2-Acylamino-5-chlorobenzophenones with enhanced selectivity towards malaria parasites

Article abstract of DOI:10.1016/j.ejmech.2011.01.056

Previously we described a series of 5-acylaminobenzophenones with considerable antimalarial activity. Unfortunately, most compounds also displayed high cytotoxicity resulting in low selectivity towards malaria parasites. Through the replacement of the 5-acylamino moiety by simple chlorine and further modifications of the 2-acylamino residue we could obtain inhibitors with improved selectivity towards malaria parasites combined with an acceptable reduction of antimalarial activity.

Full text of DOI:10.1016/j.ejmech.2011.01.056

European Journal of Medicinal Chemistry 46 (2011) 1331e1342
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
2-Acylamino-5-chlorobenzophenones with enhanced selectivity towards malaria
parasites
Swetlana Heinrich a, Mirko Altenkämper a, Benjamin Bechem a, Johann Perruchon a, Regina Ortmann a,
,
Hans-Martin Dahse b, Yulin Wang c, Michael Lanzer c, Martin Schlitzer a
*
a Institut für Pharmazeutische Chemie, Philipps-Universität Marburg, Marbacher Weg 6, Marburg 35032, Germany
b Leibniz-Institut für Naturstoff-Forschung und Infektionsbiologie e. V. Hans-Knöll-Institut, Beutenbergstrasse 11a, 07745 Jena, Germany
c Institut für Parasitologie, Universität Heidelberg, Im Neuenheimer feld 24, Heidelberg 69120, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Previously we described a series of 5-acylaminobenzophenones with considerable antimalarial activity.
Unfortunately, most compounds also displayed high cytotoxicity resulting in low selectivity towards
malaria parasites. Through the replacement of the 5-acylamino moiety by simple chlorine and further
modifications of the 2-acylamino residue we could obtain inhibitors with improved selectivity towards
malaria parasites combined with an acceptable reduction of antimalarial activity.
Received 19 August 2010
Received in revised form
21 January 2011
Accepted 26 January 2011
Available online 3 February 2011
Ó 2011 Elsevier Masson SAS. All rights reserved.
Keywords:
Antimalarial agents
Plasmodium falciparum
Benzophenone derivatives
QSAR
Enhanced selectivity
1. Introduction
5-substituent is converted into an electron-withdrawing and,
second, a more or less spacious lipophilic substituent is added. Often
Almost half of the world’s population, especially in the
developing countries is affected by malaria. The relatively few
drugs available to fight this disease are continuously threatened
by the development of resistance [1,2]. The urgent need for the
development of novel agents against malaria which preferable
should act through hitherto unexploited mechanisms of action is
undisputed.
Recently, we described 2,5-diaminobenzophenones carrying
acyl or sulfonyl residues at the 5-amino group with significant
antimalarial activity [3]. However, compounds also displayed
considerable cytotoxicity and therefore unsatisfactory selectivity
towards malaria parasites. Best representative in terms of activity
and selectivity was the di-isopropyl urea derivative 1 with an IC50 of
110 nM and a selectivity index (CC50/IC50 (Plasmodium falciparum))
of 36. In comparison to the parent non-acylated or non-
sulfonylated 5-amino derivative 2 the N-modified compounds were
up to 70fold more active (Fig. 1). Acylation of the 5-amino group
changes two molecular properties: first, the electron-donating
more lipophilic compounds also display enhanced cytotoxicity. We
therefore speculated that the replacement of the 5-acylamino
moiety could reduce cytotoxicity while possibly antimalarial
activity could be preserved. We chose the readily available 2-amino-
5-chlorobenzophenone (3) as the basic scaffold of this series. We
extensively varied the acyl residue at the 2-amino group to explore
the influence of this moiety on antimalarial activity as well as the
selectivity towards the parasites.
2. Results and discussion
2.1. Chemistry
Synthesis (Scheme 1) of the target compounds is following the
route established [3,4] for this type of compounds. Briefly,
commercially available 2-amino-5-chlorobenzophenone (3) was
acylated with appropriate
a-chloro or a-bromo acyl chlorides.
Then, the -halogene was replaced by different amines to obtain
a
compounds 5, 9,10 and 11. In case of the amino acid derivatives 6e8
acylation was carried out with N-boc-protected amino acids using
phosphorous oxychloride activation in pyridine. The resulting boc-
protected amino acid derivatives 6 were deprotected by HCl in
* Corresponding author. Tel.: þ49 6421 28 25698; fax: þ49 6421 28 25953.
E-mail address: schlitzer@staff.uni-marburg.de (M. Schlitzer).
0223-5234/$ e see front matter Ó 2011 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2011.01.056

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S. Heinrich et al. / European Journal of Medicinal Chemistry 46 (2011) 1331e1342
R2
NH
O
O
O
O
O
O
l
C
NH2
O
l
C
NH
O
O
c
a
R2
NH
b
N
H
O
O
N
H
N
H
N
H2N
N
H
N
O
O
N
O
N
6
3
1
2
R2
NH2
R2
O
O
l
C
NH
O
l
C
NH R1
O
Fig. 1. 1 di-isopropyl urea derivative IC50 ¼ 110 nM, 2 5-amino derivative IC50 ¼ 6.5
mM.
d
dioxane to obtain the amino acid derivatives 7 as hydrochlorides.
Carbamoylation of 7 with methylpiperazine carbamoyl chloride
yielded the urea-amino acid derivatives 8 (Scheme 2).
7
8
Scheme 2. Synthesis of chlorobenzophenone derivatives: a) b) Boc-protec-ted amino
acids, phosphorylchloride, pyridine, ꢁ15 ꢂC to rt, 0.5 h; c) HCl (4M) in dioxane, rt 2 h;
d) 4-methylpiperazine-1-carbonylchloride, dichloromethane.
2.2. Antimalarial activity
In vitro antiplasmodial activity of the compounds was deter-
mined using a standard cell proliferation assay in which synchro-
nized blood stage cultures of the P. falciparum clone Dd2 were
incubated with different concentrations of the compound for 72 h
before the half maximal growth inhibition coefficient (IC50-value)
was determined. In parallel, the IC50-value of the Dd2 strain for the
established antimalarial drugs chloroquine and quinine (137 ꢀ
11 nM and 284 ꢀ 18 nM, respectively) were determined. The
chloroquine and quinine IC50-values were consistent with pub-
lished data [5].
The methylpiperazinyl derivative 5a is the direct 5-chloro
analogue of the series of 5-acylamino-substituted benzophenones
we described previously [3]. Its antimalarial activity with an IC50
value of 3.54 mM falls well within the range of activity of most of the
5-acylamino-benzophenones [3]. Replacement of the N-methyl
group by an ethyl residue (5b) did not change antimalarial activity
growth of cultured malaria parasites with an IC50 of 330 nM. Due to
the higher antimalarial activity of 5j and an acceptable cytotoxicity,
an improved selectivity index of 150 was obtained for this
compound. Replacement of the piperazine heterocycle by piperi-
dine (5k) or piperidone (5l) reduced antimalarial activity 2e3fold.
Since in case of the piperazine-based compound pair 5a/5j
a hydroxyethyl residue had considerably improved antimalarial
activity, we also added this residue to the 4-position of the piper-
idine. However in this case, this modification further reduced
antimalarial activity (5m; IC50 ¼ 15
mM). Replacement of the
methylpiperazinyl residue by morpholinyl (5n), thiomorpholinyl
(5o) or S-oxo-thiomorpholinyl (5p) resulted in less active
compounds, while the imidazolyl derivative 5q was nearly as active
as the methylpiperazinyl derivative 5a.
In the next series, we replaced the nitrogen-containing
heterocycle by a simple amino group resulting in the phenylglycine
derivatives 7a-c. The racemic phenylglycine derivative 7a showed
(IC50 ¼ 3.62
m
M). Further elongation of the N-alkyl residue reduced
activity (5c; IC50 ¼ 6.23
mM). More spacious residues like phenyl
an IC50 of 6.71
heterocylic derivatives where the single nitrogen is directly con-
nected to the -position of the acyl residue. In case of the phenyl-
mM and therefore, an activity comparable to the
(5d), nitrophenyl (5e) and benzyl (5f) let to inactive compounds.
Replacement of piperazinyl’s methyl substituent by formyl (5g) did
not alter antimalarial activity as did not the introduction of an
ethoxycarbonyl moiety (5h). The more spacious tert-butylox-
a
glycine derivatives a marked difference in activity is seen with the
stereoisomers. While the IC50 values obtained for the racemate and
the R-enantiomer where comparable, the S-enantiomer did not
ycarbonyl residue produced a less active derivative (5i; IC50
¼
8.21 M). In contrast, addition of a hydroxyl group to the terminal
m
show any activity at 16 mM. A boc-protective group on the amino
carbon of the ethyl residue of 5b improved antimalarial activity
10fold. The hydroxyethylpiperazinyl derivative 5j inhibited the
group attenuated the stereo differentiation. Both enantiomers
(6a,b) are of comparable activity. Replacement of the phenylglycine
in 7a by racemic glycine and serine resulted in inactive compounds
(7d, e), while the phenylalanine (7f) (IC50 ¼ 14.11
mM) and trypto-
R2
O
phane (7g) (IC50 ¼ 12.13 M) derivatives showed some activity
m
although both were less active than the R-phenylglycine derivative
(7b). Since considerable activity has only recorded with compounds
having a second amino group, we focussed our attention on this
type of compounds. First, we added a N-methylpiperazinylcarbonyl
moiety to the amino group of the R- and S-phenylglycine derivative.
Again the R-enatiomer 8a of the resulting ureas 8 was more active
than the S-enatiomer 8b. However, the difference was not that
pronounced as with the unsubstituted phenylglycine derivatives
l
C
NH2
O
l
NH
O
l
C
C
a
b
3
4
R2
O
with IC50 values of 1.35 mM and 4.21 mM, respectively. Replacement
of the piperazine heterocycle by two open chain diamines of
different length resulted in two compounds (9a, b) being slightly
l
C
NH R1
O
more active (IC50’s 2.20 and 1.57
derivative 5a.
mM) than the methylpiperazinyl
5 9 10 11
, , ,
Highest activity was obtained so far with the hydroxyethyl-
substituted piperazinyl compound 5j. We speculated that the
terminal hydroxyl group could form hydrogen bonds to the puta-
tive target acting as a hydrogen bond donor or acceptor. Therefore,
Scheme 1. Synthesis of chlorobenzophenone derivatives: a)
chlorides, toluene, reflux; b) different amines, acetonitrile, reflux.
a
-chloro or
a
-bromo acyl

S. Heinrich et al. / European Journal of Medicinal Chemistry 46 (2011) 1331e1342
1333
Table 1
Structure and antimalarial activity of target compounds.
a
Cmpd.
R1
R2
IC P. falciparum (
m
m)
CC50
63
(
m
M
)
SIb
50
5a
3.54 ꢀ 1.86
3.62 ꢀ 1.76
6.23 ꢀ 0.96
>20
18
5b
5c
5d
5e
76
21
6
38
>98
>90
5
>20
5
5f
>20
>118
6
5g
5h
3.77 ꢀ 0.73
4.26 ꢀ 0.83
50
64
13
15
5i
5j
8.21 ꢀ 1.64
0.33 ꢀ 0.11
>94
11
49
150
5k
5l
10.23 ꢀ 2.62
7.43 ꢀ 1.22
63
27
6
4
5m
15.00 ꢀ 0. 98
19
1
5n
5o
5p
6.72 ꢀ 1.03
11.47 ꢀ 1.49
9.02 ꢀ 1.02
39
6
10
8
>111
71
(continued on next page)

1334
S. Heinrich et al. / European Journal of Medicinal Chemistry 46 (2011) 1331e1342
Table 1 (continued ).
a
Cmpd.
R1
R2
IC P. falciparum (
m
m)
CC50
55
(
m
M
)
SIb
50
5q
7a
7b
4.51 ꢀ 0.89
6.71 ꢀ 2.90
9.25 ꢀ 1.44
12
37
12
6
1
7c
7d
7e
7f
>16
43
3
6 > 20
nd
>20
128
nd
38
>20
14.11 ꢀ 3.46
3
7g
12.13 ꢀ 3.81
6
0.5
6a
6b
6.18 ꢀ 1.90
8.47 ꢀ 1.19
>108
>108
17
13
8a
8b
1.35 ꢀ 0.83
4.21 ꢀ 0.63
60
72
45
17
9a
9b
2.20 ꢀ 0.33
1.57 ꢀ 0.21
45
79
21
50
10a
10b
>3
>3
>99
33
34
>102

