COX-1/COX-2 inhibitors based on the methanone moiety

Article abstract of DOI:10.1016/S0223-5234(01)01330-7

This paper focuses on the synthesis and the in vitro testing of dual COX-1/COX-2 inhibitors. Starting from structures of non-steroidal anti-inflammatory drugs (NSAIDs) the diaryl methanone element was chosen as a lead. Modifications were carried out on this scaffold to obtain potent inhibitors of the COX enzymes. The N-(2-aroylphenyl)sulphonamides and -amides were studied in detail, and to consolidate the data evaluated the corresponding 3- and 4-regioisomers were also investigated. The potency and the enzyme selectivity were varied by structural modifications of the lead.

Full text of DOI:10.1016/S0223-5234(01)01330-7

Eur. J. Med. Chem. 37 (2002) 147–161
Original article
COX-1/COX-2 inhibitors based on the methanone moiety
Gerd Dannhardt a,*, Bernd L. Fiebich b, Johannes Schweppenha¨user a
a Institute of Pharmacy, Fachbereich Chemie und Pharmazie, Johannes Gutenberg, Uni6ersity of Mainz, Staudingerweg 5,
D-55099 Mainz, Germany
b Department of Psychiatry and Psychotherapy, Albert-Ludwigs-Uni6ersity, D-79104 Freiburg, Germany
Received 17 July 2001; received in revised form 5 December 2001; accepted 6 December 2001
Abstract
This paper focuses on the synthesis and the in vitro testing of dual COX-1/COX-2 inhibitors. Starting from structures of
non-steroidal anti-inflammatory drugs (NSAIDs) the diaryl methanone element was chosen as a lead. Modifications were carried
out on this scaffold to obtain potent inhibitors of the COX enzymes. The N-(2-aroylphenyl)sulphonamides and -amides were
studied in detail, and to consolidate the data evaluated the corresponding 3- and 4-regioisomers were also investigated. The
´
potency and the enzyme selectivity were varied by structural modifications of the lead. © 2002 Published by Editions scientifiques
et me´dicales Elsevier SAS.
Keywords: N-(Aroylphenyl)amides and -sulphonamides; COX-1/COX-2 inhibition; Structure–activity relationships
1. Introduction
a lead for NS-398 and flosulide. Diarylmethanones such
as ketoprofen, tiaprofenic acid, tolmetine, and ketoro-
lac are used in the therapy of inflammation.
The objective of this study was to correlate the
structural parameters with the inhibitory potency and
the enzyme selectivity, i.e. to evaluate the significance of
Prostaglandins are important biological mediators of
inflammation, originating from biotransformation of
arachidonic acid catalysed by cyclooxygenase [1]. In
spite of some adverse side effects [2,3], cyclooxygenase
inhibitors are the drugs to suppress inflammatory pro-
cesses. Two isoenzymes of cyclooxygenase have been
identified: COX-1 and COX-2 [4,5]. Selective inhibition
of COX-2 [6] or dual inhibition of COX-1 and COX-2
[7] is under discussion as a promising principle in the
treatment of inflammatory diseases. For several rea-
sons, including increased cardiovascular risks, the im-
portant role of COX-2 produced prostaglandins in the
response of the mucosa to irritants and in healing and
other critical aspects the accuracy of selective COX-2
inhibition as the principle tenet is under debate [8–10].
A number of substituted sulphonamides are known
as anti-inflammatory agents (Fig. 1) [11–13]. The first
substances were diflumidone and nimesulide, which was
* Correspondence and reprints.
E-mail address: dannhrdt@mail.uni-mainz.de (G. Dannhardt).
Fig. 1. Structures of COX-inhibitors.
´
0223-5234/02/$ - see front matter © 2002 Published by Editions scientifiques et me´dicales Elsevier SAS.
PII: S0223-5234(01)01330-7

148
G. Dannhardt et al. / European Journal of Medicinal Chemistry 37 (2002) 147–161
Table 1
the aryl substituents, of the carbonyl-moiety as the
linking element, the impact of the sulphonamide and
the amide group, and the contribution of the functional
moiety at different positions on the phenyl ring. In this
context, we also studied the meaning of the rotation
phenomena of the two aromatic rings (Fig. 2).
The compounds were tested in vitro to evaluate their
COX-1/COX-2 inhibitory activity.
N-(Aroylphenyl)sulphonamides and -amides
Compound
R
R%
RCO-position
2. Chemistry
1a
1b
1c
1d
1e
2a
2b
2c
2d
2e
ph
CH3
CH3
CH3
CH3
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
3
3
3
4
4
4
2
2
2
2
2
2
2
3
3
3
4
4
4
4-CH3ꢀph
4-CH3ꢀSꢀph
4-phꢀph
4-tert-butylꢀph CH3
ph
ph
ph
ph
ph
ph
ph
ph
4-CH3ꢀph
The compounds, synthesised are summarised in
Table 1 and Fig. 3.
The synthesis of the N-(aroylphenyl)sulphonamides
and -amides 1a, 2a–h, 5, 6a–b, 7, 2a–b, 9, 10a–c,
12a–c, 13a–c started with commercially available
amines and sulphonyl chlorides or carbonyl chlorides.
Adapted to procedures described by Walsh [14] and
Miyachi et al. [15], 2-aminobenzoic acid with methane-
sulphonyl chloride in aqueous sodium carbonate gave
rise to 2-methylsulphonylamido benzoic acid which was
transformed to the chloride and subsequently by
Friedel-Crafts acylation to N-(aroylphenyl)sulphona-
mides 1b–c (Fig. 4).
The synthesis of 1d is likewise possible but to obtain
a compound with greater purity we chose the procedure
of Guilhemat et al. [16] and reacted 1-phenylbenzene
isatoic anhydride and AlCl3 at 110 °C for 8 h. The
corresponding amine together with methanesulphonyl
chloride yielded the desired product 1d (Fig. 5).
Another strategy was used to synthesise 1e, 2i and 2j.
The reaction sequence is outlined in Fig. 6.
2-Aminophenyl-2-thienyl methanone, the basic moie-
ty of the compounds 3, 4a–b and 11a–c was synthe-
sised according to a procedure of Hunziker et al. [17].
The amides and sulphonamides were obtained using the
corresponding sulphonyl and carbonyl chlorides.
Due to the structural complexity of this group, the
sulphonamides 14–20 were prepared using two diffe-
rent strategies. Compound 17 can be obtained directly
from 1a with dimethylsulphate in absolute THF, 1a and
1,2-ethanedithiol-boron trifluoride etherate gave rise to
18 [18], LiAlH4 reduction of 1a led to 19. Starting
material for the sulphonamides 14–16 and 20 were
commercially available amines. In the case of 16 the
2-amino-6-methoxyphenyl-phenylmethanone was syn-
thesised according to a procedure of Walsh [14]. The
data of the compounds are summarised in Table 2.
ph
4-CH3ꢀph
4-Clꢀph
4-CH3ꢀOꢀph
4-tert-butylꢀph
3,5-bis-tri-Fꢀph
2-naphthyl
2-thienyl
2f
2g
2h
2I
2j
3
4a
4b
5
6a
6b
7
8a
8b
9
10a
10b
10c
11a
11b
11c
12a
12b
12c
13a
13b
13c
4-CH3ꢀph
4-tert-butylꢀph 4-CH3ꢀph
2-thienyl
2-thienyl
2-thienyl
ph
ph
ph
ph
ph
ph
ph
ph
ph
ph
2-thienyl
2-thienyl
2-thienyl
ph
ph
ph
CH3
4-CH3ꢀph
4-Clꢀph
CH3
4-CH3ꢀph
4-Clꢀph
CH3
4-CH3ꢀph
4-Clꢀph
CH3
ph
4-CH3ꢀph
4-Clꢀph
ph
4-CH3ꢀph
4-Clꢀph
ph
4-CH3ꢀph
4-Clꢀph
ph
4-CH3ꢀph
4-Clꢀph
ph
ph
ph
3. Pharmacology
The compounds were tested for their inhibitory po-
tency against COX-1 in an intact cell assay described
earlier [29]. Porcine blood was used as the enzyme
source and the isolated platelets as the source for
COX-1 activity. The cells were incubated with the
compounds and stimulated with calcium ionophore A
23187. The amount of malondialdehyde (MDA) was
determined by fluorometry. IC50 values were calculated
with the program GRAFIT, Erithacus Software Ltd.,
Fig. 2. R=aryl; R%R¦=O; R%=OH, R¦=H; R%,R¦=H; R§=CH3,
aryl; X=SO2, CO.

G. Dannhardt et al. / European Journal of Medicinal Chemistry 37 (2002) 147–161
149
Fig. 3. Modified sulphonamides.
UK. Amfenac, diclofenac, indomethacin and ketopro-
fen were used as reference standards (IC50 values see
Fig. 7).
To determine the COX-2 activity the method of
Fiebich et al. [30] was applied. The inhibition of LPS-
induced COX-2 in human monocytes was calculated
using monocytes from the peripheral blood of healthy
donors and the PGE2 assay.
The increase of potency of anti-inflammatories is
often correlated with the lipophilicity using the thio-
phene approach [31] but our tests show that the
thienoyl sulphonamides 3, 4a–b possess less potency
than the corresponding aroyl sulphonamides 1a–c. The
highest inhibitory activity is found for the tosyl-
sulphonamides (1b: 0.05; 2b: 0.35; 4a: 1.06 mM).
4. Results and discussion
Table 1 and Fig. 3 summarise the compounds tested.
All the compounds were screened for their COX-1
inhibitory potency. Some of them were also tested to
ascertain COX-2 inhibition. The results are listed in
Table 3.
4.1. N-(Aroylphenyl)sulphonamides
The N-(2-benzoylphenyl)methanesulphonamides 1a–e
differ only at position 4% of R. For none of these
compounds can any noticeable inhibitory activity
against COX-2 be found. The unsubstituted 1a and the
methylsulphanyl derivative 1c inhibit COX-1 equipo-
tently. A significant increase of inhibitory potency is
observed for the 4%-methyl compound 1b (IC50=0.05
mM). Bulky substituents such as a phenyl (1d) or a
tert-butyl residue (1e) result in a lack of COX-1 inhibi-
tion. These findings are confirmed in the 2 series by 2j.
In the arylsulphonyl series 2a–j no inhibition of
COX-2 are found, but most of the compounds are more
potent or equipotent COX-1 inhibitors than the lead
1a. The para-methylsulphonamide 2b is the most potent
COX-1 inhibitor, but the activity decreases if position
4% of the aroyl moiety is substituted, especially with a
bulky residue such as the tert-butyl group (2j).
Fig. 4. (a) ClꢀSO2CH3, aq. Na2CO3; (b) SOCl2; (c) AlCl3–C6H5ꢀR,
CH2Cl2.
Fig. 5. (a) AlCl3/110 °C/8 h; (b) concd. HCl; (c) CH3SO2ꢀCl,
CH2Cl2–pyridine.

