Synthesis, structure, and cholinergic effect of novel neuroprotective compounds bearing the tacrine pharmacophore

Article abstract of DOI:10.3987/COM-08-S(N)83

Novel tacrine congeners with side ligands suitable for optimal interaction with the peripheral and catalytic sites of acetyl- and butyrylcholinesterase (AChE and BuChE) have been synthesized using either 9-isothiocyanato-1,2,3,4-tetrahyhroacridine or 9-chloro-1,2,3,4-tetrahydroacridine which represent convenient synthons by reaction with various substituted amines. The synthesized compounds were tested for their inhibition of AChE and BuChE whereby a morpholine and a furfuryl derivative were found to be the most potent AChE and BuChE inhibitors, respectively, with the latter compound comparable in activity to tacrine.

Full text of DOI:10.3987/COM-08-S(N)83

HETEROCYCLES, Vol. 76, No. 2, 2008
1219
HETEROCYCLES, Vol. 76, No. 2, 2008, pp. 1219 - 1235. © The Japan Institute of Heterocyclic Chemistry
Received, 31st March, 2008, Accepted, 28th May, 2008, Published online, 2nd June, 2008. COM-08-S(N)83
SYNTHESIS, STRUCTURE, AND CHOLINERGIC EFFECT OF NOVEL
NEUROPROTECTIVE COMPOUNDS BEARING THE TACRINE
PHARMACOPHORE†
Slávka Hamuľaková,1 Pavol Kristian,1,* Daniel Jun,2 Kamil Kuča,2 Ján Imrich,1
Ivan Danihel,1 Stanislav Böhm,3 and Karel D. Klika4
1
Institute of Chemistry, Faculty of Science, P. J. Šafárik University, SK-041 67
2
Košice, Slovak Republic. Email: pavol.kristian@upjs.sk Center for Advanced
Studies and Department of Toxicology, Faculty of Military Health Sciences,
3
University of Defense, CZ-500 01 Hradec Králové, Czech Republic Department
of Organic Chemistry, Institute of Chemical Technology, CZ-166 28 Prague, Czech
4
Republic Department of Chemistry, University of Turku, FIN-20014 Turku,
Finland
Abstract – Novel tacrine congeners with side ligands suitable for optimal
interaction with the peripheral and catalytic sites of acetyl- and
butyrylcholinesterase (AChE and BuChE) have been synthesized using either
9-isothiocyanato-1,2,3,4-tetrahyhroacridine or 9-chloro-1,2,3,4-tetrahydroacridi-
ne which represent convenient synthons by reaction with various substituted
amines. The synthesized compounds were tested for their inhibition of AChE and
BuChE whereby a morpholine and a furfuryl derivative were found to be the
most potent AChE and BuChE inhibitors, respectively, with the latter compound
comparable in activity to tacrine.
INTRODUCTION
For the therapeutic treatment of Alzheimer’s disease, two main strategies are currently being pursued.
The first strategy tackles the formation of extracellular β-amyloid protein senile plaques and
neurofibrillary tangles of hyperphosphorylated τ-protein1 whilst the second intensively studied clinical
† Dedicated to Professor Dr. Ryoji Noyori on the occasion of his 70th birthday.

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HETEROCYCLES, Vol. 76, No. 2, 2008
method focuses on acetylcholinesterase (AChE) inhibition.2 The first AChE inhibitor drug approved for
the treatment of Alzheimer’s disease was 9-amino-1,2,3,4-tetrahydroacridine (tacrine, Cognex®), though
it exhibits severe side effects, e.g. hepatotoxicity and gastrointestinal antagonism, which represent
important disadvantages.3 Various tacrine derivatives such as hydroxy4 and halogenated5 derivatives, bis6
and hetero/homodimers,7 and tetracyclic tacrines,8 amongst others,9 have been synthesized in an effort to
mitigate the side effects concomitant with increasing efficiency. In previous work we reported the
synthesis of a novel AChE inhibitor, viz. 2-[(1,2,3,4-tetrahodroacridin-9-yl)imino]-3-substituted
1,3-thiazolidin-4-ones, using 9-isothiocyanato-1,2,3,4,-tetrahydroacridine (1) as synthon.10 Some of those
synthesized compounds, e.g. the 3-cyclohexyl derivative, exhibited 100-fold higher affinity towards
AChE in comparison to butyrylcholinesterase (BuChE).11 Since BuChE too inactivates the
neurotransmitter acetylcholine, this enzyme is also a suitable therapeutic target for Alzheimer’s disease,
which is characterized by a cholinergic deficit. Selective and reversible inhibition of brain BuChE may
thus represent a treatment by improving cognition and modulating neuropathological markers.12,13
In this work, we focus on constructing novel tacrine derivatives possessing structural requirements for
optimal binding to the AChE peripheral site wherein the aim was to synthesize new multipotent
compounds that can exhibit greater pharmacological properties leading to a synergic and effective
treatment of Alzheimer’s disease. For this purpose, we derivatized the pharmacophore tacrine structure
with suitable substituents which are able interact with the target sites of AChE, such as the anionic,
esterific, and hydrophobic centers. For the synthesis, two synthons, 9-isothiocyanato-1,2,3,4-
tetrahydroacridine (1) and 9-chloro-1,2,3,4-tetrahydroacridine (2) were utilized, with various substituted
amines as the side ligands {1-(2-aminoethyl)piperazine (3a), 4-(2-aminoethyl)morpholine,
4-methoxyaniline, N,N-dimethylethylamine, and furfurylamine}.
RESULTS AND DISCUSSION
Synthesis
Synthon 9-isothiocyanato-1,2,3,4-tetrahydroacridine (1, Scheme 1) was used to prepare four derivatives,
8a−d, using the amines 1-(2-aminoethyl)piperazine (for 8a), 4-(2-aminoethyl)morpholine (for 8b),
4-methoxyaniline (for 8c), and N,N-dimethylethylamine (for 8d). Because of the presence of both primary
and secondary amino groups in 1-(2-aminoethyl)piperazine (3a), the preparation of derivative 8a required
selective protection of the primary and secondary amino groups in 1-(2-aminoethyl)piperazine (3a)
according to literature methods14,15 prior to reaction of the amine with 1. Thus, 3a was first treated with
ethyl trifluoroacetate to selectively protect the NH2 group followed by treatment with di-tert-butyl
dicarbonate [(Boc)2O] to protect the NH group to yield piperazine 4a. Removal of the trifluoroacetyl
grouping under basic conditions then yielded 5a which was subsequently reacted with synthon 1 to yield

