Synthesis, cardiovascular activity, and electrochemical oxidation of nitriles of 5-ethoxycarbonyl-2-methylthio-1,4-dihydropyridine-3-carboxylic acid

Article abstract of DOI:10.1023/B:COHC.0000044570.13567.74

Nitriles of 4-aryl-5-ethoxycarbonyl-2-methylthio-1,4-dihydropyridine-3- carboxylic acid have been obtained by the methylation of 1,4-dihydropyridine-2- thiolates; of 1,4-dihydropyridine-2(3H)-thiones in the presence of a stoichiometric amount of piperidine, and of a mixture of 1,4,5,6-tetrahydro- and 1,4-dihydropyridine-2-thiolates with methyl iodide. One-pot multicomponent synthesis has also been used in the condensation of ethyl 2- arylmethyleneacetoacetate, 2-cyanothioacetamide, piperidine, and methyl iodide; of ethyl acetoacetate, 3-aryl-2-cyanothioacrylamide, piperidine, and methyl iodide; and of ethyl acetoacetate, an aromatic aldehyde, 2-cyanothioacetamide, piperidine, and methyl iodide. The latter, a five-component method, takes place rapidly and under mild conditions, it is efficient (yields of 75-96%, economy of time, labour, and resources) and "green" (there is no need to synthesize lachrymators, such as 3-aryl-2-cyanothioacrylamides).The cardiovascular activity and the electrochemical oxidation of the synthesized 2-methylthio-1,4-dihydropyridines have been investigated. A comparative analysis has been carried out of the ability towards electrochemical oxidation as a function of the electronic properties of the substituent at position 4 of the heterocycle.

Full text of DOI:10.1023/B:COHC.0000044570.13567.74

Chemistry of Heterocyclic Compounds, Vol. 40, No. 7, 2004
SYNTHESIS, CARDIOVASCULAR ACTIVITY,
AND ELECTROCHEMICAL OXIDATION OF
NITRILES OF 5-ETHOXYCARBONYL-2-METHYL-
THIO-1,4-DIHYDROPYRIDINE-3-CARBOXYLIC ACID
A. Krauze, L. Baumane, L. Sile, L. Chernova, M. Vilums, R. Vitolina, G. Duburs,
and J. Stradins
Nitriles of 4-aryl-5-ethoxycarbonyl-2-methylthio-1,4-dihydropyridine-3-carboxylic acid have been
obtained by the methylation of 1,4-dihydropyridine-2-thiolates; of 1,4-dihydropyridine-2(3H)-thiones in
the presence of a stoichiometric amount of piperidine, and of a mixture of 1,4,5,6-tetrahydro- and
1,4-dihydropyridine-2-thiolates with methyl iodide. One-pot multicomponent synthesis has also been
used in the condensation of ethyl 2-arylmethyleneacetoacetate, 2-cyanothioacetamide, piperidine, and
methyl iodide; of ethyl acetoacetate, 3-aryl-2-cyanothioacrylamide, piperidine, and methyl iodide; and
of ethyl acetoacetate, an aromatic aldehyde, 2-cyanothioacetamide, piperidine, and methyl iodide. The
latter, a five-component method, takes place rapidly and under mild conditions, it is efficient (yields of
75-96%, economy of time, labour, and resources) and "green" (there is no need to synthesize
lachrymators, such as 3-aryl-2-cyanothioacrylamides).The cardiovascular activity and the
electrochemical oxidation of the synthesized 2-methylthio-1,4-dihydropyridines have been investigated.
A comparative analysis has been carried out of the ability towards electrochemical oxidation as a
function of the electronic properties of the substituent at position 4 of the heterocycle.
Keywords: 1,4-dihydropyridines, cardiovascular activity, one-pot multicomponent synthesis,
electrochemical oxidation.
Many of the widely studied esters of 4-substituted 1,4-dihydropyridine-3,5-dicarboxylic acids possess
marked cardiovascular activity and many preparations for the treatment of cardiovascular diseases have been
created from them [1-4]. An important role, determining the activity of these compounds, is played by the
presence of alkoxycarbonyl groups at positions 3 or 5, a methyl group at positions 2 or 6, and an aryl group at
position 4. Nitrophenyl, alkoxyphenyl, and halogen-substituted phenyl groups are characterized as effective
pharmacophores [1].
2-Alkylthio-1,4-dihydropyridines display cardiovascular [5], hepatoprotective [6], antioxidant (AOA)
[7], and antiradical (ARA) [8] activity, however these compounds are still insufficiently studied
pharmacologically.
__________________________________________________________________________________________
Latvian Institute of Organic Synthesis, Riga LV-1006; e-mail: lbaumane@osi.lv. Translated from
Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 1022-1035, July. 2004. Original article submitted April 2,
2004.
876
0009-3122/04/4007-0876©2004 Springer Science+Business Media, Inc.

