Synthesis and cytotoxic activity of acronycine analogues in the benzo[c]pyrano[3,2-h]acridin-7-one and naphtho[1,2-b][1,7] and [1,10]-phenanthrolin-7(14H)-one series

Article abstract of DOI:10.1248/cpb.53.1540

Condensation of 1-bromo-2-naphthalenecarboxylic acid (9) with 7-methoxy-2,2-dimethyl-2H-1-benzopyran-5-ylamine (13) followed by acid-mediated cyclization afforded 6-methoxy-3,3-dimethyl-3,14-dihydro-7H-benzo[c]pyrano[3,2- h]acridin-7-one (15), which was further methylated into 6-methoxy-3,3,14- trimethyl-3,14-dihydro-7H-benzo[c]pyrano[3,2-h]acridin-7-one (benzo[c]acronycine) (3) and 6,7-dimethoxy-3,3-dimethyl-3H-benzo[c]pyrano[3,2-h] acridine (4). Osmium tetroxide oxidation of 15 gave the (±)-cis-diol 16, which afforded the benzopyranoacridine and benzopyranoacridone esters 17-22 upon acylation. Condensation of 9 with suitable aminoquinolines 23-25 afforded the carboxylic naphthylquinolylamines 26-28. Cyclization gave the corresponding naphtho[1,2-b][1,10]-phenanthrolin-7(14H)-ones 29 and 30, and naphtho[1,2-b][1,7]-phenanthrolin-7(14H)-one 31, which were subsequently N-methylated to the desired 14-methylnaphtho[1,2-b][1,10] and [1,7]-phenanthrolinones 6, 7, and 8. Benzo[c]pyrano[3,2-h]acridin-7-one derivatives 3, 16, and 22 displayed cytotoxic activities within the same range of magnitude as acronycine itself, whereas 7-alkoxybenzo[c]pyrano[3,2-h]acridine and 7-acyloxybenzo[c]pyrano[3,2-h]acridine derivatives 4 and 17-21 were less active when tested against L1210 murine leukemia cells in vitro. Naphthophenanthrolinones 6-8 were devoid of significant antiproliferative activity, but compounds 29-31 bearing no substituent on the nitrogen atom at position 14 were more potent.

Full text of DOI:10.1248/cpb.53.1540

1
540
Chem. Pharm. Bull. 53(12) 1540—1546 (2005)
Vol. 53, No. 12
Synthesis and Cytotoxic Activity of Acronycine Analogues in the
Benzo[c]pyrano[3,2-h]acridin-7-one and Naphtho[1,2-b][1,7] and [1,10]-
Phenanthrolin-7(14H)-one Series
a
a
b
c
Jean-Bernard BONGUI, Abdelhakim ELOMRI, Dominique CAHARD, François TILLEQUIN,
d
d
,a
Bruno PFEIFFER, Alain PIERRÉ, and Elisabeth SEGUIN*
a
Laboratoire de Pharmacognosie de l’Université de Rouen-Haute Normandie, UMR 6014 CNRS, Faculté de Pharmacie;
b
2
2, Boulevard Gambetta, F-76183 Rouen Cedex 1, France: UMR 6014 CNRS de l’IRCOF, Université de Rouen; 1 rue
c
Tesnière, F-76821 Mont Saint Aignan Cedex, France: Laboratoire de Pharmacognosie de l’Université René Descartes,
U.M.R. 8638 C.N.R.S, Faculté des Sciences Pharmaceutiques et Biologiques; 4, Avenue de l’Observatoire, F-75006 Paris,
France: and Institut de Recherches Servier, Division Recherche Cancérologie; 125 Chemin de Ronde, 78290 Croissy sur
d
Seine, France. Received June 9, 2005; accepted August 8, 2005
Condensation of 1-bromo-2-naphthalenecarboxylic acid (9) with 7-methoxy-2,2-dimethyl-2H-1-benzopyran-
-ylamine (13) followed by acid-mediated cyclization afforded 6-methoxy-3,3-dimethyl-3,14-dihydro-7H-
5
benzo[c]pyrano[3,2-h]acridin-7-one (15), which was further methylated into 6-methoxy-3,3,14-trimethyl-3,14-di-
hydro-7H-benzo[c]pyrano[3,2-h]acridin-7-one (benzo[c]acronycine) (3) and 6,7-dimethoxy-3,3-dimethyl-3H-
benzo[c]pyrano[3,2-h]acridine (4). Osmium tetroxide oxidation of 15 gave the (ꢀ)-cis-diol 16, which afforded the
benzopyranoacridine and benzopyranoacridone esters 17—22 upon acylation. Condensation of 9 with suitable
aminoquinolines 23—25 afforded the carboxylic naphthylquinolylamines 26—28. Cyclization gave the corre-
sponding naphtho[1,2-b][1,10]-phenanthrolin-7(14H)-ones 29 and 30, and naphtho[1,2-b][1,7]-phenanthrolin-
7(14H)-one 31, which were subsequently N-methylated to the desired 14-methylnaphtho[1,2-b][1,10] and [1,7]-
phenanthrolinones 6, 7, and 8. Benzo[c]pyrano[3,2-h]acridin-7-one derivatives 3, 16, and 22 displayed cytotoxic
activities within the same range of magnitude as acronycine itself, whereas 7-alkoxybenzo[c]pyrano[3,2-h]acri-
dine and 7-acyloxybenzo[c]pyrano[3,2-h]acridine derivatives 4 and 17—21 were less active when tested against
L1210 murine leukemia cells in vitro. Naphthophenanthrolinones 6—8 were devoid of significant antiprolifera-
tive activity, but compounds 29—31 bearing no substituent on the nitrogen atom at position 14 were more potent.
Key words acronycine; benzo[c]acronycine; naphthophenanthrolinone; cytotoxicity
The pyranoacridone alkaloid acronycine (1), isolated from nism of its action implies alkylation of the 2-amino group of
1—3)
Acronychia baueri SCHOTT (Rutaceae)
has shown antitu- DNA guanine residues by the carbocation resulting from the
mor properties in a panel of murine solid tumor models, in- elimination of the ester-leaving group at position 1 of the
1
0—13)
cluding S-180 and AKR sarcomas, X-5563 myeloma, S-115 drug.
4,5)
carcinoma, and S-91 melanoma.