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G. Dannhardt et al. / European Journal of Medicinal Chemistry 37 (2002) 147–161
4.4. Comparison of N-(aroylphenyl)sulphonamides and
N-(aroylphenyl)benzamides
As mentioned above, N-(aroylphenyl)sulphonamides
are selective COX-1 inhibitors. Most of the investigated
N-(aroylphenyl)benzamides are potent COX-1 and
COX-2 inhibitors with a varying selectivity profile. The
Table 2
Fig. 6. (a) AlCl3–C6H5ꢀR, CH2Cl2; (b) hydrogen (10 bar), Pd–C; (c)
R%ꢀSO2ꢀCl, CH2Cl2–pyridine.
IC50 values of compounds tested (mM or percentage of inhibition at
a concentration of 10 mM)
Compound
COX-1
COX-2
COX-1/COX-2
Consequently, we investigated the regioisomeric 3-
and N-(4-benzoylphenyl)sulphonamides 5, 6a, 6b and 7,
8a–b. Compound 5 (0.25 mM) is fourfold more potent
than 1a (1.12 mM) and 16-fold more potent than 7 (4.11
mM). These results are in agreement with Harrington et
al. [11] and Moore and Harrington [12] testing 3-ben-
zoyl fluoroalkanesulphonamides. The arylsulphona-
mides 8a–b and 6a–b inhibit COX-1 in the low
micromolar range. The tosylamides 8a (0.23 mM) and
6a (0.67 mM) are more potent than the corresponding
4-chloro-sulphonamides 8b (0.33 mM) and 6b (2.73
mM). In contrast to methanesulphonamides 7 the aryl-
sulphonamide derivatives 8a and 8b are the most potent
compounds in this series.
1a
1b
1c
1d
1e
1.12
0.05
1.31
\10
\10
13.7
36.9
n.t.
10.3
0%
2a
2b
2c
2d
2e
2f
2g
2h
2i
0.40
0.35
0.58
1.00
1.70
1.83
1.40
1.08
2.95
\10
n.t.
n.t.
9%
n.t.
n.t.
n.t.
n.t.
n.t.
n.t.
10%
2j
3
4a
4b
2.77
1.06
ꢀ10
n.t.
n.t.
0%
4.2. Modified sulphonamides
Compounds 14–20 show no or poor (20) enzyme
inhibiting potency. These results indicate that modifica-
tions of the carbonyl moiety or the restriction of the
rotation of both aryl rings are detrimental to the acti-
vity. Evidently the ketone function is a prerequisite for
COX-1 and COX-2 potency.
5
6a
6b
0.25
0.67
2.73
n.t.
n.t.
5%
7
8a
8b
4.11
0.23
0.33
n.t.
n.t.
20%
9
\10
n.t.
n.d.
4.3. N-(Aroylphenyl)benzamides
10a
10b
10c
2.09
0.32
0.18
2.55
0.61
0.24
0.82
0.52
0.75
The N-(aroylphenyl)amides were prepared to test
whether the sulphonamide moiety is pharmacophore in
essence.
11a
11b
11c
0.42
0.11
0.05
2.63
3.00
24%
0.16
0.04
n.d.
The benzamides 10a–c inhibit the COX-1 enzyme
with the activity increasing from the unsubstituted com-
pound to the chloro derivative 10c (IC50=0.18 mM).
Compounds 10a–c are balanced dual inhibitors of
COX-1 and COX-2 (COX-1/COX-2 ratio: 0.52–0.82).
The thienoyl-derivatives 11a–c represent potent
COX-1 inhibitors. Compound 11c was identified as one
of the most potent COX-1 inhibitors (IC50=0.05 mM),
however, in contrast to the corresponding benzoyl com-
pounds 10a–c the thienoyl-derivatives 11a–c inhibit the
COX-2 enzyme less potently (see Table 3).
12a
12b
12c
0.49
0.39
0.42
1.80
3.30
1.67
0.27
0.12
0.25
13a
13b
13c
2.93
3.98
0.58
n.t.
10
25%
n.d.
0.40
n.d.
14
15
16
17
18
19
20
\10
\10
\10
\10
\10
\10
\10
n.t.
n.t.
n.t.
n.t.
n.t.
n.t.
n.t.
The 3-benzoyl derivatives 12a–c are equipotent
COX-1 inhibitors and more potent than the corre-
sponding 4-regioisomers 13a–c. Compounds 12a–c and
13a–c preferentially inhibit the COX-1 isoform.
n.t., not tested; n.d., not determined.

G. Dannhardt et al. / European Journal of Medicinal Chemistry 37 (2002) 147–161
151
Fig. 7. IC50 values for COX-1 and COX-2 inhibition of indomethacin, amfenac, diclofenac and ketoprofen [32].
benzamides 10a–c are equipotent dual inhibitors of
COX-1 and COX-2.
6. Experimental
In general benzamide derivatives are more potent
than the corresponding sulphonamides except the
sulphonamides 2a and 8a which inhibit the COX-1
enzyme more potently than the benzamides 10a and 13b.
6.1. Chemistry
Melting points were measured on a Bu¨chi appara-
tus (Dr Tottoli) and were not corrected. IR spectra
(KBr disks unless otherwise stated) were recorded on
a Beckmann IR Model 4220 spectrophotometer. 1H-
NMR-spectra were obtained on a Bruker AC 200
(200 MHz) or Bruker AC 300 (300 MHz) and were
consistent with proposed structures (solvent: CDCl3
unless otherwise stated). Chemical shifts are described
in parts per million. Tetramethylsilane was used as
internal standard. Coupling constants (J) are reported
in Hertz. Mass spectra (electron impact) were ob-
tained on a Varian MAT 311 A. Thinlayer chro-
matography (TLC) was carried out with E. Merck
silica gel 60 F254 plates. CC were conducted over SiO2
in glass tubes (30×500 mm) under pressure (N2, 0.8
bar). Analyses indicated by the element symbols were
within 90.4% of the theoretical values. All chemicals
were of analytical grade. Yields are reported in per-
cent from their theoretically calculated value.
5. Summary and conclusions
Starting
with
N-(2-benzoylphenyl)methanesul-
phonamide (1a) as a lead, variations of the benzoyl,
aniline and sulphonamide moiety were produced. In
addition the exchange of benzoyl by a 2-thienoyl residue
was performed. A substituent at position 4%of the 2-ben-
zoyl moiety led to 1b, the most potent COX-1 inhibitor.
The shift from mesyl to tosyl derivatives increased
COX-1-inhibition.
Based on these results the molecules were modified
systematically to postulate the following structure–ac-
tivity relationships:
(a) flexibility of the molecule seems to be a prerequisite
for interaction with the amino acids of the inner
surface of the COX-channel;
(b) the carbonyl moiety as a link between the two aryl
rings allows an orientation to each other which is
optimum for intermolecular bonding. In addition it
is a hydrogen acceptor;
6.2. General procedure for the preparation of
sulphonamides and carbonamides (Method A)
(c) the NH-group may serve as the donor of inter-
molecular hydrogen bonds;
(d) increasing lipophilicity does not enhance the COX
inhibitory potency.
The corresponding 3- and 4-regioisomers reinforced
the structure–activity relationships discussed above. In
general, arylsulphonamides preferentially inhibit COX-
1 but the corresponding amides are more potent. Some
N-(aroylphenyl) amides are balanced dual COX-1 and
COX-2 inhibitors.
To a stirred and cooled (ice bath) solution of the
amine and 1.5 equiv. pyridine in dry CH2Cl2 a solu-
tion of the SOCl2, or carbonyl chloride, was added.
The solution was stirred for 3 h at room temperature
(r.t.) before being hydrolysed with water. The organic
layer was separated, washed three times with water,
Na2CO3 and water and finally dried with Na2SO4.
The solvent was evaporated under reduced pressure
to yield the crude product, which was usually purified
by CC.

