# Patent

## Title
N-substituted azacycles

## Abstract

N-substituted azacycle derivative compounds represented by formula (I):




    
    
        wherein m, q, r, t and u are independently selected from 0 or 1; and p is 0, 1, 2, or 3; and A, B, D, X, Y, R, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10 and R11 are fully described herein. The compounds being particularly useful in compositions comprising an insecticidally effective amount of at least one compound of formula I, and an insecticidally compatible carrier are also disclosed; along with methods of controlling insects comprising applying said compositions to a locus where insects are present or are expected to be present.

## Background
This application claims the benefit of U.S. Provisional Application No. 60/510,568, filed Oct. 10, 2003 and U.S. Provisional Application No. 60/609,533, filed Sep. 13, 2004.


FIELD OF THE INVENTION
The present invention generally relates to novel compounds, processes and intermediates useful in preparing such compounds, compositions containing such compounds and the use of such compounds in controlling insects. In particular, it pertains to N-substituted azacycle derivatives, N-oxides, and agriculturally acceptable salts thereof, compositions of these insecticides, and methods for their use in controlling insects.
BACKGROUND OF THE INVENTION
A longstanding worldwide demand exists for new, effective, less costly, and safe means to control pests in agricultural crops, greenhouse crops, nursery crops, ornamentals, turfs, forestry, stored food and fiber products, structures, livestock, households, and public and animal health. Agricultural crop costs incurred by pests exceed billions of dollars annually in decreased crop yields, reduced crop quality and increased harvesting costs. Agricultural crops include wheat, corn, soybeans, potatoes, and cotton to name a few. Soil-bourne insects, such as termites and white grubs, cause millions of dollars of damage to structures, turfs and ornamentals. Household pests, such as flies, ants and cockroaches, carry disease and are undesirable in peoples' homes. In addition to these pests, many blood-feeding insects are vectors for pathogenic microorganisms that threaten human and animal health, or are annoying at the least. Insecticides are desired which can control these pests without damaging crops, turfs, ornamentals or structures, and which have no deleterious effects to mammals and other living organisms.
A number of patents disclose a variety of insecticidally active azacycle derivatives. For example, as set forth in U.S. Pat. No. 5,569,664, compounds of the following structure are reported to be insecticidally active:




where U is selected from —(CH2)n— and ethylidine, where n is 1, 2, or 3; Q is selected from hydrogen, hydroxy, sulfhydryl, and fluorine; V is selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, alkylthio, alkylsulfinyl, alkylsilyloxy, dialkylamino, cyano, nitro, hydroxy, and phenyl; W is selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, nitro, amino, phenoxy, and phenylalkoxy; X is selected from hydrogen, hydroxy, halogen, alkyl, alkoxyalkyl, alkoxy, cycloalkylalkoxy, haloalkoxy, alkenyloxy, alkynyloxy, alkylsilyloxy, alkylthio, haloalkylthio, cyano, cyanoalkoxy, nitro, amino, monoalkylamino, dialkylamino, alkylaminoalkoxy, alkylcarbonylamino, alkoxycarbonylamino, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, aminocarbonyloxy, phenyl, phenylalkoxy, ohenoxy, and phenoxyalkyl; Y and Z are independently selected from hydrogen and alkoxy; R1 and R2 are independently selected from phenyl substituted with halogen, alkyl, haloalkyl, haloalkoxy, alkoxyalkyl, hydroxy, arylthio, alkoxy, dialkylamino, dialkylaminosulfonyl, hydroxyalkylaminocarbonyl, alkylsulfonyloxy, and haloalkylsulfonyloxy; and the corresponding N-oxides and agriculturally acceptable salts.
As set forth in U.S. Pat. No. 5,639,763 compounds of the following structure are reported to be insecticidally active:




where U is selected from —(CH2)n— and ethylidine, where n is 1, 2, or 3; Q is selected from hydrogen, hydroxy, sulfhydryl, and fluorine; V is selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, alkylthio, alkylsulfinyl, alkylsilyloxy, dialkylamino, cyano, nitro, hydroxy, and phenyl; Y and Z are independently selected from hydrogen and alkoxy; W and X taken together is —OCH2CH2O—, —CH2C(CH3)2O—, —OC(CH3)2O—, or —N═C(C2H5)O—; R1 and R2 are independently selected from phenyl substituted with halogen, alkyl, haloalkyl, haloalkoxy, alkoxyalkyl, hydroxy, arylthio, alkoxy, dialkylamino, dialkylaminosulfonyl, hydroxyalkylaminocarbonyl, alkylsulfonyloxy, and haloalkylsulfonyloxy; and the corresponding N-oxides and agriculturally acceptable salts.
As set forth in U.S. Pat. No. 5,795,901 compounds of the following structure are reported to be insecticidally active:




where V, W, Y, and Z are hydrogen; X is alkoxy, cycloalkoxy, alkoxycarbonyl, alkoxycarbonylamino, or a five- or six-membered heteroaryl or heteroaryloxy, each heteroaryl optionally substituted with halogen, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, or haloalkoxyalkyl; R1 and R2 are independently selected from haloalkyl, phenyl substituted with halogen, halothio, haloalkyl, or haloalkoxy; or a five- or six-membered heteroaryl substituted with halogen or alkyl; R3 is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, dialkylaminoalkyl, alkylaminocarbonyloxyalkyl, alkylthioalkyl, alkylsulfonylalkyl, alkylcarbonyloxyalkyl, alkoxycarbonylalkyl, carboxyalkyl, carboxyarylalkyl, arylcarbonyl, sulfonato, or sulfonatoalkyl, and may bear a negative charge resulting in an inner salt, and a separate anion is chloride, bromide, iodide, or a phenyl, or alkyl sulfate or sulfonate.
As set forth in U.S. Pat. No. 5,939,438 compounds of the following structure are reported to be insecticidally active:




where R is hydrogen, halogen, alkyl, alkoxy, or dialkylamino; R1 is hydrogen, alkyl, haloalkyl, alkoxyalkyl, alkylcarbonyl, or alkylaminocarbonyl; Q is fluoro or hydroxy; X is oxygen or NR2; Z is halogen, haloalkyl, haloalkoxy, pentahalothio, haloalkylthio, haloalkylsulfinyl, haloalkylsulfonyl, or —OCF2O— attached to two adjacent carbon atoms of the phenyl ring; n is 0 or 1; and, when X is NR2, R2 is hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, or R1 and R2 taken together may be —CmH2m—, or —C2H4OC2H4—, where m is 3-9; and their agriculturally acceptable salts.
As set forth in U.S. Pat. No. 6,017,931 compounds of the following structure are reported to be insecticidally active:




where V, W, and Z are hydrogen; X is selected from alkoxy, haloalkoxy, alkoxyalkyl, cycloalkylalkoxyl, halocycloalkylalkoxy, alkoxycarbonyl, haloalkoxycarbonyl, cycloalkylalkoxylcarbonyl, halocycloalkylalkoxylcarbonyl, alkoxyalkoxycarbonyl, alkoxycarbonylamino, haloalkoxycarbonylamino, cycloalkylalkoxycarbonylamino, halocycloalkylalkoxycarbonylamino, alkylaminocarbonyl, haloalkylaminocarbonyl, cyanoalkoxycarbonylamino, phenylcarbonylamino, and phenoxycarbonyl, each cycloalkyl moiety or phenyl ring optionally substituted with halogen; Y is selected from hydrogen or halogen; R1 and R2 are independently selected from phenyl or pyridyl, each substituted with haloalkyl, haloalkoxy, or alkylthio, and the corresponding N-oxides and agriculturally acceptable salts.
As set forth in U.S. Pat. No. 6,030,987 compounds of the following structure are reported to be insecticidally active:




where V, W, Y and Z are hydrogen; X is a five- or six-membered heterocycle optionally substituted with halogen, alkyl, alkoxy, alkoxyalkyl, cyano, aminocarbonyl, haloalkyl, haloalkoxy, or haloalkoxyalkyl; and the heterocycle is optionally connected to the phenyl ring through a —O—, —S—, —(CH2)p—, —C(O)—, or —O(CR3R4)q— linkage; R1 and R2 are independently selected from phenyl or pyridyl, each substituted with haloalkyl, or haloalkoxy; R3 and R4 are independently selected from hydrogen and methyl; n and p are independently 1, 2, or 3; and q is 1 or 2, and the corresponding N-oxides and agriculturally acceptable salts.
As set forth in U.S. Pat. No. 6,184,234 compounds of the following structure are reported to be insecticidally active:




where V, W, Y and Z are hydrogen; X is a five- or six-membered heterocycle optionally substituted with bromine, chlorine, fluorine, alkyl, alkoxy, alkoxyalkyl, cyano, aminocarbonyl, haloalkyl, haloalkoxy, or haloalkoxyalkyl; and the heterocycle is optionally connected to the phenyl ring through a —O—, —S—, —(CH2)p—, —C(O)—, or —O(CR3R4)q— linkage; R1 and R2 are independently selected from i) phenyl or pyridyl, each substituted with pentahalothio, haloalkylthio, haloalkylsulfinyl, or haloalkylsulfonyl; ii) phenyl substituted with —OC(M)2O—, where M is bromine, chlorine, or fluorine to provide a dihalobenzodioxolyl fused ring; or iii) pyridyl substituted with —OC(M)2O—, to provide a dihalodioxoleneopyridyl fused ring; R3 and R4 are independently selected from hydrogen and methyl; n and p are independently 1, 2, or 3; and q is 1 or 2, and the corresponding N-oxides and agriculturally acceptable salts.
As set forth in United States Statutory Invention Registration H1,838 compounds of the following structure are reported to be insecticidally active:




where m is 2 or 3; n is 0 or 1; W is hydrogen or alkoxy; X is hydrogen, alkoxy, cycloalkylalkoxy, haloalkoxyimino, or a five- or six-membered heteroaryl or heteroaryloxy in which one or more hetero atoms may be optionally substituted with alkyl; R1 and R2 are independently selected from hydrogen, haloalkyl, halothio, or haloalkoxy; and when n is 1, Y represents (a) an N-oxide of the ring nitrogen; or (b) an agriculturally acceptable anionic salt of the ring nitrogen; or (c) forms an OR3 linkage in which R3 is selected from hydrogen, alkyl, alkoxycarbonylalkyl, hydroxycarbonylethyl in association with an agriculturally acceptable anion resulting in an ionic salt, or R3 is an oxycarbonylalkyl group bearing a negative charge resulting in an inner salt.
As set forth in United States Statutory Invention Registration H1,996 photostable, agriculturally acceptable acid salts of an organic or inorganic acid of the following structure are reported to be insecticidally active:




where R is alkoxycarbonyl, alkoxycarbonylamino, cycloalkylalkoxy, 2-alkyl-2H-tetrazol-5-yl, or 2-haloalkyl-2H-tetrazol-5-yl; R1 is trihaloalkyl, or trihaloalkoxy; n is 0, or 1; and said salt is at least 2.5 times more photostable than its non-ionic parent and is derived from hydrochloric acid, hydrobromic acid, boric acid, phosphoric acid, maleic acid, fumaric acid, phthalic acid, D-glucuronic acid; the sulfonic acid R2SO3H where R2 is alkyl, haloalkyl, hydroxyalkyl, D-10-camphoryl, or phenyl optionally substituted with alkyl or halogen; the carboxylic acid R3CO2H where R3 is hydrogen, alkyl, trihaloalkyl, carboxyl, phenyl optionally substituted with alkyl or halogen, or pyridyl; the boronic acid R4B(OH)2 where R4 is alkyl or phenyl optionally substituted with alkyl or halogen; the phosphonic acid R5PO3H2 where R5 is alkyl, haloalkenyl, or phenyl optionally substituted with alkyl or halogen; the sulfuric acid R6OSO3H where R6 is hydrogen or alkyl; or the alkanoic acid X—(CH2)qCO2H where q is 0 to 11, X is halogen, trihaloalkyl, haloalkenyl, cyano, aminocarbonyl, or CO2R7 where R7 is hydrogen or alkyl.
As set forth in United States Statutory Invention Registration H2,007 compounds of the following structures are reported to be insecticidally active:




where A and B are independently selected from lower alkyl; U is selected from lower alkylidene, lower alkenylidene, and CH-Z, where Z is selected from hydrogen, lower alkyl, lower cycloalkyl, or phenyl; R is —CHR3R4 where R3 and R4 are independently selected from phenyl, optionally substituted with halogen, lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, lower alkenyl, or phenyl; R1 is phenyl, naphthyl, tetrazolylphenyl, phenylcyclopropyl, phenoxyphenyl, benzyloxyphenyl, pyridylphenyl, pyridyloxyphenyl, or thiadiazolyloxyphenyl, each optionally substituted with halogen, cyano, hydroxy, lower alkyl, lower haloalkyl, lower alkoxy, amino, lower dialkylamino, nitro, lower haloalkylsulfonyloxy, lower alkylcarbonyloxy, lower alkylcarbonylamino, lower alkoxycarbonyl, lower alkoxyalkoxycarbonyl, lower cycloalkylalkoxycarbonyl, lower alkoxyalkylalkoxycarbonyl, lower alkoxycarbonylamino, alkoxythiocarbonylamino, lower alkyldithiocarbonylamino, lower dialkyldioxolylalkoxycarbonylamino, or halophenylamino; or lower alkyl substituted with any one of the foregoing cyclic R1 groups; m is 2 or 3; and n is 1, 2, or 3.
As set forth in unexamined Japanese Patent Application 2002-220372 compounds of the following structures are reported to be insecticidally active:




where R1 and R2 are independently selected from hydrogen, halogen, lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, or lower alkylsulfonyloxy; R2 is selected from hydrogen, lower alkyl, lower alkenyl, lower alkoxyalkyl, or lower alkylcarbonyl; X and Y are independently oxygen or sulfur; R3 is selected from lower alkenyl, or lower alkynyl, which are optionally substituted with hydroxy, halogen, lower alkoxy, lower haloalkoxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, lower cycloalkyl, lower alkoxyalkoxy, amino, lower alkylamino, lower dialkylamino, lower alkoxycarbonyl, nitro, cyano, trimethylsilyl, phenyl, or lower cycloalkenyl; and the corresponding N-oxides and salts.
As set forth in PCT Publication WO 02/068392A1 compounds of the following structures are reported to be insecticidally active:




where R1 and R2 are independently selected from halogen, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkoxy, haloC1-C6alkoxy, —S(═O)p—R9, or SF5; R3 is hydrogen, hydroxy, C1-C6alkoxy, or —OC(═O)—C1-C6alkyl; R4 is hydrogen, halogen, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkoxy, haloC1-C6alkoxy, or —S(═O)p—R9, or —SCN; R5 and R6 are independently selected from C1-C12alkyl, haloC1-C1-2alkyl, C2-C12alkenyl, haloC2-C12alkenyl, C2-C12alkynyl, haloC2-C12alkynyl, C3-C8cycloalkyl, —C(═O)—OR7, —C(═S)—OR8, —C(═Y)-ZR8, —S(═O)p—R9, aryl, arylC1-C6alkyl, heterocycle, heterocycleC1-C6alkyl, each substituted in the ring from one to five times independently of one another by halogen, hydroxy, cyano, nitro, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkoxy, haloC1-C6alkoxy; or in common together with the nitrogen atom to which they are attached to form a heterocyclic ring which is substituted or unsubstituted; Y is oxygen or sulfur; X is a bond, —NR10—, or sulfur; R7 is C1-C6alkoxy-C1-C6alkyl, C1-C6alkylthio-C1-C6alkyl, C1-C6alkylamino-C1-C6alkyl, C3-C6alkynyl, C1-C6alkyl-S(═O)p—C1-C6alkyl, C3-C8cycloalkyl, aryl, aryl-C1-C6alkyl, heterocyclyl, or heterocyclyl-C1-C6alkyl each substituted in the ring from one to five times independently of one another by halogen, cyano, nitro, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkoxy, or haloC1-C6alkoxy; R8 is C1-C6alkyl, haloC1-C6alkyl, C1-C6alkoxy-C1-C6alkyl, C1-C6alkylthio-C1-C6alkyl, C2-C6alkenyl, C3-C6alkynyl, C1-C6alkyl-S(═O)p—C1-C6alkyl, C3-C8cycloalkyl, aryl, aryl-C1-C6alkyl, heterocyclyl, or heterocyclyl-C1-C6alkyl, or is C3-C8cycloalkyl, aryl, aryl-C1-C6alkyl, heterocyclyl, or heterocyclyl-C1-C6alkyl each substituted in the ring from one to five times independently of one another by halogen, cyano, nitro, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkoxy, or haloC1-C6alkoxy; R9 is C1-C6alkyl, C3-C8cycloalkyl, haloC1-C6alkyl, or benzyl; R10 is hydrogen, C1-C6alkyl, C3-C8cycloalkyl, haloC1-C6alkyl, or benzyl; p is 0, 1, or 2; q is 0 or 1; and, where appropriate, E/Z isomers, E/Z isomer mixtures and/or toutomers, each in free form or in salt form.
As set forth in PCT Publication WO 200020409A1 compounds of the following structures are reported to be insecticidally active:




where R1 is halo, C1-C4alkyl, C1-C4alkoxy, C1-C4haloalkyl, C1-C4haloalkoxy; R2 is hydrogen, hydroxyl, halo, C1-C4alkyl, C1-C4alkoxy, C1-C4alkoxycarbonyl, C1-C4alkylthio, C1-C4alkylsulfonyl, optionally substituted phenyl or carbamoyl; Z is O or S(O)p, p is 0 or 2; and m and n are 0 or 1.
As set forth in PCT Publication WO 03/022808A1 compounds of the following structures are reported to be insecticidally active:




where R1 is an aryl or heteroaryl that is optionally identically or differently substituted once or several times; R2 and R3 are independently selected from aryl or heteroaryl that is optionally identically or differently substituted once or several times, whereby both groups can also be bridged by a common substitutent; M is optionally substituted (CH2)I, where I is 1, 2 or 3, CO or —HNC(O); X is H, OH, halogen, OR4 or CN; Y is (O), H, OH, OR4, R4; (in the last four groups, in which nitrogen has a positive charge, in combination with a corresponding anion); R4 is identical or different and represents C1-C4alkyl, C1-C4alkanoyl, C1-C4haloalkyl; m is 0, 1, 2, 3 or 4; and n is 0 or 1.
There is no disclosure or suggestion in any of the citations set forth above of the azacycle derivatives of the present invention.
SUMMARY OF THE INVENTION
In accordance with the present invention, it has now been found that N-substituted azacycle derivatives of Formula I and salts thereof having a substituent X as indicated in the Formula have improved insecticidal activity. The compounds of formula I are represented by the following general formula I:




wherein;

    m, q, r, t and u are independently selected from 0 or 1; and p is 0, 1, 2, or 3;
    X is selected from halogen, hydroxyl, hydroxyalkyl, alkyl, alkoxy, haloalkyl, haloalkoxy, thio, alkylthio, acetoxyalkyl, azidoalkyl, aminoalkyl, acetylaminoalkyl, alkylsulfonyl, alkylsulfoxy, pentahalothio, cyano, nitro, acetyloxy, alkylsulfonyloxy, alkylcarbonyl, alkoxycarbonyl, aryl, or aryloxy;
    Y is selected from hydrogen, halogen, alkyl, haloalkyl, hydroxyl, hydroxyalkyl, alkoxy, haloalkoxy, thio, alkylthio, pentahalothio, cyano, nitro, alkylsulfonyl, alkylsulfoxy, alkylsulfonyloxy, alkylcarbonyl, alkoxycarbonyl, aryl, or aryloxy; or
    X and Y taken together with —OCR12R13O—, form a 1,3-dioxolane ring; where
    R12 and R13 are independently selected from hydrogen, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkylthio, cyano, nitro, alkylsulfonyloxy, alkylcarbonyl, alkoxycarbonyl, aryl, or aryloxy; or
    R12 and R13 taken together with (═O), form 1,3-dioxol-2-one ring;
    R1, R2, R3, R4, and R5 are independently selected from hydrogen, halogen, alkyl, haloalkyl, hydroxyl, hydroxyalkyl, alkoxy, haloalkoxy, thio, alkylthio, haloalkylthio, pentahalothio, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyloxy, haloalkylsulfonyloxy, alkylcarbonyl, alkoxycarbonyl, dialkoxyalkylcarbonyl, alkoxycarbonylamino, alkylaminoxyalkyl, alkoxyiminoalkyl, alkenyloxyiminoalkyl, aryl, aryloxy, dioxanyl, dioxolanyl or either of R1 and R2, or R2 and R3, or R3 and R4, or R4 and R5 taken together with —OC(R19)2O—, —OC(R19)2(R19)2O—, —OC(R19)2(R19)2—, —OC(R19)═N—, or —SC(R19)═N—, forming a benzo-fused ring, where R19 is hydrogen, halogen, alkyl or haloalkyl; and, wherein at least one of R1, R2, R3, R4, and R5 is other than hydrogen;
    R7, R8, R9, R10, and R11 are independently selected from hydrogen, halogen, alkyl, hydroxy, hydroxyalkyl, hydroxyalkoxy, alkoxy, alkoxyalkyl, alkoxyiminoalkyl, haloalkoxyiminoalkyl, cyanoalkoxyiminoalkyl, cyanoiminothioalkylamino, alkenyloxyiminoalkyl, alkynyloxyiminoalkyl, cycloalkoxy, cycloalkylalkoxy, phenoxy, alkoxycarbonylphenoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkylthio, alkylsulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, cycloalkylaminosulfonyl, alkenyloxy, alkynyloxy, haloalkenyloxy, alkylsulfonyloxy, optionally substituted arylalkoxy, cyano, nitro, amino, alkylamino, alkylcarbonylamino, alkoxycarbonylamino, cycloalkylalkoxycarbonylamino, alkenyloxycarbonylamino, alkynyloxycarbonylamino, haloalkylcarbonylamino, alkoxyalkoxycarbonylamino, alkoxycarbonylamino, alkoxycarbonyloxy, alkenylaminocarbonyloxy, alkynylaminocarbonyloxy, (alkyl)(alkoxycarbonyl)amino, alkylsulfonylamino, optionally substituted (heteroaryl)(alkoxycarbonyl)amino, optionally substituted arylcarbonylamino, alkoxycarbonyl, alkylaminocarbonyloxy, alkylaminocarbonylamino, dialkylaminocarbonylamino, alkylamino(thiocarbonyl)amino, dialkylphosphoroureidyl, acetoxyalkoxy, sulfonyloxyalkoxy, dialkoxyalkoxy, trialkoxyalkoxy, dialkoxyalkylacetal, trialkoxymethylorthoester, cyclic acetal, optionally substituted cyclic acetal, optionally substituted thienyl, optionally substituted 1,3-thiazolylalkoxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted aryloxyalkyl, optionally substituted arylaminocarbonyloxy, optionally substituted arylalkoxycarbonylamino, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted pyrrolyl, optionally substituted pyrazolyl, optionally substituted pyrazinyloxy, optionally substituted cycloalkylcarbonylamino, optionally substituted 1,3-oxazolinyl, optionally substituted 1,3-oxazolinyloxy, optionally substituted 1,3-oxazolinylamino, optionally substituted 1,2,4-triazolyl, optionally substituted 1,2,3-thiadiazolyl, optionally substituted 1,2,5-thiadiazolyl, optionally substituted 1,2,5-thiadiazolyloxy, optionally substituted 2H-tetrazolyl, optionally substituted pyridyl, optionally substituted pyridyloxy, optionally substituted pyridylamino, optionally substituted pyrimidinyl, optionally substituted pyrimidinyloxy, optionally substituted 3,4,5,6-tetrahydropyrimidinyloxy, optionally substituted pyridazinyloxy, or optionally substituted 1,2,3,4-tetrahydronaphthalenyl, wherein the optional substituent is selected from one or more of halogen, alkyl, haloalkyl, alkoxy, cyano, nitro, amino, alkylcarbonyl, alkoxycarbonyl, alkoxyiminoalkyl, dialkylacetal, alkylthiol, alkylsulfoxide, or alkoxycarbonylamino; and, wherein at least one of R7, R8, R9, R10, and R11 is other than hydrogen;
    R is alkyl, cycloalkyl, alkenyl, alkoxycarbonyl, optionally substituted pyrid-2-yl wherein the optional substituent is selected from hydrogen, halogen, haloalkoxy or haloalkyl, or
    substituted phenyl have the following structure,






where

    R14, R15, R16, R17, and R18 are independently selected from hydrogen, halogen, alkyl, haloalkyl, hydroxyl, hydroxyalkyl, alkoxy, haloalkoxy, thio, alkylthio, haloalkylthio, pentahalothio, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyloxy, haloalkylsulfonyloxy, alkylcarbonyl, alkoxycarbonyl, dialkoxyalkylcarbonyl, alkoxycarbonylamino, alkylaminoxyalkyl, alkoxyiminoalkyl, alkenyloxyiminoalkyl, aryl, aryloxy, dioxanyl, dioxolanyl or either of R14 and R15, or R15 and R16, or R16 and R17, or R17 and R18 taken together with —OC(R19)2O—, —OC(R19)2(R19)2O—, —OC(R19)2(R19)2—, —OC(R19)═N—, or —SC(R19)═N—, forming a benzo-fused ring, where R19 is hydrogen, halogen, alkyl or haloalkyl; and, wherein at least one of R14, R15, R16, R17, and R18 is other than hydrogen;
    A is selected from —CH2—, —CH2CH2—, —CH2CH2CH2—, —OCH2CH2—, —OCH2CH2CH2—, —OCH2CH2CH2CH2—, —OCH2CH(OH)CH2—, —NHCH2CH2—, —N(CH3)CH2CH2—, —N[C(═O)CH3]CH2CH2—, or —N[C(═O)OCH3]CH2CH2—;
    B is selected from —O—, —S—, —CH2O—, —OCH2—, —OC(═O)NH—, —OC(═O)O—, or —NHSO2—;
    when p is 1, 2, or 3;
    D is —CH2—;
    R6 is selected from alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, dialkylaminoalkyl, alkylaminocarbonyloxyalkyl, alkylthioalkyl, alkylsulfonylalkyl, alkylcarbonyloxyalkyl, alkoxycarbonylalkyl, carboxyalkyl, arylalkyl, arylcarbonyl, sulfonato, or sulfonatoalkyl, and may bear a negative charge resulting in an inner salt; and a separate ion is chloride, bromide, iodide, or an alkyl or phenyl sulfate or sulfonate; and

agriculturally-acceptable salts thereof.



