Design and synthesis of novel α(1a) adrenoceptor-selective antagonists. 1. Structure-activity relationship in dihydropyrimidinones

Article abstract of DOI:10.1021/jm990200p

Dihydropyrimidinones such as compound 12 exhibited high binding affinity and subtype selectivity for the cloned human α(1a) receptor. Systematic modifications of 12 led to identification of highly potent and subtype- selective compounds such as (+)-30 and

Full text of DOI:10.1021/jm990200p

4764
J . Med. Chem. 1999, 42, 4764-4777
Design a n d Syn th esis of Novel r1a Ad r en ocep tor -Selective An ta gon ists. 1.
Str u ctu r e-Activity Rela tion sh ip in Dih yd r op yr im id in on es
Dhanapalan Nagarathnam,†,∇ Shou Wu Miao,† Bharat Lagu,*,† George Chiu,† J ames Fang,† T. G. Murali Dhar,†
J ack Zhang,† Sriram Tyagarajan,† Mohammad R. Marzabadi,† Fengqi Zhang,† Wai C. Wong,† Wanying Sun,†
Dake Tian,† J ohn M. Wetzel,† Carlos Forray,‡ Raymond S. L. Chang,§ Theodore P. Broten,§ Richard W. Ransom,§
Terry W. Schorn,§ Tsing B. Chen,§ Stacey O’Malley,§ Paul Kling,§ Kathryn Schneck,§ Robert Bendesky,§
Charles M. Harrell,§ 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 22, 1999
Dihydropyrimidinones such as compound 12 exhibited high binding affinity and subtype
selectivity for the cloned human R1a receptor. Systematic modifications of 12 led to identification
of highly potent and subtype-selective compounds such as (+)-30 and (+)-103, with high binding
affinity (Ki ) 0.2 nM) for R1a receptor and greater than 1500-fold selectivity over R1b and R1d
adrenoceptors. The compounds were found to be functional antagonists in human, rat, and
dog prostate tissues. Compound (+)-103 exhibited excellent selectively to inhibit intraureth-
ral pressure (IUP) as compared to lowering diastolic blood pressure (DBP) in mongrel dogs
(Kb(DBP)/Kb(IUP) ) 40) suggesting uroselectivity for R1a-selective compounds.
In tr od u ction
(Chart 1). The claims of uroselectivity exhibited by tam-
sulosin have been challenged by some researchers.19,20
Benign prostatic hyperplasia (BPH) is a urological
disorder in the aging male population which leads to a
variety of symptoms including hesitancy in starting the
urine flow, poor stream of urine flow, dribbling, nocturia,
increased frequency of urination, and large residual
volumes.1-3 Obstructive symptoms associated with BPH
result from a combination of two components: mechan-
ical constriction of the urethra due to increased prostatic
mass and a dynamic component attributable to in-
creased noradrenergic tone in the hyperplasic pros-
tate.4,5
As a part of our research program for the treatment
of BPH, we have synthesized antagonists that bind
selectively to the R1a subtype compared to R1b and R1d
adrenoceptors.6-8 We have previously shown that the
R1a receptor subtype mediates the contraction of lower
urinary tract and prostate smooth muscles.9,10 It has
been demonstrated that that R1a-selective antagonists
are able to effectively block the contraction of prostatic
smooth muscle caused by a nonselective R1 agonist after
in vivo administration, without significant effects on
blood pressure.7 In contrast, nonselective R1 antagonists,
terazosin11 and doxazosin,12 show significant effects on
lowering blood pressure at the doses required to block
the contraction of prostate caused by an R1 agonist in
the dog model. This apparent lack of selectivity for R1a
receptor could contribute to some undesirable side
effects such as orthostatic hypotension, dizziness, as-
thenia, and nasal congestion in patients.13 After our
initial reports,5,9,10 several R1a antagonists such as
tamsulosin,14 KMD-3213,15 RS-97078,16 GG-818,17 and
A-13170118 have been reported to exhibit uroselectivity
Recently, we described the synthesis of a number of
dihydropyridines such as 1 and 2 which were found to
be potent and subtype-selective anatgonists for the R1a
adrenoceptor (Chart 2).6,7 Although these compounds
bear structural resemblance to the known calcium
channel antagonist niguldipine, 1 and 2 show negligible
affinity for the L-type calcium channel.5,7 Dihydropyri-
dine 2, however, showed poor oral bioavailability in rats
(5%). It is possible that the poor pharmacokinetic profile
of 1 may be due to a rapid conversion of the dihydro-
pyridine moiety into a pyridine moiety by oxidative
metabolism. We reasoned that a dihydropyrimidinone
in place of the dihydropyridine nucleus would not
undergo such oxidative metabolism and, therefore,
might exhibit a better pharmacokinetic profile. We were
intrigued by the reports that certain dihydropyrimidi-
none derivatives adopt solid-state molecular conforma-
tions similar to dihydropyridines and show comparable
pharmacological activity as calcium channel antago-
nists.21-23 We therefore decided to synthesize a series
of dihydropyrimidinone analogues of 1 and 2 and
evaluate their binding affinities and selectivity for the
R1a adrenoceptor. In our initial design, we retained some
of the optimal structural features derived from the
dihydropyridine SAR, such as the nitrophenyl group and
the distance between the dihydropyrimidinone moiety
and piperidine end group. Synthesis and SARs in the
dihydropyrimidinone are described in this paper.
Ch em istr y
The synthesis of compounds 9-12 is shown in Scheme
1. Dihydropyrimidine intermediates such as 5 were
prepared utilizing a procedure similar to that described
by Atwal et al.21-23 Reaction of the benzylidine deriva-
tive 3 with O-methylisourea (4) in the presence of
NaHCO3 in DMF gave the dihydropyrimidine 5 as a
† Department of Chemistry, Synaptic Pharmaceutical Corp.
‡ Department of Pharmacology, Synaptic Pharmaceutical Corp.
§ Department of Pharmacology, Merck & Co.
| Department of Drug Metabolism, Merck & Co.
∇ Present address: Bayer Corp., West Haven, CT.
Present address: RiboGene Inc., Heyward, CA.
10.1021/jm990200p CCC: $18.00 © 1999 American Chemical Society
Published on Web 10/27/1999

Novel R1a Adrenoceptor-Selective Antagonists. 1
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23 4765
Ch a r t 1
Ch a r t 2
dihydropyrimidine 5. The absolute stereochemistry of
the enantiomers was not assigned. The same sequence
was repeated to obtain pure enantiomers of all the
dihydropyrimidinones which are described in this paper.
Compound (+)-5 on reaction with 4-nitrophenyl chlo-
roformate followed by reaction with amine 8 and
subsequent treatment with aqueous HCl yielded (+)-
12. A similar sequence of reactions starting with
compound (-)-5 gave (-)-12.
Scheme 3 describes the synthesis of dihydropyrimi-
dinone analogues with modifications at the C-4 and C-5
positions. The methyl group at the C-4 position was
changed to an ethyl group by starting with benzylidine
16 derived from the propionylacetic ester. A 2-cyano-
ethyl ester group provided a convenient access to modify
the methyl ester substituent to other ester derivatives
or amides.7 The benzylidine derivatives 15 and 16 were
reacted with O-methylisourea (4) to give the dihydro-
pyrimidines 17 and 18, respectively. Compounds 17 and
18, upon reaction with 4-nitrophenyl chloroformate,
gave the carbamate esters 19 and 20, which upon fur-
ther reaction with amine 8, followed by treatment with
aqueous HCl, gave 22 and 23, respectively. Hydrolysis
of the 2-cyanoethyl ester with aqueous NaOH gave
carboxylic acids 24 and 28. Reaction of these carboxylic
acids with the corresponding alcohols in the presence
of DMAP and EDC gave esters 25 and 29, and a similar
reaction with amines gave amides 26, 27, 30, and 31.
Compounds (+)-30 and (-)-30 were synthesized from
the resolved enantiomers of dihydropyrimidine 18 by
the procedure similar to the one described for resolution
of 12.
mixture of amine-imine tautomers. This compound,
upon reaction with 4-nitrophenyl chloroformate, gave
the carbamate ester 6. Compound 6 was obtained via
regiospecific acylation at the N-1 nitrogen.21 The regio-
chemical preference was seen presumably to achieve
conjugation of the double bond with the carbonyl group
of the methyl ester. Reaction of 6 with 3-[4,4-diphen-
ylpiperidin-1-yl]propylamine (7)5 and 3-[4-methoxycar-
bonyl-4-phenylpiperidin-1-yl]propylamine (8)7 gave the
dihydropyrimidine derivatives 9 and 10, respectively,
which on treatment with aqueous HCl gave the dihy-
dropyrimidinones 11 and 12.
The resolution of enantiomers of the dihydropyrimi-
dine 5 was achieved in two steps by using chiral aux-
iliary as shown in Scheme 2. First, the p-nitrophenyl-
oxy carbamate 6, derived from 5, was reacted with (S)-
(-)-R-methylbenzylamine to obtain a mixture of dia-
stereomeric amides 13 and 14,21,22 and the diastereo-
mers were separated by flash column chromatography.
The R-methylbenzylaminocarbonyl moiety was then
removed by treatment with 1,8-diazabicyclo[5.4.0]undec-
7-ene (DBU) to give the (+) and (-) enantiomers of
Schemes 4 and 5 depict the synthesis of dihydropy-
rimidinones 77-85, (+)-103, and (+)-104 by using the

4766 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23
Nagarathnam et al.
Sch em e 1a
a
(i) NaOAc, DMF; (ii) 4-nitrophenyl chloroformate, NaHCO3, CH2Cl2, H2O; (iii) HCl/THF.
Sch em e 2a
Sch em e 3a
a
(i) (S)-(-)-R-Methylbenzylamine; (ii) separation of diastereo-
mers; (iii) DBU.
sequence of reactions similar to the ones described
previously.
Resu lts a n d Discu ssion
The binding profiles for the R1 receptors of several
structurally similar dihydropyridines and dihydropyri-
midinones are summarized in Table 1. The dihydropy-
rimidinone 11, containing a diphenylpiperidine side
chain, had Ki ) 5 nM at the cloned human R1a adreno-
ceptor as compared to its dihydropyridine analogue 1
(Ki ) 0.4 nM). Interestingly, the dihydropyrimidinone
12, which contains 4-methoxycarbonyl-4-phenylpiperi-
dine in the side chain, displayed better binding affinity
(Ki ) 0.5 nM) than its dihydropyridine analogue 2 (Ki
) 2.4 nM). The subtype selectivity, however, was better
for the dihydropyridine compounds (1 and 2) than the
dihydropyrimidinones (11 and 12). Encouraged by these
preliminary results, we tested both enantiomers of
compound 12 in the binding assay. The more active
enantiomer (+)-12 showed higher affinity and improved
a
(i) O-Methylisourea, NaHCO3, EtOH; (ii) 4-nitrophenyl chlo-
roformate, NaHCO3, CH2Cl2, H2O; (iii) amine 8 (H2NR′′′); (iv) 6 N
HCl; (v) NaOH, acetone; (vi) EDC, DMAP, amine/alcohol,
CH2Cl2.
subtype selectivity (>100-fold) for R1a over the race-
mate and (-)-12. In addition, (+)-12 showed >400-fold
selectivity over R2 adrenoceptor subtypes and even
greater selectivity over the rat L-type calcium chan-
nel (Ki > 10 µM). The active enantiomer (+)-12 showed
10% oral bioavailability with a 90-min half-life in the
rat and <10% bioavailability in the dog. These initial
results prompted us to further investigate this ser-

Novel R1a Adrenoceptor-Selective Antagonists. 1
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23 4767
Sch em e 4a
a
(i) Piperidine/HOAc; (ii) O-methylisourea, NaHCO3, DMF; (iii) 4-nitrophenyl chloroformate, DMAP, CH2Cl2; (iv) amine 8; (v) HCl.
Sch em e 5a
a
(i) Piperidine, benzene; (ii) O-methylurea, NaHCO3, DMF; (iii) 4-nitrophenyl chloroformate pyridine, CH2Cl2; (iv) R-(+)-phenethylamine
and separate diastereomers; (v) DBU; (vi) 4-nitrophenyl chloroformate, pyridine, CH2Cl2; (vii) amine 8; (viii) 6 N HCl; (ix) H2, Pd-C,
MeOH/water; (x) EDC, NMM, NH4OH, CH2Cl2.
ies of compounds in order to optimize the selectivity for
R1a receptor and to improve their pharmacokinetic
properties.
Replacement of the methyl ester in compound 12 with
an ethyl ester (25) did not result in a significant change
of affinity for the R1a subtype (0.5 nM vs 0.3 nM).
Interestingly, the carboxylic acid 24 showed lower R1a
affinity but greater than 150-fold selectivity over the
other two R1 subtypes. Replacement of the ester group
in 12 by a primary amide group gave compound 26,
which showed comparable binding affinity (Ki ) 0.7 nM)
but better subtype selectivity than 12. The methylamide
27 exhibited lower R1a affinity than the primary amide
26.
Compound 29, containing an ethyl group at the C-4
position, showed a binding profile quite similar to that
of 12 which contains a methyl group at the C-4 position
of the dihydropyrimidinone. Compound 30, an amide

