CCR5 antagonists as anti-HIV-1 agents. 1. Synthesis and biological evaluation of 5-oxopyrrolidine-3-carboxamide derivatives

Article abstract of DOI:10.1248/cpb.52.63

A novel lead compound, N-{3-[4-(4-fluorobenzoyl)piperidin-1-yl]propyl}-1- methyl-5-oxo-N-phenylpyrrolidine-3-carboxamide (1), was identified as a CCR5 antagonist by high-throughput screening using [¹²⁵I]RANTES and CCR5-expressing CHO cells. The IC₅₀ value of 1 was 1.9 μM. In an effort to improve the binding affinity of 1, a series of 5-oxopyrrolidine-3- carboxamides was synthesized. Introduction of 3,4-dichloro substituents to the central phenyl ring (10i, IC₅₀=0.057 μM; 11b, IC ₅₀=0.050 μM) or replacing the 1-methyl group of the 5-oxopyrrolidine moiety with a 1-benzyl group (12e, IC₅₀=0.038 μM) was found to be effective for improving CCR5 affinity. Compound 10i, 11b, and 12e also inhibited CCR5-using HIV-1 envelope-mediated membrane fusion with IC₅₀ values of 0.44, 0.19, and 0.49 μM, respectively.

Full text of DOI:10.1248/cpb.52.63

January 2004
Chem. Pharm. Bull. 52(1) 63—73 (2004)
63
CCR5 Antagonists as Anti-HIV-1 Agents. 1. Synthesis and Biological
Evaluation of 5-Oxopyrrolidine-3-carboxamide Derivatives
Shinichi IMAMURA, ,a Yuji ISHIHARA,a Taeko HATTORI,a Osamu KURASAWA,a Yoshihiro MATSUSHITA,a
*
a
Yoshihiro SUGIHARA,a Naoyuki KANZAKI,a Yuji IIZAWA,a Masanori BABA,b and Shohei HASHIGUCHI
a Pharmaceutical Research Division, Takeda Chemical Industries, Ltd.; 2–17–85 Jusohonmachi, Yodogawa-ku, Osaka
532–8686, Japan: and b Division of Antiviral Chemotherapy, Center for Chronic Viral Diseases, Faculty of Medicine,
Kagoshima University; 8–35–1 Sakuragaoka, Kagoshima 890–8520, Japan.
Received September 4, 2003; accepted October 21, 2003; published online October 24, 2003
A novel lead compound, N-{3-[4-(4-fluorobenzoyl)piperidin-1-yl]propyl}-1-methyl-5-oxo-N-phenylpyrroli-
dine-3-carboxamide (1), was identified as a CCR5 antagonist by high-throughput screening using [125I]RANTES
and CCR5-expressing CHO cells. The IC50 value of 1 was 1.9 mM. In an effort to improve the binding affinity of 1,
a series of 5-oxopyrrolidine-3-carboxamides was synthesized. Introduction of 3,4-dichloro substituents to the cen-
tral phenyl ring (10i, IC50؍0.057 mM; 11b, IC50؍0.050 mM) or replacing the 1-methyl group of the 5-oxopyrroli-
dine moiety with a 1-benzyl group (12e, IC50؍0.038 mM) was found to be effective for improving CCR5 affinity.
Compound 10i, 11b, and 12e also inhibited CCR5-using HIV-1 envelope-mediated membrane fusion with IC50
values of 0.44, 0.19, and 0.49 mM, respectively.
Key words CCR5 antagonist; chemokine; human immunodeficiency virus type 1 (HIV-1); 5-oxopyrrolidine-3-carboxamide
The development of combination antiretroviral therapy a quaternary ammonium moiety, as a small-molecule CCR5
with human immunodeficiency virus type 1 (HIV-1) reverse antagonist.23,24) Continued screening of Takeda compound
transcriptase inhibitors and protease inhibitors has provided a libraries using [125I]RANTES and Chinese hamster ovary
clinically effective method of suppressing viral load in HIV- (CHO) cells expressing human CCR5 has now identified a
1-infected individuals, and has resulted in dramatic reduc- novel lead compound, N-{3-[4-(4-fluorobenzoyl)piperidin-1-
tions in HIV-associated morbidity and mortality.1) However, yl]propyl}-1-methyl-5-oxo-N-phenylpyrrolidine-3-carbox-
no current therapies are curative,2) and HIV-1 replicates again amide (1), as a CCR5 antagonist (Fig. 1). In this paper, we
rapidly when treatment ceases.3) The complexity of the dos- describe the discovery of the lead compound and the subse-
ing regimens and the toxicity of the current anti-HIV-1 ther- quent optimization, focused on a series of 5-oxopyrrolidine-
apy make it difficult to maintain patient compliance.4) In ad- 3-carboxamides, to obtain potent CCR5 antagonists which
dition, resistance to the currently available drugs is increas- can inhibit the HIV-1 cell entry.
ing.5) Therefore, there remains a need to identify new classes
of agents with improved efficacy and less toxicity.
Chemistry
The process of HIV-1 entry into host cells is one of the at-
Target compounds were prepared by two general methods
tractive targets for inhibition of HIV-1 replication.6) Recent as outlined in Charts 2 and 3. The first method (Chart 2) was
successful studies with enfuvirtide (T-20), a peptide inhibitor utilized to investigate structure–activity relationships (SARs)
of gp41-mediated HIV-1 entry, have confirmed this process of alkyl linker length (Fig. 1, C) and piperidine moiety modi-
as a clinically relevant target.7) It has been reported that HIV- fications (Fig. 1, D). The starting carboxylic acid 2a was pre-
1 strains that cause the initial infection predominantly utilize pared by condensation of itaconic acid and methylamine
CC chemokine receptor 5 (CCR5) as a coreceptor.8) CCR5- (Chart 1).25) Coupling of the carboxylic acid 2a with aniline
using (R5) HIV-1 is isolated exclusively during the asympto- using 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hy-
matic stage, which usually persists for 5 to 10 years.9) CCR5 drochloride (EDC) and 1-hydroxybenzotriazole (HOBt) gave
is a member of the seven-transmembrane G protein-coupled anilide 3. Treatment of 3 with sodium hydride followed by
receptor superfamily.10) The natural ligands for CCR5 are the the appropriate bromochloroalkane produced chlorides 4a—
CC chemokines [regulated on activation, normal T cell ex- c. The 2-chloroethyl derivative 4d was prepared in a different
pressed and secreted (RANTES), macrophage inflammatory manner as follows. N-Alkylation of the anilide 3 with ethyl
protein 1a (MIP-1a), and MIP-1b], which have been re- bromoacetate followed by hydrolysis gave the carboxylic
ported to inhibit R5 HIV-1 infection in vitro.11) Individuals acid. The reduction of the mixed anhydride of the acid gave
homozygous for a defect in CCR5 expression have been the alcohol, which on reaction with carbon tetrachloride and
identified as being highly resistant to HIV-1 infection, while triphenylphosphine yielded 4d. The obtained chlorides 4a—
this defect does not cause a significant health problem.12—14) d were coupled with a variety of amines in the presence of
In addition, infected individuals heterozygous for the defec-
tive gene appear to exhibit delayed disease progression.15)
These observations suggest that appropriate, small-molecule
CCR5 antagonists functioning as HIV-1 entry inhibitors
could be promising anti-HIV-1 therapeutic agents.
Several research groups have reported structurally diverse
CCR5 antagonists.16—22) Our laboratories have previously de-
scribed the discovery of TAK-779, an anilide derivative with Fig. 1. Lead Compound
To whom correspondence should be addressed. e-mail: Imamura_Shin-ichi@takeda.co.jp
© 2004 Pharmaceutical Society of Japan

64
Vol. 52, No. 1
potassium iodide and potassium carbonate to provide the tar- phenyl ring (Fig. 1, B) and 5-oxopyrrolidine moiety (Fig. 1,
get compounds 5a—i. Alternatively, compounds 7a—e were A), we investigated an alternate method starting from
obtained by reductive amination of aldehyde 6 with amines piperidines 8a, b (Chart 3). The piperidines 8a, b were
using sodium triacetoxyborohydride. The aldehyde 6 was treated with acrolein in the presence of a catalytic amount of
prepared from the anilide 3 by N-alkylation with 2-(2-bro- 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in tetrahydrofu-
moethyl)-1,3-dioxolane followed by hydrolysis with hy- ran (THF) to afford b-aminoaldehydes in situ,26) which were
drochloric acid. Benzoylpiperazine derivative 5j was pre- converted to amine derivatives 9a—t by reductive amination
pared by hydrogenolysis of benzylpiperazine 5i followed by with various aryl or aralkyl amines using sodium triacetoxy-
benzoylation.
borohydride. Coupling reactions of the amines 9a—q, s, t
In order to explore the effect of substitutions on the central with 5-oxopyrrolidine-3-carboxylic acids 2a—n were carried
out via the corresponding acid chlorides to afford the targets
10a—p, 11a, b, 12a—m, 15a, b. Compound 10q was pre-
pared by the carbodiimide-mediated coupling of the amine
9r with the acid 2a. The carboxylic acids 2b—n were pre-
pared by literature methods25) from the corresponding amines
(Chart 1). Removal of the 2,4-dimethoxybenzyl group of
compound 12m with trifluoroacetic acid (TFA) gave com-
pound 13, which on N-alkylation led to compound 14a, b.
All compounds described were prepared and tested as
racemates.
Chart 1
Chart 2
Chart 3

January 2004
65
Table 1. SAR of Alkyl Linker Length
Results and Discussion
The lead compound 1 was discovered by high-throughput
screening of Takeda compound libraries using a binding
assay based on [125I]RANTES and CHO cells expressing
human CCR5. This compound was shown to have moderate
affinity for CCR5 with an IC50 value of 1.9 mM. Our initial
goal was to improve the CCR5 binding affinity. The struc-
tural feature of the lead compound 1 is 5-oxopyrrolidine-3-
carboxamide moiety. Deletion of the entire 5-oxopyrrolidin-
3-ylcarbonyl group, as in the intermediates 9, resulted in
complete loss of activity, suggesting that this moiety was re-
quired for interaction with CCR5. Therefore, our initial SAR
studies were focused on a series of 5-oxopyrrolidine-3-car-
boxamides.
CCR5a)
IC50 (mM)
Compd.
n
1
3
4
5
2
1.9
3.2
5a
5b
5c
5.0
27%b)
a) Inhibition of [125I]RANTES binding to CCR5-expressing CHO cells. b) Percent
inhibition at 10 mM.
The lead compound 1 could be divided into four subunits
(Fig. 1): 5-oxopyrrolidine substituent (A), central phenyl ring
(B), alkyl linker (C), and piperidine moiety (D). We first Table 2. SAR of Piperidine Moiety Modifications
modified the alkyl linker (C) length in order to optimize the
spacing between the two halves of the molecule. As shown in
Table 1, the lead compound 1 with a three-carbon chain
showed the best activity. Shortening the chain of 1 to two
carbons caused a marked decrease in potency (5c), while
lengthening it led to a more gradual loss of affinity, com-
pound 5a and 5b being ca. 2 and 3 times less potent than 1,
respectively.
CCR5a)
IC50 (mM)
Compd.
X
R3
1
CH
CH
CH
CO(4-F-Ph)
1.9
16%b)
3.6
With the SAR on the chain established, we then varied the
piperidine moiety (D) to investigate the role of the piperidine
ring and the substituent at the 4-position of the piperidine
(Table 2). Replacement of the 4-fluorobenzoyl group in 1
with a 4-fluorobenzyl group showed a 6-fold enhancement in
potency (11a, IC50ϭ0.31 mM), suggesting that the carbonyl
group in the lead compound 1 was not necessary for CCR5
binding. The compound 5h (IC50ϭ0.48 mM) having a benzyl
group also exhibited improved activity comparable to 11a.
Removal of the benzyl group in 5h resulted in a large de-
crease in potency (5d), indicating that the benzene ring was
essential for potent CCR5 binding affinity. Decreasing the
distance from the piperidine ring to the benzene ring (5e) re-
sulted in a loss of potency, as did increasing the distance
(7c). Constraint of the benzene ring by introduction of a dou-
ble bond (7a) or a spiro structure (5g) did not improve activ-
ity. Substitution with other groups such as a phenoxy (7d) or
benzyloxy (7e) provided no improvement in binding affinity.
