Synthesis and endectocidal activity of novel 1-(Arylsulfonyl)-1- [(trifluoromethyl)sulfonyl]methane derivatives

Article abstract of DOI:10.1021/jm970678y

We have recently synthesized a series of novel disulfonylmethane compounds that have shown anthelmintic and insecticidal (endectocidal) activity. Several analogues have shown activity against the internal nematode Haemonchus contortus. In sheep studies, these analogues have shown 100% control of this internal parasite at a 10 mg/kg rate. In vitro activity against the biting flies, Stomoxys calcitrans and Haematobia irritans, has been observed at rates as low as 25 and 2.3 ppm, respectively. Only marginal activity against the liver fluke Fasciola hepatica and Trichostrongylus colubriformis was seen. Respiratory control index values on rat liver mitochondria for this series suggested uncoupling of oxidative phosphorylation as a mechanism of action. Compound 1 is considered to be a promising agent for treatment of parasitized sheep.

Full text of DOI:10.1021/jm970678y

1092
J . Med. Chem. 1998, 41, 1092-1098
Syn th esis a n d En d ectocid a l Activity of Novel
1-(Ar ylsu lfon yl)-1-[(tr iflu or om eth yl)su lfon yl]m eth a n e Der iva tives
David I. Wickiser,* Sharon A. Wilson, Daniel E. Snyder, Karl R. Dahnke, Charles K. Smith II, and
Paul J . McDermott
Elanco Animal Health, A Division of Eli Lilly and Company, Greenfield, Indiana 46140
Received October 7, 1997
We have recently synthesized a series of novel disulfonylmethane compounds that have shown
anthelmintic and insecticidal (endectocidal) activity. Several analogues have shown activity
against the internal nematode Haemonchus contortus. In sheep studies, these analogues have
shown 100% control of this internal parasite at a 10 mg/kg rate. In vitro activity against the
biting flies, Stomoxys calcitrans and Haematobia irritans, has been observed at rates as low
as 25 and 2.3 ppm, respectively. Only marginal activity against the liver fluke Fasciola hepatica
and Trichostrongylus colubriformis was seen. Respiratory control index values on rat liver
mitochondria for this series suggested uncoupling of oxidative phosphorylation as a mechanism
of action. Compound 1 is considered to be a promising agent for treatment of parasitized sheep.
In tr od u ction
Ch em istr y
Three synthetic routes were used for the synthesis of
compound 1 and analogues. Scheme 1 was the most
utilized method and is a modification of published
procedures.9 This synthetic pathway allowed for the
greatest flexibility in varying groups on the phenyl ring.
Chloromethyl trifluoromethyl sulfide was originally
synthesized from dimethyl sulfide by chlorination with
sulfuryl chloride, followed by fluorination with antimony
trifluoride.10 This was then used to synthesize the
phenyl trifluoromethyl dithio intermediates by reaction
with sodium salts of substituted benzenethiols. These
intermediates were then oxidized to the corresponding
disulfonylmethane compounds shown in Table 1. This
required the use of strong oxidizing agents such as
potassium permanganate or hydrogen peroxide in tri-
fluoroacetic acid. Hydrogen peroxide in acetic acid
would only oxidize the sulfur adjacent to the aryl ring.
Another method involved reaction of chloromethyl
phenyl sulfide with potassium triflinate to give the
sulfonyl sulfide intermediate, followed by oxidation to
give the disulfonylmethane as shown in Scheme 1b. This
method had less general application because of the
difficulties in obtaining substituted phenyl sulfides and
in the subsequent R-chlorination step.11
Scheme 1a shows the third method utilized in this
series. It presented a more economical approach to
structure 1. The potassium salt of p-(trifluoromethoxy)-
phenyl methyl sulfone was made using potassium bis-
(trimethylsilyl)amide and then reacted with phenyltri-
fluoromethanesulfonimide to give 1 in good yield. Other
trifluoromethanesulfonating agents have been used
successfully, including triflic anhydride and N-trifyl-
imidazolide. Trifyl fluoride also works well but is
difficult to obtain commercially. Some of this work is
also described in recent patent literature.12
The search for a novel class of compounds for the
treatment of parasitic nematodes and arthropods in
domestic animals is of continuing interest. There are
several broad-spectrum agents, representing a number
of chemical classes, available for treatment of internal
parasites of animals. Only the avermectins and milbe-
mycins are used for the broad systemic control of both
internal and external parasites.1,2 Unfortunately, strains
of nematodes and arthropods have shown resistance to
commercially available anthelmintics and insecticides
including the avermectins.3-7 We have recently syn-
thesized a series of novel 1-aryl-1-[(trifluoromethyl)-
sulfonyl]methane compounds that have shown in vitro
and in vivo anthelmintic activity against susceptible
strains as well as an Ivermectin-resistant strain. They
generally have shown good activity against the abo-
masal nematode Haemonchus contortus in sheep but
were less effective against Trichostrongylus colubrifor-
mis and Fasciola hepatica (common liver fluke). This
series has also demonstrated in vitro activity against
the blood-feeding dipteral species Stomoxys calcitrans
(stable fly), the adult of which attacks both domestic
animals8 and humans. The suspected mechanism of
action of these disulfonylmethane compounds is oxida-
tive phosphorylation uncoupling as they have been
shown to uncouple rat liver mitochondria. Despite the
potential nonselectivity of uncouplers, these disulfonyl-
methanes have shown a surprising margin of safety
toward the host species. This paper describes the
chemistry, structure-activity relationship, and biologi-
cal activity of compound 1 and analogues.
