Synthesis and structure-activity relationships of phenoxypyridine derivatives as novel inhibitors of the sodium-calcium exchanger

Article abstract of DOI:10.1016/j.bmc.2004.07.038

A series of 2-phenoxypyridine derivatives were prepared and evaluated for their inhibitory activity against the reverse and forward modes of the sodium-calcium exchanger (NCX). The structure-activity relationships of these compounds on the inhibitory activity for the sodium-calcium exchanger are discussed. The sodium-calcium exchanger (NCX) is known as the transporter that controls the concentration of Ca²⁺ in cardiac myocytes. In the setting of heart failure and myocardial ischemia-reperfusion, NCX underlies an arrhythmogenic transient inward current responsible for delayed after-depolarizations and nonreentrant initiation of ventricular tachycardia. NCX is an attractive target for treatment in heart failure and myocardial ischemia-reperfusion. We have designed and synthesized a series of phenoxypyridine derivatives, based on compound 3. These derivatives have been evaluated for their inhibitory activity against both the reverse and forward mode of NCX in CCL39 cells. We have discovered several novel potent NCX inhibitors (39q, 48k), which have a high selectivity for reverse NCX inhibitory activity.

Full text of DOI:10.1016/j.bmc.2004.07.038

Bioorganic & Medicinal Chemistry 12 (2004) 5039–5056
Synthesis and structure–activity relationships of
phenoxypyridine derivatives as novel inhibitors of the
sodium–calcium exchanger
a
a
a
Takahiro Kuramochi,a, Akio Kakefuda, Hiroyoshi Yamada, Ippei Sato,
*
Taku Taguchib and Shuichi Sakamotoc
aInstitute for Drug Discovery Research, Yamanouchi Pharmaceutical Co. Ltd, 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan
bQA & RA Division, Yamanouchi Pharmaceutical Co. Ltd, 3-17-1 Hasune, Itabashi-Ku, Tokyo 174-8612, Japan
cInstitute for Technology Development, Yamanouchi Pharmaceutical Co. Ltd, 160-2 akahama, Takahagi, Ibaraki 318-0001, Japan
Received 24 June 2004; revised 17 July 2004; accepted 17 July 2004
Available online 7 August 2004
Abstract—The sodium–calcium exchanger (NCX) is known as the transporter that controls the concentration of Ca2+ in cardiac
myocytes. In the setting of heart failure and myocardial ischemia-reperfusion, NCX underlies an arrhythmogenic transient inward
current responsible for delayed after––depolarizations and nonreentrant initiation of ventricular tachycardia. NCX is an attractive
target for treatment in heart failure and myocardial ischemia-reperfusion. We have designed and synthesized a series of phenoxy-
pyridine derivatives, based on compound 3. These derivatives have been evaluated for their inhibitory activity against both the
reverse and forward mode of NCX in CCL39 cells. We have discovered several novel potent NCX inhibitors (39q, 48k), which have
a high selectivity for reverse NCX inhibitory activity.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
reverse mode NCX inhibitors are currently considered
beneficial in treating the above diseases.8
Ca2+ is an important second messenger in most cell
types, and controls contraction in myocytes. The so-
dium–calcium exchanger (NCX) plays an important role
in maintaining the calcium balance in cardiac myo-
cytes,1 but in the setting of heart failure and myocardial
ischemia-reperfusion, an increase in Na+ levels leads to a
calcium overload via the NCX.2–7 This is also responsi-
ble for contractile dysfunction. Approaches that inhib-
ited the NCX could have potential anti-arrhythmic
effects in pathophysiological states, such as heart failure
or myocardial ischemia-reperfusion. NCX typically
functions in the forward mode but can also function in
the reverse mode. The reverse mode of NCX has a more
important role with regards to calcium overload. Conse-
quently, selective inhibition of the reverse NCX mode
could provide a novel therapeutic approach to the
prevention and treatment of reperfusion arrhythmias,
aberrant myocardial contracture, and necrosis. Indeed,
Recently, several NCX inhibitors have been identified
(Fig. 1).9–12 The arylguanidine compound 1 has been re-
ported, which is based on a known sodium–proton ex-
changer (NHE) inhibitor.9 A series of phenoxybenzyl
derivatives 2–310,11 and a qunazoline derivative 412 have
also been reported. KB-R7943 (2) has been shown to
have an IC50 value of 0.32lM and exhibits a greater
effect on the reverse NCX than on the forward NCX
in single cardiac ventricular cells of the guinea pig with
the whole-cell voltage-clamp technique.13 Compound 3
has been reported as a potent NCX inhibitor.11 The
NCX inhibitory structure–activity relationships of these
compounds have not been reported in detail to date. We
focused on compound 3 and planned to create novel and
more selective reverse NCX inhibitors. In order to im-
prove inhibitory activity and selectivity for the reverse
NCX, modifications to the 3-fluorobenzylphenyl, amide,
and pyrrolidine functions were undertaken.
Keywords: Sodium–calcium exchanger; NCX; transporter; Anti-
arrhythmias.
In this paper, we describe the results of our work on the
synthesis and structure–activity relationships of these
potent and selective reverse NCX inhibitors.
*
Corresponding author. Tel.: +81-29-8525111; fax: +81-29-
8525387; e-mail: kuramochi.takahiro@yamanouchi.co.jp
0968-0896/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2004.07.038

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T. Kuramochi et al. / Bioorg. Med. Chem. 12 (2004) 5039–5056
Cl
S
NH2
NH
NO2
H
N
H
N
O
O2N
NH2
NH O
1
2
O
N
O
N
N
F
N
H
O
N
N
H
O
3
4
Figure 1. Several inhibitors of sodium–calcium exchanger: (1) aroylguanidine analogue; (2) KB-R7943; (3) patented compound of JP11092454;
(4) SM-15811.
2. Chemistry
reaction and subsequent hydrolysis gave intermediates
21–24, respectively.
The synthesis schemes of the novel N-(6-phenoxypyri-
din-3-yl)acylamide derivatives 39a–w, compounds
40–43, 6-{4-[(3-fluorobenzyl)oxy]phenoxy}nicotinamide
derivatives 48a–m and compound 47 are summarized
in Schemes 1–4. In Scheme 1, intermediates 15–24 were
prepared from starting materials 5–14. Intermediates 15
and 16 were prepared from 5 and 6, respectively, via O-
alkylation with 3-fluorobenzylbromide. Intermediate 17
was obtained from compound 7 via condensation with
3-fluorobenzoic acid. Reductive alkylation of 8 with 3-
fluorobenzaldehyde afforded intermediate 18. Reaction
of 9 with 3-fluorobenzaldehyde followed by the removal
of the methyl group with BBr3 afforded the intermediate
19. Compound 10 was converted into 20 via condensa-
tion with 3-fluoroaniline and removal of the associated
benzyl group. O-alkylation of compounds 11–14 with
3-fluorobenzylbromide followed by a Baeyer–Villiger
We described the synthesis of intermediates 37a–x as
shown in Scheme 2. Compounds 26 and 27 were con-
verted to intermediates 33 and 34 via condensation with
2-chloro-5-nitropyridine, followed by a Baeyer–Villiger
reaction, and subsequent hydrolysis. Condensation of
29 with 2-chloro-5-nitropyridine followed by benzyl re-
moval afforded compound 35. Condensation of 28 with
2-chloro-5-nitropyridine and subsequent reduction with
sodium borohydride of the aldehyde afforded alcohol
derivative 36. Condensation of compounds 15–25 with
2-chloro-5-nitropyridine afforded intermediates 37a–
c,g,h,j,l,r,t,v,w, respectively. Alkylation of 33 and 34
with 3-fluorobenzylbromide afforded intermediates 37u
and 37s. Under Mitsunobu conditions, the reaction of
35 with 2-(3-fluorophenyl)ethanol and 36 with 3-fluoro-
phenol gave 37e and 37f, respectively. Alkylation of 35
OH
OBn
a
f, g
H
N
OH
F
F
OH
O
HO2C
HO
O
5
6
2-position
3-position
2-position
3-position
10
20
15
16
OH
O
R1
OH
OH
O
R1
b
a, h, i
F
F
N
O
H2N
Me
H
HO
7
17
R1 = Me
21
22
R1 = Me
R1 = OMe
11
12
R1 = OMe
OH
OH
c
F
N
Me
18
N
H
R2
R2
OH
8
CHO
a, h, i
F
O
HO
OH
OMe
d, e
R2 = Cl
R2 = OMe
R2 = Cl
R2 = OMe
F
13
14
23
24
(MeO)2(O)P
9
19
Scheme 1. Synthesis of intermediates 15–24. Reagents and conditions: (a) 3-fluorobenzylbromide, K2CO3, DMF; (b) 3-fluorobenzoic acid, (COCl)2,
DMF, dichloroethane, then Et3N, 7; (c) 3-fluorobenzaldehyde, NaBH(OAc)3, AcOH, THF; (d) NaH, 15-crown-5, 3-fluorobenzaldehyde, THF;
(e) BBr3, CH2Cl2, À78°C, then MeOH; (f) (COCl)2, DMF, dichloroethane, then Et3N, 3-fluoroaniline; (g) pentamethylbenzene, TFA;
(h) m-chloroperbenzoic acid, CH2Cl2; (i) K2CO3, MeOH.

T. Kuramochi et al. / Bioorg. Med. Chem. 12 (2004) 5039–5056
5041
R2
R2
26
27
28
29
RA = Ac, R1 = H, R2 = Me
R1
R3
OH
OH
R1
RA
OH
RA = CHO, R1 = Cl, R2 = H
RA = CHO, R1 = R2 = H
RA = OBn, R1 = R2 = H
Me O
X
26-28
29
15-25
25
a
a, b
a
R2
R2
R2
R1
R3
O
R1
RA
O
N
R1
O
c, d
e, or f
N
N
NO2
NO2
NO2
HO
X
30-32
33-35
37a-h, 37j, 37l-x
R1 = H, R2 = Me
R1 = Cl, R2 = H
R1 = R2 = H
RA = Ac, R1 = H, R2 = Me
RA = CHO, R1 = Cl, R2 = H
RA = CHO, R1 = R2 = H
33
34
35
30
31
32
h
O
N
O
N
g
HO
NO2
NO2
OHC
32
36
R2
O
O
O
R1
O
F
O
N
R3
O
N
N
NO2
NO2
F
X
2
4
NO2
F
N
3
NO2
O
R3 = Me
37e X = -CH2CH 2O-
37f X = -O-CH2-
37c
37a 2-position
37b 3-position
37x 4-position
R3 = cyclohexyl -CH2-
R3 = 2-pyridyl -CH2-
R3 = 3-pyridyl -CH2-
R3 = 4-pyridyl -CH2-
R3 = 2-thienyl-CH2-
R3 = 3-thienyl-CH2-
37d
37m
37n
37o
37p
37q
R1 = Me, R2 = H
R1 = Cl, R2 = H
37r
37s
37t
37u
37v
37w
37g
X = (E) -CH=CH-
37h X = -NHCO-
37j X = -CONH-
37l X = -CH2N(Me)-
R1 = OMe, R2 = H
R1 = H, R2 = Me
R1 = H, R2 = Cl
R1 = H, R2 = OMe
O
O
Me
O
i
i
F
N
F
N
N
37h
37j
NO2
NO2
N
Me
O
37i
37k
Scheme 2. Synthesis of intermediates 37a–x. Reagents and conditions: (a) 2-chloro-5-nitropyridine, K2CO3, DMF, 100°C; (b) pentamethylbenzene,
TFA; (c) m-chloroperbenzoic acid, CH2Cl2; (d) K2CO3, MeOH; (e) R3–Br, K2CO3, DMF; (f) R3–OH, DEAD, PPh3, THF; (g) NaBH4, MeOH,
THF; (h) 3-fluorophenol, DEAD, PPh3, THF; (i) NaH, MeI, THF.
with several halides afforded 37d, 37m–q, and 37x. Com-
pounds 37h and 37j were converted to 37i and 37k via
alkylation with methyl iodide.
6-{4-[(3-Fluorobenzyl)oxy]phenoxy}nicotinamide deriv-
atives 48a–m, and compound 47 were synthesized from
2-chloro-5-cyanopyridine as illustrated in Scheme 4.
Condensation of compound 44 with 4-benzyloxyphenol
followed by debenzylation and O-alkylation with
3-fluorobenzylbromide gave compound 45. Subsequent
reduction of 45 followed by condensation with
chloroacetic anhydride and alkylation with pyrrolidine
afforded compound 47. Hydrolysis of the cyano
function of compound 45 followed by condensa-
tion with a selection of amines afforded compounds
48a–m.
Reduction of compounds 37a–x gave amino derivatives
38a–x. Condensation of compounds 38a–w with chloro-
acetic anhydride followed by alkylation with pyrrolidine
afforded the N-(6-phenoxypyridin-3-yl)acylamide deriv-
atives 39a–w (Scheme 3). 3-Fluorophenylethyl derivative
40 was obtained via hydrogenation of compound 39f.
Compound 41 was prepared from 38x in five steps, as
follows: trifluoroacetylation of amino group: methyl-
ation of the trifluoroacetylamino group using iodo-meth-
ane: hydrolysis of the trifluoroacetyl group; amidation
with chloroacetic anhydride and alkylation with pyrrol-
idine. Compound 42 was prepared by the acylation of
compound 38x with 2-bromopropionyl bromide fol-
lowed by alkylation with pyrrolidine. Acylation of com-
pound 38x with acryloyl chloride followed by alkylation
gave compound 43.
3. Results and discussion
In order to measure the inhibitory effect of the synthe-
sized compounds on the reverse mode of NCX activity,
a Na+-dependent Ca2+ influx assay was performed
according to reported protocols, using 45Ca and CCL39 cells

