Urotensin-II receptor antagonists: Synthesis and SAR of N-cyclic azaalkyl benzamides

Article abstract of DOI:10.1016/j.bmcl.2008.06.019

SAR exploration of the central diamine, benzyl, and terminal aminoalkoxy regions of the N-cyclic azaalkyl benzamide series led to the identification of very potent human urotensin-II receptor antagonists such as 1a with a K_i of 4 nM. The synthesis and structure-activity relationships (SAR) of N-cyclic azaalkyl benzamides are described.

Full text of DOI:10.1016/j.bmcl.2008.06.019

Bioorganic & Medicinal Chemistry Letters 18 (2008) 3950–3954
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Urotensin-II receptor antagonists: Synthesis and SAR of N-cyclic
azaalkyl benzamides
*
Jian Jin , Ming An, Anthony Sapienza, Nambi Aiyar, Diane Naselsky, Henry M. Sarau, James J. Foley,
Kevin L. Salyers, Steven D. Knight, Richard M. Keenan, Ralph A. Rivero, Dashyant Dhanak,
Stephen A. Douglas
Centers of Excellence for Drug Discovery, GlaxoSmithKline, 709 Swedeland Road, King of Prussia, PA 19406, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
SAR exploration of the central diamine, benzyl, and terminal aminoalkoxy regions of the N-cyclic azaalkyl
benzamide series led to the identification of very potent human urotensin-II receptor antagonists such as
1a with a Ki of 4 nM. The synthesis and structure–activity relationships (SAR) of N-cyclic azaalkyl benz-
amides are described.
Received 20 May 2008
Revised 5 June 2008
Accepted 5 June 2008
Available online 10 June 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Urotensin-II receptor antagonist
UT antagonist
N-cyclic azaalkyl benzamides
Urotensin-II (U-II), first isolated as a fish neuropeptide in the
1960’s,1 is the most potent vasoconstrictor known to date.2 Human
urotensin-II (hU-II) and its cognate receptor hUT (formerly known
as the GPR-14 receptor) are proposed to be involved in the (dys)
regulation of cardiorenal function,3 and have been implicated in
the etiology of numerous cardiorenal and metabolic diseases
including hypertension4 and heart failure.5,6 The impressive in vi-
tro and in vivo pharmacological activities of U-II has stimulated a
great deal of interest in developing small molecule UT modula-
tors.7,8 We previously reported that initial SAR exploration of a no-
vel aminoalkoxybenzyl pyrrolidine series resulted in the discovery
of a truncated sub-series exemplified by 2a.7d Herein, we describe
the synthesis, SAR, and optimization of this N-cyclic azaalkyl benz-
amide series that led to the identification of very potent human
urotensin-II receptor antagonists such as 1a.
Compound 2a showed good hUT receptor binding affinity with
a Ki of 200 nM (Fig. 1) in a [125I]hU-II radioligand binding assay
using HEK293 cell membranes stably expressing human recombi-
nant UT receptors9,10 and was an antagonist in a fluorometric
imaging plate reader (FLIPR) assay (measuring inhibition of hU-
II-induced [Ca2+]i-mobilization in HEK293 cells expressing human
recombinant UT receptor)9 with an IC50 of 170 nM. With the left-
hand side (LHS) phenyl moiety optimized previously,7d we focused
our attention on investigating and optimizing the central diamine,
benzyl, and terminal aminoalkoxy regions.
Cl
O
N
O
Cl
N
N
H
2a, hUT binding: Ki = 200 nM
hUT FLIPR: IC50 = 170 nM
Figure 1. In vitro profile of compound 2a.
We first explored the 3-amino pyrrolidine region, also referred
to as the central diamine region. Commercially available achiral or
optically pure Boc-protected diamines 3 were converted to the cor-
responding triamines 4 via reductive amination, deprotection, and
treatment with base (Scheme 1). Subsequent acid coupling of tri-
amines 4 with benzoic acids afforded the desired benzamides 2.
Compared to 3(S)-amino pyrrolidine (2a), 4-amino piperidine
(2b) had slightly lower affinity while piperazine (2c) and acyclic
analog 2d lost hUT binding affinity completely (Table 1). The pre-
ferred stereochemistry for 3-amino pyrrolidines was also studied.
It was found that the S and R enantiomers had very similar binding
affinity (2e vs 2f).
