New derivatives of 7-chloroquinolin-4-amine with antiprotozoal activity

Article abstract of DOI:10.1016/j.bmc.2016.12.006

Novel ω-aminoacyl and -alkyl derivatives of 7-chloroquinolin-4-amine were prepared and their structures confirmed by NMR spectroscopy. Their antiprotozoal activities were examined in vitro against the sensitive NF54 strain as well as against the multiresistant K₁strain of Plasmodium falciparum and against Trypanosoma brucei rhodesiense (STIB 900). The results were compared with the activities of clinically used drugs. Their antitrypanosomal activities were only moderate whereas their antiplasmodial activities looked very promising. Some were equal or slightly more active than chloroquine against the sensitive strain. However, in comparison to chloroquine, the activity of the new compounds was decreased much less in the resistant strain. Several possessed activity against both strains in low nanomolar concentration.

Full text of DOI:10.1016/j.bmc.2016.12.006

Accepted Manuscript
New derivatives of 7-chloroquinolin-4-amine with antiprotozoal activity
Johanna Faist, Clemens Hinteregger, Werner Seebacher, Robert Saf, Pascal
Mäser, Marcel Kaiser, Robert Weis
PII:
S0968-0896(16)31046-X
http://dx.doi.org/10.1016/j.bmc.2016.12.006
BMC 13433
DOI:
Reference:
Bioorganic & Medicinal Chemistry
To appear in:
Received Date:
Revised Date:
Accepted Date:
21 October 2016
2 December 2016
5 December 2016
Please cite this article as: Faist, J., Hinteregger, C., Seebacher, W., Saf, R., Mäser, P., Kaiser, M., Weis, R., New
derivatives of 7-chloroquinolin-4-amine with antiprotozoal activity, Bioorganic & Medicinal Chemistry (2016),
doi: http://dx.doi.org/10.1016/j.bmc.2016.12.006
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

New derivatives of 7-chloroquinolin-4-amine with
antiprotozoal activity
Johanna Faista* ● Clemens Hintereggera ● Werner Seebachera ●
Robert Safb ● Pascal Mäserc ● Marcel Kaiserc ● Robert Weisa
a Institute of Pharmaceutical Sciences, Pharmaceutical Chemistry,
University of Graz, Austria
b Institute for Chemistry and Technology of Materials (ICTM),
University of Technology Graz, Austria
c Swiss Tropical and Public Health Institute, and University of Basel,
Switzerland
Abstract Novel -aminoacyl and -alkyl derivatives of 7-
chloroquinolin-4-amine were prepared and their structures confirmed
by NMR spectroscopy. Their antiprotozoal activities were examined
in vitro against the sensitive NF54 strain as well as against the
multiresistant K1 strain of Plasmodium falciparum and against
Trypanosoma brucei rhodesiense (STIB 900). The results were
compared with the activities of clinically used drugs. Their
antitrypanosomal activities were only moderate whereas their
antiplasmodial activities looked very promising. Some were equal or
slightly more active than chloroquine against the sensitive strain.
1

However, in comparison to chloroquine, the activity of the new
compounds was decreased much less in the resistant strain. Several
possessed activity against both strains in low nanomolar
concentration.
Keywords Amines; Antiplasmodial activity; Heterocycles; NMR
spectroscopy; Nucleophilic substitutions; Quinoline
*Corresponding author. Tel.: +43-316-380-5379; fax: +43-316-380-9846
E-mail adress: johanna.faist@uni-graz.at
Introduction
The tropical infection Malaria and the neglected tropical disease Human
African Trypanosomiasis (HAT) represent great health issues in recent
years.
Malaria is caused by the bite of a female anopheles mosquito which
is infected with the protozoan genus Plasmodium. According to the World
Health Organization, there were about 214 million cases of malaria and
estimated 438 000 deaths in 2015 [1]. Four types of malaria parasites are
pathogenic for humans: Plasmodium falciparum, P. malariae, P. ovale and
P. vivax. The majority of infections are caused by Plasmodium falciparum,
2

the most deadly malaria parasite. The main problem is the major increase
of Plasmodium falciparum strains which have become resistant to previous
generations of medicines. In recent years resistance even to recommended
artemisinin-based therapies has become prevalent across an expanding area
of Southeast Asia [2]. Therefore, the development of new drugs for the
fight against the most deadly drug-resistant strains of Plasmodium
falciparum is absolutely essential [3].
HAT, also known as sleeping sickness, is transmitted by the bite of
tsetse flies that are infected with the protozoan Trypanosoma brucei. For
the first time in the last 50 years, the number of cases reported has dropped
below 10 000 in 2009 after continued control efforts. This decline of
number of cases has continued with 6314 new infections reported in 2013.
However, the estimated population at different levels of risk is about 70
million people [4]. HAT arises in two forms: Infections with T. b.
rhodesiense are acute infections, lasting from a few weeks to several
months, whereas T. b. gambiense infections which represent a large part of
the infections, are chronic illnesses, generally lasting several years without
any major signs or symptoms [5]. Sleeping sickness is fatal without
treatment. Only a couple of drugs are available for the therapy of HAT:
pentamidine, suramin, melarsoprol, eflornithine and nifurtimox. But
serious side-effects are a problem with all of them, and resistance is
3

increasing [6]. The central phase of T. b. rhodesiense infections can only be
cured with melarsoprol [5]. Unfortunately, melarsoprol causes a deadly
encephalopathy in 3-10% of the treated patients [7]. Therefore, new drugs
in the fight against Human African Trypanosomiasis are urgently needed
[8].
Our current study deals with the derivatization of the 4-amino-7-
chloroquinoline scaffold. Some of the newly synthesized compounds were
already named by Krogstad [9], but no data concerning their synthesis and
their characterization were given. The influence of different basic side-
chains at ring position 4 of the 7-chloroquinoline core on the biological
properties was investigated. The new compounds were tested in vitro for
their activities against the sensitive strain NF54 and the multiresistant K1
strain of P. falciparum as well as against T. brucei rhodesiense. Their
cytotoxicity was determined using L6 rat cells. The results were compared
to those of clinically used drugs.
Results and Discussion
Chemistry
For all routes of synthesis 4,7-dichloroquinoline was used as starting
material (Scheme 1). ω-(Quinolin-4-yl)alkanoles 1, 2 were prepared by
reaction with ω-aminoalkanoles. Upon treatment with thionyl chloride the
terminal hydroxy group was replaced by a chlorine substituent yielding
4

compounds 3, 4. New derivatives 5-9 were obtained by reaction with
secondary amines. Treatment of 4,7-dichloroquinoline with ethylendiamine
gave compound 10 [10]. This intermediate reacted in a one-pot reaction
[11] with 2-chloroacetyl chloride and subsequently with various secondary
amines to the corresponding N-(2-aminoacyl) derivatives 11-15. Their
reduction with LiAlH4 led to the loss of the chlorine atom in ring position
7. Therefore an alternative approach was applied using a borane-DMS-
complex [12] yielding the corresponding N-(ω-aminoalkyl) analogue 16.
In derivatives 18, 19, 21, 22 the cyclic secondary diamine piperazine was
used as linkage between the quinoline core and the aminoalkyl side chain.
The 4-(piperazin-1-yl)quinoline 17 was prepared from 4,7-
dichloroquinoline with excess piperazine [13]. Compound 17 was reacted
in a one-pot reaction with 2-chloroacetyl chloride and subsequently with
different secondary amines yielding the 4-[4-(2-aminoacyl)piperazin-1-
yl]quinolines 18, 19.
Compound 17 was directly transformed into its 4-(2-chloroethyl)piperazine
derivative 20 by reaction with a large excess of 1,2-dichloroethane. In a
final step the reaction of intermediate 20 with secondary amines gave
compounds 21, 22 (Scheme 1).
5

