Novel and potent small-molecule urotensin II receptor agonists

Article abstract of DOI:10.1016/j.bmc.2009.04.062

A series of analogs of the non-peptidic urotensin II receptor agonist N-[1-(4-chlorophenyl)-3-(dimethylamino)propyl]-4-phenylbenzamide (FL104) has been synthesized and evaluated pharmacologically. The enantiomers of the two most potent racemic analogues were obtained from the corresponding diastereomeric mandelic amides. In agreement with previously observed SAR, most of the agonist potency resided in the (S) enantiomers. The most potent UII receptor agonist in the new series was (S)-N-[3-dimethylamino-1-(2-naphthyl)propyl]-4-(4-chlorophenyl)benzamide (EC₅₀ = 23 nM at the urotensin II receptor).

Full text of DOI:10.1016/j.bmc.2009.04.062

Bioorganic & Medicinal Chemistry 17 (2009) 4657–4665
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Novel and potent small-molecule urotensin II receptor agonists
Fredrik Lehmann a, Erika A. Currier d, Bryan Clemons d, Lars K. Hansen b, Roger Olsson c, Uli Hacksell d,
Kristina Luthman a,
*
a Department of Chemistry, Medicinal Chemistry, University of Gothenburg, SE-412 96 Göteborg, Sweden
b Department of Chemistry, University of Tromsø, 9037 Tromsø, Norway
c ACADIA Pharmaceuticals AB, Medeon Science Park, SE-205 12 Malmö, Sweden
d ACADIA Pharmaceuticals Inc., 3911 Sorrento Valley Boulevard, San Diego, CA 92121, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of analogs of the non-peptidic urotensin II receptor agonist N-[1-(4-chlorophenyl)-3-(dimethyl-
amino)propyl]-4-phenylbenzamide (FL104) has been synthesized and evaluated pharmacologically. The
enantiomers of the two most potent racemic analogues were obtained from the corresponding diastereo-
meric mandelic amides. In agreement with previously observed SAR, most of the agonist potency resided
in the (S) enantiomers. The most potent UII receptor agonist in the new series was (S)-N-[3-dimethyl-
amino-1-(2-naphthyl)propyl]-4-(4-chlorophenyl)benzamide (EC50 = 23 nM at the urotensin II receptor).
Ó 2009 Published by Elsevier Ltd.
Received 15 December 2008
Revised 24 April 2009
Accepted 28 April 2009
Available online 3 May 2009
Keywords:
Urotensin II
Agonists
SAR
R-SAT
Parallel synthesis
1. Introduction
O
O
O
The discovery of FL104, a potent urotensin II (UII) receptor1 ago-
nist was recently reported (Fig. 1).2 This compound is more potent
than isochromanone derivative AC-7954, the first non-peptide UII-
receptor agonist (Fig. 1).3 Herein, we describe the synthesis and
pharmacological testing of a series of analogues of FL104. One of
these novel compounds, (S)-{C6}, is the most potent non-peptide
UII receptor agonist described in the literature.
NH
N
N
Cl
{A5} FL104, pEC50 7.11
Cl
AC-7954, pEC50 5.95
Figure 1. FL104 (left) and AC-7954 (right) are potent UT receptor agonists.
In our previous study of benzamide derivatives, we observed
that large substituents such as phenyl or phenoxy in the 4-position
of the benzamide moiety were beneficial to agonist potency. In the
present study, we synthesized a series of amides in which electron
withdrawing (4-chlorophenyl), donating (4-methoxyphenyl) or
sterically demanding (2-naphthyl) groups were introduced in
either the 3- or 4-positions on the benzamide ring to further ex-
plore the requirements for potent UII receptor-agonist activity. In
addition, we synthesized analogues in which the 4-chlorophenyl
group of FL104 was replaced by electron donating (4-methyl-
phenyl) or bulky (2-naphthyl) aromatic ring systems. To enable
further comparisons between SAR in the isochromanone4 and
benzamide series of UII receptor agonists, we synthesized ana-
logues in which (i) the distance between the aromatic rings and
the dimethylamino group was varied and (ii) the dimethylamino
group was replaced by a piperidine moiety.
2. Results and discussion
2.1. Chemistry
The target benzamide derivatives were synthesized in a library
format from benzoyl chlorides (formed in situ) and the appropriate
amines.
2.1.1. Synthesis of benzoic acids
The benzoic acids 2, 4, 6 and 8 were synthesized (Scheme 1)
from the corresponding 3- or 4-iodobenzoic acids in a Suzuki cou-
pling reaction,5 with boronic acids and palladium on charcoal using
microwave heating at 180 °C for 15 min. After workup (filtration,
* Corresponding author. Tel.: +46 31 772 2894; fax: +46 31 772 3840.
E-mail address: luthman@chem.gu.se (K. Luthman).
0968-0896/$ - see front matter Ó 2009 Published by Elsevier Ltd.
doi:10.1016/j.bmc.2009.04.062

4658
F. Lehmann et al. / Bioorg. Med. Chem. 17 (2009) 4657–4665
COOH
OH
OH
3. Pharmacological testing
COOH
i
R1
R2 B
R2
+
3.1. Pharmacological testing
2 R2 = 3-(4-chlorophenyl)
4 R2 = 3-(2-naphthyl)
R1 = 3-I or 4-I
Compounds {A1–E10} were tested for their ability to stimulate
the human UT-receptor using a functional R-SATTM assay previously
described.7 The results are shown in Tables 1–4.
6 R2 = 4-(4-chlorophenyl)
8 R2 = 4-(2-naphthyl)
Scheme 1. Reagents and conditions: (i) Pd/C (10%), H2O, ethanol, 180 °C, 15 min
(microwave).
3.2. Structure–activity relationships
As is apparent from Table 1 and illustrated in Figure 2, the posi-
tioning of the biphenyl is of vital importance for potency, as all 4-
biaryl derivatives ({A5–C8}) are significantly more potent than
their corresponding 3-biaryl analogues ({A1–C4}) independent on
other structural differences.
Within the 3-biaryl series it seems that the substitution pattern
in the two rings plays only a minor role for the potency as all but
two derivatives ({B4} and {C4}) exhibit EC50-values within 0.5 log
units (pEC50 5.96–6.44) (Table 1 and Fig. 2). Another trend, espe-
cially in the 4-biaryl series, is that the 4-(2-naphthyl) substituent
is least favoured of the substituents evaluated ({A4–C4} and {A8–
C8}). Throughout, all 4-substituted biaryl derivatives showed high-
er or much higher efficacies than the corresponding 3-substituted
analogues (Table 1).
OH
O
R
R
i
n
n
Cl
Cl
11 n = 1, R = 1-piperidinyl
12 n = 2, R = N(CH )
13 n = 1, R = 1-piperidinyl, 99%
14 n = 2, R = N(CH ) , 80%
3 2
3 2
NH
2
ii, iii
N
N
A
NH
2
Cl
R
NH
2
n
Cl
D n = 1, R = 1-piperidinyl, 79%
E n = 2, R = N(CH ) , 70%
B
In our previous study of isochromanone analogues,4 we ob-
served that a longer linker chain between the aromatic rings and
the amino moiety decreased the activity by around 0.5 log units.
We also established that larger amino groups than dimethylamino
decreased the agonist potency.4 In the current series of benzam-
ides, {E5} and {E10}, that have a three-carbon linker chain showed
a similar decrease (0.5 log units) in potency (Table 2) when com-
pared with the corresponding compounds with a two-carbon lin-
ker ({A5} and 18, respectively (18: pEC50: 5.85, Efficacy 158%).2
3 2
NH
2
N
C
Scheme 2. Reagents and conditions: (i) LiAlH4, THF; (ii) CH3CN, H2SO4, ꢀ15 °C; (iii)
6 M HCl reflux.
extraction and recrystallization) the corresponding acids were ob-
tained in moderate to excellent yields (65% for 8, 99% for the
others).
O
NH
N
2.1.2. Synthesis of amines
The amines A–E were synthesized from their corresponding
alcohols using a Ritter reaction as previously described6 (Scheme
2), (for the synthesis of A–C see Ref. 6).
18
Cl
In addition, the piperidinyl analogues {D5} and {D10} are less
potent that the corresponding dimethylamino derivatives (Table
2). Taken together, these results indicate that the isochromane
and benzamide series bind to and activate the UII receptor in a
similar fashion. Further support for this hypothesis comes from
computational studies.2
We have earlier shown that the more potent enantiomers in the
benzamide series of UT-agonists have the S-configuration.2 In or-
der to study the stereoselectivity of the most potent analogs syn-
thesized herein, the diastereomeric amides {A9} and {C9} were
synthesized (Table 3). The absolute configuration of (ꢀ)-{C9} was
determined using X-ray crystallography and was found to have
the (R,S)-configuration (Fig. 3).
2.1.3. Synthesis of amides
The amides {A1–C8} (Table 1) and {D5, E5, D10, E10} (Table 2)
were synthesized using a procedure previously reported (Scheme
3).2
The benzoic acids were dissolved in THF and triethylamine and
thionyl chloride were added sequentially. The resulting benzoyl
chlorides were not isolated, instead the amines A–E were added di-
rectly to the mixture. Basic workup and filtration through an ion-
exchange resin afforded the amides in moderate to excellent yields
(41–99%).
