Selenofonsartan analogues: novel selenium-containing antihypertensive compounds

Article abstract of DOI:10.1016/j.tetlet.2007.07.011

2-Butyl-4-(methylseleno)-1-[[2′-(1H-tetrazol-5-yl)-1,1′-biphenyl-4-yl]methyl]-1H-imidazole-5-carboxylic acid (4) and 2-butyl-4-(phenylseleno)-1-[[2′-(1H-tetrazol-5-yl)-1,1′-biphenyl-4-yl]methyl]-1H-imidazole-5-carboxylic acid (5) have been prepared and te

Full text of DOI:10.1016/j.tetlet.2007.07.011

Tetrahedron Letters 48 (2007) 6301–6303
Selenofonsartan analogues: novel
selenium-containing antihypertensive compounds
Rebecca L. Grange,a,b James Ziogas,c James A. Angusc and Carl H. Schiessera,b,
*
aSchool of Chemistry, The University of Melbourne, Victoria 3010, Australia
bBio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Victoria 3010, Australia
cDepartment of Pharmacology, The University of Melbourne, Victoria 3010, Australia
Received 24 May 2007; revised 25 June 2007; accepted 5 July 2007
Available online 30 July 2007
Abstract—2-Butyl-4-(methylseleno)-1-[[20-(1H-tetrazol-5-yl)-1,10-biphenyl-4-yl]methyl]-1H-imidazole-5-carboxylic acid (4) and 2-
butyl-4-(phenylseleno)-1-[[20-(1H-tetrazol-5-yl)-1,10-biphenyl-4-yl]methyl]-1H-imidazole-5-carboxylic acid (5) have been prepared
and tested for AT1 receptor antagonist properties. Both compounds proved to be potent AT1 receptor antagonists, with pKb esti-
mates indicating that these selenides are very effective at blocking AT1 receptor mediated responses.
Ó 2007 Elsevier Ltd. All rights reserved.
The renin–angiotensin cascade is responsible for the con-
version of the protein angiotensinogen to the octapeptide
hormone angiotensin II.1 Interaction of angiotensin II
with its type 1 receptors (AT1 receptors) results in vaso-
constriction (narrowing of the blood vessels), vascular
remodeling (structural alterations to resistance arteries),
renal sodium reabsorption and norepinephrine release.1
All these responses raise blood pressure and can lead to
hypertension (high blood pressure). Consequently, sup-
pressing the renin–angiotensin cascade is an effective
strategy for alleviating hypertension.2
AT1 receptor antagonists, with fonsartan (3) being ten
times more potent than losartan (1).11,12
Work in our laboratories has been directed towards the
synthesis of selenium-containing compounds of poten-
tial therapeutic value.13 With this in mind, we were
curious about the effect that sulfur/selenium exchange
may have in sulfur-containing sartans such as fonsartan
(3) and analogues (2). Described herein is the synthesis
and preliminary pharmacological testing of selenofon-
sartan analogues 2-butyl-4-(methylseleno)-1-[[20-(1H-
tetrazol-5-yl)-1,10-biphenyl-4-yl]methyl]-1H-imidazole-
5-carboxylic acid (4) and 2-butyl-4-(phenylseleno)-1-[[20-
(1H-tetrazol-5-yl)-1,10-biphenyl-4-yl]methyl]-1H-imid-
azole-5-carboxylic acid (5).
The most direct and specific method for inhibiting the
renin–angiotensin cascade is to antagonize angiotensin
II at its AT1 receptors.3 The family of drugs4–9 that
achieve this are known as sartans (selective AT1 receptor
antagonists). Important advantages of sartans over
other antihypertensives include a relative lack of side ef-
fects and an ability to protect completely against angio-
tensin II.3 Losartan (1)10 was the first sartan to be
marketed as an antihypertensive,9 and inspired the
development of many more drugs. For example, work-
ers at Hoechst Roussel patented a number of com-
pounds, including tetrazole (2) and fonsartan (3).
These compounds proved to be potent, orally active
HO
Cl
N
PhS
N
CO2H
N
N
N
N
N
MeS
N
N
CO2H
N
N
N
N
H
N
H
1
2
O
O
O
S
N
N
H
*
Corresponding author. Tel.: +61 3 8344 2432; fax: +61 3 9347
8189; e-mail: carlhs@unimelb.edu.au
H
3
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.07.011

