Synthesis and antifibrillatory activity of nibentan and its analogues

Article abstract of DOI:10.1016/S0223-5234(00)00116-1

A series of 1,5-diaminopentane derivatives, structurally related to nibentan, was synthesized and tested for antifibrillatory activity. Improved modifications of some known chemical syntheses were proposed. (±)-N-[5- (Diethylamino)-1-(4-nitrophenyl)pentyl]-benzamide hydrochloride, (±)-N-[5- (diethylamino)-1-(4-nitrophenyl)pentyl]-4-nitrobenzamide hydrochloride and (±)-N-[5-(diethylamino)-1-(4-hydroxyphenyl)pentyl]-4-nitrobenzamide hydrochloride were more potent than nibentan and possessed a longer duration of action (up to 5 h in comparison with 60-90 min for nibentan). The antifibrillatory activity of (±)-N-[5-(diethylamino)-1-(4- methoxyphenyl)pentyl]-4-nitrobenzamide hydrochloride was comparable to that of nibentan but exceeded the potency of D-sotalol and sematilide. (C) 2000 Editions scientifiques et medicales Elsevier SAS.

Full text of DOI:10.1016/S0223-5234(00)00116-1

Eur. J. Med. Chem. 35 (2000) 205−215
© 2000 Éditions scientifiques et médicales Elsevier SAS. All rights reserved
S0223523400001161/FLA
205
Original article
Synthesis and antifibrillatory activity of nibentan and its analogues
Nadejda K. Davydovaa*, Olga S. Sizovaa, Svetlana M. Vinogradovaa, Alexandre I. L’vova,
Robert G. Glushkova, Sergey D. Yuzhakovb, Michail D. Mashkovskiyb
aDepartment of Organic Synthesis, Centre of Chemistry of Drugs, Zubovskaya Str. 7, Moscow 119815, Russia
bDepartment of Pharmacology, Centre of Chemistry of Drugs, Zubovskaya Str. 7, Moscow 119815, Russia
Received 7 January 1999; revised 3 June 1999; accepted 8 June 1999
Abstract – A series of 1,5-diaminopentane derivatives, structurally related to nibentan, was synthesized and tested for antifibrillatory activity.
Improved modifications of some known chemical syntheses were proposed. (±)-N-[5-(Diethylamino)-1-(4-nitrophenyl)pentyl]-benzamide
hydrochloride, (±)-N-[5-(diethylamino)-1-(4-nitrophenyl)pentyl]-4-nitrobenzamide hydrochloride and (±)-N-[5-(diethylamino)-1-(4-
hydroxyphenyl)pentyl]-4-nitrobenzamide hydrochloride were more potent than nibentan and possessed a longer duration of action (up to 5 h
in comparison with 60–90 min for nibentan). The antifibrillatory activity of (±)-N-[5-(diethylamino)-1-(4-methoxyphenyl)pentyl]-4-
nitrobenzamide hydrochloride was comparable to that of nibentan but exceeded the potency of D-sotalol and sematilide. © 2000 Éditions
scientifiques et médicales Elsevier SAS
synthesis / antifibrillatory activity / nibentan / 1,5-diaminopentane derivatives / structure–activity relationships
1. Introduction
2. Chemistry
(±)-N-[5-(Diethylamino)-1-phenylpentyl]-4-nitrobenz-
amide hydrochloride (nibentan, 1a) is known as the
representative of new class III antiarrhythmic drugs
which is highly effective and well tolerated in patients
with atrial flutter and fibrillation or supraventricular
tachycardia [1, 2].
The aim of this work was to obtain compounds more
active than nibentan and to study the structure–activity
relationships in the series of 1,5-diaminopentane deriva-
tives by way of chemical and structural variations on the
molecule whose antiarrhythmic activity has been already
shown.
The synthetic route utilized for the preparation of
nibentan (1a) and the majority of its analogues 1b–j is
shown in figure 1.
Condensation of phenylacetonitrile (2a) or (4-
methoxyphenyl)acetonitrile (2b) with diethyl carbonate
by means of sodium ethylate in toluene gave ethyl
arylcyanoacetate sodium salts 3a or 3b, respectively.
Alkylation of sodium salts 3a and 3b with 1,4-
dibromobutane yielded the corresponding bromides 4a
and 4b. Treatment of the compounds 4a and 4b with the
amines 5a–c gave the amino derivatives 6a–d which were
decarbethoxylated with aqueous potassium hydroxide in
the presence of triethylbenzylammonium chloride to the
corresponding cyano derivatives 7a–d. Reaction of 7a–d
with hydrogen peroxide in dimethylsulfoxide gave the
1-carbamoyl derivatives 8a–d which were rearranged to
the corresponding urethanes 9a–d according to the Hoff-
man reaction by means of bromine and sodium methylate
in methanol. Hydrolysis of urethanes 9a–d with sodium
hydroxide in ethanol afforded the amines 10a–d which
In this paper we report the synthesis and the antifibril-
latory activity of a new series of 1,5-diaminopentane
derivatives which can be considered as structural ana-
logues of nibentan (table I).
*Correspondence and reprints:
davydova@dmg.genebee.msu.su

206
Table I. 1,5-Diaminopentane derivatives 1a–p.
Compound R1
R2
R3
R4
X
Yield, %
M.p. °C
Formula**
1a
1b
1c
1d
1e*
1f*
1g
1h
1i
H
H
MeO
H
H
NO2
NO2
H
H
H
H
H
OH
H
H
Et
Me
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
C6H4NO2-4
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
NH
92.6
23.0
96.6
72.0
51.7
29.0
55.8
68.8
52.0
46.6
68.5
50.0
37.0
55.6
71.0
25.7
165–167 C22H29N3O3·HCl
73–75 C29H35N3O5·HCl
110–112 C23H31N3O4·HCl
104–106 C22H29N3O3·HCl
(CH2)2C6H3(OMe)2-3,4 C6H4NO2-4
Et
Et
Et
Et
Et
CH2Ph
Et
Et
Et
Et
Et
H
Et
Et
C6H4NO2-4
C6H4NO2-3
3-pyridyl
65–66
51–53
C21H29N3O
C22H29N3O3
Ph
C6H4NO2-4
Ph
160–162 C22H28N4O5·HCl
71–72 C27H32N2O·HCl
116–117 C25H34N2O3·HCl
102–103 C23H32SN2O3·HCl
C6H4COOEt-4
C6H4SO2Me-4
C6H4NH2-4
C6H4OH-4
C6H4NO2-4
Ph
1j
1k*
1l
56–57
C22H31N3O
101–103 C22H30N2O2·HCl
130–135 C22H29N3O4·HCl
194–195 C20H26N2O·HCl
108–109 C23H31N3O2·HCl
105–107 C22H30N4O2·2HCl
1m
1n
1o
1p
C6H4CONH2-4
C6H4NO2-4
H
*As a base, **C, H, N analyses were within ± 0.4% of the calculated values.
were coupled with the appropriate chlorides of acids
11a–f in acetonitrile to yield the final products 1a–j
(figure 1).
The 1,5-diaminopentane derivatives 1k–o were synthe-
sized starting from the corresponding compounds 1a, 1c,
1h and 1i as illustrated in figure 2.
Nitro-substituted diamine 10e was synthesized starting
from non-substituted diamine 10a for the preparation of
nitrophenyl substituted final products 1f and 1g.