1´
R
Cl
OH
n
( )n
(
HN
N
)
(
)
HN
N
HN
N
n
5
8
3
2
6
c
b
Cl
Cl
Cl
5-9
3,4
1,2
H
N
H
N
NH2
a
HN
R
HN
N
1´
2´´
HN
N
R
O
e
f
Cl
N
Cl
Cl
11-15
10
16
d
Cl
N
R
2´´
H
N
Cl
O
R =
N
N
N
CH3
N
g
3´
2´
N
N
N
N
h
Cl
Cl
17
N
18,19
i
R
Cl
N
N
1´´
N
N
N
3´
2´
N
n = 1,2
j
Cl
N
Cl
N
21,22
20
Scheme 1:
(a) ω-amino-alkanol, triethylamine, 130°C, 5 h; (b) SOCl2, DMF, 24 h,
20°C; (c) method A: sec. amine, triethylamine, DMF, 10-20 h, 130°C;
method B: sec. amine, KI, 20°C, 96 h; (d) ethylenediamine, 135°C, 3 h; (e)
(1.) 2-chloroacetyl chloride, DIPEA or triethylamine, CH2Cl2, 0°C→20°C,
1 h; (2.) sec. amine, 20°C, 70-90 h; (f) borane-DMS-complex, dry THF,
95°C, 20 h; (g) piperazine, triethylamine, 130°C, 5 h; (h) (1.) 2-
chloroacetyl chloride, DIPEA, CH2Cl2, 0°C→20°C, 1 h; (2.) sec. amine,
20°C, 108-168 h; (i) 1,2-dichloroethane, triethylamine, 110°C, 48 h; (j) sec.
amine, triethylamine, MeOH, 85°C, 20 h;
6

Compounds
R
n
4-Methylpiperazin-1-yl
Dipropylamino
Azepan-1-yl
4-Methylpiperazin-1-yl
Azepan-1-yl
1
1
1
2
2
-
5
6
7
8
9
4-Methylpiperazin-1-yl
Piperidino
11, 18
12
-
Dipropylamino
Azepan-1-yl
Pyrrolidino
-
-
-
13, 19, 21
14, 16, 22
15
<Scheme 1>
The structures of all newly synthesized compounds were investigated by
nmr spectroscopy. Evaluation of the below-mentioned typical chemical
shifts provided structural evidence. Interpretation of the cross peaks in the
2D nmr spectra enabled the reliable assignment of signals. The replacement
of the chlorine atom in ring position 4 by a nitrogen caused significant
1
13
shifts of the signals in their H and C nmr spectra. In comparison to 4,7-
dichloroquinoline the resonance of the proton in ring position 3 of
1
compounds 1-22 is shifted ca. 1 ppm to lower frequencies in H nmr
spectra due to the mesomeric effect of the nitrogen substituent. Remarkable
shifts were observed in their 13C nmr spectra. For the alkylamino derivates
1-16 the resonances for C-3 and C-4a were shifted 23 and 7 ppm to lower
frequencies, respectively. The corresponding shifts for their 4-piperazinyl
analogues 17-22 were 13 ppm upfield for C-3 and 3 ppm upfield for C-4a.
7

The signals of the C-4 atoms were shifted 7 ppm to higher frequencies for
compounds 1-16 and 13 ppm downfield for compounds 17-22. The
resonances of the other ring atoms changed marginally compared to 4,7-
dichloroquinoline. The nmr data of compounds 1-4, 10, 17 were in
accordance with published data [13, 14, 15]. N-substitution of compounds
3, 4 caused a significant 1 ppm upfield shift of the resonances for the
1
adjacent methylene protons in the H spectra of compounds 5-9 due to the
replacement of a chlorine by a nitrogen atom. In addition, the N-alkylation
was confirmed by a 3.5 ppm downfield shift of the N(CH2)2 signal in the
13C nmr spectrum of compound 6. The N(CH2)2 resonances of the
corresponding cyclic amino groups of compounds 5, 7-9 were shifted 7
ppm to higher frequencies. The published NMR-data for compound 8 [16]
turned out wrong. The resonances of all NCH2 protons are between 2.4-2.8
ppm, a typical value for tertiary amines. Reference [16] gives signals at
4.37-4.40 ppm for eight of these protons instead. The ArNCH2 carbon of 8
appears at ca. 44 ppm, a common shift in case of a propyl chain. In
comparison reference [16] describes a signal at 34 ppm. Obviously the
authors picked wrong data sets. The correct nmr data of 8 are presented in
the experimental part. The N-acylation of compounds 10 and 17 was
indicated by the appearance of an additional signal for a carbonyl
13
resonance at ca. 174 ppm in the C nmr spectra of the amides 11-15 and
8

18, 19. The resonances of their NCH2 protons were shifted 0.4-0.7 ppm
downfield due to acylation, whereas the corresponding carbon signals were
shifted to lower frequencies. The vicinal N(CH2)2 signals of the piperazinyl
moiety of compound 17 were shifted 7 ppm downfield due to N-alkylation.
The reduction of the amide 14 to compound 16 caused the replacement of
the carbonyl resonance at 175 ppm by an additional signal for a methylene
group at 47 ppm. Moreover, the signal of the adjacent -methylene group
was shifted 5 ppm to higher field. The success of all N-alkylation reactions
was evident from the appearance of N(CH2)2 resonances for all tertiary
13
amino groups of compounds 5-9 and 11- 22 at 51-62 ppm in their C nmr
spectra, which is a common value.
Antiprotozoal activity
One goal of this study was the investigation of the influence of the
different aminoalkyl side-chains of the new compounds on the
antiprotozoal activity. They were tested in vitro for their activities against
the K1 strain (resistant to chloroquine and pyrimethamine) as well as
against the chloroquine sensitive strain NF54 (sensitive to all known anti-
malarial drugs) of Plasmodium falciparum. Furthermore, their activity
against Trypanosoma brucei rhodesiense was determined using microplate
9