Two synthetic approaches were used for the synthesis
of the R-methyl compound 28. Direct alkylation using
dimethyl sulfate in DMF gave small amounts of product,
S0022-2623(97)00678-X CCC: $15.00 © 1998 American Chemical Society
Published on Web 03/05/1998

(Arylsulfonyl)[(trifluoromethyl)sulfonyl]methane
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 7 1093
Sch em e 1
Ch a r t 1
nesium bromide, respectively, with the analogous 4-chlo-
rophenyl vinyl intermediate. The scheme used for each
derivative is noted in Table 1.
Biologica l Da ta a n d Str u ctu r e-Activity
Rela tion sh ip s
The compounds in Table 1 were tested for insecticidal
activity using an in vitro adult stable fly (S. calcitrans)
screen. Adult stable flies were fed serum containing
titrated levels of the experimental compounds starting
with 100 ppm. Percent mortality was determined after
24 and 48 h as compared to serum-only controls.
Activity has shown a dependence on aryl group substi-
tution. Compounds with 4- or 3,4-substitution on the
phenyl ring gave the best activity. Lipophilic, electron-
withdrawing groups in the para position generally gave
good activity. Groups such as 4-chloro (9) or 4-CF3 (14)
were active at the 25-50 ppm rate. Better in vitro
activity was seen with the 4-OCF3 (1), 3,4-dichloro (10),
4-bromo (11), 4-OCF2CF2H (23), or their R-methyl
derivatives (28, 29). Electron-donating groups such as
methyl (4) and tert-butyl (6) did not compare favorably
to the most active analogues. Strong electron-with-
drawing groups with lesser lipophilic character such as
cyano (16) or nitro (17) were not as active. Extending
the perfluoroalkyl chain to four carbons (40) did not
improve activity, regardless of the phenyl substitution.
Compound 1 was also tested in an assay (added to
blood during in vitro feeding) and was highly toxic to
buffalo fly (Haematobia irritans exigua) with an LC50
) 2.3 ppm.14 Surprisingly, very little larval blow fly
(Phormia regina) activity was observed with this series.
The flies were fed serum containing titrated levels of
compound as described for stable fly.
Sch em e 2
but primarily the dimethyl compound.13 An improved
method involved reacting 1 with formaldehyde to obtain
the corresponding vinyl compound 42. This was fol-
lowed by reduction with sodium borohydride to give the
desired compound.
The R-chloro compound could not be synthesized by
chlorination of 1. Only the dichloro 41 (Chart 1) was
obtained. However, an R-fluoro derivative (27) was
obtained by electrophilic fluorination with 1-(chloro-
methyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tet-
rafluoroborate).
Compound 42 was used as an intermediate for several
derivatives (35-38). They were afforded by Michael-
type additions to the double bond with various arylthio
groups (Scheme 2). In addition, the R-ethyl (32) and
R-benzyl (33) compounds were obtained in this fashion
by reacting methylmagnesium bromide and phenylmag-
Prior to testing in sheep, anthelmintic activity against
H. contortus was determined using a Mongolian gerbil
(Meriones unguiculatus) model, adapted from the model
previously described by Conder.15 Compounds were
orally gavaged at 25 or 50 mg/kg, and the number of
larvae present in the stomach of each gerbil was
counted. Six compounds had greater than 90% activity
at the 25 mg/kg dose (Table 2) and produced no obvious
signs of toxicity. (Levamisole, administered at 10 mg/
kg, gave 100% reduction of Haemonchus worms.) These
results, as well as respiratory control index (RCI) values

1094 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 7
Wickiser et al.
Ta ble 1
no.
R1
R2
formulaa
mpb (°C)
ASFc (in vitro) (ppm)
1
2
3
4
5
6
7
8
9
4-OCF3
H
3,5-(CF3)2
4-CH3
2,4-Cl2
4-C(CH3)3
4-F
2,6-Cl2
4-Cl
3,4-Cl2
4-Br
3-Cl, 4-F
2-Cl
4-CF3
3-CF3
4-CN
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
C9H6F6O5S2
C8H7F3O4S2
112-114 (I,II)
71-73 (I,III) (e)
110-111 (I)
223-225 (I) (f)
93-95 (I)
25
50
50
C10H5F9O4S2
C9H9F3O4S2
C8H5Cl2F3O4S2
C12H15F3O4S2
C8H6F4O4S2
C8H5Cl2F3O4S2
C8H6ClF3O4S2
C8H5ClF3O4S2
C8H6BrF3O4S2
C8H5ClF4O4S2
C8H6ClF3O4S2
C9H6F6O4S2
>100
>100
>100
100
105-107 (I) (g)
82-84 (I)
77-79 (I)
>100
118-120 (I,II)
129-131 (I,II,III)
130-131 (I,II)
109-111 (I)
101-102 (I)
119-122 (I)
98-100 (I)
134-136 (I)
148-150 (I)
116-118 (I)
95-97 (I)
50
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
>100
25
100
>100
50
C9H6F6O4S2
>100
>100
>100
>100
100
>100
>100
100
C9H6F3NO4S2
C8H6F3NO6S2
C9H9F3O5S2
4-NO2
4-OCH3
4-OSO2CF3
3-Cl, 4-SCF2CF2H
4-SC(CH3)3
4-NHSO2CF3
4-OCF2CF2H
4-SCF2CF2H