Diamine 10a was acetylated by acetic anhydride to
give the intermediate acetylated derivative 12 which was
nitrated with fuming nitric acid in concentrated sulfuric
acid to afford the compound 13 with a touch of the 3- and
2-nitro isomers in a 20:4:1 ratio, respectively. Treatment
of 13 with aqueous hydrochloric acid gave 4-nitrophenyl
substituted diamine 10e (figure 3).
Reduction of the nitro-group in 1a with iron in water in
the presence of ammonium chloride gave the amino
compound 1k. Diazotization of 1k in sulfuric acid and
subsequent hydrolysis afforded N-[5-(diethylamino)-1-
phenylpentyl]-4-hydroxybenzamide which was converted
to the hydrochloride 1l by treatment with hydrogen
chloride solution in isopropyl alcohol. Reaction of 1c
with boron tribromide in dichloromethane and subse-
quent treatment of the resulting compound with hydrogen
chloride solution in isopropyl alcohol gave the hydroxy
derivative 1m. Compound 1h was reduced with catalytic
hydrogenation in the presence of 20% palladium (II)
hydroxide on carbon to obtain the hydrochloride 1n.
Reaction of ester 1i with formamide and sodium methy-
late in methanol and subsequent treatment with hydrogen
chloride solution in isopropyl alcohol provided amide 1o
(figure 2).
3. Results and discussion
We have recently described the preparation of the
substituted phenylacetonitriles 7a–d starting from the
corresponding aryl substituted α-cyano esters 6a–d by a
phase-transfer catalysis method [3]. Hydrolysis of the
cyano-group to the amide function using hydrogen per-
oxide in dimethylsulfoxide has been previously re-
ported [4]. Our attempts to convert the amides 8a–d to
the amines 10a–d according to the Hoffman reaction by
alkaline sodium hypochlorite were not satisfactory be-
cause of side reactions and low yields of desired products.
To obtain the amines 10a–d as their carbomethoxy
derivatives in good yields we have used our own variant
Diamine 10a was coupled with the iminoester 14 to
yield the desired compound 1p (figure 3).

207
Figure 1. Synthesis of nibentan 1a and its analogues 1b–j.
of the modification of the Hoffman rearrangement with
bromine and sodium methylate in methanol [5, 6]. The
order of the reagent mixing was changed. To carry out
this reaction at 0 °C instead of –45 °C [6] bromine was
added to the solution of sodium methylate and the amide
8 in methanol. It is known that acid hydrolysis of
urethanes is very slow. Alkaline hydrolysis of urethanes
in alcoholic solution also requires a long reaction
time [7]. Thus, carbomethoxy derivatives 9a and 9b were
converted to the amines 10a and 10b with sodium
hydroxide in ethanol for 17–24 h by the above-mentioned
method [7]. We have found that the addition of triethyl-
benzylammonium chloride to the reaction mixture de-
creased the reaction time to 5–6 h and gave the higher
yields of desired amines 10. Coupling of the amines
10a–e with the chlorides of acids 11a–f in acetonitrile
directly provided the corresponding final products 1a–j as
hydrochlorides.
3.1. Structure–activity relationships
It was shown that the most of new 1,5-diaminopentane
derivatives possessed the antifibrillatory activity (ta-
ble II). The level of antifibrillatory activity depends on
the nature of the substituents R1, R3, R4 and X in the
compounds 1a–p. The presence of the nitro- or hydroxy-
groups (R1) in the 4- position of the phenyl ring in
combination with the diethylamino function (R2, R3) and
the 4-nitrophenyl or phenyl substituents (R4) increased
the antifibrillatory activity. Thus, the compounds 1f, 1g

208
Figure 3. Synthesis of compounds 1p and 10e.
Thus, replacement of the 4-nitrophenyl group (R4) in
1a by the different substituents cited above, except for
compound 1f, was unfavourable. On the contrary, intro-
duction of the nitro- and hydroxy- groups (R1) in the 4-
position of the phenyl ring increased the antifibrillatory
activity. So, the search of new substituents in this position
is the way to obtain the analogues of nibentan with higher
antifibrillatory activity.
Figure 2. Synthesis of 1,5-diaminopentane derivatives 1k–o.
4. Experimental protocols
and 1m were more active than nibentan (1a) and pos-
sessed a longer duration of action. For example, the
principal metabolite of nibentan (1m) [8] kept its anti-
fibrillatory activity level for at least 5 h. The antifibrilla-
tory activity of the 4-methoxy (R1) derivative 1c was
comparable to that of nibentan (1a).
Compound 1b with the 3,4-dimethoxyphenylethyl and
methyl groups (R2, R3) was less potent than nibentan
(1a). Replacement of the 4-nitrophenyl group (R4) in 1a
by 3-nitrophenyl, 3-pyridyl, 4-carboethoxyphenyl or
4-hydroxyphenyl ones decreased the antifibrillatory ac-
tivity of the compounds 1d, 1e, 1i and 1l. Similar results
were noted by replacement of the oxo- group in 1a by an
imido- group (compound 1p). Compounds 1h, 1n with
the benzylethylamino and ethylamino functions (R2, R3)
and phenyl substituent (R4) possessed only weak anti-
fibrillatory activity. No detectable antifibrillatory activity
was found for derivatives with the C6H4SO2Me-4 and
C6H4CONH2-4 substituents (R4; compounds 1j and 1o).
4.1. Chemistry
Melting points were determined in open capillaries and
are uncorrected. Yields of products were not optimized.
The structures of all the compounds were determined by
IR, 1H-NMR, mass-spectra and microanalyses. Chemical
purity of the final products was checked by TLC on
Silufol UV 254 plates and the location of spots was
detected by illumination with a UV lamp. The analytical
results (C, H, N) for pure compounds were within ± 0.4%
of the theoretical values. Infrared (IR) spectra were
recorded on a Perkin Elmer 599 spectrophotometer as
nujol mulls or as liquid film.
Proton nuclear magnetic resonance (1H-NMR) spectra
were recorded on a Unity + 400 Varian spectrophoto-
meter in CDCl3 or (CD3)2SO or CD3OD using tetram-
ethyl silane as the internal standard. All values of
chemical shifts (δ) are reported in ppm. Signals are
designated as follows: s, singlet; br.s, broad singlet;

Table II. Antifibrillatory activity of 1,5-diaminopentane derivatives 1a–j and l–p.