HETEROCYCLES, Vol. 76, No. 2, 2008
1221
thiourea 6a. Removal of the Boc group under acidic conditions yielded the hydrochloride 7a. To alleviate
the inherent lipophilicity and improve the aqueous solubility of the synthesized derivatives, as an example,
the hydrochloride 7a was also examined after isolation from the reaction mixture. Treatment of 7a with
NH4OH then yielded the desired product 8a.
By contrast, derivatives 8b−d were formed directly from the reaction of 1 with the appropriate amines.
The oxo analog of 8b was also afforded by the exchange reaction with mesitylnitrile oxide (MNO) to
1
yield 9b. Characterization of all of the synthesized compounds was afforded by H and 13C NMR
spectroscopy (vide infra) and elemental analysis for which acceptable results were obtained for all
compounds.
H
CF3
N
NH2
NH2
i
ii
iii
Boc
N
Boc
HN
N
N
N
N
O
4a
5a
3a
S
2´
3´
1´
HN
N
H
R
NCS
8
1
9
8a
9a
CH2Cl2
2
RNH2
CHCl3
7
H
H
N
+
N
N
5a
Boc
N
N
3
6
4a
N
10a
N
4
5
S
1
6a
8b-8d
MNO
O
iv
N
N
v
HN
N
N
R
H
HN
S
HN
H
H
N
N
2´´
S
8´´
1´´
7´´
N 3´´
4´´
N
. 3HCl
9b
HN
6´´
HN
5´´
8a
7a
2´´ 3´´
4´´
8´´
5´´
2´´
1´´
4´´
1´´
N
3´´
6´´
N
3´´
O
OMe
1´´
2´´
7´´
6´´ 5´´
R: 8b, 9b
R: 8c
R: 8d
Reagents/conditions: (i) CF3CO2Et, THF < 10 °C; (ii) (Boc)2O, THF < 10 °C; (iii) NaOH, 36 h, 35 °C;
(iv) AcOH⁄HCl; (v) NH4OH.
Scheme 1

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HETEROCYCLES, Vol. 76, No. 2, 2008
Synthon 9-chloro-1,2,3,4-tetrahydroacridine (2, Scheme 2) was used to prepare three derivatives, 10a−c,
using the amines, 1-(2-aminoethyl)piperazine (for 10a), 4-furfurylamine (for 10b), and
4-(2-aminoethyl)morpholine (for 10c). The same protective strategy was also required for 3a prior to its
reaction with 2. Thus, 5a was also used for the reaction with 2 to yield 12, which after removal of the Boc
group under acidic conditions yielded the hydrochloride 13, which was also isolated for comparative
reasons relating to solubility limitations. Treatment of 13 with NH4OH then yielded the desired product
10a. Derivatives 10b,c were formed directly from the reaction of 2 with 4-furfurylamine and
4-(2-aminoethyl)morpholine, respectively, in phenol.16 For the same considerations regarding solubility
restrictions, the hydrochloride of 10b was deliberately prepared by treatment of 10b with HCl in
methanol to yield 11b.
HN
R
Cl
RNH2
H
phenol
N
5a
N
+
phenol
Boc
N
N
N
N
2
12
10b,10c
i
ii
HN
R
5´
4´
H
N
11
H
iii
2´
N
N
N
6´
HN
. 3 HCl
N
N
N
HN
1´
3´
.
H Cl
7´
8´
11 b
13
10a
8´
7´
1´
2´
O
N
6´
O
5´
2´
1´
3´
5´
4´
3´
4´
R: 10b, 11b
R: 10c
Reagents/conditions: (i) MeOH/HCl; (ii) AcOH/HCl; (iii) NH4OH.
Scheme 2
Biological activity
The synthesized compounds 7a, 8a−d, 9b, 10b,c, and 11b were all tested for their ability to inhibit the
activity of both AChE and BuChE and the results are presented in Table 1. For comparison, tacrine and

HETEROCYCLES, Vol. 76, No. 2, 2008
1223
9-amino-7-methoxy-1,2,3,4-tetrahydroacridine hydrochloride (7-MEOTA) were used as standards. The
most promising inhibition, i.e. the lowest IC50 value, of AChE by the compounds synthesized in this work
was exhibited by 10c, closely followed by 10b and 11b. Though compounds 10b,c, and 11b failed to
match the inhibition displayed by tacrine, which was ca. an order of magnitude more effective, they were,
in fact, more effective in inhibiting AChE than 7-MEOTA. For the inhibition of BuChE, several
compounds were comparable to tacrine, viz. 8c, 9b, 10b,c, and 11b. Though none exceeded the capability
of tacrine, the IC50 value for 10b was only ca. 50% larger than tacrine. Notably, all of the tested
compounds exhibited much higher inhibitory activity towards BuChE, the only exception was 7-MEOTA.
Indeed, all compounds were more effective inhibitors of BuChE in comparison to 7-MEOTA.
Table 1. Cholinesterase-inhibitory activitiesa of 7a, 8a−d, 9b, 10b,c, and 11b
AChE
95% CI [µM]
BuChE
95% CI [µM]
Compound
IC50 [µM]
106
IC50 [µM]
17.4
7a
8a
69.4–162
8.96–15.4
252–628
8.74–34.6
1.25–2.66
11.8
1.82
8b
398
66.7
17.9–241
8c
> 5, limited by solubility
> 50, limited by solubility
0.503
4.62
0.457–0.553
1.06–20.1
8d
9b
133
1.21
118–149
1.02–1.43
0.860–1.01
0.951–1.66
0.131–0.156
3.08–4.40
0.812
0.0204
0.164
0.0823
0.0139
131
0.421–1.57
0.0149–0.0279
0.0799–0.335
0.0758–0.0894
0.00434–0.0448
55.4−311
10b
10c
0.972
1.26
11b
tacrine
0.143
7-MEOTA
3.68
a
IC50: concentration required to elicit a 50% inhibition of the enzyme; 95% CI: the 95%
confidence interval range.
As mentioned above, the most potent inhibitor of AChE was the morpholine aminoderivative 10c, but
contrastingly, the morpholine thiourea 8b was the least active inhibitor. Moreover, the thiourea
derivatives studied here were significantly less active. For example, the replacement of sulfur by oxygen
(8b → 9b) produced a compound with a three-fold increase in AChE activity and a nearly two orders of
magnitude increase in BuChE activity. Similar increases in activity have been observed for benzisoxazole
derivatives in comparison to analogous benzthiazoles.17 The limited activity of thioureas derivatives 7a
and 8a−d may be explained by two factors: the length of the bridge between the tetrahydroacridine and
the azasubstituents, which seems to be optimal for 10c, and the charge distribution within the molecule