2.1.4. Resolution of racemates
In separate experiments (ꢀ)- and (+)-{C9} were hydrolyzed and
both enantiomers of amine C were reacted with acid 6 to yield (+)-
{C6} and (ꢀ)-{C6}, respectively. Similarly, the separated diastereo-
mers of {A9} were hydrolyzed and converted into benzamides (+)
and (ꢀ)-{A9} (presumably (S) and (R)-{A5}, respectively). The (S)
enantiomers were the more potent antipodes (Table 4) and (+)-
(S)-{C6} is the most potent non-peptidic UT-receptor agonist iden-
tified so far.
To prepare the enantiomers of amines A and C, the correspond-
ing racemates were reacted with (R)-2-methoxy-2-phenylacetic
acid (9) in the presence of EDC and DMAP to produce {A9} and
{C9}, respectively (Scheme 4).
The diastereomeric amides were separated by flash chromatog-
raphy to yield (+)- and (ꢀ)-{A9} and {C9} which were subsequently
hydrolyzed using refluxing 6 M HCl. The amines (+)- and (ꢀ)-A and
C
were reacted with 4-phenylbenzoic acid and 4-(4-chloro-
Based on the results presented and previously2,6 reported stud-
ies the SAR findings for these series of compounds could be sum-
marized as defined in Figure 4.
phenyl)benzoic acid to afford amides (+)- and (ꢀ)-{A5} and {C6},
respectively, in good yields using the same method as described
above.

F. Lehmann et al. / Bioorg. Med. Chem. 17 (2009) 4657–4665
4659
Table 1
Yields, activity and efficacy of amides {A1–C8} at the UT-receptora,b
NH2
NH2
NH2
N
N
N
Cl
A
B
C
1
R = 3-phenyl
5
6
7
8
R = 4-phenyl
COOH
2
3
4
R = 3-(4-chlorophenyl)
R = 3-(4-methoxyphenyl)
R = 3-(2-naphthyl)
R = 4-(4-chlorophenyl)
R = 4-(4-methoxyphenyl)
R = 4-(2-naphthyl)
R
Acids
Amines
A
B
C
1
{A1}
{B1}
{C1}
Yield 65%
pEC50 6.24 0.23
Efficacy 92 26
Yield 65%
pEC50 6.09 0.07
Yield 95%
pEC50 6.27 0.17
Efficacy 67
Efficacy 45
4
5
2
3
4
5
6
7
8
a
{A2}
Yield 60%
pEC50 6.36 0.21
Efficacy 63 13
{B2}
Yield 74%
pEC50 6.19 0.21
Efficacy 39
{C2}
Yield 92%
pEC50 5.96 0.12
Efficacy 45
4
6
{A3}
Yield 60%
pEC50 6.24 0.03
Efficacy 78 18
{B3}
Yield 70%
pEC50 5.97 0.11
Efficacy 69 10
{C3}
Yield 67%
pEC50 6.19 0.10
Efficacy 50 16
{A4}
Yield 72%
pEC50 6.44 0.09
Efficacy 41 14
{B4}
{C4}
Yield 99%
pEC50 5.46 0.13
Yield 85%
pEC50 NAc
Efficacy NAc
Efficacy 38
9
{A5} (FL104)
{B5}
Yield 75%
pEC50 6.70 0.17
Efficacy 114 17
{C5}
Yield 95%
pEC50 6.92 0.18
Efficacy 111
Yield 50%d
pEC50 7.11 0.01
Efficacy 116 11
3
{A6}
Yield 65%
pEC50 7.12 0.04
{B6}
Yield 84%
pEC50 6.90 0.13
{C6}
Yield 72%
pEC50 7.36 0.11
Efficacy 129
Efficacy 137
2
Efficacy 108
8
5
{A7}
Yield 60%
pEC50 7.13 0.31
Efficacy 143 24
{B7}
Yield 70%
pEC50 6.46 0.21
Efficacy 119 11
{C7}
Yield 83%
pEC50 6.98 0.07
Efficacy 111
0
{A8}
Yield 72%
pEC50 6.51 0.02
{B8}
Yield 62%
pEC50 6.09 0.03
{C8}
Yield 55%
pEC50 6.28 0.05
Efficacy 77
Efficacy 131
8
Efficacy 83
4
3
Results were determined in R-SAT assays and are expressed as pEC50-values, the negative of the log EC50 in molarity. Results are the average standard deviations of 2–5
determinations of the EC50 where each compound was tested in eight doses in triplicate.
b
The % efficacy values are normalized to UII at 100%.
c
NA = No detectable activity.
For experimental details, see Ref. 2.
d
otherwise stated using a JEOL JMN-ECP400 instrument. All reac-
tions were monitored by TLC (Merck Silica Gel 60 F254) and ana-
lyzed under UV (254 nm). Melting points were recorded on a
Büchi melting point B-545 apparatus and are uncorrected. HRMS
were recorded at Inovacia (Stockholm Sweden) using an Agilent
MSD-TOF (G1969A) connected to an Agilent 1100 HPLC system.
Elemental analyses were performed at Kolbe Analytishe Laborato-
rium, (Mülheim an der Ruhr, Germany). The carboxylic acids 2, 4, 6,
8 are commercially available. The synthesis of {A5} (FL104) is de-
scribed in Ref. 2. For experimental and analysis data see Supple-
mentary data.
4. Conclusion
The optimization of FL104 lead to the discovery of (+)-(S)-{C6}
with an EC50-value of 23 nM which is the most active non-pepti-
dergic UT-receptor agonist reported today. In addition several
other low nanomolar agonists at the UT-receptor were identified,
which allowed an extended SAR to be established.
5. Experimental
5.1. General
All chemicals were purchased from Aldrich, Acros, Lancaster or
Maybridge and were used without prior purification. 1H (400 MHz)
and 13C (100 MHz) NMR spectra were recorded in CD3OD unless
5.1.1. 1-(4-Chlorophenyl)-3-(1-piperidinyl)propan-1-ol (13)
Ketone 112 (3.7 g, 14.7 mmol) was dissolved in THF (250 mL).
LAH (0.57 g, 15.0 mmol) was added slowly and the mixture was

4660
F. Lehmann et al. / Bioorg. Med. Chem. 17 (2009) 4657–4665
Table 2
Table 3
Activity and efficacy of amides {D5–E10} in the R-SATTM assay
Activity and efficacy of enantiomerically pure amides ({A9} and {C9}) in the R-SATTM at
the UT-receptora,b
O
O
OMe
H
R
R
NH
NH
COOH
N
N
(+)-(R,R)-{A9}c
pEC50 5.30 0.07
Efficacy 112 22
(ꢀ)-(R,S)-{A9}c
Cl
Cl
NH2
{D5}: R = Ph
{D10}: R = H
{E5}: R = Ph
{E10}: R = H
pEC50 6.06 0.03
Efficacy 165 10
N
a
Compd
pEC50
Efficacyb
116 11
A
Cl
{A5} (FL104)c
{D5}
{D10}
{E5}
{E10}
7.11 0.01
6.18 0.09
5.19 0.07
6.50 0.21
5.42 0.01
57
55
8
0
(+)-(R,R)-{C9}
pEC50 5.56 0.01
(ꢀ)-(R,S)-{C9}
NH
2
pEC50 6.13 0.12
Efficacy 140 11
91 12
77 23
Efficacy 53
5
N
C
a
Results were determined in R-SAT assays and are expressed as pEC50-values, the
negative of the log EC50 in molarity. Results are the average standard deviations of
2–5 determinations of the EC50 where each compound was tested in eight doses in
triplicate.
a
Results were determined in R-SAT assays and are expressed as pEC50-values, the
b
negative of the log EC50 in molarity. Results are the average standard deviations of
2–5 determinations of the EC50 where each compound was tested in eight doses in
triplicate.
The % efficacy values are normalized to UII at 100%.
For experimental details, see Ref. 2.
c
b
The % efficacy values are normalized to UII at 100%.
For experimental details, see Ref. 2.
c
NH
2
COOH
R
+
Ar
NR
2
1
n
Table 4
A - E (n = 1,2)
1 - 8, 10
Activity and efficacy of (R)- and (S)-{A5} and {C6} at the UT-receptor
O
i
O
NH
NH
O
Cl
N
N
NH
R
1
{C6}
{A5}
Cl
Ar
n
NR
2
(n = 1,2)
{A1 - E10}
a
Compd
pEC50
Efficacyb
Scheme 3. Reagents and conditions: (i) NEt3, SOCl2, rt, 41–99%. For details on
(+)-(S)-{A5}c
(ꢀ)-(R)-{A5}c
(+)-(S)-{C6}
(ꢀ)-(R)-{C6}
7.49 0.33
5.84 0.10
7.64 0.23
6.34 0.15
116 18
96 16
structures see Tables 1 and 2.
129
53
4
5
a
NH2
Results were determined in R-SAT assays and are expressed as pEC50-values, the
negative of the log EC50 in molarity. Results are the average standard deviations of
2–5 determinations of the EC50 where each compound was tested in eight doses in
triplicate.
