Design and synthesis of novel α(1a) adrenoceptor-selective antagonists. 4. Structure-activity relationship in the dihydropyrimidine series

Article abstract of DOI:10.1021/jm9902032

We have previously disclosed dihydropyridines such as 1a,b as selective α(1a) antagonists as a potential treatment for benign prostatic hyperplasia (BPH). The propensity of dihydropyridines toward an oxidation led us to find suitable replacements of the core unit. The accompanying papers describe the structure-activity relationship (SAR) of dihydropyrimidinones 2a,b as selective α(1a) antagonists. We report herein the SAR of dihydropyrimidines such as 4 and highlight the similarities and differences between the dihydropyrimidine and dihydropyrimidinone series of compounds.

Full text of DOI:10.1021/jm9902032

4804
J . Med. Chem. 1999, 42, 4804-4813
Design a n d Syn th esis of Novel r1a Ad r en ocep tor -Selective An ta gon ists. 4.
Str u ctu r e-Activity Rela tion sh ip in th e Dih yd r op yr im id in e Ser ies
Wai C. Wong,†,∇ Wanying Sun,† Bharat Lagu,*,† Dake Tian,† Mohammad R. Marzabadi,† Fengqi Zhang,†
Dhanapalan Nagarathnam,† Shou W. Miao,† J ohn M. Wetzel,† J ian Peng,† Carlos Forray,‡
Raymond S. L. Chang,§ Tsing B. Chen,§ Richard Ransom,§ Stacey O’Malley,§ Theodore P. Broten,§ Paul Kling,§
Kamlesh P. Vyas,| Kanyin Zhang,| and Charles Gluchowski†
Departments of Chemistry and Pharmacology, Synaptic Pharmaceutical Corporation, Paramus, New J ersey 07652, and
Departments of Pharmacology and Drug Metabolism, Merck & Company, Inc., West Point, Pennsylvania 19486
Received April 23, 1999
We have previously disclosed dihydropyridines such as 1a ,b as selective R1a antagonists as a
potential treatment for benign prostatic hyperplasia (BPH). The propensity of dihydropyridines
toward an oxidation led us to find suitable replacements of the core unit. The accompanying
papers describe the structure-activity relationship (SAR) of dihydropyrimidinones 2a ,b as
selective R1a antagonists. We report herein the SAR of dihydropyrimidines such as 4 and
highlight the similarities and differences between the dihydropyrimidine and dihydropyrimi-
dinone series of compounds.
In tr od u ction
It became apparent that the dihydropyrimidines such
as 3 are unstable, and we therefore decided to synthe-
size dihydropyrimidines represented by the general
structure 4. We have previously demonstrated that such
a linker variation is well-tolerated in the dihydropy-
rimidinone series resulting in compounds such as 2b
that show excellent binding affinity and selectivity for
the R1a receptor.8 The work described herein presents
the synthesis of the dihydropyrimidines such as 4 and
compares the SAR of the dihydropyrimidine series of
compounds with that of the dihydropyrimidinones de-
scribed in the accompanying papers.
Benign prostatic hyperplasia (BPH) is a progressive
condition characterized by a nodular enlargement of the
prostate resulting in obstruction of the urethra.1 Non-
selective R1 adrenoceptor antagonists such as prazosin
and terazosin are presently used for the symptomatic
relief of BPH.2 It has been reported that the functional
potency of a number of R1 antagonists to relax the
agonist-induced contraction of prostatic smooth muscle
correlates well with the binding affinity for these
antagonists for the R1a subtype at the cloned human
receptors.3 The data seem to suggest that a potent and
R1a-selective antagonist can be an attractive drug
candidate for treatment of BPH with fewer undesirable
side effects that may be associated with the other
subtypes.
We have recently disclosed the discovery of a number
of dihydropyridines such as 1a ,b (Chart 1) as selective
R1a adrenoceptor antagonists.4-6 Some of the compounds
that belong to this class, however, exhibit less than
optimal pharmacokinetic profiles. Mindful of the ten-
dency of dihydropyridines to undergo metabolic oxida-
tion, we reasoned that replacement of the dihydropyri-
dine core unit with a dihydropyrimidinone (e.g. 2a )7 or
a dihydropyrimidine (3) template might attenuate this
propensity for oxidation and result in compounds with
improved pharmacokinetic profiles. It was important
that these analogues maintain the desirable binding
affinity and subtype selectivity for the R1a receptor
observed for 1a ,b similar to that observed in the
dihydropyrimidinone series (e.g. 2a ,b).7,8 Structurally,
dihydropyrimidines (3) are more closely related to the
dihydropyridines (1a ,b) than the dihydropyrimidinones
(2a ), and we needed to synthesize compounds such as
3 in order to evaluate their pharmacological properties.
Ch em istr y
Scheme 1 depicts a general synthetic route for the
synthesis of dihydropyrimidines.9 Thus, benzylidene 5
was reacted with acetamidine to afford tetrahydropy-
rimidine 6 which was dehydrated with p-toluenesulfonic
acid without purification to afford intermediate 7. This
compound was then alkylated with either 5-bromo-1-
chloropentane or 1,5-dibromopentane to yield halide 8a
or 8b which was subsequently reacted with either a
substituted piperidine or a piperazine to obtain the
desired products 9-15 or 16-18, respectively.
Methyl ester 21 was similarly prepared from ben-
zylidene 19 (Scheme 2). To synthesize compounds 28
and 29, compound 20 was initially converted to inter-
mediate 24. Reaction of 4-methoxycarbonyl-4-piperidine
with 24 gave compound 26, which upon hydrogenolysis
afforded the carboxylic acid 27. Subsequent coupling of
27 with ammonia or methylamine gave primary amide
28 and secondary amide 29, respectively.
Syntheses of compounds 36-41 and 43 are depicted
in Scheme 3. Thus, dihydropyrimidine 7 (Scheme 3) was
reacted with 1,4-dibromobutane (30) to obtain interme-
diate 33 which was then converted into compound 36
by reaction with 4-methoxycarbonyl-4-phenylpiperidine.
Chiral dibromides 31 and 32 were prepared from known
intermediates10 and then treated with the substituted
piperidines or piperazine to synthesize analogues 36-
† Department of Chemistry, Synaptic Pharmaceutical Corp.
‡ Department of Pharmacology, Synaptic Pharmaceutical Corp.
§ Department of Pharmacology, Merck & Co.
| Department of Drug Metabolism, Merck & Co.
∇ Present address: Bayer Corp., West Haven, CT.
10.1021/jm9902032 CCC: $18.00 © 1999 American Chemical Society
Published on Web 10/26/1999

Novel R1a Adrenoceptor-Selective Antagonists. 4
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23 4805
Ch a r t 1
Sch em e 1a
a
(i) t-BuOK, DMF; (ii) p-TsOH; (iii) Br(CH2)5-Z, where Z ) Cl or Br; (iv) substituted piperidines or piperazines.
41. Reaction of 7 with R,R′-dibromo-m-xylene yielded
intermediate 42, which was subsequently elaborated to
afford 43. Compounds 50 and 51 (Scheme 4) were
synthesized from amidine 4511 and acetamide, by pro-
cedures similar to the ones described previously.
rimidinone series. The (-) enantiomer shows signifi-
cantly lower binding affinity and selectivity for the R1a
receptor over R1b, R1d, and R2 receptors. As in the case
of dihydropyrimidinones, the substitution on the C-6
aryl ring does not have a pronounced effect on the
binding and selectivity profile as evident by the binding
affinities for 9 and 25. When the methyl ester function-
ality at the C-5 position of 25 was replaced by a primary
amide or a secondary amide, the resulting compounds
(28 and 29, respectively) show lower binding affinity and
selectivity for the R1a receptor. In the dihydropyrimidi-
none series, both an ester and an amide functionality
at the C-5 position are well-tolerated.7 In vitro and in
vivo metabolism study of compound (+)-9 indicate that
the compound undergoes N-dealkylation to produce
4-methoxycarbonyl-4-phenylpiperidine as the major me-
tabolite. 4-Methoxycarbonyl-4-phenylpiperidine was
found to be an agonist of opioid receptors and has long
half-life in rats and dogs. The structural similarity
Resu lts a n d Discu ssion
The binding affinities of a number of dihydropyrim-
idines containing a 4-methoxycarbonyl-4-phenylpiperi-
dine moiety are compared with those of dihydropyridine
1a and dihydropyrimidinone 2b in Table 1. (For the
protocols for in vivo and in vitro binding studies, please
refer to ref 7.) Dihydropyrimidine 9 displays comparable
binding affinity (1.0 nM) and selectivity (>400-fold) for
the R1a receptor over R1b, R1d, and R2 receptors similar
to dihydropyridine 1a (0.2 nM) and dihydropyrimidi-
none 2b (0.1 nM). The affinity and selectivity is found
to be mainly associated with in the (+) enantiomer, an
observation which parallels the SAR in the dihydropy-

4806 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23
Wong et al.
