Discovery of N-Substituted (2-Phenylcyclopropyl)methylamines as Functionally Selective Serotonin 2C Receptor Agonists for Potential Use as Antipsychotic Medications

Article abstract of DOI:10.1021/acs.jmedchem.7b00584

A series of N-substituted (2-phenylcyclopropyl)methylamines were designed and synthesized, with the aim of finding serotonin 2C (5-HT_2C)-selective agonists with a preference for G_q signaling. A number of these compounds exhibit 5-HT_2C selectivity with a preference for G_q-mediated signaling compared with β-arrestin recruitment. Furthermore, the N-methyl compound (+)-15a, which displayed an EC₅₀ of 23 nM in the calcium flux assay while showing no β-arrestin recruitment activity, is the most functionally selective 5-HT_2C agonist reported to date. The N-benzyl compound (+)-19, which showed an EC₅₀ of 24 nM at the 5-HT_2C receptor, is fully selective over the 5-HT_2B receptor. In an amphetamine-induced hyperactivity model, compound (+)-19 showed significant antipsychotic-drug-like activity. These novel compounds shed light on the role of functional selectivity at the 5-HT_2C receptor with respect to antipsychotic activity.

Full text of DOI:10.1021/acs.jmedchem.7b00584

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Article
Discovery of N-Substituted 2-Phenylcyclopropylmethylamines
2C
as Functionally Selective Serotonin 2C (5-HT) Receptor
Agonists for Potential Use as Antipsychotic Medications
Guiping Zhang, Jianjun Cheng, John D. McCorvy, Paul J. Lorello,
Barbara J. Caldarone, Bryan L Roth, and Alan P. Kozikowski
J. Med. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jmedchem.7b00584 • Publication Date (Web): 28 Jun 2017
Downloaded from http://pubs.acs.org on June 28, 2017
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Discovery of NꢀSubstituted 2-Phenylcyclopropylmethylamines as Functionally
Selective Serotonin 2C (5-HT ) Receptor Agonists for Potential Use as
2
C
Antipsychotic Medications
†
†, #
‡
§
Guiping Zhang, Jianjun Cheng, John D. McCorvy, Paul J. Lorello, Barbara J.
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§
‡
*,†
Caldarone, Bryan L. Roth, and Alan P. Kozikowski
†
Drug Discovery Program, Department of Medicinal Chemistry and Pharmacognosy, College of
Pharmacy, University of Illinois at Chicago, Chicago, Illinois 60612, USA
‡
National Institute of Mental Health Psychoactive Drug Screening Program, and Department of
Pharmacology and Division of Chemical Biology and Medicinal Chemistry, University of North
Carolina Chapel Hill Medical School, Chapel Hill, North Carolina 27599, USA
§
Department of Neurology, Brigham and Women’s Hospital, Harvard NeuroDiscovery Center,
and Harvard Medical School, Boston, Massachusetts 02115, USA
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ABSTRACT
A series of Nꢀsubstituted 2ꢀphenylcyclopropylmethylamines were designed and
synthesized, with the aim of finding 5ꢀHT2Cꢀselective agonists with preference for G
q
signaling. A number of these compounds exhibit 5ꢀHT2C selectivity with preference
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for G ꢀmediated signaling compared with βꢀarrestin recruitment. Furthermore, the
q
Nꢀmethyl compound (+)ꢀ15a, which displayed an EC50 of 23 nM in the calcium flux
assay while showing no βꢀarrestin recruitment activity, is the most
functionallyꢀselective 5ꢀHT2C agonist reported to date. The Nꢀbenzyl compound
(
+)ꢀ19, which showed an EC50 of 24 nM at the 5ꢀHT2C receptor, is fully selective over
the 5ꢀHT2B receptor. In an amphetamineꢀinduced hyperactivity model, compound
+)ꢀ19 showed significant antipsychotic drugꢀlike activity. These novel compounds
(
shed light on the role of functional selectivity at the 5ꢀHT2C receptor with respect to
antipsychotic activity.
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INTRODUCTION
The serotonin 2C (5ꢀHT2C) receptor, a serotonin (5ꢀHT, 1, Figure 1), G
proteinꢀcoupled receptor (GPCR), has been identified as a promising drug target for
obesity and other central nervous system (CNS) disorders, such as schizophrenia and
10
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1
ꢀ6
drug addiction.
The 5ꢀHT2C receptor shares approximately 50% homology
similarity with the other two 5ꢀHT
2
subtypes, namely the 5ꢀHT2A and 5ꢀHT2B
7
receptors, where agonists respectively mediate hallucinogenic activity and cardiac
8, 9
valvulopathy.
Furthermore, the classical understanding of GPCR signaling has undergone important
changes in recent years with the recognition of the phenomenon of “functional
selectivity”, namely the ability of a specific agonist to differentially mediate multiple
q
receptor signaling events (i.e., G ꢀlinked calcium flux vs. βꢀarrestin recruitment in the
10
case of 5ꢀHT2C receptors). βꢀArrestin was named after its initially discovered ability
to arrest (turn off) GPCR signaling, and is an important downstream signaling and
regulatory factor. βꢀArrestin recruitment is responsible for desensitization,
1
1
internalization, and eventual degradation of GPCRs. It has furthermore been
demonstrated that the βꢀarrestin mediated signaling pathway functions can provide
1
2
signaling independent of Gꢀprotein pathways. Thus, a GPCR agonist that has
minimal capability to activate the βꢀarrestin signaling pathway could display
longꢀterm efficacy in regard to tolerance mediated by receptor desensitization and
downregulation. Recently, biased GPCR ligands have been suggested to offer great
therapeutic benefits as new generation drugs with enhanced efficacy and functional
13, 14
selectivity, resulting in reduced side effects.
Thus, to develop 5ꢀHT2C agonists as potential antipsychotic medications, it is essential
to explore ligands that are both G proteinꢀbiased and highly selective over 5ꢀHT2B and
5
ꢀHT2A. Most importantly, the high selectivity for 5ꢀHT2C over 5ꢀHT2B has emerged
as paramount due to the fact that chronic 5ꢀHT2B agonism leads to irreversible cardiac
valvulopathy, as illustrated by the withdrawal of fenfluramine and pergolide and the
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restriction of sales of cabergoline owing to their offꢀtarget activities at the 5ꢀHT2B
9
receptor. To date, a number of selective 5ꢀHT2 ligands have been disclosed (Figure
C
1
). In particular, lorcaserin (2) was approved by the FDA for the treatment of obesity
in 2012. It shows excellent 5ꢀHT2C agonist activity (EC50 = 9 nM, Emax = 99%), but
only moderate (100ꢀfold) selectivity over 5ꢀHT (EC = 943 ± 90 nM, E = 100%),
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2B
50
max
which is relevant to understanding the higher incidence of cardiac valve disorders
1
5
compared to placebo in clinical trails. Vabicaserin (3) with partial agonism (Emax
=
5
0%, EC50 = 12 or 102 nM depending on receptor expression level) at the 5ꢀHT2B
receptor has failed to achieve its primary endpoints in clinical trails, although a
proofꢀofꢀconcept has been achieved for the use of 5ꢀHT2C agonists in treating
16, 17
schizophrenia.
The pyrimido[3,4ꢀd]azepine, PFꢀ4479745 (5), a hybrid of
1
8
lorcaserin and CPꢀ809101 (4), displays high potency (EC = 10 nM) and moderate
50
efficacy (Emax = 67%) at 5ꢀHT2C while possessing no measurable agonism at either
19
the 5ꢀHT2A or 5ꢀHT2B receptor. The pyrido[3,4ꢀd]azepine, PFꢀ04781340 (6), is a
potent 5ꢀHT ligand (EC = 9 nM, E = 99%), with about 160ꢀfold selectivity over
2C
50
max
20
5
ꢀHT2B. Both compounds 5 and 6 were reported to have excellent ADME properties
commensurate with an orally bioavailable and CNS penetrant profile. However, to the
21
best of our knowledge, few biased 5ꢀHT2c agonists have been reported to date.
