Synthesis and evaluation of a series of novel 2-[(4- chlorophenoxy)methyl]benzimidazoles as selective neuropeptide Y Y1 receptor antagonists

Article abstract of DOI:10.1021/jm9706630

A series of novel benzimidazoles (BI) derived from the indole 2 was synthesized and evaluated as selective neuropeptide Y (NPY) Y1 receptor antagonists with the aim of developing antiobesity drugs. In our SAR approach, the (4-chlorophenoxy)methyl group at

Full text of DOI:10.1021/jm9706630

J . Med. Chem. 1998, 41, 2709-2719
2709
Syn th esis a n d Eva lu a tion of a Ser ies of Novel 2-[(4-Ch lor op h en oxy)m eth yl]-
ben zim id a zoles a s Selective Neu r op ep tid e Y Y1 Recep tor An ta gon ists
Hamideh Zarrinmayeh,* Anne M. Nunes, Paul L. Ornstein, Dennis M. Zimmerman, M. Brian Arnold,
Douglas A. Schober, Susan L. Gackenheimer, Robert F. Bruns, Philip A. Hipskind, Thomas C. Britton,
Buddy E. Cantrell, and Donald R. Gehlert
Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285
Received October 1, 1997
A series of novel benzimidazoles (BI) derived from the indole 2 was synthesized and evaluated
as selective neuropeptide Y (NPY) Y1 receptor antagonists with the aim of developing
antiobesity drugs. In our SAR approach, the (4-chlorophenoxy)methyl group at C-2 was kept
constant and a series of BIs substituted with various piperidinylalkyl groups at N-1 was
synthesized to identify the optimal spacing and orientation of the piperidine ring nitrogen
relative to the benzimidazole. The 3-(3-piperidinyl)propyl in 33 was found to maximize affinity
for the Y1 receptor. Because of the critical importance of Arg33 and Arg35 of NPY binding to
the Y1 receptor, the incorporation of an additional aminoalkyl functionality to the structure of
33 was explored. Methyl substitution was used to probe where substitution on the aromatic
ring was best tolerated. In this fashion, the C-4 was chosen for the substitution of the second
aminoalkyl functionality. Synthesis of such compounds with a phenoxy tether using the
4-hydroxybenzimidazole 11 was pursued because of their relative ease of synthesis. Func-
tionalization of the hydroxy group of 45 with a series of piperidinylalkyl groups provided the
dibasic benzimidazoles 55-62. Among them, BI 56 demonstrated a Ki of 0.0017 µM, which
was 400-fold more potent than 33. To evaluate if there was a stereoselective effect on affinity
for these BIs, the four constituent stereoisomers (69-72) of the BI 60 were prepared using the
S- and R-isomers of bromide 17. Antagonist activity of these BIs was confirmed by measuring
the ability of selected compounds to reverse NPY-induced forskolin-stimulated cyclic AMP.
The high selectivity of several BI antagonists for the Y1 versus Y2, Y4, and Y5 receptors was
also shown.
In tr od u ction
acterized Y1 antagonist and has proven to be a useful
tool for studying NPY receptors.25 However, because
of its limited potency and activity following systemic
administration, there is still a need to develop other
selective antagonist ligands for the Y1 receptor for use
as pharmacological probes and possibly as therapeutic
agents.
Neuropeptide Y (NPY) is a 36-amino-acid peptide that
was first isolated in 1982 from porcine brain.1 NPY
belongs to the pancreatic polypeptide (PP) family of
structurally related peptides and is known to be the
most abundant peptide in the central nervous system
of all the mammalian species studied to date.2 It is also
widely distributed throughout the peripheral nervous
system.3 NPY is believed to be involved in a broad
spectrum of brain functions, including food intake,4-6
blood pressure regulation,7,8 hormone secretion,9 sexual
behavior,10 and circadian rhythm.7 Chronic injection of
NPY in rats produces severe overeating, particularly of
carbohydrate and fat, that leads to the development of
obesity.6
Neuropeptide Y exerts its effect by interacting with
its receptor subtypes,11 which are distributed in both
peripheral and central tissues.12 At least six of these
receptor subtypes have been identified to date (Y1-Y6).
Until the recent discovery of the Y513,14 subtype, Y1 was
believed to be the best candidate for the feeding recep-
tor4,15 and, therefore, a target for developing antagonists
as a treatment for obesity.16-19
The discovery of other Y1 antagonists having peptide
and nonpeptide structures has been previously re-
ported.20-24 Compound 1 (BIBP3226) is the best char-
* To whom correspondence should be addressed. Tel.: (317) 276-
5964. Fax: (317) 276-5546. E-mail: Zarrinmayeh_Hamideh@Lilly.Com.
The genesis of this study was the discovery of indole
S0022-2623(97)00663-8 CCC: $15.00 © 1998 American Chemical Society
Published on Web 06/18/1998

2710 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 15
Zarrinmayeh et al.
Sch em e 1a
Ch a r t 1
a
Key: (a) (4-chlorophenoxy)acetonitrile, MeONa, MeOH, rt.
2 as a Y1 receptor ligand. Key features of this molecule
for binding to the Y1 receptor included an aminoalkyl
substituent at N-1 and a (4-chlorophenoxy)methyl sub-
stituent at C-2. Subsequent optimization of 2, per-
formed in conjunction with the research reported in this
account, afforded 3 with significantly higher Y1 receptor
affinity.26
To further expand the scope of the structure activity
studies related to 2, we chose to examine if other nuclei
could substitute for the indole nucleus in 2. We
postulated the benzimidazole (BI) as such a replacement
and recognized that a BI, while not isoelectronic to an
indole, is isosteric. Furthermore, BIs are readily pre-
pared, easily functionalized, and are often more stable
than indoles. In this paper, we describe the synthesis
of novel BIs and their characterization as Y1 antago-
nists. The structure-activity relationships of various
piperidinylalkyl groups at N-1 and the effect of a second
piperidinylalkyl group on the aromatic ring with a C-2,
(4-chlorophenoxy)methyl substituent were determined.
Scheme 1. On the basis of our SAR findings (vide infra),
for this aspect of the study we chose to use a (3-
piperidinyl)propyl group N-1-substituted BI. Alkylation
of 9 with 17 afforded a separable 3:1 mixture of the 4-
and 7-methyl compounds 37 and 38, respectively (favor-
ing the 4-methyl compound 37). Each gave the desired
BIs 40 and 41, respectively, after deprotection (Scheme
3). The structures of 40 and 41 were confirmed by NOE
spectroscopy. In MeOD4, 40 showed an NOE between
the methyl at C-4 (singlet at δ 2.65) and the proton at
C-5 (doublet at δ 7.36) and an NOE between the protons
on the methylene adjacent to N-1 (triplet at δ 4.61) and
the proton at C-7 (doublet at δ 7.61). Alkylation of 10
with 17 afforded an inseparable mixture of the 5- and
6-methyl compounds 39, which upon deprotection gave
BI 42, also as an inseparable mixture of regioisomers
(Scheme 3).
Substitution on the aromatic ring with a second
piperidinylalkyl group at C-4 was achieved by conver-
sion of 7 to the 4-hydroxy BI 11 (Scheme 1), which was
selectively O-benzylated under Mitsunobu conditions
(Ph3P, DEAD, THF, 0 °C to room temperature) to give
43 (Scheme 4). This selective protection strategy offered
us the opportunity to incorporate different aminoalkyl
groups at N-1 and C-4. Alkylation of 43 with 17 gave
44, which after hydrogenolysis of the benzyl group
yielded 45 (Scheme 4). Deprotection of 45 as before gave
46. As used for the alkylation at N-1, 45 was deproto-
nated with sodium hydride in dimethylformamide and
then reacted with 12-17, 19, and 20 to afford the
penultimate BIs 47-54, respectively. Solvolytic re-
moval of the N-BOC group as before then yielded the
desired N-1,C-4-dialkylated BIs 55-62, respectively
(Scheme 5).