Compound Doses,
Number of Number
experiments of catsa
Left ventricular fibrillation threshold (mA)b
Time after compound administration
µg/kg
Baseline
5
5 min
6
15 min
7
30 min
8
60 min
9
90 min
10
120 min
11
180 min
12
240 min
13
300 min
14
1
2
3
4
Control
1a
(Nibentan)
1b
Saline
25
100
25
100
25
100
25
100
25
100
25
6
6
16
1.1 ± 0.1
1.3 ± 0.1
1.1 ± 0.2
1.1 ± 0.2
1.2 ± 0.2
1.2 ± 0.3
1.4 ± 0.3
1.4 ± 0.4
1.4 ± 0.4
16
16
5
5
7
7
6
6
7
7
5
6
6
6
4
3
4
9
9
6
6
3
5
6
6
6
6
7.3 ± 1.6* 5.9 ± 0.9* 3.3 ± 0.4* 1.2 ± 0.2
1.2 ± 0.1 18.7 ± 0.9* 20.0 ± 0.7* 13.2 ± 1.6* 8.5 ± 1.6* 7.4 ± 1.9*
1.4 ± 0.2 6.2 ± 1.1* 5.4 ± 0.9* 1.8 ± 0.2 1.3 ± 0.1
1.3 ± 0.2 12.3 ± 2.1* 10.7 ± 2.0* 3.3 ± 0.7* 2.4 ± 0.4
1.6 ± 0.2 12.3 ± 2.2* 12.0 ± 2.6* 8.2 ± 1.2* 4.1 ± 0.7* 1.6 ± 0.3
1.5 ± 0.2 15.2 ± 2.6* 20.0 ± 1.9* 18.2 ± 1.8* 4.4 ± 0.9*
5
1c
1d
1e
7
6
1.6 ± 0.2
2.6 ± 0.3* 2.4 ± 0.3* 3.7 ± 0.2* 1.6 ± 0.2
1.5 ± 0.2 19.0 ± 0.7* 18.0 ± 1.1* 12.0 ± 1.5* 8.0 ± 2.3* 1.7 ± 0.2
2.0 ± 0.4
1.9 ± 0.3
1.9 ± 0.4 20.0 ± 1.4* 20.0 ± 1.4* 20.0 ± 1.4* 13.4 ± 3.0* 8.3 ± 5.9
1.4 ± 0.1 20.0 ± 1.7* 20.0 ± 1.7* 10.0 ± 3.2* 8.4 ± 3.7* 8.2 ± 3.7* 8.0 ± 0.6*
1.2 ± 0.2 7.2 ± 0.8* 1.3 ± 0.3
1.3 ± 0.2 20.0 ± 1.1* 20.0 ± 1.2* 1.5 ± 0.2
1.6 ± 0.3 20.0 ± 1.8* 20.0 ± 1.8* 14.0 ± 2.2* 1.8 ± 0.4
Nonactive
7
4.0 ± 1.2* 3.3 ± 0.7* 1.9 ± 0.3
8.6 ± 2.7* 8.8 ± 2.8* 5.9 ± 3.4* 2.5 ± 0.4
1f
1g
1h
5
6
6
6.0 ± 1.0
25
100
500
500
500
500
25
100
100
500
500
500
500
1 000
100
500
1i
1j
1l
1m
4
3
4
9
2.0 ± 0.3 20.0 ± 0.8* 20.0 ± 0.8* 17.0 ± 1.3* 10.5 ± 2.0* 8.3 ± 2.0* 1.4 ± 0.2
1.5 ± 0.2
1.9 ± 0.2 20.0 ± 1.0* 20.0 ± 1.1* 20.0 ± 1.1* 20.0 ± 1.0* 19.3 ± 0.9* 20.0 ± 0.9* 20.0 ± 0.8* 20.0 ± 0.8* 18.0 ± 0.6*
1.4 ± 0.2 3.0 ± 0.6* 4.0 ± 1.0* 1.5 ± 0.5
1.5 ± 0.2 20.0 ± 1.3* 20.0 ± 1.0* 12.8 ± 1.3* 2.2 ± 0.4
Nonactive
1.1 ± 0.1 20.0 ± 1.4* 7.5 ± 1.0* 1.5 ± 0.4
1.1 ± 0.4
0.9 ± 0.1 13.5 ± 5.2* 11.1 ± 1.0* 10.9 ± 2.4* 5.9 ± 1.1*
2.0 ± 0.4
2.2 ± 0.2
7.7 ± 1.7* 4.7 ± 1.0* 8.7 ± 1.9* 8.1 ± 2.7* 2.8 ± 0.3* 1.9 ± 0.4
1n
6
1o
1p
D-Sotalol
3
5
6
2.2 ± 0.7
1.8 ± 0.3
3.1 ± 0.6
1.5 ± 0.3
0.9 ± 0.1
Sematilide
6
4.9 ± 2.4
5.5 ± 1.8* 6.8 ± 2.8* 5.0 ± 1.7* 2.9 ± 0.5* 2.2 ± 0.4
6.5 ± 3.5
9.6 ± 3.3* 12.2 ± 3.0* 12.4 ± 3.4* 9.4 ± 1.9* 10.0 ± 4.3
3.7 ± 1.0
*Significantly different from baseline, P < 0.05. Absence of the asterisk indicates that P > 0.05. aThe subsequent dose of the substance was administered to the same
b
cat after restoration of the elevation of the left ventricular fibrillation threshold induced by the previous dose. Values as mean ± SEM.

210
br.sign., broad signal; d, doublet; br.d, broad doublet; t,
triplet; br.t, broad triplet; q, quadruplet; br.q, broad
quadruplet; m, multiplet.
Mass spectra (MS) were recorded on an SSQ-710
chromatograph/mass spectrometer, electron impact 70 eV
or chemical ionization; only significant m/z peaks are
reported here.
dry acetonitrile (49 mL) using the same procedure de-
scribed for compound 1a. After cooling to 0–1 °C,
acetonitrile was evaporated in vacuo. The residue was
dissolved in 2-propanol (20 mL), treated with charcoal
(2 g) and heated at reflux under stirring. After filtration,
the mother liquor was cooled to 0–5 °C. The precipitate
was filtered off, washed with 2-propanol (3 mL) to give
10.01 g of 1c. The filtrate was evaporated in vacuo. The
residue was recrystallized from 2-propanol to give 7.66 g
of 1c. The total yield was comprised 17.67 g (96.6%) of
1c. M.p. 110–112 °C (from 2-propanol). IR (Nujol):
3 220 (NH), 2 680–2 090 (N+H), 1 660 (C=O) cm–1. MS,
m/z: M+ 413, [M-Me]+ 398, [M-(CH2)4NEt2]+ 285,
4.1.1. (±)-N-[5-(Diethylamino)-1-phenylpentyl]-
4-nitrobenzamide hydrochloride 1a
A solution of 11a (14.97 g, 0.0807 mol) in dry aceto-
nitrile (46 mL) was added to a stirred solution of 10a [9]
(18.0 g, 0.0768 mol) in dry acetonitrile (20 mL) cooled to
0–5 °C. The reaction mixture was stirred at 0–5 °C for
4 h. The precipitate was filtered off, washed with
2-propanol to give 29.81 g (92.6%) of 1a. M.p.
165–167 °C (from 2-propanol).
+O≡C–C6H4NO2 150,
CH2=N+Et2 86.
