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Discovery of metaflumizone, a novel semicarbazone insecticide

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Metaflumizone, (EZ)-20-[2-(4-cyanophenyl)-1-(a, a, a -trifluoro-m-tolyl)ethylidene]-4-(trifluoromethoxy) carbanilohydrazi de, was discovered by Nihon Nohyakuinthe early 1990sandbelongs to the new class ofsemicarbazone insecticides. It is now being globallyco-developed as the animal health product, ProMeris1, in cooperation with Fort Dodge Animal Health and as an agricultural and consumer insecticide in cooperation with BASF. Metaflumizonewas developed in a synthesis program initiated from a pyrazoline insecticide lead. In this paper, we describe the development, discovery and structure activity relationships for metaflumizoneand related compounds.
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VETPAR-4102; No of Pages 5
Available online at www.sciencedirect.com
Veterinary Parasitology xxx (2007) xxx–xxx
www.elsevier.com/locate/vetpar
Discovery of metaflumizone, a novel semicarbazone insecticide
K. Takagi a,*, H. Hamaguchi b, T. Nishimatsu b, T. Konno b
a Nihon Nohyaku Co. Ltd., 19 Sunayama, Kamisu, Ibaraki 314-0255, Japan
b Nihon Nohyaku Co. Ltd., 1-2-5 Nihonbashi, Chuo-Ku, Tokyo 103-8236, Japan
Abstract
Metaflumizone, (EZ)-20-[2-(4-cyanophenyl)-1-(a,a,a-trifluoro-m-tolyl)ethylidene]-4-(trifluoromethoxy) carbanilohydrazide,
was discovered by Nihon Nohyaku in the early 1990s and belongs to the new class of semicarbazone insecticides. It is now
being globally co-developed as the animal health product, ProMeris1, in cooperation with Fort Dodge Animal Health and as an
agricultural and consumer insecticide in cooperation with BASF. Metaflumizone was developed in a synthesis program initiated
from a pyrazoline insecticide lead. In this paper, we describe the development, discovery and structure activity relationships for
metaflumizone and related compounds.
# 2007 Elsevier B.V. All rights reserved.
Keywords: ProMeris1; Semicarbazone; Metaflumizone; Pyrazoline
1. Introduction
insecticides (Fig. 1,III) and their isomers (Fig. 1,IV)
were designed by opening the central ring structure of
We focused our initial attention on the pyrazoline
the pyrazoline insecticides (Takagi et al., 1996). The
insecticides (Fig. 1,I) (Meier et al., 1992) because they
semicarbazone compounds (Fig. 1,III) provided excel-
were known to effectively control Lepidoptera (cater-
lent insecticidal activity and possessed the appropriate
pillars) and Coleoptera (beetles) and their unique and
stability. The isomers (Fig. 1,IV) were more stable than
novel structure suggested a new mode of action. In spite
their parent compounds (Fig. 1,II) but showed only
of the many insecticide patents containing a pyrazoline
moderate insecticidal activity. Optimization of the
ring, pyrazoline insecticides have not been launched,
semicarbazone insecticide leads (Fig. 1,III) led to the
presumably due to their highly lipophilic nature and
discovery of metaflumizone (Fig. 1,V). Metaflumizone is
propensity for bioaccumulation. Our attention was
an ideal candidate insecticide having activity against a
initially focused on modification of the pyrazoline ring
variety of insects and a degradation profile that is
and the preparation of isomeric compounds (Fig. 1,II).
consistent with environmental friendliness. At around the
These compounds were designed to increase biological
same time, oxadiazine insecticides, in which an oxygen
ability and reduce the potential for bioaccumulation.
atom was introduced into a pyrazoline ring, were
These compounds showed insecticidal activity similar
designed and indoxacarb (Fig. 1,VI) was discovered
to the parent pyrazolines (Fig. 1,I), but rapidly lost
(Annis et al., 1992; McCann et al., 2001). One can see
activity when exposed to light and were too labile for
that these structures (Fig. 1,I,II,V,VI) share a common
effective commercial use. Subsequently, semicarbazone
structural backbone with two phenyl rings connected
with five atoms, including three nitrogen atoms and one
carbonyl group located at similar position (Fig. 2). This
similarity among these different structures may play a
* Corresponding author.
E-mail address: takagi-kazuhiro@nichino.co.jp (K. Takagi).
key role in their insecticidal activity.
0304-4017/$ – see front matter # 2007 Elsevier B.V. All rights reserved.
doi:10.1016/j.vetpar.2007.08.031
Please cite this article in press as: Takagi, K., et al., Discovery of metaflumizone, a novel semicarbazone insecticide, Vet.
Parasitol. (2007), doi:10.1016/j.vetpar.2007.08.031