R
R
O
O
CN
CN
O
O
+
_
+
NH2
_
+
NH2
N
H
S
N
H
S
HO
4a–m
2a–m
a
c
R
C
MeI
R
O
CN
O
CN
S
+
H2N
O
+
+
+
O
+
N
S
O
N
H
H
O
H2N
O
R
D
F
MeI
MeI
O
CN
S
O
[ 1 + 5 ]
[ 1 + 5 ]
N
H
HO
5
+
+
+
H
H
H
R
O
R
CN
S
O
O
MeI
CN
N
H
O
B
+
N
H
S
N
H
1 a– m
+
H
3 a–m
A
MeI
[ 1 + 5 ]
+
2 + 4
H
2
E
MeI
2 + 4
b
R
O
CN
S
O
+
+
N
H
O
H2N
а R = H, b R = 4-OH; c R = 4-OMe; d R = 2-OMe; e R = 4-NMe2; f R = 4-Cl; g R = 3-Cl;
h R = 2-Cl; i R = 2,4-Cl2; j R = 4-NO2; k R = 3-NO2; l R = 4-CN; m R = 3-CN
877

In a continuation of investigations on the synthesis and study of the properties of 2-alkylthio-1,4-
dihydropyridines [9] and to improve the methods of obtaining them [10-11], we have synthesized a series of
new nitriles of 4-aryl-5-ethoxycarbonyl-6-methyl-2-methylthio-1,4-dihydropyridine-3-carboxylic acid 1, in
which the substituents on the 4-phenyl residue are varied widely, and have investigated their cardiovascular
activity. A comparative analysis has been carried out of the ability of 1,4-dihydropyridines 1 towards
electrochemical oxidation as a function of the electronic properties of the substituents at position 4 of the
heterocycle. Such data enable the search for biologically active substances to be carried out in a more purpose
directed manner.
In principle the important problem, the construction of 1,4-dihydropyridine-2(3H)-thione ring, is
extremely complex, since these compounds are subject to oxidation in dilute solutions. Three of the main
methods were already described in 1983 [12] and have been widely used since [13-23]. For a comparative
analysis of the methods 2-chlorophenyl and 2,4-dichlorophenyl-substituted 1,4-dihydropyridine-2(3H)-thiones
3h and 3i were obtained by the condensation of a) ethyl 2-arylmethyleneacetoacetate, 2-cyanothioacetamide, and
piperidine, b) ethyl acetoacetate, 3-aryl-2-cyanothioacrylamide, and piperidine, and c) ethyl acetoacetate,
aromatic aldehyde, 2-cyanothioacetamide, and piperidine. On acidification of the resulting mixture of salts 2 and
4 the 1,4-dihydropyridine-2(3H)-thiones 3h and 3i were obtained in overall yields of 36-60%. The overall yields,
calculated on the initial aldehyde, were 31-50% (Table 1). It should also be noted that the ethyl esters of 2-
arylmethyleneacetoacetic acid are formed as a mixture of cis and trans isomers [24] and their isolation is
extended in time and laborious, since products of a further Michael reaction are formed on heating with the
participation of ethyl acetoacetate as a methylene component. 3-Aryl-2-cyanothioacrylamides are lachrymators
and in the presence of bases are inclined to dimerize [25].
The mentioned reactions using 2-cyanothioacetamide must be carried out under mild conditions. The use
of stronger bases or boiling leads to a complex mixture (dimerization of 2-cyanothioacetamide, reaction of ethyl
acetoacetate with 2-cyanothioacetamide [26]) and a reduction in yield. The use in these syntheses of a
stoichiometric amount of piperidine [13-21] or N-methylmorpholine [22-23] was a fortunate finding. The
intermediate piperidinium thiolates 4 or 2 are poorly soluble in ethanol, which provides their rapid separation
from the reaction medium. Depending on the structure of the substituent in positions 5 and 6 and on the reaction
temperature thiolates 4 or 2 are separated [15,16]. If under the reaction conditions a mixture of compounds 4 and
2 at a ratio of approximately 1:1 is formed then the products crystallize out with more difficulty. Too much
dilution of the reaction mixture also hinders separation of the desired products and aids their oxidation to
pyridine-2(3H)-thiones and bispyridyl disulfides [14].
TABLE 1. Characteristics of the Synthesized Compounds 2-4
Found, %
Calculated, %
——————
Com-
pound
Empirical
formula
mp, °С Method Yield, %*
C
H
N
S
4h + 2h
4i + 2i
3h
A
B
C
55 (40)
63 (48)
45 (45)
A
B
C
73 (40)
65 (60)
57 (57)
C16H15ClN2O2S
57.33 4.24
57.40 4.52
8.26
8.37
9.58 129-131
9.58
A
B
C
43(31)
50 (38)
36 (36)
3i
C16H14Cl2N2O2S × 51.18 3.88
× 0.5 H2O
7.15
7.41
8.12
8.48
99-101
А
B
C
60 (33)
53 (50)
47 (47)
50.80 4.00
_______
* The overall yield calculated on the aldehyde is given in parentheses.
878

In the case of thiones 3h and 3i the salts corresponding to them are also separated as mixtures 4h + 2h
(~3:1) and 4i + 2i (~6:1), according to the 1H NMR spectra.
6-Hydroxy-1,4,5,6-tetrahydropyridine-2-thiolates 4 on thermal treatment (at times a recrystallization is
sufficient) may be converted into dihydropyridine-2-thiolates 2, but to obtain the desired products 1 the mixture
of salts 4 and 2 is practicable. A longer but productive method of obtaining pure thiolates 2 is the conversion of
thiolates 4 into thiones 3, and then back into 2-thiolates 2 by the action of piperidine. 1,4-Dihydropyridine-
2(3H)-thiones 3 are also unstable in dilute solution and are readily oxidized [7,8], however pure thiolates 2 and
thiones 3 are preserved for years under argon.
It should be noted that it is difficult to obtain thiones 3 containing electron-donating substituents in the
4-aryl group. Due to ready oxidation it was not possible to isolate thione 3d containing a 4-(2-methoxyphenyl)
substituent, and in the case of thiones 3a-c,e reaction yields were low for the same reason.