The present invention is also directed to compositions containing an insecticidally effective amount of at least one of a compound of formula I, and optionally, an effective amount of at least one of a second compound, with at least one agriculturally acceptable extender or adjuvant.
The present invention is also directed to methods of controlling insects, where control is desired, which comprise applying an insecticidally effective amount of the above composition to the locus of crops, or other areas where insects are present or are expected to be present. Other aspects of the present invention will become apparent.


DETAILED DESCRIPTION OF THE INVENTION
One aspect of the present invention relates to certain new and useful compounds, namely certain novel N-substituted azacycle derivatives as depicted in general formula I:




wherein;

    m, q, r, t and u are independently selected from 0 or 1; and p is 0, 1, 2, or 3;
    X is selected from halogen, hydroxyl, hydroxyalkyl, alkyl, alkoxy, haloalkyl, haloalkoxy, thio, alkylthio, acetoxyalkyl, azidoalkyl, aminoalkyl, acetylaminoalkyl, alkylsulfonyl, alkylsulfoxy, pentahalothio, cyano, nitro, acetyloxy, alkylsulfonyloxy, alkylcarbonyl, alkoxycarbonyl, aryl, or aryloxy;
    Y is selected from hydrogen, halogen, alkyl, haloalkyl, hydroxyl, hydroxyalkyl, alkoxy, haloalkoxy, thio, alkylthio, pentahalothio, cyano, nitro, alkylsulfonyl, alkylsulfoxy, alkylsulfonyloxy, alkylcarbonyl, alkoxycarbonyl, aryl, or aryloxy; or
    X and Y taken together with —OCR12R13O—, form a 1,3-dioxolane ring; where
    R12 and R13 are independently selected from hydrogen, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkylthio, cyano, nitro, alkylsulfonyloxy, alkylcarbonyl, alkoxycarbonyl, aryl, or aryloxy; or
    R12 and R13 taken together with (═O), form 1,3-dioxol-2-one ring;
    R1, R2, R3, R4, and R5 are independently selected from hydrogen, halogen, alkyl, haloalkyl, hydroxyl, hydroxyalkyl, alkoxy, haloalkoxy, thio, alkylthio, haloalkylthio, pentahalothio, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyloxy, haloalkylsulfonyloxy, alkylcarbonyl, alkoxycarbonyl, dialkoxyalkylcarbonyl, alkoxycarbonylamino, alkylaminoxyalkyl, alkoxyiminoalkyl, alkenyloxyiminoalkyl, aryl, aryloxy, dioxanyl, dioxolanyl or either of R1 and R2, or R2 and R3, or R3 and R4, or R4 and R5 taken together with —OC(R19)2O—, —OC(R19)2(R19)2O—, —OC(R19)2(R19)2—, —OC(R19)═N—, or —SC(R19)═N—, forming a benzo-fused ring, where R19 is hydrogen, halogen, alkyl or haloalkyl; and, wherein at least one of R1, R2, R3, R4, and R5 is other than hydrogen;
    R7, R8, R9, R10, and R11 are independently selected from hydrogen, halogen, alkyl, hydroxy, hydroxyalkyl, hydroxyalkoxy, alkoxy, alkoxyalkyl, alkoxyiminoalkyl, haloalkoxyiminoalkyl, cyanoalkoxyiminoalkyl, cyanoiminothioalkylamino, alkenyloxyiminoalkyl, alkynyloxyiminoalkyl, cycloalkoxy, cycloalkylalkoxy, phenoxy, alkoxycarbonylphenoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkylthio, alkylsulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, cycloalkylaminosulfonyl, alkenyloxy, alkynyloxy, haloalkenyloxy, alkylsulfonyloxy, optionally substituted arylalkoxy, cyano, nitro, amino, alkylamino, alkylcarbonylamino, alkoxycarbonylamino, cycloalkylalkoxycarbonylamino, alkenyloxycarbonylamino, alkynyloxycarbonylamino, haloalkylcarbonylamino, alkoxyalkoxycarbonylamino, alkoxycarbonylamino, alkoxycarbonyloxy, alkenylaminocarbonyloxy, alkynylaminocarbonyloxy, (alkyl)(alkoxycarbonyl)amino, alkylsulfonylamino, optionally substituted (heteroaryl)(alkoxycarbonyl)amino, optionally substituted arylcarbonylamino, alkoxycarbonyl, alkylaminocarbonyloxy, alkylaminocarbonylamino, dialkylaminocarbonylamino, alkylamino(thiocarbonyl)amino, dialkylphosphoroureidyl, acetoxyalkoxy, sulfonyloxyalkoxy, dialkoxyalkoxy, trialkoxyalkoxy, dialkoxyalkylacetal, trialkoxymethylorthoester, cyclic acetal, optionally substituted cyclic acetal, optionally substituted thienyl, optionally substituted 1,3-thiazolylalkoxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted aryloxyalkyl, optionally substituted arylaminocarbonyloxy, optionally substituted arylalkoxycarbonylamino, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted pyrrolyl, optionally substituted pyrazolyl, optionally substituted pyrazinyloxy, optionally substituted cycloalkylcarbonylamino, optionally substituted 1,3-oxazolinyl, optionally substituted 1,3-oxazolinyloxy, optionally substituted 1,3-oxazolinylamino, optionally substituted 1,2,4-triazolyl, optionally substituted 1,2,3-thiadiazolyl, optionally substituted 1,2,5-thiadiazolyl, optionally substituted 1,2,5-thiadiazolyloxy, optionally substituted 2H-tetrazolyl, optionally substituted pyridyl, optionally substituted pyridyloxy, optionally substituted pyridylamino, optionally substituted pyrimidinyl, optionally substituted pyrimidinyloxy, optionally substituted 3,4,5,6-tetrahydropyrimidinyloxy, optionally substituted pyridazinyloxy, or optionally substituted 1,2,3,4-tetrahydronaphthalenyl, wherein the optional substituent is selected from one or more of halogen, alkyl, haloalkyl, alkoxy, cyano, nitro, amino, alkylcarbonyl, alkoxycarbonyl, alkoxyiminoalkyl, dialkylacetal, alkylthiol, alkylsulfoxide, or alkoxycarbonylamino; and, wherein at least one of R7, R8, R9, R10, and R11 is other than hydrogen;
    R is alkyl, cycloalkyl, alkenyl, alkoxycarbonyl, optionally substituted pyrid-2-yl wherein the optional substituent is selected from hydrogen, halogen, haloalkoxy or haloalkyl, or
    substituted phenyl have the following structure,






where

    R14, R15, R16, R17, and R18 are independently selected from hydrogen, halogen, alkyl, haloalkyl, hydroxyl, hydroxyalkyl, alkoxy, haloalkoxy, thio, alkylthio, haloalkylthio, pentahalothio, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyloxy, haloalkylsulfonyloxy, alkylcarbonyl, alkoxycarbonyl, dialkoxyalkylcarbonyl, alkoxycarbonylamino, alkylaminoxyalkyl, alkoxyiminoalkyl, alkenyloxyiminoalkyl, aryl, aryloxy, dioxanyl, dioxolanyl or either of R14 and R15, or R15 and R16, or R16 and R17, or R17 and R18 taken together with —OC(R19)2O—, —OC(R19)2(R19)2-0—, —OC(R19)2(R19)2—, —OC(R19)═N—, or —SC(R19)═N—, forming a benzo-fused ring, where R19 is hydrogen, halogen, alkyl or haloalkyl; and, wherein at least one of R14, R15, R16, R17, and R18 is other than hydrogen;
    A is selected from —CH2—, —CH2CH2—, —CH2CH2CH2—, —OCH2CH2—, —OCH2CH2CH2—, —OCH2CH2CH2CH2—, —OCH2CH(OH)CH2—, —NHCH2CH2—, —N(CH3)CH2CH2—, —N[C(═O)CH3]CH2CH2—, or —N[C(═O)OCH3]CH2CH2—;
    B is selected from —O—, —S—, —CH2O—, —OCH2—, —OC(═O)NH—, —OC(═O)O—, or —NHSO2—;
    when p is 1, 2, or 3;
    D is —CH2—;
    R6 is selected from alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, dialkylaminoalkyl, alkylaminocarbonyloxyalkyl, alkylthioalkyl, alkylsulfonylalkyl, alkylcarbonyloxyalkyl, alkoxycarbonylalkyl, carboxyalkyl, arylalkyl, arylcarbonyl, sulfonato, or sulfonatoalkyl, and may bear a negative charge resulting in an inner salt; and a separate ion is chloride, bromide, iodide, or an alkyl or phenyl sulfate or sulfonate; and

agriculturally-acceptable salts thereof.



Within the scope set forth above, preferred compounds of the present invention are those of formula I wherein m, q and p are 0; t and u are 1; A is —CH2—; X is selected from halogen, hydroxyl or alkoxycarbonyl; Y is selected from hydrogen, halogen or hydroxyl; R1, R2, R3 and R4 are independently selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, —CH2(OH)CH3, —CH═NOC2H5, 1,3-dioxolan-2-yl, or R2 and R3 taken together with —OCF2O—; R5 is hydrogen; R7, R10 and R11 are hydrogen; R5 is selected from hydrogen, halogen, alkyl or alkoxy; R9 is selected from alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, cyclopropylmethoxy, 2-halophenoxy, 3-halophenoxy, 4-halophenoxy, pyrimidin-2-yl, pyrid-2-yl, 3-halo-pyrid-2-yl, 3-alkyl-pyrid-2-yloxy, 4-alkyl-pyrid-2-yloxy, 5-alkyl-pyrid-2-yloxy, 6-alkyl-pyrid-2-yloxy, 3-halo-pyrid-2-yloxy, 3-trihaloalkyl-pryid-2-yloxy, 3-cyano-pyrid-2-yloxy, 5-cyano-pyrid-2-yloxy, 6-dialkoxyalkyl-pyrid-2-yloxy, pyrid-2-yloxy, CO2CH(CH3)2, —CH═NOCH3, —CH═NOC2H5, —CH═NOCH2CF3, —CH═NOCH2CH═CH2, —CH═NOCH2CN, —CH═NOCH(CH3)2, —CH═NOCH2C≡CH, —CH═NOCH2CH2F, —CH═NOCH2CH2OCH3, —CH═NOCH2OC2H5, —CH═NOCH2CH2OCH2CH2OCH3, —NHCO2CH3, —NHCO2C2H5, —NHCO2CH(CH3)2, —NHCO2CH2-c-C3H5, —CH(OH)C6H5-p-Cl, —OC(═O)NHCH3, —OC(═O)NHC2H5, —OC(═O)NHCH(CH3)2, —NHC(SCH3)═NCN, pyrimidin-2-yloxy, 6-halo-pyridazin-3yloxy, 6-alkoxy-pyridazin-3yloxy, 6-alkyl-pyridazin-3yloxy, 2-alkyl-2H-tetrazol-5-yl, 1,3-dioxan-2-yl or 5,5-dialkyl-1,3-dioxan-2-yl; and R is phenyl substituted with R14, R15, R16, R17, and R18,




where

    R14, R15, R16 and R17 are independently selected from halogen, haloalkyl, haloalkoxy or R15 and R16 taken together with —OCF2O—; and R18 is hydrogen.


Within the scope set forth above, more preferred compounds of the present invention are those of formula I wherein X is selected from halogen, —CO2C2H5 or hydroxyl; and R9 is selected from —OC2H5, —OC3H7, —OCH(CH3)2, —OCH2CH2OCH3, —OCH2CH2CH2OCH3, cyclopropylmethoxy, 2-chlorophenoxy, 3-chlorophenoxy, 4-chlorophenoxy, pyrimidin-2-yl, pyrid-2-yl, 3-chloro-pyrid-2-yl, 3-methyl-pyrid-2-yloxy, 4-methyl-pyrid-2-yloxy, 5-methyl-pyrid-2-yloxy, 6-methyl-pyrid-2-yloxy, 3-chloro-pyrid-2-yloxy, 3-trifluoromethyl-pryid-2-yloxy, 3-cyano-pyrid-2-yloxy, 5-cyano-pyrid-2-yloxy, 6-dimethoxymethyl-pyrid-2-yloxy, pyrid-2-yloxy, —CO2CH(CH3)2, —CH═NOCH3, —CH═NOC2H5, —CH═NOCH2CF3, —CH═NOCH2CH═CH2, —CH═NOCH2CN, —CH═NOCH(CH3)2, —CH═NOCH2C≡CH, —CH═NOCH2CH2F, —CH═NOCH2CH2OCH3, —CH═NOCH2OC2H5, —CH═NOCH2CH2OCH2CH2OCH3, —NHCO2CH3, —NHCO2C2H5, —NHCO2CH(CH3)2, —NHCO2CH2-c-C3H5, —CH(OH)C6H5-p-Cl, —OC(═O)NHCH3, —OC(═O)NHC2H5, —OC(═O)NHCH(CH3)2, —NHC(SCH3)═NCN, pyrimidin-2-yloxy, 6-chloro-pyridazin-3yloxy, 6-methoxy-pyridazin-3yloxy, 6-methyl-pyridazin-3yloxy, 2-methyl-2H-tetrazol-5-yl, 2-ethyl-2H-tetrazol-5-yl, 1,3-dioxan-2-yl or 5,5-dimethyl-1,3-dioxan-2-yl.
Within the scope set forth above, even more preferred compounds of the present invention are those of formula I wherein X is selected from fluorine, —CO2C2H5 or hydroxyl; Y is selected from hydrogen, fluorine, chlorine or hydroxyl; R1, R2, R3 and R4 are independently selected from hydrogen, halogen, alkyl, tert-butyl, methoxy, trifluoromethyl, difluoromethoxy, trifluoromethoxy, —OCF2CHFCF3, —CH2(OH)CH3, —CH═NOC2H5, 1,3-dioxolan-2-yl, or R2 and R3 taken together with —OCF2O—; R5 is hydrogen; R9 is selected from —OCH2CH2OCH3, —CH═NOCH3, —CH═NOC2H5, —CH═NOCH2CN, —CH═NOCH2CH2OCH3, —NHCO2CH(CH3)2, —OC(═O)NHCH(CH3)2, pyrimidin-2-yl, pyrid-2-yl, 3-chloro-pyrid-2-yl, 3-methyl-pyrid-2-yloxy, 4-methyl-pyrid-2-yloxy, 5-methyl-pyrid-2-yloxy, 6-methyl-pyrid-2-yloxy, 3-chloro-pyrid-2-yloxy, 3-trifluoromethyl-pryid-2-yloxy, 3-cyano-pyrid-2-yloxy, 5-cyano-pyrid-2-yloxy, 6-dimethoxymethyl-pyrid-2-yloxy, pyrid-2-yloxy, pyrimidin-2-yloxy, 6-chloro-pyridazin-3yloxy, 6-methoxy-pyridazin-3yloxy or 6-methyl-pyridazin-3yloxy; and R is phenyl substituted with R14, R15, R16, R17, and R18,




where

    R14, R15, R16 and R17 are independently selected from fluorine, chlorine, trifluoromethyl, difluoromethoxy, trifluoromethoxy, —OCF2CHFCF3 or R15 and R16 taken together with —OCF2O—.


Within the scope set forth above, most preferred compounds of the present invention are those of formula I wherein X is hydroxyl; Y is hydrogen; R3 is haloalkoxy; R9 is selected —OCH2CH2OCH3, —CH═NOCH3, —CH═NOC2H5, —CH═NOCH2CN, —CH═NOCH2CH2OCH3, —NHCO2CH(CH3)2, OC(═O)NHCH(CH3)2, pyrid-2-yloxy, pyrid-2-yl, 3-cyano-pyrid-2-yloxy, 5-methyl-pyrid-2-yloxy, pyrimidin-2-yloxy, pyrimidin-2-yl, 6-chloro-pyridazin-3-yloxy or 6-methoxy-pyridazin-3-yloxy; and R16 is haloalkoxy.
An embodiment of the present invention is a compound of formula I:




wherein;

    m, q and r are independently selected from 0 or 1; t and u are 1; and p is 0;
    X is selected from halogen, hydroxyl, hydroxyalkyl, alkyl, alkoxy, haloalkyl, haloalkoxy, thio, alkylthio, acetoxyalkyl, azidoalkyl, aminoalkyl, acetylaminoalkyl, alkylsulfonyl, alkylsulfoxy, pentahalothio, cyano, nitro, acetyloxy, alkylsulfonyloxy, alkylcarbonyl, alkoxycarbonyl, aryl, or aryloxy;
    Y is selected from hydrogen, halogen, alkyl, haloalkyl, hydroxyl, hydroxyalkyl, alkoxy, haloalkoxy, thio, alkylthio, pentahalothio, cyano, nitro, alkylsulfonyl, alkylsulfoxy, alkylsulfonyloxy, alkylcarbonyl, alkoxycarbonyl, aryl, or aryloxy; or
    X and Y taken together with —OCR12R13O—, form a 1,3-dioxolane ring; where
    R12 and R13 are independently selected from hydrogen, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkylthio, cyano, nitro, alkylsulfonyloxy, alkylcarbonyl, alkoxycarbonyl, aryl, or aryloxy; or
    R12 and R13 taken together with (═O), form 1,3-dioxol-2-one ring;
    R1, R2, R3, R4, and R5 are independently selected from hydrogen, halogen, alkyl, haloalkyl, hydroxyl, hydroxyalkyl, alkoxy, haloalkoxy, thio, alkylthio, haloalkylthio, pentahalothio, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyloxy, haloalkylsulfonyloxy, alkylcarbonyl, alkoxycarbonyl, dialkoxyalkylcarbonyl, alkoxycarbonylamino, alkylaminoxyalkyl, alkoxyiminoalkyl, alkenyloxyiminoalkyl, aryl, aryloxy, dioxanyl, dioxolanyl or either of R1 and R2, or R2 and R3, or R3 and R4, or R4 and R5 taken together with —OC(R19)2O—, —OC(R19)2(R19)2O—, —OC(R19)2(R19)2—, —OC(R19)═N—, or —SC(R19)═N—, forming a benzo-fused ring, where R19 is hydrogen, halogen, alkyl or haloalkyl; and, wherein at least one of R1, R2, R3, R4, and R5 is other than hydrogen;
    R7, R8, R9, R10, and R11 are independently selected from hydrogen, halogen, alkyl, hydroxy, hydroxyalkyl, hydroxyalkoxy, alkoxy, alkoxyalkyl, alkoxyiminoalkyl, haloalkoxyiminoalkyl, cyanoalkoxyiminoalkyl, cyanoiminothioalkylamino, alkenyloxyiminoalkyl, alkynyloxyiminoalkyl, cycloalkoxy, cycloalkylalkoxy, phenoxy, alkoxycarbonylphenoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkylthio, alkylsulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, cycloalkylaminosulfonyl, alkenyloxy, alkynyloxy, haloalkenyloxy, alkylsulfonyloxy, optionally substituted arylalkoxy, cyano, nitro, amino, alkylamino, alkylcarbonylamino, alkoxycarbonylamino, cycloalkylalkoxycarbonylamino, alkenyloxycarbonylamino, alkynyloxycarbonylamino, haloalkylcarbonylamino, alkoxyalkoxycarbonylamino, alkoxycarbonylamino, alkoxycarbonyloxy, alkenylaminocarbonyloxy, alkynylaminocarbonyloxy, (alkyl)(alkoxycarbonyl)amino, alkylsulfonylamino, optionally substituted (heteroaryl)(alkoxycarbonyl)amino, optionally substituted arylcarbonylamino, alkoxycarbonyl, alkylaminocarbonyloxy, alkylaminocarbonylamino, dialkylaminocarbonylamino, alkylamino(thiocarbonyl)amino, dialkylphosphoroureidyl, acetoxyalkoxy, sulfonyloxyalkoxy, dialkoxyalkoxy, trialkoxyalkoxy, dialkoxyalkylacetal, trialkoxymethylorthoester, cyclic acetal, optionally substituted cyclic acetal, optionally substituted thienyl, optionally substituted 1,3-thiazolylalkoxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted aryloxyalkyl, optionally substituted arylaminocarbonyloxy, optionally substituted arylalkoxycarbonylamino, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted pyrrolyl, optionally substituted pyrazolyl, optionally substituted pyrazinyloxy, optionally substituted cycloalkylcarbonylamino, optionally substituted 1,3-oxazolinyl, optionally substituted 1,3-oxazolinyloxy, optionally substituted 1,3-oxazolinylamino, optionally substituted 1,2,4-triazolyl, optionally substituted 1,2,3-thiadiazolyl, optionally substituted 1,2,5-thiadiazolyl, optionally substituted 1,2,5-thiadiazolyloxy, optionally substituted 2H-tetrazolyl, optionally substituted pyridyl, optionally substituted pyridyloxy, optionally substituted pyridylamino, optionally substituted pyrimidinyl, optionally substituted pyrimidinyloxy, optionally substituted 3,4,5,6-tetrahydropyrimidinyloxy, optionally substituted pyridazinyloxy, or optionally substituted 1,2,3,4-tetrahydronaphthalenyl, wherein the optional substituent is selected from one or more of halogen, alkyl, haloalkyl, alkoxy, cyano, nitro, amino, alkylcarbonyl, alkoxycarbonyl, alkoxyiminoalkyl, dialkylacetal, alkylthiol, alkylsulfoxide, or alkoxycarbonylamino; and, wherein at least one of R7, R8, R9, R10, and R11 is other than hydrogen;
    R is alkyl, cycloalkyl, alkenyl, alkoxycarbonyl, optionally substituted pyrid-2-yl wherein the optional substituent is selected from hydrogen, halogen, haloalkoxy or haloalkyl, or
    substituted phenyl have the following structure,






where

    R14, R15, R16, R17, and R18 are independently selected from hydrogen, halogen, alkyl, haloalkyl, hydroxyl, hydroxyalkyl, alkoxy, haloalkoxy, thio, alkylthio, haloalkylthio, pentahalothio, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyloxy, haloalkylsulfonyloxy, alkylcarbonyl, alkoxycarbonyl, dialkoxyalkylcarbonyl, alkoxycarbonylamino, alkylaminoxyalkyl, alkoxyiminoalkyl, alkenyloxyiminoalkyl, aryl, aryloxy, dioxanyl, dioxolanyl or either of R14 and R15, or R15 and R16, or R16 and R17, or R17 and R18 taken together with —OC(R19)2O—, —OC(R19)2(R19)2O—, —OC(R19)2(R19)2—, —OC(R19)═N—, or —SC(R19)═N—, forming a benzo-fused ring, where R19 is hydrogen, halogen, alkyl or haloalkyl; and, wherein at least one of R14, R15, R16, R17, and R18 is other than hydrogen;
    A is selected from —CH2—, —CH2CH2—, —CH2CH2CH2—, —OCH2CH2—, —OCH2CH2CH2—, —OCH2CH2CH2CH2—, —OCH2CH(OH)CH2—, —NHCH2CH2—, —N(CH3)CH2CH2—, —N[C(═O)CH3]CH2CH2—, or —N[C(═O)OCH3]CH2CH2—;
    B is selected from —O—, —S—, —CH2O—, —OCH2—, —OC(═O)NH—, —OC(═O)O—, or —NHSO2—;