5042
T. Kuramochi et al. / Bioorg. Med. Chem. 12 (2004) 5039–5056
R2
R2
R1
R3
O
R1
R3
O
a
b, c
O
37a-x
N
N
N
N
H
X
NH2
X
38a-x
39a-w
R2
O
O
O
R1
O
F
O
4
N
R3
O
N
N
NH2
NH2
F
X
2
NH2
F
N
3
NH2
O
R3 = Me
38c
38d
38e X = -CH2CH 2O-
38f X = -O-CH2-
X = (E)-CH=CH-
38h X = -NHCO-
38i X = -N(Me)CO-
38j X = -CONH-
38k X = -CON(Me)-
38l X = -CH2N(Me)-
R3 = cyclohexyl -CH2-
R3 = 2-pyridiyl -CH2-
R3 = 3-pyridyl -CH2-
R3 = 4-pyridyl -CH2-
R3 = 2-thienyl-CH2-
R3 = 3-thienyl-CH2-
38a 2-position
38b 3-position
38x 4-position
R1 = Me, R2 = H
R1 = Cl, R2 = H
38r
38s
38t
38g
38m
38n
38o
38p
38q
R1 = OMe, R2 = H
R1 = H, R2 = Me
R1 = H, R2 = Cl
38u
38v
38w
R
1 = H, R2 = OMe
O
N
O
O
O
d
N
N
F
F
N
N
H
N
H
39f
40
O
O
e, f, g, b, c
N
F
N
N
38x
38x
O
Me
41
O
O
O
O
h, c
F
i, j
N
N
F
N
38x
N
N
H
N
O
O
H
Me
42
43
Scheme 3. Synthesis of compounds 39a–w, 40–43. Reagents and conditions: (a) SnClÆH2O, THF, 70°C or Fe, NH4Cl, H2O, EtOH, 90°C or Pd–C,
H2, THF; (b) (ClCH2CO)2O, CHCl3; (c) K2CO3, pyrrolidine, MeCN, 90°C; (d) Pd–C, H2, MeOH; (e) TFAA, CH2Cl2; (f) MeI, K2CO3, 2-butanone,
reflux; (g) NaOH, MeOH; (h) 2-bromopropionyl bromide, NaHCO3, AcOEt–H2O; (i) Et3N, THF, acryloyl chloride; (j) pyrrolidine, K2CO3, MeCN,
80°C.
O
O
Cl
H
N
a, b, c
d, e
F
N
F
N
O
CN
O
R4
N
CN
O
44
45
48a-m
f
O
O
g, h
H
F
N
NH2
F
N
N
N
O
O
O
46
47
Scheme 4. Synthesis of compounds 47, 48a–m. Reagents and conditions: (a) 4-benzyloxyphenol, K2CO3, DMF, 100°C; (b) pentamethylbenzene,
TFA; (c) 3-fluorobenzylbromide, K2CO3, MeCN, 80°C; (d) 5M NaOH, EtOH, reflux; (e) WSCÆHCl, HOBt, THF, R4NH2; (f) BH3ÆTHF, THF;
(g) (ClCH2CO)2O, CHCl3; (h) K2CO3, pyrrolidine, MeCN, 90°C.
stably expressing NCX1.1.10 A concentration-response
curve was drawn to determine the concentration re-
quired to prevent 50% of the influx of 45Ca (reverse
mode NCX) induced by a Na+ overload. The inhibitory
effect of the synthesized compounds on forward mode
NCX activity was assayed by a cell necrosis assay, which
also used NCX1.1-expressing CCL39 cells. Again a con-
centration-response curve was drawn to determine the
concentration required to induce 50% of the cell necrosis
by a Ca2+ overload.14
The inhibitory potencies of our novel compounds were
thus evaluated in reverse mode and forward mode
NCX assays. These compounds were then compared
to KB-R7943 (2) and compound 3 (Fig. 1).
The structure–activity relationships of our novel series
of NCX inhibitors are summarized in Tables 1–3.
Both KB-R7943 (2) and patented compound 3 were
examined as reference compounds. KB-R7943 (2) is

T. Kuramochi et al. / Bioorg. Med. Chem. 12 (2004) 5039–5056
5043
Table 1. Inhibitory activity of phenoxypyridine derivatives against the sodium–calcium exchanger
R2
R1
O
O
4
N
N
2
N
H
R3
X
3
Compd
Position
R3–X–
R1
R2
45Ca influxa IC50 (lM)c
Cell necrosisb EC50 (lM)c
Selectivityd
39a
39b
39c
39d
39e
39f
39g
40
2
3
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
3-F–C6H4–CH2O–
3-F–C6H4–CH2O–
MeO–
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Cl
>100
31
NTe
NTe
NTe
NTe
52
––
––
––
––
>100
44
11
Cyclohexyl–CH2O–
3-F–C6H4–(CH2)2O–
3-F–C6H4–OCH2–
3-F–C6H4–(E)–CH@CH–
3-F–C6H4–(CH2)2–
3-F–C6H4–NHCO–
3-F–C6H4–N(Me)CO–
3-F–C6H4–CONH–
3-F–C6H4–CON(Me)–
3-F–C6H4–CH2N(Me)–
2–Pyridyl–CH2O–
3–Pyridyl–CH2O–
4–Pyridyl–CH2O–
2-Thienyl–CH2O–
3-Thienyl–CH2O–
3-F–C6H4–CH2O–
3-F–C6H4–CH2O–
3-F–C6H4–CH2O–
3-F–C6H4–CH2O–
3-F–C6H4–CH2O–
3-F–C6H4–CH2O–
4.7
2.7
6.3
60
17
NTe
70
––
3.6
39
19
39h
39i
39j
39k
39l
39m
39n
39o
39p
39q
39r
39s
39t
39u
39v
39w
2
NTe
NTe
NTe
NTe
NTe
>100
>100
>100
80
––
––
––
––
––
25
10
>100
9.6
9.5
3.9
1.7
1.3
0.60
2.0
3.6
5.8
5.7
4.8
2.8
5.1
0.94
>10
>25
>58
62
58
97
Me
Cl
>100
NTe
51
>50
––
OMe
H
8.8
57
72
10
15
29
H
H
OMe
83
24
4.7
36
3
4
3-F–C6H4–CH2O–
H
H
34
a Activity at the NCX1.1 expressed in CCL39 cells. 45Ca influx mean NCX inhibitory activity for reverse mode.
b Activity at the NCX1.1 expressed in CCL39 cells. Cell necrosis mean NCX inhibitory activity for forward mode.
c IC50 values and EC50 values were determined in a single experimental run in triplicate.
d Ratio of EC50 value of Cell necrosis and IC50 value of 45Ca influx.
e Not tested.
one of the most well known reverse NCX inhibitors,
which is used as a model for testing the effects of heart
failure disease.15 In our 45Ca influx assay KB-R7943
(2) exhibited an IC50 value of 5.1lM against reverse
NCX, whereas compound 3 exhibited an IC50 value of
0.94lM for reverse NCX. Compound 3, which showed
an EC50 value of 34lM for cell necrosis induced by inhi-
bition of NCX forward mode, also showed a higher
selectivity than KB-R7943 (2). Consequently, com-
pound 3 was selected as a lead compound.16 We studied
these compoundsꢀ structure–activity relationships as
they were not known. This study led us to introduce sev-
eral linkages connecting the 3-fluorophenyl moiety with
the phenoxy part of compound 3, and to transform the
3-fluorophenyl group to various hetero-aryl groups. We
also converted the amide linkage and pyrrolidine moiety
into inverse amides and several other functional groups.
Initially, a number of phenoxypyridine derivatives with
various structural motifs were prepared, in order to
identify the optimum 3-fluorophenylmethyloxyphenyl
moiety. The results of this optimization exercise are
shown in Table 1. Substitution at both the 2-position
and 3-position with a 3-fluorophenylmethyloxy unit
led to a substantial decrease in reverse NCX inhibitory
activity (compounds 39a,b). Changing the 3-fluorophen-
ylmethyl group into another group such as a methoxy
group (39c) or cyclohexylmethoxy group (39d) also
caused a strong reduction in the observed potency.
These results suggested that the 3-fluorophenyl ring
and its position play an important and significant role
with regards to activity. We then examined modifica-
tions to the linker (–CH2O–) connecting the 3-fluoro-
phenyl moiety with the phenoxy unit. The length of
linker was increased in compound 39e and a 12-fold de-
crease in activity was observed. Consequently, other lin-
ker systems such as AOCH2A (39f), ACH@CHA (39g),
amide (39h–k) and ACH2N(Me)A (40) were examined.
Compounds 39g–l gave a reduction in reverse NCX
activity. These results indicate that both a straight con-
formation of the linker unit (such as in 39g) and the
polarity of the linking unit (such as in 39h–k) are detri-
mental to NCX activity, whereas the –CH2O– linker
unit is beneficial with respect to activity. The 2-pyridyl
derivative (39m) showed a 10-fold decrease in the reverse
NCX inhibitory activity compared to compound 3.
However, the 4-pyridyl derivative (39o) showed only a

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T. Kuramochi et al. / Bioorg. Med. Chem. 12 (2004) 5039–5056
Table 2. Inhibitory activity of phenoxypyridine derivatives against the sodium–calcium exchanger
O
F
N
N
Y
O
Compd
Y
45Ca influxa IC50 (lM)c
Cell necrosisb EC50 (lM)c
Selectivityd
>9.0
O
41
11
>100
N
Me
O
42
2.1
26
40
N
H
Me
O
O
43
1.6
2.4
0.78
1.8
44
58
45
47
27
24
57
26
N
H
H
N
47
H
N
48a
48b
O
O
H
N
Me
N
48c
3
6.3
NTe
34
––
36
O
O
0.94
N
H
For footnotes a–e refer to Table 1.
Table 3. Inhibitory activity of phenoxypyridine derivatives against the sodium–calcium exchanger
O
H
F
N
N
R4
Cell necrosisb EC50 (lM)c
O
O
Compd
R4
45Ca influxa IC50 (lM)c
Selectivityd
41
N
48d
0.90
37
48e
48f
2.0
2.6
32
16
23
N
Me
Ph
>60
N
N-Et2
OMe
48g
48h
1.3
1.4
36
28
>100
>71
48i
1.5
NTe
––
48j
6.1
55
9.0
48k
0.79
>100
>120
48l
2.8
7.1
>100
NTe
>36
––
48m
N
48a
3
0.78
0.94
45
34
57
36
For footnotes a–e refer to Table 1.

T. Kuramochi et al. / Bioorg. Med. Chem. 12 (2004) 5039–5056
5045
2-fold decrease in the reverse NCX inhibitory activity
when compared to compound 3. This indicates that
hydrophilicity is disfavored at the nearest part of the lin-
ker. Compound 39q, containing a 3-thienyl group,
showed an IC50 value of 0.6lM for reverse NCX. This
compound also had a higher selectivity (ratio of forward
to reverse = 97) for reverse NCX when compared to
compound 3. Introduction of some substituents into
the phenoxy moiety did not improve reverse NCX inhib-
itory activity (compounds 39r–w).
inhibitor. As a result of structural modifications based
upon compound 48a, we found a novel reverse NCX
inhibitor in compound 48k, which has both a potent
inhibitory activity and a high selectivity for the reverse
mode. Compounds 39q and 48k have IC50 values of
0.60 and 0.79lM for reverse NCX, respectively, and
higher selectivity when compared to compound 3. Com-
pounds 39q and 48k when compared to KB-R7943 (2),
showed a 6-fold and 8-fold increase in potency respec-
tively. Further research of this series to discover potent
and selective NCX inhibitors for the reverse mode is in
progress and will be reported in the near future.
We converted the amide function of compound 3 into
another amide linker (Table 2). The N-methyl amide
derivative (41) showed a 12-fold decrease in the inhibi-
tion of reverse NCX. Replacement of the amide function
with several other amide linkers and inverse amide lin-
kers as in compounds 42, 43, 47, 48a, and 48b showed
equivalent or slightly less potent inhibitory activity for
reverse NCX. These indicated that changes in the amide
part are well tolerated as regards activity. Among them,
the inversion of the amide bond (compound 48a)
showed equivalent activity and similar selectivity com-
pared to compound 3. The a-methyl amide derivative
42 showed a 2-fold decrease in inhibitory activity; this
indicates that introduction of substituents at this posi-
tion might be unfavorable to inhibitory action. Intro-
duction of the N-methyl amide template (compound
48c) showed a 8-fold decrease in inhibitory activity when
compared to compound 48a. The introduction of the N-
methyl amide template (41, 48c) appears not to be toler-
ated with regards to reverse NCX inhibitory activity.
5. Experimental
5.1. Chemistry
Melting points were determined with a Yanaco MP-
500D melting point apparatus or a Buchi B-545 melting
¨
point apparatus and are uncorrected. H NMR spectra
1
were recorded on a JEOL JNM-LA300 or a JNM-
EX400 spectrometer and the chemical shifts are ex-
pressed in d (ppm) values with tetramethylsilane as an
internal standard (in NMR description, s = singlet,
d = doublet, t = triplet, m = multiplet, and br = broad
peak). Mass spectra were recorded on a Hitachi M-80
or a JEOL JMS-LX2000 spectrometer. The elemental
analyses were performed with a Yanaco MT-5 microan-
alyzer (C, H, N) and were within 0.4% of theoretical
values. Drying of organic solutions during workup was
done over anhydrous Na2SO4.
Finally, we attempted to convert the pyrrolidine unit
into another functional group based on compound 48a
(Table 3). The replacement of the pyrrolidine unit with
several other groups such as amino, methoxy, and alkyl
that is piperidino and cyclohexyl groups (compounds
48d–i) led to slightly reduced activity compared to 48a.
Cyclohexyl derivative 48i and methoxy derivative 48h
showed similar activity compared to piperidino deriva-
tive 48e. This indicated that the basic functional groups
might not be important for reverse NCX inhibitory
activity. These results prompted us to exchange the pyr-
rolidino unit with various phenyl ring systems (com-
pounds 48j–m). Benzyl amide derivative 48k showed
equivalent activity and higher selectivity compared to
48a; whereas neutral substituents (compounds 48h,
48k) showed a tendency to reduce the forward NCX
inhibitory activity.
5.1.1. 2-(3-Fluorobenzyloxy)phenol (15). To the mixture
of 2-hydroxyphenol (5) (5.39g, 49mmol) and K2CO3
(6.76g, 49mmol), DMF (150mL) was added 3-fluoro-
benzylbromide (2.0mL, 16.3mmol) at room tempera-
ture. The mixture was stirred at room temperature for
5h. Water was added to the reaction mixture. The
mixture was partitioned between AcOEt and water.
The organic layer was washed with brine, dried, and
evaporated under reduced pressure. The residue was
purified by column chromatography on silica gel (hex-
ane/AcOEt = 10:1–8:1) to give 15 (2.62g, 74%) as a col-
1
orless oil. H NMR (400MHz, DMSO-d6): d 5.12 (2H,
s), 6.68–6.74 (1H, m), 6.75–6.84 (2H, m), 6.97 (1H, dd,
J = 8.3, 1.5Hz), 7.10–7.17 (1H, m), 7.28–7.37 (2H, m),
7.38–7.45 (1H, m), 9.00 (1H, s); MS (FAB) m/z 218
(MÀH)À.
5.1.2. 3-(3-Fluorobenzyloxy)phenol (16). Compound 16
was prepared from 3-hydroxyphenol (6) by a procedure
similar to that described for 15. Compound 16 was ob-
tained as a brown oil (65%). 1H NMR (400MHz,
DMSO-d6): d 5.06 (2H, s), 6.35–6.46 (3H, m), 7.06
(1H, t, J = 8.3Hz), 7.11–7.18 (1H, m), 7.23–7.29 (2H,
m), 7.40–7.47 (1H, m), 9.41 (1H, s); MS (FAB) m/z
218 (MÀH)À.
4. Conclusion
A series of 2-phenoxypyridine derivatives have been pre-
pared and evaluated for their inhibitory activities and
selectivities for the reverse mode of NCX versus the for-
ward mode. Compound 3 was selected as a lead com-
pound. By modifying the phenoxybenzyl moiety, we
found the thienylmethoxyphenyl structure (compound
39q) to enhance reverse NCX inhibitory activity and
to increase selectivity. By modifying the amide moiety,
compound 48a, possessing the novel 6-phenoxynicotina-
mide structure, was identified as a novel reverse NCX
5.1.3. 3-Fluoro-N-(4-hydroxyphenyl)benzamide (17). To
the mixture of 3-fluorobenzoic acid (2.83g, 20mmol)
and dichloroethane (50mL), dimethylformamide
(0.2mL) was added (COCl)2 (1.84mL, 21mmol) at room

