Design, synthesis, and structure-activity relationships of phthalimide- phenylpiperazines: A novel series of potent and selective {1a)-adrenergic receptor antagonists

Article abstract of DOI:10.1021/jm9905918

Beginning from the screening hit and literature α₁-adrenergic compounds, a hybridized basic skeleton A was proposed as the pharmacophore for potent and selective α(1a)-AR antagonists. Introduction of a hydroxy group to increase the flexibility

Full text of DOI:10.1021/jm9905918

J . Med. Chem. 2000, 43, 2183-2195
2183
Design , Syn th esis, a n d Str u ctu r e-Activity Rela tion sh ip s of
P h th a lim id e-P h en ylp ip er a zin es: A Novel Ser ies of P oten t a n d Selective
r1a -Ad r en er gic Recep tor An ta gon ists
Gee-Hong Kuo,*,† Catherine Prouty,† William V. Murray,† Virginia Pulito,† Linda J olliffe,† Peter Cheung,†
Sally Varga,† Mary Evangelisto,† and J ian Wang‡
Drug Discovery Division, Analytical Development, Global Chemical & Pharmaceutical Development Division,
The R.W. J ohnson Pharmaceutical Research Institute, 1000 Route 202, P.O. Box 300, Raritan, New J ersey 08869
Received November 30, 1999
Beginning from the screening hit and literature R1-adrenergic compounds, a hybridized basic
skeleton A was proposed as the pharmacophore for potent and selective R1a-AR antagonists.
Introduction of a hydroxy group to increase the flexibility afforded B which served as the
screening model and resulted in the identification of the second-generation lead 1. Using the
Topliss approach, a number of potent and selective R1a-AR antagonists were discovered. In all
cases, binding affinity and selectivity at the R1a-AR of S-hydroxy enantiomers were higher
than those of the R-hydroxy enantiomers. As compared to the des-hydroxy analogues, the
S-hydroxy enantiomers had slightly lower binding affinity at R1a-AR but gained more than
2-fold selectivity for R1a-AR over R1b-AR, and 2- to 6-fold selectivity for R1a-AR over R1d-AR.
They also had less cross activities against a panel of 25-35 peripheral and CNS receptors.
The S-hydroxy enantiomers 23 and 24 (Ki ) 0.29 nM, 0.33 nM; R1b/R1a >5690, >6060; R1d/R1a
) 186, 158, respectively) were slightly less potent but much more selective at R1a-AR than
tamsulosin (Ki ) 0.13 nM, R1b/R1a ) 14.8, R1d/R1a ) 1.4). In the functional assay, the S-hydroxy
enantiomers 20, 23, and 24 were less potent than tamsulosin in inhibiting contractions of rat
prostate tissue but more selective in the inhibition of tissue contractions of rat prostate versus
rat aorta. Compound 24 was selected as the development candidate for the treatment of BPH.
In tr od u ction
cause side effects such as postural hypotension, dizzi-
ness, and syncope that may in part be attributed to a
result of their nonselective affinity to R1A-AR subtype.11
Tamsulosin,12 the first R1A-AR “selective” antagonist for
the treatment of BPH, was approved in the United
States in 1997 (Scheme 1). It has been shown to have
The R1-adrenergic receptors (R1-AR) are a family of
G-protein coupled seven-transmembrane receptors which
are involved in the regulation of the cardiovascular and
central nervous systems.1 At least three native R1-AR
subtypes, R1A, R1B, and R1D have been characterized
pharmacologically in tissues.1-3 It has been demon-
strated that the R1A-AR mediates the smooth muscle
contraction in human prostate.4,5 Some studies suggest
that the R1B-AR mediates contraction of the rat spleen6
modest selectivity for R1a-AR over R1b-AR (Ki of R1a
)
0.13 nM, Ki of R1b ) 1.92 nM, R1b/R1a ) 14.8) and almost
no selectivity for R1a-AR over R1d-AR (Ki of R1d ) 0.18
nM, R1d/R1a ) 1.4). Clinical studies indicate that tam-
sulosin has less effect on blood pressure and causes less
symptomatic orthostatic hypotension than previous non
subtype selective R1-AR antagonists.13a However, it still
shows side effects such as abnormal ejaculation and
dizziness.13b-d The goal of our research project is to
develop a potent and selective R1a-AR antagonist which
may be useful for the treatment of BPH with minimal
side effects.
and vasoconstriction of large human arteries.7 The R1D
-
AR mediates contraction of the rat aorta.8 Molecular
cloning techniques allowed the preparation of three
cloned R1-AR subtypessR1a, R1b, and R1dsfor a number
of species including human.2,4
Benign prostatic hyperplasia (BPH) is the most com-
mon benign tumor in men. It occurs in over 50% of the
male population above age 60, and leads to a variety of
urological symptoms including increased frequency in
urination, nocturia, and delay in starting the urine flow.
Advanced BPH may result in urinary-tract infections,
inability to urinate, and kidney damage. Several non
subtype selective R1-AR antagonists such as prazosin,
tetrazosin,9 and doxazosin10 are being used for the
treatment of BPH by relaxing the smooth muscle tone
of the prostate. These compounds have been shown to
Lea d Gen er a tion
The R. W. J ohnson, PRI library compounds were
screened for all three subtypes of R1-AR binding affinity
using 125I-HEAT as the radiolabeled ligand.14 This study
resulted in the discovery of the first-generation lead
RWJ 37914, a potent and selective R1a-AR antagonist
(Ki of R1a ) 16.5 nM, Ki of R1b >2000 nM, and Ki of R1d
) 2871 nM) (Scheme 1). Therefore, RWJ 37914 had
>120-fold higher affinity for the R1a-AR over R1b-AR and
174-fold higher affinity for the R1a-AR over R1d-AR. In
comparison to tamsulosin, RWJ 37914 showed greater
selectivity but weaker binding affinity at the R1a-AR.
* To whom correspondence should be addressed. Tel: 908-704-4330.
Fax: 908-526-6469. E-mail: gkuo@prius.jnj.com.
† Drug Discovery Division.
‡ Analytical Development, Global Chemical & Pharmaceutical De-
velopment Division.
10.1021/jm9905918 CCC: $19.00 © 2000 American Chemical Society
Published on Web 05/09/2000

2184 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 11
Kuo et al.
Sch em e 1
Sch em e 2
molecule if needed. After a number of analogues of
compound B were prepared and tested, the second-
generation lead 1 (R1a ) 1.5 nM, R1b >1835 nM, and
R1d ) 75 nM) was identified. Compound 1 had >1220-
fold higher affinity for the R1a-AR over R1b-AR and 50-
fold higher affinity for the R1a-AR over R1d-AR. In
comparison to the first-generation lead RWJ 37914,
compound 1 showed improved binding affinity (11-fold)
and maintained high selectivity at the R1a-AR.
Ch em istr y
All of the racemic hydroxy compounds 1-18 had been
synthesized via the route shown in Scheme 3. The
molecules were assembled by an amide bond formation
of the phthalimide carboxylic acids 34 and the primary
amines 38. Compound 34 (Table 1) were easily prepared
by refluxing 1,2,4-benzenetricarboxylic anhydride with
the substituted aniline derivatives in glacial acetic acid.
The requisite amines 38 were prepared in two steps.
Alkylation of either the commercially available alkox-
yphenylpiperazines 36a -b or isopropoxyphenylpipera-
zine 36c21 with azido-tosylate 3520 gave azido-pipera-
zines 37. Hydrogenation of 37 gave the amines 38. The
amines 38 were coupled with carboxylic acids 34 using
either EDCI, HOBT (method A), or HATU (method B)
to give the desired product 1-18. In general, the HATU
coupling reagent gave higher yields (Table 2).
In an effort to improve the R1a-AR binding affinity,
we decided to modify the lead structure based upon
other R1a-AR antagonists: tamsulosin, Rec-15/2739,15
KMD-3213,16 and SNAP-508917 (Scheme 1). Since the
positively charged nitrogen atom was suggested to play
a major role in the binding to the important aspartic
acid residue of R1-AR,18,19 we overlapped tamsulosin,
Rec-15/2739, KMD-3213, and SNAP-5089 using the
basic aliphatic nitrogen as the anchor atom. The study
revealed that the degree of structure diversity in the
left-hand side of the molecules was greater than that
in the right-hand side of the molecules. We therefore
proposed a hybridized molecule A as the pharmacophore
that would allow exploration of the space in the left-
hand side of the molecule while maintaining the fixed
(o-isopropoxyphenyl)piperazine moiety in the right-hand
side of the molecule (Scheme 2). We also introduced a
hydroxy group (compound B), that could serve as a
handle to modify the pharmacokinetic properties of the
Optically active S-hydroxy compounds (20, 22-25)
were prepared as shown in Scheme 4 starting from the
optically active S-azido-tosylate S-35.22 The R-hydroxy
enantiomers (19 and 21) were prepared from the cor-
responding R-azido-tosylate (Table 3).
Preparation of the des-hydroxy compounds (26-30)
is shown in Scheme 5. Alkylation of piperazine 36c with
N-Boc-protected 3-bromopropylamine gave the pipera-
zine derivative 40. Removal of the protecting group,
followed by the coupling reaction with carboxylic acid
34, gave the des-hydroxy compounds (Table 3).
The preparation of the O-methylated compound 31
was shown in Scheme 6. Methylation of the hydroxy-
azido-piperazine 37c gave compound 41. Hydrogenation
of 41 followed by amide bond formation with carboxylic
acid 34a gave the O-methylated compound 31 (Table
3).

Synthesis of Phthalimide-Phenylpiperazines
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 11 2185
Sch em e 3a
a
(i) 1,2,4-Benzenetricarboxylic anhydride, glacial acetic acid, 130 °C; (ii) NMP, 100 °C; (iii) 10% Pd/C, H2, CH3OH; (iv) method A: 34,
EDCl, HOBT, DMAP, CH2Cl2; method B: 34, HATU, CH2Cl2.
Ta ble 1. Characterization of Phthalimide Carboxylic Acid
Topliss approach took into account the electronic, lipo-
philic, and steric factors for substitution on a phenyl
ring. We first prepared the unsubstituted-phenyl 4,
4-chlorophenyl 5, 3,4-dichlorophenyl 6, and 4-methoxy-
phenyl 7 analogues. All four compounds had comparable
R1a-AR potency, with compound 7 being the most potent
one (Ki ) 0.77 nM). As compared to 3-fluorophenyl 1,
34
X
yield (%)
MSa
4-methoxyphenyl 7 showed further improvement at R1a-
AR affinity (∼2-fold) and maintained the high selectivity
for R1a-AR over either R1b-AR or R1d-AR. These initial
studies suggested that compounds with electron-with-
drawing substituents (1 and 6) had lower R1a-AR bind-
ing affinity. Therefore, we proceeded to synthesize
analogues under the branch of 4-chlorophenyl 5 and
4-methoxyphenyl 7 of the Topliss tree. Compounds 8,
9, and 10 all possessed similar high R1a-AR potency (Ki
) 0.66 nM, 0.76 nM, and 0.80 nM, respectively) and
high selectivity as compared to that of 7 except 3-chlo-
rophenyl 9 which showed relatively lower selectivity for
R1a-AR over R1b-AR (800-fold versus >2600-fold). Re-
placement of the 4-methyl group with a bulky 4-tert-
butyl group (compound 11) led to a significant decrease
of R1a-AR affinity (Ki ) 3.05 nM). Since the 4-dimethyl-
aminophenyl 10 was equipotent to 4-methoxyphenyl 7,
we chose to synthesize another polar analogue, 4-hy-
droxyphenyl 12. Compound 12 also possessed R1a-AR
potency and selectivity comparable to that of compound
7.
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
3-F
H
4-Cl
3,4-Cl2
4-OCH3
4-CH3
3-Cl
4-N(CH3)2
4-NO2
4-C(CH3)3
3-CH3
4-OH
77
84
92
91
87
89
91
71
97
89
b
85
77
b
91
97
284
266
300
334
296
280
300
309
311
322
280
282
296
284
326
356
2-OCH3
4-F
3,4-(OCH3)2
3,4,5-(OCH3)3
Electrospray mass spectra, m/z M-H+. Commercially avail-
able from Salor.
a
b
Resu lts a n d Discu ssion
Lea d Op tim iza tion . With the second-generation
lead 1 in hand, we briefly reexamined the structure-
activity relationships (SAR) of the alkoxy-substituted
phenylpiperazines at the R1 site of compounds 1-3
(Table 4). Indeed, compound 1 which has the sterically
bulkier o-isopropoxy moiety adopted from RWJ 37914
was superior to the less bulky o-ethoxy 2 or o-methoxy
3 for both R1a-AR binding affinity (Ki ) 1.5 nM versus
4.25 nM or 22 nM) and selectivity (R1b/R1a >1220-fold
versus >470-fold or >90-fold; R1d/R1a ) 50-fold versus
32-fold or 25-fold, respectively).
To ensure that we did not miss the optimal substit-
uents at the X site, we also prepared 3-methylphenyl
13, 2-methoxyphenyl 14, and 4-fluorophenyl 15 under
the branch of 3-chlorophenyl 9 as well as 4-nitrophenyl
16 under the branch of 3,4-dichlorophenyl 6 of the
Topliss tree. Indeed, none of them was more potent than
compound 7 although the majority still maintained the
high selectivity at R1a-AR. Comparing 2-methoxyphenyl
14 (Ki ) 1.47 nM) and 4-methoxyphenyl 7, the ortho-
substitution suffered about a 2-fold decrease in R1a-AR
binding affinity. The lower potency of 4-fluorophenyl 15
Therefore we focused our efforts optimizing at the X
site employing the Topliss approach23,24 while maintain-
ing the optimal isopropyl group at R1 (Table 4). The