Replacement of the basic piperidine with a less basic piper-
5d
5e
5f
H
Ph
4-Cl-Ph
COH
5.2
5g
2.1
5h
5i
5j
CH
N
N
CH2Ph
CH2Ph
COPh
0.48
1.9
12%b)
7a
1.2
7b
7c
7d
7e
11a
CH
CH
CH
CH
CH
CHPh2
(CH2)2Ph
OPh
OCH2Ph
CH2(4-F-Ph)
51%b)
1.1
1.6
1.5
0.31
a) Inhibition of [125I]RANTES binding to CCR5-expressing CHO cells. b) Percent
inhibition at 10 mM.
azine failed to maintain activity (5i, j). Since the 4-ben- Moving the trifluoromethyl group to the 3-position of the
zylpiperidine derivatives (5h, 11a) had an improved potency phenyl ring (10l) restored binding potency comparable to that
compared to the lead 1, this component was utilized for fur- of 5h, while the bis-trifluoromethyl derivative 10n showed
ther exploration.
lower potency. The 3-cyano compound 10o was a poorer in-
We next turned our attention to modification of the central hibitor, indicating that this moiety does not prefer polar sub-
phenyl ring (B) (Table 3). Introduction of a methyl group at stituents.
the 3- or 4-position of the phenyl ring resulted in a 3- or 5-
When a chlorine atom was introduced at the 4-position of
fold improvement in the binding potency (10b, 10c), while the phenyl (10h), lower potency than the unsubstituted com-
the 2-methyl derivative 10a showed lower potency than the pound 5h was observed, but the 3-chloro derivative 10g ex-
unsubstituted compound 5h. The activity of 4-tert-butyl hibited 4-fold improvement in the binding affinity over 5h.
compound 10d was better than 5h. 3,4-Disubstitution as in Furthermore, the 3,4-dichlorinated derivative 10i was found
indan-5-yl derivative 10e also increased affinity compared to to show 8-fold enhancement in inhibitory effect compared to
5h. When the electron-donating methoxy group was intro- 5h with an IC50 value of 0.057 mM. Fluorinated (R4ϭF) ana-
duced at the 4-position of the phenyl ring (10f), 3-fold reduc- logue of 10i also showed good activity (11b, IC50ϭ
tion in potency was observed. Substitution at the 4-position 0.050 mM). Replacement of the 3,4-dichloro group by 3-
of the phenyl ring with electron-withdrawing groups such as chloro-4-fluoro (10j) or 3,4-difluoro (10k) group decreased
trifluoromethyl (10m) and cyano (10p) also lowered potency. the activity. Extension of the phenyl ring by a methylene unit

66
Vol. 52, No. 1
Table 4. SAR of Substitution on the 5-Oxopyrrolidine Moiety
Table 3. SAR of Substitution on the Central Phenyl Ring
CCR5a)
IC50 (mM)
Compd.
R1
R2
CCR5a)
IC50 (mM)
Compd.
R2
m
R4
5h
12a
12b
12c
12d
12e
12f
12g
12h
12i
Me
n-Bu
c-Hex
c-HexCH2
Ph
PhCH2
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
0.48
0.13
0.11
0.23
5h
10a
10b
10c
10d
10e
10f
10g
10h
10i
10j
10k
10l
10m
10n
10o
10p
10q
11b
H
2-Me
3-Me
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
1
0
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
F
0.48
4.7
0.16
0.089
0.16
0.18
1.5
0.12
1.2
0.057
0.6
4-Me
0.31
4-t-Bu
3,4-(CH2)3-
4-MeO
3-Cl
0.038
0.033
0.086
0.22
0.33
0.36
0.082
0.24
0.57
0.075
0.034
0.044
0.043
2-Cl-PhCH2
3-Cl-PhCH2
4-Cl-PhCH2
4-Me-PhCH2
Ph(CH2)2
(furan-2-yl)CH2
(pyridin-4-yl)CH2
H
4-Cl
3,4-diCl
3-Cl, 4-F
3,4-diF
3-CF3
4-CF3
3,5-bis(CF3)
3-CN
4-CN
H
3,4-diCl
12j
12k
12l
2.1
0.51
3.5
13
14a
14b
15a
15b
CF3CH2
2-Me-PhCH2
PhCH2
28%b)
4.1
3-Cl
3,4-diCl
25%b)
0.31
0.050
PhCH2
a) Inhibition of [125I]RANTES binding to CCR5-expressing CHO cells.
a) Inhibition of [125I]RANTES binding to CCR5-expressing CHO cells. b) Percent
inhibition at 10 mM.
was tolerated as seen with the benzyl derivative 10q.
While studying the central phenyl fragment, we simultane-
ously investigated substitutions at the 1-position of the 5-ox-
opyrrolidine moiety (A) (Table 4). Removal of the 1-methyl
group led to compound 13, which was equipotent with the 1-
methyl derivative 5h. Replacing the methyl group by a butyl
(12a) provided a 4-fold increase in potency, and replacing by
a 2,2,2-trifluoroethyl group (14a) showed a 6-fold improve-
ment. These results led us to explore introduction of more
bulky substituents to increase potency. The 1-benzyl deriva-
tive 12e (IC50ϭ0.038 mM) showed Ͼ10-fold enhancement in
potency, whereas the 1-phenyl derivative 12d exhibited com-
parable activity to the 1-methyl derivative (5h). Extension of
the benzyl as a phenylethyl (12j) showed similar potency
compared to phenyl (12d), indicating the benzyl substituent
(12e) was optimal for CCR5 binding. Saturation of the ben-
zene ring in 12e affording 12c resulted in a loss of potency,
suggesting that the aromatic ring was necessary for potent
activity.
Substitution on the benzyl group was then investigated. In-
troduction of a chlorine atom at the 2-position of the benzyl
was found to be tolerated (12f), while 3- or 4-chloro deriva-
tives (12g, h) showed lower potency than the unsubstituted
compound 12e. A similar trend was observed for methyl sub-
stituted analogues (12i, 14b). Replacement of the benzyl
with a furan-2-ylmethyl (12k) led to a moderate loss in bind-
ing, while the pyridin-4-ylmethyl analogue (12l) resulted in
6-fold reduction of activity.
Fig. 2. NOESY Correlations of 10i
tion of 3-chloro (15a) or 3,4-dichloro (15b) substituents did
not significantly change the activity.
On the basis of NMR analysis, we speculated about the re-
quired conformation of the 5-oxopyrrolidine-3-carboxamide
derivatives for CCR5 binding. The synthesized compounds
have a central N,N-disubstituted amide moiety as a structural
feature. It has been known that N-methylanilides prefer the E
form in which the phenyl ring is trans to the amide oxy-
gen.27,28) In the E form, the plane of the phenyl ring is almost
1
perpendicular to the amide plane. The H-NMR analysis of
the N-phenyl derivatives in this study revealed that most of
the derivatives exist as an almost single rotameric form in so-
lution at room temperature. The conformation of 10i (free
base) was determined by a NOESY experiment in CDCl3 at
300 K (Fig. 2). H-a (d 3.04) was found to correlate with H-b
(d 7.30) and H-c (d 7.02) in the NOESY spectrum, whereas
no cross peak was observed between H-a and H-d (d 3.69).
These results suggested that 10i and probably other N-phenyl
derivatives have an E form in solution. The preference of the
E form in this series might contribute to the receptor binding.
Finally, the activities of selected compounds for inhibition
of HIV-1 cell entry were examined by a HIV-1 envelope-me-
diated membrane fusion assay using R5 HIV-1 (JR-FL strain)
envelope-expressing COS-7 cells and CCR5-expressing
MOLT-4 cells. The most potent CCR5 antagonists 10i, 11b,
The previously discussed SAR of substitutions on the cen-
tral phenyl ring of the 1-methyl-5-oxopyrrolidine derivatives
(Table 3) was then applied to the 1-benzyl analogues. In the
case of the 1-benzyl-5-oxopyrrolidine derivatives, introduc-

January 2004
67
6.70. Found: C, 57.17; H, 5.21; N, 6.48. 2m: Yield 15%, mp 190—191 °C
(H2O–MeOH). Anal. Calcd for C11H12N2O3: C, 59.99; H, 5.49; N, 12.72.
Found: C, 59.68; H, 5.55; N, 12.46. 2n: Yield 72%, mp 122—123 °C (i-
PrOH–Et2O). Anal. Calcd for C14H17NO5: C, 60.21; H, 6.14; N, 5.02. Found:
C, 59.96; H, 6.15; N, 5.07.
and 12e inhibited the membrane fusion with IC50 values of
0.44, 0.19, and 0.49 mM, respectively. These results demon-
strated that the 5-oxopyrrolidine-3-carboxamide derivatives
could block R5 HIV-1 cell entry by preventing the binding of
the R5 HIV-1 envelope to CCR5. The selectivity profile of
compound 11b for other chemokine receptors was evaluated
using a binding assay. The IC50 values for CCR1, CCR2,
CCR4, and CCR7 were all greater than 3 mM.
1-Methyl-5-oxo-N-phenylpyrrolidine-3-carboxamide (3) To a stirred
solution of 2a (8.59 g, 60 mmol), aniline (5.59 g, 60 mmol), and HOBt
(8.92 g, 66 mmol) in N,N-dimethylformamide (DMF) (60 ml) was added
EDC (17.25 g, 90 mmol), and the mixture was stirred at room temperature
for 4 h. The mixture was concentrated in vacuo, diluted with saturated aque-
ous NaHCO3 (120 ml), and extracted with dichloromethane (DCM)
(5ϫ120 ml). The organic layer was dried (MgSO4), filtered, and concen-
trated in vacuo. The residue was purified by column chromatography on sil-
ica gel (EtOAc/MeOH 1/0 to 9/1) to afford 3 (11.04 g, yield 84%) as a white
Conclusion
We have succeeded in the identification of a novel lead
compound as a small-molecule CCR5 antagonist through
high-throughput screening. The original lead 1 inhibited the
1
solid, mp 163—165 °C. H-NMR (CDCl3) d 2.67 (1H, dd, Jϭ17.1, 9.9 Hz),
2.81 (1H, dd, Jϭ17.1, 8.4 Hz), 2.88 (3H, s), 3.15—3.31 (1H, m), 3.58 (1H,
binding of [125I]RANTES to CCR5 with an IC50 value of dd, Jϭ9.6, 9.6 Hz), 3.77 (1H, dd, Jϭ9.6, 7.0 Hz), 7.14 (1H, t, Jϭ7.3 Hz),
7.34 (2H, dd, Jϭ8.0, 7.3 Hz), 7.53 (2H, d, Jϭ8.0 Hz), 7.60 (1H, br s). Anal.
Calcd for C12H14N2O2: C, 66.04; H, 6.47; N, 12.84. Found: C, 66.00; H,
6.44; N, 12.89.
N-(3-Chloropropyl)-1-methyl-5-oxo-N-phenylpyrrolidine-3-carboxam-
ide (4a) To an ice-cooled stirred solution of 3 (2.00 g, 9.2 mmol) in DMF
(20 ml) was added NaH (60% in oil, 733 mg, 18 mmol). After 1 h the mix-
ture was treated with 1-bromo-3-chloropropane (1.81 ml, 18 mmol), stirred
for 30 min, removed from the ice bath, and stirred for an additional 1 h. The
mixture was diluted with water (100 ml) and extracted with EtOAc
(3ϫ50 ml). The organic layer was dried (MgSO4), filtered, and concentrated
1.9 mM. Systematic modification of the lead 1, focused on a
series of 5-oxopyrrolidine-3-carboxamides, resulted in the
identification of compounds with improved binding affinity.
The most potent CCR5 antagonists 10i (IC50ϭ0.057 mM),
11b (IC50ϭ0.050 mM), and 12e (IC50ϭ0.038 mM) inhibited
HIV-1 envelope-mediated membrane fusion with IC50 values
of 0.44, 0.19, and 0.49 mM, respectively. Further efforts di-
rected toward additional improvement of potency will be re-
ported in due course.
in vacuo. The residue was purified by column chromatography on silica gel
(EtOAc/MeOH 1/0 to 9/1) to afford 4a (2.43 g, yield 90%) as a colorless oil.
1H-NMR (CDCl3) d 1.95—2.15 (2H, m), 2.24 (1H, dd, Jϭ17.0, 9.3 Hz),
Experimental
Reagents and solvents were used as obtained from commercial suppliers 2.68 (1H, dd, Jϭ17.0, 8.5 Hz), 2.77 (3H, s), 2.95—3.25 (1H, m), 3.19 (1H, t,
without further purification. Column chromatography was carried out on Jϭ8.8 Hz), 3.56 (2H, t, Jϭ6.6 Hz), 3.65 (1H, dd, Jϭ8.8, 7.0 Hz), 3.80—3.90
Merck silica gel 60 (230—400 mesh) or ICN basic alumina (activity III). (2H, m), 7.10—7.25 (2H, m), 7.35—7.55 (3H, m).
The yields reported were not optimized. Melting points were determined on
a Yanagimoto micro melting point apparatus and are uncorrected. H-NMR to that described for 4a from the corresponding bromochloroalkanes.
The following compounds 4b, c were prepared using a procedure similar
1
spectra were recorded on a Varian Gemini 200 (200 MHz) spectrometer.