S. Heinrich et al. / European Journal of Medicinal Chemistry 46 (2011) 1331e1342
1335
Table 1 (continued ).
a
Cmpd.
R1
R2
IC P. falciparum (
m
m)
CC50
65
(
m
M
)
SIb
50
10c
10d
10e
3.32 ꢀ 0.45
0.98 ꢀ 0.35
2.56 ꢀ 0.72
22
40
39
41
15
11a
11b
11c
11d
0.84 ꢀ 0.22
0.60 ꢀ 0.21
0.56 ꢀ 0.17
0.28 ꢀ 0.11
38
17
17
16
45
28
31
59
11e
0.95 ꢀ 0.27
0.18 ꢀ 0.09
17
17
18
94
11f
nd ¼ not determine.
a
Cytotoxicity (Hela cells).
SI ¼ selectivity index ¼ CC50 (HeLa)/IC50 (P.falciparum).
b
we placed several polar functions capable to act as hydrogen bond
acceptors or as hydrogen bond donor/acceptors. The compounds
10a-e failed in showing antimalarial activity superior to 5j. There-
fore, we kept the hydroxyethyl piperazinyl moiety and varied the
phenyl residue. All six compounds 11a-f displayed submicromolar
antimalarial activity with the biphenylyl (11d) (IC50 ¼ 280 nM) and
the 2-naphthyl derivative (11f) (IC50 ¼ 180 nM) being slightly more
active than the phenyl derivative 5j (IC50 ¼ 330 nM).
3. Conclusion
In our preceding paper we described a series of 5-acylamino-
benzophenones with considerable antimalarial activity. There
value was however reduced by high cytotoxicity and therefore low
selectivity of most compounds. We speculated that it might
possible to separate antimalarial from unwanted cytotoxic activity.
Through replacement of the 5-acylamino moiety by a simple
chlorine and modification or the 2-acylamino residue we obtained
inhibitors which were slightly less active against cultured malaria
parasites but showed improved selectivity against the parasites.
The selectivity index could be improved 4fold from 36 to 150.
Because of these results we are encouraged to continue our
investigations with this class of antimalarials.
2.3. Cytotoxicity
Cytotoxicity of selected compounds was evaluated against HeLa
cells. Viability of the cells was determined after a 72 h incubation
period using methylene blue staining and photometric evaluation
(Table 1). Most compounds showed cytotoxicity against HeLa cells
in the two digit micromolar range. There is no obvious correlation
between cytotoxicity and antimalarial activity indicating a different
mechanism of antimalarial and cytotoxic action. Two of the
compounds with highest antimalarial activity 5j and 11f show
selectivity indices of 150 and 94, respectively, the first being an
acceptable value.
4. Experimental
4.1. Chemistry
1H NMR and 13C NMR spectra were recorded on a Jeol Lambda
500 delta, a Jeol JNM-GX-400, a Jeol Eclipse 500 and a Jeol Eclipse

1336
S. Heinrich et al. / European Journal of Medicinal Chemistry 46 (2011) 1331e1342
400 spectrometer. Mass spectra were obtained with a Vacuum
Generator VG 7070H using a Vector 1 data acquisition system from
Teknivent, an AutoSpec mass spectrometer from Micromass, an API
2000 LC-MS-MS system of PE SCIEX using Analyst 1.2 of Applied
Biosystems/MDS SCIEX and on a MStation JMS 700 from Jeol using
Jeol Mass Data System MS-MP9021D 2.30. IR spectra were recorded
on a Nicolet 510PFTIR spectrometer, a Jasco FT/IR 410 FTIR, a Perkin
Elmer Paragon 1000 FTIR or a Bruker alpha-P spectrometer.
Microanalyses were obtained with a CH analyzer according to Dr.
Salzer from Labormatic, a HewlettePackard CHN analyzer type 185,
and a Vario EL from Elementar. Melting points were obtained with
a Reichert Austria microscope and are uncorrected. Column chro-
matography was carried out using silica gel 60 (0.062e0.200 mm)
from Machery-Nagel and silica gel 60 (0.040e0.063 mm) from
Merck.
1H), 7.25e7.31 (m, 3H), 7.36e7.38 (m, 2H), 7.45e7.48 (m, 2H),
7.52e7.55 (m, 2H), 7.64 (m, 1H), 7.77e7.79 (m, 2H), 8.55 (m, 1H),
11.60 (s, 1H); 13C NMR (100 MHz, CDCl3) dC (ppm) ¼ 45.83, 54.79,
76.92, 123.08, 126.11, 127.46, 128.33, 128.60, 128.71, 128.92, 130.04,
131.91, 133.06, 133.34, 135.38, 137.78, 137.97, 171.12, 197.06; IR (KBr):
n
(cmꢁ1): ¼ 3178, 2938, 2798, 1692, 1639, 1595, 1565, 1504, 1446,
1394, 1307, 1281, 1245, 1179, 1163, 1141, 1119, 1099, 1078, 1019, 1011,
946, 878, 862, 820, 762, 736, 700, 648, 537; MS (EI, 70 eV): m/z 188
(100), 190 (23), 406 (12), 447 (15) [M]þ, 448 (5) [Mþ1]þ; (EI-HRMS):
calcd: 447.1714, found: 447.1748.
4.1.4.2. (R,S)-N-(2-benzoyl-4-chlorophenyl)-2-(4-ethyl-1-piperazinyl)-
2-phenylacetamide (5b). According to general procedure 2 from
(R,S)-N-(2-benzoyl-4-chlorophenyl)-2-chloro-2-phenylacetamide
(1.9 g, 5.0 mmol) and N-ethylpiperazine (1.7 g, 15.0 mmol). Purifi-
cation: chromatography (silicagel, ethylacetate) to give a light brown
1
4.1.1. Generalprocedure1:activationofvariousacidsasacidchlorides
and reaction with aromatic amines
crystalline solid: yield 1.29 g (56%). Mp 113 ꢂC; H NMR (400 MHz,
CDCl3) dH (ppm) ¼ 1.03 (t, 3H, J ¼ 7.2 Hz), 2.39e2.43 (q, 2H,
J ¼ 7.2 Hz), 2.47e2.62 (m, 8H), 3.96 (s, 1H), 7.25e7.30 (m, 3H),
7.34e7.37 (m, 2H), 7.45e7.47 (m, 2H), 7.51e7.55 (m, 2H), 7.63e7.66
(m, 1H), 7.77e7.79 (m, 2H), 8.54e8.56 (m, 1H), 11.59 (s, 1H); 13C NMR
(100 MHz, CDCl3) dC (ppm) ¼ 11.90, 52.09, 52.44, 76.65, 123.25,
126.35, 127.63, 128.46, 128.76, 128.85, 129.15, 130.23, 132.01, 133.23,
The various carboxylic acids were dissolved in dichloromethane
and 0.2 mL oxalylchloride per mmol acid was added. The mixture
was stirred for 2 h and the volatiles were evaporated in vacuo. The
resulting acyl chlorides were dissolved in dioxane (approx. 30 mL)
and added to a solution of the appropriate aromatic amine in hot
toluene (approx. 50 mL). The mixtures were heated under reflux for
2 h. After the solvent was removed in vacuo, the crude products
were purified by recrystallization, or chromatographed on silica gel.
133.47, 135.58, 137.93, 138.11, 171.14, 196.96; IR (KBr):
n
(cmꢁ1) ¼
3855, 3745, 3676, 3630, 3184, 2966, 2818, 1695, 1654, 1636, 1596,
1560, 1501, 1445, 1395, 1310, 1280, 1243, 1155, 1017, 948, 859, 762,
737, 726, 700, 647, 536; MS (EI, 70 eV): m/z 84 (9), 91 (15), 202 (100),
204 (23), 461 (9) [M]þ, 462 (3) [Mþ1]þ; MS (EI-HRMS) calcd:
461.1870, found: 461.1873.
4.1.2. General procedure 2: Substitution of the halogene of 2-chloro-
(phenyl)acetylchloride derivates with amines
The 2-chloro-(phenyl)acetylchloride derivative was dissolved in
freshly distilled acetonitrile, 3 equivalents of the amine were added
and the mixture was heated under reflux for 24e48 h. After
removing the acetonitrile under reduced pressure, the obtained
solid was dissolved in ethyl acetate and was purified either by
column chromatography or by washing with a saturated solution of
K2CO3, drying over Na2SO4 and removing the solvent under
reduced pressure. In case further purification was neccessary, the
crude product was recrystallized, or chromatographed on silica gel.
4.1.4.3. (R,S)-N-(2-benzoyl-4-chlorophenyl)-2-(4-propyl-1-piper-
azinyl)-2-phenylacetamide (5c). According to general procedure 2
from (R,S)-N-(2-benzoyl-4-chlorophenyl)-2-chloro-2-phenylacetamide
(1.9 g, 5.0 mmol), N-propyl piperazine dihydrobromide (4.4 g,
15.0 mmol) and sodium hydrogencarbonate (2.5 g, 30.0 mmol).
Purification: the crude compound was dissolved in a minimal
amount of dichloromethane and then precipitated by dropwise
addition of n-pentane to give a light brown crystalline solid.: yield
1.38 mg (58%). Mp 125 ꢂC; 1H NMR (400 MHz, CDCl3) dH
(ppm) ¼ 0.87e0.92 (m, 3H), 1.47e1.58 (m, 2H), 2.28e2.71 (m, 10H),
3.98 (s, 1H), 7.27e7.28 (m, 3H), 7.34e7.36 (m, 2H), 7.46e7.48 (m,
2H), 7.52e7.55 (m, 2H), 7.63e7.67 (m, 1H), 7.76e7.78 (m, 2H),
8.55e8.58 (m, 1H), 11.62 (s, 1H); 13C NMR (100 MHz, CDCl3) dC
(ppm) ¼ 11.85, 19.55, 52.71, 60.24, 77.20, 123.04, 126.05, 127.48,
128.37, 128.59, 128.73, 128.93, 130.02, 131.92, 133.07, 133.39, 135.23,
4.1.3. General procedure 3: Deprotection of N-boc groups
Boc-protecting compounds were dissolved in a solution of HCl
(4 m) in dioxane and were stirred at room temperature for 2 h.
Then, the solvent was removed in vacuo to obtain the hydrochloric
salt precipitates.
4.1.4. General procedure 4: acylation of amines with Boc-protected
amino acids
137.78, 137.96, 170.95, 197.29; IR (KBr):
n
(cmꢁ1) ¼ 3200, 2956,
2821,1691, 1643, 1597, 1560, 1501, 1445, 1394, 1309, 1279, 1241, 1156,
1099, 1011, 943, 802, 763, 736, 699, 648; MS (FAB): m/z 476 (100)
[M þ H]þ, 477 (32) [M]þ, 478 (37) [M þ H]þ; MS (FAB-HRMS) calcd:
476.2105, found: 476.2113.
Protected amino acids and primary amines were dissolved in
dry pyridine. The solution was cooled to ꢁ15 ꢂC and phosphoryl
chloride was added dropwise with vigorous stirring. The reaction
being complete after a total of 0.5 h. The mixture was then
quenched with crushed ice/water (100 mL) and was extracted three
times with ethylacetate. The combined organic layers were washed
with saturated NaHCO3 solution and brine, dried over Na2SO4. Then
the solvent was removed under reduced pressure. In case further
purification was neccessary, the crude product was recrystallized,
or chromatographed on silica gel.
4.1.4.4. (R,S)-N-(2-benzoyl-5-chlorophenyl)-2-phenyl-2-(4-phenyl-
piperazin-1-yl)acetamide (5d). According to general procedure 2
from (R,S)-N-(2-benzoyl-4-chlorophenyl)-2-chloro-2-phenylacetamide
(1.9 g, 5.0 mmol) and N-phenylpiperazine (2.4 g, 15.0 mmol).
Purification: chromatography (silicagel, ethylacetate) to give
a yellow crystalline solid: yield 1.30 g (51%); Mp 102 ꢂC; 1H NMR
(500 MHz, CDCl3) dH (ppm) ¼ 2.46e2.57 (m, 4H), 3.14e3.19 (m, 4H),
3.90 (s, 1H), 6.70e6.78 (m, 3H), 7.12e7.13 (m, 2H), 7.29e7.34 (m,
3H), 7.39e7.43 (m. 2H), 7.46e7.53 (m, 4H), 7.61e7.65 (m, 1H),
7.72e7.75 (m, 2H), 8.57 (m, 1H), 11.71 (s, 1H); 13C NMR (125 MHz,
CDCl3) dC (ppm) ¼ 48.82, 51.53, 77.00, 115.95, 119.62, 123.03, 127.50,
128.45, 128.59, 128.79, 128.94, 129.08, 130.05, 131.07, 131.65, 132.05,
4.1.4.1. (R,S)-N-(2-benzoyl-4-chlorophenyl)-2-(4-methyl-piperazinyl)-
2-phenylacetamide (5a). According to general procedure 2 from
(R,S)-N-(2-benzoyl-4-chlorophenyl)-2-chloro-2-phenylacetamide
(1.9 g, 5.0 mmol) and N-methylpiperazine (1.5 g, 15.0 mmol). Puri-
fication: chromatography (silicagel, ethylacetate) to give a light
yellow crystalline solid: yield 1.28 g (57%). Mp 122 ꢂC; 1H NMR
(400 MHz, CDCl3) dH (ppm) ¼ 2.27 (s, 3H), 2.51 (s, br, 8H), 3.94 (s,
133.04, 133.40, 135.30, 137.72, 138.02, 170.99, 197.13; IR (KBr):
n
(cmꢁ1) ¼ 3855, 3745, 3676, 3630, 2826, 1735, 1696, 1648, 1598,