To efficiently explore the right-hand side (RHS) amino alkoxy
moiety and substituent(s) on the RHS phenyl ring, we developed
a robust solid-phase synthetic route outlined in Scheme 2. Resin-
bound pyrrolidine 5 was prepared from commercially available
optically pure Boc-protected 3(S)-amino pyrrolidine following
* Corresponding author. Tel.: +1 610 270 4881; fax: +1 610 270 4490.
E-mail addresses: jian.jin@gsk.com, jianjin19380@yahoo.com (J. Jin).
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.06.019

J. Jin et al. / Bioorg. Med. Chem. Lett. 18 (2008) 3950–3954
3951
Table 2
H
SAR of the aminoalkoxyphenyl moiety
O
a, b, c
R N
R N
Cl
Boc
N
R'
O
HN
R'
N
4
3
Cl
N
Ar
N
H
O
d
O
R N
Compound
Ar
hUT binding Kia (nM)
N
R'
N
R1
N
N
O
O
2
2a
200
Scheme 1. Reagents and conditions: (a) 4-(3-dimethylaminopropoxy) benzalde-
hyde, PS-BHÀ4 , NH4Cl, EtOH, rt; (b) 4 M HCl in 1,4-dioxane, MeOH, rt; (c) PS-
carbonate, MeOH, rt; (d) benzoic acids, PS-EDC, DCM, rt.
7a
7b
>3000
Table 1
O
N
SAR of the central diamine moiety
>10,000
O
O
R N
O
O
O
N
R'
N
N
N
N
N
N
R1
7c
7d
7e
7f
97
108
47
41
61
( )
( )
( )
( )
Compound
R1
hUT binding Kia (nM)
R
N
R'
Cl
O
N
2a
2b
2c
2d
2e
3,4-Dichloro
3,4-Dichloro
3,4-Dichloro
3,4-Dichloro
4-Bromo
200
N
H
500
N
N
H
Br
>10,000
>10,000
320
N
N
N
O
7g
N
H
N
Br
O
N
N
N
N
H
7h
7i
1000
3500
1500
5.5
Br
O
2f
4-Bromo
350
N
H
N
N
O
a
Mean of at least two determinations.
Br
O
7j
literature procedures.7d,11 Reductive amination of 5 with hydroxyl
benzaldehydes afforded resin-bound phenols 6. Mitsunobu
reaction of 6 with various amino alcohols and subsequent resin
cleavage produced the desired compounds 7.11 Moving the 3-dim-
ethylaminopropoxy from the para-position (2a) to the meta-(7a) or
ortho-(7b) position resulted in significant affinity loss (Table 2).
N-Methylpyrrolidin-3-yloxy compound 7c, a mixture of two dia-
stereoisomers, was slightly more potent than the 3-dimethylami-
nopropoxy analog 2a. A halo group such as bromo and chloro at
the 3-position modestly enhanced binding affinity (7e–f vs 7c, 7g
vs 2a) while a 3-methyl substituent did not provide affinity
enhancement (7d vs 7c). The aminoalkoxy moiety was further
optimized via holding the 3-bromo group constant. While 2-(pyrr-
olidin-1-yl)ethoxy (7h), 2-(morpholin-4-yl)ethoxy (7i) and 2-(pip-
erizin-4-yl)ethoxy (7j) had significantly lower affinity compared to
N-methylpyrrolidin-3-yloxy (7c) and 3-dimethylaminopropoxy
(2a), cyclic secondary amines such as piperidin-4-yloxy (1a) and
NH
Br
O
NH
7k
7m
Br
O
NH
44
Br
O
1a
4
NH
N
Br
O
7n
230
Br
a
Mean of at least two determinations.

3952
J. Jin et al. / Bioorg. Med. Chem. Lett. 18 (2008) 3950–3954
O
OH
R1
O
a
Cl
Cl
Cl
N
NH
N
N
DMHB
DMHB
Cl
6
5
N
O
O
R1
b, c
R'
R
Cl
Cl
N
N
H
7
Scheme 2. Reagents and conditions: (a) various hydroxybenzaldehydes, Na(OAc)3BH, 10% of HOAc in NMP, rt; (b) various amino alcohols, DIAD, PPh3, THF, À78 °C—rt; (c) 50%
of TFA in DCE, rt.
pyrrolidin-3(R)-yloxy (7k) were preferred. Pyrrolidin-3(R)-yloxy
(7k) was 8-fold more potent than pyrrolidin-3(S)-yloxy (7m). Add-
ing a large alkyl group such as benzyl to the piperidine significantly
reduced binding affinity (7n vs 1a).
