Synthesis of potent leukotriene A4 hydrolase inhibitors. Identification of 3-[methyl[3-[4-(phenylmethyl)phenoxy]propyl]amino]propanoic acid

Article abstract of DOI:10.1021/jm0200916

Leukotriene B₄ (LTB₄) is a potent, proinflammatory mediator involved in the pathogenesis of a number of diseases including inflammatory bowel disease, psoriasis, rheumatoid arthritis, and asthma. The enzyme LTA₄ hydrolase

Full text of DOI:10.1021/jm0200916

3482
J . Med. Chem. 2002, 45, 3482-3490
Syn th esis of P oten t Leu k otr ien e A4 Hyd r ola se In h ibitor s. Id en tifica tion of
3-[Meth yl[3-[4-(p h en ylm eth yl)p h en oxy]p r op yl]a m in o]p r op a n oic Acid
Thomas D. Penning,*,† Mark A. Russell,† Barbara B. Chen,† Helen Y. Chen,† Chi-Dean Liang,†
Matthew W. Mahoney,† J ames W. Malecha,† J ulie M. Miyashiro,† Stella S. Yu,† Leslie J . Askonas,‡
J ames K. Gierse,‡ Elizabeth I. Harding,‡ Maureen K. Highkin,‡ J ames F. Kachur,‡ Suzanne H. Kim,‡
Doreen Villani-Price,‡ E. Yvonne Pyla,‡ Nayereh S. Ghoreishi-Haack,‡ and Walter G. Smith‡
Department of Medicinal Chemistry and Departments of Inflammatory Diseases Research and Molecular Pharmacology,
Pharmacia Corporation, 4901 Searle Parkway, Skokie, Illinois 60077
Received February 28, 2002
Leukotriene B4 (LTB4) is a potent, proinflammatory mediator involved in the pathogenesis of
a number of diseases including inflammatory bowel disease, psoriasis, rheumatoid arthritis,
and asthma. The enzyme LTA4 hydrolase represents an attractive target for pharmacological
intervention in these disease states, since the action of this enzyme is the rate-limiting step in
the production of LTB4. Our previous efforts focused on the exploration of a series of analogues
related to screening hit SC-22716 (1, 1-[2-(4-phenylphenoxy)ethyl]pyrrolidine) and resulted in
the identification of potent, orally active inhibitors such as 2. Additional structure-activity
relationship studies around this structural class resulted in the identification of a series of R-,
â-, and γ-amino acid analogues that are potent inhibitors of the LTA4 hydrolase enzyme and
demonstrated good oral activity in a mouse ex vivo whole blood LTB4 production assay. The
efforts leading to the identification of clinical candidate SC-57461A (8d , 3-[methyl[3-[4-
(phenylmethyl)phenoxy]propyl]amino]propanoic acid) are described.
In tr od u ction
lead that inhibited LTA4 hydrolase with an IC50 of 0.20
µM and demonstrated good cellular activity in a calcium
ionophore-stimulated human whole blood assay, inhibit-
ing the production of LTB4 with an IC50 of 0.79 µM.
However, 1 demonstrated poor oral activity in a mouse
ex vivo whole blood LTB4 production assay (9% inhibi-
tion at 10 mg/kg). These efforts resulted in the identi-
fication of potent, orally active analogues such as 2,
which had IC50 values of 0.043 and 0.055 µM in the
enzyme and whole blood assays and demonstrated good
oral activity in the mouse ex vivo assay (93% inhibition
at 10 mg/kg). In the present study, we describe our
efforts on a unique series of R-, â-, and γ-amino acid
analogues developed from these earlier leads in an effort
to further optimize the oral efficacy of this class. A
number of these analogues were potent inhibitors of
LTA4 hydrolase and showed excellent oral activity in
the mouse ex vivo assay, resulting in the identification
of clinical candidate SC-57461A (8d ).
Leukotriene B4 (LTB4) is a 5-lipoxygenase (5-LO)-
derived metabolite of arachidonic acid that is synthe-
sized by a number of cell types, including eosinophils,
neutrophils (PMNs), and macrophages.1 LTB4 is a
potent proinflammatory mediator that plays a signifi-
cant role in the amplification of many inflammatory
disease states2 including inflammatory bowel disease
(IBD),3 psoriasis,4 rheumatoid arthritis,5 gout,6 and
asthma.7 LTB4 also stimulates the production of various
cytokines and may play a role in immunoregulation.8-11
In addition, LTB4 is a mediator of inflammatory pain12
and binds to peroxisome proliferator-activated receptor
(PPARR), which could affect the duration of an inflam-
matory response to LTB4.13
Leukotriene A4 (LTA4) hydrolase is a zinc-containing
enzyme14 that stereospecifically catalyzes the hydrolysis
of the unstable epoxide LTA4 to LTB4, the rate-limiting
step in the biosynthesis of LTB4. LTA4 hydrolase is a
cytosolic, monomeric enzyme that is ubiquitously dis-
tributed in mammalian tissues.15 Selective inhibitors of
LTA4 hydrolase would preferentially block the formation
of LTB4 (vs the cysteinyl leukotrienes LTC4, LTD4, and
LTE4) and thus would be an attractive pharmacological
target.
Ch em istr y
Our previous report described a detailed structure-
activity study of initial lead 1, which included numerous
modifications of the amino functional group. In the
present study, we sought to broaden the scope of this
work by investigating a series of acyclic amino acid
analogues. The initial series shown in Table 1 main-
tained the diphenylmethane functionality while varying
the length of the linkers between the oxygen and
nitrogen atoms (x linker) and the nitrogen and carboxy-
late functionality (y linker). Secondary amines, as well
as methyl-substituted tertiary amines, were also ex-
plored. A second series (Table 2) varied the aryl func-
tionality while maintaining an optimized right-hand-
side amino acid moiety. The third series shown in Table
A variety of inhibitors of LTA4 hydrolase have been
reported over the past several years, a topic that has
recently been reviewed.16 Our previously described
efforts17 focused on the exploration of a series of
analogues related to screening hit SC-22716 (1), an early
* To whom correspondence should be addressed. Phone: (847)982-
7563. Fax: (847) 982-4714. E-mail: thomas.d.penning@pharmacia.com.
† Department of Medicinal Chemistry.
‡ Departments of Inflammatory Diseases Research and Molecular
Pharmacology.
10.1021/jm0200916 CCC: $22.00 © 2002 American Chemical Society
Published on Web 06/27/2002

Leukotriene A4 Hydrolase Inhibitors
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 16 3483
Ta ble 1. Amino Acid Modifications
a
IC50 (µM)
ED90 (mg/kg)
compd
x
y
R1
R2
rhLTA4 hydrolase
human whole blood
mouse ex vivo
1 (SC-22716)
2
3a
4a
5a
6a
7a
8a
8b
9a
9b
10a
10b
11a
5c
8c
0.2 (2)
0.043
2.5 (2)
0.22 (1)
3.7
10.7 (2)
3.0 (2)
0.084
0.14 (2)
0.014
0.0013
0.007
0.018
0.25
0.79
0.055
>30(2)
0.59
9% @ 10 mg/kg
93% @ 10 mg/kg
b
62% @ 10 mg/kg
b
b
22% @ 10 mg/kg
54% @ 10 mg/kg
g10
g10
g10
3
70% @ 10 mg/kg
10
g10
3-10
1-3
b
2
2
2
2
3
3
3
4
4
4
4
5
2
3
3
4
4
4
1
2
3
4
1
2
2
1
1
2
2
1
3
2
2
1
1
2
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
Me
Me
Me
Me
Et
Me
Et
Et
Et
Et
H
Et
H
Et
H
Et
Me
Et
H
Et
H
2.5 (2)
2.5 (2)
1.1
0.45
0.28
0.35
0.23
0.076
0.49
0.42
0.46
0.11
0.049
3.3 (2)
0.45
0.45
0.19
0.0025
6.6
0.11
8d (SC-57461A)
9c
9d
10c
b
b
Et
>10
0.52
a
b
Average of at least three determinations except where noted in parentheses. Not determined.
a phenol with chloronitrile 26 (prepared from 1-bromo-
3-chloropropane and N-methyl-â-alaninenitrile) gave,
after hydrolysis of the nitrile, the target amino acid. In
cases where a secondary amino ester was produced, the
amine was methylated under reductive amination con-
ditions using aqueous formaldehyde and sodium cy-
anoborohydride to provide the N-methylamino ester. All
esters were converted to their respective carboxylic acids
either under acidic conditions for methyl and ethyl
esters or under catalytic hydrogenolysis conditions for
benzyl esters.
