Discovery of cyantraniliprole, a potent and selective anthranilic diamide ryanodine receptor activator with cross-spectrum insecticidal activity

Article abstract of DOI:10.1016/j.bmcl.2013.09.076

Anthranilic diamides are an exceptionally active class of insect control chemistry that selectively activates insect ryanodine receptors causing mortality from uncontrolled release of calcium ion stores in muscle cells. Work in this area led to the succes

Full text of DOI:10.1016/j.bmcl.2013.09.076

Bioorganic & Medicinal Chemistry Letters 23 (2013) 6341–6345
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of cyantraniliprole, a potent and selective anthranilic
diamide ryanodine receptor activator with cross-spectrum
insecticidal activity
⇑
Thomas P. Selby , George P. Lahm, Thomas M. Stevenson, Kenneth A. Hughes, Daniel Cordova,
I. Billy Annan, James D. Barry, Eric A. Benner, Martin J. Currie, Thomas F. Pahutski
DuPont Crop Protection, Stine-Haskell Research Center, 1094 Elkton Road, Newark, DE 19711, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 18 July 2013
Revised 17 September 2013
Accepted 23 September 2013
Available online 1 October 2013
Anthranilic diamides are an exceptionally active class of insect control chemistry that selectively acti-
vates insect ryanodine receptors causing mortality from uncontrolled release of calcium ion stores in
muscle cells. Work in this area led to the successful commercialization of chlorantraniliprole for control
of Lepidoptera and other insect pests at very low application rates. In search of lower logP analogs with
improved plant systemic properties, exploration of cyano-substituted anthranilic diamides culminated in
the discovery of a second product candidate, cyantraniliprole, having excellent activity against a wide
range of pests from multiple insect orders. Here we report on the chemistry, biology and structure–activity
trends for a series of cyanoanthranilic diamides from which cyantraniliprole was selected for commercial
development.
Keywords:
Ryanodine receptor
Anthranilic diamides
Chlorantraniliprole
Cyantraniliprole
Calcium channels
Ó 2013 Published by Elsevier Ltd.
Calcium channels are an attractive biological target for insect
control due to the important role they play in multiple cell func-
tions such as muscle contraction, neurotransmitter release and fer-
tilization.1–4 The ryanodine receptor (RyR) is a non-voltage gated
calcium channel located in the sarcoplasmic reticulum of muscle
cells that regulates the release of intracellular calcium stores crit-
ical for muscle function.5,6
The name is derived from the natural product ryanodine, a plant
metabolite from Ryania speciosa that affects calcium release by
locking channels in the partially open state.7,8
We previously reported on the discovery of a new synthetic
class of anthranilic diamide RyR activators which led to the com-
mercialization of chlorantraniliprole (1a, DPX-E2Y45, RynaxypyrÒ),
an insect control agent with outstanding activity against a wide
range of lepidopteran pests and other ‘plant-chewing’ insects
(Fig. 1).9–13 Chlorantraniliprole binds to a site on the RyR distinct
from that of ryanodine and its low toxicity to mammals is attrib-
uted to the high selectivity for insect versus mammalian RyRs.14–16
In contact-systemic screening on ‘sap-feeding’ pests (insects
that feed on the fluids of plants and also referred to as ‘sucking/
piercing’ pests), 1b, a 4,6-dichloroanthranilamide analog of chlo-
rantraniliprole, demonstrated strong activity against the hemipter-
an pest Myzus persicae (green peach aphid) while maintaining
excellent potency against Lepidoptera (Fig. 1). However, in straight
systemic tests where plant uptake and translocation of the com-
pound are essential since there is no direct contact with the insect,
1b showed reduced efficacy versus that observed in the contact-
systemic screen. This result was consistent with a measured logP
(HPLC, pH 7) of 2.9, high for plant systemic movement where a
log below 2 would be preferred.18–22 Nevertheless, the encouraging
contact activity against a hemipteran insect, where 1b was applied
directly to the pest on the plant, prompted a search for lower logP
analogs that might possess improved systemic properties.
