WO1997026252A1 - Piperazines insecticides n-heterocyclylalkyle- ou n-[(polycyclyle)-alkyle]-n'-substituees - Google Patents

Piperazines insecticides n-heterocyclylalkyle- ou n-[(polycyclyle)-alkyle]-n'-substituees Download PDF

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WO1997026252A1
WO1997026252A1 PCT/US1997/000804 US9700804W WO9726252A1 WO 1997026252 A1 WO1997026252 A1 WO 1997026252A1 US 9700804 W US9700804 W US 9700804W WO 9726252 A1 WO9726252 A1 WO 9726252A1
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compound
phenyl
hydrogen
methyl
alkyl
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PCT/US1997/000804
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English (en)
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Ian R. Silverman
Syed F. Ali
Daniel H. Cohen
John W. Lyga
Kirk A. Simmons
Thomas G. Cullen
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Fmc Corporation
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Priority to AU15809/97A priority Critical patent/AU1580997A/en
Publication of WO1997026252A1 publication Critical patent/WO1997026252A1/fr

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    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members 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
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Definitions

  • the present invention relates to methods for controlling insects.
  • it relates to control by application of certain N-heterocyclylalkyl- or N-[(polycyclyl)alkyl]-N'-substituted piperazine derivatives to locus where insect control is needed.
  • certain N-heterocyclylalkyl- or N-[(polycyclyl)alkyl]-N'-substituted piperazine derivatives to locus where insect control is needed.
  • the use of the compounds of the invention as insecticides is heretofore unknown. It has now been found that compounds of the following structure and their agriculturally acceptable salts are active as insecticides:
  • a and B are independently selected from lower alkyl;
  • U is selected from lower alkyl, lower alkenyl, CH-Z, where Z is independently selected from hydrogen, lower alkyl, lower cycloalkyl, and phenyl;
  • R is selected from phenyl, optionally substituted with halogen, lower alkyl, lower alkoxy, phenyl, or phenoxy, and from polycyclyl, optionally substituted with halogen, lower alkyl, or lower alkoxy, where polycyclyl is a dibenzocyclo(C 5 . 8 )alkyl;
  • R 3 and R 4 are independently selected from phenyl, optionally substituted with halogen, lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, lower alkenyl, or phenyl;
  • R 1 is phenyl, naphthyl, tetrazolylphenyl, phenylcyclopropyl, phenoxy- phenyl, benzyloxyphenyl, pyridylphenyl, pyridyloxyphenyl, thiadiazolyloxy- phenyl, benzothienyl, benzimidazolyl, indolyl, pyrrolyl, or quinolyl, each optionally substituted with halogen, cyano, hydroxy, lower alkyl, lower halo ⁇ alkyl, lower alkoxy, amino, lower dialkylamino, nitro, lower haloalkylsulfonyl ⁇ oxy, lower alkylcarbonyloxy, lower alkylcarbonylamino, lower alkoxycarbonyl, lower alkoxyalkoxycarbonyl, lower cycloalkylalkoxycarbonyl, lower alkoxyalkylalkoxycarbonyl, lower alk
  • D, E, and G are independently selected from hydrogen, halogen, cyano, hydroxy, lower alkyl, lower haloalkyl, lower alkoxy, nitro, lower halo ⁇ alkylsulfonyloxy, lower alkylcarbonyloxy, lower alkylcarbonylamino, arylcar ⁇ bonylamino, lower alkylcarbonyl, lower alkoxycarbonyl, or D and E taken together may form the group -O(CH2)0-, and J is hydrogen or lower alkyl; m is 2 or 3 and n is 1 , 2, or 3; and halogen is chlorine, fluorine, or bromine, lower means having from 1 to 6 carbon atoms and any aliphatic chain of three or more carbons may be straight or branched.
  • Preferred compounds are those in which
  • R 3 and R 4 are independently selected from chlorophenyl, fluoro ⁇ phenyl, methylphenyl, trifluoromethylphenyl, methoxyphenyl, and trifluoro- methoxyphenyl;
  • R 1 is phenyl, tetrazolylphenyl, pyridylphenyl, pyridyloxyphenyl; each optionally substituted with halogen, cyano, hydroxy, lower alkyl, lower haloalkyl, lower alkoxy, amino, lower dialkylamino, lower alkylcarbonyloxy, lower alkylcarbonylamino, lower alkoxycarbonyl, lower alkoxyalkoxycarbonyl, lower cycloalkylalkoxycarbonyl, lower alkoxyalkylalkoxycarbonyl, or lower alkoxycarbonylamino; or lower alkyl substituted with any one of the foregoing cyclic R 1 groups; or 3-R 2 , where R 2 is
  • D is hydrogen, hydroxy, chloro, fluoro, methyl, methoxy, or phenylcarbonylamino
  • E and G are independently selected from hydrogen, chloro, fluoro, methyl, and methoxy, with the proviso that when R 1 is lower dialkylaminophenyl, R 3 and R 4 are each trifluoromethoxyphenyl; m and n are 2; and halogen is chlorine or fluorine, for aliphatic groups lower means having from 1 to 3 carbon atoms and for alicyclic groups lower means having 3 to 6 carbons.
  • R 3 and R 4 are independently selected from 4-chlorophenyl, 4- fluorophenyl, 4-methylphenyl, 4-trifluoromethylphenyl, and 4-trifluoro- methoxyphenyl;
  • R 1 is phenyl substituted in the 4-position with lower dialkylamino, lower alkoxycarbonylamino, tetrazolyl, pyridyl, or pyridyloxy; each tetrazolyl or pyridyl group optionally substituted with halogen, cyano, lower alkyl, lower haloalkyl, or lower alkoxy; or 3-R 2 , where R 2 is where D is hydrogen, 4-chloro, 4-fluoro, 4-hydroxy, or 4-phenylcarbo- nylamino; E is hydrogen, 5-chloro, 5-methyl, or 6-fluoro; G is hydrogen or 5-methoxy; m and n are 2; and halogen is chlorine or fluorine, for aliphatic groups lower means having from 1 to 3 carbon atoms and for alicyclic groups lower means having 3 to 6 carbons.
