CA2189573A1 - N-(5-isothiazolyl)amide pesticides - Google Patents
N-(5-isothiazolyl)amide pesticidesInfo
- Publication number
- CA2189573A1 CA2189573A1 CA 2189573 CA2189573A CA2189573A1 CA 2189573 A1 CA2189573 A1 CA 2189573A1 CA 2189573 CA2189573 CA 2189573 CA 2189573 A CA2189573 A CA 2189573A CA 2189573 A1 CA2189573 A1 CA 2189573A1
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- Canada
- Prior art keywords
- alkyl
- halo
- substituted
- phenyl
- formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
- C07D275/02—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings not condensed with other rings
- C07D275/03—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
- A01N43/80—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Dentistry (AREA)
- Pest Control & Pesticides (AREA)
- Plant Pathology (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Agronomy & Crop Science (AREA)
- General Health & Medical Sciences (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- Environmental Sciences (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
Abstract
This invention relates to novel N-(5-isothinzolyl)amide compounds of formula (1, 2, or 3), and compositions useful as nematicides, insecticides, miticides, and plant fungicides. The present invention also provides nematicidal, insecticidal, miticidal, and fungicidal methods.
Description
p I r~
wo ssBI448 ~ 2 ~ 8 9 5 7 3 1 ~l"~Jn~ -~07 N--( 5--ISO~TT~ T YT )AMIDE PESTICIDES
Field of the Invention This invention relates to novel N- ~ 5-iso~h; A7~1 yl ) amide ~ , _ ' useful as nematicides, 5 insecticides, miticides, and plant flln~ici~ c. The present invention also provides nematicidal, insecticidal, miticidal, and fungicidal methods.
There is an acute need for new nematicides, insecticides, miticides, and plant fungicides.
10 Available nematicides typically have high -1 iAn toxicity and must be used at high rates. A nematicide that can be applied at lower rates and that has lower l iAn toxicity would L~ ~,r~senL a Si~nifjt-Ant advance .
Mites and insects are developing resictance to the miticides and insecticides in current use. Resistance to insecticides in anthropods is widespread, with at least 400 species resistant to one or more insecticides. The dev~lt ,~ L of resistance to some of ~0 the older insecticides, such as DDT, the I-Arh -, and the t,LJ~ t~fiphAtes is well knt~wn. But re~i~tance has even developed to some of the newer pyrethroid insecticides and miticides. Similarly, target pathogens are rapidly developing resistance to 25 currently used fungicides. At least 50 species of fungi have developed resist~nce to the ~C~n7imi~ ol~
flln7ici~s Even recently introduced flln~it-;rl~c, like the aCylA1Anin~c~ which initially exhibited ~Y-ell~nt control of potato late blight and grape downy mildew in 30 the field, have become less effective ~ecause of resistance. Therefore a need exists for new insecticides, miticides, and flln~;t i~i~c~ and wo 95/31448 ~ 2 1 8 9 5 7 3 ~ J~. ' ~o7 particularly for ~ ollnrl~ that have new or atypica modes of action.
Summary of the Invention This invention provides c~ represented by Formula (l) r (2) r and (3) r below:
--~N--C--y _Z~ R _~_N=C ~?CN--C--Y--Z
(1) (2) (3) wherein:
R and Rl are each ;n~lPL~ Lly inr;r~rr~n~lr~n~ly H, 0 (Cl-C4) alkyl~ (Cl-C4) alkyl optionally substituted with CH2CH(OCH3)2, halo~ (Cl-C4) alkoxy, or (CH2)n~ wherein i~ is O or NRl and n is an integer 1-4; halo(cl-c4)alkyl; deuterio (Cl-C4) alkyl; (Cl-C4) acyl; (Cl-C4) alkyl-CO2-E. wherein E is H, (Cl-C4) alkyl, or a cation, such as, for example, sodium~
potassium~ or i ; trifluoroacetyl; alkoxymethyl;
~ydlv.~ ~hyl; ~ormyl; (R2)2NS(O)X; benzyl; or benzy optionally substituted with ~Cl-C4) alkyl~ (Cl-C4) alkoxy~ halo, halo (Cl-C4) alkyl;
Each R2 is i nrir~rr~nri ~,ntly lower alkyl, aryl, or together form with nitrogen a s~Lu~c-Led (C3-C7) ring such as morpholino~ piperidinyl~ pyrrolidinyl;
x is an integer from o to 2;
R3 and R4 are each in~-~p~nrlr~ntly H, (Cl-C4) alkyl~
25 halogen I, (Cl-C4) alkoxy, halo (Cl-C4) alkoxy~ (Cl-C4 W09S131448 `' '' 2~89573 r~ 07 ! ~
c;lrho-lkrxy, halo (Cl-C4) alkyl, or together form a saturated or unsaturated six membered carbon ring;
Y-Z together form a (C2-Cl1) saturated or unsaturated hydrocarbon chain, straight chain or 5 bL~ ed, optionally ;n~ Ain~ a hetero atom selected from O, NR5, S, SO, SO2, or SiR6R7, and optionally substituted with one or more groups in~l~pPn~ipntly selected from (C1-C4) alkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, branched (C3-C7) alkyl, (C3-C7) cycloalkyl, 10 (C3-C7) cy~lnalkPnyl, halo, halo (C1-C4) alkyl, halo (C1-C4) alkoxy, hydroxy, or (C1-C4) acyl;
R5 is H, (Cl-C4) alkyl, or (C1-C4) acyl;
R6 and R7 are ;n~ l,ly (Cl-C4) alkyl, (C3-C4) branched alkyl, phenyl, or substituted phenyl; or Y iB a bond, CHD, CD2, C=O, or a bivalent hydrocarbon radical one to f ive carbon atoms long, optionally substituted with (C1-C4) alkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, branched (C3-C7) alkyl, (C3-C7) cycloalkyl, (C3-C7) cy~ A1kPnyl, halo, halo (Cl-C4) alkyl, halo (C1-C4) alkoxy, hydroxy, CN, (C1-C4) acyl, (Cl-C4) alkoxycarbonyl, aryloxycarbonyl, hydroxy (C1-C4) alkyl, (C1-C4) alkoxy (Cl-C4) alkyl, methylene, methylene optionally substituted with one or more groups in~lppen~lpnt3y selected from llydl~ly6l-; (Cl-C4) alkyl; (C1-C4) alkoxy; SH; S-lower alkyl; NH2; NH-lower alkyl or N,N-di-lower alkyl, optionally substituted with carboxy, c-qrho~1 knYy, or carboaryloxy; NHOE; NHO-lower alkyl; N-lower alkyl-OH; N-lower alkyl-lower alkl; O-lower alkyl; OH; morpholino; ~irPri~inyl;
pyrrolidinyl; ~hi~ - yl~olino; or methylene forming part of a (Cs-C6) saturated or uns~LuL..~ed ring optionally WO95/31448 ~ ?~S '2189573 r~ o7 . .
including 1 or 2 hetero atoms selected from o, S, or N~S;
Z i8 (a) aryl or S (b) (C3-C8) cycloalkyl or cycloalkenyl, optionally substituted with one or more groups ;n~ L.~ r~ Lly selected from (C1-C4) alkyl, (C1-C4) alkoxy, halo (C1-C4) alkyl, halo (C1-C4) alkoxy, halo, hydroxy, or (C1-C4 ) acyl; where aryl is (a) a phenyl group optionally substituted with one or more groups ;n~lr~ nrlr~ ly selected from:
halo, I, (C3-C8 ) cycloalkyl, (C3-C8) cycloalkenyl, phenoxy, substituted phenoxy, phenylthio, substituted phenylthio, phenyl, substituted phenyl, NO2, o --C--R8, where R8 is (C1-C7) alkyl, halo (C1-C7) alkyl, (C3-C7) branched alkyl, halo (C3-C7~
branched alkyl, (C3-C7) cycloalkyl, halo (C3-C7) cycloalkyl, (Cl-C7) alkoxy, hydroxy, phenyl, substituted phenyl, phenoxy, or substituted phenoxy, WO95131448 , ~ ~ r ~ t c r ~
;~` ?l 89s73 --c-c--R8, wherein R8 cannot be hydroxy, OH, CN, SiR9R10R11 or OSiR9R10R11, where R9,R10 and R11 are in~ n~ly ~C1-C4) alkyl, (C3-C4) branched alkyl, phenyl, or substituted phenyl, NR12R13, where R12 and R13 are; nr~r~rr~nrlr~ntly H, (C1_CQ) alkyl, or (C1-C4) acyl, S(o)R14, So2R14, or oSo2Rl4~ where R14 is (cl-clo) alkyl, phenyl, or substituted phenyl;
a (C1-C12)saturated or unsa~uLdl_~d hydrocarbon chain, straight chain or branched optionally ;nr~ rl;n~ a hetero atc~n selected from O, 5, 50, 52, NRS, or siR6R7, where R5, R6 and R7 are as defined above, and op~ionally substituted with halo, halo (C1-C4) alkoxy, hydroxy, (C3-C8) cycloalkyl or cycloalkenyl, (C1-C4) acyl, phenoxy, substituted phenoxy, phenyl, substituted phenyl, phenylthio, substituted phenylthio, or cyano;
(C1-C7) alkoxy optionally substituted with halo, phenyl, substituted phenyl, (C3-C8) cycloalkyl or cyr l~lk~nylr phenoxy, or substituted phenoxy; or (C1-C7) alkylthio optionally substituted with halo, phenyl, substituted phenyl, (C3-C8) cycloalkyl or cycloalkenyl, phenoxy or substituted phenoxy;
WO95/31448 ;~ S 2 1 89573 P~ ,5. ~07 .
(b) a furyl group of formula (3) ~R
O (3) where Rl5 iB H, halo, halomethyl, CN, NO2, (Cl-C4) alkyl, (C3-C4) hr~n~h~d alkyl, phenyl, (Cl-C4) alkoxy;
(c) a thienyl group of the formula (4) S (4) where R16 is H, halo, halomethyl, CN, N02, (Cl-C4) alkyl, (C3-C4) branched alkyl, phenyl, (Cl-C4) alkoxy, or thienyl;
(d) a group of formula (5) or (6) --~--R1s --~ --R1s G (5:~ G~ (6~
where R1s is as defined in paragraph (b), J is N or CH, and G i~ O, NR17, or S, provided that if J is not N
then G is NR, where R17 is H, (C1-C4) alkyl, (C1-C4) 15 acyl, phenylsul~onyl, or substituted phenylsulfonyl;
(e) a group selected fror~
optionally substituted naphthyl, dihydronaphthyl, tetrahydronaphthyl, and decahydronaphthyl;
optionally substituted indolyl;
1, 3 _~n~ l; oY~1 yl;
wo ssBI448 ~ 2 ~ 8 9 5 7 3 1 ~l"~Jn~ -~07 N--( 5--ISO~TT~ T YT )AMIDE PESTICIDES
Field of the Invention This invention relates to novel N- ~ 5-iso~h; A7~1 yl ) amide ~ , _ ' useful as nematicides, 5 insecticides, miticides, and plant flln~ici~ c. The present invention also provides nematicidal, insecticidal, miticidal, and fungicidal methods.
There is an acute need for new nematicides, insecticides, miticides, and plant fungicides.
10 Available nematicides typically have high -1 iAn toxicity and must be used at high rates. A nematicide that can be applied at lower rates and that has lower l iAn toxicity would L~ ~,r~senL a Si~nifjt-Ant advance .
Mites and insects are developing resictance to the miticides and insecticides in current use. Resistance to insecticides in anthropods is widespread, with at least 400 species resistant to one or more insecticides. The dev~lt ,~ L of resistance to some of ~0 the older insecticides, such as DDT, the I-Arh -, and the t,LJ~ t~fiphAtes is well knt~wn. But re~i~tance has even developed to some of the newer pyrethroid insecticides and miticides. Similarly, target pathogens are rapidly developing resistance to 25 currently used fungicides. At least 50 species of fungi have developed resist~nce to the ~C~n7imi~ ol~
flln7ici~s Even recently introduced flln~it-;rl~c, like the aCylA1Anin~c~ which initially exhibited ~Y-ell~nt control of potato late blight and grape downy mildew in 30 the field, have become less effective ~ecause of resistance. Therefore a need exists for new insecticides, miticides, and flln~;t i~i~c~ and wo 95/31448 ~ 2 1 8 9 5 7 3 ~ J~. ' ~o7 particularly for ~ ollnrl~ that have new or atypica modes of action.
Summary of the Invention This invention provides c~ represented by Formula (l) r (2) r and (3) r below:
--~N--C--y _Z~ R _~_N=C ~?CN--C--Y--Z
(1) (2) (3) wherein:
R and Rl are each ;n~lPL~ Lly inr;r~rr~n~lr~n~ly H, 0 (Cl-C4) alkyl~ (Cl-C4) alkyl optionally substituted with CH2CH(OCH3)2, halo~ (Cl-C4) alkoxy, or (CH2)n~ wherein i~ is O or NRl and n is an integer 1-4; halo(cl-c4)alkyl; deuterio (Cl-C4) alkyl; (Cl-C4) acyl; (Cl-C4) alkyl-CO2-E. wherein E is H, (Cl-C4) alkyl, or a cation, such as, for example, sodium~
potassium~ or i ; trifluoroacetyl; alkoxymethyl;
~ydlv.~ ~hyl; ~ormyl; (R2)2NS(O)X; benzyl; or benzy optionally substituted with ~Cl-C4) alkyl~ (Cl-C4) alkoxy~ halo, halo (Cl-C4) alkyl;
Each R2 is i nrir~rr~nri ~,ntly lower alkyl, aryl, or together form with nitrogen a s~Lu~c-Led (C3-C7) ring such as morpholino~ piperidinyl~ pyrrolidinyl;
x is an integer from o to 2;
R3 and R4 are each in~-~p~nrlr~ntly H, (Cl-C4) alkyl~
25 halogen I, (Cl-C4) alkoxy, halo (Cl-C4) alkoxy~ (Cl-C4 W09S131448 `' '' 2~89573 r~ 07 ! ~
c;lrho-lkrxy, halo (Cl-C4) alkyl, or together form a saturated or unsaturated six membered carbon ring;
Y-Z together form a (C2-Cl1) saturated or unsaturated hydrocarbon chain, straight chain or 5 bL~ ed, optionally ;n~ Ain~ a hetero atom selected from O, NR5, S, SO, SO2, or SiR6R7, and optionally substituted with one or more groups in~l~pPn~ipntly selected from (C1-C4) alkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, branched (C3-C7) alkyl, (C3-C7) cycloalkyl, 10 (C3-C7) cy~lnalkPnyl, halo, halo (C1-C4) alkyl, halo (C1-C4) alkoxy, hydroxy, or (C1-C4) acyl;
R5 is H, (Cl-C4) alkyl, or (C1-C4) acyl;
R6 and R7 are ;n~ l,ly (Cl-C4) alkyl, (C3-C4) branched alkyl, phenyl, or substituted phenyl; or Y iB a bond, CHD, CD2, C=O, or a bivalent hydrocarbon radical one to f ive carbon atoms long, optionally substituted with (C1-C4) alkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, branched (C3-C7) alkyl, (C3-C7) cycloalkyl, (C3-C7) cy~ A1kPnyl, halo, halo (Cl-C4) alkyl, halo (C1-C4) alkoxy, hydroxy, CN, (C1-C4) acyl, (Cl-C4) alkoxycarbonyl, aryloxycarbonyl, hydroxy (C1-C4) alkyl, (C1-C4) alkoxy (Cl-C4) alkyl, methylene, methylene optionally substituted with one or more groups in~lppen~lpnt3y selected from llydl~ly6l-; (Cl-C4) alkyl; (C1-C4) alkoxy; SH; S-lower alkyl; NH2; NH-lower alkyl or N,N-di-lower alkyl, optionally substituted with carboxy, c-qrho~1 knYy, or carboaryloxy; NHOE; NHO-lower alkyl; N-lower alkyl-OH; N-lower alkyl-lower alkl; O-lower alkyl; OH; morpholino; ~irPri~inyl;
pyrrolidinyl; ~hi~ - yl~olino; or methylene forming part of a (Cs-C6) saturated or uns~LuL..~ed ring optionally WO95/31448 ~ ?~S '2189573 r~ o7 . .
including 1 or 2 hetero atoms selected from o, S, or N~S;
Z i8 (a) aryl or S (b) (C3-C8) cycloalkyl or cycloalkenyl, optionally substituted with one or more groups ;n~ L.~ r~ Lly selected from (C1-C4) alkyl, (C1-C4) alkoxy, halo (C1-C4) alkyl, halo (C1-C4) alkoxy, halo, hydroxy, or (C1-C4 ) acyl; where aryl is (a) a phenyl group optionally substituted with one or more groups ;n~lr~ nrlr~ ly selected from:
halo, I, (C3-C8 ) cycloalkyl, (C3-C8) cycloalkenyl, phenoxy, substituted phenoxy, phenylthio, substituted phenylthio, phenyl, substituted phenyl, NO2, o --C--R8, where R8 is (C1-C7) alkyl, halo (C1-C7) alkyl, (C3-C7) branched alkyl, halo (C3-C7~
branched alkyl, (C3-C7) cycloalkyl, halo (C3-C7) cycloalkyl, (Cl-C7) alkoxy, hydroxy, phenyl, substituted phenyl, phenoxy, or substituted phenoxy, WO95131448 , ~ ~ r ~ t c r ~
;~` ?l 89s73 --c-c--R8, wherein R8 cannot be hydroxy, OH, CN, SiR9R10R11 or OSiR9R10R11, where R9,R10 and R11 are in~ n~ly ~C1-C4) alkyl, (C3-C4) branched alkyl, phenyl, or substituted phenyl, NR12R13, where R12 and R13 are; nr~r~rr~nrlr~ntly H, (C1_CQ) alkyl, or (C1-C4) acyl, S(o)R14, So2R14, or oSo2Rl4~ where R14 is (cl-clo) alkyl, phenyl, or substituted phenyl;
a (C1-C12)saturated or unsa~uLdl_~d hydrocarbon chain, straight chain or branched optionally ;nr~ rl;n~ a hetero atc~n selected from O, 5, 50, 52, NRS, or siR6R7, where R5, R6 and R7 are as defined above, and op~ionally substituted with halo, halo (C1-C4) alkoxy, hydroxy, (C3-C8) cycloalkyl or cycloalkenyl, (C1-C4) acyl, phenoxy, substituted phenoxy, phenyl, substituted phenyl, phenylthio, substituted phenylthio, or cyano;
(C1-C7) alkoxy optionally substituted with halo, phenyl, substituted phenyl, (C3-C8) cycloalkyl or cyr l~lk~nylr phenoxy, or substituted phenoxy; or (C1-C7) alkylthio optionally substituted with halo, phenyl, substituted phenyl, (C3-C8) cycloalkyl or cycloalkenyl, phenoxy or substituted phenoxy;
WO95/31448 ;~ S 2 1 89573 P~ ,5. ~07 .
(b) a furyl group of formula (3) ~R
O (3) where Rl5 iB H, halo, halomethyl, CN, NO2, (Cl-C4) alkyl, (C3-C4) hr~n~h~d alkyl, phenyl, (Cl-C4) alkoxy;
(c) a thienyl group of the formula (4) S (4) where R16 is H, halo, halomethyl, CN, N02, (Cl-C4) alkyl, (C3-C4) branched alkyl, phenyl, (Cl-C4) alkoxy, or thienyl;
(d) a group of formula (5) or (6) --~--R1s --~ --R1s G (5:~ G~ (6~
where R1s is as defined in paragraph (b), J is N or CH, and G i~ O, NR17, or S, provided that if J is not N
then G is NR, where R17 is H, (C1-C4) alkyl, (C1-C4) 15 acyl, phenylsul~onyl, or substituted phenylsulfonyl;
(e) a group selected fror~
optionally substituted naphthyl, dihydronaphthyl, tetrahydronaphthyl, and decahydronaphthyl;
optionally substituted indolyl;
1, 3 _~n~ l; oY~1 yl;
2, 6-dimethyl q Tr yholinyl; and l-adamantyl;
WO95/31448 " '~ 9 57 3 r -~u~ ~07 ( f ~ a group of the formula R2 m ~o-llet wherein m is 4; R20 are ;nARp~-nA~ntly H, halo, lower alkyl, lower alkoxy, haloalkyl, h~ Alk~yy~ N02, CN, 5 lower alkyl carbonyl, phenoxy, or substituted phenoxy, provided that at least two Of R20 are selected from H
and F; and Het is pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl, optionally substituted with one or more groups selected from halo, lower alkyl, lower alkoxy, 10 haloalkyl, h:llo~lk~yy, N02, CN, and lower alkyl carbonyl;
(g) a group of the formula A
x2--x~
wherein one of X2 and X3 i6 N and the other is CR23;
lS R2l is -T-R22, phenyl, substituted phenyl, ~Cl-C1o) alkyl, halo, or halo (Cl-Cg) alkyl, where T is O or S, and R22 is (Cl-C4) alkyl, (C3-C7) branched alkyl, halo (Cl-C7) alkyl, halo (C3-C7) b-c-ncl~ed alkyl, (Cl-C4) 20 alkoxy (C1-C4) alkyl, or naphthyl or phenyl, either of which may be optionally substituted with up to three groups selected from halo, (cl-clo) alkyl, branched (C3-C7) alkyl, halo (C1-C7) alkyl, hydroxy (C1-C7) alkyl, (C1-C4) alkoxy, halo (C1-C4) alkoxy, phenoxy, 25 substituted phenoxy, phenyl, substituted phenyl, CN, NO2, OH, (C1-C4) alkanoyloxy, or benzyloxy;
W095131448 ~ ~189573 ~ '~' R23 is:
~, halo, (C3-C8) cycloalkyl, ( C3--Cg ) cyr 1OA 1 k-~ny1, phenoxy, substituted phenoxy, phenylthio, substituted phenylthio, phenyl, substituted phenyl, N02, --C--R8 where R8 is (Cl-C7) alkyl, halo (Cl-C7) alkyl, (C3-C7) branched alkyl, halo (C3-C7) branched alkyl, (C3-C7) cycloalkyl, halo (C3-C7) cycloalkyl, (Cl-C7~ alkoxy, phenyl, substituted phenyl, or hydroxy, acetoxy, O~, CN, SiR9RlORll or OsiR9RloRll~ where R9,R10 and are ;n~lPIPI~r~ ly (Cl-C4) alkyl, (C3-C4) bLClLl~ lled alkyl, phenyl, or substituted phenyl, NR12R13, where R12 and R13 are in~lrrr~n,ir~ntly ~, ~Cl-C4) alkyl, or (Cl-C4) acyl, s(o)R14, or So2R14, where R14 is (Cl-C10) alkyl, phenyl, or substituted phenyl;
wog~/31 ~ 9~73 a (C~-C12) saturated or unsaturated hydrocarbon chain, straight chain or branched optionally ;n~ 8;ng a hetero atom selected from 0, S, SO, S02, NRS, or SiR6R7, where R5, R6 and R7 are as defined above, and optionally substituted with halo, halo (Cl-C4 ) alkoxy, hydroxy, (C3-C8 ) cycloalkyl or cycloalkenyl, (C1-C4) acyl, phenoxy, substituted phenoxy, phenyl, substituted phenyl, phenylthio, substituted phenylthio, or cyano;
(Cl-C7) alkoxy optionally substituted with halo, phenyl, substituted phenyl, (C3-C8) cycloalkyl or cycloalkenyl, phenoxy, or substituted phenoxy; or (C1-C7) alkylthio optionally substituted with halo, phenyl, substituted phenyl, (C3-C8) cycloalkyl or cyr~o~lk~nyl~ phenoxy or substituted phenoxy .
W is O, S(O)y~ wherein y is an integer from O to 2, or NR24;
G is (Cl-C4) alkyl, aryl, (Cl-C4) acyl, NR25R26, deuterio (Cl-C4) alkyl, halo (Cl-C4) alkyl, benzyl, or benzyl optionally substituted with (Cl-C4) alkyl, (Cl-C4) alkoxy, halo, halo (Cl-C4) alkyl; or W-G together are halo, SH, or NR25R26;
R24 is H, OH, (C1-C4) alkyl, (Cl-C4) alkoxy, aryl, (Cl-C4) acyl, NR25R26, benzyl, or benzyl optionally substituted with (Cl-C4) alkyl, (Cl-C4) alkoxy, halo, halo (C1-C4) alkyl; and R25 and R26 are ;nrl.oron-lontly H, (Cl-C4) alkyl, 30 aryl, acyl, or together form with nitrogen a s~LuLc.~ed _ g _ W g5/3 448 2 ~ , r-~o o ~ 1 8 9 5 7 3 (C3-C7) ring such as morpholino, piperidinyl, pyrrolidinyl The invention al~o provides a method of inhibiting a nematode population which comprises applying to the 5 locus of a - ~ode, a r -~ode inactivating amount of a compound of the Formula (1), (2), or (3) as defined above The invention also provides a method of inhibiting ~n insect or mite population which comprise~ applying 10 to the locus of the insect or arachnid an effective insect or mite inactivating amount of a ~ ~; of Formula (1), (2), or (3) The invention also provides a method of inhibiting plant pathogens which comprises applying an effective 15 amount of a compound of Formula ( 1 ), ( 2 ), or ( 3 ) to a locus of the pathogen WOgS/31448 ~ i 2~ 8q573 .~ 07 Det~i 1 r~ Description of the Invention Unless otherwise indicated, the terms below are defined as follows:
The term "halo" or "haloqen" refers to a F, Cl, or 5 Br ~tom.
The terms " alkyl ", " alkoxy ", " acyl ", " haloal kyl, ~hAlo~lk~xy", ~alkylsulfinyl", and "alkylsulfonyl"
refer to straight chain and branched chain groups.
The terms "aryl", "Ar", "substituted phenyl", 10 "substituted phenoxy", "substituted phenylthio", and ~substituted phenylsulfonyl" refer to such groups wherein the phenyl ring is substituted with up to three groups in~l-L~ r~, Lly selected from halo, I, (Cl-Clo) alkyl, branched (C3-C6) alkyl, halo (Cl-C7l alkyl, 15 hydroxy (Cl-C7) alkyl, (Cl-C7) alkoxy, halo (C1-C7) alkoxy, phenoxy, substituted phenoxy, phenyl, substituted phenyl, NO2, OH, CN, (C1-C4) alkanoyl, benzoyl, (C1-C4) alkanoyloxy, or benzoyloxy.
The terms "substituted naphthyl" and "substituted 20 indolyl" refQr to these ring systems substituted with one or more groups in~lrrDnrlDntly selected from halo, halo (C1-C4) alkyl, CN, NO2, (C1-C4) alkyl, (C3-C4) branched alkyl, phenyl, (C1-C4) alkoxy, or halo (C1-C4) alkoxy .
Z5 The term "carbocyclic ring" refers to a saLu ~Led or unsaturated carbocyclic ring containing five or six carbon atoms.
The term Runsaturated hydrocarbon chain" refers to a hydrocarbon chain containing one or more sites of unsaturation.
W095MI448 ~ - 2`1 ~9573 I~~ 07 The term "~PLC" refers to a high pressure li~uid (;l1LI , ~YI1Y .
The term "TLC" refers to thin layer LOylaphy.
The term "bivalent hydrocarbon radical" refers to bivalent radicals derived from normal alkanes by removal of llyd.vy 1l atoms from each of the two terminal carbon atoms of the chain, e.g. methylene, ethylene, trimethylene, tetramethylene, etc.
lo The term ~substituted amino" refers to an amino group that is substituted with one or two (Cl-C4) alkyl groups or one (Cl-C4) alkanoyl group.
The term "lower alkyl" refers to (Cl-C6) straight hydrocarbon chains and (C3-C6) bl~lnu1,ed and cyclic 15 hydrocarbon groups.
The terms " lower alkenyl " and " lower alkynyl "
refer to (C2-C6) straight IIYdLUI;O~LbV11 chains and (C3-C6) branched hydLu~ bull groups cr~ntAinin~ at least one unsaturated bond.
The terms "lower alko~cy" and "lower alkylthio"
refer to O-lower alkyl and S-lower alkyl groups.
The term "haloalkyl" refers to lc~wer alkyl groups substituted with one or more halo atoms.
The term ''deut~ri~Alkyl~ refers to lower alkyl groups substituted with one or more deuterium atoms.
The term "methylene" refer5 to =CE~2-Unless otherwise indicated, when it is stated that a group may be substituted with one or more WOg~/31448 ~ ~ _ p O r ~ 21 8 9 5 73 p~""~ c~-~07 substituents sDlQrteA from an identified class, it is intended that the substituents may be in~ ,Lly selected from the class. Throughout this ~ , all t~ ,~ dLUL~:S are given in degrees Celcius, and all 5 percQntA~QQ are weight percentages unless otherwise st~ted.
Preferred r ~
Preferred _ , ol~n~lc of Formula ( 1 ), ( 2 ), or ( 3 ) include the following classes:
0 (a) ~ Ulld;:~ of Formula (1), (2), or (3) wherein Y is C~2;
(b) , ' of Formula (1), (2), or (3) wherein Z is a substituted phenyl group as def ined in paragraph (a) of the foregoing definition of aryl;
(C) _ __ ~Iq of Formula (1), (2), or (3) wherein Z is a phenyl group substituted with a (C2-C4) alkoxy group;
(d) , ` of Formula (1), (2), or (3) wherein Z is a phenyl group subsituted with a (C3-C7) 20 branched alkoxy group;
(e) _ ,__ ' of Formula (1), (2), or (3) wherQin Z is a phenyl group substituted with a halo (C2-C4 ) alkoxy group;
(f) , _ ~Q of Formula (1), (2), or (3) 25 wherein Z is a phenyl group substituted with a halo (C3-C7) },L~ ,lled alkoxy group;
(g) , lq of Formula (1), (2), (3) wherein Z is a phenyl group substituted with a phenoxy or substituted phenoxy group;
WO95/3U48 t ~ r t ~ ~ ~ 2 ~ 8~5 73 r~ 07 ( h ) ~ of any of the f oregoing groups (c) to (g) wherein the phenyl group is ~,- hctituted in the 4-position;
(i) compounds of Formula (1), (2), or (3) 5 wherein R3 is (Cl-C4) alkyl and R4 is E~ or halo, or more preferred are ~ -ul~ds of Formula (1), (2), (3) wherein R3 is methyl or ethyl and R4 is bromo or chloro;
ullds of Formula ( 1 ) or ( 3 ) wherein 10 R or Rl is ethyl, methoxymethyl, or ethoxyethyl; and (k) ~ ' of Formula ( 1 ) or ( 3 ) wherein Y is methylene, optionally substituted with NH2, NH-lower alkyl, or N,N-di-lower alkyl, optionally substituted with carboxy, cArhoAlktw~y~ or carboaryloxy.
Synthesis The ~ ~ '- of this invention are made using well known chemical pl~,ceduLes. The required starting materials are commercially available, or they are readily syn~h~i7~d using standard ~L~ ZdUL~5.
2~ For example, ~ ~ .u.~ds of Formula ( 1 ) can be prepared using the process illustrated in Scheme 1:
Scheme 1 R
R3_~, N~R
O SOCI~ (4) R3~ ~~ C - Y--Z
;~--Y--C--OE~ solven Z--Y--C Cl solvenr li R
(6) (5~ S
WO 95131448 ~ i f . ~ S 2 ~ 8 9 5 7 3 ,~ 1~.,~ s ~o7 In this ~LUU'adU'~/ the acid derivative (6) is mixed with an excess mûlar amount of thionyl chloride and the resulting mixture is heated at reflux fûr approximately one to three hours to yield the acid 5 chloride derivative (5). The amine derivative (4) is dissolved in a 5ufficient quantity of an organic solvent, such as, for example xylene or toluene, with heating. The acid chlûride (5) is added with continued heating for one to twelve hours, then the resulting o mixture is allowed to coûl. Separation u~;1;7in~
standard t~ hn;~l~ yields the desired, ~ of Formula ( 1 ) .
