Pesticidal compounds
11512054 · 2022-11-29
Assignee
Inventors
- Rupsha Chaudhuri (Navi Mumbai, IN)
- Sunderraman Sambasivan (Mumbai, IN)
- Arun Narine (Ludwigshafen, DE)
- Ashokkumar Adisechan (Navi Mumbai, IN)
- Devendra Vyas (Navi Mumbai, IN)
Cpc classification
C07D401/12
CHEMISTRY; METALLURGY
C07D417/12
CHEMISTRY; METALLURGY
A01N47/18
HUMAN NECESSITIES
C07D405/12
CHEMISTRY; METALLURGY
C07D231/56
CHEMISTRY; METALLURGY
A01N47/30
HUMAN NECESSITIES
C07D407/12
CHEMISTRY; METALLURGY
International classification
C07D401/12
CHEMISTRY; METALLURGY
C07D405/12
CHEMISTRY; METALLURGY
A01N47/30
HUMAN NECESSITIES
C07D231/56
CHEMISTRY; METALLURGY
Abstract
The present invention relates to the compounds of formula (I), and the N-oxides, stereoisomers, tautomers and agriculturally or veterinarily acceptable salts thereof wherein the variables are defined according to the description, formula (I). The compounds of formula (I), as well as the N-oxides, stereoisomers, tautomers and agriculturally or veterinarily acceptable salts thereof, are useful for combating or controlling invertebrate pests, in particular arthropod pests and nematodes. The invention also relates to a method for controlling invertebrate pests by using these compounds and to plant propagation material and to an agricultural and a veterinary composition comprising said compounds. ##STR00001##
Claims
1. A compound of formula I ##STR00258## wherein A.sup.1 is N or CR.sup.A; A.sup.2 is N or CR.sup.B; A.sup.3 is N or CR.sup.B1; W is O, S(═O).sub.m, or NR.sup.6; R.sup.A, R.sup.B and R.sup.B1 independently of each other are H, halogen, N.sub.3, OH, CN, NO.sub.2, —SCN, —SF.sub.5, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy, C.sub.2-C.sub.6-alkenyl, tri-C.sub.1-C.sub.6-alkylsilyl, C.sub.2-C.sub.6-alkynyl, C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkoxy, C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-cycloalkoxy, C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkyl-C.sub.3-C.sub.6-cycloalkoxy, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl and cycloalkoxy moieties are unsubstituted or substituted with halogen, C(═O)—OR.sup.a, NR.sup.bR.sup.c, C.sub.1-C.sub.6-alkylene-NR.sup.bR.sup.c, O—C.sub.1-C.sub.6-alkylene-NR.sup.bR.sup.c, C.sub.1-C.sub.6-alkylene-CN, NH—C.sub.1-C.sub.6-alkylene-NR.sup.bR.sup.c, C(═O)—NR.sup.bR.sup.c, C(═O)—R.sup.d, SO.sub.2NR.sup.bR.sup.c, or S(═O).sub.mR.sup.e, phenyl, phenoxy, phenylcarbonyl, phenylthio, or —CH.sub.2-phenyl, wherein the phenyl rings are unsubstituted or substituted with R.sup.f; Q is —N═C(X)—, —N(R.sup.2)—C(═NR)—, or —N(R.sup.2)—C(═S)—; wherein Ar is bound to either side of Q; X is identical or different, H, halogen, SR.sup.7, OR.sup.8, N(R.sup.3).sub.2, —CR.sup.4═N(OCH.sub.3), CN, C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, C.sub.3-C.sub.6-cycloalkyl, wherein the alkyl, alkenyl, alkynyl and cycloalkyl moieties are unsubstituted or substituted with halogen; phenyl, or —CH.sub.2-phenyl, wherein the phenyl rings are unsubstituted or substituted with R.sup.5; R.sup.5 is halogen, N.sub.3, OH, CN, NO.sub.2, —SCN, —SF, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy, C.sub.2-C.sub.6-alkenyl, tri-C.sub.1-C.sub.6-alkylsilyl, C.sub.2-C.sub.6-alkynyl, C1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkoxy, C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-cycloalkoxy, C.sub.3-C.sub.6-cycloalkylthio, C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.6-cycloalkoxy-C.sub.1-C.sub.4-alkyl, wherein the alkyl, alkoxy, alkylthio, alkenyl, alkynyl, cycloalkyl, cycloalkoxy and cycloalkylthio moieties are unsubstituted or substituted with halogen, C(O)—OR.sup.a, NR.sup.bR.sup.c, C.sub.1-C.sub.6-alkylen-NR.sup.bR.sup.c, O—C.sub.1-C.sub.6-alkylen-NR.sup.bR.sup.c, C.sub.1-C.sub.6-alkylen-CN, NH—C.sub.1-C.sub.6-alkylen-NR.sup.bR.sup.c, C(O)—NR.sup.bR.sup.c, C(O)—R.sup.d, SO.sub.2NR.sup.bR.sup.c, or S(═O).sub.mR.sup.e; R.sup.2 is H, C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.6-cycloalkoxy-C.sub.1-C.sub.4-alkyl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl and cycloalkoxy moieties are unsubstituted or substituted with halogen, C(O)—OR.sup.a, C.sub.1-C.sub.6-alkylen-NR.sup.bR.sup.c, C.sub.1-C.sub.6-alkylen-CN, C(O)—NR.sup.bR.sup.c, C(O)—R.sup.d, SO.sub.2NR.sup.bR.sup.c, S(═O).sub.mR.sup.e, phenyl, or —CH.sub.2-phenyl, wherein the phenyl rings are unsubstituted or substituted with R.sup.f; R is identical or different, H, CN, C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, C.sub.3-C.sub.6-cycloalkyl, wherein the alkyl, alkenyl, alkynyl and cycloalkyl moieties are unsubstituted or substituted with halogen, SR.sup.7, OR.sup.8, N(R.sup.3).sub.2, phenyl, or —CH.sub.2-phenyl, wherein the phenyl rings are unsubstituted or substituted with R.sup.5; R.sup.4 is H, halogen, C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.6-cycloalkoxy-C.sub.1-C.sub.4-alkyl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl and cycloalkoxy moieties are unsubstituted or substituted with halogen, C(═O)—OR.sup.a, C.sub.1-C.sub.6-alkylene-NR.sup.bR.sup.c, C.sub.1-C.sub.6-alkylene-CN, C(═O)—NR.sup.bR.sup.c, C(═O)—R.sup.d, phenyl, or —CH.sub.2-phenyl, wherein the phenyl rings are unsubstituted or substituted with R.sup.f; R.sup.7 is C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.6-cycloalkoxy-C.sub.1-C.sub.4-alkyl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl and cycloalkoxy moieties are unsubstituted or substituted with halogen, C(═O)—OR.sup.a, C.sub.1-C.sub.6-alkylene-NR.sup.bR.sup.c, C.sub.1-C.sub.6-alkylene-CN, C(═O)—NR.sup.bR.sup.c, C(═O)—R.sup.d, phenyl, or —CH.sub.2-phenyl, wherein the phenyl rings are unsubstituted or substituted with R.sup.f; R.sup.8 is C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.6-cycloalkoxy-C.sub.1-C.sub.4-alkyl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl and cycloalkoxy moieties are unsubstituted or substituted with halogen, C(═O)—OR.sup.a, C.sub.1-C.sub.6-alkylene-NR.sup.bR.sup.c, C.sub.1-C.sub.6-alkylene-CN, C(═O)—NR.sup.bR.sup.c, C(═O)—R.sup.d, SO.sub.2NR.sup.bR.sup.c, phenyl, or —CH.sub.2-phenyl, wherein the phenyl rings are unsubstituted or substituted with R.sup.f; R.sup.3, R.sup.6 are, identical or different, H, C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.6-cycloalkoxy-C.sub.1-C.sub.4-alkyl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl and cycloalkoxy moieties are unsubstituted or substituted with halogen, C(═O)—OR.sup.a, C.sub.1-C.sub.6-alkylene-NR.sup.bR.sup.c, C.sub.1-C.sub.6-alkylene-CN, C(═O)—NR.sup.bR.sup.c, C(═O)—R.sup.d, SO.sub.2NR.sup.bR.sup.c, S(═O).sub.mR.sup.e, phenyl, or —CH.sub.2-phenyl, wherein the phenyl rings are unsubstituted or substituted with R.sup.f; Ar is phenyl or 5- or 6-membered hetaryl, which are unsubstituted or substituted with R.sup.Ar, wherein R.sup.Ar is halogen, N.sub.3, OH, CN, NO.sub.2, —SCN, —SF, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy, C.sub.2-C.sub.6-alkenyl, tri-C.sub.1-C.sub.6-alkylsilyl, C.sub.2-C.sub.6-alkynyl, C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkoxy, C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-cycloalkoxy, C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.6-cycloalkoxy-C.sub.1-C.sub.4-alkyl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl and cycloalkoxy moieties are unsubstituted or substituted with halogen, C(═O)—OR.sup.a, NR.sup.bR.sup.c, C.sub.1-C.sub.6-alkylene-NR.sup.bR.sup.c, O—C.sub.1-C.sub.6-alkylene-NR.sup.bR.sup.c, C.sub.1-C.sub.6-alkylene-CN, NH—C.sub.1-C.sub.6-alkylene-NR.sup.bR.sup.c, C(═O)—NR.sup.bR.sup.c, C(═O)—R.sup.d, SO.sub.2NR.sup.bR.sup.c, or S(═O).sub.mR.sup.e, phenyl, phenoxy, phenylcarbonyl, phenylthio or —CH.sub.2-phenyl, wherein phenyl rings are unsubstituted or substituted with R.sup.f; R.sup.1 is a moiety of formula Y—Z-T-R.sup.11 or Y—Z-T-R.sup.12; wherein Y is —CR.sup.ya═N—, wherein the N is bound to Z; NR.sup.yc—C(═O)—, wherein C(═O) is bound to Z; or —NR.sup.yc—C(═S)—, wherein C(═S) is bound to Z; Z is a single bond; —NR.sup.zc—C(═O)—, wherein C(═O) is bound to T; —NR.sup.zc—C(═S)—, wherein C(═S) is bound to T; —N═C(S—R.sup.za)—, wherein T is bound to the carbon atom; or —NR.sup.zc—C(S—R.sup.za)═, wherein T is bound to the carbon atom; T is O, N or N—R.sup.T; R.sup.11 is C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkyl-C.sub.3-C.sub.6-cycloalkoxy, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl and cycloalkoxy moieties are unsubstituted or substituted with halogen, C.sub.1-C.sub.6-alkylene-NR.sup.bR.sup.c, C.sub.1-C.sub.6-alkylene-CN, C(═O)—NR.sup.bR.sup.c, C(═O)—R.sup.d, aryl, arylcarbonyl, aryl-C.sub.1-C.sub.4-alkyl, aryloxy-C.sub.1-C.sub.4-alkyl, hetaryl, carbonyl-hetaryl, hetaryl-C.sub.1-C.sub.4-alkyl or hetaryloxy-C.sub.1-C.sub.4-alkyl, wherein the phenyl rings are unsubstituted or substituted with R.sup.g and wherein the hetaryl is a 5- or 6-membered monocyclic hetaryl or a 8-, 9- or 10-membered bicyclic hetaryl; R.sup.12 is a radical of the formula A.sup.1; ##STR00259## wherein # indicates the point of attachment to T; R.sup.121, R.sup.122, R.sup.123 are, identical or different, H, halogen, C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.6-alkoxy, C.sub.2-C.sub.6-alkenyloxy, C.sub.2-C.sub.6-alkynyloxy, C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.6-alkylcarbonlyoxy, C.sub.1-C.sub.6-alkenylcarbonlyoxy, C.sub.3-C.sub.6-cycloalkylcarbonlyoxy, wherein the alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, alkynyloxy and cycloalkyl moieties are unsubstituted or substituted with halogen, or NR.sup.bR.sup.c, or one of R.sup.121, R.sup.122, R.sup.123 may also be oxo; R.sup.124 is H, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.6-alkoxy, or C.sub.2-C.sub.6-alkenyloxy, wherein the alkyl, alkoxy, alkenyl and alkenyloxy moieties are unsubstituted or substituted with halogen; and where R.sup.ya is H, halogen, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.6-cycloalkyl, C.sub.1-C.sub.4-alkyl-C.sub.3-C.sub.6-cycloalkyl, C.sub.1-C.sub.4-alkyl-C.sub.3-C.sub.6-cycloalkoxy, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl and cycloalkoxy moieties