Identification of a dihydropyridine as a potent α(1a) adrenoceptor- selective antagonist that inhibits phenylephrine-induced contraction of the human prostate

Article abstract of DOI:10.1021/jm980077m

A number of novel dihydropyridine derivatives based upon 1,4-dihydro-3- (methoxycarbonyl)-2,6-dimethyl-4-(4-nitrophenyl)-5-((3-(4,4- dihyphenylpiperidin-1-yl)propyl)aminocarbonyl)pyridine (4) have been synthesized and tested at cloned human α adrenoceptors as well as the rat L- type calcium channel. Within this compound series, 5-(aminocarbonyl)-1,4- dihydro-2,6-dimethyl-4-(4-nitrophenyl)-3-((3-(4,4-diphenylpiperidin-1- yl)propyl)aminocarbonyl)pyridine (19)displayed good binding affinity and selectivity for the α(1a) adrenoceptor (pK(i) = 8.73) and potently inhibited (pA₂ = 9.23) phenylephrine-induced contraction of the human prostate.

Full text of DOI:10.1021/jm980077m

J . Med. Chem. 1998, 41, 2643-2650
2643
Id en tifica tion of a Dih yd r op yr id in e a s a P oten t r1a Ad r en ocep tor -Selective
An ta gon ist Th a t In h ibits P h en ylep h r in e-In d u ced Con tr a ction of th e Hu m a n
P r osta te
Wai C. Wong,*,† George Chiu,†,| J ohn M. Wetzel,† Mohammad R. Marzabadi,† Dhanapalan Nagarathnam,†
Diana Wang,†, J ames Fang,†,∇ Shou Wu Miao,†,# Xingfang Hong,†,# Carlos Forray,‡ Pierre J .-J . Vaysse,§
Theresa A. Branchek,‡ and Charles Gluchowski†,@
Departments of Chemistry, Pharmacology, and Cell Biology, Synaptic Pharmaceutical Corporation, 215 College Road,
Paramus, New J ersey 07652
Rui Tang and Herbert Lepor
Department of Urology, New York University Medical Center, New York, New York 10021
Received February 3, 1998
A number of novel dihydropyridine derivatives based upon 1,4-dihydro-3-(methoxycarbonyl)-
2,6-dimethyl-4-(4-nitrophenyl)-5-((3-(4,4-diphenylpiperidin-1-yl)propyl)aminocarbonyl)pyri-
dine (4) have been synthesized and tested at cloned human R adrenoceptors as well as the rat
L-type calcium channel. Within this compound series, 5-(aminocarbonyl)-1,4-dihydro-2,6-
dimethyl-4-(4-nitrophenyl)-3-((3-(4,4-diphenylpiperidin-1-yl)propyl)aminocarbonyl)pyridine (19)
displayed good binding affinity and selectivity for the R1a adrenoceptor (pKi ) 8.73) and potently
inhibited (pA2 ) 9.23) phenylephrine-induced contraction of the human prostate.
Ch a r t 1
In tr od u ction
Benign prostatic hyperplasia (BPH) is a progressive
condition which is characterized by a nodular enlarge-
ment of prostatic tissue resulting in obstruction of the
urethra.1 This condition 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, a poor urine stream, and hesitancy
or delay in starting the urine flow. Several R1 adreno-
ceptor antagonists of the quinazoline class such as
prazosin, terazosin, doxazosin, and alfuzosin (Chart 1)
are being used clinically for the treatment of BPH by
relaxing the smooth muscle of the prostate.2 However,
these agents have been shown to cause significant side
effects including dizziness, decreased blood pressure,
nasal congestion, and impotence,3 presumably as a
result of their lack of selectivity for any one of the three
R1 adrenoceptor subtypes (R1a, R1b, and R1d).4 Tamsu-
losin,5 a compound not belonging to the quinazoline
class, is another R1 antagonist indicated for BPH (Chart
1). Newer R1 antagonists under development for treat-
ing BPH include 1 (Rec 15/2739),6 2 (SL 89.0591),7 and
3 (KMD 3213)8 (Chart 2).
BPH with reduced side effects than nonselective R1
antagonists. However, when we initiated these studies,
no subtype-selective R1a antagonists had been reported.
Recently, reports from this laboratory revealed that
compound 4 (SNAP 5089; Chart 2), a niguldipine
analogue, is a selective R1a antagonist which is relatively
devoid of calcium channel activity.10 We wanted to
further explore the structure-activity relationship of
this class of compounds at the R1a adrenoceptor. In
addition, 4 is difficult to handle due to the fact that it
is very lipophilic and tends to adhere to tissues and
container walls. Therefore, an analogue which is less
lipophilic and will not adhere to tissues and container
With the cloning and characterization of the three
human R1 adrenoceptor subtypes, we were able to
demonstrate that the R1a subtype is the predominant
receptor mediating smooth muscle contraction in human
prostate.9 This discovery suggested that an R1a-selective
antagonist will show better efficacy in the treatment of
† Department of Chemistry.
‡ Department of Pharmacology.
§ Department of Cell Biology.
| Current address: FMC Corp., Princeton, NJ .
Current address: Yale University, New Haven, CT.
#
Current address: Merck and Co., Rahway, NJ .
∇ Current address: Novartis Pharmaceuticals Corp., Summit, NJ .
@ Current address: RiboGene, Inc., Hayward, CA.
S0022-2623(98)00077-6 CCC: $15.00 © 1998 American Chemical Society
Published on Web 06/16/1998

2644 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 14
Notes
Ch a r t 2
Sch em e 1. Hantzsch Synthesis of Dihydropyridines 7-18 and 20-26
Sch em e 2. Synthesis of Compound 19
Sch em e 3. Synthesis of Compound 27
walls is needed for development. Herein we describe
our initial results regarding the design and synthesis
of analogues of 4.11
Syn th esis
The compounds in this study were prepared by one
of two methods. In the first method (Scheme 1), the
dihydropyridine ring was assembled by the Hantzsch
reaction12 at the very last step of the synthesis. Hence,
an appropriate enamine 5 was reacted with a benzal-
dehyde and a â-ketoamide 6 to provide compounds 7-18
and 20-26 (Tables 1-3). The â-ketoamides 6 used in
this study were prepared13 by reaction of the corre-
sponding amines with either diketene or a Meldrum’s
acid derivative.14 In the second method (Schemes 2-4),
a double protection strategy15 was used in which a
dihydropyridine ring with an easily removable group at

Notes
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 14 2645
Sch em e 4. Synthesis of Compounds 28 and 29
Ta ble 1. Modifications at C-4 of the Dihydropyridine Ring
and at the Piperidine Ring
the C-3 and/or C-5 positions was assembled earlier in
the synthesis. The removable group was subsequently
replaced by the desired side chains to afford 19 and 27-
29 (Table 4). This strategy allowed for flexibility in
attaching different side chains to a common intermedi-
ate. For example, in the preparation of compound 19
(Scheme 2), enamine 5d was reacted with p-nitroben-
zaldehyde and acetoacetate 3019 to give dihydropyridine
31 which was then hydrolyzed and coupled with amine
3210 to afford 19. Likewise, intermediate 34 (Scheme
3), which was obtained from the reaction of enamine
5c and benzylidene 33, was hydrogenolyzed and then
coupled to amine 32 to provide 27. In the preparation
of compounds 28 and 29 (Scheme 4), enamine 3519 was
reacted with benzylidene 33 to afford dihydropyridine
36. Then the benzyloxy group, after hydrogenolysis,
was replaced by amine 32. Subsequently, the 2-cyano-
ethyl group was hydrolyzed, and the resulting acid 38
was treated with ammonia to give primary amide 28 or
with methylamine to yield secondary amide 29.
