Synthesis, pharmacology and pharmacokinetics of 3-(4-Arylpiperazin-1-ylalkyl)-uracils as uroselective α1A-antagonists

Article abstract of DOI:10.1016/S0960-894X(03)00305-6

Predominance in the urethra and prostate of the α_1A-adrenoceptor subtype, which is believed to be the receptor mediating noradrenaline induced smooth muscle contraction in these tissues, led to the preparation of α_1A-selective antagonists to be tested as uroselective compounds for the treatment of benign prostatic hyperplasia. Thus, a number of selective α_1A-adrenoceptor antagonists were synthesized and assayed in vitro for potency and selectivity. Dog pharmacokinetic parameters of 12 (RO700004) and its metabolite 40 (RO1104253) were established. The relative selectivity of intravenously administered 12, 40 and standard prazosin to inhibit hypogastric nerve stimulation-induced increases in intraurethral prostatic pressure versus phenylephrine-induced increases in diastolic blood pressure in anesthetized dogs was 76, 71 and 0.6, respectively.

Full text of DOI:10.1016/S0960-894X(03)00305-6

Bioorganic & Medicinal Chemistry Letters 13 (2003) 1873–1878
Synthesis, Pharmacology and Pharmacokinetics of 3-(4-Aryl-
piperazin-1-ylalkyl)-uracils as Uroselective ꢀ1A-Antagonists
F. J. Lopez,* L. Arias, R. Chan, D. E. Clarke, T. R. Elworthy, A. P. D. W. Ford,
A. Guzman, S. Jaime-Figueroa, J. R. Jasper, D. J. Morgans, Jr., F. Padilla,
A. Perez-Medrano, C. Quintero, M. Romero, L. Sandoval, S. A. Smith,
T. J. Williams and D. R. Blue
Roche Bioscience, 3431 Hillview Ave, Palo Alto, CA 94304, USA
Received 17 December 2002; accepted 5 March 2003
Abstract—Predominance in the urethra and prostate of the a1A-adrenoceptor subtype, which is believed to be the receptor med-
iating noradrenaline induced smooth muscle contraction in these tissues, led to the preparation of a1A-selective antagonists to be
tested as uroselective compounds for the treatment of benign prostatic hyperplasia. Thus, a number of selective a1A-adrenoceptor
antagonists were synthesized and assayed in vitro for potency and selectivity. Dog pharmacokinetic parameters of 12 (RO700004)
and its metabolite 40 (RO1104253) were established. The relative selectivity of intravenously administered 12, 40 and standard
prazosin to inhibit hypogastric nerve stimulation-induced increases in intraurethral prostatic pressure versus phenylephrine-induced
increases in diastolic blood pressure in anesthetized dogs was 76, 71 and 0.6, respectively.
# 2003 Elsevier Science Ltd. All rights reserved.
Competitive a1-adrenoceptor antagonists such as dox-
azosin, terazosin, prazosin, alfuzosin and tamsulosin
have been shown to be effective in relieving urinary
outflow obstruction and reducing symptom scores in
patients with benign prostatic hyperplasia (BPH).1
However, the usefulness of a1-adrenoceptor antagonists
in BPH is offset by their dose-limiting cardiovascular
effects, including postural hypotension, particularly
during initial dosing.2 The discovery and definition of
the a1A-, a1B- and a1D-adrenoceptor subtypes3 offers the
potential for more selective agents. Recently, much
interest has focused on the role of the a1A-adrenoceptor
subtype in BPH, as a result of studies demonstrating
that this subtype predominates in the urethra and pros-
tate of man,4 and it has been claimed to be the receptor
mediating noradrenaline induced smooth muscle con-
traction in these tissues.5 Thus, considerable effort has
been dedicated to identify a subtype selective a1A- over
and others14 have found potent and selective a1A-adre-
noceptor antagonists. However, clinical efficacy for the
treatment of symptomatic BPH with these compounds
has yet to be demonstrated.
In this study, we report the preparation and the in vitro
a1-adrenoceptor affinity profile of a series of a1A adre-
noceptor selective 3-(4-arylpiperazin-1-ylalkyl)-uracil
antagonists. Pharmacokinetic data and in vivo pharma-
cology in dog of selected compounds are also presented.
