Synthesis of anticancer compounds, III (Bioorg Med Chem Lett 17, 6091, 2007), carbinol derivatives of azanaphthoquinone annelated pyrroles

Article abstract of DOI:10.1007/s00706-008-0024-3

A series of carbinols has been synthesized by attachment of different piperidinyl side chains to the quinone structure of azanaphthoquinone annelated pyrroles. The synthesized compounds were screened for their cytotoxic activities. Compared to previously

Full text of DOI:10.1007/s00706-008-0024-3

Monatsh Chem (2009) 140:309–313
DOI 10.1007/s00706-008-0024-3
ORIGINAL PAPER
Synthesis of anticancer compounds, III (Bioorg Med Chem Lett
17, 6091, 2007), carbinol derivatives of azanaphthoquinone
annelated pyrroles
Nipawan Pongprom Æ Gerhard Mu¨ller Æ
Peter Schmidt Æ Wolfgang Holzer Æ Helmut Spreitzer
Received: 25 April 2008 / Accepted: 9 June 2008 / Published online: 17 September 2008
Ó Springer-Verlag 2008
Abstract A series of carbinols has been synthesized by
attachment of different piperidinyl side chains to the qui-
none structure of azanaphthoquinone annelated pyrroles.
The synthesized compounds were screened for their cyto-
toxic activities. Compared to previously published results,
they exhibited only moderate activities, thus showing that
the existence of the quinone moiety seems to be essential
for anticancer activities of this group.
compounds is cardiotoxicity. Moreover, some results sug-
gest that the cardiotoxicity might be related to the 5,8-
dihydroxy substitution pattern in this compound [4]. In the
search for analogs with lower cardiotoxicity, BBR 2778 (2)
was developed as an aza-bioisosteric chemotype of mito-
xantrone lacking the 5,8-dihydroxy substitution pattern [4].
This compound is currently in phase III clinical trials in
patients with non-Hodgkin’s lymphoma and exhibits a
better therapeutic index and no cardiotoxicity [5]
(Scheme 1).
Keywords Azanaphthoquinone Á Anticancer agents Á
Heterocycles Á Carbinols
As a part of the studies on the synthesis of pharma-
ceutical active compounds as potential anticancer
compounds [6–8], azanaphthoquinone annelated pyrrolo
oximes 3 were successfully synthesized by our group [1].
With the annelated aromatic systems, oximes 3 should have
a sufficiently large planar shape, and therefore these
compounds seem to be potentially intercalating agents. But
it could be demonstrated by standard DNA intercalating
UV experiments that these oximes did not intercalate.
Indeed, these compounds exert their antiproliferative/
cytotoxic effects by arresting cells in the G2/M phase and
activation of apoptosis pathways [1]. The biological eval-
uation showed remarkable anticancer activities of these
oximes. However, the major drawbacks of these oximes
were the formation of E and Z isomers, respectively, and in
general the easy metabolic cleavage of the oxime group. To
overcome these disadvantages, we decided to explore the
replacement of the oxime pattern by a piperidinyl carbinol
or piperidylidene moiety, respectively, to furnish the pro-
posed target structure of types 4 and 5. Both modifications
should lead to more stable compounds, and moreover,
because of the symmetry, no E/Z isomers could exist.
Variation of N-substituents of the piperidine ring should be
investigated in an attempt to improve the potency of
activity.
Introduction
The anthracene-9,10-dione derivative, mitoxantrone (1),
plays an important role in fighting cancer. The anticancer
activity of mitoxantrone is probably multiplex, including
DNA intercalation complexes, interference of topoiso-
merase II, and free radical intermediate formation [2, 3].