Nitriles of 4-aryl-5-ethoxycarbonyl-2-methylthio-1,4-dihydropyridine-3-carboxylic acids 1 were
obtained by six methods, A) by the methylation of 1,4-dihydropyridine-2-thiolates 2, B) by the methylation of
1,4-dihydropyridine-2(3H)-thiones 3 in the presence of a stoichiometric amount of piperidine, C) by the
methylation of mixtures of 1,4,5,6-tetrahydro- and 1,4-dihydropyridine-2-thiolates 4 and 2, D) by the
condensation of ethyl 2-arylmethyleneacetoacetate, 2-cyanothioacetamide, piperidine, and methyl iodide, E) by
the condensation of ethyl acetoacetate, 3-aryl-2-cyanothioacrylamide, piperidine, and methyl iodide, and F) by
the condensation of ethyl acetoacetate, an aromatic aldehyde, 2-cyanothioacetamide, piperidine, and methyl
iodide. In the case of methods C-F it is necessary to acidify the reaction mixture to complete the reaction.
Allowing for the above, the target 2-methylthio-1,4-dihydropyridines 1 were obtained by the six
methods, including the methylation of thiolates 2 and of thiones 3. Methods of four-component synthesis (D, E)
have insignificant advantages since the overall yields calculated on the initial aldehyde were higher. In the case
of methods A-C yields were 24-50% and in the case of methods D and E 33-80%. Method F, the condensation of
ethyl acetoacetate with aromatic aldehydes and 2-cyanothioacetamide in the presence of piperidine and
subsequent action of methyl iodide, was the most productive, as indicated by the yields of reaction products
(75-96%) and also by economy of labour and resources. The use of methods of multicomponent synthesis
enables the preparation of 2-methylthio-1,4-dihydropyridine 1d, which is not successful by the stepwise
synthesis. It should be noted that in the case of methods C, D, E, and F 1,4-dihydropyridines 1 are formed with
6-hydroxy-1,4,5,6-tetrahydropyridines 5 as contaminant. On acidifying the reaction mixture of compounds 1 + 5
the final dehydration of 5 occurs with the formation of 1,4-dihydropyridines 1 exclusively.
It has therefore been shown that, on obtaining 1,4-dihydropyridines 1 by the stepwise methods A-E,
significant reductions of product yields arise both in the synthesis of the initial ethyl esters of
2-arylmethyleneacetoacetic acids and 3-aryl-2-cyanothioacrylamides and also on isolating the unstable
1,4-dihydropyridine-2(3H)-thiones 3. The five-component synthesis of 2-methylthio-1,4-dihydropyridines
(method F), proceeding rapidly and under mild conditions, is efficient and "green", since the need to synthesize
3-aryl-2-cyanothioacrylamides, which are lachrymators, becomes superfluous.
The structures of compounds 1-5 were proved spectroscopically. In the IR spectra the most characteristic
absorption bands were for the stretching vibrations of the cyano group, which are observed at 2156 cm-1 for
mixtures of salts 2 and 4, at 2190-2204 cm-1 for nitriles of 1,4-dihydropyridine-3-carboxylic acids 1, and at
1
2248-2250 cm-1 for 1,4-dihydropyridine-2(3H)-thiones 3. In the H NMR spectra of compounds 4 the most
characteristic signals were for the H-4 and H-5 protons at 2.68-2.72 and 4.64-4.72 ppm as doublets with
coupling constants ~12 Hz, which indicates the trans-diaxial disposition of these protons [18]. In the case of
salts 2 and 1,4-dihydropyridines 1 the signals of the H-4 protons were at 4.53-5.30 ppm. In the 1H NMR spectra
of thiones 3 the signals of the most characteristic protons H-3 and H-4 were strongly broadened and overlapped
due to the thione–enethiol tautomeric equilibrium and cis–trans isomerism.
1
The characteristics of the synthesized compounds and the data of H NMR and IR spectra are given in
Tables 1-4.
879

TABLE 2. Characteristics of the Synthesized Compounds 1
Found, %
Calculated, %
——————
Com-
pound
Empirical
formula
mp, °С Method Yield, %*
C
H
N
S
1a
1b
C17H18N2O2S
64.94
64.94
5.72
5.77
8.91
8.91
10.20
10.20
123-125
[3]
A
D
90 (50)
53 (52)
C17H18N2O3S ×
× H2O
58.64
58.61
5.63
5.78
8.08
8.04
8.89
9.12
146-148
[27]
E
81 (46)
1c
1d
1e
C18H20N2O3S
62.78
62.77
62.53
62.77
61.93
62.28
5.77
5.86
5.84
5.86
6.48
6.60
8.06
8.13
8.04
8.13
11.31
11.46
9.25
9.31
9.06
9.31
8.57
8.75
150-152
E
E
B
97 (33)
77 (55)
67 (28)
C18H20N2O3S
163-165
140-142
C19H23N3O2S ×
× 0.5 H2O
1f
C17H17ClN2O2S
62.28
58.53
4.79
4.91
7.84
8.03
8.95
9.19
116-118
[3]
A
D
82 (36)
74 (56)
1g
1h
C17H17ClN2O2S
C17H17ClN2O2S
58.49
58.53
58.50
58.53
4.86
4.91
4.80
4.91
7.96
8.03
7.93
8.10
9.09
9.19
9.12
9.19
127-128
F
81 (81)
174-176
B
C
D
E
F
76 (24)
96 (46)
80 (58)
91 (69)
96 (96)
1i
1j
C17H16Cl2N2O2S
C17H17N3O4S
53.31
53.27
4.10
4.21
7.21
7.31
8.32
8.37
186-188
161-162
C
D
E
F
79 (47)
86 (47)
86 (80)
78 (78)
56.76
56.81
4.77
4.77
11.52
11.69
8.90
8.92
B
D
67 (37)
57 (38)
1k
1l
C17H17N3O4S
C18H17N3O3S
C18H17N3O2S
56.54
56.81
63.84
63.70
63.22
63.70
4.77
4.77
4.95
5.05
4.84
5.05
11.69
11.69
12.22
12.38
12.33
12.38
8.69
8.92
9.27
9.45
9.40
9.45
102-104
107-109
135-137
B
B
F
83 (41)
48 (24)
75 (75)
1m
_______
* Yields calculated on the aldehyde are given in parentheses.
