredients described above are referred to hereinabove by a so-called “common name”, the relevant “ISO common name” or another “common name” being used in individual cases. If the designation is not a “common name”, the nature of the designation used instead is given in round brackets for the particular compound; in that case, the IUPAC name, the IUPAC/Chemical Abstracts name, a “chemical name”, a “traditional name”, a “compound name” or a “development code” is used. CAS Reg. No” means the Chemical Abstracts Registry Number.
[0446] The active ingredient mixture of the compounds of formula I selected from Tables 1 to 88 and P with active ingredients described above comprises a compound selected from Tables 1 to 88 and P and an active ingredient as described above preferably in a mixing ratio of from 100:1 to 1:6000, especially from 50:1 to 1:50, more especially in a ratio of from 20:1 to 1:20, even more especially from 10:1 to 1:10, very especially from 5:1 and 1:5, special preference being given to a ratio of from 2:1 to 1:2, and a ratio of from 4:1 to 2:1 being likewise preferred, above all in a ratio of 1:1, or 5:1, or 5:2, or 5:3, or 5:4, or 4:1, or 4:2, or 4:3, or 3:1, or 3:2, or 2:1, or 1:5, or 2:5, or 3:5, or 4:5, or 1:4, or 2:4, or 3:4, or 1:3, or 2:3, or 1:2, or 1:600, or 1:300, or 1:150, or 1:35, or 2:35, or 4:35, or 1:75, or 2:75, or 4:75, or 1:6000, or 1:3000, or 1:1500, or 1:350, or 2:350, or 4:350, or 1:750, or 2:750, or 4:750. Those mixing ratios are by weight.
[0447] The mixtures as described above can be used in a method for controlling pests, which comprises applying a composition comprising a mixture as described above to the pests or their environment, with the exception of a method for treatment of the human or animal body by surgery or therapy and diagnostic methods practised on the human or animal body.
[0448] The mixtures comprising a compound of formula I selected from Tables 1 to 88 and P and one or more active ingredients as described above can be applied, for example, in a single “ready-mix” form, in a combined spray mixture composed from separate formulations of the single active ingredient components, such as a “tank-mix”, and in a combined use of the single active ingredients when applied in a sequential manner, i.e. one after the other with a reasonably short period, such as a few hours or days. The order of applying the compounds of formula I selected from Tables 1 to 88 and P and the active ingredients as described above is not essential for working the present invention.
[0449] The compositions according to the invention can also comprise further solid or liquid auxiliaries, such as stabilizers, for example unepoxidized or epoxidized vegetable oils (for example epoxidized coconut oil, rapeseed oil or soya oil), antifoams, for example silicone oil, preservatives, viscosity regulators, binders and/or tackifiers, fertilizers or other active ingredients for achieving specific effects, for example bactericides, fungicides, nematocides, plant activators, molluscicides or herbicides.
[0450] The compositions according to the invention are prepared in a manner known per se, in the absence of auxiliaries for example by grinding, screening and/or compressing a solid active ingredient and in the presence of at least one auxiliary for example by intimately mixing and/or grinding the active ingredient with the auxiliary (auxiliaries). These processes for the preparation of the compositions and the use of the compounds I for the preparation of these compositions are also a subject of the invention.
[0451] The application methods for the compositions, that is the methods of controlling pests of the abovementioned type, such as spraying, atomizing, dusting, brushing on, dressing, scattering or pouring—which are to be selected to suit the intended aims of the prevailing circumstances—and the use of the compositions for controlling pests of the abovementioned type are other subjects of the invention. Typical rates of concentration are between 0.1 and 1000 ppm, preferably between 0.1 and 500 ppm, of active ingredient. The rate of application per hectare is generally 1 to 2000 g of active ingredient per hectare, in particular 10 to 1000 g/ha, preferably 10 to 600 g/ha.
[0452] A preferred method of application in the field of crop protection is application to the foliage of the plants (foliar application), it being possible to select frequency and rate of application to match the danger of infestation with the pest in question. Alternatively, the active ingredient can reach the plants via the root system (systemic action), by drenching the locus of the plants with a liquid composition or by incorporating the active ingredient in solid form into the locus of the plants, for example into the soil, for example in the form of granules (soil application). In the case of paddy rice crops, such granules can be metered into the flooded paddy-field.