Sch em e 2a
a
(i) Br(CH2)5Br; (ii) 4-methoxycarbonyl-4-phenylpiperidine; (iii) H2, Pd-C; (iv) NH3 or MeNH2, EDC.
ties associated with it,13 raised concerns regarding
safety upon chronic administration. We therefore de-
cided to replace the 4-methoxycarbonyl-4-phenylpiperi-
dine moiety with some preferred piperidines and pip-
erazines.8,14 Binding profiles of these compounds are
presented in Table 2.
Sch em e 3
The methoxycarbonyl group on the 4-position of the
piperidine ring of (+)-9 does not appear to be essential
for the binding affinity as evident from the binding
profile for compound 10 (Table 2). An analogue of 10
containing an o-trifluoromethyl group on the phenyl ring
(9b) show increased affinity for the rat L-type calcium
channel, whereas compound 12 containing a 4-(2-
methoxyphenyl)piperidine moiety displays a binding
and selectivity profile similar to 10. Substitution of the
methoxycarbonyl group on the 4-position of the piperi-
dine in (+)-9 with a cyano group results in compound
13 which shows high binding affinity and good selectiv-
ity for the R1a receptor. The diarylpiperidine-containing
compounds (+)-14 and (+)-15 also exhibit excellent
between this metabolite and a known sedative, mep-
eridine,12 which has sedative and habit-forming proper-
Sch em e 4a
a
(i) Br(CH2)5Br; (ii) 4-cyano-4-phenylpiperidine.

Novel R1a Adrenoceptor-Selective Antagonists. 4
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23 4807
Ta ble 1. Effect of C-5 and C-6 Substituents on R1 Binding
Affinities at Recombinant Human R1 and R2 Adrenoceptors
group on the linker, such as the one in (+)-37, results
in a 15-fold decrease in the binding affinity for R1a
receptor. Interestingly, compound (+)-38, a close ana-
logue of (+)-37, which differs only in the substitution
at the 4-position of the piperidine ring (CN instead of
CO2Me), displays a similar binding profile for R1 recep-
tors but has improved selectivity over the R2 receptors.
It is important to note that the absolute configuration
at the carbon bearing the methyl group is crucial and
the (S) isomer is found to give compounds that show
significantly better binding and selectivity profiles than
the (R) isomer (compound (+)-38 versus compound (+)-
39). A similar observation was made for the piperazine-
containing compounds (+)-40 and (+)-41 for their
binding affinity at the R1a receptor. Both compounds,
however, fail to meet the required criteria of 100-fold
selectivity over the R2 adrenoceptors. The initial ratio-
nale behind design of these substituted linkers was to
slow the metabolic N-dealkylation at the carbon bearing
the piperidine or piperazine.8 Analysis of the metabo-
lites of some of the compounds presented in Table 3,
however, revealed that N-dealkylation still remains to
be the major metabolic pathway.
Ki (nM)a,b
fold selective of
compd
R
R′
R1a
R1b
R1d
R1a over R2a,b,c
1a
2b
9
0.2 180
0.1 140
1.0 480
0.1 190
630
150
680
180
550
700
690
>1000
>1000
>1000
>500
<25
3,4-di-F OMe
(+)-9 3,4-di-F OMe
(-)-9 3,4-di-F OMe
25
28
29
13
700
0.5 160
4.2 410
2,4-di-F OMe
2,4-di-F NH2
>1000
<10
2,4-di-F NHMe 14
870 1900
<80
a
Ki values obtained by displacement of [3H]prazosin from cloned
b
human receptors. All Ki values are (5% SE or less for n > 2. In
cases where n ) 2, both Ki values are within 2-fold of each other
and the values shown are the average of the two experiments.
binding profiles. Compounds 17 and 18 that contain
substituted phenylpiperazine moieties show good bind-
ing affinities for the R1a receptor, as is the case with
dihydropyrimidinone series. Compound 16 displays poor
selectivity for the R1a receptor over R2 adrenoceptors.
Similar substitution in the dihydropyrimidinone series
leads to compounds with significantly higher selectivity
for the R1a receptor over R2 receptors.
Modifications at the C-2 and C-4 positions of the
dihydropyrimidine core were briefly explored, and some
representative examples are shown in Table 4. These
positions appear to accommodate bulky groups as
indicated by the binding and selectivity profiles for 50
and 51.
The results from a number of in vitro and in vivo
assays for (+)-14, (+)-15, and (+)-18 are summarized
in Table 5. All three compounds show greater than 100-
fold selectivity for the R1a receptor over R1b, R1d, and R2
receptors and greater than 10000-fold selectivity over
rat L-type calcium channel. Compound (+)-14 displayed
binding affinity at isolated human prostate of 0.33 nM
which is good agreement with the binding affinity
(Ki ) 0.4 nM) at the cloned human R1a receptor.
Compound (+)-14 shows a much lower binding affinity
for isolated human aorta (Ki ) 110 nM) as expected
based on the selectivity for the R1a over R1d receptor in
The effect of modification of the tether linking the
dihydropyrimidine core unit with piperidines or pipera-
zines on the binding profiles of the resulting compounds
is shown in Table 3. A linker comprising a five-
methylene spacer, as in (+)-9, was found to be the
optimal, yielding compounds with good binding affinity
and selectivity for the R1a receptor. Compound 36
containing a four-methylene tether shows a 30-fold
decrease in the binding affinity for the R1a receptor
resulting in poor selectivity over R2 receptors. Compound
43 with a conformationally restricted linker exhibits a
suboptimal binding profile. The presence of a methyl
Ta ble 2. Effect of Substituted Piperidines and Piperazines on R1 Binding Affinities at Recombinant Human R1 and R2 Adrenoceptors
Ki (nM)a,b
fold selective of
compd
R
R′
R1a
R1b
R1d
R1a over R2a,b,c
(+)-9
10
11
12
13
(+)-14
(+)-15
16
17
(+)-18
H
H
CF3
OMe
H
H
CO2Me
H
H
H
CN
Ph
4-Me-Ph
0.1
0.4
1.1
0.3
1.0
0.4
0.1
0.4
0.5
0.6
190
93
180
220
1100
120
1100
180
440
65
>500
>300
>150c
>100
>300
>180
>400
<100
>100
>100
500
140
490
100
250
67
Me
OMe
CO2Me
CONH2
34
240
79
580
a,b
Please see notes in Table 1. c Selectivity for R1a over rat L-type Ca2+ channel < 100.

4808 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23
Wong et al.
Ta ble 3. Effect of Linker Variation on R1 Binding Affinities at Recombinant Human R1 and R2 Adrenoceptors
Ki (nM)a,b
fold selective of
compd
Z
R
R1a
R1b
R1d
R1a over R2a,b,c
(+)-9
36
43
(+)-37
13
(+)-38
(+)-39
(+)-18
(+)-40
(+)-41
(CH2)3
(CH2)2
3′,5′-phenyl
(CH2)2CH-(S)-CH3
(CH2)3
(CH2)2CH-(S)-CH3
(CH2)2CH-(R)-CH3
(CH2)3
CO2Me
CO2Me
CO2Me
CO2Me
CN
0.1
3.6
6.8
1.6
1.0
1.2
22
0.6
3.5
480
440
320
430
490
480
1700
240
810
1500
680
610
570
>500
<80
>130
<50
910
1100
1100
1600
580
1700
1700
>300
>120
<10
>130
<100
<10
CN
CN
(CH2)2CH-(S)-CH3
(CH2)2CH-(R)-CH3
20
a,b
Please see notes in Table 1.
rations are in good agreement.7,8 The reasons behind
this apparent discrepancy are presently not well-
understood. The current pharmacological evidence can-
not account for the behavior of human prostate as a
function of R1a and the rat prostate as R1L adreno-
ceptors.17-19 It appears that the discrepancies in the
binding affinities and functional potencies are due to
some specific biophysical properties of certain com-
pounds that are sensitive to differences in the conditions
of the assays and do not support the existence of R1L
receptors.20
Ta ble 4. Effect of C-2 and C-4 Substituents on R1 Binding
Affinities at Recombinant Human R1 and R2 Adrenoceptors
Ki (nM)a,b
fold selective of
compd
R
R′
R1a R1b
R1d
R1a over R2a,b,c
Compounds (+)-15 and (+)-18 show suboptimal phar-
macokinetic profiles with 20% oral bioavailability in rats
but less than 10% oral bioavailability in dogs.
13
50
51
Me
Me
Me
MeOCH2 0.4 310
0.4 400
1.0 490 1100
>300
>700
>4000
480
680
MeOCH2 Me
a,b
Please see notes in Table 1.
Con clu sion
the binding assays.15,16 Dihydropyrimidinones show
similar selectivity profiles in the tissue binding experi-
ments.
