Synthesis of novel pyrido [3′,2′:5,6]thiopyrano[3,2-b]indol-5(6H)-ones and 6H-pyrido[3′,2′:5,6]thiopyrano[4,3-b]quinolines, two new heterocyclic ring systems

Article abstract of DOI:10.1002/jhet.5570390522

The synthesis of new pyrido [3′,2′: 5,6]thiopyrano [3,2-b]indol-5 (6H)-ones was accomplished by the Fischer-indole cyclization of some 2,3-dihydro-3-phenylhydrazonothiopyrano[2,3-b]pyridin-4(4H)-ones, obtained from the 2,3-dihydro-3-hydroxymethylenethiopy

Full text of DOI:10.1002/jhet.5570390522

Sep-Oct 2002
Synthesis of Novel Pyrido[3',2':5,6]thiopyrano[3,2-b]indol-5(6H)-ones
and 6H-Pyrido[3',2':5,6]thiopyrano[4,3-b]quinolines, two New
Heterocyclic Ring Systems
1001
Antonio Da Settimo, Anna Maria Marini*, Giampaolo Primofiore,
Federico Da Settimo, Silvia Salerno, Francesca Simorini,
Gianluca Pardi, Concettina La Motta, and Daniele Bertini
Dipartimento di Scienze Farmaceutiche, Via Bonanno 6, 56126 Pisa, Italy
Received February 14, 2002
The synthesis of new pyrido[3',2':5,6]thiopyrano[3,2-b]indol-5(6H)-ones was accomplished by the
Fischer-indole cyclization of some 2,3-dihydro-3-phenylhydrazonothiopyrano[2,3-b]pyridin-4(4H)-ones,
obtained from the 2,3-dihydro-3-hydroxymethylenethiopyrano[2,3-b]pyridin-4(4H)-one, by the Japp-
Klingemann reaction.
6H-Pyrido[3',2':5,6]thiopyrano[4,3-b]quinolines were obtained by reaction of 2,3-dihydrothiopyrano-
[2,3-b]pyridin-4(4H)-ones with o-aminobenzaldehyde or 5-substituted isatins. The preparation of some
derivatives, functionalized with an alkylamino-substituted side chain, is also described.
J. Heterocyclic Chem., 39, 1001(2002).
In the ongoing search for new effective antitumor
recently, they were used for the synthesis of new pyridoth-
iopyrano[4,3-b]indole system 1 [12], which is structurally
related to the novel heterocycle A.
agents, a wide variety of new derivatives with completely
different chemical structures have been prepared and
tested. Among them, polycondensed nitrogen heterocycles
having a planar structure are effective moieties for drugs
endowed with antineoplastic activity. Their mechanism of
action is correlated with the capacity to intercalate with the
macromolecule of DNA [1-4], and to interfere with the
activity of Topoisomerases I and II, two enzymes capable
of modifying the topological state of DNA [5-9].
On the basis of these considerations, a large part of our
studies was directed towards the design and synthesis of
planar heteropolycyclic derivatives, structurally related to
biologically active drugs, as new potential antitumor
agents. In the last few years we have reported the synthesis
of several new compounds, bearing benzimidazole or
purine moieties, which exhibited interesting antiprolifera-
tive activity, because of their ability to form a complex
with DNA and to inhibit the Topoisomerase II [10-11].
In the present paper we wish to report the synthesis of
derivatives of two new tetracyclic heteroaromatic systems
of general formula A and B.
Notwithstanding the undoubted importance of the planar
aromatic ring systems, the addition of groups or side
chains which project from one or both the grooves of the
DNA double helix and which interact like external binder
moiety, appears to be crucial for drug activity. Indeed, a
large number of anti-tumor compounds have been modi-
fied by linking to a DNA intercalator a suitable basic side
chain, thus modulating the biological properties and
increasing solubility under physiological conditions [19-
21]. More recently, in the literature, it is also reported that
flexible basic side chains, linked to the chromophore moi-
ety by a carbonyl spacer, play an important role in enhanc-
ing DNA-binding properties [22,23]. Taking it into
account, we accomplished the synthesis of two derivatives
of B, in which a carboxamidodimethylaminoalkyl side
chain has been inserted in the 7 position of the heterotetra-
cyclic system.