Beside cytotoxic side effects, the major drawback of
mitoxantrone (1) and related anthraquinone anticancer
N. Pongprom (&) Á W. Holzer Á H. Spreitzer (&)
Department of Drug and Natural Product Synthesis,
University of Vienna, Althanstrasse 14, Vienna 1090, Austria
e-mail: npongprom@sci.ubu.ac.th
H. Spreitzer
e-mail: helmut.spreitzer@univie.ac.at
G. Mu¨ller Á P. Schmidt
Zentaris GmbH, Drug Discovery and Preclinical Development,
Weismuellerstrasse 45, Frankfurt 60314, Germany
123

310
N. Pongprom et al.
H
N
H
N
NH2
NH2
OH
O
HN
HN
OH
OH
O
HN
HN
OH
N
Pd/C, HCO2NH4
reflux; 66%
4b
N
OH
O
O
N
N
H
1
2
O
4c
K2CO3, ClCH2CH2NMe2.HCl
R
N
CH3
DMF, 60 o
C
H3C
X
N
R
N
R
N
NaH, ClCH2CH2NMe2.HCl
DMF, 60 oC; 24%
N
O
H
OH
OH
N
CH3
CH3
N
N
N
N
N
N
N
N
N
O
O
O
O
O
N
N
3
N
CH3
N
CH3
4
5
CH3
CH3
N
H3C
H3C
N
H3C
H3C
a: X = OH
b: X = N
4d
: R = N
(35%)
(54%)
(33%)
Me2
O
Me2
4e
: R = OH
4f: R = O
N
7
CH3
Me
H3C
Scheme 1
Scheme 3
O
HO
R
CH3
formate and 10% Pd-C in methanol [9] to give 4c as shown
in Scheme 3. Compound 4c prompted us to attach side
chains at the piperidine ring by N-alkylation. However,
under strong conditions, sodium hydride in DMF at 60 °C,
the reaction of 4c with N,N-dimethylaminoethyl chloride
gave selectively O-alkylation, thus furnishing carbinol
ether 7. In order to obtain the N-alkylated product 4d, we
employed the mild conditions using K2CO3 in DMF at
room temperature for 60 h, thus leading solely to 4d. This
method was also employed for the synthesis of carbinols 4e
and 4f.
N
H
H
H
H
H
N
N
N
N
H
OH
O
O
N
N
CH3
6
CH3
4
H3C
H3C
N
N
(85%)
(56%)
N
a: R =
b: R =
Me
O
4a
N
N
Bn
CH3
H3C
Scheme 2
Results and discussions
Compound 6 was prepared as previously described [1].
Reaction with Grignard reagents prepared from 4-chloro-
piperidine derivatives gave carbinol 4a and N-benzyl
protected derivative 4b, respectively (Scheme 2).
The structure elucidations of O-alkylated 7 and N-
alkylated 4d were based on 13C NMR experiment regard-
ing those of staring material 4c. In comparison with 4c, the
signal of C-4 in compound 7 showed a significant shift
from 73.5 to 80.2 ppm (no shift of C-4 could be observed
in 4d). N-alkylated products of type 4 showed a significant
shift of the carbon atoms adjacent to the nitrogen of the
piperidine ring.
Compound 4a was investigated for structure elucidation.
The structure elucidation was confirmed by nuclear Over-
hauser enhancement (NOE) experiments. Only irradiation
at C(3)–H and C(5)–H showed significant enhancements of
piperidinyl protons, while there was no such enhancement
effect when irradiated at C(8)–H (Scheme 2). These results
indicated unambiguously that the Grignard reaction
occurred regioselectively at the C-4 carbonyl group of
compound 6. We suggest that steric hindrance caused by
the amino ethyl group attached to the pyrrole ring as well
as the electronic activation by the p-positioned nitrogen of
the pyridine ring system favored the attack of the Grignard
reagent at C-4 of quinone 6.
In the following, the carbinol 4a was submitted to
dehydration reaction (Scheme 4). A series of reactions
(pyridinium-4-toluene sulfonate (PPTS)/toluene; 4-toluene
sulfonic acid in toluene/acetonitrile [10], glacial acetic
acid/2 N H2SO4 [11]; trifluoroacetic acid/CH2Cl2 [12])
have been tried, but unfortunately dehydrated product 5a
could not be obtained. Reaction of 4a with acetic anhydride
for 4 h [13] gave only acetate 8 as shown in Scheme 4.
Carbinol 4a was also treated with POCl3 in pyridine for
dehydration [14], but workup via column chromatography
(eluting with EtOAc/MeOH; 1/1) just furnished methyl
ether 9. We suppose that compound 9 was obtained after
reaction of the primarily formed chloride intermediate with
methanol during the chromatographic separation. After
many attempts, it was strongly suggested that dehydration
reaction is prohibited due to the rigid and flat structure of
To prepare a series with different groups attached at the
nitrogen of the piperidine ring, cleavage of the N-benzyl
protecting group of 4b has to be worked out. The cleavage
of the N-benzyl group under traditional high pressure cat-
alytic hydrogenation using H2/Pd-C in methanol failed.
