New imidazoline/α2-adrenoceptors affecting compounds-4(5)-(2-aminoethyl)imidazoline (dihydrohistamine) derivatives. Synthesis and receptor affinity studies

Article abstract of DOI:10.1016/j.bmc.2010.11.039

Compilation of agmatine structure and imidazoline moiety leads to a new group of imidazoline/α₂-adrenoceptor ligands, 4(5)-(2-aminoethyl)imidazoline derivatives. In this study the exploration of previously unknown 4(5)-(2-aminoethyl)imidazolines including the analogues of reported imidazoline and α₂-aderenoceptors ligands: clonidine, rilmenidine, idazoxan, efaroxan, antazoline, tracizoline is described. The synthesis of a variety of novel 4(5)-(2-aminoethyl)imidazolines and their I ₁, I₂, α₂-adrenoceptors affinities are reported.

Full text of DOI:10.1016/j.bmc.2010.11.039

Bioorganic & Medicinal Chemistry 19 (2011) 156–167
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
New imidazoline/
a2-adrenoceptors affecting
compounds—4(5)-(2-aminoethyl)imidazoline (dihydrohistamine)
derivatives. Synthesis and receptor affinity studies
Adam P. Treder a, , Ryszard Andruszkiewicz a, , Włodzimierz Zgoda b, Aleksandra Walkowiak a,
⇑
⇑
Celeste Ford c, Alan L. Hudson c
a Department of Pharmaceutical Technology and Biochemistry, The Faculty of Chemistry, Gdan´sk University of Technology, Narutowicza St 11/12, 80-952 Gdan´sk, Poland
b Department of Medicinal Chemistry, Medical University of Gdan´sk, De˛binki St. 1 80-952 Gdan´sk, Poland
c Department of Pharmacology, 947 Medical Sciences Building, University of Alberta, Edmonton, Canada T6G 2R3
a r t i c l e i n f o
a b s t r a c t
Article history:
Compilation of agmatine structure and imidazoline moiety leads to a new group of imidazoline/a2-adre-
Received 20 August 2010
Revised 16 November 2010
Accepted 17 November 2010
Available online 25 November 2010
noceptor ligands, 4(5)-(2-aminoethyl)imidazoline derivatives. In this study the exploration of previously
unknown 4(5)-(2-aminoethyl)imidazolines including the analogues of reported imidazoline and 2-ade-
renoceptors ligands: clonidine, rilmenidine, idazoxan, efaroxan, antazoline, tracizoline is described. The
a
synthesis of a variety of novel 4(5)-(2-aminoethyl)imidazolines and their I1, I2,
affinities are reported.
a2-adrenoceptors
Keywords:
Dihydrohistamine derivatives
Receptor studies
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
clonidine, rilmenidine, idazoxan, efaroxan, antazoline and tracizo-
line. In this work the synthetic methods and I/
a
2 receptors affinity
Imidazolines are a numerous family of biologically active com-
pounds known from comprehensive therapeutic applications. Most
recent hypotheses connect activity of imidazolines with three
studies are reported.
NH
H2N
N
H
NH2
NH2
types of imidazoline receptors (I1, I2 and I3) and a2-adrenoceptors
H
R
Agmatine
in different parts of CNS and peripheral tissues. These molecular
targets are responsible for the versatile biological activities of
imidazolines discussed in many reviews: antihypertensive, antial-
lergic, antihypertensive, antidiabetic, sympatholytic, analgetic and
anxiety-relieving properties.1–3
HN
N
HN
N
R
2-Imidazolines
R = aryl, alkyl, arylalkyl
Several compounds were reported as the natural ligands of imi-
dazoline receptors, including b-carbolines,4,5 imidazolacetic acid
ribotide6 and agmatine.7
2. Results and discussion
We have recently reported a new group of compounds (4(5)-(2-
aminoethyl)imidazoline derivatives) that are structural analogues
of imidazoline ring and the natural ligand of imidazoline recep-
tors—agmatine.8 This group of heterocyclic compounds posses
much higher affinity to imidazoline receptors than agmatine itself.
That study lead us to a hypothesis that the imidazoline ring deriv-
atization of known I/a2 ligands in 4(5) position may lead to a new
group of biologically active compounds.
2.1. Chemistry
The syntheses of 4(5)-(2-aminoethyl)imidazoline derivatives
were performed with the modified methods reported recently.9 The
synthetic pathway began with the preparation of the selectively
N4-protected (2S)- and (2R)-1,2,4-triaminobutane (1a and 1b)
according to the literature procedure10 starting from L or
acid.
D-glutamic
In this study we describe the further exploration of previously
unknown 4(5)-(2-aminoethyl)imidazolines including the analogues
2.1.1. [4(5)S]-4(5)-(2-Aminoethyl)-2-benzylaminoimidazoline
dihydrobromide (5)
Compound 5 was synthesized using modified method reported
for 2-benzylaminoimidazoline preparation (Scheme 1).11 In the
first step the cyclic thiourea 2 was obtained from 1a and CS2.12
of known synthetic imidazoline and
a2-adreno receptors ligands:
⇑
Corresponding authors.
E-mail address: ryszarda@chem.pg.gda.pl (R. Andruszkiewicz).
0968-0896/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2010.11.039

A. P. Treder et al. / Bioorg. Med. Chem. 19 (2011) 156–167
157
Then compound 2 was reacted with EtI yielding 3. The ethylmerca-
S
NH4SCN
PhCOCl
acetone
S
a
b
pto-group of 3 was substituted with benzylamine according to the
reported method11 and further the benzyloxycarbonyl group of 4
was cleaved with HBr in AcOH yielding 5.
HN NH2
HN NH
R
R
COPh
(9a-13a)
R1
2.1.2. 2-Arylamino 4(5)-(2-aminoethyl)imidazoline derivatives
A series of 4(5)-(N-benzyloxycarbonyl-2-aminoethyl)-2-aryla-
minoimidazolines (6c–16c, 6e–16e) were synthesized from
selectively protected triaminobutanes (1a or 1b) using isothioureas
iodides (6b–16b) as cyclisation agents (Scheme 2).13,14 N-Substi-
tuted thioureas were purchased from commercial sources (6a–8a,
14a–16a) or were prepared from appropriate amines according to
the reported method (9a–13a).17 The isothioureas (6b–16b) were
prepared from appropriate thioureas and MeI or EtI in alkylation
reactions according to the literature procedure.15 The excess of dia-
mine over isothiourea hydroiodide in cyclisation reaction was not
necessary. The triaminobutane derivatives 1a or 1b were reacted
with isothioureas in a 1:1molar ratio. The benzyloxycarbonyl groups
were cleaved with HBr in AcOH yielding (6d–16d, 13f–16f).
S
S
c
HN NH
HI
HN NH2
R
R
(6b-16b)
(6a-16a)
d
(6b-15b)
(16b)
-
-
R1 = Me
R1 = Et
z
NH2
NH
H
H
(S) or (R)
2HBr
(S) or (R)
HCl
e
HN
R
N
HN
R
N
NH
NH
(6d-16d) - (S)
(13f-16f) - (R)
(6c-16c) - (S)
(13e-16e) - (R)
2.1.3. [4(5)S]-4(5)-(2-aminoethyl)-2-
[dicyclopropylmethyl)amino]imidazoline dihydrochloride
(17d), a guanidine analogue of rilmenidine
Synthesis of 17d was performed applying the isothiourea deriva-
tives cyclisation method13,14 of vicinal diamines to obtain triamin-
obutane derivative 1a and isothiourea 17b. Dicyclopropylm
ethylamine 17a was obtained from dicyclopropylketone as re-
ported.16 17a was converted into thiourea applying the literature
method17 and alkylated with MeI yielding 17b.
R=
F
F
Br
Br
(6)
(7)
(9)
(8)
O
N
N
Cl
(11)
(12)
(13)
(10)
Due to the lability of dicyclopropylmethyl group in acidic con-
ditions, HBr in glacial acetic acid was not suitable as benzyloxycar-
bonyl group remover. The protecting group of 17c was cleaved
with H2/Pd/C yielding 17d (Scheme 3).
Cl
Cl
CF3
Cl
Cl
(16)
(15)
(14)
2.1.4. Tolazoline (19) and naphazoline (21a,21b) analogues
The synthesis of 19, 21a, 21b was designed applying iminoest-
ers hydrochlorides as cyclisation agents of vicinal diamines, using
in this case triaminobutane derivatives 1a and 1b. The iminoesters
of phenyl- and naphthylacetic acids were prepared as previously
reported18,19 and were reacted with selectively protected triamin-
obutanes 1a or 1b yielding 18, 20a or 20b. The cleavage of benzyl-
oxycarbonyl groups was performed with HBr in AcOH (Scheme 4).
Scheme 2. Reagents and conditions: (a) RNH2, 30 min, reflux; (b) 2.5 M NaOH,
40 min, 90 °C; (c) MeI or EtI, MeOH, 3 h, reflux; (d) 1a or 1b, n-pentanol, 24 h,
reflux; (e) HBr/AcOH, 3 h, rt.
CH3
S
NH2
O
a,b
c,d,e
HN
f
NH
(17b)
(17a)
2.1.5. [4(5)S]-(25a) and [4(5)R]-4(5)-(2-Aminoethyl)-2-(2-ethyl-
2,3-dihydro-1-benzofurane-2)imidazoline dihydrobromide
(25b) (efaroxane analogues)
z
NH2
NH
H
H
g
HN
N
NH
HN
N
NH
The racemic methyl ester 22 was obtained according to the
2HCl
HCl
reported procedure20 and converted into corresponding amide
(17d)
(17c)
NH2
NH2
z
z
Scheme 3. Reagents and conditions: (a) NH2OH, pyridine, 4 h, 100 °C; (b) LiAlH4,
THF, Et2O, 6 h, reflux; (c) NaSCN, PhCOCl, acetone, 1.5 h, reflux; (d) 2.5 M NaOH,
1.5 h, 90 °C; (e) MeI, MeOH, 3 h, reflux; (f) 1a, n-pentanol, 24 h reflux; (g) H2, 10%
Pd/C, MeOH, 4 h.
NH
NH
H
H
S
a,b
c
H
HN NH
S
HN
N
H2N
(1a)
HI
(2)
(3)
with NH3/MeOH. Then the amide was dehydrated with POCl3/pyr-
idine21,22 yielding 23 (Scheme 5). Nitrile 23 was converted in situ
into iminoester with sodium ethoxide21,23 and reacted with 1a or
1b yielding 24a or 24b (Scheme 6). Finally the N-protecting ben-
zyloxycarbonyl groups were removed with HBr in AcOH.
z
z
NH
NH
NH2
H
S
H
H
d
e
HN
N
HN
N
HN
N
2HBr
HI
NH
Ph
(4)
NH
Ph
2.1.6. 4(5)S]-(29a) and [4(5)R]-4(5)-(2-Aminoethyl)-2-(2,3-
dihydro-1,4-benzodioxane-2)imidazoline(29b) dihydrobromide
(idazoxane analogues)
(3)
(5)
Scheme 1. Reagents and conditions: (a) EtOH, H2O, Et3N, CS2, 5 h, 60 °C; (b) HCl,
9 h, reflux; (c) EtI, MeOH, 2 h, reflux; (d) PhCH2NH2, t-BuOH, 5 h, reflux; (e) HBr/
AcOH, 3 h, rt.
The racemic nitrile 26 was obtained and converted into imino-
ester 27 according to the reported procedure (Scheme 7).24 Then