S. Heinrich et al. / European Journal of Medicinal Chemistry 46 (2011) 1331e1342
1337
1570, 1497, 1449, 1395, 1282, 1238, 1140, 1013, 945, 761, 698; MS
(FAB): m/z 509 (100) [M]þ, 510 (36) [M þ H]þ, 511 (38) [M]þ, 512
(12) [M þ H]þ; MS (FAB-HRMS) calcd: 510.1948, found: 510.1958.
204 (62), 461 (2) [M]þ; MS (ESI): m/z 462 (100) [M þ H]þ; MS (ESI-
HRMS) calcd: 462.1584, found: 462.1623.
4.1.4.8. (R,S)-N-(2-benzoyl-4-chlorophenyl)-2-[4-(ethoxycarbonyl)-
1-piperazinyl]-2-phenylacetamide (5h). According to general
procedure 2 from (R,S)-N-(2-benzoyl-4-chlorophenyl)-2-chloro-2-
phenyl-acetamide (1.9 g, 5.0 mmol) and N-carbethoxypiperazine
(2.4 g, 15.0 mmol). Purification: chromatography (silicagel, ethyl-
acetate/isohexane 2:3) to give a yellow solid: yield 2.10 g (83%). Mp
77 ꢂC; 1H NMR (500 MHz, CDCl3) dH (ppm) ¼ 1.22 (t, 3H, J ¼ 7.1 Hz),
2.36e2.50 (m, 4H), 3.58 (s, br, 4H), 4.01 (s,1H), 4.09 (q, 2H, J ¼ 7.1 Hz),
7.28e7.37 (m, 5H), 7.47e7.56 (m, 4H), 7.63e7.67 (m, 1H), 7.74e7.78
(m, 2H), 8.59 (m, 1H), 11.81 (s, 1H); 13C NMR (125 MHz, CDCl3) dC
(ppm) ¼ 14.72, 43.55, 51.36, 61.41, 77.03, 123.08, 125.82, 127.63,
128.58, 128.71, 128.87, 129.12, 130.07, 132.34, 133.15, 133.64, 134.95,
4.1.4.5. (R,S)-N-(2-benzoyl-4-chlorphenyl)-2-[4-(4-nitrophenyl)-1-
piperazinyl]-2-phenylacetamide (5e). According to general proce-
dure 2 from (R,S)-N-(2-benzoyl-4-chlorophenyl)-2-chloro-2-phe-
nylacetamide (1.9 g, 5.0 mmol) and 1-(4-nitrophenyl)piperazine
(3.1 g, 15.0 mmol). While cooling down a white solid was removed.
The solvent was evaporated and the compound was purified with
column chromatography (silica gel, ethyl acetate/isohexane 1:1)
and dried under vacuum to afford an orange solid: yield 2.08 g
(75%). Mp 113 ꢂC; 1H NMR (500 MHz, CDCl3) dH (ppm) ¼ 2.64 (s, br,
4H), 3.54 (s, br, 4H), 4.06 (s, 1H), 6.75e6.22 (m, 2H), 7.30e7.38 (m,
3H), 7.39e7.44 (m, 2H), 7.49e7.55 (m, 4H), 7.63e7.67 (m, 1H),
7.72e7.75 (m, 2H), 8.08e8.12 (m, 2H), 8.50 (m, 1H), 11.79 (s, 1H); 13C
NMR (CDCl3, 100 MHz) dC (ppm): 46.77, 50.97, 77.21, 112.69, 123.08,
125.80, 125.91, 127.77, 128.63, 128.77, 128.96, 129.98, 130.47, 132.27,
133.14, 133.62, 137.72, 137.94, 138.59, 139.87, 142.82, 154.63, 197.46;
137.89, 138.19, 155.46, 170.85, 197.44; IR (KBr):
n
(cmꢁ1) ¼ 3244,
2978, 2831,1698,1645,1596,1568,1499,1431,1395,1302,1282,1244,
1178, 1157, 1119, 1033, 1012, 945, 763, 701; MS (ESI): m/z 91 (10), 105
(17),175 (22), 219 (25), 231 (10), 245 (8), 246 (6), 247 (100), 248 (94),
249 (26), 257 (6), 504 (3), 505 (3) [M]þ, 506 (1) [M þ H]þ, 507 (1)
[M]þ; MS (ESI-HRMS) calcd: 506.1847, found: 506.1858.
IR (KBr):
n
(cmꢁ1) ¼ 3745, 1700, 1696, 1685, 1654, 1648, 1597,1570,
1560, 1507, 1448, 1395, 1324, 1283, 1243, 1115, 1009, 945, 928, 829,
753, 700, 668; MS (EI, 70 eV): m/z 91 (24),105 (13), 165 (8), 175 (21),
231 (9), 257 (8), 266 (15), 280 (6), 296 (100), 297 (87), 298 (17), 554
(9) [M]þ, 555 (3) [Mþ1]þ, 556 (3) [M]þ, 557 (1) [Mþ1]þ; MS (EI-
HRMS) calcd: 554.1721, found: 554.1677.
4.1.4.9. tert-Butyl-4-(2-(2-benzoyl-4-chlorophenylamino)-2-oxo-1-
phenylethyl)piperazine-1-carboxylate (5i). According to general
procedure 2 from (R,S)-N-(2-benzoyl-4-chlorophenyl)-2-chloro-2-
phenylacetamide (1.9 g, 5.0 mmol) and N-boc-piperazine (2.8 g,
15.0 mmol). Purification: chromatography (silicagel, ethylacetate/
isohexane 2:3) to give a yellowish solid: yield 437 mg (18%). Mp
86 ꢂC; 1H NMR (500 MHz, CDCl3) dH (ppm) ¼ 1.42 (m, 9H),
2.32e2.49 (m, 4H), 3.49e3.56 (m, 4H), 3.99 (s, 1H), 7.27e7.38 (m,
5H), 7.46e7.56 (m, 4H), 7.63e7.67 (m, 1H), 7.74e7.77 (m, 2H), 8.59
(m, 1H), 11.79 (s, 1H); 13C NMR (125 MHz, CDCl3) dC (ppm) ¼ 28.39,
51.38, 76.86, 79.63, 122.99, 125.76, 127.51, 128.45, 128.60, 128.76,
129.00, 129.97, 132.21, 133.02, 133.52, 135.00, 137.82, 138.10, 154.59,
4.1.4.6. (R,S)-N-(2-benzoyl-4-chlorophenyl)-2-(4-benzyl-1-piperazinyl)-
2-phenylacetamide (5f). According to general procedure 2 from
(R,S)-N-(2-benzoyl-4-chlorophenyl)-2-chloro-2-phenylacetamide
(1.9 g, 5.0 mmol) and N-benzylpiperazine (2.6 g, 15.0 mmol).
Purification: the crude compound was dissolved in a minimal
amount of dichloromethane and then precipitated by dropwise
addition of n-pentane to give a white cristalline solid: yield 1.97 g
(75%). Mp 157 ꢂC; 1H NMR (400 MHz, CDCl3) dH (ppm) ¼ 2.53 (s, br,
8H), 3.49 (d, 1H, J ¼ 13.3 Hz), 3.53 (d, 1H, J ¼ 13.3 Hz), 3.96 (s, 1H),
7.27e7.36 (m, 10H), 7.45e7.48 (m, 2H), 7.53e7.57 (m, 2H),
7.64e7.69 (m, 1H), 7.77e7.80 (m, 2H), 8.53e8.56 (m, 1H), 11.60 (s,
1H); 13C NMR (100 MHz, CDCl3) dC (ppm) ¼ 2.75, 62.82, 76.72,
123.08, 126.22, 127.09, 127.46, 128.18, 128.28, 128.59, 128.65,
128.98, 129.27, 129.68,130.08, 131.81, 133.06,133.28, 135.38, 137.75,
170.83, 197.33; IR (KBr):
n
(cmꢁ1) ¼ 2975, 2928, 1696, 1648, 1596,
1569, 1500, 1453, 1422, 1395, 1365, 1283, 1247, 117, 1135, 1003, 944,
874, 833, 761, 701, 654; MS (EI, 70 eV): m/z 42 (3), 55 (3), 56 (4), 105
(9), 175 (19), 219 (83), 220 (27), 221 (3), 257 (7), 275 (7), 276 (66),
277 (9), 534 (1) [M]þ, 535 (1) [Mþ1]þ, 536 (0.3) [M]þ; MS (ESI): m/z
478 (22), 534 (100) [M þ H]þ, 1067 [2 (M þ H)]þ; MS (ESI-HRMS)
calcd: 534.2160, found: 534.2134.
137.88, 171.17, 196.97; IR (KBr):
n
(cmꢁ1) ¼ 3745, 2928, 2798, 2711,
2632, 2503, 2478, 1701, 1691, 1654, 1640, 1590, 1566, 1496, 1461,
1452, 1401, 1364, 1345, 1307, 1247, 1142, 1124, 1089, 1050, 1028,
1004, 938, 798, 743, 698, 489, 463, 430; MS (EI, 70 eV): m/z 77 (11),
91 (100), 92 (11), 105 (22), 118 (10), 134 (13), 146 (16),175 (12), 266
(57), 523 (12) [M]þ, 524 (5) [Mþ1]þ; MS (EI-HRMS) calcd:
523.2027, found: 523.2005; MS (FAB): m/z 524 (100) [M þ H]þ, 525
(37) [M]þ, 526 (39) [M þ H]þ; MS (FAB-HRMS) calcd: 524.2105,
found: 524.2133.
4.1.4.10. (R,S)-N-(2-benzoyl-4-chlorophenyl)-2-[4-(2-hydroxyethyl)-
piperazinyl]-2-phenylacetamide (5j). According to general proce-
dure 2 from (R,S)-N-(2-benzoyl-4-chlorophenyl)-2-chloro-2-phe-
nylacetamide (1.9 g, 5.0 mmol) and N-(2-hydroxyethyl)piperazine
(2.0 g, 15.0 mmol). Purification: chromatography (silicagel, ethyl-
acetate/isohexane 3:2, then ethylacetate) to give a light brown
crystalline solid: yield 1.29 g (54%). Mp 157 ꢂC; 1H NMR (400 MHz,
CDCl3) dH (ppm) ¼ 2.45e2.70 (m, 8H), 3.58e3.60 (t, 2H, J ¼ 5.2 Hz),
3.99 (s,1H), 7.26e7.32 (m, 3H), 7.35e7.37 (m, 2H), 7.46e7.49 (m, 2H),
7.52e7.55 (m, 2H), 7.63e7.67 (m, 1H), 7.76e7.78 (m, 2H), 8.55e8.57
(m, 1H), 11.64; 13C NMR (100 MHz, CDCl3) dC (ppm) ¼ 52.26, 57.43,
59.26, 77.00, 123.14, 125.85, 125.99, 127.62, 128.72, 128.88, 129.01,
130.09, 132.17, 133.19, 133.60, 135.23, 137.89, 138.10, 170.86, 197.27;
4.1.4.7. (R,S)-N-(2-benzoyl-4-chlorphenyl)-2-[4-formyl-1-piperazinyl]-
2-phenylacetamide (5g). According to general procedure 2 from
(R,S)-N-(2-benzoyl-4-chlorophenyl)-2-chloro-2-phenylacetamide
(1.9 g, 5.0 mmol) and N-piperazincarbaldehyde (1.7 g, 15.0 mmol).
Purification: chromatography (silicagel, ethylacetate) to give
a white crystalline solid: yield 1.27 g (55%). Mp 150 ꢂC; 1H NMR
(400 MHz, CDCl3) dH (ppm) ¼ 2.40e2.56 (m, 4H), 3.50 (t, 2H,
J ¼ 5.1 Hz), 3.62e3.71 (m, 2H), 4.05 (s, 1H), 7.28e7.37 (m, 5H),
7.48e7.56 (m, 4H), 7.64e7.67 (m, 1H), 7.73e7.76 (m, 2H), 7.97 (s,
1H), 8.59 (m, 1H), 11.86 (s, 1H); 13C NMR (100 MHz, CDCl3) dC
(ppm) ¼ 39.82, 45.47, 50.97, 51.93, 76.65, 123.08, 125.71, 127.74,
128.75, 128.97, 129.09, 130.06, 132.45, 133.24, 133.77, 134.63, 135.21,
IR (KBr):
n
(cmꢁ1) ¼ 3290, 2945, 2830, 1696, 1647, 1594, 1567, 1501,
1451, 1395, 1283, 1251, 1179, 1157, 1135, 1071, 1012, 950, 878, 825,
800, 746, 731, 700; MS (FAB): m/z 478 (100) [M þ H]þ, 479 (31) [M]þ,
480 (37) [M þ H]þ; MS (FAB-HRMS) calcd: 478.1897, found:
478.1895.
4.1.4.11. (R,S)-N-(2-benzoyl-4-chlorophenyl)-2-[1-piperidyl]-2-phe-
nylacetamide (5k). According to general procedure 2 from (R,S)-N-
(2-benzoyl-4-chlorophenyl)-2-chloro-2-phenylacetamide (1.9 g,
5.0 mmol) and piperidine (1.3 g, 15.0 mmol). Purification:
137.86, 138.17, 160.71, 170.50, 197.65; IR (KBr):
1689, 1660, 1636, 1565, 1503, 1443, 1393, 1317, 1304, 1279, 1244,
n
(cmꢁ1) ¼ 3180,
1156, 1007, 706; MS (EI, 70 eV): m/z 105 (11), 175 (14), 203 (100),

