Synthesis and biological activity of allosteric modulators of GABA B receptors, Part 1. N-(Phenylpropyl)-1-arylethylamines

Article abstract of DOI:10.1071/CH06163

A series of 15 analogues of fendiline, and 34 derivatives of N-(3-phenylpropyl)-1-arylethylamine have been prepared for evaluation as positive allosteric modulators of GABA_B receptors. The most active (EC₅₀, 10 nM) was N-(3,3-diphenylpropyl)-1-(3-chloro-4-methoxyphenyl) ethylamine 6g. CSIRO 2006.

Full text of DOI:10.1071/CH06163

Full Paper
CSIRO PUBLISHING
www.publish.csiro.au/journals/ajc
Aust. J. Chem. 2006, 59, 445–456
Synthesis and Biological Activity of Allosteric Modulators of GABAB
Receptors, Part 1. N-(Phenylpropyl)-1-arylethylamines∗
David I. B. Kerr,A,C Jennifer Ong,A Michael V. Perkins,B Rolf H. Prager,B,D
and Ni Made PuspawatiB
A Department of Anaesthesia and Intensive Care, University of Adelaide, Adelaide SA 5005, Australia.
B School of Chemistry, Physics and Earth Sciences, Flinders University, Adelaide SA 5001, Australia.
C Deceased, July 2005.
D Corresponding author. Email: rolf.prager@flinders.edu.au
A series of 15 analogues of fendiline, and 34 derivatives of N-(3-phenylpropyl)-1-arylethylamine have been prepared
for evaluation as positive allosteric modulators of GABAB receptors. The most active (EC50, 10 nM) was N-(3,3-
diphenylpropyl)-1-(3-chloro-4-methoxyphenyl)ethylamine 6g.
Manuscript received: 15 May 2006.
Final version: 5 July 2006.
Cl
Introduction
The flow of information along nerve fibres requires trans-
mission of the signals across the synapse to the adjacent
cell.[1] γ-Aminobutyric acid (GABA, 1, Fig. 1) is one
of the major inhibitory neurotransmitters which regulates
synaptic transmission and neuronal excitability in the mam-
malian central and peripheral nervous system.[2–4] Defects in
GABA-ergic transmission can cause a variety of neurologi-
cal and psychiatric diseases such as spasticity,[5] epilepsy,[6]
and Huntington’s[7] and Parkinson’s[8] diseases. GABAB
receptors are also implicated in drug addiction related to
alcohol[9,10] and cocaine.[11]
CO2H
H2N
H2N
CO2H
1
2
Fig. 1.
H
N
H
N
MeO
3
4
GABA has been implicated in the regulation of many
physiological processes and it activates three pharmacolog-
ically distinct classes of receptors, GABAA, GABAB, and
GABAC.[12] GABAA and GABAB receptors can be further
sub-divided into three categories, presynaptic, postsynaptic,
and autoreceptors.[12,13] The GABAB receptor was originally
defined on the basis that it is sensitive to the agonist baclofen
2 and insensitive to the antagonist bicuculline.[14–16]
GABAB receptors are coupled to G-proteins, which when
activated induce either a decrease in calcium (Ca2+) influx or
an increase in potassium (K+) membrane conductance, the
latter leading to inhibitory postsynaptic potentials mediat-
ing membrane hyperpolarizations.[17] Metabotropic GABAB
receptors belong to Family 3 of G-protein-coupled recep-
tors (GPCRs), which show extensive similarities in sequence
structure to metabotropic glutamate receptors (mGluRs),
extracellular Ca2+ sensing receptors (CaSRs), and some
pheromone as well as taste receptors.[18,19] They all possess
Fig. 2.
a molecular structure that is characterized by its seven
transmembrane-spanning domain and a large extracellular
N-terminal ligand binding domain, which contains a so-
called ‘Venus flytrap’ ligand-binding site.[20]
Allosteric (other shape) modulation of GPCR function is
now well recognized as an important feature of their phar-
macology, particularly among receptors of Family 1 and
Family 3.[21] Such compounds, unrelated in structure to the
orthosteric ligand, have been found most often by screening
techniques, and embrace negative and positive modulators
of receptor function. At the molecular level, allosteric lig-
ands are considered to combine at a site on the receptor
molecule, other than that occupied by the true orthosteric
ligand, and often may induce an alteration of the recep-
tor’s molecular structure in such a way as to change the
∗Part 2: D. I. B. Kerr, J. Khalafy, J. Ong, M. V. Perkins, R. H. Prager, N. M. Puspawati, M. Rimaz, Aust. J. Chem. 2006, 59, 457. doi: 10.1071/CH06167
© CSIRO 2006 10.1071/CH06163 0004-9425/06/070445

446
D. I. B. Kerr et al.
binding of the orthosteric ligand.[22] In Family 3 receptors
most, if not all, allosteric modulators bind at the heptahelical
domain.
Results and Discussion
Synthesis of Analogues of N-[3,3-Diphenylpropyl]-
α-methylbenzylamine (Fendiline)
Nemeth et al.[23,24] showed that a variety of phenylalkyl-
amines are potent allosteric modulators at extracellular
CaSRs. These amines include the lead compound fendiline
(N-[3,3-diphenylpropyl]-α-methylbenzylamine 3; Fig. 2) and
several N-[3-phenylpropyl]-α-methyl benzylamines, such as
(4, NPS 467).
The general synthetic procedure is essentially that
of Nemeth et al.,[23,24] involving condensation of
3,3-diphenylpropylamine5(R3 =H)withasubstitutedaceto-
phenone in the presence of excess titanium isopropoxide,
followed by reduction with sodium cyanoborohydride, which
afforded the compounds 6a–6i (Scheme 1).
The synthesis of compound 6h required access to 3-(4-
chlorophenyl)-3-phenylpropylamine 7, and was carried out
as summarized in Scheme 2. While catalytic hydrogena-
tion of the intermediate nitrile 8 gave 7, accompanied by
partially reduced products, lithium aluminium hydride reduc-
tion was more satisfactory. Reductive alkylation of 7 with
the appropriate acetophenone gave 6h as a mixture of two
diastereoisomers (13:87 ratio).
The short-chain analogues 9a and 9b were prepared by the
general method of Barmore et al.[27] using addition of amines
to the diisobutylaluminium complex derived from the nitrile
10 (Scheme 3). The required nitrile 10 was made from the
corresponding chloro compound by the method of Zieger and
Wo;[28] substitution with sodium cyanide was unsuccessful.
Similarly, the ‘abnormal’ chain length compounds 11 and
12 (Fig. 3)[24] were prepared for comparison.
The ability of these new positive and negative modulators
led to modelling of their binding sites at the CaSRs.[25] There
is some disagreement as to the precise structure of theTM1–7
domains in the calcium-sensing receptor, but the pivotal role
of the glutamate residue E837 near the top of TM7 of the
heptahelical domain is generally recognized, since this acidic
residue provides ionic bonding with the amine nitrogen of the
phenylalkylamines. In addition, there are two hydrophobic
pockets which accept the benzyl or naphthyl ring of the N-α-
benzyl moiety and the aromatic terminal of the phenylpropyl
moiety, respectively.
We have recently found that the compounds reported
by Nemeth et al.[23,24] are also extremely potent positive
allosteric modulators of the GABAB receptor.[26] This project
aims to develop further positive allosteric modulators with
high potencies and selectivity for GABAB receptors by
exploring the structure–action profile of phenylalkylamines.
R1
R2
R3
6a
6b
6c
6d
6e
H
H
H
H
H
H
H
H
H
R3
R1
R2
R3
R1
R2
H
OMe
Cl
1. Ti(PriO)4
Cl
H
N
ꢀ
O
OMe OMe
OCH2O
H2N
2. NaBH3CN
Ph
Ph
6f OMe Br
6g OMe Cl
5
6h
H
OMe Cl
6i OMe
H
H
Scheme 1.
CN
O
NH2
MeO
COMe
NaH, CNCH2PO(OEt)2
88%
LiAlH4
68%
6h
1. Ti(PriO)4
2. NaBH3CN
Cl
Cl
Cl
8
7
Scheme 2.
CN
O
Ph
NH2
1. DIBAL,
R
1. NaBH4, 90%
2. HCl, 95%
H
N
R
2. NaBH3CN
Cl
Cl
3. Me3SiCl/TiCl4
H
Cl
10
9a R ꢁ H
9b R ꢁ OMe
Scheme 3.
Br
Br
Br2
ꢀ
H
N
H
H
N
N
EtO
EtO
EtO
Br
13h
13n
13o
Scheme 4.

Synthesis and Biological Activity of Allosteric Modulators of GABAB Receptors
447
Synthesis of 3-Phenylpropylamine Analogues
The adjacent phenylalanine (F832, 765, or 720) could pro-
vide π-stacking for the α-methylbenzylamine (Fig. 6). The
analogous CaSR site has been modelled,[32] and assumes
the importance of the glutamic carboxyl group and two
hydrophobic pockets, which bind to the α-methylbenzyl and
phenylpropyl group.
It was noticed that potentiation of GABA by several of the
above compounds was sensitive to protonation of the amino
group, namely whether they were administered as the free
base or hydrochloride salt, the latter being about one-third as
active as the free base (see Table 1). Therefore, the environ-
ment around the nitrogen was modified to determine whether
it needed an attached hydrogen atom for hydrogen bonding.
This led to the synthesis of compounds 17–20 (Fig. 7).
A series of compounds 13a–13p (Fig. 4) was pre-
pared as above, mostly by reductive alkylation of the
3-arylpropylamine with the corresponding acetophenone.
With a view to synthesizing the brominated analogue, the
corresponding acetophenone was required. Bromination of
3-methoxybenzaldehyde surprisingly gave only a single
mono bromination product which was assigned the struc-
ture 14, confirmed by a NOESY experiment which showed
a correlation between the methoxy signal and H2 and H4.
Alkylation of 14 with methyl lithium followed by oxidation
with Jones’ reagent gave 6-bromo-3-methoxyacetophenone
which was used to prepare 13m.
Interestingly, bromination of 13h gave a mixture of 13n
and 13o (Scheme 4); the structures were established by
1H NMR analysis, COSY, NOESY, and accurate mass data.
In particular, the NOESY spectrum of 13n showed a nuclear
Overhauser effect between H4 and OCH2, H2 and OCH2,
and H2 and CH3.
Two of the analogues in this series, fendiline 15 (Fig. 5)
and the 1-naphthyl analogues 16 were prepared in both enan-
tiomeric forms by reductive alkylation of hydrocinnamalde-
hyde with (R)-(+)- and (S)-(−)-α-methylbenzylamine and
(R)-(+)- and (S)-(−)-1-(1-naphthyl)ethylamine respectively.