2186 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 11
Ta ble 2. Characterization of Phthalimido Phenylpiperazine
Kuo et al.
compd
R1
X
yield (%)
method
MSa
formula
analysis
1
2
3
4
5
6
i-C3H7
C2H5
CH3
i-C3H7
i-C3H7
i-C3H7
3-F
3-F
3-F
H
4-Cl
3,4-Cl2
23
20
47
26
15
6
32
27
27
13
26
46
23
30
26
43
0
A
A
B
A
A
A
B
A
A
A
A
B
A
A
A
B
A
B
B
B
561
547
533
543
577
611
C31H33FN4O5
C30H31FN4O5‚0.3H2O
C29H29FN4O5
C31H34N4O5‚0.5H2O
C31H33ClN4O5‚0.2H2O
C31H32Cl2N4O5
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
7
8
9
10
11
12
13
14
15
16
i-C3H7
i-C3H7
i-C3H7
i-C3H7
i-C3H7
i-C3H7
i-C3H7
i-C3H7
i-C3H7
i-C3H7
4-OCH3
4-CH3
3-Cl
4-N(CH3)2
4-C(CH3)3
4-OH
3-CH3
2-OCH3
4-F
573
557
577
586
599
559
557
573
561
588
C32H36N4O6
C32H36N4O5
C31H33ClN4O5‚0.3H2O
C33H39N5O5
C, H, N
C, H, N
C, H, N
C, H, N
b
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C35H42N4O5
C31H34N4O6‚0.5H2O
C32H36N4O5‚1.6H2O
C32H36N4O6
C31H33FN4O5‚0.2H2O
C31H33N5O7‚0.3H2O
4-NO2
13
28
10
17
18
i-C3H7
i-C3H7
3,4-(OCH3)2
3,4,5-(OCH3)3
603
633
C33H38N4O7‚0.2H2O
C34H40N4O8‚0.5H2O
C, H, N
C, H, N
a
b
Electrospray mass spectra, m/z M + H+. HRMS, calcd 599.3233, found 599.3232.
Sch em e 4a
a
(i) NMP, 100 °C; (ii) 10% Pd/C, H2, CH3OH; (iii) method A: 34, EDCl, HOBT, DMAP, CH2Cl2; method B: 34, HATU, CH2Cl2.
(Ki ) 1.50 nM) and 4-nitrophenyl 16 (Ki ) 1.80 nM) was
consistent with the earlier observation that electron-
withdrawing substituents seemed slightly detrimental
to the R1a-AR affinity. We thus decided to prepare two
more analogues, 3,4-dimethoxyphenyl 17 and 3,4,5-
trimethoxyphenyl 18. The additional electron-donating
groups in the phenyl ring, however, gave no improve-
ment at the R1a-AR potency (Ki ) 0.98 nM and 1.22 nM).
Up to this point, the SAR studies at the X site via the
Topliss approach led to several R1a-AR potent and
selective compounds. For example, compounds 4, 7-10,
12, and 13 were highly potent (Ki <1 nM) and selective
for R1a-AR over either R1b-AR (majority being >1000-
fold) or R1d-AR (majority being >50-fold).
7 were synthesized. For compound 1, the S-enantiomer
20 was about 8-fold more potent than the R-enantiomer
19 at R1a-AR (Ki ) 1.02 nM versus 8.0 nM), highly
selective for R1a-AR over R1b-AR (>1960 versus >250),
and around 23-fold more selective for R1a-AR over R1d-
AR (186 versus 8). It is interesting to note that the same
trend was also observed for compound 7. The S-
enantiomer 22 was about 9-fold more potent than the
R-enantiomer 21 at R1a-AR (Ki ) 0.23 nM versus 2.09
nM), highly selective for R1a-AR over R1b-AR (>7610
versus >960), and around 22-fold more selective for R1a-
AR over R1d-AR (539 versus 25). It is not uncommon that
the binding of the ligand to the receptor is highly
stereospecific because the interacting proteins are also
chiral in nature. We were pleased to see that both the
binding affinity and selectivity at R1a-AR of S-enanti-
omer 20 and 22 were improved over the corresponding
racemates 1 and 7. The S-enantiomers 23-25 were also
On the basis of the potency, selectivity, hydrophobic
π parameters, and electronic σ values, compounds 1, 7,
8, 10, and 12 were selected for further evaluation at the
R2 site (Table 5). Both enantiomers of compounds 1 and

Synthesis of Phthalimide-Phenylpiperazines
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 11 2187
Ta ble 3. Characterization of Phthalimido Phenylpiperazine
compd
R2
X
yield (%)
method
MSa
formula
analysis
19
20
21
22
23
24
25
26
27
28
29
30
31
R-OH
S-OH
R-OH
S-OH
S-OH
S-OH
S-OH
H
H
H
H
H
3-F
3-F
15
43
17
27
52
41
17
23
41
26
23
34
29
A
B
A
A
B
B
B
A
B
B
B
A
B
561
561
573
573
557
586
559
545
557
541
570
543
575
C
C
31H33FN4O5
31H33FN4O5
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
b
4-OCH3
4-OCH3
4-CH3
4-N(CH3)2
4-OH
C32H36N4O6‚H2O
C32H36N4O6‚0.5H2O
C32H36N4O5
C33H39N5O5‚0.3H2O
C
C
31H34N4O6‚0.5H2O
31H33FN4O4
3-F
4-OCH3
4-CH3
4-N(CH3)2
4-OH
C32H36N4O5‚H2O
C32H36N4O4‚0.2H2O
C33H39N5O4‚0.7H2O
C31H34N4O5‚0.3H2O
OCH3
3-F
C32H35FN4O5
a
b
Electrospray mass spectra, m/z M + H+. HRMS, calcd 575.2670, found 575.2672.
Sch em e 5a
R1b-AR (at least >4350 versus >2000), and were about
2-9-fold (186-298 versus 94-32) more selective for R1a-
AR over R1d-AR as compared to the corresponding
racemates 8, 10, and 12.
To examine the influence of the hydroxy group on the
potency and selectivity at R1a-AR, the des-hydroxy
compounds 26-30 were prepared. In comparison to the
des-hydroxy compounds 26, 27, 29, and 30 (except
4-methylphenyl 28), the S-hydroxy enantiomers (20, 22,
24, and 25) sacrificed about 2-fold binding affinity at
R1a-AR but gained more than 2-fold selectivity for R1a-
AR over R1b-AR, and increased about 2-6-fold selectivity
for R1a-AR over R1d-AR. Conversion of hydroxy com-
pound 1 to the corresponding methoxy compound 31 led
to a 5-fold loss of potency (Ki ) 1.5 nM versus 6.9 nM)
at R1a-AR.
The optimization at the R1, X, and R2 position of 1
resulted in the identification of a number of equal or
slightly less potent but much more selective compounds
than tamsulosin at R1a-AR.
a
(i) (Boc)2O, CH2Cl2; (ii) 36c, Cs2CO3, CH3CN, reflux; (iii) 25%
TFA/CH2Cl2; (iv) method A: 34, EDCl, HOBT, DMAP, CH2Cl2;
method B: 34, HATU, CH2Cl2.
Sch em e 6a
Lea d Selection
Three S-hydroxy compounds (20, 23, and 24), three
des-hydroxy compounds (26, 27, and 28), and tamsu-
losin were chosen for receptor selectivity screen against
a panel of 25-35 peripheral and central nervous system
receptor binding assays (MDS Panlabs). Only those
assays with significant response (higher than 50%
inhibition at 1 µM concentration) were summarized in
Table 6. It was very interesting to note that, in general,
all three S-hydroxy compounds had less cross activities
than those three des-hydroxy compounds. For compari-
son purpose, Ki values of 24 and tamsulosin were listed
in Table 7. Both 24 and tamsulosin showed significant
binding affinities to dopamine and serotonin receptors.
These results were not too surprising due to the fact
that R-AR subtypes share about 45% identity with
serotoninergic and dopaminergic receptors.25 However,
compound 24 had at least a 30-fold difference between
R1a-AR and all tested receptors while tamsulosin had
less than 10-fold selectivity between R1a-AR and dopam-
ine D3 (2.2-fold) or serotonin 5-HT1A (6.1-fold).
a
(i) NaH, CH3I, THF; (ii) 10% Pd/C, H2, CH3OH; (iii) 34a ,
HATU, CH2Cl2.
prepared and evaluated. In all three cases, the S-
enantiomers were about 2-fold (Ki ) 0.29 -0.46 nM
versus 0.66-0.88 nM) more potent at R1a-AR, main-
tained at least the same high selectivity for R1a-AR over

2188 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 11
Ta ble 4. Binding Affinities at Cloned Human R1-AR Subtypesa
Kuo et al.
Ki ( SEM (nM)b
R1b
Ki ratio
compd
R1
X
R1a
R1d
R
1b/R1a
R
1d/R1a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
i-C3H7
C2H5
CH3
3-F
3-F
3-F
H
4-Cl
3,4-Cl2
4-OCH3
4-CH3
3-Cl
4-N(CH3)2
4-C(CH3)3
4-OH
3-CH3
2-OCH3
4-F
4-NO2
3,4-(OCH3)2
3,4,5-(OCH3)3
1.50 ( 0.30
4.25 ( 1.15
22.00 ( 4.00
0.9 ( 0.01
0.95 ( 0.03
1.19 ( 0.03
0.77 ( 0.12
0.66 ( 0.07
0.76 ( 0.11
0.80 ( 0.15
3.05 ( 0.45
0.88 ( 0.08
0.9 ( 0.00
>2000, 1835
>2000, >2000
>2000, >2000
>2000, 1640
606 ( 137
75 ( 1
137 ( 1
540 ( 152
65 ( 4
>1220
>470
>90
50
32
25
72
58
43
66
94
54
50
25
32
81
49
74
21
57
125
i-C3H7
i-C3H7
i-C3H7
i-C3H7
i-C3H7
i-C3H7
i-C3H7
i-C3H7
i-C3H7
i-C3H7
i-C3H7
i-C3H7
i-C3H7
i-C3H7
i-C3H7
>1820
55 ( 14
51 ( 1
640
1030
1225 ( 45
>2000, >2000
>2000, >2000
605 ( 64
>2000, 1600
>2000, >2000
>2000, >2000
>2000, >2000
1639 ( 111
1658, >2000
>2000, >2000
>2000, >2000
>2000, >2000
51 ( 8
>2600
>3030
800
>2000
>650
>2270
>2220
1110
>1100
>1110
>2040
>1640
62 ( 3
41 ( 4
40 ( 4
75 ( 14
28 ( 4
73 ( 16
72 ( 2
1.47 ( 0.22
1.50 ( 0.10
1.80 ( 0.20
0.98 ( 0.23
1.22 ( 0.28
111 ( 6
38 ( 5
56 ( 3
152 ( 32
a
b
Displacement of 125I-HEAT from R1-AR subtypes as described in the Experimental Section. SEM: standard error mean.
Ta ble 5. Binding Affinities at Cloned Human R1-AR Subtypesa
Ki ( SEM (nM)b
R1b
Ki ratio
1b/R1a
compd
R2
X
R1a
R1d
R
R
1d/R1a
19
20
21
22
23
24
25
26
27
28
29
30
31
R-OH
S-OH
R-OH
S-OH
S-OH
S-OH
S-OH
H
H
H
H
H
3-F
3-F
8.00 ( 0.87
1.02 ( 0.08
2.09 ( 0.11
0.23 ( 0.00
0.29 ( 0.01
0.33 ( 0.03
0.46 ( 0.07
0.41 ( 0.03
0.11 ( 0.01
0.16 ( 0.06
0.18 ( 0.01
0.20 ( 0.04
6.90 ( 0.10
0.13 ( 0.02
>2000, >2000
>2000, >2000
>2000, >2000
1750, >2000
1650, >2000
>2000, >2000
>2000, >2000
482 ( 51
63 ( 4
190 ( 35
52 ( 4
>250
>1960
>960
>7610
>5690
>6060
>4350
1180
8
186
25
4-OCH3
4-OCH3
4-CH3
4-N(CH3)2
4-OH
124 ( 5
54 ( 11
52 ( 5
539
186
158
298
54
145
231
83
137 ( 13
22 ( 2
3-F
4-OCH3
4-CH3
4-N(CH3)2
4-OH
361 ( 103
16 ( 1
3280
>2000, >2000
465 ( 131
37 ( 0
>12500
15 ( 1
2580
255 ( 16
10 ( 3
1270
50
59
1.4
OCH3
3-F
>2000, >2000
1.92 ( 0.17
407 ( 71
0.18 ( 0.02
>290
32, tamsulosin
14.8
a
b
Displacement of 125I-HEAT from R1-AR subtypes as described in the Experimental Section. SEM: standard error mean.
Since these S-hydroxy compounds (20, 23, and 24)
were found to be more selective than those des-hydroxy
compounds (26, 27, and 28) for R1a-AR over 25-35
receptors, they were further examined in the functional
assay. Antagonist activity was assessed by inhibition
of (()-norepinephrine-induced contractions in isolated
rat prostate which predominantly express the R1A-AR
subtype and aorta tissues which predominantly express
the R1D-AR subtype (MDS Panlabs). Because most
compounds showed nonparallel shifts of dose-response
curves with either tissue, affinity were reported as pKB
values in Table 8.26 Although all three antagonists (20,
23, and 24) were less potent than tamsulosin in their
ability to inhibit rat prostate contractions (pKB ) 7.81,
6.78, and 7.39, respectively, versus 9.33), they displayed
greater tissue selectivity for inhibition of rat prostate
contractions over rat aorta contractions (ratio ) 22.6,
7.6, and 35.2, respectively, versus (26.9)). Tamsulosin
actually showed a reversed selectivity (26.9-fold) with
higher potency to inhibit rat aorta contraction over rat
prostate contraction (pKB ) 10.76 versus 9.33). Cur-
rently, the apparent discrepancies between the binding
affinity at R1a-AR and functional potency in the rat
prostate tissues of 20, 23, and 24 are not well under-
stood. However, there are two possible explanations.
First, the difference might be explained by the fact
that these antagonists are inverse agonists (negative
antagonists), and hence their affinity is system-
dependent.27a Second, the difference might suggest the
existence of the putative R1L-AR subtype.27b