Slightly lower logP fluorine-containing anthranilic diamides
were subsequently reported by Clark et al. to have only a limited
improvement in systemic activity.17 However, we continued to
pursue a wide range of polar groups on the anthranilic core with
an emphasis on nitrile substitution. This effort culminated in the
discovery of cyantraniliprole (1c, DPX-HGW86, Cyazypyr™), a sec-
ond product candidate to emerge from this chemistry class having
cross-spectrum activity against a range of insect orders, including
Lepidoptera (i.e., caterpillars), Hemiptera (i.e., aphids and white
flies) and Coleoptera (i.e., beetles).23,24 This Letter focuses on the
synthesis, biology and structure–activity relationships for
a
series of cyano-substituted anthranilic diamides that led to
cyantraniliprole.
Introduction of a nitrile group at the 4-position on the anthra-
nilamide ring was initially accomplished via palladium-catalyzed
⇑
Corresponding author.
E-mail address: thomas.p.selby@usa.dupont.com (T.P. Selby).
0960-894X/$ - see front matter Ó 2013 Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.bmcl.2013.09.076

6342
T. P. Selby et al. / Bioorg. Med. Chem. Lett. 23 (2013) 6341–6345
O
O
4
R2
I
NHR4
4
OH
NHMe
a
OH
2a
NH
O
b
NH
6
OH
OH
Me
5
R1
O
O
O
CF3
O
NC
O
NHR4
N
Br
N
N
OH
1
N
N
OH
N
7
NH
Cl
HN
R1
Ryanodine
R4 = H, Me, i-Pr
R3
Cl
O
N
N
Chlorantraniliprole,1a (R1 = Me, R2 = Cl)
1b, (R1 = Cl,R2 = Cl )
a
N
O
O
N
NC
Cyantraniliprole,1c (R1 = Me,R2 = CN)
Cl
c
R1 = Me, Cl
2
R3
Figure 1. Ryanodine and anthranilic diamides.
R3 = halogen, CF3
R1
N
N
R4 = H, Me, i-Pr
N
6
Cl
cross-coupling of a 4-iodoanthranilic diamide with cyanide. As
outlined in Scheme 1, iodobenzoxazinones of formula 2 were made
by sequential treatment of pyridylpyrazole acids 3 with 1.1 equiv
of triethylamine and methanesulfonyl chloride, followed by one
equiv of iodoanthranilic acid 4, 2.1 equiv of triethylamine and an-
other 1.1 equiv of methanesulfonyl chloride.23,25
6a R1 = Me, R3 = alkyl
6b R1 = Cl, R3 = alkyl
Scheme 2. Reagents and conditions: (a) methylamine (1 M in THF), neat isopro-
pylamine (3 equiv) or concd NH4OH, THF, 25 °C, 3 h, 80–85%) (b) CuCN (10 equiv),
Pd(PPh3)4 (10 mol %), CuI (20 mol %), THF, reflux, 5 h, 20–35%. (c) CuCN (5 equiv),
Pd(PPh3)4 (10 mol %), CuI (25–40 mol %), THF, reflux, 5 h, 50–60%.
Ring opening of iodobenzoxazinone 2a with amines gave the
respective 4-iodoanthranilic diamides 5 that were cross-coupled
with cuprous cyanide by heating in the presence of Pd(PPh3)4
and cuprous iodide in THF to afford the corresponding 4-cyano-
anthranilic diamides 7 in modest yields (Scheme 2). Reversing
the order of these two steps was found to be preferred.
Iodobenzoxazinones 2 were coupled with cyanide to afford cya-
nobenzoxazinones 6 that on ring opening with amines gave 4-
cyanoanthranilic diamides of formula 7 (Scheme 2) in good yield.25
For expanded tests where larger quantities of 4-cyanoanthrani-
lic diamides 7 were needed, an alternative synthesis of precursors
6a was employed as outlined in Scheme 3.