1338
S. Heinrich et al. / European Journal of Medicinal Chemistry 46 (2011) 1331e1342
chromatography (silicagel, ethylacetate/isohexane 1:1) to give
a yellowish solid: yield 1.25 g (57%). Mp 116 ꢂC; 1H NMR (500 MHz,
CDCl3) dH (ppm) ¼ 1.42 (s, br, 2H), 1.61e1.66 (m, 4H), 2.26e2.47 (m,
4H), 3.96 (s, 1H), 7.27e7.36 (m, 3H), 7.34e7.36 (m, 2H), 7.46e7.47
(m, 1H), 7.59 (dm, 3H), 7.79 (m, 2H), 8.57 (m, 2H), 11.65 (s, 1H); 13C
NMR (125 MHz, CDCl3) dC (ppm) ¼ 24.31, 25.77, 52.77, 77.49, 123.06,
126.33, 127.28, 128.02, 128.47, 128.53, 129.09, 129.99, 131.75, 132.93,
7.27e7.34 (m, 3H), 7.36e7.40 (m, 2H), 7.47e7.57 (m, 4H), 7.63e7.67
(m, 1H), 7.76e7.79 (m, 2H), 8.55e8.57 (m, 1H), 11.74 (s, 1H); 13C NMR
(125 MHz, CDCl3) dC (ppm) ¼ 52.14, 66.82, 77.39, 123.13, 125.98,
127.62, 128.56, 128.71, 128.87, 129.07, 130.10, 132.18, 133.17, 133.55,
135.05, 137.86, 138.10, 170.88, 197.34; IR (KBr):
n
(cmꢁ1
)
¼
2850, 2833, 1685, 1644, 1599, 1577, 1565, 1500, 1453, 1444, 1390,
1321, 1309, 1290, 1275, 1243, 1181, 1158, 1130, 1112, 1068, 1031, 1015,
946, 924, 878, 860; MS (EI, 70 eV): m/z 91 (12), 105 (24), 106 (3), 118
(6), 174 (7), 176 (100), 177 (71), 178 (11), 230 (4), 231 (8), 257 (4), 434
(1) [M]þ, 435 (1) [3M þ 1]þ, 436 (1) [M]þ; MS (ESI): m/z 435 (100)
[M þ H]þ; MS (ESI-HRMS) calcd: 435.1475, found: 435.1486.
133.16, 135.60, 137.83, 138.00, 171.75, 196.86; IR (KBr):
n
(cmꢁ1) ¼
3183, 2933, 1693, 1642, 1597, 1564, 1505, 1445, 1393, 1308, 1280,
1243, 1179, 1156, 1101, 945, 880, 861, 809, 800, 762, 735, 700, 673,
661, 643, 537, 454; MS (EI, 70 eV): m/z 84 (3), 91 (7), 56 (4), 105 (6),
106 (5), 172 (4), 173 (3), 174 (100), 175 (63), 230 (3), 231 (4), 257 (3),
430 (6), 432 (2) [M]þ, 433 (1) [Mþ1]þ, 434 (0.2) [M]þ; MS (ESI): m/z
433 (100) [M þ H]þ, MS (ESI-HRMS); calcd: 433.1683, found:
433.1706.
4.1.4.15. (R,S)-N-(2-benzoyl-4-chlorophenyl)-2-phenyl-2-thiomorph-
olin-oacetamide (5o). According to general procedure 2 from (R,S)-
N-(2-benzoyl-4-chlorophenyl)-2-chloro-2-phenylacetamide (1.9 g,
5.0 mmol), thiomorpholine (1.4 mL, 15.0 mmol) and triethylamine
(2.1 mL, 15.0 mmol). The product crystallized from the reaction
mixture and after drying in vacuo, afford a light brow solid; yield
1.24 g (54%). Mp 70 ꢂC; 1H NMR (500 MHz, DMSO-d6) dH
(ppm) ¼ 2.45e2.88 (m, 8H), 4.09 (s, 1H), 7.27e7.39 (m, 5H),
7.46e7.57 (m, 4H), 7.62e7.68 (m, 1H), 7.74e7.82 (m, 2H), 8.60 (m,
1H), 11.75 (s, 1H); 13C NMR (125 MHz, DMSO-d6) dC (ppm) ¼ 27.82,
53.62, 77.29, 122.96, 125.91, 127.50, 128.38, 128.61, 128.69, 129.23,
130.45, 132.09, 133.07, 133.45, 134.61, 137.81, 138.96, 170.97,197.19;
4.1.4.12. (R,S)-N-(2-benzoyl-4-chlorophenyl)-2-[4-oxopiperidin-1-
yl]-2-phenylacetamide (5l). According to general procedure 2 from
(R,S)-N-(2-benzoyl-4-chlorophenyl)-2-chloro-2-phenylacetamide
(1.9 g, 5.0 mmol) und 4-piperidone hydrochloride hydrate (2.5 g,
15.0 mmol). For the release of 4-piperidone sodium hydro-
gencarbonate was added. Molecular sieves was added to remove
the water. After the addition of n-pentane a white solid precipi-
tated. The compound was purified with column chromatography
(silica gel, ethyl acetate/isohexane 2:3) and dried under vacuum to
afford a yellow solid: yield 350 mg (66%). Mp 95 ꢂC; 1H NMR
(500 MHz, CDCl3) dH (ppm) ¼ 2.59 (s, 4H), 2.72 (s, br, 2H), 2.80 (s, br,
2H), 4.18 (s, 1H), 7.26e7.47 (m, 5H), 7.46e7.55 (m, 4H), 7.63e7.67
(m, 1H), 7.74e7.75 (m, 2H), 8.61 (m, 1H), 11.99 (s, 1H); 13C NMR
(125 MHz, CDCl3) dC (ppm) ¼ 41.14, 51.12, 75.90, 122.96, 125.64,
127.53, 127.62, 128.65, 128.83, 128.87, 129.99, 132.33, 133.14, 133.67,
IR (KBr):
n
(cmꢁ1) ¼ 2828, 1700, 1646, 1595, 1568, 1499, 1446, 1395,
1283, 1247, 1179, 1158, 1104, 953, 942, 804, 760, 734, 700, 675, 646;
MS (EI, 70 eV): m/z 105 (5), 136 (2), 164 (8), 192 (100), 193 (34), 194
(13), 195 (2), 230 (2), 231 (2), 257 (3), 258 (2), 448 (2), 450 (0.8)
[M]þ, 451 (0.2) [Mþ1]þ; MS (ESI): m/z 192 (4), 451 (100) [M þ H]þ,
901 (3) [2 (M þ H)]þ; MS (ESI-HRMS) calcd: 451.1247, found:
451.1256.
135.14, 137.76, 138.16, 166.06, 192.99, 203.68; IR (KBr)
n
(cmꢁ1) ¼
3241, 1696, 1646, 1569, 1501, 1448, 1395, 1283, 1246, 699; MS (EI,
70 eV): m/z 105 (55),106 (63),118 (61),189 (100), 230 (44), 231 (64),
304 (58), 319 (70), 347 (72), 349 (30), 446 (4) [M]þ, 447 (1) [Mþ1]þ,
448 (1) [M]þ; MS (ESI): m/z 337 (8), 447 (100) [M]þ; MS (ESI-HRMS)
calcd: 447.1475, found: 447.1467.
4.1.4.16. (R,S)-N-(2-benzoyl-4-chlorophenyl)-2-(1-oxo-4-thiomorpholin-
4-yl)-2-phenylacetamide (5p). (R,S)-N-(2-benzoyl-4-chlorophenyl)-
2-phenyl-2-thio-morpholino-acetamide (881 mg, 2.0 mmol) and
potassium peroxomonosulfate (2.0 g, 7.3 mmol) were dissolved in
15 mL THF/15 mL Ethanol/10 mL H2O and stirred overnight at rt.
Then the solvent was removed in vacuo. The resulting residue was
extracted with ethylacetate and dried over MgSO4. The compound
was purified with column chromatography (silica gel, ethyl acetate/
isohexane 1:1 (remove unwanted fractions) and then pure ethanol)
to afford a yellow solid: yield 161 mg (17%). Mp 82 ꢂC; 1H NMR
(500 MHz, CDCl3) dH (ppm) ¼ 2.64e2.70 (m, 1H), 2.79e2.99 (m,
4H), 3.05e3.17 (m, 2H), 3.28e3.36 (m, 1H), 4.19 (s, 1H, CH),
7.30e7.38 (m, 3H), 7.48e7.57 (m, 4H), 7.60e7.70 (m, 2H), 7.73e7.79
4.1.4.13. (R,S)-N-(2-benzoyl-4-chlorophenyl)-2-(4-(2-hydroxyethyl)-
piperidin-1-yl)-2-phenylacetamide (5m). According to general
procedure 2 from (R,S)-N-(2-benzoyl-4-chlorophenyl)-2-chloro-2-
phenylacetamide (496 mg, 1.3 mmol) und 4-piperidinethanol
(500 mg, 3.9 mmol) and triethylamine (0.6 mL, 4.3 mmol). Purifi-
cation: chromatography (silicagel, ethylacetate/isohexane 1:1) to
give a yellow solid: yield 508 mg (76%). Mp 103 ꢂC; 1H NMR
(500 MHz, CDCl3) dH (ppm) ¼ 1.35e1.59 (m, 8H), 1.77 (m, 1H), 2.19
(m, 1H), 2.70 (d, 1H, J ¼ 10.5 Hz), 2.95 (d, 1H, J ¼ 11.7 Hz), 3.65 (dd,
2H,J ¼ 5.5, 6.4 Hz), 3.97 (s, 1H), 7.27e7.38 (m, 5H), 7.46e7.49 (m,
2H), 7.54 (m, 2H), 7.65 (m, 1H), 7.78 (m, 2H), 8.57 (m, 1H), 11.63 (s,
1H); 13C NMR (125 MHz, CDCl3) dC (ppm) ¼ 31.91, 32.02, 32.17,
39.14, 50.16, 53.79, 60.41, 77.37, 122.96, 126.28, 127.30, 128.06,
128.47, 128.52, 129.01, 130.00, 131.65, 133.00, 133.15, 135.50, 137.69,
(m, 2H), 8.39 (m, 1H), 8.63 (m, 1H), 11.95 (s, 1H); IR (KBr):
n
(cmꢁ1) ¼ 2923, 1735, 1718, 1701, 1695, 1685, 1676, 1654, 1648, 1617,
1596, 1577, 1570, 1560, 1554, 1540, 1534, 1507, 1459, 1448, 1396,
1282, 1249, 1159, 1059, 1031, 949, 807, 737, 701; MS (EI, 70 eV): m/z
105 (58), 132 (49), 180 (31), 190 (31), 192 (84), 193 (30), 208 (100),
209 (52), 258 (84), 260 (41), 448 (30), 466 (56) [M]þ, 467 (16)
[Mþ1]þ, 468 (23) [M]þ, 469 (7) [Mþ1]þ; MS (ESI): m/z 467 (100)
[M þ H]þ, 489 (23) [M þ Na]þ, 933 (14) [2 (M þ H)]þ; MS (EI-HRMS)
calcd: 466.1118, found: 466.1099.
137.87, 171.62, 196.83; IR (KBr):
n
(cmꢁ1) ¼ 2924, 1692, 1641, 1563,
1502, 1393, 1278, 1241, 1156, 945, 736, 702, 647; MS (EI, 70: eV) m/z
91 (10), 105 (14), 128 (5), 180 (5), 216 (6), 218 (100), 219 (72), 220
(11), 257 (11), 258 (7), 259 (5), 476 (2) [M]þ, 477 (1) [M þ H]þ; MS
(EI-HRMS) calcd: 476.1867, found: 476. 1880.
4.1.4.17. (R,S)-N-(2-benzoyl-4-chlorophenyl)-2-[1H-imidazol-1-yl]-
2-phenylacetamide (5q). According to general procedure 2 from
(R,S)-N-(2-benzoyl-4-chlorophenyl)-2-chloro-2-phenylacetamide
(1.9 g, 5.0 mmol) and imidazole (1.0 g, 15.0 mmol). Purification:
chromatography (silicagel, ethylacetate/isohexane 1:1) to give
a orange solid: yield 937 mg (45%). Mp 61 ꢂC; 1H NMR (500 MHz,
CDCl3) dH (ppm) ¼ 6.01 (s, 1H), 7.10 (m, 2H), 7.40e7.43 (m, 5H),
7.48e7.57 (m, 4H), 7.60e7.66 (m, 3H), 7.72 (s, 1H), 8.60 (m, 1H),
11.09 (s, 1H); 13C NMR (125 MHz, CDCl3) dC (ppm) ¼ 65.89, 119.11,
123.05,124.96,128.21,128.52,128.58,129.45,129.48,129.67,129.86,
4.1.4.14. (R,S)-N-(2-benzoyl-4-chlorophenyl)-2-morpholino-2-phenyl-
acetylamide (5n). According to general procedure 2 from (R,S)-N-(2-
benzoyl-4-chlorophenyl)-2-chloro-2-phenylacetamide (1.9 g,
5.0 mmol) and morpholine (1.3 g, 15.0 mmol). Purification: chro-
matography (silicagel, ethylacetate/n-pentane 1:3) to give
a yellowish solid: yield 1.88 g (86%). Mp 121 ꢂC; 1H NMR (500 MHz,
CDCl3) dH (ppm) ¼ 2.42e2.54 (m, 4H), 3.79 (m, 4H), 3.96 (s, 1H),