[0453] The compounds of the invention and compositions thereof are also be suitable for the protection of plant propagation material, for example seeds, such as fruit, tubers or kernels, or nursery plants, against pests of the abovementioned type. The propagation material can be treated with the compound prior to planting, for example seed can be treated prior to sowing. Alternatively, the compound can be applied to seed kernels (coating), either by soaking the kernels in a liquid composition or by applying a layer of a solid composition. It is also possible to apply the compositions when the propagation material is planted to the site of application, for example into the seed furrow during drilling. These treatment methods for plant propagation material and the plant propagation material thus treated are further subjects of the invention. Typical treatment rates would depend on the plant and pest/fungi to be controlled and are generally between 1 to 200 grams per 100 kg of seeds, preferably between 5 to 150 grams per 100 kg of seeds, such as between 10 to 100 grams per 100 kg of seeds.
[0454] The term seed embraces seeds and plant propagules of all kinds including but not limited to true seeds, seed pieces, suckers, corns, bulbs, fruit, tubers, grains, rhizomes, cuttings, cut shoots and the like and means in a preferred embodiment true seeds.
[0455] The present invention also comprises seeds coated or treated with or containing a compound of formula I. The term “coated or treated with and/or containing” generally signifies that the active ingredient is for the most part on the surface of the seed at the time of application, although a greater or lesser part of the ingredient may penetrate into the seed material, depending on the method of application. When the said seed product is (re)planted, it may absorb the active ingredient. In an embodiment, the present invention makes available a plant propagation material adhered thereto with a compound of formula (I). Further, it is hereby made available, a composition comprising a plant propagation material treated with a compound of formula (I).
[0456] Seed treatment comprises all suitable seed treatment techniques known in the art, such as seed dressing, seed coating, seed dusting, seed soaking and seed pelleting. The seed treatment application of the compound formula (I) can be carried out by any known methods, such as spraying or by dusting the seeds before sowing or during the sowing/planting of the seeds.
Biological Examples
Example B1: Bemisia tabaci (Cotton White Fly): Feeding/Contact Activity
[0457] Cotton leaf discs were placed on agar in 24-well microtiter plates and sprayed with aqueous test solutions prepared from 10'000 ppm DMSO stock solutions. After drying the leaf discs were infested with adult white flies. The samples were checked for mortality 6 days after incubation. The following compounds resulted in at least 80% mortality at an application rate of 200 ppm: P9, P13 and P14.
Example B2: Diabrotica balteata (Corn Root Worm)
[0458] Maize sprouts placed onto an agar layer in 24-well microtiter plates were treated with aqueous test solutions prepared from 10'000 ppm DMSO stock solutions by spraying. After drying, the plates were infested with L2 larvae (6 to 10 per well). The samples were assessed for mortality and growth inhibition in comparison to untreated samples 4 days after infestation. The following compounds gave an effect of at least 80% in at least one of the two categories (mortality or growth inhibition) at an application rate of 200 ppm: P1, P2, P3, P4, P5, P6, P7, P8, P9, P10, P11, P12, P13, P14, and P15.
Example B3: Euschistus heros (Neotropical Brown Stink Bug)
[0459] Soybean leaves on agar in 24-well microtiter plates were sprayed with aqueous test solutions prepared from 10'000 ppm DMSO stock solutions. After drying the leaves were infested with N2 nymphs. The samples were assessed for mortality and growth inhibition in comparison to untreated samples 5 days after infestation. The following compounds gave an effect of at least 80% in at least one of the two categories (mortality or growth inhibition) at an application rate of 200 ppm:
P1, P3, P8, P9, P10, P13, P14, and P15
Example B4: Myzus persicae (Green Peach Aphid): Feeding/Contact Activity
[0460] Sunflower leaf discs were placed onto agar in a 24-well microtiter plate and sprayed with aqueous test solutions prepared from 10'000 ppm DMSO stock solutions. After drying, the leaf discs were infested with an aphid population of mixed ages. The samples were assessed for mortality 6 days after infestation. The following compounds resulted in at least 80% mortality at an application rate of 200 ppm: P10, P13, P14 and P15.
