Inhibitors of the glycine transporter type-2 (GlyT-2): synthesis and biological activity of benzoylpiperidine derivatives.

Article abstract of DOI:10.1016/j.bmc.2004.05.044

A series of benzoylpiperidine analogs related to 4a was prepared, and their ability to inhibit the uptake of [(14)C]-glycine in COS7 cells transfected with human glycine transporter type-2 (GlyT-2) was evaluated. Small structural changes to the benzoylpiperidine region of the molecule led to a significant decrease in GlyT-2 inhibitory activity. In contrast, the distal aryl ring was more tolerant to functional group modifications and could accommodate a variety of substitutes at the C-2 or C-3 positions. Comparable activities to 4a were obtained by replacing the anilino nitrogen with an ether linkage 27 or by exchanging the isopropoxy ether moiety with an isopropyl amino group 15. A distinct preference for a 2-carbon tether (n=1) was observed relative to the corresponding 3-carbon homolog (n=2).

Full text of DOI:10.1016/j.bmc.2004.05.044

Bioorganic & Medicinal Chemistry 12 (2004) 4511–4532
Inhibitors of the glycine transporter type-2 (GlyT-2): synthesis and
biological activity of benzoylpiperidine derivatives
*
ꢀ
Ronald L. Wolin, Alejandro Santillan, Jr., Liu Tang, Charles Huang,
Xiaoxia Jiang and Timothy W. Lovenberg
Johnson & Johnson Pharmaceutical Research and Development, LLC, 3210 Merryfield Row, San Diego, CA 92121, USA
Received 23 March 2004; accepted 24 May 2004
Available online 6 July 2004
Abstract—A series of benzoylpiperidine analogs related to 4a was prepared, and their ability to inhibit the uptake of [14C]-glycine in
COS7 cells transfected with human glycine transporter type-2 (GlyT-2) was evaluated. Small structural changes to the benzoylpipe-
ridine region of the molecule led to a significant decrease in GlyT-2 inhibitory activity. In contrast, the distal aryl ring was more
tolerant to functional group modifications and could accommodate a variety of substitutes at the C-2 or C-3 positions. Comparable
activities to 4a were obtained by replacing the anilino nitrogen with an ether linkage 27 or by exchanging the isopropoxy ether
moiety with an isopropyl amino group 15. A distinct preference for a 2-carbon tether (n ¼ 1) was observed relative to the corre-
sponding 3-carbon homolog (n ¼ 2).
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
effects of glycine are regulated by an efficient glycine
transporter system that allows for the re-uptake of gly-
cine back into the pre-synaptic neuron.6 As a result,
compounds that display an ability for inhibiting the re-
uptake of glycine should also accentuate the post-syn-
aptic inhibitory activity of the glycinergic receptor, and
as such, may be useful for the treatment of certain CNS
conditions such as tinnitus,7 spasticity8 and neuropathic
pain.9
The two primary inhibitory neurotransmitters in the
central nervous system (CNS) are c-aminobutyric acid
(GABA) and glycine. Currently, there are two known
glycine transporters expressed in the central nervous
system; GlyT-1 and GlyT-2.1 Separate genes encode
each transporter and these proteins can be pharmaco-
logically distinguished by their sensitivity to sarcosine
(N-methylglycine).2 Both the rat and human GlyT-2
transporters have been cloned and share ꢀ93% sequence
homology at the amino acid level.3 Moreover, detailed
A high-throughput-screening (HTS) campaign of our in-
house library identified 4a as a compelling hit-to-lead
candidate for inhibiting the uptake of [14C]-Glycine into
COS7 cells transfected with the human GlyT-2 trans-
porter. Related compounds containing a cyclic tether,
which are present in analogs such as Mazapertine10 (1),
the piperidine derivative 2 and the homopiperazine
derivative 3 were all devoid of GlyT-2 activity. More-
over, 4a possessed excellent selectivity for the GlyT-2
isoform, as evidenced by its lack of affinity for the GlyT-
1 transporter which exhibited an IC50 > 10,000 nM.
Based in part on these findings, we initiated a chemistry
effort aimed at improving the potency of 4a as a GlyT-2
antagonist (Fig. 1).11 The compounds prepared in this
study probed modifications to each of the three regions
present in the parent compound 4a; the distal aryl ring
(Fig. 2), the tether (Fig. 3), and the benzoylpiperidine
moiety (Figs. 4 and 5).
3
binding studies have been conducted using H-strych-
nine, which provides evidence that glycine is the major
inhibitory amino acid operating in the brainstem and
spinal cord of vertebrates, and exerts its effects post-
synaptically at the strychnine-sensitive glycinergic
receptor.4;5 Thus, when glycine binds to its specific
receptor it induces the opening of a ligand-gated chlo-
ride channel which in turn causes an increase in chloride
ion (Clꢁ) conductance along the post-synaptic mem-
brane. This process leads to a hyperpolarized state in the
post-synaptic neuron and ultimately raises the threshold
for neuronal firing. Furthermore, the physiological
* Corresponding author. Fax: +1-858-784-3116; e-mail: rwolin@
prdus.jnj.com
0968-0896/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2004.05.044

4512
R. L. Wolin et al. / Bioorg. Med. Chem. 12 (2004) 4511–4532
Benzoylpiperidine
Tether
Region
Distal Aryl
Region
Region
O
O
O
N
H
N
O
N
N
2
3
X
N
H
n
n
4
1, X = N, n = 1
2, X = C, n = 1
3, X = N, n = 2
4a, n = 1, IC (GlyT-2) = 0.54 µM
50
IC (GlyT-2) >10 µM
50
4b, n = 2, IC (GlyT-2) = 4.0 µM
50
Figure 1.
O
X
H
H
N
2
R
O
3
N
N
H
N
N
H
N
S
Compd
R
Compd
R
3-OCH(CH3)2
2-OC5H9
3-OCH3
2-OC5H11
2-OCH3
2-OPh
2-OH
H
2-NO2
2-NH2
2-NHCH(CH3)2
2-NHSO2CH3
2-NHCONHPh
2-NHCONHCH2Ph
2-Br
2-Cl
3-Br
3-Cl
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
X
Compd
36
37
38
39
OCH(CH3)2
NO2
NH2
NHCH(CH3)2
Figure 4. Thiophene analogs.
2-CH(CH3)2
2-(3-Thienyl)
2-(Ph-2-OCH3)
O
H
O
Figure 2. Distal aryl ring variations.
N
R2
N
H
N
R1
O
N
2
O
X
R1
R2
Compd
40
3
Y
n
Homopiperidine
41
42
43
44
Pyrrolidine
Compd
26
27
28
29
30
31
32
33
O-i Pr
X
NH
n
1
1
1
1
1
1
2
1
1
1
Y
NCH3
NH
NCH3
NCH3
NCH3
NH
NH
NH
NH
NH
Ethyl
Ethyl
2
2
2
3
3
2
2
3
2
2
Morpholine
4-Hydroxypiperidine
NCH3
NCH3
NH
NCH3
O
O
O
CH2
S
Figure 5. Amide variations.
with 2-chloroethylamine in refluxing isopropanol to
provide 48. Alternatively, treatment of 47 with oxazo-
lidinone in refluxing ethylene glycol dimethyl ether
(DME) also provided 48.12 Alkylation of 47 with 3-
chloropropylamine afforded the homologated analog 49.
Carbodiimide mediated coupling13 between 3-formyl
benzoic acid (50) and piperidine furnished adduct 51.
Treatment of 51 with amines 48 and 49 under reductive
amination conditions provided 4a and 4b, respectively.14
34
35
Figure 3. Tether variations.
2. Chemistry
Two synthetic routes were employed for assembling
analogs related to 4 and are outlined in Scheme 1.
Treatment of 2-nitrophenol 45 with isopropyl iodide in
the presence of potassium carbonate in DMF provided
the corresponding isopropyl ether 46. Exposure of 46 to
hydrogen in the presence of Pd/C catalyst in EtOH
afforded aniline 47, which subsequently was alkylated
Our initial structure–activity studies focused on the
distal aryl ring of 4a (Fig. 1) and were designed to
evaluate the nature and position of substituents attached
to the aromatic ring. Toward that goal, an array of
analogs was assembled that varied the position, steric,
and lipophilic properties of the aryl substituent. Thus,

R. L. Wolin et al. / Bioorg. Med. Chem. 12 (2004) 4511–4532
4513
Scheme 1. Reagents: (a) isopropyl iodide, K2CO3, DMF; (b) H2, 10% Pd/C, EtOH; (c) 2-choloroethylamine, i-PrOH, reflux; (d) 3-chloropropyl-
amine, i-PrOH; (e) 47–HCl salt, oxazolidinone, ethylene gylcol dimethylether; (f) piperidine, EDCI, HOBT, DMF; (g) Na(OAc)3BH, 1,2-dichlo-
roethane.
58, which was reduced to aniline 59 after exposure to
hydrogen in the presence of Pd/C catalyst. Alkylation of
59 using isopropyl iodide in DMF containing K2CO3
followed by removal of the N-Boc group provided 15. In
a similar fashion, sulfonlylation of 59 and subsequent
deprotection afforded 16.
The urea derivatives 17 and 18 were assembled as out-
lined in Scheme 4 utilizing the aforementioned inter-
mediate 57. The more basic amine was protected using
Scheme 2. Reagents: (a) R–Br, K2CO3, DMF; (b) Na2S2O4, THF–
H2O; (c) H2, 10% Pd/C, EtOH; (d) HCl salt, oxazolidinone, ethylene
Boc anhydride. Subsequent reduction of the nitro group
and urea formation using the appropriate isocyanate
furnished 60. Removal of both the Boc and benzyl
protecting groups furnished the primary amine, which
was treated with aldehyde 51 under reductive amination
conditions to yield the targeted compounds 17–18.
glycol dimethylether; (e) 2-chloroethylamine, i-PrOH; (f) 51,
Na(OAc)3BH, 1,2-dichloroethane.
nitrophenol 52 was converted to aniline 53 utilizing the
two-step sequence outlined in Scheme 2.15 Subsequent
conversion of 53 to the ethylenediamine analogs 5–12
was achieved in an identical manner to that described
for 4a and 4b. The unsubstituted analog 12 was obtained
using this route with aniline as the starting material.
Halogenated analogs 19–22 were obtained beginning
from commercially available anilines 61 as depicted in
Scheme 5.15 As was discussed previously, alkylation of
61 with 2-chloroethylamine gave diamine 62, which was
subsequently treated with aldehyde 51 to yield the target
compounds 19–22.
The substituted anilino derivatives 13–16 were obtained
as outlined in Scheme 3. Accordingly, treatment of 2-
fluoronitrobenzene (55) with either ethylenediamine or
monobenzyl ethylenediamine furnished 56 or 57,
respectively.16 Further treatment of 56 with aldehyde 51
under reductive amination conditions provided 13.
Reduction of 13 under hydrogenation conditions fur-
nished aniline 14. Alternatively, selective protection of
the benzylic nitrogen provided the N-Boc intermediate
Our efforts also investigated the replacement of the C-2
alkoxy with a carbon substituent. The synthesis of the
deoxygenated analog 23 followed the identical route
utilized for the halogen substituted analogs depicted in
Scheme 5. The synthesis of 23 utilized the commercially
available 2-isopropylaniline (61, X ¼ 2-CH(CH3)2). The
introduction of the 2-thienyl and 2-methoxyphenyl
Scheme 3. Reagents: (a) ethylenediamine or N-benzylethylenediamine, CH3CN; (b) 51, Na(OAc)3BH, 1,2-dichloroethane; (c) (Boc)2O, CH2Cl2;
(d) H2, Pd/C, EtOH; (e) isopropyl iodide, K2CO3, DMF; (f) R–SO2Cl, Et3N, CH2Cl2; (g) CF3CO2H, CH2Cl2.

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R. L. Wolin et al. / Bioorg. Med. Chem. 12 (2004) 4511–4532
Scheme 4. Reagents: (a) (Boc)2O, CH2Cl2; (b) H2, Pd/C, EtOH, 1 atm; (c) R–NCO, Et3N, CH2Cl2; (d) CF3CO2H, CH2Cl2; (e) H2, Pd/C, EtOAc–
HOAc (5:1, v/v) 50 psi; (f) 51, Na(OAc)3BH, 1,2-dichloroethane.
Scheme 5. Reagents: (a) 2-chloroethylamine, i-PrOH, reflux; (b) 51, Na(OAc)3BH, 1,2-dichloroethane.
moieties was accomplished via Suzuki coupling17 be-
tween arylbromide 19 and the requisite boronic acid to
furnish adducts 24 and 25, respectively, as seen in
Scheme 6.
analog 32. Interestingly, when the alkylation of 65 was
attempted with N-(2-bromoethyl)phthalimide using the
same set of conditions as above, elimination to the vinyl
phthalimide resulted, and no alkylation of 65.
We also probed the importance of the chain length and
the nature of the heteroatom(s) present in the tether
joining the two aryl segments in 4a by the synthesis of
compounds 26–35 (Schemes 7–10). Our initial studies
aimed to identify what effect, if any, hydrogen bonding
has on biological activity. To address the importance of
these interactions the nitrogen atoms present in the te-
ther region of 4a were successively alkylated (Scheme 7).
Exposure of 4a to iodomethane in the presence of
K2CO3 led to the methylation at the more reactive
benzylic nitrogen to afford 26. Alternatively, 4a was
converted to the N-Boc derivative 63, which was sub-
sequently treated with NaH and MeI to provided 64.
Removal of the Boc protecting group with TFA gave 27.
The synthesis of 28 was achieved by methylating 27
employing the conditions utilized to generate 26. The
synthesis of the analogous 3-isopropoxy targets, 29 and
30, were obtained in a similar manner and are summa-
rized in Scheme 7.
The 3-isopropoxy analog 33 was prepared starting from
resorcinol monobenzoate 69 as outlined in Scheme 9.
Alkylation of 68 under Mitsunobu conditions followed
by Boc deprotection furnished the desired amine 69.
Addition of aldehyde 51 to 69 in the presence of
Na(OAc)3BH provided 70, which was hydrolyzed to
phenol 71 and alkylated with 2-iodopropane furnishing
the target compound 33.
The carbon isostere 34 was prepared as shown in
Scheme 10. Treatment of 3-(2-hydroxyphenyl)propionic
acid (72) with K2CO3 and 2-iodopropane provided the
bis-isopropyl adduct 73. Subjecting 73 to methanolic
ammonia gave rise to the corresponding amide 74,
which was reduced with LiAlH4 to amine 75. Reductive
amination with 51 gave the carbon congener 34.
Replacement of the anilino nitrogen of 4a with sulfur
was accomplished as outlined in Scheme 11. Sequential
alkylation of thiophenol 76 with N-(2-bromo-
ethyl)phthalimide and 2-iodopropane produced 77. Re-
moval of the phthalimide moiety with hydrazine and
subjecting the resulting amine with 51 under reductive
amination conditions provided the sulfur isostere 34.
The synthesis of 31, which replaces the anilino nitrogen
with an oxygen is shown in Scheme 8. This route in-
volved initial alkylation of 65 with N-t-Boc-ethanol-
amine under Mitsunobu18 conditions to provide adduct
66. Removal of the N-Boc group and subsequent
treatment with 51 under reductive amination conditions
afforded the ether derivative 31. Alternatively, treatment
of 2-(isopropoxy)phenol 66 with K2CO3 in DMF fol-
lowed by the addition of N-(3-bromopropyl)phthalimide
provided 67. Hydrolysis of the phthalimide moiety with
hydrazine and subsequent treatment with 51 under
reductive amination conditions gave the propylamine
Our studies also investigated replacements for the ben-
zoyl moiety by replacing it with thiophene bioisosteres
as outlined in Scheme 12. Carbodiimide mediated cou-
pling between 78 and piperidine produced the thio-
phene-2-carboxaldehyde 79, which upon exposure to 48
under reductive amination conditions afforded the thio-
phene isostere 36. The aniline derivatives 38 and 39 were
Scheme 6. Reagents: (a) Ar–B(OH)2, Pd(PPh3)4, EtOH–toluene (1:4), Na2CO3.

R. L. Wolin et al. / Bioorg. Med. Chem. 12 (2004) 4511–4532
4515
Scheme 7. Reagents: (a) MeI, K2CO3, DMF; (b) (Boc)2O, CH2Cl2; (c) MeI, NaH, DMF; (d) CF3CO2H, CH2Cl2.
Scheme 8. Reagents: (a) N-t-Boc-ethanolamine, DBAD, Ph3P, THF; (b) CF3CO2H, CH2Cl2; (c) 51, Na(OAc)3BH, 1,2-dichloroethane; (d) N-(3-
bromopropyl)phthalimide, K2CO3, DMF; (e) NH2NH2, EtOH.
Scheme 9. Reagents: (a) N-t-Boc-ethanolamine, DBAD, Ph3P, THF; (b) CF3CO2H, CH2Cl2; (c) 51, Na(OAc)3BH, 1,2-dichloroethane; (d) NaOH,
THF–H2O; (e) 2-iodopropane, K2CO3, DMF.
accessed by treatment of 79 with amine 56 to provide 37.
Reduction of 37 under hydrogenation conditions fur-
nished aniline 38. Alternatively, protection of the ben-
zylic nitrogen and reduction of the nitro group gave
aniline 81, which was alkylated with 2-iodopropane to
afford compound 82. Removal of the N-Boc group in 82
afforded the desired isostere 39.
Lastly, a series of compounds designed to probe the
importance of the piperidine amide in 4a were synthe-
sized and their preparation is outlined in Scheme 13.
Thus, reductive amination of methyl(3-formyl benzoic
acid) (83) with 48 provided ester 84. Further treatment
of 84 with a series of amines under Weinreb and co-
workers conditions19 furnished amides 40–44.