H
OMe
COOH
R1
N
+
b
A - C
9
The % efficacy values are normalized to UII at 100%.
c
For experimental details, see Ref. 2.
i
O
NH
5.1.2. 1-(4-Chlorophenyl)-3-(1-piperidinyl)propan-1-amine (D)
Compound 13 (3.0 g, 11.8 mmol) was dissolved in acetonitrile
(5 mL) and stirred on an ice-salt bath. H2SO4 (15 mL) was added
slowly. After 18 h NaOH pellets were added until pH 14. The mix-
ture was extracted with EtOAc (2 ꢁ 150 mL). The organic phases
were combined and washed with water (200 mL) and brine
(200 mL) and concentrated to obtain the corresponding acetamide
as a yellow oil. HCl (6 M) (40 mL) was then added and the solution
was refluxed for 3 days. H2O (100 mL) and NaOH pellets were
added slowly to the mixture until pH 14. The mixture was ex-
tracted with EtOAc (2 ꢁ 100 mL) and the organic phases were com-
bined and washed with water (100 mL) and brine (100 mL) and
concentrated to afford D as a yellow oil (2.35 g, 79%). 1H NMR
(CDCl3) d 1.35–1.42 (m, 2H), 1.51–1.59 (m, 4H), 1.70–1.81 (m,
3H), 2.19–2.40 (m, 5H), 3.96 (t, 1H, J = 6.6 Hz), 7.26 (s, 4H). 13C
NMR (CDCl3) d 24.6, 26.1 (2 C:s), 36.4, 54.8 (2 C:s), 54.9, 56.8,
127.8 (2 C:s), 128.6 (2 C:s), 132.5, 145.2.
MeO
N
R1
{A9 - C9}
Scheme 4. Reagents and conditions: (i) EDC, DMAP rt, 44–49%.
stirred for 18 h. NaOH (1 M) (100 mL) was added dropwise until pH
14. The resulting mixture was extracted twice with EtOAc
(150 mL + 100 mL). The organic phases were combined, washed
with water (200 mL) and brine (200 mL) and concentrated to afford
13 as a yellow oil (3.7 g, 99%). 1H NMR (CDCl3) d 1.43–1.50 (m, 2H),
1.60–1.68 (m, 4H), 1.77–1.81 (m, 2H), 2.45–2.67 (m, 6H), 4.91 (dd,
1H, J = 3.6, 7.2 Hz), 7.29 (s, 4H). 13C NMR (CDCl3) d 24.4, 26.3 (2
C:s), 33.8, 54.8, 57.9 (2 C:s), 75.3, 127.2 (2 C:s), 128.5 (2 C:s),
132.5, 143.9.

F. Lehmann et al. / Bioorg. Med. Chem. 17 (2009) 4657–4665
4661
5.1.4. 1-(4-Chlorophenyl)-4-dimethylamino-butan-1-amine (E)
Compound 14 (1.25 g, 5.5 mmol) was reacted according to the
same procedure as described for 13 to afford E as a yellow oil
(0.87 g, 70%). 1H NMR (CDCl3) d 1.29–1.67 (m, 4H), 2.16 (s, 6H),
2.21 (t, 2H, J = 7.3 Hz), 3.88 (t, 1H, J = 6.9 Hz), 7.27 (s, 4H). 13C
NMR (CDCl3) d 24.7, 37.4, 45.6 (2 C:s), 55.7, 59.7, 127.8 (2 C:s),
128.6 (2 C:s), 132.5, 145.0.
meta
para
5.2. General procedure for the synthesis of amide derivatives
{A1}–{E10}
The benzoic acid (0.5 mmol) was dissolved in THF (75 mL/g)
and triethylamine (0.14 mL, 1 mmol) was added. Under vigorous
stirring SOCl2 (0.05 mL, 0.6 mmol) was added dropwise and the
mixture was stirred at rt for 10 min. A 25 mg/mL solution of the
amine (100 mg, 0.44–0.50 mmol) in THF was added slowly and
the reaction mixture was stirred for another 2 h. The mixture
was poured into NaOH (1 M) and extracted twice with EtOAc.
The combined organic phases were washed (water, brine) and con-
centrated. The crude oil was dissolved in CH2Cl2 and applied to a
SAX-2 ion-exchange column, washed with CH2Cl2 and MeOH. The
product was eluted using methanolic NH3 (2 M), and concentrated.
The pure products were converted to the corresponding hydrochlo-
ride salts for analysis, storage and biological testing. The salts were
hygroscopic and turned into slight yellow oils immediately after
isolation.
Figure 2. Comparison of pEC50 values with respect to the position of the biphenyl in
amides {A1–C8}.
5.2.1. N-[1-(4-Chlorophenyl)-3-dimethylaminopropyl]-3-
phenylbenzamide HCl {A1}
Reaction of 3-phenylbenzoic acid with A yielded 120 mg (65%)
{A1} which was converted to the hydrochloride salt. 1H NMR d
2.29–2.48 (m, 2H), 2.91 (s, 6H), 3.16–3.32 (m, 2H), 5.26 (dd, 1H,
J = 5.9, 9.9 Hz), 7.34–7.49 (m, 7H), 7.55 (t, 1H, J = 7.7 Hz), 7.67 (d,
2H, J = 7.3 Hz), 7.80 (d, 1H, J = 8.8 Hz), 7.85 (d, 1H, J = 7.0 Hz),
8.11 (s, 1H). 13C NMR d 30.3, 42.2, 42.6, 51.1, 55.3, 125.8, 126.2,
126.8 (2 C:s), 127.6, 128.3 (2 C:s), 128.6 (2 C:s), 128.7 (2 C:s),
128.9, 130.2, 133.3, 134.4, 140.1, 140.2, 141.6, 168.6. HRTofMS
calcd for C24H25ClN2O (M+) m/z 392.1655, found 392.1663.
Figure 3. The crystal structure of (ꢀ)-{C9} as determined by X-ray diffraction.
ORTEPIII view showing the atom-labelling scheme with thermal ellipsoids drawn at
20% probability.
5.2.2. N-[1-(4-Chlorophenyl)-3-dimethylaminopropyl]-3-(4-
chlorophenyl)benzamide HCl {A2}
naphthyl too large
both 4-Cl
lipophilic substitution advantageous
and 4-OMe
preferably para to carbonyl
allowed
Reaction of 3-(4-chlorophenyl)benzoic acid with A yielded
120 mg (60%) of {A2} which was converted to the hydrochloride
salt. 1H NMR d 2.29–2.38 (m, 1H), 2.43–2.53 (m, 1H), 2.90 (s,
6H), 3.16–3.34 (m, 2H), 5.24 (dd, 1H, J = 5.5, 9.5 Hz), 7.37 (d, 2H,
J = 8.1 Hz), 7.43 (d, 2H, J = 8.1 Hz), 7.49 (d, 2H, J = 8.1 Hz), 7.52
(dd, 1H, J = 7.7, 7.9 Hz), 7.66 (d, 2H, J = 8.1 Hz), 7.77 (d, 1H,
J = 7.7 Hz), 7.87 (d, 1H, J = 7.9 Hz), 8.11 (s, 1H). 13C NMR d 30.3,
42.2, 42.5, 51.1, 55.3, 125.7, 126.6, 128.3 (2 C:s), 128.4 (2 C:s),
128.6 (2 C:s), 128.8 (2 C:s), 129.0, 130.0, 133.3, 133.6, 134.5,
138.7, 140.1, 140.2, 168.4. HRTofMS calcd for C24H24Cl2N2O (M+)
m/z 426.1266, found 426.1273.
(
S
)-configuration
dimethylamino optimal
H
N
H
A
N
can be extended
O
(cinnamic and propionic acid
derivatives well tolerated)
ethylene better
than propylene
B
ureas and carbamates tolerated
but not ethers or sulfamides
para Cl much more active than Me,
naphthyl instead of phenyl well tolerated
5.2.3. N-[1-(4-Chlorophenyl)-3-dimethylaminopropyl]-3-(4-
methoxyphenyl)benzamide HCl {A3}
Figure 4. Summary of SAR results from this study and those in Refs. 2 and 6.
Reaction of 3-(4-methoxyphenyl)benzoic acid with A yielded
120 mg (60%) of {A3} which was converted to the hydrochloride
salt. 1H NMR d 2.28–2.49 (m, 2H), 2.90 (s, 6H), 3.16–3.29 (m,
2H), 3.82 (s, 3H), 5.26 (dd, 1H, J = 5.9, 9.5 Hz), 7.00 (d, 2H,
J = 8.8 Hz), 7.39 (d, 2H, J = 8.1 Hz), 7.47–7.53 (m, 3H), 7.61 (d, 2H,
J = 8.8 Hz), 7.74–7.80 (m, 2H), 8.06 (d, 1H, J = 1.8 Hz). 13C NMR d
30.3, 42.2, 42.5, 51.1, 54.5, 55.3, 114.1 (2 C:s), 125.3, 125.5, 127.9
(2 C:s), 128.3 (2 C:s), 128.6 (2 C:s), 128.8, 129.7, 132.4, 133.2,
134.3, 140.2, 141.2, 159.8, 168.7. HRTofMS calcd for C25H27ClN2O2
(M+) m/z 422.1761, found 422.1765.
5.1.3. 1-(4-Chlorophenyl)-4-dimethylamino-butan-1-ol (14)
Ketone 122 (1.5 g, 6.6 mmol) was reacted according to the same
procedure as described for 13 to afford 14 as a yellow oil (1.2 g,
80%). 1H NMR (CDCl3) d 1.65–1.78 (m, 3H), 1.89–1.99 (m, 1H),
2.29 (s, 6H), 2.32–2.40 (m, 2H), 4.61 (d, 1H, J = 8.8 Hz), 7.22–7.31
(m, 4H). 13C NMR (CDCl3) d 24.7, 39.7, 44.9 (2 C:s), 59.8, 72.8,
127.2 (2 C:s), 128.2 (2 C:s), 132.2, 144.6.