4768 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23
Nagarathnam et al.
Ta ble 1. Binding Profiles of Dihydropyrimidinones versus
Dihydropyridines at Recombinant Human R1 Adrenoceptors
Ta ble 2. Binding Profile of Dihydropyrimidinones with C-4
and C-5 Modifications at Recombinant Human R1
Adrenoceptors
Ki (nm)a,b
Ki (nM)a,b
compd
terazosin
1
2
R1a
R1b
1.9
74
3700
27
28
81
19
R1d
3.5
160
8800
120
100
180
80
compd
R′
R′′
R1a
R1b
28
1600
15
100
100
37
160
360
130
139
R1d
6.9
0.4
2.4
5.0
0.5
0.4
2.1
12
24
25
26
27
29
30
(+)-30
(-)-30
31
Me
Me
Me
Me
Me
Et
Et
Et
Et
Et
MeO
HO
EtO
0.5
10
100
2600
91
140
270
81
290
740
420
398
11 (R ) Ph)
0.3
0.7
2.1
0.8
0.5
0.2
1.9
1.2
12 (R ) CO2Me)
(+)-12 (R ) CO2Me)
(-)-12 (R ) CO2Me)
H2N
MeNH
MeO
H2N
H2N
H2N
Ki values obtained by displacement of [3H]prazosin from cloned
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.
a
b
MeNH
a,b
For note, see Table 1.
analogue of 29, showed improved binding affinity and
subtype selectivity. The methylamide 31 exhibited a
lower affinity for R1a (Ki ) 1.2 nM) than the correspond-
ing primary amide 30 but still showed greater than 100-
fold selectivity against the R1b and R1d subtypes.
The improved R1a adrenoceptor binding and selectivity
profile of 30 prompted further characterization of the
pure enantiomers of the compound. The (+) enantiomer
of the compound (+)-30 exhibited superior binding and
selectivity profile compared to its antipode (-)-30 and
the racemate. This observation is consistent with the
observation about the binding profile of the enantiomers
of 12 that was described previously. Compound (+)-30
showed greater than 1000-fold selectivity for the R1a
receptor over a number of recombinant human G-
protein coupled receptors such as R2a, R2b, and R2c
adrenoceptors, histamine H2, and 5HT (1A, 1B, 1D, and
2A) and for the rat L-type calcium channel. The selec-
tivity over the histamine H1 receptor was 100-fold.
The binding affinity of (+)-30 at the recombinant
rat,25 dog,26 and human R1a adrenoceptors correlated
well with the functional potency of the compound to
antagonize the phenylephrine-induced contraction of
isolated rat, dog, and human prostate tissues (Table 5).
Compound (+)-30 showed an oral bioavailability of 13%
(iv: 1 mg/kg dose, AUC ) 18 µmol min/L; po: 3 mg/kg
dose, AUC ) 9 µmol min/L) in rats and 32% (iv: 1 mg/
kg dose, AUC ) 23 µmol min/L; po: 3 mg/kg dose, AUC
) 25 µmol min/L) in dogs with plasma half-life of 1.6
and 3.2 h, respectively.
Ta ble 3. Binding Profile of Dihydropyrimidinones with C-6
Phenyl Ring Modifications at Recombinant Human R1
Adrenoceptors
Ki (nM)a,b
compd
R
R1a
R1b
R1d
12
77
78
79
80
81
82
83
84
85
4-NO2
4-Me
3-Me
4-Cl
3-Cl
4-F
0.5
8.0
1.8
4.5
1.1
1.2
1.5
0.1
0.2
0.1
28
77
110
48
50
78
67
45
88
27
100
220
220
170
180
180
150
140
180
93
3-F
3,4-F2
2,4-F2
3,4-furazan
a,b
For note, see Table 1.
C-4 position (77 and 79) of the phenyl ring reduced the
R1a affinity by about 10-fold. When the methyl or chloro
substituent was placed at the 3-position (78 and 80) an
improved R1a binding profile was observed. A fluoro
group at the 3- or 4-position (81 and 82) reduced the
R1a affinity and selectivity. The compounds containing
difluoro substituents at the 3,4- or 2,4-positions gave
compounds 83 and 84 which displayed improved binding
affinities for the R1a adrenoceptor and >400-fold selec-
tivity over R1b and R1d. A 3,4-benzofurazanyl group,
which has been used as an isostere for a nitrophenyl
group in other programs,21,22 was incorporated to give
compound 85 which showed good binding and selectivity
profile for the R1a receptor. The easy accessibility of 3,4-
and 2,4-difluorobenzaldehydes prompted us to use these
substituents as the preferred groups on the C-6 phenyl
ring for the synthesis of close analogues of 30 as shown
Table 4.
The presence of a nitro substituent on the C-6 phenyl
group of (+)-30 was deemed to be a liability due to its
potential for toxicity upon chronic administration.24
A
search was undertaken to synthesize analogues of (+)-
30, with suitable replacements for the nitro group
without compromising the desirable in vitro and in vivo
profile of (+)-30. We decided to explore the SAR of the
C-6 phenyl group by initially synthesizing analogues of
12 rather than 30 because the synthetic route to make
analogues of 12 is shorter than that for 30. The results
of this study are summarized in Table 3. Replacement
of the nitro group with a methyl or chloro group at the

Novel R1a Adrenoceptor-Selective Antagonists. 1
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23 4769
Ta ble 4. Binding Profile of (+)-30 and Its Close Analogues at
Recombinant Human R1 Adrenoceptors
In the in situ rat prostate assay, compound (+)-103
inhibited the contractile response to phenylephrine with
AD50 ) 20 µg/kg but needed a much higher dose (AD50
> 3 mg/kg) for inhibition of blood pressure effect elicited
by phenylephrine in pithed rats. In contrast, the non-
selective R1 antagonist, terazosin, did not show much
separation for doses required to inhibit the contractile
response (AD50 ) 52 µg/kg) versus doses required to
lower blood pressure (AD50 ) 65 µg/kg). In the phenyl-
ephrine-stimulated urethral and arterial pressure ex-
periments in anesthetized dogs, compound (+)-103 was
found to inhibit intraurethral pressure (IUP) at doses
40-fold lower than those required to reduce diastolic
blood pressure (DBP). The nonselective R1 antagonist
terazosin, in comparison, did not show difference in
potency against these two effects in the same model (Kb-
(IUP) ) 16.4 µg/kg and Kb(DBP) ) 15.7 µg/kg). The ratio
of Kb(IUP) over Kb(DBP) is one index of uroselectivity,
i.e., selectivity of an antagonist for mediating urethral
versus cardiovascular effects. This model is considered
to be a good predictor of clinical urodynamic and hemo-
dynamic profiles in humans,28 and on the basis of the
results described above, (+)-103 will be expected to
show less cardiovascular liability than terazosin. Com-
pound (+)-103 showed an oral bioavailability of 19% and
26% and plasma half-life of 2.0 and 2.5 h in rats and
dogs, respectively. Interestingly, although (+)-103 showed
a short plasma half-life (2 h) in rats, it showed a longer
duration of action (>4 h) in the in situ rat prostate
experiment.
Ki (nM)a,b
compd
R
R1a
R1b
R1d
(+)-30
(+)-103
(+)-104
4-NO2
3,4-F2
2,4-F2
0.2
0.2
0.2
360
260
340
740
350
440
a,b
For note, see Table 1.
Ta ble 5. Comparison of Binding Affinities of (+)-30 and
(+)-103 at the R1a Adrenoceptors and Antagonism of
Phenylephrine- or A-61603-Induced Contractions (Kb) of (+)-30
and (+)-103 in Isolated Prostate Tissue
(+)-30
(+)-103
species
Ki (nM)
Kb (nM)
Ki (nM)
Kb (nM)
rat
dog
human
0.58
1.9
0.19
2.0a
0.27
1.30
0.21
1.00a
3.70a
0.39b
0.85a
0.04b
a
b
Phenylephrine was used as agonist. A-61603 was used as
agonist.
The compounds (+)-103 [SNAP 6201(+)] and (+)-104
displayed almost identical binding and selectivity pro-
files. In the initial binding experiments, (+)-103 showed
comparable binding affinity at the recombinant rat,25
dog,26 and human9 R1a adrenoceptors (Ki ) 0.3, 1.3, and
0.2 nM, respectively) which correlated well with the
potencies of the compound to antagonize phenylephrine-
or A-61603-induced contraction of the prostate tissues
as shown in Table 5. Thus the profile for (+)-103 looked
strikingly similar to that of (+)-30, and the compound
was selected for detailed characterization.
In vitro and in vivo metabolism experiment with (+)-
103 revealed a significant formation of 4-methoxycar-
bonyl-4-phenylpiperidine, which is an analogue of the
known µ-opioid agonist, meperidine.29 Issues relating
to (+)-103 metabolism will be further discussed in the
accompanying papers.
Su m m a r y
We have designed and synthesized a novel series of
dihydropyrimidinones as potent and selective R1a adreno-
ceptor antagonists. Compound 12 was identified as a
lead compound with good binding affinity and subtype
selectivity for the R1a receptor. Systematic modification
of 12 led to the discovery of 30 as a potent and selective
antagonist in the binding and functional assays. A 3,4-
difluoro analogue of 30 was synthesized, and the result-
ing compound (+)-103 (SNAP 6201) showed high affinity
and selectivity for the R1a adrenoceptor subtype. In the
anesthetized dog model, this compound showed 40-fold
selectivity to reduce the IUP versus DBP supporting our
notion that this compound may be uroselective. On the
basis of the lack of cardiovascular effects and the
superior pharmacodynamic profiles of these R1a-selective
compounds in the animal models, we believe that they
could offer a significant improvement over the current
treatments of BPH.
In Vitr o a n d in Vivo Eva lu a tion of (+)-103. The
results from a number of in vivo and in vitro experi-
ments on (+)-103 and terazosin are summarized in
Table 6. While terazosin showed no subtype selectivity
for the R1a receptor, (+)-103 showed >1000-fold selectiv-
ity for the R1a receptor over a number of recombinant
human G-protein coupled receptors such as R2 and 5HT
(1A, 1B, 1D, and 2A) receptors as well as the rat L-type
calcium channel. The selectivity for the R1a receptor over
the histamine H1 receptor was found to be 140-fold
based on the binding affinities of (+)-103 for the cloned
human receptors.
Compound (+)-103 was found to potently antagonize
norepinephrine-induced contraction of isolated prostate
and vas deferens tissues which predominantly express
the R1a subtype in rat, dog, and human. It, however,
failed to inhibit the norepinephrine-induced contractions
in the isolated rat aorta which predominantly express
the R1d subtype, at concentrations up to 1 µM.27 The
nonselective R1 antagonist terazosin, on the other hand,
antagonizes the norepinephrine-induced contractions in
isolated rat aorta with almost identical Kb (19 and 25
nM, respectively). These results are in good agreement
with the selectivity observed in the binding assays for
the R1a receptor over the R1d receptor.
Exp er im en ta l Section
Melting points were determined on a Mel-Temp apparatus
and are uncorrected. All 1H and 13C NMR spectra were
recorded on a QE Plus 300 MHz spectrometer. Elemental
analyses were performed by Robertson Microlit Laboratories,
Inc., Madison, NJ . Reactions were monitored by TLC (Merck
type 60 F254), and flash column chromatography was done on
silica gel (Merck type 60 for column chromatography; 230-