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A. P. Treder et al. / Bioorg. Med. Chem. 19 (2011) 156–167
(S) or (R)
H
OH
OH
O
O
(S) or (R)
NH2
(S) or (R)
H
O
O
z
NH
a
b
NH2
OEt
HCl
a
b
CN
NH2
H
NH
HN
N
HN
N
(27)
(26)
2HBr
HCl
2HCl
R
R
H2N
Scheme 7. Reagents and conditions: (a) CH2CClCN, acetone, 18 h, reflux; (b) EtOH,
(1a,1b)
(18,20a,20b)
(19,21a,21b)
2 M HCl/Et2O.
(18,19) - R=Ph
(20a,20b,21a,21b) - R=Naph
(1a,18,19,20a,21a) - (S)
(1b,20b,21b) - (R)
(S) or (R)
H
(S) or (R)
H
z
NH
OEt
NH
HCl
NH2
2HBr
a
O
b
O
HN
HCl
N
O
HN
N
O
Scheme 4. Reagents and conditions: (a) PhCH2(NH)OEtꢀHCl or Naph
CH2(NH)OEtꢀHCl, EtOH, Et3N; (b) HBr/AcOH, 3 h, rt.
(27)
O
O
Br
MeOOC
CHO
a,b,c,d,e
f,g
(28a,28b)
(29a,29b)
O
O
F
Scheme 8. Reagents and conditions: (a) 1a or 1b, Et3N, EtOH, 4 h, reflux; (b)
COOMe
(22a)
CN
HBr/AcOH, 3 h, rt.
(23)
Scheme 5. Reagents and conditions: (a) t-BuOK, dioxane, 18 h, rt; (b) H2 10% Pd/C,
MeOH, 24 h, rt; (c) 1 M NaOH, THF, 24 h, rt; (d) NaH, DMF, PhCH3, 16 h, 110–120 °C;
(e) SOCl2, MeOH, 24 h, rt; (f) 24% NH3/MeOH, 48 h, rt; (g) POCl3, pyridine, 3 h, reflux.
z
NH2
3HBr
H
NH
H
c,d
a,b
HN
N
N
HN
Cl
N
ClCH2CN
HCl
Ph
compound 27 was reacted with 1a or 1b yielding 28a or 28b. The
N-benzyloxycarbonyl groups were cleaved with HBr in AcOH
(Scheme 8).
Ph
(30c)
(30a)
Scheme 9. Reagents and conditions: (a) EtOH, 2 M HCl/Et2O; (b) 1a, EtONa, EtOH,
1.5 h, reflux; (c) PhCH2(Ph)NH, EtOH, 24 h, reflux; (d) HBr/AcOH, 3 h, rt.
2.1.7. 4(5)S]-4(5)-(2-Aminoethyl)-2-[(N-benzyl-N-phenyl)
aminomethyl]imidazoline trihydrobromide (antazoline
analogue) (30c)
The synthesis of antazoline analogue was performed according
to the reported method25 using 2-(chloromethyl)imidazoline26
derivative as a substrate. Chloroacetonitrile was converted into
iminoacetate and reacted with 1a yielding 30a. Compound 30a
was next condensed with N-benzylaniline and further the N-ben-
zyloxycarbonyl group was cleaved with HBr in AcOH yielding
30c (Scheme 9).
z
NH2
H
NH
H
c
a,b
HN
N
HN
N
PhCN
2HBr
Ph
HCl
Ph
(31a)
(31b)
Scheme 10. Reagents and conditions: (a) EtOH, 2 M HCl/Et2O; (b) 1a, Et3N, EtOH,
3 h, reflux; (c) HBr/AcOH, 3 h, rt.
2.1.8. 4(5)S]-4(5)-(2-Aminoethyl)-2-phenylimidazoline
dihydrobromide (31b)
The imidazoline 31a was synthesized from 1a and iminoester
hydrochloride obtained from benzonitrile (Scheme 10). The
N-protecting group was removed using standard HBr in AcOH
method yielding 31b.
32a or 33a. The N-benzyloxycarbonyl groups were removed with
HBr in AcOH (Scheme 11). Due to the lability of the double bond
in tracizoline analogue, the HBr/AcOH treatment was shortened
to 30 min.
2.1.9. 4(5)S]-4(5)-(2-Aminoethyl)-2-(2-fluorophenyl)imidazoline
dihydrobromide (32b) and [4(5)S]-4(5)-(2-aminoethyl)-2-[(E)-2-
phenylethenyl]imidazoline dihydrobromide (33b) (tracizoline
analogue)
Imidazolines 32a and 33a were synthesized using the recently
reported vicinal diamines cyclisation method into imidazoline ring
with aldehydes and N-bromosuccinimide.27 1a was reacted appro-
priately with 2-fluorobenzaldehyde or cinnamaldehyde yielding
2.2.
studies
a2-Adrenoceptor and imidazoline I1 and I2 receptors affinity
The newly prepared imidazoline ligands were investigated for
the affinity to 2-adrenoceptor, imidazoline I1 and imidazoline I2
a
binding sites. Clonidine hydrochloride was enclosed as reference
compound. The affinity studies were performed using kidney and
brain male Sprague–Dawley rats P2 membranes as was reported
recently.28 The results are shown in Table 1. Clonidine and agma-
tine were enclosed as reference compounds.
(S) or (R)
H
(S) or (R)
NH2
(S) or (R)
H
z
NH
NH2
2HBr
Looking through the reported data (e.g., for clonidine)29–32 it is
clear that affinity values are very variable to species, tissues and
type of radioligand. As a conclusion form the literature studies—
a
b
NH2
H
HN
HCl
N
HN
N
2HCl
O
O
H2N
compound posses the affinity to I or
a2-adrenoceptors if Ki or
IC50 is close to 1000 nM or below this value. If the reported Ki or
IC50 were below 100 nM the affinities were described as high.
The affinity values are very variable to species, tissues and type
of radioligand. In this study several compounds with moderate
(1a,1b)
(24a,24b)
(25a,25b)
Scheme 6. Reagents and conditions: (a) 23, EtONa, EtOH, 12 h, rt; (b) HBr/AcOH,
affinities to I1, I2 and a2-adrenoceptors were discovered.
3 h, rt.

A. P. Treder et al. / Bioorg. Med. Chem. 19 (2011) 156–167
159
affinities to both I and
a
2-adrenoceptors. The same situation takes
z
NH2
H
NH
H
place for the other analogues of I/a2 ligands. Compared to the re-
ported values for different ligands and tissues there is serious drop
in I2 affinity in naphazoline (21a, 21b)33–37 and idazoxane (29a,
29b).33–37 Analogous conclusions may be drawn from the affinities
CHO
b
a
HN
F
N
F
HN
F
N
2HBr
HCl
to a2-adrenoceptors. The analogues of naphazoline (21a, 21b) and
(32a)
(32b)
idazoxane (29a, 29b) indicate much lower affinities to a2-adreno-
ceptors than the authentic compounds.34,35,38
z
NH2
H
NH
H
CHO
In several cases both enantiomers/diastereomeric mixtures were
examined (13d, 13f, 14d, 14f, 15d, 15f, 16d, 16f, 21a, 21b, 25a, 25b,
29a, 29b). We observed interesting affinity differences between the
enantiomers or diastereomeric mixtures [4(5)S]/[4(5)R]. The results
show strong influence of 4(5)-substituent configuration on the affin-
ities values. In most cases [4(5)S] compounds indicates higher I1
affinities, but for idazoxane analogues (29a, 29b). The samesituation
c
a
HN
N
HN
N
2HBr
HCl
(33a)
(33b)
take place for I2 and
a2-adrenoceptor affinities, except efaroxane
(25a, 25b) and idazoxane (29a, 29b) analogues for which better re-
Scheme 11. Reagents and conditions: (a) 1a, SuNBr, CH2Cl2, 13 h, 0 °C to rt; (b)
HBr/AcOH, 3 h, rt; (c) HBr/AcOH, 0.5 h, rt.
sults were obtained for [4(5)R] diastereomeric mixtures.
3. Conclusions
Table 1
Binding affinities to I1, I2 and
and clonidine
a2-adrenoceptors for prepared compounds, agmatine
In summary, we have described a new group of agmatine/imi-
dazoline ring analogues, 4(5)-(2-aminoethyl)imidazoline deriva-
tives. Some of the new compounds posses moderate affinities to
Compounds
I1 IC50 (nM)
I2 Ki (nM)
a2 Ki (nM)
(configuration)
I1, I2 and
a2-adrenoceptors. The obtained values of Ki, IC50 are
5 (S)
7 (S)
100,900
3700
7498
5539
lower than reported for synthetic imidazoline ligands, but much
higher than the natural ligand of imidazoline receptor-agmatine it-
self. The most valuable results were obtained for [4(5)S] enantio-
mers or [4(5)S] diastereomeric mixtures. With reference to our
present studies, 4(5)-(2-aminoethyl)imidazolines may be a new
group of compounds that affects the cardiovascular system by
I/a2 mediated response.
18,830
21,770
81,250
24,890
20,270
>10,00,000
15,650
39,570
1762
1553
8 (S)
9 (S)
10 (S)
11 (S)
93,140
59,380
79,770
33,900
>10,00,000
7781
8509
1482
6334
1310
13,060
25,800
9376
7018
19,660
445
12 (S)
13d (S)
13f (R)
14d (S)
14f (R)
15d (S)
15f (R)
16d (S)
16f (R)
17d (S)
19 (S)
21a (S)
21b (R)
25a (S)
25b (R)
29a (S)
29b (R)
30c (S)
31b (S)
32b (S)
33b (S)
Clonidine
Agmatinea
4907
854
92,520
12,700
47,690
2432
16,920
3007
26,690
1899
4. Experimental
4.1. General
1249
7749
2716
9564
4315
>100,000
277,600
>100,000
583,400
1008
32,540
5112
2652
11,620
72,860
116,600
17,220
366.2
27,980
59,360
1001
5727
23,320
964
Starting materials were obtained from commercial sources and
were used without further purification. Reaction process was fol-
lowed by thin layer chromatography (TLC) with commercial silica
gel plates (Merck, Silica Gel F254 on aluminium sheets). Column
chromatography was done on Silica Gel 60, 0.063–0.200 mm
(Merck). 1H NMR spectra were recorded on Varian Unity Plus
500 MHz and Varian Gemini 200 MHz spectrometers. 13C NMR
spectra were recorded on Varian Gemini 200 MHz Spectrometer.
MSFAB spectra were recorded on Trio-3, VG, Great Britain. Melting
points are uncorrected. Microanalyses were performed on Carlo
Erba CHNS-O-EA1180 instrument for C, H, N.
46,260
2548
18,890
8115
83,770
20,350
869
24,020
5412
9612
19,060
3560
27,600
11,240
364.5
481,800
43,070
178,600
3896
8.7
36,532 3080 416,700 118,800 31,700 11,000
a
Result drawn from the literature, 4 obtained in similar experimental conditions
4.1.1. 4(5)S]-4(5)-(N-Benzyloxycarbonyl-2-aminoethyl)-2-
ethylmercaptoimidazoline hydroiodide (3)
using Wistar rats tissues.
(2S)-N4-Benzyloxycarbonyl-1,2,4-triaminobutane dihydrochlo-
ride 1a (388 mg, 1.25 mmol) was dissolved in a mixture of H2O
(4 ml) and ethanol (8 ml) and Et3N (0.35 ml) was added. The solution
was cooled in ice bath and CS2 (0.38 ml, 5 mmol) was added
dropwise. The resulting mixture was stirred for 5 h at 60 °C. After
cooling concd HCl (0.2 ml) was added and the solution was refluxed
for 9 h. The volatiles were removed under reduced pressure yielding
an oilyresidue. It wassuspendedin1 M KHSO4 (30 ml)andextracted
with CHCl3 (3 ꢁ 30 ml). The organic layer was dried with Na2SO4 and
evaporated yielding a crude yellow oil of 2. It was purified by column
chromatography on silica gel using CHCl3/acetone (5:1) as an eluent.
Yield of 2: 289 mg (83%), oil.
Compounds 14d, 15d, 15f, 25a indicate moderate affinities to I1
receptors. In case of I2 receptor affinity the most interesting results
were obtained for 14d and 21a. Some of the new compounds show
also interesting affinities to a2-adrenoceptors: 14d, 13d, 21a, 25b.
The other compounds indicate low or no affinity (Ki, IC50 >100,000
or >10,00,000 nM).
Estimation of the affinities is compared with two reference
compounds—clonidine and agmatine. None of the obtained com-
pounds show the clonidine affinity level for I and a2-adrenoceptors
but majority of them is still much above the values reported for
Compound 2 (788 mg, 2.82 mmol) was dissolved in MeOH
(20 ml) and EtI (0.34 ml, 4.2 mmol) was added. The resulting mix-
ture was refluxed for 2 h. The volatiles were removed under reduced
agmatine.
Analyzing the closest analogues of clonidine (16d, 16f), it is clear
that the substituent in 4(5) position distinctly diminishes the