C of Formula ( 1 ) and ( 3 ) can be prepared using the process illus~Led below:
R3~_N~2 SOClz N--s Z-Y-COOH Z-Y-COCl solvent solvent R3~,~?--N--C --Y--Z
(A) R3_~--(1) (3) The above _ Ju~ of Formula ( 1 ) and ( 3 ) are obtained by ~lea of the carbonyl derviative (A) in the presence of a phase transfer reagent, such as, for example, benzyl triethyli ; bromide, a base, ~uch Wo 95/31448 ~ r~ 07 51s~ 2~573 as, for example, sodium hydroxide, in amthylene chloride/water ~[Lixture.
The above c of formula (1) and (3) can also be obtained by heating the amide A with a dialkyl 5 sulfate in the presence of potassium carbonate in a inert solvent such as, for example, benzene.
The above ~1~ of Formula ( 1 ) and ( 3 ) can also be obtained under non-aqueous conditions using sodium or potassium hydride and alkyl halide in an 10 aprotic solvent such as, for example, ethyl ether or tetrallydL~f UlCI-- .
C~ 1S of Formula (1) where Y is substituted with methylene or substituted methylene, R~ o R3~' N - C--C--Z
~--S R IllethyIeneor (Ib) substitutedmethylene 15 . can be prepared by using the processes illustrated in Scheme 2:
Scheme 2 WO 9~131448 r~ .,,5'~ 07 C~3o--C--N ~ C~ ) 2 R~ O
R ~_y-C--C~2--z orIIC( NrNe~hYI.)~ ) N-C-l~--Z
(lo~ N_5 R ~ I
1. base ROH or/ R 5R2~NH
''. CS, /1 Il- , , R~N
WO95/31448 " '~ 9 57 3 r -~u~ ~07 ( f ~ a group of the formula R2 m ~o-llet wherein m is 4; R20 are ;nARp~-nA~ntly H, halo, lower alkyl, lower alkoxy, haloalkyl, h~ Alk~yy~ N02, CN, 5 lower alkyl carbonyl, phenoxy, or substituted phenoxy, provided that at least two Of R20 are selected from H
and F; and Het is pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl, optionally substituted with one or more groups selected from halo, lower alkyl, lower alkoxy, 10 haloalkyl, h:llo~lk~yy, N02, CN, and lower alkyl carbonyl;
(g) a group of the formula A
x2--x~
wherein one of X2 and X3 i6 N and the other is CR23;
lS R2l is -T-R22, phenyl, substituted phenyl, ~Cl-C1o) alkyl, halo, or halo (Cl-Cg) alkyl, where T is O or S, and R22 is (Cl-C4) alkyl, (C3-C7) branched alkyl, halo (Cl-C7) alkyl, halo (C3-C7) b-c-ncl~ed alkyl, (Cl-C4) 20 alkoxy (C1-C4) alkyl, or naphthyl or phenyl, either of which may be optionally substituted with up to three groups selected from halo, (cl-clo) alkyl, branched (C3-C7) alkyl, halo (C1-C7) alkyl, hydroxy (C1-C7) alkyl, (C1-C4) alkoxy, halo (C1-C4) alkoxy, phenoxy, 25 substituted phenoxy, phenyl, substituted phenyl, CN, NO2, OH, (C1-C4) alkanoyloxy, or benzyloxy;
W095131448 ~ ~189573 ~ '~' R23 is:
~, halo, (C3-C8) cycloalkyl, ( C3--Cg ) cyr 1OA 1 k-~ny1, phenoxy, substituted phenoxy, phenylthio, substituted phenylthio, phenyl, substituted phenyl, N02, --C--R8 where R8 is (Cl-C7) alkyl, halo (Cl-C7) alkyl, (C3-C7) branched alkyl, halo (C3-C7) branched alkyl, (C3-C7) cycloalkyl, halo (C3-C7) cycloalkyl, (Cl-C7~ alkoxy, phenyl, substituted phenyl, or hydroxy, acetoxy, O~, CN, SiR9RlORll or OsiR9RloRll~ where R9,R10 and are ;n~lPIPI~r~ ly (Cl-C4) alkyl, (C3-C4) bLClLl~ lled alkyl, phenyl, or substituted phenyl, NR12R13, where R12 and R13 are in~lrrr~n,ir~ntly ~, ~Cl-C4) alkyl, or (Cl-C4) acyl, s(o)R14, or So2R14, where R14 is (Cl-C10) alkyl, phenyl, or substituted phenyl;
wog~/31 ~ 9~73 a (C~-C12) saturated or unsaturated hydrocarbon chain, straight chain or branched optionally ;n~ 8;ng a hetero atom selected from 0, S, SO, S02, NRS, or SiR6R7, where R5, R6 and R7 are as defined above, and optionally substituted with halo, halo (Cl-C4 ) alkoxy, hydroxy, (C3-C8 ) cycloalkyl or cycloalkenyl, (C1-C4) acyl, phenoxy, substituted phenoxy, phenyl, substituted phenyl, phenylthio, substituted phenylthio, or cyano;
(Cl-C7) alkoxy optionally substituted with halo, phenyl, substituted phenyl, (C3-C8) cycloalkyl or cycloalkenyl, phenoxy, or substituted phenoxy; or (C1-C7) alkylthio optionally substituted with halo, phenyl, substituted phenyl, (C3-C8) cycloalkyl or cyr~o~lk~nyl~ phenoxy or substituted phenoxy .
W is O, S(O)y~ wherein y is an integer from O to 2, or NR24;
G is (Cl-C4) alkyl, aryl, (Cl-C4) acyl, NR25R26, deuterio (Cl-C4) alkyl, halo (Cl-C4) alkyl, benzyl, or benzyl optionally substituted with (Cl-C4) alkyl, (Cl-C4) alkoxy, halo, halo (Cl-C4) alkyl; or W-G together are halo, SH, or NR25R26;
R24 is H, OH, (C1-C4) alkyl, (Cl-C4) alkoxy, aryl, (Cl-C4) acyl, NR25R26, benzyl, or benzyl optionally substituted with (Cl-C4) alkyl, (Cl-C4) alkoxy, halo, halo (C1-C4) alkyl; and R25 and R26 are ;nrl.oron-lontly H, (Cl-C4) alkyl, 30 aryl, acyl, or together form with nitrogen a s~LuLc.~ed _ g _ W g5/3 448 2 ~ , r-~o o ~ 1 8 9 5 7 3 (C3-C7) ring such as morpholino, piperidinyl, pyrrolidinyl The invention al~o provides a method of inhibiting a nematode population which comprises applying to the 5 locus of a - ~ode, a r -~ode inactivating amount of a compound of the Formula (1), (2), or (3) as defined above The invention also provides a method of inhibiting ~n insect or mite population which comprise~ applying 10 to the locus of the insect or arachnid an effective insect or mite inactivating amount of a ~ ~; of Formula (1), (2), or (3) The invention also provides a method of inhibiting plant pathogens which comprises applying an effective 15 amount of a compound of Formula ( 1 ), ( 2 ), or ( 3 ) to a locus of the pathogen WOgS/31448 ~ i 2~ 8q573 .~ 07 Det~i 1 r~ Description of the Invention Unless otherwise indicated, the terms below are defined as follows:
The term "halo" or "haloqen" refers to a F, Cl, or 5 Br ~tom.
The terms " alkyl ", " alkoxy ", " acyl ", " haloal kyl, ~hAlo~lk~xy", ~alkylsulfinyl", and "alkylsulfonyl"
refer to straight chain and branched chain groups.
The terms "aryl", "Ar", "substituted phenyl", 10 "substituted phenoxy", "substituted phenylthio", and ~substituted phenylsulfonyl" refer to such groups wherein the phenyl ring is substituted with up to three groups in~l-L~ r~, Lly selected from halo, I, (Cl-Clo) alkyl, branched (C3-C6) alkyl, halo (Cl-C7l alkyl, 15 hydroxy (Cl-C7) alkyl, (Cl-C7) alkoxy, halo (C1-C7) alkoxy, phenoxy, substituted phenoxy, phenyl, substituted phenyl, NO2, OH, CN, (C1-C4) alkanoyl, benzoyl, (C1-C4) alkanoyloxy, or benzoyloxy.
The terms "substituted naphthyl" and "substituted 20 indolyl" refQr to these ring systems substituted with one or more groups in~lrrDnrlDntly selected from halo, halo (C1-C4) alkyl, CN, NO2, (C1-C4) alkyl, (C3-C4) branched alkyl, phenyl, (C1-C4) alkoxy, or halo (C1-C4) alkoxy .
Z5 The term "carbocyclic ring" refers to a saLu ~Led or unsaturated carbocyclic ring containing five or six carbon atoms.
The term Runsaturated hydrocarbon chain" refers to a hydrocarbon chain containing one or more sites of unsaturation.
W095MI448 ~ - 2`1 ~9573 I~~ 07 The term "~PLC" refers to a high pressure li~uid (;l1LI , ~YI1Y .
The term "TLC" refers to thin layer LOylaphy.
The term "bivalent hydrocarbon radical" refers to bivalent radicals derived from normal alkanes by removal of llyd.vy 1l atoms from each of the two terminal carbon atoms of the chain, e.g. methylene, ethylene, trimethylene, tetramethylene, etc.
lo The term ~substituted amino" refers to an amino group that is substituted with one or two (Cl-C4) alkyl groups or one (Cl-C4) alkanoyl group.
The term "lower alkyl" refers to (Cl-C6) straight hydrocarbon chains and (C3-C6) bl~lnu1,ed and cyclic 15 hydrocarbon groups.
The terms " lower alkenyl " and " lower alkynyl "
refer to (C2-C6) straight IIYdLUI;O~LbV11 chains and (C3-C6) branched hydLu~ bull groups cr~ntAinin~ at least one unsaturated bond.
The terms "lower alko~cy" and "lower alkylthio"
refer to O-lower alkyl and S-lower alkyl groups.
The term "haloalkyl" refers to lc~wer alkyl groups substituted with one or more halo atoms.
The term ''deut~ri~Alkyl~ refers to lower alkyl groups substituted with one or more deuterium atoms.
The term "methylene" refer5 to =CE~2-Unless otherwise indicated, when it is stated that a group may be substituted with one or more WOg~/31448 ~ ~ _ p O r ~ 21 8 9 5 73 p~""~ c~-~07 substituents sDlQrteA from an identified class, it is intended that the substituents may be in~ ,Lly selected from the class. Throughout this ~ , all t~ ,~ dLUL~:S are given in degrees Celcius, and all 5 percQntA~QQ are weight percentages unless otherwise st~ted.
Preferred r ~
Preferred _ , ol~n~lc of Formula ( 1 ), ( 2 ), or ( 3 ) include the following classes:
0 (a) ~ Ulld;:~ of Formula (1), (2), or (3) wherein Y is C~2;
(b) , ' of Formula (1), (2), or (3) wherein Z is a substituted phenyl group as def ined in paragraph (a) of the foregoing definition of aryl;
(C) _ __ ~Iq of Formula (1), (2), or (3) wherein Z is a phenyl group substituted with a (C2-C4) alkoxy group;
(d) , ` of Formula (1), (2), or (3) wherein Z is a phenyl group subsituted with a (C3-C7) 20 branched alkoxy group;
(e) _ ,__ ' of Formula (1), (2), or (3) wherQin Z is a phenyl group substituted with a halo (C2-C4 ) alkoxy group;
(f) , _ ~Q of Formula (1), (2), or (3) 25 wherein Z is a phenyl group substituted with a halo (C3-C7) },L~ ,lled alkoxy group;
(g) , lq of Formula (1), (2), (3) wherein Z is a phenyl group substituted with a phenoxy or substituted phenoxy group;
WO95/3U48 t ~ r t ~ ~ ~ 2 ~ 8~5 73 r~ 07 ( h ) ~ of any of the f oregoing groups (c) to (g) wherein the phenyl group is ~,- hctituted in the 4-position;
(i) compounds of Formula (1), (2), or (3) 5 wherein R3 is (Cl-C4) alkyl and R4 is E~ or halo, or more preferred are ~ -ul~ds of Formula (1), (2), (3) wherein R3 is methyl or ethyl and R4 is bromo or chloro;
ullds of Formula ( 1 ) or ( 3 ) wherein 10 R or Rl is ethyl, methoxymethyl, or ethoxyethyl; and (k) ~ ' of Formula ( 1 ) or ( 3 ) wherein Y is methylene, optionally substituted with NH2, NH-lower alkyl, or N,N-di-lower alkyl, optionally substituted with carboxy, cArhoAlktw~y~ or carboaryloxy.
Synthesis The ~ ~ '- of this invention are made using well known chemical pl~,ceduLes. The required starting materials are commercially available, or they are readily syn~h~i7~d using standard ~L~ ZdUL~5.
2~ For example, ~ ~ .u.~ds of Formula ( 1 ) can be prepared using the process illustrated in Scheme 1:
Scheme 1 R
R3_~, N~R
O SOCI~ (4) R3~ ~~ C - Y--Z
;~--Y--C--OE~ solven Z--Y--C Cl solvenr li R
(6) (5~ S
WO 95131448 ~ i f . ~ S 2 ~ 8 9 5 7 3 ,~ 1~.,~ s ~o7 In this ~LUU'adU'~/ the acid derivative (6) is mixed with an excess mûlar amount of thionyl chloride and the resulting mixture is heated at reflux fûr approximately one to three hours to yield the acid 5 chloride derivative (5). The amine derivative (4) is dissolved in a 5ufficient quantity of an organic solvent, such as, for example xylene or toluene, with heating. The acid chlûride (5) is added with continued heating for one to twelve hours, then the resulting o mixture is allowed to coûl. Separation u~;1;7in~
standard t~ hn;~l~ yields the desired, ~ of Formula ( 1 ) .
C of Formula ( 1 ) and ( 3 ) can be prepared using the process illus~Led below:
R3~_N~2 SOClz N--s Z-Y-COOH Z-Y-COCl solvent solvent R3~,~?--N--C --Y--Z
(A) R3_~--(1) (3) The above _ Ju~ of Formula ( 1 ) and ( 3 ) are obtained by ~lea of the carbonyl derviative (A) in the presence of a phase transfer reagent, such as, for example, benzyl triethyli ; bromide, a base, ~uch Wo 95/31448 ~ r~ 07 51s~ 2~573 as, for example, sodium hydroxide, in amthylene chloride/water ~[Lixture.
The above c of formula (1) and (3) can also be obtained by heating the amide A with a dialkyl 5 sulfate in the presence of potassium carbonate in a inert solvent such as, for example, benzene.
The above ~1~ of Formula ( 1 ) and ( 3 ) can also be obtained under non-aqueous conditions using sodium or potassium hydride and alkyl halide in an 10 aprotic solvent such as, for example, ethyl ether or tetrallydL~f UlCI-- .
C~ 1S of Formula (1) where Y is substituted with methylene or substituted methylene, R~ o R3~' N - C--C--Z
~--S R IllethyIeneor (Ib) substitutedmethylene 15 . can be prepared by using the processes illustrated in Scheme 2:
Scheme 2 WO 9~131448 r~ .,,5'~ 07 C~3o--C--N ~ C~ ) 2 R~ O
R ~_y-C--C~2--z orIIC( NrNe~hYI.)~ ) N-C-l~--Z
(lo~ N_5 R ~ I
1. base ROH or/ R 5R2~NH
''. CS, /1 Il- , , R~N
3.alkYI halidel /: ROHorRSHH~ or H.
Q --~?, N - C - C - Z ~ R~
( I 1) .~lkyl S~ ~s-~lkYl 113~ H o,S-~lkyl llrNHR
11~ 1111 R~ O
` J R ~ y - C - C--z N_5 R ~C~
( 15) A 3 ~ ethylene derivatives (3) wherein the methylene i5 substituted with N(CH3)2 may be prepared by treating the N-(S-isothiazolyl)amide (10) with the appropriate 5 N,N-dialkylc~lrhr~ami~ di-alkylacetal in the presence of toluene with heating. The N,N-dialkyl derivatives (11) can be converted to their NHR24 derivatives by treating with the appropriate amine to give (12). The N-(5-isothiazolyl)am.ides (10) can also be c~ ve:LLed to o S,S-ketene acetals (14) and optionally, to cyclic systems ( 15 ) .
C~ of Formula (2) where W = O, S, or NR24 can be prepared using the process illustrated in Scheme 3:
5 Scheme 3 SUBSTITUTE SHEET (RULE 26J
WO 95131448 ~ 5. ~ 07 c ` 2189~73 R3~_ n R3~.~ 21 =C
(I) (9) (2) The carbonyl derivative (1~ i5 treated with Lawesson's reagent to give the thione (9) which can be converted to ~m;~linP~ where W-G = NR25R26 or NHR25 with 5 primary and secondary aminefi. The thione can also be S-alkylated using a dialkyl sulfate or alkyl iodide in the p- ~s. n~ e of potassium c;~rhnn~t~ to give, ~e (2) where W=S and G is alkyl, which in turn, can be reacted with nucleophiles such as, for example, OR-, ~lH2R24, NEIR24R25, or NR24R25R26 to give other ~
Of (2)-wo 95/31448 ~~
~ 21 895i3 r~ ,. 07 EXA~LE5 The following Tables I, II, and II_ identify Clr1c of Formula ( 1 ), ( 2 ), and ( 3 ), respectively, 5 that were prepared by the processes illustrated in the foregoing schemes.
TA~3LF' I
~:x y Z .R R3 R~ ~p C
CH2~ OCH2CF3 H CH3 Br 95--96 CH2~ f?CH2CF3 H CH3 H 162--163 3CH2~?CH2CF3 H CH3 Cl 117-118 :CH2~_~?CH2CF3 H C~33 Cl 143--144 --''H2~cfcH?)3 H ~-H3 :~ 136-1~37 H2 ~3_~Cl H -H203 Cl 124-125 CH2~ OCHF2 H CH3 ~r 110-111 CH2~OCH3 H C2?3 Cl 113-114 CH2~0CH2CF3 H CH203 Cl 112-113 13 CH2 ~3C(CH3)3 H CH3 3r 110--111 11 CEf2 ~C(CE~?)3 H 02C~3 Cl 114-llS
;2 CH2 ~O~Cl R CH3 Br 131--132 .3 CH2 --'-H2CH2~ CF3 d ca3 Cl 14q--145 '~ CH2 ~C~CH3)3 H CE3 Cl 114-llS
!5 C!32 ~-CF3 H CH3 Cl 170-171 15 CE12 ~O~f~CF3 H C~'f3 Cl 126--127 17 CH2 O H CE~3 Cl 192-193 ~ N
18 CE~2 ~~ o-~CF3 H CH3 Cl 70-75 !9 CH2 ~--O--~Cl H CEf3 Cl 177-179 20 CH2 ~O ~' ~Cl H CH3 Cl 166-167 SUBSTITUTE SHEET (RULE 26) WO 95131448 r~ 5 '~ '~07 S 2 1 ~573 21 CH2 ~_ _N3 H CH3 Cl 161-164 22 CH2 ~ N Cl H CH3 Cl 124--125 23 CH2 ~ H CH3 Cl 17~--175 24 C32 ~o~3 H CH3 Cl 107-108 25 Cl}2 ~ O~N--3 Cl H C~33 Cl 137-138 26 CH2 ~_~--Cl H C!I3 Cl gl~lsY
aCH~(aH~.C
27 CH2 ~_~Cl H CH3 Cl 223--224 ClCH~(aH ~ ~,C
28 CH2 ~oC1~2CF3 H CKzCU3 CH3 127-128 29 CH2 --CH2--~ Cl H CH3 Cl 152-153 30 CH2 H C!~3 Cl 16 _ ~o~N 7 168 31 CH2 ~ ~_ COF3 H C~33 Cl 134-135 O~N~
32 CH2 ~ ~--OCII~CF3 H C~(cH3)2 Br 76-77 33 C~2 ~o~3CF3 H CU2C~3 Cl 100--101 34 CE12 ~O~ H CH3 Cl 157.5--35 CH2 ~ oc~2cF3 H C~C~33)3 Br 129-130 36 C~2 ~ --O~ C~N H C~2CE~3 Cl 147--148 37 CE12 F H C~3 Cl 14 -~~Cl 1 143 38 C112 ~;,~--O~CF3 H CE13 Cl 106-108 39 CE12 ~ oci32CF3 H C~3 Cl 138--140 40 CH2 ( ~ B CE13 Cl 109--120 ~_ o~
41 CH2 ~--O~CF3 C~3 C~3 Cl 84-86.5 -- 20 _ SUBSTITUTE SHEET (RULE 26) WO 95/31448 1 RA ~ S , 2 1 ~ 9 5 7 3 r~ r ç.~7 42CH2 E~ CH3 Cl 109--114 ~ ~ Nt 43CH2 ~0C~2CF3 CH3 ~a2~5 78-80 44CH2 ~,3 H CB3 Cl 167-168 45C~2 ~ ~ CF3 CH3 Cl 125--129 46 ~_~ C83 Cl 75-80 47C~2 ~ C~3 C1 146-147 48CH2 ~OCF2CHF2 CH3 Cl 121-122 49CH2 {~(~OC83 C~3 Cl 141-142 50C~2 _~3C(CB3)3 H C~;2C~3 N 137-139 51C~2 ~OC~2CF3 ~ c~2C~l2cll3 Cl 112-113 52CH2 ~ OCH2CF3 C113 P 147-148 53CH2 ~--C(CH3)3 H Cll2c!l2c~3 ~ 137-139 54C~2 ~OCH2CF3 H 32C~3 Br 110-112 55CH2 ~--OCB(CH3)CF3 li c~3 Cl 80-83 56CH2 ~ O~~ ~>~ CF3 CE12CB3 CE3 Cl oil 57C112 F 8 a/2~3 Cl 154-155 ~O~Cl 58C~2 ~;3~ O~ Cl ~ c~2~a3 Br 108-109 59CH2 ~ ~ F ~3 C~3 Cl 121-lZ2 60CH2 ~oc82CF2CF2A CA3 Cl 132--133 61CH2 F CA3 Cl 133--135 ~ (~ N02 62CA2 ~ O~ Ar A CA3 C1 141--142 63CA2C82 ~ ~ CF3 CE3 Cl 125-126 64CH2 ~o~cN H CH3 Cl 178-179 65CA2 ~OCH2~F ~ CH3 Cl 141-143 SUBSTITUTE SHEET (RULE 26) WO 9S/31448 . 2 ~ 8 ~ 5 7 3 P~ J.,. S. - 6~'~07 66C~2 ~ CF3 C~3 CQ3 Cl 8i--86.5 67C~z $ ~ CF3 CD3 C~3 Cl 84--89 68CQ2 ~CF3 CQ2CQ3 CQ3 Cl oil 69Cli2 ~~ ~~ CF3 C~2cH2cB3 c~3 Cl oil 70C~2 ~O~CF~ ~2C~c~cH3)3 c~3 Cl oil 71C~2 ~CF3 C~3 c~2ai3 Cl oil 72CcEiN~c~33~2 ~ O~CF3 C~3 Cl 194-200 73CQ2 ~CN CQ3 C82CH3 Cl Oil 74C~3 ~CF3 C~3 C~3 Cl 150-153 75C~2 ~ 0~ CFl c~2CD3 Ci33 Cl oil 76C~ hu(c~3~2 ~- O~- CF3 C~3 Cl 130-77C~ c2!{s ~--O~CF3 C83 132;5 78C~llc2~35 ~3O~CP3 C~3 Cl 133-137 79C~2 ~ ~ CF3 C~3 Cl 96-98 80C82 ~O~CF3 C82CO2C28s c~3 Cl oil 81CQ2 ~ O~=~ CF3 C82C=CQ2 CQ3 Cl 031 (B~ ~ ~CF3 CQ3 Cl 183-187 33c-cNe2 ~O~CF3 C83 Cl 160-165 84C~2 ~3--o~CF3 CQ(C83)2 C~3 Cl oil SUBSTITUTE SHEET (RULE 26J
W095/31~ r ~ P8 ~-~ 2~189573 r~
85CH2 ~~ ~ CF3 CH2~ CH3 Cl oil a6CH2 ~O~CN CD3 C2H5 Cl 91--93 87CHCH3 _~ 0~ CN CE3 C2H5 Cl oil a8CHCD3 ~ 0~ CN CD3 C2E5 Cl oil 89CD2 _~ 0~ CF3 E CE3 Cl 124--128 90C=CH08 ~;3~ ~ CF3 E CE3 Cl 118822.-5 91CH2 ~ 0~ CN CH2CH3 C2E5 Cl oil 92C~l(c~3)2 ~o~CN E C2E5 Cl 165-166 93CE2 ~~ ~ CF3 CE2CE3 C2E5 Cl oil SUESTITUTE SHEET (RULE26) .
WO9~/31448 ~ 2189~73 r~l~u~ s.~s307 gqC-O ~ CN C2~5 Cl 173-177 95C~lC21~s ~CN C2E~5 Cl 167.5-96C~1~23)2 ~3O~3CF3 C2~5 C1 164.5_ 9 7C~( C~3 ) 2 ~ N--3~ C2 ~ 5 C 1 16 2 -98C~C3}17 ~o~ )-CF3 c~3 Cl 117-123 99C-C;BC2~5 ~o~ CF3 C2~5 Cl 114-117 100C~C213s ~O--~_>-CF3 C2~5 Cl ao-86 101C~c3~7 ~ ~CF3 C~33 Cl 117-125 102C)~2 ~ C~ Cl C2H5 C2~5 Cl oil 103C32 ~~O~Br C2~5 C2~5 Cl Oil CB2~~ ~--CF3 C2~5 C2~5 Cl oil lC5-C-CN~ ~--O~CF3 C33 Cl 163--170 106C~2 ~ --O~CF3 C~20C~3 c~3 Cl oil 107C~(Q3)2 ~_~CP3 C2~5 Cl lq6-lq9 108CB2 ~_OCH2CP3 C235 C235 Cl oil 109C~EC2~3s ~31--OC~12CF3 C~32C33 Cl lZ0-127 110C~3c2~s ~ CF3 138.5 111C--o F 3 C112C~3 Cl 125-126 ~CF3 112C~3C2~s ~CF3 ca2CH3 Cl 143--113C~C2~35 ~_ ~Br C2~5 Cl 157-159 114CE2 ~CF3 CB2oc~32cB3 C~33 Cl oil _ 24 --SUBSTITUTE SHEET (RULE 26) WO 95/31448 ~ t~ ~; 2 1 8 9 5 7 3 115C~CXCCE!3 ~o~cF3 N CN3 Cl 115536.55--116C~L3C4eg ~--o~cF3 N CN3 Cl 11129i55-117~-~Wco~3~2 ~_ _~1- CF3 N C113 CL 1111145-118c~c~c~c~l3 ~3~ ~CF3 N CN3 Cl 116656.55-119CN2 ~3--oCFzCF2N H C2~5 Cl 112--114 120c~C113~2 ~OCF2CF2H N C285 Cl 95--105 121CN2 ~3--oCF2CF2~ , c~2CN3 C2~5 Cl oil 122C~3C2~s ~ C2N5 Cl 100-~Z~) OCF2CF2N ~ 101:5 123c~32 ~ 0~ CN H C2ii5 Cl 119~318.-5 124~2 ~ - o~CN C2~5 Cl 175.5-125C=O ~3 ~ CF3 H C~3 Cl 12~g73.95--126CN2 ~CsN11 c~3 Cl 87--88.5 127CN2 ~1--C~EI11 C2N~ CN3 Cl oil 123C~OCc3 ~O~CF3 CN3 Cl goil /
129C~2~2C~ ~ ~ CF3 H CN3 Cl 120-lZ3 130C~ oCE2CF3 N C2N5 C} 126--127 C=CIIN~ ~ ~ CF3 C~3 Cl I29--133 132CN2 ~ ~3 CF3 n--blltyl c~3 C1 oil 133C~G33)2 ~30C~2CF3 N CE3 Cl i216il5--134c~C2~3s fi~ CE3 Cl 161-163 ~ oC~2cF3 135C~3 ~ O~CF3 CN3 C1 oil 136C~2 ~O~CF3 N CE3 Cl 233.5--(dec) 137 ~ --0~ CF3 CE3 Cl cli1 138o _ ~'1~~CF3 N C~3 C1 172-173 SUBSTITUTE SHEET (RULE 26) WO95131448 ~ P& ~ 2~89573 r ~ 07 139C-NNF32 - ~ - o~cF3 H CH3 C1 161-174 140CH3~ O~ CF3 H CH3 Cl 233-240 NH
O=C
C~N-141C(~c2Hs)2 ~O~CF3 H CN3 Cl oil 142c~ c~ ~ ~ o~ cF3 H CH3 Cl 11239i.55--143'C 2~, ~O~CF3 H Cr33 Cl oil 144~ -2h3C~2CI22~ CF3 H CE3 Cl 195--196 145C~ccO,c~c~ ~0~3CF H CH3 Cl 131_ 146~ D3C~2~2~ ~ ~_o_~-CF3 H CE13 Cl 134-5 147~~ 2~-~02~ ~ ~~_ CF3 H C~3 Cl 186_ 143CE12 ~--O~CF3 H C2~5 N2 135--138 149CH2 ~ O~ CF3 CH20C33 C2H5 3r oil 150~U2~2~3 ~ oC~2CF3 E C2~5 Cl 1219il5--151C~'~"2'2; ~_oc32CF3 c2~s Cl 122-138 152CH2 F~_ 3 C113 3 126--127 CF3 r SUBSTITUTE SHEET (RULE 26) WO 9S/31448 ~ 8 9 5 7 3 r ~ o7 153 CH2 ~--CF3 C~12OC~3 c~3 Br 83--85.5 154 C~2 ~ 0~ CF3 a C~3 i3r 106-111 155 C~2 ~~ ~ C~20C~2CY3 c~3 Br oil 156 C~2 ~O~CF3 C~20C~2C113 C83 i3r oil 157 C~2 ~ CF3 C~20C~3 c2~s Cl 5Z-56 158 CH2 F C820C~32C~3 C2H5 i3r oil ~CF3 159 C~2 ~ cU2oc~2c1l3 C2H5 Cl oil ~CF3 160 C~2 F C820CE13 C2~5 Rr oil ~CF3 -- 27 _ SUBSTITUTE SHEET (RULE 26) WO9S/31448 , ~1 J~i~, 21 8~573 ~ o7 161C32 (~ 0-nCIa9 C2H5 CH3 Cl oil 162CH2 ~~o~cF3 Ca2CN C33 Cl oil 163CH2 ~ - o~cF3 CH2~ CH3 Cl oil 164C~l(CE3)z ~ OC~Hg H CH3 Cl 1S4-lSS
165CH2 ~--OCH2CF3 C2H5 C33 3r 159-160 166C~2 _~9 E CH3 Cl lg3--14~
167 ~o~3_~,o~ H C2H5 3r 128-130 168CHOH ~ocll2cF3 E C33 3r 137--140 169C~li(cE3)2 ~--OCH2CF3 H C33 3r 129--133 170C~(C113)2 ~3--oC1~2CF3 E CH3 H 145--148 171CH2 ~--OCH2CF3 CH2Cl H 146--148 172CH2 ~OCEzCF3 R4 ~or21 225--227 173CE2 ~o~3r C2H5 Cl 155--156 174CH2 1~ E CH3 Cl 1 --~O~F 59 161 175CH2 F~ E C2HS Cl 140--1~1 ~O~F
176C32 ~--OCE2CF3 H CH2Cl Cl 80--81 177CH2 ~~~C~ E CHZCl Cl 157--160 SU~ 111 IJ I t ~HEEr (RULE 26) ~O 95/31448 ~ 8 9 5 7 3 . ~ r , 178 C~2 1 ~ C285 Cl 128-130 ~O~CF3 179 C~2 / N C83 Cl 135-138 ~o~CF3 18C C~2 F ~ C285 Cl 18-81 ~ CF
181 C~2 F~ ~ CH3 Cl 157-158 ~O~CI
182 C~~ 3)2 ~o_~Cl C2~5 Cl 164-166 183 c~8C2~ ~0~ Cl C2u5 Cl 118--121 184 C~2 ~o~cF3 C2~5 Br 79_81 as C~2~ ~o~Cl C285 Cl gl~
186 C82 ~o--~--CF3 C2H5 C285 Br oil 187 c=o ~o-~cl C2~5 Cl 108-109 188 C82 ~O~C~ C2~5 CB3 Cl oil 189 C82 ~O~CF3 C82CC~ C83 Cl oil 190 C82 ~3_oCB2CF3 C2~5 CB3 Cl oil lgl C~2 ~-OC~89 C83 Cl 100-102 192 C~2 ~-CC~89 C285 C83 Cl oil SUBSTITUTE SHEET (RULE 26) WO 95131448 ,~ ,"~ ~ n ~ ~, r~ 07 ~1 89573 193C~2 ~--o~~3~CF3 C112CN c~3 Cl Oil 19~C~E2 ~ 3CF3 _<¦ C~3 Cl sil 195C~:N(c~3)2 (~ OC~H9 H CH3 C1 L54--lSS
196CH2 ~30c112CF3 C2H5 CH3 Br oil 197OE2 ~--OCH2CF3 CD2CD3 c~3 3r oil 198C~N(c~t3)2 ~_OOE2CF3 H C2N5 Br 168--169 1 9 9 C~HC ~
2 5 ~30OE2CF3 H C2H5 ~r oil 200C=O ~--OOE2CF3 H C2H5 Br 100--101 201C'CNEO~ ~O~CF3 H CH3 Cl d~o 2 0 2 C~C2~s ~o~cF3 C2H5 Br oil 203CH2 ~O_~_ CH20c1l2cll3 c2~s Br oil 204C~2 ~--O~CP3 Clt2CN C2H5 Br oil 205C~2 ~3CF~H C2j35 Br oi l 206C82 ~CF.H C2~t5 C2~5 Br oil 207C~C~3)2 ~CF.H H C2~5 Br 109--111 208 c~c~cu2cOo~
~--OCB2CF3 H C2E15 Br 124--126 209 ~- , ~OCEt2CF3 C2H5 Br 137--143 210C82 ~CF C2H5 C2Et5 Br 80--82 _ 30 --SU~STITUTE SHEET (RULE 26) WO 95/3~44 e.~ ~s ~ 2 ~ 8 95 73 r~ 07 211 C~2 ~(lCF.CF.H C2~5 C2H5 Br oil 212 C~2 ~--OCH2CF3 C2H5 C2H5 3r Oil 213 C~2 ~ CF3 CH20CH3 CH3 Br oil 214 CH2 ~ ~CF CH20C~3 c~3 Cl oil 215 CH2 ~--~CF C~20C2H5 CH3 Cl oil 216 CH2 ~--'~CF H C~3 Cl 143--144 217 C COOCH3 ~ocB2cF3 a C2H5 cl 44--47 HH o SUBSTITUTE SHEET (RULE 26) ! !;.
