Synthesis and antiallergic activity of dimethyl-2- (phenylcarbamoyl)ethylsulfonium p-toluenesulfonate derivatives

Article abstract of DOI:10.1021/jm970285z

The derivatives of dimethyl-2-(phenylcarbamoyl)ethylsulfonium p- toluenesulfonates were synthesized and evaluated for antiallergic activity. The 2,3-dihydroxyethoxy group was introduced to the phenyl ring from the standpoint of lipophilicity and electronic effects of substituent. The IgE- induced rat passive cutaneous anaphylaxis (PCA) was inhibited by oral administration of several substituted 2-[(4- propoxyphenyl)carbamoyl]ethyldimethylsulfonium p-toluenesulfonate derivatives. Among them (±)-2-[N-[4-(3-ethoxy-2- hydroxypropoxy)phenyl]carbamoyl]ethyldimethylsulfonium p-toluenesulfonate (1a, IPD-1151T) was found to possess considerable activity in the PCA test, and it was launched as Suplatast tosilate in Japan.

Full text of DOI:10.1021/jm970285z

3330
J . Med. Chem. 1998, 41, 3330-3336
Syn th esis a n d An tia ller gic Activity of
Dim eth yl-2-(p h en ylca r ba m oyl)eth ylsu lfon iu m p-Tolu en esu lfon a te Der iva tives
Yukio Tada,*,† Ichiro Yamawaki,† Shuichi Ueda,‡ Hiroshi Matsumoto,‡ Naosuke Matsuura,‡ Mitsugi Yasumoto,†
Akihide Koda,§ and Mikio Hori§
Hanno Research Center, Taiho Pharmaceutical Company, Ltd., 1-27 Misugidai, Hanno, Saitama 357, J apan,
Biological Laboratory, Taiho Pharmaceutical Company, Ltd., Hiraishi, Ebisuno, Kawauchi-cho, Tokushima 771-01, J apan,
and Gifu Pharmaceutical University, 5-6-1, Mitahora-higashi, Gifu 502, J apan
Received April 30, 1997
The derivatives of dimethyl-2-(phenylcarbamoyl)ethylsulfonium p-toluenesulfonates were
synthesized and evaluated for antiallergic activity. The 2,3-dihydroxyethoxy group was
introduced to the phenyl ring from the standpoint of lipophilicity and electronic effects of
substituent. The IgE-induced rat passive cutaneous anaphylaxis (PCA) was inhibited by oral
administration of several substituted 2-[(4-propoxyphenyl)carbamoyl]ethyldimethylsulfonium
p-toluenesulfonate derivatives. Among them (()-2-[N-[4-(3-ethoxy-2-hydroxypropoxy)phenyl]-
carbamoyl]ethyldimethylsulfonium p-toluenesulfonate (1a , IPD-1151T) was found to possess
considerable activity in the PCA test, and it was launched as Suplatast tosilate in J apan.
In tr od u ction
Ch em istr y
The N-substituted 2-carbamoylethyldimethylsulfo-
nium p-toluenesulfonate derivatives (2, 3, 4a -m ) listed
in Tables 1 and 2 were prepared by the general
procedures outlined in Scheme 1. Treatment of methyl
The â2-agonists and steroids have been used as
antiallergy drugs for the treatment of bronchi asthma,
allergic nose catarrh, and nettle rash. Recently, the
release inhibitors of allergic chemical mediators have
come to be widely used. Disodium cromoglycate (DSCG)1
was developed as this type of drug for the first time,
but it is ineffective in oral administration, since it is
poorly absorbed by the gastrointestinal tract.2 Tra-
nilast,3 Ketotifen,4 and Azelastine5 are utilized in the
oral treatment of allergic diseases (Chart 1). These
drugs are considered to inhibit the degranulation of the
mast cell induced by the antigen.
7
3-(methylthio)propionate (7) with 25% aqueous NH3
gave 2-carbamoylethyl methyl sulfide (8). Cyclohexyl-
amine (9) was condensed with 3-(methylthio)propionyl
chloride in the presence of triethylamine to give 2-(cy-
clohexylcarbamoyl)ethyl methyl sulfide (10). Other
N-substituted carbamoylethyl methyl sulfides (12a -m )
were similarly prepared from aniline derivatives (11a -
m ). Methylation of these sulfides (8, 10, 12a -m ) with
methyl p-toluenesulfonate8 afforded N-substituted 2-car-
bamoylethyldimethylsulfonium p-toluenesulfonate de-
rivatives (2, 3, 4a -m ) in good yields. Dimethyl 2-[N-
(4-substituted propoxyphenyl)carbamoyl]ethylsulfonium
p-toluenesulfonate derivatives (1a -f, 5a ,b, 6a -c) listed
in Table 3 were prepared by a variety of synthetic
pathways depicted in Schemes 2 and 3. Nitrobenzene
compounds (15a -f, 19a ,b) were prepared from epichlo-
rohydrins (13, 18b,f). Condensation of epichlorohydrin
(13) with p-nitrophenol in the presence of pyridine as a
catalyst followed by treatment with 5 N KOH gave
glycidyl p-nitrophenyl ether (14a ). Compound 14a was
converted into the 4-(3-alkoxy-2-hydroxypropoxy)ni-
trobenzene compounds (15a ,c-e) by treatment with
appropriate kinds of alcohol. 4-(3-Phenoxy-2-hydroxy-
propoxy)nitrobenzene (15b) and 4-(3-methoxy-2-hydroxy-
propoxy)nitrobenzene (15f) were similarly prepared
from phenyl glycidyl ether (18b) or methyl glycidyl ether
(18f),9 respectively. 4-(2,3-Dialkoxypropoxy)nitroben-
zene compounds (19a ,b) were readily prepared from
15a ,b by treatment with sodium hydride followed by
alkylation with the appropriate alkyl iodide. Reduction
of the nitro compounds (15a -f, 19a ,b) with 10% Pd-
C10 in ethanol afforded aniline compounds (16a -f,
20a ,b). Compounds 16a -f and 20a ,b were condensed
with 3-(methylthio)propionyl chloride in the presence
Type I allergic reaction is caused by the IgE antibody.
