Novel series of substituted biphenylmethyl urea derivatives as MCH-R1 antagonists for the treatment of obesity

Article abstract of DOI:10.1016/j.bmc.2007.02.049

We have designed and synthesized two novel series of MCH-R1 antagonists based on a substituted biphenylmethyl urea core. SAR was explored, suggesting that optimal binding with the receptor was achieved when the biphenylmethyl group and the linker were sub

Full text of DOI:10.1016/j.bmc.2007.02.049

Bioorganic & Medicinal Chemistry 15 (2007) 3896–3911
Novel series of substituted biphenylmethyl urea derivatives as
MCH-R1 antagonists for the treatment of obesity
´
Silvia Galiano, Javier Ceras, Nuria Cirauqui, Silvia Perez, Laura Juanenea,
Gildardo Rivera, Ignacio Aldana* and Antonio Monge
Unidad en Investigacio´n y Desarrollo de Medicamentos, Centro de Investigacio´n en Farmacobiologı´a Aplicada (CIFA),
University of Navarra, c/Irunlarrea s/n, 31080 Pamplona, Spain
Received 12 December 2006; revised 16 February 2007; accepted 26 February 2007
Available online 3 March 2007
Abstract—We have designed and synthesized two novel series of MCH-R1 antagonists based on a substituted biphenylmethyl urea
core. SAR was explored, suggesting that optimal binding with the receptor was achieved when the biphenylmethyl group and the
linker were substituted on the same nitrogen of the urea moiety. Compound 1-(30-cyano-4-biphenylmethyl)-3-(2-hydroxy-1,1-
dimethylethyl)-1-{2-[1-(4-methylbenzyl)-4-piperidinyl]ethyl}urea 2t showed the best antagonist binding activity to the MCH-R1
with a 43 nM Ki.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
to obesity and insulin resistance.7 Two G-protein-coupled
receptors bind to MCH namely MCH-R1 and MCH-R2.8
Although it is not yet clear what role MCH-R2 plays
in vivo, recent research suggests that MCH-R1 is impli-
cated in mediating the orexigenic effects of MCH.
MCH-R1 knock-out mice are hyperactive, hypermeta-
bolic, have reduced fat mass, insulin, and leptin levels,
and are mildly hyperphagic.9,10 Thus, antagonists of
MCH-R1 may provide a novel target for developing po-
tential agents for treatment of obesity.11
Obesity is a worldwide epidemic.1 Its rising prevalence
throughout the world, together with its increased associ-
ated morbidity,2 has become a real health challenge in
this century and therefore, the treatment of obesity is
now of great importance. Identified by WHO as one
of the top ten global earth problems, current estimates
hold that over 30% of adults in the United States suffer
from obesity. The lack of efficacy of the available obes-
ity drugs makes obesity one of the most attractive ther-
apeutic targets.3
Several companies have published their attempts to
identify small molecule MCH receptor antagonists with
a wide range of structural types12–15 (Fig. 1). Among
them, aminotetralin T-226296 (compound I), which
exhibited high affinity for the MCH-R1 receptor (IC50
value of 5.5 nM) and >90% suppression of MCH stimu-
lated food intake at 30 mpk in lean rats, was the first re-
ported MCH-R1 antagonist. SNAP-7941 (II) has
also been identified as a potent antagonist at MCH-
R1, showing a pA2 = 9.24 in a phosphoinositide accu-
mulation assay. In vivo studies with SNAP-7941
demonstrated that the compound, after systematic
administration, was able to inhibit the effects of centrally
administered MCH, and had a moderate effect on palat-
able consumption when compared with fenfluramine. At
1 or 10 mg_kg ip SNAP 7941 antagonized MCH-stimu-
lated food intake in rats. However, in rats with DIO,
SNAP7941 produced a sustained reduction in body
Melanin concentrating hormone (MCH) is a cyclic
19-amino acid neuropeptide, expressed throughout the
brain, predominantly in mammalian neurons in the lat-
eral hypothalamus and the zona incerta.4 MCH is believed
to play a critical role as a regulator of feeding behavior
and energy balance based on several lines of evidence.
Intracerebroventricular injection of MCH stimulates
feeding in rats and mice, and MCH mRNA levels are
up-regulated by fasting in both leptin deficient ob/ob
and wild type mice.5 MCH knockout mice result in a lean
and hyperphagicphenotype and have an increased metab-
olism.6 In contrast, overexpression of MCH peptide leads
Keywords: MCH; MCH-R1 antagonist; Obesity; Biphenylmethyl urea.
*
Corresponding author. Tel.: +34 948 425653; fax: +34 948 425652;
e-mail: ialdana@unav.es
0968-0896/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2007.02.049

S. Galiano et al. / Bioorg. Med. Chem. 15 (2007) 3896–3911
3897
F
F
O
MeO2C
MeO
N
O
N
N
H
N
H
N
N
H
N
H
O
O
F
II. SNAP-7941 (Synaptic)
I. T-226296 (Takeda)
pA2=9.24
IC50=5.5 nM
N
N
H
N
H
N
F
H
N
F
F
N
N
O
N
O
O
N
F
H
CN
III. Abbott
IC50=12 nM
IV. (Schering-Plough)
Ki=2.7 nM
Figure 1. Small molecule MCH-R1 antagonists.
weight that was greater than that elicited by fenfluramine,
an effective anorectic agent, in humans.16 Abbot has re-
ported the discovery of a series of MCH-R1 antagonists
baseduponindazolessuchascompoundIIIwithpotential
bindings. Recently, Schering-Plough reported biarylurea
derivatives such as compound IV which exhibited
in vivo efficacy in rodent obesity models.
2. Chemistry
Preparation of series 1 derivatives is outlined in Scheme 1.
Carbamate derivative 5 was synthesized in three steps
from commercially available N-Boc-aminopiperidine
via: (i) alkylation with 4-methylbenzyl bromide; (ii) N-
Boc deprotection of the amine via urethane hydrolysis;
and (iii) reaction with p-nitrophenyl chloroformate 5.
The preparation of amine derivatives involves a four-
step procedure starting from commercially available 3-
hydroxy-3-methyl-2-butanone 6. Treatment of 6 with
N-bromosuccinimide in the presence of the previously
prepared catalyst ‘NaHSO4ÆSiO2’ provided the methylk-
etone bromide 7. Conversion of the bromide to the
corresponding amines (13–17) was accomplished via
treatment with 4-biphenylmethyl amine derivatives 8–
12 previously prepared via a Suzuki coupling between
p-bromobenzylamine and a variety of substituted aryl-
boronic acids.17 Condensation of amines 13–17 with
p-nitrophenylcarbamate derivative 5 in methanol and
triethylamine led to the desired urea derivatives 1f–j.
The direct reaction of carbamate 5 with 4-biphenylmeth-
yl amine derivatives 8–12 yielded compounds 1a–e.
In spite of the overall structural diversity, most of these
templates share a key pharmacophore that contains four
common parts: an aromatic region attached to a carbox-
amide/urea core, which in turn is connected via a linker
to a basic amine (Fig. 2).
As part of our research of antiobesity drugs and based
on the pharmacophore, we have designed a novel struc-
ture (series 1 and 2) in order to find potential MCH-R1
antagonists. Our strategy included three-component ap-
proach as delineated in Figure 3: introduction of substi-
tuted biphenylmethyl scaffold in the aromatic region (C1
region); introduction of an urea moiety as the central
core (C2 region), and incorporation of a basic amine
via a linker in the form of a substituted piperidine ring
(C3 region). Furthermore, one of the nitrogens of the
urea group would be trisubstituted (Fig. 3).
Compounds of series 2 were synthesized by the general
route shown in Scheme 2. Condensation of commer-
cially available 4-piperidine ethanol with p-meth-
ylbenzylbromide under reflux in acetonitrile gave
compound 18, which was converted to aldehyde 19 by
Herein, we report the synthesis and SAR studies at MCH-
R1 of two novel series of substituted biphenylmethyl urea
derivatives.
H
N
H
N
O
aromatic region
N
linker
O
basic amine
N
O
N
H
N
H
N
aromatic region
linker
basic amine
urea core
carboxamide/urea core
Figure 2. Example of common features of one of the reported MCH-R1 antagonist molecules.

3898
S. Galiano et al. / Bioorg. Med. Chem. 15 (2007) 3896–3911
C3
C2
R1
C3
O
O
N
O
N
aromatic region
C1
R
linker
N
N
H
N
H
N
basic amine
N
H
N
H
R1
C1
R
C2
Series 2
carboxamide/urea core
Series 1
Figure 3. Design of our MCH-R1 antagonist structures.
H
N
H
N
O
O
b
a
H2N
O
NH
O
N
N
3
4
c
R
H
N
O
O
g
N
5
H
N
O2N
HN
O
N
+
1a-e
R
O
O
d
e
Br
O
f
HO
HO
NH
8-12
HO
6
7
13-17
R
O
H
N
N
HO
O
N
1f-j
Scheme 1. Reagents and conditions: (a) p-methylbenzylbromide, EtOH, DIEA, N2, rt, 4 h, 66%; (b) DCM, 4 N HCl, dioxane, 1 N NaOH, rt, 2 h,
98%; (c) p-nitrophenylchloroformate, THF, 0 ꢁC, N2, DIEA, 4 h, 36%; (d) i—NaHSO4ÆH2O, H2O, SiO2, 15 min, 120 ꢁC, 48 h; ii—CCl4, NBS,
NaHSO4ÆSiO2, 80 ꢁC, 2 h, 75% in two steps; (e) i—arylboronic acid, p-bromobenzylamine, CH3CN, 1 N K2CO3, reflux, N2, Pd(PPh3)4, 12 h, 80%;
ii—MeOH, NEt3, rt, 6 h; (f) N2, 6 h, rt, 9%; (g) MeOH, NEt3, 6 h, 1 M HCl, 36%.
Swern oxidation with dimethylsulfoxide (DMSO) and
oxalyl chloride.18 Suzuki coupling in order to obtain
4-phenylbenzylamine derivatives 8–12, as described in
Scheme 1, followed by reductive amination of the alde-
hyde 19 afforded compounds 20–24. Treatment of
resulting amines with appropriate isocyanates via
Curtius rearrangement19 using diphenylphosphorylazide
(DPPA) in the presence of triethylamine provided the
desired urea derivatives 2a–e. In cases where the
isocyanate contains hydroxy groups, they were
protected by conversion to an ester group (2f–o),
coupled with the corresponding isocyanates and then
deprotected to give the final urea analogs 2p–z, as
outlined in Schemes 2 and 3.
pounds 1a–e displayed higher in vitro affinity than the
corresponding trisubstituted analogs 1f–j. The disubsti-
tuted urea analogs (entries 1a–e) displayed modest affin-
ity for MCH-R1, the most potent urea derivatives of
this series being 1d and 1c (Ki = 186 and 425 nM,
respectively). However, substitution of R1 with 3-hy-
droxy-3-methyl-2-butanone in the urea moiety (entries
1f–j) was much less tolerated by the receptor.
Furthermore, the substitution of biphenylmethyl group
in C1 region resulted in improved affinity (1a–d). In
addition, as demonstrated by compounds 1c and 1d,
compounds with 2-methoxy and 3-cyano substitution
were more potent than the 4-methoxy and 4-fluoro ana-
logs 1b and 1a.
3. Results and discussion
In an attempt to improve the MCH-R1 in vitro activity,
we examined the effect of modifying the position of the
biaryl substituent and changing the distance between the
urea scaffold and the piperidine group of the pharmaco-
phore, as can be observed in Figure 3.
In vitro MCH-R1 binding data for compounds 1a–j are
summarized in Table 1. In general, series 1 ureas
showed moderate potency. The disubstituted urea com-