4770 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23
Nagarathnam et al.
Ta ble 6. Summary and Comparison of the in Vitro and in Vivo Properties of (+)-103 and Terazosin
assay
antagonist/agonist
(+)-103
0.2
>1000
>1000
0.3
>1000
2.5
0.1
20
terazosin
Ki R1a human clones (nM)
[3H]prazosin
[3H]prazosin
[3H]rauwolscine
A-61603
norepinephrine
norepinephrine
A-61603
phenylephrine
phenylephrine
phenylephrine
phenylephrine
phenylephrine
4.0
R
1b,1d/R1a
2a,b,c/R1a
<1.0
<10
25
R
Kb rat prostate (nM)
Kb rat aorta (nM)
19
Kb rat vas deferens (nM)
Kb human prostate (nM)
AD50 (in situ rat prostate)
AD50(DBP) rat (µg/kg)
duration of action rat (h)
Kb(IUP)a dog (µg/kg)
Kb (DBP)b dog (µg/kg)
rat F, t1/2 (h)
25
52
65
>4
16.4
15.7
49%, 7.5
>3000
>4
4.2
187
15%,c 2.0
26%,d 2.5
dog F, t1/2 (h)
a
b
Intraurethral pressure. Diastolic blood pressure. c iv: 1 mg/kg dose, AUC ) 70 µmol min/L. po: 3 mg/kg dose, AUC ) 47 µmol
d
min/L. iv: 1 mg/kg dose, AUC ) 29 µmol min/L. po: 3 mg/kg dose, AUC ) 25 µmol min/L.
400 mesh) in the solvent systems indicated. Optical rotations
were measured on a J ASCO DIP-370 digital polarimeter.
Abbreviations: EDC, 1-(3-dimethylaminopropyl)-3-ethylcar-
bodiimide hydrochloride; DMAP, 4-(N,N-dimethylamino)pyri-
dine; NMM, N-methylmorpholine. The yields reported are of
the isolated purified compounds and are not optimized.
5-Met h oxyca r b on yl-4-m et h yl-6-(4-n it r op h en yl)-1-{N-
[3-(4,4-d ip h en ylp ip er id in -1-yl)p r op yl]ca r b oxa m id o}-2-
oxo-1,2,3,6-tetr a h yd r op yr im id in e (11). (a ) 1,6-Dih yd r o-
5-m eth oxyca r bon yl-2-m eth oxy-4-m eth yl-6-(4-n itr op h en -
yl)p yr im id in e (5). A mixture of methyl 2-{(4-nitrophenyl)-
methylene}-3-oxobutyrate (3; 12.46 g, 0.05 mol), O-methyl-
isourea hydrogen sulfate (4; 10.32 g, 0.06 mol), and NaOAc
(9.84 g, 0.06 mol) in DMF (50 mL) was stirred and heated at
70-75 °C for 4 h. The mixture was cooled and poured into
ice-water (300 mL). The precipitate formed was filtered,
washed with water, and dried. The crude product was purified
by flash column chromatography on silica gel using 10-30%
powder upon trituration with hexanes and drops of EtOAc
(1.10 g, 88%). Mp: 95-96 °C. H NMR (CDCl3): δ 1.61-1.71
(m, 2 H), 2.26-2.33 (m, 2 H), 2.38 (s, 3 H), 2.39-2.50 (m, 8
H), 3.20-3.41 (m, 2 H), 3.65 (s, 3 H), 3.89 (s, 3 H), 6.65 (s, 1
H), 6.84 (br t, 1 H, NH), 7.08-7.29 (m, 10 H), 7.40 (d, J ) 8.7
Hz, 2 H), 8.03 (d, J ) 8.6 Hz, 2 H). Anal. (C35H39N5O6‚0.75CH2-
Cl2) C, H, N.
1
(d ) 5-Meth oxyca r bon yl-4-m eth yl-6-(4-n itr op h en yl)-1-
{N-[3-(4,4-d ip h en ylp ip er id in -1-yl)p r op yl]ca r boxa m id o}-
2-oxo-1,2,3,6-tetr a h yd r op yr im id in e (11). To a stirred so-
o
lution of 9 (0.208 g, 0.33 mmol) in THF (10 mL) at 5 C under
argon was added 3 N HCl (6 mL) and the mixture was allowed
to warm to room temperature. After 2 h, solvents were
evaporated completely, and the residue was treated with 40
mL of 10% NaHCO3. The product was extracted with CH2Cl2
(2 × 15 mL) and the combined extracts were dried (MgSO4).
Solvent was evaporated and the residue was crystallized from
1
hexane and EtOAc (0.20 g, 97%). Mp: 197-198 °C. H NMR
1
EtOAc in hexanes as the gradient eluent (9.8 g, 64%). The H
(CDCl3): δ 1.63-1.67 (m, 2 H), 2.23-2.28 (m, 2 H), 2.34 (s, 3
H), 2.37-2.42 (m, 8 H), 3.20-3.41 (m, 2 H), 3.69 (s, 3 H), 6.75
(s, 1 H), 7.08-7.26 (m, 11 H), 7.46 (d, J ) 8.7 Hz, 2 H), 8.08
(d, J ) 8.7 Hz, 2 H), 8.77 (br t, 1 H, NH). Anal. (C34H37N5O6)
C, H, N.
NMR analysis of the product showed it to be a 19:1 mixture
of the amine-imine tautomers, which was used as such in the
1
next step. H NMR (CDCl3): δ 2.32, 2.38 (2 s, 3 H), 3.59, 3.70
(2 s, 3 H), 3.72, 3.85 (2 s, 3 H), 5.40, 5.66 (s, d, J ) 3 Hz, 1 H),
5.50, 6.08 (s, d, J ) 3 Hz, 1 H), 7.43, 7.45 (2 d, J ) 9 Hz, 2 H),
8.10, 8.11 (2 d, J ) 9 Hz, 2 H).
5-Meth oxycar bon yl-1-{N-[3-(4-m eth oxycar bon yl-4-ph en -
ylp ip er id in -1-yl)p r op yl]ca r boxa m id o}-4-m eth yl-6-(4-n i-
tr op h en yl)-2-oxo-1,2,3,6-tetr a h yd r op yr im id in e (12). Pre-
pared from 6 (0.47 g, 1 mmol) and 3-[4-methoxycarbonyl-4-
phenylpiperidin-1-yl]propylamine (8; 0.332 g, 1.2 mmol, 1.2
equiv) following the procedure described above to give com-
pound 10, which on treatment with HCl gave product 12 (0.55
(b) 1,6-Dih ydr o-2-m eth oxy-5-m eth oxycar bon yl-4-m eth -
yl-6-(4-n itr op h en yl)-1-[(4-n itr op h en yloxy)ca r bon yl]p yr i-
m id in e (6). To a well-stirred mixture of compound 5 (5.7 g,
18.7 mmol), NaHCO3 (6.27 g, 0.074 mol), CH2Cl2 (200 mL),
and water (50 mL) at 0-5 °C was added 4-nitrophenyl
chloroformate (4.41 g, 2.18 mmol) in 5 min and the mixture
was allowed to warm to room temperature. After 10 h, two
layers were separated; the CH2Cl2 layer was washed with
saturated aqueous NaHCO3 solution (3 × 50 mL) and dried
(MgSO4), and the solvent was evaporated. The residue was
recrystallized from CH2Cl2 and hexanes to give the product 6
1
g, 86%). Mp: 180-181 °C. H NMR (CDCl3): δ 1.60-1.80 (m,
2 H), 1.85-1.95 (m, 2 H), 2.03-2.10 (m, 2 H), 2.28-2.33 (m, 2
H), 2.35 (s, 3 H), 2.48-2.50 (m, 2 H), 3.20-3.40 (m, 2 H), 3.60
(s, 3 H), 3.68 (s, 3 H), 6.75 (s, 1 H), 7.20-7.34 (m, 6 H), 7.46
(d, J ) 8.8 Hz, 2 H), 8.07 (d, J ) 8.8 Hz, 2 H), 8.78 (br t, 1 H,
NH). Anal. (C30H35N5O8) C, H, N.
1
as white crystals (12.8 g, 89%). H NMR (CDCl3): δ 2.48 (s, 3
P r ep a r a tion of (+)-12 a n d (-)-12. (a ) (-)-1,6-Dih yd r o-
2-m eth oxy-5-m eth oxycar bon yl-4-m eth yl-6-(4-n itr oph en yl)-
1-{N-[2-p h en yleth yl]ca r boxa m id o}p yr im id in e (13) a n d
(+)-1,6-Dih yd r o-2-m eth oxy-5-m eth oxyca r bon yl-4-m eth -
yl-6-(4-n itr op h en yl)-1-{N-[2-p h en yleth yl] ca r boxa m id o}-
p yr im id in e (14). To a stirred solution of 6 (2.66 g, 5.6 mmol)
in anhydrous THF (80 mL) at room temperature under argon
atmosphere was added a solution of (S)-(-)-R-methylbenzyl-
amine (0.82 g, 6.78 mmol, 1.2 equiv) in THF (5 mL) and the
stirring was continued for 6 h. Solvent was evaporated from
the reaction mixture, and the residue was redissolved in CH2-
Cl2 (50 mL). The solution was washed with 5% NaHCO3 (3 ×
25 mL) and brine (50 mL) and dried (MgSO4). Solvent was
evaporated and the residue was purified by flash chromatog-
raphy on silica gel using 5-30% EtOAc in hexane as the
gradient eluent. The first major product to elute was 13 and
this compound was crystallized from isopropyl ether (0.85 g,
34%). Mp: 119-120 °C. [R]D ) -329 (c ) 1.3, CH2Cl2). 1H NMR
(CDCl3): δ 1.47 (d, J ) 7 Hz, 3 H), 2.40 (s, 3 H), 3.61 (s, 3 H),
H), 3.69 (s, 3 H), 3.94 (s, 3 H), 6.34 (s, 1 H), 7.36 (d, J ) 9.1
Hz, 2 H), 7.46 (d, J ) 8.7 Hz, 2 H), 8.14 (d, J ) 8.7 Hz, 2 H),
8.26 (d, J ) 9.1 Hz, 2 H). Mp: 168-169 °C. Anal. (C21H18N4O9)
C, H, N.
(c) 1,6-Dih yd r o-1-{N-[3-(4,4-d ip h en ylp ip er id in -1-yl)-
p r op yl]ca r boxa m id o} -2-m eth oxy-5-m eth oxyca r bon yl-4-
m eth yl-6-(4-n itr op h en yl)p yr im id in e (9). To a stirred mix-
ture of 6 (0.940 g, 2 mmol) and K2CO3 (0.552 g, 4 mmol) in
anhydrous THF (20 mL) at room temperature under argon
atmosphere was added a solution of 3-[4,4-diphenylpiperidin-
1-yl]propylamine (7; 0.882 g, 3 mmol, 1.5 equiv) in THF (5 mL)
and the stirring was continued for 1 h. Solvent was evaporated
from the reaction mixture and the residue was redissolved in
CH2Cl2 (50 mL). It was washed with 5% NaHCO3 (3 × 25 mL)
and brine (50 mL) and dried (MgSO4). Solvent was evaporated
and the residue was purified by flash column chromatography
on silica gel using 10% methanol in EtOAc as the eluent to
give the desired product 9 as an oil which became a white

Novel R1a Adrenoceptor-Selective Antagonists. 1
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23 4771
3.95 (s, 3 H), 4.96 (quint, J ) 6.5 Hz, 2 H), 6.66 (s, 1 H), 6.82
(d, J ) 6.8 Hz, 1 H, NH), 7.22-7.36 (m, 5 H), 7.43 (d, J )
8.6 Hz, 2 H), 8.09 (d, J ) 8.6 Hz, 2 H). Anal. (C23H24N4O6) C,
H, N.
to give the product 18 as a white solid (2.95 g, 50%). The 1H
NMR analysis of the product showed it to be a 5:1 mixture of
the amine-imine tautomers and was used as such in the next
step.
The second major compound to elute was 14 and it was
crystallized from isopropyl ether (0.92 g, 36%). Mp: 138-140
°C. [R]D ) +172 (c ) 1.131, CH2Cl2). 1H NMR (CDCl3): δ 1.47
(d, J ) 7 Hz, 3 H), 2.42 (s, 3 H), 3.64 (s, 3 H), 3.91 (s, 3 H),
4.99 (quint, J ) 6.5 Hz, 2 H), 6.70 (s, 1 H), 6.81 (d, J ) 6.8 Hz,
1 H, NH), 7.22-7.35 (m, 5 H), 7.36 (d, J ) 8.6 Hz, 2 H), 8.04
(d, J ) 8.6 Hz, 2 H). Anal. (C23H24N4O6) C, H, N.
(b) (+)-5- Meth oxyca r bon yl-1-{N-[3-(4-m eth oxyca r bo-
n yl-4-ph en ylpiper idin -1-yl)pr opyl] car boxam ido}-4-m eth -
yl-6-(4-n it r op h e n yl)-2-oxo-1,2,3,6-t e t r a h yd r op yr im i-
d in e [(+)-10]. A solution of 14 (0.226 g, 0.5 mmol) and DBU
(0.076 g, 0.5 mmol) in CH2Cl2 (10 mL) was stirred and refluxed
for 4 h and the solvent was evaporated. The residue was
purified by column chromatography using 30% EtOAc in
(b) 5-(2-Cya n oeth oxyca r bon yl)-1,6-d ih yd r o-4-eth yl-2-
m eth oxy-6-(4-n itr op h en yl)-1-[(4-n itr op h en yloxy)ca r bo-
n yl]p yr im id in e (20). Prepared from 18 (2.64 g, 7.36 mmol)
and 4-nitrophenyl chloroformate (1.485 g, 7.36 mmol) using a
similar procedure described earlier to give the product 20 as
1
a viscous oil (1.70 g, 44%). H NMR (CDCl3): δ 1.24 (t, J ) 7
Hz, 3 H), 2.61-2.68 (m, 2 H), 2.88-2.92 (m, 2 H), 3.97 (s, 3
H), 4.32 (t, J ) 7 Hz, 2 H), 6.34 (s, 1 H), 7.37 (d, J ) 9.2 Hz,
2 H), 7.50 (d, J ) 8.7 Hz, 2 H), 8.18 (d, J ) 8.7 Hz, 2 H), 8.28
(d, J ) 9.2 Hz, 2 H).
(c) 5-(2-Cya n oeth oxyca r bon yl)-4-eth yl-1-{N-[3-(4-m eth -
oxyca r bon yl-4-p h en ylp ip er id in -1-yl)p r op yl]ca r boxa m i-
d o}-2-oxo-6-(4-n it r op h en yl)-1,2,3,6-t et r a h yd r op yr im i-
d in e (23). To a well-stirred mixture of 20 (0.940 g, 2 mmol)
and K2CO3 (0.552 g, 4 mmol) in anhydrous THF (20 mL) at
room temperature under argon atmosphere was added a
solution of amine 8 (0.882 g, 3 mmol, 1.5 equiv) in THF (5
mL) and the stirring was continued for 1 h. Solvent was
evaporated from the reaction mixture; the residue was redis-
solved in CH2Cl2 (50 mL), washed with 5% NaHCO3 (3 × 25
mL) and brine (50 mL), and dried (MgSO4). Solvent was
evaporated and the residue was purified by flash chromatog-
raphy on silica gel using 10% methanol in EtOAc as the eluent
to give 5-(2-cyanoethoxycarbonyl)-1,6-dihydro-4-ethyl-2-meth-
oxy-1-{N-[3-(4-methoxycarbonyl-4-phenylpiperidin-1-yl)propyl]-
carboxamido}-6-(4-nitrophenyl)pyrimidine (21) as an oil, which
on trituration with hexanes and drops of EtOAc became a
white powder (1.71 g, 80%). Mp: 62-63 °C. 1H NMR (CDCl3):
δ 1.16 (t, J ) 7.5 Hz, 3 H), 1.62-1.78 (m, 2 H), 1.80-1.84 (m,
2 H), 2.06-2.18 (m, 2 H), 2.28-2.36 (m, 2 H), 2.50-2.53 (m, 4
H), 2.58-2.63 (m, 2 H), 2.70-2.84 (m, 4 H), 3.25-3.40 (m, 2
H), 3.61 (s, 3 H), 3.92 (s, 3 H), 4.26 (m, 2 H), 6.66 (s, 1 H), 6.82
(br t, 1 H, NH), 7.22-7.33 (m, 6 H), 7.43 (d, J ) 7.8 Hz, 2 H),
8.10 (d, J ) 7.8 Hz, 2 H). Anal. (C34H40N6O8‚0.1C6H12‚0.5H2O)
C, H, N. This compound upon treatment with aqueous HCl
and subsequent workup as described earlier gave product 23,
which was used in the next step without further characteriza-
tion.
(d ) 4-Eth yl-1-{N-[3-[4-(4-m eth oxyca r bon yl)-4-p h en ylp i-
p er id in -1-yl]p r op yl] ca r boxa m id o}-6-(4-n itr op h en yl)-2-
oxo-1,2,3,6-tetr a h yd r op yr im id in e-5-ca r boxylic Acid (28).
To a stirred solution of 23 (4.40 g, 6.8 mmol) in acetone (50
mL) at 0 °C was added aqueous NaOH solution (1 N, 27.2 mL,
4 equiv) dropwise and the stirring was continued until the
disappearance of the starting material (1 h). Most of the
acetone from the mixture was evaporated under reduced
pressure while keeping the temperature at 0 °C and the
residue pH was adjusted to 7.0 by the addition of 1 N HCl.
The white precipitate of the carboxylic acid 24 formed was
filtered and dried under vacuum (3.59 g, 89%). 1H NMR
(CDCl3): δ 1.07 (t, J ) 7.5 Hz, 3 H), 1.55-1.70 (m, 2 H), 1.72-
1.84 (m, 2 H), 1.84-2.15 (m, 2 H), 2.20-2.40 (m, 4 H), 2.70-
2.90 (m, 2 H), 3.10-3.40 (m, 4 H), 3.51 (s, 3 H), 6.54 (s, 1 H),
7.18-7.38 (m, 6 H), 7.41 (d, J ) 7.8 Hz, 2 H), 8.15 (d, J ) 7.8
Hz, 2 H), 8.79 (br t, 1 H, N H), 10.05 (br s, 1 H, COOH). This
product was used in the next step without further character-
ization.
hexanes as the eluent to give (+)-5 (0.120 g, 79%). [R]D
+14.5° (c ) 0.6, CH2Cl2).
)
Compound (+)-5 (0.12 g, 0.393 mmol) was reacted with
4-nitrophenyl chloroformate (0.095 g, 0.472 mmol) as described
earlier. After 2 h, saturated aqueous NaHCO3 solution (10 mL)
was added and the stirring continued for 30 min. The two
layers were separated, the CH2Cl2 layer was washed with
saturated aqueous NaHCO3 solution (3 × 5 mL) and dried
(Na2SO4), and the solvent was evaporated. The residue was
redissolved in THF (10 mL) and mixed with K2CO3 (0.11 g,
0.8 mmol). To this was added a solution of amine 8 (0.138 g,
0.5 mmol) in THF (5 mL) and the mixture was stirred for 2 h.
The solid was removed by filtration and the filtrate was cooled
to 0-5 °C. To this was added 6 N HCl (0.5 mL) and the stirring
was continued for 3 h. THF was evaporated from the mixture;
the residue was redissolved in CH2Cl2 (20 mL), washed with
10% NaHCO3 (4 × 5 mL), and dried (MgSO4). Solvent was
evaporated and the residue was purified by column chroma-
tography using 1:1 hexanes/EtOAc to 100% EtOAc as gradient
eluent. The oily product (+)-12 was crystallized from hexanes
and EtOAc (0.19 g, 82%). Mp: 137-139 °C. [R]D ) +108 (c )
0.665, CH2Cl2). 1H NMR (CDCl3): δ 1.60-1.80 (m, 2 H), 1.85-
1.95 (m, 2 H), 2.03-2.10 (m, 2 H), 2.28-2.33 (m, 2 H), 2.35 (s,
3 H), 2.48-2.50 (m, 2 H), 3.20-3.40 (m, 2 H), 3.60 (s, 3 H),
3.68 (s, 3 H), 6.75 (s, 1 H), 7.20-7.34 (m, 5 H), 7.46 (d, J ) 8.8
Hz, 2 H), 7.60 (br s, 1 H, N H), 8.07 (d, J ) 8.8 Hz, 2 H), 8.78
(br t, 1 H, NH). Anal. (C30H35N5O8‚0.2CH2Cl2‚0.2EtOAc) C, H,
N.
(-)-5- Meth oxyca r bon yl-1-{N-[3-(4-m eth oxyca r bon yl-
4-p h en ylp ip er id in -1-yl)p r op yl]ca r boxa m id o}-4-m eth yl-
6-(4-n itr oph en yl)-2-oxo-1,2,3,6-tetr ah ydr opyr im idin e [(-)-
12]. A solution of 13 (0.35 g, 0.774 mmol) and DBU (0.117 g,
0.774 mmol) in CH2Cl2 (10 mL) was stirred and refluxed for 8
h and the solvent evaporated. The crude product was purified
by column chromatography using 30% EtOAc in hexanes as
the eluent to give 0.152 g of (-)-5. This compound upon
completion of the sequence of the reactions described above
gave (-)-12 (0.19 g, 64%). Mp: 138-140 °C. [R]D ) -106 (c )
0.395, CH2Cl2). 1H NMR (CDCl3): δ 1.60-1.80 (m, 2 H), 1.85-
1.95 (m, 2 H), 2.03-2.10 (m, 2 H), 2.28-2.33 (m, 2 H), 2.35 (s,
3 H), 2.48-2.50 (m, 2 H), 3.20-3.40 (m, 2 H), 3.60 (s, 3 H),
3.68 (s, 3 H), 6.75 (s, 1 H), 7.20-7.34 (m, 6 H), 7.46 (d, J ) 8.8
Hz, 2 H), 8.07 (d, J ) 8.8 Hz, 2 H), 8.78 (br t, 1 H, NH). Anal.
(C30H35N5O8‚0.4CH2Cl2) C, H, N.
(e) 4-Eth yl-5-m eth oxyca r bon yl-1-{N-[3-[4-(4-m eth oxy-
ca r bon yl)-4-p h en ylp ip er id in -1-yl]p r op yl]ca r boxa m id o}-
6-(4-n itr oph en yl)-2-oxo-1,2,3,6-tetr ah ydr opyr im idin e (29).
A mixture of the carboxylic acid 28 (0.350 g, 0.59 mmol), EDC
(0.2264 g, 1.18 mmol, 2 equiv), and DMAP (0.1443 g, 1.18
mmol, 2 equiv) in anhydrous CH2Cl2 was stirred at room
temperature for 2 h. To this was added methanol (5 mL) and
the stirring was continued for 12 h. The reaction mixture was
worked-up and purified using a similar process described above
to obtain the product 29 as a white powder. Yield: 68%. Mp:
75-77 °C. 1H NMR (CDCl3): δ 1.19 (t, J ) 7.5 Hz, 3 H), 1.68-
1.73 (m, 2 H), 1.90-2.00 (m, 2 H), 2.03-2.14 (m, 2 H), 2.32 (t,
J ) 7.1 Hz, 2 H), 2.49-2.53 (m, 2 H), 2.61-2.95 (m, 4 H), 3.22-
P r ep a r a tion of Com p ou n d s 29-30, a n d 31. (a ) 5-(2-
Cya n oeth oxyca r bon yl)-1,6-d ih yd r o-4-eth yl-2-m eth oxy-6-
(4-n itr op h en yl) p yr im id in e (18). A mixture of 2-cyanoethyl
3-{(4-nitrophenyl)methylene}-4-oxopentanoate7 (16; 5.00 g,
16.54 mmol), O-methylisourea hydrogen sulfate (3.422 g, 19.85
mmol), and NaHCO3 (2.78 g, 33.08 mol) in EtOH (70 mL) was
stirred and heated at 85-90 °C for 5 h. The solid was removed
by filtration and ethanol was evaporated from the filtrate. The
residue was redissolved in EtOAc (300 mL), washed with water
(2 × 100 mL), and dried (Na2SO4) and the solvent evaporated.
The crude product was purified by flash column chromatog-
raphy on silica gel using CHCl3/methanol (30:1) as the eluent,

