Structure-activity relationship studies on 1-[2-(4- phenylphenoxy)ethyl]pyrrolidine (SC-22716), a potent inhibitor of leukotriene A4 (LTA4) hydrolase

Article abstract of DOI:10.1021/jm990496z

Leukotriene B₄ (LTB₄) is a pro-inflammatory mediator that has been implicated in the pathogenesis of a number of diseases including inflammatory bowel disease (IBD) and psoriasis. Since the action of LTA₄ hydrolase is the rate-limiting step for LTB₄ production, this enzyme represents an attractive pharmacological target for the suppression of LTB₄ production. From an in- house screening program, SC-22716 (1, 1-[2-(4- phenylphenoxy)ethyl]pyrrolidine) was identified as a potent inhibitor of LTA₄ hydrolase. Structure-activity relationship (SAR) studies around this structural class resulted in the identification of a number of novel, potent inhibitors of LTA₄ hydrolase, several of which demonstrated good oral activity in a mouse ex vivo whole blood assay.

Full text of DOI:10.1021/jm990496z

J . Med. Chem. 2000, 43, 721-735
721
Str u ctu r e-Activity Rela tion sh ip Stu d ies on
1-[2-(4-P h en ylp h en oxy)eth yl]p yr r olid in e (SC-22716), a P oten t In h ibitor of
Leu k otr ien e A4 (LTA4) Hyd r ola se
Thomas D. Penning,* Nizal S. Chandrakumar, Barbara B. Chen, Helen Y. Chen, Bipin N. Desai,
Stevan W. Djuric, Stephen H. Docter, Alan F. Gasiecki, Richard A. Haack, J ulie M. Miyashiro, Mark A. Russell,
Stella S. Yu, David G. Corley, Richard C. Durley, Brian F. Kilpatrick, Barry L. Parnas, Leslie J . Askonas,
J ames K. Gierse, Elizabeth I. Harding, Maureen K. Highkin, J ames F. Kachur, Suzanne H. Kim, Gwen G. Krivi,
Doreen Villani-Price, E. Yvonne Pyla, Walter G. Smith, and Nayereh S. Ghoreishi-Haack
Departments of Medicinal Chemistry, Structure-Activity Screening Program, Inflammatory Diseases Research, and Molecular
Pharmacology, Searle Research and Development, Monsanto Company, 4901 Searle Parkway, Skokie, Illinois 60077
Received September 29, 1999
Leukotriene B4 (LTB4) is a pro-inflammatory mediator that has been implicated in the
pathogenesis of a number of diseases including inflammatory bowel disease (IBD) and psoriasis.
Since the action of LTA4 hydrolase is the rate-limiting step for LTB4 production, this enzyme
represents an attractive pharmacological target for the suppression of LTB4 production. From
an in-house screening program, SC-22716 (1, 1-[2-(4-phenylphenoxy)ethyl]pyrrolidine) was
identified as a potent inhibitor of LTA4 hydrolase. Structure-activity relationship (SAR) studies
around this structural class resulted in the identification of a number of novel, potent inhibitors
of LTA4 hydrolase, several of which demonstrated good oral activity in a mouse ex vivo whole
blood assay.
In tr od u ction
strate itself, LTA4.12,13 After the discovery of the zinc-
containing nature of LTA4 hydrolase, inhibitors of other
Zn2+-containing metalloproteinases, such as bestatin14
and captopril,15 were shown to inhibit LTA4 hydrolase.
A series of bestatin analogues and related R-keto-â-
amino acid transition-state mimics16 were reported as
inhibitors of LTA4 hydrolase, as well as a related series
that incorporated a zinc-chelating thiol or hydroxamate
moiety.17 The hydroxamic acid kelatorphan and some
related analogues were recently reported and were
among the most potent inhibitors of LTA4 hydrolase
described to date.18 However, these analogues were
unable to penetrate cell membranes as evidenced from
their lack of activity in a human whole blood assay.
More recently, thiol SA654119 and a screening hit from
a microorganism20 have also been reported.
Leukotriene B4 (LTB4) is a 5-lipoxygenase (5-LO)-
derived metabolite of arachidonic acid which is synthe-
sized by a number of cell types, including eosinophils,
neutrophils (PMNs), and macrophages.1 LTB4 is a pro-
inflammatory mediator that is a potent stimulant of
human neutrophils, inducing chemotaxis, aggregation,
degranulation, adherence, and priming of inflammatory
cells. There is substantial evidence that LTB4 may play
a significant role in the amplification of many inflam-
matory disease states2 including inflammatory bowel
disease (IBD),3 psoriasis,4 rheumatoid arthritis,5 gout,6
and inflammatory lung diseases7 such as asthma. A
therapeutic agent which inhibits the biosynthesis of
LTB4 therefore may be useful for the treatment of these
inflammatory conditions.
Leukotriene A4 (LTA4) hydrolase is a 69 kDa zinc-
containing enzyme8 which stereospecifically catalyzes
the hydrolysis of the unstable epoxide LTA4 to the diol
LTB4. This process is the rate-limiting step in the
biosynthesis of LTB4. In addition to its epoxide hydro-
lase activity, the enzyme also possesses intrinsic ami-
nopeptidase activity toward a variety of substrates.9
LTA4 hydrolase is a cytosolic, monomeric enzyme which
is ubiquitously distributed in mammalian tissues,10 even
in cell types that do not express 5-LO.11 Compounds
which selectively inhibit LTA4 hydrolase would prefer-
entially block the formation of LTB4 and thus be an
attractive pharmacological target.
In the present study, we describe a unique series of
nonpeptidic, presumably non-zinc-chelating inhibitors
of LTA4 hydrolase.
Ch em istr y
An initial chemical lead, SC-22716 (1), was identified
through the Monsanto Structure-Activity Screening
Program. SC-22716 was found to be a potent, competi-
tive, reversible inhibitor of both the hydrolase and
peptidase activity of human LTA4 hydrolase21 (IC50
)
0.20 and 0.23 µM, respectively). Since LTA4 hydrolase
is an intracellular enzyme, good cellular penetration is
a prerequisite for a successful drug candidate. SC-22716
was able to penetrate cellular membranes, with an IC50
of 0.79 µM in a human whole blood LTB4 production
assay. However, the compound showed no activity when
dosed orally in a mouse ex vivo whole blood LTB4
production assay (9% inhibition at 10 mg/kg). On the
basis of these findings, a number of analogues were
synthesized to explore the SAR of this series. These
Several inhibitors of LTA4 hydrolase have been re-
ported over the past few years. One approach involved
inhibitors based on the structure of the natural sub-
* To whom correspondence should be addressed. Phone: 847-982-
7563. Fax: 847-982-4714. E-mail: thomas.d.penning@monsanto.com.
10.1021/jm990496z CCC: $19.00 © 2000 American Chemical Society
Published on Web 02/08/2000

722 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 4
Penning et al.
Sch em e 1a
a
(a) (1) Ar1C(O)Cl, pyridine, CH2Cl2, (2) AlCl3, ∆; (b) 1-(2-chloroethyl)pyrrolidine-HCl, K2CO3, DMF, ∆; (c) NaBH4, EtOH, H2O; (d) H2,
4% Pd/C, MeOH, AcOH; (e) Et3SiH, TFA, CH2Cl2; (f) (1) t-BuLi, THF, (2) Ar1CHO; (g) Ar1Li, THF.
efforts were directed at improving both the enzyme
potency and ex vivo activity of this novel lead.
an aryl (Ar1) lithium to 4-[2-(1-pyrrolidinyl)ethoxy]-
benzaldehyde (36). Reduction of 34 then provided 2. The
synthesis of analogues in which the amine moiety was
other than pyrrolidine is described in Scheme 2. Alky-
lation of phenol 33 with a commercially available
chloroethylamine in the presence of K2CO3 or NaH
provided 3. Alternatively, the phenol could be alkylated
with tert-butyl bromoacetate to give 37 followed by
reduction with lithium aluminum hydride (LAH) to the
corresponding alcohol and tosylation to afford 38. Reac-
tion of tosylate 38 with an amine in DMF/K2CO3
provided 3. In addition, tert-butyl ester 37 could be
hydrolyzed to the acid with trifluoroacetic acid and
coupled with an amine using disuccinyl carbonate (DSC)
in DMF to give the corresponding amide 39. Reduction
with LAH provided 3. Diphenyl ether analogues 4
(Scheme 3) were synthesized using a standard Ullmann
coupling to give phenol 40, followed by alkylation with
1-(2-chloroethyl)pyrrolidine.
Initially, the biphenyl moiety of 1 was replaced with
a diphenylmethyl functional group. This compound (2a )
was nearly an order of magnitude more potent at
inhibiting the hydrolase activity of LTA4 hydrolase and,
in addition, was more potent in the human whole blood
and mouse ex vivo assays. On the basis of these results,
the 2a structure was used as a template for further
exploration. Examples in which the tertiary amine was
pyrrolidine were synthesized simply by alkylation of a
phenol with commercially available 1-(2-chloroethyl)-
pyrrolidine as shown in Scheme 1. Phenols which were
not commercially available were prepared using a
variety of literature methods. Scheme 1 outlines the
preparation of phenols via benzophenones and/or di-
arylcarbinols. Two distinct methods were utilized. The
first involved Friedel-Crafts/Fries methodology to pro-
vide benzophenone 31, followed by alkylation with 1-(2-
chloroethyl)pyrrolidine to give 32. A two-step reduction
using NaBH4 to generate the carbinol, followed by a
deoxygenation using either catalytic hydrogenation or
trifluoroacetic acid/triethylsilane, gave 2. Alternatively,
reversal of the final two steps (two-step deoxygenation
to give 33, followed by alkylation) also provided 2. The
second method involved addition of an aryllithium to
an aryl carboxaldehyde, followed by reduction of the
resultant carbinol 34, to provide 2. This was ac-
complished either by addition of the lithium anion
generated from 1-[2-(4-bromophenoxy)ethyl]pyrrolidine
(35) to an aryl (Ar1) carboxaldehyde or by addition of
Resu lts a n d Discu ssion
Table 1 highlights the results obtained from modifica-
tion of the amine moiety of 2a . In general, the steric
environment about the amine had little effect on the
potency of inhibition of LTA4 hydrolase or LTB4 produc-
tion in human whole blood. Compounds ranging from
the minimal structure 3a to the sterically congested 3j
had very similar IC50s in both assays. In general, the
majority of these analogues had IC50s of 200 nM or less
in both enzyme and human whole blood assays. Di-
methylamine 3b, along with 3a , were the most potent
compounds against the enzyme, with IC50s of 6 and 9
nM, respectively. Compound 3b was the most potent in
the whole blood assay with an IC50 ) 73 nM. Com-
pounds 3g and 3i were among the least potent, particu-
larly in the whole blood assay. A comparator inhibitor,
kelatorphan, demonstrated equivalent enzyme potency
to some of our more potent analogues; however, it was
unable to penetrate whole cells in the human whole

SAR Studies on 1-[2-(4-Phenylphenoxy)ethyl]pyrrolidine
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 4 723
Sch em e 2a
a
(a) NaH or K2CO3, DMF, ClCH2CH2NR2, ∆; (b) NaH, BrCH2CO2t-Bu, THF; (c) LAH, THF; (d) p-toluenesulfonyl chloride, pyridine,
CH2Cl2; (e) HNR2, K2CO3, DMF, ∆; (f) TFA, CH2Cl2, MeOH; (g) disuccinylcarbonate (DSC), DMF, pyridine, HNR2.
Sch em e 3a
Ta ble 1. Amine Modifications
a
(a) 4-Iodoanisole, KOH, cat. Cu, ∆; (b) BBr3, CH2Cl2; (c) 1-(2-
chloroethyl)pyrrolidine-HCl, K2CO3, DMF, ∆.
blood assay. The majority of these compounds showed
very poor oral activity in the mouse ex vivo whole blood
LTB4 production assay. While 1 was essentially inactive
(9% inhibition at 10 mg/kg) in the ex vivo assay, 2a and
3a showed moderate oral activity, with 35% and 53%
inhibition of LTB4 production at 10 mg/kg. All other
analogues in Table 1 demonstrated diminished oral
activity in this assay. Selected ex vivo assay results are
summarized in Table 6. Since pyrrolidine 2a was one
of the more potent amines investigated, it was used as
a template to probe the effects of further modification
of this molecule.
Table 2 outlines modifications of the linker atom(s)
between the A and B aryl rings. The initial chemical
lead 1 was relatively potent in both the enzyme and
whole blood assays with IC50s of 0.20 and 0.79 µM,
respectively. Insertion of a methylene or ether linkage
into the biphenyl moiety (2a and 4a ) increased potency
almost an order of magnitude in both assays. In addi-
a
tion, both had improved oral activity in the ex vivo
model (35% and 25% inhibition, respectively, at 10 mg/
kg). Increasing the oxidation level of the methylene
group (6 and 7) dramatically decreased potency in both
hydrolase and whole blood assays. However, difluoro-
methylene 5 was essentially equipotent to 2a . Two atom
linkers were also investigated, with -CH2CH2-,
-CH2O-, -CH2S-, and -CH2NH2- combinations giv-
ing reasonably potent compounds, particularly 9, 13,
and 15. In addition, 15 showed a 56% inhibition of LTB4
Average of at least three determinations except where noted
in parentheses.
production at 10 mg/kg in the ex vivo assay. Again, as
with the methylene analogues, any increase in oxidation
level, such as sulfide 10 to sulfoxide 11 or sulfone 12,
methylene 14 to amide 16, or ethyl 8 to ethenyl 17,
resulted in a dramatic decrease in enzyme inhibitory
potency. This study demonstrated that methylene and
ether linkers were optimal for enzyme and whole blood

724 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 4
Ta ble 2. Aryl-Linker Modifications
Penning et al.
Ta ble 4. A-Ring Modifications
a
Average of at least three determinations except where noted
b
in parentheses. - ) not determined.
Ta ble 3. Amine-Linker Modifications
a
Average of at least three determinations except where noted
b
in parentheses. - ) not determined.
a
Average of at least three determinations except where noted
b
in parentheses. - ) not determined.
potency and, along with 15, were the only analogues in
Table 2 to show any significant oral activity. Since
analogues containing these two linker groups were
somewhat more synthetically accessible, additional
analogues utilized only these two linkers.
While maintaining the diphenylmethane and pyrro-
lidine moieties, we explored a number of modifications
to the linker atoms between the B-ring and amine
moiety (Table 3). Essentially all specified modifications
resulted in diminished potency relative to 2a . Replace-
ment of the oxygen atom of 2a with sulfur or carbon
(21 or 23) resulted in a 20- to 30-fold reduction in
potency in the LTA4 hydrolase assay, although 23 did
show moderate oral activity (44% inhibition at 10 mg/
kg) in the ex vivo assay. Introduction of unsaturation
to 23 improved potency somewhat, but 24 was still 10-
fold less potent than 2a . Analogues in which the oxygen
atom was replaced with either nitrogen or sulfoxide (20
and 22) were essentially inactive against the enzyme.
Insertion of a methylene unit between the phenyl ring
and oxygen atom (25) resulted in a 100-fold decrease in
potency relative to 2a . Alkyl substitution of this linker
(19) also substantially decreased potency. The oxyethyl
linker appeared to be optimal at this site, in terms of
chain length, substitution, and heteroatom identity and
location.
A number of A-ring modifications were also explored
(Table 4). In general, an aromatic or heteroaromatic

