A synthesis of new pyrrolo[3,2-c]quinolines

Article abstract of DOI:10.1002/jhet.5570380335

A synthesis of pyrrolo[3,2-c]quinolines substituted in the 7- and 8- positions by methoxy groups and in the 3- position by an amido group is described. The structures were designed to have a crescent shape, a planar fused cyclic moiety with two ortho methoxy groups and ionisable amino or aminidinic group at pH 7.

Full text of DOI:10.1002/jhet.5570380335

May-Jun 2001
A Synthesis of New Pyrrolo[3,2-c]Quinolines
755
Fabienne Dudouit [a], Raymond Houssin and Jean-Pierre Hénichart*
Institut de Chimie Pharmaceutique Albert Lespagnol, Université de Lille 2
3 rue du Professeur Laguesse, 59006 Lille, France
Received November 6, 2000
A synthesis of pyrrolo[3,2-c]quinolines substituted in the 7- and 8- positions by methoxy groups and in
the 3- position by an amido group is described. The structures were designed to have a crescent shape, a
planar fused cyclic moiety with two ortho methoxy groups and ionisable amino or amidinic group at pH 7.
J. Heterocyclic Chem., 38, 755 (2001).
Topoisomerase inhibitors possess significant anticancer
The synthesis of 11 proceeded according to Scheme
1. Ester 4 [4] was saponified with aqueous sodium
hydroxide and the resulting β-ketoacid 5 was
submitted to decarboxylation by heating at 200° in
phenyl ether to give dihydroquinolinone 6 which was
treated with phosphorous oxychloride. The crude chlo-
ride derivative 7 [5],[6] was immediately condensed
with phenylhydrazine in ethanol to give 8. A Michael
addition of the more acidic phenylhydrazinic NH on
ethyl propiolate gave 9 which was easily converted to
10 at reflux of DMF by a Fischer indole-type synthesis
[7]. Finally, saponification of 10 gave 11 in a moderate
yield.
activity against many solid tumours including breast,
ovarian, and lung carcinomas. Two major classes of
inhibitors exist: topoisomerase poisons and catalytic
inhibitors [1]. Our work has focused on the action mecha-
nism of topoisomerase poisons which is primarily based
on the ability to inhibit the religation of DNA cleavage
induced by topoisomerase enzymes. Topoisomerase
poisons like camptothecin [2] (Figure 1) chiefly bind to
both the active site of the enzyme and DNA by hydrogen
bonding, whereas netropsin [3] (Figure 1) essentially
binds to the minor groove of DNA, thereby preventing the
approach of topoisomerase.
Camptohecin
Netropsin
Coralyne
Fagaronine
1
2
2
R = C(=NH)NH
2
R = CH NH
2
2
R = CH
Figure 1
Molecules 1 and 2 were designed to combine these two
Compounds 1, 2 and 3 were synthesized according to
Scheme 2 and using the techniques of peptidic synthesis.
Carboxylic acid 11 was coupled with 4-aminobenzami-
dine or 4-cyanoaniline in the presence of benzotriazol-1-
yloxytris(pyrrolidino)phosphonium hexafluorophosphate
(PyBOP) in dimethylformamide to give amides 1 and 3.
Similarly, the coupling of 11 with the aniline derivative 12
in the same conditions resulted in amide 13. The
carbamoyl group of 2 was classically removed by treatment
of 13 with trifluoroacetic acid in methylene chloride.
Biological experiments are currently in progress to test
DNA affinity, anti-proliferation properties and topo-
isomerase inhibition of these compounds.
inhibition mechanisms and to offer a different sequence selec-
tivity toward DNA. They contain the pyrroloquinoline struc-
ture of camptothecin and the pyrrolocarboxamide moiety of
netropsin. Moreover, they present the crescent shapes of both
reference compounds as well as a roughly planar tricyclic
moiety where the homocycle was substituted with two ortho
methoxy groups, like some topoisomerase inhibitors such as
Coralyne and Fagaronine (Figure 1). In addition, a cationic
amino or amidino group, as in netropsin, was appended to the
ring system in order to further enhance their DNA binding
affinities. For the purpose of comparison, the synthesis of
non cation-containing compound 3 was undertaken.