R6 is selected from alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, dialkylaminoalkyl, alkylaminocarbonyloxyalkyl, alkylthioalkyl, alkylsulfonylalkyl, alkylcarbonyloxyalkyl, alkoxycarbonylalkyl, carboxyalkyl, arylalkyl, arylcarbonyl, sulfonato, or sulfonatoalkyl, and may bear a negative charge resulting in an inner salt; and a separate ion is chloride, bromide, iodide, or an alkyl or phenyl sulfate or sulfonate.
Another embodiment of the present invention is a compound of formula I:




wherein;

    r is selected from 0 or 1; m, q and p are 0; t and u are 1;
    A is —CH2—;
    X is selected from halogen or hydroxyl;
    Y is selected from hydrogen or hydroxyl;
    R1, R2, R3 and R4 are independently selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy or —CH═NOC2H5;
    R5 is hydrogen;
    R7, R8, R10 and R11 are hydrogen;
    R9 is selected from —OC2H5, —OC3H7, —OCH(CH3)2, —OCH2CH2OCH3, —OCH2CH2CH2OCH3, cyclopropylmethoxy, 2-chlorophenoxy, 3-chlorophenoxy, 4-chlorophenoxy, pyrimidin-2-yl, pyrid-2-yl, 3-chloro-pyrid-2-yl, 3-methyl-pyrid-2-yloxy, 4-methyl-pyrid-2-yloxy, 5-methyl-pyrid-2-yloxy, 6-methyl-pyrid-2-yloxy, 3-chloro-pyrid-2-yloxy, 3-trifluoromethyl-pryid-2-yloxy, 3-cyano-pyrid-2-yloxy, 5-cyano-pyrid-2-yloxy, 6-dimethoxymethyl-pyrid-2-yloxy, pyrid-2-yloxy, CO2CH(CH3)2, —CH═NOCH3, —CH═NOC2H5, —CH═NOCH2CF3, —CH═NOallyl, —CH═NOCH2CH═CH2, —CH═NOCH2CN, —CH═NOCH(CH3)2, —CH═NOCH2C≡CH, —CH═NOCH2CH2F, —CH═NOCH2CH2OCH3, —CH═NOCH2OC2H5, —CH═NOCH2CH2OCH2CH2OCH3, —NHCO2CH3, —NHCO2C2H5, —NHCO2CH(CH3)2, —NHCO2CH2-c-C3H5, —CH(OH)C6H5-p-Cl, —OC(═O)NHCH3, —OC(═O)NHC2H5, —OC(═O)NHCH(CH3)2, —NHC(SCH3)═NCN, pyrimidin-2-yloxy, 6-chloro-pyridazin-3yloxy, 6-methoxy-pyridazin-3yloxy, 6-methyl-pyridazin-3yloxy, 2-methyl-2H-tetrazol-5-yl, 2-ethyl-2H-tetrazol-5-yl, 1,3-dioxan-2-yl or 5,5-dimethyl-1,3-dioxan-2-yl; and
    R is phenyl substituted with R14, R15, R16, R17, and R18,






where

    R16 is selected from haloalkyl or haloalkoxy, and R14, R15, R17 and R18 are hydrogen.


Another embodiment of the present invention is a compound of formula I-H or I-J:




wherein,

    R3 is haloalkyl or haloalkoxy;
    R9 is selected from —OCH2CH2OCH3, pyrid-2-yloxy, pyrid-2-yl, 3-cyano-pyrid-2-yloxy, 5-methyl-pyrid-2-yloxy, pyrimidin-2-yloxy, pyrimidin-2-yl, 6-chloro-pyridazin-3-yloxy or 6-methoxy-pyridazin-3-yloxy; and R16 is haloalkyl or haloalkoxy.


Yet another embodiment of the present invention is the compound:




namely, 4-{bis[4-(trifluoromethoxy)phenyl]methyl}-4-hydroxy-1-[(4-(2-pyridyloxy)phenyl)methyl]piperidin-1-oxide, and agriculturally-acceptable salts thereof.

In certain cases the compounds within the scope of formula I may possess asymmetric centers, which can give rise to optical enantiomorphs and diastereomers. Compounds within the scope of formula I may exist in two or more forms, i.e., polymorphs, which are significantly different in physical and chemical properties. Compounds within the scope of formula I may also exist as tautomers, which are in equilibrium. Compounds within the scope of formula I may also possess acidic or basic moieties, which may allow for the formation of agriculturally acceptable salts or agriculturally acceptable metal complexes.
This invention includes the use of such enantiomorphs, polymorphs, tautomers, salts and metal complexes. Agriculturally acceptable salts and metal complexes include, without limitation, for example, ammonium salts, the salts of organic and inorganic acids, such as hydrochloric acid, oleic acid, octanoic acid, 2-ethylhexanoic acid, alkyl sulfonic acid, ethanesulfonic acid, trifluoroacetic acid, methylbenzenesulfonic acid, phosphoric acid, gluconic acid, pamoic acid, and other acid salts, and the alkali metal and alkaline earth metal complexes with, for example, sodium, potassium, lithium, magnesium, calcium, and other metals.
The methods of the present invention are predicated on causing an insecticidally effective amount of a compound of formula I to be present within insects in order to kill or control the insects. Preferred insecticidally effective amounts are those that are sufficient to kill the insect. It is within the scope of the present invention to cause a compound of formula I to be present within insects by contacting the insects with a derivative of that compound, which derivative is converted within the insect to a compound of formula I. This invention includes the use of such compounds, which can be referred to as pro-insecticides.
Another aspect of the present invention relates to compositions containing an insecticidally effective amount of at least one compound of formula I, and, optionally, an effective amount of at least one second compound, with at least one agriculturally acceptable extender or adjuvant.
Another aspect of the present invention relates to methods of controlling insects by applying an insecticidally effective amount of a composition set forth above to a locus of crops such as, without limitation, cereals, cotton, vegetables, and fruits, other areas where insects are present or are expected to be present, or adjacent to areas where insects are present or are expected to be present.
The present invention also includes the use of the compounds and compositions set forth herein for control of insects in greenhouse crops, nursery crops, ornamentals, turfs, forestry, stored food and fiber products, structures, livestock, households, and public and animal health, for example, ants, flies, cockroaches, white grubs, dry wood termites and subterranean termites as well as other insects; and also for use in promotion of animal and human health as pharmaceutical agents and compositions thereof.
As used in this specification and unless otherwise indicated the substituent terms “alkyl”, “alkenyl”, “alkynyl”, “alkoxy”, “alkenyloxy”, and “alkynyloxy” used alone or as part of a larger moiety, includes straight or branched chains of at least one or two carbon atoms, as appropriate to the substituent, and preferably up to 12 carbon atoms, more preferably up to ten carbon atoms, most preferably up to seven carbon atoms, wherein “alkenyl” has at least one carbon to carbon double bond, and “alkynyl” has at least one carbon to carbon triple bond. The term “aryl” refers to an aromatic ring structure, including fused rings, having four to ten carbon atoms, for example, phenyl and naphthyl. The term “heteroaryl” refers to an aromatic ring structure, including fused rings, having four to ten carbon atoms, and in which one or more of the atoms in the ring is other than carbon, for example, sulfur, oxygen, or nitrogen. The term “THF” refers to tetrahydrofuran. The term “DMSO” refers to methyl sulfoxide. The term “DMF” refers to N,N-dimethylformamide. The term “halogen” or “halo” refers to fluorine, bromine, iodine, or chlorine. The term “ambient temperature” or “room temperature” often abbreviated as “RT”, for example, in reference to a chemical reaction mixture temperature, refers to a temperature in the range of 20° C. to 30° C.
Scheme 1 below illustrates a general procedure for synthesizing compounds of formula I, where, for example, m, p, and q are 0; t and u are 1; r is 0 or 1, and if r is 1 an N-oxide is formed; R is phenyl substituted with R14, R15, R16, R17 and R18; X is OH or F; Y, R1, R2, R4, R5, R14, R15, R17, R18, R7, R8, R10 and R11 are H; R3 and R16 are —OCF3; and R9 is pyrimidin-2-yloxy.







In a first step as depicted in Scheme 1, an appropriately substituted alcohol, for example, the known compound (4-pyrimidin-2-yloxyphenyl)methan-1-ol, is halogenated with, for example thionyl chloride, to afford the corresponding 2-[4-(chloromethyl)phenoxy]pyrimidine (A). Intermediate (A) is then reacted under basic conditions with an appropriately substituted cyclic amine derivative, for example, the known compound 4-piperidone hydrochloride monohydrate, to afford the corresponding 1-[(4-pyrimidin-2-yloxyphenyl)methyl]piperidin-4-one (B). A mixture of intermediate (B) and an appropriately substituted haloalkyl derivative, for example bis(trifluoromethoxyphenyl)bromomethane, is reacted in the presence of n-butyl lithium, to afford the corresponding 4-{bis[4-(trifluoromethoxy)phenyl]methyl}-1-[(4-pyrimidin-2-yloxyphenyl)methyl]piperidin-4-ol (I-A). Intermediate (I-A) is then oxidized, with for example hydrogen peroxide, in an appropriate solvent, to form an N-oxide, a compound of formula I-C. In a separate synthesis, intermediate (I-A) is reacted with a thiohalide, for example (dimethylamino)sulfur trifluoride, to provide halogen-derived compounds of formula I-D, wherein X is, for example fluorine. Examples 1 and 3, set forth below, provide detailed methods to how compounds of formula I (-A, -C and -D) shown in Scheme 1 were prepared.
Scheme 2 below illustrates a general procedure for synthesizing compounds of formula I similar to those set forth in Scheme 1, differing in that Y is OH; X is OH; r is 0; and R9 is 2-methyl-2H-tetrazol-5-yl.







In a first step as depicted in Scheme 2, an appropriately substituted phenyl derivative, for example, the known compound 2-methyl-5-(4-methylphenyl)-1,2,3,4-tetrazole, is brominated with, for example N-bromosuccinimide and light, to afford the corresponding 5-[4-(bromomethyl)phenyl]-2-methyl-1,2,3,4-tetrazole (A1). Intermediate (A1) is then reacted under basic conditions with an appropriately substituted cyclic amine derivative, for example, the known compound 4-piperidone hydrochloride monohydrate, to afford the corresponding 1-{[4-(2-methyl-1,2,3,4-tetrazol-5-yl)phenyl]methyl}piperidin-4-one (B1). Intermediate (B1) is then reacted under acidic conditions with, for example sodium cyanide, to afford the corresponding nitrile compound, 4-hydroxy-1-{[4-(2-methyl(1,2,3,4-tetrazol-5-yl))phenyl]methyl}piperidine-4-carbonitrile (C1). Intermediate (C1) is esterified under acidic conditions with, for example ethanol, to afford the corresponding ethyl 4-hydroxy-1-{[4-(2-methyl-(1,2,3,4-tetrazol-5-yl))phenyl]methyl}piperidine-4-carboxylate (D1). The Grignard of an appropriately substituted halophenyl derivative, for example 4-trifluoromethoxybromobenzene, is reacted with intermediate (D1) to provide compounds of formula I-B, wherein X and Y are, for example hydroxyl. Example 2, set forth below, provides detailed methods to how compounds of formula I (-B) shown in Scheme 2 were prepared.
Scheme 3 below illustrates a general procedure for synthesizing compounds of formula I similar to those set forth in Scheme 1, differing in that Y is Cl; X is —CO2C2H5; r is 0; R3 and R16 are —CF3; and R9 is pyrid-2-yloxy.







In a first step as depicted in Scheme 3, an appropriately substituted piperidine, for example, the known compound ethyl 1-[(tert-butyl)oxycarbonyl]piperidine-4-carboxylate, is enolated, with for example lithium diisopropylamide, and then reacted under basic conditions with an appropriately substituted phenyl ketone, for example di-4-(trifluoromethyl)phenyl ketone, to afford the corresponding ethyl 1-[(tert-butyl)oxycarbonyl]-4-{bis[4-(trifluoromethyl)phenyl]hydroxymethyl}piperidine-4-carboxylate (A2). Intermediate (A2) is then chlorinated with, for example thionyl chloride, to afford the corresponding ethyl 1-[(tert-butyl)oxycarbonyl]-4-{bis[4-(trifluoromethyl)phenyl]chloromethyl}piperidine-4-carboxylate (B2). The (tert-butyl)oxycarbonyl group is cleaved under acidic conditions from the piperidine ring of (B2), to afford the corresponding 4-{bis[4-(trifluoromethyl)phenyl]chloromethyl}piperidine-4-carboxylate (C2). Intermediate (C2) is then reacted under basic conditions with an appropriately substituted haloalkylphenyl derivative, for example 2-[4-(chloromethyl)phenoxy]pyridine, to provide compounds of formula I-D, wherein X is, for example an alkoxycarbonyl and Y is, for example chlorine. Example 4, set forth below, provides detailed methods to how compounds of formula I (-D) shown in Scheme 3 were prepared.
Scheme 4 below illustrates a general procedure for synthesizing compounds of formula I, where, for example, m, p, and q are 0; t and u are 1; r is 0 or 1, and if r is 1 an N-oxide is formed; R is phenyl substituted with R14, R15, R16, R17 and R18; X is OH; Y, R1, R2, R4, R5, R14, R15, R17, R18, R7, R8, R10 and R11 are H; R3 and R16 are —OCF3; and R9 is pyrid-2-yloxy.







In the first step as depicted in Scheme 4, two appropriately substituted aryl halides, for example, the known compound 4-bromo-1-(trifluoromethoxy)benzene (A3), were cross-coupled with a Grignard reagent and an alkyl formate, for example, ethyl formate to form bis[4-(trifluoromethoxy)phenyl]methan-1-ol (B3). Intermediate (B3) was then reacted under acidic conditions with hydrogen bromide, to afford the corresponding bis(trifluoromethoxyphenyl)bromomethane (C3). Intermediate (C3) was then lithiated, for example with butyl lithium, and then reacted with an appropriately N-substituted piperidin-4-one, formula (D3), for example 1-benzylpiperidin-4-one, at a temperature in the range of −85° C. to −60° C. to afford the corresponding 4-{bis[4-(trifluoromethoxy)phenyl]methyl}-1-benzylpiperidin-4-ol (E3). Intermediate (E3) was then reacted with an acid, for example formic acid, in the presence of a catalyst, for example a palladium catalyst, to form the hydrogen chloride salt of 4-{bis[4-(trifluoromethoxy)phenyl]methyl}piperidin-4-ol (F3). Next, an appropriately substituted phenol, for example, the known compound 4-hydroxybenzaldehyde, was cross-coupled with a halopyridine, for example 2-chloropyridine, in the presence of potassium carbonate and a catalytic amount of copper oxide at a temperature in the range of 145° C. to 170° C. to form 4-(2-pyridyloxy)benzaldehyde (G3). Intermediate (F3) was then cross-coupled with Intermediate (G3) in the presence of sodium triacetoxyborohydride to form 4-{bis[4-(trifluoromethoxy)phenyl]methyl}-1-[(4-(2-pyridyloxy)phenyl)methyl]piperidin-4-ol (I-A). Intermediate (I-A) was then oxidized with hydrogen peroxide at a temperature in the range of 40° C. to 55° C. to form a compound of formula I-C.
Scheme 5 below illustrates a general procedure for synthesizing compounds of formula I, where, for example, m, p, and q are 0; t and u are 1; r is 0 or 1, and if r is 1 an N-oxide is formed; R is phenyl substituted with R14, R15, R16, R17 and R18; X is OH; Y, R1, R2, R4, R5, R14, R15, R17, R18, R7, R8, R10 and R11 are H; R3 and R16 are —OCF3; and R9 is pyrid-2-yloxy.







