Design and synthesis of novel α(1a) adrenoceptor-selective antagonists. 2. Approaches to eliminate opioid agonist metabolites via modification of linker and 4-methoxycarbonyl-4-phenylpiperidine moiety

Article abstract of DOI:10.1021/jm990201h

We have previously described compound 1a as a high-affinity subtype selective α(1a) antagonist. In vitro and in vivo evaluation of compound 1a showed its major metabolite to be a μ-opioid agonist, 4-methoxycarbonyl-4- phenylpiperidine (3). Several dihydropyrimidinone analogues were synthesized with the goal of either minimizing the formation of 3 by modification of the linker or finding alternative piperidine moieties which when cleaved as a consequence of metabolism would not give rise to μ-opioid activity. Modification of the linker gave several compounds with good {1a) binding affinity (K(i) = < 1 nM) and selectivity (>300 fold over α(1b) and α(1d)). In vitro analysis in the microsomal assay revealed these modifications did not significantly affect N-dealkylation and the formation of the piperidine 3. The second approach, however, yielded several piperidine replacements for 3, which did not show significant μ-opioid activity. Several of these compounds maintained good affinity at the α(1a) adrenoceptor and selectivity over α(1b) and α(1d). For example, the piperidine fragments of (+)-73 and (+)-83, viz. 4-cyano-4-phenylpiperidine and 4-methyl-4-phenylpiperidine, were essentially inactive at the μ-opioid receptor (IC₅₀ > 30 μM vs 3 μM for 3). Compounds (+)-73 and (+)-83 were subjected to detailed in vitro and in vivo characterization. Both these compounds, in addition to their excellent selectivity (> 880-fold) over α(1b) and α(1d), also showed good selectivity over several other recombinant human G-protein coupled receptors. Compounds (+)-73 and (+)-83 showed good functional potency in isolated human prostate tissues, with K(b)s comparable to their in vitro α(1a) binding data. In addition, compound (+)-73 also exhibited good uroselectivity (DBP K(b)/IUP K(b) > 20-fold) in the in vivo experiments in dogs, similar to 1a.

Full text of DOI:10.1021/jm990201h

4778
J . Med. Chem. 1999, 42, 4778-4793
Design a n d Syn th esis of Novel r1a Ad r en ocep tor -Selective An ta gon ists. 2.
Ap p r oa ch es To Elim in a te Op ioid Agon ist Meta bolites via Mod ifica tion of Lin k er
a n d 4-Meth oxyca r bon yl-4-p h en ylp ip er id in e Moiety1,2
T. G. Murali Dhar,†, Dhanapalan Nagarathnam,† Mohammad R. Marzabadi,*,† Bharat Lagu,† Wai C. Wong,†
George Chiu,† Sriram Tyagarajan,† Shou Wu Miao,† Fengqi Zhang,† Wanying Sun,† Dake Tian,† Quanrong Shen,†
J ack Zhang,† J ohn M. Wetzel,† Carlos Forray,‡ Raymond S. L. Chang,§ Theodore P. Broten,§ Terry W. Schorn,§
Tsing Bao Chen,§ Stacy O’Malley,§ Richard Ransom,§ Kathryn Schneck,§ Robert Bendesky,§ Charles M. Harrell,§
Kamlesh P. Vyas,| Kanyin Zhang,| J ohn Gilbert,| Douglas J . Pettibone,§ Michael A. Patane,∇ Mark G. Bock,∇
Roger M. Freidinger,∇ and Charles Gluchowski†
Departments of Chemistry and Pharmacology, Synaptic Pharmaceutical Corporation, Paramus, New J ersey 07652, and
Departments of Pharmacology, Drug Metabolism, and Medicinal Chemistry, Merck & Company, Inc.,
West Point, Pennsylvania 19486
Received April 23, 1999
We have previously described compound 1a as a high-affinity subtype selective R1a antagonist.
In vitro and in vivo evaluation of compound 1a showed its major metabolite to be a µ-opioid
agonist, 4-methoxycarbonyl-4-phenylpiperidine (3). Several dihydropyrimidinone analogues
were synthesized with the goal of either minimizing the formation of 3 by modification of the
linker or finding alternative piperidine moieties which when cleaved as a consequence of
metabolism would not give rise to µ-opioid activity. Modification of the linker gave several
compounds with good R1a binding affinity (Ki ) < 1 nM) and selectivity (>300-fold over R1b
and R1d). In vitro analysis in the microsomal assay revealed these modifications did not
significantly affect N-dealkylation and the formation of the piperidine 3. The second approach,
however, yielded several piperidine replacements for 3, which did not show significant µ-opioid
activity. Several of these compounds maintained good affinity at the R1a adrenoceptor and
selectivity over R1b and R1d. For example, the piperidine fragments of (+)-73 and (+)-83, viz.
4-cyano-4-phenylpiperidine and 4-methyl-4-phenylpiperidine, were essentially inactive at the
µ-opioid receptor (IC50 > 30 µM vs 3 µM for 3). Compounds (+)-73 and (+)-83 were subjected
to detailed in vitro and in vivo characterization. Both these compounds, in addition to their
excellent selectivity (>880-fold) over R1b and R1d, also showed good selectivity over several other
recombinant human G-protein coupled receptors. Compounds (+)-73 and (+)-83 showed good
functional potency in isolated human prostate tissues, with Kbs comparable to their in vitro
R1a binding data. In addition, compound (+)-73 also exhibited good uroselectivity (DBP Kb/
IUP Kb > 20-fold) in the in vivo experiments in dogs, similar to 1a .
In tr od u ction
metabolic pathway depicted in Chart 1, with the pre-
dominant (>50%) formation of 2 and 4-methoxycarbo-
nyl-4-phenylpiperidine (3). Compound 2 was found to
be devoid of R1a antagonist activity and showed negli-
gible cross-reactivity at several other G-protein coupled
receptors and the L-type calcium channel. Metabolite
We have been interested3-5 in developing R1a adreno-
ceptor6-selective antagonists due to their potential to
provide significant improvement in the treatment of
benign prostatic hyperplasia (BPH)7-9 over the clinically
used nonselective R1 adrenoceptor antagonists such as
terazosin10 and doxazosin.11 In the preceding article,2
we presented the biological rationale for design of R1a
adrenoceptor-selective antagonists. Therein, we pre-
sented the design and synthesis of several dihydropy-
rimidinone derivatives as potent R1a adrenoceptor-
selective antagonists. We identified compound 1a as the
lead candidate with excellent functional potency in the
isolated human prostate tissue and presented data that
showed good uroselectivity in dogs.
3, however, was found to be a µ-opioid agonist (IC50
)
3 µM) and is a close analogue of the µ-opioid agonist
meperidine (IC50 ) 1.1 µM).12 Hydrolysis of the piperi-
dine-4-methoxycarbonyl ester to form the carboxylic acid
4 has been shown to occur. Meperidine is well-known
for the undesirable narcotic and sedative properties. In
addition, 3 showed a long plasma half-life (>12 h) in
rats and dogs that raised concerns that this metabolite
3 may lead to opioid agonist liabilities on chronic
administration of 1a . These findings prompted us to
search for compounds devoid of this potential liability.
In vitro evaluation of 1a in human liver microsomes
and in vivo evaluation in rat and dog defined the
We set out to attain these goals by two major
approaches: (i) minimize the metabolic formation of
4-methoxycarbonyl-4-phenylpiperidine (3) by modifica-
tion of the linker and (ii) replace this piperidine portion
with other piperidines that do not have the µ-opioid
† Department of Chemistry, Synaptic Pharmaceutical Corp.
‡ Department of Pharmacology, Synaptic Pharmaceutical Corp.
§ Department of Pharmacology, Merck & Co.
| Department of Drug Metabolism, Merck & Co.
∇ Department of Medicinal Chemistry, Merck & Co.
Current address: Bristol Myers Squibb Corp., Princeton, NJ .
10.1021/jm990201h CCC: $18.00 © 1999 American Chemical Society
Published on Web 10/27/1999

Novel R1a Adrenoceptor-Selective Antagonists. 2
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23 4779
Ch a r t 1
Sch em e 1a
a
(i) EtOH, reflux; (ii) HPLC separation of enantiomers; (iii) RaNi (H2); (iv) 6 N HCl; (v) H2, Pd-C, MeOH/water; (vi) EDC, NMM,
NH4OH, CH2Cl2.
Sch em e 2

4780 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23
Murali Dhar et al.
Sch em e 3a
a
(i) PTS, toluene; (ii) NaBH3CN; (iii) H2, Pd-C, MeOH/water; (iv) Cu2O, HOAc, BF3‚OEt2, THF; (v) HPLC separation; (vi) LiHMDS,
4-nitrophenyl chloroformate; (vii) HCl; (viii) H2, Pd-C, MeOH/water; (ix) EDC, NMM, NH4OH, CH2Cl2.
agonist activity. The results from these studies are
summarized here.
reaction with piperidine 3 gave 18 (Scheme 2). Alkyla-
tion of dihydropyrimidine 15 with benzyl 2-bromo-
acetate gave 19, which upon hydrogenation provided the
carboxylic acid 20. The 2-aminoethylpiperidine side
chain 21 was prepared by reaction of piperidine 3 with
2-bromoethylamine. Subsequently, the carboxylic acid
20 was coupled with amine 21 in the presence of DMAP
and EDC to provide 22.
Ch em istr y
Schemes 1-3 describe the syntheses of compounds
with linker modifications. Piperidine 3 was reacted with
crotononitrile (5), and the resultant racemic nitrile 6
was resolved via chiral HPLC (Scheme 1). The indi-
vidual enantiomers were then reduced to the enantio-
meric amine 7 by Raney nickel-catalyzed hydrogenation.
Independently, these amines were reacted with the (4-
nitrophenyl)carbamoyldihydropyrimidine 82 and sub-
sequently treated with HCl to afford the benzyl esters
9 and 10. These compounds on hydrogenation gave the
carboxylic acids 11 and 12, which upon coupling with
ammonia gave products 13 and 14.
The piperidinylpiperidine derivative 24 was obtained
by condensation of N-benzyl-4-piperidone (23) with
piperidine 3 and subsequent reduction of the intermedi-
ate with NaBH3CN (Scheme 3). Hydrogenation of 24
with 10% Pd-C gave the piperidinylpiperidine 25,
which on reaction with dihydropyrimidine 262 and
treatment with HCl gave 27. The racemic dihydropy-
rimidinone 32 was prepared by reaction of 3,4-difluo-
robenzaldehyde (30) with methyl 4-methoxyacetoacetate
(28) and urea (29) in the presence of Cu2O, boron
Reaction of dihydropyrimidine 15 with 5-bromo-1-
chloropentane (16) gave the chloride 17 which on

Novel R1a Adrenoceptor-Selective Antagonists. 2
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23 4781
Sch em e 4
Sch em e 5a
trifluoride-etherate, and acetic acid.13 Compound 32
was resolved using a chiral HPLC column. The (+)
enantiomer of 32 was reacted with LiHMDS followed
by treatment with 4-nitrophenyl chloroformate to give
the dihydropyrimidine carbamate ester 34. Compound
34, upon reaction with amine 25, gave product 36. The
3,4,5-trifluorophenyl-substituted dihydropyrimidine ana-
logue 37 was prepared using a similar procedure.
Compound 41 was prepared from the dihydropyrimidine
benzyl ester intermediate 38 and amine 25 following a
similar sequence of reactions described for 13 and 14
in Scheme 1.
Schemes 4-7 describe the syntheses of compounds
with piperidine replacements. The spirocyclic piper-
idines 42a -42g14,15 were alkylated with 1-N-(tert-bu-
toxycarbonyl)-3-bromopropylamine, and the resulting
BOC-protected aminopiperidines 44 were treated with
TFA to give the 3-aminopropylpiperidines 45a -45g
(Scheme 4). These amines, upon reaction with the
pyrimidine 26 followed by treatment with HCl, gave
46-52. Using a similar procedure, compound 56 was
synthesized from 26 and 3-(4,4-diphenylpiperidin-1-yl)-
propylamine.3 The diarylpiperidines 54a -54d were
synthesized via a Friedel-Crafts reaction of 4-hydroxy-
4-arylpiperidines 53a -53d with substituted benzenes.
Reaction of 26 with HCl followed by treatment with
3-bromopropylamine gave the 3-bromopropylcarbam-
oyldihydropyrimidine 55. The diarylpiperidines 54a -
54d were reacted with the bromide 55 to afford products
57-60.
a
(i) K2CO3; (ii) NaH, Ac2O; (iii) H2, 10% Pd-C; (iv) HCl.
bonyl piperidine position. Reaction of 4-hydroxy-4-
phenylpiperidine (61) with 1-N-(benzyloxycarbonyl)-3-
bromopropylamine (62) gave 63 which on acetylation
with acetic anhydride followed by hydrogenolysis gave
65a . Side chains 65b-65e were synthesized following
reported methods.3,5 Reaction of 26 with amines 65a -
65e followed by treatment with HCl gave 66-70.
The synthesis of 73 is described in Scheme 6. Dihy-
dropyrimidine 382 was reacted with 3-(4-cyano-4-phen-
ylpiperidin-1-yl)propylamine (65d ) and subsequently
treated with HCl to afford the benzyl ester 71, which
upon catalytic hydrogenation gave carboxylic acid 72.
Scheme 5 summarizes the synthesis of a series of
compounds with modifications at the C-4 methoxycar-

4782 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23
Murali Dhar et al.
Sch em e 6a
a
(i) Amine 65d ; (ii) HCl; (iii) H2, Pd-C, MeOH/water; (iv) EDC, NMM, NH4OH, CH2Cl2.
Sch em e 7. Synthesis of 79-83a
a
(i) NaH; (ii) TFA; (iii) (a) BOC-NH-CH2CH2CH2Br, K2CO3, KI, acetone, (b) TFA; or (a) 3-bromopropylphthalimide, K2CO3, KI, DMF,
(b) H2N-NH2, methanol.
Acid 72 was then converted to the amide 73 by reaction
with ammonia in the presence of EDC and NMM.
Compound 79 was synthesized by the reaction of
pyrimidinone 342 with amine 65d . The 4-aryl-4-cyan-
opiperidines 76a -76c were synthesized from the cor-
responding 4-arylacetonitriles 75a -75c by dialkylation
with N-tert-butoxycarbonyl-bis(2-chloroethyl)amine (74)
followed by treatment with TFA. The 3-aminopropyl
moiety was introduced as described above or by reaction
with 3-bromopropylphthalimide and subsequent treat-
ment with hydrazine. Side chains 78a -78c were re-
acted with the pyrimidinone 34 to provide compounds
80-82. Compound 83 was synthesized by reaction of
34 with 3-(4-phenyl-4-methylpiperidin-1-yl)propylamine
(65e).
minimize the N-dealkylation resulted in the two dia-
stereomers 13 and 14 (Scheme 1). Among these, 13
showed higher binding affinity for the R1a adrenoceptor
than 14. Compound 13 was 20 times weaker than 1a
but showed >300-fold subtype selectivity (Table 1).
Changing the amide linker (CONHCH2CH2CH2) be-
tween dihydropyrimidinone and piperidine moieties to
an all carbon alkyl chain (CH2CH2CH2CH2CH2) gave
compound 18. Rearrangement of the CONHCH2CH2CH2
linker to CH2CONHCH2CH2 gave 22 which reduced the
distance between the two nitrogens by a methylene unit,
while keeping the number of bonds between the dihy-
dropyrimidinone and the piperidine constant.3,4 Both
compounds 18 and 22 showed good R1a binding and
selectivity profile (Ki ) 0.1-0.2 nM, >1200-fold). In
another approach, we conformationally restricted the
linker with a piperidinyl moiety to minimize the N-
dealkylation. The initial compound 27 in this series
exhibited a significantly lower R1a binding affinity (19
nM vs 0.1 nM for 1c). However, when the dihydropyrim-
idinone C-4 methyl (R2) group was changed to a 2-meth-
oxymethyl (36) the R1a affinity improved (Ki ) 7.5 nM).
Further improvement was seen (Ki ) 1.7 nM) when a
third fluorine was added on the C-6 phenyl ring to yield
the dihydropyrimidinone 37 (Ki ) 1.7 nM, >1800-fold).
We also synthesized a close analogue of our earlier lead
compound 1b with this piperidylpiperidine modification
(41); however, the compound showed a comparatively
lower R1a affinity (81 nM).
Resu lts a n d Discu ssion
Initially, we used compound 1a , its 2,4-difluoro ana-
logue 1b, or 1c (see Chart 1) for the modifications of
the linker and the piperidine. Later, we also made
additional modifications on the dihydropyrimidinone
moiety. In the first part of the discussion we present
the structure-activity relationship (SAR) with respect
to the R1a binding affinity and selectivity of the resultant
compounds. Subsequent discussions focus on the opioid
activity of putative piperidine metabolites and ad-
ditional in vitro and in vivo characterization.
Effect of Mod ifica tion of th e Lin k er on Bin d in g
Affin ities. Introduction of a methyl group on the linker
carbon adjacent to the piperidine nitrogen in order to
Effect of Sp ir ocyclic P ip er id in e Mod ifica tion s

