1096
X. Li et al. / Bioorg. Med. Chem. Lett. 10 (2000) 1093±1096
While some of the comparators and currently marketed
tamsulosin/Flomax1 show greater absolute anity for
all a1-AR subtypes, none are as selective as compounds
1c and 1h. Expanded biological pro®ling of key activ-
ities is presently underway.
Compound 5b: To a solution of d-Valerolactam 4b (6.1g, 61
mmol) in 100 mL toluene at 0 C under N2 was added NaH
o
(95% tech, 1.7 g, 71 mmol) and the resulting suspension was
stirred for 1 h. tert-Butyl-bromoacetate (9.5 mL, 64 mmol)
was added slowly and the reaction mixture was warmed to
room temperature. After 10 h saturated ammonium chloride
solution was added and the organic layer was separated. It was
washed with brine (3Â) and water, dried over sodium sulfate,
®ltered and concentrated to give a colorless oil (13.0 g, 100%).
1H NMR (300 MHz, CDCl3) d 4.01 (s, 2H), 3.34 (t, J=5.9 Hz,
2H), 2.42 (m, 2H), 1.85 (m, 4H), 1.47 (s, 9H). MS m/z (MH+)
214.
Acknowledgement
We wish to thank Dr. Gee-Hong Kuo for helpful dis-
cussions.
The oil (13.0 g, 61 mmol) was dissolved in methylene chlo-
ride (40 mL) followed by addition of tri¯uoroacetic acid (20
mL) and the reaction mixture was stirred under nitrogen for 4
h. Volatiles were removed in vacuo aording 8.8 g of 5b as
light-brown oil in 92% yield. This oil is used without further
puri®cation. 1H NMR (300 MHz, CD3OD) d 4.08 (s, 2H), 3.40
(t, J=5.7 Hz, 2H), 2.38 (t, J=5.7 Hz, 2H), 1.85 (m, 4H). MS
m/z (MH+) 158.
Compound 1c: A mixture of acid 5 (4.2 g, 27 mmol), amine
3c (7.1 g, 27 mmol), EDCI (5.6 g, 30 mmol), HOBt (4.0 g, 30
mmol) and DMAP (0.3 g, 1.5 mmol) in dichloromethane (100
mL) was allowed to stir at room temperature under nitrogen
atmosphere overnight. Saturated aqueous solution of potas-
sium carbonate was added and the organic layer was sepa-
rated. It was then washed with water (Â3), dried (over sodium
sulfate), ®ltered, and the ®ltrate was concentrated in vacuo.
The crude product was puri®ed by column chromatography
on silica gel eluting with 2±3% MeOH in CH2Cl2 providing
the title compound in 78% yield as a white solid (8.4 g, 21
mmol). 1H NMR (300 MHz, CDCl3): d 6.89 (m, 4H), 6.68 (bs,
1H), 4.58 (m, 1H), 4.01 (s, 2H), 3.38 (m, 4H), 3.10 (bs, 4H),
2.63 (bs, 4H), 2.54 (t, J=6.1 Hz, 2H), 2.43 (m, 2H), 1.82 (m,
4H), 1.33 (d, J=6.1 Hz, 6H). MS m/z (MH+) 403.
References and Notes
1. Harrison, J. K.; Pearson, W. R.; Lynch, K. R. Trends
Pharmacol. Sci. 1991, 12, 62.
2. Goetz, A. S.; King, H. K.; Ward, S. D.; True, T. A.; Rimele,
T. J.; Saussy, D. L., Jr. Eur. J. Pharmacol. 1995, 272, R5.
3. General procedure for the synthesis of compounds 1b±h:
Compound 3c: A mixture of 2-isopropoxyphenylpiperazine (2a,
6.6 g, 30 mmol), N-(2-bromoethyl)-phthalimide (7.6 g, 30
mmol) and potasssium carbonate (6.2 g, 45 mmol) in acetoni-
trile (100 mL) was allowed to heat at re¯ux overnight (ca. 12 h).
The reaction mixture was cooled to room temperature, the
precipitate was ®ltered o and the ®ltrate was concentrated in
vacuo. Puri®cation by column chromatography on silica gel
using 30% ethyl acetate/hexanes as eluent aorded the desired
product as a light-yellow solid (9.0 g, 23 mmol, 76%). 1H NMR
(300 MHz, CDCl3) d 7.85 (m, 2H), 7.71 (m, 2H), 6.89 (m, 4H),
4.59 (m, 1H), 3.87 (t, J=6.7 Hz, 2H), 3.05 (bs, 4H), 2.70 (2t,
J=6.6 Hz, 6H), 1.34 (d, J=6.0 Hz, 6H). MS m/z (MH+) 394.
The light-yellow solid (7.5 g, 19 mmol) was then dissolved in
warm ethanol (70.0 mL), methyl hydrazine (20.0 mL) was
added and the reaction mixture was allowed to heat at re¯ux
for 3 h. It was then cooled to room temperature and con-
centrated in vacuo aording the desired crude product 3c as
an oil (5.0 g. 19 mmol, 100%). 1H NMR (300 MHz, CDCl3) d
6.91 (m, 4H), 4.60 (m, 1H), 3.12 (bs, 4H), 2.86 (t, J=6.2 Hz,
2H), 2.64 (bs, 4H), 2.51 (t, J=6.2 Hz, 2H), 2.31 (bs, 2H), 1.34
(d, J=6.1 Hz, 6H). MS m/z (MH+) 264.
4. Swern, D.; Mancuso, A. J.; Huang, S.-L. J. Org. Chem.
1978, 43, 2480.
5. Pulito,V. L.; Li, X.; Varga, S. S.; Mulcahy, L. S.; Clark, K.
S.; Pekow, C. A.; Halbert, S. A.; Reitz, A. B.; Murray, W. V.;
Jollie, L. K. An investigation of the uroselective properties of
four novel Alpha-1a adrenoceptor subtype-selective antago-
nists. J. Pharmacol. Exp. Ther., in press.