pKi
compd
X
R1 R1a R1b R1d R2a R2b R2c
Ca
terazosin
8.16 8.71 8.46 6.26 7.51 6.65
4
7
8
9
10
11
12
13
14
15
16
4-NO2
4-Cl
4-CN
4-OMe
4-Me
Ph 9.46 6.66 6.27 5.92 6.10 6.43 6.27
Ph 8.75 6.91 6.35 5.67 5.64 6.00 <6
Ph 8.74 6.82 6.42 6.12 5.90 6.06 <6
Ph 8.15 6.69 6.31 5.66 5.82 5.94 <6
Ph 8.86 6.57 6.50 5.89 6.04 6.38 <6
Ph 8.95 6.65 6.52 5.95 6.06 6.24 <6
Ph 8.73 6.94 6.49 6.04 5.90 6.80 <6
3,4-OCH2O
3,4-Cl2
3-OMe-4-NO2 Ph 8.83 6.79 6.50 6.20 6.24 6.40 <6
3,4-benzo
4-NO2
Ph 7.44 6.86 6.13 5.80 6.05 6.20 6.43
H
H
9.64 7.87 7.18 6.56 6.66 7.09 <6
9.28 7.38 6.90 6.96 7.04 7.32 <6
4-Cl-3-NO2
Biologica l Meth od s
Resu lts a n d Discu ssion
Stably transfected cloned human R adrenoceptors
were used in this study. The displacement of [3H]-
prazosin from the R1a, R1b, and R1d receptors9 and the
displacement of [3H]rauwolscine from the R2a, R2b, and
R2c receptors20 were used to calculate the binding
affinities (pKi) of the test compounds (average SEM <
0.07). The incubation time for radioligand binding
assays was 30 min.21 Antagonism at R1 receptors was
established by measuring changes in intracellular cal-
cium ion concentrations in the absence and presence of
norepinephrine. The affinities at the L-type calcium
channel were determined from the displacement of [3H]-
nitrendipine from rat brain homogenate.22 This assay
was necessary to ensure weak calcium channel activity
for our compounds since many dihydropyridines are
well-known as calcium channel inhibitors. For prostate
contraction studies, fresh human prostatic tissue was
obtained from male patients aged 50-80 years undergo-
ing prostatectomy for BPH. The contractile response
induced by phenylephrine was determined as described
elsewhere.9 The antagonist dissociation constant (pA2)
was determined by Schild analysis.
In an attempt to study the structure-activity rela-
tionship of analogues of 4 at the R1a adrenoceptor, we
modified each substituent on the dihydropyridine ring
in a systematic manner. First, the phenyl group at the
C-4 position of the dihydropyridine ring (compounds
7-14, Table 1) was modified. The substituents on the
phenyl group were chosen to include those with electron-
donating and electron-withdrawing properties as well
as with different steric demands. The results indicated
that while R1a antagonist affinity was maintained with
a range of substituents, only the 4-methyl and 3,4-
methylenedioxy compounds (10 and 11) maintained the
affinity (Ki ∼ 1 nM) and selectivity (>200-fold) of 4. It
is well-known that meta-substituents on dihydropy-
ridines tend to favor calcium channel affinity while
para-substituents abolish or greatly reduce affinity.23
Therefore, it is interesting to note that compounds 11-
13 showed only weak affinity (Ki > 1 µM) at the rat
L-type calcium channel even though the phenyl groups
of these compounds were meta,para-disubstituted.
In this series, when one phenyl group was removed
from the 4-position of the piperidine ring (compounds

2646 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 14
Notes
Ta ble 2. Modifications at C-2, C-3, and C-6 of the
Ta ble 3. Modifications of the Linker Chain
Dihydropyridine Ring
pKi
compd
R
n
R1a
R1b
R1d
R2a
R2b
R2c
Ca
pKi
24
4
25
26
H
H
H
Me
1
2
3
2
8.06 7.11 5.94 6.35 6.29 6.61 <6
compd
17 CN
18 COMe
19 CONH2
(+)-19 CONH2
(-)-19 CONH2
X
Y
R1a R1b R1d R2a R2b R2c Ca
9.46 6.66 6.27 5.92 6.10 6.43
7.83 6.87 6.48 6.19 6.43 6.55 <6
7.69 6.62 6.30 6.17 6.31 6.61 <6
6.27
Me 7.25 6.78 6.36 6.20 6.08 6.32 <6
Me 8.93 6.58 6.29 6.22 6.36 6.43 <6
Me 8.73 6.48 6.22 6.43 6.38 6.49 <6
Me 7.68 6.35 6.40 6.52 6.39 6.52
Me 9.00 6.44 6.65 6.82 6.55 6.78
Ta ble 4. Modifications at C-3 of the Dihydropyridine Ring
20 CONHMe Me 8.35 6.31 6.12 6.40 6.03 6.49 <6
21 CONMe2 Me 7.23 5.93 5.77 6.02 5.74 6.09 <6
22 CONH2
23 CONH2
Et
8.97 6.61 6.33 6.45 6.59 6.72
i-Pr 7.27 6.79 6.46 6.17 6.42 6.37
15 and 16, Table 1), affinity at the R1a receptor was
maintained. Unfortunately, the affinity at the other R
receptors was increased resulting in significantly lower
selectivity for the R1a receptor. It is plausible that the
aromatic group on the piperidine ring of these two
compounds enjoys more rotational freedom than those
of the diarylpiperidine analogues (4, 7-14) such that
more desirable conformations may be achieved for a
better fit in most of the R receptors. In addition, despite
the presence of a m-nitro substituent on compound 16,
the affinity at the rat L-type calcium channel was
greatly diminished.