The electrochemical oxidation of compounds 1 was carried out in anhydrous acetonitrile at the
stationary glass-graphite electrode. Compounds were adsorbed onto the surface of the electrode since the
electrolysis was carried out in the presence of surface-active camphor at 0.1% concentration. For all the
1,4-dihydropyridine derivatives 1 (except for 1e) one irreversible oxidation peak was recorded in the potential
range Ep = 1.28-1.44 V relative to the saturated calomel electrode (Table 5). Polarograms were also recorded for
compounds 1a and 1f at the rotating disk electrode with a ring, and their characteristics were compared with
results obtained previously for compounds close in structure [11]. The electrochemical oxidation of compounds
1 proceeds along the previously established route. At the disk electrode one oxidation wave arises at a half-wave
potential E1/2 = 1.03 (for 1a) or E1/2 = 1.08 V (for 1f), but at the ring electrode waves were recorded for the
electroreduction products: E1/2 = -1.08, –1.80 (for 1a) and E1/2 = -1.01, -1.73 V (for 1f), indicating the formation
of the corresponding pyridinium cation and pyridine as the oxidation products [11, 28-33].
The molecules of compounds 1a-m have unsymmetrical substituents on the heterocycle, consequently it
seemed of interest to clarify how the electronic properties of the cyano group in position 3 and the thiomethyl
group in position 2 of the heterocycle influence electrooxidizability in comparison with the symmetrical
3,5-diethoxycarbonyl-2,6-dimethyl-4-phenyl derivative of 1,4-dihydropyridine. Cyclic voltammerric curves were
recorded under the same experimental conditions for the model compounds 3,5-diethoxycarbonyl-2,6-dimethyl-
880

4-phenyl-1,4-dihydropyridine (6) and 3-cyano-5-ethoxycarbonyl-2,6-dimethyl-4-phenyl-1,4-dihydropyridine
(7). It was shown that replacement of the ethoxycarbonyl group by cyano hinders the removal of the first
electron by 90 mV (Ep = 1.13 for 6 and Ep = 1.22 V for 7). Further replacement of a methyl group by thiomethyl
(compound 1a) in position 2 of the heterocycle hinders electrooxidation still more by 90 mV (Ep = 1.22 for 7 and
Ep = 1.32 V for 1a).
When considering the influence of substituents in the phenyl ring at position 4 of a 1,4-dihydropyridine,
it was established that meta and para nitro groups hinder the electrooxidation by 120 and 140 mV respectively
(compounds 1k and 1j). Compounds substituted in the ortho position (1d and 1h) were oxidized more readily
than the corresponding para- and meta-substituted compounds, due to intramolecular interactions.
4-(p-Dimethylaminophenyl)-1,4-dihydropyridine 1e is oxidized stepwise with the formation of several oxidation
TABLE 3. Spectral Characteristics of Compounds 1
Com-
pound
IR spectrum, ν, cm-1
1Н NMR spectrum (CDCl3), δ, ppm
1a
1702 (C=O);
2198 (C≡N);
3278 (NH)
1.13 and 4.03 (5H, t and q, ОC2H5); 2.36 (3H, s, 6-CH3);
2.44 (3Н, s, SCH3); 4.68 (1H, s, H-4); 6.34 (1H, br. s, NH);
7.22 (4Н, m, C6H5)
1b
1654, 1680 sh
(C=O);
1.16* and 4.03 (5H, t and q, ОC2H5); 2.32 (3H, s, 6-CH3);
2.42 (3Н, s, SCH3); 4.53 (1H, s, 4-H);
6.74 and 7.00 (4Н, d and d, C6H4); 8.14 (1H, br. s, NH)
2202 (C≡N);
3190 (NH)
1c
1d
1e
1f
1676, 1698 (C=O); 1.16 and 4.03 (5H, t and q, ОC2H5); 2.37 (3H, s, 6-CH3);
2.47 (3Н, s, SCH3); 3.77 (3Н, s, ОCH3); 4.63 (1H, s, H-4);
