3934
G. Chiu et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3930–3934
13. (a) Schwinn, D. A.; Price, D. T.; Narayan, P. Mayo Clinic
Proc. 2004, 79, 1423; (b) Roehrborn, C. G.; Schwinn, D. J.
Urol. 2004, 171, 1029; (c) Sarma, P. K. S.; Tiwari, A.; Pal,
A. Expert Opin. Ther. Patents 2005, 15, 1333; (d) Daniels,
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14. Chiu, G.; Li, S.; Connolly, P. J.; Pulito, V. L.; Liu, J.;
Middleton, S. A. Bioorg. Med. Chem. Lett. 2007,
evaluated for their ability to bind to cloned human a1a,
a1b, and a1d adrenergic receptor subtypes as well as the
dopamine D2 receptor. The effect of aromatic substitu-
tion and fluorination of the alkoxy side-chain and phe-
nyl ring on binding affinity and selectivity has been
investigated. We discovered several compounds (cis-5,
6, 7, 11, and 20) that showed equal affinity for both
a1a and a1d adrenoceptor subtypes, with very good selec-
tivity over the a1b subtype. This selectivity profile pro-
vides a great improvement over the commercial drug
tamsulosin. Future work will further explore the issue
of metabolic stability, and progress will be reported in
due course.
15. Unpublished results.
16. The isomers with higher Rf values in TLC are the cis
isomers. The isomers with lower Rf values are the trans
isomers. The assignment is based on the NMR pattern of
similar (piperazinyl)cyclohexylsulfonamide compound
with known cis or trans configuration.
17. NMR and MS data of representative compounds.
Compound cis-5 NMR: d (CDCl3) 1.33 (d, J = 6.0 Hz,
6H), 1.4–1.9 (m, 12H), 2.22 (m, 3H), 2.8–3.1 (m, 3H), 3.44
(m, 1H), 3.92 (s, 3H), 3.94 (s, 3H), 4.52 (m, 1H), 5.08 (d,
J = 7.5 Hz, NH, 1H), 6.8–7.6 (m, 7H) MS: 517 (M+1).
Compound trans-5 NMR: d (CDCl3) 1.25 (m, 4H), 1.34
(d, J = 6.0 Hz, 6H), 1.65 (m, 2H), 1.8–2.1 (m, 6H), 2.30
(m, 3H), 2.95 (m, 3H), 3.08 (m, 1H), 3.93 (s, 3H), 3.95 (s,
3H), 4.52 (m, 1H), 4.90 (d, J = 7.3 Hz, NH, 1H), 6.8–7.6
(m, 7H). MS: 517 (M+1).
Acknowledgments
We express our gratitude to Ms. Sally Varga and Ms.
Aida Howell for their technical assistance in this
research.
References and notes
Compound cis-6 NMR: d (CDCl3) 1.32 (d, J = 5.8 Hz,
6H), 1.53 (m, 4H), 1.6–1.8 (m, 6H), 1.82 (br d, 2H), 2.20
(m, 3H), 2.91 (m, 1H), 3.00 (br d, 2H), 3.45 (m, 1H), 4.52
(m, 1H), 4.90 (br s, NH, 1H), 6.8–7.8 (m, 7H) MS: 493
(M+1).
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Compound trans-6 NMR: d (CDCl3) 1.22 (m, 4H), 1.35
(d, J = 6.1 Hz, 6H), 1.64 (m, 2H), 1.80 (bd, 2H), 1.92 (br t,
4H), 2.28 (m, 3H), 2.93 (m, 3H), 3.10 (m, 1H), 4.50 (m,
1H), 4.60 (br s, NH, 1H), 6.8–7.8 (m, 7H). MS: 493 (M+1).
Compound cis-11 NMR: d (CDCl3) 1.4–1.8 (m, 10H), 1.84
(br d, 2H), 2.25 (m, 3H), 2.90 (m, 3H), 3.42 (m, 1H), 3.92
(s, 3H), 3.94 (s, 3H), 4.35 (q, J = 15 Hz, 2H), 5.20 (d,
J = 7.8 Hz, NH, 1H), 6.7–7.6 (m, 7H) MS: 557 (M+1).
Compound trans-11 NMR: d (CDCl3) 1.1–1.4 (m, 4H),
1.65 (m 2H), 1.8–2.0 (m, 6H), 2.30 (m, 3H), 2.93 (m, 3H),
3.04 (m, 1H), 3.92 (s, 3H), 3.94 (s, 3H), 4.33 (q,
J = 14.8 Hz, 2H), 4.80 (d, J = 8.1 Hz, NH, 1H), 6.7–7.5
(m, 7H) MS: 557 (M+1).
Compound cis-18 NMR: d (CDCl3) 1.4–1.6 (m, 4H), 1.6–
1.8 (m, 6H), 1.82 (br d, 2H), 2.25 (m, 3H), 2.88 (m, 1H),
2.95 (br d, 1H), 3.40 (m, 1H), 3.92 (s, 3H), 3.94 (s, 3H),
4.16 (dt, J1 = 13 Hz, J2 = 3.0 Hz, 2H), 5.02 (d, J = 7.8 Hz,
NH, 1H), 6.10 (tt, J1 = 38 Hz, J2 = 2.0 Hz, 1H), 6.8–7.6
(m, 7H) MS: 539 (M+1).
Compound trans-18 NMR: d (CDCl3) 1.1–1.4 (m, 4H),
1.66 (m, 2H), 1.80 (br d, 2H), 1.90 (br d, 2H), 2.27 (m,
3H), 2.93 (m, 3H), 3.05 (m, 1H), 3.94 (s, 3H), 3.96 (s, 3H),
4.15 (dt, J1 = 13.5 Hz, J2 = 3.1 Hz, 2H), 4.60 (d,
J = 7.8 Hz, NH, 1H), 6.10 (tt, J1 = 38 Hz, J2 = 2.0 Hz,
1H), 6.7–7.6 (m, 7H) MS: 539 (M+1).
10. Blue, D. R. Jr; Grino, P. B.; Jung, D. T.; et al. [abstract]
In: Proceedings of the Fifth International Consultation on
BPH; June 25, 2000.
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Compound cis-20 NMR: d (CDCl3) 1.36 (d,J = 6.0Hz,
6H), 1.4–2.0 (m, 12H), 2.33 (m, 3H), 2.91 (m, 1H), 3.10 (br
d, 1H), 3.40 (m, 2H), 3.45 (m, 1H), 3.96 (s, 3H), 3.98 (s,
3H), 4.52 (m, 1H), 5.20 (d, J = 7.5 Hz, NH, 1H), 6.8–7.6
(m, 6H) MS: 535 (M+1).
Compound trans-20 NMR: d (CDCl3) 1.26 (m, 4H), 1.35
(d, J = 6.1 Hz, 6H), 1.64 (m, 2H), 1.8–2.0 (m, 6H), 2.32
(m, 3H), 2.90 (m, 3H), 3.04 (m, 1H), 3.94 (s, 3H), 3.98 (s,
3H), 4.52 (m, 1H), 4.70 (d, J = 7.8 Hz, NH, 1H), 6.7–7.6
(m, 6H) MS: 535 (M+1).
12. Cavalli, A.; Lattion, A. L.; Hummler, E., et al. Proc. Natl.
Acad. Sci. U.S.A. 1997, 94, 11589.