Selective 5-hydroxytryptamine 2c receptor agonists derived from the lead compound tranylcypromine: Identification of drugs with antidepressant-like action

Article abstract of DOI:10.1021/jm801354e

We report here the design, synthesis, and pharmacological properties of a series of compounds related to tranylcypromine (9), which itself was discovered as a lead compound in a high-throughput screening campaign. Starting from 9, which shows modest activity as a 5-HT_2C agonist, a series of 1-aminomethyl-2- phenylcyclopropanes was investigated as 5-HT_2C agonists through iterative structural modifications. Key pharmacophore feature of this new class of ligands is a 2-aminomethyl-trans-cyclopropyl side chain attached to a substituted be zene ring. Among the tested compounds, several were potent and efficacious 5-HT_2C receptor agonists with selectivity over both 5-HT_2A and 5-HT2B receptors in functional assays. The most promising compound is 37, with 120- and 14-fold selectivity over 5-HT _2A and 5-HT_2B, respectively (EC₅₀) 585, 65, and 4.8 nM at the 2A, 2B, and 2C subtypes, respectively). In animal studies, compound 37 (10-60 mg/kg) decreased immobility time in the mouse forced swim test.

Full text of DOI:10.1021/jm801354e

J. Med. Chem. 2009, 52, 1885–1902
1885
Selective 5-Hydroxytryptamine 2C Receptor Agonists Derived from the Lead Compound
Tranylcypromine: Identification of Drugs with Antidepressant-Like Action
Sung Jin Cho,†,§ Niels H. Jensen,‡,§ Toru Kurome,† Sudhakar Kadari,† Michael L. Manzano,| Jessica E. Malberg,|
Barbara Caldarone,| Bryan L. Roth,*,‡ and Alan P. Kozikowski*,†
Drug DiscoVery Program, Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy (M/C781), UniVersity of
Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612-7230, Department of Pharmacology, Psychiatry, ComprehensiVe Cancer
Center, Center for Neurobiology DiVision of Medicinal Chemistry and Natural Products, and NIMH PsychoactiVe Drug Screening Program,
UniVersity of North Carolina Medical School, Chapel Hill, CB 7365, North Carolina 27599, Psychogenics, Inc., Tarrytown, New York 10591
ReceiVed October 27, 2008
We report here the design, synthesis, and pharmacological properties of a series of compounds related to
tranylcypromine (9), which itself was discovered as a lead compound in a high-throughput screening campaign.
Starting from 9, which shows modest activity as a 5-HT2C agonist, a series of 1-aminomethyl-2-
phenylcyclopropanes was investigated as 5-HT2C agonists through iterative structural modifications. Key
pharmacophore feature of this new class of ligands is a 2-aminomethyl-trans-cyclopropyl side chain attached
to a substituted benzene ring. Among the tested compounds, several were potent and efficacious 5-HT2C
receptor agonists with selectivity over both 5-HT2A and 5-HT2B receptors in functional assays. The most
promising compound is 37, with 120- and 14-fold selectivity over 5-HT2A and 5-HT2B, respectively (EC50
) 585, 65, and 4.8 nM at the 2A, 2B, and 2C subtypes, respectively). In animal studies, compound 37
(10-60 mg/kg) decreased immobility time in the mouse forced swim test.
Introduction
Serotonin (5-HTa) (1) mediates or regulates a wide variety
of behaviors including cognition, emotion, attention, and appetite
among others.1,2 The diverse effects of this neurotransmitter are
related to the extensive projections of serotonergic neurons
throughout the brain and to the presence of at least 14 different
receptor subtypes in humans.3-5 The 5-HT2 subtype family
includes the 5-HT2A, 5-HT2B, and 5-HT2C receptors. The 5-HT2A
receptor mediates the hallucinogenic activity of drugs such as
lysergic acid diethylamide (LSD) and is a major target for
treating schizophrenia as well as insomnia.6 The 5-HT2B receptor
mediates the potentially lethal valvulopathic side effects of
several compounds that were used as prescription drugs.7-9 Two
decades after its initial identification, the 5-HT2C receptor has
only recently emerged as a promising target in the treatment of
depression, anxiety, eating disorders, obsessive-compulsive
disorder, chronic pain conditions, obesity, epilepsy, and erectile
dysfunction.10-19 The 5-HT2C receptor is abundantly expressed
throughout the central nervous system (CNS) and displays high-
affinity interactions with a wide variety of psychiatric medica-
tions.20-23 Due to the serious side effects caused by the
activation of the pharmacologically and structurally closely
related subtypes,24 it is essential that 5-HT2C agonists developed
for clinical use have a high specificity and subtype selectivity.
To date, a number of designed synthetic compounds have been
identified that show 5-HT2C receptor agonistic activity (Figure
Figure 1. The classical 5-HT2C receptor agonist m-CPP and several
more recently developed 5-HT2C ligands.
1).18,25-31 Several compounds have shown efficacy in preclinical
animal models and are currently being tested in clinical trials.32
Despite recent progress in obtaining crystal structures of G
protein-coupled receptors,33-35 information about the structure
and function of 5-HT receptors is still restricted to homology
modeling using rhodopsin or ꢀ-adrenergic receptors as a starting
template. However, it is well-known that there are inherent
limitations in the use of such homology models for drug design
purposes36 and they still lack sufficient predictive power for
drug discovery.37 Therefore, we based our search for selective
5-HT2C receptor agonists on high-throughput chemical library
screening to identify a suitable lead structure followed by
stepwise activity-guided chemical modification. Using this
approach, we have identified the reversible monoamine oxidase
(MAO) inhibitor tranylcypromine 938,39 as a lead compound
* To whom correspondence should be addressed. For B.L.R.: phone,
919-966-7535; fax, 919-843-5788; E-mail: bryan_roth@med.unc.edu. For
A.P.K.: phone, 312-996-7577; fax, 312-996-7107; E-mail, kozikowa@
uic.edu.
†
University of Illinois at Chicago.
University of North Carolina at Chapel Hill.
These authors contributed equally to this work.
Psychogenics, Inc.
‡
§
|
a Abbreviations: 5-HT, 5-hydroxytryptamine (serotonin); LSD, lysergic
acid diethylamide; CNS, central nervous system; MAO, monoamine oxidase;
SAR, structure-activity relationship; SERT, 5-HT transporter; NET,
norepinephrine transporter; DAT, dopamine transporter.
10.1021/jm801354e CCC: $40.75
2009 American Chemical Society
Published on Web 03/13/2009

1886 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 7
Cho et al.
chlorides or aryl- and alkylisocyanates to afford the correspond-
ing amides and urethanes. An alkynyl group was also success-
fully introduced as a side chain appendage into the arylcyclo-
propane by the Sonogashira coupling reaction (86-90)50
(Scheme 4).
Figure 2. Structures of 9 and its analogues.
To prepare the pure enantiomers of 14a (Scheme 5), we first
converted the intermediate carboxylic acid formed in the
cyclopropanation step into its diastereomeric amides. This was
brought about by coupling the racemic carboxylic acid 12a with
(R)-phenylglycinol.46 The resulting diastereomeric pair was then
separated by silica gel column chromatography. The choice of
(R)-phenylglycinol as the alcohol component was based on its
successful use in the resolution of other racemic carboxylic acids
and the ease of cleavage of the resulting diastereomers under
acidic conditions that involves an N,O-acyl transfer. The
carboxylic acids (+)-12a and (-)-12a, whose optical rotations
were compared with the known compounds in the literature,51
were then converted individually to (+)- and (-)-trans-(2-
phenylcyclopropyl)methylamine hydrochloride ((+)-14a and
(-)-14a) using the same method as described above.52
from screening the Prestwick Drug Library of 800 compounds
(Figure 2).40
In initial experiments, we then examined the effects of side
chain homologation, stereochemistry, and amine substitution in
5-HT2A, 5-HT2B, and 5-HT2C functional calcium flux assays
(Figure 2). The trans-2-phenylcyclopropylmethylamine hydro-
chloride 14a turned out to be a potent (EC50 ) 13 nM),
moderately selective, and fully efficacious (Emax ) 96%) agonist
at the 5-HT2C receptor. Thus, this core structure was selected
for substitution screening in all of the subsequent SAR studies.
Several ring-unsubstituted N-alkyl derivatives of trans-ami-
nomethyl-2-phenylcyclopropane (14a) have previously been
found to have sympathomimetic activity in animal tests, but
these effects were probably mediated by a 5-HT2C independent
mechanism.41,42
Biological Results and Discussion. In Vitro SAR Studies.
The functional activity of the compounds was determined by
measuring Gq mediated transient intracellular calcium mobiliza-
tion in HEK-293 cells stably expressing the human 5-HT2A,
human 5-HT2B, and human 5-HT2C (INI) receptors.53 The results
are summarized in Tables 1, 2, and 3. Throughout the course
of the project, different batches of cell lines or passages were
used. In contrast to binding affinities, the potencies in functional
assays can vary strongly depending on cell type, receptor
expression level, and passage number. Direct comparisons of
the potencies and efficacies are only valid within the bounds of
each particular table section. In overexpressing cell lines such
as those utilized in the current screening, it is common to
observe EC50 potency concentrations much lower than the Ki
binding constant, particularly when antagonist radioligands are
used for competition binding studies.54
Chemistry. Both the trans- and cis-(2-phenylcyclopropyl)-
methylamine hydrochlorides were prepared as structurally more
flexible analogues of the lead compound 9 starting from styrene
10 (Scheme 1). Cyclopropanation was carried out using ethyl
diazoacetate in the presence of Cu(acac)2 as a catalyst.43 The
ester product was obtained as a 2:1 racemic mixture of the trans
and cis isomers. After separation of the configurational isomers
on silica gel, the resulting ester isomers trans-11a and cis-11b
were converted to the corresponding amine hydrochlorides 14a
and 14b, respectively, employing a standard sequence of
reactions involving amide formation, followed by borane
reduction.
N-Monomethylation of the amino group in compound 9
(Figure 2, n ) 0) and of the elongated cyclopropylmethylamine
derivative (Figure 2, n ) 1) was carried out by reduction of the
corresponding N-formyl derivatives. Formylation of the amine
with acetic formic anhydride followed by in situ borane-dimethyl
sulfide reduction afforded the corresponding N-methylamines.44
The products 15 and 16 obtained in this way were free of any
contamination by the dialkylation product. The N,N-dimethy-
lamine derivative 17 of compound 9 was prepared by reductive
N-alkylation using an excess of 37% aqueous formaldehyde and
NaBH3CN according to a literature procedure.45,46 The monoiso-
propyl and monobenzylamine analogues 18-20 were prepared
by similar reductive N-alkylation protocols47,48 (Scheme 2).
Next, we explored the activity of derivatives bearing various
substituents on the aromatic ring or having the aromatic ring
replaced by the larger naphthyl ring or by a biphenyl structure
(Figure 3). The substituted phenyl and naphthyl derivatives
26-61 were synthesized from the corresponding styrenes 22,
followed by application of the same chemistry used in the
preparation of 14a and 14b. Some of styrenes were prepared
from the corresponding aldehydes 21 by Wittig chemistry
(Scheme 3).
The trans isomer 14a with its side chain elongated by one
methylene group was much more potent (EC50 ) 13 nM) at
the 5-HT2C receptor as compared to its parent compound 9 and
the cis isomer 14b was much less active than the trans isomer
14a (Table 1). The trans-aminomethyl-2-phenylcyclopropane
14a and several of its N-mono- and N-dialkyl analogues have
previously been described as centrally active sympathomimetic
compounds that cause hyperlocomotion, reverse reserpine-
induced depressant effects in a model of antidepressant activity,
and cause anorexia similar to compound 9,41 while the fully
unsubstituted compound 14a was devoid of MAO inhibitory
activity in a tryptamine potentiation model.42 This behavioral
and biochemical profile and the different structure-activity
relationships suggest a non-5-HT2C-mediated mechanism for
these early ring-unsubstituted compounds, perhaps through
inhibition of monoamine reuptake.
Assay of the two enantiomers revealed that the (S,S)-
stereoisomer (+)-14a was significantly more potent than its
(R,R)-isomer (-)-14a. We have observed the same stereochem-
ical preference for the corresponding 2-bromo-substituted enan-
tiomeric pair (+)-29 and (-)-29 (Table 2).
Alkylation of the amine nitrogen in analogues 15-20 led to
sharply decreased 5-HT2C receptor potency in comparison to
the parent compounds 9 or 14a. Compound 9 and its potent
analogues 14a (racemic) and (+)-14a were full agonists at the
5-HT2C receptor and displayed a high selectivity over the 5-HT2A
receptor and a 3- to 7-fold selectivity over the 5-HT2B receptor.
The N-Boc protected aminomethylcyclopropane derivatives
62-64 were very useful intermediates for the preparation of
other analogues. The bromophenyl derivatives 29, 36, or 43 were
thus used as convenient starting materials to generate a limited
number of biphenyl and heteroarylphenyl derivatives 66-74
by means of the Suzuki coupling reaction.49 Some of amide
and amine substituted phenyl derivatives 78 and 80-84 were
prepared through Pd catalyzed conversion of the bromo group
to an amine. These amines were reacted in turn with acid

SelectiVe 5-HT 2C Receptor Agonists from Tranylcypromine
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 7 1887
Scheme 1a
a Reagents and conditions: (a) N2CHCO2Et, Cu(acac)2, CH2Cl2, reflux, 5 h. (b) 2 N KOH, MeOH. (c) (i) SOCl2, toluene, 80 °C, 3 h; (ii) NH3 (liquid),
toluene/CH2Cl2. (d) (i) BH3/THF, reflux, 20 h; (ii) 1 M HCl, 0 °C.
Scheme 2a
At the 5-HT2B receptor, the 3-hydroxy analogue 40 has
about a 10-fold higher potency than the corresponding
3-methyl analogue 37, while both compounds were essentially
equipotent at the 5-HT2C receptor. This might indicate a
hydrogen bond interaction between compound 40 and the
5-HT2B receptor that is absent in the 5-HT2C-40 complex,
making compound 37 one of the most selective compounds
in the current series.
5-HT2A potencies of most tested compounds were above or
around 0.5 µM, resulting in a generally good 5-HT2A over
5-HT2C selectivity. Additionally, most compounds were partial
agonists at the 5-HT2A receptor but full agonists at the 5-HT2C
a Reagents and conditions: (a) acetic formic anhydride, BH3 ·SMe2/THF.
(b) HCHO (excess), NaBH3CN, acetonitrile/H2O. (c) acetone or benzalde-
hyde, NaBH3CN, MeOH.
receptor. 2-Chloro and 2-bromo substitutions resulted in in-
creased 5-HT2A potency, a trend also seen at the other two
receptors.
We also prepared and tested the biphenyl and heteroaryl-
phenyl derivatives 66-74, the 2- and 3-acetamido, 2- and
Figure 3. Aromatic substitution screening of trans-(2-phenylcyclo-
3-benzamido, 2-benzylamino, and 2-(4-chlorophenyl)urea ana-
logues 78, 80-84, and a series of extended alkynyl derivatives
86-90 (Table S1, Supporting Information). Most of these
compounds were inactive or had potencies above 1 µM at all
tested receptors. None of these compounds had a 5-HT2C potency
below 100 nM.
The basic ring-monosubstituted derivatives presented in this
publication do not reach the same level of selectivity as the
5-HT2C agonists that are currently in clinical trials; in our hands
the potent compound (+)-29 displayed about 5-fold less 5-HT2C
over 5-HT2B selectivity as compared to 7.
A molecular overlay of several of the new selective 5-HT2C
agonists prepared by other research groups with one of our more
selective compounds 37 reveals the molecular features common
to all these compounds, which include a similarly aligned
positively charged nitrogen atom (blue) positioned above the
plane of an aromatic ring, which is substituted with hydrophobic
group(s), such as chloro, methyl, ethyl, or trifluoromethyl (Figure
4).
A selection of compounds was then subjected to binding
experiments together with 7 as a reference compound (Table
3). Compounds 37 (3-Me), 41 (4-F), and 53 (2-Cl, 4-F) had
comparable 5-HT2C binding affinities. Compound 41 was as
5-HT2C-selective as 7, while 29, (+)-29, and 37 where less
selective. Since earlier data suggested sympathomimetic effects
for the unsubstituted parent compound 14a,41,42 we also tested
these compounds on all three monoamine reuptake transporters.
None of the compounds had submicromolar binding affinities
at SERT (5-HT transporter), NET (norepinephrine transporter),
and DAT (dopamine transporter).
propyl)methylamine hydrochloride analogues.
As a preliminary summary, the initial SAR studies established
the following essential features responsible for high 5-HT2C
receptor potency: a cyclopropyl ring attached to a phenyl group
carrying a primary aminomethyl group in trans orientation. On
the basis of these preliminary observations, our further work
focused on variations in the phenyl ring of this core structure.
In the following four rounds of structural exploration and
functional screening, we systematically tested the effects of
mono- and disubstitutions at the phenyl ring (Table 2). Selected
compounds from previous optimization rounds, the known
5-HT2C agonist WAY 629 (1,2,3,4,8,9,10,11-octahydro-[1,4]di-
azepino[6,7,1-jk]carbazole) (6)29 and lorcaserin ((1R)-8-chloro-
2,3,4,5-tetrahydro-1-methyl-1H-3-benzazepine) (7)30 as well as
1 were included as reference compounds for comparison
purposes.
All tested compounds were highly efficacious 5-HT2C ago-
nists. Mono- and disubstituted analogues carrying chloro and
bromo substitutions in the 2-position were consistently more
potent than their respective fluoro, trifluoromethyl, methyl,
methoxy, or hydroxy analogues.
In the 3-position, potency was less strongly influenced by
the tested substituents and tended to decrease with molecular
size from fluoro, methyl, and hydroxy over chloro to bromo
and trifluoromethyl.
In the 4-position, the optimal substitution was a fluoro group.
Any replacement by other halogens, methyl, trifluoromethyl,
methoxy, or hydroxy groups resulted in a sharp decrease in
5-HT2C potency and selectivity over 5-HT2B activity.
Qualitatively similar trends of these substituent effects on
potency and selectivity were observed between mono- and
disubstituted compounds. However, the tested disubstitutions
did not result in additive effects on potency or selectivity.
In Vivo Studies: Evaluation of a 5-HT2C Agonist for
Antidepressant Potential. 5-HT2C agonists have been reported
to have antidepressant-like properties in multiple animal
models, indicating that the 5-HT2C receptor may be a desired
target for CNS therapeutic effects. Compound 37 is one of

1888 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 7
Cho et al.
Scheme 3a
a Reagents and conditions: (a) methyltriphenylphosphonium bromide, NaH, THF, 20 h. (b) N2CHCO2Et, Cu(acac)2, CH2Cl2, reflux, 5 h. (c) 2 N KOH,
MeOH. (d) (i) SOCl2, toluene, 80 °C, 3 h; (ii) NH3 (liquid), toluene/CH2Cl2. (e) (i) BH3/THF, reflux, 20 h; (ii) 1 M HCl, 0 °C; (f) BBr3, CH2Cl2, -78 °C.
Scheme 4a
a Reagents and conditions: (a) Boc2O, triethylamine, CH2Cl2. (b) Ar-B(OH)2, Pd(PPh3)4, K2CO3, dimethoxyethane, 80 °C, 20 h. (c) TFA, CH2Cl2, rt. (d)
(i) benzophenone imine, Pd(OAc)2, BINAP, Cs2CO3, toluene, 80 °C; (ii) NaOAc, NH2OH·HCl, MeOH, rt, 2 h. (e) RCHO, NaBH3CN, MeOH. (f) various
anhydrides, DMAP, CH2Cl2. (g) R′CtCH, Pd(PPh3)2Cl2, PPh3, CuI, triethylamine, reflux. (h) 2 M HCl, rt.

