Diaryldiamines with dual inhibition of the histamine H3 receptor and the norepinephrine transporter and the efficacy of 4-(3-(methylamino)-1- phenylpropyl)-6-(2-(pyrrolidin-1-yl)ethoxy)naphthalen-1-ol in pain

Article abstract of DOI:10.1021/jm100666w

A series of compounds was designed as dual inhibitors of the H₃ receptor and the norepinephrine transporter. Compound 5 (rNET K_i = 14 nM; rH₃R K_i = 37 nM) was found to be efficacious in a rat model of osteoarthritic pain.

Full text of DOI:10.1021/jm100666w

J. Med. Chem. 2010, 53, 7869–7873 7869
DOI: 10.1021/jm100666w
Diaryldiamines with Dual Inhibition of the Histamine H3 Receptor and the Norepinephrine Transporter
and the Efficacy of 4-(3-(Methylamino)-1-phenylpropyl)-6-(2-(pyrrolidin-1-yl)ethoxy)naphthalen-1-ol
in Pain
Robert J. Altenbach,* Lawrence A. Black, Marina I. Strakhova, Arlene M. Manelli, Tracy L. Carr, Kennan C. Marsh,
Jill M. Wetter, Erica J. Wensink, Gin C. Hsieh, Prisca Honore, Tiffany Runyan Garrison, Jorge D. Brioni, and
Marlon D. Cowart
Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park,
Illinois 60064-6100, United States
Received June 2, 2010
A series of compounds was designed as dual inhibitors of the H3 receptor and the norepinephrine
transporter. Compound 5 (rNET Ki=14 nM; rH3R Ki=37 nM) was found to be efficacious in a rat
model of osteoarthritic pain.
Introduction
neuropathic pain.12 Inhibition of NE uptake is requisite for
the pain efficacy of 2, since NET selective inhibitors such as
reboxetine have been shown to be effective in pain models,13
whereas, serotonin-selective reuptake inhibitors (SSRIs) have
been shown clinically to have only limited analgesic effects.14
We hypothesized that since H3 and NET blockers have pain
efficacy and can increase NE levels, an agent combining both
activities would be highly effective. We therefore targeted
compounds with dual activity of H3R antagonism and NET
inhibition. One of our strategies to design such molecules was
to combine pharmacophores of NET inhibition and H3
antagonism into one molecule. This approach has been used
by others to provide H3 antagonists with dual pharma-
cology.15
The histamine 3 receptor (H3Ra) is primarily located in the
central nervous system and is one of four histamine receptors
known.1 Histamine H3 receptors are localized on presynaptic
terminals, and H3 antagonists have been widely reported to
increase the levels of several neurotransmitters, including
histamine, acetylcholine, norepinephrine (NE), and others.2,3
H3R antagonists are currently being evaluated clinically for
the treatment of conditions such as attention deficit hyper-
activity disorder, Alzheimer’s disease, narcolepsy, and pain.4
H3 antagonists such as thioperamide have been reported to
be active in models of pain.5 More recently, the H3R antago-
nist GSK-189254 (1) was reported to be efficacious in pre-
clinical models of neuropathic pain and was examined in a
phase I electrical hyperalgesia model.6,7 The efficacy of hista-
mine H3 antagonists can be rationalized as likely due to
increases in levels of monoamines that are recognized to
modulate pain sensation, such as NE. Norepinephrine is
thought to be involved in the descending inhibitory pain
pathways and to act through sites in the dorsal horn of the
spinal cord via presynaptic R2 (particularlyR2A) adrenoceptors
in primary nociceptive terminals.8 Agents that activate R2
adrenergic receptors, such as clonidine,9 are effective in pain.
The norepinephrine transporter (NET) is located presy-
naptically on noradrenergic neurons and, in addition to
enzymatic degradation and diffusion, is a primary mechanism
for terminating the actions of NE by removing NE from the
nerve synapse.10 Blockade of NET results in an increase in the
levels of NE, as has been shown by microdialysis studies.11
The nonselective serotonin-norepinephrine reuptake inhibi-
tor (SNRI) duloxetine (2) is used clinically for the treatment of
Compound 3,16 a synthetically more accessible phenyl ana-
logue of 2 with similar affinity for NET, was selected as the
NET pharmacophore (see Figure 1). Our initial target, 4, was
chosen with the anticipation that appending an H3R pharma-
cophore on the naphthalene ring of 3 would maintain the
NET activity. Our results are discussed herein.