Attempts to resolve the racemic 13a with camphorsulfonyl
chloride[29] were not successful; the resulting sulfonamides
could not be adequately separated by chromatography. The
resolution of 13a in small quantities has been reported using
chiral HPLC.[23,30]
Analogues with Additional Hydrogen-Bonding Potential
We have synthesized a small group of urea or amide-based
analogues with the potential to bind strongly to the (aspar-
tic) acid carboxyl group of TM7, and which would also
restrict the conformation of the spacer group. Since the 1-(1-
naphthyl)ethylamine and the 2-chlorophenylpropyl groups
appeared to be among the most active sub-groups for the
calcium modulator,[24] the ureas 21–23 (Fig. 8) were synthe-
sized by the reaction of the amine with either 2-chlorophenyl
isocyanate or isothiocyanate, respectively.
While 21–23 contained two hydrogen-bonding groups,
they contained only two atoms in the spacer group, which
we found to be considerably less active than three atoms.[33]
Accordingly, the amides 24 and 25 appeared suitable sub-
strates to test whether a basic nitrogen was necessary in
addition to the chain length, and a comparison of the confor-
mationally more rigid cinnamide 25 with the conformation-
ally more mobile dihydro compound 24 would be instructive
before embarking on the synthesis of more conformationally
restricted analogues.
Synthesis of N-[3-Phenylpropyl]-α-methylbenzylamines
Substituted on the Nitrogen Atom
Kerr and Ong[31] suggest that, in the GABAB receptor, an
aspartic acid group at the top of transmembraneTM7 replaces
the glutamic acid present in the CaSR. This acidic group
would bind to the basic group of arylalkylamine, either elec-
trostatically if it is protonated, or through hydrogen bonding.
Synthesis of Shorter and Elongated Alkyl Chain Analogues
of N-[3-Phenylpropyl]-α-methylbenzylamine
The spacing between the two aryl groups was probed by the
synthesis of the higher homologues 26 and 27, the shorter
analogue 28, and the des-methyl compounds 29 and 30
(Fig. 9).
Ph
H
N
N
H
Ph
Cl
11
12
H
N
H
N
Fig. 3.
H
H
Me
Me
(R)(ꢀ)-15
(R)(ꢀ)-16
R1
R2
R3 R4
13a
H
OMe
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Br
H
Fig. 5.
13b HH Cl
13c Cl
Cl
13d OMe OMe
Asparticic acid carboxyl
-OCH2-
H
13e
13f
OH
13g OH OMe
R1
R2
R4
Br
O
13h
13i
13j
13k
13l
H
OEt
O
H
N
OMe Cl
OMe Br
H
H
MeO
CHO
N
Hydrophobic pocket
OMe Cl
R3
O
14
OMe Cl
Cl
13m Br
OMe Cl
OEt
OMe Br
OMe Cl Br
13n
13o
13p
H
H
H
H
Spacer group
Hydrophobic pocket
Fig. 4.
Fig. 6.

448
D. I. B. Kerr et al.
X
H2N
Me
N
Me Me
N
N
MeO
MeO
MeO
ꢀ
17 X ꢁ O
18 X ꢁ NH
19
20
Fig. 7.
R
H
H
N
H
N
H
N
N
X
O
Cl
O
Cl
21 X ꢁ O, R ꢁ Cl
22 X ꢁ S, R ꢁ Cl
23 X ꢁ S, R ꢁ H
24
25
Fig. 8.
H
N
H
N
H
N
R
MeO
MeO
R
Cl
Cl
26 R ꢁ H
27 R ꢁ OMe
28 R ꢁ Me
30 R ꢁ H
29
Fig. 9.
Biological Evaluation
hyperpolarization generated by a given baclofen concentra-
tion was not only increased in amplitude, but the duration also
became prolonged.This suggests that the modulators in some
way prevented desensitization, and that the dissociation of the
agonist was delayed by the modulator, or that the activation
of the G-proteins was prolonged. In our studies, the mod-
ulator also potentiates the inhibitory effects of baclofen on
the release of GABA and glutamate, through their actions at
presynaptic auto and hetero-receptors. It is most probable that
these effects on receptors are due to an increase in G-protein
coupling, as a result of an action at the seven-transmembrane
region.A most important observation, if these compounds are
ever to have any clinical applications, is that they are acting as
GABAB-receptor potentiators at much lower concentrations
than that required to modulate extracellular CaSRs.
A standard electrophysiological recording on rat brain slices
was routinely used in evaluating the activities and potencies
of putative allosteric modulators at GABAB receptors.
The method has been previously described.[26,33,34] The
compounds described above were examined for their pharma-
cological effects in enhancing baclofen-induced hyperpolar-
izing responses at GABAB post-synaptic receptors. Baclofen
is a classical selective agonist at GABAB receptor sites,[15,16]
and is commonly used in rat brain preparations to stimu-
late these receptors to induce a neuronal response. Herein we
summarize the results of the effects of the test compounds
in modulating baclofen-mediated function using grease gap
recording in rat neocortical slices.[33–35]
Our results on the potentiating effects of the test com-
pounds on baclofen-induced hyperpolarizing responses in rat
brain slices are summarized in Tables 1–3. The responses
induced by baclofen are dose-dependent, with baclofen gen-
erating an EC50 value of ∼10 µM.[34] The potencies of the
variouscompoundsaremeasuredastheirrespectiveEC50 val-
ues where the EC50 is defined as the concentration of the drug
giving a response equal to 50% of the maximally effective
concentration in potentiating the baclofen response.
The results summarized inTables 1–3 show that among all
the compounds tested, 3-Cl-4-MeO-fendiline 6g (Table 1) is
still by far the most effective potentiator of GABAB receptor-
mediated actions in rat brain slices, with an EC50 of 10 nM for
the free base and an EC50 of 30 nM for the HCl salt. Indeed,
this is the most potent and active modulator reported.[30] The
potentiating actions were mediated by GABAB receptors, as
the responses to baclofen were reversibly antagonized by
specific GABAB receptor antagonists such as Sch 50911,
and the responses to GABAA receptor agonists were not
affected by the modulators examined (data not shown). The
modulators when applied alone had no detectable effect on
the tissues, indicating that they had no intrinsic activity at
the receptor sites. In the presence of the modulators, the
Effect of Oxygen Substituents on Phenylethylamine Ring
Comparison of fendiline (3 ≡ 6a) (EC50 20 µM; Table 1)
and its methoxylated derivative 6b (EC50 3 µM) indi-
cates that incorporation of a meta-methoxy group in the
phenylethylamine ring markedly increases the activity. A
second methoxyl, as in 3,4-(OMe)2 6d slightly improved
the activity (EC50 ∼2 µM). However, the 3,4-OCH2O sub-
stituent 6e decreases the activity (EC50 ∼15 µM). This result
suggests that the second alkoxy group is required mainly for
the hydrophobic interaction of its alkyl group, as seen with
halogen substitution (see below).
This finding is supported by comparing the activity
(Table 2) of the unsubstituted phenylpropylamine (R-15;
Table 2; EC50 3 µM) with its hydroxylated derivative 13f
(EC50 > 100 µM), which suggested that introduction of a
hydrophilic hydroxyl group at the meta position consid-
erably decreases the activity. The 3,4(-OMe)2 substituents
(13d) again increase the activity (EC50 1 µM) while the 3,4-
OCH2O group 13e decreases the activity (EC50 10 µM). The
incorporation of the 3-OMe into the benzylamine ring, 13a
markedly increases the activity (EC50 0.6 µM,) as was seen

Synthesis and Biological Activity of Allosteric Modulators of GABAB Receptors
449
Table 1. Pharmacological activity (EC50) of fendiline
derivatives as GABAB potentiators
All numerical data on the concentration–response curves
were expressed as approximate EC50 values (n = 6–12)
activity, probably because of congestion in the hydrophobic
pocket (Fig. 6). However, the presence of an ortho chloro sub-
stituent in the phenylpropylamine moiety (Table 2), as seen in
comparing phenylpropylamines 13a (EC50 0.6 µM) and 13k
(EC50 0.3 µM), leads to an increase in activity. Again, the
presence of halogens in the methylbenzylamine ring gener-
ally leads to increase in activity. While bromination reduces
the activity (phenylpropylamine 13j is six times less active
than phenylpropylamine 13a, and the presence of a Br ortho
to the alkyl group as in 13n lead to a further reduction in
activity), chlorination appears to increase the activity.
Fendiline itself 6a (Table 1) has an EC50 of 20 µM, but
the 3,4-dichloro derivative 6c has an EC50 of 1 µM.The EC50
of 4-methoxyfendiline 6i is 5 µM, but its 3-chloro derivative
6g has an EC50 of 10 nM, and is one of the two most potent
potentiators. In the phenylpropylamine series (Table 2), chlo-
rination at C4 13b markedly reduces the activity (EC50 of
20 µM for free base and EC50 of 50 µM for HCl salt), as
does 3,4-dichlorination 13c (EC50 100 µM), but again the
most active compound was the 3-Cl 4-MeO analogue 13i,
with an EC50 ∼100 nM.
Compound
Activity
6a
20 µM
6b
6c
3 µM
1 µM
6d
6e
6f
2 µM
15 µM
2 µM
6f·HCl
10 µM
10 nM (0.01 µM)
25 µM
5 µM
6g
6h
6i
Table 2. Pharmacological activity (EC50
) of 3-arylpropyl-
1-arylethylamines as GABAB potentiators
All numerical data on the concentration–response curves were
expressed as approximate EC50 values (n = 6–12)
Compound
Activity
Compound
Activity
13a
13b
13c
13d
13e
13f
13g
13h
13i
0.6 µM
20 µM
13m
13n
10 µM
20 µM
Conformational Modelling
100 µM
1 µM
13o
13p
Not tested
10 µM
The lower activity of compound with the Br ortho to the
alkylamine, 13n, compared to that with Br meta, 13j, could
be considered in terms of their most favoured conformations.