4516
R. L. Wolin et al. / Bioorg. Med. Chem. 12 (2004) 4511–4532
Scheme 13. Reagents: (a) 48, Na(OAc)3BH, 1,2-dichloroethane; (b) R1
R2–NH, AlMe3, toluene.
Scheme 10. Reagents: (a) 2-iodopropane, K2CO3, DMF; (b) NH3–
MeOH; (c) LAH, THF; (d) 51, Na(OAc)3BH, 1,2-dichloroethane.
3. Results and discussion
were 6-fold less potent than 4a. Similar to the results
observed for phenol 11, the unsubstituted aniline 14
was also devoid of activity. Within the halogenated
series of derivatives, the C-2 bromo 19, and C-2 chloro
20 analogs were equivalent in activity (IC50’s ¼ 1.0 and
1.2 lM, respectively) and only slightly less potent than
4a. The C-3 halogen analogs (21 and 22) were also
equipotent, but 6-fold less active than 4a. The C-2 car-
bon-linked analogs containing either an isopropyl or
thienyl substituent 23 and 24, respectively, displayed
moderate GlyT-2 inhibitory activity, however, the
methoxyphenyl analog 25 was devoid of activity.
GlyT-2 inhibitory activity was determined by the ability
of compounds to inhibit the uptake of [14C]-glycine in
COS-7 cells transfected with the human glycine trans-
porter-2 (GlyT-2).20 As the data in Table 1 indicates,
replacement of the isopropyl ether moiety at the C-2
position with cyclopentyl 6, 2-pentanyl 8, methyl 9, or
phenyl unit 10 afforded compounds that were 2.5–3.5-
fold less potent than 4a. Relocating the isopropoxy
group 5 or the methoxy substituent 7 to the C-3 position
was well tolerated and only resulted in a 2-fold decrease
in potency. The absence of activity (IC50’s > 10 lM) for
the phenol derivative 11 clearly indicates that an ether
moiety is important for retaining biological activity.
Replacing the C-2 ether moiety with a methylsulfon-
amide 16, phenyl urea 17, or a benzyl urea 17 revealed
that a nonbasic nitrogen was important for maintaining
biological activity. However, as a group, these analogs
The results for modifications carried out to the tether
are provided in Table 2. Direct comparison of 4a and 4b
clearly show that inclusion of the 2-carbon tether is
preferred relative to the 3-carbon tether by 10-fold.
Focusing on the N-methylated analogs (26–30) it is
apparent that methylation of the benzylic nitrogen de-
Scheme 11. Reagents: (a) N-(2-bromoethyl)phthalimide, K2CO3, DMF; (b) 2-iodopropane, K2CO3, DMF; (c) NH2NH2, EtOH; (d) 51,
Na(OAc)3BH, 1,2-dichloroethane.
Scheme 12. Reagents: (a) piperidine, EDCI, HOBT, DMF; (b) Na(OAc)3BH, 1,2-dichloroethane; (c) H2, Pd/C, EtOH; (d) (Boc)2O, Et3N, CH2Cl2;
(e) 2-iodopropane, K2CO3, DMF; (f) HCl–dioxane, CH2Cl2.

R. L. Wolin et al. / Bioorg. Med. Chem. 12 (2004) 4511–4532
Table 1. GlyT-2 antagonist activity for substituted aryl ring derivatives
4517
O
H
N
2
R
3
N
H
N
Compound
R
IC50 (lM)
Compound
R
IC50 (lM)
4a
5
2-OCH(CH3)2
3-OCH(CH3)2
2-OC5H9
3-OCH3
2-OC5H11
2-OCH3
2-OPh
0.54a
1.00
1.20
0.80
3.16
2.50
3.00
>10
>10
5.00
>10
15
16
17
18
19
20
21
22
23
24
25
2-NHCH(CH3)2
2-NHSO2Ph
2-NHCONHPh
2-NHCONHCH2Ph
2-Br
0.63a
3.10
3.00
3.00
1.00
1.20
3.00
3.00
2.50
0.95
>10
6
7
8
9
2-CI
3-Br
10
11
12
13
14
2-OH
3-CI
H
2-NO2
2-NH2
2-CH(CH3)2
2-(3-Thienyl)
2-(Ph-2-OCH3)
a Compounds 4a and 15 had IC50’s >10,000 nM at the GlyT-1 transporter.
Table 3. GlyT-2 antagonist activity for the thiophene derivatives
stroys biological activity when the isopropoxy unit is
attached at the C-2 position. In contrast, methylation of
the anilino nitrogen leads to a decrease in potency, but it
is not completely abolished. Interestingly, methylation
of the benzylic nitrogen does not significantly affect
GlyT-2 inhibitory activity when the isopropoxy unit is
appended to the C-3 position (i.e., compounds 29 and
30). Additionally, in comparing compounds 4a and 5, it
is apparent that the length of the tether plays a greater
role in GlyT-2 inhibition than does the location of the
isopropoxy substituent. The carbon 34 and sulfur 35
analogs maintained moderate activity while lacking the
ability to serve as a hydrogen bond donor. Interestingly,
the two oxygen isosteres 31 and 32 displayed an almost
identical profile to the nitrogen analogs 4a and 4b, with
31 being equivalent in potency to the lead 4a.
H
2
R
3
N
O
N
N
H
S
Compound
X
IC50 (lM)
36
37
38
39
2-OCH(CH3)2
2NO2
2NH2
3.1
>10
>10
3.1
2-NHCH(CH3)2
Table 4. GlyT-2 antagonist activity for various amide derivatives
O
O
H
N
R2
N
H
N
The data from Table 3 indicate that greater diversity
within this series can be achieved by replacing the ben-
zene ring with a thiophene bioisostere, but this trans-
formation does not lead to an improvement in GlyT-2
inhibitory activity.
R1
Com-
pound
R1
Piperidine
R2
Piperidine
IC50
(lM)
4a
40
41
42
43
44
0.54
1.80
3.00
10.0
10.0
10.0
Homopiperidine
Pyrrolidine
Ethyl
Homopiperidine
Pyrrolidine
Ethyl
Table 2. GlyT-2 antagonist activity for tether modified derivatives
Morpholine
4-Hydroxypiperidine
Morpholine
4-Hydroxypiperidine
O
2
O
X
3
Y
N
n
Lastly, the amide congeners included in Table 4 reveal
the highly sensitive nature of this region to minor
structural changes. Only the homologous ring-expanded
and ring-contracted analogs (40 and 41, respectively)
displayed measurable GlyT-2 inhibitory activity. The
N,N-diethyl 42, morpholino 43, and 4-hydroxypiperi-
dine 44 analogs were essentially inactive as GlyT-2
inhibitors.
Compound
O-i-Pr
X
n
Y
ICF50 (lM)
4a
4b
5
2
2
3
2
2
2
3
3
2
2
2
2
2
NH
NH
NH
NH
NCH3
NCH3
NH
NCH3
0
1
2
1
1
1
1
1
1
1
2
1
1
1
NH
NH
0.54
4.00
1.00
>10
3.54
>10
1.60
1.60
0.40
3.00
1.60
3.98
1.60
NH
NCH3
NH
26
27
28
29
30
31
32
33
34
35
NCH3
NCH3
NCH3
NH
4. Conclusion
0
NH
NH
0
A study aimed at improving the GlyT-2 inhibitory
activity of 4a was undertaken. Two compounds, 15 and
31, were identified as having potency equal to the initial
CH2
S
NH
NH

4518
R. L. Wolin et al. / Bioorg. Med. Chem. 12 (2004) 4511–4532
lead 4a. However, the benzoylpiperidine region (Fig. 1)
was unable to tolerate minor structural modifications
without a concomitant loss of activity. On the other
hand, the distal aromatic and tether region were able to
accommodate moderate alterations. The most potent
compounds resulting from this study, 4a, 15, and 31,
were more than 20-fold selective for the GlyT-2 trans-
porter over the GlyT-1 transporter. While these studies
did not lead to an overall improvement in GlyT-2
inhibitory activity, we were able to demonstrate that
moderately potent and highly selective ligands could be
developed for this transporter.
was extracted with EtOAc (3 ꢂ 100 mL). The combined
organic layers were washed with brine, dried (MgSO4),
filtered, and concentrated under reduced pressure. The
crude residue was purified by column chromatography
(CH2Cl2) to provide a tan oil (2.2 g, 26%). MS (ESI):
mass calculated for C9H13NO, 151.10; m=z found, 152.1
1
[MþH]þ. H NMR (400 MHz, CDCl3) d 6.81–6.68 (m,
4H), 4.52 (hp, J ¼ 6:1 Hz, 1H), 3.64 (br s, 2H), 1.35 (d,
J ¼ 6:1 Hz, 6H).
5.2.2. C. N1-(2-Isopropoxy-phenyl)-ethane-1,2-diamine.
To a solution of 2-isopropoxy-phenylamine (2.18 g,
14.4 mmol) in isopropanol (20 mL) was added 2-chloro-
ethylamine hydrochloride (2.3 g, 20 mmol), and the
mixture was stirred at 85 °C for 24 h. Triethylamine
(1.46 g, 14.4 mmol) was added, and the resulting mixture
was stirred at 85 °C for 24 h. The reaction mixture was
made basic using 1 N NaOH (40 mL), and the aqueous
layer was extracted with EtOAc (3 ꢂ 100 mL). The
combined organic layers were washed with brine, dried
(MgSO4), filtered, and concentrated under reduced
pressure. The crude residue was purified by column
chromatography (1:10:150 NH4OH/CH3OH/CH2Cl2,
then with 10% CH3OH/CH2Cl2) to give a brown oil
(0.59 g, 21%). MS (ESI): mass calculated for
C11H18N2O, 194.14; m=z found, 195.1 [MþH]þ. 1H
NMR (400 MHz, CDCl3) d 6.84 (dt, J ¼ 7:6, 1.4 Hz,
1H), 6.77 (dd, J ¼ 8:0, 1.4 Hz, 1H), 6.65–6.61 (m, 2H),
4.52 (hp, J ¼ 6:1 Hz, 1H), 3.22 (t, J ¼ 5:8 Hz, 2H), 2.94
(t, J ¼ 6:0 Hz, 2H), 1.61 (br s, 2H), 1.35 (d, J ¼ 6:1 Hz,
6H). 13C NMR (100 MHz, CDCl3) d 144.9, 139.2, 121.2,
116.4, 112.5, 110.2, 70.6, 46.5, 41.2, 22.3.
5. Experimental
5.1. General
NMR spectra were obtained on either a Bruker model
DPX400 (400 MHz) or DPX500 (500 MHz) spectrome-
ter. The format of the 1H NMR data below is: chemical
shift in ppm down field of the tetramethylsilane refer-
ence (multiplicity, coupling constant J in Hz, integra-
tion). Mass spectra were obtained on an Agilent series
1100 MSD using electrospray ionization (ESI) in either
positive or negative mode as indicated. The ‘mass cal-
culated’ for a molecular formula is the monoisotopic
mass of the compound. Flash column chromatography
was accomplished using the ISCO Foxy 200 system and
one of the following commercially available, prepacked
columns: Biotage 40S (SiO2; 40 g), Biotage 40M (SiO2;
90 g), Biotage 40L (SiO2; 120 g), Biotage 65M (SiO2;
300 g), or ISCO Redisep (SiO2; 10, 12, 35, 40, or 120 g).
Preparative TLC was accomplished using PLC plates
(20 ꢂ 20 cm silica gel 60 F254, 0.5 mm).
5.2.3. D. 3-(Piperidine-1-carbonyl)-benzaldehyde. To a
solution of 3-formyl-benzoic acid (2.0 g, 13 mmol) in
DMF (130 mL) was added piperidine (1.25 g,
14.7 mmol), and the resulting solution was stirred at
25 °C for 15 min. The solution was treated with HOBt
(2.7 g, 20 mmol) and EDCI (3.8 g, 20 mmol), and the
reaction mixture was stirred at 25 °C for 18 h. The
mixture was partitioned with H2O (250 mL) and EtOAc
(300 mL), and the organic layer was washed with 1 M
NaOH (100 mL), 1 M HCl (100 mL) then brine
(100 mL), dried (Na2SO4), filtered, and concentrated
under reduced pressure to provide a colorless oil (2.21 g,
76%). MS (ESI): mass calculated for C13H15NO2,
217.11; m=z found, 218.1 [MþH]þ. 1H NMR (400 MHz,
CDCl3) d 10.04 (s, 1H), 7.94–7.90 (m, 2H), 7.68–7.57 (m,
2H), 3.73 (br s, 2H), 3.34 (br s, 2H), 1.70–1.54 (m, 6H).
5.2. (3-{[2-(2-Isopropoxy-phenylamino)-ethylamino]-
methyl}-phenyl)-piperidin-1-yl-methanone (4a)
To a solution of 2-nitrophenol (0.14 g, 1.0 mmol) in
DMF (2 mL) was added K2CO3 (0.69 g, 5.0 mmol), and
the resulting suspension was stirred for 15 min. 2-Iodo-
propane (0.34 g, 2.0 mmol) was added. The reaction
mixture was stirred at 25 °C overnight, then was diluted
with ethyl acetate (EtOAc, 20 mL), and washed with
H2O (10 mL), 1 N NaOH (2 ꢂ 20 mL), satd NaHCO3
(2 ꢂ 20 mL) and then brine (20 mL). The organic layer
was dried (Na2SO4), filtered, and concentrated under
reduced pressure to provide a yellow oil (0.141 g, 77%).
1H NMR (400 MHz, CDCl3) d 7.76 (dd, J ¼ 1:5, 8.0 Hz,
1H), 7.48 (dt, J ¼ 1:6, 8.7 Hz, 1H), 7.07 (d, J ¼ 8:4 Hz,
1H), 6.98 (t, J ¼ 8:2 Hz, 1H), 4.67 (hp, J ¼ 6:1 Hz, 1H),
1.39 (d, J ¼ 6:1 Hz, 6H).
5.2.4. E. (3-{[2-(2-Isopropoxy-phenylamino)-ethylamino]-
methyl}-phenyl)-piperidin-1-yl-methanone. To a solution
of N1-(2-isopropoxy-phenyl)-ethane-1,2-diamine (0.228
g, 1.17 mmol) in 1,2-dichloroethane (2.8 mL) was added
a solution of 3-(piperidine-1-carbonyl)-benzaldehyde
(0.213 g, 0.980 mmol), and the mixture was stirred at
25 °C for 15 min. The mixture was treated with
NaBH(OAc)3 (0.311 g, 1.47 mmol), and the resulting
suspension was stirred at 25 °C for 5 h. The suspension
was partitioned with 1 M NaOH (25 mL) and EtOAc
5.2.1. B. 2-Isopropoxy-phenylamine. To a solution of 1-
isopropoxy-2-nitro-benzene (10 g, 55 mmol) in THF
(100 mL) was added a solution of sodium hydrosulfite
(48 g, 280 mmol) in H2O (200 mL). The reaction mixture
was stirred at 25 °C for 1 h then at 55 °C for 2 h. The
mixture was treated with 1 N HCl (50 mL), followed by
1 N NaOH (50 mL) to neutralize the solution, and then