S. Heinrich et al. / European Journal of Medicinal Chemistry 46 (2011) 1331e1342
1339
132.89, 133.11, 133.98, 134.07, 137.13, 137.37, 137.88, 166.67, 198.16;
5H), 8.61e8.89 (m, 3H), 11.14 (s, 1H); 13C NMR (125 MHz, CDCl3) dC
(ppm) ¼ 66.22, 125.25, 127.84, 128.22, 128.57, 128.66, 128.79,
128.98, 129.52, 131.02, 132.55, 133.01, 133.05, 133.48, 135.79,
IR (KBr):
n
(cmꢁ1) ¼ 2924, 1700, 1578, 1506, 1394, 1283, 1245, 1077,
947, 808, 696, 664; MS (EI, 70 eV): m/z 103 (24), 105 (43), 157 (80),
158 (100), 159 (66), 180 (66), 182 (29), 258 (93), 259 (36), 260 (61),
415 (21) [M]þ, 416 (6) [Mþ1]þ, 417 (7) [M]þ, 418 (2) [Mþ1]þ; MS
(EI-HRMS) calcd: 415.1088, found: 415.1108.
165.65, 192.41; IR (KBr):
n
(cmꢁ1) ¼ 2924, 2677, 1700, 1685, 1636,
1597, 1499, 1396, 1307, 1286, 1251, 1158, 953, 761, 696, 669, 646;
MS (EI, 70 eV): m/z 106 (73), 107 (45), 230 (76), 231 (82), 232 (57),
233 (43), 241 (66), 243 (76), 45 (100), 346 (71), 347 (66), 364 (9)
[Mþ], 365 (3) [Mþ1]þ, 366 (2) [M]þ, 367 (0.4) [Mþ1]þ; MS (ESI):
m/z 365 (100) [M þ H]þ, 729 (28) [2M þ H]þ; MS (ESI-HRMS)
calcd: 365.1057, found: 365.1092.
4.1.4.18. (R)-tert-butyl-2-(2-benzoyl-4-chlorophenylamino)-2-oxo-
1-phenylethylcarbamate (6a). According to general procedure 4
from 2-amino-5-chlorobenzophenone (1.2 g, 5.0 mmol) and Boc-l-
a-phenylglycine (1.3 g, 5.0 mmol) were dissolved in pyridine
(w12 mL) and stirred with phosphorylchloride (0.5 mL). Purifica-
tion: recrystallization from ethanol to give a light brown solid: yield
1.56 mg (67%). Mp 132 ꢂC; 1H NMR (500 MHz, CDCl3) dH (ppm) ¼
1.40 (s, 9H), 5.28 (s,1H), 5.70 (s,1H), 7.29e7.33 (m,1H), 7.37 (m, 2H),
7.45e7.51 (m, 6H), 7.60e7.67 (m, 3H), 8.61 (m, 1H), 11.19 (s, 1H); 13C
NMR (125 MHz, CDCl3) dC (ppm) ¼ 28.26, 56.89, 73.84, 122.89,
124.67, 127.42, 127.72, 128.60, 128.74, 129.31, 129.90, 132.86, 132.96,
4.1.4.22. (S)-N-(2-benzoyl-4-chlorophenyl)-2-phenylglycinamide
hydrochloride (7c). According to general procedure 3 from (S)-N-
(2-benzoyl-4-chlorophenyl)-2-N0-tert-butoxycarbonylphenyl gly-
cinamide (929 mg, 2.0 mmol) with a solution of HCl (4 M) in
dioxane (40 mL). Brown solid: yield 700 mg (87%). Mp 170 ꢂC; 1H
NMR (500 MHz, CDCl3) dH (ppm) ¼ 5.15 (s, 1H), 7.31e7.48 (m, 6H),
7.54e7.62 (m, 4H), 7.65e7.69 (m, 3H), 8.63e8.77 (m, 3H), 10.98 (s,
1H); 13C NMR (125 MHz, CDCl3) dC (ppm) ¼ 55.71, 120.53, 126.37,
128.62, 128.99, 129.37, 129.43, 129.55, 130.32, 131.82, 133.73, 134.08,
134.06, 137.50, 137.84, 138.67, 151.34, 169.29, 198.02; IR (KBr):
n
(cmꢁ1) ¼ 3367, 2977, 1691, 1654, 1636, 1580, 1500, 1458, 1396, 1368,
1316, 1287, 1251, 1169, 1102, 1048, 1024, 947, 843, 812, 764, 741, 719,
701, 670; MS (EI, 70 eV): m/z 105 (55), 106 (100), 150 (54), 206 (37),
231 (34), 241 (28), 243 (30), 257 (37), 258 (38), 345 (47), 388 (54),
390 (34), 464 (1) [M]þ,466 (1) [M]þ; MS (EI-HRMS) calcd: 464.1503,
found: 464.1497.
136.46, 137.84, 139.09, 165.78, 196.86; IR (KBr):
n
(cmꢁ1) ¼ 2924,
2677, 1700, 1685, 1636, 1597, 1499, 1396, 1307, 1286, 1251, 1158, 953,
761, 696, 669, 646; MS (EI, 70 eV): m/z 86 (41), 106 (72), 107 (44),
230 (69), 231 (75), 232 (42), 241 (63), 243 (72), 258 (43), 345 (100),
346 (57), 347 (52), 364 (4) [M]þ, 365 (1) [Mþ1]þ, 366 (2) [M]þ; MS
(ESI): m/z 347 (24), 365 (100) [M þ H]þ; MS (ESI-HRMS) calcd:
365.1057, found: 365.1061.
4.1.4.19. (R)-tert-butyl-2-(2-benzoyl-4-chlorophenylamino)-2-oxo-
1-phenylethylcarbamate (6b). According to general procedure 4
from 2-amino-5-chlorobenzophenone (4.6 g, 20.0 mmol) and boc-
d-phenylglycine (5.0 g, 20.0 mmol). Purification: recrystallization
from ethanol to give a white light brown solid: yield 3.92 mg (42%).
Mp 132 ꢂC; 1H NMR (500 MHz, CDCl3) dH (ppm) ¼ 1.41 (s, 9H), 5.28
(s, 1H), 5.71 (s, 1H), 7.29e7.33 (m, 1H), 7.35e7.38 (m, 2H), 7.45e7.51
(m, 6H), 7.60e7.66 (m, 3H), 8.61 (m, 1H), 11.19 (s, 1H); 13C NMR
(125 MHz, CDCl3) dC (ppm) ¼ 28.21, 59.56, 80.02, 122.89, 124.69,
127.43, 127.72, 128.60, 128.74, 129.31, 129.90, 132.85, 132.97, 134.05,
4.1.4.23. (R,S)-N-(2-benzoyl-4-chlorphenyl)-alaninamide hydrochlo-
ride (7d). According to general procedure 3 from (R,S)-N-(2-
benzoyl-4-chlorphenyl)-N-tert-butoxycarbonylalaninamid (1.5g,
3.7 mmol) with a solution of HCl (4 m) in dioxane (10 mL). Yellow
solid: yield 1184 mg (94%). Mp 165 ꢂC; 1H NMR (500 MHz, DMSO-
d6) dH (ppm) ¼ 0.94 (d, 3H, J ¼ 7.0 Hz), 3.93 (q, 1H, J ¼ 6.9 Hz,), 7.42
(d, 1H, J ¼ 2.5 Hz), 7.48e7.53 (m, 3H), 7.62e7.66 (m, 1H), 7.67e7.70
(m, 3H), 8.25 (s, 3H, NHþ3 ),11.06 (s, 1H); 13C NMR (125 MHz, DMSO-
d6) dC (ppm) ¼ 15.74, 48.11, 125.86, 128.37, 128.82, 129.14, 129.65,
137.47, 137.85, 138.68, 168.25, 169.15, 198.17; IR (KBr):
n
(cmꢁ1) ¼
3367, 2977, 1691, 1654, 1636, 1580, 1499, 1458, 1396, 1368, 1316,
1287, 1251, 1169, 1102, 1048, 1024, 947, 843, 764, 719, 701, 670; MS
(EI, 70 eV): m/z 105 (45), 106 (100), 150 (39), 206 (32), 230 (26), 231
(33), 241 (26), 243 (32), 258 (27), 345 (59), 346 (28), 390 (47), 464
(1) [M]þ, 465 (0.2), [Mþ1]þ, 466 (0.7) [M]þ; MS (EI-HRMS) calcd:
464.1503, found: 464.1490.
131.26, 133.06, 133.57, 136.12, 168.03, 192.68; IR (KBr):
n
(cmꢁ1) ¼
3308, 3187, 2969, 2693, 2499, 1691, 1604, 1535, 1477, 1448, 1388,
1274, 1234, 1121, 1000, 962, 826, 750, 698, 641; MS (EI, 70 eV): m/z
88 (15), 105 (31), 154 (18), 180 (24), 195 (12), 205 (11), 207 (15), 214
(25), 230 (92), 241 (96), 243 (97), 255 (22), 259 (74) 268 (15), 283
(100), 303 (23), [M þ HCl]þ.
4.1.4.20. (R,S)-N-(2-benzoyl-4-chlorphenyl)-phenylglycinamide
hydrochloride (7a). According to general procedure 3 from (R,S)-N-(2-
benzoyl-4-chlorphenyl)-N-tert-butoxycarbonyl-phenylglycinamide
(464 mg, 1 mmol) with a solution of HCl (4 m) in dioxane (20 mL).
Yellow solid: yield 212 mg (53%). Mp 210 ꢂC; 1H NMR (500 MHz,
DMSO-d6) dH (ppm) ¼ 5.22 (s, 1H, CH), 7.33e7.38 (m, 5H), 7.43 (t,
2H, J ¼ 7.9 Hz), 7.56e7.59 (m, 1H), 7.63e7.68 (m, 5H), 8.75 (s, 3H),
11.22 (s, 1H); 13C NMR (125 MHz, DMSO-d6) dC (ppm) ¼ 56.20,
125.94, 128.58, 128.91, 129.34, 129.45, 129.58, 129.79, 130.24,
131.76, 133.39, 133.62, 133.71, 134.23, 136.52, 166.45, 193.11; IR
4.1.4.24. (R,S)-N-(2-benzoyl-4-chlorphenyl)-serinamide hydrochloride
(7e). According to general procedure 3 from (R,S)-N-(2-benzoyl-
4-chlorphenyl)-N-tert-butoxycarbonyl-O-tert-butyl-serin-amide
(0.5 g, 1.1 mmol) with a solution of HCl (4 m) in dioxane (15 mL).
Yellow solid: yield 284 mg (80%). 1H NMR (500 MHz, DMSO-d6) dH
(ppm) ¼ 2.08 (s, 1H), 3.11e3.22 (m,1H), 3.91e4.01 (m, 1H), 5.46 (t,
1H, J ¼ 4.6 Hz), 7.39e7.73 (m, 8H), 8.22 (s, 3H),11.06 (s,1H), 13C NMR
(125 MHz, DMSO-d6) dC (ppm) ¼ 59.53, 73.63, 125.75, 128.31,
128.91, 129.29, 129.60, 131.36, 133.06, 133.24, 133.36, 133.55, 133.73,
136.12, 165.65, 193.03; IR (KBr):
n
(cmꢁ1) ¼ 3195, 2923, 1738, 1654,
(KBr):
n
(cmꢁ1) ¼ 3427, 2854, 2605, 1701, 1638, 1597, 1579,1498,
1596, 1523, 1396,1288, 1254, 1119, 953, 871, 830, 741, 700; MS (EI,
70 eV): m/z 59 (42), 77 (11), 86 (33), 88 (40), 101 (10), 105 (33), 116
(53), 154 (9), 214 (10), 227 (12), 231 (94), 241 (40), 243 (24), 258
(13), 272 (42), 288 (35), 300 (19), 318 (2), [M þ HCl]þ; MS (EI-
HRMS) calcd: 319.0844, found: 319.0875.
1396, 1309, 1288, 1255, 1119, 956, 763, 695; MS (ESI): m/z 365
(100), [M þ H]þ; MS (EI-HRMS) calcd: 365.1051, found: 365.1079.
4.1.4.21. (R)-N-(2-benzoyl-4-chlorophenyl)-2-phenylglycinamide
hydrochloride (7b). According to general procedure 3 from (R)-N-(2-
benzoyl-4-chlorophenyl)-2-N-tert-butoxycarbonylphenylglycinamide
(929 mg, 2.0 mmol) with a solution of HCl (4 M) in dioxane
(40 mL). Purification: recrystallization from ethanol to give
a yellow solid: yield 531 mg (66%). Mp 170 ꢂC; 1H NMR (500 MHz,
CDCl3) dH (ppm) ¼ 5.20 (s, 1H), 7.31e7.45 (m, 8H), 7.55e7.69 (m,
4.1.4.25. (R,S)-N-(2-benzoyl-4-chlorphenyl)-phenylalaninamide
hydrochloride (7f). Accordingto general procedure3 from (R,S)-N-(2-
benzoyl-4-chlorphenyl)-N-tert-butoxycarbonylphenylalaninamide
(1.5 g, 3.1 mmol) with a solution of HCl (4 m) in dioxane (10 mL).
Yellow solid: yield 1271 mg (98%). Mp 205 ꢂC; 1H NMR (500 MHz,