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HETEROCYCLES, Vol. 76, No. 2, 2008
whereby significant negative charge is present on the thiourea sulfur (vide infra).
Structure
To prove the structure of the compounds and facilitate signal assignments, sets of 1D proton and carbon
spectra and 2D correlation spectra (H,H-COSY, NOESY, gH,C-HSQC, and gH,C-HMBC) were acquired
wherein the tetrahydroacridine skeleton of the compounds was observed to exhibit typical aliphatic and
aromatic spin systems. The structure of the quinoline moiety in the tetrahydroacridine skeleton, in
particular, as well as the NMR chemical shifts is in agreement with the NMR and X-ray findings for
4-aminosubstituted quinolines.18 Of note, the three-bond H,C correlations allowed assignment of the
quaternary acridine carbons C-4a, 8a, 9, 9a, and 10a signals which are very sensitive to structural changes
or to hydrochlorination. Thioureas 6a and 8a−d displayed a typical C=S carbon resonance at 180 ppm
which was significantly shielded upon transformation to urea 9b (160 ppm) due to the S → O
transformation. A smaller electron-withdrawing effect by the NHCONH group (9b) in comparison to
NHCSNH (8b) reduces the proton and carbon chemical shifts of the C-1" segment by 0.28 and 4.6 ppm,
respectively. The chemical shift of the acridine C-9 carbon of the thioureas lies in the range 137−141 ppm,
but this is deshielded to 149−151 ppm when an amino substituent (10a−c) is introduced.
The N-10 atom of the acridinyl moiety is well known19 for a propensity to retain a proton, i.e. the HN-10
tautomer dominates (see Figure) and the presence of this tautomer is evident by the diagnostically
shielded19a,b C-5 signal in this instance (typically ca. 119 ppm). Of the compounds examined here, only
6a and the three hydrochlorides 7a, 11b, and 13 displayed shielded signals for C-5 (within the range
119−122 ppm), for the rest C-5 resonated within the range 128−129 ppm. Clearly for the protonated
H
indicates unknown preference
between s-cis/s-trans and
for the E/Z configuration
N
N
NH
?
?
?
10
R
S
compounds, N-10 is one of the sites of protonation. For the enigmatic 6a, the stereochemistry regarding
E/Z configuration about the C9=N double bond and with respect to s-cis/s-trans conformation could not
be ascertained. Thus, with the exception of 6a, 1,2,3,4-tetrahodroacridinyl systems do not possess the
same propensity to retain a proton under neutral conditions but do so upon protonation. To elucidate
structure−reactivity relationships with regard to AChE or BuChE inhibition, modeling studies of selected
compounds were conducted using DFT at the B3LYP/6-311+G(d,p) level of theory. In particular, the

HETEROCYCLES, Vol. 76, No. 2, 2008
1225
length of the connecting bridge, the introduction of additional heteroatoms, and electronic effects (e.g.
partial atomic charges) all play a significant role in altering cholinesterase inhibition, e.g. for
benzisoxazole derivatives.17 Figure 1 depicts example structures.
Figure 1. Optimized structures for the most and least active morpholine derivatives 10c and 8b,
respectively, using DFT at the B3LYP/6-311+G(d,p) level of theory.
From the structures of the compounds it follows that there are the potential for 3 (10a−c) to 6 (8a−d, 9b)
hydrogen bonds to form utilizing the tacrine moiety nitrogens, the oxygens of furfuryl or morpholine, the
nitrogen of piperazine, and the sulfur (oxygen) and nitrogens of the thiourea (urea) segments. However,
the charges on the nitrogen atoms of the tacrine moiety as determined by the quantum chemical
calculations do not correlate with the observed inhibitions. For example, in comparison to tacrine, the
most active (10c) and the least active (8b) derivatives provide the order tacrine > 10c > 8b, but the
charges on N-10 yield the order tacrine > 10c = 8b whilst for N-3', the order is tacrine > 8b > 10c (see
Tables 1−3). Similarly, the charges on the R substituent cannot be related to the AChE/BuChE inhibitory
activity. An interesting result is that a large decrease in the inhibition of the enzymes occurs if
thiourea/urea is present in the molecule, e.g. derivative 10c is about 400× more active than 8b which
sports a thiourea group. As the charge differences on the aforesaid atoms (Tables 2 and 3) are not
significant, we can suppose that the differences in inhibition are not dependent on electron distribution,
but rather on structural factors. One such factor could be prolongation of the side chain (r values are
presented in Tables 2 and 3) with another the possible conjugation of the nitrogen and sulfur/oxygen
atoms of the thiourea/urea mioety. A consequence of this could be the finding from the quantum chemical
optimizations of 8a−d and 9b that the C9-N3´-C2´-S atoms lie practically in the same plane. Beside this
in the same plane lie also the C9-N3´-C2´-N1´-C atoms (Table 2).Results for the structural parameter
values in relation to partial atomic charges, internuclei distances and dihedral angles are collected in

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HETEROCYCLES, Vol. 76, No. 2, 2008
Tables 2 and 3.
Table 2. Parameter values derived from DFT calculations of compounds 8a−d, 9b and tacrine
Atomic charge, Q
Dihedral angles o
r[Å]a
Cmpd
N-10
N-1'
C-2'
N-3'
N-3''
N-6''
S
O
O(=C)
C9N3'C2'S
N3'C2N1'C1''
-0.09
-0.08
-0.01
-0.09
-0.16
-
+0.59
+0.53
+0.60
+0.56
+0.41
-
-0.21
-0.17
-0.20
-0.26
-
+0.03
-0.09
-
-0.18
-0.83
-0.85
-0.80
-0.83
-
-
-
5.89
5.88
3.69 b
5.89
5.85
-
6.9
0.7
2.9
11.1
5.3c
-
179.0
178.9
179.3
177.8
177.1
8a
8b
8c
8d
9b
td
−0.29
−0.29
−0.31
−0.28
−0.29
−0.40
-
-
-
-
-
-0.37
-
-0.44
-
-0.05
-0.09
-
-
-
-
-
-0.38
-
-0.39
-
a Internuclei distances are between the thiourea nitrogens N-3' and X where X represents the N, O, or C atoms of the R group.
b Value is for the ipso carbon C-1". c Dihedral angle C9N3'C2'O. d t = tacrine.
Table 3. Parameter values derived from DFT calculations of compounds 10a−c
Atomic charge, Q
Cmpd
N-10
−0.30
−0.29
−0.29
N-11
−0.24
−0.20
−0.23
N-3'
N-6'
O-1'
−
O-6'
r [Å]
2.908
2.51a
2.886
−0.15
−0.22
−
10a
10b
10c
−
−0.32
−0.10
−0.27
−
−
−0.09
−0.37
a Internuclei distance for the N-11 furfuryl C-2'.
EXPERIMENTAL
Melting points were determined on a Boetius hot-stage apparatus and are uncorrected. NMR spectra were
recorded on a Varian Mercury Plus spectrometer. 1H and 13C NMR spectra were acquired at 400 and 100
MHz, respectively, in deuteriochloroform (CDCl3) or hexadeuteriodimethylsulfoxide (DMSO-d6).
Chemical shifts are given in δ relative to tetramethylsilane (= 0 ppm for both nuclei). The biological
evaluation of products was conducted in the Department of Toxicology, Hradec Králové. DFT
quantum-chemical calculation were performed using the Gaussian 03 program at the
B3LYP/6-311+G(d,p) level of theory.20,21 Atomic charges were calculated using the 6-311++G(2d,2p)
basis set.
Chemicals
Chemicals used for synthetic work were of laboratory purity grade. Human recombinant acetylcholin
esterase (AChE; EC 3.1.1.7), human plasma butyrylcholinesterase (BuChE; EC 3.1.1.8), bovine serum