R. L. Wolin et al. / Bioorg. Med. Chem. 12 (2004) 4511–4532
4519
1
(50 mL), and the organic layer was washed with brine
(25 mL), dried (Na2SO4), filtered, and concentrated un-
der reduced pressure. The crude residue was purified by
column chromatography (0–5% CH3OH/CH2Cl2) to
provide the desired product as a colorless oil (0.256 g,
66%). MS (ESI): mass calculated for C24H33N3O2,
found, 195.2 [MþH]þ. H NMR (400 MHz, CDCl3) d
7.04 (t, J ¼ 8:1 Hz, 1H), 6.27–6.19 (m, 2H), 6.19 (br s,
1H), 4.51 (hp, J ¼ 6:1 Hz, 1H), 3.41–3.22 (m, 6H), 2.93
(br s, 2H), 1.31 (d, J ¼ 6:1 Hz, 6H). 13C NMR
(100 MHz, CDCl3) d 158.9, 149.3, 129.8, 105.8, 104.4,
100.8, 69.5, 44.8, 40.1, 21.9.
1
395.26; m=z found, 396.3 [MþH]þ, 418.3 [MþNa]þ. H
NMR (400 MHz, CDCl3) d 7.40–7.23 (m, 4H), 6.85–6.76
(m, 2H), 6.65–6.60 (m, 2H), 4.51 (hp, J ¼ 6:1 Hz, 1H),
3.84 (s, 3H), 3.69 (br s, 2H), 3.31 (br s, 2H), 3.27 (t,
J ¼ 5:9 Hz, 2H), 2.91 (t, J ¼ 6:0 Hz, 2H), 1.66–1.49 (br
m, 6H), 1.35 (d, J ¼ 6:1 Hz, 6H). 13C NMR (100 MHz,
CDCl3) d 170.2, 145.0, 140.4, 139.3, 136.6, 129.0, 128.4,
126.4, 125.3, 121.2, 116.4, 112.5, 110.3, 53.2, 48.7, 48.1,
43.3, 43.0, 26.5, 25.6, 24.5, 22.3.
5.4.2. B. (3-{[2-(3-Isopropoxy-phenylamino)-ethylamino]-
methyl}-phenyl)-piperidin-1-yl-methanone. MS (ESI):
mass calculated for C24H33N3O2, 395.26; m=z found,
396.4 [MþH]þ, 418.4 [MþNa]þ. H NMR (400 MHz,
1
CDCl3) d 7.34–7.23 (m, 4H), 7.03 (t, J ¼ 8:0 Hz, 1H), 4.49
(hp, J ¼ 6:1 Hz, 1H), 3.80 (s, 2H), 3.69 (br s, 2H), 3.30 (br
s, 2H), 3.18 (t, J ¼ 5:5 Hz, 2H), 2.85 (t, J ¼ 5:5 Hz, 2H),
1.65–1.45 (m, 6H), 1.30 (d, J ¼ 6:0 Hz, 6H). 13C NMR
(100 MHz, CDCl3) d 170.1, 158.9, 149.7, 140.4, 136.4,
129.7, 128.9, 128.3, 126.2, 125.1, 105.8, 104.2, 100.6, 69.3,
53.1, 48.6, 47.8, 43.2, 42.9, 26.4, 25.4, 24.4, 22.0.
5.3. (3{[3-(2-Isopropoxy-phenylamino)-propylamino]-meth-
yl}-phenyl)-piperidin-1-yl-methanone (4b)
5.3.1. A. N1-(2-Isopropoxy-phenyl)-propane-1,3-diamine.
To a solution of 2-isopropoxy-phenylamine (0.50 g,
3.3 mmol) in isopropanol (7 mL) was added Et3N
(0.67 g, 6.6 mmol) and 3-chloropropylamine hydrochlo-
ride (0.515 g, 3.96 mmol). The reaction mixture was he-
ated to 50 °C for 24 h, then to 90 °C for 24 h. The
mixture was treated with saturated NaHCO3 (20 mL),
EtOAc (40 mL) and H2O (20 mL), and then the aqueous
layer was back-extracted with EtOAc (3 ꢂ 40 mL). The
combined organic layers were washed with brine, dried
(MgSO4), filtered, and concentrated under reduced
pressure. The resulting residue was purified by column
chromatography (50–100% EtOAc/hexanes) to provide
an amber oil (0.10 g, 15%). MS (ESI): mass calculated
5.5. (3-{[2-(2-Cyclopentyloxy-phenylamino)-ethylamino]-
methyl}-phenyl)-piperidin-1-yl-methanone (6)
The title compound was prepared similarly to 4a, steps
A–E substituting iodocyclopentane for 2-iodopropane
in step A.
5.5.1. A. 1-Cyclopentyloxy-2-nitro-benzene. 1H NMR
(400 MHz, CDCl3) d 7.77 (dd, J ¼ 8:7, 1.7 Hz, 1H),
7.50–7.46 (m, 1H), 7.08–7.06 (m, 1H), 6.99–6.94 (m,
1H), 4.92–4.88 (m, 1H), 1.94–1.90 (m, 4H), 1.87–1.81
(m, 2H), 1.65–1.62 (m, 2H).
1
for C12H20N2O, 208.16; m=z found, 209.1 [MþH]þ. H
NMR (400 MHz, CDCl3) d 6.85–6.81 (m, 1H), 6.77–6.60
(m, 1H), 6.66–6.60 (m, 2H), 4.51 (hp, J ¼ 6:1 Hz, 1H),
3.27 (t, J ¼ 6:6 Hz, 2H), 3.10 (t, J ¼ 7:0 Hz, 2H), 2.06
(p, J ¼ 6:7 Hz, 2H), 1.34 (d, J ¼ 6:1 Hz, 6H).
5.5.2. B. 2-Cyclopentyloxy-phenylamine. To a solution of
1-cyclopentyloxy-2-nitro-benzene (5.0 g, 24 mmol) in
ethanol (EtOH, 95 mL) was added Pd on carbon (Pd/C;
10 wt %, 5.14 g), and the resulting suspension was stirred
under H2 (50 psi) at 25 °C for 6 h. The suspension was
filtered (Celiteâ), and the filtrate was concentrated under
reduced pressure. The crude residue was purified by
column chromatography (5–10% EtOAc/hexanes) to
provide the desired product (3.6 g, 84%). MS (ESI):
mass calculated for C11H15NO, 177.12; m=z found, 178.1
5.3.2. B. (3-{[3-(2-Isopropoxy-phenylamino)-propylamino]-
methyl}-phenyl)-piperidin-1-yl-methanone.
The
title
compound was prepared similarly to 4a, steps D and E,
substituting N1-(2-isopropoxy-phenyl)-propane-1,3-dia-
mine for N1-(2-isopropoxy-phenyl)-ethane-1,2-diamine
in step E. MS (ESI): mass calculated for C25H35N3O2,
409.27; m=z found, 410.3 [MþH]þ. 1H NMR (400 MHz,
CDCl3) d 7.37–7.32 (m, 3H), 7.26–7.22 (m, 1H), 6.87–
6.82 (m, 1H), 6.78–6.76 (m, 1H), 6.64–6.60 (m, 2H),
4.54–4.45 (m, 1H), 3.84 (br s, 2H), 3.71 (br s, 2H), 3.32
(br s, 2H), 3.21 (t, J ¼ 6:7 Hz, 2H), 2.78 (t, J ¼ 6:8 Hz,
2H), 1.90–1.84 (m, 2H), 1.67 (br s, 4H), 1.51 (br s, 2H),
1.33 (d, J ¼ 6:1 Hz, 6H).
1
[MþH]þ. H NMR (400 MHz, CDCl3) d 6.80–6.68 (m,
4H), 4.80–4.76 (m, 1H), 1.94–1.85 (m, 4H), 1.83–1.73
(m, 2H), 1.68–1.58 (m, 2H).
5.5.3. C. N1-(2-Cyclopentyloxy-phenyl)-ethane-1,2-di-
amine. 1H NMR (400 MHz, CDCl3) d 6.82 (dt,
J ¼ 7:6, 1.3 Hz, 1H), 6.76–6.74 (m, 1H), 6.66–6.61 (m,
2H), 4.78–4.74 (m, 1H), 3.38 (br s, 2H), 3.29 (t,
J ¼ 5:7 Hz, 2H), 3.06–2.91 (m, 2H), 1.96–1.87 (m, 4H),
1.86–1.75 (m, 2H), 1.69–1.55 (m, 2H).
5.4. (3-{[2-(3-Isopropoxy-phenylamino)-ethylamino]-meth-
yl}-phenyl)-piperidin-1-yl-methanone (5)
The title compound was prepared similarly to 4a, steps
C–E, substituting 3-isopropoxyphenylamine for 2-iso-
propoxyphenylamine in step C.
5.5.4. D. (3-{[2-(2-Cyclopentyloxy-phenylamino)-ethyl-
amino]-methyl}-phenyl)-piperidin-1-yl-methanone.
MS
(ESI): mass calculated for C26H35N3O2, 421.27, m=z
5.4.1. A. N1-(3-Isopropoxy-phenyl)-ethane-1,2-diamine.
MS (ESI): mass calculated for C11H18N2O, 194.14; m=z
1
found, 422.3 [MþH]þ. H NMR (400 MHz, CDCl3) d

4520
R. L. Wolin et al. / Bioorg. Med. Chem. 12 (2004) 4511–4532
7.41–7.39 (m, 1H), 7.35–7.32 (m, 2H), 7.26–7.24 (m,
1H), 6.83 (dt, J ¼ 7:6, 1.4 Hz, 1H), 6.76 (dd, J ¼ 7:6,
1.2 Hz, 1H), 6.65–6.61 (m, 2H), 4.80–4.75 (m, 1H), 3.85
(s, 2H), 3.70 (br s, 2H), 3.32 (br s, 2H), 3.27 (t,
J ¼ 5:8 Hz, 2H), 2.92 (t, J ¼ 5:8 Hz, 2H), 1.96–1.73 (m,
7H), 1.67–1.57 (m, 6H), 1.50 (br s, 2H).
5.7.3. C. N1-[2-(1-Ethyl-propoxy)-phenyl]-ethane-1,2-di-
amine. MS (ESI): mass calculated for C13H22N2O,
222.17; m=z found, 223.3 [MþH]þ.
5.7.4. D. [3-({2-[2-(1-Ethyl-propoxy)-phenylamino]-ethyl-
amino}-methyl)-phenyl]-piperidin-1-yl-methanone.
MS
(ESI): mass calculated for C26H37N3O2, 423.29, m=z
found, 424.5 [MþH]þ, 446.5 [MþNa]þ. 1H NMR
(400 MHz, CDCl3) d 7.40–7.39 (m, 1H), 7.34–7.31 (m,
2H), 7.26–7.24 (m, 1H), 6.85–6.81 (m, 1H), 6.76–6.74
(m, 1H), 6.64–6.60 (m, 2H), 4.12 (p, J ¼ 5:8 Hz, 1H),
3.85 (br s, 2H), 3.70 (br s, 2H), 3.30–3.27 (m, 4H), 2.92
0.96 (t, J ¼ 5:9 Hz, 2H), 1.73–1.66 (m, 8H), 1.49 (br s,
2H), 0.95 (t, J ¼ 7:4 Hz, 6H). 13C NMR (100 MHz,
CDCl3) d 170.2, 145.5, 140.3, 139.2, 136.6, 129.0, 128.4,
126.4, 125.3, 121.0, 116.3, 112.2, 110.2, 80.6, 53.2, 48.7,
48.0, 43.2, 43.1, 26.4, 26.1, 25.6, 24.5, 9.6.
5.6. (3{[2-(3-Methoxy-phenylamino)-ethylamino]-methyl}-
phenyl)-piperidin-1-yl-methanone (7)
The title compound was prepared similarly to 4a, steps
C–E, substituting 3-methoxy-phenylamine for 2-iso-
propoxy-phenylamine in step C.
5.6.1. A. N1-(3-Methoxy-phenyl)-ethane-1,2-diamine. MS
(ESI): mass calculated for C9H14N2O, 166.11; m=z
1
found, 167.1 [MþH]þ. H NMR (400 MHz, DMSO-d6,
HCl salt) d 8.18 (br s, 2H), 7.00–6.96 (m, 1H), 6.22–6.15
(m, 3H), 5.93 (br s, 1H), 3.67 (s, 3H), 3.35–3.26 (m, 2H),
5.93 (br s, 2H). 13C NMR (100 MHz, DMSO-d6) d
160.4, 149.4, 129.7, 105.4, 101.9, 98.0, 54.7, 25.5.
5.8. (3-{[2-(2-Methoxy-phenylamino)-ethylamino]-methyl}-
phenyl)-piperidin-1-yl-methanone (9)
The title compound was prepared similarly to 4a, steps
C–E, substituting 2-methoxy-phenylamine for 2-iso-
propoxy-phenylamine in step C.
5.6.2. B. (3-{[2-(3-Methoxy-phenylamino)-ethylamino]-
methyl}-phenyl)-piperidin-1-yl-methanone. MS (ESI):
mass calculated for C22H29N3O2, 367.23, m=z found,
368.3 [MþH]þ, 390.3 [MþNa]þ. H NMR (400 MHz,
5.8.1. A. N1-(2-Methoxy-phenyl)-ethane-1,2-diamine. MS
(ESI): mass calculated for C9H14N2O, 166.11, m=z
1
CDCl3) d 7.37–7.23 (m, 4H), 7.06 (t, J ¼ 8:1 Hz, 1H),
6.25 (dt, J ¼ 8:0, 2.2 Hz, 2H), 6.18 (t, J ¼ 2:2 Hz, 1H),
2.10 (s, 2H), 3.75 (s, 3H), 3.69 (br s, 2H), 3.31 (br s, 2H),
3.21 (t, J ¼ 5:6 Hz, 2H), 2.89 (t, J ¼ 5:9 Hz, 2H), 1.66
(br s, 4H), 1.49 (br s, 2H). 13C NMR (100 MHz, CDCl3)
d 170.1, 160.7, 149.7, 140.1, 136.6, 129.9, 129.0, 128.4,
126.4, 125.4, 106.0, 102.5, 98.8, 55.0, 53.1, 48.7, 47.8,
43.1, 26.4, 25.5, 24.5.
1
found, 167.1 [MþH]þ. H NMR (400 MHz, CDCl3) d
8.17 (br s, 2H), 6.83–6.76 (m, 2H), 6.62–6.56 (m, 2H),
5.19 (br t, J ¼ 4:3 Hz, 1H), 3.76 (s, 3H), 3.37–3.32 (br t,
J ¼ 4:9, 4.6 Hz, 2H), 2.95 (t, J ¼ 4:8 Hz, 2H). 13C NMR
(100 MHz, DMSO-d6) d 146.6, 137.3, 121.0, 116.2,
110.0, 109.2, 55.3, 37.7.
5.8.2. B. (3-{[2-(2-Methoxy-phenylamino)-ethylamino]-
methyl}-phenyl)-piperidin-1-yl-methanone. MS (ESI):
mass calculated for C22H29N3O2, 367.23; m=z found,
5.7. [3-({[2-(1-Ethyl-propoxy)-phenylamino]-ethylamino}-
methyl)-phenyl]-piperidin-1-yl-methanone (8)
1
368.3 [MþH]þ, 390.2 [MþNa]þ. H NMR (400 MHz,
The title compound was prepared similarly to 4a, steps
A–E substituting 3-iodopentane for 2-iodopropane in
step A.
CDCl3) d 7.38–7.31 (m, 3H), 7.26–7.23 (m, 1H), 6.85 (dt,
J ¼ 7:6, 1.3 Hz, 1H), 6.75 (dd, J ¼ 7:9, 1.3 Hz, 1H), 6.65
(dt, J ¼ 7:6, 1.4 Hz, 1H), 6.61 (d, J ¼ 7:8 Hz, 2H), 3.85–
3.81 (m, 5H), 3.69 (br s, 2H), 3.31 (br s, 2H), 3.26 (t,
J ¼ 5:8 Hz, 2H), 2.91 (t, J ¼ 6:0 Hz, 2H), 1.65 (br s,
4H), 1.49 (br s, 2H). 13C NMR (100 MHz, CDCl3) d
170.1, 146.8, 140.2, 138.1, 136.5, 129.0, 128.3, 126.3,
125.3, 121.1, 116.4, 109.8, 109.3, 55.3, 53.1, 48.6, 47.9,
43.1, 43.0, 26.4, 25.5, 24.4.
1
5.7.1. A. 1-(1-Ethyl-propoxy)-2-nitro-benzene. H NMR
(400 MHz, CDCl3) d 7.77 (dd, J ¼ 5:1, 1.7 Hz, 1H),
7.50–7.46 (m, 1H), 7.08–7.06 (m, 1H), 6.99–6.94 (m,
1H), 4.92–4.88 (m, 1H), 1.94–1.90 (m, 4H), 1.87–1.81
(m, 2H), 1.65–1.62 (m, 2H). 13C NMR (100 MHz,
CDCl3) d 151.4, 133.6, 125.4, 119.6, 115.5, 81.3, 32.7,
23.8.
5.9. (3-{[2-(2-Phenoxy-phenylamino)-ethylamino]-methyl}-
phenyl)-piperidin-1-yl-methanone (10)
5.7.2. B. 2-(1-Ethyl-propoxy)-phenylamine. MS (ESI):
mass calculated for C11H17NO, 179.13, m=z found, 180.1
The title compound was prepared similarly to 4a, steps
C–E substituting 2-phenoxy-phenylamine for 2-iso-
propoxy-phenylamine in step C.
1
[MþH]þ. H NMR (400 MHz, CDCl3) d 6.78–6.66 (m,
4H), 4.12 (p, J ¼ 5:8 Hz, 1H), 3.55 (br s, 2H), 1.73–1.66
(m, 4H), 0.96 (t, J ¼ 7:5 Hz, 6H). 13C NMR (100 MHz,
CDCl3) d 145.9, 137.1, 120.8, 118.3, 115.2, 113.2, 80.5,
26.1, 9.6.
5.9.1. A. N1-(2-Phenoxy-phenyl)-ethane-1,2-diamine. MS
(ESI): mass calculated for C14H16N2O, 228.13; m=z