Synthetic approaches to general structure 1 are pre-
sented in Schemes 1–4.
a
1B- and a1D-adrenoceptor antagonist.6 Our group7 as
well as groups at Merck/Synaptic,8 Johnson & John-
son,9 Kissei,10 Abbott,11 Japan Tobacco,12 Recordati,13
Arylpiperazines 2 and 3 (Scheme 1) were the starting
synthetic cores for all final compounds. Preparation of
arylpiperazine 2 has been described before.7 Prepara-
tion of 3 is presented in Scheme 1.15 Thus, tri-
fluoroethylation of 5-fluoro-2-nitrophenol 4 gave ether
5 in 98% yield.16 Reduction of the nitro group with
*Corresponding author. Fax:+1-650-852-1875; e-mail: francisco.
lopez-tapia@roche.com
0960-894X/03/$ - see front matter # 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0960-894X(03)00305-6

1874
F.J.Lopez et al./ Bioorg.Med.Chem.Lett.13 (2003) 1873–1878
Scheme 1. Reagents and conditions: (a) CF3CH2OTf, Cs2CO3, NMP,
98%; (b) Ni2B, 1 M HCl, MeOH, 60 ꢀC; (c) (ClCH2CH2)2NH.HCl,
K2CO3, Diglyme, 220 ꢀC, 40% two steps.
.
Scheme 4. Reagents and conditions: (a) Br(CH2)3NH2 HBr, Et3N,
toluene, reflux, 13%; (b) 2, NaHCO3, CH3CN, reflux, 43%; (c) COCl2,
toluene, reflux, 77%; (d) Cl(CH2)3Br, K2CO3, CH3CN, 63%; (e) 5,6-
dihydrouracil, n-Bu4NF, THF, 26%; (f) Cl(CH2)3Br, n-Bu4NF, THF,
83%; (g) 2, K2CO3, NaI, CH3CN, reflux, 68%; (h) HCO2NH4, Pd/C,
MeOH, reflux, 81%.
Table 1. Compounds prepared according to Scheme 2
Entry
n
R1
R2
R3
R4 in 6
9
2
4
3
3
3
3
3
3
3
3
3
3
3
3
3
F
F
H
F
F
F
F
H
F
F
F
F
F
H
F
H
H
H
H
H
H
H
Me
Me
H
Me
Me
Me
Me
H
Et
i-Pr
Me
BOC
BOC
Bn
BOC
SEM
SEM
BOC
Bn
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Scheme 2. Reagents and conditions: (a) for R4=Bn or SEM: K2CO3,
Cl(CH2)nBr, DMF, 60–96%; (b) for R4=BOC: NaH, Cl(CH2)nBr,
DMF, 34–89%; (c) for R4=BOC: 3, neat, 210 ꢀC, 22–69%; (d) for
R4=Bn: 2, K2CO3, NaI, CH3CN, reflux, 52–80%; (e) for R4=SEM:
3, K2CO3, NaI, CH3CN, reflux, 61–88%; (f) for R4=Bn: HCO2NH4,
Pd/C, MeOH, reflux, 31–57%; (g) for R4=SEM: n-Bu4NF, THF, or
40% HF, CH3CN, 70 ꢀC, 62–88%.
H
F
Cl
Bn
BOC
SEM
SEM
SEM
Bn
H
H
H
H
OMe
NMe2
CF3
CH2OH
H
SEM
gave the final deprotected products directly, while the
treatment of 1-benzyl and 1-SEM-3-chloroalkyluracils 7
with arylpiperazines 2 and 3, respectively, furnished
intermediate 8. Hydrogenation or treatment with n-
Bu4NF or HF deprotected 8 (R4=benzyl, R4=SEM,
respectively) to give the final products.21 Table 1 shows
all products prepared by these synthetic routes. Also
indicated in the table is the protecting group R4 used in
the starting uracil derivatives 6 for each compound.