4a
a or b
6a
d
O
CO2H
NC
NC
O
c
NH2
O
N
H
Me
8
Me
9
Heating 4a with cuprous cyanide under Rosenmund–von Braun
conditions gave cyanoanthranilic acid 8 in moderate yield.26 Cop-
per-catalyzed exchange of iodide with sodium cyanide in the pres-
ence of a diamine ligand gave an improved yield. Treatment of 8
with diphosgene gave isatoic anhydride 9 which on reacting with
acid chlorides of pyrazole acids 3 afforded good yields of cya-
nobenzoxazinones 6a.
Regioisomeric 4-chloro-6-cyanoanthranilic diamides of formula
10 were made by the method in Scheme 4. Cyanide was first cou-
pled with 4-chloro-6-iodoanthranilic acid 11 via palladium-medi-
ation to give 4-chloro-6-cyanoanthranilic acid 12.27 Reacting 12
with pyrazole acids 3 in the presence of methanesulfonyl chloride
and base by the same reaction sequence described in Scheme 1
Scheme 3. Reagents and conditions: (a) CuCN (1.2 equiv), DMF, 140 °C, 18 h, 50%
(b) NaCN (1.2 equiv), N,N’-dimethylethylenediamine (2 equiv), CuI (10 mol %), KI
(20 mol %), PhCl, 120 °C, 24 h, 70% (c) diphosgene (1.5 equiv), dioxane, 60 °C, 85%
(d) (i) Compound 3 (1 equiv), oxalyl chloride (1.5 equiv), DMF (cat.), CH2Cl2 (ii)
Compound 9 (1 equiv), MeCN, 85 °C, 75%.
O
4
Cl
NHMe
CO2H
NH2
Cl
CO2H
Cl
a
NH
b,c
6
NH2
CN
R3
O
I
CN
12
N
N
N
10
11
Cl
R3 = Br, CF3
O
R3
Scheme 4. Reagents and conditions: (a) CuCN (3 equiv), Pd(PPh3)4 (10 mol %), CuI
(40 mol %), THF, reflux, 5 h, 40% (b) (i) Compound 3 (1 equiv), MeSO2Cl (1.1 equiv),
Et3N (1.1 equiv), 0–5 °C, 10 min (ii) Compound 12 (1 equiv), 0 °C, 5 min (iii) Et3N
(2.1 equiv), MeCN, 0–10 °C, 45 min (iv) MeSO2Cl (1.1 equiv), MeCN, 0–25 °C, 12 h,
50–55% (c) methylamine (1 M in THF) , THF, 25 °C, 3 h, 70 %.
I
O
CO2H
I
N
a
HO2C
R3
N
N
+
R1
2
N
N
NH2
Cl
R1
N
N
3
4
Cl
2a R1 = Me, R3 = CF3
gave the corresponding benzoxazinones that on ring opening with
methylamine afforded 10.
3a R3 = CF3
4a R1 = Me
4b R3 = Cl
2b R1 = Me, R3 = Br
2c R1 = Cl, R3 = CF3
3b R3 = Br
3c R3 = Cl
Preparation of cyanopyrazole and cyanopyridine containing
diamides 13 and 14, respectively, are outlined in Scheme 5. Cou-
pling of commercially available pyrazoles 15a and 15b with 2,3-
dichloropyridine and 2-chloro-3-cyanopyridine by heating in
DMF in the presence of potassium carbonate gave the correspond-
ing pyridylpyrazoles 16. Lithiation of 16 followed by trapping with
2d R1 = Cl, R3 = Br
Scheme 1. Reagents and conditions: (a) (i) Compound 3 (1 equiv), MeSO2Cl (1.1
equiv), Et3N (1.1 equiv), 0–5 °C, 10 min (ii) Compound 4 (1 equiv), 0 °C, 5 min (iii)
Et3N (2.1 equiv), MeCN, 0–10 °C, 45 min (iv) MeSO2Cl (1.1 equiv), MeCN, 0–25 °C,
12 h, 60–65%.