SAR Studies on 1-[2-(4-Phenylphenoxy)ethyl]pyrrolidine
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 4 725
Ta ble 5. B-Ring Modifications
eliminated any inhibitory activity, while meta- and
para-substituted analogues (2b,c,e,f) maintained good,
but diminished potency relative to 2a . Many heterocyclic
derivatives showed good potency with IC50s of less than
100 nM in the hydrolase assay, including 3-pyridyl (2h ),
2- and 5-thiazolyl (2i,k ), furyl (2l,m ), and thienyl (2n ).
One particularly potent analogue was biphenyl 4b, with
an IC50 of 6.6 nM in the hydrolase assay. Likewise, a
related analogue, phenyloxazole 4d , also had very good
potency in both hydrolase and whole blood assays. In
addition, it was in this class of analogues that we first
demonstrated encouraging oral activity. p-Methoxy
analogue 2b, thiazole 2k , and thiophene 2n all showed
a significant potency enhancement over 2a in the ex vivo
assay, with 74%, 57%, and 63% inhibition, respectively,
at 10 mg/kg vs 35% for 2a . Even more promising was
the oral activity of phenyloxazolidine 4c and phenylox-
azole 4d , which inhibited LTB4 production in the ex vivo
assay 83% and 93%, respectively, at 10 mg/kg. In
general, unsubstituted phenyl and several heteroaryls
and biaryls at this position were optimal for good in vitro
potency. In addition, it was within the heterocyclic, and
more specifically, the phenyloxazole class of analogues
that significant progress was made toward obtaining
satisfactory oral activity.
Table 5 summarizes modifications that were carried
out on the B-ring of 2a . m-Biphenyl analogue 29 had
diminished hydrolase inhibitory activity relative to 1,
while trans-cyclohexyl analogue 30 was inactive. Like-
wise, the analogous cis-cyclohexyl analogue was also
inactive (data not shown). Any substituents on the
central phenyl ring of 2a , other than fluoro (i.e., 2o,p s
which were about equipotent to 2a ), resulted in a
dramatic decrease in potency in both hydrolase and
whole blood assays (2q,r ,s,t,u ). A number, of other
substituents on this phenyl ring, including -CONH2,
Ac-, -NO2, -NH2, and -NHAc, also demonstrated
diminished potency (data not shown). Only two hetero-
cyclic analogues, pyridine 2w and thiophene 2x, showed
good potency in both assays. All other heterocycles were
very poor inhibitors. It is interesting to note that
pyridine analogue 2w , unlike pyridine 2v, was among
the most potent of our inhibitors. Unsubstituted phenyl
appeared to be optimal at this site, with pyridine 2w
and thiophene 2x also showing good activity. However,
these modifications failed to provide any enhancement
in oral activity relative to 2a in the mouse ex vivo assay.
a
Average of at least three determinations except where noted
b
in parentheses. - ) not determined.
Ta ble 6. Mouse ex Vivo Data for Selected Analogues
mouse ex vivo
One class of compounds that is potential competition
for LTA4 hydrolase inhibitors is 5-lipoxygenase (5-LO)
inhibitors. We investigated two standard 5-LO inhibi-
tors, zileuton and a second-generation analogue, A-78773,
as comparators in our in vivo and ex vivo assays. The
results are shown in Tables 1 and 6. As expected,
neither zileuton nor A-78773 inhibited LTA4 hydrolase.
In the human whole blood assay, many of our inhibitors
were significantly more potent than zileuton and a few
were equipotent to A-78773. Both 5-LO inhibitors
demonstrated excellent oral activity in the mouse ex
vivo model, giving essentially maximal inhibition at 10
mg/kg. In this study, one of our LTA4 hydrolase inhibi-
tors, 4d , demonstrated similar potency with 93% inhibi-
tion at 10 mg/kg.
compd
%inhibition @ 10 mg/kg
1
2a
2b
2k
2n
3a
4a
4c
4d
15
23
zileuton
A-78773
9%
35%
74%
57%
63%
53%
25%
83%
93%
56%
44%
g95%
g94%
group was required at this site for optimal potency (i.e.,
see 27), although cyclohexyl (28) had reasonably good
potency against the enzyme. Ortho substitution (2d )
Selected compounds from this series also inhibited the
peptidase activity of the LTA4 hydrolase enzyme with

726 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 4
Penning et al.
1
field H spectra were recorded on GE QE-300 and Varian VXR-
400 spectrometers at 300 and 400 MHz, respectively. Chemical
shifts are reported in parts per million relative to internal
tetramethylsilane. High resolution mass spectra were obtained
on a Finnigan MAT-8430 instrument with electron impact (EI)
or fast atom bombardment (FAB) ionization. Microanalyses
were performed by the Searle Physical Methodology Depart-
ment. Unless noted otherwise, elemental data for all new
compounds are within (0.4% of the theoretical values. All
yields reported are unoptimized.
very similar IC50s (generally within an order of magni-
tude). However, unlike many of the zinc-chelating
inhibitors such as kelatorphan,18 these compounds did
not block the protease activity of other zinc-containing
aminopeptidases, such as neutral endopeptidase (NEP)
or angiotensin converting enzyme (ACE), at concentra-
tions of up to 100 µM. In addition, extended X-ray
absorption fine structure (EXAFS) spectroscopy of the
zinc-containing LTA4 hydrolase enzyme carried out
either in the presence or absence of a related inhibitor,
SC-57461, was similar within the first coordination shell
of the Zn atom (data not shown). This provides evidence
for a lack of interaction of this class of inhibitors with
the zinc atom of the enzyme. These data will be reported
at a later date.
P r oced u r e A: Alk yla tion of a P h en ol w ith 1-(2-Ch lo-
r oeth yl)p yr r olid in e. A solution of a phenol, 1-2 equivalents
of 1-(2-chloroethyl)pyrrolidine‚HCl, and 2-3 equivalents of
powdered K2CO3 in DMF was stirred at 80-90 °C for 12-48
h. The solution was cooled, poured into water, and extracted
with Et2O or EtOAc. The combined organic extracts were
washed with water and brine, dried over Na2SO4, and con-
centrated in vacuo. The crude product was purified by flash
chromatography on silica gel using hexane/EtOAc or CH2Cl2/
MeOH/NH4OH mixtures to give the desired product.
P r oced u r e B: Alk yla tion of a P h en ol w ith a Ch lor o-
eth yla m in e. To a solution of a phenol in DMF was added 1-2
equivalents of a 50% NaH dispersion in oil, and the mixture
stirred for 10 min. The appropriate 1-(2-chloroethyl)amine was
added, and the mixture stirred at 80 °C for 2 h. The reaction
mixture was cooled, and water and EtOAc were added. The
organic layer was separated, washed with water, dried over
Na2SO4, filtered, and concentrated in vacuo. The crude product
was converted to the HCl salt using ethanolic HCl to provide
the desired product.
P r oced u r e C: Na BH4 Red u ction of a Ben zop h en on e.
To a solution of a benzophenone in EtOH was added a solution
of 0.5-0.75 equivalents of NaBH4 in water. The mixture was
stirred at 25 °C for 2 h and the reaction quenched with 3 N
NaOH. The mixture was extracted with ether and the ether
washed with brine, dried over Na2SO4, and concentrated to
provide the corresponding alcohol.
P r oced u r e D: Red u ction of Dia r ylca r bin ols Usin g
Ca ta lytic Hyd r ogen a tion . A diarylcarbinol in 60:40 MeOH/
AcOH was hydrogenated in the presence of catalytic 4% Pd/C
in a Parr shaker under 5 psi H2 for 5 h. The solution was
filtered and made basic with 10% NaOH. Extraction with
EtOAc and concentration gave the desired product.
P r oced u r e E: Red u ction of Dia r ylca r bin ols Usin g
TF A/Tr ieth ylsila n e. To a solution of a diarylcarbinol in CH2-
Cl2 was added a large excess of trifluoroacetic acid (TFA) and
Et3SiH. After being stirred at 25 °C for 1-30 h, the mixture
was concentrated and poured into CH2Cl2 and 2 N NaOH, and
the CH2Cl2 was separated, washed with brine, dried over Na2-
SO4, and concentrated. Flash chromatography on silica gel
using a CH2Cl2/MeOH/NH4OH mixture gave the desired
product.
P r oced u r e F : Ad d ition of 1-[2-(4-Lith iop h en oxy)eth yl]-
p yr r olid in e to a n Ald eh yd e. To a solution of 1-[2-(4-
bromophenoxy)ethyl]pyrrolidine (2f, step 1) in THF at -78 °C
was added 2 equivalents of 1.8 M t-BuLi in hexanes, and the
mixture was stirred at -78 °C for 4 h. A solution of 1
equivalent of an appropriate aldehyde in THF was added, and
the mixture was stirred at -78 °C for 30 min followed by
warming to 0 °C. The reaction was quenched with H2O, and
the solution was extracted with EtOAc. The extracts were
dried over Na2SO4 and concentrated. Flash chromatography
on silica gel using a CH2Cl2/EtOH/NH4OH mixture provided
the corresponding alcohol.
P r oced u r e G: Ben zoyla tion of a P h en ol. To a stirred
solution of a phenol and 1 equivalent of pyridine in CH2Cl2
was added 1 equivalent of benzoyl chloride over 15 min. The
solution was stirred at 25 °C for 4 h, poured onto crushed ice,
warmed to 25 °C, and stirred for 18 h. The mixture was
extracted with EtOAc, and the extracts were washed succes-
sively with 10% aqueous HCl, water, 10% aqueous NaOH,
water, and brine. The organic layer was dried over MgSO4,
filtered, and concentrated to provide the crude benzoate. This
was treated with 1.6 equivalents of AlCl3 in portions and
Con clu sion s
We have discovered a novel series of potent nonpep-
tidic, presumably non-zinc-chelating inhibitors of LTA4
hydrolase. Many analogues showed excellent potency in
a human whole blood LTB4 production assay, and a few
demonstrated good oral activity in a mouse ex vivo
whole blood assay. Further SAR studies on this series
of LTA4 hydrolase inhibitors, with a primary emphasis
on further modification of the amine moiety, will be
reported shortly.
Exp er im en ta l Section
Biologica l Meth od s. Hu m a n LTA4 Hyd r ola se Assa y.
Recombinant human LTA4 hydrolase was prepared as previ-
ously described21 and stored at -20 °C as a stock solution in
50 mM Tris buffer pH 8.0 containing 150 mM NaCl, 2.5 mM
â-mercaptoethanol, and 50% glycerol (specific activity ) 650
nmol/min/mg). LTA4 substrate was prepared from the methyl
ester in THF (Biomol, Plymouth Meeting, PA) by room
temperature incubation with 30 molar equivalents of LiOH
for 18 h, and it was stored at -80 °C until used. Enzyme was
diluted into assay buffer (0.1 M potassium phosphate pH 7.4,
5 mg/mL fatty acid free bovine serum albumin, and 10%
DMSO), and 250 ng (18 nM final assay concentration) in 25
µL was incubated with test compound, also in assay buffer,
for 10 min at room temperature. LTA4 substrate was diluted
in assay buffer without DMSO to a concentration of 350 ng/
mL, and 25 µL (8 ng) was added. The reaction (total volume
200 µL) was allowed to proceed at room temperature for 10
min. A 25 µL sample was added to 500 µL of assay buffer
without DMSO to stop the reaction. LTB4 was quantified in
the diluted sample by a commercially available enzyme-linked
immunoassay (ELISA, Cayman Chemical Co., Ann Arbor, MI).
Hu m a n Wh ole Blood Assa y. Human blood collected in
heparin was diluted 1:4 with RPMI-1640 media (GIBCO BRL,
Grand Island, NY), and 200 µL was added per well in 96-well
microtiter plates. Compounds diluted in DMSO (1%) were
added to the blood in duplicate and allowed to incubate for 15
min at 37 °C in a humidified incubator (5% CO2). Calcium
ionophore A23187 (20 µg/mL, 1% DMSO final concentration)
was added and the incubation continued for 10 min. The
incubation was terminated by centrifugation (833 g, 10 min,
4 °C), and the supernatants were analyzed for LTB4 by ELISA.
Mou se ex Vivo Wh ole Blood Assa y. Test compounds were
administered in physiologic saline with 2% DMSO and 1%
Tween-80 to adult male outbred mice (CD-1, 20-30 g, 5-8
animals/treatment group) by gavage. One hour after dosing,
blood was collected on heparin from the retroorbital sinus and
added to microtiter plates (100 µL) along with an equal volume
of RMPI-1640 media. Calcium ionophore A23187 (20 µL/mL
final concentration) was added, and the mixture incubated at
37 °C for 10 min in a humidified incubator. The incubation
was terminated by centrifugation and the supernatants ana-
lyzed for LTB4 by ELISA.
Ch em istr y. Melting points were determined using a Thomas-
Hoover melting point apparatus and are uncorrected. High