SelectiVe 5-HT 2C Receptor Agonists from Tranylcypromine
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 7 1889
Scheme 5a
a Reagents and conditions: (a) (R)-phenylglycinol, EDCI, HOBT, CH2Cl2. (b) H2SO4, 100 °C.
Table 1. Functional Activity and Selectivity of the Lead Compound 9 and its Initial Analogues 14-20 and 26 at Human 5-HT2A, 5-HT2B, and 5-HT2C
Receptors in Calcium Flux Assays Using Stably Transfected HEK-293 Cells
a Tested in independent screening campaigns using different cell lines/passages. b Percent of maximal activation by 5-HT; activation at 10 µM for compounds
without EC50 value. c n: Number of concentration curves from g2 (typically g3) independent experiments. NA: Emax e 12%.
the most potent and selective ligands for the 5-HT2C receptor
in the current series (120-fold selectivity over 2A and 14-
fold selectivity over 2B, EC50 ) 585, 65, and 4.8 nM at the
2A, 2B, and 2C subtypes, respectively, see Table 2). On the
basis of this in vitro profile, compound 37 was chosen for
an initial in vivo profiling in the mouse forced swim test,
which is a commonly used assay to validate antidepressant-
like properties of compounds.
In the mouse forced swim test, compound 37 (10-60 mg/
kg) produced a dose-dependent decrease in immobility time
compared to vehicle (F(4.45) ) 8.865, p < 0.001). Posthoc
analysis indicated that compound 37 produced a significant
decrease in immobility at all three doses tested (28%, 38%, and
38% decrease in the 10, 30, and 60 mg/kg groups, respectively,
(p < 0.05)). For comparison, the reference selective serotonin
reuptake inhibitor sertraline (92) (10 mg/kg) was used as a
positive control in the same study. Both 92 (p < 0.001) and
compound 37 significantly reduced the immobility time, indica-
tive of an antidepressant-like effect (Figure 5). The results also
demonstrate that compound 37 possesses drug-like properties
in vivo and that it is centrally active. The antidepressant-like
effects together with the absence of monoamine reuptake
transporter binding are in agreement with previous studies,
which demonstrated that 5-HT2C agonists have antidepressant-

1890 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 7
Cho et al.

SelectiVe 5-HT 2C Receptor Agonists from Tranylcypromine
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 7 1891

1892 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 7
Cho et al.
a new scaffold for 5-HT2C drug discovery, which may in turn
lead to novel therapeutics for use in a variety of CNS related
disorders.
Experimental Section
Chemistry. 1H and 13C NMR spectra were obtained with a
Bruker Avance spectrometer at 300 and 75 MHz or a Bruker
Avance spectrometer at 400 and 100 MHz, respectively. 1H
chemical shifts (δ) were reported in ppm downfield from internal
Me4Si. Mass spectra were measured in positive mode electrospray
ionization (ESI). The HRMS data were obtained on a Micromass
Q-TOF-2TM, ThermoFinnigan LTQFT. and Shimadzu LCMSIT-
TOF instruments. Optical rotations were measured with an AU-
TOPOL IV (Rudolph Research Analytical) instrument. TLC was
performed on silica gel 60F254 glass plates; column chromatography
was performed using Merck silica gel (230-400 mesh). Analytical
HPLC was performed using a Shimadzu LC-10AD system equipped
with the following columns: Column 1: ACE 5 AQ C18 UltraInert
column (4.6 mm × 250 mm; 5 µm). Column 2: Waters µ-Bondapak
C18 column (3.9 mm × 300 mm; 5 µm). Column 3: ACE 3 AQ
C
18 UltraInert column (4.6 mm × 100 mm; 3.5 µm). Chiralcel OJ
(4.6 mm × 250 mm, DAICEL) and Chiralpak AD (10.0 mm ×
250 mm, DAICEL) were used for Chiral HPLC analysis. HPLC
data were recorded using following methods. Method A: H2O/
MeCN (0.1% TFA), 90/10 f 0/100 in 18 min, + 2 min isocratic,
flow rate of 1.6 mL/min, λ ) 254, 280 nm. Method B: H2O/MeCN
(0.1% TFA), 100/0 f 0/100 in 20 min, + 2 min isocratic, flow
rate of 1.6 mL/min, λ ) 254, 280 nm. Method C: H2O/MeCN (0.1%
TFA), 70/30 f 0/100 in 21 min, + 7 min isocratic, flow rate of
1.3 mL/min, λ ) 254, 280 nm. Method D: H2O/MeCN (0.1% TFA),
90/10 f 0/100 in 20 min, + 7 min isocratic, flow rate of 1 mL/
min, λ ) 254, 280 nm. Method E: H2O/MeCN (0.1% TFA), 100/0
f 0/100 in 30 min, + 3 min isocratic, flow rate of 1.3 mL/min, λ
) 254, 280 nm. Starting materials were obtained from Aldrich,
Alfa Aesar, or Acros. Solvents were obtained from Fisher Scientific
or Aldrich and were used without further purification unless noted
otherwise.
Figure 4. Overlay of the 3-methyl bearing analogue 37 (orange) with
7 (purple) and the BMS pyrazinoisoindoline (8)31 (light blue) shows
the expected similarities in structure. See Figure 1 for structures.
General Procedure for the Synthesis of trans- and cis-(2-
Phenylcyclopropyl)methylamine Hydrochloride (14a and 14b).
Step A: trans- and cis-2-Phenylcyclopropanecarboxylic Acid
Ethyl Ester (11a and 11b). Under dry conditions, Cu(acac)2 (78
mg, 0.3 mmol) was dissolved in anhydrous CH2Cl2 (20 mL). After
the solution was stirred for 5 min, a few drops of phenylhydrazine
were added and stirring was continued. To this solution was added
styrene (1.15 mL, 10 mmol). The mixture was stirred at 40 °C for
5 min, and a solution of ethyl diazoacetate (1.56 mL, 15 mmol) in
CH2Cl2 (20 mL) was added via syringe pump over 5 h at 40 °C.
After stirring for one more hour followed by the addition of CH2Cl2
(50 mL), the mixture was washed successively with sat. aq NaHCO3
(×2) and H2O (×2). The organic portion was dried over Na2SO4
and all volatiles were removed in vacuo. The isomers were separated
by silica gel chromatography (hexane/Et2O 20:1) to afford the title
compounds as colorless oils (trans-isomer 11a: 1.19 g, 67% yield)
and (cis-isomer 11b: 490 mg, 27% yield). 11a: 1H NMR (300 MHz,
CDCl3) δ 7.30 (m, 2 H), 7.24 (m, 1 H), 7.13 (d, J ) 7.1 Hz, 2 H),
4.20 (q, J ) 7.1 Hz, 2 H), 2.54 (m, 1 H), 1.93 (m, 1 H), 1.63 (m,
1 H), 1.37-1.29 (m, 4 H). 13C NMR (75 MHz, CDCl3) δ 173.3,
Figure 5. The effect of compounds 37 and 92 in the mouse forced
swim test. Compound 37 (10-60 mg/kg, ip) or the reference compound
92 (10 mg/kg, ip) was administered 30 min prior to testing. Both
compounds 92 and 37 produced a significant decrease in immobility,
which reached significance at all doses tested. These data are indicative
of an antidepressant-like effect and in vivo drug-like central activity.
like properties in both acute and chronic preclinical models used
to predict antidepressant efficacy.20,22
Conclusions
5-HT2C agonists have demonstrated efficacy in preclinical
models of depression, obesity, and psychosis.23,55 The present
work reports the chemical synthesis of 67 new side-chain
analogues of the monoamine oxidase inhibitor 9, which were
identified as a new class of 5-HT2C agonists. Starting from
compound 9, a selective but only moderately potent 5-HT2C
agonist, we have undertaken a structural optimization campaign
that has led to a potent and moderately selective agonist that
demonstrates antidepressant-like effects in a commonly used
behavioral assay. Moreover, preliminary results based on the
work presented in this article suggest the possibility of
compounds with improved selectivity profiles comparable to
drugs currently in clinical trials. This study therefore presents
1
140.0, 128.4, 126.4, 126.1, 60.6, 26.1, 24.1, 17.0, 14.2. 11b: H
NMR (300 MHz, CDCl3) δ 7.29-7.21 (m, 5 H), 3.90 (q, J ) 7.1
Hz, 2 H), 2.60 (m, 1 H), 2.10 (m, 1 H), 1.74 (m, 1 H), 1.35 (m, 1
H), 0.99 (t, J ) 7.1 Hz, 3 H). 13C NMR (75 MHz, CDCl3) δ 170.1,
136.5, 129.2, 127.8, 126.6, 60.1, 25.4, 21.7, 14.0, 11.0.
Step B: trans-2-Phenylcyclopropanecarboxylic Acid (12a). A
solution of 11a (128 mg, 0.726 mmol) in MeOH (1 mL) was added
to KOH (406 mg, 7.26 mmol) in MeOH (3 mL) at 0 °C. The
mixture was stirred at rt overnight, and then poured into water and
extracted with CH2Cl2. The organic layer was discarded, and the
aqueous phase was acidified with 10% HCl and extracted with
CH2Cl2 (×2). The combined organic phases were dried over Na2SO4
and all volatiles were removed in vacuo. The acid was isolated as

SelectiVe 5-HT 2C Receptor Agonists from Tranylcypromine
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 7 1893
white powders and further purified by recrystallization from hexane
(80 mg, 68% yield). H NMR (300 MHz, CDCl3) δ 10.3 (br s, 1
Na2SO4, filtered, and concentrated. The crude residue was purified
by silica gel column chromatography (EtOAc/Et2O 1:2) to afford
the (-)-isomer with a higher Rf value (650 mg, 23% yield) and
the (+)-isomer with a lower Rf value (703 mg, 25% yield) as
colorless solids. (+)-91: 1H NMR (300 MHz, MeOD-d4) δ
7.35-7.10 (m, 9 H), 5.02 (t, J ) 6.3 Hz, 1 H), 3.75 (m, 2 H), 2.34
(m, 1 H), 2.03 (m, 1 H), 1.53 (m, 1 H), 1.27 (m, 1 H). 13C NMR
(75 MHz, MeOD-d4) δ 173.6, 141.2, 140.4, 128.5, 128.4, 127.4,
127.0, 126.3, 126.1, 65.3, 56.4, 25.8, 24.8, 15.2. (-)-91: 1H NMR
(300 MHz, MeOD-d4) δ 7.36-7.13 (m, 9 H), 5.03 (t, J ) 6.3 Hz,
1 H), 3.75 (m, 2 H), 2.42 (m, 1 H), 2.03 (m, 1 H), 1.46 (m, 1 H),
1.24 (m, 1 H). 13C NMR (75 MHz, MeOD-d4) δ 173.6, 141.2, 140.4,
128.5, 128.4, 127.4, 127.0, 126.2, 126.0, 65.2, 56.3, 25.7, 24.8,
15.4.
1
H), 7.34-7.22 (m, 3 H), 7.14 (d, J ) 7.0 Hz, 2 H), 2.64 (m, 1 H),
1.93 (m, 1 H), 1.70 (m, 1 H), 1.44 (m, 1 H). 13C NMR (75 MHz,
CDCl3) δ 180.2, 139.9, 128.9, 127.1, 126.7, 27.5, 24.4, 17.9.
cis-2-Phenylcyclopropanecarboxylic Acid (12b). Prepared by
the same procedure as described for 12a (233 mg, 77% yield). 1H
NMR (400 MHz, CDCl3) δ 7.29-7.20 (m, 5 H), 2.65 (m, 1 H),
2.05 (m, 1 H), 1.68 (m, 1 H), 1.40 (m, 1 H). 13C NMR (100 MHz,
CDCl3) δ 177.2, 135.8, 129.2, 127.9, 126.8, 26.6, 21.4, 12.0.
Step C: trans-2-Phenylcyclopropanecarboxylic Acid Amide
(13a). Several drops of dimethylformamide and thionyl chloride
(13.5 mL, 185 mmol) were added dropwise to a solution of 12a
(2.0 g, 12.3 mmol) in toluene (40 mL). After stirring at 80 °C for
3 h, the reaction mixture was concentrated under vacuum. The
resulting residue was dissolved in toluene (10 mL), and the resulting
solution was added to liquid ammonia at -78 °C. After stirring at
-78 °C for 30 min and then at rt for 30 min, CH2Cl2 (25 mL) was
added to the mixture at -78 °C and the resulting mixture was stirred
at rt overnight. After addition of EtOAc, the mixture was washed
with sat. aq NH4Cl (×2), dried over Na2SO4, and all volatiles were
removed in vacuo. The title compound was isolated as a pearly
yellow powder and further purified by recrystallization from hexane/
EtOAc (1.72 g, 87% yield). 1H NMR (300 MHz, DMSO-d6) δ 7.60
(br s, 1 H), 7.29-7.10 (m, 5 H), 6.91 (br s, 1 H), 2.21 (m, 1 H),
1.82 (m, 1 H), 1.32 (m, 1 H), 1.18 (m, 1 H). 13C NMR (75 MHz,
DMSO-d6) δ 173.8, 142.1, 129.2, 126.8, 126.6, 26.4, 24.8, 16.1.
cis-2-Phenylcyclopropanecarboxylic Acid Amide (13b). Pre-
pared by the same procedure as described for 13a (128 mg, 56%
yield). 1H NMR (400 MHz, DMSO-d6) δ 7.40 (br s, 1 H),
7.21-7.20 (m, 4 H), 7.13 (m, 1 H), 6.59 (br s, 1 H), 2.36 (m, 1 H),
1.97 (m, 1 H), 1.45 (m, 1 H), 1.13 (m, 1 H). 13C NMR (100 MHz,
DMSO-d6) δ 170.9, 138.2, 129.4, 127.9, 126.2, 24.3, 23.4, 9.9.
Step D: trans-(2-Phenylcyclopropyl)methylamine Hydrochlo-
ride (14a). To a solution of 13a (1.6 g, 9.93 mmol) in anhydrous
THF (40 mL) was added dropwise 1 M borane/THF solution (39.7
mL) at 0 °C. The mixture was heated under reflux at 70 °C
overnight and then was quenched by the careful addition of 10%
aq HCl. After stirring at rt for 1 h, the THF was removed by
evaporation and the residual aqueous solution was washed with
Et2O (×2), neutralized with 10% NaOH, and then extracted with
Et2O (×4). The combined organic layers were dried over Na2SO4
and concentrated until the volume was reduced to about 20 mL.
To the solution was added 1 M HCl in Et2O (20 mL, 20 mmol) at
0 °C. After stirring at 0 °C for 15 min and at rt for 1 h, the mixture
was concentrated under vacuum. The resulting residue was purified
by recrystallization from ethanol/Et2O to afford the title compound
as a white solid (1.54 g, 86% yield). HPLC purity: 11.9 min, 95.4%
(column 1, method C). 1H NMR (300 MHz, MeOD-d4) δ 7.29-7.24
(m, 2 H), 7.18-7.13 (m, 3 H), 3.01 (d, J ) 7.4 Hz, 2 H), 2.03 (m,
1 H), 1.41 (m, 1 H), 1.14-1.05 (m, 2 H). 13C NMR (75 MHz,
MeOD-d4) δ 141.6, 128.4, 126.0, 125.9, 43.9, 22.2, 19.8, 14.0. MS
(ESI) m/z 148.1 [MH+]. HRMS (ESI) calculated for C10H14N+
[MH+] 148.1126, found 148.1127.
Step B: (+)-trans-2-Phenylcyclopropanecarboxylic Acid
((+)-12a). A solution of (+)-91 (150 mg, 0.534 mmol) in dioxane
(5 mL) was added to 3 N H2SO4 (5 mL). The mixture was stirred
at 100 °C for 24 h and then poured into water and extracted with
CH2Cl2 (×3). The combined organic phases were dried over
MgSO4, filtered, and concentrated. The crude residue was purified
by silica gel column chromatography (EtOAc/hexane 1:2) to afford
1
the title compound as a colorless solid (73 mg, 84% yield). H
NMR (300 MHz, CDCl3) δ 10.3 (br s, 1 H), 7.34-7.22 (m, 3 H),
7.14 (d, J ) 7.0 Hz, 2 H), 2.64 (m, 1 H), 1.93 (m, 1 H), 1.70 (m,
1 H), 1.44 (m, 1 H). 13C NMR (75 MHz, CDCl3) δ 180.2, 139.9,
128.9, 127.1, 126.7, 27.5, 24.4, 17.9; [R]D +389° (c 0.61, CHCl3)
[lit. 405° (c 1.0, CHCl3)51].
(-)-trans-2-Phenylcyclopropanecarboxylic Acid ((-)-12a).
Prepared by the same procedure as described for (+)-12a. 1H NMR
(300 MHz, CDCl3) δ 9.76 (br s, 1 H), 7.34-7.22 (m, 3 H), 7.14
(d, J ) 7.0 Hz, 2 H), 2.64 (m, 1 H), 1.93 (m, 1 H), 1.70 (m, 1 H),
1.44 (m, 1 H). 13C NMR (75 MHz, CDCl3) δ 180.2, 139.9, 128.9,
127.1, 126.7, 27.5, 24.4, 17.9; [R]D -396° (c 0.72, CHCl3) [lit.
-410° (c 1.0, CHCl3)51].
Step C: (+)-trans-(S,S)-(2-Phenylcyclopropyl)methylamine
Hydrochloride ((+)-14a). Refer to the general procedure for the
synthesis of 14a described above with substituting (+)-trans-2-
phenyl-cyclopropanecarboxylic acid (+)-12a for (()-12a in Step
C. HPLC purity: 12.8 min, 97.9% (column 1, method C). 1H NMR
(MeOD-d4) δ 7.29-7.24 (m, 2 H), 7.18-7.13 (m, 3 H), 3.01 (d, J
) 7.4 Hz, 2 H), 2.02 (m, 1 H), 1.41 (m, 1 H), 1.14-1.06 (m, 2 H).
13C NMR (MeOD-d4) δ 141.6, 128.4, 126.0, 125.9, 43.9, 22.2, 19.8,
14.0. MS (ESI) m/z 148.2 [MH+]. HRMS (ESI) calculated for
C10H14N+ [MH+] 148.1126, found 148.11202; [R]D +72.9° (c 0.45,
MeOH).
(-)-trans-(R,R)-(2-Phenylcyclopropyl)methylamine Hydrochlo-
ride ((-)-14a). Prepared by the same procedure as described for
(+)-14a. HPLC purity: 12.6 min, 98.1% (column 1, method C).
1H NMR (300 MHz, MeOD-d4) δ 7.29-7.24 (m, 2 H), 7.18-7.13
(m, 3 H), 3.01 (d, J ) 7.4 Hz, 2 H), 2.06-2.02 (m, 1 H), 1.42 (m,
1 H), 1.13-1.05 (m, 2 H). 13C NMR (75 MHz, MeOD-d4) δ 141.6,
128.4, 126.0, 125.9, 43.9, 22.2, 19.8, 14.0. MS (ESI) m/z 148.2
[MH+]. HRMS (ESI) calculated for C10H14N+ [MH+] 148.1126,
found 148.11200; [R]D -71.3° (c 0.45, MeOH).
trans-N-Methyl-(2-phenylcyclopropyl)amine (15). Acetic for-
mic anhydride was generated by dropwise addition of formic acid
(0.36 mL, 9.6 mmol) to acetic anhydride (0.73 mL, 7.8 mmol).
The mixture was kept on ice and then heated at 50 °C for 2 h. The
mixture was cooled to rt, and THF (5 mL) was added. This mixture
(0.6 mL, 0.3 mmol) was added to a solution of 9 (50 mg, 0.3 mmol)
in THF (1 mL) at -15 °C, followed by addition of N-methylmor-
pholine (45 µL, 0.3 mmol). The resulting mixture was stirred at
-15 °C for 30 min and at rt for 1 h, insoluble materials were filtered
out, and the solution was concentrated in vacuo. The crude residue
(65 mg) was dissolved in THF (1.2 mL), and to the solution was
added 1.0 M solution of borane dimethylsulfide complex in THF
(0.75 mL). After the mixture was stirred at 65 °C overnight, the
reaction was quenched by 10% aq HCl. The mixture was concen-
trated under reduced pressure to remove THF, and the residual
aqueous solution was washed with Et2O (×1), neutralized with 10%
aq NaOH, and then extracted with Et2O (×3). The combined organic
cis-(2-Phenylcyclopropyl)methylamine Hydrochloride (14b). Pre-
pared by the same procedure as described for 14a (26.8 mg, 47%
1
yield). HPLC purity: 12.4 min, 95.5% (column 1, method C). H
NMR (300 MHz, MeOD-d4) δ 7.35-7.24 (m, 5 H), 2.99-2.94
(m, 1 H), 2.20 (m, 1 H), 1.49 (m, 1 H), 1.25-1.18 (m, 1 H), 1.08
(m, 1 H). 13C NMR (75 MHz, MeOD-d4) δ 137.3, 129.1, 128.5,
126.8, 40.5, 21.1, 15.5, 8.3. MS (ESI) m/z 148.1 [MH+]. HRMS
(ESI) calculated for C10H14N+ [MH+] 148.1126, found 148.1123.
General Procedure for the Preparation of Optically Pure
Ligand ((+)- and (-)-14a). Step A: (+)- and (-)-trans-2-Phenyl-
cyclopropanecarboxylic Acid (2-Hydroxy-1-phenylethyl)amide ((+)-
and (-)-91). To a stirred solution of 12a (1.62 g, 10.0 mmol) in
CH2Cl2 (20 mL) were added (R)-(-)-2-phenylglycinol (2.06 g, 15.0
mmol), HOBT (1.35 g, 10.0 mmol), and EDC ·HCl (2.88 g, 15.0
mmol). The mixture was stirred at 0 °C for 1 h followed at rt
overnight. The reaction mixture was washed with 5% aq citric acid,
sat. aq NaHCO3, and sat. NaCl. The organic layer was dried over