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VETPAR-4102; No of Pages 5
2
K. Takagi et al. / Veterinary Parasitology xxx (2007) xxx–xxx
Fig. 1. The evolution of chemical design from pyrazoline insecticides to semicarbazone insecticides and oxadiazine insecticides.
2. Discovery of the semicarbazone insecticides
a.i./L at 4 days after application in a treated diet
bioassay against larvae of the common cutworm moth
In our early discovery phase, semicarbazone
(Spodoptera litura). The EC50 values cited are the
derivatives (Fig. 1,III) were synthesized by a simple
screening concentrations that produced approximately
one- or two-step reaction from substituted phenyl
50% mortality in the test insects. This illustrates the
benzyl ketone intermediates (Fig. 3,VII). These phenyl
optimization process conducted by changing substitu-
benzyl ketone intermediates were synthesized by well-
ents at eight positions, R1, R2, R3, R4, X, Y, Z, W on the
known route corresponding to the character and the
general semicarbazone structure (Fig. 1,III).
position of each substituent in Fig. 4.
The comparison of insecticidal activity for com-
Insecticidal activities of semicarbazone derivatives
pounds 1–6 indicated that substitutions at R1–R4, except
(Fig. 1,III) are shown in Table 1 as the EC50 value in mg
a methyl group at R2, decreased activity. The
comparison of the activity profiles for the Y substituent
(Table 1, compounds 7–12), showed that the substitu-
tion at the para-position of the benzene ring tended to
increase insecticidal activity. Electron-withdrawing
groups such as a nitro or cyano moeity showed higher
activity. The 4-cyano group showed good activity and
was fixed as the Y substituent since phenyl benzyl
ketone intermediates (Fig. 3,VII) were easily synthe-
Fig. 2. Common structural backbone of the pyrazoline-type insecti-
cides.
sized using p-tolunitrile and benzoate and the 4-cyano
Please cite this article in press as: Takagi, K., et al., Discovery of metaflumizone, a novel semicarbazone insecticide, Vet.
Parasitol. (2007), doi:10.1016/j.vetpar.2007.08.031

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VETPAR-4102; No of Pages 5
K. Takagi et al. / Veterinary Parasitology xxx (2007) xxx–xxx
3
Fig. 3. Synthetic route of semicarbazone derivatives.
group was conducive to a wide range of substituents at
optimization by changing the substituent at the meta-
X on the benzene ring. Contrary to our expectation,
position, the steric effect of substituted groups
compound 11 (Table 1) where the methyl moiety was
contributed to the insecticidal activity. Smaller groups
substituted at R2 position of compound 10 (Table 1) had
like halogen or methyl showed the best activity and
decreased insecticidal activity.
more bulky substituents decreased activity drastically.
During comparison of the activity profiles for the X
A second tendency could be seen that lipophilic
substitution of the benzene ring, substitutions at the
substituents showed good activity. However, electronic
meta-position were most favorable, but substitutions at
profiles of the substituents did not affect the activity. As
the ortho- or para-position decreased the activity. This
a result, the trifluoromethyl group was found to be the
tendency was apparently different from that of pyrazo-
best substituent as X (Table 1, compounds 13–17).
line insecticides in which the substitution at para-
To produce the Z substitutions on the benzene ring
position was best (Meier et al., 1992). During the
(Table 1, compounds 18–20), reactions using phenyl
Table 1
Insecticidal activity of semicarbazone derivatives against larvae of Spodoptera litura
No.
R1
R2
R3
R4
X
Y
Z
W
EC50 value
(mg a.i./L)
1
H
H
H
H
H
H
4-OCF3
O
30
2
CH3
H
H
H
H
H
4-OCF3
O
>1000
3
H
CH3
H
H
H
H
4-OCF3
O
1–3
4
H
H
CH3
H
H
H
4-OCF3
O
100–300
5
H
H
OH
H
H
H
4-OCF3
O
300–1000
6
H
H
=O
H
H
4-OCF3
O
300–1000
7
H
H
H
H
H
2-Cl
4-OCF3
O
>1000
8
H
H
H
H
H
3-Cl
4-OCF3
O
30–100
9
H
H
H
H
H
4-Cl
4-OCF3
O
3
10
H
H
H
H
H
4-CN
4-OCF3
O
1
11
H
CH3
H
H
H
4-CN
4-OCF3
O
30–100
12
H
H
H
H
H
4-NO2
4-OCF3
O
0.3–1
13
H
H
H
H
2-Cl
H
4-OCF3
O
300
14
H
H
H
H
3-Cl
H
4-OCF3
O
30–100
15
H
H
H
H
4-Cl
H
4-OCF3
O
>1000
16a
H
H
H
H
3-CF3
4-CN
4-OCF3
O
0.3–1
17
H
H
H
H
4-CF3
4-CN
4-OCF3
O

18
H
H
H
H
H
4-CN
H
O

19
H
H
H
H
H
4-CN
4-Cl
O
30–100
20
H
H
H
H
3-CF3
4-CN
4-CF3
O
1–10
21
H
H
H
H
3-CF3
4-CN
4-OCF3
S

–: Not tested (<50% at 500 ppm, first screening).
a Metaflumizone.
Please cite this article in press as: Takagi, K., et al., Discovery of metaflumizone, a novel semicarbazone insecticide, Vet.
Parasitol. (2007), doi:10.1016/j.vetpar.2007.08.031