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G. Dannhardt et al. / European Journal of Medicinal Chemistry 37 (2002) 147–161
Table 3
Physical data of compounds synthesised.
Compound
m.p. (°C)
IR (KBr)
1H-NMR (200 MHz), l (ppm), J (Hz)/MS (EI, 70 eV): m/z
1a
108 (106–107
[19])
1625 (CꢁO), 1325, 1150
(SO2ꢀN)
3.08 (s, 3H, CH3), 7.11 (ddd, 3J=7.9 Hz, 3J=7.6 Hz, 4J=1.2 Hz, 1H,
Harom.), 7.47–7.52 (m, 2H, Harom.), 7.56–7.64 (m, 3H, Harom.), 7.68–7.70 (m,
2H, Harom.), 7.81 (dd, 3J=8.3 Hz, 4J=0.7 Hz, 1H, Harom.), 10.28 (s, 1H,
NH)
’
’
275.0 [23%, M+ ], 196.1 [30%, M+ −SO2CH3], 105.1 (12%, C6H5CO+
)
1b
96
1630 (CꢁO), 1335, 1150
(SO2ꢀN)
2.43 (s, 3H, ArCH3), 3.04 (s, 3H, SO2CH3), 7.13 (dd, 3J=7.8 Hz, 3J=7.3
Hz, 1H, Harom.), 7.28 (d, 3J=7.8 Hz, 2H, AA%), 7.52–7.62 (m, 4H, Harom.),
7.78 (d, 3J=8.3 Hz, 1H, Harom.), 10.11 (s, 1H, NH)
’
’
290.2 [24%, M+ ], 210.8 [100%, M+ −SO2CH3], 119.3 (42%,
CH3C6H5CO+), 91.3 (27%, C7H+7
)
1c
1d
1e
127
145
158
1630 (CꢁO), 1320, 1155
(SO2ꢀN)
2.53 (s, 3H, SꢀCH3), 3.04 (s, 3H, SO2CH3), 7.13 (dd, 3J=7.8 Hz, 3J=7.3
Hz, 1H, Harom.), 7.28 (d, 3J=8.8 Hz, 2H, AA%), 7.52–7.80 (m, 5H, Harom.),
10.00 (s, 1H, NH)
’
’
321.2 [57%, M+ ], 241.9 [24%, M+ −SO2CH3], 194.9 (23%), 84.2 (100%)
1640 (CꢁO), 1340, 1155
(SO2ꢀN)
3.07 (s, 3H, CH3), 7.16 (dd, 3J=7.6 Hz, 1H, Harom.), 7.39–7.82 (m, 12H,
Harom.), 10.21 (s, 1H, NH)
’
’
351.7 [36%, M+ ], 372.7 [100%, M+ −SO2CH3], 181.1 (22%,
C6H5C6H4CO+
)
1630 (CꢁO), 1330, 1150
(SO2ꢀN)
1.37 (s, 9H, tBu), 3.05 (s, 3H, CH3), 7.15 (ddd, 3J=7.9 Hz, 3J=7.4 Hz,
4J=1.2 Hz, 1H, Harom.), 7.51 (d, 3J=8.5 Hz, 2H, AA%), 7.58 (ddd, 3J=7.9
Hz, 3J=7.6 Hz, 4J=1.7 Hz, 1H, Harom.), 7.66 (d, 3J=8.3 Hz, 2H, BB%),
7.66 (d, 3J=8.3 Hz, 2H, BB%), 7.80 (dd, 3J=8.3 Hz, 4J=1.0 Hz, 1H,
H
arom.), 10.16 (s, 1H, NH)
’
’
331.6 [48%, M+ ], 251.1 [21%, M+ −SO2CH3], 237.0 (41%), 196.3 (100%),
56.0 (79%)
2a
2b
135
1625 (CꢁO), 1320, 1170
(SO2ꢀN)
7.07 (dd, 3J=7.8 Hz, 4J=1.0 Hz, 1H, Harom.), 7.23–7.59 (m, 10H, Harom.),
7.67–7.80 (m, 3H, Harom.), 10.14 (s, 1H, NH)
’
’
337.2 [34%, M+ ], 196.3 [100%, M+ −SO2CH3], 105.0 (14%, C6H5CO+),
77.0 (53%, C6H+5
2.20 (s, 3H, CH3), 7.01 (d, 3J=7.9 Hz, 2H, AA%), 7.06–7.10 (m, 1H,
arom.), 7.34–7.40 (m, 5H, Harom.), 7.47–7.56 (m, 4H, Harom.), 7.76–7.78 (m,
)
119 (127 [20])
1630 (CꢁO), 1390, 1165
(SO2ꢀN)
H
1H, Harom.), 9.97 (s, 1H, NH)
’
’
351.4 [61%, M+ ], 196.1 [100%, M+ −SO2C6H4CH3], 91.4 (37%, C7H7+
)
2c
2d
124
1630 (CꢁO), 1320, 1175,
(SO2ꢀN)
7.09–7.79 (m, 14H, Harom.), 9.96 (s, 1H, NH)
’
’
371.7 [26%, M+ ], 196.3 [100%, M+ −SO2C6H4Cl], 77.2 (24%, C6H5+
)
98 (92–100 [21]) 3260 (NꢀH), 1635 (CꢁO),
1345, 1160 (SO2ꢀN)
3.67 (s, 3H, OCH3), 6.67 (d, 3J=8.8 Hz, 2H, AA%), 7.08 (dd, 3J=7.8 Hz,
3J=7.83 Hz, 1H, Harom.), 7.34–7.62 (m, 9H, Harom.), 7.77 (d, 3J=8.3 Hz,
1H, Harom.), 9.92 (s, 1H, NH)
’
’
367.5 [64%, M+ ], 196.4 [100%, M+ −SO2C6H4OCH3], 171.2 (46%,
SO2C6H4OCH+3 ), 107.2 (43%, C6H4OCH+3 ), 77.3 (51%, C6H5+
)
2e
135
3180 (NꢀH), 1640 (CꢁO),
1345, 1180 (SO2ꢀN)
1.18 (s, 9H, tBu), 7.08 (dd, 3J=7.8 Hz, 3J=7.3 Hz, 1H, Harom.), 7.29 (d,
3J=8.5 Hz, 2H, AA%), 7.35–7.55 (m, 7H, Harom.), 7.62 (d, 3J=8.5 Hz, 2H,
BB%), 7.80 (d, 3J=8.3 Hz, 1H, Harom.), 10.17 (s, 1H, NH)
’
’
393.7 [31%, M+ ], 196.3 [100%, M+ −SO2C6H4tBu]
2f
98
3250 (NꢀH), 1645 (CꢁO),
1365, 1130 (SO2ꢀN)
7.18–7.82 (m, 10H, Harom.), 8.06 (s, 1H, Harom.), 10.00 (s, 1H, NH)
’
474.4 [22%, M+ ], 196.8 (100%)
2g
2h
118
124
3180 (NꢀH), 1640 (CꢁO),
1340, 1170 (SO2ꢀN)
7.01–7.86 (m, 15H, Harom.), 8.20 (s, 1H, Harom.), 10.07 (s, 1H, NH)
’
’
387.2 [68%, M+ ], 196.2 [100%, M+ −SO2C10H7], 127.5 (68%, C10H7+
)
1630 (CꢁO), 1325, 1155
(SO2ꢀN)
6.84 (dd, 3J=3.9 Hz, 4J=1.5 Hz, 1H, thiophenH-4), 7.12 (dd, 3J=7.8 Hz,
4J=1.5 Hz, 1H, Harom.), 7.35–7.61 (m, 9H, Harom.), 7.84 (d, 3J=8.3 Hz,
1H, Harom.), 10.22 (s, 1H, NH)
’
’
343.4 [45%, M+ ], 278.5 (23%), 196.5 [100%, M+ −SO2C4H3S], 147.1 (10%,
SO2C4H3S+), 105.3 (29%, C6H5CO+), 77.3 (36%, C6H5+
)