Novel R1a Adrenoceptor-Selective Antagonists. 2
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23 4783
Ta ble 1. R1 Binding Profile of Linker-Modified Dihydropyrimidinones
Ki (nM)a
R1b
0.6
250
220
compd
prazosin
R′
R′′
R′′′
X
R1a
R1d
0.3
340
340
0.6
0.2
0.2
0.1
4.2
58
0.1
0.2
SNAP 6201 (1a )
H2N
H2N
MeO
H2N
H2N
MeO
MeO
MeO
Et
Et
Me
Et
Et
Me
Me
Me
3,4-F2
2,4-F2
3,4-F2
3,4-F2
3,4-F2
3,4-F2
3,4-F2
3,4-F2
CO-NH-(CH2)3-
CO-NH-(CH2)3-
CO-NH-(CH2)3-
CO-NH-(CH2)2-(CHMe)-
CO-NH-(CH2)2-(CHMe)-
-(CH2)5-
1b
1c
13
14
18
22
27
45
140
1480
1450
140
1050
1940
2100
2260
150
610
2260
-CH2-CO-NH-(CH2)2-
19
36
37
MeO
MeO
MeOCH2
MeOCH2
3,4-F2
7.5
1.7
2630
3130
5280
5370
3,4,5-F3
41
H2N
Et
2,4-F2
81
15500
14700
a
All Ki values are (5% SE or less for n > 2. In the case of n ) 2, both Ki values were within 2-fold of each other and the value shown
is the average of the two values.
on Bin d in g Affin it ies. The spirocyclic piperidine
analogues were designed to avoid the formation of the
piperidine-4-carboxylic acid derivatives such as 4 and
to obtain piperidines with minimal µ-opioid activity. The
variations included systematic modification of the pi-
peridine 4-phenyl and 4-methoxycarbonyl moieties into
lactones, ethers, and carbocycles (Table 2). The 6-5
spirocyclic lactone derivative 46 showed a 40-fold lower
R1a binding affinity (Ki 4.5 nM vs 0.1 nM for 1c), and
the reverse lactone (COO vs OCO) analogue 47 exhib-
ited similar R1a affinity (7.9 nM). The 6-5 spirocyclic
ether (48) and the indane (49) analogues, however,
exhibited improved binding affinity (Ki ) 0.3 and 1.1
nM) and selectivity (>200-fold) for the R1a adrenoceptor.
The corresponding 6-6 spirocyclic piperidine analogues
50-52 showed significant improvement in the R1a
binding and selectivity relative to their five-membered
counterparts 47-49. However, these compounds showed
significant cross-reactivity at either the R2 receptor (e.g.
46 g 26-fold selectivity over R2a, R2c) or histamine
receptor (e.g. 46 g 27-fold selectivity over H1) (Table
2).
Effect of Diar ylpiper idin e Modification s on Bin d-
in g Affin ities. When tested at the µ-opioid receptor,
4,4-diphenylpiperidine (54a ) showed an IC50 > 17 µM.
This result suggested that we could use diarylpiper-
idines as replacements for 3 and thereby minimize the
µ-opioid liability. Substitution of the piperidine moiety
of 1c with 4,4-diphenylpiperidine resulted in compound
56 with good R1a affinity (Ki ) 1.85 nM); however, it
showed only ∼20-fold selectivity over the R1b subtype
(Table 3). Further modification of the phenyl rings with
a bis-4-chloro substitution (54b) resulted in lower af-
finity (57, Ki ) 6.9 nM); however, a bis-4-fluoro substi-
tution (54c) improved the R1a binding as well as the
selectivity (58, Ki ) 0.16 nM, >125-fold). A 2- and 4′-
dimethyl substitution (54d ) improved the R1a affinity
of the analogue 59 to Ki ) 0.06 nM and the subtype
selectivity to over 1300-fold.
The µ-opioid activities of the diarylpiperidines are
summarized in Table 4. We identified 4,4-bis(3,5-di-
methylphenyl)piperidine (54e) to have weak activity at
the µ-opioid receptor (IC50 ) 27 µM). Its dihydropyrim-
idinone derivative 60 showed 4.6 nM affinity at the R1a
adrenoceptor with >186-fold over R1b and R1d adreno-
ceptors.
Effect of Mod ifica tion s of th e 4-Meth oxyca r bo-
n yl Moiety of P ip er id in e on Bin d in g Affin ities. In
this section, we replaced the 4-methoxycarbonyl group
of the piperidine with acetoxy, methoxy, cyano, hydro-
gen, and methyl groups (Table 5). The reverse ester
derivative 66 showed 3-fold less affinity (Ki ) 0.3 nM
vs 0.1 nM) than its methoxycarbonyl analogue 1c but
showed improved subtype selectivity (>2000-fold for
both R1b and R1d). Replacement of the 4-methoxycarbo-
nyl group with methoxy (67) resulted in 10-fold lower
R1a affinity but retained good selectivity over R1b and
R1d (>250-fold). Interestingly, the analogue of 1c un-
substituted at position 4 (68) retained good affinity (Ki
) 0.21 nM) and selectivity (>170-fold). The 4-cyano-
substituted compound 69 exhibited a significantly re-
duced affinity (Ki ) 3.2 nM) and subtype selectivity

4784 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23
Murali Dhar et al.
Ta ble 2. R1 Binding Profile of Spirocyclic
Piperidine-Substituted Dihydropyrimidinones
Ta ble 3. R1 Binding Profile of Diarylpiperidine-Substituted
Dihydropyrimidinones
Ki (nM)a
compd
R
R1a
R1b
45
R1d
Ki (nM)a
1c
46
0.1
4.5
140
1560
1490
compd
R1
R2
R1a
R1b
R1d
1c
56
57
58
59
60
0.1
1.9
6.9
0.2
0.06
4.6
45
36
84
20
80
140
190
560
120
250
750
H
4-Cl
4-F
2-CH3
3,5-dimethyl
H
4-Cl
4-F
4-CH3
3,5-dimethyl
47
7.9
2820
1940
860
a
All Ki values are (5% SE or less for n > 2. In the case of n )
2, both Ki values were within 2-fold of each other and the value
shown is the average of the two values.
48
49
50
0.3
1.1
0.2
400
410
250
210
230
330
improved suggested that either the levels of the piperi-
dine metabolite were not significantly changed or the
presence of a new linker had changed the route of the
metabolism. In either case, the poor PK performance of
the analogues precluded any further work in this area.
On the other hand, in the second approach several
final products and their piperidines showed decreased
µ-opioid activity. For example, compounds (+)-73 and
(+)-83 and their piperidine fragments, 4-cyano-4-phen-
ylpiperidine and 4-methyl-4-phenylpiperidine, were es-
sentially inactive at the opioid receptor (IC50 > 30 µM
vs 3 µM for 3).
51
0.20
0.4
490
310
620
910
52
In Vitr o a n d in Vivo P r op er ties of (+)-73 a n d (+)-
83. Compounds (+)-73 and (+)-83 were characterized
in further in vitro and in vivo assays. Table 7 sum-
marizes the in vivo properties of (+)-73 and (+)-83 in
comparison to SNAP 6201 and terazosin. Both (+)-73
and (+)-83, in addition to their excellent selectivities
over R1b and R1d, were also found to be selective over
several recombinant human G-protein coupled recep-
tors. The panel of G-protein coupled receptors included
R2a, R2b, R2c adrenoceptors, histamine-H1, and -H2, 5HT-
1A, -1B, -1D, and -2A, and dopamine (D1, D3, D5)
receptors and also at the rat L-type calcium channel,
with selectivities ranging from 280-fold to greater than
1000-fold.
a
All Ki values are (5% SE or less for n > 2. In the case of n )
2, both Ki values were within 2-fold of each other and the value
shown is the average of the two values.
(>70-fold) at the R1a adrenoceptor. Substitution with a
methyl group, however, provided compound 70 with
excellent (>540-fold) R1 adrenoceptor subtype selectiv-
ity. Synthesis of a close analogue of 1b with 4-cyano-
4-phenylpiperidine resulted in compound (+)-73, which
showed good R1a binding (Ki ) 0.67 nM) affinity and
>900-fold subtype selectivity.
Compounds (+)-73 and (+)-83 showed good potencies
with respect to the prostate in rat, dog, and human
tissues, whereas terazosin showed good potencies in the
prostate as well as the aorta (19 nM). In addition, in
the phenylephrine-stimulated urethral pressure experi-
ments in dog, compound (+)-73 showed good potency
(IUP Kb ) 14 µg/kg) and uroselectivity (DBP Kb/IUP Kb
) >20) compared to the poor selectivity seen for
terazosin (DBP Kb/IUP Kb ) ∼1).
Synthesis of additional analogues of 69 and 70 with
a C-4 methoxymethyl group instead of a methyl group
resulted in compounds 79 and 83 (Table 6), respectively,
with excellent R1a adrenoceptor binding profile. Further
modification of the phenyl group of 4-phenyl-4-cyanopi-
peridine with a fluoro substitution provided several
compounds (80-82) with good R1a affinity, with the
4-fluoro analogue 82 being the best (Ki ) 0.06 nM)
among these compounds (Table 6).
Meta bolism a n d Op ioid Activity. We tested linker-
modified analogues 13, 18, 22, and 37 in the isolated
rat/human liver microsomes and/or for their oral bio-
availability and half-life in rats. The PK results revealed
no improvement in half-life or bioavailability as com-
pared to 1a -1c. The fact that the half-life and/or
bioavailability of linker-modified analogues were not
The pharmacokinetic profile of (+)-73 was determined
in male Sprague-Dawley rats and in male beagle dogs
at 1 mg/kg iv and 3 mg/kg oral dose with quantification
via HPLC. The results showed 8% oral bioavailability
in rats with 35-min t1/2 and 19% oral bioavailability and
138-min t1/2 in dogs (Table 7). Using the HPLC quan-
tification assay, (+)-83 in the dog showed longer plasma

Novel R1a Adrenoceptor-Selective Antagonists. 2
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23 4785
Ta ble 4. Effect of 4,4′-Diaryl Substitution on Opioid Activity (IC50, µM) of Selected Piperidinesa
compd
R1
R2
opioid binding, [3H]DAMGO (µM)
normeperidine
phenyl
phenyl
2-methylphenyl
carbethoxy
phenyl
4-methylphenyl
3,5-dimethylphenyl
1.1
17
6
54a
54d
54e
3,5-dimethylphenyl
27
a
All IC50 values are (30% SE or less for n > 2. In the case of n ) 2, both IC50 values were within 2-fold of each other and the value
shown is the average of the two values.
Ta ble 5. R1a Binding Profile of Dihydropyrimidinones 66-70
<1 nM) and selectivity (>300-fold over R1b and R1d) were
obtained. In vitro analysis in the microsomal assay
revealed these modifications did not significantly affect
N-dealkylation and formation of the piperidine 3. In
addition, none of the compounds tested showed signifi-
cant improvement in the pharmacokinetic profile, com-
pared to 1a .
In the second approach, however, we successfully
identified several piperidines devoid of the µ-opioid
activity, as replacements for 3. For example, the piper-
idine pieces of (+)-73 and (+)-83, viz. 4-cyano-4-phen-
ylpiperidine and 4-methyl-4-phenylpiperidine, were es-
sentially inactive at the µ-opioid receptor (IC50 > 30 µM
vs 3 µM for 3). Compounds (+)-73 and (+)-83 were
subjected to further in vitro and in vivo characterization.
Both these compounds, in addition to their excellent
selectivity (>880-fold) over R1b and R1d, also showed good
selectivity over several recombinant human G-protein
coupled receptors. Similar to 1a , compound (+)-73 also
exhibited good in vivo functional potency (IUP Kb ) 14
µg/kg) in the dogs with a DBP Kb/IUP Kb ratio of >20
versus no selectivity seen for the nonselective R1 adreno-
ceptor antagonist terazosin. Compound (+)-83 in the
isolated human prostate tissues showed good functional
potency comparable to its in vitro binding affinity at the
human R1a adrenoceptor (Kb ) 0.66 nM vs Ki ) 0.14
nM). Neither (+)-73 nor (+)-83, however, showed sig-
nificantly improved pharmacokinetic profiles over 1b.
Another approach to address the issue of opioid active
metabolites is described in the accompanying paper.24
Ki (nM)a
compd
R′
R′′
R′′′
R
R1a
R1b
R1d
1c
66
67
68
69
70
(+)-73
a
MeO
MeO
MeO
MeO
MeO
MeO
H2N
Me
Me
Me
Me
Me
Me
Et
3,4-F2
3,4-F2
3,4-F2
3,4-F2
3,4-F2
3,4-F2
2,4-F2
CO2Me
OCOMe
OMe
H
0.1
0.3
1
0.2
3.2
0.5
0.7
45
700
250
36
340
270
610
140
780
370
150
230
480
1280
CN
Me
CN
All Ki values are (5% SE or less for n > 2. In the case of n )
2, both Ki values were within 2-fold of each other and the value
shown is the average of the two values.
Ta ble 6. R1a Binding Profile of Dihydropyrimidinones 79-83
Ki (nM)a
Exp er im en ta l Section
compd
R1
R
R1a
R1b
R1d
All protocols for the chemical and biological (in vitro and in
vivo) experiments are described in the preceding manuscript.2
(+)-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 e t h oxyca r b on yl-4-p h e n ylp ip e r id in -1-yl)-2-
m eth ylp r op yl]ca r boxa m id o}-2-oxo-1,2,3,6-tetr a h yd r op y-
r im id in e (14). (a ) 3-(4-Meth oxyca r bon yl-4-p h en ylp ip er i-
din -1-yl)-3-m eth ylpr opion itr ile (6). To a solution of 4-meth-
oxycarbonyl-4-phenylpiperidine (3.48 g, 15.8 mmol) in MeOH
(25 mL) was added crotononitrile (5.32 g, 79.0 mmol) and the
mixture was heated at reflux temperature for 4 h. Methanol
and excess crotononitrile were evaporated and the residue was
purified by column chromatography on silica gel (30-100%
EtOAc in hexanes). 1H NMR (CDCl3): δ 1.16 (d, J ) 6.0 Hz, 3
H), 1.86-1.96 (m, 2 H), 2.28-2.60 (m, 6 H), 2.68-2.80 (m, 2
H), 2.96-3,02 (m, 1 H), 3.62 (s, 3 H), 7.20-7.36 (m, 5 H).
(b ) 3-(4-Met h oxyca r b on yl-4-p h en ylp ip er id in -1-yl)-3-
m eth ylp r op ion itr ile (7). The racemic 3-(4-methoxycarbonyl-
4-phenylpiperidin-1-yl)-3-methylpropionitrile (1.53 g) was re-
solved by chiral HPLC [Chiralcel OD 20 × 250 mm #369-703-
30604]; λ 254 nm; hexanes/ethanol, 80/20; 80 mg/injection;
retention time of the desired enantiomer: 18.18 min. The first
desired product was used to synthesize product 13 and the
second peak to 14 (31 wt % isolation of the first peak and 35%
of the second peak from the racemate).
1c
79
80
81
82
(+)-83
0.1
0.1
5.2
0.2
0.06
0.5
45
130
730
150
30
140
260
930
180
110
640
CN
CN
CN
CN
Me
H
2-F
3-F
4-F
H
440
a
All Ki values are (5% SE or less for n > 2. In the case of n )
2, both Ki values were within 2-fold of each other and the value
shown is the average of the two values.
half-life (6.5 h vs 2.5 h for 1a ). Compound (+)-83 showed
23% bioavailability and a half-life of 24 min in the rat
(Table 7).
Su m m a r y
A series of dihydropyrimidinone analogues were
synthesized with the goal of either minimizing the
formation of meperidine-like metabolite 3 or finding
replacement moieties that were devoid of the µ-opioid
agonist activity. The initial approach involved the
introduction of a methyl group on the linker carbon
adjacent to the piperidine, all-alkyl carbon linker, and
conformational restriction of the linker into a piperidine.
Several compounds with good R1a binding affinity (Ki )
(c) (+)-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)-3-m eth ylpr opyl]car boxam ido}-2-oxo-1,2,3,6-tetr ah y-