  • N-heterocyclylalkyl- or N-[(polycyclyl)alkyl]-N'-substituted piperazine derivatives of the present invention were prepared by methods known to one skilled in the art. A number of synthesis routes were employed in obtaining the targeted compounds.
  • the diaryl methanol _(___ is then treated with thionyl chloride affording a (substituted diaryl)methyl chloride (E), for example, (2-chloro- phenyl)(4-chlorophenyl)methyl chloride.
  • E substituted diaryl
  • the so-prepared diaryl methyl chloride _E_ ⁇ can then be reacted with piperazine to form the N-[(substituted diaryl)methyl]piperazine (F).
  • the piperazine ⁇ ____ can be reacted with an appropriate halide ⁇ G ⁇ , affording the targeted N-(substituted alkyl)-N'-[(sub- stituted diaryl)methyl]piperazine ____, for example, N-(4-chloroindol-3-yl- methyl)-N'-[(4-chlorophenyl)(2-chlorophenyl)methyl)piperazine.
  • a substituted indole ( ⁇ ) capable of undergoing a Mannich-type reaction is condensed with formaldehyde and the N-substituted piperazine in dioxane and acetic acid to afford the targeted N-(substituted alkyl)-N'-(R-substituted)- piperazine ⁇ J], for example, N-(benzo[b]thien-3-ylmethyl)-N'-[bis(4-chloro- phenyl)methyl]piperazine.
  • Example 1 provides the detailed procedure for this route.
  • those compounds in which Z is other than hydrogen are prepared by first reacting a substituted indole (I) with phos ⁇ phorus oxychloride and N,N-dimethylformamide, affording the corresponding substituted aldehyde _K_.
  • K is in turn condensed with N-[(substituted diaryl)- methyl]piperazine (F) to form the imine and then reacted with the appropri ⁇ ate alkyl or aryl magnesium halide, for example, phenyl magnesium chloride, affording the targeted N-[(alkyl)(substituted indole)alkyl]- or N-[(aryl)(substitu- ted heterocyclyl)alkyl]-N'-[(substituted diaryl)methyl]piperazine (L), for example, N-[(phenyl)(4-chloroindol-3-yl)methyl]-N'-[bis(4-chlorophenyl)- methyl]piperazine.
  • the appropri ⁇ ate alkyl or aryl magnesium halide for example, phenyl magnesium chloride
  • the substituted indole (]) can also be reacted with an aldehyde and N-[(substituted diaryl)methyl]piperazine ___ under acidic conditions, affording the targeted N-[(alkyl)(substituted heterocyclyl)alkyl]- or N-[(aryl)(substituted heterocyclyl)alkyl]-N'-[(substituted diaryl)methyl]pipera- zine ⁇ L ⁇ .
  • Examples 2 and 4 provide detailed procedures for this route.
  • Compounds having the F structure are particularly useful intermediates.
  • the compound with R 3 and R 4 each trifluoromethoxyphenyl i.e., N-[bis(4- trifluoromethoxyphenyl)methyl]piperazine, is thought to be novel and has the following NMR spectrum, proton assignment in ppm in CDCI 3 : 2.41 (m, 4H); 2.54 (d of m, 2H); 2.98 (m, 2H); 3.39 (t, 1H); 7.15 (d, 4H); 7.40 (d 4H).
  • N-[(substituted diaryl)methyl]piperazine (F) can be reacted with an appropriately substituted aldehyde for example, 4-dimethyl- aminobenzaldehyde, under acidic conditions and at 100 °C, affords the targeted N-(substituted alkyl)-N'-[(substituted diaryl)methyl]piperazine (MJ.
  • Example 5 provides the detailed procedure for this route. Schema 3 outlines routes to compounds where the tether U is varied.
  • An acid chloride (N) is derivatized with an appropriate N-[(substituted diaryl)- methyl]piperazine _f_ , affording the targeted N-[(substituted)alkylcarbonyl]- N'-[(substituted diaryl)methyl]piperazine (O).
  • the piperazine (O) can also be prepared by derivatizing a substituted carboxylic acid ____, for example, 2- methyl-3-indoleacetic acid, with an appropriate N-[(substituted diaryl)methyl]- piperazine (F).
  • the piperazine ⁇ 0 ⁇ is then converted to the targeted N- (substituted alkyl)-N'-[(substituted diaryl)methyl]piperazine ⁇ J ⁇ , for example, N-[2-(2-methylindol-3-yl)ethyl]-N'-[bis(4-fluorophenyl)methyl]piperazine.
  • Example 6 provides the detailed procedure for this route.
  • a cinnamic acid (Q) may be reacted with lithium aluminum hydride and thionyl chloride, as previously described, to form a substituted allyl chloride ___ ⁇ .
  • R 1 is heterocyclyl Schema 2
  • R 1 is a substituted indole + Z- CHO -»- k
  • Step A Synthesis of (2-chlorophenyl)(4-chlorophenyl)methanol as an intermediate Under a nitrogen atmosphere, 1.7 grams ( 0.044 mole) of sodium boro- hydride pellets was added to 100 ml of stirred ethanol. To this was added 10.0 grams (0.040 moles) of 2,4'-dich.orobenzophenone in one portion. Upon completion of the addition the reaction mixture was stirred at ambient temperature for about 18 hours. After this time the ethanol was removed under reduced pressure, and the resulting residue was taken up in 250 mL of aqueous 5% sodium hydroxide solution. The solution was extracted with two 100 mL portions of diethyl ether.
  • Step B Synthesis of (2-chlorophenyl)(4-chlorophenyl)methyl chloride as an intermediate A stirred solution of 9.0 grams (0.036 mole) of (2-chlorophenyl)(4- chlorophenyl)methanol in 90 mL of chloroform was cooled to 0 °C, and 5.3 mL (0.072 mole) of thionyl chloride was added.