assays. Their cytotoxicity was examined with rat skeletal myoblasts (L-6
cells). Chloroquine, melarsoprol and podophyllotoxin served as standards.
The antitrypanosomal activity and selectivity of all new compounds
was only moderate. The 4-[2-(dipropylamino)ethyl]amino quinoline 6
showed the highest antitrypanosomal activity (IC50 = 0.14 µM). It also had
the best selectivity among the new compounds (SI: 106.7).
Concerning the antiplasmodial activity, most of the newly
synthesized compounds exhibited very persuading activities.
Representatives of the N-[-(dialkylamino)alkyl]quinolin-4-amine series
showed compared to chloroquine (P.f.NF54: 0.0039 µM) similar
(P.f.NF54: 6, 7, 8: 0.0031-0.0038 µM) or slightly decreased (P.f.NF54: 5,
9: 0.0063-0.0066 µM) activity against the sensitive NF54 strain of
Plasmodium falciparum. The linker between the terminal amino group and
the quinoline moiety is an alkylamino chain of 3-4 atoms. An elongation
of the linker by an additional alkylamino or an acetamido group leads to a
decrease of antiplasmodial activity (P.f.NF54: 11-16: 0.011-0.036 µM), but
the compounds still possess antiplasmodial activity in low nanomolar
concentrations. The reduction the amido group in the linker of compound
14 to a secondary amino group in 16 decreased the cytotoxicity. However,
the antiplasmodial activity remained almost unaffected indicating that the
influence of the amido group is negligible. The larger distance between the
10

quinoline ring and the terminal amino group could also explain the
comparably low activity of the 4-piperazinyl quinolines (P.f.NF54: 18, 19,
21, 22: 0.070-0.230 µM) (Table 1).
Table 1
Activities of compounds 5-22 against T.brucei rhodesiense, P.falciparum NF54, P.falciparum
K1 and L-6 cells, expressed as IC50 (µM).a
P.f. NF54 b
IC50 (µM)
T.brucei
Compounds rhodesiense
IC50 (µM)
Cytotoxicity
L-6 cells
IC50 (µM)
S.I.=
IC50 (Cyt.)/IC50
(P.f.NF54)
P.f. K1c IC50
S.I.=
S.I.=
IC50 (Cyt.)/IC50 (T.b.r.)
IC50 (Cyt.)/IC50 (P.f.K1)
(µM)
0.69
0.14
0.59
1.14
0.78
18.32
1.28
0.94
0.28
0.74
1.28
2.02
1.46
1.07
1.61
24.25
106.7
22.42
15.93
25.58
2.08
18.54
23.36
50.78
62.69
59.48
39.52
48.27
53.11
15.76
0.0066
0.0033
0.0033
0.0031
0.0063
0.036
0.011
0.014
0.011
0.018
0.011
0.14
2535
4527
4009
5858
3167
1057
2157
1568
1293
2577
6921
570.3
306.4
516.6
362.4
23313
0.036
0.0098
0.016
0.031
0.038
2.87
0.092
0.030
0.055
0.075
0.066
0.28
464.7
1524
16.73
14.94
13.23
18.16
19.95
38.05
23.73
21.96
14.22
46.39
76.13
79.84
70.47
56.83
25.37
90.92
7.78
5
6
7
8
9
826.9
585.8
525.0
13.26
257.9
732.0
258.5
618.5
1153
285.1
227.3
645.8
338.3
606.1
11
12
13
14
15
16
18
19
21
22
CQ
MEL
POD
0.23
0.11
0.070
0.0039
0.31
0.088
0.075
0.15
0.01
778.0
0.012
CQ = chloroquine; MEL = melarsoprol; POD = podophyllotoxine
a Values represent the average of four determinations (two determinations of two independent experiments)
b active against all known anti-malarial drugs
c Resistant to chloroquine and pyrimethamine
<Table 1>
In resistant strains of Plasmodium falciparum the activity of chloroquine is
seriously decreased by resistance mechanisms in the vacuoles of the
parasites [17]. This is the reason why the usage of chloroquine is extremely
11

restricted nowadays. The majority of the new compounds 5-22 possessed
much higher activity (P.f.K1: 0.0098-0.092 µM) against the multiresistant
K1 strain than chloroquine (P.f.K1: 0.15 µM). They show good selectivity
indices (SI: 227.3-1524). The N-[-(dipropylamino)ethyl]quinolin-4-amine
6 is the most promising in this series. It retains activity in low nanomolar
concentration (P.f.K1: 0.0098 µM) and exhibits the highest selectivity index
(SI: 1524). The resistance index (RI) is defined as the ratio of the IC50 of a
resistant line to that of a sensitive strain. Thus, the higher the RI, the higher
the level of resistance. The RI of chloroquine (RI: 38.5) in P.f.K1 versus
P.f.NF54 demonstrates a significant inactivation of the drug. The newly
prepared compounds had far better RI-values than chloroquine with the
exception of compound 11 (RI: 79.7). The antiplasmodial activities of the
4-piperazinylquinolines 18, 19, 21, 22 as well as of compounds with a
terminal dipropylamino group 6, 13 differed only slightly between the
sensitive and the resistant strain, which is obvious from their RIs (RI: 0.8-
2.97). All remaining compounds showed a distinct decrease of activity in
the resistant strain (RI: 4.17-10.0). The most promising compound is N-[-
(dipropylamino)ethyl]quinolin-4-amine 6. It exhibited higher activity than
chloroquine in both strains (P.f.NF54: 0.0033 µM vs. 0.0039 µM; P.f.K1:
0.0098 µM vs. 0.15 µM). Its far better RI (2.97 vs. 38.5) indicates that the
12

antiplasmodial activity of compound 6 is only slightly influenced by the
reaction mechanisms that inactivate chloroquine in P.f.K1.
Therefore the emphasis for future studies will be placed on the synthesis of
further modified 4-amino-7-chloroquinolines with low RI to circumvent
resistance (Table 2).
Table 2
resistance index RI = ratio of the IC50 (µM) for the resistant versus the sensitive strain
resistance index
Compounds
P.f. K1 IC50 (µM)
P.f. NF54 IC50 (µM)
RI
0.15
0.0039
0.0066
0.0033
0.0033
0.0031
0.0063
0.036
0.011
0.014
0.011
0.018
0.011
0.14
CQ
5
6
7
8
38.5
5.45
0.036
0.0098
0.016
0.031
0.038
2.87
0.092
0.030
0.055
0.075
0.066
0.28
2.97
4.85
10.0
6.03
79.7
8.36
2.14
5.00
4.17
6.00
2.00
1.35
0.80
1.07
9
11
12
13
14
15
16
18
19
21
22
0.31
0.088
0.075
0.23
0.11
0.070
<Table 2>
Conclusion
This paper dealt with the syntheses and the antitrypanosomal and
antiplasmodial activities of new ω-aminoacyl and ω-aminoalkyl substituted
derivatives of 7-chloroquinolin-4-amine. The biological activities of the
new compounds are heterogeneous. All newly synthesized compounds
13