However, its moderate
In a continuation of recent studies of the structure–activity
potency and poor solubility in aqueous solvents severely relationships in the acronycine series,
1
4—17)
we describe here
hampered the subsequent clinical trials, which were rapidly the synthesis and biological activities of 6-methoxy-3,3,14-
discontinued, due to modest therapeutic effects and dose-lim- trimethyl-3,14-dihydro-7H-benzo[c]pyrano[3,2-h]acridin-7-
6)
iting gastrointestinal toxicity after oral administration. Con- one (ꢀbenzo[c]acronycine) (3) and 6,7-dimethoxy-3,3-di-
sequently, the development of structural analogues with in- methyl-3H-benzo[c]pyrano[3,2-h]acridine (4). These isomers
creased potency and/or better water solubility was highly de- 3 and 4 of benzo[b]acronycine (5) were prepared together
sirable.
with some corresponding derivatives in the cis-1,2-dihy-
Our efforts to design more potent derivatives were guided droxy-1,2-dihydro series to determine the influence of the
by the hypothesis of bioactivation of the 1,2-double bond of position of the additional aromatic ring fused onto the basic
7)
acronycine into the corresponding epoxide in vivo. The tetracyclic pyranoacridone core of acronycine on the cyto-
high reactivity of acronycine 1,2-epoxide, which readily re- toxic activity. Also, the three compounds 6—8 in which the
acts with water to give the corresponding cis and trans diols, dimethylpyran ring present in 3 and 4 is replaced by a pyri-
suggested that this compound could be the active metabolite
of acronycine, able to alkylate some nucleophilic target
within the tumor cell. Accordingly, significant improvements
in terms of potency were obtained with derivatives modified
in the pyran ring, which had a similar reactivity toward nu-
cleophilic agents as acronycine epoxide but improved chemi-
cal stability. Such compounds are exemplified by diesters of
8)
cis-1,2-dihydroxy-1,2-dihydroacronycine and diesters of
cis-1,2-dihydroxy-6-methoxy-3,3,14-trimethyl-1,2,3,14-
tetrahydro-7H-benzo[b]pyrano[3,2-h]acridin-7-one in the re-
9)
lated benzo[b]acronycine series. A representative of this lat-
ter type of compounds, diacetate 2, developed under the code
S23906-1 is currently in phase I clinical trials. The mecha-
∗
To whom correspondence should be addressed. e-mail: Elisabeth.Seguin@univ-rouen.fr
© 2005 Pharmaceutical Society of Japan

December 2005
1541
dine, were synthesized with the aim of improving their solu-
bility in biocompatible solvents, which is a critical point in
this chemical series. The basic nitrogen atom of the newly in-
troduced pyridine ring was expected to offer the opportunity
to prepare water-soluble salts in acidic medium.
Chemistry
The strategy used to build up the pentacyclic basic core
of benzo[c]acronycine (3) was similar to that previously
1
8)
developed for the syntheses of acronycine,
6-deme-
19)
11)
thoxyacronycine, and 6-demethoxybenzo[b]acronycine,
of 7-methoxy-2,2-di-
methyl-2H-1-benzopyran-5-ylamine or 2,2-dimethyl-2H-1-
benzopyran-5-ylamine with an appropriate ortho-haloaro-
matic acid.
2
0)
through Ullmann condensation
2
1)
19)
The required 1-bromonaphthalene-2-carboxylic acid (9)
was prepared in 92% overall yield from commercially avail-
able 1-bromo-2-methylnaphthalene (10) through a three-step
process successively involving benzylic radical dibromina-
tion to 1-bromo-2-dibromo-methylnaphthalene (11), hydroly-
sis into the corresponding 1-bromo-2-naphthalene-carbalde-
hyde (12), and oxidation into the corresponding carboxylic
22)
acid.
Condensation of 9 and 7-methoxy-2,2-dimethyl-2H-1-ben-
21)
zopyran-5-ylamine (13) gave the corresponding carboxylic
diarylamine 14 in 18% yield. Cyclization to the correspond-
ing acridone 15 was achieved in 27% yield by the use of tri-
fluoroacetic anhydride in dichloromethane, which had previ-
ously given good results in the course of related synthe-
1
1,18,19)
ses.
Classic reactions previously developed in the
Chart 1
acronycine and benzo[b]acronycine series to obtain N-methyl
derivatives using methyl iodide or dimethyl sulfate, either in
the presence of sodium hydride in dimethylformamide or
under phase transfer conditions, gave 6,7-dimethoxy-3,3-di-
methyl-3H-benzo[c]pyrano[3,2-h]acridine (4) as the single
reaction product. Formation of the desired benzo[c]acro-
nycine (3) could only be ensured when the reaction was
performed with methyl iodide and potassium carbonate
in acetone. Nevertheless, 3 was obtained in a low 5% yield
under those mildly alkaline conditions, accompanied by 4,
which was isolated in 11% yield.
The (ꢁ)-cis-diol 16 was conveniently obtained in 81%
yield by catalytic osmium tetroxide oxidation of 15, using N-
methylmorpholine N-oxide to regenerate the oxidative
8,9)
agent. Treatment of 16 with one equivalent of various acyl
anhydrides resulted in the acylation of the tautomeric hy-
droxyacridine form of the acridone skelton, giving, for exam-
ple, the corresponding 2,7-diacetate 17 and 1,2,7-triacetate
1
8 when treated with acetic anhydride, and 7-monopropi-
onate 19, 2,7-dipropionate 20, and 1,2,7-tripropionate 21
upon treatment with propionic anhydride. In contrast, acyla-
tion of diol 16 with N,Nꢂ-carbonyldiimidazole in 2-butanone
under reflux afforded almost quantitatively the acridone
cyclic carbonate 22.
Access to 6-methoxy-14-methylnaphtho[1,2-b][1,10]-
phenanthrolin-7(14H)-one (6), 14-methylnaphthro[1,2-b]-
[1,10]-phenanthrolin-7(14H)-one (7), and 14-methylnaph-
tho[1,2-b][1,7]-phenanthrolin-7(14H)-one (8) was suggested
2
3)
by our previous work on related benzophenantholinones.
20)
Thus Ullmann condensation of 1-bromonaphthalene-2-car-
boxylic acid (9) with 6-methoxy-8-aminoquinoline (23), 8-
Chart 2

1
542
Vol. 53, No. 12
Table 1. Inhibition of L1210 Cell Proliferation by Benzo[c]pyrano[3,2- benzo[c]acronycine series, the significant increase in the
h]acridin-7-one Derivatives 3, 4, and 15—22 in Comparison with
Acronycine (1) and Benzo[b]acronycine (5)
steric hindrance at the reactive benzylic position 1 implied in
the alkylation process should result in a decreased reactivity
toward DNA when compared with benzo[b]acronycine deriv-
atives.
Compound 1
5
3
4
15 16 17 18 19 20 21 22
IC50 (mM) 23 1.9 12.1 58 49 6.7 15.5 26.2 14.5 11.7 26 10
The reduced potency of 7-alkoxybenzo[c]pyrano[3,2-
h]acridine 4 and 7-acyloxy benzo[c]pyrano[3,2-h]acridine
derivatives 18 and 21 compared with the corresponding
benzo[c]pyrano[3,2-h]acridin-7-ones 3 and 22 is also worth
noting. Thus the tricyclic acridin-7-one system appears to be
an important structural requirement to observe antiprolifera-
tive activity in the acronycine series.