1340
S. Heinrich et al. / European Journal of Medicinal Chemistry 46 (2011) 1331e1342
DMSO-d6) dH (ppm) ¼ 2.55 (dd, 1H, J ¼ 14.3, 4.8 Hz), 2.73 (dd, 1H.
J ¼ 14.3, 4.8 Hz), 4.21e4.25 (m, 1H, J ¼ 4.6 Hz), 7.21e7.24 (m, 1H),
7.26e7.29 (m, 4H), 7.41 (d, 1H, J ¼ 2.5 Hz), 7.51e7.56 (m, 3H),
7.61e7.65 (m, 1H), 7.69 (dd, 1H, J ¼ 7.0 Hz), 7.73e7.75 (m, 2H), 8.22
(s, 3H), 11.35 (s, 1H);13C NMR (125 MHz, DMSO-d6) dC
(ppm) ¼ 35.86, 53.68, 125.79, 127.09, 128.35, 128.43, 128.74, 128.93,
129.43, 129.74, 131.12, 133.06 133.33, 133.54, 134.62, 136.14, 166.92,
a small amount of dichloromethane and washed with water. The
collected organic phases were dried over anhydrous sodium sulfate
and evaporated off in vacuo to afford a yellow-orange solid: yield
255 mg (52%). Mp 75 ꢂC; 1H NMR (500 MHz, CDCl3) dH (ppm) ¼ 2.31
(s, 3H), 2.38e2.57 (m, 4H), 3.49e3.59 (m, 4H), 5.47 (d, 1H,
J ¼ 5.1 Hz), 5.62 (d, 1H, J ¼ 5.1 Hz), 7.27e7.32 (m, 1H), 7.34e7.37 (m,
2H), 7.40e7.52 (m, 6H), 7.59e7.65 (m, 3H), 8.61 (m, 1H), 11.26 (s,
1H); 13C NMR (125 MHz, CDCl3) dC (ppm) ¼ 43.49, 45.84, 50.96,
54.01, 122.94, 124.85, 127.81, 127.85, 128.75, 128.88, 129.46, 130.03,
132.99, 133.11, 134.19, 137.90, 138.01, 138.80, 156.55, 170.31, 198.41;
192.74; IR (KBr):
n
(cmꢁ1) ¼ 3239, 3050, 2801, 2678, 2604, 1700,
1632, 1595, 1578, 1516, 1487, 1392, 1308, 1295, 1254, 1392, 1255,
1159, 1118, 978, 951, 833, 752, 701, 654; MS (EI, 70 eV): m/z 91 (12),
105 (13), 120 (28), 131 (18), 166 (11), 180 (10), 206 (15), 230 (14),
241 (92), 243 (75), 257 (16), 269 (100), 271 (89), 332 (11), 360 (91),
378 (2), [M þ HCl]þ; MS (EI-HRMS) calcd: 379.1208, found:
379.1224.
IR (KBr):
n
(cmꢁ1) ¼ 3314, 1700, 1696, 1685, 1636, 1597, 1577, 1560,
1507, 1448, 1396, 1289, 1254, 1176, 1158, 1002, 947, 737, 700, 652;
MS (FAB): m/z 175 (5), 200 (21), 232 (30), 260 (26), 307 (18), 347
(11), 491 (62) [M þ H]þ; MS (FAB-HRMS) calcd: 491.1850, found:
491.1888M þ H]þ.
4.1.4.26. (R,S)-N-(2-benzoyl-4-chlorphenyl)-tryptophanamide
hydrochloride (7g). According to general procedure 3 from (R,S)-N-
(2-benzoyl-4-chlorphenyl)-N-tert-butoxycarbonyltryptophanamide
(0.5 g, 1 mmol) with a solution of HCl (4 M) in dioxane (20 mL).
Yellow solid: yield 403 mg (89%). Mp 227 ꢂC; 1H NMR (500 MHz,
DMSO-d6) dH (ppm) ¼ 2.65e2.81 (m, 2H), 4.08e4.20 (m, 1H),
6.97e7.01 (m, 1H), 7.06e7.10 (m, 1H), 7.20 (d, 1H, J ¼ 2.4 Hz),
7.33e7.36 (m, 1H), 7.43 (d, 1H, J ¼ 2.5 Hz), 7.51e7.57 (m, 3H),
7.59e7.64 (m, 1H), 7.68e7.77 (m, 4H), 8.12 (s, 3H), 11.03 (s, 1H),
11.25 (s, 1H); 13C NMR (125 MHz, DMSO-d6) dC (ppm) ¼ 26.27,
52.84, 106.45, 111.31, 118.34, 118.56, 121.09, 124.95, 125.77, 126.81,
128.34, 128.86, 129.05, 129.77, 131.27, 133.06, 133.47, 133.56, 136.16,
4.1.4.29. (R,S)-N-(2-benzoyl-4-chlorophenyl)-2-[(2-dimethyl-amino-
ethyl)-methylamino]-2-phenylacetamide (9a). According to general
procedure 2 from (R,S)-N-(2-benzoyl-4-chlorophenyl)-2-chloro-2-
phenylacetamide (1.9 g, 5.0 mmol) and N,N,N0-trimethylethy-
lendiamine (1.4 mL, 15.0 mmol) and triethylamine (2.1 mL,
15.0 mmol). The compound was purified with column chroma-
tography (silica gel, ethyl acetate/isohexane 1:1 (remove unwanted
fractions) and then pure ethanol) to afford a white solid: yield
584 mg (26%). Mp 107 ꢂC; 1H NMR (500 MHz,CDCl3) dH
(ppm) ¼ 2.07 (s, 6H), 2.22 (s, 3H), 2.40e2.56 (m, 4H), 4.11 (s, 1H),
7.27e7.32 (m, 3H), 7.35e7.39 (m, 2H), 7.46e7.55 (m, 4H), 7.61e7.66
(m, 1H), 7.76e7.79 (m, 2H), 8.51e8.54 (m, 1H), 11.58 (s, 1H); 13C
NMR (125 MHz, CDCl3) dC (ppm) ¼ 40.55, 45.84, 53.55, 57.53, 76.70,
123.23, 126.63, 127.60, 128.25, 128.63, 129.21, 130.10, 131.94, 133.07,
136.21, 167.34, 192.77; IR (KBr):
n
(cmꢁ1) ¼ 3400, 2954, 2180, 1711,
1644, 1524, 1327,1296, 1246, 976, 743, 703; MS (ESI): m/z 418 (100),
[M þ H]þ; MS (EI-HRMS) calcd: 418.1317, found: 418.1295.
133.32, 135.79, 137.94, 137.97, 171.63, 197.09; IR (KBr):
n
4.1.4.27. (R)-N-(2-(2-benzoyl-4-chlorophenylamino)-2-oxo-1-phenyl-
ethyl)-4-methylpiperazin-1-carbamide (8a). From (R)-N-(2-benzoyl-
4-chlorophenyl)-2-phenyl-glycinamide hydrochloride (402 mg,
1.0 mmol) and 4-methyl-1-piperazine carbonylchloride (199 mg,
1.0 mmol), under addition of triethylamine. The glycineamide
derivative was solved under ice cooling. Triethylamine and the
piperazine derivative were slowly added and stirred vigorously and
then slowly warm up to room temperature. After stirring for 72 h
the solvent was removed in vacuo. The remaining solid was solved
in a small amount of dichloromethane and washed with water. The
collected organic phases were dried over anhydrous sodium sulfate
and the solvent evaporated off in vacuo. Purification with column
chromatography (silica gel, ethyl acetate/methanol 3:1) afford
a yellow-orange solid: yield 140 mg (28%). Mp 79 ꢂC; 1H NMR
(500 MHz, CDCl3) dH (ppm) ¼ 2.27 (s, 3H), 2.30e2.43 (m, 4H),
3.39e3.56 (m, 4H), 5.48 (d, 1H, J ¼ 5.1 Hz), 5.54 (d, 1H, J ¼ 5.1 Hz),
7.29e7.33 (m, 1H), 7.34e7.39 (m, 2H), 7.46e7.52 (m, 6H), 7.59e7.68
(m, 3H), 8.63 (m, 1H), 11.26 (s, 1H); 13C NMR (125 MHz, CDCl3) dC
(ppm) ¼ 43.66, 46.04, 54.54, 60.48, 122.70, 124.5, 127.56, 128.50,
128.62, 129.25, 129.82, 132.56, 132.76, 132.84, 133.93, 137.80, 137.84,
(cmꢁ1) ¼ 3280, 2952, 2813, 2763, 1694, 1645, 1596, 1568, 1500,
1453, 1395, 1278, 1252, 1158, 1118, 1095, 1038, 947, 851, 806, 766,
735, 703, 671, 652, 634; MS (ESI): m/z 450 (100) [M þ H]þ, 899 (3)
[2M þ H]þ; MS (ESI-HRMS) calcd: 450.1948, found: 450.1924.
4.1.4.30. (R,S)-N-(2-benzoyl-4-chlorophenyl)-2-[(3-(dimethylamino)-
propyl)methyl-amino]-2-phenylacetamide (9b). According to general
procedure 2 from (R,S)-N-(2-benzoyl-4-chlorophenyl)-2-chloro-2-
phenylacetamide (1.9 g, 5.0 mmol) and N,N,N0-trimethyl-1,3-prop-
andiamine (1.7 g, 15.0 mmol). The compound was purified with
column chromatography (silica gel, ethyl acetate/isohexane 1:1
(remove unwanted fractions) and then pure ethanol). After drying
under vacuo, the solid was precipitated (dichloromethane/n-
pentane) to afford a white-yellow solid: yield 873 mg (38%). Mp
101 ꢂC; 1H NMR (500 MHz, CDCl3) dH (ppm) ¼ 1.87e2.09 (m, 2H),
2.22 (s, 3H), 2.41e2.48 (m, 2H), 2.51 (s, 6H), 2.81e3.26 (m, 2H), 4.08
(s, 1H), 7.27e7.34 (m, 5H), 7.46e7.55 (m, 4H), 7.61e7.67 (m, 1H),
7.68e7.72 (m, 2H), 8.57e8.61 (m, 1H), 11.66 (s, 1H); 13C NMR
(125 MHz, CDCl3) dC (ppm) ¼ 23.16, 39.62, 43.69, 52.22, 56.53, 77.21,
122.95, 125.47, 127.48, 128.41, 128.66, 128.69, 129.09, 129.84, 132.40,
138.64, 156.37, 170.13, 198.11; IR (KBr):
n
(cmꢁ1) ¼ 3307, 2937, 2796,
133.13, 133.82, 135.11, 137.99, 138.26, 171.10, 197.97; IR (KBr): n
1700, 1641, 1597, 1577, 1497, 1396, 1289, 1244, 1176, 1158, 1002, 947,
762, 699; MS (ESI): m/z 260 (18), 491 (100) [M þ H]þ, 981 (12) [2
(M þ H)]þ; MS (ESI-HRMS) calcd: 491.1850, found: 491.1863.
(cmꢁ1) ¼ 3249, 2952, 2821, 2777, 1691, 1644, 1596,1566, 1501, 1449,
1395, 1305, 1278, 1250, 1159, 1128, 1096, 1081, 1034, 948, 854, 812,
762, 737, 699, 671, 654, 636; MS (EI, 70 eV): m/z 57 (51), 85 (32), 91
(30), 105 (39), 115 (59), 118 (24), 120 (67), 134 (100), 135 (32), 205
(52), 404 (27), 463 (26) [M]þ, 464 (8) [ Mþ1]þ, 465 (9) [M]þ, 466 (3)
[Mþ1]þ; MS (EI-HRMS) calc.: 463.2027, found: 463.2052.
4.1.4.28. (R)-N-(2-(2-benzoyl-4-chlorophenylamino)-2-oxo-1-phenyl-
ethyl)-4-methylpiperazin-1-carboxamide (8b). From (R)-N-(2-benzoyl-
4-chlorophenyl)-2-phenyl-glycinamide hydrochloride (402 mg,
1.0 mmol) and 4-methyl-1-piperazine carbonylchloride (199 mg,
1.0 mmol), under addition of triethylamine. The glycine amide
derivative was solved under ice cooling. Triethylamine and the
piperazine derivative were slowly added and stirred vigorously and
slowly warmed up to room temperature. After stirring for 72 h the
solvent was removed in vacuo. The remaining solid was solved in
4.1.4.31. (R,S)-Methyl-2-(4-(2-(2-benzoyl-4-chlorophenylamino)-2-
oxo-1-phenylethyl)piperazin-1-yl) acetate (10a). (R,S)-N-(2-benzoyl-
4-chlorophenyl)-2-phenyl-2-(piperazin-1-yl)-acetamide (2.7 g,
5.3 mmol) and NaHCO3 (1.6 g, 18.6 mmol) were suspended in
acetone. To the stirring mixture methyl-2-chloroacetate (0.5 mL,
5.8 mmol) was added dropwise over a 3 min period. The reaction