R. L. Wolin et al. / Bioorg. Med. Chem. 12 (2004) 4511–4532
4521
1
found, 229.2 [MþH]þ. H NMR (400 MHz, CDCl3) d
1H), 6.63 (d, J ¼ 7:7 Hz, 2H), 3.85 (s, 2H), 3.70 (br s,
2H), 3.31 (br s, 2H), 3.25 (t, J ¼ 5:7 Hz, 2H), 2.93 (t,
J ¼ 5:7 Hz, 2H), 1.67 (br s, 4H), 1.50 (br s, 2H), 1.26 (br
s, 2H).
8.19 (br s, 1H), 7.28–6.67 (m, 9H), 3.55–3.15 (m, 4H).
13C NMR (100 MHz, CDCl3) d 144.2, 137.7, 129.6,
124.5, 123.1, 118.7, 118.6, 118.0, 112.7, 41.5, 39.0.
5.9.2. B. (3-{[2-(2-Phenoxy-phenylamino)-ethylamino]-
methyl}-phenyl)-piperidin-1-yl-methanone. MS (ESI):
mass calculated for C27H31N3O2, 429.24; m=z found,
430.4 [MþH]þ. 1H NMR (400 MHz, CDCl3) d 7.36–7.22
(m, 6H), 7.05–6.95 (m, 4H), 6.84 (dd, J ¼ 7:8, 1.4 Hz,
1H), 6.75 (dd, J ¼ 8:0, 1.4 Hz, 1H), 6.64 (dt, J ¼ 7:8,
1.4 Hz, 1H), 4.54 (br s, 1H), 3.76 (s, 2H), 3.69 (br s, 2H),
3.39–3.25 (m, containing a t, J ¼ 5:8 Hz, 4H), 2.85 (t,
J ¼ 6:0 Hz, 2H), 1.85 (br s, 1H), 1.65 (br s, 4H), 1.48 (br
s, 2H). 13C NMR (100 MHz, CDCl3) d 170.2, 157.5,
143.1, 141.7, 140.5, 140.5, 136.6, 136.5, 129.6, 128.9,
128.4, 127.7, 126.3, 125.6, 125.3, 124.9, 122.6, 119.3,
117.3, 116.7, 111.6, 64.5, 53.1, 48.7, 47.9, 43.1, 26.4,
25.5, 24.5.
5.12. (3-{[2-(2-Nitro-phenylamino)-ethylamino]-methyl}-
phenyl)-piperidin-1-yl-methanone (13)
5.12.1. A. N1-(2-Nitro-phenyl)-ethane-1,2-diamine. To a
mixture of ethylenediamine (1.05 g, 17.5 mmol) and
K2CO3 (2.44 g, 17.7 mmol) in anhydrous CH3CN
(300 mL) heated to 70 °C, a solution of o-fluoronitro-
benzene (1.25 g, 8.87 mmol) in CH3CN (50 mL) was
added drop wise over 2 h. The resulting suspension was
stirred at 70 °C for 1 h, and then allowed to cool to 25 °C
and stirred for 18 h. The suspension was filtered, and the
filtrate was concentrated under reduced pressure. The
crude residue was partitioned between water (200 mL)
and CH2Cl2 (200 mL), and the organic layer was washed
with water (2 ꢂ 200 mL), dried (Na2SO4), filtered, and
concentrated under reduced pressure to provide a bright
yellow semisolid (1.5 g, 78%). MS (ESI): mass calculated
5.10. (3{[2-(2-Hydroxy-phenylamino)-ethylamino]-methyl}-
phenyl)-piperidin-1-yl-methanone (11)
1
for C8H11N3O2, 181.09; m=z found, 182.1 [MþH]þ. H
NMR (400 MHz, CDCl3) d 8.26 (br s, 1H), 8.17 (dd,
J ¼ 8:6, 1.6 Hz, 1H), 7.46–7.41 (m, 1H), 6.86 (dd,
J ¼ 8:7, 0.82 Hz, 1H), 6.63–6.62 (m, 1H), 3.39 (q,
J ¼ 5:7 Hz, 2H), 3.06 (t, J ¼ 5:7 Hz, 2H). 13C NMR
(100 MHz, CDCl3) d 40.8, 45.7, 113.4, 115.3, 127.1,
136.2, 145.6 ppm.
The title compound was prepared similarly to 4a, steps
C–E, substituting 2-aminophenol for 2-isopropoxy-
phenylamine in Step C.
5.10.1. A. 2-(2-Amino-ethylamino)-phenol. MS (ESI):
mass calculated for C8H12N2O, 152.09; m=z found, 153.1
1
[MþH]þ. H NMR (400 MHz, D2O) d 6.77–6.71 (m,
5.12.2. B. (3-{[2-(2-Nitro-phenylamino)-ethylamino]-
methyl}-phenyl)-piperidin-1-yl-methanone.
2H), 6.64–6.57 (m, 2H), 3.31 (t, J ¼ 6:1 Hz, 2H), 3.05 (t,
J ¼ 6:0 Hz, 2H). 1H NMR (400 MHz, DMSO-d6) d 9.35
(br s, 1H), 8.21 (br s, 2H), 6.72 (dd, J ¼ 7:7, 1.3 Hz, 1H),
6.63 (dt, J ¼ 7:7, 1.3 Hz, 1H), 6.55 (dd, J ¼ 7:8, 1.3 Hz,
1H), 6.44 (dt, J ¼ 7:5, 1.4 Hz, 1H). 13C NMR (100 MHz,
D2O) d 144.5, 136.3, 121.7, 119.3, 115.3, 112.8, 41.0,
38.8.
The
title
compound was prepared similarly to 4a, steps D and E,
substituting N1-(2-nitro-phenyl)-ethane-1,2-diamine for
N1-(2-isoproxy-phenyl)-ethane-1,2-diamine in step E,
yielding a bright yellow semisolid (2.18 g, 89%). MS
(ESI): mass calculated for C21H26N4O3, 282.20; m=z
found, 283.2 [MþH]þ, 405.2 [MþNa]þ. 1H NMR
(400 MHz, CDCl3) d 8.38 (br s, 1H), 8.15 (dd, J ¼ 8:6,
1.6 Hz, 1H), 7.44–7.33 (m, 4H), 7.29–7.25 (m, 1H), 6.83
(dd, J ¼ 8:6, 0.7 Hz, 1H), 6.64–6.60 (m, 1H), 3.87 (s,
2H), 3.70 (br s, 2H), 3.38 (q, J ¼ 5:8 Hz, 2H), 3.33 (br s,
2H), 3.06 (t, J ¼ 5:8 Hz, 2H), 1.67 (br s, 4H), 1.50 (br s,
2H). 13C NMR (100 MHz, CDCl3) d 170.2, 145.4, 140.5,
136.7, 136.2, 131.9, 129.0, 128.5, 126.8, 126.4, 125.4,
115.2, 113.9, 53.5, 48.8, 47.3, 43.1, 42.6, 26.5, 25.6, 24.6.
5.10.2. B. (3-{[2-(2-Hydroxy-phenylamino)-ethylamino]-
methyl}-phenyl)-piperidin-1-yl-methanone. MS (ESI):
mass calculated for C21H27N3O2, 353.21; m=z found,
1
354.1 [MþH]þ, 376.1 [MþNa]þ. H NMR (400 MHz,
CDCl3) d 7.33–7.21 (m, 4H), 6.74–6.70 (m, 1H), 6.62–
6.50 (m, 3H), 3.79 (s, 3H), 3.69 (br s, 2H), 3.28 (br s,
2H), 3.21 (t, J ¼ 5:3 Hz, 2H), 2.82 (t, J ¼ 5:5 Hz, 2H),
1.64 (br s, 4H), 1.45 (br s, 2H). 13C NMR (100 MHz,
CDCl3) d 170.4, 145.3, 139.6, 137.4, 136.2, 129.5, 128.4,
126.7, 125.4, 120.3, 117.9, 114.8, 112.5, 52.9, 48.7, 47.7,
43.9, 43.2, 26.4, 25.5, 24.4.
5.13. (3-{[2-(2-Amino-phenylamino)-ethylamino]-methyl}-
phenyl)-piperidin-1-yl-methanone (14)
To a solution of (3-{[2-(2-nitro-phenylamino)-ethyl-
amino]-methyl}-phenyl)-piperidin-1-yl-methanone (0.060
g, 0.16 mmol) in EtOH (1.6 mL) was added cyclohexa-
diene (0.55 mL) followed by Pd/C (10 wt %, 0.02 g), and
the resulting suspension was heated to 100 °C for 45 min.
The suspension was filtered (Celiteâ), and the filtrate
was concentrated under reduced pressure. The crude
residue was purified by column chromatography (0–5%
CH3OH/CH2Cl2) to provide the product as a colorless
oil (0.034 g, 61%). MS (ESI): mass calculated for
5.11. {3-[(2-Phenylamino-ethylamino)-methyl]-phenyl}-
piperidin-1-yl-methanone (12)
The title compound was prepared similarly to 4a, steps
D and E, substituting N1-phenylethane-1,2-diamine for
N1-(2-isopropoxy-phenyl)-ethane-1,2-diamine in step E.
1H NMR (400 MHz, CDCl3) d 7.38–7.32 (m, 3H), 7.26–
7.25 (m, 1H), 7.19–7.14 (m, 2H), 6.70 (t, J ¼ 7:4 Hz,

4522
R. L. Wolin et al. / Bioorg. Med. Chem. 12 (2004) 4511–4532
C21H28N4O, 352.23; m=z found, 353.2 [MþH]þ, 375.2
[MþNa]þ. 1H NMR (400 MHz, CDCl3) d 7.38–7.32 (m,
3H), 7.26–7.24 (m, 1H), 6.80 (d t, J ¼ 5:4, 1.9 Hz, 1H),
6.72–6.64 (m, 3H), 3.84 (br s, 2H), 3.70 (br s, 2H), 3.32
(br s, 2H), 3.21 (t, J ¼ 5:7 Hz, 2H), 2.94 (t, J ¼ 5:7 Hz,
2H), 1.67 (br s, 4H), 1.50 (br s, 1H). 13C NMR
(100 MHz, CDCl3) d 170.3, 140.7, 137.7, 136.7, 134.6,
129.1, 128.4, 126.5, 125.3, 120.5, 118.7, 116.3, 112.0,
53.3, 48.1, 43.8, 29.7, 26.5, 24.6 ppm.
was added K2CO3 (0.092 g, 0.67 mmol). 2-Iodopropane
(0.112 g, 0.66 mmol) was added to the resulting suspen-
sion, and the mixture was stirred at 50 °C for 6 h. The
reaction mixture was partitioned with CH2Cl2 (30 mL)
and 1 N NaOH (30 mL), and the organic layer was dried
(Na2SO4), filtered, and concentrated under reduced
pressure. The crude residue was purified by column
chromatography (0–5% CH3OH/CH2Cl2) to provide a
colorless oil (0.032 g, 49%). MS (ESI): mass calculated
for C29H42N4O3, 494.33; m=z found, 495.3 [MþH]þ,
1
517.3 [MþNa]þ. H NMR (400 MHz, CDCl3) d 7.36–
5.14. (3-{[2-(2-Isopropylamino-phenylamino)-ethylamino]-
methyl}-phenyl)-piperidin-1-yl-methanone (15)
7.32 (m, 1H), 7.28–7.24 (m, 4H), 6.77–6.53 (m, 4H),
4.51–4.46 (m, 2H), 3.69 (br s, 2H), 3.58 (br s, 2H), 3.42
(br s, 1H), 3.28 (br s, 2H), 3.23 (t, J ¼ 6:0 Hz, 2H), 1.66
(br s, 4H), 1.51–1.44 (m, 11H), 1.22 (d, J ¼ 6:3 Hz, 6H).
5.14.1. A. [2-(2-Nitro-phenylamino)-ethyl]-[3-(piperidine-
1-carbonyl)-benzyl]-carbamic acid tert-butyl ester. To a
solution of (3-{[2-(2-nitro-phenylamino)-ethylamino]-
methyl}-phenyl)-piperidin-1-yl-methanone
(2.18 g,
5.14.4. D. (3-{[2-(2-Isopropylamino-phenylamino)-ethyl-
amino]-methyl}-phenyl)-piperidin-1-yl-methanone. To a
solution of [2-(2-isopropylamino-phenylamino)-ethyl]-
[3-(piperidine-1-carbonyl)-benzyl]-carbamic acid tert-
butyl ester (0.026 g, 0.053 mmol) in CH2Cl2 (0.53 mL)
was added 1 M HCl in dioxane (0.10 mL), and the
mixture was stirred at 25 °C for 1 h. The reaction mix-
ture was partitioned with 1 M NaOH (20 mL) and
CH2Cl2 (20 mL), and the organic layer was dried
(MgSO4), filtered, and concentrated under reduced
pressure to give the desired product as a white solid
(0.020 g, 96%). MS (ESI): mass calculated for
C24H34NO, 394.27; m=z found, 395.2 [MþH]þ, 417.3
[MþNa]þ. 1H NMR (400 MHz, CDCl3) d 7.40–7.32 (m,
3H), 7.27–7.24 (m, 1H), 6.80–6.73 (m, 2H), 6.69–6.66
(m, 2H), 3.85 (s, 2H), 3.70 (br s, 2H), 3.58 (hp,
J ¼ 6:3 Hz, 1H), 3.32 (br s, 2H), 3.21 (t, J ¼ 5:8 Hz,
2H), 2.94 (t, J ¼ 5:8 Hz, 2H), 1.67 (br s, 4H), 1.50 (br s,
2H), 1.23 (d, J ¼ 6:3 Hz, 6H).
5.70 mmol) in CH2Cl2 (25 mL) was added a solution of
di-tert-butyl-dicarbonate (1.24 g, 5.68 mmol) in CH2Cl2
(32 mL), and the resulting solution was stirred at 25 °C
for 2 h. The solvent was removed in vacuo, and the
residue was partitioned between water (100 mL) and
EtOAc (100 mL). The organic layer was dried (Na2SO4),
filtered, and concentrated under reduced pressure. The
crude residue was purified by column chromatography
(0–8% CH3OH/CH2Cl2) to provide a bright yellow
semisolid (2.36 g, 86%). MS (ESI): mass calculated for
C26H34N4O5, 482.25; m=z found, 483.2 [MþH]þ, 505.2
1
[MþNa]þ. H NMR (400 MHz, CDCl3) d 8.24 (br s,
1H), 8.09 (d, J ¼ 8:5 Hz, 1H), 7.44–7.27 (m, 5H), 6.88–
6.83 (m, 1H), 6.61 (t, J ¼ 7:6 Hz, 1H), 4.50–4.54 (m,
2H), 3.68–3.30 (m, 8H), 1.65 (br s, 4H), 1.48 (br s, 11H).
13C NMR (100 MHz, CDCl3) d 170.1, 156.0, 145.6,
139.0, 137.2, 136.5, 132.2, 129.0, 128.3, 126.9, 126.4,
126.0, 115.7, 114.0, 80.8, 51.6, 50.3, 49.0, 46.1, 45.6,
43.3, 41.5, 28.6, 26.7, 25.9, 24.8.
5.15. N-(2-{2-[3-(Piperidine-1-carbonyl)-benzylamino]-
ethylamino}-phenyl)-methanesulfonamide (16)
5.14.2. B. [2-(2-Amino-phenylamino)-ethyl]-[3-(piper-
idine-1-carbonyl)-benzyl]-carbamic acid tert-butyl ester.
The title intermediate was prepared analogously to
compound 14, substituting [2-(2-nitro-phenylamino)-
ethyl]-[3-(piperidine-1-carbonyl)-benzyl]-carbamic acid
tert-butyl ester for (3-{[2-(2-nitro-phenylamino)-ethyl-
amino]-methyl}-phenyl)-piperidin-1-yl-methanone, yield-
ing a tan semisolid (1.4 g, 62%). MS (ESI): mass
calculated for C26H36N4O3, 452.28; m=z found, 453.3
[MþH]þ, 475.2 [MþNa]þ. 1H NMR (400 MHz, CDCl3)
d 8.24 (br s, 1H), 8.09 (d, J ¼ 8:5 Hz, 1H), 7.44–7.27 (m,
5H), 6.88–6.83 (m, 1H), 6.61 (t, J ¼ 7:6 Hz, 1H), 4.54–
4.50 (m, 2H), 3.68–3.30 (m, 8H), 1.65 (br s, 4H), 1.48 (br
s, 11H). 13C NMR (100 MHz, CDCl3) d 170.1, 156.0,
145.6, 139.0, 137.2, 136.5, 132.2, 129.0, 128.3, 126.9,
126.4, 126.0, 115.7, 114.0, 80.8, 51.6, 50.3, 49.0, 46.1,
45.6, 43.3, 41.5, 28.6, 26.7, 25.9, 24.8.
5.15.1. A. [2-(2-Methanesulfonylamino-phenylamino)-
ethyl]-[3-(piperidine-1-carbonyl)-benzyl]-carbamic
acid
tert-butyl ester. To a solution of [2-(2-amino-phenyl-
amino)-ethyl]-[3-(piperidine-1-carbonyl)-benzyl]-carb-
amic acid tert-butyl ester (example 13, step B; 0.10 g,
0.22 mmol) in CH2Cl2 (4 mL) was added Et3N (0.033 g,
0.33 mmol) and methanesulfonyl chloride (0.028 g,
0.24 mmol), and the resulting mixture was stirred at 25 °C
for 17 h. The reaction mixture was treated with satd
NH4Cl (10 mL), H2O (10 mL) and CH2Cl2 (20 mL), and
the aqueous layer was extracted with CH2Cl2 (3 ꢂ 20 mL).
The combined organic layers were washed with brine,
dried (MgSO4), filtered, and concentrated under reduced
pressure. The crude residue was purified by preparative
TLC (30% acetone/hexanes) to provide the desired
product (0.060 g, 51%). MS (ESI): mass calculated for
C27H38N4O5S, 530.26; m=z found, 531.2 [MþH]þ.
5.14.3. C. [2-(2-Isopropylamino-phenylamino)-ethyl]-[3-
(piperidine-1-carbonyl)-benzyl]-carbamic acid tert-butyl
ester. To a solution of [2-(2-amino-phenylamino)-
ethyl]-[3-(piperidine-1-carbonyl)-benzyl]-carbamic acid
tert-butyl ester (0.060 g, 0.133 mmol) in DMF (1.3 mL)
5.15.2. B. N-(2-{2-[3-(Piperidine-1-carbonyl)-benzyl-
amino]-ethylamino}-phenyl)-methanesulfonamide. The
title compound was prepared analogously to compound