In the first step of Scheme 5, an appropriately substituted phenol, for example, the known compound 4-methyl phenol, can be cross-coupled with a halopyridine, for example 2-chloropyridine, in the presence of potassium carbonate and a catalytic amount of copper oxide at a temperature in the range of 145° C. to 170° C. to form 2-(4-methylphenoxy)pyridine (A4). Intermediate (A4) can then be halogenated with, for example bromine, to form 2-[4-(bromomethyl)phenoxy]pyridine (B4). Intermediate (F3), made as in Scheme 4, can then be cross-coupled with Intermediate (B4) in the presence of potassium carbonate to form 4-{bis[4-(trifluoromethoxy)phenyl]methyl}-1-[(4-(2-pyridyloxy)phenyl)methyl]piperidin-4-ol (I-A). Intermediate (I-A) can then be oxidized as in Scheme 4 to form a compound of formula I-C.
One skilled in the art will, of course, recognize that the formulation and mode of application of a toxicant may affect the activity of the material in a given application. Thus, for agricultural use the present insecticidal compounds may be formulated as a granular product of relatively large particle size (for example, 8/16 or 4/8 US Mesh), as water-soluble or water-dispersible granules, as powdery dusts, as wettable powders, as emulsifiable concentrates, as aqueous emulsions, as solutions, or as any of other known types of agriculturally-useful formulations, depending on the desired mode of application. It is to be understood that the amounts specified in this specification are intended to be approximate only, as if the word “about” were placed in front of the amounts specified.
These insecticidal compositions may be applied either as water-diluted sprays, or dusts, or granules to the areas in which suppression of insects is desired. These formulations may contain as little as 0.1%, 0.2% or 0.5% to as much as 95% or more by weight of active ingredient.
Dusts are free flowing admixtures of the active ingredient with finely divided solids such as talc, natural clays, kieselguhr, flours such as walnut shell and cottonseed flours, and other organic and inorganic solids which act as dispersants and carriers for the toxicant; these finely divided solids have an average particle size of less than about 50 microns. A typical dust formulation useful herein is one containing 1.0 part or less of the insecticidal compound and 99.0 parts of talc.
Wettable powders, also useful formulations for insecticides, are in the form of finely divided particles that disperse readily in water or other dispersant. The wettable powder is ultimately applied to the locus where insect control is needed either as a dry dust or as an emulsion in water or other liquid. Typical carriers for wettable powders include Fuller's earth, kaolin clays, silicas, and other highly absorbent, readily wet inorganic diluents. Wettable powders normally are prepared to contain about 5-80% of active ingredient, depending on the absorbency of the carrier, and usually also contain a small amount of a wetting, dispersing or emulsifying agent to facilitate dispersion. For example, a useful wettable powder formulation contains 80.0 parts of the insecticidal compound, 17.9 parts of Palmetto clay, and 1.0 part of sodium lignosulfonate and 0.3 part of sulfonated aliphatic polyester as wetting agents. Additional wetting agent and/or oil will frequently be added to a tank mix for to facilitate dispersion on the foliage of the plant.
Other useful formulations for insecticidal applications are emulsifiable concentrates (ECs) which are homogeneous liquid compositions dispersible in water or other dispersant, and may consist entirely of the insecticidal compound and a liquid or solid emulsifying agent, or may also contain a liquid carrier, such as xylene, heavy aromatic naphthas, isphorone, or other non-volatile organic solvents. For insecticidal application these concentrates are dispersed in water or other liquid carrier and normally applied as a spray to the area to be treated. The percentage by weight of the essential active ingredient may vary according to the manner in which the composition is to be applied, but in general comprises 0.5 to 95% of active ingredient by weight of the insecticidal composition.
Flowable formulations are similar to ECs, except that the active ingredient is suspended in a liquid carrier, generally water. Flowables, like ECs, may include a small amount of a surfactant, and will typically contain active ingredients in the range of 0.5 to 95%, frequently from 10 to 50%, by weight of the composition. For application, flowables may be diluted in water or other liquid vehicle, and are normally applied as a spray to the area to be treated.
Typical wetting, dispersing or emulsifying agents used in agricultural formulations include, but are not limited to, the alkyl and alkylaryl sulfonates and sulfates and their sodium salts; alkylaryl polyether alcohols; sulfated higher alcohols; polyethylene oxides; sulfonated animal and vegetable oils; sulfonated petroleum oils; fatty acid esters of polyhydric alcohols and the ethylene oxide addition products of such esters; and the addition product of long-chain mercaptans and ethylene oxide. Many other types of useful surface-active agents are available in commerce. Surface-active agents, when used, normally comprise 1 to 15% by weight of the composition.
Other useful formulations include suspensions of the active ingredient in a relatively non-volatile solvent such as water, corn oil, kerosene, propylene glycol, or other suitable solvents.
Still other useful formulations for insecticidal applications include simple solutions of the active ingredient in a solvent in which it is completely soluble at the desired concentration, such as acetone, alkylated naphthalenes, xylene, or other organic solvents. Granular formulations, wherein the toxicant is carried on relative coarse particles, are of particular utility for aerial distribution or for penetration of cover crop canopy. Pressurized sprays, typically aerosols wherein the active ingredient is dispersed in finely divided form as a result of vaporization of a low-boiling dispersant solvent carrier may also be used. Water-soluble or water-dispersible granules are free flowing, non-dusty, and readily water-soluble or water-miscible. In use by the farmer on the field, the granular formulations, emulsifiable concentrates, flowable concentrates, aqueous emulsions, solutions, etc., may be diluted with water to give a concentration of active ingredient in the range of say 0.1% or 0.2% to 1.5% or 2%.
The active insecticidal compounds of this invention may be formulated and/or applied with one or more second compounds. Such combinations may provide certain advantages, such as, without limitation, exhibiting synergistic effects for greater control of insect pests, reducing rates of application of insecticide thereby minimizing any impact to the environment and to worker safety, controlling a broader spectrum of insect pests, safening of crop plants to phytotoxicity, and improving tolerance by non-pest species, such as mammals and fish.
Second compounds include, without limitation, other pesticides, plant growth regulators, fertilizers, soil conditioners, or other agricultural chemicals. In applying an active compound of this invention, whether formulated alone or with other agricultural chemicals, an effective amount and concentration of the active compound is of course employed; the amount may vary in the range of, e.g. about 0.001 to about 3 kg/ha, preferably about 0.03 to about 1 kg/ha. For field use, where there are losses of insecticide, higher application rates (e.g., four times the rates mentioned above) may be employed.
When the active insecticidal compounds of the present invention are used in combination with one or more of second compounds, e.g., with other pesticides such as herbicides, the herbicides include, without limitation, for example: N-(phosphonomethyl)glycine (“glyphosate”); aryloxyalkanoic acids such as (2,4-dichlorophenoxy)acetic acid (“2,4-D”), (4-chloro-2-methylphenoxy)acetic acid (“MCPA”), (+/−)-2-(4-chloro-2-methylphenoxy)propanoic acid (“MCPP”); ureas such as N,N-dimethyl-N′-[4-(1-methylethyl)phenyl]urea (“isoproturon”); imidazolinones such as 2-[4,5-dihydro-4-methyl-4-(1-methylethyl)-5-oxo-1H-imidazol-2-yl]-3-pyridinecarboxylic acid (“imazapyr”), a reaction product comprising (+/−)-2-[4,5-dihydro-4-methyl-4-(1-methylethyl)-5-oxo-1H-imidazol-2-yl]-4-methylbenzoic acid and (+/−)2-[4,5-dihydro-4-methyl-4-(1-methylethyl)-5-oxo-1H-imidazol-2-yl]-5-methylbenzoic acid (“imazamethabenz”), (+/−)-2-[4,5-dihydro-4-methyl-4-(1-methylethyl)-5-oxo-1H-imidazol-2-yl]-5-ethyl-3-pyridinecarboxylic acid (“imazethapyr”), and (+/−)-2-[4,5-dihydro-4-methyl-4-(1-methylethyl)-5-oxo-1H-imidazol-2-yl]-3-quinolinecarboxylic acid (“imazaquin”); diphenyl ethers such as 5-[2-chloro-4-(trifluoromethyl)phenoxy]-2-nitrobenzoic acid (“acifluorfen”), methyl 5-(2,4-dichlorophenoxy)-2-nitrobenzoate (“bifenox”), and 5-[2-chloro-4-(trifluoromethyl)phenoxy]-N-(methylsulfonyl)-2-nitrobenzamide (“fomasafen”); hydroxybenzonitriles such as 4-hydroxy-3,5-diiodobenzonitrile (“ioxynil”) and 3,5-dibromo-4-hydroxybenzonitrile (“bromoxynil”); sulfonylureas such as 2-[[[[(4-chloro-6-methoxy-2-pyrimidinyl)amino]carbonyl]amino]sulfonyl]benzoic acid (“chlorimuron”), 2-chloro-N-[[(4-methoxy-6-methyl-1,3,5-triazin-2-yl)amino]carbonyl]benzenesulfonamide (achlorsulfuron”), 2-[[[[[(4,6-dimethoxy-2-pyrimidinyl)amino]carbonyl]amino]sulfonyl]methyl]benzoic acid (“bensulfuron”), 2-[[[[(4,6-dimethoxy-2-pyrimidinyl)amino]carbonyl]amino]sulfonyl]-1-methyl-1H-pyrazol-4-carboxylic acid (“pyrazosulfuron”), 3-[[[[(4-methoxy-6-methyl-1,3,5-triazin-2-yl)amino]carbonyl]amino]sulfonyl]-2-thiophenecarboxylic acid (“thifensulfuron”), and 2-(2-chloroethoxy)-N[[(4-methoxy-6-methyl-1,3,5-triazin-2-yl)amino]carbonyl]benzenesulfonamide (“triasulfuron”); 2-(4-aryloxy-phenoxy)alkanoic acids such as (+/−)-2[4-[(6-chloro-2-benzoxazolyl)oxy]phenoxy]-propanoic acid (“fenoxaprop”), (+/−)-2-[4[[5-(trifluoromethyl)-2-pyridinyl]oxy]-phenoxy]propanoic acid (“fluazifop”), (+/−)-2-[4-(6-chloro-2-quinoxalinyl)oxy]-phenoxy]propanoic acid (“quizalofop”), and (+/−)-2-[(2,4-dichlorophenoxy)phenoxy]propanoic acid (“diclofop”); benzothiadiazinones such as 3-(1-methylethyl)-1H-1,2,3-benzothiadiazin-4(3H)-one-2,2-dioxide (“bentazone”); 2-chloroacetanilides such as N-(butoxymethyl)-2-chloro-N-(2,6-diethylphenyl)acetamide (“butachlor”), 2-chloro-N-(2-ethyl-6-methylphenyl)-N-(2-methoxy-1-methylethyl)acetamide (“metolachlor”), 2-chloro-N-(ethoxymethyl)-N-(2-ethyl-6-methylphenyl)acetamide (“acetochlor”), and (RS)-2-chloro-N-(2,4-dimethyl-3-thienyl)-N-(2-methoxy-1-methylethyl)acetamide (“dimethenamide”); arenecarboxylic acids such as 3,6-dichloro-2-methoxybenzoic acid (“dicamba”); pyridyloxyacetic acids such as [(4-amino-3,5-dichloro-6-fluoro-2-pyridinyl)oxy]acetic acid (“fluoroxypyr”), and other herbicides.
When the active insecticidal compounds of the present invention are used in combination with one or more of second compounds, e.g., with other pesticides such as other insecticides, the other insecticides include, for example: organophosphate insecticides, such as chlorpyrifos, diazinon, dimethoate, malathion, parathion-methyl, and terbufos; pyrethroid insecticides, such as fenvalerate, deltamethrin, fenpropathrin, cyfluthrin, flucythrinate, alpha-cypermethrin, biphenthrin, resolved cyhalothrin, etofenprox, esfenvalerate, tralomehtrin, tefluthrin, cycloprothrin, betacyfluthrin, and acrinathrin; carbamate insecticides, such as aldecarb, carbaryl, carbofuran, and methomyl; organochlorine insecticides, such as endosulfan, endrin, heptachlor, and lindane; benzoylurea insecticides, such as diflubenuron, triflumuron, teflubenzuron, chlorfluazuron, flucycloxuron, hexaflumuron, flufenoxuron, and lufenuron; and other insecticides, such as amitraz, clofentezine, fenpyroximate, hexythiazox, spinosad, and imidacloprid.
When the active insecticidal compounds of the present invention are used in combination with one or more of second compounds, e.g., with other pesticides such as fungicides, the fungicides include, for example: benzimidazole fungicides, such as benomyl, carbendazim, thiabendazole, and thiophanate-methyl; 1,2,4-triazole fungicides, such as epoxyconazole, cyproconazole, flusilazole, flutriafol, propiconazole, tebuconazole, triadimefon, and triadimenol; substituted anilide fungicides, such as metalaxyl, oxadixyl, procymidone, and vinclozolin; organophosphorus fungicides, such as fosetyl, iprobenfos, pyrazophos, edifenphos, and tolclofos-methyl; morpholine fungicides, such as fenpropimorph, tridemorph, and dodemorph; other systemic fungicides, such as fenarimol, imazalil, prochloraz, tricyclazole, and triforine; dithiocarbamate fungicides, such as mancozeb, maneb, propineb, zineb, and ziram; non-systemic fungicides, such as chlorothalonil, dichlofluanid, dithianon, and iprodione, captan, dinocap, dodine, fluazinam, gluazatine, PCNB, pencycuron, quintozene, tricylamide, and validamycin; inorganic fungicides, such as copper and sulphur products, and other fungicides.
When the active insecticidal compounds of the present invention are used in combination with one or more of second compounds, e.g., with other pesticides such as nematicides, the nematicides include, for example: carbofuran, carbosulfan, turbufos, aldecarb, ethoprop, fenamphos, oxamyl, isazofos, cadusafos, and other nematicides.
When the active insecticidal compounds of the present invention are used in combination with one or more of second compounds, e.g., with other materials such as plant growth regulators, the plant growth regulators include, for example: maleic hydrazide, chlormequat, ethephon, gibberellin, mepiquat, thidiazon, inabenfide, triaphenthenol, paclobutrazol, unaconazol, DCPA, prohexadione, trinexapac-ethyl, and other plant growth regulators.
Soil conditioners are materials which, when added to the soil, promote a variety of benefits for the efficacious growth of plants. Soil conditioners are used to reduce soil compaction, promote and increase effectiveness of drainage, improve soil permeability, promote optimum plant nutrient content in the soil, and promote better pesticide and fertilizer incorporation. When the active insecticidal compounds of the present invention are used in combination with one or more of second compounds, e.g., with other materials such as soil conditioners, the soil conditioners include organic matter, such as humus, which promotes retention of cation plant nutrients in the soil; mixtures of cation nutrients, such as calcium, magnesium, potash, sodium, and hydrogen complexes; or microorganism compositions which promote conditions in the soil favorable to plant growth. Such microorganism compositions include, for example, bacillus, pseudomonas, azotobacter, azospirillum, rhizobium, and soil-borne cyanobacteria.
Fertilizers are plant food supplements, which commonly contain nitrogen, phosphorus, and potassium. When the active insecticidal compounds of the present invention are used in combination with one or more of second compounds, e.g., with other materials such as fertilizers, the fertilizers include nitrogen fertilizers, such as ammonium sulfate, ammonium nitrate, and bone meal; phosphate fertilizers, such as superphosphate, triple superphosphate, ammonium sulfate, and diammonium sulfate; and potassium fertilizers, such as muriate of potash, potassium sulfate, and potassium nitrate, and other fertilizers.
The following examples further illustrate the present invention, but, of course, should not be construed as in any way limiting its scope. The examples are organized to present protocols for the synthesis of the compounds of formula I of the present invention, set forth a list of such synthesized species, and set forth certain biological data indicating the efficacy of such compounds.
EXAMPLE 1
This example illustrates the preparation of 4-{bis[4-(trifluoromethoxy)phenyl]methyl}-4-hydroxy-1-[(4-pyrimidin-2-yloxyphenyl)methyl]piperidin-1-oxide (Compound 112 in table below)
Step A Synthesis of 2-[4-(chloromethyl)phenoxy]pyrimidine as an Intermediate
A stirred solution of 2.0 grams (0.0099 mole) of (4-pyrimidin-2-yloxyphenyl)methan-1-ol (known compound) and 7 drops of pyridine in 50 mL of methylene chloride was cooled in an ice-water bath, and 0.94 mL (0.013 mole) of thionyl chloride was added dropwise. Upon completion of the addition, the reaction mixture was stirred for 3 hours at 10° C. to 20° C. The reaction mixture was then poured into ice-water and basified using sodium bicarbonate. The aqueous layer was separated from the organic layer, and was extracted one time with 75 mL of methylene chloride. The methylene chloride extract and organic layer were combined and passed through silicone coated filter paper. The fitrate was then concentrated under reduced pressure, yielding 2.1 grams of the subject compound.
Step B Synthesis of 1-[(4-pyrimidin-2-yloxyphenyl)methyl]piperidin-4-one as an Intermediate
A solution of 1.47 grams (0.0096 mole) of 4-piperidone monohydrate hydrochloride, 2.1 grams (0.0096 mole) of 2-[4-(chloromethyl)phenoxy]pyrimidine, and 4.34 grams (0.0336 mole) of bis(methylethyl)ethylamine in 35 mL of dimethylsulfoxide (DMSO) was stirred at ambient temperature for about 24 hours. The reaction mixture was then diluted with 200 mL of water and was extracted two times with 200 mL of ethyl acetate. The extracts were then combined and washed two times with 75 mL of an aqueous mixture of 10% lithium chloride. The resultant organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure to a residue. The residue was purified with column chromatography on silica get using 1:2 ethyl acetate:petroleum ether as an eluant. The appropriate fractions were combined and concentrated under reduced pressure, yielding 2.71 grams of the subject compound.
Step C Synthesis of 4-{bis[4-(trifluoromethoxy)phenyl]methyl}-1-[(4-pyrimidin-2-yloxyphenyl)methyl]piperidin-4-ol as an Intermediate
A stirred solution of 0.8 gram (0.0019 mole) of bis(trifluoromethoxyphenyl)bromomethane and 2.2 grams (0.0078 mole) of 1-[(4-pyrimidin-2-yloxyphenyl)methyl]piperidin-4-one in 50 mL of THF was chilled to −78° C., and 1.5 mL of n-butyl lithium (2.5 M) was added dropwise during a 15-minute period while maintaining the temperature of the reaction mixture between −80° C. to −70° C. The reaction mixture was then allowed to warm to about 0° C. The reaction mixture was quenched with a saturated aqueous solution of ammonium chloride, and the mixture was extracted two times with 75 mL of ethyl acetate. The combined extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure to a residue. The residue was purified with column chromatography on silica gel using 1:4 acetone:methylene chloride as an eluant. The appropriate fractions were combined and further purified by passing them through a Waters SEP-PAK® Vac 35 cc NH2 Cartridge (purchased from Waters, 34 Maple Street, Milford, Mass. 01757) using 1:4 ethyl acetate:petroleum ether as an eluant. The appropriate fractions were combined and concentrated under reduced pressure, yielding 0.42 gram of the subject compound. The NMR spectrum was consistent with the proposed structure.
Step D Synthesis of Compound 112
A solution of 0.28 gram (0.00045 mole) of 4-{bis[4-(trifluoromethoxy)phenyl]methyl}-1-[(4-pyrimidin-2-yloxyphenyl)methyl]piperidin-4-ol and 1.4 grams of 50% aqueous hydrogen peroxide in 40 mL of methanol was stirred at ambient temperature for about 4 days. The reaction mixture was then diluted with 200 mL of water and extracted twice with 200 mL each of ethyl acetate. The combined extracts were then washed twice with 75 mL each of aqueous mixture of 10% lithium chloride. The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure to a residue. The residue was purified with column chromatography on silica get using 1:2 ethyl acetate:petroleum ether as an eluant. The appropriate fractions were combined and concentrated under reduced pressure, yielding 0.29 gram of Compound 112.
EXAMPLE 2
This example illustrates the preparation of 4-{bis[4-(trifluoromethoxy)phenyl]hydroxymethyl}-1-{[4-(2-methyl(1,2,3,4-tetrazol-5-yl))phenyl]methyl}piperidin-4-ol (Compound 93 in the table below)
Step A Synthesis of 5-[4-(bromomethyl)phenyl]-2-methyl-1,2,3,4-tetrazole as an Intermediate
A stirred solution of 45 grams (0.258 mole) of 2-methyl-5-(4-methylphenyl)-1,2,3,4-tetrazole (known compound), 46 grams (1 equivalent) of N-bromosuccinimide, and a catalytic amount of benzoyl peroxide in 200 mL of carbon tetrachloride was irradiated with light during a 3.5 hour period. The mixture was then cooled in an ice bath and filtered to collect 35.1 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Step B Synthesis of 1-{[4-(2-methyl-1,2,3,4-tetrazol-5-yl)phenyl]methyl}piperidin-4-one as an Intermediate
A solution of 23 grams (0.091 mole) of 5-[4-(bromomethyl)phenyl]-2-methyl-1,2,3,4-tetrazole, 14 grams (0.091 mole) of 4-piperidone monohydrate hydrochloride, and 47 mL (3 equivalents) of N,N-diisopropylethylamine in 200 mL of dimethylsulfoxide (DMSO) was stirred for about 3 days. The reaction was quenched by pouring the reaction mixture onto 400 mL of dilute, cold sodium hydroxide. The resultant solution was extracted one time with 300 mL of ethyl acetate. An emulsion formed, which was broken up by warming it to about 35° C. The organic layer was separated and concentrated under reduced pressure to a residue. The residue was purified with column chromatography on silica gel using 40:1 methylene chloride:methanol as an eluant. The appropriate fractions were combined and concentrated under reduced pressure, yielding 9.12 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Step C Synthesis of 4-hydroxy-1-{[4-(2-methyl(1,2,3,4-tetrazol-5-yl))phenyl]methyl}piperidine-4-carbonitrile as an Intermediate
A stirred solution of 8.62 grams (0.032 mole) of 1-{[4-(2-methyl-1,2,3,4-tetrazol-5-yl)phenyl]methyl}piperidin-4-one in 100 mL of ether and 150 mL of water was cooled to about 10° C. and 3.9 grams (2.5 equivalents) of sodium cyanide was added in one portion. To this was added 6.6 mL (2.5 equivalents) of hydrochloric acid (12 M) dropwise while maintaining the reaction mixture temperature at about 10° C. Upon completion of the addition, the reaction mixture was stirred for 1.5 hours while warming to ambient temperature. The reaction mixture was then poured into 200 mL of water, to which was then added 200 mL of ethyl acetate. The organic layer was separated and concentrated under reduced pressure to yield 9.6 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Step D Synthesis of ethyl 4-hydroxy-1-{[4-(2-methyl(1,2,3,4-tetrazol-5-yl))phenyl]methyl}piperidine-4-carboxylate as an Intermediate
A solution of 9.6 grams (0.032 mole) of 4-hydroxy-1-{[4-(2-methyl(1,2,3,4-tetrazol-5-yl))phenyl]methyl}piperidine-4-carbonitrile in 200 mL of ethanol was saturated with gaseous hydrogen chloride, and then it was stirred at 55° C. for about 20 hours. The reaction mixture was allowed to cool and then it was poured onto 500 mL of ice. The resultant mixture was basified with 50% sodium hydroxide and extracted once with 300 mL of ethyl acetate. The extract was washed three times with 80 mL brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to a residue, yielding 5.14 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Step E Synthesis of Compound 93
A solution of 1.6 grams (4.5 equivalents) of magnesium and 8.9 mL (4 equivalents) of 4-trifluoromethoxybromobenzene (known compound) in 75 mL of THF was stirred and 5.14 grams (0.0149 mole) of ethyl 4-hydroxy-1-{[4-(2-methyl(1,2,3,4-tetrazol-5-yl))phenyl]methyl}piperidine-4-carboxylate was added in one portion. After a mild exotherm, the reaction mixture was heated to 50° C. where it was stirred for 2 hours. The reaction mixture was allowed to cool to ambient temperature as it stirred for 72 hours; then it was poured into 200 mL of an aqueous solution saturated with ammonium chloride. The mixture was extracted one time with 200 mL of ethyl acetate, and the extract was washed two times with 80 mL of brine. The extract was dried with magnesium sulfate, filtered and concentrated under reduced pressure to a residue. The residue was purified with column chromatography on silica gel using diethyl ether as an eluant. The appropriate fractions were combined and concentrated under reduced pressure, yielding 9.29 grams of Compound 93.
EXAMPLE 3
This example illustrates the preparation of 4-{bis[4-(trifluoromethoxy)phenyl]methyl}-4-fluoro-1-[(4-pyrimidin-2-yloxyphenyl)methyl]piperidine (Compound 192 in the table below)
A stirred solution of 0.11 gram (0.170 mmole) of 4-{bis[4-(trifluoromethoxy)phenyl]methyl}-1-[(4-pyrimidin-2-yloxyphenyl)methyl]piperidin-4-ol (prepared as in Example 1, Steps A through C) in 2.0 mL of methylene chloride was cooled to −40° C., and 18.2 μL (0.186 mmoles) of (dimethylamino)sulfur trifluoride was added. The reaction mixture was allowed to warm to ambient temperature where it stirred for 20 minutes. The reaction mixture was then poured onto 10 mL of an aqueous solution saturated with sodium bicarbonate, and the mixture was extracted with three 20 mL portions of ethyl acetate. The combined extracts were dried with sodium sulfate, filtered and concentrated under reduced pressure to a residue. The residue was purified with column chromatography on silica gel using 1:1 ethyl acetate:hexane as an eluant. The appropriate fractions were combined and concentrated under reduced pressure, yielding 85 milligrams of Compound 192. The NMR spectrum was consistent with the proposed structure.
EXAMPLE 4
This example illustrates the preparation of ethyl 4-{bis[4-(trifluoromethyl)phenyl]chloromethyl}-1-[(4-(2-pyridyloxy)phenyl)methyl]piperidine-4-carboxylate (Compound 195 in the table below)
Step A Synthesis of ethyl 1-[(tert-butyl)oxycarbonyl]-4-{bis[4-(trifluoromethyl)phenyl]hydroxymethyl}piperidine-4-carboxylate as an Intermediate
A stirred solution of 1 mL of diisopropyl amine in10 mL THF was cooled to about 0° C. and 2.55 mL of n-butyl lithium (2.5 M in hexane) was added slowly. The reaction mixture was stirred for 15 minutes, then it was cooled to −78° C. To this was then added a solution of 1.26 grams (4.9 mmole) of ethyl 1-[(tert-butyl)oxycarbonyl]piperidine-4-carboxylate (known compound) in 10 mL of THF. The reaction mixture continued to stir at −78° C. for 1 hour, then a solution of 1.56 grams (4.9 mmole) of di-4-(trifluoromethyl)phenyl ketone (known compound) in 5 mL of THF was added. Upon completion of the addition, the reaction mixture was warmed to ambient temperature during a 14 hour period. The reaction was then quenched by adding 125 mL of aqueous 5% hydrochloric acid to the reaction mixture. The mixture was then extracted with three 125 mL portions of ethyl acetate and the combined extracts were dried with sodium sulfate, filtered and concentrated under reduced pressure to a residue. The residue was purified with column chromatography on silica gel using 1:5 ethyl acetate:hexane as an eluant. The appropriate fractions were combined and concentrated under reduced pressure, yielding 2.2 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Step B Synthesis of ethyl 1-[(tert-butyl)oxycarbonyl]-4-{bis[4-(trifluoromethyl)phenyl]chloromethyl}piperidine-4-carboxylate as an Intermediate
A solution of 290 milligrams (0.504 mmole) of ethyl 1-[(tert-butyl)oxycarbonyl]-4-{bis[4-(trifluoromethyl)phenyl]hydroxymethyl}piperidine-4-carboxylate, 110 μL (1.513 mmole) of thionyl chloride, and 408 μL (5.04 mmole) of pyridine in 5 mL of methylene chloride was stirred at ambient temperature for 1 hour. The reaction mixture was then poured into 25 mL of an aqueous solution saturated with sodium bicarbonate, and the mixture was extracted with three 50 mL portions of ethyl acetate. The combined extracts were dried with sodium sulfate, filtered and concentrated under reduced pressure to a residue. The residue was purified with column chromatography on silica gel using 1:10 ethyl acetate:hexane as an eluant. The appropriate fractions were combined and concentrated under reduced pressure, yielding 240 milligrams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Step C Synthesis of ethyl 4-{bis[4-(trifluoromethyl)phenyl]chloromethyl}piperidine-4-carboxylate as an Intermediate
A solution of 190 milligrams (0.320 mmole) of ethyl 1-[(tert-butyl)oxycarbonyl]-4-{bis[4-(trifluoromethyl)phenyl]chloromethyl}piperidine-4-carboxylate and 2 mL of trifluoro acetic acid (TFA) in 0.5 mL of methylene chloride was stirred at room temperature for 10 minutes. The reaction mixture was then diluted with toluene and concentrated under reduced pressure, yielding 158 milligrams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Step D Synthesis of Compound 195
A solution of 158 milligrams (0.320 mmole) of ethyl 4-{bis[4-(trifluoromethyl)phenyl]chloromethyl}piperidine-4-carboxylate, 78 milligrams (0.352 mmole) of 2-[4-(chloromethyl)phenoxy]pyridine and 0.28 mL of diisopropylethylamine in 4 mL of DMF was stirred at room temperature for 48 hours. The reaction mixture was then poured into 20 mL of an aqueous solution saturated with sodium bicarbonate, and the mixture was extracted with three 40 mL portions of ethyl acetate. The combined extracts were dried with sodium sulfate, filtered and concentrated under reduced pressure to a residue. The residue was purified with column chromatography on silica gel using 1:5 ethyl acetate:hexane as an eluant. The appropriate fractions were combined and concentrated under reduced pressure, yielding 42 milligrams of Compound 195. The NMR spectrum was consistent with the proposed structure.
EXAMPLE 5
This example illustrates the preparation of 4-{bis[4-(trifluoromethoxy)phenyl]methyl}-4-hydroxy-1-{[4-(2-methoxyethoxy)phenyl]methyl}piperidin-1-oxide (Compound 385 in table below)
Step A Synthesis of 4-(2-methoxyethoxy)benzaldehyde as an Intermediate
A solution of 5.0 grams (0.041 mole) of 4-hydroxybenzaldehyde, 9.5 grams (0.041 mole) of p-toluene sulfonic acid 2-methoxyethyl ester, and 6.3 grams (0.046 mole) of anhydrous potassium carbonate in 50 mL of dimethylsulfoxide (DMSO) was stirred at ambient temperature for about 72 hours. The reaction mixture was then partitioned between 300 mL of an aqueous mixture of 10% lithium chloride and 100 mL of ethyl acetate. The ethyl acetate portion was washed three times; first, with 100 mL of an aqueous mixture of 10% sodium hydroxide, second, with 100 mL of an aqueous mixture of 10% lithium chloride, and, third, with 100 mL of brine. The resultant organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure to a residue. The residue was purified with column chromatography on silica gel using methylene chloride as an eluant. The appropriate fractions were combined and concentrated under reduced pressure, yielding 7.3 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Step B Synthesis of tert-butyl 4-{bis[4-(trifluoromethoxy)phenyl]methyl}-4-hydroxypiperidine carboxylate as an Intermediate
A stirred solution of 8.9 grams (0.022 mole) of bis(trifluoromethoxyphenyl)bromomethane and 4.82 grams (0.024 mole) of tert-butyl 4-oxo-1-piperidine carboxylate in 150 mL of THF was chilled to −78° C., and 9.24 mL of n-butyl lithium (2.5 M) was added dropwise during a 15-minute period while maintaining the temperature of the reaction mixture between −85° C. to −75° C. The reaction mixture was then stirred for 30 minutes while maintaining the temperature of the reaction mixture between −80° C. to −70° C. The reaction mixture was quenched with an aqueous solution saturated with ammonium chloride keeping the internal temperature at less than −55° C., then the mixture was extracted two times with 100 mL of ethyl acetate. The extracts were combined and washed once with 75 mL of an aqueous mixture of 10% lithium chloride. The combined extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure to a residue. The residue was triturated with petroleum ether and a trace of ether then filtered, yielding 3.43 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Step C Synthesis of 4-{bis[4-(trifluoromethoxy)phenyl]methyl}piperidin-4-ol as an Intermediate
A mixture of 3.0 grams (0.0057 mole) of tert-butyl 4-{bis[4-(trifluoromethoxy)phenyl]methyl}-4-hydroxypiperidine carboxylate and 25 mL of methylene chloride was chilled in a wet ice bath. A solution of 2.63 mL trifluoro acetic acid and 5 mL methylene chloride was added dropwise to the reaction mixture during a 5-minute period. The wet ice bath was removed and the reaction mixture was allowed to warm to ambient temperature. The reaction mixture was then warmed to reflux, and allowed to cool to ambient temperature. The reaction mixture was concentrated under reduced pressure. The residue can then be dissolved in 100 mL methylene chloride and reacted with 200 mL of an aqueous solution saturated with sodium carbonate. The methylene chloride layer can then be separated, dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield the subject compound.
Step D Synthesis of 4-{bis[4-(trifluoromethoxy)phenyl]methyl}-1-{[4-(2-methoxyethoxy)phenyl]methyl}piperidin-4-ol (Compound 308 in table below) as an Intermediate
A solution of 2.2 grams (0.0050 mole) of 4-{bis[4-(trifluoromethoxy)phenyl]methyl}piperidin-4-ol, 1.1 grams (0.0061 mole) of 4-(2-methoxyethoxy)benzaldehyde and 1.35 grams (0.0064 mole) of sodium triacetoxyborohydride in 25 mL of methylene chloride was stirred at ambient temperature for 18 hours. The reaction mixture was then diluted with 200 mL of water and stirred at ambient temperature for 5 hours. The phases were separated. The organic phase was washed three times; first, with 100 mL of an aqueous mixture of 10% sodium hydroxide, second, with 100 mL of an aqueous mixture of 10% lithium chloride, and, third, with 100 mL of brine. The resultant organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure to a residue. The residue was purified with column chromatography on silica gel using methylene chloride:1%-5% methanol as an eluant. The appropriate fractions were combined and concentrated under reduced pressure, yielding 2.2 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Step E Synthesis of Compound 385
A solution of 1.9 grams (0.0032 mole) of 4-{bis[4-(trifluoromethoxy)phenyl]methyl}-{[4-(2-methoxyethoxy)phenyl]methyl}piperidin-4-ol and 2.0 mL of 50% aqueous hydrogen peroxide in 25 mL of methanol was stirred at ambient temperature for about 7 days. The reaction mixture was then partitioned between 300 mL of an aqueous mixture of 10% lithium chloride and 100 mL of ethyl acetate. The aqueous phase was extracted twice with 100 mL each of ethyl acetate. The organic phase and extracts were combined and washed twice; first, with 100 mL of aqueous mixture of 10% lithium chloride, second, with 100 mL of brine. The resultant organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to a residue, yielding 1.9 gram of Compound 385. The NMR spectrum was consistent with the proposed structure.
It is well known to one of ordinary skill in the art that compounds like the compounds of formula I of the present invention can contain optically active and racemic forms. It is also well known in the art that compounds like the compounds of formula I may contain stereoisomeric forms, tautomeric forms and/or exhibit polymorphism. It is to be understood that the present invention encompasses any racemic, optically active, polymorphic, tautomeric, or stereoisomeric form, or mixtures thereof. It should be noted that it is well known in the art how to prepare optically active forms, for example by resolution of a racemic mixture, or by synthesis from optically active intermediates.
The following table sets forth some additional examples of compounds of formula I.