NH2
NH
HO
N
Cl
N
H
NH
5
ꢀHT (1)
Lorcaserin (2)
Vabicaserin (3)
HN
N
N
HN
N
Cl
NH
O
N
N
NH
N
NH
CPꢀ809101 (4)
PFꢀ4479745 (5)
PFꢀ04781340 (6)
Figure 1. Selected 5ꢀHT2C agonists.
In our prior work, tranylcypromine was identified as a hit compound in an initial
highꢀthroughput screening (HTS) assay using a library containing 800 compounds.
We developed our firstꢀgeneration potent 5ꢀHT2C agonists by homologation of the
22
side chain of tranylcypromine to 2ꢀphenylcyclopropylmethylamine (2ꢀPCPMA).
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Subsequent structureꢀactivity relationship (SAR) studies indicated that a 2ꢀalkoxy
substituent is a beneficial functional group for maintaining potency and selectivity
(Figure 2). Further fineꢀtuning of the 2ꢀalkoxy and the halogen substituents led to the
2
3, 24
identification of 11 and 12,
which showed excellent pharmacological profiles
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with regard to 5ꢀHT2C potency and selectivity over 5ꢀHT2A and 5ꢀHT . In addition,
2B
compounds 11 and 12 showed only weak βꢀarrestin recruitment efficacy (Emax = 23%
and 26%, respectively; unpublished data) similar to a series of structurally similar
2
1
benzofuranꢀbased compounds reported recently.
The achievement of optimal brain exposure, which is a critical and challenging task in
CNS drug discovery, requires a more restrictive selection of physicochemical
25ꢀ27
properties compared to orally active, peripheral drugs (Rule of 5).
Due to the
relatively low molecular weights (MW) of the 2ꢀphenylcyclopropylmethylamines (for
example, MW < 230 for 11 and 12), the addition of halogen atoms to the phenyl ring
2
3, 24
has previously been demonstrated to improve brain penetrance.
optimize drugꢀlike properties, alkylation at the basic primary amino group of the
ꢀPCPMA scaffold was envisioned to provide opportunities for additional
To further
2
nonꢀcovalent interactions with the 5ꢀHT2C receptor while also increasing the ligands’
lipophilicity. In earlier studies we found that Nꢀmethylation of
2
ꢀ(2ꢀmethoxyphenyl)cyclopropylmethylamine (8, cLogP = 1.59, LogBB = –0.04)
gave a fully G ꢀbiased 5ꢀHT2c agonist with good potency (EC50 = 23 nM, Emax = 71%;
cLogP = 2.07, LogBB = 0.26), while Nꢀmethylation of our firstꢀgeneration
q
2
2
2ꢀphenylcyclopropylmethylamine (7) led to a dramatic loss in activity. Moreover, it
has been reported that Nꢀbenzylation of phenethylamines and 5ꢀmethoxytryptamines
2
8, 29
leads to improved agonism at 5ꢀHT
Nꢀsubstitution could improve the physicochemical properties in terms of further
enhancing brain penetration, new series of Nꢀsubstituted
ꢀ(2ꢀalkoxyphenyl)cyclopropylmethylamines (Figure 2) was developed and evaluated
2
receptors.
Given that the additional
a
2
for their potency and bias profiles in continuation of our previous SAR studies, along
with behavioral tests and in vitro ADMET studies of a promising 5ꢀHT2C receptor
agonist which showed no activity at the 5ꢀHT2B receptor.
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Figure 2. Selected 5ꢀHT2C agonists based on the 2ꢀphenylcyclopropylmethylamine scaffold, and
new Nꢀsubstituted derivatives.
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RESULTS AND DISCUSSION
Chemistry
NꢀMonomethylation of compounds 8, 11, and 12 was carried out starting from
Bocꢀprotected 2ꢀ(2ꢀalkoxyphenyl)cyclopropylmethylamines (–)ꢀ13a-c reported
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3
previously by our group as synthetic intermediates. As shown in Scheme 1,
introduction of an Nꢀmethyl group with NaH and iodomethane followed by
deprotection under acidic condition (2M HCl/Et
2
O) afforded the Nꢀmethylamines
(
+)ꢀ15a-c. Since the Nꢀmethylamine (+)ꢀ15a possessing a methoxy group at the
2
ꢀposition of the phenyl ring maintained potency at 5ꢀHT2C, the present work was
focused on Nꢀsubstituted analogs of compound 8.
Scheme 1. Synthesis of NꢀMethyl Analogs (+)-15a-c
a
a
2
Reagents and conditions: (a) MeI, NaH, THF, rt; (b) 2M HCl/Et O, rt.
The synthesis of these compounds was accomplished from the cyclopropaneꢀbearing
3
0
aldehyde D and primary amine G (Scheme 2) by reductive amination or
Nꢀsubstitution reactions (Scheme 3). For example, the Nꢀalkyl derivatives 16-18 and
Nꢀarylmethyl/heteroarylmethyl derivatives 19-22, 26-32, and 34-35 were synthesized
4 3
starting from the aldehyde D and amines by treatment with NaBH or NaBH(OAc) .
The tertiary amine 23 was prepared from the phenol 22 using a Mitsunobu reaction
with 2ꢀfluoroethanol. The Nꢀarylmethyl/heteroarylmethyl derivatives 24, 33 and
,
3
6-39 were synthesized from the primary amine G and appropriate aldehydes
following the same approach, while the derivative 24 was prepared from the
intermediate tosylate 24b (Scheme 4) via a nucleophile substitution reaction.
2 2
Hydrolysis of 24 under basic condition (NaOH/H O ) smoothly afforded the amide 25.
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The intermediate cyclopropylamine 30b for the synthesis of compound 30 was
i
obtained from 2ꢀmethoxybenzonitrile 30a using EtMgBr and Ti(O Pr) , followed by
4
3
1
treatment with a Lewis acid (BF
3
•Et
2
O) (Scheme 4).
The intermediate
thiophenylmethanamines 34e and 35e required for the synthesis of compounds 34 and
35 were prepared in four steps as illustrated in Scheme 5. The commercial thiophenes
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4a and 35a were brominated with NBS followed by replacement of bromide with
tritylamine to provide 34c and 35c in high yield. The bromides 34c and 35c were
32
3
reacted with CH ONa/CuBr to afford 34d and 35d, followed by the removal of the
Trt group under acidic conditions to give 34e and 35e as acetic acid salts (Scheme 5).
a
Scheme 2. Synthesis of Intermediates D and G
a
+
ꢀ
Reagents and conditions: (a) Ph
3
P=CHC(O)N(OMe)Me, CH
2
Cl
2
3
, rt; (b) Me S (O)I ,
o
o
NaH, DMSO, rt; (c) DIBALꢀH, THF, ꢀ78 C; (d) NaBH , MeOH, 0 C to rt; (e)
4
phthalimide, PPh
3
, DEAD, THF, rt; (f) N
2
H
4
•H
2
O, EtOH, reflux.
a
Scheme 3. Synthesis of Target Compounds 16-39
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a
Reagents
and
conditions:
(a)
RNH
2
,
NaBH
4
,
MeOH;
(b)
P,
2ꢀmethoxyꢀNꢀmethylbenzylamine, NaBH
4
, MeOH; (c) 2M HCl/Et
2
O, rt; (d) Ph
3
DEAD, 2ꢀfluoroethanol, THF; (e) ArCH
2
OTs, K
2 3 3
CO , CH CN for 24; ArCHO,
NaBH(OAc)
MeOH.
