Ring-substituted 11-oxo-11H-indeno[1,2-b]quinoline-6-carboxamides with similar patterns of cytotoxicity to the dual topo I/II inhibitor DACA

Article abstract of DOI:10.1016/S0968-0896(99)00231-X

A series of ring-substituted analogues of the topoisomerase inhibitor 11-oxo-11H-indeno[1,2-b]quinoline-6-carboxamides was prepared and evaluated. The compounds were prepared by Pfitzinger reaction of the appropriate isatin-7-carboxylic acids and 1-indanones, followed by selective thermal decarboxylation of the resulting tetracyclic diacids, subsequent oxidation of the methylene group with alkaline permanganate under carefully controlled conditions, and 1,1'-carbonyldiimidazole-induced amidation. The compounds were evaluated in a panel of cell lines in culture. The largest increases in cytotoxicity (five to tenfold) were shown by 4-substituted analogues, with the 4-Cl derivative having an IC₅₀ of 8nM against the Lewis lung carcinoma. Copyright (C) 1999 Elsevier Science Ltd.

Full text of DOI:10.1016/S0968-0896(99)00231-X

Bioorganic & Medicinal Chemistry 7 (1999) 2801±2809
Ring-Substituted 11-Oxo-11H-indeno[1,2-b]quinoline-
-carboxamides with Similar Patterns of Cytotoxicity to the
Dual Topo I/II Inhibitor DACA
6
a,
a
a
a
Leslie W. Deady, * Jose Desneves, Anthony J. Kaye, Michelle Thompson,
Â
b
b
b
Graeme J. Finlay, Bruce C. Baguley and William A. Denny
aSchool of Chemistry, La Trobe University, Bundoora, Victoria, Australia 3083
bAuckland Cancer Society Research Centre, Faculty of Medical and Health Science, The University of Auckland,
Private Bag 92019, Auckland 1000, New Zealand
Received 14 May 1999; accepted 12 July 1999
AbstractÐA series of ring-substituted analogues of the topoisomerase inhibitor 11-oxo-11H-indeno[1,2-b]quinoline-6-carboxamides
was prepared and evaluated. The compounds were prepared by P®tzinger reaction of the appropriate isatin-7-carboxylic acids and
1
-indanones, followed by selective thermal decarboxylation of the resulting tetracyclic diacids, subsequent oxidation of the meth-
ylene group with alkaline permanganate under carefully controlled conditions, and 1,1'-carbonyldiimidazole-induced amidation.
The compounds were evaluated in a panel of cell lines in culture. The largest increases in cytotoxicity (®ve to tenfold) were shown
by 4-substituted analogues, with the 4-Cl derivative having an IC50 of 8 nM against the Lewis lung carcinoma. # 1999 Elsevier
Science Ltd. All rights reserved.
Introduction
compounds are non-linear tetracyclic chromophores
bearing a cationic side chain, as exempli®ed by intopli-
cine8 (1) and TAS 103
,9
10,11
(2). We recently showed
12
Topoisomerases I and II (topo I and II) play vital roles
in DNA replication and transcription by maintaining
DNA topology, are essential for cellular replication,1
and are thus attractive targets for anticancer drugs.
While the expression of either enzyme appears to be
sucient to support cell division, the time-course of
their expression di€ers markedly; levels of topo I remain
essentially constant throughout the cell cycle, while topo
II levels peak in S-phase and then decline rapidly. They
are also expressed at di€erent absolute levels in di€erent
cell types. Although one mechanism of resistance to
either topo I or topo II agents is a drop in the level of
the appropriate enzyme, the development of such resis-
tance is often accompanied by a rise in the level of the
that indenoquinolines (e.g. 3a) were also potent cyto-
toxic agents, with patterns of cell line activity consistent
with dual topo I/II inhibition. Compound 3a, which
showed in vivo activity comparable to doxorubicin and
the mixed topo I/II inhibitor13 DACA (4) in colon 38
tumors, was selected as the most promising of a number
of fused tetracyclic quinolines and quinoxalines. We
now report on the synthesis and structure±activity
relationships of a series of chromophore-substituted
analogues of 3a.
12
2
3
,4
5
,6
other enzyme.
Accordingly, there is current interest in agents capable
of simultaneous inhibition of both topo I and topo II
enzymes. Although there are few structural criteria for
7
what constitutes a `dual inhibitor', one group of such
Key words: Antitumour compounds; chemotherapy; enzyme inhibi-
tors; topoisomerase.
*
1
Corresponding author. Tel.: +61-3-9479-2561; fax: +61-3-9479-
399; e-mail: ldeady@latrobe.edu.au
0968-0896/99/$ - see front matter # 1999 Elsevier Science Ltd. All rights reserved.
PII: S0968-0896(99)00231-X

2
802
L. W. Deady et al. / Bioorg. Med. Chem. 7 (1999) 2801±2809
Results
The general synthetic strategy followed was reported
previously (Scheme 1). P®tzinger reaction of the
appropriate isatin-7-carboxylic acid (6) and 1-indanone
decarboxylated. Reaction of this with MeI and silver
oxide in DMSO methylated both acid and phenol OH
groups to give 13, and this underwent direct aminolysis
to give the required amide 3h (Table 1).
1
2
(
7) in aqueous hydroxide (with some solubilising etha-
Apart from 3h, the other amides were prepared by an
experimentally simpler procedure than those used pre-
viously12 (Scheme 3). The appropriate acid 11 was
reacted with 1,1 -carbonyldiimidazole in dioxan and
the intermediate imidazolide 14 was coupled in situ with
the required amine. The high-melting acids were gen-
erally dicult to completely purify and microanalysis
was therefore con®ned to the ®nal amides.
nol where required) gave the tetracyclic diacids (8).
Examples of decarboxylation both before (8!10) and
after (9!11) oxidation of the bridging methylene group
are reported, though the latter sequence became gen-
erally preferred, and the technique for solid-phase
thermal decarboxylation of 8 or 9 was re®ned (see
Experimental). While a number of procedures for
oxidation of the methylene group were employed, a
reaction with alkaline permanganate under carefully
controlled conditions gave generally high yields. This
method (and a number of others) failed with the 8-
methoxy compound but, after much experimentation,
0
15
Discussion
The compounds were evaluated in a panel of cell lines in
culture; the murine P388 leukemia, the murine Lewis
lung carcinoma,16 and three human leukemia (Jurkat)
1
4
reaction with nickel peroxide gave the desired result
(
8l!9l). Aluminium chloride demethylation of the cor-
1
7,18
responding methoxy compounds gave the hydroxy sub-
stituted diacids 9f and 9i (Scheme 2). This route was
also required for ultimate preparation of the required 4-
methoxy compound, since decarboxylation of 8h or 9h
was accompanied by some demethylation which com-
plicated puri®cation (only found for this isomer). The
lines that have been described in detail previously.