BIs 55, 56, 61, and 62 are racemic, while 57-60 are
each mixtures of two racemic diastereomers. The four
constituent stereoisomers of the diaminoalkylated BI 60
were prepared using the S- and R-isomers of bromide
17. The requisite isomers of 17 were prepared in seven
steps from commercially available 3-pyridinecarboxal-
dehyde (63) as shown in Scheme 6. Horner-Emmons
reaction of 63 with the sodium salt of triethyl phospho-
noacetate gave pyridine 64, which afforded piperidine
65 after hydrogenation. Classical resolution of 65 by
salt formation with (S)-(+)- or (R)-(-)-mandelic acid
yielded (R)- or (S)-66, respectively. The Mandelic acid
salts (R)- or (S)-66 were then converted to the free
Ch em istr y
Our basic synthetic strategy involved preparing the
BI nuclei, followed by alkylation with the appropriate
piperidinylalkyl halide. To further define structural
requirements for activity at N-1, we prepared a variety
of BIs substituted with various piperidinylalkyl groups,
where the spacing and orientation of the piperidine ring
nitrogen relative to the benzimidazole were varied. The
parent BI 8 was prepared by condensation of phe-
nylenediamine (4) with (4-chlorophenoxy)acetonitrile, as
shown in Scheme 1. The requisite piperidinylalkyl
halides were either commercially available (12 and 13;
Chart 1) or were prepared according to published
procedures (14-20; Chart 1).27,28 Deprotonation of 8
(NaH, DMF, 80 °C) followed by alkylation with 12 and
13 afforded the desired BIs 21 and 22 (Scheme 2).
Alternatively, alkylation with the N-BOC-protected
bromides 14-20 afforded 23-29, which gave BIs 30-
36 after deprotection with trifluoroacetic acid in dichlo-
romethane (Scheme 2).
Our ultimate goal beyond N-1 substitution was to
incorporate a second aminoalkyl functionality in these
BIs to probe for other amine recognition domains on the
receptor. To identify the best place on the aromatic ring
to incorporate this group, we prepared BIs with a
methyl group at each of the four substitutable positions
on the aromatic ring. To this end, we prepared BIs 9
and 10 from the corresponding methyl-substituted phe-
nylenediamines 5 and 6, respectively, as shown in

Benzimidazoles NPY Y1 Receptor Antagonists
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 15 2711
Sch em e 2a
a
Key: (a) NaH, KI, DMF, 80 °C; (b) TFA, CH2Cl2, rt.
Sch em e 3a
a
Key: (a) NaH, KI, DMF, 80 °C; (b) TFA, CH2Cl2, rt.
amines (R)- or (S)-65, respectively. The enantiomeric
purity of the resulting free amines was determined by
conversion of either (R)- or (S)-65 to its corresponding
Mosher’s amide ((S)-(-)-R-methoxy-R-(trifluoromethyl)-
phenylacetyl chloride, Et3N, THF, 0 °C). Capillary GC29
analysis of the corresponding amides showed the optical
purity of each enantiomer to be greater than 99%. The
absolute configuration of (R)-66 was determined by an
X-ray crystallograph of this salt, wherein the known
configuration of mandelic acid could be used to deter-
mine the stereochemistry at C-3 of the piperidine.
Protection of the amine functionality with di-tert-butyl
dicarbonate gave the desired N-BOC piperidine (R)- or
(S)-67. Selective reduction of the ester moiety with
lithium aluminum hydride afforded the primary alcohol
(R)- or (S)-68, respectively, which was treated with
bromine and triphenylphosphine in dichloromethane to
afford the desired bromides (R)- or (S)-17, respectively.
Intermediate 45 was prepared in nonracemic form by
reacting 43 with either (R)- or (S)-17, as described in
Scheme 4. Each isomer of 45 was reacted with either
R- or S-17, as described in Scheme 5, to afford (S,S)-
69, (R,R)-70, (S,R)-71, and (R,S)-72 (Chart 2). The
convention we used to designate stereochemistry for
69-72 was that the first letter refers to the configura-
tion of the (3-piperidinyl)propyl group at N-1 and the
second letter refers to the configuration of the (3-
piperidinyl)propyl group at C-4.
P h a r m a cology
Affinity of the BIs for the Y1 receptor was determined
by measuring their ability to displace [125I]peptide YY
binding to cloned human Y1 receptors expressed in AV-
12 cells.30 These data are presented in Table 1 and are
expressed as Ki’s (µM). Affinity of some selected ana-
logues for human NPY Y2, Y4, and Y5 receptors
expressed in CHO cells was also determined using [125I]-
peptide YY binding (data not shown, all Ki’s > 1 µM).
In vitro functional activity of selected compounds was
determined by their ability to antagonize 1 nM NPYs
inhibition of forskolin-stimulated cyclic AMP accumula-
tion in SK-N-MC cells.31 Cyclic AMP was quantified

2712 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 15
Zarrinmayeh et al.
Sch em e 4a
a
Key: (a) PhCH2OH, Ph3P, DEAD, THF, rt; (b) NaH, KI, DMF, 80 °C; (c) H2, 5% Pd-C, EtOAc, rt; (d) TFA, CH2Cl2, rt.
Sch em e 5a
a
Key: (a) NaH, KI, DMF, 80 °C; (b) TFA, CH2Cl2, rt.
using either the Alvarez32 method or a radioimmune
assay (Amersham Corp). These data are also shown in
Table 1.
shown in Table 1, 1-piperidine linked to the BI 8 via
ethyl and propyl groups yielded compounds 21 and 22.
Compound 21 was essentially inactive, while 22 showed
a very low Y1 receptor affinity (Ki ) 7.02 µM). Move-
ment of the piperidine nitrogen to the 2 position using
an ethyl (30) or propyl (31) linker failed to substantially
increase receptor affinity. An increase in affinity was
observed when N-1 was substituted with 3-piperidine
through ethyl, propyl, and butyl spacers to generate 32-
34. Affinity was maximized with a propyl tether (33,
Ki ) 0.70 µM). To complete this aspect of our study,
compounds 35 and 36 were prepared that linked a
4-piperidine to the BI via ethyl and propyl groups. Both
compounds showed approximately 1 µM affinity at the
Y1 receptor. Among all of the above BIs, 33 with a 3-(3-
Resu lts a n d Discu ssion
Our initial objective in this SAR was to explore the
viability of the BI platform compared to indole for the
discovery of Y1 antagonists. Next, we wanted to define
the type of aminoalkyl substitution at N-1 that would
optimize affinity of these ligands at the Y1 receptor.
Following that, we hoped to increase affinity of these
compounds by the appropriate addition of a second
aminoalkyl substituent to the BI.
Among the other functionalities at N-1, piperidinyl
alkyl groups resulted in more potent compounds. As

Benzimidazoles NPY Y1 Receptor Antagonists
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 15 2713
Sch em e 6a
a
Key: (a) Et2O3PCH2CO2Et, NaH, THF, 0 °C to rt; (b) H2, Rh/Al2O3, EtOH, 60 psi, 60 °C; (c) (R)-(-)- or (S)-(+)-Mandelic Acid, EtOAc,
70 °C; (d) K2CO3, EtOAc, rt; (e) (BOC)2O, K2CO3, THF/H2O, rt; (f) LiAlH4, Et2O, rt; (g) Br2, PPh3, pyridine, CH2Cl2, 0 °C to rt.
Ta ble 1. In Vitro Binding Affinity of Benzimidazoles at the
NPY Y1 Receptor in AV-12 Cell Line. In Vitro Functional
Activity (cAMP) of Benzimidazole 55, 56, 58-62, and 69-72 in
SK-N-MC Cell Line
Ch a r t 2
Ki (µM)a-c
AV-12 human Y1
Ki (µM)c,d
SK-N-MC cells (cAMP)
compd
1 (BIBP 3226)
2
21
22
30
31
32
33
34
35
36
40
41
42
46
55
56
57
58
59
60
61
62
(S,S)-69
(R,R)-70
(R,S)-71
(S,R)-72
0.0046 ( 0.0003
2.31 ( 0.193
>100
0.011
7.02 ( 1.02
7.86 ( 0.12
3.23 ( 0.76
1.28 ( 0.11
0.70 ( 0.13
1.21 ( 0.06
0.94 ( 0.02
0.98 ( 0.02
0.097 ( 0.002
0.400 ( 0.10
1.29 ( 0.10
5.30 ( 0.25
0.043 ( 0.0013
0.0017 ( 0.000 03
0.029 ( 0.0016
0.016 ( 0.0002
0.018 ( 0.0001
0.030 ( 0.0003
0.007 ( 0.0003
0.152 ( 0.014
0.006 ( 0.0003
0.041 ( 0.003
0.027 ( 0.001
0.017 ( 0.0004
0.240
0.0027
0.053
0.091
0.077
0.015
0.119
0.087
0.153
0.137
0.065
piperidinyl)propyl substituent at N-1 demonstrated the
highest Y1 receptor affinity, and this compound was
chosen for subsequent SAR studies.
a
In vitro binding affinity in AV-12 cells is measured by the
b
method described in ref 30. Compounds 55, 56, 57, 58, 61, (S,S)-
To further increase Y1 receptor affinity, we took
advantage of the known SAR of NPY (the two C-
terminal arginines are vital for the high affinity of
NPY). We had hoped to mimic NPY’s interaction in the
BI series by incorporating an additional aminoalkyl
functionality. We incorporated a methyl group on the
aromatic ring as a probe to identify the best position to
substitute with an additional aminoalkyl group. To this
end, we prepared the methyl-substituted BIs 40-42.