showed only weak to moderate activity against Trypanosoma brucei
rhodesiense. However, most of the compounds demonstrate good activity
against the sensitive NF54 strain and the multiresistant K1 strain of
Plasmodium falciparum.
Compounds with a short alkylamino linker of 3-4 atoms between the
terminal amino group and the quinoline core exhibited significantly higher
activities in the chloroquine-sensitive strain than analogues with longer
side chains. Some of these compounds were as active as chloroquine. An
insertion of an alkylamino or an acetamido group in the linker decreases
the antiplasmodial activity significantly. Compounds with a 4-
piperazinylquinoline moiety were the least active. This could be caused by
sterical reasons and by the larger distance between quinoline ring and
terminal amino group. Unlike chloroquine, the majority of new compounds
had small resistance indices and therefore retained activity in the resistant
strain in low nanomolar concentration. A single compound possessing a
terminal dipropylamino group and an ethylamino linker showed
antiplasmodial activity in low nanomolar concentration against a sensitive
and a multiresistant strain. Its selectivity indices as well as its resistance
index are very promising.
Experimental
14

6.1 Instrumentation and chemicals
Melting points were obtained on a digital melting point apparatus
Electrothermal IA 9200. IR spectra were recorded using a Bruker Alpha
Platinum ATR FTIR spectrometer (KBr discs). The purity (>95%) of
compounds is checked with HPLC using UV detection as a matter of
routine. NMR spectra: Varian Unity Inova 400 (298 K) 5 mm tubes, TMS
1
13
1
as internal standard. H NMR (400 MHz) and C NMR (100 MHz), H-
13
1
1
and C-resonances were assigned using H,1H- and H,13C-correlation
spectra and are numbered as given in the formulas. The resonances of the
terminal ω-dialkylamino group of compounds 5-9 are marked with a
double quote, the resonances of compounds 11-16, 18, 19, 21, 22 are
marked with a triple quote. Signal multiplicities are abbreviated as follows:
br broad, d doublet, dd double doublet, m multiplet, s singlet, t triplet, td
triple doublet, quin quintet, sex sextet. HRMS: GCT-Premier, Waters (EI,
70eV). Materials: column chromatography (CC): silica gel 60 (Merck 70 -
230 mesh, pore-diameter 60 Å), thin-layer chromatography (TLC): TLC
plates silica gel 60 F254 (Merck).
6.2 Syntheses
The routes of syntheses of compounds 1-4, 10, 17 have already been
reported elsewhere [10, 13, 16].
15

General procedures for the synthesis of 4-[(ω-aminoalkyl)amino]-7-
chloroquinolines (5-9).
Method A: 7-Chloro-N-(ω-chloroalkyl)quinolin-4-amine 3, 4, equimolar
quantities of triethylamine and an excess of the corresponding secondary
amine were refluxed at 130°C-150°C in dry dimethylformamide (DMF) for
20 hours in an atmosphere of Ar. Subsequently the reaction batch was
coevaporated with benzene. Afterwards the residue was dissolved in
CH2Cl2 and was washed with aqua dest. The organic phase was dried over
anhydrous sodium sulfate, filtered and the solvent was evaporated in vacuo
yielding compounds 5-7, 9.
Method B: 7-Chloro-N-(ω-chloroalkyl)quinolin-4-amine 4 was dissolved
in an excess of secondary amine. A catalytic amount of KI was added. The
mixture was stirred for 96 h at ambient temperature in an atmosphere of Ar.
Subsequently, benzene was added and the solvents were evaporated. The
residue was dissolved in CH2Cl2, washed with water until the aqueous
phase reacted neutral, dried over anhydrous sodium sulfate, filtered and
finally the solvent was removed in vacuo giving compound 8.
7-Chloro-N-[2-(4-methylpiperazin-1-yl)ethyl]quinolin-4-amine (5).
16

Method A: The reaction of 7-chloro-N-(2-chloroethyl)quinolin-4-amine 3
(0.300 g, 1.24 mmol), triethylamine (0.13 g, 1.24 mmol) and N-
methylpiperazine (0.62 g, 6.2 mmol) in 1 mL DMF yielded compound 5
(0.284 g, 76%). A purification by use of column chromatography was done
(silica, CH2Cl2+MeOH=19+1). IR (KBr):
= 3065, 2961, 2933, 2787,
1610, 1580, 1549, 1453, 1429, 1365, 1334, 1283, 1250, 1166, 1150, 1082,
1
1016, 875, 838, 803 cm-1; H NMR (CDCl3, 400 MHz): δ = 2.33 (s, 3H,
NCH3), 2.42-2.64 (m, 8H, 2´´-H, 3´´-H, 5´´-H, 6´´-H), 2.79 (t, J = 5.9 Hz,
2H, 2´-H), 3.32 (td, J = 5.9 , 4.1 Hz, 2H, 1´-H), 5.98 (br s, 1H, NH), 6.38
(d, J = 5.3 Hz, 1H, 3-H), 7.40 (dd, J = 9.0, 2.0 Hz, 1H, 6-H), 7.68 (d, J =
9.0 Hz, 1H, 5-H), 7.96 (d, J = 2.0 Hz, 1H, 8-H), 8.54 (d, J = 5.3 Hz, 1H, 2-
13
H) ppm; C NMR (CDCl3, 100 MHz): δ = 38.86 (C-1´), 46.03 (NCH3),
52.57 (C-2´´, C-6´´), 55.27 (C-3´´, C-5´´), 55.37 (C-2´), 99.29 (C-3),
117.33 (C-4a), 121.05 (C-5), 125.34 (C-6), 128.79 (C-8), 134.81 (C-7),
149.09 (C-8a), 149.73 (C-4), 152.12 (C-2) ppm; HRMS (EI+) calcd for
C16H21ClN4: 304.1455; found: 304.1471.
7-Chloro-N-[2-(dipropylamino)ethyl]quinolin-4-amine (6).
Method A: The reaction of 7-chloro-N-(2-chloroethyl)quinolin-4-amine 3
(0.300 g, 1.24 mmol), triethylamine (0.13 g, 1.24 mmol) and
dipropylamine (1.25 g, 12.4 mmol) in 1 mL DMF yielded compound 6
17