A conformational search of the active 13j and less active 13n
was carried out using Spartan at the AM 1 level. We have
arbitrarily compared the five lowest energy conformations for
each compound. Two differences were apparent which might
have some bearing on the differences in activity of the two
isomers. Modelling of the active 13j shows that the lone pair
of the amino group was directed at right angles to the plane
of the methylbenzyl ring, and the phenylpropyl group was
essentially linear in the lowest five conformations. Therefore
the lone pair on the nitrogen would be in the correct posi-
tion for receptor (CO2H) binding (see Fig. 6). However, the
nitrogen lone pair was in the plane of the methylbenzyl ring,
and the phenylpropyl chain was folded in the five lowest con-
formations for the less active 13n, and these conformations
might not allow for correct positioning for good recep-
tor binding. A suitable linear conformer was significantly
higher in energy. The ortho bromo analogue (13p), which
has intermediate activity, but contain an ortho chlorine in the
phenylpropylamine ring, has also been modelled in the hope
that the chlorine would induce a conformational change in
the lower energy conformers; however, calculations showed
that 13p has a similar conformational distribution to that of
13n. While at this stage our analysis is not comprehensive,
we propose it as a working hypothesis (see Fig. 6).
10 µM
>100 µM
50 µM
20 µM
100 nM (0.1 µM)
3 µM
(R)-15
(S)-15
(R)-16
(S)-16
17
18
19
20
3 µM
Inactive
0.6 µM
Inactive
Inactive
Inactive
Inactive
ca 100 µM
13j
13k
13l
0.3 µM
1 µM
Table 3. Pharmacological activity (EC50) of chain-
modified arylethylamines as GABAB potentiators
All numerical data on the concentration–response curves
were expressed as approximate EC50 values (n = 6–12)
Compound
Activity
9a
9b
11
12
21
22
23
26
27
28
29
30
300 µM
25 µM
300 µM
50 µM
>100 µM
>100 µM
70 µM
100 µM
10 µM
30 µM
Inactive
Inactive
in the fendiline series. The further addition of a 4-hydroxyl
group 13g again leads to decrease in activity (EC50 50 µM).
Replacement of 3-OMe 13a (EC50 0.6 µM) with the bulkier
3-OEt group in 13h also reduces the activity (EC50 20 µM).
Comparison of Fendiline and Phenylpropylamine Series
Comparing 3-OMe-fendiline 6b (EC50 3 µM) with the
3-OMe-propylamine 13a (EC50 0.6 µM), and fendiline 6a
(EC50 20 µM; Table 1) with the unsubstituted phenylpropy-
lamine 15 (EC50 3 µM; Table 2), clearly suggests that the
phenylpropylamine series fits better at the receptor than those
with two phenyl groups. However, in the two most active
Effect of Introduction of Halogens
Comparison of fendiline derivatives 6b (EC50 3 µM) and
6h (EC50 25 µM) shows that the presence of a para chloro
group in the diphenylpropyl group considerably decreases the

450
D. I. B. Kerr et al.
MeO
Cl
for the synthesis of (R)-6g or (R)-13i. However, we believe
the test results for the racemic mixtures, particularly for 6g,
are indicative of activity of the R-enantiomers as suggested
by the lack of activity of (S)-15 and (S)-16.
NH2
H
Me
31
Fig. 10.
Conclusions
compounds, the 3-chloro-4-methoxy derivatives, it is the
fendiline 6g (EC50 10 nM) which is the more active (13i,
EC50 100 nM). The compound 13l, bearing the best substitu-
tion pattern in the methylbenzylamine ring, and the preferred
ortho chlorination in the phenylpropylamine ring was highly
active, but its Ca2+ modulation now became comparable to
its GABAB modulation.
The 3,3ꢀ-diarylpropyl-1-arylethylamines and 3-arylpropyl-
1-arylethylamines reported herein represent a novel class of
GABAB receptor modulators where they potentiate baclofen-
induced responses in the brain. 3-Chloro-4-methoxyfendiline
appears to be the most potent, acting at nanomolar levels
(EC50 10 nM). These GABAB modulators may represent a
novel therapeutic strategy for the treatment of various neu-
rological and pathological diseases mentioned previously
without the side effects of full GABAB receptor agonists.
Effect of Chain Length
Changing the chain length in the phenylpropyl chain in
the fendiline series from three methylenes to only two as
in 11 (EC50 300 µM), or insertion of an extra methylene
group into the α-methylbenzyl group, as in 12 (EC50 50 µM)
both resulted in decreasing the activity (Table 3). Likewise in
the phenylpropylamine series, the addition of one methylene
chain into the phenylethylamine ring as in 26 and 27 (Table 3)
reduced the activity from 0.6 µM to 10 µM in the 3-methoxy
series, and from 3 µM to 100 µM in the unsubstituted series.
The presence of the α-methyl group was clearly desirable, as
its removal in 29 and 30 (Table 3) greatly decreased activity.
When the phenyl ring was replaced by a 1-naphthyl, as in 16,
the activity generally increased (Ph EC50 3 µM, Naphth EC50
0.6 µM), but 16 induced an oscillatory response (Table 2). A
urea linkage was now introduced, resulting in a shorter chain
length but a more rigid conformation (Table 3, 21–23). The
activity was essentially abolished, but we cannot ascertain
whether this is due to the low solubility of the compounds, or
that H-bonding induced binding to other sites on the protein
molecule.
Experimental
All solvents used were freshly distilled and dried according to the meth-
ods of Perrin et al.[36] Melting points were determined on a Reichert
hot stage microscope and are uncorrected. 1H (200 MHz) and 13C
(75.5 MHz) NMR spectra were recorded on a Gemini Varian 300 spec-
trometer in deuterated chloroform with tetramethylsilane as internal
standard, unless otherwise stated. Infrared spectra were recorded on a
Perkin–Elmer 1600 FT-infrared spectrophotometer, using fused sodium
chloride cells, measured as Nujol mulls or films. Optical rotations were
measured on a Polaar 21 instrument (OpticalActivity) at 589.44 nm and
18◦C, unless otherwise noted, and are reliable to 1◦. Reidel–de Haen
Silica gel S (pH 7, granulation 32–63 mm) was used for all column
chromatography. Merck silica gel 60 F 254 aluminium-backed sheets
were used for analytical thin-layer chromatography. GC-MS analysis
was carried out with a Varian Saturn 4D instrument using a Zebron ZB-
5 5% phenyl polysiloxane column (30 m, 0.25 mm ID). Electrospray
ionization mass spectra (EIMS), using a Bruker 4.7T FTMS ultra high-
resolution spectrometer, reporting the (MH)+• and some fragmentation
ions, were determined at Monash University, Melbourne.
Compound 23 was prepared by a literature procedure.[37] Methods
for obtaining the data in Tables 1–3 have been detailed elsewhere.[26]
(R,S)-N-(3,3-Diphenylpropyl)-1-(3-methoxyphenyl)ethylamine 6b
Effect of Substitution on Nitrogen
A
mixture of 3-methoxyacetophenone (1.5 g, 10 mmol), N-3,3-
diphenylpropylamine (2.11 g, 10 mmol), and titanium isopropoxide
(2.1 g, 12.5 mmol) was stirred at room temperature under nitrogen
overnight. Subsequently, sodium cyanoborohydride (0.60 g, 10 mmol)
in ethanol (10 mL) was added dropwise over 2 min. The reaction mix-
ture was stirred overnight at room temperature. Water (100 mL) was
added followed by ether (250 mL). The inorganic salts were filtered off
and the ether extract was collected. The aqueous phase was extracted
thoroughly with ether (3 × 250 mL). The combined ether extract was
dried over K2CO3 then concentrated under vacuum to yield a thick oil
(2.85 g). The oil then was converted into the corresponding hydrochlo-
ride salt by solution in the minimum volume of ethanol, followed by the
addition of concentrated hydrochloric acid and ether. The white solid
hydrochloride salt was collected by vacuum filtration (2.36 g, 62%), mp.
165–168◦C. (Found: [M + H]+ 346.2190; C24H28NO requires [M]+
346.2173). Hydrochloride salt: δH 1.68 (d, J 6.9, 3H), 2.63 (m, 4H),
3.85 (s, 3H), 3.93 (q, J 6.9, 1H), 4.06 (t, J 7.2, 1H), 6.86 (dd, J 2.2, 10.2,
1H), 7.00 (d, J 7.6, 1H), 7.03–7.30 (m, 12H), 9.78 (s, 1H, NH), 10.30
(s, 1H, NH). δC 20.6 (CH3), 31.0 (CH2), 44.1 (CH2), 48.3 (CH), 55.6
(CH), 58.8 (CH3), 112.2 (CH), 115.6 (CH), 119.9 (CH), 126.7 (CH),
126.8 (CH), 127.8 (CH), 127.9 (CH), 128.7 (CH), 128.8 (CH), 130.5
(CH), 137.4 (CH), 142.8 (C), 143.2 (C), 160.6 (C).
The simplest modification of the compounds was to com-
pare the activity of the free base with that of its hydrochloride
salt. Considering that the pH of the Krebs solution was 7.2–
7.4, we had anticipated that all amines would be present as
the free bases, but in all cases where both free base and
hydrochloride were independently tested, there was a differ-
ence, and the hydrochloride routinely was approximately half
to one third as active as the free base (Table 1, 6f). Substi-
tution on the nitrogen atom also had considerable bearing on
activity (Table 2). Replacement of NH by NMe, N–CONH2,
or N–C(NH2)=NH abolished the activity completely. The
last two moieties were designed to possibly increase binding
with an acidic group (of a Glu or Asp amino acid), assumed
to be at the binding site. Surprisingly, the methiodide of the
N-methyl derivative 20 showed some, but decreased activity.
Stereochemistry of the α-Methylbenzyl Moiety
As can be seen from Table 2, the modulatory activity of
GABAB potentiators was stereoselective, R-isomers 15 and
21 being active while the S-isomers were inactive. At this
stage we have not resolved the amine 31 (Fig. 10), required
(R,S)-N-(3,3-Diphenylpropyl)-1-(3,4-dichlorophenyl)ethylamine 6c
A mixture of 3,4-dichloroacetophenone (1.89 g, 10 mmol), N-3,3-
diphenylpropylamine (2.11 g, 10 mmol), and titanium isopropoxide

Synthesis and Biological Activity of Allosteric Modulators of GABAB Receptors
451
(3.55 g, 12.5 mmol) was reacted as above to give 6c as a yellow oil
(2.05 g, 53%) characterized as the hydrochloride salt, mp. 168–172◦C.
(Found: [M + H]+ 384.1281; C23H2435Cl2N requires [M]+ 384.1280).
Free base: δH 1.27 (d, J 6.4, 3H), 2.23 (m, 2H), 2.41 (m, 4H), 3.65 (q,
J 6.4, 1H), 4.02 (t, J 7.6, 1H), 7.05–7.39 (m, 13H). δC 24.3 (CH3), 35.9
(CH2), 45.9 (CH2), 48.9 (CH), 57.3 (CH), 125.9 (CH), 126.1 (CH),
127.6 (CH), 127.7 (CH), 128.4 (CH), 128.5 (CH), 130.2 (CH), 130.3
(CH), 132.2 (CH), 144.5 (C), 144.8 (C), 146.2 (C).