Chemistry
The synthesis of 4 is shown in Scheme 1. Alkylation of 1117
with N-(2-chloroethyl)pyrrolidine followed by debenzylation
provided naphthol 12. Under Mitsunobu conditions, reaction
between 12 and Boc-protected amino alcohol 13,18 followed
bydeprotectionwithTFA, provided thedesired product4 and
an unexpected product, 5. An improved yield of 5 was
obtained by the reaction of 12 with 3-(methylamino)-1-phe-
nylpropan-1-ol (20) in TFA (see Supporting Information).
Diphenylamine 15 was alkylated with the 2-carbon or the
3-carbon-linked chloroalkylamines (1619 or 1720) to provide
intermediates 18 and 19, respectively (see Scheme 2). These
intermediates were deprotected catalytically to provide 6
and 7.
*To whom correspondence should be addressed. Phone: 847-935-
4194. Fax: 847-937-9195. E-mail: robert.j.altenbach@abbott.com.
a Abbreviations: H3R, histamine 3 receptor; PK, pharmacokinetic;
NE, norepinephrine; NET, norepinephrine transporter; NRI, norepi-
nephrine reuptake inhibitor; OA, osteoarthritis; SERT, serotonin trans-
porter; SNRI, serotonin-norepinephrine reuptake inhibitor; SSRI,
selective serotonin reuptake inhibitor.
As shown in Scheme 3, phenol was reacted with amino
alcohol 20 or 21 in the presence of acid (TFA) to provide, after
Boc protection, 22 and 23, respectively. The initial reaction
r
2010 American Chemical Society
Published on Web 10/14/2010
pubs.acs.org/jmc

7870 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 21
Altenbach et al.
Figure 1. H3R antagonist 1, SNRIs 2 and 3, dual H3R-antagonists-NET inhibitors 4 and 5, and NET inhibitors 10a and 10b.
Scheme 1a
Scheme 3a
a (i) N-(2-chloroethyl)pyrrolidine HCl, NaH, DMF, 70 °C; (ii) H2,
10% Pd/C, MeOH; (iii) 13, DEAD, Ph3P, THF; (iv) TFA.
3
Scheme 2a
a (i) Phenol, TFA; (ii) Boc2O, CH3CN, Δ; (iii) N-(2-chloro-
ethyl)pyrrolidine HCl, NaH, DMF, 70 °C; (iv) TFA.
3
Table 1. Binding Affinity for the Rat NET, Rat H3R, and Human H3Ra
rat H3Rc
Ki (nM)
human H3Rc
Ki (nM)
rat NETb Ki (nM)
compd
2
3.0
230
14
(2.3, 3.8)d
(200, 260)d 48
>5000
>5000
4
(47, 48)d
(32, 43)
NDe
7.4
5
(11, 19)
37
(6.2, 8.9)
(50, 150)d
(85, 150)d
(3.3, 5.5)
(12, 17)
5.4
0.72
5.2
2.9
(4.8, 6.0)d
1.6
(1.6, 1.6)d
(0.26, 0.30)d
(0.9, 2.0)
a (i) N-(2-Chloroethyl)pyrrolidine HCl, NaH, DMF, 70 °C. (ii) 18:
6
89
3
7
110
4.3
14
(0.58, 0.91)d 0.28
Cl(CH2)2NMeBn HCl (16), NaH, DMF, 70 °C. 19: Cl(CH2)3NMeBn
3
3
8
(4.4, 6.0)
(2.2, 3.7)
1.4
0.89
HCl (17), NaH, DMF, 70 °C. (iii) H2, 20% Pd(OH)2/C, IPA, 80 °C.
9
10a
(0.73, 1.08)
0.78 (0.43, 1.41) >5000
>5000
proceeded in low yield due to the major product being
alkylation of phenol ortho to the hydroxy group. Intermedi-
ates 22 and 23 were converted to 8 and 9 via O-alkylation and
Boc deprotection.
a n g 3. Values in parentheses are the upper and lower limits derived as
a result of the standard deviation. b Assessed by displacement of
[3H]nisoxetine from cell membranes isolated from rat cerebral cortex.31
c Assessed by displacement of [3H]N-R-methyl histamine from cell
membranes isolated from C6 cells expressing cloned rat or human
H3R.23 d n = 2 e ND = not determined.