Results and Discussion.
Scheme 1 shows the synthetic procedure used to afford
the title pyrido[3',2':5,6]thiopyrano[3,2-b]indol-5(6H)-
ones of general formula A. The preparation of the interme-
diate 2,3-dihydro-3-hydroxymethylenethiopyrano[2,3-b]-
pyridin-4(4H)-one 3 was accomplished from 2,3-dihy-
drothiopyrano[2,3-b]pyridin-4(4H)-one 2a, by reaction
They were prepared starting from the 2,3-dihydro-
thiopyrano[2,3-b]pyridin-4(4H)-ones 2a-b [12,13], by
known reactions employed in the literature for the obtain-
ment of analogous tetracyclic systems [14-18].
Compounds 2a-b revealed to be versatile intermediates as,

1002
A. Da Settimo, A. M. Marini, G. Primofiore, F. Da Settimo, S. Salerno, F. Simorini,
G. Pardi, C. La Motta, and D. Bertini
Vol. 39
2,3-Dihydrothiopyrano[2,3-b]pyridin-4(4H)-one 2a
[12] and the corresponding 7-methyl derivative 2b [13]
represented the starting material for the preparation of
the heterocyclic system B. Compounds 2a-b and o-
aminobenzaldehyde were allowed to react in ethanol
solution, at reflux in the presence of potassium hydrox-
ide, to yield (>60%) the desired 6H-pyrido[3',2':5,6]-
thiopyrano[4,3-b]quinolines 10a-b (Scheme 2). The
proposed structures of the products were consistent with
1
analytical, ir, H-nmr and mass spectral data. Evidence
for the structure of 10a-b derived from an examination
1
of their H-nmr spectra, in which the presence was
observed of a singlet at d@4 assigned to the methylene
group in the 6 position of the new ring system, instead
of the two triplets, ranging from d=2.81-3.01 and
d=3.24-3.43, due to 3-CH and 2-CH , respectively, of
2
2
compounds 2a-b.
Relatively simple reaction conditions were used in the
reaction between 2,3-dihydrothiopyrano[2,3-b]pyridin-
4(4H)-ones 2a-b and 5-substituted isatins, to obtain the
desired 6H-pyrido[3',2':5,6]thiopyrano[4,3-b]quinoline-7-
carboxylic acids 11a-b, 12a-b and 13a-b (Scheme 2).
Structures of compounds 11a-b, 12a-b and 13a-b were con-
firmed by physical, analytical and spectral data (Table III).
The synthesis of heterocyclic derivative 10a was car-
ried out also using the carboxylic acid 11a as starting
material. In fact, compound 11a was subjected to heating
with an excess of quinoline, at reflux temperature, in the
presence of copper chromite, to give 10a. In the ir spec-
trum of the thus obtained compound 10a, is evident the
with ethyl formate in anhydrous toluene in the presence of
sodium methoxide. Compound 3, containing a methine
active group, was able to give the desired 3-phenylhydra-
zono derivatives 4a, 5a and 6a in particularly good yields,
by coupling with the appropriately substituted diazonium
salt, by the Japp-Klingemann reaction [14-16].
Compounds 4a, 5a and 6a were directly converted to the
desired indole derivatives 7a, 8a and 9a using Fischer
cyclization, by reflux in hydrogen chloride ethanolic solu-
tion, with yields ranging from 70%-90%. The structures of
-1
absence of the absorption band at n = 1700 cm , typical
of the carboxylic group.
1
all new compounds agreed with analytical, ir, H-nmr and
As it was in our intention, carboxylic acid 11a was then
converted to the desired N-dialkylaminoalkyl amides 14
and 15, as shown in Scheme 2. Treatment of 11a with an
mass spectral data (Tables I and II). An interesting feature
of the H-nmr spectra of the derivatives 7a, 8a and 9a was
the low field signal (d@12) of the indole NH group.