Next, we replaced the methyl ester of 4 with other
functional groups (compounds 17-21, Table 2). Only
ketone 18 and amide 19 were comparable to 4 in affinity
and selectivity. Apparently, the carbonyl oxygen is
playing a role in binding to the R1a receptor because
nitrile 17 showed relatively weak affinity. It is note-
worthy that the (-)-enantiomer of 19 (obtained by chiral
HPLC resolution of the racemate, see Experimental
Section) displayed higher affinity than the racemate
although there was no overall gain in selectivity.
Moreover, substituting the primary amide with a methyl
group as in compound 20 slightly reduced the binding
affinity at the R1a receptor. Further substituting the
amide group with a second methyl produced a compound
(21) with low affinity. Therefore, the binding pocket
appears not to be compatible with tertiary amides which
are more sterically demanding than secondary amides
and esters.
pKi
compd
X
R1a
R1b
R1d
R2a
R2b
R2c Ca
27
28
29
38
COMe
CONH2
8.05 6.42 6.34 6.02 6.42 6.39 <6
8.06 5.93 5.94 6.30 6.69 6.14 <6
CONHMe 7.79 5.75 5.82 5.68 6.24 5.99
CO2H 6.50 6.01 5.76 5.93 6.70 6.11
the propyl linker chain of 4 is the optimal length and
that further substitution on the amide nitrogen ad-
versely affects binding affinity.
Since the 3,4-methylenedioxy group on the C-4 phenyl
ring appeared to be a good substitute for the nitro group
(compound 11 versus 4, Table 1), several additional
analogues (27-29 and 38) with 3,4-methylenedioxy
substitution were prepared and tested (Table 4). Com-
parison of 11, 27-29, and 38 reveals that only the
methoxycarbonyl substituent on the dihydropyridine
ring is tolerated when the phenyl group has 3,4-
methylenedioxy. This is in contrast to the tolerance of
acetyl (18), carboxamide (19), and methylcarboxamide
(20) as well as methoxycarbonyl (4) when the phenyl
ring has a 4-nitro group.
Unlike 4 which is an ester, amide 19 does not adhere
to tissues or container walls presumably because of its
reduced lipophilicity as estimated by c Log P (4.3,
BioByte Corp.) and Rf (0.23) on silica gel TLC plates
(CHCl3/MeOH/NH3, 50:9:1) versus 5.6 and 0.55, respec-
tively, for 4. Nonetheless, 19 maintains good affinity
and selectivity for the R1a adrenoceptor. In order to
determine whether an R1a-selective antagonist would be
effective in inhibiting agonist-induced smooth muscle
contraction of the prostate, 19 was assayed using human
prostatic tissue in the presence of phenylephrine ac-
cording to published procedures.9 Indeed, 19 showed a
potency (pA2) of 9.23 in the assay, which is comparable
to the binding affinity (pKi ) 8.73) at the cloned human
R1a adrenoceptor and greater than the potency of
nonselective terazosin (pA2 ) 8.48).
We replaced the methyl groups at the C-2 and C-6
positions of the dihydropyridine ring with bulkier alkyl
substituents including ethyl and isopropyl (compounds
22 and 23, Table 2). The ethyl group, but not the
isopropyl, was well-tolerated by the R1a receptor. Hence,
it is possible that the larger alkyl groups disrupt the
desirable orientation of the secondary amide linker,
leading to improper fit of the receptor site. Alterna-
tively, the isopropyl groups are simply too bulky to be
accommodated by the receptor pocket.
We also studied the consequence of modifying the
linker chain between the piperidine and dihydropyridine
rings. According to the data in Table 3, it appears that
Recently, the R1 adrenoceptor subtype in the human
prostate has been claimed by others to be of the R1L

Notes
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 14 2647
subtype.24,25 This classification remains highly contro-
versial in light of no evidence for additional genes
encoding R1 adrenoceptors and of in vitro pharmacologi-
cal evidence which indicates that the R1L subtype
displays an affinity profile toward selective R1a antago-
nists similar to that of the recombinant R1a adrenocep-
tor.26 In this regard, the close agreement between the
pKi and pA2 of 19 suggests that this antagonist does
not differentiate between the R1a and R1L subtypes.
Alternatively, this compound does not differentiate
between the binding state of the cloned R1a adrenoceptor
and that of the native receptor in human prostate.
Moreover, the findings that both 4 and 19 show weak
hypotensive activity in vivo27,28 are inconsistent with the
notion that these antagonists bind with high affinity to
the R1L adrenoceptor which was originally described to
be the predominant R1 receptors in vascular tissue
preparations.29 Thus, the pharmacodynamic profile of
19, by virtue of its R1a selectivity with high in vitro
potency in inhibiting human prostate contraction and
low hypotensive activity, suggests that this compound,
or its active enantiomer (-)-19, has the desired urose-
lectivity of a potential drug candidate for the treatment
of BPH.
6.55 (t, 1H), 5.44 (s, 1H), 4.81 (s, 1H), 3.56 (s, 3H), 3.34 (m,
1H), 3.20 (m, 1H), 2.45-2.30 (m, 8H), 2.30 (s, 3H), 2.25-2.10
(m, 2H), 2.16 (s, 3H), 1.54 (m, 2H); 13C NMR (75 MHz) δ 169.0,
168.5, 146.2, 145.8, 136.2, 132.8, 129.4, 129.2, 129.0, 127.7,
126.4, 109.6, 101.5, 57.6, 51.5, 51.1, 45.1, 41.3, 39.6, 36.8, 26.0,
20.6, 18.8; FTIR (NaCl) 1685, 1677, 1618, 1611, 1508, 1498,
1490, 1225 cm-1; CIMS m/e ) 598 (MH+). Anal. (C36H40
-
ClN3O3‚1/2H2O) C, H, N.
The following compounds were prepared in a similar fash-
ion.
4-(4-Cya n op h en yl)-1,4-d ih yd r o-3-(m eth oxyca r bon yl)-
2,6-d im et h yl-5-((3-(4,4-d ip h en ylp ip er id in -1-yl)p r op yl)-
a m in oca r bon yl)p yr id in e (8): 47% yield; pale-yellow crystals
(MeOH/ether); mp 115-118 °C; 1H NMR δ 7.46 (m, 2H), 7.36-
7.16 (m, 12H), 6.95 (br, 1H), 5.38 (s, 1H), 4.94 (s, 1H), 3.54 (s,
3H), 3.40 (m, 1H), 3.20 (m, 1H), 2.50-2.20 (m, 10H), 2.31 (s,
3H), 2.15 (s, 3H), 1.60 (m, 2H); CIMS m/e ) 589 (MH+). Anal.
(C37H40N4O3) C, H, N.