1894 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 7
Cho et al.
layers were dried over Na2SO4, filtered, and concentrated. The
residue was purified by preparative TLC (EtOAc/Et3N/MeOH 8:1:
1) to afford the title compound as a colorless oil (21 mg, 47% yield).
17.2. MS (ESI) m/z 176.1 [MH+]. HRMS (ESI) calculated for
C12H18N+ [MH+] 176.1439, found 176.1437.
trans-N-Benzyl-(2-phenylcyclopropyl)amine (19). Prepared by
the same procedure as described for 18 with benzaldehyde (27 µL,
0.266 mmol) as the starting material (15.4 mg, 23% yield). HPLC
purity: 14.6 min, 96.8% (column 1, method C). 1H NMR (300 MHz,
CDCl3) δ 7.40-7.25 (m, 9 H), 7.18 (m, 1 H), 7.03 (d, J ) 7.3 Hz,
2 H), 3.92 (s, 2 H), 2.42 (m, 1 H), 2.25 (m, br s, 1 H), 1.97 (m, 1
H), 1.14 (m, 1 H), 1.01 (m, 1 H). 13C NMR (75 MHz, CDCl3) δ
142.7, 140.7, 128.8, 128.7, 128.6, 127.4, 126.3, 125.9, 54.0, 41.6,
25.8, 17.5. MS (ESI) m/z 224.1 [MH+]. HRMS, (ESI) calculated
for C16H18N+ [MH+] 224.1439, found 224.1440.
trans-N-Benzyl-(2-phenylcyclopropylmethyl)amine (20). Pre-
pared by the same procedure as described for 18 with 14a (30 mg,
0.163 mmol) and benzaldehyde (14.9 µL, 0.147 mmol) as the
starting materials (20.8 mg, 54% yield). HPLC purity: 15.7 min,
95.1% (column 1, method C). 1H NMR (300 MHz, CDCl3) δ
7.36-7.25 (m, 7 H), 7.19-7.16 (m, 1 H), 7.10-7.07 (m, 2 H),
3.87 (s, 2 H), 2.71 (m, 1 H), 1.73 (m, 1 H), 1.69 (br s, 1 H), 0.95
(m, 1 H), 0.85 (m, 1 H). 13C NMR (75 MHz, CDCl3) δ 143.4,
140.8, 128.8, 128.7, 128.5, 127.4, 126.1, 125.9, 54.1, 54.0, 23.8,
22.5, 15.3. MS (ESI) m/z 238.1 [MH+]. HRMS (ESI) calculated
for C17H20N+ [MH+] 238.1596, found 238.1589.
General Procedure for the Synthesis of Substituted Styrene
(22). To a stirred suspension of benzaldehyde 21 (10 mmol) and
methyltriphenylphosphonium bromide (4.28 g, 12 mmol) in THF
(50 mL) was added sodium hydride (1.08 g, 45.10 mmol) under
argon purge at 0 °C. After the mixture was stirred at rt overnight,
the organic layer was washed three times with brine, dried over
Na2SO4, filtered, and concentrated. The crude product was purified
by silica gel column chromatography (hexane/Et2O 20:1) to afford
the title compound as a colorless oil (90-99% yield).
trans-(2-Naphthalen-2-ylcyclopropyl)methylamine Hydrochlo-
ride (26). Refer to the general procedure for the synthesis of 14a
described above by using 2-vinylnaphthalene as the starting
material. HPLC purity: 14.8 min, 97.7% (column 1, method C).
1H NMR (300 MHz, MeOD-d4) δ 7.81-7.77 (m, 3 H), 7.63 (s, 1
H), 7.48-7.38 (m, 2 H), 7.28 (m, 1 H), 3.06 (d, J ) 7.4 Hz, 2 H),
2.20 (m, 1 H), 1.55 (m, 1 H), 1.24 (m, 1 H), 1.15 (m, 1 H). 13C
NMR (75 MHz, MeOD-d4) δ 139.1, 134.0, 132.7, 128.1, 127.6,
127.4, 126.2, 125.3, 124.7, 124.3, 43.9, 22.4, 19.9, 14.1. MS (ESI)
m/z 198.1 [MH+]. HRMS (ESI) calculated for C14H16N+ [MH+]
198.1283, found 198.1290.
1
HPLC purity: 24.8 min, 95.2% (column 2, method C). H NMR
(300 MHz, CDCl3) δ 7.30-7.25 (m, 2 H), 7.20-7.16 (m, 1 H),
7.09-7.06 (m, 2 H), 2.54 (br s, 3 H), 2.34 (m, 1 H), 1.92 (m, 1 H),
1.76 (br s, 1 H), 1.12-1.06 (m, 1 H), 1.02-0.98 (m, 1 H). 13C
NMR (75 MHz, CDCl3) δ 142.8, 128.6, 126.3, 125.9, 43.7, 36.2,
25.3, 17.5. MS (ESI) m/z 148.1 [MH+]. HRMS (ESI) calculated
for C10H14N+ [MH+] 148.1126, found 148.1124.
trans-N-Methyl-(2-phenylcyclopropylmethyl)amine (16). Ace-
tic formic anhydride was generated as described above for 15 from
formic acid (0.18 mL, 4.8 mmol) and acetic anhydride (0.365 mL,
3.9 mmol) and THF (4.5 mL). This mixture (0.53 mL, 0.408 mmol)
was added to a solution of 14a (30 mg, 0.163 mmol) in THF (1
mL) at -15 °C, followed by addition of N-methylmorpholine (17.9
µL, 0.163 mmol). The resulting mixture was stirred at -15 °C for
30 min and at rt for 1 h, insoluble materials were filtered out, and
the mixture was concentrated in vacuo. The crude residue (42 mg)
was dissolved in THF (1.2 mL), and to the solution was added 1.0
M borane dimethylsulfide complex in THF (0.41 mL). After the
mixture was stirred at 65 °C overnight, the reaction was quenched
by 10% aq HCl. The mixture was concentrated in vacuo to remove
THF, and the residual aqueous solution was washed with Et2O (×1),
neutralized with 10% aq NaOH, and then extracted with Et2O (×3).
The combined organic layers were dried over Na2SO4, filtered, and
concentrated. The residue was purified by preparative TLC (EtOAc/
Et3N/MeOH 8:1:1) to afford the title compound as a colorless oil
(14.0 mg, 53% yield). HPLC purity: 21.0 min, 96.8% (column 2,
1
method C). H NMR (300 MHz, CDCl3) δ 7.29-7.24 (m, 2 H),
7.18-7.15 (m, 1 H), 7.10-7.07 (m, 2 H), 2.66 (br d, 2 H), 2.49
(br s, 3 H), 2.37 (br s, 1 H), 1.77 (m, 1 H), 1.38-1.32 (m, 1 H),
0.99-0.85 (m, 2 H). 13C NMR (75 MHz, CDCl3) δ 143.3, 128.7,
126.2, 125.9, 56.5, 36.5, 23.3, 22.5, 15.1. MS (ESI) m/z 162.1
[MH+]. HRMS (ESI) calculated for C11H16N+ [MH+] 162.1283,
found 162.1285.
trans-N,N-Dimethyl-(2-phenylcyclopropyl)amine (17). To a
stirred solution of 9 (34 mg, 0.2 mmol) in acetonitrile/H2O (1:1,
v/v) (5 mL) were added N-methylmorpholine (45 µL, 0.4 mmol),
37% aq formaldehyde (0.16 mL, 2.0 mmol), and sodium cy-
anoborohydride (40 mg, 0.6 mmol). Glacial acetic acid (40 µL)
was added to the mixture over 10 min, and the reaction was stirred
at rt for 30 min. To the reaction mixture was added crushed ice,
and the acetonitrile was removed in vacuo. The aqueous residue
was extracted with CH2Cl2. The combined organic layers were dried
over Na2SO4, filtered, and concentrated. The residue was purified
by preparative TLC (EtOAc/Et3N 95:5) to afford the title compound
as a colorless oil (19.7 mg, 61% yield). HPLC purity: 19.8 min,
94.8% (column 1, method C). 1H NMR (300 MHz, CDCl3) δ
7.34-7.26 (m, 2 H), 7.18 (t, J ) 7.3 Hz, 1 H), 7.09 (d, J ) 7.2
Hz, 2 H), 2.74 (d, J ) 3.6 Hz, 2 H), 2.42 (s, 6 H), 2.00 (m, 1 H),
1.83 (m, 1 H), 1.13 (m, 1 H), 0.99 (m, 1 H). 13C NMR (75 MHz,
CDCl3) δ 142.5, 128.6, 126.5, 126.0, 50.6, 45.4, 25.7, 17.6. MS
(ESI) m/z 162.1 [MH+]. HRMS (ESI) calculated for C11H16N+
[MH+] 162.1283, found 162.1279.
trans-N-Isopropyl-(2-phenylcyclopropyl)amine (18). To a stirred
solution of 9 (50 mg, 0.295 mmol) in MeOH (1 mL) were added
acetone (21.7 µL, 0.295 mmol) and sodium cyanoborohydride (22
mg, 0.354 mmol). The mixture was stirred at 0 °C for 1 h and at
rt overnight. Crushed ice was added to the reaction mixture, and
the MeOH was removed in vacuo. The aqueous residue was
extracted with CH2Cl2. The combined organic layers were dried
over Na2SO4, filtered, and concentrated. The residue was purified
by preparative TLC (EtOAc/Et3N 95:5) to afford the title compound
as a colorless oil (16.7 mg, 32% yield). HPLC purity: 8.6 min,
97.4% (column 1, method C). 1H NMR (300 MHz, CDCl3) δ
7.30-7.25 (m, 2 H), 7.19-7.14 (m, 1 H), 7.06 (d, J ) 7.3 Hz, 2
H), 3.01 (m, 1 H), 2.31 (m, 1 H), 1.90 (m, 1 H), 1.87 (br s, 1 H),
1.12 (d, J ) 6.3 Hz, 6 H), 1.07 (m, 2 H). 13C NMR (75 MHz,
CDCl3) δ 142.8, 128.6, 126.1, 125.8, 49.7, 40.7, 25.9, 23.7, 23.6,
trans-[2-(2-Fluorophenyl)cyclopropyl]methylamine Hydrochlo-
ride (27). Refer to the general procedure for the synthesis of 14a
described above by using 2-fluorostyrene as the starting material.
1
HPLC purity: 12.3 min, 95.8% (column 1, method C). H NMR
(300 MHz, MeOD-d4) δ 7.21 (m, 1 H), 7.13-7.02 (m, 3 H),
3.07-3.03 (m, 2 H), 2.16 (m, 1 H), 1.49 (m, 1 H), 1.17-1.09 (m,
1
2 H). 13C NMR (75 MHz, MeOD-d4) δ 162.1 (d, JCF ) 243.9
2
3
Hz), 128.3 (d, JCF ) 14.2 Hz), 127.81 (d, JCF ) 8.3 Hz), 127.2
(d, 3JCF ) 3.9 Hz), 124.4 (d, 4JCF ) 3.5 Hz), 115.0 (d, 2JCF ) 22.1
Hz), 43.8, 18.3, 15.7, 12.7. MS (ESI) m/z 166.1 [MH+]. HRMS
(ESI) calculated for C10H13NF+ [MH+] 166.1032, found 166.1029.
trans-[2-(2-Chlorophenyl)cyclopropyl]methylamine Hydrochlo-
ride (28). Refer to the general procedure for the synthesis of 14a
described above by using 2-chlorostyrene as the starting material.
1
HPLC purity: 6.8 min, 96.2% (column 3, method A). H NMR
(300 MHz, MeOD-d4) δ 7.38 (dd, J ) 7.4, 1.2 Hz, 1 H), 7.26-7.11
(m, 3 H), 3.25 (m, 1 H), 2.93 (m, 1 H), 2.22 (m, 1 H), 1.37 (m, 1
H), 1.12 (t, J ) 6.8 Hz, 2 H). 13C NMR (75 MHz, MeOD-d4) δ
139.8, 136.4, 130.4, 129.0, 128.7, 128.4, 44.9, 21.6, 19.7, 14.9.
MS (ESI) m/z 182.1 [MH+]. HRMS (ESI) calculated for
C10H13NCl+ [MH+] 182.0731, found 182.0738.
trans-[2-(2-Bromophenyl)cyclopropyl]methylamine Hydrochlo-
ride (29). Refer to the general procedure for the synthesis of 14a
described above by using 2-bromostyrene as the starting material.
1
HPLC purity: 14.8 min, 96.1% (column 1, method C). H NMR
(300 MHz, MeOD-d4) δ 7.57 (d, J ) 8.1 Hz, 1 H), 7.29 (t, J ) 7.0
Hz, 1 H), 7.13 (m, 2 H), 3.33 (m, 1 H), 2.89 (m, 1 H), 2.17 (m, 1
H), 1.39 (m, 1 H), 1.13 (m, 2 H). 13C NMR (75 MHz, MeOD-d4)

