Design and synthesis of novel α(1a) adrenoceptor-selective antagonists. 3. Approaches to eliminate opioid agonist metabolites by using substituted phenylpiperazine side chains

Article abstract of DOI:10.1021/jm990202+

Dihydropyrimidinones, such as 1, represent a novel class of α(1a) adrenoceptor antagonists with potential for the treatment of benign prostatic hyperplasia (BPH) (see part 1 of this series). Analysis of the metabolites of I revealed that 4-methoxycarbonyl-4-phenylpiperidine is formed as the major metabolite and is an agonist at the μ-opioid receptor. To circumvent any potential liability resulting from the metabolite, we decided to identify alternate templates devoid of agonist activity at the μ-opioid receptor to replace the 4-methoxycarbonyl-4-phenylpiperidine moiety. The present study describes the synthesis and SAR of dihydropyrimidinones linked to substituted 4-phenylpiperazine containing side chains. Compound (+)-38 was identified as a lead compound with a binding and functional profile comparable to that of 1. The putative metabolite 2-carboxamidophenylpiperazine has negligible affinity for the μ-opioid receptor.

Full text of DOI:10.1021/jm990202+

4794
J . Med. Chem. 1999, 42, 4794-4803
Design a n d Syn th esis of Novel r1a Ad r en ocep tor -Selective An ta gon ists. 3.
Ap p r oa ch es To Elim in a te Op ioid Agon ist Meta bolites by Usin g Su bstitu ted
P h en ylp ip er a zin e Sid e Ch a in s
Bharat Lagu,*,† Dake Tian,† Dhanapalan Nagarathnam,† Mohammad R. Marzabadi,† Wai C. Wong,†
Shou W. Miao,† Fengqi Zhang,† Wanying Sun,† George Chiu,† J ames Fang,† Carlos Forray,‡
Raymond S. L. Chang,§ Richard W. Ransom,§ Tsing B. Chen,§ Stacey O’Malley,§ Kanyin Zhang,|
Kamlesh P. Vyas,| and Charles Gluchowski†
Departments of Chemistry and Pharmacology, Synaptic Pharmaceutical Corporation, Paramus, New J ersey 07652, and
Departments of Pharmacology and Drug Metabolism, Merck & Company, Inc., West Point, Pennsylvania 19486
Received April 23, 1999
Dihydropyrimidinones, such as 1, represent a novel class of R1a adrenoceptor antagonists with
potential for the treatment of benign prostatic hyperplasia (BPH) (see part 1 of this series).
Analysis of the metabolites of 1 revealed that 4-methoxycarbonyl-4-phenylpiperidine is formed
as the major metabolite and is an agonist at the µ-opioid receptor. To circumvent any potential
liability resulting from the metabolite, we decided to identify alternate templates devoid of
agonist activity at the µ-opioid receptor to replace the 4-methoxycarbonyl-4-phenylpiperidine
moiety. The present study describes the synthesis and SAR of dihydropyrimidinones linked to
substituted 4-phenylpiperazine containing side chains. Compound (+)-38 was identified as a
lead compound with a binding and functional profile comparable to that of 1. The putative
metabolite 2-carboxamidophenylpiperazine has negligible affinity for the µ-opioid receptor.
Ch a r t 1
In tr od u ction
Benign prostatic hyperplasia (BPH) is a progressive
enlargement of the prostate resulting in a number of
obstructive and irritative symptoms. The incidence of
BPH increases with advancing age such that about 70%
of males over the age of 70 manifest symptoms associ-
ated with BPH.2 R1 Adrenoceptor antagonists such as
terazosin and doxazosin relax the smooth muscle in the
prostate and lower urinary tract and are currently being
used as treatments for BPH.3,4 These clinical agents,
while effective, have been associated with side effects
such as orthostatic hypotension, dizziness, asthenia, and
nasal congestion.5 The side effect profile is presumably
due to an inability of these antagonists to adequately
discriminate between the R1 receptors in the vascular
and lower urinary tracts. The predominant R1 receptor
subtype in the prostate is R1a, and functional studies
reveal that R1a receptors control the smooth muscle
tone.6 The data suggests that an R1a-selective adreno-
ceptor antagonist will provide symptomatic relief with-
out causing some of the aforementioned side effects.
Recently, we reported the discovery of dihydropyri-
dines such as SNAP 5089 as a novel class of R1a-selective
antagonists.7 Modifications in the dihydropyridine series
led to dihydropyrimidinones as a second class of R1a-
selective antagonists, and 1 (i.e. SNAP 6201) was iden-
tified as a lead compound. It was found that 4-meth-
oxycarbonyl-4-phenylpiperidine is formed via N-dealky-
lation as a major metabolite of 1 in rats and dogs.8
4-Methoxycarbonyl-4-phenylpiperidine which resembles
the known opioid agonist meperidine9 (2, Chart 1), was
3.0 µM). Meperidine is a controlled substance with
narcotic and sedative properties.10 In addition, the
4-methoxycarbonyl-4-phenylpiperidine was found to
have long plasma half-life in rats and dogs (>12 h)
which raised concerns regarding potential liabilities
such as sedation or addiction that might be associated
with the chronic administration of 1. To circumvent this
problem, a search was undertaken to find a suitable
replacement for the 4-methoxycarbonyl-4-phenylpiperi-
dine fragment. The goal was to obtain compounds which
would maintain high binding affinity (<5 nM) and
selectivity for the R1a receptor (>300-fold over R1b,d and
R
2a,b,c). The compound should exhibit good potency in a
found to be an agonist at the µ-opioid receptor (IC50
)
number of in vivo and in vivo functional assays. In
addition, it was deemed essential that the metabolites
of this compound should not be agonists at the µ-opioid
receptor. The preceding paper describes the structure-
activity relationship (SAR) in the dihydropyrimidinones
† Department of Chemistry, Synaptic Pharmaceutical Corp.
‡ Department of Pharmacology, Synaptic Pharmaceutical Corp.
§ Department of Pharmacology, Merck & Co.
| Department of Drug Metabolism, Merck & Co.
10.1021/jm990202+ CCC: $18.00 © 1999 American Chemical Society
Published on Web 10/27/1999

Novel R1a Adrenoceptor-Selective Antagonists. 3
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23 4795
Sch em e 1a
a
(a) BBr3, ref 11; (b) Na2CO3, n-BuOH, ref 11; (c) neat, 100 °C, ref 11; (d) concd H2SO4, 2 days, 73% yield; (e) K2CO3, dioxane, reflux,
10 h, 45-80% yield.
containing 4,4-disubstituted piperidine-containing side
chains,8 whereas the present study illustrates the
synthesis and SAR of dihydropyrimidinones containing
substituted 4-phenylpiperazines.
synthesized from commercially available (R)- or (S)-2-
methylpiperazines. The unsubstituted piperazine was
used as a starting material for the synthesis of 13 and
17.
The phenylpiperazines thus synthesized were then
used to obtain the target compounds via parallel syn-
thesis from common intermediate 21, as depicted in
Scheme 2. Compound 2112 was obtained by reaction of
20 with 3-aminopropyl bromide in THF at room tem-
perature, followed by treatment with dilute hydrochloric
acid in THF. Intermediate 21 was then heated in
refluxing acetone with a number of 4-phenylpiperazines
and K2CO3 to obtain the final products 23-41 in 20-
78% yield. The (+) enantiomer of 20 was used as the
starting material for the synthesis of the optically pure
compounds shown in Table 2.
The compounds in Table 3 were synthesized by a
modified procedure as shown in Scheme 3. Reaction of
N-tert-butyloxycarbonyl-3-bromopropylamine with 2′-
carboxamidophenylpiperazine (11) gave intermediate 42
which upon deprotection of the tert-butyloxy group with
trifluoroacetic acid gave 1-(3-aminopropyl)-4-(2′-car-
boxamidophenyl)piperazine (43) in 78% yield. The amine
Ch em istr y
Some of the 4-phenylpiperazines used in the present
study were purchased from commercial sources. The
synthesis of other 4-phenylpiperazines was achieved by
procedures depicted in Scheme 1.11 Compound 4 was
synthesized from the commercially available 2′-meth-
oxyphenylpiperazine (3) (eq 1). The 2′-methyl-4′-meth-
oxyphenylpiperazine (7) was synthesized by heating to
reflux bis(2-chloroethyl)amine (5), 4′-methoxy-2′-meth-
ylaniline (6), and Na2CO3 in n-butyl alcohol for 2 days
(eq 2). The 2′-cyanophenylpiperazine (10) was synthe-
sized from piperazine and 2-bromobenzonitrile accord-
ing to a known procedure11 (eq 3) and was then
converted into 2′-carboxamidophenylpiperazine (11) by
treatment with concentrated sulfuric acid (eq 4). The
phenylpiperazines 13, 17, 18, and 19 were synthesized
from 12 or 16 under identical reaction conditions as
shown in eqs 5 and 6. The compounds 18 and 19 were

4796 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23
Lagu et al.
Sch em e 2
Sch em e 3a
a
(a) N-Boc-3-bromopropylamine, K2CO3, THF, reflux, 55% yield; (b) TFA, CH2Cl2, rt, 78% yield; (c) 43, THF, rt, 49-93% yield; (d) H2,
Pd-C, 94% yield; (e) DMAP, EDC, NH3, THF, 70% yield.