Synthesis of Phthalimide-Phenylpiperazines
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 11 2189
Ta ble 6. Percent Inhibition ((SEM) of Selected Receptors at 1 µM Concentration (Panlabs)
20
23
24
26
27
28
32, tamsulosin
R2A
29 ( 5
70 ( 3
8 ( 5
19 ( 3
75 ( 3
14 ( 6
68 ( 2
70 ( 3
38 ( 3
50 ( 4
NTa
18 ( 3
73 ( 7
11 ( 6
71 ( 2
71 ( 2
47 ( 4
50 ( 3
53b
78 ( 3
78 ( 2
86 ( 3
89 ( 1
90 ( 2
97 ( 1
69 ( 4
76 ( 3
72 ( 11
87 ( 4
75 ( 7
66 ( 4
88 ( 3
95 ( 1
92 ( 4
80 ( 5
79 ( 3
76 ( 2
83 ( 2
87 ( 2
83 ( 3
32 ( 5
NT
87 ( 2
66 ( 4
83 ( 2
83 ( 1
94 ( 1
86 ( 2
20 ( 7
53 ( 3
69 ( 2
97 ( 1
NT
82 ( 1
86 ( 1
41 ( 4
53 ( 2
73 ( 1
109 ( 1
21 ( 2
22 ( 7
20 ( 5
18 ( 5
7 ( 3
R2B
R2C
dopamine D2L
55 ( 4
51 ( 3
46 ( 3
43 ( 1
67 ( 3
81 ( 7
95 ( 3
69 ( 4
-12 ( 6
49 ( 3
98 ( 3
95 ( 4
dopamine D2S
dopamine D3
dopamine D4.7
Ca+2 channel, dihydropyridine
Ca2+ channel, phenylalkylamine
histamine H1, central
histamine H1, peripheral
imidazoline I2, central
serotonin 5-HT1
serotonin 5-HT1A
serotonin 5-HT7
NT
93 ( 1
NT
57 ( 2
88 ( 3
NT
NT
97 ( 1
NT
NT
NT
NT
NT
64 ( 2
62 ( 2
115 ( 1
74 ( 2
64 ( 5
92 ( 2
90 ( 1
66 ( 3
92 ( 4
95 ( 2
90 ( 3
104 ( 2
92 ( 3
69 ( 3
90 ( 3
95 ( 3
a
b
Percent inhibition not tested. Percent inhibition tested at 10 µM concentration.
Ta ble 7. Receptor Selectivity Studies (Panlabs)
S-hydroxy enantiomers (23 and 24) were slightly less
potent but much more selective at R1a-AR. In the
functional assay, the S-hydroxy enantiomers were less
potent than tamsulosin in inhibiting rat prostate con-
tractions but more selective in inhibiting rat prostate
contractions over rat aorta contractions.
24
32, tamsulosin
assay
R1a
Ki ( SEM (nM) Ki ratio Ki ( SEM (nM) Ki ratio
0.33 ( 0.05
NDa
1
0.13 ( 0.05
63 ( 7
1
R2A
R2B
D2L
D2S
D3
ND
512
70
490
620
100
600
2.2
ND
ND
7260
6.1
169 ( 18
80 ( 15
13 ( 2
23 ( 7
25 ( 5
76
78 ( 13
0.28 ( 0.08
ND
Exp er im en ta l Section
62 ( 6
188
2303
115
2342
45
1
Ca+2(phe) 760 ( 117
Ch em istr y. H NMR spectra were measured on a Bruker
H1(cen)
5-HT1
5-HT1A
5-HT7
38 ( 7
ND
AC-300 (300 MHz) spectrometer using tetramethylsilane as
an internal standard. Elemental analyses were obtained by
Quantitative Technologies Inc. (Whitehouse, NJ ), and the
results were within 0.4% of the calculated values unless
otherwise mentioned. Melting points were determined in open
capillary tubes with a Thomas-Hoover apparatus and were
uncorrected. The optical rotation was measured at 25 °C with
an Autopol III polarimeter. Electrospray mass spectra (MS-
ES) were recorded on a Hewlett-Packard 59987A spectrometer.
High-resolution mass spectra (HRMS) were obtained on a
Micromass Autospec. E. spectrometer. The term “DMAP”
refers to (dimethylamino)pyridine, “TFA” refers to trifluoro-
acetic acid, “EDCI” refers to 1-(3-dimethylaminopropyl)-3-
ethylcarbodiimide hydrochloride, “HOBT” refers to hydroxy-
benzotriazole hydrate, “HATU” refers to O-(7-azabenzotriazol-
1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, “NMP”
refers to 1-methyl-2-pyrrolidinone.
773 ( 300
15 ( 5
944 ( 386
0.79 ( 0.11
84 ( 5
10 ( 2
30
650
a
Ki values not determined because low binding activity was
seen in the initial screen.
Ta ble 8. Rat Prostate and Aorta Tissue Contraction Studies
(Panlabs)
pKB ( SEMa
compd
rat aorta
rat prostate
ratiob
20
23
24
6.47 ( 0.10
5.90 ( 0.15
5.84 ( 0.37
10.76 ( 0.12
7.81 ( 0.29
6.78 ( 0.06
7.39 ( 0.70
9.33 ( 0.43
22.6
7.6
35.2
tamsulosin
(26.9)c
a
Antagonist dissociation equilibrium constants (pKB) were
Gen er a l P r oced u r e for th e Syn th esis of 34a -p . 2-(3-
F lu or op h en yl)-1,3-d ioxo-2,3-d ih yd r o-1H-isoin d ole-5-ca r -
boxylic Acid (34a ). A mixture of the 1,2,4-benzenetricarbox-
ylic anhydride (10 g, 52 mmol) and 3-fluoroaniline (5.77 g, 52
mmol) in glacial acetic acid (200 mL) was stirred at 130 °C
for 16 h. The light-brown solution was cooled to 20 °C to give
a yellow solid precipitate. The yellow solid was collected via
filtration and was washed thoroughly with water to remove
the trace amount of acetic acid. The product was dried at 60
°C for 36 h under vacuum to give 11.41 g (77%) of 34a as a
b
calculated as described in the Experimental Section. The ratio
of rat aorta KB/rat prostate KB. c The ratio of rat prostate KB/rat
aorta KB.
The high potency and selectivity at R1a-AR in the
binding assay and the good tissue selectivity observed
in the functional assay strongly supported that these
S-hydroxy phthalimide-phenylpiperazines be further
evaluated in pharmacokinetic studies, in vivo intrau-
rethral pressure versus mean arterial pressure studies.
As a result,28 compound 24 which had the best overall
profile was selected as the development candidate for
the treatment of BPH.
1
yellow solid: mp 268-269 °C; H NMR (DMSO-d6) δ 8.42 (d,
J ) 8.1 Hz, 1 H), 8.31 (s, 1 H), 8.09 (d, J ) 7.8 Hz, 1 H), 7.60
(m, 1 H), 7.36 (m, 3 H).
2-P h en yl-1,3-d ioxo-2,3-d ih yd r o-1H-isoin d ole-5-ca r box-
ylic Acid (34b): mp 257-259 °C; 1H NMR (DMSO-d6) δ 13.75
(brs, 1 H), 8.42 (d, J ) 7.9 Hz, 1 H), 8.31 (s, 1 H), 8.09 (d, J )
7.7 Hz, 1 H), 7.52 (m, 5 H).
Con clu sion
Starting from the library screening hit RWJ 37914
and literature candidates, compound B was used as the
screening model and resulted in the identification of the
second-generation lead 1. Using the Topliss approach,
a number of potent and selective R1a-AR antagonists
were developed. As compared to the des-hydroxy com-
pounds, in general, the S-hydroxy enantiomers were less
potent but more selective at R1a-AR against a panel of
25-35 receptors. In comparison to tamsulosin, the
2-(4-Ch lor oph en yl)-1,3-dioxo-2,3-dih ydr o-1H-isoin dole-
5-ca r boxylic Acid (34c): mp 293-294 °C; 1H NMR (DMSO-
d6) δ 13.75 (brs, 1 H), 8.42 (d, J ) 8.1 Hz, 1 H), 8.32 (s, 1 H),
8.09 (d, J ) 7.7 Hz, 1 H), 7.62 (d, J ) 8.7 Hz, 2 H), 7.51 (d, J
) 8.7 Hz, 2 H).
[2-(3,4-Dich lor o)ph en yl]-1,3-dioxo-2,3-dih ydr o-1H-isoin -
d ole-5-ca r boxylic Acid (34d ): mp 290-292 °C; 1H NMR
(DMSO-d6) δ 13.80 (brs, 1 H), 8.43 (d, J ) 8.5 Hz, 1 H), 8.32
(s, 1 H), 8.11 (d, J ) 7.7 Hz, 1 H), 7.84 (m, 2 H), 7.53 (dd, J )
8.7, 2.3 Hz, 1 H).