are unsubstituted or substituted with halogen, C(═O)—OR.sup.a, C.sub.1-C.sub.6-alkylene-NR.sup.bR.sup.c, C.sub.1-C.sub.6-alkylene-CN, C(═O)—NR.sup.bR.sup.c, C(═O)—R.sup.d, SO.sub.2NR.sup.bR.sup.c, S(═O).sub.mR.sup.e, phenyl, or —CH.sub.2-phenyl, wherein the phenyl rings are unsubstituted or substituted with R.sup.f; R.sup.yc, R.sup.zc are, identical or different, H, C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, C.sub.1-C.sub.4-alkyl-C.sub.1-C.sub.6-alkoxy, C.sub.3-C.sub.6-cycloalkyl, C.sub.1-C.sub.4-alkyl-C.sub.3-C.sub.6-cycloalkyl, or C.sub.1-C.sub.4-alkyl-C.sub.3-C.sub.6-cycloalkoxy, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl and cycloalkoxy moieties are unsubstituted or substituted with halogen; R.sup.T is H, C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, C.sub.1-C.sub.4-alkyl-C.sub.1-C.sub.6-alkoxy, C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.6-cycloalkoxy-C.sub.1-C.sub.4-alkyl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl and cycloalkoxy moieties are unsubstituted or substituted with halogen, C(═O)—OR.sup.a, C.sub.1-C.sub.6-alkylene-NR.sup.bR.sup.c, C.sub.1-C.sub.6-alkylene-CN, C(═O)—NR.sup.bR.sup.c, C(═O)—R.sup.d, SO.sub.2NR.sup.bR.sup.c, S(═O).sub.mR.sup.e, phenyl, or —CH.sub.2-phenyl, wherein the phenyl rings are unsubstituted or substituted with R.sup.f; R.sup.zc together with R.sup.T if present, may form C.sub.1-C.sub.6-alkylene or a linear C.sub.2-C.sub.6-alkenylene group, where in the linear C.sub.1-C.sub.6-alkylene and the linear C.sub.2-C.sub.6-alkenylene a CH.sub.2 moiety may be replaced by a carbonyl or a C═N—R′ and/or wherein 1 or 2 CH.sub.2 moieties may be replaced by O or S and/or wherein the linear C.sub.1-C.sub.6-alkylene and the linear C.sub.2-C.sub.6-alkenylene may be unsubstituted or substituted with R.sup.h; R.sup.za is H, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy, C.sub.2-C.sub.6-alkenyl, tri-C.sub.1-C.sub.6-alkylsilyl, C.sub.2-C.sub.6-alkynyl, C.sub.1-C.sub.4-alkyl-C.sub.1-C.sub.6-alkoxy, C.sub.3-C.sub.6-cycloalkyl, C.sub.1-C.sub.4-alkyl-C.sub.3-C.sub.6-cycloalkoxy, C.sub.1-C.sub.4-alkyl-C.sub.3-C.sub.6-cycloalkyl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl and cycloalkoxy moieties are unsubstituted or substituted with halogen, C.sub.1-C.sub.6-alkylene-NR.sup.bR.sup.c, C.sub.1-C.sub.6-alkylene-CN, C(═O)—NR.sup.bR.sup.c, C(═O)—R.sup.d, phenyl, phenylcarbonyl, or —CH.sub.2-phenyl, wherein the phenyl rings are unsubstituted or substituted with R.sup.f; R.sup.za together with R.sup.T if present, may form C.sub.1-C.sub.6-alkylene or a linear C.sub.2-C.sub.6-alkenylene group, where in the linear C.sub.1-C.sub.6-alkylene and the linear C.sub.2-C.sub.6-alkenylene a CH.sub.2 moiety may be replaced by a carbonyl or a C═N—R′ and/or wherein 1 or 2 CH.sub.2 moieties may be replaced by O or S and/or wherein the linear C.sub.1-C.sub.6-alkylene and the linear C.sub.2-C.sub.6-alkenylene may be unsubstituted or substituted with R.sup.h; R.sup.a, R.sup.b and R are, identical or different, H, C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.6-cycloalkoxy-C.sub.1-C.sub.4-alkyl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl and cycloalkoxy moieties are unsubstituted or substituted with halogen, C.sub.1-C.sub.6-alkylene-CN, phenyl, or —CH.sub.2-phenyl, wherein the phenyl rings are unsubstituted or substituted with R.sup.f; R.sup.d is H, C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.6-cycloalkoxy-C.sub.1-C.sub.4-alkyl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl and cycloalkoxy moieties are unsubstituted or substituted with halogen, phenyl, or —CH.sub.2-phenyl, wherein the phenyl rings are unsubstituted or substituted with R.sup.f; R.sup.e is C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.4-alkyl, wherein the alkyl, cycloalkyl moieties are unsubstituted or substituted with halogen, phenyl and —CH.sub.2-phenyl, wherein the phenyl rings are unsubstituted or substituted with R.sup.f; R.sup.f is halogen, N.sub.3, OH, CN, NO.sub.2, —SCN, —SF, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy, C.sub.2-C.sub.6-alkenyl, tri-C.sub.1-C.sub.6-alkylsilyl, C.sub.2-C.sub.6-alkynyl, C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkoxy, C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-cycloalkoxy, C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.6-cycloalkoxyx-C.sub.1-C.sub.4-alkyl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl and cycloalkoxy moieties are unsubstituted or substituted with halogen, C(═O)—OR.sup.a, NR.sup.bR.sup.c, C.sub.1-C.sub.6-alkylene-NR.sup.bR.sup.c, O—C.sub.1-C.sub.6-alkylene-NR.sup.bR.sup.c, C.sub.1-C.sub.6-alkylene-CN, NH—C.sub.1-C.sub.6-alkylene-NR.sup.bR.sup.c, C(═O)—NR.sup.bR.sup.c, C(═O)—R.sup.d, SO.sub.2NR.sup.bR.sup.c, or S(═O).sub.mR.sup.e; R.sup.g is halogen, N.sub.3, OH, CN, NO.sub.2, —SCN, —SF, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy, C.sub.2-C.sub.6-alkenyl, tri-C.sub.1-C.sub.6-alkylsilyl, C.sub.2-C.sub.6-alkynyl, C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkoxy, C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-cycloalkoxy, C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.6-cycloalkoxy-C.sub.1-C.sub.4-alkyl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl and cycloalkoxy moieties are unsubstituted or substituted with halogen, C(═O)—OR.sup.a, NR.sup.bR.sup.c, C.sub.1-C.sub.6-alkylene-NR.sup.bR.sup.c, O—C.sub.1-C.sub.6-alkylene-NR.sup.bR.sup.c, C.sub.1-C.sub.6-alkylene-CN, NH—C.sub.1-C.sub.6-alkylene-NR.sup.bR.sup.c, C(═O)—NR.sup.bR.sup.c, C(═O)—R.sup.d, SO.sub.2NR.sup.bR.sup.c, or S(═O).sub.mR.sup.e; R.sup.h is halogen, OH, C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.6-cycloalkyl, or CN; m is 0, 1, or 2; with a proviso that when Z is a single bond, R.sup.T is other than H; or an N-oxide, stereoisomers, tautomer, or agriculturally or veterinarily acceptable salts thereof.
2. The compound of formula I according to claim 1, wherein W is O, A.sup.1 is CR.sup.A, A.sup.2 is CR.sup.B, and A.sup.3 is N.
3. The compound of formula I according to claim 1, wherein W is N, A.sup.1 is CR.sup.A, A.sup.2 is CR.sup.B, and A.sup.3 is N.
4. The compound of formula I according to claim 1, wherein W is O, A.sup.1 is CR.sup.A, A.sup.2 is CR.sup.B, and A.sup.3 is CR.sup.B1.
5. The compound of formula I according to claim 1, wherein W is N, A.sup.1 is CR.sup.A, A.sup.2 is CR.sup.B, and A.sup.3 is CR.sup.B1.
6. The compound of formula I according to claim 1, wherein W is N, A.sup.1 is N, A.sup.2 is N, and A.sup.3 is CR.sup.B1.
7. The compound of formula I according to claim 1, wherein W is S(═O).sub.m, A.sup.1 is CR.sup.A, A.sup.2 is CR.sup.B, and A.sup.3 is CR.sup.B1.
8. The compound of formula I according to claim 1, wherein R.sup.1 is selected from formulas YZT-1 to YZT-8, wherein ##STR00260## denotes attachment to the 9 membered hetaryl; ##STR00261## wherein R.sup.11, R.sup.12, R.sup.T, R.sup.ya, R.sup.za and R.sup.zc are as defined in claim 1.
9. The compound of formula I according to claim 1, wherein Ar is selected from formulas Ar-1 to Ar-12. ##STR00262## ##STR00263##
10. A composition comprising one compound of formula I according to claim 1, an N-oxide or an agriculturally acceptable salt thereof, and a further active substance.
11. A method for combating or controlling invertebrate pests, comprising contacting said pest or its food supply, habitat or breeding grounds with a pesticidally effective amount of at least one compound according to claim 1.
12. A method for protecting growing plants from attack or infestation by invertebrate pests, comprising contacting a plant, or soil or water wherein the plant is growing, with a pesticidally effective amount of at least one compound according to claim 1.
13. Seed comprising a compound according to claim 1, or a stereoisomer or agriculturally acceptable salt thereof, in an amount of from 0.1 g to 10 kg per 100 kg of seed.
14. A compound of the formula I according to claim 1, or an agriculturally acceptable salt thereof, for use in protecting growing plants from attack or infestation by invertebrate pests.
15. A method for treating or protecting an animal from infestation or infection by invertebrate pests comprising bringing the animal in contact with a pesticidally effective amount of at least one compound of the formula I according to claim 1, a stereoisomer thereof and/or at least one veterinarily acceptable salt thereof.
Description
EXAMPLES
Preparation Examples
(1) With appropriate modification of the starting materials, the procedures as described in the preparation examples below were used to obtain further compounds of formula I. The compounds obtained in this manner are listed in the table C that follows, together with physical data.
(2) Compounds can be characterized e.g. by coupled High Performance Liquid Chromatography/mass spectrometry (HPLC/MS), by .sup.1H-NMR and/or by their melting points.
(3) Analytical HPLC—Method 1: Agilent Eclipse Plus C18, 50×4.6 mm, ID 5 μm; Elution: A=10 mM Amm. Formate (0.1% Formic Acid), B=Acetonitrile (0.1% Formic Acid), Flow=1.2 ml/min. at 30° C.; Gradient:=10% B to 100% B—3 min, hold for 1 min, 1 min—10% B. Run Time=5.01 min.
(4) Analytical HPLC—Method 2: Kinetex XB C18 1,7μ 50×2.1 mm; A=Water+0.1% TFA, B=Acetonitrile, Flow=0.8 ml/min—1.0 ml/min in 1.5 min. at 60° C.; Gradient:5% B to 100% B—1.5 min.
(5) .sup.1H-NMR: The signals are characterized by chemical shift (ppm, 6 [delta]) vs. tetramethylsilane respectively, CDCl.sub.3 for .sup.13C-NMR, by their multiplicity and by their integral (relative number of hydrogen atoms given). The following abbreviations are used to characterize the multiplicity of the signals: m=multiplet, q=quartet, t=triplet, d=doublet and s=singlet.
(6) Abbreviations used are: d for day(s), h for hour(s), min for minute(s), r.t./room temperature for 20-25° C., Rt for retention time; DMSO for dimethyl sulfoxide, OAc for acetate, EtOAc for ethyl acetate, EtOH for ethanol, THF for tetrahydrofuran, DMF for N,N-Dimethylformamide, DCM for dichloromethane, ACN for acetonitrile, TEA for triethyl amine and t-BuOH for tert-butanol.