3
, DCE for 33, 37ꢀ39; ArCHO, NaBH
4
2 2
, MeOH for 36; (f) NaOH, H O ,
a
Scheme 4. Synthesis of Intermediates 24b and 30b for Analogs 24 and 30
a
Reagents and conditions: (a) i. NaBH
4
, MeOH; ii. TsCl, TEA, DCM; (b) i. EtMgBr,
i
o
Ti(O Pr)
4
, Et
2
O, ꢀ78 C; ii. BF
3
•Et
2
O, Et O.
2
a
Scheme 5. Synthesis of Intermediates 34e-35e for Analogs 34-35
a
o
4 2
Reagents and conditions: (a) NBS, AIBN, CCl , 60 C; (b) TrtNH , DCM, rt; (c)
o
o
CH ONa, CH OH, CuBr, 100 C; (d) AcOH, 50 C.
3
3
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Unless otherwise noted, the Nꢀsubstituted derivatives were tested as racemic mixtures.
The Nꢀbenzyl derivatives of (+)-11 and (+)-12, namely 40 and 41, respectively, were
directly prepared from the enantiomers (+)-(S,S)-11 and (+)-(S,S)-12 via reductive
alkylation with 2ꢀmethoxybenzaldehyde, while the pure (–)- and (+)-isomers of 19-21
26-27, and 32 were obtained by preparative HPLC on a chiral stationary phase
Scheme 6). Compounds 40 and 41 were found to show the same sign of optical
rotation as their parent compounds (+)-11 and (+)-12. Moreover, our finding that the
+)-enantiomers of all new Nꢀarylmethyl/thiophenylmethyl compounds are more
,
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(
(
potent than their (–)-enantiomers is consistent with that previously observed for
22ꢀ24
similar scaffolds.
Thus, the absolute configuration of the (+)ꢀenantiomers was
assigned as 1S, 2S and that of the (–)-enantiomers as 1R, 2R.
a
Scheme 6. Preparation of Enantiomers 19-21, 26-27, 32, and 40-41
a
Reagents and conditions: (a) 2ꢀmethoxybenzaldehyde, NaBH , MeOH; (b) chiral
4
2
preparative HPLC separation; (c) 2M HCl/Et O, rt.
In vitro Pharmacology
2
Activity at 5-HT Receptors
Preliminary studies demonstrated that 2ꢀphenylcyclopropylmethylamines with the
phenyl ring bearing 2ꢀalkoxy and 5ꢀfluoro substituents provided excellent 5ꢀHT2C
potency and selectivity over 5ꢀHT2A and 5ꢀHT2B receptors. Moreover, the initial
Nꢀmethylation of 2ꢀ(2ꢀmethoxyphenyl)cyclopropylmethylamine (8) maintained
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potency at 5ꢀHT2C (compound (+)ꢀ15a: EC50 = 23 nM, Emax = 71%, Table 1), which
was not the case with the best ligands 11 and 12 (resulting in compounds (+)ꢀ15b and
(+)ꢀ15c). Further binding studies showed that (+)ꢀ15a had high affinity for 5ꢀHT2C (K
i
= 81 nM, see Supporting Information Table S3). Thus, the parent compound 8 was
taken as a lead to develop Nꢀsubstituted derivatives. Physicochemical properties such
as cLogP and LogBB were calculated to predict bloodꢀbrain barrier (BBB)
permeability.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Substitution with larger alkyl groups, such as cyclopropyl (compound 16) and
cyclopropylmethyl (compound 17), led to decreased potency at 5ꢀHT2C (EC50 > 300
nM; Table 1). However, in view of the lack of activity for the cyclopropylmethyl
derivative 17, it was intriguing that the even bulkier cyclohexylmethyl derivative 18
showed moderate potency (EC = 95 nM) and superior selectivity over 5ꢀHT and
50
2B
5ꢀHT2A, but with extremely low efficacy (Emax = 15%). We therefore saw an
opportunity for the introduction of an aromatic ring (Table 1), which could possibly
engage in a πꢀπ stacking interaction with the receptor.
Furthermore, Nichols et al. have demonstrated that Nꢀ(2ꢀmethoxybenzyl)ꢀsubstituted
28, 29
2
, 5ꢀdimethoxyphenethylamines exhibited enhanced agonism at 5ꢀHT
We therefore first prepared the Nꢀ(2ꢀmethoxybenzyl) analog 19. The compound
+)-19 proved to have high potency at 5ꢀHT2C (EC50 = 24 nM, Emax = 92%) and full
2
receptors.
(
selectivity against 5ꢀHT2B. In addition, it was hypothesized that a hydrogen bond
acceptor (HBA) at the ortho position of the benzyl moiety was beneficial to improve
29
the potency of Nꢀbenzylated 2,5ꢀdimethoxyphenethylamines. Movement of the
oꢀmethoxy group to the meta and para positions as in compounds (+)-20 and (+)-21,
respectively, led to decreased potency (EC50 = 231 nM and 1200 nM). Furthermore,
substituents with different electronic and steric properties acting as HBA groups at the
2
ꢀposition of the benzyl group were investigated. The phenol 22 gave modest activity
at 5ꢀHT2C (EC50 = 304 nM, Emax = 63%) but poor selectivity (0.25ꢀfold) against
5
ꢀHT2A, although it showed full selectivity over 5ꢀHT2B. The slightly bulkier
33
2
ꢀfluoroethyl derivative 23 showed good potency at 5ꢀHT2C (EC50 = 28 nM), but
only 2ꢀfold selectivity against 5ꢀHT2B (EC50 = 56 nM). The cyano and carbamoyl
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2
2
2
2
2
2
2
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3
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3
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4
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4
4
4
4
4
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5
5
5
5
5
5
5
5
5
6
derivatives 24 and 25 displayed attenuated activity (EC50 > 200 nM, Emax < 35%).
Moreover, introduction of other electronꢀwithdrawing substituents (EWG) such as F
(compound (+)-26) and Cl (compound (+)-27) resulted in significant loss of potency
at 5ꢀHT2C (EC50 > 500 nM), which suggested that an EWG attached to the phenyl ring
of the benzyl group was disadvantageous for 5ꢀHT2C activity. Additional
Nꢀmethylation of the benzylamine moiety as in analog 28 resulted in a 15ꢀfold
reduction of 5ꢀHT2C potency (EC50 = 670 nM for the racemate) compared to the
parent compound (+)-19. Additional substitution at the benzylic position of the
0
1
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3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
ꢀmethoxybenzyl moiety with a methyl and ethylene group led to the sterically
hindered analogs 29 and 30, respectively, with predicted increase in BBB penetration
based on the calculated LogBB values. Their potency at 5ꢀHT2C was, however,
reduced. Moreover, homologation of the Nꢀ(2ꢀmethoxybenzyl) moiety as in
compound 31 led to reduced potency at 5ꢀHT2C (EC50 = 615 nM) and increased
potency at 5ꢀHT2B (EC50 = 96 nM).
To explore further structural diversity, Nꢀheteroarylmethyl derivatives with altered
electron densities in the aromatic ring that might result in different pharmacokinetic
properties were investigated as depicted in Table 1. The isosteric thiophene derivative
(
+)-32 showed 120 nM potency at 5ꢀHT2C and full selectivity against 5ꢀHT2B. In line
with the Nꢀbenzyl derivatives above, (+)-32 was more potent at 5ꢀHT2C than its
–)-enantiomer (EC50 = 308 nM). Upon introduction of an additional methoxy group
(
at the 3ꢀposition of the thiophene ring (compound 33), a 2ꢀfold increased potency at
5ꢀHT2C (EC = 121 nM for the racemate) and good selectivity against 5ꢀHT were
50
2B
obtained. The regioisomers 34 and 35 displayed weaker potency at 5ꢀHT2C. In
contrast, the electronꢀdeficient pyridine derivative 36 was less potent at 5ꢀHT2C (EC50
=
433 nM) compared to (+)-32. Moreover, several benzeneꢀfused heterocyclic
derivatives (37-39) with various heteroatoms (N and S) at the 2ꢀposition of the
benzene ring were also investigated. Intriguingly, in contrast with the modest potency
at 5ꢀHT2C of the benzo[b]thiophene derivative 37 (EC50 = 777 nM) and quinoline
derivative 39 (EC50 = 530 nM), the indole derivative 38 was entirely inactive at
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5
ꢀHT2C, which possibly resulted from the absence of a hydrogen bond acceptor at the
ortho position of the aryl ring.