2190 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 11
Kuo et al.
2-(4-Met h oxyp h en yl)-1,3-d ioxo-2,3-d ih yd r o-1H -isoin -
d ole-5-ca r boxylic Acid (34e): mp 260-261 °C; 1H NMR
(DMSO-d6) δ 8.41 (d, J ) 8.5 Hz, 1 H), 8.30 (s, 1 H), 8.06 (d,
J ) 7.7 Hz, 1 H), 7.36 (d, J ) 8.8 Hz, 2 H), 7.08 (d, J ) 8.9 Hz,
2 H), 3.81 (s, 3 H).
4.06 (q, J ) 7.0 Hz, 2 H), 3.94 (m, 1 H), 3.42 (dd, J ) 12.8, 3.8
Hz, 1 H), 3.24 (dd, J ) 12.6, 5.3 Hz, 1 H), 3.12 (m, 4 H), 2.93
(m, 2 H), 2.59 (m, 3 H), 2.43 (dd, J ) 12.2, 3.7 Hz, 1 H), 1.45
(t, J ) 6.9 Hz, 3 H); FAB-HRMS (M + H+) calcd 306.1941,
found 306.1941.
2-(4-Meth ylph en yl)-1,3-dioxo-2,3-dih ydr o-1H-isoin dole-
Gen er a l P r oced u r e for th e Syn th esis of 38a-c. r-(Am i-
n om eth yl)-4-[2-(1-m eth yleth oxy)ph en yl]-1-piper azin eeth -
a n ol (38c). A 10% HCl (6 mL) solution was added to a mixture
of 37c (2.43 g, 7.6 mmol) and 10% Pd/C (1.22 g) in MeOH (60
mL), and the mixture was hydrogenated under H2 (50 psi) in
a Parr shaker for 16 h at 20 °C. The mixture was filtered
through Celite, and the filtrate was concentrated. The residue
was basified with 20% NaOH and extracted with methylene
chloride. The combined organic layers were dried (Na2SO4) and
concentrated to give 2.2 g (95%) of 38c as a yellowish oil which
was stored under nitrogen in the freezer and used without
further purification: 1H NMR (CDCl3) δ 6.91 (m, 4 H), 4.59
(m, 1 H), 3.76 (m, 1 H), 3.12 (m, 4 H), 2.83 (dd, J ) 12.7, 3.7
Hz, 2 H), 2.82 (m, 1 H), 2.25-2.68 (m, 8 H), 1.34 (d, J ) 6.1
Hz, 6 H); MS (ES) m/z 294 (M + H+).
r-(Am in om et h yl)-4-[2-(1-m et h oxy)p h en yl]-1-p ip er a -
zin eeth a n ol (38a ): white solid (93%); 1H NMR (CDCl3) δ 6.95
(m, 4 H), 3.87 (s, 3 H), 3.66 (m, 1 H), 3.10 (brs, 4 H), 2.85 (m,
3 H), 2.59 (m, 3 H), 2.44 (m, 2 H); MS (ES) m/z 266 (M + H+).
r-(Am in om e t h yl)-4-[2-(1-e t h oxy)p h e n yl]-1-p ip e r a -
zin eeth a n ol (38b): yellowish oil (87%); 1H NMR (CDCl3) δ
6.92 (m, 4 H), 4.06 (q, J ) 7.1 Hz, 2 H), 3.73 (m, 1 H), 3.12
(brs, 4 H), 2.83 (m, 3 H), 2.65 (m, 3 H), 2.43 (m, 2 H), 1.46 (t,
J ) 7.1 Hz, 3 H); MS (ES) m/z 280 (M + H+).
Gen er a l P r oced u r e for th e Syn th esis of 1-18 (Meth od
A). 2-(3-F lu or op h en yl)-2,3-d ih yd r o-N-[2-h yd r oxy-3-[4-[2-
(1-m eth yleth oxy)ph en yl]-1-piper azin yl]pr opyl]-1,3-dioxo-
1H-isoin d ole-5-ca r boxa m id e (1). A mixture of the amine
38c (226 mg, 0.77 mmol), carboxylic acid 34a (220 mg, 0.77
mmol), EDCI (151 mg, 0.78 mmol), HOBT (105 mg, 0.78
mmol), DMAP (cat.), and N,N-diisopropylethylamine (0.52 mL)
in methylene chloride (6 mL) was stirred at 20 °C for 3 h under
nitrogen. The mixture was concentrated, diluted with 5% K2-
CO3 (aq), and extracted with EtOAc. The combined organic
layer was dried (Na2SO4) and concentrated. The product was
purified by column chromatography (SiO2) to give 101 mg
(23%) of 1 as a yellow solid: 1H NMR (CDCl3) δ 8.34 (s, 1 H),
8.30 (d, J ) 7.8 Hz, 1 H), 8.04 (d, J ) 7.8 Hz, 1 H), 7.48 (m, 1
H), 7.26 (m, 1 H), 7.14 (m, 1 H), 6.91 (m, 6 H), 4.59 (m, 1 H),
4.02 (m, 1 H), 3.79 (m, 1 H), 3.45 (m, 1 H), 3.13 (m, 4 H), 2.87
(m, 2 H), 2.62 (m, 2 H), 2.50 (m, 2 H), 1.34 (d, J ) 6.0 Hz, 6
H).
1
5-ca r boxylic Acid (34f): mp 258-259 °C; H NMR (DMSO-
d6) δ 8.41 (d, J ) 7.4 Hz, 1 H), 8.30 (s, 1 H), 8.07 (d, J ) 7.8
Hz, 1 H), 7.33 (s, 4 H), 2.38 (s, 3 H).
2-(3-Ch lor oph en yl)-1,3-dioxo-2,3-dih ydr o-1H-isoin dole-
5-ca r boxylic Acid (34g): mp 283-284 °C; 1H NMR (DMSO-
d6) δ 8.42 (d, J ) 8.0 Hz, 1 H), 8.32 (s, 1 H), 8.10 (d, J ) 7.8
Hz, 1 H), 7.54 (m, 4 H).
[2-(4-Dim et h yla m in o)p h en yl]-1,3-d ioxo-2,3-d ih yd r o-
1H-isoin d ole-5-ca r boxylic Acid (34h ): mp 273-274 °C; 1H
NMR (DMSO-d6) δ 8.40 (d, J ) 8.5 Hz, 1 H), 8.28 (s, 1 H),
8.05 (d, J ) 7.8 Hz, 1 H), 7.22 (d, J ) 8.9 Hz, 2 H), 6.82 (d, J
) 8.9 Hz, 2 H), 2.96 (s, 6 H).
2-(4-Nitr op h en yl)-1,3-d ioxo-2,3-d ih yd r o-1H-isoin d ole-
1
5-ca r boxylic Acid (34i): mp 287-288 °C; H NMR (DMSO-
d6) δ 8.43 (m, 3 H), 8.34 (s, 1 H), 8.13 (d, J ) 7.7 Hz, 1 H),
7.80 (d, J ) 8.7 Hz, 2 H).
[2-(4-ter t-Bu tyl)ph en yl]-1,3-dioxo-2,3-dih ydr o-1H-isoin -
d ole-5-ca r boxylic Acid (34j): mp 282-283 °C; 1H NMR
(DMSO-d6) δ 8.42 (d, J ) 7.3 Hz, 1 H), 8.31 (s, 1 H), 8.09 (d,
J ) 7.7 Hz, 1 H), 7.56 (d, J ) 8.6 Hz, 2 H), 7.38 (d, J ) 8.6 Hz,
2 H), 1.34 (s, 9 H).
2-(4-H yd r oxyp h en yl)-1,3-d ioxo-2,3-d ih yd r o-1H -isoin -
d ole-5-ca r boxylic Acid (34l): mp >300 °C; 1H NMR (DMSO-
d6) δ 13.75 (brs, 1 H), 9.80 (s, 1 H), 8.41 (d, J ) 7.5 Hz, 1 H),
8.28 (s, 1 H), 8.05 (d, J ) 7.7 Hz, 1 H), 7.22 (d, J ) 8.6 Hz, 2
H), 6.88 (d, J ) 8.7 Hz, 2 H).
2-(2-Met h oxyp h en yl)-1,3-d ioxo-2,3-d ih yd r o-1H -isoin -
d ole-5-ca r boxylic Acid (34m ): mp 239-240 °C; 1H NMR
(DMSO-d6) δ 8.44 (d, J ) 7.9 Hz, 1 H), 8.33 (s, 1 H), 8.09 (d,
J ) 7.8 Hz, 1 H), 7.51 (t, J ) 7.6 Hz, 1 H), 7.40 (d, J ) 7.3 Hz,
1 H), 7.23 (d, J ) 8.2 Hz, 1 H), 7.10 (t, J ) 7.5 Hz, 1 H), 3.76
(s, 3 H).
[2-(3,4-Dim et h oxy)p h en yl]-1,3-d ioxo-2,3-d ih yd r o-1H -
isoin d ole-5-ca r boxylic Acid (34o): mp 271-272 °C; 1H NMR
(DMSO-d6) δ 8.41 (d, J ) 7.5 Hz, 1 H), 8.30 (s, 1 H), 8.06 (d,
J ) 7.8 Hz, 1 H), 7.09 (m, 2 H), 6.97 (dd, J ) 8.6, 2.1 Hz, 1 H),
3.82 (s, 3 H), 3.74 (s, 3 H).
[2-(3,4,5-Tr im eth oxy)p h en yl]-1,3-dioxo-2,3-d ih ydr o-1H-
isoin d ole-5-ca r boxylic Acid (34p ): mp 269-270 °C; 1H
NMR (DMSO-d6) δ 8.43 (d, J ) 8.1 Hz, 1 H), 8.31 (s, 1 H),
8.08 (d, J ) 7.8 Hz, 1 H), 6.83 (s, 2 H), 3.77 (s, 6 H), 3.73 (s, 3
H).
2-(3-F lu or op h en yl)-2,3-d ih yd r o-N-[2-h yd r oxy-3-[4-(2-
eth oxyp h en yl)-1-p ip er a zin yl]p r op yl]-1,3-d ioxo-1H-isoin -
d ole-5-ca r boxa m id e (2). Replacing 38c with 38b and fol-
lowing the same procedure as in the preparation of 1 gave 2:
1H NMR (CDCl3) δ 8.33 (s, 1 H), 8.30 (d, J ) 7.6 Hz, 1 H),
8.03 (d, J ) 7.7 Hz, 1 H), 7.48 (m, 1 H), 7.26 (m, 1 H), 7.13 (m,
1 H), 6.93 (m, 6 H), 4.05 (m, 3 H), 3.79 (m, 1 H), 3.43 (m, 1 H),
3.13 (m, 4 H), 2.87 (m, 2 H), 2.62 (m, 2 H), 2.54 (m, 2 H), 1.45
(t, J ) 6.9 Hz, 3 H).
Gen er a l P r oced u r e for th e Syn th esis of 1-18 (Meth od
B). 2-(3-F lu or op h en yl)-2,3-d ih yd r o-N-[2-h yd r oxy-3-[4-(2-
m eth oxyph en yl)-1-piper azin yl]pr opyl]-1,3-dioxo-1H-isoin -
d ole-5-ca r boxa m id e (3). The primary amine 38a (150 mg,
0.57 mmol) was dissolved in a mixture of N,N-diisopropyl-
ethylamine (290 mg, 2.26 mmol) and methylene chloride (3
mL). To this solution was added carboxylic acid 34a (160 mg,
0.57 mmol) and HATU (220 mg, 0.57 mmol). The mixture was
stirred at 20 °C for 18 h under N2. The mixture was concen-
trated, diluted with 5% K2CO3 (aq), extracted with ether, dried
(Na2SO4), and concentrated. The product was purified by
column chromatography (SiO2) to give 140 mg (47%) of 3 as a
oily solid: 1H NMR (CDCl3) δ 8.34 (s, 1 H), 8.31 (d, J ) 7.6
Hz, 1 H), 8.03 (d, J ) 7.8 Hz, 1 H), 7.48 (m, 1 H), 7.26 (m, 2
H), 7.13 (m, 2 H), 7.02 (m, 1 H), 6.92 (m, 3 H), 4.02 (m, 1 H),
3.86 (s, 3 H), 3.79 (m, 1 H), 3.42 (m, 1 H), 3.10 (m, 4 H), 2.89
(m, 2 H), 2.55 (m, 4 H).
Gen er a l P r oced u r e for th e Syn th esis of 37a -c. r-(Azi-
dom eth yl)-4-[2-(1-m eth yleth oxy)ph en yl]-1-piper azin eeth -
a n ol (37c). The fumarate salt of 1-(2-isopropoxyphenyl)-
piperazine 36c (3.91 g, 12 mmol) was basified with 20% NaOH
(aq) (100 mL) and extracted with methylene chloride. The
combined organic layers were dried (Na2SO4) and concentrated
to give 2.74 g of oil. A mixture of the oil and 1-azido-3-(p-
toluenesulfonyloxy)propan-2-ol 35 (3.25 g, 12 mmol) in NMP
was stirred at 100 °C for 36 h. The cooled mixture was diluted
with water and extracted with ether, dried (Na2SO4), and
concentrated. The product was purified by column chroma-
tography (SiO2) to give 2.92 g (76%) of 37c as a light-brown
oily solid: 1H NMR (CDCl3) δ 6.91 (m, 4 H), 4.59 (m, 1 H),
3.93 (m, 1 H), 3.67 (brs, 1 H), 3.42 (dd, J ) 12.6, 3.8 Hz, 1 H),
3.23 (dd, J ) 12.6, 5.4 Hz, 1 H), 3.12 (m, 4 H), 2.83 (m, 2 H),
2.53 (m, 3 H), 2.42 (dd, J ) 12.2, 3.8 Hz, 1 H), 1.34 (d, J ) 6.0
Hz, 6 H); MS (ES) m/z 320 (M + H+). Anal. (C16H25N5O2) C,
H, N.
r-(Azid om e t h yl)-4-[2-(1-m e t h oxy)p h e n yl]-1-p ip e r a -
zin eeth a n ol (37a ): brown oil (89%); 1H NMR (CDCl3) δ 6.85-
7.04 (m, 4 H), 3.94 (m, 1 H), 3.87 (s, 3 H), 3.42 (dd, J ) 12.7,
3.8 Hz, 1 H), 3.23 (dd, J ) 12.7, 5.4 Hz, 1 H), 3.09 (brs, 4 H),
2.87 (m, 2 H), 2.40-2.71 (m, 4 H); MS (ES) m/z 292 (M + H+).
Anal. (C14H21N5O2) C, H, N.
r-(Azidom eth yl)-4-[2-(1-eth oxy)ph en yl]-1-piper azin eeth -
a n ol (37b): white oil (66%); 1H NMR (CDCl3) δ 6.92 (m, 4 H),

