4-(10-Methyl-10H-phenothiazin-3-yl)-1,4-dihydropyridines, 4,5-dihydroindeno[1,2-b]-and 5,5-dioxo-4,5-dihydrobenzo-thieno[3,2-b]pyridines

Article abstract of DOI:10.1007/s10593-007-0035-8

Different modifications of the Hantzsch synthesis using 10-methyl-10H-phenothiazine-3-carbaldehyde gave 4-(10-methyl-10H-phenothiazin-3- yl)-substituted 1,4-dihydropyridine-3,5-di-, 5-oxo-4,5-dihydro-1H-indeno[1,2-b] pyridine-, and 5,5-dioxo-4,5-dihydro-1

Full text of DOI:10.1007/s10593-007-0035-8

Chemistry of Heterocyclic Compounds, Vol. 43, No. 2, 2007
4-(10-METHYL-10H-PHENOTHIAZIN-3-YL)-1,4-DIHYDROPYRIDINES,
4,5-DIHYDROINDENO[1,2-b]- AND 5,5-DIOXO-4,5-DIHYDROBENZO-
THIENO[3,2-b]PYRIDINES
B. Vigante, G. Tirzitis, D. Tirzite, B. Chekavichus, J. Uldrikis,
A. Sobolev, and G. Duburs
Different modifications of the Hantzsch synthesis using 10-methyl-10H-phenothiazine-3-carbaldehyde
gave 4-(10-methyl-10H-phenothiazin-3-yl)-substituted 1,4-dihydropyridine-3,5-di-, 5-oxo-4,5-dihydro-
1H-indeno[1,2-b]pyridine-,
3-carboxylic esters.
and
5,5-dioxo-4,5-dihydro-1H-5λ6-benzo[4,5]thieno[3,2-b]pyridine-
Keywords: 10-methyl-10H-phenothiazin-3-carbaldehyde, 1,4-dihydropyridine, Hantzsch synthesis,
4-(10-methyl-10H-phenothiazin-3-yl)-5-oxo-1H-4,5-dihydroindeno[1,2-b]pyridine.
Highly effective coronary dilators [1, 2] and hypotensive agents [3] have already been discovered
amongst 4-aryl- and 4-hetaryl-1,4-dihydropyridines (1,4-DHP) but this has not diminished the synthesis of novel
1,4-DHP’s with the aim of finding compounds having an altered profile of pharmacological properties. It is
known that the 1,4-DHP structure can be regarded as a pharmacophoric group or "special structure" and the
variation of the substituent in the DHP ring might be expected to give a selective action of the 1,4-DHP on
various cell membrane receptors [4].
The antioxidant activity of 1,4-DHP has been investigated [5, 6] and its correlation with pharmacological
properties discussed [7, 8]. It was found that the exchange of an o-nitrophenyl group at position 4 of the 1,4-
DHP for a polycyclic heterocyclic substituents (xanthone, azaxanthen-9-one, thioxanthen-9-one) had a marked
effect on inotropic and vasodilator activity [9, 10]. 1,4-DHP and 4,5-dihydro-indenopyridines containing
lipophilic and bulky substituents show inhibitory activity on glutathione-S-transferase [11].
At the same time, phenothiazine derivatives can possess high antioxidant, antiradical, neuroprotective,
and antitumor activity [12, 13]. In recent years phenothiazine derivatives have been investigated as
neuroprotectors of nerve cells in Alzheimer [14] and Creutzfeld-Jakob deseases [15]. In combination this
encouraged us to synthesize 1,4-DHP derivatives having the two pharmacotropic groups (1,4-DHP and
phenothiazine) in the same molecule.
To prepare the novel series of monocyclic 1,4-DHP 2, 5-oxo-4H-dihydroindeno[1,2-b]pyridines 5, and
also 5,5-dioxo-4,5-dihydrobenzothieno[3,2-b]pyridines 8 we have employed different modifications of the
Hantzsch synthesis using 10-methyl-10H-phenothiazine-3-carbaldehide 1 as the aldehyde component. Hence the
1,4-DHP 2b was prepared in 42% yield by refluxing the aldehyde 1 with acetoacetic ester and ammonia in
ethanol (Scheme 1, method A). The corresponding dimethyl ester of the 1,4-DHP-3,4-dicarboxylic acid 2a was
__________________________________________________________________________________________
Latvian Institute of Organic Synthesis, Riga LV-1006; e-mail: vigante@osi.lv. Translated from Khimiya
Geterotsiklicheskikh Soedinenii, No. 2, pp. 280-288, February, 2007. Original article submitted May 10, 2006.