Resu lts a n d Discu ssion
Table 1 details an extensive structure-activity effort
in which the length of the linkers between the oxygen
and nitrogen atoms (x linker) and between the nitrogen
and carboxylate moiety (y linker) was explored while
maintaining the diphenylmethane functionality. In ad-
dition, substitution at nitrogen and potential differences
between acids and esters were also explored. In the NH
series of analogues with a two-carbon x linker, the
analogue with a two-carbon y linker (4a ) was optimal,
with an IC50 of 0.22 and 0.59 µM in the LTA4 hydrolase
enzyme and human whole blood assays, respectively.
One-, three-, and four-carbon y linkers all had signifi-
cantly reduced potency. In the series where the x linker
is three carbons, an analogue with a two-carbon y linker
was optimal (8a ) with an IC50 of 0.084 and 0.45 µM in
the enzyme and whole blood assays. In the four-carbon
x linker series, both one- and two-carbon y linker
analogues (9a and 10a ) showed excellent potency in the
enzyme assay (IC50 ) 0.014 and 0.007 µM). A five-
carbon x linker analogue 11a showed slightly dimin-
ished enzyme potency. Although in general the acids did
show a trend toward increased potency over the esters
in the enzyme assay, this was not reflected in either
the whole blood or mouse ex vivo assays, where the
3 explored isosteric replacements for the carboxylate
functional group. Scheme 1 details the various synthetic
routes utilized in the synthesis of these analogues. In
general, all phenol starting materials either were com-
mercially available or could be easily prepared as
previously described.17,18 These phenols were alkylated
using a bromochloroalkane to give chloride 21.17 Alky-
lation of an amino ester 22 in the presence of potassium
carbonate and sodium iodide in DMF at 80 °C then
provided the desired amino esters. Similarly, the phe-
nols could be converted to tosylate 23 (alkylation with
bromo tert-butylacetate, reduction, tosylation)18 and
combined with 22 to give the amino esters. Alterna-
tively, chloride 21 was reacted with methylamine to give
24, followed by 1,4-conjugate addition to an acrylate
ester, to provide an N-methylamino ester. A phenol
could also be alkylated with bromoacetaldehyde diethyl
acetal to give, after hydrolysis of the acetal, aldehyde
25. Reductive amination with the appropriate amino
ester provided the desired amino esters. Alkylation of

3484 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 16
Ta ble 2. Aryl Modifications
Penning et al.
a
Average of at least three determinations except where noted in parentheses.
esters and acids demonstrated similar potency. It is
likely that the esters are simply converted to the
corresponding acids in the ex vivo assay, although we
currently have no data to support this. Overall, within
the NH- series, 9a ,b and 10a ,b were the most potent
inhibitors of LTA4 hydrolase, with IC50 values down to
1.3 nM for 9b. Good potencies were also seen in the
whole blood assay for these analogues. However, within
the NH- series, only 10a showed the potency that we
desired in the mouse ex vivo assay, with an ED90 of 3
mg/kg. A similar series of analogues was synthesized
in the N-methyl series, resulting in the identification
of 8d as the most potent inhibitor of the enzyme (IC50
Because of the excellent in vitro and ex vivo potency
of 8d , the amino acid portion of this analogue was
maintained in further optimization efforts focusing on
the left-hand side of the molecule. The results of this
study are detailed in Table 2. On the basis of the results
of some of our previous work, biaryls and heterocycles
were a major focus of this effort. The majority of these
analogues demonstrated significant potency in the
enzyme assay, with several showing outstanding po-
tency, including 15d , 18d , and 19d with IC50 values of
<0.0005, 0.0047, and 0.002 µM, respectively. As dem-
onstrated before, there was a trend toward increased
enzyme potency with the free carboxylic acids. Within
this series, those demonstrating the best oral activity
in the mouse ex vivo assay were 19c with an ED90 of
1-3 mg/kg and 13d and 14d , each with an ED90 value
of 3 mg/kg.
) 0.0025 µM) and whole blood LTB4 production (IC50
)
0.049 µM). In addition, this analogue demonstrated
excellent oral activity in the mouse ex vivo assay, with
an ED90 in the 1-3 mg/kg range. All other analogues
in the N-methyl series showed significantly reduced
potency.
In the final study shown in Table 3, we explored
isosteric replacements for the carboxylate moiety using

Leukotriene A4 Hydrolase Inhibitors
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 16 3485
Ta ble 3. Carboxylate Surrogates
It was assumed that this class of R-, â-, and γ-amino
acid inhibitors was distinct from previously described
classes of inhibitors containing a known zinc-binding
moiety such as a hydroxamic acid, hydroxyurea, and
thiol. This new amino acid class is distinguished from
these previous classes not only structurally but also in
their apparent mode of binding to the enzyme, primarily
in the lack of an obvious zinc-binding functional group.
Supporting evidence of this was obtained from prelimi-
nary extended X-ray absorption fine structure (EXAFS)
spectroscopy. EXAFS spectroscopy of the zinc-containing
LTA4 hydrolase enzyme carried out in either the pres-
ence or absence of 8d was similar within the first
coordination shell of the zinc atom. This provided good
evidence of a lack of interaction of this class of inhibitors
with the zinc atom of the enzyme. In addition, it appears
that the carboxylate moiety does not play a major role
in these inhibitors’ interactions with the enzyme, since
amide, ester, and acid analogues, as well as many of
our previously described17 analogues lacking the car-
boxylate functionality, all have similar potencies against
the enzyme. Likewise, the carboxylate group does not
play a major role in cell penetration, as evidenced by
analogous human whole blood data. Rather, the car-
boxylate group seems to play a significant role in the
optimization of the in vivo properties of this class of
inhibitors, presumably by improved oral absorption.
However, at this time no detailed comparative phar-
macokinetic studies have been carried out to confirm
this.
a
IC50 (µM)
rhLTA4
human
ED90 (mg/kg)
compd
R
hydrolase whole blood mouse ex vivo
8c
8d
8e
8f
8g
8h
8i
-CO2Et
0.25 (2)
0.0025
0.007
0.11
0.049
0.11
0.56 (2)
0.07
0.075
5.2 (2)
0.74
72% @ 10 mg/kg
1-3
98% @ 10 mg/kg
-CO2H
-CONH2
-tetrazole
1.65 (2)
b
-CONHSO2Me 0.0013
e1
-CONHSO2Ph 0.001
3
b
-SO3H
-SO2NH2
0.22
0.004
8j
84% @ 10 mg/kg
a
Average of at least three determinations except where noted
b
in parentheses. Not determined.
the 8d scaffold. Primary amide 8e showed potency
similar to that of the acid in both in vitro and ex vivo
assays, while tetrazole 8f showed significant reduction
in potency. Acyl sulfonamides 8g and 8h also were very
potent inhibitors of the enzyme, with IC50 values of 1.3
and 1.0 nM, respectively. In addition, 8g demonstrated
the best ex vivo potency that we had seen to date, with
ED90 e 1 mg/kg. Sulfonic acid 8i and sulfonamide 8j
were reasonably potent in the enzyme assay but showed
diminished potency in the whole blood and ex vivo
assays.