(0.265 g, 70%). IR (KBr):
= 3065, 2957, 2929, 1613, 1579, 1549, 1453,
1430, 1377, 1339, 1282, 1232, 1201, 1167, 1139, 1081, 1029, 899, 874,
1
847, 820, 799 cm-1; H NMR (CDCl3, 400 MHz): δ = 0.92 (t, J = 7.4 Hz,
6H, 3´´-H), 1.52 (sex, J = 7.4 Hz, 4H, 2´´-H), 2.46 (t, J = 7.4 Hz, 4H, 1´´-
H), 2.82 (t, J = 5.9 Hz, 2H, 2´-H), 3.25 (td, J = 5.9, 4.0 Hz, 2H, 1´-H), 6.13
(br s, 1H, NH), 6.37 (d, J = 5.4 Hz, 1H, 3-H), 7.37 (dd, J = 9.0, 2.1 Hz, 1H,
6-H), 7.65 (d, J = 9.0 Hz, 1H, 5-H), 7.95 (d, J = 2.1 Hz, 1H, 8-H), 8.53 (d,
J = 5.3 Hz, 1H, 2-H) ppm; 13C NMR (CDCl3, 100 MHz): δ = 11.89 (C-3´´),
20.35 (C-2´´), 39.69 (C-1´), 51.83 (C-2´), 55.45 (C-1´´), 99.30 (C-3),
117.44 (C-4a), 121.07 (C-5), 125.25 (C-6), 128.73 (C-8), 134.74 (C-7),
149.12 (C-8a), 149.84 (C-4), 152.11 (C-2) ppm; HRMS (EI+) calcd for
C17H24ClN3: 305.1659; found: 305.1671.
N-[2-(Azepan-1-yl)ethyl]-7-chloroquinolin-4-amine (7).
Method A: The reaction of 7-chloro-N-(2-chloroethyl)quinolin-4-amine 3
(0.300 g, 1.24 mmol), triethylamine (0.13 g, 1.24 mmol) and azepane
(0.600 g, 6.4 mmol) in 1 mL DMF yielded compound 7 (0.244 g, 65%).
IR (KBr):
= 3064, 2926, 1610, 1580, 1550, 1453, 1429, 1365, 1333,
1278, 1200, 1161, 1145, 1081, 1031, 912, 873, 805 cm-1; 1H NMR (CDCl3,
400 MHz): δ = 1.60-1.74 (m, 8H, 3´´-H, 4´´-H, 5´´-H, 6´´-H), 2.68-2.75
(m, 4H, 2´´-H, 7´´-H), 2.91 (t, J = 5.8 Hz, 2H, 2´-H), 3.22-3.28 (m, 2H, 1´-
18

H), 6.32 (br s, 1H, NH), 6.36 (d, J = 5.3 Hz, 1H, 3-H), 7.38 (dd, J = 9.0, 2.0
Hz, 1H, 6-H), 7.72 (d, J = 9.0 Hz, 1H, 5-H), 7.95 (d, J = 2.0 Hz, 1H, 8-H),
8.52 (d, J = 5.3 Hz, 1H, 2-H) ppm; 13C NMR (CDCl3, 100 MHz): δ = 26.96
(C-4´´, C-5´´), 28.47 (C-3´´, C-6´´), 39.71 (C-1´), 54.90 (C-2´´, C-7´´),
55.32 (C-2´), 99.23 (C-3), 117.38 (C-4a), 121.21 (C-5), 125.28 (C-6),
128.55 (C-8), 134.79 (C-7), 148.94 (C-8a), 149.88 (C-4), 151.93 (C-2)
ppm; HRMS (EI+) calcd for C17H22ClN3: 303.1502; found: 303.1518.
7-Chloro-N-[3-(4-methylpiperazin-1-yl)propyl]quinolin-4-amine (8).
Method B: The reaction of 7-chloro-N-(3-chloropropyl)quinolin-4-amine 4
(0.300 g, 1.24 mmol), KI and N-methylpiperazine (1.20 g, 11.8 mmol)
yielded after 96 h compound 8 (0.335 g, 85%). The structure was clarified
by one- and two-dimensional NMR spectroscopy. The published NMR-
data [16] are incorrect. IR (KBr):
= 3041, 2938, 2788, 1611, 1584,
1537, 1447, 1369, 1331, 1284, 1239, 1155, 1097, 1081, 1013, 987, 895,
1
834, 798, 760 cm-1; H NMR (CDCl3, 400 MHz): δ = 1.95 (quin, J = 5.3
Hz, 2H, 2´-H), 2.40 (s, 3H, NCH3), 2.48-2.75 (m, 10H, 2´´-H, 3´-H, 3´´-H,
5´´-H, 6´´-H), 3.35-3.40 (m, 2H, 1´-H), 6.32 (d, J = 5.4 Hz, 1H, 3-H), 7.33
(dd, J = 9.0, 2.0 Hz, 1H, 6-H), 7.59 (br s, 1H, NH), 7.89 (d, J = 9.0 Hz, 1H,
5-H), 7.94 (d, J = 2.0 Hz, 1H, 8-H), 8.51 (d, J = 5.4 Hz, 1H, 2-H) ppm; 13C
NMR (CDCl3, 100 MHz): δ = 23.32 (C-2´), 44.48 (C-1´), 46.33 (NCH3),
19

53.55 (C-2´´, C-6´´), 55.24 (C-3´´, C-5´´), 58.77 (C-3´), 98.45 (C-3),
117.46 (C-4a), 122.45 (C-5), 124.56 (C-6), 128.65 (C-8), 134.57 (C-7),
149.13 (C-8a), 150.53 (C-4), 152.23 (C-2) ppm; HRMS (EI+) calcd for
C17H23ClN4: 318.1611; found: 318.1617.
N-[3-(Azepan-1-yl)propyl]-7-chloroquinolin-4-amine (9).
Method A: The reaction of 7-chloro-N-(3-chloropropyl)quinolin-4-amine 4
(0.400 g, 1.60 mmol), triethylamine (0.16 g, 1.6 mmol) and azepane (1.6 g,
16.0 mmol) in 1 mL DMF yielded compound 9 (0.431 g, 85%). IR (KBr):
= 3065, 2961, 2933, 2787, 1610, 1580, 1549, 1452, 1365, 1334, 1283,
1
1250, 1166, 1150, 1082, 1017, 876, 838, 803 cm-1; H NMR (CDCl3, 400
MHz): δ = 1.66-1.78 (m, 8H, 3´´-H, 4´´-H, 5´´-H, 6´´-H), 1.87-1.94 (m, 2H,
2´-H), 2.72 (t, J = 5.3 Hz, 2H, 3´-H), 2.72-2.77 (m, 4H, 2´´-H, 7´´-H), 3.36-
3.41 (m, 2H, 1´-H), 6.31 (d, J = 5.4 Hz, 1H, 3-H), 7.33 (dd, J = 9.0, 1.9 Hz,
1H, 6-H), 7.75 (d, J = 9.0 Hz, 1H, 5-H), 7.81 (br s, 1H, NH), 7.93 (d, J =
13
1.9 Hz, 1H, 8-H), 8.50 (d, J = 5.4 Hz, 1H, 2-H) ppm; C NMR (CDCl3,
100 MHz): δ = 24.44 (C-2´), 26.96 (C-4´´, C-5´´), 27.31 (C-3´´, C-6´´),
44.63 (C-1´), 56.04 (C-2´´, C-7´´), 57.85 (C-3´), 98.34 (C-3), 117.58 (C-
4a), 122.07 (C-5), 124.60 (C-6), 128.52 (C-8), 134.54 (C-7), 149.12 (C-8a),
150.66 (C-4), 152.14 (C-2) ppm; HRMS (EI+) calcd for C18H24ClN3:
317.1659; found: 317.1663.
20