  • reaction mixture Upon completion of the addition the reaction mixture was allowed to warm to ambient temperature, where it stirred for about 18 hours. After this time the reaction mixture was filtered and concentrated under reduced pressure. The filtrate was taken up in hexane and subjected to column chromatography on silica gel with hexane as eluant. The product-containing fractions were combined and concentrated under reduced pressure, yielding 10.0 grams of (2-chloro- phenyl)(4-chlorophenyl)methyl chloride. The NMR spectrum was consistent with the proposed structure.
  • Step C Synthesis of N-(ethoxycarbonyl)-N'-[(2-chlorophenyl)(4-chloro phenyl)methyl]piperazine as an intermediate
  • the filtrate was cooled to ambient temperature and 200 mL of aqueous saturated sodium bicarbonate solution was added to it.
  • the mixture was extracted with two 100 mL portions of ethyl acetate.
  • the combined ethyl acetate layers were washed with two 25 mL portions of an aqueous saturated sodium chloride solution.
  • the organic layer was dried with sodium sulfate and concentrated under reduced pressure, yielding 3.2 grams of crude material.
  • the crude material was subjected to column chromatography on silica gel with 50-25% hexane in methylene chloride, followed by pure methylene chloride, as eluants.
  • the reaction mixture was then cooled to 0 °C, neutra ⁇ lized with aqueous saturated sodium bicarbonate solution, and extracted with two portions of diethyl ether. The combined extracts were washed with an aqueous saturated sodium chloride solution and dried with sodium sulfate, yielding 0.6 gram of crude material.
  • the crude material was purified by preparative TLC. Elution was accomplished with 3:2 ethyl acetate: methylene chloride. The product-containing fractions were combined and concentrated under reduced pressure, yielding 0.4 gram of N-(4-chloroindol- 3-ylmethyl)-N'-[(4-chlorophenyl)(2-chlorophenyl)methyl]piperazine.
  • the NMR spectrum was consistent with the proposed structure.
  • Step B Synthesis of N-(4-chloro-3H-indol-3-ylmethylenyl)-N'-[bis(4- chlorophenyl)methyl]piperazine as an intermediate
  • Step C Synthesis of N-[(phenyl)(4-chloroindol-3-yl)methyl]-N'-[bis(4- chlorophenyl)methyl]piperazine (Compound 59)
  • reaction mixture was stirred for 30 minutes at ambient temperature, then heated to 50-80 °C, where it stirred for two hours. After this time the homogeneous reaction mixture was cooled to ambient temperature and poured into 200 mL of an aqueous saturated ammonium chloride solution. The resulting solution was then extracted with three 100 mL portions of ethyl acetate. The combined extracts were washed with two 100 mL portions of aqueous sodium chloride solution, dried with sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to a residue, which was subjected to column chromatography on silica gel. Elution was accomplished with 7:13 ethyl acetate:hexane.
  • reaction mixture was stirred at ambient temperature for about 18 hours, after which it was poured into 50 mL of water, and the organic layer was separated. The aqueous layer was extracted with one 50 mL portion of diethyl ether. The combined organic layer and extract were washed with two 25 mL portions of water, dried with sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, yielding 8.4 grams of N-f-butyl-4-bromobenzamide, mp 126-128 °C. The NMR spectrum was consistent with the proposed structure.
  • Step B Synthesis of bis[4-(f-butylaminocarbonyl)phenyl]methanol as an intermediate Under a nitrogen atmosphere, a stirred solution of 7.8 grams ( 0.030 mole) of N-f-butyl-4-bromobenzamide in 125 mL of tetrahydrofuran was cooled to -60 °C, and 28 mL (0.063 mole) of 2M n-butyllithium in hexanes was added dropwise during a 30 minute period.
  • reaction mixture was stirred at -60 °C for 1.5 hours, then a solution of 1.2 mL (0.015 mole) of ethyl formate in 25 mL of diethyl ether was added dropwise.
  • the reaction mixture was stirred at -60 °C for an additional 1.5 hours, and 150 mL of aqueous saturated ammonium chloride solution was added dropwise, followed by 50 mL of methylene chloride and 50 mL of ethyl acetate, and then the mixture was warmed to ambient temperature.
  • the organic layer was separated and washed with one 50 mL portion of water and one 50 mL portion of an aqueous saturated sodium chloride solution .
  • Step C Synthesis of bis(4-cyanophenyl)methyl chloride as an intermediate Under a nitrogen atmosphere, a stirred solution of 2.9 grams (0.008 mole) of bis[4-(t-butylaminocarbonyl)phenyl]methanol in 25 mL (0.0340 mole) of thionyl chloride was heated at reflux for five hours. After this time the reaction mixture was concentrated under reduced pressure, yielding a residue. The residue was dissolved in about 10 mL of toluene. The solution was again concentrated under reduced pressure, yielding a residue.
  • Step D Synthesis of N'-[bis(4-cyanophenyl)methyl]piperazine as an intermediate
  • This compound was prepared in the manner of Example 3, with 0.63 gram (0.002 mole) of bis(4-cyanophenyl)methyl chloride, 0.86 gram (0.010 mole) of piperazine, and 1.4 mL (0.010 mole) of triethylamine in 20 mL of dimethyl sulfoxide as reagents and 0.1 gram (0.0005 mole) of sodium iodide as catalyst.
  • Step E Synthesis of N-(4-dimethylaminophenylmethyl)-N'-[bis(4- cyanophenyl)methyl]piperazine (Compound 118)
  • the product-containing fractions were combined and concentrated under reduced pressure, yielding 0.2 gram of a white solid.
  • the white solid was purified by column chromatography on alumina with diethyl ether as the eluant.
  • the product-containing fractions were combined and concentrated under reduced pressure, yielding 0.1 gram of N-(4-dimethylaminophenyl- methyl)-N'-[bis(4-cyanophenyl)methyl]piperazine.