R. L. Wolin et al. / Bioorg. Med. Chem. 12 (2004) 4511–4532
4523
15, step D, substituting [2-(2-methanesulfonyl-amino-
phenylamino)-ethyl]-[3-(piperidine-1-carbonyl)-benzyl]-
carbamic acid tert-butyl ester for [2-(2-isopropylamino-
phenylamino)-ethyl]-[3-(piperidine-1-carbonyl)-benzyl]-
carbamic acid tert-butyl ester, yielding the desired sul-
fonamide (0.020 g, 42%). 1H NMR (400 MHz, CDCl3) d
7.47 (br s, 1H), 7.33–7.28 (m, 2H), 7.20–7.13 (m, 3H),
6.68–6.64 (m, 2H), 3.84 (s, 2H), 3.74–3.71 (m, 2H), 3.31
(br s, 2H), 3.23 (t, J ¼ 5:5 Hz, 2H), 3.02 (s, 3H), 2.88 (t,
J ¼ 5:5 Hz, 2H), 1.67–1.50 (m, 6H).
substituting 1-[2-(2-amino-ethylamino)-phenyl]-3-phen-
yl-urea for N1-(2-isoproxy-phenyl)-ethane-1,2-diamine
in step E. MS (ESI): mass calculated for C28H33N5O2,
471.26; m=z found, 472.2 [MþH]þ. 1H NMR (400 MHz,
CDCl3) d 8.17 (br s, 1H), 7.48–7.11 (m, 9H), 7.05–6.95
(m, 1H), 6.92–6.85 (m, 1H), 6.64 (dt, J ¼ 7:6, 1.0 Hz,
1H), 6.53 (d, J ¼ 7:2 Hz, 1H), 3.73 (s, 2H), 3.65 (br s,
2H), 3.28 (br s, 2H), 3.08 (dd, J ¼ 5:6, 5.0 Hz, 2H), 2.80
(dd, J ¼ 5:5, 5.1 Hz, 2H), 2.60–2.40 (br m, 2H), 1.60 (br
s, 4H), 1.44 (br s, 2H).
5.16. 1-Phenyl-3-(2-{2-[3-(piperidine-1-carbonyl)-benzyl-
amino]-ethylamino}-phenyl)-urea (17)
5.17. 1-Benzyl-3-(2-{2-[3-(piperidine-1-carbonyl)-benzyl-
amino]-ethylamino}-phenyl)-urea (18)
5.16.1. A. N-Benzyl-N0-(2-nitro-phenyl)-ethane-1,2-di-
amine. The title intermediate was prepared analogously
to compound, example 13, step A, substituting N1-
benzyl-ethane-1,2-diamine for ethylenediamine. MS
(ESI): mass calculated for C15H17N3O2, 271.13; m=z
5.17.1. A. 1-[2-(2-Amino-ethylamino)-phenyl]-3-benzyl-
urea. Substitution of N-(2-benzylamino-ethyl)-benzene-
1,2-diamine and benzylisocyanate for [2-(2-amino-phen-
ylamino)-ethyl]-[3-(piperidine-1-carbonyl)-benzyl]-car-
bamic acid tert-butyl ester and methanesulfonylchloride
as for compound 16, step A, provided benzyl-{2-[2-(3-
benzyl-ureido)-phenylamino]-ethyl}-carbamic acid tert-
butyl ester. Analogous deprotection conditions as for
compound 15, step D, gave 1-benzyl-3-[2-(2-benzyl-
amino-ethylamino)-phenyl]-urea. The benzylamine inter-
mediate was then converted to the title intermediate by
its substitution for 1-cyclopentyloxy-2-nitro-benzene in
the procedure for compound 6, step B. 1H NMR
(400 MHz, CD3OD) d 7.35–7.30 (m, 3H), 7.28–7.08
(m, 4H), 6.80–6.76 (m, 1H), 6.74–6.68 (m, 1H), 4.38
(s, 2H), 3.49 (t, J ¼ 5:6 Hz, 2H), 3.11 (t, J ¼ 5:9 Hz,
2H).
1
found, 272.1 [MþH]þ. H NMR (400 MHz, CDCl3) d
8.40 (br s, 1H), 8.20 (dd, J ¼ 1:5, 8.6 Hz, 1H), 7.48–7.25
(m, 6H), 6.85 (d, J ¼ 8:5 Hz, 1H), 6.65 (t, J ¼ 8:3 Hz,
1H), 3.88 (s, 2H), 3.43 (dd, J ¼ 5:5, 11.4 Hz, 2H), 3.02 (t,
J ¼ 6:0 Hz, 2H).
5.16.2. B. 1-[2-(2-Benzylamino-ethylamino)-phenyl]-3-
phenyl-urea. Substitution of N-benzyl-N0-(2-nitro-phen-
yl)-ethane-1,2-diamine for (3-{[2-(2-nitro-phenylamino)-
ethylamino]-methyl}-phenyl)-piperidin-1-yl-methanone
as done for compound 15, step A, gave benzyl-[2-(2-ni-
tro-phenylamino)-ethyl]-carbamic acid tert-butyl ester,
the nitro group of which was reduced as for compound
6, step B, to provide [2-(2-amino-phenylamino)-ethyl]-
benzyl-carbamic acid tert-butyl ester. Substitution of the
ester and phenylisocyanate for [2-(2-amino-phenyl-
amino)-ethyl]-[3-(piperidine-1-carbonyl)-benzyl]-carb-
amic acid tert-butyl ester and methanesulfonylchloride
in the procedure of example 14, step A, gave benzyl-{2-
[2-(3-phenyl-ureido)-phenylamino]-ethyl}-carbamic acid
tert-butyl ester, which was converted to the title inter-
mediate as done for compound 15, step D. MS (ESI):
mass calculated for C22H24N4O, 360.20; m=z found,
361.2 [MþH]þ. 1H NMR (400 MHz, CDCl3) d 7.05–7.24
(m, 1H), 6.94–6.90 (m, J ¼ 7:3 Hz, 1H), 6.66–6.62 (m,
3H), 6.29 (br s, 1H), 4.53 (br s, 1H), 3.65 (s, 2H), 3.12 (t,
J ¼ 5:7 Hz, 2H), 2.80–2.75 (m, 2H).
5.17.2. B. 1-Benzyl-3-(2-{2-[3-(piperidine-1-carbonyl)-
benzylamino]-ethylamino}-phenyl)-urea. The title com-
pound was prepared similarly to 4a, steps D and E
substituting 1-[2-(2-amino-ethylamino)-phenyl]-3-benz-
yl-urea for N1-(2-isoproxy-phenyl)-ethane-1,2-diamine
in step E. MS (ESI): mass calculated for C29H35N5O2,
485.28, m=z found, 486.3 [MþH]þ. 1H NMR (400 MHz,
CD3OD) d 7.43–7.11 (m, 11H), 6.75 (d, J ¼ 7:6 Hz, 1H),
6.67 (dt, J ¼ 7:6, 1.1 Hz, 1H), 4.32 (s, 2H), 3.84 (s, 2H),
3.64 (br s, 2H), 4.06 (t, J ¼ 5:8 Hz, 2H), 3.02 (t,
J ¼ 5:8 Hz, 2H), 1.75–1.45 (m, 4H), 1.47 (br s, 2H).
5.18. (3-{[2-(2-Bromo-phenylamino)-ethylamino]-methyl}-
phenyl)-piperidin-1-yl-methanone (19)
5.16.3. C. 1-[2-(2-Amino-ethylamino)-phenyl]-3-phenyl-
urea. The title intermediate was prepared similarly to
compound 6, step B, substituting 1-[2-(2-benzylamino-
ethylamino)-phenyl]-3-phenyl-urea for 1-cyclopentyl-
oxy-2-nitro-benzene. MS (ESI): mass calculated for
C15H18N4O, 370.15; m=z found, 371.1 [MþH]þ. 1H
NMR (400 MHz, CDCl3) d 7.13–7.35 (m, 6H), 7.03–6.99
(m, 1H), 6.78–6.69 (m, 2H), 3.20–3.10 (m, 2H), 2.90–
2.85 (m, 2H), 2.00–2.40 (br m, 3H).
The title compound was prepared similarly to 4a, steps
C–E, substituting 2-bromo-phenylamine for 2-isoprop-
oxy-phenylamine in step C.
5.18.1. A. N1-(2-Bromo-phenyl)-ethane-1,2-diamine. MS
(ESI): mass calculated for C8H11BrN2, 214.01; m=z
1
found, 215.0 [MþH]þ. H NMR (400 MHz, CDCl3) d
7.42 (dd, J ¼ 7:8, 1.5 Hz, 1H), 7.18 (dt, J ¼ 7:4, 1.5 Hz,
1H), 6.67 (dd, J ¼ 8:1, 1.3 Hz, 1H), 6.58 (dt, J ¼ 8:0,
1.4 Hz, 1H), 3.28 (t, J ¼ 5:7 Hz, 2H), 3.04 (br s, 3H),
2.95 (t, J ¼ 5:9 Hz, 2H). 13C NMR (100 MHz, CDCl3) d
144.5, 132.5, 128.7, 117.7, 111.4, 108.8, 41.2, 37.4.
5.16.4. D. 1-Phenyl-3-(2-{2-[3-(piperidine-1-carbonyl)-
benzylamino]-ethylamino}-phenyl)-urea. The title com-
pound was prepared similarly to 4a, steps D and E,

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R. L. Wolin et al. / Bioorg. Med. Chem. 12 (2004) 4511–4532
5.18.2. B. (3-{[2-(2-Bromo-phenylamino)-ethylamino]-
methyl}-phenyl)-piperidin-1-yl-methanone. MS (ESI):
mass calculated for C21H26BrN3O, 415.13; m=z found,
416.1 [MþH]þ. 1H NMR (400 MHz, CDCl3) d 7.41–7.38
(m, 4H), 7.35–7.32 (m, 1H), 7.27–7.24 (m, 1H), 6.63–
6.61 (m 1H), 6.55 (t, J ¼ 7:5 Hz, 1H), 4.85 (br s, 1H),
3.84 (br s, 2H), 3.69 (br s, 2H), 3.31–3.23 (m, 4H), 2.94–
2.92 (m, 2H), 1.83–1.48 (m, 7H). 13C NMR (100 MHz,
CDCl3) d 170.2, 145.1, 140.5, 136.6, 132.3, 128.9, 128.4,
126.3, 125.3, 117.6, 111.3, 109.8, 53.0, 48.7, 47.5, 43.1,
26.4, 25.5, 24.5.
5.21. (3-{[2-(3-Chloro-phenylamino)-ethylamino]-methyl}-
phenyl)-piperidin-1-yl-methanone (22)
The title compound was prepared analogously to com-
pound 21, substituting 3-chloroaniline for 3-bromoani-
line. MS (ESI): mass calculated for C21H26ClN3O, 371.9;
m=z found, 372.2 [MþH]þ. 1H NMR (400 MHz, CDCl3)
d 7.29 (br s, 3H), 7.19 (br s, 1H), 6.98 (br t, J ¼ 7:9 Hz,
1H), 6.57 (d, J ¼ 7:6 Hz, 1H), 6.51 (br s, 1H), 6.41 (d,
J ¼ 7:7 Hz, 1H), 3.76 (br s, 2H), 3.63 (br s, 2H), 3.24 (br
s, 2H), 3.11 (br s, 2H), 1.60–1.43 (m, 6H).
5.19. (3-{[2-(2-Chloro-phenylamino)-ethylamino]-methyl}-
phenyl)-piperidin-1-yl-methanone (20)
5.22. (3-{[2-(2-Isopropyl-phenylamino)-ethylamino]-meth-
yl}-phenyl)-piperidin-1-yl-methanone (23)
The title compound was prepared analogously to com-
pound 21, substituting 2-chloroaniline for 3-bromoani-
line. MS (ESI): mass calculated for C26H23ClN3O,
371.18; m=z found, 372.2 [MþH]þ. 1H NMR (400 MHz,
CHCl3) d 7.40–7.10 (m, 6H), 6.91 (dd, J ¼ 8:0, 1.3 Hz,
1H), 6.84 (dt, J ¼ 7:8, 1.3 Hz, 1H), 6.66–6.59 (m, 2H),
4.82 (br s, 1H), 3.85 (s, 2H), 3.66 (br s, 2H), 3.40–
3.25 (m, 4H), 2.93 (t, J ¼ 5:6 Hz, 2H), 1.74–1.49 (m,
8H).
The title compound was prepared similarly to 4a, steps
C–E substituting 2-isopropyl-phenylamine for 2-iso-
propoxy-phenylamine in step C.
5.22.1. A. N1-(2-Isopropyl-phenyl)-ethane-1,2-diamine.
MS (ESI): mass calculated for C11H18N2, 178.15; m=z
1
found, 179.2 [MþH]þ. H NMR (400 MHz, CDCl3) d
7.14 (dd, J ¼ 7:6, 1.4 Hz, 1H), 7.09 (dt, J ¼ 7:7, 1.4 Hz,
1H), 6.73 (dt, J ¼ 7:5, 1.0 Hz, 1H), 6.64 (d, J ¼ 8:0 Hz,
1H), 3.25 (t, J ¼ 5:5 Hz, 2H), 2.99 (t, J ¼ 6:0 Hz, 2H),
2.94 (hp, J ¼ 6:7 Hz, 1H), 1.24 (d, J ¼ 6:7 Hz, 6H). 13C
NMR (100 MHz, CDCl3) d 144.7, 132.6, 126.6, 125.0,
117.5, 110.5, 45.8, 40.7, 27.0, 22.3.
5.20. (3{[2-(3-Bromo-phenylamino)-ethylamino]-methyl}-
phenyl)-piperidin-1-yl-methanone (21)
To a solution of 3-bromoaniline (0.50 g, 2.9 mmol) in
diethyl ether (Et2O, 5 mL) was added 4 M HCl in
dioxane (1 mL), and the mixture was stirred at 25 °C for
1 h. Solvent was removed under reduced pressure, and
the resulting HCl salt was dissolved in 2-(2-methoxy-
ethoxyl)ethanol (2 mL). 2-Oxazolidinone (0.429 g,
4.93 mmol) was added, and the reaction mixture was
heated to 180 °C for 24 h. The collected crude solid was
purified by column chromatography (0–10% (1%
NH4OH in MeOH)/CH2Cl2) to provide N1-(3-bromo-
phenyl)-ethane-1,2-diamine (0.10 g, 16%). 3-(Piperidine-
1-carbonyl)-benzaldehyde (example 1, step D; 0.091 g,
0.42 mmol) was added to a solution of the phenyl-dia-
mine in 1,2-dichloroethane (10 mL), and the reaction
mixture was stirred at 25 °C for 15 min. The mixture was
treated with NaBH(OAc)3 (0.128 g, 0.604 mmol), and
the resulting suspension was stirred at 25 °C for 18 h.
The suspension was partitioned with saturated NH4Cl
(20 mL) and CH2Cl2 (20 mL), and the aqueous layer was
extracted with CH2Cl2 (3 ꢂ 20 mL). The combined or-
ganic layers were washed with brine (50 mL), dried
(MgSO4), filtered, and concentrated under reduced
pressure. The crude residue was purified by column
chromatography (2–10% CH3OH/CH2Cl2) and then by
preparative TLC (10% CH3OH/CH2Cl2) to provide the
desired product (0.060 g, 34%). MS (ESI): mass calcu-
lated for C21H26BrN3O, 415.13; m=z found, 416.1
5.22.2. B. (3-{[2-(2-Isopropyl-phenylamino)-ethylamino]-
methyl}-phenyl)-piperidin-1-yl-methanone. MS (ESI):
mass calculated for C24H33N3O, 379.26; m=z found,
380.3 [MþH]þ, 402 [MþNa]þ. 1H NMR (400 MHz,
CDCl3) d 7.38–7.31 (m, 3H), 7.26–7.24 (m, 1H), 7.15–
7.08 (m, 2H), 6.73 (dt, J ¼ 7:5, 1.0 Hz, 1H), 6.63 (dd,
J ¼ 7:8, 1.0 Hz, 1H), 3.84 (s, 2H), 3.69 (br s, 2H), 3.30–
3.23 (m, containing a t at 3.25, J ¼ 5:4 Hz, 4H), 2.97–
2.89 (m, 3H), 1.66 (br s, 4H), 1.48 (br s, 2H), 1.26 (d,
J ¼ 6:8 Hz, 6H). 13C NMR (100 MHz, CDCl3) d 145.1,
140.4, 136.6, 132.5, 128.9, 128.4, 126.6, 126.4, 125.3,
124.9, 117.2, 110.5, 53.0, 48.7, 47.8, 43.3, 27.1, 26.5,
25.6, 24.5, 22.3.
5.23. Piperidin-1-yl-(3-{[2-(2-thiophen-3-yl-phenylamino)-
ethylamino]-methyl}-phenyl)-methanone (24)
Piperidin-1-yl-(3-{[2-(2-thiophen-3-yl-phenylamino)-eth-
ylamino]-methyl}-phenyl)-methanone
To a solution of (3-{[2-(2-bromo-phenylamino)-ethyl-
amino]-methyl}-phenyl)-piperidin-1-yl-methanone (0.06
g, 0.144 mmol) and 3-thiopheneboronic acid (0.037 g,
0.246 mmol) in 2 M Na2CO3/EtOH/toluene (1:1:4, 6 mL)
was added Pd(PPh3)4 (0.014 g, 0.0123 mmol) and the
resulting solution was stirred to reflux for 16 h. The
solution was treated with EtOAc (20 mmL), aqueous
saturated NaHCO3 (20 mL) and the aqueous layer was
extracted with EtOAc (3 ꢂ 30 mL). The combined or-
ganic layers were washed with brined, dried (MgSO4),
1
[MþH]þ. H NMR (400 MHz, CDCl3) d 7.28–7.26 (m,
3H), 7.21–7.16 (m, 1H), 6.93 (t, J ¼ 8:0 Hz, 1H), 6.74–
6.71 (m, 1H), 6.67 (t, J ¼ 2:0 Hz, 1H), 6.47–6.44 (m,
1H), 4.23 (br s, 1H), 3.75 (s, 2H), 3.64 (br s, 2H), 3.25 (br
s, 2H), 3.10 (t, J ¼ 5:6 Hz, 2H), 2.83–2.80 (m, 2H), 1.60–
1.43 (m, 6H).