Results
Our first target was 4, wherein an ethoxypyrrolidine H3R
moiety was appended to the naphthyl group of 3. Structure 3
was selected as supportive of facile SAR studies, as 3 is
synthetically moreaccessiblethan2, yet retains similar affinity
for the human NET.16 The design hypothesis was supported
in that the targeted structure (4) was active at H3 and NET
(Table 1). Though ∼10-fold less potent than 3 at the rat NET
(Ki = 230 nM), 4 had a binding affinity of 48 nM for the rat
H3R. Surprisingly, 5, which was formed as an unexpected
synthetic byproduct in the synthesis of 4, was very potent at
NET (Ki = 14 nM) and H3R (rat Ki = 37 nM, human Ki =
7.4 nM). Compounds 4 and 5 were shown to be antagonists of
the H3R in GTPγS binding studies.21 Thus, the accidental
byproduct 5 was found to be >10-fold more potent than 4 in
its affinity for NET. A limited number of other derivatives
structurally similar to 4 and 5 were synthesized, but a superior
naphthyl containing analogue was not found.22
The structure of 5,24 in which a diarylmethane is linked to
a methylamino group through a two-carbon chain, was
noted to have similarity to the structures of known potent
NET inhibitors desipramine (10a) and protriptyline (10b)
(wherein a diphenylamino or diphenylmethyl core is linked
to a methylamino group though a three-carbon chain; see
Figure 1). We further investigated the potential of the diaryl-
methane moiety in 5 to induce dual potency at NET and H3R
in additional analogues. To explore the importance of carbon
versus nitrogen at the diphenyl junction and a two-carbon
versus three-carbon linker, 6-9 were synthesized.

Brief Article
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 21 7871
From this, an ED50 level was calculated to be 1.2 mg/kg.
Plasma samples were taken immediately after completion of
the pain testing (45 min postdose) to determine drug levels, the
1 mg/kg dose giving 129 ng/mL, the 3 mg/kg dose giving
382 ng/mL, and the 10 mg/kg dose giving 1239 ng/mL, from
which an ED50 of 150 ng/mL (370 nM) was calculated. To
calculate the free drug level required for efficacy, the plasma
ED50 was multiplied by the free unbound fraction (33%) to
give120 nM. The observed analgesic efficacyisconsistent with
a mechanism involving inhibition of the H3 and NET sites,
since the ED50 free levels were found to be greater than the in
vitro potency of 5 at these sites (14 and 37 nM, respectively).
Compound 5 was brain permeable, as determined by
evaluation of a 3 mg/kg dose. On the basis of the free drug
principle,28 equilibrium free drug concentrations are equal in
all compartments. Thus, receptor occupancy for 5 can be
calculated. At the 1, 3, and 10 mg/kg doses, the estimated
receptor occupancies are 74%, 89%, and 97% for the rat H3R
and 88%, 96%, and 99% for the NET, respectivly.29 This
predicts that the compound should have substantial occu-
pancy at the H3 and NET sites at the pain-effective concen-
trations.
Figure 2. Efficacy of 5 in OA model of inflammatory pain (n = 12)
in rats (Sprague-Dawley). Rats were administered 5 at 0.3, 1, and
3 mg/kg ip, 2 mL/kg 30 min before testing. Data are expressed as
maximum hindlimb compressive force (CFmax) (gram force) per kg
body weight for each dose group: (//) p < 0.05 vs vehicle (One-way
analysis of variance (ANOVA), followed by Bonferroni’s post-hoc
analysis). Positive control is diclofenac 30 mg/kg in water (ip) 30 min
before testing. N is naive rat. V is vehicle treated rat.
Although we cannot entirely rule out a role for a contribu-
tion to efficacy in the OA model from inhibition of the
serotonin transporter by 5 (Ki=7 nM),13a pure selective
serotonin reuptake inhibitors have been reported to not be
clinically effective in pain.14 Compound 5 had SERT affinity
comparable to that reported for 3 (Ki=2.4 nM).16 In contrast,
6-9 had reduced affinity for SERT (all Ki >70 nM), which is
more aligned with the SERT potency of diphenylamino
analogue 10a (Ki = 20 nM).