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A. P. Treder et al. / Bioorg. Med. Chem. 19 (2011) 156–167
pressure yielding the oily product 3 that was used without further
purification. Yield: 1229 mg, (100%), oil. 1H NMR (500 MHz, CD3OD):
d (ppm) = 1.36 (t, J = 7.0, 3H, CH2CH3), 1.85–2.00 (m, 2H, CHCH2CH2),
3.05–3.40 (m, 4H, SCH2, CH2CH2NH), 3.45–3.60 (m, 1H, HNCH2CH),
3.95–4.10 (m, 1H, HNCH2CH), 4.20–4.40 (m, 1H, CH2CH(NH)CH2),
5.05 (s, 2H, OCH2Ph), 7.15–7.40 (m, 5H, C6H5). Anal. Calcd for
powder of 6d. Yield: 121 mg (97%). 1H NMR (500 MHz, DMSO-d6): d
(ppm) = 1.75–1.95 (m, 2H, CHCH2CH2), 2.77–2.95 (m, 2H,
CH2CH2NH), 3.35–3.45 (m, 1H, HNCH2CH), 3.70–3.83 (m, 1H,
HNCH2CH), 4.05–4.15 (m, 1H, CH2CH(NH)CH2), 7.25–7.50 (m, 5H,
C6H5), 7.73–7.90 (br s, 3H, NH3þ), 8.34 (s, 1H, NH), 8.58 (s, 1H, NH)
10.41 (s, 1H, NH). 13C NMR (200 MHz, MeOD): d (ppm) = 34.1,
37.6, 49.7, 54.7, 125.6, 128.9, 131.5, 136.8, 159.4. MS FAB MH+
205 (calcd for C11H16N4 M = 204.3). Anal. Calcd for C11H18Br2N4:
C, 36.09; H, 4.96; N, 15.30. Found: C, 36.19; H, 5.00; N, 15.23.
C15H24IN3O2S: C, 41.19; H, 5.53; N, 9.61; S, 7.33. Found: C, 41.11;
H, 5.63; N, 9.56; S, 7.49.
4.1.2. 4(5)S]-2-Benzylamino-4(5)-(2-aminoethyl)imidazoline
dihydrobromide (5)
4.1.5. 4(5)S]-4(5)-(N-Benzyloxycarbonyl-2-aminoethyl)-2-[(2-
bromophenyl)amino]imidazoline hydrochloride (7c)
Compound 3 (1087 mg, 2.50 mmol) was dissolved in t-BuOH
(18 ml) and benzylamine (0.44 ml, 5 mmol) was added. The mixture
was refluxed for 5 h. The volatiles were evaporated under reduced
pressure and the oily residue was suspended in H2O, alkalized with
1 M NaOH and extracted with CHCl3 (4 ꢁ 30 ml). The organic phase
was dried over MgSO4 and evaporated under reduced pressure. The
crude residue of 4 was converted into hydrochloride (5.5 M HCl in
MeOH) and then purified by column chromatography on silica gel
using CHCl3/MeOH (7:1) as eluent. Yield: 743 mg (62%), oil. 1H
NMR (200 MHz, CDCl3): d (ppm) = 1.40–1.90 (m, 2H, CHCH2CH2),
2.90–3.35 (m, 3H, CH2CH2NH, HNCH2CH), 3.45–3.70 (m, 1H,
HNCH2CH), 3.75–4.05 (m, 1H, CH2CH(NH)CH2), 4.41 (d, J = 5.5, 2H,
HNCH2Ph), 5.01 (s, 2H, OCH2Ar), 5.80–6.20 (br s, 1H, NH),
7.15–7.45 (m, 10H, HNCH2C6H5, OCH2C6H5), 8.10–8.70 (br s, 2H,
NH), 10.28–10.77 (br s, 1H, NH).
To 4 (660 mg, 1.70 mmol) a solution of HBr in AcOH (5 ml) was
added. The mixture was stirred for 3 h at rt. and then evaporated un-
der reduced pressure. The residue was dissolved in i-PrOH and pre-
cipitated with Et2O yielding a very hygroscopic creamy powder of 5:
600 mg (93%). Mp 103–106 °C. 1H NMR (200 MHz, MeOD): d
(ppm) = 1.90–2.15 (m, 2H, CHCH2CH2), 2.93–3.22 (m, 2H,
CH2CH2NH), 3.44 (dd, J1 = 6.6, J2 = 9.7, 1H, HNCH2CH), 3.88 (t,
J = 9.7, 1H, HNCH2CH), 4.14–4.33 (m, 1H, CH2CH(NH)CH2), 4.48 (s,
2H, HNCH2Ph), 7.25–7.55 (m, 5H, C6H5). 13C NMR (200 MHz, MeOD):
34.1, 37.5, 47.7, 49.5, 54.6, 128.8, 129.4, 130.3, 137.8, 160.6. MS FAB
MH+ 219(calcdforC12H18N4 M = 218.3). Anal. CalcdforC12H20Br2N4:
C, 37.92; H, 5.30; N, 14.74. Found: C, 37.95; H, 5.23; N, 14.73.
Preparation and purification of 7c was achieved according to the
general procedure A, starting from 7b (610 mg, 1.70 mmol). Yield:
386 mg (50%), oil. 1H NMR (500 MHz, CDCl3): d (ppm) = 1.65–1.87
(m, 2H, CHCH2CH2), 3.15–3.40 (m, 3H, CH2CH2NH, HNCH2CH),
3.78–3.80 (m, 1H, HNCH2CH), 4.02–4.15 (m, 1H, CH2CH(NH)CH2),
5.03 (AB system, J1 = 12.2, J2 = 21.5, 2H, OCH2Ph), 5.75–5.95 (br s,
1H, NH) 7.10–7.65 (m, 9H, C6H5, C6H4Br), 7.85–8.65 (br s, 2H, NH),
10.10–10.25 (br s, 1H, NH). Anal. Calcd for C19H22BrClN4O2: C,
50.29; H, 4.89; N, 12.35. Found: C, 50.30; H, 5.02; N, 12.21.
4.1.6. 4(5)S]-4(5)-(2-Aminoethyl)-2-[(2-bromophenyl)amino]
imidazoline dihydrobromide (7d)
Preparation and purification of 7d was carried out according to
the general procedure B, starting from 7c (154 mg, 0.34 mmol).
Yield: 139 mg (92%), extremely hygroscopic powder. 1H NMR
(200 MHz, DMSO-d6): d (ppm) = 1.72–2.03 (m, 2H, CHCH2CH2),
2.75–3.02 (m, 2H, CH2CH2NH), 3.32–3.58 (m, 1H, HNCH2CH),
3.72–3.80 (m, 1H, HNCH2CH), 4.05–4.23 (m, 1H, CH2CH(NH)CH2),
7.30–7.95 (m, 7H, C6H4Br, NH3þ), 8.38 (s, 1H, NH), 8.60 (s, 1H,
NH), 10.36 (s, 1H, NH). 13C NMR (200 MHz, MeOD):
d
(ppm) = 34.1, 37.4, 49.7, 54.9, 123.3, 130.7, 130.8, 132.0, 135.3,
135.4, 159.8. MS FAB MH+ 283, 285 (calcd for C11H15BrN4
M = 282.0, 284.0). Anal. Calcd for C11H17Br3N4: C, 29.69; H, 3.85;
N, 12.59. Found: C, 26.60; H, 3.92; N, 12.47.
4.1.7. 4(5)S]-4(5)-(N-Benzyloxycarbonyl-2-aminoethyl)-2-[(2,6-
difluorophenyl)amino]imidazoline hydrochloride (8c)
Preparation of 8c was carried out according to the general pro-
cedure A, starting from 8b (537 mg, 1.70 mmol). 8c as a hydrochlo-
ride was purified by column chromatography on Sephadex LH-20
using MeOH as eluent. Yield: 363 mg (52%), oil. 1H NMR
(200 MHz, CDCl3): d (ppm) = 1.67–2.03 (m, 2H, CHCH2CH2), 3.21–
3.63 (m, 3H, CH2CH2NH, HNCH2CH), 3.87–4.12 (m, 1H, HNCH2CH),
4.12–4.33 (m, 1H, CH2CH(NH)CH2), 5.02 (s, 2H, OCH2Ph), 5.79–6.05
(br s, 1H, NH), 6.75–7.03 (m, 2H, C6H3F2), 7.32–7.50 (m, 6H, C6H3F2,
C6H5), 8.46–8.90 (br s, 2H, NH), 9.95–10.15 (br s, 1H, NH). Anal.
Calcd for C19H21ClF2N4O2: C, 55.54; H, 5.15; N, 13.64. Found: C,
55.56; H, 5.29; N, 13.47.
4.1.3. 4(5)S]-4(5)-(N-Benzyloxycarbonyl-2-aminoethyl)-2-
phenylaminoimidazoline hydrochloride (6c). General
procedure A
S-Methyl-N-phenylisothiourea hydroiodide (6b) (472 mg,
1.69 mmol) was added to (2S)-N4-benzyloxycarbonyl-1,2,4-triam-
inobutane 1a (400 mg, 1.69 mmol) in 1-pentanol (4 ml). The reac-
tion mixture was refluxed for 24 h. The volatiles were removed
under reduced pressure. The oily residue was suspended in H2O
(20 ml), alkalized to pH 12 with 1 M NaOH and extracted with
Et2O (4 ꢁ 30 ml). The organic layer was dried with MgSO4 and
evaporated under reduced pressure. The crude product 6c was con-
verted into hydrochloride with 5.5 M HCl in MeOH and purified by
column chromatography on silica gel using CHCl3/MeOH (6:1) as
eluent. Yield: 395 mg (62%), oil. 1H NMR (200 MHz, CDCl3) d
(ppm) = 1.60–1.95 (m, 2H, CHCH2CH2), 3.15–3.45 (m, 3H,
CH2CH2NH, HNCH2CH), 3.70–3.90 (m, 1H, HNCH2CH), 3.95–4.15
(m, 1H, CH2CH(NH)CH2), 5.01 (s, 2H, OCH2Ph), 5.55–5.85 (br s,
1H, NH) 7.15–7.45 (m, 10H, C6H5, C6H5), 7.80–8.30 (br s, 2H, NH),
10.71 (s, 1H, NH). Anal. Calcd for C19H23ClN4O2: C, 60.88; H, 6.18;
N, 14.95. Found: C, 60.87; H, 6.30; N, 14.78.
4.1.8. 4(5)S]-4(5)-(2-Aminoethyl)-2-[(2,6-difluorophenyl)amino
]imidazoline dihydrobromide (8d)
Preparation and purification of 8d was completed according to
the general procedure B, starting from 8c. Yield: 131 mg, (96%),
very hygroscopic powder.1H NMR (200 MHz, DMSO-d6):
d
(ppm) = 1.70–2.05 (m, 2H, CHCH2CH2), 2.70–3.05 (m, 2H,
CH2CH2NH), 3.25–3.50 (m, 1H, HNCH2CH), 3.70–3.95 (m, 1H,
HNCH2CH), 4.05–4.30 (m, 1H, CH2CH(NH)CH2), 7.20–8.10 (m, 6H,
C6H3F2, NH3þ), 8.70 (s, 1H, NH), 8.89 (s, 1H, NH), 10.31 (s, 1H,
NH). 13C NMR (200 MHz, MeOD): d (ppm) = 34.0, 37.4, 50.0, 55.1,
113.1, 113.4, 113.7, 113.9, 114.0, 114.3, 114.4, 132.2, 132.4,
132.6, 157.6, 157.7, 159.9, 162.6, 162.7. MS FAB MH+ 241 (calcd
4.1.4. 4(5)S]-4(5)-(2-Aminoethyl)-2-phenylaminoimidazoline
dihydrobromide (6d). General procedure B
Compound 6c (127 mg, 0.34 mmol) was dissolved in HBr in AcOH
(3 ml) and stirred for 3 h at rt. The volatiles were removed under
reduced pressure. The oily yellowish residue was dissolved in i-PrOH
and precipitated with Et2O yielding an extremely hygroscopic
for
C11H14F2N4 M = 240.2). Anal. Calcd for C11H16Br2F2N4: C,
32.86; H, 4.01; N, 13.93. Found: C, 33.98; H, 4.17; N, 13.74.