Table 3
SAR of the phenethyl sub-series
O
O
N
Having identified the optimal amino alkoxy phenyl moiety, we
then investigated alternative linkers at the benzylic position. We
R
Cl
N
H
a
series of phenethyl analogs (Scheme 3).11
N
H
first prepared
Bis-nosylates 9 were synthesized from commercially available
4-hydroxyethyl phenols 8 via a one-pot procedure. Alkylation of
resin-bound amine 5 with bis-nosylates 9 and subsequent hydroly-
sis afforded phenethyl amines 10, which were then converted to
the desired products 11 via Mitsunobu reaction, resin cleavage
and simultaneous Boc group removal. Similar to benzyl amine
1a, phenethyl amine 11a had high hUT binding affinity (Table 3).
We also studied the 3-substituent on the RHS phenyl ring for the
phenethyl sub-series and found that 3-bromo (11a) and 3-chloro
(11b) were preferred, and 3-fluoro, 3-methoxy and 3-nitro did
not enhance affinity (11c–e vs 11f). The SAR in this region followed
the same trend as the benzyl series.
Cl
Compound
R
hUT binding Kia (nM)
11a
11b
11c
11d
11e
11f
3-Bromo
3-Chloro
3-Fluoro
3-Methoxy
3-Nitro
10
15
62
36
69
42
Hydrogen
a
Mean of at least two determinations.
We next explored whether the basicity of the central pyrroli-
dine was necessary for hUT binding affinity via replacing the meth-
ylene or ethylene linker with a sulfonyl linker. A solid-phase
synthesis of sulfonamides 15 is outlined in Scheme 4.12 Resin-
bound nosyl-protected diamines 13 were prepared from diamines
3 via nosylation, de-Boc, loading onto 2,6-dimethoxy-4-polysty-
rene benzyloxybenzaldehyde (DMHB-resin)13 and acid coupling.
Deprotection of 13, followed by sulfonylation of the resulting sec-
ondary amines with 3-bromo-4-hydroxy benzenesulfonyl chloride
(12), which was prepared from 2-bromophenol, and hydrolysis of
sulfonate byproducts formed during the sulfonylation step, pro-
ONosyl
a, b
OH
R
NosylO
R
HO
9
8
O
O
R
c, d
Cl
Cl
Cl
Cl
N
N
NH
N
OH
DMHB
DMHB
10
5
O
NH
R
e, f
Cl
Cl
N
N
H
O
11
Scheme 3. Reagents and conditions: (a) 2-nitrobenzenesulfonyl chloride, NaH, THF, rt; (b) ether, water, 0 °C; (c) bis-nosylates 9, tetrabutylammonium iodide, NMP, rt to
65 °C; (d) potassium trimethylsilanolate, THF, rt; (e) 4-hydroxy-N-Bocpiperidine, DIAD, PPh3, THF, À78 °C—rt; (f) 50% of TFA in DCE, rt.

J. Jin et al. / Bioorg. Med. Chem. Lett. 18 (2008) 3950–3954
3953
ing (Table 4). Furthermore, similar effects (Ki 12–140 nM) were
seen with the sulfonamides derived from azepine (15c),14 piperi-
dine (15d) and benzothiophene-leucine amide 16d (vide infra).
The stereochemistry of the 3-amino pyrrolidine was also exam-
ined. Similar to the benzyl sub-series, 3(R)-amino pyrrolidine
(15b) also showed good affinity, only slightly less potent than
the S-enantiomer 15a.
O
S
O
a
OH
R'
OH
Cl
Br
Br
N
12
O
H
b, c, d, e
Nosyl
R
Cl
Cl
R N
N
We next incorporated these newly identified affinity-enhancing
structural features into the previously reported benzothiophene-
leucine amide sub-series exemplified by 16a.7d As shown in
Table 5, 3-bromo-4-(piperidin-4-yloxy)benzyl compound 16b,
3-bromo-4-(pyrrolidin-3(R)-yloxy)phenethyl compound 16c, and
3-bromo-4-(piperidin-4-yloxy)benzene sulfonyl compound 16d
had excellent binding affinity to the hUT receptor.15 The SAR in
these regions for the benzothiophene-leucine amide sub-series
was similar to that of the truncated benzamide series (vide supra).