Example B5: Myzus persicae (Green Peach Aphid). Systemic Activity
[0461] Roots of pea seedlings infested with an aphid population of mixed ages were placed directly into aqueous test solutions prepared from 10'000 DMSO stock solutions. The samples were assessed for mortality 6 days after placing seedlings into test solutions. The following compound resulted in at least 80% mortality at a test rate of 24 ppm: P10.
Example B6: Plutella xylostella (Diamond Back Moth)
[0462] 24-well microtiter plates with artificial diet were treated with aqueous test solutions prepared from 10'000 ppm DMSO stock solutions by pipetting. After drying, the plates were infested with L2 larvae (10 to 15 per well). The samples were assessed for mortality and growth inhibition in comparison to untreated samples 5 days after infestation. The following compounds gave an effect of at least 80% in at least one of the two categories (mortality or growth inhibition) at an application rate of 200 ppm: P1, P2, P3, P4, P6, P8, P9, P10, P11, P12, P13, P14 and P15.
Example B7: Spodoptera littoralis (Egyptian Cotton Leaf Worm)
[0463] Cotton leaf discs were placed onto agar in 24-well microtiter plates and sprayed with aqueous test solutions prepared from 10'000 ppm DMSO stock solutions. After drying the leaf discs were infested with five L1 larvae. The samples were assessed for mortality, anti-feeding effect, and growth inhibition in comparison to untreated samples 3 days after infestation. Control of Spodoptera littoralis by a test sample is given when at least one of the categories mortality, anti-feedant effect, and growth inhibition is higher than the untreated sample. The following compounds resulted in at least 80% control at an application rate of 200 ppm: P1, P2, P3, P4, P5, P6, P8, P9, P10, P11, P12, P13, P14, and P15.
Example B8: Spodoptera littoralis (Egyptian Cotton Leaf Worm) Systemic Activity
[0464] Test compounds were applied by pipette from 10'000 ppm DMSO stock solutions into 24-well plates and mixed with agar. Lettuce seeds were placed onto the agar and the multi well plate was closed by another plate which contained also agar. After 7 days the compound was absorbed by the roots and the lettuce grew into the lid plate. The lettuce leaves were then cut off into the lid plate. Spodoptera eggs were pipetted through a plastic stencil onto a humid gel blotting paper and the lid plate was closed with it. The samples were assessed for mortality, anti-feedant effect and growth inhibition in comparison to untreated samples 6 days after infestation. The following compounds gave an effect of at least 80% in at least one of the three categories (mortality, anti-feeding, or growth inhibition) at a test rate of 12.5 ppm:
P10, P13, P14 and P15.
Example B9: Tetranychus urticae (Two-Spotted Spider Mite): Feeding/Contact Activity
[0465] Bean leaf discs on agar in 24-well microtiter plates were sprayed with aqueous test solutions prepared from 10'000 ppm DMSO stock solutions. After drying the leaf discs were infested with a mite population of mixed ages. The samples were assessed for mortality on mixed population (mobile stages) 8 days after infestation. The following compounds resulted in at least 80% mortality at an application rate of 200 ppm: P10 and P13.
Example B10: Thrips tabaci (Onion Thrips) Feeding/Contact Activity
[0466] Sunflower leaf discs were placed on agar in 24-well microtiter plates and sprayed with aqueous test solutions prepared from 10'000 ppm DMSO stock solutions. After drying the leaf discs were infested with a thrips population of mixed ages. The samples were assessed for mortality 6 days after infestation. The following compounds resulted in at least 80% mortality at an application rate of 200 ppm: P3 and P10.
Example B11: Aedes aegypti (Yellow Fever Mosquito)
[0467] Test solutions, at an application rate of 200 ppm in ethanol, were applied to 12 well tissue culture plates. Once the deposits were dry, five, two to five day old adult female Aedes aegypti were added to each well, and sustained with a 10% sucrose solution in a cotton wool plug. Assessment of knockdown was made one hour after introduction, and mortality was assessed at 24 and 48 hours after introduction. The following compounds gave at least 80% control of Aedes aegypti after 48 h and/or 24 h: P9, P10, P11, P13, P14 and P15.