Table II
no ~ R3 R4 W G Y Z MP C
823392 218 CE3 Cl CE3 CE2 ~O~CF 145-147 823503 219 CE3 Cl CD3 CE2 ~O~CF 165-168 82;752 220 CE3 Cl O CE2CE3 CE2 ~O~CF 138-1~1 826232 221 CE3 C1 O CE2CE2CE3 Cil2 ~>--O~CF 100-101 826321 222 CE3 Cl O H2C~C(CE3)3 CE2 ~--O~CF 149-154 826073 Z23 Cl~2c83 Cl CE3 CE2 ~ O~ CF lZ9-131 826326 224 C1~2CE3 Cl CE3 CE2 ~--o~CN 160 5 50459~ 225 CE3 Cl S CE3 CE2 ~ O~ CF 72-73.5 504595 2Z6 CE3 Cl CE3 CE12 ~-CF o-l SUBSTITUTE SHEET (RULE 26) W0 95/31448 2 1 ~3 9 5 7 3 ~ 07 504754 227 Ch'3 Cl N Ch~3 Ch'2 ~--0~cF o 504862 228 C!13 Cl N (Ch'3)2 CE12 ~ - o~cF3 509770 229 CE13 Cl S C2h-5 C113 ~ ~ CF3 5101~31 230 CC3 Cl S C3117 CE2 ~O~CF3 511477 231 C113 Cl 0 Chl2Ch~3 C~2 ~ ~ CF3 511476 232 Ch3 Cl W-G toq~th~r fo= C!12 ~o~3CF 227-229 NKN (d o~
511475 233 CY3 Cl W-Gto.7~ther forl C~2 ~30~CF 116 5_ 3(CY~2 513647 234 CE~3 Cl 0 c~2CF3 Ch'2 ~o~cF3 ~ 33 --SUBSTITUTE SHEET (RULE 26) WO 95/31448 ; ~ ' r~ 5.~ '~07 'rABLE~
(~ Y Z Rl R' R4 MP C
235 CH2 ~ CF3 CD2CD3 C~3 Cl 140--143 236 ' ~ C~3~ ~o~ C~2C02C2~5 C~3 Cl 113207.-s 237 C112 ~3~ CF cl~2C~I=CH2 C~3 Cl 92.5--238 CH2 ~O--~-- C1~2-phenyl C~3 Cl 113332.5 239C112 ~--o~CF3 C~!(C~3)2 C~3 Cl 117-119 240C~i2 ~o~CF3 CN2C02~ C~3 Cl 16~,--167 241 ~~(`` CD3 C2~5 Cl 159--160 242C112 ~3O~`` C2~5 C2115 Cl 161.5-162 .5 243C112 ~O--~--CF3 C2~5 c2~5 Cl 110_ 244C~2 ~O~ CF3 CE3 C~3 C1 165--166 245CH2 ~ ~C1 C2~15 c2Hs Cl lZ9-130 246CH2 ~3~~~3r C2H5 C2H5 Cl 129-131 247C~2 F C2H5 C2H5 Cl 143.5_ ~CF 1~5 248CH2 ~O--~--CF3 CH20CH3 CH3 C1 123.5-249C~32 ~--OCHzCF3 C2~35 C2H5 C1 104-106 SUBSTITUTE SHEET (RULE 26) WO 95/31448 2 f 8 ~ 5 7 3 . ~lIU~ 07 250CB2 ~O--~--CF3 Ci~20C2B5 Cil3 Cl 113-114 251C112 ~--o~cF3 C2~0B C83 Cl 1614665--252Ci~2 ~ - o~cF3 Cil2C02Na Ci~3 Cl 157--160 253CB2 ~)CF~Ci-.ii C2iis c285 105.5 254Cil2 ~ HI ~ C2il5 Ci~3 Cl 11043.-5 255C~12 ~--o~cF3 n^C4i~g CB3 Cl 11118.--5 256C~2 F C~2OCii3 Ci~3 Br 114.5--~ CF 115 257Cii2 F Ci~2OC2i~s Ci~3 Br 114.5--~CF 117.5 258Cil2 ~ - o~cF3 CB20C2i~5 CB3 Br 114--116 259CB2 F CB2OCil3 C2H5 Cl 135--140 ~CF
260Cil2 F C820CB2CB3 C~2CB3 Br 126--127 ~ CF
261CB2 F Cii20C83 Ci~2CB3 Br 160--164 ~CF
.
SUBSTITUTE SHEET (RULE 26) WO95131448 ~ " ~,'" ,;~ 07 262 C~2 ~O--~_CF3 C2~5 C2H5 Br 140-142 263 CH2 ~~'` C2H5 Ch3 Cl 180-182 264 CH2 ~O~ CF3 ca2cc~1 CE3 Cl 153-155 265 CH2 ~0C112CF3 C2H5 CH3 Cl 138--139 266 CH2 ~--OC~Eg C2H5 CH3 Cl 133-134 267 C}~2 ~ CF3 C!12CN CB3 Cl 130-134 26a CH2 (/ \)--OC~9 c2~5 C~3 Cl 133-134 269 CH2 ~ CF3 Cil2CN Cli3 Cl 130134 270 C}~2 ~o~ CF3 ~ CH3 Cl 121-122 271 CH2 ~3 - oc82cF3 c2a5 C~33 Br 159--160 272 CB2 ~--OCi32CP3 CD2CD3 C~3 Br 159--160 273 CH2 ~OCF.U C2HS C2~s Br 76-78 274 CH2 ~o~ CF3 CH20CH3 CH3 Br 123-126 275 CH2 F CH2OCH2CH3 CH3 Cl 114-116 ~CF
276 CH2 F C~2OCH3 CH3 Cl 129-131 ~CF
SlJBSTITUTE SHEET (RULE 26) WO 95/31448 S~ 2 1 8 9 ~ 7 3 ~ 307 l~s illustrating preparation of ~ lAry follow below.
2N NaOH 1~3C ~
3C~ N~2 ~ N~2 N-S . HCI H2o N~S
The starting acid (28.2 g, 0.187 mole) was added to ~2O (200 ml). The insolubles were filtered and the filtrate's pH was adjusted to 10.0 with the addition of 2N NaO~ (94 ml). The mixture was stirred for ~ive minutes, then extracted with ethyl ether (1 x 230 ml).
The organic layer was separated and the aqueous layer was saturated with NaCl, then extracted with ethyl ether (2 x 230 ml). The extracts were c ~n.oci and given a brine wash, dried over MgS04, the~ COnC~ LLGLed under vacuum to give the product as a yellow oil (18.9 15 g)-Na CEJ3CEI2 C~3 C113C3i2CN ~ >--<
Sodium (11.5 g, 0.5 g-atoms) and propionitrile (66g, 1.2 moles) were stirred in toluene (250 ml).
20 There was a slight exotherm and a solid began separating. After one hour, gradual heating was applied until re~lux was att2ined after a} out three hours. Reflux was maintained for one hour and the mixture was then allowed to cool, resulting in an 25 e~L~ -ly thick mass. The mixture was then washed with ethyl ether (300 ml) and placed in a large crystAll;7;n~ dish and began smoking as the ethyl ether . Water (500 ml) was added and the product WO95/31448 ~ 2~ 8~57~ C~ , was extracted into ethyl ether (2 x 500 ml). The two extracts were c ;nr~d and dried over MgSO4 and the ethyl ether was removed under vacuum, leaving a brown oil, which sol;r~;firrl. Product was then recrystAll;7-~d s from heptane-ethyl acetate (10:1) yielding about 22 g ~m.p. 38-40).
c~3 C~3CE~2~=<CI~3 H~S H~ 3c~2c~N 2 ~2N C~ N_5 The starting nitrile (7.0 g, 0.063 mole), ethanol (35 ml), tetral~ydL~,~uL~ll (THF) (35 ml), and triethylamine (2.0 g, 0.02 mole) were placed in a Carius tube, cooled, and llydloyt:l~ sull~ide (2.8 g, 0.082 mole) was bubbled in. The resulting mixture was placed in an oven at 115-120 for five hours. The solvent was removed under vacuum and the resulting mixture was dissolved in CH2C12 (250 ml) and washed with water (50 ml). Thin layer chromatography indicated mostly starting material, 80 the mixture was dissolved in ethanol (50 ml). To this solution wa8 added 30~ H22 (20 ml),and water (100 ml), then most of the ethanol was removed under vacuum. The product was extracted with CE2C12 (500 ml) and this extract was further extracted twice with lN NCl (2 x 100 ml). The acidic extracts were, ;nr~r~ and washed with CE2C12 (150 ml) and then made basic with 10N NaOH. The resulting solution wa~ then extracted with two portions O~ CH2C12 (2 x 100 ml) and ~ ' ;nr~cl and dried over MgSO4.The solvent was removed under vacuum to leave a semi-solid.
T-60 NMR indicated mostly desired product which was then recrystAlli7ed from hexane to yield about 100 mg (m.p. 84-88).
WO95/31448 s~ 2 1 8957~ 5~ ~07 CE13CE2~=<CH3 ~ H20~ ~13CE12C_~N~2 H2~1 CN PY N_5 The stGrting nitrile (6.0 g) was dissolved in pyridine (20 ml) in a Carius tube. Hydrogen sulfide 5 (2.8 9) was bubbled in. and the resulting mixture was placed in an oven at 120 for five hours. The solvent was removed under vacuum and the resulting mixture was dissolved in CH2C12 (250 ml) and washed with water ( ml). Thin layer chromatography showed more extensive 10 reaction and more impurities than material of Example 3. The solvent was removed under vacuum. To the product was added ethanol (100 ml) and 30~ H22 (20 ml). The resulting mixture became very hot. Water (200 ml) was then added and the mixture was extracted with two portions of CH2C12 (2 x 150 ml). The extracts were ~ 'in~d and e~L~ Led with lN HCl (2 x 100 ml).
These extracts were combined and washed with CH2C12 (150 ml) and before making basic with 30% NaOH. The product was then extracted twice with CH2C12 (2 x 150 20 ml) and the combined extracts were dried over MgSO4.
Thin layer chL~ ~OYLG~1~Y indicated product identical to that of Example 3, except for an additional spot which may be pyridine. This sGmple was c. in~ with the product of Example 3 and chL~ ~o~LG~hed on silica 25 gel, starting with CH2C12 and eluting the product with 5% ethyl acetate. Product was recrystAll;7c~rl from hexane to give 240 mg of white crystals (m.p. 99-100).
E~3C~--N 2 ~ N~2 WO 95/31448 ~ 5 ~07 2 ~ 8~57~ ~
The starting amine (18.9 g, 0.166 mole) was slurried in CC14 (600 ml) under an atmosphere of N2-N-chlorosllrc;n;m;~o (NCS) (22.1 g, 0.166 mole) was added to the slurry over a five minute period at 30-44 5 and stirred at room ~ ~ a~uLe overnight. Analysis by T~C silica gel 1:1 heptane/ethyl acetate showed product and no starting material present. The mixture was then diluted with ethyl ether (100 ml) and the solids were filtered. The filtrate was co.lce.~L~Led under vacuum 10 to a red oil which was dissolved in ethyl acetate (200 ml) and washed with H2O (2 x 200 ml). The organic layer was separated, given a brine wash, dried over MgSO4, then concentrated under vacuum to a brown oil which crys~ i70:1 to a brown solid (22.0 g).
O O
Il + NaH ll 6096 sodium hydride (40 g, 1 mole) in mineral oil was tirred under reflux in dry tetral-ydLuruL~I (500 ml) as a solution of ethyl propionate ( 51 g, 0 . 5 mole ) and acetonitrile (41 g, 1 mole) was added dropwise to the mixture. This mixture was maintained at reflux overnight. The mixture was then cooled and isopropanol (60 ml) was added dropwise. The solvent was removed under vacuum and after adding water (400 ml), the product was ~L- ~-ed with hexane (400 ml) and 1:1 hexane:ethyl ether (400 ml). Cc..c .I~L~ed HCl was added to the combined C:~L~IC-s to lower the pH to 6, and the solution was then extracted with two portions of ethyl ether ( 2 x 300 ml ) . The ~ ~in~d extracts 30 were washed with water and the resulting solution was dried over MgSO4. The ethyl ether was removed under vacuum to leave product as an oil (30 g).
~0-WO 95/3 1448 I-._ 1 / u ~, _ . '~07 2 t 8 9 5 7 3 NH3 CE3CE2 H S E3CE2Cr9--NE2 CH3CH2CCH2CN H2S E2N>~/ N--S
To the product of Example 6 was added dry THF (270 ml) and ethanol (200 ml~. Of this solution, 70 ml was 5 put in each of two Carius tubes. The tubes were cooled and NH3 (2.1 g) was added followed by H2S (3.0 g). The tubes were sealed and warmed in hot water to check for leaks, then placed in an oven at 110 for four hours, after which the mixture was cooled and the solvent 10 removed under vacuum. To this product was added CH2Cl2 (300 ml) and the mixture was washed with two portions of water (2 x 100 ml). The mixture was then dried over MgSO4 and the solvent was removed under vacuum.
Ethanol (100 ml) and 30% H22 (15 ml) was then added.
15 Starch-iodide paper showed no excess H2O2. Another portion of H22 (30 ml) was added before an excess was obvious . Nater ( 5 0 ml ) was then added to the mixture and the ethanol was removed under vacuum. The aqueous layer was made slightly basic and product was extracted 20 ~nto C~2C12. This product was then extracted with two portions of lN HCl ( 2 x 100 ml ), leaving black CH2Cl2 solution. The, ;nr~d aqueous ~LL~_LS were extracted with CH2Cl2 (100 ml) before making basic with NaO~ and extracting product into C~I2C12. The product was dried 25 over MgSO4 and solvent was removed under vacuum to leave 3-7 g of dark oil.
E~AMPLE 8 E3CE2C_~ C ~ E Cll C~ E2 ~1-WO95131448 .~ P~ S ~ /
"~ ~ 89573 The starting amine (3.7 g, 0.0289 mole) was dissolved in chloroform (100 ml) at room t~ UL-3 under an a~ re of N2, and the chlorine (2.25 g.
0.0317 mole) was dissolved in chloroform (120 ml). The 5 amine solution was chilled to 15 and the chlorine solution was added dropwise over a 15 minute period at 15, and a dark precipitate formed. The coQling bath was removed and the solution was heated to 50 for one hour. Heat was removed and saturated sodium 10 bicarbonate solution (100 ml) was carefully added.
After shaking, the organic layer was separated, given a brine wash, dried over MgSO4, then concentrated under vacuum to yield a dark oil (3.7 g). Chromatography using a Michel-Miller low pressure silica gel column 15 and eluting with heptane/ethyl acetate, _ in;n~ like fractions, and concentrating under vacuum yields a dark brown oil (2.8 g).
E~lPLE 9 Br ~-- CC 4 ~E2 20 The amine (3.73 g, 0.0327 mole) was slurried in CCl4 (100 ml) at room t ~ -LuLe under an a~ _~hele of N2. The N-bromos~ inim;~l- (1 ecluivalent) was added portionwise to the amine slurry over a 10 minute period at 24-30, and the mixture was stirred for 1.5 hours.
2~ Analysis by T1C silica gel (1:1 heptane/ethyl acetate) shvwed product and sQme L~ -;nirs starting amine.
Heating at 70 was applied for 1.5 hours. Analysis by TLC showed mainly product. The mixture was cooled to room temperature and ethyl ether (about 100 ml) was 30 added. The resulting mixture was chilled to 5 and filtered to yield solid material (2.6 g) which was Wo 95131448 ~ S 2 1 8 ~ 5 7 3 r~ Jv s -~07 discarded. The solution was conc~.-LL- Led under vacuum to yield a red solid (6.5 g). This material was dissolved in ethyl acetate (80 ml) and washed with H2O
(2x80 ml). The organic layer was separated and given a s brine wash, then dried over MgSO4, and concentrated under vacuum to yield a tan solid (5.24 g).
EXA~LE 10 ~3C~2C~NE2 NCS E3C~2C~
The amine (4.0 g, 0.0312 mole) was slurried in CC14 (130 ml) at room ~ CLLul~: under an atmosphere of N2. The N-chlorn~ucc;n;m;~l~ (4.25 g, 0.0312 mole) was added portionwise over a 5 minute period at 25-37, and the mixture was stirred at room ~ UL~ for 1.5 hours. Analysis by TLC silica gel (1:1 heptane/ethyl 15 acetate) showed no starting material ~ -;ning. The mixture was then diluted with ethyl ether (250 ml) and filtered. The filtrate was washed twice with water.
The organic layer was separated and given a brine wash, then dried over MgSO4, and cu..ce..LL~Led under vacuum to 20 yield a brown oil (4.65 g).
EXA~LE 1 1 N~ ,C~I~aCF3 C~2COOII C~2Cocl (a,a,a-Trifluoro-p-tolyl) acetic acid (1.20 g, 0.0059 mole) was dissolved in thionyl chloride (25 ml) 25 and heated at reflux for one hour, then concentrated under vacuum to a pale yellow oil. Analysis by NMR
WO 95131448 ~ t ,~ ~ J,.. 't $ ~ 85~73 showed starting material 1~ in;ng and the mixture was then retreated with additional thionyl chloride (25 ml) and concentrated under vacuum to give the acid ~hl~rirl.o as a pale yellow oil (1.26 g). The amine ( 0.73 9, 0.004g mole) was dissolved in warm xylenes (40 ml~ and heating was continued in an oil bath wherein the acid chloride (1.26 g, 0.0057 mole), dissolved in xylenes (10 ml), was added to the amine solution dropwise over a five minute period under an a~ re of N2 at 80-lo 100. A precipitate immediately formed. The slurry was then heated at 140 for one hour and all the precipitate dissolved. The resulting mixture was stirred overnight at room temperature. Analysis by TLC
9:1 CEI2C12/ethyl acetate silica gel showed a faint spot ;n;n~ for the starting amine. The mixture was then concentrated under vacuum to a tan solid (1.6 g).
Chromatography using a Michel-Miller low ~L~IS;:~U'~
silica gel column and eluting with 1% ethyl acetate/CH2C12, pooling like fractions, then ::~,nc~ L-~ing under vacuum yielded a light tan solid (1.2 g) recryst~ll;7scl from ethyl ether.
E~AMPLE 12 3 ~ ¢CE ~ lclle- ~ O ~ OCE12CF3 c~2coo~
The starting acid (1.20 g, 0.0051 mole) was 25 slurried in dichloromethane (20 ml) under an ~; ~h~L~:
of N2. Thionyl chl~ri~l~ (1 ml, 0.0137 mole) was added and the resulting mixture was heated at reflux temperature for 1.5 ~ours, then concentrated under vacuum to give the acid ~-hl~r;~l~ as a yellow oil. The amine (0.65 g, 0.0034 mole) was slurried at room Gl_ULt! in CE12C12 (100 ml) under an atmosphere of WO 95/31448 ~ r ~ 21 8 9 5 7 3 P~~ 07 ~2, and TEA (trietnylamine) ~0.52 g, 0-0051 20ie) was dissoived into this mixture. The above acid chloride, dissolved in CX2C12 (10 ml) was added dropwise to the amine mixture over a ten minute perlod at 23-27, and he resulting mixture was stirred at room temperature for one hour. Analysis by T~C silica gel 1:
heptane~ethyl acetate showed starting amine L~ ~ining~
so the mixture was heating at reflux temperature overnight and analysis by TLC silica gel 3 :1 heptane/ethyl acetate showed a very faint spot for the starting amine. After standing, the reaction mixture was Doured into a seDaration funnel with H2O ( 40 ml ) ~/here t~.e mixt~re ~as snaken and t.he oryanic 1 ayer was seDarate~ ana~asnea wi~ e foi owing: iO ~1 2N ~:C', 40 ml ;-2, .0 mi saturated NaHCO3, and 20 mi brine.
~he oryanic layer was separated and dried over MgSO4, ~hen concentrated under vacuum to give a dark oil ( about 1. 2 g) . Chromatography using a Michel-Miller low ~L~:SaULC! silica gel column and eluting with 596 ethyl acetate/CH2C12,, inin5 like fractions, then concentrating under vacuum yielded a tan glass, which was crys~Al1;7ed from ethyl acetate/heptane then filtered to yield a light tan solid (0.29 g).
_XAMPLE 13 O d - ~1 2 Ctt2COO~ C~2COCl The starting acid (1.25 g, 0.0048 mole) was dissolved in thionyl chloride ( 25 ml ) and heated at reflux ~ ~LULt~ for two hours, then c~,..c~.~LL~Led under vacuum to give the acid chloride as a yellow oil SUBSTITUTE SHEET (RULE 26) -WO 95/31448 ~ r 2 ~ 8 9 ~ 7 3 (1.34 g). The amine (0.80 g, 0.0041 mole) was dissolved in toluene (80 ml) and TEA (0.50 g) was added under an atmosphere of N2. The above acid chloride, dissolved in toluene ( 10 ml ) was added to the amine 5 mixture over a ten minute period at 30-35C, then the resulting mixture was heated overnight at 85.
Analysis by TLC silica gel 2 :1 ethyl acetate/heptane showed a very faint spot 1~ ;n;n~ for the starting amine. The mixture was then c~ ellLL,lLed under vacuum 10 to an oil (1.8 g). Chromatography using a Michel-Miller low pressure silica gel colu~n and eluting with 2~ ethyl acetate/CH2C12, ,- I ;n;n~ like fractions and ~o.~ LLc,Ling under vacuum yielded a solid product (0.84 g).
E~a~qPLE 14 ~11112 pyndine ¢r~2 Anthranilonitrile (29.5 g, 0.25 mole) and triethylamine (25.3 g, 0.25 moles) were stirred in pyridine (160 ml), as H2S was bubbled in for one hour.
TLC 1:1 CH2C12:ethyl acetate showed starting material L~ ;nin~, The addition of H2S was continued for an ~ 1it;~n~1 30 minutes and the mixture was stirred for one hour, then poured onto ice-H2O (700 ml). The solid was collected and washed with ~2O (31 g) (m.p. 119-121).
¢tC` ~2 _ H22 ~5 ~6-WO 95131448 ; ~ 9 5 7 3 P~ S 0~07 he starti3g Amin~h~n7~nzo--rhio~mi-l~a ( 19.3 g) was stir:ed in ethanol ~ 200 ml ), heating enough for the nitrile to dissolve. To this solution was added 30%
}~22 droE)wise, while the reaction was monitored by silica gel TLC in ethyl acetate. When starting material was gone, H2O (200 ml) was added. The product was collected by filtration and recryst~l l i 7ed from ethanol-water to give a solid (12.5 g) (m.p. 165-166).
A second crop was also collected (3.6 g) (m.p. 163-11J 165) .
Cl 1l IA3 Cl CU I TEBA ~?~ Cn2~~c3?3 __ ~?~ C~lz~o--~}CF3 ~zDH ~h,N--C--cni~ ~CF
l ~C3 i, C_N--S /B) A mixture of the amide (1.0 g, 0.00234 mole), potassium carbonate (1.15 g, 0.00829 mole), water (5 ml ), dichloromethane ( lO ml ), triethylbenzyl . i ~-bromide (TEBA, 0 . 68 g, 0 . 0025 mole ), methyl iodide ( 3 ml), and 10~ sodium hydroxide (3 ml) was stirred vigorous ly at room temperature overnight . ~he contents were diluted with dichloromethane, -he layers passed `0 through phase-separating paper, and were stripped. The residue was triturated under ether and the mixture was filtered. The filtrate was washed once with brine and was dried with ~gSO4. Cu..-e.--Lc~tion gave 960 mg of material which was ch~ ~ -to~raphed on dry pack silica.
~; Using heptane-ethyl acetate mixtures, c~ (A) was obtained as a solid (370 mg, m.p. 84-86.5), and c ~ _ ' (B) was also obtained as a ~olid ( 280 mg, m.p.
145-147) .
SUBSTITUTE SHEET (RULE26) WO 95131448 ~ P ,~ 2 1 8 9 5 7 3 P~~ 07 EXAM~LE 1 7 DM~DMA ~ 11 ~0{~-CF~
N ~ c~N~cr~
A solution of the amide (0.30 g, 0.703 mole) and dimethylfnrr irla dimethylacetal (DM??D~A) (0.17 g, 1.41 mole) in toluene ~5 ml) was heated at reflux for about seven hours, was cooled, and was stripped to dryness The residue was then triturated under a few mls of ether to afford 200 mg of 2roduct ~m.p. 194-200).
-XA~'LE 18 81 H.(X`H ~ HCI
~7~ C{!2--~30~CF~ ~ H olf ,C~,~N~C~S~~cr, 1~ N~13 1~1 A solution of the ketoamide (250 mg, 0.567 mmol)and meth~,..y. inP hydrochloride (250 mg) was heated for 4 hours at approximately 60 and was then allowed to cool. The solution was concentrated to a residue ?~ which was taken up in cold water and ether. The ethereal was then washed once with brine and was dried.
Concentration gave 230 mg of ?roduct.
EXA~LE 19 Cl ' CHlCONHNH~ Cl 8 C~?~ 2 CF~ ~ C~O~C~
'0 A solution of the ketoa~ide (250 mg, 0.567 mmol), acetic hydrazide (100 mg, 1.35 mmol), and a 0.41 M
solution of dry IIYdL~Ye~I chloride (3.28 ml, 1.35 mmol) in ethanol all in 10 ml of ethanol was heated for about three hours at 60-70 and was allowed to cool. The SUESTITUTE SHEET (RULE 26~
.
Wo95131448 ~ 21 89573 ethanol was removed in vacuo and ~he residue was partitioned between ethyl acetate/e~her/brine. The layers were separated and the organic phase was washed once with brine and was dried. Concentration gave 280 mg of a yellow solid. This material was recrys~A 1 1 i 7ed from ethyl acetate to afford 70 mg of dimeric product (m.p. 233-240). The filtrate was concentrated and the residue was chromatographed on silica gel (230-400 mesh) to afford 140 mg of monomer hydLu~one product.
M.P. 161-174 ~dec~. (Also obtained 10 mg of higher Rf r~~tPri;~l ), C~ I~ HSCHXH'SH ~1 CH2~0~C~ C ~N~C--C~O~CF~
C2H,O OCIB~
A solution of the ketoamide (250 mg, 0.567 mmol), 1; 1,2-ethanedithiol ~0.062 ml, 69 mg, 0.74 mmol), and a 1.46 ~ solution of hydLuy~ll chloride (0.39 ml, 0.57 mmol ) in ethanol, all in 3 to 5 ml ethanol was heated at reflux overnight. The dithiol (0.062 ml) was then added and the contents were ref luxerd f or 7 hours . The '!) solution was diluted with ether and was washed twice with 0.1 N NaOH and once with brine and was dried.
Concentration gave 300 mg which was chromatographed on silica (230-400 mesh) using heptane/dichloromethane eluants to afford 100 mg of ~
~5 EXAMPLE 21 1~
SUBSTITUTE SHEET ~RULE 26) WO 95131448 ~ 8 ~ ~ 7 3 r~ f~O7 Cl O
Cil3~N~C~C1~~CF3 N--5 ~ CRN_C~2C02CE2-phenyl Cl K7CO3 C~3~N,C~C~O~CF3 CH30H N--5 11 C~CE12C02EI
To a solution of the benzyl ester (1.3 g, 2.16 mmol~ in 15 ml of methanol was added potassium carbonate (0.30 g, 2.17 mmol) followed by 2-4 ml of 5 water. After several hours, the mixture (precipitate present~ was poured onto ice water which was then adjusted to pH 3 with dilute hydrochloric acid. The contents were extracted twice with ethyl acetate, the C ' 'n-~d organics were washed once with brine and were 10 dried. Co.~cen~LclLion gave 1.0 g of product which ~ras triturated with heptane/ethyl acetate to afford 680 mg of material. M.P. 177-183 (dec). This material was dissolved at reflux in approximately 50:50 heptane: ethyl acetate ( 10 ml ) . Upon cooling, the 15 solution was stirred and was treated with about 4 ml heptane. Precipitation eventually oc. uLL~d. The solid was collected to afford 270 mg of c ~1. M.P. 195-196 (dec).
o ~~ 11 1 ~ CF3 N--s 11 C}}NRC3~2C02 Cl O
NaOH CE~3~ N~C~c~0~cF3 N--5 El C~ C~ CO N~
WO95131448 ~ $~ 2189573 r~ 3Q7 To a mixture of the acid (0.185 mg, 0.361 mmol) in about 5 ml of methanol was added 2N sodium hydroxide (0.18 ml, 0.36 mmol). The mixture immediately became a solution (yellcw) but within 1 to 2 minutes began to 5 show a white precipitate which accumulated over time.
Collection and drying in vacuo at 50-60 for one hour gave 100 mg c '.
EXA~5PLE 23 C2E~5_~--NE12 + (cF3co)2o N--S
C2~15~ COCF
CH2CI~ N--S
10 A solution of the isothiazrlr ;Tl~ (2.0 g, 15.6 mmol ) was added to dichloromethane ( 25 ml ) . The mixture was cooled in ice and trifluoroacetic anhydride (3.4 ml, 5.06 g, 24.1 mmol) was added clL~ e. The solution was allowed to warm to room, - aLur~ and 15 then stirred overnight. Concentration gave 3.0 g of ~o C2~s~ 3 H2SO4 ~ IICOCF3 To a solution at 50-65 of the amide (3.0 g, 13.4 20 mmol) in about 60 ml of sulfuric acid was added dropwise about 12 ml of fuming nitric acid. An exotherm was noted during the addition of the fir~t 3 to 4 ml. The solution was heated for an additional 3 hours at 70-75 and was then cooled. The solution was 25 added to 500 ml ice water and the precipitate was W095/31448 ~ ,r ~ } 89513 P~ 07 col lect~ and air-dried to give 2.45 g of (m.p. 115-118).