126.5 (CH), 126.6 (CH), 127.3 (CH), 127.6 (CH), 127.7 (CH), 128.6
(CH), 128.7 (CH), 129.9 (C), 142.7 (C), 143.2 (C), 155.7 (C).
(R,S)-N-[3-(4-Chlorophenyl)-3-phenylpropyl]-1-(3-methoxyphenyl)-
ethylamine 6h
3-(4-Chlorophenyl)-3-phenylpropenonitrile 8
To
a suspension of sodium hydride (0.72 g, 29 mmol) in
dry N,N-dimethylformamide (15 mL) was added dropwise diethyl
cyanomethylphosphonate (2.25 mL, 14 mmol) followed by
4-chlorobenzophenone (3 g, 14 mmol) in dry DMF (10 mL). The mix-
ture was stirred for 10 h. Water (20 mL) was added, and the mixture
was extracted with ether (3 × 25 mL). The ether extract was dried
over MgSO4 and then concentrated to yield a brown liquid (3.5 g)
which was purified by flash silica gel column chromatography using
n-hexane/chloroform (1/1) as eluent to give a yellow oil (2.9 g, 88%)
which was shown by NMR analysis to be a 1:1 mixture of (E) and
(Z) isomers of 3-(4-chlorophenyl)-3-phenylpropenonitrile.[39] (Found:
[M + 1]+ 239.0512; C15H10ClN requires [M]+ 239.0502). δH 5.72 (s,
1H), 5.75 (s, 1H), 7.26–7.46 (m, 18H). δC 95.7 (CH), 117.9 (C), 128.7
(CH), 129.0 (CH), 129.1 (CH), 129.2 (CH), 129.3 (CH), 129.8 (CH),
130.1 (CH), 130.5 (CH), 131.0 (CH), 131.2 (CH), 135.8 (C), 136.4 (C),
136.9 (C), 137.6 (C), 137.7 (C), 161.9 (C), 162.0 (C).
(R,S)-N-(3,3-Diphenylpropyl)-1-(3,4-dimethoxyphenyl)ethylamine 6d
A mixture of 3,4-dimethoxyacetophenone (0.90 g, 5 mmol), N-3,3-
diphenylpropylamine (1.05 g, 5 mmol) and titanium isopropoxide (1.8 g,
6.25 mmol) was reacted as above to give 6d as a yellow oil (0.52 g,
50%). Hydrochloridesaltmp. 168–170◦C. (Found:[M + H]+ 376.2277;
C25H30NO2 requires [M]+ 376.2271). Free base: δH 1.34 (d, J 6.4, 3H),
2.29 (m, 2H), 2.51 (m, 4H), 3.69 (q, J 6.4, 1H), 3.87 (s, 3H), 3.87 (s, 3H),
4.01 (t, J 7.6, 1H), 6.80 (s, 1H), 6.89–7.28 (m, 12H). δC 24.0 (CH3), 35.6
(CH2), 45.7 (CH2), 48.8 (CH), 55.6 (2 × CH3), 57.7 (CH), 109.2 (CH),
110.7 (CH), 125.9 (CH), 127.5 (CH), 128.2 (CH), 137.7 (C), 144.4 (C),
144.6 (C), 147.6 (C), 148.7 (C).
(R,S)-N-(3,3-Diphenylpropyl)-(3,4-methylenedioxyphenyl)-
ethylamine 6e
A mixture of 3,4-methylenedioxyacetophenone (0.82 g, 5 mmol),
N-3,3-diphenylpropylamine (1.05 g, 5 mmol), and titanium isopropox-
ide (1.8 g, 6.25 mmol) was reacted as above to give 6e as a yellow oil
(0.59 g, 53%). Hydrochloride salt mp. 220–224◦C. (Found: [M + H]+
360.1954; C24H26NO2 requires [M]+ 360.1958). Free base: δH 1.29 (d,
J 6.6, 3H), 2.27 (m, 2H), 2.48 (m, 4H), 3.63 (q, J 6.6, 1H), 4.00 (t, J
7.6, 1H), 5.93 (s, 2H), 6.69 (dd, J 1.4, 6.8, 1H), 6.72 (d, J 6.8, 1H), 6.81
(d, J 1.2, 1H), 7.16–7.28 (m, 10H). δC 24.2 (CH3), 35.8 (CH2), 45.8
(CH2), 48.9 (CH), 57.9 (CH), 100.8 (CH2), 106.7 (CH), 107.9 (CH),
119.7 (CH), 126.1 (CH), 127.7 (CH), 127.8 (CH), 128.4 (CH), 139.4
(C), 144.5 (C), 144.8 (C), 146.3 (C), 147.6 (C).
3-(4-Chlorophenyl)-3-phenylpropylamine 7
The nitrile 8 (1.2 g, 5.1 mmol) in ether (5 mL) was added dropwise to
a stirred solution of lithium aluminium hydride (0.5 g, 13 mmol) in dry
ether (30 mL) at 0◦C. The mixture was refluxed for 3 h, and then was
quenched cautiously with 1 M HCl. The aqueous layer was collected,
neutralized with 1 M NaOH, and then extracted with ether. The ether
extract was dried over Na2SO4 and concentrated to afford 7, isolated
as a colourless oil (450 mg, 30%). δH 1.79 (s, 2H, NH2), 2.19 (q, J 7.8,
2H), 2.64 (t, J 7.6, 2H), 3.97 (t, J 8.0, 1H), 7.14–7.29 (m, 9H).
A mixture of 3-methoxyacetophenone (0.08 g, 0.5 mmol), amine 7
(0.13 g, 0.5 mmol), and titanium isopropoxide (0.19 g, 0.64 mmol) was
reacted as above to yield a yellow oil (250 mg), which was subjected
to flash silica gel column chromatography using dichloromethane/
methanol (9.5/0.5) as eluent to give 6h as a mixture (87:13)
of diastereoisomers (75%). (Found [M]+ 379.1707; C24H2635ClNO
requires [M]+ 379.1706). Major isomer: δH 1.31 (d, J 6.6, 3H), 2.18
(m, 2H), 2.44 (m, 2H), 3.66 (q, J 6.6, 1H), 3.80 (s, 3H), 3.98 (t, J 2.2,
1H), 6.65–6.68(m, 3H), 7.13–7.27(m, 10H). δC 24.2(CH3), 35.9(CH2),
45.8 (CH2), 48.2 (CH), 55.2 (CH), 112.1 (CH), 118.9 (CH), 126.3 (CH),
127.7 (CH), 127.8 (CH), 128.5 (CH), 129.2 (CH), 131.8 (C), 143.2 (C),
143.4 (C), 144.1 (C), 144.4 (C), 147.2 (C), 159.8 (C).
(R,S)-N-(3,3-Diphenylpropyl)-1-(3-bromo-4-methoxyphenyl)-
ethylamine 6f
A mixture of 3-bromo-4-methoxyacetophenone[38] (0.69 g, 3 mmol),
3,3-diphenylpropylamine (0.63 g, 3 mmol) and titanium isopropoxide
(1.3 mL, 12.5 mmol) was reacted as above to give 6f, isolated as
the hydrochloride, mp. 132–136◦C (350 mg, 26%). (Found: [M + H]+
424.1269; C24H2779BrNO requires [M]+ 424.1271). Free base: δH 1.37
(d, J 6.6, 3H), 2.25 (m, 2H), 2.46 (m, 2H), 3.63 (q, J 6.6, 1H), 3.91 (s,
3H), 3.98 (t, J 7.2, 1H), 6.81 (d, J 8.4, 1H), 7.12–7.33 (m, 11H), 7.49 (d,
J 2.0, 1H). Hydrochloride salt: δH 1.62 (d, J 6.6, 3H), 2.60 (m, 4H), 3.85
(s, 3H), 4.01 (q, J 7.2, 1H), 4.15 (s, 1H), 6.82 (d, J 8.4, 1H), 7.02–7.20
(m, 11H), 7.61 (d, J 2.0, 1H), 9.79 (br s, 1H, NH), 10.21 (br s, 1H, NH).
δC 20.4 (CH3), 31.2 (CH2), 44.0 (CH2), 48.3 (CH), 56.4 (CH), 57.7
(CH3), 112.1 (C), 112.7 (CH), 126.5 (CH), 127.6 (CH), 128.1 (CH),
128.7 (CH), 129.2 (CH), 133.0 (CH), 142.7 (C), 143.2 (C), 156.6 (C).
(R,S)-N-(3,3-Diphenylpropyl)-1-(4-methoxyphenyl)ethylamine 6i
A
mixture of 4-methoxyacetophenone (0.82 g, 5 mmol), N-3,3-
diphenylpropylamine (1.05 g, 5 mmol), and titanium isopropoxide (5 g,
20 mmol) was reacted as above to give 6i as a yellow oil (0.57 g,
33%). Hydrochloride salt mp. 180◦C. (Found: [M + H]+ 346.2198;
C24H28NO requires [M]+ 346.2173). Free base: δH 1.34 (d, J 6.6, 3H),
2.30 (m, 2H), 2.48 (m, 2H), 3.72, (q, J 6.6, 1H), 3.80 (s, 3H), 3.95 (t, J
7.6, 1H), 6.86 (d, J 8.8, 2H), 7.21 (m, 10H),7.40 (d, J 8.4). δC 20.5 (CH3),
31.0 (CH2), 43.9 (CH2), 48.3 (CH), 55.3 (CH), 58.1 (CH3), 114.6 (CH),
126.4 (CH), 127.6 (CH), 127.7 (CH), 128.6 (CH), 129.2 (CH), 142.8
(C), 143.3 (C), 160.1 (C).