The 4-methyl analogue 40 showed a 7-fold higher
affinity than the parent BI 33, while methyl substitution
at C-7, 41, gave only a 2-fold increase in affinity
69, (R,R)-70, (R,S)-71, and (S,R)-72 were tested at the Y2, Y4,
and Y5 receptors and had Ki values >1 µM. The method of assay
is described in ref 30. c Each number represents two measurement
(n ) 2). In vitro functional assay (cAMP) in SK-N-MC is
measured by the method described in refs 31 and 32.
d
compared to 33. Substitution at either C-5 or C-6
resulted in the less potent BI 42.
On the basis of the above observations, we chose to
probe for a second amine recognition domain with the
BIs through incorporation of aminoalkyl functionality
at C-4. We selected the use of oxygen as a link to the
aminoalkyl group because this appeared more opera-

2714 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 15
Zarrinmayeh et al.
tionally feasible. This strategy led to the synthesis of
the BIs 55-62. Among these new diaminoalkylated
BIs, 56 with a (1-piperidinyl)propyl substituent showed
the highest Y1 receptor affinity (Ki ) 0.0017 µM), while
its truncated ethyl analogue, 55, showed a lower affinity
(Ki ) 0.043 µM). The 2-piperidine linked BIs, 57 and
58, demonstrated equivalent affinity for the receptor
though significantly less than 56. The 3-piperidine
analogous 59 and 60 also had similar but lower affinity
than 56. On the other hand, the 4-piperidine BIs 61
and 62 showed very different Y1 receptor affinities, and
the ethyl-linked 4-piperidine analogue (61) demon-
strated a very high affinity of Ki ) 0.007 µM. The large
differences in the affinity of BIs 56 and 62 show the
importance of relative relationships of the two basic
nitrogens in the diaminoalkylated BIs.
F igu r e 1. Structures of indole 3 and benzimidazole 56.
Synthesis and evaluation of isomers (69-72) of 60
showed only limited stereoselectivity for binding of 60.
The most potent one, (S,S)-69, has a 7-fold higher
affinity than the mixtures of isomers, 60. Relative
affinity of the stereoisomers followed the order of S,S
> S,R > R,S > R,R. The fact that these stereoisomers
are not distinctly different may stem from a lack of
significant differentiation between the two piperidine
isomers. One could envision that each enantiomer could
interact with the amine recognition domain in the Y1
receptor in a similar fashion. In this process, each
enantiomer would occupy a similar area in space.
based antagonists interact with different binding domain
at the Y1 receptor.
Su m m a r y
A series of 2-[(4-chlorophenoxy)methyl]benzimidazoles
substituted at the N-1 and C-4 positions were prepared
and characterized as Y1 receptor antagonists. Substi-
tution at N-1 was optimized with a 3-(3-piperidinyl)-
propyl substituent, and the relative orientation of the
basic nitrogen and the BI nuclei was important for
receptor affinity. Introduction of a second aminoalkyl
functionality in the BI structure at C-4 and the relative
spatial relationships of the basic amines markedly
affected Y1 receptor affinity. The N-1, 3-(3-piperidinyl)-
propyl and C-4, [3-(1-piperidinyl)propyl]oxy 56 with
affinity of Ki ) 0.0017 µM represents a 1360-fold
increase in activity over the lead indole 2 with Ki ) 2.3
µM. The very high receptor affinity achieved with the
diamine-substituted BI and the observed SAR in this
series suggests that the amines in the BIs may be
binding similarly to the two C-terminal arginines of
NPY. The small differences in the binding affinity of
60 and its stereoisomers 69-72 showed only limited
stereoselectivity for binding of 60 to the Y1 receptor.
The BI antagonists discovered in this work, because of
their high affinities for the Y1 receptor, represent
important new tools for understanding activities medi-
ated through the Y1 receptor.
As shown in Table 1, benzimidazoles 55, 56, 58-62,
and 69-72 were evaluated in an assay for functional
activity at Y1 receptor. All demonstrated antagonist
activity at the Y1 receptor by reversing the NPY-
induced inhibition of forskolin-stimulated cAMP. The
differences between the binding and functional data
remain to be determined but may be due to the fact that
in the binding assay, affinity was measured under
equilibrium conditions; whereas in the functional assay,
the agonist (NPY) and antagonists were added at the
same time and incubated for only 15 min due to the
receptor desensitization with prolonged stimulation.
Selected Y1 antagonists such as 55-58, 61, and 69-
72 were tested for affinity to human Y2, Y4, and Y5
receptors expressed in CHO cells. These BIs showed
less than 30% inhibition of the binding of peptide YY
at a concentration of 1 µM at these receptors. Thus,
these compounds bind to the NPY Y1 receptor with high
selectivity.
Exp er im en ta l Section
Gen er a l Meth od s. Reagents used were the highest quality
available commercially. Reaction solvents were anhydrous.
All reactions were carried out under a positive pressure of dry
nitrogen. Temperatures refer to the temperature of the bath
into which the reaction vessel is immersed. Sodium hydride
refers to 60 wt % sodium hydride (Aldrich) that was washed
with hexane prior to use. All other solvents and reagents were
used as obtained. “Workup” refers to addition to the reaction
mixture of a neutral or basic aqueous solution, separation of
the organic layer, and then extraction of the aqueous layer n
times (×) with the indicated solvent. The combined organic
extracts were dried over Na2SO4, filtered, concentrated in a
vacuum, and purified as indicated. “Chromatography” refers
to flash chromatography on 230-400 mesh silica gel 60. The
reactions were generally monitored for completion using thin-
layer chromatography (TLC). Analytical gas chromatography
(GC) was performed on a Hewlett-Packard 5890 series 11 gas
chromatograph utilizing an Ultra 2 (cross-linked 5% PhMe
silicone) capillary column (25 m × 0.32 mm × 0.52 µm film
thickness). 1H NMR spectra were obtained on a GE QE-300
Hipskind et al. recently published a series of indole
NPY Y1 antagonists.26 They showed that the (4-
chlorophenoxy)methyl group was an optimal C-2 sub-
stituent on the indole nucleus for Y1 binding affinity.
This is consistent with what we have observed in the
BI series. As shown in Figure 1, 3-(3-piperidinyl)propyl
is also the optimal N-1 substituent for both BI 56 and
indole 3. On the basis of these two common structural
elements, we believe that the N-1 positions of each
series overlap with one another. However, while both
series require at least two basic amine functionalities
for high binding affinity at the Y1 receptor, the nature
of the second aminoalkyl group and its point of attach-
ment to the heteroaromatic ring system is distinctly
different, Figure 1. This may suggest that the ami-
noalkyl groups attached to the C-3 position of indole-
based NPY antagonists and the C-4 position of the BI-

Benzimidazoles NPY Y1 Receptor Antagonists
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 15 2715
or Brocker 300 spectrometer. Elemental analyses for carbon,
hydrogen, and nitrogen were determined on a Control Equip-
ment Corp. 440 elemental analyzer. The amount of solvent
present in the molecular formula was determined by 1H NMR
and microanalysis. Optical rotations were obtained using the
Perkin-Elmer 241 polarimeter and are reported at the sodium
D line (589). The enantiomers of each compound were pre-
pared using the same procedure as is described for the
racemate. Each enantiomer gave identical 1H NMR spectrum
as for the corresponding racemate.