No2 K7C03 No2 c2~5 ~ ~ C2~s~
~--NI~COCF3 aque~ N~2 A mixture of the amide (2.35 9, 8.73 mmol) and potassium carbonate (2_65 g, 19.2 mmol) in 40 ml of water and 10 ml of methanol was stirred at room temperature overnight. The mixture was adjusted to pH
6-7 with 1.0 N HC1 and was then extracted three times 10 with ether., The combined organics were then dried (MgS04). Cvllc~:..Llation gave 1.47 of comound. M.P.
131-132 .5.
C213s~N~2 ClCOC~12~0~CF3 PCH3 C2~5`~N' Cli2~0~CF3 1~ A solution of thionyl chloride (1.96 g, 16.5 mmol~
and phenylacetic acide (2.45 g, 8.27 mmol) in 20 ml of dichl~ n~ was heated at reflux for three hours and was then stripped to dryness. The liquid was then taken up in 5-10 ml of dry toluene, was added dropwise to a mixture of the amine (1.43 g, 8.26 mmol) in 20 ml of toluene. The contents were then heated at reflux overnight for 36 hours. The solution was stripped to dryness and was chromatographed on silica gel (230-400 mesh) to afford 1.22 g ofcompound (m.p. 135-138).
Wo 95131448 ~ $: I ~ 2 1 8 9 5 7 3 r ~
- Insecticide, Miticide and Nematicide Utility The ~_ _ of Formula ( 1 ), ~ 2 ~, or 13 ) show activity against a number of insects and mites. More 5 specifically, the c, _lr~- show activity against melon aphid, which is a member of the insect order F~ Lel~.
Other members of the ~omoptera include l~A~hnpp~rs, planthoppers, pear pyslla, apple sucker, scale insects, whiteflies, spittle bugs as well as numerous other host 10 specific aphid species. Activity has also been observed against greenhouse thrips, which are members of the order ~rhysanoptera. The ~ also show activity against Southern armyworm, which is a member of the insect order Lepidop~era. Other typical members 15 of this order are codling moth, cutworm, clothes moth, Tn~ 1 moth, leaf rollers, corn earworm, EULU~
corn borer, cabbage worm, cabbage looper, cotton bollworm, bagworm, eastern tent caterpillar, sod webworm, and fall armyworm.
The ~_ , _ ' - of Formula ( l ), ( 2 ), or ( 3 ) are useful for reducing populations of insects and mites, and are used in a method of inhibiting an insect or mite population which _ ~-s applying to a locus of the insect or mite an effective insect- or mite-inactivating amount of a c _ ~ of Formula ( 1 ), (2), or (3). The "locus" of insects or mites is a term used herein to refer to the environment in which the insects or mites live or where their eggs are present, ;nr~ ;n~ the air surrounding them, the food they eat, or objects which they contact. For example, plant-ingesting insects or mites can be controlled by applying the active ~ _ ' to plant parts, which the insects or mites eat, particularly the foliage. It is WO95131448 - r ~ . 2 1 8 9 5 7 3 F~ J,,5 -~07 C~ ted that the c- might also be useful to protect textiles, paper, stored grain, or seeds by applying an active ~ ~ to such substance. The term "inhibiting an insect or mite" refers to a 5 decrease in the numbers of living insects or mites; or a decrease in the number of viable insect or mite eggs.
The extent of reduction accomplished by a ~ __ depends, of course, upon the ap~1 ;At ;~n rate of the _ ~1, the particular ~ d used, and the target 10 insect or mite species. At least an insect-inactivating or mite-inactivating amount should be used. The terms "insect-inactivating amount" and "mite-inactivating amount" are used to describe the amount, which is sllff;c ;-~nt to cause a measurable 15 reduction in the treated insect or mite population.
Generally an amount in the range from about 1 to about 1000 ppm active _ ' is used.
C , ~E were tested ~or insecticidal, miticidal and nematicidal activity against eight species.
20 R~sults are reported in the following table, wherein the following abbreviations are used:
A~H refers to aster lF~fl~pp~r BAW refers to beet armyworm CA refers to cotton aphid NEM refers to peanut root knot r ~tod~
SCRW refers to southern corn root worm TBW refers to tobacco budworm TSS~S refers to two spotted spider mite WO9S/31448 ~ , 2189573 r~l,u~ s 307 .
GECR refers to German cockroach In conducting evaluations of insecticidal activity, each test ~~, ' was formulated as a 400 ppm solution, and this solution was then diluted with water to give lesser concentrations. The 400 ppm S solution was prepared by ~ ' ;n;n~ 19.2 mL of .05%
solution of Tween 20 (polyoxyethylene t20) sorbitan monolaurate) in water with a solution of 8 mg of the c, ' in 0.8 mL of acetone~EtOH (9/1).
Activity against aster leAfhnrp~r ~l~la~,Lu~Leles 10 fascifrons) was tested as follows. The test was run using concentrations of 400 ppm and 50 ppm. One ounce plastic cups c~nt~;n;n~ a cotton wick was sprayed with 0.4 mL of formulated material using a flat-fan nozzle.
The excess moisture was allowed to evaporate. Then lS five to ten carbon dioxide anesthetized adult Ir~: fhr pp~rs were added to each cup. The cups were capped and held at room temperature for 24 hours.
Percent mortality was then de~r~rm;ned.
Activity against beet armyworm (SpOdu,uLela exi~ua) 20 was evaluated as follows. The test is run using cv--c~:--LL~Lions of 400 ppm and 50 ppm. A general purpose lepidoptera artificial diet was diluted to half strength with a 596 non nutritive agar. 8 mL of this diet material was ~ pr~n~ed into one ounce diet cups.
25 One hour prior to tL. L, 35 to 40 eggs were dispensed onto the diet surface. The cups were then sprayed with formulated material through a flat-fan nozzle. Treated cups were air dried prior to sealing with plastic caps. The cups were held for 6 days at 30 room temperature. Activity was then rated based on the WO9S/31448 ~ ir t`~7~ t!~ r 21~573 ~ 9~ 07 tot~l number of live and dead larvae, and on the size of live larvae.
Activity against cotton aphid (Aphis gossy-pii) and two spotted spider mite ( :reLLally~llus urticae) was 5 evaluated as follows. Golden crookneck squash plants were grown to the F~Yr~n~ d cotyledon stage (about 6 to 8 days). The plants were infested with cotton aphids and two spotted spider mites 16 to 24 hours before application of the test material by transfer of lO infested foliage cut from a stock colony. Immediately prior to spray application of the test material the transfer foliage is removed from the squash plants.
The test is run using :orlc~ Lltions of 400 ppm and 50 ppm. The plants are sprayed with test solution using 15 an atomizing sprayer at 17 psi. Both surfaces of the leaves are covered until runoff, and then allowed to dry. Activity of each ~ ~ ' was ~ rm; n~rl three days after tleai L. Activity was rated as a percent based on the mites/aphids present in plants sprayed 20 with solvent alone.
Activity against peanut root knot r Lod~
(Meloidogy-ne arenaria) was evaluated as follows. Five untreated C~ seeds are placed into the bottom of a clear one ounce cup, 20 g of clean white sand is 25 added, and the cups were sprayed while rotating on a pedestal allowing l.0 mL of a 400 ppm solution to be deposited on the sand. To each cup was ~;Rpf-n~P~l 2.5 to 3.0 mL of qC~ n;7ecl water containing 300 to 500 nematodes. The cups were held for lO to 12 days in an 30 environmental growth chamber at a t~ ~ Lure of 76 to 85 DF and ambient humidity of 50 to 60DD. After lO to 12 days thQ cups were evaluated by inverting the cup and observing nematode mortality and feeding damage to the ~ plants.
W095/3l448 ~ '.P!~.. 2~89573 r~ 07 Activity on Southern corn LUO~ JLIII (Diabrotica .!n~cimr~tata howardi Barber) was evaluated by adding one mL of test solution containing a pL-:de~ ""nF~l concentration of test c, _ 7 to a cup containing a 5 kernel of corn in 16 g of sterile soil. This produces a soil concentration of 24 ppm. After 1.5 to 2 hours of drying, five 4th instar corn LvvL JLll- larvae were added to the individual cups. ~5ortality was measured at 3-4 days by emptying the cup onto a pan and 10 inspecting the soil for live LUOL~.JLl.._~.
Activity against tobacco budworm tNeliothis virescens) was evaluated as follows. A general purpose lepidoptera artificial diet was diluted to half strength with a 5% non nutritive agar. 8 mL of ~his 15 diet material was ~ p~n~ed into each one ounce diet cup. One hour prior to treatment 18 to 20 eggs were dispensed onto the diet surface. The cups were then sprayed with formulated material through a flat-fan nozzle. The test was run using col~c~:llLLaLions of 400 20 ppm and 50 ppm. Treated cups were air dried prior to sealing with plastic caps. The cups were held for 6 days at room , aLuL~. Activity was then rated based on the total number of live and dead larvae, and on the size of live larvae.
Activity against German cockroach ( Blattella germanicus) was evaluated as follow5. 8 mL of alfalfa based green insect diet material was dispensed into a one ounce diet cup. The cups were then sprayed with formulated material through a flat-fan nozzle. The test was run using concentrations of 400 ppm and 50 ppm. Treated cups were air dried for 24 hours and infested with five late third or early fourth instar German cockroaches. The cups were capped and held for seven days in an environmental growth chamber at a _ _ _ _ _ _ WO 95/31448 ~ 2 t ~ 7 3 I ~ 5.'~ 07 ~ , ~~ CLLUL~ of 76-85C. Activity was then rated based on the total number of live and dead insect6.
The following results are expressed as percent of orqanisms controlled.
ICIr~, ANI NB~IATICIDB DATA
Compound Ar r~ BAW CA NEM SCRW TBW TSS~I GBCR
ppm ppm ppm ppm ppm ppm ppm ppm ppm ppm ppm ppm ppm ppm ppm ppm 0~100~ 100~ 40~ 0~ 100~ 0~ 100 O O O O - O O O
O O O O O O O O
WO 95131448 ~ ~ ~ ~ 2 ~ 8 9 5 7 3 ~ 07 1~ SECrlCIDE, ~I TICII~., AN'D ~EMATICIDE DATA
Compld ALII BAW CA NEM SCR TBW TSSM CECR
ppm ppm ppm ppm 400 ppm ppm ppm ~0 ppm 50 50 50 ppm ppm ppm ppm 50 ppm ppm ppm ppm O O O O O O O O
100 100 80 o 0 0 90 o 1~60 100 o 0 0 100 0 o =
WO 95/31448 ~ " ~ , 2 ~ 8q 513 ~ s ~(i307 16100 lO0 100 0 0 100 100 100 o 0 0 0 0 0 0 20 1860 lO0 60 0 0 80 100 o l940 100 0 0 0 lO0 0 0 2180 100 0 0 0 lO0 0 0 22lO0 0 lO0 lO0 lO0 100 0 lO0 lO0lO0 100 0 0 lO0 0 80 O O O O O O O O
24lO0 100 lO0 0 0 100 lO0 40 25100 lO0 lO0 0 0 lO0 100 0 W09513~448 ;i ;~ f 9573 ~. .r Il` SECIICIDE, MTlClD, AND ~EMATICIDE DATA
Cbmpound ALH BAW CA NEM SCR TBW TSSM GECR
ppm ppm ppm ppm 400 ppm ppm ppm ppm 50 50 50 ppm ppm ppm ppm 50 ppm ppm ppm ppm O O O O O O O O
O O O O O O O O
33100 100 100 0 100 100 lO0 100 100 lO0 100 0 0 100 100 60 ~1-WO95/31448 ~ ' ?7 89573 ~ .'t-~07 WO 95/.31448 i` ~ ,r ~ 2 ~ 8 9 5 7 3 ~ s D '307 Il~-SECTICIDE, M~ICIDE, AND NEMATICIDE DATA
Compowld ALH BAW CA NEM SCR TBW TSSM GECR
ppm ppm ppm ppm 400 ppm ppm ppm ppm 50 50 50 ppm ppm ppm ppm 50 ppm ppm ppm ppm 100 100 0 0 100 lOo 60 100 0 o o 0 0 48100 100 lOo 0 100 100 100 60 5080 0 100 0 0 30 100 o o o 0 o 0 0 0 51100 100 100 0 o 100 o o 5280 100 0 o o 0 o 0 5350 0 0 o 0 o 90 0 0 0 0 o 0 0 o WO 95131448 ~ ;'r~ 2 1 8 9 $ 7 3 P~ ,JI. ~07 ~
s8100 100 100 - - 100 100 100 lQ0 100 100 - - 100 100 40 6720 100 - 0 0 100 o 40 WO 95131448 ~ 2 1 ~ 9 5 7 3 r~ 07 ~ SECTICIDE, M~ICID., AND \IEMATICIDE DATA
Compow~ Al,H BAW CA NEM SCR TBW TSSM GEClR
ppm ppm ppm ppm 400 ppm ppm ppm ppm 50 50 50 ppm ppm ppm ppm 50 ppm ppm ppm ppm 72100 lOo 100 0 100 lOo 100 100 _ 100 100 - o 0 100 0 60 77100 100 0 o 0 100. o 80 loO lOo 0 o 0 lOo 0 20 80 0 0 0 0 . 0 0 0 o -6~
WO 9~/31448 , ~ 8 9 5 7 3 P ~ 07 _ ~2 -100 100 100 0 100 100 100 100 0 H0 ~0 0 100 90 0 O O O O O O O O
O O O O O O O O
WO95131448 '` ' ^~ 1 89573 P ~ r 7 226 0 100 lO0 0 100 lO0 100 100 O O O O O O O O
89 0 100 lO0 100 lO0 100 100 lO0 0100 100 0 0 90 lQ0 0 O O O O O O O O
9260 100 100 - - 100 lO0 100 O O O O O O O O
9980 100 100 100 100 lO0 100 100 244 0 lO0 0 0 0 100 0 80 O O O O O O O O
WO95131448 ~ 2189573 r~ s~ ~07 9840 lO0 100 100 100 100 100 100 245lO0 60 100 0 100 lO0 0 lO0 23060 lO0 0 0 0 100 0 20 O O O O O O O O
24880 100 100 0 100 100 100 lO0 O O O O O O O O
O O O O O O O O
O O O O O O O O
O O O O O O O O
WO 95131448 ~ . 2 1 ~ 9 5 7 3 P~ 7 O O O O O O O O
O O O O O O O O
O O O O O O O O
WO 95/31448 ~, r ~ fS 7~ t C 2 1 8 9 5 7 3 r~ 06107 13360 lO0 100 100 0 100 100 80 060 90 100 0 40 lO0 0 1~5 0 100 0 100 0 100 0 100 O O O O O O O O
13~60 100 0 - 0 lO0 0 100 C O O - O O O O
13860 100 80 100 100 100 100 lO0 O O O - O O O O
WO 95131448 ~;", ,;~ 2 ~ 8 9 5 7 3 WO95131448 , . ~ .~.t 8 95 73 r~
WO 9S131448 5' ~ 2 1 8 9 5 7 3 r ~ 307 .
O O O O O O O O
O O O O O O O O
O O O O O O O O
O - O O O O O O
O O O O O O O O
O O O O O O O O
179 0 100 80 lO0 100 100 80 100 180 60 100 100 100 lO0 100 lO0 100 0 lO0 100 0 0 60 80 0 181 0 100 100 0 100 lO0 90 lO0 - 0 100 lO0 0 0 0 60 0 .
WO 95131448 ~ 2 1 8 ~ ~ 7 3 WO 95/31448 ~ 2 1 8 ~ 5 7 3 r~
O O O O O O O O
O O O O O O O O
O O O O O O O O
_ 40 0 0 0 0 0 .. . . .. ..
W095131448 f , 1' ~ tS ~ ~ 2~9573 11~ .'0~07 o o o o O O O
O O O O O
20g 0 0 100 100 0 90 100 40 2I1 100 100 100 0 0 gO 100 100 213 100 100 100 lOO O 100 100 100 21~ 0 100 100 ~00 0 70 90 O90 0 o o 70 0 Wo95/31448 . ~ ' 2 ~ 89573 r~ 07 Page ~ pop filing WO 9~/31448 ~ ~ 2 1 ! 8 9~5 7 3 ~ ~ c ~o7 indicates testing at 200 ppm.
Funqicide Utility The c~ _ r~ of the present invention have been found to control fungi, particularly plant pathogens.
When employed in the treatment of plant fungal r~ice~cec, the c .3c are applied to the plants in a disease inhibiting and phytologically acceptable amount. The term "disease inhibiting and phyiolo~;c~11y acceptable amount", as used herein, 70 refers to an amount of a ~ ~ of the invention which kills or inhibits the plant disease for which control is desired, but is not significantly toxic to the plant. This amount will generally be from about 1 to 1000 ppm, with lO to 500 ppm being ~Le:r~r lt:d. The 7~ exact concentration of _ .1 required varies with the fungal disease to be controlled, the type formulation employed, the method of application, the particular plant species, climate conditions and the like. A suitable application rate is typically in the 20 range from 0.10 to 4 lb/A. The ' of the invention may also be used to protect stored grain and other non-plant loci from fungal infestation.
Gre~nh~ ce Tests The following experiments were performed in the5 laboratory to determine the flln~iei~l~l efficacy of the ~~ of the invention.
The test c ' were fr~r~ ir~rl for application by dissolving 50 mg of the, _ ~1 into 1.25 ml of solvent. The solvent was prepared by mixing 50 ml of 30 "Tween 20" ~polyoxyethylene (20) sorbitan ~ lrate emulsifier) with 4?5 ml of acetone and 475 ml of etha-W0 95/31448 ~ ~" ~3 r ~ ~ 2 1 8 9 5 7 3 ~ 5~ 0~
nol. The solvent/ , ri solution was diluted to125 ml with ~l~ion;~e~d water. The resulting formulation contains 400 ppm test chemical. Lower co.lce~ L~llons were obtained by serial dilution with the 5 solvent-sur~actant mixture.
The formulated test ~ c were applied by foliar spray. The following plant pathoger~s and their co~x~cpon~ g plants were employed.
Pathogen ~c i ~na~ n ~ost in following Table ~rysiphe graminis tritici ERYSGT wheat (powdery mildew) Pyricularia oryzae ( rice PYRIOR rice bla$t ) Puccinid recondita P~JCCRT wheat tritici (lea~ rust) ,h.1i_~ ;A nodorum L13PTNO wheat ( glume ~lotch ) Pla$1nopara viticola PLASVI grape ( downy mildew ) ZO The formulated techniçal ~ I, clc were sprayed on all foliar sur~aces o~ the host ~lants (Qr cut berry) to past run-off. Single pots of each host plant were placed on raised, ~evolving pedestals in a fume hoQd.
Test ~olutions were sprayed on all foliar sur~aces.
15 All treatments were allowed to dry and the plants were inQculated with the appropxiate pathogens within 2-4 hours .
The following table presents the activity of typical ~ qs Qf the p~ese~t inventio~ when 20 evaluated in this experiment. The e~fective~ess of _79--WO95131448 ~ ? ~ S r-~3 ~573 ~ 5 ~ ~07 test ,u~ds in controlling disease was rated using thQ ~follçwing sçale.
O = not tQsted aga~nst sp~rifi~- organism - = 0-19% control at 400 ppm + = 20-89% control at 400 ppm ++ = 90-100% control at 400 ppm +++ = 90-100% control at 100 ppm W0 95131448 ~ P~ 07 ¦ COMPOUN ¦ ERYSGT ¦ PYRIOR ¦ PUCCRT ¦ LEI~NO ¦ PLASV~ ¦
D NUMBER
COI~POUND ~RYSGT PYRIOR PUCCRT LEPTNO PLASVI
+ + +++ + +
2 + + + + +
3 + + +++ + +
Q --~?, N - C - C - Z ~ R~
( I 1) .~lkyl S~ ~s-~lkYl 113~ H o,S-~lkyl llrNHR
11~ 1111 R~ O
` J R ~ y - C - C--z N_5 R ~C~
( 15) A 3 ~ ethylene derivatives (3) wherein the methylene i5 substituted with N(CH3)2 may be prepared by treating the N-(S-isothiazolyl)amide (10) with the appropriate 5 N,N-dialkylc~lrhr~ami~ di-alkylacetal in the presence of toluene with heating. The N,N-dialkyl derivatives (11) can be converted to their NHR24 derivatives by treating with the appropriate amine to give (12). The N-(5-isothiazolyl)am.ides (10) can also be c~ ve:LLed to o S,S-ketene acetals (14) and optionally, to cyclic systems ( 15 ) .
C~ of Formula (2) where W = O, S, or NR24 can be prepared using the process illustrated in Scheme 3:
5 Scheme 3 SUBSTITUTE SHEET (RULE 26J
WO 95131448 ~ 5. ~ 07 c ` 2189~73 R3~_ n R3~.~ 21 =C
(I) (9) (2) The carbonyl derivative (1~ i5 treated with Lawesson's reagent to give the thione (9) which can be converted to ~m;~linP~ where W-G = NR25R26 or NHR25 with 5 primary and secondary aminefi. The thione can also be S-alkylated using a dialkyl sulfate or alkyl iodide in the p- ~s. n~ e of potassium c;~rhnn~t~ to give, ~e (2) where W=S and G is alkyl, which in turn, can be reacted with nucleophiles such as, for example, OR-, ~lH2R24, NEIR24R25, or NR24R25R26 to give other ~
Of (2)-wo 95/31448 ~~
~ 21 895i3 r~ ,. 07 EXA~LE5 The following Tables I, II, and II_ identify Clr1c of Formula ( 1 ), ( 2 ), and ( 3 ), respectively, 5 that were prepared by the processes illustrated in the foregoing schemes.
TA~3LF' I
~:x y Z .R R3 R~ ~p C
CH2~ OCH2CF3 H CH3 Br 95--96 CH2~ f?CH2CF3 H CH3 H 162--163 3CH2~?CH2CF3 H CH3 Cl 117-118 :CH2~_~?CH2CF3 H C~33 Cl 143--144 --''H2~cfcH?)3 H ~-H3 :~ 136-1~37 H2 ~3_~Cl H -H203 Cl 124-125 CH2~ OCHF2 H CH3 ~r 110-111 CH2~OCH3 H C2?3 Cl 113-114 CH2~0CH2CF3 H CH203 Cl 112-113 13 CH2 ~3C(CH3)3 H CH3 3r 110--111 11 CEf2 ~C(CE~?)3 H 02C~3 Cl 114-llS
;2 CH2 ~O~Cl R CH3 Br 131--132 .3 CH2 --'-H2CH2~ CF3 d ca3 Cl 14q--145 '~ CH2 ~C~CH3)3 H CE3 Cl 114-llS
!5 C!32 ~-CF3 H CH3 Cl 170-171 15 CE12 ~O~f~CF3 H C~'f3 Cl 126--127 17 CH2 O H CE~3 Cl 192-193 ~ N
18 CE~2 ~~ o-~CF3 H CH3 Cl 70-75 !9 CH2 ~--O--~Cl H CEf3 Cl 177-179 20 CH2 ~O ~' ~Cl H CH3 Cl 166-167 SUBSTITUTE SHEET (RULE 26) WO 95131448 r~ 5 '~ '~07 S 2 1 ~573 21 CH2 ~_ _N3 H CH3 Cl 161-164 22 CH2 ~ N Cl H CH3 Cl 124--125 23 CH2 ~ H CH3 Cl 17~--175 24 C32 ~o~3 H CH3 Cl 107-108 25 Cl}2 ~ O~N--3 Cl H C~33 Cl 137-138 26 CH2 ~_~--Cl H C!I3 Cl gl~lsY
aCH~(aH~.C
27 CH2 ~_~Cl H CH3 Cl 223--224 ClCH~(aH ~ ~,C
28 CH2 ~oC1~2CF3 H CKzCU3 CH3 127-128 29 CH2 --CH2--~ Cl H CH3 Cl 152-153 30 CH2 H C!~3 Cl 16 _ ~o~N 7 168 31 CH2 ~ ~_ COF3 H C~33 Cl 134-135 O~N~
32 CH2 ~ ~--OCII~CF3 H C~(cH3)2 Br 76-77 33 C~2 ~o~3CF3 H CU2C~3 Cl 100--101 34 CE12 ~O~ H CH3 Cl 157.5--35 CH2 ~ oc~2cF3 H C~C~33)3 Br 129-130 36 C~2 ~ --O~ C~N H C~2CE~3 Cl 147--148 37 CE12 F H C~3 Cl 14 -~~Cl 1 143 38 C112 ~;,~--O~CF3 H CE13 Cl 106-108 39 CE12 ~ oci32CF3 H C~3 Cl 138--140 40 CH2 ( ~ B CE13 Cl 109--120 ~_ o~
41 CH2 ~--O~CF3 C~3 C~3 Cl 84-86.5 -- 20 _ SUBSTITUTE SHEET (RULE 26) WO 95/31448 1 RA ~ S , 2 1 ~ 9 5 7 3 r~ r ç.~7 42CH2 E~ CH3 Cl 109--114 ~ ~ Nt 43CH2 ~0C~2CF3 CH3 ~a2~5 78-80 44CH2 ~,3 H CB3 Cl 167-168 45C~2 ~ ~ CF3 CH3 Cl 125--129 46 ~_~ C83 Cl 75-80 47C~2 ~ C~3 C1 146-147 48CH2 ~OCF2CHF2 CH3 Cl 121-122 49CH2 {~(~OC83 C~3 Cl 141-142 50C~2 _~3C(CB3)3 H C~;2C~3 N 137-139 51C~2 ~OC~2CF3 ~ c~2C~l2cll3 Cl 112-113 52CH2 ~ OCH2CF3 C113 P 147-148 53CH2 ~--C(CH3)3 H Cll2c!l2c~3 ~ 137-139 54C~2 ~OCH2CF3 H 32C~3 Br 110-112 55CH2 ~--OCB(CH3)CF3 li c~3 Cl 80-83 56CH2 ~ O~~ ~>~ CF3 CE12CB3 CE3 Cl oil 57C112 F 8 a/2~3 Cl 154-155 ~O~Cl 58C~2 ~;3~ O~ Cl ~ c~2~a3 Br 108-109 59CH2 ~ ~ F ~3 C~3 Cl 121-lZ2 60CH2 ~oc82CF2CF2A CA3 Cl 132--133 61CH2 F CA3 Cl 133--135 ~ (~ N02 62CA2 ~ O~ Ar A CA3 C1 141--142 63CA2C82 ~ ~ CF3 CE3 Cl 125-126 64CH2 ~o~cN H CH3 Cl 178-179 65CA2 ~OCH2~F ~ CH3 Cl 141-143 SUBSTITUTE SHEET (RULE 26) WO 9S/31448 . 2 ~ 8 ~ 5 7 3 P~ J.,. S. - 6~'~07 66C~2 ~ CF3 C~3 CQ3 Cl 8i--86.5 67C~z $ ~ CF3 CD3 C~3 Cl 84--89 68CQ2 ~CF3 CQ2CQ3 CQ3 Cl oil 69Cli2 ~~ ~~ CF3 C~2cH2cB3 c~3 Cl oil 70C~2 ~O~CF~ ~2C~c~cH3)3 c~3 Cl oil 71C~2 ~CF3 C~3 c~2ai3 Cl oil 72CcEiN~c~33~2 ~ O~CF3 C~3 Cl 194-200 73CQ2 ~CN CQ3 C82CH3 Cl Oil 74C~3 ~CF3 C~3 C~3 Cl 150-153 75C~2 ~ 0~ CFl c~2CD3 Ci33 Cl oil 76C~ hu(c~3~2 ~- O~- CF3 C~3 Cl 130-77C~ c2!{s ~--O~CF3 C83 132;5 78C~llc2~35 ~3O~CP3 C~3 Cl 133-137 79C~2 ~ ~ CF3 C~3 Cl 96-98 80C82 ~O~CF3 C82CO2C28s c~3 Cl oil 81CQ2 ~ O~=~ CF3 C82C=CQ2 CQ3 Cl 031 (B~ ~ ~CF3 CQ3 Cl 183-187 33c-cNe2 ~O~CF3 C83 Cl 160-165 84C~2 ~3--o~CF3 CQ(C83)2 C~3 Cl oil SUBSTITUTE SHEET (RULE 26J
W095/31~ r ~ P8 ~-~ 2~189573 r~
85CH2 ~~ ~ CF3 CH2~ CH3 Cl oil a6CH2 ~O~CN CD3 C2H5 Cl 91--93 87CHCH3 _~ 0~ CN CE3 C2H5 Cl oil a8CHCD3 ~ 0~ CN CD3 C2E5 Cl oil 89CD2 _~ 0~ CF3 E CE3 Cl 124--128 90C=CH08 ~;3~ ~ CF3 E CE3 Cl 118822.-5 91CH2 ~ 0~ CN CH2CH3 C2E5 Cl oil 92C~l(c~3)2 ~o~CN E C2E5 Cl 165-166 93CE2 ~~ ~ CF3 CE2CE3 C2E5 Cl oil SUESTITUTE SHEET (RULE26) .