4786 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23
Murali Dhar et al.
Ta ble 7. Summary and Comparison of in Vitro and in Vivo Properties of (+)-73, (+)-83, SNAP 6201, and Terazosin
assay
agonist/antagonist
(+)-73
(+)-83
SNAP 6201
terazosin
Ki, R1a human clones (nM)
[3H]prazosin
[3H]prazosin
[3H]rauwolscine
phenylephrine
norepinephrine
A-61603
phenylephrine
A-61603
phenylephrine
phenylephrine
phenylephrine
0.7
0.5
0.2
6.9
<1.0
<10.0
25
19
25
52
3
1
16.4
15.7
R
1b,1d/R1a
2a,b,c/R1a
>900
>1000
2.2
>1000
ND
>400
>280
0.4
ND
0.7
69
2
ND
ND
>1000
>1000
0.5
>1000
0.1
R
Kb rat prostate (nM)
Kb rat aorta (nM)
Kb human prostate (nM)
AD50 rat prostate (µg/kg)
duration of action rat (h)
IUPa Kb/DBPb Kb (dog)
Kb (IUP)a dog (µg/kg)
Kb (DBP)b dog (µg/kg)
opioid Ki (µM)
18
1.5
20
>4
>20
14.2
>300
51
>30
4.2
ND
187
100
4
rat F, t1/2 (h)
dog F, t1/2 (h)
8,c 0.4
32,f 2.3
23,d 0.4
ND, 6.5
15,e 2.0
26,e 2.5
49, 7.5
a
b
Intraurethral pressure. Diastolic blood pressure. c iv: 1 mg/kg dose, AUC ) 49.7 µmol min/L. po: 3 mg/kg dose, AUC ) 62.5 µmol
min/L. iv: 1 mg/kg dose, AUC ) 25.6 µmol min/L. po: 3 mg/kg dose, AUC ) 17.8 µmol min/L. e See ref 2 for details regarding SNAP
6201 and the in vitro and in vivo protocols for all compounds. f iv: 1 mg/kg dose, AUC ) 32 µmol min/L. po: 3 mg/kg dose, AUC ) 30
µmol min/L. ND, not determined; F, bioavailability.
d
d r op yr im id in e (9). To a solution of 3-(4-methoxycarbonyl-
4-phenylpiperidin-1-yl)-3-methylpropionitrile (first peak from
HPLC, 475 mg, 1.65 mmol) in MeOH (10 mL) was bubbled
NH3 gas for 15 min. Raney Ni (80 mg, prewashed with water
and then MeOH) was added to the mixture. The resulting
suspension was hydrogenated at 150 psi overnight at room
temperature. The suspension was filtered through a pad of
Celite and the filtrate was concentrated to leave the amine 7
as an oil (462 mg, 96%), which was used as such in the next
step.
To a stirred mixture of (+)-5-(benzyloxycarbonyl)-6-(3,4-
difluorophenyl)-1,6-dihydro-4-ethyl-2-methoxy-1-[(4-nitrophen-
yloxy)carbonyl]pyrimidine2 (8; 0.87 g, 1.6 mmol) in CH2Cl2 (20
mL) was added a solution of 3-[4-methoxycarbonyl-4-phenylpi-
peridin-1-yl]-3-methylpropylamine (7; 0.70 g, 1.93 mmol) and
K2CO3 (0.1 g) in THF (25 mL) at room temperature and
stirring was continued for 8 h. The suspension was diluted
with CH2Cl2 (150 mL) and washed with 10% KOH solution (2
× 10 mL). This solution was mixed with aqueous 10% HCl (2
mL) and stirred for 2 h. The mixture was treated with 10%
aqueous KOH solution (10 mL); the organic layer was sepa-
rated, dried (Na2SO4), and concentrated. The residue was
purified by column chromatography on silica gel to obtain the
product as a white foam (0.52 g), which was used in the next
step without further purification. 1H NMR (CDCl3): δ 0.92 (d,
J ) 6.0 Hz, 3 H), 1.21 (t, J ) 6.6 Hz, 3 H), 1.49-1.71 (m, 2 H),
1.83-1.87 (m, 2 H), 2.41-2.55 (m, 4 H), 2.65-2.73 (m, 4 H),
3.23-3.40 (m, 2 H), 3.64 (s, 3 H), 3.73 (t, J ) 4.5 Hz, 1 H),
5.12 (ABq, dA ) 5.05, dB ) 5.20, J ) 12.3 Hz, 2 H), 6.68 (s, 1
H), 6.98-7.37 (m, 14 H), 8.79 (t, J ) 4.2 Hz, 1 H).
(e) (+)-6-(3,4-Diflu or op h en yl)-4-eth yl-1-{N-[3-(4-m eth -
oxycar bon yl-4-ph en ylpiper idin -1-yl)-3-m eth ylpr opyl]car -
boxa m id o}-2-oxo-1,2,3,6-tetr a h yd r op yr im id in e-5-ca r box-
ylic Acid (11). A solution of 9 (0.52 g, 0.755 mmol) in MeOH
(10 mL) was added to a suspension of 10% Pd-C in MeOH
(10 mL) and water (4 mL). The resulting suspension was
hydrogenated under 100 psi for 10 h. It was then filtered
through a pad of Celite and was washed with MeOH.25
Solvents were evaporated from the filtrate and the residue was
dissolved in THF, dried (MgSO4), and concentrated to obtain
the carboxylic acid 11 (0.45 g) as a white solid.
(f) (+)-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 et h oxyca r b on yl-4-p h en ylp ip er id in -1-yl)-3-
m eth ylp r op yl]ca r boxa m id o}-2-oxo-1,2,3,6-tetr a h yd r op y-
r im id in e (13). To a solution of 11 in CH2Cl2 (40 mL) and
NMM (0.30 mL, 2.7 mmol) was added EDC (0.44 g, 1.50 mmol)
and the resulting mixture was cooled to 0 °C. Ammonia was
bubbled through this solution for 30 min and the resulting
suspension was stirred overnight at room temperature. The
mixture was washed with saturated aqueous NH4Cl solution
(20 mL) followed by brine (20 mL). The organic layer was dried
(Na2SO4) and the solvent evaporated. The residue was purified
by column chromatography on silica gel using 10% MeOH in
CH2Cl2 as the eluent to obtain product 13 as a white solid (0.18
g, 40% for two steps). [R]D ) +115 (c ) 0.25, MeOH). 1H NMR
(CDCl3): δ 0.93 (d, J ) 6.3 Hz, 3 H), 1.26 (t, J ) 7.2 Hz, 3 H),
1.49-1.71 (m, 2 H), 1.87-1.94 (m, 2 H), 2.41-2.55 (m, 4 H),
2.65-2.73 (m, 4 H), 3.28-3.42 (m, 2 H), 3.64 (s, 3 H), 3.72 (t,
J ) 4.5 Hz, 1 H), 5.82 (br s, 2 H), 6.52 (s, 1 H), 7.07-7.36 (m,
8 H), 8.08 (br s, 1 H), 8.81 (t, J ) 5.1 Hz, 1 H). It was converted
to the HCl salt by treatment with 1 N HCl in ether. Mp: 212-
216 °C. Anal. (C32H38N5O5F2Cl‚1.1CHCl3) 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 e t h oxyca r b on yl-4-p h e n ylp ip e r id in -1-yl)-3-
m eth ylp r op yl]ca r boxa m id o}-2-oxo-1,2,3,6-tetr a h yd r op y-
r im id in e (14). (a ) (+)-5-(Ben zyloxyca r b on yl)-6-(3,4-d i-
flu or oph en yl)-4-eth yl-1-{N-[3-(4-m eth oxycar bon yl-4-ph en -
ylp ip er id in -1-yl)-3-m et h ylp r op yl]ca r b oxa m id o}-2-oxo-
1,2,3,6-tetr ah ydr opyr im idin e (10). The second HPLC fraction
of 3-(4-methoxycarbonyl-4-phenylpiperidin-1-yl)-3-methylpro-
pionitrile (531 mg, 1.84 mmol) was reduced to the 3-(4-
methoxycarbonyl-4-phenylpiperidin-1-yl)-3-methylpropyl-
amine using a similar procedure described earlier. It was
reacted with 8 (0.620 g, 1.32 mmol) as described earlier to
afford the product 10 (0.660 g, 72%). 1H NMR (CDCl3): δ 0.90
(d, J ) 6.6 Hz, 3 H), 1.18 (t, J ) 7.0 Hz, 3 H), 1.42-1.53 (m,
1 H), 1.60-1.68 (m, 2 H), 1.78-1.86 (m, 1 H), 1.92-2.02 (m, 1
H), 2.18-2.26 (m, 1 H), 2.40-2.70 (m, 6 H), 2.80-2.88 (m, 1
H), 3.24-3.38 (m, 2 H), 3.61 (s, 3 H), 5.12 (ABq, dA ) 5.05, dB
) 5.20, J ) 12.3 Hz, 2 H), 6.68 (s, 1 H), 6.72 (s, 1 H), 6.97-
7.37 (m, 14 H), 8.76 (t, J ) 4.2 Hz, 1 H).
(b) (+)-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 et h oxyca r b on yl-4-p h en ylp ip er id in -1-yl)-3-
m eth ylp r op yl]ca r boxa m id o}-2-oxo-1,2,3,6-tetr a h yd r op y-
r im id in e (14). Prepared from 10 (0.660 g, 0.958 mmol) using
a similar procedure described earlier to afford the product
1
(0.293 g, 51%). H NMR (CDCl3): δ 0.90 (d, J ) 6.6 Hz, 3 H),
1.20 (t, J ) 7.0 Hz, 3 H), 1.46-1.72 (m, 3 H), 1.79-1.88 (m, 1
H), 1.92-2.02 (m, 1 H), 2.16-2.26 (m, m, 1 H), 2.40-2.80 (m,
7 H), 3.26-3.40 (m, 2 H), 3.60 (s, 3 H), 5.40 (br s, 2 H), 6.46 (s,
1 H), 6.72 (s, 1 H), 7.06-7.38 (m, 8 H), 8.78 (t, J ) 5 Hz, 1 H).
HCl salt Mp: 218-221 °C. [R]D ) + 80.0 (c ) 0.25, MeOH).
Anal. (C32H38N5O5F2Cl‚0.9 H2O) C, H, N.
6-(3,4-Diflu or op h en yl)-5-m eth oxyca r bon yl-1-{N-[5-(4-
m et h oxyca r b on yl-4-p h en yl)p ip er id in -1-yl)p en t yl]ca r -
b oxa m id o}-4-m e t h yl-2-oxo-1,2,3,6-t e t r a h yd r op yr im i-
d in e (18). (a ) 3-(5-Ch lor op en tyl)-6-(3,4-d iflu or op h en yl)-5-
m e t h oxyca r b on yl-4-m e t h yl-2-oxo-1,2,3,4-t e t r a h yd r o-
p yr im id in e (17). To a solution of 6-(3,4-difluorophenyl)-5-
methoxycarbonyl-4-methyl-2-oxo-1,2,3,4-tetrahydropyrimi-
dine (15; 0.110, 0.426 mmol) in THF (10 mL) and HMPA (1.5
mL, 0.85 mmol) at 0 °C was added NaH (0.014 g, 1.27 mmol)
in small portions over 2 min. After stirring at room temper-
ature for 2 min, 1-bromo-5-chloropentane (16; 0.22 mL, 1.70
mmol) was added and the mixture was heated at reflux
temperature for 30 min. The reaction mixture was cooled to 0