2-[(4-Ch lor op h en oxy)m eth yl]ben zim id a zole (8). To a
room-temperature solution of (4-chlorophenoxy)acetonitrile (25
g, 149 mmol) in methanol (475 mL) was added sodium
methoxide (7.7 g, 143 mmol). After 1 h at room temperature,
the reaction mixture was treated with 1,2-diaminobenzene
dihydrochloride (25.9 g, 143 mmol). After 2 h at room
temperature, water (300 mL) was poured into the reaction
mixture. The precipitated product was isolated by filtration.
This material was dried in a vacuum at 30 °C overnight to
afford 35.2 g (91%) of 8 as a beige solid, mp 184-186 °C. Anal.
(C14H11ClN2O) C, H, N.
2-[(4-Ch lor op h e n oxy)m e t h yl]-4-m e t h ylb e n zim id a -
zole (9). To a room-temperature solution of (4-chlorophenoxy)-
acetonitrile (2.68 g, 16 mmol) in methanol (52 mL) was added
sodium methoxide (0.83 g, 15.4 mmol). After 30 min at room
temperature, the reaction mixture was treated with 2,3-
diaminotoluene dihydrochloride (3 g, 15.4 mmol). After 3 h
at room temperature, the solvent was removed under vacuum.
Workup: 2 × 30 mL of sodium bicarbonate/2 × 30 mL of
water/2 × 30 mL of dichloromethane. The combined organic
extract was condensed and dried in a vacuum at 30 °C
overnight to afford 4.1 g (97%) of 9 as a light brown solid. Anal.
(C15H13ClN2O) C, H, N.
2-[(4-Ch lor op h e n oxy)m e t h yl]-5-m e t h ylb e n zim id a -
zole (10). As for 9, 4.48 g (27.6 mmol) of (4-chlorophenoxy)-
acetonitrile and 1.39 g (25.6 mmol) of sodium methoxide in
dry methanol (270 mL) was treated with 5 g (25.6 mmol) of
3,4-diaminotoluene to afford 7 g (60%) of 10 as a beige solid.
Anal. (C15H13ClN2O) C, H, N.
1-[3-[N-(ter t-Bu tyloxyca r bon yl)-2-p ip er id in yl]p r op yl]-
2-[(4-ch lor op h en oxy)m eth yl]ben zim id a zole (24). As for
21, 200 mg (0.77 mmol) of 8, 38 mg (0.93 mmol) of sodium
hydride, 285 mg (0.93 mmol) of 3-[N-(tert-butyloxycarbonyl)-
2-piperidinyl]propyl bromide, and 26 mg (0.15 mmol) of
potassium iodide in dimethylformamide (3 mL) gave 203 mg
(54%) of 24 as a white solid. Anal. (C27H34ClN3O3) C, H, N.
1-[2-[N-(ter t-Bu tyloxyca r bon yl)-3-p ip er id in yl]eth yl]-2-
[(4-ch lor op h en oxy)m eth yl]ben zim id a zole (25). As for 21,
300 mg (1.16 mmol) of 8, 56 mg (1.39 mmol) of sodium hydride,
38 mg (0.23 mmol) of potassium iodide, and 406 mg (1.39
mmol) of 2-[N-(tert-butyloxycarbonyl)-3-piperidinyl]ethyl bro-
mide in dimethylformamide (5 mL) gave 409 mg (75%) of 25
as a white solid. Anal. (C26H32ClN3O3‚0.75H2O) C, H, N.
1-[3-[N-(ter t-Bu tyloxyca r bon yl)-3-p ip er id in yl]p r op yl]-
2-[(4-ch lor op h en oxy)m eth yl]ben zim id a zole (26). As for
21, 300 mg (1.16 mmol) of 8, 56 mg (1.39 mmol) of sodium
hydride, 38 mg (0.23 mmol) of potassium iodide, and 425 mg
(1.39 mmol) of 3-[N-(tert-butyloxycarbonyl)-3-piperidinyl]pro-
pyl bromide in dimethylformamide (5 mL) gave 444 mg (79%)
of 26 as a white solid, mp 101-103 °C. Anal. (C27H34ClN3O3)
C, H, N.
1-[4-[N-(ter t-Bu tyloxyca r bon yl)-3-p ip er id in yl]bu tyl]-2-
[(4-ch lor op h en oxy)m eth yl]ben zim id a zole (27). As for 21,
100 mg (0.39 mmol) of 8, 18.5 mg (0.46 mmol) of sodium
hydride, 13 mg (0.08 mmol) of potassium iodide, and 214.5 mg
(0.46 mmol) of 4-[N-(tert-butyloxycarbonyl)-3-piperidinyl]butyl
bromide in dimethylformamide (2 mL) gave 248 mg (99%) of
27 as a white solid. Anal. (C28H36ClN3O3) C, H, N.
1-[2-[N-(ter t-Bu tyloxyca r bon yl)-4-p ip er id in yl]eth yl]-2-
[4-ch lor op h en oxy)m eth yl]ben zim id a zole (28). As for 21,
400 mg (1.55 mmol) of 8, 74 mg (1.85 mmol) of sodium hydride,
51 mg (0.31 mmol) of potassium iodide, and 540 mg (1.85
mmol) of 2-[N-(tert-butyloxycarbonyl)-4-piperidinyl]ethyl bro-
mide in dimethylformamide (6 mL) gave 633 mg (87%) of 28
as a white solid, mp 98-100 °C. Anal. (C26H32ClN3O3) C, H,
N.
1-[3-[N-(ter t-Bu tyloxyca r bon yl)-4-p ip er id in yl]p r op yl]-
2-[(4-ch lor op h en oxy)m eth yl]ben zim id a zole (29). As for
21, 200 mg (0.77 mmol) of 8, 38 mg (0.93 mmol) of sodium
hydride, 26 mg (0.15 mmol) of potassium iodide, and 285 mg
(1.39 mmol) 3-[N-(tert-butyloxycarbonyl)-4-piperidinyl]propyl
bromide in dimethylformamide (3 mL) gave 357 mg (96%) of
29 as a white solid. Anal. (C27H34ClN3O3‚0.5H2O) C, H, N.
2-[(4-Ch lor op h en oxy)m et h yl]-4-h yd r oxyb en zim id a -
zole (11). As for 9, 1 g (6 mmol) of (4-chlorophenoxy)-
acetonitrile and 0.31 g (5.7 mmol) of sodium methoxide in dry
methanol (20 mL) was treated with 1.13 g (5.7 mmol) of 2,3-
diaminophenol to afford 1.42 of 11 as a white solid. Anal.
(C14H11ClN2O2) C, H, N.
1-[2-(2-P i p e r i d i n y l)e t h y l]-2-[(4-c h lo r o p h e n o x y )-
m eth yl]ben zim id a zole Tr iflu or oa ceta te (30). A room-
temperature solution of 23 (200 mg, 0.42 mmol) in dichlo-
romethane (2 mL) was treated with trifluoroacetic acid (2 mL).
After 1 h at room temperature, the reaction mixture was
concentrated. Workup: 2 × 5 mL of water/3 × 5 mL of ether.
The combined aqueous layer was dried under the freeze-dry
system to afford 206 mg (93%) of 30 as a white solid, mp 146-
147.5 °C. Anal. (C23H25ClF3N3O3‚0.75H2O) C, H, N.
1-[3-(2-P ip er id in yl)p r op yl]-2-[(4-ch lor op h en oxy)m eth -
yl]ben zim id a zole Tr iflu or oa ceta te (31). As for 30, 200 mg
(0.41 mmol) of 24 and trifluoroacetic acid (2 mL) in dichlo-
romethane (2 mL) gave 180 mg (88%) of 31 as a white solid.
Anal. (C24H27ClF3N3O3) C, H, N.
1-[2-(3-P i p e r i d i n y l)e t h y l]-2-[(4-c h lo r o p h e n o x y )-
m eth yl]ben zim id a zole Tr iflu or oa ceta te (32). As for 30,
200 mg (0.42 mmol) of 25 and trifluoroacetic acid (2 mL) in
dichloromethane (2 mL) gave 190 mg (92%) of 32 as a white
solid, mp 141-143 °C. Anal. (C23H25ClF3N3O3) C, H, N.