Compounds 8 and 9, due to high affinity at NET and H3R
and reduced affinity at SERT, had improved in vitro selec-
tivity (>10-fold) for NET and H3 over SERT. Compound 8 is
a potential tool for further probing contributions of SERT to
in vivo pharmacologyand will beanalyzed inmore detail in an
upcoming publication, with the aim of testing in additional
pain models and understanding potential liabilities in com-
parison to a clinically used SNRI (i.e., 2).
As can be seen from Table 1, the H3R potency of 6-9
increased 7- to 50-fold relative to 5, with 7 being the most
potentof theseanalogsat ratH3R. Compound7, the analogue
most structurally similar to 10a, was the least potent for
the NET site. The fused dihydrodibenzo[b,f]azepine of 10a
apparently is critical for potent NET activity. Compound 8
was potent at NET (Ki = 4 nM) and had similar high affinity
for rat H3R (Ki = 5 nM). The3-foldhigherpotency of8 over9
at the NET may indicate a slight preference for a two-carbon
versus three-carbon linker in the presence of a diphenyl-
methane moiety. In a limited exploration of the SAR sur-
rounding 8, the phenyl group not containing the H3R moiety
was replaced with more polar heteroaromatic derivatives, all
of which resulted in a reduction in NET activity.22
Compound 5 was evaluated in detail in vitro and found to
also possess significant affinity for the serotonin transporter,
with a potency of 7.6 nM. Examination of the profile of 5 in an
in vitro microsomal turnover assay revealed that 56% of the
compound remained after 0.5 h exposure, indicating that 5 is
sufficiently stable to justify a PK study in rodent. The animal
pain models were targeted for ip dosing of compounds, so the
PK was examined by this route. A dose of 1 mg/kg (ip)
achieved a peak concentration (Cmax) of 0.21 μg/mL, reached
at 0.25 h (Tmax), with good bioavailability (Fip/iv = 43%) and
t1/2 of12h. Dosed iv (1 mg/kg), the compound demonstrateda
very high volume of distribution (Vβ =8.2 L/kg), with low
clearance (Cl = 0.46 (L/h)/kg), inducing a very long half-life
(t1/2=12 h). The rat plasma protein binding of 5 was found to
be 67%, indicating that a significant fraction (33%) of the
compound in circulation would be free unbound drug. Over-
all, 5 was thus found to have a very good PK profile to enable
testing in rodent pain models.
In summary, we were able to design compounds with
nanomolar potency and dual affinity for the H3R and the
NET. Biphenylmethyl analogue 5 displayed a balanced affi-
nity for H3R and NET, combined with excellent PK proper-
ties. This compound was found tobepotent and effective inan
osteoarthritis pain model in rat.
Experimental Section
General. Proton NMR spectra were obtained on a Varian
Mercury plus 300 or Varian UNITY plus 300 MHz instrument
with chemical shifts (δ) reported relative to tetramethylsilane as
an internal standard. Target compounds possess a purity of at
least 95% based on combustion analysis (<(0.4), performed by
QTI (Quantitative Technologies, Inc.). Column chromatogra-
phy was carried out with an Analogix IntelliFlash 280 chroma-
tography apparatus using SuperFlash compound purification
columns or on silica gel 60 (230-400 mesh). Thin-layer chro-
matography was performed using 250 mm silica gel 60 glass-
backed plates with F254 as indicator.
N-Methyl-3-phenyl-3-(6-(2-(pyrrolidin-1-yl)ethoxy)naphthalen-1-
yloxy)propan-1-amine (4) and 4-(3-(Methylamino)-1-phenylpropyl)-
6-(2-(pyrrolidin-1-yl)ethoxy)naphthalen-1-ol (5). Step 1. A solution of
12 (127 mg, 0.49 mmol), tert-butyl 3-hydroxy-3-phenylpropyl-
(methyl)carbamate (13)18 (170 mg, 0.64 mmol), and Ph3P (170 mg,
0.64 mmol) in THF (2 mL) under N2 at 0 °C was treated in por-
tions over 45 min with DEAD (100 μL, 0.64 mmol) in THF (2 mL).