S. Galiano et al. / Bioorg. Med. Chem. 15 (2007) 3896–3911
3899
HO
NH
a
HO
N
18
b
H
O
N
19
8-12
c
R
R
Method A
d
H
N
N
HN
O
N
N
20-24
2a-e
Method B
e
O
N
O
O
N
O
25:
O
O
26:
O
O
R
O
R
O
O
H
N
N
H
N
N
O
N
O
O
N
O
O
2k-o
2f-j
f
f
R
R
H
N
H
N
O
N
N
R1
R1
N
O
N
2p-u
2v-z
Scheme 2. Reagents and conditions: (a) p-methylbenzylbromide, CH3CN, N2, Cs2CO3, rt, 1–2 h, 66%; (b) DMSO, DCM, (CO)2Cl2, NEt3, N2,
ꢀ78 ꢁC, 4 h, 87%; (c) i—arylboronic acid, p-bromobenzylamine, CH3CN, 1 N K2CO3, reflux, N2, Pd(PPh3)4, 12 h, 80%; ii—MeOH, molecular sieves,
N2, rt, 12 h, NaBH(OAc)3, 4–8 h, 45% in two steps; (d) Method A. DCM, 0 ꢁC, isopropylisocyanate, 2–3 h, 5%; (e) Method B. i—AcCl, heat;
ii—DPPA, NEt3, toluene, N2, 50% in two steps; iii—DCM, 0 ꢁC, N2, 84%; (f) MeOH, rt, K2CO3, N2, 3 h, 15%.
exemplified by entries 2p (96.6 nM) versus 2a (314 nM)
and 2z (173 nM) versus 2e (258 nM), due to increased
polar character. Compounds 2t and 2p were the most
potent ureas in this series, with Ki = 43 and 96.6 nM,
respectively, at MCH-R1. Replacing the hydroxy with
an ester led to a drop in potency, as shown when the en-
try 2i (254 nM) is compared with 2t (43 nM) and 2m
(1200 nM) with 2x (167 nM).
Br
i
R
R
HO
+
B
OH
NH2
NH2
8-12
R=4-F, 4-OMe, 2-OMe, 3-CN
Scheme 3. Reagents and conditions: (i) CH3CN, 1 N K2CO3, reflux,
N2, Pd(PPh3)4, 12 h, 80%.
The SAR suggested that better affinity was obtained at
MCH-R1 when biphenylmethyl scaffold was substituted
on the same nitrogen of the urea moiety as the linker.
This statement was confirmed by activity data (2t:
Ki = 43 nM; Kb = 84 nM).
The MCH-R1 in vitro affinity of 2a–z is shown in Table 2.
In general, the introduction of a hydroxymethyl moiety
in R1 resulted in a large increase in affinity at MCH-R1,
significantly better than with the isopropyl analog, as

3900
S. Galiano et al. / Bioorg. Med. Chem. 15 (2007) 3896–3911
Table 1. Binding affinities of urea derivatives 1a–j (series 1) toward MCH-R1 receptor
O
N
N
R1
N
H
R
a
Kb (nM) (pKb SEM) (Imax %) h-MCH-R1
Compound
R
R1
Kib (nM) (pKi SEM) h-MCH-R1
1a
1b
1c
1d
1e
4-F
H
H
H
H
H
198 (6.705) (n = 2) (105)
443 (6.355 0.108) (n = 4) (93.5)
642 (6.19) (n = 2) (99.5)
411 (6.385) (n = 2) (98)
545 (6.265 0.145) (n = 2)
1460 (5.84) (n = 1)
4-OMe
2-OMe
3-CN
ꢀH
425 (6.37 0.03) (n = 2)
186 (6.73 0.15) (n = 2)
2640 (5.575 0.055) (n = 2)
1060 (5.975) (n = 2) (124)
O
O
O
O
O
1f
1g
1h
1i
4-F
4530 (5.343 0.063) (n = 3) (79)
>10,000 (<5) (n = 3)
5860 (5.23 0.06) (n = 2)
ND
HO
HO
HO
HO
HO
4-OMe
2-OMe
3-CN
ꢀH
3730 (5.428 0.236) (n = 4) (68.25)
5000 (5.30 0.094) (n = 4) (84.5)
>10,000
6050 (5.22) (n = 1)
6380 (5.195 0.075) (n = 2)
ND
1j
SEM is the standard error of the media. n is the number of experiments. ND, no data.
a MCH1(h)/GTPgS(-)/HEK-RF8-3Kb is the equilibrium dissociation constant for a competitive antagonist: the concentration that occupies 50% of
the receptors at the equilibrium. Imax is the current evoked by the concentration of agonist eliciting a maximal response.
b MCH1(h)/[3H]SNAP-7941/HEK/SPA-BF136-1. Ki is the in vitro inhibition constant.
In summary, we have designed and synthesized two
novel series of MCH-R1 antagonists based on an substi-
tuted biphenylmethyl urea core. SAR was explored, sug-
gesting that optimal binding with the receptor was
achieved when the biphenylmethyl group and the linker
were substituted on the same nitrogen of the urea moi-
ety. Compound 2t showed the best antagonist binding
activity to MCH-R1 with a 43 nM Ki.
cubated with both the agonist and the antagonist
(MCH1(h)/[3H]SNAP-7941/HEK/SPA-BF136-1) for 30 min
prior to the addition of [35S]GTPcS. Non-specific binding
was defined by using cold GTPcS (10 lM). Reaction
was stopped by rapid filtration through GF/B filters,
followed by three successive washes with ice cold buffer.
Microscint 20 was added to the GF/B filters which were
counted using a TopCount (Packard). The results are
expressed in Ki and are summarized in Tables 1 and 2.
4. Pharmacology
5. Experimental
5.1. Chemistry
All of the urea derivatives described were assayed for their
ability to displace radiolabeled [35S]GTPcS in a competi-
tive binding assay. The assay was initiated with the mem-
brane preparations. CHO cells stably expressing human
MCH-R1 receptors grown at confluency (in DMEM
medium supplemented with 10% fetal calf serum, 2 mM
glutamine, 100 IU/mL penicillin, and 100 lg/mL strepto-
mycin) were harvested in PBS containing EDTA 2 mM
and then centrifuged at 1000g for 5 min (4 ꢁC). The result-
ing pellet was suspended in HEPES 20 mM (pH 7.5) con-
taining EGTA 5 mM and then homogenized using a
Kinematica polytron. The homogenate was then centri-
fuged (95,000g, 30 min, 4 ꢁC) and the resulting pellet
was suspended in 50 mM HEPES (pH 7.5), 10 mM
MgCl2, and 2 mM EGTA. Aliquots of membrane prepa-
rations were stored at ꢀ80 ꢁC until use. For [35S]GTPcS
binding on membrane preparations, these were diluted
in binding buffer (50 mM HEPES, pH 7.4, 100 mM NaCl,
3 lM GDP, 5 mM MgCl2, BSA 0.1%, and saponin 10 lg/
mL). Incubation was started by the addition of 0.2 mM
[35S]GTPcS to the membrane (25 lg/mL) and drugs,
and then followed by 45 min at room temperature. For
experiments with antagonists, the membranes were prein-
All reagents and solvents were purchased from commer-
cial sources. E. Merck (Darmstadt, Germany), Scharlau
´
(F.E.R.O.S.A., Barcelona, Spain), Panreac Quımica
S.A. (Montcada i Reixac, Barcelona, Spain), Sigma–Al-
´
drich Quımica, S.A., (Alcobendas, Madrid), Acros
Organics (Janssen Pharmaceuticalaan 3a, 2440 Geel,
Belgie¨), and Lancaster (Bischheim-Strasbourg, France).
Melting points were determined with a Mettler
FP82+FP80 apparatus (Greifense, Switzerland) and
1
have not been corrected. The H NMR spectra were re-
corded on a Bruker 400 UltrashieldTM (Bruker BioSpin
GmbH, Rheinstetten, Germany), using TMS as the
internal standard and with DMSO-d6 as the solvent;
the chemical shifts are reported in ppm (d) and the cou-
pling constant (J) values are given in Hertz (Hz). Signal
multiplicities are represented by: s (singlet), br s (broad
singlet), d (doublet), dd (double doublet), t (triplet), m
(multiplet). The IR spectra were recorded on Thermo
Nicolet FT-IR Nexus Euro (Madison, USA) using

S. Galiano et al. / Bioorg. Med. Chem. 15 (2007) 3896–3911
Table 2. Binding affinities of urea derivatives 2a–z (series 2) toward MCH-R1 receptor
3901
O
N
R1
N
H
N
R
a
Kb (nM) (pKb SEM) (Imax %) h-MCH-R1
Compound
R1
R
Kib (nM) (pKi SEM) h-MCH-R1
2a
4-F
383 (6.42) (n = 2) (113)
314 (6.505 0.155) (n = 2)
273 (6.56 0.13) (n = 3)
ND
2b
2c
2d
2e
2f
4-OMe
2-OMe
3-CN
ꢀH
467 (6.335) (n = 2) (91.5)
>10,000 (<5) (n = 2)
1010 (5.995) (n = 2) (97)
509 (6.29 0.12) (n = 2)
258 (6.59 0.84) (n = 3)
421 (6.375 0.175) (n = 2)
595 (6.225 0.125) (n = 2)
215 (6.668 0.135) (n = 4)
254 (6.595 0.055) (n = 2)
947 (6.02 0.14) (n = 2)
220
O
4-F
409 (6.39 0.142) (n = 3) (92.33)
647 (6.19 0.191) (n = 3) (111.67)
721 (6.145) (n = 2) (97.5)
233 (6.63) (n = 2) (103)
366 (6.435) (n = 2) (101.5)
O
O
O
O
O
2g
2h
2i
4-OMe
2-OMe
3-CN
ꢀH
O
O
O
O
2j
O
O
2k
4-F
196 (6.71 0.104) (n = 4) (111.75)
214 (6.67 0.05) (n = 2)
O
O
O
O
2l
4-OMe
2-OMe
3-CN
139 (6.857 0.243) (n = 3) (93.67)
170 (6.77 0.01) (n = 2)
O
O
O
O
2m
2n
ND
ND
1200
1080
O
O
O
O
O
O
O
O
2o
2p
ꢀH
260 (6.585 0.074) (n = 4) (114)
41.4 (7.385) (n = 2) (101.5)
388 (6.41 0.03) (n = 2)
O
O
4-F
96.6 (7.015 0.135) (n = 2)
HO
(continued on next page)

3902
S. Galiano et al. / Bioorg. Med. Chem. 15 (2007) 3896–3911
Table 2 (continued)
a
Kb (nM) (pKb SEM) (Imax %) h-MCH-R1
Compound
R1
R
Kib (nM) (pKi SEM) h-MCH-R1
204 (6.69) (n = 1)
2r
2s
2t
4-OMe
2-OMe
3-CN
ꢀH
93 (7.06) (n = 2) (99)
HO
134 (6.875) (n = 2) (100)
251 (6.6 0.04) (n = 2)
43 (7.36 0.01) (n = 2)
144 (6.84 0.015) (n = 2)
149 (6.825 0.145) (n = 2)
143 (6.84 0.12) (n = 3)
167 (6.78 0.1) (n = 2)
769 (6.11 0.04) (n = 2)
173 (6.76 0.01) (n = 2)
HO
HO
84 (7.077 0.252) (n = 3) (99.33)
122 (6.197 0.195) (n = 3) (105)
293 (6.535) (n = 2) (111)
2u
2v
2w
2x
2y
2z
HO
HO
4-F
HO
HO
4-OMe
2-OMe
3-CN
ꢀH
117 (6.93 0.278) (n = 3) (108)
225 (6.647 0.119) (n = 3) (94)
3900 (5.41) (n = 1) (108)
HO
HO
HO
HO
HO
HO
147 (6.835) (n = 2) (93.5)
HO
SEM is the standard error of the media. n is the number of experiments. ND, no data.
a MCH1(h)/GTPgS(-)/HEK-RF8-3Kb is the equilibrium dissociation constant for a competitive antagonist: the concentration that occupies 50% of
the receptors at the equilibrium. Imax is the current evoked by the concentration of agonist eliciting a maximal response.
b MCH1(h)/[3H]SNAP-7941/HEK/SPA-BF136-1. Ki is the in vitro inhibition constant.
KBr pellets; the frequencies are expressed in cmꢀ1
.
atmosphere 4-methylbenzylbromide (9.41 g, 50.9 mmol).
Diisopropylethylamine (14.48 g, 112 mmol) was then
added and helped to dissolve the compounds. The reac-
tion mixture was stirred under N2 atmosphere for 3–4 h,
filtered, and concentrated to dryness in vacuo. The res-
idue was recrystallized by ethanol in order to give 3
(6.21 g, yield: 66%) as a white solid. IR (KBr) m: 3361
Signal intensities are expressed by: vs (very strong),
s (strong), m (medium), and w (weak). Elemental micro-
analyses were obtained on an Elemental Analyzer
LECO CHN-900 (Michigan, USA) from vacuum-dried
samples. The analytical results for C, H, and N were
within 0.4 of the theoretical values. Mass spectra were
measured on a Agilent Technologies Model MSD/DS
5973N (mod. G2577A) mass spectrometer with direct
insertion probe (DIP) (Waldbronn, Germany) and the
ionization method was electron impact (EI, 70 eV).
(N–H), 1684 (C@O) cmꢀ1
.
1H NMR (DMSO-d6,
400 MHz) d: 1.33 (d, 2H); 1.37 (s, 9H); 1.65 (d, 2H);
1.91 (t, 2H); 2.27 (s, 3H); 2.72 (d, 2H); 3.20 (s, 1H);
3.42 (s, 2H); 6.75 (s, 1H); 7.11 (d, 2H); 7.15 (d, 2H).
Anal. Calcd for C18H28N2O2: C, 71.05%; H, 9.21%; N,
9.21%. Found: C, 71.30%; H, 9.49%; N, 9.26%.
The progress of the reactions was followed by thin-layer
chromatography and silica gel 60 (0.040–0.063 mm)
Alugramꢂ SIL G/UV254 (Layer: 0.2 mm) (Macherey-
Nagel GmbH & Co. KG. Postfach 101352. D-52313
5.3. Procedure for the preparation of 1-(4-methylbenzyl)-
4-piperidinamine (4)
Duren, Germany). Flash column chromatography was
¨
carried out using (Merck). HPLC conditions: Column
Lichrospher 100 RP18 E.C. 5 lm (20 · 0.46), Ref.
TR011567, NS N23892; mobile phase: MeOH/H2O 60/
40; flux: 1 mL/min.
Compound 3 (4 g, 13.18 mmol) was diluted in CH2Cl2
(50 mL) and submitted to dioxane (60 mL) and HCl
4 N, and stirred for 3 h. The reaction mixture was then
filtered and the solid was washed with a solution of
1 N NaOH. The organic layer was extracted with
CH2Cl2, dried over Na2SO4, and evaporated to yield
compound 4 (2.63 g, yield: 98%) as a white oil. IR
5.2. Procedure for the preparation of N-[1-(4-methylben-
zyl)-4-piperidinyl]-tert-butylcarbamate (3)
(KBr) m: 3355 (N–H2), 1292 (C–N) cmꢀ1 1H NMR
.
To a solution of N-Boc-aminopiperidine (10 g, 50 mmol)
in 100 mL of ethanol was added dropwise under N2
(DMSO-d6, 400 MHz) d: 1.20 (m, 2H); 1.63 (d, 2H);
1.89 (t, 2H); 2.27 (s, 3H); 2.43 (s, 2H); 2.49 (m, 1H);