Compounds (+)-14, (+)-15, and (+)-18 antagonize the
phenylephrine-induced contraction of isolated rat pros-
tate with a much weaker Kb (60, 27, and 7 nM,
respectively) compared to the binding affinities for
cloned human receptors (Ki ) 0.4, 0.1, and 0.6 nM,
respectively). In the dihydropyrimidinone series, the
correlations between the binding affinities of the an-
tagonists and their functional potencies in tissue prepa-
In an effort to optimize pharmacokinetic parameters,
we were able to replace the dihydropyridine moiety with
a dihydropyrimidine template. A number of dihydropy-
rimidines showed good binding affinity (<1 nM) and
selectivity (>300-fold) for R1a receptor over R1b, R1d, and
R2 receptors. Most of the compounds displayed negligible
affinity for rat L-type calcium channel. A number of
modifications on the dihydropyrimidine template, linker
chain, and piperidine or piperazine side chains are
tolerated as is the case for dihydropyrimidinones. Some
of the dihydropyrimidines, unlike the dihydropyrimidi-
Ta ble 5. Summary of the in Vitro and in Vivo Properties of (+)-14, (+)-15, and (+)-18
assay
antagonist/agonist
(+)-14
(+)-15
0.1
>1000
>400
>105
NDb
(+)-18
0.6
>300
>100
>11000
ND
Ki R1a (nM)
[3H]prazosin
[3H]prazosin
[3H]rauwolscine
[3H]nitrendipine
[3H]prazosin
[3H]prazosin
[3H]prazosin
phenylephrine
0.4
R
1b,1d/R1a
2a,b,c/R1a
>100
>180
>105
0.33
110
0.97
60
ND
R
Ca2+/R1a
Ki human prostate (nM)
Ki human aorta (nM)
Ki rat prostate (nM)
Kb rat prostate (nM)
rat F, t1/2 (h)a
ND
ND
27
ND
ND
7
17%,c 4.7
8%,e 0.5
21%,d 2.1
<10%,f 4.0
dog F, t1/2 (h)a
ND
a
b
d
Radioreceptor assay. Not determined. c iv: 1 mg/kg dose, AUC ) 35 µmol min/L. po: 3 mg/kg dose, AUC ) 21 µmol min/L. iv: 1
mg/kg dose, AUC ) 5 µmol min/L. po: 3 mg/kg dose, AUC ) 4 µmol min/L. e iv: 1 mg/kg dose, AUC ) 11 µmol min/L. po: 3 mg/kg dose,
AUC ) 8 µmol min/L (low plasma levels). f iv: 1 mg/kg dose. po: 3 mg/kg dose, low plasma levels.

Novel R1a Adrenoceptor-Selective Antagonists. 4
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23 4809
6-(3,4-Diflu or oph en yl)-1,6-dih ydr o-5-m eth oxycar bon yl-
2,4-d im et h yl-1-(5-(4-p h en ylp ip er id in -1-yl)p en t -1-yl)p y-
r im id in e (10). The procedure similar to the one described for
the synthesis of 9 was used from 8a (0.2 g, 0.52 mmol) and
4-phenylpiperidine (0.12 g, 0.75 mmol): 24% yield (0.062 g),
nones, showed only weak potency to inhibit the phen-
ylephrine-induced contraction of isolated rat prostate
tissue. The reasons for such a discrepancy are not yet
clear.
1
yellow oil; CIMS m/e ) 510 (MH+); H NMR δ 1.2-1.35 (2H,
Exp er im en ta l Section
m), 1.44-1.90 (7H, m), 1.9-2.1 (2H, m), 2.16 (3H, s), 2.28 (3H,
s), 2.3-2.55 (4H, m), 2.95-3.40 (4H, m), 3.61 (3H, s), 5.22 (1H,
s), 6.95-7.30 (3H, m). Hydrochloride salt: yellow solid; mp
130-136 °C. Anal. (C30H37F2N3O2‚2HCl‚1.2H2O‚0.6CHCl3) C,
H, N.
For the description of analytical protocols and biological
methods, please refer to ref 7.
6-(3,4-Diflu or oph en yl)-1,6-dih ydr o-5-m eth oxycar bon yl-
2,4-d im eth ylp yr im id in e (7). To a solution of acetamidine
hydrochloride (1.53 g, 16.2 mmol) in DMF (10 mL) were added
a solution of potassium tert-butoxide (1.33 g, 11.8 mmol) in
DMF (10 mL) and a solution of methyl 2-((3,4-difluorophenyl)-
methylene)-3-oxobutanoate (2.6 g, 10.8 mmol) in DMF (10 mL)
at 0 °C. After the mixture was stirred for 0.5 h at 0 °C,
p-toluenesulfonic acid monohydrate (4.1 g, 21.5 mmol) was
added. The mixture was heated at 100-120 °C for 2 h. The
reaction mixture was cooled to room temperature, quenched
with aqueous NaOH solution (2 N, 60 mL), and extracted with
ether. The organic layer was dried over Na2SO4 and evapo-
rated. The residue was purified by flash chromatography over
silica gel (ethyl acetate) to give the product in 59% yield (1.8
g) as a yellow solid: 1H NMR δ 1.98 (3H, s), 2.31 (3H, s), 3.59
(3H, s), 5.47 (1H, s), 7.03-7.05 (3H, m). Chiral HPLC resolu-
tion (Chiralcel OD 20 × 250 mm column; hexane:ethyl alcohol:
diethylamine, 90:10:0.1; 9.0 mL/min; 10.9 and 12.2 min)
afforded both (+)-7 and (-)-7.
6-(3,4-Diflu or oph en yl)-1,6-dih ydr o-5-m eth oxycar bon yl-
1-(5-(4-(2-m et h oxyp h en yl)p ip er id in -1-yl)p en t -1-yl)-2,4-
d im eth ylp yr im id in e (12). The procedure similar to the one
described for the synthesis of 9 was used from 8b (0.1 g, 0.23
mmol) and 4-(2-methoxyphenyl)piperidine hydrochloride (65
mg, 0.29 mmol): 48% yield (0.06 g), yellow oil; CIMS m/e )
540 (MH+); 1H NMR δ 1.28 (2H, m), 1.48-1.76 (6H, m), 1.98-
2.02 (4H, m), 2.17 (3H, s), 2.27 (2H, m), 2.28 (3H, s), 2.96-
3.12 (4H, m), 3.35 (1H, m), 3.62 (3H, s), 3.79 (3H, s), 5.24 (1H,
s), 6.82 (1H, d, J ) 8.0 Hz), 6.88 (1H, m), 7.00-7.18 (5H, m).
Hydrochloride salt: white solid; mp 85-88 °C. Anal. (C31H39
F2N3O3‚2HCl‚2H2O‚0.9CHCl3) C, H, N.
-
1-(5-(4-Cya n o-4-p h en ylp ip er id in -1-yl)p en t-1-yl)-6-(3,4-
d iflu or op h en yl)-1,6-d ih yd r o-5-m eth oxyca r bon yl-2,4-d i-
m eth ylp yr im id in e (13). The procedure similar to the one
described for the synthesis of 9 was used from 8b (30 mg, 0.07
mmol) and 4-cyano-4-phenylpiperidine hydrochloride (30 mg,
0.13 mmol): 59% yield (0.02 g), yellow oil; CIMS m/e ) 535
(MH+); 1H NMR δ 1.22-1.32 (2H, m), 1.47-1.52 (2H, m), 1.60
(1H, m), 1.80 (1H, m), 2.00-2.08 (4H, m), 2.17 (3H, s), 2.28
(3H, s), 2.36-2.43 (4H, m), 2.94 (2H, m), 3.05 (1H, m), 3.35
(1H, m), 3.62 (3H, s), 5.24 (1H, s), 7.01-7.15 (3H, m), 7.29-
7.39 (4H, m), 7.45 (1H, m). Hydrochloride salt: white solid;
mp 89-93 °C. Anal. (C31H36F2N4O2‚2HCl‚0.8CH2Cl2) C, H, N.