43 was then reacted with activated dihydropyrimidino-
nes of general structure 44 to obtain compounds 45-
50. To synthesize compound 52 which contains a
primary amide group at the C-5 position, 1-(3-amino-
propyl)-4-(2′-carboxamidophenyl)piperazine (43) was
treated with the activated dihydropyrimidinone 44
containing R1 as a methyl, R2 as an O-benzyl, and R3
as a 2,4-difluoro group.1 Benzyl ester 51 was converted
to the carboxylic acid via hydrogenation and subse-
quently to the primary amide via treatment with
ammonia in the presence of EDC.
pared with that of 1 and terazosin in Table 1. Com-
pounds containing phenylpiperazine side chains (except
25, 26, 29, and 35) show good binding affinities (<5 nM)
for the R1a receptor, although many of these compounds
show high binding affinities for the R1b, R1d, and the R2
adrenoceptors as well. Compounds containing either an
electron-donating or an electron-withdrawing group in
the para (24-26 and 35) or meta (27-29) position show
inferior selectivity or binding profiles compared to 1. The
compounds containing a chloro substituent or electron-
donating groups such as methyl, hydroxy, methoxy, and
ethoxy (30-34) in the ortho position on the phenyl ring
display high affinities for the R1a receptor (<1 nM).
These compounds, except for compound 33, exhibit less
than 300-fold selectivity for the R1a receptor. It is
Resu lts a n d Discu ssion
The binding affinities of dihydropyrimidinones con-
taining various 4-phenylpiperazines 23-41 are com-

Novel R1a Adrenoceptor-Selective Antagonists. 3
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23 4797
Ta ble 1. Binding Affinity of 4-Substituted
Phenylpiperazine-Containing Compounds at Recombinant
Human R1 and R2 Adrenoceptors
Ta ble 2. Effect of Ortho Electron-Withdrawing Groups on the
Binding Affinity and Selectivity at Recombinant Human R1 and
R2 Adrenoceptors
Ki (nM)a
fold
selective of
R 1d R1a over R2a,b,c
fold selective of
R1a over R2a,b,c
Ki (nM)a,b
compd R1 R2
R3
R1a
R1b
R1d
compd
R
R1a
6.9
R 1b
1
0.21 260
340
21
12
15
30
310
250
32
28
34
>3200
>55
terazosin
1 (SNAP 6201)
1.9
0.2 260
3.5
340
21
52
<10
>3200
>55
23
36
(+)-36
37
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
0.20
0.10
0.08
7.5
CN
CN
15
15
25
>600
23
24
25
26
27
28
29
30
31
32
33
34
35
36
H
4-Cl
0.2
0.8
14
7.5
17
410
>1300
>85
>65
CO2Me 0.2
4-OMe
4-COMe
3-Cl
3-CF3
3-NO2
2-Me
480
>15
38
CONH2 0.26 135
CONH2 0.12 190
>460
430 1300 1800
>2
(+)-38
(+)-39
(+)-40
>3000
>23000
>1600
>17000
0.7
4.9
12
0.3
0.2
0.6
0.1
0.1
8.4
43
150
17
15
16
18
8.8
510
15
37
120
340
9.8
14
31
31
14
610
12
>195
>60
NO2
0.01
0.05
0.02
23
13
49
Me NO2
NO2
>40
(+)-41 Me
H
>110
>190
>65
a,bPlease see notes in Table 1.
2-Cl
2-OH
test this hypothesis, a number of compounds containing
different electron-withdrawing groups were synthesized,
and the results are shown in Table 2.
2-OMe
2-OEt
2-Me, 4-OMe 16
2-CN 0.1
>360
>210
>20
>600
Compound (+)-36 does not show any improvement in
the binding affinity and selectivity at the R1a receptor
compared to the racemic compound 36. Replacement of
the cyano group with a methoxycarbonyl group results
in compound 37 which displays a similar R1 binding
profile as compound 36 but has significant cross-
reactivity at the R2 adrenoceptors. Compound 38 con-
taining a primary amide group in the ortho position
maintains the high affinity for the R1a receptor but
exhibits a much weaker binding affinity for the other
R1 and R2 receptor subtypes. Compound (+)-38, the (+)
enantiomer, shows a similar binding profile as the
racemic compound 38, an observation quite similar to
the one discussed above for compounds 36 and (+)-36.
More importantly, (+)-38 exhibits a binding and selec-
tivity profile for the R1a receptor that is strikingly
similar to that of 1. If the presence of an electron-
withdrawing group was crucial, then a stronger electron-
withdrawing nitro group at the ortho position of the
phenyl ring would be expected to improve the binding
and selectivity profile. The compounds 39-41 contain-
ing a nitro group at the ortho position of the phenyl ring
do indeed show high binding affinity and selectivity for
the R1 receptor. But, if this line of reasoning was correct,
one would expect that the order of binding affinity and
selectivity of these compounds would parallel the elec-
tron-withdrawing nature of the groups present on the
phenylpiperazines (i.e. NO2 > CN > CO2Me > CONH2).
Clearly, the binding data is not consistent with such a
hypothesis. These results indicate that the CONH2
group contributes to the observed binding and selectivity
profile of (+)-38 not only because of the its electron-
withdrawing nature but also in some other manner.
It is important to recognize that the selectivity
exhibited by compounds 39-41 is due to an increased
affinity for R1a receptor and not due to a decrease in
the binding affinity for the R1b and R1d receptor sub-
types, as seen for 1. The observed selectivity for (+)-
a
Ki values obtained by displacement of [3H]prazosin from cloned
b
human receptors. All Ki values are (5% SE or less for n > 2. In
cases where n ) 2, both Ki values are within 2-fold of each other
and the values shown are the average of the two experiments.
interesting to note that compound 35, which possesses
a methyl group in the ortho position and a methoxy
group in the para position, shows a binding and
selectivity profile similar to that of compound 25
containing a p-methoxy group rather than that of
compound 30 which contains a methyl group in the
ortho position. This observation clearly demonstrates
the detrimental effect caused by an electron-donating
group in the para position of the phenyl ring. The
presence of the electron-withdrawing cyano group at the
ortho position of the phenyl ring results in a compound
(36) that has good binding affinity at the R1a receptor
but only modest selectivity over the other R1 and R2
adrenoceptors compared to 1. It must be noted that the
binding and selectivity profile of these compounds is
significantly better than that of terazosin.
Based on these observations, compounds 33 and 36
emerged as the compounds which show good binding
affinity and a moderate selectivity for the R1a receptor.
It must be noted, however, that both compounds show
relatively high binding affinities at the R1b and R1d
subtypes as compared to 1. Modifications based on
compound 33 did not yield compounds with an improved
selectivity profile, whereas the modifications based on
compound 36 (Table 2) led to compounds that showed
weak binding affinity for the R1b and R1d receptor
subtypes while maintaining high binding affinity for the
R1a receptor.
It was initially thought that the presence of an ortho-
substituted electron-withdrawing cyano group on the
phenyl ring would decrease the basicity of the proximal
piperazine nitrogen that might be essential for the high
binding affinity and selectivity for the R1a receptor. To

4798 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23
Lagu et al.
Ta ble 4. Summary of the in Vitro and in Vivo Properties of
Ta ble 3. Binding Affinities of Different Dihydropyrimidinones
Containing 4-(2-Carboxamidophenyl)piperazine Side Chain at
Recombinant Human R1 and R2 Adrenoceptors
(+)-38 and 1
assay
antagonist/agonist
(+)-38
0.1
>1000
>1000
0.3
550
22
>4 h
1
Ki R1a (nM)
1b,1d/R1a
2a,b,c/R1a
Kb rat prostate (nM)
Kb rat aorta (nM)
AD50 rat (µg/kg)
duration of action
rat (h)
[3H]prazosin
0.2
R
R
[3H]prazosin
>1000
>1000
0.4a
[3H]rauwolscine
phenylephrine
phenylephrine
phenylephrine
phenylephrine
>1000
20
>4
opioid Ki (µM)
rat F, t1/2 (h)
dog F, t1/2 (h)
[3H]DAMGO
>30
4
Ki (nM)a,b
13%,b 2.0 15%,c 2.0
fold selective of
R1a over R2a,b,c
4%,d 2.4
26%,c 2.5
compd
R1
R2
R3
R1a R1b
R1d
a
b
(+)-38
H
H
OMe 3,4-di-F
OMe 3,4,5-tri-F 0.3
0.1 190
58
0.1 100
250
140
140
190
91
>3000
>430
>4500
>660
>1900
>160
>70
Kb ) 0.3 nM, when A-61603 was used as an agonist. iv: 3
mg/kg dose, AUC ) 88.4 µmol min/L. po: 10 mg/kg dose, AUC )
45
39.0 µmol min/L. c Reference 2. iv: 1 mg/kg dose, AUC ) 30 µmol
min/L. po: 4 mg/kg dose, AUC ) 30 µmol min/L.
d
(+)-46 OMe OMe 3,4-di-F
47
(+)-48 Me
49
50
OMe OMe 2,4,5-tri-F 0.1 130
OMe 2,4-di-F 0.1 32
3,4,5-tri-F 0.4 220
3,4-di-F 0.7 170
H
H
Me
Me
390
290
counter-screened against a number of G-protein coupled
receptors such as H1, serotonin, and the rat L-type
calcium channel receptor and showed >1000-fold selec-
tivity for the R1a receptor.13-19 The 2-carboxamidophen-
ylpiperazine was screened for cross-reactivity at the
opioid receptors and showed much weaker binding
affinity (45 µM) compared to the 4-carbomethoxy-4-
phenylpiperidine (3 µM). Some results on (+)-38 in a
number of in vitro and in vivo assays are compared with
those for our original lead compound 1, and the results
are summarized in Table 4. Compound (+)-38 showed
excellent selectivity for the rat prostate tissue which
predominantly expresses R1a subtype (Kb ) 0.28 nM),
compared to the rat aorta (Kb ) 550 nM) which
predominantly expresses the other subtypes. In the
functional assay, (+)-38 relaxed the phenylephrine-
induced contraction of the rat prostate with AD50 ) 22
µg/kg, and the duration of action was greater than 4 h,
a profile quite similar to that of 1.2 The rat oral
bioavailability and the plasma half-life of (+)-38 were
determined to be 13% and 2 h, respectively, which is
similar to that of 1 (19% and 2.1 h, respectively).