JLC is the wild-type (sensitive) line, JLA is resistant to
the topo II agents (85-fold resistant to amsacrine)
because of a reduced level of topo II, and JLD is a
similarly resistant (13-fold) to doxorubicin. IC50 values
for the compounds in the P388, LLTC and JL lines are
A
4-hydroxydiacid 9i was therefore prepared and smoothly
given in Table 1, together with ratios of IC50 values
against JL and the other two Jurkat lines (ratios JL /
JLC and JL /JL ). Values of these ratios of less than
C
A
D
C
about twofold suggest a non-topo II mediated mechan-
ism of action. Thus the mixed topo I/II inhibitor DACA
(
4) has ratios of 1.9 and 2.3, respectively (Table 1),
while 7-chloroDACA (5), which has been shown to be a
preferential topo I inhibitor,11 has ratios of 1.2 and 1.3.
The `classical' topo I inhibitor camptothecin shows
similar low ratios (Table 1). Surprisingly, the reported
dual inhibitor TAS 1031
0,11
(2) behaved in these cell
lines very much as a pure topo II inhibitor, with very
high ratios.
Although little structure±activity work has been repor-
ted with TAS 103 (2), limited studies with substituted
analogues of intoplicine (1) have shown that replacing
the OH group with either H or OMe results in a loss of
mixed inhibitory capability, giving topo I inhibitors
�
ꢀ
ꢀ
2 3
CO /55 C; (iii) heat
Scheme 1. (i) OH /H
2
O/90 C; (ii) KMnO
/AcOH/re¯ux; (v) NiO
/re¯ux.
4
/Na
ꢀ
�
ꢀ
ꢀ ꢀ
3 2
Scheme 2. (i) AlCl /NaCl/180 C; (ii) heat 300 C; (iii) Mel/Ag O/
ca. 300 C; (iv) Na
/3 M H
2
Cr
2
O
7
2
/OH /H
2
O/20 C; (vi)
ꢀ
DMF/20 C.
Na
2
Cr O
2 7
2
SO
4

L. W. Deady et al. / Bioorg. Med. Chem. 7 (1999) 2801±2809
2803
Table 1. Cell growth inhibition data for substituted N-[2-(dimethyl-
amino)ethyl]-11-oxo-11H-indeno[1,2-b]quinoline-6-carboxamides
speaking, 3- and 8-substituted analogues (3e±3g, 3l, 3m)
were similar to 3a, while 1- and 2-substituted com-
pounds (3b±3d) were more active. The biggest di€erence
was with 4-substituted compounds (3h±3k), which were
substantially more cytotoxic (three to eightfold) than 3a
in P388, LLTC and JLC (the exception was the 4-aza
compound 3p, which had similar activity to 3a). How-
ever, this was accompanied by a slight drop in relative
activity against the JL line. These results parallel those
A
IC50 (nM)a
IC50 ratios
/JL JL /JL
C
reported for DACA analogues, where the structurally
equivalent 5-substituted derivatives were more cytotoxic
than DACA itself but were relatively less e€ective
against the JLA and JLD cell lines than the wild-type
c
d
No.
Form
R
H
P388b LL JL
C
JL
A
C
D
3
1
3
3
3
3
3
3
3
3
3
3
3
3
3
3
4
a
2
b
c
d
e
f
g
h
j
k
l
m
n
o
p
A
A
A
A
A
A
A
A
A
A
A
A
A
A
B
109 91 180
154 135 217
43 34 106
438 58 68
230 114 100
134 76 102
242 175 311
62 59 105
23 23 71
13.5 15 35
21 8.2 55
330 102 119
990 53 129
1.2
1.2
0.7
1.1
2.0
1.0
1.2
1.1
2.2
2.1
1.8
1.3
1.9
0.8
1.3
1.9
1.9
85
0.9
0.9
0.7
1.2
1.9
1.0
1.6
1.2
0.8
0.9
0.4
1.0
0.9
0.9
1.5
0.9
2.3
74
e
H
JL , suggesting a mode of cytotoxicity mainly mediated
C
1-OMe
2-OMe
2-Cl
3-OMe
3-OH
3-Me
4-OMe
4-Me
4-Cl
15
by e€ects on topoisomerase II. The 2,3-dimethoxy
compound 3n was signi®cantly more active than either
of the component monomethoxy derivatives, but the
benzo analogue 3o o€ered no advantage over the parent.
Conclusions
8-OMe
8-Cl
The ring-substituted 11-oxo-11H-indeno[1,2-b]quino-
line-6-carboxamides show structure±activity relation-
2,3-diOMe 143 17 42
135 152 325
1
5
ships broadly similar to those reported earlier for
DACA analogues, with substituents on the carbon peri
to the chromophore nitrogen exerting the largest e€ect
on cytotoxicity. The 4-methyl analogue 3j was the most
cytotoxic.
A
4-aza
140 100 218
98 189 580
20 12 37
1.5 5.4
(DACA)f
f
Amsacrine
(TAS 103)
Camptothecin
2
302
2.0
384
1.4
g
5.6
a
IC50; concentration of drug to reduce cell number to 50% of control
cultures (see text).
Murine P388 leukemia.
Murine Lewis lung carcinoma.
Human Jurkat leukemia.
b
Experimental
c
d
e
Analyses indicated by symbols of the elements were
1
Side chain is CONH(CH
Data from ref 19.
Data from ref 32.
2 2 2 2
) NH(CH ) OH.
f
within ‹0.4% of the theoretical. H NMR spectra were
obtained at 300 MHz, in (CD ) SO unless stated other-
g
3
2
wise, and are referenced to Me Si. In the listings, proton
4
counts for aromatic protons (which have not been
assigned) are given only for unresolved multiplets; the
other aromatic signals are single proton doublets and
triplets with J=6±8 Hz, except the pyrido ring proton, a
singlet. In addition to the peaks listed, all carboxamides
(
2
except 12) had a common pattern for the side chain: d
.4 (s, 6H, N(CH ) , 2.7 (t, J=6 Hz, 2H, CH N), 3.75
3
2
2
(
q, J=6 Hz, 2H, NHCH ). Electrospray mass spectra
2
were recorded on a VG Bio-Q triple quadrupole mass
spectrometer, with water:MeOH:AcOH (50:50:1) as the
mobile phase. Microanalyses were performed at the
Campbell Microanalytical Laboratory, University of
Otago, New Zealand.
ꢀ
2 2 2
/CH Cl /20 C.
Scheme 3. (i) CDl/dioxan/re¯ux; (ii) H
2
N(CH
2
)
2
NMe
Isatin-7-carboxylic acid was prepared as reported.12 1-
Indanone, 6-methoxy-1-indanone, 6-methyl-1-indanone,
5,6-dimethoxy-1-indanone and 5-chloro-1-indanone
were Aldrich chemicals. 5-Methoxy-1-indanone was
9
(
with somewhat lower in vivo activity). Studies with
substituted analogues of the more closely-related
DACA (4) have suggested that substituent positioning
and steric properties are more important than electronic
20
obtained from 5-indanol, 1-acenaphthenone from 1-
21
1
9
properties.