  • the NMR spectrum was consistent with the proposed structure.
  • reaction mixture Upon completion of the addition the reaction mixture was warmed to ambient temperature during 30 minutes, where it stirred for 1.5 hours, after which the reaction mixture was concen ⁇ trated under reduced pressure to a residue. The residue was taken up in 30 mL of tetrahydrofuran and then divided into two 15 mL portions. Each 15 mL portion contained about 0.013 mole of 2-methylindol-3-ylacetyl chloride.
  • Step B Synthesis of N-(2-methylindol-3-ylacetyl)-N'-[bis(4-fluoro phenyl)methyl]piperazine as an intermediate Under a nitrogen atmosphere a 15 mL solution of 2-methylindol-3- ylacetyl chloride (0.013 mole) in tetrahydrofuran was added to a stirred solution of 3.9 grams (0.014 mole) of N-[bis(4-fluorophenyl)methyl]piper- azine and 1.1 mL (0.013 mole) of pyridine in 50 mL of dried tetrahydrofuran.
  • reaction mixture was stirred at ambient temperature for about 18 hours, after which the reaction mixture was poured into a mixture of 200 mL of ethyl acetate and 100 mL of aqueous saturated sodium bicarbonate solution. The organic layer was separated and washed with one portion of a saturated sodium chloride solution, dried with sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to a solid, which was taken up in hexane. This solution was concentrated under reduced pressure, yielding 3.2 grams of N-(2-methylindol-3-ylacetyl)- N'-[bis(4-fluorophenyl)methyl]piperazine, mp 93-103 °C.
  • Step C Synthesis of N-(2-methylindol-3-ylethyl)-N'-[bis(4-fluoro phenyl)methyl]piperazine (Compound 36)
  • a solution of 1.5 grams (0.003 mole) of N-(2-methylindol-3-ylacetyl)-N'- [bis(4-fluorophenyl)methyl]piperazine in 10.0 mL of anhydrous tetrahydro ⁇ furan was added to a stirred mixture of 0.4 gram (0.010 mole) of lithium aluminum hydride in 5.0 mL of anhydrous tetrahydrofuran.
  • reaction mixture Upon completion of the addition the reaction mixture was heated to reflux, where it stirred for 2.5 hours. The reaction mixture was cooled to 0 °C, and water was added, followed by 50 mL of aqueous 10% sodium hydroxide. The solution was warmed to ambient temperature and then extracted with ethyl acetate. The extract was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 0.7 gram of N-(2-methylindol- 3-ylethyl)-N'-[bis(4-fluorophenyl)methyl]piperazine, mp 65-73 °C. The NMR spectrum was consistent with the proposed structure.
  • Step A Synthesis of bis(4-trifluoromethylphenyl)methanol as an intermediate
  • This compound was prepared by a Grignard reaction in which 45.0 grams ( 0.2 mole) of 4-bromobenzotrifluoride, 5.0 grams (0.22 mole) of magnesium, and 34.8 grams (0.20 mole) of 4-(trifluoromethyl)benzaldehyde were the reagents, and 1000 mL of diethyl ether was the solvent.
  • the yield of bis(4-trifluoromethylphenyl)methanol was 37.0 grams.
  • Step B Synthesis of bis(4-trifluoromethylphenyl)methyl chloride as an intermediate This compound was prepared in the manner of Step B, Example 1 , with 37.0 grams (0.115 mole) of bis(4-trifluoromethylphenyl)methanol, 27.3 grams (0.231 mole) of thionyl chloride, three drops of N,N-dimethylform- amide as reagents, and 200 mL of methylene chloride as solvent. The yield of bis(4-trifluoromethylphenyl)methyl chloride was 31.8 grams. The NMR spectrum was consistent with the proposed structure.
  • Step C Synthesis of N-(ethoxycarbonyl)-N'-[bis(4-trifluoromethyl phenyl)methyl]piperazine as an intermediate
  • This compound was prepared in the manner of Step C, Example 1 , with 31.8 grams (0.094 mole) of bis(4-trifluoromethylphenyl)methyl chloride, 15.8 grams (0.1 mole) of ethyl 1 -piperazinecarboxylate, 12.9 grams (0.1 mole) of ethyl diisopropylamine, 12.4 grams (0.083 mole) of sodium iodide as reagents, and 250 mL of toluene as solvent.
  • the yield of N-(ethoxycarbo- nyl)-N'-[bis(4-trifluoromethylphenyl)methyl]piperazine was 17.9 grams.
  • the NMR spectrum was consistent with the proposed structure.
  • Step F Synthesis of 1-(2-fluoroethyl)-4-(4-methylphenyl)-1 ,2,3,5-(1 H)- tetrazole as an intermediate Under a nitrogen atmosphere, a stirred solution of 5.0 grams (0.031 mole) 4-(4-methylphenyl)-1 ,2,3,5-(1 H)-tetrazole and 4.8 grams (0.035 mole) of potassium carbonate in 150 mL of acetonitrile was heated to reflux and then cooled to ambient temperature. To this was slowly added 10.0 grams (0.078 mole) of 1-bromo-2-fluoroethane.
  • reaction mixture Upon completion of the addition the reaction mixture was placed in a water bath and cooled to 0 °C, where it stirred for one hour. After this time the reaction mixture was heated to reflux, where it stirred for three hours, and then cooled to 0 °C, where it stirred for about 18 hours. At the conclusion of this period the reaction mixture was poured into 50 mL of water. The resulting solution was extracted with three 50 mL portions of ethyl acetate. The combined extracts were concentrated under reduced pressure to a residue, which was subjected to column chromatography on silica gel. Elution was accomplished with methylene chloride and acetone.