SelectiVe 5-HT 2C Receptor Agonists from Tranylcypromine
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 7 1895
δ 140.3, 132.5, 128.2, 127.9, 127.8, 125.8, 43.8, 23.3, 18.7, 12.9.
MS (ESI) m/z 226.0 [MH+]. HRMS (ESI) calculated for
C10H13NBr+ [MH+] 226.0231, found 226.0228.
trans-[2-(3-Chlorophenyl)cyclopropyl]methylamine Hydrochlo-
ride (35). Refer to the general procedure for the synthesis of 14a
described above by using 3-chlorostyrene as the starting material.
1
HPLC purity: 7.4 min, 98.6% (column 3, method A). H NMR
trans-[2-(2-Methylphenyl)cyclopropyl]methylamine Hydrochlo-
ride (30). Refer to the general procedure for the synthesis of 14a
described above by using 2-methylstyrene as the starting material.
HPLC purity: 9.4 min, 98.5% (column 1, method E). 1H NMR (400
MHz, MeOD-d4) δ 7.13 (t, J ) 7.8 Hz, 1 H), 6.96-6.91 (m, 3 H),
7.13 (m, 2 H), 3.00 (m, 1 H), 2.28 (s, 3 H), 2.89 (m, 1 H),
(300 MHz, MeOD-d4) δ 7.27-7.05 (m, 4 H), 3.00 (d, J ) 4.1 Hz,
2 H), 2.03 (m, 1 H), 1.43 (m, 1 H), 1.11 (m, 2 H). 13C NMR (75
MHz, MeOD-d4) δ 145.4, 135.4, 131.1, 127.3, 127.2, 125.6, 44.9,
23.0, 21.3, 15.4. MS (ESI) m/z 182.1 [MH+]. HRMS (ESI)
calculated for C10H13NCl+ [MH+] 182.0731, found 182.0732.
2.01-1.96 (m, 1 H), 1.44 (m, 1 H), 1.05 (t, J ) 6.7 Hz, 1 H). 13
C
trans-[2-(3-Bromophenyl)cyclopropyl]methylamine Hydrochlo-
ride (36). Refer to the general procedure for the synthesis of 14a
described above by using 3-bromostyrene as the starting material.
NMR (100 MHz, MeOD-d4) δ 142.6, 139.0, 129.4, 127.8, 127.7,
124.1, 45.1, 23.2, 21.6, 20.8, 15.2. MS (ESI) m/z 162.1 [MH+].
HRMS (ESI) calculated for C11H16N+ [MH+] 161.1277, found
162.1270.
1
HPLC purity: 16.3 min, 95.9% (column 1, method C). H NMR
(300 MHz, MeOD-d4) δ 7.33 (d, J ) 7.8 Hz, 2 H), 7.26-7.11 (m,
2 H), 3.08-2.95 (m, 2 H), 2.07-2.01 (m, 1 H), 1.50-1.39 (m, 1
H), 1.17-1.07 (m, 2 H). 13C NMR (75 MHz, MeOD-d4) δ 144.5,
130.2, 129.2, 129.1, 124.8, 122.4, 43.7, 21.8, 20.2, 14.2. MS (ESI)
m/z 226.0 [MH+]. HRMS (ESI) calculated for C10H13NBr+ [MH+]
226.0231, found 226.0235.
trans-[2-(2-Trifluoromethylphenyl)cyclopropyl]methylamine Hy-
drochloride (31). Refer to the general procedure for the synthesis
of 14a described above by using 2-trifluoromethylstyrene as the
starting material. HPLC purity: 7.9 min, 99.3% (column 3, method
1
A). H NMR (300 MHz, DMSO-d6) δ 8.20 (s, 3 H), 7.67 (d, J )
trans-[2-(3-Methylphenyl)cyclopropyl]methylamine Hydrochlo-
ride (37). Refer to the general procedure for the synthesis of 14a
described above by using 3-methylstyrene as the starting material.
HPLC purity: 9.5 min, 99.2% (column 1, method E). 1H NMR (400
MHz, MeOD-d4) δ 7.13-7.05 (m, 3 H), 7.02-7.00 (m, 1 H),
3.25-3.21 (m, 1 H), 2.94-2.88 (m, 1 H), 2.40 (s, 3 H), 2.04-1.99
(m, 1 H), 1.46-1.41 (m, 1 H), 1.09-1.04 (m, 1 H), 0.97-0.93
(m, 1 H). 13C NMR (100 MHz, MeOD-d4) δ 140.2, 138.8, 130.8,
127.5, 127.1, 126.8, 45.1, 21.6, 20.0, 18.7, 13.9. MS (ESI) m/z 162.1
[MH+]. HRMS (ESI) calculated for C11H16N+ [MH+] 162.1277,
found 162.1270.
6.4 Hz, 1 H), 7.58 (m, 1 H), 7.40 (m, 1 H), 7.29 (d, J ) 5.8 Hz,
1 H), 3.00 (m, 1 H), 2.75 (m, 1 H), 2.15 (m, 1 H), 1.50 (m, 1 H),
1.09 (m, 2 H). 13C NMR (100 MHz, DMSO-d6) δ 140.0, 133.2,
128.6 (q, 2JCF ) 30.0 Hz), 128.0, 127.0, 126.1 (q, 3JCF ) 5.5 Hz),
1
125.1 (q, JCF ) 273.7 Hz), 42.7, 19.3, 19.2, 14.3. MS (ESI) m/z
216.1 [MH+]. HRMS (ESI) calculated for C11H13NF3 [MH+]
+
216.0995, found 216.0990.
trans-[2-(2-Methoxyphenyl)cyclopropyl]methylamine Hydro-
chloride (32). Refer to the general procedure for the synthesis of
14a described above by using 2-methoxystyrene as the starting
material. HPLC purity: 7.3 min, 97.7% (column 3, method A). 1H
NMR (300 MHz, MeOD-d4) δ 7.17-7.13 (m, 1 H), 6.94-6.82
(m, 3 H), 3.86 (s, 3 H), 2.79 (m, 2 H), 2.07-2.02 (m, 1 H),
trans-[2-(3-Trifluoromethylphenyl)cyclopropyl]methylamine Hy-
drochloride (38). Refer to the general procedure for the synthesis
of 14a described above by using 3-trifluorostyrene as the starting
material. HPLC purity: 8.4 min, 98.3% (column 3, method A). 1H
NMR (300 MHz, DMSO-d6) δ 7.94 (s, 3 H), 7.50-7.39 (m, 4 H),
2.96 (m, 1 H), 2.74 (m, 1 H), 2.12 (m, 1 H), 1.34 (m, 1 H),
1.15-1.05 (m, 2 H). 13C NMR (100 MHz, DMSO-d6) δ 143.2,
1.29-1.25 (m, 1 H), 1.09-1.02 (m, 1 H), 0.97-0.90 (m, 1 H). 13
C
NMR (75 MHz, MeOD-d4) δ 159.8, 130.7, 128.5, 127.3, 121.7,
111.4, 56.1, 45.8, 20.8, 18.2, 13.3. MS (ESI) m/z 178.1 [MH+].
HRMS (ESI) calculated for C11H16NO+ [MH+] 178.1226, found
178.1228.
2
1
129.6, 129.3, 129.0 (q, JCF ) 31.0 Hz), 124.2 (q, JCF ) 272.6
Hz), 122.6 (q, 3JCF ) 3.5 Hz), 122.4 (q, 3JCF ) 3.5 Hz), 42.7, 21.3,
20.4, 14.4. MS (ESI) m/z 216.1 [MH+]. HRMS (ESI) calculated
trans-[2-(2-Hydroxyphenyl)cyclopropyl]methylamine Hydro-
chloride (33). To a solution of 32 (80 mg, 0.451 mmol) in dry
CH2Cl2 (2 mL) under a nitrogen atmosphere at -78 °C was slowly
added a solution of boron tribromide (1.0 M in CH2Cl2, 1 mL).
The reaction mixture was allowed to warm to rt and stirred for
4 h. The brown solution was cooled with an ice bath, and to the
solution was slowly added water (2 mL). The organic layer was
separated, and the water layer was extracted with EtOAc (×4). The
combined organic layers were dried over Na2SO4 and concentrated
until the volume was reduced to about 1 mL. To the solution was
added 1 M HCl in Et2O (1 mL, 1 mmol) at 0 °C. After stirring at
0 °C for 15 min and at rt for 1 h, the mixture was concentrated in
vacuo. The resulting residue was purified by recrystallization from
ethanol/Et2O to afford the title compound as a white solid (50 mg,
68% yield). HPLC purity: 7.7 min, 97.7% (column 3, method B).
1H NMR (400 MHz, MeOD-d4) δ 7.03-6.99 (m, 1 H), 6.91 (d, J
) 7.5 Hz, 1 H), 6.79-6.73 (m, 2 H), 3.15-3.10 (m, 1 H),
2.91-2.86 (m, 1 H), 2.07-2.02 (m, 1 H), 1.24-1.20 (m, 1 H),
1.75-1.11 (m, 1 H), 1.00-0.95 (m, 1 H). 13C NMR (100 MHz,
MeOD-d4) δ 157.3, 128.4, 128.4, 127.8, 120.8, 115.7, 45.5, 19.5,
18.4, 12.6. MS (ESI) m/z 164.1 [MH+]. HRMS (ESI) calculated
for C10H14NO+ [MH+] 164.1070, found 164.1068.
for C11H13NF3 [MH+] 216.0995, found 216.0991.
+
trans-[2-(3-Methoxyphenyl)cyclopropyl]methylamine Hydro-
chloride (39). Refer to the general procedure for the synthesis of
14a described above by using 3-methoxystyrene as the starting
material. HPLC purity: 6.9 min, 98.5% (column 3, method A). 1H
NMR (300 MHz, MeOD-d4) δ 7.18-7.13 (m, 1 H), 6.72-6.69
(m, 3 H), 3.76 (s, 3 H), 2.99 (d, J ) 7.3 Hz, 2 H), 2.03-1.97 (m,
1 H), 1.44-1.39 (m, 1 H), 1.11-1.01 (m, 2 H). 13C NMR (75 MHz,
MeOD-d4) δ 161.4, 144.5, 130.5, 119.3, 113.1, 112.5, 55.8, 45.0,
23.4, 21.0, 15.2. MS (ESI) m/z 178.1 [MH+]. HRMS (ESI)
calculated for C11H16NO+ [MH+] 178.1226, found 178.1226.
trans-[2-(3-Hydroxyphenyl)cyclopropyl]methylamine Hydro-
chloride (40). Prepared by the same procedure as described for 33
with 39 as the starting material (45 mg, 70% yield). HPLC purity:
7.5 min, 97.2% (column 1, method E). 1H NMR (400 MHz, MeOD-
d4) δ 6.95 (t, J ) 7.7 Hz, 1 H), 6.51-6.45 (m, 3 H), 2.87 (m, 2 H),
1.83 (m, 1 H), 1.28 (m, 1 H), 0.96-0.91 (m, 2 H). 13C NMR (100
MHz, MeOD-d4) δ 158.6, 144.4, 130.5, 118.4, 114.1, 113.8, 45.1,
23.3, 20.9, 15.2. MS (ESI) m/z 164.1 [MH+]. HRMS (ESI)
calculated for C10H14NO+ [MH+] 164.1070, found 164.1073.
trans-[2-(3-Fluorophenyl)cyclopropyl]methylamine Hydrochlo-
ride (34). Refer to the general procedure for the synthesis of 14a
described above by using 3-fluorostyrene as the starting material.
trans-[2-(4-Fluorophenyl)cyclopropyl]methylamine Hydrochlo-
ride (41). Refer to the general procedure for the synthesis of 14a
described above by using 4-fluorostyrene as the starting material.
1
HPLC purity: 12.6 min, 95.9% (column 1, method C). H NMR
1
(300 MHz, MeOD-d4) δ 7.27 (m, 1 H), 6.98 (d, J ) 7.7 Hz, 1 H),
6.90 (m, 2 H), 3.01 (m, 2 H), 2.06 (m, 1 H), 1.44 (m, 1 H), 1.12
(m, 2 H). 13C NMR (75 MHz, MeOD-d4) δ 163.5 (d, 1JCF ) 243.0
HPLC purity: 12.7 min, 95.4% (column 1, method C). H NMR
(300 MHz, MeOD-d4) δ 7.16 (m, 2 H), 7.00 (m, 2 H), 3.01 (d, J
) 7.4 Hz, 2 H), 2.04 (m, 1 H), 1.39 (m, 1 H), 1.08 (m, 2 H). 13C
3
3
1
Hz), 144.8 (d, JCF ) 6.0 Hz), 130.1 (d, JCF ) 8.8 Hz), 122.0,
NMR (75 MHz, MeOD-d4) δ 161.8 (d, JCF ) 243.0 Hz), 137.6,
2
3
2
112.7 (d, JCF ) 22.0 Hz), 43.7, 22.0, 20.3, 14.4. MS (ESI) m/z
127.8 (d, JCF ) 7.9 Hz), 115.0 (d, JCF ) 21.7 Hz), 43.8, 21.5,
19.7, 13.9. MS (ESI) m/z 166.1 [MH+]. HRMS (ESI) calculated
for C10H13NF+ [MH+] 166.1032, found 166.1034.
166.0 [MH+]. HRMS (ESI) calculated for C10H13NF+ [MH+]
166.1032, found 166.1032.

1896 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 7
Cho et al.
trans-[2-(4-Chlorophenyl)cyclopropyl]methylamine Hydrochlo-
ride (42). Refer to the general procedure for the synthesis of 14a
described above by using 4-chlorostyrene as the starting material.
2JCF ) 17.3 Hz), 44.7, 19.8, 16.7, 14.3. MS (ESI) m/z 184.1 [MH+].
HRMS (ESI) calculated for C10H12NF2 [MH+] 184.0932, found
+
184.0931.
1
HPLC purity: 7.4 min, 98.2% (column 3, method A). H NMR
trans-[2-(2,4-Difluorophenyl)cyclopropyl]methylamine Hydro-
chloride (49). Refer to the general procedure for the synthesis of
substituted styrene and 14a described above by using 2,4-difluo-
robenzaldehyde as the starting material. HPLC purity: 8.5 min,
(300 MHz, MeOD-d4) δ 7.25 (d, J ) 8.4 Hz, 2 H), 7.12 (d, J )
8.5 Hz, 2 H), 3.00 (d, J ) 7.2 Hz, 2 H), 2.05-1.99 (m, 1 H),
1.44-1.38 (m, 1 H), 1.09 (t, J ) 6.9 Hz, 2 H). 13C NMR (75 MHz,
MeOD-d4) δ 141.7, 132.8, 129.6, 128.8, 44.9, 22.8, 21.2, 15.3. MS
(ESI) m/z 182.1 [MH+]. HRMS (ESI) calculated for C10H13NCl+
[MH+] 182.0731, found 182.0736.
1
95.5% (column 1, method C). H NMR (400 MHz, MeOD-d4) δ
7.11 (dd, J ) 15.4, 8.4 Hz, 1 H), 6.93-6.86 (m, 2 H), 3.02 (m, 2
H), 2.11-2.06 (m, 1 H), 1.43-1.40 (m, 1 H), 1.14-1.05 (m, 2 H).
13C NMR (100 MHz, MeOD-d4) δ 163.1 (d, 1JCF ) 258 Hz), 163.0
trans-[2-(4-Bromophenyl)cyclopropyl]methylamine Hydrochlo-
ride (43). Refer to the general procedure for the synthesis of 14a
described above by using 4-bromostyrene as the starting material.
1
3
3
(d, JCF ) 258 Hz), 129.7 (dd, JCF ) 9.5, JCF ) 5.4 Hz), 112.3
2
3
2
2
(dd, JCF ) 21.4, JCF ) 3.7 Hz), 104.5 (dd, JCF ) 26.1, JCF
)
26.1 Hz), 44.8, 19.3, 16.5, 13.5. MS (ESI) m/z 184.1 [MH+]. HRMS
(ESI) calculated for C10H12NF2+ [MH+] 184.0932, found 184.0930.
trans-[2-(2,6-Difluorophenyl)cyclopropyl]methylamine Hydro-
chloride (50). Refer to the general procedure for the synthesis of
substituted styrene 14a described above by using 2,6-difluoroben-
zaldehyde as the starting material. HPLC purity: 5.4 min, 96.5%
(column 3, method A). 1H NMR (300 MHz, MeOD-d4) δ 7.31-7.21
(m, 1 H), 6.98-6.89 (m, 2 H), 3.06-3.03 (m, 2 H), 1.93 (m, 1 H),
1.64 (m, 1 H), 1.26 (m, 1 H), 1.13 (m, 1 H). 13C NMR (75 MHz,
1
HPLC purity: 14.3 min, 97.4% (column 1, method C). H NMR
(400 MHz, MeOD-d4) δ 7.41 (d, J ) 8.5 Hz, 2 H), 7.08 (d, J )
8.4 Hz, 2 H), 3.05-2.96 (m, 2 H), 2.04-1.99 (m, 1 H), 1.44-1.39
(m, 1 H), 1.14-1.07 (m, 2 H). 13C NMR (100 MHz, MeOD-d4) δ
140.6, 131.0, 127.6, 119.1, 21.3, 19.6, 13.7. MS (ESI) m/z 225.9
[MH+]. HRMS (ESI) calculated for C10H13NBr+ [MH+] 226.0231,
found 226.0233.
trans-[2-(4-Methylphenyl)cyclopropyl]methylamine Hydrochlo-
ride (44). Refer to the general procedure for the synthesis of 14a
described above by using 4-methylstyrene as the starting material.
1
3
MeOD-d4) δ 162.5 (d, JCF ) 246.5 Hz), 128.5 (d, JCF ) 10.7
2
1
Hz), 116.5, 111.4 (d, JCF ) 26.1 Hz), 43.9, 17.0, 11.7, 11.6. MS
HPLC purity: 6.5 min, 98.8% (column 1, method D). H NMR
(ESI) m/z 184.1 [MH+]. HRMS (ESI) calculated for C10H12NF2
+
(400 MHz, MeOD-d4) δ 6.92 (d, J ) 7.9 Hz, 2 H), 6.86 (d, J )
7.9 Hz, 2 H), 2.78 (d, J ) 7.4 Hz, 2 H), 2.13 (s, 3 H), 1.81-1.76
(m, 1 H), 1.22-1.18 (m, 1 H), 0.90-0.82 (m, 2 H). 13C NMR (100
MHz, MeOD-d4) δ 139.9, 136.6, 130.1, 127.0, 45.4, 23.0, 21.7,
21.1, 15.0. MS (ESI) m/z 162.1 [MH+]. HRMS (ESI) calculated
for C11H16N+ [MH+] 161.1277, found 162.1272.
[MH+] 184.09323; found 184.09316.
trans-[2-(3,4-Difluorophenyl)cyclopropyl]methylamine Hydro-
chloride (51). Refer to the general procedure for the synthesis of
substituted styrene and 14a described above by using 3,4-difluo-
robenzaldehyde as the starting material. HPLC purity: 8.6 min,
1
96.4% (column 1, method C). H NMR (400 MHz, MeOD-d4) δ
trans-[2-(4-Trifluoromethylphenyl)cyclopropyl]methylamine Hy-
drochloride (45). Refer to the general procedure for the synthesis
of 14a described above by using 4-trifluorostyrene as the starting
material. HPLC purity: 8.4 min, 99.3% (column 3, method A). 1H
NMR (300 MHz, DMSO-d6) δ 8.17 (s, 3 H), 7.61 (d, J ) 8.0 Hz,
2 H), 7.33 (d, J ) 8.0 Hz, 2 H), 2.96 (m, 1 H), 2.75 (m, 1 H), 2.14
(m, 1 H), 1.40 (m, 1 H), 1.12 (t, J ) 7.0 Hz, 2 H). 13C NMR (100
MHz, MeOD-d4) δ 147.6, 129.0 (q, 2JCF ) 32.3 Hz), 127.7, 126.2
7.17-7.05 (m, 2 H), 6.98-5.97 (m, 1 H), 2.98 (m, 2 H), 2.10-2.06
(m, 1 H), 1.44 (m, 1 H), 1.12-1.09 (m, 2 H). 13C NMR (100 MHz,
MeOD-d4) δ 151.6 (dd, 1JCF ) 245.7, 2JCF ) 12.8 Hz), 150.0 (dd,
2
3
4
1JCF ) 244.1, JCF ) 12.7 Hz), 140.6 (dd, JCF ) 5.9, JCF ) 3.6
3
4
2
Hz), 123.7 (dd, JCF ) 6.1, JCF ) 3.3 Hz), 118.2 (d, JCF ) 17.3
2
Hz), 116.1 (d, JCF ) 17.9 Hz), 44.9, 22.6, 21.3, 15.3. MS (ESI)
m/z 184.1 [MH+]. HRMS (ESI) calculated for C10H12NF2+ [MH+]
184.0932, found 184.0930.
3
1
(q, JCF ) 3.3 Hz), 125.7 (q, JCF ) 270.8 Hz), 45.1, 23.2, 21.7,
16.1. MS (ESI) m/z 216.1 [MH+]. HRMS (ESI) calculated for
trans-[2-(4-Chloro-2-fluorophenyl)cyclopropyl]methylamine Hy-
drochloride (52). Refer to the general procedure for the synthesis
of substituted styrene and 14a described above by using 4-chloro-
2-fluorobenzaldehyde as the starting material. HPLC purity: 7.4
C11H13NF3 [MH+] 216.0995, found 216.0989.
+
trans-[2-(4-Methoxyphenyl)cyclopropyl]methylamine Hydro-
chloride (46). Refer to the general procedure for the synthesis of
14a described above by using 4-methoxystyrene as the starting
material. HPLC purity: 5.7 min, 99.1% (column 3, method A). 1H
NMR (300 MHz, MeOD-d4) δ 7.05 (d, J ) 8.3 Hz, 2 H), 6.81 (d,
J ) 8.3 Hz, 2 H), 3.74 (s, 3 H), 2.98 (d, J ) 6.8 Hz, 2 H), 1.95 (m,
1 H), 1.31 (m, 1 H), 1.01 (m, 2 H). 13C NMR (75 MHz, MeOD-d4)
δ 159.7, 134.6, 128.3, 115.0, 55.8, 45.1, 22.7, 20.5, 14.7. MS (ESI)
m/z 178.1 [MH+]. HRMS (ESI) calculated for C11H16NO+ [MH+]
178.1226, found 178.1226.
trans-[2-(4-Hydroxyphenyl)cyclopropyl]methylamine Hydro-
chloride (47). Prepared by the same procedure as described for 33
with 46 as the starting material (38 mg, 72% yield). HPLC purity:
6.1 min, 99.2% (column 3, method B). 1H NMR (300 MHz, MeOD-
d4) δ 6.96 (d, J ) 8.4 Hz, 2 H), 6.68 (d, J ) 8.4 Hz, 2 H), 2.96 (d,
J ) 7.3 Hz, 2 H), 1.95-1.89 (m, 1 H), 1.29 (m, 1 H), 1.03-0.92
(m, 2 H). 13C NMR (75 MHz, MeOD-d4) δ 157.0, 133.3, 128.4,
116.3, 45.2, 22.7, 20.4, 14.5. MS (ESI) m/z 164.1 [MH+]. HRMS
(ESI) calculated for C10H14NO+ [MH+] 164.1070, found 164.1069.
1
min, 94.4% (column 3, method A). H NMR (400 MHz, MeOD-
d4) δ 7.13-7.07 (m, 3 H), 3.13-3.00 (m, 2 H), 2.16-2.12 (m, 1
H), 1.57-1.52 (m, 1 H), 1.17-1.11 (m, 2 H). 13C NMR (100 MHz,
1
3
MeOD-d4) δ 162.8 (d, JCF ) 247.9 Hz), 133.4 (d, JCF ) 10.4
Hz), 129.6 (d, 3JCF ) 4.9 Hz), 128.6 (d, 2JCF ) 14.4 Hz), 125.7 (d,
4JCF ) 3.6 Hz), 116.7 (d, JCF ) 25.9 Hz), 44.7, 19.5, 16.6, 14.1.
2
MS (ESI) m/z 200.1 [MH+]. HRMS (ESI) calculated for
C10H12NFCl+ [MH+] 200.0637, found 200.0639.
trans-[2-(2-Chloro-4-fluorophenyl)cyclopropyl]methylamine
Hydrochloride (53). Refer to the general procedure for the
synthesis of substituted styrene and 14a described above by using
2-chloro-4-fluorobenzaldehyde as the starting material. HPLC
purity: 7.2 min, 98.2% (column 3, method A). 1H NMR (400 MHz,
MeOD-d4) δ 7.20-7.17 (m, 2 H), 7.03-6.99 (m, 1 H), 3.27-3.22
(m, 1 H), 2.96-2.91 (m, 1 H), 2.19-2.14 (m, 1 H), 1.44-1.39
(m, 1 H), 1.17-1.07 (m, 2 H). 13C NMR (100 MHz, MeOD-d4) δ
162.6 (d, 1JCF ) 247.0 Hz), 137.0 (d, 3JCF ) 10.3 Hz), 136.0, 130.3
3
2
2
(d, JCF ) 8.8 Hz), 117.4 (d, JCF ) 25.2 Hz), 115.2 (d, JCF
)
21.2 Hz), 44.8, 21.1, 19.5, 13.8. MS (ESI) m/z 200.1 [MH+]. HRMS
(ESI) calculated for C10H12NFCl+ [MH+] 200.0637, found 200.0633.
trans-[2-(2,3-Dichlorophenyl)cyclopropyl]methylamine Hydro-
chloride (54). Refer to the general procedure for the synthesis of
substituted styrene and 14a described above by using 2,3-dichlo-
robenzaldehyde as the starting material. HPLC purity: 8.7 min,
trans-[2-(2,3-Difluorophenyl)cyclopropyl]methylamine Hydro-
chloride (48). Refer to the general procedure for the synthesis of
substituted styrene 14a described above by using 2,3-difluoroben-
zaldehyde as the starting material. HPLC purity: 8.7 min, 95.1%
(column 1, method C). 1H NMR (400 MHz, MeOD-d4) δ 7.08-7.05
(m, 2 H), 6.87-6.86 (m, 1 H), 3.08-3.02 (m, 2 H), 2.21-2.16
(m, 1 H), 1.58-1.51 (m, 1 H), 1.16 (t, J ) 6.9 Hz, 2 H). 13C NMR
(100 MHz, MeOD-d4) δ 151.9 (dd, 1JCF ) 246.0, 2JCF ) 13.0 Hz),
1
98.7% (column 3, method A). H NMR (400 MHz, MeOD-d4) δ
7.37 (d, J ) 6.9 Hz, 1 H), 7.22 (dd, J ) 7.9, 7.9 Hz, 1 H), 7.10 (d,
J ) 7.8 Hz, 1 H), 3.32-3.25 (m, 1 H), 2.98-2.93 (m, 1 H),
1
2
2
150.9 (dd, JCF ) 245.4, JCF ) 13.0 Hz), 132.3 (d, JCF ) 10.9
2
3
Hz), 125.6 (dd, JCF ) 7.2, JCF ) 4.8 Hz), 123.2 (m), 116.0 (d,
2.29-2.24 (m, 1 H), 1.49-1.45 (m, 1 H), 1.21-1.10 (m, 2 H). 13
C

