Sulfonimidamide analogs of oncolytic sulfonylureas

Article abstract of DOI:10.1021/jm960673l

A series of sulfonimidamide analogs of the oncolytic diarylsulfonylureas was synthesized and evaluated for (1) in vitro cytotoxicity against CEM cells, (2) in vivo antitumor activity against subaxillary implanted 6C3HED lymphosarcoma, and (3) metabolic breakdown to the o-sulfate of p- chloroaniline. The separated enantiomers of one sulfonimidamide analog displayed very different activities in the in vivo screening model. In general, several analogs demonstrated excellent growth inhibitory activity in the 6C3HED model when dosed orally or intraperitoneally. A correlative structure-activity relationship to the oncolytic sulfonylureas was not apparent.

Full text of DOI:10.1021/jm960673l

1018
J . Med. Chem. 1997, 40, 1018-1025
Su lfon im id a m id e An a logs of On colytic Su lfon ylu r ea s†,1
J ohn E. Toth,* Gerald B. Grindey,‡ William J . Ehlhardt, J ames E. Ray, George B. Boder, J esse R. Bewley,
Kim K. Klingerman, Susan B. Gates, Sharon M. Rinzel, Richard M. Schultz, Leonard C. Weir, and
J ohn F. Worzalla
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285
Received September 26, 1996X
A series of sulfonimidamide analogs of the oncolytic diarylsulfonylureas was synthesized and
evaluated for (1) in vitro cytotoxicity against CEM cells, (2) in vivo antitumor activity against
subaxillary implanted 6C3HED lymphosarcoma, and (3) metabolic breakdown to the o-sulfate
of p-chloroaniline. The separated enantiomers of one sulfonimidamide analog displayed very
different activities in the in vivo screening model. In general, several analogs demonstrated
excellent growth inhibitory activity in the 6C3HED model when dosed orally or intraperito-
neally. A correlative structure-activity relationship to the oncolytic sulfonylureas was not
apparent.
A substantial effort in these laboratories has been
directed to the discovery of oncolytic agents demonstrat-
ing growth inhibitory activities in murine-based solid
tumor models and displaying novel modes of action.2-5
This approach, which relies on the empirical develop-
ment of a structure-activity relationship (SAR), has
been coupled to extensive focused preclinical pharma-
F igu r e 1. Oncolytic diarylsulfonylureas.
cology, metabolism, and toxicology studies and has
provided the foundation for the clinical studies of the
antimetabolite gemcitabine, the antifolates DDATHF
and LY231514, and a lead oncolytic diarylsulfonylurea
LY181984 (Figure 1), from whose study sulofenur was
derived.6
Ch em istr y
The synthesis of sulfonimidamide analogs of the
hypoglycemic agent tolbutamide17,18 and the sulfonyl-
urea herbicides19 has previously been reported. Our
synthetic efforts, which were briefly reported in a recent
publication,20 are detailed here. These sulfonimidamide
analogs listed in Table 1 were synthesized as depicted
in Scheme 1.
The requisite arylsulfinyl chlorides 6 were synthe-
sized by one of the following methods: (A) alkali metal
sulfinate salts 1 were purchased or synthesized by the
reduction of the corresponding sulfonyl chloride;21 these
in turn were converted to the sulfinyl chloride with
excess thionyl chloride;22 (B) treatment of an aryl sulfide
2 or disulfide 3 with sulfuryl chloride;23-25 the sulfides
and disulfides were commercially available or synthe-
sized via the oxidation/Pummerer rearrangement/
alkaline hydrolysis of appropriately substituted thio-
anisoles 426 or via the Newman-Kwart reaction of
appropriately substituted phenols;27 (C) sulfide 2 was
converted to the sulfenyl chloride 528 which was con-
verted, through the sulfenyl isocyanate 7, to the sulfen-
ylurea 8 and oxidized to the sulfinylurea 9.
A noteworthy improvement over procedures previ-
ously published for the synthesis of the key sulfinyl-
ureas 9 involved the conversion of sulfinyl chlorides 6
to sulfinyl isocyanates 7, with silver cyanate in ether,
as detailed by J a¨hnchen and Westphal.29 Simple filtra-
tion of the precipitated silver salts followed by treatment
of the ether solution of the sulfinyl isocyanates 7 with
amine often resulted in the precipitation of analytically
pure sulfinylureas 9. Chlorination of the sulfinylureas
9 with either N-chlorobenzotriazole or tert-butyl hy-
pochlorite provided the intermediate sulfonimidoyl chlo-
rides 10, which were reacted with an excess of an amine
at low temperature in THF. Some primary and second-
ary amines used produced a mixture of the desired
sulfonimidamide analog 11 and a rearranged sulfon-
These diarylsulfonylureas display broad spectrum
antitumor activity against syngeneic and human xe-
nograft tumors carried in mice through a thoroughly
investigated but as yet unidentified mechanism of
action.7,8 Phase I studies of sulofenur defined the dose-
limiting toxicity of this agent as methemoglobenemia
and hemolytic anemia, non-life-threatening toxicities
more commonly associated with aniline metabolism
rather than nonspecific cytotoxicity.9-14 The unpredict-
able onset of these toxicities, however, complicated the
clinical study of sulofenur. Recently published su-
lofenur metabolism studies identified p-chloroaniline
and its o-sulfate 65 as urinary metabolites in mice, rats,
monkeys, and humans, providing direct evidence for the
in vivo liberation of p-chloroaniline from sulofenur.12,14
Recent SAR studies limited to the exploration of the
diaryl domains of the sulfonylurea structure have been
reported.15,16 In approaching the challenge of identify-
ing other clinical candidates, however, our efforts turned
toward the synthesis and study of analogs in which one
of the sulfonamide oxygen atoms had been replaced by
a nitrogen atom. The resulting sulfonimidamide struc-
tures possessed another nitrogen terminus from which
the SAR could be explored, in addition to creating a
stereogenic sulfur center. This paper describes the
synthesis, metabolism, and antitumor activity of sul-
fonimidamide analogs of the oncolytic sulfonylureas.
† Dedicated to the memory of Gerry Grindey.
‡ Deceased November 16, 1993.
X Abstract published in Advance ACS Abstracts, February 15, 1997.