  • Step G Synthesis of 4-[1 -(2-fluoroethyl)-1 ,2,3,5-(1 H)-tetrazol-4- yljbenzyl bromide as an intermediate Under a light source a stirred solution of 2.8 grams (0.013 mole) of 1-(2- fluoroethyl)-4-(4-methylphenyl)-1 ,2,3,5-(1 H)-tetrazole, 2.4 grams (0.013 mole) of N-bromosuccinimide, and 0.19 gram (0.0008 mole) of benzoyl peroxide in 100 mL of carbon tetrachloride was heated to reflux. Once at reflux the reaction mixture was stirred for five hours.
  • Step H Synthesis of N- ⁇ 4-[1-(2-fluoroethyl)-1 ,2,3,5-(1 H)-tetrazol-4-yl] phenylmethyl ⁇ -N'-[bis(4-trifluoromethylphenyl)methyl] piperazine (Compound 150)
  • This compound was prepared in the manner of Example 6, with 0.81 gram (0.002 mole) of N-[bis(4-trifluoromethylphenyl)methyl]piperazine, 0.59 gram (0.002 mole) of 4-[1-(2-fluoroethyl)-1 ,2,3,5-(1 H)-tetrazol-4-yl]benzyl bromide, 0.81 gram (0.006 mole) of N,N-diisopropylethylamine as reagents, and 25 mL of dimethyl sulfoxide as solvent.
  • the ether extracts were combined and washed with one 100 mL portion of aqueous 5% sodium hydroxide, followed by one 100 mL portion of aqueous 10% lithium chloride.
  • the organic layer and extracts were combined, dried with sodium sulfate, and filtered.
  • the filtrate was concentrated under reduced pressure to yield a residue, which was subjected to column chromatography on silica gel. Elution was accomplished with 15-20% acetone in petroleum ether mixtures.
  • the product-containing fractions were combined and concentrated under reduced pressure, yielding 13.5 grams of 4-(pyrid-2-yloxy)benzaldehyde.
  • the NMR spectrum was consistent with the proposed structure.
  • Step A This compound was prepared in the manner of Step A, Example 1 , with 1.87 grams ( 0.052 mole) of sodium borohydride, 13.5 grams (0.068 moles) of 4-(pyrid-2-yloxy)benzaldehyde as reagents, and 200mL of ethanol as solvent. The yield of 4-(pyrid-2-yloxy)benzyl alcohol was 13.0 grams. The NMR spectrum was consistent with the proposed structure.
  • Step C Synthesis of 4-(pyrid-2-yloxy)benzyl chloride as an intermediate This compound was prepared in the manner of Step B, Example 1 , with
  • Step D Synthesis of N-[4-(pyrid-2-yloxy)phenylmethyl]-N'-[bis(4- trifluoromethylphenyl)methyl]piperazine (Compound 151 )
  • This compound was prepared in the manner of Example 3, with 1.15 grams (0.003 mole) of N-[bis(4-trifluoromethylphenyl)methyl]piperazine, 0.66 gram (0.003 mole) of 4-(pyrid-2-yloxy) benzyl chloride, 1.3 grams (0.01 mole) of N,N-diisopropylethylamine in 10 mL of dimethyl sulfoxide as reagents and 0.1 gram (0.0005 mole) of sodium iodide as catalyst..
  • N-heterocyclylalkyl- or N-[(polycyclyl)alkylJ-N'-substituted piperazine derivatives of the present invention were incorporated into an artificial diet for evaluation of insecticidal activity against the tobacco budworm (Heliothis virescens [Fabricius]) in the following manner.
  • Stock solutions of the test chemical in dimethyl sulfoxide were prepared for each rate of application.
  • One hundred microliters of each of the stock solutions was manually stirred into 50 mL of a molten (65-70 °C) wheat germ-based artificial diet.
  • the 50 mL of molten diet containing the test chemical was poured evenly into twenty wells in the outer four rows of a twenty-five well, five row plastic tray. Each well in the tray was about 1 cm in depth, with an opening of 3 cm by 4 cm at the lip. Molten diet containing only dimethylsulfoxide at the levels used in the test chemical-treated diet was poured into the five wells in the third row of the tray. Each tray therefore contained one test chemical at a single rate of application, together with an untreated control.
  • the rates of application expressed as the negative log of the molar concentration, and the corresponding concentrations of the stock solution prepared for each rate are shown below:
  • Single second instar tobacco budworm larvae were placed in each well. The larvae were selected at a stage of growth at which they uniformly weigh about 5 mg each. Upon completion of infestation, a sheet of clear plastic was heat-sealed over the top of the tray using a common household flat iron. The trays were held at 25 °C at 60% relative humidity for five days in a growth chamber. Lighting was set at 14 hours of light and 10 hours of darkness. After the 5-day exposure period, mortality counts were taken, and the surviving insects were weighed. From the weights of the surviving insects that fed on the treated diet as compared to those insects that fed on the untreated diet, the percent growth inhibition caused by each test chemical was determined.
  • the compounds of the present invention caused significant inhibition of the growth of the tobacco budworm.
  • the most efficacious compounds were 38, 146, 147, 148, 150, and 151.
  • the data from the diet test are given in Table 3.
  • N-heterocyclylalkyl- or N-[(polycyclyl)alkyl]-N'-substituted piperazines derivatives causing high growth inhibition in the diet test were also tested for insecticidal activity in foliar evaluations against the tobacco budworm.
  • Percent control is derived from the total number of dead insects (TD) plus the total number of moribund insects (TM) as compared to the total number of insects (Tl) in the test:
  • test plants were also observed for phytotoxicity and for reduction of feeding damage as compared to an untreated control.
  • the active compounds of the invention are formulated into insecticidal compositions by admixture in insecticidally effective amount with adjuvants and carriers normally employed in the art for facilitating the dispersion of active ingredients for the particular utility desired, recognizing the fact that the formulation and mode of application of a toxicant may affect the activity of the material in a given application.
  • the present insecticidal compounds may be formulated as granules of relatively large particle size, as water-soluble or water- dispersible granules, as powdery dusts, as wettable powders, as emuisifiable concentrates, as solutions, or as any of several other known types of formulations, depending on the desired mode of application.