A. P. Treder et al. / Bioorg. Med. Chem. 19 (2011) 156–167
161
4.1.9. 4(5)S]-4(5)-(N-Benzyloxycarbonyl-2-aminoethyl)-2-[(4-
bromophenyl)amino]imidazoline hydrochloride (9c)
by column chromatography on silica gel using CHCl3/MeOH (6:1)
as eluent. Yield: 292 mg (42%), oil. 1H NMR (200 MHz, CDCl3): d
(ppm) = 1.80–2.00 (m, 2H, CHCH2CH2), 3.10–3.45 (m, 3H,
CH2CH2NH, HNCH2CH), 3.70–3.90 (m, 1H, HNCH2CH), 3.95–4.25
(m, 1H, CH2CH(NH)CH2), 5.03 (s, 2H, OCH2Ph), 5.80–6.00 (br s,
1H, NH), 7.10–7.40 (m, 9H, C6H5, C6H4Cl), 8.09 (s, 1H, NH), 8.24
(s, 1H, NH), 10.81 (s, 1H, NH). Anal. Calcd for C19H22Cl2N4O2: C,
55.75; H, 5.42; N, 13.69. Found: C, 55.63; H, 5.57; N, 13.51.
Compound 9c was synthesized according to the general proce-
dure A, starting from 9b (634 mg, 1.70 mmol). The product 9c as
hydrochloride was purified by column chromatography on silica
gel using CHCl3/MeOH (5:1) as eluent. Yield: 324 mg (42%), oil.
1H NMR (200 MHz, CDCl3):
d
(ppm) = 1.60–2.00 (m, 2H,
CHCH2CH2), 3.15–3.50 (m, 3H, CH2CH2NH, HNCH2CH), 3.76–3.97
(m, 1H, HNCH2CH), 3.98–4.20 (m, 1H, CH2CH(NH)CH2), 5.03 (s,
2H, OCH2Ph), 5.60–5.95 (br s, 1H, NH), 7.10–7.60 (m, 9H, C6H5,
C6H4Br), 7.95–8.40 (br s, 2H, NH), 10.78 (s, 1H, NH). Anal. Calcd
for C19H22BrClN4O2: C, 50.29; H, 4.89; N, 12.35. Found: C, 50.24;
H, 4.83; N, 12.43.
4.1.14. 4(5)S]-4(5)-(2-Aminoethyl)-2-[(3-
chlorophenyl)amino]imidazoline dihydrobromide (11d)
Compound 11d was prepared according to the general proce-
dure B, starting from 11c (139 mg, 0.34 mmol). The product 11d
was precipitated from mixture of MeOH and i-PrOH with Et2O.
Yield: 128 mg (94%), white hygroscopic powder. Mp 203–205 °C.
4.1.10. 4(5)S]-4(5)-(2-Aminoethyl)-2-[(4-bromophenyl)amino]
imidazoline dihydrobromide (9d)
1H NMR (200 MHz, DMSO-d6):
d (ppm) = 1.75–2.10 (m, 2H,
Compound 9d was prepared according to the general procedure
B, starting from 9c (154 mg, 0.34 mmol). Yield: 144 mg (95%),
white powder. Mp 167–170 °C. 1H NMR (200 MHz, DMSO-
d6 + TFA): d (ppm) = 1.75–2.05 (m, 2H, CHCH2CH2), 2.75–3.05 (m,
2H, CH2CH2NH), 3.32 (dd, J1 = 7.0, J2 = 9.9, 1H, HNCH2CH), 3.41 (t,
J = 9.9, 1H, HNCH2CH), 4.05–4.25 (m, 1H, CH2CH(NH)CH2), 7.21
(d, J = 8.7, 2H, C6H4Br), 7.58 (d, J = 8.7, 2H, C6H4Br), 7.70–8.10 (br
s, 3H, NH3þ), 8.50 (s, 1H, NH), 8.76 (s, 1H, NH), 10.62 (s, 1H, NH).
13C NMR (200 MHz, MeOD): d (ppm) = 34.1, 37.4, 49.7, 54.8,
122.2, 127.7, 134.4, 136.1, 159.5. MS FAB MH+ 283, 285 (calcd for
CHCH2CH2), 2.75–3.05 (m, 2H, CH2CH2NH), 3.33 (dd, J1 = 7.0,
J2 = 9.8, 1H, HNCH2CH), 3.77 (t, J = 9.9, 1H, HNCH2CH), 4.02–4.24
(m, 1H, CH2CH(NH)CH2), 7.16–7.48 (m, 4H, C6H4Cl), 7.65–8.10 (br
s, 3H, NH3þ), 8.56 (s, 1H, NH), 8.81 (s, 1H, NH), 10.70 (s, 1H, NH).
13C NMR (200 MHz, MeOD): d (ppm) = 34.1, 37.5, 49.7, 54.8,
124.1, 125.7, 128.9, 132.7, 136.6, 138.3, 159.4. MS FAB MH+ 239,
241 (calcd for C11H15ClN4 M = 238.1, 240.1). Anal. Calcd for
C11H17Br2ClN4: C, 32.98; H, 4.28; N, 13.99. Found: C, 32.79; H,
4.35; N, 13.90.
C
11H15BrN4 M = 282.0, 284.0). Anal. Calcd for C11H17Br3N4: C,
4.1.15. 4(5)S]-4(5)-(N-Benzyloxycarbonyl-2-aminoethyl)-2-
[(pyridyl-3)amino]imidazoline dihydrochloride (12c)
29.69; H, 3.85; N, 12.59. Found: C, 29.51; H, 4.00; N, 12.47.
Preparation of 12c was achieved according to the general proce-
dure A, starting from 12b (502 mg, 1.70 mmol). The product 12c
was extracted with CHCl3 (3 ꢁ 20 ml, drying with MgSO4), con-
verted into hydrochloride (5.5 M HCl in MeOH) and purified by
two step column chromatography. Firstly, column chromatography
on silica gel using CHCl3/MeOH/AcOH (4:1:0.1) as eluent and then
on Sephadex LH-20 using MeOH. Yield: 154 mg (22%), oil. 1H NMR
4.1.11. 4(5)S]-4(5)-(N-Benzyloxycarbonyl-2-aminoethyl)-2-[(4-
metoxyphenyl)amino]imidazoline hydrochloride (10c)
Compound 10c was obtained according to the general proce-
dure A, starting from 10b (551 mg, 1.70 mmol). The product 10c
was isolated by extraction with CHCl3 (3 ꢁ 30 ml, drying with
MgSO4), converted into hydrochloride (5.5 M HCl in MeOH) and
purified by column chromatography on silica gel using CHCl3/
MeOH (6:1) as eluent. Yield: 213 mg (31%), oil. 1H NMR
(200 MHz, CDCl3): d (ppm) = 1.60–1.95 (m, 2H, CHCH2CH2), 3.15–
3.45 (m, 3H, CH2CH2NH, HNCH2CH), 3.70–3.90 (m, 4H, HNCH2CH,
CH3O), 3.95–4.20 (m, 1H, CH2CH(NH)CH2), 5.01 (s, 2H, OCH2Ph),
5.55–5.90 (br s, 1H, NH), 6.85 (d, J = 8.9, 2H, C6H4OCH3), 7.15 (d,
J = 8.9, 2H, C6H4OCH3), 7.25–7.45 (m, 5H, C6H5), 7.60–8.40 (br s,
2H, NH), 10.25–10.45 (br s, 1H, NH). Anal. Calcd for C20H25ClN4O2:
C, 59.33; H, 6.22; N, 8.76. Found: C, 59.25; H, 6.34; N, 8.57.
(200 MHz, CDCl3):
d (ppm) = 1.65–1.95 (m, 2H, CHCH2CH2),
3.15–3.45 (m, 3H, CH2CH2NH, HNCH2CH), 3.75–3.95 (m, 1H,
HNCH2CH), 4.00–4.20 (m, 1H, CH2CH(NH)CH2), 5.04 (s, 2H,
OCH2Ph), 5.65–5.85 (br s, 1H, NH), 7.28–7.38 (m, 5H, C6H5), 7.50–
7.75 (m, 2H, C5H4N), 8.25–8.75 (br s, 4H, C5H4N, NH), 10.35–
10.75 (br s, 1H, NH). Anal. Calcd for C18H23Cl2N5O2: C, 52.43; H,
5.62; N, 16.99. Found: C, 52.25; H, 5.80; N, 16.82.
4.1.16. 4(5)S]-4(5)-(2-Aminoethyl)-2-[(pyridyl-3)amino]imidaz
oline trihydrobromide (12d)
4.1.12. 4(5)S]-4(5)-(2-Aminoethylo)-2-[(4-metoxyphenyl)
amino]imidazoline dihydrobromide (10d)
Compound 12d was prepared according to the general proce-
dure B, starting from 12c (128 mg, 0.31 mmol). The product was
precipitated form MeOH with EtO2. Yield: 101 mg (73%), beige
powder. Mp 257–259 °C. 1H NMR (200 MHz, DMSO-d6 + TFA): d
(ppm) = 1.70–2.10 (m, 2H, CHCH2CH2), 2.75–3.05 (m, 2H,
CH2CH2NH), 3.37 (dd, J1 = 7.1, J2 = 9.8, 1H, HNCH2CH), 3.80 (t,
J = 9.8, 1H, HNCH2CH), 4.05–4.30 (m, 1H, CH2CH(NH)CH2), 7.65–
8.25 (m, 6H, C5H4N, NH3þ), 8.62–8.72 (m, 1H, C5H4N), 8.79 (s, 1H,
NH), 9.01 (s, 1H, NH), 10.70–11.10 (br s, 1H, NH). 13C NMR
(200 MHz, D2O): d (ppm) = 34.9, 38.7, 50.1, 56.1, 131.3, 138.8,
140.1, 142.7, 143.9, 160.2. MS FAB MH+ 206 (calcd for C10H15N5
M = 205.3). Anal. Calcd for C10H18Br3N5: C, 26.81; H, 4.05; N,
15.63. Found: C, 26.71; H, 4.24; N, 15.75.
Compound 10d was obtained according to the general procedure
B, starting from 10c (138 mg, 0.34 mmol). Yield: 128 mg (95%),
hygroscopic white powder. Mp 147–151 °C. 1H NMR (200 MHz,
DMSO-d6 + TFA): d (ppm) = 1.70–2.10 (m, 2H, CHCH2CH2), 2.70–
3.05 (m, 2H, CH2CH2NH), 3.24–3.42 (m, 1H, HNCH2CH), 3.65–3.85
(m, 4H, HNCH2CH, CH3O), 3.95–4.20 (m, 1H, CH2CH(NH)CH2), 6.96
(d, J = 8.9, 2H, C6H4OCH3), 7.17 (d, J = 8.9, 2H, C6H4OCH3), 7.60–8.10
(br s, 3H, NH3þ), 8.23 (s, 1H, NH), 8.51 (s, 1H, NH), 10.27 (s, 1H,
NH). 13C NMR (200 MHz, MeOD): d (ppm) = 34.1, 37.6, 49.7, 54.7,
56.6, 116.6, 128.1, 129.1, 160.0, 160.9. MS FAB MH+ 235 (calcd
for C12H18N4O M = 234.3). Anal. Calcd for C12H20Br2N4O: C, 36.38;
H, 5.09; N, 14.14. Found: C, 36.52; H, 5.15; N, 14.03.
4.1.17. 4(5)S]-4(5)-(N-Benzyloxycarbonyl-2-aminoethyl)-2-[(6-
methylpyridyl-2)amino]imidazoline dihydrochloride (13c)
Compound 13c was prepared according to the general proce-
dure A, starting from 13b (525 mg, 1.70 mmol). The product 13c
was extracted with CHCl3 (3 ꢁ 20 ml, drying with MgSO4), con-
verted into dihydrochloride (5.5 M HCl in MeOH) and purified by
column chromatography using CHCl3/MeOH (7:1) as eluent. Yield:
4.1.13. 4(5)S]-4(5)-(N-Benzyloxycarbonyl-2-aminoethyl)-2-[(3-
chlorophenyl)amino]imidazoline hydrochloride (11c)
Compound 11c was prepared according to the general proce-
dure A, starting from 11b (558 mg, 1.70 mmol). The product 11c
was extracted with CHCl3 (3 ꢁ 30 ml, drying with MgSO4),
converted into hydrochloride (5.5 M HCl in MeOH) and purified

