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S. M. Bromidge et al. / Bioorg. Med. Chem. 7 (1999) 2767±2773
Summary
determined using a Fisons VG 302 single quadrupole mass
spectrometer. Solvents and reagents were of commercial
grade and used without puri®cation. Chromatography
where required was performed on Merck Art. 7734 silica
gel or Fluka silica gel 60 (60739).
In conclusion we have used a synthetically accessible
model series of phenyl ureas (A) to generate a large data
set of 5-HT2C binding anities and selectivities and
rapidly elucidate SAR. Extrapolation of these results to
the more active but synthetically complex 1-(3-pyr-
idylcarbamoyl) indoline series (B) allowed us to target
optimal substitution patterns and identify potent and
selective 5-HT2C/2B antagonists such as (57±59B, 64±
65B and 67B).
The compounds were prepared from commercially
available or known anilines and indolines12 according to
the following general procedure. The preparations of
(50A) and (26B) are detailed as representative examples.
NMR spectral data and melting points of representative
phenyl ureas are illustrated in Table 6.
N-(3-Chloro-4-methylphenyl)-N0-(3-pyridyl) urea (50A).
Nicotinoyl azide (0.40 g, 2.7 mmol) [CAUTION! Heat-
ing this material in the absence of solvent can lead to
explosive decomposition. Larger-scale (ca. 20 g or
above) preparations following this procedure are
noticeably exothermic on reaching 70±80ꢁC, and
copious volumes of nitrogen are rapidly evolved.
Appropriate precautions for the storage and utilisation
of this reagent are strongly advised] was stirred at
re¯ux under nitrogen atmosphere in dry toluene
(10 mL) for 1 h, with gas evolution. The solution was
cooled to ambient temperature, and 3-chloro-4-methyl-
aniline (0.30 mL, 2.4 mmol) was added. The resultant
suspension was stirred for 1 h, when the solid was ®l-
tered o, washed with 1:1 toluene/dichloromethane, and
dried in vacuo at 70ꢁC. This gave the title compound
(0.64 g, 85%) as a white solid. The hydrochloride salt
Experimental
Melting points are uncorrected. The elemental analyses
were within 0.4% of the theoretical values. HPLC analysis
of test compounds was carried out on a Gilson 712 HPLC
system, using a model 231 sample injector, 306 pump with
806 manomeric module detector. A Hypersil BDS C18
3 mM (100Â3 mm i.d.) column was used with elution
under the following conditions: eluant A 0.1% TFA/H2O
v/v, eluant B 0.1% TFA/CH3CN v/v; ¯ow rate 0.7 mL/
min. The elution gradient was 0% B held for 0.5 min, then
linearly increased to 75% B over 24.5min, then held for
5 min. The UV detection wavelength was 218 nm. All ®nal
compounds were greater than 95% pure as judged by area
under the curve. NMR spectra were recorded on a Bruker
AC-200, AC-250 or AM-400 spectrometer using Me4Si as
internal standard. Electron impact mass spectra were
Table 6. 1H NMR spectral data and melting points of some representative phenyl ureas (A)
Cmpd.
1H NMR (d6-DMSO d: ppm J=Hz)
mp (ꢁC)
180±184
7A
7.3 (2H, m), 7.55 (2H, m), 7.95 (1H, d, J=8), 8.0 (1H, s), 8.2 (1H, d, J=4), 8.6 (1H, d, J=2),
9.0 (1H, s), 9.2 (1H, s)
8A (HCl)
14A
2.3 (3H, s), 6.85 (1H, d, J=7), 7.2 (1H, t, J=8), 7.3 (2H, m), 7.9 (1H, dd, J=8.5), 8.3 (1H, m),
8.5 (1H, d, J=5), 9.1 (1H, d, J=2), 9.5 (1H, s), 10.35 (1H, s)
7.3 (3H, m), 7.5 (2H, d, J=9), 7.95 (1H, m), 8.2 (1H, m), 8.6 (1H, d, J=2),
8.9 (1H, s), 9.0 (1H, s)
182±183
207±209
185±187
206±210
5A
7.0 (1H, m), 7.3 (3H, m), 7.7 (1H, s), 7.95 (1H, m), 8.2 (1H, m), 8.6 (1H, d, J=2),
8.95 (1H, s), 9.05 (1H, s)
7.25±7.42 (2H, m), 7.50 (1H, d, J=7), 7.83±7.90 (2H, m), 8.23 (1H, d, J=3),
8.62 (1H, d, J=1), 8.98 (1H, s), 9.23 (1H, s)
61A
62A
23A
7.02±7.48 (4H, m), 7.94 (1H, m), 8.19 (1H, m), 8.59 (1H, m), 8.87 (1H, s), 8.92 (1H, s)
1.32 (3H, t, J=8), 4.30 (2H, q, J=8), 7.34 (1H, dd, J=7.4), 7.60 (2H, m), 7.86±8.02 (3H, m),
8.21 (1H, m), 8.63 (1H, m), 8.96 (1H, s), 9.24 (1H, s)
190±191
156±160
45A
63A
47A
70A
68A
43A
29A
51A
53A
54A
3.82 (3H, s), 7.30 (2H, m), 7.78±8.00 (3H, m), 8.25 (1H, m), 8.64 (1H, m), 9.08 (1H, s),
9.39 (1H, s)
170±171
168±171
262±264
214±216
196±199
170±175
210
2.28 (3H, s), 7.21±7.39 (3H, m), 7.83±8.00 (2H, m), 8.20 (1H, m), 8.61 (1H, m),
8.89 (2H, m)
7.28±7.56 (2H, m), 7.80±8.06 (3H, m), 8.26 (1H, m), 8.64 (1H, s), 9.17 (1H, s),
9.54 (1H, s)
7.37 (1H, dd, J=7.4), 7.87 (1H, m, J=7), 7.97 (1H, m, J=7), 8.14±8.29 (3H, m),
8.67 (1H, m), 9.22 (1H, s), 9.81 (1H, s)
7.33 (1H, dd, J=7.4), 7.59±7.71 (2H, m), 7.95 (1H, m), 8.10 (1H, m), 8.22 (1H, m),
8.63 (1H, m), 9.04 (1H, s), 9.32 (1H, s)
7.41 (2H, m), 7.76±7.88 (2H, m), 7.99 (1H, d, J=7), 8.25 (1H, br.s), 8.68 (1H, br.s),
9.13 (1H, s), 9.37 (1H, s)
4.00 (3H, s), 7.16±7.45 (3H, m), 7.98 (1H, m, J=7 Hz), 8.23 (1H, m), 8.48±874 (3H, m),
9.60 (1H, s)
1.16 (3H, t, J=5), 2.64 (2H, q, J=5), 7.20±7.40 (3H, m), 7.67 (1H, s), 7.94 (1H, m),
8.20 (1H, d, J=2), 8.60 (1H, d, J=1), 8.90 (2H, m)
0.91 (3H, t, J=5), 1.56 (2H, q, J=5), 2.60 (2H, t, J=5), 7.20±7.35 (3H, m),
7.68 (1H, s), 7.94 (1H, m), 8.19 (1H, d, J=2), 8.59 (1H, d, J=1), 8.92 (2H, m)
1.42 (9H, s), 7.20±7.40 (3H, m), 7.66 (1H, d, J=2), 7.93 (1H, m), 8.19 (1H, d, J=5),
8.60 (1H, d, J=2), 8.90 (2H, m)
193±196
184±186
190±193