  • insecticidal compositions may be applied either as water-diluted sprays, or dusts, or granules to the areas in which insect control is desired.
  • These formulations may contain as little as 0.1%, 0.2% or 0.5% to as much as 95% or more by weight of active ingredient.
  • Dusts are free flowing admixtures of the active ingredients with finely divided solids such as talc, natural clays, kieselguhr, flours such as walnut shell and cottonseed flours, and other organic and inorganic solids which act as dispersants and carriers for the toxicant; these finely divided solids have an average particle size of less than about 50 microns.
  • a typical dust formulation useful herein is one containing 1.0 part or less of the insecticidal compound and 99.0 parts of talc.
  • Wettable powders are in the form of finely divided particles which disperse readily in water or other dispersant.
  • the wettable powder is ultimately applied to the locus where insect control is desired either as a dry dust or as an emulsion in water or other liquid.
  • Typical carriers for wettable powders include Fuller's earth, kaolin clays, silicas, and other highly absorbent, readily wet, inorganic diluents. Wettable powders normally are prepared to contain about 5-80% of active ingredient, depending on the absorbency of the carrier, and usually also contain a small amount of a wetting, dispersing, or emulsifying agent to facilitate dispersion.
  • a useful wettable powder formulation contains 80.8 parts of the insecticidal compound, 17.9 parts of Palmetto clay, and 1.0 part of sodium lignosulfonate and 0.3 part of sulfonated aliphatic polyester as wetting agents.
  • Other useful formulations for insecticidal applications are emuisifiable concentrates (ECs) which are homogeneous liquid compositions dispersible in water or other dispersant, and may consist entirely of the insecticidal compound and a liquid or solid emulsifying agent, or may also contain a liquid carrier, such as xylene, heavy aromatic naphthas, isophorone, or other non- volatile organic solvent.
  • ECs emuisifiable concentrates
  • these concentrates are dispersed in water or other liquid carrier, and normally applied as a spray to the area to be treated.
  • the percentage by weight of the essential active ingredient may vary according to the manner in which the composition is to be applied, but in general comprises 0.5 to 95% of active ingredient by weight of the insecticidal composition.
  • Flowable formulations are similar to ECs except that the active ingredient is suspended in a liquid carrier, generally water.
  • Flowables like ECs, may include a small amount of a surfactant, and contain active ingredient in the range of 0.5 to 95%, frequently from 10 to 50%, by weight of the composition.
  • flowables may be diluted in water or other liquid vehicle, and are normally applied as a spray to the area to be treated.
  • Typical wetting, dispersing, or emulsifying agents used in agricultural formulations include, but are not limited to, the alkyl and alkylaryl sulfonates and sulfates and their sodium salts; alkylaryl polyether alcohols; sulfated higher alcohols; polyethylene oxides; sulfonated animal and vegetable oils; sulfonated petroleum oils; fatty acid esters of poiyhydric alcohols and the ethylene oxide addition products of such esters; and the addition product of long-chain mercaptans and ethylene oxide.
  • Many other types of useful surface-active agents are available in commerce.
  • the surface-active agents, when used, normally comprise from 1 to 15% by weight of the composition.
  • Other useful formulations include suspensions of the active ingredient in a relatively non-volatile solvent such as water, corn oil, kerosene, propylene glycol, or other suitable solvents.
  • Still other useful formulations for insecticidal applications include simple solutions of the active ingredient in a solvent in which it is completely soluble at the desired concentration, such as acetone, alkylated naphthalenes, xylene, or other organic solvents.
  • Granular formulations, wherein the toxicant is carried on relatively coarse particles, are of particular utility for aerial distribution or for penetration of cover crop canopy.
  • Pressurized sprays, typically aerosols wherein the active ingredient is dispersed in finely divided form as a result of vaporization of a low boiling dispersant solvent carrier, such as carbon dioxide, propane, or butane, may also be used.
  • Water- soluble or water-dispersible granules are also useful formulations for insecticidal application of the present compounds.
  • Such granular formulations are free-flowing, non-dusty, and readily water-soluble or water- miscible.
  • the soluble or dispersible granular formulations described in U.S. patent No. 3,920,442 are useful herein with the present insecticidal compounds.
  • the granular formulations, emuisifiable concentrates, flowable concentrates, solutions, etc. may be diluted with water to give a concentration of active ingredient in the range of say 0.1% or 0.2% to 1.5% or 2%.
  • the active insecticidal compounds of this invention may be formulated and/or applied with other insecticides, fungicides, nematicides, plant growth regulators, fertilizers, or other agricultural chemicals.
  • an effective amount and concentration of the active compound is applied to the locus where control is desired.
  • the locus may be, e.g., the insects themselves, plants upon which the insects feed, or the insect habitat.
  • the composition of the active compound may be applied to and optionally incorporated into the soil.
  • the effective amount may be as low as, e.g. about 10 to 500 g/ha, preferably about 100 to 250 g/ha.
  • U is CH2
  • J is H
  • m and n are 2
  • Ph is phenyl
  • R is Fill, R 1 is 3-R 2 , U is CH2, J is H, m and n are 2, Ph is phenyl
  • R is Fill, R 1 is 3-R 2 U is CHZ E G and J are H, is H, Ph is phenyl
  • R is Fill, R is 3-R 2 , U is CH2, J is H, Ph is phenyl
  • U is CH2
  • J is H
  • m and n are 2
  • Ph is phenyl
  • R 1 is 3-R 2 , U is (CH2)2, D, E, G and J are H, m and n are 2
  • U is CH2 A and B are H, Ph is phenyl
  • U is CH2, A and B are H, Ph is phenyl
  • U is CH2, A and B are H, Ph is phenyl
  • the rate of application is expressed as the negative log of the molar concentration of the test compound in the diet.
  • Percent growth inhibition is derived from the total weight of the insects (IW) at each rate of application in the test relative to the total weight of insects in an untreated control,
  • % Gr. Inh. ⁇ [IW (control) - IW (test)] / IW (control) ⁇ x 100
  • a minus % growth inhibition indicates that the insects weii termination of the test than those in the untreated control.