4772 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23
Nagarathnam et al.
1
3.40 (m, 2 H), 3.61 (s, 3 H), 3.69 (s, 3 H), 6.45 (s, 1H), 7.09-
7.35 (m, 5 H), 7.46 (d, J ) 7.8 Hz, 2 H), 8.09 (d, J ) 7.8 Hz, 2
H), 8.79 (br t, 1 H, NH). Anal. (C31H37N5O8‚0.7H2O) C, H, N.
5-Carboxamido-4-ethyl-1-{N-[3-(4-methoxycarbonylphen-
ylpiper idin -1-yl) pr opyl]car boxam ido}-6-(4-n itr oph en yl)-
2-oxo-1,2,3,6-tetr a h yd r op yr im id in e (30). A mixture of car-
boxylic acid 28 (0.350 g, 0.59 mmol), EDC (0.2264 g, 1.18 mmol,
2 equiv), and DMAP (0.1443 g, 1.18 mmol, 2 equiv) in
anhydrous CH2Cl2 was stirred at room temperature for 2 h.
To this was added 40% aqueous NH3 (0.6 mL) and the stirring
was continued for 12 h. The mixture was diluted with CH2Cl2
(100 mL) and washed with saturated aqueous NH4Cl solution
(3 × 20 mL). Solvent was evaporated after drying over MgSO4
and the residue was purified by column chromatography on
silica gel using CHCl3-MeOH-2 M NH3 in MeOH (500/16/8)
as the eluent to obtain the desired product 30 as a pale yellow
powder (0.24 g, 69%). mp 107-109 °C. 1H NMR (CDCl3): δ
1.20 (t, J ) 7.5 Hz, 3 H), 1.66-1.72 (m, 2 H), 1.79-2.00 (m, 3
H), 2.00-2.20 (m, 2 H), 2.29-2.35 (m, 2 H), 2.42-2.60 (m, 2
H), 2.62-2.82 (m, 3 H), 3.20-3.40 (m, 2 H), 3.60 (s, 3 H), 5.70
(br m, 2 H, NH2), 6.59 (s, 1 H), 7.20-7.39 (m, 6 H), 7.52 (d, J
) 7.8 Hz, 2 H), 8.13 (d, J ) 7.8 Hz, 2 H), 8.82 (t, 1 H). Anal.
(C30H36N6O7‚0.8H2O) C, H, N.
4-Eth yl-5-(N-m eth ylca r boxa m id o)-1-{N-[3-(4-m eth oxy-
ca r b on ylp h en ylp ip er id in -1-yl)p r op yl]ca r b oxa m id o}-6-
(4-n itr op h en yl)-2-oxo-1,2,3,6-tetr a h yd r op yr im id in e (31).
Prepared from the carboxylic acid 28 and methylamine fol-
lowing a similar procedure described for compound 30. Yield:
48%. Mp: 160-162 °C. 1H NMR (CDCl3): δ 1.19 (t, J ) 7.5
Hz, 3 H), 1.68-1.73 (m, 2 H), 1.90-2.00 (m, 2 H), 2.03-2.14
(m, 2 H), 2.32 (t, J ) 7.1 Hz, 2 H), 2.49-2.53 (m, 2 H), 2.61-
2.95 (m, 4 H), 2.80 (d, J ) 5 Hz, 3 H), 3.22-3.40 (m, 2 H), 3.61
(s, 3 H), 3.69 (s, 3 H), 5.60 (bs, 1 H, NH), 6.50 (s, 1 H), 7.20-
7.40 (m, 5 H), 7.46 (d, J ) 7.8 Hz, 2 H), 8.09 (d, J ) 7.8 Hz, 2
H), 8.79 (br t, 1 H, NH). Anal. (C31H38N6O7Cl‚1.2CH2Cl2) C,
H, N.
(26). Yield: 71%. Mp: 202-204 °C. H NMR (CDCl3): δ 1.69
(t, J ) 6.9 Hz, 2 H), 1.85-1.90 (m, 2 H), 2.03-2.14 (m, 2 H),
2.30 (s, 3 H), 2.48-2.53 (m, 2 H), 2.76-2.81 (m, 2 H), 3.22-
3.41 (m, 2 H), 3.45 (s, 3 H), 3.61 (s, 3 H), 5.61 (br s, 2 H, NH),
6.61 (s, 1 H, NH), 7.09-7.34 (m, 5 H), 7.51 (d, J ) 7.8 Hz, 2
H), 8.12 (d, J ) 7.8 Hz, 2 H), 8.82 (br t, 1 H, NH). Anal.
(C29H34N6O7‚0.3EtOAc) C, H, N.
1-{N-[3-[4-(4-Met h oxyca r b on yl)-4-p h en ylp ip er id in -1-
yl]p r op yl]ca r boxa m id o}-4-m eth yl-5-(N-m eth ylca r boxa -
m id o)-6-(4-n it r op h en yl)-2-oxo-1,2,3,6-t et r a h yd r op yr im -
1
id in e (27). Yield: 88%. Mp: 168-170 °C. H NMR (CDCl3):
δ 1.66-1.71 (m, 2 H), 1.90-1.95 (m, 2 H), 2.03-2.14 (m, 2 H),
2.23 (s, 3 H), 2.32 (t, J ) 7.1 Hz, 2 H), 2.49-2.53 (m, 2 H),
2.78-2.81 (m, 4 H), 3.22-3.41 (m, 2 H), 3.64 (s, 3 H), 5.58 (br
s, 1 H, NH), 6.56 (s, 1 H, NH), 7.09-7.34 (m, 5 H), 7.47 (d, J
) 7.4 Hz, 2 H), 8.09-8.13 (d, J ) 7.4 Hz, 2 H), 8.83 (br t, 1 H,
NH). Anal. (C30H37N6O7Cl‚1.2CH2Cl2) C, H, N.
(+)-5-Car boxam ido-4-eth yl-1-{N-[3-(4-m eth oxycar bon yl-
4-p h en ylp ip er id in -1-yl) p r op yl]ca r boxa m id o}-6-(4-n itr o-
p h en yl)-2-oxo-1,2,3,6-tetr a h yd r op yr im id in e [(+)-30]. (a )
5-(2-C y a n o e t h o x y c a r b o n y l)-1,6-d i h y d r o -4-e t h y l-2-
m e t h o x y -6-(4-n i t r o p h e n y l)-1-{N -[2-p h e n y le t h y l]-
ca r boxa m id o}p yr im id in e (32). To a stirred solution of 20
(17.5 g, 33.43 mmol) in anhydrous THF (200 mL) at room
temperature under argon atmosphere was added (R)-(+)-R-
methylbenzylamine (4.86 g, 40.11 mmol) and the stirring was
continued for 16 h. Solvent was evaporated from the reaction
mixture and the residue was purified by flash chromatography
on silica gel using toluene/EtOAc (20:3) as the eluent. The first
major product to elute was 32 as a viscous oil (6.11 g, 36%).
1
[R]D ) +299.5 (c ) 1.95, CHCl3). H NMR (CDCl3): δ 1.18 (t,
J ) 7 Hz, 3 H), 1.47 (d, J ) 7 Hz, 3 H), 2.61 (t, 2 H), 2.7-2.92
(m, 2 H), 3.98 (s, 3 H), 4.20-4.32 (m, 2 H), 4.96 (quint, J )
6.5 Hz, 2 H), 6.66 (s, 1 H), 6.82 (d, J ) 6.8 Hz, 1 H, NH), 7.22-
7.36 (m, 5 H), 7.45 (d, J ) 8.6 Hz, 2 H), 8.11 (d, J ) 8.6 Hz, 2
H). The second major compound to elute was 33, the other
diastereomer (5.92 g, 35%). [R]D ) -105.1 (c ) 3.9, CHCl3).
1H NMR (CDCl3): δ 1.20 (t, J ) 7 Hz, 3 H), 1.48 (d, J ) 7 Hz,
3 H), 2.62 (t, 2 H), 2.82 (q, 2 H), 3.94 (s, 3 H), 4.20-4.32 (m,
2 H), 4.96 (quint, J ) 6.5 Hz, 2 H), 6.69 (s, 1 H), 6.84 (d, J )
6.8 Hz, 1 H, NH), 7.22-7.36 (m, 5 H), 7.39 (d, J ) 8.6 Hz, 2
H), 8.06 (d, J ) 8.6 Hz, 2 H).
P r ep a r a tion of P r od u cts 24-27. These products were
synthesized using a similar procedure described for 29-31.
5-(2-Cya n oeth oxyca r bon yl)-1,6-d ih yd r o-2-m eth oxy-4-
m eth yl-6-(4-n itr op h en yl)-1-[(4-n itr op h en yloxy)ca r bon yl]-
1
p yr im id in e (19). Yield : 68%. H NMR (CDCl3): δ 2.50 (s, 3
H), 2.67 (t, J ) 7 Hz, 2 H), 3.97 (s, 3 H), 4.32 (t, J ) 7 Hz, 2
H), 6.34 (s, 1 H), 7.37 (d, J ) 9.2 Hz, 2 H), 7.50 (d, J ) 8.7 Hz,
2 H), 8.18 (d, J ) 8.7 Hz, 2 H), 8.28 (d, J ) 9.2 Hz, 2 H).
5-(2-Cya n oeth oxyca r bon yl)-1-{N-[3-(4-m eth oxyca r bo-
n yl-4-ph en ylpiper idin -1-yl)pr opyl]car boxam ido}-4-m eth -
yl-6-(4-n it r op h e n yl)-2-oxo-1,2,3,6-t e t r a h yd r op yr im i-
(b) (+)-5-(2-Cya n oeth oxyca r bon yl)-1,6-dih yd r o-4-eth yl-
2-m eth oxy-6-(4-n itr op h en yl) p yr im id in e [(+)-18]. To a
stirred solution of 32 (2.62 g, 5.182 mmol) in toluene (40 mL)
was added DBU (0.237, 1.55 mmol) at room temperature and
the resulting solution was heated at 90 °C for 3.5 h. The
solvent was evaporated and the residue was purified by flash
column chromatography on silica gel using CHCl3/EtOAc (9:
1) as the eluent, to give 1.32 g (71%) of (+)-18. [R]D ) + 4.0 (c
) 3.25, CHCl3).
(c) (+)-5-(2-Cya n oeth oxyca r bon yl)-1,6-d ih yd r o-4-eth yl-
2-m eth oxy-6-(4-n itr op h en yl)-1-[(4-n itr op h en yloxy)ca r -
bon yl]p yr im id in e [(+)-20]. Prepared using a similar proce-
dure described earlier to give the product as a white solid (2.25
g, 95%). 1H NMR (CDCl3): δ 1.24 (t, J ) 7 Hz, 3 H), 2.61-
2.68 (m, 2 H), 2.88-2.92 (m, 2 H), 3.97 (s, 3 H), 4.32 (t, J ) 7
Hz, 2 H), 6.34 (s, 1 H), 7.37 (d, J ) 9.2 Hz, 2 H), 7.50 (d, J )
8.7 Hz, 2 H), 8.18 (d, J ) 8.7 Hz, 2 H), 8.28 (d, J ) 9.2 Hz, 2
H). [R]D ) + 317 (c ) 3.9, CHCl3).
(d ) (+)-5-(2-Cya n oeth oxyca r bon yl)-4-eth yl-1-{N-[3-(4-
m eth oxyca r bon yl-4-p h en ylp ip er id in -1-yl)p r op yl]ca r box-
a m id o}-6-(4-n itr op h en yl)-2-oxo-1,2,3,6-tetr a h yd r o p yr i-
m id in e [(+)-23]. Prepared from (+)-20 (3.60 g, 6.878 mmol)
and amine 8 (2.47 g, 8.94 mmol) following a similar procedure
described earlier to obtain the desired product as a white
powder (4.40 g, 98.5%). 1H NMR (CDCl3): δ 1.23 (t, J ) 7.5
Hz, 3 H), 2.0-2.1 (m, 2 H), 2.40-2.95 (m, 12 H), 3.25-3.50
(m, 4 H), 3.65 (s, 3 H), 4.27-4.32 (m, 2 H), 6.64 (s, 1 H), 7.20-
7.33 (m, 5 H), 7.49 (d, J ) 7.8 Hz, 2 H), 8.08 (d, J ) 7.8 Hz, 2
H), 8.70-8.90 (m, 2 H). [R]D ) +112 (c ) 2.15, CHCl3). This
product was used in the next step without further analysis.
1
d in e (22). Yield: 70%. H NMR (CDCl3): δ 2.00-2.10 (m, 2
H), 2.41 (s, 3 H), 2.40-2.95 (m, 10 H), 3.25-3.40 (m, 4 H),
3.62 (s, 3 H), 4.20-4.32 (m, 2 H), 6.71 (s, 1 H), 7.20-7.33 (m,
5 H), 7.49 (d, J ) 7.8 Hz, 2 H), 8.08 (d, J ) 7.8 Hz, 2 H), 8.70-
8.90 (m, 2 H).
1-{N-[3-[4-(4-Met h oxyca r b on yl)-4-p h en ylp ip er id in -1-
yl]p r op yl]ca r b oxa m id o}-4-m et h yl-6-(4-n it r op h en yl)-2-
oxo-1,2,3,6-tetr a h yd r op yr im id in e-5-ca r boxylic Acid (24).
1
Yield: 89%. Mp: 195 °C dec. H NMR (CDCl3): δ 1.60-2.00
(m, 4 H), 2.00-2.20 (m, 2 H), 2.25 (s, 3 H), 2.49-2.53 (m, 2
H), 2.76-2.80 (m, 4 H), 3.34-3.41 (m, 2 H), 3.61 (s, 3 H), 6.60
(s, 1 H, NH), 7.21-7.40 (m, 5 H), 7.40 (d, J ) 7.8 Hz, 2 H),
8.18 (d, J ) 7.8 Hz, 2 H), 8.81 (br t, 1 H, NH), 10.02 (bs, 1 H).
Anal. (C29H33N5O8‚1.05CH2Cl2) C, H, N.
5-E t h oxyca r b on yl-1-{N-[3-[4-(4-m et h oxyca r b on yl)-4-
p h en ylp ip er id in -1-yl]p r op yl]ca r boxa m id o}-4-m eth yl-6-
(4-n itr op h en yl)-2-oxo-1,2,3,6-tetr a h yd r op yr im id in e (25).
1
Yield: 67%. Mp: 76-78 °C. H NMR (CDCl3): δ 1.22 (t, J )
7.2 Hz, 3 H), 1.90-2.10 (m, 4 H), 2.31 (t, J ) 7.1 Hz, 2 H),
2.35 (s, 3 H), 2.49-2.53 (m, 2 H), 2.76-2.80 (m, 2 H), 3.34-
3.41 (m, 2 H), 3.61 (s, 3 H), 4.14 (q, J ) 7.1 Hz, 2 H), 6.74 (s,
1 H, NH), 7.21-7.35 (m, 5 H), 7.48 (d, J ) 7.8 Hz, 2 H), 8.09
(d, J ) 7.8 Hz, 2 H), 8.81 (br t, 1 H, NH). Anal. (C31H37N5O8‚
0.2CH2Cl2) C, H, N.
5-Ca r b oxa m id o-1-{N -[3-[4-(4-m e t h oxyca r b on yl)-4-
p h en ylp ip er id in -1-yl]p r op yl]ca r boxa m id o}-4-m eth yl-6-
(4-n it r o p h e n y l)-2-o x o -1,2,3,6-t e t r a h y d r o p y r im id in e
(e) (+)-5-Ca r boxa m id o-4-eth yl-1-{N-[3-(4-m eth oxyca r -
bon yl-4-p h en ylp ip er id in -1-yl) p r op yl]ca r boxa m id o}-6-(4-