Example C-1
1-(2-isopropylphenyl)-3-[(E)-[1-methyl-3-[N-[4(trifluoromethoxy)phenyl]carbamimidoyl]indazol-6-yl]methyleneamino]thiourea (C-1)
Step 1: Synthesis of 6-bromo-3-iodo-1H-indazole
(7) A mixture of 6-bromo-1H-indazole (1 g) and Potassium hydroxide (0.570 g) in DMF (15 mL) was stirred at 0° C. and Iodine (1.93 g) was added. The mixture was stirred at ambient temperature for 3 h and Sodium thiosulphate solution (5% in water) was subsequently added. The mixture was extracted with EtOAc and the extracts dried over anhydrous Sodium sulphate and evaporated invacuo and the residue obtained was subjected to silica gel flash column chromatography, eluting with a gradient of EtOAc and Heptane to obtain the title compound as a white solid (1.5 g). HPLC/MS (method 1): Rt: 1.89 min; m/z=320.8 (M-1)+; .sup.1H NMR (500 MHz, DMSO-d6) δ 13.68 (s, 1H), 7.87 (s, 1H), 7.45 (d, J=8.6 Hz, 1H), 7.38 (d, J=8.6 Hz, 1H).
Step 2: Synthesis of 6-bromo-3-iodo-1-methyl-indazole
(8) To a mixture of 6-bromo-3-iodo-1H-indazole (1.6 g) and Potassium carbonate (1.03 g) in THE (15 mL) was added Methyl iodide (0.84 g) drop-wise. The reaction mixture was subsequently diluted with water, extracted with EtOAc, the ethyl acetate extracts dried over sodium sulphate and concentrated under reduced pressure. The resultant residue was subjected to silica gel flash column chromatography eluting with a gradient of EtOAc and Heptane to get the title compound as a off-white solid. (1.2 g). .sup.1H NMR (500 MHz, DMSO-d6) 8.04 (s, 1H), 7.39-7.29 (m, 2H), 4.06 (s, 3H).
Step 3: Synthesis of 6-bromo-1-methyl-indazole-3-carbonitrile
(9) To a nitrogen degassed solution of 6-bromo-3-iodo-1-methyl-indazole (0.1 g) in DMF (4 mL) was added Zinc cyanide (0.040 g), (diphenylphosphino)ferrocene (0.008 g) and Tris(dibenzylideneacetone)dipalladium(0) (0.016 g) and the mixture was heated at 60° C. for 3 h. The mixture was subsequently diluted with water and extracted with EtOAc and the organic extracts dried over anhydrous sodium sulphate and evaporated invacuo. The resultant residue was subjected to Silica gel flash column chromatography eluting with a gradient of Ethyl acetate and Heptane to afford the title compound as a yellow solid (0.04 g). .sup.1H NMR (500 MHz, DMSOd6) δ 8.31 (dd, J=1.7, 0.7 Hz, 1H), 7.86 (dd, J=8.7, 0.7 Hz, 1H), 7.55 (dd, J=8.7, 1.6 Hz, 1H), 4.19 (s, 3H).
Step 4: Synthesis of 6-bromo-1-methyl-N-[4-(trifluoromethoxy) phenyl] indazole-3-carboxamidine
(10) To a stirred solution of 6-bromo-1-methyl-indazole-3-carbonitrile (0.08 g) in Toluene (3 mL) was added 4-(trifluoromethoxy)aniline (0.06 g) and a 2 M solution of Trimethyl aluminum in toluene (0.036 g). The mixture was heated in a sealed tube at 90° C. for 2 h and subsequently cooled to ambient temperature. A solution of Potassium hydroxide was added dropwise and the mixture extracted with EtOAc. The organic extracts were dried over anhydrous Sodium sulphate, evaporated invacuo and the resultant solid was subjected to neutral Alumina flash column chromatography, eluting with a gradient of EtOAc and Heptane to obtain the title compound as a white solid. (0.04 g). HPLC/MS (method 1): Rt=1.67 min; m/z=413.10 (M+1).sup.+; .sup.1H NMR (500 MHz, DMSO-d6) δ 8.27 (d, J=8.7 Hz, 1H), 8.08 (d, J=1.6 Hz, 1H), 7.37 (dd, J=8.6, 1.6 Hz, 1H), 7.30 (d, J=8.3 Hz, 2H), 7.04 (d, J=8.3 Hz, 2H), 6.34 (s, 2H), 4.12 (s, 3H).
Step 5: Synthesis of 1-methyl-N-[4-(trifluoromethoxy)phenyl]-6-vinyl-indazole-3-carboxamidine
(11) A solution of 6-bromo-1-methyl-N-[4-(trifluoromethoxy)phenyl]indazole-3-carboxamidine (0.063 g) in 1,4-Dioxane (3 mL) was degassed with Nitrogen gas. Tri-n-butyl vinyl tin (0.073 g) and [1,1′-Bis(diphenylphosphino)ferrocene] dichloropalladium(II) (0.006 g) were subsequently added and the mixture heated at 100° C. for 2 h. The mixture was subsequently cooled to ambient temperature, diluted with water and extracted with EtOAc. The organic layers were dried over sodium sulfate and concentrated under reduced pressure and resultant residue subjected to Silica gel flash column chromatography eluting with a gradient of EtOAc/Heptane to get the title compound as a viscous liquid (0.035 g). HPLC/MS (method 1): Rt:1.590 min; m/z=361.40 (M+1).sup.+.
Step 6: Synthesis of 6-formyl-1-methyl-N-[4-(trifluoromethoxy)phenyl]indazole-3-carboxamidine
(12) To a stirred solution of 1-methyl-N-[4-(trifluoromethoxy)phenyl]-6-vinyl-indazole-3-carboxamidine (1.4 g) in 1,4-Dioxane (15 mL) was added a solution of Osmium tetroxide (0.050 g) in water (8 mL). The mixture was stirred for 12 h and Sodium sulfite solution (0.5%) was subsequently added and the mixture extracted with EtOAc. The organic extracts were dried over Sodium sulfate, and the residue obtained was subjected to Silica gel flash column chromatography eluting with a gradient of EtOAc and Heptane to obtain the title compound as viscous oil (0.65 g). HPLC/MS (method 1): Rt=1.413 min; m/z=363.40 (M+1).sup.+; .sup.1H NMR (500 MHz, DMSO-d6) 10.17 (s, 1H), 8.50 (d, J=8.4 Hz, 1H), 8.41 (s, 1H), 7.73 (d, J=8.4 Hz, 1H), 7.31 (d, J=8.3 Hz, 2H), 7.06 (d, J=8.3 Hz, 2H), 6.40 (s, 2H), 4.24 (s, 3H).
Step 7: Synthesis of 1-(2-isopropylphenyl)-3-[(E)-[1-methyl-3-[N-[4-(trifluoromethoxy)phenyl]carbamimidoyl]indazol-6-yl]methyleneamino]thiourea
(13) A mixture of 6-formyl-1-methyl-N-[4-(trifluoromethoxy)phenyl]indazole-3-carboxamidine (0.56 g) and 1-amino-3-(2-isopropylphenyl)thiourea (0.29 g) in Acetonitrile (7 mL) was heated at 80° C. for 2 h. The mixture was cooled to ambient temperature and the precipitated solids were filtered and subjected to neutral Alumina column chromatography using a gradient of Dichloromethane and Methanol as eluent to afford the title compound as a yellow solid (0.260 g) HPLC/MS (method 1): Rt=1.76 min; m/z=554.25 (M+1).sup.+; .sup.1H NMR (500 MHz, DMSO-d6); δ 11.93 (s, 1H), 10.01 (s, 1H), 8.30 (d, J=3.7 Hz, 2H), 8.13 (s, 1H), 7.91 (d, J=8.7 Hz, 1H), 7.44-7.17 (m, 5H), 7.05 (d, J=8.4 Hz, 2H), 6.31 (s, 2H), 4.16 (s, 1H), 3.26-3.03 (m, 1H), 1.20 (d, J=6.9 Hz, 6H).
Example C-2
6-[(E)-[(E)-[3-(2-isopropylphenyl)-4-oxo-thiazolidin-2-ylidene]hydrazono]methyl]-1-methyl-N-[4-(trifluoromethoxy)phenyl]indazole-3-carboxamidine (C-2)
(14) A mixture of 1-(2-isopropylphenyl)-3-[(E)-[1-methyl-3-[N-[4-trifluoromethoxy)phenyl]carbamimidoyl]indazol-6-yl]methyleneamino]thiourea (0.20 g), Sodium acetate (0.06 g) and Methyl bromo acetate (0.066 g) in Acetonitrile (4 mL) was stirred at ambient temperature for 48 h. The reaction mixture was subsequently diluted with water and extracted with EtOAc and the organic layer was dried over anhydrous Sodium sulphate and evaporated invacuo. The residue obtained was subjected to column chromatography over neutral alumina, eluting with a gradient of Dichloromethane and Methanol to obtain the title compound as a yellow solid (0.050 g).
(15) HPLC/MS (method 1): Rt=1.73 min; m/z=594.35 (M+1).sup.+; .sup.1H NMR (500 MHz, DMSO-d6); δ 8.45 (s, 1H), 8.41-8.27 (m, 1H), 7.98 (s, 1H), 7.74 (d, J=8.6 Hz, 1H), 7.50 (dt, J=15.1, 7.8 Hz, 2H), 7.42-7.19 (m, 4H), 7.09 (s, 2H), 6.46 (s, 2H), 4.35-4.12 (m, 5H), 2.95-2.71 (m, 1H), 1.16 (dd, J=17.2, 6.8 Hz, 6H).
Example C-3
1-[(E)-[3-[(Z)—N,N′-dimethyl-N-[4-(trifluoromethoxy)phenyl]carbamimidoyl]-1-methyl-indazol-6-yl]methyleneamino]-3-(2-isopropylphenyl)thiourea (C-3)
Step 1: Synthesis of 6-bromo-N,N′,1-trimethyl-N-[4-(trifluoromethoxy)phenyl]indazole-3-carboxamidine
(16) Sodium hydride (0.174 g) was added portion-wise to a stirred solution of 6-bromo-1-methyl-N-[4-(trifluoromethoxy)phenyl]indazole-3-carboxamidine (1.2 g) in DMF (15 mL) at 0° C. Methyl iodide (1.65 g, 11.65 mmol) was subsequently added. The mixture was stirred at ambient temperature for 16 h and saturated ammonium chloride solution was added. The mixture was subsequently extracted with EtOAc, the organic extracts dried over anhydrous Sodium sulfate and concentrated under reduced pressure. The residue obtained was subjected to flash column chromatography over neutral alumina, eluting with a gradient of Dichloromethane and Methanol to get the title compound as an off white solid (0.65 g). HPLC/MS (method 1): Rt=1.59 min; m/z=443.15 (M+1).sup.+; .sup.1H NMR (500 MHz, DMSO-d6); 7.96 (s, 1H), 7.32 (d, J=8.6 Hz, 1H), 7.23-7.12 (m, 1H), 6.86 (d, J=8.3 Hz, 2H), 6.51 (d, J=8.4 Hz, 2H), 3.99 (s, 3H), 2.96 (s, 6H).
Step 2: Synthesis of N,N′,1-trimethyl-N-[4-(trifluoromethoxy)phenyl]-6-vinyl-indazole-3-carboxamidine
(17) A mixture of 6-bromo-N,N′,1-trimethyl-N-[4-(trifluoromethoxy)phenyl]indazole-3-carboxamidin (0.62 g), tri-butyl-vinyl tin (0.67 g) and [1,1′-Bis(diphenylphosphino) ferrocene]dichloropalladium(II) (0.052 g) in 1,4—Dioxane (15 mL) was heated at 100° C. for 12 h. The mixture was cooled to ambient temperature, diluted with EtOAc and filtered through Celite. The filtrate was successively washed with water and a solution of Sodium chloride and the organic layer was separated, dried over anhydrous Sodium sulfate and concentrated under reduced pressure. The residue obtained was subjected to neutral Alumina column chromatography eluting with a gradient of Ethyl acetate and Heptane to obtain the title compound as a viscous liquid (0.52 g). HPLC/MS (method 1): Rt=1.56 min; m/z=389.45 (M+1).sup.+.
Step 3: Synthesis of 6-formyl-N,N′,1-trimethyl-N-[4-(trifluoromethoxy)phenyl]indazole-3-carboxamidine
(18) To a stirred solution of N,N′-1-trimethyl-N-[4-(trifluoromethoxy)phenyl]-6-vinyl-indazole-3-carbox amidine (0.58 g) in 1,4-Dioxane (8 mL) was added a solution of Osmium tetroxide (0.019 g) in water (4 mL), followed by the addition of Sodium periodate (1.0 g). The mixture was stirred for 12 h at ambient temperature and a 0.5% solution of Sodium sulfite was added and the mixture extracted with EtOAc. The organic extracts were dried over anhydrous Sodium sulphate and evaporated invacuo and the residue obtained was subjected to neutral Alumina column chromatography to obtain the title compound as a viscous liquid (0.27 g). HPLC/MS (method 1): Rt=1.44 min; m/z=391.4 (M+1).sup.+.