N-(4-Chlorobutyl)-1-methyl-5-oxo-N-phenylpyrrolidine-3-carboxam-
Two-dimensional NOESY spectra were recorded on a Bruker DMX 600 ide (4b) Yield 96%, oil. 1H-NMR (CDCl3) d 1.58—1.89 (4H, m), 2.23
(600 MHz) spectrometer. Chemical shifts are given in ppm with tetramethyl- (1H, dd, Jϭ16.7, 9.3 Hz), 2.60—2.80 (4H, m), 2.97—3.25 (2H, m), 3.50—
silane (organic solvents) or 3-(trimethylsilyl)propionic-2,2,3,3-d4 acid, 3.81 (5H, m), 7.11—7.20 (2H, m), 7.36—7.53 (3H, m).
sodium salt (D2O) as an internal standard, and coupling constants (J) are
N-(5-Chloropentyl)-1-methyl-5-oxo-N-phenylpyrrolidine-3-carboxam-
given in hertz (Hz). Mass spectra were recorded using an LC/MS system ide (4c) Yield 96%, oil. 1H-NMR (CDCl3) d 1.35—1.87 (6H, m), 2.23
consisting of a Hewlett-Packard 1100 HPLC instrument and a Waters ZMD (1H, dd, Jϭ16.3, 9.3 Hz), 2.60—2.80 (4H, m), 2.95—3.24 (2H, m), 3.52
mass detector (ESI positive). Compound purity was checked by elemental (2H, t, Jϭ6.4 Hz), 3.59—3.77 (3H, m), 7.10—7.20 (2H, m), 7.38—7.53
analysis or analytical HPLC. Elemental analyses were carried out by Takeda (3H, m).
Analytical Laboratories Ltd. Analytical HPLC was performed on a Shi-
N-(2-Chloroethyl)-1-methyl-5-oxo-N-phenylpyrrolidine-3-carboxam-
madzu LC-10A system using a Shiseido CAPCELL PAK C18 UG120 col- ide (4d). Step 1: Ethyl 2-{[(1-Methyl-5-oxopyrrolidin-3-yl)carbonyl]-
umn (2.0ϫ50 mm, 3 mM). Chromatographic conditions were as follows: mo- anilino}acetate To an ice-cooled stirred solution of 3 (2.00 g, 9.2 mmol) in
bile phases, Aϭ0.1% TFA/H2O, Bϭ0.1% TFA/MeCN; gradient (A/B), DMF (20 ml) was added NaH (60% in oil, 916 mg, 23 mmol). After 1 h the
0 min (90/10), 4 min (5/95), 5.5 min (5/95), 5.51 min (90/10), 8 min (90/10); mixture was treated with ethyl bromoacetate (3.05 ml, 28 mmol), stirred for
flow rate, 0.5 ml/min; detection, UV 220 nm. Retention times (tR) and purity 30 min, removed from the ice bath, and stirred for an additional 6 h. The
(area percent) are reported.
mixture was poured into ice-cooled 0.5 N HCl (100 ml) and extracted with
EtOAc (3ϫ50 ml). The organic layer was dried (MgSO4), filtered, and con-
centrated in vacuo. The residue was purified by column chromatography on
5-Oxopyrrolidine-3-carboxylic Acids (2a—n) Compounds 2a—n
were prepared according to literature procedures.25) 2a29): Yield 35%, mp
151—152 °C (EtOH). Anal. Calcd for C6H9NO3: C, 50.35; H, 6.34; N, 9.79. silica gel (EtOAc/MeOH 1/0 to 95/5) to afford the product (2.43 g, yield
Found: C, 50.04; H, 6.42; N, 6.91. 2b: Yield 67%, oil. Anal. Calcd for 87%) as a white solid, mp 72—74 °C. 1H-NMR (CDCl3) d 1.28 (3H, t,
C9H15NO3: C, 58.36; H, 8.16; N, 7.56. Found: C, 58.20; H, 8.20; N, 7.36.
2c25)
C11H17NO3: C, 62.54; H, 8.11; N, 6.63. Found: C, 62.41; H, 7.95; N, 6.46.
Jϭ7.2 Hz), 2.28 (1H, dd, Jϭ16.4, 9.4 Hz), 2.75 (1H, dd, Jϭ16.4, 7.8 Hz),
Yield 62%, mp 186—187 °C (MeOH–Et2O). Anal. Calcd for 2.78 (3H, s), 3.10—3.35 (2H, m), 3.60—3.80 (1H, m), 4.22 (2H, q,
Jϭ7.2 Hz), 4.26 (1H, d, Jϭ17.1 Hz), 4.45 (1H, d, Jϭ17.1 Hz), 7.30—7.55
:
2d: Yield 50%, mp 96—97 °C (MeOH–Et2O). Anal. Calcd for C12H19NO3: (5H, m).
C, 63.98; H, 8.50; N, 6.22. Found: C, 63.85; H, 8.22; N, 6.02. 2e25): Yield
Step 2: 2-{[(1-Methyl-5-oxopyrrolidin-3-yl)carbonyl]anilino}acetic
90%, mp 188—189 °C (MeOH). Anal. Calcd for C11H11NO3: C, 64.38; H, Acid To a stirred solution of the product from step 1 (1.83 g, 6.0 mmol) in
5.40; N, 6.83. Found: C, 64.34; H, 5.53; N, 6.91. 2f25): Yield 76%, mp
144—145 °C (MeOH). Anal. Calcd for C12H13NO3: C, 65.74; H, 5.98; N,
MeOH (20 ml) was added 8 N NaOH (1.5 ml), and the mixture was stirred at
room temperature for 10 h. The mixture was treated with 1 N HCl (13 ml)
6.39. Found: C, 65.80; H, 5.84; N, 6.48. 2g: Yield 77%, mp 158—159 °C and concentrated in vacuo. The residue was dissolved in EtOAc, dried
(MeOH). Anal. Calcd for C12H12ClNO3: C, 56.81; H, 4.77; N, 5.52. Found: (MgSO4), filtered, and concentrated in vacuo to give the product (1.54 g,
1
C, 56.64; H, 4.70; N, 5.31. 2h: Yield 69%, mp 148—149 °C (MeOH–Et2O). yield 93%). H-NMR (CDCl3) d 2.35 (1H, dd, Jϭ17.0, 9.0 Hz), 2.75—2.95
Anal. Calcd for C12H12ClNO3: C, 56.81; H, 4.77; N, 5.52. Found: C, 56.58; (1H, m), 2.80 (3H, s), 3.10—3.35 (2H, m), 3.65—3.80 (1H, m), 4.31 (1H, d,
H, 4.71; N, 5.31. 2i: Yield 66%, mp 158—159 °C (MeOH–Et2O). Anal. Jϭ17.4 Hz), 4.45 (1H, d, Jϭ17.4 Hz), 7.30—7.55 (5H, m).
Calcd for C12H12ClNO3: C, 56.81; H, 4.77; N, 5.52. Found: C, 56.52; H,
Step 3: N-(2-Hydroxyethyl)-1-methyl-5-oxo-N-phenylpyrrolidine-3-
4.66; N, 5.29. 2j: Yield 79%, mp 154—155 °C (MeOH). Anal. Calcd for carboxamide To a stirred solution of the product from step 2 (829 mg,
C13H15NO3: C, 66.94; H, 6.48; N, 6.00. Found: C, 66.85; H, 6.46; N, 5.86.
2k30): Yield 60%, mp 185—186 °C (MeOH). Anal. Calcd for C13H15NO3: C,
66.94; H, 6.48; N, 6.00. Found: C, 66.60; H, 6.48; N, 5.74. 2l: Yield 63%,
mp 155—156 °C (EtOH). Anal. Calcd for C10H11NO4: C, 57.41; H, 5.30; N,
3.0 mmol) and Et3N (627 ml, 4.5 mmol) in THF (15 ml) at Ϫ15 °C was added
ethyl chloroformate (430 ml, 4.5 mmol), and the mixture was stirred at from
Ϫ15 to Ϫ10 °C for 30 min. Then, a solution of NaBH4 (227 mg, 6.0 mmol)
in water (1.5 ml) was added at Ϫ10 °C, and the mixture was stirred at from

68
Vol. 52, No. 1
Ϫ10 to 0 °C for 1 h. The mixture was treated with 1 N HCl at 0 °C, and the
organic solvent was removed in vacuo. The residue was extracted with
DCM, and the organic layer was dried (MgSO4), filtered, and concentrated in
vacuo. The residue was purified by column chromatography on silica gel
(EtOAc/MeOH 1/0 to 95/5) to afford the product (662 mg, yield 84%) as a
62.63; H, 7.99; N, 10.96. Found: C, 62.63; H, 7.80; N, 10.99.
1-Methyl-5-oxo-N-phenyl-N-[3-(4-phenylpiperidin-1-yl)propyl]pyrro-
lidine-3-carboxamide Fumarate (5e) Compound 5e was prepared from
4a and 4-phenylpiperidine hydrochloride in 42% yield, amorphous solid. 1H-
NMR (D2O) d 1.70—2.30 (6H, m), 2.45 (1H, dd, Jϭ17.3, 9.0 Hz), 2.65 (1H,
dd, Jϭ17.3, 5.7 Hz), 2.77 (3H, s), 2.80—4.00 (12H, m), 6.67 (2H, s), 7.25—
7.65 (10H, m). Anal. Calcd for C26H33N3O2·C4H4O4·0.8H2O: C, 65.51; H,
7.07; N, 7.64. Found: C, 65.53; H, 6.97; N, 7.65.
1
colorless oil. H-NMR (CDCl3) d 2.27 (1H, dd, Jϭ16.9, 9.5 Hz), 2.71 (1H,
dd, Jϭ16.9, 8.4 Hz), 2.78 (3H, s), 3.00—3.25 (1H, m), 3.22 (1H, t,
Jϭ8.9 Hz), 3.66 (1H, dd, Jϭ8.9, 6.6 Hz), 3.70—4.10 (4H, m), 7.15—7.30
(2H, m), 7.30—7.55 (3H, m).
N-{3-[4-(4-Chlorophenyl)-4-hydroxypiperidin-1-yl]propyl}-1-methyl-
5-oxo-N-phenylpyrrolidine-3-carboxamide Fumarate (5f) Compound 5f
was prepared from 4a and 4-(4-chlorophenyl)-4-hydroxypiperidine in 60%
Step 4: N-(2-Chloroethyl)-N-phenyl-1-methyl-5-oxo-3-pyrrolidinecar-
boxamide (4d) A mixture of the product from step 3 (659 mg, 2.5 mmol),
triphenylphosphine (857 mg, 3.3 mmol), and carbon tetrachloride (10 ml)
was stirred at reflux for 1 h. After cooling, the insoluble materials were re-
moved by filtration. The filtrate was concentrated in vacuo, and the residue
was purified by column chromatography on silica gel (EtOAc/MeOH 1/0 to
95/5) to give an oil which solidified. The solid was triturated with Et2O and
filtered to afford 4d (366 mg, yield 52%) as a slightly brown solid, which
1
yield, amorphous solid. H-NMR (free base, CDCl3) d 1.44—1.95 (7H, m),
2.03—2.91 (10H, m), 2.97—3.25 (3H, m), 3.60—3.84 (3H, m), 7.13—7.54
(9H, m). Anal. Calcd for C26H32ClN3O3·C4H4O4·H2O: C, 59.65; H, 6.34; N,
6.96. Found: C, 59.63; H, 6.22; N, 6.83.
1-Methyl-5-oxo-N-phenyl-N-[3-(spiro[indene-1,4؅-piperidin]-1؅-yl)-
propyl]pyrrolidine-3-carboxamide Fumarate (5g) Compound 5g was
prepared from 4a and spiro[indene-1,4Ј-piperidine]32) in 43% yield, amor-
phous solid. 1H-NMR (D2O) d 1.45—1.65 (2H, m), 1.95—2.20 (2H, m),
2.30—2.55 (3H, m), 2.67 (1H, dd, Jϭ17.2, 6.2 Hz), 2.77 (3H, s), 3.20—3.45
(5H, m), 3.42 (1H, t, Jϭ9.8 Hz), 3.59 (1H, dd, Jϭ9.8, 5.4 Hz), 3.65—3.80
(2H, m), 3.80—3.95 (2H, m), 6.63 (2H, s), 6.97 (1H, d, Jϭ5.8 Hz), 7.02
(1H, d, Jϭ5.8 Hz), 7.25—7.70 (9H, m). Anal. Calcd for C28H33N3O2·
C4H4O4·1.0H2O: C, 66.53; H, 6.80; N, 7.27. Found: C, 66.60; H, 6.62; N,
7.30.
N-[3-(4-Benzylpiperazin-1-yl)propyl]-1-methyl-5-oxo-N-phenylpyrro-
lidine-3-carboxamide Dihydrochloride (5i) Compound 5i was prepared
from 4a and 1-benzylpiperazine in 51% yield, amorphous solid. 1H-NMR
(D2O) d 1.90—2.10 (2H, m), 2.44 (1H, dd, Jϭ17.1, 9.2 Hz), 2.64 (1H, dd,
Jϭ17.1, 6.5 Hz), 2.76 (3H, s), 3.15—3.70 (13H, m), 3.70—4.00 (2H, m),
4.38 (2H, s), 7.30—7.40 (2H, m), 7.45—7.65 (8H, m). Anal. Calcd for
C26H34N4O2·2HCl·1.2H2O: C, 59.02; H, 7.31; Cl, 13.40; N, 10.59. Found:
C, 59.00; H, 7.34; Cl, 13.36; N, 10.49.
1
was used immediately in the subsequent reaction. H-NMR (CDCl3) d 2.25
(1H, dd, Jϭ16.9, 9.3 Hz), 2.70 (1H, dd, Jϭ16.9, 8.2 Hz), 2.78 (3H, s),
2.95—3.25 (1H, m), 3.21 (1H, t, Jϭ8.9 Hz), 3.55—3.75 (3H, m), 4.00 (1H,
dt, Jϭ13.9, 6.2 Hz), 4.11 (1H, dt, Jϭ13.9, 6.6 Hz), 7.20—7.30 (2H, m),
7.35—7.55 (3H, m).