Many of these acyclic amino acid analogues were
among the most potent inhibitors of LTA4 hydrolase
described to date, with IC50 values in the subnanomolar
to low nanomolar range. In addition, many demon-
strated excellent oral activity in the mouse ex vivo
assay. On the basis of its overall profile and ease of
synthesis, 8d was selected for further development. An
overview of the in vitro and in vivo studies with 8d has
been recently reported.19,20 In summary, 8d demon-
strated excellent potency against LTA4 hydrolase (IC50
) 0.0025 µM) and in a human whole blood LTB4
production assay (IC50 ) 0.049 µM).19 It also showed
excellent potency when dosed orally in the mouse ex vivo
assay, inhibiting the production of LTB4 with an ED50
of 0.2 mg/kg and an ED90 of 1-3 mg/kg.20 In addition,
8d was orally efficacious in a rat peritoneal LTB4
production model (ED50 ) 1 mg/kg) and in a rat reversed
passive dermal arthus model (ED50 ) 0.3 mg/kg and
ED90 ) 3-10 mg/kg) and demonstrated both oral (ED50
< 0.8 mg/kg) and topical (ED50 ) 0.11 mg/ear) efficacy
in a mouse arachidonic acid-induced ear edema model.20
In a phase II animal efficacy study in cotton-top tama-
rins,21,22 8d showed excellent efficacy when given orally
for 8 weeks at a dose of 10 mg/kg, b.i.d. In this model of
spontaneous colitis, which is similar to ulcerative colitis
in humans, 8d significantly reduced LTB4 levels (>90%
at mid-treatment) in rectal dialysates, as well as
improved stool consistency scores and histology scores
in colonic biopsies of these animals. These data provided
the impetus for the advancement of this compound into
human clinical trials for the treatment of inflammatory
bowel disease. Unfortunately, in preclinical safety stud-
ies, accumulation of a long-lived metabolite in adipose
tissue along with some mild hepatic toxicity precluded
8d from further development.23,24
Con clu sion s
In summary, we have described a detailed SAR study
on a unique series of amino acid based inhibitors of
LTA4 hydrolase, resulting in the identification of a
number of analogues that demonstrated exceptional
potency in our enzyme, whole cell, and ex vivo assays.
Clinical candidate 8d was identified and demonstrated
significant efficacy in a cotton-top tamarin model of
spontaneous colitis, as well as in other animal models
of inflammation. Unfortunately, prior to entering hu-
man phase I clinical trials, toxicity findings precluded
this compound from further development. Efforts aimed
at circumventing these toxicity issues have been carried
out and will be reported in due course.
Exp er im en ta l Section
Biologica l Meth od s. The human LTA4 hydrolase, human
whole blood LTB4 production, and mouse ex vivo whole blood
LTB4 production assays have been described previously.19,20
Ch em istr y. Melting points were determined using a Thomas-
Hoover melting point apparatus and are uncorrected. High-
1
field H NMR 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 Meth-
odology Department. Unless noted otherwise, elemental data
for all new compounds are within (0.4% of the theoretical
values. All yields reported are unoptimized. All phenol starting
materials were purchased from commercial sources or syn-
thesized as described herein or previously.17,18
P r oced u r e A. N-[4-[4-(P h en ylm eth yl)p h en oxy]bu tyl]-
glycin e Eth yl Ester (9a ). Step 1. P r ep a r a tion of 1-Ben zyl-
4-(4-ch lor obu toxy)ben zen e. To a solution of 4-hydroxy-

3486 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 16
Sch em e 1. Summary of Synthetic Routes
Penning et al.
diphenylmethane (3.7 g, 20 mmol) in 10 mL of DMF was added
NaH (0.8 g of a 60% dispersion in oil, 20 mmol), and the
mixture was stirred at 25 °C for 30 min. A solution of 1-bromo-
4-chlorobutane (3.4 g, 20 mmol) in 5 mL of DMF was added
dropwise, and the mixture was stirred at 25 °C for 18 h. The
mixture was poured into Et2O and water, and the ether layer
was separated, washed with water (2×), dried over Na2SO4,
and concentrated to provide, after chromatography on silica
using 95:5 heptane/EtOAc, the title compound: 1H NMR
(CDCl3) δ 1.94 (m, 4H), 3.61 (t, J ) 6 Hz, 2H), 3.92 (s, 2H),
3.97 (t, J ) 6 Hz, 2H), 6.81 (d, J ) 9 Hz, 2H), 7.09 (d, J ) 9
Hz, 2H), 7.18 (m, 3H), 7.27 (m, 2H).
Step 2. P r epar ation of N-[4-[4-(P h en ylm eth yl)ph en oxy]-
bu tyl]glycin e Eth yl Ester . The product of step 1 (1.4 g, 5
mmol), glycine ethyl ester hydrochloride (0.7 g, 5 mmol), K2-
CO3 (0.6 g, 4.3 mmol), and NaI (150 mg, 1 mmol) were stirred
in 25 mL of DMF at 80 °C for 18 h. The mixture was cooled
and poured into Et2O and water. The ether layer was sepa-
rated and the water layer washed with ether (2×). The
combined ether extracts were washed with water (2×), dried
over Na2SO4, and concentrated to give, after chromatography
on silica using a gradient of 70:30:1 to 40:60:1 heptane/EtOAc/
Et3N, 9a (1.7 g, 99%): 1H NMR (CDCl3) δ 1.28 (t, J ) 7 Hz,
3H), 1.60 (br, 1H), 1.66 (m, 2H), 1.82 (m, 2H), 2.68 (t, J ) 7
Hz, 2H), 3.41 (s, 2H), 3.91 (s, 2H), 3.95 (t, J ) 7 Hz, 2H), 4.19
(q, J ) 7 Hz, 2H), 6.81 (d, J ) 9 Hz, 2H), 7.09 (d, J ) 9 Hz,
2H), 7.18 (m, 3H), 7.27 (m, 2H). Anal. (C21H27NO3) C, H, N.
P r oced u r e B. N-[2-[4-(P h en ylm eth yl)p h en oxy]eth yl]-
glycin e Eth yl Ester , Hyd r och lor id e (3a ). To a stirred
solution of tosylate 22 (2-[4-(phenylmethyl)phenoxy]ethyl 4-
methylbenzenesulfonate18) (10.0 g, 26.7 mmol) in 130 mL of
dimethylformamide (DMF) was added glycine (7.45 g, 53.4
mmol) followed by K2CO3 (11.1 g, 80.1 mmol), and the reaction
mixture was stirred at 65 °C for 18 h. The mixture was cooled
and concentrated. Water was added, followed by extraction (3
× 100 mL) with EtOAc. The combined organic layers were
dried over Na2SO4 and concentrated to provide the crude
product, which was converted to the HCl salt, 3a : 1H NMR

Leukotriene A4 Hydrolase Inhibitors
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 16 3487
(CD3OD) δ 1.32 (t, J ) 8 Hz, 3H), 3.53 (t, J ) 5 Hz, 2H), 3.91
(s, 2H), 4.08 (s, 2H), 4.29 (m, 4H), 6.93 (d, J ) 9 Hz, 2H), 7.16
(m, 5H), 7.24 (d, J ) 8 Hz, 2H). Anal. (C19H23NO3‚HCl‚0.1H2O)
C, H, N.
mg), and the mixture was refluxed for 18 h. The mixture was
cooled and concentrated, and the residue was dissolved in
ether. The ether solution was washed with water (3 × 10 mL),
dried over Na2SO4, and concentrated to provide the aldehyde:
1H NMR (CDCl3) δ 9.84 (s, 1H). A portion of the crude aldehyde
(1.0 g, 4.4 mmol), ethyl 4-aminobutyrate hydrochloride (680
mg, 4.0 mmol), and KOH (56 mg, 1.0 mmol) were stirred in
10 mL of EtOH, and a solution of sodium cyanoborohydride
(NaBH3CN, 122 mg, 1.94 mmol) in 5 mL of EtOH was added.
The mixture was stirred at 25 °C for 30 min, and the mixture
was filtered and concentrated. The residue was dissolved in
ether and washed with water, dried over Na2SO4, and con-
centrated. Chromatography on silica gel using a gradient of
40:60:1 to 20:60:1 heptane/EtOAc/Et3N furnished 5a (0.10 g,
7%): 1H NMR (CDCl3) δ 1.24 (t, J ) 7 Hz, 3H), 1.82 (p, J ) 7
Hz, 2H), 2.37 (t, J ) 7 Hz, 2H), 2.70 (t, J ) 7 Hz, 2H), 2.98 (t,
J ) 5 Hz, 2H), 3.91 (s, 2H), 4.02 (t, J ) 5 Hz, 2H), 4.12 (q, J
) 7 Hz, 2H), 6.82 (d, J ) 9 Hz, 2H), 7.09 (d, J ) 9 Hz, 2H),
7.18 (m, 3H), 7.27 (m, 2H). Anal. (C21H27NO3‚0.4H2O) C, H,
N.