1-[3-(3-P ip er id in yl)p r op yl]-2-[(4-ch lor op h en oxy)m eth -
yl]ben zim id a zole Tr iflu or oa ceta te (33). As for 30, 200 mg
(0.41 mmol) of 26 and trifluoroacetic acid (2 mL) in dichlo-
romethane (2 mL) gave 198 mg (96%) of 33 as a white solid.
Anal. (C24H27ClF3N3O3) C, H, N.
1-[2-(1-P i p e r i d i n y l)e t h y l]-2-[(4-c h lo r o p h e n o x y )-
m eth yl]ben zim id a zole (21). To a solution of 8 (500 mg, 2.04
mmol) in dimethylformamide (10 mL) was added sodium
hydride (98 mg, 2.4 mmol). After 30 min at room temperature,
the reaction mixture was treated with the hydrochloride salt
of the 2-(1-piperidinyl)ethyl chloride (442 mg 2.4 mmol),
potassium carbonate (422 mg, 3.06 mmol), and potassium
iodide (68 mg, 0.41 mmol). The reaction mixture was heated
to 80 °C for 3 h. The mixture was cooled to room temperature.
Workup: 3 × 20 mL of water/2 × 20 mL of ether. The
combined organic layer was dried, concentrated, and subjected
to chromatography (0:30:70%-5:35:60% triethylamine/ethyl
acetate/hexanes two-step gradient) to afford 543.3 mg (72%)
of 21 as a white solid. Anal. (C21H24ClN3O) C, H, N.
1-[3-(1-P ip er id in yl)p r op yl]-2-[(4-ch lor op h en oxy)m eth -
yl]ben zim id a zole (22). As for 21, 300 mg (1.16 mmol) of 8,
56 mg (1.39 mmol) of sodium hydride, 275 mg (1.39 mmol) of
the hydrochloride salt of the 3-(1-piperidinyl)propyl chloride,
240 mg (1.74 mmol) of potassium carbonate, and 38 mg (0.23
mmol) of potassium iodide in dimethylformamide (5 mL) gave
232 mg (52%) of 22 as
ClN3O‚0.25H2O) C, H, N.
a white solid. Anal. (C22H26-
1-[2-[N-(ter t-Bu tyloxyca r bon yl)-2-p ip er id in yl]eth yl]-2-
[(4-ch lor op h en oxy)m eth yl]ben zim id a zole (23). As for 21,
200 mg (0.97 mmol) of 8, 46 mg (1.19 mmol) of sodium hydride,
339 mg (1.16 mmol) 2-[N-tert-butyloxycarbonyl)-2-piperidinyl]-
ethyl bromide, and 32 mg (0.19 mmol) of potassium iodide in
dimethylformamide (5 mL) gave 394.2 mg (86%) of 23 as a
white solid, mp 135-136 °C. Anal. (C26H32ClN3O3) C, H, N.
1-[4-(3-P i p e r i d i n y l)b u t y l]-2-[(4-c h lo r o p h e n o x y )
m eth yl]ben zim id a zole Tr iflu or oa ceta te (34). As for 30,
130 mg (0.2 mmol) of 27 and trifluoroacetic acid (2 mL) in
dichloromethane (1.5 mL) gave 98 mg (94%) of 34 as a white
solid. Anal. (C25H29ClF3N3O3) C, H, N.

2716 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 15
Zarrinmayeh et al.
1-[2-(4-P ip er id in yl)eth yl]-2-[(4-ch lor op h en oxy)m eth yl-
]ben zim id a zole Tr iflu or oa ceta te (35). As for 30, 200 mg
(0.42 mmol) of 28 and trifluoroacetic acid (2 mL) in dichlo-
romethane (2 mL) gave 190 mg (92%) of 35 as a white solid,
mp 155-157 °C. Anal. (C25H26ClF6N3O5) C, H, N.
1-[3-(4-P ip er id in yl)p r op yl]-2-[(4-ch lor op h en oxy)m eth -
yl]ben zim id a zole Tr iflu or oa ceta te (36). As for 30, 350 mg
(0.72 mmol) of 29 and trifluoroacetic acid (3 mL) in dichlo-
romethane (3 mL) gave 354 mg (98%) of 36 as a white solid,
mp 161-163 °C. Anal. (C24H27ClF3N3O3) C, H, N.
1-[3-[N-(ter t-Bu tyloxyca r bon yl)-3-p ip er id in yl]p r op yl]-
2-[(4-ch lor oph en oxy)m eth yl]-4-m eth ylben zim idazole an d
1-[3-[N-(ter t-bu tyloxyca r bon yl)-3-p ip er id in yl]p r op yl]-2-
[(4-ch lor op h en oxy)m et h yl]-7-m et h ylben zim id a zole (37
a n d 38). As for 21, 200 mg (0.73 mmol) of 9, 35 mg (0.9 mmol)
of sodium hydride, 275 mg (0.9 mmol) of 3-[N-(tert-butyloxy-
carbonyl)-3-piperidinyl]propyl bromide, and 24 mg (0.14 mmol)
of potassium iodide in dimethylformamide (3 mL) gave 199
mg (55%) of 37 (Anal. (C28H36ClN3O3‚H2O) C, H, N) and 66
mg (18%) of 38, both as white solids. Anal. (C28H36ClN3O3)
C, H, N.
1-[3-[N-(ter t-Bu tyloxyca r bon yl)-3-p ip er id in yl]p r op yl]-
2-[(4-ch lor op h en oxy)m et h yl]-5/6-m et h ylb en zim id a zole
(39). As for 21, 200 mg (0.73 mmol) of 10, 35 mg (0.9 mmol)
of sodium hydride, 275 mg (0.9 mmol) of 3-[N-(tert-butyloxy-
carbonyl)-3-piperidinyl]propyl bromide, and 24 mg (0.14 mmol)
of potassium iodide in dimethylformamide (3 mL) gave 132
mg (36%) of 39 as a 1:1 mixture of inseparable regioisomers.
Anal. (C28H36ClN3O3) C, H, N.
1-[3-(3-P ip er id in yl)p r op yl]-2-[(4-ch lor op h en oxy)m e-
th yl]-4-m eth ylben zim id a zole Tr iflu or oa ceta te (40). As
for 30, 900 mg (1.81 mmol) of 37 and trifluoroacetic acid (5
mL) in dichloromethane (5 mL) gave 859 mg (93%) of 40 as a
beige solid. Anal. (C25H29ClF3N3O3) C, H, N.
1-[3-(3-P ip er id in yl)p r op yl]-2-[(4-ch lor op h en oxy)m e-
th yl]-7-m eth ylben zim id a zole Tr iflu or oa ceta te (41). As
for 30, 50 mg (0.1 mmol) of 38 and trifluoroacetic acid (1 mL)
in dichloromethane (1 mL) gave 28 mg (54%) of 41 as a beige
solid. Anal. (C25H29ClF3N3O3‚1.5H2O) C, H, N.
1-[3-(3-P ip er id in yl)p r op yl]-2-[(4-ch lor op h en oxy)m e-
th yl]-5/6-m eth ylben zim id a zole Tr iflu or oa ceta te (42). As
for 30, 120 mg (0.24 mmol) of 39 and trifluoroacetic acid (2
mL) in dichloromethane (2 mL) gave 125 mg (100%) of 42 as
a beige solid. Anal. (C27H30ClF6N3O5) C, H, N.
2-[(4-Ch lor op h en oxy)m et h yl]-4-(b en zyloxy)b en zim i-
d a zole (43). To a room-temperature solution of 11 (500 mg,
1.8 mmol) and triphenylphosphine (572 mg, 2.2 mmol) in
tetrahydrofuran (18 mL) were added benzyl alcohol (236 mg,
2.2 mmol) and diethyl azodicarboxylate (380 mg, 2.2 mmol).
After 6 h at room temperature, the solvent was removed under
vacuum. Workup (3 × 20 mL water/3 × 20 mL ethyl acetate)
and chromatography (0-40% ethyl acetate/hexanes four-step
gradient) afforded 351 mg (53%) of the product 43 as a white
solid. Anal. (C21H17ClN2O2) C, H, N.
1-[3(S)-[N-(ter t-Bu tyloxyca r bon yl)-3-p ip er id in yl]p r o-
p yl]-2-[(4-ch lor op h en oxy)m eth yl]-4-h yd r oxyben zim id a -
zole ((S)-(-)-45): 93% yield; [R]D ) -11° (c ) 1, CH2Cl2). Anal.