Scheme 3. Reagents and conditions: (a) NaH, 1-cyanocyclopropyl-
methyl methanesulfonate, DMF, 50 ꢀC, 70%; (b) HCl concd, acetic
acid, reflux, 90%; (c) methyl chloroformate, THF, À5 ꢀC; NaBH4,
H2O, 90%; (d) MsCl, Et3N, DCM, 0–5 ꢀC; (e) 2, K2CO3, NaI,
CH3CN, reflux, 65-84%; (f) HCO2NH4, Pd/C, MeOH, 62–85%;
(g) 3-benzyloxy-2,2-dimethylpropionyl chloride, benzene, 0 ꢀC, 86%;
(h) LiAlH4, THF, reflux, 96%; (i) p-TsCl, Et3N, DMAP, DCM, 95%;
(j) NaH, HMPA, 6a, 85 ꢀC, 73%; (k) 1-bromo-3-chloropropane,
n-Bu4NF, THF, 97%.
Scheme 3 shows the preparation of compounds 26, 28
and 31.21 Deprotonation of 1-benzylthymine 6a18a with
sodium hydride followed by treatment with 1-cyanocy-
clopropylmethyl methanesulfonate22 provided cyclopro-
pyl intermediate 24. Subsequent hydrolysis of the cyano
group and reduction of the resulting carboxylic acid in a
two-step sequence (methyl chloroformate/sodium boro-
hydride) gave alcohol 25. Activation of the alcohol as its
mesylate and treatment with arylpiperazine 2 gave, after
removal of the benzyl group, cyclopropyl derivative 26.
For the preparation of gem-dimethyl derivative 28,
arylpiperazine 2 was treated with 3-benzyloxy-2,2-dime-
thylpropionyl chloride,23 followed by reduction of the
resulting amide and debenzylation to obtain alcohol 27.
The hydroxyl group was activated as the tosylate, which
was reacted with the sodium salt of 1-benzylthymine in
nickel boride,17 followed by treatment with bis(chloro-
ethyl)amine at 220 ꢀC gave 3. Different uracil derivatives
6 were then utilized to prepare most of the final com-
pounds (Scheme 2). Uracils 6, N-1 protected as ben-
zyl,18 2-(trimethylsilyl)ethoxymethyl (SEM)19 or tert-
butoxycarbonyl (BOC),20 were transformed to the N-3
chloroalkyl intermediates 7. The reaction of 1-BOC-3-
chloroalkyluracils 7 and arylpiperazine 3 at 200–220 ꢀC

F.J.Lopez et al./ Bioorg.Med.Chem.Lett.13 (2003) 1873–1878
1875
HMPA at 85 ꢀC to obtain, after removal of the benzyl
group, compound 28. Azathymine derivative 31 was
prepared from 1-benzyl-6-azathymine 2924 following
standard conditions. Scheme 4 shows the preparation of
34, 36 and 39. Isatoic anhydride 32 was opened with 3-
bromopropylamine, and the resulting bromide was
coupled with arylpiperazine 2 to obtain 33. Closure to
the quinazolinedione system was achieved with phos-
gene in toluene at reflux to furnish 34. For the prepara-
tion of the dihydrouracil 36, arylpiperazine 3 was
reacted with 1-bromo-3-chloropropane to obtain chlo-
ride 35, which was then treated with 5,6-dihydrouracil.
Derivative 39, in which the propyl chain is attached to
the uracil ring N-1 rather than N-3, was obtained start-
ing from 3-benzylthymine 3725 following standard con-
ditions.
11 (RS-100329) or 12 (RO700004) is higher than that of
9 or 10, while the cyclopropyl and gem-dimethyl com-
pounds, 26 and 28, offer no improvement. Uracil deri-
vative 13, with no substitution at either the 5- or
6-position, and dihydrouracil 36 are somewhat less
selective (a1D/a1A or rat aorta/RBN ratio) than analo-
gue 12. Substitution at the uracil ring provides further
insight into different sterically and electronically
demanding groups. 5-Ethyl and 5-isopropyl-uracil deri-
vatives, 14 and 15, respectively, although potent and
selective, offer no advantage over 11 or 12. However,
5,6-dimethyl-uracil 16 displays both very high affinity
(pKi 10.4, pA2/pKB 9.5) and selectivity (a1B/D/a1A over
100). Quinazolinedione 34 also shows high potency at
the a1A-adrenoceptor subtype (pKi 10.2, pA2/pKB 9) but
low selectivity (rat aorta/RBN ratio 4). Among deriva-
tives with electron-withdrawing groups at uracil ring
position 5, such as 18, 19 and 22, the fluorouracil deri-
vative 18 compares very well to analogue 12. However,
compounds 20 and 21, which have electron-donating
groups at C-5 of the uracil ring, do not show improve-
ment in potency or selectivity. 6-Azathymine derivative
31 shows nanomolar potency at subtype a1A, but low
selectivity over a1D. Attachment of the propyl side chain
Table 2 shows the biological data for all compounds.