P r oced u r e E. N-Meth yl-N-[3-[4-[4-(2-th ia zolyl)p h en ox-
y]p h en oxy]p r op yl]-â-a la n in e (17d ). Step 1. P r ep a r a tion
of 3-(Meth yl-[3-[4-(4-th ia zol-2-ylp h en oxy)p h en oxy]p r o-
p yl]a m in o)p r op ion itr ile. To a suspension of powdered KOH
(63 mg, 1.1 mmol) in 1 mL of DMSO was added a solution of
4-(4-thiazol-2-ylphenoxy)phenol (200 mg, 0.74 mmol) in 2 mL
of DMSO. The mixture was stirred at room temperature for 5
min and 26 (methyl 3-(3-chloropropylamino)propionitrile) (118
mg, 0.74 mmol) in 1 mL of DMSO. The mixture was heated at
45 °C for 4 h, cooled, and partitioned between water and ether.
The aqueous layer was separated and extracted with ether (2
× 10 mL). The combined extracts were dried over Na2SO4 and
concentrated, and the residue was flash-chromatographed on
silica using ethyl acetate to give the title compound (112 mg,
39%) as a crystalline solid: mp 63-64 °C. 1H NMR (CDCl3) δ
7.90 (m, 2H), 7.81 (d, 1H, J ) 4 Hz), 7.27 (d, 1H, J ) 4 Hz),
7.00 (m, 4H), 6.91 (m, 2H), 4.03 (t, 2H, J ) 7 Hz), 2.74 (t, 2H,
J ) 7 Hz), 2.60 (t, 2H, J ) 7 Hz), 2.47 (t, 2H, J ) 7 Hz), 2.30
(s, 3H), 1.95 (m, 2H).
P r oced u r e C. N-Meth yl-N-[3-[4-(2-th ien ylm eth yl)p h en -
oxy]p r op yl]-b-a la n in e Meth yl Ester (18c). Step 1. P r ep a -
r a tion of 2-[4-(Ch lor op r op oxy)ben zyl]th iop h en e. To a
solution of 4-(2-thienylmethyl)phenol17 (1.23 g, 6.5 mmol) in
13 mL of methyl ethyl ketone was added K2CO3 (4.53 g, 32.5
mmol), and the mixture was stirred at 25 °C for 15 min.
1-Bromo-3-chloropropane (0.66 mL, 6.5 mmol) was added, and
the mixture was heated at 85 °C for 19 h and at 95 °C for 8 h.
The mixture was concentrated and the crude product parti-
tioned between water and EtOAc. The organic layer was
separated and the water layer extracted with EtOAc. The
combined EtOAc extracts were washed with brine and con-
centrated to give a yellow oil. Flash chromatography on silica
gel using 95:5 hexane/EtOAc provided the title compound (1.04
g, 60%) as a colorless oil: 1H NMR (CDCl3) δ 2.22 (p, J ) 6
Hz, 2H), 3.74 (t, J ) 6 Hz, 2H), 4.10 (s and t, J ) 6 Hz, 4H),
6.78 (d, 1H), 6.85 (d, J ) 9 Hz, 2H), 6.92 (dd, 1H), 7.16 (t, J )
8 Hz, 3H).
Step 2. P r ep a r a tion of N-Meth yl-N-[3-[2-th ien ylm eth -
yl)p h en oxy]p r op yl]a m in e. To a solution of the product of
step 1 (0.57 g, 2.1 mmol) in 5 mL of acetonitrile was added
40% aqueous methylamine (17 mL, 215 mmol), and the
mixture was heated at 60 °C for 7 h and at 25 °C for 17 h. The
mixture was concentrated and the aqueous solution extracted
with EtOAc (2 × 10 mL). The organic extracts were combined
and acidified to pH 1 with 1 N HCl. The white precipitate that
formed was filtered and washed with 1 N HCl and hexane to
provide 0.47 g (75%) of the HCl salt of the title compound: 1H
NMR (CDCl3/CD3OD) δ 2.27 (p, J ) 6 Hz, 2H), 2.72 (m, 2H),
2.93 (s, 3H), 3.18 (m, 2H), 4.07 (t, J ) 6 Hz, 2H), 4.09 (s, 2H),
6.79 (d, 1H), 6.85 (d, J ) 9 Hz, 2H), 6.92 (dd, 1H), 7.16 (t, J )
8 Hz, 3H). Conversion to the free base was carried out by
dissolution in 20 mL of 10% NaOH and extraction with Et2O
(2 × 30 mL). The combined extracts were dried over Na2SO4
and concentrated to give the title compound as a pale-yellow
oil.
Step 2. P r epar ation of N-Meth yl-N-[3-[4-[4-(2-th iazolyl)-
p h en oxy]p h en oxy]p r op yl]-â-a la n in e. A solution of the
compound from step 1 (100 mg, 0.25 mmol) in 2 mL of 6 N
HCl was heated at 90 °C for 17 h. The solution was cooled
and brought to pH 8 with 10% NaOH. Extraction with CH2-
Cl2 (3 × 15 mL) and concentration provided the crude product,
which was flash-chromatographed on silica using 85:14:1 CH2-
Cl2/MeOH/NH4OH to give 17d (40 mg, 39%) as a crystalline
solid: mp 143-144 C; 1H NMR (CD3OD) δ 2.22 (m, 2H), 2.59
(m, 2H), 2.82 (s, 3H), 3.27 (m, 4H) 4.11 (t, 2H, J ) 6 Hz), 6.96
(m, 2H), 7.01 (s, 4H), 7.55 (d, 1H, J ) 4.0 Hz), 7.81 (d, 1H, J
) 4.0 Hz), 7.87 (m, 2H). Anal. (C22H24N2O4S‚1.0H2O) C, N; H,
calcd, 6.09; found, 5.57. HRMS m/z 413.1535 (calcd for
Step 3. P r ep a r a tion of N-Meth yl-N-[3-[4-(2-th ien yl-
m eth yl)p h en oxy]p r op yl]-â-a la n in e Meth yl Ester . To a
solution of the product of step 2 (0.41 g, 1.6 mmol) in 8 mL of
CH2Cl2 was added methyl acrylate (0.19 mL, 2.1 mmol), and
the mixture was stirred at 25 °C for 18.5 h. An additional 0.2
mL (0.2 mmol) of methyl acrylate was added, and the mixture
was stirred for an additional 2 h. The mixture was concen-
trated to give a colorless oil. Flash chromatography on silica
gel using 10:1 CH2Cl2/MeOH gave 18c (0.38 g, 68%) as a pale-
yellow oil: 1H NMR (CD3OD) δ 1.93 (p, J ) 6 Hz, 2H), 2.26 (s,
3H), 2.48 (t, J ) 6 Hz, 2H), 2.53 (t, J ) 6 Hz, 2H), 2.72 (t, J )
6 Hz, 2H), 3.65 (s, 3H), 3.99 (t, J ) 6 Hz, 2H), 4.09 (s, 2H),
6.78 (d, J ) 3 Hz, 1H), 6.83 (d, J ) 9 Hz, 2H), 6.91 (dd, J ) 5,
3 Hz, 1H), 7.13 (m, 3H). Anal. (C19H25NO3S‚0.2H2O) C, H, N.
C
22H24N2O4S (M + 1), 413.1551).
P r oced u r e F . Eth yl 3-[Meth yl-[3-[4-(p h en ylm eth yl)-
p h en oxy]p r op yl]a m in o]p r op a n oa te (8c). To a solution of
8a (170 mg, 0.5 mmol) and 37% aqueous formaldehyde (0.2
mL, 5 mmol) in 3 mL of CH3CN was added NaBH3CN (50 mg,
0.8 mmol), and the mixture was stirred at 25 °C for 15 min.
Three drops of AcOH were added over 45 min to maintain a
neutral pH. The mixture was concentrated, and the residue
was dissolved in ether and 2 N KOH. The ether layer was
separated and washed with 0.5 N KOH followed by 1 N HCl
(3×). The combined HCl extracts were neutralized with KOH
and extracted with ether (3×). The combined extracts were
dried over Na2SO4 and concentrated. Chromatography on silica
gel using a gradient of 95:5:1 to 90:10:1 toluene/EtOAc/Et3N
furnished 8c (100 mg, 56%): 1H NMR (CDCl3) δ 1.23 (t, J )
7 Hz, 3H), 1.92 (p, J ) 7 Hz, 2H), 2.24 (s, 3H), 2.45 (t, J ) 7
Hz, 2H), 2.52 (t, J ) 7 Hz, 2H), 2.71 (t, J ) 7 Hz, 2H), 3.91 (s,
2H), 3.97 (t, J ) 7 Hz, 2H), 4.10 (q, J ) 7 Hz, 2H), 6.81 (d, J
) 9 Hz, 2H), 7.08 (d, J ) 9 Hz, 2H), 7.17 (m, 3H), 7.27 (m,
2H). Anal. (C22H29NO3) C, H, N.