S. Galiano et al. / Bioorg. Med. Chem. 15 (2007) 3896–3911
3903
2.69 (d, 2H); 7.09 (d, 2H); 7.14 (d, 2H). MS (EI, 70 eV):
m/z (%) = 205 ([MÆ]+, 10), 189 (75), 113 (100), 99 (52), 85
(45).
5.6.1. Procedure for the preparation of (40-fluoro-4-
biphenyl)methylamine (8). The title compound was
synthesized from p-bromobenzylamine and p-fluor-
ophenylboronic acid according to the experimental pro-
cedure of Section 5.6 in order to provide 8 (7.2 g, yield:
77%) as a beige solid. Mp 270–272 ꢁC. IR (KBr) m: 3413
(NH2) cmꢀ1. 1H NMR (DMSO-d6, 400 MHz) d: 4.05 (d,
2H); 7.27–7.31 (m, 2H); 7.60 (d, 2H, J = 8.3 Hz); 7.71–
7.75 (m, 4H); 8.60 (br s, 2H). Anal. Calcd for
C13H12FN: C, 77.61%; H, 5.97%; N, 6.96%. Found: C,
77.25%; H, 6.30%; N, 6.51%.
5.4. Procedure for the preparation of N-[1-(4-methylben-
zyl)-4-piperidinyl]-4-nitrophenylcarbamate (5)
To a solution of compound 4 (2 g, 9.80 mmol) in anhy-
drous THF (50 mL) was added p-nitrophenylchlorofor-
mate (2.17 g, 10.80 mmol) and was stirred at 0 ꢁC, under
N2 atmosphere. Finally, DIEA (1.39 g, 10.80 mmol) was
added to the reaction mixture, which was stirred at this
temperature for about 4 h. The reaction mixture was fil-
tered to obtain compound 5 (1.30 g, yield: 36%) as a white
solid. Mp 195–196 ꢁC. IR (KBr) m: 3217 (N–H), 1752
5.6.2. Procedure for the preparation of (40-methoxy-4-
biphenyl)methylamine (9). The title compound was
synthesized from p-bromobenzylamine and p-meth-
oxyphenylboronic acid according to the experimental
procedure of Section 5.6 in order to provide 9 (8.5 g,
yield: 88%) as a beige solid. Mp 273–275 ꢁC. IR (KBr)
1
(C@O) cmꢀ1. H NMR (DMSO-d6, 400 MHz) d: 1.90
(t, 2H); 2.02 (d, 2H); 2.33 (s, 3H); 3.00 (d, 2H); 3.31 (d,
2H); 3.59 (s, 1H); 4.19 (d, 2H); 7.26 (d, 2H); 7.40 (d,
2H); 7.48 (d, 2H); 8.35 (d, 2H); 10.73 (s, 1H). Anal. Calcd
for C20H23N3O4: C, 65.04%; H,6.23%; N, 11.38%. Found:
C, 65.20%; H, 6.40%; N, 11.35%. MS (EI, 70 eV): m/z
(%) = 369 ([MÆ]+, 5), 323 (2), 230 (40), 202 (3), 105 (100).
1
m 3416 (NH2); 1251 (C–O) cmꢀ1. H NMR (DMSO-d6,
400 MHz) d: 3.79 (s, 3H); 4.01 (s, 2H); 7.03 (d, 2H,
J = 8.7 Hz); 7.56 (d, 2H, J = 8.6 Hz); 7.59–7.69 (m,
4H); 8.56 (s, 2H). Anal. Calcd for C14H15NO: C,
78.87%; H, 7.04%; N, 6.57%. Found: C, 78.95%; H,
7.16%; N, 6.25%.
5.5. Procedure for the preparation of 1-bromo-3-hydroxy-
3-methyl-2-butanone (7)
5.6.3. Procedure for the preparation of (20-methoxy-4-
biphenyl)methylamine (10). The title compound was
synthesized from p-bromobenzylamine and o-meth-
oxyphenylboronic acid according to the experimental
procedure of Section 5.6 in order to provide 10 (7.68 g,
yield: 80%) as a beige solid. Mp 240–245 ꢁC. IR (KBr) m:
5.5.1. Preparation of NaHSO4ÆSiO2 catalyst. SiO2
(1.00 equiv) was added to a solution of NaHSO4ÆH2O
(1.00 equiv) in water and the reaction mixture was stir-
red for 15 min. The mixture was then heated slowly until
the formation of a white solid. Finally, this solid was
dried at 120 ꢁC for 48 h in a stove.
1
3406 (NH2); 1259 (C–O) cmꢀ1. H NMR (DMSO-d6,
400 MHz) d: 3.76 (s, 3H); 4.04 (s, 2H); 7.04 (t, 1H,
J = 7.4 Hz); 7.12 (d, 1H, J = 8.3 Hz); 7.28 (d, 1H,
J = 6.0 Hz); 7.34 (t, 1H, J = 4.2 Hz); 7.45–7.53 (m, 4H);
8.46 (s, 2H). Anal. Calcd for C14H15NO: C, 78.87%; H,
7.04%; N, 6.57%. Found: C, 78.55%; H, 7.01%; N, 6.87%.
5.5.2. Synthesis of 1-bromo-3-hydroxy-3-methyl-2-
butanone (7). N-Bromosuccinimide (NBS) (4.18 g,
23.48 mmol) was added to a solution of 3-hydroxy-3-
methyl-2-butanone 6 (2.00 g, 19.58 mmol) in CCl4
(100 mL). The mixture was stirred and NaHSO4ÆSiO2
was added (1.76 g, 9.79 mmol). The mixture was then stir-
red under reflux to 80 ꢁC for 2 h. The reaction mixture was
filtered and then evaporated. The residue was purified by
flash column chromatography (CH2Cl2/MeOH 99:1) in
order to obtain 6 (2.63 g, yield: 75%) as a beige oil. IR
5.6.4. Procedure for the preparation of (30-cyano-4-
biphenyl)methylamine (11). The title compound was
synthesized from p-bromobenzylamine and m-cya-
nophenylboronic acid according to the experimental
procedure of Section 5.6 in order to provide 11
(5.95 g, yield: 85%) as a beige solid. Mp 187–189 ꢁC.
(KBr) m: 3441 (O–H), 1710 (C@O)cmꢀ1 1H NMR
.
1
(DMSO-d6, 400 MHz) d: 1.24 (s, 6H); 4.71 (s, 2H). MS
(EI, 70 eV): m/z (%) = 181 ([MÆ]+, 5), 142 (18), 135 (10),
105 (100), 97 (30).
IR (KBr) m: 3372 (NH2); 2225 (CN) cmꢀ1. H NMR
(DMSO-d6, 400 MHz) d: 3.97–4.08 (m, 2H); 7.48 (d,
1H); 7.60–7.70 (m, 3H); 7.80–7.86 (m, 2H); 8.06 (d,
1H, J = 7.9 Hz); 8.19 (s, 1H). Anal. Calcd for
C14H12N2: C, 80.74%; H, 5.81%; N, 13.45%. Found:
C, 80.96%; H, 5.91%; N, 13.28%.
5.6. General procedure for the preparation of 4-biphenyl-
methylamine derivatives (8–11)
In
a
250 mL tricol, p-bromobenzylamine (8.64 g,
5.7. General procedure for the preparation of 1-(4-biphenyl-
methyl)-3-[1-(4-methyl benzyl)-4-piperidinyl]urea derivatives
(1a–e)
0.046 mmol) was added to a solution of the appropriate
arylboronic acid (6.5 g, 0.046 mmol) in dry acetonitrile
(90 mL). Then, a solution of 1 N K2CO3 (93 mL) was
added and the mixture was stirred and heated at reflux
under N2 atmosphere. After 15 min, tetrakis(triphenyl-
phosphine)palladium (0) (2.68 g, 0.002 mmol) was
added. The reaction was found completed after 8 h.
The mixture was then filtered and evaporated in vacuo.
After adding HCl, the crude product was obtained and
washed with CH2Cl2 and MeOH in order to afford 8–
11 derivatives.
The appropriate 4-biphenylmethyl amine derivatives 8–
12 (1.20 equiv) and compound 5 (1.00 equiv) was dis-
solved in methanol (30 mL) and triethylamine
(1.00 equiv) were added to the reaction medium. After
6 h of stirring, the solvent was evaporated and the reac-
tion mixture washed with NaHCO3 and extracted with
dichloromethane, then washed with HCl 1 M and
extracted with dichloromethane. The organic layer was