Binding affinity estimates (pKi) refer to the inhibition of
[3H]-prazosin binding to CHO-K1 cell membranes or
whole cells expressing human cloned a1A-, a1B-, a1D
-
adrenoceptors. Below the a1B and a1D pKi values, in
parenthesis, is the ratio of a1B over a1A, and a1D over
a1A affinities, respectively. Functional affinity estimates
(pA2/pKB) refer to the antagonist inhibition of in vitro
noradrenaline-stimulated contractions of rabbit bladder
at N-1 of uracil ring, rather than at N-3, lowers the a1A
-
over a1D-adrenoceptor selectivity to 10 from 50 (39 vs
11).
neck (RBN) and rat aortic rings, representative of a1A
-
and a1D-adrenoceptors, respectively.26 Below the rat
aorta pA2/pKB values, in parenthesis, is the ratio of rat
aorta over RBN affinities. As can be observed, there is
good correlation of pKi with pA2/pKB values at a1A- and
Metabolism of compound 12 was assessed by incu-
bation with hepatic microsomes from rat, dog, monkey
and human in the presence of NADPH. Figure 1 shows
the radiochromatograms of [14C]-12 metabolism in the
four species. The similarity of dog and human profiles is
clear. Table 3 shows the relative rate of metabolism of
selected compounds by dog liver microsomes. The
diminution of metabolism rate of compound 12 (0.6)
compared to 11 (1.0) can be attributed to blockade of
aromatic hydroxylation by fluoro-substitution. Indeed,
phenol [(i.e., 1, R1=OH, X=(CH2)3, R2=H and
a1D-adrenoceptors. The majority of compounds bind to
the a1A-adrenoceptor in the nanomolar range, and
demonstrate selectivity over the other two subtypes in
both radioligand binding and functional affinity assays.
The length and substitution pattern of the linker between
the uracil and the piperazinyl rings seem optimal for a
straight 3-carbon chain. Thus the pA2/pKB selectivity of
Table 2. Affinity estimates (pKi and pA2/pKB)a for compounds described in Schemes 2–4
Entry
pKi a1A
pKi a1B (a1B/a1A
)
pKi a1D (a1D/a1A
)
pA2/pKB RBN
pA2/pKB rat aorta (Aorta/RBN)
9
9.3Æ0.05
9.8Æ0.1
9.6Æ0.1
8.9Æ0.1
8.9Æ0.1
9.1Æ0.1
8.6Æ0.2
10.4Æ0.5
8.8Æ0.2
9.6Æ0.1
9.0Æ0.2
8.8Æ0.2
8.2Æ0.2
NDc
9.1Æ0.1
8.4Æ0.05
9.5Æ0.1
10.2Æ0.1
9.0Æ0.05
8.7Æ0.3
7.8Æ0.1(32)
8.0Æ0.1(63)
7.5Æ0.1 (126)
7.1Æ0.1 (63)
7.0Æ0.2 (79)
7.1Æ0.1 (100)
7.0Æ0.2 (40)
7.8Æ0.05 (398)
6.8Æ0.2 (158)
7.0Æ0.1 (398)
7.3Æ0.2 (50)
6.8Æ0.2 (100)
6.7Æ0.3 (32)
7.7Æ0.2
8.6Æ0.04 (5)
NDc
8.5Æ0.05
9.2Æ0.2
9.2Æ0.1
8.9Æ0.1
8.5bÆ0.02
9.1Æ0.2
8.4Æ0.1
9.5Æ0.2
8.7bÆ0.1
8.9Æ0.05
8.7Æ0.1
8.8Æ0.04
8.2bÆ0.03
9.1bÆ0.2
8.6Æ0.05
7.8Æ0.1
8.7Æ0.01
9.0Æ0.1
8.6bÆ0.05
8.5bÆ0.2
8.0Æ0.1 (2.9)
8.3Æ0.2 (7.9)
7.9Æ0.2 (20)
6.8Æ0.1 (126)
7.0Æ0.1 (32)