SAR Studies on 1-[2-(4-Phenylphenoxy)ethyl]pyrrolidine
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 4 727
heated to 160 °C for 2 h. After cooling and treatment with ice/
concentrated HCl, the mixture was extracted with EtOAc and
the extracts washed twice with 10% NaOH. The combined
aqueous extracts were washed with EtOAc and acidified with
concentrated HCl. The resulting precipitate was filtered,
washed with water, and dried to provide the product.
1-[2-(4-P h en ylp h en oxy)eth yl]p yr r olid in e (1). The title
compound was prepared from 4-phenylphenol and 1-(2-
chloroethyl)pyrrolidine‚HCl using procedure A to provide 1 as
an off-white solid: 1H NMR (CDCl3) δ 1.82 (m, 4 H), 2.64 (m,
4 H), 2.93 (t, J ) 5 Hz, 2H), 4.16 (t, J ) 5 Hz, 2H), 6.99 (d, J
) 9 Hz, 2H), 7.30 (m, 1H), 7.41 (t, J ) 8 Hz, 2H), 7.53 (m,
4H). Anal. (C18H21NO) C, H, N.
(d, J ) 9 Hz, 2H), 7.07 (m, 4H), 8.48 (d, J ) 6 Hz, 2H). Anal.
(C18H22N2O‚0.3H2O) C, H, N.
3-[4-[2-(1-P yr r olid in yl)eth oxy]p h en yl m eth yl]p yr id in e
(2h ). The title compound was prepared from 3-pyridinecar-
boxyaldehyde using procedure F, followed by procedure D, to
provide 2h : 1H NMR (CDCl3) δ 1.80 (m, 4H), 2.60 (m, 4H),
2.88 (t, J ) 6 Hz, 2H), 3.90 (s, 2H), 4.08 (t, J ) 6 Hz, 2H), 6.55
(d, J ) 9 Hz, 2H), 7.08 (d, J ) 9 Hz, 2H), 7.17(dd, J ) 9 Hz,
6 Hz, 1H), 7.44 (d, J ) 9 Hz, 1H), 8.44 (dd, J ) 6 Hz, 2 Hz,
1H), 8.49 (d, J ) 2 Hz, 1H). Anal. (C18H22N2O‚0.2H2O) C, H,
N.
2-[4-[2-(1-P yr r olidin yl)eth oxy]ph en yl]th iazole (2i). Step
1: P r ep a r a tion of 4-[2-(1-P yr r olid in yl)eth oxy]ben za ld e-
h yd e. The title compound was prepared from 4-hydroxybenz-
aldehyde and 1-(2-chloroethyl)-pyrrolidine‚HCl using proce-
dure A to provide the title compound (72%) as a yellow oil:
1H NMR (CDCl3) δ 1.83 (m, 4H), 2.63 (m, 4H), 2.92 (t, J ) 6
Hz, 2H), 4.19 (t, J ) 6 Hz, 2H), 7.02 (d, J ) 9 Hz, 2H), 7.82 (d,
J ) 9 Hz, 2H), 9.90 (s, 1H); HRMS m/z 219.1239 (calcd for
1-[2-(4-P h en ylm eth yl)ph en oxyeth yl]pyr r olidin e Hydr o-
ch lor id e (2a ). The title compound was prepared from 4-benz-
ylphenol and 1-(2-chloroethyl)pyrrolidine‚HCl using procedure
A to provide the free base (69%) as a light yellow oil: 1H NMR
(CDCl3) δ 1.78 (m, 4H), 2.60 (m, 4H), 2.86 (t, J ) 6 Hz, 2H),
3.91 (s, 2H), 4.07 (t, J ) 6 Hz, 2H), 6.84 (d, J ) 9 Hz, 2H),
7.09 (d, J ) 9 Hz, 2H), 7.22 (m, 5H). Anal. Calcd for C19H23
-
C
13H17NO2, 219.1259).
NO: C, 81.10; H, 8.24; N, 4.98. Found: C, 81.10; H, 8.36; N,
4.95. A solution of the amine in Et2O was treated with
ethanolic HCl to provide the HCl salt 2a as a tan solid: mp
163-165 °C. Anal. (C19H23NO‚HCl‚0.2H2O) C, H, N.
1-[2-[4-[4-(Me t h oxyp h e n yl)m e t h yl]p h e n oxy]e t h yl]-
p yr r olid in e (2b). The title compound was prepared from
4-anisaldehyde using procedure F, followed by procedure D,
to provide 2b: 1H NMR (CDCl3) δ 1.80 (m, 4H), 2.62 (m, 4H),
2.89 (t, J ) 6 Hz, 2H), 3.77 (s, 3H), 3.85 (s, 2H), 4.08 (t, J ) 6
Hz, 2H), 6.83 (m, 4H), 7.08 (m, 4H). Anal. (C20H25NO2‚0.2 H2O)
C, H, N.
1-[2-[4-[(3-Me t h oxyp h e n yl)m e t h yl]p h e n oxy]e t h yl]-
p yr r olid in e (2c). The title compound was prepared from
3-anisaldehyde using procedure F, followed by procedure D,
to provide 2c: 1H NMR (CDCl3) δ 1.80 (m, 4H), 2.61 (m, 4H),
2.88 (t, J ) 6 Hz, 2H), 3.75 (s, 3H), 3.89 (s, 2H), 4.08 (t, J ) 6
Hz, 2H), 6.75 (m, 2H), 6.85 (d, J ) 9 Hz, 2H), 7.10 (d, J ) 9
Hz, 2H), 7.21 (m, 2H). Anal. (C20H25NO2‚0.4H2O) C, H, N.
1-[2-[4-[2-(Me t h oxyp h e n yl)m e t h yl]p h e n oxy]e t h yl]-
p yr r olid in e (2d ). The title compound was prepared from
2-anisaldehyde using procedure F, followed by procedure D,
to provide 2d : 1H NMR (CDCl3) δ 1.79 (m, 4H), 2.60 (m, 4H),
2.86 (t, J ) 6 Hz, 2H), 3.80 (s, 3H), 3.90 (s, 2H), 4.06 (t, J ) 6
Hz, 2H), 6.85 (m, 4H), 7.11 (m, 4H). Anal. (C20H25NO2) C, N;
H, calcd, 8.09; found, 7.61.
Step 2: P r ep a r a tion of R-[4-[2-(1-P yr r olid in yl)eth oxy]-
p h en yl]-2-th ia zolem eth a n ol. To a solution of thiazole (0.5
g, 5.87 mmol) in THF (15 mL) at 0 °C was added 1.6 M n-BuLi
in hexanes (3.75 mL, 6 mmol), and the mixture was stirred at
0 °C for 15 min. This solution was added to a solution of the
product from step 1 (1.1 g, 5.0 mmol) in THF (20 mL) at -78
°C and the mixture stirred for 45 min. The reaction mixture
was quenched with saturated NH4Cl and poured into Et2O and
water. The ether layer was washed with brine, dried over Na2-
SO4, and concentrated. Flash chromatography on silica gel
using a gradient of 100:1:0.5 to 100:2:0.5 CH2Cl2/MeOH/NH4-
OH gave the title compound (1.12 g, 74%) as a light brown
solid: 1H NMR (CDCl3) δ 1.88 (m, 4H), 2.59 (m, 4H), 2.83 (t,
J ) 6 Hz, 2H), 3.98 (t, J ) 6 Hz, 2H), 5.72 (br, 1H), 5.96 (s,
1H), 6.81 (d, J ) 8.6 Hz, 2H), 7.25 (d, J ) 3.3 Hz, 1H), 7.34 (d,
J ) 8.6 Hz, 2H), 7.68 (d, J ) 3.3 Hz, 1H). Anal. (C16H20N2O2S‚
0.3H2O) C, H, N.
Step 3: P r ep a r a tion of 2-[4-[2-(1-P yr r olid in yl)eth oxy]-
p h en yl]th ia zole. The product of step 2 was reduced using
procedure E to give the starting alcohol (21%), along with 2i
(37%) as a yellow oil: 1H NMR (CDCl3) δ 1.80 (m, 4H), 2.62
(m, 4H), 2.90 (t, J ) 6 Hz, 2H), 4.11 (t, J ) 6 Hz, 2H), 4.28 (s,
2H), 6.89 (d, J ) 8.5 Hz, 2H), 7.20 (d, J ) 3.5 Hz, 1H), 7.23 (d,
J ) 8.5 Hz, 2H), 7.71 (d, J ) 3.3 Hz, 1H); HRMS m/z 288.1290
(calcd for C16H20 N2OS, 288.1297).
1-[2-[4-[(4-C h lo r o p h e n y l)m e t h y l]p h e n o x y ]e t h y l]-
p yr r olid in e (2e). The title compound was prepared from
4-chloro-4′-hydroxybenzophenone and 1-(2-chloroethyl)pyrro-
lidine‚HCl using procedure A, followed by reduction using
procedures C and E, to give 2e as a light yellow oil: 1H NMR
(CDCl3) δ 1.80 (m, 4H), 2.62 (m, 4H), 2.89 (t, J ) 6.0 Hz, 2H),
3.87 (s, 2H), 4.08 (t, J ) 6.0 Hz, 4H), 6.84 (d, J ) 8.7 Hz, 2H),
7.05 (d, J ) 8.7 Hz, 2H), 7.09 (d, J ) 8.6 Hz, 2H), 7.23 (d, J )
8.5 Hz, 2H). Anal. (C19H22ClNO) C, H, N.
1-[2-[4-[(3-C h lo r o p h e n y l)m e t h y l]p h e n o x y ]e t h y l]-
p yr r olid in e (2f). Step 1: P r ep a r a tion of 1-[2-(4-Br o-
m op h en oxy)eth yl]p yr r olid in e. The title compound was
prepared from 4-bromophenol and 1-(2-chloroethyl)pyrrolidine‚
HCl using procedure A to provide the title compound (48%)
as a light yellow oil.
4-[[4-[2-(1-P y r r o li d i n y l)e t h o x y ]p h e n y l]m e t h y l]-
th ia zole (2j). Step 1: P r ep a r a tion of 1-Br om o-3-(4-m eth -
oxyp h en yl)-2-p r op a n on e. To a solution of 4-methoxyphen-
ylacetic acid (3.32 g, 20 mmol) in benzene (30 mL) was added
oxalyl chloride (2.0 mL, 23 mmol) followed by 1 drop of DMF.
The mixture was stirred at 25 °C for 1.5 h and concentrated.
To a solution of the crude acid chloride in Et2O (50 mL) at 0
°C was added ethereal diazomethane until N2 evolution ceased.
HBr(g) was bubbled through the solution at 0 °C for 30 min.
The solution was washed with water, dilute NaHCO3, and
brine and the ether layer dried over Na2SO4 and concentrated
to provide a brown oil (4.79 g, 98%) which was used without
further purification: 1H NMR (CDCl3) δ 3.80 (s, 3H), 3.89 (s,
2H), 3.92 (s, 2H), 6.88 (d, J ) 9 Hz, 2H), 7.15 (d, J ) 9 Hz,
2H).
Step s 2 a n d 3: P r ep a r a tion of 1-[2-[4-[(3-Ch lor op h en -
yl)m eth yl]p h en oxy]eth yl]p yr r olid in e. The title compound
was prepared from the product of step 1 and 3-chlorobenzal-
dehyde using procedure F, followed by reduction using proce-
dure E, to give 2f as a colorless oil: 1H NMR (CDCl3) δ 1.81
(m, 4H), 2.65 (m, 4H), 2.91 (t, J ) 6.0 Hz, 2H), 3.88 (s, 2H),
4.10 (t, J ) 6.0 Hz, 2H), 6.85 (d, J ) 8.8 Hz, 2H), 7.06 (m,
3H), 7.16 (m, 3H). Anal. (C19H22ClNO‚0.3H2O) C, H, N, Cl.
4-[4-[2-(1-P yr r olid in yl)eth oxy]p h en yl m eth yl]p yr id in e
(2g). The title compound was prepared from 4-pyridinecar-
boxyaldehyde using procedure F, followed by procedure D, to
provide 2g: 1H NMR (CDCl3) δ 1.80 (m, 4H), 2.60 (m, 4H),
2.89 (t, J ) 6 Hz, 2H), 3.90 (s, 2H), 4.08 (t, J ) 6 Hz, 2H), 6.86
Step 2: P r ep a r a tion of 4-[(4-Meth oxyp h en yl)m eth yl]-
th ia zole. A solution of thioformamide in dioxane was prepared
by refluxing formamide (1.5 mL, 43 mmol) and P2S5 (3.3 g,
7.3 mmol) in 70 mL of dioxane for 2 h. The solution was added
to a solution of the product from step 1 (1.0 g, 4.1 mmol) and
2 g of MgCO3 in 10 mL of dioxane, and the mixture was
refluxed for 1 h. The mixture was cooled and poured into Et2O
and 1 N NaOH. The ether layer was washed with brine, dried
over Na2SO4, and concentrated. Flash chromatography using
a gradient of 10:1 to 5:1 hexane/EtOAc provided the title
compound (0.52 g, 62%) as a colorless oil: 1H NMR (CDCl3) δ
3.78 (s, 3H), 4.14 (s. 2H), 6.83 (s, 1H), 6.87 (d, J ) 9 Hz, 2H),
7.20 (d, J ) 9 Hz, 2H), 8.78 (s, 1H).

728 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 4
Penning et al.
Step 3: P r ep a r a tion of 4-(4-Th ia zolylm eth yl)p h en ol.
To a solution of the product from step 2 (0.52 g, 2.53 mmol) in
CH2Cl2 (10 mL) at -78 °C was added 8 mL of 1 N BBr3 in
CH2Cl2, and the mixture was stirred at -78 °C for 20 min and
at 25 °C for 16 h. The mixture was poured into H2O, and the
organic layer was washed with brine, dried over Na2SO4, and
concentrated to provide the product as a boronic acid com-
plex: 1H NMR (CDCl3) δ 4.74 (s, 2H), 5.13 (br, 1H), 6.87 (d, J
) 9 Hz, 2H), 7.04 (s, 1H), 7.13 (d, J ) 9 Hz, 2H), 10.33 (s, 1H).
The product was stirred in 10:1 MeOH/concentrated HCl at
25 °C for 25 h and the mixture concentrated to give the title
compound as an oil: 1H NMR (CDCl3) δ 4.08 (s, 2H), 6.64 (d,
J ) 9 Hz, 2H), 6.93 (d, J ) 1.5 Hz, 1H), 7.00 (d, J ) 9 Hz, 2H),
8.02 (br, 1H), 8.80 (d, J ) 1.5 Hz, 1H).
Step 4: P r ep a r a tion of 4-[[4-[2-(1-P yr r olid in yl)eth oxy]-
p h en yl]m eth yl]th ia zole. The title compound was prepared
from the product of step 3 and 1-(2-chloroethyl)pyrrolidine‚
HCl using procedure A to provide 2j (44%) as a light yellow
oil: 1H NMR (CDCl3) δ 1.80 (m, 4H), 2.63 (m, 4H), 2.90 (t, J
) 6 Hz, 2H), 4.08 (t, J ) 6 Hz, 2H), 4.11 (s, 2H), 6.83 (s, 1H),
6.88 (d, J ) 9 Hz, 2H), 7.19 (d, J ) 9 Hz, 2H), 8.66 (s, 1H);
HRMS m/z 288.1286 (calcd for C16H20N2OS, 288.1296).
5-[[4-[2-(1-P y r r o li d i n y l)e t h o x y ]p h e n y l]m e t h y l]-
th ia zole (2k ). Step 1: P r ep a r a tion of r-[4-[2-(1-P yr r o-
lid in yl)eth oxy]p h en yl]-5-th ia zolem eth a n ol. To a solution
of 2-trimethylsilylthiazole (1.09 g, 6.9 mmol) in THF (25 mL)
at -78 °C was added 1.6 M n-BuLi in hexanes (4.5 mL, 7.2
mmol), and the mixture was warmed to -50 °C for 1 min and
cooled to -78 °C. A solution of 4-[2-(1-pyrrolidinyl)ethoxy]-
benzaldehyde (2i, step 1) (1.4 g, 6.4 mmol) in THF (6 mL) was
added, and the mixture was stirred at -78 °C for 45 min. The
reaction mixture was quenched with saturated NH4Cl and
poured into Et2O and water. The ether layer was washed with
brine, dried over Na2SO4, and concentrated. Flash chroma-
tography on silica gel using a gradient of 100:2:0.5 to 100:3:
0.5 CH2Cl2/MeOH/NH4OH gave 0.42 g (20%) of the title
compound: 1H NMR (CDCl3) δ 1.78 (m, 4H), 2.59 (m, 4H), 2.86
(t, J ) 6 Hz, 2H), 4.00 (t, J ) 6 Hz, 2H), 5.17 (br, 1H), 5.99 (s,
1H), 6.83 (d, J ) 9 Hz, 2H), 7.31 (m, 2H), 7.54 (s, 1H), 8.64 (s,
1H).
(CDCl3) δ 1.78 (m, 4H), 2.60 (m, 4H), 2.88 (t, J ) 7 Hz, 2H),
3.90 (s, 2H), 4.05 (t, J ) 7 Hz, 2H), 6.63 (d, J ) 10 Hz, 2H),
7.00 (t, J ) 8 Hz, 1H), 7.15-7.40 (m, 5H); HRMS m/z 299.1681
(calcd for C19H22FNO, 299.1685).
1-[2-[2-F lu or o-4-(p h en ylm eth yl)p h en oxy]eth yl]p yr r o-
lid in e (2p ). 3-Fluoro-4-hydroxybenzophenone was prepared
from 2-fluorophenol using procedure G. This was alkylated
with 1-(2-chloroethyl)pyrrolidine‚HCl using procedure A and
reduced using procedures C and D to provide 2p : 1H NMR
(CDCl3) δ 1.79 (m, 4H), 2.63 (m, 4H), 2.92 (t, J ) 7 Hz, 2H),
3.89 (s, 2H), 4.14 (t, J ) 7 Hz, 2H), 6.80-6.95 (m, 3H), 7.15-
7.35 (m, 5H); HRMS m/z 299.1678 (calcd for C19H22FNO,
299.1685).
1-[2-[2-Ch lor o-4-(p h en ylm eth yl)p h en oxy]eth yl]p yr r o-
lid in e (2q). 3-Chloro-4-hydroxybenzophenone was prepared
from 2-chlorophenol using procedure G. This was alkylated
with 1-(2-chloroethyl)pyrrolidine‚HCl using procedure A and
reduced using procedures C and E to provide 2q: 1H NMR
(CDCl3) δ 1.79 (m, 4H), 2.65 (m, 4H), 2.93 (t, J ) 7 Hz, 2H),
3.89 (s, 2H), 4.12 (t, J ) 7 Hz, 2H), 6.85 (d, J ) 8 Hz, 1H),
7.00 (dd, J ) 8 Hz, 2 Hz, 1H), 7.12-7.35 (m, 6H); HRMS m/z
315.1385 (calcd for C19H2235ClNO, 315.1390).
1-[2-[3-Meth oxy-4-(p h en ylm eth yl)p h en oxy]eth yl]p yr -
r olid in e (2r ). The title compound was prepared from 3-meth-
oxyphenol in the same manner as described for the preparation
of 2s to provide 2r : 1H NMR (CDCl3) δ 1.80 (m, 4H), 2.60 (m,
4H), 2.88 (t, J ) 7 Hz, 2H), 3.77 (s, 3H), 3.89 (s, 2H), 4.08 (t,
J ) 7 Hz, 2H), 6.41 (dd, J ) 8 Hz, 3 Hz, 1H), 6.50 (d, J ) 3
Hz, 1H), 6.93 (d, J ) 8 Hz, 1H), 7.13-7.30 (m, 5H); HRMS
m/z 311.1895 (calcd for C20H25NO2, 311.1885).
1-[2-[2-Meth oxy-4-(p h en ylm eth yl)p h en oxy]eth yl]p yr -
r olid in e (2s). 2-Methoxyphenol (2.0 g, 16.1 mmol), benzoic
acid (2.0 g, 16.4 mmol), and 50 mL of polyphosphoric acid
(PPA) were heated at 120 °C for 1 h. The mixture was cooled,
treated with 50 g of ice, and poured into H2O. The mixture
was extracted with EtOAc, and the extracts were washed
successively with water, 5% aqueous Na2SO3, and brine. The
solution was dried over MgSO4, filtered, and concentrated to
provide, after flash chromatography on silica gel using a
gradient of 1:9 to 1:4 EtOAc/hexane, 3-methoxy-4-hydroxy-
benzophenone (0.47 g, 13%): HRMS m/z 228.0796 (calcd for
Step 2: P r ep a r a tion of 5-[[4-[2-(1-P yr r olid in yl)eth oxy]-
p h en yl]m eth yl]th ia zole. The title compound was prepared
using procedure E from the product of step 1 to provide 2k as
a yellow oil (70%): 1H NMR (CDCl3) δ 1.80 (m, 4H), 2.61 (m,
4H), 2.90 (t, J ) 6 Hz, 2H), 4.09 (t, J ) 6 Hz, 2H), 4.12 (s, 2H),
6.86 (d, J ) 9 Hz, 2H), 7.14 (d, J ) 9 Hz, 2H), 7.62 (s, 1H),
8.66 (s, 1H); HRMS m/z 288.1299 (calcd for C16H20N2OS,
288.1296).
C
14H12O3, 228.0786). This was alkylated with 1-(2-chloroethyl)-
pyrrolidine‚HCl using procedure A and reduced using proce-
dures C and E to provide 2s: 1H NMR (CDCl3) δ 1.80 (m, 4H),
2.62 (m, 4H), 2.93 (t, J ) 7 Hz, 2H), 3.80 (s, 3H), 3.93 (s, 2H),
4.12 (t, J ) 7 Hz, 2H), 6.70 (m, 2H), 6.83 (d, J ) 8 Hz, 1H),
7.15-7.32 (m, 5H); HRMS m/z 311.1875 (calcd for C20H25NO2,
311.1885).
1-[2 -[4 -[(3-F u r a n y l )m e t h y l ]p h e n o x y ]e t h y l ]p y r -
r olid in e (2l). The title compound was prepared from 3-fural-
dehyde using procedure F, followed by procedure D, to provide
2l: 1H NMR (CDCl3) δ 1.80 (m, 4H), 2.64 (m, 4H), 2.90 (t, J )
6 Hz, 2H), 3.70 (s, 2H), 4.09 (t, J ) 6 Hz, 2H), 6.23 (s, 1H),
6.35 (d, J ) 9 Hz, 2H),7.11 (d, J ) 9 Hz, 2H), 7.20 (s, 1H),
7.35 (m, 1H); MS m/z 271 (M+).
1-[2 -[4 -[(2-F u r a n y l )m e t h y l ]p h e n o x y ]e t h y l ]p y r -
r olid in e (2m ). The title compound was prepared from 2-fural-
dehyde using procedure F, followed by procedure D, to provide
2m : 1H NMR (CDCl3) δ 1.86 (m, 4H), 2.77 (m, 4H), 3.01 (t, J
) 6 Hz, 2H), 3.90 (s, 2H), 4.15 (t, J ) 6 Hz, 2H), 5.97 (d, J )
4 Hz, 1H), 6.29 (m, 1H), 6.85 (d, J ) 9 Hz, 2H), 7.14 (d, J ) 9
Hz, 2H), 7.32 (m, 1H); MS m/z 271 (M+).
1 -[2 -[4 -[(3 -T h i e n y l )m e t h y l ]p h e n o x y ]e t h y l ]p y r -
r olid in e (2n ). The title compound was prepared from
3-thiophenecarboxaldehyde using procedure F, followed by
procedure D, to provide 2n : 1H NMR (CDCl3) δ 1.80 (m, 4H),
2.61 (m, 4H), 2.89 (t, J ) 6 Hz, 2H), 3.90 (s, 2H), 4.09 (t, J )
6 Hz, 2H), 6.88 (m, 4H), 7.10 (d, J ) 9 Hz, 2H), 7.23 (m, 1H).
Anal. (C17H21NOS) C, H, N.
1-[2-[3-F lu or o-4-(p h en ylm eth yl)p h en oxy]eth yl]p yr r o-
lid in e (2o). 2-Fluoro-4-hydroxybenzophenone was prepared
from 3-fluorophenol using procedure G. This was alkylated
with 1-(2-chloroethyl)pyrrolidine‚HCl using procedure A and
reduced using procedures C and D to provide 2o: 1H NMR
1-[2-[3-Meth yl-4-(p h en ylm eth yl)p h en oxy]eth yl]p yr r o-
lid in e (2t). 2-Methyl-4-hydroxybenzophenone was prepared
from 3-methylphenol using procedure G. This was alkylated
with 1-(2-chloroethyl)pyrrolidine‚HCl using procedure A and
reduced using procedures C and E to provide 2t: 1H NMR
(CDCl3) δ 1.80 (m, 4H), 2.20 (s, 3H), 2.62 (m, 4H), 2.88 (t, J )
7 Hz, 2H), 3.91 (s, 2H), 4.08 (t, J ) 7 Hz, 2H), 6.70 (dd, J ) 8
Hz, 3 Hz, 1H), 6.76 (d, J ) 3 Hz, 1H), 7.00 (d, J ) 8 Hz, 1H),
7.07-7.29 (m, 5H); HRMS m/z 295.1914 (calcd for C20H25NO,
295.1936).
1-[2-[2-Meth yl-4-(p h en ylm eth yl)p h en oxy]eth yl]p yr r o-
lid in e (2u ). 3-Methyl-4-hydroxybenzophenone was prepared
from 2-methylphenol using procedure G. This was alkylated
with 1-(2-chloroethyl)pyrrolidine‚HCl using procedure A and
reduced using procedures C and E to provide 2u : 1H NMR
(CDCl3) δ 1.79 (m, 4H), 2.18 (s, 3H), 2.63 (m, 4H), 2.91 (t, J )
7 Hz, 2H), 3.88 (s, 2H), 4.08 (t, J ) 7 Hz, 2H), 6.73 (d, J ) 7
Hz, 1H), 6.95 (d and overlapping s, J ) 7 Hz, 2H), 7.15-7.31
(m, 5H); HRMS m/z 295.1945 (calcd for C20H25NO, 295.1936).
2-(P h e n ylm e t h yl)-5-[2-(1-p yr r olid in yl)e t h oxy]p yr i-
d in e (2v). Step 1: P r ep a r a tion of 2-(P h en ylm eth yl)-3-
h yd r oxyp yr id in e. A solution of 1,2-bis(chlorodimethylsilyl)-
ethane (6.36 g, 29.5 mmol) in 11 mL of CH2Cl2 was added to
2-aminomethylfuran (2.6 mL, 29.5 mmol) and Et3N in 19 mL
of CH2Cl2 at 0 °C, and the mixture was stirred at 25 °C for 2
h. The mixture was filtered and concentrated. To a solution