Table 2. Inhibition of L1210 Cell Proliferation by Naphtho[1,2-b][1,7]
and [1,10]-phenanthrolin-7(14H)-one Derivatives in Comparison with
Acronycine (1) and Benzo[b]acronycine (5) and Benzo[c]acronycine (3)
Compound
1
5
3
6
7
8
29
30
31
Finally, in the benzo[c]acronycine series, the replacement
of the dimethylpyran ring by a pyridine resulted in a signifi-
cant reduction of the cytotoxic activity, in good agreement
with our previous work on the comparison of acronycine
IC50 (mM)
23 1.9 12.1 ꢅ100 30
85
37
9.7
80
aminoquinoline (24), and 5-aminoquinoline (25) afforded the derivatives with the related 12H-benzo[b][1,7] and [1,10]-
2
3)
corresponding carboxylic naphthylquinolylamines 26—28 in phenanthrolin-7-ones.
1—48% yield. Concentrated sulfuric acid permitted the cy-
4
Experimental
clization of 26—28 in 40—46% yield into the corresponding
naphtho[1,2-b][1,10]-phenanthrolin-7(14H)-ones 29 and 30,
and naphtho[1,2-b][1,7]-phenanthrolin-7(14H)-one 31, re-
Chemistry The melting points were determined on a Leica VM appara-
tus and are not corrected. IR spectra (nmax in cm ) were obtained in potas-
sium bromide pellets on a Perkin-Elmer 257 instrument. UV spectra (lmax in
ꢃ1
23)
spectively. Finally, methylation at N-14 with methyl iodide nm) were determined in spectroscopic-grade MeOH on a Beckman Model
1
13
3
4 spectrophotometer. H-NMR [d (ppm), J (Hz)] and C-NMR spectra
under phase-transfer catalysis conditions smoothly afforded
the desired 14-methylnaphtho[1,2-b][1,10] and [1,7]-phenan-
throlinones 6, 7, and 8.
were recorded at 300 MHz and 75 MHz, respectively, using a Bruker
AC-300 spectrometer. When necessary, the signals were unambiguously
1
1
1
1
13
1
assigned by 2D NMR techniques: H– H COSY, H– H NOESY, C– H
1
3
1
HETCOR, and C– H COLOC. These experiments were performed using
standard Bruker microprograms. Mass spectra were recorded with a Nermag
R-10-10C spectrometer, using electron impact (EI-MS) and/or chemical ion-
ization (DCI-MS; reagent gas: NH ) techniques. Flash column chromatogra-
phy was performed using silica gel 60 Merck (35—70 mm) with an overpres-
sure of 300 mbar.
Pharmacology
The study of the biological properties of the new deriva-
tives was carried out in vitro using the L1210 murine
leukemia cell line. The results (IC50 values) are reported in
Tables 1 and 2, respectively. In contrast with our previous ob-
3
1-Bromo-2-(dibromomethyl)naphthalene (11) A suspension of 1-
servations on the benzo[b]acronycine series, fusion of an ad- bromo-2-methylnaphtalene (10) (11.3 g, 51.1 mmol), N-bromosuccinimide
(
21 g, 126.5 mmol), and dibenzoyl peroxide (2.1 g, 126.5 mmol) in dry CCl4
ditional aromatic ring in position [c] onto the acronycine
tetracyclic core did not result in an increase in cytotoxicity.
The three more potent new compounds 3, 16, and 22 dis-
(250 ml) was refluxed for 24 h. After cooling, the suspension was filtered.
The mixture was washed with saturated aqueous NaHSO (250 ml). The or-
ganic layer was dried over anhydrous Na SO and evaporated under reduced
3
2
4
played cytotoxic activities within the same range of magni- pressure. Flash chromatography of the residue on silica gel (solvent:
tude as acronycine (1) itself. All of them belong to the CH
Cl /cyclohexane 1 : 9) gave 11 (18.70 g, 97%) as yellow crystals, mp
2
2
ꢃ1
8
3
1
9 °C. IR (KBr) cm : 2940, 745. UV l
(EtOH) nm (log e): 300 (4.77),
max
benzo[c]pyrano[3,2-h]acridin-7-one series, and it should be
emphasized that compounds belonging to the isomeric 7-hy-
droxybenzo[c]pyrano[3,2-h]acridine series, exemplified by 4
and 17—21, were less active.
1
02 (4.65), 312 (3.48), 335 (3.52). H-NMR (300 MHz, CDCl ) d: 7.51 (s,
3
H, H-CBr ), 7.58 (td, 1H, Jꢀ8, 2 Hz, C6-H), 7.66 (td, 1H, Jꢀ8, 2 Hz, C7-
2
H), 7.84 (dd, 1H, Jꢀ8, 2 Hz, C5-H), 7.91 (d, 1H, Jꢀ9 Hz, C4-H), 8.08 (d,
1H, Jꢀ9 Hz, C3-H), 8.32 (dd, 1H, Jꢀ8, 2 Hz, C8-H). C-NMR (75 MHz,
1
3
CDCl ) d: 41.2 (d, CHBr ), 119.5 (s, C-2), 126.7 (d, C-4), 127.9 (d, C-6),
Naphtho[1,2-b][1,10] and [1,7]-phenanthrolin-7(14H)-one
3
2
1
1
28.2 (d, C-5), 128.3 (d, C-3), 128.4 (d, C-8), 129.0 (d, C-7), 131.1 (s, C-1),
34.6 (s, C-8a), 137.9 (s, C-4a). EI-MS m/z: 382, 380, 378, 376 [M] . Anal.
6
—8 were devoid of significant activity. In both series, the
ꢄ
compounds bearing no substituent on the nitrogen atom at
Calcd for C H Br : C, 34.87; H, 1.86; Br, 63.27. Found: C, 34.77; H, 1.82;
1
1
7
3
position 14, such as 29—31, were more potent than their cor- Br, 63.12.
responding N-methylated counterparts 6—8.
1-Bromo-2-naphthalenecarbaldehyde (12) To a solution of potassium
acetate (10 g, 26.4 mmol) in acetic acid (130 ml) was added 11 (10 g,
2
(
6.4 mmol). The mixture was refluxed for 24 h. A solution of 2 N HCl
40 ml) was added and the mixture was refluxed for 4 h. After cooling and
evaporating the solvent, the residue was partitioned between AcOEt (300 ml)
Results and Discussion
Considering the structure–activity relationships in the
acronycine series, introduction of an additional aromatic ring and 2 N HCl (200 ml). The organic layer was washed with saturated aqueous
SO , and evaporated
linearly fused in position [b] on the natural alkaloid basic NaCl, treated with charcoal, dried over anhydrous Na
2
4
under reduced pressure to give 12 (6.2 g, 99%) as yellow crystals, mp
skeleton had previously resulted in a dramatic increase in
ꢃ1
9
,11,24)
116 °C. IR (KBr) cm : 3010, 2900, 1715. UV lmax (EtOH) nm (log e): 250
the antiproliferative activity.