(R,S)-N-(3,3-Diphenylpropyl)-1-(3-chloro-4-methoxyphenyl)-
ethylamine 6g
A mixture of 3-chloro-4-methoxyacetophenone[38] (0.80 g, 4.33 mmol),
3,3-diphenylpropylamine (0.91, 4.33 mmol) and titanium isopropoxide
(1.6 mL, 5.25 mmol) was reacted in the usual way to give 6g, iso-
lated as the hydrochloride salt (850 mg, 46%), mp. 192–195◦C. (Found:
[M + H]+ 380.1774; C24H2735ClNO requires [M]+ 380.1776). Free
base: δH 1.30 (d, J 6.4, 3H), 2.27 (m, 2H), 2.46 (m, 2H), 3.66 (q, J 6.4,
1H), 3.86 (s, 3H), 4.05 (t, J 7.2, 1H), 6.85 (d, J 8.4, 1H), 7.09–7.35 (m,
12H). δC 24.2 (CH3), 35.9 (CH2), 45.7 (CH2), 48.8 (CH), 55.9 (CH),
57.1 (CH3), 111.8 (CH), 122.1 (CH), 125.6 (CH), 126.0 (CH), 127.6
(CH), 127.7 (CH), 128.1 (CH), 128.2 (CH), 139.0 (C), 144.5 (C), 144.8
(C), 153.6 (C). Hydrochloride salt: δH 1.66 (d, J 5.6, 3H), 2.61 (br, 4H),
3.90 (s, 3H), 3.96 (br, 2H), 6.92 (d, J 8.0, 1H), 7.11–7.55 (m, 12H),
9.79 (br s, 1H, NH), 10.20 (br s, 1H, NH). δC 20.3 (CH3), 31.1 (CH2),
44.0 (CH2), 48.3 (CH), 56.2 (CH), 57.8 (CH3), 112.8 (CH), 123.0 (CH),
N-[2-(4-Chlorophenyl)-2-phenylethyl]-1-(R)-methylbenzylamine 9
1-(4-Chlorophenyl)benzyl Chloride
To a solution of 1-(4-chlorophenyl)benzyl alcohol[40] (9.9 g,
45 mmol)inethanol(100 mL)wasaddedconcentratedhydrochloricacid
(12.5 mL).The reaction mixture was refluxed overnight.The two phases
were separated and the bottom layer was diluted with ether, washed with
saturated NaHCO3, brine, dried over Na2SO4 and then concentrated to
yield 1-(4-chlorophenyl)benzyl chloride, isolated as yellow oil (10.09 g,
95%). δH 5.33 (bs, 1H), 7.28–7.34 (m, 9H).

452
D. I. B. Kerr et al.
1-(4-Chlorophenyl)phenylacetonitrile
To stirred solution of 1-(4-chlorophenyl)benzyl chloride
(3.55 g, 12.5 mmol) was reacted as above to give 13c as a yel-
low oil (1.70 g, 55%). The corresponding hydrochloride salt was
obtained as a white solid, mp. 128–130◦C. (Found: [M + H]+ 308.0968;
C17H2035Cl2N requires [M]+ 308.0967). Free base: δH 1.33 (d, J 6.6,
3H), 1.81 (quin, J 7.4, 2H), 2.51 (m, 2H), 2.66 (m, 2H), 3.73 (q, J 6.6,
1H), 7.15–7.47 (m, 8H). δC 24.3 (CH3), 31.7 (CH2), 33.4 (CH2), 47.1
(CH2), 57.4 (CH), 125.7 (CH), 126.0 (CH), 128.2 (2 × CH), 128.5 (CH),
130.2 (C), 132.2 (C), 141.9 (C), 146.4 (C).
a
(1.19 g, 5 mmol) and trimethylsilyl cyanide (0.50 g, 5 mmol) in dry
dichloromethane (25 mL) was added titanium tetrachloride (0.5 mL)
dropwise at 0◦C. After 2 h, the reaction mixture was quenched with
methanol (10 mL) and the product was extracted with dichloromethane.
The organic phase was washed with water, 10% NaHCO3, water,
dried over Na2SO4, and then concentrated to yield an orange oil
(0.92 g, 81%) which was purified by silica gel column chromatog-
raphy with n-hexane/chloroform (50/50) as eluent to yield 1-(4-
chlorophenyl)phenylacetonitrile as a white solid (0.53 g), mp. 70◦C
(lit[41] mp. 74–75◦C). δH 5.12 (s, 1H), 7.29–7.39 (m, 9H). δC 41.9 (CH),
119.2 (C), 127.6 (CH), 128.5 (CH), 129.1 (CH), 129.3 (CH), 129.3 (C),
134.4 (C), 135.4 (C).
To a solution of 1-(4-chlorophenyl)phenylacetonitrile (0.11 g,
0.5 mmol) in dry dichloromethane (1 mL) was added dropwise 1.5 M
diisobutylaluminium hydride (0.4 mL) at −78◦C. The mixture was
stirred at room temperature for 3 h and then cooled to 0◦C. (R)-(+)-
α-methylbenzylamine (0.26 mL, 1 mmol) was added and the reaction
mixture was stirred at 0◦C for 3 h, then added to a solution of sodium
borohydride (0.03 g, 5 mmol) in ethanol (0.5 mL) and the reaction mix-
ture was stirred at room temperature for 1 h. The solution then was
quenched with 10% hydrochloric acid (0.5 mL), neutralized with 1 M
sodium hydroxide (0.5 mL) and then extracted with ether (3 × 5 mL).
The combined organic extracts were washed with water (3 × 1 mL),
dried over MgSO4, and concentrated to yield a yellow oil (0.3 g) which
was purified by preparative thin layer chromatography on alumina using
n-hexane/chloroform (1/9) as eluent to give compound (9) (0.15 g)
as a yellow oil. (Found: [M + H]+ 336.1515; C22H2235ClN requires
[M + H]+ 336.1519). δH 1.29 (d, J 7.8, 3H), 1.40 (bs, 1H, NH), 3.06
(m, 2H), 3.77 (q, J 7.8, 1H), 4.13 (t, J 7.2, 1H), 7.02–7.38 (m, 13H). δC
24.3 (CH3), 50.7 (CH2), 52.2 (CH), 58.4 (CH), 57.7 (CH), 132.2 (CH),
141.3 (CH), 141.7 (C), 142.2 (C), 142.7 (C), 145.4 (C).
(R,S)-N-(3-Phenylpropyl)-1-(3,4-dimethoxyphenyl)ethylamine 13d
A
mixture of 3,4-dimethoxyacetophenone (1.80 g, 10 mmol),
3-phenylpropylamine (1.35 g, 10 mmol), and titanium isopropoxide
(3.55 g, 12.5 mmol) was reacted as above to give 13d as a pale yellow oil
(1.72 g, 58%). The corresponding hydrochloride salt was obtained as a
white solid, mp. 176–177◦C. (Found: [M + H]+ 300.1955; C19H26NO2
requires [M]+ 300.1958). Free base: δH 1.34 (d, J 6.4, 3H), 1.81 (quin,
J 7.8, 2H), 2.55 (m, 4H), 3.70 (q, J 6.4, 1H), 3.85 (s, 3H), 3.70 (s, 3H),
6.80 (d, J 1.0, 2H), 6.87 (s, 1H), 7.11–7.26 (m, 5H). δC 23.9 (CH3), 31.3
(CH2), 33.5 (CH2), 47.0 (CH2), 55.8 (2 × CH3), 58.1 (CH), 109.4 (CH),
110.8 (CH), 118.8 (CH), 125.7 (CH), 128.2 (CH), 137.4 (C), 141.9 (C),
147.9 (C), 149.0 (C).
(R,S)-N-(3-Phenylpropyl)-1-(3,4-methylenedioxyphenyl)-
ethylamine 13e
A mixture of 3,4-methylenedioxyacetophenone (1.64 g, 10 mmol),
3-phenylpropylamine (1.35 g, 10 mmol), and titanium isopropoxide
(3.55 g, 12.5 mmol) was reacted as above to yield 13e as a pale yellow oil
(1.10 g, 39%). The corresponding hydrochloride salt was obtained as a
white solid, mp. 188–190◦C. (Found: [M + H]+ 284.1641; C18H22NO2
requires [M]+ 284.1645). Free base: δH 1.36 (d, J 6.4, 3H), 1.83 (quin,
J 7.4, 2H), 2.53 (m, 2H), 2.66 (m, 2H), 3.72 (q, J 6.4, 1H), 5.93 (s, 2H),
6.78 (d, J 1.0, 2H), 6.91 (s, 1H), 7.17–7.30 (m, 5H). δC 24.1 (CH3), 31.5
(CH2), 33.4 (CH2), 46.9 (CH2), 57.9 (CH), 100.6 (CH2), 106.5 (CH),
107.8 (CH), 119.6 (CH), 125.5 (CH), 128.1 (CH), 139.4 (C), 141.9 (C),
146.2 (C), 147.6 (C).
(R,S)-N-(3-Phenylpropyl)-1-(3-methoxyphenyl)ethylamine 13a
A
mixture of 3-methoxyacetophenone (1.50 g, 10 mmol),
(R,S)-N-(3-Phenylpropyl)-1-(3-hydroxyphenyl)ethylamine 13f
3-phenylpropylamine (1.35 g, 10 mmol), and titanium isopropoxide
(3.55 g, 12.5 mmol) was reacted in the usual way to yield 13a as a
colourless oil (1.58 g, 59%). Free base: δH 1.37 (d, J 6.6, 3H), 1.82 (m,
2H), 2.60 (m, 4H), 3.75 (q, J 6.6, 1H), 3.81 (s, 3H), 6.79 (qd, J 1.8,
4.6, 1H), 6.90–6.93 (m, 2H), 7.17–7.32 (m, 6H). δC 24.2 (CH3), 31.8
(CH2), 33.6 (CH2), 47.3 (CH2), 55.1 (CH), 58.3 (CH3), 112.2 (CH),
119.0 (CH), 125.7 (CH), 128.2 (CH), 128.3 (CH), 129.3 (CH), 142.1
(C), 147.5 (C), 159.8 (C).
The free base was converted to its hydrochloride salt, isolated as
a white solid, mp. 118◦C. (Found: [M + 1]+ 270.1845; C18H24NO
requires [M]+ 270.1858). Hydrochloride salt: δH 1.82 (d, J 6.6, 3H),
2.20 (m, 2.51, t, J 7, 2H), 2.64 (t, J 7, 2H), 3.86 (s, 3H), 4.11 (t, J
6.6,1H), 6.88 (dd, J, 1H), 7.04–7.33 (m, 8H), 9.78 (s, 1H, NH), 10.17
(s, 1H, NH). δC 20.5 (CH3), 27.2 (CH2), 32.6 (CH2), 45.1 (CH2), 55.6
(CH), 59.1 (CH3), 112.3 (CH), 115.6 (CH), 119.9 (CH), 126.1 (CH),
128.3 (CH), 130.3 (CH), 137.5 (C), 139.9 (C), 160.4 (C).