0009-3122/07/4302-0225©2007 Springer Science+Business Media, Inc.
225

obtained under the above conditions but in 37% yield. With the aim of increasing the yield of the dimethyl ester
2a we carried out the condensation of phenothiazine 1 with methyl β-aminocrotonate by refluxing in ethanol in
the presence of glacial acetic acid (Scheme 1, method B). The best method for preparing 2a and also the
unsymmetrically 3,5-disubstituted 1,4-DHP 2c proved to be a two stage synthesis (Scheme 1, method C) by
initial synthesis of the 2-(10-methyl-10H-phenothiazin-3-ylmethylene)acetoacetic acid esters 3a,b and
subsequent cyclization with methyl β-aminocrotonate.
Sheme 1
Me
N
Me
N
O
O
S
S
C
C
1
H
H
1
COOR1
Me
COOR1
Me
ROOC
ROOC
Me
+
+
Me
O
H2N
NH2
O
Me
N
B
A
R = R1
R = R1
S
COOR1
ROOC
Me
Me
N
H
2a–c
Me
N
C
S
R1
ROOC
Me
ROOC
O
OOC
Me
D
1
+
+
Me
O
NH2
3a,b
A: NH4OН, EtOH, t°; B: EtOH/AcOH, t°; C: EtOH/AcOH, t°; D: C6H6, piperidine /AcOH, t°;
2a R = R1 = Me; b R = R1 = Et; c R = Me, R1 = Et; 3 a R = Me, b R = Et
The corresponding ylidene derivatives 3a,b were prepared by refluxing acetoacetic acid esters with the
10-methyl-10H-phenothiazine-3-carbaldehyde 1 in benzene in the presence of piperidine acetate with azeotropic
distillation of water [16].
We have previously shown that 5-oxo-4,5-dihydroindeno[1,2-b]pyridines [17] and 1,4-dihydro-
benzothieno[3,2-b]pyridine 5,5-dioxides [18] which contain aryl substituents at position 4 have high coronary
dilator and antioxidant activity [19-21]. 5-Oxo-4,5-dihydroindeno[1,2-b]pyridines with heterocyclic substituents
[3-pyridyl-, 4-(3-phenylpyrazolyl)-] at position 4 shown marked antitumor activity [22].
226

TABLE 1. Physicochemical Characteristics of Compounds 2-8
Found, %
Calculated, %
——————
Com-
pound
Empirical
formula
mp, °С*
Yield, %
С
H
N
S
2a
C24H24N2O4S
65.6
66.0
5.6
5.5
6.3
6.4
7.0
7.4
175-177
37 (A), 45 (B),
70 (C)
2b
2c
3a
3b
4
C26H28N2O4S
C25H26N2O4S
C19H17NO3S
C20H19NO3S
C23H15NO2S
C28H22N2O3S
C29H24N2O2S2
C28H20N2O3S
C29H22N2O2S2
C22H15NO3S2
67.0
67.2
66.3
66.6
67.5
67.2
67.7
68.0
74.8
74.8
71.8
72.1
70.4
70.1
71.4
72.4
6.1
6.1
5.8
5.8
5.0
5.1
5.5
5.4
3.9
4.1
4.7
4.8
4.5
4.9
4.2
4.3
6.0
6.0
6.2
6.2
4.1
4.1
4.1
4.0
3.6
3.8
5.8
6.0
5.2
5.6
6.2
6.0
6.6
6.9
6.9
7.1
9.0
9.5
8.7
9.1
8.7
8.7
6.9
6.9
12.4
12.9
6.5
6.9
164
169
42 (A)
65 (C)
81
125-127
92-97
226
73
81
5a
5b
6a
6b
7
255
69
180-183
282
70
75
69.9
70.4
65.2
65.2
4.6
4.5
3.5
3.7
5.6
5.7
3.5
3.5
12.7
13.0
15.5
15.8
173-175
252-254
66
84
8a
8b
C27H22N2O4S2
C28H24N2O4S2
63.7
64.5
64.7
65.1
4.5
4.4
4.6
4.7
5.1
5.6
5.2
5.4
12.1
12.8
12.3
12.4
200-204
172-175
56
69
_______
* Solvents for crystallization: methanol (compound 2a), aqueous
methanol (2b and 2c), ethanol (3a,b), acetic acid (4, 5a,b), mixture of
ethanol and acetic acid (5 : 1) (6a).