T. P. Selby et al. / Bioorg. Med. Chem. Lett. 23 (2013) 6341–6345
6343
R3
Table 1
R3
Log Ps of selected anthranilic diamides
R3
O
N
N
HO2C
R2
a or b
N
N
c
4
NHR4
R5
N
R5
N
H
N
N
NH
6
15a R3 = CN
R3 = CN, R5 = Cl
R1
15b R3 = CF3
R3 = CF3, R5 = CN
16
17
R3
O
O
N
N
O
N
Cl
Cl
NHMe
NH
NHMe
R5
13 R3 = CN
R5 = Cl
NH2
18
*
Me
3
Entry
R1
R2
Cl
R3
Br
R4
R5
Cl
LogP
R3
Me
O
N
14 R3 = CF3
1a
Me
Me
Me
Me
Me
H
3.0 (m)
3.2 (c)
2.9 (m)
3.6 (c)
2.6 (m)
2.3 (c)
3.1 (m)
2.7 (c)
2.7 (m)
2.5 (c)
3.6 (c)
2.3 (m)
2.5 (c)
3.6 (c)
2.5 (m)
2.6 (c)
2.2 (m)
2.3 (c)
3.4 (c)
2.8 (c)
2.8 (c)
2.9 (c)
2.9 (c)
2.3 (c)
2.5 (c)
1.6 (m)
1.3 (c)
2.3 (c)
N
d
N
R5 = CN
1b
1c
7a
7b
Cl
Cl
Br
Cl
Cl
Cl
Cl
R5
3
Me
Me
Me
CN
CN
CN
Br
Scheme 5. Reagents and conditions: (a) Compound 15a, 2,3-dichloropyridine,
potassium carbonate (2 equiv), DMF, 130–140 °C, 55% (b) Compound 15b, 2-chloro-
3-cyanopyridine, potassium carbonate (2 equiv), DMF, 130–140 °C, 60% (c) (i)
Compound 16, LDA (1.5 equiv), THF, À78 °C (ii) CO2 (iii) HCl (aq), 50–60% (d) (i) 17,
(COCl)2, DMF (cat.), CH2Cl2, ambient temp (ii) Compound 18, (i-Pr)2EtN, THF, 0–
25 °C, 40–50%.
CF3
CF3
7c
7d
Me
Me
CN
CN
CF3
Br
i-Pr
Cl
Cl
H
7e
7f
Me
Me
CN
CN
Br
Cl
i-Pr
Me
Cl
Cl
X
O
4
O
H2N
b,c
NHMe
NH
CO2H
NH2
7g
Me
CN
Cl
H
Cl
H2N
a
7h
7i
7j
10a
10b
13
14
19
Me
Cl
Cl
CN
CN
Me
Me
Me
CN
CN
CN
Cl
Cl
Cl
Cl
Br
i-Pr
Me
Me
Me
Me
Me
Me
Me
Cl
Cl
Cl
Cl
Cl
Cl
CN
Cl
8
Me
20
O
Me
Br
CF3
Br
CF3
CN
CF3
Br
d
N
N
N
1c
Cl
Cl
19 X = O
21 X = S
CONH2
CSNH2
21
Me
Br
Me
Cl
Scheme 6. Reagents and conditions: (a) concd H2SO4, 25 °C, 80% (b) (i) Compound 3
(where R3 = Br) (1 equiv), MeSO2Cl (1.1 equiv), Et3N (1.1 equiv), 0–5 °C, 10 min (ii)
Compound 20 (1 equiv), 0 °C, 5 min (iii) Et3N (2.1 equiv), MeCN, 0–10 °C, 45 min (iv)
MeSO2Cl (1.1 equiv), MeCN, 0–25 °C, 12 h, 45% (c) methylamine (1 M in THF), THF,
25 °C, 3 h, 60 %. (d) (NH4)2S (7 equiv), MeOH, microwave, 80 °C, 30%.
*
LogP numbers are measured HPLC (pH 7) values (m) or calculated values (c) from
Biobyte clogP software. Measured values were determined on a Zorbax SB C18
column at 40 °C using 5 mM ammonium acetate in acetonitrile gradient. Retention
times were compared to retention times of standards with known values of shake-
flask octanol–water partition coefficient in the same system.