Therefore, the drug that specifically inhibits IgE anti-
body formation will be expected to be efficacious for the
fundamental treatment of type I allergic diseases.
We have studied the chemical and biological proper-
ties of sulfonium compounds. The sulfonium moiety has
been mainly considered to mimic the quaternary am-
monium salt in the medical field; however, S-methyl-
methionine was found to have the antiulcer activity as
a novel biological activity of sulfonium compounds for
the first time. Furthermore, when S-methylmethionine
was given to guinea pigs, it appeared to increase the
formation of antibodies to allergen from horse serum.6
Therefore, we expected sulfonium compounds to have
some immunological activities, and we synthesized
various kinds of sulfonium compounds to find a suitable
clinical candidate for the treatment of allergic disorders.
In this paper we describe the syntheses of a series of
dimethyl-2-(phenylcarbamoyl)ethylsulfonium p-toluene-
sulfonates and their evaluation in IgE antibody-medi-
ated passive cutaneous anaphylaxis (PCA) in rats.
† Taiho Pharmaceutical Co., Ltd., Saitama.
‡ Taiho Pharmaceutical Co., Ltd., Tokushima.
§ Gifu Pharmaceutical University.
S0022-2623(97)00285-9 CCC: $15.00 © 1998 American Chemical Society
Published on Web 08/01/1998

Antiallergic Activity of Sulfonium p-Toluenesulfonates
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 18 3331
Ch a r t 1
Sch em e 1a
o-nitrophenol and m-nitrophenol, respectively, followed
by treatment with EtOH, the reduction of nitro group,
and condensation with 3-(methythio)propionyl chloride.
Sulfides (17a ,g,h ) were converted to the 2-acetyl com-
pounds (22a -c) with acetyl chloride, followed by meth-
ylation with methyl p-toluenesulfonate to afford 2-[N-
[(2-acetoxy-3-ethoxypropoxy)phenyl]carbamoyl]ethyl-
dimethyl p-tolueneuslfonates (6a -c).
Resu lts a n d Discu ssion
Dimethyl-2-(phenylcarbamoyl)ethylsulfonium p-tolu-
enesulfonate derivatives were tested for their ability to
inhibit the PCA reaction in rats.11 Among some car-
bamoylethyldimethylsulfonium derivatives (2, 3, 4a ),
phenylcarbamoyl compound 4a was most effective at
100 mg/kg, (ip) in the PCA test (Table 1). Therefore,
compound 4a was chosen as a lead compound.
Table 2 shows the data on various substituted phen-
ylcarbamoyl derivatives designed to investigate elec-
tronic effects of the aryl group.12 At 50 mg/kg, (ip) in
the PCA test, trifluoromethyl (4b), chloro (4d ), and
fluoro (4e) compounds were inactive. On the other
hand, acetyl (4c), carboxymethyl (4f), methyl (4g),
methoxy (4h ), and hydroxy (4i) compounds were more
active than 4a . Compounds with electron-donating
groups such as methyl, methoxy, and hydroxy substit-
uents were preferable for inhibition of the PCA reaction
compared to those with electron-withdrawing groups
such as trifluoromethyl, chloro, and fluoro except for the
acetyl substituent.
On the other hand, compounds with hydrophilic
groups such as carboxymethyl, acetyl, hydroxy, and
methoxy substituents were more effective than those
with hydrophobic groups such as chloro, fluoro, and
trifluoromethyl except for the methyl substituent.
Consequently, the alkoxy substituent was chosen for
further studies; therefore we synthesized the propoxy
(4j) and 2,3-dihydroxypropoxy (4k ) compounds. The
2,3-dihydroxypropoxy substituent is the important moi-
ety of DSCG. Both compounds 4j,k were active, and
compound 4k was more active than 4j at doses of 20
and 50 mg/kg (ip).
To ascertain the biological effects of the hydroxy
substituent attached to the propoxy moiety, the toxicity
of compounds 4j-m was tested. Compound 4j bearing
no hydroxy group had high toxicity, a 2- or 3-hydroxy-
propoxy moiety (4l, 4m ) had reduced toxicity, and a 2,3-
a
(a) 25% aq NH3, rt, 12 h; (b) 3-(methylthio)propionyl chloride,
triethylamine, ether, rt, 3 h; (c) methyl p-toluenesulfonate, CH2Cl2,
rt, 5 days.
of triethylamine to give 2-[N-(4-substituted propoxyphen-
yl)carbamoyl]ethyl methyl sulfides 17a -f and 21a ,b,
respectively. Methylation of sulfides (17a -f, 21a ,b)
with methyl p-toluenesulfonate finally afforded dimeth-
yl-2-[(substituted 4-propoxyphenyl)carbamoyl]ethyl-
sulfonium p-toluenesulfonates (1a -f, 5a ,b) in appropri-
ate yields (Scheme 2).