4662
F. Lehmann et al. / Bioorg. Med. Chem. 17 (2009) 4657–4665
5.2.4. N-[1-(4-Chlorophenyl)-3-dimethylaminopropyl]-3-(2-
naphthyl)benzamide HCl {A4}
5.2.9. N-[3-Dimethylamino-1-(4-methylphenyl)propyl]-3-(4-
chlorophenyl)benzamide HCl {B2}
Reaction of 3-(2-naphthyl)benzoic acid with A yielded 150 mg
(72%) of {A4} which was converted to the hydrochloride salt. 1H
NMR d 2.28–2.38 (m, 1H), 2.43–2.53 (m, 1H), 2.87 (s, 6H), 3.14–
3.33 (m, 2H), 5.26 (dd, 1H, J = 8.1, 13.6 Hz), 7.36 (d, 2H,
J = 8.8 Hz), 7.47–7.58 (m, 5H), 7.77–7.90 (m, 6H), 8.14 (s, 1H),
8.27 (s, 1H). 13C NMR d 30.2, 42.1, 42.5, 51.1, 55.4, 124.9, 125.6,
126.0, 126.1, 126.2, 126.4, 127.3, 128.0, 128.3 (2 C:s), 128.4,
128.6 (2 C:s), 129.0, 130.4, 133.0, 133.3, 133.8, 134.4, 137.3,
140.2, 141.3, 168.6. HRTofMS calcd for C28H27ClN2O (M+) m/z
442.1812, found 442.1816.
Reaction of 3-(4-chlorophenyl)benzoic acid with B yielded
150 mg (74%) of {B2} which was converted to the hydrochloride
salt. 1H NMR d 2.20 (s, 3H), 2.21–2.28 (m, 1H), 2.31–2.42 (m,
1H), 2.80 (s, 6H), 3.05–3.10 (m, 1H), 3.17–3.26 (m, 1H), 5.14 (dd,
1H, J = 5.6, 9.2 Hz), 7.08 (d, 2H, J = 8.0 Hz), 7.29 (d, 2H, J = 8.0 Hz),
7.32 (d, 2H, J = 8.0 Hz), 7.42 (dd, 1H, J = 7.6, 7.8 Hz), 7.54 (d, 2H,
J = 8.0 Hz), 7.64 (d, 1H, J = 7.6 Hz), 7.78 (d, 1H, J = 7.8 Hz), 8.01 (s,
1H). 13C NMR d 24.0, 34.6, 46.2, 46.6, 55.5, 59.6, 129.9, 130.6 (2
C:s), 132.4 (2 C:s), 132.9 (2 C:s), 133.1, 133.3 (2 C:s), 134.0,
137.7, 138.7, 138.8, 141.5, 142.3, 142.8, 144.1, 172.4. HRTofMS
calcd for C25H27ClN2O (M+) m/z 406.1812, found 406.1814.
5.2.5. N-[1-(4-Chlorophenyl)-3-dimethylaminopropyl]-4-(4-
chlorophenyl)benzamide HCl {A6}
5.2.10. N-[3-Dimethylamino-1-(4-methylphenyl)propyl]-3-(4-
methoxyphenyl)benzamide HCl {B3}
Reaction of 4-(4-chlorophenyl)benzoic acid with A yielded
130 mg (65%) of {A6} which was converted to the hydrochloride
salt. 1H NMR d 2.29–2.37 (m, 1H), 2.41–2.50 (m, 1H), 2.91 (s,
6H), 3.17–3.33 (m, 2H), 5.23 (dd, 1H, J = 5.5, 9.9 Hz), 7.38 (d, 2H,
J = 8.4 Hz), 7.44 (d, 2H, J = 8.4 Hz), 7.49 (d, 2H, J = 8.4 Hz), 7.63 (d,
2H, J = 8.4 Hz), 7.70 (d, 2H, J = 8.4 Hz), 7.96 (d, 2H, J = 8.4 Hz). 13C
NMR d 30.3, 42.2, 42.6, 51.0, 55.3, 126.6 (2 C:s), 128.0 (2 C:s),
128.2 (2 C:s), 128.3 (2 C:s), 128.6 (2 C:s), 128.8 (2 C:s), 132.7,
133.3, 133.9, 138.4, 140.1, 143.2, 168.3. HRTofMS calcd for
C24H24Cl2N2O (M+) m/z 426.1266, found 426.1267.
Reaction of 3-(4-methoxyphenyl)benzoic acid with B yielded
140 mg (70%) of {B3} which was converted to the hydrochloride
salt. 1H NMR d 2.20 (s, 3H), 2.21–2.27 (m, 1H), 2.30–2.38 (m,
1H), 2.79 (s, 6H), 3.03–3.10 (m, 1H), 3.15–3.21 (m, 1H), 3.74 (s,
3H), 5.13 (dd, 1H, J = 5.6, 9.4 Hz), 6.89 (d, 2H, J = 8.4 Hz), 7.09 (d,
2H, J = 7.6 Hz), 7.28 (d, 2H, J = 7.6 Hz), 7.39 (dd, 1H, J = 7.6,
8.0 Hz), 7.50 (d, 2H, J = 8.4 Hz), 7.63 (d, 1H, J = 8.0 Hz), 7.70 (d,
1H, J = 7.6 Hz), 7.98 (s, 1H). 13C NMR d 23.9, 34.6, 46.2, 46.7, 55.4,
58.6, 59.6, 118.2 (2 C:s), 129.4, 129.5, 130.6 (2 C:s), 131.9 (2 C:s),
132.9, 133.3 (2 C:s), 133.6, 136.5, 138.6, 141.5, 142.3, 145.2,
163.8, 172.5. HRTofMS calcd for C26H30N2O2 (M+) m/z 402.2307,
found 402.2324.
5.2.6. N-[1-(4-Chlorophenyl)-3-dimethylaminopropyl]-4-(4-
methoxyphenyl)benzamide HCl {A7}
Reaction of 4-(4-methoxyphenyl)benzoic acid with A yielded
120 mg (60%) of {A7} which was converted to the hydrochloride
salt. 1H NMR d 2.29–2.37 (m, 1H), 2.41–2.51 (m, 1H), 2.90 (s,
6H), 3.17–3.33 (m, 2H), 3.78 (s, 3H), 5.24 (dd, 1H, J = 5.5, 9.5 Hz),
6.97 (d, 2H, J = 8.8 Hz), 7.36 (d, 2H, J = 8.4 Hz), 7.48 (d, 2H,
J = 8.4 Hz), 7.56 (d, 2H, J = 8.8 Hz), 7.64 (d, 2H, J = 8.0 Hz), 7.93 (d,
2H, J = 8.0 Hz). 13C NMR d 30.4, 42.1, 42.6, 51.0, 54.5, 55.3, 114.1
(2 C:s), 126.1 (2 C:s), 127.9 (2 C:s), 128.0 (2 C:s), 128.3 (2 C:s),
128.6 (2 C:s), 131.6, 131.9, 133.2, 140.3, 144.2, 160.0, 168.4.
HRTofMS calcd for C25H27ClN2O2 (M+) m/z 422.1761, found
422.1777.
5.2.11. N-[3-Dimethylamino-1-(4-methylphenyl)propyl]-3-(2-
naphthyl)benzamide HCl {B4}
Reaction of 3-(2-naphthyl)benzoic acid with B yielded 180 mg
(85%) of {B4} which was converted to the hydrochloride salt. 1H
NMR d 2.19 (s, 3H), 2.20–2.26 (m, 1H), 2.35–2.44 (m, 1H), 2.79 (s,
6H), 3.01–3.09 (m, 1H), 3.12–3.20 (m, 1H), 5.16 (dd, 1H, J = 6.0,
9.6 Hz), 7.07 (d, 2H, J = 8.0 Hz), 7.30 (d, 2H, J = 8.0 Hz), 7.36–7.46
(m, 3H), 7.69 (dd, 1H, J = 2.0, 8.4 Hz), 7.73–7.82 (m, 5H), 8.05 (s,
1H), 8.18 (s, 1H). 13C NMR d 24.0, 34.6, 46.2, 46.6, 55.5, 59.5,
129.0, 129.7, 130.0, 130.1, 130.2, 130.4, 130.6 (2 C:s), 131.4,
132.1, 132.5, 133.0, 133.3 (2 C:s), 134.4, 137.0, 137.9, 138.7,
141.4, 141.5, 142.4, 145.3, 172.6. HRTofMS calcd for C29H30N2O
(M+) m/z 422.2358, found 422.2358.
5.2.7. N-[1-(4-Chlorophenyl)-3-dimethylaminopropyl]-4-(2-
naphthyl)benzamide HCl {A8}
Reaction of 4-(2-naphthyl)benzoic acid with A yielded 150 mg
(72%) of {A8} which was converted to the hydrochloride salt. 1H
NMR d 2.29–2.38 (m, 1H), 2.44–2.53 (m, 1H), 2.89 (s, 6H), 3.16–
3.24 (m, 2H), 5.25 (dd, 1H, J = 4.8, 9.2 Hz), 7.36 (d, 2H, J = 9.9 Hz),
7.43–7.51 (m, 4H), 7.72 (d, 1H, J = 8.8 Hz), 7.79–7.89 (m, 5H),
8.01 (d, 2H, J = 8.1 Hz), 8.08 (s, 1H). 13C NMR d 30.3, 42.3, 42.6,
51.2, 55.4, 124.7, 125.7, 126.1, 126.3, 126.9 (2 C:s), 127.4, 128.1
(2 C:s), 128.2, 128.3 (2 C:s), 128.4, 128.6 (2 C:s), 132.4, 133.1,
133.2, 133.7, 137.0, 140.3, 144.3, 168.4. HRTofMS calcd for
C28H27ClN2O (M+) m/z 442.1812, found 442.1822.