SAR Studies on 1-[2-(4-Phenylphenoxy)ethyl]pyrrolidine
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 4 729
of this crude product (4.5 g, 18.8 mmol) in 50 mL of THF at
-78 °C was added 1.7 M t-BuLi in hexanes (12.2 mL, 20.7
mmol), and the mixture was stirred at -40 °C for 2 h.
Benzaldehyde (3.0 g, 28.2 mmol) was added and the mixture
stirred at 25 °C for 1 h. Next 10% aqueous HCl was added
and the mixture refluxed for 18 h. The mixture was cooled,
diluted with Et2O, and extracted with 10% HCl. The acid
extracts were neutralized with 10% NaOH and extracted with
Et2O. The extracts were dried over Na2SO4 and concentrated
to provide the title compound: 1H NMR (CDCl3) δ 4.10 (s, 2H),
7.04 (d, J ) 9 Hz, 1H), 7.17 (dd, J ) 9, 4 Hz, 1H), 7.23 (m,
5H), 8.17 (d, J ) 4 Hz, 1H).
heated to 120 °C for 40 h. The mixture was cooled, poured into
100 mL to H2O, and extracted with Et2O. The extracts were
washed with water and brine, dried over MgSO4, filtered, and
concentrated to provide the title compound (0.43 g, 7%) as an
oil: 1H NMR (CDCl3) δ 1.80 (m, 4H), 2.60 (m, 4H), 2.89 (t, J
) 7 Hz, 2H), 4.18 (t, J ) 7 Hz, 2H), 6.23 (dd, J ) 3 Hz, 2 Hz,
1H), 6.55 (dd, J ) 7 Hz, 2 Hz, 1H), 6.70 (dd, J ) 7 Hz, 3 Hz,
1H); HRMS m/z 197.0873 (calcd for C10H15NOS, 197.0874).
Step 2: P r epar ation of 1-[2-[[5-(P h en ylm eth yl)-2-th ien -
yl]oxy]eth yl]p yr r olid in e Hyd r och lor id e. To a solution of
the product of step 1 (0.42 g, 2.12 mmol) in 4 mL of THF at 0
°C was added 1.6 M n-BuLi in THF (1.5 mL, 2.4 mmol). The
mixture was slowly warmed to 25 °C, stirred for 15 min, and
cooled to 0 °C, and 0.26 mL (2.2 mmol) of benzyl bromide was
added. After being stirred for 30 min, the mixture was poured
into water and extracted with of EtOAc. The extracts were
washed with water and brine, dried over MgSO4, filtered, and
concentrated. Purification by reverse phase HPLC eluting with
a MeOH/1% aqueous NH4OH gradient, followed by treatment
with ethereal HCl, provided 2x (0.06 g, 9%): 1H NMR (CDCl3)
δ 1.79 (m, 4H), 2.58 (m, 4H), 2.84 (t, J ) 7 Hz, 2H), 3.98 (s,
2H), 4.10 (t, J ) 7 Hz, 2H), 6.02 (d, J ) 3 Hz, 1H), 6.39 (d, J
) 3 Hz, 1H), 7.15-7.35 (m, 5H); HRMS m/z 287.1346 (calcd
for C17H21NOS, 287.1344).
5-(P h e n ylm e t h yl)-2-[2-(1-p y r r olid in yl)e t h o x y ]t h i-
a zole (2y). Step 1: P r ep a r a tion of 2-[2-(1-P yr r olid in yl)-
eth oxy]th ia zole. 1-(2-Hydroxyethyl)pyrrolidine (10 mL, 85.5
mmol) was treated with 0.5 g of NaH (50% dispersion in oil,
10.4 mmol) in small portions over 15 min and stirred an
additional 30 min. 2-Bromothiazole (1.6 g, 9.6 mmol) was
added and the mixture stirred at 25 °C for 18 h. The reaction
mixture was poured into water and extracted with EtOAc and
the extracts were washed with water and brine, dried over
MgSO4, filtered, and concentrated. Purification by flash chro-
matography on silica gel using a gradient of 1:1 Et2O/hexane
to 100% ether (saturated with NH4OH) provided 1.4 g (74%)
of the title compound: 1H NMR (CDCl3) δ 1.80 (m, 4H), 2.60
(m, 4H), 2.90 (t, J ) 7 Hz, 2H), 4.53 (t, J ) 7 Hz, 2H), 6.68 (d,
J ) 4 Hz, 1H), 7.11 (d, J ) 4 Hz, 1H); HRMS m/z 199.0924
(calcd for C9H15N2OS, 199.0905).
Step 2: P r ep a r a tion of r-P h en yl-2-[2-(1-p yr r olid in yl)-
eth oxy]-5-th ia zolem eth a n ol. To a solution of the product
of step 1 (0.1 g, 0.5 mmol) in 5 mL of THF at -40 °C was added
1.6 M n-BuLi in THF (0.38 mL, 0.6 mmol) dropwise. The
mixture was stirred at 0 °C for 1 h, and benzaldehyde (0.1
mL, 1.0 mmol) was added. After being stirred at 0 °C for 15
min, the mixture was poured into water and extracted with
EtOAc. The extracts were washed with water and brine, dried
over MgSO4, filtered, and concentrated to afford 0.10 g (66%)
of the title compound: 1H NMR (CDCl3) δ 1.79 (m, 4H), 2.58
(m, 4H), 2.88 (t, J ) 7 Hz, 2H), 4.47 (t, J ) 7 Hz, 2H), 5.91 (s,
1H), 6.88 (s, 1H), 7.28-7.45 (m, 5H); HRMS m/z 305.1326
(calcd for C18H21N2O2S, 305.1324).
Step 2: P r ep a r a tion of 2-(P h en ylm eth yl)-5-[2-(1-p yr -
r olid in yl)eth oxy]p yr id in e. The product of step 1 was alky-
lated with 1-(2-chloroethyl)pyrrolidine‚HCl using the proce-
dure described in step 2 for the preparation of 30 to give 2v:
1H NMR (CDCl3) δ 1.79 (m, 4H), 2.62 (m, 4H), 2.89 (t, J ) 6
Hz, 2H), 4.09 (s, 2H), 4.11 (t, J ) 6 Hz, 2H), 7.00 (d, J ) 8 Hz,
1H), 7.12 (dd, J ) 8, 3 Hz, 1H), 7.24 (m, 5H), 8.26 (d, J ) 3
Hz, 1H). Anal. (C18H22N2O‚0.3H2O) C, H, N.
5-P h en ylm eth yl-2-[2-(1-p yr r olid in yl)eth oxy]p yr id in e
(2w ). Step 1: P r ep a r a tion of (6-Ch lor o-3-p yr id in yl)-
p h en ylm eth a n on e. To a solution of 6-chloronicotinic acid (1.0
g, 6.35 mmol) in 10 mL of THF at 25 °C was added oxalyl
chloride (0.56 mL, 6.35 mmol), followed by a drop of DMF.
After gas evolution, the solution was concentrated and the
crude acid chloride stirred in 20 mL benzene. AlCl3 (2.1 g, 15.9
mmol) was added and the reaction mixture refluxed for 1.5 h.
The mixture was cooled and poured into EtOAc and water,
and the organic layer was dried over Na2SO4 and concentrated.
Flash chromatography on silica gel provided the title com-
pound (1.4 g, 100%) as a yellow solid: mp 55-56.5 °C; 1H NMR
(CDCl3) δ 7.52 (m, 3H), 7.66 (t, J ) 8 Hz, 1H), 7.80 (d, J ) 8
Hz, 3H), 8.11 (dd, J ) 9, 2 Hz, 1H), 8.78 (d, J ) 2 Hz, 1H).
Step 2: P r ep a r a tion of P h en yl [6-[2-(1-P yr r olid in yl)-
eth oxy]-3-pyr idin yl]m eth an on e. To pyrrolidinoethanol (0.304
g, 1.84 mmol) in 20 mL of benzene was added 75 mg of NaH
(60% dispersion in oil, 1.84 mmol). After the mixture was
stirred at 25 °C for 10 min, the product from step 1 (0.40 g,
1.84 mmol) was added, and the mixture was stirred at 25 °C
for 4 h. The mixture was poured into EtOAc and water, and
the organic layer was dried over Na2SO4 and concentrated.
Radial band chromatography on silica gel using a gradient of
1:1 hexane/EtOAc to 100% EtOAc provided the title compound
(0.48 g, 88%): 1H NMR (CDCl3) δ 1.81 (m, 4H), 2.62 (m, 4H),
2.91 (t, J ) 6 Hz, 2H), 4.54 (t, J ) 6 Hz, 2H), 6.88 (d, J ) 9
Hz, 1H), 7.49 (m, 2H), 7.58 (m, 1H), 7.77 (m, 2H), 8.09 (dd, J
) 9, 2 Hz, 1H), 8.60 (d, J ) 2 Hz, 1H). Anal. (C18H20N2O2‚
0.2H2O) C, H, N.
Step 3: P r ep a r a tion of 5-(P h en ylm eth yl)-2-[2-(1-p yr -
r olid in yl)eth oxy]th ia zole. The product of step 2 was reduced
using procedure E to provide 2y (74%): 1H NMR (CDCl3) δ
1.79 (m, 4H), 2.59 (m, 4H), 2.88 (t, J ) 7 Hz, 2H), 3.97 (s, 2H),
4.48 (t, J ) 7 Hz, 2H), 6.83 (s, 1H), 7.19-7.35 (m, 5H); HRMS
m/z 289.1373 (calcd for C16H21N2OS, 289.1375).
Step s 3 a n d 4: P r ep a r a tion of 5-P h en ylm eth yl-2-[2-
(1-p yr r olid in yl)eth oxy]p yr id in e. The product of step 2 was
reduced using procedures C and D to give 2w : 1H NMR
(CDCl3) δ 1.98 (m, 4H), 3.18 (m, 4H), 3.33 (t, J ) 5 Hz, 2H),
3.89 (s, 2H), 4.60 (t, J ) 5 Hz, 2H), 6.67 (d, J ) 8 Hz, 1H),
7.22 (m, 5H), 7.38 (dd, J ) 8, 2 Hz, 1H), 7.99 (d, J ) 2 Hz,
1H). Anal. (C18H22N2O‚0.3H2O) C, H; N: calcd, 9.73; found:
N, 9.25.
5-(P h e n y lm e t h y l)-2-[2-(1-p y r r o lid in y l)e t h o x y ]o x -
a zole (2z). Step 1: P r ep a r a tion of 5-(P h en ylm eth yl)-2-
(3H)-oxa zolon e. To a solution of potassium cyanate (0.32 g,
4.0 mmol) and Et3N (0.46 g, 4.5 mmol) in 2 mL of DMF at 100
°C was added a solution of benzyl chloromethyl ketone (0.5 g,
2.96 mmol) in 1 mL of DMF, and the mixtures was stirred at
100 °C for 3 h. The reaction mixture was cooled, poured into
10% aqueous HCl, and extracted with EtOAc. The extracts
were washed successively with 10% aqueous HCl, water, and
brine, dried over MgSO4, filtered, and concentrated. Purifica-
tion by flash chromatography on silica gel using a gradient of
1:4 to 1:1 EtOAc/hexane provided the title compound (0.55 g,
100%): 1H NMR (CD3OD) δ 3.72 (s, 2H), 6.40 (s, 1H), 7.18-
1-[2-[[5-(P h en ylm et h yl)-2-t h ien yl]oxy]et h yl]p yr r oli-
d in e Hyd r och lor id e (2x). Step 1: P r ep a r a tion of 1-[2-(2-
Th ien yloxy)eth yl]p yr r olid in e. To 1-(2-hydroxyethyl)pyrro-
lidine (20 mL, 171 mmol) were added sodium pellets (1.3 g,
56.5 mmol). After the initial reaction subsided, the mixture
was heated to 80 °C until the sodium was dissolved, and the
solution was cooled to 25 °C. To this solution was added copper-
(II) oxide (1.2 g, 15 mmol), sodium iodide (0.025 g, 0.17 mmol),
and 2-bromothiophene (5 g, 30.7 mmol). This mixture was
7.35 (m, 5H); HRMS m/z 175.0632 (calcd for
C10H9NO2,
175.0633).