A
mixture of 3-hydroxyacetophenone (0.68 g, 5 mmol),
3-phenylpropylamine (0.70 g, 5 mmol), and titanium isopropoxide
(1.85 mL, 6.25 mmol) was reacted as above to yield 13f as a white solid
(0.69 g, 47%), mp. 90–94◦C. (Found [M + H]+ 256.1696; C17H22NO
requires [M]+ 256.1696). δH 1.35 (d, J 6.6, 3H), 1.81 (quin, J 7.2, 2H),
2.56 (m, 4H), 3.72 (q, J 6.6, 1H), 4.99 (bs, OH), 6.71–6.84 (td, J 7.4,
4.4, 3H), 7.10 (m, 6H). δC 22.9 (CH3), 30.7 (CH2), 33.4 (CH2), 46.9
(CH2), 58.2 (CH), 113.3 (CH), 115.1 (CH), 119.0 (CH), 125.8 (CH),
128.3 (CH), 129.7 (CH), 141.6 (C), 145.3 (C), 157.0 (C).
(R,S)-N-(3-Phenylpropyl)-1-(4-hydroxy-3-methoxyphenyl)-
ethylamine 13g
A mixture of 4-hydroxy-3-methoxyacetophenone (0.83 g, 5 mmol),
3-phenylpropylamine (0.70 g, 5 mmol), and titanium isopropoxide
(1.85 mL, 6.25 mmol) was reacted as above to obtain 13g as a white
solid (0.65 g, 45%), mp. 142–143◦C. (Found: [M + 1]+ 286.1810;
C18H24NO2 requires [M]+ 286.1807). δH 1.36 (d, J 6.6, 3H), 1.81 (quin,
J 7.2, 2H), 2.56 (m, 4H), 3.71 (q, J 6.6, 1H), 3.89 (s, 3H), 6.75 (dd, J 1.8,
8.0, 1H), 6.85 (d, J 8.0, 1H), 7.11–7.27 (m, 5H). δC 23.9 (CH3), 31.3
(CH2), 33.6 (CH2), 47.1 (CH2), 55.9 (CH), 58.2 (CH3), 108.8 (CH),
114.1 (CH), 119.6 (CH), 125.8 (CH), 128.3 (CH), 136.6 (C), 141.9 (C),
144.7 (C), 146.7 (C).
(R,S)-N-(3-Phenylpropyl)-1-(4-chlorophenyl)ethylamine 13b
A
mixture
of
4-chloroacetophenone
(1.54 g,
10 mmol),
3-phenylpropylamine (1.35 g, 10 mmol), and titanium isopropoxide
(3.55 g, 12.5 mmol) was reacted as above to yield 13b as a yellow oil
(1.20 g, 44%). The corresponding hydrochloride salt was obtained as a
white solid, mp. 160–164◦C. (Found: [M + 1]+ 274.1369; C17H21ClN
requires [M]+ 274.1363). Free base: δH 1.32 (d, J 6.8, 3H), 1.78 (q, J
7.8, 2H), 2.55 (m, 4H), 3.73 (q, J 6.8, 1H), 7.10–7.28 (m, 9H). δC 24.3
(CH3), 31.8 (CH2), 33.6 (CH2), 47.2 (CH2), 57.7 (CH), 125.7 (CH),
127.9 (CH), 128.3 (CH), 128.5 (CH), 132.3 (C), 142.0 (C), 144.3 (C).
(R,S)-N-(3-Phenylpropyl)-1-(3-ethoxyphenyl)ethylamine 13h
A
mixture of 3-ethoxyacetophenone[24] (0.70 g, 5 mmol),
3-phenylpropylamine (0.70 g, 5 mmol), and titanium isopropoxide
(1.85 mL, 6.25 mmol) was reacted as above to afford 13h as a yellow oil
(0.62 g, 44%). (Found: [M + 1]+ 284.2018; C19H26NO requires [M]+
284.2014). δH 1.39 (d, J 6.6, 3H), 1.46 (t, J 7.2, 3H), 1.84 (m, 2H), 2.62
(m, 4H), 3.76 (q, J 6.6, 1H), 4.08 (q, J 7.2, 2H), 6.81–6.86 (m, 1H),
(R,S)-N-(3-Phenylpropyl)-1-(3,4-dichlorophenyl)ethylamine 13c
A
mixture of 3,4-dichloroacetophenone (1.89 g, 10 mmol),
3-phenylpropylamine (1.35 g, 10 mmol), and titanium isopropoxide

Synthesis and Biological Activity of Allosteric Modulators of GABAB Receptors
453
6.91–6.95 (m, 2H), 7.18–7.31 (m, 6H). δC 14.8 (CH3), 24.2 (CH3), 31.8
(CH2), 33.5 (CH2), 47.2 (CH2), 58.2 (CH), 63.1 (CH2), 112.5 (CH),
112.6 (CH), 118.7 (CH), 125.6 (CH), 128.2 (CH), 129.2 (CH), 142.1
(C), 147.4 (C), 159.0 (C).
3.89 (s, 3H), 6.88 (d, J 8.4, 1H), 7.11–7.30 (m, 5H), 7.34 (d, J 2.2, 1H).
δC 24.1 (CH3), 29.8 (CH2), 31.2 (CH2), 47.0 (CH2), 56.1 (CH), 57.3
(CH3), 112.0 (CH), 122.3 (C), 125.9 (CH), 126.7 (CH), 127.2 (CH),
128.4 (CH), 129.4 (CH), 130.3 (CH), 133.8 (C), 138.5 (C), 139.5 (C),
153.8 (C).
(R,S)-N-(3-Phenylpropyl)-1-(3-chloro-4-methoxyphenyl)-
ethylamine 13i
(R,S)-N-[3-(2-Chlorophenyl)propyl]-1-(6-bromo-3-methoxyphenyl)-
ethylamine 13m
A mixture of 3-chloro-4-methoxyacetophenone (0.76 g, 4.11 mmol),
3-phenylpropylamine (0.55 g, 4.11 mmol), and titanium isopropox-
ide (0.57 g, 5.25 mmol) was reacted as above to produce 13i as a
yellow oil (0.58 g, 48%). The corresponding hydrochloride salt was
obtained as a white solid, mp. 145–148◦C. (Found: [M + H]+ 304.1460;
C18H2335ClNO requires [M]+ 304.1463). Free base: δH 1.31 (d, J 6.6,
3H), 1.78 (m, 2H), 2.57 (m, 4H), 3.68 (q, J 6.6, 1H), 3.89 (s, 3H), 6.88
(d, J 8.4, 1H), 7.13–7.33 (m, 8H). δC 24.1 (CH3), 31.6 (CH2), 33.6
(CH2), 47.1 (CH2), 56.2 (CH), 57.4 (CH3), 112.1 (CH), 122.4 (CH),
125.8 (CH), 128.3 (CH), 128.5 (CH), 138.8 (C), 141.1 (C), 142.1 (C),
153.9 (C).
A mixture of 6-bromo-3-methoxyacetophenone (0.69 g, 3.0 mmol),
3-(2-chlorophenyl)propylamine (0.51 g, 3.0 mmol), and titanium iso-
propoxide (1.3 mL, 4.25 mmol) was reacted as above to yield 13m as
a yellow oil (0.47 g, 43%). The corresponding hydrochloride salt was
obtained as a white solid, mp. 144–146◦C. (Found: [M + H]+ 382.0571;
C18H2279BrNO35Cl requires [M]+ 382.0568). Free base: δH 1.39 (d, J
6.6, 3H), 1.87 (m, 2H), 2.65 (m, 4H), 3.81 (s, 3H), 4.30 (q, J 6.6, 1H),
6.69 (dd, J 3.2, 12.1, 1H), 7.10–7.33 (m, 5H), 7.40 (d, J 8.8, 1H). δC
22.6 (CH3), 29.8 (CH2), 31.1 (CH2), 46.9 (CH2), 55.3 (CH), 56.7 (CH3),
112.7(CH), 113.8(C), 114.2(CH), 126.6(CH), 129.2(CH), 130.1(CH),
133.2 (CH), 133.7 (C), 139.5 (C), 144.8 (C), 159.3 (C).
(R,S)-N-(3-Phenylpropyl)-1-(3-bromo-4-methoxyphenyl)-
ethylamine 13j
Bromination of 13h
A solution of bromine (25 µL) in carbon tetrachloride (1 mL) was
added slowly with stirring to a solution of 13h (141 mg) in carbon
tetrachloride (1 mL) at room temperature. After 2 h, the solvent was
evaporated, 1 M NaOH (2 mL) was added, and the mixture extracted
with ether (3 × 10 mL), and the dried extract evaporated to give a
yellow oil (240 mg) which was purified by chromatography (hexane/
dichloromethane) to give three fractions.The first (40 mg) was identified
as the reactant. The second fraction was a yellow oil (50 mg), identi-
fied as the mono brominated product 13n. (Found: [M + 1]+ 362.1114;
C19H2579BrNO requires [M]+ 362.1120). δH 1.45 (t, J 7, 3H), 1.85 (d,
J 6, 3H), 2.4 (m, 6H), 4.05 (q, J 7, 2H), 4.31 (q, J 6, 1H), 6.68 (dd, J 3,
8, 1H), 7.00 (d, J 3, 1H), 7.1–7.3 (m, 5H), 7.40 (d, J 8, 1H). A nOe was
observed between the quartet at δ 4.05 and the triplet at δ 1.45, and the
doublets at δ 6.68 and 7.00.
A mixture of 3-bromo-4-methoxyacetophenone (0.68 g, 3.0 mmol),
3-phenylpropylamine (0.40 g, 3.0 mmol), and titanium isopropoxide
(1.3 mL, 4.25 mmol) was reacted as above to yield 13j as a colour-
less oil (0.55 g, 53%). The corresponding hydrochloride salt was
obtained as a white solid, mp. 157–160◦C. (Found: [M + H]+ 348.0958;
C18H2379BrNO requires [M]+ 348.0958). Free base: δH 1.31 (d, J 6.6,
3H), 1.78 (m, 2H), 2.57 (m, 4H), 3.68 (q, J 6.6, 1H), 3.89 (s, 3H), 6.88
(d, J 8.4, 1H), 7.13–7.33 (m, 8H). δC 24.1 (CH3), 31.6 (CH2), 33.6
(CH2), 47.1 (CH2), 56.2 (CH), 57.4 (CH3), 112.1 (CH), 122.4 (CH),
125.8 (CH), 128.3 (CH), 128.5 (CH), 138.8 (C), 141.1 (C), 142.1 (C),
153.9 (C).
(R,S)-N-[3-(2-Chlorophenyl)propyl]-(3-methoxyphenyl)-
ethylamine 13k
The third fraction (20 mg) was the dibromo compound 13o, isolated
as a yellow oil. (Found: [M + 1]+ 440.0228; C19H2479Br2NO requires
440.0225).