  • Percent control is derived from the total number of dead insects (TD) plus the total number of moribund insects (TM) as compared to the total number of insects (Tl) used in the test,

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention se rapporte à des composés de la structure (a) qui sont des insecticides efficaces, structure dans laquelle A et B représentent indépendamment alkyle inférieur; U représente alkylidène inférieur, alcénylidène inférieur ou CH-Z où Z représente hydrogène, alkyle inférieur, cycloalkyle inférieur ou phényle; R représente phényle ou un dibenzocyclo(C5-8)alkyle, chacun étant éventuellement substitué, ou la structure (b) dans laquelle R3 et R4 sont indépendamment sélectionnés parmi phényle, éventuellement substitués avec halogène, alkyle inférieur, haloalkyle inférieur, alcoxy inférieur, haloalcoxy inférieur, alcényle inférieur ou phényle; R1 est sélectionné parmi une variété de substituants tels que 3-R2 où R2 représente la structure (c) dans laquelle D, E et G représentent hydrogène, hydroxy, halogène, cyano, hydroxy, alkyle inférieur, haloalkyle inférieur, alcoxy inférieur, nitro, haloalkylsulfonyloxy inférieur, alkylcarboxylato inférieur, alkylcarbonylamino inférieur, alkylcarbonyle inférieur, alcoxycarbonyle inférieur, arylcarbonylamino; D et E réunis peuvent former le groupe -O(CH¿2?)O-; J représente hydrogène ou alkyle inférieur; m vaut 2 ou 3, n vaut 1, 2 ou 3; et halogène représente chlore, brome ou fluor.
PCT/US1997/000804 1996-01-19 1997-01-15 Piperazines insecticides n-heterocyclylalkyle- ou n-[(polycyclyle)-alkyle]-n'-substituees WO1997026252A1 (fr)

Priority Applications (1)

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AU15809/97A AU1580997A (en) 1996-01-19 1997-01-15 Insecticidal n-heterocyclylalkyl- or n-{(polycyclyl)-alkyl}-n'-substituted piperazines

Applications Claiming Priority (4)

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US1023796P 1996-01-19 1996-01-19
US60/010,237 1996-01-19
US08/780,371 USH2007H1 (en) 1996-01-19 1997-01-09 Insecticidal N-heterocyclylalkyl-or N-[(polycyclyl)alkyl]-N′substituted piperazines
US08/780,371 1997-01-09

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WO1997026252A1 true WO1997026252A1 (fr) 1997-07-24

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US6130235A (en) * 1998-05-22 2000-10-10 Scios Inc. Compounds and methods to treat cardiac failure and other disorders
WO2000059895A1 (fr) * 1999-04-07 2000-10-12 Uniroyal Chemical Company, Inc. Derives pesticides de tetrazole
US6184226B1 (en) 1998-08-28 2001-02-06 Scios Inc. Quinazoline derivatives as inhibitors of P-38 α
WO2001049677A1 (fr) * 1999-12-30 2001-07-12 H. Lundbeck A/S Derives de phenylpiperazinyle
WO2001049678A1 (fr) * 1999-12-30 2001-07-12 H. Lundbeck A/S Derives phenyl-piperazine substitues, leur preparation et utilisation
US6340685B1 (en) 1998-05-22 2002-01-22 Scios, Inc. Compounds and methods to treat cardiac failure and other disorders
US6410540B1 (en) 1998-08-28 2002-06-25 Scios, Inc. Inhibitors of p38-αkinase
US6448257B1 (en) 1998-05-22 2002-09-10 Scios, Inc. Compounds and methods to treat cardiac failure and other disorders
US6514975B1 (en) * 1997-05-19 2003-02-04 Pfizer Inc Anti-inflammatory piperazinyl-benzyl-tetrazole derivatives and intermediates thereof
US6541477B2 (en) 1999-08-27 2003-04-01 Scios, Inc. Inhibitors of p38-a kinase
EP1339708A2 (fr) * 2000-11-20 2003-09-03 Scios Inc. Inhibiteurs de type indole de kinase p38
US6696443B2 (en) 2000-11-20 2004-02-24 Scios, Inc. Piperidine/piperazine-type inhibitors of p38 kinase
WO2004065380A1 (fr) * 2003-01-14 2004-08-05 Arena Pharmaceuticals Inc. Derives aryles et heteroaryles tri-substitues en position 1,2,3 en tant que modulateurs de metabolisme et prophylaxie et traitement de troubles lies au metabolisme
US6821966B2 (en) 2000-11-20 2004-11-23 Scios, Inc. Inhibitors of p38 kinase
US6864260B2 (en) 1999-09-17 2005-03-08 Scios, Inc. Indole-type derivatives as inhibitors of p38 kinase
US6867209B1 (en) 1998-05-22 2005-03-15 Scios, Inc. Indole-type derivatives as inhibitors of p38 kinase
EP1572668A2 (fr) * 2002-12-18 2005-09-14 Fmc Corporation Piperidines et piperazines n-(arylmethyle substitues)-4-(methyle disubstitues)
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WO2007018460A1 (fr) * 2005-08-08 2007-02-15 Astrazeneca Ab Agents thérapeutiques
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US7244441B2 (en) 2003-09-25 2007-07-17 Scios, Inc. Stents and intra-luminal prostheses containing map kinase inhibitors
WO2007096251A1 (fr) * 2006-02-22 2007-08-30 Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. Inhibiteurs de cpt dans le système nerveux central en tant que médicaments antidiabétiques et/ou anti-obésité
EP1927594A1 (fr) * 2003-01-14 2008-06-04 Arena Pharmaceuticals, Inc. Dérivés d'aryle et d'hétéroaryle 1,2,3-trisubstitués en tant que modulateurs du métabolisme et la prévention et le traitement de maladies liées à celui-ci, telles que le diabète et l'hyperglycémie