In an effort to discover potent and selective 5ꢀHT2C agonists in a series of
Nꢀsubstituted
2ꢀ(2ꢀmethoxyphenyl)cyclopropylmethylamines,
the
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Nꢀ(2ꢀmethoxybenzyl) derivative (+)-19 has been established as the best ligand in
terms of selectivity for 5ꢀHT2C. Introduction of the Nꢀ(2ꢀmethoxybenzyl) group onto
the previously reported 5ꢀHT2Cꢀselective ligands 11 and 12 also gave very high
5
ꢀHT2C potency (40, EC50 = 9.2 nM, Emax = 97%; 41, EC50 = 2.4 nM, Emax = 93%),
but poor selectivity against 5ꢀHT2B (40, EC50 = 113 nM; 41, EC50 = 24 nM) and
ꢀHT2A (40, EC50 = 28 nM; 41, EC50 = 24 nM). Furthermore, to identify potential
5
offꢀtarget activity, compound (+)-19 was profiled against a panel of serotonin
receptors, dopamine receptors, monoamine transporters, and other selected CNS
targets (see Supporting Information Table S2). Compound (+)-19 showed good
i i
selectivity with much higher binding affinity for 5ꢀHT2C (K = 78 nM) than 5ꢀHT2B (K
=
411 nM) and 5ꢀHT (K = 492 nM). None of the other screened targets were found
2A
i
to display any significant offꢀtarget affinity for compound (+)-19. Taken together,
compound (+)-19 represents a good candidate for further studies in terms of both its
5
ꢀHT2C and selectivity.
Table 1. Functional Activity and Selectivity of Nꢀsubstituted Derivatives 15a-c
a
and 16-41 at 5-HT
2
Receptors in the Calcium Flux Assay
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1
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2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
5
-HT2C
5-HT2B
5-HT2A
1
2
3
Compd.
R
R
R
cLogP
LogBB
pEC50
(EC50, nM)
E
max
pEC50
E
max
pEC50
E
max
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(%)
(EC50, nM)
8.84 ± 0.03
(1.46)
(%)
(EC50, nM)
8.63 ± 0.02
(2.35)
(%)
9
8
7
.78 ± 0.02
serotonin
lorcaserin
(+)ꢀ15a
ꢀ
ꢀ
100 ±0.5
100 ±1.1
100 ±0.7
(
0.17)
.58 ± 0.01
(2.64)
6.36 ± 0.03
(433)
6.61 ± 0.01
(248)
100 ±0.7
71 ± 1.5
15 ± 1.4
NA
80 ± 1.6
54 ± 1.1
NA
68 ± 0.5
79 ± 1.0
19 ± 2.5
NA
.65 ± 0.05
7.05 ± 0.04
(89)
6.57 ± 0.02
(271)
Me
allyl
H
Me
Me
Me
2.07
2.63
2.16
2.42
2.84
4.35
0.26
0.40
0.31
0.37
0.56
1.07
(
23)
7.89 ± 0.25
13)
6.55 ± 0.25
(284)
(+)ꢀ15b
H
H
NA
NA
(
(+)ꢀ15c
2ꢀfluoroethyl
NA
NA
NA
6.10 ± 1.40
6.19 ± 0.52
(641)
5.96 ± 1.22
(1090)
(±)ꢀ16
(±)ꢀ17
(±)ꢀ18
70 ± 0.7
NA
14 ± 0.2
NA
69 ± 0.4
43 ± 0.9
NA
(
399)
5
.37 ± 4.33
NA
NA
NA
(
4260)
7
6
7
5
6
.02 ± 0.25
15 ± 1.8
104 ±2.1
92 ± 1.3
85 ± 6.5
83 ± 2.9
NA
NA
NA
(95)
.99 ± 0.05
(103)
6.24 ± 0.06
(570)
7.15 ± 0.04
(72)
(–)ꢀ19
72 ± 2.3
NA
94 ± 1.4
63 ± 2.1
97 ± 6.8
70 ± 4.2
NA
3
3
3
.86
.86
.86
0.72
0.72
0.72
.63 ± 0.04
6.86 ± 0.07
(139)
(+)ꢀ19
NA
NA
NA
NA
NA
NA
(
23.5)
.58 ± 0.11
(2600)
5.17 ± 0.08
(6840)
(–)-20
NA
.64 ± 0.08
5.43 ± 0.06
(3700)
(+)ꢀ20
NA
(
231)
(–)ꢀ21
Me
H
NA
NA
NA
NA
OMe
5
.92 ± 0.09
1200)
6.52 ± 0.06
304)
.55 ± 0.17
28)
.61 ± 0.11
245)
(+)ꢀ21
71 ± 3.4
63 ± 2.2
16 ± 1.1
30 ± 2.7
31 ± 0.5
90 ± 4.1
78 ± 2.5
NA
NA
(
OH
7.11 ± 0.06
(77)
(±)-22
(±)ꢀ23
(±)ꢀ24
(±)ꢀ25
3.06
3.91
3.30
2.24
0.90
0.79
0.81
0.16
NA
76 ± 2.0
80 ± 1.2
63 ± 2.3
67 ± 0.8
78 ± 2.9
63 ± 3.0
(
7
6
6
5
6
7.25 ± 0.15
(56)
6.40 ± 0.03
(398)
11 ± 0.7
82 ± 1.7
82 ± 0.8
NA
(
CN
6.62 ± 0.04
(238)
6.14 ± 0.06
(721)
(
.39 ± 0.25
(409)
6.48 ± 0.30
(335)
5.88 ± 0.02
(1310)
.79 ± 0.07
5.73 ± 0.06
(1880)
(–)ꢀ26
NA
NA
(
1640)
.30 ± 0.06
502)
3
.82
0.80
5.73 ± 0.07
(1880)
(+)ꢀ26
NA
(
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5.73 ± 0.1
72 ± 4.4
5.53 ± 0.06
(2990)
(
–)ꢀ27
NA
NA
NA
NA
NA
NA
NA
84 ± 3.9
64 ± 3.5
24 ± 1.4
106 ±2.9
102 ±2.9
59 ± 1.8
59 ± 1.6
34 ± 1.5
102 ±2.7
89 ± 1.5
100 1.5
66 ± 2.9
70 ± 2.8
NA
Cl
(
1860)
.28 ± 0.06
529)
.17 ± 0.10
670)
4.57
0.90
6
6
5
6
5.45 ± 0.07
(3530)
(+)ꢀ27
94 ± 2.7
49 ± 2.6
81 ± 2.6
77 ± 2.2
51 ± 3.1
81 ± 1.5
60 ± 1.7
66 ± 1.8
65 ± 1.0
65 ± 1..3
65 ± 2.5
94 ± 3.0
NA
(
OMe
OMe
5.60 ± 0.08
(2540)
(±)ꢀ28
(±)ꢀ29
(±)ꢀ30
(±)ꢀ31
Me
Me
4.17
4.12
4.07
4.06
0.94
0.83
1.07
0.78
NA
(
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
.59 ± 0.05
(2550)
6.62 ± 0.06
(238)
NA
.06 ± 0.05
6.18 ± 0.05
(655)
NA
(874)
6
.21 ± 0.1
(615)
7.02 ± 0.14
(96)
6.51 ± 0.06
(307)
17 ± 1.1
NA
6
.51 ± 0.03
6.17 ± 0.04
(674)
(–)ꢀ32
NA
NA
NA
NA
NA
(
308)
6.92 ± 0.06
120)
.92 ± 0.06
121)
6.64 ± 0.03
228)
.26 ± 0.04
556)
6.36 ± 0.07
433)
3
.31
0.66
6.36 ± 0.08
(438)
(+)ꢀ32
NA
(
6
6.83 ± 0.06
(148)
(±)ꢀ33
3.30
3.30
3.30
2.83
5.00
3.81
3.75
4.48
3.91
0.68
0.68
0.68
0.44
0.94
0.55
0.31
0.91
0.79
NA
(
Me
H
6.84 ± 0.04
(145)
(±)ꢀ34
(±)ꢀ35
(±)ꢀ36
(±)ꢀ37
(±)ꢀ38
(±)ꢀ39
NA
(
6
6.33 ± 0.03
(463)
NA
(
6.56 ± 0.20
(274)
5.89 ± 0.06
(1290)
32 ± 3.3
79 ± 1.7
NA
(
6
.11 ± 0.06
(777)
6.09 ± 0.04
(807)
5.65 ± 0.06
(2220)
HN
NA
NA
NA
6
8
.28 ± 0.07
(530)
7.06 ± 0.04
(87)
6.34 ± 0.03
(460)
84 ± 3.1
97 ± 1.3
93 ± 1.1
73 ± 1.4
28 ± 2.2
22 ± 2.0
69 ± 1.3
80 ± 1.7
78 ± 1.1
OMe
OMe
.05 ± 0.04
6.95 ± 0.17
(113)
7.56 ± 0.05
(28)
(+)ꢀ40
allyl
H
H
(
9.2)
8.65 ± 0.03
2.4)
7.61 ± 0.22
(24)
7.62 ± 0.03
(24)
(+)ꢀ41
2ꢀfluoroethyl
(
a
All new compounds were tested as HCl salts except compound 36, which was tested as the free
base. Pharmacological data were acquired with recombinant, stably expressed human 5ꢀHT
receptors in the HEKꢀ293 cell line, using a fluorescence imaging plate reader (FLIPR) assay.