We have previously reported that the H3R antagonist 1 is
effective in an osteoarthritis (OA) pain model in rats.25 Com-
pound 2 was also found efficacious in the same rat model,26 a
result that is consistent with its reported clinical efficacy27 in
OA in the clinic. The dual potency inhibitor 5 was also tested
in this rat OA model.26a Compound 5 was dosed ip 20 days
after injection of monoiodoacetate into the knee joint and was
found to be potent and effective, with 70% efficacy at a dose
3 mg/kg and 93% efficacy at a dose of 10 mg/kg (Figure 2).

7872 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 21
Altenbach et al.
The mixture was stirred at room temperature overnight,
concentrated, and chromatographed, eluting with 2-10%
(9:1 MeOH/NH4OH) in CH2Cl2 to provide the desired Boc-
protected intermediates.
6-(2-(Pyrrolidin-1-yl)ethoxy)naphthalen-1-ol (12). Step 1. A
solution of 1117 (1.1 g, 4.5 mmol) in DMF (20 mL) under N2 was
treated with NaH (60% dispersion, 1.1 g, 27 mmol), stirred for
15 min, treated with N-(2-chloroethyl)pyrrolidine HCl (1.5 g,
3
Step 2. This residue was treated with TFA (2 mL), heated to
60 °C for 2 min, concentrated, and directly chromatographed,
eluting with 2-10% (9:1 MeOH.NH4OH) in CH2Cl2 to provide
5 (5 mg, 12%) as the less polar isomer (1H NMR (CDCl3) δ 1.85
(m, 5H), 2.13-2.28 (m, 1H), 2.37-2.48 (m, 2H), 2.49 (s, 3H),
2.69-2.83 (m, 5H), 3.01 (t, J = 5.9 Hz, 2H), 4.24 (t, J = 5.9 Hz,
2H), 4.79 (dd, J = 13.1, 2.9 Hz, 1H), 6.74 (d, J = 8.5 Hz, 1H),
7.01 (d, J = 2.4 Hz, 1H), 7.07 (d, J = 8.5 Hz, 1H), 7.13 (dd, J =
9.2, 2.7 Hz, 1H), 7.18-7.25 (m, 1H), 7.28-7.33 (m, 4H), 8.30 (d,
J = 9.2 Hz, 1H); MS (DCI/NH3) m/z 405 (M þ H)þ) and 4 as the
more polar isomer (20 mg, 48%) (1H NMR (CDCl3) δ 1.83 (m,
4H), 2.04-2.20 (m, 1H), 2.25-2.39 (m, 1H), 2.43 (s, 3H), 2.66 (m,
4H), 2.78-2.89 (m, 2H), 2.97 (t, J = 5.9 Hz, 2H), 4.23 (t, J = 6.1
Hz, 2H), 5.44 (dd, J = 8.3, 4.8 Hz, 1H), 6.48 (d, J = 7.5 Hz, 1H),
7.07-7.43 (m, 9H), 8.32 (d, J = 9.5 Hz, 1H); MS (DCI/NH3) m/z
9.0 mmol), stirred for 15 min, heated to 70 °C for 1 h, cooled,
treated with water (50 mL), and extracted with Et2O (3 times).
The combined Et2O layers were washed with brine, dried
(MgSO4), filtered, concentrated, and chromatographed, eluting
with 2-10% (9:1 MeOH/NH4OH) in CH2Cl2 to provide the
intermediate product 1-(2-(5-(benzyloxy)naphthalen-2-yloxy)-
ethyl)pyrrolidine (1.27 g, 81%).
Step 2. The intermediate from step 1 (1.26 g, 3.63 mmol) and
10% Pd/C (250 mg) in MeOH (5 mL) was stirred under H2
(1 atm) for 2 h, diluted to ∼100 mL with CH2Cl2, stirred under
N2 for 15 min, and filtered to remove the solids. The filtrate was
concentrated and chromatographed, eluting with 2-10% (9:1
MeOH/NH4OH) in CH2Cl2 to provide 12 (0.92 g, 98%), which
solidified on standing. 1H NMR (CDCl3) δ 1.85 (m, 4H), 2.72
(m, 4H), 2.99 (t, J = 5.8 Hz, 2H), 4.21 (t, J = 5.9 Hz, 2H), 6.64
(dd, J = 6.3, 2.0 Hz, 1H), 7.02-7.07 (m, 2H), 7.18-7.24 (m,
2H), 8.00-8.06 (m, 1H); MS (DCI/NH3) m/z 258 (M þ H)þ.