1,4-Dih ydr o-3-(m eth oxycar bon yl)-4-(4-m eth oxyph en yl)-
2,6-d im et h yl-5-((3-(4,4-d ip h en ylp ip er id in -1-yl)p r op yl)-
a m in oca r bon yl)p yr id in e (9): 31% yield; white crystals
(EtOAc/hexane); mp 212-213 °C; 1H NMR δ 7.14-7.30 (m,
12H), 6.75 (d, 2H, J ) 8.4 Hz), 6.21 (br, 1H), 5.44 (s, 1H), 4.71
(s, 1H), 3.73 (s, 3H), 3.59 (s, 3H), 3.31 (m, 1H), 3.10 (m, 1H),
2.38 (m, 8H), 2.28 (s, 3H), 2.21 (s, 3H), 2.17 (m, 2H), 1.78 (m,
2H), 1.53 (m, 2H); CIMS m/e ) 594 (MH+). Anal. (C37H43N3O4)
C, H, N.
1,4-Dih yd r o-3-(m et h oxyca r b on yl)-2,6-d im et h yl-4-(4-
m eth ylp h en yl)-5-((3-(4,4-d ip h en ylp ip er id in -1-yl)p r op yl)-
a m in oca r bon yl)p yr id in e (10): 33% yield; white crystals
(EtOAc/hexane); mp 234-235 °C; 1H NMR δ 7.15-7.26 (m,
12H),7.02 (d, 2H, J ) 8.0 Hz), 6.21 (br, 1H), 5.39 (s, 1H), 4.72
(s, 1H), 3.59 (s, 3H), 3.30 (m, 1H), 3.12 (m, 1H), 2.42 (br, 6H),
2.28 (s, 3H), 2.25 (s, 3H), 2.22 (s, 3H), 1.63 (br, 6H); FABMS
m/e ) 578 (MH+). Anal. (C37H43N3O3‚1/2H2O) C, H, N.
1,4-Dih yd r o-3-(m eth oxyca r bon yl)-2,6-d im eth yl-4-(3,4-
(m eth ylen ed ioxy)p h en yl)-5-((3-(4,4-d ip h en ylp ip er id in -1-
yl)p r op yl)a m in oca r bon yl)p yr id in e (11): 12% yield; yellow
crystals (EtOAc/hexane); mp 197-200 °C; 1H NMR δ 7.30-
7.20 (m, 8H), 7.20-7.10 (m, 2H), 6.77 (d, 1H, J ) 1.6 Hz), 6.73
(dd, 1H, J ) 7.9, 1.7 Hz), 6.63 (d, 1H, J ) 7.9 Hz), 6.29 (t,
1H), 5.86 (s, 2H), 5.56 (s, 1H), 4.70 (s, 1H), 3.59 (s, 3H), 3.33
(m, 1H), 3.16 (m, 1H), 2.50-2.30 (m, 8H), 2.27 (s, 3H), 2.20
(m, 2H), 2.18 (s, 3H), 1.55 (m, 2H); CIMS m/e ) 608 (MH+).
Anal. (C37H41N3O5) C, H, N.
4-(3,4-Dich lor op h en yl)-1,4-d ih yd r o-3-(m eth oxyca r bo-
n yl)-2,6-dim eth yl-5-((3-(4,4-diph en ylpiper idin -1-yl)pr opyl)-
a m in oca r bon yl)p yr id in e (12): 23% yield; white crystals
(EtOAc/hexane); mp 177-178 °C; 1H NMR δ 7.09-7.31 (m,
13H), 6.88 (br, 1H), 5.56 (s, 1H), 4.87 (s, 1H), 3.54 (s, 3H), 3.45
(m, 1H), 3.19 (m, 1H), 2.22-2.37 (m, 10H), 2.31 (s, 3H), 2.11
(s, 3H), 1.55 (m, 2H); FABMS m/e ) 632 (MH+). Anal.
(C36H39Cl2N3O3) C, H, N.
1,4-Dih yd r o-3-(m et h oxyca r b on yl)-4-(3-m et h oxy-4-n i-
t r op h en yl)-2,6-d im et h yl-5-((3-(4,4-d ip h en ylp ip er id in -1-
yl)p r op yl)a m in oca r bon yl)p yr id in e (13): 5% yield; brown
solid (EtOAc/hexane); mp 211-213 °C; 1H NMR δ 7.67 (d, 1H,
J ) 8.4 Hz), 7.11-7.29 (m, 11H), 6.98 (d, 1H, J ) 1.4 Hz),
6.84 (dd, 1H, J ) 1.5, 8.4 Hz), 5.69 (s, 1H), 5.00 (s, 1H), 3.82
(s, 3H), 3.55 (s, 3H), 3.42 (m, 1H), 3.20 (m, 1H), 2.33 (s, 3H),
2.28 (br, 10H), 2.11 (s, 3H), 1.55 (br, 2H); FABMS m/e ) 639
(MH+). Anal. (C37H42N4O6) C, H, N.
1,4-Dih yd r o-3-(m et h oxyca r b on yl)-2,6-d im et h yl-4-(2-
n a p h th yl)-5-((3-(4,4-d ip h en ylp ip er id in -1-yl)p r op yl)a m i-
n oca r bon yl)p yr id in e (14): 31% yield; white crystals (EtOAc/
hexane); sublimed at room temperature; 1H NMR δ 7.65-7.76
(m, 4H), 7.39-7.46 (m, 3H), 7.23-7.28 (m, 5H), 7.11-7.16 (m,
5H), 6.52 (br, 1H), 5.40 (s, 1H), 5.02 (s, 1H), 3.56 (s, 3H), 3.39
(m, 1H), 3.11 (m, 1H), 2.35 (s, 3H), 2.19 (s, 3H), 2.08 (m, 6H),
1.71 (m, 4H), 1.46 (m, 2H); FABMS m/e ) 614 (MH+). Anal.
(C40H43N3O3) C, H, N.
Con clu sion
A number of analogues of 4 have been synthesized
and tested at cloned human R adrenoceptors as well as
the rat L-type calcium channel. The methyl and me-
thylenedioxy groups are good replacements for the nitro
moiety because they still give compounds with high
affinity and selectivity for the R1a adrenoceptor. The
amide side chain containing the diphenylpiperidine
group appears to be essential for high affinity (<2 nM)
and selectivity (>150-fold) for the R1a adrenoceptor. The
methyl ester may be replaced by an acetyl or amide
group. Alkyl groups larger than ethyl at the C-2 and
C-6 positions of the dihydropyridine ring lead to com-
pounds of lower affinity. However, combining these new
features does not necessarily yield compounds with
affinity profiles comparable to that of 4. Finally, 19
displayed a potency (pA2) of 9.23 in inhibiting phenyle-
phrine-induced contraction of the human prostate smooth
muscle, suggesting that this compound (or preferrably
its (-)-enantiomer) may be effective for treating the
symptoms of BPH. Further developments in this com-
pound series will be reported in due course.