naphthylacetic acid and 5,6-dihydro-7H-1-pyrinden-7-
2
2
one (7-aza-1-indanone) from 2,3-cyclopentenopyridine
The data in Table 1 show that modi®cation of the
dimethylaminoethyl side chain of 3a (as in 12) had
relatively little e€ect on cytotoxicity, and in compounds
3b±3p this side chain was retained, to explore structure±
activity relationships for nuclear substituents. Broadly
were prepared as reported. A minor modi®cation was
made to the reported23 preparation of 7-methyl-1-inda-
none, using 200 mL of concd HCl and 4 mL EtOH (total,
added in one portion at the start) to give an improved
yield in our hands on the scale reported. This method

2
804
L. W. Deady et al. / Bioorg. Med. Chem. 7 (1999) 2801±2809
ꢀ
was added, with stirring, in portions over 30 min., to
27
ꢀ
was adapted to the preparation of 7-chloro-1-indanone,
with an important modi®cation (see below). 7-Methoxy-
mp 210±212 C (lit. mp 219±221 C]. This compound
ꢀ
mixture was then heated at 100 C for 2 h and work up
1
-indanone was prepared from chroman-4-one by minor
concd H SO4 (5 mL/g) maintained at 60±65 C. The
2
24
ꢀ
as for 6b gave 6c (74%), mp 218±220 C (dec. after
modi®cation of a literature method. The chromanone
was added to the melt of aluminium trichloride and
ꢀ
ꢀ
00 C over 20 min and maintained at this temperature
1
sodium chloride at 160 C, the temperature was raised to
ꢀ
preliminary darkening). H NMR d 7.78 (d, J=2 Hz),
8.13 (d, J=2 Hz), 10.44 (s, 1H, NH), 13.91 (s, 1H,
2
for a further 10 min. The mixture was poured into ice/
concentrated hydrochloric acid and ®ltered to give
crude 7-hydroxy-1-indanone as a black solid. Without
CO H).
2
Preparation of 11H-indeno[1,2-b]quinoline-6,10-dicarboxylic
acid (8a): example of the general P®tzinger reaction
24
puri®cation, this was methylated as reported to give 7-
methoxy-1-indanone, mp 102±103 C, in 45% yield. 4-
ꢀ
Methoxy-1-indanone, mp 102±103 C (from ethanol)
(
method A)
ꢀ
was prepared from dihydrocoumarin in 36% yield by
the same two-step procedure as for the 7-methoxy isomer.
Isatin-7-carboxylic acid (6a) (1.82 g, 9.53 mmol) was
added with stirring to 10% NaOH solution (30 mL), at
ꢀ
9
0 C under a nitrogen atmosphere. To this was added 1-
7
-Chloro-1-indanone (7i). The hydrochloride salt of 3-
indanone (7a) (0.8 g, 6.03 mmol) in small portions and
the solution was heated and stirred for a further 1 h,
cooled, then ®ltered. The ®ltrate was taken to pH 5 with
concd HCl, and a mixture of free acid and its sodium
salt separated (unreacted 6a remained in solution). This
was ®ltered o€, stirred in hot water (most dissolved),
and the pH taken to 2 with concd HCl to give 8a as a
(dimethylamino)-1-(2-chlorophenyl)propan-1-one was
2
prepared as reported, and the free base was isolated as
a golden oil in 59% yield. H NMR (CDCl ) d 2.18 (s,
5
1
3
6H, N(CH ) ), 2.65 (t, 2H, CH ), 3.06 (t, 2H, CH ),
3 2 2 2
7.25±7.45 (m, 4H, ArH). A solution of this oil (20 g) and
methyl iodide (30 mL) in benzene (200 mL) was allowed
to stand at 4 C for 16 h. The solid that formed was ®l-
tered o€ and the solvent was removed from the ®ltrate
under reduced pressure to give 1-(2-chlorophenyl)-2-
propen-1-one as a golden oil (8.6 g, 62%), suitable for
ꢀ
1
pale yellow solid (1.0 g, 54%), with mp and H NMR as
reported.12
The following acids were prepared in this manner.
1
further reaction. H NMR (CDCl ) d 6.07 (dd, 2H,
3
CH ), 6.72 (dd, 1H, CH), 7.25±7.4 (m, 4H, ArH). This
compound was cyclized as for 7-methyl-1-indanone,
except that the addition took 3 h. The product was
1-Methoxy-11H-indeno[1,2-b]quinoline-6,10-dicarboxylic
acid (8b). From 6a and 4-methoxy-1-indanone (7b), for
1 h, as a bright yellow solid (72%), mp 314±316 C. H
2
23
ꢀ
1
ꢀ
-chloro-1-indanone (14%), mp 95±96 C [lit.
8 C].
recrystallized from light petroleum (bp 60±90 C) to give
NMR d 3.88 (s, 3H, OCH ), 3.91 (s, 2H, CH ), 7.16 (d),
3
2
ꢀ
26
7
9
mp
7.50 (d), 7.55 (t), 7.69 (t), 8.48 (d), 8.58 (d).
ꢀ
2-Methoxy-11H-indeno[1,2-b]quinoline-6,10-dicarboxylic
acid (8c). From 6a and 5-methoxy-1-indanone (7c), for
1 h, as a yellow solid (74%), mp 312±315 C. H NMR d
5-Methoxyisatin-7-carboxylic acid (6b). The literature
preparation, which used concd H SO in the cycliza-
2
7
ꢀ
3.84 (s, 3H, OCH ), 4.10 (s, 2H, CH ), 7.04 (d), 7.17 (s),
1
2
4
tion step, did not work well in our hands, but close
adherence to the following conditions gave consistent
results. 5-Methoxy-2-nitrobenzoic acid (5 g) was dis-
solved in EtOH (75 mL) and hydrogenated in the pre-
sence of 10% Pd/C (0.5 g), to give 5-methoxyanthranilic
3
2
7.72 (t), 7.81 (d), 8.47 (d), 8.60 (d), 16.44 (s, CO H).
2
3-Methoxy-11H-indeno[1,2-b]quinoline-6,10-dicarboxylic
acid (8e). From 6a and 6-methoxy-1-indanone (7d), for
ꢀ
27
ꢀ
ꢀ
3.88 (s, 3H, OCH ), 4.10 (s, 2H, CH ), 7.16 (d), 7.38 (s)
1
acid (4.14 g, 84%), mp 147±149 C [lit. mp 147±148 C].
-Methoxy-2-[(hydroxyimino)acetyl]amino-benzoic acid
1 h, as a yellow solid (66%), mp 315±317 C. H NMR d
5
was prepared from this acid, and this compound
3
2
2
7
7.56 (d), 7.78 (t), 8.49 (d), 8.61 (d), 16.12 (s, CO H).
2
(
H SO (30 g) maintained at 50±55 C. The mixture was
5.0 g) was added with stirring, in portions, to 85%
ꢀ
4-Methoxy-11H-indeno[1,2-b]quinoline-6,10-dicarboxylic
acid (8h). From 6a and 7-methoxy-1-indanone (7e), for
2
4
ꢀ
then heated at 100 C for 2 h and poured onto ice
200 g). The resulting solid was ®ltered o€, dissolved in
0% NaOH solution, ®ltered, and the ®ltrate acidi®ed
ꢀ
(
1
2 h, as a yellow solid (64%), mp 285±287 C (dec. after
1
preliminary darkening). H NMR d 4.04 (s, 3H, OCH ),
3
to pH 2 with concd HCl to give the isatin (3.3 g, 74%),
ꢀ
mp 210 C].
4.30 (s, 2H, CH ), 7.15 (d), 7.30 (d), 7.58 (t), 7.82 (t),
8.58 (d), 8.71 (d).