S0022-2623(96)00673-5 CCC: $14.00 © 1997 American Chemical Society

Sulfonimidamide Analogs of Oncolytic Sulfonylureas
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 6 1019
Ta ble 1. In Vitro Cytotoxicity and in Vivo Antitumor Activity of Compounds 13-64
6C3HED
Lymphosarcomab
CEMc
IC50
inhibition µg/mL
molecular
formulaa
daily dose,
mg/kg
%
,
compound
R1
R4
R5
R2
R3
LY181984
sulofenur
13
150e
150
300
300e
150f
50
93
91
0
89
92
95
100
5
8.9d
11.2d
>20
>20
phenyl
p-tolyl
H
H
H
H
H
H
p-Cl-phenyl
p-Cl-phenyl
C13H12Cl1N3O2S1
C14H14Cl1N3O2S1
14
15(-)g
16(+)i
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
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
p-tolyl
p-tolyl
p-tolyl
p-tolyl
p-tolyl
p-tolyl
p-tolyl
p-tolyl
p-tolyl
p-tolyl
p-tolyl
p-tolyl
p-tolyl
p-tolyl
p-tolyl
p-tolyl
p-tolyl
p-tolyl
p-tolyl
p-tolyl
p-tolyl
p-tolyl
p-(AcOCH2)phenyl
p-(HOCH2)phenyl
p-formylphenyl
p-(CO2Me)phenyl
p-(CO2H)phenyl
p-ethylphenyl
p-(t-Bu)phenyl
3,4-dimethylphenyl
3,4-dimethylphenyl
3,5-dimethylphenyl
3,4,5-trimethylphenyl
3,5-dimethyl-4-Cl-phenyl
5-indanyl
H
H
H
H
H
H
acetyl
H
H
H
H
H
p-Cl-phenyl
p-Cl-phenyl
p-Cl-phenyl
p-Cl-phenyl
p-Cl-phenyl
p-Cl-phenyl
p-Cl-phenyl
C14H14Cl1N3O2S1
C14H14Cl1N3O2S1
C16H16Cl1N3O3S1
C15H16Cl1N3O2S1
C17H18Cl1N3O3S1
C19H20Cl1N3O4S1
C21H20Cl1N3O2S1
C15H16Cl1N3O2S1
C16H18Cl1N3O2S1
C16H18Cl1N3O2S1
C16H18Cl1N3O2S1
C22H22Cl1N3O2S1
C17H20Cl1N3O2S1
C17H18Cl1N3O2S1
C17H20Cl1N3O2S1
C18H22Cl1N3O2S1
C20H24Cl1N3O3S1
C22H26Cl1N3O4S1
C18H22Cl1N3O2S1
C16H18Cl1N3O3S1
C17H20Cl1N3O3S1
C20H18Cl1N3O2S1
C16H16Cl1N3O4S1
C14H14Cl1N3O3S1
C14H12Cl1N3O3S1
C15H14Cl1N3O4S1
C14H12Cl1N3O4S1
C15H16Cl1N3O2S1
C17H20ClN3O2S1
C15H16Cl1N3O2S1
C16H18Cl1N3O2S1
C15H16Cl1N3O2S1
C16H18Cl1N3O2S1
C15H15Cl2N3O2S1
C16H16Cl1N3O2S1
C17H18Cl1N3O2S1
C13H11Cl2N3O2S1
C13H11Br1Cl1N3O2S1
C14H11F3Cl1N3O2S1
C14H15N3O2S1
150h
150
300
150e
150
150
300
150
300
150
150
300
300e
300
75
>20
>20
>20
>20
9.6
84
93
98
83
87
83
63
91
87
48
69
45
86
88
53
10
85
60
89
5
methyl
methyl acetyl
methyl acetyl
H
H
methyl methyl
H
H
H
H
H
H
H
acetyl
acetyl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
acetyl
H
5.6
8.7
benzyl
H
methyl p-Cl-phenyl
p-Cl-phenyl
methyl p-Cl-phenyl
>20
>20
>20
13.8
5.3
10.9
10.0
1.4
H
methyl
ethyl
phenethyl
n-propyl
allyl
iso-propyl
n-butyl
n-butyl
n-butyl
iso-butyl
(CH2)2OH
(CH2)3OH
phenyl
H
H
H
H
H
H
H
H
H
H
acetyl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
p-Cl-phenyl
p-Cl-phenyl
p-Cl-phenyl
p-Cl-phenyl
p-Cl-phenyl
p-Cl-phenyl
p-Cl-phenyl
p-Cl-phenyl
p-Cl-phenyl
p-Cl-phenyl
p-Cl-phenyl
p-Cl-phenyl
p-Cl-phenyl
p-Cl-phenyl
p-Cl-phenyl
p-Cl-phenyl
p-Cl-phenyl
p-Cl-phenyl
p-Cl-phenyl
p-Cl-phenyl
p-Cl-phenyl
p-Cl-phenyl
p-Cl-phenyl
p-Cl-phenyl
p-Cl-phenyl
p-Cl-phenyl
p-Cl-phenyl
p-Cl-phenyl
p-Cl-phenyl
phenyl
150
300
300
75
0.4
12.5
2.9
0.7
300e
300
300e
50
>20
>20
7.0
>20
>20
5.6
>20
nd
>20
1.7
>20
16.2
20.0
12.7
6.2
>20
10.8
12.3
10.6
15.2
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
87
99
80
0
75
150f
300
243f
25
H
H
H
H
0
91
11
97
98
77
95
0
86
75
80
89
toxl
0
14
100
2
0
5
11
0
40
12
7
300
4.0j
25e
H
methyl
H
H
H
200
19k
300
150f
150
50
H
5-indanyl
methyl
H
H
H
H
H
H
H
H
H
H
H
H
H
p-chlorophenyl
p-bromophenyl
p-(CF3)phenyl
p-tolyl
p-tolyl
p-tolyl
p-tolyl
p-tolyl
p-tolyl
p-tolyl
150
150
150
300
150
600
300
300
300f
300
300e
300f
300f
H
H
H
H
H
H
H
H
3,4-Cl2phenyl
4-Br-phenyl
4-CF3-phenyl
4-F-phenyl
C14H13Cl2N3O2S
C14H13Br1N2O2S1
C15H14F3N3O2S1
C14H14F1N3O2S1
4-benzyloxyphenyl C21H21N3O3S1
4-hydroxyphenyl
4-methoxyphenyl
4-methylphenyl
n-butyl
C14H15N3O3S1
C15H17N3O3S1
C15H17N3O2S1
C12H19N3O2S1
C12H18Cl1N3O2S1
p-tolyl
p-tolyl
p-tolyl
n-butyl
H
H
H
methyl
p-Cl-phenyl
a
b
Elemental analyses (C, H, N) for all new compounds were within (0.4% of theoretical values. Lowest dose which produced >80%
tumor growth inhibition, or the highest dose tested; dosed po, BID×8 unless otherwise noted. c Concentration which inhibited the growth
of CCRF-CEM cells grown in culture for 72 h to 50% of control growth. See ref 2. e Dosed po, daily×8. f Dosed ip, daily×8. g (-)-Enantiomer
d
h
i
j
k
of 14. At 75 mg/kg, po, BID×8, 100% tumor growth inhibition with 60% lethality. (+)-Enantiomer of 14. Dosed ip, BID×8. Dosed
l
po, days 1, 3, 5, 7. At 25 mg/kg, po, BID×8, 100% lethality.
imidamide 12, the origin of which has been discussed
elsewhere.20 In those cases the yield of the desired
product 11 was increased by conducting the reaction at
low temperature and with excess amine. This synthetic
approach was limited, in general, because the reaction
of 10 with many secondary amines produced only the
rearranged sulfonimidamides 12. Another minor com-
plication associated with this synthetic plan arose
during the chlorination reaction (9 f 10). When R2 or
R3 contained competitively reactive electrophillic sites,
e.g. when R2 ) phenyl, a contaminating ring chlorinated
product was produced.
The sulfonimidamide analogs 11 could be acylated
under standard conditions. Initial acylation usually

1020 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 6
Sch em e 1. General Synthesis of Sulfonimidamidesa
Toth et al.
a
Reagents and conditions: (a) see text; (b) SO2Cl2/CCl4; (c) 1.3 equiv of AgOCN in ether; (d) 1.0 equiv of HNR2R3/ether; (e) CH3CO3H/
THF; (f) 1.05 equiv of tert-butyl hypochlorite/THF; (g) excess HNR4R5.
Sch em e 2. Synthesis of Sulfonimidamide Metabolitesa
Biologica l Eva lu a tion
Our previous experience with the evaluation of sul-
fonylureas8 led us to rely most heavily on the demon-
strated in vivo antitumor activity of these analogs
against the 6C3HED Lymphosarcoma (Gardner) im-
planted in C3H mice. This was augmented by the
determination of the in vitro cytotoxicity against CCRF-
CEM cells. These data are listed in Table 1. Chrono-
logically, 14 was the first analog synthesized and
evaluated. In contrast to the excellent activity of the
sulfonylurea LY181984 in this model, the analogous
sulfonimidamide 14 had lower activity when dosed
orally at comparable doses and schedules (89% inhibi-
tion for 14 at 300 mg/kg, qd×8 vs 93% inhibition for
LY181984 at 150 mg/kg, qd×8). The observation of this
level of activity was encouraging, however, because no
other linkage isomer of sulfonylurea had demonstrated
antitumor activity in this model. Because of the reduced
oral activity, 14 was dosed ip in the model. The
increased activity demonstrated at comparable doses
was accompanied by an increased lethality (1/10 deaths
with 92% inhibition at 150 mg/kg and 6/10 deaths with
98% inhibition at 300 mg/kg, both qd×8-ip vs 0/10
deaths with 89% inhibition at 300 mg/kg, qd×8-po). This
trend was observed within the entire sulfonimidamide
analog series. To investigate the oral absorption of 14
in mice, its plasma level was determined by HPLC after
the administration of a single oral dose in mice (see
Methods). These results are compared to those plasma
levels observed for LY181984 under similar conditions
in Figure 2. This study demonstrated significant phar-
macokinetic differences between 14 and LY181984.
a
Reagents and conditions: (a) K2CO3/aqueous MeOH; (b) MnO2/
THF; (c) NaOH/aqueous THF.
occurred cleanly at the sulfur-bearing nitrogen atom
followed by acylation at the phenyl-bearing nitrogen
atom. Thus acylation of 30 with 1 equiv of acetic
anhydride produced 31 in good yield, while peracylation
produced the analog 32, whose structure was verified
by single-crystal X-ray analysis.30 Chemical resolution
of 14 was effected by the reaction of the corresponding
sulfonimidoyl chloride with (1S,2R)-norephedrine to give
a chromatographically separable mixture of sulfur di-
astereomers. Treatment of the separated diastereomers
with lead tetraacetate provided the enantiomers of 14,
15, and 16. This preparation is detailed in ref 20.