WO9~/31448 ~ 2189~73 r~l~u~ s.~s307 gqC-O ~ CN C2~5 Cl 173-177 95C~lC21~s ~CN C2E~5 Cl 167.5-96C~1~23)2 ~3O~3CF3 C2~5 C1 164.5_ 9 7C~( C~3 ) 2 ~ N--3~ C2 ~ 5 C 1 16 2 -98C~C3}17 ~o~ )-CF3 c~3 Cl 117-123 99C-C;BC2~5 ~o~ CF3 C2~5 Cl 114-117 100C~C213s ~O--~_>-CF3 C2~5 Cl ao-86 101C~c3~7 ~ ~CF3 C~33 Cl 117-125 102C)~2 ~ C~ Cl C2H5 C2~5 Cl oil 103C32 ~~O~Br C2~5 C2~5 Cl Oil CB2~~ ~--CF3 C2~5 C2~5 Cl oil lC5-C-CN~ ~--O~CF3 C33 Cl 163--170 106C~2 ~ --O~CF3 C~20C~3 c~3 Cl oil 107C~(Q3)2 ~_~CP3 C2~5 Cl lq6-lq9 108CB2 ~_OCH2CP3 C235 C235 Cl oil 109C~EC2~3s ~31--OC~12CF3 C~32C33 Cl lZ0-127 110C~3c2~s ~ CF3 138.5 111C--o F 3 C112C~3 Cl 125-126 ~CF3 112C~3C2~s ~CF3 ca2CH3 Cl 143--113C~C2~35 ~_ ~Br C2~5 Cl 157-159 114CE2 ~CF3 CB2oc~32cB3 C~33 Cl oil _ 24 --SUBSTITUTE SHEET (RULE 26) WO 95/31448 ~ t~ ~; 2 1 8 9 5 7 3 115C~CXCCE!3 ~o~cF3 N CN3 Cl 115536.55--116C~L3C4eg ~--o~cF3 N CN3 Cl 11129i55-117~-~Wco~3~2 ~_ _~1- CF3 N C113 CL 1111145-118c~c~c~c~l3 ~3~ ~CF3 N CN3 Cl 116656.55-119CN2 ~3--oCFzCF2N H C2~5 Cl 112--114 120c~C113~2 ~OCF2CF2H N C285 Cl 95--105 121CN2 ~3--oCF2CF2~ , c~2CN3 C2~5 Cl oil 122C~3C2~s ~ C2N5 Cl 100-~Z~) OCF2CF2N ~ 101:5 123c~32 ~ 0~ CN H C2ii5 Cl 119~318.-5 124~2 ~ - o~CN C2~5 Cl 175.5-125C=O ~3 ~ CF3 H C~3 Cl 12~g73.95--126CN2 ~CsN11 c~3 Cl 87--88.5 127CN2 ~1--C~EI11 C2N~ CN3 Cl oil 123C~OCc3 ~O~CF3 CN3 Cl goil /
129C~2~2C~ ~ ~ CF3 H CN3 Cl 120-lZ3 130C~ oCE2CF3 N C2N5 C} 126--127 C=CIIN~ ~ ~ CF3 C~3 Cl I29--133 132CN2 ~ ~3 CF3 n--blltyl c~3 C1 oil 133C~G33)2 ~30C~2CF3 N CE3 Cl i216il5--134c~C2~3s fi~ CE3 Cl 161-163 ~ oC~2cF3 135C~3 ~ O~CF3 CN3 C1 oil 136C~2 ~O~CF3 N CE3 Cl 233.5--(dec) 137 ~ --0~ CF3 CE3 Cl cli1 138o _ ~'1~~CF3 N C~3 C1 172-173 SUBSTITUTE SHEET (RULE 26) WO95131448 ~ P& ~ 2~89573 r ~ 07 139C-NNF32 - ~ - o~cF3 H CH3 C1 161-174 140CH3~ O~ CF3 H CH3 Cl 233-240 NH
O=C
C~N-141C(~c2Hs)2 ~O~CF3 H CN3 Cl oil 142c~ c~ ~ ~ o~ cF3 H CH3 Cl 11239i.55--143'C 2~, ~O~CF3 H Cr33 Cl oil 144~ -2h3C~2CI22~ CF3 H CE3 Cl 195--196 145C~ccO,c~c~ ~0~3CF H CH3 Cl 131_ 146~ D3C~2~2~ ~ ~_o_~-CF3 H CE13 Cl 134-5 147~~ 2~-~02~ ~ ~~_ CF3 H C~3 Cl 186_ 143CE12 ~--O~CF3 H C2~5 N2 135--138 149CH2 ~ O~ CF3 CH20C33 C2H5 3r oil 150~U2~2~3 ~ oC~2CF3 E C2~5 Cl 1219il5--151C~'~"2'2; ~_oc32CF3 c2~s Cl 122-138 152CH2 F~_ 3 C113 3 126--127 CF3 r SUBSTITUTE SHEET (RULE 26) WO 9S/31448 ~ 8 9 5 7 3 r ~ o7 153 CH2 ~--CF3 C~12OC~3 c~3 Br 83--85.5 154 C~2 ~ 0~ CF3 a C~3 i3r 106-111 155 C~2 ~~ ~ C~20C~2CY3 c~3 Br oil 156 C~2 ~O~CF3 C~20C~2C113 C83 i3r oil 157 C~2 ~ CF3 C~20C~3 c2~s Cl 5Z-56 158 CH2 F C820C~32C~3 C2H5 i3r oil ~CF3 159 C~2 ~ cU2oc~2c1l3 C2H5 Cl oil ~CF3 160 C~2 F C820CE13 C2~5 Rr oil ~CF3 -- 27 _ SUBSTITUTE SHEET (RULE 26) WO9S/31448 , ~1 J~i~, 21 8~573 ~ o7 161C32 (~ 0-nCIa9 C2H5 CH3 Cl oil 162CH2 ~~o~cF3 Ca2CN C33 Cl oil 163CH2 ~ - o~cF3 CH2~ CH3 Cl oil 164C~l(CE3)z ~ OC~Hg H CH3 Cl 1S4-lSS
165CH2 ~--OCH2CF3 C2H5 C33 3r 159-160 166C~2 _~9 E CH3 Cl lg3--14~
167 ~o~3_~,o~ H C2H5 3r 128-130 168CHOH ~ocll2cF3 E C33 3r 137--140 169C~li(cE3)2 ~--OCH2CF3 H C33 3r 129--133 170C~(C113)2 ~3--oC1~2CF3 E CH3 H 145--148 171CH2 ~--OCH2CF3 CH2Cl H 146--148 172CH2 ~OCEzCF3 R4 ~or21 225--227 173CE2 ~o~3r C2H5 Cl 155--156 174CH2 1~ E CH3 Cl 1 --~O~F 59 161 175CH2 F~ E C2HS Cl 140--1~1 ~O~F
176C32 ~--OCE2CF3 H CH2Cl Cl 80--81 177CH2 ~~~C~ E CHZCl Cl 157--160 SU~ 111 IJ I t ~HEEr (RULE 26) ~O 95/31448 ~ 8 9 5 7 3 . ~ r , 178 C~2 1 ~ C285 Cl 128-130 ~O~CF3 179 C~2 / N C83 Cl 135-138 ~o~CF3 18C C~2 F ~ C285 Cl 18-81 ~ CF
181 C~2 F~ ~ CH3 Cl 157-158 ~O~CI
182 C~~ 3)2 ~o_~Cl C2~5 Cl 164-166 183 c~8C2~ ~0~ Cl C2u5 Cl 118--121 184 C~2 ~o~cF3 C2~5 Br 79_81 as C~2~ ~o~Cl C285 Cl gl~
186 C82 ~o--~--CF3 C2H5 C285 Br oil 187 c=o ~o-~cl C2~5 Cl 108-109 188 C82 ~O~C~ C2~5 CB3 Cl oil 189 C82 ~O~CF3 C82CC~ C83 Cl oil 190 C82 ~3_oCB2CF3 C2~5 CB3 Cl oil lgl C~2 ~-OC~89 C83 Cl 100-102 192 C~2 ~-CC~89 C285 C83 Cl oil SUBSTITUTE SHEET (RULE 26) WO 95131448 ,~ ,"~ ~ n ~ ~, r~ 07 ~1 89573 193C~2 ~--o~~3~CF3 C112CN c~3 Cl Oil 19~C~E2 ~ 3CF3 _<¦ C~3 Cl sil 195C~:N(c~3)2 (~ OC~H9 H CH3 C1 L54--lSS
196CH2 ~30c112CF3 C2H5 CH3 Br oil 197OE2 ~--OCH2CF3 CD2CD3 c~3 3r oil 198C~N(c~t3)2 ~_OOE2CF3 H C2N5 Br 168--169 1 9 9 C~HC ~
2 5 ~30OE2CF3 H C2H5 ~r oil 200C=O ~--OOE2CF3 H C2H5 Br 100--101 201C'CNEO~ ~O~CF3 H CH3 Cl d~o 2 0 2 C~C2~s ~o~cF3 C2H5 Br oil 203CH2 ~O_~_ CH20c1l2cll3 c2~s Br oil 204C~2 ~--O~CP3 Clt2CN C2H5 Br oil 205C~2 ~3CF~H C2j35 Br oi l 206C82 ~CF.H C2~t5 C2~5 Br oil 207C~C~3)2 ~CF.H H C2~5 Br 109--111 208 c~c~cu2cOo~
~--OCB2CF3 H C2E15 Br 124--126 209 ~- , ~OCEt2CF3 C2H5 Br 137--143 210C82 ~CF C2H5 C2Et5 Br 80--82 _ 30 --SU~STITUTE SHEET (RULE 26) WO 95/3~44 e.~ ~s ~ 2 ~ 8 95 73 r~ 07 211 C~2 ~(lCF.CF.H C2~5 C2H5 Br oil 212 C~2 ~--OCH2CF3 C2H5 C2H5 3r Oil 213 C~2 ~ CF3 CH20CH3 CH3 Br oil 214 CH2 ~ ~CF CH20C~3 c~3 Cl oil 215 CH2 ~--~CF C~20C2H5 CH3 Cl oil 216 CH2 ~--'~CF H C~3 Cl 143--144 217 C COOCH3 ~ocB2cF3 a C2H5 cl 44--47 HH o SUBSTITUTE SHEET (RULE 26) ! !;.
Table II
no ~ R3 R4 W G Y Z MP C
823392 218 CE3 Cl CE3 CE2 ~O~CF 145-147 823503 219 CE3 Cl CD3 CE2 ~O~CF 165-168 82;752 220 CE3 Cl O CE2CE3 CE2 ~O~CF 138-1~1 826232 221 CE3 C1 O CE2CE2CE3 Cil2 ~>--O~CF 100-101 826321 222 CE3 Cl O H2C~C(CE3)3 CE2 ~--O~CF 149-154 826073 Z23 Cl~2c83 Cl CE3 CE2 ~ O~ CF lZ9-131 826326 224 C1~2CE3 Cl CE3 CE2 ~--o~CN 160 5 50459~ 225 CE3 Cl S CE3 CE2 ~ O~ CF 72-73.5 504595 2Z6 CE3 Cl CE3 CE12 ~-CF o-l SUBSTITUTE SHEET (RULE 26) W0 95/31448 2 1 ~3 9 5 7 3 ~ 07 504754 227 Ch'3 Cl N Ch~3 Ch'2 ~--0~cF o 504862 228 C!13 Cl N (Ch'3)2 CE12 ~ - o~cF3 509770 229 CE13 Cl S C2h-5 C113 ~ ~ CF3 5101~31 230 CC3 Cl S C3117 CE2 ~O~CF3 511477 231 C113 Cl 0 Chl2Ch~3 C~2 ~ ~ CF3 511476 232 Ch3 Cl W-G toq~th~r fo= C!12 ~o~3CF 227-229 NKN (d o~
511475 233 CY3 Cl W-Gto.7~ther forl C~2 ~30~CF 116 5_ 3(CY~2 513647 234 CE~3 Cl 0 c~2CF3 Ch'2 ~o~cF3 ~ 33 --SUBSTITUTE SHEET (RULE 26) WO 95/31448 ; ~ ' r~ 5.~ '~07 'rABLE~
(~ Y Z Rl R' R4 MP C
235 CH2 ~ CF3 CD2CD3 C~3 Cl 140--143 236 ' ~ C~3~ ~o~ C~2C02C2~5 C~3 Cl 113207.-s 237 C112 ~3~ CF cl~2C~I=CH2 C~3 Cl 92.5--238 CH2 ~O--~-- C1~2-phenyl C~3 Cl 113332.5 239C112 ~--o~CF3 C~!(C~3)2 C~3 Cl 117-119 240C~i2 ~o~CF3 CN2C02~ C~3 Cl 16~,--167 241 ~~(`` CD3 C2~5 Cl 159--160 242C112 ~3O~`` C2~5 C2115 Cl 161.5-162 .5 243C112 ~O--~--CF3 C2~5 c2~5 Cl 110_ 244C~2 ~O~ CF3 CE3 C~3 C1 165--166 245CH2 ~ ~C1 C2~15 c2Hs Cl lZ9-130 246CH2 ~3~~~3r C2H5 C2H5 Cl 129-131 247C~2 F C2H5 C2H5 Cl 143.5_ ~CF 1~5 248CH2 ~O--~--CF3 CH20CH3 CH3 C1 123.5-249C~32 ~--OCHzCF3 C2~35 C2H5 C1 104-106 SUBSTITUTE SHEET (RULE 26) WO 95/31448 2 f 8 ~ 5 7 3 . ~lIU~ 07 250CB2 ~O--~--CF3 Ci~20C2B5 Cil3 Cl 113-114 251C112 ~--o~cF3 C2~0B C83 Cl 1614665--252Ci~2 ~ - o~cF3 Cil2C02Na Ci~3 Cl 157--160 253CB2 ~)CF~Ci-.ii C2iis c285 105.5 254Cil2 ~ HI ~ C2il5 Ci~3 Cl 11043.-5 255C~12 ~--o~cF3 n^C4i~g CB3 Cl 11118.--5 256C~2 F C~2OCii3 Ci~3 Br 114.5--~ CF 115 257Cii2 F Ci~2OC2i~s Ci~3 Br 114.5--~CF 117.5 258Cil2 ~ - o~cF3 CB20C2i~5 CB3 Br 114--116 259CB2 F CB2OCil3 C2H5 Cl 135--140 ~CF
260Cil2 F C820CB2CB3 C~2CB3 Br 126--127 ~ CF
261CB2 F Cii20C83 Ci~2CB3 Br 160--164 ~CF
.
SUBSTITUTE SHEET (RULE 26) WO95131448 ~ " ~,'" ,;~ 07 262 C~2 ~O--~_CF3 C2~5 C2H5 Br 140-142 263 CH2 ~~'` C2H5 Ch3 Cl 180-182 264 CH2 ~O~ CF3 ca2cc~1 CE3 Cl 153-155 265 CH2 ~0C112CF3 C2H5 CH3 Cl 138--139 266 CH2 ~--OC~Eg C2H5 CH3 Cl 133-134 267 C}~2 ~ CF3 C!12CN CB3 Cl 130-134 26a CH2 (/ \)--OC~9 c2~5 C~3 Cl 133-134 269 CH2 ~ CF3 Cil2CN Cli3 Cl 130134 270 C}~2 ~o~ CF3 ~ CH3 Cl 121-122 271 CH2 ~3 - oc82cF3 c2a5 C~33 Br 159--160 272 CB2 ~--OCi32CP3 CD2CD3 C~3 Br 159--160 273 CH2 ~OCF.U C2HS C2~s Br 76-78 274 CH2 ~o~ CF3 CH20CH3 CH3 Br 123-126 275 CH2 F CH2OCH2CH3 CH3 Cl 114-116 ~CF
276 CH2 F C~2OCH3 CH3 Cl 129-131 ~CF
SlJBSTITUTE SHEET (RULE 26) WO 95/31448 S~ 2 1 8 9 ~ 7 3 ~ 307 l~s illustrating preparation of ~ lAry follow below.
2N NaOH 1~3C ~
3C~ N~2 ~ N~2 N-S . HCI H2o N~S
The starting acid (28.2 g, 0.187 mole) was added to ~2O (200 ml). The insolubles were filtered and the filtrate's pH was adjusted to 10.0 with the addition of 2N NaO~ (94 ml). The mixture was stirred for ~ive minutes, then extracted with ethyl ether (1 x 230 ml).
The organic layer was separated and the aqueous layer was saturated with NaCl, then extracted with ethyl ether (2 x 230 ml). The extracts were c ~n.oci and given a brine wash, dried over MgS04, the~ COnC~ LLGLed under vacuum to give the product as a yellow oil (18.9 15 g)-Na CEJ3CEI2 C~3 C113C3i2CN ~ >--<
Sodium (11.5 g, 0.5 g-atoms) and propionitrile (66g, 1.2 moles) were stirred in toluene (250 ml).
20 There was a slight exotherm and a solid began separating. After one hour, gradual heating was applied until re~lux was att2ined after a} out three hours. Reflux was maintained for one hour and the mixture was then allowed to cool, resulting in an 25 e~L~ -ly thick mass. The mixture was then washed with ethyl ether (300 ml) and placed in a large crystAll;7;n~ dish and began smoking as the ethyl ether . Water (500 ml) was added and the product WO95/31448 ~ 2~ 8~57~ C~ , was extracted into ethyl ether (2 x 500 ml). The two extracts were c ;nr~d and dried over MgSO4 and the ethyl ether was removed under vacuum, leaving a brown oil, which sol;r~;firrl. Product was then recrystAll;7-~d s from heptane-ethyl acetate (10:1) yielding about 22 g ~m.p. 38-40).
c~3 C~3CE~2~=<CI~3 H~S H~ 3c~2c~N 2 ~2N C~ N_5 The starting nitrile (7.0 g, 0.063 mole), ethanol (35 ml), tetral~ydL~,~uL~ll (THF) (35 ml), and triethylamine (2.0 g, 0.02 mole) were placed in a Carius tube, cooled, and llydloyt:l~ sull~ide (2.8 g, 0.082 mole) was bubbled in. The resulting mixture was placed in an oven at 115-120 for five hours. The solvent was removed under vacuum and the resulting mixture was dissolved in CH2C12 (250 ml) and washed with water (50 ml). Thin layer chromatography indicated mostly starting material, 80 the mixture was dissolved in ethanol (50 ml). To this solution wa8 added 30~ H22 (20 ml),and water (100 ml), then most of the ethanol was removed under vacuum. The product was extracted with CE2C12 (500 ml) and this extract was further extracted twice with lN NCl (2 x 100 ml). The acidic extracts were, ;nr~r~ and washed with CE2C12 (150 ml) and then made basic with 10N NaOH. The resulting solution wa~ then extracted with two portions O~ CH2C12 (2 x 100 ml) and ~ ' ;nr~cl and dried over MgSO4.The solvent was removed under vacuum to leave a semi-solid.
T-60 NMR indicated mostly desired product which was then recrystAlli7ed from hexane to yield about 100 mg (m.p. 84-88).
WO95/31448 s~ 2 1 8957~ 5~ ~07 CE13CE2~=<CH3 ~ H20~ ~13CE12C_~N~2 H2~1 CN PY N_5 The stGrting nitrile (6.0 g) was dissolved in pyridine (20 ml) in a Carius tube. Hydrogen sulfide 5 (2.8 9) was bubbled in. and the resulting mixture was placed in an oven at 120 for five hours. The solvent was removed under vacuum and the resulting mixture was dissolved in CH2C12 (250 ml) and washed with water ( ml). Thin layer chromatography showed more extensive 10 reaction and more impurities than material of Example 3. The solvent was removed under vacuum. To the product was added ethanol (100 ml) and 30~ H22 (20 ml). The resulting mixture became very hot. Water (200 ml) was then added and the mixture was extracted with two portions of CH2C12 (2 x 150 ml). The extracts were ~ 'in~d and e~L~ Led with lN HCl (2 x 100 ml).
These extracts were combined and washed with CH2C12 (150 ml) and before making basic with 30% NaOH. The product was then extracted twice with CH2C12 (2 x 150 20 ml) and the combined extracts were dried over MgSO4.
Thin layer chL~ ~OYLG~1~Y indicated product identical to that of Example 3, except for an additional spot which may be pyridine. This sGmple was c. in~ with the product of Example 3 and chL~ ~o~LG~hed on silica 25 gel, starting with CH2C12 and eluting the product with 5% ethyl acetate. Product was recrystAll;7c~rl from hexane to give 240 mg of white crystals (m.p. 99-100).
E~3C~--N 2 ~ N~2 WO 95/31448 ~ 5 ~07 2 ~ 8~57~ ~
The starting amine (18.9 g, 0.166 mole) was slurried in CC14 (600 ml) under an atmosphere of N2-N-chlorosllrc;n;m;~o (NCS) (22.1 g, 0.166 mole) was added to the slurry over a five minute period at 30-44 5 and stirred at room ~ ~ a~uLe overnight. Analysis by T~C silica gel 1:1 heptane/ethyl acetate showed product and no starting material present. The mixture was then diluted with ethyl ether (100 ml) and the solids were filtered. The filtrate was co.lce.~L~Led under vacuum 10 to a red oil which was dissolved in ethyl acetate (200 ml) and washed with H2O (2 x 200 ml). The organic layer was separated, given a brine wash, dried over MgSO4, then concentrated under vacuum to a brown oil which crys~ i70:1 to a brown solid (22.0 g).
O O
Il + NaH ll 6096 sodium hydride (40 g, 1 mole) in mineral oil was tirred under reflux in dry tetral-ydLuruL~I (500 ml) as a solution of ethyl propionate ( 51 g, 0 . 5 mole ) and acetonitrile (41 g, 1 mole) was added dropwise to the mixture. This mixture was maintained at reflux overnight. The mixture was then cooled and isopropanol (60 ml) was added dropwise. The solvent was removed under vacuum and after adding water (400 ml), the product was ~L- ~-ed with hexane (400 ml) and 1:1 hexane:ethyl ether (400 ml). Cc..c .I~L~ed HCl was added to the combined C:~L~IC-s to lower the pH to 6, and the solution was then extracted with two portions of ethyl ether ( 2 x 300 ml ) . The ~ ~in~d extracts 30 were washed with water and the resulting solution was dried over MgSO4. The ethyl ether was removed under vacuum to leave product as an oil (30 g).
~0-WO 95/3 1448 I-._ 1 / u ~, _ . '~07 2 t 8 9 5 7 3 NH3 CE3CE2 H S E3CE2Cr9--NE2 CH3CH2CCH2CN H2S E2N>~/ N--S
To the product of Example 6 was added dry THF (270 ml) and ethanol (200 ml~. Of this solution, 70 ml was 5 put in each of two Carius tubes. The tubes were cooled and NH3 (2.1 g) was added followed by H2S (3.0 g). The tubes were sealed and warmed in hot water to check for leaks, then placed in an oven at 110 for four hours, after which the mixture was cooled and the solvent 10 removed under vacuum. To this product was added CH2Cl2 (300 ml) and the mixture was washed with two portions of water (2 x 100 ml). The mixture was then dried over MgSO4 and the solvent was removed under vacuum.
Ethanol (100 ml) and 30% H22 (15 ml) was then added.
15 Starch-iodide paper showed no excess H2O2. Another portion of H22 (30 ml) was added before an excess was obvious . Nater ( 5 0 ml ) was then added to the mixture and the ethanol was removed under vacuum. The aqueous layer was made slightly basic and product was extracted 20 ~nto C~2C12. This product was then extracted with two portions of lN HCl ( 2 x 100 ml ), leaving black CH2Cl2 solution. The, ;nr~d aqueous ~LL~_LS were extracted with CH2Cl2 (100 ml) before making basic with NaO~ and extracting product into C~I2C12. The product was dried 25 over MgSO4 and solvent was removed under vacuum to leave 3-7 g of dark oil.
E~AMPLE 8 E3CE2C_~ C ~ E Cll C~ E2 ~1-WO95131448 .~ P~ S ~ /
"~ ~ 89573 The starting amine (3.7 g, 0.0289 mole) was dissolved in chloroform (100 ml) at room t~ UL-3 under an a~ re of N2, and the chlorine (2.25 g.
0.0317 mole) was dissolved in chloroform (120 ml). The 5 amine solution was chilled to 15 and the chlorine solution was added dropwise over a 15 minute period at 15, and a dark precipitate formed. The coQling bath was removed and the solution was heated to 50 for one hour. Heat was removed and saturated sodium 10 bicarbonate solution (100 ml) was carefully added.
After shaking, the organic layer was separated, given a brine wash, dried over MgSO4, then concentrated under vacuum to yield a dark oil (3.7 g). Chromatography using a Michel-Miller low pressure silica gel column 15 and eluting with heptane/ethyl acetate, _ in;n~ like fractions, and concentrating under vacuum yields a dark brown oil (2.8 g).
E~lPLE 9 Br ~-- CC 4 ~E2 20 The amine (3.73 g, 0.0327 mole) was slurried in CCl4 (100 ml) at room t ~ -LuLe under an a~ _~hele of N2. The N-bromos~ inim;~l- (1 ecluivalent) was added portionwise to the amine slurry over a 10 minute period at 24-30, and the mixture was stirred for 1.5 hours.
2~ Analysis by T1C silica gel (1:1 heptane/ethyl acetate) shvwed product and sQme L~ -;nirs starting amine.
Heating at 70 was applied for 1.5 hours. Analysis by TLC showed mainly product. The mixture was cooled to room temperature and ethyl ether (about 100 ml) was 30 added. The resulting mixture was chilled to 5 and filtered to yield solid material (2.6 g) which was Wo 95131448 ~ S 2 1 8 ~ 5 7 3 r~ Jv s -~07 discarded. The solution was conc~.-LL- Led under vacuum to yield a red solid (6.5 g). This material was dissolved in ethyl acetate (80 ml) and washed with H2O
(2x80 ml). The organic layer was separated and given a s brine wash, then dried over MgSO4, and concentrated under vacuum to yield a tan solid (5.24 g).
EXA~LE 10 ~3C~2C~NE2 NCS E3C~2C~
The amine (4.0 g, 0.0312 mole) was slurried in CC14 (130 ml) at room ~ CLLul~: under an atmosphere of N2. The N-chlorn~ucc;n;m;~l~ (4.25 g, 0.0312 mole) was added portionwise over a 5 minute period at 25-37, and the mixture was stirred at room ~ UL~ for 1.5 hours. Analysis by TLC silica gel (1:1 heptane/ethyl 15 acetate) showed no starting material ~ -;ning. The mixture was then diluted with ethyl ether (250 ml) and filtered. The filtrate was washed twice with water.
The organic layer was separated and given a brine wash, then dried over MgSO4, and cu..ce..LL~Led under vacuum to 20 yield a brown oil (4.65 g).
EXA~LE 1 1 N~ ,C~I~aCF3 C~2COOII C~2Cocl (a,a,a-Trifluoro-p-tolyl) acetic acid (1.20 g, 0.0059 mole) was dissolved in thionyl chloride (25 ml) 25 and heated at reflux for one hour, then concentrated under vacuum to a pale yellow oil. Analysis by NMR
WO 95131448 ~ t ,~ ~ J,.. 't $ ~ 85~73 showed starting material 1~ in;ng and the mixture was then retreated with additional thionyl chloride (25 ml) and concentrated under vacuum to give the acid ~hl~rirl.o as a pale yellow oil (1.26 g). The amine ( 0.73 9, 0.004g mole) was dissolved in warm xylenes (40 ml~ and heating was continued in an oil bath wherein the acid chloride (1.26 g, 0.0057 mole), dissolved in xylenes (10 ml), was added to the amine solution dropwise over a five minute period under an a~ re of N2 at 80-lo 100. A precipitate immediately formed. The slurry was then heated at 140 for one hour and all the precipitate dissolved. The resulting mixture was stirred overnight at room temperature. Analysis by TLC
9:1 CEI2C12/ethyl acetate silica gel showed a faint spot ;n;n~ for the starting amine. The mixture was then concentrated under vacuum to a tan solid (1.6 g).
Chromatography using a Michel-Miller low ~L~IS;:~U'~
silica gel column and eluting with 1% ethyl acetate/CH2C12, pooling like fractions, then ::~,nc~ L-~ing under vacuum yielded a light tan solid (1.2 g) recryst~ll;7scl from ethyl ether.
E~AMPLE 12 3 ~ ¢CE ~ lclle- ~ O ~ OCE12CF3 c~2coo~
The starting acid (1.20 g, 0.0051 mole) was 25 slurried in dichloromethane (20 ml) under an ~; ~h~L~:
of N2. Thionyl chl~ri~l~ (1 ml, 0.0137 mole) was added and the resulting mixture was heated at reflux temperature for 1.5 ~ours, then concentrated under vacuum to give the acid ~-hl~r;~l~ as a yellow oil. The amine (0.65 g, 0.0034 mole) was slurried at room Gl_ULt! in CE12C12 (100 ml) under an atmosphere of WO 95/31448 ~ r ~ 21 8 9 5 7 3 P~~ 07 ~2, and TEA (trietnylamine) ~0.52 g, 0-0051 20ie) was dissoived into this mixture. The above acid chloride, dissolved in CX2C12 (10 ml) was added dropwise to the amine mixture over a ten minute perlod at 23-27, and he resulting mixture was stirred at room temperature for one hour. Analysis by T~C silica gel 1:
heptane~ethyl acetate showed starting amine L~ ~ining~
so the mixture was heating at reflux temperature overnight and analysis by TLC silica gel 3 :1 heptane/ethyl acetate showed a very faint spot for the starting amine. After standing, the reaction mixture was Doured into a seDaration funnel with H2O ( 40 ml ) ~/here t~.e mixt~re ~as snaken and t.he oryanic 1 ayer was seDarate~ ana~asnea wi~ e foi owing: iO ~1 2N ~:C', 40 ml ;-2, .0 mi saturated NaHCO3, and 20 mi brine.
~he oryanic layer was separated and dried over MgSO4, ~hen concentrated under vacuum to give a dark oil ( about 1. 2 g) . Chromatography using a Michel-Miller low ~L~:SaULC! silica gel column and eluting with 596 ethyl acetate/CH2C12,, inin5 like fractions, then concentrating under vacuum yielded a tan glass, which was crys~Al1;7ed from ethyl acetate/heptane then filtered to yield a light tan solid (0.29 g).
_XAMPLE 13 O d - ~1 2 Ctt2COO~ C~2COCl The starting acid (1.25 g, 0.0048 mole) was dissolved in thionyl chloride ( 25 ml ) and heated at reflux ~ ~LULt~ for two hours, then c~,..c~.~LL~Led under vacuum to give the acid chloride as a yellow oil SUBSTITUTE SHEET (RULE 26) -WO 95/31448 ~ r 2 ~ 8 9 ~ 7 3 (1.34 g). The amine (0.80 g, 0.0041 mole) was dissolved in toluene (80 ml) and TEA (0.50 g) was added under an atmosphere of N2. The above acid chloride, dissolved in toluene ( 10 ml ) was added to the amine 5 mixture over a ten minute period at 30-35C, then the resulting mixture was heated overnight at 85.
Analysis by TLC silica gel 2 :1 ethyl acetate/heptane showed a very faint spot 1~ ;n;n~ for the starting amine. The mixture was then c~ ellLL,lLed under vacuum 10 to an oil (1.8 g). Chromatography using a Michel-Miller low pressure silica gel colu~n and eluting with 2~ ethyl acetate/CH2C12, ,- I ;n;n~ like fractions and ~o.~ LLc,Ling under vacuum yielded a solid product (0.84 g).
E~a~qPLE 14 ~11112 pyndine ¢r~2 Anthranilonitrile (29.5 g, 0.25 mole) and triethylamine (25.3 g, 0.25 moles) were stirred in pyridine (160 ml), as H2S was bubbled in for one hour.
TLC 1:1 CH2C12:ethyl acetate showed starting material L~ ;nin~, The addition of H2S was continued for an ~ 1it;~n~1 30 minutes and the mixture was stirred for one hour, then poured onto ice-H2O (700 ml). The solid was collected and washed with ~2O (31 g) (m.p. 119-121).
¢tC` ~2 _ H22 ~5 ~6-WO 95131448 ; ~ 9 5 7 3 P~ S 0~07 he starti3g Amin~h~n7~nzo--rhio~mi-l~a ( 19.3 g) was stir:ed in ethanol ~ 200 ml ), heating enough for the nitrile to dissolve. To this solution was added 30%
}~22 droE)wise, while the reaction was monitored by silica gel TLC in ethyl acetate. When starting material was gone, H2O (200 ml) was added. The product was collected by filtration and recryst~l l i 7ed from ethanol-water to give a solid (12.5 g) (m.p. 165-166).
A second crop was also collected (3.6 g) (m.p. 163-11J 165) .
Cl 1l IA3 Cl CU I TEBA ~?~ Cn2~~c3?3 __ ~?~ C~lz~o--~}CF3 ~zDH ~h,N--C--cni~ ~CF
l ~C3 i, C_N--S /B) A mixture of the amide (1.0 g, 0.00234 mole), potassium carbonate (1.15 g, 0.00829 mole), water (5 ml ), dichloromethane ( lO ml ), triethylbenzyl . i ~-bromide (TEBA, 0 . 68 g, 0 . 0025 mole ), methyl iodide ( 3 ml), and 10~ sodium hydroxide (3 ml) was stirred vigorous ly at room temperature overnight . ~he contents were diluted with dichloromethane, -he layers passed `0 through phase-separating paper, and were stripped. The residue was triturated under ether and the mixture was filtered. The filtrate was washed once with brine and was dried with ~gSO4. Cu..-e.--Lc~tion gave 960 mg of material which was ch~ ~ -to~raphed on dry pack silica.
~; Using heptane-ethyl acetate mixtures, c~ (A) was obtained as a solid (370 mg, m.p. 84-86.5), and c ~ _ ' (B) was also obtained as a ~olid ( 280 mg, m.p.
145-147) .
SUBSTITUTE SHEET (RULE26) WO 95131448 ~ P ,~ 2 1 8 9 5 7 3 P~~ 07 EXAM~LE 1 7 DM~DMA ~ 11 ~0{~-CF~
N ~ c~N~cr~
A solution of the amide (0.30 g, 0.703 mole) and dimethylfnrr irla dimethylacetal (DM??D~A) (0.17 g, 1.41 mole) in toluene ~5 ml) was heated at reflux for about seven hours, was cooled, and was stripped to dryness The residue was then triturated under a few mls of ether to afford 200 mg of 2roduct ~m.p. 194-200).
-XA~'LE 18 81 H.(X`H ~ HCI
~7~ C{!2--~30~CF~ ~ H olf ,C~,~N~C~S~~cr, 1~ N~13 1~1 A solution of the ketoamide (250 mg, 0.567 mmol)and meth~,..y. inP hydrochloride (250 mg) was heated for 4 hours at approximately 60 and was then allowed to cool. The solution was concentrated to a residue ?~ which was taken up in cold water and ether. The ethereal was then washed once with brine and was dried.
Concentration gave 230 mg of ?roduct.
EXA~LE 19 Cl ' CHlCONHNH~ Cl 8 C~?~ 2 CF~ ~ C~O~C~
'0 A solution of the ketoa~ide (250 mg, 0.567 mmol), acetic hydrazide (100 mg, 1.35 mmol), and a 0.41 M
solution of dry IIYdL~Ye~I chloride (3.28 ml, 1.35 mmol) in ethanol all in 10 ml of ethanol was heated for about three hours at 60-70 and was allowed to cool. The SUESTITUTE SHEET (RULE 26~
.