Compound (+)-38 showed lower bioavailability but a
similar plasma half-life in dogs (4% and 2.3 h, respec-
tively) as compared to 1 (26% and 2.4 h, respectively).
(+)-52 Me
NH2 2,4-di-F
1.3 720 1100
>600
a,bPlease see notes in Table 1.
38, in contrast, is mainly due to decreased binding
affinity at the other receptor subtypes and not because
of any enhancement in the binding affinity for the R1a
receptor. Therefore, it is possible that the unique
binding profile of (2′-carboxamidophenyl)piperazine-
containing compounds is due to unfavorable interactions
with amino acid residues at the binding sites for R1b and
R1d receptors rather than favorable interactions with
amino acid residues at the R1a receptor binding site.
The (2′-carboxamidophenyl)piperazine moiety which
emerged as the optimal subunit was then coupled with
a number of dihydropyrimidinones differing in the
substituents on the dihydropyrimidinone template, to
study the compatibility of the two subunits with each
other. The results of this study are shown in Table 3. A
change in the substitution pattern of the C-6 phenyl ring
of dihydropyrimidinone from 3,4-difluoro in (+)-38 to
3,4,5-trifluoro in 45 has a slightly deleterious effect on
the selectivity for the R1a receptor. When the C-4 group
was changed from a methyl [(+)-38] to a methoxymethyl
group (46 and 47) or an ethyl group (48), the compounds
maintain high binding affinity at the R1a but exhibit
slightly lower selectivity over the other receptors. The
nature of the group at the C-5 position has limited
influence on the observed binding and selectivity profile
of the compounds. Compound (+)-38 is significantly
better in terms of the selectivity for the R1a receptor
subtype over the R2 receptor subtypes than the com-
pounds containing methyl ketone (49 and 50). Com-
pound 52, which contains a primary amide group,
however, maintains an excellent selectivity profile but
lower binding affinity for the R1a receptor.
Con clu sion
We initiated this study to find a suitable replacement
for the 4-methoxycarbonyl-4-phenylpiperidine moiety
which was deemed to be a potential liability due to its
agonist activity at the opioid receptors. It was essential
that the compounds have good binding affinity and
selectivity for the R1a receptor. We were successful in
identifying compounds containing a 4-phenylpiperazine
devoid of agonist activity at the µ-opioid receptor.
J udicious alterations of the steric and electronic nature
of the substituents on the phenyl ring of the 4-phen-
ylpiperazines led to the identification of 2-carboxami-
dophenylpiperazine moiety as a preferred side chain
subunit having a much weaker binding affinity at the
opioid receptors (45 µM). Compound (+)-38 was identi-
fied as an antagonist with good binding affinity and
selectivity for the R1a receptor (Ki ) 0.1 nM, >1500-fold
over R1b and R1d). The compound showed good potency
in the in situ rat prostate assay model (AD50 ) 22 µg/
kg) and excellent selectivity for the prostate tissue (Kb
) 0.28 nM in rat prostate versus Kb ) 550 nM in rat
aorta).
On the basis of the results from Table 3, we conclude
that although the presence of (2′-carboxamidophenyl)-
piperazine subunit of the molecule is important, other
parameters such as the nature of the linker (alkyl
versus amide) and the substituents on the dihydropy-
rimidinone template play a subtle role in fine-tuning
the observed binding and selectivity profile of these
compounds.
In Vitr o a n d in Vivo Exp er im en ts. As a represen-
tative example, compound (+)-38 was chosen for further
in vitro and in vivo evaluation. Compound (+)-38 was

Novel R1a Adrenoceptor-Selective Antagonists. 3
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23 4799
was then dissolved in CH2Cl2 (15 mL) and trifluoroacetic acid
(5 mL) was added to the solution in a dropwise manner at room
temperature with stirring. The solvent was removed in vaccuo
after 1 h, the resulting residue was dissolved in 3:1 mixture
of chloroform and isopropyl alcohol (25 mL), and then the
solution was basified to pH 8 by addition of 10% NaOH. The
aqueous layer was separated and extracted with the 3:1 CHCl3/
IPA solution (4 × 25 mL). The organic extracts were combined
and dried over Na2SO4 and the solution was filtered. The
solvent was removed in vaccuo to obtain 1-(3-aminopropyl)-
4-(2-carboxamindophenyl)piperazine as an oil (0.35 g, 55%
yield over two steps).
P r oced u r e for th e Syn th esis of (+)-1-(3-Br om op r o-
p ylca r ba m oyl)-6-(3,4-d iflu or op h en yl)-4-m eth yl-2-oxo-1,6-
t et r a h yd r op yr im id in e-5-ca r b oxylic Acid Met h yl E st er
(21). To a well-stirred solution of (+)-6-(3,4-difluorophenyl)-
1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methyl-1-[(4-ni-
trophenyloxy)carbonyl]pyrimidine (4.1 g, 9.1 mmol) in 20
mL of THF was added 5 mL of 10% aqueous solution of HCl
at room temperature and the resulting solution was stirred
overnight. THF was removed in vacuo and the resulting
residue was extracted with EtOAc (3 × 20 mL), washed with
brine (10 mL), and then dried over Na2SO4. The solvent
was removed in vacuo to obtain (+)-6-(3,4-difluorophenyl)-
1,6-dihydro-2-oxo-5-methoxycarbonyl-4-methyl-1-[(4-nitro-
phenyloxy)carbonyl]pyrimidine as a viscous oil (3.8 g) which
was dissolved in 20 mL of THF. To this solution were added
3-bromopropylamine hydrobromide (2.33 g, 10.8 g) and NaH-
CO3 (1.81 g, 21.5 mmol) and the resulting suspension was
stirred at room temperature overnight. THF was removed in
vacuo and the resulting residue was dissolved in 10 mL of
water and then extracted with EtOAc (3 × 20 mL). The EtOAc
extracts were combined, dried over Na2SO4, and filtered and
the solvent was removed to obtain (+)-1-(3-bromopropylcar-
bamoyl)-6-(3,4-difluorophenyl)-4-methyl-2-oxo-1,6-tetrahydro-
pyrimidine-5-carboxylic acid methyl ester (3.28 g, 83%): 1H
NMR δ 2.05-2.15 (m, 2 H), 2.43 (s, 3 H), 3.40-3.56 (m, 4 H),
3.72 (s, 3 H), 6.69 (s, 1 H), 7.08-7.27 (m, 3 H), 7.57 (br s, 1 H),
8.84 (br t, 1 H). Anal. (C17H18N3O4F2Br) C, H, N.
Exp er im en ta l Section
For the description of analytical protocols and biological
methods, please refer to the Experimental Section of ref 2.
Syn th esis of P ip er a zin es. Compounds 4, 7, and 10 were
synthesized according to the known procedure.11
1-(2-Ca r boxa m id op h en yl)p ip er a zin e (4). Concentrated
sulfuric acid (15 mL) was added to 1-(2-cyanophenyl)piperazine
(1.5 g, 8.0 mmol) placed in a round-bottom flask and the
resulting slurry was stirred at room temperature for 48 h. The
reaction mixture was poured on crushed ice very slowly and
then basified (pH ) 9) with 50% solution of NaOH. The
aqueous layer was extracted several times with EtOAc, dried
over K2CO3, and filtered and the solvent was evaporated. 1-(2-
Carboxamidophenyl)piperazine was obtained as an off-white
solid (1.2 g, 73%). It was used in the next step without
1
further purification: mass spectrum 206 (M + 1, 100%); H
NMR δ 3.06-3.29 (m, 8 H), 6.14 (br, 1 H), 7.20-7.28 (m, 2 H),
7.47 (dt, J ) 1.6 Hz, J ) 6.0 Hz, 1 H), 8.16 (dd, J ) 1.7 Hz, J
) 9.6 Hz, 1 H), 9.45 (br, 1 H). Combustion analysis was
obtained on its hydrochloride salt. Anal. (C11H17N3OCl‚
0.3CHCl3) C, H, N.
1-(2-Nitr op h en yl)p ip er a zin e (17). A heterogeneous reac-
tion mixture containing 2-bromonitrobenzene (2.02 g, 10.0
mmol) and piperazine (4.3 g, 50.0 mmol) was heated at 100
°C for 10 h. The orange-red solid was extracted with ethyl
acetate and washed thoroughly with 3 N NaOH solution
followed by brine. The organic layer was separated, dried over
Na2SO4, and filtered and the solvent was removed in vacuo.
The resulting red oil was purified by column chromatography
on silica gel (1:1 hexane/EtOAc followed by 4:1 EtOAc/MeOH)
to yield 1-(2-nitrophenyl)piperazine as an orange-red oil (1.90
g, 92%): 1H NMR (CDCl3) δ 1.77 (br s, 1 H), 2.97 (br s, 8 H),
6.98 (t, J ) 7.5 Hz, 1 H), 7.09 (d, J ) 8.4 Hz, 1 H), 7.42 (dt, J
) 1.5 Hz, J ) 8.7 Hz, 1 H), 7.72 (dd, J ) 1.5 Hz, J ) 7.2 Hz,
1 H). It was characterized as a hydrochloride salt. Anal.
(C10H14N3ClO2‚0.1CHCl3) C, H, N.