5046
T. Kuramochi et al. / Bioorg. Med. Chem. 12 (2004) 5039–5056
temperature. After stirring for 2h, the mixture was
added to the mixture of 7 (2.0g, 18.3mmol) and dichlo-
roethane (30mL), Et3N (5.1mL, 37mmol) at 0°C. The
mixture was stirred at room temperature for overnight.
H2O was added, the precipitate was filtered, and dried
in vacuo to give (17) (3.40g) as a violet solid (80%).
1H NMR (400MHz, DMSO-d6): d 7.31 (2H, d,
J = 8.8Hz), 7.43–7.50 (1H, m), 7.57–7.72 (1H, m),
7.75–7.92 (3H, m), 8.00 (1H, d, J = 8.0Hz), 10.43 (1H,
s); MS (FAB) m/z 229 (MÀ2H)À.
idue were added H2O (8mL) and CHCl3 (8mL). The
mixture was stirred, the precipitate was filtered, and
dried in vacuo to afford 20 as a colorless solid (82%).
1H NMR (400MHz, DMSO-d6): d 6.84–6.92 (3H, m),
7.32–7.40 (1H, m), 7.51–7.57 (1H, m), 7.71–7.77 (1H,
m), 7.85 (2H, d, J = 8.3Hz), 10.15 (2H, d, J = 7.9Hz);
MS (FAB) m/z 232 (M+H)+.
5.1.7. 4-[(3-Fluorobenzyl)oxy]-3-methylphenol (21). To
the mixture of 11 (0.75g, 5.0mmol) and MeCN
(8mL), K2CO3 (0.83g, 6.9mmol) was added 3-fluoro-
benzylbromide (0.67mL, 5.5mmol) at room tempera-
ture. The mixture was stirred at 80°C for 1h. The
mixture was partitioned between Et2O and aqueous
NaOH. The organic layer was washed with brine and
dried, evaporated in vacuo. The residue was purified
by column chromatography on silica gel (hexane/
AcOEt = 4:1) to give 1-{4-[(3-fluorobenzyl)oxy]-3-meth-
ylphenyl}ethanone (1.26g, 98%) as a colorless solid. The
intermediate (1.26g, 4.9mmol) was dissolved in dichlo-
roethane (15mL). To the mixture was added m-chloro-
perbenzoic acid (1.37g, 6.37mmol) at 0°C. The mixture
was stirred at room temperature for overnight. m-Chlor-
operbenzoic acid (0.42g, 2.45mmol) was added to the
mixture at 0°C. The mixture was stirred at room tem-
perature for 7h. The mixture was filtered, washed with
dichloroethane. To the filtrate was added saturated
Na2SO3, the mixture was partitioned between CHCl3
and H2O. The organic layer was washed with saturated
NaHCO3 and brine, dried, and evaporated. To the mix-
ture of residue and MeOH (13mL) was added K2CO3
(1.02g, 7.35mmol). The mixture was stirred at room
temperature for 5h. The solvent was removed under re-
duced pressure. the residue was partitioned between
AcOEt and aqueous HCl. The organic layer was washed
with brine, dried, evaporated. The residue was purified
by column chromatography on silica gel (hexane/
AcOEt = 2:1) to give 21 (1.01g, 89% for two steps) as
5.1.4. 4-[(3-Fluorobenzyl)(methyl)amino]phenol (18). To
the mixture of 4-methylaminophenol (8) (0.5equiv of
H2SO4 salt, 1.72g, 10mmol) and THF (20mL), Et3N
(1.39mL, 10mmol) was added 3-fluorobenzaldehyde
(1.24g, 10mmol) at 0°C. Acetic acid (0.57mL, 10mmol)
and NaBH(OAc)3 (2.33g, 10mmol) were added to the
mixture at 0°C. The mixture was stirred at room tem-
perature for overnight. The mixture was partitioned be-
tween AcOEt and H2O. The organic layer was washed
with saturated NaHCO3, brine, dried, and evaporated
in vacuo. The residue was purified by column chroma-
tography on silica gel (hexane/AcOEt = 1:0–2:1) to give
18 (1.93g, 83%) as a light pink syrup. 1H NMR
(300MHz, CDCl3): d 2.91 (3H, br s), 4.33 (1H, s), 4.39
(2H, br s), 6.62–6.80 (4H, m), 6.88–7.04 (3H, m), 7.22–
7.31 (1H, m); MS (FAB) m/z 231 (M+H)+.
5.1.5. 4-[(E)-2-(3-Fluorophenyl)vinyl]phenol (19). To the
mixture of 9 (4.02g, 15.6mmol) and THF (30mL) was
added 60% NaH (650mg, 16.3mmol) at 0°C. 3-Fluoro-
benzaldehyde (1.5mL, 14.1mmol) and 15-crown-5
(0.08mL) were added to the mixture at 0°C. The reac-
tion mixture was stirred at room temperature for 2h.
H2O was added to the mixture. The organic layer was
extracted with AcOEt, dried, and evaporated in vacuo.
The residue was recrystallized with hexane (13mL).
The precipitate was collected to give 1-fluoro-3-[(E)-2-
(4-methoxyphenyl)vinyl]benzene (68%). The product
(790mg, 3.46mmol) was dissolved in CH2Cl2 (10mL).
To the mixture was added BBr3 of CH2Cl2 solution
(1M, 10mL) at À78°C. The mixture was stirred at
À78°C to room temperature for 5h. MeOH (3.46mmol)
was added to the mixture at À78°C. The mixture was
stirred at room temperature for 1h. The organic layer
was washed with saturated NaHCO3 and brine, dried,
evaporated. The residue was purified by column chro-
matography on silica gel (hexane/AcOEt = 3:1) to give
1
a colorless solid. H NMR (300MHz, CDCl3): d 2.24
(3H, s), 4.99 (2H, s), 5.04 (1H, br s), 6.59 (1H, dd,
J = 8.6, 2.9Hz), 6.67–6.74 (2H, m), 6.83–7.04 (1H, m),
7.12–7.21 (2H, m), 7.29–7.37 (1H, m); MS (FAB) m/z
232 (M)+.
The following compounds (22–24) were prepared by a
procedure similar to that described for 21.
5.1.8. 4-[(3-Fluorobenzyl)oxy]-3-methoxyphenol (22).
Brown oil (74% for three steps). H NMR (300MHz,
1
19 (234mg, 32%) as
a
colorless oil; 1H NMR
(400MHz, DMSO-d6): d 6.78 (2H, d, J = 8.7Hz),
6.99–7.07 (2H, m), 7.23 (1H, d, J = 8.7Hz), 7.34–7.45
(5H, m), 9.63 (1H, br s); MS (FAB) m/z 214 (M)+.
CDCl3): d 3.84 (3H, s), 5.04 (2H, s), 6.26 (1H, dd,
J = 8.6, 2.9Hz), 6.47 (1H, d, J = 2.8Hz), 6.72 (1H, d,
J = 8.6Hz), 6.93–7.01 (1H, m), 7.06–7.19 (2H, m),
7.26–7.35 (1H, m); MS (FAB) m/z 248 (M)+.
5.1.6. N-(3-Fluorophenyl)-4-hydroxybenzamide (20). 4-
(Benzyloxy)-N-(3-fluorophenyl)benzamide (3.64g, 55%
yield as a colorless solid) was prepared from 10 (5.22g,
23mmol) and 3-fluoroaniline (2.31g, 23mmol) accord-
ing to the procedure similar to that described for
17. 4-(Benzyloxy)-N-(3-fluorophenyl)benzamide (1.18g,
3.7mmol) was added to the mixture of pentamethylben-
zene (1.63g, 11mmol) and trifluoroacetic acid (8mL) at
room temperature. The mixture was stirred for 6h. The
solvent was removed under reduced pressure. To the res-
5.1.9. 2-Chloro-4-[(3-fluorobenzyl)oxy]phenol (23). White
solid (73% for three steps). 1H NMR (300MHz, CDCl3):
d 4.99 (2H, s), 5.19 (1H, s), 6.81 (1H, dd, J = 8.9,
2.9Hz), 6.91–7.05 (3H, m), 7.10–7.19 (2H, m), 7.30–
7.38 (1H, m); MS (FAB) m/z 252 (M+H)+.
5.1.10. 4-[(3-Fluorobenzyl)oxy]-2-methoxyphenol (24).
Pale yellow oil (50% for three steps). 1H NMR
(300MHz, CDCl3): d 3.86 (3H, s), 4.99 (2H, s), 5.24

T. Kuramochi et al. / Bioorg. Med. Chem. 12 (2004) 5039–5056
5047
(1H, s), 6.43 (1H, dd, J = 8.6, 2.8Hz), 6.56 (1H, d,
J = 2.7Hz), 6.82 (1H, d, J = 8.6Hz), 6.96–7.05 (1H,
m), 7.10–7.21 (2H, m), 7.29–7.38 (1H, m); MS (FAB)
m/z 248 (M)+.
2-nitropyridine as a brown powder (35g, 87%). The
compound (31g, 96mmol) was dissolved in trifluoroace-
tic acid (200mL). To the mixture was added pentameth-
ylbenzene (17g, 115mmol) at 0°C. The mixture was
partitioned between AcOEt and aqueous NaHCO3.
The organic layer was dried and concentrated in vacuo.
The residue was crystallized from AcOEt/hexane to give
35 as a yellow solid (76%). 1H NMR (400MHz, DMSO-
d6): d 6.82 (2H, d, J = 9.2Hz), 7.02 (2H, d, J = 9.2Hz),
7.15 (1H, d, J = 9.0Hz), 8.58 (1H, dd, J = 9.0, 2.8Hz),
9.02 (1H, d, J = 2.8Hz), 9.50 (1H, s); MS (FAB) m/z
233 (M+H)+.
5.1.11. 4-[(5-Nitropyridin-2-yl)oxy]benzaldehyde (32). To
the mixture of 4-hydroxybenzaldehyde 28 (1.21g,
9.90mmol), K2CO3 (1.96g, 14.2mmol) and DMF
(15mL) was added 5-chloro-2-nitropyridine (1.50g,
9.46mmol) at 0°C. The mixture was stirred at room
temperature. To the mixture was added H2O. The pre-
cipitate was filtered and dried in vacuo to afford 32 as
1
a pale brown solid (2.09g, 90%). H NMR (400MHz,
DMSO-d6): d 7.39 (1H, d, J = 8.8Hz), 7.48 (2H, d,
J = 8.8Hz), 8.03 (2H, d, J = 8.8Hz), 8.68 (1H, dd,
J = 8.8, 3.0Hz), 9.05 (1H, d, J = 2.9Hz), 10.03 (1H, s);
MS (FAB) m/z 245 (M+H)+.
5.1.15. {4-[(5-Nitropyridin-2-yl)oxy]phenyl}methanol (36).
Compound 32 (2.09g, 8.56mmol) was dissolved in
MeOH (17mL) and THF (17mL). NaBH4 (324mg,
8.56mmol) was added to the mixture at 0°C. The mix-
ture was stirred for 1h at room temperature, and was
partitioned between AcOEt and H2O. The organic layer
was washed with brine, dried, evaporated to afford 36 as
5.1.12. 4-[(5-Aminopyridin-2-yl)oxy]-3-methylphenol (33).
Intermediate 30 was prepared from 26 (1.5g, 10mmol)
by a procedure similar to that described for 32. 1-{3-
Methyl-4-[(5-nitropyridin-2-yl)oxy]phenyl}ethanone (30)
was obtained as a yellow oil (2.44g, 89%). The interme-
diate 30 (2.44g, 8.94mmol) was dissolved in dichloro-
ethane (25mL). To the mixture was added m-
chloroperbenzoic acid (2.89g, 13.4mmol) at 0°C. The
mixture was stirred at room temperature for 3days. m-
Chloroperbenzoic acid (1.93g, 8.94mmol) was added
to the mixture at 0°C. The mixture was stirred at room
temperature for 3days. The mixture was filtered, washed
with dichloroethane. To the filtrate was added saturated
Na2SO3, the mixture was partitioned between CHCl3
and H2O. The organic layer was washed with saturated
NaHCO3 and brine, dried, and evaporated. To the mix-
ture of residue and MeOH (26mL) was added K2CO3
(1.85g, 13.4mmol). The mixture was stirred at room
temperature for 1h. The solvent was removed under re-
duced pressure, the residue was partitioned between
AcOEt and aqueous HCl. The organic layer was washed
with brine, dried, evaporated. The residue was purified
by column chromatography on silica gel (hexane/
AcOEt = 4:1–3:1) to give 33 (1.31g, 59% for two steps)
1
a yellow oil (71%): H NMR (400MHz, DMSO-d6): d
4.53 (2H, d, J = 5.8Hz), 5.24 (1H, t, J = 5.6Hz), 7.18
(2H, d, J = 8.3Hz), 7.24 (1H, d, J = 9.3Hz), 7.41 (2H,
d, J = 8.3Hz), 8.62 (1H, dd, J = 9.3, 2.9Hz), 9.02 (1H,
d, J = 2.4Hz); MS (FAB) m/z 247 (M+H)+.
5.1.16. 2-{4-[2-(3-Fluorophenyl)ethoxy]phenoxy}-5-nitro-
pyridine (37a). The mixture of 15 (1.01g, 4.6mmol) and
5-nitro-2-chloropyridine (700mg, 4.42mmol), K2CO3
(915mg, 6.6mmol), and DMF (7mL) was stirred at
100°C for 4h. To the reaction mixture was added water
at room temperature. The precipitate was collected and
washed with water, dried in vacuo to afford 37a as a pale
yellow solid (1.63g, 100%). 1H NMR (400MHz,
DMSO-d6): d 5.09 (2H, s), 6.73–6.77 (1H, m), 6.97
(1H, d, J = 7.3Hz), 7.02–7.09 (2H, m), 7.23–7.33 (5H,
m), 8.59 (1H, dd, J = 9.2, 3.0Hz), 8.99 (1H, d,
J = 2.9Hz); MS (FAB) m/z 341 (M+H)+.
5.1.17. N-(3-Fluorophenyl)-N-methyl-4-[(5-nitropyridin-
2-yl)oxy]benzamide (37i). Compound 37h was prepared
from 20 by a procedure similar to that described for
32. To the mixture of 37h (350mg, 0.99mmol) and
THF (15mL), 60% of NaH (48mg, 1.20mmol) was
added MeI (0.093mL, 5mmol) at 0°C. The mixture
was stirred at room temperature for 3h. The mixture
was partitioned between AcOEt and H2O. The organic
layer was washed with brine, dried, evaporated. The res-
idue was purified by column chromatography on silica
gel (hexane/AcOEt = 3:1–2:1) to give 37i (350mg, 96%)
1
as a yellow solid. H NMR (300MHz, CDCl3): d 2.09
(3H, s), 5.23 (1H, br s), 6.67–6.76 (2H, m), 6.93 (1H,
d, J = 8.4Hz), 7.01 (1H, d, J = 9.1Hz), 8.47 (1H, dd,
J = 9.1, 2.7Hz), 9.04 (1H, d, J = 2.7Hz); MS (FAB) m/
z 247 (M)+.
5.1.13. 2-Chloro-4-[(5-nitropyridin-2-yl)oxy]phenol (34).
Compound 34 was prepared from 27 by a procedure
similar to that described for 33. Compound 34 was ob-
1
as a pale yellow oil. H NMR (400MHz, DMSO-d6):
1
tained as a yellow solid (50% for two steps). H NMR
d 3.39 (3H, s), 7.00–7.08 (2H, m), 7.13 (2H, d,
J = 8.3Hz), 7.18–7.26 (2H, m), 7.28–7.41 (3H, m), 8.52
(1H, dd, J = 8.8, 3.0Hz), 9.01 (1H, d, J = 3.0Hz); MS
(FAB) m/z 368 (M+H)+.
(300MHz, CDCl3): d 5.57 (1H, br s), 6.98–7.11 (3H, m),
7.19 (1H, d, J = 2.8Hz), 8.48 (1H, dd, J = 9.0, 2.9Hz),
9.04 (1H, d, J = 2.9Hz); MS (FAB) m/z 266 (M)+.
5.1.14. 4-[(5-Nitropyridin-2-yl)oxy]phenol (35). To the
mixture of 4-(benzyloxy)phenol 29 (25g, 125mmol), t-
BuOK (16.8g, 150mmol), and DMF (250mL) was
added 5-chloro-2-nitropyridine (19.8g, 125mmol) at
0°C. The mixture was stirred at room temperature. To
the mixture was added H2O. The precipitate was filtered
and dried in vacuo to afford 5-[4-(benzyloxy)phenoxy]-
5.1.18. 3-Fluoro-N-{4-[(5-nitropyridin-2-yl)oxy]phenyl}-
benzamide (37j). Compound 37j was prepared from 17
by a procedure similar to that described for 32. Com-
pound 37j was obtained as a pale yellow solid (13%).
1H NMR (400MHz, DMSO-d6): d 7.22–7.28 (2H, m),
7.32 (1H, d, J = 9.3Hz), 7.43–7.50 (1H, m), 7.57–7.72
(1H, m), 7.77–7.88 (4H, m), 8.63 (1H, dd, J = 9.3,