HETEROCYCLES, Vol. 76, No. 2, 2008
1227
albumin
(BSA),
9-amino-1,2,3,4-tetrahydroacridine
hydrochloride
hydrate
(tacrine),
5,5'-dithiobis-2-nitrobenzoic acid (DTNB), acetylthiocholine iodide, and butyrylthiocholine iodide were
bought from Sigma-Aldrich (Prague, Czech Republic). 9-Amino-7-methoxy-1,2,3,4-tetrahydroacridine
hydrochloride (7-MEOTA) had been synthesized previously at the Department of Toxicology, Hradec
Králové. Other chemicals were purchased from Lach-Ner (Neratovice, Czech Republic).
Cholinesterase-inhibitory activities
Cholinesterase-inhibitory activities were evaluated spectrophotometrically according to the method of
Ellman.22 Enzymes were dissolved in phosphate buffer (PB; 0.1 M, pH 7.4) containing BSA (1 g/L) and
their activity before inhibition was set to 1000 ± 50 U/L. Tested compounds were dissolved in PB or
iso-propanol with the final concentration in the mixture not exceeding 5%. The inhibition of the
cholinesterases was started in 1.5 mL plastic cuvettes by the addition of the compound solution to the
mixture of PB, DTNB, and cholinesterase. An incubation time of 5 min was followed by the enzymatic
reaction upon addition of AChE substrate acetylthiocholine or BuChE substrate butyrylthiocholine. The
final concentration of the compounds lay in the range 10−3−10−10 M and at least 12 concentrations were
employed, the final concentration of DTNB and acetyl- or butyrylthiocholine was 1 mM. Control samples
(100% enzyme activity) contained only PB or iso-propanol. The absorbance of the sample in the cuvette
was measured in triplicate at 412 nm for 1 min at 25 °C using a spectrophotometer (Helios Alfa, Thermo
Fisher Scientific, Inc., USA). IC50 values (the concentration producing 50% enzyme-activity inhibition)
were calculated by nonlinear regression analysis using GraphPad Prism software.23
4-[2-(2,2-Trifluoroacetylamino)ethyl]piperazino-1-carboxylic acid tert-butyl ester (4a). To
1-(2-aminoethyl)piperazine (1 g, 7.7 mmol) in dry THF (1 mL), ethyl trifluoroacetate (1.09 g, 7.7 mmol)
was added dropwise at 5 °C. The solution was stirred for 30 min followed by the addition of di-tert-butyl
dicarbonate [(Boc)2O] (1.68 g, 7.7 mmol) in dry THF (2 mL). Stirring was continued at rt for 24 h after
which the solvent was removed in vacuo and the residue was redissolved in EtOAc. The organic layer
was washed with saturated aqueous NaCl soln., then dried by solid Na2SO4 and evaporated to dryness in
1
vacuo. Yield 90%; mp 85−89 °C; H NMR (CDCl3) δ: 1.47 (s, 9H, 3 × CH3), 2.46 (m, 4H, CH2NCH2),
13
2.59 (m, 2H, CH2N), 3.41−3.47 (m, 6H, CH2N(CO2)CH2 + CH2NHCO), 7.15 (s, 1H, NH); C NMR
(CDCl3) δ: 28.3 (CH3)3, 36.0 (CH2NH), 43.1 (CH2N(CO2)CH2), 52.5 (CH2NCH2), 55.5 (CH2N), 79.9
1
2
(Cqt), 115.8 (q, CF3, JCF = 285.8 Hz, 154.6 (CO2), 157.1 (COCF3, JCF = 36.6 Hz). Anal. Calcd for
C13H22N3O3F3 (325.32): C, 48.00; H, 6.82; N, 12.92. Found: C, 48.11; H, 6.71; N, 13.03%.
4-(2-Aminoethyl)piperazine-1-carboxylic acid tert-butyl ester (5a). To the protected amine 4a (2.9 g, 8.9