3904
S. Galiano et al. / Bioorg. Med. Chem. 15 (2007) 3896–3911
dried with anhydrous Na2SO4 and the solvent evapo-
rated and dried. The white solid obtained was stirred
in a solution of 1 M NaOH and extracted with CH2Cl2.
The new organic layer was dried with anhydrous
Na2SO4 and the solvent evaporated in order to obtain
the desired urea derivatives 1a–e.
(d, 2H); 7.19 (t, 2H); 7.35 (d, 2H); 7.65 (d, 1H); 7.69
(d, 2H); 7.81 (d, 1H); 8.00 (dd, 1H); 8.13 (s, 1H). Anal.
Calcd for C28H30N4O: C, 76.71 %; H, 6.85%; N, 12.78%.
Found: C, 76.54%; H, 6.75%; N, 12.84 %. MS (EI,
70 eV): m/z (%) = 438 ([MÆ]+, 5), 333 (4), 234 (10), 192
(12), 105 (100).
5.7.1. Procedure for the preparation of 1-(40-fluoro-4-
biphenylmethyl)-3-[1-(4-methylbenzyl)-4-piperidinyl]urea
(1a). The title compound was synthesized from 8 and 5
according to the experimental procedure of Section 5.7
in order to provide 1a (0.18 g, yield: 77%) as a white so-
lid. Mp 270–272 ꢁC. IR (KBr) m: 3309 (NH2); 1626
5.7.5. Procedure for the preparation of 1-(4-biphenylm-
ethyl)-3-[1-(4-methylbenzyl)-4-piperidinyl]urea (1e). The
title compound was synthesized from 12 and 5 according
to the experimental procedure of Section 5.7 in order to
provide 1e (0.14 g, yield: 40%) as a white solid. Mp 173–
175 ꢁC. IR (KBr) m: 3334 (N–H); 1625 (C@O) cmꢀ1. 1H
NMR (DMSO-d6, 400 MHz) 1.32 (m, 2H); 1.74 (d, 2H);
1.99 (m, 2H); 2.28 (s, 3H); 2.68 (d, 2H); 3.38 (s, 2H); 3.49
(s, 1H); 4.23 (d, 2H); 5.90 (d, 1H, J = 7.9 Hz); 6.27 (t,
1H); 7.11 (d, 2H, J = 8.0 Hz); 7.16 (d, 2H, J = 7.9 Hz);
7.32 (d, 2H, J = 7.6 Hz); 7.36 (t, 1H); 7.69 (d, 2H);
7.45 (t, 2H, J = 7.6 Hz); 7.61 (d, 2H, J = 8.0 Hz); 7.64
(d, 2H, J = 8.2 Hz). Anal. Calcd for C27H31N3O: C,
78.45%; H, 7.51%; N, 10.17%. Found: C, 78.41%; H,
7.59%; N, 9.99%. MS (EI, 70 eV): m/z (%) = 413
([MÆ]+, 7), 308 (5), 248 (3), 167 (33), 146 (26), 105 (100).
1
(C@O) cmꢀ1. H NMR (DMSO-d6, 400 MHz) d: 1.32
(q, 2H); 1.74 (d, 2H); 2.00 (t, 2H); 2.28 (s, 3H); 2.68 (d,
2H); 3.38 (s, 2H); 4.23 (d, 2H); 5.90 (d, 1H); 6.26 (t,
1H); 7.11 (d, 2H); 7.16 (d, 2H); 7.26 (d, 2H); 7.31 (d,
2H); 7.58 (d, 2H); 7.68 (m, 2H). Anal. Calcd for
C27H30FN3O: C, 77.61%; H, 5.97%; N, 6.96%. Found:
C, 77.25%; H, 6.30%; N, 6.51%. MS (EI, 70 eV): m/z
(%) = 431 ([MÆ]+, 45), 416 (2), 326 (15), 246 (7), 185 (100).
5.7.2. Procedure for the preparation of 1-(40-methoxy-4-
biphenylmethyl)-3-[1-(4-methylbenzyl)-4-piperidinyl]urea
(1b). The title compound was synthesized from 9 and 5
according to the experimental procedure of Section 5.7
in order to provide 1b (0.05 g, yield: 14%) as a white so-
lid. Mp 189–191 ꢁC. IR (KBr) m: 3321 (N–H); 1619
5.8. General procedure for the preparation of 1-(4-biphenyl-
methyl)-1-(3-hydroxy-3-methyl-2-oxobutyl)-3-[1-(4-meth-
ylbenzyl)-4-piperidinyl]urea derivatives (1f–j)
1
(C@O) cmꢀ1. H NMR (DMSO-d6, 400 MHz) d: 1.31
The formation of 1-(4-biphenylmethylamino)-3-hydro-
xy-3-methyl-2-butanone derivatives 13–17 was first
achieved from the reaction of the appropriate 4-biphe-
nylmethyl amine derivatives 8–12 (1.00 equiv) with com-
pound 7 (1.00 equiv). When the reaction had finished,
compound 5 (1.00 equiv) was added to the same medium
of reaction, without isolation of the intermediates 13–17.
After 6 h of stirring in N2 atmosphere, the solvent was
evaporated and the product was extracted with CH2Cl2
and was eliminated and the final product was purified by
silica gel preparative thin layer and flash chromatogra-
phy (CH2Cl2/MeOH 90:10) to obtain 1f–j.
(q, 2H); 1.73 (d, 2H); 1.99 (t, 2H); 2.27 (s, 3H); 2.67
(d, 2H); 3.38 (s, 2H); 3.78 (s, 3H); 4.21 (d, 2H); 5.90
(d, 1H); 6.25 (t, 1H); 7.01 (d, 2H); 7.11 (d, 2H); 7.16
(d, 2H); 7.28 (d, 2H); 7.57 (m, 4H). Anal. Calcd for
C28H33N3O2Æ1/2H2O: C, 74.33%; H, 7.52%; N, 9.29 %.
Found: C, 73.81%; H, 7.71%; N, 9.21%. MS (EI,
70 eV): m/z (%) = 443 ([MÆ]+, 44), 182 (12), 159 (15),
146 (38), 105 (100).
5.7.3. Procedure for the preparation of 1-(20-methoxy-4-
biphenylmethyl)-3-[1-(4-methylbenzyl)-4-piperidinyl]urea
(1c). The title compound was synthesized from 10 and 5
according to the experimental procedure of Section 5.7
in order to provide 1c (0.02 g, yield: 2%) as a brown oil.
5.8.1. Procedure for the preparation of 1-(40-fluoro-4-
biphenylmethyl)-1-(3-hydroxy-3-methyl-2-oxobutyl)-3-[1-
(4-methylbenzyl)-4-piperidinyl]urea (1f). The title com-
pound was synthesized from 7, 8, and 5 according to
the same procedure of Section 5.8 in order to afford 1f
(0.19 g, yield: 13%) as a beige solid. Mp 77–79 ꢁC. IR
1
IR (KBr) m: 3312 (N–H); 1631 (C@O) cmꢀ1. H NMR
(DMSO-d6, 400 MHz) d: 1.36 (m, 2H); 1.73 (br s, 2H);
1.99 (br s, 2H); 2.28 (s, 3H); 2.68 (br s, 2H); 3.34 (s, 2H);
3.75 (s, 3H); 4.21 (d, 2H); 5.91 (d, 1H); 6.25 (m, 1H);
7.02 (t, 1H); 7.11 (d, 2H); 7.18 (m, 2H); 7.25 (d, 2H);
7.33 (m, 1H); 7.39 (d, 2H); 7.49 (d, 1H). Anal. Calcd for
C28H33N3O2Æ1/2 H2O: C, 74.33%; H, 7.52%; N, 9.29 %.
Found: C, 74.40%; H, 7.60%; N, 9.24%. MS (EI, 70 eV):
m/z (%) = 443 ([MÆ]+, 32), 338 (7), 239 (25), 197 (40), 105
(100).
(KBr) m: 3332 (N–H); 1663 (C@O) cmꢀ1 1H NMR
.
(DMSO-d6, 400 MHz) d: 1.02–1.06 (m, 6H); 1.54 (s,
2H); 1.68 (s, 2H); 1.91 (s, 2H); 2.28 (s, 3H); 2.85 (m,
2H); 3.26 (d, 1H); 3.43 (d, 2H); 4.12–4.39 (m, 2H);
4.55 (d, 2H); 5.83 (s, 1H); 7.13 (d, 2H, J = 7.1 Hz);
7.17 (br s, 2H); 7.29 (m, 4H); 7.53 (d, 1H); 7.61 (t,
2H); 7.70 (m, 2H). Anal. Calcd for C32H38N3O3F: C,
72.32%, H, 7.15%; N, 7.91%. Found: C, 72.39%; H,
7.17%; N, 7.86%. MS (EI, 70 eV): m/z (%) = 532
([MÆ]+, 2), 513 (4), 363 (4), 326 (4), 186 (100).
5.7.4. Procedure for the preparation of 1-(30-cyano-4-
biphenylmethyl)-3-[1-(4-methylbenzyl)-4-piperidinyl]urea
(1d). The title compound was synthesized from 11 and 5
according to the experimental procedure of Section 5.7
in order to provide 1d (0.11 g, yield: 47%) as a white so-
5.8.2. Procedure for the preparation of 1-(3-hydroxy-3-
methyl-2-oxobutyl)-1-(40-methoxy-4-biphenylmethyl)-3-
[1-(4-methylbenzyl)-4-piperidinyl]urea (1g). The title
compound was synthesized from 7, 9, and 5 according
to the same procedure of Section 5.8 in order to afford
lid. IR (KBr) m: 3314 (N–H); 1627 (C@O) cmꢀ1 1H
.
NMR (DMSO-d6, 400 MHz) 1.34 (q, 2H); 1.75 (d,
2H); 2.08 (br s, 2H); 2.28 (s, 3H); 2.71 (br s, 2H); 3.42
(s, 2H); 4.24 (d, 2H); 5.95 (d, 1H); 6.30 (t, 1H); 7.12

S. Galiano et al. / Bioorg. Med. Chem. 15 (2007) 3896–3911
3905
1g (0.03 g, yield: 7%) as a beige solid. Mp 73–75 ꢁC. IR
(KBr) m: 3330 (N–H); 1667 (C@O) cmꢀ1 1H NMR
5.9. Procedure for the preparation of 2-[1-(4-methylben-
zyl)-4-piperidinyl]ethanol (18)
.
(DMSO-d6, 400 MHz) d: 1.04 (d, 6H); 1.58 (s, 2H);
1.72 (s, 2H); 1.91 (s, 2H); 2.29 (s, 3H); 2.88 (m, 2H);
3.26 (d, 1H); 3.36 (d, 2H); 3.78 (s, 3H); 4.18–4.37 (dd,
2H); 4.56 (s, 2H); 5.85 (s, 1H); 7.01 (d, 2H,
J = 8.8 Hz); 7.14 (d, 2H); 7.20 (m, 4H); 7.27 (d, 2H);
7.59 (m, 4H); 7.70 (m, 2H). Anal. Calcd for
C33H41N3O4: C, 72.93%, H, 7.55%; N, 7.73%. Found:
C, 72.68%; H, 7.48%; N, 7.89%. MS (EI, 70 eV): m/z
(%) = 544 ([MÆ]+, 2), 525 (4), 486 (3), 339 (4), 197 (100).
4-Piperidine ethanol (5.19 g, 40.17 mmol) in acetonitrile
(125 mL) was treated under N2 atmosphere with p-meth-
ylbenzylbromide (7.43 g, 40.17 mmol) and cesium car-
bonate (13.09 g, 40.17 mmol). The reaction mixture
was stirred under reflux for 1–2 h, filtered, and concen-
trated to dryness in vacuo. The residue was taken up
with diethyl ether (20 mL). The obtained precipitate
was filtered and the liquid fraction was evaporated in or-
der to give 18 (6.21 g, yield: 66%) as a yellow oil. IR
5.8.3. Procedure for the preparation of 1-(3-hydroxy-3-
methyl-2-oxobutyl)-1-(20-methoxy-4-biphenylmethyl)-3-[1-
(4-methylbenzyl)-4-piperidinyl]urea (1h). The title com-
pound was synthesized from 7, 10, and 5 according to
the same procedure of Section 5.8 in order to afford 1h
(0.08 g, yield: 5%) as a beige solid. Mp 89–90 ꢁC. IR
(KBr) m: 3354 (O–H); 1285 (C–N) cmꢀ1 1H NMR
.
(DMSO-d6, 400 MHz) d: 1.06–1.15 (m, 2H); 1.32–1.35
(m, 3H); 1.58 (d, 2H); 1.81–1.87 (m, 2H); 2.27 (s, 3H);
2.74 (d, 2H); 3.38–3.44 (s, 2H); 3.49 (d, 2H); 4.32 (t,
1H, J = 5.1 Hz); 7.10 (d, 2H, J = 8.0 Hz); 7.15 (d, 2H,
J = 8.0 Hz). MS (EI, 70 eV): m/z (%) = 233 ([MÆ]+, 10),
216 (15), 202 (8), 142 (75), 105 (100).
(KBr) m: 3299 (N–H); 1665 (C@O) cmꢀ1 1H NMR
.
(DMSO-d6, 400 MHz) d: 1.06 (m, 6H); 1.57 (br s, 2H);
1.76 (br s, 2H); 1.91 (br s, 2H); 2.29 (s, 3H); 2.92–3.01
(dd, 2H); 3.26 (d, 1H); 3.54 (d, 2H); 3.75 (s, 3H);
4.23–4.34 (dd, 2H); 4.57 (s, 2H); 5.88 (s, 1H); 7.01 (t,
1H); 7.18 (m, 4H); 7.26 (m, 3H); 7.32 (d, 1H); 7.43 (d,
2H); 7.53 (d, 1H). Anal. Calcd for C33H41N3O4: C,
72.93%, H, 7.55%; N, 7.73%. Found: C, 72.75%; H,
7.51%; N, 7.79%. MS (EI, 70 eV): m/z (%) = 524 (2),
507 (5), 327 (4), 200 (32), 186 (100).
5.10. Procedure for the preparation of [1-(4-methylbenzyl)-
4-piperidinyl]acetaldehyde (19)
DMSO (4.15 mL, 58.64 mmol) in 5 mL CH2Cl2 was
added dropwise to a solution of oxalyl chloride
(9.13 g, 71.96 mmol) in CH2Cl2 (40 mL) and then stir-
red at ꢀ78 ꢁC under N2 atmosphere. After 5 min of
stirring, compound 18 (6.21 g, 26.65 mmol) was diluted
in CH2Cl2 (50 mL) and stirred for 30 min at ꢀ78 ꢁC.
Finally, triethylamine (27.44 mL, 197.23 mmol) was
added dropwise and the mixture was stirred at this
temperature for approximately 10 min. The reaction
mixture was warmed to room temperature for about
2 h, quenched with H2O, and extracted with CH2Cl2.
The organic phase was dried over anhydrous sodium
sulfate and evaporated in vacuo to afford 19 (5.37 g,
yield: 87%) as a beige oil. IR (KBr) m: 1724 (C@O);
5.8.4. Procedure for the preparation of 1-(30-cyano-4-
biphenylmethyl)-1-(3-hydroxy-3-methyl-2-oxobutyl)-3-[1-
(4-methylbenzyl)-4-piperidinyl]urea (1i). The title com-
pound was synthesized from 7, 11, and 5 according
to the same procedure of Section 5.8 in order to af-
ford 1i (0.06 g, yield: 13%) as a beige solid. Mp
128–130 ꢁC. IR (KBr) m: 3229 (N–H); 1668 (C@O)
cmꢀ1 1H NMR (DMSO-d6, 400 MHz) d: 1.06 (m,
.
1
6H); 1.26 (m, 2H); 1.75 (br s, 2H); 1.91 (br s, 2H);
2.33 (s, 3H); 2.94–3.02 (dd, 2H); 3.26 (d, 1H); 3.69
(br s, 2H); 4.29 (m, 2H); 4.64 (s, 2H); 5.96 (s, 1H);
7.26 (br s, 2H); 7.34 (d, 4H); 7.53 (d, 1H); 7.67 (t,
1H); 7.74 (d, 2H); 7.83 (d, 1H); 8.03 (d, 1H) Anal.
Calcd for C33H38N4O3ÆHCl: C, 68.93%, H, 6.79%;
N, 9.75%. Found: C, 68.85%; H, 6.69%; N, 9.67%.
MS (EI, 70 eV): m/z (%) = 538 ([MÆ]+, 2), 508 (5),
479 (3), 370 (5), 186 (100).
1265 (C–N) cmꢀ1. H NMR (DMSO-d6, 400 MHz) d:
1.16–1.20 (m, 2H); 1.58 (d, 2H); 1.78 (br s, 1H); 1.89
(t, 2H); 2.27 (s, 3H); 2.32–2.34 (m, 2H); 2.74 (d, 2H);
3.42 (s, 2H); 7.10 (d, 2H, J = 7.8 Hz); 7.15 (d, 2H,
J = 8.2 Hz); 9.65 (s, 1H). MS (EI, 70 eV): m/z
(%) = 231 ([MÆ]+, 5), 214 (15), 202 (20), 188 (56), 105
(100).
5.11. General procedure for the preparation of (4-biphenyl-
methyl)-{2-[1-(4-methylbenzyl)-4-piperidinyl]ethyl}amine
derivatives (20–24)
5.8.5. Procedure for the preparation of 1-(4-biphenyl-
methyl)-1-(3-hydroxy-3-methyl-2-oxobutyl)-3-[1-(4-methyl-
benzyl)-4-piperidinyl]urea (1j). The title compound was
synthesized from 7, 12, and 5 according to the same
procedure of Section 5.8 in order to afford 1j
(0.10 g, yield: 7%) as a beige solid. Mp 121–122 ꢁC.
Compound 19 (5.37 g, 23.25 mmol) and the appropriate
4-biphenylmethyl amine derivatives 8–12 (4.26 g,
23.25 mmol) were combined in MeOH (60 mL) and
stirred in the presence of molecular sieves at room tem-
perature, under N2 atmosphere, overnight. Triacetoxy-
sodiumborohydride (7.88 g, 37.19 mmol) was then
added and stirred for 4–8 h. The reaction was followed
by TLC (CH2Cl2/MeOH 95:5) and was found complete
after 4–8 h (it depends on the 4-phenylbenzylamine
derivative). The reaction was quenched with NaHCO3,
extracted with CH2Cl2, dried over anhydrous sodium
sulfate, and evaporated. The residue was washed with
diethyl ether and acetone in order to give the desired
amines 20–24.
IR (KBr) m: 3383 (N–H); 1672 (C@O) cmꢀ1
.
1H
NMR (DMSO-d6, 400 MHz) d: 1.06 (d, 6H); 1.38 (s,
2H); 1.66 (s, 2H); 1.81 (s, 2H); 2.39 (s, 3H); 2.99 (d,
2H); 3.29 (d, 2H); 3.58 (d,1H); 4.22–4.39 (dd, 2H);
4.65 (d, 2H); 5.76 (s, 1H); 5.96 (s, 1H); 7.20 (s, 2H);
7.31 (m, 4H); 7.36 (t, 1H); 7.46 (t, 2H); 7.66 (t,
4H). Anal. Calcd for C32H39N3O3: C, 74.85%, H,
7.60%; N, 8.18%. Found: C, 74.54%; H, 7.46%; N,
7.95%. MS (EI, 70 eV): m/z (%) = 495 (10), 436 (23),
372 (4), 310 (9), 186 (100).