Novel R1a Adrenoceptor-Selective Antagonists. 2
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23 4787
°C and carefully quenched by the addition of ice water (4 mL).
The reaction mixture was concentrated and then partitioned
between CH2Cl2 (25 mL) and water (5 mL). The organic layer
was separated, mixed with aqueous 6 N HCl (3 mL), and
stirred at room temperature for 15 min. To this was added
saturated aqueous NaHCO3 solution (15 mL) and the organic
layer was separated. It was dried (Na2SO4) and the solvent
was evaporated. The residue was purified by column chroma-
tography on silica gel (hexanes:EtOAc ) 3:2) to yield the
aqueous NH4Cl solution (4 × 10 mL). The organic layer was
dried (Na2SO4) and concentrated. The residue was purified by
preparative thin-layer chromatography on silica gel using
CHCl3/MeOH/2 M NH3 in MeOH (20:2:1) as the eluent (25 mg).
1
MH+ 585. [R]D ) + 108 (c ) 0.5, MeOH). H NMR (CDCl3): δ
1.80-2.00 (m, 2 H), 2.05-2.15 (m, 2 H), 2.20 (s, 3 H), 2.40-
2.44 (m, 2 H), 2.50-2.65 (m, 2 H), 2.70-2.95 (m, 2 H), 3.20-
3.40 (m, 2 H), 3.418, 3.473, 4.301, 4.355 (ABq, 2 H), 3.59 (s, 3
H), 3.64 (s, 3 H), 5.30 (s, 1 H), 6.60 (br t, 1 H, NH), 7.04-7.41
(m, 8 H), 7.95 (br s, 1 H, NH). HCl salt Mp: 247-250 °C. Anal.
(C30H34N6O6F2Cl) C, H, N.
1
product (0.142 g, 91%) as a syrup. H NMR (CDCl3): δ 1.42-
1.79 (m, 7 H), 2.32 (s, 3 H), 2.74-2.83 (m, 1 H), 3.51 (t, J )
6.5 Hz, 2 H), 3.69 (s, 3 H), 5.26 (s, 1 H), 7.06-7.20 (m, 3 H),
8.23 (br s, J ) 5.2 Hz, 1 H).
6-(3,4-Diflu or op h e n yl)-5-m e t h oxyca r b on yl-1-{N -(4-
[4-methoxycarbonyl-4-phenylpiperidin-1-yl]piperidin-1-yl)-
carboxamido]-4-methyl-2-oxo-1,2,3,6-tetrahydropyrimidine
(27). (a) 1-Benzyl-4-[4-methoxycarbonyl-4-phenylpiperidin-1-
yl]piperidine (24). A mixture of 4-methoxycarbonyl-4-phenylpi-
peridine (3; 6.50 g, 29.6 mmol), 1-benzyl-4-piperidone (23; 5.62
g, 29.6 mmol), and p-toluenesulfonic acid (100 mg) in toluene
(80 mL) was heated at reflux temperature for 14 h while the
water formed was trapped using a Dean-Stark apparatus.
Solvent was evaporated and the residue was dissolved in
methanol (200 mL) and cooled to 0-5 °C. Sodium cyanoboro-
hydride (1.86 g, 29.6 mmol) was added in portions in about 30
min and the mixture was stirred for 12 h. Solvent was
evaporated and the residue was treated with ice-water (400
g). The mixture was extracted with CH2Cl2 (4 × 50 mL) and
the combined extracts were washed with brine (3 × 100 mL).
The organic layer was dried (Na2SO4) and concentrated. The
residue was crystallized from 2-propanol and hexanes to get
product 24 as white crystals (8.50 g, 73%). Mp: 112-113 °C.
1H NMR (CDCl3): δ 1.50-1.60 (m, 2 H), 1.68-1.80 (m, 2 H),
1.85-2.00 (m, 4 H), 2.20-2.35 (m, 3 H), 2.50-2.60 (m, 2 H),
2.85-2.95 (br t, 4 H), 3.45 (s, 2 H), 3.60 (s, 3 H), 7.20-7.40
(m, 10 H).
(b) 4-[4-Meth oxyca r bon yl-4-p h en ylp ip er id in -1-yl]p i-
p er id in e (25). 1-Benzyl-4-[4-methoxycarbonyl-4-phenylpi-
peridin-1-yl]piperidine (24; 3.92 g, 10 mmol) was dissolved in
a freshly prepared solution of formic acid in methanol (4.4%,
200 mL) and cooled to 0 °C. To this was added 10% Pd-C (1.0
g) cautiously in about 45 min and the mixture was stirred and
allowed to warm to room temperature. After 8 h, the catalyst
was removed by filtration and washed with more methanol
(50 mL). Solvent was evaporated from the filtrate, the residue
was treated with ice-cold NaOH (6 N, 50 mL), and the mixture
was extracted with ether (4 × 50 mL). Evaporation of solvent
from the combined dried (Na2SO4) extracts left the product as
a viscous oil (2.90 g, 96%). The 1H NMR analysis confirmed
the product to be pure and was used in the next step. 1H NMR
(CDCl3): δ 1.30-1.50 (m, 2 H), 1.70-1.80 (m, 2 H), 1.85-2.00
(m, 2 H), 2.25-2.40 (m, 3 H), 2.50-2.65 (m, 4 H), 2.85-2.95
(br d, 2 H), 3.05-3.15 (br d, 2 H), 3.60 (s, 3 H), 7.20-7.40 (m,
5 H).
(b) 4-(3,4-Diflu or op h en yl)-5-m eth oxyca r bon yl-3-[5-(4-
m eth oxycar bon yl-4-ph en ylpiper idin -1-yl)pen tyl]-6-m eth -
yl-2-oxo-1,2,3,4-tetr a h yd r op yr im id in e (18). To a stirred
solution of 17 (0.173 g, 0.447 mmol) in dioxane (20 mL) were
added 4-methoxycarbonyl-4-phenylpiperidine (3; 0.196 g, 0.89
mmol) and K2CO3 (0.186 g, 1.34 mmol) and the mixture was
heated at reflux temperature for 24 h. It was cooled to room
temperature, concentrated, and partitioned between EtOAc (25
mL) and water (5 mL). The organic layer was dried (Na2SO4)
and concentrated. The crude product was purified by column
chromatography (EtOAc:MeOH, 9:1) to yield the product (0.130
g, 51%) as a colorless oil. 1H NMR (CDCl3): δ 1.27-1.52 (m, 8
H), 1.94-2.88 (m, 10 H), 3.66 (s, 9 H), 3.68 (s, 3 H), 3.65-3.68
(m, 3 H), 5.25 (s, 1 H), 7.06-7.38 (m, 9 H), 8.76 (s, 1 H). HCl
salt Mp: 140-145 °C. Anal. (C31H38F2N3O5Cl‚1.0H2O) C, H,
N.
6-(3,4-Diflu or op h en yl)-5-m et h oxyca r b on yl-1-{N-[(4-
m e t h oxyca r b on yl-4-p h e n ylp ip e r id in -1-yl)e t h yl]a ce t -
a m id o}-4-m eth oxym eth yl-2-oxo-1,2,3,6-tetr a h yd r op yr im -
idin e (22). (a) 6-(3,4-Diflu or oph en yl)-1-[(h ydr oxycar bon yl)-
m e t h y l]-5-m e t h o x y c a r b o n y l-4-m e t h y l-2-o x o -1,2,3,4-
tetr a h yd r op yr im id in e (20). A mixture of 15 (0.296 g, 1.00
mmol), benzyl 2-bromoacetate (0.229 g, 1.00 mmol), K2CO3
(600 mg), and KI (30 mg) in DMF (20 mL) was stirred and
heated at 50-55 °C for 12 h. The mixture was cooled, poured
into ice-water (150 mL), and extracted with ether (3 × 20
mL). The combined organic layers were dried (Na2SO4) and
concentrated. The residue was redissolved in THF (10 mL),
mixed with aqueous 6 N HCl (3 mL), and stirred for 2 h.
Solvent was evaporated and the residue was purified by
column chromatography on silica gel (1:1 EtOAc/hexanes) to
obtain the benzyl ester 19 (0.32 g, 75%). This intermediate
(200 mg, 0.465 mmol) was dissolved in methanol/water (4:1,
15 mL) and mixed with Pearlman’s catalyst (20 mg). The
resulting suspension was hydrogenated at 100 psi for 4 h. TLC
analysis confirmed the disappearance of the starting material.
The catalyst was removed by filtration and the solvent was
evaporated from the filtrate. The residue was dried under
vacuum and used in the next step (0.135 g).
(b )
2-[4-Met h oxyca r b on yl-4-p h en ylp ip er id in -1-yl]-
(c) 6-(3,4-Diflu or op h en yl)-5-m eth oxyca r bon yl-1-{N-(4-
[4-m eth oxyca r bon yl-4-p h en ylp ip er id in -1-yl]p ip er id in -1-
yl)ca r b oxa m id o}-4-m et h yl-2-oxo-1,2,3,6-t et r a h yd r op y-
r im id in e (27). Prepared from 26 (138 mg, 0.30 mmol) and
25 (100 mg, 0.33 mmol) using a similar procedure described
eth yla m in e (21). A mixture of 4-methoxycarbonyl-4-phen-
ylpiperidine (3; 1.2 g, 7.76 mmol), 2-bromoethylamine hydro-
bromide (3.28 g, 16 mmol), K2CO3 (2.7 g, 19.5 mmol), and KI
(0.648 g, 3.9 mmol) in 1,4-dioxane (25 mL) was heated at reflux
temperature for 36 h. Dioxane was evaporated under reduced
pressure, and the residue was treated with ice-cold 6 N NaOH
(400 mL) and extracted with CH2Cl2 (4 × 120 mL). The
combined organic layers were dried (K2CO3) and concentrated.
The residue was purified by column chromatography on silica
gel using CHCl3/MeOH/2 M NH3 in MeOH (20:2:1) as the
eluent to afford the product (0.855 g, 42%) as a viscous oil. 1H
NMR (CDCl3): δ 1.90-2.10 (m, 2 H), 2.10-2.30 (br t, 2 H),
2.40-2.50 (br t, 2 H), 2.50-2.70 (m, 4 H), 2.80-2.90 (m, 4 H),
3.64 (s, 3 H), 7.20-7.45 (m, 5 H).
(c) 6-(3,4-Diflu or op h en yl)-5-m eth oxyca r bon yl-1-{N-[(4-
m e t h oxyca r b on yl-4-p h e n ylp ip e r id in -1-yl)e t h yl]a ce t -
amido}-4-methoxymethyl-2-oxo-1,2,3,6-tetrahydropyrimidine
(22). A solution of the carboxylic acid 20 (20 mg), EDC (20
mg), DMAP (20 mg), and amine 21 (20 mg) in CH2Cl2 (10 mL)
was stirred at room temperature for 24 h. The reaction mixture
was diluted with more CH2Cl2 (20 mL) and washed with
1
earlier (108 mg, 59%). H NMR (CD3OD): δ 1.70-1.85 (m, 2
H), 2.05-2.30 (m, 4 H), 2.80-3.00 (m, 4 H), 3.00-3.20 (br t, 2
H), 3.35-3.45 (m, 1 H), 3.55-3.65 (m, 4 H), 3.67 (s, 3 H), 3.69
(s, 3 H), 5.80 (s, 1 H), 7.00-7.60 (m, 8 H). Anal. (C33H37N4O6F2-
Cl‚0.4CH2Cl2) C, H, N.
(+)-6-(3,4-Diflu or op h en yl)-5-m eth oxyca r bon yl-1-{N-(4-
[4-m eth oxyca r bon yl-4-p h en ylp ip er id in -1-yl]p ip er id in -1-
yl)ca r boxa m id o}-4-m eth oxym eth yl-2-oxo-1,2,3,6-tetr a h y-
d r op yr im id in e (36). (a ) 6-(3,4-Diflu or op h en yl)-5-m et h -
oxycar bon yl-4-m eth oxym eth yl-2-oxo-1,2,3,6-tetr ah ydr opy-
r im id in e (32). To a well-stirred mixture of methyl 4-meth-
oxyacetoacetate (28; 50 g, 0.351 mol), 3,4-difluorobenzaldehyde
(30; 51.39 g, 0.351 mmol), and urea (29; 31.64 g, 0.527 mol) in
THF (300 mL) at room temperature were added copper(I) oxide
(5.06 g, 0.035 mol) and acetic acid (2.05 mL) sequentially
followed by dropwise addition of boron trifluoride-diethyl
etherate (56 mL, 0.456 mole). The mixture was stirred and

4788 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23
Murali Dhar et al.
heated at reflux temperature for 8 h, whereupon TLC (1/1
EtOAc/hexanes) indicated completion of the reaction. It was
cooled and poured into a mixture of ice (500 g) and NaHCO3
(100 g) and the resulting mixture was filtered through Celite.
The Celite pad was washed with CH2Cl2 (400 mL). The organic
layer was separated from the filtrate and the aqueous layer
was extracted with more CH2Cl2 (3 × 300 mL). The combined
organic extracts were dried (Na2SO4) and the solvent was
evaporated. The crude product was purified by flash column
chromatography on silica gel (50% EtOAc in hexanes, then
EtOAc) to give the product 32 as a pale yellow foam, which on
trituration with hexanes became a white powder (103 g, 94%).
1H NMR (CDCl3): δ 3.47 (s, 3 H), 3.65 (s, 3 H), 4.65 (s, 2 H),
5.39 (s, 1 H), 6.60 (br s, 1 H, NH), 7.00-7.20 (m, 3 H), 7.72 (br
s, 1 H, NH).
(b ) (+)-6-(3,4-Diflu or op h en yl)-5-m et h oxyca r b on yl-4-
m eth oxym eth yl-2-oxo-1,2,3,6-tetr a h yd r op yr im id in e [(+)-
32]. The 32 was resolved by chiral HPLC [Chiralcel OD 20 ×
250 mm #369-703-30604]; λ 254 nm; hexanes/ethanol, 90/10;
85 mg/injection; retention time of the desired enantiomer:
16.94 min. The first enantiomer peak to elute gave (+)-32 (40-
42 wt % isolation of the desired enantiomer from the race-
mate). [R]D ) +84 (c ) 0.5, CHCl3).
(c) (+)-6-(3,4-Diflu or op h en yl)-5-m et h oxyca r b on yl-4-
m et h oxym et h yl-1-[(4-n it r op h en yloxy)ca r b on yl]-2-oxo-
1,2,3,6-tetr a h yd r op yr im id in e (34). To a solution of (+)-32
(1.98 g, 6.34 mmol) in anhydrous THF (20 mL) at -78 °C under
argon atmosphere was added a solution of LiHMDS in THF
(1.0 M, 18.0 mL, 18.0 mmol) over 2-3 min and the mixture
was stirred for 10 min. This solution was added over 6 min
via a cannula to a stirred solution of 4-nitrophenyl chlorofor-
mate (4.47 g, 22.2 mmol) in THF (20 mL) at -78 °C. The
stirring was continued for 10 min and the mixture was poured
onto ice (50 g) and extracted with CHCl3 (2 × 50 mL). The
combined extracts were dried (Na2SO4) and the solvent was
evaporated. The residue was purified by flash column chro-
matography using hexanes/EtOAc (4:1 to 3.5:1) as eluent. The
product was obtained as a yellow syrup, which on trituration
with hexanes became a white powder (2.4 g, 79%). 1H NMR
(CDCl3): δ 3.52 (s, 3 H), 3.74 (s, 3 H), 4.65-4.80 (q, J ) 16.5
Hz, 2 H), 6.32 (s, 1 H), 7.10-7.30 (m, 4 H), 7.36 (d, J ) 9 Hz,
2 H), 8.27 (d, J ) 9 Hz, 2 H).
(d ) (+)-6-(3,4-Diflu or op h en yl)-5-m et h oxyca r b on yl-1-
{N-(4-[4-m eth oxyca r bon yl-4-p h en ylp ip er id in -1-yl]p ip er i-
d in -1-yl)ca r b oxa m id o}-4-m et h oxym et h yl-2-oxo-1,2,3,6-
tetr a h yd r op yr im id in e (36). Prepared from 34 (120 mg, 0.25
mmol) and the amine 25 (80 mg, 0.27 mmol) using a similar
procedure described earlier to afford the product (0.146 g, 91%).
1H NMR (CD3OD): δ 1.70-1.80 (m, 2 H), 2.00-2.20 (m, 4 H),
2.80-3.00 (m, 4 H), 3.00-3.20 (br t, 2 H), 3.35-3.45 (m, 1 H),
3.40 (s, 3 H), 3.55-3.65 (m, 4 H), 3.60 (s, 3 H), 3.72 (s, 3 H),
4.60 (ABq, J ) 12 Hz, 2 H), 5.75 (s, 1 H), 7.05-7.50 (m, 8 H).
Anal. (C33H39N4O7F2Cl‚0.4CH2Cl2) C, H, N.
33 (1.34 g, 4.05 mmol), LiHMDS (4.5 mL, 1.0 M), and
4-nitrophenyl chloroformate (0.804 g, 4 mmol) using a similar
procedure described earlier (1.75 g, 85%). [R]D ) +86.8 (c )
0.5, CHCl3). 1H NMR (CDCl3): δ 3.53 (s, 3 H), 3.75 (s, 3 H),
4.65-4.80 (q, J ) 16.5 Hz, 2 H), 6.29 (s, 1 H), 7.03-7.08 (m,
2 H), 7.38 (d, J ) 9 Hz, 2 H), 8.29 (d, J ) 9 Hz, 2 H).
(d ) (+)-5-Meth oxyca r bon yl-1-{N-(4-[4-m eth oxyca r bo-
n yl-4-p h en ylp ip er id in -1-yl]p ip er id in -1-yl)ca r boxa m id o}-
4-m et h oxym et h yl-2-oxo-1,2,3,6-t et r a h yd r o-6-(3,4,5-t r i-
flu or op h en yl)p yr im id in e (37). Prepared from 35 (50 mg,
0.101 mmol) and the amine 25 (50 mg, 0.165 mmol) using a
similar procedure described earlier to afford the product (66
mg, 99%). [R] ) +135 (c ) 0.65, MeOH). HCl salt Mp: 178-
1
181 °C. H NMR (CD3OD): δ 1.70-1.80 (m, 2 H), 2.00-2.20
(m, 4 H), 2.80-3.00 (m, 4 H), 3.00-3.20 (br t, 2 H), 3.35-3.45
(m, 1 H), 3.40 (s, 3 H), 3.55-3.65 (m, 4 H), 3.60 (s, 3 H), 3.72
(s, 3 H), 4.60 (ABq, J ) 12 Hz, 2 H), 5.75 (s, 1 H), 7.05-7.50
(m, 7 H). Anal. (C33H38ClF3N4O7.0.4CH2Cl2) C, H, N.
(+)-5-Ca r b oxa m id o-6-(2,4-d iflu or op h en yl)-4-et h yl-1-
{N-(4-[4-m eth oxyca r bon yl-4-p h en ylp ip er id in -1-yl]p ip er i-
d in -1-yl)ca r b oxa m id o}-2-oxo-1,2,3,6-t et r a h yd r op yr im i-
dine (41).(a)(+)-5-Benzyloxycarbonyl-6-(2,4-difluorophenyl)-
4-eth yl-1-{N-(4-[4-m eth oxyca r bon yl-4-p h en ylp ip er id in -
1 -y l ] p i p e r i d i n -1 -y l ) c a r b o x a m i d o }-2 -o x o -1 ,2 ,3 ,6 -
tetr a h yd r op yr im id in e (39). To a solution of 382 (140 mg,
0.254 mmol) and 25 (82 mg, 0.272 mmol) in THF (15 mL) was
added K2CO3 (0.50 g). The resulting suspension was stirred
over 10 h at room temperature before filtered. The filtrate was
cooled in an ice bath and 6 N HCl (5 mL) was added. The
resulting mixture was warmed to room temperature and
stirred for 30 min before adjusting the pH to 8 with aqueous
10% NaOH. The mixture was extracted with EtOAc (50 mL).
The organic layer was washed with 10% K2CO3 (20 mL) and
brine (50 mL), dried (K2CO3), and concentrated and the residue
was purified by column chromatography on silica gel (CHCl3/
MeOH/2 N NH3 in MeOH ) 100:3:1) to afford the desired
1
product (184 mg, 97%). [R] ) +72 (c ) 0.58, CHCl3). H NMR
(CDCl3): δ 1.19 (t, J ) 7 Hz, 3 H), 1.55-1.70 (m, 4 H), 1.80-
1.94 (m, 2 H), 2.10-2.38 (m, 4 H), 2.48-2.60 (m, 2 H), 2.62-
2.85 (m, 4 H), 3.61 (s, 3 H), 4.86-5.06 (m, 2 H), 6.64-6.74 (m,
2 H), 7.03-7.12 (m, 2 H), 7.22-7.38 (m, 10 H).
(b) (+)-6-(2,4-Diflu or op h en yl)-4-eth yl-1-{N-(4-[4-m eth -
oxyca r bon yl-4-p h en ylp ip er id in -1-yl]p ip er id in -1-yl)ca r -
boxa m id o}-2-oxo-1,2,3,6-tetr a h yd r op yr im id in e-5-ca r box-
ylic Acid (40). To a solution of 39 (166 mg, 0.240 mmol) in
MeOH (10 mL) was added 10% Pd-C (25 mg) in portions in
about 10 min. The resulting suspension was hydrogenated at
100 psi for 6 h at room temperature. The mixture was filtered
through a pad of Celite and the filtrate was concentrated to
leave the product as a white solid (135 mg, 92%).25 The product
was used in the next step without further purification. [R] )
+ 96 (c ) 0.75, 20% MeOH-CHCl3).
(c) (+)-5-Ca r boxa m id o-6-(2,4-d iflu or op h en yl)-4-eth yl-
1-{N-(4-[4-m et h oxyca r b on yl-4-p h en ylp ip er id in -1-yl]p i-
p er id in -1-yl)ca r b oxa m id o}-2-oxo-1,2,3,6-t et r a h yd r op y-
r im id in e (41). To a solution of 40 (115 mg, 0.188 mmol) in
CH2Cl2 (30 mL) were added EDC (107 mg, 0.564 mmol) and
DMAP (69 mg, 0.564 mmol). The resulting mixture was stirred
at room temperature for 1 h. Then NH3 gas was bubbled
through the solution for 3 h. The resulting mixture was stirred
over 2 days before washed with aqueous NH4Cl (30 mL × 3)
and brine (3 × 30 mL). The organic phase was dried (K2CO3),
concentrated, and purified by column chromatography (CHCl3/
MeOH/2 M NH3 in MeOH ) 100:4:1) to afford the product as
a white solid (80 mg, 70%). [R] ) + 107° (c ) 0.88, CHCl3). 1H
NMR (CDCl3): δ 1.05-1.25 (m, 6 H), 1.65-1.98 (m, 4 H), 2.06-
2.38 (m, 4 H), 2.46-2.80 (m, 6 H), 3.10-3.33 (m, 2 H), 3.61 (s,
3 H), 6.53 (s, 1 H), 6.75-6.95 (m, 3 H), 7.20-7.38 (m, 5 H),
7.60-7.70 (m, 1 H), 11.20-11.30 (m, 1 H). HCl salt Mp: 122-
124 °C. Anal. (C32H38N5O5ClF2‚0.25CHCl3) C, H, N.
(+)-5-Met h oxyca r b on yl-1-{N-(4-[4-m et h oxyca r b on yl-
4-phenylpiperidin-1-yl]piperidin-1-yl)carboxamido}-4-meth-
oxymethyl-2-oxo-1,2,3,6-tetrahydro-6-(3,4,5-trifluorophenyl)-
p yr im id in e (37). (a ) 5-Met h oxyca r b on yl-4-m et h oxy-
m eth yl-1,2,3,6-tetr a h yd r o-2-oxo-6-(3,4,5-tr iflu or op h en yl)-
p yr im id in e (33). Prepared from 3,4,5-trifluorobenzaldehyde
(37.0 g, 230 mmol), methyl 4-methoxyacetoacetate (33.6 g, 230
mmol), and urea (20.7 g, 345 mmol) using a similar procedure
described earlier. The product was obtained as a white powder
(72.9 g, 94%).
(b ) (+)-5-Met h oxyca r b on yl-4-m et h oxym et h yl-2-oxo-
1,2,3,6-tetr ah ydr o-6-(3,4,5-tr iflu or oph en yl)pyr im idin e [(+)-
33]. The racemic 33 was resolved by chiral HPLC [Chiralcel
OD 20 × 250 mm #369-703-30604]; λ 254 nm; hexanes/ethanol,
90/10; 80 mg/injection; retention time of the desired enanti-
omer: 16.94 min. The first enantiomer peak to elute gave (+)-
33 (40-42 wt % isolation of the desired enantiomer from the
racemate). [R]D ) +86.8 (c ) 0.5, CHCl3).
6-(3,4-Diflu or op h en yl)-1-{N-[3-[4-(6′-h yd r oxyp h en yl-
ison ip ecotic a cid la cton e)-1-yl]p r op yl]ca r boxa m id o}-5-
m et h oxyca r b on yl-4-m et h yl-2-oxo-1,2,3,6-t et r a h yd r op y-
r im id in e (46). (a ) N-(ter t-Bu toxyca r bon yla m in op r op yl)-
(c) (+)-5-Met h oxyca r b on yl-4-m et h oxym et h yl-2-oxo-
1,2,3,6-t et r a h yd r o-6-(3,4,5-t r iflu or op h en yl)-1-[(4-n it r o-
p h en yloxy)ca r bon yl]p yr im id in e (35). Prepared from (+)-