CO2 gave pyridylpyrazole acids 17 that were converted to the acid
chlorides and coupled with anthranilic methylamide 18 to afford
13 and 14, respectively.
Preparation of a 4-carboxamidoanthranilic diamide (19) is
shown in Scheme 6. Hydrolysis of the nitrile group of anthranilic
acid 8 in concentrated sulfuric acid gave 4-carboxamido anthra-
nilic acid 20 which was converted to a benzoxazinone by the same
method as in Scheme 1 followed by ring opening with methyl-
amine to afford 19.
This resulted in an increase of water solubility from 2 ppm for 1a
(20 °C) to approximately 15 ppm for 1c, thus conferring enhanced
xylem mobility for upward plant movement. Although the HPLC
logP values in Table 2 were referenced to the logPow of standards,
the reason for the log unit discrepancy between the HPLC and
shake-flask values for 1c was unclear but a welcomed result.
The intrinsic activity of these compounds was measured in a
functional assay where the first full length recombinant insect
RyR, Drosophila melanogaster RyR, was stably expressed in an insect
cell line (Sf9) as previously described.14 Subsequently, RyRs from
both lepidopteran and hemipteran insects were cloned and ex-
pressed in Sf9 cells.
Table 2 summarizes anthranilic diamide potency as EC50 values
(50% effective concentrations) against the following three insect
recombinant RyRs: dipteran RyR from Drosophila melanogaster
(fruit fly), lepidopteran RyR from Heliothis virescens (tobacco bud-
worm) and hemipteran RyR generated as a chimera from Myzus
persicae (green peach aphid) and Perigrinus maidis (corn plant
hopper).
The 4-thiocarboxamido anthranilic diamide 21 was made by
heating 4-cyanoanthranilamide 1c with excess ammonium sulfide
in a microwave (Scheme 6).
Table 1 summarizes estimated (HPLC, pH 7) and calculated logP
values for a selection of prepared anthranilic diamides. The mea-
sured logP values for 1a (chlorantraniliprole), 1b and 1c (cyantra-
niliprole) were 3.0, 2.9 and 2.6, respectively. Lipophilicity as
measured (HPLC) or calculated by logP for cyanoanthranilic diam-
ides 7a–7j, 10a, 10b, 13, and 14 varied between values of 3.6 and
2.2. Carboxamido anthranilamide 19 (R2 = CONH2) had a measured
logP of 1.6 and thiocarboxamido anthranilamide 21 (R2 = CSNH2)
had calculated logP of 2.3.
In these recombinant cell lines, anthranilic diamides stimulated
a calcium response, comprising an initial transient internal calcium
store release that then triggered sustained calcium elevation from
external calcium entry via voltage-independent channels. Unlike
In shake-flask studies, the measured logPow for 1c was 1.9 (pH7,
22 °C), significantly lower than the HPLC estimated value of 2.6 and
a log unit lower than that of 1a with a logPow of 2.9 (pH7, 20 °C).