162
A. P. Treder et al. / Bioorg. Med. Chem. 19 (2011) 156–167
271 mg (37%), oil. 1H NMR (200 MHz, CDCl3): d (ppm) = 1.70–2.05
(m, 2H, CHCH2CH2), 2.51 (s, 3H, CH3), 3.15–3.65 (m, 3H, CH2CH2NH,
HNCH2CH), 3.75–4.00 (m, 1H, HNCH2CH), 4.15–4.35 (m, 1H,
CH2CH(NH)CH2), 5.09 (s, 2H, OCH2Ph), 5.30–5.85 (br s, 1H, NH),
6.82–7.06 (m, 2H, C5H3N(CH3)), 7.27–7.42 (m, 5H, C6H5), 7.51 (t,
J = 7.8, C5H3N(CH3)), 8.30–9.10 (br s, 1H, NH), 9.35–10.25 (br s,
1H, NH), 11.97 (s, 1H, NH). Anal. Calcd for C19H25Cl2N5O2: C,
53.53; H, 5.91; N, 16.43. Found: C, 53.57; H, 6.04; N, 16.38.
M = 272.1, 274.1). Anal. Calcd for C11H16Br2Cl2N4: C, 30.37; H,
3.71; N, 12.88. Found: C, 30.30; H, 3.60; N, 12.70.
4.1.22. 4(5)R]-4(5)-(2-Aminoethyl)-2-[(2,4-dichlorophenyl)
amino]imidazoline dihydrobromide (14f)
Compound 14f was obtained according to the procedures A and
B, starting from 1b (390 mg, 1.65 mmol). Yield: 244 mg (34%),
white powder. Mp 263–265 °C. 1H NMR (200 MHz, MeOD): d
(ppm) = 1.96–2.24 (m, 2H, CHCH2CH2), 2.94–3.22 (m, 2H,
CH2CH2NH), 3.52 (dd, J1 = 6.6, J2 = 10.1, 1H, HNCH2CH), 3.94 (t,
J = 9.9, 1H, HNCH2CH), 4.20–4.40 (m, 1H, CH2CH(NH)CH2), 7.45–
7.59 (m, 2H, C6H3Cl2), 7.66–7.74 (m, 1H C6H3Cl2). 13C NMR
(200 MHz, MeOD): 34.1, 37.4, 49.3, 54.9, 130.3, 131.6, 131.8,
132.8, 134.0, 136.5, 159.8. MS FAB MH+ 273, 275 (calcd for
4.1.18. 4(5)S]-4(5)-(2-Aminoethyl)-2-[(6-methylpyridyl-2)
amino]imidazoline trihydrobromide (13d)
Compound 13d was obtained according to the general proce-
dure B, starting from 13c (132 mg, 0.31 mmol). The product 13d
was precipitated from mixture of MeOH and i-PrOH with Et2O.
Yield: 122 mg (85%), white powder. Mp 228–230 °C. 1H NMR
C11H14Cl2N4 M = 272.1, 274.1). Anal. Calcd for C11H16Br2Cl2N4: C,
(200 MHz, DMSO-d6 + TFA):
d
(ppm) = 1.80–2.10 (m, 2H,
30.37; H, 3.71; N, 12.88. Found: C, 30.29; H, 3.76; N, 12.70.
CHCH2CH2), 2.51 (s, 3H, CH3), 2.75–3.05 (m, 2H, CH2CH2NH), 3.43
(dd, J1 = 6.6, J2 = 10.3, 1H, HNCH2CH), 3.87 (t, J = 10.3, 1H,
HNCH2CH), 4.10–4.30 (m, 1H, CH2CH(NH)CH2), 6.90 (d, J = 8.1,
1H, C5H3N(CH3)), 7.01 (d, J = 7.6, 1H, C5H3N(CH3)), 7.69 (t, J = 7.8,
1H, C5H3N(CH3)), 7.80–8.10 (br s, 3H, NH3þ), 9.07 (s, 2H, NH),
11.95 (s, 1H, NH) 13C NMR (200 MHz, MeOD): d (ppm) = 24.2,
34.0, 37.4, 49.6, 54.1, 111.4, 121.1, 141.4, 151.6, 157.6, 158.8. MS
FAB MH+ 220 (calcd for C11H17N5 M = 219.3). Anal. Calcd for
4.1.23. 4(5)S]-4(5)-(N-Benzyloxycarbonyl-2-aminoethyl)-2-[(3-
trifluoromethylphenyl)amino]imidazoline hydrochloride (15c)
Compound 15c was prepared according to the general proce-
dure A, starting from 15b (592 mg, 1.70 mmol). Yield: 308 mg
(41%), oil. 1H NMR (500 MHz, CDCl3): d (ppm) = 1.68–1.93 (m,
2H, CHCH2CH2), 3.17–3.45 (m, 3H, CH2CH2NH, HNCH2CH), 3.70–
3.92 (m, 1H, HNCH2CH), 4.06–4.25 (m, 1H, CH2CH(NH)CH2), 5.00
(s, 2H, OCH2Ph), 5.68–5.80 (br s, 1H, NH), 7.20–7.55 (m, 9H, C6H5,
C6H4CF3), 8.15–8.35 (br s, 2H, NH), 11.00–11.12 (br s, 1H, NH). Anal.
Calcd for C20H22ClF3N4O2: C, 54.24; H, 5.01; N, 12.65. Found: C,
54.35; H, 5.03; N, 12.57.
C11H20Br3N5: C, 28.60; H, 4.36; N, 15.16. Found: C, 28.55; H,
4.30; N, 15.24.
4.1.19. 4(5)R]-4(5)-(2-Aminoethyl)-2-[(6-methylpyridyl-2)
amino]imidazoline trihydrobromide (13f)
Compound 13f was synthesized according to the procedures for
13c and 13d, starting from 1b (470 mg, 1.98 mmol). Yield of 13f:
400 mg (43%), white powder. Mp 232–235 °C. 1H NMR (200 MHz,
MeOD): d (ppm) = 2.00–2.24 (m, 2H, CHCH2CH2), 2.58 (s, 3H,
CH3), 3.02–3.22 (m, 2H, CH2CH2NH), 3.62 (dd, J1 = 6.6, J2 = 10.3,
1H, HNCH2CH), 4.04 (t, J = 10.3, 1H, HNCH2CH), 4.27–4.48 (m, 1H,
CH2CH(NH)CH2), 6.97 (d, J = 8.1, 1H, C5H3N(CH3)), 7.08 (d, J = 7.5,
1H, C5H3N(CH3)), 7.74 (t, J = 7.9, 1H, C5H3N(CH3)). 13C NMR
(200 MHz, MeOD): d (ppm) = 24.2, 34.1, 37.4, 49.6, 54.2, 111.5,
121.1, 141.5, 151.5, 157.6, 158.8. MS FAB MH+ 220 (calcd for
4.1.24. 4(5)S]-4(5)-(2-Aminoethyl)-2-[(3-trifluoromethylphenyl)
amino]imidazoline dihydrobromide (15d)
Compound 15d was prepared according to the general proce-
dure B, starting from 15c (150 mg, 0.34 mmol). Yield: 134 mg
(91%), extremely hygroscopic powder. 1H NMR (500 MHz, DMSO-
d6 + TFA): d (ppm) = 1.78–1.98 (m, 2H, CHCH2CH2), 2.78–2.95 (m,
2H, CH2CH2NH), 3.35–3.45 (m, 1H, HNCH2CH), 3.80 (t, J = 9.8, 1H,
HNCH2CH), 4.08–4.16 (m, 1H, CH2CH(NH)CH2), 7.55–7.75 (m, 4H,
C6H4CF3), 7.77–7.95 (br s, 3H, NH3þ), 8.57 (s, 1H, NH), 8.77 (s, 1H,
NH), 10.62 (s, 1H, NH). 13C NMR (200 MHz, MeOD):
d
C
11H17N5 M = 219.3). Anal. Calcd for C11H20Br3N5: C, 28.60; H,
(ppm) = 34.1, 37.5, 49.7, 54.9, 122.3, 122.4, 122.5, 122.6, 122.7,
125.2, 125.3, 125.4, 125.5, 128.0, 129.5, 132.5, 133.1, 133.8,
137.8, 159.6. MS FAB MH+ 273 (calcd for C12H15F3N4 M = 272.3).
Anal. Calcd for C12H17Br2F3N4: C, 33.20; H, 3.95; N, 12.91. Found:
C, 33.19; H, 3.98; N, 12.95.
4.36; N, 15.16. Found: C, 28.51; H, 4.26; N, 15.19.
4.1.20. 4(5)S]-4(5)-(N-Benzyloxycarbonyl-2-aminoethyl)-2-
[(2,4-dichlorophenyl)amino]imidazoline hydrochloride (14c)
Compound 14c was prepared according to the general proce-
dure A, starting from 14b (593 mg, 1.70 mmol). Yield: 279 mg
(37%), oil. 1H NMR (200 MHz, CDCl3): d (ppm) = 1.75–2.00 (m, 2H,
CHCH2CH2), 3.10–3.50 (m, 3H, CH2CH2NH, HNCH2CH), 3.85–4.00
(m, 1H, HNCH2CH), 4.00–4.30 (m, 1H, CH2CH(NH)CH2), 5.00 (s,
2H, OCH2Ph), 5.70–6.10 (br s, 1H, NH), 7.10–7.60 (m, 8H, C6H5,
C6H3Cl2), 8.10–8.60 (br s, 2H, NH), 9.90–10.40 (br s, 1H, NH). Anal.
Calcd for C19H21Cl3N4O2: C, 51.43; H, 4.77; N, 12.63. Found: C,
51.37; H, 4.83; N, 12.69.
4.1.25. 4(5)R]-4(5)-(2-Aminoethyl)-2-[(3-trifluoromethyl
phenyl)amino]imidazoline hydrochloride (15f)
Compound 15f was prepared according to the general proce-
dures A and B, starting from 1b (202 mg, 0.852 mmol). Yield:
156 mg (36%), extremely hygroscopic powder. 1H NMR (500 MHz,
DMSO-d6 + TFA): d (ppm) = 1.78–1.98 (m, 2H, CHCH2CH2), 2.78–
2.98 (m, 2H, CH2CH2NH), 3.37 (dd, J1 = 7.3, J2 = 9.8, 1H, HNCH2CH),
3.81 (t, J = 9.8, 1H, HNCH2CH), 4.08–4.20 (m, 1H, CH2CH(NH)CH2),
7.55–7.75 (m, 4H, C6H4CF3), 7.77–8.00 (br s, 3H, NH3þ), 8.65 (s,
1H, NH), 8.89 (s, 1H, NH), 10.80 (s, 1H, NH). 13C NMR (200 MHz,
MeOD): d (ppm) = 34.1, 37.5, 50.1, 54.9, 122.3, 122.4, 122.5,
122.6, 122.7, 125.3, 125.4, 125.4, 125.5, 128.0, 129.5, 132.5,
133.1, 133.8, 137.8, 159.6. MS FAB MH+ 273 (calcd for
4.1.21. 4(5)S]-4(5)-(2-Aminoethyl)-2-[(2,4-dichlorophenyl)
amino]imidazoline dihydrobromide (14d)
Compound 14d was obtained according to the general proce-
dure B, starting from 14c (151 mg, 0.34 mmol). Yield: 133 mg
(90%), white powder. Mp 260–263 °C. 1H NMR (200 MHz, DMSO-
d6): d (ppm) = 1.72–2.05 (m, 2H, CHCH2CH2), 2.70–3.05 (m, 2H,
CH2CH2NH), 3.30–3.50 (m, 1H, HNCH2CH), 3.70–3.92 (m, 1H,
HNCH2CH), 4.05–4.25 (m, 1H, CH2CH(NH)CH2), 7.42–7.66 (m, 2H,
C6H3Cl2), 7.75–8.06 (br s, 4H, NH3þ, C6H3Cl2), 8.47 (s, 1H, NH),
8.68 (s, 1H, NH), 10.43 (s, 1H, NH). 13C NMR (200 MHz, MeOD): d
(ppm) = 33.8, 37.1, 49.3, 54.6, 130.0, 131.3, 131.5, 132.5, 133.8,
136.2, 159.5. MS FAB MH+ 273, 275 (calcd for C11H14Cl2N4
C12H15F3N4 M = 272.3). Anal. Calcd for C12H17Br2F3N4: C, 33.20; H,
3.95; N, 12.91. Found: C, 33.27; H, 4.12; N, 12.99.
4.1.26. 4(5)S]-4(5)-(2-Aminoethyl)-2-[(2,6-dichlorophenyl)
amino]imidazoline dihydrobromide (16d)
Compound 16d was obtained according to the general
procedures A and B, starting from 16b (924 mg, 2.45 mmol). Yield
of 16d: 341 mg (32%), extremely hygroscopic white powder.