Alternatively, debenzylation was successful by catalytic
transfer hydrogenation utilizing anhydrous ammonium
123

Synthesis of anticancer compounds
311
CH3
N
noted, chemicals were purchased from commercial sup-
pliers and used without further purification.
General procedure for the synthesis of carbinols
4a and 4b
4a
N
N
O
The Grignard reagents were generated as described: The
alkyl halide (4 mmol) in dry THF (1 cm3) was added
dropwise to Mg turnings (4 mmol) in THF (2 cm3) under
Ar. The mixture was stirred and refluxed for 1 h. The
obtained Grignard mixture was transferred to a reaction
flask and cooled to 0 °C in an ice bath. Compound 6
(1 mmol) in dry THF (5 cm3) was added dropwise under
Ar. The reaction mixture was stirred as described. Then a
saturated aqueous solution of NH4Cl was added. The
organic layers were dried (Na2SO4), filtered, and
concentrated.
POCl3, pyridine
rt, 18 h; 18%
Ac2O,
N
5a
CH3
reflux; 32%
H3C
CH3
CH3
N
N
O
Ac
O
Me
N
N
N
N
O
O
9
N
8
N
CH3
CH3
H3C
H3C
1-[2-(Dimethylamino)ethyl]-4-hydroxy-4-
(1-methylpiperidin-4-yl)-1H-pyrrolo[3,2-g]isoquinolin-
9(4H)-one (4a, C21H28N4O2)
Scheme 4
The reaction mixture was refluxed for 4 h. After column
chromatography (aluminum oxide, EtOAc/MeOH; 9/1)
0.312 g of 4a (85%) were obtained as oil. M.p.: 89–
the envisaged products of type 5, which exhibit a massive
steric hindrance between the aromatic protons of C-3/C-5
and the near methylene groups of the piperidinyl ring.
The synthesized compounds 4a–f, 7, 8, 9, were
screened for antiproliferative activities against three
cancer cell lines, cervix cancer (KB), brain cancer (SF-
268), and ovarian carcinoma (SK-OV-3), by tetrazolium-
based (XXT) cytotoxicity assays. The primary screen
was carried out at the concentration of 3.16 lg/cm3. It
was observed in the course of the experiments that these
compounds exhibited lower than 50% of inhibition at
this concentration. In comparison with compounds of
type 3, it is evident that lack of the quinone moiety of
the target structure led to a massive decrease of the
biological activity.
1
91 °C; H NMR (200 MHz, CDCl3): d = 0.70–0.95 (m,
1H), 0.96–1.14 (m, 1H), 1.55–1.90 (m, 4H), 2.07 (s, 3H),
2.19 (s, 6H), 2.32–2.48 (m, 1H) 2.50–2.65 (m, 1H), 2.55 (t,
J = 6.8 Hz, 2H), 2.72–2.92 (m, 1H), 4.27–4.60 (m, 2H),
6.33 (d, J = 2.6 Hz, 1H), 6.98 (d, J = 2.6 Hz, 1H), 7.66
(d, J = 5.2 Hz, 1H), 8.64 (d, J = 5.2 Hz, 1H), 9.20 (s, 1H)
ppm; 13C NMR (50 MHz, CDCl3): d = 26.2, 26.6, 45.3,
46.0, 46.6, 49.1, 55.5, 55.8, 59.7, 73.4, 107.8, 120.6, 124.5,
128.0, 131.1, 138.8, 148.1, 152.0, 156.4, 173.8 ppm; IR
(KBr): m = 3,416, 2,938, 2,788, 1,647, 1,587 cm-1; MS:
m/z (%) = 368 (M?, 0.3), 350 (1.3), 272 (2.6), 196 (9.7),
58 (100).