Novel R1a Adrenoceptor-Selective Antagonists. 1
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23 4773
n it r op h en yl)-2-oxo-1,2,3,6-t et r a h yd r op yr im id in e [(+)-
30]. To a stirred solution of (+)-23 (4.40 g, 6.8 mmol) in acetone
(50 mL) at 0 °C was added aqueous NaOH solution (1 N, 27.2
mL, 4 equiv) dropwise and the stirring continued until the
disappearance of the starting material by TLC (1 h). Most of
the acetone from the mixture was evaporated under reduced
pressure while maintaining the temperature at 0 °C and the
pH of the residue was adjusted to 7.0 by the addition of 1 N
HCl. The white precipitate of the carboxylic acid (+)-28 formed
3.72 (s, 3 H), 3.98 (s, 3 H), 6.38 (s, 1 H), 7.24-7.41 (m, 6 H),
8.26-8.34 (m, 2 H).
(b) 79. Yield : 84%. Mp: 65-68 °C. 1H NMR (CDCl3): δ
1.66-1.75 (m, 2 H), 1.90-2.18 (m, 4 H), 2.30-2.44 (m, 5 H),
2.50-2.62 (m, 2 H), 2.80-2.90 (m, 2 H), 3.25-3.44 (m, 2 H),
3.65 (s, 3 H), 3.73 (s, 3 H), 6.70 (s, 1 H), 7.15-7.48 (m, 8 H),
8.81 (b t, 1 H, NH). Anal. (C30H35N4O6Cl) C, H, N.
6-(3-Ch lor oph en yl)-5-m eth oxycar bon yl-1-{N-[3-(4-m eth -
oxyca r bon yl-4-p h en ylp ip er id in -1-yl)p r op yl]ca r boxa m i-
d o}-4-m eth yl-2-oxo-1,2,3,6-tetr a h yd r op yr im id in e (80). (a)
6-(3-Chlorophenyl)-1,6-dihydro-2-methoxy-5-methoxycarbonyl-
1
was filtered and dried under vacuum (3.59 g, 89%). H NMR
(CDCl3): δ 1.07 (t, J ) 7.5 Hz, 3 H), 1.55-1.70 (m, 2 H), 1.72-
1.84 (m, 2 H), 1.84-2.15 (m, 2 H), 2.20-2.40 (m, 4 H), 2.70-
2.90 (m, 2 H), 3.10-3.40 (m, 4 H), 3.51 (s, 3 H), 6.54 (s, 1 H),
7.18-7.38 (m, 6 H), 7.41 (d, J ) 7.8 Hz, 2 H), 8.15 (d, J ) 7.8
Hz, 2 H), 8.79 (br t, 1 H, N H), 10.05 (br S, 1 H, COOH). This
product was used in the next step without further character-
ization.
4-methyl-1-[(4-nitrophenyloxy)carbonyl]pyrimidine
(63).
Yield: 50%. 1H NMR (CDCl3): δ 2.45 (s, 3 H), 3.68 (s, 3 H),
3.95 (s, 3 H), 6.25 (s, 1 H), 6.92-8.30 (m, 8 H).
1
(b) 80 HCl. Yield: 88%. Mp: 132-136 °C. H NMR (CD3-
OD): δ 1.90-2.12 (m, 4 H), 2.38 (s, 3 H), 2.78-2.91 (m, 2 H),
2.94-3.14 (m, 4 H), 3.30-3.40 (m, 2 H), 3.50-3.60 (m, 2 H),
3.72 (s, 3 H), 3.74 (s, 3 H), 6.60 (s, 1 H), 7.20-7.52 (m, 9 H).
Anal. (C30H36N4O6Cl2) C, H, N.
A mixture of carboxylic acid (+)-28 (0.350 g, 0.59 mmol),
EDC (0.226 g, 1.18 mmol, 2 equiv), and DMAP (0.144 g, 1.18
mmol, 2 equiv) in anhydrous CH2Cl2 was stirred at room
temperature for 2 h. To this was added 40% aqueous ammonia
(0.6 mL) and the stirring was continued for 12 h. The mixture
was diluted with CH2Cl2 (100 mL) and washed with saturated
aqueous NH4Cl solution (3 × 20 mL). Solvent was evaporated
from the dried (MgSO4) CH2Cl2 solution and the residue was
purified by column chromatography on silica gel using CHCl3-
MeOH-2 M NH3 in MeOH (500/16/8) as the eluent to give
(+)-30 as a pale yellow powder (0.24 g, 69%). Mp: 107-109
6-(4-Flu or oph en yl)-5-m eth oxycar bon yl-1-{N-[3-(4-m eth -
oxyca r bon yl-4-p h en ylp ip er id in -1-yl)p r op yl]ca r boxa m i-
d o}-4-m eth yl-2-oxo-1,2,3,6-tetr a h yd r op yr im id in e (81). (a )
6-(4-F lu or op h en yl)-1,6-d ih yd r o-2-m et h oxy-5-m et h oxy-
ca r bon yl-4-m eth yl-1-[(4-n itr op h en yloxy)ca r bon yl]p yr i-
1
m id in e (64). Yield: 68%. H NMR (CDCl3): δ 2.45 (s, 3 H),
3.68 (s, 3 H), 3.95 (s, 3 H), 6.25 (s, 1 H), 6.92-8.30 (m, 8 H).
1
(b) 81 HCl. Yield: 84%. Mp: 140-144 °C. H NMR (CD3-
OD): δ 1.90-2.12 (m, 4 H), 2.38 (s, 3 H), 2.78-2.91 (m, 2 H),
2.94-3.14 (m, 4 H), 3.30-3.40 (m, 2 H), 3.50-3.60 (m, 2 H),
3.62 (s, 3 H), 3.66 (s, 3 H), 6.94-7.52 (m, 9 H). Anal.
(C30H36N4O6ClF) C, H, N.
1
°C. H NMR (CDCl3): δ 1.20 (t, J ) 7.5 Hz, 3 H), 1.66-1.72
(m, 2 H), 1.79-2.00 (m, 3 H), 2.00-2.20 (m, 2 H), 2.29-2.35
(m, 2 H), 2.42-2.60 (m, 2 H), 2.62-2.82 (m, 3 H), 3.20-3.40
(m, 2 H), 3.60 (s, 3 H), 5.70 (br m, 2 H, NH2), 6.59 (s, 1 H),
7.20-7.39 (m, 6 H), 7.52 (d, J ) 7.8 Hz, 2 H), 8.13 (d, J ) 7.8
6-(3-Flu or oph en yl)-5-m eth oxycar bon yl-1-{N-[3-(4-m eth -
oxyca r bon yl-4-p h en ylp ip er id in -1-yl)p r op yl]ca r boxa m i-
d o}-4-m eth yl-2-oxo-1,2,3,6-tetr a h yd r op yr im id in e (82). (a )
6-(3-F lu or op h en yl)-1,6-d ih yd r o-2-m et h oxy-5-m et h oxy-
ca r bon yl-4-m eth yl-1-[(4-n itr op h en yloxy)ca r bon yl]p yr i-
Hz, 2 H), 8.82 (t, 1 H). [R]D ) +115.7 (c ) 1.4, CHCl ). Anal.
3
(C30H36N6O7‚0.8H2O) C, H, N.
P r ep a r a tion of Com p ou n d s 77-85. These compounds
were prepared using the general procedure described for 83.
Some final products were characterized as free bases and the
rest of them were characterized as their HCl salts.
1
m id in e (65). Yield: 46%. H NMR (CDCl3): δ 2.50 (s, 3 H),
3.66 (s, 3 H), 3.85 (s, 3 H), 6.30 (s, 1 H), 6.92-7.30 (m, 3 H),
7.35 (d, J ) 7 Hz, 2 H), 7.50 (d, J ) 6.8 Hz, 1 H), 8.20 (d, J )
7 Hz, 2 H).
5-Meth oxycar bon yl-1-{N-[3-(4-m eth oxycar bon yl-4-ph en -
n ylp ip er id in -1-yl)p r op yl]ca r b oxa m id o}-4-m et h yl-6-(4-
m eth ylp h en yl)-2-oxo-1,2,3,6-tetr a h yd r op yr im id in e (77).
(a ) 1,6-Dih yd r o-2-m eth oxy-5-m eth oxyca r bon yl-4-m eth yl-
6-(4-m eth ylp h en yl)-1-[(4-n itr op h en yloxy)ca r bon yl]p yr i-
1
(b) 82 HCl. Yield: 83%. Mp: 120-124 °C. H NMR (CD3-
OD): δ 1.92-2.18 (m, 4 H), 2.38 (s, 3 H), 2.82-2.92 (m, 2 H),
2.95-3.18 (m, 4 H), 3.35-3.42 (m, 2 H), 3.50-3.68 (m, 2 H),
3.70 (s, 3 H), 3.71 (s, 3 H), 6.60 (s, 1 H), 6.95-7.52 (m, 9 H).
Anal. (C30H36N4O6ClF‚0.25C6H14) C, H, N.
1
m id in e (60). Yield: 63%. H NMR (CDCl3): δ 2.33 (s, 3 H),
6-(3,4-Diflu or op h en yl)-5-m eth oxyca r bon yl-1-{N-[3-(4-
m eth oxyca r bon yl-4-p h en ylp ip er id in -1-yl)p r op yl]ca r box-
am ido}-4-m eth yl-2-oxo-1,2,3,6-tetr ah ydr opyr im idin e (83).
(a ) Meth yl 2-{(3,4-Diflu or op h en yl)m eth ylen e}-3-oxobu -
tyr a te (50). A mixture of 3,4-difluorobenzaldehyde (41; 14.2
g, 0.1 mol), methyl acetoacetate (34; 12.2 g, 0.105 mol),
piperidine (0.430 g, 5 mmol), and acetic acid (0.30 g, 5 mmol)
in benzene (150 mL) was stirred and refluxed with a Dean-
Stark trap for 8 h. Benzene was evaporated; the residue was
dissolved in EtOAc (200 mL) and washed with brine (50 mL),
saturated KHSO4 solution (50 mL), and saturated NaHCO3
solution in sequence. The EtOAc solution was dried (MgSO4),
solvent evaporated under reduced pressure, and the residue
purified by column chromatography on silica gel (EtOAc/
hexanes, 10-15%). The product 50 was obtained as a yellow
oil (0.98 g, 98%) and was used in the next step without any
further characterization.
(b ) 6-(3,4-Diflu or op h en yl)-1,6-d ih yd r o-2-m et h oxy-5-
m eth oxyca r bon yl-4-m eth ylp yr im id in e (57). A mixture of
50 (8.8 g, 36.6 mmol), O-methylisourea hydrogen sulfate (9.4
g, 55 mmol), and NaHCO3 (12.3 g, 0.146 mol) in DMF (30 mL)
was stirred and heated at 70 °C for 16 h. The mixture was
cooled, diluted with EtOAc (300 mL), washed with water (5 ×
300 mL) and brine (300 mL), and dried (MgSO4). Solvent was
evaporated and the crude product was purified by flash column
chromatography on silica gel using 10-20% EtOAc in hexanes
as the gradient eluent, to leave the product 57 as an oil (3.82
g, 30%). 1H NMR (CDCl3): δ 2.32, 2.39 (2 s, 3 H), 3.58, 3.64 (2
s, 3 H), 3.72, 3.85 (2 s, 3 H), 5.55 (s, 1 H), 6.13-7.80 (m, 4 H).
2.50 (s, 3 H), 3.72 (s, 3 H), 3.98 (s, 3 H), 6.38 (s, 1 H), 7.24-
7.60 (m, 6 H), 8.26-8.34 (d, J ) 7 H, 2 H).
(b) 77. Yield: 93%. Mp: 43-46 °C. 1H NMR (CDCl3): δ
1.62-1.78 (m, 4 H), 1.90-2.04 (m, 2 H), 2.04-2.16 (m, 2 H),
2.30 (s, 3 H), 2.30-2.36 (m, 2 H), 2.39 (s, 3 H), 2.50-2.58 (m,
2 H), 2.78-2.88 (m, 2 H), 3.24-3.44 (m, 2 H), 3.64 (s, 3 H),
3.70 (s, 3 H), 6.48 (s, 1 H), 6.78 (s, 1 H), 7.05-7.40 (m, 9 H),
8.82 (b t, 1 H, NH). Anal. (C31H38N4O6‚0.5C4H8O2) C, H, N.
5-Meth oxycar bon yl-1-{N-[3-(4-m eth oxycar bon yl-4-ph en -
ylp ip e r id in -1-yl)p r op yl]ca r b oxa m id o}-4-m e t h yl-6-(3-
m eth ylp h en yl)-2-oxo-1,2,3,6-tetr a h yd r op yr im id in e (78).
(a ) 1,6-Dih yd r o-2-m eth oxy-5-m eth oxyca r bon yl-4-m eth yl-
6-(3-m eth ylp h en yl)-1-[(4-n itr op h en yloxy)ca r bon yl]p yr i-
m id in e (61). Yield: 62%. 1H NMR (CDCl3): δ 2.35 (s, 3H),
2.50 (s, 3 H), 3.70 (s, 3 H), 3.98 (s, 3 H), 6.38 (s, 1 H), 7.24-
7.60 (m, 6 H), 8.26-8.34 (d, J ) 7 H, 2 H).
(b) 78 HCl. Yield: 73%. Mp: 130-135 °C. 1H NMR
(CDCl3): δ 1.62-1.78 (m, 4 H), 1.90-2.04 (m, 2 H), 2.04-2.16
(m, 2 H), 2.30 (s, 3 H), 2.30-2.36 (m, 2 H), 2.39 (s, 3 H), 2.50-
2.58 (m, 2 H), 2.78-2.88 (m, 2 H), 3.24-3.44 (m, 2 H), 3.64 (s,
3 H), 3.70 (s, 3 H), 6.48 (s, 1 H), 6.78 (s, 1 H), 7.05-7.40 (m, 9
H), 8.82 (b t, 1 H, NH). Anal. (C31H39N4O6Cl) C, H, N.
6-(4-Ch lor oph en yl)-5-m eth oxycar bon yl-1-{N-[3-(4-m eth -
oxyca r bon yl-4-p h en ylp ip er id in -1-yl)p r op yl]ca r boxa m i-
d o}-4-m eth yl-2-oxo-1,2,3,6-tetr a h yd r op yr im id in e (79). (a )
6-(4-Ch lor op h en yl)-1,6-d ih yd r o-2-m et h oxy-5-m et h oxy-
ca r bon yl-4-m eth yl-1-[(4-n itr op h en yloxy)ca r bon yl]p yr i-
1
m id in e (62). Yield: 63%. H NMR (CDCl3): δ 2.50 (s, 3 H),