The potential metabolites of 14 were synthesized as
depicted in Scheme 2. Because ceric ammonium nitrate
oxidation of 14 did not yield the desired benzylic-
oxygenated products cleanly, the requisite functionality
was incorporated from 4-(methylthio)benzyl alcohol.26
Alkaline hydrolysis of the acetoxy sulfonimidamide 37
provided the hydroxy-substituted analog 38, the major
plasma metabolite of 14. Oxidation of 38 with manga-
nese dioxide gave the aldehyde 39. Although more
thorough oxidation of the alcohol 38 provided the acid
41, it was more convenient to incorporate the acid
oxidation state from the commercially available disul-
fide, 4,4′-dithiobisbenzoic acid, and synthesize the acid
41 by direct alkaline hydrolysis of the ester 40.
Plasma levels of 14 were ∼10-fold lower than
LY181984 after a comparable oral dose, and the half-
life of 14 was considerably shorter. In addition, a single,
more polar, plasma metabolite of 14 was observed in
concentrations similar to the parent. This study sug-
gested that a twice daily oral dosing protocol might
exhibit increased antitumor activity, and that was
verified by experiment (96% inhibition at 100 mg/kg,
bid×8-po). The observation of the polar metabolite
directed our synthetic effort to compounds 38, 39, and
41, based on the well-documented oxidative metabolism

Sulfonimidamide Analogs of Oncolytic Sulfonylureas
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 6 1021
sulfonimidamide nitrogen atom, as in analog 18, en-
hanced antitumor potency (good antitumor activity at
half the dose of 14). Dimethylation of the sulfonimida-
mide nitrogen atom, as in 23, was unproductive. Other
analogs within the homologous series possessed in-
creased in vitro cytotoxicity, but showed no additional
in vivo antitumor activity enhancement. Phenyl sub-
stitution, as in 36, decreased activity. Acetylation of
the sulfonimidamide nitrogen atom of 14 to produce 17,
while lowering the pKa (from 10.5 for 14 to 5.6 for 17)
also reduced the antitumor activity. Acetylation of the
methyl analog 18 to produce 19 increased the in vitro
cytotoxicity while reducing the antitumor activity. In
region C, the diacetyl analog of 18, 20, and the methyl
analog of 14, 22, also showed reduced antitumor activ-
ity. Further experiments to determine if these region
B and C methyl and acetyl analogs were functioning as
prodrugs were not performed.
F igu r e 2. Plasma levels of 14 (9), its metabolite 38 (b), and
LY181984 (2) in C3H mice, following a single 300 mg/kg po
dose.
The clinical studies of sulofenur had demonstrated
that a significant route of metabolism involved linkage
hydrolysis to release p-chloroaniline. The p-chloro-
aniline could be quantitated by the measurement of its
oxidation product, 2-amino-5-chlorophenyl sulfate 65 in
the urine. Previous work had shown that, in mice, after
oral dosing of various substituted sulfonylureas, the
urinary excretion of 65 correlated to the degree of
methemoglobinemia measured, strongly suggesting,
along with other evidence, that the dose-limiting tox-
icities of sulofenur were caused by the release and
metabolism of p-chloroaniline.14 This mouse model was
extended to the study of this sulfonimidamide series.
While the cleavage of the sulfonylurea linkage to
release p-chloroaniline probably occurs by an enzymatic
mechanism, it should be noted that acid-catalyzed
hydrolysis is also possible. The sulfonamide hydrogen
atom in the sulfonylurea structure is weakly acidic (pKa
≈ 6.1), and at a pH e pKa, the sulfonylurea undergoes
significant hydrolysis. For example, in 2% acetonitrile/
25 mM sodium phosphate buffer at 37 °C, there is
observed about 25% decomposition of sulofenur to form
p-chloroaniline and indan-5-sulfonamide over 24 h at
pH ) 5.8,14 In contrast, these diarylsulfonimidamides
do not undergo detectable hydrolysis in the pH range
of 2-8 over 24 h.32
The metabolic breakdown of five sulfonimidamides,
as characterized by the urinary excretion of 65, is listed
in Table 2 and compared to LY181984 and sulofenur.
For the reasons explained above, the observation of
significant amounts of 65 in the urine of mice treated
with sulfonimidamides was surprising. One must con-
clude that this cleavage results from an enzymatic
process and that this data provides a credible alterna-
tive to the simple chemical hydrolysis mechanism of
diarylsulfonylurea cleavage. Even more intriguing was
the observation that while both enantiomers of 14
appeared to be equally well absorbed, and formed the
major urinary metabolite 41 to an equivalent extent,
that enantiomer 15, possessing antitumor activity,
produced greater than 10-fold more 65 than the anti-
tumor inactive enantiomer (16).
F igu r e 3. Generalized sulfonimidamide.
of the tolyl group.31 The cytotoxicity and antitumor
activity of these analogs is presented in Table 1.
As in the case of sulfonylureas, no correlation between
the in vitro cytotoxicity and the in vivo antitumor
efficacy was observed. In consideration of the limita-
tions (i.e., absorption, distribution, and metabolism) of
an empirical in vivo SAR study, the following observa-
tions relating structure and in vivo antitumor activity
were made. Reference is made to the following regions
of the analog structures as defined in Figure 3.
Compared to the corresponding sulfonylurea
LY181984, the sulfonimidamide 14 was not as well
orally absorbed, exhibited different mouse pharmaco-
kinetics, and could be dosed (either po or ip) at nontoxic
levels that produced significant antitumor activity in
the 6C3HED model. It is interesting to note that the
antitumor activity of the racemate 14 could be ascribed
to the enantiomer 15. The sulofenur analog 49 also
demonstrated good antitumor activity in this model
when dosed ip. It was not active when dosed orally. The
sulfonimidamide analog 38, the primary plasma me-
tabolite of 14, demonstrated excellent antitumor activity
(po) while the corresponding sulfonylurea was inactive
in this model.8 The sulfonimidamide 44 demonstrated
excellent antitumor activity when dosed ip, and in
contrast to most other sulfonimidamide analogs, exhib-
ited significant toxicity (5/8 deaths) when dosed po at
the same level. The corresponding sulfonylurea was
very active when dosed orally.8 Other productive
substitutions in the A region were limited to non-
sterically-demanding alkyl groups and halogen atoms
positioned meta or para to the sulfonimidamide func-
tion, with superior activity associated with para sub-
stitution. In the D region, a para-positioned bromine
or chlorine atom was required for superior activity. To
summarize for regions A and D, there appeared to be
little structural correlation for the preferred route of
administration and the in vivo antitumor activities
between the sulfonylureas and their sulfonimidamide
analogs. The only absolute shared structural feature
was the necessity of a para-substituted aromatic residue
in both the A and D regions.
Discu ssion
The sulfonimidamides exhibit two significantly dif-
ferent molecular properties in comparison to the analo-
gous sulfonylureas. The first is that the sulfonimida-
In region B, the addition of a methyl group to the

1022 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 6
Toth et al.
Ta ble 2. Measurement of Sulfonimidamide Metabolic
gel 60 (230-400 mesh ASTM). All solvents and chemicals
were used as purchased without further purification. tert-
Butyl hypochlorite was obtained from TCI America. Reactions
were run under nitrogen.
Cleavagea
Biologica l Meth od s. In vivo antitumor testing proce-
dures,8 in vitro cytotoxicity procedures,8 and pharmacokinetic
methods12,14 have been described previously.
Met h od A. N-[(4-Met h ylp h en yl)su lfin yl]-N′-(4-ch lo-
r op h en yl)u r ea (9b). A dry 250 mL three-neck round-bottom
flask fitted with a mechanical stirrer, addition funnel, and
nitrogen line was charged with silver cyanate (20.8 g, 138.6
mmol) and 70 mL of ether. This mixture was cooled to 0 °C
and the addition funnel charged with a solution of crude
p-toluenesulfinyl chloride22 (16.95 g, 97.05 mmol) in 70 mL of
ether; the sulfinyl chloride solution was added dropwise to the
cyanate mixture with vigorous stirring over 30 min, keeping
the temperature at 0 °C. After the cooling bath was removed
and the mixture stirred at room temperature for 2 h, the
suspended silver chloride was removed by filtration and the
yellow sulfinyl isocyanate solution was transfered to a dry 1
L three-neck flask. A solution of p-chloroaniline (11.2 g, 87.8
mmol) in 200 mL of ether was added dropwise to the ice-cold
sulfinyl isocyanate solution over 15 min. After the mixture
was warmed to room temperature and stirred overnight, the
resulting solid was collected by filtration and rinsed with 1 L
of ether. Vacuum drying at 40 °C for 4 h gave 20.93 g (77%)
of 9b as a white to light purple solid: mp 163-164 °C; Rf (10/
1, EtOAc/HOAc) ) 0.63; 1H NMR (DMSO-d6) δ 2.38 (s, 3H,
CH3), 7.33 (d, 2H, J ) 8.8, Ar-H), 7.41-7.46 (m, 4H, Ar-H),
7.63 (d, 2H, J ) 8.1, Ar-H), 8.83 (s, 1H, NH), and 9.56 (s, 1H,
SONH); 13C NMR (DMSO-d6) δ 21.3, 120.8, 125.2, 127.0, 129.2,
130.2, 137.9, 141.6, 142.0, and 153.2; IR(KBr) 3274, 3158, 1698,
1247, 1207, 1178, and 1096 cm-1; FDMS(DMSO) m/ e 308, 310
(M+).