4-OH
4-OSO2CH3
4-Cl
4-OCF3
3,4-Cl2
C9H6F6O7S3
C10H6ClF7O4S3
C12H15F3O4S3
C9H7F6NO6S3
C10H7F7O5S2
C10H7F7O4S3
C8H7F3O5S2
126-128 (I)
135-140 (I)
163-165 (I)
122-123 (I)
112-114 (I)
99-101 (I) (h)
111-112 (I)
45-47 (j)
25
>100
>100
>100
H
H
F
C9H9F3O7S3
C8H5ClF4O4S2
C10H8F6O5S2
C9H7Cl2F3O4S2
C9H8ClF3O4S2
C9H8ClF3O4S3
C10H10ClF3O4S2
C15H12ClF3O4S2
C16H10Cl2F6O4S2
C16H11F7O5S3
C17H11F9O6S3
C16H11F7O5S3
C16H11ClF6O5S3
C9H6F6OS2
CH3
CH3
CH3
SCH3
CH2CH3
C6H5CH2
4-CF3C6H4CH2
4-FC6H4SCH2
4-OCF3C6H4SCH2
3-FC6H4SCH2
4-ClC6H4SCH2
H (Chart 1)
H (Chart 1)
R,R-Cl2
81-82 (j)
25
25
50
102-104
4-Cl
4-Cl
4-Cl
4-Cl
112-113
142 dec (II) (j)
72-74 (j)
>100
50
91-92
92 dec (j)
76-77 (IV)
130 dec (IV)
48 dec (IV)
68-69 (IV)
>100
100
50
3,4-Cl2
4-OCF3
4-OCF3
4-OCF3
4-OCF3
4-OCF3
4-OCF3
4-OCF3
50
50
50
>100
C12H6F12O5S2
C9H4Cl2F6O5S2
120-121 (II)
103-104 (I)
25
>100
a
b
Analytical results were within (0.4% of the calculated values for all compounds. Recrystallized from EtOH unless otherwise noted:
(e) hexane, (f) iPrOH, (g) EtOH/H2O, (h) benzene, (j) chromatographed only; (I) Scheme 1, (II) Scheme 1a, (III) Scheme 1b, (IV) Scheme
2. c Lowest concentration (ppm) of compounds in bovine serum vs adult stable fly giving >90% mortality.
(denoting oxidative phosphorylating potential) and stable
fly results, were used to select compounds for sheep
testing.
Ta ble 2
gerbil test
(in vivo)a,b
H. contortus (sheep)
adult stable fly
no.
(% reduction)c
(days of activity)d
The endectocidal activity was determined by admin-
istering the compound intraruminally to parasitized
sheep. Two sheep were each given a single injection of
compound at a dosage of 10 mg/kg of body weight (BW).
Blood samples were collected daily for 14 days post-
treatment. Insecticidal activity against S. calcitrans
was determined by 48-h exposure to posttreatment
serum. Anthelmintic activity was determined by worm
egg counts expressed as eggs per gram of feces (EPG)
and by the number of worms present upon necropsy.
At the 10 mg/kg dose, compound 1 gave 100% control
of H. contortus and insecticidal activity was seen for 10
days posttreatment (Table 2). No adverse effects to the
sheep were observed. It also gave 100% worm reduction
at 5 mg/kg, but activity fell off below that rate. When
1 was administered in a single dose at 10 mg/kg to sheep
1
9
10
14
28
35
100
100
100
100
100
100
100
100
100
100
100
100
10
3
1
0
6
6
a
Expressed as percent reduction of H. contortus worms in
gerbils dosed at 25 mg/kg of BW of compound by single oral gavage
in DMSO/H2O vehicle. Gerbils dosed orally with Levamisole in
b
DMSO/H2O at 25 mg/kg gave 100% reduction of H. contortus.
c Expressed as percent reduction of H. contortus worms in sheep
dosed at 10 mg/kg of BW of compound by single ir injection in
PEG 200 vehicle. Based on total worm counts at necropsy and
compared to average nematode counts in untreated control group.
d
Number of days posttreatment in which >90% mortality of ASF
was seen following exposure of insects to serum from sheep treated
with 10 mg/kg of BW of compound by single ir injection in PEG
200 vehicle.

(Arylsulfonyl)[(trifluoromethyl)sulfonyl]methane
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 7 1095
Ta ble 3
phoric uncouplers have been studied extensively. Im-
portant features include strong electron-withdrawing
groups, acidic protons, and optimal lipophilicity.25-28 For
this series, a pKa between 4 and 6 appeared to be
necessary. Log P values (octanol/water) as an indicator
of lipophilicity ranged from 1.0 to 3.0 for active com-
pounds. The acidity and lipophilicity of 1 (pKa ) 4.1,
log P ) 2.2) appeared to be the best balance for H.
contortus and S. calcitrans activity. Traditional uncou-
plers such as DNP and CCCP have the acidic proton
attached to oxygen or nitrogen. One unique feature of
this series is the acidic proton is attached to carbon. We
presume uncouplers of this type are not common
because of the difficulty of finding structures with very
acidic protons attached to carbon, yet having the
prerequisite lipophilicity.
a
no.
pKa
log Pb
RCI IC50c (µM)
1
6
7
9
4.1
5.1
4.6
4.4
4.0
4.0
6.2
4.6
2.2
2.4
1.3
1.9
1.7
1.0
3.0
1.5
2950
2800
3150
4000
3987
5404
710
10
14
28
DNPd
1000
927
Closantel
a
b
Determined in aqueous solution. Partition coefficient deter-
mined by chromatographic techniques. c Uncoupler concentration
(µM) that reduced the respiratory control index (RCI) by 50% of
coupled rat liver mitochondria. The oxidative phosphorylation
uncouplers 2,4-dinitrophenol (DNP) and Closantel are included
for comparative purposes.