730 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 4
Penning et al.
Step 2: P r ep a r a tion of 5-(P h en ylm eth yl)-2-[2-(1-p yr -
r olid in yl)eth oxy]oxa zole. The title compound was prepared
from the product of step 1 and 1-(2-chloroethyl)pyrrolidine‚
HCl using procedure A to provide 2z (43%): 1H NMR (CDCl3)
δ 1.75 (m, 4H), 2.51 (m, 4H), 2.68 (t, J ) 7 Hz, 2H), 3.60 (t, J
) 7 Hz, 2H), 3.70 (s, 2H), 6.18 (t, J ) 1 Hz, 1H), 7.20-7.46
(m, 5H); HRMS m/z 272.1512 (calcd for C16H20N2O2, 272.1525).
2-[4-(P h en ylm eth yl)p h en oxy]eth a n a m in e Hyd r och lo-
r id e (3a ). Step 1: P r ep a r a tion of ter t-Bu tyl [4-(P h en yl-
m eth yl)p h en oxy]a ceta te. To a stirred suspension of 3.2 g
of NaH (50% dispersion in oil, 67 mmol) in 100 mL of DMF
was added 4-hydroxydiphenylmethane (10 g, 54 mmol). The
mixture was stirred at 25 °C for 30 min and cooled to 0 °C,
and catalytic n-Bu4NI and tert-butyl bromoacetate (9.6 mL,
65 mmol) were added. After 30 min, the mixture was poured
into 2 N HCl and ice and the mixture extracted with Et2O.
The extracts were washed with saturated KHSO4 and satu-
rated K2CO3, dried over Na2SO4, and concentrated. Purification
by flash chromatography on silica gel using 1:9 Et2O/hexane
provided the title compound (15.0 g, 93%) as a colorless oil:
1H NMR (CDCl3) δ 1.48 (s, 9H), 3.92 (s, 2H), 4.48 (s, 2H), 6.82
(d, J ) 8 Hz, 2H), 7.09 (d, J ) 8 Hz, 2H), 7.17 (m, 3H), 7.26
(m, 2H).
Step 2: P r ep a r a tion of 2-[4-(P h en ylm eth yl)p h en oxy]-
eth yl 4-Meth ylben zen esu lfon a te. To a stirred suspension
of lithium aluminum hydride (LAH, 500 mg, 13.2 mmol) in
THF was added the product of step 1 (2.8 g, 10 mmol), and
the mixture was stirred at 25 °C for 4 h. The reaction was
quenched with 2 mL of H2O and stirred for 1 h. The mixture
was filtered, the solid was washed with THF, and the filtrate
was concentrated to provide 2.05 g (90%) of a white solid,
which was used without further purification: 1H NMR (CDCl3)
δ 3.92 (s, 2H), 3.93 (t, 2H), 4.04 (t, J ) 5 Hz, 2H), 6.84 (d, J )
8 Hz, 2H), 7.10 (d, J ) 8 Hz, 2H), 7.18 (m, 3H), 7.27 (m, 2H).
To a solution of this alcohol (2.3 g, 10 mmol) in 20 mL of CH2-
Cl2 and 10 mL of pyridine at 0 °C was added p-toluenesulfonyl
chloride (1.9 g, 10 mmol), and the mixture was stirred at 0 °C
for 30 min and at 25 °C for 16 h. The mixture was concen-
trated, dissolved in 25 mL of EtOAc, washed with H2O, dried
over Na2SO4, filtered, and concentrated. Recrystallization from
Et2O, gave 3.5 g (92%) of a white solid: 1H NMR (CDCl3) δ
2.45 (s, 3H), 3.90 (s, 2H), 4.10 (t, J ) 4 Hz, 2H), 4.33 (t, J ) 4
Hz, 2H), 6.71 (d, J ) 8 Hz, 2H), 7.05 (d, J ) 8 Hz, 2 H), 7.25
(m, 7H), 7.79 (d, J ) 8 Hz, 2H). Anal. (C22H22O4S) C, H.
Step 3: P r ep a r a tion of 2-[4-(P h en ylm eth yl)p h en oxy]-
eth a n a m in e Hyd r och lor id e. A mixture of the product of
step 2 (12.0 g, 31.4 mmol) and NaN3 (2.78 g, 42.8 mmol) in
100 mL of DMF was heated at 60 °C for 5 h. The mixture was
cooled and partitioned between Et2O and water. The aqueous
layer was extracted with EtOAc, and the extracts were washed
with brine, dried over Na2SO4, filtered, and concentrated to
afford 8.5 g of a yellow oil, which was used without further
purification: 1H NMR (CDCl3) δ 3.47 (t, 2H), 3.89 (s, 2H), 4.03
(t, 2H), 7.05 (m, 9H). To a stirred suspension of SnCl2 (10.0 g,
52.7 mmol) in 40 mL of MeOH was added a solution of the
crude azide in 20 mL of MeOH dropwise over 15 min, and the
mixture was stirred at 25 °C for 1 h. The mixture was
concentrated and the residue partitioned between 10% NaOH
and Et2O and filtered through Celite. The aqueous layer was
extracted with EtOAc, and the combined organic extracts were
washed with brine, dried over Na2SO4, and concentrated. The
HCl salt was formed by treatment with HCl/dioxane to provide,
after recrystallization from MeOH, 3a (5.7 g, 69%) as a white
solid: 1H NMR (CDCl3) δ 1.48 (br, 2H), 3.04 (t, 2H), 3.92 (t,
2H), 3.90 (s, 2H), 7.05 (m, 9H). Anal. (C15H17NO‚HCl) C, H,
N, Cl.
N ,N -D i e t h y l-2-[4-(p h e n y lm e t h y l)p h e n o x y ]e t h a -
n a m in e Hyd r och lor id e (3c). The title compound was pre-
pared from 4-benzylphenol and N,N-diethylaminoethyl chloride‚
HCl using procedure B to provide 3c (37%) as a white solid:
1H NMR (CD3OD) δ 1.35 (t, J ) 5 Hz, 6H), 3.30 (q, J ) 5 Hz,
4H), 3.57 (t, J ) 3 Hz, 2H), 3.90 (s, 2H) 4.30 (t, J ) 3 Hz, 2H),
6.90 (d, J ) 8 Hz, 2H), 7.15 (m, 5H), 7.25 (m, 2H). Anal.
(C19H25NO‚HCl) C, H, N.
N,N-Bis(1-m eth yleth yl)-2-[4-(p h en ylm eth yl)p h en oxy]-
eth a n a m in e Hyd r och lor id e (3d ). The title compound was
prepared from 4-benzylphenol and N,N-diisopropylaminoethyl
chloride‚HCl using procedure B to provide 3d (49%) as a white
solid: 1H NMR (CD3OD) δ 1.43 (t, J ) 4 Hz, 12H), 3.60 (t, J
) 3 Hz, 2H), 3.80 (m, 2H), 3.90 (s, 2H), 4.28 (t, J ) 3 Hz, 2H),
6.90 (d, J ) 8 Hz, 2H), 7.15 (m, 5H), 7.25 (m, 2H). Anal.
(C21H29NO‚HCl‚0.3H2O) C, H, N.
1-[2-[4-(P h en ylm eth yl)p h en oxy]eth yl]p ip er id in e Hy-
d r och lor id e (3e). The title compound was prepared from
4-benzylphenol and 1-(2-chloroethyl)piperidine‚HCl using pro-
cedure B to provide 3e (52%) as a white solid: 1H NMR (CDCl3)
δ 1.46 (m, 2H), 1.60 (m, 4H), 2.51 (m, 4H), 2.75 (t, J ) 8 Hz,
2H), 3.90 (s, 2H), 4.07 (t, J ) 8 Hz, 2H), 6.87 (d, J ) 9 Hz,
2H), 7.07 (d, J ) 9 Hz, 2H), 7.15 (m, 3H), 7.26 (t, J ) 9 Hz,
2H). Anal. (C20H25NO‚HCl) C, H, N.
Hexa h yd r o-1-[2-[4-(p h en ylm eth yl)p h en oxy]eth yl]-1H-
a zep in e Hyd r och lor id e (3f). Step 1: P r ep a r a tion of 2-[4-
(P h en ylm eth yl)p h en oxy]p r op a n oic Acid . To a solution of
tert-butyl [4-(phenylmethyl)phenoxy]acetate (3a , step 1) (9.60
g, 34.5 mmol) in 50 mL of CH2Cl2 and 5 mL of MeOH at 0 °C
was added 50 mL of trifluoroacetic acid, and the mixture was
stirred at 0 °C for 20 min and 25 °C overnight. The reaction
mixture was concentrated and recrystallized from Et2O/hexane
to give the title compound (6.12 g, 73%) as a white solid: 1H
NMR (CDCl3) δ 3.93 (s, 2H), 4.64 (s, 2H), 6.84 (d, J ) 9 Hz,
2H), 7.11 (d, J ) 9 Hz, 2H), 7.18 (m, 3H), 7.27 (m, 2H). Anal.
(C15H14O3‚0.1H2O) C, H.
Step 2: P r ep a r a tion of Hexa h yd r o-1-[[4-(p h en ylm eth -
yl)p h en oxy]a cetyl]-1H-a zep in e. To a solution of the product
of step 1 (800 mg, 3.31 mmol) in 10 mL of DMF and 2 mL of
pyridine were added N,N′-disuccinimidyl carbonate (DSC, 842
mg, 3.29 mmol) and catalytic 4-(dimethylamino)pyridine, and
the mixture was stirred at 25 °C for 50 min. Hexamethylene-
imine (330 mg, 3.33 mmol) was added and the mixture stirred
at 25 °C overnight. The mixture was concentrated and
partitioned between EtOAc and saturated KHSO4. The organic
extracts were dried over Na2SO4 and concentrated to provide,
after purification by flash chromatography on silica gel using
7:3 Et2O/hexane, the title compound (800 mg, 75%) as a white
solid: 1H NMR (CDCl3) δ 1.57 (m, 4H), 1.74 (m, 4H), 3.50 (dd,
J ) 11, 6 Hz, 2H), 3.54 (dd, J ) 11, 6 Hz, 2H), 3.93 (s, 2H),
4.67 (s, 2H), 6.88 (d, J ) 8 Hz, 2H), 7.10 (d, J ) 8 Hz, 2H),
7.18 (m, 3H), 7.28 (m, 2H). Anal. (C21H25NO2‚0.1H2O) C, H,
N.
St ep 3: P r ep a r a t ion of H exa h yd r o-1-[2-[4-(p h en yl-
m eth yl)p h en oxy]eth yl]-1H-a zep in e Hyd r och lor id e. To a
stirred suspension of LAH (400 mg, 10.5 mmol) in 10 mL of
THF at 25 °C was added the product from step 2 (700 mg,
2.16 mmol). The mixture was stirred at 25 °C for 3 h, quenched
with 1 mL of water, and diluted with EtOAc. The mixture was
filtered and the filtrate concentrated to afford a colorless oil.
Conversion to the HCl salt and recrystallization from EtOH/
Et2O provided 3f (545 mg, 73%) as a white solid: 1H NMR
(CD3OD) δ 1.76 (m, 4H), 1.94 (m, 4H), 3.45 (m, 4H), 3.61 (t, J
) 7 Hz, 2H), 3.92 (s, 2H), 4.34 (t, J ) 7 Hz, 2H), 6.96 (d, J )
9 Hz, 2H), 7.15 (m, 5H), 7.23 (m, 2H). Anal. (C21H27NO‚HCl‚
0.2H2O) C, H, N.
N ,N -D im e t h y l-2-[4-(p h e n y lm e t h y l)p h e n o x y ]e t h a -
n a m in e Hyd r och lor id e (3b). The title compound was pre-
pared from 4-benzylphenol and N,N-dimethylaminoethyl
chloride‚HCl using procedure B to provide 3b (37%) as a white
solid: 1H NMR (CD3OD) δ 3.05 (s, 6H), 3.55 (t, J ) 5 Hz, 2H),
3.90 (s, 2H), 4.30 (t, J ) 5 Hz, 2H), 6.92 (d, J ) 8 Hz, 2H),
7.15 (m, 5H), 7.25 (m, 2H). Anal. (C17H21NO‚HCl‚0.2H2O) C,
H, N.
4-[2-[4-(P h en ylm eth yl)p h en oxy]eth yl]m or p h olin e Hy-
d r och lor id e (3g). The title compound was prepared from 2-[4-
(phenylmethyl)phenoxy]ethyl 4-methylbenzenesulfonate (3a ,
step 2) and morpholine, using the procedure described in step
1 for the preparation of 3h , to provide 3g (23%): 1H NMR (CD3-
OD) δ 3.31 (br, 2H), 3.53 (br, 2H), 3.61 (t, J ) 5 Hz, 2H), 3.84
(br, 2H), 3.90 (s, 2H), 4.03 (br, 2H), 4.36 (t, J ) 5 Hz, 2H),