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S. Galiano et al. / Bioorg. Med. Chem. 15 (2007) 3896–3911
5.11.1. Procedure for the preparation of (40-fluoro-4-
biphenylmethyl)-{2-[1-(4-methylbenzyl)-4-piperidinyl]ethyl}-
amine (20). The title compound was synthesized from 19
and 8 according to the experimental procedure of Sec-
tion 5.11 in order to provide 20 (0.73 g, yield: 44%) as
1H); 1.53–1.60 (m, 4H); 1.90 (t, 2H); 2.27 (s, 3H);
2.76–2.82 (m, 4H); 3.47 (s, 2H); 4.03 (s, 2H); 7.11 (d,
2H, J = 7.8 Hz); 7.17 (d, 2H, J = 7.9 Hz); 7.38 (t, 1H,
J = 7.3 Hz); 7.47 (t, 2 H, J = 7.6 Hz); 7.60 (d, 2H,
J = 8.1 Hz); 7.67–7.40 (m, 2H). Anal. Calcd for
C28H34N2: C, 84.42%; H, 8.54%; N, 7.03%. Found: C,
84.40%; H, 8.48%; N, 6.73%.
1
a beige oil. IR (KBr) m: 3354 (N–H) cmꢀ1. H NMR
(DMSO-d6, 400 MHz) d: 1.05–1.13 (m, 2H); 1.35 (t,
3H); 1.56 (d, 2H); 1.83 (t, 2H); 2.27 (s, 3H); 2.72 (d,
2H); 3.47 (s, 4H); 3.67 (s, 2H); 7.08–7.15 (m, 4H); 7.27
(t, 2H); 7.39 (d, 2H, J = 7.9 Hz); 7.58 (t, 2H); 7.68 (t,
2H). MS (EI, 70 eV): m/z (%) = 416 ([MÆ]+, 15), 397
(12), 245 (4), 231 (100), 213 (10).
5.12. General Procedure for the preparation of 1-(4-biphenyl-
methyl)-3-isopropyl-1-{2-[1-(4-methylbenzyl)-4-piperidinyl]-
ethyl}urea derivatives. Method A (2a–e)
A solution of 20–24 (1.00 equiv) in 20 mL of anhydrous
dichloromethane was stirred at room temperature under
N2 atmosphere. Isopropylisocyanate (1.2 equiv) was then
added at 0 ꢁC and stirred at this temperature for about 2–
3 h. The reaction was found complete by TLC (CH2Cl2/
MeOH 95:5). The reaction was quenched with H2O, ex-
tracted with CH2Cl2, and the organic phase was dried
over Na2SO4 and evaporated. The crude product was
purified by flash column chromatography (CH2Cl2/
MeOH) in order to obtain the urea analogs 2a–e.
5.11.2. Procedure for the preparation of (40-methoxy-4-
biphenylmethyl)-{2-[1-(4-methylbenzyl)-4-piperidinyl]ethyl}-
amine (21). The title compound was synthesized from 19
and 9 according to the experimental procedure of Sec-
tion 5.11 in order to provide 21 (0.80 g, yield: 40%) as
1
a beige oil. IR (KBr) m: 3346 (N–H) cmꢀ1. H NMR
(DMSO-d6, 400 MHz) d: 1.09–1.15 (m, 4H); 1.32–1.36
(m, 1H); 1.54–1.60 (m, 2H); 1.91 (br s, 2H); 2.27 (s,
3H); 2.77–2.85 (m, 2H); 2.91–2.97 (m, 2H); 3.42–3.48
(m, 4H); 3.79 (s, 3H); 7.03 (d, 2H, J = 8.7 Hz); 7.11 (d,
2H, J = 7.6 Hz); 7.15 (d, 2H); 7.29 (t, 2H); 7.53–7.67
(m, 4H). MS (EI, 70 eV): m/z (%) = 428 ([MÆ]+, 5), 407
(4), 323 (5), 245 (5), 197 (100).
5.12.1. Procedure for the preparation of 1-(40-fluoro-4-
biphenylmethyl)-3-isopropyl-1-{2-[1-(4-methylbenzyl)-4-
piperidinyl]ethyl}urea (2a). The title compound was
synthesized from 20 and isopropylisocyanate according
to the experimental procedure of Section 5.12 and
the crude product was purified by flash column
chromatography (CH2Cl2/MeOH 97:3) and preparative
thin-layer chromatography (CH2Cl2/MeOH 90:10) to
provide 2a (0.02 g, yield: 4%) as a beige oil. IR (KBr)
5.11.3. Procedure for the preparation of (20-methoxy-4-
biphenylmethyl)-{2-[1-(4-methylbenzyl)-4-piperidinyl]ethyl}-
amine (22). The title compound was synthesized from 19
and 10 according to the experimental procedure of Sec-
tion 5.11 in order to provide 22 (0.97 g, yield: 70%) as a
1
beige oil. IR (KBr) m: 3345 (N–H) cmꢀ1
.
1H NMR
m: 3380 (N–H); 1739 (C@O) cmꢀ1. H NMR (DMSO-
(DMSO-d6, 400 MHz) d: 1.08–1.14 (m, 2H); 1.32–1.38
(m, 3H); 1.52–1.58 (m, 2H); 1.81–1.86 (m, 2H); 2.27 (s,
3H); 2.74 (br s, 2H); 2.91 (br s, 2H); 3.31–3.45 (m,
4H); 3.77 (s, 3H); 7.02 (t, 1H); 7.08–7.15 (m, 3H); 7.26
(d, 1H); 7.34 (d, 1H); 7.38–7.60 (m, 6H). MS (EI,
70 eV): m/z (%) = 428 ([MÆ]+, 3), 323 (8), 231 (100), 212
(5), 197 (66).
d6, 400 MHz) d: 1.01–1.05 (s, 9H); 1.33–1.35 (m, 2H);
1.58 (d, 2H); 1.82–1.85 (m, 2H); 2.27 (s, 3H); 2.74 (d,
2H); 3.18 (s, 2H); 3.42 (s, 2H); 3.64–3.71 (m, 1H); 4.23
(d, 2H); 5.75 (s, 1H); 7.09–7.16 (m, 4H); 7.25–7.33 (m,
4H); 7.58 (t, 2H, J = 4.1 Hz); 7.66–7.70 (m, 2H). MS
(EI, 70 eV): m/z (%) = 501 ([MÆ]+, 8), 478 (2), 396 (27),
316 (30), 105 (100).
5.11.4. Procedure for the preparation of (30-cyano-4-
biphenylmethyl)-{2-[1-(4-methylbenzyl)-4-piperidinyl]ethyl}-
amine (23). The title compound was synthesized from 19
and 11 according to the experimental procedure of Sec-
tion 5.11 in order to provide 23 (1.50 g, yield: 34%) as a
5.12.2. Procedure for the preparation of 3-isopropyl-1-(40-
methoxy-4-biphenylmethyl)-1-{2-[1-(4-methylbenzyl)-4-
piperidinyl]ethyl}urea (2b). The title compound was syn-
thesized from 21 and isopropylisocyanate according to
the experimental procedure of Section 5.12 and the crude
product was purified by preparative thin-layer chroma-
tography (CH2Cl2/MeOH 90:10) to provide 2b (0.04 g,
yield: 4%) as a beige oil. IR (KBr) m: 3346 (N–H); 1617
beige oil. IR (KBr) m: 3354 (N–H) cmꢀ1 1H NMR
.
(DMSO-d6, 400 MHz) d: 1.08 (br s, 2H); 1.32–1.37 (m,
3H); 1.56 (br s, 2H); 1.84 (t, 2H); 2.27 (s, 3H); 2.72–
2.75 (m, 2H); 3.42 (br s, 4H); 3.63–3.78 (m, 2H);
7.08–7.15 (m, 4H); 7.28 (t, 2H); 7.42–7.48 (m, 2H);
7.65–7.70 (m, 2H); 7.79 (d, 1H); 8.00 (d, 1H); 8.12 (s,
1H). MS (EI, 70 eV): m/z (%) = 423 ([MÆ]+, 9), 397 (6),
321 (9), 231 (100), 216 (32).
1
(C@O) cmꢀ1. H NMR (DMSO-d6, 400 MHz) d: 1.02–
1.07 (m, 7H); 1.12 (d, 2H); 1.35 (m, 2H); 1.57 (d, 2H);
1.91 (m, 2H); 2.25 (s, 3H); 2.77 (s, 2H); 3.18 (d, 2H);
3.34 (s, 2H); 3.84 (m, 1H); 4.42 (d, 2H); 5.96 (s, 1H);
7.00 (d, 2H); 7.11 (d, 2H); 7.14 (d, 2H); 7.25 (d, 2H,
J = 8.2 Hz); 7.54–7.59 (m, 4H). MS (EI, 70 eV): m/z
(%) = 513 ([MÆ]+, 4), 428 (3), 408 (7), 295 (4), 105 (100).
5.11.5. Procedure for the preparation of (4-biphenylmeth-
yl)-{2-[1-(4-methylbenzyl)-4-piperidinyl]ethyl}amine (24).
The title compound was synthesized from 19 and p-phe-
nylbenzylamine 12 commercially available according to
the experimental procedure of Section 5.11 in order to
provide 24 (0.5 g, yield: 39%) as a white solid. Mp
5.12.3. Procedure for the preparation of 3-isopropyl-1-(20-
methoxy-4-biphenylmethyl)-1-{2-[1-(4-methylbenzyl)-4-
piperidinyl]ethyl}urea (2c). The title compound was
synthesized from 22 and isopropylisocyanate according
to the experimental procedure of Section 5.12 and the
crude product was purified by preparative thin-layer
1
187–189 ꢁC. IR (KBr) m: 3430 (N–H) cmꢀ1. H NMR
(DMSO-d6, 400 MHz) d: 1.10–1.18 (m, 2H); 1.33 (br s,