N-(In d a n ylsu lfin yl)-N′-(4-ch lor op h en yl)u r ea (9l). In-
dan-5-sulfonyl chloride36 (10.8 g, 50 mmol) in 75 mL of acetone
was treated over 10 min with a solution consisting of NaHSO3
(12.6 g, 100 mmol) and NaHCO3 (8.4 g, 100 mmol) in 150 mL
of water. This mixture was heated at reflux (60 °C) for 1 h,
during which time it became homogeneous. The cooled reac-
tion mixture was washed with CH2Cl2 (1 × 100 mL). Evapo-
ration of the aqueous to dryness under vacuum gave a solid
residue which was extracted with CH3OH (1 × 300 mL). This
extract was filtered and evaporated to a volume of about 50
mL. Addition of 200 mL of ether precipitated a solid which
was collected by filtration. Vacuum drying yielded 10.1 g
(99%) of sodium indan-5-sulfinate: 1H NMR (D2O) δ 2.05 (m,
2H, CH2), 2.88 (m, 4H, 2CH2), 7.4 (m, 2H, 2Ar-H), and 7.5 (s,
1H, Ar-H); FABMS (D2O) m/ e 227 (M+), 205 (M + H - Na)+.
Indan-5-sulfinyl chloride (4.2 g, 21.1 mmol) [prepared from
sodium indan-5-sulfinate (6.1 g, 29.9 mmol) and thionyl
chloride (15 mL, 206 mmol)]22 was reacted, as for 9b , with
silver cyanate (4.4 g, 29.6 mmol) and p-chloroaniline (3.5 g,
27.5 mmol) to provide 4.48 g (45%) of 9l: mp 140-142 °C; Rf
(1/9, MeOH/CHCl3) ) 0.68; 1H NMR (DMSO-d6) δ 2.02-2.1
(m, 2H, CH2), 2.89-2.94 (m, 4H, 2CH2), 7.32-7.49 (m, 6H, Ar-
H), 7.60 (s, 1H, Ar-H), 8.82 (s, 1H, exchanges with D2O, NH),
and 9.53 (s, 1H, exchanges with D2O, NH); IR (KBr) 3425,
3313, 1655, 1547, 1492, 1401, 1089, 820, and 589 cm-1; FDMS
(DMSO) m/ e 334, 336 (M+).
% dose converted to
b
compound
pKa
µmol of 65
65
41
sulofenur
LY181984
14
15(-)
16(+)
18
6.2
6.1
10.5
0.37c
1.02c
<0.2
0.58 ( 0.10
not detected
1.2
4.7 ( 0.8
<0.3
18 ( 1
17 ( 3
12.3
10.8
49
<0.15d
a
Groups of two to four mice were given single 100 mg/kg oral
doses of each compound, and combined urine was collected 0-24
h; the amount of metabolite 65 excreted into the urine in 24 h per
b
mouse was determined as described in ref 14. Determined in
solutions of 2:1 DMF:water. c See ref 14. Limited oral absorption.
d
mides are very weak acids (9 < pKa < 11) while the
sulfonylureas are weak acids (5 < pKa < 7). As a result,
the in vivo distribution of ionized vs un-ionized sulfon-
ylurea could be significantly affected by local compart-
ment pH. Indeed, in vitro studies have characterized
pH-dependent cytotoxicity and accumulation of these
sulfonylureas in the pH range 6.0-7.4, that pH range
within which the concentrations of both the ionized and
un-ionized forms of the sulfonylurea would be expected
to be significant.33-35 In contrast, the sulfonimidamides
would circulate and distribute as neutral species. The
second relative difference is the hydrolytic stability.
Sulfonimidamides, unlike sulfonylureas, would not be
expected to undergo simple chemical hydrolysis in vivo.
Our observations, however, demonstrate that not only
is the product of p-chloroaniline metabolism, 65, ob-
served after dosing of sulfonimidamides but it is formed
in the same relative magnitude as from sulofenur
stereospecifically from one sulfonimidamide enantiomer
(15) of the racemate (14). These data suggest that the
cleavage of p-chloroaniline from the sulfonimidamide
occurs via an enzymatic mechanism similar to that
postulated for the cleavage of the sulfonylureas.14 It is
interesting to note that this same enantiomer (15) also
showed significant 6C3HED antitumor activity, whereas
no activity was observed for the enantiomer (16) which
was not metabolically cleaved. Sulofenur had demon-
strated excellent activity, when dosed orally, against the
human tumor xenografts MX-1, CX-1, LX-1, GC3, and
VRC5 carried in nude mice.7 Two of the more 6C3HED-
active sulfonimidamide analogs, 38 and 44, exhibited
only modest antitumor activity in these models when
dosed by either po or ip routes to toxicity, and for that
reason, the sulfonimidamide series has not been devel-
oped further.
Meth od B. N-[[4-(Acetoxym eth yl)p h en yl]su lfin yl]-N′-
(4-ch lor op h en yl)u r ea (9d ). A solution of the 4-(hydroxy-
methyl)phenyl disulfide37 (2.65 g, 9.52 mmol) in CH2Cl2 (75
mL) was treated with catalytic DMAP under nitrogen followed
by Et3N (4.0 mL, 28.6 mmol) and acetic anhydride (2.24 mL,
23.8 mmol). One hour later, the reaction mixture was washed
with 1 N HCl solution, water, and brine and dried (Na2SO4);
filtration followed by evaporation yielded the crude product,
which was combined with a similarly prepared lot of crude
product [from 1.27 g, 4.56 mmol of 4-(hydroxymethyl)phenyl
disulfide] and purified by silica gel flash chromatography
(ether/hexane) to provide 4.45 g (87%) of 4-(acetoxymethyl)-
Exp er im en ta l Section
Gen er a l P r oced u r e. Melting points were determined with
a Thomas-Hoover capillary melting point apparatus and are
uncorrected. NMR spectra were acquired on a GE QE-300
spectrometer at 300 MHz (proton) and 75 MHz (carbon).
Heteroatom-proton assignments were made on the basis of
D2O exchange. Coupling constants are reported in Hertz. TLC
was performed on silica gel 60 F254 plates from E. Merck.