4-(1-Benzylpiperidin-4-yl)-1-[2-(dimethylamino)ethyl]-
4-hydroxy-1H-pyrrolo[3,2-g]isoquinolin-9(4H)-one
(4b, C27H32N4O2)
Experimental
The reaction mixture was stirred at 0 °C for 30 min and
45 °C for 18 h. After column chromatography (aluminum
oxide, EtOAc/MeOH; 9/1) 0.250 g of 4b (56%) was
1H NMR spectra were recorded on a Bruker DPX200
spectrometer (1H 200 MHz, 13C 50 MHz). Chemical
shifts are reported in ppm using TMS as internal stan-
dard. The IR spectra were recorded on a Perkin-Elmer
FT-IR spectrometer Spectrum 1000. Mass spectra were
recorded on a Shimadzu DI 50-QP 5000 or Shimadzu
GCMS-QP5050A. Melting points were determined using
a Kofler-type Leica Galen III micro hot-stage micro-
scope. Thin layer chromatography was performed on
aluminum-oxide plates from Merck (no. 1.05550:
0.2 mm). Column chromatography was performed on
Aluminia B, activity III from ICN. Unless otherwise
1
obtained as oil. H NMR (200 MHz, CDCl3): d = 0.72–
0.95 (m, 1H), 1.00–1.18 (m, 1H), 1.62–1.97 (m, 4H), 2.26
(s, 6H), 2.62 (t, J = 6.7 Hz, 2H), 2.62–2.78 (m, 1H), 2.70–
3.08 (m, 2H), 3.38 (s, 2H), 4.30–4.65 (m, 2H), 6.36 (d,
J = 2.6 Hz, 1H), 7.01 (d, J = 2.6 Hz, 1H), 7.12–7.30 (m,
5H), 7.67 (d, J = 5.2 Hz, 1H), 8.69 (d, J = 5.2 Hz, 1H),
9.25 (s, 1H) ppm; 13C NMR (50 MHz, CDCl3): d = 26.3,
26.7, 45.3, 46.6, 49.8, 53.5, 53.6, 59.6, 63.1, 73.6, 107.7,
120.6, 124.6, 126.9, 128.0, 128.1, 129.1, 131.1, 137.9,
138.7, 148.1, 151.1, 156.2, 173.8 ppm; IR (KBr):
m = 3,405, 2,935, 2,799, 1,645, 1,586 cm-1; MS: m/z
123

312
N. Pongprom et al.
(%) = 444 (M?, 0.8), 426 (1.4), 372 (1.0), 272 (5.7), 58
1-[2-(Dimethylamino)ethyl]-4-hydroxy-4-[1-(2-hydroxy-
ethyl)piper-idin-4-yl]-1H-pyrrolo[3,2-g]isoquinolin-
9(4H)-one (4e, C22H30N4O3)
(100).
1-[2-(Dimethylamino)ethyl]-4-hydroxy-4-(piperidin-4-yl)-
1H-pyrrolo[3,2-g]isoquinolin-9(4H)-one
(4c, C20H26N4O2)
The reaction mixture was stirred at room temperature for
28 h to give 4e (0.058 g, 54%) as oil. 1H NMR (200 MHz,
CDCl3): d = 0.70–0.94 (m, 1H), 0.98–1.14 (m, 1H), 1.70–
2.00 (m, 4H), 2.22 (s, 6H), 2.40 (t, J = 5.2 Hz, 2H), 2.50–
2.68 (m, 1H), 2.58 (t, J = 6.7 Hz, 2H), 2.67–2.85 (m, 1H),
2.85–3.02 (m, 1H), 3.20–3.65 (br s, 1H), 3.49 (t, J =
5.2 Hz, 2H), 4.25–4.65 (m, 2H), 6.36 (d, J = 2.5 Hz, 1H),
7.01 (d, J = 2.5 Hz, 1H), 7.66 (d, J = 5.1 Hz, 1H), 8.63
(d, J = 5.1 Hz, 1H), 9.18 (s, 1H) ppm; 13C NMR (50 MHz,
CDCl3): d = 26.1, 26.5, 45.2, 46.6, 49.4, 53.3, 53.6, 57.7,
59.3, 59.6, 73.4, 107.7, 120.5, 124.6, 128.0, 131.2, 138.4,
148.1, 152.0, 156.2, 173.7 ppm; IR (KBr): m = 3,422,
2,932, 2,788, 1,734, 1,653 cm-1; MS: m/z (%) = 398 (M?,
0.4), 380 (1.5), 367 (4.8), 350 (3.3), 272 (17.2), 58 (100).