G. Dannhardt et al. / European Journal of Medicinal Chemistry 37 (2002) 147–161
153
Table 3 (continued).
Compound
m.p. (°C)
IR (KBr)
1H-NMR (200 MHz), l (ppm), J (Hz)/MS (EI, 70 eV): m/z
2i
125 (123 [20])
1630 (CꢁO), 1320, 1155
(SO2ꢀN)
2.21 (s, 3H, CH3), 2.43 (s, 3H, CH3), 7.01 (d, 3J=7.9 Hz, 2H, AA%), 7.09
(dd, 3J=7.6 Hz, 4J=1.2 Hz, 1H, Harom.), 7.18 (d, 3J=7.9 Hz, 2H, AA%),
7.29 (d, 3J=8.3 Hz, 2H, BB%), 7.36 (dd, 3J=7.9 Hz, 4J=1.4 Hz, 1H,
Harom.), 7.50 (dd, 3J=8.3 Hz, 4J=1.4 Hz, 1H, Harom.), 7.54 (d, 3J=8.3 Hz,
2H, BB%), 7.78 (dd, 3J=8.3 Hz, 4J=1.0 Hz, 1H, Harom.), 9.88 (s, 1H, NH)
’
’
365.2 [32%, M+ ], 210.2 [100%, M+ −SO2C6H4CH3], 91.1 (42%, C7H7+
)
2j
3
118
3250 (NꢀH), 1630 (CꢁO),
1600, 1340, 1170 (SO2ꢀN)
1.35 (s, 9H, tBu), 2.21 (s, 3H, CH3), 7.01 (d, 3J=8.1 Hz, 2H, AA%), 7.09
(ddd, 3J=7.6 Hz, 4J=1.0 Hz, 1H, Harom.), 7.31–7.56 (m, 8H, Harom.),
7.77–7.80 (m, 1H, Harom.) 9.94 (s, 1H, NH)
’
407.0 [47%, M+ ], 196.1 (100%), 91.1 (28%, C7H+7 ), 57.6 (36%, tBu+
)
yellow liquid
124 (125 [22])
3280 (NꢀH), 1625 (CꢁO),
1340, 1170 (SO2ꢀN)
3.01 (s, 3H, CH3), 7.15–7.21 (m, 2H, Harom.), 7.53–7.61 (m, 2H, Harom.),
7.76–7.89 (m, 3H, Harom.), 7.86 (dd, 3J=7.8 Hz, 4J=1.5 Hz, 1H, Harom.),
9.55 (s, 1H, NH)
’
’
281.8 [20%, M+ ], 202.4 [37%, M+ −SO2CH3]
4a
3230 (NꢀH), 1310, 1170
(SO2ꢀN)
2.14 (s, 3H, CH3), 6.91 (d, 3J=8.3 Hz, 2H, AA%), 7.01–7.10 (m, 2H, Harom.),
7.17 (ddd, 3J=7.8 Hz, 4J=1.5 Hz, 1H, Harom.), 7.44 (d, 3J=8.3 Hz, 2H,
BB%), 7.56 (ddd, 3J=8.3 Hz, 4J=1.5 Hz, 1H, Harom.), 7.69–7.77 (m, 2H,
Harom.), 9.26 (s, 1H, NH)
’
’
357.0 [41%, M+ ], 202.3 [100%, M+ −SO2C6H4CH3], 91.1 (41%, C7H7+
)
4b
5
134
3240 (NꢀH), 1620 (CꢁO),
1350, 1180 (SO2ꢀN)
7.04–7.10 (m, 4H, Harom.), 7.22 (ddd, 3J=7.8 Hz, 3J=7.3 Hz, 4J=1.0 Hz,
1H, Harom.), 7.48 (d, 3J=8.3 Hz, 2H, BB%), 7.58 (ddd, 3J=7.8 Hz, 3J=7.3
Hz, 4J=1.5 Hz, 1H, Harom.), 7.72–7.78 (m, 2H, Harom.), 9.22 (s, 1H, NH)
’
’
377.8 [27%, M+ ], 202.4 [100%, M+ −SO2C6H4Cl], 111.2 (35%, C4H3SCO+
)
100 (99–101 [23]) 3260 (NꢀH), 1650 (CꢁO),
1330, 1150 (SO2ꢀN)
3.04 (s, 3H, CH3), 7.09 (s, 1H, NH), 7.42–7.65 (m, 7H, Harom.), 7.77–7.82 (m,
2H, Harom.
275.5 [96%, M+ ], 196.4 [27%, M+ −SO2CH3], 105.1 (100%, C6H5CO+),
77.4 (70%, C6H+5
)
’
’
)
6a
118
130
3300 (NꢀH), 1670 (CꢁO),
1330, 1170 (SO2ꢀN)
2.35 (s, 3H, CH3), 7.18–7.70 (m, 14H, Harom. and NH)
’
351.7 [38%, M+ ], 105.7 (32%, C6H5CO+), 91.6 (80%, C7H+7 ), 84.3 (100%),
77.3 (32%, C6H+5 ), 64.6 (21%, SO+2
)
6b
7
3220 (NꢀH), 1645 (CꢁO),
1350, 1170 (SO2ꢀN)
7.36–7.71 (m, 19H, Harom. and NH)
’
371.5 [79%, M+ ], 178.2 (83%), 105.0 (100%, C6H5CO+), 77.4 (68%, C6H5+
)
137 (145–147 [24]) 3230 (NꢀH), 1645 (CꢁO),
1320, 1150 (SO2ꢀN)
3.12 (s, 3H, CH3), 7.32 (d, 3J=8.6 Hz, 2H, AA%), 7.41 (s, 1H, NH),
7.46–7.51 (m, 2H, Harom.), 7.60 (dddd, 3J=7.4 Hz, 4J=1.3 Hz, 1H,
benzoylH-4), 7.75–7.78 (m, 2H, Harom.), 7.83 (d, 3J=8.6 Hz, 2H, BB%)
’
’
274.9 [58%, M+ ], 197.9 [23%, M+ −C6H5], 105.1 (33%, C6H5CO+), 79.3
(70%, SO2CH+3
)
8a
8b
177 (175 [25])
3230 (NꢀH), 1645 (CꢁO),
1350, 1155 (SO2ꢀN)
2.37 (s, 3H, CH3), 7.14–7.26 (m, 4H, Harom.), 7.40–7.59 (m, 4H, Harom.),
7.68–7.77 (m, 6H, Harom. and NH)
’
’
351.3 [88%, M+ ], 274.4 [29%, M+ −C6H5], 155.0 (46%, C6H4NHSO+2 ),
105.0 (26%, C6H5CO+), 91.1 (100%, C7H+7 ), 77.4 (30%, C6H5+
)
160
3220 (NꢀH), 1640 (CꢁO),
1350 (SO2ꢀN), 1320, 1150
(SO2ꢀN)
7.17 (d, 3J=8.8 Hz, 2H, AA%), 7.41–7.61 (m, 6H, Harom.), 7.68–7.81 (m, 6H,
Harom. and NH)
’
’
’
371.6 [86%, M+ ], 294.3 [49%, M+ −C6H5], 196.3 [28%, M+ −SO2C6H4Cl],
168.2 (100%), 140.8 (41%, C6H4SO+2 ), 105.0 (54%, C6H5CO+), 77.4 (60%,
C6H+5
)
9
85 (83–84 [26])
3300 (NꢀH), 1695 (CꢁO),
1630 (CꢁO)
2.22 (s, 3H, CH3), 7.08 (dd, 3J=7.9 Hz, 4J=1.2 Hz, 1H, Harom.), 7.46–7.71
(m, 7H, Harom.), 8.62 (d, 3J=8.3 Hz, 1H, Harom.), 10.81 (s, 1H, NH)
’
’
238.9 [44%, M+ ], 196.0 [100%, M+ −CH3CO]
10a
90
3290 (NꢀH), 1655 (CꢁO),
1610 (CꢁO)
7.13 (ddd, 3J=8.0 Hz, 3J=7.3 Hz, 4J=1.2 Hz, 1H, Harom.), 7.47–7.74 (m,
10H, Harom.), 8.07 (dd, 3J=8.0 Hz, 4J=1.7 Hz, 2H, Harom.), 8.90 (dd,
3J=8.6 Hz, 4J=1.0 Hz, 1H, Harom.), 11.98 (s, 1H, NH)
’
’
301.1 [26%, M+ ], 195.9 [39%, M+ −C6H5CO], 105.1 (100%, C6H5CO+),
77.3 (47%, C6H+5
)