SAR Studies on 1-[2-(4-Phenylphenoxy)ethyl]pyrrolidine
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 4 731
6.93 (d, J ) 8 Hz, 2H), 7.15 (m, 5H), 7.23 (m, 2H). Anal.
(C19H23NO2‚HCl‚0.3H2O) C, H, N.
prepared from 2-[4-(phenylmethyl)phenoxy]ethyl 4-methyl-
benzenesulfonate (3a , step 2) and 2-benzyl-2,5-diazabicyclo-
[2.2.1]heptane dihydroiodide22 using the procedure described
in step 1 for the preparation of 3h to provide a viscous yellow
oil (79%): 1H NMR (CDCl3) δ 1.71 (q, J ) 8 Hz, 2H), 2.84 (m,
6H), 3.27 (s, 1H), 3.40 (s, 1H), 3.71 (q, J ) 14 Hz, 2H), 3.90 (s,
2H), 4.02 (t, J ) 5 Hz, 2H), 7.10 (m, 14H).
1-[2-[4-(P h en ylm eth yl)p h en oxy]eth yl]p ip er a zin e (3h ).
Step 1: P r ep a r a tion of 1-Acetyl-4-[2-[4-(p h en ylm eth yl)-
p h en oxy]eth yl]p ip er a zin e. A mixture of 2-[4-(phenylmeth-
yl)phenoxy]ethyl 4-methylbenzenesulfonate (3a , step 2) (1.0
g, 2.6 mmol), N-acetypiperazine (0.4 g, 3.1 mmol), and K2CO3
(1.0 g, 7.2 mmol) in 5 mL of DMF was heated to 80 °C for 16
h. The mixture was concentrated and the residue dissolved in
EtOAc. The solution was washed with water, dried over
MgSO4, and concentrated. The residue was purified by flash
chromatography on silica gel using 85:14:1 CHCl3/EtOH/NH4-
OH to give the title compound as a white solid: 1H NMR
(CDCl3) δ 2.08 (s, 3H), 2.53 (t, J ) 5 Hz, 2H), 2.58 (t, J ) 5
Hz, 2H), 2.81 (t, J ) 6 Hz, 2H), 3.47 (t, J ) 5 Hz, 2H), 3.63 (t,
J ) 5 Hz, 2H), 3.92 (s, 2H), 4.08 (t, J ) 6 Hz, 2H), 6.83 (d, J
) 8 Hz, 2H), 7.10 (d, J ) 8 Hz, 2H), 7.14-7.22 (m, 3H), 7.28,
(t, J ) 8 Hz, 2H). Anal. (C21H26N2O2‚1.1HCl‚0.1H2O) C, H, N,
Cl
St ep 2: P r ep a r a t ion of 1-[2-[4-(P h en ylm et h yl)p h en -
oxy]eth yl]p ip er a zin e. The product of step 1 and excess 3 N
HCl were heated on a steam bath for 16 h, and the mixture
was concentrated to provide 3h as a white solid: 1H NMR
(DMSO-d6) δ 3.50 (m, 10H), 3.88 (s, 2H), 4.36 (br, 2H), 6.92
(d, J ) 8 Hz, 2H), 7.13-7.23 (m, 5H), 7.27 (t, J ) 8 Hz, 2H),
9.70 (br, 2H), 12.05 (br, 1H). Anal. (C19H24N2O‚2HCl) C, H, N,
Cl.
St ep 2: P r ep a r a t ion of 2-[2-[4-(P h en ylm et h yl)p h en -
oxy]eth yl]-2,5-d ia za bicyclo[2.2.1]h ep ta n e Dih yd r och lo-
r id e. The product from step 1 (1.0 g, 2.5 mmol) in 20 mL of
EtOH was hydrogenated in the presence of 20% Pd(OH)2/C
under 60 psi H2 at 25 °C for 24 h. The mixture was filtered
and concentrated, followed by purification on a silica gel prep
plate, eluting with 79:20:1 CHCl3/EtOH/NH4OH. Conversion
to the dihydrochloride salt with dioxane/HCl and recrystalli-
zation from EtOH/Et2O afforded 3l (250 mg, 26%) as a white
solid: 1H NMR (DMSO-d6): δ 1.45 (d, J ) 9 Hz, 1H), 1.65 (d,
J ) 9 Hz, 1H), 1.75 (s, 1H), 2.45 (d, J ) 10 Hz, 1H), 2.77 (m,
4H), 3.00 (d, J ) 10 Hz, 1H), 3.75 (s, 1H), 3.85 (t, J ) 5 Hz,
2H), 7.05 (m, 9H). Anal. (C20H26Cl2N2O‚0.5H2O) C, H, N.
1-[2-(4-P h en oxyp h en oxy)eth yl]p yr r olid in e (4a ). The
title compound was prepared from 4-phenoxyphenol and 1-(2-
chloroethyl)pyrrolidine‚HCl using procedure A to give 4a
(76.5%) as a light yellow oil: 1H NMR (CDCl3) δ 1.81 (m, 4H),
2.63 (m, 4H), 2.91 (t, J ) 6 Hz, 2H), 4.10 (t, J ) 6 Hz, 2H),
6.97 (m, 7H), 7.08 (d, 2H), 7.29 (dd, J ) 9 Hz, 2H). Anal.
(C18H21NO2) C, H, N.
1-Meth yl-4-[2-[4-(p h en ylm eth yl)p h en oxy]eth yl]p ip er -
a zin e Dih yd r och lor id e (3i). The title compound was pre-
pared from 1-methylpiperazine and 2-[4-(phenylmethyl)-
phenoxy]ethyl 4-methylbenzenesulfonate (3a , step 2), as
described in step 1 for the preparation of 3h , to give, after
conversion to the HCl salt with ethanolic HCl and recrystal-
lization from EtOH/Et2O, 3i (26.5%) as a white solid: 1H NMR
(CDCl3) δ 1.59 (m, 4H), 2.80 (s, 3H), 3.19 (m, 2H), 3.40 (m,
4H), 3.92 (s, 2H), 4.30 (m, 2H), 6.81 (d, J ) 8 Hz, 2H), 7.10
(m, 2H), 7.18 (m, 3H), 7.30 (m, 2H). Anal. (C20H26N2O‚2HCl)
C, H, N.
2,6-Dim eth yl-1-[2-[4-(p h en ylm eth yl)p h en oxy]eth yl]p i-
p er id in e Hyd r och lor id e (3j). Step 1: P r ep a r a tion of
2,6-Dim eth yl-1-[[4-(p h en ylm eth yl)p h en oxy]a cetyl]p ip er -
id in e. The title compound was prepared from 4-benzylphenol
and 1-(2-chloroacetyl)-2,6-dimethylpiperidine using procedure
B to provide a white solid (47%): Anal. (C22H27NO2‚0.1H2O):
C, H, N.
Step 2: P r ep a r a tion of 2,6-Dim eth yl-1-[2-[4-(p h en yl-
m eth yl)p h en oxy]eth yl]p ip er id in e Hyd r och lor id e. The
title compound was prepared from the product from step 1
using the procedure described in step 3 for the preparation of
3f, to yield the free base (0.33 g, 52%) as a colorless gum.
Treatment with ethanolic HCl furnished the HCl salt 3j: 1H
NMR (CD3OD) δ 1.36 (d, J ) 5 Hz, 3H), 1.46 (d, J ) 5 Hz,
3H), 2.20 (m, 6H), 3.50 (m, 2H) 3.75 (m, 1H) 3.90 (s, 2H) 4.18
(m, 1H) 4.32 (m, 2H), 6.90 (d, J ) 8 Hz, 2H), 6.87 (m, 5H),
7.25 (m, 2H). Anal. (C22H29NO‚HCl) C, H, N.
2-[2-[4-(P h en ylm et h yl)p h en oxy]et h yl]-2-a za b icyclo-
[2.2.2]oct-5-en e (3k ). 1,3-Cyclohexadiene (801 mg, 10 mmol),
37% aqueous formaldehyde (819 mg, 10 mmol), 3a (2.0 g, 8.8
mmol), and 8.8 mL of 1 N HCl were placed in a Parr bottle
and heated at 55 °C for 48 h. The mixture was cooled and
concentrated and the residue partitioned between EtOAc and
10% aqueous Na2CO3. The aqueous layer was extracted with
EtOAc, and the extracts were washed with brine, dried over
K2CO3, and concentrated. Purification on a silica gel prep plate,
eluting with 97.5:2:0.5 CH2Cl2/CH3OH/NH4OH, afforded 3k
(375 mg, 13%) as a light brown oil: 1H NMR (CDC13) δ 1.27
(m, 2H), 1.54 (m, 1H), 1.98 (m, 1H), 2.10 (m, 1H), 2.49 (m,
1H), 2.60 (p, J ) 5 Hz, 1H), 2.92 (p, J ) 5 Hz, 1H), 3.05 (m,
1H), 3.42 (m, 1H), 3.90 (s, 2H), 3.98 (m, 2H), 6.35 (m, 2H),
6.75-7.30 (m, 9H). Anal. (C22H25NO‚0.2H2O) C, H, N.
2-[2-[4-(P h en ylm eth yl)ph en oxy]eth yl]-2,5-diazabicyclo-
[2.2.1]h ep ta n e Dih yd r och lor id e (3l). Step 1: P r ep a r a tion
of 2-(P h en ylm eth yl)-5-[2-[4-(p h en ylm eth yl)p h en oxy]eth -
yl]-2,5-d ia za bicyclo[2.2.1]h ep ta n e. The title compound was
1-[2-[4-([1,1′-Bip h en yl]-4-yloxy)p h en oxy]eth yl]p yr r oli-
d in e (4b). Step 1: P r ep a r a tion of 4-(4-Meth oxyp h en oxy)-
1,1′-bip h en yl. A mixture of 4-phenylphenol (1.78 g, 10.3
mmol) and KOH (0.98 g, 16.2 mmol) was heated to 190 °C for
1.5 h. 4-Iodoanisole (2.03 g, 8.5 mmol) was added followed by
catalytic copper powder (53 mg). The mixture was heated to
205 °C under argon for 2 h. The reaction was cooled to 25 °C,
10% NaOH was added, and the mixture was extracted with
Et2O. The extracts were washed with water and brine, dried
over MgSO4, filtered, and concentrated to give a pale yellow
solid. The crude product was washed with MeOH to provide
the title compound (0.59 g, 25%) as a light yellow solid: 1H
NMR (CDCl3) δ 3.82 (s, 3H), 6.89 (m, 2H), 7.02 (m, 4H), 7.44
(m, 7H).
Step 2: P r ep a r a tion of 4-([1,1′-Bip h en yl]-4-yloxy)-
p h en ol. The product of step 1 (0.39 g, 1.4 mmol) was stirred
in CH2Cl2 (4 mL) at -78 °C, and 1 N BBr3 in CH2Cl2 (1.6 mL)
was added. After being stirred at 0 °C for 30 min and 25 °C
for 2 h, the mixture was poured into H2O. The organic layer
was washed with brine, dried over MgSO4, and concentrated
to give the title compound as an off-white solid (0.36 g, 98%):
1H NMR (CDCl3) δ 6.84 (m, 2H), 7.00 (m, 4H), 7.45 (m, 7H).
Anal. (C18H14O2‚0.2H2O) C, H.
Step 3: P r ep a r a tion of 1-[2-[4-([1,1′-Bip h en yl]-4-yloxy)-
p h en oxy]eth yl]p yr r olid in e. The title compound was pre-
pared from the product of step 2 and 1-(2-chloroethyl)-
pyrrolidine‚HCl using procedure A to give 4b (39%) as an off-
white solid: 1H NMR (CDCl3) δ 1.82 (m, 4H), 2.64 (m, 4H),
2.91 (t, J ) 6 Hz, 2H), 4.11 (t, J ) 6 Hz, 2H), 6.97 (m, 4H),
7.44 (m, 7H). Anal. (C25H27NO2‚0.2H2O) C, H, N.
4,5-Dih yd r o-2-[4-[4-[2-(1-p yr r olid in yl)e t h oxy]p h e n -
oxy]p h en yl]oxa zole (4c). The title compound was prepared
from 4-cyanophenol using the procedures described in steps
1, 2, and 3 for the preparation of 4b, followed by step 1 for the
preparation of 4d , to give 4c: 1H NMR (CDCl3) δ 1.80 (m, 4H),
2.65 (m, 4H), 2.92 (t, J ) 6 Hz, 2H), 4.00-4.15 (m, 4H), 4.41
(t, J ) 8 Hz, 2H), 6.91 (m, 4H), 7.00 (d, J ) 10 Hz, 2H), 7.88
(d, J ) 10 Hz, 2H).
2-[4-[4-[2-(1-P yr r olid in yl)e t h oxy]p h e n oxy]p h e n yl]-
oxa zole (4d ). St ep 1: P r ep a r a t ion of 4,5-Dih yd r o-2-[4-
(4-m eth oxyp h en oxy)p h en yl]oxa zole. ZnCl2 (0.78 g, 5.3
mmol) was fused under argon, and a mixture of 4-(4-methoxy-
phenoxy)benzonitrile (4c, step 1) (0.54 g, 2.2 mmol) in 8 mL
of ethanolamine was added. After being stirred at 130-140
°C for 4 h, the reaction mixture was cooled, diluted with CH2-
Cl2, and washed with water and brine. The organic layer was
dried over MgSO4 and concentrated in vacuo. Purification by

732 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 4
Penning et al.
flash chromatography on silica gel using 20:1 CH2Cl2/MeOH
provided the title compound (0.29 g, 49%) as a white solid:
1H NMR (CDCl3) δ 3.82 (s, 3H), 4.05 (t, J ) 8 Hz, 2H), 4.41 (t,
J ) 8 Hz, 2H), 6.91 (m, 4H), 7.01 (d, J ) 10 Hz, 2H), 7.89 (d,
J ) 10 Hz, 2H).
Step 2: P r ep a r a tion of 2-[4-(4-Meth oxyp h en oxy)p h en -
yl]oxa zole. A mixture of product of step 1 (149 mg, 0.59 mmol)
and NiO2 (838 mg, 8.9 mmol) in benzene (10 mL) was heated
to reflux overnight. The reaction mixture was cooled and
filtered through Celite, and the filtrate was concentrated to
give the title compound (100 mg, 63%) as a white solid: 1H
NMR (CDCl3) δ 3.83 (s, 3H), 6.97 (m, 6H), 7.20 (s, 1H), 7.69
(s, 1H), 7.97 (d, J ) 10 Hz, 2H).
Step s 3 a n d 4: P r ep a r a tion of 2-[4-[4-[2-(1-P yr r olid i-
n yl)eth oxy]p h en oxy]p h en yl]oxa zole. The title compound
was prepared using the procedures described in steps 2 and 3
for the preparation of 4b, to provide 4d : 1H NMR (CDCl3) δ
1.82 (m, 4H), 2.65 (m, 4H), 2.92 (t, J ) 6 Hz, 2H), 4.12 (t, J )
6 Hz, 2H), 6.98 (m, 6H), 7.20 (s, 1H), 7.68 (s, 1H), 7.98 (d, J )
10 Hz, 2H). Anal. (C21H22N2O3‚0.2H2O) C, H, N.
Step 2: P r ep a r a tion of 1-[2-[4-[(P h en ylm eth yl)th io]-
p h en oxy]eth yl]p yr r olid in e Hyd r och lor id e. The title com-
pound was prepared from the product of step 1 and 1-(2-
chloroethyl)pyrrolidine‚HCl using procedure A to provide the
free base (50%) as a yellow solid: 1H NMR (CDCl3) δ 1.80 (br,
4H), 2.63 (br, 4H), 2.98 (t, J ) 5 Hz, 2H), 3.98 (s, 2H), 4.08 (t,
J ) 5 Hz, 2H), 6.80 (d, J ) 10 Hz, 2H), 7.22 (m, 7H). Anal.
(C19H23NOS‚0.2H2O) C, H, N. Treatment of a CH2Cl2 solution
of the amine with HCl (g) provided the hydrochloride salt 10
as a white solid. Anal. (C19H23NOS‚HCl‚0.4H2O) C, H, N.
1-[2-[4-[(P h e n y lm e t h y l)s u lfin y l]p h e n o x y ]e t h y l]-
p yr r olid in e (11). To a solution of 10 (57 mg, 0.16 mmol) in
10 mL of CH2Cl2 at 0 °C was added 80-85% mCPBA (36 mg,
0.17 mmol), and the reaction mixture was stirred for 1 h. The
mixture was poured into aqueous NaHCO3 and extracted with
EtOAc. The extracts were dried over MgSO4, filtered, and
concentrated to afford 11 (19 mg, 36%) as a yellow solid: 1H
NMR (CDCl3) δ 1.85 (br, 4H), 2.68 (br, 4H), 2.95 (t, J ) 5 Hz,
2H), 4.10 (m, 4H), 6.95 (m, 4H), 7.27 (m, 5H). Anal. (C19H23
-
NO2S‚0.3H2O) C, H, N.
1-[2-[4-[(P h e n y lm e t h y l)s u lfo n y l]p h e n o x y ]e t h y l]-
p yr r olid in e (12). To a solution of 10 (126 mg, 0.36 mmol) in
10 mL of CH2Cl2 was added 80-85% mCPBA (158 mg, 0.73
mmol), and the reaction was stirred at 25 °C overnight. The
mixture was poured into aqueous NaHCO3 and extracted with
EtOAc. The extracts were dried over MgSO4, filtered, and
concentrated to afford 12 (10 mg, 7%) as a yellow solid: 1H
NMR (CDCl3) δ 1.85 (br, 4H), 2.66 (br, 4H), 2.95 (t, J ) 5 Hz,
2H), 4.14 (t, J ) 5 Hz, 2H), 5.46 (s, 2H), 7.07 (m, 9H); HRMS
m/z 345.1403 (calcd for C19H29NO3S, 345.1399).
1 -[ 2 -[ 4 -[ ( P h e n y l t h i o ) m e t h y l ] p h e n o x y ] e t h y l ] -
p yr r olid in e (13). Step 1: P r ep a r a tion of 4-[2-(1-P yr r o-
lid in yl)eth oxy]ben zen em eth a n ol. To a solution of 4-[2-(1-
pyrrolidinyl)ethoxy]benzaldehyde (2i, step 1) (669 mg, 3.05
mmol) in 10 mL of EtOH was added 133 mg (3.52 mmol) of
NaBH4 in 2 mL of H2O. The mixture was stirred at 25 °C for
12 h and quenched with 10% NaOH. The mixture was
extracted EtOAc, and the extracts were dried over MgSO4,
filtered, and concentrated to afford the title compound as a
yellow oil: 1H NMR (CDCl3) δ 1.83 (br, 4H), 2.64 (br, 4H),.
2.85 (t, J ) 5 Hz, 2H), 3.08 (m, 1H), 4.03 (t, J ) 5 Hz, 2H),
4.60 (s, 2H), 6.83 (d, J ) 10 Hz, 2H), 7.25 (d, J ) 10 Hz, 2H).
Step 2: P r ep a r a tion of 1-[2-[4-[(P h en ylth io)m eth yl]-
p h en oxy]eth yl]p yr r olid in e. To a solution of the crude
product from step 1 (330 mg, 3.0 mmol) and 488 mg (2.2 mmol)
of thiophenol in 40 mL of ethylene dichloride was added ZnI2
(1.4 g, 4.4 mmol), and the mixture was refluxed for 24 h. After
cooling, the mixture was poured into 100 mL of H2O and the
aqueous layer extracted with CH2Cl2. The extracts were dried
over MgSO4, filtered, and concentrated to afford a yellow oil.
Purification by flash chromatography on silica gel using 98:
1:1 CH2Cl2/MeOH/NH4OH furnished 13 as a yellow waxy
solid: 1H NMR (CDCl3) δ 1.76 (br, 4H), 2.58 (br, 4H), 2.86 (t,
J ) 5 Hz, 2H), 4.03 (m, 4H), 6.76 (d, J ) 10 Hz, 2H), 7.17 (m,
7H). Anal. (C19H23NOS‚0.4H2O) C, H, N.
N -[ 4 -[ 2 -( 1 -P y r r o l i d i n y l ) e t h o x y ] p h e n y l ] b e n -
zen em eth a n a m in e (14). To a solution of 16 (208 mg, 0.67
mmol) in 25 mL of THF was added 436 mg (11.5 mmol) of LAH.
The mixture was stirred at 25 °C for 5 h and quenched with
H2O. The mixture was extracted with EtOAc, and the extracts
were washed with brine and dried over MgSO4. The crude
yellow oil was filtered through silica gel to afford 14 (76 mg,
38%) as a yellow solid: 1H NMR (CDCl3) δ 1.83 (br, 4H), 2.64
(br, 4H), 2.88 (t, J ) 5 Hz, 2H), 4.07 (t, J ) 5 Hz, 2H), 4.29 (s,
2H), 6.60 (d, J ) 10 Hz, 2H), 6.80 (d, J ) 10 Hz, 2H), 7.30 (m,
5H). Anal. (C19H24N2O‚0.3H2O) C, H, N.
1-[2-[4-[(D iflu o r o )p h e n y lm e t h y l]p h e n o x y ]e t h y l]-
p yr r olid in e (5). Benzophenone 6 (0.5 g, 1.69 mmol), 1,2-
ethanedithiol (0.28 mL, 3.38 mmol) and BF3‚2AcOH (0.47 mL,
3.38 mmol), were stirred at 25 °C for 21 h. The mixture was
poured into EtOAc and aqueous NaHCO3, and the organic
layer was washed with 15% NaOH and brine, dried over Na2-
SO4, and concentrated to give the crude thioketal. A solution
of 1,3-dibromo-5,5-dimethylhydantoin (0.48 g, 1.69 mmol) in
CH2Cl2 (5 mL) was cooled to -78 °C, and hydrogen fluoride-
pyridine (0.8 mL, 3.5 mmol) was added, followed by a solution
of the thioketal in 3 mL of CH2Cl2. After being stirred at -78
°C for 1 h, the mixture was poured into CH2Cl2 and aqueous
NaHCO3, and the organic layer was washed with brine, dried
over Na2SO4, and concentrated to give the crude product. Flash
chromatography on silica gel using a gradient of 2:1 hexane/
EtOAc to 100% EtOAc provided 5 (0.11 g, 20%) as a light
yellow oil: 1H NMR (CDCl3) δ 1.82 (4H, m), 2.65 (4H, m), 2.82
(2H, t), 4.15 (2H, t), 6.94 (2H, d), 7.44 (7H, m); HRMS m/z
317.1583 (calcd for C19H21F2NO, 317.1591).
[4-[2-(1-P yr r olid in yl)e t h oxy]p h e n yl]p h e n ylm e t h a -
n on e (6). The title compound was prepared from 4-hydroxy-
benzophenone and 1-(2-chloroethyl)-pyrrolidine‚HCl using
procedure A to provide 6 (73%) as a colorless oil: 1H NMR
(CDCl3) δ 1.82 (m, 4H), 2.64 (m, 4H), 2.96 (t, J ) 6 Hz, 2H),
4.19 (t, J ) 6 Hz, 2H), 6.98 (d, J ) 9 Hz, 2H), 7.46 (m, 2H),
7.57 (m, 1H), 7.79 (m, 4H). Anal. (C19H21NO2) C, H, N.
r-P h e n y l -4 -[2 -(1 -p y r r o l i d i n y l )e t h o x y ]b e n z e n e -
m eth a n ol (7). Compound 6 was reduced using procedure C
to provide 7 as a white solid: mp 103-104 °C; 1H NMR (CDCl3)
δ 1.75 (m, 4H), 2.53 (m, 4H), 2.79 (t, J ) 6 Hz, 2H), 3.98 (t, J
) 6 Hz, 2H), 4.21 (br, 1H), 5.70 (s, 1H), 6.79 (d, J ) 9 Hz, 2H),
7.17-7.41 (m, 7H). Anal. (C19H23NO2) C, H, N.
1-[2-[4-(2-P h en yleth yl)p h en oxy]eth yl]p yr r olid in e (8).
Compound 17 (0.103 g, 0.35 mmol) was hydrogenated in MeOH
(20 mL) with catalytic 4% Pd/C under 5 psi H2 at 25 °C for 4
h. The solution was concentrated and filtered through silica
gel using EtOAc to give 8 (0.093 g, 90%) as a colorless oil: 1H
NMR (CDCl3) δ 1.83 (m, 4H), 2.62 (m, 4H), 2.87 (m, 6H), 4.09
(t, J ) 6 Hz, 2H), 6.83 (d, J ) 9 Hz, 2H), 7.08 (d, J ) 9 Hz,
2H), 7.19 (m, 3H), 7.28 (m, 2H); HRMS m/z 295.1928 (calcd
for C20H25NO, 295.1936).
1-[2-[4-(P h en ylm eth oxy)ph en oxy]eth yl]pyr r olidin e (9).
The title compound was prepared from 4-(benzyloxy)phenol
and 1-(2-chloroethyl)-pyrrolidine‚HCl using procedure A to
provide 9 (64%) as an amber oil: 1H NMR (CDCl3) δ 7.37 (m,
5H), 6.92 (m, 4H), 5.03 (s, 2H), 4.13 (t, J ) 5 Hz, 2H), 2.93 (t,
J ) 5 Hz, 2H), 2.69 (br, 4H), 1.86 (br, 4H). Anal. (C19H23NO2‚
0.1 H2O) C, H, N.
N -P h e n y l-4-[2-(1-p y r r o li d i n y l)e t h o x y ]b e n z e n e -
m eth a n a m in e (15). To a solution of aniline (1.5 g, 16.1 mmol)
in 10 mL of MeOH was added 4-[2-(1-pyrrolidinyl)ethoxy]-
benzaldehyde (2i, step 1) (0.6 g, 2.7 mmol), followed by 2 mL
of 5 N methanolic HCl and sodium cyanoborohydride (0.12 g,
1.9 mmol). The mixture was stirred at 25 °C for 48 h and
quenched with 10% NaOH. The mixture was extracted with
EtOAc, and the extracts were dried over MgSO4, filtered, and
1-[2-[4-[(P h en ylm et h yl)t h io]p h en oxy]et h yl]p yr r oli-
d in e Hyd r och lor id e (10). St ep 1: P r ep a r a t ion of 4-
[(P h en ylm eth yl)th io]p h en ol. The title compound was pre-
pared from 4-hydroxythiophenol and benzylbromide using
procedure A to afford a pale orange solid (24%): Anal. (C13H13
OS) C, H.
-