2-Acetoxy-3-ethoxypropoxy derivatives (6a -c) were
prepared according to the outlined procedures in
Scheme 3. Sulfides (17g,h ) were also similarly pre-
pared from epichlorohydrin (13) by condensation with

3332 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 18
Tada et al.
Sch em e 2a
a
(a) p-Nitrophenol, pyridine, 90 °C, 5 h; (b) KOH, actone-H2O, rt, 2 h; (c) R1OH, H2SO4, 80 °C, 6 h; (d) 10% Pd-C, H2, EtOH, 8 h; (e)
3-(methylthio)propionyl chloride, triethylamine, CH2Cl2, 10 °C, 3 h; (f) methyl p-toluenesulfonate, CH2Cl2, rt, 5 days; (g) R2I, NaH, DMF,
rt, 12 h.
dihydroxypropoxy moiety (4k ) had the lowest toxicity
according to the value of LD5013 (Table 4). These results
suggested that the hydroxy moiety of the propoxy
substituent may have an effect of reducing toxicity.
Although compound 4k had potent activity at intra-
peritoneal administration, it had no suitable activity
after oral administration (Table 2). The sulfonium
moiety and 2,3-dihydroxypropoxy substituent are hy-
drophilic; consequently the low lipophilicity of compound
4k may result in poor absorption. Therefore, lipophilic
groups were introduced into compound 4k on the 2- or
3-hydroxy moiety of propoxy substituent.
Table 3 shows the physical and biological data of 4k
derivatives prepared for the optimization of oral po-
tency. As a measure of the lipophilicity, the substituent
lipophilicity of the substituted propoxy group (πcalcd) was
calculated by CLOGP14 (Table 5). The activity of ethoxy
(1a ) and methoxy (1b) compounds improved with the
increase in lipophilicity, but more lipophilic propoxy (1c)
and butoxy (1d ) compounds reduced their activity. To
confirm these results, more lipophilic cyclohexyloxy (1e)
and phenoxy (1f) derivatives were tested and had little
activity as expected (Figure 1).
1a , but the structural isomers of 6a , ortho derivative
6b and meta derivative 6c, had less activity than
compounds 6a and 1a . Therfore, the para position is
considered to be most favorable for substitution on the
phenyl ring. Consequently, we selected 1a as the
candidate compound for clinical trial, considering 1a
was synthesized easier than 6a .
Compound 1a (IPD-1151T) is a new type of antialler-
gic agent and suppressed IgE synthesis without having
a direct effect on B cells,15,16 the synthesis of interleu-
kin-4 and interleukin-5 in Th2 cells, the expression of
local eosinophilia that is regulated by Th2 cells,18 and
the induction of mast cells.19 Therefore compound 1a
will be used for the fundamental treatment of type I
allergic diseases.
Compound 1a contains a chiral center, the physico-
chemical properties and biological profile of the indi-
vidual enantiomers were investigated, and 1a was
classified into a mixture of racemic compound crystals.18
There were no remarkable differences between 1a and
enantiomers in suppression of the synthesis of inter-
leukin-4 in mouse helper T cells and acute toxicity.20
Therefore compound 1a was selected as an agent for the
treatment of bronchial asthma, atopic dermatitis, and
allergic rhinitis, and it was launched as Suplatast
tosilate in 1995 in J apan.
In the case of 2,3-dialkoxy-substituted compounds,
2,3-dimethoxy (5a ) and more lipophilic 2,3-diethoxy (5b)
compounds were less active than 1a . 2-Acetoxy-3-
ethoxy compound (6a ) had almost the same activity as

Antiallergic Activity of Sulfonium p-Toluenesulfonates
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 18 3333
Sch em e 3a
in CH2Cl2 (100 mL) and added to methyl p-toluenesulfonate
(23.3 g, 0.125 mol). The mixture was stirred for 5 days at room
temperature, and then ether (200 mL) was added. A crystal-
lized solid was collected by filtration and recrystallized from
ethanol-ether to give 36.6 g (29.3%) of 2: mp 114-116 °C;
1H NMR (DMSO-d6) δ 10.13 (2H, s, NH2), 7.43 (2H, d, J ) 7.8
Hz, tosyl H3,5), 7.04 (2H, d, J ) 7.8 Hz, tosyl H2,6), 3.35 (2H, t,
J ) 6.2 Hz, S+CH2), 2.82 (6H, s, (CH3)2S+), 2.62 (2H, t, J )
6.2 Hz, S+CH2CH2), 2.22 (3H, s, tosyl CH3). Anal. (C12H19
NO4S2‚1/4H2O) C, H, N.
-
Meth od B. Syn th esis of 2-[N-(4-(Tr iflu or om eth yl)-
p h en yl)ca r ba m oyl]eth yld im eth ylsu lfon iu m p-Tolu en e-
su lfon a te (4b). 3-(Methylthio)propionyl chloride (13.9 g, 0.10
mol) was added dropwise to a solution of p-(trifluoromethyl)-
aniline (11b) (16.1 g, 0.10 mol) and triethylamine (15.2 g, 0.15
mol) in ether (150 mL) below 10 °C. The mixture was stirred
for 3 h at room temperature and then filtered. The filtrate
was washed successively with 1 N HCl (50 mL), saturated
NaHCO3 (50 mL), and H2O (50 mL). The ethereal layer was
separated, dried (MgSO4), and evaporated. The residue was
dissolved in CH2Cl2 (20 mL), and methyl p-toluenesulfonate
(18.3 g, 0.10 mol) was added to the solution. The mixture was
stirred for 5 days at room temperature, and ether (200 mL)
was added. A crystallized solid was collected by filtration and
recrystallized from ethanol-ether to afford 26.8 g (59.6%) of
4b: mp 164-165 °C; 1H NMR (DMSO-d6) δ 10.20 (1H, s, NH),
7.80 (2H, d, J ) 9.0 Hz, aromatic H2,6), 7.69 (2H, d, J ) 9.0
Hz, aromatic H3,5), 7.46 (2H, d, J ) 7.8 Hz, tosyl H3,5), 7.11
(2H, d, J ) 7.8 Hz, tosyl H2,6), 3.54 (2H, t, J ) 6.2 Hz, S+CH2),
3.03 (2H, t, J ) 6.2 Hz, S+CH2CH2), 2.94 (6H, s, (CH3)2S+),
2.31 (3H, s, tosyl CH3). Anal. (C19H22NO4S2F3) C, H, N.