In contrast, introduction
1
(
4.83), 302 (4.64), 312 (3.47), 331 (3.51). H-NMR (300 MHz, CDCl ) d:
3
of an additional aromatic ring angularly fused in position
7.50 (td, 1H, Jꢀ8, 2 Hz, C6-H), 7.78 (d, 1H, Jꢀ9 Hz, C4-H), 7.87 (td, 1H,
[
c] on the acronycine tetracyclic system did not lead to a Jꢀ8, 2 Hz, C7-H), 7.94 (d, 1H, Jꢀ9 Hz, C3-H), 7.97 (dd, 1H, Jꢀ8, 2 Hz,
13
significant increase in the activity. This result is consistent C5-H), 8.50 (dd, 1H, Jꢀ8, 2 Hz, C8-H), 10.72 (s, 1H, H-CO). C-NMR
(
75 MHz, CDCl ) d: 123.7 (s, C2), 124.0 (d, C-4), 128.0 (d, C-6), 128.1 (d,
with the mechanism of action postulated for acronycine
and benzo[b]acronycine, which involves bioactivation into
the corresponding 1,2-epoxide able to alkylate nucleo-
3
C-5), 128.2 (d, C-3), 128.3 (d, C-8), 128.4 (d, C-7), 131.2 (s, C-1), 132.0 (s,
C-8a), 134.9 (s, C-4a), 192.9 (s, CHO). EI-MS m/z: 236, 234 [M] , 207,
ꢄ
2
05. Anal. Calcd for C H BrO: C, 56.20; H, 3.00; Br, 33.99. Found: C,
11 7
8—11)
philic DNA sites within the tumor cell.
In the 56.01; H, 3.02; Br, 34.06.

December 2005
-Bromo-2-naphthalenecarboxylic Acid (9) To a mixture of 12 (1 g,
1543
1
6-Methoxy-3,3,14-trimethyl-3,14-dihydro-7H-benzo[c]pyrano[3,2-h]-
4.23 mmol) and t-butyl alcohol (70 ml) was added 2-methyl-2-butene (4 ml). acridin-7-one (3) and 6,7-Dimethoxy-3,3-dimethyl-3H-benzo[c]pyrano-
A 100 ml aqueous solution of NaClO (3.35 g, 39 mmol) and NaH PO ·H O [3,2-h]acridine (4) Methyl iodide (800 mg, 1.68 mmol) was added to a
2
2
4
2
(
4.03 g, 29.3 mmol) was added dropwise over a period of 20 min. This re-
mixture of 6-methoxy-3,3-dimethyl-3,14-dihydro-7H-benzo[c]pyrano[3,2-h]-
acridin-7-[3,2-h]acridin-7-one (15) (400 mg, 1.12 mmol) and potassium
carbonate (774 mg, 5.6 mmol) in dry acetone (20 ml). The mixture was
stirred at room temperature for 24 h and partitioned between CH Cl (60 ml)
sulted in a clear solution, which was stirred for 24 h at room temperature.
The t-butyl alcohol was removed by rotary evaporation, and the mixture was
treated with H O (25 ml) and washed with hexane (20 ml). The aqueous
2
2
2
layer was then acidified to pH ca. 1 and extracted with ether (3ꢆ100 ml). and H O (30 ml). The aqueous phase was extracted with CH Cl (2ꢆ60 ml),
2
2
2
The organic extracts were combined, and the solvent was evaporated under and the combined organic phase was dried over anhydrous Na CO , filtered,
2
3
reduced pressure. Flash chromatography of the residue on silica gel (solvent: and evaporated under reduced pressure. Flash chromatography of the residue
CH Cl /cyclohexane 1 : 9) gave 9 (1.01 g, 95%) as whitish crystals, mp on silica gel (solvent: CH Cl ) gave 6-methoxy-3,3,14-trimethyl-3,14-dihy-
2
2
2
2
ꢃ1
1
(
77—179 °C. IR (KBr) cm : 3450, 2940, 1690, 1662. UV l (EtOH) nm dro-7H-benzo[c]pyrano[3,2-h]acridin-7-one (3) (22 mg, 5%) as yellow crys-
max
1
log e): 245 (4.67), 284 (3.65), 285 (3.62), 304 (4.72). H-NMR (300 MHz,
tals and 6,7-dimethoxy-3,3-dimethyl-3H-benzo[c]pyrano[3,2-h]acridine (4)
(46 mg, 11%) as a yellow amorphous solid.
6-Methoxy-3,3,14-trimethyl-3,14-dihydro-7H-benzo[c]pyrano[3,2-
DMSO-d ) d: 7.68 (td, 1H, Jꢀ8, 2 Hz, C6-H), 7.70 (d, 1H, Jꢀ9 Hz, C4-H),
6
7
1
.76 (td, 1H, Jꢀ8, 2 Hz, C7-H), 8.05 (dd, 1H, Jꢀ8, 2 Hz, C5-H), 8.06 (d,
ꢃ1
H, Jꢀ9 Hz, C3-H), 8.32 (dd, 1H, Jꢀ8, 2 Hz, C8-H), 12.53 (br s, 1H, D O h]acridin-7-one (3): mp 180 °C. IR (KBr) cm : 3380, 2945, 1640, 1586,
2
13
exch., COOH). C-NMR (75 MHz, DMSO-d ) d: 120.9 (s, C2), 126.5 (d, 1490, 1370, 1082, 810. UV l (MeOH) nm (log e): 267 (4.71), 277 (4.78),
6
max
1
C-4), 128.5 (d, C-6), 129.2 (d, C-5), 129.4 (d, C-3), 129.7 (d, C-8), 129.8 (d, 285 (3.44), 382 (3.87). H-NMR (300 MHz, CDCl ) d: 1.55 (s, 6H, C3-
3
C-7), 132.4 (s, C-1), 134.6 (s, C-8a), 135.5 (s, C-4a), 176.6 (s, COOH). EI-
(CH ) ), 3.70 (s, 3H, N-CH ), 4.00 (s, 3H, O-CH ), 5.68 (d, 1H, Jꢀ10 Hz,
3 2 3 3
ꢄ
MS m/z: 252, 250 [M] , 207, 205. Anal. Calcd for C H BrO : C, 52.62; H, C2-H), 6.40 (s, 1H, C5-H), 6.86 (d, 1H, Jꢀ10 Hz, C1-H), 7.60 (td, 1H, Jꢀ7,
1
1
7
2
2
.81; Br, 31.82. Found: C, 52.51; H, 2.84; Br, 32.01.