SelectiVe 5-HT 2C Receptor Agonists from Tranylcypromine
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 7 1897
NMR (100 MHz, MeOD-d4) δ 142.4, 134.5, 133.9, 129.7, 128.9,
127.2, 44.8, 22.5, 19.8, 14.2. MS (ESI) m/z 216.0 [MH+]. HRMS
(ESI) calculated for C10H12NCl2+ [MH+] 216.0341, found 216.0338.
trans-[2-(6-Chloro-2-fluoro-3-methylphenyl)cyclopropyl]methyl-
amine Hydrochloride (61). Refer to the general procedure for the
synthesis of 14a described above by using 1-chloro-3-fluoro-4-
methyl-2-vinylbenzene (1 g, 5.8 mmol) as the starting material.
trans-[2-(2,4-Dichlorophenyl)cyclopropyl]methylamine Hydro-
chloride (55). Refer to the general procedure for the synthesis of
substituted styrene and 14a described above by using 2,4-dichlo-
robenzaldehyde as the starting material. HPLC purity: 8.3 min,
1
HPLC purity: 13.03 min, 95.6% (column 1, method D). H NMR
(400 MHz, MeOD-d4) δ 7.16-7.04 (m, 2 H), 3.22-3.11 (m, 1 H),
3.0-2.91 (m, 1 H), 2.22 (s, 3 H), 1.88-181 (m, 1 H), 1.56-1.45
(m, 1 H), 1.21-1.11 (m, 2 H). 13C NMR (100 MHz, MeOD-d4) δ
1
93.7% (column 3, method A). H NMR (400 MHz, MeOD-d4) δ
1
2
161.6 (d, JCF ) 245.4 Hz), 133.5, 129.8, 125.8 (d, JCF ) 16.4
Hz), 125.2, 123.8, 43.5, 17.5, 15.2, 12.9, 12.5. MS (ESI) m/z
214.1[MH+]. HRMS (ESI) calculated for C11H14NFCl+ [MH+]
214.0793, found 214.0786.
7.43 (d, J ) 1.9 Hz, 1 H), 7.26 (dd, J ) 8.3, 1.9 Hz, 1 H), 7.12 (d,
J ) 8.4 Hz, 1 H), 3.25-3.20 (m, 1 H), 2.96-2.91 (m, 1 H),
2.22-2.17 (m, 1 H), 1.45-1.40 (m, 1 H), 1.18-1.09 (m, 2 H). 13
C
NMR (100 MHz, MeOD-d4) δ 138.9, 137.1, 133.8, 130.0, 129.9,
128.5, 44.7, 21.1, 19.7, 14.0. MS (ESI) m/z 216.0 [MH+]. HRMS
(ESI) calculated for C10H12NCl2+ [MH+] 216.0341, found 216.0338.
trans-[2-(2-Bromophenyl)cyclopropylmethyl]carbamic Acid
tert-Butyl Ester (62). To a solution of 29 (1.63 g, 6.21 mmol) and
Boc2O (1.35 g, 8.07 mmol) in Et2O (75 mL) was added 10% aq
NaOH (14.9 mL, 37.2 mmol) at 0 °C. The mixture was stirred at
0 °C for 30 min and then at rt for 7 h. To the resulting mixture
were added crushed ice and Et2O. The organic layer was further
washed with water (×1), dried over Na2SO4, and concentrated in
vacuo. The residue was purified by silica gel chromatography
(hexane/EtOAc 10:1) to afford the title compounds as colorless oils
trans-[2-(4-Fluoro-3-methylphenyl)cyclopropyl]methylamine Hy-
drochloride (56). Refer to the general procedure for the synthesis
of 14a described above by using 1-fluoro-2-methyl-4-vinylbenzene
as the starting material. HPLC purity: 11.69 min, 99.6% (column
1
1, method E). H NMR (400 MHz, MeOD-d4) δ 7.08-6.84 (m, 3
H), 3.07-2.91 (m, 1 H), 2.22 (s, 3 H), 2.04-1.92 (m, 1 H),
1.42-1.28 (m, 1 H), 1.12-0.96 (m, 2 H).13C NMR (100 MHz,
MeOD-d4) δ δ161.0 (d, 1JCF ) 241.4 Hz), 136.7, 128.8, 124.6 (d,
3JCF ) 7.9 Hz), 124.2, 114.2 (d, 2JCF ) 25.5 Hz), 43.4, 21.1, 19.2,
13.3, 13.0. MS (ESI) m/z 163.0 [MH+]. HRMS (ESI) calculated
for C11H15NF+ [MH+] 180.1183, found 180.1187.
1
(1.71 g, 84% yield). H NMR (300 MHz, CDCl3) δ 7.44 (d, J )
8.5 Hz, 2 H), 7.40 (d, J ) 8.5 Hz, 2 H), 7.30-7.19 (m, 3 H), 7.00
(d, J ) 7.2 H, 1 Hz), 4.45 (br s, 1 H), 3.05-2.95 (m, 2 H), 1.76
(m, 1 H), 1.46 (s, 9 H), 1.26 (m, 1 H), 0.94 (m, 1 H), 0.77 (m, 1
H). 13C NMR (75 MHz, CDCl3) δ 156.2, 141.6, 140.5, 139.6, 133.4,
131.2, 130.0, 128.8, 128.2, 126.1, 125.3, 79.6, 44.9, 28.8, 23.3,
20.6, 14.3.
trans-[2-(2-Chloro-6-methylphenyl)cyclopropyl]methylamine Hy-
drochloride (57). Refer to the general procedure for the synthesis
of 14a described above by using 1-chloro-3-methyl-2-vinylbenzene
as the starting material. HPLC purity: 13.76 min, 96.7% (column
trans-[2-(3-Bromophenyl)cyclopropylmethyl]carbamic Acid
tert-Butyl Ester (63). Prepared by the same procedure as described
for 62 (1.59 g, 99% yield). 1H NMR (300 MHz, CDCl3) δ 7.29 (d,
J ) 6.8 Hz, 1 H), 7.20 (s, 1 H), 7.12 (t, J ) 7.8 Hz, 1 H), 6.99 (d,
J ) 7.6 Hz, 1 H), 4.70 (br s, 1 H), 3.22-3.11 (m, 2 H), 1.80-1.76
(m, 1 H), 1.47 (s, 9 H), 1.33-1.27 (m, 1 H), 0.94 (t, J ) 6.9 Hz,
2 H). 13C NMR (75 MHz, CDCl3) δ 156.5, 145.5, 130.2, 129.3,
129.1, 124.9, 122.9, 28.8, 23.8, 22.0, 14.8.
1
1, method E). H NMR (400 MHz, MeOD-d4) δ 7.24-7.18 (m, 1
H), 7.14-7.09 (m, 2 H), 3.56-3.45 (m, 1H), 2.81-2.70 (m, 1H),
2.44 (s, 3H), 1.86-1.77 (m, 1H), 1.48-1.35 (m, 1 H), 1.27-1.17
(m, 1 H), 1.02-0.92 (m, 1H). 13C NMR (100 MHz, MeOD-d4) δ
140.8, 135.7, 135.6, 128.7, 127.5, 127.0, 43.6, 19.3, 18.9, 18.8,
14.2. MS (ESI) m/z 179.1 [MH+]. HRMS (ESI) calculated for
C11H15NCl+ [MH+] 196.0888, found 196.0892.
trans-[2-(4-Bromophenyl)cyclopropylmethyl]carbamic Acid
tert-Butyl Ester (64). Prepared by the same procedure as described
trans-[2-(2-Bromo-4-methylphenyl)cyclopropyl]methylamine Hy-
drochloride (58). Refer to the general procedure for the synthesis
of 14a described above by using 2-bromo-4-methyl-1-vinylbenzene
as the starting material. HPLC purity: 16.41 min, 96.8% (column
1
for 62 (356 mg, 82% yield). H NMR (300 MHz, CDCl3) δ 7.38
(d, J ) 8.3 Hz, 2 H), 6.93 (d, J ) 8.3 Hz, 2 H), 4.69 (br s, 1 H),
3.18-3.11 (m, 2 H), 1.79-1.76 (m, 2 H), 1.47 (s, 9 H), 1.28 (m,
2 H), 0.94-0.90 (m, 2 H). 13C NMR (75 MHz, CDCl3) δ 156.0,
142.0, 131.7, 128.0, 127.0, 79.9, 45.0, 28.8, 23.7, 21.9, 14.8.
trans-[2-(4′-Fluorobiphenyl-2-yl)cyclopropyl]methylamine Hy-
drochloride (66). Step A: Compound 62 (30 mg, 0.092 mmol),
Pd(PPh3)4 (10.4 mg, 0.009 mmol), and 4-fluorophenylboronic acid
(32.2 mg, 0.23 mmol) were dissolved in dimethoxyethane (DME)
(4 mL), and the mixture was degassed for 1 min and stirred for 10
min at rt. To the mixture was added 2 M aq K2CO3 (0.115 mL,
0.23 mmol). The mixture was degassed again for 1 min and stirred
at 85 °C overnight. The resulting mixture was cooled to ambient
temperature and poured into a mixture of 0.1 N HCl/EtOAc (15
mL/15 mL). After partition, the organic layer was washed with
water, filtered, and concentrated. The residue was purified by
preparative TLC (hexane/EtOAc 4:1) to afford the title compound
as a colorless oil (31 mg, 99% yield). 1H NMR (300 MHz, CDCl3)
δ 7.38 (dd, J ) 8.6, 5.5 Hz, 2 H), 7.32-7.12 (m, 5 H), 7.01 (d, J
) 7.7 Hz, 1 H), 4.38 (br s, 1 H), 3.07 (m, 1 H), 2.92 (m, 1 H),
1.77 (m, 1 H), 1.46 (s, 9 H), 1.20 (m, 1 H), 0.95 (m, 1 H), 0.76 (m,
1
1, method E). H NMR (400 MHz, MeOD-d4) δ 7.41 (s, 1 H),
7.09 (d, J ) 7.9 Hz, 1 H), 7.0 (d, J ) 7.9 Hz, 1 H), 3.37-3.24 (m,
1 H), 2.92-2.81 (m, 1 H), 2.29 (s, 3 H), 2.17-2.06 (m, 1 H),
1.40-1.26 (m, 1 H), 1.13-1.02 (m, 2H). 13C NMR (100 MHz,
MeOD-d4) δ 136.5, 135.1, 130.9, 126.5, 125.3, 123.6, 41.9, 20.9,
17.6, 16.6, 10.8. MS (ESI) m/z 224.0 [MH+]. HRMS (ESI)
calculated for C11H15NBr+ [MH+] 240.0382, found 240.0388.
trans-[2-(2,3-Dimethylphenyl)cyclopropyl]methylamine Hydro-
chloride (59). Refer to the general procedure for the synthesis of
14a described above by using 1,2-dimethyl-3-vinylbenzene as the
starting material. HPLC purity: 12.92 min, 98.4% (column 1,
method E). 1H NMR (400 MHz, MeOD-d4) δ 7.03-6.80 (m, 3 H),
3.27-3.15 (m, 1H), 2.97-2.83 (m, 1 H), 2.33 (s, 3H), 2.27 (s, 3
H), 2.08-1.94 (m, 1H), 1.46-1.32 (m, 1 H), 1.11-1.0 (m, 1H),
0.95-0.88 (m, 1 H). 13C NMR (100 MHz, MeOD-d4) δ 138.4,
136.0, 135.7, 127.7, 125.0, 123.9, 43.6, 20.8, 19.1, 17.1, 14.0, 12.2.
MS (ESI) m/z 159.1 [MH+]. HRMS (ESI) calculated for C12H18N+
[MH+] 176.1434, found 176.1436.
1
1 H). 13C NMR (75 MHz, CDCl3) δ 162.4 (d, JCF ) 246 Hz),
156.2, 142.0, 139.7, 138.0 (d, 4JCF ) 3.3 Hz), 131.4 (d, 3JCF ) 7.9
trans-[2-(3,4-Dimethylphenyl)cyclopropyl]methylamine Hydro-
chloride (60). Refer to the general procedure for the synthesis of
14a described above by using 1,2-dimethyl-4-vinylbenzene as the
starting material. HPLC purity: 13.03 min, 99.2% (column 1,
2
Hz), 130.2, 128.1, 126.1, 125.6, 115.6 (d, JCF ) 21.3 Hz), 79.6,
45.0, 28.8, 23.1, 20.8, 14.0.
Step B: To a solution of trans-[2-(4′-fluorobiphenyl-4-yl)cyclo-
propylmethyl]carbamic acid tert-butyl ester (30 mg) in CH2Cl2 (1
mL) was added TFA (0.1 mL) at 0 °C. After standing at 0 °C for
30 min and at rt for 1 h, the mixture was concentrated. The residue
was dissolved in CH2Cl2 (1 mL), and 1 M HCl in Et2O (0.3 mL)
was added to the solution. The mixture was let stand at 0 °C for
30 min, and concentrated. The resulting white solid was purified
by recrystallization from ethanol/Et2O to afford the title compound
1
method E). H NMR (400 MHz, MeOD-d4) δ 7.0 (d, J ) 7.8 Hz,
1 H), 6.89 (s, 1 H), 6.82 (d, J ) 7.8 Hz, 1 H), 3.02 (m, 2 H), 2.25
(s, 3 H), 2.21 (s, 3 H), 1.97-1.89 (m, 1 H), 1.40-1.29 (m, 1H),
1.08-0.95 (m, 2 H). 13C NMR (100 MHz, MeOD-d4) δ 138.4,
136.0, 133.7, 129.11, 126.8, 122.8, 43.5, 21.4, 19.1, 18.3, 17.9,
13.2. MS (ESI) m/z 159.1[MH+]. HRMS (ESI) calculated for
C12H18N+ [MH+] 176.1434, found 176.1433.