5048
T. Kuramochi et al. / Bioorg. Med. Chem. 12 (2004) 5039–5056
2.9Hz), 9.04 (1H, d, J = 2.9Hz), 10.42 (1H, br s); MS
(FAB) m/z 354 (M+H)+.
38c (744mg, 56%) as a pale yellow solid. 1H NMR
(400MHz, DMSO-d6): d 3.73 (3H, s), 5.00 (2H, s),
6.69 (1H, d, J = 8.3Hz), 6.87–6.94 (4H, m), 7.05 (1H,
dd, J = 8.3, 3.0Hz), 7.50 (1H, d, J = 3.0Hz); MS
(FAB) m/z 217 (M+H)+.
5.1.19.
3-Fluoro-N-methyl-N-{4-[(5-nitropyridin-2-yl)-
oxy]phenyl}benzamide (37k). Compound 37k was pre-
pared from 37j by a procedure similar to that described
for 37i. Compound 37k was obtained as a pale yellow
solid (49%). 1H NMR (400MHz, DMSO-d6): d 3.40
(3H, s), 7.07–7.18 (5H, m), 7.22 (1H, d, J = 8.8Hz),
7.27–7.35 (3H, m), 8.64 (1H, dd, J = 8.8, 2.9Hz), 9.02
(1H, d, J = 3.0Hz); MS (FAB) m/z 368 (M+H)+.
The following compounds (38g,l,r,t,v,w) were prepared
by a procedure similar to that described for 38c.
5.1.23. 6-{4-[(E)-2-(3-Fluorophenyl)vinyl]phenoxy}pyri-
din-3-amine (38g). From compound 19 (57% for two
steps) as a colorless solid. H NMR (300MHz, CDCl3):
1
5.1.20.
6-{2-[(3-Fluorobenzyl)oxy]phenoxy}pyridin-3-
d 5.14 (2H, s), 6.80 (1H, d, J = 8.3Hz), 6.88 (2H, d,
J = 8.8Hz), 7.04–7.19 (3H, m), 7.32 (1H, d,
J = 16.6Hz), 7.38–7.47 (3H, m), 7.54–7.60 (3H, m);
MS (FAB) m/z 307 (M+H)+.
amine (38a). The mixture of 15 (1.01g, 4.6mmol) and
5-nitro-2-chloropyridine (700mg, 4.42mmol), K2CO3
(915mg, 6.6mmol), and DMF (7mL) was stirred at
100°C for 4h. To the reaction mixture was added water
at room temperature. The precipitate was collected and
washed with water, dried in vacuo to afford 2-{4-[2-(3-
fluorophenyl)ethoxy]phenoxy}-5-nitropyridine (37a) as
a pale yellow solid (1.63g). Compound 37a was dis-
solved in THF (40mL), SnCl2Æ2H2O (4.99g, 22mmol)
was added to the mixture. The mixture was stirred at
70°C for 2h and recooled to room temperature. To
the reaction mixture were added 1M NaOH and celite
(10g). The mixture was filtrated through a celite pad,
washed with THF. The filtrate was partitioned between
AcOEt and H2O. The organic layer was washed
and dried, evaporated under pressure. The residue was
purified by column chromatography on silica gel (hex-
ane/AcOEt = 2:1–3:2) to give 38a (922mg, 67% for
two steps) as a brown oil. 1H NMR (400MHz,
DMSO-d6): d 4.92 (2H, s), 5.07 (2H, s), 6.72 (1H, d,
J = 8.3Hz), 6.91–6.99 (2H, m), 7.00–7.14 (6H, m),
7.30–7.37 (1H, m), 7.45 (1H, d, J = 2.9Hz); MS (FAB)
m/z 311 (M+H)+.
5.1.24. 6-{4-[(3-Fluorobenzyl)(methyl)amino]phenoxy}py-
ridin-3-amine (38l). From compound 18 (99% for two
1
steps) as a yellow syrup: H NMR (300MHz, CDCl3):
d 2.99 (3H, s), 3.44 (2H, br s), 4.47 (2H, s), 6.67–6.74
(3H, m), 6.89–7.07 (6H, m), 7.24–7.32 (1H, m), 7.69
(1H, d, J = 3.1Hz); MS (FAB) m/z 324 (M+H)+.
5.1.25. 6-{4-[(3-Fluorobenzyl)oxy]-3-methylphenoxy}py-
ridin-3-amine (38r). From compound 21 (100% for two
steps) as a pale yellow oil. 1H NMR (300MHz, CDCl3):
d 2.27 (3H, s), 3.48 (2H, br s), 5.04 (2H, s), 6.72 (1H, d,
J = 8.6Hz), 6.78–6.93 (3H, m), 6.97–7.08 (2H, m), 7.13–
7.22 (2H, m), 7.30–7.38 (1H, m), 7.69 (1H, d,
J = 2.9Hz); MS (FAB) m/z 325 (M+H)+.
5.1.26. 6-{4-[(3-Fluorobenzyl)oxy]-3-methoxyphenoxy}-
pyridin-3-amine (38t). From compound 22 (81% for
1
two steps) as a yellow oil. H NMR (300MHz, CDCl3):
d 3.50 (2H, br s), 3.85 (3H, s), 5.10 (2H, s), 6.53 (1H, dd,
J = 8.8, 2.8Hz), 6.67–6.75 (2H, m), 6.82 (1H, d,
J = 8.6Hz), 6.94–7.03 (1H, m), 7.07 (1H, dd, J = 8.6,
3.1Hz), 7.15–7.22 (2H, m), 7.27–7.37 (1H, m), 7.71
(1H, d, J = 3.1Hz); MS (FAB) m/z 350 (M+H)+.
5.1.21.
6-{3-[(3-Fluorobenzyl)oxy]phenoxy}pyridin-3-
amine (38b). Compound 38b was prepared from 16 by
a procedure similar to that described for 38a. Com-
pound 38b was obtained as a brown oil (100% for two
1
steps). H NMR (400MHz, DMSO-d6): d 5.09 (2H, s),
5.1.27. 6-{2-Chloro-4-[(3-fluorobenzyl)oxy]phenoxy}pyri-
din-3-amine (38v). From compound 23 (74% for two
5.13 (2H, s), 6.51 (1H, dd, J = 8.3, 2.5Hz), 6.61 (1H, t,
J = 2.4Hz), 6.72–6.77 (2H, m), 7.08 (1H, dd, J = 8.7,
3.0Hz), 7.12–7.29 (4H, m), 7.39–7.47 (1H, d,
J = 2.9Hz) 7.57 (1H, d, J = 2.9Hz); MS (FAB) m/z
311 (M+H)+.
1
steps) as a yellow oil. H NMR (300MHz, CDCl3): d
3.47 (2H, br), 5.03 (2H, s), 6.78 (1H, dd, J = 8.6,
0.6Hz), 6.87 (1H, dd, J = 8.8, 2.9Hz), 6.98–7.21 (6H,
m), 7.31–7.40 (1H, m), 7.63 (1H, dd, J = 2.9, 0.6Hz);
MS (FAB) m/z 345 (M+H)+.
5.1.22. 6-(4-Methoxyphenoxy)pyridin-3-amine (38c).
Compound 37c was prepared from 4-methoxyphenol
(25) (822mg, 6.63mmol) by a procedure similar to that
described for 37a. 2-(4-Methoxyphenoxy)-5-nitropyr-
idine (37c) was obtained as a pale yellow solid (1.50g,
97% yield). To the EtOH (30mL) solution of 37c were
added powder of Fe (1.70g, 30mmol) and water
(3mL) solution of NH4Cl (261mg, 4.9mmol) at room
temperature. The mixture was stirred at 90°C for 6h,
it was cooled at room temperature and filtered and
washed with CHCl3. The filtrate was partitioned be-
tween CHCl3 and water, the organic layer was washed
with 1M NaOH and brine, dried, and evaporated under
pressure. The residue was purified by column chroma-
tography on silica gel (hexane/AcOEt = 2:1–3:2) to give
5.1.28. 6-{4-[(3-Fluorobenzyl)oxy]-2-methoxyphenoxy}-
pyridin-3-amine (38w). From compound 24 (73% for
two steps) as a yellow solid: 1H NMR (300MHz,
CDCl3): d 3.42 (2H, br s), 3.75 (3H, s), 5.03 (2H, s),
6.51 (1H, dd, J = 8.8, 2.7Hz), 6.65 (1H, d, J = 2.7Hz),
6.74 (1H, d, J = 8.6Hz), 6.98–7.08 (3H, m), 7.14–7.23
(2H, m), 7.31–7.39 (1H, m), 7.64 (1H, d, J = 2.9Hz);
MS (FAB) m/z 341 (M+H)+.
5.1.29.
6-[4-(Cyclohexylmethoxy)phenoxy]pyridin-3-
amine (38d). Compound 37d was prepared from 35 by
a procedure similar to that described for 15. The mixture
of 37d (348mg, 1.06mmol), THF (10mL), and 10% of
palladium-activated carbon (35mg) was stirred at room

T. Kuramochi et al. / Bioorg. Med. Chem. 12 (2004) 5039–5056
5049
temperature under H2 (normal atmosphere) for over-
night. The mixture was filtered, the filtrate was concen-
trated under reduced pressure to give 38d as a beige solid
5.1.34. N-{4-[(5-Aminopyridin-2-yl)oxy]phenyl}-3-fluoro-
benzamide (38j). Compound 38j was prepared from
compound 37j by a procedure similar to that described
for 38c. Compound 38j was obtained as a beige solid
1
(49% for two steps): H NMR (400MHz, DMSO-d6): d
1
0.97–1.10 (2H, m), 1.10–1.32 (3H, m), 1.60–1.84 (6H,
m), 3.73 (2H, d, J = 6.4Hz), 5.00 (2H, s), 6.68 (1H, d,
J = 8.8Hz), 6.88 (4H, s), 7.04 (1H, dd, J = 8.8, 2.9Hz),
7.49 (1H, d, J = 2.9Hz); MS (FAB) m/z 299 (M+H)+.
(41%). H NMR (400MHz, DMSO-d6): d 5.08 (2H, s),
6.76 (1H, d, J = 8.8Hz), 6.94–6.99 (2H, m), 7.08 (1H,
dd, J = 8.3, 2.9Hz), 7.41–7.48 (1H, m), 7.53–7.63 (2H,
m), 7.68–7.73 (2H, m), 7.73–7.84 (2H, m), 10.28 (1H,
s); MS (FAB) m/z 323 (M+H)+.
5.1.30. 6-{4-[2-(3-Fluorophenyl)ethoxy]phenoxy}pyridin-
3-amine (38e). To the mixture of 35 (581mg, 2.50mmol)
and THF (10mL), Ph3P (852mg, 3.25mmol) were added
a solution of DEAD (0.512mL, 3.25mmol) and 2-(3-
fluorophenyl)ethanol (420mg, 3.00mmol) in THF
(5mL) at 0°C. The mixture was stirred at room temper-
ature for 6h. The mixture was partitioned between
AcOEt and aqueous NaOH, the organic layer was
washed with brine, dried, and evaporated under reduced
pressure. The residue was purified by column chroma-
tography on silica gel (hexane/AcOEt = 1:0–4:1) to give
37e (904mg,) as a yellow syrup. Compound 38e was pre-
pared from 37e by a procedure similar to that described
for 38c. Compound 38e was obtained as a yellow syrup
(93% for two steps). 1H NMR (300MHz, CDCl3): d 3.08
(2H, t, J = 6.8Hz), 3.47 (2H, br s), 4.15 (2H, t,
J = 6.8Hz), 6.71 (1H, d, J = 8.6Hz), 6.84–7.08 (7H,
m), 7.23–7.31 (2H, m), 7.68 (1H, d, J = 2.9Hz); MS
(FAB) m/z 325 (M+H)+.
5.1.35.
6-[4-(Pyridin-2-ylmethoxy)phenoxy]pyridin-3-
amine (38m). Compound 37m was prepared from com-
pound 35 by a procedure similar to that described for
15. Compound 38m was prepared from 37m by a proce-
dure similar to that described for 38c. Compound 38m
1
was obtained as a colorless oil (79% for two steps). H
NMR (400MHz, DMSO-d6): d 5.02 (2H, s), 5.15 (2H,
s), 6.70 (1H, d, J = 8.3Hz), 6.92 (2H, d, J = 9.0Hz),
6.99 (2H, d, J = 9.0Hz), 7.05 (1H, dd, J = 8.8, 2.9Hz),
7.32–7.37 (1H, m), 7.49–7.54 (2H, m), 7.82–7.87 (1H,
m), 8.58 (1H, d, J = 4.9Hz); MS (FAB) m/z 294
(M+H)+.
The following compounds (38n,o–q,s,u,x) were prepared
by a procedure similar to that described for 38m.
5.1.36. 6-[4-(Pyridin-3-ylmethoxy)phenoxy]pyridin-3-
amine (38n). From compound 35 (73% for two steps)
1
as a pale yellow oil. H NMR (400MHz, DMSO-d6):
5.1.31. 6-{4-[(3-Fluorophenoxy)methyl]phenoxy}pyridin-
3-amine (38f). Compound 37f was prepared from 36
by a procedure similar to that described for 37e. Com-
pound 37f was obtained as a colorless solid (42%). Com-
pound 38f was prepared from 37f by a procedure similar
to that described for 38c. Compound 38f was obtained
d 5.01 (2H, s), 5.12 (2H, s), 6.70 (1H, d, J = 8.3Hz),
6.92 (2H, d, J = 9.3Hz), 7.00 (2H, d, J = 9.3Hz), 7.05
(1H, dd, J = 8.8, 2.9Hz), 7.40–7.45 (1H, m), 7.50 (1H,
d, J = 2.9Hz), 7.85–7.89 (1H, m), 8.55 (1H, dd,
J = 4.9, 1.5Hz), 8.67 (1H, d, J = 2.0Hz); MS (FAB) m/
z 294 (M+H)+.
1
as a beige solid (93%). H NMR (400MHz, DMSO-
d6): d 5.06 (2H, s), 5.11 (2H, s), 6.73–6.80 (2H, m),
6.83–6.92 (2H, m), 6.96 (2H, d, J = 8.3Hz), 7.08 (1H,
dd, J = 8.8, 3.0Hz), 7.28–7.35 (1H, m), 7.41 (2H, d,
J = 8.3Hz), 7.55 (1H, d, J = 2.9Hz); MS (FAB) m/z
311 (M+H)+.
5.1.37. 6-[4-(Pyridin-4-ylmethoxy)phenoxy]pyridin-3-
amine (38o). From compound 35 (51% for two steps)
1
as a pale yellow oil. H NMR (400MHz, DMSO-d6):
d 5.01 (2H, s), 5.16 (2H, s), 6.70 (1H, d, J = 8.8Hz),
6.92 (2H, d, J = 9.3Hz), 6.98 (2H, d, J = 9.3Hz), 7.05
(1H, dd, J = 9.0, 3.0Hz), 7.44 (2H, d, J = 5.9Hz), 7.49
(1H, d, J = 2.9Hz), 8.54–8.59 (2H, m); MS (FAB) m/z
294 (M+H)+.
5.1.32.
4-[(5-Aminopyridin-2-yl)oxy]-N-(3-fluorophen-
yl)benzamide (38h). Compound 37h was prepared from
compound 20 by a procedure similar to that described
for 37a. Compound 38h was prepared from 37h by a
procedure similar to that described for 38d. Compound
38h was obtained as a colorless solid (92% for two
5.1.38. 6-[4-(2-Thienylmethoxy)phenoxy]pyridin-3-amine
(38p). From compound 35 (38% for two steps) as a pale
1
yellow oil. H NMR (400MHz, DMSO-d6): d 5.00 (2H,
1
steps). H NMR (400MHz, DMSO-d6): d 5.21 (2H, s),
s), 5.25 (2H, s), 6.69 (1H, d, J = 8.8Hz), 6.87–7.08 (6H,
m), 7.20 (1H, d, J = 3.6Hz), 7.50 (1H, d, J = 3.2Hz),
7.55 (1H, d, J = 4.8Hz); MS (FAB) m/z 299 (M+H)+.
6.86 (1H, d, J = 8.7Hz), 6.88–6.95 (1H, m), 7.03–7.08
(2H, m), 7.12 (1H, dd, J = 8.3, 2.9Hz), 7.34–7.42 (1H,
m), 7.53–7.57 (1H, m), 7.60 (1H, d, J = 2.9Hz), 7.72–
7.78 (1H, m), 7.92–7.97 (2H, m), 10.34 (1H, s); MS
(FAB) m/z 324 (M+H)+.
5.1.39. 6-[4-(3-Thienylmethoxy)phenoxy]pyridin-3-amine
(38q). From compound 35 (100% for two steps) as a pale
1
yellow oil. H NMR (400MHz, DMSO-d6): d 5.01 (2H,
5.1.33. 4-[(5-Aminopyridin-2-yl)oxy]-N-(3-fluorophenyl)-
N-methylbenzamide (38i). Compound 38i was prepared
from compound 37i by a procedure similar to that de-
scribed for 38d. Compound 38i was obtained as a color-
s), 5.51 (2H, s), 6.69 (1H, d, J = 8.3Hz), 6.89–6.99 (4H,
m), 7.05–7.08 (1H, m), 7.17–7.19 (1H, m), 7.50 (1H, d,
J = 2.9Hz), 7.54–7.57 (2H, m); MS (FAB) m/z 299
(M+H)+.
1
less oil (98%): H NMR (400MHz, DMSO-d6): d 3.38
(3H, m), 5.17 (2H, s), 6.73–6.80 (3H, m), 6.95–7.08
(3H, m), 7.13–7.18 (1H, m), 7.23–7.33 (3H, m), 7.56
(1H, d, J = 2.9Hz); MS (FAB) m/z 338 (M+H)+.
5.1.40. 6-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenoxy}pyri-
din-3-amine (38s). From compound 34 (79% for two
steps) as a yellow oil. H NMR (300MHz, CDCl3): d
1