TABLE 1







N-Substituted Azacycles









I









 







Where


m, p, q and r are 0; t and u are 1; R is phenyl substituted with R14, R15, R16, R17, R18;


X is OH; A is —CH2—; and R5, R7, R8, R10, R11 and Y are H:









I-A









 

















Compd












No.
R1
R2
R3
R4
R9
R14
R15
R16
R17
R18





 1
Cl
H
H
H
pyrimidin-2-yloxy
H
H
H
H
Cl


 2
H
H
CF3
H
pyrimidin-2-yloxy
H
H
OCF3
H
H


 3
H
Cl
H
Cl
pyrimidin-2-yloxy
H
H
CF3
H
H


 4
H
F
Cl
H
pyrimidin-2-yloxy
H
H
Cl
F
H


 5
H
H
CF3
H
pyrimidin-2-yloxy
H
OCH3
H
OCH3
H


 6
H
Cl
Cl
H
pyrimidin-2-yloxy
H
Cl
Cl
H
H


 7
H
H
CF3
H
pyrimidin-2-yloxy
H
H
Cl
H
H


 8
H
F
H
H
pyrimidin-2-yloxy
H
H
H
F
H


 9
H
Cl
Cl
H
pyrimidin-2-yloxy
H
H
CF3
H
H


 10
H
F
H
F
pyrimidin-2-yloxy
H
F
H
F
H


 11
H
F
H
F
pyrimidin-2-yloxy
H
H
CF3
H
H


 12
H
H
CF3
H
pyrimidin-2-yloxy
H
H
H
F
H


 13
H
H
CF3
H
pyrimidin-2-yloxy
Cl
H
H
Cl
H


 14
H
H
CF3
H
pyrimidin-2-yloxy
H
H
H
Cl
H


 15
Cl
H
Cl
H
pyrimidin-2-yloxy
H
H
CF3
H
H


 16
H
H
CF3
H
pyrimidin-2-yloxy
H
H
CF3
H
H


 17
H
H
CF3
H
pyrimidin-2-yloxy
H
H
F
F
H


 18
H
H
CF3
H
pyrimidin-2-yloxy
H
H
H
H
Cl


 19
H
H
OCF3
H
pyrimidin-2-yloxy
H
H
OCF3
H
H


 20
H
H
OCF3
H
pyrimidin-2-yl
H
H
OCF3
H
H


 21
H
H
OCF3
H
pyrid-2-yloxy
H
H
OCF3
H
H


 22
H
H
CF3
H
pyrid-2-yloxy
H
H
CF3
H
H


 23
H
H
Cl
H
2-ethyl-2H-tetrazol-5-yl
H
H
Cl
H
H


 24
H
H
H
Cl
2-ethyl-2H-tetrazol-5-yl
H
H
H
Cl
H


 25
H
H
OCF3
H
2-ethyl-2H-tetrazol-5-yl
H
H
OCF3
H
H


 26
H
Cl
Cl
H
2-ethyl-2H-tetrazol-5-yl
H
H
Cl
Cl
H


 27
H
H
CF3
H
2-ethyl-2H-tetrazol-5-yl
H
H
CF3
H
H


 28
H
H
OCF3
H
CH═NOC2H5
H
H
OCF3
H
H


 29
H
H
OCF3
H
NHC(═O)OCH(CH3)2
H
H
OCF3
H
H


 30
H
H
OCF3
H
3-(CF3)pyrid-2-yloxy
H
H
OCF
H
H


 31
H
H
CF3
H
CH═NOCH3
H
H
CF3
H
H


 32
H
H
CF3
H
CH═NOC3H7
H
H
CF3
H
H


 33
H
H
CF3
H
CH═NOCH(CH3)2
H
H
CF3
H
H


 34
H
H
CF3
H
CH═NOCH2CH═CH2
H
H
CF3
H
H


 35
H
H
CF3
H
CH═NOCH2C≡CH
H
H
CF3
H
H


 36
H
H
CF3
H
CH═NOC2H5
H
H
CF3
H
H


 37
H
H
OCF3
H
CH═NOCH3
H
H
OCF3
H
H


 38
H
H
OCF3
H
CH═NOC3H7
H
H
OCF3
H
H


 39
H
H
OCF3
H
CH═NOCH(CH3)2
H
H
OCF3
H
H


 40
H
H
OCF3
H
CH═NOCH2CH═CH2
H
H
OCF3
H
H


 41
H
H
OCF3
H
CH═NOCH2C≡CH
H
H
OCF3
H
H


 42
H
H
OCF3
H
CH═NOC2H5
H
H
OCF3
H
H


 43
H
H
CF3
H
CH═NOC2H5
F
H
CF3
H
H


 44
H
H
CF3
H
CH═NOC2H5
Cl
H
CF3
H
H


 45
H
H
OCF3
H
phenoxy
H
H
OCF3
H
H


 46
H
H
OCF3
H
4-(1-methylethyoxycarbonyl)phenoxy
H
H
OCF3
H
H


 47
H
H
OCF3
H
4-(methoxycarbonyl)phenoxy
H
H
OCF3
H
H


 48
H
H
OCF3
H
6-chloro-pyridazin-3yloxy
H
H
OCF3
H
H


 49
H
H
CF3
H
6-chloro-pyridazin-3yloxy
H
H
CF3
H
H


 50
H
H
OCF3
H
NHCO2CH3
H
H
OCF3
H
H


 51
H
H
OCF3
H
NHCO2C2H5
H
H
OCF3
H
H


 52
H
H
OCF3
H
NHCO2CH2CH═CH2
H
H
OCF3
H
H


 53
H
H
OCF3
H
NHCO2CH2C≡CH
H
H
OCF3
H
H


 54
H
H
CF3
H
NHCO2CH(CH3)2
H
H
CF3
H
H


 55
H
H
CF3
H
NHCO2CH3
H
H
CF3
H
H


 56
H
H
CF3
H
NHCO2CH2CH═CH2
H
H
CF3
H
H


 57
H
H
CF3
H
OC(═O)NHCH3
H
H
CF3
H
H


 58
H
H
CF3
H
OC(═O)NHC2H5
H
H
CF3
H
H


 59
H
H
CF3
H
OC(═O)NHCH(CH3)2
H
H
CF3
H
H


 60
H
H
CF3
H
OC(═O)NHCH2CH═CH2
H
H
CF3
H
H


 61
H
H
OCF3
H
OC(═O)NHCH3
H
H
OCF3
H
H


 62
H
H
OCF3
H
OC(═O)NHC2H5
H
H
OCF3
H
H


 63
H
H
OCF3
H
OC(═O)NHCH(CH3)2
H
H
OCF3
H
H


 64
H
H
OCF3
H
OC(═O)NHCH2CH═CH2
H
H
OCF3
H
H


 65
H
H
OCF3
H
OC(═O)NHCH2C≡CH
H
H
OCF3
H
H


 66
H
H
CF3
H
OCH3
H
H
CF3
H
H


 67
H
H
CF3
H
OC2H5
H
H
CF3
H
H


 68
H
H
CF3
H
OC3H7
H
H
CF3
H
H


 69
H
H
CF3
H
cyclopentoxy
H
H
CF3
H
H


 70
H
H
OCF3
H
OCH3
H
H
OCF3
H
H


 71
H
H
OCF3
H
OC2H5
H
H
OCF3
H
H


 72
H
H
OCF3
H
OC3H7
H
H
OCF3
H
H


 73
H
H
OCF3
H
OCH(CH3)2
H
H
OCF3
H
H


 74
H
H
OCF3
H
cyclopentoxy
H
H
OCF3
H
H


 75
H
H
OCHF2
H
pyrid-2-yloxy
H
H
OCHF2
H
H


 76
H
H
OCHF2
H
pyrimidin-2-yloxy
H
H
OCHF2
H
H


 77
H
H
OCHF2
H
CH═NOC2H5
H
H
OCHF2
H
H


 78
H
H
OCHF2
H
OC(═O)NHCH(CH3)2
H
H
OCHF2
H
H


 79
H
H
OCHF2
H
NHCO2CH(CH3)2
H
H
OCHF2
H
H


 80
H
H
OCHF2
H
OC3H7
H
H
OCHF2
H
H


 81
H
H
OCF2CHF2
H
pyrid-2-yloxy
H
H
OCF2CHF2
H
H


 82
H
H
OCF2CHF2
H
pyrimidin-2-yloxy
H
H
OCF2CHF2
H
H


 83
H
H
OCF2CHF2
H
6-chloro-pyridazin-3yloxy
H
H
OCF2CHF2
H
H


 84
H
H
OCF2CHF2
H
OC3H7
H
H
OCF2CHF2
H
H


 85
H
H
OCF2CHF2
H
OC(═O)NHCH(CH3)2
H
H
OCF2CHF2
H
H


 86
H
H
OCF2CHF2
H
NHCO2CH(CH3)2
H
H
OCF2CHF2
H
H


 87
H
H
OCF2CHF2
H
OCO2CH(CH3)2
H
H
OCF2CHF2
H
H


 88
H
H
SF5
H
pyrimidin-2-yloxy
H
H
SF5
H
H


 89
H
H
SF5
H
pyrimidin-2-yloxy
H
H
CF3
H
H


 90
H
H
OCF3
H
CO2CH(CH3)2
H
H
OCF3
H
H










where 


m, p, q and r are 0; t and u are 1; R is phenyl substituted with R14, R15, R16, R17, R18;


X and Y are OH; A is —CH2—; and R1, R2, R4, R5, R14, R15, R17, R18, R7, R8, R10, and


R11 are H:









I-B









 










Compd.





No.
R3
R9
R16





 91
OCF3
OC3H7
OCF3


 92
CF3
OC3H7
CF3


 93
OCF3
2-methyl-2H-tetrazol-5-yl
OCF3


 94
CF3
pyrid-2-yloxy
CF3


 95
CF3
pyrimidin-2-yloxy
CF3


 96
CF3
6-chloro-pyridazin-3yloxy
CF3


 97
CF3
6-methoxy-pyridazin-3yloxy
CF3


 98
CF3
2-ethyl-2H-tetrazol-5-yl
CF3


 99
CF3
CH═NOCH3
CF3


100
CF3
CH═NOCH2CH═CH2
CF3


101
CF3
CH═NOCH2C≡CH
CF3


102
CF3
4-(1-methylethoxycarbonyl)phenoxy
CF3


103
OCF3
CH═NOCH2C≡CH
OCF3


104
OCF3
pyrid-2-yloxy
OCF3


105
OCF3
pyrimidin-2-yloxy
OCF3


106
OCF3
6-chloro-pyridazin-3yloxy
OCF3


107
OCF3
6-methoxy-pyridazin-3yloxy
OCF3


108
OCF3
CH═NOCH3
OCF3


109
OCF3
CH═NOCH2CH═CH2
OCF3


110
OCF3
4-(1-methylethoxycarbonyl)phenoxy
OCF3










where


m, p, and q are 0; t and u are 1; r is 1, forming an N-oxide; R is phenyl substituted


with R14, R15, R16, R17, R18;


X is OH; A is —CH2—; and R1, R4, R5, R15, R18, R7, R8,


R10, and R11 are H:









I-C









 














Compd.









No.
R2
R3
R9
R14
R16
R17
Y





111
H
CF3
pyrid-2-yloxy
H
CF3
H
H


112
H
OCF3
pyrimidin-2-yloxy
H
OCF3
H
H


113
H
CF3
2-ethyl-2H-tetrazol-5-yl
H
CF3
H
H


114
H
OCF3
2-ethyl-2H-tetrazol-5-yl
H
OCF3
H
H


115
F
Cl
pyrimidin-2-yloxy
H
Cl
F
H


116
H
OCF3
pyrimidin-2-yl
H
OCF3
H
H


117
H
OCF3
pyrid-2-yloxy
H
OCF3
H
H


118
H
OCF3
CH═NOC2H5
H
OCF3
H
H


119
H
OCF3
NHC(═O)OCH(CH3)2
H
OCF3
H
H


120
H
CF3
pyrimidin-2-yloxy
H
CF3
H
H


121
H
CF3
OC3H7
H
CF3
H
OH


122
H
OCF3
2-methyl-2H-tetrazol-5-yl
H
OCF3
H
OH


123
H
OCF3
OC3H7
H
OCF3
H
OH


124
H
CF3
CH═NOCH3
H
CF3
H
H


125
H
CF3
CH═NOC3H7
H
CF3
H
H


126
H
CF3
CH═NOCH(CH3)2
H
CF3
H
H


127
H
CF3
CH═NOCH2CH═CH2
H
CF3
H
H


128
H
CF3
CH═NOCH2C≡CH
H
CF3
H
H


129
H
CF3
CH═NOC2H5
H
CF3
H
H


130
H
OCF3
CH═NOCH3
H
OCF3
H
H


131
H
OCF3
CH═NOC3H7
H
OCF3
H
H


132
H
OCF3
CH═NOCH(CH3)2
H
OCF3
H
H


133
H
OCF3
CH═NOCH2CH═CH2
H
OCF3
H
H


134
H
OCF3
CH═NOCH2C≡CH
H
OCF3
H
H


135
H
OCF3
CH═NOC2H5
H
OCF3
H
H


136
H
CF3
CH═NOC2H5
H
CF3
H
H


137
H
CF3
CH═NOC2H5
H
CF3
H
H


138
H
OCF3
phenoxy
H
OCF3
H
H


139
H
OCF3
4-(1-methylethyoxycarbonyl)phenoxy
H
OCF3
H
H


140
H
OCF3
4-(methoxycarbonyl)phenoxy
H
OCF3
H
H


141
H
OCF3
6-chloro-pyridazin-3yloxy
H
OCF3
H
H


142
H
CF3
6-chloro-pyridazin-3yloxy
H
CF3
H
H


143
H
OCF3
NHCO2CH3
H
OCF3
H
H


144
H
OCF3
NHCO2C2H5
H
OCF3
H
H


145
H
OCF3
NHCO2CH2CH═CH2
H
OCF3
H
H


146
H
OCF3
NHCO2CH2C≡CH
H
OCF3
H
H


147
H
CF3
NHCO2CH(CH3)2
H
CF3
H
H


148
H
CF3
NHCO2CH3
H
CF3
H
H


149
H
CF3
NHCO2CH2CH═CH2
H
CF3
H
H


150
H
CF3
OC(═O)NHCH3
H
CF3
H
H


151
H
CF3
OC(═O)NHC2H5
H
CF3
H
H


152
H
CF3
OC(═O)NHCH(CH3)2
H
CF3
H
H


153
H
CF3
OC(═O)NHCH2CH═CH2
H
CF3
H
H


154
H
OCF3
OC(═O)NHCH3
H
OCF3
H
H


155
H
OCF3
OC(═O)NHC2H5
H
OCF3
H
H


156
H
OCF3
OC(═O)NHCH(CH3)2
H
OCF3
H
H


157
H
OCF3
OC(═O)NHCH2CH═CH2
H
OCF3
H
H


158
H
OCF3
OC(═O)NHCH2C≡CH
H
OCF3
H
H


159
H
CF3
OCH3
H
CF3
H
H


160
H
CF3
OC2H5
H
CF3
H
H


161
H
CF3
OC3H7
H
CF3
H
H


162
H
CF3
cyclopentoxy
H
CF3
H
H


163
H
OCF3
OCH3
H
OCF3
H
H


164
H
OCF3
OC2H5
H
OCF3
H
H


165
H
OCF3
OC3H7
H
OCF3
H
H


166
H
OCF3
OCH(CH3)2
H
OCF3
H
H


167
H
OCF3
cyclopentoxy
H
OCF3
H
H


168
H
OCHF2
pyrid-2-yloxy
H
OCHF2
H
H


169
H
OCHF2
pyrimidin-2-yloxy
H
OCHF2
H
H


170
H
OCHF2
CH═NOC2H5
H
OCHF2
H
H


171
H
OCHF2
OC(═O)NHCH(CH3)2
H
OCHF2
H
H


172
H
OCHF2
NHCO2CH(CH3)2
H
OCHF2
H
H


173
H
OCHF2
OC3H7
H
OCHF2
H
H


174
H
OCF2CHF2
pyrid-2-yloxy
H
OCF2CHF2
H
H


175
H
OCF2CHF2
pyrimidin-2-yloxy
H
OCF2CHF2
H
H


176
H
OCF2CHF2
6-chloro-pyridazin-3yloxy
H
OCF2CHF2
H
H


177
H
OCF2CHF2
OC3H7
H
OCF2CHF2
H
H


178
H
OCF2CHF2
OC(═O)NHCH(CH3)2
H
OCF2CHF2
H
H


179
H
OCF2CHF2
NHCO2CH(CH3)2
H
OCF2CHF2
H
H


180
H
OCF2CHF2
OCO2CH(CH3)2
H
OCF2CHF2
H
H


181
H
SF5
pyrid-2-yloxy
H
SF5
H
H


182
H
OCF3
pyrid-2-yloxy
Cl
OCF3
H
H


183
H
CF3
pyrid-2-yloxy
Cl
CF3
H
H


184
H
OCF3
pyrimidin-2-yloxy
Cl
OCF3
H
H


185
H
OCF3
CH═NOC2H5
Cl
OCF3
H
H


186
H
OCF3
6-chloro-pyridizin-3yloxy
Cl
OCF3
H
H


187
H
OCF3
pyrid-2-yloxy
Cl
Cl
H
H


188
H
OCF3
pyrid-2-yloxy
F
OCF3
H
H


189
H
OCF3
pyrimidin-2-yloxy
F
OCF3
H
H


190
H
OCF3
CH═NOC2H5
F
OCF3
H
H


191
H
OCF3
CO2CH(CH3)2
H
OCF3
H
H










where


m, p, q and r are 0; t and u are 1; R is phenyl substituted with R14,R15, R16, R17, R18;


A is —CH2—; and R1, R2, R4, R5, R14, R15, R17, R7, R8, R10 and R11 are H:









I-D









 












Compd.