5.2.12. N-[3-Dimethylamino-1-(4-methylphenyl)propyl]-4-
phenylbenzamide HCl {B5}
Reaction of 4-phenylbenzoic acid with B yielded 140 mg (75%)
of {B5} which was converted to the hydrochloride salt. 1H NMR d
2.23 (s, 3H), 2.27–2.34 (m, 2H), 2.81 (s, 6H), 3.08–3.12 (m, 1H),
3.16–3.22 (m, 1H), 5.15 (dd, 1H, J = 5.6, 9.4 Hz), 7.12 (d, 2H,
J = 8.0 Hz), 7.26–7.31 (m, 4H), 7.36 (tt, 1H, J = 1.6, 6.8 Hz), 7.70 (d,
2H, J = 8.0 Hz), 7.62 (d, 2H, J = 8.4 Hz), 7.87 (d, 2H, J = 8.4 Hz). 13C
NMR d 23.9, 34.6, 46.2, 46.7, 55.4, 59.6, 130.6 (2 C:s), 130.7 (2
C:s), 130.9 (2 C:s), 131.9, 132.0 (2 C:s), 132.8 (2 C:s), 133.3 (2
C:s), 136.7, 141.5, 142.2, 143.9, 148.6, 172.5. HRTofMS calcd for
C25H28N2O (M+) m/z 372.2202, found 372.2218.
5.2.8. N-[3-Dimethylamino-1-(4-methylphenyl)propyl]-3-
phenylbenzamide HCl {B1}
Reaction of 3-phenylbenzoic acid with B yielded 120 mg (65%)
of {B1} which was converted to the hydrochloride salt. 1H NMR d
2.19 (s, 3H), 2.20–2.28 (m, 1H), 2.34–2.42 (m, 1H), 2.77 (s, 3H),
2.78 (s, 3H), 3.05–3.10 (m, 1H), 3.15–3.19 (m, 1H), 5.14 (dd, 1H,
J = 5.6, 9.6 Hz), 7.07 (d, 2H, J = 8.0 Hz), 7.22–7.35 (m, 5H), 7.42 (t,
1H, J = 7.6 Hz), 7.56 (d, 2H, J = 7.2 Hz), 7.66 (d, 1H, J = 8.0 Hz),
7.78 (d, 1H, J = 7.6 Hz), 8.04 (s, 1H). 13C NMR d 24.0, 34.6, 46.2,
46.6, 55.5, 59.5, 129.9, 130.3, 130.6 (2 C:s), 130.9 (2 C:s), 131.6,
132.8 (2 C:s), 133.0, 133.3 (2 C:s), 134.1, 138.6, 141.4, 142.5,
144.2, 145.5, 172.6. HRTofMS calcd for C25H28N2O (M+) m/z
372.2202, found 372.2204.
5.2.13. N-[3-Dimethylamino-1-(4-methylphenyl)propyl]-4-(4-
chlorophenyl)benzamide HCl {B6}
Reaction of 4-(4-chlorophenyl)benzoic acid with B yielded
170 mg (84%) of {B6} which was converted to the hydrochloride
salt. 1H NMR d 2.23 (s, 3H), 2.24–2.38 (m, 2H), 2.82 (s, 6H), 3.05–
3.13 (m, 1H), 3.16–3.22 (m, 1H), 5.13 (dd, 1H, J = 5.6, 9.2 Hz),
7.11 (d, 2H, J = 8.0 Hz), 7.29 (d, 2H, J = 8.0 Hz), 7.36 (d, 2H,
J = 8.4 Hz), 7.55 (d, 2H, J = 8.4 Hz), 7.62 (d, 2H, J = 8.0 Hz), 7.87 (d,
2H, J = 8.0 Hz). 13C NMR d 23.9, 34.6, 46.2, 46.7, 55.4, 59.6, 130.6
(2 C:s), 130.7 (2 C:s), 132.1 (2 C:s), 132.4 (2 C:s), 132.9 (2 C:s),

F. Lehmann et al. / Bioorg. Med. Chem. 17 (2009) 4657–4665
4663
133.3 (2 C:s), 137.0, 138.0, 141.5, 142.2, 142.6, 147.1, 172.3.
HRTofMS calcd for C25H27ClN2O (M+) m/z 406.1812, found
406.1816.
6.83 (d, 2H, J = 8.4 Hz), 7.32–7.37 (m, 3H), 7.45–7.49 (m, 2H),
7.52–7.60 (m, 2H), 7.68–7.78 (m, 4H), 7.87 (s, 1H), 8.02 (s, 1H).
13C NMR d 34.5, 46.3, 46.6, 55.9, 58.6, 59.5, 118.1 (2 C:s), 128.6,
129.4, 129.5, 129.6, 130.0, 130.2, 131.5, 131.8, 132.0 (2 C:s),
132.6, 132.9, 133.7, 136.4, 137.1, 137.5, 138.5, 142.8, 145.1,
163.8, 172.8. HRTofMS calcd for C29H30N2O2 (M+) m/z 438.2307,
found 438.2324.
5.2.14. N-[3-Dimethylamino-1-(4-methylphenyl)propyl]-4-(4-
methoxyphenyl)benzamide HCl {B7}
Reaction of 4-(4-methoxyphenyl)benzoic acid with B yielded
140 mg (70%) of {B7} which was converted to the hydrochloride
salt. 1H NMR d 2.20 (s, 3H), 2.21–2.28 (m, 1H), 2.30–2.41 (m,
1H), 2.79 (s, 3H), 2.80 (s, 3H), 3.05–3.11 (m, 1H), 3.16–3.22 (m,
1H), 3.71 (s, 3H), 5.13 (dd, 1H, J = 5.6, 9.6 Hz), 6.89 (d, 2H,
J = 8.8 Hz), 7.08 (d, 2H, J = 8.0 Hz), 7.29 (d, 2H, J = 8.0 Hz), 7.48 (d,
2H, J = 8.8 Hz), 7.55 (d, 2H, J = 8.4 Hz), 7.84 (d, 2H, J = 8.4 Hz). 13C
NMR d 23.9, 34.7, 46.2, 46.6, 55.4, 58.6, 59.6, 118.2 (2 C:s), 130.1
(2 C:s), 130.5 (2 C:s), 131.9 (2 C:s), 132.0 (2 C:s), 133.2 (2 C:s),
135.9, 136.1, 141.4, 142.5, 148.2, 164.1, 172.4. HRTofMS calcd for
C26H30N2O2 (M+) m/z 402.2307, found 402.2314.
5.2.19. N-[3-Dimethylamino-1-(2-naphthyl)propyl]-3-
(2naphthyl)benzamide HCl {C4}
Reaction of 3-(2-naphthyl)benzoic acid with C yielded 200 mg
(99%) of {C4} which was converted to the hydrochloride salt. 1H
NMR d 2.34–2.40 (m, 1H), 2.47–2.52 (m, 1H), 2.75 (s, 3H), 2.77 (s,
3H), 3.06–3.13 (m, 1H), 3.20–3.32 (m, 1H), 5.36 (dd, 1H, J = 5.6,
9.6 Hz), 7.32–7.39 (m, 4H), 7.41–7.45 (m, 1H), 7.56 (dd, 1H,
J = 1.6, 8.4 Hz), 7.65–7.78 (m, 7H), 7.80–7.84 (m, 2H), 7.88 (s, 1H),
8.02 (s, 1H), 8.20 (s, 1H). 13C NMR d 34.5, 46.2, 46.6, 55.9, 59.5,
128.6, 129.0, 129.5, 129.7, 129.9, 130.0, 130.1, 130.2 (2 C:s),
130.4, 131.4, 131.5, 131.8, 132.1, 132.4, 132.6, 133.0, 134.4,
137.0, 137.1, 137.6, 137.9, 138.6, 141.4, 142.7, 145.3,
172.6. HRTofMS calcd for C32H30N2O (M+) m/z 458.2358, found
458.2363.
5.2.15. N-[3-Dimethylamino-1-(4-methylphenyl)propyl]-4-(2-
naphthyl)benzamide HCl {B8}
Reaction of 4-(2-naphthyl)benzoic acid with B yielded 130 mg
(62%) of {B8} which was converted to the hydrochloride salt. 1H
NMR d 2.17 (s, 3H), 2.19–2.27 (m, 1H), 2.30–2.38 (m, 1H), 2.76 (s,
6H), 3.00–3.09 (m, 1H), 3.11–3.17 (m, 1H), 5.10 (dd, 1H, J = 5.2,
8.4 Hz), 7.05 (d, 2H, J = 8.0 Hz), 7.26 (d, 2H, J = 8.0 Hz), 7.32–7.38
(m, 2H), 7.61 (dd, 1H, J = 1.2, 8.4 Hz), 7.66–7.77 (m, 5H), 7.87 (d,
2H, J = 6.8 Hz), 7.96 (s, 1H). 13C NMR d 24.0, 34.7, 46.2, 46.7, 55.5,
59.6, 128.8, 129.8, 130.2, 130.3, 130.6 (2 C:s), 131.0 (2 C:s),
131.4, 132.1 (2 C:s), 132.2, 132.5, 133.3 (2 C:s), 136.7, 137.2,
137.8, 141.1, 141.4, 142.5, 148.3, 172.4. HRTofMS calcd for
C29H30N2O (M+) m/z 422.2358, found 422.2362.