N-[3-(4-Benzylpiperidin-1-yl)propyl]-1-methyl-5-oxo-N-phenylpyrro-
lidine-3-carboxamide Hydrochloride (5h) A mixture of 4a (400 mg,
1.4 mmol), 4-benzylpiperidine (239 ml, 1.4 mmol), KI (225 mg, 1.4 mmol),
K2CO3 (282 mg, 2.0 mmol) in MeCN (20 ml) was stirred at reflux for 24 h.
The mixture was concentrated in vacuo, diluted with water (15 ml), and ex-
tracted with EtOAc (3ϫ30 ml). The organic layer was dried (MgSO4), fil-
tered, and concentrated in vacuo. The residue was purified by column chro-
matography on silica gel (EtOAc/MeOH 1/0 to 9/1) to afford an oil
(344 mg). The oil was dissolved in Et2O and treated with 1 N HCl (Et2O so-
lution, 2 ml). The resulting precipitate was filtrated, washed with Et2O, and
dried in vacuo over KOH to give 5h (282 mg, yield 44%) as an amorphous
solid. 1H-NMR (D2O) d 1.35—1.65 (2H, m), 1.75—2.10 (5H, m), 2.45 (1H,
dd, Jϭ17.7, 8.7 Hz), 2.55—2.75 (1H, m), 2.63 (2H, d, Jϭ6.8 Hz), 2.77 (3H,
s), 2.80—3.00 (2H, m), 3.00—3.70 (7H, m), 3.75—3.90 (2H, m), 7.20—
7.45 (7H, m), 7.45—7.65 (3H, m). Anal. Calcd for C27H35N3O2·
HCl·0.5H2O: C, 67.69; H, 7.78; Cl, 7.40; N, 8.77. Found: C, 67.58; H, 7.75;
Cl, 7.17; N, 8.59.
N-[3-(4-Benzoylpiperazin-1-yl)propyl]-1-methyl-5-oxo-N-phenyl-
pyrrolidine-3-carboxamide Fumarate (5j). Step 1: 1-Methyl-5-oxo-N-
phenyl-N-[3-(piperazin-1-yl)propyl]pyrrolidine-3-carboxamide A mix-
ture of the free base of 5i (463 mg, 1.1 mmol) and palladium hydroxide on
carbon (20%, 93 mg) in MeOH (10 ml) was stirred under a hydrogen atmos-
phere at room temperature for 16 h. The catalyst was removed by filtration
and washed with MeOH. The filtrate was concentrated in vacuo to give the
The following compounds 5a—g, i were prepared using a procedure simi-
lar to that described for 5h from the chlorides 4a—d and the corresponding
amines.
1
product (364 mg, yield 99%) as a colorless oil. H-NMR (CDCl3) d 1.60—
1.85 (2H, m), 2.15—2.60 (9H, m), 2.60—2.90 (3H, m), 2.77 (3H, s), 2.95—
3.20 (1H, m), 3.19 (1H, t, Jϭ8.9 Hz), 3.64 (1H, dd, Jϭ8.9, 6.8 Hz), 3.65—
3.80 (2H, m), 7.10—7.20 (2H, m), 7.30—7.55 (3H, m).
N-{4-[4-(4-Fluorobenzoyl)piperidin-1-yl]butyl}-1-methyl-5-oxo-N-
phenylpyrrolidine-3-carboxamide Fumarate (5a) Compound 5a was
prepared from 4b and 4-(4-fluorobenzoyl)piperidine hydrochloride31) in 80%
Step 2: N-[3-(4-Benzoylpiperazin-1-yl)propyl]-1-methyl-5-oxo-N-
phenylpyrrolidine-3-carboxamide Fumarate (5j) To an ice-cooled
stirred solution of the product from step 1 (192 mg, 0.56 mmol) and Et3N
(101 ml, 0.72 mmol) in THF (5 ml) was added benzoyl chloride (78 ml,
0.67 mmol), and the mixture was stirred for 1 h. The mixture was concen-
trated in vacuo, diluted with saturated aqueous NaHCO3 (15 ml), and ex-
tracted with EtOAc (3ϫ30 ml). The organic layer was dried (MgSO4), fil-
tered, and concentrated in vacuo. The residue was purified by column chro-
matography on silica gel (EtOAc/MeOH 1/0 to 4/1) to afford the free base
(221 mg, 0.49 mmol) as an oil, which was treated with fumaric acid (57 mg,
0.49 mmol) to yield 5j (228 mg, yield 72%) as an amorphous solid. 1H-NMR
(D2O) d 1.90—2.15 (2H, m), 2.44 (1H, dd, Jϭ17.6, 9.0 Hz), 2.65 (1H, dd,
Jϭ17.6, 6.0 Hz), 2.76 (3H, s), 3.10—4.00 (15H, m), 6.63 (2H, s), 7.30—
7.40 (2H, m), 7.40—7.65 (8H, m). Anal. Calcd for C26H32N4O3·
C4H4O4·0.9H2O: C, 62.03; H, 6.56; N, 9.65. Found: C, 61.97; H, 6.36; N,
9.35.
1-Methyl-5-oxo-N-(3-oxopropyl)-N-phenylpyrrolidine-3-carboxamide
(6). Step 1: N-[2-(1,3-Dioxolan-2-yl)ethyl]-1-methyl-5-oxo-N-phenyl-
pyrrolidine-3-carboxamide To an ice-cooled stirred solution of 3 (2.40 g,
11 mmol) in DMF (22 ml) was added NaH (60% in oil, 880 mg, 22 mmol).
After 1 h the mixture was treated with 2-(2-bromoethyl)-1,3-dioxolane
(2.58 ml, 22 mmol) and stirred at 80 °C for 12 h. The mixture was concen-
trated in vacuo, diluted with water (45 ml), and extracted with DCM
(3ϫ45 ml). The organic layer was dried (MgSO4), filtered, and concentrated
in vacuo. The residue was purified by column chromatography on silica gel
(EtOAc/MeOH 1/0 to 9/1) followed by crystallization from i-Pr2O/EtOAc to
give the product (2.47 g, yield 70%) as a white solid., mp 108—110 °C. 1H-
NMR (CDCl3) d 1.91 (2H, td, Jϭ7.3, 4.4 Hz), 2.23 (1H, dd, Jϭ16.9,
9.1 Hz), 2.70 (1H, dd, Jϭ16.9, 8.0 Hz), 2.77 (3H, s), 2.95—3.15 (1H, m),
3.18 (1H, t, Jϭ9.1 Hz), 3.66 (1H, dd, Jϭ9.1, 6.9 Hz), 3.75—4.00 (6H, m),
1
yield, amorphous solid. H-NMR (free base, CDCl3) d 1.39—1.64 (4H, m),
1.71—2.43 (9H, m), 2.60—2.80 (4H, m), 2.86—3.27 (5H, m), 3.59—3.68
(3H, m), 7.06—7.20 (4H, m), 7.35—7.53 (3H, m), 7.97 (2H, dd, Jϭ8.9,
5.5 Hz). Anal. Calcd for C28H34FN3O3·C4H4O4·0.5H2O: C, 63.56; H, 6.50;
N, 6.95. Found: C, 63.36; H, 6.64; N, 6.90.
N-{5-[4-(4-Fluorobenzoyl)piperidin-1-yl]pentyl}-1-methyl-5-oxo-N-
phenylpyrrolidine-3-carboxamide Fumarate (5b) Compound 5b was
prepared from 4c and 4-(4-fluorobenzoyl)piperidine hydrochloride in 91%
1
yield, amorphous solid. H-NMR (free base, CDCl3) d 1.22—1.63 (6H, m),
1.68—1.92 (4H, m), 1.97—2.40 (5H, m), 2.60—2.80 (4H, m), 2.91—3.28
(5H, m), 3.58—3.76 (3H, m), 7.06—7.21 (4H, m), 7.35—7.53 (3H, m), 7.96
(2H, dd, Jϭ8.8, 5.5 Hz). Anal. Calcd for C29H36FN3O3·C4H4O4·0.5H2O: C,
64.06; H, 6.68; N, 6.79. Found: C, 64.17; H, 6.92; N, 6.65.
N-{2-[4-(4-Fluorobenzoyl)piperidin-1-yl]ethyl}-1-methyl-5-oxo-N-
phenylpyrrolidine-3-carboxamide Fumarate (5c) Compound 5c was
prepared from 4d and 4-(4-fluorobenzoyl)piperidine hydrochloride in 20%
yield, amorphous solid. 1H-NMR (D2O) d 1.75—2.30 (4H, m), 2.43 (1H, dd,
Jϭ17.6, 9.4 Hz), 2.55—2.75 (1H, m), 2.76 (3H, s), 3.05—4.00 (10H, m),
4.05—4.30 (2H, m), 6.66 (2H, s), 7.29 (2H, t, Jϭ8.8 Hz), 7.30—7.45 (2H,
m), 7.45—7.65 (3H, m), 8.06 (2H, dd, Jϭ8.7, 5.5 Hz). Anal. Calcd for
C26H30FN3O3·C4H4O4·1.5H2O: C, 60.60; H, 6.27; N, 7.07. Found: C, 60.68;
H, 6.13; N, 7.15.
1-Methyl-5-oxo-N-phenyl-N-[3-(piperidin-1-yl)propyl]pyrrolidine-3-
carboxamide Hydrochloride (5d) Compound 5d was prepared from 4a
and piperidine in 48% yield, amorphous solid. 1H-NMR (D2O) d 1.30—2.10
(8H, m), 2.46 (1H, dd, Jϭ17.2, 9.0 Hz), 2.66 (1H, dd, Jϭ17.2, 6.0 Hz),
2.75—3.20 (4H, m), 2.78 (3H, s), 3.20—3.65 (3H, m), 3.42 (1H, t,
Jϭ10.0 Hz), 3.57 (1H, dd, Jϭ10.0, 5.5 Hz), 3.75—3.95 (2H, m), 7.30—7.40
(2H, m), 7.50—7.70 (3H, m). Anal. Calcd for C20H29N3O2·HCl·0.2H2O: C,

January 2004
69
4.93 (1H, t, Jϭ4.4 Hz), 7.15—7.25 (2H, m), 7.35—7.55 (3H, m).
2.55 (2H, d, Jϭ6.6 Hz), 2.85—3.00 (2H, m), 3.13 (2H, t, Jϭ6.4 Hz), 6.51
Step 2: 1-Methyl-5-oxo-N-(3-oxopropyl)-N-phenylpyrrolidine-3-car- (2H, d, Jϭ8.4 Hz), 6.98 (2H, d, Jϭ8.4 Hz), 7.10—7.35 (5H, m). Treatment
boxamide (6) The product from step 1 (1.95 g, 6.1 mmol) was dissolved in
with 4 N HCl (EtOAc solution, 8 ml) in i-PrOH (20 ml) gave 9d (4.52 g,
1 N HCl (10 ml), and the mixture was stirred at room temperature for 18 h. yield 57%) as a white solid, mp 186—192 °C (dec). 1H-NMR (DMSO-d6) d
The mixture was extracted with DCM (3ϫ20 ml), and the organic layer was 1.40—1.90 (5H, m), 2.00—2.25 (2H, m), 2.31 (3H, s), 2.45—2.60 (2H, m),
dried (MgSO4), filtered, and concentrated in vacuo to give 6 (1.66 g, yield 2.70—2.95 (2H, m), 2.95—3.55 (6H, m), 7.10—7.45 (9H, m). Anal. Calcd
1
99%) as an oil. H-NMR (CDCl3) d 2.23 (1H, dd, Jϭ16.6, 9.4 Hz), 2.60— for C22H30N2·2HCl·0.5H2O: C, 65.34; H, 8.22; Cl, 17.53; N, 6.93. Found:
2.80 (3H, m), 2.77 (3H, s), 2.95—3.15 (1H, m), 3.18 (1H, t, Jϭ9.1 Hz), 3.61 C, 65.24; H, 8.38; Cl, 17.37; N, 6.98.
(1H, dd, Jϭ9.1, 6.9 Hz), 3.98 (1H, dt, Jϭ14.0, 6.6 Hz), 4.14 (1H, dt,
The following compounds 9a—c, e—t were prepared using a procedure
Jϭ14.0, 6.9 Hz), 7.10—7.25 (2H, m), 7.35—7.55 (3H, m), 9.77 (1H, t, similar to that described for 9d from piperidines 8a, b36) and the correspond-
Jϭ1.9 Hz).
ing amines.