Synthesis of Phthalimide-Phenylpiperazines
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 11 2191
2-P h en yl-2,3-d ih yd r o-N-[2-h yd r oxy-3-[4-[2-(1-m et h yl-
eth oxy)ph en yl]-1-piper azin yl]pr opyl]-1,3-dioxo-1H-isoin -
d ole-5-ca r boxa m id e (4): light-tan solid; H NMR (CDCl3) δ
(m, 1 H), 4.01 (m, 1 H), 3.79 (m, 1 H), 3.43 (m, 1 H), 3.12 (m,
4 H), 2.85 (m, 2 H), 2.54 (m, 4 H), 2.43 (s, 3 H), 1.35 (d, J )
6.0 Hz, 6 H).
1
8.33 (s, 1 H), 8.30 (d, J ) 7.6 Hz, 1 H), 8.04 (d, J ) 7.7 Hz, 1
H), 7.53 (m, 2 H), 7.44 (d, 3 H), 6.90 (m, 5 H), 4.59 (m, 1 H),
4.00 (m, 1 H), 3.77 (m, 1 H), 3.44 (m, 1 H), 3.12 (m, 4 H), 2.85
(m, 2 H), 2.52 (m, 4 H), 1.35 (d, J ) 6.1 Hz, 6 H).
2-(2-Meth oxyp h en yl)-2,3-d ih yd r o-N-[2-h yd r oxy-3-[4-[2-
(1-m eth yleth oxy)ph en yl]-1-piper azin yl]pr opyl]-1,3-dioxo-
1H-isoin d ole-5-ca r boxa m id e (14): off-white solid; 1H NMR
(CDCl3) δ 8.31 (s, 1 H), 8.27 (d, J ) 8.4 Hz, 1 H), 8.02 (d, J )
7.9 Hz, 1 H), 7.45 (brt, J ) 7.2 Hz, 1 H), 7.08 (m, 2 H), 6.88
(m, 6 H), 4.61 (m, 1 H), 4.00 (m, 1 H), 3.80 (m, 4 H), 3.46 (m,
1 H), 3.13 (m, 4 H), 2.88 (m, 2 H), 2.55 (m, 4 H), 1.35 (d, J )
6.0 Hz, 6 H).
2-(4-F lu or op h en yl)-2,3-d ih yd r o-N-[2-h yd r oxy-3-[4-[2-
(1-m eth yleth oxy)ph en yl]-1-piper azin yl]pr opyl]-1,3-dioxo-
1H-isoin d ole-5-ca r boxa m id e (15): light-tan solid; 1H NMR
(CDCl3) δ 8.32 (s, 1 H), 8.28 (d, J ) 7.8 Hz, 1 H), 8.03 (d, J )
7.7 Hz, 1 H), 7.43 (m, 2 H), 7.23 (t, J ) 8.7 Hz, 2 H), 7.04 (m,
1 H), 6.91 (m, 4 H), 4.59 (m, 1 H), 4.00 (m, 1 H), 3.80 (m, 1 H),
3.42 (m, 1 H), 3.12 (m, 4 H), 2.86 (m, 2 H), 2.53 (m, 4 H), 1.35
(d, J ) 6.0 Hz, 6 H).
2-(4-Nitr op h en yl)-2,3-d ih yd r o-N-[2-h yd r oxy-3-[4-[2-(1-
m eth yleth oxy)p h en yl]-1-p ip er a zin yl]p r op yl]-1,3-d ioxo-
1H-isoin d ole-5-ca r boxa m id e (16): light-tan solid; 1H NMR
(CDCl3) δ 8.36 (m, 3 H), 8.07 (d, J ) 7.8 Hz, 1 H), 7.77 (d, J )
8.9 Hz, 2 H), 7.09 (m, 1 H), 6.90 (m, 5 H), 4.59 (m, 1 H), 4.02
(m, 1 H), 3.76 (m, 1 H), 3.43 (m, 1 H), 3.13 (m, 4 H), 2.86 (m,
2 H), 2.56 (m, 4 H), 1.35 (d, J ) 6.0 Hz, 6 H).
[2-(3,4-Dim eth oxy)p h en yl]-2,3-d ih yd r o-N-[2-h yd r oxy-
3-[4-[2-(1-m et h ylet h oxy)p h en yl]-1-p ip er a zin yl]p r op yl]-
1,3-d ioxo-1H-isoin d ole-5-ca r boxa m id e (17): light-tan solid;
1H NMR (CDCl3) δ 8.31 (s, 1 H), 8.28 (d, J ) 8.0 Hz, 1 H),
8.02 (d, J ) 7.7 Hz, 1 H), 6.92 (m, 8 H), 4.59 (m, 1 H), 4.01 (m,
1 H), 3.93 (s, 3 H), 3.90 (s, 3 H), 3.80 (m, 1 H), 3.44 (m, 1 H),
3.12 (m, 4 H), 2.85 (m, 2 H), 2.53 (m, 4 H), 1.35 (d, J ) 6.0 Hz,
6 H).
[2-(3,4,5-Tr im eth oxy)ph en yl]-2,3-dih ydr o-N-[2-h ydr oxy-
3-[4-[2-(1-m et h ylet h oxy)p h en yl]-1-p ip er a zin yl]p r op yl]-
1,3-d ioxo-1H-isoin d ole-5-ca r boxa m id e (18): off-white solid;
1H NMR (CDCl3) δ 8.32 (s, 1 H), 8.29 (d, J ) 8.0 Hz, 1 H),
8.02 (d, J ) 7.6 Hz, 1 H), 6.92 (m, 5 H), 6.65 (s, 2 H), 4.59 (m,
1 H), 4.01 (m, 1 H), 3.89 (s, 3 H), 3.88 (s, 6 H), 3.76 (m, 1 H),
3.43 (m, 1 H), 3.12 (m, 4 H), 2.85 (m, 2 H), 2.56 (m, 4 H), 1.35
(d, J ) 6.0 Hz, 6 H).
(R)-r-(Azid om et h yl)-4-[2-(1-m et h ylet h oxy)p h en yl]-1-
p ip er a zin eet h a n ol (R-37c). The fumarate salt of 1-(2-
isopropoxyphenyl)-piperazine 36c (112.5 g, 345 mmol) was
basified with 20% NaOH (aq) (500 mL) and extracted with
methylene chloride (3×). The combined organic extracts were
dried (Na2SO4) and concentrated to give about 70 g of oil. A
mixture of the oil and (2S)-3-azido-2-hydroxypropyl p-toluene-
sulfonate S-3522 (91 g, 335 mmol) was stirred at 100 °C in NMP
in the presence of triethylamine (70 g, 690 mmol) for 30 h.
The cooled mixture was diluted with water and extracted with
ether (3 × 500 mL), back-washed once with NaCl (sat.) (100
mL), dried (Na2SO4), and concentrated. The product was
purified by column chromatography (SiO2) and recrystallized
from methylene chloride/hexane to give 70.6 g (66%) (98.8%
ee assay by reverse phase chiralcel AD column, 4.6 × 150 mm,
mobile phase: 95/5/0.1 of hexane/ethanol/diethylamine, reten-
2-(4-Ch lor op h en yl)-2,3-d ih yd r o-N-[2-h yd r oxy-3-[4-[2-
(1-m eth yleth oxy)ph en yl]-1-piper azin yl]pr opyl]-1,3-dioxo-
1
1H-isoin d ole-5-ca r boxa m id e (5): off-white solid; H NMR
(CDCl3) δ 8.33 (s, 1 H), 8.30 (d, J ) 8.0 Hz, 1 H), 8.03 (d, J )
7.7 Hz, 1 H), 7.50 (d, J ) 8.8 Hz, 2 H), 7.41 (d, J ) 8.8 Hz, 2
H), 6.91 (m, 5 H), 4.59 (m, 1 H), 4.00 (m, 1 H), 3.79 (m, 1 H),
3.43 (m, 1 H), 3.12 (m, 4 H), 2.85 (m, 2 H), 2.52 (m, 4 H), 1.35
(d, J ) 6.1 Hz, 6 H).
[2-(3,4-Dich lor o)p h en yl]-2,3-d ih yd r o-N-[2-h yd r oxy-3-
[4-[2-(1-m eth yleth oxy)p h en yl]-1-p ip er a zin yl]p r op yl]-1,3-
1
d ioxo-1H-isoin d ole-5-ca r boxa m id e (6): light-tan solid; H
NMR (CDCl3) δ 8.34 (s, 1 H), 8.30 (d, J ) 7.9 Hz, 1 H), 8.03
(d, J ) 7.7 Hz, 1 H), 7.63 (d, J ) 2.2 Hz, 1 H), 7.58 (d, J ) 8.7
Hz, 1 H), 7.37 (dd, J ) 8.5, 2.3 Hz, 1 H), 7.09 (m, 1 H), 6.90
(m, 4 H), 4.59 (m, 1 H), 4.02 (m, 1 H), 3.79 (m, 1 H), 3.43 (m,
1 H), 3.13 (m, 4 H), 2.86 (m, 2 H), 2.54 (m, 4 H), 1.35 (d, J )
6.1 Hz, 6 H).
2-(4-Meth oxyp h en yl)-2,3-d ih yd r o-N-[2-h yd r oxy-3-[4-[2-
(1-m eth yleth oxy)ph en yl]-1-piper azin yl]pr opyl]-1,3-dioxo-
1
1H-isoin d ole-5-ca r boxa m id e (7): off-white solid; H NMR
(CDCl3) δ 8.31 (s, 1 H), 8.29 (d, J ) 7.5 Hz, 1 H), 8.02 (d, J )
7.7 Hz, 1 H), 7.33 (d, J ) 8.9 Hz, 2 H), 7.02 (d, J ) 9.0 Hz, 2
H), 6.94 (m, 5 H), 4.59 (m, 1 H), 4.01 (m, 1 H), 3.85 (s, 3 H),
3.79 (m, 1 H), 3.42 (m, 1 H), 3.12 (m, 4 H), 2.85 (m, 2 H), 2.52
(m, 4 H), 1.35 (d, J ) 6.0 Hz, 6 H).
2-(4-Met h ylp h en yl)-2,3-d ih yd r o-N-[2-h yd r oxy-3-[4-[2-
(1-m eth yleth oxy)ph en yl]-1-piper azin yl]pr opyl]-1,3-dioxo-
1H-isoin d ole-5-ca r boxa m id e (8): light-tan solid; 1H NMR
(CDCl3) δ 8.32 (s, 1 H), 8.28 (d, J ) 7.6 Hz, 1 H), 8.02 (d, J )
7.7 Hz, 1 H), 7.31 (m, 4 H), 6.92 (m, 5 H), 4.59 (m, 1 H), 4.00
(m, 1 H), 3.79 (m, 1 H), 3.43 (m, 1 H), 3.12 (m, 4 H), 2.85 (m,
2 H), 2.55 (m, 4 H), 2.42 (s, 3 H), 1.34 (d, J ) 6.0 Hz, 6 H).
2-(3-Ch lor op h en yl)-2,3-d ih yd r o-N-[2-h yd r oxy-3-[4-[2-
(1-m eth yleth oxy)ph en yl]-1-piper azin yl]pr opyl]-1,3-dioxo-
1H-isoin d ole-5-ca r boxa m id e (9): light-tan solid; 1H NMR
(CDCl3) δ 8.33 (s, 1 H), 8.30 (d, J ) 7.8 Hz, 1 H), 8.04 (d, J )
7.7 Hz, 1 H), 7.43 (m, 3 H), 6.92 (m, 6 H), 4.58 (m, 1 H), 4.02
(m, 1 H), 3.79 (m, 1 H), 3.46 (m, 1 H), 3.12 (m, 4 H), 2.87 (m,
2 H), 2.55 (m, 4 H), 1.35 (d, J ) 5.9 Hz, 6 H).
2-[4-(Dim eth ylam in o)ph en yl]-2,3-dih ydr o-N-[2-h ydr oxy-
3-[4-[2-(1-m et h ylet h oxy)p h en yl]-1-p ip er a zin yl]p r op yl]-
1,3-d ioxo-1H-isoin d ole-5-ca r boxa m id e (10): light brown
1
solid; H NMR (CDCl3) δ 8.29 (s, 1 H), 8.27 (d, J ) 8.0 Hz, 1
H), 8.01 (d, J ) 7.8 Hz, 1 H), 7.23 (s, 2 H), 6.90 (m, 5 H), 6.80
(d, J ) 8.9 Hz, 2 H), 4.60 (m, 1 H), 4.00 (m, 1 H), 3.76 (m, 1
H), 3.44 (m, 1 H), 3.12 (m, 4 H), 3.00 (s, 6 H), 2.85 (m, 2 H),
2.52 (m, 4 H), 1.35 (d, J ) 6.3 Hz, 6 H).
[2-(4-ter t-Bu tyl)p h en yl]-2,3-d ih yd r o-N-[2-h yd r oxy-3-[4-
[2-(1-m eth yleth oxy)p h en yl]-1-p ip er a zin yl]p r op yl]-1,3-d i-
oxo-1H-isoin d ole-5-ca r boxa m id e (11): light-tan solid; 1H
NMR (CDCl3) δ 8.32 (s, 1 H), 8.28 (d, J ) 7.7 Hz, 1 H), 8.02
(d, J ) 7.8 Hz, 1 H), 7.53 (d, J ) 8.5 Hz, 2 H), 7.35 (d, J ) 8.5
Hz, 2 H), 6.93 (m, 5 H), 4.59 (m, 1 H), 4.03 (m, 1 H), 3.79 (m,
1 H), 3.43 (m, 1 H), 3.13 (m, 4 H), 2.89 (m, 2 H), 2.55 (m, 4 H),
1.34 (d, J ) 6.5 Hz, 15 H).
2-(4-Hyd r oxyp h en yl)-2,3-d ih yd r o-N-[2-h yd r oxy-3-[4-[2-
(1-m eth yleth oxy)ph en yl]-1-piper azin yl]pr opyl]-1,3-dioxo-
1H-isoin d ole-5-ca r boxa m id e (12): off-white solid; 1H NMR
(CDCl3) δ 8.26 (m, 2 H), 7.98 (d, J ) 8.1 Hz, 1 H), 7.24 (s, 2
H), 7.04 (m, 1 H), 6.90 (m, 6 H), 4.59 (m, 1 H), 4.03 (m, 1 H),
3.78 (m, 1 H), 3.45 (m, 1 H), 3.13 (m, 4 H), 2.87 (m, 2 H), 2.55
(m, 4 H), 1.35 (d, J ) 6.0 Hz, 6 H).
25
tion time ) 9.217 min) of R-37c as a off-white oily solid: [R]D
) -3.6° (c ) 1, CH3OH); 1H NMR (CDCl3) δ 6.91 (m, 4 H),
4.59 (m, 1 H), 3.93 (m, 1 H), 3.67 (brs, 1 H), 3.42 (dd, J ) 12.6,
3.8 Hz, 1 H), 3.23 (dd, J ) 12.6, 5.4 Hz, 1 H), 3.12 (m, 4 H),
2.83 (m, 2 H), 2.53 (m, 3 H), 2.42 (dd, J ) 12.2, 3.8 Hz, 1 H),
1.34 (d, J ) 6.0 Hz, 6 H); MS (ES) m/z 320 (M + H+). Anal.
(C16H25N5O2) C, H, N.
(S)-r-(Am in om eth yl)-4-[2-(1-m eth yleth oxy)p h en yl]-1-
p ip er a zin eeth a n ol (S-38c). Replacing 37c with R-37c and
following the same procedure as in the preparation of 38c gave
S-38c (96%) as a yellowish oil which was stored under nitrogen
25
2-(3-Met h ylp h en yl)-2,3-d ih yd r o-N-[2-h yd r oxy-3-[4-[2-
(1-m eth yleth oxy)ph en yl]-1-piper azin yl]pr opyl]-1,3-dioxo-
1H-isoin d ole-5-ca r boxa m id e (13): light-tan solid; 1H NMR
(CDCl3) δ 8.32 (s, 1 H), 8.29 (d, J ) 7.6 Hz, 1 H), 8.02 (d, J )
7.7 Hz, 1 H), 7.37 (m, 1 H), 7.23 (m, 2 H), 6.92 (m, 6 H), 4.59
in the freezer and used without further purification: [R]D
)
1
+23.6° (c ) 1, CHCl3); H NMR (CDCl3) δ 6.91 (m, 4 H), 4.59
(m, 1 H), 3.76 (m, 1 H), 3.12 (m, 4 H), 2.83 (dd, J ) 12.7, 3.7
Hz, 2 H), 2.82 (m, 1 H), 2.24-2.69 (m, 8 H), 1.34 (d, J ) 6.1
Hz, 6 H); MS (ES) m/z 294 (M + H+).