Wo95131448 ~ 21 89573 ethanol was removed in vacuo and ~he residue was partitioned between ethyl acetate/e~her/brine. The layers were separated and the organic phase was washed once with brine and was dried. Concentration gave 280 mg of a yellow solid. This material was recrys~A 1 1 i 7ed from ethyl acetate to afford 70 mg of dimeric product (m.p. 233-240). The filtrate was concentrated and the residue was chromatographed on silica gel (230-400 mesh) to afford 140 mg of monomer hydLu~one product.
M.P. 161-174 ~dec~. (Also obtained 10 mg of higher Rf r~~tPri;~l ), C~ I~ HSCHXH'SH ~1 CH2~0~C~ C ~N~C--C~O~CF~
C2H,O OCIB~
A solution of the ketoamide (250 mg, 0.567 mmol), 1; 1,2-ethanedithiol ~0.062 ml, 69 mg, 0.74 mmol), and a 1.46 ~ solution of hydLuy~ll chloride (0.39 ml, 0.57 mmol ) in ethanol, all in 3 to 5 ml ethanol was heated at reflux overnight. The dithiol (0.062 ml) was then added and the contents were ref luxerd f or 7 hours . The '!) solution was diluted with ether and was washed twice with 0.1 N NaOH and once with brine and was dried.
Concentration gave 300 mg which was chromatographed on silica (230-400 mesh) using heptane/dichloromethane eluants to afford 100 mg of ~
~5 EXAMPLE 21 1~
SUBSTITUTE SHEET ~RULE 26) WO 95131448 ~ 8 ~ ~ 7 3 r~ f~O7 Cl O
Cil3~N~C~C1~~CF3 N--5 ~ CRN_C~2C02CE2-phenyl Cl K7CO3 C~3~N,C~C~O~CF3 CH30H N--5 11 C~CE12C02EI
To a solution of the benzyl ester (1.3 g, 2.16 mmol~ in 15 ml of methanol was added potassium carbonate (0.30 g, 2.17 mmol) followed by 2-4 ml of 5 water. After several hours, the mixture (precipitate present~ was poured onto ice water which was then adjusted to pH 3 with dilute hydrochloric acid. The contents were extracted twice with ethyl acetate, the C ' 'n-~d organics were washed once with brine and were 10 dried. Co.~cen~LclLion gave 1.0 g of product which ~ras triturated with heptane/ethyl acetate to afford 680 mg of material. M.P. 177-183 (dec). This material was dissolved at reflux in approximately 50:50 heptane: ethyl acetate ( 10 ml ) . Upon cooling, the 15 solution was stirred and was treated with about 4 ml heptane. Precipitation eventually oc. uLL~d. The solid was collected to afford 270 mg of c ~1. M.P. 195-196 (dec).
o ~~ 11 1 ~ CF3 N--s 11 C}}NRC3~2C02 Cl O
NaOH CE~3~ N~C~c~0~cF3 N--5 El C~ C~ CO N~
WO95131448 ~ $~ 2189573 r~ 3Q7 To a mixture of the acid (0.185 mg, 0.361 mmol) in about 5 ml of methanol was added 2N sodium hydroxide (0.18 ml, 0.36 mmol). The mixture immediately became a solution (yellcw) but within 1 to 2 minutes began to 5 show a white precipitate which accumulated over time.
Collection and drying in vacuo at 50-60 for one hour gave 100 mg c '.
EXA~5PLE 23 C2E~5_~--NE12 + (cF3co)2o N--S
C2~15~ COCF
CH2CI~ N--S
10 A solution of the isothiazrlr ;Tl~ (2.0 g, 15.6 mmol ) was added to dichloromethane ( 25 ml ) . The mixture was cooled in ice and trifluoroacetic anhydride (3.4 ml, 5.06 g, 24.1 mmol) was added clL~ e. The solution was allowed to warm to room, - aLur~ and 15 then stirred overnight. Concentration gave 3.0 g of ~o C2~s~ 3 H2SO4 ~ IICOCF3 To a solution at 50-65 of the amide (3.0 g, 13.4 20 mmol) in about 60 ml of sulfuric acid was added dropwise about 12 ml of fuming nitric acid. An exotherm was noted during the addition of the fir~t 3 to 4 ml. The solution was heated for an additional 3 hours at 70-75 and was then cooled. The solution was 25 added to 500 ml ice water and the precipitate was W095/31448 ~ ,r ~ } 89513 P~ 07 col lect~ and air-dried to give 2.45 g of (m.p. 115-118).
No2 K7C03 No2 c2~5 ~ ~ C2~s~
~--NI~COCF3 aque~ N~2 A mixture of the amide (2.35 9, 8.73 mmol) and potassium carbonate (2_65 g, 19.2 mmol) in 40 ml of water and 10 ml of methanol was stirred at room temperature overnight. The mixture was adjusted to pH
6-7 with 1.0 N HC1 and was then extracted three times 10 with ether., The combined organics were then dried (MgS04). Cvllc~:..Llation gave 1.47 of comound. M.P.
131-132 .5.
C213s~N~2 ClCOC~12~0~CF3 PCH3 C2~5`~N' Cli2~0~CF3 1~ A solution of thionyl chloride (1.96 g, 16.5 mmol~
and phenylacetic acide (2.45 g, 8.27 mmol) in 20 ml of dichl~ n~ was heated at reflux for three hours and was then stripped to dryness. The liquid was then taken up in 5-10 ml of dry toluene, was added dropwise to a mixture of the amine (1.43 g, 8.26 mmol) in 20 ml of toluene. The contents were then heated at reflux overnight for 36 hours. The solution was stripped to dryness and was chromatographed on silica gel (230-400 mesh) to afford 1.22 g ofcompound (m.p. 135-138).
Wo 95131448 ~ $: I ~ 2 1 8 9 5 7 3 r ~
- Insecticide, Miticide and Nematicide Utility The ~_ _ of Formula ( 1 ), ~ 2 ~, or 13 ) show activity against a number of insects and mites. More 5 specifically, the c, _lr~- show activity against melon aphid, which is a member of the insect order F~ Lel~.
Other members of the ~omoptera include l~A~hnpp~rs, planthoppers, pear pyslla, apple sucker, scale insects, whiteflies, spittle bugs as well as numerous other host 10 specific aphid species. Activity has also been observed against greenhouse thrips, which are members of the order ~rhysanoptera. The ~ also show activity against Southern armyworm, which is a member of the insect order Lepidop~era. Other typical members 15 of this order are codling moth, cutworm, clothes moth, Tn~ 1 moth, leaf rollers, corn earworm, EULU~
corn borer, cabbage worm, cabbage looper, cotton bollworm, bagworm, eastern tent caterpillar, sod webworm, and fall armyworm.
The ~_ , _ ' - of Formula ( l ), ( 2 ), or ( 3 ) are useful for reducing populations of insects and mites, and are used in a method of inhibiting an insect or mite population which _ ~-s applying to a locus of the insect or mite an effective insect- or mite-inactivating amount of a c _ ~ of Formula ( 1 ), (2), or (3). The "locus" of insects or mites is a term used herein to refer to the environment in which the insects or mites live or where their eggs are present, ;nr~ ;n~ the air surrounding them, the food they eat, or objects which they contact. For example, plant-ingesting insects or mites can be controlled by applying the active ~ _ ' to plant parts, which the insects or mites eat, particularly the foliage. It is WO95131448 - r ~ . 2 1 8 9 5 7 3 F~ J,,5 -~07 C~ ted that the c- might also be useful to protect textiles, paper, stored grain, or seeds by applying an active ~ ~ to such substance. The term "inhibiting an insect or mite" refers to a 5 decrease in the numbers of living insects or mites; or a decrease in the number of viable insect or mite eggs.
The extent of reduction accomplished by a ~ __ depends, of course, upon the ap~1 ;At ;~n rate of the _ ~1, the particular ~ d used, and the target 10 insect or mite species. At least an insect-inactivating or mite-inactivating amount should be used. The terms "insect-inactivating amount" and "mite-inactivating amount" are used to describe the amount, which is sllff;c ;-~nt to cause a measurable 15 reduction in the treated insect or mite population.
Generally an amount in the range from about 1 to about 1000 ppm active _ ' is used.
C , ~E were tested ~or insecticidal, miticidal and nematicidal activity against eight species.
20 R~sults are reported in the following table, wherein the following abbreviations are used:
A~H refers to aster lF~fl~pp~r BAW refers to beet armyworm CA refers to cotton aphid NEM refers to peanut root knot r ~tod~
SCRW refers to southern corn root worm TBW refers to tobacco budworm TSS~S refers to two spotted spider mite WO9S/31448 ~ , 2189573 r~l,u~ s 307 .
GECR refers to German cockroach In conducting evaluations of insecticidal activity, each test ~~, ' was formulated as a 400 ppm solution, and this solution was then diluted with water to give lesser concentrations. The 400 ppm S solution was prepared by ~ ' ;n;n~ 19.2 mL of .05%
solution of Tween 20 (polyoxyethylene t20) sorbitan monolaurate) in water with a solution of 8 mg of the c, ' in 0.8 mL of acetone~EtOH (9/1).
Activity against aster leAfhnrp~r ~l~la~,Lu~Leles 10 fascifrons) was tested as follows. The test was run using concentrations of 400 ppm and 50 ppm. One ounce plastic cups c~nt~;n;n~ a cotton wick was sprayed with 0.4 mL of formulated material using a flat-fan nozzle.
The excess moisture was allowed to evaporate. Then lS five to ten carbon dioxide anesthetized adult Ir~: fhr pp~rs were added to each cup. The cups were capped and held at room temperature for 24 hours.
Percent mortality was then de~r~rm;ned.
Activity against beet armyworm (SpOdu,uLela exi~ua) 20 was evaluated as follows. The test is run using cv--c~:--LL~Lions of 400 ppm and 50 ppm. A general purpose lepidoptera artificial diet was diluted to half strength with a 596 non nutritive agar. 8 mL of this diet material was ~ pr~n~ed into one ounce diet cups.
25 One hour prior to tL. L, 35 to 40 eggs were dispensed onto the diet surface. The cups were then sprayed with formulated material through a flat-fan nozzle. Treated cups were air dried prior to sealing with plastic caps. The cups were held for 6 days at 30 room temperature. Activity was then rated based on the WO9S/31448 ~ ir t`~7~ t!~ r 21~573 ~ 9~ 07 tot~l number of live and dead larvae, and on the size of live larvae.
Activity against cotton aphid (Aphis gossy-pii) and two spotted spider mite ( :reLLally~llus urticae) was 5 evaluated as follows. Golden crookneck squash plants were grown to the F~Yr~n~ d cotyledon stage (about 6 to 8 days). The plants were infested with cotton aphids and two spotted spider mites 16 to 24 hours before application of the test material by transfer of lO infested foliage cut from a stock colony. Immediately prior to spray application of the test material the transfer foliage is removed from the squash plants.
The test is run using :orlc~ Lltions of 400 ppm and 50 ppm. The plants are sprayed with test solution using 15 an atomizing sprayer at 17 psi. Both surfaces of the leaves are covered until runoff, and then allowed to dry. Activity of each ~ ~ ' was ~ rm; n~rl three days after tleai L. Activity was rated as a percent based on the mites/aphids present in plants sprayed 20 with solvent alone.
Activity against peanut root knot r Lod~
(Meloidogy-ne arenaria) was evaluated as follows. Five untreated C~ seeds are placed into the bottom of a clear one ounce cup, 20 g of clean white sand is 25 added, and the cups were sprayed while rotating on a pedestal allowing l.0 mL of a 400 ppm solution to be deposited on the sand. To each cup was ~;Rpf-n~P~l 2.5 to 3.0 mL of qC~ n;7ecl water containing 300 to 500 nematodes. The cups were held for lO to 12 days in an 30 environmental growth chamber at a t~ ~ Lure of 76 to 85 DF and ambient humidity of 50 to 60DD. After lO to 12 days thQ cups were evaluated by inverting the cup and observing nematode mortality and feeding damage to the ~ plants.
W095/3l448 ~ '.P!~.. 2~89573 r~ 07 Activity on Southern corn LUO~ JLIII (Diabrotica .!n~cimr~tata howardi Barber) was evaluated by adding one mL of test solution containing a pL-:de~ ""nF~l concentration of test c, _ 7 to a cup containing a 5 kernel of corn in 16 g of sterile soil. This produces a soil concentration of 24 ppm. After 1.5 to 2 hours of drying, five 4th instar corn LvvL JLll- larvae were added to the individual cups. ~5ortality was measured at 3-4 days by emptying the cup onto a pan and 10 inspecting the soil for live LUOL~.JLl.._~.
Activity against tobacco budworm tNeliothis virescens) was evaluated as follows. A general purpose lepidoptera artificial diet was diluted to half strength with a 5% non nutritive agar. 8 mL of ~his 15 diet material was ~ p~n~ed into each one ounce diet cup. One hour prior to treatment 18 to 20 eggs were dispensed onto the diet surface. The cups were then sprayed with formulated material through a flat-fan nozzle. The test was run using col~c~:llLLaLions of 400 20 ppm and 50 ppm. Treated cups were air dried prior to sealing with plastic caps. The cups were held for 6 days at room , aLuL~. Activity was then rated based on the total number of live and dead larvae, and on the size of live larvae.
Activity against German cockroach ( Blattella germanicus) was evaluated as follow5. 8 mL of alfalfa based green insect diet material was dispensed into a one ounce diet cup. The cups were then sprayed with formulated material through a flat-fan nozzle. The test was run using concentrations of 400 ppm and 50 ppm. Treated cups were air dried for 24 hours and infested with five late third or early fourth instar German cockroaches. The cups were capped and held for seven days in an environmental growth chamber at a _ _ _ _ _ _ WO 95/31448 ~ 2 t ~ 7 3 I ~ 5.'~ 07 ~ , ~~ CLLUL~ of 76-85C. Activity was then rated based on the total number of live and dead insect6.
The following results are expressed as percent of orqanisms controlled.
ICIr~, ANI NB~IATICIDB DATA
Compound Ar r~ BAW CA NEM SCRW TBW TSS~I GBCR
ppm ppm ppm ppm ppm ppm ppm ppm ppm ppm ppm ppm ppm ppm ppm ppm 0~100~ 100~ 40~ 0~ 100~ 0~ 100 O O O O - O O O
O O O O O O O O
WO 95131448 ~ ~ ~ ~ 2 ~ 8 9 5 7 3 ~ 07 1~ SECrlCIDE, ~I TICII~., AN'D ~EMATICIDE DATA
Compld ALII BAW CA NEM SCR TBW TSSM CECR
ppm ppm ppm ppm 400 ppm ppm ppm ~0 ppm 50 50 50 ppm ppm ppm ppm 50 ppm ppm ppm ppm O O O O O O O O
100 100 80 o 0 0 90 o 1~60 100 o 0 0 100 0 o =
WO 95/31448 ~ " ~ , 2 ~ 8q 513 ~ s ~(i307 16100 lO0 100 0 0 100 100 100 o 0 0 0 0 0 0 20 1860 lO0 60 0 0 80 100 o l940 100 0 0 0 lO0 0 0 2180 100 0 0 0 lO0 0 0 22lO0 0 lO0 lO0 lO0 100 0 lO0 lO0lO0 100 0 0 lO0 0 80 O O O O O O O O
24lO0 100 lO0 0 0 100 lO0 40 25100 lO0 lO0 0 0 lO0 100 0 W09513~448 ;i ;~ f 9573 ~. .r Il` SECIICIDE, MTlClD, AND ~EMATICIDE DATA
Cbmpound ALH BAW CA NEM SCR TBW TSSM GECR
ppm ppm ppm ppm 400 ppm ppm ppm ppm 50 50 50 ppm ppm ppm ppm 50 ppm ppm ppm ppm O O O O O O O O
O O O O O O O O
33100 100 100 0 100 100 lO0 100 100 lO0 100 0 0 100 100 60 ~1-WO95/31448 ~ ' ?7 89573 ~ .'t-~07 WO 95/.31448 i` ~ ,r ~ 2 ~ 8 9 5 7 3 ~ s D '307 Il~-SECTICIDE, M~ICIDE, AND NEMATICIDE DATA
Compowld ALH BAW CA NEM SCR TBW TSSM GECR
ppm ppm ppm ppm 400 ppm ppm ppm ppm 50 50 50 ppm ppm ppm ppm 50 ppm ppm ppm ppm 100 100 0 0 100 lOo 60 100 0 o o 0 0 48100 100 lOo 0 100 100 100 60 5080 0 100 0 0 30 100 o o o 0 o 0 0 0 51100 100 100 0 o 100 o o 5280 100 0 o o 0 o 0 5350 0 0 o 0 o 90 0 0 0 0 o 0 0 o WO 95131448 ~ ;'r~ 2 1 8 9 $ 7 3 P~ ,JI. ~07 ~
s8100 100 100 - - 100 100 100 lQ0 100 100 - - 100 100 40 6720 100 - 0 0 100 o 40 WO 95131448 ~ 2 1 ~ 9 5 7 3 r~ 07 ~ SECTICIDE, M~ICID., AND \IEMATICIDE DATA
Compow~ Al,H BAW CA NEM SCR TBW TSSM GEClR
ppm ppm ppm ppm 400 ppm ppm ppm ppm 50 50 50 ppm ppm ppm ppm 50 ppm ppm ppm ppm 72100 lOo 100 0 100 lOo 100 100 _ 100 100 - o 0 100 0 60 77100 100 0 o 0 100. o 80 loO lOo 0 o 0 lOo 0 20 80 0 0 0 0 . 0 0 0 o -6~
WO 9~/31448 , ~ 8 9 5 7 3 P ~ 07 _ ~2 -100 100 100 0 100 100 100 100 0 H0 ~0 0 100 90 0 O O O O O O O O
O O O O O O O O
WO95131448 '` ' ^~ 1 89573 P ~ r 7 226 0 100 lO0 0 100 lO0 100 100 O O O O O O O O
89 0 100 lO0 100 lO0 100 100 lO0 0100 100 0 0 90 lQ0 0 O O O O O O O O
9260 100 100 - - 100 lO0 100 O O O O O O O O
9980 100 100 100 100 lO0 100 100 244 0 lO0 0 0 0 100 0 80 O O O O O O O O
WO95131448 ~ 2189573 r~ s~ ~07 9840 lO0 100 100 100 100 100 100 245lO0 60 100 0 100 lO0 0 lO0 23060 lO0 0 0 0 100 0 20 O O O O O O O O
24880 100 100 0 100 100 100 lO0 O O O O O O O O
O O O O O O O O
O O O O O O O O
O O O O O O O O
WO 95131448 ~ . 2 1 ~ 9 5 7 3 P~ 7 O O O O O O O O
O O O O O O O O
O O O O O O O O
WO 95/31448 ~, r ~ fS 7~ t C 2 1 8 9 5 7 3 r~ 06107 13360 lO0 100 100 0 100 100 80 060 90 100 0 40 lO0 0 1~5 0 100 0 100 0 100 0 100 O O O O O O O O
13~60 100 0 - 0 lO0 0 100 C O O - O O O O
13860 100 80 100 100 100 100 lO0 O O O - O O O O
WO 95131448 ~;", ,;~ 2 ~ 8 9 5 7 3 WO95131448 , . ~ .~.t 8 95 73 r~
WO 9S131448 5' ~ 2 1 8 9 5 7 3 r ~ 307 .
O O O O O O O O
O O O O O O O O
O O O O O O O O
O - O O O O O O
O O O O O O O O
O O O O O O O O
179 0 100 80 lO0 100 100 80 100 180 60 100 100 100 lO0 100 lO0 100 0 lO0 100 0 0 60 80 0 181 0 100 100 0 100 lO0 90 lO0 - 0 100 lO0 0 0 0 60 0 .
WO 95131448 ~ 2 1 8 ~ ~ 7 3 WO 95/31448 ~ 2 1 8 ~ 5 7 3 r~
O O O O O O O O
O O O O O O O O
O O O O O O O O
_ 40 0 0 0 0 0 .. . . .. ..
W095131448 f , 1' ~ tS ~ ~ 2~9573 11~ .'0~07 o o o o O O O
O O O O O
20g 0 0 100 100 0 90 100 40 2I1 100 100 100 0 0 gO 100 100 213 100 100 100 lOO O 100 100 100 21~ 0 100 100 ~00 0 70 90 O90 0 o o 70 0 Wo95/31448 . ~ ' 2 ~ 89573 r~ 07 Page ~ pop filing WO 9~/31448 ~ ~ 2 1 ! 8 9~5 7 3 ~ ~ c ~o7 indicates testing at 200 ppm.
Funqicide Utility The c~ _ r~ of the present invention have been found to control fungi, particularly plant pathogens.
When employed in the treatment of plant fungal r~ice~cec, the c .3c are applied to the plants in a disease inhibiting and phytologically acceptable amount. The term "disease inhibiting and phyiolo~;c~11y acceptable amount", as used herein, 70 refers to an amount of a ~ ~ of the invention which kills or inhibits the plant disease for which control is desired, but is not significantly toxic to the plant. This amount will generally be from about 1 to 1000 ppm, with lO to 500 ppm being ~Le:r~r lt:d. The 7~ exact concentration of _ .1 required varies with the fungal disease to be controlled, the type formulation employed, the method of application, the particular plant species, climate conditions and the like. A suitable application rate is typically in the 20 range from 0.10 to 4 lb/A. The ' of the invention may also be used to protect stored grain and other non-plant loci from fungal infestation.
Gre~nh~ ce Tests The following experiments were performed in the5 laboratory to determine the flln~iei~l~l efficacy of the ~~ of the invention.
The test c ' were fr~r~ ir~rl for application by dissolving 50 mg of the, _ ~1 into 1.25 ml of solvent. The solvent was prepared by mixing 50 ml of 30 "Tween 20" ~polyoxyethylene (20) sorbitan ~ lrate emulsifier) with 4?5 ml of acetone and 475 ml of etha-W0 95/31448 ~ ~" ~3 r ~ ~ 2 1 8 9 5 7 3 ~ 5~ 0~
nol. The solvent/ , ri solution was diluted to125 ml with ~l~ion;~e~d water. The resulting formulation contains 400 ppm test chemical. Lower co.lce~ L~llons were obtained by serial dilution with the 5 solvent-sur~actant mixture.
The formulated test ~ c were applied by foliar spray. The following plant pathoger~s and their co~x~cpon~ g plants were employed.
Pathogen ~c i ~na~ n ~ost in following Table ~rysiphe graminis tritici ERYSGT wheat (powdery mildew) Pyricularia oryzae ( rice PYRIOR rice bla$t ) Puccinid recondita P~JCCRT wheat tritici (lea~ rust) ,h.1i_~ ;A nodorum L13PTNO wheat ( glume ~lotch ) Pla$1nopara viticola PLASVI grape ( downy mildew ) ZO The formulated techniçal ~ I, clc were sprayed on all foliar sur~aces o~ the host ~lants (Qr cut berry) to past run-off. Single pots of each host plant were placed on raised, ~evolving pedestals in a fume hoQd.
Test ~olutions were sprayed on all foliar sur~aces.
15 All treatments were allowed to dry and the plants were inQculated with the appropxiate pathogens within 2-4 hours .
The following table presents the activity of typical ~ qs Qf the p~ese~t inventio~ when 20 evaluated in this experiment. The e~fective~ess of _79--WO95131448 ~ ? ~ S r-~3 ~573 ~ 5 ~ ~07 test ,u~ds in controlling disease was rated using thQ ~follçwing sçale.
O = not tQsted aga~nst sp~rifi~- organism - = 0-19% control at 400 ppm + = 20-89% control at 400 ppm ++ = 90-100% control at 400 ppm +++ = 90-100% control at 100 ppm W0 95131448 ~ P~ 07 ¦ COMPOUN ¦ ERYSGT ¦ PYRIOR ¦ PUCCRT ¦ LEI~NO ¦ PLASV~ ¦
D NUMBER
COI~POUND ~RYSGT PYRIOR PUCCRT LEPTNO PLASVI
+ + +++ + +
2 + + + + +
3 + + +++ + +
4 + +++ ++ + +++
+ + + + +++
6 + + ++ + +++
7 + + ++ + +++
8 + + + + +++
9 + +++ +++ + +++
+ + ++ + +++
1 1 + + +++ + +++
12 + + ++ + +++
13 + +
1 4 + +++ +++ + +++
1 5 + + + _ +++
1 6 +
17 + + + _ +
18 + + + + +
19 -- + + _ +
+
21 + +
2 2 + +
23 + + + +
24 + + + + +++
wogsal448 ;r~ i$qS73 ~
25-- + + _ +++
26 - + + + ++
27-- _ + + +
28 + + + + +++
29-- +
30 _ + + +
3 1 +
32 + + + + ++
33 + + + + +++
34-- _ +
35-- _ _ _ +
36 + + + + +++
37 +
38 + + + + +++
39 + + + + +++
40 + + + +
42 +
43 + +
44-- + _ _ +
45 +
46 + + + + +
47 + + + + +
4 8 ++ +++ + + +++
4 9 + + + + +++
50 +
WO 95/31448 ,.~,,i~ ,t ~ 2 1 8 9 5 7 3 r~ 07 I¦ COMPOUN ERYSGT PYRIOR ¦ PUCCRT ¦ LEPTNO ¦ PLASVI ¦
D NUMBER
+ + + + +++
6 + + ++ + +++
7 + + ++ + +++
8 + + + + +++
9 + +++ +++ + +++
+ + ++ + +++
1 1 + + +++ + +++
12 + + ++ + +++
13 + +
1 4 + +++ +++ + +++
1 5 + + + _ +++
1 6 +
17 + + + _ +
18 + + + + +
19 -- + + _ +
+
21 + +
2 2 + +
23 + + + +
24 + + + + +++
wogsal448 ;r~ i$qS73 ~
25-- + + _ +++
26 - + + + ++
27-- _ + + +
28 + + + + +++
29-- +
30 _ + + +
3 1 +
32 + + + + ++
33 + + + + +++
34-- _ +
35-- _ _ _ +
36 + + + + +++
37 +
38 + + + + +++
39 + + + + +++
40 + + + +
42 +
43 + +
44-- + _ _ +
45 +
46 + + + + +
47 + + + + +
4 8 ++ +++ + + +++
4 9 + + + + +++
50 +
WO 95/31448 ,.~,,i~ ,t ~ 2 1 8 9 5 7 3 r~ 07 I¦ COMPOUN ERYSGT PYRIOR ¦ PUCCRT ¦ LEPTNO ¦ PLASVI ¦
D NUMBER
5 1 +
52 + + + + +
53 + + + + +++
54 + + + + ++
++
56 -- _ _ _ +
57 + + + +
58 + + + + +++
5 9 + + + + +++
52 + + + + +
53 + + + + +++
54 + + + + ++
++
56 -- _ _ _ +
57 + + + +
58 + + + + +++
5 9 + + + + +++
6 1 +
62 + + + + +++
71 + + + _ +
72 ++ + ++ + +
76 -- -- _ _ _ B~
WO 9S/31448 ~ 8 ~ 5 7 3 F~ 7 168 ++ ++ - 0 169 ++ + - 0 170 -- + - 0 171 - + - 0 166 + + - 0 167 -- + -- 0 172 -- + _ o 173 - + - 0 175 - ~ - 0 1?8 + + - 0 182 + + - 0 184 ++ + - 0 185 + + - o 186 + -- _ o 188 + + - 0 263 -- _ _ o 189 ++ - - 0 190 ++ +++ - O
WO9S/31448 ~ j~, P,~ 89573 P~ 07 191 + + - O +
193 + + - 0 +++
194 -- -- -- 0 +
196 + + - 0 +
271 - - - 0 _519530 192 + + - 0 ++
269 - + - 0 ++
1 95 + + - 0 +++
270 + - - 0 +
197 ++ + - 0 +
272 + -- -- 0 199 + + - O +
201 + - 0 +++
203 ++ + + 0 205 ++ + - 0 +++
198 + + - 0 ++
202 + + - 0 +
204 + + - 0 +++
206 ++ ++ - 0 +
273 + + - 0 +
208 + + - 0 ++
210 - + - 0 212 + +++ +++ 0 +
214 +++ + +++ 0 ++
WO 95/31448 ~ ' t ~ ~ ~ 8 9~S 7 207 + + - 0 +++
209 - + ++ 0 ++
211 ++ + - 0 +
213 +++ + + 0 ++
215 +++ + +++ 0 ++
216 + + +++ 0 ++
275 + + +++ 0 ++
276 + + +++ 0 +
133 + + - 0 +++
134 + + - 0 +
135 + - - 0 +
136 - + - 0 +
137 + - -- 0 +
138 + + - 0 +
139 + + - 0 +
141 -- -- -- 0 +
142 + + 0 0 ++
143 ++ + - 0 ++
144 + + - 0 +
145 + + - 0 +
146 ++ + - 0 ++
147 + + ++ 0 ++
149 ++ + - 0 +
150 ++ +++ - O ++
WO 9S/31448 ,' ~ 2 1 8 9 5 7 3 r~ l~U ~ r ~o7 151 + + +++ O ++
152 + + + 0 +++
153 ++ + + o 256 + + +++ o 15~ + + +++ O +++
155 ++ + +++ 0 +
257 + + +++ 0 +
156 ++ + + 0 +
258 + + ++ 0 +++
157 +++ + ++ 0 +
259 - + + 0 158 +++ + + 0 +
260 + + + 0 +
159 +++ + ++ 0 +
160 +++ + ++ 0 +
261 - + + 0 +
wo 95/31448 ; r ~ C ;~ i 8 9 5 7 3 . ~ . r ~7 Compositions The ~ c of Formula ~ 2 ), or l 3 ) may be applied in the form of compositions which are important s of the invention, and which comprise a 5 ~ _ ~1 of Formula ( 1 ), ( 2 ~, or ( 3 ) and a phyfolr~Ji, ~l ly-acceptable inert carrier. The compositions are either concentrated formulations which are disper~ed in water for application, or are dust or granular formulations which are applied without further 10 treatment. The compositions are p.~lJaLe!d according to pLOC_IlUL~::S and formulae which are conventional in the agricultural ~h~micAl art, but which are novel and important because of the presence therein of the c,, ~ of this inve~tion. Some description of the 15 ~ tinr1 of the compositions will be given, however, to assure that agricultural chemists can readily prepare any desired composition.
The dispc~rcir~nc in which the r~l ~ ' are applied are most often aqueous susr~ncionc or lcjnnc 20 prepared from concentrated formulations of the com-pounds. Such water-soluble, water-cucp~n~lAhl~ or lcifi~hle formulations are either solids usually known as wettable powders, or liquids usually known as ~mlllcif;Ahlr~ r~-n~ntrates or aqueous suspensions.
25 Wettable powders, which may be c~npacted to form water dispersible granules, comprise an intimate mixture of the active , ~-llnr~, an inert carrier and surfactants.
The concentration of the active ~ is usually from about 10% to about 90% by weight. The inert 30 carrier is usually chosen from among the attapulgite clays, the i illonite clays, the r1;A --~rllc e3rths or the purifie~ ;cat~ T ffective su~fact~nts cr~nprising from abol~t ~-5& to ~bout 1~ of WO 95/31448 .~ 2 1 8 9 5 7 3 r-~ 07 the wettable powder, are found among the sulfonated lignins, the condensed naphthalenesulfonates, the naphthAlen~-clllfonates, the alkylh~ ulfonates, the alkyl sulfates, and non-ionic surfactants such as 5 ethylene oxide adducts of alkyl phenols.
r lI:if;Ahle concentrates of the~ _ comprise a convenient ~,..c~ LL~ILion of a r __ ~, such as from about 50 to about 500 grams per liter of liquid, equivalent to about 5% to about 50%, dissolved 10 in an inert carrier which is either a water m;~-;
solvent or a mixture of water-immiscible organic solvent and, 1 ~; f; l~rS . Useful organic solvents include aromatics, especially the xylenes, and the petroleum fractions, ~spe~iAl ly the high-boiling 15 naphthalenic and olef;n;c portions of petroleum such as heavy aromatic naphtha. Other organic solvents may also be used, such as the terpenic solvents including rosin derivatives, aliphatic ketones such as cyf~ , and complex Alc~hnl~ such as 20 2-ethoxyethanol. Suitable emulsifiers for 1s!~jf;~hlP
C~II LL a. Les are chosen f rom conv~nt ion;~ l non i r~n i surfactants, ~uch as those discussed above.