2
27
mp 236±240 C (dec. with preliminary darkening) [lit.
ꢀ
4-Methyl-11H-indeno[1,2-b]quinoline-6,10-dicarboxylic
acid (8j). From 6a and 7-methyl-1-indanone (7g), for
5
-Chloroisatin-7-carboxylic acid (6c). 5-Chloro-2-nitro-
28
ꢀ
benzoic acid was reduced by a procedure reported for
the 4-chloro isomer, to give 5-chloroanthranilic acid in
8 h, as a light yellow solid (64%), mp 300±302 C (with
1
decarboxylation). H NMR d 2.84 (s, 3H, CH ), 4.28 (s,
3
ꢀ
29
ꢀ
8
5% yield, mp 205±206 C [lit. mp 204 C]. A solution
of this compound in boron tri¯uoride/MeOH complex
20 mL/g) was stirred and heated at re¯ux for 50 h, to
give methyl 5-chloroanthranilate in 70% yield, mp 62±
2H, CH ), 7.36 (d), 7.50±7.62 (m, 2 H), 7.84 (t), 8.57 (d),
8.67 (d).
2
(
4-Chloro-11H-indeno[1,2-b]quinoline-6,10-dicarboxylic
acid (8k). From 6a and 7-chloro-1-indanone (7i) for 1
ꢀ ꢀ
27
64 C [lit. mp 68±69 C]. The isonitroso intermediate
was prepared as reported from this ester in 67% yield,
2
7
ꢀ
1
h, as a fawn solid (78%), mp 295±298 C (dec). H NMR

L. W. Deady et al. / Bioorg. Med. Chem. 7 (1999) 2801±2809
2805
d 4.16 (s, 2H, CH ), 7.40 (d), 7.47 (t), 7.57 (d), 7.76 (t),
7.65 (m), 7.92 (t), 8.23 (d), 8.65 (d), 8.80 (d), 8.86 (d,
J=4.0 Hz).
2
8.51 (d), 8.61 (d).
8
-Methoxy-11H-indeno[1,2-b]quinoline-6,10-dicarboxylic
Preparation of 11-oxo-11H-indeno[1,2-b]quinoline-6,10-
dicarboxylic acid (9a): example of a general oxidation
reaction
acid (8l). From 5-methoxyisatin-7-carboxylic acid (6b)
and 1-indanone (7a). The crude solid was stirred with
ethanol and ®ltered to give the dark red/tan product
ꢀ
(
66%), mp >300 C, which contained ca. 15% of the
1
Compound 8a (3.0 g) was added to a solution of
ꢀ
starting isatin. H NMR d 3.82 (s, 3H, OCH ), 3.96 (s,
Na CO (3.0 g) in water (120 mL) with stirring, at 55 C
2
3
3
2H, CH ), 7.41±7.57 (m, 3 H), 7.72 (d), 7.85±7.88 (m, 2
H).
until the acid was dissolved. Potassium permanganate
(3.6 g) was then added and the mixture was heated and
stirred for ca. 10 min (until a spot of reaction mixture on
®lter paper gave no pink color), then ®ltered through
Celite, washed with 10% Na CO , then water, and the
2
Acenaphtho[1,2-b]quinoline-8,12-dicarboxylic acid (8o).
From 6a and 1-acenaphthenone 7k, for 1 h, as a yellow
2
3
ꢀ
.91 (t), 8.08 (d), 8.25 (d), 8.29 (d), 8.38 (d), 8.42 (d),
1
solid (64%), mp 330±338 C. H NMR d 7.74 (t), 7.79 (t)
7
®ltrate was acidi®ed to pH 2 with concd HCl. The solid
that formed was ®ltered to give the product as a yellow
ꢀ
1
8.53 (d).
solid (2.5 g, 80%), mp >300 C. H NMR d 7.74 (t),
.83±7.91 (m, 3H), 8.07±8.15 (m, 2H), 8.46 (d).
7
Preparation of 3-methyl-11H-indeno[1,2-b]quinoline-
,10-dicarboxylic acid (8g): example of the general
P®tzinger reaction (method B)
The following oxo acids were prepared in this manner.
6
2-Chloro-11-oxo-11H-indeno[1,2-b]quinoline-6,10-dicar-
boxylic acid (9d). From 8d (a 1.5 weight excess of
Isatin-7-carboxylic acid (6a) (2.5 g, 13.08 mmol) was
added with stirring to 10% NaOH solution (40 mL), at
re¯ux under a nitrogen atmosphere. To this was added,
in portions, a solution of 6-methyl-1-indanone (7f)
Na CO was used) as a yellow solid (with trace amount
2
3
ꢀ
7.82±7.95 (m, 3H), 8.06 (d), 8.11 (d), 8.42 (d).
1
of starting material) (70%), mp 275±276 C. H NMR d
(
1.0 g, 6.84 mmol) in EtOH (40 mL), and the solution
was heated and stirred for a further 3 h. The solution
was cooled, concd to half the volume under reduced
pressure and ®ltered. The ®ltrate was treated as in
method A to give 8g as a pale yellow solid (1.25 g, 58%),
3-Methoxy-11-oxo-11H-indeno[1,2-b]quinoline-6,10-di-
carboxylic acid (9e). From 8e as a yellow solid (81%),
ꢀ
7.34 (s), 7.65±7.75 (m, 2 H), 7.98 (d), 8.39 (d).
1
mp >295 C. H NMR d 3.96 (s, 3H, OCH ), 7.15 (d),
3
ꢀ
1
mp 288±290 C (with decarboxylation). H NMR d 2.43
(
7
s, 3H, CH ), 4.12 (s, 2H, CH ), 7.38 (d), 7.53 (d), 7.74±
.83 (m, 2 H), 8.52 (d), 8.63 (d).
3-Methyl-11-oxo-11H-indeno[1,2-b]quinoline-6,10-dicar-
boxylic acid (9g). From 8g as a yellow solid (75%), mp
3
2
ꢀ
3H, CH ), 7.53 (d), 7.75 (d), 7.84 (t), 7.89 (s), 8.10 (d),
1
2
88±290 C (with decarboxylation). H NMR d 2.52 (s,
The following acids were prepared in this manner.
3
8
.45 (d).
2-Chloro-11H-indeno[1,2-b]quinoline-6,10-dicarboxylic
acid (8d). From 6a and 5-chloro-1-indanone (7h), as a
yellow solid (62%), mp >295 C (dec.). H NMR d 4.23
4-Methoxy-11-oxo-11H-indeno[1,2-b]quinoline-6,10-di-
carboxylic acid (9h). From 8h as a yellow solid (58%),
ꢀ
s, 2H, CH ), 7.64 (d), 7.78 (t), 7.87 (s), 8.09 (d), 8.54
1
ꢀ
7.50 (d), 7.67 (t), 7.86 (t), 8.15 (d), 8.63 (d).
1
(
mp >300 C. H NMR d 4.04 (s, 3H, OCH ), 7.41 (d),
2
3
(
d), 8.64 (d).