Novel R1a Adrenoceptor-Selective Antagonists. 2
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23 4789
4-(6′-h yd r oxyp h en yl)ison ip ecotic Acid La cton e. To a
stirred solution of the 4-phenylisonipecotic acid lactone15 (42a ;
0.736 g, 3.64 mmol) in dioxane (20 mL) were added N-(tert-
butoxycarbonyl)-3-bromopropylamine (43; 0.953 g, 4 mmol)
and K2CO3 (1.00 g, 7.28 mmol) and the mixture was heated
at reflux temperature for 24 h. The reaction mixture was cooled
to room temperature, concentrated, and partitioned between
CHCl3 (40 mL) and water (5 mL). The organic layer was dried
(Na2SO4) and concentrated. The crude product was purified
by column chromatography (EtOAc:MeOH, 9:1) to yield the
(42c; 0.566 g, 3.27 mmol) and N-(tert-butoxycarbonyl)-3-
bromopropylamine (0.772 g, 3.27 mmol) using a similar
procedure described earlier to give the product (0.856 g, 79%).
1H NMR (CDCl3): δ 1.45 (s, 9 H), 1.63-2.04 (m, 6 H), 2.33-
2.52 (m, 4 H), 2.87 (d, J ) 11.0 Hz, 2 H), 3.20 (br s, 2 H), 5.07
(s, 2 H), 5.6 (br s, 1 H), 7.13-7.28 (m, 4 H).
(b ) N-(Am in op r op yl)-4-(isob en zofu r a n yl)p ip er id in e
(45c). Prepared from 42 (0.50 g, 1.51 mmol) using a similar
procedure described earlier (0.340 g, 98%).
(c) 6-(3,4-Diflu or op h en yl)-1-{N-[[4-(isoben zofu r a n yl)-
piper idin -1-yl]pr opyl]car boxam ido}-5-m eth oxycar bon yl-
4-m eth yl-2-oxo-1,2,3,6-tetr a h yd r op yr im id in e (48). Pre-
pared from 26 (0.052 g, 0.112 mmol) and 45c (0.032 g, 0.123
mmol) using a similar procedure described earlier (0.040 g,
1
product as a colorless oil (0.574 g, 44%). H NMR (CDCl3): δ
1.46 (s, 9 H), 1.73 (t, J ) 6.3 Hz, 2 H), 2.00-2.05 (m, 4 H),
2.59 (t, J ) 6.3 Hz, 2 H), 2.70-2.84 (m, 4 H), 3.24 (d, J ) 5.8
Hz, 2 H), 5.59 (br s, 1 H), 7.12 (t, J ) 8.1 Hz), 7.28-7.33 (m,
2 H).
1
64%). H NMR (CDCl3): δ 1.73-1.78 (m, 7 H), 1.93-2.04 (m,
(b ) N-(3-Am in op r op yl)-4-(6′-h yd r oxyp h en yl)ison ip e-
cotic Acid La cton e (45a ). To N-(tert-butoxycarbonylamino-
propyl)-4-(6′-hydroxyphenyl)isonipecotic acid lactone (0.254 g,
0.707 mmol) in CH2Cl2 (5 mL) was added trifluoroacetic acid
(1 mL) and the solution stirred at room temperature for 1 h.
It was concentrated, neutralized with aqueous 10% KOH
solution and extracted with CH2Cl2 (25 mL). The organic layer
was dried (Na2SO4) and concentrated to give 0.183 g (100%)
of the product which was used as such in the next step.
(c) 6-(3,4-Diflu or op h en yl)-1-{N-[3-[4-(6′-h yd r oxyp h en -
ylison ip ecotic a cid la cton e)-1-yl] p r op yl]ca r boxa m id o}-
5-m et h oxyca r b on yl-4-m et h yl-2-oxo-1,2,3,6-t et r a h yd r o-
p yr im id in e (46). Prepared from amine 45a (0.054 g, 0.207
mmol) and 26 (0.080 g, 0.173 mmol) using a similar procedure
described earlier to give the product (0.055 g, 56%) as a syrup.
1H NMR (CDCl3): δ 1.63-1.76 (m, 4 H), 2.14-2.19 (m, 2 H),
2.40-2.48 (m, 7 H), 2.86 (d, J ) 11 Hz, 2 H), 3.30-3.41 (m, 2
H), 3.68 (s, 3 H), 6.68 (s, 1 H), 7.01-7.17 (m, 3 H), 7.38 (d, J
) 7.4 Hz, 1 H), 7.49 (t, J ) 7.4 Hz, 1 H), 7.63 (t, J ) 7.4 Hz,
1 H), 7.83 (d, J ) 7.4 Hz, 1 H), 8.83 (t, J ) 5.4 Hz, 1 H). HCl
salt Mp: 173-176 °C. Anal. (C27H31F2N4O6Cl‚1.0H2O) C, H,
N.
2 H), 2.33-2.48 (m, 6 H), 2.83 (d, J ) 11.8 Hz, 2 H), 3.35-
3.41 (m, 2 H), 3.71 (s, 3 H), 5.06 (s, 2 H), 6.75 (s, 1 H), 7.04-
7.26 (m, 7 H), 8.82 (t, J ) 5.1 Hz, 1 H). HCl salt Mp: 178-182
°C. Anal. (C29H34F2N4O5Cl2‚0.6H2O) C, H, N.
6-(3,4-Diflu or op h en yl)-1-{N-[[4-(d ih yd r oin d en yl)p i-
p er id in -1-yl]p r op yl]ca r boxa m id o}-5-m eth oxyca r bon yl-
4-m et h yl-2-oxo-1,2,3,6-t et r a h yd r op yr im id in e (49). (a )
N-(ter t-Bu toxycar bon ylam in opr opyl)-4-(dih ydr oin den yl)-
p ip er id in e. Prepared from 4-(dihydroindenyl)piperidine15
(42d ; 0.790 g, 4.22 mmol) and N-(tert-butoxycarbonyl)-3-
bromopropylamine (1.10 g, 4.64 mmol) using a similar proce-
dure described earlier (0.886 g, 61%). 1H NMR (CDCl3): δ 1.46
(s, 9 H), 1.55 (d, J ) 11.3 Hz, 2 H), 1.69 (t, J ) 6.3 Hz, 2 H),
1.88-2.47 (m, 6 H), 2.47 (t, J ) 6.3 Hz, 2 H), 2.88 (t, J ) 3.3
Hz, 4 H), 3.23 (d, J ) 5.6 Hz, 2 H), 5.85 (br s, 1 H), 7.18 (s, 4
H).
(b) N-(3-Am in op r op yl)-4-(d ih yd r oin d en yl)p ip er id in e
(45d ). Prepared from 42d (0.180 g, 0.52 mmol) using a similar
procedure described earlier (0.156 g, 100%).
(c) 6-(3,4-Diflu or op h en yl)-1-{N-[[4-(d ih yd r oin d en yl)-
piper idin -1-yl]pr opyl]car boxam ido}-5-m eth oxycar bon yl-
4-m eth yl-2-oxo-1,2,3,6-tetr a h yd r op yr im id in e (49). Pre-
pared from 26 (0.050 g, 0.108 mmol) and N-(3-aminopropyl)-
4-(dihydroindenyl)piperidine (45d ; 0.053 g, 0.216 mmol) using
a similar procedure described earlier (0.060 g, 100%). 1H NMR
(CDCl3): δ 1.52 (d, J ) 13.2 Hz, 2 H), 1.70-2.07 (m, 8 H),
2.12 (t, J ) 10.3 Hz, 2 H), 2.42 (s, 4 H), 2.86-2.91 (m, 3 H),
3.32-3.43 (m, 2 H), 3.72 (s, 3 H), 6.71 (s, 1 H), 7.04-7.19 (m,
7 H), 8.82 (t, J ) 5.2 Hz, 1 H). HCl salt Mp: 150-153 °C. Anal.
(C30H36F2N4O6Cl2) C, H, N.
6-(3,4-Diflu or op h en yl)-5-m eth oxyca r bon yl-4-m eth yl-2-
oxo-1-{N-[[spir o(isoben zofu r an -1(3H),4′-piper idin )-3-on e]-
1-pr opyl]car boxam ido}-1,2,3,6-tetr ah ydr opyr im idin e (47).
(a )
N -(t er t -B u t o x y c a r b o n y la m i n o p r o p y l)s p i r o -
(isoben zofu r a n -1(3H),4′-p ip er id in )-3-on e. Prepared from
spiro(isobenzofuran-1(3H),4′-piperidin)-3-one15 (42b; 0.393 g,
19.3 mmol) and N-(tert-butoxycarbonyl)-3-bromopropylamine
(0.506 g, 21.2 mmol) using a similar procedure described
earlier to give the required product as a colorless oil (0.438 g,
1
6-(3,4-Diflu or op h en yl)-5-m eth oxyca r bon yl-4-m eth yl-2-
oxo-1-{N-[[spir o(isoben zopyr an -1(3H),4′-piper idin )-3-on e]-
1-pr opyl]car boxam ido}-1,2,3,6-tetr ah ydr opyr im idin e (50).
(a ) N-(ter t-Bu toxyca r bon yla m in op r op yl)sp ir o(isoben zo-
pyr an -1(3H),4′-piper idin )-3-on e. Prepared from spiro(isoben-
zopyran-1(3H),4′-piperidin)-3-one15 (42e; 0.242 g, 1.11 mmol)
and N-(tert-butoxycarbonyl)-3-bromopropylamine (0.291 g, 1.22
mmol) using a similar procedure described earlier (0.237 g,
63%). H NMR (CDCl3): δ 1.46 (s, 9 H), 1.70-1.76 (m, 4 H),
2.19-2.23 (m, 2 H), 2.47-2.57 (m, 4 H), 2.95 (d, J ) 11 Hz, 2
H), 3.24 (d, J ) 5.89 Hz, 2 H), 5.50 (s, 1 H), 7.40 (d, J ) 7.35
Hz, 1 H), 7.55 (t, J ) 7.35 Hz, 1 H), 7.68 (d, J ) 7.35 Hz, 1 H),
7.89 (d, J ) 7.36 Hz, 1 H).
(b) N-(3-Am in op r op yl)sp ir o(isoben zofu r a n -1(3H),4′-p i-
p er id in )-3-on e (45b). Prepared from N-(tert-butoxycarbonyl-
aminopropyl)spiro(isobenzofuran-1(3H),4′-piperidin)-3-one (0.438
g, 12.1 mmol) and trifluoroacetic acid (1 mL) using a similar
procedure described earlier to give the amine 45b (0.150 g,
47%) which was used as such in the next step.
1
57%). H NMR (CDCl3): δ 1.39 (s, 9 H), 1.65 (t, J ) 6.47 Hz,
2 H), 1.96 (d, J ) 15.6 Hz, 2 H), 2.22 (t, J ) 2.5 Hz, 2 H),
2.46-2.56 (m, 4 H), 2.80-2.84 (m, 2 H), 3.17-3.18 (m, 2 H),
3.73 (s, 2 H), 5.58 (br s, 1 H), 7.12 (s, 1 H), 7.22-7.27 (m, 3 H).
(c) 6-(3,4-Diflu or op h en yl)-5-m eth oxyca r bon yl-4-m eth -
yl-2-oxo-1-{N-[[sp ir o(isoben zofu r a n -1(3H),4′-p ip er id in )-
3-on e]-1-p r op yl]ca r boxa m id o}-1,2,3,6-tetr a h yd r op yr im -
id in e (47). Prepared from 26 (0.060 g, 0.129 mmol) and 45b
(0.037 g, 0.142 mmol) using a similar procedure described
(b) N-(Am in op r op yl)sp ir o(isoben zop yr a n -1(3H),4′-p i-
p er id in )-3-on e (45e). Prepared from N-(tert-butoxycarbonyl-
aminopropyl)spiro(isobenzopyran-1(3H),4′-piperidin)-3-one (0.237
g, 0.72 mmol) using a similar procedure described earlier
(0.150 g, 87%).
1
earlier to give the product (0.072 g, 97%) as a syrup. H NMR
(CDCl3): δ 1.63-1.76 (m, 4 H), 2.14-2.19 (m, 2 H), 2.40-2.48
(m, 7 H), 2.86 (d, J ) 11 Hz, 2 H), 3.30-3.41 (m, 2 H), 3.68 (s,
3 H), 6.68 (s, 1 H), 7.01-7.17 (m, 3 H), 7.38 (d, J ) 7.4 Hz, 1
H), 7.49 (t, J ) 7.4 Hz, 1 H), 7.63 (t, J ) 7.4 Hz, 1 H), 7.83 (d,
J ) 7.4 Hz, 1 H), 8.83 (t, J ) 5.4 Hz, 1 H). HCl salt Mp: 185-
187 °C. Anal. (C29H32F2N5O6Cl2‚1.0H2O) C, H, N.
6-(3,4-Diflu or op h en yl)-1-{N-[[4-(isob en zofu r a n yl)p i-
p er id in -1-yl]p r op yl]ca r boxa m id o}-5-m eth oxyca r bon yl-
4-m et h yl-2-oxo-1,2,3,6-t et r a h yd r op yr im id in e (48). (a )
N-(ter t-Bu toxycar bon ylam in opr opyl)-4-(isoben zofu r an yl)-
p ip er id in e. Prepared from 4-(isobenzofuranyl)piperidine15
(c) 6-(3,4-Diflu or op h en yl)-5-m eth oxyca r bon yl-4-m eth -
yl-2-oxo-1-{N-[[sp ir o(isoben zop yr a n -1(3H),4′-p ip er id in )-
3-on e]-1-p r op yl}]a r boxa m id o}-1,2,3,6-tetr a h yd r op yr im -
id in e (50). Prepared from 26 (0.077 g, 0.166 mmol) and
N-(aminopropyl)spiro(isobenzopyran-1(3H),4′-piperidin)-3-
one (45e; 0.050 g, 0.183 mmol) using a similar procedure
1
described earlier (0.072 g, 72%). H NMR (CDCl3): δ 1.72 (t,
J ) 6.1 Hz, 2 H), 1.93 (d, J ) 16.2 Hz, 2 H), 2.19 (t, J ) 6.9
Hz, 2 H), 2.38 (s, 3 H), 2.43-2.55 (m, 4 H), 2.81 (s, 2 H), 3.28-
3.42 (m, 2 H), 3.67 (s, 3 H), 3.73 (s, 3 H), 6.66 (s, 1 H), 7.0-
7.25 (m, 4 H), 7.28 (s, 2 H), 7.45 (s, 1 H), 8.82 (t, J ) 5.2 Hz,