(C27H34ClN3O4) C, H, N.
1-[3(R)-[N-(ter t-Bu tyloxyca r bon yl)-3-p ip er id in yl]p r o-
p yl]-2-[(4-ch lor op h en oxy)m eth yl]-4-h yd r oxyben zim id a -
zole ((R)-(+)-45): 74% yield; [R]D ) +11° (c ) 1, CH2Cl2).
Anal. (C27H34ClN3O4) C, H, N.
1-[3-(3-P ip er id in yl)p r op yl]-2-[(4-ch lor op h en oxy)m e-
th yl]-4-h yd r oxyben zim id a zole Tr iflu or oa ceta te (46). As
for 30, 250 mg (0.5 mmol) of 45 and trifluoroacetic acid (2 mL)
in dichloromethane (3 mL) gave 194 mg (75%) of 46 as a
colorless semisolid material. Anal. (C24H27ClF3N3O4) C, H,
N.
1-[3-[N-(ter t-Bu tyloxyca r bon yl)-3-p ip er id in yl]p r op yl]-
2-[(4-ch lor op h en oxy)m eth yl]-4-[[2-(1-p ip er id in yl)eth yl]-
oxy]ben zim id a zole (47). A room-temperature solution of 45
(100 mg, 0.2 mmol) in dimethylformamide (2 mL) was treated
with sodium hydride (10 mg, 0.24 mmol). After 30 min at room
temperature, the reaction mixture was treated with the
hydrochloride salt of the 2-(1-piperidinyl)ethyl chloride (44 mg,
0.24 mmol), potassium carbonate (41 mg, 0.3 mmol), and
potassium iodide (7 mg, 0.04 mmol). The reaction mixture was
heated at 80 °C for 3 h. The mixture was cooled to room
temperature. Workup: 3 × 10 mL of water/2 × 10 mL of ether.
The combined organic layer was dried, concentrated, and
subjected to chromatography (0:40:60%-10:40:50% triethy-
lamine/ethyl acetate/hexanes two-step gradient) to afford 109
mg (89%) of 47 as a white semisolid. Anal. (C34H47ClN4O4‚
1.5H2O) C, H, N.
1-[3-[N-(ter t-Bu tyloxyca r bon yl)-3-p ip er id in yl]p r op yl]-
2-[(4-ch lor oph en oxy)m eth yl]-4-[[3-(1-piper idin yl)pr opyl]-
oxy]ben zim id a zole (48). As for 47, 100 mg (0.2 mmol) of
45, 10 mg (0.24 mmol) of sodium hydride, 47 mg (0.24 mmol)
of hydrochloride salt of the 3-(1-piperidinyl)propyl chloride, 41
mg (0.3 mmol) of potassium carbonate, and 7 mg (0.04 mmol)
potassium iodide in dimethylformamide (2 mL) gave 101 mg
(76%) of 48 as a colorless semisolid material. Anal. (C35H49
ClN4O4‚2H2O) C, H, N.
-
1-[3-[N-(ter t-Bu tyloxyca r bon yl)-3-p ip er id in yl]p r op yl]-
2-[(4-ch lor op h en oxy)m eth yl]-4-[[2-[N-(ter t-bu tyloxyca r -
b on yl)-2-p ip er id in yl]et h yl]oxy]b en zim id a zole (49). As
for 47, 100 mg (0.2 mmol) of 45, 10 mg (0.24 mmol) of sodium
hydride, 70 mg (0.24 mmol) of 2-[N-(tert-butyloxycarbonyl)-2-
piperidinyl]ethyl bromide, and 7 mg (0.04 mmol) of potassium
iodide in dimethylformamide (2 mL) gave 108 mg (76%) of 49
as a colorless semisolid material. Anal. (C39H55ClN4O6) C, H,
N.
1-[3-[N-(ter t-Bu tyloxyca r bon yl)-3-p ip er id in yl]p r op yl]-
2-[(4-ch lor op h en oxy)m eth yl]-4-[[3-(N-(ter t-bu tyloxyca r -
bon yl)-2-p ip er id in yl]p r op yl]oxy]ben zim id a zole (50). As
for 47, 100 mg (0.2 mmol) of 45, 10 mg (0.24 mmol) of sodium
hydride, 74 mg (0.24 mmol) of 3-[N-(tert-butyloxycarbonyl)-2-
piperidinyl]propyl bromide, and 7 mg (0.04 mmol) of potassium
iodide in dimethylformamide (2 mL) gave 132 mg (91%) of 50
as a colorless semisolid material. Anal. (C40H57ClN4O6) C, H,
N.
1-[3-[N-(ter t-Bu tyloxyca r bon yl)-3-p ip er id in yl]p r op yl]-
2-[(4-ch lor op h en oxy)m et h yl]-4-(b en zyloxy)b en zim id a -
zole (44). As for 21, 350 mg (0.96 mmol) of 43, 46 mg (1.1
mmol) of sodium hydride, 32 mg (0.19 mmol) of potassium
iodide, and 352 mg (1.1 mmol) of 3-[N-(tert-butyloxycarbonyl)-
3-piperidinyl]propyl bromide in dimethylformamide (4 mL)
1-[3-[N-(ter t-Bu tyloxyca r bon yl)-3-p ip er id in yl]p r op yl]-
2-[(4-ch lor op h en oxy)m eth yl]-4-[[2-[N-(ter t-bu tyloxyca r -
b on yl)-3-p ip er id in yl]et h yl]oxy]b en zim id a zole (51). As
for 47, 75 mg (0.15 mmol) of 45, 8 mg (0.18 mmol) of sodium
hydride, 53 mg (0.18 mmol) of 2-[N-(tert-butyloxycarbonyl)-3-
piperidinyl]ethyl bromide, and 7 mg (0.04 mmol) of potassium
iodide in dimethylformamide (2 mL) gave 32 mg (80%) of 51
as a colorless semisolid material. Anal. (C39H55ClN4O6) C, H,
N.
gave 250 mg (44%) of 44 as a white solid. Anal. (C34H40
-
ClN3O4) C, H, N.
1-[3-[N-(ter t-Bu tyloxyca r bon yl)-3-p ip er id in yl]p r op yl]-
2-[(4-ch lor op h en oxy)m et h yl]-4-h yd r oxyb en zim id a zole
(45). A room-temperature solution of 44 (245 mg, 0.42 mmol)
in dry ethyl acetate (5 mL) was degassed and then was treated
with 5% Pd-C (245 mg). The reaction was stirred at room
temperature under an atmospheric pressure of hydrogen for
2 h. The reaction was filtered through a layer of Celite cake,
and the catalyst was washed with warm ethyl acetate (3 × 10
mL). The filtrate was condensed under vacuum to provide 165
mg (78%) of the pure product 45 as a white solid. Anal.
(C27H34ClN3O4) C, H, N.
1-[3-[N-(ter t-Bu tyloxyca r bon yl)-3-p ip er id in yl]p r op yl]-
2-[(4-ch lor op h en oxy)m eth yl]-4-[[3-[N-(ter t-bu tyloxyca r -
bon yl)-3-p ip er id in yl]p r op yl]oxy]ben zim id a zole (52). As
for 47, 500 mg (1.8 mmol) of 11, 160 mg (4 mmol) of sodium
hydride, 1220 mg (4 mmol) of 3-[N-(tert-butyloxycarbonyl)-3-
piperidinyl]propyl bromide, and 115 mg (0.72 mmol) of potas-

Benzimidazoles NPY Y1 Receptor Antagonists
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 15 2717
sium iodide in dimethylformamide (8 mL) gave 880 mg (67%)
of 52 as a colorless semisolid material. Anal. (C40H57ClN4O6)
C, H, N.
of 50 and trifluoroacetic acid (1.5 mL) in dichloromethane (1.5
mL) gave 71 mg (85%) of 58 as a semisolid material. Anal.
(C34H43ClF6N4O6‚0.75H2O) C, H, N.