P r oced u r e D. Eth yl 4-[[2-[4-(P h en ylm eth yl)p h en oxy]-
eth yl]am in o]bu tan oate (5a). Step 1. P r epar ation of 1-Ben -
zyl-4-(2,2-d ieth oxyeth oxy)ben zen e. To a solution of 4-hy-
droxydiphenylmethane (18.4 g, 100 mmol) in 50 mL of DMF
was added NaH (4 g of a 60% dispersion in oil, 100 mmol),
and the mixture was stirred for 30 min. A solution of
bromoacetaldehyde diethyl acetal (19.7 g, 100 mmol) in 20 mL
of DMF was added dropwise, and the mixture was stirred at
25 °C for 20 h. The mixture was poured into ether and water,
and the ether layer was separated, washed with water, dried
over Na2SO4, and concentrated. Chromatography on silica gel
using a gradient of 98:2 to 97:3 heptane/EtOAc furnished the
title compound (20 g, 67%): 1H NMR (CDCl3) δ 1.23 (t, J ) 7
Hz, 6H), 3.62 (m, 2H), 3.75 (m, 2H), 3.92 (s, 2H), 3.97 (d, J )
6 Hz, 2H), 4.82 (t, J ) 6 Hz, 1H), 6.83 (d, J ) 9 Hz, 2H), 7.08
(d, J ) 9 Hz, 2H), 7.17 (m, 3H), 7.26 (m, 2H).
Step 2: P r ep a r a tion of Eth yl 4-[[2-[4-(P h en ylm eth yl)-
p h en oxy]et h yl]a m in o]b u t a n oa t e. To a solution of the
compound from step 1 (6.0 g, 20 mmol) in 30 mL of THF and
1 mL of H2O was added catalytic p-toluenesulfonic acid (150
P r oced u r e G. N-Meth yl-N-[3-[4-(2-th ien ylm eth yl)p h en -
oxy]p r op yl]-â-a la n in e, Hyd r och lor id e (18d ). To a solution

3488 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 16
Penning et al.
of 18c (0.28 g, 0.81 mmol) in 5 mL of THF was added 1 mL of
6 N HCl, and the mixture was stirred at 75 °C for 14 h. The
mixture was concentrated, and the white solid residue was
recrystallized from MeOH/Et2O to give 18d (0.14 g, 47%) as a
white solid: 1H NMR (CD3OD) δ 2.23 (p, J ) 6 Hz, 2H), 2.87
(t, J ) 6 Hz, 2H), 2.93 (s, 3H), 3.40 (m, 4H), 4.08 (s, 2H), 4.10
(t, J ) 6 Hz, 2H), 6.78 (d, J ) 3 Hz, 1H), 6.88 (m, 3H), 7.14
(m, 3H). Anal. (C18H23NO3S‚HCl) C, H, N.
P r oced u r e H. N-Meth yl-N-[4-[4-(p h en ylm eth yl)p h en -
oxy]bu tyl]glycin e (9d ). The benzyl ester of 9d (prepared
using general procedure F) (100 mg, 0.24 mmol) in 20 mL of
EtOH with catalytic 4% Pd/C (25 mg) was hydrogenated in a
Parr shaker under 5 psi of H2 at 25 °C for 2 h. The mixture
was filtered and concentrated to give, after recrystallization
from EtOAc, 9d (20 mg, 24%) as a white solid: 1H NMR
(CD3OD) δ 1.88 (m, 4H), 2.85 (s, 3H), 3.18 (t, J ) 7 Hz, 2H),
3.53 (s, 2H), 3.92 (s, 2H), 3.99 (t, J ) 7 Hz, 2H), 6.81 (d, J )
9 Hz, 2H), 7.10 (d, J ) 9 Hz, 2H), 7.18 (m, 3H), 7.27 (m, 2H).
Anal. (C20H25NO3‚0.5H2O) C, H, N.
(q, J ) 6 Hz, 2H), 6.79 (d, J ) 9 Hz, 2H), 7.08 (d, J ) 9 Hz,
2H), 7.16 (m, 3H), 7.27 (m, 2H). Anal. (C22H29NO3‚0.5H2O) C,
H, N.
Meth yl 4-[Meth yl[2-[4-(p h en ylm eth yl)p h en oxy]eth yl]-
a m in o]bu ta n oa te (5c). 1H NMR (CDCl3) δ 1.81 (p, J ) 7 Hz,
2H), 2.32 (s, 3H), 2.37 (t, J ) 7 Hz, 2H), 2.48 (t, J ) 7 Hz, 2H),
2.78 (t, J ) 6 Hz, 2H), 3.64 (s, 3H), 3.92 (s, 2H), 4.02 (t, J ) 6
Hz, 2H), 6.83 (d, J ) 9 Hz, 2H), 7.09 (d, J ) 9 Hz, 2H), 7.18
(m, 3H), 7.27 (m, 2H). Anal. (C21H27NO3‚0.2H2O) C, H, N.
3-[Meth yl[3-[4-(p h en ylm eth yl)p h en oxy]p r op yl]a m in o]-
p r op a n oic Acid , Hyd r och lor id e (8d ). 1H NMR (CDCl3/CD3-
OD) δ 2.33 (m, 2H), 2.85 (s, 3H), 2.95 (t, J ) 7 Hz, 2H), 3.31
(m, 2H), 3.38 (m, 2H), 3.92 (s, 2H), 4.07 (t, J ) 7 Hz, 2H), 6.81
(d, J ) 9 Hz, 2H), 7.11 (d, J ) 9 Hz, 2H), 7.18 (m, 3H), 7.28
(m, 2H). Anal. (C20H25NO3‚HCl) C, H, N.
3-[Meth yl[3-[4-(p h en ylm eth yl)p h en oxy]p r op yl]a m in o]-
1
p r op a n oic Acid (8d ). Mp 121-123 °C; H NMR (CD3OD) δ
2.21 (p, J ) 6 Hz, 2H), 2.55 (t, J ) 6 Hz, 2H), 2.85 (s, 3H),
3.28 (t, 2H), 3.30 (t, 2H), 3.88 (s, 2H), 4.08 (t, J ) 6 Hz, 2H),
6.87 (d, J ) 9 Hz, 2H), 7.09 (d, J ) 9 Hz, 2H), 7.15 (m, 3H),
7.23 (m, 2H). Anal. (C20H25NO3) C, H, N.
N-[2-[4-(P h en ylm eth yl)ph en oxy]eth yl]-â-alan in e Meth -
1
yl Ester (4a ). H NMR (CDCl3) δ 1.72 (br, 1H), 2.54 (t, J ) 6
N-Met h yl-N-[4-[4-(p h en ylm et h yl)p h en oxy]b u t yl]gly-
Hz, 2H), 2.95 (t, J ) 6 Hz, 2H), 2.99 (t, J ) 6 Hz, 2H), 3.68 (s,
3H), 3.91 (s, 2H), 4.03 (t, J ) 6 Hz, 2H), 6.82 (d, J ) 9 Hz,
2H), 7.08 (d, J ) 9 Hz, 2H), 7.18 (m, 3H), 7.27 (m, 2H). Anal.
(C19H23NO3) C, H, N.
1
cin e Eth yl Ester (9c). H NMR (CDCl3) δ 1.27 (t, J ) 7 Hz,
3H), 1.66 (m, 2H), 1.78 (m, 2H), 2.38 (s, 3H), 2.53 (t, J ) 7 Hz,
2H), 3.25 (s, 2H), 3.92 (s, 2H), 3.95 (t, J ) 7 Hz, 2H), 4.18 (q,
J ) 7 Hz, 2H), 6.80 (d, J ) 9 Hz, 2H), 7.08 (d, J ) 9 Hz, 2H),
7.17 (m, 3H), 7.27 (m, 2H). Anal. (C22H29NO3‚0.2H2O) C, H,
N.