6302
R. L. Grange et al. / Tetrahedron Letters 48 (2007) 6301–6303
with previous estimates obtained for fonsartan in vascu-
H
H
N
N
lar tissue.20 The pKb estimates of 10.5 and 9.9 for com-
pounds 4 and 5 confirm that the selenosartans remain
potent AT1 receptor antagonists. Further results on
the characterization of the AT1 receptor antagonist
properties of these compounds will be reported in due
course.
CO2H
CO2Et
Br
a, b
N
N
6
7
c
H
N
SEM
N
d, e
CO2Et
SeR
CO2Et
N
N
Br
Acknowledgments
8
9: R = Me
10: R = Ph
We thank the Australian Research Council through
the Centres of Excellence program for financial support.
We thank Dr. Walter Thomas, Baker Heart Research
Institute, Melbourne, Australia, for providing the
CHO cells expressing the AT1A receptor and Mark
Ross-Smith for conducting the intracellular calcium
measurements.
Scheme 1. Reagents and conditions: (a) SOCl2 then EtOH/CH2Cl2
(91%); (b) Br2, KHCO3, DMF, 70 °C (90%); (c) NaH then SEM-Cl
(73%); (d) tBuLi then RSeSeR, THF, ꢀ78 °C (52%: R = Me, 67%:
R = Ph); (e) TFA/CH2Cl2 (81%: R = Me, 92%: R = Ph).
RSe
CO2H
Br
N
N
References and notes
a – c
N
N
N
N
1. Reid, I. A. Adv. Physiol. Educ. 1998, 20, S236.
2. Zaman, M. A.; Oparil, S.; Calhoun, D. A. Nat. Rev. Drug
Discov. 2002, 1, 621.
N
N
Tr
N
N
H
3. Mancia, G. Angiotensin II Receptor Antagonists: Current
Perspectives, 2nd ed.; Informa Healthcare: Abingdon,
2006.
4. Timmermans, P. B. M. W. M.; Wong, P. C.; Chiu, A. T.;
Herblin, W. F. Trends Pharmacol. Sci. 1991, 12, 55.
5. Timmermans, P. B. M. W. M.; Wong, P. C.; Chiu, A. T.;
Herblin, W. F.; Benfield, P.; Carini, D. J.; Lee, R. J.;
Wexler, R. R.; Saye, J. M.; Smith, R. D. Pharmacol. Rev.
1993, 45, 205.
11
4: R = Me
5: R = Ph
Scheme 2. Reagents and conditions: (a) 9 or 10, K2CO3, DMF, 70 °C
(47%: R = Me, 41%: R = Ph); (b) EtOH, reflux (86%: R = Me, 97%:
R = Ph); (c) NaOH, EtOH, H2O, reflux (50%: R = Me, 70%: R = Ph).
Our preparation of selenosartans (4, 5) began with
2-butyl-1H-imidazole-4(5)carboxylic acid (6), prepared
as described by Yanagisawa,14 which was esterified
and subsequently treated with bromine in DMF to
afford ethyl 5(4)-bromo-2-butyl-1H-imidazole-4(5)-
carboxylate (7) in a good yield (Scheme 1). It is interest-
ing to note that bromide 7 appears to be novel and that
similar attempts to chlorinate ethyl 2-butyl-1H-imidaz-
ole-4(5)-carboxylate met with a failure.15 Further reac-
tion with SEM chloride afforded the protected
imidazole 8,16 contaminated with 20% of the alternative
nitrogen-regioisomer. After flash chromatography, the
major isomer was further treated with tert-butyllithium
and then either dimethyl or diphenyl diselenide to
afford, after deprotection, imidazoles 9 and 10 in
moderate yields.
6. Goodfriend, T. L.; Elliott, M. E.; Catt, K. J. N. Engl. J.
Med. 1996, 334, 1649.
7. Johnston, C. I.; Naitoh, M.; Burrell, L. M. J. Hypertens.
1997, 15, S3.
8. Burnier, M.; Brunner, H. R. Lancet 2000, 355, 637.
9. Wexler, R. R.; Greenlee, W. J.; Irvin, J. D.; Goldberg, M.
R.; Prendergast, K.; Smith, R. D.; Timmermans, P. B. M.
W. M. J. Med. Chem. 1996, 39, 625.
10. Duncia, J. V.; Chiu, A. T.; Carini, D. J.; Gregory, G. B.;
Johnson, A. L.; Price, W. A.; Wells, G. J.; Wong, P. C.;
Calabrese, J. C.; Timmermans, P. B. M. W. M. J. Med.
Chem. 1990, 33, 1312.
11. Caille, J. C.; Corbier, A.; Fortin, M.; Hamon, G.;
Jouquey, S.; Vevert, J. P. U.S. Patent 5,412,101, 1991;
Chem. Abstr. 1992, 116, 214499g; Deprez, P.; Guillaume,
J.; Becker, R.; Corbier, A.; Didierlaurent, S.; Fortin, M.;
Frechet, D.; Hamon, G.; Heckmann, B.; Heitsch, H.;
Kleemann, H.-W.; Vevert, J.-P.; Vincent, J.-C.; Wagner,
A.; Zhang, J. J. Med. Chem. 1995, 38, 2357.
12. Ha¨user, W.; Dendorfer, A.; Nguyen, T.; Dominiak, P.
Kidney Blood Press. Res. 1998, 21, 29.
With imidazoles 9 and 10 in hand, they were smoothly
coupled to the trityl-protected biphenyl core structure
11, prepared according to the protocol of Carini and
co-workers17 to afford, after deprotection, selenofonsar-
tan analogues 4 and 5 in moderate yields (Scheme 2).18
13. Aumann, K. M.; Scammells, P. J.; White, J. M.; Schiesser,
C. H. Org. Biomol. Chem. 2007, 5, 1276, and references
cited therein.
14. Yanagisawa, H.; Amemiya, Y.; Kanazaki, T.; Shimoji, Y.;
Fujimoto, K.; Kitahara, Y.; Sada, T.; Mizuno, M.; Ikeda,
M.; Miyamoto, S.; Furukawa, Y.; Kioke, H. J. Med.
Chem. 1996, 39, 323.
15. Boschelli, H. D.; Connor, D. T. Heterocycles 1993, 35,
121.
Chinese hamster ovary cells stably expressing the rat
AT1A receptor19 were used to assess the potency of
the fonsartan analogues. Angiotensin II-induced in-
creases in intracellular calcium were effectively inhibited
by 30 nM of each of the compounds synthesized. In pre-
liminary experiments, an estimate of 10.3 for the pKb of
the known fonsartan analogue 2 compares favourably
16. The ambiguity in structure assignment is a result of the
mobility of the imidazolyl proton.