5050
T. Kuramochi et al. / Bioorg. Med. Chem. 12 (2004) 5039–5056
3.52 (2H, br s), 5.11 (2H, s), 6.75 (1H, d, J = 8.6Hz),
6.91–6.93 (2H, m), 6.97–7.11 (2H, m), 7.14–7.25 (2H,
m), 7.31–7.39 (2H, m), 7.68 (1H, d, J = 2.9Hz); MS
(FAB) m/z 345 (M+H)+.
5.1.44. N-(6-{3-[(3-Fluorobenzyl)oxy]phenoxy}pyridin-3-
yl)-2-pyrrolidin-1-ylacetamide dihydrochloride (39b).
White powder (25% for two steps): mp 141–146°C; H
1
NMR (400MHz, DMSO-d6): d 1.84–2.08 (4H, m),
3.08–3.20 (2H, m), 3.56–3.67 (2H, m), 4.28 (2H, d,
J = 5.4Hz), 5.13 (2H, s), 6.68 (1H, dd, J = 8.0, 2.2Hz),
6.67 (1H, t, J = 2.2Hz), 6.86 (1H, dd, J = 8.0, 2.2Hz),
7.05 (1H, d, J = 8.8Hz), 7.13–7.19 (1H, m), 7.25–7.34
(3H, m), 7.41–7.47 (1H, m), 8.09 (1H, dd, J = 8.8,
2.9Hz), 8.42 (1H, d, J = 2.4Hz), 10.41 (1H, br s),
11.15 (1H, s); MS (FAB) m/z 422 (M+H)+. Anal. Calcd
for C24H24FN3O3Æ1.4HClÆ0.5H2O: C, 59.86; H, 5.53; N,
8.73; Cl, 10.31. Found: C, 59.71; H, 5.46; N, 8.76; Cl,
10.54.
5.1.41. 6-{4-[(3-Fluorobenzyl)oxy]-2-methylphenoxy}py-
ridin-3-amine (38u). From compound 33 (87% for two
1
steps) as a yellow oil. H NMR (300MHz, CDCl3): d
2.16 (3H, s), 3.44 (2H, br s), 5.02 (2H, s), 6.66 (1H, d,
J = 8.6Hz), 6.78 (1H, dd, J = 8.6, 2.9Hz), 6.86 (1H, d,
J = 2.7Hz), 6.93 (1H, d, J = 8.8Hz), 6.97–7.02 (1H,
m), 7.05 (1H, dd, J = 8.6, 2.9Hz), 7.13–7.22 (2H, m),
7.30–7.38 (1H, m), 7.66 (1H, d, J = 2.9Hz); MS (FAB)
m/z 325 (M+H)+.
5.1.45. N-[6-(4-Methoxyphenoxy)pyridin-3-yl]-2-pyrrol-
idin-1-ylacetamide hydrochloride (39c). White powder
(90% for two steps): mp 182–184°C; 1H NMR
(400MHz, DMSO-d6): d 1.84–2.07 (4H, m), 3.05–3.25
(2H, br), 3.53–3.70 (2H, br), 3.76 (3H, s), 4.26 (2H, s),
6.93–7.08 (5H, m), 8.04 (1H, dd, J = 8.8, 2.9Hz), 8.36
(1H, d, J = 3.0Hz), 10.35 (1H, br s), 11.04 (1H, s); MS
(FAB) m/z 328 (M+H)+. Anal. Calcd for
C18H21N3O3ÆHCl: C, 59.42; H, 6.09; N, 11.55; Cl, 9.74.
Found: C, 59.14; H, 6.07; N, 11.53; Cl, 9.61.
5.1.42.
6-{4-[(3-Fluorobenzyl)oxy]phenoxy}pyridin-3-
amine (38x). From compound 35 (86% for two steps)
as an orange syrup. 1H NMR (300MHz, CDCl3): d
3.48 (2H, br s), 5.03 (2H, s), 6.72 (1H, dd, J = 8.6,
0.5Hz), 6.91–7.08 (6H, m), 7.14–7.20 (2H, m), 7.29–
7.38 (1H, m), 7.69 (1H, dd, J = 3.0, 0.6Hz); MS
(FAB) m/z 311 (M+H)+.
5.1.43. N-(6-{2-[(3-Fluorobenzyl)oxy]phenoxy}pyridin-3-
yl)-2-pyrrolidin-1-ylacetamide dihydrochloride (39a). To
the mixture of 38a (922mg, 2.97mmol) and CHCl3
(10mL) was added (ClCH2CO)O (533mg, 3.12mmol)
at 0°C. The reaction mixture was stirred at room tem-
perature for 2h. It was concentrated under reduced pres-
sure, the residue was dissolved in EtOAc. The organic
layer was washed with 1M NaOH, water, and brine,
dried, and evaporated under reduced pressure to afford
2-chloro-N-(6-{2-[(3-fluorobenzyl)oxy]phenoxy}pyridin-
3-yl)acetamide (1.12g, 98%) as a brown oil. The crude
compound was dissolved in MeCN (14mL). To the mix-
ture was added K2CO3 (440mg, 3.19mmol) and pyrrol-
idine (1.21mL, 14.5mmol) at room temperature. The
reaction mixture was stirred at 80°C for 2h. The reac-
tion mixture was cooled to room temperature and parti-
tioned between AcOEt and water. The organic layer
was washed with brine and dried, evaporated under red-
uced pressure. The residue was purified by column
chromatography on silica gel (CHCl3/MeOH/
NH4OH = 100:1:0.1–70:1:0.1) to give the free base of
39a (444mg). This material was converted to its hydro-
chloride salt by treating it with 4M HCl(g)/dioxane
(0.32mL). The crude salt was crystallized from EtOH/
AcOEt to give 39a as a colorless solid (311mg, 23% yield
for two steps from 38a): mp 186–187°C; 1H NMR
(400MHz, DMSO-d6): d 1.84–2.08 (4H, m), 3.06–3.20
(2H, m), 3.54–3.68 (2H, m), 4.26 (2H, d, J = 5.4Hz),
5.08 (2H, s), 6.85 (1H, d, J = 9.8Hz), 6.95 (1H, d,
J = 7.3Hz), 6.98–7.10 (3H, m), 7.14–7.23 (3H, m),
7.27–7.34 (1H, m), 8.05 (1H, dd, J = 8.8, 2.9Hz), 8.34
(1H, d, J = 2.4Hz), 10.39 (1H, br s), 11.06 (1H, s);
MS (FAB) m/z 422 (M+H)+. Anal. Calcd for
C24H24FN3O3Æ2HClÆ0.2H2O: C, 57.88; H, 5.34; N,
8.44; Cl, 14.24. Found: C, 57.99; H, 5.22; N, 8.41; Cl,
13.99.
5.1.46. N-{6-[4-(Cyclohexylmethoxy)phenoxy]pyridin-3-
yl}-2-pyrrolidin-1-ylacetamide hydrochloride (39d). White
1
powder (76% for two steps): mp 221–223°C; H NMR
(400MHz, DMSO-d6): d 0.98–1.11 (2H, m), 1.14–1.32
(3H, m), 1.62–2.07 (10H, m), 3.06–3.21 (2H, m), 3.56–
3.67 (2H, m), 3.77 (2H, d, J = 5.8Hz), 4.26 (2H, s),
6.92–7.04 (5H, m), 8.03 (1H, dd, J = 8.8, 2.9Hz), 8.35
(1H, d, J = 2.9Hz), 10.31 (1H, br s), 11.00 (1H, s); MS
(FAB) m/z 410 (M+H)+. Anal. Calcd for
C24H31N3O3HCl: C, 64.63; H, 7.23; N, 9.42; Cl, 7.95.
Found: C, 64.41; H, 7.33; N, 9.41; Cl, 7.92.
5.1.47. N-(6-{4-[2-(3-Fluorophenyl)ethoxy]phenoxy}pyri-
din-3-yl)-2-pyrrolidin-1-ylacetamide oxalate (39e). Beige
1
powder (70% for two steps): mp 140–141°C; H NMR
(400MHz, DMSO-d6): d 1.86–1.93 (4H, m), 3.07 (2H,
t, J = 6.8Hz), 3.99 (2H, s), 4.21 (2H, t, J = 6.8Hz),
6.94–7.09 (6H, m), 7.16–7.22 (2H, m), 7.33–7.39 (1H,
m), 8.03 (1H, dd, J = 8.8, 2.5Hz), 8.33 (1H, d,
J = 2.4Hz), 10.61 (1H, br s); MS (FAB) m/z 436
(M+H)+. Anal. Calcd for C25H26N3O3FÆC2H2O4: C,
62.32; H, 5.42; N, 8.14; F, 3.68. Found: C, 62.15; H,
5.14; N, 8.15; F, 3.69.
5.1.48. N-(6-{4-[(3-Fluorophenoxy)methyl]phenoxy}pyri-
din-3-yl)-2-pyrrolidin-1-ylacetamide hydrochloride (39f).
1
White powder (86% for two steps): mp 202–203°C; H
NMR (400MHz, DMSO-d6): d 1.85–2.07 (4H, br s),
3.04–3.30 (2H, br), 3.46–3.70 (2H, br), 4.27 (2H, s),
5.12 (2H, s), 6.75–6.80 (1H, m), 6.85–6.95 (2H, m),
7.09 (1H, d, J = 8.7Hz), 7.13 (2H, d, J = 8.3Hz), 7.29–
7.37 (1H, m), 7.49 (2H, d, J = 8.8Hz), 8.09 (1H, dd,
J = 8.8, 2.5Hz), 8.40 (1H, d, J = 2.9Hz), 10.35 (1H,
br s), 11.08 (1H, s); MS (FAB) m/z 422 (M+H)+.
Anal. Calcd for C24H24N3O3FÆHCl: C, 62.95; H, 5.50;
N, 9.18; Cl, 7.74; F, 4.15. Found: C, 62.84; H, 5.43;
N, 9.19; Cl, 7.80; F, 4.25.
The following compounds (39b–j, 39l–w) were prepared
by a procedure similar to that described for 39a.