N-[3-(4-Benzylidenepiperidin-1-yl)propyl]-1-methyl-5-oxo-N-phenyl-
N-[3-(4-Benzylpiperidin-1-yl)propyl]aniline Dihydrochloride (9a)
pyrrolidine-3-carboxamide Hydrochloride (7a) To a stirred mixture of 6 Yield 47%, mp 215—217 °C (dec). 1H-NMR (DMSO-d6) d 1.40—1.90 (5H,
(274 mg, 1.0 mmol), 4-benzylidenepiperidine hydrochloride33) (231 mg, m), 2.00—2.25 (2H, m), 2.45—2.60 (2H, m), 2.83 (2H, br t, Jϭ11.4 Hz),
1.1 mmol) in THF (10 ml) was added Et3N (209 ml, 1.5 mmol) followed by 3.12 (2H, br t, Jϭ7.2 Hz), 3.29 (2H, br t, Jϭ6.9 Hz), 3.41 (2H, br d,
NaBH(OAc)3 (318 mg, 1.5 mmol), and the mixture was stirred at room tem- Jϭ12.6 Hz), 7.05—7.50 (10H, m). Anal. Calcd for C21H28N2·2HCl·0.5H2O:
perature for 6 h. The mixture was diluted with saturated aqueous NaHCO3
C, 64.61; H, 8.00; N, 7.18. Found: C, 64.71; H, 7.92; N, 7.32.
(15 ml) followed by water (10 ml) and extracted with EtOAc (3ϫ20 ml). The
N-[3-(4-Benzylpiperidin-1-yl)propyl]-2-methylaniline Dihydrochlo-
organic layer was dried (MgSO4), filtered, and concentrated in vacuo. The ride (9b) Yield 69%, mp 160—165 °C (dec). 1H-NMR (DMSO-d6) d
residue was purified by column chromatography on silica gel (EtOAc/MeOH 1.40—2.25 (7H, m), 2.32 (3H, s), 2.45—3.50 (10H, m), 6.90—7.40 (9H,
1/0 to 6/1) to afford an oil (376 mg). The oil was dissolved in MeOH and m). Anal. Calcd for C22H30N2·2HCl·1.0H2O: C, 63.91; H, 8.29; N, 6.78.
treated with 1 N HCl (Et2O solution, 2 ml). The solution was concentrated in
vacuo to give a foam, which was triturated with Et2O, filtered, and dried in
Found: C, 64.01; H, 8.18; N, 6.74.
N-[3-(4-Benzylpiperidin-1-yl)propyl]-3-methylaniline Dihydrochlo-
vacuo over KOH yielding 7a (380 mg, yield 81%) as an amorphous solid. ride (9c) Yield 67%, mp 173—178 °C (dec). 1H-NMR (DMSO-d6) d
1H-NMR (D2O) d 1.90—2.15 (2H, m), 2.30—4.00 (17H, m), 2.78 (3H, s), 1.40—2.25 (7H, m), 2.31 (3H, s), 2.45—3.50 (10H, m), 6.95—7.40 (9H,
6.61 (1H, s), 7.25—7.65 (10H, m). Anal. Calcd for C27H33N3O2·HCl· m). Anal. Calcd for C22H30N2·2HCl·0.2H2O: C, 66.22; H, 8.18; N, 7.02.
0.7H2O: C, 67.47; H, 7.42; Cl, 7.38; N, 8.74. Found: C, 67.48; H, 7.44; Cl,
7.40; N, 8.70.
Found: C, 66.30; H, 8.12; N, 6.99.
N-[3-(4-Benzylpiperidin-1-yl)propyl]-4-tert-butylaniline Dihydrochlo-
The following compounds 7b—e were prepared using a procedure similar ride (9e) Yield 51%, mp 203—213 °C (dec). 1H-NMR (DMSO-d6) d 1.27
to that described for 7a from the corresponding amines.
N-{3-[4-(Diphenylmethyl)piperidin-1-yl]propyl}-1-methyl-5-oxo-N-
(9H, s), 1.40—1.90 (5H, m), 2.00—2.20 (2H, m), 2.45—2.60 (2H, m),
2.75—2.95 (2H, m), 3.00—3.70 (6H, m), 7.10—7.40 (7H, m), 7.44 (2H, d,
phenylpyrrolidine-3-carboxamide Fumarate (7b) Compound 7b was Jϭ8.4 Hz). Anal. Calcd for C25H36N2·2HCl·0.2H2O: C, 68.07; H, 8.77; N,
prepared from 4-(diphenylmethyl)piperidine hydrochloride34) in 70% yield, 6.35. Found: C, 68.10; H, 8.80; N, 6.35.
1
amorphous solid. H-NMR (DMSO-d6) d 1.00—1.30 (2H, m), 1.30—1.75
N-[3-(4-Benzylpiperidin-1-yl)propyl]indan-5-amine Dihydrochloride
(4H, m), 1.95—2.55 (5H, m), 2.62 (3H, s), 2.80—3.10 (3H, m), 3.13 (1H, t,
Jϭ9.2 Hz), 3.37 (1H, dd, Jϭ9.2, 6.1 Hz), 3.50—3.70 (4H, m), 3.54 (1H, d, (2H, m), 1.87—1.93 (3H, m), 2.08—2.15 (4H, m), 2.61 (2H, d, Jϭ6.6 Hz),
Jϭ11.0 Hz), 6.57 (2H, s), 7.05—7.55 (15H, m). Anal. Calcd for 2.82—2.94 (6H, m), 3.10—3.18 (2H, m), 3.26—3.54 (4H, m), 7.12 (1H, d,
(9f) Yield 28%, mp 172—175 °C (dec). 1H-NMR (D2O) d 1.42—1.50
C33H39N3O2·C4H4O4·0.3H2O: C, 70.41; H, 6.96; N, 6.66. Found: C, 70.48;
H, 7.06; N, 6.67.
Jϭ7.8 Hz), 7.24—7.41 (7H, m). Anal. Calcd for C24H32N2·2HCl·0.25H2O:
C, 67.67; H, 8.25; N, 6.57. Found: C, 67.73; H, 7.97; N, 6.50.
1-Methyl-5-oxo-N-phenyl-N-{3-[4-(2-phenylethyl)piperidin-1-yl]-
N-[3-(4-Benzylpiperidin-1-yl)propyl]-4-methoxyaniline Dihydrochlo-
propyl}pyrrolidine-3-carboxamide Hydrochloride (7c) Compound 7c ride (9g) Yield 38%, mp 154—159 °C (dec). 1H-NMR (DMSO-d6) d
was prepared from 4-(2-phenylethyl)piperidine hydrochloride in 62% yield, 1.40—1.95 (5H, m), 1.95—2.20 (2H, m), 2.45—2.65 (2H, m), 2.70—3.00
amorphous solid. 1H-NMR (D2O) d 1.30—1.85 (5H, m), 1.85—2.15 (4H, (2H, m), 3.00—3.55 (6H, m), 3.76 (3H, s), 7.02 (2H, d, Jϭ8.8 Hz), 7.10—
m), 2.45 (1H, dd, Jϭ17.7, 8.7 Hz), 2.55—3.65 (12H, m), 2.77 (3H, s), 7.45 (7H, m). Anal. Calcd for C22H30N2O·2HCl·0.4H2O: C, 63.12; H, 7.90;
3.75—3.95 (2H, m), 7.20—7.45 (7H, m), 7.50—7.65 (3H, m). Anal. Calcd N, 6.69. Found: C, 63.12; H, 7.84; N, 6.78.
for C28H37N3O2·HCl·1.0H2O: C, 66.98; H, 8.03; N, 8.37. Found: C, 66.99;
H, 8.10; N, 8.31.
N-[3-(4-Benzylpiperidin-1-yl)propyl]-3-chloroaniline Dihydrochloride
(9h) Yield 41%, mp 199—202 °C (dec). 1H-NMR (DMSO-d6) d 1.53—
1-Methyl-5-oxo-N-[3-(4-phenoxypiperidin-1-yl)propyl]-N-phenyl- 2.01 (7H, m), 2.50—2.55 (2H, m), 2.66—2.92 (2H, m), 3.08—3.20 (4H, m),
pyrrolidine-3-carboxamide Hydrochloride (7d) Compound 7d was pre- 3.38—3.44 (2H, m), 6.61—6.69 (3H, m), 7.07—7.30 (6H, m). Anal. Calcd
pared from 4-phenoxypiperidine hydrochloride35) in 78% yield, amorphous for C21H27ClN2·2HCl·0.1H2O: C, 60.39; H, 7.04; N, 6.71. Found: C, 60.33;
solid. 1H-NMR (DMSO-d6) d 1.70—2.35 (7H, m), 2.35—2.55 (1H, m), 2.63 H, 6.93; N, 6.84.
(3H, s), 2.85—3.85 (11H, m), 4.40—4.80 (1H, m), 6.90—7.10 (3H, m),
N-[3-(4-Benzylpiperidin-1-yl)propyl]-4-chloroaniline Dihydrochloride
7.20—7.60 (7H, m). Anal. Calcd for C26H33N3O3·HCl·0.8H2O: C, 64.20; H, (9i) Yield 70%, mp 155—159 °C (dec). 1H-NMR (DMSO-d6) d 1.40—
7.38; N, 8.64. Found: C, 64.17; H, 7.50; N, 8.66.
1.90 (5H, m), 1.90—2.10 (2H, m), 2.45—2.60 (2H, m), 2.70—2.95 (2H, m),
N-{3-[4-(Benzyloxy)piperidin-1-yl]propyl}-1-methyl-5-oxo-N-phenyl-
2.95—3.50 (6H, m), 6.85 (2H, d, Jϭ9.2 Hz), 7.10—7.40 (7H, m). Anal.
pyrrolidine-3-carboxamide Hydrochloride (7e) Compound 7e was pre- Calcd for C21H27ClN2·2HCl: C, 60.66; H, 7.03; N, 6.74. Found: C, 60.85; H,
pared from 4-(benzyloxy)piperidine hydrochloride in 75% yield, amorphous 6.81; N, 6.79.
solid. 1H-NMR (D2O) d 1.70—2.40 (6H, m), 2.46 (1H, dd, Jϭ17.4, 8.8 Hz),
2.66 (1H, dd, Jϭ17.4, 6.1 Hz), 2.78 (3H, s), 3.00—3.65 (9H, m), 3.75—4.00
(3H, m), 4.64 (2H, s), 7.30—7.45 (2H, m), 7.45 (5H, s), 7.50—7.65 (3H, 1.49—1.76 (5H, m), 1.91—1.96 (2H, m), 2.50—2.55 (2H, m), 2.79—3.17
N-[3-(4-Benzylpiperidin-1-yl)propyl]-3,4-dichloroaniline Dihydro-
chloride (9j) Yield 53%, mp 200—203 °C (dec). H-NMR (DMSO-d6) d
1
m). Anal. Calcd for C27H35N3O3·HCl·0.6H2O: C, 65.27; H, 7.55; N, 8.46. (6H, m), 3.38—3.44 (2H, m), 6.68 (1H, dd, Jϭ8.8, 2.8 Hz), 6.75 (1H, d,
Found: C, 65.27; H, 7.63; N, 8.51.
Jϭ2.6 Hz), 7.17—7.30 (6H, m). Anal. Calcd for C21H26Cl2N2·2HCl·
N-[3-(4-Benzylpiperidin-1-yl)propyl]-4-methylaniline Dihydrochlo-
0.5H2O: C, 54.92; H, 6.36; N, 6.10. Found: C, 55.11; H, 6.64; N, 6.37.
ride (9d) To
a
stirred solution of 4-benzylpiperidine (8a) (3.51 g,
N-[3-(4-Benzylpiperidin-1-yl)propyl]-3-chloro-4-fluoroaniline Dihydro-
1
20 mmol) and DBU (30 ml, 0.2 mmol) in THF (40 ml) was added dropwise a chloride (9k) Yield 40%, mp 195—197 °C (dec). H-NMR (DMSO-d6) d
solution of acrolein (90%, 1.49 ml, 20 mmol) in THF (5 ml) at Ϫ20 °C, and 1.53—1.75 (5H, m), 1.94—2.02 (2H, m), 2.50—2.55 (2H, m), 2.80—2.85
the mixture was stirred at Ϫ20 to Ϫ10 °C for 1 h. The mixture was treated (2H, m), 3.07—3.10 (4H, m), 3.38—3.45 (2H, m), 6.67—6.73 (1H, m), 6.84
with p-toluidine (2.14 g, 20 mmol) followed by NaBH(OAc)3 (8.48 g, (1H, dd, Jϭ6.0, 3.0 Hz), 7.13—7.34 (6H, m). Anal. Calcd for
40 mmol) at Ϫ10 °C and allowed to warm to room temperature. After 23 h, C21H26ClFN2·2HCl·0.5H2O: C, 56.96; H, 6.60; N, 6.33. Found: C, 57.12; H,
the mixture was diluted with aqueous NaHCO3 and extracted with EtOAc. 6.43; N, 6.46.
The organic layer was dried (MgSO4), filtered, and concentrated in vacuo.