154
G. Dannhardt et al. / European Journal of Medicinal Chemistry 37 (2002) 147–161
Table 3 (continued).
Compound
m.p. (°C)
81 (75 [27])
IR (KBr)
1H-NMR (200 MHz), l (ppm), J (Hz)/MS (EI, 70 eV): m/z
10b
3290 (NꢀH), 1685 (CꢁO),
1635 (CꢁO)
2.42 (s, 3H, CH3), 7.11 (ddd, 3J=7.9 Hz, 3J=7.4 Hz, 4J=1.2 Hz, 1H,
Harom.), 7.31 (d, 3J=7.9 Hz, 2H, AA%), 7.45–7.74 (m, 7H, Harom.), 7.97 (d,
3J=8.4 Hz, 2H, BB%), 8.88–8.91 (m, 1H, Harom.), 11.93 (s, 1H, NH)
’
’
314.9 [28%, M+ ], 210.3 [29%, M+ −C6H5CO], 119.2 (100%, CH3C6H4CO+),
91.3 (43%, C7H+7
)
10c
11a
104 (103–104 [26]) 1690 (CꢁO), 1625 (CꢁO)
7.12 (dd, 3J=7.8 Hz, 3J=7.3 Hz, 1H, Harom.), 7.45–7.72 (m, 9H, Harom.),
8.02 (d, 3J=8.3 Hz, 2H, BB%), 8.83–8.87 (m, 1H, Harom.), 12.00 (s, 1H, NH)
’
’
335.0 [22%, M+ ], 230.4 [35%, M+ −C6H5CO], 139.3 (100%, ClC6H4CO+),
111.3 (48%, C6H4Cl+
)
136
141
93
3230 (NꢀH), 1650 (CꢁO)
3280 (NꢀH), 1650 (CꢁO)
7.16–7.23 (m, 2H, Harom.), 7.48–7.59 (m, 3H, Harom.), 7.62–7.68 (m, 2H,
H
arom.), 7.76 (dd, 3J=4.9 Hz, 4J=1.1 Hz, 1H, Harom.), 7.90 (dd, 3J=7.9
Hz, 4J=1.7 Hz, 1H, Harom.), 8.01–8.04 (m, 2H, Harom.), 8.80 (dd, 3J=8.4
Hz, 4J=0.7 Hz, 1H, Harom.), 11.39 (s, 1H, NH)
’
’
306.4 [19%, M+ ], 195.7 [42%, M+ −C4H3SCO], 107.7 (100%, C6H5CO+),
76.9 (51%, C6H+5
)
11b
11c
2.42 (s, 3H, CH3), 7.16–7.21 (m, 2H, Harom.), 7.30 (d, 3J=8.1 Hz, 2H, AA%),
7.61–7.67 (m, 2H, Harom.), 7.76 (dd, 3J=5.0 Hz, 4J=1.1 Hz, 1H, thiophen),
7.87–7.93 (m, 3H, BB% and thiophen), 8.79 (dd, 3J=8.5 Hz, 4J=0.8 Hz, 1H,
thiophen), 11.34 (s, 1H, NH)
’
’
320.6 [31%, M+ ], 209.9 [33%, M+ −C4H3SCO], 118.7 (100%,
CH3C6H4CO+), 90.8 (67%, C7H+7
)
3330 (NꢀH); 1675 (CꢁO),
1620 (CꢁO)
7.15–7.24 (m, 3H, Harom.), 7.45 (d, 3J=8.3 Hz, 2H, AA%), 7.61–7.78 (m, 3H,
Harom.), 7.88–7.97 (m, 3H, BB% and Harom.), 8.75 (d, 3J=8.3 Hz, 1H, Harom.),
11.42 (s, 1H, NH)
’
’
341.6 [16%, M+ ], 230.4 [28%, M+ −C4H3SCO], 202.4 [11%,
M
’
+ −COC6H4Cl], 139.3 (100%, ClC6H4CO+), 111.2 (84%, C4H3SCO+
)
12a
12b
12c
125
112
135
3290 (NꢀH), 1630 (CꢁO)
3310 (NꢀH), 1635 (CꢁO)
3290 (NꢀH), 1625 (CꢁO)
7.42–7.61 (m, 8H, Harom.), 7.78 (m, 2H, Harom.), 7.87 (m, 2H, Harom.), 7.94
(dd, 4J=1.7 Hz, 1H, Harom.), 8.12 (ddd, 3J=8.3 Hz, 4J=1.7 Hz, 1H,
Harom.), 8.26 (s, 1H, NH)
’
300.9 [28%, M+ ], 105.1 (100%, C6H5CO+), 77.2 (34%, C6H5+
)
2.41 (s, 3H, CH3), 7.25 (d, 3J=8.1 Hz, 2H, AA%), 7.44–7.61 (m, 5H, Harom.),
7.76–7.80 (m, 4H, Harom.), 7.92 (dd, 4J=1.7 Hz, 1H, Harom.), 8.11 (ddd,
3J=7.9 Hz, 4J=1.8 Hz, 1H, Harom.), 8.16 (s, 1H, NH)
’
314.9 [31%, M+ ], 119.0 (100%, CH3C6H4CO+), 91.0 (86%, C7H7+
)
7.40 (d, 3J=8.6 Hz, 2H, AA%), 7.43–7.49 (m, 3H, Harom.), 7.52 (ddd, 3J=7.6
Hz, 4J=1.4 Hz, 1H, Harom.), 7.59 (dddd, 3J=7.6 Hz, 4J=1.3 Hz, 1H,
Harom.), 7.74–7.77 (m, 2H, Harom.), 7.82 (d, 3J=8.6 Hz, 2H, BB%), 7.95 (dd,
4J=1.7 Hz, 1H, Harom.), 8.12 (ddd, 3J=7.9 Hz, 4J=1.8 Hz, 1H, Harom.),
8.34 (s, 1H, NH)
’
334.3 [31%, M+ ], 138.6 (100%, ClC6H4CO+), 110.9 (36%, ClC6H4+
)
13a
13b
150
179
3330 (NꢀH), 1630 (CꢁO)
3320 (NꢀH), 1640 (CꢁO)
7.45–7.52 (m, 4H, Harom.), 7.55–7.62 (m, 2H, Harom.), 7.76–7.91 (m, 8H,
Harom.), 8.15 (s, 1H, NH)
’
300.9 [39%, M+ ], 105.0 (100%, C6H5CO+), 77.3 (43%, C6H5+
)
2.42 (s, 3H, CH3), 7.28 (d, 3J=8.1 Hz, 2H, AA%), 7.45–7.50 (m, 2H, Harom.),
7.58 (ddd, 3J=7.4 Hz, 4J=1.4 Hz, 1H, Harom.), 7.76–7.80 (m, 6H, Harom.),
7.85 (dd, 3J=8.8 Hz, 2H, BB%), 8.15 (s, 1H, NH)
’
314.9 [59%, M+ ], 119.1 (100%, CH3C6H4CO+), 91.1 (29%, C7H7+
)
13c
14
163
3280 (NꢀH), 1650 (CꢁO)
7.46–7.51 (m, 4H, AA% and AA%), 7.59 (dddd, 3J=7.4 Hz, 4J=1.3 Hz, 1H,
arom.), 7.76–7.79 (m, 4H, Harom.), 7.83–7.88 (m, 4H, BB% and BB%), 8.05 (s,
1H, NH)
334.4 [18%, M+ ], 138.7 (100%, ClC6H4CO+), 110.9 (30%, ClC6H4+
H
’
)
108 (105–107 [28]) 3150–3000 (NꢀH),
1655 (CꢁO)
2.67 (s, 3H, CH3CO), 3.06 (s, 3H, SO2CH3), 7.15 (ddd, 3J=7.6 Hz, 4J=1.2
Hz, 1H, Ar), 7.56 (ddd, 3J=7.6 Hz, 4J=1.7 Hz, 1H, Ar), 7.75 (dd, 3J=8.3
Hz, 4J=1.0 Hz, 1H, Ar), 7.93 (dd, 3J=7.9 Hz, 4J=1.4 Hz, 1H, Ar), 11.34
(s, 1H, NH)
’
’
’
212.9 [41%, M+ ], 198.1 [23%, M+ −CH3], 134.1 [100%, M+ −SO2CH3],
’
118.8 [43%, M+ −NHSO2CH3], 106.0 (56%)

G. Dannhardt et al. / European Journal of Medicinal Chemistry 37 (2002) 147–161
155
Table 3 (continued).
Compound
m.p. (°C)
IR (KBr)
1H-NMR (200 MHz), l (ppm), J (Hz)/MS (EI, 70 eV): m/z
3.12 (s, 3H, CH3), 7.18–7.64 (m, 7H, Ar), 9.29 (s, 1H, NH)
15
179
129
3260 (NꢀH), 1685 (CꢁO)
’
’
273.0 [84%, M+ ], 194.8 [100%, M+ −SO2CH3], 166.9 (23%), 138.8 (29%)
16
17
18
3180 (NꢀH), 1660 (CꢁO),
1325, 1160 (SO2ꢀN)
2.87 (s, 3H, SO2CH3), 3.60 (s, 3H, OCH3), 6.79 (d, 3J=8.3 Hz, 1H, Ar),
7.31–7.75 (m, 8H, Ar and NH)
’
’
’
304.6 [30%, M+ ], 225.6 [100%, M+ −SO2CH3], 210.6 [89%, M+ −SO2CH3
u. ꢀCH3], 148.6 (37%), 104.9 (49%, C6H5CO+), 76.9 (45%, C6H5+
)
128
121
1670 (CꢁO), 1340, 1170
(SO2ꢀN)
2.78 (s, 3H, CH3), 3.17 (s, 3H, CH3), 7.39–7.59 (m, 7H, Ar), 7.77–7.81 (m,
2H, Ar)
’
’
289.2 [3%, M+ ], 209.9 [100%, M+ −SO2CH3], 132.0 (23%), 104.9 (10%,
C6H5CO+), 91.0 (13%, C6H4NCH+3 ), 77.3 (26%, C6H5+
)
3250 (NꢀH), 1385, 1155
(SO2ꢀN)
2.54 (s, 3H, CH3), 3.32–3.51 (m, 4H, CH2CH2), 7.01 (s, 1H, NH), 7.08 7.17
(m, 1H, Ar), 7.28–7.38 (m, 4H, Ar), 7.53–7.60 (m, 2H, Ar), 7.68–7.73 (m,
1H, Ar), 7.82–7.87 (m, 1H, Ar)
’
’
350.7 [25%, M+ ], 289.9 [20%, M+ −SCH2CH2], 272.2 [20%,
M
’
+ −SO2CH3], 243.9 (100%), 211.8 (43%), 92.3 (37%, SCH2CH2S+
)
19
20
115
117
3440 (OꢀH), 3250 (NꢀH),
1330, 1150 (SO2ꢀN)
DMSO-d6, 2.59 (s, 3H, CH3), 6.09 (s, 1H, CH), 6.40 (s, 1H, OH), 7.16–7.42
(m, 9H, Ar), 8.96(s, 1H, NH)
’
’
277.0 [13%, M+ ], 198.0 [100%, M+ −SO2CH3], 180.0 (98%), 120.2 (35%),
104.9 (31%, C6H5CO+), 77.4 (22%, C6H4+
)
3290 (NꢀH), 1310, 1150
(SO2ꢀN)
2.59 (s, 3H, CH3), 4.01 (s, 2H, CH2), 6.20 (s, 1H, NH), 7.13–7.33 (m, 8H,
Ar), 7.50–7.54 (m, 1H, Ar)
’
261.6 [22%, M+ ], 182.4 (100%, C6H5CH2C6H4NH+
)
6.3. General procedure for the preparation of carbonyl
chlorides (Method B)
rated, washed three times with water, Na2CO3 and
water and finally dried with Na2SO4. The solvent was
evaporated under reduced pressure to yield the crude
product, which was usually purified by CC.
6.3.1. Carbonyl chlorides 6ia SOCl2
The HCO3 was refluxed with an excess of SOCl2 for
3 h. The excess SOCl2 was distilled at a water jet pump
and the residue dissolved with CH2Cl2 and washed
briefly with ice-water. The organic layer was separated,
washed three times with water, Na2CO3 and water and
finally dried with Na2SO4. The solvent was evaporated
under reduced pressure to yield the crude product,
which was not usually purified any further.
6.5. N-(2-Benzoylphenyl)methanesulphonamide (1a)
To a stirred solution of 1.97 g (10 mmol) 2-
aminophenyl-phenylmethanone and 1.19 g (15 mmol)
pyridine in 100 mL dry CH2Cl2 1.38 g (12 mmol)
methanesulphonyl chloride were added dropwise. The
solution was stirred for 3 h at r.t. before it was hy-
drolysed with the equivalent amount of water. The
organic layer was separated, washed three times with
water, Na2CO3 and water and finally dried with
Na2SO4. The solvent was evaporated under reduced
pressure yielding a yellow oil. CC (PE–EE=1:1)
yielded yellow crystals (1.39 g, 51%). Anal. Calc. for
C14H13NO3S: C, 61.08; H, 4.76. Found: C, 60.63; H,
5.10%; N.
6.3.2. Carbonyl chlorides 6ia PCl5
To a cooled (ice bath) solution of HCO3 in
CH2Cl2·PCl5 was added. The ice bath was removed and
the mixture was stirred under reflux for 2 h. For
Friedel-Crafts-acylation the mixture was not further
purified.
6.4. General procedure for the Friedel-Crafts-reaction
(Method C)
6.6. 2-Methylsulphonylamidobenzoic acid (VII)
On an ice bath, dry AlCl3 was suspended in dry
CH2Cl2 and stirred vigorously. To this mixture, a solu-
tion of the carbonyl chloride or alkyl halide in CH2Cl2
and subsequently the aromatic compound (solved in
CH2Cl2) was added dropwise. After stirring over night
at r.t. the complex was hydrolysed with crushed ice and
acidified with diluted HCl. The organic layer was sepa-
To a cooled solution (ice bath) of 1.36 g (10 mmol)
2-amino-benzoic acid in 30 mL saturated aq. Na2CO3,
methanesulphonyl chloride (1.38 g, 12 mmol) were
added. The solution was stirred over night and allowed
to warm up to r.t. The solution was acidified with
concd. HCl and the precipitate collected and dried. The
precipitate was used without any further purification.