(+)-6-(3,4-Diflu or op h en yl)-1,6-d ih yd r o-5-m eth oxyca r -
bon yl-2,4-d im eth yl-1-(5-(4,4-d ip h en ylp ip er id in -1-yl)p en t-
1-yl)p yr im id in e ((+)-14). The procedure similar to the one
described for the synthesis of 9 was used from 8b (0.4 g, 0.93
mmol) and 4,4-diphenylpiperidine hydrochloride (0.33 g, 1.21
mmol): 35% yield (0.21 g), yellow oil; CIMS m/z 586 (MH+);
1H NMR δ 1.26 (2H, m), 1.44-1.65 (4H, m), 2.18 (3H, s), 2.20
(2H, m), 2.31 (3H, s), 2.47 (8H, m), 3.08 (1H, m), 3.32 (1H, m),
3.64 (3H, s), 5.24 (1H, s), 7.02-7.25 (13H, m). Chiral HPLC
separation (Chiralcel OD 20 × 250 mm column; λ ) 254 nm;
hexane:isopropyl alcohol, 60:40; 9.0 mL/min; 17.5 min) gave
the title enantiomer. Hydrochloride salt: pale yellow solid; mp
6-(3,4-Diflu or oph en yl)-1,6-dih ydr o-5-m eth oxycar bon yl-
1-(5-(4-m eth oxyca r bon yl-4-p h en ylp ip er id in -1-yl)p en t-1-
yl)-2,4-d im eth ylp yr im id in e (9). A mixture of (()-8a (0.67
g, 1.73 mmol), 4-methoxycarbonyl-4-phenylpiperidine (0.76 g,
3.47 mmol), potassium carbonate (0.96 g, 6.95 mmol), and
sodium iodide (0.52 g, 3.47 mmol) in 1,4-dioxane (15 mL) was
heated at reflux overnight. The solid was then filtered off and
the solvent was evaporated. The residue was purified by flash
chromatography over silica gel (4:1 ethyl acetate-2 M am-
monia in methanol) to give the title compound in 78% yield
1
(0.77 g) as a yellow oil: CIMS m/e ) 568 (MH+); H NMR δ
1.23-1.28 (2H, m), 1.43-1.51 (2H, m), 1.77-2.13 (8H, m), 2.16
(3H, s), 2.28 (3H, s), 2.47-2.55 (2H, m), 2.74-2.81 (2H, m),
3.00-3.12 (1H, m), 3.22-3.38 (1H, m), 3.613 (3H, s), 3.615 (3H,
s), 5.22 (1H, s), 6.99-7.35 (3H, m). Anal. (C32H39F2N3O4‚2HCl‚
2.3H2O) C, H, N. Chiral HPLC resolution (Chiralcel OD 20 ×
250 mm column; λ ) 254 nm; hexane:isopropyl alcohol, 80:20;
9.0 mL/min; 17.5 and 38.7 min) afforded the pure enantiomers.
(+)-9 (HCl salt): mp 118-120 °C; [R]D ) 63.0 (22.5 mg/mL
MeOH). (-)-9 (HCl salt): mp 119-121 °C; [R]D ) - 62.3 (24
mg/mL MeOH).
150-153 °C; [R]D ) 60.0 (2.95 mg/mL, MeOH). Anal. (C36H41
F2N3O2‚2HCl‚0.9CHCl3) C, H, N.
-
1-(5-Ch lor op en t -1-yl)-6-(3,4-d iflu or op h en yl)-1,6-d ih y-
d r o-5-m eth oxyca r bon yl-2,4-d im eth ylp yr im id in e (8a ). To
a suspension of NaH (90 mg, 60% dispersion in mineral oil,
2.25 mmol) in THF (7 mL) was added a solution of 7 (0.6 g,
2.14 mmol) in THF (8 mL) at 0 °C. After 20 min, 1-bromo-5-
chloropentane (1 mL, 7.59 mmol) was added. The reaction
mixture was then refluxed overnight. After removal of the
solvent, the residue was purified by flash chromatography over
silica gel (ethyl acetate) to give the product in 75% yield (0.614
g) as a yellow oil: 1H NMR δ 1.42-1.75 (6H, m), 2.17 (3H, s),
2.28 (3H, s), 3.05-3.45 (2H, m), 3.49 (2H, t, J ) 5.9 Hz), 3.63
(3H, s), 5.23 (1H, s), 7.01-7.15 (3H, m).
1-(5-Br om open t-1-yl)-6-(3,4-diflu or oph en yl)-1,6-dih ydr o-
5-m eth oxyca r bon yl-2,4-d im eth ylp yr im id in e (8b). To a
suspension of NaH (310 mg, 60% dispersion in mineral oil,
7.75 mmol) in THF (10 mL) was added a solution of 7 (2.0 g,
7.14 mmol) and HMPA (1.28 g, 7.14 mmol) in THF (15 mL) at
0 °C. After 15 min, 1,5-dibromopentane (3.9 mL, 28.56 mmol)
was added. The mixture was heated at reflux for 30 min before
it was filtered. The filtrate was concentrated and the residue
was purified by flash chromatography over silica gel (ethyl
acetate) to give the product in 64% yield (1.95 g) as a yellow
oil: 1H NMR δ 1.39-1.69 (4H, m), 1.81-1.96 (2H, m), 2.17
(3H, s), 2.29 (3H, s), 3.09 (1H, m), 3.31 (1H, m), 3.36 (2H, t,
J ) 6.6 Hz), 3.62 (3H, s), 5.22 (1H, s), 7.01-7.23 (3H, m).
(+)-8b was similarly prepared from (-)-7.
(+)-6-(3,4-Diflu or op h en yl)-1,6-d ih yd r o-5-m eth oxyca r -
b on yl-2,4-d im et h yl-1-(5-(4-(2-m et h ylp h en yl)-4-(4-m et h -
ylph en yl)piper idin -1-yl)pen t-1-yl)pyr im idin e ((+)-15). The
procedure similar to the one described for the synthesis of 9
was used from (+)-8b (0.18 g, 0.42 mmol) and 4,4-diphenyl-
piperidine hydrochloride (0.14 g, 0.46 mmol): 91% yield (0.24
1
g), yellow oil; CIMS m/e ) 614 (MH+); H NMR δ 1.25 (2H,
m), 1.4-1.65 (4H, m), 2.18 (3H, s), 2.19 (2H, m), 2.28 (3H, s),
2.29 (3H, s), 2.31 (3H, s), 2.45 (8H, m), 3.08 (1H, m), 3.30 (1H,
m), 3.64 (3H, s), 5.24 (1H, s), 6.93-7.17 (11H, m). Hydrochlo-
ride salt: white solid; mp 158-161 °C; [R]D ) 72.7 (1.65 mg/
mL, MeOH). Anal. (C38H45F2N3O2‚2HCl‚2H2O‚0.8CHCl3) C, H,
N.
6-(3,4-Diflu or op h en yl)-5-m et h oxyca r b on yl-1-(5-(4-(2-
m eth oxyph en yl)piper azin -1-yl)pen t-1-yl)-2,4-dim eth ylpy-
r im id in e (16). The procedure similar to the one described for
the synthesis of 9 was used from 8b (0.1 g, 0.233 mmol) and
4-(2-methoxyphenyl)piperazine (92 mg, 0.48 mmol): 55% yield
1
(70 mg), yellow oil; CIMS m/e ) 541 (MH+); H NMR δ 1.31
(2H, m), 1.50-1.62 (4H, m), 2.18 (3H, s), 2.29 (3H, s), 2.36 (2H,
m), 2.61 (4H, m), 3.05 (5H, m), 3.32 (1H, m), 3.63 (3H, s), 3.83
(3H, s), 5.24 (1H, s), 6.84-7.21 (7H, m). Hydrochloride salt:
white solid; mp 162-164 °C. Anal. (C30H38F2N4O3‚3HCl‚
0.6H2O) C, H, N.

4810 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23
Wong et al.
6-(3,4-Diflu or op h en yl)-1,6-d ih yd r o-5-m eth oxyca r bon y-
l-(5-(4-(2-m eth oxyca r bon ylp h en yl)p ip er a zin -1-yl)p en t-1-
yl)-2,4-d im eth ylp yr im id in e (17). The procedure similar to
the one described for the synthesis of 9 was used from 8b (0.1
g, 0.23 mmol) and 4-(2-methoxycarbonylphenyl)piperazine (80
mg, 0.36 mmol): 44% yield (0.059 g), yellow oil; CIMS m/e )
1-(5-Br om open t-1-yl)-6-(2,4-diflu or oph en yl)-1,6-dih ydr o-
5-m eth oxyca r bon yl-2,4-d im eth ylp yr im id in e (23). To a
suspension of NaH (0.405 g, 60% dispersion in mineral oil, 10.1
mmol) in THF (20 mL) was added a solution of 21 (2.7 g, 9.64
mmol) in THF (10 mL) at 0 °C. After 20 min, 1-bromo-5-
chloropentane (3.8 mL, d 1.408, 28.8 mmol) was added. The
reaction mixture was then refluxed overnight. After the
removal of the solvent, the residue was purified by flash
chromatography over silica gel (ethyl acetate) to give the
product in 79% yield (2.91 g) as a yellow oil: 1H NMR δ 1.25-
1.75 (6H, m), 1.86 (3H, s), 2.21 (3H, s), 3.0 (1H, m), 3.2 (1H,
m), 3.37 (2H, t, J ) 7.6 Hz), 3.43 (3H, s), 5.50 (1H, s), 6.60
(2H, m), 7.25 (1H, m).
1
569 (MH+); H NMR δ 1.22 (2H, m), 1.47-1.53 (4H, m), 2.17
(3H, s), 2.29 (3H, s), 2.35 (2H, m), 2.56 (4H, t, J ) 4.7 Hz),
3.04 (4H, t, J ) 4.7 Hz), 3.10 (1H, m), 3.35 (1H, m), 3.63 (3H,
s), 3.85 (3H, s), 5.24 (1H, s), 6.93-7.08 (5H, m), 7.37 (1H, m),
7.68 (1H, m). Hydrochloride salt: white solid; mp 82-86 °C.