The esters of 5-oxo-1H-4,5-dihydroindeno[1,2-b]pyridine-3-carboxylic and thiocarboxylic acids 5a,b
were prepared by condensation of 2-(10-methyl-10H-phenothiazin-3-ylmethylene)indane-1,3-dione (4) with
methyl β-aminocrotonate and the S-ethyl ester of acetothioacetic acid in the presence of ammonium acetate by
analogy with a previously reported method [23] (Scheme 2). In turn, the ylidene derivative of 1,3-indanedione 4
was synthesized by refluxing 10-methyl-10H-phenothiazine-3-carbaldehyde with 1,3-indanedione in acetic acid
using piperidine acetate as catalyst.
The 5-oxo-4H-1,4-dihydroindeno[1,2-b]pyridines were oxidized to the corresponding pyridines 6a,b
using sodium nitrite in acetic acid.
The 2-methyl-4-(10-methyl-10H-phenothiazin-3-yl)-5,5-dioxo-4,5-dihydro-1H-5λ6-benzo[4,5]thieno[3,2-b]-
pyridine-3-carboxylic acid esters 8a,b were synthesized by cyclocondensation of the 2-(10-methyl-10H-
phenothiazin-3-ylmethylene) derivative of benzo[b]thiophen-3(2H)-one 1,1-dioxide 7 with β-aminocrotonates in
glacial acetic acid. In turn, the ylidene derivative of the 1,1-dioxide 7 was prepared in high yield by
condensation of the 10-methyl-10H-phenothiazine-3-carbaldehyde 1 with dioxide 7 in glacial acetic acid in the
presence of piperidine acetate as catalyst.
The structure of the synthesized 10-methyl-10H-phenothiazin-3-yl derivatives of the monocyclic and
polycyclic 1,4-DHP 2, 5 and 8 were established from their spectroscopic characteristics (Tables 2 and 3).
227

228

TABLE 2. Spectroscopic Characteristics of Compounds 2-8
Com-
IR spectrum, ν, cm-1
UV spectrum, λmax, nm (log ε)
pound
2a
1600, 1630, 1665, 1710, 3365
1600, 1630, 1650, 1690, 3340
1610, 1650, 1695, 3340
207 (4.58), 233 sh. (4.47), 255 (4.55),
339 (3.94)
2b
2c
207 (4.58), 233 sh. (4.48), 255 (4.57),
339 (3.96)
207 (4.60), 233 sh. (4.51), 255 (4.57),
339 (3.97)
3a
3b
4
1600, 1620, 1650, 1680, 1720
1600, 1620, 1645, 1680, 1720
1620, 1650, 1680, 1720
245 (4.33), 306 (4.36), 413 (4.11)
246 (4.33), 305 (4.34), 412 (4.09)
250 (4.45), 267 sh. (4.25), 331 (4.18),
371 (4.08), 505 (4.29)
5a
5b
1610, 1640, 1670, 1710, 3180, 3260
1600, 1630, 1645, 1670, 3160, 3240
233 (4.54), 256 (4.73), 303 (4.11),
473 (3. 48)
233 sh. (4.53), 256 (4.79), 305 (4.24),
490 (3.70)
6a
6b
7
1610, 1710, 1730
1610, 1640, 1675, 1710
—
—
—
210 (4.52), 255 sh. (4.11), 328 (3.61),
375 sh. (3.48), 520 (4.25)
8a
8b
—
—
234 sh. (4.25), 258 (4.81), 290 sh. (3.10),
380 sh. (3.50)
230 sh. (4.20), 259 (4.75), 288 sh. (3.20),
380 sh. (3.62)
TABLE 3. 1H NMR Spectra of Compounds 2-8
Com-
pound
Chemical shifts, δ, ppm (SSCS, J, Hz) (DMSO-d6)
2a
2.18 (6H, s, 2,6-CH3), 3.18 (3H, s, NCH3), 3.47 (6H, s, 3,5-CH3), 4,71 (1H, s, 4-CH),