4790 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23
Murali Dhar et al.
1 H). HCl salt Mp: 165-168 °C. Anal. (C30H34F2N4O6Cl2‚
2.0H2O) C, H, N.
off-white solid was filtered through a sintered glass funnel and
washed with 50 mL of CH2CL2 and 50 mL of Et2O. The off-
white powder was dried under vacuum and used in the next
step without further purification (0.36 g, 35% yield). Mass
spectrum (ESMS, MH+) was consistent with the proposed
structure. The regiochemistry of the methyl groups was
assigned based on the symmetrical nature of the 1H NMR
spectrum and lack of splitting for the aromatic protons. The
1H NMR spectrum was also recorded in DMSO-d6 and was
1-{N-[[4-(Ben zop yr a n yl)p ip er id in -1-yl]p r op yl]ca r box-
am ido}-6-(3,4-diflu or oph en yl)-5-m eth oxycar bon yl-4-m eth -
yl-2-oxo-1,2,3,6-tetr a h yd r op yr im id in e (51). (a ) [4-(Ben -
zopyr an yl)piper idin -1-yl]pr opylam in e (45f). Prepared using
a similar procedure described for 45e.
(b) 1-{N-[[4-(Ben zop yr a n yl)p ip er id in -1-yl]p r op yl]ca r -
boxa m id o}-6-(3,4-d iflu or op h en yl)-5-m eth oxyca r bon yl-4-
m eth yl-2-oxo-1,2,3,6-tetr a h yd r op yr im id in e (51). Prepared
from 26 (0.048 g, 0.103 mmol) and [4-(benzopyranyl)piperidin-
1-yl]propylamine (45f; 0.053 g, 0.207 mmol) using a similar
procedure described earlier (0.066 g, 100%). [R]D ) +69 (c )
1
identical to the one in CD3OD. Mp: ) 246-252 °C. H NMR
(CD3OD): δ 2.24 (s, 12 H), 2.59 (br s, 4 H), 3.17 (br s, 4 H),
6.82 (s, 2 H), 6.91 (s, 4 H). Mass spectrum (ESMS, MH+, low
res.): 293 (100%). Anal. Calcd for C21H28ClN.0.5CH2Cl2: C,
69.35; H, 7.85; N, 3.76. Found: C, 69.76; H, 7.61; N, 3.99.
1
1.32, CHCl3). H NMR (CDCl3): δ 1.70-2.06 (m, 6 H), 2.43-
2.47 (m, 7 H), 2.75-2.82 (m, 4 H), 3.33-3.42 (m, 2 H), 3.72 (s,
3 H), 3.89 (t, J ) 5.1 Hz, 2 H), 6.71 (s, 1 H), 7.05-7.21 (m, 7
H), 8.85 (t, J ) 5.2 Hz, 1 H). HCl salt Mp: 150-152 °C. Anal.
(C30H36F2N4O5Cl2‚2.5H2O) C, H, N.
6-(3,4-Diflu or op h en yl)-5-m eth oxyca r bon yl-4-m eth yl-2-
oxo-1-{N-[[4-(t et r a lin yl)p ip er id in -1-yl]p r op yl]ca r b ox-
a m id o}-1,2,3,6-tetr a h yd r op yr im id in e (52). (a ) N-(ter t-
Bu t oxyca r b on yla m in op r op yl)-4-(t et r a lin yl)p ip er id in e.
Prepared from 4-(tetralinyl)piperidine15 (42g; 0.512 g, 2.56
mmol) and N-(tert-butoxycarbonyl)-3-bromopropylamine (0.666
g, 2.80 mmol) using a similar procedure described earlier
(0.258 g, 28%). 1H NMR (CDCl3): δ 1.47 (s, 9 H), 1.59-2.83
(m, 18 H), 3.23-3.25 (m, 2 H), 6.27 (br s, 1 H), 7.05-7.14 (m,
2 H).
1-(3-Br om op r op ylca r ba m oyl)-6-(3,4-d iflu or op h en yl)-5-
m et h oxyca r b on yl-4-m et h yl-2-oxo-1,2,3,6-t et r a h yd r op y-
r im id in e (55). To a well-stirred solution of 26 (4.1 g, 9.1
mmol) in THF (20 mL) was added aqueous HCl (10%, 10 mL)
at room temperature and the resulting solution was stirred
overnight. THF was evaporated under reduced pressure and
the resulting residue was extracted with EtOAc (3 × 20 mL),
washed with brine (10 mL), and then dried (Na2SO4). The
solvent was evaporated under reduced pressure to obtain (+)-
6-(3,4-difluorophenyl)-5-methoxycarbonyl-4-methyl-1-[(4-nitro-
phenyloxy)carbonyl]-2-oxo-1,2,3,6-tetrahydropyrimidine as a
viscous oil (3.8 g). It was redissolved in THF (20 mL) and mixed
with 3-bromopropylamine hydrobromide (2.33 g, 10.8 g) and
NaHCO3 (1.81 g, 21.5 mmol) and the resulting suspension was
stirred at room temperature overnight. Solvent was evaporated
under reduced pressure and the resulting residue was treated
with water (10 mL) and then extracted with EtOAc (3 × 20
mL). The EtOAc extracts were combined and dried (Na2SO4)
and the solvent was evaporated to obtain the product (3.28 g,
(b) N-(Am in opr opyl)-4-(tetr alin yl)piper idin e (45g). Pre-
pared from N-(tert-butoxycarbonylaminopropyl)-4-(tetralinyl)-
piperidine (0.258 g, 0.720 mmol) using a similar procedure
described earlier (0.183 g, 99%).
(c) 6-(3,4-Diflu or op h en yl)-5-m eth oxyca r bon yl-4-m eth -
yl-2-oxo-1,2,3,6-tetr a h yd r o-1-{N-[[4-(tetr a lin yl)p ip er id in -
1-yl]p r op yl]ca r boxa m id o}p yr im id in e (52). Prepared from
26 (0.025 g, 0.054 mmol) and N-(aminopropyl)-4-(tetralinyl)-
piperidine (45g; 0.029 g, 0.010 mmol) using a similar procedure
1
83%). H NMR (CDCl3): 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.
1
described earlier (0.026 g, 87%). H NMR (CDCl3): δ 1.57 (d,
Rea ction of P ip er id in es 54a -54d a n d (3-Br om op r o-
p yl)ca r ba m oyld ih yd r op yr im id in on e 55. A mixture of 55
(45 mg, 0.10 mmol), 4,4-diarylpiperidine hydrochloride (0.10
mmol), and diisopropylethylamine (0.5 mL) in dioxane (2.0 mL)
was heated at reflux temperature for 2 days. The mixture was
cooled and the crude product was purified by preparative thin-
layer chromatography on silica gel using 2-3% MeOH in
EtOAc as eluent. The products were converted to their HCl
salts by treatment with 1 N HCl in ether.
J ) 13.2 Hz, 2 H), 1.73-2.27 (m, 9 H), 2.41 (s, 6 H), 2.75 (s, 4
H), 3.31-3.45 (m, 2 H), 3.71 (s, 3 H), 6.70 (s, 1 H), 7.00-7.39
(m, 6 H), 7.48 (d, J ) 7.7 Hz, 1 H), 8.83 (s, 1 H). HCl salt Mp:
148-152 °C. Anal. (C31H38F2N4O5Cl2‚1.0H2O) C, H, N.
6-(3,4-Diflu or 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}-5-m eth oxyca r bon yl-4-m eth yl-
2-oxo-1,2,3,6-tetr a h yd r op yr im id in e (56). Prepared from 26
(231 mg, 0.500 mmol) and 3-(4,4-diphenylpiperidin-1-yl)-
propylamine3 (220 mg, 0.750 mmol) using a similar procedure
described earlier (286 mg, 93%). HCl salt Mp: 161-164 °C.
1H NMR (CDCl3): R 1.25 (m, 4 H), 1.68 (q, J ) 7.6 Hz, 2 H),
2.39 (s, 3 H), 2.60-2.20 (m, 6 H), 3.60-3.20 (m, 3 H), 3.69 (s,
3 H), 6.67 (s, 1 H), 7.80 (b, 1 H), 8.81 (m, 1 H). Anal.
(C34H37F2N4O4Cl‚0.25C6H14) C, H, N.
1-{[3-[Bis-4-(4-ch lor op h en yl)p ip er id in -1-yl]p r op yl]ca r -
boxa m id o}-6-(3,4-d iflu or op h en yl)-5-m eth oxyca r bon yl-4-
m eth yl-2-oxo-1,2,3,6-tetr a h yd r op yr im id in e (57). (a ) Bis-
4-(4-ch lor oph en yl)piper idin e Hydr och lor ide (54a).Prepared
from 4-(4-chlorophenyl)-4-hydroxypiperidine and chloroben-
zene. Yield: 92%. 1H NMR (CD3OD): δ 7.60-7.30 (m, 8 H),
3.18 (m, 4 H), 2.65 (m, 4 H). Anal. (C17H18N1Cl3) C, H, N.
Gen er a l P r oced u r e for th e P r ep a r a tion of Com p ou n d s
57-60. Gen er a l P r oced u r e for th e P r ep a r a tion of 4,4-
Dia r ylp ip er id in es 54a -54d . A mixture of 4-aryl-4-hydrox-
ypiperidine (53a -53d ; 0.50 g), substituted benzene (3.0 mL),
and AlCl3 (1.0 g) was stirred at room temperature for 3 days.
The reaction mixture was treated with ice-water (10 mL) and
diluted with tert-butyl methyl ether; the resulting hydrochlo-
ride salt formed was filtered, washed with water and ether,
dried, and used in the next step after spectral characterization.
Full experimental details for 54e will be given below due to
the unexpected product (54e) obtained from the Friedel-Crafts
reaction of 4-hydroxy-4-(4-methylphenyl)piperidine and m-
xylene. Other examples of this highly unusual reaction will
be reported in due course.
Bis-4-(3,5-d im eth ylp h en yl)p ip er id in e Hyd r och lor id e
(54e). To a turbid solution of 4-hydroxy-4-(4-methylphenyl)-
piperidine (3.14 mmol, 0.60 g) in m-xylene (10 mL) at room
temperature was added anhydrous aluminum chloride (4.32
mmol, 0.58 g) in one portion (isotherm was observed) and the
resulting suspension was allowed to stir overnight under argon
atmosphere. The dark solution was then poured over an ice-
water bath and was stirred vigorously for 1 h. The resulting
(b) 1-{[3-[Bis-4-(4-ch lor op h en yl)p ip er id in -1-yl]p r op yl]-
car boxam ido}-6-(3,4-diflu or oph en yl)-5-m eth oxycar bon yl-
4-m eth yl-2-oxo-1,2,3,6-tetr a h yd r op yr im id in e (57). Yield:
1
71%. H NMR (CDCl3): δ 8.83 (t, J ) 7 Hz, 1 H), 7.40-6.90
(m, 12 H), 6.03 (br s, 1 H), 3.72 (s, 3 H), 3.60-3.20 (m, 2 H),
2.76 (m, 2 H), 2.58 (m, 4 H), 2.39 (s, 3 H), 1.85 (q, J ) 7.6 Hz,
2 H), 1.42 (m, 4 H). Anal. (C34H35Cl3N4F2O4‚1.0 Et2O) C, H,
N.
6-(3,4-Diflu or op h en yl)-1-{[3-[4-bis(4-flu or op h en yl)p i-
p er id in -1-yl]p r op yl]ca r boxa m id o}-5-m eth oxyca r bon yl-
4-m eth yl-2-oxo-1,2,3,6-tetr ah ydr opyr im idin e (58). (a) Bis-
4-(4-flu or oph en yl)piper idin e Hydr och lor ide (54b).Prepared
from 4-(4-fluorophenyl)-4-hydroxypiperidine and fluoroben-
zene. Yield: 69%. 1H NMR (CD3OD): δ 7.40-7.05 (m, 8 H),
3.19 (m, 4 H), 2.65 (m, 4 H).
(b) 6-(3,4-Diflu or op h en yl)-1-{[3-[4-bis(4-flu or op h en yl)-
piper idin -1-yl]pr opyl]car boxam ido}-5-m eth oxycar bon yl-
4-m eth yl-2-oxo-1,2,3,6-tetr a h yd r op yr im id in e (58). Yield:
1
80%. H NMR (CDCl3): δ 8.81 (m, 1 H), 7.80 (b, 1 H), 7.30-
6.80 (m, 11 H), 6.67 (s, 1 H), 3.69 (s, 3 H), 3.60-3.20 (m, 3 H),