Aqueous susp~nç~ n~ comprise su~p~n~ n of water-insoluble _ '~ of this invention, dispersed 25 in an aqueous vehicle at a concentrati~n i n the range from about 5% to about 50% by weight. Suspensions are prepared by finely grinding the - ', and vigorously mixing it into a vehicle co~prised of water and 30 surfactants chosen from the same types discussed above.
Inert ingredients, such as inorganic salts and synthetic or natural gums, may also be added, to increase the density and viscosity of the aqueous WO95/31448 \ , ~ ~r ~ C 2 1 r ~ o7 vehicle. It is often most effective to grind and mix the . _ ~ at the same time by preparing the a~ueous mixture, and h~ j i7iTlg it in an implement such as a sand mill, ball mill, or piston-type homogenizer.
The ~ _ '- may also be applied as granular compositions, which are part;r~ rly useful for applications to the soil. Granular compositions usually contain from about 0.5% to about 10% by weight of the .1, dispersed in an inert carrier which consists entirely or in large part of clay or a similar inexpensive substance. Such compositions are usually prepared by dissolving the c _ rl in a suitable solvent, and applying it to a granular carrier which has been pre-formed to the appropriate particle size, in the range of from about 0 . 5 to 3 mm. Such compositions may also be formulated by making a dough or paste of the carrier and ~_ ', and crushing and drying to obtain the desired granular particle size.
Dusts crnt~ining the ~- are prepared simply 2n by intimately mixing the c ~ ' in p_ .lele:d form with a suitable dusty agricultural carrier, such as kaolin clay, ground volcanic rock and the like. Dusts can suitably contain from about 1% to about 10% of the ..
It is equally practicalS when desirable for any reason, to apply the ~ in the form of a solution in an appropriate organic solvent, usually a bland petroleum oil, such as the spray oils, which are widely used in agricultural chemistry.
Insecticides and miticides are generally applied in the form of a dispersion of the active ingredient in a liquid carrier. It is conventional to refer to Wo95/31448 C-l~ ? ~ ` 21 8 95 73 ~ 5,r application rates in terms of the concentration of active ingredient in the carrier. The most widely used carrier is water.
The compounds of Formula ( 1 ), ( 2 ), or ( 3 ) can also 5 be applied in the form of an aerosol composition. In such compositions the active - ~1 is dissolved or dispersed in an inert carrier, which is a ~Le_~u~ -generating propellant mixture. The aerosol composition is packaged in a container from which the 10 mixture is dispensed through an atomizing valve.
Propellant mixtures comprise either low-boiling h~loc:~rh~7nc, which may be mixed with organic solvents, or aqueous sUsp~ncinnC pLc~uLized with inert gases or gaseous lly~lLucdLlJulls .
The actual amount of ~oun~l to be applied to loci of insects and mites is not critical and can readily be det~rn~in~d by those skilled in the art in view of the ~ l~c above. In general, concentrations of from 10 ppm to 5000 ppm of c~, ~ are ~ ecLed to 20 provide good control. With many of the c ,_ ~-, c~ ;e~LLations of from lO0 to 1500 ppm will suffice.
For field crops, such a_ soybeans and cotton, a suitable application rate for the ~c is about 0.5 to 1.5 lb/A, typically applied in 50 gal/A of spray Iormulation containing 1200 to 3600 ppm of, Il For citrus crops, a suitable application rate is from abont lO0 to 1500 galtA cpray formulation, which is a rate of lO0 to lO00 ppm.
The locus to which a _ ~ _ d is applied can be any locus inhabited by an insect or arachnid, for example, vegetable crops, fruit and nut trees, grape vines, and ornamental plants. Tnr h as many mite species are specific to a particular host, the WO 95/31448 ~ ~ ~ r ~"} ~ 8 q~ 7 ~i r~lJ~ JI ~07 . . ~
foregoing list of mite species provides t- ,lification o~ the wide range of settings in which the pre6ent can be used.
Because o~ the unique ability of mite eggs to 5 resist toxicant action, repeated applications may be desirable to control newly emerged larvae, as is true of other known acaricides.
62 + + + + +++
71 + + + _ +
72 ++ + ++ + +
76 -- -- _ _ _ B~
WO 9S/31448 ~ 8 ~ 5 7 3 F~ 7 168 ++ ++ - 0 169 ++ + - 0 170 -- + - 0 171 - + - 0 166 + + - 0 167 -- + -- 0 172 -- + _ o 173 - + - 0 175 - ~ - 0 1?8 + + - 0 182 + + - 0 184 ++ + - 0 185 + + - o 186 + -- _ o 188 + + - 0 263 -- _ _ o 189 ++ - - 0 190 ++ +++ - O
WO9S/31448 ~ j~, P,~ 89573 P~ 07 191 + + - O +
193 + + - 0 +++
194 -- -- -- 0 +
196 + + - 0 +
271 - - - 0 _519530 192 + + - 0 ++
269 - + - 0 ++
1 95 + + - 0 +++
270 + - - 0 +
197 ++ + - 0 +
272 + -- -- 0 199 + + - O +
201 + - 0 +++
203 ++ + + 0 205 ++ + - 0 +++
198 + + - 0 ++
202 + + - 0 +
204 + + - 0 +++
206 ++ ++ - 0 +
273 + + - 0 +
208 + + - 0 ++
210 - + - 0 212 + +++ +++ 0 +
214 +++ + +++ 0 ++
WO 95/31448 ~ ' t ~ ~ ~ 8 9~S 7 207 + + - 0 +++
209 - + ++ 0 ++
211 ++ + - 0 +
213 +++ + + 0 ++
215 +++ + +++ 0 ++
216 + + +++ 0 ++
275 + + +++ 0 ++
276 + + +++ 0 +
133 + + - 0 +++
134 + + - 0 +
135 + - - 0 +
136 - + - 0 +
137 + - -- 0 +
138 + + - 0 +
139 + + - 0 +
141 -- -- -- 0 +
142 + + 0 0 ++
143 ++ + - 0 ++
144 + + - 0 +
145 + + - 0 +
146 ++ + - 0 ++
147 + + ++ 0 ++
149 ++ + - 0 +
150 ++ +++ - O ++
WO 9S/31448 ,' ~ 2 1 8 9 5 7 3 r~ l~U ~ r ~o7 151 + + +++ O ++
152 + + + 0 +++
153 ++ + + o 256 + + +++ o 15~ + + +++ O +++
155 ++ + +++ 0 +
257 + + +++ 0 +
156 ++ + + 0 +
258 + + ++ 0 +++
157 +++ + ++ 0 +
259 - + + 0 158 +++ + + 0 +
260 + + + 0 +
159 +++ + ++ 0 +
160 +++ + ++ 0 +
261 - + + 0 +
wo 95/31448 ; r ~ C ;~ i 8 9 5 7 3 . ~ . r ~7 Compositions The ~ c of Formula ~ 2 ), or l 3 ) may be applied in the form of compositions which are important s of the invention, and which comprise a 5 ~ _ ~1 of Formula ( 1 ), ( 2 ~, or ( 3 ) and a phyfolr~Ji, ~l ly-acceptable inert carrier. The compositions are either concentrated formulations which are disper~ed in water for application, or are dust or granular formulations which are applied without further 10 treatment. The compositions are p.~lJaLe!d according to pLOC_IlUL~::S and formulae which are conventional in the agricultural ~h~micAl art, but which are novel and important because of the presence therein of the c,, ~ of this inve~tion. Some description of the 15 ~ tinr1 of the compositions will be given, however, to assure that agricultural chemists can readily prepare any desired composition.
The dispc~rcir~nc in which the r~l ~ ' are applied are most often aqueous susr~ncionc or lcjnnc 20 prepared from concentrated formulations of the com-pounds. Such water-soluble, water-cucp~n~lAhl~ or lcifi~hle formulations are either solids usually known as wettable powders, or liquids usually known as ~mlllcif;Ahlr~ r~-n~ntrates or aqueous suspensions.
25 Wettable powders, which may be c~npacted to form water dispersible granules, comprise an intimate mixture of the active , ~-llnr~, an inert carrier and surfactants.
The concentration of the active ~ is usually from about 10% to about 90% by weight. The inert 30 carrier is usually chosen from among the attapulgite clays, the i illonite clays, the r1;A --~rllc e3rths or the purifie~ ;cat~ T ffective su~fact~nts cr~nprising from abol~t ~-5& to ~bout 1~ of WO 95/31448 .~ 2 1 8 9 5 7 3 r-~ 07 the wettable powder, are found among the sulfonated lignins, the condensed naphthalenesulfonates, the naphthAlen~-clllfonates, the alkylh~ ulfonates, the alkyl sulfates, and non-ionic surfactants such as 5 ethylene oxide adducts of alkyl phenols.
r lI:if;Ahle concentrates of the~ _ comprise a convenient ~,..c~ LL~ILion of a r __ ~, such as from about 50 to about 500 grams per liter of liquid, equivalent to about 5% to about 50%, dissolved 10 in an inert carrier which is either a water m;~-;
solvent or a mixture of water-immiscible organic solvent and, 1 ~; f; l~rS . Useful organic solvents include aromatics, especially the xylenes, and the petroleum fractions, ~spe~iAl ly the high-boiling 15 naphthalenic and olef;n;c portions of petroleum such as heavy aromatic naphtha. Other organic solvents may also be used, such as the terpenic solvents including rosin derivatives, aliphatic ketones such as cyf~ , and complex Alc~hnl~ such as 20 2-ethoxyethanol. Suitable emulsifiers for 1s!~jf;~hlP
C~II LL a. Les are chosen f rom conv~nt ion;~ l non i r~n i surfactants, ~uch as those discussed above.
Aqueous susp~nç~ n~ comprise su~p~n~ n of water-insoluble _ '~ of this invention, dispersed 25 in an aqueous vehicle at a concentrati~n i n the range from about 5% to about 50% by weight. Suspensions are prepared by finely grinding the - ', and vigorously mixing it into a vehicle co~prised of water and 30 surfactants chosen from the same types discussed above.
Inert ingredients, such as inorganic salts and synthetic or natural gums, may also be added, to increase the density and viscosity of the aqueous WO95/31448 \ , ~ ~r ~ C 2 1 r ~ o7 vehicle. It is often most effective to grind and mix the . _ ~ at the same time by preparing the a~ueous mixture, and h~ j i7iTlg it in an implement such as a sand mill, ball mill, or piston-type homogenizer.
The ~ _ '- may also be applied as granular compositions, which are part;r~ rly useful for applications to the soil. Granular compositions usually contain from about 0.5% to about 10% by weight of the .1, dispersed in an inert carrier which consists entirely or in large part of clay or a similar inexpensive substance. Such compositions are usually prepared by dissolving the c _ rl in a suitable solvent, and applying it to a granular carrier which has been pre-formed to the appropriate particle size, in the range of from about 0 . 5 to 3 mm. Such compositions may also be formulated by making a dough or paste of the carrier and ~_ ', and crushing and drying to obtain the desired granular particle size.
Dusts crnt~ining the ~- are prepared simply 2n by intimately mixing the c ~ ' in p_ .lele:d form with a suitable dusty agricultural carrier, such as kaolin clay, ground volcanic rock and the like. Dusts can suitably contain from about 1% to about 10% of the ..
It is equally practicalS when desirable for any reason, to apply the ~ in the form of a solution in an appropriate organic solvent, usually a bland petroleum oil, such as the spray oils, which are widely used in agricultural chemistry.
Insecticides and miticides are generally applied in the form of a dispersion of the active ingredient in a liquid carrier. It is conventional to refer to Wo95/31448 C-l~ ? ~ ` 21 8 95 73 ~ 5,r application rates in terms of the concentration of active ingredient in the carrier. The most widely used carrier is water.
The compounds of Formula ( 1 ), ( 2 ), or ( 3 ) can also 5 be applied in the form of an aerosol composition. In such compositions the active - ~1 is dissolved or dispersed in an inert carrier, which is a ~Le_~u~ -generating propellant mixture. The aerosol composition is packaged in a container from which the 10 mixture is dispensed through an atomizing valve.
Propellant mixtures comprise either low-boiling h~loc:~rh~7nc, which may be mixed with organic solvents, or aqueous sUsp~ncinnC pLc~uLized with inert gases or gaseous lly~lLucdLlJulls .
The actual amount of ~oun~l to be applied to loci of insects and mites is not critical and can readily be det~rn~in~d by those skilled in the art in view of the ~ l~c above. In general, concentrations of from 10 ppm to 5000 ppm of c~, ~ are ~ ecLed to 20 provide good control. With many of the c ,_ ~-, c~ ;e~LLations of from lO0 to 1500 ppm will suffice.
For field crops, such a_ soybeans and cotton, a suitable application rate for the ~c is about 0.5 to 1.5 lb/A, typically applied in 50 gal/A of spray Iormulation containing 1200 to 3600 ppm of, Il For citrus crops, a suitable application rate is from abont lO0 to 1500 galtA cpray formulation, which is a rate of lO0 to lO00 ppm.
The locus to which a _ ~ _ d is applied can be any locus inhabited by an insect or arachnid, for example, vegetable crops, fruit and nut trees, grape vines, and ornamental plants. Tnr h as many mite species are specific to a particular host, the WO 95/31448 ~ ~ ~ r ~"} ~ 8 q~ 7 ~i r~lJ~ JI ~07 . . ~
foregoing list of mite species provides t- ,lification o~ the wide range of settings in which the pre6ent can be used.
Because o~ the unique ability of mite eggs to 5 resist toxicant action, repeated applications may be desirable to control newly emerged larvae, as is true of other known acaricides.
Claims (69)
1. A compound of Formula (1), (2), or (3),below:
(1) (2) (3) wherein:
R and R1 are each independently independently H, (C1-C4) alkyl, (C1-C4) alkyl optionally substituted with CH2CH(OCH3)2, halo, (C1-C4) alkoxy, or , wherein B is O or NR1 and n is an integer 1-4; halo(C1-C4)alkyl; deuterio (C1-C4) alkyl; (C1-C4) acyl; (C1-C4) alkyl-CO2-E. wherein E is H, (C1-C4) alkyl, or a cation, such as, for example, sodium, potassium, or ammonium; trifluoroacetyl; alkoxymethyl;
hydroxymethyl; formyl; (R2)2NS(O)X; benzyl; or benzyl optionally substituted with (C1-C4) alkyl, (C1-C4) alkoxy, halo, halo (C1-C4) alkyl;
Each R2 is independently lower alkyl, aryl, or together form with nitrogen a saturated (C3-C7) ring such as morpholino, piperidinyl, pyrrolidinyl;
x is an integer from 0 to 2;
R3 and R4 are each independently H, (C1-C4) alkyl, halogen, I, (C1-C4) alkoxy, halo (C1-C4) alkoxy, (C1-C4 carboalkoxy, halo (C1-C4) alkyl, or together form a saLulated or unsaturated six membered carbon ring;
Y-Z together form a (C2-C11) saturated or unsaturated hydrocarbon chain, straight chain or branched, optionally including a hetero atom selected from O, NR5, S, SO, SO2, or SiR6R7, and optionally substituted with one or more groups independently selected from (C1-C4) alkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, branched (C3-C7) alkyl, (C3-C7) cycloalkyl, (C3-C7) cycloalkenyl, halo, halo (C1-C4) alkyl, halo (C1-C4) alkoxy, hydroxy, or (C1-C4) acyl;
R5 is H, (C1-C4) alkyl, or (C1-C4) acyl;
R6 and R7 are independently (C1-C4) alkyl, (C3-C4) branched alkyl, phenyl, or substituted phenyl; or Y is a bond, CHD, CD2, C=O, or a bivalent hydrocarbon radical one to five carbon atoms long, optionally substituted with (C1-C4) alkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, branched (C3-C7) alkyl, (C3-C7) cycloalkyl, (C3-C7) cycloalkenyl, halo, halo (C1-C4) alkyl, halo (C1-C4) alkoxy, hydroxy, CN, (C1-C4) acyl, (C1-C4) alkoxycarbonyl, aryloxycarbonyl, hydroxy (C1-C4) alkyl, (C1-C4) alkoxy (C1-C4) alkyl, methylene, methylene optionally substituted with one or more groups independently selected from hydrogen; (C1-C4) alkyl; (C1-C4) alkoxy; SH; S-lower alkyl; NH2; NH-lower alkyl or N,N-di-lower alkyl, optionally substituted with carboxy, carboalkoxy, or carboaryloxy; NHOH; NHO-lower alkyl; N-lower alkyl-OH; N-lower alkyl-lower alkyl; O-lower alkyl; OH; morpholino; piperididinyl;
pyrrolidinyl; thiomorpholino; or methylene forming part of a (C5-C6) saturated or unsaturated ring optionally including 1 or 2 hetero atoms selected from O, S, or NR5;
Z is (a) aryl or (b) (C3-C8) cycloalkyl or cycloalkenyl, optionally substituted with one or more groups independently selected from (C1-C4) alkyl, (C1-C4) alkoxy, halo (C1-C4) alkyl, halo (C1-C4) alkoxy, halo, hydroxy, or (C1-C4) acyl; where aryl is (a) a phenyl group optionally substituted with one or more groups independently selected from:
halo, I, (C3-C8) cycloalkyl, (C3-C8) cycloalkenyl, phenoxy, substituted phenoxy, phenylthio, substituted phenylthio, phenyl, substituted phenyl, NO2, , where R8 is (C1-C7) alkyl, halo (C1-C7) alkyl, (C3-C7) branched alkyl, halo (C3-C7) branched alkyl, (C3-C7) cycloalkyl, halo (C3-C7) cycloalkyl, (C1-C7) alkoxy, hydroxy, phenyl, substituted phenyl, phenoxy, or substituted phenoxy, , wherein R8 cannot be hydroxy, OH, CN, SiR9R10R11 or OSiR9R10R11, where R9, R10 and R11 are independently (C1-C4) alkyl, (C3-C4) branched alkyl, phenyl, or substituted phenyl, NR12R13, where R12 and R13 are independently H, (C1-C4) alkyl, or (C1-C4) acyl, S(O)R14, SO2R14, or OSO2R14, where R14 is (C1-C10) alkyl, phenyl, or substituted phenyl;
a (C1-C12) saturated or unsaturated hydrocarbon chain, straight chain or branched optionally including a hetero atom selected from O, S, SO, SO2, NR5, or SiR6R7, where R5, R6 and R7 are as defined above, and optionally substituted with halo, halo (C1-C4) alkoxy, hydroxy, (C3-C8) cycloalkyl or cycloalkenyl, (C1-C4) acyl, phenoxy, substituted phenoxy, phenyl, substituted phenyl, phenylthio, substituted phenylthio, or cyano;
(C1-C7) alkoxy optionally substituted with halo, phenyl, substituted phenyl, (C3-C8) cycloalkyl or cycloalkenyl, phenoxy, or substituted phenoxy; or (C1-C7) alkylthio optionally substituted with halo, phenyl, substituted phenyl, (C3-C8) cycloalkyl or cycloalkenyl, phenoxy or substituted phenoxy;
(b) a furyl group of formula (3) (3) where R15 is H, halo, halomethyl, CN, NO2, (C1-C4) alkyl, (C3-C4) branched alkyl, phenyl, (C1-C4) alkoxy;
(c) a thienyl group of the formula (4) (4) where R16 is H, halo, halomethyl, CN, NO2, (C1-C4) alkyl, (C3-C4) branched alkyl, phenyl, (C1-C4) alkoxy, or thienyl;
(d) a group of formula (5) or (6) (5) (6) where R15 is as defined in paragraph (b), J is N or CH, and G is O, NR17, or S, provided that if J is not N
then G is NR, where R17 is H, (C1-C4) alkyl, (C1-C4) acyl, phenylsulfonyl, or substituted phenylsulfonyl;
(e) a group selected from optionally substituted naphthyl, dihydronaphthyl, tetrahydronaphthyl, and decahydronaphthyl;
optionally substituted indolyl;
1,3-benzodioxolyl;
2,6-dimethyl-4-morpholinyl; and 1-adamantyl;
(f) a group of the formula wherein m is 4; R20 are independently H, halo, lower alkyl, lower alkoxy, haloalkyl, haloalkoxy, NO2, CN, lower alkyl carbonyl, phenoxy, or substituted phenoxy, provided that at least two of R20 are selected from H
and F; and Het is pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl, optionally substituted with one or more groups selected from halo, lower alkyl, lower alkoxy, haloalkyl, haloalkoxy, NO2, CN, and lower alkyl carbonyl;
(g) a group of the formula wherein one of X2 and X3 is N and the other is CR23;
R21 is -T-R22, phenyl, substituted phenyl, (C1-C10) alkyl, halo, or halo (C1-C8) alkyl, where T is O or S, and R22 is (C1-C4) alkyl, (C3-C7) branched alkyl, halo (C1-C7) alkyl, halo (C3-C7) branched alkyl, (C1-C4) alkoxy (C1-C4) alkyl, or naphthyl or phenyl, either of which may be optionally substituted with up to three groups selected from halo, (C1-C10) alkyl, branched (C3-C7) alkyl, halo (C1-C7) alkyl, hydroxy (C1-C7) alkyl, (C1-C4) alkoxy, halo (C1-C4) alkoxy, phenoxy, substituted phenoxy, phenyl, substituted phenyl, CN, NO2, OH, (C1-C4) alkanoyloxy, or benzyloxy;
R23 is H, halo, I, (C3-C8) cycloalkyl, (C3-C8) cycloalkenyl, phenoxy, substituted phenoxy, phenylthio, substituted phenylthio, phenyl, substituted phenyl, NO2, , where R8 is (C1-C7) alkyl, halo (C1-C7) alkyl, (C3-C7) branched alkyl, halo (C3-C7) branched alkyl, (C3-C7) cycloalkyl, halo (C3-C7) cycloalkyl, (C1-C7) alkoxy, phenyl, substituted phenyl, or hydroxy, acetoxy, OH, CN, SiR9R10R11 or OSiR9R10R11, where R9,R10 and R11 are independently (C1-C4) alkyl, (C3-C4) branched alkyl, phenyl, or substituted phenyl, NR12R13, where R12 and R13 are independently H, (C1-C4) alkyl, or (C1-C4) acyl, S(O)R14, or SO2R14, where R14 is (C1-C10) alkyl, phenyl, or substituted phenyl;
a (C1-C12) saturated or unsaturated hydrocarbon chain, straight chain or branched optionally including a hetero atom selected from O, S, SO, SO2, NR5, or SiR6R7, where R5, R6 and R7 are as defined above, and optionally substituted with halo, halo (C1-C4) alkoxy, hydroxy, (C3-C8) cycloalkyl or cycloalkenyl, (C1-C4) acyl, phenoxy, substituted phenoxy, phenyl, substituted phenyl, phenylthio, substituted phenylthio, or cyano;
(C1-C7) alkoxy optionally substituted with halo, phenyl, substituted phenyl, (C3-C8) cycloalkyl or cycloalkenyl, phenoxy, or substituted phenoxy; or (C1-C7) alkylthio optionally substituted with halo, phenyl, substituted phenyl, (C3-C8) cycloalkyl or cycloalkenyl, phenoxy or substituted phenoxy.
W is O, S(Q)y, wherein y is an integer from 0 to 2, or NR24;
G is (C1-C4) alkyl, aryl, (C1-C4) acyl, NR25R26, deuterio (C1-C4) alkyl, halo (C1-C4) alkyl, benzyl, or benzyl optionally substituted with (C1-C4) alkyl, (C1-C4) alkoxy, halo, halo (C1-C4) alkyl; or W-G together are halo, SH, or NR25R26;
R24 is H, OH, (C1-C4) alkyl, (C1-C4) alkoxy, aryl, (C1-C4) acyl, NR25R26, benzyl, or benzyl optionally substituted with (C1-C4) alkyl, (C1-C4) alkoxy, halo, halo (C1-C4) alkyl; and R25 and R26 independently H, (C1-C4) alkyl, aryl, acyl, or together form with nitrogen a saturated (C3-C7) ring such as morpholino, piperidinyl, pyrrolidinyl.
(1) (2) (3) wherein:
R and R1 are each independently independently H, (C1-C4) alkyl, (C1-C4) alkyl optionally substituted with CH2CH(OCH3)2, halo, (C1-C4) alkoxy, or , wherein B is O or NR1 and n is an integer 1-4; halo(C1-C4)alkyl; deuterio (C1-C4) alkyl; (C1-C4) acyl; (C1-C4) alkyl-CO2-E. wherein E is H, (C1-C4) alkyl, or a cation, such as, for example, sodium, potassium, or ammonium; trifluoroacetyl; alkoxymethyl;
hydroxymethyl; formyl; (R2)2NS(O)X; benzyl; or benzyl optionally substituted with (C1-C4) alkyl, (C1-C4) alkoxy, halo, halo (C1-C4) alkyl;
Each R2 is independently lower alkyl, aryl, or together form with nitrogen a saturated (C3-C7) ring such as morpholino, piperidinyl, pyrrolidinyl;
x is an integer from 0 to 2;
R3 and R4 are each independently H, (C1-C4) alkyl, halogen, I, (C1-C4) alkoxy, halo (C1-C4) alkoxy, (C1-C4 carboalkoxy, halo (C1-C4) alkyl, or together form a saLulated or unsaturated six membered carbon ring;
Y-Z together form a (C2-C11) saturated or unsaturated hydrocarbon chain, straight chain or branched, optionally including a hetero atom selected from O, NR5, S, SO, SO2, or SiR6R7, and optionally substituted with one or more groups independently selected from (C1-C4) alkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, branched (C3-C7) alkyl, (C3-C7) cycloalkyl, (C3-C7) cycloalkenyl, halo, halo (C1-C4) alkyl, halo (C1-C4) alkoxy, hydroxy, or (C1-C4) acyl;
R5 is H, (C1-C4) alkyl, or (C1-C4) acyl;
R6 and R7 are independently (C1-C4) alkyl, (C3-C4) branched alkyl, phenyl, or substituted phenyl; or Y is a bond, CHD, CD2, C=O, or a bivalent hydrocarbon radical one to five carbon atoms long, optionally substituted with (C1-C4) alkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, branched (C3-C7) alkyl, (C3-C7) cycloalkyl, (C3-C7) cycloalkenyl, halo, halo (C1-C4) alkyl, halo (C1-C4) alkoxy, hydroxy, CN, (C1-C4) acyl, (C1-C4) alkoxycarbonyl, aryloxycarbonyl, hydroxy (C1-C4) alkyl, (C1-C4) alkoxy (C1-C4) alkyl, methylene, methylene optionally substituted with one or more groups independently selected from hydrogen; (C1-C4) alkyl; (C1-C4) alkoxy; SH; S-lower alkyl; NH2; NH-lower alkyl or N,N-di-lower alkyl, optionally substituted with carboxy, carboalkoxy, or carboaryloxy; NHOH; NHO-lower alkyl; N-lower alkyl-OH; N-lower alkyl-lower alkyl; O-lower alkyl; OH; morpholino; piperididinyl;
pyrrolidinyl; thiomorpholino; or methylene forming part of a (C5-C6) saturated or unsaturated ring optionally including 1 or 2 hetero atoms selected from O, S, or NR5;
Z is (a) aryl or (b) (C3-C8) cycloalkyl or cycloalkenyl, optionally substituted with one or more groups independently selected from (C1-C4) alkyl, (C1-C4) alkoxy, halo (C1-C4) alkyl, halo (C1-C4) alkoxy, halo, hydroxy, or (C1-C4) acyl; where aryl is (a) a phenyl group optionally substituted with one or more groups independently selected from:
halo, I, (C3-C8) cycloalkyl, (C3-C8) cycloalkenyl, phenoxy, substituted phenoxy, phenylthio, substituted phenylthio, phenyl, substituted phenyl, NO2, , where R8 is (C1-C7) alkyl, halo (C1-C7) alkyl, (C3-C7) branched alkyl, halo (C3-C7) branched alkyl, (C3-C7) cycloalkyl, halo (C3-C7) cycloalkyl, (C1-C7) alkoxy, hydroxy, phenyl, substituted phenyl, phenoxy, or substituted phenoxy, , wherein R8 cannot be hydroxy, OH, CN, SiR9R10R11 or OSiR9R10R11, where R9, R10 and R11 are independently (C1-C4) alkyl, (C3-C4) branched alkyl, phenyl, or substituted phenyl, NR12R13, where R12 and R13 are independently H, (C1-C4) alkyl, or (C1-C4) acyl, S(O)R14, SO2R14, or OSO2R14, where R14 is (C1-C10) alkyl, phenyl, or substituted phenyl;
a (C1-C12) saturated or unsaturated hydrocarbon chain, straight chain or branched optionally including a hetero atom selected from O, S, SO, SO2, NR5, or SiR6R7, where R5, R6 and R7 are as defined above, and optionally substituted with halo, halo (C1-C4) alkoxy, hydroxy, (C3-C8) cycloalkyl or cycloalkenyl, (C1-C4) acyl, phenoxy, substituted phenoxy, phenyl, substituted phenyl, phenylthio, substituted phenylthio, or cyano;
(C1-C7) alkoxy optionally substituted with halo, phenyl, substituted phenyl, (C3-C8) cycloalkyl or cycloalkenyl, phenoxy, or substituted phenoxy; or (C1-C7) alkylthio optionally substituted with halo, phenyl, substituted phenyl, (C3-C8) cycloalkyl or cycloalkenyl, phenoxy or substituted phenoxy;
(b) a furyl group of formula (3) (3) where R15 is H, halo, halomethyl, CN, NO2, (C1-C4) alkyl, (C3-C4) branched alkyl, phenyl, (C1-C4) alkoxy;
(c) a thienyl group of the formula (4) (4) where R16 is H, halo, halomethyl, CN, NO2, (C1-C4) alkyl, (C3-C4) branched alkyl, phenyl, (C1-C4) alkoxy, or thienyl;
(d) a group of formula (5) or (6) (5) (6) where R15 is as defined in paragraph (b), J is N or CH, and G is O, NR17, or S, provided that if J is not N
then G is NR, where R17 is H, (C1-C4) alkyl, (C1-C4) acyl, phenylsulfonyl, or substituted phenylsulfonyl;
(e) a group selected from optionally substituted naphthyl, dihydronaphthyl, tetrahydronaphthyl, and decahydronaphthyl;
optionally substituted indolyl;
1,3-benzodioxolyl;
2,6-dimethyl-4-morpholinyl; and 1-adamantyl;
(f) a group of the formula wherein m is 4; R20 are independently H, halo, lower alkyl, lower alkoxy, haloalkyl, haloalkoxy, NO2, CN, lower alkyl carbonyl, phenoxy, or substituted phenoxy, provided that at least two of R20 are selected from H
and F; and Het is pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl, optionally substituted with one or more groups selected from halo, lower alkyl, lower alkoxy, haloalkyl, haloalkoxy, NO2, CN, and lower alkyl carbonyl;
(g) a group of the formula wherein one of X2 and X3 is N and the other is CR23;
R21 is -T-R22, phenyl, substituted phenyl, (C1-C10) alkyl, halo, or halo (C1-C8) alkyl, where T is O or S, and R22 is (C1-C4) alkyl, (C3-C7) branched alkyl, halo (C1-C7) alkyl, halo (C3-C7) branched alkyl, (C1-C4) alkoxy (C1-C4) alkyl, or naphthyl or phenyl, either of which may be optionally substituted with up to three groups selected from halo, (C1-C10) alkyl, branched (C3-C7) alkyl, halo (C1-C7) alkyl, hydroxy (C1-C7) alkyl, (C1-C4) alkoxy, halo (C1-C4) alkoxy, phenoxy, substituted phenoxy, phenyl, substituted phenyl, CN, NO2, OH, (C1-C4) alkanoyloxy, or benzyloxy;
R23 is H, halo, I, (C3-C8) cycloalkyl, (C3-C8) cycloalkenyl, phenoxy, substituted phenoxy, phenylthio, substituted phenylthio, phenyl, substituted phenyl, NO2, , where R8 is (C1-C7) alkyl, halo (C1-C7) alkyl, (C3-C7) branched alkyl, halo (C3-C7) branched alkyl, (C3-C7) cycloalkyl, halo (C3-C7) cycloalkyl, (C1-C7) alkoxy, phenyl, substituted phenyl, or hydroxy, acetoxy, OH, CN, SiR9R10R11 or OSiR9R10R11, where R9,R10 and R11 are independently (C1-C4) alkyl, (C3-C4) branched alkyl, phenyl, or substituted phenyl, NR12R13, where R12 and R13 are independently H, (C1-C4) alkyl, or (C1-C4) acyl, S(O)R14, or SO2R14, where R14 is (C1-C10) alkyl, phenyl, or substituted phenyl;
a (C1-C12) saturated or unsaturated hydrocarbon chain, straight chain or branched optionally including a hetero atom selected from O, S, SO, SO2, NR5, or SiR6R7, where R5, R6 and R7 are as defined above, and optionally substituted with halo, halo (C1-C4) alkoxy, hydroxy, (C3-C8) cycloalkyl or cycloalkenyl, (C1-C4) acyl, phenoxy, substituted phenoxy, phenyl, substituted phenyl, phenylthio, substituted phenylthio, or cyano;
(C1-C7) alkoxy optionally substituted with halo, phenyl, substituted phenyl, (C3-C8) cycloalkyl or cycloalkenyl, phenoxy, or substituted phenoxy; or (C1-C7) alkylthio optionally substituted with halo, phenyl, substituted phenyl, (C3-C8) cycloalkyl or cycloalkenyl, phenoxy or substituted phenoxy.