6.7-7.2 (7H, m, arom.), 8.76 (1Н, s, NH)
2b
2c
1.11 (6H, t, J = 7.5, 3,5-CH3), 2.22 (6H, s, 2,6-CH3), 3.29 (3H, s, NCH3), 3.96 (4H, q,
J = 7.5, 3,5-OCH2), 4.37 (1H, s, 4-CH), 6.7-7.2 (7H, m, arom.), 8.73 (1Н, s, NH)
1.11 (3H, t, J = 7.5, 3-CH3), 2.20 (6H, s, 2,6-CH3), 3.20 (3H, s, NCH3),
3.47 (3H, s, 5-OCH3), 3.96 (2H, q, J = 7.5, 3-OCH2), 4.71 (1H, s, 4-CH),
6.7-7.6 (7H, m, arom.), 8.76 (1Н, s, NH)
3a
3b
2.40 (3H, s, COCH3), 3.36 (3H, s, NCH3), 3.87 (3H, s, COOCH3),
6.9-7.4 (7H, m, arom.), 7.64 (1Н, s, CH=)
1.20 (3H, t, J = 7.5, OCH2CH3), 2.33 (3H, s, CH3), 3.24 (3H, s, NCH3),
4.20 (2H, q, J = 7.5, OCH2), 6.9-7.4 (7H, m, arom.), 7.56 (1Н, s, CH=)
4
3.33 (3H, s, NCH3), 6.9-8.5 (12H, m, arom. + CH=)
5a
2.45 (3H, s, 2-CH3), 3.27 (3H, s, NCH3), 3.44 (3H, s, COOCH3), 4.62 (1H, s, 4-CH),
6.7-7.5 (11H, m, arom.), 10.04 (1Н, s, NH)
5b
1.09 (3H, t, J = 7.8, SCH2CH3), 2.44 (3H, s, 2-CH3), 2.73 (2H, q, J = 7.8, SCH2),
3.29 (3H, s, NCH3), 4.86 (1H, s, 4-CH), 6.7-7.6 (11H, m, arom.), 10.24 (1Н, s, NH)
6a
6b
2.60 (3H, s, 2-CH3), 3.60 (3H, s, OCH3), 3.84 (3H, s, NCH3), 7.27-8.0 (11H, m, arom.)
0.87 (3H, t, J = 7.8, SCH2CH3), 2.60 (3H, s, 2-CH3), 2.76 (2H, q, J = 7.8, SCH2),
3.82 (3H, s, NCH3), 7.2-8.0 (11H, m, arom.)
7
3.45 (3H, s, NCH3), 7.06-7.27 (5H, m, arom. + CH=),
8.02-8.30 (7H, m, phenothiazine protons)
8a
8b
2.11 (3H, s, 2-CH3), 3.16 (3H, s, OCH3), 3.22 (3H, s, NCH3), 4.61 (1H, s, 4-CH),
6.67-7.89 (11H, m, arom. protons + phenothiazine protons), 9.93 (1H, s, NH)
1.08 (3H, t, J = 7.0, СH3), 2.34 (3H, s, 2-CH3), 3.21 (3H, s, OCH3), 3.28 (3H, s, NCH3),
3.96 (2H, q, J = 7.0, OCH2), 6.90-8.27 (11H, m, arom. protons + phenothiazine protons),
9.88 (1H, s, NH)
229

Using the method given in [11] the ability of the series of compounds synthesized to inhibit the in vitro
activity of glutathione-S-transferase was tested. It was found that the polycyclic indeno-1,4-DHPs 5 showed the
clearest inhibitory activity when compared with the monocyclic 1,4-DHPs 2. At a concentration of 5×10-5 M
compound 5a inhibits this activity by 56% and the corresponding sulfur compound 5b by 98% at this
concentration (at a concentration an order lower, i.e. 5×10-6 M by 74%). Corresponding to compound 5b the
pyridine derivative 6b shows 92% inhibition at a concentration of 5×10-5 M. At the same concentration the
starting compound 4 also inhibits by 67-70%. Hence we propose that, the ability of the investigated compounds
to inhibit the in vitro activity of glutathione-S-transferase requires a phenothiazine component in the molecule
conjugated with a 2-methyleneindanedione group since the starting N-methylphenothiazine shows an inhibition
of only 29% at a concentration of 5×10-5 M.