5.2.20. N-[3-Dimethylamino-1-(2-naphthyl)propyl]-4-
phenylbenzamide HCl {C5}
Reaction of 4-phenylbenzoic acid with C yielded 170 mg (95%)
of {C5} which was converted to the hydrochloride salt. 1H NMR d
2.33–2.40 (m, 1H), 2.47–2.52 (m, 1H), 2.77 (s, 3H), 2.79 (s, 3H),
3.09–3.16 (m, 2H), 5.34 (dd, 1H, J = 5.6, 9.6 Hz), 7.28 (d, 2H,
J = 8.8 Hz), 7.32–7.36 (m, 3H), 7.44 (d, 2H, J = 8.8 Hz), 7.52 (d, 2H,
J = 8.4 Hz), 7.56 (dd, 1H, J = 1.2, 8.4 Hz), 7.68–7.77 (m, 3H), 7.88–
7.92 (m, 3H). 13C NMR d 34.5, 46.2, 46.6, 55.9, 59.5, 128.6, 129.4,
130.0, 130.2, 130.8 (2 C:s), 130.9 (2 C:s), 131.5, 131.8, 131.9,
132.1 (2 C:s), 132.6, 132.8 (2 C:s), 136.6, 137.1, 137.6, 142.8,
143.8, 148.6, 172.5. HRTofMS calcd for C28H28N2O (M+) m/z
408.2202, found 408.2204.
5.2.16. N-[3-Dimethylamino-1-(2-naphthyl)propyl]-3-
phenylbenzamide HCl {C1}
Reaction of 3-phenylbenzoic acid with C yielded 170 mg (95%)
of {C1} which was converted to the hydrochloride salt. 1H NMR d
2.40–2.43 (m, 1H), 2.50–2.53 (m, 1H), 2.82 (s, 6H), 3.13–3.17 (m,
1H), 3.23–3.28 (m, 1H), 5.37 (dd, 1H, J = 4.8, 7.6 Hz), 7.26–7.29
(m, 1H), 7.34–7.40 (m, 4H), 7.46 (t, 1H, J = 6.0 Hz), 7.57–7.60 (m,
3H), 7.70 (d, 1H, J = 6.0 Hz), 7.75–7.84 (m, 4H), 7.90 (s, 1H), 8.08
(s, 1H). 13C NMR d 34.4, 46.3, 46.6, 55.9, 59.6, 128.6, 129.5, 129.9,
130.0, 130.2, 130.3, 130.8 (2 C:s), 131.4, 131.6, 131.8, 132.5,
132.8 (2 C:s), 132.9, 134.1, 137.2, 137.6, 138.6, 142.5, 144.2,
145.6, 172.8. HRTofMS calcd for C28H28N2O (M+) m/z 408.2202,
found 408.2206.
5.2.21. N-[3-Dimethylamino-1-(2-naphthyl)propyl]-4-(4-
chlorophenyl)benzamide HCl {C6}
Reaction of 4-(4-chlorophenyl)benzoic acid with C yielded
140 mg (72%) of {C6} which was converted to the hydrochloride
salt. 1H NMR d 2.36–2.40 (m, 1H), 2.48–2.52 (m, 1H), 2.77 (s,
3H), 2.78 (s, 3H), 3.08–3.15 (m, 1H), 3.21–3.27 (m, 1H), 5.34 (dd,
1H, J = 5.6, 9.6 Hz), 7.28 (d, 2H, J = 8.4 Hz), 7.31–7.36 (m, 2H),
7.44 (d, 2H, J = 8.4 Hz), 7.52 (d, 2H, J = 8.4 Hz), 7.56 (dd, 1H,
J = 1.2, 8.4 Hz), 7.69–7.77 (m, 3H), 7.88–7.92 (m, 3H). 13C NMR d
34.5, 46.2, 46.6, 55.9, 59.5, 128.6, 129.4, 130.0, 130.2, 130.7 (2
C:s), 131.5, 131.8, 132.2 (2 C:s), 132.4 (2 C:s), 132.6, 132.9 (2
C:s), 136.9, 137.1, 137.5, 137.9, 142.4, 142.9, 147.0, 172.3.
HRTofMS calcd for C28H27ClN2O (M+) m/z 442.1812, found
442.1818.
5.2.17. N-[3-Dimethylamino-1-(2-naphthyl)propyl]-3-(4-
chlorophenyl)benzamide HCl {C2}
Reaction of 3-(4-chlorophenyl)benzoic acid with C yielded
180 mg (92%) of {C2} which was converted to the hydrochloride
salt. 1H NMR d 2.36–2.51 (m, 2H), 2.81 (s, 6H), 3.10–3. 20 (m,
2H), 5.34 (dd, 1H, J = 5.6, 10.4 Hz), 7.33–7.41 (m, 4H), 7.43–7.47
(m, 1H), 7.55–7.59 (m, 3H), 7.67–7.83 (m, 5H), 7.88 (s, 1H), 8.05
(s, 1H). 13C NMR d 34.4, 46.2, 46.6, 55.8, 59.5, 128.6, 129.5, 129.8,
130.0, 130.2, 130.6, 131.4, 131.8, 132.4 (2 C:s), 132.6, 132.8 (2
C:s), 133.0, 134.0, 137.2, 137.6, 137.7, 138.7, 142.5, 142.8, 144.2,
172.6. HRTofMS calcd for C28H27ClN2O (M+) m/z 442.1812, found
442.1816.
5.2.22. N-[3-Dimethylamino-1-(2-naphthyl)propyl]-4-(4-
methoxyphenyl)benzamide HCl {C7}
Reaction of 4-(4-methoxyphenyl)benzoic acid with C yielded
160 mg (83%) of {C7} which was converted to the hydrochloride
salt. 1H NMR d 2.35–2.39 (m, 1H), 2.45–2.48 (m, 1H), 2.76 (s,
3H), 2.77 (s, 3H), 3.09–3.12 (m, 1H), 3.18–3.22 (m, 1H), 3.68 (s,
3H), 5.33 (dd, 1H, J = 5.6, 9.4 Hz), 6.82 (d, 2H, J = 8.8 Hz), 7.33–
7.38 (m, 2H), 7.43 (d, 2H, J = 8.8 Hz), 7.52–7.56 (m, 3H), 7.70–
7.78 (m, 3H), 7.85–7.88 (m, 3H). 13C NMR d 34.5, 46.2, 46.6, 55.8,
58.6, 59.5, 118.2 (2 C:s), 128.6, 129.4, 130.0, 130.2 (2 C:s), 130.3,
131.5, 131.8, 131.9 (2 C:s), 132.1 (2 C:s), 132.6, 135.8, 136.0,
137.1, 137.6, 142.8, 148.2, 164.0, 172.5. HRTofMS calcd for
C29H30N2O2 (M+) m/z 438.2307, found 438.2322.
5.2.18. N-[3-Dimethylamino-1-(2-naphthyl)propyl]-3-(4-
methoxyphenyl)benzamide HCl {C3}
Reaction of 3-(4-methoxyphenyl)benzoic acid with C yielded
130 mg (67%) of {C3} which was converted to the hydrochloride
salt. 1H NMR d 2.32–2.51 (m, 2H), 2.80 (s, 6H), 3.08–3.11 (m,
1H), 3.21–3.31 (m, 1H), 3.66 (s, 3H), 5.34 (dd, 1H, J = 4.2, 7.2 Hz),

4664
F. Lehmann et al. / Bioorg. Med. Chem. 17 (2009) 4657–4665
5.2.23. N-[3-Dimethylamino-1-(2-naphthyl)propyl]-4-
(2-naphthyl)benzamide HCl {C8}
J = 7.6 Hz), 7.21–7.27 (m, 3H), 7.32–7.39 (m, 5H), 7.65–7.72 (m,
4H). 13C NMR d 32.3, 46.4 (2 C:s), 54.6, 59.3, 60.3, 87.6, 128.4,
129.2, 130.0, 130.2, 131.0 (2 C:s), 131.1, 131.4, 131.7, 132.4 (2
C:s), 132.5, 137.1, 137.5, 141.6, 142.0, 176.2.
Reaction of 4-(2-naphthyl)benzoic acid with C yielded 110 mg
(55%) of {C8} which was converted to the hydrochloride salt. 1H
NMR d 2.33–2.39 (m, 1H), 2.42–2.56 (m, 1H), 2.78 (s, 3H), 2.79
(s, 3H), 3.10–3.14 (m, 1H), 3.20–3.27 (m, 1H), 5.35 (dd, 1H,
J = 5.6, 9.6 Hz), 7.34–7.39 (m, 4H), 7.56 (d, 1H, J = 8.4 Hz), 7.62
(dd, 1H, J = 1.6, 8.8 Hz), 7.70–7.79 (m, 8H), 7.88 (s, 1H), 7.94 (d,
2H, J = 8.4 Hz), 7.99 (s, 1H). 13C NMR d 34.5, 46.2, 46.6, 55.9, 59.6,
128.6, 128.8, 129.4, 129.8, 130.0, 130.2 (2 C:s), 130.3, 131.0 (2
C:s), 131.4, 131.5, 131.8, 132.2 (3 C:s), 132.5, 132.6, 136.6, 137.1,
137.2, 137.6, 137.8, 141.0, 142.8, 148.4, 172.5. HRTofMS calcd for
C32H30N2O (M+) m/z 458.2358, found 458.2362.