Step: 4 Synthesis of 1-[(E)-[3-[(Z)—N,N′-dimethyl-N-[4-(trifluoromethoxy)phenyl]carbamimidoyl]-1-methyl-indazol-6-yl]methyleneamino]-3-(2-isopropylphenyl)thiourea
(19) A mixture of 6-formyl-N,N′,1-trimethyl-N-[4-(trifluoromethoxy)phenyl]indazole-3-carboxamidine (0.25 g) and 1-amino-3-(2-isopropylphenyl)thiourea (0.134 g) in THE (4 mL) was heated at 70° C. for 3 h. The mixture was concentrated under reduced and the residue obtained was purified by preparative HPLC to afford the title compound as a yellow solid (0.1 g). HPLC/MS (method 1): Rt=1.72 min; m/z=582.35 (M+1).sup.+; .sup.1H NMR (500 MHz, DMSO-d6) δ 11.93 (s, 1H), 10.0 (s, 1H), 8.21 (m, 1H), 8.10 (m, 1H), 7.98-7.96 (m, 1H), 7.53-7.52 (m, 1H), 7.36-7.35 (m, 1H), 7.32-7.30 (m, 1H), 7.22-7.19 (m, 2H), 7.17-7.15 (m, 2H), 7.05-7.04 (m, 2H), 4.13 (d, J=1.4 Hz, 3H), 3.50 (s, 3H), 3.28 (s, 3H), 3.11-3.08 (m, 1H) 1.16-1.17 (m, 6H).
Example C-4
[(2S,3R,4R,5S,6S)-3,4,5-trimethoxy-6-methyl-tetrahydropyran-2-yl]N-[1-methyl-3-[methyl-[4-(trifluoromethoxy)phenyl]carbamothioyl]indazol-6-yl]carbamate (C-4)
(20) A solution of [(2S,3R,4R,5S,6S)-3,4,5-trimethoxy-6-methyl-tetrahydropyran-2-yl] N-[1-methyl-3-[methyl-[4-(trifluoromethoxy)phenyl]carbamoyl]indazol-6-yl]carbamate (0.070 g) Lawesson's reagent (0.072 g) in pyridine was heated at 110° C. for 16 h. The reaction was then allowed to cool to room temperature, the precipitate was isolated by filtration and purified by column reverse-phase chromatography eluting with a gradient of acetonitrile/water to afford [(2S,3R,4R,5S,6S)-3,4,5-trimethoxy-6-methyl-tetrahydropyran-2-yl] N-[1-methyl-3-[methyl-[4-(trifluoromethoxy)phenyl]carbamothioyl]indazol-6-yl]carbamate (47 mg). HPLC/MS (method 2): Rt=1.29 min; m/z=613 (M+); .sup.1H NMR (500 MHz, CDCl.sub.3) δ 7.96 (d, J=8.7 Hz, 1H), 7.72 (s, 1H), 7.14-7.01 (m, 5H), 6.77 (dd, J=8.7, 1.8 Hz, 1H), 6.18 (d, J=2.0 Hz, 1H), 5.30 (s, 1H), 3.95 (s, 3H), 3.80-3.64 (m, 6H), 3.63-3.48 (m, 13H), 3.22 (t, J=9.5 Hz, 1H), 1.33 (d, J=6.2 Hz, 4H).
Example C-5
1-[(E)-[3-[(Z)—N-(4-hydroxyphenyl)-N′-methoxy-carbamimidoyl]-1-methyl-indazol-6-yl]methyleneamino]-3-(2-isopropylphenyl)thiourea (C-5)
Step 1: Synthesis of 6-bromo-1H-indazole-3-carbaldehyde
(21) To the stirring solution of 6-bromo-1H-indole (10 g) in Acetone (200 mL), was added solution of Sodium nitrite (28.155g) in Water (50 mL) at 0° C. Mixture was stirred for 10 min and 2N HCl (120 mL) was added dropwise by dropping funnel at 0°. Mixture was continued to stir for 1 h. The reaction mixture was concentrated and the solid was filtered. The solid was washed with cold acetone (20 mL) and dried under vacuum to afford 6-bromo-1H-indazole-3-carbaldehyde as brown solid (5.5 g). HPLC/MS (method 1): Rt=2.2 min, m/z=225 (M+); .sup.1H NMR (500 MHz, DMSO-d6) δ 14.28 (s, 1H), 10.19 (s, 1H), 8.08 (d, J=8.5 Hz, 1H), 7.97 (d, J=1.5 Hz, 1H), 7.51 (dd, J=8.6, 1.7 Hz, 1H).
Step 2: Synthesis of 6-bromo-1-methyl-indazole-3-carbaldehyde
(22) To the stirring solution of 6-bromo-1H-indazole-3-carbaldehyde (3.1 g) in dry THE (30 mL), were added Methyl iodide (2.94 g) and Potassium carbonate (3.9 g) at room temperature under inert atmosphere. The reaction mixture was continued to stir for 12 h at room temperature. Reaction mixture was diluted with ethyl acetate and washed with water. The mixture was concentrated under reduced pressure and the residue obtained was purified by column chromatography eluting with a gradient of Ethyl acetate and Heptane to afford the title compound (2.3 g). .sup.1H NMR (300 MHz, DMSO-d6) δ 13.17 (s, 1H), 8.14 (d, J=1.5 Hz, 1H), 7.99 (dd, J=8.7, 0.7 Hz, 1H), 7.45 (dd, J=8.6, 1.6 Hz, 1H).
Step 3: Synthesis of 6-bromo-1-methyl-indazole-3-carboxylic acid
(23) To the stirring solution of 6-bromo-1-methyl-indazole-3-carbaldehyde (3.5 g) in ACN (30 mL) and Water (10 mL), was added Potassium permanganate (3.4 g) at room temperature under inert atmosphere. Reaction was continued for 12 h at room temperature. Reaction mixture was diluted with water and filtered through a celite bed. The filtrate pH was adjusted up to ˜2-3 using 1N HCl. Precipitated product was filtered through a filter paper and dried under reduced pressure to afford the title compound (2.3 g). HPLC/MS (method 1): Rt=1.56 min; m/z=255 (M+); .sup.1H NMR (300 MHz, DMSO-d6) δ 8.14 (d, J=1.5 Hz, 1H), 7.99 (dd, J=8.7, 0.7 Hz, 1H), 7.45 (dd, J=8.6, 1.6 Hz, 1H), 4.13 (s, 3H).
Step 4: Synthesis of 6-bromo-1-methyl-N-[4-(trifluoromethoxy)phenyl]indazole-3-carboxamide
(24) To the stirring solution of 6-bromo-1-methyl-indazole-3-carboxylic acid (0.3 g) in DCM (5 mL) was added TEA (0.39 g) and para-trifluoro methoxy aniline (0.208 g). Reaction mixture was stirred for 5 min and Propylphosphonic anhydride (50% in EtOAc, 2.24 ml) was added. Mixture was stirred for 16 h at room temperature. Reaction mixture was diluted with DCM and washed with water. The mixture was concentrated under reduced pressure and the residue obtained was purified by column chromatography eluting with a gradient of Ethyl acetate and Heptane to afford the title compound (0.280 mg). HPLC/MS (method 1): Rt=2.233 min; m/z=414 (M+); .sup.1H NMR (500 MHz, DMSO-d6) δ 10.65 (s, 1H), 8.19 (s, 1H), 8.15 (d, J=8.6 Hz, 1H), 8.01 (d, J=8.9 Hz, 2H), 7.48 (d, J=8.6 Hz, 1H), 7.37 (d, J=8.6 Hz, 2H), 4.20 (s, 3H).
Step 5: Synthesis of 6-bromo-N′-hydroxy-1-methyl-N-[4-(trifluoromethoxy)phenyl]indazole-3-carboxamidine
(25) 6-bromo-1-methyl-N-[4-(trifluoromethoxy)phenyl]indazole-3-carboxamide (2 g) was heated in SOCl.sub.2 (6 mL) at 120° C. for 16 h. After completion the reaction mixture was concentrated and dried under vacuum. To the residue EtOH (20 mL) was added and cooled to 0° C. TEA (1.95 g) and Hydroxyl amine hydrochloride (1 g) was added and heated at 90° C. for 2-4 h. Reaction mixture was quenched with brine and extracted with EtOAc. The mixture was concentrated under reduced pressure and the residue obtained was purified by column chromatography eluting with a gradient of Ethyl acetate and Heptane to afford the title compound (1.6 g). HPLC/MS (method 1): Rt=1.94 min; m/z=431(M+1); .sup.1H NMR (500 MHz, DMSO-d6) δ 10.89 (s, 1H), 8.60 (s, 1H), 8.03 (d, J=1.5 Hz, 1H), 7.82 (d, J=8.6 Hz, 1H), 7.32 (m, 1H) 7.07 (d, J=8.6 Hz, 2H), 6.74 (d, J=9.0 Hz, 2H), 3.99 (s, 3H).
Step 6: Synthesis of 6-bromo-N′-methoxy-1-methyl-N-[4-(trifluoromethoxy)phenyl]indazole-3-carboxamidine
(26) To the stirring solution of 6-bromo-N′-hydroxy-1-methyl-N-[4-(trifluoromethoxy)phenyl]indazole-3-carboxamidine (1.5 g) in DMF (10 mL) was added Potassium carbonate (1.28 g) and Methyl iodide (0.527 g). Reaction mixture was stirred for 4 h at room temperature. The reaction mixture was quenched with cold water and solid was filtered. Solid was dissolved in EtOAc, washed with brine, dried over anhydrous sodium sulphate and filtered. The filtrate was concentrated under reduced pressure and the residue obtained was purified by column chromatography eluting with a gradient of Ethyl acetate and Heptane to afford the title compound (0.04 g). .sup.1H NMR (500 MHz, DMSO-d6) δ 8.83 (s, 1H), 8.04 (dd, J=1.7, 0.6 Hz, 1H), 7.82 (dd, J=8.7, 0.6 Hz, 1H), 7.33 (dd, J=8.6, 1.6 Hz, 1H), 7.14-7.00 (m, 2H), 6.77 (d, J=9.0 Hz, 2H), 4.00 (s, 3H), 3.91 (s, 3H).
Step 7: Synthesis of N′-methoxy-1-methyl-N-[4-(trifluoromethoxy)phenyl]-6-vinyl-indazole-3-carboxamidine
(27) To the stirring solution of 6-bromo-N′-methoxy-1-methyl-N-[4-(trifluoromethoxy)phenyl] indazole-3-carboxamidine (0.25 g) in Toluene (5 mL), was added [1,1′-Bis(diphenylphosphino) ferrocene] dichloropalladium(II) (0.025 g). N.sub.2 gas was purged to the mixture for 5 min. Ethyl-tributyl-tin (0.268 g) was added and heated at 110° C. for 4 h. Reaction mixture was quenched with brine and extracted with EtOAc. The mixture was concentrated under reduced pressure and the residue obtained was purified by column chromatography eluting with a gradient of Ethyl acetate and Heptane to afford the title compound (0.170 g). HPLC/MS (method 1): Rt=2.299 min; m/z=391 (M+1); .sup.1H NMR (500 MHz, DMSO-d6) δ 8.80 (s, 1H), 7.80 (d, J=8.5 Hz, 1H), 7.71 (s, 1H), 7.38 (dd, J=8.5, 1.3 Hz, 1H), 7.11-7.05 (m, 2H), 6.88 (dd, J=17.6, 10.9 Hz, 1H), 6.81-6.75 (m, 2H), 5.98 (dd, J=17.6, 1.0 Hz, 1H), 5.40-5.34 (m, 1H), 4.02 (s, 3H), 3.9 (s, 3H).