(S,S)-1-[3(S)-[N-(ter t-Bu tyloxyca r bon yl)-3-p ip er id in yl]-
p r op yl]-2-[(4-ch lor op h en oxy)m eth yl]-4-[[3(S)-[N-(ter t-bu -
t yloxyca r b on yl)-3-p ip er id in yl]p r op yl]oxy]b en zim id a -
zole ((S,S)-52). As for 47, 200 mg (0.73 mmol) of 11, 64 mg
(1.6 mmol) of sodium hydride, and 490 mg (1.6 mmol) of 3(S)-
[N-(tert-butyloxycarbonyl)-3-piperidinyl]propyl bromide in di-
methylformamide (3 mL) gave 248 mg (47%) of (S,S)-52 as a
colorless semisolid material. Anal. (C40H57ClN4O6‚0.5H2O) C,
H, N.
Bis([-[3-(3-P ip er id in yl)p r op yl]-2-[(4-ch lor op h en oxy)-
m eth yl]-4-[[2-(3-piper idin yl)eth yl]oxy]ben zim idazole] Tr i-
flu or oa ceta te (59). As for 30, 30 mg (0.04 mmol) of 51 and
trifluoroacetic acid (0.5 mL) in dichloromethane (1 mL) gave
31 mg (100%) of 59 as a semisolid material. Anal. (C33H41
-
ClF6N4O6) C, H, N.
Bis[1-[3-(3-P ip er id in yl)p r op yl]-2-[(4-ch lor op h en oxy)-
m e t h y l]-4-[[3-(3-p ip e r id in y l)p r o p y l]o x y ]b e n zim id a -
zole] Tr iflu or oa ceta te (60). As for 30, 860 mg (1.2 mmol)
of 52 and trifluoroacetic acid (5 mL) in dichloromethane (5 mL)
gave 893 mg (100%) of 60 as a semisolid material. Anal.
(C34H43ClF6N4O6) C, H, N.
Tr is[1-[3-(3-P ip er id in yl)p r op yl]-2-[4-ch lor op h en oxy)-
m eth yl]-4-[[2-(4-piper idin yl)eth yl]oxy]ben zim idazole] Tr i-
flu or oa ceta te (61). As for 30, 100 mg (0.14 mmol) of 53 and
trifluoroacetic acid (2 mL) in dichloromethane (2 mL) gave 108
(R ,R )-1-[3(R )-[N -(t er t -Bu t yloxyca r b on yl)-3-p ip e r i-
d in yl]p r op yl]-2-[(4-ch lor op h en oxy)m et h yl]-4-[[3(R)-[N-
(ter t-bu tyloxyca r bon yl)-3-p ip er id in yl]p r op yl]oxy]ben z-
im id a zole ((R,R)-52). As for 47, 200 mg (0.73 mmol) of 11,
64 mg (1.6 mmol) of sodium hydride, and 490 mg (1.6 mmol)
of 3(R)-[N-(tert-butyloxycarbonyl)-3-piperidinyl]propyl bromide
in dimethylformamide (3 mL) gave 300 mg (57%) of (R,R)-52
as a semisolid material. Anal. (C40H57ClN4O6) C, H, N.
(S,R)-1-[3(S)-[N-(ter t-Bu tyloxyca r bon yl)-3-p ip er id in yl]-
p r op yl]-2-[(4-ch lor op h en oxy)m et h yl]-4-[[3(R)-[N-(ter t-
bu tyloxyca r bon yl)-3-p ip er id in yl]p r op yl]oxy]ben zim id a -
zole ((S,R)-52). As for 47, 200 mg (0.40 mmol) of (S)-45, 19
mg (0.48 mmol) of sodium hydride, and 147 mg (0.48 mmol)
of 3(R)-[N-(tert-butyloxycarbonyl)-3-piperidinyl]propyl bromide
in dimethylformamide (2 mL) gave 200 mg (69%) of (S,R)-52
as a semisolid material. Anal. (C40H57ClN4O6‚2H2O) C, H, N.
(R ,S )-1-[3(R )-[N -(t er t -B u t y lo x y c a r b o n y l)-3-p ip e r i-
d in yl]p r op yl]-2-[(4-ch lor op h en oxy)m et h yl]-4-[[3(S)-[N-
(ter t-bu tyloxyca r bon yl)-3-p ip er id in yl]p r op yl]oxy]ben z-
im id a zole ((R,S)-52). As for 47, 75 mg (0.15 mmol) of (R)-
45, 7 mg (0.18 mmol) of sodium hydride, and 55 mg (0.18
mmol) of 3(S)-[N-(tert-butyloxycarbonyl)-3-piperidinyl]propyl
bromide in dimethylformamide (1 mL) gave 96 mg (88%) of
(R,S)-52 as a semisolid material. Anal. (C40H57ClN4O6) C, H,
N.
1-[3-[N-(ter t-Bu tyloxyca r bon yl)-3-p ip er id in yl]p r op yl]-
2-[(4-ch lor op h en oxy)m eth yl]-4-[[2-[N-(ter t-bu tyloxyca r -
b on yl)-4-p ip er id in yl]et h yl]oxy]b en zim id a zole (53). As
for 47, 100 mg (0.2 mmol) of 45, 10 mg (0.24 mmol) of sodium
hydride, 70 mg (0.24 mmol) of 2-[N-(tert-butyloxycarbonyl)-4-
piperidinyl]ethyl bromide, and 7 mg (0.04 mmol) of potassium
iodide in dimethylformamide (2 mL) gave 128 mg (90%) of 53
as a semisolid material. Anal. (C39H55ClN4O6) C, H, N.
1-[3-[N-(ter t-Bu tyloxyca r bon yl)-3-p ip er id in yl]p r op yl]-
2-[(4-ch lor op h en oxy)m eth yl]-4-[[3-[N-(ter t-bu tyloxyca r -
bon yl)-4-p ip er id in yl]p r op yl]oxy]ben zim id a zole (54). As
for 47, 75 mg (0.15 mmol) of 45, 8 mg (0.18 mmol) of sodium
hydride, 55 mg (0.18 mmol) of 3-[N-(tert-butyloxycarbonyl)-4-
piperidinyl]propyl bromide, and 7 mg (0.04 mmol) of potassium
iodide in dimethylformamide (2 mL) gave 100 mg (92%) of 54
as a semisolid material. Anal. (C40H57ClN4O6) C, H, N.
Tr is[1-[3-(3-P ip er id in yl)p r op yl]-2-[(4-ch lor op h en oxy)-
m eth yl]-4-[[2-(1-piper idin yl)eth yl]oxy]ben zim idazole] Tr i-
flu or oa ceta te (55). As for 30, 100 mg (0.14 mmol) of 47 and
trifluoroacetic acid (2 mL) in dichloromethane (2 mL) gave 129
mg (91%) of 61 as a semisolid material. Anal. (C35H42
-
ClF9N4O8) C, H, N.
Bis[1-[3-(3-P ip er id in yl)p r op yl]-2-[(4-ch lor op h en oxy)-
m e t h y l]-4-[[3-(4-p ip e r id in y l)p r o p y l]o x y ]b e n zim id a -
zole] Tr iflu or oa ceta te (62). As for 30, 95 mg (0.13 mmol)
of 54 and trifluoroacetic acid (2 mL) in dichloromethane (2 mL)
gave 76 mg (77%) of 62 as a semisolid material. Anal. (C34H43
-
ClF6N4O6) C, H, N.
3-P yr id ylp r op en oic Acid Eth yl Ester (64). A solution
of triethyl phosphonoacetate (100 g, 446 mmol) in tetrahydro-
furan (500 mL) at 0 °C was treated with sodium hydride (17.4
g, 436 mmol) and stirred for 0.5 h. After being stirred for an
additional 1 h at room temperature, this solution was cooled
to 0 °C again and was treated with a solution of 3-pyridin-
ecarboxaldehyde 63 (39 g, 363 mmol) in tetrahydrofuran (500
mL) gradually. After the reaction mixture was stirred at 0
°C for 3 h, it was allowed to warm to room temperature and
stirred for an additional 6 h. Workup: 3 × 500 mL of water/2
× 500 mL of ethyl acetate. The combined organic layer was
dried, concentrated, and subjected to chromatography (10-
30% ethyl acetate/hexanes three-step gradient) to afford 62.5
g (97%) of the pure product 64.
3-(3-P ip er id in yl)p r op ion ic Acid Eth yl Ester (65).
A
solution of 64 (68 g, 379 mmol) in ethanol (500 mL) was treated
with 5% rhodium on aluminum oxide (25 g). The mixture was
kept under 60 psi of hydrogen at 60 °C for 12 h. The mixture
was filtered through a layer of Celite. The filtrate was
concentrated and subjected to chromatography (0-5% methanol/
dichloromethane five-step gradient) to afford 60.7 g (87%) of
the pure product 65.