4774 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23
Nagarathnam et al.
(c) 6-(3,4-Diflu or op h en yl)-1,6-d ih yd r o-2-m et h oxy-5-
m eth oxyca r bon yl-4-m eth yl-1-[(4-n itr op h en yloxy)ca r bo-
n yl]p yr im id in e (65). To a solution of 57 (2.82 g, 9.52 mmol)
and DMAP (1.16 g, 9.52 mmol) in CH2Cl2 (50 mL), at 0-5 °C,
was added 4-nitrophenyl chloroformate (1.82 g, 9.04 mmol) and
the mixture was allowed to warm to room temperature. After
12 h, solvent was evaporated and the residue was purified by
flash column chromatography (SiO2, EtOAc/hexanes, 10-15%)
to obtain the product 65 as white crystals (3.72 g, 85%), mp
to be a mixture of amine/imine tautomers and was used in
the next step without further characterization.
(c) 5-(Ben zyloxyca r bon yl)-6-(3,4-d iflu or op h en yl)-1,6-
d ih yd r o-4-eth yl-2-m eth oxy-1-[(4-n itr op h en yloxy)ca r bo-
n yl]p yr im id in e (91). To a well-stirred solution of 89 (17.0 g,
44 mmol) and DMAP (6.99 g, 57 mmol) in CH2Cl2 (200 mL)
was added a powder of 4-nitrophenyl chloroformate (11.54 g,
57 mmol) at room temperature. The reaction mixture was
stirred for 12 h and then the solvent was removed in vacuum.
The residue was purified by chromatography (SiO2, EtOAc/
hexanes 10-30%) to get 91 as a colorless viscous oil (12.6 g,
50%). 1H NMR (CDCl3): δ 1.24 (t, J ) 7.2 Hz, 3 H), 2.81-2.98
(m, 3 H), 3.97 (s, 3 H), 5.14 (ABq, dA) 5.08, dB) 5.20, J ) 12.3
Hz, 2 H), 6.28 (s, 3 H), 7.03-7.29 (m, 8 H), 7.35 (d, J ) 9.2
Hz, 2 H), 8.26 (d, J ) 9.2 Hz, 2 H).
1
172-174 °C. H NMR (CDCl3): δ 2.51 (s, 3 H), 3.72 (s, 3 H),
3.97 (s, 3 H), 6.26 (s, 1 H), 7.00-7.30 (m, 3 H), 7.38 (d, J ) 9.3
Hz, 2 H), 8.32 (d, J ) 9.3 Hz, 2 H).
6-(3,4-Diflu or op h en yl)-5-m eth oxyca r bon yl-1-{N-[3-(4-
m eth oxyca r bon yl-4-p h en ylp ip er id in -1-yl)p r op yl]ca r box-
am ido}-4-m eth yl-2-oxo-1,2,3,6-tetr ah ydr opyr im idin e (83).
Prepared from 65 and amine 8 using a similar procedure
described earlier followed by treatment with HCl. Yield: 97%.
Mp: 130-134 °C. 1H NMR (CD3OD): δ 1.92-2.16 (m, 4 H),
2.38 (s, 3 H), 2.82-3.20 (m, 6 H), 3.35-3.68 (m, 4 H), 3.70 (s,
3 H), 3.72 (s, 3 H), 6.60 (s, 1 H), 7.08-7.48 (m, 8 H). Anal.
(C30H35N4O6F2Cl‚0.25H2O) C, H, N.
(d ) 5-(Ben zyloxyca r bon yl)-6-(3,4-d iflu or op h en yl)-1,6-
d i h y d r o -4-e t h y l-2-m e t h o x y -1-{N -[2-p h e n y le t h y l]-
ca r boxa m id o}p yr im id in e (92). To a stirred mixture of 91
(12.6 g, 22.86 mmol) in THF (150 mL) was added a solution of
(R)-(+)-R-methylbenzylamine (3.53 mL, 27.44 mmol) at room
temperature. The stirring was continued for 12 h and the
solvent was evaporated under vacuum. The yellow residue was
dissolved in CHCl3 (200 mL) and washed with 10% K2CO3
solution (2 × 30 mL). The organic layer was dried (Na2SO4)
and solvent was evaporated under vacuum. The resulting
mixture of diastereomers was separated by column chroma-
tography over silica gel with hexanes:ether (9:1 to 4:1). First
major product to elute was 92 as a colorless oil (3.8 g, 60%).
[R]D ) + 267 (c ) 0.76, CHCl3). 1H NMR: δ 1.22 (t, J ) 7.5
Hz, 3 H), 1.52 (d, J ) 6.9 Hz, 3 H), 2.88 (q, J ) 6.0 Hz, 2 H),
3.99 (s, 3 H), 4.99 (m, 1 H), 5.09 (ABq, dA) 5.00, dB) 5.19, J
) 12.6 Hz, 2 H), 6.66 (s, 1 H), 6.99-7.36 (m, 13 H). Second
major product to elute was (-)-5-(benzyloxycarbonyl)-6-(3,4-
diflu or oph en yl)-1,6-dih ydr o-4-et h yl-2-m et h oxy-1-{N-[2-
phenylethyl]carboxamido}pyrimidine (93) (3.2 g, 51.2%).
6-(2,4-Diflu or op h en yl)-5-m eth oxyca r bon yl-1-{N-[3-[4-
(4-m e t h oxyca r b on yl)-4-p h e n ylp ip e r id in -1-yl]p r op yl]-
ca r boxa m id o}-4-m eth yl-2-oxo-1,2,3,6-tetr a h yd r op yr im i-
dine (84). (a) 6-(2,4-Difluorophenyl)-1,6-dihydro-2-methoxy-
5-m eth oxycar bon yl-4-m eth yl-1-[(4-n itr oph en yloxy)car bo-
1
n yl]p yr im id in e (66). Yield: 14%. H NMR (CDCl3): δ 2.51
(s, 3 H), 3.72 (s, 3 H), 4.00 (s, 3 H), 6.60 (s, 1 H), 6.80-7.20
(m, 3 H), 7.40 (d, J ) 9.3 Hz, 2 H), 8.34 (d, J ) 9.3 Hz, 2 H).
1
(b) 84 HCl. Yield: 93%. Mp: 115-118 °C. H NMR (CD3-
OD): δ 1.92-2.14 (m, 4 H), 2.38 (s, 3 H), 2.82-2.92 (m, 2 H),
2.95-3.18 (m, 4 H), 3.35-3.42 (m, 2 H), 3.58-3.68 (m, 2 H),
3.72 (s, 3 H), 3.74 (s, 3 H), 6.66 (s, 1 H), 7.27-7.90 (m, 8 H).
Anal. (C31H36N4O7F2‚1.25C3H6O) C, H, N.
6-(Ben zofu r a za n -5-yl)-5-m et h oxyca r b on yl-1-{N-[3-(4-
m eth oxyca r bon yl-4-p h en ylp ip er id in -1-yl)p r op yl]ca r box-
am ido}-4-m eth yl-2-oxo-1,2,3,6-tetr ah ydr opyr im idin e (85).
(a ) 6-(Ben zofu r a za n -5-yl)-1,6-d ih yd r o-2-m eth oxy-5-m eth -
oxyca r bon yl-4-m eth yl-1-[(4-n itr op h en yloxy)ca r bon yl]-
p yr im id in e (67). Yield: 89%. Mp: 180-183 °C. 1H NMR
(CDCl3): δ 2.54 (s, 3 H), 3.75 (s, 3 H), 3.98 (s, 3 H), 6.37 (s, 1
H), 7.40 (d, J ) 9.3 Hz, 2 H), 7.52 (d, J ) 9.0 Hz, 1 H), 7.68 (s,
1 H), 7.84 (d, J ) 9.0 Hz, 1 H), 8.32 (d, J ) 9.3 Hz, 2 H).
[R]D ) -146.89 (c ) 0.38, CHCl3). 1H NMR(CDCl3):
1.22 (t, J ) 7.2 Hz, 3 H), 1.49 (d, J ) 6.6 Hz, 3 H), 2.88 (q, J
δ
) 6.0 Hz, 2 H), 3.94 (s, 3 H), 5.03 (m, 1 H), 5.11 (ABq, dA
5.02, dB ) 5.19, J ) 12.6 Hz, 2 H), 6.68 (s, 1 H), 6.91-7.34 (m,
13 H).
)
(e) (+)-5-(Ben zyloxyca r bon yl)-6-(3,4-d iflu or op h en yl)-
1,6-d ih yd r o-4-eth yl-2-m eth oxyp yr im id in e [(+)-89]. To a
stirred solution of 92 (1.83 mmol, 1.0 g) in toluene (10 mL)
was added DBU (0.81 mmol, 0.12 mL) at room temperature
and the resulting solution was refluxed for 5 h and then stirred
for 12 h at room temperature. The solvent was evaporated and
the residue was purified by flash column chromatography on
silica gel with 3:1 EtOAc/hexanes as the eluting system to give
(+)-89 (0.56 g, 77%).
1
(b) 85 HCl. Yield: 92%. Mp: 183-185 °C. H NMR (CD3-
OD): δ 1.92-2.14 (m, 4 H), 2.38 (s, 3 H), 2.82-2.92 (m, 2 H),
2.95-3.18 (m, 4 H), 3.35-3.42 (m, 2 H), 3.58-3.68 (m, 2 H),
3.72 (s, 3 H), 3.74 (s, 3 H), 6.70 (s, 1 H), 7.27-7.90 (m, 8 H).
Anal. (C30H35N6O7Cl‚0.25 H2O) C, H, N.
(+)-5-Ca r b oxa m id o-6-(3,4-d iflu or op h en yl)-4-et h yl-1-
{N-[3-(4-m eth oxyca r bon yl-4-p h en ylp ip er id in -1-yl)p r op y-
l]ca r boxa m id o}-2-oxo-1,2,3,6-tetr a h yd r op yr im id in e [(+)-
103]. (a ) Ben zyl 3-[(3,4-Diflu or op h en yl)m eth ylen e]-4-
oxop en ta n oa te (87). A solution of benzyl propionylacetate
(86; 36.3 g, 176 mmol), 3,4-difluorobenzaldehyde (41; 25.0 g,
176 mmol), piperidine (0.86 mL, 9.0 mmol), and acetic acid
(0.49 mL, 9.0 mmol) were refluxed with removal of water using
Dean-Stark apparatus for 5 h. The solvent was removed
under vacuum and the residue was dissolved in EtOAc. It was
washed with water (100 mL) followed by brine (100 mL) and
dried (Na2SO4). Solvent was evaporated to get pale yellow
syrup (60.2 g). It was used in the next step without further
purification.
(f) (+)-5-(Ben zyloxyca r bon yl)-6-(3,4-d iflu r op h en yl)-1,6-
d ih yd r o-4-eth yl-2-m eth oxy-1-[(4-n itr op h en yloxy)ca r bo-
n yl]p yr im id in e [+-(91)]. To a well-stirred solution of (+)-89
(17.0 g, 44.04 mmol) and DMAP (6.99 g, 57.25 mmol) in CH2-
Cl2 (200 mL) was added a powder of 4-nitrophenyl chlorofor-
mate (11.54 g, 57.25 mmol) at room temperature. The reaction
mixture was stirred for 12 h and then the solvent was
evaporated under vacuum. The residue was purified by chro-
matography (SiO2, EtOAc/hexanes 10-30%) to get (+)-91 as
a colorless viscous oil (19.3 g, 76%).
(g) (+)-5-(Ben zyloxyca r bon yl)-6-(3,4-d iflu or op h en yl)-
4-eth yl-1-{N-[3-(4-m eth oxyca r bon yl-4-p h en ylp ip er id in -
1-yl)p r op yl]ca r boxa m id o}-2-oxo-1,2,3,6-tetr a h yd r op yr i-
m id in e [(+)-99]. To a stirred mixture of (+)-91 (0.55 g, 1.12
mmol) in THF (5 mL) was added a solution of 3-[4-methoxy-
carbonyl-4-phenylpiperidin-1-yl]propylamine (8; 0.31 g, 1.12
mmol) in THF (5 mL) at room temperature. The stirring was
continued for 12 h. A solution of 10% HCl in water (2 mL)
was added and stirred for 2 h. The solvent was then evaporated
under vacuum and the residue was extracted with ethyl
acetate (3 × 10 mL). It was washed with 10% aq KOH solution
and dried (Na2SO4) and solvent was evaporated under vaccum
to obtain (+)-99 as a white foam (0.73 g, 96.6%), the purity of
(b) 5-(Ben zyloxyca r bon yl)-6-(3,4-d iflu or op h en yl)-1,6-
d ih yd r o-4-eth yl-2-m eth oxyp yr im id in e (89). A suspension
of 87 (16.0 g, 48.0 mmol), O-methylisourea hydrogen sulfate
(16.65 g, 97 mmol), and NaHCO3 (16.3 g, 130 mmol) in DMF
(190 mL) was stirred at 70 °C for 20 h. After cooling to room
temperature, the mixture was filtered and the filtrate was
diluted with EtOAc (300 mL), then washed with water (4 ×
100 mL) and brine (200 mL), and dried (Na2SO4). After
removal of solvents, the residue was purified by column
chromatography (SiO2, EtOAc/hexanes, 10-30%) to get 89 as
which was characterized as its HCl salt. Anal. (C37H41
-
1
a colorless oil (10.6 g, 58%). The H NMR analysis showed it
ClF2N4O6‚0.5CHCl3) C, H, N.