Vol. 38
F. Dudouit, R. Houssin, and J.-P. Hénichart
756
Scheme 1
Scheme 2
spectrometer; chemical shifts are reported in parts per million rela-
tive to the internal standard tetramethylsilane and the splitting
patterns are designated as follows: s singlet, bs broad singlet, d
doublet, t triplet, q quartet, m multiplet. The spectra confirmed the
proposed structures. The mass spectra were recorded on a quadri-
polar Finnigan TSQ 700 instrument in electron impact mode.
Elemental analyses for C, H, N were performed by the 'Service
Central d'Analyses' at the CNRS, Vernaison, France.
EXPERIMENTAL
Melting points were determined on a Büchi 535 apparatus using
the capillary method and are uncorrected. Analytical tlc was
performed on precoated Kieselgel 60F plates (Merck); the spots
254
were located by uv light (254 and 366 nm). Column chromato-
graphy was performed on silicagel 60 230-400 Mesh purchased
from Merck. H nmr spectra were recorded on a Bruker AC 300
1

May-Jun 2001
A Synthesis of New Pyrrolo[3,2-c]Quinolines
757
1,4-Dihydro-6,7-dimethoxy-4-oxoquinoline-3-carboxylic
Acid (5).
1
199-203°. H nmr (dimethylsulfoxide-d ): δ 1.29 (t, J = 7.1 Hz,
6
3H), 3.96 (s, 3H), 3.97 (s, 3H), 4.59 (q, J = 7.1 Hz, 2H), 6.79 (s,
1H), 7.85 (s, 1H), 8.90 (s, 1H), 8.95 (s, 1H), 9.50 (bs, 1H). ms
(electron impact) m/z 300, 301 (M+H).
Anal. Calcd. for C
Found: C, 64.15; H, 5.28; N, 9.28.
A mixture of 4 [4] (4 g, 14 mmol) and 10% aqueous sodium
hydroxide (10 ml, 29 mmol) was stirred at reflux for 18 hours.
The solvent was removed and the residue was extracted with
ethyl acetate after addition of water. The aqueous phase was
acidified with 3 M hydrochloric acid. After concentration, acid 5
precipitated and was purified through recrystallization from
H N O : C, 63.99; H, 5.37; N, 9.33.
16 16 2 4
7,8-Dimethoxy-1H-pyrrolo[3,2-c]quinoline-3-carboxylic Acid
(11).
1
water (1.57 g, 45%). mp 274-276° (lit.[5] 276°). H nmr
A solution of 10 (0.5 g, 1.8 mmol) in methanol (10 ml) with
10% sodium hydroxide (1.4 ml, 3.6 mmol) was stirred at room
temperature for 18 hours and evaporated in vacuo. The resulting
residue was extracted with methylene chloride and washed with
water. The aqueous layer was removed, acidified with 1 M
hydrochloric acid and extracted with methylene chloride. After
evaporation, the resulting residue was purified through recrystal-
(dimethylsulfoxide-d ): δ 3.94 (s, 3H), 3.99 (s, 3H), 7.01 (s,
6
1H), 7.52 (s, 1H), 8.40 (s, 1H), 10.51 (bs, 1H, exchangeable in
deuterium oxide).
Anal. Calcd. for C
H NO : C, 57.83; H, 4.45; N, 5.62.
12 11 5
Found: C, 57.88; H, 4.40; N, 5.61.
1,4-Dihydro-6,7-dimethoxy-4-oxoquinoline (6).
lization from water to give 11 as a white solid (0.26 g, 55%).
Acid 5 (1 g, 4.9 mmol) and phenyl ether (10 ml) were heated
at reflux for 18 hours. Chromatography on silica gel with 5%
methanol/methylene chloride was followed by recrystallization
with ethyl acetate to afford 6 (0.55 g, 55%). mp 234-237° (lit.[5]
1
mp > 260°. H nmr (dimethylsulfoxide-d ): δ 3.93 (s, 6H), 6.60
6
(s, 1H), 6.91 (s, 1H), 7.28 (s, 1H), 8.70 (bs, 1H), 10.02 (s, 1H).
ms (electron impact) m/z 272, 273 (M+H).
1
Anal. Calcd. for C H N O : C, 61.76; H, 4.44; N, 10.29.
236-237°). H nmr (dimethylsulfoxide-d ): δ 3.82 (s, 3H), 3.83
14 12 2 4
6
Found: C, 61.42; H, 4.73; N, 10.31.
(s, 3H), 7.23 (s, 1H), 7.54 (d, J = 7.0 Hz, 1H), 8.46 (d, J = 7.0
Hz, 1H), 8.50 (s, 1H), 10.00 (bs, 1H).
7,8-Dimethoxy-3-(4-amidinoanilinocarbonyl)-1H-pyrrolo-
[3,2-c]quinoline (1).
Anal. Calcd. for C
H NO : C, 64.38; H, 5.40; N, 6.83.
11 11 3
Found: C, 64.32; H, 5.46; N, 6.79.
A solution of 11 (0.2 g, 0.73 mmol), 4-aminobenzamidine
dihydrochloride (0.18 g, 0.8 mmol), benzotriazol-1-yloxy-
tris(pyrrolidino)phosphonium hexafluorophosphate (0.45 g,