T. Kuramochi et al. / Bioorg. Med. Chem. 12 (2004) 5039–5056
5051
5.1.49. N-(6-{4-[(E)-2-(3-Fluorophenyl)vinyl]phenoxy}-
pyridin-3-yl)-2-pyrrolidin-1-ylacetamide hydrochloride
(FAB) m/z 435 (M+H)+. Anal. Calcd for C25H27N4O2-
FÆC2H2O4: C, 61.82; H, 5.57; N, 10.68; F, 3.62. Found:
C, 61.80; H, 5.57; N, 10.81; F, 3.65.
(39g). White powder (93% for two steps): mp 260–
261°C; 1H NMR (400MHz, DMSO-d6): d 1.86–2.06
(4H, m), 3.08–3.20 (2H, m), 3.57–3.66 (2H, m), 4.28
(2H, d, J = 5.4Hz), 7.06–7.15 (4H, m), 7.22 (1H, d,
J = 16.6Hz), 7.37 (1H, d, J = 16.6Hz), 7.40–7.50 (3H,
m), 7.65 (2H, d, J = 8.8Hz), 8.10 (1H, dd, J = 8.8,
3.0Hz), 8.42 (1H, d, J = 3.0Hz), 10.35 (1H, br s),
11.10 (1H, s); MS (FAB) m/z 418 (M+H)+. Anal. Calcd
for C25H24N3O2FÆ1.25HClÆ0.5H2O: C, 63.61; H, 5.60;
N, 8.90; Cl, 9.39; F, 4.02. Found: C, 63.69; H, 5.48;
N, 8.93; Cl, 9.39; F, 4.01.
5.1.54. N-{6-[4-(Pyridin-2-ylmethoxy)phenoxy]pyridin-3-
yl}-2-pyrrolidin-1-ylacetamide dihydrochloride (39m).
1
White powder (50% for two steps): mp 216–218°C; H
NMR (400MHz, DMSO-d6): d 1.84–2.07 (4H, m),
3.07–3.18 (2H, m), 3.56–3.65 (2H, m), 4.26 (2H, d,
J = 5.9Hz), 5.26 (2H, s), 7.02 (1H, d, J = 8.8Hz), 7.07
(4H, s), 7.49–7.54 (1H, m), 7.69 (1H, d, J = 7.8Hz),
8.00–8.06 (2H, m), 8.34 (1H, d, J = 2.4Hz), 8.67 (1H,
d, J = 4.9Hz), 10.25 (1H, br s), 10.93 (1H, s); MS
(FAB) m/z 405 (M+H)+. Anal. Calcd for C23H24N4O3-
FÆ2HClÆ3.2H2O: C, 53.81; H, 5.89; N, 10.91. Found:
C, 54.00; H, 5.93; N, 10.95.
5.1.50. N-(3-Fluorophenyl)-4-({5-[(pyrrolidin-1-ylacetyl)-
amino]pyridin-2-yl}oxy)benzamide hydrochloride (39h).
1
White powder (88% for two steps): mp 259–261°C; H
NMR (400MHz, DMSO-d6): d 1.85–2.07 (4H, m),
3.11–3.18 (2H, m), 3.53–3.70 (2H, m), 4.28 (2H, s),
6.90–6.97 (1H, m), 7.19 (1H, d, J = 8.8Hz), 7.25 (2H,
d, J = 8.8Hz), 7.35–7.43 (1H, m), 7.56–7.60 (1H, m),
7.74–7.80 (1H, m), 8.02 (2H, d, J = 8.7Hz), 8.10–8.15
(1H, m), 8.42–8.45 (1H, m), 10.20–10.30 (1H, br),
10.44 (1H, s), 10.96–11.04 (1H, m); MS (FAB) m/z 435
(M+H)+. Anal. Calcd for C24H23N4O3FÆHClÆ0.7H2O:
C, 59.61; H, 5.29; N, 11.59; Cl, 7.33; F, 3.93. Found:
C, 59.56; H, 5.21; N, 11.60; Cl, 7.24; F, 3.72.
5.1.55. N-{6-[4-(Pyridin-3-ylmethoxy)phenoxy]pyridin-3-
yl}-2-pyrrolidin-1-ylacetamide dihydrochloride (39n).
1
White powder (11% for two steps): mp 175–176°C; H
NMR (400MHz, DMSO-d6): d 1.82–2.08 (4H, m),
3.06–3.20 (2H, m), 3.56–3.66 (2H, m), 4.26 (2H, d,
J = 4.9Hz), 5.30 (2H, s), 7.03 (1H, d, J = 8.7Hz), 7.09
(4H, s), 7.91–7.96 (1H, m), 8.05 (1H, dd, J = 8.8,
3.0Hz), 8.36 (1H, d, J = 2.4Hz), 8.46 (1H, d,
J = 7.8Hz), 8.82 (1H, d, J = 4.9Hz), 8.89 (1H, s),
10.31 (1H, br s), 11.02 (1H, s); MS (FAB) m/z 405
(M+H)+. Anal. Calcd for C23H24N4O3FÆ2HClÆ3.3H2O:
C, 51.98; H, 6.07; N, 10.45. Found: C, 52.29; H, 5.91;
N, 10.67.
5.1.51. N-(3-Fluorophenyl)-N-methyl-4-({5-[(pyrrolidin-1-
ylacetyl)amino]pyridin-2-yl}oxy)benzamide hydrochloride
(39i). White powder (78% for two steps): mp 160–
162°C; 1H NMR (400MHz, DMSO-d6): d 1.85–2.06
(4H, m), 3.07–3.22 (2H, m), 3.38 (3H, s), 3.50–3.70
(2H, m), 4.27 (2H, s), 6.94–7.09 (5H, m), 7.16–7.21
(1H, m), 7.28–7.35 (3H, m), 8.09 (1H, dd, J = 8.8,
2.9Hz), 8.41 (1H, d, J = 3.0Hz), 10.37 (1H, s), 11.14
(1H, s); MS (FAB) m/z 449 (M+H)+. Anal. Calcd for
C25H25N4O3FÆHClÆ0.1H2O: C, 61.65; H, 5.43; N,
11.51; Cl, 7.28; F, 3.90. Found: C, 61.45; H, 5.38; N,
11.60; Cl, 7.08; F, 3.74.
5.1.56. N-{6-[4-(Pyridin-4-ylmethoxy)phenoxy]pyridin-3-
yl}-2-pyrrolidin-1-ylacetamide dihydrochloride (39o).
1
White powder (44% for two steps): mp 210–215°C; H
NMR (400MHz, DMSO-d6): d 1.84–2.08 (4H, m),
3.07–3.19 (2H, m), 3.57–3.67 (2H, m), 4.27 (2H, s),
5.44 (2H, s), 7.03 (1H, d, J = 8.8Hz), 7.09 (4H, s), 7.96
(2H, d, J = 6.4Hz), 8.06 (1H, dd, J = 8.8, 3.0Hz), 8.36
(1H, d, J = 2.4Hz), 8.87 (2H, d, J = 6.3Hz), 10.37
(1H, br s), 11.09 (1H, s); MS (FAB) m/z 405 (M+H)+.
Anal. Calcd for C23H24N4O3Æ2HClÆ1.7H2O: C, 54.38;
H, 5.83; N, 11.03; Cl, 13.96. Found: C, 54.64; H, 5.82;
N, 11.01; Cl, 13.61.
5.1.52. 3-Fluoro-N-[4-({5-[(pyrrolidin-1-ylacetyl)amino]-
pyridin-2-yl}oxy)phenyl]benzamide hydrochloride (39j).
1
White powder (91% for two steps): mp 240–245°C; H
NMR (400MHz, DMSO-d6): d 1.85–2.08 (4H, m),
3.07–3.19 (2H, m), 3.57–3.72 (2H, m), 4.27 (2H, d,
J = 5.4Hz), 7.07 (1H, d, J = 8.8Hz), 7.12 (2H, d,
J = 9.3Hz), 7.43–7.49 (1H, m), 7.57–7.64 (1H, m),
7.70–7.86 (4H, m), 8.07 (1H, dd, J = 8.8, 2.5Hz), 8.39
(1H, d, J = 2.5Hz), 10.30 (1H, br s), 10.41 (1H, s),
11.01 (1H, s); MS (FAB) m/z 435 (M+H)+. Anal. Calcd
for C24H23N4O3FÆ1.3HClÆ1.2H2O: C, 57.25; H, 5.35; N,
11.31; Cl, 9.15; F, 3.77. Found: C, 57.19; H, 5.11; N,
11.34; Cl, 9.02; F, 3.87.
5.1.57. 2-Pyrrolidin-1-yl-N-{6-[4-(2-thienylmethoxy)phen-
oxy]pyridin-3-yl}acetamide hydrochloride (39p). White
1
powder (72% for two steps): mp 162–164°C; H NMR
(400MHz, DMSO-d6): d 1.83–2.07 (4H, m), 3.05–3.20
(2H, m) 3.54–3.67 (2H, m), 4.25 (2H, s) 5.29 (2H, s),
7.01 (1H, d J = 8.8Hz), 7.03–7.06 (5H, m), 7.21–7.23
(1H, m), 7.55–7.58 (1H, m), 8.04 (1H, dd, J = 8.8,
2.5Hz), 8.35 (1H, d, J = 2.9Hz), 10.26 (1H, br s),
10.94 (1H, s); MS (FAB) m/z 410 (M+H)+. Anal. Calcd
for C22H23N3O3SÆHClÆ0.3H2O: C, 58.54; H, 5.49; N,
9.31; Cl, 7.85; S, 7.10. Found: C, 58.17; H, 5.52; N,
9.09; Cl, 7.74; S, 7.49.
5.1.53. N-(6-{4-[(3-Fluorobenzyl)(methyl)amino]phenoxy}-
pyridin-3-yl)-2-pyrrolidin-1-ylacetamide oxalate (39l).
1
White powder (48% for two steps): mp 195–196°C; H
5.1.58. 2-Pyrrolidin-1-yl-N-{6-[4-(3-thienylmethoxy)-
phenoxy]pyridin-3-yl}acetamide hydrochloride (39q).
NMR (400MHz, DMSO-d6): d 1.88–1.94 (4H, m),
3.02 (3H, s), 3.15–3.23 (4H, m), 4.02 (2H, s), 4.57 (2H,
s), 6.72 (2H, d, J = 9.3Hz), 6.90–6.95 (3H, m), 7.01–
7.11 (3H, m), 7.34–7.41 (1H, m), 8.00 (1H, dd, J = 8.8,
3.0Hz), 8.31 (1H, d, J = 2.9Hz), 10.63 (1H, s); MS
1
White powder (81% for two steps): mp 184–186°C; H
NMR (400MHz, DMSO-d6): d 1.85–2.07 (4H, m),
3.06–3.20 (2H, m), 3.56–3.66 (2H, m), 4.26 (2H, s),
5.09 (2H, s), 7.01 (1H, d, J = 9.3Hz), 7.02–7.07 (4H,

5052
T. Kuramochi et al. / Bioorg. Med. Chem. 12 (2004) 5039–5056
m), 7.29 (1H, dd, J = 4.8, 1.4Hz), 7.55–7.60 (2H, m),
8.04 (1H, dd, J = 8.7, 2.4Hz), 8.36 (1H, d, J = 2.9Hz),
10.30 (1H, br s), 10.97 (1H, s); MS (FAB) m/z 410
(M+H)+. Anal. Calcd for C22H23N3O3SÆHClÆH2O: C,
56.95; H, 5.65; N, 9.06; Cl, 7.64; S, 6.91. Found: C,
56.92; H, 5.67; N, 8.90; Cl, 7.67; S, 7.30.
(2H, m), 7.16–7.28 (3H, m), 7.28–7.34 (2H, m), 7.43–
7.50 (1H, m), 8.07 (1H, dd, J = 8.8, 2.8Hz), 8.28 (1H,
d, J = 3.0Hz), 10.68 (1H, s); MS (FAB) m/z 456
(M+H)+. Anal. Calcd for C24H23N3O3ClFÆC2H2O4: C,
57.20; H, 4.62; N, 7.70; Cl, 6.49; F, 3.48. Found: C,
57.03; H, 4.61; N, 7.73; Cl, 6.28; F, 3.51.
5.1.64. N-(6-{4-[(3-Fluorobenzyl)oxy]-2-methoxyphenoxy}-
pyridin-3-yl)-2-pyrrolidin-1-ylacetamide oxalate (39w).
White powder (72% for two steps): mp 172–174°C; H
5.1.59. N-(6-{4-[(3-Fluorobenzyl)oxy]-3-methylphenoxy}-
pyridin-3-yl)-2-pyrrolidin-1-ylacetamide oxalate (39r).
White powder (44% for two steps): mp 174–176°C; H
1
1
NMR (400MHz, DMSO-d6): d 1.87–1.97 (4H, m),
3.15–3.28 (4H, m), 3.67 (3H, s), 4.04 (2H, s), 5.15 (2H,
s), 6.60 (1H, dd, J = 8.8, 2.9Hz), 6.81 (1H, d,
J = 2.9Hz), 6.93 (1H, d, J = 8.8Hz), 7.03 (1H, d,
J = 8.8Hz), 7.15–7.21 (1H, m), 7.29–7.36 (2H, m),
7.43–7.50 (1H, m), 7.98 (1H, dd, J = 8.8, 2.9Hz), 8.24
(1H, d, J = 2.2Hz), 10.65 (1H, s); MS (FAB) m/z 452
(M+H)+. Anal. Calcd for C25H26N3O3FÆC2H2O4: C,
59.88; H, 5.21; N, 7.76; F, 3.51. Found: C, 59.94; H,
5.13; N, 7.79; F, 3.80.
NMR (400MHz, DMSO-d6): d 1.83–1.87 (4H, m),
2.22 (3H, s), 3.08–3.23 (4H, br), 3.97 (2H, s), 5.15 (2H,
s), 6.87–6.92 (1H, m), 6.93–7.03 (3H, m), 7.13–7.20
(1H, m), 7.28–7.35 (2H, m), 7.43–7.50 (1H, m), 8.03
(1H, dd, J = 8.7, 2.1Hz), 8.33 (1H, d, J = 2.2Hz),
10.61 (1H, s); MS (FAB) m/z 436 (M+H)+. Anal. Calcd
for C25H26N3O3FÆ0.9C2H2O4: C, 62.34; H, 5.42; N, 8.14;
F, 3.68. Found: C, 62.64; H, 5.39; N, 8.18; F, 3.67.
5.1.60. N-(6-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenoxy}-
pyridin-3-yl)-2-pyrrolidin-1-ylacetamide oxalate (39s).
1
5.1.65. 3-Fluoro-N-methyl-N-[4-({5-[(pyrrolidin-1-ylacet-
yl)amino]pyridin-2-yl}oxy)phenyl]benzamide hydrochlo-
ride (39k). Compound 38k was prepared from 37k by
a procedure similar to that described for 38d. Com-
pound 39k was prepared from 38k by a procedure sim-
ilar to that described for 39a. Compound 39k was
obtained as a colorless solid (87% for three steps): mp
189–190°C; 1H NMR (400MHz, DMSO-d6): d 1.82–
2.04 (4H, m), 3.05–3.15 (2H, m), 3.38 (3H, m), 3.53–
3.67 (2H, m), 4.26 (2H, s), 6.99–7.06 (3H, m),
7.07–7.18 (3H, m), 7.21–7.38 (3H, m), 8.06 (1H, dd,
J = 8.8, 2.5Hz), 8.37 (1H, d, J = 2.5Hz), 10.20
(1H, br s), 10.88–10.95 (1H, m); MS (FAB) m/z 449
(M+H)+. Anal. Calcd for C25H25N4O3FÆHClÆ0.5H2O:
C, 60.79; H, 5.51; N, 11.34; Cl, 7.18; F, 3.85. Found:
C, 60.90; H, 5.41; N, 11.32; Cl, 7.03; F, 3.58.
White powder (50% for two steps): mp 178–180°C; H
NMR (400MHz, DMSO-d6): d 1.83–1.93 (4H, m),
3.01–3.13 (4H, m), 3.88 (2H, s), 5.24 (2H, s), 7.02–7.11
(2H, m), 7.15–7.22 (1H, m), 7.23–7.35 (4H, m), 7.44–
7.45 (1H, m), 8.08 (1H, dd, J = 8.8, 2.9Hz), 8.35 (1H,
d, J = 2.9Hz), 10.56 (1H, s); MS (FAB) m/z 456
(M+H)+. Anal. Calcd for C24H23N3O3FClÆ0.7C2H2O4:
C, 58.79; H, 4.74; N, 8.10; Cl, 6.83; F, 3.66. Found: C,
58.96; H, 4.72; N, 8.17; Cl, 6.85; F, 3.69.
5.1.61. N-(6-{4-[(3-Fluorobenzyl)oxy]-3-methoxyphenoxy}-
pyridin-3-yl)-2-pyrrolidin-1-ylacetamide oxalate (39t).
1
White powder (83% for two steps): mp 159–161°C; H
NMR (400MHz, DMSO-d6): d 1.84–1.94 (4H, m),
3.12 (4H, br s), 3.75 (3H, s), 3.93 (2H, s), 5.10 (2H, s),
6.60 (1H, dd, J = 8.8, 2.2Hz), 6.80 (1H, d, J = 2.9Hz),
6.97 (1H, d, J = 8.8Hz), 7.02 (1H, d, J = 8.8Hz), 7.13–
7.20 (1H, m), 7.25–7.32 (2H, m), 7.42–7.48 (1H, m),
8.04 (1H, d, J = 8.8, 2.9Hz), 8.35 (1H, d, J = 2.2Hz),
10.57 (1H, s); MS (FAB) m/z 452 (M+H)+. Anal. Calcd
for C25H26N3O4FÆ0.9C2H2O4: C, 60.45; H, 5.26; N, 7.89;
F, 3.57. Found: C, 60.72; H, 5.48; N, 7.84; F, 3.59.
5.1.66. N-(6-{4-[2-(3-Fluorophenyl)ethyl]phenoxy}pyri-
din-3-yl)-2-pyrrolidin-1-ylacetamide
dihydrochloride
(40). Compound 40 was prepared from 39g by a proce-
dure similar to that described for 38d. Compound 40
was obtained as a colorless solid (86%): mp 193–
195°C; 1H NMR (400MHz, DMSO-d6): d 1.84–2.08
(4H, m), 2.86–2.95 (4H, m), 2.96–3.20 (2H, m), 3.52–
3.67 (2H, m), 4.26 (2H, d, J = 5.3Hz), 6.97–7.05 (4H,
m), 7.07–7.13 (2H, m), 7.26 (2H, d, J = 8.3Hz), 7.28–
7.45 (1H, m), 8.05 (1H, dd, J = 8.8, 2.9Hz), 8.37 (1H,
d J = 2.9Hz), 10.24 (1H, s), 10.94 (1H, s); MS (FAB)
m/z 420 (M+H)+. Anal. Calcd for C25H26N3O2FÆ1.3H-
ClÆ0.8H2O: C, 62.39; H, 6.05; N, 8.73; Cl, 9.58; F,
3.95. Found: C, 62.38; H, 6.11; N, 8.71; Cl, 9.62; F, 4.12.
5.1.62. N-(6-{4-[(3-Fluorobenzyl)oxy]-2-methylphenoxy}-
pyridin-3-yl)-2-pyrrolidin-1-ylacetamide oxalate (39u).
1
White powder (56% for two steps): mp 189–190°C; H
NMR (400MHz, DMSO-d6): d 1.86–1.95 (4H, m),
2.04 (3H, s), 3.13–3.27 (4H, m), 4.03 (2H, s), 5.12 (2H,
s), 6.87 (1H, dd, J = 8.8, 2.9Hz), 6.94–7.00 (3H, m),
7.14–7.20 (1H, m), 7.27–7.33 (2H, m), 7.42–7.49 (1H,
m), 8.02 (1H, dd, J = 8.8, 3.0Hz), 8.28 (1H, d,
J = 2.9Hz), 10.65 (1H, s); MS (FAB) m/z 436
(M+H)+. Anal. Calcd for C25H26N3O3FÆC2H2O4: C,
61.71; H, 5.37; N, 8.00; F, 3.62. Found: C, 61.75; H,
5.42; N, 8.06; F, 3.59.
5.1.67. N-(6-{4-[(3-Fluorobenzyl)oxy]phenoxy}pyridin-3-
yl)-N-methyl-2-pyrrolidin-1-ylacetamide oxalate (41). To
the mixture of 38x (480mg, 1.55mmol) and CHCl3
(5mL) was added trifluoroacetic acid anhydrate
(0.44mL, 3.09mmol) at 0°C. The mixture was stirred
for 30min, concentrated in vacuo. To the residue were
added 2-butanone (5mL) and K2CO3 (1.07g,
7.75mmol), MeI (0.48mL, 7.75mmol) at room tempera-
ture. The mixture was stirred at 40°C for 2h. After
cooled at room temperature, the suspension was filtered,
5.1.63. N-(6-{2-Chloro-4-[(3-fluorobenzyl)oxy]phenoxy}-
pyridin-3-yl)-2-pyrrolidin-1-ylacetamide oxalate (39v).
1
White powder (70% for two steps): mp 183–186°C; H
NMR (400MHz, DMSO-d6): d 1.86–1.97 (4H, m),
3.13–3.27 (4H, m), 4.03 (2H, s), 5.18 (2H, s), 7.03–7.10