5.2.29. (ꢀ)-N-[3-Dimethylaminopropyl-1-(2-naphthyl)]-(R)-2-
methoxy-2-phenylacetamide HCl ((ꢀ)-C9)
[
a
]
ꢀ133.5 (c 0.29, MeOH). 1H NMR d 2.31–2.42 (m, 2H), 2.81
D
(s, 6H), 3.00–3.11 (m, 2H), 3.36 (s, 3H), 4.76 (s, 1H), 5.16 (dd, 1H,
J = 7.0, 8.1 Hz), 7.29–7.32 (m, 3H), 7.39–7.49 (m, 4H), 7.77–7.85
(m, 4H). 13C NMR d 30.1, 42.3 (2 C:s), 50.7, 55.3, 56.1, 83.5,
124.3, 125.1, 125.9, 126.1, 127.1 (2 C:s), 127.3, 127.6, 128.3 (2
C:s), 128.4, 128.5, 133.0, 133.4, 137.4, 137.9, 172.1.
5.2.24. N-[3-Dimethylaminopropyl-1-(4-methylphenyl)]-(R)-2-
methoxy-2-phenylacetamide HCl {B9}
5.2.30. N-[1-(4-Chlorophenyl)-3-(1-piperidinyl)-propyl]-4-
phenylbenzamide oxalate {D5}
Compound B (0.55 g, 2.9 mmol) was dissolved in THF (100 mL).
(R)-2-Methoxy-2-phenylacetic acid (0.48 g, 2.9 mmol), EDC (0.60 g,
3.2 mmol) and DMAP (35 mg, 0.29 mmol) were added and the mix-
ture was stirred for three days. Saturated aqueous NaHCO3
(100 mL) and EtOAc (100 mL) were added. The phases were sepa-
rated and the water phase extracted with EtOAc. The combined or-
ganic phases were washed (water, brine) and concentrated. The
residue was purified with flash chromatography using MeOH/
CH2Cl2/NEt3 (5/94.9/0.1) to afford 0.42 g (44%) of the pure diaste-
reomeric mixture which was separated by repeated flash chroma-
tography using MeOH/CH2Cl2/NEt3 (5/94.9/0.1) until the pure
diastereomers were obtained (200 mg (+), 220 mg (ꢀ)) which were
converted to their corresponding hydrochloride salt for analysis,
storage and biological testing.
Reaction of 4-phenylbenzoic acid with D yielded 115 mg (67%)
of {D5} which was converted to the hydrochloride salt. 1H NMR d
1.15–1.23 (m, 1H), 1.74–1.94 (m, 5H), 2.31–2.51 (m, 2H), 2.85–
2.92 (m, 2H), 3.11–3.31 (m, 2H), 3.51–3.60 (m, 2H), 5.23 (dd, 1H,
J = 5.5, 9.5 Hz), 7.35–7.40 (m, 3H), 7.43–7.49 (m, 4H), 7.64 (d, 2H,
J = 7.3 Hz), 7.72 (d, 2H, J = 8.1 Hz), 7.95 (d, 2H, J = 8.1 Hz). 13C
NMR d 21.3, 23.0, 23.1, 29.6, 29.7, 51.1, 53.0, 54.4, 54.6, 126.7 (2
C:s), 126.8 (2 C:s), 127.8, 127.9 (2 C:s), 128.3 (2 C:s), 128.6 (2
C:s), 128.8 (2 C:s), 132.4, 133.3, 139.8, 140.1, 144.7, 168.5. Anal.
Calcd for C27H29ClN2OꢂHCl: C, 69.1; H, 6.4; N, 6.0. Found: C, 69.5;
H, 6.5; N, 6.4.
5.2.31. N-[1-(4-Chlorophenyl)-3-(1-piperidinyl)-
propyl]benzamide oxalate {D10}
Reaction of benzoic acid with D yielded 95 mg (67%) of {D10}
which was converted to the hydrochloride salt. 1H NMR d 1.12–
1.20 (m, 1H), 1.61–1.80 (m, 5H), 2.10–2.22 (m, 2H), 2.85–2.93
(m, 2H), 3.00–3.23 (m, 4H), 5.14 (dd, 1H, J = 5.6, 9.6 Hz), 7.26 (d,
2H, J = 8.4 Hz), 7.33–7.45 (m, 5H), 7.81 (d, 2H, J = 8.4 Hz). 13C
NMR d 25.4, 27.1, 38.9, 52.5, 55.4, 57.4, 58.7, 69.7, 131.5 (2 C:s),
132.3, 132.4 (2 C:s), 132.7 (2 C:s), 135.8 (2 C:s), 137.2, 137.9,
144.6, 170.0. Anal. Calcd for C21H25ClN2OꢂHCl: C, 64.1; H, 6.7; N,
7.1. Found: C, 64.5; H, 6.5; N, 7.4.
5.2.25. (+)-N-[3-Dimethylaminopropyl-1-(4-methylphenyl)]-
(R)-2-methoxy-2-phenylacetamide HCl ((+)-B9)
[a]
+9.1 (c 0.72, MeOH). 1H NMR d 2.13–2.19 (m, 5H), 2.62 (s,
D
3H), 2.65 (s, 3H), 2.83–2.87 (m, 2H), 3.21 (s, 3H), 4.60 (s, 1H),
4.85 (dd, 1H, J = 6.0, 9.2 Hz), 7.01 (d, 2H, J = 8.0 Hz), 7.12 (d, 2H,
J = 8.0 Hz), 7.20–7.27 (m, 3H), 7.36 (d, 2H, J = 7.2 Hz). 13C NMR d
24.0, 34.5, 46.1, 46.5, 54.3, 59.3, 60.3, 87.6, 130.4 (2 C:s), 131.1 (2
C:s), 132.5 (3 C:s), 133.2 (2 C:s), 141.5, 141.6, 141.8, 176.0.
5.2.26. (ꢀ)-N-[3-Dimethylaminopropyl-1-(4-methylphenyl)]-
(R)-2-methoxy-2-phenylacetamide HCl ((ꢀ)-B9)
5.2.32. N-[1-(4-Chlorophenyl)-4-dimethylaminobutyl]-4-
phenylbenzamide oxalate {E5}
[a
]
D
ꢀ137.2 (c 0.27, MeOH). 1H NMR d 2.20–2.28 (m, 2H), 2.30
Reaction of 4-phenylbenzoic acid with E yielded 110 mg (61%)
{E5} which was converted to the oxalate salt. 1H NMR d 1.72–
2.06 (m, 4H), 2.87 (s, 6H), 3.16–3.21 (m, 2H), 5.18 (dd, 1H, J = 5.9,
9.2 Hz), 7.36–7.39 (m, 3H), 7.43–7.48 (m, 4H), 7.65 (d, 2H,
J = 7.3 Hz), 7.72 (d, 2H, J = 8.1 Hz), 7.93 (d, 2H, J = 8.1 Hz). 13C
NMR d 21.7, 32.2, 42.2 (2 C:s), 52.8, 57.2, 126.7 (2 C:s), 126.8 (2
C:s), 127.8, 127.9 (2 C:s), 128.2 (2 C:s), 128.4 (2 C:s), 128.7 (2
C:s), 132.8, 132.9, 139.8, 141.2, 144.5, 168.4. HRTofMS calcd for
C25H27ClN2O (M+) m/z 406.9597, found 406.9600.
(s, 3H), 2.80 (s, 6H), 3.00–3.04 (m, 2H), 3.33 (s, 3H), 4.72 (s, 1H),
4.95 (dd, 1H, J = 5.9, 9.1 Hz), 7.14 (d, 2H, J = 8.0 Hz), 7.23 (d, 2H,
J = 8.0 Hz), 7.31–7.39 (m, 5H). 13C NMR d 19.8, 30.3, 42.3 (2 C:s),
50.4, 55.3, 56.1, 83.4, 126.3 (2 C:s), 127.2 (2 C:s), 128.3 (2 C:s),
128.4, 129.1 (2 C:s), 137.4, 137.5, 137.7, 171.8.
5.2.27. N-[3-Dimethylaminopropyl-1-(2-naphthyl)]-(R)-2-
methoxy-2-phenylacetamide HCl {C9}
Compound C (0.70 g, 3.0 mmol) was reacted according to the
same procedure as described for B to afford 0.55 g (49%) of the pure
diastereomeric mixture of C9 which was separated by repeated
flash chromatography using MeOH/CH2Cl2/NEt3 (5/94.9/0.1) until
the pure diastereomers were obtained (250 mg (+), 300 mg (ꢀ)).
The amines were converted to their corresponding hydrochloride
salt for analysis, storage and biological testing.
5.2.33. N-[1-(4-Chlorophenyl)-4-
dimethylaminobutyl]benzamide oxalate {E10}
Reaction of benzoic acid with E yielded 60 mg (41%) of {E10}
which was converted to the oxalate salt. 1H NMR d 1.71–2.01 (m,
4H), 2.86 (s, 6H), 3.14–3.22 (m, 2H), 5.13 (dd, 1H, J = 5.8, 9.5 Hz),
7.35 (d, 2H, J = 9.2 Hz), 7.42 (d, 2H, J = 9.2 Hz), 7.45–7.47 (m, 2H),
7.53 (tt, 1H, J = 1.4, 7.3 Hz), 7.84 (dd, 2H, J = 1.4, 7.3 Hz). 13C NMR
d 21.7, 32.2, 42.1, 42.2, 52.8, 57.2, 127.2 (2 C:s), 128.1 (2 C:s),
128.3 (2 C:s), 128.4 (2 C:s), 131.5, 132.8, 134.1, 141.2, 168.7.