(R)-(-)-3-Meth yl-1-(2-n itr op h en yl)p ip er a zin e (18). To
a solution of 2-bromonitrobenzene (0.4 g, 2.0 mmol) in 1,4-
dioxane (10 mL) were added (R)-(+)-2-methylpiperazine (0.25
g, 0.25 mmol) and powdered K2CO3 (7.5 mmol, 0.8 g) and the
resulting suspension was heated at reflux for 10 h. After the
suspension was cooled, it was filtered through a sintered glass
funnel and the solvent was evaporated in vacuo. The resulting
residue was purified by column chromatography on silica gel
(1:1 hexane/EtOAc followed by 4:1 EtOAc/MeOH) to yield (R)-
(-)-3-methyl-1-(2-nitrophenyl)piperazine as an orange-red oil
(0.26 g, 78%): 1H NMR (CDCl3) δ 1.04 (d, J ) 6.3 Hz, 3 H),
1.52 (br s, 1 H), 2.47 (dt, J ) 1.5 Hz, J ) 9.9 Hz, 1 H), 2.80-
2.92 (m, 1 H), 2.97-3.13 (br m, 5 H), 7.01 (t, J ) 7.5 Hz, 1 H),
7.13 (d, J ) 8.1 Hz, 1 H), 7.46 (dt, J ) 1.5 Hz, J ) 8.7 Hz, 1
H), 7.74 (dd, J ) 1.5 Hz, J ) 7.2 Hz, 1 H). Anal. (C11H16N3-
ClO2‚0.05CHCl3) C, H, N.
(S)-(+)-3-Meth yl-1-(2-n itr op h en yl)p ip er a zin e (19). To a
solution of 2-bromonitrobenzene (0.6 g, 3.0 mmol) in 1,4-
dioxane (15 mL) were added (S)-(+)-2-methylpiperazine (0.5
g, 0.5 mmol) and powdered K2CO3 (15.0 mmol, 1.5 g) and the
resulting suspension was heated at reflux for 10 h. After the
suspension was cooled, it was filtered through a sintered glass
funnel and the solvent was evaporated in vacuo. The resulting
residue was purified by column chromatography on silica gel
(1:1 hexane/EtOAc followed by 4:1 EtOAc/MeOH) to yield (S)-
(+)-3-methyl-1-(2-nitrophenyl)piperazine as an orange oil (0.53
g, 80%): 1H NMR (CDCl3) same as described for compound
18. It was characterized as a hydrochloride salt, mp ) 170-
172 °C. Anal. (C11H16N3ClO2‚0.05CHCl3) C, H, N.
Syn th esis of 1-(3-Am in op r op yl)-4-(2-ca r boxa m in d o-
p h en yl)p ip er a zin e (43). A solution of N-tert-butyloxypropyl-
amine (0.63 mg, 2.68 mmol), potassium carbonate (1.35 g, 9.76
mmol), and 4-(2′-carboxamidophenyl)piperazine (0.5 g, 2.44
mmol) in 25 mL of 1,4-dioxane was heated to reflux for 12 h.
The solution was allowed to cool to room temperature and then
the solid was filtered off. The solvent was removed in vaccuo
and the resulting oil was purified by column chromatography
on silica gel using EtOAc as an eluent. The resulting thick oil
An identical procedure was used for the synthesis of 1-(3-
bromopropylcarbamoyl)-6-(3,4-difluorophenyl)-4-methyl-2-oxo-
1,2,3,6-tetrahydropyrimidine-5-carboxylic acid methyl ester
starting from racemic 6-(3,4-difluorophenyl)-1,6-dihydro-2-
methoxy-5-methoxycarbonyl-4-methyl-1-[(4-nitrophenyloxy)-
carbonyl]pyrimidine.
Gen er a l P r oced u r e for th e Syn th esis of Com p ou n d s
23-42. To a solution of either racemic or the (+) enantiomer
of 1-(3-bromopropylcarbamoyl)-6-(3,4-difluorophenyl)-4-meth-
yl-2-oxo-1,6-dihydropyrimidine-5-carboxylic acid methyl ester
(43 mg, 0.1 mmol) in 10 mL of anhydrous acetone was added
the amine (0.15 mmol) followed by NaHCO3 (41 mg, 0.3 mmol)
and KI (16 mg, 0.1 mmol). The resulting suspension was
heated to reflux for 10 h and then cooled to room temperature.
The solvent was removed in vacuo and the residue was purified
by flash column chromatography on silica gel with EtOAc
followed by 10% MeOH in EtOAc. The product was character-
ized by 1H NMR before converting it into a hydrochloride salt.
The product thus obtained was then dissolved in 2 mL of either
chloroform, acetone, or EtOAc. Then 0.5 mL of HCl in Et2O (1
M) was added at room temperature. The solvent was removed
in vacuo and the hydrochloride salt was characterized by
combustion analysis.
1,2,3,6-Te t r a h yd r o-1-{N -[[4-p h e n ylp ip e r a zin -1-yl]-
p r op yl]ca r boxa m id o}-4-m eth yl-6-(3,4-d iflu or op h en yl)-2-
oxop yr im id in e (23). The amine used was 4-phenylpipera-
zine: 1H NMR δ 1.68-1.74 (m, 2 H), 2.32 (s, 3 H), 2.32-2.39
(m, 2 H), 2.51-2.58 (m, 4 H), 3.12-3.20 (m, 4 H), 3.26-3.36
(m, 2 H), 3.64 (s, 3 H), 6.63 (s, 1 H), 6.80-7.23 (m, 9 H), 8.76
(t, J ) 3.9 Hz, 1 H). It was characterized as a dihydrochloride
salt, mp ) 85-90 °C. Anal. (C27H33N5F2Cl2O4‚1.7CH3OH) C,
H, N.
1,2,3,6-Tetr ah ydr o-1-{N-[[4-(4′-ch lor oph en yl)piper azin -
1-yl]pr opyl]car boxam ido}-4-m eth yl-6-(3,4-diflu or oph en yl)-
2-oxopyr im idin e (24). The amine used was 4-(4′-chlorophenyl)-

4800 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23
Lagu et al.
piperazine: 1H NMR δ 1.73-1.79 (m, 2 H), 2.40 (s, 3 H), 2.41-
2.46 (m, 2 H), 2.51 (br s, 4 H), 3.15 (br s, 4 H), 3.34-3.40 (m,
2 H), 3.71 (s, 3 H), 6.70 (s, 1 H), 6.82 (d, J ) 7.2 Hz, 2 H),
7.07-7.20 (m, 4 H), 7.19 (d, J ) 7.2 Hz, 2 H), 8.82 (t, J ) 3.9
Hz, 1 H). It was characterized as a dihydrochloride salt, mp
) 76-81 °C. Anal. (C27H32N5F2Cl3O4‚1.5H2O) C, H, N.
1,2,3,6-Tetr a h yd r o-1-{N-[[4-(4′-m eth oxyp h en yl)p ip er -
a zin -1-yl]p r op yl]ca r b oxa m id o}-4-m et h yl-6-(3,4-d iflu o-
r op h en yl)-2-oxop yr im id in e (25). The amine used was 4-(4′-
methoxyphenyl)piperazine: 1H NMR δ 1.68-1.82 (m, 2 H),
2.41 (s, 3 H), 2.41-2.47 (m, 2 H), 2.60-2.65 (m, 4 H), 3.01-
3.14 (m, 4 H), 3.35-3.43 (m, 2 H), 3.72 (s, 3 H), 3.77 (s, 3 H),
6.70 (s, 1 H), 6.81-7.18 (m, 8 H), 8.83 (t, J ) 3.9 Hz, 1 H). It
was characterized as its dihydrochloride salt (hygroscopic).
Anal. (C28H35N5F2Cl2O5‚0.25CHCl3) C, H, N.
1,2,3,6-Tetr ah ydr o-1-{N-[[4-(4′-acetoxyph en yl)piper azin -
1-yl]pr opyl]car boxam ido}-4-m eth yl-6-(3,4-diflu or oph en yl)-
2-oxopyr im idin e (26). The amine used was 4-(4′-acetoxyphen-
yl)piperazine: 1H NMR δ 1.73-1.78 (m, 2 H), 2.41 (s, 3 H),
2.41-2.47 (m, 2 H), 2.52 (s, 3 H), 2.54-2.58 (m, 4 H), 3.33-
3.59 (m, 6 H), 3.72 (s, 3 H), 6.70 (s, 1 H), 6.85 (d, J ) 9.0 Hz,
2 H), 7.05-7.20 (m, 4 H), 7.86 (d, J ) 9.0 Hz, 2 H), 8.85 (t, J
) 3.9 Hz, 1 H). It was characterized as a dihydrochloride salt.
Anal. (C29H35N5F2Cl2O5‚0.5CHCl3) C, H, N.
1,2,3,6-Tetr ah ydr o-1-{N-[[4-(3′-ch lor oph en yl)piper azin -
1-yl]pr opyl]car boxam ido}-4-m eth yl-6-(3,4-diflu or oph en yl)-
2-oxopyr im idin e (27). The amine used was 4-(3′-chlorophenyl)-
piperazine: 1H NMR δ 1.74-1.78 (m, 2 H), 2.41 (s, 3 H), 2.41-
2.48 (m, 2 H), 2.54-2.59 (m, 4 H), 3.11-3.25 (m, 4 H), 3.32-
3.40 (m, 2 H), 3.72 (s, 3 H), 6.71 (s, 1 H), 6.77-7.21 (m, 8 H),
8.84 (t, J ) 3.9 Hz, 1 H). It was characterized as its
dihydrochloride salt, mp ) 120-124 °C. Anal. (C27H32N5F2-
Cl3O4‚0.2CCl4) C, H, N.
characterized as a dihydrochloride salt, mp ) 145-149 °C.
Anal. (C27H33N5F2Cl2O5‚0.15CHCl3) C, H, N.