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T. P. Selby et al. / Bioorg. Med. Chem. Lett. 23 (2013) 6341–6345
Table 2
Table 3
Intrinsic potency of anthranilic diamides on Sf9 cells expressing recombinant insect
RyRs
Insecticidal activity of anthranilic diamides in a foliar applied test
Entry
Sf1
Ag2
Ef3
Entry
Dipteran RyR1
Lepidopteran RyR2
Mean EC50 M)
Hemipteran RyR3
EC50 Values (ppm)
(l
1a
1b
1c
7a
7b
7c
7d
7e
7f
7 g
7 h
7i
<0.1
<0.1
0.2a
0.1a
0.7c
<0.1
<0.1
0.2a
0.3c
0.4c
0.2a
<0.1
9.0a
19b
12.4a
0.9a
0.4a
1.3a
4.7a
1.5a
4.0b
2.3a
1.9a
2.7a
1.1c
1.6b
3.7a
>250
>250
>50
1.5a
1.4a
2.0b
-
1a
1b
1c
7a
7b
7c
7d
7e
7f
0.04 (0.01)
0.04 (0.01)
0.09 (0.01)
0.10 (0.01)
0.30 (0.01)
0.33 (0.02)
0.07 (0.01)
0.09 (0.01)
0.13 (0.01)
0.09 (0.01)
0.15 (0.01)
0.07 (0.01)
0.15 (0.01)
0.16 (0.01)
0.26 (0.02)
0.20 (0.01)
0.46 (0.01)
0.69 (0.12)
0.09 (0.01)
0.05 (0.02)
0.10 (0.01)
0.25 (0.02)
0.28 (0.03)
>1
0.04 (0.01)
0.06 (0.01)
0.09 (0.01)
0.12 (0.01)
0.41 (0.04)
0.48 (0.02)
0.08 (0.01)
0.07 (0.01)
0.13 (0.02)
0.09 (0.01)
0.28 (0.05)
0.06 (0.01)
0.09 (0.01)
0.19 (0.01)
0.31 (0.03)
0.25 (0.01)
0.43 (0.05)
0.52 (0.07)
0.09 (0.02)
<2.0
5.4a
3.8b
11b
4.8b
1.1c
19b
14c
>1
0.30 (0.01)
0.28 (0.02)
0.43 (0.02)
0.28 (0.01)
>1
0.15 (0.01)
0.34 (0.01)
0.45 (0.06)
0.54 (0.07)
0.16 (0.01)
0.23 (0.03)
>1
7g
7h
7i
7j
9.0b
7j
10a
10b
13
14
19
21
60c
10a
10b
13
14
19
21
20a
>250
17c
>250
4.3c
4.0c
5.7a
<0.1
16a
>250
>250
0.4b
0.8a
0.42 (0.06)
1
2
3
Spodoptera frugiperda (Sf, fall armyworm).
Aphis gossypii (Ag, cotton/melon aphid).
Empoasca fabae (Ef, potato leaf hopper). The EC50 values for Sf assess plant
1
2
3
Drosophila melanogaster.
Heliothis virescens.
Myzus persicae-Perigrinus maidis chimera. EC50 values were determined from
protection whereas the values for Ag and Ef represent mortality. The confidence
interval ranges for reported values from probit analyses are: a650% of calculated
value, b6100% of calculated value, c6200% of calculated value.
n = 3 replicates. Standard error deviations are shown in parentheses.
the plant alkaloid, ryanodine, which locks calcium channels in the
open position only when RyRs have already been activated, anthra-
nilic diamide insecticides directly activate RyR channels with chan-
nels remaining open, either fully or partially, resulting in depletion
of calcium stores.14,16
for 50% mortality against Ag and Ef. On the other hand, diamide
1b had EC50 values of <0.1, 0.9 and 1.4 ppm against Sf, Ag and Ef,
respectively. The lower logP cyanoanthranilamide 1c had a slightly
higher EC50 value of 0.2 ppm on Sf and 2.0 ppm against Ef versus 1a
and 1b, but was more active on Ag with an EC50 value of 0.4 ppm.
Some of the other 4-cyanoanthranilamides (7a–7j) in Table 3 ap-
proached 1c in overall activity but none were clearly superior. Sur-
prisingly, switching R1 and R2 resulted in a considerable loss of
activity as revealed for 10a and 10b, where R1 = CN and R2 = Cl.
Anthranilamides 13 and 14 with a nitrile group at the pyrazole
R3 or pyridine R5 position also had diminished activity. Paralleling
the cellular receptor activity in Table 2, the 4-carboxamido anthra-
nilamide 19 (R2 = CONH2) performed poorly but the thiocarboxa-
mide 21 (R2 = CSNH2), which presumably is a pro-form of 1c, was
much closer to 1c in activity.