General procedure for the synthesis of N-[2-(7-chloroquinolin-4-
ylamino)ethyl]-2-(dialkylamino)acetamides (11-15) and N-[4-(7-
chloroquinolin-4-yl)piperazin-1-yl]-2-(dialkylamino)acetamides
19)
(18,
N-(2-Aminoethyl)-7-chloroquinolin-4-amine 10, respectively 7-chloro-4-
(piperazin-1-yl)quinoline 17, and N,N-diisopropylethylamine (DIPEA) or
triethylamine were suspended in dry dichloromethane and cooled on an ice
bath in an atmosphere of argon. Chloroacetyl chloride was diluted with dry
dichloromethane and added dropwise. Then the ice bath was removed and
the mixture was stirred for 1 hour at room temperature. Afterwards the
corresponding secondary amine was slowly added dropwise and the
reaction mixture was stirred for another 70-160 hours at room temperature.
The mixture was coevaporated with benzene or toluene. The residue was
taken up in dichloromethane, washed with water, dried over anhydrous
sodium sulfate and the solvent was evaporated in vacuo. The crude product
was purified by crystallization or by column chromatography using silica
gel as stationary phase to yield compounds 11-15, 18, 19.
N-[2-(7-Chloroquinolin-4-ylamino)ethyl]-2-(4-methylpiperazin-1-
yl)acetamide (11).
21

Compound 10 (0.920 g, 4.15 mmol) and DIPEA (1.35 g, 10.5 mmol) were
reacted with chloroacetyl chloride (0.600 g, 5.31 mmol) in 10 mL of dry
dichloromethane. After addition of N-methylpiperazine (4.20 g, 42.0
mmol) the reaction mixture was stirred for 90 hours. Subsequent workup
and crystallization from acetone at -18°C yielded compound 11 (0.520 g,
35%) as a white solid. M.p. (decomp.): 187°C; IR (KBr):
= 2938, 2814,
1643, 1610, 1576, 1520, 1451, 1427, 1369, 1338, 1282, 1213, 1169, 1141,
1
1076, 1012, 896, 873, 830, 770 cm-1; H NMR (CD3OD, 400 MHz): δ =
2.24 (s, 3H, NCH3), 2.34-2.52 (m, 8H, 2´´´-H, 3´´´-H, 5´´´-H, 6´´´-H), 3.01
(s, 2H, 2´´-H), 3.51-3.56 (m, 2H, 1´-H), 3.57-3.63 (m, 2H, 2´-H), 6.64 (d, J
= 5.7 Hz, 1H, 3-H), 7.44 (dd, J = 8.9, 1.9 Hz, 1H, 6-H), 7.79 (d, J = 1.9 Hz,
1H, 8-H), 8.05 (d, J = 8.9 Hz, 1H, 5-H), 8.37 (d, J = 5.7 Hz, 1H, 2-H) ppm;
13C NMR (CD3OD, 100 MHz): δ = 39.07 (C-2´), 44.04 (C-1´), 45.97
(NCH3), 53.87 (C-2´´´, C-6´´´), 55.78 (C-3´´´, C-5´´´), 62.21 (C-2´´), 99.82
(C-3), 118.76 (C-4a), 124.44 (C-5), 126.50 (C-6), 127.47 (C-8), 136.86 (C-
7), 149.35 (C-8a), 152.25 (C-2), 153.19 (C-4), 173.89 (C-1´´) ppm; HRMS
(EI+) calcd for C18H24ClN5O: 361.1669; found: 361.1683.
N-[2-(7-Chloroquinolin-4-ylamino)ethyl]-2-piperidinoacetamide (12).
Compound 10 (0.450 g, 2.03 mmol) and DIPEA (0.630 g, 4.87 mmol) were
reacted with chloroacetyl chloride (0.340 g, 3.01 mmol) in 10 mL of dry
22

dichloromethane. After addition of piperidine (1.75 g, 20.6 mmol) the
reaction mixture was stirred for 85 hours. Subsequent workup and
crystallization from acetone at -18°C yielded compound 12 (0.270 g, 38%)
as a white solid. M.p. (decomp.): 205°C; IR (KBr): = 2935, 2856, 2789,
1647, 1611, 1580, 1521, 1452, 1429, 1369, 1336, 1305, 1282, 1215, 1163,
1141, 897, 874, 850, 810, 768 cm-1; 1H NMR (CDCl3, 400 MHz): δ = 1.38-
1.48 (m, 2H, 4´´´-H), 1.51-1.59 (m, 4H, 3´´´-H, 5´´´-H), 2.39-2.47 (m, 4H,
2´´´-H, 6´´´-H), 3.01 (s, 2H, 2´´-H), 3.37-3.43 (m, 2H, 1´-H), 3.71-3.77 (m,
2H, 2´-H), 6.28 (d, J = 5.2 Hz, 1H, 3-H), 6.84 (br s, 1H, NH), 7.38 (dd, J =
8.9, 2.2 Hz, 1H, 6-H), 7.80 (d, J = 8.9 Hz, 1H, 5-H), 7.84 (br s, 1H, NH),
7.92 (d, J = 2.2 Hz, 1H, 8-H), 8.50 (d, J = 5.2 Hz, 1H, 2-H) ppm; 13C NMR
(CDCl3, 100 MHz): δ = 23.54 (C-4´´´), 26.13 (C-3´´´, C-5´´´), 38.47 (C-2´),
46.04 (C-1´), 54.99 (C-2´´´, C-6´´´), 62.06 (C-2´´), 98.05 (C-3), 117.24 (C-
4a), 122.06 (C-5), 125.47 (C-6), 128.35 (C-8), 134.86 (C-7), 148.98 (C-8a),
150.13 (C-4), 151.85 (C-2), 174.15 (C-1´´) ppm; HRMS (EI+) calcd for
C18H23ClN4O: 346.1560; found: 346.1570.
N-[2-(7-Chloroquinolin-4-ylamino)ethyl]-2-(dipropylamino)acetamide
(13).
Compound 10 (1.09 g, 4.9 mmol) and triethylamine (1.04 g, 10.3 mmol)
were reacted with chloroacetyl chloride (0.634 g, 5.61 mmol) in 15 mL of
23