In addition to high affinity in the hUT binding assay, 1a was a
potent antagonist in the functional FLIPR assay with an IC50 of
4 nM (Fig. 2). The FLIPR potency of 1a was commensurate with
its receptor binding affinity consistent with the proposition that
the observed inhibition of intracellular calcium mobilization in
these cells was a result of hUT blockade. In mode of action studies
using the FLIPR assay, 1a was found to be an insurmountable
antagonist that significantly suppressed the maximal response of
hU-II. The observed kinetics of 1a were similar to those of known
UT antagonist palosuran,7c but distinct from those of SB-
7063757e and aminomethyl piperidines,7h which behaved as com-
petitive and reversible UT antagonists. In addition, key compounds
in the series including 1a were tested in a rat UT binding assay16
and found to have poor rat UT binding affinity (e.g. 1a,
Ki = 4100 nM). Although it is not clear what contributes to the poor
rat receptor affinity, the significant sequence differences between
human and rodent receptors8b might be a reason for the observed
receptor binding affinity difference. Known UT antagonists such as
palosuran7c showed a similar binding affinity difference between
human and rodent receptors. Compound 1a was also evaluated
Boc
N
H
R'
DMHB
13
3
O
O
O
N
i, j
Br
f, g, h
S
R
Cl
Cl
N
R'
DMHB
OH
14
O
O
O
Br
O
S
R
Cl
Cl
NH
N
R'
N
H
15
Scheme 4. Reagents and conditions: (a) ClSO3H, DCM, À3 °C—rt; (b) 2-nitro-
benzenesulfonyl chloride, pyridine, DCM, 0 °C—rt; (c) 4 M HCl in 1,4-dioxane,
MeOH, rt; (d) 2,6-dimethoxy-4-polystyrenebenzyloxy-benzaldehyde (DMHB-
resin), Na(OAc)3BH, DIEA, 1% of HOAc in NMP, rt; (e) 3,4-dichlorobenzoic acid,
DIC, HOAt, NMP, rt; (f) K2CO3 PhSH, NMP, rt; (g) 12, DCE, NMP, rt; (h) potassium
trimethylsilanolate, THF, rt; (i) 4-hydroxy-N-Bocpiperidine, DIAD, PPh3, THF,
À78 °C—rt; (j) 50% of TFA in DCE, rt.
duced resin-bound phenols 14 cleanly. 14 were then converted to
the desired products 15 via Mitsunobu reaction, resin cleavage, and
Boc deprotection. Although sulfonamide 15a was 10- to 30-fold
less potent than benzyl amine 1a and phenethyl amine 11a, 15a
still possessed good binding affinity (Ki 120 nM)—indicating the
basicity of the central pyrrolidine was not necessary for hUT bind-
Table 5
SAR of the benzothiophene-leucine amide sub-series
Table 4
SAR of the sulfonamide sub-series
O
O
O
H
N
N
O
R
S
N
H
Br
O
S
R
R
Cl
Cl
NH
N
R'
N
H
O
Compound
hUT binding Kia (nM)
Compound
R
hUT binding Kia (nM)
N
H
N
R'
N
O
16a
110
3
N
N
15a
15b
120
380
N
H
O
16b
16c
NH
Br
N
H
O
NH
18
12
15c
71
N
Br
N
H
( )
O
16d
NH
Br
S
15d
140
N
N
O O
H
a
a
Mean of at least two determinations.
Mean of at least two determinations.

3954
J. Jin et al. / Bioorg. Med. Chem. Lett. 18 (2008) 3950–3954
5. (a) Douglas, S. A.; Tayara, L.; Ohlstein, E. H.; Halawa, N.; Giaid, A. Lancet 2002,
Br
Cl
359, 1990; (b) Ng, L. L.; Loke, I.; O’Brien, R. J.; Squire, I. B.; Davies, J. E. Circulation
2002, 106, 2877; (c) Richards, A. M.; Nicholls, M. G.; Lainchbury, J. G.; Fisher, S.;
Yandle, T. G. Lancet 2002, 360, 545; (d) Lapp, H.; Boerrigter, G.; Costello-
Boerrigter, L. C.; Jaekel, K.; Scheffold, T.; Krakau, I.; Schramm, M.; Guelker, H.;
Stasch, J. P. Int. J. Cardiol. 2004, 94, 93.
O
O
Cl
N
NH
N
H
6. Russell, F. D.; Meyers, D.; Galbraith, A. J.; Bett, N.; Toth, I.; Kearns, P.; Molenaar,
P. Am. J. Physiol. 2003, 285, H1576.
1a, hUT binding Ki = 4 nM
hUT FLIPR IC50 = 4 nM
rUT binding Ki = 4,100 nM
7. (a) Flohr, S.; Kurz, M.; Kostenis, E.; Brkovich, A.; Fournier, A.; Klabunde, T.