1H-NMR
((CD3)2SO): δ 1.17 (6H, t, Me2), 0.95–1.60 (6H, m,
(CH2)3), 2.97 (2H, m, 5-CH2), 3.04 (4H, q, N(CH2)2),
3.76 (3H, s, OMe), 4.96 (1H, br.q, CH), 6.90 (2H, d, H
arom.), 7.34 (2H, d, H arom.) 8.11 (2H, d, H arom.), 8.31
4.1.2. (±)-[5-[N-Methyl-N-[2-(3,4-dimethoxyphenyl)-
ethyl]amino]pentyl]-4-nitrobenzamide hydrochloride 1b
A solution of 11a (10.48 g, 0.0565 mol) in dry aceto-
nitrile (33 mL) was added to a stirred solution of 10b
(19.18 g, 0.0538 mol) in dry acetonitrile (19 mL) cooled
to 0–5 °C. The reaction mixture was stirred at 0–5 °C for
4 h, then at 50 °C for 1 h, cooled to room temperature and
evaporated. The residual brown oil (13.7 g) was dissolved
in water (260 mL) at 80 °C. The aqueous solution was
treated with activated charcoal (3 g) under stirring. After
filtration, the mother waters were passed through a short
silica gel column. The aqueous solution was basified with
aqueous ammonia to pH 9.0, extracted with CHCl3 (2 ×
100 mL), washed with water, dried over anhydrous
Na2SO4, filtered and evaporated in vacuo. The residual
yellow oil was dissolved in dry diethyl ether and satu-
rated with HCl gas. The yellow solid was collected by
filtration and recrystallized from toluene to give 6.7 g
(23%) of 1b. M.p. 73–75 °C. The Rf value of the
principal spot is 0.63 (200 µg was applied; chloroform-
ethanol-ammonia 75:22:0.2 as mobil phase) and the total
of all secondary spots is not more than 1.0% in compari-
son with the principal spot. IR (Nujol): 3 210 (NH),
2 680–2 560 (N+H), 1 650 (C=O) cm–1. MS, m/z: [MH]+
3
(2H, d, H arom.), 9.10 (1H, d, NH, JCH, NH = 8.4 Hz).
4.1.4. (±)-N-[5-(Diethylamino)-1-phenylpentyl]-
3-nitrobenzamide hydrochloride 1d
A solution of 11b (5.54 g, 0.0299 mol) in dry aceto-
nitrile (6 mL) was added to a stirred solution of 10a [9]
(7.0 g, 0.0299 mol) in dry acetonitrile (20 mL) at room
temperature. The reaction mixture was stirred at 50 °C for
30 min, at 5–10 °C for 3 h. The solvent was evaporated in
vacuo. The residue was triturated with 2-propanol at
0–5 °C. The precipitate was filtered off to give 9.0 g
(72%) of 1d. M.p. 104–106 °C. MS, m/z: [MH]+ 384,
+
[M-Me]+ 368, O≡C–C6H4NO2 150, CH2=N+Et2 86. IR
(Nujol): 3 230 (NH), 1 660 (C=O) cm–1. 1H-NMR
((CD3)2SO): δ 1.19 (6H, t, Me2), 1.20–2.05 (6H, m,
(CH2)3), 3.00 (2H, m, 5-CH2), 3.06 (4H, br.q, N(CH2)2),
5.04 (1H, m, CH), 7.20–7.47 (5H, m, H arom.), 7.79 (1H,
t, 5-H arom.), 8.40 (2H, 2d, 4-,6-H arom.), 8.74 (1H, s,
3
2-H arom.), 9.31 (1H, d, NH, JCH, NH = 8.1 Hz).
4.1.5. (±)-N-[5-(Diethylamino)-1-
phenylpentyl]-3-pyridylamide 1e
A solution of 11d (0.48 g, 0.0034 mol) in dry aceto-
nitrile (4 mL) was added to a stirred solution of 10a [9]
(0.8 g, 0.0034 mol) in dry acetonitrile (4 mL) at room
temperature. The reaction mixture was refluxed for
30 min and cooled to room temperature. The solvent was
evaporated in vacuo. The residue was dissolved in water
(20 mL). The aqueous solution was basified with 40%
aqueous NaOH to pH 9.0, extracted with ethyl acetate
(2 × 20 mL), and washed with water. The combined
organic extracts were dried over anhydrous Na2SO4,
passed through a short silica gel column and evaporated.
The residue was triturated with heptane. The precipitate
1
506. H-NMR (CD3OD): δ 1.49 (2H, m, 3-CH2), 1.81
(2H, m, 4-CH2), 2.01 (2H, m, 2-CH2), 2.91 (3H, s, NMe),
2.90–3.50 (m, 5-CH2, (CH2)2), 3.79 (3H, s, OMe), 3.83
(3H, s, OMe), 5.15 (1H, m, CH), 6.80–6.95 (3H, m, H
arom.), 7.20–7.50 (5H, m, H arom.), 8.00–8.33 (4H, m, H
arom.), 9.08 (1H, d, NH).
4.1.3. (±)-N-[5-(Diethylamino)-1-(4-methoxyphenyl)-
pentyl]-4-nitrobenzamide hydrochloride 1c
The compound 1c was obtained in 96.6% yield from
10c (10.73 g, 0.0406 mol), 11a (7.61 g, 0.0410 mol) and

211
was filtered off to give 0.6 g (51.7%) of 1e. M.p.
4.1.8. (±)-N-[5-(Benzylethylamino)-1-phenylpentyl]-
benzamide hydrochloride 1h
1
65–66 °C. MS, m/z: M+ 339. H-NMR ((CD3)2SO): δ
0.90 (6H, t, Me2), 1.20–1.45 (4H, m, (CH2)2), 1.70–1.92
(2H, m, 2-CH2), 2.32 (2H, t, 5-CH2), 2.39 (4H, q,
N(CH2)2), 5.00 (1H, m, CH), 7.18–7.42 (5H, m, H
arom.), 7.47–9.04 (4H, m, H arom.), 8.96 (1H, d, NH,
3JCH, NH = 8.4 Hz).
A solution of 10d (2.96 g, 0.0100 mol) in dry aceto-
nitrile (2 mL) was added to a stirred solution of 11c
(1.4 g, 0.0100 mol) in dry acetonitrile (2 mL). The reac-
tion mixture was stirred at room temperature for 3 h and
evaporated in vacuo. The oily residue was triturated with
absolute diethyl ether (30 mL). The precipitate was fil-
tered off, washed with absolute diethyl ether (10 mL) to
give 3.0 g (68.8%) of 1h. M.p. 71–72 oC. The base of 1h
was obtained by dissolution of 1h (3 g) in 40% aqueous
NaOH and extracting with benzene (2 × 25 mL). After
evaporation, the residue was recrystallized from
2-propanol/water, 4:1 to give 2.2 g (80%) of the base of
1h. M.p. 89–90 °C. IR (Nujol): 3 360 (NH), 1 630 (C=O)
cm–1. MS, m/z: M+ 400, [M-CH3]+ 385, [M-Et]+ 371,
4.1.6. (±)-N-[5-(Diethylamino)-1-(4-
nitrophenyl)pentyl]-benzamide 1f
The compound 1f was obtained from 10e (2.8 g,
0.0100 mol), 11c (1.4 g, 0.0100 mol) and dry acetonitrile
(8 mL) using the procedure described for compound 1e,
but the reaction mixture was heated at 70 °C for 30 min.
40% aqueous NaOH was added to pH 8.0. The alkaline
solution was extracted with toluene (2 × 30 mL) and
washed with water. The combined organic extracts were
dried over anhydrous Na2SO4. After evaporation, the
residue was triturated with hexane and the precipitate
filtered off to give 1.1 g (29%) of 1f. M.p. 51–53 °C. MS,
[M-CH2Ph]+
309,
[M-NH(Et)CH2Ph-H]+
264,
[(CH2)4NEtCH2Ph]+ 190, [CH2=NEtCH2Ph]+ 148,
CH3CH=NH+CH2Ph 134, [PhCO]+ 105, [PhCH2]+ 91.