HRTofMS calcd for C19H23ClN2O (M+) m/z 330.8610, found
330.8613.
5.2.28. (+)-N-[3-Dimethylaminopropyl-1-(2-naphthyl)]-(R)-2-
methoxy-2-phenylacetamide HCl ((+)-C9)
[a]
+26.0 (c 1.5, MeOH). 1H NMR d 2.23–2.29 (m, 2H), 2.64 (s,
D
6H), 2.87–2.93 (m, 2H), 3.21 (s, 3H), 4.62 (s, 1H), 5.06 (t, 1H,

F. Lehmann et al. / Bioorg. Med. Chem. 17 (2009) 4657–4665
4665
anisotropically, and hydrogen atoms were treated as idealized con-
tributions. The final cycle of full-matrix least-squares refinement
on F was based on 1428 observed reflections (I > 2.00r(I)) and
6. Biological activity
6.1. R-SAT-testing
265 variable parameters and converged with unweighted and
weighted agreement factors of:
R-SATTM assays for pharmacological testing were performed as
previously described,7 with the following modifications. NIH-3T3
cells were grown to 80% confluence in Dulbecco’s modified Eagle’s
medium (DMEM) supplemented with 10% bovine calf serum (Hy-
clone) and 1% penicillin/streptomycin/glutamine (Invitrogen). Cells
were transfected in rollerbottles for 18 h with the human uroten-
sin II receptor and the b-galactosidase marker. After the 18 h trans-
fection, cells were trypsinized, harvested and frozen. Aliquots of
frozen cell batches were thawed and tested for response to control
compound to perform quality control before initiation of pharma-
cological testing, ensuring the correct pharmacological response
and sufficient sensitivity. To initiate the pharmacological assay,
cells were thawed rapidly and prepared in DMEM media contain-
ing 0.4% calf serum (Hyclone), 30% UltraCulture (Biowhittaker)
and 1% penicillin/streptomycin/gluatmine (Invitrogen), and then
added to half-area 96-well microtitre plates containing either test
compounds or reference ligands. After a five day incubation of drug
with cells in 5% ambient CO2, media was removed and reporter en-
zyme activity was measured at 420 nm. For control of the UT
receptor selectivity all compounds were tested against the m3
receptor as a negative control (data not shown).
X
X
R ¼
kFo j ꢀ j Fck=
j Fo j¼ 0:0669;
n
o
X
X
1=2
2
2
Rw
¼
½wðF2o ꢀ F2c Þ ꢄ=
½wðF2oÞ ꢄ
¼ 0:1840
The maximum and minimum peaks on the final difference Fou-
rier map corresponded to 0.641 and ꢀ0.570 e/Å3 respectively. The
absolute structure Flack parameter is 0.03(19).12
Acknowledgements
Financial support was obtained from The Knut and Alice Wal-
lenberg Foundation and The Swedish Research Council.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmc.2009.04.062.
References and notes
7. X-ray structure determination of (ꢀ)-{C9}
1. (a) Ames, R. S.; Sarau, H. M.; Chambers, J. K.; Willette, R. N.; Alyar, N. V.;
Romanic, A. M.; Louden, C. S.; Foley, J. J.; Sauermelch, C. F.; Coatney, R. W.; Ao,
Z. H.; Disa, J.; Holmes, S. D.; Stadel, J. M.; Martin, J. D.; Liu, W. S.; Glover, G. I.;
Wilson, S.; McNulty, D. E.; Ellis, C. E.; Elshourbagy, N. A.; Shabon, U.; Trill, J. J.;
Hay, D. W. P.; Ohlstein, E. H.; Bergsma, D. J.; Douglas, S. A. Nature 1999, 402,
282; (b) Douglas, S.; Aiyar, N. V.; Ohlstein, E. H.; Willette, R. N. Eur. Heart J.
2000, 21, 229; (c) Dhanak, D.; Neeb, M. J.; Douglas, S. A. Annu. Rep. Med. Chem.
2003, 38, 99; (d) Thanassoulis, G.; Huyhn, T.; Giaid, A. Peptides 2004, 25, 1789;
(e) Russell, F. D. Pharmacol. Ther. 2004, 103, 223; (f) Onan, D.; Hannan, R. D.;
Thomas, W. G. Trends Endocrin. Met. 2004, 15, 175; (g) Joyal, D.; Huynh, T.;
Aiyar, N.; Guida, B.; Douglas, S.; Giaid, A. Int. J. Cardiol. 2006, 108, 31; (h)
Douglas, S.; Dhanak, D.; Johns, D. G. Trends Pharmacol. Sci. 2004, 25, 76; (i)
Lescot, E.; Bureau, R.; Rault, S. Peptides 2008, 29, 680. and references cited
therein.
7.1. Data collection
A colourless block crystal of N-[3-dimethylaminopropyl-1-(2-
naphthyl)]-1-methoxy-2-phenyl-acetamide HCl (C24H29ClN2O2)
(ꢀ)-{C9} having approximate dimensions of 0.40 ꢁ 0.30 ꢁ
0.25 mm3 was mounted with epoxy cement on the tip of a fine
glass fibre. All measurements were made on a Nonius CAD4 dif-
fractometer with graphite monochromated Mo Ka
radiation.8 Cell
constants and an orientation matrix for data collection corre-
2. Lehmann, F.; Pettersen, A.; Currier, E. A.; Sherbukhin, V.; Olsson, R.; Hacksell,
U.; Luthman, K. J. Med. Chem. 2006, 49, 2232.
3. Croston, G. E.; Olsson, R.; Currier, E. A.; Burstein, E. S.; Weiner, D.; Nash, N.;
Severance, D.; Allenmark, S. G.; Thunberg, L.; Ma, J. N.; Mohell, N.; O’Dowd, B.;
Brann, M. R.; Hacksell, U. J. Med. Chem. 2002, 45, 4950.
4. Lehmann, F.; Currier, E. A.; Olsson, R.; Hacksell, U.; Luthman, K. Bioorg. Med.
Chem. 2005, 13, 3057.
5. Sajiki, H.; Kurita, T.; Kozaki, A.; Zhang, G.; Kitamura, Y.; Maegawa, T.; Hirota, K.
Synthesis 2005, 537 (Erratum Synthesis-Stuttgart 2005, 852).
6. Lehmann, F.; Lake, L.; Currier, E. A.; Olsson, R.; Hacksell, U.; Luthman, K. Eur. J.
Med. Chem. 2007, 42, 276.
7. (a) Bräuner-Osborne, H.; Brann, M. R. Eur. J. Pharmacol. 1996, 295, 93; (b)
Burstein, E. S.; Bräuner-Osborne, H.; Spalding, T. A.; Conklin, B. R.; Brann, M. R. J.
Neurochem. 1997, 68, 525; (c) Burstein, E. S.; Spalding, T. A.; Brann, M. R. Mol.
Pharmacol. 1997, 51, 312; (d) (a) Spalding, T. A.; Burstein, E. S.; Jorgensen, H. B.;
Hilleubanks, D.; Brann, M. R. Life Sci. 1995, 56, 1021; (b) Burstein, E. S.; Piu, F.;
Ma, J. N.; Weissman, J. T.; Currier, E. A.; Nash, N. R.; Weiner, D. M.; Spalding, T.
A.; Schiffer, H. H.; Del Tredici, A. L.; Brann, M. R. Curr. Pharm. Des. 2006, 12,
1717.
sponded to a primitive monoclinic cell with dimensions:
a ¼ 5:4068ð11Þ Å
a
¼ 90ꢃ
b ¼ 10:174ð2Þ Å b ¼ 93:02ð2Þꢃ
c ¼ 20:701ð6Þ Å
c
¼ 90ꢃ
V ¼ 1137:1ð5Þ Å3
For Z = 2 and FW = 412.94, the calculated density is 1.206 mg/
m3. The space group was determined to be P21 (#4). The data were
collected at a temperature of 298(2) K to a maximum 2h value of
51.92°.
7.2. Data reduction
8. Enraf-Nonius. CAD4-PC Software. Version 1.1 Enraf-Nonius; Delft, The
Netherlands, 1992.
9. McArdle, P.; Higgins, T. XCAD4; National University of Ireland: Galway, Ireland,
1995.
10. McArdle, P. OSCAIL-X for Windows.Version 1.0.7; Crystallography Centre,
Chemistry Department, NUI: Galway, Ireland, 2005.
11. Sheldrick, G. M. SHELXL97 and SHELXS97; University of Göttingen: Germany,
1997.
A total of 2492 reflections including Friedel equivalents were
collected of which 2366 were unique and observed (Rint = 0.0113).
The linear absorption coefficient,
l, for Mo Ka radiation is
0.189 mmꢀ1, and no absorption correction was applied. The data
were corrected for Lorentz and polarization effects.9
7.3. Structure solution and refinement
12. Flack, H. D. A. Acta Crystallogr., Sect. A 1983, 39, 876.
The structure was solved by direct methods and expanded using
Fourier techniques.10,11 The non-hydrogen atoms were refined