1,2,3,6-Tetr a h yd r o-1-{N-[[4-(4′-m eth oxyp h en yl)p ip er -
a zin -1-yl]p r op yl]ca r b oxa m id o}-4-m et h yl-6-(3,4-d iflu o-
r op h en yl)-2-oxop yr im id in e (33). The amine used was 4-(2′-
methoxyphenyl)piperazine: 1H NMR δ 1.62-1.76 (m, 2 H),
2.41 (s, 3 H), 2.45-2.58 (m, 6 H), 3.01-3.14 (m, 4 H), 3.35-
3.43 (m, 2 H), 3.65 (s, 3 H), 3.77 (s, 3 H), 6.72 (s, 1 H), 6.69-
7.02 (m, 8 H), 8.83 (t, J ) 3.9 Hz, 1 H). It was characterized
as its dihydrochloride salt, mp ) 69-72 °C. Anal. (C28H35N5F2-
Cl2O5‚0.25CHCl3) C, H, N.
1,2,3,6-Tetr ah ydr o-1-{N-[[4-(2′-eth oxyph en yl)piper azin -
1-yl]pr opyl]car boxam ido}-4-m eth yl-6-(3,4-diflu or oph en yl)-
2-oxop yr im id in e (34). The amine used was 4-(2′-ethoxyphen-
yl)piperazine: 1H NMR δ 1.45 (t, J ) 6.9 Hz, 3 H), 1.73-1.82
(m, 2 H), 2.41 (s, 3 H), 2.41-2.47 (m, 2 H), 2.63 (br s, 4 H),
3.10 (br s, 4 H), 3.34-3.42 (m, 2 H), 3.72 (s, 3 H), 4.06 (q, J )
6.6 Hz, 2 H), 6.71 (s, 1 H), 6.83-7.17 (m, 8 H), 8.81 (t, J ) 3.9
Hz, 1 H). It was characterized as a dihydrochloride salt, mp
) 84-90 °C. Anal. (C29H32N5F2Cl2O5‚2.0H2O) C, H, N.
1,2,3,6-Tetr ah ydr o-1-{N-[[4-(4′-m eth oxy-2′-m eth ylph en -
yl)p ip er a zin -1-yl]p r op yl]ca r boxa m id o}-4-m eth yl-6-(3,4-
d iflu or op h en yl)-2-oxop yr im id in e (35). The amine used
was 4-(4′-methoxy-2′-methylphenyl)piperazine: yellow oil; 1H
NMR δ 1.71-1.76 (m, 2 H), 2.24 (s, 3 H), 2.38 (s, 3 H), 2.38-
2.43 (m, 2 H), 2.54-2.59 (m, 4 H), 2.81-2.84 (m, 4 H), 3.29-
3.37 (m, 2 H), 3.68 (s, 3 H), 3.72 (s, 3 H), 6.64 (d, J ) 3.0 Hz,
1 H), 6.67 (s, 1 H), 6.71 (d, J ) 2.7 Hz, 1 H), 6.92 (d, J ) 8.4
Hz, 1 H), 7.00-7.23 (m, 3 H), 7.50 (br s, 1 H), 8.77 (t, J ) 5.4
Hz, 1 H). It was characterized as a dihydrochloride salt, mp
) 85-90 °C. Anal. (C27H33N5F2Cl2O5‚0.2CHCl3) C, H, N.
(+)- a n d (()-1,2,36-Tetr a h yd r o-1-{N-[[4-(2-cya n op h en -
yl)piper azin -1-yl]pr opyl]car boxam ido}-4-m eth yl-6-(3,4-di-
flu or op h en yl)-2-oxop yr im id in e (36 a n d 37). The amine
used was 4-(2′-cyanophenyl)piperazine. The product was ana-
lyzed as its dihydrochloride salt (hygroscopic): [R]D ) + 51.8
(c ) 0.2, MeOH) for 37(+); mass spectrum 553 (M + 1, 18%);
1H NMR δ 1.72-1.78 (m, 2 H), 2.38 (s, 3 H), 2.39-2.47 (m, 2
H), 2.54-2.64 (m, 4 H), 3.17-3.39 (m, 6 H), 3.67 (s, 3 H), 6.66
(s, 1 H), 6.93-7.19 (m, 4 H), 7.42-7.52 (m, 3 H), 7.78 (dd, J )
1.2 Hz, J ) 7.8 Hz, 1 H), 8.78 (br t, 1 H). Anal. (C28H32N6F2-
Cl2O4‚0.4CHCl3) C, H, N.
1,2,3,6-Tetr a h yd r o-1-{N-[[4-(3′-tr flu or om eth ylp h en yl)-
p ip er a zin -1-yl]p r op yl]ca r boxa m id o}-4-m eth yl-6-(3,4-d i-
flu or op h en yl)-2-oxop yr im id in e (28). The amine used was
4-(3′-trifluoromethylphenyl)piperazine: 1H NMR δ 1.74-1.80
(m, 2 H), 2.41 (s, 3 H), 2.41-2.49 (m, 2 H), 2.56-2.63 (m, 4
H), 3.21-3.27 (m, 4 H), 3.36-3.45 (m, 2 H), 3.72 (s, 3 H), 6.71
(s, 1 H), 7.04-7.38 (m, 8 H), 8.84 (t, J ) 3.9 Hz, 1 H). It was
characterized as a dihydrochloride salt. Anal. (C28H32N5F5-
Cl2O4‚0.8 acetone) C, H, N.
1,2,3,6-Tetr a h yd r o-1-{N-[[4-(3′-n itr op h en yl)p ip er a zin -
1-yl]pr opyl]car boxam ido}-4-m eth yl-6-(3,4-diflu or oph en yl)-
2-oxopyr im idin e (29). The amine used was 4-(3′-nitrophenyl)-
piperazine: 1H NMR δ 1.75-1.80 (m, 2 H), 2.41 (s, 3 H), 2.41-
2.47 (m, 2 H), 2.57-2.61 (m, 4 H), 3.26-3.31 (m, 4 H), 3.38-
3.44 (m, 2 H), 3.72 (s, 3 H), 6.70 (s, 1 H), 7.08-7.68 (m, 8 H),
8.81 (t, J ) 3.9 Hz, 1 H). Anal. (C27H32N6F2Cl2O6) C, H, N.
1,2,3,6-Tetr ah ydr o-1-{N-[[4-(2′-m eth ylph en yl)piper azin -
1-yl]pr opyl]car boxam ido}-4-m eth yl-6-(3,4-diflu or oph en yl)-
2-oxop yr im id in e (30). The amine used was 4-(2′-methylphen-
yl)piperazine: 1H NMR δ 1.75-1.80 (m, 2 H), 2.29 (s, 3 H),
2.42 (s, 3 H), 2.41-2.48 (m, 2 H), 2.58-2.62 (m, 4 H), 2.91-
2.97 (m, 4 H), 3.35-3.42 (m, 2 H), 3.72 (s, 3 H), 6.71 (s, 1 H),
6.97-7.26 (m, 8 H), 8.81 (t, J ) 3.9 Hz, 1 H). It was
characterized as a dihydrochloride salt, mp ) 66-71 °C. Anal.
(C28H35N5F2Cl2O4‚1.75 acetone) C, H, N.
1,2,3,6-Tetr ah ydr o-1-{N-[[4-(2′-ch lor oph en yl)piper azin -
1-yl]pr opyl]car boxam ido}-4-m eth yl-6-(3,4-diflu or oph en yl)-
2-oxopyr im idin e (31). The amine used was 4-(2′-chlorophenyl)-
piperazine: 1H NMR δ 1.79-1.84 (m, 2 H), 2.42 (s, 3 H), 2.49-
2.54 (m, 2 H), 2.68 (br s, 4 H), 3.11 (br s, 4 H), 3.38-3.43 (m,
2 H), 3.72 (s, 3 H), 6.70 (s, 1 H), 6.81-7.34 (m, 8 H), 8.82 (t, J
) 3.9 Hz, 1 H). It was characterized as a dihydrochloride salt,
mp ) 98-102 °C. Anal. (C27H32N5F2Cl3O4‚0.5CHCl3) C, H, N.
1,2,3,6-Tet r a h yd r o-1-{N-[[4-(2′-h yd r oxyp h en yl)p ip er -
a zin -1-yl]p r op yl]ca r b oxa m id o}-4-m et h yl-6-(3,4-d iflu o-
r op h en yl)-2-oxop yr im id in e (32). The amine used was 4-(2′-
hydroxyphenyl)piperazine: colorless oil; 1H NMR δ 1.72-1.78
(m, 2 H), 2.39 (s, 3 H), 2.40-2.44 (m, 2 H), 2.55-2.57 (m, 4
H), 2.85-2.88 (m, 4 H), 3.30-3.38 (m, 2 H), 3.68 (s, 3 H), 6.68
(s, 1 H), 6.79-7.18 (m, 9 H), 8.79 (t, J ) 5.4 Hz, 1 H). It was
1,2,3,6-Tetr a h yd r o-1-{N-[[4-(2′-ca r bom eth oxyp h en yl)-
p ip er a zin -1-yl]p r op yl]ca r boxa m id o}-4-m eth yl-6-(3,4-d i-
flu or op h en yl)-2-oxop yr im id in e (38). The amine used was
4-(2′-carbomethoxyphenyl)piperazine: 1H NMR δ 1.75-1.80
(m, 2 H), 2.42 (s, 3 H), 2.41-2.49 (m, 2 H), 2.58-2.64 (m, 4
H), 3.02-3.10 (m, 4 H), 3.35-3.41 (m, 2 H), 3.72 (s, 3 H), 3.88
(s, 3 H), 6.70 (s, 1 H), 7.09-7.18 (m, 6 H), 7.41 (dt, J ) 0.9 Hz,
J ) 8.1 Hz, 1 H), 7.72 (dd, J ) 1.5 Hz, J ) 7.5 Hz, 1 H), 8.82
(t, J ) 3.9 Hz, 1 H). It was characterized as a dihydrochloride
salt. Anal. (C29H35N5F2Cl2O6‚0.18CHCl3) C, H, N.