7.2Æ0.1 (79)
6.8Æ0.1 (40)
7.1Æ0.2 (251)
7.3Æ0.2 (50)
7.1Æ0.2 (63)
7.0Æ0.1 (50)
6.8Æ0.1 (100)
6.4Æ0.04 (63)
7.5Æ0.3 (40)
7.3Æ0.1 (25)
6.3bÆ0.3 (32)
7.7Æ0.2 (10)
8.4Æ0.1 (4)
10
11
12
13
14
15
16
17
18
19
20
21
22
26
28
31
34
36
39
7.9Æ0.1 (50)
7.2Æ0.1 (50)
7.5Æ0.1 (25)
7.6Æ0.2 (32)
NDc
8.3Æ0.1 (126)
7.3Æ0.2 (50)
7.6Æ0.03 (100)
8.0Æ0.2 (10)
7.5Æ0.2 (20)
7.0Æ0.2 (16)
8.2Æ0.3
7.2Æ0.1 (79)
6.4Æ0.1 (100)
7.4Æ0.02 (126)
8.3Æ0.1 (79)
6.9Æ0.1 (126)
7.0Æ0.1 (50)
7.8Æ0.1 (18)
6.9Æ0.1 (32)
8.1Æ0.2 (25)
8.7Æ0.2 (32)
7.5Æ0.1 (32)
7.7Æ0.2 (10)
6.9Æ0.1 (50)
7.1Æ0.1 (25)
aValues are meanÆSE mean, nꢁ3, unless otherwise noted.
bn=2.
cNot determined.

1876
F.J.Lopez et al./ Bioorg.Med.Chem.Lett.13 (2003) 1873–1878
Scheme 6. Reagents and conditions: (a) NBS, CF3CO2H, H2O,
DMSO; 10% NaHCO3, 57%; (b) p-TsOH, H2O, DMSO, 60 ꢀC, 33%.
40 show that both enantiomers are present in about 1:1
ratio in biologically produced 40. Relative stereo-
chemistry of this diol compound was assigned by the
synthetic preparation of both cis- and trans-diols and by
NOE NMR studies (Scheme 6).
Figure 1. Metabolism of [14C]-12 by hepatic microsomes.
Table 3. In vitro relative rate of metabolism of selected compounds
by dog liver microsomes
Table 4 shows the affinity at the a1A-, a1B- and a1D
adrenoceptor subtypes, the selectivity (a1B/a1A and a1D
-
/
Entry
Rel. rate met.a
Entry
Rel. rate met.a
a1A ratios), and the relative rate of metabolism in dog
microsomes of metabolites 23 and 40. Parent compound
12 is included for comparison purposes. Both 23 and 40
showed higher metabolic stability during incubation
with microsomes than 12 or any derivative in Table 3. In
11
12
13
14
16
1.0
0.6
1.1
1.4
6.4
18
20
21
36
0.5
0.2
0.4
1.0
addition, the cis-diol 40 showed a selectivity for the a1A
-
aRates of metabolism relative to compound 11 that is set to 1.0.
over a1B/D-adrenoceptors of over 30 in both radioligand
and functional studies, and an affinity of over pKi 8 at
the a1A subtype. The pharmacokinetic profiles of 12 and
40 in dogs are shown in Table 5. Compound 40 has a
terminal half life about 4 times longer than 12 following
iv administration to dogs (11 vs 2.5 h) as a result of a 4-
fold increase in the volume of distribution (4.0 vs 0.93
L/kg, respectively), while clearance remains about the
same.
R3=Me)] was isolated and identified as one of the
metabolites from incubation of compound 11 with dog
liver microsomes. On the other hand, compounds 18, 20
and 21 are quite comparable to 12, and the very potent
and selective compound 16 (see Table 2) undergoes
metabolism six times as fast as 11.