Exp er im en ta l Section
Melting points (uncorrected) were determined on a Mel-
Temp apparatus in open capillary tubes. Unless otherwise
indicated, CDCl3 was used as solvent for 1H NMR spectra
which were recorded on a GE QE Plus 300-MHz spectrometer.
Mass spectra were obtained by Oneida Research Services, Inc.
Elemental analyses were performed at Robertson Microlit
Laboratories, Inc.
4-(4-Ch lor op h en yl)-1,4-d ih yd r o-5-(m eth oxyca r bon yl)-
2,6-d im et h yl-3-((3-(4,4-d ip h en ylp ip er id in -1-yl)p r op yl)-
a m in oca r bon yl)p yr id in e (7). N-(3-(4,4-Diphenylpiperidin-
1-yl)propyl)acetoacetamide10 (6a ; 200 mg, 0.53 mmol) was
mixed with methyl 3-aminocrotonate (61 mg, 0.53 mmol) and
4-chlorobenzaldehyde (74 mg, 0.53 mmol) in 2-propanol (5 mL).
The mixture was heated at reflux for 3 days, and the resulting
precipitate, after cooling to room temperature, was filtered off
to give an almost white solid (134 mg). It was recrystallized
twice from chloroform/hexane to afford white crystals (99 mg,
1,4-Dih yd r o-3-(m eth oxyca r bon yl)-2,6-d im eth yl-4-(4-n i-
tr oph en yl)-5-((3-(4-ph en ylpiper idin -1-yl)pr opyl)am in ocar -
bon yl)p yr id in e (15): 33% yield; yellow crystalline solid
1
31% yield): mp 240-242 °C; H NMR δ 7.30-7.12 (m, 14H),

2648 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 14
Notes
1
(CH2Cl2/ether/hexane); H NMR δ 8.07 (dt, 2H, J ) 8.8, 1.9
Each enantiomer was obtained as a yellowish powder after
recrystallization from Et2O/CH2Cl2.
(+)-19: [R]D ) 91.2 (c 0.32, CHCl3). Anal. (C35H39N5O4) C,
H, N.
(-)-19: [R]D ) -90.0 (c 0.38, CHCl3). Anal. (C35H39N5O4)
C, H, N.
Hz), 7.42 (dt, 2H, J ) 8.8, 1.9 Hz), 7.30 (m, 2H), 7.19 (m, 3H),
7.00 (t, 1H, J ) 4.5 Hz), 6.28 (br s, 1H), 5.00 (s, 1H), 3.53 (s,
3H), 3.43 (m, 1H), 3.23 (m, 1H), 2.98 (dm, 1H, J ) 11.2 Hz),
2.80 (dm, 1H, J ) 11.2 Hz), 2.32 (s, 3 H), 2.26-2.53 (m, 3H),
2.12 (s, 3 H), 1.42-2.10 (m, 8 H); CIMS m/e ) 533 (MH+).
Hydrochloride salt: mp 159-160 °C. Anal. (C30H36N4O5‚HCl‚
1/2H2O) C, H, N.
1,4-Dih yd r o-2,6-d im eth yl-5-(m eth yla m in oca r bon yl)-4-
(4-n it r op h e n yl)-3-((3-(4,4-d ip h e n ylp ip e r id in -1-yl)p r o-
p yl)a m in oca r bon yl)p yr id in e (20): 7% yield; yellowish pow-
der (CH2Cl2/Et2O); mp 134 °C; 1H NMR δ 8.06 (d, 2H, J ) 8.7
Hz), 7.42 (d, 2H, J ) 8.7 Hz), 7.00-7.40 (m, 11H), 5.28 (br,
1H), 5.20 (s, 1H), 4.92 (s, 1H), 3.00-3.50 (m, 2 H), 2.69 (d,
3H, J ) 4.8 Hz), 2.24 (s, 3H), 2.09 (s, 3H), 1.20-2.70 (m, 12H);
CIMS m/e ) 608 (MH+). Anal. (C36H41N5O4) C, H, N.
1,4-Dih yd r o-2,6-d im eth yl-3-(d im eth yla m in oca r bon yl)-
4-(4-n itr oph en yl)-5-((3-(4,4-diph en ylpiper idin -1-yl)pr opyl)-
a m in oca r bon yl)p yr id in e (21): 8% yield; yellowish powder
4-(4-Ch lor o-3-n itr op h en yl)-1,4-d ih yd r o-3-(m eth oxyca r -
b on yl)-2,6-d im et h yl-5-((3-(4-p h en ylp ip er id in -1-yl)p r o-
p yl)a m in oca r bon yl)p yr id in e (16): 29% yield; yellow crys-
tals (EtOAc); mp 191-192 °C; 1H NMR δ 7.74 (d, 1H, J ) 2.1
Hz), 7.44 (dd, 1H, J ) 8.3, 2.1 Hz), 7.37 (d, 1H, J ) 8.3 Hz),
7.33-7.15 (m, 5H), 6.97 (t, 1H), 5.47 (s, 1H), 4.97 (s, 1H), 3.55
(s, 3H), 3.45 (m, 1H), 3.25 (m, 1H), 3.00 (m, 1H), 2.85 (m, 1H),
2.55-2.37 (m, 3H), 2.34 (s, 3H), 2.17 (s, 3H), 2.00-1.40 (m,
8H); FABMS m/e ) 567 (MH+). Anal. (C30H35ClN4O5) C, H,
N.
1
(EtOAc/hexane); mp 135 °C; H NMR δ 8.08 (d, 2H, J ) 8.7
Hz), 7.39 (d, 2H, J ) 8.7 Hz), 7.00-7.30 (m, 10H), 6.35 (br,
1H), 5.00 (s, 1H), 4.86 (s, 1H), 3.19 (m, 2H), 2.37 (br, 6H), 2.23
(s, 3 H), 1.77 (s, 3H), 1.20-3.00 (m, 12H), CIMS m/e ) 622
(MH+). Anal. (C37H43N5O4‚1/2H2O) C, H, N.
5-(Am in oca r bon yl)-2,6-d ieth yl-1,4-d ih yd r o-4-(4-n itr o-
p h en yl)-3-((3-(4,4-d ip h en ylp ip er id in -1-yl)p r op yl)a m i-
n oca r bon yl)p yr id in e (22): 5% yield; yellowish powder (CH2-
Cl2/Et2O); mp 119-123 °C. Anal. (C37H43N5O4‚3/2H2O) C, H,
N.
5-(Am in oca r bon yl)-1,4-d ih yd r o-2,6-d iisop r op yl-4-(4-n i-
tr op h en yl)-3-((3-(4,4-d ip h en ylp ip er id in -1-yl)p r op yl)a m i-
n oca r bon yl)p yr id in e (23): 7% yield; yellowish powder
(CH2Cl2/Et2O); mp 76-80 °C. Anal. (C39H47N5O4‚1/2H2O) C,
H, N.