Method C. Synth esis of (()-2-[N-[4-(3-Eth oxy-2-h ydr oxy-
p r op oxy)p h en yl]ca r ba m oyl]eth yld im eth ylsu lfon iu m p-
Tolu en esu lfon a te (1a ). A mixture of p-nitrophenol (50.0 g,
0.36 mol), epichlorohydrin (13) (31.5 g, 0.34 mol), and pyridine
(3 drops) was stirred for 6 h at 90 °C. The reaction mixture
was concentrated. The residue was dissolved in acetone (200
mL), and 5 N KOH (150 mL) was added to the solution. The
mixture was stirred for 2 h at room temperature, and then
acetone was removed. The residue was extracted with CHCl3
(500 mL). The extracts were washed with water, dried
(MgSO4), and concentrated. The residue was dissolved in
EtOH (300 mL), and H2SO4 (4 drops) was added to the solution.
The reaction mixture was refluxed for 6 h, and then EtOH
was removed. The residue was poured into water (200 mL)
and extracted with CHCl3 (500 mL). The extracts were
washed with water, dried (MgSO4), and concentrated. The
residue was distilled under reduced pressure to give 58.9 g of
the nitro compound (15a ) (bp 180-181 °C/2-3 mmHg).
A
solution of the nitro compound (15a ) (58.9 g, 0.24 mol) in EtOH
(250 mL) along with 10% Pd-C was hydrogenated at room
temperature until 1 equiv of hydrogen had been used (8 h).
The solution was filtered, and the filtrate was concentrated
under reduced pressure to give 47.6 g of aniline compound
(16a ). 3-(Methylthio)propionyl chloride (32.0 g, 0.23 mol) was
added dropwise to a solution of the aniline compound (16a )
(47.6 g, 0.23 mol) and triethylamine (34.8 g, 0.35 mol) in CH2-
Cl2 (350 mL) below 10 °C. The mixture was stirred for 3 h at
room temperature and then filtered. The filtrate was washed
successively with 1 N HCl (150 mL), saturated NaHCO3 (150
mL), and H2O (150 mL). The CH2Cl2 layer was separated,
dried (MgSO4), and evaporated. The residue was dissolved in
CH2Cl2 (50 mL), and methyl p-toluenesulfonate (42.1 g, 0.23
mol) was added to the solution. The mixture was stirred for
5 days at room temperature and was added to ether (500 mL).
A crystallized solid was collected by filtration and was
recrystallized from ethanol-ether to give 63.4 g (37.4%) of
1a : mp 86-87 °C; NMR (DMSO-d6) δ 10.13 (1H, s, NH), 7.51
(2H, d, J ) 9.0 Hz, aromatic H2,6), 7.50 (2H, d, J ) 7.8 Hz,
tosyl H3,5), 7.16 (2H, d, J ) 7.8 Hz, tosyl H2,6), 6.89 (2H, d, J
) 9.0 Hz, aromatic H3,5), 4.43 (1H, broad, OH), 3.88 (3H, broad,
OCH2CH), 3.52 (2H, t, J ) 6.2 Hz, S+CH2), 3.46 (2H, broad,
CH2OEt), 3.43 (2H, q, J ) 7.0 Hz, OCH2CH3), 2.93 (6H, s,
(CH3)2S+), 2.93 (2H, t, J ) 6.2 Hz, S+CH2CH2), 2.28 (3H, s,
a
(a) o,m,p-Nitrophenol, pyridine, 90 °C, 5 h; (b) KOH, acetone-
H2O, rt, 2 h; (c) EtOH, H2SO4, 80 °C, 6 h; (d) 10% Pd-C, H2, EtOH,
8 h; (e) 3-(methylthio)propionyl chloride, triethylamine, CH2Cl2,
10 °C, 3 h; (f) acetyl chloride, pyridine, benzene, 10 °C, 3 h; (g)
methyl p-toluenesulfonate, CH2Cl2, rt, 5 days.
Exp er im en ta l Section
Melting points were determined with a Yamagimoto MP-3
micromelting point apparatus and are uncorrected. 1H NMR
spectra were obtained in DMSO-d6 with Me4Si as internal
standard on a J EOL LMN-FX 100 spectrometer. Analytical
results for compounds followed by elemental symbols are
within (0.4% of theory and were determined on a Perkin-
Elmer model 240 CHN analyzer. Column chromatography
was performed with Merck silica gel 60.
Meth od A. Syn th esis of 2-Ca r ba m oyleth yld im eth yl-
su lfon iu m p-Tolu en esu lfon a te (2). Methyl 3-(methylthio)-
propionate (7) (33.5 g, 0.25 mol) was added to a 25% aqueous
NH3 solution (900 mL), and the mixture was stirred for 12 h
at room temperature. The reaction mixture was extracted
with CHCl3 (500 mL). The extracts were washed with water,
dried (MgSO4), and concentrated. The residue was dissolved

3334 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 18
Tada et al.