Chlorantraniliprole (1a) stimulated RyR-mediated calcium re-
lease with an EC50 range of 0.04–0.05
receptors. The hemipteran lead 1b showed similar potency with
an activity range of 0.04–0.1 M whereas 1c (cyantraniliprole)
was slightly less potent overall, falling in a range of 0.09–
0.25
M. Other nitrile analogs where R2 = cyano (7a–7j) also gave
high levels of activation with EC50 values between 0.06 and
0.48 M, except for 7b, 7c and 7h being over 1 M on Lepidopteran
lM against all three insect
l
l
l
l
RyR. Regioisomeric nitriles 10a and 10b with cyano at the 6 versus
4 anthranilic position (R1 = CN and R2 = Cl), 13 with cyano on the
pyrazole (R3 = CN) and 14 with cyano on the pyridine (R5 = CN)
A direct comparison of the insecticidal activity of 1c (cyantranil-
iprole) versus 1a (chlorantraniliprole) against pests from three in-
sect orders (Hemiptera, Lepidoptera and Coleoptera) is outlined in
Table 4. All of the EC50 values reflect insect mortality and further
demonstrate the scope of cross-spectrum insect control provided
by 1c.
In advanced laboratory and greenhouse systemic tests, 1c
continued to outperform its higher logP counterparts on a range
of sap-feeding insects. Although 1a and 1c had comparable
potencies in activating hemipteran RyRs, physical properties
were less potent with EC50 values between 0.16 and 0.54 lM.
Although carboxamide 19 (R2 = CONH2) was much less active than
its nitrile counterpart 1c, the 4-thiocarboxamide 21 (R2 = CSNH2)
was surprisingly much closer to 1c in potency, falling in the
0.09–0.42 lM range. Although the cell culture was not analytically
assayed, there is precedent for a thiocarbxamide group serving as a
pro-form of cyano in cell culture medium so partial or full conver-
sion of 21 to 1c might have occurred.28
In comparing anthranilic diamide activation to mammalian
RyRs, 1c was found to be nearly 500-fold less potent against the
most sensitive mammalian receptor isoform tested (mouse
RyR1), revealing a substantial difference in insect versus mamma-
lian target site selectivity.29,30
Table 4
Chlorantraniliprole versus Cyantraniliprole against pests of different insect orders.
Table 3 summarizes insecticidal activity as EC50 values in ppm
from foliar-applied tests that reflect predominantly contact activ-
ity against the lepidopteran (chewing) pest Spodoptera frugiperda
(Sf, fall armyworm) and two hemipteran sap-feeding (sucking-
piercing) insects: Aphis gossypii (Ag, cotton/melon aphid), and
Empoasca fabae (Ef, potato leaf hopper). The EC50 values in Table 3
are the effective concentrations that gave 50% plant protection
from feeding by Sf and 50% mortality in the case of Ag, and Ef.
Chlorantraniliprole (1a) had an EC50 value less than 0.1 ppm
against Sf but required higher concentrations of 12.4 and 1.5 ppm
Scientific name
Insect order
1a
1c
EC50 Values (ppm)
Myzus persicae
Bemisia tabaci
Plutella xylostella
Heliothis virescens
Leptinotarsa decemlineata
Hemiptera
Hemiptera
Lepidoptera
Lepidoptera
Coleoptera
5.00
0.80
0.05
0.04
<0.1
1.10
0.08
0.07
0.21
<0.1
These EC50 values represent mortality and the confidence intervals are 650% of the
calculated value.

T. P. Selby et al. / Bioorg. Med. Chem. Lett. 23 (2013) 6341–6345
6345
9. Lahm, G. P.; Selby, T. P.; Freudenberger, J. H.; Stevenson, T. M.; Myers, B. J.;
Seburyamo, G.; Smith, B. K.; Flexner, L.; Clark, C. E.; Cordova, D. Bioorg. Med.
Chem. Lett. 2005, 15, 4898.
10. Lahm, G. P.; Stevenson, T. M.; Selby, T. P.; Freudenberger, J. H.; Cordova, D.;
Flexner, L.; Bellin, C. A.; Dubas, C. A.; Smith, B. K.; Hughes, K. A.; Hollingshaus, J.
G.; Clark, C. E.; Benner, E. A. Bioorg. Med. Chem. Lett. 2007, 17, 6274.