N-3-(2-Chlorophenyl)propylamine
To a stirred solution of aluminium hydride (1.0 g, 26 mmol) in dry
ether (50 mL) at 0◦C was added dropwise 2-chlorocinnamonitrile (2.0 g,
12 mmol) in ether (10 mL). The reaction mixture was refluxed for 4 h.
The mixture was cooled to 0◦C and 1 M hydrochloric acid was added
slowly.The aqueous layer was neutralized with 1 M NaOH and extracted
with ether. The ether layer was dried over Na2SO4 and concentrated
to yield N-3-(2-chlorophenyl)propylamine as a pale yellow oil (2.01 g,
98%). δH 1.54 (bs, 2H, NH2), 1.72 (m, 2H), 2.72 (m, 4H), 7.04–7.30 (m,
4H). δC 30.7 (CH2), 33.3 (CH2), 41.7 (CH2), 126.6 (CH), 127.0 (CH),
129.2 (CH), 130.1 (CH), 133.7 (C), 139.6 (C).
(R)-N-(3-Phenylpropyl)-1-phenylethylamine 15
A
mixture of (R)-α-methylbenzylamine (0.60 g, 5 mmol),
3-phenylpropanal (0.67 g, 5 mmol), and titanium isopropoxide (1.065 g,
6.25 mmol) was reacted as above to yield (R)-15 as yellow oil (0.50 g,
49%). δH 1.40 (d, J 6.8, 3H), 1.83 (quin, J 7.2, 2H), 2.58 (m, 4H), 3.80
(q, J 6.8, 1H), 7.15–7.36 (m, 10H). δC 23.2 (CH3), 30.5 (CH2), 33.8
(CH2), 46.7 (CH2), 58.5 (CH), 125.8 (CH), 126.9 (CH), 127.5 (CH),
128.3 (CH), 128.7 (CH), 141.5 (C), 145.2 (C).
The (S)-enantiomer was obtained in the same way from (S)-α-
methylbenzylamine.
A mixture of 3-methoxyacetophenone (0.75 g, 5.0 mmol), 3-(2-
chlorophenyl)propylamine (0.85 g, 5.0 mmol), and titanium isopropox-
ide (1.80 g, 6.25 mmol) was reacted as above to yield 13k as a yellow oil
(250 mg, 24%). The corresponding hydrochloride salt was obtained as a
white solid, mp. 135–140◦C. (Found: [M + 1]+ 304.1473; C18H23ClNO
requires [M]+ 304.1468). Free base: δH 1.36 (d, J 6.6, 3H), 1.80 (m, 2H),
2.54 (m, 2H), 2.75 (m, 2H), 3.78 (q, J 6.6, 1H), 3.81 (s, 3H), 6.77 (dd,
J 1.2, 3.4, 1H), 6.90 (dd, J 2.4, 5.6, 2H), 7.11–7.33 (m, 5H). δC 23.6
(CH3), 29.3 (CH2), 31.1 (CH2), 46.8 (CH2), 55.2 (CH), 58.4 (CH3),
112.1 (CH), 119.2 (CH), 126.7 (CH), 127.3 (CH), 129.5 (CH), 130.3
(CH), 133.9 (C), 139.4 (C), 145.8 (C), 159.8 (C).
(R)-N-(3-Phenylpropyl)-1-(1-napthyl)ethylamine 16
A
mixture of R-α-(1-naphthyl)ethylamine (0.40 mL, 2.5 mmol),
3-phenylpropanal (0.33 mL, 2.5 mmol), and titanium isopropoxide
(0.53 g, 3.25 mmol) was reacted as above to yield pure (R)-16 as a yellow
oil (650 mg, 90%). The free base was converted to the correspond-
ing hydrochloride salt, mp. 130–138◦C. (Found: [M + 1]+ 290.1920;
C21H24N requires [M]+ 290.1909). Free base: δH 1.56 (d, J 6.8, 3H),
1.90 (quin, J 7.4, 2H), 2.63 (m, 4H), 4.71 (q, J 6.8, 1H), 7.10–7.28 (m,
3H), 7.46–7.56 (m, 4H), 7.72–7.79 (m, 2H), 7.86–7.91 (m, 2H), 8.12
(d, J 9.6, 1H). δC 23.2 (CH3), 31.2 (CH2), 33.5 (CH2), 47.2 (CH2), 53.6
(CH), 122.7 (CH), 123.1 (CH), 125.4 (CH), 125.6 (CH), 125.8 CH),
125.9 (CH), 127.5 (CH), 128.3 (CH), 128.5 (CH), 128.9 (CH), 129.4
(C), 131.2 (C), 133.9 (C), 141.8 (ArC).
(R,S)-N-[3-(2-Chlorophenyl)propyl]-1-(3-chloro-4-methoxyphenyl)-
ethylamine 13l
A mixture of 3-chloro-4-methoxyacetophenone (0.37 g, 2.0 mmol),
3-(2-chlorophenyl)propylamine (0.34 g, 2.0 mmol), and titanium iso-
propoxide (0.9 mL, 3 mmol) was reacted as above to yield 13l as a pale
yellow oil (250 mg, 37%). The corresponding hydrochloride salt was
obtained as a white solid, mp. 198–200◦C. (Found: [M + H]+ 338.1072;
C18H2235Cl2NO requires [M]+ 338.1073). Free base: δH 1.34 (d, J 6.6,
3H), 1.79 (m, 2H), 2.51 (m, 2H), 2.72 (m, 2H), 3.71 (q, J 6.6, 1H),
The (S)-enantiomer was obtained in the same way.
(R,S)-N-(3-Phenylpropyl)-N-[1-(3-methoxyphenyl)ethyl]Urea 17
A solution of NPS 467 13a (0.27 g, 1 mmol) in glacial acetic acid
(0.5 mL) and water (0.5 mL) was treated dropwise with sodium cyanate

454
D. I. B. Kerr et al.
(0.13 g, 2 mmol) in water (1 mL) at 35◦C. The reaction mixture was
stirred overnight, cooled to 0◦C and extracted with ether. The extract
was washed with saturated aqueous Na2CO3, dried over Na2SO4, and
concentrated to yield a glass (0.14 g, 45%), which could not be induced
to crystallize. (Found: [M + H]+ 313.1906; C19H25N2O2 requires [M]+
313.1911). δH 1.49 (d, J 7.2, 3H), 1.74 (dd, J 2.0, 6.1, 2H), 2.49 (t, J
7.2, 2H), 2.98 (m, 2H), 3.79 (s, 3H), 5.44 (q, J 7.2, 1H), 6.82 (m, 3H),
7.08 (dd, J, 2H), 7.26 (m, 4H). δC 17.3 (CH3), 30.9 (CH2), 33.2 (CH2),
43.3 (CH2), 53.0 (CH), 55.3 (CH3), 112.5 (CH), 113.2 (CH), 112.1
(CH), 119.4 (CH), 126.1 (CH), 128.3 (CH), 128.5 (CH), 129.5 (CH),
140.9 (C), 143.1 (C), 158.6 (C), 159.8 (CO). νmax (KBr/cm−1) 3359
(br), 1650, 1257.
10, 1H), 7.89 (d, J 10, 1H), 8.0 (dd, J 9.5, 1.0, 1H), 8.20 (d, J 9, 1H).
δC (DMSO) 23.1, 45.7, 121.2, 121.8, 123.0, 123.3, 124.0, 126.5, 126.6,
127.2, 128.3, 128.4, 129.6, 130.0, 131.2, 134.4, 137.6, 141.4, 154.8.
N-2-Chlorophenyl-Nꢀ-1-(1-naphthyl)ethyl Thiourea 22
The use of 2-chlorophenyl isothiocyanate, as above, gave 22 as white
crystals (61%) from ethyl acetate, mp. 162–164◦C. (Found: [M]+
340.0812; C19H17ClN2S requires [M]+ 340.0801). δH (DMSO) 1.67
(d, J 6.6, 3H), 6.28 (m, 1H), 7.22 (t, J 8.1, 1H), 7.33 (t, J 7.5, 1H), 7.50
(d, J 8.1, 1H), 7.55–7.65 (m, 4H), 7.85 (d, J 6.9, 1H), 7.92 (d, J 7.8, 1H),
8.01 (d, J 8.1, 1H), 8.21 (d, J 8.1, 1H), 8.64 (d, J 8.1, 1H), 9.05 (br s,
1H), 8.64 (d, J 8.1, 1H). δC (DMSO) 21.4, 50.1, 123.8, 124.9, 126.4,
126.7, 127.3, 127.3, 127.5, 127.8, 128.6, 129.9, 130.2, 131.6, 134.4,
137.6, 139.6, 181.5.
N-[1-(3-Methoxyphenyl)ethyl]-N-(3-phenylpropyl)guadinium
Sulfate 18
A mixture of 13a (0.27 g, 1 mmol), and S-methylisothiouronium sulfate
(0.14 g, 0.5 mmol) in ethanol (5 mL) and water (5 mL) was refluxed for
3 h. The solvent was then evaporated to give a colourless gel (0.150 g),
which was triturated with acetone to yield 18 in the acetone-soluble
fraction as a pale yellow gel. (Found: [M + H]+ 312.2080; C19H26N3O
requires [M]+ 312.2143). δH 1.91 (d, J 6.8, 3H), 2.30 (m, 2H), 2.62 (t,
J 6.8, 2H), 2.84 (m, 2H), 3.95 (s, 3H), 4.35 (q, J 6.6, 1H), 7.05 (dd,
J 2.2, 2.4, 1H), 7.20–7.38 (m, 7H), 7.39–7.45 (d, J 1.2, 1H). δC 20.3
(CH3), 26.7 (CH2), 32.5 (CH2), 44.8 (CH2), 55.3 (CH), 58.1 (CH3),
113.2 (CH), 114.3 (CH), 119.9 (CH), 125.9 (CH), 128.3 (CH), 130.1
(CH), 138.4 (C), 140.4 (C), 160.1 (C), 161.9 (C), 163.4 (C).