Novel R1a Adrenoceptor-Selective Antagonists. 2
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23 4791
2.60-2.20 (m, 6 H), 2.39 (s, 3 H), 1.68 (q, J ) 7.6 Hz, 2 H),
1.25 (m, 4 H). Anal. (C34H35F4N4O4Cl‚1H2O) C, H, N.
6-(3,4-Diflu or op h en yl)-1-{N-[3-[4-(4-m et h ylp h en yl)-4-
(2-m eth ylp h en yl)p ip er id in -1-yl]p r op yl]ca r boxa m id o}-5-
m et h oxyca r b on yl-4-m et h yl-2-oxo-1,2,3,6-t et r a h yd r op y-
r im id in e (59). (a ) 4-(4-Meth ylp h en yl)-4-(2-m eth ylp h en yl)-
p ip er id in e Hyd r och lor id e (54c). Yield: 99%. MS: 266 (M
+ 1, 100%). Anal. (C19H24NCl‚0.15CH2Cl2) C, H, N.
(b) 6-(3,4-Diflu or op h en yl)-5-m eth oxyca r bon yl-4-m eth -
yl-1-{N-[3-[4-(4-m eth ylp h en yl)-4-(2-m eth ylp h en yl)p ip er i-
d in -1-yl]p r op yl]ca r boxa m id o}-2-oxo-1,2,3,6-tetr a h yd r o-
p yr im id in e (59). Yield: 64%. HCl salt Mp: 143-147 °C. [R]D
) +79.8° (c ) 0.25, MeOH). Anal. (C37H44N4O4F2Cl‚0.5CH2-
Cl2) C, H, N.
6-(3,4-Diflu or oph en yl)-1-{[3-[4-bis(3,5-dim eth ylph en yl)-
piper idin -1-yl]pr opyl]car boxam ido}-5-m eth oxycar bon yl-
4-m eth yl-2-oxo-1,2,3,6-tetr a h yd r op yr im id in e (60). Yield:
77%. Mp: 176-180 °C. [R] ) +93.6 (c ) 0.28, MeOH). 1H NMR
(CDCl3): δ 8 (m, 2 H), 2.25 (s, 12 H), 2.30 (t, J ) 6.9 Hz, 2 H),
2.37-2.42 (m, 7 H), 2.47 (br s, 4 H), 3.22-3.41 (m, 2 H), 3.71
(s, 3 H), 6.68 (s, 1 H), 6.77 (s, 2 H), 6.85 (s, 4 H), 7.01-7.20
(m, 4 H), 8.77 (t, J ) 5.4 Hz, 1 H). Anal. (C38H45F2N4O4Cl‚
0.7CH2Cl2) C, H, N.
1-{N-[3-[4-Acetoxy-4-p h en ylp ip er id in -1-yl]p r op yl]ca r -
boxa m id o}-6-(3,4-d iflu or op h en yl)-5-m eth oxyca r bon yl-4-
m eth yl-2-oxo-1,2,3,6-tetr a h yd r op yr im id in e (66). (a )
N-Benzyloxycarbonyl-3-(4-hydroxy-4-phenylpiperidin-1-yl)-
p r op yla m in e (63). A mixture of 4-hydroxy-4-phenylpiperidine
(61; 5.00 g, 0.028 mol), N-benzyloxycarbonyl-3-bromopropyl-
amine (62; 8.45 g, 0.031 mol), and K2CO3 (7.795 g, 0.0564 mol)
in acetone (200 mL) was stirred and heated at reflux temper-
ature for 12 h. Acetone was evaporated at reduced pressure,
and the residue was treated with ice-cold water (400 mL) and
extracted with CH2Cl2 (4 × 120 mL). Solvent was evaporated
from the combined dried (Na2SO4) extracts and the residue
was found to be pure product (9.50 g, 91%) by TLC and 1H
NMR. It was used in the next step as such without any further
purification.
4-(3,4-Diflu or op h en yl)-6-m eth yl-2-oxo-3-{(4-m eth oxy-
4-ph en ylpiper idin -1-yl)pr opyl}-5-m eth oxycar bon yl-1,2,3,4-
tetr a h yd r op yr im id in e (67). To a solution of 26 (0.06 g, 0.129
mmol) in dry CH2Cl2 (10 mL) was added 3-(4-methoxy-4-
phenylpiperidin-1-yl)propylamine5 (65b; 0.072 g, 0.259 mmol)
and the solution was stirred at room temperature for 24 h.
The reaction mixture was stirred for another 1 h after addition
of 6 N HCl (2 mL). It was basified with 10% aqueous KOH
solution (pH ) 9) and extracted with CH2Cl2 (3 × 10 mL). The
combined organic layer was dried (Na2SO4) and concentrated.
The residue was purified by flash chromatography on silica
gel (EtOAc:MeOH, 9:1) to obtain the product as a syrup (0.056
g, 77%). 1H NMR (CDCl3): δ 1.76-2.00 (m, 4 H), 2.39-2.44
(m, 6 H), 2.72-2.85 (m, 2 H), 2.95 (s, 3 H), 3.30 (m, 2 H), 3.71
(s, 3 H), 6.70 (s, 1 H), 7.04-7.41 (m, 8 H), 8.83 (t, J ) 5.2 Hz,
1 H). HCl salt Mp: 170-174 °C. Anal. (C29H36F2N4O5Cl‚
1.3H2O) C, H, N.
6-(3,4-Diflu or op h en yl)-5-m eth oxyca r bon yl-4-m eth yl-2-
oxo-1-{N-[3-(4-ph en ylpiper idin -1-yl)pr opyl]car boxam ido}-
1,2,3,6-tetr a h yd r op yr im id in e (68). Prepared from 26 (100
mg, 0.217 mmol) and 3-(4-phenylpiperidin-1-yl)propylamine
(65c; 95 mg, 0.433 mmol) using a similar procedure described
earlier (105 mg, 89%). 1H NMR (CDCl3): δ 1.76-1.90 (m, 6
H), 2.02-2.25 (m, 2 H), 2.45 (s, 3 H), 2.46-2.58 (m, 2 H), 3.02-
3.10 (m, 2 H), 3.36-3.46 (m, 2 H), 3.68 (s, 3 H), 3.98 (s, 3 H),
6.60 (s, 1 H), 7.02-7.38 (m, 8 H). HCl salt Mp: 133-136 °C.
Anal. (C28H33F2N4O4Cl‚0.2CH2Cl2) C, H, N.
(+)-1-{N-[[4-Cya n o-4-p h en ylp ip er id in -1-yl]p r op yl]ca r -
boxa m id o}-6-(3,4-d iflu or op h en yl)-5-m eth oxyca r bon yl-4-
m eth yl-2-oxo-1,2,3,6-tetr a h yd r op yr im id in e (69). Prepared
from 26 (30 mg, 0.067 mmol) and 65d (30 mg, 0.123 mmol)
using a similar procedure described earlier to afford the
product (30 mg, 81%). (M + 1): 552. 1H NMR (CDCl3): δ 1.70-
1.78 (m, 2 H), 2.04-2.16 (m, 2 H), 2.34 (s, 3 H), 2.35-2.43 (m,
2 H), 2.44-2.52 (m, 4 H), 2.98-3.02 (m, 2 H), 3.32-3.42 (m, 2
H), 3.64 (s, 3 H), 6.68 (s, 1 H), 7.02-7.49 (m, 8 H), 8.84 (t, J )
7 Hz, 1 H). HCl salt Mp: 140-143 °C. Anal. (C29H32F2N5O4Cl)
C, H, N.
6-(3,4-Diflu or op h en yl)-5-m eth oxyca r bon yl-4-m eth yl-1-
{N-[3-(4-m et h yl-4-p h en ylp ip er id in -1-yl)p r op yl]ca r b ox-
am ido}-2-oxo-1,2,3,6-tetr ah ydr opyr im idin e (70). Prepared
from 26 and 65e5 using a similar procedure described earlier
in 0.16 mmol scale. Yield: 71%. [R]D ) + 92.7 (c ) 0.18,
MeOH). 1H NMR (CDCl3): δ 1.21 (s, 3 H), 1.69-1.87 (m, 6 H),
2.09-2.15 (m, 2 H), 2.31 (t, J ) 7.5 Hz, 2 H), 2.32-2.50 (m, 4
H), 2.40 (s, 3 H), 3.30-3.36 (m, 2 H), 3.71 (s, 3 H), 6.69 (s, 1
H), 7.02-7.38 (m, 9 H), 8.78 (t, J ) 5.7 Hz, 1 H). The HCl salt
was hygroscopic. Anal. (C29H35N4O4F2Cl‚0.7CH2Cl2) C, H, N.
(+)-5-Car boxam ido-1-{N-[3-(4-cyan o-4-ph en ylpiper idin -
1-yl)p r op yl]ca r boxa m id o}-6-(2,4-d iflu or op h en yl)-4-eth yl-
2-oxo-1,2,3,6-tetr a h yd r op yr im id in e (73). (a ) (+)-5-(Ben -
zyloxyca r b on yl)-1-{N-[3-(4-cya n o-4-p h en ylp ip er id in -1-
yl)p r op yl]ca r boxa m id o}-6-(2,4-d iflu or op h en yl)-4-eth yl-
2-oxo-1,2,3,6-tetr a h yd r op yr im id in e (71). A mixture of (+)-
5-(benzyloxycarbonyl)-6-(2,4-difluorophenyl)-1,6-dihydro-4-
ethyl-2-methoxy-1-[(4-nitrophenyloxy)carbonyl]pyrimidine2 (38;
6.50 g, 11.81 mmol) and 3-[4-cyano-4-phenylpiperidin-1-yl]-
propylamine5 (65d ; 3.60 g, 15.36 mmol) in THF (500 mL) was
stirred at room temperature for 18 h. It was cooled to 0 °C
and aqueous 10% HCl (2 mL) was added and stirred for 2 h.
The mixture was washed with aqueous NaOH (0.5 N, 30 mL)
and dried (Na2SO4) and the solvent evaporated. The residue
was purified by column chromatography on silica gel using
CHCl3/MeOH/2 M NH3 in MeOH (100/2/1) as the eluent to
obtain product 71 as a white foamy solid (7.05 g, 93%). 1H
NMR (CDCl3): δ 1.16 (t, J ) 7.5 Hz, 3 H), 1.64-1.68 (m, 2 H),
1.99-2.08 (m, 4 H), 2.34-2.42 (m, 4 H), 2.60-2.80 (m, 2 H),
2.89 (br d, J ) 12 Hz, 2 H), 3.18-3.40 (m, 2 H), 5.26 (q, J )
11 Hz, 2 H), 6.60-7.45 (m, 14 H), 8.86 (br t, 1 H, NH).
(b) N-Ben zyloxyca r bon yl-3-(4-a cetoxy-4-p h en ylp ip er i-
d in -1-yl)p r op yla m in e. To a solution of 63 (0.50 g, 1.36 mmol)
in THF (20 mL) at 0 °C was added NaH (60% suspension in
paraffin, 65 mg, 1.63 mmol) and the mixture was stirred for
1.5 h. To this suspension was added acetyl bromide (0.12 mL,
1.63 mmol) and the mixture was stirred at 0 °C for 30 min
and at room temperature for 3 h. Solvent was evaporated and
the residue was mixed with CH2Cl2 (100 mL) and washed with
water (2 × 20 mL). The organic layer was dried (Na2SO4) and
concentrated to obtain the product as a viscous oil (0.485 g,
1
87%). The H NMR showed this product to be pure and it was
used in the next step without any further purification. 1H NMR
(CDCl3): δ 1.82-1.92 (m, 4 H), 2.01 (s, 3 H), 2.24-2.33 (m, 2
H), 2.42-2.50 (m, 4 H), 2.78-2.84 (m, 2 H), 3.24 (m, 2 H), 5.05
(s, 2 H), 6.00 (br s, 1 H), 7.28-7.38 (m, 10 H).
(c) 3-(4-Acet oxy-4-p h en ylp ip er id in -1-yl)p r op yla m in e
(65a ). A mixture of N-benzyloxycarbonyl-3-(4-acetoxy-4-phen-
ylpiperidin-1-yl)propylamine (3.0 g, 7.3 mmol) and 10% Pd-C
(0.3 g) in 1.0 M NH3 in MeOH (50 mL) was hydrogenated at
70 psi at room temperature for 4 h. The catalyst was removed
by filtration and the solvent was evaporated to leave the
product as a viscous oil (2.01 g, 99%). 1H NMR showed it to be
pure product and was used in the next step without any
1
purification. H NMR (CDCl3): δ 1.70-1.82 (m, 4 H), 2.01 (s,
3 H), 2.25-2.35 (m, 2 H), 2.42-2.55 (m, 4 H), 2.82-2.92 (m, 4
H), 7.18-7.36 (m, 5 H).
(d ) 1-{N-[3-[4-Acetoxy-4-p h en ylp ip er id in -1-yl]p r op yl]-
car boxam ido}-6-(3,4-diflu or oph en yl)-5-m eth oxycar bon yl-
4-m eth yl-2-oxo-1,2,3,6-tetr a h yd r op yr im id in e (66). Pre-
pared from 26 (0.295 g, 0.64 mmol) and 65a (0.23 g, 0.832
mmol) using a similar procedure described earlier (0.210 g,
1
55%). H NMR (CDCl3): δ 1.70-1.78 (m, 2 H), 2.02 (s, 3 H),
(b ) 1-{N-[3-(4-Cya n o-4-p h en ylp ip er id in -1-yl)p r op yl]-
ca r boxa m id o}-6-(2,4-d iflu or op h en yl)-4-eth yl-1,2,3,6-tet-
r a h yd r o-2-oxop yr im id in e-5-ca r boxylic Acid (72). To a
suspension of 10% Pd-C (2.1 g) in MeOH (100 mL) and H2O
(20 mL) was added a solution of 71 (7.55 g, 11.2 mL) in
2.22-2.30 (m, 2 H), 2.34 (s, 3 H), 2.36-2.44 (m, 4 H), 2.72-
2.80 (m, 2 H), 3.24-3.40 (m, 2 H), 3.68 (s, 3 H), 6.66 (s, 1 H),
7.02-7.32 (m, 8 H), 8.80 (t, J ) 7 Hz, 1 H). HCl salt Mp: 95-
97 °C. Anal. (C30H35N4O6F2Cl‚0.8CHCl3) C, H, N.