S. Galiano et al. / Bioorg. Med. Chem. 15 (2007) 3896–3911
3907
chromatography (CH2Cl2/MeOH 90:10) to provide 2c
(0.09 g, yield: 6%) as a beige oil. IR (KBr) m: 3338 (N–
H); 1636 (C@O) cmꢀ1. 1H NMR (DMSO-d6, 400 MHz)
d: 1.02–1.07 (m, 7H); 1.12 (d, 2H); 1.35 (m, 2H); 1.57 (d,
2H); 1.91 (m, 2H); 2.25 (s, 3H); 2.77 (s, 2H); 3.18 (d,
2H); 3.34 (s, 2H); 3.84 (m, 1H); 4.42 (d, 2H); 5.96 (s,
1H); 7.00 (d, 2H); 7.11 (d, 2H); 7.14 (d, 2H); 7.25 (d,
2H, J = 8.2 Hz); 7.54–7.59 (m, 4H). MS (EI, 70 eV): m/z
(%) = 428 (2), 412 (3), 385 (2), 337 (8), 298 (100).
of a Curtius rearrangement and using DPPA (12.50 g,
45.42 mmol) in the presence of NEt3 (4.59 g,
45.42 mmol) in 100 mL of dry toluene was stirred under
reflux for 12–15 h under N2 atmosphere. The reaction
mixture was then evaporated in order to obtain 25
(6.8 g, yield: 87%) as an orange-beige oil. IR (KBr) m:
2256 (N@C@O); 1746 (C@O) cmꢀ1
.
1H NMR
(DMSO-d6, 400 MHz) d: 1.22 (s, 6H); 1.99 (s, 3H);
4.11 (s, 2H). MS (EI, 70 eV): m/z (%) = 157 ([MÆ]+, 5),
141 (10), 125 (3), 113 (5), 94 (100).
5.12.4. Procedure for the preparation of 1-(30-cyano-4-
biphenylmethyl)-3-isopropyl-1-{2-[1-(4-methylbenzyl)-4-
piperidinyl]ethyl}urea (2d). The title compound was
synthesized from 23 and isopropylisocyanate according
to the experimental procedure of Section 5.12 and the
crude product was purified by silica gel column chroma-
tography (CH2Cl2/MeOH 95:5) to afford 2d (0.02 g,
yield: 2%) as a beige oil. IR (KBr) m: 3353 (N–H);
5.13.2. Procedure for the synthesis of 1,1-di(acetyloxym-
ethyl)propyl isocyanate (26)
5.13.2.1. Acylation. First, the hydroxy group of
2,20-Bis(hydroxymethyl)butyric acid (5 g, 43.87 mmol)
was acetylated by heating it in neat AcCl
(15.65 mL, 219.36 mmol) until its dissolution. The
reaction mixture was then cooled to room tempera-
ture and then evaporated in order to obtain a color-
less oil (9.87 g, 97%). IR (KBr) m: 1752 (C@O)
1
1627 (C@O) cmꢀ1. H NMR (DMSO-d6, 400 MHz) d:
1.04–1.09 (m, 9H); 1.28–1.36 (m, 2H); 1.55 (d, 2H);
1.79 (t, 2H); 2.27 (s, 3H); 2.70 (d, 2H); 3.09–3.18 (m,
2H); 3.35 (m, 2H); 3.78–3.86 (m, 1H); 4.36–4.45 (d,
2H); 5.99 (t, 1H,); 7.08–7.16 (m, 4H); 7.30–7.52 (d,
2H); 7.67 (t, 1H); 7.72 (d, 2H, J = 8.3 Hz); 7.81 (m,
1H); 8.01 (t, 1H); 8.15 (d, 1H). MS (EI, 70 eV): m/z
(%) = 508 ([MÆ]+, 4), 403 (10), 318 (14), 231 (62), 105
(100).
cmꢀ1 1H NMR (DMSO-d6, 400 MHz) d: 0.98 (t,
.
3H); 1.59 (q, 3H); 2.14 (s, 6H); 4.27 (s, 4H); 12.68
(br s, 1H).
5.13.2.2. Isocyanate formation. The compound ob-
tained in the acylation (9.87 g, 42.54 mmol) by means
of a Curtius rearrangement and using DPPA (9.17 g,
42.54 mmol) in the presence of NEt3 (4.30 g,
42.54 mmol) in 60 mL of dry toluene was stirred un-
der reflux for 4 h under N2 atmosphere. The reaction
mixture was then evaporated in order to obtain 26
(7.36 g, 76%) as a beige oil. IR (KBr) m: 2255
5.12.5. Procedure for the preparation of 1-(4-biphenyl-
methyl)-3-isopropyl-1-{2-[1-(4-methylbenzyl)-4-piperidi-
nyl]ethyl}urea (2e). The title compound was synthesized
from 24 and isopropylisocyanate according to the
experimental procedure of Section 5.12 and the crude
product was purified by flash column chromatography
(CH2Cl2/MeOH 95:5) to provide 2e (0.14 g, yield: 9%)
as a yellow oil. IR (KBr) m: 3362 (N–H); 1621 (C@O)
1
(N@C@O); 1750 (C@O) cmꢀ1. H NMR (DMSO-d6,
400 MHz) d: 0.92 (t, 3H, J = 7.5 Hz); 1.62–1.69 (m,
2H); 2.07 (s, 6H); 4.12 (s, 4H). MS (EI, 70 eV): m/z
(%) = 228 ([MÆ]+, 2), 215 (3), 188 (15), 169 (5), 114
(100).
cmꢀ1 1H NMR (DMSO-d6, 400 MHz) d: 1.06 (s,
.
9H); 1.35 (d, 2H); 1.56 (d, 2H); 1.80 (s, 2H); 2.27 (s,
3H); 2.70 (d, 2H); 3.15 (d, 2H); 3.42 (s, 2H); 3.80–
3.85 (m, 1H); 4.44 (s, 2H); 6.00 (d, 1H); 7.09 (d, 2H,
J = 7.9 Hz); 7.13 (d, 2H, J = 8.0 Hz); 7.28 (d, 2H, J =
8.0 Hz); 7.35 (t, 1H, J = 7.3 Hz); 7.45 (t, 2H,
J = 7.6 Hz); 7.61–7.66 (m, 4H). MS (EI, 70 eV): m/z
(%) = 483 ([MÆ]+, 10), 468 (3), 378 (43), 316 (44), 167
(100).
5.13.3. General procedure for the preparation of urea
derivatives (2f–o). A solution of corresponding amines
20–24 (1.00 equiv) in anhydrous dichloromethane was
stirred at 0 ꢁC under N2 atmosphere. The appropriate
isocyanate 25 or 26 was then added dropwise at 0 ꢁC,
and the reaction mixture was again stirred at this tem-
perature for 5 h. Upon completion, the reaction mixture
was filtered and evaporated in order to obtain the de-
sired protected ureas 2f–o.
5.13. Procedure for the preparation of urea derivatives.
Method B (2f–z)
5.13.3.1. Procedure for the synthesis of 3-[1-(acetyl-
oxymethyl)-1-methylethyl]-1-(40-fluoro-4-biphenylmethyl)-
1-{2-[1-(4-methylbenzyl)-4-piperidinyl]ethyl}urea (2f).
The title compound was synthesized from 20 and 25
according to the same procedure of Section 5.13.3 in
order to afford 2f (1.15 g, yield: 84%) as a beige oil.
IR (KBr) m: 3411 (N–H); 1737 (ester C@O); 1654
5.13.1. Procedure for the synthesis of 1-(acetyloxymeth-
yl)-1-methyl-ethylisocyanate (25)
5.13.1.1. Acylation. First, the hydroxy group of 2,2-
dimethyl-3-hydroxypropionic acid (5 g, 42.37 mmol)
was acetylated by heating it in neat AcCl (15.12 mL,
211.86 mmol) until its dissolution. The reaction mixture
was then cooled to room temperature and evaporated in
order to obtain a colorless oil (7.92 g, yield: 97%). IR
(urea C@O) cmꢀ1 1H NMR (DMSO-d6, 400 MHz)
.
d: 1.19 (m, 3H); 1.22 (s, 6H); 1.36 (br s, 2H); 1.65
(d, 2H); 2.05 (m, 3H); 2.28 (s, 3H); 2.88 (d, 2H);
3.17 (d, 2H); 3.34 (m, 2H); 3.79 (s, 2H); 4.11 (d,
2H); 4.44 (s, 2H); 5.76 (s, 1H); 7.11–7.15 (m, 4H);
7.19-7.31 (m, 4H); 7.61 (m, 2H); 7.69–7.71 (m, 2H).
MS (EI, 70 eV): m/z (%) = 573 ([MÆ]+, 3), 468 (15),
388 (17), 337 (4), 231 (100).
(KBr) m: 3324 (O–H); 1747 (C@O)cmꢀ1 1H NMR
.
(DMSO-d6, 400 MHz) d: 1.10 (s, 6H); 1.97 (s, 3H);
3.87 (s, 2H); 12.63 (br s, 1H).
5.13.1.2. Isocyanate formation. The compound ob-
tained in the acylation (7.92 g, 54.25 mmol) by means