2192 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 11
Kuo et al.
(S)-2-(3-F lu or op h en yl)-2,3-d ih yd r o-N-[2-h yd r oxy-3-[4-
[2-(1-m eth yleth oxy)p h en yl]-1-p ip er a zin yl]p r op yl]-1,3-d i-
oxo-1H-isoin d ole-5-ca r boxa m id e (20). Replacing 38a with
S-38c and following the procedure as in the preparation of 3
(m, 1 H), 3.79 (m, 1 H), 3.46 (m, 1 H), 3.13 (m, 4 H), 2.88 (m,
2 H), 2.63 (m, 2 H), 2.51 (m, 2 H), 1.34 (d, J ) 6.0 Hz, 6 H).
(R)-2-(4-Meth oxyp h en yl)-2,3-d ih yd r o-N-[2-h yd r oxy-3-
[4-[2-(1-m eth yleth oxy)p h en yl]-1-p ip er a zin yl]p r op yl]-1,3-
d ioxo-1H-isoin d ole-5-ca r boxa m id e (21): off-white solid;
[R]D25 ) -9.3° (c ) 1, CHCl3); 1H NMR (CDCl3) δ 8.32 (s, 1 H),
8.28 (d, J ) 7.5 Hz, 1 H), 8.03 (d, J ) 7.7 Hz, 1 H), 7.34 (d, J
) 8.8 Hz, 2 H), 7.04 (d, J ) 9.0 Hz, 2 H), 6.91 (m, 5 H), 4.59
(m, 1 H), 4.01 (m, 1 H), 3.86 (s, 3 H), 3.81 (m, 1 H), 3.43 (m, 1
H), 3.13 (m, 4 H), 2.86 (m, 2 H), 2.53 (m, 4 H), 1.35 (d, J ) 6.2
Hz, 6 H).
[3-[4-[2-(1-Meth yleth oxy)ph en yl]-1-piper a zin yl]p r op yl-
ca r ba m ic Acid , 1,1-Dim eth yleth yl Ester (40). 3-Bromopro-
pylamine hydrobromide 39 (5 g, 22.8 mmol) was dissolved in
10% NaOH (50 mL) and extracted with methylene chloride.
The combined extracts were dried (Na2SO4) and concentrated.
To the free base in methylene chloride was added (Boc)2O (5.23
g, 23.9 mmol), and this mixture was stirred at 20 °C for 4 h.
The methylene chloride reaction mixture was washed with
water, diluted citric acid (6%), NaHCO3 (aq), and NaCl (aq),
dried (Na2SO4), and concentrated. The product was purified
by column chromatography (SiO2) to yield the Boc-protected
amine (4.84 g, 89%). The fumarate salt of 1-(2-isopropoxyphe-
nyl)-piperazine 36c (5.1 g, 15 mmol) was basified with 20%
NaOH (aq) (100 mL), extracted with methylene chloride, dried
(Na2SO4), and concentrated to give a yellow oil (3.15 g). A
mixture of the yellow oil, the Boc-protected amine (3.42 g, 14.3
mmol), and Cs2CO3 (4.66 g, 14.3 mmol) in CH3CN (50 mL) was
heated at reflux overnight. The solid was filtered off, and the
filtrate was concentrated. The product was purified by column
chromatography (SiO2) to give 4.4 g (81%) of 40 as a thick oil:
MS (ES) m/z 378 (M + H+). Anal. (C21H35N3O3) C, H, N.
25
(method B) gave 20 (43%) as a light-tan solid: [R]D ) +8.3°
1
(c ) 1, CHCl3); H NMR (CDCl3) δ 8.34 (s, 1 H), 8.30 (d, J )
7.8 Hz, 1 H), 8.04 (d, J ) 7.8 Hz, 1 H), 7.48 (m, 1 H), 7.26 (m,
1 H), 7.14 (m, 1 H), 6.91 (m, 6 H), 4.59 (m, 1 H), 4.02 (m, 1 H),
3.79 (m, 1 H), 3.45 (m, 1 H), 3.13 (m, 4 H), 2.87 (m, 2 H), 2.62
(m, 2 H), 2.50 (m, 2 H), 1.34 (d, J ) 6.0 Hz, 6 H).
(S)-2-(4-Meth oxyp h en yl)-2,3-d ih yd r o-N-[2-h yd r oxy-3-
[4-[2-(1-m eth yleth oxy)p h en yl]-1-p ip er a zin yl]p r op yl]-1,3-
d ioxo-1H-isoin d ole-5-ca r boxa m id e (22). Replacing 38c,
34a with S-38c, 34e and following the procedure as in the
preparation of 1 (method A) gave 22 (27%) as a light-tan solid;
[R]D25 ) +9.2° (c ) 1, CHCl3); 1H NMR (CDCl3) δ 8.31 (s, 1 H),
8.28 (d, J ) 7.5 Hz, 1 H), 8.02 (d, J ) 7.7 Hz, 1 H), 7.34 (d, J
) 8.8 Hz, 2 H), 7.03 (d, J ) 9.0 Hz, 2 H), 6.90 (m, 5 H), 4.59
(m, 1 H), 4.00 (m, 1 H), 3.86 (s, 3 H), 3.80 (m, 1 H), 3.43 (m, 1
H), 3.12 (m, 4 H), 2.86 (m, 2 H), 2.52 (m, 4 H), 1.35 (d, J ) 6.2
Hz, 6 H).
(S)-2-(4-Meth ylp h en yl)-2,3-d ih yd r o-N-[2-h yd r oxy-3-[4-
[2-(1-m eth yleth oxy)p h en yl]-1-p ip er a zin yl]p r op yl]-1,3-d i-
25
oxo-1H-isoin d ole-5-ca r boxa m id e (23): off-white solid; [R]D
1
) +11.7° (c ) 0.2, CHCl3); H NMR (CDCl3) δ 8.32 (s, 1 H),
8.28 (d, J ) 7.8 Hz, 1 H), 8.01 (d, J ) 7.8 Hz, 1 H), 7.31 (m, 4
H), 7.02 (m, 1 H), 6.90 (m, 4 H), 4.59 (m, 1 H), 4.01 (m, 1 H),
3.79 (m, 1 H), 3.43 (m, 1 H), 3.12 (m, 4 H), 2.85 (m, 2 H), 2.55
(m, 4 H), 2.42 (s, 3 H), 1.35 (d, J ) 6.0 Hz, 6 H).
(S)-2-[4-(Dim eth yla m in o)p h en yl]-2,3-d ih yd r o-N-[2-h y-
dr oxy-3-[4-[2-(1-m eth yleth oxy)ph en yl]-1-piper azin yl]pr o-
p yl]-1,3-d ioxo-1H-isoin d ole-5-ca r boxa m id e (24): light-tan
25
solid; [R]D ) +9.6° (c ) 0.2, CHCl3); 1H NMR (CDCl3) δ 8.29
Gen er al P r ocedu r e for th e Syn th esis of 26-30 (Meth od
A). 2-(3-F lu or op h en yl)-2,3-d ih yd r o-N-[3-[4-[2-(1-m eth yl-
eth oxy)ph en yl]-1-piper azin yl]pr opyl]-1,3-dioxo-1H-isoin -
d ole-5-ca r boxa m id e (26). The Boc-protected amine 40 (3.97
g, 10.5 mmol) was dissolved in 25% TFA/methylene chloride
(50 mL) and stirred at 20 °C for 5 h. The solvent was
evaporated, and the residue was dissolved in 20% NaOH (aq)
(100 mL) and stirred for 40 min. The free base was extracted
into methylene chloride (3×), and the solvent was evaporated
to give 3.0 g (95%) of the free amine as a light yellow oil. A
solution of this free amine (3.0 g, 10.8 mmol) and N,N-
diisopropylethylamine (5.6 g, 43.3 mmol) in methylene chloride
(80 mL) was added to a mixture containing EDCI (2.08 g, 10.8
mmol), HOBT (1.46 g, 10.8 mmol), a catalytic amount of DMAP
(5 mol %), and carboxylic acid 34a (3.09 g, 10.8 mmol) and
stirred overnight at 20 °C under N2. The reaction mixture was
washed with 5% K2CO3 (aq), NaCl (aq), dried (Na2SO4), and
concentrated. The product was purified by column chroma-
tography (SiO2) to give 1.34 g (23%) of 26 as a light yellow
solid: 1H NMR (CDCl3) δ 9.22 (brs, 1 H), 8.34 (m, 2 H), 7.99
(d, J ) 8.1 Hz, 1 H), 7.46 (m, 1 H), 7.18 (m, 3 H), 6.89 (m, 4
H), 4.57 (m, 1 H), 3.67 (m, 2 H), 3.09 (m, 4 H), 2.71 (m, 6 H),
1.87 (m, 2 H), 1.33 (d, J ) 6.1 Hz, 6 H).
Gen er al P r ocedu r e for th e Syn th esis of 26-30 (Meth od
B). 2-(4-Meth oxyp h en yl)-2,3-d ih yd r o-N-[3-[4-[2-(1-m eth -
ylet h oxy)p h en yl]-1-p ip er a zin yl]p r op yl]-1,3-d ioxo-1H -
isoin d ole-5-ca r boxa m id e (27). The free amine of 40 (1 equiv)
obtained as above (method A) was stirred with carboxylic acid
34e (1 equiv) and HATU (1 equiv) in methylene chloride
overnight and worked up as above to give 27 as an off-white
solid: 1H NMR (CDCl3) δ 9.11 (brs, 1 H), 8.30 (m, 2 H), 7.97
(d, J ) 8.2 Hz, 1 H), 7.28 (m, 2 H), 7.01 (d, J ) 7.0 Hz, 2 H),
6.90 (m, 4 H), 4.57 (m, 1 H), 3.86 (s, 3 H), 3.67 (m, 1 H), 3.09
(m, 4 H), 2.70 (m, 6 H), 1.86 (m, 2 H), 1.33 (d, J ) 6.0 Hz, 6
H).
(s, 1 H), 8.27 (d, J ) 8.0 Hz, 1 H), 8.00 (d, J ) 7.7 Hz, 1 H),
7.23 (s, 2 H), 6.90 (m, 5 H), 6.80 (d, J ) 8.9 Hz, 2 H), 4.59 (m,
1 H), 4.00 (m, 1 H), 3.78 (m, 1 H), 3.44 (m, 1 H), 3.12 (m, 4 H),
3.00 (s, 6 H), 2.85 (m, 2 H), 2.52 (m, 4 H), 1.35 (d, J ) 6.1 Hz,
6 H).
(S)-2-(4-Hyd r oxyp h en yl)-2,3-d ih yd r o-N-[2-h yd r oxy-3-
[4-[2-(1-m eth yleth oxy)p h en yl]-1-p ip er a zin yl]p r op yl]-1,3-
d ioxo-1H-isoin d ole-5-ca r boxa m id e (25): off-white solid;
25
[R]D ) +8.2° (c ) 0.2, CHCl3); 1H NMR (CDCl3) δ 8.26 (m, 2
H), 7.98 (d, J ) 8.1 Hz, 1 H), 7.24 (s, 2 H), 7.05 (m, 1 H), 6.90
(m, 6 H), 4.59 (m, 1 H), 4.03 (m, 1 H), 3.78 (m, 1 H), 3.44 (m,
1 H), 3.13 (m, 4 H), 2.85 (m, 2 H), 2.55 (m, 4 H), 1.35 (d, J )
6.0 Hz, 6 H).
(S)-r-(Azid om et h yl)-4-[2-(1-m et h ylet h oxy)p h en yl]-1-
p ip er a zin eeth a n ol (S-37c). Replacing (2S)-3-azido-2-hydrox-
ypropyl p-toluenesulfonate S-35 with (2R)-3-azido-2-hydrox-
ypropyl p-toluenesulfonate R-35 and following the same
procedure as in the preparation of R-37c gave S-37c (50%)
(99.3% ee assay by reverse phase chiralcel AD column, 4.6 ×
150 mm, mobile phase: 95/5/0.1 of hexane/ethanol/diethy-
lamine, retention time ) 8.383 min) as a off-white oily solid:
25
1
[R]D ) +3.4° (c ) 1, CH3OH); H NMR (CDCl3) δ 6.92 (m, 4
H), 4.59 (m, 1 H), 3.92 (m, 1 H), 3.67 (brs, 1 H), 3.42 (dd, J )
12.6, 3.8 Hz, 1 H), 3.23 (dd, J ) 12.6, 5.4 Hz, 1 H), 3.12 (m, 4
H), 2.83 (m, 2 H), 2.53 (m, 3 H), 2.42 (dd, J ) 12.2, 3.8 Hz, 1
H), 1.34 (d, J ) 6.0 Hz, 6 H); MS (ES) m/z 320 (M + H+).
(R)-r-(Am in om eth yl)-4-[2-(1-m eth yleth oxy)p h en yl]-1-
p ip er a zin eeth a n ol (R-38c). Replacing 37c with S-37c and
following the same procedure as in the preparation of 38c gave
R-38c (90%) as a yellowish oil which was stored under nitrogen
25
in the freezer and used without further purification: [R]D
)
1
-22.5° (c ) 1, CHCl3); H NMR (CDCl3) δ 6.91 (m, 4 H), 4.59
(m, 1 H), 3.76 (m, 1 H), 3.12 (m, 4 H), 2.83 (dd, J ) 12.7, 3.7
Hz, 2 H), 2.82 (m, 1 H), 2.25-2.68 (m, 8 H), 1.34 (d, J ) 6.1
Hz, 6 H); MS (ES) m/z 294 (M + H+).
2-(4-Met h ylp h en yl)-2,3-d ih yd r o-N-[3-[4-[2-(1-m et h yl-
eth oxy)ph en yl]-1-piper azin yl]pr opyl]-1,3-dioxo-1H-isoin -
(R)-2-(3-F lu or op h en yl)-2,3-d ih yd r o-N-[2-h yd r oxy-3-[4-
[2-(1-m eth yleth oxy)p h en yl]-1-p ip er a zin yl]p r op yl]-1,3-d i-
1
d ole-5-ca r boxa m id e (28): light-tan solid; H NMR (CDCl3)
25
oxo-1H-isoin d ole-5-ca r boxa m id e (19): light-tan solid; [R]D
δ 9.12 (brs, 1 H), 8.31 (m, 2 H), 7.98 (d, J ) 8.2 Hz, 1 H), 7.28
(m, 4 H), 6.90 (m, 4 H), 4.57 (m, 1 H), 3.66 (m, 2 H), 3.08 (m,
4 H), 2.80 (m, 6 H), 2.42 (m, 3 H), 1.86 (m, 2 H), 1.33 (d, J )
6.0 Hz, 6 H).
) -8.4° (c ) 1, CHCl3); 1H NMR (CDCl3) δ 8.35 (s, 1 H), 8.30
(d, J ) 7.8 Hz, 1 H), 8.04 (d, J ) 7.8 Hz, 1 H), 7.48 (m, 1 H),
7.26 (m, 1 H), 7.15 (m, 1 H), 6.92 (m, 6 H), 4.59 (m, 1 H), 4.03