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HETEROCYCLES, Vol. 76, No. 2, 2008
mmol) in MeOH (40 mL), 0.22 M aqueous NaOH (45 mL) was added dropwise over the course of 1 h
whilst ensuring the temperature of the reaction mixture did not exceed 15 °C. After raising the
temperature of the solution to rt, the stirring was continued for 36 h at 35 °C. The MeOH was then
removed in vacuo and the water−oil mixture obtained was extracted with CHCl3 (2 × 10 mL). The CHCl3
phases were combined, dried over Na2SO4 to which activated carbon had been added, and the mixture
stirred for 30 min. After the solvent was removed under reduced pressure, the product 5a was obtained as
a yellow oil. Yield 85%; 1H NMR (CDCl3) δ: 1.46 (s, 9H, 3 × CH3), 2.39 (t, 4H, CH2NCH2, J = 4.8 Hz),
2.43 (t, 2H, CH2N, J = 6.4 Hz), 2.80 (t, 2H, CH2NH2, J = 6.4 Hz), 3.43 (t, 4H, CH2N(CO2)CH2, J = 4.8
13
Hz); C NMR (CDCl3) δ: 28.4 (CH3)3, 38.6 (CH2NH2), 43.1 (CH2N(CO2)CH2), 53.0 (CH2NCH2), 61.1
(CH2N), 79.5 (Cquart), 154.7 (CO2).
4-{2-[3-(1,2,3,4-Tetrahydroacridin-9-yl)thioureido]ethyl}-piperazine-1-carboxylic acid tert-butyl ester
(6a). To a solution of 9-isothiocyanato-1,2,3,4-tetrahydroacridine 1 (0.41 mmol) in dry CH2Cl2 (10 mL),
protected amine 5a (0.41 mmol) was added and the reaction mixture stirred at rt for 20 h. The precipitate
that formed was collected by filtration, washed with Et2O and dried to provide a yellow solid. Yield 85%;
mp 178−180 °C; 1H NMR (CDCl3) δ: 1.44 (s, 9H, 3 × CH3), 1.82-1.97 (m, 4H, 2 × CH2, H-2, H-3), 2.43
(m, 4H, 2 × CH2, H-4", H-8"), 2.56−2.68 (m, 4H, 2 × CH2, H-1, H-2"), 3.11 (t, 2H, CH2, H-4, J = 6.0 Hz),
3.22−3.41 (m, 6H, 3 × CH2, H-5", H-7", H-1"), 7.44 (m, 1H, CH, H-7), 7.63 (ddd, 1H, CH, H-6, J = 8.4,
13
6.8, 1.2 Hz), 7.93 (dd, 1H, CH, H-8, J = 8.4, 1.2 Hz), 7.99 (d, 1H, CH, H-5, J = 8.4 Hz); C NMR
(CDCl3) δ: 21.7, 22.2 (C-2, C-3), 24.5 (C-1), 28.4 (CH3), 29.7 (C-4), 39.2 (C-1"), 43.6 (C-5", C-7"), 52.7
(C-4", C-8"), 57.5 (C-2"), 80.0 (C), 120.3 (C-8a), 122.0 (C-5), 124.2 (C-8), 125.8 (C-7), 131.4 (C-6),
132.9 (C-9a), 140.5 (C-9), 154.5, 154.5, 155.6 (C-4a, C-10a, CO2), 175.7 (C=S). Anal. Calcd for
C25H35N5O2S (469.65): C, 63.94; H, 7.51; N, 14.91. Found: C, 64.02; H, 7.62; N, 15.03%.
3'-(1,2,3,4-Tetrahydroacridin-9-yl)-1'-piperazinoethylthiourea trihydrochloride (7a). The Boc
protecting group of 6a (0.28 g, 0.25 mmol) was removed by stirring the material in acetic acid (5 mL) and
conc. HCl (0.5 mL) at rt for 1.5 h. After removing the acid in vacuo, the resulting oil was treated with a
1:1 mixture of EtOH and Et2O (1 mL) and the corresponding trihydrochloride was obtained as
yellow-brown powder. Yield 90%; mp 171−174 °C; 1H NMR (DMSO-d6) δ: 1.86, 1.92 (m, 4H, 2 × CH2,
H-2, H-3), 2.92 (m, 2H, CH2, H-1), 3.34 (m, 2 × 2H, CH2, H-2", H-4), 3.43 (m, 4H, 2 × CH2, H-5", H-7"),
3.50 (m, 4H, 2 × CH2, H-4", H-8"), 3.96 (m, 2H, CH2, H-1"), 7.84 (dd, 1H, CH, H-7, J = 8.2, 7.4 Hz),
8.03 (dd, 1H, CH, H-6, J = 8.2, 7.4 Hz), 8.17 (d, 1H, CH, H-8, J = 8.2 Hz), 8.36 (d, 1H, CH, H-5, J = 8.2
Hz), 8.85 (t, 1H, NH-1", J = 5.4 Hz), 9.93 (s, 2H, 2 × NH), 10.96 (s, 1H, NH); 13C NMR (DMSO-d6) δ:

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1229
20.2 (C-3), 20.6 (C-2), 24.4 (C-1), 28.6 (C-4), 38.6 (C-1"), 39.7 (C-5", C-7"), 48.0 (C-4", C-8"), 54.1
(C-2"), 120.0 (C-5), 124.6 (C-8a), 124.9 (C-8), 128.3 (C-7), 129.7 (C-9a), 133.1 (C-6), 137.3 (C-10a),
149.1 (C-9), 157.8 (C-4a), 181.6 (C=S). Anal. Calcd for C20H30N5SCl3 (478.92): C, 50.16; H, 6.31; N,
14.62. Found: C, 50.45; H, 6.30; N, 14.59%.
3'-(1,2,3,4-Tetrahydroacridin-9-yl)-1'-piperazinoethyl thiourea (8a). Compound 7a (0.2 g, 0.4 mmol)
was treated with 2 M NH4OH solution (13 mL) with stirring for 15 min and then extracted with CHCl3 (8
mL). The organic layer was washed with water (3 mL) and then dried over Na2SO4. Removal of the
1
solvent under reduced pressure afforded a yellow powder. Yield 95%; mp 163−166 °C; H NMR
(DMSO-d6) δ: 1.80 (m, 2H, CH2, H-2) 1.88 (m, 2H, CH2, H-3), 2.25 (m, 4H, 2 × CH2, H-4", H-8"), 2.37
(m, 2H, CH2, H-2"), 2.58 (m, 4H, 2 × CH2, H-5", H-7"), 2.82 (m, 2H, CH2, H-1), 3.04 (t, 2H, CH2, H-4, J
= 6.4 Hz), 3.51 (m, 2H, CH2, H-1"), 7.40 (s, 1H, NH), 7.50 (dd, 1H, CH, H-7, J = 8.0, 7.3 Hz), 7.65 (dd,
1H, CH, H-6, J = 8.0, 7.3 Hz), 7.76 (d, 1H, CH, H-8, J = 8.0 Hz), 7.89 (d, 1H, CH, H-5, J = 8.0 Hz); 13C
NMR (DMSO-d6) δ: 21.9 (C-2), 22.3 (C-3), 24.5 (C-1), 33.3 (C-4), 41.1 (C-1"), 45.3 (C-5", C-7"), 53.7
(C-4", C-8"), 56.7 (C-2"), 123.0 (C-8), 124.8 (C-8a), 125.6 (C-7), 128.0 (C-5), 128.5 (C-6), 128.8 (C-9a),
139.8 (C-9), 146.6 (C-10a), 159.6 (C-4a), 180.6 (C=S). Anal. Calcd for C20H27N5S (369.53): C, 65.01; H,
7.36; N, 18.95. Found: C, 65.11; H, 7.39; N, 18.85%.
General procedure for the synthesis of 3'-(1,2,3,4-tetrahydroacridin-9-yl)-1'-substituted thioureas 8b−d
To a solution of 9-isothiocyanato-1,2,3,4-tetrahydroacridine 1 (1 mmol) in CHCl3 (20 mL), the
corresponding amine (1 mmol) was added dropwise with stirring. Stirring was continued at rt until a
precipitate had been deposited. This was collected by filtration, washed with Et2O, and then dried.
3'-(1,2,3,4-Tetrahydroacridin-9-yl)-1'-morpholinoethylthiourea (8b). White powder; yield 90%; mp
167−171 °C; 1H NMR (CDCl3) δ: 1.91 (m, 2H, CH2, H-2), 2.00 (m, 2H, CH2, H-3), 2.08 (m, 4H, 2 × CH2,
H-4", H-8"), 2.33 (m, 2H, CH2, H-2"), 2.95 (m, 2H, CH2, H-1), 3.10 (m, 4H, 2 × CH2, H-5", H-7"), 3.17
(t, 2H, CH2, H-4, J = 6.4 Hz), 3.58 (dt, 2H, CH2, H-1", J = 5.4, 5.2 Hz), 6.30 (s, 1H, NH), 7.50 (dd, 1H,
CH, H-7, J = 8.4, 7.2 Hz), 7.68 (dd, 1H, CH, H-6, J = 8.8, 7.2 Hz), 7.88 (d, 1H, CH, H-8, J = 8.4 Hz),
13
8.04 (d, 1H, CH, H-5, J = 8.8 Hz); C NMR (CDCl3) δ: 22.4 (C-2), 22.7 (C-3), 25.3 (C-1), 33.9 (C-4),
41.2 (C-1"), 52.6 (C-4", C-8"), 55.7 (C-2"), 66.5 (C-5", C-7"), 122.5 (C-8), 124.0 (C-8a), 126.8 (C-7),
128.9 (C-9a), 129.1 (C-5), 129.5 (C-6), 137.6 (C-9), 147.5 (C-10a), 160.6 (C-4a), 180.2 (C=S). Anal.
Calcd for C20H26ON4S (370.51): C, 64.83; H, 7.07; N, 15.12. Found: C, 64.91; H, 7.14; N, 15.02%.
3'-(1,2,3,4-Tetrahydroacridin-9-yl)-1'-(4-methoxyphenyl)thiourea (8c). White powder; yield 80%; mp