N-Phenyl-4-(2-(pyrrolidin-1-yl)ethoxy)aniline (15). Compound
14 (3.3 g, 18 mmol), NaH (60% dispersion, 0.71 g, 18 mmol),
405 (M þ H)þ. Anal. (C26H32N2O2 0.1H2O) C, H, N).
3
N1-Methyl-N2-phenyl-N2-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-
ethane-1,2-diamine (6). A solution of 18 (245 mg, 0.570 mmol) and
Pearlman’s catalyst (145 mg) in IPA (3 mL) under H2 was heated
to 80 °C for 4 h, stirred at room temperature overnight, diluted
with CH2Cl2 (50 mL), stirred for 5 min under N2, and filtered. The
filtrate was concentrated and chromatographed, eluting with
4-20% (9:1 MeOH/NH4OH) in CH2Cl2 to provide 6 (111 mg,
57%). 1H NMR (CDCl3) δ 1.81 (m, 4H), 2.43 (s, 3H), 2.63 (m,
4H), 2.82 (t, J = 6.6 Hz, 2H), 2.90 (t, J = 5.9 Hz, 2H), 3.78 (t, J =
6.6 Hz, 2H), 4.10 (t, J = 5.9 Hz, 2H), 6.72-6.81 (m, 3H), 6.87-6.94
(m, 2H), 7.04-7.10 (m, 2H), 7.13-7.20 (m, 2H); MS (DCI/NH3)
and N-(2-chloroethyl)pyrrolidine HCl (1 g, 5.9 mmol) were pro-
3
cessed using the procedures for 12, step 1. Chromatography,
eluting with 3:1 to 0:1 EtOAc/[4:1:1 EtOAc/HCO2H/H2O] on
1
silica gel, gave 15 (1.66 g, 100%). H NMR (CDCl3) δ 1.81 (m,
4H), 2.63 (m, 4H), 2.89 (t, J = 5.9 Hz, 2H), 4.09 (t, J = 6.1 Hz,
2H), 5.48 (bs, 1H), 6.79-6.93 (m, 5H), 7.02-7.09 (m, 2H),
7.17-7.24 (m, 2H); MS (DCI/NH3) m/z 283 (M þ H)þ.
N1-Benzyl-N1-methyl-N2-phenyl-N2-(4-(2-(pyrrolidin-1-yl)-
ethoxy)phenyl)ethane-1,2-diamine (18). Compound 15 (170
mg, 0.60 mmol) and NaH (60% dispersion, 240 mg, 6.0 mmol)
under N2 in DMF (3 mL) was stirred for 5 min, treated with
1619 (200 mg, 0.90 mmol), stirred for 10 min, heated to 70 °C
for 1 h, cooled, and partitioned between Et2O (75 mL) and 0.1
M NaOH (25 mL). The Et2O layer was washed with brine,
dried (MgSO4), filtered, concentrated, and chromatographed,
eluting with 2-10% (9:1 MeOH/NH4OH) in CH2Cl2 to
provide 18 (250 mg, 98%). 1H NMR (CDCl3) δ 1.82 (m,
4H), 2.24 (s, 3H), 2.58-2.70 (m, 6H), 2.91 (t, J = 5.9 Hz,
2H), 3.52 (s, 2H), 3.74-3.83 (m, 2H), 4.10 (t, J = 6.1 Hz, 2H),
6.65-6.75 (m, 3H), 6.85-6.93 (m, 2H), 7.00-7.07 (m, 2H),
7.09-7.16 (m, 2H), 7.21-7.33 (m, 5H); MS (DCI/NH3) m/z
430 (M þ H)þ.
m/z 340 (M þ H)þ. Anal. (C21H29N3O 0.3H2O) C, H, N.