To a stirred suspension of 4b (0.249 g, 0.56 mmol) and
10% Pd-C (0.301 g) in dry MeOH (10 cm3), anhydrous
ammonium formate (0.500 g) was added in a single
portion under Ar. The reaction mixture was stirred at
reflux for 4 h. Then the catalyst was removed by
filtration through celite. The filtrates were removed in
vacuo. After chromatographic purification (aluminum
oxide, EtOAc/MeOH; 9/1) 4c (0.131 g, 66%) was
obtained as semisolid. 1H NMR (200 MHz, CDCl3):
d = 0.55–0.80 (m, 1H), 1.00–1.20 (m, 2H), 1.80–2.02
(m, 3H), 2.25 (s, 6H), 2.40–2.58 (m, 1H), 2.59 (t,
J = 6.7 Hz, 2H), 2.75–2.90 (m, 1H), 2.94–3.10 (m, 1H),
4.30–4.65 (m, 2H), 6.36 (d, J = 2.5 Hz, 1H), 7.02 (d,
J = 2.5 Hz, 1H), 7.68 (d, J = 5.1 Hz, 1H), 8.71 (d,
J = 5.1 Hz, 1H), 9.27 (s, 1H) ppm; 13C NMR (50 MHz,
CDCl3): d = 27.3, 27.6, 45.4, 46.3, 46.7, 46.5, 50.0,
59.7, 73.5, 107.6, 120.6, 124.6, 128.1, 131.1, 138.8,
148.1, 152.0, 156.3, 173.9 ppm; IR (KBr): m = 3,412,
2,936, 2,778, 1,645, 1,587 cm-1; MS: m/z (%) = 354
(M?, 1.5), 336 (2.8), 318 (1.6), 58 (100).
1-[2-(Dimethylamino)ethyl]-4-hydroxy-4-[1-(2-methoxy-
ethyl)pipe-ridin-4-yl]-1H-pyrrolo[3,2-g]isoquinolin-
9(4H)-one (4f, C23H32N4O3)
The reaction mixture was stirred at room temperature for
30 h to provide 4f (0.040 g, 33%) as oil. 1H NMR
(200 MHz, CDCl3): d = 0.95–1.12 (m, 2H), 1.40–1.65
(m, 1H), 1.78–2.18 (m, 4H), 2.33 (s, 6H), 2.56 (t, J =
5.3 Hz, 2H), 2.71 (t, J = 6.8 Hz, 2H), 2.82–3.00 (m, 1H),
3.02–3.20 (m, 1H), 3.27 (s, 3H), 3.48 (t, J = 5.3 Hz, 2H),
4.35–4.70 (m, 2H), 6.38 (d, J = 2.5 Hz, 1H), 7.05
(d, J = 2.5 Hz, 1H), 7.68 (d, J = 5.2 Hz, 1H), 8.67 (d,
J = 5.2 Hz, 1H), 9.24 (s, 1H) ppm; 13C NMR (CDCl3):
d = 25.5, 25.9, 45.2, 46.4, 49.1, 53.8, 54.1, 57.6, 58.8,
59.5, 69.3, 73.6, 107.9, 120.4, 124.6, 127.9, 131.4, 138.0,
148.2, 152.3, 155.8, 173.8 ppm; IR (KBr): m = 3,418,
2,938, 2,819, 1,647, 1,588 cm-1; MS: m/z (%) = 413
(M??1, 0.7), 394 (1.8), 367 (27.8), 310 (4.7), 58 (100).
General procedure for the synthesis of carbinols 4d–f
A solution of the corresponding alkyl halides (0.40 mmol)
in DMF (2 cm3) was added to a suspension mixture of 4c
(0.100 g, 0.28 mmol) and K2CO3 (0.128 g, 0.70 mmol) in
DMF (2 cm3) at 0 °C. The reaction mixture was stirred at
room temperature until completion of the reaction. After-
ward H2O was added, and all solvents were removed in
vacuo. The crude product was purified by column chro-
matography (aluminum oxide, EtOAc/MeOH; 9/1).