pEC50 and Emax values are shown as the mean ± SEM (n = 3). EC50 values were calculated from
averaged pEC50 values
.
“NA” indicates no activity up to 10 ꢁM. “−” indicates structures of 5ꢀHT
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1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
and lorcaserin are not shown. cLogP and LogBB values were calculated for the free bases using
the ACD Percepta program.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
5
-HT2C Functional Selectivity
Recently, we have discovered benzofuranꢀbased compounds as functionally selective
21
5ꢀHT2C agonists with weak βꢀarrestin recruitment activities. However, no fully
biased 5ꢀHT2C agonist has been disclosed to date. The functional selectivity of the
above 5ꢀHT ꢀselective Nꢀsubstituted 2ꢀphenylcyclopropylmethylamines was
2
C
investigated and compared to lorcaserin and 5ꢀHT. βꢀArrestin recruitment activity was
21, 34
tested using reported methods
q
in parallel with a G ꢀmediated calcium flux assay
using the same drug dilutions. The relative activities (log Emax/EC ) were calculated
50
to account for partial agonist differences. As shown in Table 2 and Figure 3,
compounds (+)ꢀ15a and (+)ꢀ32 showed no βꢀarrestin recruitment activity, which
q
indicates that these compounds exclusively signal via G ꢀmediated calcium flux. The
Nꢀ(2ꢀmethoxybenzyl) derivative (–)-19 also displayed preference for G
q
ꢀmediated
calcium flux with weak potency (> 1 µM) for βꢀarrestin recruitment activity, whereas
its (+)-enantiomer showed stronger potency for βꢀarrestin recruitment (EC50 = 70 nM)
albeit with much reduced efficacy (Emax = 43%) compared to the reference ligand,
lorcaserin (EC50 = 40 nM, Emax = 97%). The Nꢀ(2ꢀmethoxybenzyl) derivatives of 11
q
and 12, namely (+)-40 and (+)-41, respectively, had a preference for G signaling
driven mainly by their weaker βꢀarrestin recruitment efficacy (Emax = 56 and 54%,
respectively) compared to lorcaserin (Emax = 97%).
a
Table 2. Functional Selectivity for 5-HT -Selective Agonists
2C
G
q
calcium flux
Emax
β-arrestin-2
Emax
Compd.
pEC50
Log(Emax
pEC50
( EC50, nM)
7.82 ± 0.03
(15)
Log(Emax
(
EC50, nM)
(%)
/ EC50
)
(%)
/ EC50)
9.74 ± 0.02
0.18)
.68 ± 0.04
2.1)
5
-HT
100 ± 0.9
101 ± 1.4
9.85
100 ± 1.0
97 ± 2.1
7.82
(
8
7.40 ± 0.05
(40)
Lorcaserin
8.68
7.38
(
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7.64 ± 0.05
23)
(
+)-15a
+)-19
71 ± 1.4
92 ± 1.3
104 ± 2.1
60 ± 0.7
97 ± 1.3
93 ± 1.1
7.49
7.58
7.00
6.70
8.02
8.59
NA
NA
43 ± 0.9
ND
ꢀ
(
7
6
6
8
.62 ± 0.04
(24)
7.16 ± 0.04
(70)
(
6.79
.99 ± 0.05
(
–)-19
> 1,000
NA
ꢀ
(103)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
.92 ± 0.06
(120)
(
+)-32
NA
ꢀ
7.39
.04 ± 0.04
7.64 ± 0.05
(22.7)
(+)-40
+)-41
56 ± 1.0
54 ± 1.0
(
9.2)
8.62 ± 0.03
2.4)
7.96 ± 0.05
(11)
(
7.69
(
a
Data were acquired with the human 5ꢀHT2CꢀINI receptor isoform measuring G
q
calcium flux
(
FLIPR) and βꢀarrestinꢀ2 recruitment (Tango). Emax values are shown as the mean ± SEM (n =
3), and assays were conducted in parallel with the same drug dilutions. “NA” indicates no
activity up to 10 ꢁM. “ND” indicates not determined because of no saturable Emax
.
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Figure 3. Profiling of 5ꢀHT2C functional selectivity measuring G ꢀcalcium flux (FLIPR, red) and
q
βꢀarrestinꢀ2 recruitment (Tango, blue). Data were acquired with the human 5ꢀHT2CꢀINI receptor
isoform. Emax values are shown as the mean (n = 3), and assays were conducted in parallel with the
same drug dilutions.
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Evaluation in Animal Models of Antipsychotic Drug-like Activity.
In vitro pharmacology profiles identified the Nꢀ(2ꢀmethoxybenzyl) compound (+)-19
as the most potent 5ꢀHT2C agonist (EC50 = 24 nM, Emax = 92%) with full selectivity
over 5ꢀHT2B in the present series of compounds. As the absence of 5ꢀHT2B agonism is
necessary to avoid potential cardiovascular side effects, compound (+)-19 was
selected for further in vivo studies in the amphetamine (AMPH)ꢀinduced and
phencyclidine (PCP)ꢀinduced hyperactivity models (details of the behavioral studies
are provided in the Experimental Section), which are both wellꢀrecognized models to
evaluate the possible antipsychotic activities of compounds.
Amphetamine (AMPH)ꢀinduced Hyperactivity Model. In this model, adult male
C57BL/6J mice were administered saline (vehicle), lorcaserin (as the positive control,
3
mg/kg), or the test compound (+)-19 (10 and 20 mg/kg), and locomotor activity was
monitored for 15 min (baseline). As shown in Figure 4A, lorcaserin decreased
baseline locomotion while the compound (+)-19 (10 and 20 mg/kg) had no effect.