Metabolites of compound 12 formed in dog liver
microsomes were isolated and identified by mass spec-
trometric analysis, and structure formulas are shown in
Scheme 5. Peak numbers under each compound refer to
the retention times of the compounds in the radio-
chromatogram from dog liver microsomes (see Fig. 1).
Syntheses (Scheme 2 for 23 and Scheme 6 for 40) of
different metabolites confirmed the assignment. Isola-
tion of milligram quantities of 40 from a microsomal
incubation was accomplished for enantiomeric analysis.
Chiral HPLC studies27 with both biological and synthetic
The effects on the prostate versus diastolic blood pres-
sure (DBP) of 12 and 40, compared to the non-selective
a1-adrenoceptor antagonist prazosin, were studied in
dogs to evaluate their in vivo selectivity. Thus, pento-
barbital-anesthetized male mongrel dogs were adminis-
tered non-cumulative intravenous doses (0.03–300 mg/
kg) of prazosin, 12 or 40 to inhibit increases in intraur-
ethral pressure (IUP; balloon catheter) induced by
hypogastric nerve stimulation (HGNS; 20–50 V, 10 Hz,
10 s) as well as phenylephrine (PE)-induced increases in
diastolic blood pressure (DBP; femoral artery).28 Pra-
zosin non-selectively inhibited PE-induced increases in
DBP (PE-DBP) and HGNS-induced increases in IUP
(HGNS-IUP) yielding
a selectivity ratio of 0.6
(PE-DBP/HGNS-IUP). In marked contrast both 12 and
40 selectively inhibited HGNS-IUP over PE-DBP
yielding selectivity ratios of 7628 and 71, respectively.
In summary, the present study shows a number of
-
compounds to be high affinity antagonists at the a1A
adrenoceptor subtype, with considerable selectivity over
the a1B- and a1D-subtypes, in both radioligand binding
and functional studies. Compound 12 has a similar in
vitro profile in human and dog microsomes, forming
mainly metabolites 3, 23, and racemic 40. Metabolite 40
also shows nanomolar activity on the a1A-subtype
Scheme 5. Formation of metabolites of 12 from dog and human liver
microsomes. The peak numbers refer to the retention times in radio-
chromatogram shown in Figure 1, and the asterisk in structures shows
the radiolabeled carbon.

F.J.Lopez et al./ Bioorg.Med.Chem.Lett.13 (2003) 1873–1878
1877
Table 4. Affinity estimates (pKi and pA2/pKB)a and in vitro rate of metabolismc of 12, 23 and 40 by dog liver microsomes
Entry
pKi a1A
pKi a1B (a1B/a1A
)
pKi a1D (a1D/a1A
)
pA2/pKB RBN
pA2/pKB
Rat aorta (aorta/RBN)
Rel rate metc (Dog)
12
23
40
8.9Æ0.1
8.1Æ0.2
8.3Æ0.1
7.1Æ0.1 (63)
6.8Æ0.2 (20)
6.6Æ0.2 (63)
7.2Æ0.1 (50)
7.2Æ0.1 (7.9)
6.9Æ0.1 (33)
8.9Æ0.1
8.2bÆ0.1
8.5Æ0.1
6.8Æ0.1 (126)
7.0Æ0.1 (16)
6.6Æ0.1 (79)
0.6
0.1
0
aValues are meanÆSE mean, nꢁ3, unless otherwise noted.
bn=2.
cRelative rate of metabolism with respect to 11 (see Table 3).
Table 5. Single-dose pharmacokinetics of 12 and 40 in dogsa
Langer, S. Z.; Lefkowitz, R. J.; Minneman, K. P.; Ruffolo, R.
J.Pharmacol.Rev. 1995, 47, 267.
Compd:
Route:
12
40
4. (a) Price, D.; Schwinn, D. A.; Lomasney, J. W.; Allen, L. F.;
Caron, M. G.; Lefkowitz, R. J. J.Urol. 1993, 150, 546. (b)
Faure, C.; Pimoule, C.; Vallancien, G.; Langer, S. Z.; Gra-
ham, D. Life Sci. 1994, 54, 1595. (c) Taniguchi, N.; Ukai, Y.;
Tanaka, T.; Yano, J.; Kimura, K.; Moriyama, N.;
Kawabe, K. Naunyn Schmiedeberg’s Arch.Pharmacol.