2 Hz, C11-H), 7.62 (td, 1H, Jꢀ7, 2 Hz, C12-H), 7.68 (d, 1H, Jꢀ9 Hz, C9-H),
1
-[(7-Methoxy-2,2-dimethyl-2H-1-benzopyran-5-yl)amino]-2-naph- 7.91 (dd, 1H, Jꢀ7, 2 Hz, C10-H), 8.29 (d, 1H, Jꢀ9 Hz, C8-H), 8.37 (dd, 1H,
1
3
thalenecarboxylic Acid (14) A solution of 7-methoxy-2,2-dimethyl-2H-1-
benzopyran-5-yl)amine (13) (244 mg, 1.19 mmol), 1-bromonaphtalene-2-
carboxylic acid (9) (300 mg, 1.19 mmol), potassium acetate (234 mg,
Jꢀ7, 2 Hz, C13-H). C-NMR (75 MHz, CDCl ) d: 29.2 (q, C3-(CH ) ),
3 3 2
50.5 (q, N-CH ), 56.3 (q, O-CH ), 76.8 (s, C-3), 95.9 (d, C-5), 105.8 (s, C-
3
3
14b), 112.2 (s, C-6a), 120.5 (d, C-1), 122.7 (d, C-8), 124.2 (d, C-9), 125.6 (d,
2.38 mmol), cupric acetate monohydrate (10 mg), and triethylamine (0.6 ml, C-13), 125.7 (d, C-11), 125.8 (s, C-7a), 125.9 (d, C-2), 128.5 (s, C-13a),
1
.19 mmol) in 2-propanol (20 ml) was heated under reflux for 24 h. After
128.8 ((d, C-10)ꢄ(d, C-12)), 136.2 (s, C-9a), 146.3 (s, C-13b), 150.2 (s, C-
14a), 158.8 (s, C-4a), 162.0 (s, C-6), 178.7 (s, C7). DCI-MS m/z: 372
cooling, the reaction mixture was evaporated under reduced pressure and the
residue was partitioned between CH Cl (150 ml) and 1 N HCl (100 ml). The
ꢄ
[MH] . Anal. Calcd for C H NO : C, 77.61; H, 5.70; N, 3.77. Found: C,
2
2
24 21
3
aqueous phase was extracted with CH Cl (3ꢆ50 ml). The combined organic 77.72; H, 5.74; N, 3.72.
2
2
phase was dried over anhydrous Na SO , filtered, and evaporated under re-
duced pressure. Flash chromatography of the residue on silica gel (solvent:
6,7-Dimethoxy-3,3-dimethyl-3H-benzo[c]pyrano[3,2-h]acridine (4): IR
(KBr) cm : 3240, 2880, 1596, 1483, 1372, 1140, 1073, 840. UV lmax
2
4
ꢃ1
CH Cl ) gave 14 (64 mg, 18%) as yellow crystals, mp 120 °C. IR (KBr) (MeOH) nm (log e): 215 (3.73), 242 (3.24), 287 (4.72), 324 (3.50), 342
2
2
ꢃ1
1
cm : 3350, 2950, 1670, 1620, 1240. UV l
(MeOH) nm (log e): 283
(3.56), 386 (3.68). H-NMR (300 MHz, CDCl ) d: 1.56 (s, 6H, C3-(CH ) ),
max
3
3 2
1
(
4.48), 312 (4.45), 362 (3.58). H-NMR (300 MHz, CDCl ) d: 1.50 (s, 6H, 4.04 (s, 3H, C6-O-CH ), 4.05 (s, 3H, C7-O-CH ), 5.56 (d, 1H, Jꢀ10 Hz, C2-
3
3
3
C2ꢂ-(CH ) ), 3.51 (s, 3H, O-CH ), 5.61 (d, 1H, Jꢀ10 Hz, C3ꢂ-H), 5.63 (d,
H), 6.56 (s, 1H, C5-H), 7.63 (d, 1H, Jꢀ9 Hz, C9-H), 7.70 (td, 1H, Jꢀ8,
H, Jꢀ2 Hz, C8ꢂ-H), 6.13 (d, 1H, Jꢀ2 Hz, C6ꢂ-H), 6.89 (d, 1H, Jꢀ10 Hz, 2 Hz, C11-H), 7.73 (td, 1H, Jꢀ8, 2 Hz, C12-H), 7.85 (d, 1H, Jꢀ10 Hz, C1-
C4ꢂ-H), 7.29 (td, 1H, Jꢀ8, 1.5 Hz, C6-H), 7.47 (d, 1H, Jꢀ9 Hz, C4-H), 7.51 H), 7.86 (dd, 1H, Jꢀ8, 2 Hz, C10-H), 8.08 (d, 1H, Jꢀ9 Hz, C8-H), 9.47 (dd,
3
2
3
1
1
3
(
1
td, 1H, Jꢀ8, 1.5 Hz, C7-H), 7.78 (dd, 1H, Jꢀ8, 1.5 Hz, C5-H), 7.85 (dd, 1H, Jꢀ8, 2 Hz, C13-H). C-NMR (75 MHz, CDCl ) d: 28.2 (q, C3-(CH ) ),
3
3
2
H, Jꢀ8, 1.5 Hz, C8-H), 8.58 (d, 1H, Jꢀ9 Hz, C3-H), 10.41 (br s, 1H, D O 56.2 (q, C6-O-CH ), 63.6 (q, C7-O-CH ), 77.7 (s, C-3), 98.1 (d, C-5), 108.7
2 3 3
1
3
exch., NH), 11.27 (br s, 1H, D O exch., COOH). C-NMR (75 MHz,
(s, C-14b), 110.0 (s, C-6a), 117.7 (s, C-7a), 119.1 (d, C-1), 120.0 (d, C-8),
2
CDCl ) d: 27.7 (q, –C2ꢂ-(CH ) C2ꢂ), 55.1 (q, O-CH ), 76.0 (s, C-2ꢂ), 96.8 125.2 ((d, C-9)ꢄ(d, C-13), 125.6 (d, C-11), 126.7 (d, C-2), 127.6 (d, C-12),
3
3
2
3
(d, C-6ꢂ), 99.8 (d, C-8ꢂ), 107.2 (s, C-4ꢂa), 112.9 (s, C-2), 117.4 (d, C-4ꢂ), 128.8 (d, C-10), 131.5 (s, C13a), 134.3 (s, C-9a), 146.8 (s, C-13b), 148.8 (s,
1
1
4
21.9 (d, C-4), 125.3 (d, C-6), 126.4 (d, C-5), 126.6 (s, C-8a), 127.2 (d, C-3), C-14a), 154.8 (s, C-7), 156.6 (s, C-4a), 161.9 (s, C6). DCI-MS m/z: 372
ꢄ
27.6 (d, C-8), 128.1 (d, C-3ꢂ), 128.7 (d, C-7), 137.3 (s, C-5ꢂ), 142.3 (s, C-
[MH] . Anal. Calcd for C H NO : C, 77.61; H, 5.70; N, 3.77. Found: C,
24 21 3
a), 147.3 (s, C-1), 154.8 (s, C-8ꢂa), 160.4 (s, C-7ꢂ), 173.5 (s, COOH). DCI-
77.57; H, 5.62; N, 3.73.
ꢄ
MS m/z: 376 [MH] . Anal. Calcd for C H NO : C, 73.58; H, 5.64; N, 3.73.
Found: C, 73.62; H, 5.67; N, 3.76.