1
Table I
Physical and Spectral Data of Compounds 4a, 5a and 6a
1
Compound
X
Yield
M.p.°C
H nmr (d ppm)
Ms
m/z
Molecular
Formula
Analysis (%)
Calcd./Found
(%) (Recrystallization
solvent)
C
H
N
4a
5a
6a
H
Cl
85
65
81
176-180
(Ethanol)
4.25-4.44 (s, 2H, 2-CH ), 6.83-6.88 (d, 2H, Ar-H),
2
269
C
H
N OS
62.44 4.12 15.60
62.53 4.43 15.40
14 11
3
7.45-7.53 (m, 3H, ArH), 7.64-7.74 (m, 2H, Ar-H),
8.90-8.95 (m, 1H, ArH), 12.68 (s, 1H, NH-exch.)
126-130
(Ethanol)
4.24-4.38 (s, 2H, 2-CH ), 7.29-7.59 (m, 5H, Ar-H), 303
C
H
ClN OS
55.35 3.32 13.83
55.64 3.37 13.61
14 10
3
2
8.27-8.31 (d, 1H, ArH), 8.58 (m, 1H, ArH), 13.41
(s, 1H, NH-exch.)
OCH
132-135
(Ethanol)
3.75 (s, 3H, -OCH ), 4.21-4.34 (s, 2H, 2-CH ),
299
C
H N O S
60.19 4.38 14.04
59.88 4.06 13.94
3
15 13 3 2
3
2
6.94-6.98 (d, 2H, Ar-H), 7.25-7.42 (m, 3H, ArH),
8.25-8.29 (d, 1H, Ar-H), 8.54-8.59 (m, 1H, ArH),
13.79 (s, 1H, NH-exch.)

Sep-Oct 2002
Synthesis of Novel Pyrido[3',2':5,6]thiopyrano[3,2-b]indol-5(6H)-ones
1003
Table II
Physical and Spectral Data of Compounds 7a, 8a and 9a
1
Compound
X
Yield
M.p.°C
H nmr (d ppm)
Ms
m/z
Molecular
Formula
Analysis (%)
Calcd./Found
H
(%) (Recrystallization
solvent)
C
N
7a
H
62
>300
(Ethanol)
7.25 (t, 1H, ArH), 7.55 (t, 1H, ArH), 7.62-7.74 (m, 252
3H, Ar-H), 8.88-8.95 (m, 2H, ArH), 12.67 (s, 1H,
NH-exch.)
C
H N OS
66.65 3.19 11.10
66.53 3.43 10.90
14
8 2
8a
9a
Cl
67
46
>300
7.32-8.96 (m, 6H, ArH), 12.86 (s, 1H, NH-exch.)
286
C
H ClN OS
58.64 2.46 9.77
58.37 2.37 9.61
63.82 3.57 9.92
63.88 3.56 9.74
14
7
2
(Ethanol)
247-250
(Ethanol)
OCH
3.78 (s, 3H, -OCH ), 7.01-8.93 (m, 6H, ArH),
3
282
C H N O S
15 10 2 2
3
12.95 (s, 1H, NH-exch.)
EXPERIMENTAL
excess of thionyl chloride afforded the intermediate acyl
chloride 16, which was allowed to react with an excess of
the appropriate dimethylaminoalkylamine, in anhydrous
toluene, to give the target compounds 14 and 15. The new
acyl chloride 16 was characterized as ethyl ester 17.