1898 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 7
Cho et al.
as a white solid (16 mg, 66% yield). HPLC purity: 7.8 min, 97.7%
(column 3, method A). 1H NMR (400 MHz, MeOD-d4) δ 7.43-7.39
(m, 2 H), 7.33-7.24 (m, 2 H), 7.22-7.13 (m, 4 H), 2.96 (m, 1 H),
2.54 (m, 1 H), 1.96 (m, 1 H), 1.31 (m, 1 H), 1.00 (m, 1 H), 0.93
(m, 1 H). 13C NMR (100 MHz, MeOD-d4) δ 163.6 (d, 1JCF ) 245
21.2, 15.3. MS (ESI) m/z 249.2 [MH+]. HRMS (ESI) calculated
for C17H17N2 [MH+] 249.13863, found 249.13861.
+
trans-C-[2-(3-Benzofuran-2-ylphenyl)cyclopropyl]methylamine Hy-
drochloride (72). Prepared by the same procedure as described for
68 with 2-benzofuranboronic acid (37.3 mg, 0.23 mmol) as the
starting material (21 mg, 101% and 85% yields). HPLC purity:
12.5 min, 98.4% (column 3, method A). 1H NMR (400 MHz,
MeOD-d4) δ 7.71 (d, J ) 6.5 Hz, 2 H), 7.61 (d, J ) 7.5 Hz, 1 H),
7.52 (d, J ) 7.8 Hz, 1 H), 7.37 (t, J ) 8.0 Hz, 1 H), 7.29 (d, J )
7.3 Hz, 1 H), 7.23 (t, J ) 7.6 Hz, 1 H), 7.19 (br s, 1 H), 7.15 (d,
J ) 7.8 Hz, 1 H), 3.05 (m, 2 H), 2.13 (m, 1 H), 1.51 (m, 1 H),
1.21 (m, 1 H), 1.14 (m, 1 H). 13C NMR (100 MHz, MeOD-d4) δ
157.2, 156.4, 143.6, 132.0, 130.7, 130.2, 127.4, 125.7, 124.3, 123.8,
123.7, 122.2, 112.0, 102.7, 79.3, 45.0, 23.4, 21.1, 15.2. MS (ESI)
m/z 264.2 [MH+]. HRMS (ESI) calculated for C18H18NO+ [MH+]
264.13829, found 264.13811.
trans-[2-(4′-Fluorobiphenyl-4-yl)cyclopropyl]methylamine Hy-
drochloride (73). Prepared by the same procedure as described for
66 with 64 (34 mg, 0.104 mmol) and 4-fluorophenylboronic acid
(36.5 mg, 0.261 mmol) as the starting materials (14 mg, 62% and
86% yields). HPLC purity: 18.0 min, 96.4% (column 1, method
C). 1H NMR (400 MHz, MeOD-d4) δ 7.70 (m, 2 H), 7.51 (d, J )
8.1 Hz, 2 H), 7.22 (d, J ) 8.1 Hz, 2 H), 7.16 (m, 2 H), 3.03 (d, J
) 7.4 Hz, 2 H), 2.06 (m, 1 H), 1.49 (m, 1 H), 1.13 (m, 2 H) (ppm).
13C NMR δ 157.0, 140.9, 138.2, 137.5, 128.6, 128.5, 126.9, 126.5,
115.6, 115.3, 43.9, 21.9, 20.0, 14.1. MS (ESI) m/z 242.1 [MH+].
HRMS (ESI) calculated for C16H17NF+ [MH+] 242.1345, found
242.1344.
4
3
Hz), 143.3, 139.6, 139.3 (d, JCF ) 3.4 Hz), 132.4 (d, JCF ) 8.0
2
Hz), 130.9, 129.0, 127.5, 127.2, 116.1 (d, JCF ) 21.5 Hz), 44.8,
22.3, 20.3, 15.2. MS (ESI) m/z 242.2 [MH+]. HRMS (ESI)
calculated for C16H17NF+ [MH+] 242.13395, found 242.13373.
trans-C-[2-(2-Benzofuran-2-ylphenyl)cyclopropyl]methy-
lamine Hydrochloride (67). Prepared by the same procedure as
described for 66 with 2-benzofuranboronic acid (37.3 mg, 0.23
mmol) as the starting material (22 mg, 111% and 76% yields).
1
HPLC purity: 10.5 min, 98.9% (column 3, method A). H NMR
(400 MHz, MeOD-d4) δ 7.77 (d, J ) 7.2 Hz, 1 H), 7.66 (d, J )
7.5 H, 1 Hz), 7.55 (d, J ) 8.0 Hz, 1 H), 7.39-7.25 (m, 5 H), 7.14
(s, 1 H), 3.21 (m, 1 H), 2.84 (m, 1 H), 2.42 (m, 1 H), 1.50 (m, 1
H), 1.15 (m, 1 H), 1.05 (m, 1 H). 13C NMR (100 MHz, MeOD-d4)
δ 157.0, 156.2, 139.9, 132.5, 130.6, 130.2, 129.8, 128.7, 127.9,
125.7, 124.2, 122.3, 112.0, 106.8, 45.1, 23.1, 19.8, 14.8. MS (ESI)
m/z 264.1 [MH+]. HRMS (ESI) calculated for C18H18NO+ [MH+]
264.13829, found 264.13814.
trans-[2-(4′-Fluorobiphenyl-3-yl)cyclopropyl]methylamine Hy-
drochloride (68). Prepared by the same procedure as described for
66 with 63 (30 mg, 0.092 mmol) and 4-fluorophenylboronic acid
(32.2 mg, 0.23 mmol) as the starting materials (18 mg, 115% and
63% yields). HPLC purity: 18.2 min, 97.3% (column 3, method
A). 1H NMR (400 MHz, MeOD-d4) δ 7.63-7.60 (m, 1 H),
7.40-7.33 (m, 3 H), 7.17 (t, J ) 8.8 Hz, 1 H), 7.11 (d, J ) 7.5
Hz, 1 H), 3.09-3.00 (m, 2 H), 2.14-2.09 (m, 1 H), 1.52-1.47
(m, 1 H), 1.21-1.16 (m, 1 H), 1.14-1.09 (m, 1 H). 13C NMR (100
trans-[2-(4-Furan-2-ylphenyl)cyclopropyl]methylamine Hydro-
chloride (74). Prepared by the same procedure as described for 66
with 64 (30 mg, 0.092 mmol) and 2-furanboronic acid (25.7 mg,
0.23 mmol) as the starting materials (18 mg, 98% and 82% yields).
1
MHz, MeOD-d4) δ 164.0 (d, JCF ) 245 Hz), 143.5, 141.7, 138.8
4
3
1
(d, JCF ) 3.2 Hz), 130.2, 130.0 (d, JCF ) 8.1 Hz), 126.0, 125.9,
125.8, 116.6 (d, 2JCF ) 21.7 Hz), 45.0, 23.4, 21.1, 15.2. MS (ESI)
m/z 242.1 [MH+]. HRMS (ESI) calculated for C16H17NF+ [MH+]
242.13395, found 242.13373.
HPLC purity: 13.6 min, 96.5% (column 3, method A). H NMR
(400 MHz, MeOD-d4) δ 7.60 (d, J ) 8.2 Hz, 2 H), 7.53 (s, 1 H),
7.17 (d, J ) 8.1 Hz, 2 H), 6.70 (m, 1 H), 6.50 (s, 1 H), 3.02 (d, J
) 7.4 Hz, 2 H), 2.07-2.01 (m, 1 H), 1.44 (m, 1 H), 1.18-1.08
(m, 2 H). 13C NMR δ 154.2, 142.1, 140.9, 129.3, 126.3, 123.8,
111.7, 104.6, 43.8, 22.0, 20.0, 14.1. MS (ESI) m/z 214.1 [MH+].
HRMS (ESI) calculated for C14H16NO+ [MH+] 214.1232, found
214.1228.
trans-[2-(2-Aminophenyl)cyclopropylmethyl]carbamic Acid
tert-Butyl Ester (75). Step A: To a mixture of Pd(OAc)2 (3.4 mg,
0.015 mmol), BINAP (19.1 mg, 0.031 mmol), and 62 (50 mg, 0.153
mmol) in toluene (3 mL) were added benzophenone imine (0.051
mL, 0.306 mmol) and Cs2CO3 (125 mg, 0.383 mmol) under
nitrogen. The resulting mixture was stirred at 100 °C overnight,
diluted with EtOAc, filtered, and concentrated. The residue was
purified by preparative TLC (hexane/EtOAc 3:1) to afford the
corresponding diphenyl ketimine compound as a colorless oil (51.9
mg, a mixture of starting material and the product). 1H NMR (300
MHz, CDCl3) δ 7.50 (d, J ) 6.9 Hz, 2 H), 7.46 (m, 3 H), 7.28 (m,
3 H), 7.16 (m, 2 H), 6.86 (m, 2 H), 6.79 (m, 1 H), 6.39 (m, 1 H),
4.88 (br s, 1 H), 3.34-3.23 (m, 2 H), 1.87 (m, 1 H), 1.45 (s, 9 H),
1.28 (m, 1 H), 0.93 (m, 1 H), 0.85 (m, 1 H). 13C NMR (75 MHz,
CDCl3) δ 168.3, 156.2, 150.9, 139.9, 136.7, 131.1, 129.8, 129.5,
129.1, 128.7, 128.3, 127.8, 126.1, 123.8, 119.8, 79.4, 45.4, 28.9,
22.9, 18.8, 12.9.
Step B: To a solution of the ketimine adduct (35 mg, 0.188
mmol) in MeOH (0.8 mL) at rt were added NaOAc (16.2 mg, 0.197
mmol) and NH2OH ·HCl (10.3 mg, 0.148 mmol). The mixture was
stirred at rt for 2 h, diluted with CH2Cl2, and purified by preparative
TLC (hexane/EtOAc 2:1) to afford the title compound as a colorless
oil (20.5 mg, 95% yield). 1H NMR (400 MHz, CDCl3) δ 7.05 (m,
1 H), 6.98 (d, J ) 7.3 Hz, 1 H), 6.69 (m, 2 H), 4.89 (br s, 1 H),
3.42-3.36 (m, 1 H), 3.16-3.11 (m, 1 H), 1.65 (m, 1 H), 1.48 (s,
9 H), 1.14 (m, 1 H), 0.94 (m, 1 H), 0.80 (m, 1 H). 13C NMR (100
MHz, CDCl3) δ 156.3, 146.3, 127.8, 127.2, 125.5, 117.9, 114.6,
79.4, 44.2, 28.4, 20.2, 14.1, 9.7.
trans-[2-(4′-Chlorobiphenyl-3-yl)cyclopropyl]methylamine Hy-
drochloride (69). Prepared by the same procedure as described for
68 with 4-chlorophenylboronic acid (36.0 mg, 0.23 mmol) as the
starting material (17 mg, 82% and 83% yields). HPLC purity: 17.9
1
min, 97.7% (column 1, method C). H NMR (400 MHz, MeOD-
d4) δ 7.58 (d, J ) 8.4 Hz, 2 H), 7.43 (d, J ) 8.1 Hz, 2 H),
7.40-7.33 (m, 3 H), 7.12 (d, J ) 7.5 Hz, 2 H), 3.02 (m, 2 H), 2.09
(m, 2 H), 1.46 (m, 1 H), 1.18 (m, 1 H), 1.10 (m, 1 H). 13C NMR
(100 MHz, MeOD-d4) δ 143.6, 141.5, 141.2, 134.6, 130.3, 130.1,
129.7, 126.3, 126.0, 125.9, 45.0, 23.4, 21.1, 15.2. MS (ESI) m/z
258.2 [MH+]. HRMS (ESI) calculated for C16H17NCl+ [MH+]
258.10440, found 258.10422.
trans-[2-(4′-Trifluoromethybiphenyl-3-yl)cyclopropyl]methyl-
amine Hydrochloride (70). Prepared by the same procedure as
described for 68 with 4-trifluoromethylphenylboronic acid (43.7
mg, 0.23 mmol) as the starting material (15 mg, 66% and 81%
1
yields). HPLC purity: 17.6 min, 95.6% (column 1, method C). H
NMR (400 MHz, MeOD-d4) δ 7.81 (d, J ) 8.2 Hz, 2 H), 7.75 (d,
J ) 8.4 Hz, 2 H), 7.51-7.47 (m, 2 H), 7.41 (t, J ) 7.7 Hz, 1 H),
7.19 (d, J ) 7.7 Hz, 1 H), 3.07-3.00 (m, 2 H), 2.16-2.11 (m, 1
H), 1.52-1.48 (m, 1 H), 1.24-1.20 (m, 1 H), 1.16-1.11 (m, 1 H).
13C NMR (100 MHz, MeOD-d4) δ 144.4, 141.8, 139.2, 128.4,
126.8, 125.0, 124.9, 124.9, 124.4, 124.3, 43.1, 21.5, 19.2, 13.3.
MS (ESI) m/z 292.2 [MH+]. HRMS (ESI) calculated for
C17H17NF3 [MH+] 292.13076, found 292.13050.
+
trans-[2-(4′-Cyanobiphenyl-3-yl)cyclopropyl]methylamine Hy-
drochloride (71). Prepared by the same procedure as described for
68 with 4-cyanophenylboronic acid (33.8 mg, 0.23 mmol) as the
starting material (20 mg, 94% and 75% yields). HPLC purity: 13.6
1
min, 97.9% (column 3, method A). H NMR (400 MHz, MeOD-
d4) δ 7.81 (s, 4 H), 7.49 (m, 1 H), 7.48 (s, 1 H), 7.41 (t, J ) 7.6
Hz, 1 H), 7.21 (d, J ) 7.6 Hz, 1 H), 3.10-3.01 (m, 2 H), 2.17-2.12
(m, 1 H), 1.55-1.47 (m, 1 H), 1.24-1.19 (m, 1 H), 1.16-1.11
(m, 1 H). 13C NMR (100 MHz, MeOD-d4) δ 147.2, 144.0, 140.7,
133.9, 130.5, 129.1, 127.3, 126.3, 126.2, 119.9, 112.0, 45.0, 23.4,
trans-[2-(3-Aminophenyl)cyclopropylmethyl]carbamic Acid
tert-Butyl Ester (76). Prepared by the same procedure as described
for 75 with 63 (120 mg, 0.368 mmol) as the starting material (33