R. L. Wolin et al. / Bioorg. Med. Chem. 12 (2004) 4511–4532
4525
filtered, and the solvent was removed under reduced
pressure. The crude residue was purified by preparative
TLC (10% MeOH/CH2Cl2) to provide the desired
product 0.0168 g (28%) as a tan oil. MS (ESI): mass
calculated for C25H29N3OS, 419.20; m=z found, 420.2
and concentrated under reduced pressure. The crude
residue was purified by preparative TLC (2% CH3OH/
CH2Cl2) to provide a colorless oil (0.015 g, 47%). MS
(ESI): mass calculated for C26H35N3O2, 409.27; m=z
found, 410.5 [MþH]þ, 432.4 [MþNa]þ. 1H NMR
(400 MHz, CDCl3) d 7.46 (d, J ¼ 7:6 Hz, 1H), 7.36–7.31
(m, 2H), 7.27–7.25 (m, 1H), 6.84 (dt, J ¼ 7:8, 1.3 Hz,
1H), 6.78 (dt, J ¼ 7:8, 1.3 Hz, 1H), 6.63 (dt, J ¼ 7:8,
1.6 Hz, 1H), 6.58 (dt, J ¼ 7:8, 1.6 Hz, 1H), 4.53 (hp,
J ¼ 6:1 Hz, 1H), 3.70 (br s, 2H), 3.60 (br s, 2H), 3.31 (br
s, 2H), 3.20 (t, J ¼ 6:1 Hz, 2H), 2.73 (t, J ¼ 6:1 Hz, 2H),
2.20 (s, 3H), 1.62–1.46 (m, 6H), 1.37 (d, J ¼ 6:1 Hz, 6H).
1
[MþH]þ. H NMR (400 MHz, CDCl3) d 7.35–7.16 (m,
10H), 6.76–6.69 (m, 2H), 3.79 (br s, 2H), 3.70 (br s, 2H),
3.30–3.24 (m, 4H), 2.88 (t, J ¼ 6:0 Hz, 2H), 1.66–1.48
(br m, 6H).
5.24. (3-{[3-(2-Isopropoxy-phenoxy)-propylamino]-meth-
yl}-phenyl)-piperidin-1-yl-methanone (25)
5.26. [(3-({2-[(2-Isopropoxy-phenyl)-methyl-amino]-ethyl-
amino}-methyl)-phenyl]-piperidin-1-yl-methanone (27)
The title compound was prepared similarly to com-
pound 24, substituting 2-methoxybenzeneboronic acid
for 3-thiopheneboronic acid.
5.26.1.
A.
[2-(2-Isopropoxy-phenylamino)-ethyl]-[3-
(piperidine-1-carbonyl)-benzyl]-carbamic acid tert-butyl
ester. To a solution of (3-{[2-(2-isopropoxy-phen-
ylamino)-ethylamino]-methyl}-phenyl)-piperidin-1-yl-
methanone (0.133 g, 0.336 mmol) in CH2Cl2 (3.5 mL)
was added di-tert-butyl dicarbonate (0.073 g, 0.33
mmol), and the resulting solution was stirred at 25 °C
for 45 min. The solvent was removed under reduced
pressure, and the crude residue was purified by column
chromatography (0–5% CH3OH/CH2Cl2) to provide a
colorless oil (0.144 g, 86%). 1H NMR (CDCl3, 400 MHz)
d 7.35–7.32 (m, 1H), 7.28–7.22 (m, 4H), 6.83–6.76 (m,
2H), 6.64–6.57 (m, 2H), 4.55–4.45 (m, 3H), 3.68 (br s,
2H), 3.50 (br s, 1H), 3.37 (br s, 1H), 3.31–3.26 (m, 5H),
1.66–1.62 (m, 6H), 1.50 (br s, 9H), 1.34 (d, J ¼ 6:1 Hz,
6H).
5.24.1. A. 2-[3-(2-Isopropoxy-phenoxy)-propyl]-isoindole-
1,3-dione. The crude residue was purified by column
chromatography (5–20% EtOAc/hex) to provide the
desire product 0.956 g (87%). 1H NMR (400 MHz,
CDCl3) d 7.87–7.82 (m, 2H), 7.73–7.69 (m, 2H), 6.93–
6.86 (m, 4H), 4.46 (hp, J ¼ 6:1 Hz, 1H), 4.06 (t,
J ¼ 6:2 Hz, 2H), 3.92 (t, J ¼ 7:1 Hz, 2H), 2.20 (p,
J ¼ 6:4 Hz, 2H), 1.33 (d, J ¼ 6:1 Hz, 6H).
5.24.2. B. 3-(2-Isopropoxy-phenoxy)-propylamine. The
resulting residue was purified by column chromatogra-
phy (20–50% EtOAc/hex) to provide the desired product
0.267 g (45%). MS (electrospray): exact mass calculated
1
for C12H19NO2, 209.29, m=z found, 210.2, [MþH]þ. H
NMR (400 MHz, CDCl3) d 6.91–6.83 (m, 4H), 4.46 (hp,
J ¼ 6:1 Hz, 1H), 4.07 (t, J ¼ 5:9 Hz, 2H), 2.97 (t,
J ¼ 6:5 Hz, 2H), 1.99 (p, J ¼ 6:2 Hz, 2H), 1.32 (d,
J ¼ 6:1 Hz, 6H).
5.26.2. B. {2-[(2-Isopropoxy-phenyl)-methyl-amino]-
ethyl}-[3-(piperidine-1-carbonyl)-benzyl]-carbamic acid
tert-butyl ester. To a solution of [2-(2-isopropoxy-phen-
ylamino)-ethyl]-[3-(piperidine-1-carbonyl)-benzyl]-car-
bamic acid tert-butyl ester (0.077 g, 0.16 mmol) in DMF
(1.6 mL) cooled to 0 °C was added NaH (0.062 g,
1.6 mmol), and the resulting suspension was allowed to
warm to 25 °C over 30 min. The suspension was cooled
to 0 °C, and iodomethane (0.22 g, 1.6 mmol) was added.
This suspension was allowed to warm to 25 °C over 4 h
and then was partitioned with EtOAc (25 mL) and H2O
(25 mL). The aqueous layer was back-extracted with
EtOAc (25 mL). The combined organic layers were
washed with brine (25 mL), dried (Na2SO4) and filtered,
and the filtrate was concentrated under reduced pres-
sure. The crude residue was purified by preparative TLC
(5% CH3OH/CH2Cl2) to provide a colorless oil (0.028 g,
35%). MS (ESI): mass calculated for C30H43N3O4,
509.33; m=z found, 510.5 [MþH]þ.
5.24.3. C. (3-{[3-(2-Isopropoxy-phenoxy)-propylamino]-
methyl}-phenyl)-piperidin-1-yl-methanone. MS (electro-
spray): exact mass calculated for C25H34N2O3, 410.26,
m=z found, 411.4, [MþH]þ. 1H NMR (400 MHz,
CDCl3) d 7.41–7.38 (m, 2H), 7.33 (t, J ¼ 7:5 Hz, 1H),
7.27–7.25 (m, 1H), 6.95–6.85 (m, 4H), 4.45 (hp,
J ¼ 6:1 Hz, 1H), 4.08 (t, J ¼ 6:0 Hz, 2H), 3.87 (br s,
2H), 3.69 (br s, 2H), 3.31 (br s, 2H), 2.87 (t, J ¼ 6:6 Hz,
2H), 2.06–2.00 (m, 2H), 1.65 (br s, 4H), 1.48 (br s, 2H),
1.31 (d, J ¼ 6:1 Hz, 6H).
5.25. [3-({[2-(2-Isopropoxy-phenylamino)-ethyl]-methyl-
amino}-methyl)-phenyl]-piperidin-1-yl-methanone (26)
To a solution of (3-{[2-(2-isopropoxy-phenylamino)-
ethylamino]-methyl}-phenyl)-piperidin-1-yl-methanone
(0.032 g, 0.081 mmol) in DMF (0.8 mL) was added
K2CO3 (0.022 g, 0.16 mmol) and iodomethane (0.03 g,
0.2 mmol), and the resulting suspension was stirred at
25 °C for 45 min. The suspension was partitioned with
EtOAc (20 mL) and H2O (20 mL), and the organic layer
was washed with brine (20 mL), dried (Na2SO4), filtered,
5.26.3. C. [3-({2-[(2-Isopropoxy-phenyl)-methyl-amino]-
ethylamino}-methyl)-phenyl]-piperidin-1-yl-methanone.
The title compound was prepared analogously to com-
pound 15, step D, substituting {2-[(2-isopropoxy-
phenyl)-methyl-amino]-ethyl}-[3-(piperidine-1-carbonyl)-
benzyl]-carbamic acid tert-butyl ester for [2-(2-iso-
propylamino-phenylamino)-ethyl]-[3-(piperidine-1-car-
bonyl)-benzyl]-carbamic acid tert-butyl ester. MS (ESI):

4526
R. L. Wolin et al. / Bioorg. Med. Chem. 12 (2004) 4511–4532
mass calculated for C25H35N3O2, 409.27; m=z found,
bined organic layers were washed with brine (40 mL),
dried (MgSO4), and filtered. The filtrate was concen-
trated under reduced pressure. The crude residue was
purified by preparative TLC (5% CH3OH/CH2Cl2) to
provide a tan oil (8.7 mg, 18%). MS (ESI): mass calcu-
lated for C26H37N3O2, 423.29; m=z found, 424.5
1
410.4 [MþH]þ, 432.4 [MþNa]þ. H NMR (400 MHz,
CDCl3) d 7.44–7.33 (m, 4H), 7.06–7.00 (m, 2H), 6.93–
6.88 (m, 2H), 4.55 (hp, J ¼ 6:0 Hz, 1H), 4.02 (s, 2H),
3.69 (br s, 2H), 3.31 (br s, 2H), 3.19 (t, J ¼ 5:9 Hz, 2H),
2.90 (t, J ¼ 5:9 Hz, 2H), 2.70 (s, 3H), 1.66 (br s, 4H),
1.49 (br s, 2H), 1.29 (d, J ¼ 6:0 Hz, 6H).
1
[MþH]þ. H NMR (400 MHz, CDCl3) d 7.42–7.26 (m,
4H), 7.08 (t, J ¼ 8:1 Hz, 1H), 6.29–6.21 (m, 3H), 4.52
(hp, J ¼ 6:0 Hz, 1H), 3.70–3.31 (br m, 8 H), 2.92 (br s,
3H), 2.68 (br s, 2H), 2.33 (br s, 3H), 1.67–1.50 (br m,
8H), 1.32 (d, J ¼ 6:0 Hz, 6H).
5.27. {3-[({2-[(2-Isopropoxy-phenyl)-methyl-amino]-ethyl}-
methyl-amino)-methyl]-phenyl}-piperidin-1-yl-methanone
(28)
MS (ESI): mass calculated for C26H37N3O2, 323.29; m=z
5.30. (3-{[2-(2-Isopropoxy-phenoxy)-ethylamino]-methyl}-
phenyl)-piperidin-1-yl-methanone (31)
1
found, 324.5 [MþH]þ. H NMR (400 MHz, CDCl3) d
7.71 (dd, J ¼ 5:9, 3.3 Hz, 1H), 7.53 (dd, J ¼ 5:9, 3.3 Hz,
1H), 7.30–7.33 (m, 2H), 6.93–6.82 (m, 4H), 4.59 (hp,
J ¼ 6:1 Hz, 1H), 3.70 (br s, 2H), 3.52 (s, 2H), 3.31 (br s,
2H), 3.25 (t, J ¼ 7:3 Hz, 2H), 2.80 (s, 3H), 2.63 (t,
J ¼ 7:3 Hz, 2H), 2.19 (s, 3H), 1.67 (br s, 6H), 1.35 (d,
J ¼ 6:1 Hz, 6H).
5.30.1. A. [2-(2-Isopropoxy-phenoxy)-ethyl]-carbamic
acid tert-butyl ester. To a solution of 2-isopropoxy-
phenol (0.50 g, 3.3 mmol) in THF (5 mL) was added a
suspension of polymer-supported PPh3 (2.2 g) and (2-
hydroxy-ethyl)-carbamic acid tert-butyl ester (0.53 g,
3.3 mmol) in THF (2 mL). The mixture was cooled to
0 °C, treated with di-tert-butylazodicarboxylate (1.1 g,
4.9 mmol), and then allowed to warm to 25 °C over 18 h.
The resulting mixture was filtered (Celiteâ), and the fil-
trate was concentrated under reduced pressure. The
crude residue was purified by column chromatography
(520% EtOAc/hexanes) to provide the desired product
5.28. [3-({[2-(3-Isopropoxy-phenylamino)-ethyl]-methyl-
amino}-methyl)-phenyl]-piperidin-1-yl-methanone (29)
To a solution of (3-{[2-(3-isopropoxy-phenylamino)-
ethylamino]-methyl}-phenyl)-piperidin-1-yl-methanone
(0.048 g, 0.12 mmol) in CH3CN (10 mL) was added a
solution of formaldehyde (0.0029 g, 0.097 mmol) in
CH3CN (5 mL), followed by sodium cyanoborohydride
(0.006 g, 0.1 mmol) and acetic acid (two drops), and the
resulting solution was stirred at 25 °C for 15 h. The
solution was treated with aqueous satd NaHCO3
(20 mL), H2O (20 mL) and EtOAc (30 mL). The aqueous
layer was back-extracted with EtOAc (3 ꢂ 40 mL), and
the combined organic layers were washed with brine
(40 mL), dried (MgSO4), and filtered. The filtrate was
concentrated under reduced pressure. The crude residue
was purified by preparative TLC (5% CH3OH/CH2Cl2)
to provide a tan oil (0.0063 g, 13%). MS (ESI): mass
calculated for C25H35N3O2, 409.27; m=z found, 410.2
1
(0.75 g, 78%). H NMR (400 MHz, CDCl3) d 6.97–6.88
(m, 4H), 4.49 (hp, J ¼ 6:1 Hz, 1H), 4.06 (t, J ¼ 5:1 Hz,
2H), 3.50–3.46 (m, 2H), 1.45 (s, 9H), 1.37 (d, J ¼ 6:1 Hz,
6H).
5.30.2. B. (3-{[2-(2-Isopropoxy-phenoxy)-ethylamino]-
methyl}-phenyl)-piperidin-1-yl-methanone. Substitution
of [2-(2-isopropoxy-phenoxy)-ethyl]-carbamic acid tert-
butyl ester for [2-(2-isopropylamino-phenylamino)-
ethyl]-[3-(piperidine-1-carbonyl)-benzyl]-carbamic acid
tert-butyl ester in compound 15, step D, provided 2-(2-
isopropoxy-phenoxy)-ethylamine. Using the procedure
similar to 4a, steps D and E, the amine intermediate was
then converted to the title compound by its substitution
for 2-isopropoxy-phenyl-ethane-1,2-diamine in step E.
MS (ESI): mass calculated for C24H32N2O3, 396.24; m=z
1
[MþH]þ. H NMR (400 MHz, CDCl3) d 7.39–7.26 (m,
4H), 7.04 (t, J ¼ 8:0 Hz, 1H), 6.26–6.16 (m, 3H), 4.15
(hp, J ¼ 6:0 Hz, 1H), 3.71–3.61 (m, 4H), 3.31–3.20 (m,
4H), 2.72 (br s, 2H), 2.26 (br s, 2H), 1.66–1.50 (m, 8H),
1.32 (d, J ¼ 6:0 Hz, 6H).
1
found, 397.2 [MþH]þ. H NMR (400 MHz, CDCl3) d
7.43–7.34 (m, 3H), 7.28–7.26 (m, 1H), 6.96–6.89 (m,
4H), 4.47 (hp, J ¼ 6:1 Hz, 1H), 4.13 (t, J ¼ 5:04 Hz,
2H), 3.91 (br s, 2H), 3.70 (br s, 2H), 3.34 (br s, 2H), 3.03
(t, J ¼ 5:0 Hz, 2H), 1.67 (br s, 4H), 1.51 (br s, 2H), 2.63
(d, J ¼ 6:1 Hz, 6H).
5.29. {3-[({2-[(3-Isopropoxy-phenyl)-methyl-amino]-ethyl}-
methyl-amino)-methyl]-phenyl}-piperidin-1-yl-methanone
(30)
To a solution of (3-{[2-(3-isopropoxy-phenylamino)-
ethylamino]-methyl}-phenyl)-piperidin-1-yl-methanone
(0.048 g, 0.12 mmol) in CH3CN (10 mL) was added a
solution of formaldehyde (0.040 g, 1.3 mmol) in CH3CN
(5 mL), sodium cyanoborohydride (0.080 g, 1.3 mmol)
and acetic acid (two drops), and the resulting solution
was stirred at 25 °C for 15 h. The reaction mixture was
treated with aqueous saturated NaHCO3 (20 mL), H2O
(20 mL) and EtOAc (30 mL). The aqueous layer was
back-extracted with EtOAc (3 ꢂ 40 mL), and the com-
5.31. (3-{[3-(2-Isopropoxy-phenoxy)-propylamino]-meth-
yl}-phenyl)-piperidin-1-yl-methanone (32)
5.31.1. A. 2-[3-(2-Isopropoxy-phenoxy)-propyl]-isoindole-
1,3-dione. To a solution of 2-isopropoxy-phenol (0.50 g,
3.3 mmol) in DMF (5 mL) was added K2CO3 (2.3 g,
17 mmol), and the resulting suspension was stirred at
25 °C for 15 min. A solution of 2-(3-bromo-propyl)-is-
oindole-1,3-dione (0.97 g, 3.6 mmol) in DMF (2 mL) was
added, and the reaction mixture was heated to 80 °C for