(ꢀ)-cis-1,2-Dihydroxy-6-methoxy-3,3-dimethyl-2,3-dihydro-1H-
benzo[c]pyrano[3,2-h]acridin-7-one (16) To a solution of osmium tetrox-
2
3
21
4
6
-Methoxy-3,3-dimethyl-3,14-dihydro-7H-benzo[c]pyrano[3,2- ide (2.5% in 2-methyl-2-propanol) (0.49 ml) and 4-methylmorpholine N-
h]acridin-7-one (15) Trifluoroacetic anhydride (1.34 ml, 9.71 mmol) was oxide monohydrate (380 mg, 1 mmol) in t-BuOHTHF–H O (10/3/1: v/v/v,
2
added to a solution of 1-[(7-methoxy-2,2-dimethyl-2H-1-benzopyran-5- 20 ml) was added 15 (307 mg, 0.86 mmol). The reaction mixture was stirred
yl)amino]-naphtalene-2-carboxylic acid (14) (728 mg, 1.94 mmol) in CH Cl
at room temperature for 2 d. Saturated aqueous NaHSO was added, and the
2
2
3
(14 ml). The mixture was stirred at room temperature for 6 d, evaporated
mixture was stirred at room temperature for 1 h and extracted with CH Cl2
2
under reduced pressure, and taken up by CH Cl (150 ml) and saturated (3ꢆ100 ml). The organic layers were evaporated under reduced pressure to
2
2
aqueous NaHCO (150 ml). The aqueous phase was extracted with CH Cl
give a yellow solid, which was purified by crystallization in acetone to afford
16 (272 mg, 81%), mp 176 °C. IR (KBr) cm : 3385, 3255, 2892, 1595,
3
2
2
ꢃ1
(2ꢆ100 ml). The combined organic phase was shaken for 5 min with 1 N
aqueous NaOH (50 ml), dried over anhydrous Na SO , filtered, and evapo- 1460, 1380, 1144, 1040. UV l (MeOH) nm (log e): 244 (3.72), 290
2
4
max
1
rated under reduced pressure. Flash chromatography of the residue on silica
gel (solvent: CH Cl , then CH Cl /MeOH 98 : 2) gave 15 (187 mg, 27%) as
yellow crystals, mp 226 °C. IR (KBr) cm : 3360, 2980, 1632, 1610, 1547, (s, 3H, O-CH ), 5.30 (d, 1H, Jꢀ6 Hz, HO-C1), 5.52 (d, 1H, Jꢀ6 Hz, HO-
(4.80), 324 (3.21), 343 (3.28). H-NMR (300 MHz, CDCl ) d: 1.02 (s, 3H,
3
C3-(CH ) ), 1.04 (s, 3H, C3-(CH ) ), 3.72 (dd, 1H, Jꢀ6, 4.5 Hz, C2-H), 3.80
2
2
2
2
3
a
3 b
ꢃ1
3
1
473, 1359, 1130, 1075. UV l
(MeOH) nm (log e): 263 (4.70), 277
C2), 6.19 (s, 1H, C5-H), 6.33 (dd, 1H, Jꢀ6, 4.5 Hz, C1-H), 7.59 (d, 1H,
max
1
(
4.75), 290 (3.41), 383 (3.83). H-NMR (300 MHz, CDCl ) d: 1.51 (s, 6H, Jꢀ9 Hz, C9-H), 7.72 (td, 1H, Jꢀ7, 2 Hz, C11-H), 7.74 (td, 1H, Jꢀ7, 2 Hz,
3
C3-(CH ) ), 3.98 (s, 3H, O-CH ), 5.67 (d, 1H, Jꢀ10 Hz, C2-H), 6.23 (s, 1H,
C12-H), 8.00 (dd, 1H, Jꢀ7, 2 Hz, C10-H), 8.11 (d, 1H, Jꢀ9 Hz, C8-H), 8.26
3
2
3
13
C5-H), 6.68 (d, 1H, Jꢀ10 Hz, C1-H), 7.54 (d, 1H, Jꢀ9 Hz, C9-H), 7.59 (td,
H, Jꢀ7, 2 Hz, C11-H), 7.61 (td, 1H, Jꢀ7, 2 Hz, C12-H), 7.87 (dd, 1H,
Jꢀ7, 2 Hz, C10-H), 8.06 (d, 1H, Jꢀ9 Hz, C8-H), 8.38 (dd, 1H, Jꢀ7, 2 Hz,
(dd, 1H, Jꢀ7, 2 Hz, C13-H), 11.83 (br s, 1H, D O exch., NH). C-NMR
2
1
(75 MHz, CDCl ) d: 25.0 (q, C3-(CH ) ), 25.3 (q, C3-(CH ) ), 56.8 (q, O-
3
3
a
3 b
CH ), 65.3 (d, C-1), 71.2 (d, C-2), 80.3 (s, C-3), 95.2 (d, C-5), 100.3 (s, C-
3
1
3
C13-H), 8.61 (br s, 1H, D O exch., NH). C-NMR (75 MHz, CDCl ) d: 14b), 108.7 (s, C-6a), 119.2 (s, C-7a), 122.1 (d, C-8), 122.3 (d, C-9), 123.5
2
3
27.6 (q, C3-(CH ) ), 56.2 (q, O-CH ), 77.2 (s, C-3), 94.5 (d, C-5), 99.7 (s, C- (d, C-13), 127.8 (d, C-11), 129.9 (d, C-12), 130.0 (d, C-10), 130.2 (d, C-13a),
3
2
3
1
4b), 107.8 (s, C-6a), 114.5 (d, C-1), 119.5 (d, C-8), 121.9 (d, C-9), 123.2 (d, 135.9 (s, C-9a), 137.1 (s, C-13b), 144.9 (s, C-14a), 158.0 (s, C-4a), 162.0 (s,
ꢄ
C-13), 126.2 ((s, C-7a)ꢄ(d, C-11)), 127.5 (d, C-2), 128.3 (d, C-12), 128.5 (s, C-6), 176.0 (s, C7). DCI-MS m/z: 392 [MH] . Anal. Calcd for C H NO :
23
21
5
C-13a), 129.1 (d, C-9), 135.3 (s, C-9a), 137.9 (s, C-13b), 142.8 (s, C-14a),
C, 70.58; H, 5.41; N, 3.58. Found: C, 70.42; H, 5.47; N, 3.56.
(ꢀ)-cis-1-Hydroxy-6-methoxy-3,3-dimethyl-2,3-dihydro-1H-
Anal. Calcd for C H NO : C, 77.29; H, 5.36; N, 3.92. Found: C, 77.38; H, benzo[c]pyrano[3,2-h]-acridine-2,7-diyle Diacetate (17), and (ꢀ)-cis-6-
ꢄ
1
57.5 (s, C-4a), 162.6 (s, C-6), 176.7 (s, C7). DCI-MS m/z: 358 [MH] .
23
19
3
5
.31; N, 4.01.
Methoxy-3,3-dimethyl-2,3-dihydro-1H-benzo[c]pyrano-[3,2-h]acridine-

1
544
Vol. 53, No. 12
ꢄ
1
,2,7-triyle Triacetate (18) In a cooled mixture (0 °C) of acetic anhydride [MH] . Anal. Calcd for C H NO : C, 69.79; H, 5.63; N, 3.13. Found: C,
2
6
25
6
(
0
0.059 ml, 0.77 mmol) and dry pyridine (5 ml) was added 16 (180 mg,
.45 mmol). The mixture was stirred at room temperature for 24 h and
69.91; H, 5.67; N, 3.12.