A. P. Treder et al. / Bioorg. Med. Chem. 19 (2011) 156–167
163
1H NMR (500 MHz, DMSO-d6):
d
(ppm) = 1.76–1.93 (m, 2H,
CH2CH(NH)CH2), 5.07 (s, 2H, OCH2Ph), 5.80–6.30 (br s, 1H, NH),
7.20–7.45 (m, 5H, C6H5), 7.55–8.40 (br s, 3H, NH). Anal. Calcd for
CHCH2CH2), 2.78–2.95 (m, 2H, CH2CH2NH), 3.37–3.45 (m,
1H, HNCH2CH), 3.77–3.87 (m, 1H, HNCH2CH), 4.04–4.18 (m, 1H,
CH2CH(NH)CH2), 7.45–7.55 (m, 1H, C6H3Cl2), 7.60–7.70 (m, 2H,
C6H3Cl2), 7.67–7.95 (br s, 3H, NH3þ), 8.59 (s, 1H, NH), 8.78 (s,
C20H29ClN4O2: C, 61.14; H, 7.44; N, 14.26. Found: C, 60.98; H,
7.43; N, 14.13.
1H, NH), 10.55 (s, 1H, NH). 13C NMR (200 MHz, MeOD):
d
4.1.30. 4(5)S]-4(5)-(2-Aminoethyl)-2-[(dicyclopropylmethyl)
amino]imidazoline dihydrochloride (17d)
(ppm) = 34.1, 37.3, 49.7, 55.0, 130.9, 132.8, 136.3, 159.5. MS FAB
MH+ 273, 275 (calcd for C11H14Cl2N4 M = 272.1, 274.1). Anal. Calcd
for C11H16Br2Cl2N4: C, 30.37; H, 3.71; N, 12.88. Found: C, 30.19; H,
3.90; N, 12.75.
Compound 17c (122 mg, 0.311 mmol) was dissolved in MeOH
(15 ml) and hydrogenated over 10% Pd/C (20 mg) for 4 h. Then
the catalyst was filtered off, the product was converted into dihy-
drochloride (5.5 M HCl in MeOH) and precipitated from MeOH
with Et2O. Yield: 84 mg (92%), oil. 1H NMR (500 MHz, DMSO-d6):
4.1.27. 4(5)R]-4(5)-(2-Aminoethyl)-2-[(2,6-dichlorophenyl)
amino]imidazoline dihydrobromide (16f)
Compound 16fwas prepared according to the general procedures
A and B, starting from 1b (200 mg, 0.844 mmol). Yield: 111 mg
(30%), extremely hygroscopic white powder. 1H NMR (500 MHz,
d
(ppm) = 0.15–0.60 (m, 8H, 2 ꢁ C2H4CH), 0.95–1.05 (m, 2H,
2 ꢁ C2H4CH), 1.65–1.78 (m, 2H, CHCH2CH2), 2.65–2.83 (m, 3H,
(C3H5)2CH, CH2CH2NH), 3.21 (dd, J1 = 6.8, J2 = 9.3, 1H, HNCH2CH),
3.66 (t, J = 9.3, 1H, HNCH2CH), 3.97–4.05 (m, 1H, CH2CH(NH)CH2),
DMSO-d6 + TFA):
d
(ppm) = 1.75–1.92 (m, 2H, CHCH2CH2),
5.90–8.90 (br s, 6H, NH). 13C NMR (200 MHz, MeOD):
d
2.75–2.95 (m, 2H, CH2CH2NH), 3.37–3.45 (m, 1H, HNCH2CH),
3.77–3.87 (m, 1H, HNCH2CH), 4.08–4.20 (m, 1H, CH2CH(NH)CH2),
7.42–7.67 (m, 4H, C6H4Cl2), 7.70–8.00 (br s, 3H, NH3þ), 8.66 (s, 1H,
NH), 8.75–9.03 (br s, 1H, NH), 10.63 (s, 1H, NH). 13C NMR
(200 MHz, MeOD): d (ppm) = 34.1, 37.3, 49.7, 55.0, 130.9, 132.8,
136.3, 159.6. MS FAB MH+ 273, 275 (calcd for C11H14Cl2N4
M = 272.1, 274.1). Anal. Calcd for C11H16Br2Cl2N4: C, 30.37; H,
3.71; N, 12.88. Found: C, 30.22; H, 3.90; N, 12.70.
(ppm) = 2.9, 3.0, 3.9, 4.0, 16.5, 16.6, 34.1, 37.5, 49.8, 54.4, 62.7,
160.0. MS FAB MH+ 223 (calcd for C12H22N4 M = 222.3). Anal. Calcd
for C12H24Br2N4: C, 37.52; H, 6.30; N, 14.58. Found: C, 37.39; H,
6.44; N, 14.50.
4.1.31. 4(5)S]-2-Benzyl-4(5)-(N-benzyloxycarbonylo-2-
aminoethyl)imidazoline hydrochloride (18)
Ethyl phenyliminoacetate hydrochloride (319 mg, 1.6 mmol)
was added to the solution of 1a and Et3N (0.17 ml, 1.25 mmol) in
99.9% anhyd EtOH (3 ml). The reaction mixture was refluxed for
2 h and the volatiles were evaporated under reduced pressure.
The residue was suspended in H2O (20 ml), alkalized with 1 M
NaOH and extracted with CHCl3 (3 ꢁ 15 ml, drying with Na2SO4).
The organic layer was evaporated yielding an oil of crude (42).
The product was converted into hydrochloride (5.5 M HCl in
MeOH) and purified by column chromatography on silica gel using
CHCl3/MeOH (7:1) as eluent. Yield: 320 mg (68%), oil. 1H NMR
(200 MHz, CDCl3): d (ppm) = 1.50–1.95 (m, 2H, CHCH2CH2), 3.10–
3.45 (m, 3H, CH2CH2NH, HNCH2CH), 3.65–4.25 (m, 4H, HNCH2CH,
CH2CH(NH)CH2, CCH2C6H5), 5.04 (s, 2H, OCH2Ph), 5.90–6.30 (br s,
1H, NH), 6.95–7.75 (m, 10H, C6H5, C6H5), 8.40–9.10 (br s, 1H,
NH), 10.20–10.60 (br s, 1H, NH). Anal. Calcd for C20H24ClN3O2: C,
64.25; H, 6.47; N, 11.24. Found: C, 64.22; H, 6.33; N, 11.43.
4.1.28. N-(Dicyclopropylmethyl)-S-methylisothiourea
hydroiodide (17b)
NaSCN (1230 mg, 16.18 mmol) was dissolved in acetone (40 ml)
and benzoyl chloride was added (1.81 ml, 16.18 mmol). The reac-
tion mixture was refluxed for 40 min. Then dicyclopropylmethyl-
amine 17a (1710 mg, 15.41 mmol) in acetone (40 ml) was added
dropwise. The reaction mixture was refluxed for 90 min and then
poured into cold water (400 ml). The product—N-benzoyl-N0-(dicy-
clopropylmethyl)urea was extracted with CHCl3 (4 ꢁ 75 ml, drying
with MgSO4). Yield: 3980 mg (94%), yellowish oil.
To (3980 mg, 14.49 mmol) of N-benzoyl-N0-(dicyclopropylm-
ethyl)urea 2.5 M NaOH (180 ml) was added. The reaction mixture
was heated at 90 °C for 90 min. After cooling, the solution was first
acidified with concd HCl then thoroughly alkalized with 20% NH3
(aq). The resulting viscous precipitate of thiourea was used in the
next step without further purification.
N-(Dicyclopropylmethyl)urea (680 mg, 4.0 mmol) was dis-
solved in MeOH (12 ml) and MeI (0.3 ml, 4.8 mmol) was added.
The reaction mixture was refluxed for 3 h. Then the volatiles were
evaporated under reduced pressure and the residue of (17b) was
crystallized from MeOH/Et2O. Yield: 774 mg (62%), white crystals.
Mp 145–147 °C. 1H NMR (200 MHz, DMSO-d6): d (ppm) = 0.20–
0.65 (m, 8H, 2 ꢁ C2H4CH), 0.95–1.18 (m, 2H, 2 ꢁ C2H4CH), 2.61 (s,
3H, SCH3), 2.95–3.10 (t, J = 7.7, 1H, (C3H5)2CH), 8.30–9.80 (br s,
3H, NH). Anal. Calcd for C9H17IN2S: C, 34.62; H, 5.49; N, 8.97; S,
10.27. Found: C, 34.75; H, 5.63; N, 8.82; S, 10.18.
4.1.32. 4(5)S]-4(5)-(2-Aminoethylo)-2-benzylimidazoline dihyd
robromide (19)
Compound 19 was prepared according to the general procedure
B. The product was crystallized from MeOH/i-PrOH/Et2O. Yield:
314 mg (88%), white powder. Mp 222–225 °C. 1H NMR (200 MHz,
MeOD): d (ppm) = 1.95–2.25 (m, 2H, CHCH2CH2), 2.90–3.25 (m,
2H, CH2CH2NH3þ), 3.67 (dd, J1 = 7.4, J2 = 11.4, 1H, HNCH2CH), 4.00
(s, 2H, CH2C6H5), 4.07 (t, J = 11.4, 1H, HNCH2CH), 4.40–4.60 (m,
1H, CH2CH(NH)CH2), 7.20–7.60 (m, 5H, C6H5). 13C NMR
(200 MHz, MeOD): d (ppm) = 34.0, 34.2, 37.3, 51.4, 56.7, 129.7,
130.6, 130.7, 133.6, 171.4. MS FAB MH+ 204 (calcd for C12H17N3
M = 203.3). Anal. Calcd for C12H19Br2N3: C, 39.48; H, 5.25; N,
11.51. Found: C, 39.30; H, 5.09; N, 11.43.
4.1.29. 4(5)S]-4(5)-(N-Benzyloxycarbonyl-2-aminoethyl)-2-
[dicyclopropylmethyl)amino]imidazoline hydrochloride (17c)
Compound 17c was prepared according to the general proce-
dure A, starting from 17b (530 mg, 1.70 mmol). The product 17c
was extracted with Et2O (3 ꢁ 30 ml, drying with MgSO4), con-
verted into hydrochloride (5.5 M HCl in MeOH) and purified by
two step column chromatography. Firstly, column chromatography
on silica gel using CHCl3/MeOH (4:1) as eluent and next on Sepha-
dex LH-20 using MeOH. Yield: 147 mg (22%), oil. 1H NMR
4.1.33. 4(5)S]-4(5)-(N-Benzyloxycarbonyl-2-aminoethyl)-2-
[(naphthyl-1)methylene]imidazoline hydrochloride (20a)
Ethyl (naphthyl-1)iminoacetate hydrochloride (380 mg,
1.52 mmol) was added to a solution of 1a (464 mg, 1.50 mmol)
and Et3N (208 ll, 1.50 mmol) in 99.9% EtOH (8 ml). The reaction
mixture was refluxed for 3 h and the volatiles were evaporated un-
der reduced pressure. The oil residue was suspended in H2O
(15 ml), alkalized with 1 M NaOH and extracted with CHCl3
(4 ꢁ 20 ml, drying with MgSO4). The organic layer was evaporated
yielding an oil of crude (46a). The product was converted into
hydrochloride (5.5 M HCl in MeOH) and purified by column chro-
(200 MHz, CDCl3):
d
(ppm) = 0.20–0.70 (m, 8H, 2 ꢁ C2H4CH),
0.80–1.13 (m, 2H, 2 ꢁ C2H4CH), 1.55–2.00 (m, 2H, CHCH2CH2),
2.86–3.08 (m, 1H, (C3H5)2CH), 3.10–3.48 (m, 3H, CH2CH2NH,
HNCH2CH), 3.54–3.78 (m, 1H, HNCH2CH), 3.85–4.10 (m, 1H,

164
A. P. Treder et al. / Bioorg. Med. Chem. 19 (2011) 156–167
matography on silica gel using CHCl3/MeOH (20:3) as eluent. Yield:
391 mg (62%), oil. 1H NMR (500 MHz, CDCl3): d (ppm) = 1.48–1.84
(m, 2H, CHCH2CH2), 3.00–3.20 (m, 2H, CH2CH2NH), 3.27–3.43 (m,
1H, HNCH2CH), 3.70–3.85 (m, 1H, HNCH2CH), 4.00–4.12 (m, 1H,
CH2CH(NH)CH2), 4.34 (s, 2H, CH2C10H7), 4.92 (s, 2H, OCH2Ph),
5.80–6.05 (br s, 1H, NH), 7.16–7.25 (m, 5H, C6H5), 7.33–8.05 (m,
filtrated, washed with hexane and discarded. The filtrate was evap-
orated under reduced pressure yielding an oil of 23, 1460 mg
(95%). 1H NMR (500 MHz, CDCl3): d (ppm) = 1.23 (t, J = 7.3, 3H,
CH2CH3), 2.03–2.22 (m, 2H, CCH2CH3), 3.31 (d, J = 16.1, 1H,
C6H4(O)CH2C), 3.63 (d, J = 16.1, 1H, C6H4(O)CH2C), 6.84–6.99 (m,
2H, C6H4(O)CH2), 7.18–7.24 (m, 2H, C6H4(O)CH2).
7H,
C10H7), 10.00–10.40 (br s, 2H, NH). Anal. Calcd for
C
24H26ClN3O2: C, 68.00; H, 6.18; N, 9.91. Found: C, 67.94; H,
4.1.38. 4(5)S]-4(5)-(N-Benzyloxycarbonyl-2-aminoethyl)-2-(2-
ethyl-2,3-dihydro-1-benzofurane-2)imidazoline hydrochloride
(24a)
6.15; N, 9.79.
Compound 23 (216 mg, 1.25 mmol) was dissolved in 99.9%
EtOH (2 ml) and 2.68 M EtONa in EtOH (70 ll, 0.188 mmol) was
4.1.34. 4(5)S]-4(5)-(2-Aminoethyl)-2-[(naphthyl-1)methylene]
imidazoline dihydrobromide (21a)
added. The reaction mixture was stirred at rt overnight. Then the
resulting mixture of iminoester was added to 1a (387 mg,
1.25 mmol) in 99.9% EtOH (5 ml). The reaction mixture was re-
fluxed for 4 h. The volatiles were evaporated and the crude 24a
was purified by column chromatography on silica gel using
CHCl3/MeOH (7:1) as eluent. Yield: 451 mg (84%), oil. 1H NMR
(500 MHz, CDCl3): d (ppm) = 0.95–1.05 (m, 3H, CH2CH3), 1.63–
1.79 (m, 1H, CHCH2CH2), 1.91–2.02 (m, 1H, CHCH2CH2), 2.13–
2.27 (m, 1H, CCH2CH3), 2.35–2.52 (m, 1H, CCH2CH3), 3.27–3.39
(m, 1H, CH2CH2NH), 3.43–3.53 (m, 1H, CH2CH2NH), 3.56–3.63 (m,
2H, HNCH2CH, C6H4(O)CH2C), 3.71–3.82 (m, 1H, C6H4(O)CH2C),
3.98–4.08 (m, 1H, HNCH2CH), 4.20–4.38 (m, 1H, CH2CH(NH)CH2),
5.03 (AB system, J1 = 12.2, J2 = 26.4, 2H, OCH2C6H5), 6.05–6.23 (br
s, 1H, NH), 6.89–6.98 (m, 2H, C6H4(O)CH2), 7.10–7.19 (m, 2H,
C6H4(O)CH2), 7.26–7.40 (m, 5H, C6H5), 9.60–11.00 (br s, 2H, NH).
Anal. Calcd for C23H28ClN3O3: C, 64.25; H, 6.56; N, 9.77. Found: C,
64.07; H, 6.58; N, 9.90.
Compound 21 was obtained according to the general procedure
B, starting from 20a. The product was crystallized from MeOH/
Et2O. Yield: 40 mg (96%), beige powder. Mp 294–297 °C. 1H NMR
(200 MHz, DMSO-d6): d (ppm) = 1.70–2.00 (m, 2H, CHCH2CH2),
2.75–3.05 (m, 2H, CH2CH2NH3þ), 3.55 (dd, J1 = 7.6, J2 = 11.4, 1H,
HNCH2CH), 3.92 (t, J = 11.4, 1H, HNCH2CH), 4.25–4.47 (m, 3H,
CH2CH(NH)CH2), C10H7CH2), 7.55–8.15 (m, 10H, C10H7, NH3þ). 13C
NMR (200 MHz, MeOD): d (ppm) = 31.7, 34.0, 37.2, 51.3, 56.7,
124.1, 127.1, 127.7, 128.7, 129.1, 130.1, 130.5, 130.8, 133.2,
135.8, 171.8. MS FAB MH+ 254 (calcd for C16H19N3 M = 253.3). Anal.
Calcd for C16H21Br2N3: C, 46.29; H, 5.10; N, 10.12. Found: C, 46.33;
H, 5.17; N, 10.06.
4.1.35. 4(5)R]-4(5)-(2-Aminoethyl)-2-[(naphthyl-1)methylene]
imidazoline dihydrobromide (21b)
Compound 21b was synthesized according to the procedure for
20a and 21a, starting from 1b (533 mg, 1.72 mmol). Yield: 414 mg
(58%), beige powder. Mp 307–309 °C. 1H NMR (200 MHz, MeOD): d
(ppm) = 1.90–2.20 (m, 2H, CHCH2CH2), 2.90–3.18 (m, 2H,
CH2CH2NH3þ), 3.65 (dd, J1 = 7.4, J2 = 11.6, 1H, HNCH2CH), 4.04 (t,
J = 11.4, 1H, HNCH2CH), 4.35–4.55 (m, 3H, CH2CH(NH)CH2),
4.1.39. 4(5)S]-4(5)-(2-Aminoethyl)-2-(2-ethyl-2,3-dihydro-1-
benzofurane-2)imidazoline dihydrobromide (25a)
Compound 25a was obtained according to the general procedure
B, starting from 24a (400 mg, 0.931 mmol). Product was crystallized
from MeOH/i-PrOH/Et2O. Yield: 364 mg (93%), white powder. Mp
207–210 °C. 1H NMR (500 MHz, DMSO-d6 + TFA): d (ppm) = 0.91 (t,
J = 7.3, 3H, CH2CH3), 1.78–1.98 (m, 2H, CHCH2CH2), 1.98–2.19 (m,
2H, CCH2CH3), 2.78–3.03 (m, 2H, CH2CH2NH), 3.38 (d, J = 16.6, 1H,
C6H4(O)CH2C), 3.56 (d, J = 16.1, 1H, C6H4(O)CH2C), 3.61–3.72 (m,
1H, HNCH2CH), 3.98 (dd, J1 = 11.2, J2 = 22.5, 1H, HNCH2CH), 4.33–
4.46 (m, 1H, CH2CH(NH)CH2), 6.85–6.97 (m, 2H, C6H4(O)CH2),
7.12–7.27 (m, 2H, C6H4(O)CH2), 7.70–8.10 (br s, 3H, NH3þ), 10.40–
10.65 (br s, 2H, NH). 13C NMR (200 MHz, MeOD): d (ppm) = 8.3,
33.5, 33.6, 34.0, 34.1, 37.2, 41.4, 41.6, 51.5, 57.2, 87.8, 111.4, 123.6,
125.8, 126.4, 130.1, 159.0, 175.0. MS FAB MH+ 260 (calcd for
C
10H7CH2), 7.45–7.72 (m, 4H, C10H7), 7.86–8.40 (m, 3H, C10H7).
13C NMR (200 MHz, MeOD): d (ppm) = 31.8, 34.0, 37.1, 51.3, 56.7,
124.1, 127.1, 127.7, 128.7, 129.1, 130.1, 130.5, 130.8, 133.2,
135.8, 171.8. MS FAB MH+ 254 (calcd for C16H19N3 M = 253.3). Anal.
Calcd for C16H21Br2N3: C, 46.29; H, 5.10; N, 10.12. Found: C, 46.38;
H, 5.07; N, 9.99.
4.1.36. 2-Ethyl-2,3-dihydro-1-benzofurane-2-carboxylic acid
amide (22b)
To 2-ethyl-2,3-dihydro-1-benzofurane-2-carboxylic acid methyl
ester 22a (2050 mg, 9.95 mmol), 24% NH3 in MeOH (60 ml) was
added. The reaction mixture was stirred for 48 h in rt. The volatiles
were evaporated under reduced pressure and the residue was crys-
tallized from AcOEt/hexane. Yield: 1730 mg (91%), white powder.
Mp 95–96 °C. 1H NMR (500 MHz, CDCl3): d (ppm) = 0.96 (t, J = 7.5,
3H, CH2CH3), 1.91–1.98 (m, 1H, CCH2CH3), 2.10–2.17 (m, 1H,
CCH2CH3), 3.18 (d, J = 16.1, 1H, C6H4(O)CH2C), 3.58 (d, J = 16.1, 1H,
C6H4(O)CH2C), 5.61–5.78 (br s, 1H, CONH2), 6.61–6.76 (br s, 1H,
CONH2), 6.83–6.95 (m, 2H, C6H4(O)CH2), 7.13–7.20 (m, 2H,
C6H4(O)CH2).
C15H21N3O M = 259.3). Anal. Calcd for C15H23Br2N3O: C, 42.78; H,
5.50; N, 9.98. Found: C, 42.60; H, 5.67; N, 9.79.
4.1.40. 4(5)R]-4(5)-(2-Aminoethyl)-2-(2-ethyl-2,3-dihydro-1-
benzofurane-2)imidazoline dihydrobromide (25b)
Compound 25b was prepared according to the procedure ap-
plied for 24a and 25a, starting from 1b (360 mg, 1.16 mmol). Yield
355 mg (73%), white powder. Mp 206–208 °C. 1H NMR (500 MHz,
DMSO-d6 + TFA): d (ppm) = 0.91 (t, J = 7.3, 3H, CH2CH3), 1.80–1.97
(m, 2H, CHCH2CH2), 1.98–2.19 (m, 2H, CCH2CH3), 2.79–3.04 (m,
2H, CH2CH2NH), 3.38 (d, J = 16.6, 1H, C6H4(O)CH2C), 3.57 (d,
J = 16.1, 1H, C6H4(O)CH2C), 3.62–3.70 (m, 1H, HNCH2CH), 3.98
(dd, J1 = 11.2, J2 = 22.4, 1H, HNCH2CH), 4.33–4.48 (m, 1H,
CH2CH(NH)CH2), 6.85–6.98 (m, 2H, C6H4(O)CH2), 7.12–7.28 (m,
2H, C6H4(O)CH2), 7.70–8.10 (br s, 3H, NH3þ), 10.40–10.65 (br s,
2H, NH). 13C NMR (200 MHz, MeOD): d (ppm) = 8.3, 33.5, 33.6,
34.0, 34.1, 37.3, 41.5, 41.7, 51.6, 57.2, 87.8, 87.9, 111.4, 123.6,
125.9, 126.5, 130.1, 159.0, 175.0. MS FAB MH+ 260 (calcd for
4.1.37. 2-Ethyl-2,3-dihydro-1-benzofurane-2-carboxylic acid
nitrile (23)
To 22b anhydrous pyridine (20 ml) was added. The solution was
cooled in ice bath and POCl3 (2.75 ml, 30.01 mmol) was added
dropwise. The reaction mixture was refluxed for 3 h. The volatiles
were removed under reduced pressure and the oily residue was
suspended in 1 M KHSO4 and extracted with CH2Cl2 (4 ꢁ 40 ml,
drying with MgSO4). The organic layer was evaporated. The oily
residue was dissolved in minimal volume of hexane: AcOEt
(10:1) and left in refrigerator overnight. The dark precipitate was
C15H21N3O M = 259.3). Anal. Calcd for C15H23Br2N3O: C, 42.78; H,
5.50; N, 9.98. Found: C, 42.64; H, 5.47; N, 9.84.