dry dichloromethane. After addition of dipropylamine (5.13 g, 50.7 mmol)
the reaction mixture was stirred for 70 hours. Subsequent workup and
crystallization from acetone at -18°C yielded compound 13 (0.530 g, 30%)
as a white solid. M.p.: 149°C; IR (KBr):
= 2961, 2873, 2808, 1650,
1610, 1579, 1519, 1451, 1427, 1370, 1337, 1306, 1248, 1215, 1140, 1078,
897, 877, 848, 813, 771 cm-1; 1H NMR (CDCl3, 400 MHz): δ = 0.82 (t, J =
7.3 Hz, 6H, 3´´´-H), 1.40 (sex, J = 7.3 Hz, 4H, 2´´´-H), 2.40 (t, J = 7.3 Hz,
4H, 1´´´-H), 3.09 (s, 2H, 2´´-H), 3.36-3.41 (m, 2H, 1´-H), 3.71-3.76 (m,
2H, 2´-H), 6.28 (d, J = 5.2 Hz, 1H, 3-H), 6.77 (br s, 1H, NH-Ar), 7.38 (dd,
J = 9.0, 2.0 Hz, 1H, 6-H), 7.80 (d, J = 9.0 Hz, 1H, 5-H), 7.90-7.94 (m, 2H,
13
8H, NH-CO), 8.50 (d, J = 5.2 Hz, 1H, 2-H) ppm; C NMR (CDCl3, 100
MHz): δ = 11.73 (C-3´´´), 20.38 (C-2´´´), 38.41 (C-2´), 46.04 (C-1´), 57.39
(C-1´´´), 58.52 (C-2´´), 98.05 (C-3), 117.24 (C-4a), 122.01 (C-5), 125.43
(C-6), 128.44 (C-8), 134.79 (C-7), 149.09 (C-8a), 150.06 (C-4), 151.97 (C-
2), 175.36 (C-1´´) ppm; HRMS (EI+) calcd for C19H27ClN4O: 362.1873;
found: 362.1889.
N-[2-(7-Chloroquinolin-4-ylamino)ethyl]-2-(azepan-1-yl)acetamide
(14).
Compound 10 (0.419 g, 1.89 mmol) and DIPEA (0.562 g, 4.35 mmol) were
reacted with chloroacetyl chloride (0.272 g, 2.41 mmol) in 10 mL of dry
24

dichloromethane. After addition of azepane (1.88 g, 18.9 mmol) the
reaction mixture was stirred for 72 hours. Subsequent workup and
crystallization
from
acetone
at
-18°C
yielded
compound 14 (0.300 g, 38%) as a white solid. M.p. (decomp.): 188°C; IR
(KBr):
= 2922, 2852, 1654, 1610, 1580, 1522, 1450, 1427, 1369, 1335,
1
1305, 1215, 1140, 1077, 876, 848, 812, 768 cm-1; H NMR (CDCl3, 400
MHz): δ =1.59 (br s, 8H, 3´´´-H, 4´´´-H, 5´´´-H, 6´´´-H), 2.62-2.68 (m, 4H,
2´´´-H, 7´´´-H), 3.19 (s, 2H, 2´´-H), 3.38-3.78 (m, 2H, 1´-H), 3.72-3.78 (m,
2H, 2´-H), 6.28 (d, J = 5.4 Hz, 1H, 3-H), 6.89 (br s, 1H, NH), 7.38 (dd, J =
9.0, 2.0 Hz, 1H, 6-H), 7.81 (d, J = 9.0 Hz, 1H, 5-H), 7.91 (br s, 1H, NH),
7.93 (d, J = 2.0 Hz, 1H, 8-H), 8.49 (d, J = 5.4 Hz, 1H, 2-H) ppm; 13C NMR
(CDCl3, 100 MHz): δ = 26.75 (C-4´´´, C-5´´´), 28.26 (C-3´´´, C-6´´´),
38.46 (C-2´), 46.06 (C-1´), 56.53 (C-2´´´, C-7´´´), 61.47 (C-2´´), 98.04 (C-
3), 117.19 (C-4a), 122.11 (C-5), 125.49 (C-6), 128.18 (C-8), 134.92 (C-7),
148.78 (C-8a), 150.22 (C-4), 151.67 (C-2), 174.72 (C-1´´) ppm; HRMS
(EI+) calcd for C19H25ClN4O: 360.1717; found: 360.1731.
N-[2-(7-Chloroquinolin-4-ylamino)ethyl]-2-pyrrolidinoacetamide (15).
Compound 10 (0.855 g, 3.86 mmol) and DIPEA (1.18 g, 9.2 mmol) were
reacted with chloroacetyl chloride (0.566 g, 5.01 mmol) in 10 mL of dry
dichloromethane. After addition of pyrrolidine (2.79 g, 38.7 mmol) the
25

reaction mixture was stirred for 85 hours. Subsequent workup and
crystallization from acetone at -18°C yielded compound 15 (0.300 g, 38%)
as a white solid. M.p. (decomp.): 195°C; IR (KBr): = 2960, 2795, 2360,
1
1655, 1611, 1579, 1525, 1427, 1370, 1217, 1140, 876, 849 cm-1; H NMR
(CDCl3, 400 MHz): δ =1.76-1.81 (m, 4H, 3´´´-H, 4´´´-H), 2.57-2.61 (m,
4H, 2´´´-H, 5´´´-H), 3.22 (s, 2H, 2´´-H), 3.37-3.41 (m, 2H, 1´-H), 3.72-3.76
(m, 2H, 2´-H), 6.28 (d, J = 5.4 Hz, 1H, 3-H), 6.80-6.84 (br, 1H, NH-Ar),
7.37 (dd, J = 9.1, 2.1 Hz, 1H, 6-H), 7.11-7.17 (br, 1H, NHCO), 7.80 (d, J =
9.1 Hz, 1H, 5-H), 7.92 (d, J = 2.1 Hz, 1H, 8-H), 8.49 (d, J = 5.4 Hz, 1H, 2-
13
H) ppm; C NMR (CDCl3, 100 MHz): δ = 23.97 (C-3´´´, C-4´´´), 38.46
(C-2´), 46.00 (C-1´), 54.62 (C-2´´´, C-5´´´), 58.99 (C-2´´), 98.08 (C-3),
117.28 (C-4a), 122.08 (C-5), 125.45 (C-6), 128.38 (C-8), 134.84 (C-7),
149.06 (C-8a), 150.13 (C-4), 151.90 (C-2), 174.28 (C-1´´) ppm; HRMS
(EI+) calcd for C17H21ClN4O: 332.1404; found: 332.1414.
N-[4-(7-Chloroquinolin-4-yl)piperazin-1-yl]-2-(4-methylpiperazin-1-yl)
acetamide (18).
Compound 17 (0.499 g, 2.01 mmol) and DIPEA (0.650 g, 5.03 mmol) were
reacted with chloroacetyl chloride (0.309 g, 2.74 mmol) in 10 mL of dry
dichloromethane. After addition of N-methylpiperazine (1.65 g, 20.5
mmol) the reaction mixture was stirred for 160 hours. Subsequent workup
26