Flash chromatography was carried out on EM Science silica
1
phenyl disulfide: mp 52-54 °C; Rf (EtOAc) ) 0.69; H NMR
(CDCl3) δ 2.11 (s, 3H, COCH3), 5.08 (s, 2H, ArCH2-OAc), 7.31
(d, 2H, J ) 8.2 Hz, Ar-H), and 7.50 (d, 2H, J ) 8.3 Hz, Ar-H);
IR (CHCl3) 3028, 3013, 1735, 1494, 1380, 1362, 1231, 1210,

Sulfonimidamide Analogs of Oncolytic Sulfonylureas
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 6 1023
Ta ble 3. Physical Properties and Method of Synthesis of Sulfinylureas
substituents
9
R1
R2
R3
methoda
molecular formulab
a
phenyl
p-tolyl
p-tolyl
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
p-Cl-phenyl
p-Cl-phenyl
p-Cl-phenyl
p-Cl-phenyl
p-Cl-phenyl
p-Cl-phenyl
p-Cl-phenyl
p-Cl-phenyl
p-Cl-phenyl
p-Cl-phenyl
p-Cl-phenyl
p-Cl-phenyl
p-Cl-phenyl
p-Cl-phenyl
p-Cl-phenyl
phenyl
3,4-Cl2-phenyl
p-Br-phenyl
p-CF3-phenyl
p-F-phenyl
p-(benzyloxy)phenyl
p-(methoxy)phenyl
p-methylphenyl
n-butyl
Ac
Ac
A
B
B
B
B
B
C
B
B
A
B
B
B
A
A
A
A
A
A
A
A
A
B
C13H11Cl1N2O2S1
C14H13Cl1N2O2S1
C15H15Cl1N2O2S1
C16H15Cl1N2O4S1
C15H13Cl1N2O4S1
C15H15Cl1N2O2S1
C17H19Cl1N2O2S1
C15H15Cl1N2O2S1
C15H15Cl1N2O2S1
C16H17Cl1N2O2S1
C15H14Cl2N2O2S1
C16H15Cl1N2O2S1
C13H11Cl2N3O2S1
C13H11BrCl1N3O2S1
C14H10F3Cl1N2O2S1
C14H14N2O2S1
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
p-(AcOCH2)phenyl
p-(CO2Me)phenyl
p-ethylphenyl
p-(t-Bu)phenyl
3,4-dimethylphenyl
3,5-dimethylphenyl
3,4,5-trimethylphenyl
3,5-dimethyl-4-Cl-phenyl
5-indanyl
p-Cl-phenyl
p-Br-phenyl
p-(CF3)phenyl
p-tolyl
p-tolyl
p-tolyl
p-tolyl
p-tolyl
p-tolyl
p-tolyl
p-tolyl
p-tolyl
C14H12Cl2N2O2S1
C14H13Br1N2O2S1
C15H13F3N2O2S1
s
t
d
C14H13F1N2O2S1
u
v
w
x
y
C21H20N2O3S1
C15H16N2O3S1
C15H16N2O2S1
e
C12H18N2O2S1
n-butyl
p-Cl-phenyl
C11H15Cl1N2O2S1
a
b
Method of preparation of sulfinyl chloride (see text). All compounds gave satisfactory C, H, N analyses. c Commercially available
sodium sulfinate. Characterized by 300 MHz NMR and conversion to 58. e Characterized by 300 MHz NMR and conversion to 63.
d
1028, and 1015 cm-1; FDMS (DMSO) 362 (M+). Anal Calcd
for C18H18O4S2: C, 59.65; H, 5.01. Found: C, 59.90; H, 5.08.
The sulfinyl chloride was prepared from 4-(acetoxymethyl)-
phenyl disulfide by the method of Youn and Herrmann24 and
1712, 1701, 1602, 1550, 1492, 1444, 1052, 832, and 661 cm-1
;
FDMS (DMSO) m/ e 322, 324 (M+).
N-[(3,4,5-Tr im eth ylph en yl)su lfin yl]-N′-(4-ch lor oph en yl)-
u r ea (9j). A three-neck 1000 mL round-bottom flask, fitted
with a mechanical stirrer, thermometer, addition funnel, and
nitrogen purge, was charged with 3,4,5-trimethylphenol (35.80
g, 0.26 mol) and 200 mL of DMF. Sodium hydride (60%
dispersion in mineral oil, 11.60 g, ∼0.29 mol) was cautiously
added in portions with vigorous stirring over 20 min. The
resulting mixture was stirred 30 min under nitrogen. N,N-
Dimethylthiocarbamoyl chloride (39.0 g, 0.3 mol), dissolved in
30mL of DMF, was added dropwise to the sodium trimeth-
ylphenolate mixture, maintaining an internal temperature of
<60 °C. After the addition was complete, the reaction mixture
was heated at 90 °C for 40 min and then cooled to room
temperature. Following dilution with 300 mL of cold water,
the solution was poured into 350 mL of aqueous KOH, stirred
briefly, and placed in the refrigerator for 2 h. The resulting
solid was isolated by filtration, rinsed with 200 mL of water,
and dissolved in ether (500 mL). The organic phase was
washed with water (1 × 100 mL) and brine (1 × 100 mL) and
dried (MgSO4). Filtration and evaporation gave 62 g of crude
product. Recrystallization from 100 mL of MeOH gave 35.8 g
of O-(3,4,5-trimethylphenyl) N,N-dimethylthiocarbamate as a
light yellow solid (61%): mp 90-91 °C; Rf (3/7, EtOAc/hexane)
) 0.45; 1H NMR (CDCl3) δ 2.16 (s, 3H, CH3), 2.30 (s, 6H, 2CH3),
3.33 and 3.46 (s, 6H, NCH3), and 6.74 (s, 2H, Ar-H); IR (CHCl3)
2983, 2871, 1535, 1479, 1398, 1304, 1276, 1217, 1179, 1121,
1026, 924, and 867 cm-1; UV (EtOH) λmax (ꢀ) 205.4 (25 402)
and 250.8 (14 013) nm; FDMS (DMSO) m/ e 223 (M+). Anal
Calcd for C12H17N1O1S1: C, 64.54; H, 7.67; N, 6.27. Found:
C, 64.77; H, 7.87; N, 6.33.
1
used without purification: IR (film) 1750 and 1160 cm-1; H
NMR (CDCl3) δ 2.16 (s, 3H, COCH3), 5.21 (s, 2H, ArCH2-OAc),
7.60 (d, 2H, J ) 8.2 Hz, Ar-H), and 7.89 (d, 2H, J ) 8.3 Hz,
Ar-H).
As in the preparation of 9b, 4-(acetoxymethyl)benzenesulfin-
yl chloride (22.9 mmol), silver cyanate (5.46 g, 36.4 mmol), and
p-chloroaniline (2.92 g, 22.9 mmol) provided, after vacuum
drying at 25 °C, 6.15 g (73.4%) of 9d : mp 131-133 °C; 1H NMR
(DMSO-d6) δ 2.07 (s, 3H, CO-CH3), 5.16 (s, 2H, ArCH2-OAc),
7.34 (d, 2H, J ) 8.8 Hz, Ar-H), 7.44 (d, 2H, J ) 8.8 Hz, Ar-H),
7.59 (d, 2H, J ) 8.1 Hz, Ar-H), 7.75 (d, 2H, J ) 8.1 Hz, Ar-H),
8.84 (s, 1H, exchanges with D2O, N-H), and 9.67 (s, 1H,
exchanges with D2O, N-H); IR (KBr) 3264, 3195, 3130, 1746,
1689, 1668, 1609, 1551, 1495, 1481, 1245, 1225, 1094, 1067,
1028, and 1010 cm-1; FDMS (DMSO) m/ e 366, 368 (M+).
N-[(3,4-Dim eth ylp h en yl)su lfin yl]-N′-(4-ch lor op h en yl)-
u r ea (9h ). According to the method of Youn and Herrmann,23
a solution of 3,4-dimethylthiophenol (4.79 g, 34.7 mmol) in 120
mL of toluene at -60oC was treated with glacial acetic acid
(2.0 mL, 35 mmol), followed by dropwise addition of a solution
of sulfuryl chloride (5.75 mL, 69.4 mmol) in 20 mL of toluene.
The cooling bath was removed, and after 18 h, additional
sulfuryl chloride (2.88 mL, 34.7 mmol) was added to consume
the remaining thiol. Evaporation provided 6.6 g (100%) of the
crude orange sulfinyl chloride: 1H NMR (CDCl3) δ 2.34 (s, 6H,
2CH3), 7.37 (d, 1H, J ) 7.9 Hz, Ar-H), 7.62 (d, 1H, J ) 7.9 Hz,
Ar-H), 7.67 (s, 1H, Ar-H).
As in the preparation of 9b, 3,4-dimethylbenzenesulfinyl
chloride (6.6 g, 34.7 mmol), silver cyanate (6.8g, 45 mmol), and
p-chloroaniline (4.9 g, 38 mmol) gave 9.14 g (82%) of 9h : mp
The O-(3,4,5-trimethylphenyl) N,N-dimethylthiocarbamate
(27.40 g, 0.12 mol) was heated neat under nitrogen to a
temperature of 290 °C; rearrangement to product was conve-
niently monitored by TLC (30% EtOAC/hexane) and was
complete after 4 h. A small sample was purified by silica gel
flash chromatography (3/7, EtOAC/hexane) and recrystallized
1
129-130 °C; Rf (10/10/2, EtOAc/EE/AcOH) ) 0.75; H NMR
(DMSO-d6) δ 2.29 (s, 3H, CH3), 2.30 (s, 3H, CH3), 7.32-7.51
(m, 7H, Ar-H), 8.81 (s, 1H, exchanges with D2O, NH), and 9.52
(s, 1H, exchanges with D2O, NH); IR (KBr) 3427, 3319, 3209,

1024 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 6
Toth et al.