4792 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23
Murali Dhar et al.
methanol (100 mL) and the mixture was hydrogenated at 80
psi for 14 h.25 The black suspension was filtered through a
pad of Celite and washed thoroughly with MeOH (2.0 L) and
MeOH/CHCl3 (1:2, 200 mL). Solvent was evaporated from the
combined filtrate to leave the product 72 as a white solid (6.06
g, 98%). It was used in the next step without further purifica-
tion.
intermediate. It was dissolved in MeOH (40 mL) and treated
with hydrazine (3.0 mL). The resulting mixture was heated
at reflux temperature overnight. The white solid formed was
filtered and the solvent was evaporated from the filtrate. The
residue was purified by column chromatography on silica gel
using CHCl3:MeOH:2 M NH3 in MeOH (100:8:4) as the eluent
to yield the desired amine 78a (607 mg, 55%) as a colorless
oil.
(c) (+)-5-Ca r boxa m id o-1-{N-[3-(4-cya n o-4-p h en ylp i-
per idin -1-yl)pr opyl]car boxam ido}-6-(2,4-diflu or oph en yl)-
4-eth yl-2-oxo-1,2,3,6-tetr a h yd r op yr im id in e (73). A mix-
ture of 72 (6.30 g, 11.2 mmol), EDC (4.29 g, 22.4 mmol, 2
equiv), and DMAP (3.41 g, 27.95 mmol, 2.5 equiv) in anhydrous
CH2Cl2 (400 mL) was stirred at room temperature for 2 h. To
this was added 40% aqueous NH3 (6.13 g, 5 equiv) and the
stirring continued for 12 h. The mixture was diluted with CH2-
Cl2 (200 mL) and washed with saturated aqueous NH4Cl
solution (3 × 200 mL). Solvent was evaporated from the dried
(Na2SO4) organic layer and the residue was purified by column
chromatography on silica gel using CHCl3-MeOH-2 M NH3
in methanol (100/2/1) as the eluent to obtain the desired
(c) 1-{[3-[4-Cya n o-4-(2-flu or op h en yl)p ip er id in -1-yl]-
p r op yl]ca r boxa m id o}-6-(3,4-d iflu or op h en yl)-5-m eth oxy-
ca r b on yl-4-m et h oxym et h yl-2-oxo-1,2,3,6-t et r a h yd r op y-
r im id in e (80). Prepared from 34 (25 mg, 0.052 mmol) and
1-N-(3-aminopropyl)-4-cyano-4-(2-fluorophenyl)piperidine (78a ;
26 mg, 0.10 mmol) using a similar procedure described earlier
1
(25 mg, 81%). H NMR (CDCl3): δ 1.70-1.78 (m, 2 H), 2.00-
2.08 (m, 4 H), 2.38-2.50 (m, 4 H), 2.94-3.00 (m, 2 H), 3.30-
3.47 (m, 2 H), 3.48 (s, 3 H), 3.70 (s, 3 H), 4.68 (s, 2 H), 6.67 (s,
1 H), 6.97-7.45 (m, 7 H), 7.69 (br s, 1 H), 8.97 (t, J ) 7 Hz, 1
H). HCl salt Mp: 132-135 °C. Anal. (C30H33F3N5O5Cl‚0.5CH2-
Cl2) C, H, N.
1
product as a white powder (5.45 g, 87%). H NMR (CDCl3): δ
(+)-1-{[3-[4-Cyan o-4-(3-flu or oph en yl)piper idin -1-yl]pr o-
p yl]ca r boxa m id o}-6-(3,4-d iflu or op h en yl)-5-m eth oxyca r -
bon yl-4-m eth oxym eth yl-2-oxo-1,2,3,6-tetr a h yd r op yr im -
idin e (81). (a) 4-Cyan o-4-(3-flu or oph en yl)piper idin e (76b).
Prepared from 3-fluorophenylacetonitrile (1.35 g, 10.0 mmol),
N-tert-butoxycarbonyl-bis(2-chloroethyl)amine (2.42 g, 10.0
mmol), and NaH (0.76 g, 95%, 30 mmol) using a similar
procedure described earlier (995 mg, 32%).
(b ) 1-N-(3-Am in op r op yl)-4-cya n o-4-(3-flu or op h en yl)-
p ip er id in e (78b). Prepared from 76b (995 mg, 3.20 mmol)
and N-(3-bromopropyl)phthalimide (965 mg, 3.60 mmol) using
a similar procedure described earlier (colorless oil, 640 mg,
58%).
(c)(+)-1-{[3-[4-Cya n o-4-(3-flu or op h en yl)p ip er id in -1-yl]-
p r op yl]ca r boxa m id o}-6-(3,4-d iflu or op h en yl)-5-m eth oxy-
ca r b on yl-4-m et h oxym et h yl-2-oxo-1,2,3,6-t et r a h yd r op y-
r im id in e (81). Prepared from 34 (25 mg, 0.052 mmol) and
78b (26 mg, 0.10 mmol) using a similar procedure described
earlier (25 mg, 81%). 1H NMR (CDCl3): δ 1.70-1.78 (m, 2 H),
2.00-2.08 (m, 4 H), 2.38-2.50 (m, 4 H), 2.94-3.00 (m, 2 H),
3.30-3.47 (m, 2 H), 3.48 (s, 3 H), 3.70 (s, 3 H), 4.68 (s, 2 H),
6.67 (s, 1 H), 6.97-7.45 (m, 7 H), 7.69 (br s, 1 H), 8.97 (t, J )
7 Hz, 1 H). HCl salt Mp: 124-127 °C. Anal. (C30H33F3N5O5-
Cl‚0.5CH2Cl2) C, H, N.
(+)-1-{N-[3-[4-Cya n o-4-(4-flu or op h en yl)p ip er id in -1-yl]-
p r op yl]ca r boxa m id o}-6-(3,4-d iflu or op h en yl)-5-m eth oxy-
ca r b on yl-4-m et h oxym et h yl-2-oxo-1,2,3,6-t et r a h yd r op y-
r im id in e (82). (a ) 4-Cya n o-4-(4-flu or op h en yl)p ip er id in e
(76c). Prepared from 4-fluorophenylacetonitrile (1.35 g, 10.0
mmol), N-tert-butoxycarbonyl-bis(2-chloroethyl)amine (2.42 g,
10.0 mmol), and NaH (0.76 g, 95%, 30 mmol) using a similar
procedure described earlier (2.0 g, 64%).
1.18 (t, J ) 7.6 Hz, 3 H), 1.66-1.68 (m, 4 H), 2.04-2.09 (m, 4
H), 2.36-2.44 (m, 4 H), 2.60-2.78 (m, 2 H), 2.91 (br d, 2 H),
3.20-3.40 (m, 2 H), 5.70 (br s, 2 H), 6.55 (s, 1 H), 6.64-6.84
(m, 2 H), 7.20-7.55 (m, 6 H), 8.88 (br t, 1 H, NH). HCl salt
Mp: 196-197 °C. [R]D ) +126 (c ) 0.505, 1:1 CHCl3/MeOH).
Anal. (C29H33N6O3F2Cl) C, H, N.
(+)-1-{N-[[4-Cya n o-4-p h en ylp ip er id in -1-yl]p r op yl]ca r -
boxa m id o}-6-(3,4-d iflu or op h en yl)-5-m eth oxyca r bon yl-4-
m eth oxym eth yl-2-oxo-1,2,3,6-tetr a h yd r op yr im id in e (79).
To a solution of 34 (223 mg, 46.8 mmol) in CH2Cl2 (20 mL)
was added 3-(4-cyano-4-phenylpiperidin-1-yl)propylamine (65d;
137 mg, 56 mmol). The resulting mixture was stirred at room
temperature for 2 h and the solvent evaporated. The residue
was purified by column chromatography on silica gel (CHCl3/
MeOH/2 M NH3 in MeOH ) 100:12:6) to afford the desired
product (230 mg, 82%). [R]D ) 129° (c ) 0.625, CHCl3). 1H NMR
(CDCl3) δ 1.70-1.78 (m, 2 H), 2.00-2.20 (m, 4 H), 2.38-2.50
(m, 4 H), 2.94-3.00 (m, 2 H), 3.25-3.45 (m, 2 H), 3.45 (s, 3
H), 3.67 (s, 3 H), 4.65 (s, 2 H), 6.65 (s, 1 H), 6.97-7.45 (m, 8
H), 7.65 (br s, 1 H), 8.92 (t, J ) 7 Hz, 1 H). HCl salt Mp: 118-
119 °C. Anal. (C30H35F2N5O5Cl‚1.2H2O) C, H, N.
1-{[3-[4-Cyan o-4-(2-flu or oph en yl)piper idin -1-yl]pr opyl]-
carboxamido}-6-(3,4-difluorophenyl)-5-methoxycarbonyl-4-
m eth oxym eth yl-2-oxo-1,2,3,6-tetr a h yd r op yr im id in e (80).
(a ) 4-Cya n o-4-(2-flu or op h en yl)p ip er id in e (76a ). To a solu-
tion of 2-fluorophenylacetonitrile (75a ; 1.35 g, 10 mmol) and
N-tert-butoxycarbonyl-bis(2-chloroethyl)amine (74; 2.42 g, 10
mmol) in DMF (30 mL) at 0 °C was added NaH (0.76 g, 95%,
30 mmol) carefully over 10 min. The resulting suspension was
stirred and heated at 60 °C for 24 h. The reaction mixture
was cooled and quenched with ice-water (100 mL) and the
mixture was extracted with EtOAc (50 mL × 3). The combined
organic layers were dried (MgSO4) and concentrated and the
residue was purified by column chromatography on silica gel
(20% EtOAc/hexanes) to yield the BOC-protected piperidine.
It was dissolved in CH2Cl2 (10 mL) and treated with TFA (10
mL). The resulting mixture was stirred for 3 h and the solvent
was evaporated. The residue was treated with aqueous 1 N
NaOH, adjusted the pH to 10, and extracted with CH2Cl2 (3
× 30 mL). The organic extracts were dried (K2CO3), concen-
trated, and purified by column chromatography on silica gel
(80% EtOAc in hexanes) to yield the desired piperidine 76a
(933 mg, 30%).
(b ) 1-N-(3-Am in op r op yl)-4-cya n o-4-(4-flu or op h en yl)-
p ip er id in e (78c). Prepared from 76c (1.55 g, 5.0 mmol) and
N-(3-bromopropy)phthalimide (1.480 g, 5.50 mmol) using a
similar procedure described earlier (colorless oil, 1.10 g, 64%).
(c) (+)-1-{N-[3-[4-Cya n o-4-(4-flu or op h en yl)p ip er id in -
1-yl]p r op yl]ca r boxa m id o}-6-(3,4-d iflu or op h en yl)-5-m eth -
oxyca r bon yl-4-m eth oxym eth yl-2-oxo-1,2,3,6-tetr a h yd r o-
p yr im id in e (82). Prepared from 34 (25 mg, 0.052 mmol) and
78c (26 mg, 0.10 mmol) using a similar procedure described
1
earlier (30 mg, 96%). H NMR (CDCl3): δ 1.74 (m, 2 H), 2.06
(m, 4 H), 2.49 (m, 4 H), 3.00 (m, 2 H), 3.40 (m, 2 H), 3.48 (s, 3
H), 3.70 (s, 3 H), 4.67 (s, 2 H), 6.67 (s, 1 H), 7.08 (m, 4 H), 7.18
(m, 1 H), 7.48 (m, 2 H), 7.67 (bs, 1 H), 8.97 (bt, 1 H). HCl salt,
(b) 1-N-(3-Am in op r op yl)-4-cya n o-4-(2-flu or op h en yl)-
p ip er id in e (78a ). To a solution of 4-cyano-4-(2-fluorophenyl)-
piperidine (76a ; 933 mg, 3.00 mmol) and N-(3-bromopropyl)-
phthalimide (965 mg, 3.60 mmol) in DMF (20 mL) were added
K2CO3 (2.00 g) and KI (100 mg). The resulting suspension was
stirred vigorously at 80 °C for 12 h and then quenched with
ice-water (60 mL). The mixture was extracted with EtOAc (3
× 50 mL). The combined organic layers was dried (MgSO4),
concentrated, and purified by column chromatography on silica
gel (30% EtOAc in hexanes) to yield the phthalimide-protected
white solid; Mp: 103-106 °C. CIMS: m/e ) 600 (MH+). [R]D
)
106.0 (c ) 0.205, MeOH). Anal. (C30H33F3N5O5Cl‚0.9CHCl3) C,
H, N.
(+)-1-{N-[3-[4-Meth yl-4-p h en ylp ip er id in -1-yl]p r op yl]-
car boxam ido}-6-(3,4-diflu or oph en yl)-5-m eth oxycar bon yl-
4-m eth oxym eth yl-2-oxo-1,2,3,6-tetr ah ydr opyr im idin e (83).
Prepared from 34 and amine 65e using a similar procedure
described earlier. Yield: 0.12 g (81%). [R]D ) + 82.1 (c ) 0.31,
MeOH). 1H NMR (CDCl3): δ 1.14 (s, 3 H), 1.61-1.72 (m, 4 H),

Novel R1a Adrenoceptor-Selective Antagonists. 2
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23 4793
(8) Garraway, W. M.; Collins, G. N.; Lee, R. J . High Prevalence of
Benign Prostatic Hypertrophy in the Community. Lancet 1991,
338, 469-471.
2.03-2.08 (m, 2 H), 2.25 (t, J ) 7.2 Hz, 2 H), 2.30-2.42 (m, 4
H), 3.19-3.31 (m, 2 H), 3.40 (s, 3 H), 3.63 (s, 3 H), 4.60 (s, 2
H), 6.60 (s, 1 H), 6.97-7.29 (m, 8 H), 7.63 (br s, 1 H), 8.78 (t,
(9) Monda, J . M.; Oesterling, J . E. Medical Management of Benign
Prostatic Hyperplasia. Infect. Urol. 1994, 47-59.
J
) 5.7 Hz, 1 H). The HCl salt was hygroscopic. Anal.
(C30H37N4O5F2Cl‚1.0CH2Cl2) C, H, N.
(10) Lepor, H. Role of Alpha-Adrenergic Blockers in the Treatment
of Benign Prostatic Hyperplasia. Prostate Suppl. 1990, 3, 75-
84.
(11) 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.
(12) Creese, I.; Snyder, S. H. Receptor Binding and Pharmacological
Activity of Opiates in the Guinea-pig Intestine. J . Pharmacol.
Exp. Ther. 1975, 194, 205-219.
(13) Hu, E. H.; Sidler, D. R.; Dolling, U.-H. Unprecedented Catalytic
Three Component One-Pot Condensation Reaction: An Efficient
Synthesis of 5-Alkoxycarbonyl-4-aryl-3,4-dihydropyrimidin-
2(1H)-ones. J . Org. Chem. 1998, 63, 3454-3457.
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
displacement assays. We also thank Dr. J ohn Zgombick
for providing us with the serotonin cross-reactivity data.
Refer en ces
(1) Presented in parts: (a) Murali Dhar, T. G.; Tyagarajan, S.;
Marzabadi, M. R.; Nagarathnam, D.; Miao, S. W.; Lagu, B.;
Wong, W. C.; Chiu, G.; Fang, J .; Forray, C.; Gluchowski, C.
Design, Synthesis, and Evaluation of Dihydropyrimidinones as
Alpha-1a Selective Antagonists: 3. Modification of the Piperidine
Moiety. 214th ACS National Meeting, Las Vegas, NV, Sept 7-11,
1997; MEDI #84. (b) Nagarathnam, D.; Wong, W. C.; Lagu, B.;
Miao, S. W.; Tyagarajan, S.; Sun, W.; Zhang, J .; Shen, Q.; Tian,
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T. B.; O′Malley, S.; Ransom, R.; Schneck, K.; Bendesky, R.;
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Freidinger, R. M. Design, Synthesis, and Evaluation of Dihy-
dropyrimidinones as Alpha-1a Selective Antagonists: 6. Syn-
thesis and Structure-Activity Relationship of SNAP 6552 and
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J .; Pettibone, D. J .; Freidinger, R. M. Design, Synthesis, and
Evaluation of Dihydropyrimidinones as Alpha-1a Selective
Antagonists: 7. Modification of the Diarylpiperidine Moiety.
215th ACS National Meeting, Dallas, TX, Mar 29-Apr 2, 1998;
MEDI #67.
(2) Please see the preceding paper: Nagarathnam, D.; Miao, S. W.;
Chiu, G.; Fang, J .; Lagu, B.; Murali Dhar, T. G.; Zhang, J .;
Tyagarajan, S.; Marzabadi, M. R.; Zhang, F.; Wong, W. C.; Sun,
W.; Tian, D.; Wetzel, J . M.; Forray, C.; Chang, R. S. L.; Broten,
T. P.; Schorn, T. W.; Chen, T. B.; O’Malley, S.; Ransom, R.;
Schneck, K.; Bendesky, R.; Harrell, C. M.; Gluchowski, C. Design
and Synthesis of Novel R1a Adrenoceptor-Selective Antagonists.
1. Structure-Activity Relationship in Dihydropyrimidinones. J .
Med. Chem. 1999, 42, 4764-4777.
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