3
N1-Methyl-N3-phenyl-N3-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-
propane-1,3-diamine (7). Compound 19 (100 mg, 0.225 mmol) via
the procedure for 6 provided 7 (49 mg, 61%). 1H NMR (CDCl3) δ
1.75-1.87 (m, 6H), 2.41 (s, 3H), 2.63 (m, 6H), 2.90 (t, J = 6.1 Hz,
2H), 3.69 (t, J = 7.5 Hz, 2H), 4.10 (t, J = 5.9 Hz, 2H), 6.70-6.77
(m, 3H), 6.86-6.94 (m, 2H), 7.02-7.09 (m, 2H), 7.12-7.20 (m,
2H); MS (DCI/NH3) m/z 354 (M þ H)þ. Anal. (C22H31N3O
3
0.3H2O) C, H, N.
N-Methyl-3-phenyl-3-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-
propan-1-amine (8).32 Compound 22 (455 mg, 1.33 mmol) via the
procedures for 12, step 1, and 4 and 5, step 2, provided 8 (300 mg,
96%). 1H NMR (CDCl3) δ 1.79 (m, 4H), 2.19 (q, J = 7.5 Hz,
2H), 2.37 (s, 3H), 2.52 (t, J = 7.1 Hz, 2H), 2.60 (m, 4H), 2.86 (t,
J = 6.1 Hz, 2H), 3.94 (t, J=7.7 Hz, 1H), 4.06 (t, J = 5.9 Hz, 2H),
6.83 (d, J = 8.7 Hz, 2H), 7.14 (d, J = 8.3 Hz, 2H), 7.16-7.31 (m,
5H); MS (DCI/NH3) m/z 339 (M þ H)þ.
N1-Benzyl-N1-methyl-N3-phenyl-N3-(4-(2-(pyrrolidin-1-yl)-
ethoxy)phenyl)propane-1,3-diamine (19). Compounds 15 (65
mg, 0.23 mmol) and 1720 (110 mg, 0.46 mmol) were processed
1
N-Methyl-4-phenyl-4-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-
butan-1-amine (9).32 Compound 23 via the procedures for 12,
via the procedure for 18 to provide 19 (107 mg, 105%). H
NMR (CDCl3) δ 1.73-1.89 (m, 6H), 2.16 (s, 3H), 2.42 (t, J =
6.9 Hz, 2H), 2.64 (m, 4H), 2.91 (t, J = 6.1 Hz, 2H), 3.45 (s, 2H),
3.69 (t, J = 7.1 Hz, 2H), 4.10 (t, J = 5.9 Hz, 2H), 6.69-6.79
(m, 3H), 6.85-6.93 (m, 2H), 7.01-7.08 (m, 2H), 7.11-7.19 (m,
2H), 7.20-7.35 (m, 5H); MS (DCI/NH3) m/z 444 (M þ H)þ.
tert-Butyl 3-(4-Hydroxyphenyl)-3-phenylpropyl(methyl)carbamate
(22). Step 1. Compound 20 (1.76 g, 10.6 mmol) in TFA (5 mL)
was treated with phenol (1 g, 10.63 mmol), stirred at room tempera-
ture for 3 days, concentrated, treated with 1 M NaOH and extracted
with CH2Cl2 (3 times). The combined CH2Cl2 layers were dried
(MgSO4), filtered, concentrated, and chromatographed, eluting with
2%-10% (9:1 MeOH/NH4OH) in CH2Cl2 to provide 4-(3-
(methylamino)-1-phenylpropyl)phenol as the more polar isomer
(351 mg, 13.7%).
Step 2. This intermediate (343 mg, 1.42 mmol) was treated
with Boc2O (0.37 g, 1.7 mmol) in CH3CN (5 mL), swirled until
homogeneous, heated to near reflux for 1 min, cooled, concen-
trated, and directly chromatographed, eluting with 5:1 to 1:1
hexane/EtOAc to provide the title compd (462 mg, 95%).