SAR Studies on 1-[2-(4-Phenylphenoxy)ethyl]pyrrolidine
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 4 733
concentrated to give an amber oil. Purification on silica gel
using 97:2:1 CH2Cl2/MeOH/NH4OH, conversion to the HCl salt,
and recrystallization from MeOH/Et2O gave 15 (0.434 g, 54%)
as a white solid: 1H NMR (CDCl3) δ 1.83 (br, 4H), 2.64 (br,
4H), 2.90 (t, J ) 5 Hz, 2H), 3.92 (m, 1H), 4.10 (t, J ) 5 Hz,
2H), 4.24 (s, 2H), 6.68 (m, 3H), 6.88 (d, J ) 10 Hz, 2H), 7.22
(m, 4H); HRMS m/z 296.1902 (calcd for C19H24N2O, 296.1889).
N-[4-[2-(1-P yr r olid in yl)eth oxy]p h en yl]ben za m id e (16).
Step 1: P r ep a r a tion of N-(4-Hyd r oxyp h en yl)ben za m id e.
A solution of 4-aminophenol (4.06 g, 37.2 mmol), benzoyl
chloride (4.5 mL, 38.8 mmol), and triethylamine (7 mL, 50.2
mmol) in 40 mL of THF was stirred at 25 °C for 24 h. The
mixture was poured into 100 mL of H2O and extracted with
EtOAc. The extracts were dried over NaSO4, filtered, and
concentrated to afford a yellow solid. Recrystallization from
EtOAc/hexane gave the title compound (4.0 g, 50%) as a white
solid: 1H NMR (CDCl3) δ 6.84 (d, J ) 10 Hz, 2H), 7.51 (m,
5H), 7.87 (d, J ) 10 Hz, 2H). Anal. (C13H11NO2) C, H, N.
Step 2: P r ep a r a tion of N-[4-[2-(1-P yr r olid in yl)eth oxy]-
p h en yl]ben za m id e. The title compound was prepared from
the product of step 1 and 1-(2-chloroethyl)pyrrolidine‚HCl
using procedure A to provide 16 (0.62 g, 39%) as a yellow
solid: 1H NMR (CDCl3) δ 1.82 (br, 5H), 2.64 (br, 4H), 2.93 (t,
J ) 5 Hz, 2H), 4.13 (t, J ) 5 Hz, 2H), 6.94 (d, J ) 10 Hz, 2H),
7.51 (m, 4H), 7.73 (br, 1H), 7.87 (d, J ) 10 Hz, 2H); HRMS
m/z 310.1696 (calcd for C19H22N2O2, 310.1682).
crystalline CO2 complex: mp 166-168 °C; 1H NMR (CDCl3) δ
2.04 (m, 2H), 2.12 (m, 2H), 2.89 (m, 2H), 3.36 (m, 2H), 3.50 (s,
2H), 3.81 (m, 2H), 4.43 (m, 2H), 5.91 (s, 1H), 7.32 (m, 9H).
Anal. (C19H24N2‚CO2‚HCl‚0.6H2O) C, H, N, Cl.
1-[2-[4-(P h en ylm eth yl)ph en ylth io]eth yl]pyr r olidin e Hy-
d r och lor id e (21). Step 1: P r ep a r a tion of 4-Ben zylth io-
p h en ol. 4-Benzylphenol (25 g, 0.136 mol) was dissolved in a
solution of KOH (7.6 g, 0.136 mol) in 90 mL of water and the
solution cooled to 0 °C. A solution of dimethylthiocarbamoyl
chloride (22.3 g, 0.181 mol) in THF (40 mL) was added
dropwise, and the mixture was warmed to 25 °C and made
basic with 10% KOH. The mixture was extracted with Et2O,
and the extracts were washed with brine, dried over Na2SO4,
and concentrated. The brown oil was flushed through a pad
of silica gel with 1:1 Et2O/hexane and recrystallized from
MeOH/hexane to provide a yellow solid (17.5 g). This was
heated neat at 290 °C for 45 min and cooled. KOH (5.6 g, 100
mmol), water (7 mL), and ethylene glycol (50 mL) were added,
and the mixture was refluxed for 1 h. After cooling, the mixture
was poured into cold water and extracted with CH2Cl2. The
aqueous layer was acidified with concentrated HCl and
extracted with CH2Cl2. The combined extracts were dried over
Na2SO4 and concentrated to provide the title compound (7.3
g, 27%) as a light yellow oil: 1H NMR (CDCl3) δ 3.38 (s, 1H),
3.92 (s, 2H), 7.04 (d, J ) 9 Hz, 2H), 7.18 (m, 5H), 7.27 (d, J )
9 Hz, 2H). Anal. (C13H12S) C, H, S.
St ep 2: P r ep a r a t ion of 1-[2-[4-(P h en ylm et h yl)p h en -
ylth io]eth yl]p yr r olid in e Hyd r och lor id e. The title com-
pound was prepared from the product of step 1 and 1-(2-
chloroethyl)pyrrolidine‚HCl using procedure A to provide, after
treatment with ethanolic HCl, 21 (92%) as a white solid: mp
137-139 °C; H NMR (CDCl3) δ 2.02 (m, 2H), 2.18 (m, 2H),
2.77 (m, 2H), 3.18 (m, 2H), 3.41 (m, 2H), 3.78 (m, 2H), 3.96 (s,
2H), 7.10-7.41 (m, 9H). Anal. (C19H23NS‚HCl) C, H, N, Cl.
1-[2-[4-(2-P h en ylet h en yl)p h en oxy]et h yl]p yr r olid in e
(17). The title compound was prepared from trans-4-hydroxy-
stilbene and 1-(2-chloroethyl)pyrrolidine‚HCl using procedure
A to provide 17 (69%) as a white solid: mp 104-104.5 °C; 1H
NMR (CDCl3) δ 1.82 (m, 4H), 2.63 (m, 4H), 2.92 (t, J ) 6 Hz,
2H), 4.14 (t, J ) 6 Hz, 2H), 6.92 (d, J ) 8.7 Hz, 2H), 7.01 (d,
J ) 13.4 Hz, 1H), 7.37 (m, 8H). Anal. (C20H23NO) C, H, N.
1-[2-[4-(tr a n s-2-P h en ylcyclop r op yl)p h en oxy]et h yl]-
p yr r olid in e (18). To 17 (0.10 g, 0.34 mmol) in 10 mL of Et2O
at 0 °C was added catalytic Pd(OAc)2 followed by excess
ethereal diazomethane. The mixture was warmed to 25 °C,
filtered, and concentrated. Flash chromatography using a
gradient of 2:1 hexane/EtOAc to 100% EtOAc provided 18 (96
mg, 92%) as a light yellow oil: 1H NMR (CDCl3) δ 1.38 (t, J )
7 Hz, 2H), 1.81 (m, 4H), 2.10 (m, 2H), 2.62 (m, 4H), 2.90 (t, J
) 6 Hz, 2H), 4.09 (t, J ) 6 Hz, 2H), 6.87 (d, J ) 9 Hz, 2H),
7.07 (d, J ) 9 Hz, 2H), 7.15 (m, 3H), 7.28 (d, J ) 9 Hz, 2H).
Anal. (C21H25NO‚0.7H2O) C, H, N.
1-[2-[4-(P h en ylm eth yl)ph en oxy]pr opyl]pyr r olidin e Hy-
d r och lor id e (19). Step 1: P r ep a r a tion of ter t-Bu tyl 2-[4-
(P h en ylm eth yl)p h en oxy]p r op a n oa te. To a solution of tert-
butyl [4-(phenylmethyl)phenoxy]acetate (3a , step 1) (2.78 g,
9.3 mmol) in 100 mL of THF at -78 °C was added 2 M lithium
diisopropylamide in heptane/THF/ethylbenzene (6 mL, 12
mmol), and the mixture was stirred at -78 °C for 40 min.
Methyl iodide (1.0 mL, 16 mmol) was added, and the mixture
warmed to 25 °C. The mixture was concentrated and parti-
tioned between Et2O and saturated KHSO4. The ether extracts
were dried over Na2SO4 and concentrated. Purification by flash
chromatography on silica gel using 1:4 Et2O/hexane provided
the title compound (2.76 g, 95%): 1H NMR (CDCl3) δ 1.43 (s,
9H), 1.56 (t, J ) 7 Hz, 3H), 3.91 (s, 2H), 4.58 (q, J ) 7 Hz,
1H), 6.79 (d, J ) 9 Hz, 2H), 7.06 (d, J ) 9 Hz, 2H), 7.14 (m,
3H), 7.25 (m, 2H).
Step 2: P r ep a r a tion of 1-[2-[4-(P h en ylm eth yl)p h en ox-
y]p r op yl]p yr r olid in e Hyd r och lor id e. The title compound
was prepared from the product of step 2 using the three-step
procedure described for the preparation of 3f to give 19: 1H
NMR (CD3OD) δ 1.30 (d, J ) 6 Hz, 3H), 2.08 (br, 4H), 3.40
(br, 4H), 3.42 (dd, J ) 11, 1 Hz, 1H), 3.51 (dd, J ) 11, 9 Hz,
1H), 4.80 (m, 1H), 6.94 (d, J ) 9 Hz, 2H), 7.15 (m, 5H), 7.23
(m, 2H). Anal. (C20H25NO‚HCl) C, H, N.
N-[4-(P h en ylm eth yl)ph en yl]-1-pyr r olidin e Eth an am in e
Hyd r och lor id e (20). The title compound was prepared from
4-benzylaniline and 1-(2-chloroethyl)pyrrolidine‚HCl using
procedure A to provide the free base (48%) as a colorless oil.
The HCl salt was generated with ethanolic HCl and the solid
recrystallized from CH2Cl2/hexane to give 20 as a white
1
1 -[ 2 -[ 4 -( P h e n y l m e t h y l ) p h e n y l s u l f i n y l ] e t h y l ] -
p yr r olid in e Hyd r och lor id e (22). A solution of 21 (0.5 g, 1.5
mmol) and 80-85% mCPBA (0.32 g, 1.5 mmol) in CH2Cl2 (20
mL) was stirred at 0 °C for 2 h. The mixture was concentrated
and purified by flash chromatography on silica gel using a
gradient of 100:1:1 to 100:4:1 CH2Cl2/MeOH/NH4OH. Treat-
ment with ethanolic HCl provided 22 (0.37 g, 71%) as a white
1
solid: mp 180-182 °C (d); H NMR (CDCl3) δ 1.78 (m, 4H),
2.55 (m, 4H), 2.67 (dt, J ) 12, 7 Hz, 1H), 2.99 (m, 3H), 4.03 (s,
2H), 7.19 (m, 2H), 7.31 (m, 5H), 7.58 (d, J ) 9 Hz, 2H). Anal.
(C19H23NOS‚HCl) C, H, N, Cl.
1-[3-[4-(P h en ylm eth yl)p h en yl]p r op yl]p yr r olid in e Hy-
d r och lor id e (23). Step 1: P r ep a r a tion of Meth yl (2E)-3-
[4-(P h en ylm et h yl)p h en yl]-2-p r op en oa t e. A solution of
4-benzylbenzoic acid (8.5 g, 40 mmol) in 10 mL of oxalyl
chloride was stirred at 25 °C for 2 h. The solution was
concentrated, and a solution of the crude acid chloride and
catalytic 10% Pd/C in THF/2,6-lutidine was hydrogenated in
a Parr shaker under 5 psi H2 for 6 h. The mixture was filtered,
washed with 1 N HCl and brine, dried over Na2SO4, and
concentrated. A solution of the crude aldehyde (8.0 g, 40 mmol)
and methyl (triphenylphosphoranylidene)acetate (13.6 g, 40
mmol) in 100 mL of THF was stirred at reflux for 10 h. The
mixture was cooled and concentrated. Purification by flash
chromatography on silica gel using hexane/EtOAc furnished
the title compound (6.8 g, 67%): 1H NMR (CDCl3) δ 3.79 (s,
3H), 3.99 (s, 2H), 6.38 (d, J ) 14 Hz, 1H), 7.20 (m, 5H), 7.28
(m, 2H), 7.44 (d, J ) 8 Hz, 2H), 7.67 (d, J ) 14 Hz, 1H).
Step 2: P r ep a r a tion of 1-[1-Oxo-3-[4-(p h en ylm eth yl)-
p h en yl]p r op yl]p yr r olid in e. A solution of the product of step
1 (2.4 g, 9.5 mmol) and catalytic Raney nickel in MeOH was
hydrogenated under 5 psi H2 for 15 min. The mixture was
filtered and concentrated to provide the saturated ester
(100%): 1H NMR (CDCl3) δ 2.61 (t, J ) 9 Hz, 2H), 2.91 (t, J )
9 Hz, 2H), 3.66 (s, 3H), 3.94 (s, 2H), 7.11 (s, 4H), 7.18 (m, 3H),
7.27 (m, 2H). A solution of pyrrolidine (0.76 mL, 9.0 mmol) in
CH2Cl2 and 2 M AlMe3 in toluene (4.5 mL, 9.0 mmol) was
stirred at 25 °C for 30 min. A solution of the crude ester (2.3
g, 9.0 mmol) in CH2Cl2 was added, and the mixture was
refluxed for 7 h. The mixture was diluted with cold 1 N HCl