Novel R1a Adrenoceptor-Selective Antagonists. 1
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23 4775
(h ) 6-(3,4-Diflu or op h en yl)-4-eth yl-1-{N-[3-(4-m eth oxy-
ca r bon yl-4-p h en ylp ip er id in -1-yl)p r op yl]ca r boxa m id o}-
2-oxo-1,2,3,6-tetr ah ydr opyr im idin e-5-car boxylic Acid [(+)-
101]. To a suspension of 10% Pd-C (0.14 g, 20% by wt) in
MeOH (3 mL) was added the solution of (+)-99 at room
temperature with constant stirring. A balloon filled with H2
was attached and the reaction mixture was stirred for 48 h.
The black suspension was filtered through a pad of Celite and
the filtrate was concentrated under vacuum. The residue was
purified by column chromatography (SiO2, 10% MeOH in
EtOAc) to obtain (+)-101 as a white solid. mp 184-186 °C.
[R]D ) + 142 (c ) 0.25, CHCl3). Anal. (C30H35ClF2N4O6‚
0.3CHCl3) C, H, N.
described earlier to give (+)-90 as a viscous oil (6.15 g, 78%).
[R]D ) + 296 (c ) 1.07 g, CHCl3).
(f) (+)-5-(Ben zyloxyca r bon yl)-6-(2,4-d iflu or op h en yl)-
1,6-d ih yd r o-4-eth yl-2-m eth oxy-1-[(4-n itr op h en yloxy)ca r -
bon yl]p yr im id in e [(+)-94]. Prepared from (+)-90 (4.1 g,
10.62 mmol) following a similar procedure described earlier
(5.37 g, 92%).
(g) (+)-5-(Ben zyloxyca r bon yl)-6-(2,4-d iflu or op h en yl)-
4-eth yl-1-{N-[3-(4-m eth oxyca r bon yl-4-p h en ylp ip er id in -
1-yl)p r op yl]ca r boxa m id o}-2-oxo-1,2,3,6-tetr a h yd r op yr i-
m id in e [(+)-100]. Prepared from (+)-94 (0.55 g, 1.12 mmol)
and 3-[4-methoxycarbonyl-4-phenylpiperidin-1-yl]propylamine
(8; 0.31 g, 1.12 mmol) followed by treatment with HCl, using
a similar procedure described earlier. Yield: 99%. Mp: 50-
54 °C. [R]D ) +109 (c ) 0.98, CHCl3).
(h ) 6-(2,4-Diflu or op h en yl)-4-eth yl-1-{N-[3-(4-m eth oxy-
ca r bon yl-4-p h en ylp ip er id in -1-yl)p r op yl]ca r boxa m id o}-
2-oxo-1,2,3,6-tetr ah ydr opyr im idin e-5-car boxylic Acid [(+)-
102]. Prepared using a similar procedure described earlier for
(+)-102. Yield: 97%. Mp: 145 °C dec. [R]D ) +148 (c ) 1.1,
CHCl3).
(i) (+)-5-Ca r boxa m id o-6-(3,4-d iflu or op h en yl)-4-eth yl-
1-{N-[3-(4-m eth oxyca r bon yl-4-p h en ylp ip er id in -1-yl)p r o-
p yl]ca r b oxa m id o}-2-oxo-1,2,3,6-t et r a h yd r op yr im id in e
[(+)-103]. To a solution of carboxylic acid (+)-101 (0.22 g, 0.375
mmol) in CH2Cl2 (3 mL) were added DMAP (0.14 g, 1.12 mmol)
and EDC (0.21 g, 1.12 mmol) under argon and the resulting
solution was stirred at room temperature for 2 h. To this was
then added saturated NH4OH (0.3 mL) and the solution was
stirred for 48 h. The solution was washed with water (5 mL)
and dried over (Na2SO4). The solvent was evaporated under
vacuum and the residue was purified by column chromatog-
raphy (SiO2, 10% MeOH in CHCl3) to obtain (+)-103 as a white
solid (0.1 g, 45%). HCl salt mp 136-138 °C. [R]D ) +111.44 (c
(+)-5-Ca r b oxa m id o-6-(2,4-d iflu or op h en yl)-4-et h yl-1-
{N-[3-(4-m et h oxyca r b on yl-4-p h en ylp ip er id in -1-yl)p r o-
p yl]ca r b oxa m id o}-2-oxo-1,2,3,6-t et r a h yd r op yr im id in e
[(+)-104]. Prepared from (+)-102 (0.22 g, 0.375 mmol) using
a similar procedure described earlier. Yield: 58%. Mp: 72-
1
1
) 0.18, MeOH). H NMR (CDCl3): δ 1.21 (t, J ) 7.5 Hz, 3 H),
76 °C. [R]D ) +131.7 (c ) 0.86, CHCl3). H NMR (CDCl3): δ
1.60-1.75 (m, 2 H), 1.92-2.10 (m, 2 H), 2.33 (t, J ) 6.6 Hz, 2
H), 2.44-2.52 (m, 2 H), 2.53-2.84 (m, 4 H), 3.27-3.32 (m, 2
H), 3.60 (s, 3 H), 5.60 (br s, 2 H), 6.47 (s, 1 H), 7.05-7.33 (m,
8 H), 8.80 (br t, 1 H). Anal. (C30H35ClF2N4O6‚1.0CHCl3) C, H,
N.
1.21 (t, J ) 7.5 Hz, 3 H), 1.60-1.75 (m, 2 H), 1.95-2.0 (m, 2
H), 2.00-2.20 (m, 2 H), 2.30 (t, J ) 6.6 Hz, 2 H), 2.44-2.60
(m, 2 H), 2.58-2.84 (m, 4 H), 3.27-3.35 (m, 2 H), 3.60 (s, 3
H), 6.00 (br s, 2 H), 6.55 (s, 1 H), 6.70-6.90 (m, 2 H), 7.05-
7.33 (m, 6 H), 8.50 (s, 1 H), 8.85 (br t, 1 H, NH). (C30H35
-
(+)-5-Ca r b oxa m id o-6-(2,4-d iflu or op h en yl)-4-et h yl-1-
{N-[3-(4-m et h oxyca r b on yl-4-p h en ylp ip er id in -1-yl)p r o-
p yl]ca r b oxa m id o}-2-oxo-1,2,3,6-t et r a h yd r op yr im id in e
[(+)-104]. (a ) Ben zyl 3-[(2,4-Diflu or op h en yl)m eth ylen e]-
4-oxop en ta n oa te (88). Prepared from benzyl propionylac-
etate (157 g, 0.758 mol) and 2,4-difluorobenzaldehyde (107.65
g, 0.758 mol) following a similar procedure described above
(251 g).
(b) 5-(Ben zyloxyca r bon yl)-6-(2,4-d iflu or op h en yl)-1,6-
d ih yd r o-4-eth yl-2-m eth oxyp yr im id in e (90). Prepared us-
ing a similar procedure described above and the product was
obtained as a pale yellow oil (39 g, 42%).
ClF2N4O6‚0.9 CHCl3) C, H, N.
Biologica l Meth od s. Bin d in g Assa ys: Equilibrium com-
petition binding assays were performed in membrane prepara-
tions from cells lines expressing the recombinant human, rat,
and dog25 R1 adrenoceptors using [3H]prazosin as ligand as
described elsewhere.6,10 The affinities at the L-type calcium
channel were determined from the displacement of [3H]-
nitrendipine from rat brain membrane preparations.30 Binding
affinities (Ki) at the human R2a, R2b, and R2c adrenoceptors,
histamine H1 and H2, and 5HT 1A, 1B, 1D, and 2A receptors
were determined by radioligand competition binding assays
in membrane preparations of cells expressing the human
recombinant receptors, as described elsewhere.31-36 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.
(c) 5-(Ben zyloxyca r bon yl)-6-(2,4-d iflu or op h en yl)-1,6-
d ih yd r o-4-eth yl-2-m eth oxy-1-[(4-n itr op h en yloxy)ca r bo-
n yl]p yr im id in e (94). Prepared from 90 (22.5 g, 59.3 mmol)
and 4-nitrophenyl chloroformate (15.3 g, 75.8 mmol) using a
similar procedure described above to give the product as a
F u n ction a l r1 An ta gon ism in Isola ted Ra t, Dog, a n d
Hu m a n P r osta te Tissu es: Assays were performed using
phenylephrine (rat and dog prostates) or A6160337 (human
prostate) as the agonists, and Kb values were determined as
described previously.38
1
viscous oil (32.0 g, 98%). H NMR (CDCl3): δ 1.24 (t, J ) 7.2
Hz, 3 H), 2.81-3.00 (m, 2 H), 4.00 (s, 3 H), 5.14 (ABq, dA
)
5.08, dB ) 5.16, J ) 12.3 Hz, 2 H), 6.59 (s, 1 H), 6.75-6.81 (m,
2 H), 7.18-7.40 (m, 8 H), 8.28 (d, J ) 9.0 Hz, 2 H).
[3H]P r a zosin /[125I]HEAT Bin d in g in Hu m a n a n d Dog
P r osta te Mem br a n es: Competition binding assays in human
prostate membrane preparations were performed using [3H]-
prazosin and in rat and dog prostate membranes using [125I]-
(d ) 5-(Ben zyloxyca r bon yl)-6-(2,4-d iflu or op h en yl)-1,6-
d ih yd r o-4-e t h yl-2-m e t h oxy-1-{N -[2-p h e n yle t h yl]ca r -
boxa m id o}p yr im id in e (95). To a stirred solution of 94 (32
g, 58.17 mmol) in CH2Cl2 (200 mL) was added (R)-(+)-R-
methylbenzylamine (9.16, 75.6 mmol) at room temperature
and the stirring was continued for 12 h. The mixture was
diluted with CH2Cl2 (200 mL) and washed with 0.5 N NaOH
solution (2 × 60 mL). The organic layer was dried (Na2SO4)
and filtered and solvent evaporated. The resulting mixture of
diastereomers was separated by column chromatography
(SiO2, 3% EtOAc in toluene). The first major product to elute
was 95 (12.15 g, 38%). [R]D ) + 214 (c ) 1.5, CHCl3). 1H NMR
(CDCl3) δ 1.13 (t, J ) 7.5 Hz, 3 H), 1.43 (d, J ) 7 Hz, 3 H),
2.78 (q, J ) 6.0 Hz, 2 H), 3.97 (s, 3 H), 4.99 (m, 1 H), 5.09
(ABq, dA ) 5.00, dB ) 5.19, J ) 12.6 Hz, 2 H), 6.76 (s, 1 H),
6.66-7.40 (m, 13 H). The second major product to elute
was the other diastereomer 96 and no effort was made to
isolate it.
HEAT as described previously.7,
29
In Vitr o Meta bolism Exp er im en ts: The in vitro metabo-
lism was studied using suspensions of freshly isolated hepa-
tocytes and microsomal preparations from rat, dog, and
human. The compounds were incubated with liver microsomal
protein and NADPH for 60 min. Following centrifugation, the
supernatant was dried, reconstituted with 30% acetonitrile,
and analyzed by electrospray LC-MS/MS.
In Situ Ra t P r osta te Exp er im en t: Male Sprague-
Dawley rats (300-400 g) were anesthetized with urethane and
placed on a thermostatically controlled heating pad to main-
tain rectal temperature at 37 °C. A short piece of PE 205
tubing was placed through a small incision in the trachea to
facilitate breathing, and the left femoral vein was cannulated
for drug administration. The prostate was exposed through a
midline incision, freed from adherent connective tissue, and
the bladder neck suture was placed through the rear aspect
(e) (+)-5-(Ben zyloxyca r bon yl)-6-(2,4-d iflu or op h en yl)-
1,6-d ih yd r o-4-eth yl-2-m eth oxyp yr im id in e [(+)-90]. Pre-
pared from 95 (11.15 g, 20.41 mmol) using a similar procedure