A. P. Treder et al. / Bioorg. Med. Chem. 19 (2011) 156–167
165
4.1.41. 4(5)S]-4(5)-(N-Benzyloxycarbonyl-2-aminoethyl)-2-(2,3-
2.68 M EtONa in EtOH (380
ll, 1.02 mmol) and 99.9% EtOH
dihydro-1,4-benzodioxane-2)imidazoline hydrochloride (28a)
(5 ml) were added to 1a (318 mg, 1.02 mmol). To the resulting
mixture, the iminoester obtained as above (161 mg, 1.02 mmol)
was added. The reaction mixture was refluxed for 1.5 h. The vola-
tiles were evaporated under reduced pressure and the product
30a was purified by column chromatography on silica gel using
CHCl3/MeOH (3:1) as eluent. Yield: 144 mg (42%), oil. 1H NMR
(500 MHz, CDCl3): d (ppm) = 1.77–1.98 (m, 2H, CHCH2CH2), 3.25–
3.40 (m, 2H, CH2CH2NH), 3.52–3.62 (m, 1H, HNCH2CH), 3.97–4.08
(m, 1H, HNCH2CH), 4.27–4.39 (m, 1H, CH2CH(NH)CH2), 4.61 (s,
2H, ClCH2C), 5.02 (AB system, J1 = 12.8, J2 = 17.7, 2H, OCH2C6H5),
6.22–6.33 (br s, 1H, NH), 7.25–7.40 (m, 5H, C6H5), 10.75–10.95
(br s, 2H, NH). Anal. Calcd for C14H19Cl2N3O2: C, 50.61; H, 5.76;
N, 12.65. Found: C, 50.58; H, 5.71; N, 12.76.
To a solution of 26 in 99.9% EtOH (253 ll), 2 M HCl in anhyd
Et2O (10 ml) were added. The reaction mixture was kept in a refrig-
erator (4 °C) for 3 days. The resulting precipitate was filtered,
washed with anhyd Et2O and dried in desiccator. Yield of iminoest-
er hydrochloride 27: 771 mg (73%), white powder. Mp 122–125 °C.
To 1a 99.9% EtOH (5 ml) and Et3N (162 ll, 1.16 mmol) were
added. To the resulting solution the iminoester hydrochloride 27
(283 mg, 1.16 mmol) was added. The reaction mixture was re-
fluxed for 4 h. Then the volatiles were evaporated and the residue
was suspended in 1 M NaOH (20 ml) and extracted with Et2O
(4 ꢁ 40 ml, drying with MgSO4). The organic layer was evaporated
under reduced pressure. The crude product 28a was converted into
hydrochloride (5.5 M HCl in MeOH) and purified by column chro-
matography on silica gel using CHCl3/MeOH (7:1) as eluent. Yield:
281 mg (58%), oil. 1H NMR (200 MHz, CDCl3): d (ppm) = 1.55–1.95
(m, 2H, CHCH2CH2), 3.15–3.45 (m, 2H, CH2CH2NH), 3.65–3.78 (m,
1H, HNCH2CH), 3.95–4.15 (m, 1H, HNCH2CH), 4.18–4.35 (m, 1H,
CH2CH(NH)CH2), 4.45–4.60 (m, 1H, OCH2CH), 4.90–5.03 (m, 1H,
OCH2CH), 5.09 (s, 2H, OCH2C6H5), 5.45–5.55 (m, 1H, OCH(C)CH2),
6.60–6.80 (br s, 1H, NH), 6.80–7.00 (m, 4H, C6H4O2), 7.25–7.40
(m, 5H, C6H5), 10.10–10.65 (br s, 2H, NH). Anal. Calcd for
4.1.45. 4(5)S]-2-[(N-Benzyl-N-phenyl)aminomethyl]-4(5)-(N-
benzyloxycarbonyl-2-aminoethyl)imidazoline hydrochloride
(30b)
N-Benzylaniline (564 mg, 3.08 mmol) and 99.9% EtOH (5 ml)
were added to 30a (155 mg, 0.467 mmol). The reaction mixture
was refluxed for 24 h., then cooled and 5.5 M HCl in MeOH (1.5 ml)
was added. The volatiles were evaporated under reduced pressure
and the product was purified by column chromatography on silica
gel using CHCl3/MeOH (6:1) as eluent. Yield: 90 mg (38%).1H NMR
(200 MHz, CDCl3): d (ppm) = 1.40–2.15 (m, 2H, CHCH2CH2), 2.93–
3.22 (m, 2H, CH2CH2NH), 3.25–3.50 (m, 1H, HNCH2CH), 3.75–3.93
(m, 1H, HNCH2CH), 3.95–4.18 (m, 1H, CH2CH(NH)CH2), 4.28–4.78
(m, 4H, NCH2C, NCH2C6H5), 5.00 (s, 2H, OCH2C6H5), 5.78–6.00 (br s,
1H, NH), 6.63–6.98 (m, 3H, NC6H5), 7.07–7.60 (m, 13H, OCH2C6H5,
NCH2C6H5, NC6H5, NH), 10.04 (s, 1H, NH), 10.68 (s, 1H, NH). Anal.
Calcd for C27H32Cl2N4O2: C, 62.91; H, 6.26; N, 10.87. Found: C,
62.88; H, 6.23; N, 10.93.
C21H24ClN3O4: C, 60.36; H, 5.79; N, 10.06. Found: C, 60.40; H,
5.85; N, 10.15.
4.1.42. 4(5)S]-4(5)-(2-Aminoethyl)-2-(2,3-dihydro-1,4-
benzodioxane-2)imidazoline dihydrobromide (29a)
Compound 29a was obtained according to the general proce-
dure B, starting from 28a. The product was crystallized from
i-PrOH/Et2O. Yield: 272 mg (85%), white powder. Mp 188–190 °C.
1H NMR (500 MHz, DMSO-d6 + TFA): d (ppm) = 1.70–2.03 (m, 2H,
CHCH2CH2), 2.78–3.05 (m, 2H, CH2CH2NH), 3.62 (dd, J1 = 8.1,
J2 = 19.2, 1H, HNCH2CH), 4.00 (t, J = 11.7, 1H, HNCH2CH), 4.35–
4.05 (m, 3H, CH2CH(NH)CH2, OCH2CH), 5.57–5.65 (m, 1H,
OCH(C)CH2), 6.80–7.05 (m, 4H, C6H4O2), 7.75–8.10 (br s, 3H,
NH3þ), 10.56 (s, 1H, NH), 10.66 (d, J = 12.7, 1H, NH). 13C NMR
(200 MHz, MeOD): d (ppm) = 33.9, 37.1, 51.6, 57.2, 65.9, 66.0,
69.9, 70.0, 119.0, 119.1, 124.0, 124.3, 142.8, 144.5, 168.6. MS FAB
MH+ 248 (calcd for C13H17N3O2 M = 247.3). Anal. Calcd for
C13H19Br2N3O2: C, 38.16; H, 4.68; N, 10.27. Found: C, 38.19; H,
4.50; N, 10.21.
4.1.46. 4(5)S]-4(5)-(2-Aminoethyl)-2-[(N-benzyl-N-phenyl)
aminomethyl]imidazoline trihydrobromide (30c)
Compound 30c was prepared according to the general procedure
B, starting from 30b (78 mg, 0.151 mmol). The product was
crystallized from i-PrOH/Et2O. Yield: 69 mg (83%). Mp 205–207 °C.
1H NMR (200 MHz, DMSO-d6 + TFA): d (ppm) = 1.75–2.10 (m, 2H,
CHCH2CH2), 2.75–3.10 (m, 2H, CH2CH2NH), 3.57 (dd, J1 = 7.3,
J2 = 11.4, 1H, HNCH2CH), 3.94 (t, J = 11.4, 1H, HNCH2CH), 4.28–4.48
(m, 1H, CH2CH(NH)CH2), 4.61 (s, 2H, NCH2C6H5), 4.72 (s, 2H, NCH2C),
6.55–6.85 (m, 3H, NC6H5), 7.18–7.50 (m, 8H, OCH2C6H5, NCH2C6H5,
NC6H5, NH), 7.80–8.15 (br s, 3H, NH3þ), 10.20 (s, 1H, NH), 10.33 (s,
1H, NH). 13C NMR (200 MHz, MeOD): d (ppm) = 33.9, 37.2, 49.9,
51.4, 56.4, 56.6, 56.9, 115.2, 116.8, 120.5, 128.8, 130.1, 130.8,
133.5, 149.4, 172.2. MS FAB MH+ 309 (calcd for C19H24N4
M = 308.4). Anal. Calcd for C19H27Br3N4: C, 41.40; H, 4.94; N, 10.17.
Found: C, 41.29; H, 5.15; N, 10.29.
4.1.43. 4(5)R]-4(5)-(2-Aminoethyl)-2-(2,3-dihydro-1,4-
benzodioxane-2)imidazoline dihydrobromide (29b)
Synthesis of 29b was carried out according to the procedures for
28a and 29a, starting from (1b) (381 mg, 1.23 mmol). Yield:
256 mg (51%), white powder. Mp 191–193 °C. 1H NMR (500 MHz,
DMSO-d6 + TFA): d (ppm) = 1.79–2.03 (m, 2H, CHCH2CH2), 2.77–
3.03 (m, 2H, CH2CH2NH), 3.60–3.73 (m, 1H, HNCH2CH), 4.00 (t,
J = 11.7, 1H, HNCH2CH), 4.37–4.05 (m, 3H, CH2CH(NH)CH2,
OCH2CH), 5.57–5.65 (m, 1H, OCH(C)CH2), 6.80–7.05 (m, 4H,
C6H4O2), 7.75–8.10 (br s, 3H, NH3þ), 10.56 (s, 1H, NH), 10.65 (d,
J = 13.7, 1H, NH). 13C NMR (200 MHz, MeOD): d (ppm) = 33.9,
37.1, 51.6, 57.2, 66.0, 66.1, 69.9, 70.0, 119.0, 119.1, 124.0, 124.3,
142.8, 144.5, 168.6. MS FAB MH+ 248 (calcd for C13H17N3O2
M = 247.3). Anal. Calcd for C13H19Br2N3O2: C, 38.16; H, 4.68; N,
10.27. Found: C, 38.20; H, 4.54; N, 10.09.
4.1.47. 4(5)S]-4(5)-(N-Benzyloxycarbonyl-2-aminoethyl)-2-
phenylimidazoline hydrochloride (31a)
99.9% EtOH (93
ll, 1.60 mmol) and 2 M HCl in Et2O (1.5 ml)
were added to benzonitrile (164
l
l, 1.60 mmol). The reaction mix-
ture was kept at 4–5 °C for 10 days. The precipitate of iminoester
was filtered off, washed with anhyd Et2O and dried in desiccator.
Yield: 100 mg (34%).
Compound 1a (167 mg, 0.54 mmol) dissolved in 99.9% EtOH
(5 ml) and Et3N (75 ll, 0.54 mmol) was added to the iminoester
4.1.44. 4(5)S]-4(5)-(N-Benzyloxycarbonyl-2-aminoethyl)-2-
(chloromethyl)imidazoline hydrochloride (30a)
obtained as above (100 mg, 0.544 mmol). The reaction mixture
was refluxed for 3 h. The volatiles were removed under reduced
pressure. The oily residue was suspended in 1 M NaOH (10 ml) and
extracted with CHCl3 (4 ꢁ 10 ml, drying with MgSO4). The organic
layer was evaporated and the crude (31a) was converted into hydro-
chloride with 5.5 M HCl in MeOH. The product was purified by col-
umn chromatography on silica gel using CHCl3/MeOH (5:1). Yield:
Chloroacetonitrile (316
ll, 5 mmol) was added to 99.9% EtOH
(291 l, 5 mmol) in 2 M HCl in Et2O. The reaction mixture was kept
l
for 2 days in 4 °C. The precipitate of iminoester was filtered off,
washed with anhyd Et2O and dried in a desiccator. Yield: 699 mg
(88%), white powder. Mp 85–86 °C.