Next the mice were given saline or amphetamine (3 mg/kg), and activity was
measured for an additional 90 min. The results showed that lorcaserin reduced
35, 36
amphetamineꢀinduced hyperactivity consistent with other 5ꢀHT2C agonists,
whereas responses to 10 and 20 mg/kg of (+)-19 were differentiated by dose (Figure
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A and 4B). Although the low dose (10 mg/kg) of (+)-19 had no significant effect, the
higher dose (20 mg/kg) decreased the hyperlocomotion such that its effects were
similar to those of lorcaserin. Thus, compound (+)-19 (20 mg/kg) showed an
antipsychotic action by blocking amphetamineꢀinduced hyperactivity with no effect
on spontaneous motor activity.
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Phencyclidine
(PCP)ꢀinduced
hyperactivity
model.
In
contrast
to
amphetamineꢀinduced hyperactivity, lorcaserin showed a tendency to suppress
PCPꢀinduced hyperactivity at the beginning of the test session, but there was no
overall reduction in activity that was statistically significant. While the low dose (10
mg/kg) of (+)ꢀ19 increased locomotion, the higher dose (20 mg/kg) had no effect on
PCPꢀinduced hyperlocomotion (Figure 4C and 4D). In general, it has been
37, 38
demonstrated that 5ꢀHT2C agonists decrease PCPꢀinduced hyperactivity.
The
locomotion enhancement observed with the lower dose of (+)ꢀ19 could result from
other offꢀtarget effects on PCP. For example, from our in vitro ADMET results (Table
3), (+)ꢀ19 exhibits strong inhibition (85.6%, Table 3) of human cytochrome P450
39
(CYP) 3A4 (in the mouse mainly its highly homologous 3A11) which is the same
40
enzyme that has been reported to metabolize PCP. Alternatively, the 5ꢀHT2A
agonism of (+)ꢀ19 (EC50 = 139 nM, Emax = 63%, Table 1) might also explain its effect
on PCPꢀinduced locomotor activity. The 5ꢀHT2A/2C agonist DOI (5ꢀHT , EC = 57
2A
50
41
nM, Emax = 46%; 5ꢀHT2C, EC50 = 178 nM, Emax = 90%) has been shown to
4
2
potentiate the locomotor effects of PCP. These results indicate that (+)ꢀ19 at doses
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of either 10 or 20 mg/kg does not possess an antipsychoticꢀlike profile in the
PCPꢀinduced locomotion model.
In summary, (+)ꢀ19 has superiority over lorcaserin based on its behavioral profile in
decreasing amphetamineꢀinduced hyperactivity without having an effect on
spontaneous activity. Further studies are required to determine the precise mechanism
of the enhancement of PCP using the lower dose (+)ꢀ19.
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Figure 4. Evaluation of compound (+)-19 in animal models of antipsychotic drugꢀlike activity. (A)
Locomotor activity reflecting baseline responses (0ꢀ15 min) and AMPHꢀinduced hyperactivity
with reductions by lorcaserin and (+)ꢀ19 (20ꢀ105 min). (B) Cumulative baseline locomotor
activities (0ꢀ15 min), AMPHꢀinduced hyperactivities, and reductions by lorcaserin and (+)ꢀ19
(20ꢀ105 min); ^ p < 0.05, compared to SalꢀSal group, baseline; * p < 0.05 compared to SalꢀAMPH,
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PostꢀAMPH. (C) Locomotor activity reflecting baseline responses (0ꢀ15 min) and PCPꢀinduced
hyperactivity with effects by lorcaserin and (+)ꢀ19 (20ꢀ75 min). (B) Cumulative baseline
locomotor activities (0ꢀ15 min), PCPꢀinduced hyperactivities, and effects by lorcaserin and (+)ꢀ19
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(
20ꢀ75 min); ^ p < 0.05, compared to SalꢀSal group, baseline; * p < 0.05 compared to SalꢀPCP,
PostꢀPCP. N = 8ꢀ10 mice/group.
ADMET Studies (In vitro).
Due to its efficacy in the amphetamineꢀinduced hyperactivity model, compound
(
+)-19 was evaluated for selected in vitro ADMET properties (Table 3) to qualify it as
a possible candidate for further development. Compared with the structurally similar
parent 2ꢀ(5ꢀchlorophenyl)cyclopropylmethylamines (+)-9 and (+)-10 previously
reported by us, the Nꢀbenzylated derivative (+)-19 displayed higher human plasma
2
3
protein binding (82%, (+)-19; 75%, (+)-9; 57%, (+)-10) as a result of its enhanced
lipophilicity, as the cLogP is a highly correlated indicator that determines protein
binding properties. In the recombinant CYP inhibition assay, (+)-19 showed low
inhibition of CYP 1A2 and CYP 2C9, and relatively higher inhibition of CYP 2D6
and CYP 3A4 at 10 ꢁM (> 50%). Compound (+)-19 was found to have a halfꢀlife of
4
3 min in the human hepatocyte stability assay, which may be a consequence of the
4
3
presence of the electronꢀrich Nꢀbenzyl group. Moreover, moderate hERG inhibition
IC50 = 1.4 ꢁM) was detected.
Table 3. In Vitro ADMET Data for Compound (+)-19
(
Assay
(+)-19
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PPB at 10 ꢁM (%)
human
mouse
1A2
82.0
92.0
20.5
9.3
a
CYP inhibition at 10 ꢁM (%)
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C9
2D6
A4
68.9
85.6
43.0
7.8
3
b
T
1/2 (min)
human
mouse
c
hERG IC (ꢁM)
1.4
5
0
a
The CYP inhibition test was performed using human liver microsomes.
Phenacetin, tolbutamide, dextromethorphan, and midazolam were used as test
b
substrates for the 1A2, 2C9, 2D6, and 3A4 isoforms, respectively. The
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concentration of hepatocytes was 0.5 × 10 cells/mL, and (+)-19 was tested at 1
c
ꢁ
M. hERG inhibition was tested on CHO cells using the automated
patchꢀclamp method.
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Conclusions
New Nꢀsubstituted 2ꢀphenylcyclopropylmethylamines have been characterized as
reasonably selective 5ꢀHT2C receptor agonists with novel patterns of functional
selectivity. The Nꢀmethyl compound (+)ꢀ15a, which displayed an EC50 of 23 nM at
10
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5
ꢀHT2C with no βꢀarrestin recruitment activity, is the first potent and at the same time
fully G ꢀbiased 5ꢀHT2C agonist reported to date, while the Nꢀbenzyl compound (+)ꢀ19
q
with an EC50 of 24 nM at 5ꢀHT2C is fully selective over 5ꢀHT2B. The potency and lack
of detectable arrestin recruitment of (+)ꢀ15a make it a valuable chemical probe to
better understand biased 5ꢀHT2C signaling. Moreover, although (+)ꢀ19 had a relatively
short halfꢀlife in the hepatocyte stability assay, preliminary in vivo studies in an
amphetamineꢀinduced hyperactivity model indicate that (+)ꢀ19 shows potential
antipsychotic effects. Further compound optimization to develop better drugꢀlike
analogs is in progress.