No.
X
Y
R3
R9
R16





192
F
H
OCF3
pyrimidin-2-yloxy
OCF3


193
F
H
CF3
pyrid-2-yloxy
CF3


194
F
H
CF3
pyrimidin-2-yloxy
CF3


195
C(═O)OC2H5
Cl
CF3
pyrid-2-yloxy
CF3


196
C(═O)OC2H5
H
CF3
pyrid-2-yloxy
CF3


197
C(═O)OC2H5
F
CF3
pyrid-2-yloxy
CF3


198
C≡N
Cl
CF3
pyrid-2-yloxy
CF3


199
OH
CH3
CF3
pyrid-2-yloxy
CF3


200
OH
CH(CH3)2
CF3
pyrid-2-yloxy
CF3


201
CH2OH
H
CF3
pyrid-2-yloxy
CF3


202
OH
CH3
CF3
pyrimidin-2-yl
CF3


203
OH
CH3
CF3
CH═NOCH3
CF3


204
OH
CH3
OCF3
pyrid-2-yl
OCF3


205
OH
CH3
OCF3
pyrimidin-2-yl
OCF3


206
OH
CH3
OCF3
CH═NOCH3
OCF3


207
C(═O)OCH3
CH3
OCF3
pyrid-2-yl
OCF3


208
OSO2CH3
CH3
OCF3
pyrid-2-yl
OCF3


209
SH
H
OCF3
pyrid-2-yl
OCF3


210
C(═O)OH
H
OCF3
pyrid-2-yl
OCF3










where


m, p, q and r are 0; t and u are 1; R is phenyl substituted with R14, R15, R16, R17, R18;


R1, R2, R4, R5, R14, R15, R17, R18, R7, R8, R10 and R11 are H; A is —CH2—; and X and Y


are taken together with —OCR12R13O—, forming a 1,3-dioxolane ring:









I-E









 












Compd.







No.
R3
R9
R12
R13
R16





211
CF3
pyrid-2-yloxy
H
H
CF3


212
CF3
pyrimidin-2-yloxy
H
H
CF3


213
CF3
6-chloro-pyridazin-3yloxy
H
H
CF3


214
CF3
2-ethyl-2H-tetrazol-5-yl
H
H
CF3


215
CF3
OC3H7
H
H
CF3


216
CF3
CH═NOCH3
H
H
CF3


217
CF3
CH═NOC2H5
H
H
CF3


218
CF3
pyrid-2-yloxy
CH3
CH3
CF3


219
CF3
pyrimidin-2-yloxy
CH3
CH3
CF3


220
CF3
6-chloro-pyridazin-3yloxy
CH3
CH3
CF3


221
CF3
2-ethyl-2H-tetrazol-5-yl
CH3
CH3
CF3


222
CF3
OC3H7
CH3
CH3
CF3


223
CF3
CH═NOCH3
CH3
CH3
CF3


224
CF3
CH═NOC2H5
CH3
CH3
CF3


225
CF3
OC(═O)NHCH(CH3)2
CH3
CH3
CF3










where


m, p, q and r are 0; t and u are 1; r is 1, forming an N-oxide; R is phenyl substituted


with R14, R15, R16, R17, R18; R1, R2, R4, R5, R14, R15, R17, R18, R7, R8, R10 and R11 are


H; A is —CH2—; and X and Y are taken together with —OCR12R13O—, forming a 1,3-


dioxolane ring:









I-F









 












Compd.







No.
R3
R9
R12
R13
R16





226
CF3
pyrid-2-yloxy
H
H
CF3


227
CF3
pyrimidin-2-yloxy
H
H
CF3


228
CF3
6-chloro-pyridizin-3yloxy
H
H
CF3


229
CF3
2-ethyl-2H-tetrazol-5-yl
H
H
CF3


230
CF3
OC3H7
H
H
CF3


231
CF3
CH═NOCH3
H
H
CF3


232
CF3
CH═NOC2H5
H
H
CF3


233
CF3
pyrid-2-yloxy
CH3
CH3
CF3


234
CF3
pyrimidin-2-yloxy
CH3
CH3
CF3


235
CF3
6-chloro-pyridizin-3yloxy
CH3
CH3
CF3


236
CF3
2-ethyl-2H-tetrazol-5-yl
CH3
CH3
CF3


237
CF3
OC3H7
CH3
CH3
CF3


238
CF3
CH═NOCH3
CH3
CH3
CF3


239
CF3
CH═NOC2H5
CH3
CH3
CF3


240
CF3
OC(═O)NHCH(CH3)2
CH3
CH3
CF3










where


p, q and r are 0; t and u are 1; R is phenyl substituted with R14, R15, R16, R17, R18;


A is —CH2—; and R1, R2, R4, R5, R14, R15, R17, R18, R7, R8, R10 and R11 are H:









I-G









 













Compd.








No.
R3
R9
X
Y
B
R16





241
CF3
pyrid-2-yloxy
OH
H
O
CF3


242
CF3
pyrid-2-yloxy
OH
CH3
O
CF3


243
CF3
pyrimidin-2-yloxy
OH
H
O
CF3


244
CF3
CH═NOCH3
OH
H
O
CF3


245
CF3
pyrid-2-yloxy
OH
H
OC(═O)NH
CF3


246
OCF3
pyrid-2-yloxy
OH
H
O
OCF3


247
OCF3
pyrid-2-yloxy
OH
CH3
O
OCF3


248
OCF3
pyrid-2-yloxy
F
H
O
OCF3


249
OCF3
pyrid-2-yloxy
F
CH3
O
OCF3


250
OCF3
pyrid-2-yloxy
F
H
OC(═O)NH
OCF3


251
OCF3
CH═NOCH3
F
H
O
OCF3


252
OCF3
pyrid-2-yloxy
OH
H
NHSO2
OCF3


253
OCF3
pyrid-2-yloxy
OH
H
OCH2
OCF3


254
OCF3
pyrid-2-yloxy
OH
H
CH2O
OCF3










where


m, p, q and r are 0; t and u are 1; R is phenyl substituted with R14, R15, R16, R17, R18;


X is OH; A is —CH2—; and R1, R2, R4, R5, R7, R8, R10, R11, R14,


R15, R17, R18 and Y are H:









I-H









 










Compd





No.
R3
R9
R16





255
OCF3
6-methyl-pyridazin-3-yloxy
OCF3


256
CHO
pyrid-2-yloxy
OCF3


257
C(CH3)3
pyrid-2-yloxy
OCF3


258
OCF3
CH═NOCH2CH2OCH2CH2OCH3
OCF3


259
OCF3
CH═NOCH2OCH2CH3
OCF3


260
OCH3
pyrid-2-yloxy
OCF3


261
Br
pyrid-2-yloxy
OCF3


262
CH3
pyrid-2-yloxy
OCF3


263
OCF3
1,3-dioxolan-2-yl
OCF3


264
CF3
1,3-dioxolan-2-yl
CF3


265
CF3
pyrid-2-yloxy
OCF3


266
OCF3
CH═NOCH2CH2OCH3
OCF3


267
Cl
pyrid-2-yloxy
Cl


268
F
pyrid-2-yloxy
OCF3


269
OCHF2
pyrid-2-yloxy
OCF3


270
CF3
CH═NOH
CF3


271
OCF3
3-methyl-pyrid-2-yloxy
OCF3


272
OCF3
5-methyl-pyrid-2-yloxy
OCF3


273
OCF3
CH(OCH2CH3)2
OCF3


274
OCF3
6-methoxy-pyridazin-3-yloxy
OCF3


275
OCF3
CH═NOCH2C≡N
OCF3


276
OCF3
6-methyl-pyrid-2-yloxy
OCF3


277
OCF3
C(Cl)═NOCH3
OCF3


278
OCF3
4-chlorophenylCH(OH)
OCF3


279
OCF3
OCH2C(═O)OCH2CH3
OCF3


280
OCF3
5,5-dimethyl-1,3-dioxan-2-yl
OCF3


281
OCF3
3-cyano-pyrid-2-yloxy
OCF3


282
OCF3
pyrid-2-yl-CH(OH)
OCF3


283
OCF3
5-cyano-pyrid-2-yloxy
OCF3


284
OCF3
pyrid-2-yloxy
CH═NOCH2CH═C(CH3)CH2—





CH2CH═C(CH3)2


285
OCF3
C(═O)NHOCH3
OCF3


286
OCF3
3-chlorophenoxy
OCF3


287
OCF3
pyrid-2-yloxy
CH(OH)CH3


288
H
pyrid-2-yloxy
OCF3


289
OCF3
4-chlorophenyl-CH(OC(═O)CH3)
OCF3


290
OCF3
4-chlorophenoxy
OCF3


291
CF3
OCH2C(═O)OCH2CH3
CF3


292
OCF3
1,3-dioxan-2-yl
OCF3


293
OCF3
OCH2CH═C(Cl)2
OCF3


294
OCF3
3-(dimethoxymethyl)-pyrid-2-yl
OCF3


295
1,3-dioxolan-
pyrid-2-yloxy
OCF3



2-yl




296
OCF3
C(C≡N)═NOCH3
OCF3


297
OCF3
2-chlorophenoxy
OCF3


298
OCF3
OC(═O)NH-cyclopropane
OCF3


299
CF3
cyclopropylmethoxy
CF3


300
OCF3
OC(═O)NHC3H7
OCF3


301
OCF3
CH═NOCH2CF3
OCF3


302
CF3
OH
CF3


303
CF3
OCH(CH3)2
CF3


304
OCF3
phenylmethoxy
OCF3


305
OCF3
CH═NHOCH2CH═C(CH3)CH2CH2—
OCF3




CH═C(CH3)2



306
OCF2CHFCF3
pyrimidin-2-yloxy
OCF2CHFCF3


307
CF3
6-chloro-pyridazin-3-yloxy
CF3


308
OCF3
OCH2CH2OCH3
OCF3


309
OCF3
pyrid-2-yl
OCF3


310
OCF3
NHC(═O)OCH2CH2CH3
OCF3


311
OCF3
OC(═O)NHC(CH3)3
OCF3


312
OCF3
CH═NOCH2CH2F
OCF3


313
CF3
NHC(═O)OCH2CH2CH3
CF3


314
Cl
pyrid-2-yloxy
OCF3


315
OCF3
cyclopropylmethoxy
OCF3


316
CF3
phenylmethoxy
CF3


317
OCF3
OC(═O)NHCH2C(═O)OC2H5
OCF3


318
CF3
NHC(═O)OCH2CH3
CF3


319
CF3
NHC(═O)OCH2-cyclopropane
CF3


320
OCF3
OC(═O)NH-cyclopentane
OCF3


321
OCF3
4-methyl-pyrid-2-yloxy
OCF3


322
OCF3
3-chloro-pyrid-2-yloxy
OCF3


323
OCF3
OC(═O)NHCH2(3,4-
OCF3




dichlorophenyl)



324
OCF3
OC(═O)NH(4-chlorophenyl)
OCF3


325
Cl
pyrimidin-2-yloxy
OCF3


326
OCF3
OC(═O)NHC4H9
OCF3


327
OCF3
NHC(═O)OCH2-cyclopropane
OCF3


328
Cl
CH═NOC2H5
OCF3


329
OCF3
OC(═O)NH-cyclohexane
OCF3


330
CF3
C(═O)OCH(CH3)2
CF3


331
CF3
OH
CF3


332
OCF3
NHC(═O)C(CH2CH2)C≡N
OCF3


333
CF3
NHC(═O)C(CH2CH2)C≡N
CF3










where


m, p, and q are 0; t and u are 1; r is 1, forming an N-oxide; R is phenyl substituted


with R14, R15, R16, R17, R18; X is OH, A is —CH2—; and R1, R2, R4, R5, R7, R8, R10, R11,


R14, R15 , R17, R18 and Y are H:









I-J









 










Compd





No.
R3
R9
R16





334
CHO
pyrid-2-yloxy
OCF3


335
C(CH3)3
pyrid-2-yloxy
OCF3


336
OCF3
CH═NOCH2CH2OCH2CH2OCH3
OCF3


337
OCF3
CH═NOCH2OCH2CH3
OCF3


338
OCH3
pyrid-2-yloxy
OCF3


339
Br
pyrid-2-yloxy
OCF3


340
CH3
pyrid-2-yloxy
OCF3


341
OCF3
1,3-dioxolan-2-yl
OCF3


342
CF3
1,3-dioxolan-2-yl
CF3


343
CF3
pyrid-2-yloxy
OCF3


344
OCF3
CH═NOCH2CH2OCH3
OCF3


345
Cl
pyrid-2-yloxy
Cl


346
F
pyrid-2-yloxy
OCF3


347
OCHF2
pyrid-2-yloxy
OCF3


348
CF3
CH═NOH
CF3


349
OCF3
3-methyl-pyrid-2-yloxy
OCF3


350
OCF3
5-methyl-pyrid-2-yloxy
OCF3


351
OCF3
CH(OCH2CH3)2
OCF3


352
OCF3
6-methoxy-pyridazin-3-yloxy
OCF3


353
OCF3
CH═NOCH2C≡N
OCF3


354
OCF3
6-methyl-pyrid-2-yloxy
OCF3


355
OCF3
C(Cl)═NOCH3
OCF3


356
OCF3
4-chlorophenylCH(OH)
OCF3


357
OCF3
OCH2C(═O)OCH2CH3
OCF3


358
OCF3
5,5-dimethyl-1,3-dioxan-2-yl
OCF3


359
OCF3
3-cyano-pyrid-2-yloxy
OCF3


360
OCF3
pyrid-2-yl-CH(OH)
OCF3


361
OCF3
5-cyano-pyrid-2-yloxy
OCF3


362
OCF3
pyrid-2-yloxy
CH═NOCH2CH═C(CH3)CH2—





CH2CH═C(CH3)2


363
OCF3
C(═O)NHOCH3
OCF3


364
OCF3
3-chlorophenoxy
OCF3


365
OCF3
pyrid-2-yloxy
CH(OH)CH3


366
H
pyrid-2-yloxy
OCF3


367
OCF3
4-chlorophenyl-CH(OC(═O)CH3)
OCF3


368
OCF3
4-chlorophenoxy
OCF3


369
CF3
OCH2C(═O)OCH2CH3
CF3


370
OCF3
1,3-dioxan-2-yl
OCF3


371
OCF3
OCH2CH═C(Cl)2
OCF3


372
OCF3
3-(dimethoxymethyl)-pyrid-2-yl
OCF3


373
1,3-dioxolan-
pyrid-2-yloxy
OCF3



2-yl




374
OCF3
C(C≡N)═NOCH3
OCF3


375
OCF3
2-chlorophenoxy
OCF3


376
OCF3
OC(═O)NH-cyclopropane
OCF3


377
OCF3
OC(═O)NHC3H7
OCF3


378
OCF3
CH═NOCH2CF3
OCF3


379
CF3
OH
CF3


380
CF3
OCH(CH3)2
CF3


381
OCF3
phenylmethoxy
OCF3


382
OCF3
CH═NHOCH2CH═C(CH3)CH2CH2—
OCF3




CH═C(CH3)2



383
CF3
cyclopropylmethoxy
CF3


384
CF3
6-chloro-pyridazin-3-yloxy
CF3


385
OCF3
OCH2CH2OCH3
OCF3


386
OCF3
pyrid-2-yl
OCF3


387
OCF3
NHC(═O)OCH2CH2CH3
OCF3


388
OCF3
OC(═O)NHC(CH3)3
OCF3


389
OCF3
CH═NOCH2CH2F
OCF3


390
CF3
NHC(═O)OCH2CH2CH3
CF3


391
Cl
pyrid-2-yloxy
OCF3


392
OCF3
cyclopropylmethoxy
OCF3


393
CF3
phenylmethoxy
CF3


394
OCF3
OC(═O)NHCH2C(═O)OC2H5
OCF3


395
CF3
NHC(═O)OCH2CH3
CF3


396
CF3
NHC(═O)OCH2-cyclopropane
CF3


397
OCF3
OC(═O)NH-cyclopentane
OCF3


398
OCF3
4-methyl-pyrid-2-yloxy
OCF3


399
OCF3
3-chloro-pyrid-2-yloxy
OCF3


400
OCF3
OC(═O)NHCH2(3,4-
OCF3




dichlorophenyl)



401
OCF3
OC(═O)NH(4-chlorophenyl)
OCF3


402
Cl
pyrimidin-2-yloxy
OCF3


403
OCF3
OC(═O)NHC4H9
OCF3


404
OCF3
NHC(═O)OCH2-cyclopropane
OCF3


405
Cl
CH═NOC2H5
OCF3


406
OCF3
OC(═O)NH-cyclohexane
OCF3


407
CF3
C(═O)OCH(CH3)2
CF3


408
CF3
OH
CF3


409
OCF2CHFCF3
pyrimidin-2-yloxy
OCF2CHFCF3


410
OCF3
CH═NOCH2C(═O)NH2
OCF3


411
OCF3
3-chloro-pyrid-2-yl
OCF3


412
OCF3
6-chloro-pyridazin-3-yloxy
OCF3


413
OCF3
6-methyl-pyridazin-3-yloxy
OCF3


414
OCF3
NHC(═O)C(CH2CH2)C≡N
OCF3


415
CF3
NHC(═O)C(CH2CH2)C≡N
CF3










where


m, p, q and r are 0; t and u are 1; R is phenyl substituted with R14, R15, R16, R17, R18;


X and Y are OH; R3 and R16 are OCF3; A is —CH2—; and R1, R2, R4, R5, R14, R15, R17,


R18, R7, R8, R10, and R11 are H:









I-K















Compd.



No.
R9





416
2-ethyl-2H-tetrazol-5-yl


417
CH═NOCH2CH3


418
CHO


419
NHC(═O)OCH(CH3)2


420
NHC(═O)C(CH2CH2)C≡N










where


m, p, and q are 0; t and u are 1; r is 1, forming an N-oxide; R is phenyl substituted


with R14, R15, R16, R17, R18; A is —CH2—; and R1, R2, R4, R5, R14, R15, R17, R18, R7, R8,


R10, and R11 are H:









I-L









 












Compd.







No.
R3
R9
R16
X
Y





421
OCF3
pyrid-2-yloxy
OCF3
OH
OH


422
OCF3
pyrimidin-2-yloxy
OCF3
OH
OH


423
OCF3
NHC(═O)OCH(CH3)2
OCF3
OH
OH


424
OCF3
CH═NOCH2CH3
OCF3
OH
OH


425
OCF3
6-chloro-pyridazin-3-yloxy
OCF3
OH
OH


426
OCF3
2-ethyl-2H-tetrazol-5-yl
OCF3
OH
OH


428
OCF3
NHC(═O)C(CH2CH2)C≡N
OCF3
OH
OH


429
CF3
NHC(═O)C(CH2CH2)C≡N
CF3
OH
OH


430
OCF3
pyrid-2-yloxy
OCF3
OH
F












431
OCF3
pyrid-2-yloxy
OCF3
X and Y taken







together with







bridging group







—O—



432
OCF3
pyrimidin-2-yloxy
OCF3
X and Y taken







together with







bridging group







—O—










where


m, p, q and r are 0; t and u are 1; R is phenyl substituted with R14, R15, R16, R17, R18;


A is —CH2—; and R7, R8, R11, R14 and Y are H:









I-M









 



















Compd














No.
R1
R2
R3
R4
R5
R9
R10
R15
R16
R17
R18
X





433
Cl
H
Cl
H
H
pyrid-2-yloxy
H
H
OCF3
H
H
OH


434
F
H
H
H
H
pyrimidin-2-yloxy
H
H
H
H
F
OH


435
H
CH3
Cl
H
H
pyrid-2-yloxy
H
H
OCF3
H
H
OH


436
CH3
H
Cl
H
H
pyrid-2-yloxy
H
H
OCF3
H
H
OH


437
Cl
H
H
H
H
pyrid-2-yloxy
H
H
OCF3
H
H
OH


438
Cl
Cl
H
H
H
pyrid-2-yloxy
H
H
OCF3
H
H
OH


439
H
Cl
H
H
H
pyrid-2-yloxy
H
H
OCF3
H
H
OH


440
H
H
CH═NO—
H
H
pyrid-2-yloxy
H
H
OCF3
H
H
OH





C2H5











441
H
Cl
Cl
H
H
pyrid-2-yloxy
H
H
OCF3
H
H
OH


442
H
Cl
H
Cl
H
pyrid-2-yloxy
H
H
OCF3
H
H
OH


443
Cl
H
H
Cl
H
pyrid-2-yloxy
H
H
OCF3
H
H
OH


444
Cl
H
Cl
H
H
CH═NOC2H5
H
H
OCF3
H
H
OH


445
F
H
Cl
H
H
pyrid-2-yloxy
H
H
OCF3
H
H
OH

















446
H
H
R3 and R4 taken
H
pyrid-2-yloxy
H
H
R16 and R17 taken
H
OH





together with




together with







bridging group




bridging group







—OC(F2)O—




—OC(F2)O—





















447
H
H
OCF3
H
H
pyrid-2-yloxy
OCH3
H
OCF3
H
H
OH


448
H
H
CF3
H
H
pyrimidin-2-yloxy
H
H
CF3
H
H
CH2OH


449
H
H
CF3
H
H
OCH2-
H
H
CF3
H
H
CH2N═N═N








cyclopropane








450
H
H
CF3
H
H
OCH2-
H
H
CF3
H
H
CH2NH2








cyclopropane








451
H
H
CF3
H
H
pyrimidin-2-yloxy
H
H
CF3
H
H
CH2NH—














C(═O)—CH3


452
H
H
CF3
H
H
pyrimidin-2-yloxy
H
H
CF3
H
H
CH2O—C(═O)—














CH3










where


m, p, and q are 0; t and u are 1; r is 1, forming an N-oxide; R is phenyl substituted


with R14, R15, R16, R17, R18; A is —CH2—; and R7, R8, R11, R14


and Y are H:









I-N









 



















Compd














No.
R1
R2
R3
R4
R5
R9
R10
R15
R16
R17
R18
X





453
Cl
H
Cl
H
H
CH═NOC2H5
H
H
OCF3
H
H
OH


454
Cl
H
Cl
H
H
pyrid-2-yloxy
H
H
OCF3
H
H
OH


455
H
Cl
Cl
H
H
pyrid-2-yloxy
H
H
OCF3
H
H
OH


456
Cl
Cl
H
H
H
pyrid-2-yloxy
H
H
OCF3
H
H
OH


457
H
Cl
H
Cl
H
pyrid-2-yloxy
H
H
OCF3
H
H
OH


458
H
Cl
H
H
H
pyrid-2-yloxy
H
H
OCF3
H
H
OH


459
Cl
H
H
H
H
pyrid-2-yloxy
H
H
OCF3
H
H
OH


460
Cl
H
H
Cl
H
pyrid-2-yloxy
H
H
OCF3
H
H
OH


461
CH3
H
Cl
H
H
pyrid-2-yloxy
H
H
OCF3
H
H
OH


462
H
CH3
Cl
H
H
pyrid-2-yloxy
H
H
OCF3
H
H
OH


463
F
H
Cl
H
H
pyrid-2-yloxy
H
H
OCF3
H
H
OH

















464
H
R2and R3 taken
H
H
pyrid-2-yloxy
H
R15and R16 taken
H
H
OH




together with




together with







bridging




bridging







group




group







—OC(F2)O—




—OC(F2)O—






















465
H
H
OCF3
H
H
pyrid-2-yloxy
OCH3
H
OCF3
H
H
OH


466
H
H
CF3
H
H
pyrimidin-2-yloxy
H
H
CF3
H
H
CH2NH—














C(═O)—CH3


467
H
H
CF3
H
H
OCH2-cyclopropane
H
H
CF3
H
H
CH2N═N═N


468
H
H
CF3
H
H
pyrimidin-2-yloxy
H
H
CF3
H
H
CH2O—C(═O)—














CH3










where


m, p, q and r are 0; t and u are 1; R is phenyl substituted with R14, R15, R16, R17, R18; R3 and R16 are OCF3; and R1, R2, R4, R5,


R14, R15, R17, R18, R10 and R11 are H:









I-P









 













Compd.








No.
X
Y
A
R7
R8
R9





470
OH
H
OCH2CH(OH)CH2
H
H
Cl


471
OH
H
OCH2CH(OH)CH2
H
Cl
H


472
OH
H
OCH2CH(OH)CH2
Cl
H
H


473
OH
H
OCH2CH2CH2
H
H
Cl


474
OH
H
CH2CH2
H
H
Cl


475
OH
H
OCH2CH2
H
H
Cl


476
OH
H
OCH2CH2CH2CH2
H
H
Cl


477
OH
H
OCH2CH2
H
H
Br










where


m, p, and q are 0; t and u are 1; r is 1, forming an N-oxide; R is phenyl substituted


with R14, R15, R16, R17, R18; R3 and R16 are OCF3; and R1, R2, R4, R5, R7, R8, R10,


R11, R14, R15, R17, R18 and Y are H:









I-Q









 










Compd.