5-Cya n o-1,4-d ih yd r o-2,6-d im eth yl-4-(4-n itr op h en yl)-3-
((3-(4,4-d ip h en ylp ip er id in -1-yl)p r op yl)a m in oca r bon yl)-
p yr id in e (17): 2% yield; yellowish oil; 1H NMR δ 8.21 (m,
2H), 7.50 (m, 2H), 7.0-7.2 (m, 10H), 5.71 (s, 1H), 4.8 (s, 1H),
3.0-3.6 (m, 2H), 2.18 (s, 3H), 2.11 (s, 3H), 1.40-2.80 (m, 12H).
Hydrochloride salt: colorless crystals (MeOH/Et2O); mp 252
°C dec. Anal. (C35H37N5O3‚HCl‚1/2H2O) C, H, N.
5-Acetyl-1,4-d ih yd r o-2,6-d im eth yl-4-(4-n itr op h en yl)-3-
((3-(4,4-d ip h en ylp ip er id in -1-yl)p r op yl)a m in oca r bon yl)-
p yr id in e (18): 18% yield; yellow solid (CH2Cl2/EtOAc); 1H
NMR (CDCl3-CD3OD, 1:1) δ 8.03 (d, 2H, J ) 8.7 Hz), 7.35 (d,
2H, J ) 8.7 Hz), 7.23 (m, 8H), 7.10 (m, 2 H), 5.06 (br s, 1H),
3.19 (m, 2H), 2.46 (m, 8H), 2.33 (s, 3H), 2.22 (m, 2H), 2.10 (s,
3H), 2.02 (s, 3H), 1.60 (m, 2 H); CIMS m/e ) 593 (MH+).
Hydrochloride salt: mp 173-174 °C. Anal. (C36H40N4O4‚HCl‚
H2O) C, H, N.
1,4-Dih yd r o-3-(m eth oxyca r bon yl)-2,6-d im eth yl-4-(4-n i-
t r op h en yl)-5-((2-(4,4-d ip h en ylp ip er id in -1-yl)et h yl)a m i-
n oca r bon yl)p yr id in e (24): 37% yield; yellow solid; 1H NMR
δ 8.07 (d, 2H, J ) 8.7 Hz), 7.47 (d, 2H, J ) 8.7 Hz), 7.24-7.32
(m, 8H), 7.13-7.17 (m, 2H), 6.14 (t, 1H, J ) 4.9 Hz), 5.69 (s,
1H), 4.94 (s, 1H), 3.57 (s, 3H), 3.24 (m, 2H), 2.40-2.42 (m, 8H),
2.32 (m, 2H), 2.31 (s, 3H), 2.29 (s, 3H). Hydrochloride salt:
mp 170-171 °C. Anal. (C35H38N4O5‚HCl‚1/2H2O) C, H, N.
1,4-Dih yd r o-3-(m eth oxyca r bon yl)-2,6-d im eth yl-4-(4-n i-
t r op h en yl)-5-((4-(4,4-d ip h en ylp ip er id in -1-yl)b u t yl)a m i-
n oca r bon yl)p yr id in e (25): 31% yield; yellow solid; 1H NMR
δ 8.08 (d, 2H, J ) 8.6 Hz), 7.41 (d, 2H, J ) 8.6 Hz), 7.22-7.30
(m, 8H), 7.11-7.19 (m, 2H), 6.13 (s, 1H), 5.73 (m, 1H), 4.91 (s,
1H), 3.60 (s, 3H), 2.38-2.44 (m, 8H), 2.27 (s, 3H), 2.24 (m, 2H),
2.12 (s, 3H), 1.40 (m, 4H). Hydrochloride salt: mp 166-167
°C. Anal. (C37H42N4O5‚HCl‚3/4H2O) C, H, N.
1,4-Dih yd r o-3-(m eth oxyca r bon yl)-2,6-d im eth yl-4-(4-n i-
tr op h en yl)-5-((3-(4,4-d ip h en ylp ip er id in -1-yl)p r op yl)m e-
th yla m in oca r bon yl)p yr id in e (26): light-yellow solid; 1H
NMR δ 8.07 (d, 2H, J ) 8.4 Hz), 7.33 (d, 2H, J ) 8.4 Hz), 7.24
(m, 8H), 7.12 (m, 2H), 6.39 (br, 1H), 4.89 (br s, 1H), 3.49 (s,
3H), 3.31 (br, 2H), 2.47 (br, 11H), 2.32 (br s, 3H), 2.21 (br, 2H),
1.70 (br s, 3H), 1.64 (br, 2H); CIMS m/e ) 623 (MH+).
Hydrochloride salt: mp 179-180 °C. Anal. (C37H43N4O5‚HCl‚
1/2H2O) C, H, N.
5-Acet yl-1,4-d ih yd r o-2,6-d im et h yl-4-(3,4-(m et h ylen e-
d ioxy)p h en yl)-3-((3-(4,4-d ip h en ylp ip er id in -1-yl)p r op yl)-
a m in oca r bon yl)p yr id in e (27). To a well-stirred suspension
of 10% Pd/C (3.0 g) in cold methanol (200 mL, 0 °C) under
argon were added formic acid (8.8 mL) and 34 (6.0 g, 15.5
mmol). The mixture was stirred at room temperature for 15
min before the catalyst was removed by filtration. The filtrate
was concentrated to give the carboxylic acid as a white powder
(4.9 g, 85%). A portion (0.150 g, 0.495 mmol) was mixed with
4-(dimethylamino)pyridine (0.121 g, 1 mmol), 1-(3-(dimethyl-
amino)propyl)-3-ethylcarbodiimide hydrochloride (0.190 g, 1
mmol), and 3-(4,4-diphenylpiperidin-1-yl)propylamine (32;
0.189 g, 0.644 mmol) in CH2Cl2 (40 mL) and stirred at room
temperature for 12 h. Then the mixture was washed with
saturated NH4Cl solution (3 × 40 mL) and dried (MgSO4). The
residue obtained from evaporation of the solvent was flash-
chromatographed over silica gel eluting with CHCl3/MeOH/2
5-(Am in oca r b on yl)-1,4-d ih yd r o-2,6-d im et h yl-4-(4-n i-
tr op h en yl)-3-((3-(4,4-d ip h en ylp ip er id in -1-yl)p r op yl)a m i-
n oca r bon yl)p yr id in e (19). A solution of 3-aminocrotona-
mide (3.87 g, 38.6 mmol), 4-nitrobenzaldehyde (5.83 g, 38.6
mmol), and 2-cyanoethyl acetoacetate19 (3.00 g, 19.3 mmol) in
EtOH (100 mL) was heated at reflux for 48 h. The reaction
mixture was filtered and the filtrate concentrated to give a
brown oil which was dissolved in CHCl3 (with the addition of
a small amount of acetone to obtain a homogeneous solution),
washed twice with water, and dried over Na2SO4. After
filtration and removal of solvent, the residue (31) was dissolved
in MeOH and treated with 2 N KOH solution at 0 °C. The
mixture was stirred at 0 °C for 0.5 h. After the MeOH was
removed in vacuo, the aqueous layer was washed twice with
EtOAc and then acidified with hydrochloric acid to pH 1. The
solid precipitate was collected by filtration and washed with
a small amount of cold water to give a yellow powder.