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EXPERIMENTAL SECTION
General. All chemicals and solvents were purchased from SigmaꢀAldrich or Fisher
Scientific, and were used as obtained without further purification. Microwave
reactions were run in a Biotage Initiator microwave reactor. Synthetic intermediates
0
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9
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f
were purified on 230−400 mesh silica gel using a Teledyne CombiFlash R flash
1
13
chromatograph. H and C NMR spectra were recorded on Bruker DPXꢀ400 or
AVANCEꢀ400 spectrometers at 400 MHz and 100 MHz, respectively. NMR chemical
shifts are reported in δ (ppm) using residual solvent peaks as standards (CDCl
3
–7.26
(
H), 77.16 (C); CD OD–3.31 (H), 49.00 (C)). Mass spectra were measured using an
3
LCMSꢀITꢀTOF (Shimadzu) mass spectrometer in ESI mode. Preparative HPLC
purification of synthetic intermediates was performed on a Shimadzu LCꢀ8A
instrument with an ACE 5AQ column (150 × 21.2 mm, particle size 5 ꢁm; eluent: 8 –
2
100% MeOH (0.05% TFA)/ H O (0.05% TFA) gradient, 30 min; flow rate: 17
mL/min; UV detection at 254 and 280 nm). Chiral separation of racemic
intermediates was conducted by preparative HPLC on RegisPack (25 cm × 21.1 mm,
particle size 10 ꢁm) or ChromegaChiral CCJ (25 cm × 20 mm, particle size 10 ꢁm)
chiral columns with isopropanol (0.05% diethylamine, DEA)/ nꢀhexane (0.05% DEA)
as the eluent. The purity of all final compounds (greater than 95% in all cases) was
determined by analytical HPLC on an ACE 3AQ C column (150 × 4.6 mm, particle
18
2
size 3 ꢁm; eluent: MeOH (0.05% TFA)/ H O (0.05% TFA) gradient, 25 min; flow
rate: 1.0 mL/min). Specific rotations were recorded on a Rudolph Research Autopol
IV automatic polarimeter.
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The synthetic procedures, chiral separation methods, and characterization data of all
intermediates can be found in the Supporting Information. All intermediates subjected
to chiral preparative HPLC separation were prepared with an optical purity of > 90%
ee (determined by analytical HPLC using a RegisPack (25 cm × 4.6 mm, 10 ꢁm) or
ChromegaChiral CCJ (25 cm × 4.6 mm, 10 ꢁm) chiral column and isopropanol
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19
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(0.05% DEA)/ nꢀhexane (0.05% DEA) as the eluent).
General Method A: Preparation of HCl Salts 15a-c. The NꢀBocꢀamines 14a-c were
dissolved in 2M HCl (g) in diethyl ether (5 equiv.) and stirred at room temperature for
2
4ꢀ48 h. The white solids formed were collected by filtration, washed with diethyl
ether, and dried under vacuum to give the HCl salts as white solids.
General Method B: Preparation of HCl Salts 16-22, 26-32, and 34-35 from the
Intermediate Aldehyde D. The aldehyde D was prepared according to the reported
24
procedure. Aldehyde D (1.0 equiv.) and amines (1.2 equiv.) were reacted under
reductive amination condition (NaBH (1.5 equiv.)/MeOH). The reaction mixtures
4
were quenched with water and extracted with DCM. The organic phases were washed
with brine, dried over sodium sulfate, concentrated, and purified by preparative HPLC
3
to give the trifluoroacetate salts. The salts were neutralized with aq. NaHCO , and the
resulting solutions were extracted with DCM. The organic layers were dried over
sodium sulfate and concentrated to provide the desired compounds as free bases. For
1
9-21, 26-27, and 32, the obtained racemic free bases were separated by chiral
preparative HPLC to afford their enantiomers (see Supporting Information). The
racemic or enantiopure free bases were dissolved in 2M HCl (g) in diethyl ether (3
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equiv.) and stirred at room temperature for 1ꢀ2 h. The white solids formed were
collected by filtration, washed with diethyl ether, and dried under vacuum to give the
HCl salts as white solids in high yields (80ꢀ95%).
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General Method C: Preparation of HCl Salts 24-25, 33, and 36-39 from the
Intermediate Cyclopropylmethylamine G. The cyclopropylmethylamine G was
24
prepared according to the reported procedure. The listed compounds were prepared
from the cyclopropylmethylamine G (1.0 equiv.) and ArCHO (1.0 equiv.) or
2 4
ArCH OTs (1.0 equiv.) via reductive amination (NaBH (1.5 equiv.)/MeOH or
NaBH(OAc) (2.0 equiv.)/DCE) or nucleophile substitution reactions (base/CH CN),
3
3
respectively. The crude products were purified by preparative LC and reacted with
M HCl/Et O to afford the HCl salts as white solids according to the similar
2
2
procedure described in General Method B.
(+)-1-[(1S,2S)-2-(5-Fluoro-2-methoxyphenyl)cyclopropyl]-Nꢀmethylmethanamine
Hydrochloride (15a). Obtained from the intermediate 14a (56 mg, 0.18 mmol)
1
employing General Method A (40 mg, 90% yield). H NMR (CDCl
3
) δ 9.61 (s, 2H),
6
3
3
.88 – 6.82 (m, 1H), 6.76 (dd, J = 9.0, 4.6 Hz, 1H), 6.66 (dd, J = 9.3, 3.0 Hz, 1H),
.85 (s, 3H), 3.10 (dd, J = 13.1, 7.1 Hz, 1H), 3.02 (dd, J = 13.0, 7.6 Hz, 1H), 2.75 (s,
1
3
H), 2.25 – 2.07 (m, 1H), 1.52 – 1.37 (m, 1H), 1.21 – 1.09 (m, 2H); C NMR
(CDCl
3
) δ 157.2 (d, J = 238.2 Hz), 154.5 (s), 130.6 (d, J = 7.4 Hz), 113.3 (d, J = 23.9
Hz), 113.1 (d, J = 22.5 Hz), 111.2 (d, J = 8.5 Hz), 56.2 (s), 52.9 (s), 32.1 (s), 17.8 (s),
+
1
6.9 (s), 13.0 (s); HRMS (ESI) calculated for C H FNO ([M+H] ), 210.1289; found,
12
17
20
D
2
10.1269. [α]
3
+18.0 (c 0.1, CHCl ).
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(
+)-1-[(1S,2S)-2-[2-(Allyloxy)-5-fluorophenyl]cyclopropyl]-Nꢀmethylmethanamin
e Hydrochloride (15b). Obtained from the intermediate 14b (188 mg, 0.56 mmol)
1
employing General Method A (140 mg, 93% yield). H NMR (CDCl
3
) δ 9.62 (s, 2H),
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
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6
1
1
2
.82 (td, J = 8.4, 3.0 Hz, 1H), 6.75 (dd, J = 8.9, 4.6 Hz, 1H), 6.65 (dd, J = 9.3, 3.0 Hz,
H), 6.14 – 6.02 (m, 1H), 5.41 (dd, J = 17.2, 1.4 Hz, 1H), 5.30 (dd, J = 10.5, 1.4 Hz,
H), 4.54 (d, J = 5.3 Hz, 2H), 3.21 – 3.06 (m, 1H), 3.05 – 2.92 (m, 1H), 2.73 (s, 3H),
13
3
.25 – 2.17 (m, 1H), 1.53 – 1.41 (m, 1H), 1.15 (t, J = 7.1 Hz, 2H); C NMR (CDCl )
δ 157.3 (d, J = 238.7 Hz), 153.4 (s), 133.4 (s), 131.0 (d, J = 7.3 Hz), 118.0 (s), 113.2
(d, J = 23.8 Hz), 113.1 (d, J = 22.6 Hz), 112.7 (d, J = 8.4 Hz), 69.9 (s), 52.8 (s), 32.2
+
(s), 17.9 (s), 17.0 (s), 13.0 (s); HRMS (ESI) calculated for C14
H
19FNO ([M+H] ),
2
D
0
236.1445; found, 236.1408. [α]
3
+20.3 (c 0.1, CHCl ).