1H NMR (CDCl3) δ 1.41 (s, 9H), 2.22 (q, J = 7.8 Hz, 2H),
2.80 (s, 3H), 3.06-3.22 (m, 2H), 3.81 (t, J = 7.8 Hz, 1H), 6.74
1
step 1, and 4 and 5, step 2, provided 9. H NMR (CDCl3) δ
1.26-1.51 (m, 2H), 1.79 (m, 4H), 2.04 (q, J = 7.8 Hz, 2H), 2.39
(s, 3H), 2.61 (m, 6H), 2.87 (t, J = 5.9 Hz, 2H), 3.83 (t, J = 7.8
Hz, 1H), 4.06 (t, J = 6.1 Hz, 2H), 6.82 (d, J = 8.8 Hz, 2H), 7.13
(d, J = 8.8 Hz, 2H), 7.15-7.30 (m, 5H); MS (DCI/NH3) m/z
353 (M þ H)þ. For salt formation, a solution of 9 (1.71 g, 4.85
mmol) was dissolved in EtOH (10 mL), treated with maleic
acid (1.18 g, 10.2 mmol), heated until the solution became
homogeneous, filtered, concentrated to ∼10 mL total volume,
treated with EtOAc (100 mL), and set aside overnight. The
solution was decanted off, and the oil was treated with EtOAc.
This process was repeated until crystallization occurred. The
crystals were collected by filtration, washed with EtOAc, and
1
dried to provide 1.80 g (63%) 9 as the dimaleic acid salt. H
NMR (DMSO-d6) δ 1.38-1.52 (m, 2H), 1.82-2.11 (m, 6H),
2.90 (t, J=7.6 Hz, 2H), 2.98-3.46 (m, 7H), 3.52 (bs, 2H), 3.90
(t, J=7.8 Hz, 1H), 4.22 (t, J = 4.7 Hz, 2H), 6.02 (s, 3.1H), 6.92
(d, J=8.8 Hz, 2H), 7.13-7.21 (m, 1H), 7.21-7.32 (m, 4H), 7.25
(d, J=8.8 Hz, 2H), 8.19 (s, 1.5H), 9.59 (s, 0.5H); MS (ESIþ)
m/z 353 (M þ H)þ. Anal. (C23H32N2O 2C4H4O4) C, H, N.
3

Brief Article
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 21 7873
(d, J = 7.8 Hz, 2H), 7.08 (d, J = 8.5 Hz, 2H), 7.21 (d, 5H); MS
(DCI/NH3) m/z 342 (M þ H)þ.
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tert-Butyl 4-(4-Hydroxyphenyl)-4-phenylbutyl(methyl)carbamate
(23). Compound 2130 (65 mg, 0.36 mmol) and phenol (102 mg, 1.09
mmol) via the procedure for 22, Step 1, provided a mixture
of 4-(4-(methylamino)-1-phenylbutyl)phenol and 2-(4-(methyl-
amino)-1-phenylbutyl)phenol. This mixture of was treated with
Boc2O (38 mg, 0.17 mmol) in CH3CN (2 mL), heated for 2 min at
reflux, cooled, concentrated, and directly chromatographed, elut-
ing with a gradient of 1:1 to 0:1 hexane/[9:1 CH2Cl2/EtOAc] to
provide 23 as the more polar isomer. 1H NMR (CDCl3) δ
1.34-1.53 (m, 11H), 1.96 (q, J = 7.5 Hz, 2H), 2.76 (s, 3H), 3.21
(bs, 2H), 3.84 (t, J = 7.7 Hz, 1H), 4.94 (bs, 0.4H), 5.06 (bs, 0.5H),
6.74 (d, J = 8.3 Hz, 2H), 7.08 (d, J = 8.7 Hz, 2H), 7.12-7.30 (m,
5H); MS (DCI/NH3) m/z 356 (M þ H)þ.
Supporting Information Available: Analogues of 4, 5, and 8;
functional antagonism of 4-7, 9; estimated receptor occupancy
of 5; full experimental details; alternative syntheses of 5, 8 and 9;
rat NET binding protocol. This material is available free of
charge via the Internet at http://pubs.acs.org.
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active on glucose homeostasis in a rat model of type II diabetes. 2.
Syntheses and biological activities of 1,4-dialkyl-, 1,4-dibenzyl, and
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(21) See Supporting Information for GTPγS data on 4-7 and 9.
(22) See Supporting Information for analogues of 4, 5, and 8.
(23) Esbenshade, T. A.; Krueger, K. M.; Miller, T. R.; Kang, C. H.;
Denny, L. I.; Witte, D. G.; Yao, B. B.; Fox, G. B.; Faghih, R.;
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