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S. Galiano et al. / Bioorg. Med. Chem. 15 (2007) 3896–3911
5.13.3.2. Procedure for the synthesis of 3-[1-(acetyl-
J = 7.6 Hz); 7.61–7.66 (m, 4H). MS (EI, 70 eV): m/z
(%) = 555 ([MÆ]+, 9), 450 (32), 388 (23), 231 (97), 167
(100).
oxymethyl)-1-methylethyl]-1-(40-methoxy-4-biphenyl-
methyl)-1-{2-[1-(4-methylbenzyl)-4-piperidinyl]ethyl}
urea (2g). The title compound was synthesized from 21
and 25 according to the same procedure of Section
5.13.3 in order to afford 2g (1.26 g, yield: 96%) as a beige
5.13.3.6. Procedure for the synthesis of 3-[1,1-di(acet-
yloxymethyl)propyl]-1-(40-fluoro-4-biphenylmethyl)-1-{2-[1-
(4-methylbenzyl)-4-piperidinyl]ethyl}urea (2k). The title
compound was synthesized from 20 and 26 according
to the same procedure of Section 5.13.3 in order to af-
ford 2k (0.96 g, yield: 95%) as a beige oil. IR (KBr) m:
oil. IR (KBr) m: 3330 (N–H), 1651 (C@O) cmꢀ1 1H
.
NMR (DMSO-d6, 400 MHz) d: 1.04–1.10 (m, 3H);
1.21 (s, 6H); 1.33–1.38 (m, 2H); 1.53–1.65 (m, 2H);
1.86–1.88 (m, 2H); 2.07 (s, 3H); 2.25 (s, 3H); 2.74 (d,
2H); 3.39 (t, 2H); 3.64 (t, 2H); 4.12 (s, 2H); 4.43 (s,
2H); 6.73–6.99 (m, 4H); 7.10–7.17 (m, 4H); 7.24–7.30
(m, 2H); 7.53–7.68 (m, 2H). MS (EI, 70 eV): m/z
(%) = 585 ([MÆ]+, 3), 452 (30), 388 (45), 368 (5), 105
(100).
3342 (N–H), 1639 (urea C@O) cmꢀ1
.
1H NMR
(DMSO-d6, 400 MHz) d: 0.90 (t, 3H, J = 7.5 Hz); 1.12
(m, 2H); 1.40 (br s, 2H); 1.60–1.67 (m, 2H); 1.75 (t,
2H, J = 7.6 Hz); 1.99 (s, 6H); 2.01–2.07 (m, 1H); 2.27
(s, 3H); 2.77 (d, 2H); 3.20 (t, 2H); 4.10–4.18 (m, 8H);
4.46 (s, 2H); 5.76 (s, 1H); 7.09–7.21 (m, 4H); 7.28–7.33
(m, 4H); 7.60 (t, 2H); 7.67–7.70 (m, 2H). MS (EI,
70 eV): m/z (%) = 645 ([MÆ]+, 4), 585 (7), 540 (15), 480
(56), 231 (100).
5.13.3.3. Procedure for the synthesis of 3-[1-(acetyl-
oxymethyl)-1-methylethyl]-1-(20-methoxy-4-biphenyl
methyl)-1-{2-[1-(4-methylbenzyl)-4-piperidinyl]ethyl}urea
(2h). The title compound was synthesized from 22 and
25 according to the same procedure of Section 5.13.3
in order to afford 2h (1.05 g, yield: 70%) as a beige oil.
IR (KBr) m: 3324 (N–H), 1735 (ester C@O); 1658 (urea
5.13.3.7. Procedure for the synthesis of 3-[1,1-di(acet-
yloxymethyl)propyl]-1-(40-methoxy-4-biphenylmethyl)-1-
{2-[1-(4-methylbenzyl)-4-piperidinyl]ethyl}urea (2l). The
title compound was synthesized from 21 and 26 accord-
ing to the same procedure of Section 5.13.3 in order to
afford 2l (2.34 g, yield: 79.9%) as a beige oil. This prod-
uct was purified with SPE (solid phase extraction) using
a C-18 E cartridge and water–acetonitrile as a mobile
phase. IR (KBr) m: 3420 (N–H), 1740 (ester C@O);
1
C@O) cmꢀ1. H NMR (DMSO-d6, 400 MHz) d: 1.17
(s, 1H); 1.23 (s, 6H); 1.26 (m, 2H); 1.34 (m, 2H); 1.61
(d, 2H); 2.03 (s, 3H); 2.27 (s, 3H); 2.88 (d, 2H); 3.17
(d, 2H); 3.34 (m, 2H); 3.45 (m, 2H); 3.75 (s, 3H); 4.12
(s, 2H); 4.34 (s, 2H); 5.76 (s, 1H); 6.96 (m, 1H); 7.11
(m, 4H); 7.22 (m, 1H); 7.33 (m, 1H); 7.50 (m, 1H);
7.66-7.83 (m, 2H); 8.04 (t, 1H); 8.17 (d, 1H). MS (EI,
70 eV): m/z (%) = 452 (3), 388 (10), 368 (7), 231 (45),
105 (100).
1654 (urea C@O) cmꢀ1
.
1H NMR (DMSO-d6,
400 MHz) d: 0.77 (t, 3H); 1.07 (t, 1H); 1.13 (d, 2H);
1.36 (d, 2H); 1.56 (d, 2H); 1.74 (m, 2H); 1.98 (s, 6H);
2.27 (s, 3H); 2.75 (d, 2H); 3.16–3.21 (m, 4H); 3.39 (s,
2H); 3.79 (s, 3H); 4.13–4.27 (dd, 4H); 4.44 (s, 2H);
5.52 (s, 1H); 7.02 (d, 2H); 7.11 (d, 2H, J = 8.0 Hz);
7.15 (d, 2H,J = 8.0 Hz); 7.27 (d, 2H,J = 8.3 Hz); 7.56–
7.59 (m, 4H). MS (EI, 70 eV): m/z (%) = 642 (2), 597
(4), 552 (3), 492 (16), 231 (100).
5.13.3.4. Procedure for the synthesis of 3-[1-(acetyl-
oxymethyl)-1-methylethyl]-1-(30-cyano-4-biphenylmethyl)-
1-{2-[1-(4-methylbenzyl)-4-piperidinyl]ethyl}urea
(2i).
The title compound was synthesized from 23 and 25
according to the same procedure of Section 5.13.3 in
order to afford 2i (0.85 g, yield: 89%) as a brown oil.
IR (KBr) m: 3294 (N–H), 2229 (CN); 1738 (ester
5.13.3.8. Procedure for the synthesis 3-[1,1-di(acetyl-
oxymethyl)propyl]-1-(20-methoxy-4-biphenylmethyl)-1-
{2-[1-(4-methylbenzyl)-4-piperidinyl]ethyl}urea (2m). The
title compound was synthesized from 22 and 26 accord-
ing to the same procedure of Section 5.13.3 in order to
afford 2m (0.97 g, yield: 78.9%) as a beige oil. IR
C@O); 1651 (C@O) cmꢀ1
.
1H NMR (DMSO-d6,
400 MHz) d: 1.15 (s, 1H); 1.17 (s, 6H); 1.22 (m, 2H);
1.43 (br s, 2H); 1.80 (m, 2H); 2.07 (s, 3H); 2.27 (s,
3H); 2.73 (br s, 2H); 3.17 (m, 2H); 3.36 (m, 2H); 3.50
(m, 2H); 3.90 (s, 2H); 4.10 (s, 2H); 5.76 (s, 1H); 7.09–
7.13 (m, 4H); 7.20–7.24 (m, 2H); 7.50 (m, 1H); 7.67–
7.72 (m, 2H); 7.78–7.83 (m, 1H); 8.03 (m, 1H); 8.16 (d,
1H). MS (EI, 70 eV): m/z (%) = 475 (4), 454 (4), 388
(8), 295 (9), 231 (100).
(KBr) m: 3358 (N–H), 1658 (urea C@O) cmꢀ1 1H
.
NMR (DMSO-d6, 400 MHz) d: 0.76–0.85 (m, 4H);
1.11 (m, 2H); 1.40 (d, 2H); 1.48 (m, 1H); 1.59 (d, 2H);
1.64–1.67 (m, 2H); 1.85 (s, 2H); 2.01 (s, 6H); 2.27 (s,
3H); 2.76 (d, 2H, J = 10.0 Hz); 3.20 (m, 2H); 3.38 (d,
2H, J = 6.7 Hz); 3.75 (s, 3H); 4.12 (d, 4H); 4.13–4.25
(m, 2H); 5.93 (s, 1H); 7.01 (t, 1H, J = 7.4 Hz); 7.09 (m,
3H); 7.14 (d, 2H); 7.26 (d, 2H); 7.33 (t, 1H); 7.40 (d,
2H); 7.50 (m, 1H). MS (EI, 70 eV): m/z (%) = 657
([MÆ]+, 2), 597 (2), 552 (3), 492 (5), 114 (100).
5.13.3.5. Procedure for the synthesis of 3-[1-(acetyl-
oxymethyl)-1-methylethyl]-1-(4-biphenylmethyl)-1-{2-[1-(4-
methylbenzyl)-4-piperidinyl]ethyl}urea (2j). The title com-
pound was synthesized from 24 and 25 according to the
same procedure of Section 5.13.3 in order to afford 2j
(0.50 g, yield: 64%) as
a beige oil. IR (KBr)
m: 3420 (N–H), 1737 (ester C@O); 1647 (urea C@O)
5.13.3.9. Procedure for the synthesis of 3-[1,1-di(acet-
yloxymethyl)propyl]-1-(30-cyano-4-biphenylmethyl)-1-{2-
[1-(4-methylbenzyl)-4-piperidinyl]ethyl}urea (2n). The title
compound was synthesized from 23 and 26 according
to the same procedure of Section 5.13.3 in order
to afford 2n (1.00 g, yield: 93%) as a brown oil. IR
(KBr) m: 3338 (N–H), 1739 (ester C@O); 1642 (urea
1
cmꢀ1. H NMR (DMSO-d6, 400 MHz) d: 1.18 (t, 3H);
1.24 (s, 6H); 1.36 (br s, 2H); 1.69 (d, 2H); 2.03 (s, 3H);
2.30 (s, 3H); 3.00–3.05 (m, 4H); 3.17 (d, 2H); 3.93 (s,
2H); 4.15 (s, 2H); 4.45 (s, 2H); 5.76 (s, 1H); 7.09 (d,
2H, J = 7.9 Hz); 7.13 (d, 2H, J = 8.0 Hz); 7.28 (d, 2 H,
J = 8.0 Hz); 7.35 (t, 1H, J = 7.3 Hz); 7.45 (t, 2H,

S. Galiano et al. / Bioorg. Med. Chem. 15 (2007) 3896–3911
3909
1
C@O) cmꢀ1. H NMR (DMSO-d6, 400 MHz) d: 0.75–
the same procedure as of Section 5.13.4 in order to af-
ford a beige oil, which was purified twice by preparative
thin-layer chromatography (CH2Cl2/MeOH 90:10) to
give 2r (0.02 g, yield: 2%) as a beige oil. IR (KBr) m:
0.83 (m, 3H); 1.04–1.06 (m, 2H); 1.42 (br s, 2H); 1.65
(br s, 2H); 1.72–1.81 (m, 2H); 1.97 (t, 1H); 2.01 (s, 6H);
2.26 (s, 3H); 2.72 (t, 2H); 3.17 (d, 2H); 3.37 (s, 2H);
4.10–4.27 (m, 6H); 7.08–7.15 (m, 4H); 7.32 (t, 2H,
J = 8.4 Hz); 7.47 (d, 1H); 7.64 (t, 2H); 7.77 (d, 1H,
J = 7.2 Hz); 7.97 (d, 1H, J = 7.0 Hz); 8.08 (s, 1H). MS
(EI, 70 eV): m/z (%) = 460 (2), 337 (2), 256 (4), 186 (15),
114 (100).
3342 (N–H), 1639 (urea C@O) cmꢀ1
.
1H NMR
(DMSO-d6, 400 MHz) d: 0.86–0.90 (m, 2H); 1.05–1.36
(m, 9H); 1.57 (br s, 2H); 1.86 (br s, 2H); 2.27 (s, 3H);
2.76 (br s, 2H); 3.12 (br s, 2H); 3.35 (d, 2H); 4.12 (br
s, 2H); 4.42 (br s, 2H); 6.73–6.76 (m, 4H); 7.10–7.16
(m, 4H); 7.26–7.30 (m, 2H); 7.58–7.69 (m, 2H). MS
(EI, 70 eV): m/z (%) = 428 (12), 346 (5), 323 (10), 295
(8), 231 (100).
5.13.3.10. Procedure for the synthesis of 3-[1,1-di(acet-
yloxymethyl)propyl]-1-(4-biphenylmethyl)-1-{2-[1-(4-methyl-
benzyl)-4-piperidinyl]ethyl}urea (2o). The title compound
was synthesized from 24 and 26 according to the same
procedure of Section 5.13.3 in order to afford 2o
(0.80 g, 86%) as a yellow oil. IR (KBr) m: 3414 (N–H),
5.13.4.3. Procedure for the synthesis of 3-(2-hydroxy-
1,1-dimethylethyl)-1-(20-methoxy-4-biphenylmethyl)-1-
{2-[1-(4-methylbenzyl)-4-piperidinyl]ethyl}urea (2s). The
title compound was synthesized from 2h according to
the same procedure as of Section 5.13.4 in order to af-
ford a beige oil, which was purified by flash column
chromatography (CH2Cl2/MeOH 95:5) and then with
silica gel thin layer preparative (CH2Cl2/MeOH 90:10)
to afford 2s (8.5 mg, yield: 1%) as a beige oil. IR
1740 (ester C@O); 1652 (urea C@O) cmꢀ1. H NMR
1
(DMSO-d6, 400 MHz) d: 0.91 (t, 3H, J = 7.5 Hz);
1.17–1.21 (m, 2H); 1.39 (br s, 2H); 1.61–1.66 (m, 2H);
1.77 (t, 2H, J = 7.6 Hz); 1.98 (s, 6H); 2.02 (s, 1H); 2.07
(s, 2H); 2.28 (s, 3H); 2.84 (d, 2H); 3.22 (d, 2H,
J = 7.1 Hz); 3.54 (s, 2H); 4.12 (d, 4H); 4.27 (d, 2H);
4.48 (s, 2H); 7.12 (d, 2H, J = 7.8 Hz); 7.20–7.25 (m,
2H); 7.30–7.37 (m, 3H); 7.43–7.47 (m, 2H); 7.63 (t,
4H). MS (EI, 70 eV): m/z (%) = 627 ([MÆ]+, 3), 567 (5),
522 (12), 462 (32), 130 (100).
(KBr) m: 3413 (N–H), 1628 (urea C@O) cmꢀ1 1H
.
NMR (DMSO-d6, 400 MHz) d: 1.17 (s, 6H); 1.20 (s,
1H); 1.22 (m, 2H); 1.33 (br s, 2H); 1.60 (br s, 2H);
2.27 (s, 3H); 2.83 (d, 2H); 3.10 (d, 2H); 3.29 (m, 2H);
3.45 (m, 2H); 3.75 (s, 3H); 4.34 (s, 2H); 5.07 (br s,
1H); 5.36 (s, 2H); 5.76 (s, 1H); 7.08–7.20 (m, 5H);
7.34 (m, 1H); 7.50 (m, 1H); 7.64–7.73 (m, 2H); 7.81
(d, 1H); 8.02 (d, 1H); 8.15 (s, 1H). MS (EI, 70 eV):
m/z (%) = 542 ([MÆ]+, 2), 427 (3), 346 (5), 323 (5), 231
(100).
5.13.4. General procedure for the preparation of urea
derivatives (2p–z). A solution of the appropriate urea
derivatives 2f–o (1.0 g, 1.88 mmol) in methanol
(80 mL) and 1 g K2CO3 (1.00 g, 7.25 mmol) was stirred
at room temperature under N2 atmosphere. The reac-
tion was completed after 3 h of stirring, and then filtered
and evaporated in vacuo. The residue was washed with
water and quenched with dichloromethane. The organic
layer was dried over NaSO4, filtered, concentrated, and
purified with flash column chromatography (CH2Cl2/
MeOH 95:5) and then with silica gel thin layer prepara-
tive (CH2Cl2/MeOH 90:10) to afford the desired urea
derivatives 2p–z.
5.13.4.4. Procedure for the synthesis of 1-(30-cyano-4-
biphenylmethyl)-3-(2-hydroxy-1,1-dimethylethyl)-1-{2-[1-
(4-methylbenzyl)-4-piperidinyl]ethyl}urea (2t). The title
compound was synthesized from 2i according to the same
procedure as of Section 5.13.4 in order to afford a brown
oil which was purified with silica gel column chromatog-
raphy (CH2Cl2/MeOH 95:5) and then with silica gel
thin layer preparative (CH2Cl2/MeOH 90:10) to afford
2t (4.4 mg, yield: 0.6%) as a yellow oil. IR (KBr) m:
5.13.4.1. Procedure for the synthesis of 1-(40-fluoro-4-
biphenylmethyl)-3-(2-hydroxy-1,1-dimethylethyl)-1-{2-[1-
(4-methylbenzyl)-4-piperidinyl]ethyl}urea (2p). The title
compound was synthesized from 2f according to the same
procedure as of Section 5.13.4 in order to afford a beige
oil, which was purified with flash column chromatogra-
phy (CH2Cl2/MeOH 95:5) and then with silica gel thin
layer preparative (CH2Cl2/MeOH 90:10) to give 2p
(12 mg, yield: 12%) as a beige oil. IR (KBr) m: 3411 (N–
3355 (N–H), 1624 (urea C@O) cmꢀ1
.
1H NMR
(DMSO-d6, 400 MHz) d: 0.83 (m, 3H); 1.19 (s, 6H);
1.56 (d, 2H); 1.80 (m, 2H); 2.27 (s, 3H); 2.71 (d, 2H);
3.17 (m, 2H); 3.32 (br s, 2H); 3.50 (s, 2H); 4.14 (s,
2H); 4.45 (s, 2H); 5.15 (br s, 1H); 5.76 (s, 1H); 7.08–
7.16 (m, 4H); 7.32–7.36 (m, 2H); 7.50 (d, 1H); 7.64–
7.73 (m, 2H); 7.81 (d, 1H); 8.02 (d, 1H); 8.15 (s, 1H).
MS (EI, 70 eV): m/z (%) = 507 (2), 477 (2), 423 (4),
.394 (2), 105 (100).
H), 1623 (urea C@O) cmꢀ1 1H NMR (DMSO-d6,
.
400 MHz) d: 0.85–0.87 (m, 1H); 0.99–1.03 (m, 2H); 1.23
(s, 6H); 1.34 (m, 2H); 1.57 (d, 2H); 1.82–1.91 (d, 2H);
2.27 (s, 3H); 2.73 (br s, 2H); 3.17 (s, 2H); 3.35 (br s, 2H);
4.10 (d, 2H); 4.43 (s, 2H); 5.11 (br s, 1H); 5.38 (s, 1H);
7.09–7.18 (m, 4H); 7.23–7.30 (m, 4H); 7.59–7.61 (d, 2H,
J = 4.0 Hz); 7.67–7.71 (m, 2H). MS (EI, 70 eV): m/z
(%) = 531 ([MÆ]+, 4), 500 (3), 416 (13), 346 (7), 231 (100).
5.13.4.5. Procedure for the synthesis of 1-(4-biphe-
nylmethyl)-3-(2-hydroxy-1,1-dimethylethyl)-1-{2-[1-(4-
methylbenzyl)-4-piperidinyl]ethyl}urea (2u). The title
compound was synthesized from 2j according to the
same procedure as of Section 5.13.4 in order to afford
a brown oil which was purified with silica gel column
chromatography (CH2Cl2/MeOH 95:5) and then with
silica gel thin layer preparative (CH2Cl2/MeOH 90:10)
to afford 2u (0.24 g, yield: 52%) as a yellow oil. IR
5.13.4.2. Procedure for the synthesis of 3-(2-hydroxy-
1,1-dimethylethyl)-1-(40-methoxy-4-biphenylmethyl)-1-
{2-[1-(4-methylbenzyl)-4-piperidinyl]ethyl}urea (2r). The
title compound was synthesized from 2g according to
(KBr) m: 3364 (N–H), 1635 (urea C@O) cmꢀ1
.
1H
NMR (DMSO-d6, 400 MHz) d: 0.87 (t, 3H); 1.20 (s,