156
G. Dannhardt et al. / European Journal of Medicinal Chemistry 37 (2002) 147–161
Yield: 1.76 g (82%), m.p. 183 °C (Ref. [33]: 189–
190 °C).
EE=4:1; Rf=0.50) yielded 2.11 g (37%) of white
crystals (m.p. 101 °C).
6.7. N-[2-(4-Methylbenzoyl)phenyl]methanes-
ulphonamide (1b)
6.12. (2-Aminophenyl)[4-(tert-butyl)phenyl]-
methanone (X)
1.08 g VII (5 mmol) was transformed according to
Method B. Ten millilitres SOCl2 were added to car-
bonyl chloride, and subsequently reacted with 0.92 g
C6H5CH3 (10 mmol) and 0.80 g AlCl3 (6 mmol) in 30
mL CH2Cl2 (Method C). The crude product was recrys-
tallised with PE–CH2Cl2 yielding 0.93 g (64%) of white
crystals. Anal. (C15H15NO3S): C, H, N, S.
Compound IX (1.50 g, 5.30 mmol) in 50 mL MeOH
were hydrogenated with 0.10 g Pd–C (10%) and H2 (5
bar) at r.t. for 6 h. The mixture was filtered over celite®
and the solvent evaporated under reduced pressure. CC
of the crude product (PE–EE=8:1; Rf=0.24) yielded
1.02 g (76%) of yellow crystals (m.p. 120 °C).
6.13. (N-{2-[(4-tert-Butyl)benzoyl]phenyl}-
methanesulphonamide (1e)
6.8. N-[2-(4-Methylsulphanylbenzoyl)-
phenyl]methanesulphonamide (1c)
Compound X (0.76 g, 3.0 mmol) were reacted with
0.45 g pyridine (6.0 mmol) and 0.52 g methanesulpho-
nyl chloride (4.50 mmol) in 50 mL CH2Cl2 according to
Method A. CC of the crude product (PE–EE=5:1;
Rf=0.20) yielded 0.36 g (36%) of yellow solid. Anal.
(C18H21NO3S): C, H, N.
Compound VII (1.61 g, 7.5 mmol) was transformed
according to Method B with 15 mL SOCl2 to carbonyl
chloride, which was subsequently reacted with 2.33 g
1-methylsulphanylbenzene (18.8 mmol) and 1.20 g
AlCl3 (9.0 mmol) in 50 mL CH2Cl2 (Method C). CC of
the crude product (PE–EE=2:1; Rf=0.33) yielded
0.90 g (38%) of yellow crystals. Anal. (C15H15NO3S2):
C, H, N.
6.14. 2-Benzoyl-1-phenylsulphonamidobenzene (2a)
2-Aminophenyl-phenylmethanone (1.97 g, 10.0
mmol) were reacted with 1.19 g pyridine (15.0 mmol)
and 1.69 g 1-benzenesulphonyl chloride (12.0 mmol) in
50 mL CH2Cl2 according to Method A. CC of the
crude product (PE–EE=4:1; Rf=0.42) yielded 2.13 g
(63%) of yellow crystals. Anal. (C19H15NO3S): C, H, N,
S.
6.9. 2-Aminophenyl-4-phenylphenylmethanone (VIII)
A stirred mixture of 7.71 g 1-phenylbenzene (50
mmol), 1.63 g isatoic anhydride (10 mmol) and 6.0 g
AlCl3 (45 mmol) was melted for 8 h at 110 °C. The
resulting black product was dissolved in 300 mL
CH2Cl2. The organic layer was separated, washed three
times with water, Na2CO3 and water and finally dried
with Na2SO4. CC of the crude product (PE–CH2Cl2=
4:1; Rf=0.36) yielded 1.01 g (37%) of a yellow liquid.
6.15. 2-Benzoyl-1-(4-methylphenylsulphonamido)-
benzene (2b)
2-Aminophenyl-phenylmethanone (3.95 g, 20.0
mmol) were reacted with 2.37 g pyridine (30.0 mmol)
and 4.19 g 4-methyl-1-benzenesulphonyl chloride (22.0
mmol) in 100 mL CH2Cl2 according to Method A. The
crude product was recrystallised with PE–CH2Cl2
6.10. N-[2-(2-Phenylbenzoyl)phenyl]methane-
sulphonamide (1d)
Compound VIII (0.50 g, 1.83 mmol) was reacted with
0.29 g pyridine (3.66 mmol) and 0.25 g methanesulpho-
nyl chloride (2.20 mmol) in 30 mL CH2Cl2 according to
Method A. CC of the crude product (PE–CH2Cl2=
3:1; Rf=0.27) yielded 0.24 g (38%) of yellow crystals.
Anal. (C20H17NO3S): C, H, N, S.
yielding 6.15
g (88%) of yellow crystals. Anal.
(C20H17NO3S): C, H, N.
6.16. 2-Benzoyl-1-(4-chlorophenylsulphonamido)-
benzene (2c)
6.11. [4-(tert-Butyl)phenyl](2-nitrophenyl)-
methanone (IX)
2-Aminophenyl-phenylmethanone (1.97 g, 10.0
mmol), 1.19 g pyridine (15.0 mmol) and 2.53 g 4-
chloro-1-benzenesulphonyl chloride (12.0 mmol) were
reacted in 50 mL CH2Cl2 according to Method A. The
crude product was recrystallised with PE–CH2Cl2
2-Nitro-1-benzenecarbonyl chloride (3.73 g, 22
mmol) were reacted with 2.68 g 1-(tert-butyl)benzene
(20 mmol) and 5.33 g AlCl3 (40 mmol) in 30 mL
CH2Cl2 (Method C). CC of the crude product (PE–
yielding 2.79
g (75%) of yellow crystals. Anal.
(C19H14ClNO3S): C, H, N, Cl, S.

G. Dannhardt et al. / European Journal of Medicinal Chemistry 37 (2002) 147–161
157
6.17. 2-Benzoyl-1-(4-methoxy-phenylsulphonamido)-
benzene (2d)
product (PE–CH2Cl2=4:1; Rf=0.23) yielded 1.15 g
(68%) of white solid. Anal. (C17H13NO3S2): C, H, N.
2-Aminophenyl-phenylmethanone (1.97 g, 10.0
mmol) were reacted with 1.19 g pyridine (15.0 mmol)
and 1.69 g 4-methoxy-1-benzenesulphonyl chloride
(12.0 mmol) in 50 mL CH2Cl2 according to Method A.
CC of the crude product (PE–EE=2:1; Rf=0.40)
6.22. (4-Methylphenyl)(2-nitrophenyl)methanone (XI)
2-Nitro-1-benzenecarbonyl chloride (3.73 g, 22
mmol) were reacted with 1.84 g C6H5CH3 (20 mmol)
and 5.33 g AlCl3 (40 mmol) in 50 mL CH2Cl2 (Method
C). The crude product was recrystallised with PE–
CH2Cl2 yielding 2.88 g (60%) of yellow crystals [m.p.
154 °C (Ref. [34]: 155 °C)].
yielded 2.06
g (56%) of yellow crystals. Anal.
(C20H17NO4S): C, H, N.
6.18. 2-Benzoyl-1-[4-(tert-butyl)phenylsulphonamido]-
benzene (2e)
6.23. (2-Aminophenyl)(4-methylphenyl)methanone (XII)
2-Aminophenyl-phenylmethanone (1.97 g, 10.0
mmol) were reacted with 1.19 g pyridine (15.0 mmol)
and 2.79 g 4-tert-butyl-1-benzenesulphonyl chloride
(12.0 mmol) in 50 mL CH2Cl2 according to Method A.
The crude product was recrystallised with PE–Et2NH
9:1 (50 mL) yielding the Et2NH salt which was dis-
solved in CH2Cl2 and washed with diluted HCl. The
organic layer was separated, washed twice with water
and dried with Na2SO4. The product was recrystallised
with PE–CH2Cl2 yielding 1.76 g (48%) of yellow crys-
tals. Anal. Calc. for C23H23NO3S: C, 70.20; H, 5.89.
Found: C, 70.95; H, 5.41%; N.
Compound XI (0.72 g, 3.0 mmol) in 50 mL MeOH
were hydrogenated with 0.08 g Pd–C (10%) and H2 (5
bar) at r.t. for 6 h. The mixture was filtered over celite®
and the solvent evaporated under reduced pressure to
yield a yellow liquid (0.63 g, 99%; m.p. Ref. [35]:
82–83 °C). The crude product was used without fur-
ther purification.
6.24. N1-[2-(4-Methylbenzoyl)phenyl]-4-
methyl-1-benzenesulphonamide (2i)
Compound XII (0.68 g, 3.0 mmol) were reacted with
0.48 g pyridine (6.0 mmol) and 0.88 g 4-methyl-1-ben-
zenesulphonyl chloride (4.5 mmol) in 50 mL CH2Cl2
according to Method A. CC of the crude product
(PE–CH2Cl2=4:1; Rf=0.37) yielded 0.67 g (56%) of
white solid. Anal. (C21H19NO3S): C, H, N.
6.19. N1-(Benzoylphenyl)-3,5-di(trifluoromethyl)-
1-benzenesulphonamid (2f)
2-Aminophenyl-phenylmethanone (0.33 g, 1.6 mmol)
were reacted with 0.20 g pyridine (2.50 mmol) and 0.63
g 3,5-bis(trifluoromethyl)benzenesulphonyl chloride (2.0
mmol) in 20 mL CH2Cl2 according to Method A. The
crude product was recrystallised with PE–CH2Cl2
6.25. N1-{2-[4-(tert-Butyl)benzoyl]phenyl}-4-
methyl-1-benzenesulphonamide (2j)
yielding 0.39
g
(52%) of yellow solid. Anal.
(C21H13F6NO3S): C, H, N, S.
Compound X (0.63 g, 2.5 mmol) were reacted with
0.37 g pyridine (5.0 mmol) and 0.72 g 4-methyl-1-ben-
zenesulphonyl chloride (3.8 mmol) in 50 mL CH2Cl2
according to Method A. CC of the crude product
(PE–EE=5:1; Rf=0.25) yielded 0.42 g (41%) of white
solid. Anal. (C24H25NO3S): C, H, N.
6.20. N2-(2-Benzoylphenyl)-2-naphthalenesulphonamide
(2g)
2-Aminophenyl-phenylmethanone (0.99 g, 5.0 mmol)
were reacted with 0.59 g pyridine (7.5 mmol) and 1.36
g 2-naphthalenesulphonyl chloride (6.0 mmol) in 50 mL
CH2Cl2 according to Method A. CC of the crude
product (PE–EE=2:1; Rf=0.40) yielded 1.05 g (54%)
of colourless crystals. Anal. (C23H17NO3S) C, H, N.
6.26. N-[2-(2-Thienylcarbonyl)phenyl]methanesul-
phonamide (3)
(2-Aminophenyl)(2-thienyl)methanone (0.45 g, 2.2
mmol) (synthesised according to the procedure de-
scribed by Hunziker et al. [17]) were reacted with 0.26 g
pyridine (3.3 mmol) and 0.30 g methanesulphonyl chlo-
ride (2.64 mmol) in 50 mL CH2Cl2 according to
Method A. CC of the crude product (PE–EE=2:1;
Rf=0.20) yielded 0.25 g (41%) of a yellow liquid. Anal.
Calc. for C12H11NO3S2: C, 51.23, H and N, 4.98.
Found: C, 52.28; H and N, 4.41%.
6.21. N2-(2-Benzoylphenyl)-2-thiophenesulphonamide
(2h)
2-Aminophenyl-phenylmethanone (0.99 g, 5.0 mmol)
were reacted with 0.59 g pyridine (7.5 mmol) and 1.07
g 2-thiophenesulphonyl chloride (6.0 mmol) in 50 mL
CH2Cl2 according to Method A. CC of the crude