from ether/hexane to provide an analytical sample of S-(3,4,5-
trimethylphenyl) dimethylthiocarbamate: mp 80-81 °C; Rf (3/
7, EtOAc/hexane) ) 0.25; 1H NMR (CDCl3) δ 2.18 (s, 3H, CH3),
2.29 (s, 6H, 2CH3), 3.07 (bs, 6H, NCH3), and 7.16 (s, 2H, Ar-
H); IR (CHCl3) 3011, 2932, 1655, 1474, 1367, 1261, and 1099
cm-1; UV (EtOH) λmax (ꢀ) 212.4 (23 432) nm; FDMS (MeOH)
m/ e 223 (M+). Anal. Calcd for C12H17N1O1S1: C, 64.54; H,
7.67; N, 6.27. Found: C, 64.79; H, 7.71; N, 6.10.
was concentrated in vacuo and the resulting residue dissolved
in 350 mL of EtOAc and washed with 1 N HCl solution (1 ×
100 mL), water (1 × 100 mL), and brine (1 × 50 mL). After
drying (Na2SO4), filtration and evaporation gave a foam (10
g). Trituration with warm toluene (120 mL) followed by
cooling gave a white crystalline product which was collected
by filtration, rinsed with chilled toluene (20 mL), and vacuum-
dried to yield 3.89 g (55%) of the product: mp 79-81 °C; Rf
(1/9, MeOH/ CHCl3) ) 0.69; 1H NMR (DMSO-d6) δ 2.37 (s, 3H,
CH3), 2.40 (d, 3H, J ) 4.9 Hz, NCH3), 7.20 (d, 2H, J ) 8.8 Hz,
Ar-H), 7.40 (d, 2H, J ) 8.1 Hz, Ar-H), 7.47 (d obscuring NH,
3H, J ) 8.8 Hz, 1H exchanges with D2O, Ar-H + NH), 7.72 (d,
2H, J ) 8.2 Hz, Ar-H), and 9.33 (s, 1H, exchanges with D2O,
NH); 13C NMR (DMSO-d6) δ 21.4, 28.1, 120.0, 125.4, 127.7,
128.6, 130.0, 136.3, 140.0, 143.4, and 156.8; IR (KBr) 3357,
1630, 1592, 1526, 1399, 1278, 1232, 1121, 1090, 1082, 1011,
927, 829, 774, and 687 cm-1; UV (EtOH) λmax (ꢀ) 204.6 (37 504),
254.6 (27 729) nm; FDMS (DMSO) m/ e 337, 339 (M+).
The crude S-(3,4,5-trimethylphenyl) dimethylthiocarbamate
(30 g, 0.13 mol) was dissolved in 350 mL of MeOH and 30 mL
of water. Potassium hydroxide (35 g, 0.6 mol) was added, and
the mixture was heated at reflux for 3 h. After the mixture
was cooled and removing the MeOH removed in vacuo, the
residue was diluted with water (500 mL) and washed with
ether (3 × 100 mL). The aqueous layer was acidified with
concentrated HCl and extracted with CH2Cl2 (3 × 100 mL);
the combined organic extract was dried (Na2SO4) and evapo-
rated to yield 16.4 g of an orange oil. Vacuum distillation
provided 13.3 g (72%) of 3,4,5-trimethylthiophenol as a clear
oil: bp 68-70 °C (0.25 mmHg); Rf (3/7, EtOAc/hexane) ) 0.63;
1H NMR (CDCl3) δ 2.13 (s, 3H, CH3), 2.25 (s, 6H, 2CH3), 3.33
(s, 1H, exchanges with D2O, SH), and 6.97 (s, 2H, Ar-H); IR-
(CHCl3) 3010, 2978, 1589, 1475, 1444, 1379, 1196, 886, and
853 cm-1; UV (EtOH) λmax (ꢀ) 212.0 (23 084) and 240.8 (7803)
nm; EIMS (MeOH) m/ e 152 (M+), 137, 119, 91. Anal. Calcd
for C9H12S1: C, 70.99; H, 7.94. Found: C, 70.89; H, 8.08.
The sulfinyl chloride was prepared from 3,4,5-trimethyl-
thiophenol (10 g, 66 mmol) by the method of Youn and
Herrmann23 and used without purification: 1H NMR (CDCl3)
δ 2.28 (s, 3H, CH3), 2.40 (s, 6H, 2CH3), and 7.52 (s, 2H, Ar-H).
As in the preparation of 9b, 3,4,5-trimethylbenzenesulfinyl
chloride (13.3 g, 65.7 mmol), silver cyanate (12.8 g, 85.4 mmol),
and p-chloroaniline (9.2 g, 72 mmol) gave 9.01 g (41%) of 9j:
mp 144-145 °C; Rf (1/9, MeOH/CHCl3) ) 0.66; 1H NMR
(DMSO-d6) δ 2.18 (s, 3H, CH3), 2.31 (s, 6H, 2CH3), 7.33 (d,
2H, J ) 8.8 Hz, Ar-H), 7.36 (s, 2H, Ar-H), 7.43 (d, 2H, J ) 8.8
Hz, Ar-H), 8.81 (bs, 1H, exchanges with D2O, NH), and 9.50
(s, 1H, exchanges with D2O, NH); IR (KBr) 3427, 3314, 1655,
1586, 1492, 1470, 1133, 821, and 618 cm-1; FDMS (DMSO)
m/ e 336, 338 (M+).
Met h od C. N-[(3,5-Dim et h ylp h en yl)su lfin yl]-N′-(4-
ch lor op h en yl)u r ea (9i). As in the preparation of 9b, 3,5-
dimethylbenzenesulfenyl chloride28 (13.9 g, 80.7 mmol), silver
cyanate (16 g, 107 mmol), and p-chloroaniline (12.4 g, 97.2
mmol) provided 10.8 g (46%) of crude 8i. Silica gel flash
chromatography (EtOAc/hexane) afforded 1.92 g (8%) of 8i: mp
180-181 °C; Rf (1/9, MeOH/CHCl3) ) 0.74; 1H NMR (DMSO-
d6) δ 2.22 (s, 6H, 2CH3), 6.79 (s, 1H, Ar-H), 6.80 (s, 2H, Ar-H),
7.29 (d, 2H, J ) 8.8Hz, Ar-H), 7.48 (d, 2H, J ) 8.8Hz, Ar-H),
8.15 (s, 1H, exchanges with D2O, NH), and 9.11 (s, 1H,
exchanges with D2O, NH); IR (KBr) 3268, 1641, 1602, 1551,
1462, 1089, 834, and 681 cm-1; FDMS (DMSO) m/ e 306, 308
(M+). Anal. Calcd for C15H15Cl1N2O1S1: C, 58.72; H, 4.93; N,
9.13. Found: C, 58.45; H, 5.13; N, 9.19.
N-[[(4-Ch lor op h en yl)a m in o]ca r b on yl]-N′-a cet yl-N′,4-
d im eth ylben zen esu lfon im id a m id e (19). A slurry of 18 (5.1
g, 15.1 mmol) in 120 mL of CH2Cl2 was treated with Et3N (4.2
mL, 30 mmol) and DMAP (30 mg, 0.25 mmol), followed by
acetic anhydride (1.62 mL, 16.7 mmol) dropwise. After being
stirried for 1 h, the reaction solution was washed with 1 N
aqueous HCl (1 × 50 mL), water (1 × 50 mL), and brine (1 ×
50 mL); drying (Na2SO4), filtration, and evaporation gave 5.4
g of a white solid. Silica gel flash chromatography (2/3, EtOAc/
hexane) afforded 3.32 g of 19 and a small amount of 20.
Recrystallization from EtOAc/hexane yielded 2.6 g (45%) of
19: mp 150-151 °C; Rf
(1/1, EtOAc/hexanes) ) 0.40; 1H NMR
(DMSO-d6) δ 2.21 (s, 3H, Ar-CH3), 2.41 (s, 3H, OAc), 3.28 (s,
3H, N-CH3), 7.28 (d, 2H, J ) 8.7 Hz, Ar-H), 7.45 (d, 2H, J )
8.1 Hz, Ar-H), 7.54 (d, 2H, J ) 8.7 Hz, Ar-H), 7.98 (d, 2H, J )
8.1 Hz, Ar-H), and 9.74 (s, 1H, exchanges with D2O, NH); IR-
(CHCl3) 3450, 1702, 1664, 1590, 1510, 1399, 1268, and 1121
cm-1; UV (EtOH) λmax (ꢀ) 204.8 (41 076) and 259.0 (24 346) nm;
FDMS (DMSO) m/ e 379, 381 (M+).