(ꢁ)-cis-1-Hydroxy-6-methoxy-3,3-dimethyl-2,3-dihydro-1H-benzo-
ꢃ1
poured onto ice-water (10 ml). The precipitate was filtered, washed with [c]pyrano[3,2-h]acridine-2,7-diyle Dipropionate (20): IR (KBr) cm : 3350,
water (5ꢆ20 ml), and dried under a vacuum over P O . Column chromatog-
2885, 1595, 1580, 1460, 1390, 1125, 1083, 809. UV lmax (MeOH) nm
raphy over silica gel (20—45 mm) (solvent: CH Cl , then CH Cl /MeOH (log e): 214 (3.82), 225 (3.81), 245 (3.33), 290 (4.83), 326 (3.21), 343
2
5
2
2
2
2
1
9
2 : 2) gave 17 (120 mg, 25%) and 18 (142 mg, 33%) as yellow amorphous (3.29), 399 (3.25). H-NMR (300 MHz, CDCl ) d: 1.17 (t, 3H, Jꢀ8 Hz,
3
solids.
ꢁ)-cis-1-Hydroxy-6-methoxy-3,3-dimethyl-2,3-dihydro-1H-benzo-
CH -CH -CO-O-C2), 1.43 (t, 3H, Jꢀ8 Hz, CH -CH -CO-O-C7), 1.46 (s,
3 2 3 2
(
3H, C3-(CH ) ), 1.54 (s, 3H, C3-(CH ) ), 2.44 (q, 2H, Jꢀ8 Hz, CH -CH -
3 a 3 b 3 2
ꢃ1
[c]pyrano[3,2-h]acridine-2,7-diyle diacetate (17): IR (KBr) cm : 3250, CO-O-C2), 2.89 (q, 2H, Jꢀ8 Hz, CH -CH -CO-O-C7), 3.98 (s, 3H, O-CH ),
3
2
3
2
890, 1583, 1476, 1389, 1122, 1040, 815. UV lmax (MeOH) nm (log e): 214
5.61 (d, 1H, Jꢀ5 Hz, C1-H), 5.83 (d, 1H, Jꢀ5 Hz, C2-H), 6.51 (s, 1H, C5-
(
3.82), 225 (3.79), 246 (3.32), 292 (4.83), 326 (3.22), 343 (3.29), 400 (3.25). H), 7.72 (br s, 1H, D O exch., HO-C1), 7.67 (d, 1H, Jꢀ9 Hz, C9-H), 7.70
2
1
H-NMR (300 MHz, CDCl ) d: 1.45 (s, 3H, C3-(CH ) ), 1.56 (s, 3H, C3- (td, 1H, Jꢀ8, 2 Hz, C11-H), 7.73 (td, 1H, Jꢀ8, 2 Hz, C12-H), 7.78 (d, 1H,
(
3
3 a
CH ) ), 2.15 (s, 3H, CH -CO-O-C2), 2.55 (s, 3H, CH -CO-O-C7), 4.00 (s,
Jꢀ9 Hz, C8-H), 7.86 (dd, 1H, Jꢀ8, 2 Hz, C10-H), 9.17 (dd, 1H, Jꢀ8, 2 Hz,
3
b
3
3
1
3
3H, O-CH ), 5.59 (d, 1H, Jꢀ5 Hz, C1-H), 5.82 (d, 1H, Jꢀ5 Hz, C2-H), 6.52
C13-H). C-NMR (75 MHz, CDCl ) d: 9.0 (q, CH -CH -CO-O-C7), 9.2 (q,
3
3 3 2
(s, 1H, C5-H), 7.58 (br s, 1H, D O exch., HO-C1), 7.68 (d, 1H, Jꢀ9 Hz, C9-
CH -CH -CO-O-C2), 23.9 (q, C3-(CH ) ), 24.7 (q, C3-(CH ) ), 27.5 (t, CH -
3 2 3 a 3 b 3
2
H), 7.71 (td, 1H, Jꢀ8, 2 Hz, C11-H), 7.73 (td, 1H, Jꢀ8, 2 Hz, C12-H), 7.79
d, 1H, Jꢀ9 Hz, C8-H), 7.88 (dd, 1H, Jꢀ8, 2 Hz, C10-H), 9.15 (dd, 1H,
CH -CO-O-C7), 27.6 (t, CH -CH -CO-O-C2), 56.2 (q, O-CH ), 63.4 (d, C-
1), 71.3 (d, C-2), 78.1 (s, C-3), 99.0 (d, C-5), 106.5 (s, C-14b), 110.0 (s, C-
Jꢀ8, 2 Hz, C13-H). C-NMR (75 MHz, CDCl ) d: 20.8 (q, CH -CO-O-C2), 6a), 116.8 (s, C-7a), 118.6 (d, C-8), 124.9 (d, C-9), 127.1 (d, C-13), 127.5 (d,
2
3
2
3
(
13
3
3
2
0.9 (q, CH -CO-O-C7), 23.9 (q, C3-(CH ) ), 24.7 (q, C3-(CH ) ), 56.3 (q, C-11), 128.1 (d, C-12), 129.5 (d, C-10), 129.9 (s, C-13a), 134.2 (s, C-9a),
3
3
a
3
b
O-CH ), 63.4 (d, C-1), 71.5 (d, C-2), 78.1 (s, C-3), 99.0 (d, C-5), 106.4 (s, C- 147.6 (s, C-13b), 149.8 (s, C-7), 152.1 (s, C-14a), 154.2 (s, C-4a), 155.7 (s,
3
1
4b), 109.9 (s, C-6a), 116.7 (s, C-7a), 118.6 (d, C-8), 124.8 (d, C-9), 127.1 C-6), 172.2 (s, CH -CH -CO-O-C7), 174.5 (s, CH -CH -CO-O-C2). DCI-
3 2 3 2
ꢄ
(
d, C-13), 127.6 (d, C-11), 128.1 (d, C-12), 129.6 (d, C-10), 130.2 (s, C-13a), MS m/z: 504 [MH] . Anal. Calcd for C H NO : C, 69.17; H, 5.80; N, 2.78.
29 29 7
1
34.2 (s, C-9a), 147.6 (s, C-13b), 149.8 (s, C-7), 152.5 (s, C-14a), 154.2 (s, Found: C, 69.12; H, 5.69; N, 2.86.
(ꢁ)-cis-6-Methoxy-3,3-dimethyl-2,3-dihydro-1H-benzo[c]pyrano[3,2-
C-4a), 155.7 (s, C-6), 168.8 (s, CH -CO-O-C7), 171.1 (s, CH -CO-O-C2).
DCI-MS m/z: 476 [MH] . Anal. Calcd for C H NO : C, 68.20; H, 5.30; N, h]acridine-1,2,7-triyle Tripropionate (21): IR (KBr) cm : 3245, 2892, 1592,
3
3
ꢄ
ꢃ1
2
7
25
7
2
.95. Found: C, 68.27; H, 5.23; N, 3.02.
