D. J. Bennett et al. / Bioorg. Med. Chem. Lett. 13 (2003) 1971–1975
1975
Table 6. Parameter values extracted from closed loop infusions to
maintain 60% BSR for 1 h periods
sodium methoxide (0.23 g, 4.2 mmol) added with stirring. The
resultant solution was then stirred at room temperature for 30
min prior to the addition of ammonium chloride (0.5 g). The
solvent was then removed under reduced pressure and diethyl
ether (200 mL) added. The precipitate was removed by fil-
tration and the filtrate evaporated under reduced pressure to
give a yellow oil. Chromatography of this oil on silica using
Parameter
44 (n=4)
Propofol 1 (n=5)
Infusion Rate mmol kgꢀ1minꢀ1
Stability of BSR (%)
Time to 30% BSR (min)
Time to righting (min)
5.0ꢂ0.4
2.5ꢂ0.3
2.4ꢂ0.1
6.8ꢂ0.4
4.9ꢂ0.3
4.1ꢂ0.6
5.4ꢂ0.9
21.8ꢂ1.7
toluene as the eluent afforded the title compound (6.3 g, 48%)
1
as a clear oil. HNMR (CDCl ): d 3.48 (s, 3H), 3.82 (s, 6H),
3
3.85–3.94 (m, 1H), 4.01–4.09 (m, 1H), 4.66 (t, 1H), 6.60 (d,
2H), 7.17 (t, 1H).
agent to propofol for the induction and maintenance of
anaesthesia in rats. Despite the lack of a direct corre-
lation between in vitro and in vivo activity, modulation
of GABAergic function may explain at least in part the
anaesthetic activity possessed by the analogues dis-
closed.
2-[N-(Hexahydro-4-oxazepinyl)]-3-methoxypropionic acid,
2,6-dimethoxyphenyl ester (26).
2-Bromo-3-methoxypropionic acid, 2,6-dimethoxyphenyl
ester (2.6 g, 8.2 mmol) was dissolved in toluene (30 mL) with
stirring. Triethylamine (2.5 mL, 18.2 mmol) and hexahydro-
1,4-oxazepine (1 g, 9.9 mmol) were then added and the reac-
tion mixture heated at 100 ꢃC under nitrogen overnight. The
reaction mixture was then cooled to room temperature and
diluted with diethyl ether (100 mL). The precipitate was
removed by filtration and washed with diethyl ether (100 mL).
The combined organic fractions were then extracted with 1N
HCl (100 mL). The aqueous phase was subsequently basified
to pH14 with 4M NaOH and extracted with diethyl ether (100
mLꢄ2). The combined organic fractions were dried over
sodium sulphate, filtered and concentrated under reduced
pressure to give a yellow oil. Chromatography of this oil on
basic alumina using toluene/ethyl acetate gradient as the elu-
ent afforded the title compound (0.7 g, 26%) as a clear oil
which crystallised on standing. Positive Ion ESI (M+H)+
339.9.
2-[N-(Hexahydro-4-oxazepinyl)]-3-methoxypropionic acid,
2,6-dimethoxyphenyl ester hydrochloride (1:1) salt (26.HCl).
Hydrogen chloride gas was passed through a solution of 2-
[N-(hexahydro-4-oxazepinyl)]-3-methoxypropionic acid, 2,6-
dimethoxyphenyl ester (0.7 g) in anhydrous dichloromethane
for 1–2 min. Most of the dichloromethane was then removed
under reduced pressure and the hydrochloride salt precipitated
by the addition of dry diethyl ether. The resulting white solid
Acknowledgements
The authors would like to thank the Analytical Chemistry
Department, Organon, Newhouse.
References and Notes
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50, 513. (b) Fulton, B.; Sorkin, E. M. Drugs 1995, 50, 636. (c)
Langley, M. S.; Heel, R. C. Drugs 1988, 35, 334.
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ton, N. M.; Hutchinson, E. J.; Lambert, J. J.; Maidment,
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Peters, J. A.; Rees, D. C.; Stevenson, D.; Sundaram, H. J.
Med. Chem. 1997, 40, 1668.
was filtered off and washed with diethyl ether to give the title
1
compound (0.7 g, 90%). HNMR (CDCl +sodium carbon-
3
ate): d 1.85–2.02 (m, 2H), 2.95–3.04 (m, 2H), 3.05–3.17 (m,
2H), 3.43 (s, 3H), 3.67–3.87 (m, 12H), 3.93 (t, 1H), 6.60 (d,
2H), 7.13 (t, 1H).
Positive Ion ESI (M+H)+ 339.9.
6. (a) Lambert, J. J.; Belelli, D.; Shepherd, S.; Muntoni, A.-L.;
Pistis, M.; Peters, J. A. Spec. Publ.-R. Soc. Chem. 1998, 220,
121. (b) Olsen, R. W. Toxicol. Lett. 1998, 100-101, 193. (c)
Lambert, J. J.; Belelli, D.; Hill-Venning, C.; Peters, J. A.
Trends Pharmacol. Sci. 1995, 16, 295.
5. 2-Bromo-3-methoxypropionic acid, 2,6-dimethoxyphenyl
ester.
2-Bromoacrylic acid, 2,6-dimethoxyphenyl ester (12 g, 42
mmol) was dissolved in methanol (300 mL, HPLC grade) and
7. Vijn, P. C. M.; Sneyd, J. R. Br. J. Anaesth. 1998, 81, 415.