However, the fact that 5b is significantly more effective than 5a shows that the effect of the remaining
dihydropyridine part of the molecule must be taken into account.
EXPERIMENTAL
IR spectra were recorded on a UR-20 instrument (in nujol), UV spectra were taken on a Specord M40
1
Carl Zeiss Jena spectrometer in ethanol. H NMR spectra were recorded on Bruker WH 90/DC (90 MHz) and
Varian Mercury (200 MHz) instruments with TMS as internal standard. Monitoring of the course of the reaction
and the purity of the synthesized compounds was carried out using TLC on Merck Silicagel 60 F254 UV-254
plates with chloroform–hexane–acetone (9 : 7 : 1) as eluent. The basic characteristics of the compounds synthe-
sized are given in Tables 1 and 2.
10-Methyl-10H-phenothiazine was prepared by a known method [24] from phenothiazine via
alkylation with methyl iodide in hexametapol (HMPA).
10-Methyl-10H-phenothiazine-3-carbaldehyde (1) was prepared by Vilsmeier-Haack formylation of
10-methyl-10H-phenothiazine [25].
3,5-Dimethoxycarbonyl-2,6-dimethyl-4-(10-methyl-10H-phenothiazin-3-yl)-1,4-dihydropyridine
(2a). Method B. A mixture of compound 1 (2.41 g, 10 mmol), methyl β-aminocrotonate (3.45 g, 30 mmol),
ethanol (70 ml), and glacial acetic acid (2 ml) was refluxed for 8 h. Solvent was distilled of in vacuo and the
residue was triturated with water (100 ml). The precipitated material was filtered off, dried, dissolved in acetone
(20 ml), and passed thorough a silica gel column (l = 40 cm, d = 2 cm) using chloroform–hexane–acetone–ethanol
(9 : 7: 2 : 1) as eluent. The fraction with Rf 0.56 was collected. After removal of solvent the residue was crystallized
from methanol to give the dihydropyridine 2a. Yield 1.95 g (45%), mp 173-175°C.
3,5-Diethoxycarbonyl-2,6-dimethyl-4-(10-methyl-10H-phenothiazin-3-yl)-1,4-dihydropyridine (2b). A.
A mixture of compound 1 (2.41 g, 10 mmol), acetoacetic ester (2.60 g, 20 mmol) and 25% aqueous ammonia
solution (5 ml) in ethanol (100 ml) was refluxed for 8 h. Solvent was removed in vacuo and the residue was
chromatographed as described before. The fraction with Rf 0.66 was collected. After removal of solvent the
residue was crystallized from aqueous methanol (~ 70%) to give the colorless dihydropyridine 2b. Yield 1.95 g
(42%), mp 164°C.
3,5-Dimethoxycarbonyl-2,6-dimethyl-4-(10-methyl-10H-phenothiazin-3-yl)-1,4-dihydropyridine (2a)
was prepared using method A from aldehyde 1 and methyl acetoacetate in 37% yield.
5-Ethoxycarbonyl-3-methoxycarbonyl-2,6-dimethyl-4-(10-methyl-10H-phenothiazin-3-yl)-1,4-dihydro-
pyridine (2c). C. Compound 3 (3.53 g, 10 mmol) and methyl β-aminocrotonate (1.7 g, 15 mmol) were refluxed for
7 h in a mixture of ethanol (70 ml) and acetic acid (30 ml). Solvent was evaporated in vacuo and the oil
produced was chromatographed as described before. The fraction with Rf 0.62 was collected. The colorless
substance was crystallized from aqueous methanol to give the dihydropyridine 2c. Yield 3 g (65%), mp 169°C.
230

3,5-Dimethoxycarbonyl-2,6-dimethyl-4-(10-methyl-10H-phenothiazin-3-yl)-1,4-dihydropyridine
(2a) was prepared similarly from methyl 2-(10-methyl-10H-phenothiazin-3-ylmethylene)acetoacetate 3a (3.39 g,
10 mmol). Yield 3 g (70%).