R. L. Wolin et al. / Bioorg. Med. Chem. 12 (2004) 4511–4532
4527
1
18 h. The mixture was filtered, and the filtrate was di-
luted with 1:1 Et2O/EtOAc (100 mL), washed with H2O
(2 ꢂ 20 mL) then brine (20 mL), dried (MgSO4), filtered,
and concentrated under reduced pressure. The crude
residue was purified by column chromatography (5–20%
EtOAc/hexanes) to provide the desire product (0.956 g,
87%). 1H NMR (400 MHz, CDCl3) d 7.87–7.82 (m, 2H),
7.73–7.69 (m, 2H), 6.93–6.86 (m, 4H), 4.46 (hp,
J ¼ 6:1 Hz, 1H), 4.06 (t, J ¼ 6:2 Hz, 2H), 3.92 (t,
J ¼ 7:1 Hz, 2H), 2.20 (p, J ¼ 6:4 Hz, 2H), 1.33 (d,
J ¼ 6:1 Hz, 6H).
clear oil. H NMR (400 MHz, CDCl3) d 7.17–7.12 (m,
2H), 6.85–6.81 (m, 2H), 4.99 (hp, J ¼ 6:3 Hz, 1H), 4.56
(hp, J ¼ 6:1 Hz, 1H), 2.91 (t, J ¼ 7:8 Hz, 2H), 2.57 (t,
J ¼ 7:8 Hz, 2H), 1.34 (d, J ¼ 6:1 Hz, 6H), 1.20 (d,
J ¼ 6:3 Hz, 6H).
5.32.2. B. 3-(2-Isopropoxy-phenyl)-propionamide. To a
solution of 3-(2-isopropoxy-phenyl)-propionic acid iso-
propyl ester (0.19 g, 0.8 mmol) in methanol (6.0 mL) in a
sealed tube cooled to ꢁ78 °C was bubbled nitrogen for
5 min. The solution was sealed and allowed to warm to
25 °C and stirred for 24 h. The solution was cooled to
ꢁ78 °C, uncapped, transferred to a flask and the solvent
was removed under reduced pressure. The crude residue
was purified by column chromatography (0–15%
MeOH–CH2Cl2) to provide the desired product 0.10 g
(69%) as white solid. 1H NMR (400 MHz, CDCl3) d
7.19–7.15 (m, 2H), 6.88–6.84 (m, 2H), 5.47 (br s, 1H),
5.27 (br s, 1H), 4.58 (hp, J ¼ 6:1 Hz, 1H), 2.94 (t,
J ¼ 7:7 Hz, 2H), 2.57 (t, J ¼ 7:7 Hz, 2H), 1.35 (d,
J ¼ 6:0 Hz, 6H).
5.31.2. B. 3-(2-Isopropoxy-phenoxy)-propylamine. To a
solution of 2-[3-(2-isopropoxy-phenoxy)-propyl]-isoin-
dole-1,3-dione in EtOH (6 mL) was added hydrazine
(0.448 g, 14.0 mmol), and the reaction mixture was he-
ated to 50 °C for 30 min. The solvent was removed under
reduced pressure, and the crude residue was partitioned
between CH2Cl2 (50 mL) and H2O (50 mL). The aque-
ous layer was extracted with CH2Cl2 (3 ꢂ 50 mL), and
the combined organic layers were washed with brine,
dried (MgSO4), filtered, and concentrated under reduced
pressure. The resulting residue was purified by column
chromatography (20–50% EtOAc/hexanes) to provide
the desired product (0.267 g, 45%). MS (ESI): mass
calculated for C12H19NO2, 209.29; m=z found, 210.2
5.32.3. C. 3-(2-Isopropoxy-phenyl)-propylamine. To a
solution of 3-(2-isopropoxy-phenyl)-propionamide
(0.07 g, 0.34 mmol) in THF (6.8 mL) was added lithium
aluminum hydride (0.05 g, 1.35 mmol) and the resulting
suspension was stirred at reflux for 2 h. The suspension
was cooled to 0 °C and treated sequentially with H2O
(0.10 mL), 10% NaOH (0.10 mL) and H2O (0.15 mL).
The resulting solid was filtered and washed with EtOAc
(50 mL), and the organic layer dried (Na2SO4), filtered,
and the solvent was removed under reduced pressure to
provide the desired product 0.05 g (65%) as a colorless
oil. MS (electrospray): exact mass calculated for
C12H19NO, 193.15, m=z found, 194.2 [MþH]þ.
1
[MþH]þ. H NMR (400 MHz, CDCl3) d 6.91–6.83 (m,
4H), 4.46 (hp, J ¼ 6:1 Hz, 1H), 4.07 (t, J ¼ 5:9 Hz, 2H),
2.97 (t, J ¼ 6:5 Hz, 2H), 1.99 (p, J ¼ 6:2 Hz, 2H), 1.32
(d, J ¼ 6:1 Hz, 6H).
5.31.3. C. (3-{[3-(2-Isopropoxy-phenoxy)-propylamino]-
title
methyl}-phenyl)-piperidin-1-yl-methanone.
The
compound was prepared similarly to 4a steps D and
Esubstituting 3-(2-isopropoxy-phenoxy)-propylamine
for N1-(2-isopropoxy-phenyl)-ethane-1,2-diamine. MS
(ESI): mass calculated for C25H34N2O3, 410.26; m=z
1
found, 411.4 [MþH]þ. H NMR (400 MHz, CDCl3) d
5.32.4. D. (3-{[3-(2-Isopropoxy-phenyl)-propylamino]-
methyl}-phenyl)-piperidin-1-yl-methanone. MS (electro-
spray): exact mass calculated for C25H34N2O2, 394.26,
7.41–7.38 (m, 2H), 7.33 (t, J ¼ 7:5 Hz, 1H), 7.27–7.25
(m, 1H), 6.95–6.85 (m, 4H), 4.45 (hp, J ¼ 6:1 Hz, 1H),
4.08 (t, J ¼ 6:0 Hz, 2H), 3.87 (br s, 2H), 3.69 (br s, 2H),
3.31 (br s, 2H), 2.87 (t, J ¼ 6:6 Hz, 2H), 2.06–2.00 (m,
2H), 1.65 (br s, 4H), 1.48 (br s, 2H), 1.31 (d, J ¼ 6:1 Hz,
6H).
m=z found, 395.3 [MþH]þ, 417.3 [MþNa]þ. H NMR
1
(400 MHz, CDCl3) d 7.38–7.32 (m, 3H), 7.27–7.24
(m, 1H), 7.15–7.10 (m, 2H), 6.86–6.82 (m, 2H), 4.53
(hp, J ¼ 6:1 Hz, 1H), 3.81 (s, 2H), 3.70 (br s, 2H),
3.32 (br s, 2H), 2.68–2.62 (m, 4H), 1.85–1.77 (m, 2H),
1.67 (br s, 4H), 1.50 (br s, 2H), 1.32 (d, J ¼ 6:1 Hz,
6H).
5.32. (3-{[3-(2-Isopropoxy-phenyl)-propylamino]-methyl}-
phenyl)-piperidin-1-yl-methanone (33)
5.32.1. A. 3-(2-Isopropoxy-phenyl)-propionic acid isoprop-
yl ester. To a solution of 3-(2-hydroxy-phenyl)-prop-
ionic acid (0.94 g, 5.7 mmol) in DMF (11.3 mL) was
added K2CO3 (3.9 g, 28.3 mmol) and 2-iodopropane
(1.9 g, 11.3 mmol) and the resulting suspension was
stirred at 25 °C for 15 h. The suspension was partitioned
with EtOAc (75 mL) and H2O (50 mL) and the organic
layer was washed with 1 M NaOH (2 ꢂ 50 mL), brine
(50 mL), dried (Na2SO4), filtered, and the solvent was
removed under reduced pressure. The crude oil was
purified by column chromatography (0–30% EtOAc–
hexanes) to provide the desired product 0.51 g (36%) as a
5.33. (3-{[3-(2-Isopropoxy-phenyl)-propylamino]-methyl}-
phenyl)-piperidin-1-yl-methanone (34)
5.33.1. A. 3-(2-Isopropoxy-phenyl)-propionic acid isoprop-
yl ester. To a solution of 3-(2-hydroxy-phenyl)-prop-
ionic acid (0.94 g, 5.7 mmol) in DMF (11.3 mL) was
added K2CO3 (3.9 g, 28 mmol) and 2-iodopropane
(1.9 g, 11 mmol), and the resulting suspension was stir-
red at 25 °C for 15 h. The suspension was partitioned
with EtOAc (75 mL) and H2O (50 mL), and the organic
layer was washed with 1 M NaOH (2 ꢂ 50 mL) then
brine (50 mL), dried (Na2SO4), and filtered. The filtrate

4528
R. L. Wolin et al. / Bioorg. Med. Chem. 12 (2004) 4511–4532
was concentrated under reduced pressure yielding a
crude oil, which was purified by column chromatogra-
phy (0–30% EtOAc/hexanes) to provide a colorless oil
by K2CO3 (1.1 g, 7.9 mmol), and the suspension was
stirred at 25 °C for 2 h. The suspension was then diluted
with H2O (200 mL), and the resulting mixture was ex-
tracted with EtOAc (2 ꢂ 100 mL). The combined or-
ganic layers were washed with H2O (2 ꢂ 100 mL), dried
(Na2SO4) and filtered, and the filtrate was concentrated
under reduced pressure. The crude oil was purified by
column chromatography (0–30% EtOAc/hexanes) to
provide a light yellow solid (1.8 g, 76%). MS (ESI): mass
calculated for C16H13NO3 S, 299.06; m=z found, 432.4
[MþNa]þ. 1H NMR (400 MHz, CDCl3) d 7.85 (dd,
J ¼ 5:4, 3.0 Hz, 2H), 7.73 (dd, J ¼ 5:4, 3.0 Hz, 2H), 7.56
(d, J ¼ 8:0 Hz, 1H), 7.26–7.21 (m, 1H), 7.00 (s, 1H), 6.95
(dd, J ¼ 7:9, 1.3 Hz, 1H), 6.88 (dt, J ¼ 7:9, 1.3 Hz, 1H),
3.90 (t, J ¼ 6:2 Hz, 2H), 3.05 (t, J ¼ 6:2 Hz, 2H).
1
(0.51 g, 36%). H NMR (400 MHz, CDCl3) d 7.17–7.12
(m, 2H), 6.85–6.81 (m, 2H), 4.99 (hp, J ¼ 6:3 Hz, 1H),
4.56 (hp, J ¼ 6:1 Hz, 1H), 2.91 (t, J ¼ 7:8 Hz, 2H), 2.57
(t, J ¼ 7:8 Hz, 2H), 1.34 (d, J ¼ 6:1 Hz, 6H), 1.20 (d,
J ¼ 6:3 Hz, 6H).
5.33.2.
B.
3-(2-Isopropoxy-phenyl)-propionamide.
Ammonia gas was bubbled through a ꢁ78 °C solution
of 3-(2-isopropoxy-phenyl)-propionic acid isopropyl es-
ter (0.19 g, 0.76 mmol) in CH3OH (6.0 mL) for 5 min.
The reaction tube was sealed, and the solution was al-
lowed to warm to 25 °C, and stirred for 24 h. The
solution was then cooled to ꢁ78 °C, and the tube was
unsealed. The solution was concentrated under reduced
pressure. The crude residue was purified by column
chromatography (0–15% CH3OH/CH2Cl2) to provide a
white solid (0.10 g, 69%). 1H NMR (400 MHz, CDCl3) d
7.19–7.15 (m, 2H), 6.88–6.84 (m, 2H), 5.47 (br s, 1H),
5.27 (br s, 1H), 4.58 (hp, J ¼ 6:1 Hz, 1H), 2.94 (t,
J ¼ 7:7 Hz, 2H), 2.57 (t, J ¼ 7:7 Hz, 2H), 1.35 (d,
J ¼ 6:0 Hz, 6H).
5.34.2. B. 2-[2-(2-Isopropoxy-phenylsulfanyl)-ethyl]-iso-
indole-1,3-dione. The title intermediate was prepared
similarly to 4a, step A, substituting 2-[2-(2-hydroxy-
phenylsulfanyl)-ethyl]-isoindole-1,3-dione for 2-nitro-
phenol. MS (ESI): mass calculated for C19H19NO3S,
1
341.11; m=z found, 342.2 [MþH]þ, 364.1 [MþNa]þ. H
NMR (400 MHz, CDCl3) d 7.81 (dd, J ¼ 5:6, 3.1 Hz,
2H), 7.70 (dd, J ¼ 5:6, 3.1 Hz, 2H), 7.53 (dd, J ¼ 7:8,
1.7 Hz, 1H), 7.14–7.09 (m, 1H), 6.89–6.81 (m, 2H), 4.58
(hp, J ¼ 6:0 Hz, 1H), 3.91 (t, J ¼ 7:3 Hz, 2H), 3.21 (t,
J ¼ 7:3 Hz, 2H), 1.38 (d, J ¼ 6:0 Hz, 6H).
5.33.3. C. 3-(2-Isopropoxy-phenyl)-propylamine. To a
solution of 3-(2-isopropoxy-phenyl)-propionamide
(0.070 g, 0.34 mmol) in THF (6.8 mL) was added lithium
aluminum hydride (0.051 g, 1.34 mmol), and the result-
ing suspension was stirred at reflux for 2 h. The sus-
pension was cooled to 0 °C and treated sequentially with
H2O (0.10 mL), 10% NaOH (0.10 mL) and H2O
(0.15 mL). The resulting solid was filtered off and wa-
shed with EtOAc (50 mL). The combined filtrates were
dried (Na2SO4), filtered, and concentrated under re-
duced pressure to provide a colorless oil (0.050 g, 65%).
MS (ESI): mass calculated for C12H19NO, 193.15; m=z
found, 194.2 [MþH]þ.
5.34.3. C. 2-(2-Isopropoxy-phenylsulfanyl)-ethylamine.
The title intermediate was prepared analogously to
compound 32, step B, substituting 2-[2-(2-isopropoxy-
phenylsulfanyl)-ethyl]-isoindole-1,3-dione for 2-[3-(2-
isopropoxy-phenoxy)-propyl]-isoindole-1,3-dione. 1H
NMR (400 MHz, CDCl3) d 7.30 (dd, J ¼ 7:6, 1.5 Hz,
1H), 7.15 (dt, J ¼ 7:6, 1.5 Hz, 1H), 6.90–6.84 (m, 2H),
4.57 (hp, J ¼ 6:2 Hz, 1H), 2.96 (t, J ¼ 5:9 Hz, 2H), 2.86
(t, J ¼ 5:9 Hz, 2H), 1.52 (br s, 2H), 1.37 (d, J ¼ 6:2 Hz,
6H).
5.33.4. D. (3-{[3-(2-Isopropoxy-phenyl)-propylamino]-
methyl}-phenyl)-piperidin-1-yl-methanone.
5.34.4. D. (3-{[2-(2-Isopropoxy-phenylsulfanyl)-ethyl-
amino]-methyl}-phenyl)-piperidin-1-yl-methanone.
The
title
The
compound was prepared similarly to 4a, steps D and E,
substituting 3-(2-isopropoxy-phenyl)-propylamine for
N1-(2-isopropoxy-phenyl)-ethane-1,2-diamine in step E.
MS (ESI): mass calculated for C25H34N2O2, 394.26; m=z
found, 395.3 [MþH]þ, 417.3 [MþNa]þ. 1H NMR
(400 MHz, CDCl3) d 7.38–7.32 (m, 3H), 7.27–7.24 (m,
1H), 7.15–7.10 (m, 2H), 6.86–6.82 (m, 2H), 4.53 (hp,
J ¼ 6:1 Hz, 1H), 3.81 (s, 2H), 3.70 (br s, 2H), 3.32 (br s,
2H), 2.68–2.62 (m, 4H), 1.85–1.77 (m, 2H), 1.67 (br s,
4H), 1.50 (br s, 2H), 1.32 (d, J ¼ 6:1 Hz, 6H).
title compound was prepared similarly to 4a, steps D
and E, substituting 2-(2-isopropoxy-phenylsulfanyl)-
ethylamine for N1-(2-isopropoxy-phenyl)-ethane-1,2-
diamine in step D. MS (ESI): mass calculated for
C24H32N2O2S, 412.22; m=z found, 413.2 [MþH]þ, 435.2
[MþNa]þ. 1H NMR (400 MHz, CDCl3) d 7.35–7.23 (m,
5H), 7.15 (dt, J ¼ 7:7, 1.5 Hz, 1H), 6.89–6.84 (m, 2H),
4.57 (hp, J ¼ 6:2 Hz, 1H), 3.80 (s, 2H), 3.70 (br s, 2H),
3.31 (br s, 2H), 3.06 (t, J ¼ 6:4 Hz, 2H), 2.84 (t,
J ¼ 6:4 Hz, 2H), 1.94 (br s, 1H), 1.66 (br s, 4H), 1.49 (br
s, 2H), 1.36 (d, J ¼ 6:2 Hz, 6H).
5.34. (3-{[2-(2-Isopropoxy-phenylsulfanyl)-ethylamino]-
methyl}-phenyl)-piperidin-1-yl-methanone (35)
5.35. (5-{[2-(2-Isopropoxy-phenylamino)-ethylamino]-
methyl}-thiophen-3-yl)-piperidin-1-yl-methanone (36)
5.34.1. A. 2-[2-(2-Hydroxy-phenylsulfanyl)-ethyl]-isoin-
dole-1,3-dione. To a solution of 2-mercaptophenol
(1.0 g, 7.9 mmol) in DMF (80 mL) was added 2-(2-bro-
mo-ethyl)-isoindole-1,3-dione (1.8 g, 7.1 mmol) followed
5.35.1. A. 4-(Piperidine-1-carbonyl)-thiophene-2-carbal-
dehyde. The title intermediate was prepared similarly to
4a, step D, substituting 5-formyl-thiophene-3-carboxylic