Melting points were determined using a Reichert Köfler hot-
stage apparatus and are uncorrected. Infrared spectra were
obtained on a PYE/UNICAM Model PU 9561 spectrophotometer

1004
A. Da Settimo, A. M. Marini, G. Primofiore, F. Da Settimo, S. Salerno, F. Simorini,
G. Pardi, C. La Motta, and D. Bertini
Vol. 39
Table III
Physical and Spectral Data of Compounds 10a-b, 11a-b and 12a-b
1
Compound
R
X
Yield
M.p.°C
H nmr (d ppm)
Ms
m/z
Molecular
Formula
Analysis (%)
Calcd./Found
H
(%) (Recrystallization
solvent)
C
N
10a
10b
H
H
H
45
30
248-250
(Ethanol)
280-283
(Ethanol)
4.36 (s, 2H, 6-CH ); 7.30-8.13 (m, 1H, ArH);
8.44-8.52 (m, 5H, ArH); 8.75 (d, 1H, ArH)
294
308
C
C
H N O S
16 10 2 2
65.29 3.42 9.52
65.58 3.15 9.33
66.22 3.92 9.08
66.48 3.67 8.93
2
CH
2.49 (s, 3H, 3-CH ); 4.34 (s, 2H, 6-CH );
H N O S
17 12 2 2
3
3
3
3
2
7.24 (d, 1H, ArH); 7.53-8.11 (m, 4H, ArH);
8.63 (d, 1H, ArH)
11a
11b
H
F
F
51
31
248-250
(Ethanol)
278-281
(Ethanol)
4.40 (s, 2H, 6-CH ); 7.30-8.78 (m, 6H, ArH)
312
326
C
H FN O S
61.53 2.90 8.97
61.27 3.06 9.03
62.57 3.39 8.58
62.52 3.55 8.31
2
16
9
2 2
CH
2.52 (s, 3H, 3-CH ); 4.39 (s, 2H, 6-CH ); 7.25
C H FN O S
17 11 2 2
3
2
(d, 1H, ArH); 7.53-7.80 (m, 2H, ArH); 8.06-
8.24 (m, 1H, ArH); 8.62 (d, 1H, ArH)
12a
12b
H
Br
Br
33
28
261-264
(Ethanol)
265-268
(Ethanol)
4.40 (s, 2H, 6-CH ); 7.31-7.97 (m, 1H, ArH);
373
387
C
H BrN O S
51.49 2.43 7.50
51.25 2.71 7.37
52.73 2.86 7.23
52.50 2.71 6.98
2
16
9
2 2
8.00-8.11 (m, 3H, ArH); 8.45-8.79 (m, 2H, ArH)
CH
2.50 (s, 3H, 3-CH ); 4.38 (s, 2H, 6-CH );
C H BrN O S
17 11 2 2
3
2
7.25 (d, 1H, ArH); 7.85-8.10 (m, 3H, ArH);
8.62 (d, 1H, ArH)
as Nujol mulls. Nuclear magnetic resonance spectra were
recorded on a Varian Gemini 200 spectrometer, in dimethyl-d6
sulfoxide solution. Mass spectra were obtained on a Hewlett-
Packard 5988 A spectrometer using a direct injection probe and
an electron beam energy of 70 eV. Magnesium sulfate was always
used as the drying agent. Evaporations were made in vacuo
(rotating evaporator). Analytical tlc were carried out on Merck
0.2 mm precoated silica gel aluminium sheets (60 F-254).
Elemental analyses were performed by our Analytical
Laboratory.
2,3-Dihydro-3-phenylhydrazonothiopyrano[2,3-b]pyridin-
4(4H)-ones 4a, 5a and 6a.
General Procedure.
A solution of 1.5 mmoles of 3 in 8 ml of methanol was added
to an aqueous saturated solution of 4.6 mmoles of sodium
acetate. After cooling at 0 °C, a solution of the suitable diazo-
nium salt, obtained from the appropriately p-substituted aniline in
diluted hydrochloric acid and sodium nitrite, was added dropwise
in slight excess. An orange precipitate is immediately formed.
The mixture was stirred for half an hour at 0 °C and for 3 hours at
room temperature. The solid was collected and washed with
water to give crude compounds 4a, 5a and 6a, Table I.
2,3-Dihydro-3-hydroxymethylenethiopyrano[2,3-b]pyridin-
4(4H)-one (3).
Pyrido[3',2':5,6]thiopyrano[3,2-b]indol-5(6H)-ones 7a, 8a and
9a.