(+)- a n d (()-1,2,36-Tetr a h yd r o-1-{N-[[4-(2-ca r boxa m i-
d op h en yl)p ip er a zin -1-yl]p r op yl]ca r boxa m id o}-4-m eth yl-
6-(3,4-d iflu or op h en yl)-2-oxop yr im id in e (38). The amine
used was 4-(2′-carboxamidophenyl)piperazine, 84% yield. Com-
bustion analysis was obtained on its hydrochloride salt, mp )
190-193 °C; [R]D ) +98.8 (c ) 0.31, MeOH); 1H NMR δ 1.65-
1.75 (m, 2 H), 2.41 (s, 3 H), 2.39-2.41 (m, 1 H), 2.45-2.58 (m,
2 H), 2.97 (br t, J ) 4.5 Hz, 4 H), 3.31-3.37 (m, 1 H), 3.66 (s,
3 H), 6.55 (br d, J ) 4.5 Hz, 1 H), 6.65 (s, 1 H), 6.99-7.19 (m,
5 H), 7.39 (t, J ) 8.7 Hz, 1 H), 8.10 (dd, J ) 1.5 Hz, J ) 9.3
Hz, 1 H), 8.84 (br t, 1 H), 9.52 (br d, J ) 4.5 Hz, 1 H). Anal.
(C28H34N6F2Cl2O5‚0.35EtOAc) C, H, N.
(+)-1,2,3,6-Tet r a h yd r o-1-{N-[[4-(2-n it r op h en yl)p ip er -
a zin -1-yl]p r op yl]ca r b oxa m id o}-4-m et h yl-6-(3,4-d iflu o-
r op h en yl)-2-oxop yr im id in e [(+)-39]. The amine used was
4-(2′-nitrophenyl)piperazine, 29% yield. The product was
analyzed as its hydrochloride salt, mp ) 133-136 °C; [R]D
)
+ 56.7 (c ) 0.11, MeOH); 1H NMR δ 1.75-1.80 (m, 2 H), 2.42
(s, 3 H), 2.41-2.49 (m, 2 H), 2.57-2.62 (m, 4 H), 3.02-3.10
(m, 4 H), 3.29-3.51 (m, 2 H), 3.72 (s, 3 H), 6.71 (s, 1 H), 6.94
(br s, 1 H), 7.09-7.18 (m, 5 H), 7.47 (dt, J ) 0.9 Hz, J ) 8.4

Novel R1a Adrenoceptor-Selective Antagonists. 3
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23 4801
Hz, 1 H), 7.75 (dd, J ) 1.5 Hz, J ) 8.1 Hz, 1 H), 8.82 (t, J )
3.9 Hz, 1 H). Anal. (C27H31N6F2ClO6‚0.20CH2Cl2) C, H, N.
(chloroform/MeOH/2 N ammonia in MeOH ) 100:12:6) to
afford the desired product (227 mg, 88%), [R]D ) +124° (c )
0.75 in chloroform). The compound was converted to HCl salt
by dissolving in 1 N HCl in ether followed by concentration to
dryness: mp ) 118-120 °C; 1H NMR (CDCl3) δ 1.69-1.76 (m,
4 H), 2.39-2.43 (m, 2 H), 2.53-2.60 (m, 2 H), 2.98-3.01 (m, 4
H), 3.30-3.44 (m, 2 H), 3.44 (s, 3 H), 3.67 (s, 3 H), 4.64 (s, 2
H), 6.64 (s, 1 H), 7.04-7.45 (m, 6 H), 7.69 (s, 1 H), 8.10-8.13
(d, J ) 8 Hz, 1 H), 8.86 (t, 1 H, J ) 7 Hz). Anal. (C29H36F2N6-
Cl2O6‚0.3ether‚0.6H2O) C, H, N.
1-{3-[4-(2-Ca r ba m oylp h en yl)p ip er a zin -1-yl]p r op ylca r -
b a m oyl}-5-m et h oxyca r b on yl-4-m et h oxym et h yl-2-oxo-
6-(2,4,5-tr iflu or oph en yl)-1,2,3,6-tetr ah ydr opyr im idin e (47).
(a ) 1-{3-[4-(2-Ca r ba m oylp h en yl)p ip ir a zin -1-yl]p r op ylca r -
ba m oyl}-2-m eth oxy-5-m eth oxyca r bon yl-4-m eth oxym eth -
yl-6-(2,4,5-tr iflu or oph en yl)-1,6-dih ydr opyr im idin e. A mix-
ture of 2-methoxy-5-methoxycarbonyl-4-methoxymethyl-1-(4-
nitrophenyloxy)carbonyl-6-(2,4,5-trifluorophenyl)-1,6-dihydro-
pyrimidine (15 mg, 0.03 mmol) and 3-[4-(2-carbamoylphenyl)-
piperazin-1-yl]propylamine (12 mg, 0.04 mmol) was stirred
at room temperature for 2 days. The solvent was evaporated
and the residue was separated on a preparative TLC plate
(CHCl3/MeOH, 10:1) to get the title compound (9 mg, 49%
yield) as a white solid: 1H NMR (CDCl3) δ 1.69-1.74 (m, 4
H), 2.42 (t, J ) 6.9 Hz, 2H), 2.54-2.60 (m, 2 H), 2.98 (t, J )
4.5 Hz, 4 H), 3.31-3.40 (m, 2 H), 3.43 (s, 3 H), 3.65 (s, 3 H),
4.04 (s, 3 H), 4.55 (ABm, 2 H), 5.79 (br s, 1 H), 6.77 (s, 1 H),
6.79-6.87 (m, 1 H), 7.01-7.22 (m, 4 H), 7.43 (dt, J ) 7.8
Hz, 1.5 Hz, 1 H), 8.11 (dd, J ) 8.1 Hz, 1.5 Hz, 1 H), 9.38 (br
s, 1 H).
(+)-1,2,3,6-Tetr a h yd r o-5-m eth oxyca r bon yl-4-m eth yl-2-
oxo-1-{N-[[2(R)-m eth yl-4-(2-n itr op h en yl)p ip er a zin -1-yl]-
p r op yl]ca r b oxa m id o}-6-(3,4-d iflu or op h e n yl)p yr im i-
d in e [(+)-40]. The amine used was 2(R)-methyl-4-(2′-car-
boxamidophenyl)piperazine (0.02 g, 14% yield). The product
was analyzed as its hydrochloride salt, mp ) 135-138 °C; [R]D
1
) + 63.5 (c ) 0.2, MeOH); H NMR δ 1.04 (d, J ) 6.0 Hz, 3
H), 1.63-1.78 (m, 2 H), 2.33-2.49 (m, 3 H), 2.42 (s, 3 H), 2.55-
2.92 (m, 5 H), 3.00-3.10 (m, 3 H), 3.33-3.39 (m, 2 H), 3.72 (s,
3 H), 6.70 (s, 1 H), 6.99-7.17 (m, 6 H), 7.46 (dt, J ) 0.9 Hz, J
) 8.1 Hz, 1 H), 7.74 (dd, J ) 1.5 Hz, J ) 8.1 Hz, 1 H), 8.81 (t,
J ) 3.9 Hz, 1 H). Anal. (C28H33N6F2ClO6‚1.0CHCl3) C, H, N.
(+)-1,2,3,6-Tet r a h yd r o-1-{N-[[2(S)-m et h yl-4-(2-n it r o-
p h en yl)p ip er a zin -1-yl]p r op yl]ca r boxa m id o}-4-m eth yl-6-
(3,4-d iflu or op h en yl)-2-oxop yr im id in e [(+)-41]. The amine
used was 2(S)-methyl-4-(2′-carboxamidophenyl)piperazine, 10%
yield. The product was analyzed as its hydrochloride salt, mp
) 150-153 °C; [R]D ) + 58.3 (c ) 0.3, MeOH); 1H NMR δ 1.04
(d, J ) 6.0 Hz, 3 H), 1.71-1.78 (m, 2 H), 2.33-2.49 (m, 3 H),
2.42 (s, 3 H), 2.55-2.92 (m, 5 H), 3.00-3.10 (m, 3 H), 3.34-
3.42 (m, 2 H), 3.72 (s, 3 H), 6.71 (s, 1 H), 7.01-7.32 (m, 6 H),
7.46 (dt, J ) 0.7 Hz, J ) 8.4 Hz, 1 H), 7.74 (dd, J ) 1.5 Hz, J
) 8.4 Hz, 1 H), 8.82 (t, J ) 3.9 Hz, 1 H). Anal. (C28H33N6F2-
ClO6‚0.20CH2Cl2) C, H, N.