R. L. Grange et al. / Tetrahedron Letters 48 (2007) 6301–6303
6303
17. Carini, D. J.; Duncia, J. V.; Aldrich, P. E.; Chui, A. T.;
Johnson, A. L.; Pierce, M. E.; Price, W. A.; Santella, J. B.;
Wells, G. J.; Wexler, R. R.; Wong, P. C.; Yoo, S. E.;
Timmermans, P. B. M. W. M. J. Med. Chem. 1991, 34,
2525.
crystals (70%): mp = 143–144 °C; 1H NMR (CDCl3/
CD3OD) 0.84 (t, J = 7.4 Hz, 3H), 1.29 (sextet,
d
J = 7.5 Hz, 2H), 1.56 (quintet, J = 7.6 Hz, 2H), 2.57–
2.61 (m, 2H), 5.50 (s, 2H), 6.69 (d, J = 8.0 Hz, 2H), 7.09
(d, J = 8.0 Hz, 2H), 7.30–7.33 (m, 3H), 7.45 (d,
J = 7.6 Hz, 1H), 7.50–7.54 (m, 1H), 7.57–7.62 (m, 1H),
7.64–7.66 (m, 2H), 7.86 (d, J = 7.2 Hz, 1H); 13C NMR
(CDCl3/CD3OD) d 13.5, 22.1, 26.6, 29.6, 48.2, 120.8,
122.9, 125.8, 127.7, 128.0, 128.6, 128.8, 129.4, 130.6,
130.8, 131.2, 134.3, 136.8, 138.3, 139.8, 140.8, 154.6, 155.1,
18. Compound 4: white solid (50%): mp = 137–139 °C; 1H
NMR (CDCl3/CD3OD) d 0.88 (t, J = 7.4 Hz, 3H), 1.35
(sextet, J = 7.1 Hz, 2H), 1.62 (quintet, J = 7.6 Hz, 2H),
2.43 (s, 3H), 2.63–2.66 (m, 2H), 5.52 (s, 2H), 6.91 (d,
J = 8.0 Hz, 2H), 7.07 (d, J = 7.6 Hz, 2H), 7.45 (d,
J = 7.2 Hz, 1H), 7.51 (t, J = 7.4 Hz, 1H), 7.59 (t,
J = 7.4 Hz, 1H), 7.81 (d, J = 7.6 Hz, 1H); 13C NMR
(CDCl3/CD3OD) d 4.7, 13.6, 22.3, 26.8, 29.9, 48.0, 119.6,
123.0, 125.7, 128.0, 129.3, 130.6, 130.8, 131.1, 136.9, 138.2,
140.8, 141.3, 154.5, 155.1, 162.5; 77Se NMR (CDCl3/
CD3OD) d 195.2; Mass spectrum (ESI) 497 ([M+H]+);
HRMS calcd for C2H25N6O2Se [M+H]+ 497.1205, found
497.1196; mmax 1691, 1482 cmꢀ1. Compound 5: yellow
161.9; 77Se NMR (CDCl3/CD3OD)
d 383.8; Mass
spectrum (ESI) 559 ([M+H]+); HRMS calcd for
C28H27N6O2Se [M+H]+ 559.1361, found 559.1334; mmax
1687, 1478 cmꢀ1
.
19. Thomas, W. G.; Motel, T. J.; Kule, C. E.; Karoor, V.;
Baker, K. M. Mol. Endocrinol. 1998, 12, 1513.
20. Jin, D.; Song, K.; Oka, Y.; Takai, S.; Shiota, N.;
Miyazaki, M. Jpn. J. Pharmacol. 1997, 75, 259.