4-[2-(Dimethylamino)ethoxy]-1-[2-(dimethylamino)ethyl]-
4-(piperidinyl)-1H-pyrrolo[3,2-g]isoquinolin-9(4H)-one
(7, C24H35N5O2)
1-[2-(Dimethylamino)ethyl]-4-{1-[2-(dimethylamino)
ethyl]piperidin-4-yl}-4-hydroxy-1H-pyrrolo
NaH (60% suspension in mineral oil, 0.089 g, 1.1 mmol)
was washed three times with dry hexane under Ar before
suspended in DMF (1 cm3). The mixture was cooled to
0 °C, and then 4c (0.149 g, 0.42 mmol) in DMF (1.5 cm3)
was added dropwise. The reaction mixture was stirred at
0 °C for an additional 0.5 h. N,N-dimethylaminoethyl
chloride (0.091 g, 0.63 mmol) in DMF (2 cm3) was added
slowly. The reaction mixture was stirred at 60 °C for 4 h.
Then it was diluted with water. All solvents were
concentrated in vacuo. The crude product was purified by
column chromatography (aluminum oxide, EtOAc to
EtOAc/MeOH, 7/3). Compound 7 (0.043 g, 24%) was
[3,2-g]isoquinolin-9(4H)-one (4d, C24H35N5O2)
The reaction mixture was stirred at room temperature for
1
60 h giving 4d (0.042 g, 35%) as oil. H NMR (CDCl3):
d = 0.60–0.95 (m, 1H), 1.00–1.30 (m, 1H), 1.70–1.98 (m,
4H), 2.16 (s, 6H), 2.21 (s, 6H), 2.60 (t, J = 6.6 Hz, 2H),
2.50–2.68 (m, 1H), 2.70–2.85 (m, 1H), 2.90–3.07 (m, 1H),
3.33 (s, 4H), 4.28–4.68 (m, 2H), 6.37 (d, J = 2.3 Hz, 1H),
7.01 (d, J = 2.3 Hz, 1H), 7.77 (d, J = 5.2 Hz, 1H), 8.64
(d, J = 5.2 Hz, 1H), 9.20 (s, 1H) ppm; 13C NMR (CDCl3):
d = 26.2, 26.7, 45.3, 45.4, 46.7, 49.4, 52.8, 53.7, 53.8,
59.7, 61.5, 73.5, 107.7, 120.9, 124.5, 128.0, 131.3, 138.8,
148.0, 151.9, 156.0, 173.8; IR (KBr): m = 3,419, 2,946,
2,788, 1,646, 1,465 cm-1; MS: m/z (%) = 425 (M?, 0.3),
407 (0.8), 367 (5.7), 58 (100).
1
obtained as oil. H NMR (200 MHz, CDCl3): d = 0.52–
0.90 (m, 2H), 0.92–1.18 (m, 2H), 1.80–2.00 (m, 2H), 2.17
(s, 6H), 2.28 (s, 6H), 2.43 (t, J = 6.1 Hz, 2H), 2.46–2.58
123

Synthesis of anticancer compounds
313
(m, 1H), 2.68 (t, J = 6.7 Hz, 2H), 2.75–2.88 (m, 1H),
2.90–3.10 (m, 2H), 3.14–3.30 (m, 1H), 4.30–4.65 (m, 2H),
6.26 (d, J = 2.5 Hz, 1H), 7.02 (d, J = 2.5 Hz, 1H), 7.58
(d, J = 5.2 Hz, 1H), 8.74 (d, J = 5.2 Hz, 1H), 9.35 (s, 1H)
ppm; 13C NMR (50 MHz, CDCl3): d = 27.4, 27.6, 45.7,
45.9, 46.4, 46.7, 47.3, 50.3, 59.2, 60.0, 62.9, 80.2, 107.9,
120.3, 126.3, 129.8, 131.3, 135.2, 148.7, 152.1, 153.5,
173.8 ppm; IR (KBr): m = 3,415, 2,935, 2,769, 1,647,
1,585, 1,456 cm-1; MS: m/z (%) = 426 (M? ? 1, 0.7),
338 (18.3), 293 (1.5), 58 (100).