Synthesis of Phthalimide-Phenylpiperazines
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 11 2193
[2-(4-Dim eth yla m in o)p h en yl]-2,3-d ih yd r o-N-[3-[4-[2-(1-
m eth yleth oxy)p h en yl]-1-p ip er a zin yl]p r op yl]-1,3-d ioxo-
1H-isoin d ole-5-ca r boxa m id e (29): light brown solid; 1H
NMR (CDCl3) δ 9.04 (brs, 1 H), 8.28 (m, 2 H), 7.96 (d, J ) 7.6
Hz, 1 H), 7.20 (d, J ) 8.9 Hz, 2 H), 6.86 (m, 6 H), 4.57 (m, 1
H), 3.66 (m, 2 H), 3.08 (m, 4 H), 3.01 (s, 6 H), 2.75 (m, 6 H),
1.86 (m, 2 H), 1.33 (d, J ) 6.0 Hz, 6 H).
Assay kit (Hercules, CA) following membrane solubilization
with Triton X-100.
Com p etitive Bin d in g Assa ys. Assays were done in 96-
well plates with a 200 µL final volume per well. Test compound
concentrations for competition curves ranged from 0.1 pM to
10 µM in half-log increments. Next, 0.1 µg of R1a- or R1b-AR-
expressing membrane protein, or 2.6 µg of R1d-AR-expressing
membrane protein, were added to TNE buffer with a final
concentration of 50 pM [125I] HEAT (2200Ci/mmol) and the
appropriate concentration of test compound. Following a 25
°C incubation for 1 h, the plates were filtered onto GF/C
filterplates (Packard Instruments Co., Meriden, CT) and
washed with ice cold saline and 0.05% Tween-20. Levels of
radioactivity were determined using a Packard TopCount
liquid scintillation counter. Competition curves were analyzed
with the use of the curve-fitting capabilities of GraphPad
Prism software (GraphPad Software, Inc., San Diego, CA). The
concentration of antagonist needed to inhibit specific binding
by 50% (IC50) was used to calculate Ki values according to the
relationship Ki ) IC50/(1 + [radioligand]/Kd), where the Kd is
the dissociation constant of the radioligand at the receptor.30
2-(4-Hyd r oxyp h en yl)-2,3-d ih yd r o-N-[3-[4-[2-(1-m eth yl-
eth oxy)ph en yl]-1-piper azin yl]pr opyl]-1,3-dioxo-1H-isoin -
1
d ole-5-ca r boxa m id e (30): light-tan solid; H NMR (CDCl3)
δ 8.96 (brs, 1 H), 8.29 (m, 2 H), 7.95 (d, J ) 7.9 Hz, 1 H), 7.18
(d, J ) 8.4 Hz, 2 H), 6.86 (m, 6 H), 4.56 (m, 1 H), 3.64 (m, 2
H), 3.10 (m, 4 H), 2.71 (m, 6 H), 1.87 (m, 2 H), 1.33 (d, J ) 6.0
Hz, 6 H).
1-(3-Azid o-2-m et h oxyp r op yl)-4-[2-(1-m et h ylet h oxy)-
p h en yl]p ip er a zin e (41). Compound 37c (0.8 g, 2.5 mmol)
was dissolved in anhydrous THF (50 mL) and cooled to 0 °C.
Sodium hydride (60% dispersion in mineral oil, 0.2 g, 5.0 mmol)
was added, the solution was stirred for 10 min, and CH3I (0.53
g, 3.8 mmol) was added. The reaction mixture was stirred at
0 °C for 2 h. The second portions of sodium hydride (0.1 g, 2.5
mmol) and CH3I (0.15 mL) were added, and this mixture was
stirred for another 2 h at 0 °C. The reaction was quenched
with saturated NH4Cl (aq), the organic solvent was evaporated,
and the aqueous layer was extracted with methylene chloride
(3×), dried (Na2SO4), and concentrated. The product was
purified by column chromatography (SiO2) to give 0.69 g (83%)
of 41 as oily solid: 1H NMR (CDCl3) δ 6.90 (m, 4 H), 4.60 (m,
1 H), 3.50 (m, 5 H), 3.35 (m, 1 H), 3.18 (m, 4 H), 2.55 (m, 6 H),
1.32 (d, J ) 6.1 Hz, 6 H); MS (ES) m/z 334 (M + H+).
2-(3-F lu or op h en yl)-2,3-d ih yd r o-N-[2-m et h oxy-3-[4-[2-
(1-m eth yleth oxy)ph en yl]-1-piper azin yl]pr opyl]-1,3-dioxo-
1H-isoin d ole-5-ca r boxa m id e (31). A 10% HCl solution (0.3
mL) was added to a mixture of 41 (0.64 g, 1.9 mmol) and 10%
Pd/C (0.13 g) in MeOH (5 mL). This mixture was hydrogenated
under H2 (50 psi) in a Parr shaker overnight and filtered
through Celite, and the filtrate was concentrated. The residue
was basified with 20% NaOH (aq), extracted with methylene
chloride (3×), dried (Na2SO4), and concentrated to give the free
amine (∼100%) as a yellow oil. The amine was used directly
without further purification: MS (ES) m/z 308 (M + H+).
The amine (0.15 g, 0.49 mmol) was dissolved in a mixture
of methylene chloride (4 mL) and N,N-diisopropylethylamine
(0.25 g,1.95 mmol). To this solution was added a mixture of
HATU (0.185 g, 0.49 mmol) and carboxylic acid 34a (0.14 g,
0.49 mmol), and the reaction was stirred overnight under N2
at 20 °C. The solvent was evaporated, and the product was
purified by flash chromatography (SiO2) to give 0.08 g (29%)
of 31 as a light yellow solid: 1H NMR (CDCl3) δ 8.36 (m, 2 H),
8.18 (brs, 1 H), 8.02 (d, J ) 7.7 Hz, 1 H), 7.47 (m, 1 H), 7.22
(m, 3 H), 7.00 (m, 1 H), 6.87 (m, 3 H), 4.57 (m, 1 H), 3.76 (m,
3 H), 3.50 (s, 3 H), 3.22 (m, 10 H), 1.35 (d, J ) 6.0 Hz, 6 H).
Biology. Recep tor Bin d in g Assa ys. DNA Clon in g, COS
Cell Tr a n sfection , a n d Mem br a n e P r ep a r a tion . The
cDNA clones encoding the three human R1-AR subtypes were
obtained by reverse transcription-polymerase chain reaction
amplification from human hippocampus and prostate polyA+
RNA libraries (Clontech, Palo Alto, CA). cDNA clones were
verified by sequence analysis, and any deviation from pub-
lished sequence was corrected by site-directed mutagenesis.
cDNAs were subcloned into the pcDNA3 mammalian expres-
sion vector (Invitrogen Corp, Carlsbad, CA). COS-1 cells were
transfected by the standard DEAE-dextran method with
chloroquine shock.29 Each tissue culture dish was inoculated
with 3.5 × 106 cells and transfected with 10 µg of DNA. At 72
h post-transfection, the cells were scraped into TE buffer (50
mM Tris-HCl, 5 mM EDTA, pH 7.4). The cell suspension was
disrupted with a Brinkman Polytron, setting 8, for 10 s. The
disrupted cells were centrifuged at 1000g for 10 min at 4 °C.
Supernatants were centrifuged at 34500g for 20 min at 4 °C.
The membrane pellets were suspended in TNE buffer (50 mM
Tris-HCl, 150 mM NaCl, 5 mM EDTA, pH 7.4). The protein
concentration was determined with the Bio-Rad DC Protein
Ra d ioliga n d Bin d in g Stu d ies (P a n la bs). The percent
inhibition of radioligand binding activity in the presence of 1
µM of each tested compound was determined in duplicate.
Radioligand binding assays for each of the monoamine recep-
tors and calcium channels examined were performed in a 50
mM Tris-HCl, 150 mM NaCl, 5 mM EDTA, pH 7.4 buffer. The
method for each receptor or Ca2+ channel is summarized here
and was performed essentially as described in the references
noted. The recombinant human R2a- and R2c-adrenergic, dopam-
inergic D2L, D2S, D3, D4.7, and serotonergic 5-HT1A and 5-HT7
receptors were expressed in CHO cells, from which membranes
were prepared as described for the R1-adrenoceptors. Competi-
tion binding assays to the R2a- and R2c-adrenergic receptors
were performed using the [3H]MK912 radioligand and an
incubation period of 60 min at 25 °C.31 WB4101 (10 µM) was
used to determine the level of nonspecific binding. Rat kidney
cortical membranes were the source of the R2b-adrenergic
receptors, and [3H]yohimbine at 25 °C for 30 min was used to
determine the level of binding activity.32 Phentolamine (10 µM)
was used to measure nonspecific binding. For D2L and D4.7 the
level of binding of [3H]spiperone was determined following a
25 °C incubation for 120 min, and a 37 °C incubation for D2S
and D3 for 120 min.33-39 Haloperidol (10 µM) was used to
determine nonspecific binding levels of the D2L, D2S, and D4.7
receptors; and 25 µM S(-)sulpiride was used to determine the
nonspecific binding for the D3 receptor. The level of binding
of [3H]8-OH-DPAT at the 5-HT1A receptor following a 60 min
incubation at 25 °C was determined.40 Metergoline (10 µM)
was used to measure nonspecific binding. Binding of [3H]LSD
to the 5-HT7 receptor was measured following a 120 min
incubation at 37 °C, with 5 µM 5-HT used to determine
nonspecific binding.41,42 Membranes from rat cerebral cortex
were used as the source of serotonin 5-HT1 receptors, dihy-
dropyridine-sensitive Ca2+ L channels, and imidazoline I2
receptors. [3H]5-HT was used in the binding studies for the
5-HT1 receptor, with a 10 min incubation at 37 °C, and 10 µM
5-HT for determination of nonspecific binding.43 Binding to the
dihydropyridine-sensitive Ca2+ L channels was measured with
the radioligand [3H]nitrendipine in a 25 °C incubation for 90
min.44,45 Nifedipine (1 µM) was used to determine the degree
of nonspecific binding. Binding at 25 °C for 30 min of the
radioligand [3H]idazoxan was used to measure the activity at
the imidazoline I2 receptor.46,47 Nonspecific binding was de-
termined in the presence of 1 µM idazoxan. Guinea pig brain
and guinea pig lung were the sources of central and peripheral
histamine H1 receptors, respectively. The radioligand used to
assay binding activity at the histamine receptors was [3H]-
pyrilamine with a 25 °C incubation for 60 min for the central
receptors and 30 min for the peripheral receptors.48,49 Pyril-
amine (1 µM) and 1 µM mepyramine were used to determine
nonspecific binding levels for the central and peripheral H1
receptors, respectively. Following the incubation period, the
membranes were filtered and washed three to four times prior