T. Kuramochi et al. / Bioorg. Med. Chem. 12 (2004) 5039–5056
5053
the filtrate was concentrated in vacuo to give yellow so-
lid. The intermediate was dissolved in MeOH (5mL).
NaOH (1M, 2.3mL, 2.3mmol) was added to the mix-
ture. The mixture was stirred for 1h, concentrated in va-
cuo. The residue was partitioned between CHCl3 and
H2O. The organic layer was dried, evaporated. The
residue was purified by column chromatography on
silica gel (CHCl3/MeOH = 99:1) to give 6-{4-[(3-fluoro-
benzyl)oxy]phenoxy}-N-methylpyridin-3-amine (495mg,
99% for three steps). Compound 41 was prepared from
6-{4-[(3-fluorobenzyl)oxy]phenoxy}-N-methylpyridin-3-
amine by a procedure similar to that described for 39a.
Compound 41 was obtained as a colorless solid (48% for
two steps): mp 155–156°C; 1H NMR (400MHz,
DMSO-d6): d 1.81–1.95 (4H, m), 3.10–3.30 (7H, m),
3.88 (1.6H, s), 4.39 (0.4H, s), 5.15 (2H, s), 7.05–7.21
(6H, m), 7.27–7.33 (2H, m), 7.43–7.49 (1H, m), 7.75–
7.81 (0.2H, m), 7.91 (0.8H, dd, J = 8.8, 2.4Hz), 8.06–
8.09 (0.2H, m), 8.17 (0.8H, d, J = 2.4Hz); MS (FAB)
m/z 436 (M+H)+. Anal. Calcd for C25H26N3O3FÆ
C2H2O4: C, 61.71; H, 5.37; N, 8.00; F, 3.62. Found: C,
61.66; H, 5.33; N, 8.10; F, 3.70.
tioned between CHCl3 and aqueous HCl. The organic
layer was washed with aqueous NaOH, dried, evapo-
rated. The residue was purified by column chromato-
graphy on silica gel (CHCl3/MeOH = 99:1) to give
intermediate (314mg, 86%). The mixture of intermediate
and toluene (2mL) pyrrolidine (0.69mL, 8.23mmol) was
stirred at 80°C. After cooling at room temperature, the
mixture was partitioned between CHCl3 and aqueous
NaOH. The organic layer was washed, dried, evapo-
rated. The residue was purified by column chromatogra-
phy on silica gel (CHCl3/MeOH = 98:2–92:8) to give the
free base of 43 (415mg). This material was converted to
its hydrochloride salt by treating it with 4M HCl(g)/
AcOEt (0.25mL). The crude salt was crystallized from
EtOH/AcOEt to give 43 as a colorless solid (196mg,
50% for two steps): mp 190–191°C; 1H NMR
(400MHz, DMSO-d6): d 1.79–2.08 (4H, m), 2.78 (2H,
t, J = 7.7Hz), 2.79–3.02 (2H, m), 3.37–3.55 (4H, m),
5.13 (2H, s), 6.96 (1H, d, J = 8.8Hz), 7.04 (4H, s),
7.13–7.20 (1H, m), 7.26–7.34 (1H, m), 7.40–7.49 (2H,
m), 8.03 (1H, dd, J = 8.8, 2.9Hz), 8.32 (1H, d,
J = 2.9Hz), 10.51 (1H, s), 10.67 (1H, br s); MS (FAB)
m/z 436 (M+H)+. Anal. Calcd for C25H26N3O3FÆHCl:
C, 63.62; H, 5.77; N, 8.90; Cl, 7.51; F, 4.03. Found: C,
63.53; H, 5.60; N, 8.88; Cl, 7.46; F, 4.41.
5.1.68. N-(6-{4-[(3-Fluorobenzyl)oxy]phenoxy}pyridin-3-
yl)-2-pyrrolidin-1-ylpropanamide oxalate (42). To the
mixture of 38x (510mg, 1.64mmol), AcOEt (3mL) and
H2O (3mL), NaHCO3 (166mg, 1.97mmol) was added
2-bromopropionyl bromide (0.19mL, 1.81mmol) at
0°C. The mixture was stirred at room temperature for
10min. The mixture was partitioned between CHCl3
and 1M NaOH. The organic layer was dried and con-
centrated in vacuo. The residue was crystallized from
AcOEt/hexane to give 2-bromo-N-(6-{4-[(3-fluoro-
5.1.70. 6-{4-[(3-Fluorobenzyl)oxy]phenoxy}nicotinonitrile
(45). 6-[4-Benzyloxy)phenoxy]nicotinonitrile was pre-
pared from 2-chloro-5-nitropyridine (44) by a procedure
similar to that described for 37a. 6-[4-(benzyloxy)phen-
oxy]nicotinonitrile was converted to 6-(4-hydroxyphen-
oxy)nicotinonitrile by a procedure of de-benzylation
using pentamethylbenzene similar to that described for
20. Compound 45 was prepared from 6-(4-hydroxy-
phenoxy)nicotinonitrile by a procedure similar to that
described for 15. Compound 45 was obtained as a beige
powder (73% for three steps). 1H NMR (300MHz,
CDCl3): d 5.07 (2H, s), 6.98–7.09 (6H, m), 7.15–7.21
(2H, m), 7.33–7.40 (1H, m), 7.90 (1H, dd, J = 8.6,
2.4Hz), 8.46–8.47 (1H, m); MS (FAB) m/z 321 (M+H)+.
benzyl)oxy]phenoxy}pyridin-3-yl)propanamide as
a
white solid (554mg, 76%). The compound (544mg,
1.22mmol) was dissolved in CH3CN (6mL). K2CO3
(220mg, 1.59mmol) and pyrrolidine (0.52mL,
6.11mmol) were added to the mixture at room tempera-
ture. The mixture was stirred at 80°C for 80min. The
mixture was partitioned between CHCl3 and 1M
NaOH. The organic layer was dried and concentrated
in vacuo. The residue was purified by column chroma-
tography on silica gel (CHCl3/MeOH = 98:2) to give
the free base of 42. This material was converted to its
oxalate by treating it with oxalic acid (110mg,
1.22mmol) in MeOH. The mixture was concentrated
in vacuo. The crude salt was crystallized from AcOEt/
hexane to give 42 as a colorless solid (448mg, 70%):
mp 133–135°C; 1H NMR (400MHz, DMSO-d6): d
1.48 (3H, br s), 1.80–1.95 (4H, m), 3.02–3.20 (4H, m),
3.86 (1H, br s), 5.14 (2H, s), 6.99 (1H, d, J = 8.8Hz),
7.04 (4H, s), 7.13–7.20 (1H, m), 7.27–7.33 (2H, m),
7.42–7.48 (1H, m), 8.07 (1H, d, J = 8.0Hz), 8.36 (1H,
s), 10.77 (1H, br s); MS (FAB) m/z 436 (M+H)+. Anal.
Calcd for C25H26N3O3FÆC2H2O4: C, 61.71; H, 5.37; N,
8.00; F, 3.62. Found: C, 61.95; H, 5.36; N, 8.06; F, 3.81.
5.1.71.
[(6-{4-[(3-Fluorobenzyl)oxy]phenoxy}pyridin-3-
yl)methyl]amine (46). To the mixture of 45 (801mg,
2.50mmol) and THF (10mL) was added 1.0M THF
solution of BH3–THF complex (5.5mL, 5.5mmol) at
0°C. The mixture was stirred at room temperature for
8h. To the mixture were added MeOH (5mL) and 1M
HCl (5mL) at 0°C. The mixture was stirred at 70°C
for 1h. NaOH (1M) was added to the mixture at 0°C.
The mixture was partitioned between CHCl3 and brine.
The organic layer was dried, evaporated under reduced
pressure. The residue was purified by column chroma-
tography on silica gel (CHCl3/MeOH = 98:2–92:8) to
1
give 46 as a light yellow oil (402mg, 50%). H NMR
(300MHz, CDCl3): d 3.83 (2H, s), 5.06 (2H, s), 6.85
(1H, d, J = 8.4Hz), 6.94–7.09 (5H, m), 7.14–7.22 (2H,
m), 7.31–7.39 (1H, m), 7.67 (1H, dd, J = 8.4, 2.4Hz),
8.10 (1H, d, J = 2.5Hz); MS (FAB) m/z 325 (M+H)+.
5.1.69. N-(6-{4-[(3-Fluorobenzyl)oxy]phenoxy}pyridin-3-
yl)-3-pyrrolidin-1-ylpropanamide hydrochloride (43). To
the mixture of 38x (330mg, 1.00mmol) and THF
(5mL), Et3N (0.17mL, 1.20mmol) was added acryloyl
chloride (0.09mL, 1.1mmol) at 0°C. After stirring at
room temperature for 30min, the mixture was parti-
5.1.72. N-[(6-{4-[(3-Fluorobenzyl)oxy]phenoxy}pyridin-3-
yl)methyl]-2-pyrrolidin-1-ylacetamide hydrochloride (47).
Compound 47 was prepared from 46 and 2-bromopro-
pionyl bromide by a procedure similar to that described