W is O, S(Q)y, wherein y is an integer from 0 to 2, or NR24;
G is (C1-C4) alkyl, aryl, (C1-C4) acyl, NR25R26, deuterio (C1-C4) alkyl, halo (C1-C4) alkyl, benzyl, or benzyl optionally substituted with (C1-C4) alkyl, (C1-C4) alkoxy, halo, halo (C1-C4) alkyl; or W-G together are halo, SH, or NR25R26;
R24 is H, OH, (C1-C4) alkyl, (C1-C4) alkoxy, aryl, (C1-C4) acyl, NR25R26, benzyl, or benzyl optionally substituted with (C1-C4) alkyl, (C1-C4) alkoxy, halo, halo (C1-C4) alkyl; and R25 and R26 independently H, (C1-C4) alkyl, aryl, acyl, or together form with nitrogen a saturated (C3-C7) ring such as morpholino, piperidinyl, pyrrolidinyl.
2. A compound of Claim 1 wherein:
Y is CH2 or methylene, optionally substituted with NH2, NH-lower alkyl, or N,N-di-lower alkyl, optionally substituted with carboxy, carboalkoxy, or carboaryloxy;
Z is substituted phenyl;
R or R1 is H, ethyl, methoxymethyl, or ethoxymethyl;
R3 is (C1-C4) alkyl; and R4 is H or halo.
Y is CH2 or methylene, optionally substituted with NH2, NH-lower alkyl, or N,N-di-lower alkyl, optionally substituted with carboxy, carboalkoxy, or carboaryloxy;
Z is substituted phenyl;
R or R1 is H, ethyl, methoxymethyl, or ethoxymethyl;
R3 is (C1-C4) alkyl; and R4 is H or halo.
3. A compound of Claim 2 wherein Z is:
a phenyl group substituted with a (C2-C4) alkoxy group;
a phenyl group substituted with a (C3-C7) branched alkoxy group;
a phenyl group substituted with a halo (C2-C4) alkoxy group;
a phenyl group substituted with a halo (C3-C7) branched alkoxy group;
a phenyl group substituted with a phenoxy or substituted phenoxy group;
a phenyl group substituted with a (C3-C5) branched alkyl group.
a phenyl group substituted with a (C2-C4) alkoxy group;
a phenyl group substituted with a (C3-C7) branched alkoxy group;
a phenyl group substituted with a halo (C2-C4) alkoxy group;
a phenyl group substituted with a halo (C3-C7) branched alkoxy group;
a phenyl group substituted with a phenoxy or substituted phenoxy group;
a phenyl group substituted with a (C3-C5) branched alkyl group.
4. A compound of Claim 3 wherein the phenyl group is monosubstituted in the 4-position.
5. A compound of Claim 3 wherein R3 is methyl or ethyl and R4 is bromo or chloro.
6. A compound Claim 3 wherein R or R1 is ethyl, methoxymethyl, or ethoxymethyl.
7. A compound of claim 3 of the formula
8. A compound of claim 3 of the formula
9. A compound of claim 3 of the formula
10. A compound of claim 3 of the formula
11. A compound of claim 3 of the formula
12. A compound of claim 3 of the formula
13. A compound of claim 3 of the formula
14. A compound of claim 3 of the formula
15. A compound of claim 3 of the formula
16. A compound of claim 3 of the formula
17. A compound of claim 3 of the formula
18. A compound of claim 3 of the formula
19. A compound of claim 3 of the formula
20. A compound of claim 3 of the formula
21. A compound of claim 3 of the formula
22. A compound of claim 3 of the formula
23. A compound of claim 3 of the formula
24. A compound of claim 3 of the formula
25. A compound of claim 3 of the formula
26. A compound of claim 3 of the formula
27. A compound of claim 3 of the formula
28. A compound of claim 3 of the formula
29. A compound of claim 3 of the formula
30. A compound of claim 3 of the formula
31. A compound of claim 3 of the formula
32. A compound of claim 3 of the formula
33. A compound of claim 3 of the formula
34. A compound of claim 3 of the formula
35. A compound of claim 3 of the formula
36. A compound of claim 3 of the formula
37. A compound of claim 3 of the formula
38. A compound of claim 3 of the formula
39. A compound of claim 3 of the formula
40. A compound of claim 3 of the formula
41. A compound of claim 3 of the formula
42. A compound of claim 3 of the formula
43. A compound of claim 3 of the formula
44. A compound of claim 3 of the formula
45. A compound of claim 3 of the formula
46. A compound of claim 3 of the formula
47. A compound of claim 3 of the formula
48. A compound of claim 3 of the formula
49. A compound of claim 3 of the formula
50. A compound of claim 3 of the formula
51. A compound of claim 3 of the formula
52. A compound claim 3 of the formula
53. A compound of claim 3 of the formula
54. A compound of claim 3 of the formula
55. A compound of claim 3 of the formula
56. A compound of claim 3 of the formula
57. A compound of claim 3 of the formula
58. A compound of claim 3 of the formula
59. A compound of claim 3 of the formula
60. A compound of claim 3 of the formula
61. A composition comprising an insecticidal, namaticidal, miticidal, or fungicidally effective amount of an N-(5-isothiazolyl)amide compound of Formula (1), (2), or (3), below:
(1) (2) (3) wherein:
R and R1 are each independently independently H, (C1-C4) alkyl, (C1-C4) alkyl optionally substituted with CH2CH(OCH3)2, halo, (C1-C4) alkoxy, or , wherein B is O or NR1 and n is an integer 1-4; halo(C1-C4)alkyl; deuterio (C1-C4) alkyl; (C1-C4) acyl; (C1-C4) alkyl-CO2-E. wherein E is H, (C1-C4) alkyl, or a cation, such as, for example, sodium, potassium, or ammonium; trifluoroacetyl; alkoxymethyl;
hydroxymethyl; formyl; (R2)2NS(O)X; benzyl; or benzyl optionally substituted with (C1-C4) alkyl, (C1-C4) alkoxy, halo, halo (C1-C4) alkyl;
Each R2 is independently lower alkyl, aryl, or together form with nitrogen a saturated (C3-C7) ring such as morpholino, piperidinyl, pyrrolidinyl;
x is an integer from 0 to 2;
R3 and R4 are each independently H, (C1-C4) alkyl, halogen, I, (C1-C4) alkoxy, halo (C1-C4) alkoxy, (C1-C4 carboalkoxy, halo (C1-C4) alkyl, or together form a saturated or unsaturated six membered carbon ring;
Y-Z together form a (C2-C11) saturated or unsaturated hydrocarbon chain, straight chain or branched, optionally including a hetero atom selected from O, NR5, S, SO, SO2, or SiR6R7, and optionally substituted with one or more groups independently selected from (C1-C4) alkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, branched (C3-C7) alkyl, (C3-C7) cycloalkyl, (C3-C7) cycloalkenyl, halo, halo (C1-C4) alkyl, halo (C1-C4) alkoxy, hydroxy, or (C1-C4) acyl;
R5 is H, (C1-C4) alkyl, or (C1-C4) acyl;
R6 and R7 are independently (C1-C4) alkyl, (C3-C4) branched alkyl, phenyl, or substituted phenyl; or Y is a bond, CHD, CD2, C=O, or a bivalent hydrocarbon radical one to five carbon atoms long, optionally substituted with (C1-C4) alkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, branched (C3-C7) alkyl, (C3-C7) cycloalkyl, (C3-C7) cycloalkenyl, halo, halo (C1-C4) alkyl, halo (C1-C4) alkoxy, hydroxy, CN, (C1-C4) acyl, (C1-C4) alkoxycarbonyl, aryloxycarbonyl, hydroxy (C1-C4) alkyl, (C1-C4) alkoxy (C1-C4) alkyl, methylene, methylene optionally substituted with one or more groups independently selected from hydrogen; (C1-C4) alkyl; (C1-C4) alkoxy; SH; S-lower alkyl; NH2; NH-lower alkyl or N,N-di-lower alkyl, optionally substituted with carboxy, carboalkoxy, or carboaryloxy; NHOH; NHO-lower alkyl; N-lower alkyl-OH; N-lower alkyl-lower alkyl; O-lower alkyl; OH; morpholino; piperidinyl;
pyrrolidinyl; thiomorpholino; or methylene forming part of a (C5-C6) saturated or unsaturated ring optionally including 1 or 2 hetero atoms selected from O, S, or NR5;
Z is (a) aryl or (b) (C3-C8) cycloalkyl or cycloalkenyl, optionally substituted with one or more groups independently selected from (C1-C4) alkyl, (C1-C4) alkoxy, halo (C1-C4) alkyl, halo (C1-C4) alkoxy, halo, hydroxy, or (C1-C4) acyl; where aryl is (a) a phenyl group optionally substituted with one or more groups independently selected from:
halo, I, (C3-C8) cycloalkyl, (C3-C8) cycloalkenyl, phenoxy, substituted phenoxy, phenylthio, substituted phenylthio, phenyl, substituted phenyl, NO2, , where R8 is (C1-C7) alkyl, halo (C1-C7) alkyl, (C3-C7) branched alkyl, halo (C3-C7) branched alkyl, (C3-C7) cycloalkyl, halo (C3-C7) cycloalkyl, (C1-C7) alkoxy, hydroxy, phenyl, substituted phenyl, phenoxy, or substituted phenoxy, , wherein R8 cannot be hydroxy, OH, CN, SiR9R10R11 or OSiR9R10R11, where R9,R10 and R11 are; independently (C1-C4) alky1, (C3-C4) branched alkyl, phenyl, or substituted phenyl, NR12R13, where R12 and R13 are independently H, (C1-C4) alkyl, or (C1-C4) acyl, S(O)R14, SO2R14, or OSO2R14, where R14 is (C1-C10) alkyl, phenyl, or substituted phenyl;
a (C1-C12)saturated or unsaturated hydrocarbon chain, straight chain or branched optionally including a hetero atom selected from O, S, SO, SO2, NR5, or SiR6R7, where R5, R6 and R7 are as defined above, and optionally substituted with halo, halo (C1-C4) alkoxy, hydroxy, (C3-C8) cycloalkyl or cycloalkenyl, (C1-C4) acyl, phenoxy, substituted phenoxy, phenyl, substituted phenyl, phenylthio, substituted phenylthio, or cyano;
(C1-C7) alkoxy optionally substituted with halo, phenyl, substituted phenyl, (C3-C8) cycloalkyl or cycloalkenyl, phenoxy, or substituted phenoxy; or (C1-C7) alkylthio optionally substituted with halo, phenyl, substituted phenyl, (C3-C8) cycloalkyl or cycloalkenyl, phenoxy or substituted phenoxy;
(b) a furyl group of formula (3) (3) where R15 is H, halo, halomethyl, CN, NO2, (C1-C4) alkyl, (C3-C4) branched alkyl, phenyl, (C1-C4) alkoxy;
(c) a thienyl group of the formula (4) (4) where R16 is H, halo, halomethyl, CN, NO2, (C1-C4) alkyl, (C3-C4) branched alkyl, phenyl, (C1-C4) alkoxy, or thienyl;
(d) a group of formula (5) or (6) (5) (6) where R15 is as defined in paragraph (b), J is N or CH, and G is O., NR17, or S, provided that if J is not N
then G is NR, where R17 is H, (C1-C4) alkyl, (C1-C4) acyl, phenylsulfonyl, or substituted phenylsulfonyl;
(e) a group selected from optionally substituted naphthyl, dihydronaphthyl, tetrahydronaphthyl, and decahydronaphthyl;
optionally substituted indolyl;
1,3-benzodioxolyl;
2,6-dimethyl-4-morpholinyl; and 1-adamantyl;
(f) a group of the formula wherein m is 4; R20 are independently H, halo, lower alkyl, lower alkoxy, haloalkyl, haloalkoxy NO2, CN, lower alkyl carbonyl, phenoxy, or substituted phenoxy, proYided that at least two of R20 are selected from H
and F; and Het is pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl, optionally substituted with one or more groups selected from halo, lower alkyl, lower alkoxy, haloalkyl, haloalkoxy, NO2, CN, and lower alkyl carbonyl;
(g) a group of the formula wherein one of X2 and X3 is N and the other is CR23;
R21 is -T-R22, phenyl, substituted phenyl, (C1-C10) alkyl, halo, or halo (C1-C8) alkyl, where T is O or S, and R22 is (C1-C4) alkyl, (C3-C7) branched alkyl, halo (C1-C7) alkyl, halo (C3-C7) branched alkyl, (C1-C4) alkoxy (C1-C4) alkyl, or naphthyl or phenyl, either of which may be optionally substituted with up to three groups selected from halo, (C1-C10) alkyl, branched (C3-C7) alkyl, halo (C1-C7) alkyl, hydroxy (C1-C7) alkyl, (C1-C4) alkoxy, halo (C1-C4) alkoxy, phenoxy, substituted phenoxy, phenyl, substituted phenyl, CN, NO2, OH, (C1-C4) alkanoyloxy, or benzyloxy;
R23 is:
H, halo, I, (C3-C8) cycloalkyl, (C3-C8) cycloalkenyl, phenoxy, substituted phenoxy, phenylthio, substituted phenylthio, phenyl, substituted phenyl, NO2, , where R8 is (C1-C7) alkyl, halo (C1-C7) alkyl, (C3-C7) branched alkyl, halo (C3-C7) branched alkyl, (C3-C7) cycloalkyl, halo (C3-C7) cycloalkyl, (C1-C7) alkoxy, phenyl, substituted phenyl, or hydroxy, acetoxy, OH, CN, SiR9R10R11 or oSiR9R10R11, where R9,R10 and R11 are independently (C1-C4) alkyl, (C3-C4) branched alkyl, phenyl, or substituted phenyl, NR12R13, where R12 and R13 are independently H, (C1-C4) alkyl, or (C1-C4) acyl, S(O)R14, or SO2R14, where R14 is (C1-C10) alkyl, phenyl, or substituted phenyl;
a (C1-C12) saturated or unsaturated hydrocarbon chain, straight chain or branched optionally including a hetero atom selected from O, S, SO, SO2, NR5, or SiR6R7, where R5, R6 and R7 are as defined above, and optionally substituted with halo, halo (C1-C4) alkoxy, hydroxy, (C3-C8) cycloalkyl or cycloalkenyl, (C1-C4) acyl, phenoxy, substituted phenoxy, phenyl, substituted phenyl, phenylthio, substituted phenylthio, or cyano;
(C1-C7) alkoxy optionally substituted with halo, phenyl, substituted phenyl, (C3-C8) cycloalkyl or cycloalkenyl, phenoxy, or substituted phenoxy; or (C1-C7) alkylthio optionally substituted with halo, phenyl, substituted phenyl, (C3-C8) cycloalkyl or cycloalkenyl, phenoxy or substituted phenoxy.
W is O, S(O)y, wherein y is an integer from 0 to 2, or NR24;
G is (C1-C4) alkyl, aryl, (C1-C4) acyl, NR25R26, deuterio (C1-C4) alkyl, halo (C1-C4) alkyl, benzyl, or benzyl optionally substituted with (C1-C4) alkyl, (C1-C4) alkoxy, halo, halo (C1-C4) alkyl; or W-G together are halo, SH, or NR25R26;
R24 is H, OH, (C1-C4) alkyl, (C1-C4) alkoxy, aryl, (C1-C4) acyl, NR25R26, benzyl, or benzyl optionally substituted with (C1-C4) alkyl, (C1-C4) alkoxy, halo, halo (C1-C4) alkyl; and R25 and R26 are independently H, (C1-C4) alkyl, aryl, acyl, or together form with nitrogen a saturated (C3-C7) ring such as morpholino, piperidinyl, pyrrolidinyl.
(1) (2) (3) wherein:
R and R1 are each independently independently H, (C1-C4) alkyl, (C1-C4) alkyl optionally substituted with CH2CH(OCH3)2, halo, (C1-C4) alkoxy, or , wherein B is O or NR1 and n is an integer 1-4; halo(C1-C4)alkyl; deuterio (C1-C4) alkyl; (C1-C4) acyl; (C1-C4) alkyl-CO2-E. wherein E is H, (C1-C4) alkyl, or a cation, such as, for example, sodium, potassium, or ammonium; trifluoroacetyl; alkoxymethyl;
hydroxymethyl; formyl; (R2)2NS(O)X; benzyl; or benzyl optionally substituted with (C1-C4) alkyl, (C1-C4) alkoxy, halo, halo (C1-C4) alkyl;
Each R2 is independently lower alkyl, aryl, or together form with nitrogen a saturated (C3-C7) ring such as morpholino, piperidinyl, pyrrolidinyl;
x is an integer from 0 to 2;
R3 and R4 are each independently H, (C1-C4) alkyl, halogen, I, (C1-C4) alkoxy, halo (C1-C4) alkoxy, (C1-C4 carboalkoxy, halo (C1-C4) alkyl, or together form a saturated or unsaturated six membered carbon ring;
Y-Z together form a (C2-C11) saturated or unsaturated hydrocarbon chain, straight chain or branched, optionally including a hetero atom selected from O, NR5, S, SO, SO2, or SiR6R7, and optionally substituted with one or more groups independently selected from (C1-C4) alkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, branched (C3-C7) alkyl, (C3-C7) cycloalkyl, (C3-C7) cycloalkenyl, halo, halo (C1-C4) alkyl, halo (C1-C4) alkoxy, hydroxy, or (C1-C4) acyl;
R5 is H, (C1-C4) alkyl, or (C1-C4) acyl;
R6 and R7 are independently (C1-C4) alkyl, (C3-C4) branched alkyl, phenyl, or substituted phenyl; or Y is a bond, CHD, CD2, C=O, or a bivalent hydrocarbon radical one to five carbon atoms long, optionally substituted with (C1-C4) alkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, branched (C3-C7) alkyl, (C3-C7) cycloalkyl, (C3-C7) cycloalkenyl, halo, halo (C1-C4) alkyl, halo (C1-C4) alkoxy, hydroxy, CN, (C1-C4) acyl, (C1-C4) alkoxycarbonyl, aryloxycarbonyl, hydroxy (C1-C4) alkyl, (C1-C4) alkoxy (C1-C4) alkyl, methylene, methylene optionally substituted with one or more groups independently selected from hydrogen; (C1-C4) alkyl; (C1-C4) alkoxy; SH; S-lower alkyl; NH2; NH-lower alkyl or N,N-di-lower alkyl, optionally substituted with carboxy, carboalkoxy, or carboaryloxy; NHOH; NHO-lower alkyl; N-lower alkyl-OH; N-lower alkyl-lower alkyl; O-lower alkyl; OH; morpholino; piperidinyl;
pyrrolidinyl; thiomorpholino; or methylene forming part of a (C5-C6) saturated or unsaturated ring optionally including 1 or 2 hetero atoms selected from O, S, or NR5;
Z is (a) aryl or (b) (C3-C8) cycloalkyl or cycloalkenyl, optionally substituted with one or more groups independently selected from (C1-C4) alkyl, (C1-C4) alkoxy, halo (C1-C4) alkyl, halo (C1-C4) alkoxy, halo, hydroxy, or (C1-C4) acyl; where aryl is (a) a phenyl group optionally substituted with one or more groups independently selected from:
halo, I, (C3-C8) cycloalkyl, (C3-C8) cycloalkenyl, phenoxy, substituted phenoxy, phenylthio, substituted phenylthio, phenyl, substituted phenyl, NO2, , where R8 is (C1-C7) alkyl, halo (C1-C7) alkyl, (C3-C7) branched alkyl, halo (C3-C7) branched alkyl, (C3-C7) cycloalkyl, halo (C3-C7) cycloalkyl, (C1-C7) alkoxy, hydroxy, phenyl, substituted phenyl, phenoxy, or substituted phenoxy, , wherein R8 cannot be hydroxy, OH, CN, SiR9R10R11 or OSiR9R10R11, where R9,R10 and R11 are; independently (C1-C4) alky1, (C3-C4) branched alkyl, phenyl, or substituted phenyl, NR12R13, where R12 and R13 are independently H, (C1-C4) alkyl, or (C1-C4) acyl, S(O)R14, SO2R14, or OSO2R14, where R14 is (C1-C10) alkyl, phenyl, or substituted phenyl;
a (C1-C12)saturated or unsaturated hydrocarbon chain, straight chain or branched optionally including a hetero atom selected from O, S, SO, SO2, NR5, or SiR6R7, where R5, R6 and R7 are as defined above, and optionally substituted with halo, halo (C1-C4) alkoxy, hydroxy, (C3-C8) cycloalkyl or cycloalkenyl, (C1-C4) acyl, phenoxy, substituted phenoxy, phenyl, substituted phenyl, phenylthio, substituted phenylthio, or cyano;
(C1-C7) alkoxy optionally substituted with halo, phenyl, substituted phenyl, (C3-C8) cycloalkyl or cycloalkenyl, phenoxy, or substituted phenoxy; or (C1-C7) alkylthio optionally substituted with halo, phenyl, substituted phenyl, (C3-C8) cycloalkyl or cycloalkenyl, phenoxy or substituted phenoxy;
(b) a furyl group of formula (3) (3) where R15 is H, halo, halomethyl, CN, NO2, (C1-C4) alkyl, (C3-C4) branched alkyl, phenyl, (C1-C4) alkoxy;
(c) a thienyl group of the formula (4) (4) where R16 is H, halo, halomethyl, CN, NO2, (C1-C4) alkyl, (C3-C4) branched alkyl, phenyl, (C1-C4) alkoxy, or thienyl;
(d) a group of formula (5) or (6) (5) (6) where R15 is as defined in paragraph (b), J is N or CH, and G is O., NR17, or S, provided that if J is not N
then G is NR, where R17 is H, (C1-C4) alkyl, (C1-C4) acyl, phenylsulfonyl, or substituted phenylsulfonyl;
(e) a group selected from optionally substituted naphthyl, dihydronaphthyl, tetrahydronaphthyl, and decahydronaphthyl;
optionally substituted indolyl;
1,3-benzodioxolyl;
2,6-dimethyl-4-morpholinyl; and 1-adamantyl;
(f) a group of the formula wherein m is 4; R20 are independently H, halo, lower alkyl, lower alkoxy, haloalkyl, haloalkoxy NO2, CN, lower alkyl carbonyl, phenoxy, or substituted phenoxy, proYided that at least two of R20 are selected from H
and F; and Het is pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl, optionally substituted with one or more groups selected from halo, lower alkyl, lower alkoxy, haloalkyl, haloalkoxy, NO2, CN, and lower alkyl carbonyl;
(g) a group of the formula wherein one of X2 and X3 is N and the other is CR23;
R21 is -T-R22, phenyl, substituted phenyl, (C1-C10) alkyl, halo, or halo (C1-C8) alkyl, where T is O or S, and R22 is (C1-C4) alkyl, (C3-C7) branched alkyl, halo (C1-C7) alkyl, halo (C3-C7) branched alkyl, (C1-C4) alkoxy (C1-C4) alkyl, or naphthyl or phenyl, either of which may be optionally substituted with up to three groups selected from halo, (C1-C10) alkyl, branched (C3-C7) alkyl, halo (C1-C7) alkyl, hydroxy (C1-C7) alkyl, (C1-C4) alkoxy, halo (C1-C4) alkoxy, phenoxy, substituted phenoxy, phenyl, substituted phenyl, CN, NO2, OH, (C1-C4) alkanoyloxy, or benzyloxy;
R23 is:
H, halo, I, (C3-C8) cycloalkyl, (C3-C8) cycloalkenyl, phenoxy, substituted phenoxy, phenylthio, substituted phenylthio, phenyl, substituted phenyl, NO2, , where R8 is (C1-C7) alkyl, halo (C1-C7) alkyl, (C3-C7) branched alkyl, halo (C3-C7) branched alkyl, (C3-C7) cycloalkyl, halo (C3-C7) cycloalkyl, (C1-C7) alkoxy, phenyl, substituted phenyl, or hydroxy, acetoxy, OH, CN, SiR9R10R11 or oSiR9R10R11, where R9,R10 and R11 are independently (C1-C4) alkyl, (C3-C4) branched alkyl, phenyl, or substituted phenyl, NR12R13, where R12 and R13 are independently H, (C1-C4) alkyl, or (C1-C4) acyl, S(O)R14, or SO2R14, where R14 is (C1-C10) alkyl, phenyl, or substituted phenyl;
a (C1-C12) saturated or unsaturated hydrocarbon chain, straight chain or branched optionally including a hetero atom selected from O, S, SO, SO2, NR5, or SiR6R7, where R5, R6 and R7 are as defined above, and optionally substituted with halo, halo (C1-C4) alkoxy, hydroxy, (C3-C8) cycloalkyl or cycloalkenyl, (C1-C4) acyl, phenoxy, substituted phenoxy, phenyl, substituted phenyl, phenylthio, substituted phenylthio, or cyano;
(C1-C7) alkoxy optionally substituted with halo, phenyl, substituted phenyl, (C3-C8) cycloalkyl or cycloalkenyl, phenoxy, or substituted phenoxy; or (C1-C7) alkylthio optionally substituted with halo, phenyl, substituted phenyl, (C3-C8) cycloalkyl or cycloalkenyl, phenoxy or substituted phenoxy.
W is O, S(O)y, wherein y is an integer from 0 to 2, or NR24;
G is (C1-C4) alkyl, aryl, (C1-C4) acyl, NR25R26, deuterio (C1-C4) alkyl, halo (C1-C4) alkyl, benzyl, or benzyl optionally substituted with (C1-C4) alkyl, (C1-C4) alkoxy, halo, halo (C1-C4) alkyl; or W-G together are halo, SH, or NR25R26;
R24 is H, OH, (C1-C4) alkyl, (C1-C4) alkoxy, aryl, (C1-C4) acyl, NR25R26, benzyl, or benzyl optionally substituted with (C1-C4) alkyl, (C1-C4) alkoxy, halo, halo (C1-C4) alkyl; and R25 and R26 are independently H, (C1-C4) alkyl, aryl, acyl, or together form with nitrogen a saturated (C3-C7) ring such as morpholino, piperidinyl, pyrrolidinyl.
62. A composition of Claim 61 wherein:
Y is CH2 or methylene, optionally substituted with NH2, NH-lower alkyl, or N,N-di-lower alkyl, optionally substituted with carboxy, carboalkoxy, or carboaryloxy;
Z is substituted phenyl;
R or R1 is H, ethyl, methoxymethyl, or ethoxymethyl;
R3 is (C1-C4) alkyl; and R4 is H or halo.
Y is CH2 or methylene, optionally substituted with NH2, NH-lower alkyl, or N,N-di-lower alkyl, optionally substituted with carboxy, carboalkoxy, or carboaryloxy;
Z is substituted phenyl;
R or R1 is H, ethyl, methoxymethyl, or ethoxymethyl;
R3 is (C1-C4) alkyl; and R4 is H or halo.
63. A composition of Claim 62 wherein Z is a phenyl group substituted with a (C2-C4) alkoxy group;
a phenyl group subsituted with a (C3-C7) branched alkoxy group;
a phenyl group substituted with a halo (C2-C4) alkoxy group;
a phenyl group substituted with a halo (C3-C7) branched alkoxy group;
a phenyl group substituted with a phenoxy or substituted phenoxy group;
a phenyl group substituted with a (C3-C5) branched alkyl group.
a phenyl group subsituted with a (C3-C7) branched alkoxy group;
a phenyl group substituted with a halo (C2-C4) alkoxy group;
a phenyl group substituted with a halo (C3-C7) branched alkoxy group;
a phenyl group substituted with a phenoxy or substituted phenoxy group;
a phenyl group substituted with a (C3-C5) branched alkyl group.
64. A composition of Claim 63 wherein the phenyl group is monosubstituted in the 4-position.
65. A composition o Claim 63 wherein R3 is methyl or ethyl and R4 is bromo or chloro.
66. A composition of Claim 63 wherein R or R1 is ethyl, methoxymethyl, or ethoxymethyl.
67. A method of inhibiting an insect or mite which comprises applying to the locus of the insect or arachnid an effective insect or mite inactivating amount of a compound of claim 1.
68. A method o inhibiting a nematode which comprises applying to the locus of the nematode, a nematode inactivating amount of a compound of claim 1.
69. A method of inhibiting a plant pathogen which comprises applying to the locus of the pathogen, a pathogen inactivating amount of a compound of claim 1.
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US24518494A | 1994-05-17 | 1994-05-17 | |
US08/245,184 | 1994-05-17 |
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AU (1) | AU2641295A (en) |
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US5741818A (en) | 1995-06-07 | 1998-04-21 | University Of Saskatchewan | Semicarbazones having CNS activity and pharmaceutical preparations containing same |
DE19542372A1 (en) * | 1995-11-14 | 1997-05-15 | Bayer Ag | Acylated 5-aminoisothiazoles |
DE19628569A1 (en) * | 1996-07-16 | 1998-01-22 | Bayer Ag | Substituted N- (5-isothiazolyl) thioamides |
DE19630814A1 (en) * | 1996-07-31 | 1998-02-05 | Bayer Ag | Substituted N-isothiazolyl (thio) amides |
KR20010020201A (en) | 1997-04-22 | 2001-03-15 | 코센시스 인크 | Carbocyclic and heterocyclic substituted semicarbazones and thiosemicarbazones and the use thereof |
DE19727162A1 (en) * | 1997-06-26 | 1999-01-07 | Bayer Ag | Substituted amino heterocyclylamides |
DE19736545A1 (en) * | 1997-08-22 | 1999-02-25 | Bayer Ag | New acylated 5-amino-isothiazole derivatives |
GB9816654D0 (en) * | 1998-07-30 | 1998-09-30 | Zeneca Ltd | Chemical compounds |
DE19846008A1 (en) * | 1998-10-06 | 2000-04-13 | Bayer Ag | Phenylacetic acid heterocyclylamide |
ATE251621T1 (en) * | 1999-04-20 | 2003-10-15 | Syngenta Ltd | PESTICIDES INDAZOLE OR BENZOTRIAZOLE DERIVATIVES |
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DE1924830A1 (en) * | 1968-07-06 | 1970-11-19 | Merck Patent Gmbh | New process for the preparation of 5-acylamino-isothiazole derivatives |
US4013675A (en) * | 1975-05-05 | 1977-03-22 | Ppg Industries, Inc. | N-(3-methyl-5-isothiazolyl)-2-methylpentanamide |
GB1548397A (en) * | 1976-06-01 | 1979-07-11 | Lilly Industries Ltd | Acylated amino-isoxazoles and aminoisothiazoles |
US4059433A (en) * | 1976-06-18 | 1977-11-22 | Fmc Corporation | 3-Alkoxyisothiazole derivatives as herbicides |
-
1995
- 1995-05-17 CA CA 2189573 patent/CA2189573A1/en not_active Abandoned
- 1995-05-17 JP JP7529898A patent/JPH10503171A/en active Pending
- 1995-05-17 WO PCT/US1995/006307 patent/WO1995031448A1/en active Application Filing
- 1995-05-17 AU AU26412/95A patent/AU2641295A/en not_active Abandoned
Also Published As
Publication number | Publication date |
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JPH10503171A (en) | 1998-03-24 |
WO1995031448A1 (en) | 1995-11-23 |
AU2641295A (en) | 1995-12-05 |
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