N -Ace t yl-N -[[(4-ch lor op h e n yl)a m in o]ca r b on yl]-N ′-
a cetyl-N′,4-d im eth ylben zen esu lfon im id a m id e (20). In a
manner similar to the synthesis of 19, 18 (3.38 g, 10 mmol),
Et3N (7 mL, 50 mmol), DMAP (100 mg, 0.8 mmol), and acetic
anhydride (3.4 mL, 35 mmol) in 75 mL of CH2Cl2 gave a yellow
solid, 3.06 g. Recrystallization from 100 mL of EtOAc/hexane
(3/7) yielded 20 as a white solid, 2.33 g (55%): mp 138-139
°C; Rf (1/1, EtOAc/hexane) ) 0.27; 1H NMR (CDCl3) δ 2.30 (s,
3H, Ar-CH3), 2.41 (s, 3H, OAc), 2.67 (s, 3H, OAc), 3.28 (s, 3H,
N-CH3), 7.17-7.22 (m, 4H, Ar-H), 7.34 (d, 2H, J ) 8.4 Hz, Ar-
H), and 7.45 (d, 2H, J ) 8.6 Hz, Ar-H); IR (CHCl3) 1702, 1492,
1371, 1256, 1149, 1093, 1015 and 926 cm-1; UV (EtOH) λmax
(ꢀ) 203.4 (36 566), 223.6 (23 490), and 238.6 (20 158) nm; FDMS
(DMSO) m/ e 421, 423 (M+).
N-[[(4-Ch lor op h en yl)a m in o]ca r bon yl]-N′,N′-4-tr im eth -
ylben zen esu lfon im id a m id e (23). In a manner similar to
the synthesis of 18, 14 (6.2 g, 20 mmol) was reacted with
N-chlorobenzotriazole (3.2 g, 21 mmol) and dimethylamine (10
mL, 151 mmol) at -20 °C. Recrystallization of the crude
product from 100 mL of warm toluene gave 4.2 g (59%) of 23:
mp 183-184 °C; Rf (1/9, MeOH/CHCl3) ) 0.80; 1H NMR
(DMSO-d6) δ 2.39 (s, 3H, CH3), 2.66 (s, 6H, 2CH3), 7.23 (d, 2H,
J ) 8.8 Hz, Ar-H), 7.44 (d, 2H, J ) 8.2 Hz, Ar-H), 7.51 (d, 2H,
J ) 8.8 Hz, Ar-H), 7.72 (d, 2H, J ) 8.2 Hz, Ar-H), and 9.50
(bs, 1H, exchanges with D2O, NH); IR (KBr) 3285, 1630, 1536,
1284, 1127, and 958 cm-1; UV (EtOH) λmax (ꢀ) 205.0 (37 973),
255.0 (28 328) nm; FDMS (DMSO) m/ e 351, 353 (M+).
N-[[(4-Ch lor op h en yl)a m in o]ca r bon yl]-N′-(2-h yd r oxy-
eth yl)-4-m eth ylben zen esu lfon im id a m id e (34). In a man-
ner similar to the synthesis of 18, 14 (3.08 g, 10.0 mmol),
N-chlorobenzotriazole (1.54 g, 10.0 mmol), and ethanolamine
(1.95 mL, 32.3 mmol) gave 6.0 g of a foam. Purification by
silica gel flash chromatography (EtOAc/hexane) followed by
recrystallization from toluene gave 1.48 g (40%) of 34: mp
112.5-114 °C; Rf (EtOAc) ) 0.43; 1H NMR (DMSO-d6) δ 2.79-
2.88 (m, 2H, CH2N), 3.32 (s, 3H, Ar-CH3), 3.35-3.41 (m, 2H,
CH2OH), 4.70 (t, 1H, J ) 5.5 Hz, exchanges with D2O,
CH2OH), 7.21 (d, 2H, J ) 8.8 Hz, Ar-H), 7.40 (d, 2H, J ) 8.1
Hz, Ar-H), 7.48 (d, 2H, J ) 8.8 Hz, Ar-H), 7.65 (t, 1H, J ) 5.9
A solution of 8i (2.53 g, 8.7 mmol) in 50 mL of THF was
cooled to 0 °C. Peracetic acid (32%, 1.6 mL, 8.6 mmol) was
added dropwise. Two hours later additional peracetic acid (0.2
mL, 1.07 mmol) was added to complete the oxidation. After
the mixture was diluted with 150 mL of water and stirred for
30 min, the solid was collected by filtration and rinsed with
100 mL of water to yield, after drying, 2.16 g (81%) of 9i: mp
114-115 °C; Rf (1/9, MeOH/ CHCl3) ) 0.65; 1H NMR (DMSO-
d6) δ 2.35 (s, 6H, 2CH3), 7.23-7.46 (m, 7H, Ar-H), 8.83 (s, 1H,
exchanges with D2O, NH), and 9.58 (s, 1H, exchanges with
D2O, NH); IR (KBr) 3427, 3313, 1654, 1609, 1550, 1492, 1402,
1136, 1041, 821, and 503 cm-1; FDMS (DMSO) m/ e 322, 324
(M+).
Su lfon im id a m id es. N-[[(4-Ch lor op h en yl)a m in o]ca r -
bon yl]-N′,4-d im eth ylben zen esu lfon im id a m id e (18).
A
flame-dried, 500 mL three-neck round-bottom flask was
charged with 200 mL of dry THF and 9b (6.48 g, 21.0 mmol).
N-Chlorobenzotriazole (3.39 g, 22.07 mmol) was added in one
portion and stirring continued another 25 min. The resulting
solution was added dropwise to 100 mL of methylamine at -78
°C over 10 min. The cooling bath was removed and stirring
continued at room temperature for 3 h. The reaction solution

Sulfonimidamide Analogs of Oncolytic Sulfonylureas
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 6 1025
(11) Brown, T.; O’Rourke, T.; Craig, J .; Havlin, K.; Kuhn, J .; Cagnola,
J .; Hamilton, M.; Grindey, G. B.; Satterlee, W.; Von Hoff, D.
Orally administered LY186641: A phase I clinical and phar-
macologic study on a daily X 21 schedule. Proc. Am. Soc. Clin.
Oncol. 1989, 8, 70.
(12) Ehlhardt, W. J . Metabolism and disposition of the anticancer
agent sulofenur in rat, mouse, monkey and human. Drug Metab.
Dispos. 1991, 19 (2), 370-5.
(13) Ehlhardt, W. J .; Howbert, J . J . Metabolism and disposition of
p-chloroaniline in rat, mouse and monkey. Drug Metab. Dispos.
1991, 19 (2), 366-9.
(14) Ehlhardt, W. J .; Woodland, J . M.; Worzalla, J . F.; Bewley, J . R.;
Grindey, G. B.; Todd, G. C.; Toth, J . E.; Howbert, J . J .
Comparison of metabolism and toxicity to the structure of the
anticancer agent sulofenur and related sulfonylureas. Chem. Res.
Toxicol. 1992, 5 (5), 667-73.
(15) Mohamadi, F.; Spees, M. M.; Grindey, G. B. Sulfonylureas: A
new Class of Cancer Therapeutic Agents. J . Med. Chem. 1992,
35, 3012-16.
(16) Mohamadi, F.; Spees, M. M.; Grindey, G. B. Antineoplastic
Bicyclicsulfonylureas. Bioorg. Med. Chem. Lett. 1992, 2 (9), 987-
92.
Hz, exchanges with D2O, CH2NH), 7.75 (d, 2H, J ) 8.1 Hz,
Ar-H), and 9.33 (s, 1H, exchanges with D2O, NH); IR (CHCl3)
1634, 1591, 1510, 1398, 1305, 1274, 1230, 1123, 1092, 1047
and 830 cm-1; UV (EtOH) λmax (ꢀ) 204 (38 740), 223 (16 076),
255 (28 541), 311.8 (629) nm; FDMS (DMSO) m/ e 367, 369
(M+).
N-[[(4-Ch lor op h en yl)a m in o]ca r bon yl]-N′-p h en yl-4-m e-
th ylben zen esu lfon im id a m id e (36). In a manner similar to
the synthesis of 18, 14 (6.2 g, 20 mmol), N-chlorobenzotriazole
(3.2 g, 21 mmol), and aniline (2.0 g, 21 mmol) gave the crude
36 as a foam (10.6 g). Silica gel flash chromatography (1/9,
MeOH/CHCl3), followed by recrystallization from 75 mL of
warm toluene, gave 4.8 g (59%) of the 36 as a white solid: mp
160-161.5 °C; Rf(1/9, MeOH/CHCl3) ) 0.77; 1H NMR (DMSO-
d6) δ 2.32 (s, 3H, CH3), 7.00-7.26 (m, 7H, Ar-H), 7.35 (d, 2H,
J ) 8.2 Hz, Ar-H), 7.53 (d, 2H, J ) 8.8 Hz, Ar-H), 7.75 (d, 2H,
J ) 8.2 Hz, Ar-H), 9.46 (bs, 1H, exchanges with D2O, NH),
and 10.30 (bs, 1H, exchanges with D2O, NH); 13C NMR
(DMSO-d6) δ 21.3, 120.2, 121.1, 124.5, 125.7, 127.7, 128.8,
129.5, 130.0, 136.9, 137.9, 139.9, 143.8, and 156.2; IR (KBr)
3353, 3166, 1637, 1590, 1495, 1398, 1287, 1214, 1124, and 685
cm-1; UV (EtOH) λmax (ꢀ) 205.8 (44 356), 255.2 (34 798) nm;
FDMS (DMSO) m/ e 399, 401 (M+).