No.
X
A
R9





478
OH
OCH2CH2
Cl


479
OH
CH2CH2
Cl


480
OH
OCH2CH2CH2CH2
Cl


481
OH
OCH2CH2CH2
Cl


482
OH
OCH2CH2
Br










where


m, p, and q are 0; t and u are 1; r is 1, R is phenyl substituted with R14, R15, R16, R17, R18;


X is OH; A is —CH2—; and R1, R2, R4, R5, R7, R8, R10,


R11, R14, R15, R17, R18 and Y are H:









I-R









 











Compd






No.
R3
R9
R16
−Salt





483
OCF3
CH═NOC2H5
OCF3
3-hydroxypropanesulfonic acid


484
OCF3
CH═NOC2H5
OCF3
2-ethoxypropanoic acid


485
OCF3
6-chloro-pyridazin-3-yloxy
OCF3
2-ethylhexanoic acid


486
OCF3
CH═NOC2H5
OCF3
2-ethylhexanoic acid


487
OCF3
CH═NOC2H5
OCF3
1,1,2,2,3,3,4,4,4-nonafluorobutanesulfonic acid


488
CF3
6-chloro-pyridazin-3-yloxy
CF3
2-hydroxypropane-1,2,3-tricarboxylic acid


489
OCF3
CH═NOCH2C(═O)NH2
OCF3
2-hydroxypropane-1,2,3-tricarboxylic acid


490
OCF3
CH═NOC2H5
OCF3
((4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptyl)methanesulfonic






acid


491
OCF3
CH═NOC2H5
OCF3
ethanesulfonic acid


492
OCF3
6-chloro-pyridazin-3-yloxy
OCF3
2-hydroxypropane-1,2,3-tricarboxylic acid


493
OCF3
CH═NOC2H5
OCF3
cyclohexanecarboxylic acid


494
OCF3
CH═NOC2H5
OCF3
2-hydroxypropane-1,2,3-tricarboxylic acid


495
OCF3
CH═NOC2H5
OCF3
1,1,2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-heptadecafluorooctanesulfonic acid


496
OCF3
pyrid-2-yloxy
OCF3
1,1,2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-heptadecafluorooctanesulfonic acid


497
OCF3
pyrid-2-yloxy
OCF3
-C1


498
OCF3
pyrid-2-yloxy
OCF3
((4S)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptyl)methanesulfonic






acid


499
OCF3
pyrid-2-yloxy
OCF3
2-ethylhexanoic acid


500
OCF3
pyrid-2-yloxy
OCF3
3-hydroxypropanesulfonic acid


501
OCF3
CH(Cl)═NOCH3
OCF3
2-hydroxypropane-1,2,3-tricarboxylic acid


502
OCF3
pyrid-2-yloxy
OCF3
cyclohexanecarboxylic acid


503
OCF3
pyrid-2-yloxy
OCF3
2-ethoxypropanoic acid


504
OCF3
pyrid-2-yloxy
OCF3
2-hydroxypropane-1,2,3-tricarboxylic acid


505
OCF3
pyrid-2-yloxy
OCF3
((4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptyl)methanesulfonic






acid


506
OCF3
pyrid-2-yloxy
OCF3
ethanesulfonic acid


507
OCF3
CH═NOC2H5
OCF3
((4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptyl)methanesulfonic






acid


508
OCF3
pyrid-2-yloxy
OCF3
1,1,2,2,3,3,4,4,4-nonafluorobutanesulfonic acid


509
OCF3
pyrid-2-yloxy
OCF3
3,7-dimethyloct-6-enoic acid


510
OCF3
pyrid-2-yloxy
OCF3
2-hydroxyacetic acid


511
OCF3
pyrid-2-yloxy
OCF3
adamantanecarboxylic acid


512
OCF3
pyrid-2-yloxy
OCF3
pentanedioic acid


513
OCF3
pyrid-2-yloxy
OCF3
(9E)octadec-9-enoic acid


514
OCF3
pyrid-2-yloxy
OCF3
heptanedioic acid


515
OCF3
pyrid-2-yloxy
OCF3
4-dodecylbenzenesulfonic acid


516
OCF3
pyrid-2-yloxy
OCF3
hexanedioic acid


517
OCF3
pyrid-2-yloxy
OCF3
octanoic acid


518
CF3
6-chloro-pyridazin-3-yloxy
CF3
ethanesulfonic acid


519
CF3
6-chloro-pyridazin-3-yloxy
CF3
3-((1Z)-2-chloro-3,3,3-trifluoroprop-1-enyl)-2,2-






dimethylcyclopropanecarboxylic acid


520
CF3
6-chloro-pyridazin-3-yloxy
CF3
1,1,2,2,3,3,4,4,5,5,6,6,7,7,8,8,9,9,9-nonadecafluorononanesulfonic






acid










where


m, p and r are 0; t and u are 1; R is phenyl substituted


with R14, R15, R16, R17, R18;


X is OH; A is —CH2—; R3 and R16 are OCF3; and R1, R2, R4, R5, R7, R8, R10,


R11, R14, R15, R17 and R18 are H:









I-S









 












Compd







No.
q
Y
R6
R9
−Salt





521
1
OH
(methylethoxy)-carboxamide-
NHC(═O)OCH(CH3)2
−Cl





phenyl-4-meth-yl




522
0
H
—
pyrid-2-yloxy
H•−Cl










where


m, p, and q are 0; t and u are 1; R is phenyl substituted


with R14, R15, R16, R17, R18;


R1, R2, R4, R5, R14, R15, R17, R18, R7, R8, R10 and R11 are H;


A is —CH2—; and X and Y are taken together with —OC(═O)O—, forming a 1,3 dioxol-2-one ring:









I-T









 







note if r = 1, the n-oxide is formed:











Compd.






No.
r
R3
R9
R16





523
0
CF3
pyrid-2-yloxy
CF3


524
0
CF3
pyrimidin-2-yloxy
CF3


525
0
CF3
6-chloro-pyridazin-3yloxy
CF3


526
0
CF3
2-ethyl-2H-tetrazol-5-yl
CF3


527
0
CF3
OC3H7
CF3


528
0
CF3
CH═NOCH3
CF3


529
0
CF3
CH═NOC2H5
CF3


530
0
CF3
pyrid-2-yloxy
CF3


531
0
CF3
pyrimidin-2-yloxy
CF3


532
0
CF3
6-chloro-pyridazin-3yloxy
CF3


533
0
CF3
2-ethyl-2H-tetrazol-5-yl
CF3


534
0
CF3
OC3H7
CF3


535
0
CF3
CH═NOCH3
CF3


536
0
CF3
CH═NOC2H5
CF3


537
0
CF3
OC(═O)NHCH(CH3)2
CF3


538
1
CF3
pyrid-2-yloxy
CF3


539
1
CF3
pyrimidin-2-yloxy
CF3


540
1
CF3
6-chloro-pyridazin-3yloxy
CF3


541
1
CF3
2-ethyl-2H-tetrazol-5-yl
CF3


542
1
CF3
OC3H7
CF3


543
1
CF3
CH═NOCH3
CF3


544
1
CF3
CH═NOC2H5
CF3


545
1
CF3
pyrid-2-yloxy
CF3


546
1
CF3
pyrimidin-2-yloxy
CF3


547
1
CF3
6-chloro-pyridazin-3yloxy
CF3


548
1
CF3
2-ethyl-2H-tetrazol-5-yl
CF3


549
1
CF3
OC3H7
CF3


550
1
CF3
CH═NOCH3
CF3


551
1
CF3
CH═NOC2H5
CF3


552
1
CF3
OC(═O)NHCH(CH3)2
CF3


553
0
OCF3
pyrid-2-yloxy
OCF3


554
0
OCF3
pyrimidin-2-yloxy
OCF3


555
0
OCF3
6-chloro-pyridazin-3yloxy
OCF3


556
0
OCF3
2-ethyl-2H-tetrazol-5-yl
OCF3


557
0
OCF3
OC3H7
OCF3


558
0
OCF3
CH═NOCH3
OCF3


559
0
OCF3
CH═NOC2H5
OCF3


560
0
OCF3
pyrid-2-yloxy
OCF3


561
0
OCF3
pyrimidin-2-yloxy
OCF3


562
0
OCF3
6-chloro-pyridazin-3yloxy
OCF3


563
0
OCF3
2-ethyl-2H-tetrazol-5-yl
OCF3


564
0
OCF3
OC3H7
OCF3


565
0
OCF3
CH═NOCH3
OCF3


566
0
OCF3
CH═NOC2H5
OCF3


567
0
OCF3
OC(═O)NHCH(CH3)2
OCF3


568
1
OCF3
pyrid-2-yloxy
OCF3


569
1
OCF3
pyrimidin-2-yloxy
OCF3


570
1
OCF3
6-chloro-pyridazin-3yloxy
OCF3


571
1
OCF3
2-ethyl-2H-tetrazol-5-yl
OCF3


572
1
OCF3
OC3H7
OCF3


573
1
OCF3
CH═NOCH3
OCF3


574
1
OCF3
CH═NOC2H5
OCF3


575
1
OCF3
pyrid-2-yloxy
OCF3


576
1
OCF3
pyrimidin-2-yloxy
OCF3


577
1
OCF3
6-chloro-pyridazin-3yloxy
OCF3


578
1
OCF3
2-ethyl-2H-tetrazol-5-yl
OCF3


579
1
OCF3
OC3H7
OCF3


580
1
OCF3
CH═NOCH3
OCF3


581
1
OCF3
CH═NOC2H5
OCF3


582
1
OCF3
OC(═O)NHCH(CH3)2
OCF3










where


m, p, q and r are 0; t and u are 1; R is phenyl substituted


with R14, R15, R16, R17, R18;


X is OH; A is —CH2—; R3 and R16 are OCF3; and R1, R2, R4, R5, R10, R11, R14,


R15, R17, R18 and Y are H:









I-U









 










Compd





No.
R7
R8
R9





583
H
H
OCH2CH2OCH2CH2OCH3


584
H
H
OCH2CH2CH2OCH3


585
H
H
6-methoxy-pyrid-2-yloxy


586
H
methoxy
OCH2CH2OCH3


587
H
Cl
OCH2CH2OCH3


588
Cl
H
OCH2CH2OCH3










where


m, p, and q are 0; t and u are 1; r is 1, forming an N-oxide; R is phenyl substituted


with R14, R15, R16, R17, R18;


X is OH; A is —CH2—; R3 and R16 are OCF3; and R1, R2,


R4, R5, R10, R11, R14, R15, R17, R18 and Y are H:









I-V









 










Compd





No.
R7
R8
R9





589
H
H
OCH2CH2OCH2CH2OCH3


590
H
H
OCH2CH2CH2OCH3


591
H
H
6-methoxy-pyrid-2-yloxy


592
H
methoxy
OCH2CH2OCH3


593
H
Cl
OCH2CH2OCH3


594
Cl
H
OCH2CH2OCH3









The following table sets forth physical characterizing data for compounds of formula I:







TABLE 2







Physical Characteristics









Cmpd

Physical State/Melting Point


No.
Emperical Formula
(° C.)