Eth yl 5-[[2-[4-(P h en ylm eth yl)p h en oxy]eth yl]a m in o]-
1
p en ta n oa te (6a ). H NMR (CDCl3) δ 1.25 (t, J ) 7 Hz, 3H),
1.55 (m, 2H), 1.67 (m, 2H), 2.32 (t, J ) 7 Hz, 2H), 2.69 (t, J )
7 Hz, 2H), 2.99 (t, J ) 5 Hz, 2H), 3.92 (s, 2H), 4.04 (t, J ) 5
Hz, 2H), 4.12 (q, J ) 7 Hz, 2H), 6.83 (d, J ) 9 Hz, 2H), 7.08
Eth yl [Meth yl[4-[4-(p h en ylm eth yl)p h en oxy]bu tyl]a m i-
1
n o]p r op a n oa te (10c). H NMR (CDCl3) δ 1.25 (t, J ) 7 Hz,
3H), 1.62 (m, 2H), 1.77 (m, 2H), 2.23 (s, 3H), 2.40 (t, J ) 7 Hz,
2H), 2.46 (t, J ) 7 Hz, 2H), 2.70 (t, J ) 7 Hz, 2H), 3.91 (s, 2H),
3.93 (t, J ) 7 Hz, 2H), 4.13 (q, J ) 7 Hz, 2H), 6.81 (d, J ) 9
Hz, 2H), 7.09 (d, J ) 9 Hz, 2H), 7.18 (m, 3H), 7.27 (m, 2H).
Anal. (C23H31NO3) C, H, N.
(d, J ) 9 Hz, 2H), 7.17 (m, 3H), 7.27 (m, 2H). Anal. (C22H29
NO3‚0.3H2O) C, N; H, calcd, 8.27; found, 7.80.
-
Eth yl N-[3-[4-(P h en ylm eth yl)ph en oxy]pr opyl]glycin ate
1
(7a ). H NMR (CDCl3) δ 1.27 (t, J ) 8 Hz, 3H), 1.69 (br, 1H),
1.96 (p, J ) 6 Hz, 2H), 2.69 (t, J ) 6 Hz, 2H), 3.41 (s, 2H),
3.91 (s, 2H), 4.02 (t, J ) 6 Hz, 2H), 4.18 (q, J ) 8 Hz, 2H),
6.82 (d, J ) 9 Hz, 2H), 7.08 (d, J ) 9 Hz, 2H), 7.18 (m, 3H),
7.27 (m, 2H). Anal. (C20H25NO3) C, H, N.
3-[[3-[4-[(4-F lu or op h e n yl)m e t h yl]p h e n oxy]p r op yl]-
1
m eth yla m in o]p r op a n oic Acid , Hyd r och lor id e (12d ). H
NMR (CD3OD) δ 2.23 (p, J ) 6 Hz, 2H), 2.87 (t, J ) 6 Hz,
2H), 2.92 (s, 3H), 3.40 (m, 4H), 3.88 (s, 2H), 4.09 (t, J ) 6 Hz,
2H), 6.88 (d, J ) 9 Hz, 2H), 6.97 (dd, J ) 9 Hz, 2H), 7.10 (d,
J ) 9 Hz, 2H), 7.26 (dd, J ) 9 Hz, 2H). Anal. (C20H24FNO3‚
HCl‚0.2H2O) C, H, N.
Eth yl 3-[[3-[4-(P h en ylm eth yl)p h en oxy]p r op yl]a m in o]-
1
p r op a n oa te (8a ). H NMR (CDCl3) δ 1.24 (t, J ) 7 Hz, 3H),
1.78 (br, 1H), 1.93 (p, J ) 6 Hz, 2H), 2.50 (t, J ) 6 Hz, 2H),
2.79 (t, J ) 7 Hz, 2H), 2.88 (t, J ) 7 Hz, 2H), 3.91 (s, 2H), 3.99
(t, J ) 6 Hz, 2H), 4.12 (q, J ) 7 Hz, 2H), 6.82 (d, J ) 9 Hz,
2H), 7.08 (d, J ) 9 Hz, 2H), 7.17 (m, 3H), 7.26 (m, 2H). Anal.
(C21H27NO3‚0.2H2O) C, H, N.
3-[Met h yl[3-(4-p h en oxyp h en oxy)p r op yl]a m in o]p r o-
p a n oic Acid (13d ). 1H NMR (CDCl3) δ 2.22 (p, J ) 6 Hz, 2H),
2.54 (s, 3H), 2.60 (t, J ) 6 Hz, 2H), 2.92 (t, J ) 6 Hz, 4H), 4.02
(t, J ) 6 Hz, 2H), 6.86 (d, J ) 9 Hz, 2H), 6.95 (m, 4H), 7.05
(m, 1H), 7.29 (m, 2H). Anal. (C19H23NO4‚0.2H2O) C, H, N.
N-[3-[4-(4-F lu or op h en oxy)p h en oxy]p r op yl]-N-m eth yl-
N-[3-[4-(P h en ylm eth yl)ph en oxy]pr opyl]-â-alan in e (8b).
1
Mp 148-149 °C; H NMR (CD3OD) δ 2.15 (p, J ) 6 Hz, 2H),
2.49 (t, J ) 6 Hz, 2H), 3.17 (t, J ) 7 Hz, 2H), 3.22 (t, J ) 7 Hz,
2H), 3.88 (s, 2H), 4.10 (t, J ) 6 Hz, 2H), 6.89 (d, J ) 8 Hz,
2H), 7.10 (d, J ) 8 Hz, 2H), 7.16 (m, 3H), 7.24 (m, 2H). Anal.
(C19H23NO3‚0.6H2O) C, H, N.
1
â-a la n in e (14d ). H NMR (CD3OD) δ 2.27 (p, J ) 6 Hz, 2H),
2.88 (t, J ) 6 Hz, 2H), 2.94 (s, 3H), 3.42 (m, 4H), 4.11 (t, J )
6 Hz, 2H), 6.93 (m, 6H), 7.04 (dd, J ) 10 Hz, 2H). Anal. (C19H22
-
FNO4‚HCl‚0.2H2O) C, N, Cl; H, calcd, 6.09; found, 5.61. HRMS
m/z 347.1540 (calcd for C19H22FNO4, 347.1533).
N-[4-[4-(P h en ylm eth yl)p h en oxy]bu tyl]glycin e (9b). Mp
1
167-170 °C; H NMR (CD3OD) δ 1.86 (m, 4H), 3.07 (t, J ) 6
N-[3-[4-([1,1′-Bip h en yl]-4-yloxy)p h en oxy]p r op yl]-N-
m eth yl-â-a la n in e, Hyd r och lor id e (15d ). 1H NMR (CD3OD)
δ 2.28 (p, J ) 6 Hz, 2H), 2.89 (t, J ) 6 Hz, 2H), 2.96 (s, 3H),
3.43 (m, 4H), 4.12 (t, J ) 6 Hz, 2H), 6.99 (m, 6H), 7.29 (dd, J
) 8 Hz, 1H), 7.40 (dd, J ) 8 Hz, 2H), 7.56 (d, J ) 9 Hz, 4H).
Anal. (C25H27NO4‚HCl‚0.8H2O) C, H, N, Cl.
N-Meth yl-N-[3-[4-[4-(2-oxa zolyl)p h en oxy]p h en oxy]p r o-
p yl]-â-a la n in e, Hyd r och lor id e (16d ). Anal. (C22H24N2O5‚
1.5HCl‚H2O) C, H, Cl; N, calcd, 5.97; found, 5.32. HRMS m/z
397.1773 (calcd for C22H24N2O5 (M + 1), 397.1763).
Hz, 2H), 3.48 (s, 2H), 3.88 (s, 2H), 3.99 (t, J ) 6 Hz, 2H), 6.83
(d, J ) 9 Hz, 2H), 7.08 (d, J ) 9 Hz, 2H), 7.15 (m, 3H), 7.23
(m, 2H). Anal. (C19H23NO3‚0.2H2O) C, H, N.
Eth yl 3-[4-[4-(P h en ylm eth yl)p h en oxy]bu tyla m in o]-
p r op a n oa te (10a ). 1H NMR (CDCl3) δ 1.24 (t, J ) 7 Hz, 3H),
1.37 (br, 1H), 1.63 (m, 2H), 1.79 (m, 2H), 2.49 (t, J ) 7 Hz,
2H), 2.66 (t, J ) 7 Hz, 2H), 2.88 (t, J ) 7 Hz, 2H), 3.90 (s, 2H),
3.92 (t, J ) 7 Hz, 2H), 4.13 (q, J ) 7 Hz, 2H), 6.80 (d, J ) 9
Hz, 2H), 7.08 (d, J ) 9 Hz, 2H), 7.17 (m, 3H), 7.26 (m, 2H).