(17) J ohnson, C. R.; J onsson, E. U.; Bacon, C. C. Preparation and
Reactions of Sulfonimidoyl Chlorides. J . Org. Chem. 1979, 44,
2055-61.
(18) J ohnson, C. R.; Wambsgans, A. Sulfonimidoyl Chlorides by
Oxidation of Sulfinamides with tert-Butyl Hypochlorite. J . Org.
Chem. 1979, 44, 2278-80.
(19) Hillemann, C. L. Herbicidal Pyrimidines. US Patent 4,666,506,
1987 (DuPont).
Ack n ow led gm en t. The authors wish to express
their appreciation for the analytical and spectral ser-
vices provided by the Physical Chemistry Department
at the Lilly Research Laboratories and for quantities
of 9b provided by Bennie Foster, Dave Hunden, and
Elizabeth Aaron.
(20) Toth, J . E.; Ray, J .; Deeter, J . Synthesis and Resolution of
Sulfonimidamide Analogs of Sulfonylureas. J . Org. Chem. 1993,
58, 3469-72.
(21) Field, L.; Lee, C. Sulfinic Acids and Related Compounds: 24.
Monothioquinone S,S-Dioxides and Their Relation to Convergent
Syntheses Involving Hydroxyarenesulfonyl Chlorides. J . Org.
Chem. 1990, 55, 2558-63.
(22) Kurzer, F. p-Toluenesulfonyl Chloride. Organic Syntheses; J ohn
Wiley & Sons, Inc.: New York, 1963; Collect. Vol. IV, pp 937-
9.
(23) Youn, J .-H.; Hermann, R. Direct Conversion of Thiols to Sulfinyl
Chlorides by Sulfuryl Chloride. Synthesis 1987, 72-3.
(24) Youn, J .-H.; Hermann, R. A Simple and Efficient Preparation
of Sulfinyl Chlorides from Disulfides and Sulfuryl Chloride.
Tetrahedron Lett. 1986, 27, 1493-4.
Su p p or tin g In for m a tion Ava ila ble: Tables listing final
atomic coordinates for compound 32, equivalent isotropic
displacement parameters, anisotropic displacement param-
eters for non-hydrogen atoms, bond angles, and bond lengths
(9 pages). Ordering information is given on any current
masthead page.
(25) Kee, M.-L.; Douglass, I. B. The Synthesis of Sulfinyl Chlorides.
A Review. Org. Prep. Proc. 1970, 2 (3), 235-44.
(26) Young, R. N.; Gauthier, J . Y.; Coombs, W. The Methyl Group as
A Protecting Group for Arylthiols: A Mild and Efficient Method
for the Conversion of Methyl Aryl Sulfides to Arylthiols.
Tetrahedron Lett. 1984, 25 (17), 1753-56.
Refer en ces
(1) Presented, in part, at the ACCR Special Conference on Novel
Strategies Against Resistant Cancers, November 17-21, 1995,
Ft. Myers, FL. Poster A24.
(2) Grindey G. B. Current Status of Cancer Drug Development:
Failure or Limited Success? Cancer Cells 1990, 2 (6), 163-71.
(3) Grindey, G. B.; Boder, G. B.; Harper, R. W.; Howbert, J . J .; Poore,
G. A.; Reider, B. J .; Shaw, W. N.; Todd, G. C. Identification of
diarylsulfonylureas as novel antitumor agents. Proc. Am. Assoc.
Cancer Res. 1986, 27, 277.
(4) Grindey, G. B.; Boder, G. B.; Grossman, C. S.; Howbert, J . J .;
Poore, G. A.; Shaw, W. N.; Todd, G. C.; Worzalla, J . F. Further
development of diarylsulfonylureas as novel anticancer drugs.
Proc. Am. Assoc. Cancer Res. 1987, 28, 309.
(5) Grindey, G. B. Identification of diarylsulfonylureas as novel
anticancer drugs. Proc. Am. Assoc. Cancer Res. 1988, 29, 535.
(6) Pearce, H. L. Anticancer drug development at Lilly Research
Laboratories. Ann. Oncol. 1995, 6 (Suppl. 1), S55-62.
(7) Howbert, J . J . Sulofenur. Drugs Future 1991, 16 (6), 517-20.
(8) Howbert, J . J .; Grossman, C. S.; Crowell, T. A.; Rieder, B. J .;
Harper, R. W.; Kramer, K. E.; Tao, E. V.; Aikens, J .; Poore, G.
A.; Rinzel, S. M.; Grindey, G. B.; Shaw, W. N.; Todd, G. C. Novel
Agents Against Solid Tumors: The Diarylsulfonylureas. Syn-
thesis, Activities, and Analysis of Quantitative Structure-
Activity Relationships. J . Med. Chem. 1990, 33, 2393-407.
(9) Taylor, C. W.; Alberts, D. S.; Ketcham, M. A.; Satterlee, W. G.;
Holdsworth, M. T.; Plezia, P. M.; Peng, Y.-M.; McCloskey, T. M.;
Roe, D. J .; Hamilton, M. Salmon, S. E. Clinical Pharmacology
of a novel diarylsulfonylurea anticancer agent. J . Clin. Oncol.
1989, 7, 1733-40.
(27) Newman, M. S.; Karnes, H. A. The Conversion of Phenols to
Thiophenols via Dialkylthiocarbamates. J . Org. Chem. 1966, 31,
3980-84.
(28) Harpp, D. N.;Friedlander, B. T.,Smith, R. A. The Synthesis of
Thiocyanates from Sulfenyl Chlorides and Trimethylsilyl Cya-
nide. Synthesis 1979, 181-2.
(29) J a¨hnchen, G.; Westphal, G. Zur Darstellung von p-Toluolsulfi-
nylisocyanat. (The Preparation of p-Toluenesulfinylisocyanate.)
Z. Chem. 1969, 8, 305.
(30) X-ray data has been filed with the Cambridge Crystallographic
Data Center.
(31) Thomas, R. C.; Ikeda, G. J . The metabolism of tolbutamide in
man and in the rat. J . Med. Chem. 1966, 9, 507-10.
(32) William J . Ehlhardt, J ohn E. Toth. Unpublished results.
(33) Tannock, I.; Lee, C.; Thakar, J .; Houghton, P. pH-Dependent
activity of the diarylsulfonylurea N-(5-indanylsulphonyl)-N′-(4-
chlorophenyl)-urea. Cell. Pharmacol. 1995, 2, 193-8.
(34) Sosinski, J .; Chapin, C.; Thakar, J . H.; Houghton, P. J . Influence
of Extracellular pH on the Accumulation and Cytotoxicity of
N-(4-Methylphenylsulfonyl)-N′-(4-chlorophenyl)urea in Human
Cell Lines. Cancer Commun. 1991, 3 (12), 373-81.
(35) Rockwell S.; Grindey, G. B. Diarylsulfonylureas and Radio-
therapy I. In Vitro Studies with N-(5-Indanylsulfonyl)-N′-(4-
chlorophenyl)-urea (Sulofenur). Cancer Commun. 1991, 3 (4),
103-8.
(36) Tao, E. V.; Aikens, J . Indane sulfonyl chloride: Eur. Pat. Appl.
EP 254,577, 1988.
(37) Grice, R.; Owen, L. N. Cytotoxic Compounds. Part IV. Substi-
tuted Benzyl Halides. J . Chem. Soc. 1963, 1947-54.
(10) Hainsworth, J . D.; Hande, K. R.; Satterlee, W. G.; Kuttesch, J .;
J ohnson, D. H.; Grindey, G. B.; J ackson, L. E.; Greco, F. A. Phase
I Clinical Study of N-[(4-chlorophenyl)-amino]carbonyl-2,3-di-
hydro-1H-indene-5-sulfonamide (LY186641). Cancer Res. 1989,
49, 5217-20.
J M960673L