Anal. (C31H38F2N4O4‚3HCl‚0.7CHCl3) C, H, N.
(+)-1-(5-(4-(2-Am in oca r b on yl)p h en ylp ip er a zin -1-yl)-
p en t-1-yl)-6-(3,4-d iflu or op h en yl)-1,6-d ih yd r o-5-m eth oxy-
ca r bon yl-2,4-d im eth ylp yr im id in e ((+)-18). The procedure
similar to the one described for the synthesis of 9 was used
from 8b (1 g, 2.33 mmol) and 4-(2-aminocarbonylphenyl)-
piperazine (0.65 g, 3.17 mmol): 98% yield (1.3 g), yellow oil;
CIMS m/e ) 554 (MH+); 1H NMR δ 1.24-1.32 (2H, m), 1.46-
1.55 (4H, m), 1.85 (2H, m), 2.17 (3H, s), 2.28 (3H, s), 2.34 (2H,
m), 2.56 (2H, m), 3.00 (4H, t, J ) 4.7 Hz), 3.10 (1H, m), 3.32
(1H, m), 3.62 (3H, s), 5.23 (1H, s), 5.91 (1H, m), 7.00-7.23 (5H,
m), 7.43 (1H, m), 8.10 (1H, m), 9.45 (1H, m). Chiral HPLC
separation (Chiralcel OD 20 × 250 mm column; λ ) 254 nm;
hexane:ethyl alcohol, 85:15; 12 mL/min; 26.2 min) gave the
title enantiomer which was converted to a hydrochloride salt:
white solid; mp 167-168 °C; [R]D ) 121.5 (30 mg/mL MeOH).
Anal. (C30H37F2N5O3‚2.5HCl‚0.1Et2O) C, H, N.
Ben zyl 3-Oxo-2-(2,4-d iflu or ob en zylid en yl)b u t a n oa t e
(20). A mixture of 2,4-difluorobenzaldehyde (7.1 g, 50 mmol),
benzyl acetoacetate (12.48 g, 65 mmol), acetic acid (0.15 g, 2.5
mmol), piperidine (0.212 g, 2.5 mmol), and 2-propanol (300 mL)
was stirred at room temperature for 2 days. After removal of
the solvent, the residue was dissolved in ethyl acetate, washed
with saturated KHSO4, saturated NaHCO3, and water, and
then dried over Na2SO4. The solvent was evaporated, and the
residue was flash-chromatographed over silica gel (1:5 ethyl
acetate-hexane) to give the product in 91% yield (14.3 g) as a
yellow solid: 1H NMR δ 2.39 (3H, s), 5.26 (2H, s), 6.80 (2H,
m), 7.15 (1H, m), 7.3-7.34 (5H, m), 7.63 (1H, s).
6-(2,4-Diflu or oph en yl)-1,6-dih ydr o-5-m eth oxycar bon yl-
2,4-d im eth ylp yr im id in e (21). To a solution of acetamidine
hydrochloride (2.84 g, 30 mmol) in DMF (20 mL) were added
a solution of potassium tert-butoxide (2.46 g, 21.8 mmol) in
DMF (20 mL) and a solution of 19 (2.84 g, 20 mmol) in DMF
(20 mL) at 0 °C. After the mixture was stirred for 0.5 h at 0
°C, p-toluenesulfonic acid monohydrate (7.6 g, 39.8 mmol) was
added. The mixture was heated at 100-120 °C for 2 h. The
reaction mixture was cooled to room temperature, quenched
with 2 N NaOH solution (100 mL), and extracted with ether.
The organic layer was dried over Na2SO4 and evaporated. The
residue was purified by flash chromatography over silica gel
(ethyl acetate) to give the product in 49% yield (2.74 g) as a
yellow solid: 1H NMR δ 1.93 (3H, s), 2.33 (3H, s), 3.55 (3H, s),
5.75 (1H, s), 6.75 (2H, m), 7.23 (1H, m).
5-Ben zyloxyca r b on yl-1-(5-b r om op en t -1-yl)-6-(2,4-d i-
flu or op h en yl)-1,6-d ih yd r o-2,4-d im eth ylp yr im id in e (24).
To a suspension of NaH (123 mg, 60% dispersion in mineral
oil) in THF (5 mL) was added a solution of 22 (1.0 g, 2.8 mmol)
and HMPA (0.5 g, 2.8 mmol) in THF (5 mL) at 0 °C. After 15
min, 1,5-dibromopentane (1.53 mL, 11.2 mmol) was added. The
reaction mixture was then refluxed for 30 min. The solid was
filtered off. After the removal of the solvent, the residue was
purified by flash chromatography over silica gel (ethyl acetate)
to give the product in 78% yield (1.1 g) as a yellow oil: 1H
NMR δ 1.40-1.90 (6H, m), 2.10 (3H, s), 2.37 (3H, s), 3.10 (1H,
m), 3.25 (1H, m), 3.35 (2H, t, J ) 6.6 Hz), 4.94 (1H, d, J )
12.4 Hz), 5.10 (1H, d, J ) 12.4 Hz), 5.63 (1H, s), 6.64-6.79
(2H, m), 7.10-7.36 (6H, m).
6-(2,4-Diflu or oph en yl)-1,6-dih ydr o-5-m eth oxycar bon yl-
1-(5-(4-m eth oxyca r bon yl-4-p h en ylp ip er id in -1-yl)p en t-1-
yl)-2,4-d im eth ylp yr im id in e (25). The procedure similar to
the one described for the synthesis of 9 was used from 23 (0.4
g, 1.04 mmol) and 4-methoxycarbonyl-4-phenylpiperidine (0.45
g, 2.05 mmol): 25% yield (0.15 g), yellow oil; CIMS m/e ) 568
(MH+); 1H NMR δ 1.27 (2H, m), 1.45-1.75 (4H, m), 1.92-2.11
(4H, m), 2.09 (3H, s), 2.23 (2H, m), 2.34 (3H, s), 2.51 (2H, m),
2.81 (2H, m), 3.05 (1H, m), 3.30 (1H, m), 3.56 (3H, s), 3.61
(3H, s), 5.61 (1H, s), 6.71-6.78 (2H, m), 7.20-7.38 (6H, m).
Hydrochloride salt: pale yellow solid; mp 128-132 °C. Anal.
(C32H39F2N3O4‚2HCl‚H2O‚CHCl3) C, H, N.
5-Ben zyloxyca r bon yl-6-(2,4-d iflu or op h en yl)-1,6-d ih y-
dr o-1-(5-(4-m eth oxycar bon yl-4-ph en ylpiper idin -1-yl)pen t-
1-yl)-2,4-d im eth ylp yr im id in e (26). The procedure similar
to the one described for the synthesis of 9 was used from 23
(1.62 g, 3.2 mmol) and 4-methoxycarbonyl-4-phenylpiperidine
(1.4 g, 6.4 mmol): 66% yield (1.36 g), yellow oil; 1H NMR δ
1.25 (2H, m), 1.46-1.70 (4H, m), 1.90-2.07 (4H, m), 2.08 (3H,
s), 2.23 (2H, m), 2.36 (3H, s), 2.51 (2H, m), 2.81 (2H, m), 3.05
(1H, m), 3.25 (1H, m), 3.61 (3H, s), 4.93 (1H, d, J ) 12.5 Hz),
5.09 (1H, d, J ) 12.5 Hz), 5.63 (1H, s), 6.62 (1H, m), 6.78 (1H,
m), 7.10-7.36 (11H, m).
5-Ca r b oxy-6-(2,4-d iflu or op h en yl)-1,6-d ih yd r o-1-(5-(4-
m eth oxyca r bon yl-4-p h en ylp ip er id in -1-yl)p en t-1-yl)-2,4-
d im eth ylp yr im id in e (27). A solution of 26 (0.36 g, 0.56
mmol) in methanol (20 mL) was subjected to hydrogenation
with a H2 balloon in the presence of 5% palladium on carbon
(36 mg). The reaction was carried out at room temperature
for 30 min. The catalyst was then filtered off and the solvent
was removed in vacuo to give the product in quantitative yield
(0.31 g) as an off-white solid: 1H NMR δ 1.30 (2H, m), 1.52
(3H, m), 2.05-2.28 (4H, m), 2.55 (2H, m), 2.93 (2H, m), 2.24
(3H, s), 2.32 (3H, s), 3.30 (1H, m), 3.55 (1H, m), 3.60 (3H, s),
5.95 (1H, s), 6.96 (2H, m, 7.20-7.45 (6H, m).