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HETEROCYCLES, Vol. 76, No. 2, 2008
White powder; yield 80%; mp 189−190 °C; 1H NMR (DMSO-d6) δ: 1.83 (m, 2H, CH2, H-2), 1.87 (m, 2H,
CH2, H-3), 2.85, 2.91 (2 × m, 2H, CH2, H-1), 3.03 (m, 2H, CH2, H-4), 3.74 (s, 3H, OCH3), 6.91 (m, 2H, 2
× CH, H-3", H-5"), 7.31 (m, 2H, 2 × CH, H-2", H-6"), 7.52 (dd, 1H, CH, H-7, J = 8.4, 6.0 Hz), 7.65 (dd,
1H, CH, H-6, J = 8.8, 6.0 Hz), 7.83 (d, 1H, CH, H-8, J = 8.4 Hz), 7.89 (d, 1H, CH, H-5, J = 8.8 Hz), 9.50
(bs, 1H, NH) 9.63 (bs, 1H, NH); 13C NMR (DMSO-d6) δ: 21.8 (C-2), 22.3 (C-3), 24.6 (C-1), 33.3 (C-4),
55.1 (OCH3), 113.7 (C-3", C-5"), 123.2 (C-8), 124.9 (C-8a), 125.5 (C-7), 126.6 (C-2", C-6"), 128.0 (C-5),
128.4 (C-6), 128.7 (C-9a), 131.8 (C-1"), 140.8 (C-9), 146.5 (C-10a), 156.8 (C-4"), 159.4 (C-4a), 180.6
(C=S). Anal. Calcd for C21H21ON3S (363.48): C, 69.39; H, 5.82; N, 11.56. Found: C, 69.42; H, 5.90; N,
11.47%.
3'-(1,2,3,4-Tetrahydroacridin-9-yl)-1'-[2-(dimethylamino)ethyl]thiourea (8d). Yellow powder; yield
80%; mp 178−180 °C; 1H NMR (CDCl3) δ: 1.80−2.04 (m, 10H, 2 × NCH3, 2 × CH2, H-2, H-3), 2.29 (m,
2H, CH2, H-2"), 2.93 (m, 2H, CH2, H-1), 3.15 (m, 2H, CH2, H-4), 3.59 (m, 2H, CH2, H-1"), 6.46 (bs, 1H,
NH), 7.50 (m, 2H, CH2, H-7), 7.66 (m, CH2, H-6), 7.89 (d, 1H, CH, H-8, J = 7.2 Hz), 8.01 (d, 1H, CH,
13
H-5, J = 8.0 Hz), 8.20 (s, 1H, NH); C NMR (CDCl3) δ: 22.4 (C-2), 22.7 (C-3), 25.4 (C-1), 34.0 (C-4),
42.7 (C-1"), 44.7 (2 × NCH3), 56.9 (C-2"), 122.5 (C-8), 124.0 (C-8a), 126.6 (C-7), 128.7 (C-9a), 128.9
(C-5), 129.4 (C-6), 137.8 (C-9), 147.4 (C-10a), 160.5 (C-4a), 180.2 (C=S). Anal. Calcd for C18H24N4S
(328.48): C, 65.82; H, 7.36; N, 17.06. Found: C, 65.93; H, 7.36; N, 17.13%.
3'-(1,2,3,4-Tetrahydroacridin-9-yl)-1'-morpholinoethylurea (9b). To a solution of 3'-(1,2,3,4-
tetrahydroacridin-9-yl)-1'-morpholinoethylthiourea (8b) (0.45 mmol) in dry MeCN (5 mL), mesitylnitrile
oxide (0.45 mmol) was added. The mixture was allowed to stir for 6 h at rt following which the solvent
was evaporated under reduced pressure and the solid collected by filtration and dried. Yield 75%; mp
203−205 °C; 1H NMR (CDCl3) δ: 1.87 (m, 2H, CH2, H-2), 1.96 (m, 2H, CH2, H-3), 2.28 (m, 4H, 2 × CH2,
H-4", H-8"), 2.37 (m, 2H, CH2, H-2"), 2.91 (m, 2H, CH2, H-1), 3.13 (m, 2H, CH2, H-4), 3.30 (m, 2H,
CH2, H-1"), 3.38 (m, 4H, 2 × CH2, H-5", H-7"), 5.25 (bs, 1H, NH), 7.44 (dd, 2H, CH2, H-7, J = 8.4, 6.8
Hz ), 7.63 (dd, 2H, CH2, H-6, J = 8.0, 6.8 Hz ), 7.94 (d, 1H, CH, H-8, J = 8.4 Hz), 7.99 (d, 1H, CH, H-5,
J = 8.0 Hz); 13C NMR (CDCl3) δ: 22.5 (C-2), 22.7 (C-3), 25.3 (C-1), 33.9 (C-4), 36.6 (C-1"), 53.1 (C-4",
C-8"), 57.6 (C-2"), 66.6 (C-5", C-7"), 122.5 (C-8), 124.5 (C-8a), 126.0 (C-7), 127.8 (C-9a), 128.8 (C-5),
129.0 (C-6), 138.9 (C-9), 147.3 (C-10a), 156.3 (C-4a), 160.2 (C=O). Anal. Calcd for C20H26O2N4
(354.45): C, 67.77; H, 7.39; N, 15.81. Found: C, 67.96; H, 7.49; N, 15.85%.
N-(Piperazinoethyl)-N-(1,2,3,4-tetrahydroacridin-9-yl)amine (10a). Compound 13 (0.2 g, 0.48 mmol)
was treated with 2 M NH4OH solution (13 mL). The mixture was stirred for 15 min and then extracted