1H-NMR (CD3OD): δ 1.33 (3H, s, Me), 1.30–2.10 (6H,
m, (CH2)3), 3.00–3.30 (4H, m, CH2N+CH2), 4.33 (2H, s,
CH2), 5.13 (1H, m, CH), 7.20–7.60 (10H, m, H arom.),
(3H, m, H arom.), 7.82 (2H, d, H arom.).
1
m/z: M+ 383. H-NMR (CDCl3): δ 0.98 (6H, t, Me2),
1.30–1.58 (4H, m, (CH2)2), 1.90 (2H, m, 2-CH2), 2.37
(2H, m, 5-CH2), 2.48 (4H, q, N(CH2)2), 5.17 (1H, m,
CH), 6.66 (1H, br.d, NH), 7.42 (2H, t, H arom.), 7.50 (1H,
t, 2H, d, H arom.), 7.76 (2H, d, H arom.), 8.17 (2H, d, H
arom.).
4.1.9. (±)-N-[5-(Diethylamino)-1-phenylpentyl]-
4-carboethoxybenzamide hydrochloride 1i
The compound 1i was obtained from 10a [9] (1.1 g,
0.0047 mol), 11e [10] (1.0 g, 0.0047 mol) and dry aceto-
nitrile (5 mL) using the procedure described for com-
pound 1e. The alkaline solution was extracted with
toluene (2 × 25 mL) and washed with water. The com-
bined organic extracts were dried over anhydrous
Na2SO4. After evaporation, the residue was dissolved in
a minimum of acetonitrile and HCl/EtOH was added to
pH 1.0 at 0–5 °C. The precipitate was filtered off to give
1.1 g (52%) of 1i. M.p. 116–117 °C. IR (Nujol): 1 710,
4.1.7. (±)-N-[5-(Diethylamino)-1-(4-nitrophenyl)pentyl]-
4-nitrobenzamide hydrochloride 1g
A solution of 1a (5.0 g, 0.0119 mol) in acetic anhy-
dride was added to a stirred solution of fuming HNO3
(15 mL) and concentrated H2SO4 (15 mL) cooled to
0–5 °C. The reaction mixture was stirred at 0–5 °C for
30 min, poured into ice water, basified with 40% aqueous
NaOH to pH 8.0 and extracted with ethyl acetate (2 ×
50 mL). The combined organic extracts were washed
with water, dried over anhydrous Na2SO4, and evaporated
to dryness in vacuo. The tarry residue was dissolved in a
minimum of acetonitrile and HCl/EtOH was added to pH
1.0 at 0–5 °C. The precipitate was filtered off and
recrystallized from acetonitrile to give 3.1 g (55.8%) of
1
1 635 (C=O) cm–1. H-NMR ((CD3)2SO): δ 1.18 (6H,
br.t, Me2), 1.20 (3H, t, Me), 1.32 (1H, m), 1.42 (1H, m)
(3-CH2), 1.68 (2H, m, 4-CH2), 1.78 (1H, m), 1.95 (1H,
m) (2-CH2), 2.96 (2H, br.t, 5-CH2), 3.05 (4H, q,
N(CH2)2), 4.33 (2H, q, CH2), 5.02 (1H, m, CH), 7.21
(1H, t, H arom.), 7.33 (2H, t, H arom.), 7.44 (2H, d, H
arom.), 8.03 (4H, m, H arom.), 9.12 (1H, d, NH,
3JCH, NH = 8.4 Hz), 10.35 (1H, br.s, N+H).
1
1g (p- isomer/o-, m- isomers, 95%/5%). In the H-NMR
4.1.10. (±)-N-[5-(Diethylamino)-1-phenylpentyl]-
4-methylsulphonylbenzamide hydrochloride 1j
The compound 1j was obtained in 46.6% yield from
10a [9] (1.0 g, 0.0043 mol), 11f [11] (0.93 g, 0.0043 mol)
and dry acetonitrile (20 mL) using the same procedure
described for compound 1i. M.p. 102–103 °C. IR (Nujol):
1 650 (C=O), 1 300, 1 150 (MeSO2) cm–1. 1H-NMR
spectral information the chemical shift values for the
major isomer 1g only are given. MS, m/z: M+ 428.
1H-NMR (CDCl3): δ 1.35 (3H, t), 1.45 (3H, t) (Me2),
1.60–2.43 (6H, m, (CH2)3), 2.84–3.36 (6H, m, N(CH2)2,
5-CH2), 5.20 (1H, m, CH), 7.62 (2H, d, H arom.), 8.15
(2H, d, H arom.), 8.24 (2H, d, H arom.), 8.38 (2H, d, H
arom.), 9.36 (1H, d, NH), 11.20 (1H, br.s, N+H).

212
((CD3)2SO): δ 1.17 (6H, t, Me2), 1.31 (1H, m), 1.42 (1H,
m) (2-CH2), 1.68 (2H, m, 4-CH2), 1.78 (1H, m), 1.94
(1H, m) (2-CH2), 2.96 (2H, q, 5-CH2), 3.05 (4H, m,
N(CH2)2), 3.26 (3H, s, Me), 5.03 (1H, m, CH), 7.23 (1H,
t, H arom.), 7.33 (2H, t, H arom.), 7.42 (2H, d, H arom.),
(4H, m, N(CH2)2), 4.97 (1H, m, CH), 6.80 (2H, d, H
arom.), 7.40 (1H, t, H arom.), 7.60 (2H, t, H arom.), 7.77
(2H, d, H arom.), 7.78 (2H, d, H arom.), 8.56 (1H, d,
NH), 10.25 (1H, br.s, N+H).
8.0–8.14 (4H, m, H arom.), 9.15 (1H, d, NH, 3JCH, NH
=
4.1.13. (±)-N-[5-(Diethylamino)-1-(4-hydroxyphenyl)-
pentyl]-4-nitrobenzamide hydrochloride 1m
8.0 Hz), 10.05 (1H, br.s, N+H).
Under a nitrogen atmosphere, to a stirred solution of 1c
(1.0 g, 0.0022 mol) in dry dichloromethane (60 mL)
cooled to –70 °C, was added dropwise a solution of BBr3
in the same solvent (18 mL). The reaction mixture was
stirred for 3 h at –70 °C and for 2 h at room temperature,
then poured into ice water. Saturated NaHCO3 aqueous
solution was added and stirred at room temperature for
1 h. The aqueous phase was extracted with ethyl acetate
(3 × 50 mL). The combined organic extracts were washed
with water, dried over MgSO4 and evaporated in vacuo.
The residue was dissolved in 2-propanol (2 mL) and
HCl/i-PrOH was added to pH 2.0. The solvent was
removed in vacuo. The residual oil was triturated with
2-propanol and diethyl ether. The precipitate was filtered
off to give 0.36 g (37%) of 1m. M.p. 130–135 °C. MS,
m/z: M+ 399. 1H-NMR ((CD3)2SO): δ 1.17 (6H, t, Me2),
1.20–2.05 (6H, m, (CH2)3), 3.03 (2H, m, 5-CH2), 3.05
(4H, m, N(CH2)2), 4.95 (1H, m, CH), 6.71 (2H, d, H
arom.), 7.21 (2H, d, H arom.), 8.10 (2H, d, H arom.), 8.26
4.1.11. (±)-N-[5-(Diethylamino)-1-
phenylpentyl]-4-aminobenzamide 1k
To a stirred mixture of iron (18.0 g, 0.3223 mol),
ammonium chloride (2.25 g, 0.0421 mol) and water
(55 mL) heated to 95 °C, was added a solution of 1a
(25.0 g, 0.0595 mol) in hot water (50 mL). The reaction
mixture was refluxed for 30 min. The precipitate was
filtered off and washed with a hot water. The filtrate was
cooled to room temperature, basified with 40% aqueous
NaOH to pH 9.0, extracted with ethyl acetate (3 ×
150 mL) and washed with water. The combined organic
extracts were dried over anhydrous Na2SO4 and evapo-
rated in vacuo. The residue was triturated with hexane
and a cream-coloured solid filtered off to give 15.0 g
(68.5%) of 1k. M.p. 56–57 °C. MS, m/z: M+ 353.