NMR (200 MHz, CDCl3): d = 0.70–1.10 (m, 2H), 1.20–
1.44 (m, 1H), 1.55–1.97 (m, 4H), 2.11 (s, 3H), 2.29 (s, 6H),
2.50–2.65 (m, 1H), 2.68 (t, J = 6.8 Hz, 2H), 2.75–2.90 (m,
1H), 2.93 (s, 3H), 4.35–4.60 (m, 2H), 6.25 (d, J = 2.5 Hz,
1H), 7.05 (d, J = 2,5 Hz, 1H), 7.54 (d, J = 5.2 Hz, 1H),
8.74 (d, J = 5.2 Hz, 1H), 9.37 (s, 1H) ppm; 13C NMR
(50 MHz, CDCl3): d = 26.4, 26.7, 45.7, 46.1, 47.3, 49.6,
52.4, 55.6, 55.9, 60.0, 80.6, 108.0, 120.2, 126.4, 130.0,
131.3, 134.8, 148.8, 152.2, 153.1, 173.8 ppm; IR
(KBr):m = 3,425, 2,923, 2,852, 1,653 cm-1; MS: m/z
(%) = 382 (M?, 3.7), 350 (4.9), 286 (2.9), 58 (100).
1-[2-(Dimethylamino)ethyl]-4-(1-methylpiperidin-4-yl)-
9-oxo-4,9-dihydro-1H-pyrrolo[3,2-g]isoquinolin-4-yl
acetate (8, C23H30N4O3)
Acknowledgments N. Pongprom thanks The Royal Thai Govern-
ment Scholarship for financial support throughout her PhD program.
The carbinol 4a (0.260 g, 0.76 mmol) was dissolved in dry
Ac2O (10 cm3). The reaction mixture was stirred and
refluxed for 4 h. Ac2O was removed in vacuo. The crude
product was purified by column chromatography (alumi-
num oxide, EtOAc/MeOH, 9/1 ? 8/2) to give compound 8
(0.100 g, 32%) as oil. 1H NMR (200 MHz, CDCl3):
d = 0.70–1.10 (m, 2H), 1.32–1.50 (m, 1H), 1.55–1.70
(m, 1H), 1.72–1.98 (m, 3H), 2.02 (s, 3H), 2.11 (s, 3H), 2.26
(s, 6H), 2.66 (t, J = 6.8 Hz, 2H), 2.50–2.70 (m, 1H),
2.75–2.90 (m, 1H), 4.25–4.65 (m, 2H), 6.11 (d,
J = 2.5 Hz, 1H), 6.98 (d, J = 2.5 Hz, 1H), 7.30 (d,
J = 5.2 Hz, 1H), 8.66 (d, J = 5.2 Hz, 1H), 9.35 (s, 1H)
ppm; 13C NMR (50 MHz, CDCl3): d = 21.4, 25.6, 26.1,
45.6, 45.9, 47.2, 48.3, 55.2, 55.5, 59.9, 79.4, 106.1, 118.1,
124.9, 127.9, 131.1, 134.8, 148.8, 152.0, 152.6, 168.4,
173.6 ppm; IR (KBr): m = 3,423, 2,939, 2,782, 1,747,
1,646, 1,587 cm-1; MS: m/z (%) = 411 (M? ? 1, 0.2),
350 (19.4), 280 (3.0), 58 (100).
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1-[2-(Dimethylamino)ethyl]-4-methoxy-4-
(1-methylpiperidin-4-yl)-1H-pyrrolo[3,2-g]
isoquinolin-9(4H)-one (9, C22H30N4O2)
The carbinol 4a (0.282 g, 0.77 mmol) was dissolved in
absolute pyridine (5 cm3). POCl3 (0.6 cm3, 2.13 mmol)
was added dropwise under Ar at 0 °C. The mixture was
stirred at room temperature for 18 h. Pyridine was removed
in vacuo, and the crude product was purified by column
chromatography (aluminum oxide, EtOAc to EtOAc/
MeOH, 1/1). The starting material (0.050 g, 18%) was
13. Kaiser C, Fowler PJ, Tedeschi DH, Lester BM, Garvey E, Zirkle
CL (1974) J Med Chem 17:57
14. Villani FJ, Mann TA, Welfer EA, Hannon J, Larca LL, Landon
MJ, Spivak W, Vashi D (1975) J Med Chem 18:1
1
recovered, and 9 (0.035 g, 12%) was obtained as oil. H
123