4776 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23
Nagarathnam et al.
Tang, R.; Lepor, H. Identification of a Dihydropyridine as a
Potent R1a Adrenoceptor Selective Antagonist that Inhibits
Phenylephrine-Induced Contraction of the Human Prostate. J .
Med. Chem. 1998, 41, 2643-2650.
and secured to the tail. The anterior portion of the prostate
was attached to a force transducer, and a resting tension of 2
g was applied to the tissue. Animals were pretreated with
atropine (1 mg/kg) and prolanolol (1 mg/kg). Preliminary
experiments demonstrated that responses to phenylephrine
(10 µg/kg) and (R)-A-6160330 (30 ng/kg) were stable for at least
5 h. For AD50 (dose of an antagonist to produce 50% inhibition)
determinations, animals were treated with rising noncumula-
tive doses of antagonist at 20-min intervals. Agonist was
administered 5 min after each antagonist dose. AD50 values
were determined with GraphPad Prism. In the duration of
action studies, agonist was administered 5 min following
antagonist and every 30 min thereafter for up to 4 h.
In Vivo F u n ction a l Assa ys: Male mongrel dogs (9-14 kg)
were anesthetized with pentobarbital sodium (35 mg/kg, iv
plus 4-5 mg/kg/h iv infusion). The dogs were intubated and
ventilated with room air using a Harvard instruments positive
displacement large animal ventilator. Polyethylene catheters
were placed in the aorta via the femoral artery and vena cava
via the femoral veins (two catheters, one in each vein) for the
measurement of arterial pressure and the administration of
drugs, respectively. A Millar microtip pressure transducer was
advanced into the urethra via the bladder dome and positioned
so that the tip of the transducer was in the prostatic urethra.
The position of the catheter was verified by gently squeezing
the prostate and noting the large change in urethral pressure.
The catheter was held in position by ligatures at the bladder
dome, bladder neck, and distal urethra. Phenylephrine, an R1
adrenergic agonist, was administered intravenously (0.1-300
mg/kg, bolus) in order to construct control dose-response
curves for changes in intraurethral pressure (IUP) and dias-
tolic blood pressure (DBP). Inhibition of phenylephrine dose-
response curves by successive doses of antagonist (30, 100, 300
mg/kg, iv) was determined for both IUP and DBP. The potency
is given as the Kb (µg/kg) as determined by the method of
Arunlaksana and Schild.39 Relative selectivity was calculated
as the ratio of DBP and IUP Kb values.
(8) Nagarathnam, D.; Wetzel, J . M.; Miao, S. W.; Marzabadi, M.
R.; Chiu, G.; Wong, W. C.; Hong, X.; Fang, J .; Forray, C.;
Branchek, T. A.; Heydorn, W. E.; Chang, R. S. L.; Broten, T.;
Schorn, T. W.; Gluchowski, C. Design and Synthesis of Novel
Alpha-1a Adrenoceptor Selective Dihydropyridine Antagonists
for the Treatment of Benign Prostatic Hyperplasia. J . Med.
Chem. 1998, 41, 5320-5333.
(9) Forray, C.; Bard, J . A.; Wetzel, J . M.; Chiu, G.; Shapiro, E.; Tang,
R.; Lepor, H.; Hartig, P. R.; Weinshank, R. L.; Branchek, T. A.;
Gluchowski, C. The R1 adrenoceptor that mediates smooth
muscle contraction in human prostate has the pharmacological
properties of the cloned human R1c subtype. Mol. Pharmacol.
1994, 45, 703-708.
(10) Gong, G.; Chiu, G.; Gluchowski, C.; Branchek, T.; Hartig, P.;
Pettinger, W. A.; Forray, C. R1c-Adrenergic Antagonists and
Orthostatic Hypotension in the Rat. Faseb J . 1994, 8, A353.
(11) Lepor, H. Role of Alpha-Adrenergic Blockers in the Treatment
of Benign Prostatic Hyperplasia. Prostate Suppl. 1990, 3, 75-
84.
(12) J ankegt, R. A.; Chapple, C. R. Efficacy and safety of the Alpha-1
Blocker Doxazosin in the Treatment of Benign Prostatic Hyper-
plasia. Analysis of 5 Studies. Eur. Urol. 1993, 24, 319-325.
(13) Lepor, H. Long-Term Efficacy and Safety of Terazosin in Patients
with Benign Prostatic Hyperplasia. Urology 1995, 45, 406-413.
(14) Kawabe, K.; Ueno, A.; Takimoto, Y.; Aso, Y.; Kato, H.; Use of
an Alpha-1 blocker, YM617, in the Treatment of Benign Prostatic
Hypertrophy. J . Urol. 1990, 144, 908-912.
(15) Moriyama, N.; Akiyama, K.; Murata, S.; Taniguchi, J .; Ishida,
N.; Yamazaki, S.; Kawabe, K. KMD-3213, a novel R1A-adreno-
ceptor antagonist, potently inhibits the functional R1-adreno-
ceptor in human prostate. Eur. J . Pharmacol. 1997, 331, 39-
42.
(16) Elworthy, T. R.; Ford, A. P. D. W.; Bantle, G. W.; Morgans, J r.,
D. J .; Ozer, R. S.; Palmer, W. S.; Repke, D. B.; Romero, M.;
Sandoval, L.; Sjogren, E. B.; Talama´s, F. X.; Vazquez, A.; Wu,
H.; Arredondo, N. F.; Blue, J r., D. R.; DeSousa, A.; Groos, L.
M.; Kava, M. S.; Lesnick, J . D.; Vimont, R. L.; Williams, T. J .;
Zhu, Q.-M.; Pfister, J . R.; Clarke, D. E. N-Arylpiperazinyl-N′-
propylamino Derivatives of Heteroaryl Amides as Functional
Uroselective R1-Adrenoceptor Antagonists. J . Med. Chem. 1997,
40, 2674-2687.
(17) Adkison, K. K.; Halm, K. A.; Shaffer, J . E.; Drewry, D.;
Sinhababu, A. K.; Bermann, J . Discovery of a potent and
selective R1A Antagonist. Utilization of a Rapid Screening
Method to Obtain Pharmacokinetic Parameters. In Integration
of Pharmaceutical Discovery and Development: Case Studies;
Borchardt et al., Ed.; Plenum Press: New York, 1998; pp 423-
443.
P h a r m a cok in etic Assa ys: Male Sprague-Dawley rats
(0.2-0.25 kg) and male beagle dogs (ca. 8 kg) were dosed with
1-3 mg/kg iv and 3-10 mg/kg oral doses (3-4 animals), and
the plasma samples were analyzed from 0.08-24 h, using
standard protocols either by radioreceptor assay or by LC-
MS/MS quantification. Computation of pharmacokinetic pa-
rameters was performed with the aid of TOPFIT software.
(18) Meyer, M. D.; Altenbach, R. J .; Basha, F. Z.; Caroll, W. A.; Drizin,
I.; Elmore, S. W.; Ehrlich, P. P.; Lebold, S. A.; Tietje, K.; Sippy,
K. B.; Wendt, M. D.; Plata, D. J .; Plagge, F.; Buckner, S. A.;
Brune, M. E.; Hancock, A. A.; Kerwin, J r., J . F. Synthesis and
Pharmacological Characterization of 3-[2-(3aR,9bR)-cis-6-
Methoxy-2,3,3a,4,5, 9b-hexahydro-1H-benz[e]isoindol-2-yl)eth-
yl]pyrido[3′,4′:4, 5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione (A-
131701): A Uroselective R1a Adrenoceptor Antagonist for the
Symptomatic Treatment of Benign Prostatic Hyperplasia. J .
Med. Chem. 1997, 40, 3141-3143.
(19) Kenny, B. A.; Naylor, A. M.; Carter, A. J .; Read, A. M.;
Greengrass, P. M.; Wyllie, M. G. Effects of alpha-1 adrenoceptor
antagonists on prostatic pressure and blood pressure in anaes-
thetized dog. Urology 1994, 44, 52-57.
(20) Blue, D.; Zhu, Q. M.; Isom, P.; Young, S.; Larson, M.; Clarke, D.
Effect of a1 adrenoceptor (R1-AR) antagonists in dog prostate/
blood pressure models. Faseb J . 1996, 10, A425.
(21) Atwal, K. S.; Rovnyak, G. C.; Kimball, D. S.; Floyd, D. M.;
Moreland, S.; Swanson, B. N.; Gougoutas, J . Z.; Schwartz, J .;
Smillie, K. S.; Malley, M. F. Dihydropyrimidine Calcium Chan-
nel Blockers: 2. 3-Substituted-4-aryl-1,4-dihydro-6-methyl-5-
pyrimidinecarboxylic Acid Esters as Potent Mimics of Dihydro-
pyrimidines. J . Med. Chem. 1990, 33, 2629-2635.
(22) Atwal, K. S.; Rovnyak, G. C.; Schwartz, J .; Moreland, S.;
Hedberg, A.; Gougoutas, J . Z.; Malley, M. F.; Floyd, D. Dihy-
dropyrimidine Calcium Channel Blockers: 2-Heterosubstituted
4-Aryl-1,4-dihydro-6-methyl-5-pyrimidinecarboxylic Acid Esters
as Potent Mimics of Dihydropyrimidines. J . Med. Chem. 1990,
33, 1510-1515.
(23) Atwal, K. S.; Rovnyak, G. C.; O′Reilly, B. C.; Schwartz, J .
Substituted 1,4-Dihydropyrimidines. 3. Synthesis of Selectively
Functionalized 2-Hetero-1,4-dihydropyrimidines. J . Org. Chem.
1989, 54, 5898-5907.
(24) Wermuth, C. G. The Practice of Medicinal Chemistry; Academic
Press: New York, 1996; Chapter 30.
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 radioligand
displacements assays. We also thank Dr. J ohn Zgombick
for providing us with the serotonin cross-reactivity data.
We thank Dr. Roger Freidinger, Dr. Douglas Pettibone,
and Dr. Thomas Baillie (Merck & Co.) for helpful
discussions.
Refer en ces
(1) Kirby, R. S.; Christmas, T. J . Benign Prostatic Hyperplasia;
Gower Medical Publishing: London, England, 1993.
(2) 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.
(3) Garraway, W. M.; Collins, G. N.; Lee, R. J .; High Prevalence of
Benign Prostatic Hypertrophy in the Community. Lancet 1991,
338, 469-471.
(4) Kenny, B.; Ballard, S.; Blagg, J . Fox, D. Pharmacological Options
in the Treatment of Benign Prostatic Hyperplasia J . Med. Chem.
1997, 40, 1293-1315.
(5) Monda, J . M.; Oesterling, J . E. Medical Management of Benign
Prostatic Hyperplasia. Infect. Urol. 1994, 47-59.
(6) Wetzel, J . M.; Miao, S. W.; Forray, C.; Borden, L. A.; Branchek,
T. A.; Gluchowski, C. Discovery of R1a-Adrenergic Receptor
Antagonists Based on the L-Type Ca2+ Channel Antagonist
Niguldipine. J . Med. Chem. 1995, 38, 1579-1581.
(7) Wong, W. C.; Chiu, G.; Wetzel, J . M.; Marzabadi, M. R.;
Nagarathnam, D.; Wang, D.; Fang, J .; Miao, S. W.; Hong, X.;
Forray, C.; Vaysse, P. J .-J .; Branchek, T. A.; Gluchowski, C.;

Novel R1a Adrenoceptor-Selective Antagonists. 1
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23 4777
(25) Laz, T. M.; Forray, C.; Smith, K. E.; Bard, J . A.; Vaysse, P. J .;
Branchek, T. A.; Weinshank, R. L. The rat homologue of the
bovine alpha-1c-adrenergic receptor shows the pharmacological
properties of the classical alpha-1A subtype. Mol. Pharmacol.
1994, 46, 414-422.
(33) Gajtkowski, G. A.; Norris, D. B.; Rising, T. J .; Wood, T. P. Specific
binding of 3H-tiotidine to histamine H2 receptors in guinea pig
cerebral cortex. Nature 1983, 304, 65-67.
(34) Fargin, A.; Raymond, J .; Lohse, M.; Kobilka, B.; Caron, M.;
Lefkowitz, R. The genomic clone G-21, which resembles the
R-adrenergic receptor sequence, encodes the 5-HT1a receptor.
Nature 1988, 335, 358-360.
(26) Properties of recombinant R1 receptors in dog will be published
elsewhere.
(27) Buckner, S. A.; Oheim, K.; Morse, P.; Knepper, S.; Hancock, A.
A. Alpha-1-adrenoceptor induced contracility in rat aorta is
mediated by the alpha-1D subtype. Eur. J . Pharmacol. 1996,
297, 241-248.
(28) Andersson, K. E.; Lepor, H.; Wyllie, M. G. Prostatic R1-Adreno-
ceptors and Uroselectivity. Prostate 1996, 30, 202-215.
(29) Smith, A. P.; Lee, N. M.; Loh, H. H. In Principles of Pharmacol-
ogy; Munson, P. L., Ed.; Chapman and Hall: New York; pp 399-
416.
(30) Bolger, G. T.; Gengo, P.; Klockowski, R.; Luchowski, E.; Siegel,
H.; J anis, R. A.; Triggle, A. M.; Triggle, D. J . Characterization
of Binding of the Ca2+ Channel Antagonist, [3H]Nitrendipine,
to Guinea-Pig Ileal Smooth Muscle. J . Pharmacol. Exp. Ther.
1983, 225, 291-309.
(31) Weinshank, R. L.; Zgombick, J . M.; Macchi, M.; Adham, N.;
Lichtblau, H.; Branchek, T. A.; Hartig, P. R. Cloning, Expression,
and Pharmacological Characterization of a Human R2b-Adren-
ergic Receptor. Mol. Pharmacol. 1990, 38, 681-688.
(32) Chang, R. S.; Tran, V. T.; Snyder, S. H. Heterogeneity of
histamine H1-receptors: species variations in [3H]mepyramine
binding of brain membranes. J . Neurochem. 1979, 32, 1653-
1663.
(35) Weinshank, R. L.; Zgombick, J . M.; Macchi, M. J .; Branchek, T.
A. Human serotonin 1D receptor is encoded by a subfamily of
two distinct genes: 5-HT1DR and 5-HT1Dâ. Proc. Natl. Acad. Sci.
U.S.A. 1992, 3630-3634.
(36) Branchek, T.; Adham, N.; Macchi, M.; Kao, H. T.; Hartig, P. R.
[3H]-DOB(4-bromo-2,5-dimethoxyphenylisopropylamine) and [3H]-
Ketanserin label two affinity states of the cloned human 5-hy-
droxytryptamine2 receptor. Mol. Pharmacol. 1990, 38, 604-609.
(37) Knepper, S. M.; Buckner, S. A.; Brune, M. E.; DeBernardis, J .
F.; Meyer, M. D.; Hancock, A. A. A-61603, a potent alpha-1
adrenergic receptor agonist, selective for the alpha-1a receptor
subtype. J . Pharmacol. Exp. Ther. 1995, 274, 97-103.
(38) O′Malley, S. O.; Chen. T. B.; Francis, B. E.; Gibson, R. E.; Burns,
H. D.; DiSalvo, J .; Bayne, M. L.; Wetzel, J . M.; Nagarathnam,
D.; Marzabadi, M. R.; Gluchowski, C.; Chang. R. S. L. Charac-
terization of Specific Binding of [125I]-L-762,459, A Selective
Alpha-1A Radioligand, to Rat and Human Tissues. Eur. J .
Pharmacol. 1998, 348, 287-295.
(39) Arulaksana, O.; Schild, H. O. Some quantitative uses of drug
antagonists. Br. J . Pharmacol. 1959, 14, 48-58.
J M990200P