S. Heinrich et al. / European Journal of Medicinal Chemistry 46 (2011) 1331e1342
1341
mixture was refluxed for 22 h. Then the suspension was filtered and
the residue was washed with acetone. After concentrating the
filtrate, the solvent was removed in vacuo to obtain the crude
product. Purification: recrystallization from acetone to give
a yellow solid: yield 1790 mg (67%). Mp 140 ꢂC; 1H NMR (400 MHz,
CDCl3) dH (ppm) ¼ 2.58 (m, br, 4H), 2.70 (m, br, 4H), 3.24 (s, 2H),
3.70 (s, 3H), 4.00 (s, 1H), 7.27e7.33 (m, 3H), 7.35e7.37 (m, 2H),
7.46e7.49 (m, 2H), 7.52e7.56 (m, 2H), 7.64e7.68 (m, 1H), 7.76e7.79
(m, 2H H-Aryl), 8.56e8.58 (m, 1H), 11.66 (s, br, 1H); 13C NMR
(100 MHz, CDCl3) dC (ppm) ¼ 51.08, 51.75, 52.86, 59.21, 76.73,
123.03, 126.05, 127.54, 128.31, 128.61, 128.73, 129.05, 130.07, 132.07,
133.08, 133.42, 135.15, 137.89, 138.06, 170.53, 171.07, 197.12; IR
(400 MHz, CDCl3) dH (ppm) ¼ 1.10 (t, 6H, J ¼ 6.7 Hz), 2.52 (s, br, 4H),
2.61 (s, br, 4H), 2.97 (s, 2H), 3.98 (s, 1H), 4.01e4.13 (m, 1H), 6.85 (s, br,
1H), 7.28e7.33 (m, 3H), 7.36e7.39 (m, 2H), 7.46e7.49 (m, 2H),
7.51e7.56 (m, 2H), 7.63e7.67 (m, 1H), 7.75e7.78 (m, 2H), 8.56 (m, 1H),
11.67 (s, 1H); 13C NMR (100 MHz, CDCl3) dC (ppm) ¼ 22.78, 40.63,
53.15, 61.42, 76.82, 122.99, 125.93, 127.55, 128.46, 128.66, 128.80,
128.94, 130.27, 132.08, 133.16, 133.42, 135.21, 137.69, 137.97, 170.89,
184.96,197.15; IR (KBr):
n
(cmꢁ1) ¼ 3284, 3062, 2968, 2825,1674,1596,
1569, 1502, 1396, 1282, 1246, 1157, 1131, 879, 831, 803, 763, 729, 701,
652; MS (FAB): m/z 533 (100) [M þ H]þ, 534 (35) [M]þ, 535 (38)
[M þ H]þ; MS (FAB-HRMS) calcd: 533.2319, found: 533.2310.
(ATR):
n
(cmꢁ1) ¼ 3223, 2831, 1756, 1688, 1653, 1569, 1504, 1396,
4.1.4.35. (R,S)-N-(2-benzoyl-4-chlorophenyl)-2-(4-(2-(dimethylamino)
1281, 1245, 1161, 1019, 948, 880, 808, 739, 457; MS (ESI): m/z 506
ethyl)piperazin-1-yl)phenylacetamide
(10e). (R,S)-N-(2-benzoyl-4-
(100) [M þ H]þ; MS (EI-HRMS) calcd: 505.1768, found: 505.1758.
chlorophenyl)-2-phenyl-2-(piperazin-1-yl)-acetamide (0.6 g, 1.4
mmol) and NaHCO3 (0.4 g, 4.8 mmol) were suspended in Propanol/
Methanol (1:1). To the stirring mixture 2-chloro-N,N-dimethyle-
thanamine (0.2 g, 1.6 mmol) was added dropwise over a 3 min
period. The reaction mixture was subsequently refluxed for 48h. The
solvent was removed via rotary evaporation. Purification: chroma-
tography silicagel, dichlormethane/methanol/NH3 940:50:10, to give
a light yellow solid: yield 89 mg (13%). Mp 108 ꢂC; 1H NMR
(400 MHz, CDCl3) dH (ppm) ¼ 2.56 (s, 6H), 2.41e2.58 (m, br, 12H),
3.96 (s, 1H), 7.27e7.37 (m, 5H), 7.45e7.55 (m, 4H), 7.63e7.68 (m, 1H),
7.75e7.79 (m, 2H), 8.54e8.57 (m, 1H), 11.62 (s, br, 1H); 13C NMR
(100 MHz, CDCl3) dC (ppm) ¼ 45.75, 53.26, 56.12, 56.63, 76.87,123.09,
126.15, 127.45, 128.31, 128.55, 128.66, 129.05, 130.08, 131.87, 133.07,
4.1.4.32. (R,S)-2-(4-(2-(2-benzoyl-4-chlorophenylamino)-2-oxo-1-
phenylethyl)piperazin-1-yl)acetic acid (10b). A stirred solution
of (R,S)-Methyl-2-(4-(2-(2-benzoyl-4-chlorophenylamino)-2-oxo-
1-phenylethyl)piperazin-1-yl)-acetate (0.8 g, 1.5 mmol) in THF/
MeOH (3:1) was treated with 1.5 equiv of a 1m solution of LiOH in
H2O. The resulting solution was stirred at rt for 24h. The reaction
mixture was then poured into 1 N HCl and extracted with ethyl-
acetate. The organic layer was separated, dried over NaSO4, and the
solvents were removed in vacuo. Purification: chromatography
silicagel, dichlormethane/methanol 20:1, to give a light yellow
solid: yield 420 mg (57%). Mp 131 ꢂC; 1H NMR (400 MHz, CDCl3) dH
(ppm) ¼ 2.67e2.70 (m, 1H), 2.79e2.82 (m, 1H), 3.00e3.03 (m, 1H),
3.21e3.27 (m,1H), 3.57e3.65 (m, br, 2H), 3.74e3.86 (m, br, 2H), 3.90
(s, 2H), 4.21 (s, 1H), 7.32e7.38 (m, br, 5H), 7.51e7.59 (m, br,
4H),7.67e7.74 (m, br, 3H), 8.62 (d, 1H, J ¼ 8.8 Hz,), 11.97 (s, 1H); 13C
NMR (100 MHz, CDCl3) dC (ppm) ¼ 43.32, 46.73, 63.72, 64.13, 65.85,
75.06, 122.73, 125.04, 127.93, 128.81, 128.94, 129.14, 129.24, 130.06,
132.94, 133.54, 133.75, 134.25, 137.64, 138.02, 166.01, 169.47, 198.68;
133.38, 135.24, 137.76, 137.92, 171.12, 196.07; IR (ATR):
n
(cmꢁ1) ¼ 3187, 2921, 2821, 1688, 1640, 1501, 1446, 1277, 1240, 944,
698, 647, 453, 411; MS (ESI): m/z 505 (100), [M þ H]þ; MS (EI-HRMS)
calcd: 505.2398, found: 505.2370.
4.1.4.36. (R,S)-N-(2-benzoyl-4-chlorophenyl)-2-(4-fluorophenyl)-2-
(4-(2-hydroxyethyl)piperazin-1-yl)acetamide (11a). According to
general procedure 2 from N-(2-benzoyl-4-chlorophenyl)-2-bromo-
2-4-(fluorophenyl)-acetamide (2.6 g, 5.8 mmol) und N-(2-hydrox-
yethyl)piperazine (2.1 mL, 17.4 mmol) and triethylamine (1.6 mL,
11.6 mmol). Purification: chromatography (silicagel, acetone) to
give a light yellow solid: yield 2459 mg (85%). Mp 155 ꢂC; 1H NMR
(300 MHz, CDCl3) dH (ppm) ¼ 2.50e2.58 (m, br, 6H), 2.62e2.65 (m,
4H), 3.57 (t, 2H, J ¼ 5.4 Hz), 3.99 (s, 1H), 6.97e7.03 (m, 2H),
7.32e7.37 (m, 2H), 7.46e7.56 (m, 4H), 7.63e7.69 (m, 1H), 7.52e7.78
(m, 2H), 8.56 (d,1H, J ¼ 9.7 Hz),11.64 (s, br,1H); 13C NMR (75.5 MHz,
CDCl3) dC (ppm) ¼ 52.55, 57.72, 59.11, 75.92, 115.5,3 115.84, 123.05,
126.03, 127.63, 128.64, 130.05, 130.52, 130.63, 130.94, 132.03, 133.12,
IR (ATR):
n
(cmꢁ1) ¼ 3294, 2245, 1688, 1595, 1571, 1496, 1449, 1285,
1249, 1153, 1001, 902, 724, 699, 643, 427; MS (ESI): m/z 492 (100)
[M þ H]þ; MS (EI-HRMS) calcd: 491.1612, found: 491.1620.
4.1.4.33. (R,S)-2-(4-(2-amino-2-oxoethyl)piperazin-1-yl)-N-(2-benzoyl-
4-chlorophenyl)-2-phenylacetamide
chlorophenyl)-2-phenyl-2-(piperazin-1-yl)-acetamide
(10c). (R,S)-N-(2-benzoyl-4-
(0.7 g,
1.5 mmol) and NaHCO3 (0.4 g, 4.5 mmol) were dissolved in meth-
anol. After adding 2-bromoacetamide (0.3g, 2.1 mmol) dropwise
over a period of 2 min, the reaction mixture was refluxed for 16 h.
The solvent was removed via rotary evaporation. Purification:
chromatography silicagel, ethylacetate/methanol 6:0.1, to give
a light yellow solid: yield 571 mg (72%). Mp 205 ꢂC; 1H NMR
(400 MHz, CDCl3) dH (ppm) ¼ 2.52 (m, br, 4H), 2.66 (m, br, 4H), 3.24
(s, 2H), 4.00 (s, 1H), 5.65 (s, br, 1H), 7.00 (s, br, 1H), 7.30e7.34 (m,
5H), 7.46e7.56 (m, 4H), 7.64e7.68 (m, 1H), 7.76e7.78 (m, 2H), 8.56
(d, 1H, J ¼ 8.8 Hz), 11.68 (s, br, 1H); 13C NMR (100 MHz, CDCl3) dC
(ppm) ¼ 51.42, 53.21, 61.20, 76.76, 123.05, 125.95, 127.57, 128.45,
128.67, 128.78, 129.08, 130.06, 132.05, 133.13, 133.46, 135.06, 137.75,
133.45, 137.72, 137.91, 170.72, 197.24; IR (ATR):
n
(cmꢁ1) ¼ 3181,
3116, 2945, 2809, 1688, 1639, 1566, 1502, 1244, 1227, 1156, 946, 691,
644, 407; MS (ESI): m/z 496 (100) [M þ H]þ; MS (EI-HRMS) calcd:
496.1802, found: 496.1803.
4.1.4.37. (R,S)-N-(2-benzoyl-4-chlorophenyl)-2-(4-(2-hydroxy-
ethyl)-piperazin-1-yl)-2-(4-trifluoro-methyl)phenyl-acetamide
(11b). According to general procedure 2 from N-(2-benzoyl-4-
chlorophenyl)-2-bromo-2-(4-(trifluoromethyl)phenyl)acetamide
(2.3 g, 4.6 mmol) und N-(2-hydroxyethyl)piperazine (1.7 mL,
13.8 mmol) and triethylamine (1.3 mL, 9.2 mmol) Purification:
chromatography (silicagel, acetone) to give a light yellow solid:
yield 1590 mg (63%). Mp 162 ꢂC; 1H NMR (500 MHz, CDCl3) dH
(ppm) ¼ 2.52e2.58 (m, br, 6H), 2.65 (s, br, 4H), 3.57 (t, 2H,
J ¼ 5.4 Hz), 4.09 (s, 1H), 7.48e7.59 (m, br, 8H), 7.64e7.68 (m, 1H),
7.77 (dd, 2H, J ¼ 8.2 Hz, J ¼ 1.2 Hz), 8.55 (d, 1H, J ¼ 8.9 Hz), 11.69
(s, br, 1H); 13C NMR (125 MHz, CDCl3) dC (ppm) ¼ 52.47, 57.73,
59.02, 76.1, 123.03, 125.64, 126.03, 127.84, 128.65, 129.45, 130.06,
137.92,170.85,173.12,197.15; IR (ATR):
n
(cmꢁ1) ¼ 3490, 3369, 2815,
1695, 1645, 1505, 1298, 1282, 1251, 943, 724, 697, 686, 649; MS (EI,
70 eV): m/z 56 (5), 77 (6), 91 (10),104 (10), 232(100), 257 (3) 490 (3)
[M]þ; MS (EI-HRMS) calcd: 490.1772, found: 490.1754.
4.1.4.34. (R,S)-N-(2-benzoyl-4-chlorophenyl)-2-[4-(2-(isopropylamino)-
2-oxoethyl)-piperazin-1-yl]-2-phenylacetamide (10d). According to
general procedure
2 from (R,S)-N-(2-benzoyl-4-chlorophenyl)-2-
chloro-2-phenylacetamide (1.9 g, 5.0 mmol) and N-(isopropyl)-1-pi-
perazinacetamide (2.8 g, 15.0 mmol). Purification: chromatography
(silicagel, ethylacetate/isohexane 2:3, then ethylacetate) to give
a yellow crystalline solid: yield 1.41 g (53%). Mp 78 ꢂC; 1H NMR
132.16, 133.17, 133.52, 137.74, 139.04, 170.62, 197.22; IR (ATR):
n
(cmꢁ1) ¼ 3237, 2944, 2882, 2820, 1688, 1646, 1497, 1322, 1159, 1113,