1997, 355, 412.
IV
PO
IV
PO
T1/2 (h)
2.5
0.26
0.93
100
2.8
NCb
NCb
78
11
0.25
4.0
10
CL (L/h/kg)
Vd (L/kg)
Bioavailability (%)
NCb
NCb
111
100
5. (a) Forray, C.; Bard, J. A.; Wetzel, J. M.; Chiu, G.; Sha-
piro, E.; Tang, R.; Lepor, H.; Hartig, P. R.; Weinshank, R. L.;
Branchek, T. A.; Gluchowski, C. Mol.Pharmacol. 1994, 45,
703. (b) Hatano, A.; Takahashi, H.; Tamaki, M.; Komeyama,
T.; Koizumi, T.; Takeda, M. Br.J.Pharmacol. 1994, 113, 723.
(c) Marshall, I.; Burt, R. P.; Chapple, C. R. Br.J.Pharmacol.
1995, 115, 781.
a0.3 mg/kg (12 as hydrochloride salt, and 40 as oxalate salt) both PO
and IV (four dogs in cross-over design for each 12 and 40).
bNot calculated.
adrenoceptor, and selectivity over a1B- and a1D-sub-
types higher than 30. Pharmacokinetic studies in dog
showed both 12 and 40 to have a bioavailability of over
75%, although 40 has a terminal half life about 4 times
as long as 12 (10–11 vs 2.5–2.8 h, respectively). Finally,
in vivo preclinical pharmacological studies (HGNS-IUP
vs PE-DBP) clearly demonstrate the uroselectivity of
compounds 12 and 40 (RO1104253). 12 was assessed in
clinical trials for the treatment of symptomatic BPH.29
The cardiovascular effects of 12 were evaluated in two
ascending-dose studies (single oral doses from 0.5 to 20
mg; multiple oral doses from 5 to 40 mg, once daily for
8 days) in healthy subjects (Phase 1). In the single-dose
study, increases in supine and orthostatic heart rate (10–
12 bpm) were observed with the 20 mg dose without
clinical symptoms or hypotension. In the multiple-dose
study, syncope associated with orthostatic hypotension
was observed in one of six subjects in both the 30 and 40
mg groups. No clinically significant changes in blood
pressure, or related symptoms, were observed at lower
doses. In Phase 2, oral doses from 2.5 to 15 mg were
administered once daily for 12 weeks. 12 was well tol-
erated in BPH patients (ꢁ50 years) with increased mean
peak urine flow rate (Qmax) of 2–3.5 mL/s. There was no
apparent effect of 12 on vital signs or on orthostatic
blood pressure compared to placebo. Development of
12 (RO700004, RS-100975) was discontinued, however,
due to lack of clinically significant symptomatic
improvement.29
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References and Notes
1. (a) Forray, C.; Noble, S. A. Expert Opin.Invest.Drugs
1999, 8, 2073. (b) Chess-Williams, R. Expert Opin.Pharmac-
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2. Hieble, J. P. Pharm.Acta Helvetiae 2000, 74, 163.
3. Hieble, J. P.; Bylund, D.; Clarke, D. E.; Eikenburg, D. C.;
15. All compounds have been characterized spectroscopically

1878
F.J.Lopez et al./ Bioorg.Med.Chem.Lett.13 (2003) 1873–1878
(1H NMR and/or 13C NMR, IR, MS) and elemental compo-
sition for final compounds established by combustion analysis.
16. The corresponding mesylate or tosylate of tri-
fluoroethanol, instead of triflate (see Scheme 1), gave at best
15% yield of 5 under the same or eating conditions.
17. (a) Nose, A.; Kudo, T. Chem.Pharm.Bull. 1989, 37, 816.
(b) Seltzman, H. H.; Berrang, B. D. Tetrahedron Lett. 1993,
34, 3083.