d
To date, compound 1 has been most active against
hematophagous species, probably due to high serum
binding ability. It also has the longest duration of
activity in sheep testing (Table 2). This spectrum of
activity against internal parasites appeared to be
consistent with literature reports of other uncouplers,
such as Rafoxanide and Closantel.29-32
infected with either T. columbriformis or the trematode
F. hepatica, little effect was seen.
A beneficial feature of this series has been the low
level of mammalian toxicity. In sheep, at rates up to
30 mg/kg for compound 1 and 40 mg/kg for other
analogues such as 10, no deaths have occurred and only
minor transient toxicological effects to the host have
been observed. These effects consisted of a slightly
elevated body temperature and an increased respiratory
rate that were seen for 1-2 h immediately posttreat-
ment.
Several other analogues were tested in sheep and
showed activity. The intermediate disulfide 39 was
tested in sheep at 10 mg/kg. This compound gave
similar results to 1. The disulfide presumably was
oxidized to the active compound 1 by the host animal,
as is seen with certain benzimidazole anthelmintics.16
The R-methyl analogue (28) also was quite active at 10
mg/kg. Compounds 9, 10, and 14 gave 100% control of
H. contortus at that rate. The R,R-dichloro analogue
(41) surprisingly gave 95% control of both H. contortus
and stable fly at 10 mg/kg, presumably by in vivo
chlorine reduction, even though it had no in vitro stable
fly activity (Table 1).
Compound 1 was also administered to sheep infected
with an Ivermectin-resistant strain of H. contortus.17
The compound at 10 mg/kg BW effectively removed the
resistant strain of H. contortus and again showed 100%
efficacy against stable fly through day 10 posttreatment.
These data, in addition to the mode of action and the
unique class of chemistry, lead us to believe that this
series will control Ivermectin-resistant Haemonchus.
However, further studies at various rates with a larger
number of sheep would be necessary for verification.
Con clu sion s
These studies have demonstrated that the application
of disulfonylmethanes can be an effective method of
controlling certain internal and external parasites in
domestic animals with a single dose. Future work will
better define other routes of administration, dosing
vehicles, etc., as well as effectiveness in other species
of domestic and companion animals. Several analogues
in this series were active against both fourth larval
stage H. contortus in gerbils and adults in sheep. These
compounds become systemic rapidly and are thought to
bind to serum proteins. This would seem to suggest
they require ingestion by the parasite for significant
activity to occur. This accounts for the activity against
adult stable fly, buffalo fly, and H. contortus. However,
lack of activity against larval blow fly or T. colubriformis
shows the relative narrow therapeutic spectrum of this
class of compounds as compared with currently mar-
keted endectocides.
Exp er im en ta l Section
The benzenethiols and aryl methyl sulfones used as precur-
sors were commercially available, as was chloromethyl tri-
fluoromethyl sulfide. All commercially available chemicals and
solvents were used without further purification. EM Science
silica gel 60 was used for flash chromatography with the
appropriate solvent. Melting points were determined with a
Thomas-Hoover capillary apparatus and are uncorrected. All
new compounds gave satisfactory NMR, elemental analysis,
and mass spectrometry results. NMR chemical shifts are
expressed in δ (ppm) values with tetramethylsilane as the
internal standard. The following instrumentation was used:
Varian Gemini-300 spectrometer, Mattson 3000 FTIR spec-
trometer, VG70SE field desorption mass spectrometer, Control
Equipment Corp. 440 elemental analyzer.
[[4-(Tr iflu or om eth oxy)p h en yl]th io][(tr iflu or om eth yl)-
th io]m eth a n e (39) (Sch em e 1). To a stirred solution of
sodium methoxide (5.6 g, 0.103 mol) in 500 mL of methanol
was added p-(trifluoromethoxy)benzenethiol (20 g, 0.103 mol)
dropwise over 15 min. The reaction mixture was stirred for
30 min, and chloromethyl trifluoromethyl sulfide (17.1 g, 0.114
mol) was added dropwise over 10 min. The reaction mixture
was refluxed for 18 h, poured into 500 mL of H2O, and
Mech a n ism of Action Stu d ies
The mechanism of action of the disulfonylmethanes
is thought to be through the uncoupling of oxidative
phosphorylation. These proton ionophores disrupt mi-
tochondrial pH gradients and the oxidative phosphory-
lation of ADP, thus disrupting energy production.18-21
Several analogues have been evaluated for their ability
to uncouple rat liver mitochondria, as measured by RCI
values. These values were obtained by the methods
described in the literature.22-24 The effects of these
compounds on RCIs indicated uncoupling ability about
one-third as potent as that of 2,4-dinitrophenol (DNP)
(Table 3). The structural requirements for protono-

1096 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 7
Wickiser et al.
1
extracted twice with ether (300 mL). The ether layer was
washed with H2O, dried over MgSO4, and concentrated to give
a yellow oil. The crude oil was purified on silica gel with
hexane eluent to afford 26.3 g (83%) of 39 as a colorless oil:
1H NMR (CHCl3-d1) δ 7.5 (d, 2 ArH), 7.2 (d, 2 ArH), 4.3 (s, 2
CH2). Anal. (C9H6F6OS2) C, H.