Ta ble 1. Physical Properties and Antiallergic Activity of Dimethyl-2-(N-substituted carbamoyl)ethylsulfonium p-Toluenesulfonates
PCA inhibition (%)d
compd
R
formulaa
mp (°C)b
method of prepc
yield (%)
50e
100e
2
3
4a
H
C6H11
C6H5
C12H19NO4S2
C18H29NO4S2
C18H23NO4S2
114-116
187-188
144-146
A
B
B
29
52
66
2.4 ( 0.1 (7)
9.0 ( 0.4 (7)
-8.3 ( 1.4 (7)
13.7 ( 0.7 (8)
17.0 ( 1.8 (8)
27.1 ( 3.6 (7)
a
Elemental analyses for C, H, N were within (0.4% of the calculated values. bRecrystallization solvent was EtOH-ether. c Letters
d
refer to methods of preparation and are described in the Experimental Section. Inhibition (%) ( SD in homologous PCA in rats. The
number of animals is shown in parentheses. e Dose (mg/kg, ip).
Ta ble 2. Physical Properties and Antiallergic Activity of Dimethyl-2-(N-substituted carbamoyl)ethylsulfonium p-Toluenesulfonates
4b-m
PCA inhibition (%)d
compd
R
formulaa
mp (°C)b
method of prepc
yield (%)
20e
50e
4b
4c
4d
4e
4f
4g
4h
4i
CF3
COCH3
Cl
C19H22F3 NO4S2
C20H25NO5S2
C18H22ClNO4S2
164-165
149.5-150.5
155-156
122-123
oil
169-170
119-123
178-180
149-150
oil
B
B
B
B
B
B
B
B
B
B
60
11
45
57
51
48
22
23
64
43
-7.8 ( 0.5 (6)
9.0 ( 0.5 (7)
-0.2 ( 0.1 (8)
4.0 ( 0.6 (7)
14.9 ( 0.9 (7)
18.9 ( 2.6 (7)
-4.4 ( 0.2 (7)
21.9 ( 3.3 (7)
13.8 ( 1.4 (7)
38.7 ( 6.1 (7)
1.4 ( 0.1 (7)f
-10.3 (0.8 (6)
25.1 ( 2.9 (7)
0.3 ( 0.1 (8)
1.2 ( 0.1 (7)
25.5 ( 1.6 (7)
22.0 ( 2.3 (7)
17.4 ( 1.1 (7)
9.7 ( 0.3 (7)
29.8 ( 2.7 (7)
34.9 ( 3.9 (7)
18.6 ( 1.4 (7)f
F
C18H22FNO4S2
CH2COOH
CH3
OCH3
OH
OCH2CH2CH3
OCH2CH(OH)CH2OH
C20H25NO6S2
C19H25NO4S2
C19H25NO5S2
C18H23NO5S2
C21H29NO5S2
C21H29NO7S2
4j
4k
4l
4m
OCH2CH2CH2OH
OCH2CH(OH)CH3
C21H29NO6S2
C21H29NO6S2
oil
oil
B
B
51
59
a-d
See corresponding footnotes of Table 1. e Dose (mg/kg, ip). f At po administration.
Ta ble 3. Physical Properties and Antiallergic Activity of 2-[N-[(2,3-Disubstituted propoxy)phenyl]carbamoyl]ethyldimethylsulfonium
p-Toluenesulfonate Derivatives 1a -f, 5a ,b, and 6a -c
PCA inhibition (%)d
compd
R1
R2
position
formulaa
mp (°C)b
method of prepc yield (%)
20e
50e
1a
1b
1c
1d
1e
1f
5a
5b
6a
6b
6c
CH2CH3
CH3
(CH2)2CH3
(CH2)3CH3
C6H11
C6H5
CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH3
H
H
H
H
H
H
4
4
4
4
4
4
4
4
4
2
3
C23H33NO7S2 86-87
C22H31NO7S2 144-146
C24H35NO7S2 oil
C25H37NO7S2 oil
C27H39NO7S2 oil
C27H33NO7S2 132-133
C23H33NO7S2 88-90
C25H37NO7S2 107-108
C25H35NO8S2 89-91
C25H35NO8S2 oil
C
D
C
C
C
D
E
E
F
37
30
21
35
29
13
33
33
58
45
48
28.9 ( 4.5 (6)
17.7 ( 0.9 (7)
16.3 ( 1.1 (7)
7.9 ( 0.7 (7)
35.5 ( 7.4 (7)
24.8 ( 1.6 (8)
13.8 ( 1.2 (6)
4.4 ( 0.4 (6)
10.2 ( 0.2 (7) -7.4 ( 0.6 (7)
14.4 ( 1.2 (7)
17.9 ( 1.2 (7)
0.1 ( 0.1 (7)
35.1 ( 2.7 (6)
-2.0 ( 0.1 (7)
18.2 ( 1.0 (7)
4.6 ( 0.3 (7)
10.5 ( 1.0 (8)
5.1 ( 0.3 (6)
30.2 ( 3.4 (7)
20.0 ( 1.6 (7)
17.7 ( 1.4 (7)
CH3
CH2CH3
COCH3
COCH3
COCH3
F
F
C25H35NO8S2 oil
a-d
See corresponding footnotes of Table 1. e Dose (mg/kg, po).
tosyl CH3), 1.10 (3H, t, J ) 7.0 Hz, OCH2CH3). Anal. (C23H33
-
pressure to give 47.5 g of the aniline compound (16b).