A solution of ethyl formate (0.65 ml, 8 mmoles) in anhydrous
toluene (3 ml) was added dropwise to a suspension of freshly
prepared sodium methoxide (0.184 g, 8 mmoles of sodium in 2
ml of absolute methanol) in the same solvent (3 ml). The ice-
cooled mixture was treated dropwise with stirring, under nitro-
gen atmosphere, with a solution of 2,3-dihydrothiopyrano[2,3-
b]pyridin-4(4H)-one 2a (0.660 g, 4 mmoles) in anhydrous
toluene (8 ml). Stirring was continued at room temperature for
24 hours. The toluene layer was separated off and the sodium
salt of 3 was treated with water and acidified at 0 °C with
hydrochloric acid to give 3 (0.547 g, 71% yield). An analytical
sample was obtained by recrystallization from petroleum ether
40-60 °C, m.p. 188-190 °C; 1H-nmr (deuteriochloroform) : d
3.93 (s, 2H, 2-CH2), 7.26-7.32 (m, 2H, 3-CHOH, Ar-H), 8.19-
8.52 (m, 2H, ArH); ms: m/z = 193 (M+).
General Procedure.
A solution of 0.1 mmole of phenylhydrazono derivatives 4a,
5a or 6a in 2 ml of hydrogen chloride ethanolic solution was
refluxed for 20 minutes. After cooling, the orange precipitate was
collected and washed with ethanol to give crude indoles 7a, 8a
and 9a, which were purified by recrystallization, Table II.
3-Unsubstituted- 10a and 3-Methyl-6H-pyrido[3',2':5,6]thio-
pyrano[4,3-b]quinoline 10b.
General Procedure.
A suspension of 2,3-dihydrothiopyrano[2,3-b]pyridin-4(4H)-
one 2a or 7-methyl derivative 2b (2 mmoles) and 0.242 g (2
mmoles) of o-aminobenzaldehyde in 12 ml of ethanol, in the
presence of 0.10 g of potassium hydroxide, was refluxed until
Anal. Calcd. for C9H7NO2S: C, 55.95; H, 3.65; N, 7.25.
Found: C, 56.25; H, 3.69; N, 7.64.

Sep-Oct 2002
Synthesis of Novel Pyrido[3',2':5,6]thiopyrano[3,2-b]indol-5(6H)-ones
1005
disappearance of the starting reagents (20-24 hours, tlc analysis:
petroleum ether 60-80 °C/ethyl acetate 7:3 as the eluting system).
After cooling, the crude precipitate was collected to give com-
pounds 10a-b, which were purified by recrystallization from
ethanol.
crude amides 14 or 15 as dark viscous oils, which were purified
by column chromatography (alumina grade I, 70-230 mesh, chlo-
roform as eluent) to give solid amides 14 and 15, which were
crystallized from toluene-petroleum ether 60-80 °C.
1
Compound 14 was obtained in 46% yield, mp 127-130 °C; H
Compound 10a was obtained in 69% yield, m.p.190-192 °C;
1H-nmr: d 4.40 (s, 2H, 6-CH2), 7.28-8.80 (m, 8H, Ar-H); ms: m/z
= 250 (M+).
nmr: d 2.31 (s, 6H, N(CH3)2); 2.58 (t, 2H, CH2CH2N(CH3)2);
3.48 (t, 2H, CH2CH2N(CH3)2); 4.33 (s, 2H, 6-CH2); 7.29-8.80
(m, 7H, Ar-H); ms: m/z = 364 (M ).
+
Anal. Calcd. for C20H20N4OS: C, 65.91; H, 5.53; N, 15.37;
Anal. Calcd. for C15H10N2S: C, 71.97; H, 4.03; N, 11.19.
Found: C, 72.28; H, 4.34; N, 11.33.
Compound 10b was obtained in 61% yield, m.p.154-157 °C;
1H-nmr: d 2.48 (s, 3H, 3-CH3), 4.37 (s, 2H, 6-CH2), 7.18 (d, 1H,
Ar-H, J=21 Hz), 7.45-8.24 (m, 5H, ArH), 8.61 (d, 1H, ArH, J=21
Hz); ms: m/z = 264 (M+).
Found: C, 65.74; H, 5.53; N, 15.59.
Compound 15 was obtained in 30% yield, mp 122-123 °C; H
1
nmr: d 1.70-1.87 (m, 2H, CH 2CH2CH2N); 2.16 (s, 6H,
N(CH3)2); 2.33 (t, 2H, CH2CH2CH2N); 3.46 (t, 2H,
CH2CH2CH2N); 4.26 (s, 2H, 6-CH2); 7.31-8.82 (m, 7H, Ar-H);
+
ms: m/z = 378 (M ).