20. 1-BOC-thymine, 1-BOC-5-isopropyluracil and 1-BOC-5-
fluorouracil (see column R4, entries 9, 15 and 18, Table 1) were
obtained from the corresponding uracil derivatives (BOC2O,
4-DMAP cat, MeCN, 25 ꢀC, 68–92%) according to: Jaime-
Figueroa, S.; Zamilpa, A.; Guzman, A.; Morgans, D. J., Jr.
Synth.Commun. 2001, 31, 3739.
21. All final compounds were transformed to their hydro-
chloride (HCl gas/MeOH), fumarate (fumaric acid/MeOH) or
oxalate (oxalic acid/MeOH) salts.
22. 1-Cyanocyclopropylmethyl methansulfonate was prepared
(MsCl, Et3N, MDC, 0 ꢀC, 80%) from the corresponding alco-
hol.30
23. Luhmann, U.; Luettke, W. Chem.Ber. 1972, 1350.
24. 1-Benzyl-6-azathymine 29 was prepared from 6-azathy-
mine (TBAF, benzylbromide 2 equiv, 25 ꢀC, THF, then
HCO2NH4, 10% Pd/C, MeOH, reflux, 67%).25
18. (a) 1-Benzylthymine and 1-benzyl-5-trifluoromethyluracil
(see column R4, entries 11 and 22, Table 1) were obtained
from thymine and 5-trifluoromethyluracil (K2CO3, benzyl-
bromide, 25 ꢀC, DMF, 60 and 70% yield, respectively)
according to Kundu, N. G.; Sikdar, S.; Hertzberg, R. P.;
Schmitz, S. A.; Khatri, S. G. J.Chem.Soc,. Perkin Trans.1
1985, 1295. (b) 1-Benzyl-5,6-dimethyluracil (see column R4,
entry 16, Table 1) was obtained from 5,6-dimethyluracil
(hexamethyldisilazane, DMF, then benzyl bromide, 35%)
according to Drossner, R.; Eschenfelder, V. Justus Liebigs
Ann.Chem. 1972, 762, 160. 1-Benzyl-6-methyluracil (see col-
umn R4, entry 17, Table 1) was obtained from 6-methyluracil
(TBAF, benzylbromide 2 equiv, 25 ꢀC, THF, then HCO2NH4,
10% Pd/C, MeOH, reflux, 35%).25
19. 1-SEM-uracil, 1-SEM-5-ethyluracil, 1-SEM-5-chlorour-
acil, 1-SEM-5-methoxyuracil, 1-SEM-5-dimethylaminouracil
and 1-SEM-5-hydroxymethyluracil (see column R4, entries 13,
14, 19–21 and 23, Table 1) were prepared from the corre-
sponding uracil derivatives (hexamethyldisilazane, ammonium
sulfate, reflux, then SEM-Cl, 25 ꢀC, 55–94%) according to:
Arias, L.; Guzman, S.; Jaime-Figueroa, S.; Lopez, F. J.; Mor-
gans, D. J., Jr.; Padilla, F.; Perez-Medrano, A.; Quintero, C.;
Romero, M.; Sandoval, L. Synlett 1997, 1233.
25. Botta, M.; Summa, V.; Saladino, R.; Nicoletti, R. Synth.
Commun. 1991, 21, 2181.
26. Williams, T. J.; Blue, D. R.; Daniels, D. V.; Davis, B.;
Elworthy, T.; Gever, J. R.; Kava, M. S.; Morgans, D.; Padilla,
F.; Tassa, S.; Vimont, R. L.; Chapple, C. R.; Chess-Williams,
R.; Eglen, R. M.; Clarke, D. E.; Ford, A. P. D. W. Br.
J.Pharmacol. 1999, 127, 252.
27. Ultron ES-OVM column, 16% methyl alcohol/84% 50
mM K3PO4, pH 7.4, 0.75 mL/min, 235 nm UV detection.
28. Blue, D. R.; Ford, A. P. D. W.; Morgans, D. J.; Padilla,
F.; Clarke, D. E. Neurourol.Urodynam. 1996, 15, 345.
29. Blue, D.; Zinner, N.; Grino, P.; Crager, M.; Ford, A.
J.Urol. 2002, 167 (Suppl), 265.
30. Saunders, M.; Krause, N. J.Am.Chem.Soc.
8050.
1988, 110,