[[4-(Tr iflu or om e t h oxy)p h e n yl]su lfon yl][(t r iflu or o-
m eth yl)su lfon yl]m eth a n e (1). To a solution of 39 (26.3 g,
0.085 mol) dissolved in 250 mL of TFA was added 50 mL of
H2O2 (30%) dropwise over 1 h, keeping the temperature below
45 °C. The reaction mixture was stirred overnight at room
temperature. The mixture was slowly heated to 70 °C and
maintained there for a total of 8 h. The reaction mixture was
cooled and poured into 500 mL of ice water. The resulting
precipitate was filtered, washed with H2O, dried, and recrys-
tallized from EtOH to give 26.7 g (84%) of 1 as a white solid:
mp 112-114 °C; 1H NMR (CHCl3-d1) δ 8.1 (d, 2 ArH), 7.45 (d,
2 ArH), 4.85 (s, 2 CH2). Anal. (C9H6F6O5S2) C, H.
[(4-Ch lor op h en yl)su lfon yl][(tr iflu or om eth yl)su lfon yl]-
m eth a n e (9) (Sch em e 1a ). Potassium bis(trimethylsilyl)-
amide (22.0 g, 0.11 mol) was dissolved in THF (200 mL), and
the solution was cooled to 0 °C. To this solution was added
4-chlorophenyl methyl sulfone (10.0 g, 0.0524 mol) as a solid
in one portion. The white suspension was stirred for 20 min
at 0 °C, and N-phenyltrifluoromethanesulfonimide (18.7 g,
0.0524 mol) was added as a solid in one portion. The
suspension that formed was refluxed for 2 h, cooled, filtered,
and rinsed with ether to give the potassium salt of 9 (13.8 g,
0.0382 mol, 73% yield) as a white solid. To obtain the free
acid, the potassium salt (8.00 g, 22.2 mmol) was suspended in
CH2Cl2 (150 mL), concentrated HCl (10 mL) was added in one
portion, and the mixture was stirred for 18 h. The aqueous
layer was separated and extracted with CH2Cl2 (100 mL). The
combined organic extracts were dried, concentrated under
reduced pressure, and recrystallized from EtOH to give 7.1 g
(99%) of 9 as a white solid: mp 118-120 °C; 1H NMR (CHCl3-
d1) δ 8.0 (d, 2 ArH), 7.65 (d, 2 ArH), 4.95 (s, 2 CH2). Anal.
(C8H6ClF3O4S2) C, H.
77; H NMR (CHCl3-d1) δ 8.0 (d, 2 ArH), 7.3-7.5 (m, 4 ArH),
7.1 (d, 2 ArH), 4.6 (t, 1H), 3.6-3.8 (m, 2 CH2). Anal.
(C16H11F7O5S3) C, H.
1-[[4-(Tr iflu or om et h oxy)p h en yl]su lfon yl]-1-[(t r iflu o-
r om eth yl)su lfon yl]eth a n e (28). To a solution of 42 (5.7 g,
0.015 mol) in 150 mL of EtOH was added sodium borohydride
(1.18 g, 0.031 mol) in three portions. The temperature rose
to 35 °C spontaneously, and stirring continued for 4 h. An
additional amount of sodium borohydride was added (200 mg),
and the reaction mixture was stirred overnight at room
temperature. The reaction mixture was filtered, poured into
150 mL of H2O, and acidified and the solid collected. This
material was then purified on silical gel using CH2Cl2 as eluent
1
to give 2.4 g (42%) of 28 as a white solid: mp 81-82 °C; H
NMR (CHCl3-d1) δ 8.1 (d, 2 ArH), 7.5 (d, 2 ArH), 4.7 (q, 1H),
1.9 (d, 3 CH3). Anal. (C10H8F6O5S2) C, H.
[[4-(Tr iflu or om e t h oxy)p h e n yl]su lfon yl][(t r iflu or o-
m eth yl)su lfon yl]d ich lor om eth a n e (41). To a stirred solu-
tion of 1 in 90 mL of acetic acid was added dropwise slowly at
room temperature 20 mL of SO2Cl2 in 5 mL of acetic acid. The
reaction mixture was stirred for 1 h and heated to 70 °C for
12 h. The mixture was poured into 250 mL of H2O, and the
resulting precipitate was collected and recrystallized from
EtOH to give 3.1 g (88%) of 41 as a white solid: mp 103-104
°C; 1H NMR (CHCl3-d1) δ 8.2 (d, 2 ArH), 7.5 (d, 2 ArH). Anal.
(C9H4Cl2F6O5S2) C, H.
[(4-Ch lor op h en yl)su lfon yl][(tr iflu or om eth yl)su lfon yl]-
flu or om eth a n e (27). The potassium salt of 9 (0.107 g, 0.003
mol) was dissolved in acetonitrile (5 mL), and 1-(chloromethyl)-
4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)
(0.120 g, 0.0040 mol) was added as a solid in one portion. The
mixture was stirred for 3 h and concentrated under reduced
pressure. The residue was taken up in ether (50 mL) and
washed with water (2 × 25 mL). The evaporated crude
material was subjected to column chromatography on silica
gel using CH2Cl2 and EtOAc as eluents to give 0.050 g (50%)
of 27 as a white solid: mp 45-47 °C dec; 1H NMR (DMSO-d6)
δ 7.9-8.5 (m, 4H). Anal. (C8H5ClF4O4S2) C, H.
1-[(4-Ch lor op h en yl)su lfon yl]-1-[(tr iflu or om eth yl)su l-
fon yl]p r op a n e (32). P a r t A. To the potassium salt of 9 (0.25
g, 0.0007 mol) in 12 mL of H2O was added 0.25 mL of 37%
formaldehyde, and the mixture stirred for 30 min. The
reaction mixture was acidified to pH 2, extracted with CH2-
Cl2, dried, and evaporated. This material was chromato-
graphed with ether to give 0.11 g of yellow oil which was used
for part B.