N-[3-(4-Benzylpiperidin-1-yl)propyl]-3,4-difluoroaniline Dihydrochlo-
The residue was purified by column chromatography on silica gel ride (9l) Yield 53%, mp 175—177 °C (dec). 1H-NMR (DMSO-d6) d
(EtOAc/MeOH 1/0 to 4/1) to afford the free base of 9d (4.07 g) as an oil. 1H- 1.53—1.75 (5H, m), 1.94—1.98 (2H, m), 2.51—2.54 (2H, m), 2.66—2.84
NMR (CDCl3) d 1.15—1.95 (9H, s), 2.23 (3H, s), 2.42 (2H, t, Jϭ6.8 Hz), (2H, m), 3.06—3.10 (4H, m), 3.38—3.44 (2H, m), 6.51—6.55 (1H, m),

70
Vol. 52, No. 1
(3H, m), 2.21 (3H, s), 2.45—3.25 (6H, m), 2.51 (2H, d, Jϭ6.6 Hz), 2.75
(0.5ϫ3H, s), 2.76 (0.5ϫ3H, s), 3.40—3.80 (1H, m), 4.00—4.25 (1H, m),
7.00—7.35 (9H, m). Anal. Calcd for C28H37N3O2·HCl·0.7H2O: C, 67.71; H,
8.00; N, 8.46. Found: C, 67.68; H, 7.97; N, 8.50.
N-[3-(4-Benzylpiperidin-1-yl)propyl]-1-methyl-N-(3-methylphenyl)-5-
oxopyrrolidine-3-carboxamide Hydrochloride (10b) Yield 84%, amor-
phous solid. 1H-NMR (free base, CDCl3) d 1.05—1.95 (9H, m), 2.10—2.40
(3H, m), 2.38 (3H, s), 2.51 (2H, d, Jϭ6.6 Hz), 2.55—2.90 (3H, m), 2.76
(3H, s), 2.95—3.25 (2H, m), 3.55—3.75 (3H, m), 6.85—7.00 (2H, m),
7.05—7.35 (7H, m). Anal. Calcd for C28H37N3O2·HCl·0.5H2O: C, 68.20; H,
7.97; N, 8.52. Found: C, 68.18; H, 8.12; N, 8.63.
N-[3-(4-Benzylpiperidin-1-yl)propyl]-N-(4-tert-butylphenyl)-1-methyl-
5-oxopyrrolidine-3-carboxamide Hydrochloride (10d) Yield 75%,
amorphous solid. 1H-NMR (DMSO-d6) d 1.31 (9H, s), 1.35—1.95 (7H, m),
2.11 (1H, dd, Jϭ16.4, 9.6 Hz), 2.35—2.60 (3H, m), 2.60—3.50 (9H, m),
2.63 (3H, s), 3.55—3.75 (2H, m), 7.10—7.40 (7H, m), 7.51 (2H, d,
Jϭ8.4 Hz). Anal. Calcd for C31H43N3O2·HCl·0.6H2O: C, 69.34; H, 8.48; N,
7.83. Found: C, 69.27; H, 8.52; N, 7.82.
N-[3-(4-Benzylpiperidin-1-yl)propyl]-N-(indan-5-yl)-1-methyl-5-ox-
opyrrolidine-3-carboxamide Hydrochloride (10e) Yield 69%, amor-
phous solid. 1H-NMR (D2O) d 1.44—1.58 (2H, m), 1.88—2.14 (7H, m),
2.44—2.49 (1H, m), 2.60—2.69 (3H, m), 2.77 (3H, s), 2.81—2.98 (6H, m),
3.06—3.14 (2H, m), 3.28—3.53 (5H, m), 3.76—3.82 (2H, m), 7.08 (1H, d,
Jϭ8.2 Hz), 7.22—7.43 (7H, m). Anal. Calcd for C30H39N3O2·HCl·1.5H2O:
C, 67.08; H, 8.07; N, 7.82. Found: C, 67.19; H, 7.97; N, 8.01.
N-[3-(4-Benzylpiperidin-1-yl)propyl]-N-(4-methoxyphenyl)-1-methyl-
5-oxopyrrolidine-3-carboxamide Hydrochloride (10f) Yield 88%, amor-
phous solid. 1H-NMR (D2O) d 1.35—1.65 (2H, m), 1.75—2.10 (5H, m),
2.45 (1H, dd, Jϭ17.7, 9.7 Hz), 2.55—2.75 (1H, m), 2.63 (2H, d, Jϭ7.0 Hz),
2.75—3.00 (2H, m), 2.78 (3H, s), 3.00—3.20 (2H, m), 3.20—3.65 (5H, m),
3.70—3.90 (2H, m), 3.89 (3H, s), 7.13 (2H, d, Jϭ8.8 Hz), 7.20—7.45 (7H,
m). Anal. Calcd for C28H37N3O3·HCl·0.6H2O: C, 65.83; H, 7.73; N, 8.22.
Found: C, 65.79; H, 7.70; N, 8.06.
N-[3-(4-Benzylpiperidin-1-yl)propyl]-N-(3-chlorophenyl)-1-methyl-5-
oxopyrrolidine-3-carboxamide Hydrochloride (10g) Yield 79%, amor-
phous solid. 1H-NMR (D2O) d 1.40—1.55 (2H, m), 1.85—2.03 (5H, m),
2.47—2.95 (9H, m), 3.06—3.59 (7H, m), 3.71—3.85 (2H, m), 7.25—7.55
(9H, m). Anal. Calcd for C27H34ClN3O2·HCl·0.7H2O: C, 62.71; H, 7.10; N,
8.13. Found: C, 62.77; H, 7.05; N, 8.24.
N-[3-(4-Benzylpiperidin-1-yl)propyl]-N-(4-chlorophenyl)-1-methyl-5-
oxopyrrolidine-3-carboxamide Hydrochloride (10h) Yield 86%, amor-
phous solid. 1H-NMR (D2O) d 1.35—1.65 (2H, m), 1.80—2.10 (5H, m),
2.45 (1H, dd, Jϭ17.6, 9.6 Hz), 2.55—2.75 (1H, m), 2.64 (2H, d, Jϭ7.2 Hz),
2.75—3.65 (9H, m), 2.78 (3H, s), 3.65—3.95 (2H, m), 7.20—7.45 (7H, m),
7.59 (2H, d, Jϭ8.6 Hz). Anal. Calcd for C27H34ClN3O2·HCl·0.6H2O: C,
62.93; H, 7.08; N, 8.15. Found: C, 63.04; H, 7.14; N, 8.16.
6.67—6.77 (1H, m), 7.11—7.34 (6H, m). Anal. Calcd for C21H26F2N2·
2HCl·0.2H2O: C, 59.92; H, 6.80; N, 6.65. Found: C, 59.93; H, 6.67; N,
6.74.
N-[3-(4-Benzylpiperidin-1-yl)propyl]-3-(trifluoromethyl)aniline Dihy-
1
drochloride (9m) Yield 56%, mp 167—173 °C (dec.). H-NMR (DMSO-
d6) d 1.40—2.10 (7H, m), 2.45—2.60 (2H, m), 2.60—2.95 (2H, m), 2.95—
3.30 (2H, m), 3.13 (2H, t, Jϭ6.6 Hz), 3.41 (2H, br d, Jϭ11.6 Hz), 6.75—
6.95 (3H, m), 7.10—7.40 (6H, m). Anal. Calcd for C22H27F3N2·
2HCl·0.8H2O: C, 56.97; H, 6.65; N, 6.04. Found: C, 56.87; H, 6.64; N,
6.10.
N-[3-(4-Benzylpiperidin-1-yl)propyl]-4-(trifluoromethyl)aniline Dihy-
drochloride (9n) Yield 36%, mp 166—168 °C (dec). 1H-NMR (DMSO-
d6) d 1.56—1.75 (5H, m), 1.95—2.06 (2H, m), 2.50—2.55 (2H, m), 2.80—
2.90 (2H, m), 3.04—3.18 (4H, m), 3.38—3.45 (2H, m), 6.70 (2H, d,
Jϭ8.6 Hz), 7.16—7.40 (7H, m). Anal. Calcd for C22H27F3N2·2HCl: C,
58.80; H, 6.50; N, 6.23. Found: C, 58.64; H, 6.47; N, 6.32.
N-[3-(4-Benzylpiperidin-1-yl)propyl]-3,5-bis(trifluoromethyl)aniline
Dihydrochloride (9o) Yield 19%, mp 182—185 °C (dec). 1H-NMR
(DMSO-d6) d 1.50—1.76 (5H, m), 1.91—1.97 (2H, m), 2.50—2.55 (2H,
m), 2.80—2.86 (2H, m), 3.08—3.24 (4H, m), 3.40—3.47 (2H, m), 7.05—
7.34 (8H, m). Anal. Calcd for C23H26F6N2·2HCl·1.0H2O: C, 51.60; H, 5.65;
N, 5.23. Found: C, 51.69; H, 5.54; N, 5.43.
3-{[3-(4-Benzylpiperidin-1-yl)propyl]amino}benzonitrile (9p) Yield
43%, oil. 1H-NMR (CDCl3) d 1.20—1.40 (2H, m), 1.41—1.95 (7H, m),
2.42—2.49 (2H, m), 2.56—2.60 (2H, m), 2.91—2.98 (2H, m), 3.11—3.19
(2H, m), 6.68—6.74 (2H, m), 6.89—6.93 (1H, m), 7.14—7.30 (6H, m).
4-{[3-(4-Benzylpiperidin-1-yl)propyl]amino}benzonitrile (9q) Yield
50%, oil. 1H-NMR (CDCl3) d 1.19—1.39 (2H, m), 1.45—1.96 (7H, m),
2.42—2.49 (2H, m), 2.56—2.60 (2H, m), 2.90—2.97 (2H, m), 3.15—3.24
(2H, m), 6.17—6.30 (1H, br s), 6.45 (2H, d, Jϭ9.0 Hz), 7.14—7.42 (7H, m).
N-Benzyl-3-(4-benzylpiperidin-1-yl)propan-1-amine (9r) Yield 44%,
1
oil. H-NMR (CDCl3) d 1.10—1.88 (10H, m), 2.35 (2H, t, Jϭ7.5 Hz), 2.52
(2H, d, Jϭ6.6 Hz), 2.66 (2H, t, Jϭ6.8 Hz), 2.88—3.00 (2H, m), 3.78 (2H, s),
7.11—7.36 (10H, m).
N-{3-[4-(4-Fluorobenzyl)piperidin-1-yl]propyl}aniline Dihydrochlo-
ride (9s) Yield 54%, mp 227—230 °C (dec). 1H-NMR (DMSO-d6) d
1.35—1.90 (5H, m), 1.95—2.20 (2H, m), 2.45—2.60 (2H, m), 2.83 (2H, br
t, Jϭ11.5 Hz), 3.11 (2H, br t, Jϭ7.4 Hz), 3.24 (2H, br t, Jϭ6.8 Hz), 3.42
(2H, br d, Jϭ10.6 Hz), 6.90—7.20 (9H, m). Anal. Calcd for C21H27FN2·
2HCl·0.8H2O: C, 60.96; H, 7.45; N, 6.77. Found: C, 61.02; H, 7.37; N,
6.76.
3,4-Dichloro-N-{3-[4-(4-fluorobenzyl)piperidin-1-yl]propyl}aniline Di-
hydrochloride (9t) Yield 48%, mp 203—209 °C (dec). 1H-NMR (DMSO-
d6) d 1.35—2.05 (7H, m), 2.45—2.60 (2H, m), 2.60—3.30 (6H, m), 3.41
(2H, br d, Jϭ10.6 Hz), 6.57 (1H, dd, Jϭ8.8, 2.7 Hz), 6.75 (1H, d, Jϭ2.7 Hz),
7.05—7.30 (5H, m). Anal. Calcd for C21H25Cl2FN2·2HCl·0.5H2O: C, 52.85;
H, 5.91; N, 5.87. Found: C, 52.90; H, 6.12; N, 5.94.
N-[3-(4-Benzylpiperidin-1-yl)propyl]-1-methyl-N-(4-methylphenyl)-5-
oxopyrrolidine-3-carboxamide Hydrochloride (10c) To an ice-cooled
stirred solution of 2a (358 mg, 2.5 mmol) and DMF (23 ml, 0.3 mmol) in
DCM (10 ml) was added oxalyl chloride (256 ml, 3.0 mmol), and the mixture
was stirred at 0 °C for 15 min. The mixture was removed from the ice bath
and stirred for an additional 1 h. The mixture was added dropwise to a
stirred solution of 9d (395 mg, 1.0 mmol) and Et3N (1.39 ml, 10 mmol) in
DCM (15 ml) at Ϫ20 °C. The resulting mixture was allowed to warm to 0 °C
and stirred for 1 h before being quenched with saturated aqueous NaHCO3
(15 ml). The organic solvent was removed in vacuo, and the residue was ex-
tracted with EtOAc (3ϫ15 ml). The organic layer was washed with saturated
aqueous NaHCO3 (3ϫ5 ml) and brine (5 ml), dried (MgSO4), filtered, and
concentrated in vacuo. The residue was purified by column chromatography
on silica gel (EtOAc/MeOH 1/0 to 9/1) to afford the free base (442 mg) as an
oil. The oil was dissolved in MeOH and treated with 1N HCl (Et2O solution,
2 ml). The solution was concentrated in vacuo to give a foam, which was
triturated with Et2O, filtered, and dried in vacuo over KOH yielding 10c
(409 mg, yield 85%) as an amorphous solid. 1H-NMR (DMSO-d6) d 1.30—
1.95 (7H, m), 2.11 (1H, dd, Jϭ16.5, 9.9 Hz), 2.30—2.60 (3H, m), 2.35 (3H,
s), 2.60—3.50 (9H, m), 2.63 (3H, s), 3.50—3.75 (2H, m), 7.10—7.40 (9H,
m). Anal. Calcd for C28H37N3O2·HCl·0.6H2O: C, 67.96; H, 7.98; Cl, 7.16;
N, 8.49. Found: C, 67.99; H, 7.94; Cl, 7.45; N, 8.28.