J. Med. Chem. 2002, 45, 1799; (b) Croston, G. E.; Olsson, R.; Currier, E. A.;
Burstein, E. S.; Weiner, D.; Nash, N.; Severance, D.; Allenmark, S. G.; Thunberg,
L.; Ma, J.; Mohell, N.; O’Dowd, B.; Brann, M. R.; Hacksell, U. J. Med. Chem. 2002,
45, 4950; (c) Clozel, M.; Binkert, C.; Birker-Robaczewska, M.; Boukhadra, C.;
Ding, S.; Fischli, W.; Hess, P.; Mathys, B.; Morrison, K.; Muller, C.; Muller, C.;
Nayler, O.; Qiu, C.; Rey, M.; Scherz, M. W.; Velker, J.; Weller, T.; Xi, J.; Ziltener, P.
J. Pharmacol. Exp. Ther. 2004, 311, 204; (d) Jin, J.; Dhanak, D.; Knight, S. D.;
Widdowson, K.; Aiyar, N.; Naselsky, D.; Sarau, H. M.; Foley, J. J.; Schmidt, D. B.;
Bennett, C. D.; Wang, B.; Warren, G. L.; Moore, M. L.; Keenan, R. M.; Rivero, R.
A.; Douglas, S. A. Bioorg. Med. Chem. Lett. 2005, 15, 3229; (e) Douglas, S. A.;
Behm, D. J.; Aiyar, N. V.; Naselsky, D.; Disa, J.; Brooks, D. P.; Ohlstein, E. H.;
Gleason, J. G.; Sarau, H. M.; Foley, J. J.; Buckley, P. T.; Schmidt, D. B.; Wixted, W.
E.; Widdowson, K.; Riley, G.; Jin, J.; Gallagher, T. F.; Schmidt, S. J.; Ridgers, L.;
Christmann, L. T.; Keenan, R. M.; Knight, S. D.; Dhanak, D. Br. J. Pharmacol. 2005,
145, 620; (f) Lehmann, F.; Pettersen, A.; Currier, E. A.; Sherbukhin, V.; Olsson, R.;
Hacksell, U.; Luthman, K. J. Med. Chem. 2006, 49, 2232; (g) Luci, D. K.; Ghosh, S.;
Smith, C. E.; Qi, J.; Wang, Y.; Haertlein, B.; Parry, T. J.; Li, J.; Almond, H. R.; Minor,
L. K.; Damiano, B. P.; Kinney, W. A.; Maryanoff, B. E.; Lawson, E. C. Bioorg. Med.
Chem. Lett. 2007, 17, 6489; (h) Jin, J.; Wang, Y.; Wang, F.; Shi, D.; Erhard, K. F.;
Wu, Z.; Guida, B. F.; Lawrence, S. K.; Behm, D. J.; Disa, J.; Vaidya, K. S.; Evans, C. ;
McMillan, L. J.; Rivero, R. A.; Neeb, M. J.; Douglas, S. A. Bioorg. Med. Chem. Lett.
2008, 18, 2860.
Figure 2. In vitro profile of compound 1a.
in cytochrome P450 (CYP450) and selectivity versus other 7TM
receptors. 1a had CYP450 3A4 (IC50 1.9 M) and 2D6 (IC50
2.2 M) liability, but was clean again 1A2, 2C9 and 2C19 isozymes.
l
l
1a was 10- to 30-fold selective for hUT over 5HT1A (Ki = 38 nM),
5HT1D (Ki = 140 nM), 5HT2B (Ki = 140 nM), 5HT2C (Ki = 85 nM)
and D2 (Ki = 100 nM), and greater than 1000-fold selective for
hUT over 5HT1E (Ki > 10,000 nM), 5HT1F (Ki = 7200 nM), 5HT6
(Ki = 4100 nM) and b2 (Ki > 10,000 nM). In rat pharmacokinetic
(PK) studies (dosed at 0.5 mg/kg (iv) and 2.6 mg/kg (po) in Spra-
gue–Dawley rats), 1a had low oral bioavailability and high
in vivo clearance. Surprisingly, 1a showed low to moderate intrin-
sic clearance (human: 4.3 mL/min/g liver; rat 4.8 mL/min/g liver)
in the in vitro human and rat liver microsome stability studies.