8
-Chloro-11H-indeno[1,2-b]quinoline-6,10-dicarboxylic
acid (8m). From 5-chloroisatin-7-carboxylic acid (6c)
1 mol) and 1-indanone (7a) (1.16 mol) for 8 h. This
4-Methyl-11-oxo-11H-indeno[1,2-b]quinoline-6,10-dicar-
boxylic acid (9j). From 8j as a pale yellow solid (76%),
mp 292±295 C (with decarboxylation). H NMR d
ꢀ
2.84 (s, 3H, CH ), 7.60±7.75 (m, 3H), 7.85 (t), 8.11 (d),
1
(
solid was extracted with hot EtOH and the insoluble
brown solid (1.8 g from 2.5 g of 6c) was a 4:1 mixture of
3
8.48 (d).
1
8m and 6c, suitable for the oxidation detailed below. H
NMR d 4.16 (s, 2H, CH ), 7.58±7.7 (m, 2 H), 7.76 (d),
4-Chloro-11-oxo-11H-indeno[1,2-b]quinoline-6,10-dicar-
boxylic acid (9k). From 8k as an orange solid (67%),
mp 290±292 C (with decarboxylation). H NMR d 7.72
2
8.08 (d), 8.37 (d, J=2 Hz, 1 H), 8.77 (d, J=2 Hz, 1 H).
ꢀ
(t), 7.80±7.95 (m, 3H), 8.16 (d), 8.65 (d).
1
2,3-Dimethoxy-11H-indeno[1,2-b]quinoline-6,10-dicarb-
oxylic acid (8n). From 6a and 5,6-dimethoxy-1-inda-
ꢀ
none (7j), as an orange solid (41%), mp >280 C (dec.).
1
8-Chloro-11-oxo-11H-indeno[1,2-b]quinoline-6,10-dicar-
boxylic acid (9m). From 8m as an orange solid (40%),
H NMR d 3.84±3.87 (m, 6H, OCH ), 3.96 (s, 2H,
3
ꢀ
1
CH ), 7.14 (s), 7.21 (s), 7.67 (t), 8.44 (d), 8.53 (d).
containing ca. 15% 8m by NMR) mp ca. 270 C. H
NMR d 7.71 (t), 7.82±7.87 (m, 2H), 7.95 (s), 7.98 (d),
8.25 (s).
2
0 0
H-Pyrido[3 ,2 :4,5]cyclopenta[1,2-b]quinoline-6,10-dicarb-
5
oxylic acid (8p). from 6a and 5,6-dihydro-7H-1-pyr-
inden-7-one (7l). The crude product was extracted with
hot EtOH and the insoluble black solid (70%) was the
2,3-Dimethoxy-11-oxo-11H-indeno[1,2-b]quinoline-6,10-
dicarboxylic acid (9n). From 8n as an orange solid
ꢀ
1
ꢀ
1
product, mp >295 C. H NMR d 4.37 (s, 2H, CH ),
(77%) mp > 300 C. H NMR d 3.88 (s, 3H, OCH ),
2
3

2
806
L. W. Deady et al. / Bioorg. Med. Chem. 7 (1999) 2801±2809
3
8
.99 (s, 3H, OCH ), 7.09 (s), 7.20 (s), 7.60 (t), 7.86 (d),
3
.32 (d).
NMR d 2.81 (s, 3H, CH ), 7.55±7.75 (m, 3H), 7.81 (t),
8.41 (d), 8.50 (d), 8.85 (s).
3
1-Methoxy-11-oxo-11H-indeno[1,2-b]quinoline-6-car-
boxylic acid (11b). From 10b as a yellow solid (64%),
4-Chloro-11-oxo-11H-indeno[1,2-b]quinoline-6-carboxylic
acid (11k). A fawn solid (70%) (with a trace amount of
a minor component), mp >300 C. H NMR d 7.72 (t),
ꢀ
.29 (d), 7.53 (d), 7.75±7.8 (m, 2 H), 8.34 (d), 8.47 (d),
1
ꢀ
ꢀ
7.80±7.95 (m, 3H), 8.49 (d), 8.65 (d), 8.99 (s).
1
mp 286±291 C. H NMR (80 C) d 3.98 (s, 3H, OCH ),
3
7
8.68 (s).
8
oxylic acid (11l). A yellow solid (65%), mp 235±245 C
(dec.). Too insoluble to determine NMR spectrum.
-Methoxy-11-oxo-11H-indeno[1,2-b]quinoline-6-carb-
ꢀ
8
-Methoxy-11-oxo-11H-indeno[1,2-b]quinoline-6,10-di-
carboxylic acid (9l). A mixture of 8l (0.7 g), nickel per-
1
4
oxide (0.7 g) and sodium hydroxide (0.7 g) in water
20 mL) was stirred at room temperature overnight,
(
2,3-Dimethoxy-11-oxo-11H-indeno[1,2-b]quinoline-6-carb-
oxylic acid (11n). A yellow solid (15%) mp (DMSO)
then ®ltered through Celite and the ®ltrate was acidi®ed
to pH 2 (concd HCl) to give a yellow precipitate. This
was collected by ®ltration to give 9l as a pale yellow solid
(0.47 g, 65%) mp >300 C. H NMR d 3.93 (s, 3H,
OCH ) 7.28 (s), 7.67 (t) 7.79±7.85 (m, 2 H), 7.96 (d),
ꢀ
OCH ), 7.36 (s), 7.46 (s), 7.49 (t), 8.34 (d), 8.46 (d), 8.66 (s).
1
>310 C. H NMR d 3.93 (s, 3H, OCH ), 4.04 (s, 3H,
3
3
ꢀ
1
1-Methoxy-11H-indeno[1,2-b]quinoline-6-carboxylic acid
(10b). A light yellow solid (75%), mp (EtOH) 260±
3
7
.98 (s).
ꢀ
CH ), 7.24 (d), 7.57 (t), 7.67 (d), 7.78 (t), 8.35 (d), 8.53
1
2
65 C. H NMR d 3.94 (s, 3H, OCH ), 4.04 (s, 2H,
3
2
Preparation of 11-oxo-11H-indeno[1,2-b]quinoline-6-
carboxylic acid (11a): example of the general
decarboxylation procedure
(
d), 8.78 (s), 16.59 (s, 1H, CO H).
2
2
-Methoxy-11H-indeno[1,2-b]quinoline-6-carboxylic acid
ꢀ
1
The ®nely ground diacid 9a (0.5 g) was placed in a cold
®
heated with a Bunsen burner until decarboxylation was
complete (ca. 5 min). The sublimate that formed was
collected to give 11a as light yellow needles (0.31 g,
(10c). A cream solid (70%), mp (EtOH) 171±175 C. H
NMR d 3.87 (s, 3H, OCH ), 4.08 (s, 2H, CH ), 7.16 (d),
7.32 (s), 7.73 (t), 7.97 (d), 8.29 (d), 8.50 (d), 8.65 (s), 16.6
nger sublimation apparatus at 0.5 mmHg and gently
3
2
(s, 1H, CO H).
2
ꢀ
1
7
3
2%), mp 357±359 C. H NMR d 7.72 (t), 7.77±7.91 (m,
H), 8.06 (d), 8.42 (d), 8.49 (d), 8.69 (s).