1
C29H27Cl2N3O2
Solid Foam


2
C31H27F6N3O3
Solid


3
C30H26Cl2F3N3O2
—


4
C29H25Cl2F2N3O2
Solid Foam


5
C32H32F3N3O4
Solid


6
C29H25C14N3O2
Solid Foam


7
C30H27ClF3N3O2
Solid


8
C29H27F2N3O2
—


9
C30H26Cl2F3N3O2
—


10
C29H25F4N3O2
—


11
C30H26F5N3O2
—


12
C30H27F4N3O2
Solid


13
C30H26Cl2F3N3O2
Solid


14
C30H27ClF3N3O2
Solid


15
C30H26Cl2F3N3O2
—


16
C31H27F6N3O2
—


17
C30H26F5N3O2
Oil


18
C30H27ClF3N3O2
Solid


19
C31H27F6N3O4
Solid, 68-79


20
C31H27F6N3O3
Solid, 59-65


21
C32H28F6N2O4
—


22
C32H28F6N2O2
Solid


23
C28H29Cl2N5O
—


24
C28H29Cl2N5O
Solid


25
C30H29F6N5O3
Solid/Solid Foam


26
C28H27Cl4N5O
Solid Foam


27
C30H29F6N5O
Solid Foam


28
C30H30F6N2O4
Liquid


29
C31H32F6N2O5
Solid, 82-85


30
C33H27F9N2O4
—


91
C30H31F6NO5
Solid, 52-57


92
C30H31F6NO3
Solid, 65-70


93
C29H27F6N5O4
Solid


111
C32H28F6N2O3
Solid


112
C31H27F6N3O5
Solid, 198-202


113
C30H29F6N5O2
—


114
C30H29F6N5O4
Solid


115
C29H25Cl2F2N3O3
Solid Foam


116
C31H27F6N3O4
Solid, 213-215


117
C32H28F6N2O5
Solid


118
C30H30F6N2O5
Solid, 82-184


119
C31H32F6N2O6
Solid, 149-162


120
C31H27F6N3O3
Solid


121
C30H31F6NO4
Solid, 151-154


122
C29H27F6N5O5
Solid, 208-211


123
C30H31F6NO6
Solid, 219-221


192
C31H26F7N3O3
Solid


193
C32H27F7N2O
Solid


194
C31H26F7N3O
Solid


195
C35H31ClF6N2O3
Solid


255
C32H29F6N3O4
Solid


256
C32H29F3N2O4
Solid Foam, 54-57


257
C35H37F3N2O3
Solid Foam, 71-75


258
C33H36F6N2O6
Liquid


259
C31H32F6N2O5
Liquid


260
C32H31F3N2O4
Solid Foam, 54-56


261
C31H28BrF3N2O3
Solid Foam, 52-54


262
C32H31F3N2O3
Semi-Solid, 54-57


263
C30H29F6NO5
Oil/Solid, 55-65


264
C30H29F6NO3
Yellow Amorphous Solid


265
C32H28F6N2O3
Solid Foam, 55-58


266
C31H32F6N2O5
Liquid


267
C30H28Cl2N2O2
Solid Foam 68-71


268
C31H28F4N2O3
Solid Foam, 60-63


269
C32H29F5N2O4
Solid Foam, 54-56


270
C28H26F6N2O2
Solid


271
C33H30F6N2O4
Solid


272
C33H30F6N2O4
Solid


273
C32H35F6NO5
Oil


274
C32H29F6N3O5
Solid


275
C30H27F6N3O4
Solid


276
C33H30F6N2O4
Solid


277
C29H27ClF6N2O4
Liquid


278
C34H30ClF6NO4
Solid Foam, 67-70


279
C31H31F6NO6
Solid


280
C33H35F6NO5
Solid, 63-68


281
C33H27F6N3O4
Solid


282
C33H30F6N2O4
Solid Foam, 53-56


283
C33H27F6N3O4
Solid


284
C42H46F3N3O4
Oil


285
C29H28F6N2O5
Solid, 83-92


286
C33H28ClF6NO4
Syrup


287
C33H33F3N2O4
Solid Foam, 50-53


288
C31H29F3N2O3
Solid Foam, 49-53


289
C36H32ClF6NO5
Solid Foam, 58-64


290
C33H28ClF6NO4
Syrup


291
C31H31F6NO4
Solid


292
C31H31F6NO5
Solid, 68-75


293
C30H27Cl2F6NO4
Oil


294
C35H34F6N2O6
Glass


295
C34H33F3N2O5
Solid Foam, 52-56


296
C30H27F6N3O4
Liquid


297
C33H28ClF6NO4
Solid, 45-47


298
C31H30F6N2O5
Semi Solid


299
C31H31F6NO2
Solid


300
C31H32F6N2O5


301
C30H27F9N2O4
Oil


302
C27H25F6NO2
Solid


303
C30H31F6NO2
Solid


304
C34H31F6NO4
Solid


305
C38H42F6N2O4
Syrup


306
C35H29F12N3O4
Solid


307
C31H26ClF6N3O2
Solid


308
C30H31F6NO5
Glass


309
C32H28F6N2O3
Solid


310
C31H32F6N2O5
Oil


311
C32H34F6N2O5


312
C30H29F7N2O4
Oil


313
C31H32F6N2O3
Solid


314
C31H28ClF3N2O3
Solid, 61-85/Solid Foam,




65-95


315
C31H31F6NO4
Solid


316
C34H31F6NO2
Solid


317
C32H32F6N2O7


318
C30H30F6N2O3
Solid


319
C32H32F6N2O3
Oil


320
C33H34F6N2O5


321
C33H30F6N2O4
Solid


322
C32H27ClF6N2O4
Solid


323
C35H30Cl2F6N2O5


324
C34H29ClF6N2O5


325
C30H27ClF3N3O3
Solid, 75-81


326
C32H34F6N2O5


327
C32H32F6N2O5
Solid


328
C29H30ClF3N2O3
Solid Foam, 54-57


329
C34H36F6N2O5


330
C31H31F6NO3
Solid


331
C27H25F6NO4
Solid


335
C35H37F3N2O4
Solid, 108-112


336
C33H36F6N2O7
Solid, 137-142


337
C31H32F6N2O6
Solid, 173-176


338
C32H31F3N2O5
Solid, 98-104


339
C31H28BrF3N2O4
Solid, 103-107


340
C32H31F3N2O4
Solid, 85-90


341
C30H29F6NO6
Solid, 164-185


342
C30H29F6NO4
Yellow Solid


343
C32H28F6N2O4
Solid, 118-121


344
C31H32F6N2O6
Solid, 165-174


345
C30H28Cl2N2O3
Solid, 95-101


346
C31H28F4N2O4
Solid, 94-96


347
C32H29F5N2O5
Solid, 98-118


349
C33H30F6N2O5
Solid


350
C33H30F6N2O5
Solid


351
C32H35F6NO6
Solid


353
C30H27F6N3O5
Solid, 136-140


354
C33H30F6N2O5
Solid


355
C29H27ClF6N2O5
Solid, 181-184


357
C31H31F6NO7
Solid


358
C33H35F6NO6
Solid, 210-212


359
C33H27F6N3O5
Solid


370
C31H31F6NO6
Solid, 212-214


371
C30H27Cl2F6NO5
Oil


372
C35H34F6N2O7
Solid


375
C33H28ClF6NO5
Solid Foam, 70-74


378
C30H27F9N2O5
Solid, 192-194


380
C30H31F6NO3
Solid


381
C34H31F6NO5
Solid


383
C31H31F6NO3
Solid


384
C31H26ClF6N3O3
Solid


385
C30H31F6NO6
Solid


387
C31H32F6N2O6
Oil


389
C30H29F7N2O5
Solid, 193-195


390
C31H32F6N2O4
Solid


391
C31H28ClF3N2O4
Solid, 62-66


392
C31H31F6NO5
Solid


393
C34H31F6NO3
Solid


395
C30H30F6N2O4
Solid


396
C32H32F6N2O4
Solid


399
C32H27ClF6N2O5
Solid, 200-203


402
C30H27ClF3N3O4
Solid, 84-88


404
C32H32F6N2O6
Solid


405
C29H30ClF3N2O4
Solid, 77-82


407
C31H31F6NO4
Solid


409
C35H29F12N3O5
Solid


410
C30H29F6N3O6
Solid, 210-213


411
C32H27ClF6N2O4
Solid, 204-207


412
C31H26ClF6N3O5
Solid, 210-212


413
C32H29F6N3O5
Solid


416
C30H29F6N5O4
Solid


417
C30H30F6N2O5
Solid


418
C28H25F6NO5
Solid


419
C31H32F6N2O6
Solid


421
C32H28F6N2O6
Solid


422
C31H27F6N3O6
Solid


423
C31H32F6N2O7
Solid


424
C30H30F6N2O6
Solid


425
C31H26ClF6N3O6
Solid


426
C30H29F6N5O5
Solid


430
C32H27F7N2O5
Solid


431
C32H26F6N2O5
Solid


432
C31H25F6N3O3
Solid


433
C31H27Cl2F3N2O3
Solid Foam, 69-71


434
C29H27F2N3O2
Solid Foam


435
C32H30ClF3N2O3
Solid Foam, 60-64


436
C32H30ClF3N2O3
Solid Foam, 59-62


437
C31H28ClF3N2O3
Solid Foam, 59-62


438
C31H27Cl2F3N2O3
Solid Foam, 59-63


439
C31H28ClF3N2O3
Solid Foam, 55-58


440
C34H34F3N3O4
Solid Foam, 53-56


441
C31H27Cl2F3N2O3
Solid Foam, 60-64


442
C31H27Cl2F3N2O3
Solid Foam, 58-62


443
C31H27Cl2F3N2O3
Solid Foam, 55-59


444
C29H29Cl2F3N2O3
Solid Foam, 55-59


445
C31H27ClF4N2O3
Solid Foam, 60-63


446
C32H26F4N2O6
Oil/Solid Foam, 60-64


447
C33H30F6N2O5
Solid


448
C32H29F6N3O2
Solid


449
C32H34F6N4O
Solid


450
C32H34F6N2O
Solid


451
C34H32F6N4O2
Solid


452
C34H31F6N3O3
Solid


453
C29H29Cl2F3N2O4
Solid, 83-86


454
C31H27Cl2F3N2O4
Solid, 101-105


455
C31H27Cl2F3N2O4
Solid, 100-104


456
C31H27Cl2F3N2O4
Solid, 79-82


457
C31H27Cl2F3N2O4
Solid, 98-102


458
C31H28ClF3N2O4
Solid, 85-89


459
C31H28ClF3N2O4
Solid, 98-102


460
C31H27Cl2F3N2O4
Solid Foam, 76-80


461
C32H30ClF3N2O4
Solid, 145-149


462
C32H30ClF3N2O4
Solid, 89-92


463
C31H27ClF4N2O4
Solid, 84-87


464
C32H26F4N2O7
Solid Foam, 72-77


465
C33H30F6N2O6
Solid


466
C34H32F6N4O3
Solid


467
C32H32F6N4O2
Solid


468
C34H31F6N3O4
Solid


470
C29H28ClF6NO5
Solid Foam, 42-45


471
C29H28ClF6NO5
Solid Foam, 42-44


472
C29H28ClF6NO5
Solid Foam, 43-45


473
C29H28ClF6NO4
Syrup


474
C28H26ClF6NO3
Syrup


475
C28H26ClF6NO4
Syrup


476
C30H30ClF6NO4
Oil


477
C28H26BrF6NO4
Syrup


478
C28H26ClF6NO5
Solid, 54-58


479
C28H26ClF6NO4
Solid, 55-60


480
C30H30ClF6NO5
Semi-Solid


481
C29H28ClF6NO5
Solid, 57-61


482
C28H26BrF6NO5
Solid, 60-65


483
C30H31F6N2O5•C3H7O4S
Solid, 120-128


484
C30H31F6N2O5•C5H9O3
Solid, 74-80


485
C31H27ClF6N3O5•C8H15O2
Solid, 190-194


486
C30H31F6N2O5•C8H15O2
Solid, 53-65


487
C30H31F6N2O5•C4F9O3S
Solid, 85-94


488
C31H27ClF6N3O3•C6H7O7
Solid, 132-142


489
C30H30F6N3O6•C6H7O7
Solid, 113-123


490
C30H31F6N2O5•C10H15O4S
Solid, 123-131


491
C30H31F6N2O5•C2H5O3S
Solid, 188-192


492
C31H27ClF6N3O5•C6H7O7
Solid, 135-144


493
C30H31F6N2O5•C7H11O2
Solid, 78-88


494
C30H31F6N2O5•C6H7O7
Solid, 114-119


495
C30H31F6N2O5•C8F17O3S
Solid, 74-84


496
C32H29F6N2O5•C8F17O3S
Solid, 96-101


497
C32H29F6N2O5•Cl
Solid, 140-143


498
C32H29F6N2O5•C10H15O4S
Solid, 122-136


499
C32H29F6N2O5•C8H15O2
Solid, 55-65


500
C32H29F6N2O5•C3H7O4S
Solid, 111-128


501
C29H29ClF6N2O5•C6H7O7
Solid, 96-115


502
C32H29F6N2O5•C7H11O2
Solid, 80-85


503
C32H29F6N2O5•C5H9O3
Solid, 75-81


504
C32H29F6N2O5•C6H7O7
Solid, 195-197


505
C32H29F6N2O5•C10H15O4S
Solid, 121-132


506
C32H29F6N2O5•C2H5O3S
Solid, 168-184


507
C30H31F6N2O5•C10H15O4S
Solid, 118-119


508
C32H29F6N2O5•C4F9O3S
Solid, 94-104


509
C32H29F6N2O5•C10H17O2
Solid, 43-58


510
C32H29F6N2O5•C2H3O3
Solid, 87-103


511
C32H29F6N2O5•C11H15O2
Solid, 100-125


512
C32H29F6N2O5•C5H7O4
Solid, 80-85


513
C32H29F6N2O5•C18H33O2
Liquid


514
C32H29F6N2O5•C7H11O4
Solid, 78-88


515
C32H29F6N2O5•C18H29O3S
Solid, 85-97


516
C32H29F6N2O5•C6H9O4
Solid, 78-90


517
C32H29F6N2O5•C8H15O2
Solid, 44-65


518
C31H27ClF6N3O3•C2H5O3S
Solid


519
C31H27ClF6N3O3•C9H9ClF3O2
Solid, 112-117


520
C31H27ClF6N3O3•C8F17O3S
Solid


521
C42H46F6N3O8•Cl
Solid,


522
C32H29F6N2O4•ClH
Solid, 78-82









Candidate insecticides were evaluated for activity against the tobacco budworm (Heliothis virescens [Fabricius]) in a surface-treated diet test.
In this test one mL of molten (65-70° C.) wheat germ-based artificial diet was pipetted into each well of a four by six (24 well) multi-well plate (ID# 430345-15.5 mm dia.×17.6 mm deep; Corning Costar Corp., One Alewife Center, Cambridge, Mass. 02140). The diet was allowed to cool to ambient temperature before treatment with candidate insecticide.
For a determination of insecticidal activity, solutions of the candidate insecticides were prepared for testing using a Packard 204DT Multiprobe® Robotic System (Packard Instrument Company, 800 Research Parkway, Meriden, Conn. 06450), in which the robot first diluted a standard 50 millimolar DMSO solution of candidate insecticide with a 1:1 water/acetone solution (V/V) in a ratio of 1:7 stock solution to water/acetone. The robot subsequently pipetted 40 microliters of the so-prepared solution onto the surface of the diet in each of three wells in the 24 multi-well plate. The process was repeated with solutions of seven other candidate insecticides. Once treated, the contents of the multi-well plate were allowed to dry, leaving 0.25 millimoles of candidate insecticide on the surface of the diet, or a concentration of 0.25 millimolar. Appropriate untreated controls containing only DMSO on the diet surface were also included in this test.
For evaluations of the insecticidal activity of a candidate insecticide at varying rates of application, the test was established as described above using sub-multiples of the standard 50 millimolar DMSO solution of candidate insecticide. For example, the standard 50 millimolar solution was diluted by the robot with DMSO to give 5, 0.5, 0.05, 0.005, 0.0005 millimolar, or more dilute solutions of the candidate insecticide. In these evaluations there were six replicates of each rate of application placed on the surface of the diet in the 24 multi-well plate, for a total of four rates of application of candidate insecticide in each plate.
In each well of the test plate was placed one second instar tobacco budworm larvea, each weighing approximately five milligrams. After the larvae were placed in each well, the plate was sealed with clear polyfilm adhesive tape. The tape over each well was perforated to ensure an adequate air supply. The plates were then held in a growth chamber at 25° C. and 60% relative humidity for five days (light 14 hours/day).
After the five-day exposure period insecticidal activity for each rate of application of candidate insecticide was assessed as percent inhibition of insect weight relative to the weight of insects from untreated controls, and percent mortality when compared to the total number of insects infested.
Insecticidal activity data at selected rates of application from this test are provided in Table 3. The test compounds of formula I are identified by numbers that correspond to those in Table 1.







TABLE 3





Insecticidal Activity of Test Compounds Applied to the


Surface of the Diet of Tobacco Budworm

















Cmpd. No


















1
2
3
4
5
6
7
8
9
10





Percent Mortality
 0
100
100
100
 0
 83
100
 0
100
 0


Percent Growth
57
100
100
100
97
100
100
41
100
50


Inhibition












Cmpd. No


















11
12
13
14
15
16
17
18
19
20





Percent Mortality
 33
 0
100
100
100
100
 83
100
100
100


Percent Growth
100
100
100
100
100
100
100
100
100
100


Inhibition












Cmpd. No


















21
22
23
24
25
26
27
28
29
30





Percent Mortality
100
100
100
 0
100
100
100
100
100
100


Percent Growth
100
100
100
98
100
100
100
100
100
100


Inhibition












Cmpd. No


















91
92
93
111
112
113
114
115
116
117





Percent Mortality
100
100
100
100
100
100
100
 50
100
100


Percent Growth
100
100
100
100
100
100
100
100
100
100


Inhibition












Cmpd. No


















118
119
120
121
122
123
192
193
194
195





Percent Mortality
100
100
100
100
100
100
100
100
100
100


Percent Growth
100
100
100
100
100
100
100
100
100
100


Inhibition












Cmpd. No


















255
256
257
258
259
260
261
262
263
264





Percent Mortality
100
 17
100
100
100
100
100
100
100
 33


Percent Growth
100
100
100
100
100
100
100
100
100
100


Inhibition












Cmpd. No


















265
266
267
268
269
270
271
272
273
274





Percent Mortality
100
100
100
100
100
100
100
100
100
100


Percent Growth
100
100
100
100
100
100
100
100
100
100


Inhibition












Cmpd. No


















275
276
277
278
279
280
281
282
283
284





Percent Mortality
100
100
100
100
 83
100
100
100
100
 17


Percent Growth
100
100
100
100
100
100
100
100
100
100


Inhibition












Cmpd. No


















285
286
287
288
289
290
291
292
293
294





Percent Mortality
100
100
100
100
100
100
 17
100
100
100


Percent Growth
100
100
100
100
100
100
100
100
100
100


Inhibition












Cmpd. No

















295
297
298
299
300
301
302
303
304





Percent Mortality
100
100
100
100
100
100
 17
100
100


Percent Growth
100
100
100
100
100
100
100
100
100


Inhibition












Cmpd. No


















305
306
307
308
309
310
311
312
313
314





Percent Mortality
 0
100
100
100
100
100
100
100
100
100


Percent Growth
31
100
100
100
100
100
100
100
100
100


Inhibition












Cmpd. No

















315
316
317
319
320
321
322
323
324





Percent Mortality
100
 67
100
100
100
100
100
 33
 33


Percent Growth
100
100
100
100
100
100
100
100
100


Inhibition












Cmpd. No


















325
3256
327
328
329
330
331
335
336
337





Percent Mortality
100
100
100
100
 67
100
 50
100
100
100


Percent Growth
100
100
100
100
100
100
100
100
100
100


Inhibition












Cmpd. No


















338
339
340
341
342
343
344
345
346
347





Percent Mortality
100
100
100
100
100
100
100
100
100
100


Percent Growth
100
100
100
100
100
100
100
100
100
100


Inhibition












Cmpd. No


















349
350
351
353
354
355
357
358
359
370





Percent Mortality
100
100
100
100
100
100
 0
100
100
100


Percent Growth
100
100
100
100
100
100
100
100
100
100


Inhibition












Cmpd. No


















371
372
375
378
380
381
383
384
385
387





Percent Mortality
100
100
100
100
100
100
100
100
100
100


Percent Growth
100
100
100
100
100
100
100
100
100
100


Inhibition












Cmpd. No

















389
390
391
392
393
396
399
402
404





Percent Mortality
100
100
100
100
100
 67
100
100
100


Percent Growth
100
100
100
100
100
100
100
100
100


Inhibition












Cmpd. No


















405
407
409
410
411
412
413
416
417
418





Percent Mortality
100
100
100
100
100
100
100
100
100
 0


Percent Growth
100
100
100
100
100
100
100
100
100
83


Inhibition












Cmpd. No

















419
421
422
423
424
425
426
430
431





Percent Mortality
100
100
100
100
100
100
100
100
100


Percent Growth
100
100
100
100
100
100
100
100
100


Inhibition












Cmpd. No


















432
433
434
435
436
437
438
439
440
441





Percent Mortality
100
100
 0
100
100
100
100
100
100
100


Percent Growth
100
100
56
100
100
100
100
100
100
100


Inhibition












Cmpd. No


















442
443
444
445
446
447
448
449
450
451





Percent Mortality
100
100
100
100
100
100
 0
 0
 50
 0


Percent Growth
100
100
100
100
100
100
96
78
100
100


Inhibition












Cmpd. No


















452
453
454
455
456
457
458
459
460
461





Percent Mortality
 0
100
100
100
100
100
100
100
100
100


Percent Growth
100
100
100
100
100
100
100
100
100
100


Inhibition












Cmpd. No

















462
463
464
465
466
467
468
470
471





Percent Mortality
100
100
100
100
 17
 50
 17
17
 0


Percent Growth
100
100
100
100
100
100
100
89
82


Inhibition












Cmpd. No


















472
473
474
475
476
477
478
479
480
481





Percent Mortality
17
100
 83
100
67
100
100
100
100
100


Percent Growth
93
100
100
100
100
100
100
100
100
100


Inhibition












Cmpd. No


















482
483
484
485
486
487
488
489
490
491





Percent Mortality
100
100
100
100
100
100
100
100
100
100


Percent Growth
100
100
100
100
100
100
100
100
100
100


Inhibition












Cmpd. No


















492
493
494
495
496
497
498
499
500
501





Percent Mortality
100
100
100
100
100
100
100
100
100
100


Percent Growth
100
100
100
100
100
100
100
100
100
100


Inhibition












Cmpd. No


















502
503
504
505
506
507
508
509
510
511





Percent Mortality
100
100
100
100
100
100
100
100
100
100


Percent Growth
100
100
100
100
100
100
100
100
100
100


Inhibition












Cmpd. No



















512
513
514
515
516
517
518
519
520
521
522





Percent Mortality
100
100
100
100
100
100
100
100
100
 50
100


Percent Growth
100
100
100
100
100
100
100
100
100
100
100


Inhibition





These tests were conducted with 0.25 millimoles of candidate insecticide on the surface of the diet






As set forth in the foregoing Table 3, most of the compounds therein provided 100% mortality and 100% growth inhibition of tobacco budworm.
While this invention has been described with an emphasis upon preferred embodiments, it will be understood by those of ordinary skill in the art that variations of the preferred embodiments may be used and that it is intended that the invention may be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications encompassed within the spirit and scope of the invention as defined by the following claims.

## Claims

1. A compound of formula I:



wherein m, q and p are 0; t and u are 1; A is —CH2—; X is selected from halogen, hydroxyl or alkoxycarbonyl; Y is selected from hydrogen, halogen or hydroxyl; R1, R2, R3 and R4 are independently selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, —CH2(OH)CH3, —CH═NOC2H5, 1,3-dioxolan-2-yl, or R2 and R3 taken together with —OCF2O—; R5 is hydrogen; R7, R10 and R11 are hydrogen; R8 is selected from hydrogen, halogen, alkyl or alkoxy; R9 is selected from alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, cyclopropylmethoxy, 2-halophenoxy, 3-halophenoxy, 4-halophenoxy, pyrimidin-2-yl, pyrid-2-yl, 3-halo-pyrid-2-yl, 3-alkyl-pyrid-2-yloxy, 4-alkyl-pyrid-2-yloxy, 5-alkyl-pyrid-2-yloxy, 6-alkyl-pyrid-2-yloxy, 3-halo-pyrid-2-yloxy, 3-trihaloalkyl-pryid-2-yloxy, 3-cyano-pyrid-2-yloxy, 5-cyano-pyrid-2-yloxy, 6-dialkoxyalkyl-pyrid-2-yloxy, pyrid-2-yloxy, CO2CH(CH3)2, —CH═NOCH3, —CH═NOC2H5, —CH═NOCH2CF3, —CH═NOCH2CH═CH2, —CH═NOCH2CN, —CH═NOCH(CH3)2, —CH═NOCH2C≡CH, —CH═NOCH2CH2F, —CH═NOCH2CH2OCH3, —CH═NOCH2OC2H5, —CH═NOCH2CH2OCH2CH2OCH3, —NHCO2CH3, —NHCO2C2H5, —NHCO2CH(CH3)2, —NHCO2CH2-c-C3H5, —CH(OH)C6H5-p-Cl, —OC(═O)NHCH3, —OC(═O)NHC2H5, —OC(═O)NHCH(CH3)2, —NHC(SCH3)═NCN, pyrimidin-2-yloxy, 6-halo-pyridazin-3-yloxy, 6-alkoxy-pyridazin-3-yloxy, 6-alkyl-pyridazin-3-yloxy, 2-alkyl-2H-tetrazol-5-yl, 1,3-dioxan-2-yl or 5,5-dialkyl-1,3-dioxan-2-yl; and R is phenyl substituted with R14, R15, R16, R17, and R18,





where
R14, R15, R16 and R17 are independently selected from halogen, haloalkyl, haloalkoxy or R15 and R16 taken together with —OCF2O—; and R18 is hydrogen and

agriculturally-acceptable salts thereof.

2. The compound of claim 1, wherein X is selected from halogen, —CO2C2H5 or hydroxyl; and R9 is selected from —OC2H5, —OC3H7, —OCH(CH3)2, —OCH2CH2OCH3, —OCH2CH2CH2OCH3, cyclopropylmethoxy, 2-chlorophenoxy, 3-chlorophenoxy, 4-chlorophenoxy, pyrimidin-2-yl, pyrid-2-yl, 3-chloro-pyrid-2-yl, 3-methyl-pyrid-2-yloxy, 4-methyl-pyrid-2-yloxy, 5-methyl-pyrid-2-yloxy, 6-methyl-pyrid-2-yloxy, 3-chloro-pyrid-2-yloxy, 3-trifluoromethyl-pryid-2-yloxy, 3-cyano-pyrid-2-yloxy, 5-cyano-pyrid-2-yloxy, 6-dimethoxymethyl-pyrid-2-yloxy, pyrid-2-yloxy, —CO2CH(CH3)2, —CH═NOCH3, —CH═NOC2H5, —CH═NOCH2CF3, —CH═NOCH2CH═CH2, —CH═NOCH2CN, —CH═NOCH(CH3)2, —CH═NOCH2C≡CH, —CH═NOCH2CH2F, —CH═NOCH2CH2OCH3, —CH═NOCH2OC2H5, —CH═NOCH2CH2OCH2CH2OCH3, —NHCO2CH3, —NHCO2C2H5, —NHCO2CH(CH3)2, —NHCO2CH2-c-C3H5, —CH(OH)C6H5-p-Cl, —OC(═O)NHCH3, —OC(═O)NHC2H5, —OC(═O)NHCH(CH3)2, —NHC(SCH3)═NCN, pyrimidin-2-yloxy, 6-chloro-pyridazin-3-yloxy, 6-methoxy-pyridazin-3-yloxy, 6-methyl-pyridazin-3-yloxy, 2-methyl-2H-tetrazol-5-yl, 2-ethyl-2H-tetrazol-5-yl, 1,3-dioxan-2-yl or 5,5-dimethyl-1,3-dioxan-2-yl.

3. The compound of claim 2, wherein X is selected from fluorine, —CO2C2H5 or hydroxyl; Y is selected from hydrogen, fluorine, chlorine or hydroxyl; R1, R2, R3 and R4 are independently selected from hydrogen, halogen, alkyl, tert-butyl, methoxy, trifluoromethyl, difluoromethoxy, trifluoromethoxy, —OCF2CHFCF3, —CH2(OH)CH3, —CH═NOC2H5, 1,3-dioxolan-2-yl or R2 and R3 taken together with —OCF2O—; R5 is hydrogen; R9 is selected from —OCH2CH2OCH3, —CH═NOCH3, —CH═NOC2H5, —CH═NOCH2CN, —CH═NOCH2CH2OCH3, —NHCO2CH(CH3)2, —OC(═O)NHCH(CH3)2, pyrimidin-2-yl, pyrid-2-yl, 3-chloro-pyrid-2-yl, 3-methyl-pyrid-2-yloxy, 4-methyl-pyrid-2-yloxy, 5-methyl-pyrid-2-yloxy, 6-methyl-pyrid-2-yloxy, 3-chloro-pyrid-2-yloxy, 3-trifluoromethyl-pryid-2-yloxy, 3-cyano-pyrid-2-yloxy, 5-cyano-pyrid-2-yloxy, 6-dimethoxymethyl-pyrid-2-yloxy, pyrid-2-yloxy, pyrimidin-2-yloxy, 6-chloro-pyridazin-3-yloxy, 6-methoxy-pyridazin-3-yloxy or 6-methyl-pyridazin-3yloxy; and R is phenyl substituted with R14, R15, R16, R17, and R18,




where
R14, R15, R16 and R17 are independently selected from fluorine, chlorine, trifluoromethyl, difluoromethoxy, trifluoromethoxy, —OCF2CHFCF3 or R15 and R16 taken together with —OCF2O—.

4. The compound of claim 3, wherein X is hydroxyl; Y is hydrogen; R3 is haloalkoxy; R9 is selected —OCH2CH2OCH3, —CH═NOCH3, —CH═NOC2H5, —CH═NOCH2CN, —CH═NOCH2CH2OCH3, —NHCO2CH(CH3)2, —OC(═O)NHCH(CH3)2, pyrid-2-yloxy, pyrid-2-yl, 3-cyano-pyrid-2-yloxy, 5-methyl-pyrid-2-yloxy, pyrimidin-2-yloxy, pyrimidin-2-yl, 6-chloro-pyridazin-3-yloxy or 6-methoxy-pyridazin-3-yloxy; and R16 is haloalkoxy.

5. A compound of formula I:




wherein;
r is selected from 0 or 1; m, q and p are 0; t and u are 1;
A is —CH2—;
X is selected from halogen or hydroxyl;
Y is selected from hydrogen or hydroxyl;
R1, R2, R3 and R4 are independently selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy or —CH═NOC2H5;
R5 is hydrogen;
R7, R8, R10 and R11 are hydrogen;
R9 is selected from —OC2H5, —OC3H7, —OCH(CH3)2, —OCH2CH2OCH3, —OCH2CH2CH2OCH3, cyclopropylmethoxy, 2-chlorophenoxy, 3-chlorophenoxy, 4-chlorophenoxy, pyrimidin-2-yl, pyrid-2-yl, 3-chloro-pyrid-2-yl, 3-methyl-pyrid-2-yloxy, 4-methyl-pyrid-2-yloxy, 5-methyl-pyrid-2-yloxy, 6-methyl-pyrid-2-yloxy, 3-chloro-pyrid-2-yloxy, 3-trifluoromethyl-pryid-2-yloxy, 3-cyano-pyrid-2-yloxy, 5-cyano-pyrid-2-yloxy, 6-dimethoxymethyl-pyrid-2-yloxy, pyrid-2-yloxy, CO2CH(CH3)2, —CH═NOCH3, —CH═NOC2H5, —CH═NOCH2CF3, —CH═NOallyl, —CH═NOCH2CH═CH2, —CH═NOCH2CN, —CH═NOCH(CH3)2, —CH═NOCH2C≡CH, —CH═NOCH2CH2F, —CH═NOCH2CH2OCH3, —CH═NOCH2OC2H5, —CH═NOCH2CH2OCH2CH2OCH3, —NHCO2CH3, —NHCO2C2H5, —NHCO2CH(CH3)2,—NHCO2CH2-c-C3H5, —CH(OH)C6H5-p-Cl, —OC(═O)NHCH3, —OC(═O)NHC2H5, —OC(═O)NHCH(CH3)2, —NHC(SCH3)═NCN, pyrimidin-2-yloxy, 6-chloro-pyridazin-3-yloxy, 6-methoxy-pyridazin-3-yloxy, 6-methyl-pyridazin-3-yloxy, 2-methyl-2H-tetrazol-5-yl, 2-ethyl-2H-tetrazol-5-yl, 1,3-dioxan-2-yl or 5,5-dimethyl-1,3-dioxan-2-yl; and
R is phenyl substituted with R14, R15, R16, R17, and R18,





where
R16 is selected from haloalkyl or haloalkoxy, and R14, R15, R17 and R18 are hydrogen.

6. A compound of formula I-H:




wherein,
R3 is haloalkyl or haloalkoxy;
R9 is selected from —OCH2CH2OCH3, pyrid-2-yloxy, pyrid-2-yl, 3-cyano-pyrid-2-yloxy, 5-methyl-pyrid-2-yloxy, pyrimidin-2-yloxy, pyrimidin-2-yl, 6-chloro-pyridazin-3-yloxy or 6-methoxy-pyridazin-3-yloxy; and
R16 is haloalkyl or haloalkoxy.

7. A compound of formula I-J:




wherein,
R3 is haloalkyl or haloalkoxy;
R9 is selected from —OCH2CH2OCH3, pyrid-2-yloxy, pyrid-2-yl, 3-cyano-pyrid-2-yloxy, 5-methyl-pyrid-2-yloxy, pyrimidin-2-yloxy, pyrimidin-2-yl, 6-chloro-pyridazin-3-yloxy or 6-methoxy-pyridazin-3-yloxy; and
R16 is haloalkyl or haloalkoxy.

8. The compound:




namely, 4-{bis[4-(trifluoromethoxy)phenyl]methyl}-4-hydroxy-1-[(4-(2-pyridyloxy)phenyl)methyl]piperidin-1-oxide, and agriculturally-acceptable salts thereof.

9. A composition containing an insecticidally effective amount of a compound of claim 1 in admixture with at least one agriculturally acceptable extender or adjuvant.

10. A composition containing an insecticidally effective amount of a compound of claim 2 in admixture with at least one agriculturally acceptable extender or adjuvant.

11. A composition containing an insecticidally effective amount of a compound of claim 3 in admixture with at least one agriculturally acceptable extender or adjuvant.

12. A composition containing an insecticidally effective amount of a compound of claim 4 in admixture with at least one agriculturally acceptable extender or adjuvant.

13. A composition containing an insecticidally effective amount of a compound of claim 5 in admixture with at least one agriculturally acceptable extender or adjuvant.

14. A composition containing an insecticidally effective amount of a compound of claim 6 in admixture with at least one agriculturally acceptable extender or adjuvant.

15. A composition containing an insecticidally effective amount of a compound of claim 7 in admixture with at least one agriculturally acceptable extender or adjuvant.

16. A composition containing an insecticidally effective amount of a compound of claim 8 in admixture with at least one agriculturally acceptable extender or adjuvant.

17. A method of controlling insects, comprising applying an insecticidally effective amount of a composition of claim 9 to a locus where insects are present or are expected to be present.

18. A method of controlling insects, comprising applying an insecticidally effective amount of a composition of claim 10 to a locus where insects are present or are expected to be present.

19. A method of controlling insects, comprising applying an insecticidally effective amount of a composition of claim 11 to a locus where insects are present or are expected to be present.

20. A method of controlling insects, comprising applying an insecticidally effective amount of a composition of claim 12 to a locus where insects are present or are expected to be present.

21. A method of controlling insects, comprising applying an insecticidally effective amount of a composition of claim 13 to a locus where insects are present or are expected to be present.

22. A method of controlling insects, comprising applying an insecticidally effective amount of a composition of claim 14 to a locus where insects are present or are expected to be present.

23. A method of controlling insects, comprising applying an insecticidally effective amount of a composition of claim 15 to a locus where insects are present or are expected to be present.

24. A method of controlling insects, comprising applying an insecticidally effective amount of a composition of claim 16 to a locus where insects are present or are expected to be present.