Anal. Calcd. for C16H12N2S: C, 72.70; H, 4.57; N, 10.59.
Found: C, 71.28; H, 4.16; N, 10.24.
Anal. Calcd. for C21H22N4OS: C, 66.64; H, 5.86; N, 14.80;
Found: C, 66.77; H, 6.16; N, 14.92.
6H-Pyrido[3',2':5,6]thiopyrano[4,3-b]quinoline 10a from 11a.
6H-Pyrido[3',2':5,6]thiopyrano[4,3-b]quinoline-7-carboxylic
Acid Ethyl Ester 17.
A mixture of 6H-Pyrido[3',2':5,6]thiopyrano[4,3-b]quinoline-
7-carboxylic acid 11a (0.200 g, 0.7 mmole), copper chromite
(0,060 g) in 5 ml of freshly distilled quinoline, was refluxed for 2
hours. After cooling, the precipitate obtained was collected by
filtration affording the crude derivative10a (0.122 g, 68% yield),
which was washed with water and purified by recrystallization
from ethanol, m.p.191-193 °C.
A suspension of acyl chloride 16 (0.27 mmole) in anhydrous
toluene (10 ml) and absolute ethanol (3 ml) was stirred at room
temperature for 24 hours and then heated (70 °C) for 2 hours. The
resulting solution was concentrated in vacuo to dryness to yield
crude ethyl ester 17, which was purified by recrystallization from
ethanol giving pure 17, (37 mg, 42% yield), mp 182-185 °C; 1H
nmr: d 1.42 (t, 3H, CH2CH3), 4.36 (s, 2H, 6-CH2), 4.57 (q, 2H,
3-Unsubstituted- 11a, 3-Methyl-6H-pyrido[3',2':5,6]thiopy-
rano[4,3-b]quinoline-7-carboxylic Acid 11b and Corresponding
9-Fluoro- 12a-b and 9-Chloro- 13a-b Derivatives.
+
CH2CH3), 7.31-8.81 (m, 7H, Ar-H); ms: m/z = 322 (M ).
Anal. Calcd. for C18H14N2O2S: C, 67.06; H, 4.38; N, 8.69;
Found: C, 67.00; H, 4.64; N, 8.70.
General Procedure.
Acknowledgments.
To a suspension of 2,3-dihydrothiopyrano[2,3-b]pyridin-
4(4H)-one 2a or 7-methyl derivative 2b (5.4 mmoles) and the
appropriately 5-substituted isatin (6 mmoles) in 5 ml of ethanol
were added 3 ml of 0.2% sodium hydroxide aqueous solution.
The reaction mixture was refluxed until disappearance of the
starting reagents (18-24 hours, tlc analysis: chloroform/methanol
7:3 as the eluting system). After cooling, the solution obtained
was acidified with concentrated hydrochloric acid until pH 5,
affording the crude acids 11a-b, 12a-b and 13a-b, which were
purified by recrystallization from ethanol (Table III).
This work was supported by grants from the Ministry of
University and Scientific and Technological Research (MURST)
(Research fund 60%).
REFERENCES AND NOTES
*
Author to whom all correspondence should be addressed.
[1] E. Borowski, D. Shugar, in "Molecular Aspects of
Chemotherapy", Pergamon Press, New York, (1991).
[2] U. Pindur and G. Fisher, Curr. Med. Chem., 3, 379 (1996),
and references therein.
6H-Pyrido[3',2':5,6]thiopyrano[4,3-b]quinoline-7-carbonyl
Chloride (16).
[3] F. Zunino, F. Animati and G. Capranico, Curr. Pharm.
Des., 1, 83 (1995).
[4] A. P. Krapcho, M. J. Maresch, M. P. Hacker, L.
Hazelhurst, E. Menta, A. Oliva, S. Spinelli, G. Beggiolin, F. C.
Giuliani, G. Pezzoni and S. Tognella, Curr. Med. Chem., 2, 803
(1995), and references therein.