0.88 mmol) and N-ethyldiisopropylamine (0.5 ml, 2.9 mmol)
in dimethylformamide (10 ml) was stirred at room tempera-
ture for 24 hours. The mixture was diluted with water and
extracted with ethyl acetate. The organic layer was removed
and then treated with 1 M hydrochloric acid. Separation and
neutralization of the aqueous layer with sodium bicarbonate,
followed by extraction with ethyl acetate gave a clear solu-
6,7-Dimethoxy-4-[2-(1-phenylhydrazino)]quinoline (8).
A mixture of 6 (0.5 g, 2.4 mmol) and phosphorus oxychloride
(1.13 ml, 12 mmol) was heated for a few minutes. The mixture
was concentrated and the residue diluted with toluene. After
evaporation of the solvent, the resulting oil was poured onto ice
and made basic with aqueous 10% ammonium hydroxide. The
mixture was extracted with ethyl acetate. The organic layer was
washed with water, dried over magnesium sulfate, evaporated to
give crude 7 (0.41 g, 80%). A solution of crude 7 (1 g, 4.5
mmol) in ethanol (20 ml) was added to phenylhydrazine (2.2 ml,
22.5 mmol). The mixture was heated at reflux for 18 hours. The
solvent was removed and the product purified by chromato-
graphy with 50% ethyl acetate/heptane, followed by recrystal-
lization from ethanol to give 8 as a pale yellow solid (0.71 g,
tion of 1 which was evaporated in vacuo (0.1 g, 30%). mp >
1
260°. H nmr (dimethylsulfoxide-d ): δ 3.98 (s, 6H), 6.77 (s,
6
1H), 7.81 (s, 1H), 7.95 (d, J = 8.1 Hz, 2H), 8.10 (d, J = 8.1
Hz, 2H), 8.15 (s, 1H), 8.20 (bs, 3H), 8.69 (s, 1H), 10.50 (bs,
1H), 11.56 (bs, 1H). ms (electron impact) m/z 389, 390
(M+H).
1
54%). mp 240-243°. H nmr (dimethylsulfoxide-d ): δ 3.80 (s,
6
Anal. Calcd. for C
H N O : C, 64.77; H, 4.92; N, 17.98.
3H), 3.83 (s, 3H), 7.45 (s, 1H), 7.58 (d, J = 7.2 Hz, 1H), 7.65-
7.95 (m, 5H), 8.51 (d, J = 7.2 Hz, 1H), 8.57 (s, 1H), 10.50 (bs,
2H). ms (electron impact) m/z 393, 394 (M+H).
21 19 5 3
Found: C, 64.81; H, 4.88; N, 17.72.
7,8-Dimethoxy-3-(4-(tert-butoxycarbonylaminomethyl)anilino-
carbonyl)-1H-pyrrolo[3,2-c]quinoline (13).
Anal. Calcd. for C
H N O : C, 69.37; H, 5.48; N, 14.28.
17 16 3 2
Found: C, 69.24; H, 5.32; N, 14.37.
A solution of 11 (0.2 g, 0.73 mmol), amine 12 [8] (0.18 g, 0.8
mmol), benzotriazol-1-yloxytris(pyrrolidino)phosphonium-
hexafluorophosphate (0.45 g, 0.88 mmol), N-ethyldiisopropyl-
amine (0.5 ml, 2.9 mmol) in dimethylformamide (5 ml) was
stirred for 24 hours. Water (10 ml) was added and the mixture
extracted with methylene chloride. The product was purified by
chromatography with 20% methanol/methylene chloride to give
Ethyl 7,8-Dimethoxy-1H-pyrrolo[3,2-c]quinoline-3-carboxy-
late (10).
A solution of ethyl propiolate (0.16 ml, 1.63 mmol) and 8
(0.4 g, 1.36 mmol) in methanol (10 ml) was heated at reflux for
18 hours. The solvent was removed and the product was purified
by chromatography, eluted by 50% ethyl acetate/cyclohexane to
give 9 (0.3 g, 56%).
1
13 as a tan product (0.1 g, 28%). mp > 260°. H nmr (dimethyl-
A solution of crude 9 (0.3 g, 1 mmol) in dimethylformamide
(25 ml) was heated at reflux for 24 hours. The solvent was evap-
orated, the resulting residue was extracted with ethyl acetate and
the extract was washed with water. The organic layer was dried
over magnesium sulfate, evaporated, and the residue purified by
chromatography on silica gel with 5% methanol/methylene
chloride to give 10 as a pure tan solid (0.19 g, 30%). mp
sulfoxide-d ): δ 1.40 (s, 9H), 3.93 (s, 3H), 3.96 (s, 3H), 5.00 (s,
6
2H), 6.89 (s, 1H), 7.18 (d, J = 7.2 Hz, 2H), 7.64 (d, J = 7.2 Hz,
2H), 7.68 (bs, 1H), 7.75 (s, 1H), 7.80 (bs, 1H), 8.10 (s, 1H), 8.71
(s, 1H), 10.50 (bs, 1H), 11.90 (s, 1H). ms (electron impact) m/z
476, 477 (M+H).
Anal. Calcd. for C
H N O : C, 65.53; H, 5.92; N, 11.76.
26 28 4 5
Found: C, 65.42; H, 5.73; N, 11.51.