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VETPAR-4102; No of Pages 5
4
K. Takagi et al. / Veterinary Parasitology xxx (2007) xxx–xxx
Fig. 4. Synthetic route of phenyl benzyl ketone intermediates.
isocyanate were conducted. Lipophilic substituents
Compound 16 (Table 1), metaflumizone, was
such as trifluoromethyl and trifluoromethoxy groups
selected as the best candidate on the basis of the
at the para-position showed good activity similar to that
structure activity relationships developed. Metaflumi-
shown in the optimization of pyrazoline insecticides
zone in its native state consists of two isomers (90%
(Meier et al., 1992). Compound 21 (Table 1) with a
E-isomer and 10% Z-isomer). The E-isomer showed
sulfur atom as W was obtained by the reaction using
10-fold higher activity than did the Z-isomer against
phenyl isothiocyanate instead of phenyl isocyanate, but
lepidopterous larvae, and a hydrogenated analog had the
this compound showed low activity.
same activity as the E-isomer (Fig. 5, Table 2).
Table 2
Insecticidal activity of the E- and Z-isomers and a hydrogenated
analog of metaflumizone against larvae of Spodoptera litura
EC50 value (mg a.i./L)
E-Isomer
0.3–1
Z-Isomer
1–3
Hydrogenated analog
0.3–1
Fig. 5. Chemical structure of the E- and Z-isomers and a hydroge-
nated analog of metaflumizone.
Fig. 6. Isomerization and hydrolysis of semicarbazone derivatives.
Please cite this article in press as: Takagi, K., et al., Discovery of metaflumizone, a novel semicarbazone insecticide, Vet.
Parasitol. (2007), doi:10.1016/j.vetpar.2007.08.031

+ Models
VETPAR-4102; No of Pages 5
K. Takagi et al. / Veterinary Parasitology xxx (2007) xxx–xxx
5
Most semicarbazone derivatives were synthesized as
agricultural crop protection. In addition to the broad
mixtures of E- and Z-isomers. In many cases, the E-
insecticidal spectrum on crop pests, metaflumizone also
isomer was the major product that was separated by
showed excellent activity against termites, e.g. Copto-
column chromatography or recrystalization. These
termes formosanus (Takagi et al., 2005), and fleas, e.g.
isomers were identified by NMR (NOE sub spectrum).
Ctenocephalides felis (Yamaguchi et al., 2005). This
The isomers were converted easily to the other isomers
broad spectrum of insecticidal activity has allowed for
(E to Z, Z to E) when exposed to light and in the
the extension to non-crop uses such as wood protection
presence of acid catalyst (Fig. 6). Furthermore, these
and animal health.
semicarbazone derivatives were readily hydrolyzed to
the ketones and semicarbazides in aqueous media, but
Acknowledgments
were generally stable in the crystalline state.
The authors would like to thank their colleagues for
3. Conclusion
their great enthusiasm and incessant efforts during the
course of the discovery works summarized in this paper.
Of the thousand or more semicarbazone derivatives
evaluated, metaflumizone was selected as the best
References
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veterinary insecticide. The major E-isomers on the C N
Annis, G.D., Barnette, W.E., McCann, S.F., Wing, K.D., 1992.
double bond, showed higher activity than minor Z-
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Meier, G.A., Silverman, I.R., Ray, P.S., Cullen, T.G., Ali, S.F., Marek,
ring. However, this difference did not seem to be
F.L., Webster, C.A., 1992. Insecticidal dihydropyrazoles with
consequential,
because
rapid
isomerization
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observed to a steady-state ratio of about 90:10 (E:Z).
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The rapid hydrolysis of metaflumizone and related
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compounds in water and its photo degradation under
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sunlight resulted in the desired environmentally benign
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profile.
Barnette, W.E., Wing, K.D., 2001. The discovery of indoxacarb:
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Metaflumizone derivatives showed excellent activity
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against insect pests in the order Lepidoptera, Coleop-
Takagi, K., Ohtani, T., Nishida, T., Hamaguchi, H., Nishimatsu, T.,
tera, Diptera and Hymenoptera, and demonstrated a
Kanaoka, A., 1996. Hydrazinecarboxymide derivatives, a process
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Takagi, K., Wada, Y., Yamaguchi, R., 2005. Ant controllers and
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throids and benzoylphenylureas, suggesting a new
Yamaguchi, R., Nishimatsu, T., Takagi, K., 2005. Ectoparasitic insect
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6903237B2.
Please cite this article in press as: Takagi, K., et al., Discovery of metaflumizone, a novel semicarbazone insecticide, Vet.
Parasitol. (2007), doi:10.1016/j.vetpar.2007.08.031

Document Outline

  • Discovery of metaflumizone, a novel semicarbazone insecticide
    • Introduction
    • Discovery of the semicarbazone insecticides
    • Conclusion
    • Acknowledgments
    • References

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