1H-NMR ((CD3)2SO): δ 0.88 (6H, t, Me2), 1.16–1.46
(4H, m, (CH2)2), 1.66–1.88 (2H, m, 2-CH2), 2.29 (2H, t,
5-CH2), 2.40 (4H, q, N(CH2)2), 4.94 (1H, m, CH), 5.59
(2H, s, NH2), 6.52 (2H, d, H arom.), 7.15–7.38 (5H, m, H
arom.), 7.60 (2H, d, H arom.), 8.22 (1H, d, NH, 3JCH, NH
= 8.6 Hz).
3
(2H, d, H arom.), 9.07 (1H, d, NH, JCH, NH = 8.0 Hz),
9.33 (1H, s, OH), 9.74 (1H, br.sign, N+H).
4.1.14. (±)-N-[5-(Ethylamino)-1-phenylpentyl]-
benzamide hydrochloride 1n
4.1.12. (±)-N-[5-(Diethylamino)-1-phenylpentyl]-
A mixture of 1h (2.5 g, 0.0057 mol), absolute ethanol
(100 mL) and 20% Pd–C (200 mg) was subjected to
hydrogenation at room temperature. The catalyst was
filtered, washed with absolute ethanol (2 × 20 mL), and
the ethanol was evaporated in vacuo. The precipitate was
triturated with absolute diethyl ether and recrystallized
from EtOH/Et2O to give 1.1 g (55.6%) of 1n. M.p.
194–195 °C. IR (Nujol): 3 340, 3 285 (NH), 1 630 (C=O)
cm–1. MS, m/z: M+ 310, [M-CH3]+ 295, [M-NHEt]+ 266,
[M-(CH2)4NHEt]+ 210, [M-NHCOPh]+ 190, [190-Et-H]+
160, [190-CH2NHEt]+ 132, [PhCO]+ 105, [CH2=CH-
CH=NH+Et] 84, Ph+ 77, [CH2=NHEt]+ 59. 1H-NMR
((CD3)2SO): δ 1.16 (3H, t, Me), 1.00–2.00 (6H, m,
(CH2)3), 2.82–2.86 (4H, m, CH2N+CH2), 5.00 (1H, m,
CH), 7.20–7.60 (5H, m, H arom.), 7.20–7.60 (3H, m, H
arom.), 7.90 (2H, d, H arom.), 8.85 (2H, m, N+H2), 8.87
(1H, d, NH).
4-hydroxybenzamide hydrochloride 1l
To a stirred solution of 1k (20.0 g, 0.0566 mol) in
concentrated H2SO4 (10 mL) and H2O (130 mL) cooled
to 0 °C, was added dropwise a solution of NaNO2 (4.5 g,
0.0652 mol) in H2O (20 mL) at 0–5 °C. The reaction
mixture was stirred at 0 °C for 30 min, poured into
boiling water (300 mL), stirred at 95 °C for 15 min, and
cooled to room temperature. 40% aqueous NaOH was
added to pH 9.0 and the aqueous phase was extracted
with ethyl acetate (2 × 150 mL) and washed with water.
The combined organic extracts were dried over anhy-
drous Na2SO4 and evaporated in vacuo. The residue was
dissolved in acetone and petroleum ether was added. The
precipitate was filtered off, dissolved in a minimum of
2-propanol, and HCl/i-PrOH was added to pH 1.0. The
solvent was removed in vacuo and the residue was
triturated with acetone. The precipitate was filtered off to
give 10.0 g (50%) of 1l. M.p. 101–103 °C. MS, m/z: M+
354. 1H-NMR ((CD3)2SO): δ 1.17 (6H, t, Me2),
1.20–1.48 (4H, m, 3-CH2), 1.66 (2H, m, 4-CH2),
1.70–1.95 (2H, m, 2-CH2), 2.95 (2H, m, 5-CH2), 3.02
4.1.15. (±)-N-[5-(Diethylamino)-1-phenylpentyl]-
4-carbamidobenzamide hydrochloride 1o
Under a nitrogen atmosphere, to a stirred mixture of 1i
(0.6 g, 0.0013 mol), formamide (0.18 mL, 0.2 g,

213
0.0044 mol) and dry DMF (10 mL) was added a solution
of sodium (0.03 g, 0.0013 g-a) in methanol (1 mL) at
100 °C. The reaction mixture was heated at 100 °C for
1 h, cooled to room temperature and water (20 mL) was
added. The precipitate was filtered off, dissolved in a
minimum of acetonitrile and HCl/EtOH was added to pH
1.0. After evaporation, the residue was triturated with
diethyl ether. The precipitate was filtered off to give 0.4 g
with water (250 mL), dried over anhydrous Na2SO4 and
passed through a short alimina column. The solvent was
evaporated in vacuo to give 32.0 g of 8b as an oil. 2.0 g
of crude product was refluxed in hexane (40 mL) and
cooled to room temperature. After decanting of the
hexane layer, the treatment was reiterated to give 1.5 g of
pure product 8b as a white solid. M.p. 73–76 °C. IR
(Liquid film): 3 400 (NH), 1 650 (C=O) cm–1. MS, m/z:
[MH+] 385, [PhCH(CONH2)(CH2)4N(Me)CH2]+ 233,
[CH2Ph(OMe)2-3,4] 151, [PhCH2]+ 91.
1
(71%) of 1o. M.p. 108–109 °C. H-NMR ((CD3)2SO): δ
1.18 (6H, t, Me2), 1.31 (1H, m), 1.42 (1H, m, 3-CH2),
1.68 (2H, m, 4-CH2), 1.78 (1H, m), 1.94 (1H, m)
(2-CH2), 2.96 (2H, q, 5-CH2), 3.05 (4H, m, N(CH2)2),
5.03 (1H, m, CH), 7.22 (1H, t, H arom.), 7.33 (2H, t, H
arom.), 7.42 (2H, d, H arom.), 7.50 (1H, br.s, NH), 8.12
(1H, br.s, NH), 7.95 (4H, m, H arom.), 8.97 (1H, d, NH,
3JCH, NH = 8.4 Hz), 10.11 (1H, br.s, N+H).
4.1.18. (±)-Methyl-N-[5-[N-[2-(3,4-dimethoxyphenyl)-
ethyl]methylamino]-1-phenylpentyl]carbamate 9b
A solution of 8b (30.0 g, 0.0780 mol) in methanol
(145 mL) was added to a stirred solution of sodium
(5.95 g, 0.2588 g-a) in methanol (145 mL). Bromine
(6.6 mL, 20.47 g, 0.1281 mol) was added dropwise to the
reaction mixture at 0 °C. The mixture was refluxed for
20 min, cooled to room temperature, water (460 mL) was
added and extracted with CH2Cl2 (2 × 300 mL). The
combined organic extracts were washed with water (2 ×
600 mL), dried over anhydrous Na2SO4 and evaporated
in vacuo to give 32.0 g of 9b as an oil. The crude product
was used for the next reaction. MS, m/z: M+ 414.