Vol. 38
F. Dudouit, R. Houssin, and J.-P. Hénichart
758
7,8-Dimethoxy-3-(4-(aminomethyl)anilinocarbonyl)-1H-
pyrrolo[3,2-c]quinoline (2).
(d, J = 7.2 Hz, 2H), 8.00 (s, 1H), 8.90 (s, 1H), 10.50 (bs, 2H).
ms (electron impact): 372, 373 (M+H).
Anal. Calcd. for C21H16N4O3: C, 67.71; H, 4.34; N, 15.06.
Found: C, 67.35; H, 4.28; N, 15.11.
A solution of 13 (0.3 g, 0.6 mmol) in methylene chloride (5
ml) was cooled at 0° and acidified with a few drops of
trifluoroacetic acid. The mixture was stirred for 2 hours at
room temperature and evaporated. The resulting product was
dissolved in a minimum of water. Following neutralization
with sodium bicarbonate, the resulting precipitate was
collected by filtration to give 2 as a tan product (0.12 g, 50%).
mp > 260°. 1H nmr (dimethylsulfoxide-d6): δ 3.95 (s, 6H),
4.03 (s, 2H), 6.78 (d, J = 8.0 Hz, 3H), 7.64 (d, J = 8.0 Hz, 2H),
7.80 (s, 1H), 8.00 (bs, 2H), 8.05 (s, 1H), 8.66 (s, 1H), 8.90 (s,
1H), 10.50 (bs, 1H), 11.00 (bs, 1H). ms (electron impact) m/z
376, 377 (M+H).
REFERENCES AND NOTES
[*] Tel: +33-3-20-96-43-74; Fax: +33-3-20-96-43-61; E-mail:
henicha@phare.univ-lille2.fr
[a] Current address: Cancer Drug Research Laboratory, Division
of Medical Oncology, Department of Medicine and Chemistry, McGill
University, Royal Victoria Hospital, 687 Pine Avenue West, Montreal,
Quebec, H3A 1A1, Canada.
[1] G. Capranico, M. Binaschi, M. E. Borgnetto, F. Zunino and
M. Palumbo, Trends Pharmacol. Sci., 18, 323 (1997).
[2] A. Tanizawa, K. W. Kohn and Y. Pommier, Nucl. Acids Res.,
21, 5157 (1993).
Anal. Calcd. for C21H20N4O3: C, 67.01; H, 5.36; N, 14.88.
Found: C, 66.75; H, 5.06; N, 15.03.
[3] A. Bell, L. Kittler, G. Lober and C. Zimmer, Investigational
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7,8-Dimethoxy-3-(4-cyanoanilinocarbonyl)-1H-pyrrolo[3,2-c]-
quinoline (3).
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Benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexa-
fluorophosphate (0.45 g, 0.88 mmol), 4-cyanoaniline (0.1 g, 0.8
mmol) and N-ethyldiisopropylamine (0.5 ml, 2.9 mmol) were
added to 11 (0.2 g, 0.7 mmol) in dimethylformamide (10 ml).
The reaction was stirred for 24 hours at room temperature after
which it was diluted with 20 ml of water and extracted with
methylene chloride. The organic layer was dried over magne-
sium sulfate, evaporated and the resulting residue purified by
chromatography (20% methanol/methylene chloride) to give 3
(0.1 g, 25%). mp > 260°. 1H nmr (dimethylsulfoxide-d6): δ 3.96
(s, 6H), 6.85 (s, 1H), 7.82 (s, 1H), 7.85 (d, J = 7.2 Hz, 2H), 7.95
[8] F. Dudouit, J-F. Goossens, R. Houssin, J-P. Hénichart, P.
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