3(R)-(3-P ip er id in yl)p r op ion ic Acid Eth yl Ester Ma n -
d elic Acid Sa lt ((R)-(+)-66). A solution of 65 (52 g, 281
mmol) in warm ethyl acetate (300 mL) was added to a solution
of (S)-(+)-mandelic acid (42.7 g, 281 mmol) in warm ethyl
acetate (300 mL). The mixture was mixed by stirring for 10
min. It was left at room temperature for 24 h. The resulting
crystals were filtered, dried, and recrystallized again with
ethyl acetate (300 mL). After 12 h, the salt crystals were
filtered and subsequently dried to afford 47.4 g (50%) of very
pure salt (R)-(+)-66 as white crystals, [R]D ) +51.6° (c ) 1,
CH2Cl2).
3(S)-(3-P ip er id in yl)p r op ion ic Acid Eth yl Ester Ma n -
d elic a cid ((S)-(-)-66). A solution of 65 (27 g, 146 mmol) in
warm ethyl acetate (150 mL) was added to a solution of (R)-
(-)-mandelic acid (22.2 g, 146 mmol) in warm ethyl acetate
(150 mL). The mixture was mixed by stirring for 10 min. It
was left at room temperature for 24 h. The resulting crystals
were filtered, dried, and recrystallized again with ethyl acetate
(100 mL). After 12 h, the salt crystals were filtered and
subsequently dried to afford 22.6 g (46%) of very pure salt (S)-
(-)-66 as white crystals, [R]D ) -49.9° (c ) 1, CH2Cl2).
mg (93%) of 55 as a semisolid material. Anal. (C35H42
-
ClF9N4O8) C, H, N.
Bis[1-[3-(3-P ip er id in yl)p r op yl]-2-[(4-ch lor op h en oxy)-
m e t h y l]-4-[[3-(1-p ip e r id in y l)p r o p y l]o x y ]b e n zim id a -
zole] Tr iflu or oa ceta te (56). As for 30, 100 mg (0.2 mmol)
of 48 and trifluoroacetic acid (2 mL) in dichloromethane (2 mL)
gave 103 mg (85%) of 56 as a semisolid material. Anal.
(C34H43ClF6N4O6) C, H, N.
Tr is[1-[3-(3-P ip er id in yl)p r op yl]-2-[(4-ch lor op h en oxy)-
m eth yl]-4-[[2-(2-piper idin yl)eth yl]oxy]ben zim idazole] Tr i-
flu or oa ceta te (57). As for 30, 30 mg (0.04 mmol) of 49 and
trifluoroacetic acid (1 mL) in dichloromethane (1 mL) gave 27
mg (87%) of 57 as a semisolid material. Anal. (C35H42
-
ClF9N4O8) C, H, N.
Bis[1-[3-(3-P ip er id in yl)p r op yl]-2-[(4-ch lor op h en oxy)-
m e t h y l]-4-[[3-(2-p ip e r id in y l)p r o p y l]o x y ]b e n zim id a -
zole] Tr iflu or oa ceta te (58). As for 30, 80 mg (o.11 mmol)
3(S)-(3-P ip er id in yl)p r op ion ic Acid E t h yl E st er ((S)-
(-)-65). A slurry of ((S)-(-)-66) salt (30 g, 89.1 mmol) in ethyl
acetate (300 mmol) was treated with the aqueous solution of

2718 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 15
Zarrinmayeh et al.
potassium carbonate (300 mL of 10%). The free amine was
extracted by ethyl acetate. The organic layer was washed with
water (3 × 300 mL), dried, and concentrated in a vacuum to
afford 16.5 g (100%) of the pure free amine (S)-(-)-65 as a
colorless oil, [R]D ) -8.5° (c ) 1, CH2Cl2).
X-ray crystallography of (R)-(+)-66, and NMR spectra of more
than 90% of the final products and their immediate precursors
(18 pages). Ordering information is given on any current
masthead page.
3(S)-[N-(ter t-Bu t yloxyca r b on yl)-3-p ip er id in yl]p r op i-
on ic Acid Eth yl Ester ((S)-(-)-67). A solution of (S)-(-)-
65 (9.2 g, 49.5 mmol) in a mixture of THF/H2O (250 mL; 1:1)
was treated with potassium carbonate (8.2 g, 59.4 mmol) and
di-tert-butyl dicarbonate (13 g, 59.4 mmol). The reaction
mixture was stirred at room temperature for 6 h. Workup: 3
× 200 mL of water/2 × 200 mL of ethyl acetate. The combined
organic layer was dried, concentrated, and subjected to chro-
matography (10-25% ethyl acetate/hexanes two-step gradient)
to afford 14 g (99%) of the pure product (S)-(-)-67 as a solid.
3(S )-[N -(t er t -Bu t yloxyca r b on yl)-3-p ip e r id in yl]p r o-
p a n ol ((S)-(-)-68). A room-temperature solution of (S)-(-)-
67 (13.2 9, 46.4 mmol) in ether (400 mL) was slowly treated
with lithium aluminum hydride (1.8 g, 46.4 mmol). After being
stirred at room temperature for 4 h, the reaction mixture was
slowly poured into an aqueous solution of sodium hydroxide
(200 mL, 15%). Workup: 3 × 200 mL of water/2 × 200 mL of
ether. The combined organic layer was dried and concentrated
to afford 10.2 g (91%) of alcohol (S)-(-)-68 that was directly
used in the next step.
3(S)-[N-(ter t-Bu tyloxyca r bon yl)-3-p ip er id in yl]p r op yl
Br om id e ((S)-(-)-17). A solution of triphenylphosphine (15.5
g, 59 mmol) in dichloromethane (170 mL) at 0 °C was treated
with bromine until the solution turned pale yellow. To this
mixture was added a solution of alcohol (S)-(-)-68 (10.2 g, 42.1
mmol) and pyridine (7.7 g, 59 mmol) in dichloromethane (50
mL). The reaction mixture was allowed to warm to room
temperature and stirred for 6 h. Workup (3 × 200 mL of
water/2 × 200 mL of ether). The combined organic layer was
dried, concentrated, and subjected to chromatography (10%
ethyl acetate/hexanes two-step gradient) to afford 9.5 g (73%)
of the pure oily product (S)-(-)-17.
Bis[(S,S)-1-[3(S)-(3-P iper idin yl)pr opyl]-2-[(4-ch lor oph e-
n oxy)m et h yl]-4-[[3(S)-(3-p ip er id in yl)p r op yl]oxy]b en z-
im id a zole] Tr iflu or oa ceta te ((S,S)-69). As for 30, 240 mg
(0.33 mmol) of (S,S)-52 and trifluoroacetic acid (3 mL) in
dichloromethane (3 mL) gave 242 mg (97%) of (S,S)-69 as a
semisolid material, [R]D ) -11.8° (c ) 1, MeOH). Anal.
(C34H43ClF6N4O6) C, H, N.
Bis[(R,R)-1-[3(R)-(3-P iper idin yl)pr opyl]-2-[(4-ch lor oph e-
n oxy)m et h yl]-4-[[3(R)-(3-p ip er id in yl)p r op yl]oxy]b en z-
im id a zole] Tr iflu or oa ceta te ((R,R)-70). As for 30, 255 mg
(0.35 mmol) of (R,R)-52 and trifluoroacetic acid (3 mL) in
dichloromethane (3 mL) gave 264 mg (100%) of (R,R)-70 as a
semisolid material, [R]D ) +12.8° (c ) 1, MeOH). Anal.
(C34H43ClF6N4O6) C, H, N.
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Bis[(S,R)-1-[3(S)-(3-P iper idin yl)pr opyl]-2-[(4-ch lor oph e-
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Ack n ow led gm en t. The authors would like to thank
Dr. J ames Monn and Dr. J ohn Ward for helpful discus-
sions, Mr. J on Paschal for the “NOE” NMR spectroscopy
of 40 and 41, Ms. J ennifer Olkowski for the X-ray crystal
structure of (R)-66, and Mr. Robert Murff for preparing
a large quantity of compound 65.
Su p p or tin g In for m a tion Ava ila ble: Combustion analy-
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Benzimidazoles NPY Y1 Receptor Antagonists
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