SelectiVe 5-HT 2C Receptor Agonists from Tranylcypromine
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 7 1899
1
mg, 67% yield). H NMR (400 MHz, CDCl3) δ 7.07 (t, J ) 7.8
(br s, 1 H), 7.53 (d, J ) 8.8 Hz, 2 H), 7.29-7.22 (m, 3 H), 7.04 (t,
J ) 6.9 Hz, 1 H), 6.90 (d, J ) 6.9 Hz, 1 H), 6.95 (t, J ) 7.2 Hz,
1 H), 4.98 (br t, J ) 6.2 Hz, 1 H), 3.93 (m, 1 H), 3.23 (m, 1 H),
1.61 (m, 1 H), 1.50 (s, 9 H), 1.19 (m, 1 H), 0.83-0.72 (m, 2 H).
13C NMR (75 MHz, CDCl3) δ 158.5, 153.3, 139.7, 138.8, 129.2,
128.9, 127.6, 127.4, 127.1, 122.3, 120.2, 119.3, 81.5, 40.6, 28.8,
21.2, 16.2, 6.5.
Step B: Prepared by the same deprotection procedure as
described for 66 (18 mg, 79% yield). HPLC purity: 8.1 min, 99.5%
(column 3, method A). 1H NMR (300 MHz, MeOD-d4) δ 7.48 (d,
J ) 8.8 Hz, 2 H), 7.29 (d, J ) 8.9 Hz, 2 H), 7.24-7.12 (m, 2 H),
7.03 (d, J ) 7.6 Hz, 1 H), 3.11-2.95 (m, 2 H), 2.12-2.05 (m, 1
H), 1.44-1.38 (m, 1 H), 1.14-1.09 (m, 2 H). 13C NMR (100 MHz,
MeOD-d4) δ 155.1, 138.5, 137.1, 135.0, 128.8, 127.6, 126.7, 125.6,
125.5, 124.8, 120.5, 44.0, 19.3, 18.7, 13.0. MS (ESI) m/z 316.2
[MH+]. HRMS (ESI) calculated for C17H19N3OCl+ [MH+] 316.12112,
found 316.12080.
trans-N-[3-(2-Aminomethylcyclopropyl)phenyl]acetamide Hy-
drochloride (83). Prepared by the same procedure as described for
80 with 75 (5.8 mg, 0.0221 mmol) and benzoyl chloride (0.0039
mL, 0.0332 mmol) as the starting materials (3.3 mg, 94% and 60%
yields). 1H NMR (300 MHz, MeOD-d4) δ 7.47 (s, 1 H), 7.25-7.19
(m, 2 H), 6.90 (d, J ) 6.4 Hz, 1 H), 3.01 (d, J ) 7.4 Hz, 2 H),
2.13 (s, 3 H), 2.01 (m, 1 H), 1.42 (m, 1 H), 1.10 (m, 2 H). 13C
NMR (100 MHz, MeOD-d4) δ 171.9, 143.6, 140.2, 130.0, 123.0,
119.0, 118.9, 45.0, 24.0, 23.4, 21.1, 15.2. MS (ESI) m/z 205.2
[MH+]. HRMS (ESI) calculated for C12H17N2O+ [MH+] 205.13354,
found 205.13341.
Hz, 1 H), 6.56 (dd, J ) 1.4 Hz, 7.9 Hz, 1 H), 6.52 (d, J ) 7.6 Hz,
1 H), 6.46 (s, 1 H), 4.70 (br s, 1 H), 3.22 (m, 1 H), 3.10 (m, 1 H),
1.73 (m, 1 H), 1.47 (s, 9 H), 1.28 (m, 1 H), 0.91 (m, 1 H). 13C
NMR (100 MHz, CDCl3) δ 155.5, 144.9, 143.6, 128.9, 116.4, 112.7,
44.4, 28.0, 22.4, 21.5, 13.8.
trans-[3-(2-Aminomethylcyclopropyl)phenyl]benzylamine Hy-
drochloride (78). Step A: Compound 76 (15 mg, 0.0572 mmol)
was dissolved in MeOH (0.5 mL) containing benzaldehyde (0.0052
mL, 0.0512 mmol) at 0 °C. To the mixture was added NaCNBH3
(4.3 mg, 0.0686 mmol). The resulting mixture was stirred at 0 °C
for 1 h and at rt overnight and directly purified by preparative TLC
(hexane/EtOAc 1:1) to afford the title compound as a colorless oil
1
(9.9 mg, 49% yield). H NMR (400 MHz, CDCl3) δ 7.38-7.35
(m, 4 H), 7.32-7.28 (m, 1 H), 7.08 (t, J ) 7.8 Hz, 1 H), 6.47-6.42
(m, 2 H), 6.37 (s, 1 H), 4.68 (br s, 1 H), 4.33 (s, 2 H), 4.07 (br s,
1 H), 3.26-3.23 (m, 1 H), 3.12-3.05 (m, 1 H), 1.72 (m, 1 H),
1.47 (s, 9 H), 1.28 (m, 1 H), 0.89 (m, 2 H). 13C NMR (100 MHz,
CDCl3) δ 155.8, 148.2, 143.7, 139.4, 129.2, 128.6, 127.5, 127.2,
114.9, 110.4, 110.2, 79.1, 48.3, 44.8, 28.4, 22.7, 22.1, 14.2.
Step B: Prepared by the same deprotection procedure as
described for 66 (5.6 mg, 76% yield). HPLC purity: 4.4 min, 94.4%
(column 3, method A). 1H NMR (400 MHz, MeOD-d4) δ 7.45-7.41
(m, 6 H), 7.28 (d, J ) 8.0 Hz, 1 H), 7.20-7.18 (m, 2 H), 4.60 (s,
2 H), 3.03 (m, 2 H), 2.11 (m, 1 H), 1.48 (m, 1 H), 1.17-1.12 (m,
2 H). 13C NMR (100 MHz, MeOD-d4) δ 146.0, 132.4, 131.6, 131.4,
130.9, 130.3, 128.3, 121.7, 121.5, 56.8, 44.7, 23.1, 21.6, 15.6. MS
(ESI) m/z 253.2 [MH+]. HRMS (ESI) calculated for C17H21N2
+
[MH+] 253.16993, found 253.16979.
trans-N-[3-(2-Aminomethylcyclopropyl)phenyl]benzamide Hy-
drochloride (84). Prepared by the same procedure as described for
80 with 76 (7.0 mg, 0.0234 mmol) and benzoyl chloride (0.0047
mL, 0.040 mmol) as the starting materials (4.3 mg, 97% and 74%
trans-N-[2-(2-Aminomethylcyclopropyl)phenyl]acetamide Hy-
drochloride (80). Step A: To compound 75 (7.0 mg, 0.0267 mmol)
and DMAP (3.3 mg, 0.0267 mmol) in CH2Cl2 (0.3 mL) was added
acetic anhydride (0.004 mL, 0.0423 mmol) at 0 °C. The resulting
mixture was stirred at 0 °C for 1 h and rt overnight and directly
purified by preparative TLC (hexane/EtOAc 1:1) to afford the title
1
yields). HPLC purity: 4.8 min, 99.6% (column 3, method A). H
NMR (300 MHz, MeOD-d4) δ 7.94 (d, J ) 7.2 Hz, 2 H), 7.62-7.51
(m, 4 H), 7.13-7.09 (m, 2 H), 7.41 (d, J ) 8.1 Hz, 1 H), 7.28 (t,
J ) 7.8 Hz, 1 H), 6.97 (d, J ) 7.6 Hz, 1 H), 3.02 (d, J ) 7.4 Hz,
2 H), 2.06 (m, 1 H), 1.46 (m, 1 H), 1.17 (m, 1 H), 1.10 (m, 1 H).
13C NMR (100 MHz, MeOD-d4) δ 169.1, 143.6, 140.1, 136.4,
133.1, 130.0, 129.8, 128.7, 123.6, 120.2, 120.0, 45.0, 23.4, 21.1,
15.2. MS (ESI) m/z 267.1 [MH+]. HRMS (ESI) calculated for
C17H19N2O+ [MH+] 267.14919, found 267.14899.
General Procedure for t-Boc Deprotection. The protected
amine was dissolved in a 2 N HCl solution in diethyl ether, and
the reaction mixture was stirred at ambient temperature for 12-24
h. A white precipitate formed after several minutes to hours. The
mixture was stirred until the reaction was complete by TLC and
worked up as described below.
trans-{2-[2-(6-Hydroxyhex-1-ynyl)phenyl]cyclopropyl}methylamine
Hydrochloride (86). Step A: Compound 62 (50 mg, 0.153 mmol),
Pd(PPh3)2Cl2 (8.6 mg, 0.012 mmol), PPh3 (6.4 mg, 0.024 mmol),
CuI (4.7 mg, 0.024 mmol), and 5-hexyn-1-ol (0.037 mL, 0.337
mmol) were dissolved in triethylamine (TEA) (1.4 mL), and the
mixture was degassed for 1 min and stirred at 85 °C overnight.
The resulting mixture was cooled to ambient temperature and
poured into a mixture of 0.1 N HCl/EtOAc (3 mL/3 mL). After
partition, the organic layer was washed with water, filtered, and
concentrated. The residue was purified by silica gel chromatography
(hexane/Et2O 4:1) to afford the title compound as a colorless oil
(30 mg, 57% yield).
Step B: Refer to the general procedure for t-Boc deprotection
described above. The mixture was concentrated and washed with
ethanol/Et2O to afford the title compound as a brown oil (22 mg,
90% yield). HPLC purity: 7.9 min, 94.7% (column 3, method A).
1H NMR (400 MHz, MeOD-d4) δ 7.24-7.08 (m, 3 H), 6.94 (d, J
) 7.6 Hz, 1 H), 5.74 (t, J ) 7.1 Hz, 1 H), 3.52 (t, J ) 6.1 Hz, 2
H), 2.62 (m, 1 H), 2.38-2.33 (m, 1 H), 2.09-2.06 (m, 1 H),
1.57-1.50 (m, 4 H), 1.29 (m, 1 H), 1.02-0.95 (m, 3 H). 13C NMR
(100 MHz, MeOD-d4) δ 143.3, 140.8, 132.3, 130.8, 127.5, 126.7,
90.5, 81.2, 62.8, 45.1, 33.4, 30.0, 26.1, 21.7, 20.3, 12.3. MS (ESI)
m/z 244.2 [MH+]. HRMS (ESI) calculated for C16H22NO+ [MH+]
244.1696, found 244.1688.
1
compound as a colorless oil (7.2 mg, 89% yield). H NMR (300
MHz, CDCl3) δ 8.63 (br. s, 1 H), 8.09 (d, J ) 7.9 Hz, 1 H), 7.21
(t, J ) 7.6 Hz, 1 H), 7.06-6.96 (m, 2 H), 4.89 (br s, 1 H), 3.58
(m, 1 H), 3.05 (m, 1 H), 1.84 (m, 1 H), 1.46 (s, 9 H), 1.27 (m, 1
H), 1.24 (m, 1 H), 0.83 (m, 1 H). 13C NMR (75 MHz, CDCl3) δ
169.7, 157.4, 138.0, 131.5, 127.1, 126.5, 124.4, 122.5, 80.4, 43.7,
30.1, 28.8, 24.8, 22.4, 18.1.
Step B: Prepared by the same deprotection procedure as
described for 66 (3.6 mg, 77% yield). HPLC purity: 4.8 min, 97.0%
(column 3, method A). 1H NMR (400 MHz, MeOD-d4) δ 7.22-7.20
(m, 3 H), 6.99 ((m, 3 H), 3.08 (m, 1 H), 2.94 (m, 1 H), 1.96 (m,
1 H), 1.32 (m, 1 H), 1.16 (m, 1 H), 1.08 (m, 1 H). 13C NMR (100
MHz, MeOD-d4) δ 172.6, 138.1, 137.2, 128.1, 127.6, 127.2, 126.0,
45.0, 23.1, 21.2, 19.8, 14.0. MS (ESI) m/z 205.2 [MH+]. HRMS
(ESI) calculated for C12H17N2O+ [MH+] 205.13354, found 205.13345.
trans-N-[2-(2-Aminomethylcyclopropyl)phenyl]benzamide Hy-
drochloride (81). Prepared by the same procedure as described for
80 with 75 (5.8 mg, 0.0221 mmol) and benzoyl chloride (0.0039
mL, 0.0332 mmol) as the starting materials (3.5 mg, 100% and
53% yields). HPLC purity: 6.48 min, 99.2% (column 3, method
1
A). H NMR (300 MHz, MeOD-d4) δ 8.05 (d, J ) 7.3 Hz, 2 H),
7.64 (t, J ) 7.3 Hz, 1 H), 7.56 (t, J ) 7.4 Hz, 2 H), 7.33-7.27 (m,
3 H), 7.07 (m, 1 H), 3.01 (m, 1 H), 2.86 (m, 1 H), 2.01 (m, 1 H),
1.38 (m, 1 H), 1.21 (m, 1 H), 1.05 (m, 1 H). 13C NMR (100 MHz,
MeOD-d4) δ 169.4, 138.7, 137.5, 135.3, 133.3, 129.8, 128.8, 128.4,
127.7, 127.6, 126.3, 45.0, 21.2, 20.2, 13.7. MS (ESI) m/z 267.1
[MH+]. HRMS (ESI) calculated for C17H19N2O+ [MH+] 267.14919,
found 267.14900.
trans-1-[2-(2-Aminomethylcyclopropyl)phenyl]-3-(4-chlorophe-
nyl)urea Hydrochloride (82). Step A: To a solution of 75 (30.0
mg, 0.114 mmol) in THF (5 mL) were added DMAP (2.8 mg, 0.023
mmol) and 4-chlorophenyl isocyanate (0.022 mL, 0.172 mmol) at
rt. The mixture was stirred at 50 °C overnight and directly purified
by preparative TLC (hexane/EtOAc 1:1) to afford the title
1
compound as a colorless oil (29.1 mg, 61% yield). H NMR (300
MHz, CDCl3) δ 8.42 (br s, 1 H), 8.32 (d, J ) 8.2 Hz, 1 H), 8.08

1900 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 7
Cho et al.
trans-[2-(3-Ethynylphenyl)cyclopropyl]methylamine Hydrochlo-
ride (87). Pd(PhCN)2Cl2 (1.8 mg, 0.0045 mmol) and CuI (0.6 mg,
0.003 mmol) were added to a dry vial, which was then sparged
with argon and charged with dioxane (0.3 mL). P(t-Bu)3 (1.0 M in
dioxane, 9.2 µL, 0.009 mmol), HN(i-Pr)2 (13.3 µL, 0.184 mol), 63
(50 mg, 0.153 mmol), and ethynyltrimethylsilane (26 µL, 0.184
mmol) were added to the stirred reaction mixture. During the
reaction, precipitation of [H2N(i-Pr)2]Br was observed. After stirring
at 50 °C overnight, the reaction mixture was diluted with EtOAc
(5 mL), filtered through a small pad of silica gel, concentrated,
and purified by silica gel chromatography (hexane/Et2O 4:1) to
afford the title compound as brown powder (58 mg, 57% yield).
To a stirred solution of trans-[2-(3-trimethylsilanylethynylphe-
nyl)cyclopropylmethyl]carbamic acid tert-butyl ester (58 mg, 0.17
mmol) in THF (1.5 mL) was added TBAF solution (1.0 M in THF,
0.255 mL, 0.255 mmol) slowly under argon purge to give a deep-
dark solution. After 1 h, the reaction mixture was diluted with
EtOAc (5 mL). The organic layer was washed with water, filtered
and concentrated, and purified by silica gel chromatography
(hexane/Et2O 4:1) to afford the title compound as brown powder
(58 mg, 57% yield). Refer to the general procedure for t-Boc
deprotection described above. The crude precipitate was filtered
and purified by recrystallization from ethanol/Et2O to afford the
title compound as a white solid (22 mg, 90% yield). HPLC purity:
9.3 min, 99.4% (column 1, method D). 1H NMR (400 MHz, MeOD-
d4) δ 7.28-7.22 (m, 3 H), 7.13 (d, J ) 6.8 Hz, 1 H), 3.45 (s, 1 H),
3.04-2.93 (m, 2 H), 2.02-1.97 (m, 1 H), 1.42-1.38 (m, 1 H),
1.33-1.04 (m, 2 H). 13C NMR (100 MHz, MeOD-d4) δ 143.3,
130.8, 130.7, 129.7, 127.6, 124.0, 78.7, 44.9, 23.0, 21.1, 15.2. MS
(ESI) m/z 272.1 [MH+]. HRMS (ESI) calculated for C12H14N+
[MH+] 172.1121, found 172.1122.
trans-{2-[3-(6-Hydroxyhex-1-ynyl)phenyl]cyclopropyl}methylam-
ine Hydrochloride (88). Refer to the general procedure for the
synthesis of 86 described above with substitution of 63 for 62. The
crude precipitate was filtered and purified by recrystallization from
ethanol/Et2O to afford the title compound as a white solid (21 mg,
86% yield). HPLC purity: 5.8 min, 94.8% (column 1, method C).
1H NMR (400 MHz, MeOD-d4) δ 7.19-7.05 (m, 3 H), 6.97 (d, J
) 7.2 Hz, 1 H), 3.51 (t, J ) 5.9 Hz, 2 H), 2.90 (m, 2 H), 2.34 (t,
J ) 6.7 Hz, 2 H), 1.93-1.88 (m, 1 H), 1.63-1.55 (m, 4 H),
1.34-1.29 (m, 1 H), 1.02-0.96 (m, 2 H). 13C NMR (100 MHz,
MeOD-d4) δ 143.1, 130.3, 130.1, 129.5, 126.6, 125.6, 90.7, 81.9,
62.6, 44.9, 32.9, 26.4, 23.1, 21.7, 19.9, 15.2. MS (ESI) m/z 244.2
[MH+]. HRMS (ESI) calculated for C16H22NO+ [MH+] 244.1696,
found 244.1688.
trans-{2-[3-(3-Hydroxy-3-methylbut-1-ynyl)phenyl]cyclopropyl}-
methylamine Hydrochloride (89). Refer to the general procedure
for the synthesis of 86 described above with substitution of 63 for
62 and 2-methylbut-3-yn-2-ol for 5-hexyn-1-ol (17 mg, 98% and
85% yields). HPLC purity: 8.5 min, 95.4% (column 3, method A).
1H NMR (400 MHz, MeOD-d4) δ 7.26-7.16 (m, 3 H), 7.12-7.10
(m, 1 H), 3.04-2.95 (m, 2 H), 2.01-1.98 (m, 1 H), 1.51-1.38
(m, 7 H), 1.13-1.05 (m, 2 H). 13C NMR (100 MHz, MeOD-d4) δ
143.3, 130.4, 130.3, 129.7, 127.4, 124.2, 91.6, 85.6, 65.9, 44.9,
31.5, 28.9, 23.0, 21.1, 15.1. MS (ESI) m/z 230.1 [MH+]. HRMS
(ESI) calculated for C15H20NO+ [MH+] 230.1539, found 230.1537.
trans-{2-[4-(6-Hydroxyhex-1-ynyl)phenyl]cyclopropyl}methylam-
ine Hydrochloride (90). Refer to the general procedure for the
synthesis of 76 described above with substitution of 64 for 62. The
crude precipitate was filtered and purified by recrystallization from
ethanol/Et2O to afford the title compound as a white solid (21 mg,
86% yield). HPLC purity: 7.7 min, 99.0% (column 3, method A).
1H NMR (300 MHz, MeOD-d4) δ 7.25 (d, J ) 8.2 Hz, 2 H), 7.04
(d, J ) 8.2 Hz, 2 H), 3.60 (t, J ) 6.1 Hz, 2 H), 2.98 (m, 2 H),
2.47-2.40 (m, 2 H), 2.00-1.95 (m, 1 H), 1.71-1.63 (m, 4 H),
1.39 (m, 1 H), 1.11-1.04 (m, 2 H). 13C NMR (100 MHz, MeOD-
d4) δ 142.5, 132.7, 127.0, 123.2, 90.5, 81.8, 62.6, 44.9, 33.0, 26.5,
23.2, 21.3, 19.9, 15.4. MS (ESI) m/z 244.2 [MH+]. HRMS (ESI)
calculated for C16H22NO+ [MH+] 244.1696, found 244.1689.
Biological Methods. Calcium Flux Assays. Calcium flux assays
were performed essentially as described earlier.44 HEK 293 cells
stably expressing the human 5-HT2A, 5-HT2B, or 5-HT2C (INI) receptor
were seeded and incubated for 20 h in serum-free DMEM
containing 50 U/mL penicillin and 50 µg/mL streptomycin sulfate
in tissue culture-treated black clear-bottom 384-well plates (Greiner,
Germany); plates were coated with 20 µL/well of 50 mg/L poly
L-lysine (Sigma, P-1524) in PBS. The cells were preincubated for
75 min at 37 °C in a humidified incubator with 20 µL of
reconstituted fura-4 based calcium dye (Calcium Plus Assay Kit,
Molecular Devices) in assay buffer (Hanks’ balanced salt solution
containing calcium and magnesium (Invitrogen, 14065-056), 50 mM
HEPES, 2.5 mM probenecid, 100 mg/L ascorbic acid, pH 7.4). The
plates were allowed to cool to rt over 10 min and were transferred
to a FLIPR Tetra fluorescence image plate reader (Molecular
Devices). The test compounds in 15 µL assay buffer were
automatically added and fluorescence (excitation: 470-495 nm,
emission: 515-575 nm) was measured every second for 3 min.
The baseline was averaged from 10 data points immediately before
the additions and results were exported as the maximal response
over baseline during 60 s after addition. Compounds were measured
at seven concentrations from 10 µM to 10 pM in triplicate. EC50
values and Emax values were obtained from nonlinear curve fitting
against a sigmoidal dose-response model using Prism (Graphpad).
Behavior. Animals. C57BL/6J male mice (9 weeks of age at
testing) were obtained from Jackson Laboratory (Bar Harbor, ME).
Mice were housed four to a cage in a colony room maintained at
22 °C on a 12 h light-dark cycle. All animal experiments were
conducted in accordance with the NIH Guide for the Care and Use
of Laboratory Animals and the PsychoGenics Animal Care and Use
Committee.
Mouse Forced Swim Test. Procedures were based on those
previously described.48 Mice were individually placed into clear
glass cylinders (i.e., 15 cm tall × 10 cm wide, 1 L beakers)
containing 23 ( 1 °C water 12 cm deep (approximately 800 mL).
The time the animal spent immobile was recorded every 1 min
over a 6 min trial. Immobility was described as the postural position
of floating in the water. After testing, mice were dried and returned
to their home cage.
Drugs. Sertraline was purchased from a commercial vendor
(Sigma, St. Louis, MO). All compounds were dissolved in 10%
DMSO vehicle in saline 30 min prior to testing. All compounds
were administered ip, 1 mL/kg dosing volume.
Statistics. ANOVA was performed to determine the effects of
test treatment, followed by posthoc analysis using Fisher’s PLSC.
Acknowledgment. This work was supported in part by NIH
grant(R01DA022317,granteeAlanP.Kozikowski),(RO1MH61887,
NO1MH80032, and U19MH82441, grantee Bryan L. Roth) and
NIDA fellowship (2006-2007). This work was supported by
the Korea Research Foundation Grant funded by the Korean
Government (KRF-2007-357-C00071). We thank Dr. Rong He
for help with the preparative of the manuscript and Dr. Arsen
Gaysin for help with generating the data reported. S. J. Cho
expresses appreciation to Dr. Suresh Tipparaju, Dr. Annamaria
Lilienkampf, Dr. Sophie Gaudrel-Grosay, and Dr. Ki Duk Park
for helpful discussions.
Supporting Information Available: Functional activity of
compounds 66-74, 78, 80-84, and 86-90. Copy of original
spectroscopic data and purity assessment of key compounds 29 and
37. This material is available free of charge via the Internet at http://
pubs.acs.org.
References
(1) Hoyer, D.; Martin, G. 5-HT receptor classification and nomenclature:
towards a harmonization with the human genome. Neuropharmacology
1997, 36, 419–428.
(2) Roth, B. L. Multiple serotonin receptors: clinical and experimental
aspects. Ann. Clin. Psychiatry 1994, 6, 67–78.
(3) Kroeze, W. K.; Roth, B. L. The molecular biology of serotonin
receptors: therapeutic implications for the interface of mood and
psychosis. Biol. Psychiatry 1998, 44, 1128–1142.