5054
T. Kuramochi et al. / Bioorg. Med. Chem. 12 (2004) 5039–5056
1
for 39a. Compound 47 was obtained as a colorless solid
(53% for two steps): mp 154–155°C; 1H NMR
(400MHz, DMSO-d6): d 1.82–2.02 (4H, br), 2.95–3.18
(2H, br), 3.43–3.62 (2H, br), 4.06 (2H, s), 4.31 (2H, d,
J = 5.9Hz), 5.14 (2H, s), 6.95 (1H, d, J = 8.3Hz), 7.04
(4H, s), 7.14–7.20 (1H, m), 7.27–7.33 (2H, m), 7.42–
7.49 (1H, m), 7.75 (1H, dd, J = 8.3, 2.4Hz), 8.05 (1H,
d, J = 2.4Hz), 9.08–9.14 (1H, m), 10.19 (1H, br s); MS
(FAB) m/z 436 (M+H)+. Anal. Calcd for C25H26N3O3-
FÆHCl: C, 63.62; H, 5.77; N, 8.90; Cl, 7.51; F, 4.03.
Found: C, 63.53; H, 5.76; N, 9.08; Cl, 7.52; F, 4.08.
powder (23% for two steps): mp 139–140°C; H NMR
(400MHz, DMSO-d6): d 1.92 (4H, br s), 2.98 (3H, s),
3.21–3.40 (6H, m), 3.76 (2H, br s), 5.15 (2H, s), 7.02
(1H, d, J = 8.3Hz), 7.04–7.14 (4H, m), 7.14–7.21 (1H,
m), 7.28–7.34 (2H, m), 7.43–7.49 (1H, m), 7.90–8.01
(1H, m), 8.24 (1H, s); MS (FAB) m/z 450 (M+H)+.
Anal. Calcd for C26H28N3O3FÆC2H2O4: C, 62.33; H,
5.60; N, 7.79; F, 3.52. Found: C, 62.39; H, 5.73; N,
7.87; F, 3.61.
5.1.76. 6-{4-[(3-Fluorobenzyl)oxy]phenoxy}-N-(2-piperi-
din-1-ylethyl)nicotinamide oxalate (48d). White powder
(59% for two steps): mp 143–144°C; 1H NMR
(400MHz, DMSO-d6): d 1.51 (2H, br s), 1.68–1.75
(4H, m), 3.09–3.17 (6H, m), 3.57–3.64 (2H, m), 5.15
(2H, s), 7.03–7.12 (5H, m), 7.14–7.21 (1H, m), 7.28–
7.34 (2H, m), 7.43–7.49 (1H, m), 8.24 (1H, dd, J = 8.8,
2.5Hz), 8.59 (1H, d, J = 2.5Hz), 8.87 (1H, t,
J = 5.3Hz),; MS (FAB) m/z 450 (M+H)+. Anal. Calcd
for C26H28N3O3FÆC2H2O4Æ0.1H2O: C, 62.12; H, 5.62;
N, 7.76; F, 3.51. Found: C, 62.00; H, 5.58; N, 7.81; F,
3.61.
5.1.73. 6-{4-[(3-Fluorobenzyl)oxy]phenoxy}-N-(2-pyrroli-
din-1-ylethyl)nicotinamide oxalate (48a). To the mixture
of 45 (1.4g, 4.4mmol) and EtOH (15mL) was added
5M NaOH (8.7mL). The mixture was stirred at 100°C
for 3.5h. The solvent was removed under reduced pres-
sure. HCl (2M) was added at 0°C. The precipitate was
filtered and dried in vacuo to afford beige powder
as 6-{4-[(3-fluorobenzyl)oxy]phenoxy}nicotinic acid
(1.5g, 100%). To the mixture of 6-{4-[(3-fluoro-
benzyl)oxy]phenoxy}nicotinic acid (373mg, 1.10mmol)
and (2-pyrrolidin-1-ylethyl)amine (114mg, 1.00mmol),
THF (10mL) and 1H-1,2,3-benzotriazol-1-ol (68mg,
0.50mmol) was added 1-ethyl-3-(3-dimethylaminopro-
pyl)-carbodiimide hydrochloride (211mg, 1.10mmol).
The mixture was stirred at room temperature for 11h.
The mixture was partitioned between CHCl3 and aque-
ous NaOH. The organic layer was dried and concen-
trated under reduced pressure. The residue was
purified by column chromatography on silica gel
(CHCl3/MeOH = 98:2–92:8) to give the free base of
48a (462mg). This material was converted to its oxalate
salt by treating it with oxalic acid (90mg, 1.00mmol) in
MeOH (10mL). The mixture was concentrated in vacuo.
The crude salt was crystallized from CH3 CN/AcOEt to
give 48a as a colorless solid (316mg, 60% for two steps
5.1.77. 6-{4-[(3-Fluorobenzyl)oxy]phenoxy}-N-[(1-meth-
ylpiperidin-4-yl)methyl]nicotinamide (48e). White powder
(23% for two steps): mp 142–149°C; 1H NMR
(400MHz, DMSO-d6): d 1.10–1.22 (2H, m), 1.41–1.54
(1H, m), 1.58–1.66 (2H, m), 1.75–1.84 (2H, m), 2.13
(3H, s), 2.70–2.77 (2H, m), 3.11–3.16 (2H, m), 5.15
(2H, s), 7.00–7.12 (5H, m), 7.14–7.20 (1H, m), 7.28–
7.33 (2H, m), 7.42–7.49 (1H, m), 8.22 (1H, dd, J = 8.3,
2.4Hz), 8.49–8.53 (1H, m), 8.57 (1H, d, J = 2.5Hz);
MS (FAB) m/z 450 (M+H)+; HRMS: (M+H)+ Calcd
for C26H28N3O3F, 450.2193. Found: 450.2191.
5.1.78. N-[(1-Benzylpiperidin-4-yl)methyl]-6-{4-[(3-fluoro-
benzyl)oxy]phenoxy}nicotinamide (48f). White powder
(54% for two steps): mp 136–137°C; 1H NMR
(400MHz, DMSO-d6): d 1.11–1.24 (2H, m), 1.47–1.58
(1H, m), 1.59–1.67 (2H, m), 1.83–1.92 (2H, m), 2.75–
2.82 (2H, m), 3.11–3.17 (2H, m), 3.43 (2H, br s), 5.15
(2H, s), 7.02 (1H, d, J = 8.8Hz), 7.04–7.12 (4H, m),
7.14–7.34 (8H, m), 7.42–7.49 (1H, m), 8.21 (1H, dd,
J = 8.8, 2.4Hz), 8.47–8.51 (1H, m), 8.56 (1H, d,
J = 2.5Hz); MS (FAB) m/z 526 (M+H)+. Anal. Calcd
for C32H32N3O3F: C, 73.12; H, 6.14; N, 7.99; F, 3.61.
Found: C, 72.93; H, 6.15; N, 8.00; F, 3.84.
1
from 45): mp 115–118°C; H NMR (400MHz, DMSO-
d6): d 1.83–1.95 (4H, m), 3.23–3.31 (6H, m), 3.55–3.62
(2H, m), 5.15 (2H, s), 7.02–7.12 (5H, m), 7.14–7.20
(1H, m), 7.28–7.34 (2H, m), 7.42–7.49 (1H, m), 8.25
(1H, dd, J = 8.8, 2.4Hz), 8.59 (1H, d, J = 2.4Hz), 8.87
(1H, t, J = 5.6Hz); MS (FAB) m/z 436 (M+H)+. Anal.
Calcd for C25H26N3O3FÆC2H2O4: C, 61.71; H, 5.37; N,
8.00; F, 3.62. Found: C, 61.99; H, 5.38; N, 8.00; F, 3.70.
The following compounds (48b–m) were prepared by a
procedure similar to that described for 48a.
5.1.79. N-[2-(Diethylamino)ethyl]-6-{4-[(3-fluorobenz-
yl)oxy]phenoxy}nicotinamide oxalate (48g). White
powder (65% for two steps): mp 128–129°C; H NMR
(400MHz, DMSO-d6): d 1.18 (6H, t, J = 7.4Hz), 3.09–
3.20 (6H, m), 3.55–3.62 (2H, m), 5.15 (2H, s), 7.03–
7.13 (5H, m), 7.14–7.21 (1H, m), 7.28–7.34 (2H, m),
7.43–7.49 (1H, m), 8.24 (1H, dd, J = 8.3, 2.4Hz), 8.59
(1H, d, J = 2.5Hz), 8.90–8.95 (1H, m); MS (FAB) m/z
438 (M+H)+. Anal. Calcd for C25H28N3O3FÆC2H2O4:
C, 61.47; H, 5.73; N, 7.93; F, 3.60. Found: C, 61.46;
H, 5.70; N, 7.98; F, 3.81.
5.1.74. 6-{4-[(3-Fluorobenzyl)oxy]phenoxy}-N-(3-pyrroli-
din-1-ylpropyl)nicotinamide oxalate (48b). Beige powder
(57% for two steps): mp 139–140°C; 1H NMR
(400MHz, DMSO-d6): d 1.82–1.98 (6H, m), 3.05–3.15
(2H, m), 3.27–3.38 (2H, m), 3.50–3.95 (4H, br), 5.15
(2H, s), 7.05–7.13 (5H, m), 7.14–7.21 (1H, m), 7.27–
7.34 (2H, m), 7.43–7.50 (1H, m), 8.21 (1H, d, J =
8.8Hz), 8.58 (1H, s), 8.64 (1H, br s); MS (FAB) m/z
450 (M+H)+. Anal. Calcd for C26H28N3O3FÆC2H2O4:
C, 62.33; H, 5.60; N, 7.79; F, 3.52. Found: C, 62.16;
H, 5.58; N, 7.87; F, 3.52.
1
5.1.80. 6-{4-[(3-Fluorobenzyl)oxy]phenoxy}-N-(2-meth-
oxyethyl)nicotinamide hydrobromide (48h). Colorless
solid (52% for two steps): mp 110–115°C; 1H NMR
5.1.75. 6-{4-[(3-Fluorobenzyl)oxy]phenoxy}-N-methyl-N-
(2-pyrrolidin-1-ylethyl)nicotinamide oxalate (48c). White

T. Kuramochi et al. / Bioorg. Med. Chem. 12 (2004) 5039–5056
5055
(400MHz, DMSO-d6): d 3.26 (3H, s), 3.39–3.48 (4H, m),
5.2. Pharmacology
5.15 (2H, s), 7.01–7.13 (6H, m), 7.14–7.21 (1H, m), 7.28–
7.34 (2H, m), 7.43–7.49 (1H, m), 8.23 (1H, dd, J = 8.8,
2.5Hz), 8.58 (1H, d, J = 2.4Hz), 8.60 (1H, br s); MS
(FAB) m/z 397 (M+H)+. Anal. Calcd for C22H21N2O4-
FÆHBrÆ0.7H2O: C, 56.09; H, 5.07; N, 5.95. Found: C,
56.12; H, 4.70; N, 5.98.
5.2.1. 45Ca influx assay. We examined the inhibitory ef-
fects of several compounds on Na+/Ca2+ exchange for
reverse mode in NCX1.1-expressed CCL39 cells accord-
ing to the reported protocols.10 The cells were loaded
with Na+ by incubation with monensin-BSS (10lM
monensin, 1mM ouabain, 10mM Hepes/Tris (pH7.4),
146mM NaCl, 4mM KCl, 2mM MgCl2, 10mM of glu-
cose, and 0.1% BSA) at 37°C for 30min. 45Ca2+ uptake
was initiated by switching the medium to Na+-free BSS
(10lM verapamil, 1mM ouabain, 10mM Hepes/Tris
(pH7.4), 146mM choline chloride, 4mM KCl, 2mM
MgCl2, 10mM of glucose, 0.1% BSA, and 0.1mM
CaCl2) containing 55.5kBq/mL 45CaCl2 and test com-
pounds. After 15min incubation at room temperature,
the cells were washed three times with ice-cold wash-buf-
fer (10mM LaCl3, 120mM choline chloride, and 10mM
Hepes/Tris (pH7.4)) and solubilized with 0.1M NaOH.
The radioactivity was measured by using a TopCount
Microplate Scintillation Counter (Packard Instrument
Company). Concentration-response curve was drawn
to determine the concentration inducing 50% influx of
45Ca induced by Na+ overload. IC50 values were deter-
mined in a single experimental run in triplicate.
5.1.81. N-(Cyclohexylmethyl)-6-{4-[(3-fluorobenzyl)-oxy]-
phenoxy}nicotinamide (48i). White powder (72% for two
steps): mp 149–151°C; 1H NMR (400MHz, DMSO-d6):
d 0.84–0.97 (2H, m), 1.07–1.25 (3H, m), 1.46–1.79 (6H,
m), 3.10 (2H, t, J = 6.8Hz), 5.15 (2H, s), 7.02 (1H, d,
J = 8.3Hz), 7.04–7.12 (4H, m), 7.28–7.34 (2H, m),
7.43–7.49 (1H, m), 8.22 (1H, dd, J = 8.3, 2.5Hz), 8.46
(1H, t, J = 5.8Hz), 8.56 (1H, d, J = 1.9Hz); MS (FAB)
m/z 435 (M+H)+. Anal. Calcd for C26H27N2O3F: C,
71.87; H, 6.26; N, 6.45; F, 4.37. Found: C, 71.93; H,
6.41; N, 6.35; F, 4.15.
5.1.82.
6-{4-[(3-Fluorobenzyl)oxy]phenoxy}-N-phenyl-
nicotinamide (48j). White powder (72% for two steps):
mp 163–164°C; 1H NMR (400MHz, DMSO-d6): d
5.16 (2H, s), 7.08–7.21 (7H, m), 7.29–7.38 (4H, m),
7.43–7.49 (1H, m), 7.72–7.77 (2H, m), 8.34 (1H, dd,
J = 8.8, 2.4Hz), 8.69 (1H, d, J = 2.5Hz), 10.28 (1H, s);
MS (FAB) m/z 415 (M+H)+. Anal. Calcd for
C25H19N2O3F: C, 72.45; H, 4.62; N, 6.76; F, 4.58.
Found: C, 72.50; H, 4.52; N, 6.72; F, 4.54.
5.2.2. Cell necrosis assay.14 NCX1.1-expressed CCL39
cells were incubated with ionomycin-BSS (10lM iono-
mycin, 1mM ouabain, 10mM Hepes/Tris (pH7.4),
146mM NaCl, 4mM KCl, 2mM MgCl2, 10mM of glu-
cose, and 0.1% BSA) containing test compounds at
37°C for 30min. The cells were washed three times with
PBS and dyed with Crystal Violet for 15min. The cells
were washed three times with PBS and the intracellular
dye of necrosis cells was solubilized with EtOH and
absorbance at 595nm was measured. Concentration-re-
sponse curve was drawn to determine the concentration
inducing 50% cell necrosis induced by Ca2+ overload.
EC50 values were determined in a single experimental
run in triplicate.
5.1.83.
N-Benzyl-6-{4-[(3-fluorobenzyl)oxy]phenoxy}-
nicotinamide (48k). White powder (71% for two steps):
mp 105–106°C; 1H NMR (400MHz, DMSO-d6): d
4.48 (2H, d, J = 5.9Hz), 5.15 (2H, s), 7.03–7.13 (5H,
m), 7.14–7.20 (2H, m), 7.23–7.36 (6H, m), 7.42–7.49
(1H, m), 8.27 (1H, dd, J = 8.8, 2.5Hz), 8.63 (1H, d,
J = 2.5Hz), 9.03 (1H, t, J = 5.9Hz); MS (FAB) m/z
429 (M+H)+. Anal. Calcd for C26H21N2O3F: C, 72.88;
H, 4.94; N, 6.54; F, 4.53. Found: C, 73.06; H, 5.00; N,
6.52; F, 4.43.
5.1.84. 6-{4-[(3-Fluorobenzyl)oxy]phenoxy}-N-(2-phenyl-
ethyl)nicotinamide (48l). White powder (82% for two
steps): mp 138–139°C; 1H NMR (400MHz, DMSO-
d6): d 2.84 (2H, t, J = 7.6Hz), 3.44–3.57 (2H, m), 5.15
(2H, s), 7.02–7.13 (5H, m), 7.14–7.34 (8H, m), 7.43–
7.48 (1H, m), 8.19 (1H, dd, J = 8.8, 2.4Hz), 8.54 (1H,
d, J = 2.5Hz), 8.62 (1H, t, J = 5.6Hz); MS (FAB) m/z
443 (M+H)+. Anal. Calcd for C27H23N2O3F: C, 73.29;
H, 5.24; N, 6.33; F, 4.29. Found: C, 73.36; H, 5.27; N,
6.37; F, 4.13.
Acknowledgements
We wish to thank Mr. Takayuki Sato for evaluating the
inhibitory activity of compounds against the sodium–
calcium exchanger. We would like to express our grati-
tude to Dr. Minoru Okada, Dr. Toshihiro Watanabe
and Mr. Toshio Uemura for helpful support in the prep-
aration of this manuscript and are also grateful to Mr.
Masashi Funatsu for measurements of experimental
data.
5.1.85. 6-{4-[(3-Fluorobenzyl)oxy]phenoxy}-N-(3-phenyl-
propyl)nicotinamide (48m). White powder (78% for two
steps): mp 109–110°C; 1H NMR (400MHz, DMSO-
d6): d 1.77–1.87 (2H, m), 2.63 (2H, t, J = 7.8Hz), 3.24–
3.31 (2H, m), 5.15 (2H, s), 7.02–7.13 (5H, m), 7.16–
7.33 (8H, m), 7.42–7.48 (1H, m), 8.21 (1H, dd, J = 8.3,
2.4Hz), 8.52 (1H, t, J = 5.3Hz), 8.57 (1H, d, J =
2.4Hz); MS (FAB) m/z 457 (M+H)+. Anal. Calcd for
C28H25N2O3F: C, 73.69; H, 5.52; N, 6.14; F, 4.16.
Found: C, 73.87; H, 5.55; N, 6.24; F, 4.00.
References and notes
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interesting.
´
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