Step 8: Synthesis of 6-formyl-N′-methoxy-1-methyl-N-[4-(trifluoromethoxy)phenyl]indazole-3-carboxamidine
(28) To the stirring solution of N′-methoxy-1-methyl-N-[4-(trifluoromethoxy)phenyl]-6-vinyl-indazole-3-carboxamidine (0.07g) in Dioxane (2 mL) and Water (1 mL), was added Osmium tetraoxide (0.001 g) and Sodium periodate (0.095 g) at 0° C. Reaction mixture was continued to stir at 0° C. to room temperature for 2 h. Reaction mixture was quenched with brine and extracted with EtOAc. The mixture was concentrated under reduced pressure and the residue obtained was purified by column chromatography eluting with a gradient of Ethyl acetate and Heptane to afford the title compound (0.04 g). HPLC/MS (method 1): Rt=1.99 min, m/z=391 (M−); .sup.1H NMR (500 MHz, DMSO-d6) δ 10.12 (s, 1H), 8.88 (s, 1H), 8.35 (s, 1H), 8.01 (d, J=8.5 Hz, 1H), 7.66 (dd, J=8.5, 1.1 Hz, 1H), 7.07 (d, J=8.7 Hz, 2H), 6.79-6.73 (m, 2H), 4.11 (s, 3H), 3.91 (s, 3H).
Step 9: Synthesis of 1-(2-isopropylphenyl)-3-[(E)-[3-[(Z)—N′-methoxy-N-[4-(trifluoromethoxy)phenyl]carbamimidoyl]-1-methyl-indazol-6-yl]methyleneamino]thiourea
(29) To the stirring solution of 6-formyl-N′-methoxy-1-methyl-N-[4-(trifluoromethoxy)phenyl]indazole-3-carboxamidine (0.16 g) in EtOH (2 mL), was added semi carbazide (0.085 g) and heated at 90° C. for 3 h. The mixture was concentrated under reduced pressure and the residue obtained was purified by column chromatography eluting with a gradient of Ethyl acetate and Heptane to afford the title compound (0.08 g). HPLC/MS (method 1): Rt=2.24 min; m/z=584 (M+); .sup.1H NMR (500 MHz, DMSO-d6) δ 11.92 (s, 1H), 10.00 (s, 1H), 8.84 (s, 1H), 8.27 (s, 1H), 8.05 (s, 1H), 7.91 (d, J=8.6 Hz, 1H), 7.80 (d, J=8.6 Hz, 1H), 7.40-7.28 (m, 2H), 7.24 (d, J=4.1 Hz, 2H), 7.08 (d, J=8.5 Hz, 2H), 6.81-6.75 (m, 2H), 4.06 (s, 3H), 3.91 (s, 3H), 3.14 (p, J=6.9 Hz, 1H), 1.20 (d, J=6.8 Hz, 6H).
Example C-6
6-[(E)-[(Z)-[3-(2-isopropylphenyl)-5-oxo-thiazolidin-2-ylidene]hydrazono]methyl]-N′-methoxy-1-methyl-N-[4-(trifluoromethoxy)phenyl]indazole-3-carboxamidine (C-6)
(30) To the stirring solution of 1-(2-isopropylphenyl)-3-[(E)-[3-[(Z)—N′-methoxy-N-[4-(trifluoromethoxy)phenyl] carbamimidoyl]-1-methyl-indazol-6-yl]methyleneamino]thiourea (0.12 g) in EtOH (2 mL), was added Sodium acetate (0.037 g) and Methyl bromo acetate (0.035 g).
(31) Reaction mixture was stirred for 16 h at room temperature. Reaction mixture was diluted with EtOAc and washed with water. The mixture was concentrated under reduced pressure and the residue obtained was purified by column chromatography eluting with a gradient of Ethyl acetate and Heptane to afford the title compound (0.05 g). HPLC/MS (method 1): Rt=2.29 min; m/z=624 (M+); .sup.1H NMR (500 MHz, DMSO-d6) δ 8.84 (s, 1H), 8.42 (s, 1H), 7.95-7.89 (m, 2H), 7.68 (d, J=8.5 Hz, 1H), 7.56-7.43 (m, 2H), 7.35 (td, J=7.6, 1.6 Hz, 1H), 7.32-7.24 (m, 1H), 7.08 (d, J=8.6 Hz, 2H), 6.82-6.73 (m, 2H), 4.34-4.10 (m, 2H), 4.02 (s, 3H), 3.92 (s, 3H), 2.80 (p, J=6.9 Hz, 1H), 1.16 (dd, J=15.0, 6.8 Hz, 6H).
Example 20
Synthesis of 6-[(E)-[(Z)-[3-(2-isopropylphenyl)-4-oxo-thiazolidin-2-ylidene]hydrazono]methyl]-N′[4-(trifluoromethoxy)phenyl]-1,2-benzothiazole-3-carboxamidine (C-20)
Step-1: Synthesis of 6-bromo-1,2-benzothiazole-3-carbonitrile
(32) To a stirred solution of 6-bromo-1,2-benzothiazole-3-carboxamide (4.5 g) in Phosphoryl chloride (45 mL) was heated at 120° C. for 3 h. After completion of the reaction Phosphoryl chloride was removed under reduced pressure, crude was dissolved in water (50 mL). The mixture was extracted with EtOAc and the extracts were dried over anhydrous sodium sulphate and evaporated invacuo and the residue obtained was subjected to silica gel flash column chromatography, eluting with a gradient of EtOAc and Heptane to obtain the title compound (2.8 g).
Step-2: Synthesis of 6-bromo-N′-[4-(trifluoromethoxy)phenyl]-1,2-benzothiazole-3-carboxamidine
(33) To a stirred solution of 6-bromo-1,2-benzothiazole-3-carbonitrile (3.4 g) in Toluene (35.0 mL) was added 4-(trifluoromethoxy)aniline (3.023 g) and a (2 M) solution of Trimethyl aluminum in Toluene (14.22 mL). The mixture was heated at 110° C. for 16 h and subsequently cooled to ambient temperature. A solution of Potassium hydroxide was added dropwise and the mixture extracted with EtOAc. The organic extracts was dried over anhydrous sodium sulphate, evaporated invacuo and the resultant solid was subjected to silica gel flash column chromatography, eluting with a gradient of EtOAc and Heptane to obtain the title compound (5.0 g). HPLC/MS (method 1): Rt=2.32 min; m/z=417.10 (M+2).sup.+.
Step-3: Synthesis of N′-[4-(trifluoromethoxy)phenyl]-6-vinyl-1,2-benzothiazole-3-carboxamidine
(34) A solution of 6-bromo-N′-[4-(trifluoromethoxy)phenyl]-1,2-benzothiazole-3-carboxamidine (1.1 g) in Toulene (15 mL) was degassed with Nitrogen gas. Tri-n-butyl vinyl tin (1.25 mL) and [1,1′-Bis(diphenylphosphino)ferrocene] dichloropalladium(II) (0.110 g) were subsequently added and the mixture heated at 110° C. for 4 h. The mixture was subsequently cooled to ambient temperature, diluted with water and extracted with EtOAc. The organic extracts were dried over sodium sulfate and concentrated under reduced pressure and resultant residue subjected to silica gel flash column chromatography eluting with a gradient of EtOAc and Heptane to get the title compound (0.800 g). HPLC/MS (method 1): Rt=2.21 min; m/z=364 (M+1).sup.+.
Step-4: Synthesis of 6-formyl-N′-[4-(trifluoromethoxy)phenyl]-1,2-benzothiazole-3-carboxamidine
(35) To a stirred solution of N′-[4-(trifluoromethoxy)phenyl]-6-vinyl-1,2-benzothiazole-3-carboxamidine (1.0 g) in 1,4-Dioxane (6.0 mL) were added a solution of Osmium tetroxide (0.021 g) in Water (4.0 mL), Sodium periodate (1.29 g). The mixture was stirred for 4 h and Sodium sulfite solution (0.5%) was subsequently added and the mixture extracted with EtOAc. The organic extracts were dried over sodium sulfate, and the residue obtained was subjected to silica gel flash column chromatography eluting with a gradient of EtOAc and Heptane to obtain the title compound (0.500 g). HPLC/MS (method 1): Rt=1.972 min; m/z=366 (M+1)+;
Step-5: Synthesis of 1-(2-isopropylphenyl)-3-[(E)-[3-[(Z)—N′-[4-(trifluoromethoxy)phenyl]carbamimidoyl]-1,2-benzothiazol-6-yl]methyleneamino]thiourea
(36) A mixture of 6-formyl-N′-[4-(trifluoromethoxy)phenyl]-1,2-benzothiazole-3-carboxamidine (0.250 g), 1-amino-3-(2-isopropylphenyl)thiourea (0.143 g) in Acetic acid (2.0 mL) was stirred at ambient temperature for 2 h. The reaction mixture was dissolved in Water (50 mL). The mixture was extracted with EtOAc and the extracts dried over anhydrous sodium sulphate and evaporated invacuo and the residue obtained was subjected to silica gel flash column chromatography, eluting with a gradient of EtOAc and Heptane to obtain the title compound (0.230 g) HPLC/MS (method 1) Rt: 2.24 min; m/z=557 (M+1).sup.+; .sup.1H NMR (300 MHz, DMSOd6) δ 12.00 (s, 1H), 10.11 (s, 1H), 9.00 (d, J=8.7 Hz, 1H), 8.70 (s, 1H), 8.30 (s, 1H), 8.18 (dd, J=8.8, 1.4 Hz, 1H), 7.42-7.29 (m, 4H), 7.29-7.17 (m, 2H), 7.10 (d, J=8.3 Hz, 2H), 6.73 (s, 2H), 3.14 (p, J=6.8 Hz, 1H), 1.19 (d, J=6.9 Hz, 6H).
Example 21
Synthesis of 6-[(E)-[(Z)-[3-(2-isopropylphenyl)-4-oxo-thiazolidin-2-ylidene]hydrazono]methyl]-N′[4-(trifluoromethoxy)phenyl]-1,2-benzothiazole-3-carboxamidine (C-21)
(37) A mixture of 1-(2-isopropylphenyl)-3-[(E)-[3-[(Z)—N′-[4-(trifluoromethoxy)phenyl]carbamimidoyl]-1,2-benzothiazol-6-yl]methyleneamino]thiourea (0.230 g), Methyl bromo acetate (0.95 g) in EtOH (10 mL), was added Sodium acetate (0.051 g) at 0° C. The mixture was stirred at ambient temperature for 16 h. Water (50 mL) was subsequently added. The mixture was extracted with EtOAc and the organic extracts were dried over anhydrous sodium sulphate and evaporated invacuo and the residue obtained was subjected to silica gel flash column chromatography, eluting with a gradient of EtOAc and heptane to obtain the title compound (0.080 g). HPLC/MS (method 1): Rt: 2.29 min; m/z=597 (M+1).sup.+; .sup.1H NMR (300 MHz, DMSO-d6) δ 9.06 (d, J=8.7 Hz, 1H), 8.51 (d, J=14.5 Hz, 2H), 7.95 (d, J=8.7 Hz, 1H), 7.57-7.42 (m, 2H), 7.41-7.23 (m, 4H), 7.10 (d, J=8.7 Hz, 2H), 6.73 (s, 2H), 4.35-4.04 (m, 2H), 2.80 (p, J=6.7 Hz, 1H), 1.15 (dd, J=8.9, 6.8 Hz, 6H).
Example C-24
1-(2-isopropylphenyl)-3-[(E)-[1-methyl-3-[(E)-[4-(trifluoromethoxy)phenyl]iminomethyl]indazol-6-yl]methyleneamino]thiourea (C-24)
Step 1: Synthesis of Methyl 3-formyl-1H-indazole-6-carboxylate
(38) To the stirring solution of Methyl 1H-indole-6-carboxylate (5 g) in Acetone (100 mL), was added solution of Sodium nitrite (15.75 g) in water (27 mL) at 0° C. Mixture was stirred for 10 min and 2N HCl (64 mL) was added dropwise by dropping funnel at 0° C. Mixture was continued to stir for 12 h. The reaction mixture was concentrated and the solid was filtered. The solid was washed with cold acetone (20 mL) and dried under vacuum to afford title compound as solid (5 g). HPLC/MS (method 1): Rt=1.483 min, m/z=203.4 (M+1).sup.+.
Step 2: Synthesis of Methyl 3-formyl-1-methyl-indazole-6-carboxylate
(39) To the stirring solution of Methyl 3-formyl-1H-indazole-6-carboxylate (3.9 g) in dry THE (39 mL), were added Methyl iodide (4.067 g) and Potassium carbonate (5.28 g) at room temperature under inert atmosphere. The reaction mixture was continued to stir for 12 h at room temperature. Reaction mixture was diluted with EtOAc and washed with water. The organic layers were dried over Sodium sulfate and concentrated under reduced pressure and resultant residue subjected to Silica gel flash column chromatography eluting with a gradient of EtOAc/Heptane to afford the title compound (3 g). HPLC/MS (method 1): Rt=1.648 min, m/z=217.90 (M+1).sup.+.