and
purification
by
column
chromatography
(silica,
dichloromethane+methanol=29+1) yielded compound 18 (0.180 g, 23%) as
a colorless oil. IR (KBr):
= 2924, 1642, 1423, 1379, 1281, 1012, 867
1
cm-1; H NMR (CDCl3, 400 MHz): δ = 2.29 (s, 3H, NCH3), 2.37-2.50 (m,
4H, 2´´´-H, 6´´´-H), 2.50-2.61 (m, 4H, 3´´´-H, 5´´´-H), 3.15-3.25 (m, 4H,
2´-H, 6´-H), 3.26 (s, 2H, 2´´-H), 3.88-3.95 (m, 4H, 3´-H, 5´-H), 6.85 (d, J =
5.0 Hz, 1H, 3-H), 7.47 (dd, J = 9.0, 2.0 Hz, 1H, 6-H), 7.96 (d, J = 9.0 Hz,
1H, 5-H), 8.07 (d, J = 2.0 Hz, 1H, 8-H), 8.76 (d, J = 5.0 Hz, 1H, 2-H) ppm;
13C NMR (CDCl3, 100 MHz): δ = 41.72 (C-5´), 45.69 (C-3´), 46.01
(NCH3), 52.11 (C-2´), 52.83 (C-6´), 53.10 (C-3´´´, C-5´´´), 55.08 (C-2´´´,
C-6´´´), 61.65 (C-2´´), 109.27 (C-3), 121.85 (C-4a), 124.79 (C-5), 126.56
(C-6), 129.11 (C-8), 135.15 (C-7), 150.23 (C-8a), 151.97 (C-2), 156.47 (C-
4), 168.30 (C-1´´) ppm; HRMS (EI+) calcd for C20H26ClN5O: 387.1826;
found: 387.1831.
N-[4-(7-Chloroquinolin-4-yl)piperazin-1-yl]-2-(dipropylamino)
acetamide (19).
Compound 17 (0.497 g, 2.01 mmol) and DIPEA (0.668 g, 5.17 mmol) were
reacted with chloroacetyl chloride (0.290 g, 2.57 mmol) in 10 mL of dry
dichloromethane. After addition of dipropylamine (2.11 g, 20.8 mmol) the
reaction mixture was stirred for 108 hours. Subsequent workup and
27

purification
dichloromethane+methanol=29+1 and then 19+1) yielded compound 19
(0.240 g, 31%) as a colorless oil. IR (KBr): = 2926, 1647, 1577, 1422,
by
column
chromatography
(silica,
1380, 1229, 1014, 868, 824 cm-1; 1H NMR (CDCl3, 400 MHz): δ = 0.90 (t,
J = 7.3 Hz, 6H, 3´´´-H), 1.49 (sex, J = 7.3 Hz, 4H, 2´´´-H), 2.46 (t, J = 7.3
Hz, 4H, 1´´´-H), 3.16-3.23 (m, 4H, 2´-H, 6´-H), 3.33 (s, 2H, 2´´-H), 3.86-
3.91 (m, 2H, 5´-H), 3.95-4.00 (m, 2H, 3´-H), 6.84 (d, J = 5.1 Hz, 1H, 3-H),
7.46 (dd, J = 8.9 Hz, 2.0 Hz, 1H, 6-H), 7.96 (d, J = 8.9 Hz, 1H, 5-H), 8.06
13
(d, J = 2.0 Hz, 1H, 8-H), 8.74 (d, J = 5.1 Hz, 1H, 2-H) ppm; C NMR
(CDCl3, 100 MHz): δ = 11.94 (C-3´´´), 19.92 (C-2´´´), 41.66, 45.42 (C-3´,
C-5´), 52.09, 52.59 (C-2´, C-6´), 56.32 (C-1´´´), 58.97 (C-2´´), 109.21 (C-
3), 121.83 (C-4a), 124.81 (C-5), 126.51 (C-6), 129.02 (C-8), 135.08 (C-7),
150.16 (C-8a), 151.93 (C-2), 156.51 (C-4), 169.89 (C-1´´) ppm; HRMS
(EI+) calcd for C21H29ClN4O: 388.2030; found: 388.2027.
N-(2-{[2-(Azepan-1-yl)ethyl]amino}ethyl)-7-chloroquinolin-4-ylamine
(16).
The reaction of compound 14 (0.720 g, 2.00 mmol) with 5.0 mL borane-
dimethyl sulfide complex (borane-DMS-complex 2 M in THF; 10.0 mmol)
in 30 mL of dry tetrahydrofuran (THF) was carried out in the reported way
28

[12]. The workup gave a yellow resin which was taken up in water,
acidified with conc. HCl and extracted with 150 mL tert-butylmethyl ether
(MTBE). The aqueous phase was alkalized with 2 N NaOH and extracted
with 250 mL MTBE. The combined organic phases were washed with
water, dried over anhydrous sodium sulfate, filtered and the solvent was
evaporated in vacuo. Crystallization from a minimum amount of hot
acetone yielded compound 16 (0.385 g, 56%) as colorless crystals. M.p.:
88°C; IR (KBr):
= 2923, 2830, 1580, 1543, 1423, 1355, 1325, 1280,
1206, 1144, 1117, 1073, 1004, 967, 877, 837, 800, 764, 636 cm-1; 1H NMR
(CDCl3, 400 MHz): δ = 1.50-1.62 (m, 8H, 3´´´-H, 4´´´-H, 5´´´-H, 6´´´-H),
2.57-2.64 (m, 6H, 2´´-H, 2´´´-H, 7´´´-H), 2.68 (t, J = 5.5 Hz, 2H, 1´´-H),
3.01 (t, J = 5.4 Hz, 2H, 2´-H), 3.33 (q, J = 5.4 Hz, 2H, 1´-H), 6.05 (br t, J =
5.0 Hz, 1H, NH), 6.38 (d, J = 5.4 Hz, 1H, 3-H), 7.32 (dd, J = 9.0, 2.1 Hz,
1H, 6-H), 7.73 (d, J = 9.0 Hz, 1H, 5-H), 7.93 (d, J = 2.1 Hz, 1H, 8-H), 8.51
(d, J = 5.4 Hz, 1H, 2-H) ppm; 13C NMR (CDCl3, 100 MHz): δ = 26.91 (C-
4´´´, C-5´´´), 28.21 (C-3´´´, C-6´´´), 41.91 (C-1´), 46.83 (C-1´´), 47.43 (C-
2´), 55.33 (C-2´´´, C-7´´´), 56.91 (C-2´´), 99.05 (C-3), 117.33 (C-4a),
121.39 (C-5), 124.94 (C-6), 128.51 (C-8), 134.57 (C-7), 149.06 (C-8a),
149.84 (C-4), 151.96 (C-2) ppm; HRMS (EI+) calcd for C19H27ClN4:
345.1846; found: 345.1817.
7-Chloro-4-[4-(2-chloroethyl)piperazin-1-yl]quinoline (20).
29