3-(Methylthio)propionyl chloride (33.4 g, 0.24 mol) was added
dropwise to a solution of the aniline compound (16b) (47.5 g,
0.24 mol) and triethylamine (35.8 g, 0.36 mol) in CH2Cl2 (350
mL) below 10 °C. The mixture was stirred for 2 h at room
temperature and then filtered. The filtrate was washed
successively with 1 N HCl (150 mL), saturated NaHCO3 (150
mL), and water (150 mL). The CH2Cl2 layer was separated,
dried (MgSO4), and evaporated. The residue was dissolved in
CH2Cl2 (50 mL), and methyl p-toluenesulfonate (43.9 g, 0.24
mol) was added to the solution. The mixture was stirred for
5 days at room temperature, and then ether (500 mL) was
added. A crystallized solid was collected by filtration and was
recrystallized from ethanol-ether to give 58.3 g (30%) of 1b:
mp 144-146 °C; NMR (DMSO-d6) δ 10.13 (1H, s, NH), 7.50
NO7S2) C, H, N.
Meth od D. Syn th esis of (()-2-[N-[4-(3-Meth oxy-2-
h yd r oxyp r op oxy )p h e n yl]c a r b a m o yl]e t h y ld im e t h y l-
su lfon iu m p-Tolu en esu lfon a te (1b). A mixture of p-nitro-
phenol (50 g, 0.36 mol), glycidyl methyl ether (18b) (34.8 g,
0.40 mol), and pyridine (3 drops) was stirred for 6 h at 90 °C.
The reaction mixture was extracted with CHCl3 (500 mL). The
extracts were washed successively with 2 N NaOH and water,
dried (MgSO4), and concentrated to give 57.0 g of the nitro
compound (15b) (bp 182-185 °C/3-4 mmHg). A solution of
the nitro compound (15b) (57.0 g, 0.25 mol) in EtOH (250 mL)
along with 10% Pd-C was hydrogenated at room temperature
until 1 equiv of hydrogen had been used (8 h). The solution
was filtered, and the filtrate was concentrated under reduced

Antiallergic Activity of Sulfonium p-Toluenesulfonates
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 18 3335
Ta ble 4. LD50 (ip) in Mice of Dimethyl-2-[N-(4-substituted
propoxyphenyl)carbamoyl]ethylsulfonium p-Toluenesulfonates
Cl2 (150 mL) below 10 °C. The mixture was stirred for 3 h at
room temperature and then filtered. The filtrate was washed
successively with 1 N HCl (150 mL), a saturated NaHCO3
solution (150 mL), and water (150 mL). The CH2Cl2 layer was
separated, dried (MgSO4), and evaporated. The residue was
dissolved in CH2Cl2 (50 mL), and methyl p-toluenesulfonate
(24.2 g, 0.13 mol) was added to the solution. The mixture was
stirred for 5 days at room temperature, and then ether (500
mL) was added. A crystallized solid was collected by filtration
and recrystallized from ethanol-ether to give 33.2 g (33.2%)
of 5b: mp 88-90 °C; NMR (DMSO-d6) δ 10.16 (1H, s, NH),
7.51 (2H, d, J ) 9.0 Hz, aromatic H2,6), 7.50 (2H, d, J ) 7.8
Hz, tosyl H3,5), 7.12 (2H, d, J ) 7.8 Hz, tosyl H2,6), 6.90 (2H, d,
J ) 9.0 Hz, aromatic H3,5), 3.96 (2H, broad, OCH2CH), 3.52
(2H, t, J ) 6.4 Hz, S+CH2), 3.48 (2H, broad, CH2OCH3), 3.47
(1H, m, OCH2CH), 3.36 (3H, s, OCH3), 3.27 (3H, s, OCH3), 2.93
(6H, s, (CH3)2S+), 2.93 (2H, t, J ) 6.4 Hz, S+CH2CH2), 2.28
(3H, s, tosyl CH3). Anal. (C23H33NO7S2) C, H, N.
compd
LD50 (mg/kg)a
4j
4k
4l
97
1040
324
4m
495
a
The value of LD50 was determined in male ddY mice (n ) 5)
by the up-down method described in ref 13.
Ta ble 5. Calculated Lipophilicity (πcalcd) of Substituted
Propoxy Groups
a
compd
propoxy group
πcalcd
4k
1a
1b
1c
1d
1e
1f
OCH2CH(OH)CH2OH
OCH2CH(OH)CH2OCH2CH3
OCH2CH(OH)CH2OCH3
OCH2CH(OH)CH2O(CH2)2CH3
OCH2CH(OH)CH2O(CH2)3CH3
OCH2CH(OH)CH2OC6H11
OCH2CH(OH)CH2OC6H5
-1.78
-0.63
-1.16
-0.10
0.43
Meth od F . Syn th esis of (()-2-[N-[4-(3-Eth oxy-2-a ce-
toxypr opoxy)ph en yl]car bam oyl]eth yldim eth ylsu lfon iu m
p-Tolu en esu lfon a te (6a ). Acetyl chloride (8.27 g, 0.10 mol)
was added dropwise to a solution of 2-[[4-(3-ethoxy-2-hydroxy-
propoxy)phenyl]carbamoyl]ethyl methyl sulfide (17a ) (30.0 g,
0.10 mol) and pyridine (0.13 mol) in benzene (300 mL) below
10 °C. The mixture was stirred for 3 h at room temperature.