6.13 (1H, br. s, NH); 6.83 and 7.18 (4Н, d and d, C6H4)
2192, 2200 (C≡N);
3224, 3266 (NH)
1700 (C=O);
2190(C≡N);
3280 (NH)
1.00 and 3.98 (5H, t and q, ОC2H5); 2.37 (3H, s, 6-CH3);
2.42 (3Н, s, SCH3); 3.86 (3Н, s, ОCH3); 5.15 (1H, s, H-4);
6.18 (1H, s, NH); 6.8-7.3 (4Н, m, C6H4)
1680 (C=O);
2194 (C≡N);
3226, 3278 (NH)
1.17 and 4.04 (5H, t and q, ОC2H5); 2.35 (3H, s, 6-CH3);
2.44 (3Н, s, SCH3); 2.90 [4Н, s, N(CH3)2]; 4.57 (1H, s, H-4);
6.22 (1H, br. s, NH); 6.17 and 7.08 (4Н, d and d, C6H4)
1688 (C=O);
2202 (C≡N);
3280 (NH)
1.13 and 4.04 (5H, t and q, ОC2H5); 2.35 (3H, s, 6-CH3);
2.42 (3Н, s, SCH3); 4.66 (1H, s, H-4); 6.52 (1H, br. s, NH);
7.1-7.4 (4Н, m, C6H4)
1g
1h
1i
1686 (C=O);
2196(C≡N);
3284 (NH)
1.13 and 4.04 (5H, t and q, ОC2H5); 2.35 (3H, s, 6-CH3);
2.43 (3Н, s, SCH3); 4.65 (1H, s, H-4); 6.30 (1H, br. s, NH);
7.0-7.3 (4Н, m, C6H4)
1688 (C=O);
2194 (C≡N);
3290 (NH)
1.08 and 3.98 (5H, t and q, ОC2H5); 2.37 (3H, s, 6-CH3);
2.42 (3Н, s, SCH3); 5.30 (1H, s, H-4); 6.40 (1H, br. s, NH);
7.0-7.4 (4Н, m, C6H4)
1708 (C=O);
2194 (C≡N);
3304 (NH)
1.12 and 3.98 (5H, t and q, ОC2H5); 2.38 (3H, s, 6-CH3);
2.45 (3Н, s, SCH3); 5.27 (1H, s, H-4); 6.18 (1H, br. s, NH);
7.22 and 7.38 (4Н, m, C6H4)
1j
1640 (C=O);
2204(C≡N);
3195, 3260 (NH)
1.15 and 4.08 (5H, t and q, ОC2H5); 2.43 (3H, s, 6-CH3);
2.51 (3Н, s, SCH3); 4.83 (1H, s, H-4); 6.14 (1H, br. s, NH);
7.44 and 8.20 (4Н, d and d, C6H4)
1k
1l
1646, 1670 (C=O); 1.14 and 4.06 (5H, t and q, ОC2H5); 2.37 (3H, s, 6-CH3);
2.47 (3Н, s, SCH3); 4.82 (1H, s, H-4); 6.58 (1H, br. s, NH);
7.4-8.2 (4Н, m, C6H4)
2202(C≡N);
3316 (NH)
1634 (C=O);
2198, 2222 (C≡N);
3192, 3250 (NH)
1.12 and 4.06 (5H, t and q, ОC2H5); 2.38 (3H, s, 6-CH3);
2.48 (3Н, s, SCH3); 4.77 (1H, s, H-4); 6.18 (1H, s, NH);
7.37 and 7.64 (4Н, d and d, C6H4)
1m
1700 (C=O);
2198, 2218 (C≡N);
3320 (NH)
1.14 and 4.03 (5H, t and q, ОC2H5); 2.38 (3H, s, 6-CH3);
2.47 (3Н, s, SCH3); 4.72 (1H, s, H-4); 6.43 (1H, br. s, NH);
7.40-7.65 (4Н, m, C6H4)
_______
* CDCl3 + DMSO.
881

TABLE 4. Spectral Characteristics of Compounds 2-4
IR spectrum,
Com-
pound
1Н NMR spectrum (CDCl3), δ, ppm (J, Hz)
ν, сm-1
2h + 4h 1720 (C=O);
2156 (C≡N);
0.91 and 3.96 (5H, t and q, ОС2Н5); 1.48 (3H, s, 6-СН3);
1.6-.8 [6H, m, (CH2)3]; 2.68 and 4.72 (2H, d and d, J = 12, H-5 and Н-4);
2.9-.1 [4H, m, N(CH2)2]; 5.82 (1H, br. s, ОH); 6.58 (1H, br. s, NH);
7.0-.5 (4Н, m, C6H4); 1.07 and 3.96 (5H, t and q, ОС2Н5);
1.6-.8 [6H, m, (CH2)3]; 2.35 (3H, s, 6-СН3);
3170 (NH);
3400 (OH)
2.9-.1 [4H, m, N(CH2)2]; 5.18 (1H, s, H-4); 7.0-.5 (4Н, m, C6H4)
2i + 4i
1720 (C=O);
2156 (C≡N);
3206 (NH);
3406 (OH)
0.97 and 3.98 (5H, t and q, ОС2Н5); 1.48 (3H, s, 6-СН3);
1.6-.8 [6H, m, (CH2)3]; 2.72 and 4.64 (2H, d and d, J = 12.2,
H-5 and Н-4); 2.9-3.1 [4H, m, N(CH2)2]; 5.84 (1H, br. s, ОH);
~ 6.6 (1H, br. s, NH); 7.1-7.5 (4Н, m, C6H4);
1.08 and 3.98 (5H, t and q, ОС2Н5); 1.6-1.8 [6H, m, (CH2)3];
2.34 (3H, s, 6-СН3); 2.9-3.1 [4H, m, N(CH2)2]; 5.12 (1H, s, H-4);
7.1-7.5 (4Н, m, C6H4)
3h
3i
1702 (C=O);
2248 (C≡N);
3280 (NH)
1.16, 4.10 and 4.20 (5H, t and q, ОС2Н5);
2.50 and 2.62 (3H, s and s, 6-СН3); 4.9-5.3 (2H, m, Н-3 and H-4);
6.9-7.6 (4Н, m, C6H4); 8.42 (1H, br. s, NH)
1698 (C=O);
2250 (C≡N);
3230 (NH)
1.20, 4.14 and 4.20 (5H, t and q, ОС2Н5);
2.54 and 2.63 (3H, s and s, 6-СН3); 4.9-5.3 (2H, m, H-3 and Н-4);
6.98, 7.22, 7.52 (3Н, d, J = 10, dd, J = 2 and 10, d, J = 2, C6H3);
8.98 (1Н, br. s, NH).