11. Lahm, G. P.; Myers, B. J.; Selby, T. P.; Stevenson, T. M. U.S. Patent 6,747,047,
2004.
12. Lahm, G. P.; Selby, T. P.; Stevenson, T. M. U. S. Patent 7,232,836, 2007.
13. Lahm, G. P.; Stevenson, T. M.; Selby, T. P.; Freudenberger, J. H.; Dubas, C. M.;
Smith, B. K.; Cordova, D.; Flexner, L.; Clark, C. E.; Bellin, C. A.; Hollingshaus, J. G.
In Pesticide Chemistry: Crop Protection, Public Health and Environmental Safety;
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14. Cordova, D.; Benner, E. A.; Sacher, M. D.; Rauh, J. J.; Sopa, J. S.; Lahm, G. P.;
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T.P., Stevenson, T.M., Flexner, L., Gutteridge, S., Rhoades, D.F., Wu, L., Smith,
R.M., Tao, Y. In: Lyga, J.W., Theodoridis, G., editors. ACS Symposium Series:
Synthesis and Chemistry of Agrochemicals VII; Washington, DC, 2007; Chapter
17, pp 223–234.
16. Cordova, D.; Benner, E. A.; Sacher, M. D.; Rauh, J. J.; Sopa, J. S.; Lahm, G. P.;
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clearly are crucial for the enhanced control of sucking/piercing
insects by 1c where improved systemic properties, such as lower
logP and higher water solubility, aid in plant uptake and
translocation.
Translation of activity from the greenhouse to field was con-
firmed where 1c controlled a wide range of insects, including
aphids, leafhoppers, planthoppers, whiteflies, leaf-feeding beetles,
leafminers, fruit flies, psyllids, weevils and caterpillars at applica-
tion rates generally between 10 and 200 grams of active ingredient
per hectare, depending on the specific pest group. Plant protection
resulted from rapid cessation of plant feeding with excellent trans-
laminar movement into leaf tissue when foliar applied or by up-
ward plant movement in soil applications.
In summary, cyantraniliprole (1c) was active against a wide
range of insects on a variety of crops in worldwide field evaluations
coupled with a favorable environmental-fate profile and remark-
able selectivity for insect over mammalian forms of RyRs. It repre-
sents the first anthranilic diamide from the IRAC (Insecticide
Resistance Action Committee) mode-of action Group 28 (Ryano-
dine Receptor Modulators) to target sap-feeding aphid pests with
no evidence to date suggesting cross-resistance with other com-
mercial aphid insecticides having a different mode of action.31
Comprising a combination of favorable attributes, cyantraniliprole
holds great promise as a pest management tool to growers
globally.
19. Satchivi, N. M.; Stoller, E. W.; Wax, L. M.; Briskin, D. P. Pestic. Biochem. Physiol.
2006, 84, 83.
20. Sicbaldi, F.; Sacchi, G. A.; Trevisan, M.; Del Re, A. A. M. Pestic. Sci. 1997, 50, 111.
21. Bromilow, R. H.; Chamberlain, K. Monograph-British Plant Growth Regulator
Group 18 (Mech. Regul. Transp. Processes) 1989, 113.
Acknowledgment
22. Grayson, B. T.; Kleier, D. A. Pestic. Sci. 1990, 30, 67.
23. Hughes, K. A.; Lahm, G. P.; Selby, T. P.; Stevenson, T. M. U.S. Patent 7,247,647,
2007.
24. Lahm, G. P.; Selby, T. P.; Stevenson, T. M.; Cordova, D.; Annan, I. B.; Andaloro, J.
T. Pyrazolylpyridine Activators of the Ryanodine Receptor. In Bioactive
Heterocyclic Compound Classes; Lamberth, C., Dinges, J., Eds.; Wiley-VCH,
2012; pp 251–263.
The authors wish to thank all those who made technical contri-
butions to this program, especially the chemists and biologists in-
volved in the preparation, characterization and evaluation of
compounds.
25. As representative of the methods for making benzoxazinones of formula 2
(where R1 = Me and R3 = Br), cyanobenzoxazinones of formula
6 and
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