SelectiVe 5-HT 2C Receptor Agonists from Tranylcypromine
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 7 1901
(4) Kroeze, W. K.; Sheffler, D. J.; Roth, B. L. G-protein-coupled receptors
at a glance. J. Cell Sci. 2003, 116, 4867–4869.
(5) Kroeze, W. K.; Kristiansen, K.; Roth, B. L. Molecular biology of
serotonin receptors structure and function at the molecular level. Curr.
Top. Med. Chem. 2002, 2, 507–528.
(6) Nichols, D. E. Hallucinogens. Pharmacol. Ther. 2004, 101, 131–181.
(7) Rothman, R. B.; Baumann, M. H.; Savage, J. E.; Rauser, L.; McBride,
A.; Hufeisen, S. J.; Roth, B. L. Evidence for possible involvement of
5-HT2B receptors in the cardiac valvulopathy associated with fenflu-
ramine and other serotonergic medications. Circulation 2000, 102,
2836–2841.
pyrazino[1,2-a]quinoxalines. Bioorg. Med. Chem. Lett. 2000, 10, 1991–
1994.
(29) Sabb, A. L.; Vogel, R. L.; Welmaker, G. S.; Sabalski, J. E.; Coupet,
J.;Dunlop,J.;Rosenzweig-Lipson,S.;Harrison,B.Cycloalkyl[b][1,4]ben-
zodiazepinoindoles are agonists at the human 5-HT2C receptor. Bioorg.
Med. Chem. Lett. 2004, 14, 2603–2607.
(30) Smith, B. M.; Smith, J. M.; Tsai, J. H.; Schultz, J. A.; Gilson, C. A.;
Estrada, S. A.; Chen, R. R.; Park, D. M.; Prieto, E. B.; Gallardo, C. S.;
Sengupta, D.; Dosa, P. I.; Covel, J. A.; Ren, A.; Webb, R. R.; Beeley,
N. R.; Martin, M.; Morgan, M.; Espitia, S.; Saldana, H. R.; Bjenning,
C.; Whelan, K. T.; Grottick, A. J.; Menzaghi, F.; Thomsen, W. J.
Discovery and structure-activity relationship of (1R)-8-chloro-2,3,4,5-
tetrahydro-1-methyl-1H-3-benzazepine (Lorcaserin), a selective sero-
tonin 5-HT2C receptor agonist for the treatment of obesity. J. Med.
Chem. 2008, 51, 305–313.
(31) Wacker, D. A.; Varnes, J. G.; Malmstrom, S. E.; Cao, X.; Hung, C. P.;
Ung, T.; Wu, G.; Zhang, G.; Zuvich, E.; Thomas, M. A.; Keim, W. J.;
Cullen, M. J.; Rohrbach, K. W.; Qu, Q.; Narayanan, R.; Rossi, K.;
Janovitz, E.; Lehman-McKeeman, L.; Malley, M. F.; Devenny, J.;
Pelleymounter, M. A.; Miller, K. J.; Robl, J. A. Discovery of (R)-9-
ethyl-1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino[2,1-a]isoindol-6(2H)-
one, a selective, orally active agonist of the 5-HT2C receptor. J. Med.
Chem. 2007, 50, 1365–1379.
(32) Wacker, D. A.; Miller, K. J. Agonists of the serotonin 5-HT2C receptor:
preclinical and clinical progression in multiple diseases. Curr. Opin.
Drug. DiscoVery DeV. 2008, 11, 438–445.
(33) Cherezov, V.; Rosenbaum, D. M.; Hanson, M. A.; Rasmussen, S. G.;
Thian, F. S.; Kobilka, T. S.; Choi, H. J.; Kuhn, P.; Weis, W. I.;
Kobilka, B. K.; Stevens, R. C. High-resolution crystal structure of an
engineered human ꢀ2-adrenergic G protein-coupled receptor. Science
2007, 318, 1258–1265.
(34) Rasmussen, S. G.; Choi, H. J.; Rosenbaum, D. M.; Kobilka, T. S.;
Thian, F. S.; Edwards, P. C.; Burghammer, M.; Ratnala, V. R.;
Sanishvili, R.; Fischetti, R. F.; Schertler, G. F.; Weis, W. I.; Kobilka,
B. K. Crystal structure of the human ꢀ2 adrenergic G-protein-coupled
receptor. Nature 2007, 450, 383–387.
(35) Rosenbaum, D. M.; Cherezov, V.; Hanson, M. A.; Rasmussen, S. G.;
Thian, F. S.; Kobilka, T. S.; Choi, H. J.; Yao, X. J.; Weis, W. I.;
Stevens, R. C.; Kobilka, B. K. GPCR engineering yields high-
resolution structural insights into ꢀ2-adrenergic receptor function.
Science 2007, 318, 1266–1273.
(36) Rohl, C. A.; Strauss, C. E.; Chivian, D.; Baker, D. Modeling
structurally variable regions in homologous proteins with rosetta.
Proteins 2004, 55, 656–677.
(37) Ferrara, P.; Gohlke, H.; Price, D. J.; Klebe, G.; Brooks, C. L., III.
Assessing scoring functions for protein-ligand interactions. J. Med.
Chem. 2004, 47, 3032–3047.
(8) Roth, B. L. Drugs and valvular heart disease. N. Engl. J. Med. 2007,
356, 6–9.
(9) Loke, Y. K.; Derry, S.; Pritchard-Copley, A. Appetite suppressants
and valvular heart diseasesa systematic review. BMC Clin. Pharma-
col. 2002, 2, 6.
(10) Rocha, B. A.; Goulding, E. H.; O’Dell, L. E.; Mead, A. N.; Coufal,
N. G.; Parsons, L. H.; Tecott, L. H. Enhanced locomotor, reinforcing,
and neurochemical effects of cocaine in serotonin 5-hydroxytryptamine
2C receptor mutant mice. J. Neurosci. 2002, 22, 10039–10045.
(11) Tecott, L. H.; Sun, L. M.; Akana, S. F.; Strack, A. M.; Lowenstein,
D. H.; Dallman, M. F.; Julius, D. Eating disorder and epilepsy in mice
lacking 5-HT2C serotonin receptors. Nature 1995, 374, 542–546.
(12) Chou-Green, J. M.; Holscher, T. D.; Dallman, M. F.; Akana, S. F.
Compulsive behavior in the 5-HT2C receptor knockout mouse. Physiol.
BehaV. 2003, 78, 641–649.
(13) Delgado, P. L.; Moreno, F. A. Hallucinogens, serotonin and obsessive-
compulsive disorder. J. PsychoactiVe Drugs 1998, 30, 359–366.
(14) Martin, J. R.; Bos, M.; Jenck, F.; Moreau, J.; Mutel, V.; Sleight, A. J.;
Wichmann, J.; Andrews, J. S.; Berendsen, H. H.; Broekkamp, C. L.;
Ruigt, G. S.; Kohler, C.; Delft, A. M. 5-HT2C receptor agonists:
pharmacological characteristics and therapeutic potential. J. Pharmacol.
Exp. Ther. 1998, 286, 913–924.
(15) Roth, B. L.; Shapiro, D. A. Insights into the structure and function of
5-HT2 family serotonin receptors reveal novel strategies for therapeutic
target development. Expert Opin. Ther. Targets 2001, 5, 685–695.
(16) Miller, K. J. Serotonin 5-HT2C receptor agonists: potential for the
treatment of obesity. Mol. InterV. 2005, 5, 282–291.
(17) Roth, B. L.; Lopez, E.; Patel, S.; Kroeze, W. K. The multiplicity of
serotonin receptors: Uselessly diverse molecules or an embarrassment
of riches? Neuroscientist 2000, 6, 252–262.
(18) Isaac, M. Serotonergic 5-HT2C receptors as a potential therapeutic target
for the design antiepileptic drugs. Curr. Top. Med. Chem. 2005, 5,
59–67.
(19) Millan, M. J.; Peglion, J. L.; Lavielle, G.; Perrin-Monneyron, S. 5-HT2C
receptors mediate penile erections in rats: actions of novel and selective
agonists and antagonists. Eur. J. Pharmacol. 1997, 325, 9–12.
(20) Cryan, J. F.; Lucki, I. Antidepressant-like behavioral effects mediated
by 5-hydroxytryptamine2C receptors. J. Pharmacol. Exp. Ther. 2000,
295, 1120–1126.
(38) Burger, A.; Walter, C. R., Jr.; Bennet, W. B.; Turnbull, L. B.
Arylcycloalkylamines. Science 1950, 112, 306.
(39) Burger, A.; Yost, W. L. Arylcycloalkylamines. I. 2-Phenylcyclopro-
pylamine. J. Am. Chem. Soc. 1948, 70, 2198–2201.
(21) Giorgetti, M.; Tecott, L. H. Contributions of 5-HT2C receptors to
multiple actions of central serotonin systems. Eur. J. Pharmacol. 2004,
488, 1-9.
(40) Prestwick Drug Library; Prestwick Chemical: Illkirch, France, 2006;
http://www.prestwickchemical.fr/ (accessed March 3, 2009).
(41) Teotino, U. M.; Bella, D. D.; Gandini, A.; Benelli, G. Chemical and
biological properties of some aminomethyl-2-phenylcyclopropane
derivatives. Pharmacological comparison with tranylcypromine.
J. Med. Chem. 1967, 10, 1091–1096.
(42) Zirkle, C. L.; Kaiser, C.; Tedeschi, D. H.; Tedeschi, R. E.; Burger, A.
2-Substituted Cyclopropylamines. II. Effect of Structure Upon Monoam-
ine Oxidase-Inhibitory Activity as Measured in Vivo by Potentiation
of Tryptamine Convulsions. J. Med. Pharm. Chem. 1962, 5, 1265–
1284.
(43) Yoshida, S.; Meyer, O. G.; Rosen, T. C.; Haufe, G.; Ye, S.; Sloan,
M. J.; Kirk, K. L. Fluorinated phenylcyclopropylamines. 1.
Synthesis and effect of fluorine substitution at the cyclopropane
ring on inhibition of microbial tyramine oxidase. J. Med. Chem.
2004, 47, 1796–1806.
(44) Krishnamurthy, S. A highly efficient and general N-monomethylation
of functionalized primary amines via formylationsborane:methyl
sulfide reduction. Tetrahedron Lett. 1982, 23, 3315–3318.
(45) Balboni, G.; Salvadori, S.; Guerrini, R.; Negri, L.; Giannini, E.; Bryant,
S. D.; Jinsmaa, Y.; Lazarus, L. H. Synthesis and opioid activity of
N,N-dimethyl-Dmt-Tic-NH-CH(R)-R′ analogues: acquisition of potent
δ antagonism. Bioorg. Med. Chem. 2003, 11, 5435–5441.
(46) Arvidsson, L. E.; Johansson, A. M.; Hacksell, U.; Nilsson, J. L.;
Svensson, K.; Hjorth, S.; Magnusson, T.; Carlsson, A.; Lindberg, P.;
Andersson, B. N,N-Dialkylated monophenolic trans-2-phenylcyclo-
propylamines: novel central 5-hydroxytryptamine receptor agonists.
J. Med. Chem. 1988, 31, 92–99.
(22) Rosenzweig-Lipson, S.; Sabb, A.; Stack, G.; Mitchell, P.; Lucki, I.;
Malberg, J. E.; Grauer, S.; Brennan, J.; Cryan, J. F.; Sukoff Rizzo,
S. J.; Dunlop, J.; Barrett, J. E.; Marquis, K. L. Antidepressant-like
effects of the novel, selective, 5-HT2C receptor agonist WAY-163909
in rodents. Psychopharmacology (Berlin) 2007, 192, 159–170.
(23) Marquis, K. L.; Sabb, A. L.; Logue, S. F.; Brennan, J. A.; Piesla,
M. J.; Comery, T. A.; Grauer, S. M.; Ashby, C. R., Jr.; Nguyen,
H. Q.; Dawson, L. A.; Barrett, J. E.; Stack, G.; Meltzer, H. Y.;
Harrison, B. L.; Rosenzweig-Lipson, S. WAY-163909 [(7bR,10aR)-
1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta-[b][1,4]diazepino[6,7,
1hi]indole]: A novel 5-hydroxytryptamine 2C receptor-selective
agonist with preclinical antipsychotic-like activity. J. Pharmacol.
Exp. Ther. 2007, 320, 486–496.
(24) Berger, M.; Gray, J. A.; Roth, B. L. The Expanded Biology of
Serotonin. Annu. ReV. Med. 2009, 60, 355–366.
(25) Lacivita, E.; Leopoldo, M. Selective agents for serotonin2C (5-HT2C
)
receptor. Curr. Top. Med. Chem. 2006, 6, 1927–1970.
(26) Nilsson, B. M. 5-Hydroxytryptamine 2C (5-HT2C) receptor agonists
as potential antiobesity agents. J. Med. Chem. 2006, 49, 4023–4034.
(27) Siuciak, J. A.; Chapin, D. S.; McCarthy, S. A.; Guanowsky, V.; Brown,
J.; Chiang, P.; Marala, R.; Patterson, T.; Seymour, P. A.; Swick, A.;
Iredale, P. A. CP-809,101, a selective 5-HT2C agonist, shows activity
in animal models of antipsychotic activity. Neuropharmacology 2007,
52, 279–290.
(28) Welmaker, G. S.; Nelson, J. A.; Sabalski, J. E.; Sabb, A. L.; Potoski,
J. R.; Graziano, D.; Kagan, M.; Coupet, J.; Dunlop, J.; Mazandarani,
H.; Rosenzweig-Lipson, S.; Sukoff, S.; Zhang, Y. Synthesis and
5-hydroxytryptamine (5-HT) activity of 2,3,4,4a-tetrahydro-1H-
pyrazino[1,2-a]quinoxalin-5-(6H)ones and 2,3,4,4a,5,6-hexahydro-1H-
(47) Kawamoto, H.; Ozaki, S.; Itoh, Y.; Miyaji, M.; Arai, S.; Nakashima,
H.; Kato, T.; Ohta, H.; Iwasawa, Y. Discovery of the first potent and
selective small molecule opioid receptor-like (ORL1) antagonist:
1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-

1902 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 7
Cho et al.
1,3-dihydro-2H-benzimidazol-2-one (J-113397). J. Med. Chem. 1999,
42, 5061–5063.
(48) Chandrasekhar, S.; Reddy, C. R.; Ahmed, M. A single step reductive
amination of carbonyl compounds with polymethylhydrosiloxane-
Ti((OPr)-Pr-i)(4). Synlett 2000, 1655–1657.
(49) Miyaura, N.; Suzuki, A. Palladium-Catalyzed Cross-Coupling Reac-
tions of Organoboron Compounds. Chem. ReV. 1995, 95, 2457–2483.
(50) DeVasher, R. B.; Moore, L. R.; Shaughnessy, K. H. Aqueous-phase,
palladium-catalyzed cross-coupling of aryl bromides under mild
conditions, using water-soluble, sterically demanding alkylphosphines.
J. Org. Chem. 2004, 69, 7919–7927.
(51) Overberger, C. G.; Shimokawa, Y. Synthesis and Optical Properties
of Asymmetric Polyamides Derived from Optically Active Cyclic
Dicarboxylic Acids. Macromolecules 1971, 4, 718–725.
antagonists as potential antipsychotic agents. J. Med. Chem. 2000,
43, 3923–3932.
(53) Jensen, N. H.; Rodriguiz, R. M.; Caron, M. G.; Wetsel, W. C.;
Rothman, R. B.; Roth, B. L. N-Desalkylquetiapine, a Potent Norepi-
nephrine Reuptake Inhibitor and Partial 5-HT1A Agonist, as a Putative
Mediator of Quetiapine’s Antidepressant Activity. Neuropsychophar-
macology 2007, 33, 2303–2312.
(54) Egan, C.; Grinde, E.; Dupre, A.; Roth, B. L.; Hake, M.; Teitler, M.;
Herrick-Davis, K. Agonist high and low affinity state ratios predict
drug intrinsic activity and a revised ternary complex mechanism at
serotonin 5-HT2A and 5-HT2C receptors. Synapse 2000, 35, 144–150.
(55) Dunlop, J.; Marquis, K. L.; Lim, H. K.; Leung, L.; Kao, J.; Cheesman,
C.; Rosenzweig-Lipson, S. Pharmacological profile of the 5-HT2C
receptor agonist WAY-163909; therapeutic potential in multiple
indications. CNS Drug ReV. 2006, 12, 167–177.
(52) Zhang, X.; Hodgetts, K.; Rachwal, S.; Zhao, H.; Wasley, J. W.;
Craven, K.; Brodbeck, R.; Kieltyka, A.; Hoffman, D.; Bacolod,
M. D.; Girard, B.; Tran, J.; Thurkauf, A. trans-1-[(2-Phenylcyclo-
propyl)methyl]-4-arylpiperazines: mixed dopamine D2/D4 receptor
JM801354E