peaks at extremely positive potentials. A similar phenomenon was observed previously when oxidizing the
corresponding symmetrical 1,4-dihydropyridines [34]. Facilitation of the oxidation of compound 1e is explained
by the prior electrooxidation of the dimethylamino group. To check this hypothesis oxidation of compound 1e
was carried out at the rotating disk electrode and at the ring electrode were recorded waves for the reduction of
the oxidized products. It turned out that in the process of the electrooxidation of 1e four waves were formed with
half-wave potentials E1/2 = 0.42, 0.80, 1.12, and 2.00 V relative to the Ag/AgNO3 reference electrode (it is
probable that at the stationary electrode the fourth wave is hidden by separation of the background). At the ring
electrode, depending on the degree of oxidation of 1e, two oxidized products are detected capable of being
reduced at potentials E1/2 = -1.29 V (oxidation was carried out at the potential of the limiting current of the third
wave) and E1/2 = -0.80 V (oxidation proceeds at the potential of the stationary current of the fourth wave), which
corresponds to the pyridinium cation with various substituents at position 4 of the heterocycle. From the values
of the reduction potentials it may be proposed that in the first stage the substituent partially retained electron-
donating properties, and in the second the product contains a markedly electron-withdrawing substituent.
TABLE 5. Values of the Potentials of Oxidation Peaks on Cyclic Scanning
of the Potential of the Stationary Electrode (Ep) for Compounds 1a-m in
Acetonitrile on a Base of 0.1 M (C4H9)4PF6 with Added 0.1% Camphor
Com-
pound
Com-
pound
No
Еp, V
No
Еp, V
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
1.32
1.32
8
1h
1i
1.36
1.40
1.44
1.42
1.42
1.39
9
1.33
10
11
12
13
1j
1.28
0.79; 0.99; 1.50
1.42
1k
1l
1m
1g
1.42
882

The characteristics of the influence of substituents in the phenyl ring are mainly in agreement with the
data given previously for symmetrical 3,5-dicarbethoxy-2,6-dimethyl-4-phenyl-substituted 1,4-dihydropyridines
in [34,35]. However the introduction of a chlorine atom into the para or meta position of the phenyl ring
(compounds 1f and 1g), in difference to the symmetrical 1,4-dihydropyridines, hinders oxidation like a nitro
group in the meta position. Attempts were undertaken by the method of correlation-statistical analysis to trace
quantitatively the influence of substituents in the phenyl ring on the electrooxidation potentials Ep. A linear
correlation is observed with the Taft σ* constants. Nine representatives of the series (except for 1d-g) fit onto a
correlation straight line with parameters ρ* = 0.120 V (r = 0.977, ∆S = 0.011), and if 1c and 1m are also
excluded from the equation then the remaining representatives of the series practically lie on the straight line
with ρ* = 0.133 (r = 0.992, ∆S = 0.006). It is possible that the noted deviations from the straight line are caused
by the specific properties of certain substituents, since the electro-oxidation potentials of 1,4-dihydropyridines at
solid electrodes depends not only on electronic and steric effects but also on adsorbability, coplanarity, and the
orientation of electroactive molecules on the electrode surface [36-38]. The sensitivity constant ρ* for the
influence of substituents in the phenyl ring for compounds of the type of 1 differs little in size from that for
symmetrical 4-phenyl-substituted 3,5-diethoxycarbonyl-2,6-dimethyl-1,4-dihydropyridines (ρ* = 0.15 [34]).
Consequently replacement of a methyl group by a thiomethyl in position 2 and an ethoxycarbonyl group by
cyano in position 3 of the heterocycle has no significant influence on the effect of the substituents in the phenyl
ring.
The cardiovascular activity of nitriles of 2-methylthio-1,4-dihydropyridine-3-carboxylic acid 4 was
studied in experimental animals, in cats, dogs, and spontaneously hypertensive rats (SHR), and the acute toxicity
was studied in mice. As is seen from Table 6 compounds 1f and 1k in high doses cause an increase in coronary
bloodflow by 25-40% for 3-10 min, simultaneously reducing systemic arterial pressure by 29-53%. In
experiments in dogs 1,4-dihydropyridine 1a at low doses displays a more marked coronary dilatating action
(30-58%) with a duration of 10-20 min, while not changing the systemic arterial pressure and pulse rate.
Compound 1k, containing the pharmacophoric 3-nitrophenyl group, gives an insignificant hypotensive effect in
experiments in SHR.
The investigated compounds had low toxicity. The lethal dose was greater than 1000 mg/kg.
TABLE 6. Effect of 2-Methylthio-1,4-dihydropyridines 1 on Parameters of
the Cardiovascular System and Their Acute Toxicity
Hypotensive
Increase
Duration
of effect,
min
Change Hypotensive
activity
in SHR
(10mg/kg),
mm Hg
Com-
pound
Dose,
mg/kg
in coronary
blood flow,
%
LD50,
mg/kg ip
in pulse
rate, %
activity,
%
1а
0.01
0.1
30*
58*
10
20
n. i.
n. i.
n. i.
n. i.