Acenaphtho[1,2-b]quinoline-8-carboxylic acid (10o). A
ꢀ
1
yellow solid (57%), mp 158±160 C. H NMR d 7.64 (t),
.76 (d) 7.84 (t), 7.88 (d), 8.08±8.11 (m, 2H), 8.17 (d),
8.28 (d) 8.35 (d), 8.93 (s).
7
The following monoacids were prepared in this manner
from the corresponding diacid.
0
boxylic acid (10p). An o€ white solid (46%), mp 264±
0
5
H - Pyrido[3 ,2 :4,5]cyclopenta[1,2 - b]quinoline - 10 - car-
2-Chloro-11-oxo-11H-indeno[1,2-b]quinoline-6-carboxylic
acid (11d). A yellow solid (79%), mp >300 C.
NMR d 7.82 (t), 7.90±7.95 (m, 2H), 8.10 (d), 8.43 (d),
ꢀ
1
ꢀ
4.2 Hz), 7.86 (t), 8.24 (d), 8.44 (d), 8.62 (d), 8.86 (d,
1
H
265 C. H NMR d 4.26 (s, 2H, CH ), 7.64 (dd, J=7.8,
2
8.49 (d), 8.91 (s).
J=4.2 Hz), 8.92 (s).
3-Methoxy-11-oxo-11H-indeno[1,2-b]quinoline-6-carboxylic
acid (11e). A yellow solid (43%), mp >295 C. H NMR
8-Chloro-11-oxo-11H-indeno[1,2-b]quinoline-6-carboxylic
acid (11m). Finely ground diacid 9m was heated on a
hot-stage until it decarboxylated, then for a further
ꢀ
1
d 4.0 (s, 3H, OCH ), 7.20 (d), 7.46 (s), 7.8±7.85 (m, 2 H),
3
ꢀ
8.40 (d), 8.47 (d), 8.80 (s).
5 min to give a black solid (89%) mp >300 C, which
was used in the amidation reaction without further
treatment. The NMR spectrum was poorly resolved.
3-Hydroxy-11-oxo-11H-indeno[1,2-b]quinoline-6-carb-
oxylic acid (11f). The sublimate was extracted with hot
EtOH, and the yellow insoluble material was the pro-
duct (42%), mp >295 C. H NMR d 6.98 (d), 7.30 (s),
7
2-Methoxy-11-oxo-11H-indeno[1,2-b]quinoline-6-car-
boxylic acid (11c). A mixture of 10c (0.5 g, 1.7 mmol)
and glacial acetic acid (20 mL) was stirred and heated to
re¯ux. Two drops of concentrated H SO were added
ꢀ
.63 (d), 7.73 (t), 8.25±8.31 (m, 2 H), 8.66 (s).
1
2
4
3-Methyl-11-oxo-11H-indeno[1,2-b]quinoline-6-carboxylic
acid (11g). A yellow solid (69%), mp >295 C.
and the solution turned clear. The solution was removed
from the heat, Na Cr O (1.5 g, 5.0 mmol) was added
carefully in small portions, and the mixture was re¯uxed
for 1 h, then cooled to 4 C for 16 h. The solid which
separated was ®ltered and a second crop was obtained
ꢀ
1
H
2
2
7
NMR d 2.52 (s, 3H, CH ), 7.52 (d), 7.75 (d), 7.80 (t),
3
ꢀ
7.88 (s), 8.44 (d), 8.50 (d), 8.85 (s).
4
oxylic acid (11i). A yellow solid (56%), mp >295 C.
H NMR d 7.24 (d), 7.33 (d), 7.53 (t), 7.80 (t), 8.41 (d),
-Hydroxy-11-oxo-11H-indeno[1,2-b]quinoline-6-carb-
ꢀ
from the ®ltrate, to give 11c as a yellow solid (0.23 g,
ꢀ
ꢀ
1
44%), mp (ethylene glycol) 340±342 C. H NMR (80 C)
1
d 3.96 (s, 3H, OCH ), 7.37 (s) 7.39 (d), 7.75 (t), 7.98 (d),
3
8
.59 (d), 8.83 (s), 11.41 (s, 1H, OH), 16.50 (s, 1H, CO H).
8.33 (d), 8.47 (d), 8.72 (s).
2
0
0
4-Methyl-11-oxo-11H-indeno[1,2-b]quinoline-6-carboxylic
acid (11j). A light yellow solid (56%), mp >300 C. H
5-Oxo-5H-pyrido[3 ,2 :4,5]cyclopenta[1,2-b]quinoline-10-
carboxylic acid (11p). A mixture of 10p (0.5 g) in 3 M
ꢀ
1

L. W. Deady et al. / Bioorg. Med. Chem. 7 (1999) 2801±2809
2807
H SO (23 mL) was heated to re¯ux. To this was added,
2
The following amides were prepared in this manner
from the appropriate imidazolides 14 (not isolated).
4
in small portions, a solution of Na Cr O (0.75 g) in 3 M
2
2
7
H SO (13 mL). This was then heated and stirred for a
2
4
further 2 h, cooled, water (75 mL) was added and the
product was ®ltered o€ as a tan solid (0.38 g, 72%), mp
N-[2-(Dimethylamino)ethyl]-1-methoxy-11-oxo-11H-in-
deno[1,2-b]quinoline-6-carboxamide (3b). As an orange
solid (61%), mp (MeCN) 198±200 C. H NMR
ꢀ
d), 8.57 (d), 8.99 (d, J=4.4 Hz), 9.03 (s).
1
ꢀ
1
>
(
295 C. H NMR d 7.70 (m), 7.88 (t), 8.27 (d), 8.48
(CDCl ) d 4.04 (s, 3H, OCH ), 7.04 (d), 7.60±7.69 (m,
3
3
2
NH). The sample retained a little MeCN after pro-
longed drying at 1 mmHg/20 C, and decomposed
slightly when heated.
H), 7.95±8.02 (m, 2H), 8.42 (s), 8.84 (d), 11.3 (s, 1H,
4-Hydroxy-11-oxo-11H-indeno[1,2-b]quinoline-6,10-di-
carboxylic acid (9i). Aluminum trichloride (2.0 g,
ꢀ
15 mmol) and NaCl (0.4 g, 6.8 mmol) were stirred and
heated to 160 C under a nitrogen atmosphere. To this
ꢀ
was added 9h (0.4 g, 1.1 mmol) and the temperature was
N-[2-(Dimethylamino)ethyl]-2-methoxy-11-oxo-11H-in-
deno[1,2-b]quinoline-6-carboxamide (3c). As bright yel-
ꢀ
80 C (ca. 10 min). The resultant mixture was poured
slowly raised to 195 C (ca. 10 min) and then cooled to
1
ꢀ
onto 10% HCl (60 mL), which was stirred and heated at
ꢀ
1
low needles (47%), mp (MeCN) 199±201 C. H NMR
(CDCl ) d 3.91 (s, OCH ), 7.14 (dd), 7.25 (d, J=2.3 Hz),
3
3
ꢀ
1
00 C for 2 h, then cooled. Filtration gave the product
7.55 (t), 7.88 (d), 8.18 (d), 8.28 (s), 8.82 (d), 11.24 (s, 1H,
NH). Anal. calcd for C H N O : C, 70.4; H, 5.6; N,
11.2. Found: C, 70.3; H, 5.4; N, 11.1%.
ꢀ
.28 (d), 7.34 (d), 7.56 (t), 7.86 (t), 8.15 (d), 8.66 (d),
1
as a yellow solid (0.33 g, 86%), mp >300 C. H NMR d
22
21
3
3
7
11.54 (s, 1H, OH), 16.35 (s, 1H, CO H).