Step 3: Synthesis of Methyl 3-(1,3-dioxolan-2-yl)-1-methyl-indazole-6-carboxylate
(40) To the stirring solution of Methyl 3-formyl-1-methyl-indazole-6-carboxylate (3 g) in Toluene (30 mL), were added p-Toluenesulfonic acid (0.262 g) and Ethelene glycol (2.56 g) at room temperature under inert atmosphere. Reaction was continued to stir at 105° C. for 12 h. Reaction mixture was diluted with EtOAc and washed with aqeuous sodium bicarbonate solution. The organic layers were dried over Sodium sulfate and concentrated under reduced pressure and resultant residue subjected to Silica gel flash column chromatography eluting with a gradient of EtOAc/Heptane to afford the title compound (1.5 g). HPLC/MS (method 1): Rt=1.590 min, m/z=262.85 (M+1).sup.+.
Step 4: Synthesis of [3-(1,3-dioxolan-2-yl)-1-methyl-indazol-6-yl]methanol
(41) To the stirring solution of Methyl 3-(1,3-dioxolan-2-yl)-1-methyl-indazole-6-carboxylate (1.5 g) in DCM (15 mL), was added DIBAL-H (1.79 g) and mixture was stirred at −78° C. for 2 h. Reaction mixture was quenched with aqueous sodium bicarbonate solution and extracted with DCM. The organic layers were dried over Sodium sulfate and concentrated under reduced pressure and resultant residue subjected to Silica gel flash column chromatography eluting with a gradient of EtOAc/Heptane to afford the title compound (1.5 g).
(42) HPLC/MS (method 1): Rt=1.204 min, m/z=234.85 (M+1).sup.+.
Step 5: Synthesis of 3-(1,3-dioxolan-2-yl)-1-methyl-indazole-6-carbaldehyde
(43) To a stirring solution of [3-(1,3-dioxolan-2-yl)-1-methyl-indazol-6-yl]methanol (1.5 g) in dry DCM (15 mL), were added Dess Martin Periodinane (2.715 g) and Sodium bicarbonate (0.538 g) at room temperature under inert atmosphere. The reaction mixture was continued to stir for 12 h at room temperature. Reaction mixture was diluted with DCM and washed with water. The organic layers were dried over Sodium sulfate and concentrated under reduced pressure and resultant residue subjected to Silica gel flash column chromatography eluting with a gradient of EtOAc/Heptane to afford the title compound (0.9 g). HPLC/MS (method 1): Rt=1.458 min, m/z=232.9 (M+1).sup.+.
Step 6: Synthesis of 1-[(E)-[3-(1,3-dioxolan-2-yl)-1-methyl-indazol-6-yl]methyleneamino]-3-(2-isopropylphenyl)thiourea
(44) To the stirring solution of 3-(1,3-dioxolan-2-yl)-1-methyl-indazole-6-carbaldehyde (0.85 g) in EtOH (10 mL), was added 1-amino-3-(2-isopropylphenyl)thiourea (0.766 g) and mixture was stirred at 85° C. for 3 h. The precipitated product was filtered though a paper and dried under reduced pressure to afford the title compound (1.4 g). HPLC/MS (method 1): Rt=1.939 min, m/z=424 (M+1).sup.+.
Step 7: Synthesis of 1-[(E)-(3-formyl-1-methyl-indazol-6-yl)methyleneamino]-3-(2-isopropylphenyl)thiourea
(45) To the stirring solution of 1-[(E)-[3-(1,3-dioxolan-2-yl)-1-methyl-indazol-6-yl]methyleneamino]-3-(2-isopropylphenyl)thiourea (1.4 g) in Acetone (14 mL) was added p-Toluenesulfonic acid (0.063 g) room temperature under inert atmosphere. Reaction mixture was stirred for 12 h at room temperature. Reaction mixture was neutralised with aqueous sodium bicarbonate solution and extracted with EtOAc. The organic layers were dried over Sodium sulfate and concentrated under reduced pressure and resultant residue subjected to Silica gel flash column chromatography eluting with a gradient of EtOAc/Heptane to afford the title compound (0.9 g).
(46) HPLC/MS (method 1): Rt=1.931 min, m/z=379.9 (M+1).sup.+.
Step 8: Synthesis of 1-(2-isopropylphenyl)-3-[(E)-[1-methyl-3-[(E)-[4-(trifluoromethoxy)phenyl]iminomethyl]indazol-6-yl]methyleneamino]thiourea
(47) To the stirring solution of 1-[(E)-(3-formyl-1-methyl-indazol-6-yl)methyleneamino]-3-(2-isopropylphenyl)thiourea (0.65 g) in Ethanol (7 mL) were added 4-(Trifluoromethoxy)aniline (0.334 g) and Acetic acid (2-3 drops) at room temperature under inert atmosphere. The reaction mixture was continued to stir at 85° C. for 3 h. The mixture was concentrated under reduced pressure and the residue obtained was purified by column chromatography eluting with a gradient of Ethyl acetate and Heptane to afford the title compound (0.2 g). HPLC/MS (method 1): Rt=2.338 min; m/z=537 (M+1).sup.+.
Example C-25
(2Z)-3-(2-isopropylphenyl)-2-[(E)-[1-methyl-3-[(E)-[4-(trifluoromethoxy)phenyl]iminomethyl]indazol-6-yl]methylenehydrazono]thiazolidin-4-one (C-25)
(48) To the stirring solution of 1-(2-isopropylphenyl)-3-[(E)-[1-methyl-3-[(E)-[4-(trifluoromethoxy) phenyl]iminomethyl]indazol-6-yl]methyleneamino]thiourea (0.3 g) in EtOH (6 mL), were added Sodium acetate (0.092 g) and Methyl-2-bromoacetate (0.102 g). Reaction mixture was stirred for 12 h at room temperature. Reaction mixture was diluted with ethyl acetate and washed with water. The organic layers were dried over Sodium sulfate and concentrated under reduced pressure and resultant residue subjected to Silica gel flash column chromatography eluting with a gradient of EtOAc/Heptane to afford the title compound (0.07 g). HPLC/MS (method 1): Rt=2.379 min; m/z=578.85 (M+1).sup.+; .sup.1H NMR (300 MHz, DMSO-d6) δ 8.87 (s, 1H), 8.47 (s, 1H), 8.43 (d, J=8.5 Hz, 1H), 8.02 (s, 1H), 7.83 (d, J=8.3 Hz, 1H), 7.55-7.40 (m, 6H), 7.31 (dd, J=17.7, 7.2 Hz, 2H), 4.40-4.04 (m, 5H), 2.7-2.9 (m, 1H), 1.16 (dd, J=10.3, 6.8 Hz, 6H).
Example C-26
1-(2-isopropylphenyl)-3-[(E)-[1-methyl-3-[N-[4-(trifluoromethoxy)phenyl]carbamimidoyl]pyrazolo[3,4-b]pyridin-6-yl]methyleneamino]thiourea (C-26)
Step 1: Synthesis of 6-chloro-1-methyl-3-vinyl-pyrazolo[3,4-b]pyridine
(49) A solution of 6-chloro-3-iodo-1-methyl-pyrazolo[3,4-b]pyridine (3.8 g) in 1,4-Dioxane (50 mL) was degassed with Nitrogen gas. Tri-n-butyl vinyl tin (4.925 g) and Bis(triphenylphosphine)palladium(II) dichloride (0.454 g) were subsequently added and the mixture heated at 100° C. for 3 h. The mixture was subsequently cooled to ambient temperature, diluted with water and extracted with EtOAc. The organic layers were dried over Sodium sulfate and concentrated under reduced pressure and resultant residue subjected to Silica gel flash column chromatography eluting with a gradient of EtOAc/Heptane to get the title compound (1.6 g). .sup.1H NMR (300 MHz, Chloroform-d) δ 8.15 (d, J=8.4 Hz, 1H), 7.23 (s, 2H), 7.15 (d, J=8.4 Hz, 1H), 6.94 (dd, J=18.0, 11.4 Hz, 1H), 6.03 (dd, J=18.0, 0.9 Hz, 1H), 5.56 (dd, J=11.4, 0.9 Hz, 1H), 4.10 (s, 3H).
Step 2: Synthesis of 6-chloro-1-methyl-pyrazolo[3,4-b]pyridine-3-carbaldehyde
(50) To a stirred solution of 6-chloro-1-methyl-3-vinyl-pyrazolo[3,4-b]pyridine (3.6 g) in 1,4-Dioxane (100 mL) was added a solution of Osmium tetroxide (0.236 g) in water (70 mL). To this solution Sodium periodate (7.957 g) was added in portion and the mixture was stirred for 12 h at room temperature. Sodium sulfite solution (0.5%) was subsequently added and the mixture extracted with EtOAc. The organic extracts were dried over Sodium sulfate, and the residue obtained was subjected to Silica gel flash column chromatography eluting with a gradient of EtOAc/Heptane to obtain the title compound (3.4 g). HPLC/MS (method 1): .sup.1H NMR (300 MHz, DMSO-d6) δ 10.11 (s, 1H), 8.55 (d, J=8.4 Hz, 1H), 7.55 (d, J=8.4 Hz, 1H), 4.18 (s, 3H).
Step 3: Synthesis of 6-chloro-1-methyl-pyrazolo[3,4-b]pyridine-3-carbonitrile
(51) To a stirred solution of 6-chloro-1-methyl-pyrazolo[3,4-b]pyridine-3-carbaldehyde in acetonitrile was added Triethylamine (20 mL) and Hydroxylamine hydrochloride (1.25 g) and the mixture was heated at 65° C. for 3 h. After the starting material was consumed, the reaction mixture was cooled to 0° C. then more Triethylamine (6 mL) was added to it followed by dropwise addition of Trifluoroacetic anhydride (10 mL) maintaining the temperature at 0° C. The reaction mixture was stirred at room temperature for 3 h and then was poured into an ice-water under stirring. The precipitated solid was filtered, washed with water and dried to obtain the title compound (2.2 g).
(52) HPLC/MS (method 1): Rt=1.553 min; m/z=No Ionization; 1H NMR (300 MHz, DMSO-d6) δ 8.53 (d, J=8.5 Hz, 1H), 7.57 (d, J=8.5 Hz, 1H), 4.15 (s, 3H).
Step 4: 6-chloro-1-methyl-N-[4-(trifluoromethoxy)phenyl]pyrazolo[3,4-b]pyridine-3-carboxamidine
(53) To a stirred solution of 6-chloro-1-methyl-pyrazolo[3,4-b]pyridine-3-carbonitrile (1.9 g) in Toluene (40 mL) was added 4-(trifluoromethoxy)aniline (1.747 g) and a 2 M solution of Trimethyl aluminum in toluene (0.923 g). The mixture was heated in a sealed tube at 90° C. for 4 h and subsequently cooled to ambient temperature. A solution of Potassium hydroxide was added dropwise and the mixture was extracted with EtOAc. The organic extracts were dried over anhydrous Sodium sulphate, evaporated in vacuo and the resultant solid was subjected to neutral Alumina flash column chromatography, eluting with a gradient of EtOAc/Heptane to obtain the title compound (2.4 g). HPLC/MS (method 1): Rt=1.618 min; m/z=370.95 (M+1).sup.+.
Step 5: 1-methyl-N-[4-(trifluoromethoxy)phenyl]-6-vinyl-pyrazolo[3,4-b]pyridine-3-carboxamidine
(54) A solution 6-chloro-1-methyl-N-[4-(trifluoromethoxy)phenyl]pyrazolo[3,4-b]pyridine-3-carboxamidine (1.3 g) in 1,4-Dioxane (20 mL) was degassed with Nitrogen gas. Tri-n-butyl vinyl tin (1.445 g) and [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.128 g) were subsequently added and the mixture was heated at 100° C. for 4 h. The mixture was subsequently cooled to ambient temperature, diluted with water and extracted with EtOAc. The organic layers were dried over Sodium sulfate and concentrated under reduced pressure and resultant residue subjected to Silica gel flash column chromatography eluting with a gradient of EtOAc/Heptane to get the title compound (0.85 g). HPLC/MS (method 1): Rt:1.516 min; m/z=362.25 (M).sup.+.