>1000
>5000
1f
0.1
1.0
5.0
40
25
25
3
6
10
8↓
41↓
36↓
41↓
14↓
29↓
53↓
25↓
34↓
14↓
31↓
27↓
1k
0.1
1.0
5.0
n. i.
30
36
13↓ 6 h
>2000
5
10
_______
*Coronary blood flow was measured fluorometrically in dogs
(intravenously).
883

EXPERIMENTAL
Chemical Section. The IR spectra of the initial compounds were taken on a Perkin-Elmer 580B
1
spectrometer in nujol. The H NMR spectra were recorded on a Bruker WH 90/DC (90 MHz) spectrometer in
CDCl3, internal standard was HMDS (δ 0.05 ppm). A check on the progress of reactions and the homogeneity of
substances was effected by TLC on Silufol UV 254 plates, eluent was chloroform–hexane–acetone, 2:1:1.
Compounds were recrystallized from ethanol. The initial ethyl esters of 2-arylmethyleneacetoacetic acid were
synthesized according to [39], and the 3-aryl-2-cyanothioacrylamides according to [25]. Yields of products were:
ethyl 2-phenylmethyleneacetoacetate 80%, ethyl 2-(4-chlorophenyl)methyleneacetoacetate 75%, ethyl 2-(2-
chlorophenyl)methyleneacetoacetate 72%, ethyl 2-(2,4-dichlorophenyl)methyleneacetoacetate 55%, ethyl 2-(4-
nitrophenyl)methyleneacetoacetate 66%, ethyl 2-(3-nitrophenyl)methyleneacetoacetate 80%, 2-cyano-3-(4-
hydroxyphenyl)thioacrylamide 57%, 2-cyano-3-(4-methoxyphenyl)thioacrylamide 81%, 2-cyano-3-(2-methoxy-
phenyl)thioacrylamide 72%, 2-cyano-3-(4-dimethylaminophenyl)thioacrylamide 88%, 3-(2-chlorophenyl)-2-
cyanothioacrylamide 76%, and 3-(2,4-dichlorophenyl)-2-cyanothioacrylamide 93%. Yields of thiolates were 2a
69% [14], 2f 59% [14], and thiones 3e 48% [14], 3k 61% [15], and 3l 24% [21].
Cyclic voltammetric curves were recorded on a PAR 170 (USA) electrochemical system using a three-
electrode cell with a stationary glass-graphite electrode. The reference electrode was an aqueous saturated
calomel electrode, fitted with a transfer bridge for working in nonaqueous solvents. Electrochemical
investigations by the method of a rotating disk electrode with a ring were carried out in equipment consisting of
a PAR (USA) Ring-Disk-Electrode System Model 636 and a Bruker E 350 twin potentiostat. The disk and ring
electrodes were prepared from glass-graphite. The calculated efficiency coefficient of the electrodes [40] was
0.39 and the rate of rotation of electrodes was 2000 rpm. All potentials were measured relative to a 0.1 N silver
reference electrode (Ag/AgNO3). All investigations were carried out in nonaqueous acetonitrile, purified by the
procedure of [41], with the addition of 0.1% camphor. Depolarizer concentration was 5.10-4 M. Base electrolyte
was 1·10-1 M tetrabutylammonium hexafluorophosphate.
General Methods for the Synthesis of Nitriles of 4-Aryl-3-cyano-5-ethoxycarbonyl-6-methyl-2-
thioxo-1,4-dihydropyridine-3-carboxylic Acids (3). a) A mixture of ethyl 2-arylmethyleneacetoacetate
(5 mmol) and 2-cyanothioacetamide (5 mmol) in ethanol (15-20 ml) was heated briefly to dissolve the starting
materials, piperidine (6 mmol) was added, and the mixture stirred for 10-30 min. The solid formed was filtered
off and washed with ethanol (5-10 ml) cooled to 0°C. A mixture of compounds 4h and 2h, and 4i and 2i was
obtained by this method (see Table 2 for 1H NMR spectra). The mixture of salts 2 and 4 (5 mmol) and 1 M HCl
in ethanol (10 ml) was heated briefly and stirred for 10-20 min at room temperature. The resulting solid was
filtered off, washed with ethanol (5-10 ml) cooled to 0°C, and with water (10 ml). Compounds 3h and 3i were
obtained by this method.
b) A mixture of ethyl acetoacetate (5 mmol) and 3-aryl-2-cyanothioacrylamide (5 mmol) in ethanol
(15-20 ml) was heated briefly to dissolve the starting materials. Piperidine (6 mmol) was added, and the mixture
stirred for 10-30 min. The resulting solid was filtered off, and washed with ethanol (5-10 ml) cooled to 0°C.
Mixtures of compounds 2d and 4d, 2h and 4h, and 2i and 4i were obtained by this method (see Table 4 for
1H NMR spectra). The mixture of salts 2 and 4 (5 mmol) and 1M HCl in ethanol (10 ml) was heated briefly and
stirred for 10-20 min at room temperature. The resulting solid was filtered off, washed with ethanol (5-10 ml)
cooled to 0°C, and with water (10 ml). Compounds 3h and 3i were obtained by this method.
c) A mixture of aromatic aldehyde (5 mmol), 2-cyanothioacetamide (5 mmol), and piperidine (1 mmol)
in ethanol (15-20 ml) was heated briefly to effect solution. Then ethyl acetoacetate (5 mmol) and piperidine
(5 mmol) were added with stirring at room temperature. The resulting solid was filtered off, and washed with
ethanol (5-10 ml) cooled to 0°C. Mixtures of compounds 2d and 4d, 2h and 4h, and 2i and 4i were obtained by
1
this method (see Table 4 for H NMR spectra ). Mixtures of salts 4 and 2 (5 mmol) and 1 M HCl in ethanol
(10 ml) were heated briefly and stirred for 10-20 min at room temperature. The resulting solid was filtered off,
washed with ethanol (5-10 ml) cooled to 0°C, and with water (10 ml). Compounds 3h and 3i were obtained by
this method.