US7393851B2 (en) 2002-10-09 2008-07-01 Scios, Inc. Azaindole derivatives as inhibitors of p38 kinase
US7470699B2 (en) 2003-07-11 2008-12-30 Arena Pharmaceuticals, Inc. Trisubstituted aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto
US7615550B2 (en) 2002-10-16 2009-11-10 Glaxo Group Limited Substituted piperazines,(1,4) diazepines, and 2,5-diazabicyclo (2.2.1)iieptanes as histamine H1 and/or H3 antagonists or histamine H3 reverse antagonists
CN105198788A (zh) * 2015-09-30 2015-12-30 蒋军荣 一种吲哚氧代乙酰(n-二芳甲基)哌嗪衍生物及其制备方法和应用
EP3670498A1 (fr) * 2018-12-17 2020-06-24 Gottfried Wilhelm Leibniz Universität Hannover Composés pour le traitement de l'infection par le virus hepaci et procédé permettant de déterminer la thérapie de l'infection par le virus hepaci, en particulier d'une infection par vhc
US10894787B2 (en) 2010-09-22 2021-01-19 Arena Pharmaceuticals, Inc. Modulators of the GPR119 receptor and the treatment of disorders related thereto
US11007175B2 (en) 2015-01-06 2021-05-18 Arena Pharmaceuticals, Inc. Methods of treating conditions related to the S1P1 receptor
US11884626B2 (en) 2015-06-22 2024-01-30 Arena Pharmaceuticals, Inc. Crystalline L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclo-penta [b]indol-3-yl)acetic acid(Compound1) for use in S1P1 receptor-associated disorders

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US6130235A (en) * 1998-05-22 2000-10-10 Scios Inc. Compounds and methods to treat cardiac failure and other disorders
US6340685B1 (en) 1998-05-22 2002-01-22 Scios, Inc. Compounds and methods to treat cardiac failure and other disorders
US7189739B2 (en) 1998-05-22 2007-03-13 Scios, Inc. Compounds and methods to treat cardiac failure and other disorders
US6867209B1 (en) 1998-05-22 2005-03-15 Scios, Inc. Indole-type derivatives as inhibitors of p38 kinase
US6448257B1 (en) 1998-05-22 2002-09-10 Scios, Inc. Compounds and methods to treat cardiac failure and other disorders
US6476031B1 (en) 1998-08-28 2002-11-05 Scios, Inc. Quinazoline derivatives as medicaments
US6184226B1 (en) 1998-08-28 2001-02-06 Scios Inc. Quinazoline derivatives as inhibitors of P-38 α
US6277989B1 (en) 1998-08-28 2001-08-21 Scios, Inc. Quinazoline derivatives as medicaments
US6410540B1 (en) 1998-08-28 2002-06-25 Scios, Inc. Inhibitors of p38-αkinase
WO2000059895A1 (fr) * 1999-04-07 2000-10-12 Uniroyal Chemical Company, Inc. Derives pesticides de tetrazole
US6541477B2 (en) 1999-08-27 2003-04-01 Scios, Inc. Inhibitors of p38-a kinase
US6864260B2 (en) 1999-09-17 2005-03-08 Scios, Inc. Indole-type derivatives as inhibitors of p38 kinase
US7304048B2 (en) 1999-09-17 2007-12-04 Scios, Inc. Indole-type derivatives as inhibitors of p38 kinase
US7238712B2 (en) 1999-09-17 2007-07-03 Scios, Inc. Indole-type derivatives as inhibitors of p38 kinase
US7189726B2 (en) 1999-09-17 2007-03-13 Scios, Inc. Benzofuran derivatives as inhibitors of p38-α kinase
US6699864B2 (en) 1999-12-30 2004-03-02 H. Lundbeck A/S Substituted phenyl-piperazine derivatives, their preparation and use
WO2001049678A1 (fr) * 1999-12-30 2001-07-12 H. Lundbeck A/S Derives phenyl-piperazine substitues, leur preparation et utilisation
WO2001049677A1 (fr) * 1999-12-30 2001-07-12 H. Lundbeck A/S Derives de phenylpiperazinyle
US6821966B2 (en) 2000-11-20 2004-11-23 Scios, Inc. Inhibitors of p38 kinase
US6890938B2 (en) 2000-11-20 2005-05-10 Scios, Inc. Indole-type inhibitors of p38 kinase
US6696443B2 (en) 2000-11-20 2004-02-24 Scios, Inc. Piperidine/piperazine-type inhibitors of p38 kinase
EP1339708A2 (fr) * 2000-11-20 2003-09-03 Scios Inc. Inhibiteurs de type indole de kinase p38
US7291613B2 (en) 2000-11-20 2007-11-06 Scios, Inc. Inhibitors of p38 kinase
US7214679B2 (en) 2000-11-20 2007-05-08 Scios, Inc. Piperidine/piperazine-type inhibitors of p38 kinase
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US7393851B2 (en) 2002-10-09 2008-07-01 Scios, Inc. Azaindole derivatives as inhibitors of p38 kinase
US7615550B2 (en) 2002-10-16 2009-11-10 Glaxo Group Limited Substituted piperazines,(1,4) diazepines, and 2,5-diazabicyclo (2.2.1)iieptanes as histamine H1 and/or H3 antagonists or histamine H3 reverse antagonists
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JP2006511621A (ja) * 2002-12-18 2006-04-06 エフ　エム　シー　コーポレーション Ｎ―（置換アリールメチル）―４―（二置換メチル）ピペリジン及びピペラジン
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US7232824B2 (en) 2003-09-30 2007-06-19 Scios, Inc. Quinazoline derivatives as medicaments
WO2007018460A1 (fr) * 2005-08-08 2007-02-15 Astrazeneca Ab Agents thérapeutiques
WO2007096251A1 (fr) * 2006-02-22 2007-08-30 Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. Inhibiteurs de cpt dans le système nerveux central en tant que médicaments antidiabétiques et/ou anti-obésité
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