4.1.16. (±)-N-[5-(Diethylamino)-1-phenylpentyl]-
4-nitrobenzamidine hydrochloride 1p
A solution of 10a [9] (0.5 g, 0.0021 mol) in anhydrous
1,2-dichloroethane was added to a stirred mixture of
14 [12] (0.48 g, 0.0021 mol) and anhydrous 1,2-
dichloroethane (20 mL). The reaction mixture was heated
at 70–75 °C for 1.5 h, cooled to room temperature and
evaporated in vacuo. The residue was chromatographed
on a short silica gel column with 2-propanol as eluent.
Appropriate fractions were combined and evaporated in
vacuo. The residue was dissolved in water (10 mL),
basified with 5% aqueous NaHCO3 to pH 8.0, extracted
with CHCl3 (2 × 5 mL), and dried over CaCl2. The
solvent was removed in vacuo, the residue was dissolved
in a minimum of 2-propanol, HCl/i-PrOH was added to
pH 1.0. After evaporation, the residue was triturated with
dry diethyl ether. The precipitate was filtered off to give
4.1.19. (±)-1-Amino-5-[N-[2-(3,4-dimethoxyphenyl)-
ethyl]methylamino]-1-phenylpentane 10b
The mixture of sodium hydroxide (36.66 g,
0.9165 mol), water (62 mL), ethanol (62 mL) and 9b
(32.0 g, 0.0772 mol) was refluxed under stirring for 24 h.
The reaction mixture was cooled to room temperature,
poured into water (1 200 mL) and extracted with toluene
(2 × 300 mL). The combined organic extracts were dried
over anhydrous Na2SO4 and evaporated to dryness in
vacuo to give 19.18 g of 10b as an oil. The crude product
was used for the next reaction. MS, m/z: M+ 356.
1
0.25 g (25.7%) of 1p as a hygroscopic substance. H-
NMR ((CD3)2SO): δ 1.16 (6H, t, Me2), 1.30–1.50 (2H,
m, 3-CH2), 1.75 (2H, m, 4-CH2), 1.87 (1H, m), 2.13 (1H,
m) (2-CH2), 3.00 (2H, m, 5-CH2), 3.01 (4H, q, N(CH2)2,
5.32 (1H, q, CH), 7.30–7.66 (5H, m, H arom.), 8.03 (2H,
d, H arom.), 8.39 (2H, d, H arom.), 9.90 (1H, s), 9.95 (1H,
s) (C=NH, N+H), 10.45 (1H, br.s, N+H), 10.72 (1H, d,
4.1.20. (±)-6-Diethylamino-2-(4-
methoxyphenyl)hexanamide 8c
The compound 8c was obtained from 7c [3] (16.7 g,
0.0609 mol), potassium hydroxide (1.71 g, 0.0305 mol),
hydrogen peroxide, 30 wt.% solution in water (16 mL)
and DMSO (80 mL) using the procedure described for
compound 8b. The reaction mixture was stirred at room
temperature for 6 h, water (90 mL) was added and
extracted with diethyl ether (2 × 120 mL). The combined
organic extracts were washed with water (2 × 100 mL),
dried over anhydrous Na2SO4 and evaporated in vacuo.
The residue was recrystallized from heptane/benzene, 2:1
to give 12.95 g (72.8%) of 8c. M.p. 53–55 °C. MS, m/z:
[MH+] 293, [293-NH2]+ 277, [293-HCONH2]+ 248,
CH2=N+Et2 86. IR (Nujol): 3 450, 3 370 (NH), 1 660
(C=O) cm–1. 1H-NMR (CDCl3): δ 0.97 (6H, t, Me2), 1.23
3
NH, JCH, NH = 8.0 Hz).
4.1.17. (±)-6-[N-[2-(3,4-Dimethoxyphenyl)ethyl]-
methylamino]-2-phenylhexanamide 8b
Hydrogen peroxide, 30 wt.% solution in water (30 mL)
was added dropwise to the mixture of 7b [3] (38.5 g,
0.1051 mol), potassium hydroxide (3.5 g, 0.0624 mol)
and DMSO (150 mL) under stirring at 5–10 °C. The
reaction mixture was stirred at room temperature for 1 h,
water was added and extracted with CH2Cl2 (2 ×
200 mL). The combined organic extracts were washed

214
(2H, m, CH2), 1.44 (2H, m, CH2), 1.75 (1H, m), 2.16
(1H, m, 2-CH2), 2.34 (2H, t, 5-CH2), 2.46 (4H, q,
N(CH2)2), 3.32 (1H, t, CH), 3.78 (3H, s, OMe), 5.55 (1H,
br.sign.), 5.69 (1H, br.sign.) (NH2), 7.13 (2H, d, H arom.),
7.21 (2H, d, H arom.).
precipitate was filtered off to give 10.67 g (82.26%) of
8d. M.p. 57–58 °C. IR (Nujol): 1 660 (C=O) cm–1.
4.1.24. (±)-Methyl-N-[5-N-Benzylethylamino)-
1-phenylpentyl]carbamate 9d
The compound 9d was obtained from 8d (10.6 g,
0.0326 mol), sodium (2.24 g, 0.0978 g-a), bromine
(2.0 mL, 6.1 g, 0.0382 mol) and methanol (45 mL) using
the procedure described for compound 9b. The reaction
mixture was stirred at room temperature for 10 min,
heated at reflux for 10 min and cooled to room tempera-
ture. Water (200 mL) was added to the reaction mixture
and extracted with toluene (3 × 100 mL). The combined
organic extracts were washed with water (3 × 50 mL),
dried over anhydrous Na2SO4 and evaporated to dryness
in vacuo to give 11.0 g of 9d as an oil. The crude product
was used for the next reaction. IR (liquid film): 3 310
(NH), 1 700 (C=O) cm–1. MS, m/z: [MH+] 355, [M-Ph]+
277, CH2=N+EtCH2Ph 148, [Ph CH2]+ 91.
4.1.21. (±)-Methyl-N-[diethylamino-1-(4-
methoxyphenyl) pentyl]carbamate 9c
The compound 9c was obtained from 8c (15.7 g,
0.0537 mol), sodium (3.8 g, 0.1653 g-a), bromine
(3.5 mL, 10.86 g, 0.0679 mol) and methanol (140 mL)
using the procedure described for compound 9b. Water
(240 mL) was added to the reaction mixture and extracted
with toluene (2 × 200 mL). The combined organic ex-
tracts were washed with water (2 × 100 mL), dried over
anhydrous Na2SO4 and evaporated in vacuo to give
16.74 g of 9c as an oil. The crude product was used for
the next reaction. MS, m/z: M+ 322, [M-HNCOOMe]
1
248, CH=N+Et2 86. H-NMR (CDCl3): δ 0.98 (6H, t,
Me2), 1.27, 1.45 (4H, m, (CH2)2), 1.72 (2H, m, 2-CH2),
2.36 (2H, m, 5-CH2), 2.48 (4H, q, N(CH2)2), 3.62 (3H, s,
COOMe), 3.78 (3H, s, OMe), 4.55 (1H, q, CH), 4.93 (1H,
br.sign., NH), 6.85 (2H, d, H arom.), 7.18 (2H, d, H
arom.).