In summary, SAR exploration of multiple regions of the N-cyclic
azaalkyl benzamide series led to the identification of very potent
human urotensin-II receptor antagonists such as 1a and key struc-
tural motifs necessary for achieving high hUT binding affinity.
8. For recent reviews, see: (a) Jin, J.; Douglas, S. A. Expert Opin. Ther. Patents 2006,
16, 467; (b) Dhanak, D.; Neeb, M. J.; Douglas, S. A. Ann. Rep. Med. Chem. 2003,
38, 99.
9. For radioligand binding and [Ca2+]i-mobilization assay details, see Ref. 2.
10. (a) The radioligand binding assay was used as the primary assay to generate
SAR.; (b) The biological assay results in the paper are a mean of at least two
determinations unless otherwise noted.; (c) All target compounds in the paper
were purified by preparative HPLC, characterized by 1H NMR and/or LCMS, and
had purity greater than 90%.
Acknowledgments
11. For experimental details, see: Dhanak, D.; Knight, S. D.; Jin, J.; Keenan, R. M.
WO Patent 2001045711-A1, 2001; Chem. Abstr. 2001, 135, 76785.
12. (a) For experimental details, see: Dhanak, D.; Knight, S. D.; Jin, J.; Rivero, R. A.
WO Patent 2002078641-A2, 2002; Chem. Abstr. 2002, 137, 294884.; (b) Dhanak,
D.; Knight, S. D.; Jin, J.; Rivero, R. A.; Sapienza, A. WO Patent 2002079188-A1,
2002; Chem. Abstr. 2002, 137, 294980.
We thank Bing Wang for NMR, Qian Jin for LC/MS, and Carl Ben-
nett for purification.
References and notes
13. (a) Jin, J.; Graybill, T. L.; Wang, M. A.; Davis, L. D.; Moore, M. L. J. Comb. Chem.
2001, 3, 97; (b) Available from Polymer Laboratories, part number: 1466-6689,
1. (a) Bern, H. A.; Lederis, K. J. Endocrinol. 1969, 45, xi; (b) Bern, H. A.; Pearson, D.;
Larson, B. A.; Nishioka, R. S. Recent Prog. Horm. Res. 1985, 41, 533.
150–300 lM, 1.5 mmol/g loading.
2. Ames, R. S.; Sarau, H. M.; Chambers, J. K.; Willette, R. N.; Aiyar, N. V.; Romanic,
A. M.; Louden, C. S.; Foley, J. J.; Sauermelch, C. F.; Coatney, R. W.; Ao, Z.; Disa, J.;
Holmes, S. D.; Stadel, J. M.; Martin, J. D.; Liu, W. S.; Glover, G. I.; Wilson, S.;
McNulty, D. E.; Ellis, C. E.; Elshourbagy, N. A.; Shabon, U.; Trill, J. J.; Hay, D. W.;
Ohlstein, E. H.; Bergsma, D. J.; Douglas, S. A. Nature 1999, 401, 282.
3. Douglas, S. A.; Dhanak, D.; Johns, D. G. Trends Pharmacol. Sci. 2004, 25, 76.
4. (a) Matsushita, M.; Shichiri, M.; Imai, T.; Iwashina, M.; Tanaka, H.; Takasu, N.;
Hirata, Y. J. Hypertens. 2001, 19, 2185; (b) Cheung, B. M.; Leung, R.; Man, Y. B.;
Wong, L. Y. J. Hypertens. 2004, 22, 1341.
14. Compound 15c is a racemic mixture of two enantiomers.
15. (a) Compounds 16b, 16c and 16d were prepared similarly as 1a, 11a and 15a.
For experimental details, see: Dhanak, D.; Knight, S. D.; Warren, G. L.; Jin, J.;
Widdowson, K. L.; Keenan, R. M. WO Patent 2001045700-A1, 2001; Chem.
Abstr. 2001, 135, 71313.; (b) Dhanak, D.; Knight, S. D.; Jin, J.; Rivero, R. A. WO
Patent 2002079155-A1, 2002; Chem. Abstr. 2002, 137, 294885.
16. For rat UT receptor radioligand binding assay details, see: Elshourbagy, N. A.;
Douglas, S. A.; Shabon, U.; Harrison, S.; Duddy, G.; Sechler, J. L.; Ao, Z.; Maleeff,
B. E.; Naselsky, D.; Disa, J.; Aiyar, N. V. Br. J. Pharmacol. 2002, 136, 9.