2
N-[2-(Dimethylamino)ethyl]-2-chloro-11-oxo-11H-indeno-
[1,2-b]quinoline-6-carboxamide (3d). Twice the volume
of 1,4-dioxane as in the general method was used, and
the re¯ux time was 7 h (with more 1,1 -carbonyldiimi-
dazole (0.3 g) added after 4 h). The intermediate imida-
3-Hydroxy-11-oxo-11H-indeno[1,2-b]quinoline-6,10-di-
carboxylic acid (9f). This was prepared in 65% yield
ꢀ
0
from 9e, as for 9i, as a green solid, mp 295±298 C (with
1
decarboxylation). H NMR d 7.03 (d), 7.35 (s), 7.72 (d),
7
.82 (t), 8.07 (d), 8.42 (d), 11.3 (br s, 1H, OH).
zolide was then reacted as for 3a to give 3d as a pale
ꢀ
1
yellow solid (90%), mp (EtOH) 236±238 C. H NMR
(CDCl ) d 7.60±7.65 (m, 2 H), 7.75 (s), 7.95 (d), 8.32 (d),
Methyl 4-methoxy-11-oxo-11H-indeno[1,2-b]quinoline-6-
carboxylate (13). A mixture of hydroxyacid 11i (0.6 g,
2
3
8.39 (s), 8.88 (d), 11.1 (s, 1H, NH). Anal. calcd for
C H ClN O : C, 66.5, H, 4.8; N, 11.1. Found: C, 66.4;
H, 4.6; N, 11.2%.
.1 mmol), silver(I) oxide (1.9 g, 8.2 mmol) and CH3I
21
18
3
2
(
9 mL) in dry DMF (25 mL) was stirred at room tem-
perature for 16 h, and then water (200 mL) was added.
The solid which separated was ®ltered o€, washed with
water and dried. This was extracted (Soxhlet) with
N-[2-(Dimethylamino)ethyl]-3-methoxy-11-oxo-11H-in-
deno[1,2-b]quinoline-6-carboxamide (3e). As a cream
solid (52%), mp (MeCN) 219±221 C. H NMR
ꢀ
1
CHCl , and the solvent removed under reduced pressure
3
ꢀ
1
to give 13 (0.5 g, 76%), mp 165±167 C. H NMR
(
(CDCl ) d 3.99 (s, OCH ), 6.98 (dd), 7.62 (t), 7.77±7.81
3
3
CDCl ) d 4.09±4.11 (m, 6H, OCH , CO CH ), 7.20 (d),
(m, 2 H), 7.98 (d), 8.36 (s), 8.85 (d), 11.24 (s, 1H, NH).
Anal. calcd for C H N O : C, 70.4, H, 5.6; N, 11.2.
Found: C, 70.3; H, 5.3; N, 11.1%.
3
3
2
3
7.46±7.52 (m, 2 H), 7.55 (d), 7.97 (d), 8.14 (d), 8.34 (s).
22
21
3
3
Preparation of N-[2-(dimethylamino)ethyl]-11-oxo-11H-
indeno[1,2-b]quinoline-6-carboxamide (3a): example of
the amidation reaction
N-[2-(Dimethylamino)ethyl]-3-hydroxy-11-oxo-11H-in-
deno[1,2-b]quinoline-6-carboxamide (3f). The imidazo-
lide in dioxan solvent was prepared in the standard way.
N,N-Dimethylethylenediamine was added directly and
the solution was stirred for 16 h. The solvent was
removed under reduced pressure. The residue was dis-
solved in water and, after 1 h, the water was removed
under reduced pressure. The residue was extracted with
0
Oxoacid 11a (0.3 g, 1.09 mmol) and 1,1 -carbonyldiimi-
dazole (0.5 g) in dry dioxan (20 mL) were heated under
re¯ux until dissolution was complete (ca. 3 h). The solvent
was removed in vacuo and the residue was dissolved in
dichloromethane (30 mL). The organic layer was washed
twice with warm water (20 mL), and dried over MgSO4.
A solution of N,N-dimethylethylenediamine (0.12 g,
ꢀ
hot light petroleum (bp 60±90 C) and the insoluble
material was stirred with cold MeCN, ®ltered and
1.36 mmol) in CH Cl (3 mL) was added and the whole
was stirred at room temperature for 16 h, then washed
recrystallized from EtOH to give 3f as a yellow solid
ꢀ
2
2
1
(33%), mp 230±233 C. H NMR (CDCl ) d 6.10 (d),
3
with 10% Na CO3 solution (2Â20 mL), warm water
6.80 (s), 6.93 (d), 7.57 (t), 7.85 (d), 8.04 (s), 8.76 (d),
11.05 (br s, 1H, NH). After prolonged drying this sample
retained 0.5 mol of EtOH, apparent in the NMR spec-
trum. Anal. calcd for C H N O .0.5C H OH.H O: C,
2
(
2Â20mL) and dried (MgSO ). The solvent was removed
4
and the residue was recrystallized from EtOH to give
a (0.24 g, 65%), identical with a previous sample.12
Imidazolide 14a could be obtained at the intermediate
stage by removal of the solvent, as an orange/red solid, mp
3
[
21
19
3
3
2
5
2
65.7; H, 6.0; N, 10.4. Found: C, 65.7; H, 6.0; N, 10.5%.
ꢀ
1
0
1
7
90±196 C (dec.). H NMR (CDCl ) d 7.11 (s, 1, H-4 ),
N-[2-(Dimethylamino)ethyl]-3-methyl-11-oxo-11H-indeno-
[1,2-b]quinoline-6-carboxamide (3g). As a pale yellow
3
0
.48±7.53 (m, 2, H-2,5 ), 7.60 (t, 1, J=6.7 Hz, H-3), 7.66
ꢀ
1
(
1
t, 1, J=7.7 Hz, H-8), 7.75 (d, 1, J=7.5 Hz, H-1), 7.80 (d,
, J=7.3 Hz, H-4), 7.88 (s, 1, H-2 ), 7.98 (d, 1, J=7.0 Hz,
solid (70%), mp (EtOH) 207±209 C. H NMR (CDCl )
3
0
H-9), 8.14 (d, 1, J=8 Hz, H-7), 8.42 (s, 1, H-10)].
d 2.65 (s, 3H, CH ), 7.34 (d), 7.61 (t), 7.72 (d), 7.93±7.97
3
(m, 2H), 8.37 (s), 8.87 (d), 11.2 (s, 1H, NH). Anal. calcd

2
808
L. W. Deady et al. / Bioorg. Med. Chem. 7 (1999) 2801±2809
1
for C H N O : C, 73.5; H, 5.9; N, 11.7. Found: C,
2
H NMR d 2.93 (t, 2H), 3.05 (t, 2H), 3.70 (t, 2H), 3.81
(q, 2H), 7.56 (t), 7.63 (t), 7.72 (t), 7.84 (d), 7.98 (d), 8.11
2
21
3
2
73.2; H, 6.1; N, 11.7%.