1-{3-[4-(2-Ca r b a m oylp h e n yl)p ip e r a zin -1-yl]p r op yl-
ca r ba m oyl}-4-m eth yl-5-m eth oxyca r bon yl-2-oxo-6-(3,4,5-
tr iflu or op h en yl)-1,2,3,6-tetr a h yd r op yr im id in e (45). (a )
Meth yl 1-{3-[4-(2-Ca r ba m oylp h en yl)p ip er a zin -1-yl]p r o-
pylcar bam oyl}-2-m eth oxy-4-m eth yl-6-(3,4,5-tr iflu or oph en -
yl)-1,6-d ih yd r op yr im id in e-5-ca r boxyla te. A solution of 1,6-
dihydro-5-methoxycarbonyl-2-methoxy-1-(4-nitrophenyloxy)-
carbonyl-6-(3,4,5-trifluorophenyl)-4-methylpyrimidine (15 mg,
0.031 mmol) and 2-[4-(3-aminopropyl)piperazin-1-yl]benzamide
(12 mg, 0.047 mmol) in CH2Cl2 (1 mL) was stirred at room
temperature for 2 days. The product was separated on a
preparative TLC plate (CHCl3/MeOH, 10:1) to get the title
compound (13.5 mg, 63% yield): 1H NMR (CDCl3)δ 1.67-1.78
(m, 4 H), 2.40 (s, 3 H), 2.41-2.47 (m, 2 H), 2.50-2.65 (m, 2
H), 2.95-3.01 (m, 4 H), 3.33-3.45 (m, 2 H), 3.65 (s, 3 H), 3.94
(s, 3 H), 5.80 (br s, 1 H), 6.56 (s, 1 H), 6.72 (br s, 1 H), 6.88-
6.93 (m, 2 H), 7.16-7.19 (m, 2 H), 7.43 (dd, J ) 8.1 Hz, 1.8
Hz, 1 H), 8.11 (dd, J ) 7.8 Hz, 1.5 Hz, 1 H), 9.37 (br s, 1 H).
(b ) 1-{3-[4-(2-Ca r b a m oylp h en yl)p ip er a zin -1-yl]p r o-
p ylca r b a m oyl}-4-m e t h yl-5-m e t h oxyca r b on yl-2-oxo-6-
(3,4,5-t r iflu or op h en yl)-1,2,3,6-t et r a h yd r op yr im id in e. A
solution of methyl 1-{3-[4-(2-carbamoylphenyl)piperazin-1-yl]-
propylcarbamoyl}-2-methoxy-4-methyl-6-(3,4,5-trifluorophenyl)-
1,6-dihydropyrimidine-5-carboxylate (10 mg, 0.019 mmol) and
HCl (6 N, 3 mL) in THF (3 mL) was stirred at room
temperature for 12 h and the solvent was removed. The residue
was dissolved in CH2Cl2 and washed with 1 N KOH solution.
The organic layer was dried (Na2SO4) and concentrated to
obtain the title compound (9.6 mg, 99% yield) as an orange
oil: 1H NMR (CDCl3) δ 1.61-1.90 (m, 6 H), 2.41 (s, 3 H), 2.60
(br s, 2 H), 3.00-3.03 (m, 2 H), 3.20-3.43 (m, 2 H), 3.55 (t, J
) 6.6 Hz, 2 H), 3.69 (s, 3 H), 6.17 (br s, 1 H), 6.64 (s, 1 H),
6.92-7.00 (m, 2 H), 7.16-7.21 (m, 2 H), 7.43 (dd, J ) 8.1 Hz,
1.8 Hz, 1 H), 7.85 (br s, 1 H), 8.11 (dd, J ) 7.8 Hz, 1.5 Hz, 1
H), 8.81 (t, J ) 5.4 Hz, H), 9.46 (br s, 1 H). Hydrochloride of
the title compound was prepared with HCl in ether, mp )
203-207 °C. Anal. (C29H35N6F3Cl2O6‚1.5C6H12) C, H, N.
(+)-1,2,3,6-Tetr ah ydr o-1-{N-[[4-(2-car boxam idoph en yl)-
piper azin -1-yl]pr opyl]car boxam ido}-5-m eth oxycar bon yl-
4-m et h oxym et h yl-6-(3,4-d iflu or op h en yl)-2-oxop yr im i-
d in e Hyd r och lor id e (46). To a solution of (+)-1,6-dihydro-
1-[N-(4-nitrophenoxy)carbonyl]-2-methoxyl-5-methoxycarbonyl-
4-methoxymethyl-6-(3,4-difluorophenyl)pyrimidine (212 mg,
0.43 mmol) in dichloromethane (20 mL) was added 1-(3-
aminopropyl)-4-(2-carboxamidophenyl)piperazine (136 mg, 0.52
mmol) at room temperature. The resulting mixture was stirred
at room temperature for 2 h before concentrated to a residue.
The residue was purified through column chromatography
(b) 1-{3-[4-(2-Ca r ba m oylp h en yl)p ip er a zin -1-yl]p r op yl-
ca r b a m oyl}-5-m e t h oxyca r b on yl-4-m e t h oxym e t h yl-2-
oxo-6-(2,4,5-t r iflu or op h en yl)-1,2,3,6-t et r a h yd r op yr im i-
d in e. A mixture of 1-{3-[4-(2-carbamoylphenyl)piperazin-1-
yl]propylcarbamoyl}-2-methoxy-5-methoxycarbonyl-4-meth-
oxymethyl-6-(2,4,5-trifluorophenyl)-1,6-dihydropyrimidine (9
mg, 0.014 mmol) in 3 mL of THF and aqueous HCl solution (6
N, 3 mL) was stirred at room temperature for 12 h. The
reaction mixture was neutralized with KOH solution (1 N),
separated, and extracted with CH2Cl2. The combined CH2Cl2
extracts were dried (Na2SO4) and concentrated to get the title
compound (8 mg, 92% yield) as a white solid: 1H NMR (CDCl3)-
δ 1.69-1.74 (m, 4 H), 2.42 (t, J ) 6.9 Hz, 2H), 2.54-2.60 (m,
2 H), 2.98 (t, J ) 4.5 Hz, 4 H), 3.31-3.40 (m, 2 H), 3.44 (s, 3
H), 3.64 (s, 3 H), 4.60 (s, 2 H), 5.80 (br s, 1 H), 6.58 (s, 1H),
6.79-6.89 (m, 1 H), 7.17-7.28 (m, 3 H), 7.40-7.46 (m, 1 H),
7.75 (br s, 1 H), 8.09-8.12 (m, 1 H), 8.89-8.93 (m, 1 H). 9.40
(br s, 1 H). Hydrochloride of the title compound was prepared
with HCl in ether, mp ) 210-215 °C. Anal. (C28H31N6F3Cl2O5‚
2.0C6H12) C, H, N.
(+)-1,2,3,6-Tetr ah ydr o-1-{N-[[4-(2-car boxam idoph en yl)-
4-p h en ylp ip er a zin -1-yl]p r op yl]ca r b oxa m id o}-5-m et h -
oxyca r bon yl-4-eth yl-6-(2,4-d iflu or op h en yl)-2-oxop yr im i-
d in e Dih yd r och lor id e (48). To a solution of (+)-1,2,3,6-
tetrahydro-1-{N-[[4-(2-carboxamidophenyl)-4-phenylpiperazin-
1-yl]propyl]carboxamido}-5-hydroxycarbonyl-4-ethyl-6-(2,4-
difluorophenyl)-2-oxopyrimidine (200 mg, 0.356 mmol) in
CH2Cl2 (10 mL) were added 1-(3-dimethylaminopropyl)-3-
ethylcarbodiimide hydrochloride (137 mg, 0.71 mmol) and
DMAP (87 mg, 0.71 mmol). The resulting mixture was stirred
at room temperature for 4 h before MeOH (10 mL) was added.
The reaction was stirred overnight and concentrated to a
residue. The residue was purified by column chromatography
(chloroform/MeOH/2 M ammonia in MeOH ) 500:14:7) to
afford the desired product (150 mg, 75%), [R]D ) +129 (c )
0.75 in chloroform). The compound was converted to HCl salt
by dissolving in 1 N HCl in ether followed by concentration to
dryness: mp ) 160-161 °C; 1H NMR (300 MHz, CDCl3) δ
1.16-1.21 (t, J ) 7 Hz, 3 H), 1.69-1.76 (m, 4 H), 2.36-2.43
(m, 2 H), 2.53-2.60 (m, 2 H), 2.70-2.80 (m, 2 H), 2.98-3.01
(m, 4 H), 3.22-3.38 (m, 2 H), 3.64 (s, 3 H), 6.66 (s, 1 H), 6.66-
6.80 (m, 2 H), 7.18-7.22 (m, 2 H), 7.35-7.44 (m, 2 H), 8.10-
8.13 (d, J ) 8 Hz, 1 H), 8.86 (t, J ) 7 Hz, 1 H). Anal.
(C29H36F2N6Cl2O5) C, H, N.

4802 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23
Lagu et al.
(()-1,2,3,6-Tetr ah ydr o-1-{N-[[4-(2-car boxam idoph en yl)-
p ip er a zin -1-yl]p r op yl]ca r b oxa m id o}-5-a cet yl-2-oxo-6-
(3,4,5-tr iflu or oph en yl)-4-m eth ylpyr im idin e Dih ydr och lo-
r id e (49). To a solution of (()-1,2,3,6-tetrahydro-1-[N-(4-
nitrophenoxy)carbonyl]-5-acetyl-2-oxo-6-(3,4,5-trifluorophenyl)-
4-methylpyrimidine (45 mg, 0.10 mmol) in methylene chloride
(10 mL) was added 1-(3-aminopropyl)-4-(2-carboxamindo-
phenyl)piperazine (26 mg, 0.10 mmol). The resulting mixture
was stirred at room temperature for 1 h before concentrated
to a residue. The residue was purified through a prepara-
tive TLC plate to yield 60 mg (93%) of the desired product.
The compound was converted to HCl salt by dissolving in 1 N
HCl in ether followed by concentration to dryness: mp )
235-240 °C; 1H NMR (300 MHz, CDCl3) δ 1.74-1.82 (m, 2
H), 2.22 (s, 3 H), 2.42 (s, 3 H), 2.40-2.50 (m, 2 H), 2.58-2.68
(m, 4 H), 2.98-3.06 (m, 4 H), 3.36-3.42 (m, 4 H), 6.73 (s,
1 H), 6.92-6.99 (m, 2 H), 7.16-7.22 (m, 2 H), 7.40-7.45
(m, 1 H), 8.08-8.11 (d, J ) 8 Hz, 1 H), 8.42 (br s, 1 H),
8.77-8.79 (t, J ) 7 Hz, 1 H). Anal. (C28H33F3N6Cl2O4‚0.4H2O)
C, H, N.