Synthesis of 2-(10-Methyl-10H-phenothiazin-3-ylmethylene)acetoacetic acid esters (3a,b) (General
Method). Aldehyde 1 (2.41 g, 10 mmol) and the corresponding ester (10 mmol) in dry benzene (150 ml) with
piperidine (0.2 ml) and glacial acetic acid (0.2 ml) were refluxed in a Dean and Stark apparatus for 3 h. The
benzene solution was washed with water and dried with anhydrous sodium sulfate. Solvent was evaporated in
vacuo and the residue was crystallized from ethanol to give orange colored crystals of 3a or 3b.
2-(10-Methyl-10H-phenothiazin-3-ylmethylene)indane-1,3-dione (4). Indane-1,3-dione (1.46 g,
10 mmol) was dissolved with heating in glacial acetic acid (60 ml). Aldehyde 1 (2.41 g, 10 mmol) and piperidine
(0.1 ml) were added to the hot solution and the product was refluxed for 10 min. After cooling, the dark-violet
crystals formed were filtered off and crystallized from AcOH to give the dihydroindeno[1,2-b]-pyridine 5a.
Yield 0.96 g (69%), mp 255°C.
3-(Ethylthio)carbonyl-2-methyl-4-(10-methyl-10H-phenothiazin-3-yl)-5-oxo-1H-4,5-dihydroindeno[1,2-
b]- pyridine (5b). Compound 4 (1.1 g, 3 mmol) was dissolved in glacial AcOH (50 ml). S-ethyl acetothioacetate
(1.46 g, 10 mmol) and ammonium acetate (2.5 g) were added and the mixture was refluxed for 10 min. Solvent
was distilled off in vacuo to half volume. After cooling, the red crystals were filtered off and crystallized from
AcOH to give the dihydroindeno[1,2-a]pyridine 5b. Yield 1.0 g (70%), mp 180-183°C.
Synthesis of 3-Substituted 2-Methyl-4-(10-methyl-10H-phenothiazin-3-yl)-5-oxoindeno[1,2-b]pyridines
6a,b (General Method). The corresponding dihydroindeno[1,2-b]pyridine 5a,b (2 mmol) was dissolved in
glacial AcOH (10 ml), sodium nitrite (1 g) was added portionwise, and the mixture was heated to 80°C over
10 min. After cooling, the product was diluted with water (20 ml) and the yellow crystalline precipitate was
filtered off and recrystallized from a mixture of ethanol and AcOH (5 : 1 by volume) to give the pyridines 6a,b
as pale-yellow colored crystals.
2-(10-Methyl-10H-phenothiazin-3-ylmethyl)-3-oxo-1,2-dihydro-1λ6-benzo[b]thiophene 1,1-dioxide
(7). The aldehyde 1 (1.2 g, 5 mmol) and benzo[b]thiophen-3(2H)-one 1,1-dioxide (0.95 g, 5.2 mmol) were
refluxed in glacial AcOH (50 ml) in the presence of piperidine as catalyst (0.1 ml) for 30 min. After cooling the
dark-violet crystals were filtered off and crystallized repeatedly from AcOH to give compound 7. Yield 1.7 g
(84%), mp 252-254°C.
3-Methoxycarbonyl-2-methyl-4-(10-methyl-10H-phenothiazin-3-yl)-4,5-dihydro-1H-5λ6-
benzo[4,5]thieno- [3,2-b]pyridine 5,5-dioxide (8a). Compound 7 (0.81 g, 2 mmol) was dissolved with
heating in glacial AcOH (30 ml) and taken to reflux. Methyl β-aminocrotonate (0.3 g, 2.5 mmol) was
added and the solution was refluxed for 30 min. After cooling and addition of water the yellow crystals were
filtered off and recrystallized from a mixture of ethanol and AcOH to give the methyl ester 8a. Yield 0.56 g
(56%), mp 200-254°C.
3-Ethoxycarbonyl-2-methyl-4-(10-methyl-10H-phenothiazin-3-yl)-4,5-dihydro-1H-5λ6-benzo[4,5]thieno-
[3,2-b]pyridine 5,5-dioxide (8b) was prepared similarly from the benzo[b]thiophen-3-one 7 and ethyl
β-aminocrotonate in 69% yield. Mp 172-174°C.
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