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G. Dannhardt et al. / European Journal of Medicinal Chemistry 37 (2002) 147–161
6.27. N1[2-(2-Thienylcarbonyl)phenyl]-4-
methyl-1-benzenesulphonamide (4a)
mmol) were reacted with 1.19 g pyridine (15.0 mmol)
and 1.38 g methanesulphonyl chloride (12.0 mmol) in
100 mL CH2Cl2 according to Method A. The crude
product was recrystallised with PE–CH2Cl2 yielding
2.09 g (76%) of pale pink crystals. Anal. Calc. for
C14H13NO3S: C, 61.07. Found: C, 60.61%; H, N.
(2-Aminophenyl)(2-thienyl)methanone (0.45 g, 2.2
mmol) (synthesised according to the procedure de-
scribed by Hunziker et al. [17]) were reacted with 0.26 g
pyridine (3.3 mmol) and 0.50 g 4-methyl-1-benzene-
sulphonyl chloride (2.64 mol) in 50 mL CH2Cl2 accord-
ing to Method A. CC of the crude product
(PE–EE=4:1; Rf=0.17) yielded 0.48 g (61%) of yel-
low crystals. Anal. (C18H15NO3S2): C, H, N.
6.33. N1-(4-Benzoylphenyl)-4-methyl-1-benenelsul-
phonamide (8a)
4-Aminophenyl-phenylmethanone (0.99 g, 5.0 mmol)
were reacted with 0.59 g pyridine (7.5 mmol) and 1.14
g 4-methyl-1-benzenesulphonyl chloride (6.0 mmol) in
50 mL CH2Cl2 according to Method A. CC of the
crude product (PE–EE=3:1; Rf=0.22) yielded 1.63 g
(93%) of a white solid. Anal. Calc. for C20H17NO3S: C,
68.90. Found: C, 68.27%; H, N.
6.28. N1-[2-(2-Thienylcarbonyl)phenyl]-4-
chloro-1-benzenesulphonamide (4b)
(2-Aminophenyl)(2-thienyl)methanone (0.45 g, 2.2
mmol) (synthesised according to the procedure de-
scribed by Hunziker et al. [17]) were reacted with 0.26 g
pyridine (3.3 mmol) and 0.56 g 4-chloro-1-benzene-
sulphonyl chloride (2.64 mmol) in 50 mL CH2Cl2 ac-
cording to Method A. CC of the crude product
(PE–EE=4:1; Rf=0.33) yielded 0.79 g (75%) of yel-
low crystals. Anal. (C17H12ClNO3S2): C, H, N.
6.34. 4-Benzoyl-1-(4-chlorophenylsulphonamido)-
benzene (8b)
4-Aminophenyl-phenylmethanone (0.99 g, 5.0 mmol)
were reacted with 0.59 g pyridine (7.5 mmol) and 1.27
g 4-chloro-1-benzenesulphonyl chloride (6.0 mmol) in
50 mL CH2Cl2 according to Method A. CC of the
crude product (PE–EE=5:2; Rf=0.29) yielded 1.73 g
(93%) of white crystals. Anal. (C19H14ClNO3S): C, H,
N.
6.29. N-(3-Benzoylphenyl)methanesulphonamide (5)
3-Aminophenyl-phenylmethanone (0.99 g, 5.0 mmol)
were reacted with 0.59 g pyridine (7.5 mmol) and 0.69
g methanesulphonyl chloride (6.0 mmol) in 50 mL
CH2Cl2 according to Method A. CC of the crude
product (PE–EE=1:1; Rf=0.56) yielded 0.99 g (72%)
of white crystals. Anal. (C14H13NO3S): C, H, N.
6.35. N1-(2-Benzoylphenyl)acetamide (9)
2-Aminophenyl-phenylmethanone (1.97 g, 10.0
mmol) were reacted with 1.19 g pyridine (15.0 mmol)
and 0.94 g ethanoyl chloride (12.0 mmol) in 50 mL
CH2Cl2 according to Method A. CC of the crude
product (PE–EE=3:1; Rf=0.47) yielded 1.46 g (61%)
of white crystals. Anal. (C15H13NO2): C, H, N.
6.30. 3-Benzoyl-1-(4-methylphenylsulphonamido)benzol
(6a)
3-Aminophenyl-phenylmethanone (0.99 g, 5.0 mmol)
were reacted with 0.59 g pyridine (7.5 mmol) and 1.14
g 4-methyl-1-benzenesulphonyl chloride (6.0 mmol) in
50 mL CH2Cl2 according to Method A. CC of the
crude product (PE–EE=2:1; Rf=0.38) yielded 1.19 g
(68 %) of white crystals. Anal. (C20H17NO3S): C, H, N.
6.36. 2-Benzoyl-1-phenylcarboxamidobenzene (10a)
2-Aminophenyl-phenylmethanone (0.99 g, 5.0 mmol)
were reacted with 0.59 g pyridine (7.5 mmol) and 0.84
g 1-benzenecarbonyl chloride (6.0 mmol) in 50 mL
CH2Cl2 according to Method A. CC of the crude
product (PE–EE=6:1; Rf=0.27) yielded 1.56 g (99%)
of a white solid. Anal. (C20H15NO2): C, H, N.
6.31. 3-Benzoyl-1-(4-chlorophenylsulphonamido)benzene
(6b)
3-Aminophenyl-phenylmethanone (0.99 g, 5.0 mmol)
were reacted with 0.59 g pyridine (7.5 mmol) and 1.27
g 4-chloro-1-benzenesulphonyl chloride (6.0 mmol) in
50 mL CH2Cl2 according to Method A. CC of the
crude product (PE–EE=3:1; Rf=0.22) yielded 1.50 g
(80%) of a white solid. Anal. (C19H14ClNO3S): C, H, N.
6.37. N1-(2-Benzoylphenyl)-4-methylbenzamide (10b)
2-Aminophenyl-phenylmethanone (1.48 g, 7.5 mmol)
were reacted with 1.58 g pyridine (20 mmol) and 1.55 g
4-methyl-1-benzenecarbonyl chloride (10.0 mmol) in 50
mL CH2Cl2 according to Method A. CC of the crude
product (PE–EE=8:1; Rf=0.25) yielded 1.59 g (67%)
of yellow crystals. Anal. (C20H15NO2): C, H, N.
6.32. N-(4-Benzoylphenyl)methanesulphonamide (7)
4-Aminophenyl-phenylmethanone (1.97 g, 10.0