A
portion of the powder (150 mg, 0.473 mmol) and 1-(3-(di-
methylamino)propyl)-3-ethylcarbodiimide hydrochloride (90.6
mg, 0.473 mmol) in CH2Cl2 (15 mL) were stirred at room
temperature for 20 min and then treated with a solution of
3-(4,4-diphenylpiperidin-1-yl)propylamine10 (32; 139 mg, 0.473
mmol) in CH2Cl2 (2 mL). The mixture was heated at reflux
overnight. Then it was washed twice with water and satu-
rated brine. After drying with Na2SO4 and removal of solvent,
a yellowish oil was obtained which was recrystallized from
CH2Cl2/Et2O. A yellowish powder (165 mg, 59% yield) was
obtained: mp 212-215 °C; 1H NMR δ 8.06 (d, 2H, J ) 8.7
Hz), 7.43 (d, 2H, J ) 8.7 Hz), 7.00-7.40 (m, 11H), 5.18 (s, 1H),
5.08 (br, 2H), 4.95 (s, 1H), 3.00-3.60 (m, 2H), 2.29 (s, 3H),
2.08 (s, 3H), 1.50-2.80 (m, 12H); CIMS m/e ) 594 (MH+). Anal.
(C35H39N5O4) C, H, N.
(+)- a n d (-)-19. The enantiomers of 19 were separated
on a chiral HPLC column as follows. Four fractions (16 mg
each in 2 mL of EtOH) were injected into a Chiralpak AS
column (20 × 25 mm; Daicel), which was eluted with EtOH-
hexane-diethylamine (10:90:0.05) at a flow rate of 9.0 mL/
min with UV detection at 300 nm. The retention times were
50 and 65 min for the (+)-isomer and (-)-isomer, respectively.

Notes
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 14 2649
M NH3 in MeOH (50:2:1) to afford the product as a white
powder (0.210 g, 72% yield): mp 94-95 °C; H NMR δ 7.35-
7.10 (m, 10H), 6.90 (br t, 1H, NH), 6.71-6.66 (m, 3H), 5.84
(m, 2H), 5.60 (s, 1H, NH), 4.84 (s, 1H), 3.57-3.40 (m, 1H),
3.02-3.20 (m, 1H), 2.40-2.20 (m, 8H), 2.28 (s, 3 H), 2.05 (s,
3H), 2.00 (s, 3H), 1.52 (m, 2H). Anal. (C37H41N3O4‚3/10CH2-
Cl2‚9/10H2O) C, H, N.
carefully 10% Pd/C (2.0 g), followed by formic acid (4.4 mL)
and 36 (4.5 g, 9.1 mmol). The mixture was stirred for 15 min.
The catalyst was removed by filtration, and the solvent was
evaporated to leave a white solid (2.8 g, 83%). A portion of
the solid (1.50 g, 4.05 mmol), 4-(dimethylamino)pyridine (0.99
g, 8.1 mmol), 1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide
hydrochloride (1.55 g, 8.1 mmol), and 3-(4,4-diphenylpiperidin-
1-yl)propylamine (32; 1.55 g, 5.26 mmol) in CH2Cl2 (270 mL)
were stirred at room temperature for 12 h. Then the mixture
was washed with saturated NH4Cl solution (3 × 50 mL) and
dried (MgSO4). The solvent was evaporated off, and the
residue was purified by flash column chromatography on silica
gel using CHCl3/MeOH/2 M NH3 in MeOH (50:2:1) as the
eluent to afford the product as a white powder (2.30 g, 88%):
mp 96-97 °C; 1H NMR (CD3OD) δ 7.25-7.10 (m, 10H), 6.64-
6.71 (m, 2H), 6.50 (d, lH, J ) 7.9 Hz), 5.74 (s, 2H), 4.81 (s,
1H), 3.15-3.20 (m, 2H), 2.70-2.85 (m, 4H), 2.50-2.65 (m, 4H),
2.35-2.45 (m, 2H), 2.14 (s, 3H), 2.06 (s, 3H).
3-Ca r boxy-1,4-d ih yd r o-2,6-d im eth yl-4-(3,4-(m eth ylen e-
d ioxy)p h en yl)-5-((3-(4,4-d ip h en ylp ip er id in -1-yl)p r op yl)-
a m in oca r bon yl)p yr id in e (38). To a stirred solution of 37
(2.20 g, 3.4 mmol) in acetone (10 mL) at 0 °C was added 1 N
NaOH (10 mL) over 10 min. The mixture was stirred for 1 h
before the acetone was evaporated and the resulting residue
adjusted to pH 7 with 1 N HCl. The product precipitated out
as a white solid which was filtered off, dried, and used without
further purification (1.92 g, 95%).
1
5-(Am in ocar bon yl)-1,4-dih ydr o-2,6-dim eth yl-4-(3,4-(m e-
th ylen ed ioxy)p h en yl)-3-((3-(4,4-d ip h en ylp ip er id in -1-yl)-
p r op yl)a m in oca r bon yl)p yr id in e (28). A mixture of 38
(0.120 g, 0.202 mmol), 4-(dimethylamino)pyridine (0.049 g,
0.404 mmol), and 1-(3-(dimethylamino)propyl)-3-ethylcarbo-
diimide hydrochloride (0.078 g, 0.404 mmol) in CH2Cl2 (20 mL)
was stirred at room temperature for 2 h. To this was added
40% aqueous ammonia (0.085 g, 1.01 mmol), and stirring was
continued for 12 h. It was washed with saturated NH4Cl
solution (3 × 15 mL) and dried (MgSO4). The residue obtained
from the evaporation of solvent was flash-chromatographed
over silica gel eluting with CHCl3/MeOH/2 M NH3 in MeOH
(50:2:1) to afford the product as a white powder (0.065 g, 54%
1
yield): mp 125-127 °C; H NMR δ 7.35-7.10 (m, 10H), 6.90
(br t, 1H, NH), 6.80-6.60 (m, 3H), 5.86 (m, 2H), 5.15 (s, 1H,
NH), 5.05 (br s, 2H, NH2), 4.63 (s, 1H), 3.57-3.40 (m, 1H),
3.20-3.02 (m, 1H), 2.40-2.10 (m, 8H), 2.26 (s, 3H), 2.08 (s,
3H), 1.52 (m, 2H). Anal. (C36H40N4O4‚3/10C6H14 /10H2O) C, H,
9
N.