166
A. P. Treder et al. / Bioorg. Med. Chem. 19 (2011) 156–167
107 mg (55%), oil. 1H NMR (200 MHz, CDCl3): d (ppm) = 1.60–2.00
(m, 2H, CHCH2CH2), 3.20–3.70 (m, 3H, CH2CH2NH, HNCH2CH),
3.85–4.10 (m, 1H, HNCH2CH), 4.15–4.40 (m, 1H, CH2CH(NH)CH2),
5.05 (s, 2H, OCH2C6H5), 6.20–6.45 (br s, 1H, NH), 7.20–8.30 (m,
10H, C6H5, C6H5), 10.62 (s, 1H, NH), 10.93 (s, 1H, NH). Anal. Calcd
for C19H22ClN3O2: C, 63.42; H, 6.16; N, 11.68. Found: C, 63.48; H,
6.23; N, 11.61.
(m, 1H, CH2CH(NH)CH2), 5.05 (s, 2H, OCH2C6H5), 6.10–6.15 (m,
1H, NH), 6.85 (d, J = 16.5, 1H, CHCHC), 7.18–7.58 (m, 10H, CHC6H5,
CH2C6H5), 8.25 (d, J = 16.5, 1H, C6H5CHCH), 10.00–10.80 (br s, 2H,
NH). Anal. Calcd for C21H24ClN3O2: C, 65.36; H, 6.27; N, 10.89.
Found: C, 65.08; H, 6.34; N, 10.73.
4.1.52. 4(5)S]-4(5)-(2-Aminoethyl)-2-[(E)-2-phenylethenyl]
imidazoline dihydrobromide (33b)
4.1.48. 4(5)S]-4(5)-(2-Aminoethyl)-2-phenylimidazoline
dihydrobromide (31b)
A solution of HBr in AcOH (5 ml) was added to 33a (240 mg,
0.623 mmol). The reaction mixture was stirred for 30 min at rt.
Then the volatiles were evaporated under reduced pressure and
the crude product was crystallized from MeOH/Et2O. Yield:
216 mg (92%), white powder. Mp 264–266 °C. 1H NMR (200 MHz,
DMSO-d6 + TFA): d (ppm) = 1.80–2.15 (m, 2H, CHCH2CH2), 2.80–
3.15 (m, 2H, CH2CH2NH), 3.64 (dd, J1 = 7.4, J2 = 11.4, 1H, HNCH2CH),
3.75–3.95 (t, J = 11.4, 1H, HNCH2CH), 4.35–4.60 (m, 1H,
CH2CH(NH)CH2), 6.83 (d, J = 16.5, 1H, CHCHC), 7.20–8.40 (m, 9H,
CHC6H5, C6H5CHCH, NH3þ), 10.36 (s, 1H, NH), 10.51 (s, 1H, NH).
13C NMR (200 MHz, MeOD): d (ppm) = 34.2, 37.4, 51.1, 56.5,
109.8, 130.1, 130.7, 133.3, 135.0, 149.1, 165.9. MS FAB MH+ 216
(calcd for C13H17N3 M = 215.3). Anal. Calcd for C13H19Br2N3: C,
41.40; H, 5.08; N, 11.14. Found: C, 41.40; H, 5.00; N, 11.19.
Preparation and purification of 31b was carried out according to
the general procedure B, starting from 31a (75 mg, 0.21 mmol). The
product was crystallized from i-PrOH with Et2O. Yield: 68 mg
(93%). Mp 195–197 °C. 1H NMR (200 MHz, DMSO-d6 + TFA): d
(ppm) = 1.80–2.20 (m, 2H, CHCH2CH2), 2.75–3.20 (m, 2H,
CH2CH2NH), 3.71 (dd, J1 = 8.06, J2 = 11.4, 1H, HNCH2CH), 4.06 (t,
J = 11.4, 1H, NCH2CH), 4.35–4.65 (m, 1H, CH2CH(NH)CH2), 7.57–
8.12 (m, 8H, C6H5, NH3þ), 10.70 (s, 2H, NH). 13C NMR (200 MHz,
MeOD): d (ppm) = 34.2, 37.4, 51.5, 56.9, 130.0, 130.8, 131.0,
136.5, 167.6. MS FAB MH+ 190 (calcd for C11H15N3 M = 189.3). Anal.
Calcd for C11H17Br2N3: C, 37.63; H, 4.88; N, 11.97. Found: C, 37.49;
H, 5.03; N, 11.93.
Acknowledgements
4.1.49. 4(5)S]-4(5)-(N-Benzyloxycarbonyl-2-aminoethyl)-2-(2-
fluorophenyl)imidazoline hydrochloride (32a)
This research was supported in part by the Polish Ministry of
Science and Higher Education, Poland (Grant N 405 041 32/2806)
and by Dr. Włodzimierz Zgoda Chemical Research Consulting &
Compound 1a (271 mg, 1.14 mmol) was dissolved in CH2Cl2
(4 ml) and the mixture was cooled in an ice bath. Then 2-fluorobenz-
aldehyde (115 ll, 1.09 mmol) was added and the resulting mixture
´
Production, Gdansk, Poland.
was stirred for 40–50 min at 0 °C. Then N-bromosuccinimide
(194 mg, 1.09 mmol) was added and the reaction mixture was stir-
red for additional 12 h at rt. The volatiles were evaporated under re-
duced pressure. The residue was suspended in 1 M NaOH (20 ml)
and extracted with CH2Cl2 (4 ꢁ 40 ml, drying with MgSO4). The or-
ganic layer was evaporated. The crude product (32a) was converted
into hydrochloride with 5.5 M HCl in MeOH and purified by column
chromatography on silica gel using CHCl3/MeOH (7:1). Yield:
254 mg (62%), oil. 1H NMR (200 MHz, CDCl3): d (ppm) = 1.70–2.15
(m, 2H, CHCH2CH2), 3.15–3.75 (m, 3H, CH2CH2NH, 1H, HNCH2CH),
3.95–4.20 (m, 1H, HNCH2CH), 4.25–4.50 (m, 1H, CH2CH(NH)CH2),
5.07 (s, 2H, OCH2C6H5), 6.10–6.30 (br s, 1H, NH), 7.10–7.70 (m, 9H,
C6H5, C6H4F), 8.25–8.50(br s, 2H, NH). Anal. Calcdfor C19H21ClFN3O2:
C, 60.40; H, 5.60; N, 11.12. Found: C, 60.31; H, 5.52; N, 11.02.
References and notes
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2281.
4.1.50. 4(5)S]-4(5)-(2-Aminoethyl)-2-(2-fluorophenyl)imidaz
oline dihydrobromide (32b)
Compound 32b was obtained according to the general proce-
dure B, starting from 32a (221 mg, 0.585 mmol). The product was
crystallized form i-PrOH/Et2O. Yield: 212 mg (98%). Mp 238–
240 °C. 1H NMR (200 MHz, DMSO-d6 + TFA): d (ppm) = 1.80–2.25
(m, 2H, CHCH2CH2), 2.83–3.18 (m, 2H, CH2CH2NH), 3.75 (dd,
J1 = 7.5, J2 = 11.4, 1H, HNCH2CH), 4.13 (t, J = 11.4, 1H, HNCH2CH),
4.47–4.68 (m, 1H, CH2CH(NH)CH2), 7.42–8.28 (m, 7H, C6H4F,
NH3þ), 10.63 (s, 1H, NH), 10.73 (s, 1H, NH). 13C NMR (200 MHz,
MeOD): d (ppm) = 34.1, 37.3, 51.5, 56.8, 112.2, 112.6, 118.3,
118.8, 127.0, 127.1, 132.0, 138.5, 138.7, 159.7, 163.3, 164.8. MS
FAB MH+ 208 (calcd for C11H14FN3 M = 207.2). Anal. Calcd for
11. Linton, B.; Hamilton, A. D. Tetrahedron 1999, 55, 6027.
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4.1.51. 4(5)S]-4(5)-(N-Benzyloxycarbonyl-2-aminoethyl)-2-[(E)-
2-phenylethenyl]imidazoline hydrochloride (33a)
Compound 33a was obtained according to the procedure ap-
plied for 32a, starting from cinnamaldehyde (251
ll, 1.99 mmol).
Yield 254 mg (33%), oil. 1H NMR (200 MHz, CDCl3):
d
(ppm) = 1.55–2.05 (m, 2H, CHCH2CH2), 3.10–3.55 (m, 3H,
CH2CH2NH, HNCH2CH), 3.75–3.95 (m, 1H, HNCH2CH), 4.05–4.25

A. P. Treder et al. / Bioorg. Med. Chem. 19 (2011) 156–167
167
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