734 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 4
Penning et al.
and extracted with EtOAc. The extracts were washed with
brine, dried over Na2SO4, and concentrated. Purification by
flash chromatography on silica gel using 1:1 hexane/EtOAc
furnished the title compound (1.8 g, 68%): 1H NMR (CDCl3) δ
1.83 (m, 4H), 2.53 (d, J ) 8 Hz, 2H), 2.94 (d, J ) 8 Hz, 2H),
3.25 (d, J ) 8 Hz, 2H), 3.45 (d, J ) 8 Hz, 2H), 3.96 (s, 2H),
7.14 (m, 7H), 7.27 (m, 2H); HRMS m/z 293.1783 (calcd for
1-[ci s-3-[4-(P h e n y lm e t h y l)p h e n y l]c y c lo b u t a n y l]-
p ip er id in e Hyd r och lor id e (26). Step 1: P r ep a r a tion of
4-Ben zylstyr en e. To a suspension of methyltriphenylphos-
phonium bromide (32 g, 90 mmol) in 300 mL of THF at 25 °C
was added potassium tert-butoxide (9.9 g, 88 mmol) in portions
over 15 min. After 45 min, 4-benzylbenzaldehyde (13.85 g, 71
mmol) in 20 mL of THF was added, and the mixture was
stirred for 16 h. Aqueous NH4Cl was added, and the organic
layer was dried over MgSO4 and concentrated. Purification by
flash chromatography on silica gel using 20:1 hexane/EtOAc
gave the title compound (12.5 g, 90%) as a yellow oil: 1H NMR
(CDCl3) δ 3.97 (s, 2H), 5.20 (d, J ) 11 Hz, 1H), 5.70 (d, J ) 18
Hz, 1H), 6.68 (dd, J ) 18, 11 Hz, 1H), 7.17 (m, 5H), 7.28 (t, J
) 7 Hz, 2H), 7.34 (d, J ) 8 Hz, 2H).
Step 2: P r ep a r a tion of 3-[4-(P h en ylm eth yl)p h en yl]-
cyclobu ta n on e. To a stirred mixture of 4-benzylstyrene (9.1
g, 47 mmol) and zinc-copper couple (prepared from 15 g of
zinc and 0.96 g of CuSO4) in 400 mL of Et2O at 40 °C was
added a solution of POCl3 (13.3 mL, 143 mmol) and trichlo-
roacetyl chloride (15.5 mL, 139 mmol) in 140 mL of Et2O over
1 h. After being stirred for 30 min at 25 °C, the mixture was
decanted and the residue washed with Et2O. The combined
ether extracts were filtered through Celite, cooled to 0 °C,
washed with cold water and aqueous NaHCO3, dried over
MgSO4, and concentrated to give the crude dichloroketone
(13.8 g). This was dissolved in 50 mL of AcOH and added
dropwise to 30 g of Zn-Cu couple in 50 mL of AcOH, and the
mixture was heated to 100 °C for 3 h. After cooling, the mixture
was diluted with Et2O and filtered through Celite. The filtrate
was treated with 150 mL of 30% NaOH, and the organic layer
was dried over MgSO4 and concentrated. Purification by flash
chromatography using 5:1 hexane/EtOAc gave the title com-
pound (7.2 g, 65%) as a viscous oil: 1H NMR (CDCl3) δ 3.10
(m, 2H), 3.33 (m, 2H), 3.50 (p, J ) 8 Hz, 1H), 3.91 (s, 2H),
7.11 (m, 7H), 7.23 (t, J ) 8 Hz, 2H).
Step 3: P r ep a r a tion of 1-[cis-3-[4-(P h en ylm eth yl)-
p h en yl]cyclobu t a n yl]p ip er id in e Hyd r och lor id e. To a
solution of the product from step 2 (0.508 g, 2.15 mmol) and
pyrrolidine (0.19 mL, 2.28 mmol) in 5 mL of EtOH was added
borane-pyridine complex (0.22 mL, 2.18 mmol), and the
mixture was stirred at 25 °C for 16 h. The mixture was
concentrated and the residue treated with 1 N HCl followed
by 1 N NaOH. The mixture was extracted with EtOAc, and
the extracts were concentrated. Purification by flash chroma-
tography on silica gel using 85:14:1 CHCl3/EtOH/NH4OH,
treatment with ethereal HCl, and recrystallization from EtOH/
Et2O afforded 26 as a white solid: 1H NMR (DMSO-d6) δ 1.89
(m, 2H), 2.00 (m, 2H), 2.34 (q, J ) 10 Hz, 2H), 2.60 (q, J ) 8
Hz, 2H), 2.90 (m, 2H), 3.14 (p, J ) 9 Hz, 1H), 3.40 (m, 2H),
3.70 (q, J ) 8 Hz, 1H), 3.91 (s, 2H), 7.22 (m, 9H), 10.95 (br,
1H). Anal. (C21H25N‚HCl) C, H, N, Cl.
1-[2-(4-H exyloxyp h en oxy)et h yl]p yr r olid in e (27). The
title compound was prepared from 4-n-hexyloxyphenol and
1-(2-chloroethyl)pyrrolidine‚HCl using procedure A to provide
27 (48%) as a light green solid: 1H NMR (CDCl3) δ 0.92 (br,
3H), 1.40 (m, 6H), 1.75 (t, J ) 4 Hz, 2H), 1.86 (br, 4 H), 2.67
(br, 4H), 2.92 (t, J ) 4 Hz), 3.89 (t, J ) 7 Hz, 2H), 4.08 (t, J )
4 Hz, 2H), 6.80 (m, 4H). Anal. (C18H29NO2‚0.2H2O) C, H, N.
C
20H23NO, 293.1779).
Step 3: P r ep a r a tion of 1-[3-[4-(P h en ylm eth yl)p h en yl]-
p r op yl]p yr r olid in e Hyd r och lor id e. To the product of step
2 (0.25 g, 0.85 mmol) in 10 mL of Et2O was added LAH (0.03
g, 0.8 mmol), and the mixture was heated to reflux for 7 h.
The mixture was cooled and quenched with H2O, followed by
1 N NaOH. The mixture was partitioned between EtOAc and
H2O, and the organic layer washed with brine, dried over Na2-
SO4, and concentrated. Treatment with ethanolic HCl provided
23 (0.20 g, 74%) as a white solid: 1H NMR (CDCl3) δ 2.00 (m,
2H), 2.22 (m, 4H), 2.34 (t, J ) 5 Hz, 4H), 2.97 (m, 2H), 3.78
(m, 2H), 3.95 (s, 2H), 7.20 (m, 9H). Anal. (C20H25N‚HCl‚0.4H2O)
C, H, N.
1-[3-[4-(P h en ylm et h yl)p h en yl]-2E-p r op en yl]p yr r oli-
d in e (24). Step 1: P r ep a r a tion of 1-[(1E)-3-Ch lor o-1-
pr open yl]-4-(ph en ylm eth yl)ben zen e. To a solution of meth-
yl (2E)-3-[4-(phenylmethyl)phenyl]-2-propenoate (23, step 1)
(2.5 g, 10.0 mmol) in 20 mL of toluene at -78 °C was added
24 mL of 1 M diisobutylaluminum hydride in hexanes, and
the mixture was stirred at -20 °C for 2 h. The reaction was
quenched with MeOH, warmed to 25 °C, filtered, and concen-
trated. The residue was triturated with 1:1 Et2O/toluene and
filtered, and the filtrate was concentrated to provide 2.0 g of
crude alcohol. To a solution of the alcohol (806 mg, 3.6 mmol)
and LiCl (162 mg, 3.8 mmol) in 5 mL of DMF at 0 °C was
added methanesulfonyl chloride (412 mg, 3.6 mmol) dropwise.
After the mixture was stirred at 0 °C for 1 h, ice water was
added and the mixture extracted with EtOAc. The extracts
were dried over MgSO4, filtered, and concentrated in vacuo to
give a yellow oil which was purified by flash chromatography
on silica gel using 9:1 hexane/EtOAc to afford the title
compound (368 mg, 42%) as a colorless oil: 1H NMR (CDCl3)
δ 3.98 (s, 2H), 4.24 (d, 2H), 6.27 (dt, J ) 10 Hz, 1H), 6.64 (d,
J ) 15 Hz, 1H), 7.25 (m, 9H). Anal. (C16H15Cl) C, H.
Step 2: P r ep a r a tion of 1-[3-[4-(P h en ylm eth yl)p h en yl]-
2E-p r op en yl]p yr r olid in e. A solution of the product of step
1 (85 mg, 0.35 mmol), pyrrolidine (32 mg, 0.45 mmol), K2CO3
(245 mg, 1.8 mmol), and n-Bu4NI (20 mg) in 10 mL of DMF
was heated at 60 °C for 12 h and poured into H2O. The mixture
was extracted with EtOAc, and the extracts were dried over
MgSO4, filtered, and concentrated. Purification on silica gel
using 98:1:1 CH2Cl2/MeOH/NH4OH afforded 24 (44 mg, 45%)
as a white solid: 1H NMR (CDCl3) δ 1.80 (br, 4H), 2.54 (br,
4H), 3.95 (d, J ) 8 Hz, 2H), 6.29 (dt, J ) 5 Hz, 2H), 6.51 (d, J
) 15 Hz, 1H), 7.24 (m, 9H). Anal. (C20H23N‚0.2H2O) C, H, N.
1 -[2 -[4 -(P h e n y l m e t h y l )p h e n y l m e t h o x y ]e t h y l ]-
p yr r olid in e Hyd r och lor id e (25). To a stirred solution of
4-benzylbenzoic acid (24.5 g, 115 mmol) in 600 mL of THF at
-78 °C was added LAH (3.7 g, 98 mmol) in portions over 5
min. The mixture was warmed to 25 °C and stirred for 16 h.
Additional LAH (0.9 g, 24 mmol) was added and the mixture
refluxed for 1.5 h. The mixture was cooled to -10 °C, treated
with water and 15% NaOH, diluted with Et2O, filtered, and
concentrated to give 22.7 g (99%) of a white solid. To a mixture
of the crude benzyl alcohol (0.4 g, 2.0 mmol) and 1-(2-
chloroethyl)pyrrolidine‚HCl (0.2 g, 1.2 mmol) in DMF was
added 0.2 g of NaH (60% dispersion in oil, 5 mmol) and the
mixture stirred at 25 °C overnight. The mixture was carefully
added to ice water and extracted with EtOAc. The extracts
were washed with water, dried over MgSO4, and concentrated.
The residue was purified by flash chromatography on silica
gel using 3:2 hexane/EtOAc containing 2% Et3N to give, after
treatment with ethereal HCl, 25 as a white solid: 1H NMR
(DMSO-d6) δ 1.87 (m, 2H), 1.93 (m, 2H), 3.00 (m, 2H), 3.34 (q,
J ) 5 Hz, 2H), 3.48 (m, 2H), 3.77 (t, J ) 5 Hz, 2H), 3.93 (s,
1 -[ 2 -[ 4 -( C y c l o h e x y l m e t h y l ) p h e n o x y ] e t h y l ] -
p yr r olid in e (28). The title compound was prepared from
cyclohexanecarboxaldehyde using procedure F, followed by
procedure D, to provide 28: 1H NMR (CDCl3) δ 0.83-1.70 (m,
11H), 1.80 (m, 4H), 2.40 (d, J ) 7 Hz, 2H), 2.60 (m, 4H), 2.88
(t, J ) 6 Hz, 2H), 4.08 (t, J ) 6 Hz, 2H), 6.82 (d, J ) 9 Hz,
2H), 7.02 (d, J ) 9 Hz, 2H). Anal. (C19H29NO2‚0.1H2O) C, H,
N.
1-[2-(3-P h en ylp h en oxy)eth yl]p yr r olid in e (29). The title
compound was prepared from 2-phenylphenol and 1-(2-
chloroethyl)pyrrolidine‚HCl using procedure A to provide 29
(48%) as a yellow oil: 1H NMR (CDCl3) δ 1.80 (m, 4 H), 2.64
(m, 4 H), 2.93 (t, J ) 5 Hz, 2H), 4.20 (t, J ) 5 Hz, 2H), 7.40
(m, 9H). Anal. (C18H21NO‚0.1H2O) C, H, N.
2H), 4.48 (s, 2H), 7.25 (m, 9H), 11.06 (br, 1H). Anal. (C20H25
-
1-[2-[(t r a n s-4-P h e n y l)c y c lo h e x y lo x y ]e t h y l]p y r r o -
lid in e (30). Step 1: P r ep a r a tion of cis- a n d tr a n s-4-
NO‚1.1HCl‚0.7H2O) C, H, N, Cl.

SAR Studies on 1-[2-(4-Phenylphenoxy)ethyl]pyrrolidine
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 4 735
(9) (a) Haeggstro¨m, J . Z.; Wetterholm, A.; Vallee, B. L.; Samuelsson,
B. Leukotriene A4 Hydrolase: An Epoxide Hydrolase with
Peptidase Activity. Biochem. Biophys. Res. Commun. 1990, 173,
431-437. (b) Minami, M.; Bito, H.; Ohishi, N.; Tsuge, H.;
Miyano, M.; Mori, M.; Wada, H.; Mutoh, H.; Shimada, S.; Izumi,
T.; Abe, K.; Shimizu, T. Leukotriene A4 Hydrolase, a Bifunctional
Enzyme. FEBS 1992, 309, 353-357. (c) Haeggstro¨m, J . Z.;
Wetterholm, A.; Medina, J . F.; Samuelsson, B. Leukotriene A4
Hydrolase: Structural and Functional Properties of the Active
Center. J . Lipid Mediators 1993, 6, 1-13.
(10) (a) Izumi, T.; Shimizu, T.; Seyama, Y.; Ohishi, N.; Takaku, F.
Tissue Distribution of Leukotriene A4 Hydrolase Activity in
Guinea Pig. Biochem. Biophys. Res. Commun. 1986, 135, 139-
145. (b) Fu, J . Y.; Haeggstro¨m, J .; Collins, P.; Meijer, J .;
Rådmark, O. Leukotriene A4 Hydrolase: Analysis of Some
Human Tissues by Radioimmunoassay. Biochim. Biophys. Acta
1989, 1006, 121-126.
P h en ylcycloh exa n ol. To a solution of 4-phenylcyclohexanone
(1.7 g, 10 mmol) in EtOH (30 mL) was added a solution of
NaBH4 (0.3 g, 7.9 mmol) in water (3 mL), and the mixture
was stirred at 25 °C for 1 h. The mixture was poured into 1 N
HCl and EtOAc, and the organic layer was washed with brine,
dried over Na2SO4, and concentrated. Flash chromatography
on silica gel using a gradient of 5:1 to 3:1 hexane/EtOAc gave
the cis-product (0.184 g, 10.4%) as a white solid [1H NMR
(CDCl3) δ 1.45 (s, 1H), 1.69 (m, 4H), 1.90 (m, 4H), 2.53 (tt, J
) 11.7, 2.9 Hz, 1H), 4.14 (br, 1H), 7.26 (m, 5H)] and the trans-
product (0.50 g, 28.4%) as a white solid [1H NMR (CDCl3) δ
1.49 (m, 4H), 1.86 (s, 1H), 1.96 (m, 2H), 2.12 (m, 2H), 2.51 (tt,
J ) 11.7, 3.3 Hz, 1H), 3.69 (tt, J ) 10.4, 4.3 Hz, 1H), 7.26 (m,
5H)].
Step 2: P r ep a r a tion of 1-[2-[(tr a n s-4-P h en yl)cyclo-
h exyloxy]eth yl]p yr r olid in e. To a solution of the trans-
product from step 1 (0.48 g, 2.7 mmol) in DMF (25 mL) was
added 0.22 g of NaH (60% dispersion in oil, 5.5 mmol), and
the mixture stirred at 25 °C for 45 min. 1-(2-Chloroethyl)-
pyrrolidine‚HCl (0.48 g, 2.8 mmol) and n-Bu4NI (1.04 g, 2.8
mmol) were added, and the mixture was stirred at 25 °C for
24 h and at 80 °C for 15 h. The mixture was poured into Et2O
and water, and the ether layer was washed with brine, dried
over Na2SO4, and concentrated. Flash chromatography on
silica gel using a gradient of 2:1 hexane/EtOAc to 100% EtOAc
gave 30 (0.283 g, 38%) as a yellow oil: 1H NMR (CDCl3) δ 1.42
(m, 4H), 1.77 (m, 4H), 1.91 (m, 2H), 2.16 (m, 2H), 2.48 (m,
1H), 2.55 (m, 4H), 2.69 (t, J ) 6 Hz, 2H), 3.29 (m, 1H), 3.64 (t,
J ) 6 Hz, 2H), 7.22 (m, 5H). Anal. (C18H27NO‚0.2H2O) C, H,
N.
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