5-Ben zyloxyca r bon yl-6-(2,4-d iflu or op h en yl)-1,6-d ih y-
d r o-2,4-d im eth ylp yr im id in e (22). To a stirred solution of
acetamidine hydrochloride (2.84 g, 30 mmol) in DMF (20 mL)
were added a solution of potassium tert-butoxide (2.46 g, 22
mmol) in DMF (20 mL) and a solution of 20 (6.32 g, 20 mmol)
in DMF (20 mL) at 0 °C. After the mixture was stirred for 15
min at 0 °C, p-toluenesulfonic acid monohydrate (7.6 g, 40
mmol) was added. The mixture was heated at 100-110 °C for
2 h. After cooling, the reaction mixture was quenched with 2
N aqueous NaOH solution and extracted with ether. The
organic layer was dried over Na2SO4 and evaporated. The
residue was purified by flash chromatography over silica gel
(20:1 ethyl acetate-2 M ammonia in methanol) to give the
product in 42% yield (1.5 g) as an off-white solid: 1H NMR δ
1.71 (3H, s), 2.20 (3H, s), 4.90 (1H, d, J ) 12.5 Hz), 5.04 (1H,
d, J ) 12.5 Hz), 5.75 (1H, s), 6.64-6.71 (2H, m), 7.04-7.22
(6H, m).
5-Am in oca r b on yl-6-(2,4-d iflu or op h en yl)-1,6-d ih yd r o-
1-(5-(4-m eth oxyca r bon yl-4-p h en ylp ip er id in -1-yl)p en t-1-
yl)-2,4-d im eth ylp yr im id in e (28). A mixture of 27 (0.2 g, 0.36
mmol), 4,4-dimethylaminopyridine (0.26 g, 2.12 mmol), 1-(3-
dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.13
g, 0.66 mmol), and CH2Cl2 (10 mL) was stirred at room
temperature for 2 h. After the addition of ammonium chloride
(0.06 g, 1.08 mmol), the mixture was stirred at room temper-
ature for 3 days. To the mixture was added another 25 mL of
CH2Cl2 and it was washed with saturated NH4Cl solution.

Novel R1a Adrenoceptor-Selective Antagonists. 4
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23 4811
After removal of the solvent, the residue was separated by
silica gel TLC plate (5:1 ethyl acetate-2 M ammonia in
methanol) to give the title compound in 7.5% yield (0.015 g)
as a yellow oil: CIMS m/e ) 553 (MH+); 1H NMR δ 1.20 (4H,
m), 1.45 (3H, m), 1.65 (1H, m), 1.92 (2H, m), 2.15 (5H, m),
2.25-2.31 (5H, m), 2.55 (2H, m), 2.80 (2H, m), 3.02 (1H, m),
3.28 (1H, m), 3.61 (3H, s), 5.37 (1H, s), 6.80 (2H, m), 7.20-
7.34 (6H, m). Hydrochloride salt: pale yellow solid; mp 77-
80 °C. Anal. (C31H38F2N4O3‚2HCl‚H2O‚0.2CHCl3‚2Et2O) C, H,
N.
solid; mp 178-181 °C. Anal. (C31H37F2N3O4‚2HCl‚1.6H2O‚
0.8CHCl3) C, H, N.
(+)-1-(5-(4-(2-Am in oca r b on yl)p h en ylp ip er a zin -1-yl)-
4(R)-m eth ylp en t-1-yl)-6-(3,4-d iflu or op h en yl)-1,6-d ih yd r o-
5-m eth oxyca r bon yl-2,4-d im eth ylp yr im id in e ((+)-41). The
procedure similar to the one described for the synthesis of 9
was used from 35 (0.3 g, 0.68 mmol) and 4-(2-aminocarbon-
ylphenyl)piperazine (0.2 g, 0.96 mmol): 52% yield (0.2 g),
yellow oil. Chiral HPLC separation (Chiralcel OD 20 × 250
mm column; λ ) 254 nm; hexane:ethyl alcohol:diethylamine,
85:15:0.1; 9.0 mL/min; 15.6 min) gave the title enantiomer:
6-(2,4-Diflu or op h en yl)-1,6-d ih yd r o-1-(5-(4-m eth oxyca r -
bon yl-4-p h en ylp ip er id in -1-yl)p en t -1-yl)-2,4-d im et h yl-5-
m eth yla m in oca r bon ylp yr im id in e (29). A mixture of 15
(0.244 g, 0.44 mmol), 4-dimethylaminopyridine (0.26 g, 2.12
mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydro-
chloride (0.13 g, 0.66 mmol), and CH2Cl2 (10 mL) was stirred
at room temperature for 2 h. After the addition of methylamine
hydrogen chloride (0.09 g, 1.32 mmol), the mixture was stirred
at room temperature overnight. To the mixture was added
another 25 mL of CH2Cl2 and it was washed with saturated
NH4Cl solution. After removal of the solvent, the residue was
flash-chramotographed over silica gel (5:1 ethyl acetate-2 M
ammonia in methanol) to give the title compound in 22% yield
1
CIMS m/e ) 568 (MH+); H NMR δ 0.89 (3 H, d, J ) 6.6 Hz),
1.05 (1H, m), 1.40 (1H, m), 1.62 (3H, m), 2.15 (2H, m), 2.22
(3H, s), 2.32 (3H, s), 2.54 (4H, m), 3.02 (2H, m), 3.12 (1H, m),
3.35 (1H, m), 3.68 (3H, s), 5.28 (1H, s), 5.85 (1H, m), 7.04-
7.24 (5H, m), 7.46 (1H, m), 8.16 (1H, m), 9.55 (1H, m).
Hydrochloride salt: pale yellow solid; mp 158-162 °C; [R]D
)
43.9 (2.05 mg/mL, MeOH). Anal. (C31H39F2N5O3‚3HCl‚H2O‚
1.1CH2Cl2) C, H, N.
(+)-1-(5-(4-(2-Am in oca r b on yl)p h en ylp ip er a zin -1-yl)-
4(S)-m eth ylp en t-1-yl)-6-(3,4-d iflu or op h en yl)-1,6-d ih yd r o-
5-m eth oxyca r bon yl-2,4-d im eth ylp yr im id in e ((+)-40). The
procedure similar to the one described for the synthesis of 9
was used from 34 (0.25 g, 0.56 mmol) and 4-(2-aminocarbon-
ylphenyl)piperazine (0.17 g, 0.83 mmol): 63% yield (0.2 g),
yellow oil. Chiral HPLC separation (Chiralcel OD 20 × 250
mm column; λ ) 254 nm; hexane:ethyl alcohol:diethylamine,
85:15:0.1; 9.0 mL/min; 27.5 min) gave the title enantiomer:
1
(0.055 g) as a yellow oil: CIMS m/e ) 567 (MH+); H NMR δ
1.25 (2H, m), 1.45 (3H, m),1.65 (1H, m), 1.92-2.05 (4H, m),
2.07 (3H, s), 2.14 (3H, s), 2.24 (2H, m), 2.50 (2H, m), 2.73 (5H,
m), 3.02 (1H, m), 3.24 (1H, m), 3.61 (3H, s), 5.37 (1H,s), 5.58
(1H, s), 6.76 (2H, m), 7.20-7.34 (6H, m). Hydrochloride salt:
pale yellow solid; mp 152-155 °C. Anal. (C32H40F2N4O3‚2HCl‚
1.6H2O‚0.8CHCl3) C, H, N.
1
CIMS m/e ) 568 (MH+); H NMR δ 0.90 (3H, d, J ) 6.6 Hz),
1.05 (1H, m), 1.40-1.65 (4H, m), 2.15 (2H, m), 2.21 (3H, s),
2.32 (3H, s), 2.54 (4H, m), 3.02 (2H, m), 3.12 (1H, m), 3.35
(1H, m), 3.64 (3H, s), 5.28 (1H, s), 5.90 (1H, m), 7.04-7.24 (5H,
m), 7.46 (1H, m), 8.14 (1H, m), 9.55 (1H, m). Hydrochloride
salt: pale yellow solid; mp 155-158 °C; [R]D ) 64.7 (2.75 mg/
mL, MeOH). Anal. (C31H39F2N5O3‚3HCl‚H2O‚0.6Et2O) C, H, N.
1-(4-Br om obu t-1-yl)-6-(3,4-diflu or oph en yl)-1,6-dih ydr o-
5-m eth oxyca r bon yl-2,4-d im eth ylp yr im id in e (33). To a
suspension of NaH (50 mg, 60% dispersion in mineral oil) in
THF (7 mL) was added a solution of 7 (0.32 g, 1.14 mmol) and
HMPA (0.205 g, 1.14 mmol) in THF (8 mL) at 0 °C. After 15
min, 1,4-dibromobutane (0.47 mL, 4.0 mmol) was added. The
reaction mixture was then refluxed for 10 min. The solid was
filtered off. After removal of the solvent, the residue was
purified by flash chromatography over silica gel (ethyl acetate)
to give the product in 44% yield (0.2 g) as a yellow oil: 1H
NMR δ 1.71-1.81 (4H, m), 2.17 (3H, s), 2.28 (3H, s), 3.12 (1H,
m), 3.36 (3H, m), 3.62 (3H, s), 5.22 (1H, s), 7.00-7.08 (3H, m).