(c) (+)-1,2,3,6-Tetr ah ydr o-1-{N-[[4-(2-car boxam idoph en -
yl)-4-p h en ylp ip er a zin -1-yl]p r op yl]ca r b oxa m id o}-5-ca r -
b oxa m id o-4-et h yl-6-(2,4-d iflu or op h en yl)-2-oxop yr im i-
d in e Dih yd r och lor id e. To a solution of (+)-1,2,3,6-tetrahy-
dro-1-{N-[[4-(2-carboxamidophenyl)-4-phenylpiperazin-1-yl]-
pr opyl]ca r boxa m ido}-5-h ydr oxyca r bon yl-4-et h yl-6-(2,4-
difluorophenyl)-2-oxopyrimidine (340 mg, 0.607 mmol) in
CH2Cl2 were added 1-(3-dimethylaminopropyl)-3-ethylcarbo-
diimide hydrochloride (233 mg, 1.21 mmol) and 4-methylmor-
pholine (122 mg, 1.21 mmol). The resulting mixture was stirred
at room temperature for 4 h before ammonium hydroxide (1
mL, 40 wt %) was added. The reaction mixture was stirred
overnight before quenched with NH4Cl (aqueous, 50 mL). The
mixture was extracted with CH2Cl2 (30 mL × 3), and the
organic layers were combined, dried over MgSO4, and concen-
trated. The residue was purified through column chromatog-
raphy (chloroform/MeOH/2 N ammonia in MeOH ) 500:16:8)
to afford the desired product (240 mg, 70%), [R] ) +138 (c )
0.75 in chloroform). The compound was converted to HCl salt
by dissolving in 1 N HCl in ether followed by concentration to
dryness: mp ) 178-180 °C; 1H NMR (300 MHz, CDCl3) δ
1.16-1.21 (t, J ) 7 Hz, 3 H), 1.65-1.68 (m, 4 H), 2.35-2.40
(m, 2 H), 2.53-2.60 (m, 3 H), 2.63-2.70 (m, 2 H), 2.98-3.01
(m, 3 H), 3.20-3.40 (m, 2 H), 6.57 (s, 1 H), 6.74-6.80 (m, 2
H), 7.14-7.19 (m, 2 H), 7.36-7.39 (m, 2 H), 8.08-8.11 (d, J )
8 Hz, 1 H), 8.89 (t, J ) 5 Hz, 1 H), 9.45-9.47 (d, J ) 5 Hz, 1
H). Anal. (C28H35F2N7Cl2O4‚2.0H2O) C, H, N.
(()-1,2,3,6-Tetr ah ydr o-1-{N-[[4-(2-car boxam idoph en yl)-
piper azin -1-yl]pr opyl]car boxam ido}-5-acetyl-2-oxo-6-(3,4-
d iflu or op h en yl)-4-m et h ylp yr im id in e Dih yd r och lor id e
(50). To a solution of (()-1,2,3,6-tetrahydro-1-[N-(4-nitrophe-
noxy)carbonyl]-5-acetyl-2-oxo-6-(3,4-difluorophenyl)-4-meth-
ylpyrimidine (44.5 mg, 0.100 mmol) in methylene chloride (10
mL) was added 1-(3-aminopropyl)-4-(2-carboxamindophenyl)-
piperazine (26 mg, 0.10 mmol). The resulting mixture was
stirred at room temperature for 1 h before concentrated to a
residue. The residue was purified through a preparative TLC
plate to yield 52 mg (83%) of the desired product. The
compound was converted to HCl salt by dissolving in 1 N HCl
in ether followed by concentration to dryness: mp ) 235-240
Ack n ow led gm en t. We thank Mr. Yong Zheng for
the technical assistance in cell culture and membrane
preparation and Mr. Boshan Li and Mr. Vincent J or-
gensen for the technical assistance in the radioligand
displacement assays. We also thank Dr. Roger Fre-
idinger (Merck & Co.) for suggestions during the prepa-
ration of this manuscript.
1
°C; H NMR (CDCl3) δ 1.74-1.82 (m, 2 H), 2.20 (s, 3 H), 2.42
(s, 3 H), 2.40-2.50 (m, 2 H), 2.58-2.68 (m, 4 H), 2.98-3.06
(m, 4 H), 3.36-3.42 (m, 4 H), 6.74 (s, 1 H), 7.02-7.09 (m, 2
H), 7.12-7.22 (m, 3 H), 7.40-7.45 (t, J ) 7 Hz, 1 H), 8.00 (br
s, 1 H), 8.09-8.12 (d, J ) 8 Hz, 1 H), 8.77-8.79 (t, J ) 7 Hz,
1 H), 9.44-9.50 (m, 1 H). Anal. (C28H34F2N6Cl2O4‚0.3Et2O) C,
H, N.
Refer en ces
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Murali Dhar, T. G.; Zhang, J .; Tyagarajan, S.; Marzabadi, M.;
Wong, W. C.; Zhang, F.; Sun, W.; Fang, J .; Zhang, J .; Tian, D.;
Forray, C.; Chang, R. S. L.; Broten, T. P.; Ransom, R. W.; Schorn,
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Bendesky, R.; Harrell, C. M.; Vyas, K.; Gluchowski, C. Design
and Synthesis of Novel R1a Adrenoceptor-Selective Antagonists.
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B.; Wong, W. C.; Chiu, G.; Tyagarajan, S.; Miao, S. W.; Zhang,
F.; Sun, W.; Tian, D.; Shen, Q.; Wetzel, J . M.; Forray, C.; Chang,
R. S. L.; Broten, T. P.; Schorn, T. W.; Chen, T. B.; O’Malley, S.;
Ransom, R. W.; Schneck, K.; Bendesky, R.; Harrell, C. M.; Vyas,
K.; Zhang, K.; Gilbert, J .; Pettibone, D. J .; Kling, P.; Patane, M.
A.; Bock, M. G.; Freidinger, R. M.; Gluchowski, C. Design and
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Approaches To Eliminate Opioid Agonist Metabolites via Modi-
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Moiety. J . Med. Chem. 1999, 42, 4778-4793.
(+)-1,2,3,6-Tetr ah ydr o-1-{N-[[4-(2-car boxam idoph en yl)-
4-p h en ylp ip er a zin -1-yl]p r op yl]ca r boxa m id o}-5-ca r box-
am ido-4-eth yl-6-(2,4-diflu or oph en yl)-2-oxopyr im idin e Di-
h yd r och lor id e (52). (a ) (+)-1,2,3,6-Tetr a h yd r o-5-ben zyl-
oxyca r bon yl-1-{N-[[4-(2-ca r boxa m id op h en yl)-4-p h en yl-
p ip er a zin -1-yl]p r op yl]ca r b oxa m id o}-4-et h yl-6-(2,4-d i-
flu or op h en yl)-2-oxop yr im id in e. To a solution of (+)-1,6-
dihydro-5-benzyloxycarbonyl-4-ethyl-6-(2,4-difluorophenyl)-2-
methoxy-1-[N-(4-nitrophenoxy)carbonyl]pyrimidine (400 mg,
0.727 mmol) in CH2Cl2 (15 mL) was added 1-(3-aminopropyl)-
4-(2-carboxamidophenyl)piperazine (229 mg, 0.873 mmol). The
resulting mixture was stirred over 2 h before concentrated to
a residue. The residue was purified through column chroma-
tography (chloroform/MeOH/2 N ammonia in MeOH ) 1000:
18:9) to afford the desired product (427 mg, 89%): [R]D ) +108
(c ) 0.58, CHCl3); 1H NMR (CDCl3) δ 1.14-1.20 (t, J ) 7 Hz,
3 H), 1.65-1.68 (m, 4 H), 2.35-2.40 (m, 2 H), 2.53-2.60 (m, 3
H), 2.68-2.80 (m, 2 H), 2.96-3.00 (m, 3 H), 3.20-3.36 (m, 2
H), 5.05 (ABq, J ) 12 Hz, J ) 2.3 Hz, 2 H), 6.63 (s, 1 H), 6.64-
6.67 (m, 1 H), 7.16-7.30 (m, 9 H), 7.42 (t, J ) 8 Hz, 1 H),
8.11-8.14 (d, J ) 8 Hz, 1 H), 8.85 (t, J ) 5.4 Hz, 1 H), 9.47-
9.51 (m, 1 H).
(b) (+)-1,2,3,6-Tetr ah ydr o-1-{N-[[4-(2-car boxam idoph en -
yl)-4-p h en ylp ip er a zin -1-yl]p r op yl]ca r boxa m id o}-4-eth yl-
6-(2,4-d iflu or op h en yl)-5-h yd r oxyca r bon yl-2-oxop yr im i-
d in e. To a solution of (+)-1,2,3,6-tetrahydro-5-benzyloxycar-
bonyl-1-{N-[[4-(2-carboxamidophenyl)-4-phenylpiperazin-1-
yl]pr opyl]ca r boxa m ido}-4-et h yl-6-(2,4-diflu or oph en yl)-2-
oxopyrimidine (426 mg, 0.65 mmol) in MeOH (100 mL) was
added Pd/C (85 mg, 10%) carefully. The resulting mixture was
left under hydrogen (80 psi) overnight. The mixture was
filtered through Celite and concentrated to afford the desired
product as a white solid (340 mg, 94%) which was used in the
next step without further purification.
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(10) The Merck Index; Budavari, S., Ed.; Merck & Co.: Rahway, NJ ,
1989; p 5734.

Novel R1a Adrenoceptor-Selective Antagonists. 3
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23 4803
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