884

General Method for the Synthesis of Nitriles of 4-Aryl-3-cyano-5-ethoxycarbonyl-6-methyl-2-
methylthio-1,4-dihydropyridine-3-carboxylic Acids (1). A. A mixture of 1,4-dihydropyridine-2(3H)-thiolate
(10 mmol) and methyl iodide (15 mmol) or dimethyl sulfate (12 mmol) in ethanol (20-40 ml) was boiled for
2-5 min on a water bath, then stirred for 1 h at room temperature. The solid which had formed was filtered off,
washed with ethanol (5-10 ml) cooled to 0°C, and with water (10 ml). Compounds 1a,f were obtained by this
method.
B. A mixture of 1,4-dihydropyridine-2(3H)-thione 3 (10 mmol), piperidine (11 mmol), and methyl
iodide (15 mmol) or dimethyl sulfate (12 mmol) in ethanol (20-40 ml) was boiled on a water bath, then stirred
for 1 h at room temperature. The resulting solid was filtered off, washed with ethanol (5-10 ml) cooled to 0°C,
and with water (10 ml). Compounds 1e,h,j,k,l were obtained by this method.
C. A mixture of 1,4,5,6-tetrahydropyridin-2(3H)-thiolate 4 (with admixture of thiolate 2) (10 mmol) and
methyl iodide (15 mmol) in ethanol (20-40 ml) was boiled on a water bath, 3 M HCl in ethanol (2 ml) was
added, and the mixture was then stirred for 1 h at room temperature. The precipitate which formed was filtered
off, washed with ethanol (5-10 ml) cooled to 0°C, and with water (10 ml). Compounds 1h,i were obtained by
this method.
D. A mixture of ethyl 2-arylmethyleneacetoacetate (5 mmol), 2-cyanothioacetamide (5 mmol), and
piperidine (6 mmol) in ethanol (15-20 ml) was boiled briefly to effect solution, and after 10 min methyl iodide
(10 mmol) was added. The mixture was boiled for 5 min on a water bath and 3 M HCl (2 ml) was added. The
resulting solid was filtered off, washed with ethanol (5-10 ml) cooled to 0°C, and with water (10 ml).
Compounds 1a,f,h,i,j were obtained by this method.
E. A mixture of ethyl acetoacetate (5 mmol), 3-aryl-2-cyanothioacrylamide, and piperidine (6 mmol) in
ethanol (15-20 ml) was boiled briefly to effect solution and after 10 min methyl iodide (10 mmol) was added.
The mixture was boiled for 5 min on a water bath and 3 M HCl in ethanol (2 ml) was added. The solid formed
was filtered off, washed with ethanol (5-10 ml) cooled to 0°C, and with water (10 ml). Compounds 1b-d,h,i
were obtained by this method.
F. A mixture of aromatic aldehyde (5 mmol), 2-cyanothioacetamide (5 mmol), and piperidine (1 mmol)
in ethanol (15-20 ml) was boiled briefly to effect solution. While stirring at room temperature, ethyl acetoacetate
(5 mmol) and piperidine (5 mmol) were added and then after 10 min methyl iodide (30 mmol) was added. The
mixture was boiled for 5 min on a water bath, and 3 M HCl in ethanol (2 ml) was added. The solid formed was
filtered off, washed with ethanol (5-10 ml) cooled to 0°C, and with water (10 ml). Compounds 1g-i,m were
obtained by this method.
Pharmacological Section. Experiments were carried out in cats of both sexes of weight 2.3-3.6 kg,
anesthetized with chloralose (90 mg/kg, ip). Systemic arterial pressure was recorded by an electromanometric
method from the common carotid artery. The dp/dt was calculated with the aid of a pressure processor (Nihon
Kohden). ECG were drawn in standard I mode. The volume rate of coronary blood flow was determined by the
method of N. V. Kaverina [42], and blood flow in the femoral artery with the aid of a MFV 1200 flowmeter
(Nihon Kohden). All records were produced on a RM 6000 (Nihon Kohden) polygraph.
In experiments on mongrel dogs of both sexes of weight 13-24 kg, anesthetized with pentobarbital
sodium (50 mg/kg, ip), systemic arterial pressure and ECG were recorded as in the experiments on cats.
Substances were dissolved in 50% dimethylacetamide and injected intra-venously through a cannula
introduced into the femoral vein.
Each substance was investigated in 3-4 animals and mean data calculated.
In the experiments on awake, spontaneously hypertensive rats of the Okamoto-Aoki line [43] the
systemic arterial pressure was determined by plethysmography [44] before administering the substance and 0.5,
1, 3, 6, and 24 h afterwards. Each dose of substance was investigated in 3-6 rats using aqueous suspensions
prepared in Tween 80, which were introduced into the stomach through a probe.
885

Acute toxicity was investigated in white random-bred mice of weight 18-24 g. A suspension of the
substance in water with added Tween 80 (0.05 ml 6% Tween per 5 mg substance) was administered
intraperitoneally. Each dose was investigated in 3-6 mice, animals were observed for 10 d. The mean lethal dose
(LD50) was determined by the method of Litchfield and Wilcoxon.
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