4.1.25. (±)-1-Amino-5-(N-Benzylethylamino)-
1-phenylpentane 10d
The compound 10d was obtained from 9d (11.0 g,
0.0339 mol), sodium hydroxide (12.6 g, 0.3150 mol),
triethylbenzylammonium chloride (0.6 g, 0.0264 mol),
ethanol (15 mL) and water (15 mL) using the procedure
described for compound 10b. The reaction mixture was
refluxed for 6 h and treated as described above to give
7.76 g of 10d. The crude product was used for the next
reaction. Dihydrochloride of 10d: m.p. 205 °C (dec.). IR
(Nujol): 1 610 (CH=CH arom.) cm–1. MS, m/z: M+ 296,
[M-NH3]+ 279, [M-Et]+ 267, [M-NH3-Et]+ 250,
4.1.22. (±)-1-Amino-5-diethylamino-
1-(4-methoxyphenyl)pentane 10c
The compound 10c was obtained using the procedure
described for compound 10b from 9c (14.16 g,
0.0439 mol), sodium hydroxide (19.0 g, 0.4750 mol),
triethylbenzylammonium chloride (0.91 g, 0.0040 mol),
ethanol (19 mL) and water (19 mL). The reaction mixture
was refluxed for 5 h and treated as described above to
give 10.73 g (92.4%) of 10c. B.p. 165–170 °C/1 mm Hg.
MS, m/z: M+ 264, CH=N+Et2 86. IR (Liquid film): 3 360,
[M-CH2Ph]+
205,
[M-PhCH2-NH3]+
188,
CH2=N+EtCH2Ph 148, [M-(CH2)2NEt2CH2Ph]+ 134,
[PhCH+NH2] 106. H-NMR ((CD3)2 SO): δ 1.21 (3H, t,
1
1
3 280 (NH2) cm–1. H-NMR (CDCl3): δ 0.98 (6H, t,
Me), 1.0–2.05 (6H, m, (CH2)3), 2.8–3.0 (4H, m,
CH2N+CH2), 4.20 (1H, m, CH), 4.25 (2H, s, CH2),
7.35–7.65 (10H, m, H arom.), 8.60 (3H, s, N+H3).
Me2), 2.18–2.65 (6H, m, (CH2)3), 2.48 (4H, q, N(CH2)2),
2.65 (2H, br.sign., NH2), 3.55 (2H, m, 5-CH2), 3.78 (3H,
s, OMe), 3.82 (1H, t, CH), 6.85 (2H, d, H arom.), 7.21
(2H, d, H arom.).
4.1.26. (±)-1-Acetylamino-5-(N-diethylamino)-
1-(4-nitrophenyl)pentane 13
4.1.23. (±)-6-N-Benzylethylamino-
2-phenylhexanamide 8d
A solution of 10a [9] (13.0 g, 0.0556 mol) in acetic
anhydride (25 mL) was stirred at room temperature for
2 h, added to the mixture of concentrated H2SO4 (50 mL)
and fuming HNO3 (50 mL) and cooled to 0 °C. The
reaction mixture was stirred at 0–5 °C for 1 h, poured into
ice water, basified with 40% aqueous NaOH to pH 9.0
and extracted with diethyl ether (3 × 50 mL). The
combined organic extracts were washed with water
(100 mL), dried over CaCl2 and evaporated to dryness in
vacuo to give 13.0 g of 13 as a yellow oil. The crude
product was used for the next reaction. MS, m/z: M+ 321.
1H-NMR ((CD3)2 SO): δ 0.89 (6H, t, Me2), 1.10–1.40
The compound 8d was obtained from 7d [3] (12.38 g,
0.0404 mol), potassium hydroxide (1.20 g, 0.0214 mol),
hydrogen peroxide, 30 wt.% solution in water (10 mL)
and DMSO (25 mL) using the procedure described for
compound 8b. The reaction mixture was stirred at 30 °C
for 1 h, cooled to room temperature, water (100 mL) was
added and extracted with toluene (2 × 100 mL). The
combined organic extracts were washed with water (2 ×
50 mL) dried over anhydrous Na2SO4 and evaporated in
vacuo. The residue was triturated with hexane. The

215
(4H, m, (CH2)2), 1.65 (2H, m, 2-CH2), 2.29 (2H, t,
5-CH2), 2.34 (4H, q, N(CH2)2), 4.83 (1H, m, CH), 7.55
(2H, d, H arom.), 8.18 (2H, d, H arom.), 8.40 (1H, d, NH,
3JNH, CH = 7.8 Hz).
only after restoration of the elevation of the left ventricu-
lar fibrillation threshold induced by the previous dose. In
most cases duration of action of each substance was
determined after administration of the most effective
dose. The duration of each experiment was up to 6–7 h.
The left ventricular fibrillation threshold in the control
group of animals receiving a placebo (1.0 mL of saline)
did not change significantly throughout the experiment.
Changes in left ventricular fibrillation threshold were
tested for statistical significance by the t-test based on
paired observation. Results are expressed as means ±
SEM in terms of mA. A P value of 0.05 or less was
considered statistically significant.
4.1.27. (±)-1-Amino-5-(N-diethylamino)-
1-(4-nitrophenyl)pentane 10e
A solution of 13 (9.0 g, 0.0280 mol) in concentrated
HCl (120 mL) was refluxed for 6 h and cooled to room
temperature. 40% aqueous NaOH was added to pH 8.0,
extracted with ethyl acetate (3 × 50 mL), washed with
water (100 mL), dried over anhydrous Na2SO4 and
passed through a short silica gel column. The solvent was
removed in vacuo to give 5.7 g of 10e as a yellow oil. The
crude product was used for the preparation of 1f and 1g.
1
MS, m/z: M+ 279. H-NMR (CDCl3): δ 0.98 (6H, t,
Acknowledgements
Me2), 1.10–1.70 (6H, m, (CH2)3), 1.76 (2H, br.s, NH2),
2.36 (2H, t, 5-CH2), 2.48 (4H, q, N(CH2)2), 4.02 (1H, t,
CH), 7.48 (2H, d, H arom.), 8.17 (2H, d, H arom.).
We are grateful to Anisimova O.S., Solov’eva N.P. and
Turchin K.F. for helpful discussion and spectral data.
4.2. Pharmacology
References
The experiments were carried out on 110 cats (body
weights 2.5–3.5 kg) anaesthetized with pentobarbital so-
dium (40–50 mg/kg i.v.) under controlled ventilation.
After opening of the pericardium, the left ventricle was
stimulated by a series of squarewave pulses (400 ms, 50
Hz) of increasing intensity applied from the stimulator
HSE-215 (Germany) until left ventricular fibrillation
occurred [13]. If necessary, defibrillation was done by
using a defibrillation discharge directly applied to the
heart from the apparatus DI-3 (Russia). The left ventricu-
lar fibrillation threshold was measured before administra-
tion of the substances until it stabilized at a constant level
(baseline), and then after intravenous administration of
the substances at 5, 15, 30, 60 min and in some cases at
120, 180, 240 and 300 min. All substances including
nibentan and known class III antiarrhythmics D-sotalol
and sematilide were injected in the cumulative effective
doses (25, 100, 500 and 1 000 µg/kg).
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