Step 6: Synthesis of 6-formyl-1-methyl-N-[4-(trifluoromethoxy)phenyl]pyrazolo[3,4-b]pyridine-3-carboxamidine
(55) To a stirred solution of 1-methyl-N-[4-(trifluoromethoxy)phenyl]-6-vinyl-pyrazolo[3,4-b]pyridine-3-carboxamidine (0.8 g) in 1,4-Dioxane (10 mL) was added a solution of Osmium tetroxide (0.028 g) in water (8 mL). To this solution Sodium periodate (0.951 g) was added in portion and the mixture was stirred for 12 h at room temperature and Sodium sulfite solution (0.5%) was subsequently added and the mixture was extracted with EtOAc. The organic extracts were dried over Sodium sulfate, and the residue obtained was subjected to Silica gel flash column chromatography eluting with a gradient of EtOAc/Heptane to obtain the title compound (0.56 g).
(56) HPLC/MS (method 1): Rt=1.396 min; m/z=362.95 (M+1).sup.+.
Step 7: Synthesis of 1-(2-isopropylphenyl)-3-[(E)-[1-methyl-3-[N-[4-(trifluoromethoxy)phenyl]carbamimidoyl]pyrazolo[3,4-b]pyridin-6-yl]methyleneamino]thiourea
(57) A mixture of 6-formyl-1-methyl-N-[4-(trifluoromethoxy)phenyl]pyrazolo[3,4-b]pyridine-3-carboxamidine (0.56 g) and 1-amino-3-(2-isopropylphenyl)thiourea (0.32 g) in Acetic acid (7 mL) was stirred at room temperature for 2 h. The mixture was poured into an ice-water and the precipitated solids were filtered and washed with water and dried to afford the title compound (0.260 g). HPLC/MS (method 1): Rt=1.76 min; m/z=555.30 (M+1).sup.+; .sup.1H NMR (300 MHz, DMSO-d6) δ 12.16 (s, 1H), 10.26 (s, 1H), 8.58 (d, J=8.6 Hz, 1H), 8.42 (d, J=8.6 Hz, 1H), 8.28 (s, 1H), 7.47-7.17 (m, 6H), 7.05 (d, J=8.3 Hz, 2H), 6.43 (s, 2H), 4.16 (s, 3H), 3.18-3.03 (m, 1H), 1.19 (d, J=6.8 Hz, 6H).
Example C-27
6-[(E)-[(Z)-[3-(2-isopropylphenyl)-4-oxo-thiazolidin-2-ylidene]hydrazono]methyl]-1-methyl-N-[4-(trifluoromethoxy)phenyl]pyrazolo[3,4-b]pyridine-3-carboxamidine (C-27)
(58) A mixture of 1-(2-isopropylphenyl)-3-[(E)-[1-methyl-3-[N-[4-(trifluoromethoxy)phenyl] carbamimidoyl] pyrazolo[3,4-b]pyridin-6-yl]methyleneamino]thiourea (0.30 g), Sodium acetate (0.18 g) and Methyl bromo acetate (0.33 g) in Acetonitrile (6 mL) was stirred at ambient temperature for 48 h. The reaction mixture was subsequently diluted with water and extracted with EtOAc and the organic layer was dried over anhydrous Sodium sulphate and evaporated invacuo. The residue obtained was subjected to column chromatography over neutral alumina, eluting with a gradient of Dichloromethane and Methanol to obtain the title compound (0.170 g). HPLC/MS (method 1): Rt=1.91 min; m/z=595.10 (M+1).sup.+; .sup.1H NMR (300 MHz, DMSO-d6) δ 8.73 (d, J=8.4 Hz, 1H), 8.26 (s, 1H), 7.95 (d, J=8.5 Hz, 1H), 7.62-7.41 (m, 2H), 7.32 (q, J=7.8, 7.4 Hz, 4H), 7.07 (d, J=8.2 Hz, 2H), 6.51 (s, 2H), 4.44-4.13 (m, 5H), 2.88-2.67 (m, 1H), 1.16 (dd, J=12.2, 6.8 Hz, 6H).
Example C-28
Synthesis of 6-[(E)-[(2Z)-2-(2-isopropylphenyl)imino-4-oxo-thiazolidin-3-yl]iminomethyl]-N′-[4-(trifluoromethoxy)phenyl]-1,2-benzothiazole-3-carboxamidine (C-28)
(59) A mixture of 6-formyl-N′-[4-(trifluoromethoxy)phenyl]-1,2-benzothiazole-3-carboxamidine (0.200 g), (2E)-3-amino-2-(2-isopropylphenyl)imino-thiazolidin-4-one (0.164 g) in Acetic acid (3 mL) was stirred at ambient temperature for 2 h. Water (50 mL) was subsequently added. The mixture was extracted with EtOAc and the extracts was dried over anhydrous sodium sulphate and evaporated invacuo and the residue obtained was subjected to silica gel flash column chromatography, eluting with a gradient of EtOAc and Heptane to obtain the title compound as a solid (0.150 g) HPLC/MS (method 1) Rt: 2.36 min; m/z=596.8 (M).sup.+; .sup.1H NMR (300 MHz, DMSO-d6) δ 9.37 (s, 1H), 9.15 (d, J=8.7 Hz, 1H), 8.80 (s, 1H), 8.14-8.04 (m, 1H), 7.39-7.26 (m, 3H), 7.25-7.05 (m, 4H), 6.88 (dd, J=7.6, 1.6 Hz, 1H), 6.76 (s, 2H), 4.17 (s, 2H), 3.02 (p, J=6.8 Hz, 1H), 1.15 (d, J=6.9 Hz, 6H).
Example C-35
1-(2-isopropylphenyl)-2-methyl-3-[(E)-[1-methyl-3-[N-[4-(trifluoromethoxy)phenyl]carbamimidoyl]indazol-6-yl]methyleneamino]isothiourea (C-35)
(60) To a stirred solution of 1-(2-isopropylphenyl)-3-[(E)-[1-methyl-3-[N-[4-(trifluoromethoxy)phenyl]carbamimidoyl]indazol-6-yl]methyleneamino]thiourea (0.2 g) in ACN (3 mL) and THE (3 mL) mixture were added Sodium acetate (0.090 g) and Methyl iodide (0.044 mL) at room temperature then the mixture was stirred for 12 h. After completion of the reaction excess solvent was distilled out and the crude was dissolved in Ethyl acetate. The organic layers were washed with water and brine solution then dried over Sodium sulfate and concentrated under reduced pressure to get the crude product. The crude product was purified by column chromatography using Ethyl acetate and Heptane as eluent to get the title compound (0.09 g).
(61) HPLC/MS (method 1): Rt=4.893 min; m/z=568.4 (M+1).sup.+; .sup.1H NMR (300 MHz, DMSO-d6) δ 9.09 (s, 1H), 8.51 (s, 1H), 8.30 (d, J=8.3 Hz, 1H), 8.19 (d, J=5.1 Hz, 1H), 8.13-7.79 (m, 2H), 7.48-7.13 (m, 9H), 7.05 (d, J=8.3 Hz, 3H), 6.32 (s, 3H), 4.13 (d, J=14.4 Hz, 5H), 3.30-3.19 (m, 1H), 2.36 (s, 3H), 1.19 (t, J=7.4 Hz, 10H).
Example C-36
6-[(E)-[(Z)-[3-(2-isopropylphenyl)thiazolidin-2-ylidene]hydrazono]methyl]-1-methyl-N-[4-(trifluoromethoxy) phenyl]indazole-3-carboxamidine (C-36)
(62) To a stirred solution of 1-(2-isopropylphenyl)-3-[(E)-[1-methyl-3-[N-[4-(trifluoromethoxy)phenyl]carbamimidoyl]indazol-6-yl]methyleneamino]thiourea (0.2 g) in Acetone (5 mL) were added Potassium carbonate (0.250 g) and 1-Bromo-2-chloro ethane (0.130 g) at room temperature and the whole reaction mixture was heated at 70° C. for 12 h. After completion of the reaction, the reaction mixture was diluted with Ethyl acetate then washed with water and brine solution. The organic layers were dried over Sodium sulfate and concentrated under reduced pressure to get the crude product. The crude product was purified by column chromatography using Ethyl acetate and Heptane as eluent to get the title compound (0.140 g). HPLC/MS (method 1): Rt=5.028 min; m/z=580.1 (M+1).sup.+; .sup.1H NMR (300 MHz, DMSO-d6) δ 8.30 (d, J=8.5 Hz, 1H), 8.24 (s, 1H), 7.81 (s, 1H), 7.67 (d, J=8.6 Hz, 1H), 7.53-7.40 (m, 1H), 7.40-7.23 (m, 5H), 7.05 (d, J=8.4 Hz, 2H), 6.31 (s, 2H), 4.11 (s, 4H), 3.90 (dt, J=9.9, 5.7 Hz, 1H), 3.37 (d, J=7.1 Hz, 5H), 3.03 (p, J=6.9 Hz, 1H), 1.19 (t, J=6.7 Hz, 6H).
Example C-37
6-[(E)-[(Z)-[3-(2-isopropylphenyl)-1,3-thiazinan-2-ylidene]hydrazono]methyl]-1-methyl-N-[4-(trifluoromethoxy)phenyl]indazole-3-carboxamidine (C-37)
(63) To a stirred solution of 1-(2-isopropylphenyl)-3-[(E)-[1-methyl-3-[N-[4-(trifluoromethoxy)phenyl]Carbamimidoyl]indazol-6-yl]methyleneamino]thiourea (0.2 g) in 2-Butanone (5 mL) were added Potassium carbonate (0.125 g) and 1-Bromo-2-chloro ethane (0.068 g) at room temperature then the mixture was heated at 100° C. for 4 h. After completion of the reaction, the reaction mixture was diluted with Ethyl acetate then washed with water and brine solution. The organic layers were dried over Sodium sulfate and concentrated under reduced pressure to get the crude product. The crude product was purified by column chromatography using Ethyl acetate and Heptane as eluent to get the title compound (0.140 g). HPLC/MS (method 1): Rt=4.704 min; m/z=594.1 (M+1).sup.+; .sup.1H NMR (300 MHz, DMSO-d6) δ 8.26 (d, J=8.5 Hz, 1H), 8.04 (s, 1H), 7.77 (s, 1H), 7.64 (d, J=8.4 Hz, 1H), 7.44-7.18 (m, 6H), 7.04 (d, J=8.3 Hz, 2H), 6.29 (s, 2H), 4.08 (s, 3H), 3.72 (s, 1H), 3.51-3.39 (m, 1H), 3.19-2.84 (m, 3H), 2.24 (s, 2H), 1.29-1.11 (m, 8H).
Example C-38
1-(2-isopropylphenyl)-3-[(E)-[1-methyl-3-[[4-(trifluoromethoxy)benzenecarboximidoyl] amino]indazol-6-yl]methyleneamino]thiourea (C-38)
Step 1: N-(6-bromo-1-methyl-indazol-3-yl)-4-(trifluoromethoxy)benzamidine
(64) A suspension of methyl 4-(trifluoromethoxy)benzenecarboximidothioate hydroiodide (1.48 g), 6-bromo-1-methyl-indazol-3-amine (0.92 g) and Pyridine (0.82 mL) in THE (10 mL) was heated at 80° C. for 16 h. The reaction mixture was concentrated to dryness (2.3 g) and the crude product was used without further purification.
Step 2: N-[1-methyl-6-[(E)-prop-1-enyl]indazol-3-yl]-4-(trifluoromethoxy)benzamidine
(65) A solution of N-(6-bromo-1-methyl-indazol-3-yl)-4-(trifluoromethoxy)benzamidine (2.3 g), [(E)prop-1-enyl]boronic acid (0.72 g), [1,1′-Bis(diphenylphosphino)ferrocene]dichloropaladium(I) (0.203 g) and Potassium Carbonate (1.5 g) in DME/H.sub.2O (20:1, 20 mL) was heated at reflux for 16 h. The reaction mixture was concentrated to dryness then diluted with DCM and washed with brine solution, dried over Magnesium Sulfate, filtered and concentrated. Purification of the crude reaction mixture by silica gel chromatography using a gradient of EtOAc/cyclohexane afforded the title compound (534 mg). HPLC/MS (method 2): Rt=0.95 min; m/z=413 (M+).