G. Dannhardt et al. / European Journal of Medicinal Chemistry 37 (2002) 147–161
159
6.38. N1-(2-Benzoylphenyl)-4-chlorobenzamide (10c)
6.43. 3-Benzoyl-1-(4-methylphenylcarboxamido)benzene
(12b)
2-Aminophenyl-phenylmethanone (0.99 g, 5 mmol)
were reacted with 0.59 g pyridine (7.5 mmol) and 1.05
g 4-chloro-1-benzenecarbonyl chloride (6.0 mmol) in 50
mL CH2Cl2 according to Method A. CC of the crude
product (PE–EE=4:1; Rf=0.33) yielded 1.08 g (64%)
of a yellow solid. Anal. (C20H14ClNO2): C, H, N.
3-Aminophenyl-phenylmethanone (0.59 g, 3.0 mmol)
were reacted with 0.36 g pyridine (4.5 mmol) and 0.56
g 4-methyl-1-benzenecarbonyl chloride (3.6 mmol) in 50
mL CH2Cl2 according to Method A. CC of the crude
product (PE–EE=2:1; Rf=0.60) yielded 0.86 (91%) of
white crystals. Anal. (C21H17NO2): C, H, N.
6.39. 1-Phenylcarboxyamido-2-(2-thienylcarbonyl)-
benzene (11a)
6.44. 3-Benzoyl-1-(4-chlorophenylcarboxamido)benzene
(12c)
(2-Aminophenyl)(2-thienyl)methanone (0.61 g, 3.0
mmol) (synthesised according to the procedure de-
scribed by Hunziker et al. [17]) were reacted with 0.48 g
pyridine (6.0 mmol) and 0.63 g benzenecarbonyl chlo-
ride (4.5 mmol) in 50 mL CH2Cl2 according to Method
A. CC of the crude product (PE–EE=4:1; Rf=0.36)
3-Aminophenyl-phenylmethanone (0.59 g, 3.0 mmol)
were reacted with 0.36 g pyridine (4.5 mmol) and 0.63
g 4-chloro-1-benzenecarbonyl chloride (3.6 mmol) in 50
mL CH2Cl2 according to Method A. CC of the crude
product (PE–EE=4:1; Rf=0.27) yielded 0.81 g (81%)
of white crystals. Anal. (C20H14ClNO2): C, H, N.
gave 0.84
g
(91%) of yellow crystals. Anal.
(C18H13NO2S): C, H, N.
6.45. 4-Benzoyl-1-phenylcarboxamidobenzene (13a)
6.40. 1-(4-Methylphenylcarboxyamido)-2-(2-
thienylcarbonyl)benzene (11b)
4-Aminophenyl-phenylmethanone (0.59 g, 3.0 mmol)
were reacted with 0.36 g pyridine (4.5 mmol) and 0.51
g 1-benzenecarbonyl chloride (3.6 mmol) in 50 mL
CH2Cl2 according to Method A. CC of the crude
product (PE–EE=2:1; Rf=0.41) yielded 0.81 g (89%)
of white crystals. Anal. (C20H15NO2): C, H, N.
(2-Aminophenyl)(2-thienyl)methanone (0.61 g, 3.0
mmol) (synthesised according to the procedure de-
scribed by Hunziker et al. [17] were reacted with 0.48 g
pyridine (6.0 mmol) and 0.70 g 4-methyl-1-benzenecar-
bonyl chloride (4.5 mmol) in 50 mL CH2Cl2 according
to Method A. CC of the crude product (PE–EE=4:1;
Rf=0.34) yielded 0.86 g (89%) of yellow crystals. Anal.
(C19H15NO2S): C, H, N.
6.46. 4-Benzoyl-1-(4-methylphenylcarboxamido)benzene
(13b)
4-Aminophenyl-phenylmethanone (0.59 g, 3.0 mmol)
were reacted with 0.36 g pyridine (4.5 mmol) and 0.56
g 4-methyl-1-benzenecarbonyl chloride (3.6 mmol) in 50
mL CH2Cl2 according to Method A. CC of the crude
product (PE–EE=2:1; Rf=0.58) yielded 0.72 g (76%)
of white crystals. Anal. (C21H17NO2): C, H, N.
6.41. N1-[2-(2-Thienylcarbonyl)phenyl]-4-chloro-
benzamide (11c)
(2-Aminophenyl)(2-thienyl)methanone (0.48 g, 2.2
mmol) (synthesised according to the procedure de-
scribed by Hunziker et al. [17]) were reacted with 0.26 g
pyridine (3.3 mmol) and 0.46 g 4-chloro-1-benzenecar-
bonyl chloride (2.64 mmol) in 50 mL CH2Cl2 according
to Method A. CC of the crude product (PE–CH2Cl2=
1:3; Rf=0.50) yielded 0.46 g (61%) of a yellow solid.
Anal. Calc. for C18H12ClNO2S: C, 63.25. Found: C,
62.79%; H, N.
6.47. 4-Benzoyl-1-(4-chlorophenylcarboxamido)benzene
(13c)
4-Aminophenyl-phenylmethanone (0.59 g, 3.0 mmol)
were reacted with 0.36 g pyridine (4.5 mmol) and 0.63
g 4-chloro-1-benzenecarbonyl chloride (3.6 mmol) in 50
mL CH2Cl2 according to Method A. CC of the crude
product (PE–EE=2:1; Rf=0.49) yielded 0.84 g (83%)
of a white solid. Anal. (C20H14ClNO2): C, H, N.
6.42. 3-Benzoyl-1-phenylcarboxamidobenzene (12a)
6.48. N-(2-Acetylphenyl)methanesulphonamide (14)
3-Aminophenyl-phenylmethanone (0.59 g, 3.0 mmol)
were reacted with 0.36 g pyridine (4.5 mmol) and 0.51
g 1-benzenecarbonyl chloride (3.6 mmol) in 50 mL
CH2Cl2 according to Method A. CC of the crude
product (PE–EE=2:1; Rf=0.48) yielded 0.85 g (94%)
of white crystals. Anal. Calc. for C20H15NO2: C, 79.71.
Found: C, 79.08%; H, N.
1-(2-Aminophenyl)-1-ethanone (0.68 g, 5.0 mmol)
were reacted with 0.59 g pyridine (7.5 mmol) and 0.69
g methanesulphonyl chloride (6.0 mmol) in 50 mL
CH2Cl2 according to Method A. The crude product
was recrystallised with PE–EE yielding 0.65 g (61%) of
white crystals. Anal. (C9H11NO3S): C, H, N.

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G. Dannhardt et al. / European Journal of Medicinal Chemistry 37 (2002) 147–161
6.49. N-(9-Oxo-9H-1-fluorenyl)methanesulphonamide
(15)
added dropwise and the mixture was heated under reflux
for 1 h at r.t. The mixture was poured into ice water and
acidified with 10% H2SO4. The organic layer was sepa-
rated dried over Na2SO4 and the solvent evaporated.
The crude product was recrystallised with PE–EE yield-
ing 0.73 g (66%) of white crystals. Anal. (C14H15NO3S):
C, H, N.
1-Amino-9H-9-fluorenone (0.45 g, 2.30 mmol) were
reacted with 0.46 g pyridine (5.8 mmol) and 0.40 g
methanesulphonyl chloride (3.45 mmol) in 50 mL
CH2Cl2 according to Method A. CC of the crude
product (PE–EE=3:1; Rf=0.22) yielded 0.18 g (29%)
of an orange solid. Anal. (C14H11NO2S): C, H, N.
6.54. N-(2-Benzylphenyl)methanesulphonamide (20)
6.50. N-(2-Benzoyl-3-methoxyphenyl)methanesul-
phonamide (16)
To a stirred solution of 1.83 g (10 mmol) 2-ben-
zylphenylamine and 2.53 g (25 mmol) Et3N in 100 mL
dry 1,2-dichloroethane, 2.29 g (20 mmol) methane-
sulphonyl chloride were added dropwise. The solution
was refluxed for 10 h before being hydrolysed with the
equivalent amount of water. The organic layer was
separated, washed three times with water, Na2CO3 and
water and finally dried with Na2SO4. The solvent was
evaporated under reduced pressure yielding a yellow oil.
CC of the crude product (PE–EE=4:1; Rf=0.18)
(2-Amino-6-methoxyphenyl)(phenyl)methanone (0.80
g, 3.5 mmol) (synthesised according to the procedure
described by Walsh [14]) were reacted with 0.42 g
pyridine (5.3 mmol) and 0.48 g methanesulphonyl chlo-
ride (4.2 mmol) in 50 mL CH2Cl2 according to Method
A. CC of the crude product (PE–EE=6:1; Rf=0.37)
yielded 0.55
g (51%) of a yellow solid. Anal.
(C15H15NO4S) C, H, N.
yielded 1.22
g
(47%) of white crystals. Anal.
(C14H15NO2S): C, H, N, S.
6.51. N-(2-Benzoylphenyl)-N-methylmethanesul-
phonamide (17)
Compound 1a (0.83 g, 3.0 mmol) were dissolved in 30
mL of absolute THF and stirred. To the stirred solution,
0.76 g dimethyl sulphate (6.0 mmol) were added drop-
wise and the mixture stirred over night. To this mixture
were added 50 mL of concd. NH3 and refluxed for 1 h.
The solution was washed three times with 50 mL
CH2Cl2. The organic layers were collected, dried over
Na2SO4 and the solvent was evaporated. CC of the crude
product (PE–EE=1:1; Rf=0.33) yielded 0.49 g (56%)
of yellow crystals. Anal. (C15H15NO2S): C, H, N.
Acknowledgements
Financial support by the Fonds der Chemischen In-
dustrie is gratefully acknowledged.
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[4] J.-Y. Fu, J.L. Masferrer, K. Seibert, et al., J. Biol. Chem. 265
(1990) 16737–16740.
6.52. N-[2-(2-Phenyl-1,3-dithiolane-2-yl)phenyl]-
methanesulphonamide (18)
[5] J.L. Masferrer, B.S. Zweifel, K. Seibert, et al., J. Clin. Invest. 86
(1990) 1375–1379.
To a cooled (ice bath) solution of 0.83 g 1a (3.0 mmol)
and 0.57 g 1,2-ethanedithiol (6.0 mmol) in 50 mL
CH2Cl2, 0.55 g boron trifluoride etherate (4 mmol) were
added dropwise. After 30 min the ice bath was removed
and the solution stirred over night at r.t. The organic
phase was washed with saturated NaHCO3 and subse-
quently with water. The organic layer was separated
dried over Na2SO4 and the solvent evaporated. CC of
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