R. L. Wolin et al. / Bioorg. Med. Chem. 12 (2004) 4511–4532
4529
acid for 3-formyl-benzoic acid. MS (ESI): mass calcu-
lated for C11H13NO2S, 223.29; m=z found, 224.0
[MþH]þ, 246.0 [MþNa]þ. 1H NMR (400 MHz, CDCl3)
9.92 (s, 1H), 7.83 (s, 1H), 7.83 (s, 1H), 3.68 (br s, 2H),
3.50 (br s, 2H), 1.71 (br s, 4H), 1.63 (br s, 2H).
(10 mL) and EtOAc (20 mL) and the organic layer was
washed with 1 N NaOH (10 mL), brine (10 mL), dried
(MgSO4), filtered, and the solvent was removed under
reduced pressure. The crude residue was purified by
preparative TLC (10% MeOH/CH2Cl2) to provide the
desired product 0.083 g (15%) as a tan oil. MS (elec-
trospray): exact mass calculated for C23H33N3O2,
383.26, m=z found, 384.3, [MþH]þ, 406.3, [MþNa]þ. 1H
NMR (400 MHz, CDCl3) d 7.39 (br d, J ¼ 7:5 Hz, 1H),
7.35–7.31 (m, 2H), 7.24 (br d, J ¼ 7:6 Hz, 1H), 6.83 (dt,
J ¼ 7:6, 1.3 Hz, 1H), 6.78–6.76 (m, 1H), 6.65–6.61 (m,
2H), 4.52 (hp, J ¼ 6:1 Hz, 1H), 3.85 (s, 3H), 3.53 (br s,
2H), 3.28 (t, J ¼ 5:9 Hz, 2H), 3.23 (br s, 2H), 2.92 (t,
J ¼ 6:0 Hz, 2H), 1.34 (d, J ¼ 6:1 Hz, 6H), 1.25–1.01 (br
m, 6H). 13C NMR (100 MHz, CDCl3) d 171.2, 145.0,
140.0, 139.2, 137.4, 128.9, 128.5, 126.1, 124.9, 121.2,
116.5, 112.6, 110.3, 70.6, 53.2, 48.0, 43.1, 39.2, 22.3,
14.2, 12.9.
5.35.2. B. (5-{[2-(2-Isopropoxy-phenylamino)-ethylamino]-
methyl}-thiophen-3-yl)-piperidin-1-yl-methanone.
The
title compound was prepared similarly to 4a, step E,
substituting 4-(piperidine-1-carbonyl)-thiophene-2-carb-
aldehyde for 3-(piperidine-1-carbonyl)-benzaldehyde.
MS (ESI): mass calculated for C22H31N3O2S, 401.21;
1
m=z found, 402.2 [MþH]þ, 424.2 [MþNa]þ. H NMR
(400 MHz, CDCl3) d 7.32 (d, J ¼ 1:4 Hz, 1H), 6.97 (d,
J ¼ 1:4 Hz, 1H), 6.84 (dt, J ¼ 7:8, 1.3 Hz, 1H), 6.78 (dd,
J ¼ 8:4, 1.1 Hz, 1H), 6.65–6.60 (m, 2H), 4.62 (br s, 1H),
4.52 (hp, J ¼ 6:2 Hz, 1H), 3.99 (s, 2H), 3.56 (br s, 4H),
3.25 (t, J ¼ 5:7 Hz, 2H), 2.94 (t, J ¼ 5:7 Hz, 2H), 1.66
(br s, 3H), 1.57 (br s, 3H), 1.36 (d, J ¼ 6:2 Hz, 6H).
5.37. 5-{[2-(2-Amino-phenylamino)-ethylamino]-methyl}-
thiophen-3-yl)-piperidin-1-yl-methanone (38)
5.36. N,N-Diethyl-3-{[2-(2-isopropoxy-phenylamino)-eth-
ylamino]-methyl}-benzamide (37)
5.37.1. A. (5-{[2-(2-Nitro-phenylamino)-ethylamino]-
The
methyl}-thiophen-3-yl)-piperidin-1-yl-methanone.
5.36.1. A. 3-{[2-(2-Isopropoxy-phenylamino)-ethylamino]-
methyl}-benzoic acid methyl ester. To a solution of N1-
title intermediate was prepared similarly to 4a, step E,
using 4-(piperidine-1-carbonyl)-thiophene-2-carbalde-
hyde and N1-(2-nitro-phenyl)-ethane-1,2-diamine. MS
(ESI): mass calculated for C19H24N4O3S, 388.49; m=z
found, 389.1 [MþH]þ, 411.1 [MþNa]þ. 1H NMR
(400 MHz, CDCl3) d 8.33 (br s, 1H), 8.17 (dd, J ¼ 8:6,
1.5 Hz, 1H), 7.45–7.41 (m, 1H), 7.34 (d, J ¼ 1:2 Hz, 1H),
7.01 (d, J ¼ 1:2 Hz, 1H), 6.58 (d, J ¼ 7:8 Hz, 1H), 6.67–
6.62 (m, 1H), 4.04 (s, 2H), 3.57 (br s, 4H), 3.42 (dd,
J ¼ 6:0, 5.5 Hz, 1H), 3.03 (t, J ¼ 6:0 Hz, 2H), 1.67 (br s,
4H), 1.60 (br s, 2H).
(2-isopropoxy-phenyl)-ethane-1,2-diamine
(0.432 g,
2.22 mmol) and 3-formyl-benzoic acid methyl ester
(0.0328 g, 2.0 mmol) in 1,2-dichloroethane (22 mL) was
added sodium triacetoxyborohydride (0.636 g, 3 mmol)
and the resulting suspension was stirred at 25 °C for 2 h.
The solution was partitioned with EtOAc (50 mL), H2O
(20 mL) and 1 N NaOH (30 mL) and the aqueous layer
was extracted with EtOAc (3 ꢂ 50 mL). The combined
organic layers were washed with brine, dried (MgSO4),
filtered and the solvent was removed under reduced
pressure. The crude residue was purified by column
chromatography (5–10% MeOH/CH2Cl2) to provide the
desire product 0.32 g (46.8%) as an orange oil. MS
(electrospray): exact mass calculated for C20H26N2O3,
342.19, m=z found, 343.2, [MþH]þ, 365.2, [MþNa]þ. 1H
NMR (400 MHz, CDCl3) d 7.99 (br s, 1H), 7.92
(apparent d, J ¼ 7:7 Hz, 1H), 7.56 (apparent d,
J ¼ 7:7 Hz, 1H), 7.39 (t, J ¼ 7:7 Hz, 1H), 6.76–6.82 (m,
2H), 6.61–6.65 (m, 2H), 4.51 (hp, J ¼ 6:0 Hz, 1H), 3.90
(s, 3H), 3.88 (s, 2H), 3.27 (t, J ¼ 5:8 Hz, 2H), 2.91 (t,
J ¼ 6:0 Hz, 2H), 1.34 (d, J ¼ 6:0 Hz, 6H). 13C NMR
(100 MHz, CDCl3) d 167.1, 145.0, 140.7, 139.3, 132.661,
130.2, 129.4, 128.4, 128.3, 121.2, 116.4, 112.6, 110.3,
53.2, 52.0, 48.1, 43.4, 39.2, 23.3, 22.3.
5.37.2. B. [2-(2-Nitro-phenylamino)-ethyl]-[4-(piperidine-
1-carbonyl)-thiophen-2-yl-methyl]-carbamic acid tert-but-
yl ester. The title intermediate was prepared analogously
to compound 15, step A, substituting (5-{[2-(2-nitro-
phenylamino)-ethylamino]-methyl}-thiophen-3-yl)-pip-
eridin-1-yl-methanone for (3-{[2-(2-nitro-phenylamino)-
ethylamino]-methyl}-phenyl)-piperidin-1-yl-methanone.
1H NMR (400 MHz, CDCl3) d 8.21–8.11 (m, 2H), 7.44
(t, J ¼ 7:6 Hz, 1H), 7.35 (d, J ¼ 1:0 Hz, 1H), 7.02–6.84
(m, 2H), 6.66 (t, J ¼ 7:7 Hz, 1H), 4.59–4.55 (m, 2H),
3.62–3.44 (m, 8H), 1.08 (br s, 4H), 1.58 (br s, 2H), 1.52
(br s, 9H).
5.36.2. B. N,N-Diethyl-3-{[2-(2-isopropoxy-phenylamino)-
ethylamino]-methyl}-benzamide. To a solution of dieth-
ylamine (0.064 g, 0.876 mmol) in toluene (1 mL) was
added trimethylaluminum (2 M in hexane, 0.0438 mL,
0.876 mmol) and the solution was stirred at 25 °C for
5 min. The solution was treated with a solution of 3-{[2-
(2-isopropoxy-phenylamino)-ethylamino]-methyl}-benz-
oic acid methyl ester (0.05 g, 0.146 mmol) in toluene
(1 mL) and the reaction mixture was stirred at 70 °C for
18 h. The reaction mixture was partitioned with H2O
5.37.3. C. [2-(2-Amino-phenylamino)-ethyl]-[4-(piper-
idine-1-carbonyl)-thiophen-2-yl-methyl]-carbamic
acid
tert-butyl ester. The title intermediate was prepared
analogously to compound 15, step B, substituting [2-
(2-nitro-phenylamino)-ethyl]-[4-(piperidine-1-carbonyl)-
thiophen-2-yl-methyl]-carbamic acid tert-butyl ester
for [2-(2-nitro-phenylamino)-ethyl]-[3-(piperidine-1-car-
1
bonyl)-benzyl]-carbamic acid tert-butyl ester. H NMR
(400 MHz, CDCl3) d 7.33 (br s, 1H), 6.90 (br s, 1H),
6.78–6.74 (m, 1H), 6.68–6.55 (m, 3H), 4.57–4.49 (m,

4530
R. L. Wolin et al. / Bioorg. Med. Chem. 12 (2004) 4511–4532
2H), 3.68–3.39 (m, 6H), 3.25 (br s, 2H), 1.65 (br s, 2H),
1.55 (br s, 4H), 1.50 (br s, 9H).
2H), 1.85–1.80 (m, 2H), 1.64–1.58 (m, 6H), 1.35 (d,
J ¼ 6:0 Hz, 6H). 13C NMR (100 MHz, CDCl3) d 171.5,
145.0, 139.6, 137.4, 128.9, 128.5, 126.3, 125.2, 121.2,
116.5, 112.6, 110.3, 70.6, 53.1, 49.7, 47.9, 46.3, 43.0,
29.5, 27.3, 26.5, 22.3.
5.37.4. D. (5-{[2-(2-Amino-phenylamino)-ethylamino]-
methyl}-thiophen-3-yl)-piperidin-1-yl-methanone.
The
title compound was prepared analogously to compound
15, step D, substituting [2-(2-amino-phenylamino)-
ethyl]-[4-(piperidine-1-carbonyl)-thiophen-2-yl-methyl]-
carbamic acid tert-butyl ester for [2-(2-isopropylamino-
phenylamino)-ethyl]-[3-(piperidine-1-carbonyl)-benzyl]-
carbamic acid tert-butyl ester. 1H NMR (400 MHz,
CDCl3) d 7.32 (d, J ¼ 1:5 Hz, 1H), 6.99 (d, J ¼ 1:5 Hz,
1H), 6.82–6.77 (m, 1H), 6.72–6.64 (m, 3H), 3.98 (s, 2H),
3.50 (br s, 4H), 3.21 (t, J ¼ 5:7 Hz, 2H), 2.96 (t,
J ¼ 5:7 Hz, 2H), 1.67 (br s, 2H), 1.58 (br s, 4H).
5.40. (3-{[2-(2-Isopropoxy-phenylamino)-ethylamino]-
methyl}-phenyl)-pyrrolidin-1-yl-methanone (41)
The title compound was prepared analogously to com-
pound 42, substituting pyrrolidine for diethylamine in
step B. MS (ESI): mass calculated for C23H31N3O2,
381.2; m=z found, 382.3 [MþH]þ, 404.3 [MþNa]þ. H
1
NMR (400 MHz, CDCl3) d 7.50 (br s, 1H), 7.43 (d,
J ¼ 7:3 Hz, 1H), 7.39–7.31 (m, 2H), 6.83 (dt, J ¼ 7:6,
1.3 Hz, 2H), 6.78–6.76 (m, 2H), 6.65–6.61 (m, 2H), 4.52
(hp, J ¼ 6:0 Hz, 1H), 3.88 (s, 3H), 3.62 (t, J ¼ 6:9 Hz,
2H), 3.93 (t, J ¼ 6:7 Hz, 2H), 3.33 (t, J ¼ 6:0 Hz, 2H),
2.95 (t, J ¼ 6:0 Hz, 2H), 1.96–1.83 (br m, 4H), 3.45 (d,
J ¼ 6:0 Hz, 6H). 13C NMR (100 MHz, CDCl3) d 169.5,
145.0, 139.0, 137.4, 129.9, 128.5, 127.1, 126.1, 121.2,
116.6, 112.6, 110.3, 70.6, 52.9, 49.6, 47.6, 46.2, 42.6,
26.3, 24.4, 22.3.
5.38. (5-{[2-(2-Isopropylamino-phenylamino)-ethyl-
amino]-methyl}-thiophen-3-yl)-piperidin-1-yl-methanone
(39)
The title compound was prepared analogously to com-
pound 15, steps C and D, substituting [2-(2-amino-
phenylamino)-ethyl]-[4-(piperidine-1-carbonyl)-thiophen-
2-yl-methyl]-carbamic acid tert-butyl ester (example 35,
step C) for [2-(2-amino-phenylamino)-ethyl]-[3-(piper-
idine-1-carbonyl)-benzyl]-carbamic acid tert-butyl ester
in step C.
5.41. N,N-Diethyl-3-{[2-(2-isopropoxy-phenylamino)-eth-
ylamino]-methyl}-benzamide (42)
5.41.1. A. 3-{[2-(2-Isopropoxy-phenylamino)-ethylamino]-
methyl}-benzoic acid methyl ester. To a solution of N1-
(2-isopropoxy-phenyl)-ethane-1,2-diamine (example 1,
step C; 0.432 g, 2.22 mmol) and 3-formyl-benzoic acid
methyl ester (0.33 g, 2.0 mmol) in 1,2-dichloroethane
(22 mL) was added sodium triacetoxyborohydride (0.6 g,
3 mmol), and the resulting suspension was stirred at
25 °C for 2 h. The resulting solution was partitioned with
EtOAc (50 mL), H2O (20 mL) and 1 N NaOH (30 mL),
and the aqueous layer was back-extracted with EtOAc
(3 ꢂ 50 mL). The combined organic layers were washed
with brine, dried (MgSO4), filtered, and concentrated
under reduced pressure. The crude residue was purified
by column chromatography (5–10% CH3OH/CH2Cl2)
to provide an orange oil (0.32 g, 46%). MS (ESI): mass
calculated for C20H26N2O3, 342.19; m=z found, 343.2
[MþH]þ, 365.2 [MþNa]þ. 1H NMR (400 MHz, CDCl3)
d 7.99 (br s, 1H), 7.91–7.94 (m, 1H), 7.57–7.55 (m, 1H),
7.39 (t, J ¼ 7:7 Hz, 1H), 6.76–6.82 (m, 2H), 6.61–6.65
(m, 2H), 4.51 (hp, J ¼ 6:0 Hz, 1H), 3.90 (s, 3H), 3.88 (s,
2H), 3.27 (t, J ¼ 5:8 Hz, 2H), 2.91 (t, J ¼ 6:0 Hz, 2H),
1.34 (d, J ¼ 6:0 Hz, 6H). 13C NMR (100 MHz, CDCl3) d
167.1, 145.0, 140.7, 139.3, 132.661, 130.2, 129.4, 128.4,
128.3, 121.2, 116.4, 112.6, 110.3, 53.2, 52.0, 48.1, 43.4,
39.2, 23.3, 22.3.
5.38.1. A. [2-(2-Isopropylamino-phenylamino)-ethyl]-[4-
(piperidine-1-carbonyl)-thiophen-2-yl-methyl]-carbamic
acid tert-butyl ester. 1H NMR (400 MHz, CDCl3) d 7.34
(d, J ¼ 1:5 Hz, 1H), 6.97 (br s, 1H), 6.77–6.57 (m, 4H),
4.50–4.54 (m, 2H), 3.43–3.62 (s, 8H), 3.25 (t, J ¼ 6:1 Hz,
2H), 1.66 (br s, 2H), 1.57 (br s, 4H), 1.51 (br s, 9H), 1.22
(d, J ¼ 6:1 Hz, 6H).
5.38.2. B. (5-{[2-(2-Isopropylamino-phenylamino)-ethyl-
amino]-methyl}-thiophen-3-yl)-piperidin-1-yl-methanone.
MS (ESI): mass calculated for C22H32N4OS, 400.58; m=z
found, 401.2 [MþH]þ, 423.2 [MþNa]þ. 1H NMR
(400 MHz, CDCl3) d 7.34 (d, J ¼ 1:5 Hz, 1H), 6.99 (br s,
1H), 6.80–6.73 (m, 2H), 6.69–6.66 (m, 2H), 4.01 (s, 2H),
3.66–3.48 (m, 5H), 3.21–3.18 (m, 2H), 2.99–2.96 (m,
2H), 1.68 (br s, 2H), 1.59 (br s, 4H), 1.25 (d, J ¼ 6:2 Hz,
6H).
5.39. Azepan-1-yl-(3-{[2-(2-isopropoxy-phenylamino)-
ethylamino]-methyl}-phenyl)-methanone (40)
The title compound was prepared analogously to com-
pound 42, substituting azepane for diethylamine in step
B. MS (ESI): mass calculated for C25H35N3O2, 409.27;
5.41.2. B. N,N-Diethyl-3-{[2-(2-isopropoxy-phenylamino)-
ethylamino]-methyl}-benzamide. To a solution of dieth-
ylamine (0.064 g, 0.88 mmol) in toluene (1 mL) was
added trimethylaluminum (2.0 M in hexane, 0.044 mL,
0.88 mmol), and the resulting solution was stirred at
25 °C for 5 min. A solution of 3-{[2-(2-isopropoxy-phen-
ylamino)-ethylamino]-methyl}-benzoic acid methyl ester
1
m=z found, 410.3 [MþH]þ, 432.3 [MþNa]þ. H NMR
(400 MHz, CDCl3) d 7.40 (br d, J ¼ 7:6 Hz, 1H), 7.35–
7.31 (m, 2H), 7.25 (br d, J ¼ 7:6 Hz, 1H), 6.83 (dt,
J ¼ 7:7, 1.3 Hz, 1H), 6.78–6.76 (m, 1H), 6.65–6.61 (m,
2H), 4.52 (hp, J ¼ 6:1 Hz, 1H), 3.86 (s, 2H), 3.66 (t,
J ¼ 5:9 Hz, 2H), 3.35–3.28 (m, 4H), 2.93 (t, J ¼ 6:0 Hz,

R. L. Wolin et al. / Bioorg. Med. Chem. 12 (2004) 4511–4532
4531
(0.05 g, 0.146 mmol) in toluene (1 mL) was added,
and the reaction mixture was stirred at 70 °C for 18 h.
The mixture was partitioned with H2O (10 mL) and
EtOAc (20 mL). The organic layer was washed with 1 N
NaOH (10 mL) then brine (10 mL), dried (MgSO4), fil-
tered, and concentrated under reduced pressure. The
crude residue was purified by preparative TLC (10%
CH3OH/CH2Cl2) to provide a tan oil (0.083 g, 15%). MS
(ESI): mass calculated for C23H33N3O2, 383.26; m=z
found, 384.3 [MþH]þ, 406.3 [MþNa]þ. 1H NMR
(400 MHz, CDCl3) d 7.39 (br d, J ¼ 7:5 Hz, 1H), 7.35–
7.31 (m, 2H), 7.24 (br d, J ¼ 7:6 Hz, 1H), 6.83 (dt,
J ¼ 7:6, 1.3 Hz, 1H), 6.78–6.76 (m, 1H), 6.65–6.61 (m,
2H), 4.52 (hp, J ¼ 6:1 Hz, 1H), 3.85 (s, 3H), 3.53 (br s,
2H), 3.28 (t, J ¼ 5:9 Hz, 2H), 3.23 (br s, 2H), 2.92 (t,
J ¼ 6:0 Hz, 2H), 1.34 (d, J ¼ 6:1 Hz, 6H), 1.25–1.01 (br
m, 6H). 13C NMR (100 MHz, CDCl3) d 171.2, 145.0,
140.0, 139.2, 137.4, 128.9, 128.5, 126.1, 124.9, 121.2,
116.5, 112.6, 110.3, 70.6, 53.2, 48.0, 43.1, 39.2, 22.3,
14.2, 12.9.
6.55 (m, 2H), 4.45 (hp, J ¼ 6:1 Hz, 1H), 4.11 (br s, 1H),
3.90–3.84 (m, 1H), 3.80 (s, 2H), 3.50 (br s, 1H), 3.26–
3.23 (m, 3H), 3.09 (br s, 1H), 2.89–2.86 (m, 2H), 1.89–
1.72 (m, 2H), 1.53–1.40 (m, 2H), 1.28 (d, J ¼ 6:1 Hz,
6H).
Acknowledgements
The authors would like to thank Dr. Jiejun Wu for his
assistance in obtaining spectroscopic data. We also
would like to acknowledge Dr. Bernhard Meurers and
Dr. Adrienne Dubin for insightful discussions.
References and notes
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The title compound was prepared analogously to com-
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1
found, 234.1 [MþH]þ. H NMR (400 MHz, CDCl3) d
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4532
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