1-(5-Br om o-4(S)-m eth ylp en t-1-yl)-6(R,S)-(3,4-d iflu or o-
p h en yl)-1,6-d ih yd r o-5-m eth oxyca r bon yl-2,4-d im eth ylp y-
r im id in e (34). To a suspension of NaH (47 mg, 60% dispersion
in mineral oil) in THF (3 mL) was added a solution of 7 (0.3 g,
1.07 mmol) and HMPA (0.193 g, 1.07 mmol) in THF (4 mL) at
0 °C. After 10 min, a solution of 31 (0.86 g, 3.53 mmol) in THF
(5 mL) was added. The reaction mixture was then refluxed
for 10 min. The solid which formed was filtered off. After
removal of the solvent, the residue was flash-chromatographed
over silica gel (20:1 ethyl acetate-2 M ammonia in methanol)
to give the product in 36% yield (0.169 g) as a yellow oil: 1H
NMR δ 0.97 (3H, d, J ) 6.5 Hz), 1.22 (1H, m), 1.35-1.80 (5H,
m), 2.18 (3H, s), 2.29 (3H, s), 3.10 (1H, m), 3.30 (2H, m), 3.63
(3H, s), 5.23 (1H, s), 6.95-7.18 (3H, m).
(+)-6-(3,4-Diflu or op h en yl)-1,6-d ih yd r o-5-m eth oxyca r -
bon yl-1-(5-(4-m eth oxyca r bon yl-4-p h en ylp ip er id in -1-yl)-
4(S)-m eth ylp en t-1-yl)-2,4-d im eth ylp yr im id in e ((+)-37).
The procedure similar to the one described for the synthesis
of 9 was used from 35 (3.50 g, 7.9 mmol) and 4-methoxycar-
bonyl-4-phenylpiperidine (3.50 g, 15.7 mmol): 44% yield (2.0
g). Chiral HPLC separation (Chiralcel OD 20 × 250 mm
column; λ ) 254 nm; hexane:isopropyl alcohol:diethylamine,
90:10:0.1; 12.0 mL/min; 11.3 min) afforded the title enanti-
1
omer: CIMS m/e ) 582 (MH+); H NMR δ 1.03 (3H, m), 1.22
(1H, m), 1.56 (1H, m), 1.77 (2H, m), 2.05-2.30 (7H, m), 2.39
(3H, s), 2.49 (3H, s), 2.73 (2H, m), 2.90 (2H, m), 3.27 (1H, m),
3.48 (1H, m), 3.81 (3H, s), 5.44 (1H, s), 7.20-7.52 (8H, m).
Hydrochloride salt: light yellow solid; mp 133-134 °C; [R]D
)
137.6 (11 mg/mL, MeOH). Anal. (C33H41F2N3O4‚2HCl‚1/2H2O)
C, H, N.
(+)-1-(5-(4-Cya n o-4-p h en ylp ip er id in -1-yl)-4(S)-m eth yl-
p en t-1-yl)-6-(3,4-d iflu or op h en yl)-1,6-d ih yd r o-5-m eth oxy-
ca r bon yl-2,4-d im eth ylp yr im id in e ((+)-38). The procedure
similar to the one described for the synthesis of 9 was used
from 34 (0.23 g, 0.515 mmol) and 4-cyano-4-phenylpiperidine
hydrochloride (0.23 g, 1.0 mmol): 32% yield (0.09 g), yellow
oil. Chiral HPLC separation (Chiralcel OD 20 × 250 mm
column; λ ) 254 nm; hexane:isopropyl alcohol:diethylamine,
80:20:0.1; 12.0 mL/min; 15.9 min) gave the title enantiomer:
1-(5-Br om o-4(R)-m et h ylp en t -1-yl)-6(R,S)-(3,4-d iflu o-
r op h en yl)-1,6-d ih yd r o-5-m et h oxyca r b on yl-2,4-d im et h -
ylp yr im id in e (35). Prepared in 32% yield from 7 and 32
according to the procedure described for 34: 1H NMR δ 0.99
(3H, d, J ) 6.6 Hz), 1.40-1.80 (4H, m), 2.20 (3H, s), 2.31 (3H,
s), 3.12 (1H, m), 3.33 (3H, m), 3.65 (3H, s), 5.26 (1H, s), 7.00-
7.20 (3H, m).
1
CIMS m/e ) 549 (MH+); [R]D ) 142.8 (6 mg/mL, MeOH); H
NMR δ 0.89 (3H, d, J ) 6.6 Hz), 1.03-1.75 (7H, m), 2.09 (4H,
m), 2.21 (3H, s), 2.31 (3H, s), 2.45 (2H, m), 2.90 (2H, m), 3.10
(1H, m), 3.35 (1H, m), 3.64 (3H, s), 5.28 (1H, s), 7.02-7.49 (8H,
m). Hydrochloride salt: light yellow solid; mp 140-141 °C.
Anal. (C32H38F2N4O2‚2HCl‚0.7CHCl3) C, H, N.
6-(3,4-Diflu or oph en yl)-1,6-dih ydr o-5-m eth oxycar bon yl-
1-(4-(4-m et h oxyca r b on yl-4-p h en ylp ip er id in -1-yl)b u t -1-
yl)-2,4-d im eth ylp yr im id in e (36). The procedure similar to
the one described for the synthesis of 9 was used from 33 (0.21
g, 0.51 mmol) and 4-methoxycarbonyl-4-phenylpiperidine (0.22
g, 1.02 mmol): 63% yield (0.18 g), yellow oil; CIMS m/e ) 554
(+)-1-(5-(4-Cya n o-4-p h en ylp ip er id in -1-yl)-4(R)-m eth yl-
p en t-1-yl)-6-(3,4-d iflu or op h en yl)-1,6-d ih yd r o-5-m eth oxy-
ca r bon yl-2,4-d im eth ylp yr im id in e ((+)-39). The procedure
similar to the one described for the synthesis of 9 was used
from 35 (0.3 g, 0.68 mmol) and 4-cyano-4-phenylpiperidine
hydrochloride (0.3 g, 1.35 mmol): 54% yield (0.2 g), yellow oil.
Chiral HPLC separation (Chiralcel OD 20 × 250 mm column;
λ ) 254 nm; hexane:ethyl alcohol:diethylamine, 85:15:0.1; 9.0
1
(MH+); H NMR δ 1.46-1.58 (4H, m), 1.92-2.0 (4H, m), 2.23
(2H, m), 2.15 (3H, s), 2.27 (3H, s), 2.5 (2H, m), 2.73 (2H, m),
3.08 (1H, m), 3.30 (1H, m), 3.613 (3H, s), 3.59 (3H, s), 5.22
(1H, s), 6.98-7.31 (8H, m). Hydrochloride salt: pale yellow

4812 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23
mL/min; 18.9 min) gave the title enantiomer: CIMS m/e )
Wong et al.
of 46 (0.8 g, 2.6 mmol) in THF (5 mL) at 0 °C. After 20 min,
1,5-dibromopentane (0.7 mL, 5.2 mmol) was added. The
mixture was then refluxed overnight. After the removal of
solvent, the residue was purified by flash chromatography over
silica gel (ethyl acetate) to give the product in quantitative
yield (1.2 g) as a yellow oil: 1H NMR δ 1.43-1.94 (6H, m),
2.34 (3H, s), 3.15 (1H, m), 3.34 (3H, s), 3.42 (2H, t, J ) 6.6
Hz), 3.69 (3H, s), 3.65-3.75 (1H, m), 4.05 (1H, d, J ) 12.9
Hz), 4.30 (1H, d, J ) 12.8 Hz), 5.31 (1H, s), 7.0-7.09 (3H, m).
1-(5-Br om open t-1-yl)-6-(3,4-diflu or oph en yl)-1,6-dih ydr o-
5-m et h oxyca r b on yl-4-m et h oxym et h yl-2-m et h ylp yr im i-
d in e (49). To a suspension of NaH (0.12 g, 60% oil dispersion,
3 mmol) in THF (5 mL) was added a solution of 47 (0.8 g, 2.58
mmol) in THF (5 mL) at 0 °C. After 20 min, 1,5-dibromopen-
tane (1.18 mL, 7.74 mmol) was added. The mixture was then
refluxed for 3 h. After the removal of the solvent, the residue
was purified by flash chromatography over silica gel (ethyl
acetate) to give the product in 78% yield (0.92 g) as a yellow
oil: 1H NMR δ 1.41-1.85 (6H, m), 2.23 (3H, s), 3.05 (1H, m),
3.35 (1H, m), 3.40 (3H, s), 3.48 (2H, t, J ) 6.3 Hz), 3.63 (3H,
s), 4.42 (1H, d, J ) 12.4 Hz), 4.48 (1H, d, J ) 12.4 Hz), 5.25
(1H, s), 7.01-7.08 (3H, m).