Anal. (C22H29NO3) C, H, N.
3-[[4-[4-(P h e n y l m e t h y l )p h e n o x y ]b u t y l ]a m i n o ]-
p r op a n oic Acid (10b). 1H NMR (CD3OD) δ 1.87 (m, 4H), 2.48
(t, J ) 6 Hz, 2H), 3.07 (t, J ) 6 Hz, 2H), 3.14 (t, J ) 6 Hz,
2H), 3.87 (s, 2H), 4.00 (t, J ) 6 Hz, 2H), 6.82 (d, J ) 8 Hz,
2H), 7.07 (d, J ) 8 Hz, 2H), 7.14 (m, 3H), 7.22 (m, 2H). Anal.
(C20H25NO3) C, H, N.
N-Meth yl-N-[3-[4-(3-th ien ylm eth yl)p h en oxy]p r op yl]-â-
1
a la n in e Meth yl Ester (19c). H NMR (CD3OD) δ 1.92 (p, J
) 6 Hz, 2H), 2.25 (s, 3H), 2.47 (t, J ) 6 Hz, 2H), 2.52 (t, J )
6 Hz, 2H), 2.71 (t, J ) 6 Hz, 2H), 3.65 (s, 3H), 3.90 (s, 2H),
3.98 (t, J ) 6 Hz, 2H), 6.81 (d, J ) 9 Hz, 2H), 6.88 (d, J ) 4
Hz, 2H), 7.09 (d, J ) 9 Hz, 2H), 7.22 (dd, J ) 5, Hz, 1H). Anal.
(C19H25NO3S) C, H, N.
N-[5-[4-(P h en ylm eth yl)p h en oxy]p en tyl]glycin e Eth yl
N -Me t h yl-N -[3-[4-(3-t h ie n yl)p h e n oxy]p r op yl]-â-a la -
1
1
Ester (11a ). H NMR (CDCl3) δ 1.27 (t, J ) 6 Hz, 3H), 1.52
(m, 4H), 1.61 (br, 1H), 1.78 (p, J ) 6 Hz, 2H), 2.63 (t, J ) 6
Hz, 2H), 3.39 (s, 2H), 3.91 (s, 2H), 3.92 (t, J ) 6 Hz, 2H), 4.19
n in e, Hyd r och lor id e (19d ). H NMR (CD3OD) δ 2.23 (p, J
) 6 Hz, 2H), 2.86 (t, J ) 6 Hz, 2H), 2.94 (s, 3H), 3.40 (m, 4H),
3.90 (s, 2H), 4.10 (t, J ) 6 Hz, 2H), 6.87 (m, 3H), 6.96 (d, J )

Leukotriene A4 Hydrolase Inhibitors
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 16 3489
3 Hz, 1H), 7.12 (d, J ) 9 Hz, 2H), 7.28 (dd, J ) 5,3 Hz, 1H).
Anal. (C18H23NO3S‚HCl‚0.9H2O) C, N; H, calcd, 6.73; found,
6.22. HRMS m/z 333.1417 (calcd for C18H23NO3S, 333.1399).
2-[Meth yl[3-[4-(p h en ylm eth yl)p h en oxy]p r op yl]a m in o]-
eth a n esu lfon ic Acid (8i). To a solution of 1-benzyl-4-(3-
chloropropoxy)benzene18 (1.0 g, 3.8 mmol) in 5 mL of DMF was
added N-methyltaurine sodium salt (617 mg, 3.8 mmol) and
Et3N (1.08 g, 10 mmol), and the mixture was stirred at 40 °C
for 60 h. The mixture was cooled and poured into water, and
the solid was filtered to provide 8i (508 mg, 37%) as a white
solid: 1H NMR (DMSO-d6) δ 2.08 (p, J ) 7 Hz, 2H), 2.83 (s,
3H), 2.91 (t, J ) 7 Hz, 2H), 3.21 (m, 2H), 3.44 (m, 2H), 3.86 (s,
2H), 4.00 (t, J ) 6 Hz, 2H), 6.87 (d, J ) 8 Hz, 2H), 7.16 (m,
5H), 7.26 (d, J ) 7 Hz, 2H), 9.06 (br, 1H). Anal. (C19H25NO4S)
C, H, N.
N-Meth yl-N-[3-[4-(3-pyr idin ylm eth yl)ph en oxy]pr opyl]-
1
â-a la n in e Meth yl Ester (20c). H NMR (CD3OD) δ 1.94 (p,
J ) 6 Hz, 2H), 2.28 (s, 3H), 2.50 (t, J ) 6 Hz, 2H), 2.56 (t, J
) 6 Hz, 2H), 2.74 (t, J ) 6 Hz, 2H), 3.66 (s, 3H), 3.92 (s, 2H),
3.98 (t, J ) 6 Hz, 2H), 6.82 (d, J ) 9 Hz, 2H), 7.08 (d, J ) 9
Hz, 2H), 7.18 (dd, J ) 8,5 Hz, 1H), 7.44 (d, J ) 8 Hz, 1H),
8.43 (d, J ) 5 Hz, 1H), 8.48 (s, 1H). Anal. (C20H26N2O3) C, H,
N.
3-[Meth yl[3-[4-(p h en ylm eth yl)p h en oxy]p r op yl]a m in o]-
p r op a n a m id e (8e). A mixture of 8d (200 mg, 0.55 mmol) and
trifluoromethylsulfonamide (90 mg, 0.6 mmol) in 2 mL of
POCl3 was stirred at 90 °C. Toluene was added until the
solution was homogeneous, and the mixture was heated at 90
°C for 4 h. The mixture was cooled and concentrated. Water
was added, and the solution was made basic with NH4OH. This
was extracted with EtOAc (3×), and the combined extracts
were dried over MgSO4 and concentrated. Flash chromatog-
raphy on silica using 94:6:1 CH2Cl2/MeOH/NH4OH provided
8e (95 mg, 53%) as a white solid: 1H NMR (CDCl3) δ 1.98 (p,
J ) 6 Hz, 2H), 2.30 (s, 3H), 2.41 (t, J ) 6 Hz, 2H), 2.63 (t, J
) 6 Hz, 2H), 2.67 (t, J ) 6 Hz, 2H), 3.92 (s, 2H), 3.98 (t, J )
6 Hz, 2H), 6.79 (d, J ) 9 Hz, 2H), 7.08 (d, J ) 9 Hz, 2H), 7.18
(m, 3H), 7.28 (m, 2H). Anal. (C20H26N2O2) C, H, N.
N-Meth yl-N-[3-[4-(p h en ylm eth yl)p h en oxy]p r op yl]-1H-
tetr a zole-5-eth a n a m in e (8f). A solution of 3-[methyl[3-[4-
(phenylmethyl)phenoxy]propyl]amino]propionitrile (prepared
using procedure E) (100 mg, 0.3 mmol), NaN3 (65 mg, 1.0
mmol), Bu3SnCl (150 mg, 0.45 mmol), and LiCl (42 mg, 1.0
mmol) in 5 mL of xylene was heated at 130 °C for 48 h. The
mixture was cooled, filtered, and concentrated. The residue
was partitioned between CH2Cl2 and water, and the water
layer was brought to pH 4 with 3 N HCl. The organic layer
was separated, dried over Na2SO4, and concentrated. Reverse-
phase chromatography on a C18 column using a gradient of
50:50 MeOH/H2O to 100% MeOH provided, after recrystalli-
zation from EtOAc, 8f (16.5 mg, 16%): 1H NMR (CDCl3) δ 2.09
(p, J ) 6 Hz, 2H), 2.53 (s, 3H), 2.94 (t, J ) 6 Hz, 2H), 3.06 (t,
J ) 6 Hz, 2H), 3.23 (t, J ) 6 Hz, 2H), 3.90 (s, 2H), 4.02 (t, J
) 6 Hz, 2H), 6.79 (d, J ) 8 Hz, 2H), 7.08 (d, J ) 8 Hz, 2H),
7.17 (m, 3H), 7.28 (m, 2H), 7.35 (br, 1H). Anal. (C20H25N5O‚
0.3H2O) C, H, N.