(P h en ylsu lfon yl)[(t r iflu or om et h yl)su lfon yl]m et h a n e
(2) (Sch em e 1b). To a solution of potassium triflinate (1.0 g,
0.0058 mol) in 6 mL of CH3CN was added chloromethyl phenyl
sulfide (0.77 g, 0.0048 mol) in one portion, and the reaction
mixture was refluxed for 18 h. The reaction mixture was
poured into 20 mL of H2O and extracted with 20 mL of CH2-
Cl2. The CH2Cl2 was evaporated to give a dark oil, which was
dissolved in 5 mL of acetic acid; 3 mL of H2O2 (30%) was added
dropwise over 10 min, and the solution was then heated to 75
°C for 1 h. The mixture was poured into 20 mL of H2O and
the solid collected, washed with H2O, dried, and recrystallized
from hexane to give 0.52 g (38%) of 2 as a white solid: mp
71-73 °C; 1H NMR (CHCl3-d1) δ 7.4-8.1 (m, 5 ArH), 4.9 (s, 2
CH2). Anal. (C8H7F3O4S2) C, H.
P a r t B. The vinyl compound (0.11 g, 0.328 mmol) was
dissolved in 10 mL of diethyl ether, and to this was added
slowly dropwise (under N2) 0.312 mL of 3.0 M methylmagne-
sium bromide. After 3 h, the reaction mixture was acidified
and the ether layer was evaporated to a sticky yellow solid.
This material was chromatographed with CH2Cl2 as eluent to
1
give 0.067 g (59%) of 32 as a white solid: mp 72-74 °C; H
1-[[4-(Tr iflu or om et h oxy)p h en yl]su lfon yl]-1-[(t r iflu o-
r om eth yl)su lfon yl]eth en e (42) (Sch em e 2). A mixture of
1 (1.0 g, 0.0027 mol) and K2CO3 (0.45 g, 0.0033 mol) was stirred
in 50 mL of H2O for 10 min; then 6 mL of formaldehyde (37%
solution in H2O) was added dropwise. The reaction mixture
was stirred overnight and filtered, the filtrate acidified, and
a gummy solid collected. This material was dissolved in CH2-
Cl2, dried over MgSO4, evaporated to dryness, and purified on
silica gel using EtOAc as eluent. The product obtained was
recrystallized from benzene to afford 0.50 g (49%) of 42 as a
NMR (CHCl3-d1) δ 7.95 (d, 2 ArH), 7.60 (d, 2 ArH), 4.44 (t,
1H), 2.38 (m, 2H), 1.34 (t, 3H). Anal. (C10H10ClF3O4S2) C, H.
[(3,4-Dich lor op h e n yl)t h io][(t r iflu or om e t h yl)t h io]-
m eth a n e (43). This compound was prepared by the general
procedure of Scheme 1 using 3,4-dichlorobenzenethiol (2.0 g,
0.011 mol), sodium methoxide (0.64 g, 0.011 mol), and chlo-
romethyl trifluoromethyl sulfide (2.0 g, 0.013 mol). The
product was purified by chromatography on silica gel using
hexane as the eluent to give 2.6 g (81%) of 43 as a clear oil:
1H NMR (CHCl3-d1) δ 7.6 (s, 1 ArH), 7.45 (d, 1 ArH), 7.3 (d, 1
ArH), 4.3 (s, 2 CH2). Anal. (C8H5Cl2F3S2) C, H.
1
white solid: mp 154-156 °C; H NMR (CHCl3-d1) δ 8.1 (d, 2
ArH), 7.7 (s, 1 H), 7.4 (d, 2 ArH), 7.2 (s, 1 H); FDMS m/z 384
Anal. (C10H6F6O5S2) C, H: calcd, 31.25; found, 30.53.
[(3,4-Dich lor op h en yl)su lfon yl][(tr iflu or om eth yl)th io]-
m eth a n e (44). To a stirred solution of 3,4-dichlorophenyl bis-
(sulfide) (43) (7.0 g, 0.024 mol) in 150 mL of acetic acid was
added slowly dropwise 30% H2O2 (8.1 g, 0.071 mol), keeping
the temperature below 30 °C. The solution was then stirred
for 2 h and heated to 65 °C for 2 h. The reaction mixture was
poured into H2O and filtered, and the resulting solid was
recrystallized from EtOH/H2O to give 5.0 g (65%) of 44 as a
white solid: mp 91-94 °C; 1H NMR (CHCl3-d1) δ 8.1 (s, 1 ArH),
7.8 (d, 2 ArH), 4.3 (s, 2H). Anal. (C8H5Cl2F3O2S2) C, H.
1-[(4-F lu or op h e n yl)t h io]-2-[[4-(t r iflu or om e t h oxy)-
ph en yl]su lfon yl]-2-[(tr iflu or om eth yl)su lfon yl]eth an e (35).