2194 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 11
Kuo et al.
(6) Burt, R. P.; Chapple, C. R.; Marshall, I. The role of capacitative
Ca+2 influx in the R1B-adrenoceptor-mediated contraction to
phenylephrine of the rat spleen. Br. J . Pharmacol. 1995, 116,
2327-2333.
(7) Hatano, A.; Takahashi, H.; Tamaki, M.; Komeyama, T.; Koizumi,
T.; Takeda, M. Pharmacological evidence of distinct R1-adreno-
ceptor subtypes mediating the contraction of human prostatic
urethra and peripheral artery. Br. J . Pharmacol. 1994, 113,
723-728.
(8) (a) Kenny, B. A.; Chalmers, D. H.; Philpott, P. C.; Naylor, A. M.
Characterization of an R1D-adrenoceptor mediating the contrac-
tile response of rat aorta to noradrenaline. Br. J . Pharmacol.
1995, 115, 981-986. (b) Aboud, R.; Shafii, M.; Docherty, J . R.
Investigation of the subtypes of R1-adrenoceptor mediating
contractions of rat aorta, vas deferens and spleen. Br. J .
Pharmacol. 1993, 109, 80-87.
(9) Lepor, H.; Henry, D.; Laddu, A. R. The efficacy and safety of
terazosin in the treatment of BPH. Prostate 1991, 18, 345-355.
(10) Holme, J . B.; Christensen, M. M.; Rasmussen, P. C.; J acobsen,
F.; Nielsen, J .; Norgaard, J . P.; Olesen, S.; Noev, I.; Wolf, H.;
Husted, S. E. 29-Week doxazosin treatment in patients with
symptomatic benign prostatic hyperplasia. Scand. J . Urol.
Nephrol. 1994, 28, 77-82.
to determining the level of radioligand binding by liquid
scintillation counting.
Ki values are reported as the mean ( SEM of three
independent experiments. Competition curves were fitted, and
IC50 values were estimated, by nonlinear least squares regres-
sion analysis using GraphPad Prism Software (GraphPad, San
Diego, CA). Ki values were derived from the IC50 values by
the Cheng-Prusoff equation.30
F u n ction a l Assa ys. Ra t Isola ted P r osta te a n d Aor ta
Tissu e Assa ys (P a n la bs). Long Evans male rats weighing
275 ( 25 g were killed by cervical dislocation, and the
abdominal aorta and prostate gland were removed. Aortic
strips 3-4 mm wide were prepared and placed in 10 mL
isolated tissue baths under a resting tension of 2 g. Prostate
strips measuring 8-10 mm in length and 1-2 mm in width
were placed under a resting tension of 2 g. Tissues were bathed
in modified Kreb’s solution of the following composition (g/L):
NaCl 6.9, KCl 0.35, KH2PO4 0.16, NaHCO3 2.1, CaCl2 0.28,
MgSO4‚7H2O 0.29, (+)-glucose 1.0. Baths were maintained at
37 °C and constantly bubbled with 95% oxygen and 5% CO2,
pH 7.4, with the solution being changed at frequent intervals
throughout the 60 min equilibration period. Tissue strips were
connected to isometric transducers connected to a strip chart
recorder. Prior to beginning concentration-response curves,
tissues were exposed to (()-norepinephrine (NE) at a concen-
tration of 1.0 µM. A response of 0.5 g tension was required for
the tissue to be used for concentration-response curves.
Following a 90 min wash period, a cumulative concentration-
response curve was obtained to NE concentrations of 0.001-
100 µM in half log increments. After completion of the
concentration-response curve, the tissue was washed for 90
min, and one of three concentrations of antagonist was added
and incubated for 5 min before a second cumulative concentra-
tion curve was obtained. In a number of cases, Schild analysis
could not be performed as a result of depression of the maximal
response by high antagonist concentrations and the resulting
nonparallel slopes of the concentration-response curves.
Estimates of affinity were obtained by the receptor dissociation
constant, KB, from the concentration-response curves, and
represented as the negative logarithm, pKB. Each NE concen-
tration-response curve was analyzed using GraphPad Prism
software to estimate midpoint location (EC50). EC50 values were
obtained in the presence and absence of antagonist and used
to calculate the antagonist dissociation equilibrium constants
according to the relationship KB ) [B]/(CR - 1), where [B] is
the antagonist concentration at which a concentration ratio
could be accurately determined and CR is the concentration
ratio.
(11) Lepor, H. The emerging role of alpha antagonists in the therapy
of benign prostatic hyperplasia. J . Androl. 1991, 12, 389-394.
(12) (a) Kawabe, K.; Ueno, A.; Takimoto, Y.; Aso, Y.; Kato, H. Use of
an R1-blocker, YM 617, in the treatment of benign prostatic
hypertrophy. J . Urol. 1990, 144, 908-912. (b) Rabasseda, X.;
Fitzpatrick, J . M. Tamsulosin, the first prostate-selective R1A
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adrenoceptor antagonist for the treatment of symptomatic
benign prostatic hyperplasia. Drugs Today 1996, 32 (Suppl. C),
1-12.
(13) (a) Djavan, B.; Marberger, M. A meta-analysis on the efficacy
and tolerability of R1-adrenoceptor antagonists in patients with
lower urinary tract symptoms suggestive of benign prostatic
obstruction. Eur. Urol. 1999, 36, 1-13. (b) Lowe, F. Alpha-1-
adrenoceptor blockade in the treatment of benign prostatic
hyperplasia. Prostate Cancer Prostatic Dis. 1999, 2, 110-119.
(c) Schulman, C. C.; Cortvriend, J .; J onas, U.; Lock, T. M. T.
W.; Vaage, S.; Speakman, M. J . Tamsulosin, the first prostate-
selective alpha-1A-adrenoceptor antagonist. Eur. Urol. 1996, 29,
145-154. (d) J ardin, A.; Andersson, K. E.; Caine, M.; et al.
Alpha-blockers in the treatment of BPH. In Denis, L.; Griffiths,
K.; Khoury, S.; Cockett, A. T. K. McConnell, J .; Chatelain, C.;
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(14) [125I] HEAT: ((()-â-([125I] Iodo-4-hydroxyphenyl)-1-ethyl-amino-
ethyl-tetralone) was obtained from NENTM Life Science Products
(Boston, MA).
(15) Testa, R.; Guarneri, L.; Taddei, C.; Poggesi, E.; Angelico, P.;
Sartani, A.; Leonardi, A.; Gofrit, O. N.; Meretyk, S.; Caine, M.
Functional antagonistic activity of Rec 15/2739, a novel alpha 1
antagonist selective for the lower urinary tract, on noradrena-
line-induced contraction of human prostate and mesenteric
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(16) Shibata, K.; Foglar, R.; Horie, K.; Obika, K.; Sakamoto, A.;
Ack n ow led gm en t. We thank Linda Mulcahy and
Deborah Loughney for helpful discussions.
Ogawa, S.; Tsujimoto, G. KMD-3213, a novel, potent, R1a
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adrenoceptor-selective antagonist: characterisation using re-
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Su p p or tin g In for m a tion Ava ila ble: Elemental analyses
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