The reaction mixture was filtered, and the filtrate was washed
with 3 N HCl (50 mL) twice and water, dried (MgSO4), and
concentrated. The residue was purified by column chroma-
tography on silica gel with ether as an eluent. The appropriate
fractions were combined and concentrated. The residue was
recrystallized from petroleum ether-ether to give 4-[[(2-
acetoxy-3-ethoxypropoxy)phenyl]carbamoyl]ethyl methyl sul-
fide (22c) (26.0 g, 76.4%). A mixture of 22c (26.0 g, 0.07 mol)
and methyl p-toluenesulfonate (54.0 g, 0.29 mol) was stirred
for 5 days at room temperature, and ether (200 mL) was added.
A crystallized solid was collected by filtration and recrystal-
lized from ethanol-ether to give 23.0 g (58.1%) of 6a : mp 89-
91 °C; NMR (DMSO-d6) δ 10.13 (1H, s, NH), 7.52 (2H, d, J )
9.0 Hz, aromatic H2,6), 7.51 (2H, d, J ) 7.8 Hz, tosyl H3,5), 7.12
(2H, d, J ) 7.8 Hz, tosyl H2,6), 6.91 (2H, d, J ) 9.0 Hz, aromatic
0.87
0.88
5a
5b
OCH2CH(OCH3)CH2OCH3
OCH2CH(OCH2CH3)CH2OCH2CH3
0.49
0.57
a
Calculated by CLOGP.
H
3,5), 5.18 (1H, m, OCH2CH), 4.08 (2H, broad, OCH2CH), 3.59
(2H, broad, CH2O), 3.52 (2H, d, J ) 6.4 Hz, S+CH2), 3.45 (2H,
q, J ) 7.1 Hz, OCH2CH3), 2.94 (6H, s, (CH3)2S+), 2.92 (2H, t,
J ) 6.4 Hz, S+CH2CH2), 2.28 (3H, s, tosyl CH3), 2.03 (3H, s,
F igu r e 1. Plot of pcalcd versus PCA inhibition (%) (20 mg/kg,
po).
COCH3), 1.02 (3H, t, J ) 7.1 Hz, OCH2CH3). Anal. (C25H35
NO8S2) C, H, N.
-
(2H, d, J ) 9.0 Hz, aromatic H2,6), 7.49 (2H, d, J ) 7.8 Hz,
tosyl H3,5), 7.12 (2H, d, J ) 7.8 Hz, tosyl H2,6), 6.89 (2H, d, J
) 9.0 Hz, aromatic H3,5), 3.88 (3H, broad, OCH2CH), 3.74 (1H,
broad, OH), 3.52 (2H, t, J ) 6.2 Hz, S+CH2), 3.40 (2H, broad,
CH2OCH3), 3.27 (3H, s, OCH3), 2.93 (6H, s, (CH3)2S+), 2.93
(2H, t, J ) 6.2 Hz, S+CH2CH2), 2.29 (3H, s, tosyl CH3). Anal.
(C22H31NO7S2) C, H, N.
Hom ologou s P a ssive Cu ta n eou s An a p h yla xis (P CA) in
Ra t. Antiserum containing homocytotropic antibody was
obtained from rats that had been immunized with 2,4-
dinitrophenyl-coupled ascaris (DNP-As) mixed with killed
Bordetella pertussis according to Tada et al.21 The antibody
titer of this serum (rat anti-DNP-As serum) was about 1:256
as estimated by the 48-h PCA. The antiserum diluted 20-fold
with 0.9% saline was injected intradermally in 0.1-mL dose
into three sites on the shaved backs of normal rats. The same
dose of physiologic saline was similarly injected into the other
side. After 48 h, the animals were given 1.0 mL of 0.25%
Evans blue solution containing 2.0 mg of antigen intrave-
nously. Thirty minutes later, the animals were sacrificed by
exsanguination, and the skins were removed to measure the
PCA bluing lesion. The amount of the dye was then estimated
colorimetrically after extraction by the method of Harada et
al.22
Meth od E. Syn th esis of (()-2-[N-[4-(2,3-Dim eth oxy-
p r op oxy)p h en yl]ca r ba m oyl]eth yld im eth ylsu lfon iu m p-
Tolu en esu lfon a te (5a ). To a solution of 4-(2-hydroxy-3-
methoxypropoxy)nitrobenzene (15b) (45.4 g, 0.20 mol) in dry
DMF (100 mL) was added NaH (5.5 g, 0.23 mol), and the
reaction mixture was stirred for 2 h at room temperature. To
the mixture was added methyl iodide (28.4 g, 0.20 mol), and
the mixture stirred for 12 h at room temperature. The reaction
mixture was concentrated and extracted with ether (200 mL).
The extracts were washed with water, dried (MgSO4), and
concentrated. The residue was purified by column chroma-
tography on silica gel with CHCl3-ether (4:1) as an eluent.
The appropriate fractions were combined and concentrated to
give 34.0 g of 4-(2,3-dimethoxypropoxy)nitrobenzene (19a ). A
solution of the nitro compound (19a ) (34.0 g, 0.14 mol) in EtOH
(100 mL) along with 1.0 g of 10% Pd/C was hydrogenated at
room temperature until 1 equiv of hydrogen had been used (8
h). The solution was filtered, and the filtrate was concentrated
under reduced pressure to give 28.0 g of the aniline compound
(20a ). 3-(Methylthio)propionyl chloride (18.4 g, 0.13 mol) was
added dropwise to a solution of the aniline compound (20a )
(28.0 g, 0.13 mol) and triethylamine (16.2 g, 0.16 mol) in CH2-
Ack n ow led gm en t. The authors are grateful to Prof.