To a solution of 42 (0.500 g, 0.0013 mol) in 25 mL of CH2Cl2
was added dropwise 4-fluorobenzenethiol (0.20 g, 0.0017 mol)
in 5 mL of CH2Cl2. The reaction mixture was stirred for 18 h,
the solvent evaporated, and the crude oil purified on silica gel
using 20% EtOAc in hexane as the eluent. The purest
fractions were combined, stirred in hexane/ether (90/10), and
filtered to give 0.415 g (62%) of 35 as a white solid: mp 76-

(Arylsulfonyl)[(trifluoromethyl)sulfonyl]methane
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 7 1097
1-[(3,4-Dich lor op h en yl)su lfon yl]-1-[(tr iflu or om eth yl)-
su lfon yl]-2-[4-(tr iflu or om eth yl)p h en yl]eth a n e (34). To a
stirred solution of 44 (1.2 g, 0.0037 mol) in 50 mL of DMF
was added slowly 60% NaH (0.160 g, 0.0040 mol) under N2,
and the mixture stirred for 30 min. Then p-(trifluoromethyl)-
benzyl bromide (1.2 g, 0.0050 mol) was added dropwise, and
the mixture stirred for 24 h. The reaction mixture was poured
into 50 mL of H2O and the gummy solid collected and dried.
The product was slurried in hexane to obtain 0.64 g (36%) of
light-yellow solid. This solid was dissolved in 20 mL of TFA,
and 1.4 mL of 30% H2O2 was added slowly. The reaction
mixture was stirred 1 h and heated to 70 °C for 3 h. The
reaction mixture was poured into H2O and the solid collected.
The product was slurried in hexane to afford 0.390 g (57%) of
solution in toluene, 0.004 45 mol) was dropwise added via
syringe. After 2 h at 0 °C, N-phenyltrifluoromethanesulfon-
imide (0.755 g, 0.00211 mol) was added as a solid in one
portion. After an additional 45 min the mixture was allowed
to warm to room temperature. The solvent was removed under
reduced pressure and the residue extracted from water (50 mL)
with CH2Cl2 (2 × 25 mL). The aqueous layer was acidified to
pH 1 and extracted with CH2Cl2 (3 × 25 mL). The evaporated
crude material was subjected to column chromatography on
silica gel using CH2Cl2 and EtOAc as eluents to give 0.306 g
(39%) of 31 as a hygroscopic pale-yellow oil which solidified
1
on standing: mp 142 °C dec; H NMR (acetone-d6) δ 7.94 (d,
2 ArH, J ) 9 Hz), 7.50 (d, 2 ArH, J ) 9 Hz), 2.94 (s, 3H). Anal.
(C9H8ClF3O4S3) C, H.
1
34 as a light-brown solid: mp 92 °C dec; H NMR (CHCl3-d1)
Nem a tod e In fection in Ger bils. Female, Mongolian
gerbils (35 g) (Meriones unguiculatus) were continuously fed
rodent meal containing 2% hydrocortisone for the entire
3-week experimental period. After a 1-week conditioning
period necessary to obtain a nematode infection in a foreign
host, the gerbils were infected with approximately 1000
exsheathed, H. contortus larvae. On day 9 postinfection, three
gerbils were sacrificed to determine the presence of an
adequate infection. Following verification of the presence of
an infection, three gerbils per treatment were orally gavaged
with each compound at 25 or 50 mg/kg. Compounds were
dissolved in either DMSO or water. Three gerbils each were
either treated with levamisole at 10 mg/kg or left untreated
to serve as a positive or negative control. Thirteen days
postinfection, the gerbils were sacrificed and the stomachs
removed. The stomachs were opened longitudinally and the
stomach and the stomach contents placed in a 50-mL conical
tube with saline and vortexed. The contents contained in the
50-mL conical tube were then incubated at 35 °C for at least
1 h. Following incubation, iodine was added to the tubes to
stain the contents and the number of worms per gerbil
determined. Efficacy was determined by comparing the aver-
age number of worms per treatment to the infected, nonmedi-
cated controls and the levamisole controls.
δ 7.95 (s, 1 ArH), 7.6-7.8 (m, 5 ArH), 7.4 (d, 1 ArH), 4.85 (t,
1H), 3.7 (m, 2H). Anal. (C16H10Cl2F6O4S2) C, H.
[(4-Hydr oxyph en yl)su lfon yl][(tr iflu or om eth yl)su lfon yl]-
m eth a n e (25). To a stirred solution of 7 (5.0 g, 0.016 mol) in
200 mL of DMSO was added dropwise KOH (5.0 g, 0.089 mol)
in 5 mL of H2O. The reaction mixture was heated to 130 °C
for 8 h and then stirred overnight at room temperature. The
reaction mixture was cooled, a small amount of H2O (20 mL)
added, the mixture acidified, and the solid filtered. Recrys-
tallization from benzene afforded 3.5 g (70%) of 25 as a white
1
solid: mp 99-101 °C; H NMR (CHCl3-d1) δ 7.8 (d, 2 ArH),
7.0 (d, 2 ArH), 4.8 (s, 2 CH2). Anal. (C8H7F3O5S2) C, H.
[[4-(Te t r a flu or oe t h oxy)p h e n yl]su lfon yl][(t r iflu or o-
m eth yl)su lfon yl]m eth a n e (23). To a solution of 60% NaH
(0.20 g, 0.005 mol) in 20 mL of DMF was added 25 (0.50 g,
0.0016 mol) portionwise. The mixture was stirred for 15 min,
and then tetrafluoroethylene gas was bubbled slowly into the
reaction mixture for 10 min. Stirring continued for 18 h. The
reaction mixture was poured into 50 mL of H2O and acidified,
and the solid was collected. Slurring in hexane gave 0.45 g
(68%) of 23 as a white solid: mp 122-123 °C; 1H NMR (CHCl3-
d1) δ 8.1 (d, 2 ArH), 7.5 (d, 2 ArH), 6.0 (m, 1 CF2H), 4.85 (s, 2
CH2). Anal. (C10H7F7O5S2) C, H.