3-[Meth yl[3-[4-(ph en ylm eth yl)ph en oxy]pr opyl]am in o]-
N-(m eth ylsu lfon yl)p r op a n a m id e (8g). A mixture of 8d
(500 mg, 1.37 mmol) and methanesulfonamide (131 mg, 1.37
mmol) in 1 mL of POCl3 was stirred at 90 °C. Toluene was
added until the solution was homogeneous, and the mixture
was heated at 90 °C for 4 h. The mixture was cooled and
concentrated. The residue was triturated with toluene and
dissolved in water. The solution was made basic with NH4OH
and extracted with EtOAc (3×). The combined extracts were
dried over MgSO4 and concentrated to provide, after flash
chromatography on silica using 95:5:1 CH2Cl2/MeOH/NH4OH,
8g (150 mg, 26%) as a white solid: 1H NMR (CDCl3) δ 2.08 (p,
J ) 7 Hz, 2H), 2.47 (s, 3H), 2.56 (t, J ) 7 Hz, 2H), 2.83 (m,
4H), 2.97 (s, 3H), 3.90 (s, 2H), 4.02 (t, J ) 6 Hz, 2H), 6.81 (d,
J ) 9 Hz, 2H), 7.10 (d, J ) 9 Hz, 2H), 7.16 (m, 3H), 7.27 (m,
2H). Anal. (C21H28N2O4S(H2O) C, H, N.
3-[Meth yl[3-[4-(ph en ylm eth yl)ph en oxy]pr opyl]am in o]-
N-(p h en ylsu lfon yl)p r op a n a m id e (8h ). To a suspension of
8d (500 mg, 1.37 mmol) in 20 mL of CH2Cl2 was added
benzenesulfonamide (219 mg, 1.37 mmol) and 4-(dimethylami-
no)pyridine (218 mg, 1.79 mmol), followed by 5 g of 4 Å
molecular sieves and 1-(3-dimethylaminopropyl)-3-ethylcar-
bodiimide hydrochloride (270 mg, 1.37 mmol). The mixture was
stirred at 25 °C for 17 h and diluted with 50 mL of CH2Cl2. A
10% aqueous HCl solution (20 mL) was added, and the organic
layer was separated. The water layer was extracted with CH2-
Cl2 (2×), and the combined extracts were dried over MgSO4
and concentrated to provide, after flash chromatography on
silica using 95:5:1 CH2Cl2/MeOH/NH4OH, 8h (130 mg, 20%)
as a white solid. Anal. (C26H30N2O4S) C, H, N.
2-[Meth yl[3-[4-(p h en ylm eth yl)p h en oxy]p r op yl]a m in o]-
eth a n esu lfon a m id e (8j). To a suspension of 8i (200 mg, 0.55
mmol) in EtOAc was added oxalyl chloride (140 mg, 1.1 mmol)
followed by a drop of DMF. The mixture was heated at 40 °C
for 15 h and concentrated. Concentrated NH4OH was added,
and the mixture was stirred at 90 °C for 4 h. The mixture was
cooled and extracted with EtOAc (3×). The combined extracts
were dried over MgSO4 and concentrated to provide, after flash
chromatography on silica using 98:2:1 CH2Cl2/MeOH/NH4OH,
8j (20 mg, 10%) as a brown solid: HRMS m/z 362.1663 (calcd
for C19H26N2O3S, 362.1664).
4-(4-Th ia zol-2-yl)p h en oxyp h en ol (Used in P r ep a r a tion
of 17d ). Step 1. P r ep a r a tion of 4-(4-Meth oxyp h en oxy)-
th ioben za m id e. To a suspension of 4-(4-methoxyphenoxy)-
benzonitrile17 (10.0 g, 44 mmol) in tert-butyl alcohol (80 mL)
was added 30 mL of dimethyl sulfoxide (DMSO) and powdered
KOH (9.1 g, 162 mmol). The mixture was heated at reflux for
2 h. The mixture was cooled and diluted with water (100 mL).
The white solid precipitate was collected by filtration and
washed with water (4 × 150 mL). The solid was concentrated
to give the title compound (9.6 g, 89%): mp 195-196 °C.
Step 2. P r ep a r a tion of 4-(4-Meth oxyp h en oxy)th ioben -
za m id e. To a suspension of the compound from step 1 (4.2 g,
17.3 mmol) in toluene (80 mL) was added Lawesson’s reagent
(7.0 g, 17.3 mmol). The mixture was heated at reflux for 3 h,
cooled, and concentrated. The residue was flash-chromato-
graphed on silica gel (1:1 hexane/ethyl acetate) to give the title
compound (2.2 g, 49%).
Step 3. P r ep a r a tion of 2-[4-(4-Meth oxyp h en oxy)p h e-
n yl]th ia zole. A mixture of oxalic acid (590 mg, 6.5 mmol) and
chloroacetaldehyde dimethyl acetal (0.75 mL, 6.5 mmol) was
heated at reflux for 1 h. The compound from step 2 (1.7 g, 6.5
mmol) was added, and the mixture was heated at reflux for 2
h. The mixture was cooled, 30% HCl (3.5 mL) was added, and
the mixture was heated to reflux for 10 min. After cooling and
dilution with water, the mixture was extracted with CH2Cl2
(3 × 10 mL). The extracts were dried over Na2SO4 and
concentrated, and the residue was flash-chromatographed (3:1
hexane/ethyl acetate) to give the title compound (925 mg, 50%)
1
as a crystalline solid: mp 92-93 °C; H NMR (CDCl3) δ 3.75
(s, 3H), 6.88 (m, 2H), 6.97 (m, 4H), 7.20 (d, 1H, J ) 4 Hz),
7.78 (d, 1H, J ) 4 Hz), 7.98 (m, 2H). Anal. Calcd for C16H13
-
NO2S: C, 67.82; H, 4.62; N, 4.94. Found: C, 67.66; H, 4.50;
N, 4.86.
Step 4. P r ep a r a tion of 4-(4-Th ia zol-2-yl)p h en oxyp h e-
n ol. To a solution of the compound from step 3 (280 mg, 1.0
mmol) in 3 mL of CH2Cl2 at -78 °C was added boron
tribromide (1.8 mL of a 1 M solution in CH2Cl2). The solution
was stirred at -78 °C for 1 h and then warmed to room
temperature over 2 h. The mixture was diluted with water
and extracted with CH2Cl2 (2 × 20 mL). The combined extracts
were dried over Na2SO4 and concentrated to give the title
compound (210 mg, 78%): 1H NMR (CD3OD) δ 6.88 (m, 4H),
6.97 (m, 4H), 7.02 (m, 2H), 7.90 (m, 3H), 8.10 (d, 1H, J ) 4
Hz).
Met h yl 3-(3-Ch lor op r op yla m in o)p r op ion it r ile (26)
(Used in Gen er a l P r oced u r e E). A solution of N-methyl-â-
alaninenitrile (5.0 g, 59.4 mmol), 1-bromo-3-chloropropane
(18.7 g, 118.9 mmol), and K2CO3 (16 g, 118.9 mmol) in 40 mL
of DMF was stirred at 50 °C for 2 h. The mixture was cooled
and diluted with 100 mL of H2O. The solution was extracted
with EtOAc (2 × 40 mL), and the combined extracts were

3490 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 16
Penning et al.
Hydrolase: A Zinc Metalloenzyme. Biochem. Biophys. Res.
Commun. 1990, 172, 965-970. (d) Minami, M.; Ohishi, N.;
Mutoh, H.; Izumi, T.; Bito, H.; Wada, H.; Seyama, Y.; Toh, H.;
Shimizu, T. Leukotriene A4 Hydrolase is a Zinc-Containing
Aminopeptidase. Biochem. Biophys. Res. Commun. 1990, 173,
620-626.
washed with brine and concentrated. Flash chromatography
on silica gel using 60:40 heptane/EtOAc provided 26 (6.2 g,
65%) as a pale-yellow oil: 1H NMR (CDCl3) δ 1.92 (p, J ) 6
Hz, 2H), 2.28 (s, 3H), 2.48 (t, J ) 6 Hz, 2H), 2.56 (t, J ) 6 Hz,
2H), 2.72 (t, J ) 6 Hz, 2H), 3.63 (t, J ) 6 Hz, 2H).
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J M0200916