N-[3-(4-Benzylpiperidin-1-yl)propyl]-N-(3,4-dichlorophenyl)-1-
methyl-5-oxopyrrolidine-3-carboxamide Hydrochloride (10i) Yield
1
77%, amorphous solid. H-NMR (D2O) d 1.35—1.65 (2H, m), 1.75—2.10
(5H, m), 2.47 (1H, dd, Jϭ18.0, 9.4 Hz), 2.55—2.75 (1H, m), 2.65 (2H, d,
Jϭ7.2 Hz), 2.75—3.20 (4H, m), 2.79 (3H, s), 3.20—3.70 (5H, m), 3.70—
3.90 (2H, m), 7.25—7.45 (6H, m), 7.63 (1H, d, Jϭ2.2 Hz), 7.72 (1H, d,
Jϭ8.4 Hz). Anal. Calcd for C27H33Cl2N3O2·HCl·0.7H2O: C, 58.80; H, 6.47;
N, 7.62. Found: C, 58.77; H, 6.41; N, 7.56.
N-[3-(4-Benzylpiperidin-1-yl)propyl]-N-(3-chloro-4-fluorophenyl)-1-
methyl-5-oxopyrrolidine-3-carboxamide Hydrochloride (10j) Yield
1
68%, amorphous solid. H-NMR (D2O) d 1.40—1.58 (2H, m), 1.89—1.96
(5H, m), 2.47—2.64 (4H, m), 2.77—2.95 (5H, m), 3.01—3.13 (2H, m),
3.32—3.56 (5H, m), 3.73—3.79 (2H, m), 7.25—7.40 (6H, m), 7.55—7.60
(2H, m). Anal. Calcd for C27H33ClFN3O2·HCl·0.75H2O: C, 60.50; H, 6.39;
N, 7.84. Found: C, 60.70; H, 6.71; N, 8.16.
N-[3-(4-Benzylpiperidin-1-yl)propyl]-N-(3,4-difluorophenyl)-1-
methyl-5-oxopyrrolidine-3-carboxamide Hydrochloride (10k) Yield
1
80%, amorphous solid. H-NMR (D2O) d 1.40—1.55 (2H, m), 1.89—2.00
(5H, m), 2.48—2.64 (4H, m), 2.77—2.94 (5H, m), 3.06—3.14 (2H, m),
3.30—3.55 (5H, m), 3.73—3.79 (2H, m), 7.20—7.46 (8H, m). Anal. Calcd
for C27H33F2N3O2·HCl·0.6H2O: C, 62.74; H, 6.86; N, 8.13. Found: C,
62.44; H, 6.88; N, 8.27.
N-[3-(4-Benzylpiperidin-1-yl)propyl]-1-methyl-5-oxo-N-[3-(trifluo-
romethyl)phenyl]pyrrolidine-3-carboxamide Hydrochloride (10l) Yield
The following compounds 10a, b, d—p were prepared using a procedure
similar to that described for 10c from the anilines 9b, c, e—q.
1
70%, amorphous solid. H-NMR (free base, CDCl3) d 1.05—1.95 (9H, m),
2.15—2.35 (3H, m), 2.51 (2H, d, Jϭ6.6 Hz), 2.60—3.10 (4H, m), 2.78 (3H,
s), 3.19 (1H, t, Jϭ9.1 Hz), 3.60—3.80 (3H, m), 7.05—7.45 (7H, m), 7.55—
7.75 (2H, m). Anal. Calcd for C28H34F3N3O2·HCl·0.6H2O: C, 61.27; H,
N-[3-(4-Benzylpiperidin-1-yl)propyl]-1-methyl-N-(2-methylphenyl)-5-
oxopyrrolidine-3-carboxamide Hydrochloride (10a) Yield 59%, amor-
phous solid. 1H-NMR (free base, CDCl3) d 1.05—1.95 (9H, m), 2.05—2.35

January 2004
71
6.65; N, 7.66. Found: C, 61.29; H, 6.60; N, 7.69.
N-[3-(4-Benzylpiperidin-1-yl)propyl]-1-methyl-5-oxo-N-[4-(trifluo-
m), 7.10—7.50 (10H, m). Anal. Calcd for C32H43N3O2·0.5H2O: C, 75.26; H,
8.68; N, 8.23. Found: C, 75.19; H, 8.37; N, 8.32.
romethyl)phenyl]pyrrolidine-3-carboxamide
Hydrochloride
(10m)
N-[3-(4-Benzylpiperidin-1-yl)propyl]-1-(cyclohexylmethyl)-5-oxo-N-
phenylpyrrolidine-3-carboxamide (12c) Yield 70%, oil. 1H-NMR
(CDCl3) d 0.80—1.03 (2H, m), 1.04—1.38 (5H, m), 1.39—1.90 (13H, m),
2.16—2.32 (3H, m), 2.51 (2H, d, Jϭ6.6 Hz), 2.61—3.20 (7H, m), 3.63—
1
Yield 70%, amorphous solid. H-NMR (DMSO-d6) d 1.44—1.57 (2H, m),
1.70—1.85 (5H, m), 2.10—2.21 (2H, m), 2.39—2.54 (3H, m), 2.64 (3H, s),
2.70—3.05 (4H, m), 3.13—3.45 (4H, m), 3.65—3.75 (2H, m), 7.16—7.34
(5H, m), 7.65—7.69 (2H, m), 7.85—7.90 (2H, m). Anal. Calcd for 3.75 (3H, m), 7.10—7.50 (10H, m). Anal. Calcd for C33H45N3O2: C, 76.85;
C28H34F3N3O2·HCl·0.5H2O: C, 61.47; H, 6.63; N, 7.68. Found: C, 61.43; H,
6.73; N, 7.97.
N-[3-(4-Benzylpiperidin-1-yl)propyl]-N-[3,5-bis(trifluoromethyl)-
H, 8.79; N, 8.15. Found: C, 76.50; H, 8.89; N, 8.18.
N-[3-(4-Benzylpiperidin-1-yl)propyl]-5-oxo-N,1-diphenylpyrrolidine-
3-carboxamide (12d) Yield 62%, oil. 1H-NMR (CDCl3) d 1.10—2.00
phenyl]-1-methyl-5-oxopyrrolidine-3-carboxamide (10n) Yield 50%, (9H, m), 2.27—2.45 (3H, m), 2.51 (2H, d, Jϭ6.6 Hz), 2.81—2.99 (3H, m),
amorphous solid. 1H-NMR (D2O) d 1.44—1.51 (2H, m), 1.89—2.01 (5H, 3.10—3.27 (1H, m), 3.62 (1H, t, Jϭ9.0 Hz), 3.71—3.79 (2H, m), 4.18 (1H,
m), 2.45—2.63 (4H, m), 2.69—2.96 (5H, m), 3.08—3.85 (9H, m), 7.25—
7.38 (5H, m), 8.06 (2H, s), 8.26 (1H, s). Anal. Calcd for C29H33F6N3O2· 76.16; H, 7.59; N, 8.33. Found: C, 75.91; H, 7.85; N, 8.35.
HCl·0.4H2O: C, 56.80; H, 5.72; N, 6.85. Found: C, 56.81; H, 6.07; N, 7.37. 1-Benzyl-N-[3-(4-benzylpiperidin-1-yl)propyl]-5-oxo-N-phenylpyrroli-
t, Jϭ9.0 Hz), 7.09—7.53 (15H, m). Anal. Calcd for C32H37N3O2·0.5H2O: C,
N-[3-(4-Benzylpiperidin-1-yl)propyl]-N-(3-cyanophenyl)-1-methyl-5- dine-3-carboxamide Hydrochloride (12e) Yield 68%, amorphous solid.
oxopyrrolidine-3-carboxamide Hydrochloride (10o) Yield 46%, amor- 1H-NMR (free base, CDCl3) d 1.15—1.33 (2H, m), 1.40—1.86 (7H, m),
phous solid. IR (KBr) 2232 cmϪ1. 1H-NMR (free base, CDCl3) d 1.16—2.00
(9H, m), 2.10—2.59 (5H, m), 2.78 (3H, s), 2.59—3.09 (3H, m), 3.09—3.40
2.23—2.36 (3H, m), 2.50 (2H, d, Jϭ6.6 Hz), 2.68—2.90 (3H, m), 2.92—
3.12 (2H, m), 3.53 (1H, dd, Jϭ7.6, 5.4 Hz), 3.64—3.72 (2H, m), 4.33 (1H,
(2H, m), 3.54—3.81 (3H, m), 7.09—7.32 (5H, m), 7.41—7.70 (4H, m). d, Jϭ14.6 Hz), 4.43 (1H, d, Jϭ14.6 Hz), 7.00—7.30 (15H, m). Anal. Calcd
Anal. Calcd for C28H34N4O2·HCl·1.5H2O: C, 64.42; H, 7.34; N, 10.73.
Found: C, 64.42; H, 7.18; N, 10.62.
for C33H39N3O2·HCl·1.5H2O: C, 69.15; H, 7.56; N, 7.33. Found: C, 68.78;
H, 7.31; N, 7.59.
N-[3-(4-Benzylpiperidin-1-yl)propyl]-N-(4-cyanophenyl)-1-methyl-5-
N-[3-(4-Benzylpiperidin-1-yl)propyl]-1-(2-chlorobenzyl)-5-oxo-N-
oxopyrrolidine-3-carboxamide Hydrochloride (10p) Yield 28%, amor- phenylpyrrolidine-3-carboxamide Hydrochloride (12f) Yield 72%,
phous solid. IR (KBr) 2230 cmϪ1. 1H-NMR (free base, CDCl3) d 1.21—1.99
(9H, m), 2.03—2.54 (6H, m), 2.78 (3H, s), 2.58—3.15 (4H, m), 3.58—3.78
amorphous solid. 1H-NMR (free base, CDCl3) d 1.10—1.35 (2H, m), 1.35—
1.85 (7H, m), 2.23—2.37 (3H, m), 2.50 (2H, d, Jϭ6.6 Hz), 2.69—2.90 (3H,
(3H, m), 7.10—7.36 (7H, m), 7.77 (2H, d, Jϭ8.0 Hz). Anal. Calcd for m), 2.96—3.18 (2H, m), 3.58 (1H, dd, Jϭ8.4, 6.2 Hz), 3.69 (2H, t,
C28H34N4O2·HCl·1.9H2O: C, 63.54; H, 7.39; N, 10.59. Found: C, 63.64; H, Jϭ7.8 Hz), 4.48 (1H, d, Jϭ15.2 Hz), 4.58 (1H, d, Jϭ15.2 Hz), 7.10—7.64
7.25; N, 10.32.
(14H, m). Anal. Calcd for C33H38ClN3O2·HCl·0.8H2O: C, 66.61; H, 6.88;
N-Benzyl-N-[3-(4-benzylpiperidin-1-yl)propyl]-1-methyl-5-oxopyrroli- N, 7.06. Found: C, 66.58; H, 6.91; N, 7.06.
dine-3-carboxamide (10q) To a stirred mixture of 2a (89 mg, 0.62 mmol),
N-[3-(4-Benzylpiperidin-1-yl)propyl]-1-(3-chlorobenzyl)-5-oxo-N-
9r (200 mg, 0.62 mmol), and HOBt hydrate (104 mg, 0.68 mmol) in MeCN phenylpyrrolidine-3-carboxamide (12g) Yield 81%, oil. 1H-NMR
(6 ml) was added 1,3-dicyclohexylcarbodiimide (DCC) (141 mg, 0.68 (CDCl3) d 1.10—1.90 (9H, m), 2.23—2.37 (3H, m), 2.50 (2H, d, Jϭ6.6 Hz),
mmol), and the mixture was stirred at 80 °C for 1 h. The mixture was con-
centrated in vacuo, diluted with EtOAc (20 ml), and filtered. The filtrate was like, Jϭ7.6 Hz), 4.30 (1H, d, Jϭ14.6 Hz), 4.41 (1H, d, Jϭ14.6 Hz), 7.00—
washed with 2 N NaOH (5 ml), dried (MgSO4), filtered, and concentrated in 7.50 (14H, m). Anal. Calcd for C33H38ClN3O2·0.5H2O: C, 71.66; H, 7.11; N,
vacuo. The residue was purified by column chromatography on alumina 7.60. Found: C, 71.87; H, 7.09; N, 7.36.