[5] L. F. Liu, Annu. Rev. Biochem., 58, 351 (1989).
[6] S. S. Insaf, M. K. Danks and D. T. Witiak, Curr. Med.
Chem., 3, 437 (1996) and references therein.
[7] G. Capranico, F. Zunino, Curr. Pharm. Des., 1, 14 (1995).
[8] Y. Pommier, G. Capranico, A. Orr and K. W. Kohn, J. Mol.
Biol., 222, 2504 (1991).
[9] G. Capranico, M. Binaschi, M. Borgnetto and M.
Palumbo, Trends Pharm. Sci., 18, 323 (1997).
[10] A. Da Settimo, A. M. Marini, G. Primofiore, F. Da
Settimo, S. Salerno, G. Viola, L. Dalla Via and S. Marciani Magno,
Eur. J. Med. Chem., 33, 685 (1998).
A suspension of 6H-pyrido[3',2':5,6]thiopyrano[4,3-b]quino-
line-7-carboxylic acid 11a (0.40 g, 1.36 mmoles) in 1 ml of
thionyl chloride and 4 ml of anhydrous toluene was refluxed (70
°C) for 16 hours. The excess thionyl chloride was distilled off,
and the residue was washed with few additional amounts of
anhydrous toluene to give pure 16, which was used without fur-
ther purification in the next reactions.
N-(Dimethylaminoalkyl)-6H-Pyrido[3',2':5,6]thiopyrano[4,3-b]-
quinoline-7-carboxamides 14 and 15.
General Procedure.
To a suspension of carbonyl chloride 16 (1.36 mmoles) in 20
ml of anhydrous toluene the appropriate N,N-dimethyl-
aminoalkylamine was added. The reaction mixture was stirred at
room temperature until no starting materials were detected by tlc
(approximately 10 hours, chloroform/methanol 9:1 as the eluting
system). The mixture obtained was evaporated to dryness to give
[11] A. Da Settimo, A. M. Marini, G. Primofiore, F. Da
Settimo, S. Salerno, L. Dalla Via, O. Gia and S. Marciani Magno,

1006
A. Da Settimo, A. M. Marini, G. Primofiore, F. Da Settimo, S. Salerno, F. Simorini,
G. Pardi, C. La Motta, and D. Bertini
Vol. 39
Farmaco, 56, 159 (2001).
418 (1976).
[12] A. Da Settimo, A. M. Marini, G. Primofiore, F. Da
Settimo, S. Salerno, C. La Motta, G. Pardi, P. L. Ferrarini and C.
Mori, J. Heterocyclic Chem., 37, 379 (2000).
[18] A. K. Kiang and F. G. Mann,J. Chem. Soc., 1909 (1951).
[19] L. M. Werbel, M. Angelo, D. W. Fry and D. F. Worth, J.
Med. Chem., 29, 1321 (1986)
[13] P. L. Ferrarini, C. Mori, M. Badawneh, V. Calderone, R.
Greco, C. Manera, A. Martinelli, P. Nieri and G. Saccomanni, Eur. J.
Med. Chem., 35, 815 (2000).
[14] R. R. Phillips, Org. React., 10, 143 (1959).
[15] A. Kent and D. McNeil, J. Chem. Soc., 8 (1938).
[16] A. J. Mears, S. H. Oakeshott and S. G. P. Plant, J. Chem.
Soc., 272 (1934).
[20] R. J. White and F. E. Durr, Invest. New Drugs, 3, 85
(1985).
[21] J. Koeller and M. Eble, Clin. Pharm., 7, 574 (1988).
[22] C. Guillonneau, A. Pierré, Y. Charton, N. Guilbaud, L.
Kraus-Berthier, S. Léonce, A. Michel, E. Bisagni and G. Atassi, J.
Med. Chem., 42, 2191 (1999).
[23] I. Antonini, P. Paolucci, L. R. Kelland, S. Spinelli, N.
Pescalli and S. Martelli, J. Med. Chem., 43, 4801 (2000).
[17] A. Fravolini, A. Croisy and P. Jacquignon, Farmaco, 31,