Example B12: Anopheles stephensi (Indian Malaria Mosquito)
[0468] Test solutions, at an application rate of 200 ppm in ethanol, were applied to 12 well tissue culture plates. Once the deposits were dry, five, two to five day old adult female Anopheles stephensi were added to each well, and sustained with a 10% sucrose solution in a cotton wool plug. Assessment of knockdown was made one hour after introduction, and mortality was assessed at 24 and 48 hours after introduction. The following compounds gave at least 80% control of Anopheles stephensi after 48 h and/or 24 h: P10 and P13.
Comparative Example
[0469] Prior art compound: Compound V12.03 described on page 196 of WO 2015/000715:
##STR00179##
[0470] Compounds of this invention:
##STR00180##
[0471] The compounds V12.03, P1 and P3 are structurally identical except for the substitution pattern at the pyridine moiety. The pyridine moiety of the prior art compound V12.03 is unsubstituted, the compounds P1 and P3 of this invention are substituted by a pyrazole and phenyl group respectively at the 6-position of the pyridine ring. The pyrazole group is substituted by trifluoromethyl and the phenyl group is substituted by chloro.
Example B13
[0472] Insecticidal action against Diabrotica balteata (Corn root worm), Plutella xylostella (Diamond black moth), and Spodoptera littoralis (Egyptian cotton leaf worm). The tests were carried out as described in biological examples B2, B6 and B7, respectively, with the larval feeding/contact activity being reported as Breakpoint (BP.sub.80) values in parts per million (i.e. the lowest concentration which gives 80% larval mortality).
TABLE-US-00013 TABLE B13 Insecticidal action against Diabrotica balteata (Corn root worm), Plutella xylostella (Diamond black moth), and Spodoptera littoralis (Egyptian cotton leaf worm). BP.sub.80 Values in ppm Compound Diabrotica Plutella Spodoptera No. Compound balteata xylostella littoralis V12.03
[0473] As is evident from Table B13, the compounds P1 and P3 according to this invention show a superior insecticidal action against Diabrotica balteata (Corn root worm), Plutella xylostella (Diamond black moth), and Spodoptera littoralis (Egyptian cotton leaf worm) compared to compound V12.03 of the prior art.
[0474] This surprising enhancement of insecticidal activity was not to be expected in view of the close structural similarity of these compounds.
Example B14: Comparison of the Insecticidal Activity of Compounds of this Invention with the Prior Art
[0475] In order to demonstrate the surprising increase in insecticidal activity in comparison with the prior art, the insecticidal activity of the following compounds have been tested:
[0476] Prior art compound: Compound V12.01 described on page 196 of WO 2015/000715:
##STR00184##
[0477] Compounds of this invention:
##STR00185##
[0478] The compounds V12.01, P4 and P5 are structurally identical except for the substitution pattern at the pyridine moiety. The pyridine moiety of the prior art compound V12.03 is unsubstituted at the 6-position, the compounds P1 and P3 of this invention are substituted by a phenyl moiety at the 6-position of the pyridine moiety. The phenyl moiety is substituted by trifluoromethyl at the 3- and 4-position respectively. In all three compounds, the 5-position of the pyridine moiety is substituted by trifluoromethyl.
Example B14
[0479] Insecticidal action against Diabrotica balteata (Corn root worm). The test were carried out as described in biological example B6 with the larval feeding contact activity being reported as Breakpoint (BP.sub.80) values in parts per million (i.e. the lowest concentration which gives 80% larval mortality).
TABLE-US-00014 TABLE B14 Insecticidal action against Diabrotica balteata (Corn root worm). BP.sub.80 Values in ppm Compound Diabrotica No. Compound balteata V12.01
Table B14: Insecticidal Action Against
[0480] As is evident from Table B14, the compounds P4 and P5 according to this invention show a superior insecticidal action against Diabrotica balteata (Corn root worm) compared to compound V12.01 of the prior art.
[0481] This surprising enhancement of insecticidal activity was not to be expected in view of the close structural similarity of these compounds.