2.67—2.83 (3H, m), 2.98—3.12 (2H, m), 3.50—3.60 (1H, m), 3.69 (2H, t-
1
(EtOAc) to afford 10q (125 mg, yield 45%) as an oil. H-NMR (CDCl3) d
N-[3-(4-Benzylpiperidin-1-yl)propyl]-1-(4-chlorobenzyl)-5-oxo-N-
1.10—1.40 (2H, m), 1.41—1.88 (7H, m), 2.19—2.78 (8H, m), 2.80 (1.5H, phenylpyrrolidine-3-carboxamide (12h) Yield 78%, oil. 1H-NMR
s), 2.88 (1.5H, s), 3.21—3.82 (5H, m), 4.48—4.73 (2H, m), 7.11—7.37 (CDCl3) d 1.10—1.90 (9H, m), 2.23—2.36 (3H, m), 2.50 (2H, d, Jϭ6.6 Hz),
(10H, m). Anal. Calcd for C28H37N3O2·0.25H2O: C, 74.38; H, 8.36; N, 9.29. 2.67—2.83 (3H, m), 2.96—3.10 (2H, m), 3.50—3.60 (1H, m), 3.69 (2H, t-
Found: C, 74.38; H, 8.49; N, 9.09.
like, Jϭ7.4 Hz), 4.35 (2H, s), 7.00—7.50 (14H, m). Anal. Calcd for
The following compounds 11a, b were prepared using a procedure similar C33H38ClN3O2·0.2H2O: C, 72.36; H, 7.07; N, 7.67. Found: C, 72.37; H,
to that described for 10c from the anilines 9s, t.
7.06; N, 7.49.
N-{3-[4-(4-Fluorobenzyl)piperidin-1-yl]propyl}-1-methyl-5-oxo-N-
N-[3-(4-Benzylpiperidin-1-yl)propyl]-1-(4-methylbenzyl)-5-oxo-N-
phenylpyrrolidine-3-carboxamide Hydrochloride (11a) Yield 43%, phenylpyrrolidine-3-carboxamide (12i) Yield 40%, oil. 1H-NMR
amorphous solid. 1H-NMR (CD3OD) d 1.30—1.70 (2H, m), 1.75—2.10
(5H, m), 2.31 (1H, dd, Jϭ17.2, 9.6 Hz), 2.56—2.71 (3H, m), 2.77 (3H, s), 2.37 (3H, m), 2.50 (2H, d, Jϭ6.6 Hz), 2.66—2.88 (3H, m), 2.95—3.15 (2H,
2.92 (2H, t-like, Jϭ12.4 Hz), 3.09—3.36 (4H, m), 3.53—3.70 (3H, m), m), 3.45—3.60 (1H, m), 3.65 (2H, t-like, Jϭ8.0 Hz), 4.44 (2H, s), 7.05—
3.70—3.90 (2H, m), 6.97—7.10 (2H, m), 7.17—7.24 (2H, m), 7.34—7.60
(5H, m). Anal. Calcd for C27H34FN3O2·HCl·1.5H2O: C, 62.96; H, 7.44; N,
8.16. Found: C, 62.99; H, 7.44; N, 8.10.
(CDCl3) d 1.10—1.37 (2H, m), 1.37—1.88 (7H, m), 2.32 (3H, s), 2.21—
7.60 (14H, m). MS m/z: 524 (MHϩ). HPLC tR 3.57 min (97%).
N-[3-(4-Benzylpiperidin-1-yl)propyl]-5-oxo-N-phenyl-1-(2-phenyl-
ethyl)pyrrolidine-3-carboxamide (12j) Yield 59%, oil. 1H-NMR (CDCl3)
d 1.12—1.37 (2H, m), 1.38—1.90 (7H, m), 2.13—2.31 (3H, m), 2.51 (2H,
N-(3,4-Dichlorophenyl)-N-{3-[4-(4-fluorobenzyl)piperidin-1-yl]-
propyl}-1-methyl-5-oxopyrrolidine-3-carboxamide Hydrochloride (11b) d, Jϭ6.6 Hz), 2.61—2.85 (5H, m), 2.92—3.06 (2H, m), 3.44 (2H, t-like,
Yield 65%, amorphous solid. 1H-NMR (CD3OD) d 1.40—1.70 (2H, m), Jϭ7.4 Hz), 3.54—3.59 (1H, m), 3.69 (2H, t-like, Jϭ7.4 Hz), 7.07—7.44
1.70—2.10 (5H, m), 2.36 (1H, dd, Jϭ17.2, 9.8 Hz), 2.50—2.70 (3H, m),
2.78 (3H, s), 2.92 (2H, t-like, Jϭ12.0 Hz), 3.08—3.60 (4H, m), 3.50—3.70
(3H, m), 3.70—3.90 (2H, m), 7.02 (2H, t, Jϭ8.8 Hz), 7.17—7.24 (2H, m),
(15H, m). Anal. Calcd for C34H41N3O2: C, 77.98; H, 7.89; N, 8.02. Found: C,
77.78; H, 7.72; N, 7.85.
N-[3-(4-Benzylpiperidin-1-yl)propyl]-1-(furan-2-ylmethyl)-5-oxo-N-
7.35 (1H, dd, Jϭ8.4, 2.2 Hz), 7.68—7.72 (2H, m). Anal. Calcd for phenylpyrrolidine-3-carboxamide (12k) Yield 18%, oil. 1H-NMR
C27H32Cl2FN3O2·HCl·1.7H2O: C, 55.19; H, 6.24; N, 7.15. Found: C, 55.14; (CDCl3) d 1.15—1.33 (2H, m), 1.40—1.86 (7H, m), 2.19—2.31 (3H, m),
H, 6.27; N, 7.15.
2.50 (2H, d, Jϭ6.6 Hz), 2.68 (1H, t, Jϭ8.8 Hz), 2.81 (2H, br d, Jϭ11.4 Hz),
The following compounds 12a—m were prepared using a procedure simi- 2.92—3.10 (1H, m), 3.18 (1H, t, Jϭ8.8 Hz), 3.57—3.73 (3H, m), 4.31 (1H,
lar to that described for 10c from the acids 2b—n and the aniline 9a.
N-[3-(4-Benzylpiperidin-1-yl)propyl]-1-butyl-5-oxo-N-phenylpyrroli-
dine-3-carboxamide (12a) Yield 46%, oil. 1H-NMR (CDCl3) d 0.88 (3H,
t, Jϭ7.2 Hz), 1.05—1.90 (13H, m), 2.22 (1H, dd, Jϭ16.8, 8.8 Hz), 2.28 (2H,
t, Jϭ7.4 Hz), 2.50 (2H, d, Jϭ6.6 Hz), 2.66 (1H, dd, Jϭ16.8, 8.8 Hz), 2.75—
d, Jϭ15.4 Hz), 4.44 (1H, d, Jϭ15.4 Hz), 6.20—6.30 (2H, m), 7.10—7.50
(11H, m). MS m/z: 500 (MHϩ). HPLC tR 3.32 min (97%).
N-[3-(4-Benzylpiperidin-1-yl)propyl]-5-oxo-N-phenyl-1-(pyridin-4-yl-
methyl)pyrrolidine-3-carboxamide (12l) Yield 63%, oil. 1H-NMR
(CDCl3) d 1.00—1.86 (9H, m), 2.24—2.41 (3H, m), 2.50 (2H, d, Jϭ6.2 Hz),
2.90 (2H, m), 2.94—3.45 (4H, m), 3.62—3.75 (3H, m), 7.10—7.50 (10H, 2.70—2.90 (3H, m), 3.02—3.15 (2H, m), 3.50—3.74 (3H, m), 4.40 (2H, s),
m). Anal. Calcd for C30H41N3O2·0.5H2O: C, 74.34; H, 8.73; N, 8.67. Found:
C, 74.60; H, 8.77; N, 8.89.
N-[3-(4-Benzylpiperidin-1-yl)propyl]-1-cyclohexyl-5-oxo-N-phenyl-
7.05—7.50 (12H, m), 8.55 (2H, d, Jϭ5.8 Hz). Anal. Calcd for C32H38N4O2·
0.5H2O: C, 73.96; H, 7.56; N, 10.78. Found: C, 73.81; H, 7.39; N, 10.74.
N-[3-(4-Benzylpiperidin-1-yl)propyl]-1-(2,4-dimethoxybenzyl)-5-oxo-
pyrrolidine-3-carboxamide (12b) Yield 57%, oil. 1H-NMR (CDCl3) d N-phenylpyrrolidine-3-carboxamide (12m) Yield 62%, oil. 1H-NMR
1.00—1.86 (19H, m), 2.15—2.32 (3H, m), 2.50 (2H, d, Jϭ6.6 Hz), 2.58— (CDCl3) d 1.10—1.90 (9H, m), 2.15—2.35 (3H, m), 2.50 (2H, d, Jϭ6.6 Hz),
2.70 (1H, m), 2.67—3.06 (3H, m), 3.18 (1H, t, Jϭ9.0 Hz), 3.56—3.94 (4H, 2.60—3.20 (5H, m), 3.40—3.75 (3H, m), 3.78 (6H, s), 4.35 (2H, s), 6.35—

72
Vol. 52, No. 1
6.50 (2H, m), 7.00—7.50 (11H, m).
N-[3-(4-Benzylpiperidin-1-yl)propyl]-5-oxo-N-phenylpyrrolidine-3-
and various concentrations of the test compounds were added to the wells.
The cell suspension was incubated at 37 °C. The mixture of D-MEM and
carboxamide (13) Compound 12m (920 mg, 1.6 mmol) was dissolved in RPMI 1640 medium supplemented with 10% FBS, 100 U/ml penicillin, and
TFA (16 ml), and the mixture was stirred at 60 °C for 3 h. The mixture was 100 mg/ml streptomycin was used as medium for membrane fusion. After an
concentrated in vacuo, diluted with saturated aqueous NaHCO3, and ex- overnight incubation, Luc-Screen (Tropix) was added to each well, and the
tracted with EtOAc. The organic layer was dried (MgSO4), filtered, and con-
mixtures were incubated at room temperature for 10 min. The luciferase ac-
centrated in vacuo. The residue was purified by column chromatography on tivity was measured with a luminometer (Wallac 1420 ARVOsx).
alumina (EtOAc/MeOH 1/0 to 4/1) to afford 13 (566 mg, yield 84%) as a
white solid, mp 112—114 °C. 1H-NMR (CDCl3) d 1.10—1.33 (2H, m),
1.38—1.87 (7H, m), 2.08—2.32 (3H, m), 2.51 (2H, d, Jϭ6.6 Hz), 2.59—
Acknowledgments We would like to thank Mr. Kenichi Kuroshima for
CCR5 binding assay; Mr. Katsunori Takashima, Dr. Hiroshi Miyake, and
2.85 (3H, m), 3.09—3.28 (2H, m), 3.55—3.75 (3H, m), 5.42 (1H, br), Ms. Shikiko Shiki for membrane fusion assay; and Ms. Mika Murabayashi
7.10—7.49 (10H, m). Anal. Calcd for C26H33N3O2·0.1H2O: C, 74.11; H, for two-dimensional NMR measurement.
7.94; N, 9.97. Found: C, 74.02; H, 7.93; N, 10.00.
N-[3-(4-Benzylpiperidin-1-yl)propyl]-5-oxo-N-phenyl-1-(2,2,2-trifluo-
roethyl)pyrrolidine-3-carboxamide (14a) To an ice-cooled stirred solu-
tion of 13 (100 mg, 0.24 mmol) in DMF (1.5 ml) was added NaH (60% in
oil, 29 mg, 0.7 mmol), and the mixture was stirred at room temperature for
30 min. The mixture was treated with 2,2,2-trifluoroethyl triflate (172 ml,
1.2 mmol), stirred at room temperature for 1 h, and concentrated in vacuo.
The residue was diluted with 1 N NaOH and extracted with EtOAc. The or-
ganic layer was dried (MgSO4), filtered, and concentrated in vacuo. The
residue was purified by column chromatography on alumina (hexane/EtOAc
1/1 to 0/1) to afford 14a (36 mg, yield 30%) as a colorless oil. 1H-NMR
(CDCl3) d 1.15—1.35 (2H, m), 1.40—1.85 (7H, m), 2.22—2.36 (3H, m),
2.51 (2H, d, Jϭ6.2 Hz), 2.65—2.90 (3H, m), 3.03—3.20 (1H, m), 3.37 (1H,
t, Jϭ8.4 Hz), 3.60—3.80 (4H, m), 3.85—4.02 (1H, m), 7.10—7.30 (8H, m),
7.32—7.50 (2H, m). MS m/z: 502 (MHϩ). HPLC tR 3.34 min (99%).
N-[3-(4-Benzylpiperidin-1-yl)propyl]-1-(2-methylbenzyl)-5-oxo-N-
phenylpyrrolidine-3-carboxamide (14b) Compound 14b was prepared
using a procedure similar to that described for 14a from 2-methylbenzylbro-
mide. Yield 63%, oil. 1H-NMR (CDCl3) d 1.10—1.90 (9H, m), 2.25 (3H, s),
2.20—2.36 (3H, m), 2.50 (2H, d, Jϭ6.4 Hz), 2.67—2.85 (3H, m), 2.95—
3.10 (2H, m), 3.40—3.60 (1H, m), 3.67 (2H, t-like, Jϭ7.8 Hz), 4.40 (2H, s),
7.00—7.50 (14H, m). MS m/z: 524 (MHϩ). HPLC tR 3.53 min (99%).
The following compounds 15a, b were prepared using a procedure similar
to that described for 10c from the acid 2f and the anilines 9h, j.
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