3910
S. Galiano et al. / Bioorg. Med. Chem. 15 (2007) 3896–3911
6H); 1.39 (br s, 2H); 1.60 (d, 2H); 1.94 (d, 2H); 2.27 (s,
3H); 2.79 (br s, 2H); 3.17 (t, 2H); 3.35 (br s, 4H); 4.14 (s,
2H); 5.13 (t, 1H); 5.40 (s, 1H); 7.11 (d, 2H); 7.16 (d, 2H);
7.30 (d, 2H); 7.35 (t, 1H); 7.46 (t, 2H); 7.61-7.66 (m, 4H).
MS (EI, 70 eV): m/z (%) = 513 ([MÆ]+, 4), 440 (5), 398
(7), 335 (20), 167 (100).
5.13.4.9. Procedure for the synthesis of 1-(30-cyano-4-
biphenylmethyl)-3-[1,1-di(hydroxymethyl)propyl]-1-{2-[1-
(4-methylbenzyl)-4-piperidinyl]ethyl}urea (2y). The title
compound was synthesized from 2n according to the
same procedure as of Section 5.13.4 in order to afford
a beige oil which was purified twice by preparative
thin-layer chromatography (CH2Cl2/MeOH 90:10) in
order to obtain 2y (0.03 g, yield: 3%) as a yellow oil.
5.13.4.6. Procedure for the synthesis of 1-(40-fluoro-4-
biphenylmethyl)-3-(1,1-di(hydroxymethyl)propyl)-1-{2-[1-
(4-methylbenzyl)-4-piperidin]ethyl}urea (2v). The title
compound was synthesized from 2k according to the
same procedure as of Section 5.13.4 in order to afford
a beige oil. The crude product was purified by flash
column chromatography (CH2Cl2/MeOH 96:4) and
preparative thin-layer chromatography (CH2Cl2/
MeOH 90:10) in order to obtain 2v (0.05 g, yield:
6%) as a beige oil. IR (KBr) m: 3401 (N–H), 1623
1
IR (KBr) m: 3355 (N–H), 1624 (urea C@O) cmꢀ1. H
NMR (DMSO-d6, 400 MHz) d: 0.75 (t, 3H); 1.24 (br
s, 3H); 1.42 (br s, 2H,); 1.64–1.68 (m, 4H); 2.28 (s,
3H); 2.78 (br s, 2H); 3.19 (t, 2H); 3.38 (t, 2H); 3.40–
3.46 (m, 6H, ); 4.47 (s, 2H); 5.05 (t, 2H); 5.33 (s, 1H);
7.14–7.18 (m, 4H); 7.34 (d, 2H, J = 8.0 Hz); 7.52 (t,
1H); 7.73 (d, 2H); 7.82 (d, 1H, J = 7.7 Hz); 8.02 (d,
1H, J = 8.1 Hz); 8.16 (s, 1H). MS (EI, 70 eV): m/z
(%) = 549 (2), 441 (2), 391 (3), 318 (15), 231 (100).
(urea C@O) cmꢀ1 1H NMR (DMSO-d6, 400 MHz)
.
d: 0.74 (t, 3H, J = 7.3 Hz); 1.21 (t, 4H); 1.42 (t, 2H);
1.65 (t, 4H); 1.78 (t, 2H); 2.27 (s, 3H); 2.70 (br s,
1H); 3.19 (t, 2H); 3.40–3.46 (m, 4H); .46 (s, 2H);
5.06 (t, 2H); 5.60 (s, 2H); 7.15-7.19 (m, 4H); 7.26–
7.32 (m, 4H); 7.61 (d, 2H, J = 8.1 Hz); 7.68-7.71 (m,
2H). MS (EI, 70 eV): m/z (%) = 562 ([MÆ]+, 8), 546
(4), 530 (5), 498 (7), 231 (100).
5.13.4.10. Procedure for the synthesis of 1-(4-biphe-
nylmethyl)-3-[1,1-di(hydroxymethyl)propyl]-1-{2-[1-(4-
methylbenzyl)-4-piperidinyl]ethyl}urea (2z). The title
compound was synthesized from 2o according to the
same procedure as of Section 5.13.4 in order to afford
a yellow oil which was purified twice by flash column
chromatography (CH2Cl2 (100) to CH2Cl2/MeOH
96:4) and preparative column in order to obtain 2z
(0.30 g, yield: 52%) as a beige oil. IR (KBr) m: 3364 (N–
5.13.4.7. Procedure for the synthesis of 3-[1,1-
di(hydroxymethyl)propyl]-1-(40-methoxy-4-biphenylmeth-
yl)-1-{2-[1-(4-methylbenzyl)-4-piperidinyl]ethyl}urea (2w).
The title compound was synthesized from 2l accord-
ing to the same procedure as of Section 5.13.4 in or-
der to afford a beige oil which was purified by silica
gel column chromatography (CH2Cl2/MeOH 96:4)
and preparative thin-layer chromatography (CH2Cl2/
MeOH 90:10) in order to obtain 2w (0.07 g, yield:
4%) as a beige oil. IR (KBr) m: 3404 (N–H), 1728
H), 1635 (urea C@O) cmꢀ1 1H NMR (DMSO-d6,
.
400 MHz) d: 0.73 (t, 3H, J = 7.4 Hz); 1.05–1.17 (m, 3H);
1.39 (br s, 2H); 1.54 (d, 2H); 1.61 (t, 2H, J = 7.4 Hz);
1.78 (t, 2H); 2.26 (s, 3H); 2.68 (d, 2H); 3.15 (d, 2H); 3.37
(s, 2H); 3.42–3.48 (m, 2H); 3.63-3.68 (m, 2H); 4.43 (s,
2H); 7.07–7.13 (m, 4H); 7.30–7.36 (m, 3H); 7.44 (t, 2H,
J = 7.6 Hz); 7.59–7.64 (m, 4H). MS (EI, 70 eV): m/z
(%) = 542 ([MÆ]+, 2), 525 (2), 453 (3), 293 (15), 231 (100).
(urea C@O) cmꢀ1 1H NMR (DMSO-d6, 400 MHz)
.
d: 0.73–0.78 (m, 3H); 1.03–1.21 (m, 3H); 1.41 (br s,
2H); 1.66 (t, 2H); 1.81–1.86 (m, 2H); 2.27 (s, 3H);
2.71 (d, 2H); 3.18 (t, 2H); 3.33–3.49 (m, 2H); 3.79
(s, 4H); 4.43 (s, 2H); 5.07 (t, 2H); 5.32 (s, 1H);
7.01 (d, 2H); 7.09–7.15 (m, 4H); 7.27 (d, 2H,
J = 8.2 Hz); 7.58 (t, 1H). MS (EI, 70 eV): m/z
(%) = 428 (15), 393 (2), 358 (8), 323 (11), 231 (100),
197 (96).
Acknowledgments
We thank the Gobierno de Navarra for grants given to
J. Ceras and N. Cirauqui. We thank Carmen Elizalde
for her help in the identification assays of this study.
References and notes
5.13.4.8. Procedure for the synthesis of 3-[1,1-
di(hydroxymethyl)propyl]-1-(20-methoxy-4-biphenylmeth-
yl)-1-{2-[1-(4-methylbenzyl)-4-piperidinyl]ethyl}urea (2x).
The title compound was synthesized from 2m according
to the same procedure as of Section 5.13.4 in order to af-
ford a beige oil which was purified twice by preparative
thin-layer chromatography (CH2Cl2/MeOH 90:10) in or-
der to obtain 2x (0.01 g, yield: 1.15%) as a beige oil. IR
(KBr) m: 3400 (N–H), 1644 (urea C@O) cmꢀ1. 1H NMR
(DMSO-d6, 400 MHz) d: 0.71–0.81 (t, 3H); 1.06–1.11
(m, 3H); 1.32 (m, 2H); 1.48 (m, 1H); 1.56 (m, 2H); 1.60–
1.68 (m, 2H); 1.82 (d, 2H); 2.27 (s, 3H); 2.73 (s, 2H);
3.37–3.41 (m, 4H); 3.77 (s, 3H); 4.21 (d, 2H); 5.75 (s,
1H); 7.02 (t, 1H); 7.09–7.14 (m, 5H); 7.25 (d, 2H,
J = 7.1 Hz); 7.33 (t, 1H); 7.41 (t, 2H); 7.51 (d, 1H). MS
(EI, 70 eV): m/z (%) = 428 (10), 368 (13), 323 (17), 231
(100), 197 (60).
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