Step 3: N-(6-formyl-1-methyl-indazol-3-yl)-4-(trifluoromethoxy)benzamidine
(66) To a stirred solution of N-[1-methyl-6-[(E)-prop-1-enyl]indazol-3-yl]-4-(trifluoromethoxy)benzamidine (0.534 g) in THF/H.sub.2O (1:1, 20 mL) was added Osmium tetroxide (2.5% solution in t-BuOH, 0.29 mL) then NalO4 (0.610 g). The reaction mixture was then stirred for 16 h and quenched with aqueous Sodium Sulfite (100 mL) and extracted with EtOAc. The organic phase was separated, dried over Magnesium Sulfate, filtered, concentrated to dryness (0.557 g) and used without further purification.
Step 4: 1-(2-isopropylphenyl)-3-[(E)-[1-methyl-3-[[4-(trifluoromethoxy)benzenecarboximidoyl]amino]indazol-6-yl]methyleneamino]thiourea
(67) A stirred solution of N-(6-formyl-1-methyl-indazol-3-yl)-4-(trifluoromethoxy)benzamidine (0.557 g) and 1-amino-3-(2-isopropylphenyl)thiourea (0.386 g) in EtOH (6 mL) was heated at 70° C. for 2 h. The resultant precipitate was isolated by filtration, washed with cold EtOH to afford the title compound (0.405 g). HPLC/MS (method 2): Rt=1.08 min; m/z=554 (M+1)+.
Example C-39
N-[6-[(E)-[(Z)-[3-(2-isopropylphenyl)-4-oxo-thiazolidin-2-ylidene]hydrazono]methyl]-1-methyl-indazol-3-yl]-4-(trifluoromethoxy)benzamidine (C-39)
(68) A stirred solution of 1-(2-isopropylphenyl)-3-[(E)-[1-methyl-3-[[4-(trifluoromethoxy) benzenecarboximidoyl]amino]indazol-6-yl]methyleneamino]thiourea (0.283 g), Methyl bromoacetate (0.16 g) and Sodium Acetate (0.17 g) in EtOH (5 mL) was heated at 50° C. for 16 h. The reaction mixture was concentrated to dryness and the resultant crude oil was purified by tituration with Acetonitrile to afford the title compound (0.313 g). HPLC/MS (method 1): RT=1.08 min; m/z=594 (M+1).sup.+. 1H NMR (400 MHz, THF-d8) δ 8.34 (s, 1H), 8.27-8.18 (m, 2H), 7.93 (d, J=8.6 Hz, 1H), 7.66-7.59 (m, 2H), 7.43 (ddd, J=17.9, 7.6, 1.5 Hz, 2H), 7.39-7.31 (m, 2H), 7.26 (td, J=7.5, 1.6 Hz, 1H), 7.15 (dd, J=7.8, 1.4 Hz, 1H), 4.10-3.94 (m, 5H), 3.57 (dq, J=2.2, 1.1 Hz, 9H), 2.87 (h, J=6.8 Hz, 1H), 2.49 (s, 5H), 1.72 (dtt, J=3.1, 2.1, 1.0 Hz, 12H), 1.20 (dd, J=10.3, 6.8 Hz, 6H).
(69) Examples listed in Table C were prepared by the procedure analogous to above example as or by derivatization thereof.
(70) ##STR00106##
(71) TABLE-US-00003 TABLE C No Ar—Q
BIOLOGICAL EXAMPLES
Example B1: Action on Yellow Fever Mosquito (Aedes aegypti)
(72) For evaluating control of yellow fever mosquito (Aedes aegypti) the test unit consisted of 96-well-microtiter plates containing 200 μl of tap water per well and 5-15 freshly hatched A. aegypti larvae.
(73) The active compounds or mixtures were formulated using a solution containing 75% (v/v) water and 25% (v/v) DMSO. Different concentrations of formulated compounds or mixtures were sprayed onto the insect diet at 2.5 μl, using a custom built micro atomizer, at two replications. For experimental mixtures in these tests identical volumes of both mixing partners at the desired concentrations respectively, were mixed together.
(74) After application, microtiter plates were incubated at 28±1° C., 80±5% RH for 2 days. Larval mortality was then visually assessed.
(75) In this test, compounds C-1, C-2, C-3, C-4, C-5, C-6, C-7, C-8, C-9, C-10, C-11, C-12, C-13, C-14, C-15, C-16, C-17, C-18, C-19, C-20, C-21, C-22, C-23, C-24, C-26, C-27, C-28, C-31, C32, C-33, C-34, C-35, C-36, C-37, C-38, C-39, C-45 and C-46 at 800 ppm showed at least 50% mortality in comparison with untreated controls.
Example B2: Action on Orchid Thrips (Dichromothrips corbetti)
(76) Dichromothrips corbetti adults used for bioassay were obtained from a colony maintained continuously under laboratory conditions. For testing purposes, the test compound is diluted in a 1:1 mixture of acetone:water (vol:vol), plus Kinetic® HV at a rate of 0.01% v/v.
(77) Thrips potency of each compound was evaluated by using a floral-immersion technique. All petals of individual, intact orchid flowers were dipped into treatment solution and allowed to dry in Petri dishes. Treated petals were placed into individual re-sealable plastic along with about 20 adult thrips. All test arenas were held under continuous light and a temperature of about 28° C. for duration of the assay. After 3 days, the numbers of live thrips were counted on each petal. The percent mortality was recorded 72 hours after treatment.
(78) In this test, compounds C-1, C-2, C-3, C-4, C-5, C-6, C-11, C-15, C-19, C-20, C-21, C-22, C23, C-26, C-27, C-28, C-29, C-30, C-31, C-32, C-33, C-34, C-35, C-36, C-37, C-38, C-39, C-42, C-43, C-44 and C-46 at 500 ppm showed at least 75% mortality in comparison with untreated controls.
Example B3: Action on Boll Weevil (Anthonomus grandis)
(79) For evaluating control of boll weevil (Anthonomus grandis) the test unit consisted of 96-well-microtiter plates containing an insect diet and 5-10 A. grandis eggs.
(80) The compounds were formulated using a solution containing 75% (v/v) water and 25% (v/v) DMSO. Different concentrations of formulated compounds were sprayed onto the insect diet at 5 μl, using a custom built micro atomizer, at two replications.
(81) After application, microtiter plates were incubated at about 25+1° C. and about 75+5% relative humidity for 5 days. Egg and larval mortality was then visually assessed.
(82) In this test, compounds C-1, C-2, C-3, C-4, C-5, C-6, C-7, C-8, C-9, C-10, C-11, C-12, C-13, C-14, C-15, C-16, C-17, C-18, C-19, C-20, C-21, C-22, C-23, C-26, C-27, C-28, C-31, C-32, C33, C-34, C-35, C-36, C-37, C-38, C-39, C-45 and C-46 at 800 ppm showed at least 75% mortality in comparison with untreated controls.
Example B4: Action on Silverleaf Whitefly (Bemisia argentifoli) (Adults)
(83) The active compounds were formulated by a Tecan liquid handler in 100% cyclohexanone as a 10,000 ppm solution supplied in tubes. The 10,000 ppm solution was serially diluted in 100% cyclohexanone to make interim solutions. These served as stock solutions for which final dilutions were made by the Tecan in 50% acetone:50% water (v/v) into 5 or 10 ml glass vials. A nonionic surfactant (Kinetic®) was included in the solution at a volume of 0.01% (v/v). The vials were then inserted into an automated electrostatic sprayer equipped with an atomizing nozzle for application to plants/insects.
(84) Cotton plants at the cotyledon stage (one plant per pot) were sprayed by an automated electrostatic plant sprayer equipped with an atomizing spray nozzle. The plants were dried in the sprayer fume hood and then removed from the sprayer. Each pot was placed into a plastic cup and about 10 to 12 whitefly adults (approximately 3-5 days old) were introduced. The insects were collected using an aspirator and a nontoxic Tygon® tubing connected to a barrier pipette tip. The tip, containing the collected insects, was then gently inserted into the soil containing the treated plant, allowing insects to crawl out of the tip to reach the foliage for feeding. Cups were covered with a reusable screened lid. Test plants were maintained in a growth room at about 25° C. and about 20-40% relative humidity for 3 days, avoiding direct exposure to fluorescent light (24 hour photoperiod) to prevent trapping of heat inside the cup. Mortality was assessed 3 days after treatment, compared to untreated control plants.
(85) In this test, compounds C-1, C-2, C-4, C-22, C-23, C-28, C-30, C-31, C-32, C-33, C-35, C-38, C-39 and C-44 at 300 ppm showed at least 75% mortality in comparison with untreated controls.
Example B5: Action on Tobacco Budworm (Heliothis virescens)
(86) For evaluating control of tobacco budworm (Heliothis virescens) the test unit consisted of 96-well-microtiter plates containing an insect diet and 15-25 H. virescens eggs.
(87) The compounds were formulated using a solution containing 75% v/v water and 25% v/v DMSO. Different concentrations of formulated compounds were sprayed onto the insect diet at 10 μl, using a custom built micro atomizer, at two replications.
(88) After application, microtiter plates were incubated at about 28+1° C. and about 80+5% relative humidity for 5 days. Egg and larval mortality was then visually assessed.
(89) In this test, compounds C-1, C-2, C-3, C-4, C-5, C-6, C-7, C-8, C-11, C-12, C-13, C-14, C-15, C-16, C-17, C-18, C-19, C-20, C-21, C-22, C-23, C-24, C-25, C-26, C-27, C-28, C-31, C-32, C33, C-34, C-35, C-36, C-37, C-38, C-39, C-45 and C-46 at 800 ppm showed at least 75% mortality in comparison with untreated controls.
Example B6: Action on Diamond Back Moth (Plutella xylostella)
(90) The active compound is dissolved at the desired concentration in a mixture of 1:1 (v/v) distilled water:acetone. Surfactant (Kinetic® HV) is added at a rate of 0.01% (v/v). The test solution is prepared at the day of use.
(91) Leaves of cabbage were dipped in test solution and air-dried. Treated leaves were placed in petri dishes lined with moist filter paper and inoculated with ten 3rd instar larvae. Mortality was recorded 72 hours after treatment. Feeding damages were also recorded using a scale of 0-100%.
(92) In this test, compounds C-1, C-2, C-3, C-4, C-5, C-6, C-7, C-8, C-10, C-11, C-12, C-13, C-14, C-15, C-17, C-18, C-19, C-20, C-21, C-22, C-23, C-24, C-25, C-26, C-27, C-28, C-29, C-30, C31, C-32, C-33, C-34, C-35, C-36, C-37, C-38, C-39, C-42, C-43, C-44, C-45 and C-46 at 500 ppm showed at least 75% mortality in comparison with untreated controls.
Example B7: Action on Southern Armyworm (Spodoptera eridania), 2nd Instar Larvae
(93) The active compounds were formulated by a Tecan liquid handler in 100% cyclohexanone as a 10,000 ppm solution supplied in tubes. The 10,000 ppm solution was serially diluted in 100% cyclohexanone to make interim solutions. These served as stock solutions for which final dilutions were made by the Tecan in 50% acetone:50% water (v/v) into 10 or 20 ml glass vials. A nonionic surfactant (Kinetic®) was included in the solution at a volume of 0.01% (v/v). The vials were then inserted into an automated electrostatic sprayer equipped with an atomizing nozzle for application to plants/insects.
(94) Lima bean plants (variety Sieva) were grown 2 plants to a pot and selected for treatment at the 1st true leaf stage. Test solutions were sprayed onto the foliage by an automated electrostatic plant sprayer equipped with an atomizing spray nozzle. The plants were dried in the sprayer fume hood and then removed from the sprayer. Each pot was placed into perforated plastic bags with a zip closure. About 10 to 11 armyworm larvae were placed into the bag and the bags zipped closed. Test plants were maintained in a growth room at about 25° C. and about 20-40% relative humidity for 4 days, avoiding direct exposure to fluorescent light (24 hour photoperiod) to prevent trapping of heat inside the bags. Mortality and reduced feeding were assessed 4 days after treatment, compared to untreated control plants.
(95) In this test, compounds C-1, C-2, C-5, C-6, C-7, C-8, C-10, C-11, C-12, C-13, C-14, C-15, C16, C-17, C-18, C-19, C-21, C-22, C-23, C-26, C-27, C-28, C-29, C-30, C-31, C-32, C-33, C-34, C-35, C-38, C-39, C-44 and C-45 at 300 ppm showed at least 75% mortality in comparison with untreated controls.