1
549 (MH+); [R]D ) 169.9 (9.5 mg/mL MeOH); H NMR δ 0.89
(3H, d, J ) 6.6 Hz), 1.05 (1H, m), 1.40 (1H, m), 1.55-1.67 (4H,
m), 2.09 (4H, m), 2.20 (1H, m), 2.21 (3H, s), 2.31 (3H, s), 2.45
(2H, m), 2.90 (2H, m), 3.10 (1H, m), 3.35 (1H, m), 3.64 (3H, s),
5.28 (1H, s), 7.02-7.20 (3H, m), 7.35-7.49 (5H, m). Hydro-
chloride salt: pale yellow solid; mp 171-172 °C. Anal.
(C32H38F2N4O2‚2HCl‚0.1CHCl3) C, H, N.
1-(3-Br om om et h ylb en zyl)-6-(3,4-d iflu or op h en yl)-1,6-
dih ydr o-5-m eth oxycar bon yl-2,4-dim eth ylpyr im idin e (42).
To a suspension of NaH (31 mg, 60% dispersion in mineral
oil) in THF (5 mL) was added a solution of 7 (0.3 g, 1.07 mmol)
and HMPA (0.193 g, 1.07 mmol) in THF (5 mL) at 0 °C. After
15 min, R,R′-dibromo-m-xylene (0.99 g, 3.75 mmol) was added.
The reaction mixture was then refluxed for 15 min. The solid
was filtered off. After the removal of the solvent, the residue
was purified by flash chromatography over silica gel (ethyl
acetate) to give the product in 91% yield (0.45 g) as a yellow
oil: 1H NMR δ 2.19 (3H, s), 2.36 (3H, s), 3.55 (3H, s), 4.18
(1H, d, J ) 16.4 Hz), 4.45 (2H, s), 4.63 (1H, d, J ) 16.5 Hz),
5.12 (1H, s), 6.99-7.34 (7H, m).
6-(3,4-Diflu or oph en yl)-1,6-dih ydr o-5-m eth oxycar bon yl-
1-(3-(4-m eth oxyca r bon yl-4-p h en ylp ip er id in -1-yl)m eth yl-
ben zyl)-2,4-d im eth ylp yr im id in e (43). A mixture of 42 (0.45
g, 0.97 mmol), 4-methoxycarbonyl-4-phenylpiperidine (0.42 g,
1.9 mmol), potassium carbonate (0.67 g, 4.86 mmol), sodium
iodide (0.14 g, 0.97 mmol), and 1,4-dioxane (10 mL) was
refluxed overnight. The solid was then filtered off and the
solvent was evaporated. The residue was purified by flash
chromatography over silica gel (20:1 ethyl acetate-2 M am-
monia in methanol) to give the title compound in 17% yield
(0.1 g) as a yellow oil: CIMS m/e ) 602 (MH+); 1H NMR δ
1.68-1.85 (2H, m), 1.95 (2H, m), 2.13 (2H, m), 2.19 (3H, s),
2.34 (3H, s), 2.49 (2H, m), 2.75 (2H, m), 3.43 (2H, s), 3.52 (3H,
s), 3.62 (3H, s), 4.18 (1H, d, J ) 16.7 Hz), 4.61 (1H, d, J )
16.7 Hz), 5.13 (1H, s), 6.99-7.36 (12H, m). Hydrochloride
salt: off-white solid; mp 181-183 °C. Anal. (C35H37F2N3O4‚
2HCl‚H2O) C, H, N.
6-(3,4-Diflu or oph en yl)-1,6-dih ydr o-5-m eth oxycar bon yl-
2-m eth oxym eth yl-4-m eth ylp yr im id in e (46). To a solution
of 2-methoxyacetamidine hydrochloride (1.4 g, 11.2 mmol) in
DMF (6 mL) were added a solution of potassium tert-butoxide
(0.69 g, 6.1 mmol) in DMF (6 mL) and a solution of 5 (1.4 g,
5.8 mmol) in DMF (6 mL) at 0 °C. After the mixture was
stirred for 0.5 h at 0 °C, p-toluenesulfonic acid monohydrate
(2.2 g, 11.6 mmol) was added. The mixture was heated at 100-
120 °C for 2.5 h. The mixture was cooled to room temperature,
quenched with 2 N NaOH solution (30 mL), and extracted with
ether. The organic layer was dried over Na2SO4 and evapo-
rated. The residue was purified by flash chromatography over
silica gel (ethyl acetate) to give the product in 44% yield (0.8
g) as a yellow oil: 1H NMR δ 2.38 (3H, s), 3.39 (3H, s), 3.63
(3H, s), 4.06 (2H, q, J ) 12.4 Hz), 5.57 (1H, s), 6.89 (1H, b),
7.04-7.15 (3H, m).
1-(5-(4-Cya n o-4-p h en ylp ip er id in -1-yl)p en t-1-yl)-6-(3,4-
d iflu or op h en yl)-1,6-d ih yd r o-5-m eth oxyca r bon yl-2-m eth -
oxym eth yl-4-m eth ylp yr im id in e (50). The procedure similar
to the one described for the synthesis of 9 was used from 48
(0.15 g, 0.33 mmol) and 4-cyano-4-phenylpiperidine hydro-
chloride (0.15 g, 0.67 mmol): 44% yield (0.08 g), yellow oil;
CIMS m/e ) 565 (MH+); 1H NMR δ 1.31-1.37 (2H, m), 1.52-
1.75 (4H, m), 2.03-2.13 (4H, m), 2.34 (3H, s), 2.40-2.51 (4H,
m), 3.00-3.04 (2H, m), 3.14 (1H, m), 3.34 (3H, s), 3.68 (3H, s),
3.70 (1H,m), 4.05 (1H, d, J ) 12.9 Hz), 4.32 (1H, d, J ) 12.9
Hz), 5.32 (1H, s), 7.05-7.19 (3H, m), 7.33-7.52 (5H, m). HCl
salt: off-white solid; mp 98-101 °C; [R]D ) 190.5 (55 mg/mL
CH2Cl2). The (+) enantiomer was obtained by chiral HPLC
separation (column: Chiralcel OD 20 × 250 mm; 2-propanol:
hexane:diethylamine, 10:90:0.1). Anal. (C32H38F2N4O3‚2HCl‚
1.1CHCl3) C, H, N.
1-(5-(4-Cya n o-4-p h en ylp ip er id in -1-yl)p en t-1-yl)-6-(3,4-
d iflu or op h en yl)-1,6-d ih yd r o-5-m eth oxyca r bon yl-4-m eth -
oxym eth yl-2-m eth ylp yr im id in e (51). Prepared from 49 and
4-cyano-4-phenylpiperidine hydrochloride according to the
procedure described for 9 as a yellow oil (29% yield): CIMS
m/e ) 565 (MH+); 1H NMR δ 1.34-1.37 (2H, m), 1.58-1.63
(4H, m), 2.12-2.26 (4H, m), 2.35 (3H, s), 2.55-2.64 (4H, m),
3.15-3.21 (3H, m), 3.40 (1H, m), 3.44 (3H, s), 3.68 (3H, s), 4.46
(1H, d, J ) 12.5 Hz), 4.56 (1H, d, J ) 12.5 Hz), 5.32 (1H, s),
7.08-7.53 (8H, m). Hydrochloride salt: yellow solid; mp 98-
100 °C. Anal. (C32H38F2N4O3‚2HCl‚CHCl3) C, H, N.
Ack n ow led gm en t. The authors thank Boshan Li
and Vincent J orgensen for performing the radioligand
displacement assays and Yong Zheng for his work in
cell culture and membrane preparations.
6-(3,4-Diflu or oph en yl)-1,6-dih ydr o-5-m eth oxycar bon yl-
4-m eth oxym eth yl-2-m eth ylp yr im id in e (47). To a stirred
solution of acetamidine hydrochloride (0.71 g, 7.5 mmol.) in
DMF (5 mL) were added a solution of potassium tert-butoxide
(0.61 g, 5.5 mmol) in DMF (5 mL) and a solution of 29 (1.35 g,
5 mmol) in DMF (5 mL) at 0 °C. After the mixture was stirred
for 15 min at 0 °C, p-toluenesulfonic acid monohydrate (1.9 g,
10 mmol) was added. The mixture was heated at 100-110 °C
for 2 h. After cooling, the reaction mixture was quenched with
2 N aqueous NaOH solution and extracted with ether. The
organic layer was dried over Na2SO4, filtered, and evaporated.
The residue was flash-chromatographed over silica gel (ethyl
acetate) to give the product in 23% yield (0.352 g) as an off-
white solid: 1H NMR δ 2.01 (3H, s), 3.41 (3H, s), 3.57 (3H, s),
4.59 (1H, d, J ) 16.2 Hz), 4.64 (1H, d, J ) 16.2 Hz), 5.46 (1H,
s), 6.98-7.06 (3H, m).
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