Tadashi Kataoka and Dr. Hiroshi Shimizu (Gifu Phar-
maceutical University) for useful discussions and valu-
able suggestions.
Su p p or tin g In for m a tion Ava ila ble: Physical property
data and 1H NMR spectral data for 1a -f, 2, 3, 4a -m , 5a ,b,
and 6a -c (8 pages). Ordering information is given on any
current masthead page.

3336 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 18
Tada et al.
(11) Goose, J .; Blair, A. M. J . N. Passive cutaneous anaphylaxis in
the rats, induced with two homologous reaginlike antibody sera,
and its specific inhibition with disodium cromoblycate. Im-
munology 1969, 6, 749.
(12) Topliss, J . Utilization of Operational Schemes for Analogue
Synthesis in Drug Design. J . Med. Chem. 1972, 15, 1006-1011.
(13) Brownlee, K. A.; Hodges, J . L.; Rosedblatt, M. J . The up-and-
down method with small samples. J . Am. Stat. Assoc. 1953, 48,
262-277.
(14) Pomona College Medicinal Chemistry Project, Claremont, CA.
(15) Matsuura, N.; Mori, H.; Nagai, H.; Koda, A. Effects of suplatast
tosilate (IPD-1151T) on antibody formation in mice. Folia
Pharmacol. J pn. 1992, 100, 485-493.
(16) Yanagihara, Y.; Kiniwa, M.; Ikizawa, K.; Yamaya, H.; Shida, T.
Suppression of IgE Production by IPD-1151T (Suplatast Tosi-
Refer en ces
(1) Cox, J . S. G. Disodium cromoglycate (FPL 670)(‘Intal’): A specific
inhibitor of reaginic antibody-antigen mechanisms. Nature
1967, 216, 1328-1329.
(2) Walker, S. R.; Evans, M. E.; Richard, A. J .; Patason J . M. Fate
of [14C]-disodium cromoglycate in man. J . Pharm. Pharmacol.
1972, 24, 525-531.
(3) Koda, A.; Nagai, H.; Watanabe, S.; Yanagihara, Y.; Sakamoto,
K. Inhibition of hypersensitivity reaction by a new drug, N(3′,4′-
dimethoxycinnamoyl)anthanilic acid(N-5′). J . Allergy Clin. Im-
munol. 1976, 57, 396-407.
(4) Martin, U.; Roemer, D. The pharmacological properties of a new
orally active antianaphylactic compound: ketotifen, a benzocy-
clopheptathiophen. Arzneim.-Forsch. 1978, 28, 770-782.
(5) Tasaka, K.; Akagi, M. Anti-allergic properties of a new histamine
antagonist,4-(p-chlorobenezyl)2-[N-methyl-oerhydoazepinyl-(4)]-
1-(2H)-phthalazinone hydrochloride (azelastine). Arzneim.-For-
sch. 1979, 29, 488-493.
(6) Bizyaev, A. I. Effect of methylmethioninesulfonium chloride on
sensitization and healing of skin wounds. In Vitam. U - Prir.,
Svoistva, Primen; Bukin, V. N., Ed.; Nauka: Moscow, USSR,
1973; pp 145-146.
(7) Baxter, R. A.; Spring, F. S. The Application of the Hofmann
Reaction to the Synthesis of Heterocyclic Compounds. Part I.
Synthesis of Alloxazine from Quinoxaline-2: 3-dicarboxylic Acid.
J . Chem. Soc., Perkin Trans. 1 1945, 229-231.
(8) Burness, D. M. Decarboxylation of Thetin Salts. J . Org. Chem.
1959, 24, 849-852.
late),
a New Dimethylsulfonium Agent: (1). Regulation of
Murine IgE Response. J pn. J . Pharmacol. 1993, 61, 23-30.
(17) Yamaya, Y.; Basaki, M.; Togawa, M.; Kojima, M.; Kiniwa, M.;
Matsuura, N. Down-regulation of Th2 cell-mediated murine
peritoneal eosinophilia byantiallergic agents. Life Sci. 1995, 56,
1647-1754.
(18) Konno, S.; Adachi, M.; Sano, K.; Gonogami, Y.; Ikeda, K.;
Okamoto, K.; Takahashi, T. Suppresive effects of IPD-1151T
(suplatast tosilate) on induction of mast cells from normal mouse
splenocytes. Eur. J . Pharmacol. 1994, 259, 15-20.
(19) Ushio, T.; Endo, K.; Yamamoto, K. Physicochemical properties
of suplatasit tosilate racemate and enantiomers. Yakugaku
Zasshi 1996, 116, 866-875.
(9) Kreighbaum, W. E.; Matier, W. L.; Dennis, R. D.; Minielli, J .
L.; Deitchman, D.; Perhach, J . L., J r.; Comer, W. T. Antihyper-
tensive Indole Derivatives of Phenoxyproxypropanolamine with
â-Adrenergic Receptor Antagonist and Vasodilating Activity. J .
Med. Chem. 1980, 23, 285-289.
(10) Smith, T.; Brown, B. The Synthesis of Heterocyclic Compounds
from Aryl Azide. I. Bromo and nitro carbazoles. J . Am. Chem.
Soc. 1951, 73, 2435-2437.
(20) Unpublished results.
(21) Tada, T.; Okamura, K. Regulation of homocytotropic antibody
formation in the rats. J . Immunol. 1971, 106, 1002-1011.
(22) Harada, M.; Takeuchi, T.; Katagiri, K. Characterization of
various types of rat cutaneous anaphylaxis from their drug-
susceptibilities. Dermatologica 1971, 142, 193-201.
J M970285Z