HETEROCYCLES, Vol. 76, No. 2, 2008
1231
with CHCl3 (8 mL). The organic layer was washed with water (3 mL), dried over Na2SO4, and the solvent
1
removed under reduced pressure. Yield 80%; oil; H NMR (CDCl3) δ: 1.86-1.96 (m, 4H, 2 × CH2, H-2,
H-3), 2.46 (m, 4H, 2 × CH2, H-4', H-8'), 2.57 (t, 2H, CH2, H-2', J = 5.2 Hz), 2.77 (t, 2H, CH2, H-1, J = 5.8
Hz), 2.93 (t, 4H, 2 × CH2, H-5', H-7', J = 4.6 Hz), 3.06 (t, 2H, CH2, H-4, J = 5.8 Hz), 3.55 (t, 2H, CH2,
H-1', J = 5.6 Hz), 5.21 (bs, 1H, NH), 7.33 (dd, 1H, CH, H-7, J = 8.4, 7.3 Hz), 7.54 (dd, 1H, CH, H-6, J =
8.0, 7.3 Hz), 7.90 (d, 1H, CH, H-5, J = 8.0 Hz), 8.02 (d, 1H, CH, H-8, J = 8.4 Hz); 13C NMR (CDCl3) δ:
22.9 (C-3), 23.2 (C-2), 25.0 (C-1), 34.0 (C-4), 45.0 (C-1'), 46.3 (C-5', C-7'), 54.0 (C-4', C-8'), 58.2 (C-2'),
116.0 (C-9a), 120.3 (C-8a), 122.8 (C-8), 123.5 (C-7), 128.2 (C-6), 128.7 (C-5), 147.4 (C-10a), 151.1
(C-9), 158.5 (C-4a). Anal. Calcd for C19H26N4 (310.44): C, 73.51; H, 8.44; N, 18.05. Found: C, 73.68; H,
8.53; N, 18.14%.
General procedure for the synthesis of N-substituted-N-(1,2,3,4-tetrahydroacridin-9-yl)amine 10b,c
To a homogeneous solution obtained from a mixture of 9-chloro-1,2,3,4-tetrahydroacridine 2 (100 mg,
0.46 mmol) in phenol (405 mg, 4.3 mmol) at 85−90 °C, the corresponding amine 3b or c (1 mmol) was
added and heating continued for 4 h at 125−130 °C. After cooling, CHCl3 (5 mL) was added and the
solution then treated with 10% aq. NaOH solution (8 mL) and water (8 mL). The organic layer was
separated and dried with CaCl2. The solvent was removed under reduced pressure and the residue purified
by flash chromatography over silica gel.
N-(Furfuryl)-N-(1,2,3,4-tetrahydroacridin-9-yl)amine (10b). Yellow crystals (cyclohexane−acetone,
1
1:1); yield 95%; mp 92−94 °C; H NMR (CDCl3) δ: 1.82-1.94 (m, 4H, 2 × CH2, H-2, H-3), 2.65 (t, 2H,
CH2, H-1, J = 6.2 Hz), 3.06 (t, 2H, CH2, H-4, J = 6.4 Hz), 4.20 (bs, 1H, NH), 4.54 (s, 2H, CH2), 6.11 (d,
1H, CH, H-3', J = 3.6), 6.29 (dd, 1H, CH, H-4', J = 3.6, 2.0 Hz), 7.37 (d, 1H, CH, H-5', J = 2.0 Hz), 7.39
(m, 1H, H-7), 7.57 (ddd, 1H, CH, H-6, J = 8.4, 6.8, 1.2 Hz), 7.93 (d, 1H, CH, H-5, J = 8.4 Hz), 7.98 (dd,
1H, CH, H-8, J = 8.4, 1.2 Hz); 13C NMR (CDCl3) δ: 22.8 (C-3), 22.9 (C-2), 24.5 (C-1), 34.1 (C-4), 46.1
(CH2), 107.3 (C-3'), 110.5 (C-4'), 118.4 (C-9a), 120.9 (C-8a), 122.6 (C-8), 124.3 (C-7), 128.4 (C-6),
128.9 (C-5), 142.3 (C-5' ), 147.4 (C-10a), 149.8 (C-9), 152.8 (C-2'), 158.8 (C-4a). Anal. Calcd for
C18H18N2O (278.35): C, 77.67; H, 6.52; N, 10.06. Found: C, 77.58; H, 6.67; N, 10.19%.
N-(Morpholinoethyl)-N-(1,2,3,4-tetrahydroacridin-9-yl)amine (10c). Yellow powder (CHCl3−MeOH,
1
9:1); yield 90%; mp 103−106 °C; H NMR (CDCl3) δ: 1.85−1.98 (m, 4H, 2 × CH2, H-2, H-3), 2.51 (m,
4H, 2 × CH2, H-4', H-8'), 2.61 (t, 2H, CH2, H-2', J = 5.8 Hz), 2.78 (m, 2H, CH2, H-1), 3.07 (m, 2H, CH2,
H-4), 3.55 (m, 2H, CH2, H-1'), 3.77 (m, 4H, 2 × CH2, H-5', H-7'), 5.12 (s, 1H, NH), 7.35 (dd, 1H, CH,