3-(2-Chorophenyl)-N-1-(1-naphthyl)ethylpropenamide 25
1-(1-Naphthyl)ethylamine (473 mL, 3 mmol) was added to a solution of
2-chlorocinnamoyl chloride (605 mg, 3 mmol) in pyridine (1 mL) and
dichloromethane (5 mL), and the mixture stirred overnight at room tem-
perature. The solvents were removed, and the residue was partitioned
between ether and 2 M HCl. The ether phase was washed with water,
dried and evaporated and the product recrystallized from ethyl acetate
as fine pale yellow crystals (742 mg, 74%), mp. 125–126◦C. (Found:
[M]+ 335.1070; C21H18ClNO requires [M]+ 335.1077). δH (DMSO)
1.61 (d, J 6.9, 3H), 5.89 (m, 1H), 6.80 (d, J 15.9, 1H), 7.42–7.47 (m,
2H), 7.53–7.64 (m, 5H), 7.72–7.75 (m, 1H), 7.78 (d, J 15.6, 1H), 7.89
(d, J 7.8, 1H), 8.01 (d, J 8.7, 1H), 8.19 (d, J 8.1, 1H), 8.67 (d, J 8.1, 1H).
δC (DMSO) 27.9, 45.2, 123.5, 124.1, 126.1, 126.4, 126.6, 127.3, 128.4,
128.5, 128.7, 129.6, 130.9, 131.4, 131.9, 133.6, 134.2, 134.4, 135.2,
140.7, 169.4.
Reaction of 13a with Methyl Iodide
A solution of 13a (0.30 g, 1 mmol) and methyl iodide (0.07 mL,
1.25 mmol) in dichloromethane (5 mL) was stirred at room temperature
for52 h.Thesolutionwasdilutedwithethertoyieldayellowgel(0.33 g).
Crystallizationfromacetone/ethergaveawhitepowderwhichwasfound
to be a mixture of the N-methylated hydroiodide and the N,N-dimethyl
quaternary salt. The two products were separated by addition of aque-
oussodium hydroxide followed by extraction with dichloromethane.The
dichloromethane extract was evaporated and the residue was extracted
with ether to yield 19 as a thick yellow oil (100 mg) and the ether insol-
uble fraction was found to be the quaternary salt 20, isolated as a white
powder (100 mg), mp. 110–114◦C.
(R)-N-4-(Phenylbutyl)-1-phenylethylamine 26
A
mixture of 4-phenylbutanal[42] (0.74 g, 5 mmol), (R)-α-
methylbenzylamine (0.60 g, 5 mmol), and titanium isopropoxide
(1.86 mL, 6.25 mmol) was reacted as above to give 26 as an oil, char-
acterized as the hydrochloride salt, mp. 140◦C. (Found: [M + 1]+
254.1918; C18H24N requires [M]+ 254.1909). The hydrochloride salt
was basified with 1 M NaOH to afford the oily free base (0.66 g). Free
base: δH 1.35 (d, J 6.6, 3H), 1.59 (m, 4H), 2.55 (m, 4H), 3.74 (q, J 6.6,
1H), 7.12–7.34 (m, 10H). δC 24.3 (CH3), 29.2 (CH2), 29.9 (CH2), 35.8
(CH2), 47.7 (CH2), 58.4 (CH), 125.6 (CH), 126.5 (CH), 126.8 (CH),
128.2 (CH), 128.4 (CH), 142.5 (C), 145.9 (C). Hydrochloride salt: δH
1.55 (m, 2H), 1.87 (d, J 6.8, 3H), 1.95 (m, 2H), 2.52 (t, J 8, 2H), 2.66 (t,
J 8.8, 2H), 4.16 (q, J 6.8, 1H), 7.16 (m, 5H), 7.41 (m, 3H), 7.57 (dd, J
2.2, 1.4, 2H). δC 20.6 (CH3), 25.6 (CH2), 28.6 (CH2), 35.2 (CH2), 45.5
(CH2), 58.8 (CH), 125.9 (CH), 127.8 (CH), 128.3 (CH), 128.4 (CH),
129.3 (CH), 129.4 (CH), 136.2 (C), 141.4 (C).
N-Methyl-N-(3-phenylpropyl)-1-(3-methoxyphenyl)ethylamine 19
(Found: [M + 1]+ 284.2013; C19H26NO requires [M]+ 284.2009).
δH 1.39 (d, J 6.8, 3H), 1.84 (m, 2H), 2.22 (s, 3H), 2.40 (m, 2H), 2.62
(m, 2H), 3.59 (q, J 6.8, 1H), 3.81 (s, 3H), 6.78 (dd, J 2.2, 2.2, 1H), 6.90
(m, 2H), 7.10–7.30 (m, 6H). δC 18.4 (CH3), 28.6 (CH2), 33.5 (CH2),
38.3 (CH2), 53.8 (CH3), 55.2 (CH), 63.6 (CH3), 112.3 (C), 113.4 (CH),
120.2 (CH), 125.7 (CH), 128.3 (CH), 129.1 (CH), 142.3 (C), 159.6 (C).
N,N-Dimethyl-N-(3-phenylpropyl)-1-(3-methoxyphenyl)-
ethylammonium Iodide 20
(R,S)-N-(4-Phenylbutyl)-1-(3-methoxyphenyl)ethylamine 27
A
mixture
of
4-phenylbutylamine
(0.75 g,
5 mmol),
(Found: [M]+ 298.2167; C20H28NO requires [M]+ 298.2165). δH
1.74 (d, J 6.8, 3H), 2.14 (quin, J 7.2, 2H), 2.77 (q, J 7.6, 2H), 3.17 (s,
3H), 3.19 (s, 3H), 3.53 (m, 2H), 3.85 (s, 3H), 3.52 (q, J 6.8, 1H), 6.96
(dd, J 2.2, 2.2, 1H), 7.09 (d, J 12.6, 1H), 7.19–7.39 (m, 7H). δC 15.2
(CH3), 24.8 (CH2), 32.3 (CH2), 48.0 (CH3), 48.7 (CH3), 55.8 (CH2),
61.9 (CH), 72.9 (CH3), 116.1 (CH), 116.8 (CH), 126.8 (CH), 128.5
(CH), 128.9 (CH), 130.5 (CH), 133.4 (C), 139.2 (C), 160.1 (C).
3-methoxyacetophenone (0.60 g, 5 mmol), and titanium isopropoxide
(1.86 mL, 6.25 mmol) was reacted as above to yield 27 as a yellow oil
(1.19 g, 75%). (Found: [M + 1]+ 284.1917; C20H30NO requires [M]+
284.2009). Free base: δH 1.35 (d, J 6.6, 3H), 1.56 (m, 4H), 2.56 (m,
4H), 3.73 (q, J 6.6, 1H), 3.82 (s, 3H), 6.85 (dd, J 11.0, 7.2, 1H), 6.90
(dd, J 2.2, 1.4, 2H), 7.12–7.34 (m, 6H). δC 24.3 (CH3), 29.1 (CH2), 29.9
(CH2), 35.7 (CH2), 47.6 (CH2), 55.1 (CH), 58.4 (CH3), 112.1 (CH),
118.9 (CH), 125.7 (CH), 128.2 (CH), 128.4 (CH), 129.3 (CH), 142.4
(C), 147.6 (C), 159.8 (C).
N-2-Chlorophenyl-Nꢀ-1-(1-naphthyl)ethyl Urea 21
2-Chlorophenyl isocyanate (460 mg, 3 mmol) was added dropwise
to a solution of 1-(1-naphthyl)-ethylamine (473 µL, 3 mmol) in
dichloromethane (5.5 mL) at room temperature, and stirred for 1 h. The
solvent was removed and the residue recrystallized from ethyl acetate
to give 21 as white needles (700 mg, 72%), mp. 195–196◦C. (Found:
[M+] 324.1020; C19H17ClN2O requires [M]+ 324.1029). δH (DMSO)
1.60 (d, J 6.5, 3H), 5.70 (q, J 6.5, 1H), 6.97 (dt, J 7.2, 0.9, 1H), 7.25
(dt, J 7.2, 0.9, 1H), 7.42 (dt, J 8.5, 0.8, 1H), 7.60 (m, 4H), 7.71 (d, J
(R,S)-N-[(2-Chlorophenyl)ethyl]-1-(3-methoxyphenyl)ethylamine 28
A
mixture of 3-methoxyacetophenone (0.75 g, 5 mmol), 2-(2-
chlorophenyl)ethylamine (0.78 g, 5 mmol), and titanium isopropoxide
(1.80 g, 6.25 mmol) was reacted as above to yield 28 as a yellow oil
(300 mg) which was converted to the white hydrochloride salt (500 mg),
mp. 166–170◦C. (Found: [M + H]+ 290.1304; C17H2135ClNO requires
[M]+ 290.1306). Free base: δH 1.35 (d, J 6.6, 3H), 2.70 (m, 2H), 2.80

Synthesis and Biological Activity of Allosteric Modulators of GABAB Receptors
455
(m, 2H), 3.79 (s, 3H), 3.80 (q, J 6.6, 1H), 6.76 (dd, J 3.6, 3.4, 1H), 6.89
All numerical data on the concentration-response curves were
(dd, J 2.4, 1.8, 2H), 7.12–7.35 (m, 5H). δC 24.3 (CH3), 34.2 (CH2), 47.1
(CH2), 55.1 (CH), 58.0 (CH3), 111.9 (CH), 112.3 (CH), 119.0 (CH),
126.7 (CH), 127.5 (CH), 129.3 (CH), 129.5 (CH), 130.6 (CH), 134.1
(C), 137.7 (C), 147.5 (C), 159.8 (C).
expressed as means standard error. Each experiment was repeated
on 6–12 slices obtained from at least six different animals. Compari-
son of the data was made using a Student’s t-test with P < 0.05 being
significant.
N-3-(2-Chlorophenylpropyl)-(3-methoxy)benzylamine 29
Acknowledgments
A mixture of 3-methoxybenzaldehyde (0.6 mL, 5.0 mmol), 3-(2-
chlorophenyl)propylamine (0.85 g, 5.0 mmol), and titanium isopropox-
ide (1.80 g, 6.25 mmol) was reacted as above to yield 29 as a yellow oil
(280 mg, 19%). (Found: [M + H]+ 290.1307; C17H2135ClNO requires
[M]+ 290.1306). δH 1.86 (quin, J 7.4, 2H), 2.70 (t, J 7.4, 2H), 2.80 (t,
J 7.4, 2H), 3.80 (s, 2H), 3.81 (s, 3H), 6.82 (dd, J 11.2, 9.2, 1H), 6.91
(dd, J 2.2, 7.4, 2H), 7.11–7.35 (m, 5H). δC 29.6 (CH2), 31.2 (CH2), 48.5
(CH2), 53.6 (CH), 55.2 (CH3), 112.8 (CH), 113.7 (CH), 126.8 (CH),
127.3 (CH), 129.5 (CH), 130.6 (CH), 133.9 (C), 139.5 (C), 141.0 (C),
159.8 (C).
N.M.P. is grateful for the award of an overseas scholarship
from Austaid.
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