(d), 8.42 (s), 8.87 (d), 11.17 (br s, 1H, NH). ESMS: m/z
362 (M+1). Anal. calcd for C H N O : C, 69.8; H,
5.3; N, 11.6. Found: C, 69.2; H, 5.5; N, 11.7%.
N-[2-(Dimethylamino)ethyl]-4-methyl-11-oxo-11H-indeno-
[
21
19
3
3
1,2-b]quinoline-6-carboxamide (3j). As a fawn solid
70%), mp (EtOH) 186±187 C. H NMR (CDCl ) d
ꢀ
.92 (s, 3H, CH ), 7.40±7.55 (m, 2H), 7.64 (t), 7.72 (d),
1
(
3
2
N-[2-(Dimethylamino)ethyl]-4-methoxy-11-oxo-11H-in-
deno[1,2-b]quinoline-6-carboxamide (3h). A solution of
ester 13 (0.4 g, 1.2 mmol) and N,N-dimethylethylenedi-
amine (0.6g, 6.8 mmol) in anhydrous 1-propanol (16 mL)
was stirred and heated at re¯ux for 2 days under an
atmosphere of nitrogen. The solvent was removed under
reduced pressure and the residue was dissolved in
3
7.98 (d), 8.43 (s), 8.87 (d), 10.8 (s, 1H, NH). Anal. calcd
for C H N O .0.5H O: C, 71.7; H, 6.0; N, 11.4.
Found: C, 71.8; H, 5.7; N, 11.6%.
2
2
21
3
2
2
N-[2-(Dimethylamino)ethyl]-4-chloro-11-oxo-11H-indeno-
[
solid (45%), mp (MeCN) 213±215 C. H NMR
1,2-b]quinoline-6-carboxamide (3k). As a pale yellow
ꢀ
1
CH Cl2 (50 mL), then washed with 10% NaHCO3
2
(
CDCl ) d 7.46 (t), 7.60±7.70 (m, 2H), 7.74 (d), 7.97 (d),
(3Â50 mL), warm water (2Â50 mL) and dried (MgSO ).
3
4
8.44 (s), 8.90 (d), 11.1 (s, 1H, NH). Anal. calcd for
C H ClN O .0.5H O: C, 64.9; H, 4.9; N, 10.8. Found:
C, 65.3; H, 4.8; N, 10.8%.
The solvent was removed under reduced pressure and
the residue was subjected to column chromatography
(alumina/CHCl ), with the fraction R =0.3 being col-
2
2
18
3
2
2
3
f
lected. The solvent was removed under reduced pressure
and the residue was recrystallized from MeCN to give
N-[2-(Dimethylamino)ethyl]-8-methoxy-11-oxo-11H-in-
deno[1,2-b]quinoline-6-carboxamide (3l). As yellow nee-
ꢀ
1
3h as a yellow solid (50 mg, 11%), mp 195±197 C. H
NMR (CDCl ) d 4.14 (s, 3H, OCH ), 7.25 (d), 7.44±7.56
(m, 2H), 7.62 (t), 7.95 (d), 8.37 (s), 8.86 (d), 11.58 (s, 1H,
ꢀ
1
dles (46%), mp (MeCN) 201±203 C. H NMR d 7.26
s), 7.50 (t), 7.65 (t), 7.81 (d), 8.27±8.29 (m, 2H), 8.54 (s),
1.24 (br s, 1H, NH). Anal. calcd for C H
3
3
(
1
NH). Anal. calcd for C H N O .H O: C, 67.4; H, 6.0;
22 21
22
21
3
3
2
N O .0.5H O: C, 68.7; H, 5.8; N, 10.9. Found: C, 68.6;
3
N, 10.85. Found: C, 67.2; H, 5.9; N, 10.7%.
3
2
H, 5.5; N, 10.9%.
In vitro growth delay assays
N-[2-(Dimethylamino)ethyl]-8-chloro-11-oxo-11H-indeno-
[
(
1,2-b]quinoline-6-carboxamide (3m). As a tan solid
31%), mp (MeCN) 232±234 C. H NMR d 7.57 (t),
Murine P388 leukemia cells, Lewis lung carcinoma cells
(LLTC), and human Jurkat leukemia cells (JL ), toge-
ꢀ
.68 (t), 7.84 (d), 7.90 (s), 8.30 (s), 8.35 (d), 8.81 (s),
1
C
7
ther with their amsacrine and doxorubicin-resistant
derivatives (JLA and JLD respectively), were obtained
11.09 (br s, 1H, NH). ESMS: m/z 380, 381, 382 (all
M+1). Anal. calcd for C H ClN O : C, 66.4; H, 4.8;
N, 11.1. Found: C, 66.3; H, 4.9; N, 11.2%.
and cultured as described.1
3,18
Growth inhibition assays
3
2
1
18
3
2
3
were performed by culturing cells at 4.5Â10 (P388), 10
3
(
LLTC), and 3.75Â10 (Jurkat lines) per well in micro-
N-[2-(Dimethylamino)ethyl]-2,3-dimethoxy-11-oxo-11H-
indeno[1,2-b]quinoline-6-carboxamide (3n). As a yellow
culture plates (150 mL per well) for 3 (P388) or 4 days in
the presence of drug. Cell growth was determined by
[ H]TdR uptake (P388) or the sulforhodamine assay.
ꢀ
1
3
30
31
solid (66%), mp (MeCN) 217±219 C. H NMR d 7.57
t), 7.68 (t), 7.84 (d), 7.90 (s), 8.30 (s), 8.35 (d), 8.81 (s),
(
Independent assays were performed in duplicate, and
coecients of variation for all assays were between 7.9
and 8.5%.
1
6
1.09 (br s, 1H, NH). Anal. calcd for C H N O : C,
23 23 3 4
8.1; H, 5.7; N, 10.4. Found: C, 67.8; H, 5.7; N, 10.4%.
N-[2-(Dimethylamino)ethyl]acenaphtho[1,2-b]quinoline-8-
carboxamide (3o). As a pale yellow solid, mp (MeCN)
Acknowledgements
ꢀ
.05 (m, 4H), 8.45±8.55 (m, 2H), 8.84 (d), 11.7 (br s, 1H,
1
1
22±124 C. H NMR (CDCl ) d 7.55±7.8 (m, 3H), 7.90±
3
8
NH). Anal. calcd for C H N O: C, 78.4; H, 5.8; N,
This work was funded by Biota Cancer Research Pty
Ltd. We thank Mr I. Thomas for recording the mass
spectra, and Drs K. Watson and G. Krippner (Biota)
for assistance with the ozonization step in the prepara-
tion of 7-aza-1-indanone.
24
21
3
11.4. Found: C, 78.4; H, 6.0; N, 11.6%.
0
0
N-[2-(Dimethylamino)ethyl]-5-oxo-5H-pyrido[3 ,2 :4,5]-
cyclopenta[1,2-b]quinoline-10-carboxamide (3p). Imida-
zolide formation took ca. 12 h re¯ux. The amide was a
pale yellow solid (53%), mp (light petroleum bp 90±
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1