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HETEROCYCLES, Vol. 76, No. 2, 2008
H-7, J = 8.4, 6.0 Hz), 7.55 (dd, 1H, CH, H-6, J = 8.4. 6.0 Hz), 7.89 (d, 1H, CH, H-5, J = 8.4 Hz), 8.01 (d,
1H, CH, H-8, J = 8.4 Hz); 13C NMR (CDCl3) δ: 22.9 (C-3), 23.2 (C-2), 25.0 (C-1), 34.1 (C-4), 44.9 (C-1'),
53.1 (C-4', C-8'), 58.1 (C-2'), 67.1 (C-5', C-7'), 116.2 (C-9a), 120.4 (C-8a), 122.7 (C-8), 123.5 (C-7),
128.2 (C-6), 128.9 (C-5), 147.6 (C-10a), 150.9 (C-9), 158.6 (C-4a). Anal. Calcd for C19H25ON3 (311.43):
C, 73.28; H, 8.09; N, 13.49. Found: C, 73.35; H, 8.02; N, 13.65%.
N(-Furfuryl)-N-(1,2,3,4-tetrahydroacridin-9-yl)amine hydrochloride (11b). To a saturated solution of
N-furfuryl-N-(1,2,3,4-tetrahydroacridin-9-yl)amine 9b (50 mg, 0.14 mmol) in acetone, a methanolic HCl
solution (250 µL) prepared from MeOH (0.9 mL) and concentrated HCl (0.1 mL) was added and stirred at
rt 1 h. The residue was treated with Et2O and the product collected by filtration as a yellow powder. Yield
90%; mp 180−184 °C; 1H NMR (DMSO-d6) δ: 1.83 (m, 4H, 2 × CH2, H-2, H-3), 2.75 (m, 2H, CH2, H-1),
3.06 (m, 2H, CH2, H-4), 5.08 (d, 2H, CH2, J = 6.4 Hz), 6.41 (m, 1H, CH, H-3'), 6.43 (m, 1H, CH, H-4'),
7.56 (dd, 1H, CH, H-7, J = 8.8, 6.8 Hz), 7.64 (m, 1H, CH, H-5'), 7.86 (dd, 1H, CH, H-6, J = 8.8, 6.8 Hz),
13
8.02 (d, 1H, CH, H-5, J = 8.8 Hz), 8.35 (t, 1H, NH, J = 6.4 Hz), 8.45 (d, 1H, CH, H-8, J = 8.8 Hz); C
NMR (DMSO-d6) δ: 20.1, 21.3 (C-2, C-3), 24.0 (C-1), 27.9 (C-4), 43.6 (CH2), 107.9 (C-3'), 110.6 (C-4'),
111.8 (C-9a), 115.7 (C-8a), 119.1 (C-5), 124.7 (C-8), 125.1 (C-7), 132.6 (C-6), 137.5 (C-10a), 142.8
(C-5'), 151.0 (C-2'), 151.3 (C-4a), 155.6 (C-9). Anal. Calcd for C18H19ON2Cl (314.81): C, 68.67; H, 6.08;
N, 8.90. Found: C, 68.80; H, 5.94; N, 8.79%.
4-[2-(1,2,3,4-Tetrahydroacridin-9-ylamino)ethyl]piperazine-1-carboxylic acid tert-butyl ester (12). To a
homogeneous solution obtained from a mixture of 9-chloro-1,2,3,4-tetrahydroacridine 2 (100 mg, 0.46
mmol) in phenol (405 mg, 4.3 mmol) at 85−90 °C, the protected amine 5a (94 mg, 0.41 mmol) was added
and heating continued for 4 h at 125−130 °C. After cooling, CHCl3 (5 mL) was added and the solution
obtained treated with 10% aq. NaOH solution (8 mL) and water (8 mL). The organic layer was separated
and dried over CaCl2. The solvent was removed under reduced pressure and the residue obtained used for
the next reaction. Yield 90%; oil; 1H NMR (CDCl3) δ: 1.47 (s, 9H, 3 × CH3), 1.92-1.98 (m, 4H, 2 × CH2,
H-2, H-3), 2.37-2.46 (m, 6H, 3 × CH2, H-2', H-4', H-8'), 2.80 (t, 2H, CH2, H-1', J = 6.0 Hz), 3.02 (t, 2H,
CH2, H-1, J = 6.2 Hz), 3.13 (t, 2H, CH2, H-4, J = 6.2 Hz), 3.43 (m, 4H, 2 × CH2, H-5", H-7"), 5.08 (s, 1H,
NH), 7.54 (ddd, 1H, CH, H-7, J = 8.6, 6.8, 1.4 Hz), 7.66 (ddd, 1H, CH, H-6, J = 8.2, 6.8, 1.4 Hz), 7.97
(dd, 1H, CH, H-5, J = 8.2, 1.4 Hz), 8.16 (dd, 1H, CH, H-8, J = 8.6, 1.4 Hz); 13C NMR (CDCl3) δ: 22.6,
22.7 (C-2, C-3), 27.5 (C-1), 28.4 (3 × CH3), 34.2 (C-4), 38.7 (C-1'), 43.7 (C-5', C-7'), 53.1 (C-4', C-8'),
61.2 (C-2'), 79.6 (C), 115.1 (C-9a), 123.7 (C-8), 125.4 (C-8a), 126.5 (C-7), 128.7 (C-5), 129.3 (C-6),
141.4 (C-9), 146.7 (C-10a), 154.8 (C=O), 159.5 (C-4a).

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N-(Piperazinoethyl)-N-(1,2,3,4-tetrahydroacridin-9-yl)amine trihydrochloride (13). The same procedure
used for the preparation of 7a was used for 13. Light brown powder; yeld 90%; mp 187−190 °C; 1H NMR
(DMSO-d6) δ: 1.84 (m, 4H, 2 × CH2, H-2, H-3), 2.80 (m, 2H, CH2, H-1), 3.07 (m, 2H, CH2, H-4),
3.17−3.63 (m, 10H, 5 × CH2, H-4', H-8', H-5', H-7', H-2'), 4.32 (m, 2H, CH2, H-1'), 7.60 (dd, 1H, CH,
H-7, J = 8.4, 6.4 Hz), 7.89 (dd, 1H, CH, H-6, J = 8.4, 6.4 Hz), 7.94 (bs, 1H, NH), 8.05 (d, 1H, CH, H-5, J
= 8.4 Hz), 8.49 (d, 1H, CH, H-8, J = 8.4 Hz ), 9.97 (bs, 2H, NH); 13C NMR (DMSO-d6) δ: 20.2, 21.5 (C-2,
C-3), 24.4 (C-1), 28.0 (C-4), 39.1, 48.2 (C-4', C-8', C-5', C-7'), 41,8 (C-1'), 55.2 (C-2'), 112.1 (C-9a),
115.9 (C-8a), 119.2 (C-5), 124.9 (C-8), 125.4 (C-7), 132.7 (C-6), 137.6 (C-9), 151.4 (C-4a), 155.7
(C-10a). Anal. Calcd for C19H29N4Cl3 (419.83): C, 54.36; H, 6.96; N, 13.35. Found: C, 54.18; H, 6.78; N,
13.40%.
ACKNOWLEDGEMENTS
Financial support for this work from the Slovak Grant Agency VEGA (grant no. 1/0476/08) and the State
NMR Program (grant no. 2003SP200280203) is gratefully acknowledged. The Czech part of the work (K.
K. and D. J.) was supported by the Ministry of Defense, Czech Republic (grant no. FVZ0000604).
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