E xp er im en t a lly In d u ced Nem a t od e In fect ion s in
Sh eep . Cross-bred ewes and wethers, approximately 3-6
months of age and 20-30 kg, were orally challenged (day 0)
with approximately 6000 susceptible third stage larvae of
either H. contortus or T. colubriformis in order to produce
monospecific nematode infections. On the basis of total
baseline fecal egg counts conducted on days 26-28 postinocu-
lation, the lambs were randomly allocated to treatment groups
and placed in individual metabolism crates. The experimental
compounds were dissolved in PEG 200 and administered via
intraruminal injection. Fecal samples were collected daily and
eggs per gram (EPG) determined for each animal. The percent
reduction in egg burden from control and from initial baseline
egg counts was calculated. When eggs counts were reduced
significantly, the sheep were necropsied and total worm counts
(TWC) for H. contortus or T. colubriformis were calculated.
The percent reduction in worm burden from controls was then
calculated as:
[[4-(Tr iflu or om et h oxy)p h en yl]su lfon yl][(p er flu or o-
bu tyl)su lfon yl]m eth a n e (40). To 4-(trifluoromethoxy)phen-
yl methyl sulfone (0.50 g, 0.0021 mol) in 10 mL of THF under
N2 was added dropwise at room temperature 0.5 M potassium
bis(trimethylsilyl)amide in toluene (4.4 mL, 0.0021 mol). The
solution was stirred for 30 min, and then perfluorobutane-
sulfonyl fluoride (0.76 g, 0.0025 mol) in 2 mL of CH2Cl2 was
added slowly. The solution darkened immediately, and stir-
ring continued for 18 h. The mixture was poured into 30 mL
of H2O, acidified to pH 1, and extracted into EtOAc. The
EtOAc layer was washed, dried, and evaporated to give a solid
which was decolorized and recrystallized from iPrOH to give
0.40 g (36%) of 40 as a light-brown solid: mp 120-121 °C; 1H
NMR (CHCl3-d1) δ 8.15 (d, 2 ArH), 7.5 (d, 2 ArH), 4.85 (s, 2
CH2). Anal. (C12H6F12O5S2) C, H.
(Met h ylt h io)m et h yl 4-Ch lor op h en yl Su lfon e (45).
(Methylthio)methyl 4-chlorophenyl sulfone was prepared ac-
cording to the procedure of Ogura (Ogura et al. Bull. Chem.
Soc. J pn. 1983, 56, 3543). Methyl sulfoxide (9.25 g, 0.118 mol)
and acetic anhydride (15.6 g, 0.153 mol) were heated at 80 °C
for 24 h and cooled. Acetic acid (90 mL), sodium acetate (9.70
g, 0.118 mol), and sodium 4-chlorobenzenesulfinate (21.8 g,
0.110 mol) were sequentially added, and the mixture was
heated at 100-120 °C for 24 h. The cooled mixture was
concentrated under reduced pressure, and brine (150 mL) was
added. The mixture was extracted with CH2Cl2 (5 × 75 mL),
and the CH2Cl2 layers were concentrated under reduced
pressure to give 27.8 g of an off-white crystalline solid. The
crystals were suspended in ether (100 mL) and filtered to give
16.2 g (62%) of 45 as a white solid: mp 91.5-94.5 °C; 1H NMR
(DMSO-d6) δ 7.92 (d, 2 ArH, J ) 9 Hz), 7.76 (d, 2 ArH, J ) 9
Hz), 4.52 (2H, s), 2.21(3H, s). Anal. (C8H9ClO2S2) C, H.
TWC(control) - TWC(treated)
× 100
TWC(control)
Ad u lt Sta ble F ly Scr een . Dental wicks were saturated
with serum containing titrated levels of experimental com-
pounds starting at 100 ppm. The dental wicks were placed in
Petri dishes along with 10 adult stable flies (S. calcitrans)
previously chilled for easier handling. Percent mortality was
determined after 24- and 48-h incubation at approximately 25
°C and 75-85% humidity when compared to a dish containing
a wick with control serum only. When determining the
insecticidal activity of compounds after treating sheep, whole
blood drawn from sheep dosed with experimental compounds
was allowed to separate for approximately 24 h. Dental wicks
were soaked in the resulting serum and placed in Petri dishes
with the adult stable flies. Percent mortality was determined
after 24 or 48 h in comparison to a serum-only control.
1-[(4-Ch lor op h en yl)su lfon yl]-1-[(tr iflu or om eth yl)su l-
fon yl](m eth ylth io)m eth a n e (31). Compound 45 (0.50 g,
0.00211 mol) was dissolved in THF (10 mL) and cooled to 0
°C. Potassium bis(trimethylsilyl)amide (8.90 mL of 0.5 M

1098 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 7
Wickiser et al.
(14) Bird, P. E.; Kemp, D. H. CSIRO Laboratories, unpublished
results.
La r va l Blow F ly P r oced u r e. Dental wicks saturated with
bovine serum (collected from whole blood obtained at a local
abattoir) and titrated levels of experimental compounds (start-
ing at 100 ppm) were placed individually in test tubes. Several
hundred larval blow fly (Phormia regina) were placed in each
test tube, and a cotton ball was placed in the top to prevent
them from crawling out of the tube. The tubes were incubated
for up to 48 h at approximately 25 °C and 75-85% humidity.
Efficacy was determined by visual inspection of each tube for
larvae movement, and the data are reported as percent
mortality as compared to a serum-only control.
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Ack n ow led gm en t. We wish to thank Dr. George O.
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