1,4-Dih yd r o-2,6-d im eth yl-5-(m eth yla m in oca r bon yl)-4-
(3,4-(m eth ylen ed ioxy)p h en yl)-3-((3-(4,4-d ip h en ylp ip er i-
d in -1-yl)p r op yl)a m in oca r bon yl)p yr id in e (29). A mixture
of 38 (0.120 g, 0.202 mmol), 4-(dimethylamino)pyridine (0.087
g, 0.707 mmol), and 1-(3-(dimethylamino)propyl)-3-ethylcar-
bodiimide hydrochloride (0.078 g, 0.404 mmol) in CH2Cl2 (20
mL) was stirred at room temperature for 2 h. To this was
added methylamine hydrochloride (0.020 g, 0.303 mmol), and
stirring was continued for 12 h. It was washed with saturated
NH4Cl solution (3 × 15 mL) and dried (MgSO4). The residue
obtained from the evaporation of solvent was flash-chromato-
graphed over silica gel eluting with CHCl3/MeOH/2 M NH3 in
MeOH (50:2:1) to afford the product as a white powder (0.065
g, 53% yield): mp 120-123 °C; 1H NMR δ 7.35-7.10 (m, 10H),
6.90 (br t, 1H, NH), 6.80-6.60 (m, 3H), 5.85 (m, 2H), 5.40 (br
s, 1H, NH), 5.03 (s, 1H, NH), 4.61 (s, 1H), 3.50-3.38 (m, 1H),
3.20-3.02 (m, 1H), 2.62 (d, 3H, J ) 4.7 Hz), 2.40-2.05 (m,
8H), 2.22 (s, 3 H), 2.00 (s, 3H), 1.50 (m, 2H). Anal. (C37H42N4O4‚
1/5C6H14‚3/5H2O) C, H, N.
Refer en ces
(1) Geller, J .; Kirschenbaum, A.; Lepor, H.; Levine, A. C. Thera-
peutic Controversies: Clinical Treatment of Benign Prostatic
Hyperplasia. J . Clin. Endocrinol. Metab. 1995, 80, 745-747.
(2) Monda, J . M.; Oesterling, J . E. Medical Management of Benign
Prostatic Hyperplasia: An Update. Infect. Urol. 1994, 47-59.
(3) Lepor, H. Long-Term Efficacy and Safety of Terazosin in Patients
with Benign Prostatic Hyperplasia. Urology 1995, 45, 406-413.
(4) The R1a, R1b, and R1d receptors were previously called R1c, R1b
,
and R1a, respectively; see: Hieble, J . P.; Bylund, D. B.; Clarke,
D. E.; Eikenburg, D. C.; Langer, S. Z.; Lefkowitz, R. J .; Minne-
man, K. P.; Ruffolo, R. R., J r., International Union of Pharma-
cology X. Recommendation for Nomenclature of R1-Adrenocep-
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(5) Kawabe, K.; Ueno, A.; Takimoto, Y.; Aso, Y.; Kato, H. YM617
Clinical Study Group. Use of an Alpha-1-blocker, YM617, in the
Treatment of Benign Prostatic Hypertrophy. J . Urol. 1990, 144,
908-912.
Ben zyl 2-(3,4-(Meth ylen ed ioxy)ben zylid en yl)-3-oxobu -
tyr a te (33). A mixture of 3,4-(methylenedioxy)benzaldehyde
(15.013 g, 0.1 mol), benzyl acetoacetate (20.18 g, 0.105 mol),
piperidine (0.41 g, 476 µL, 4.8 mmol), and acetic acid (0.288
g, 274 µL, 4.8 mmol) in 2-propanol (500 mL) was stirred at
room temperature for 48 h. The white solid, benzyl 2-((3,4-
(methylenedioxy)phenyl)methylene)-3-oxobutyrate, formed was
filtered, washed with 2-propanol (2 × 50 mL), and dried (29.84
(6) Testa, R.; Taddei, C.; Poggesi, E.; Destefani, C.; Cotecchia, S.;
Hieble, J . P.; Sulpizio, A. C.; Naselsky, D.; Bergsma, D.; Ellis,
C.; Swift, A.; Ganguly, S.; Ruffolo, R. R., J r.; Leonardi, A. Rec
15/2739 (SB 216,469): A Novel Prostate Selective Alpha-1-
adrenoceptor Antagonist. Pharmacol. Commun. 1995, 6, 79-
86.
(7) Kenny, B.; Collis, A.; Naylor, A.; Wyllie, M. R1-Adrenoceptor
Antagonists as Treatments for Benign Prostatic Hyperplasia.
Exp. Opin. Invest. Drugs 1995, 4 (10), 915-923.
1
g, 92%): mp 137-138 °C; H NMR δ 7.59 (s, 1H), 7.35-7.26
(8) Shibata, K.; Foglar, R.; Horie, K.; Obika, K.; Sakamota, A.;
(m, 5H), 6.78-6.93 (m, 3H), 6.00 (s, 2H), 5.26 (s, 1H), 2.37 (s,
Ogawa, S.; Tsujimoto, G. KMD-3213, A Novel, Potent R1a
-
3H).
Adrenoceptor-Selective Antagonist: Characterization Using Re-
combinant Human R1-Adrenoceptors and Native Tissues. Mol.
Pharmacol. 1995, 48, 250-258.
5-Acetyl-3-(ben zyloxyca r bon yl)-1,4-d ih yd r o-2,6-d im e-
th yl-4-(3,4-(m eth ylen ed ioxy)p h en yl)p yr id in e (34). A mix-
ture of 33 (18.7 g, 57.6 mmol) and 4-amino-3-penten-2-one (5c;
6.0 g, 60.5 mmol) in ethanol (200 mL) was refluxed for 12 h,
and the solvent was evaporated off. The crude product was
used without purification for the next step.
3-(Ben zyloxyca r b on yl)-5-((2-cya n oet h oxy)ca r b on yl)-
1,4-dih ydr o-2,6-dim eth yl-4-(3,4-(m eth ylen edioxy)ph en yl)-
p yr id in e (36). A mixture of 33 (8.0 g, 24.67 mmol) and
2-cyanoethyl 3-aminocrotonate19 (35; 4.83 g, 28.36 mmol) in
ethanol (250 mL) was refluxed for 24 h, and the solvent was
evaporated off. The residue was purified by column chroma-
tography on silica gel using CHCl3/hexane as the eluent to give
the desired product (5.49 g, 45%).
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3-((2-Cyan oeth oxy)car bon yl)-1,4-dih ydr o-2,6-dim eth yl-
4-(3,4-(m eth ylen ed ioxy)p h en yl)-5-((3-(4,4-d ip h en ylp ip e-
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