1342
S. Heinrich et al. / European Journal of Medicinal Chemistry 46 (2011) 1331e1342
1066, 1013, 700, 381; MS (ESI): m/z 546 (100), [M þ H]þ; MS (EI-
(300 MHz, CDCl3) dH (ppm) ¼ 2.57e2.63 (m, br, 6H), 2.67e2.69 (s,
br, 4H), 2.79 (s, br, 1H), 3.59 (t, 2H, J ¼ 5.3 Hz), 4.16 (s, 1H), 7.44e7.57
(m, br, 7H), 7.64e7.70 (m, 1H), 7.76e7.82 (m, br, 5H), 7.85 (s, 1H),
8.55 (d, 1H, J ¼ 8.8 Hz), 11.72 (s, br, 1H); 13C NMR (75.5 MHz, CDCl3)
dC (ppm) ¼ 52.66, 57.63, 59.22, 77.42, 123.13, 125.73, 126.12, 126.33,
127.63, 128.02, 128.51, 128.63, 128.74, 130.04, 132.05, 132.83, 133.12,
HRMS) calcd: 546.1810, found: 546.1771.
4.1.4.38. (R,S)-N-(2-benzoyl-4-chlorophenyl)-2-(4-bromophenyl)-2-
(4-(2-hydroxyethyl)piperazin-1-yl)-acetamide (11c). According to
general procedure 2 from N-(2-benzoyl-4-chlorophenyl)-2-bromo-
2-(4-bromophenyl)-acetamid (3.0g, 6.0 mmol) and N-(2-hydrox-
yethyl)piperazine (2.2 mL, 18 mmol) and triethylamine (1.7 mL,
12mmol). Purification: chromatography (silicagel, acetone) to give
a yellow solid: yield 2386 mg (71%). Mp 178 ꢂC; 1H NMR (500 MHz,
CDCl3) dH (ppm) ¼ 2.55e2.62 (m, br, 6H), 2.69 (s, br, 4H), 3.61 (t, 2H,
J ¼ 5.3 Hz), 3.98 (s, 1H), 7.25 (d, 2H, J ¼ 8.9 Hz), 7.45 (d, 2H,
J ¼ 8.5 Hz), 7.48e7.50 (m, 2H), 7.54 (t, 2H, J ¼ 7.7 Hz), 7.64e7.68 (m,
1H), 7.76 (dd, 2H, J ¼ 8.2 Hz, J ¼ 1.2 Hz), 8.54e8.56 (m, 1H), 11.65 (s,
br, 1H); 13C NMR (125 MHz, CDCl3) dC (ppm) ¼ 52.53, 57.64, 59.13,
76.16, 122.53, 123.04, 125.92, 127.75, 128.64, 130.04, 130.65, 131.94,
132.12, 133.12, 133.52, 134.12, 137.73, 137.83, 170.34, 197.32; IR
133.22, 133.33, 133.43, 137.86, 137.98,170.81, 197.22; IR (ATR):
n
(cmꢁ1) ¼ 3240, 2819, 1693, 1644, 1494, 1281, 1243, 1011, 947, 744,
699, 477; MS (ESI): m/z 528 (100) [M þ H]þ; MS (EI-HRMS) calcd:
528.2079, found: 528.2054.
4.2. Antimalarial activity
The multi-drug resistant P. falciparum clone Dd2 [6] was main-
tained in continuous culture as described [7] and synchronized
using the sorbitol method [8]. Drug assays based on [3H]-hypo-
xanthine incorporation were done [9] and the percent inhibition
was determined as described [10]. Each assay was repeated at least
three independent times and the mean ꢀ SEM was calculated. IC50
values were calculated from the sigmoidal dose-response curves
using a Hill function (Sigma Plot, SPSS).
(ATR):
n
(cmꢁ1) ¼ 3485, 3175, 2808, 1682, 1645, 1501, 1288, 1255,
1013, 832, 736, 698, 456, 405; MS (ESI): m/z 558 (100), [M þ H]þ;
MS (EI-HRMS) calcd: 556.1029, found: 556.1003.
4.1.4.39. (R,S)-N-(2-benzoyl-4-chlorophenyl)-2-(biphenyl-4-yl)-2-
(4-(2-hydroxyethyl)piperazin-1-yl)acetamide (11d). According to
general procedure 2 from N-(2-benzoyl-4-chlorophenyl)-2-(biphenyl-
4-yl)-2-bromo-acetamide (613 mg, 1.2 mmol) und N-(2-hydrox-
yethyl)piperazine (0.5 mL, 3.6 mmol) and triethylamine (0.3 mL,
2.4 mmol). Purification: chromatography (silicagel, acetone) to give
a light yellow solid: yield 398 mg (60%). Mp 147 ꢂC; 1H NMR
(300 MHz, CDCl3) dH (ppm) ¼ 2.50e2.59 (m, br, 6H), 2.63e2.65 (m,
br, 4H), 3.58 (t, 2H, J ¼ 5.3 Hz), 4.04 (s, 1H), 7.30e7.36 (m, 1H),
7.39e7.57 (m, br, 12H), 7.63e7.69 (m, 1H), 7.77 (d, 2H, J ¼ 1.5 Hz),
8.60 (d, 1H, J ¼ 9.6 Hz), 11.68 (s, br, 1H); 13C NMR (75.5 MHz, CDCl3)
dC (ppm) ¼ 52.65, 57.73, 59.12, 77.44, 123.13, 126.15, 127.06, 127.44,
127.54,128.66,128.73,129.33,130.03,132.04,133.02,133.42,134.23,
4.3. Cytotoxic assay
HeLa (DSM ACC 57) cells were grown in RPMI 1640 culture
medium (GIBCO BRL 21875-034) supplemented with 25
mg/mL
gentamicin sulfate (BioWhittaker 17-528Z), and 10% heat inacti-
vated fetal bovine serum (GIBCO BRL 10500-064) at 37 ꢂC in high
density polyethylene flasks (NUNC 156340). The test substances
were dissolved in DMSO (10 mg/ml) before being diluted in the cell
culture medium (1:200). The adherent HeLa cells were harvested at
the logarithmic growth phase after soft trypsinization, using 0.25%
trypsin in PBS containing 0.02% EDTA (Biochrom KG L2163). For
each experiment approximately 10,000 cells were seeded with
137.84, 138.05, 140.53, 141.32, 171.03, 197.12; IR (ATR):
n
(cmꢁ1) ¼
0.1 mL RPMI 1640 (GIBCO BRL 21875-034), containing 25 mg/mL
3193, 2942, 2819, 1693, 1640, 1499, 1485, 1277, 1237, 1011, 737, 691,
383; MS (ESI): m/z 554 (100), [M þ H]þ; MS (EI-HRMS) calcd:
554.2213, found: 554.2210.
gentamicin sulfate (BioWhittaker 17-528Z), but without HEPES, per
well of the 96-well microplates (NUNC 167008). For the cytotoxic
assay HeLa cells were preincubated for 48 h without the test
substances. The dilutions of the test substances were carried out
carefully on the monolayers of HeLa cells after the preincubation
time. The HeLa cells were further incubated for 72 h at 37 ꢂC in
a humidified atmosphere and 5% CO2. The adherent HeLa cells were
fixed with 25% glutaraldehyde and stained with a 0.05% solution of
methylene blue for 15 min. After gently washing the stain was
eluted with 0.2 ml of 0.33 M HCl per well. The optical densities
were measured at 660 nm in SUNRISE microplate reader (TECAN).
For data analysis the Magellan software (TECAN) was used.
4.1.4.40. (R,S)-N-(2-benzoyl-4-chlorophenyl)-2-(4-(2-hydroxyethyl)-
piperazin-1-yl)-2-(naphtalen-1-yl)-acetamide (11e). According to
general procedure 2 from N-(2-benzoyl-4-chlorophenyl)-2-bromo-
2-(naphtalen-1-yl)acetamide (1.4 g, 2.9 mmol) und N-(2-hydrox-
yethyl)piperazine (1.1 mL, 8.7 mmol) and triethylamine (0.8 mL,
5.8 mmol). Purification: chromatography (silicagel, acetone) to give
a light yellow solid: yield 955 mg (62%). Mp 97 ꢂC; 1H NMR
(300 MHz, CDCl3) dH (ppm) ¼ 2.61e2.69 (m, br, 6H), 2.71 (s, br, 4H),
2.96 (s, br, 1H), 3.60 (t, 2H, J ¼ 5.3 Hz), 4.86 (s, 1H), 7.39e7.57 (m, br,
7H), 7.64e7.69 (m, 2H), 7.75e7.85 (m, br, 4H), 8.40 (d, 1H,
J ¼ 8.2 Hz), 8.56 (d, 1H, J ¼ 8.8 Hz), 11.74 (s, br, 1H); 13C NMR
(75.5 MHz, CDCl3) dC (ppm) ¼ 52.33, 57.13, 58.84, 77.03, 122.62,
123.33,124.94,125.43,126.22,127.12,128.23,128.43,128.54,129.52,
131.33, 131.64, 131.84, 132.66, 133.07, 133.74, 137.43, 137.65, 170.53,
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196.05; IR (ATR):
n
(cmꢁ1) ¼ 3245, 2941, 2818, 1691, 1647, 1494,
1394, 1282, 1245, 949, 794, 776, 700, 412; MS (ESI): m/z 528.04
[M þ H]þ; MS (EI-HRMS) calcd: 528.2076, found: 528.2054.
4.1.4.41. (R,S)-N-(2-benzoyl-4-chlorophenyl)-2-(4-(2-hydroxyethyl)-
piperazin-1-yl)-2-(naphtalen-2-yl)-acetamide (11f). According to
general procedure 2 from N-(2-benzoyl-4-chlorophenyl)-2-bromo-
2-(naphtalen-2-yl)acetamide (3.0 g, 6.3 mmol) und N-(2-hydrox-
yethyl)piperazine (2.3 mL, 18.9 mmol) and triethylamine (0.9 mL,
6.3 mmol). Purification: chromatography (silicagel, acetone) to give
a light yellow solid: yield 2876 mg (86%). Mp 84 ꢂC; 1H NMR