(+)-1-[(1S,2S)-2-[5-Fluoro-2-(2-fluoroethoxy)phenyl]cyclopropyl]-Nꢀmethylmeth
anamine Hydrochloride (15c). Obtained from the intermediate 14c (70 mg, 0.20
1
mmol) employing General Method A (52 mg, 95% yield). H NMR (CDCl ) δ 9.53 (s,
3
2
H), 6.86 (td, J = 8.5, 2.7 Hz, 1H), 6.77 (dd, J = 8.9, 4.5 Hz, 1H), 6.68 (dd, J = 9.2,
2.8 Hz, 1H), 5.02 – 4.68 (m, 2H), 4.36 – 4.12 (m, 2H), 3.19 – 2.99 (m, 2H), 2.74 (s,
1
3
3
H), 2.29 – 2.17 (m, 1H), 1.52 – 1.36 (m, 1H), 1.26 – 1.07 (m, 2H); C NMR
(CDCl ) δ 157.7 (d, J = 239.6 Hz), 153.3 (s), 131.4 (d, J = 7.4 Hz), 113.7 (d, J = 23.8
Hz), 113.3 (d, J = 22.9 Hz), 112.8 (d, J = 8.5 Hz), 82.4 (d, J = 169.9 Hz), 68.5 (d, J =
9.4 Hz), 53.0 (s), 32.5 (s), 17.8 (s), 17.3 (s), 12.8 (s). HRMS (ESI) calculated for
3
1
+
20
D
C H F NO ([M+H] ), 242.1351; found, 242.1328. [α] +8.2 (c 0.1, CHCl3).
13
18
2
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Nꢀ[[2-(5-Fluoro-2-methoxyphenyl)cyclopropyl]methyl]cyclopropanamine
1
Hydrochloride (16). Prepared from cyclopropanamine employing Method B. H
NMR (CDCl ) δ 9.72 (s, 2H), 6.87 – 6.80 (m, 1H), 6.75 (dd, J = 8.9, 4.6 Hz, 1H), 6.63
dd, J = 9.3, 3.0 Hz, 1H), 3.83 (s, 3H), 3.20 (dd, J = 13.0, 6.9 Hz, 1H), 3.03 (dd, J =
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
1
–
1
3.0, 7.8 Hz, 1H), 2.78 – 2.66 (m, 1H), 2.28 – 2.15 (m, 1H), 1.59 – 1.46 (m, 1H), 1.36
13
1.07 (m, 4H), 0.91 – 0.75 (m, 2H); C NMR (CDCl
3
) δ 157.2 (d, J = 238.2 Hz),
54.4 (s), 130.9 (d, J = 7.3 Hz), 113.0 (d, J = 24.8 Hz), 112.9 (d, J = 21.2 Hz), 111.1
(d, J = 8.4 Hz), 56.1 (s), 52.2 (s), 29.5 (s), 17.8 (s), 17.0 (s), 13.5 (s), 4.1 (s), 3.8 (s);
+
HRMS (ESI) calculated for C H FNO ([M+H] ), 236.1445; found, 236.1405.
14 19
1-Cyclopropyl-Nꢀ[[2-(5-fluoro-2-methoxyphenyl)cyclopropyl]methyl]methanami
ne Hydrochloride (17). Prepared from cyclopropylmethanamine employing Method
1
B. H NMR (CDCl
3
) δ 9.65 (s, 2H), 6.84 (td, J = 8.5, 2.9 Hz, 1H), 6.75 (dd, J = 8.9,
4
.5 Hz, 1H), 6.62 (dd, J = 9.3, 2.9 Hz, 1H), 3.84 (s, 3H), 3.26 – 3.01 (m, 2H), 3.00 –
2.88 (m, 2H), 2.23 – 2.09 (m, 1H), 1.56 – 1.40 (m, 1H), 1.39 – 1.22 (m, 1H), 1.19 –
13
1
.07 (m, 2H), 0.76 – 0.64 (m, 2H), 0.55 – 0.40 (m, 2H); C NMR (CDCl
3
) δ 157.3 (d,
J = 238.3 Hz), 154.4 (s), 130.8 (d, J = 7.4 Hz), 113.1 (d, J = 24.0 Hz), 113.0 (d, J =
2
4.4 Hz), 111.2 (d, J = 8.4 Hz), 56.2 (s), 51.3 (s), 50.7 (s), 17.8 (s), 17.2 (s), 13.2 (s),
+
7.2 (s), 4.9 (s), 4.7 (s); HRMS (ESI) calculated for C15
found, 250.1545.
H
21FNO ([M+H] ), 250.1602;
1
-Cyclohexyl-Nꢀ[[2-(5-fluoro-2-methoxyphenyl)cyclopropyl]methyl]methanamin
e Hydrochloride (18). Prepared from cyclohexylmethylamine employing Method B.
1
H NMR (CDCl
3
) δ 9.52 (s, 1H), 9.43 (s, 1H), 6.88 – 6.80 (m, 1H), 6.76 (dd, J = 9.0,
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Journal of Medicinal Chemistry
1
2
3
4
5
6
7
8
9
4
2
1
.6 Hz, 1H), 6.59 (dd, J = 9.3, 3.0 Hz, 1H), 3.83 (s, 3H), 3.17 – 3.03 (m, 2H), 2.98 –
.81 (m, 2H), 2.22 – 2.11 (m, 1H), 2.04 – 1.85 (m, 3H), 1.81 – 1.62 (m, 3H), 1.50 –
13
3
.38 (m, 1H), 1.36 – 1.09 (m, 5H), 1.08 – 0.94 (m, 2H); C NMR (CDCl ) δ 157.3 (d,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
J = 238.3 Hz), 154.3 (s), 130.8 (d, J = 7.3 Hz), 113.0 (d, J = 22.8 Hz), 112.8 (d, J =
2
3.8 Hz), 111.1 (d, J = 8.4 Hz), 56.2 (s), 52.5 (s), 51. 6 (s), 34.8 (s), 31.1 (s), 31.0 (s),
2
6.0 (s), 25.5 (s), 25.4 (s), 17.8 (s), 17.3 (s), 13.0 (s); HRMS (ESI) calculated for
+
C
18
H
27FNO ([M+H] ), 292.2071; found, 292.2073.
(+)-1-[(1S,2S)-2-(5-Fluoro-2-methoxyphenyl)cyclopropyl]-Nꢀ(2-methoxybenzyl)m
ethanamine Hydrochloride ((+)-19). Prepared from 2ꢀmethoxybenzylamine
1
employing Method B including chiral separation. H NMR (CDCl
3
) δ 10.02 (s, 1H),
9
.15 (s, 1H), 7.48 (d, J = 6.7 Hz, 1H), 7.33 (t, J = 7.8 Hz, 1H), 6.95 (t, J = 7.4 Hz,
1H), 6.88 (d, J = 8.3 Hz, 1H), 6.81 (td, J = 8.6, 2.9 Hz, 1H), 6.72 (dd, J = 8.9, 4.5 Hz,
1
H), 6.59 (dd, J = 9.2, 2.9 Hz, 1H), 4.19 (m, 2H), 3.84 (s, 3H), 3.78 (s, 3H), 3.08 –
1
3
2.72 (m, 2H), 1.99 – 1.83 (m, 1H), 1.47 – 1.37 (m, 1H), 1.09 – 0.88 (m, 1H);
C
3
NMR (CDCl ) δ 157.9 (s), 157.2 (d, J = 238.3 Hz), 154.4 (d, J = 2.0 Hz), 132.2 (s),
131.2 (s), 130.7 (d, J = 7.4 Hz), 121.2 (s), 119.0 (s), 113.5 (d, J = 23.8 Hz), 113.1 (d,
J = 22.7 Hz), 111.1 (d, J = 8.4 Hz), 110.7 (s), 56.2 (s), 55.7 (s), 50.3 (s), 45.8 (s), 17.9
+
(s), 17.3 (s), 13.2 (s); HRMS (ESI) calculated for C19
H23FNO
2
([M+H] ), 316.1707;
20
found, 316.1703; [α]D +34.0 (c 0.6, CHCl3).
(–)-1-[(1R,2R)-2-(5-Fluoro-2-methoxyphenyl)cyclopropyl]-Nꢀ(2-methoxybenzyl)
methanamine Hydrochloride ((–)-19). Prepared from 2ꢀmethoxybenzylamine
1
employing General Method B including chiral separation. H NMR (CDCl
3
) δ 10.02
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