1575, 1470, 1372, 1174, 1040, 808. UV lmax (MeOH) nm (log e): 218
(
ꢁ)-cis-6-Methoxy-3,3-dimethyl-2,3-dihydro-1H-benzo[c]pyrano-[3,2- (3.72), 244 (3.28), 287 (4.68), 325 (3.52), 342 (3.57), 387 (3.62), 408 (3.65).
ꢃ1
1
h]acridine-1,2,7-triyle Triacetate (18): IR (KBr) cm : 3240, 2894, 1598,
H-NMR (300 MHz, CDCl ) d: 1.11 (t, 3H, Jꢀ8 Hz, CH -CH -CO-O-C2),
3 3 2
1
574, 1480, 1363, 1182, 1057, 810. UV lmax (MeOH) nm (log e): 218
1.28 (t, 3H, Jꢀ8 Hz, CH -CH -CO-O-C1), 1.33 (t, 3H, Jꢀ8 Hz, CH -CH -
3 2 3 2
(
3.72), 244 (3.27), 285 (4.66), 325 (3.50), 344 (3.56), 387 (3.59), 407 (3.66). CO-O-C7), 1.53 (s, 6H, C3-(CH ) ), 2.29 (q, 2H, Jꢀ8 Hz, CH -CH -CO-O-
3
2
3
2
1
H-NMR (300 MHz, CDCl ) d: 1.46 (s, 3H, C3-(CH ) ), 1.53 (s, 3H, C3- C2), 2.49 (q, 2H, Jꢀ8 Hz, CH -CH -CO-O-C1), 2.51 (q, 2H, Jꢀ8 Hz, CH -
3
3
a
3
2
3
(CH ) ), 2.09 (s, 3H, CH -CO-O-C2), 2.18 (s, 3H, CH -CO-O-C1), 2.58 (s,
CH -CO-O-C7), 3.98 (s, 3H, O-CH ), 5.51 (d, 1H, Jꢀ5 Hz, C2-H), 6.40 (s,
3
b
3
3
2
3
3
H, CH -CO-O-C7), 3.97 (s, 3H, O-CH ), 5.62 (d, 1H, Jꢀ5 Hz, C2-H), 6.34
1H, C5-H), 7.24 (d, 1H, Jꢀ5 Hz, C2-H), 7.65 (m, 2H, H-C8, H-C9), 7.69
(td, 1H, Jꢀ8, 2 Hz, C11-H), 7.75 (td, 1H, Jꢀ8, 2 Hz, C12-H), 7.83 (dd, 1H,
Jꢀ8, 2 Hz, C10-H), 9.28 (dd, 1H, Jꢀ8, 2 Hz, C13-H). C-NMR (75 MHz,
3
3
(s, 1H, C5-H), 6.95 (d, 1H, Jꢀ5 Hz, C1-H), 7.68 (d, 1H, Jꢀ9 Hz, C9-H),
1
3
7
1
2
.70 (td, 1H, Jꢀ8, 2 Hz, C11-H), 7.73 (td, 1H, Jꢀ8, 2 Hz, C12-H), 7.80 (d,
H, Jꢀ9 Hz, C8-H), 7.89 (dd, 1H, Jꢀ8, 2 Hz, C10-H), 9.17 (dd, 1H, Jꢀ8, CDCl ) d: 8.9 (q, CH -CH -CO-O-C7), 9.0 (q, CH -CH -CO-O-C1), 9.2 (q,
3
3
2
3
2
13
Hz, C13-H). C-NMR (75 MHz, CDCl ) d: 20.8 (q, CH -CO-O-C7), 20.9
CH -CH -CO-O-C2), 21.0 (q, C3-(CH ) ), 26.7 (q, C3-(CH ) ), 27.4 (t, CH -
3 2 3 a 3 b 3
3
3
(q, CH -CO-O-C1), 21.1 (q, CH -CO-O-C2), 21.3 (q, C3-(CH ) ), 26.2 (q, CH -CO-O-C7), 27.6 (t, CH -CH -CO-O-C1), 27.8 (t, CH -CH -CO-O-C2),
3
3
3
a
2 3 2 3 2
C3-(CH ) ), 56.4 (q, O-CH ), 63.0 (d, C-1), 72.4 (d, C-2), 78.3 (s, C-3), 99.2 56.1 (q, O-CH ), 62.1 (d, C-1), 72.1 (d, C-2), 77.0 (s, C-3), 98.4 (d, C-5),
3
b
3
3
(d, C-5), 104.7 (s, C-14b), 109.8 (s, C-6a), 116.3 (s, C-7a), 118.4 (d, C-8),
104.9 (s, C-14b), 109.3 (s, C-6a), 116.9 (s, C-7a), 118.7 (d, C-8), 125.9 (d,
1
1
24.8 (d, C-9), 127.2 (d, C-13), 127.4 (d, C-11), 128.1 (d, C-12), 129.3 (d, C- C-9), 126.9 (d, C-13), 127.3 (d, C-11), 127.5 (d, C-12), 129.1 (d, C-10),
0), 130.0 (s, C-13a), 134.2 (s, C-9a), 147.0 (s, C-13b), 149.8 (s, C-7), 154.8 131.3 (s, C-13a), 134.0 (s, C-9a), 148.5 ((s, C-7)ꢄ(s, C-13b)), 150.9 (s, C-
(
s, C-14a), 155.8 (s, C-4a), 156.0 (s, C-6), 168.7 (s, CH -CO-O-C7), 170.2
14a), 155.4 (s, C-4a), 157.0 (s, C-6), 172.3 (s, CH -CH -CO-O-C7), 173.2
3
3 2
ꢄ
(s, CH -CO-O-C1), 170.7 (s, CH -CO-O-C2). DCI-MS m/z: 518 [MH] . (s, CH -CH -CO-O-C1), 174.5 (s, CH -CH -CO-O-C2). DCI-MS m/z: 560
3
3
3
2
3
2
ꢄ
Anal. Calcd for C H NO : C, 67.30; H, 5.26; N, 2.71. Found: C, 67.41; H, [MH] . Anal. Calcd for C H NO : C, 68.68; H, 5.94; N, 2.50. Found: C,
29
27
8
32 33
8
5
.27; N, 2.69.
ꢀ)-cis-1,2-Dihydroxy-6-methoxy-3,3-dimethyl-7-propioxy-2,3-dihy-
dro-1H-benzo[c]pyrano[3,2-h]acridine-7-yle Propionate (19), (ꢀ)-cis-1-
68.72; H, 5.97; N, 2.46.
(ꢀ)-cis-1,2-Di-O-carbonyl-6-methoxy-3,3-dimethyl-1,2,3,14-tetrahy-
dro-7H-benzo[c]pyrano[3,2-h]acridin-7-one (22) N,Nꢂ-Carbonyldiimi-
(
Hydroxy-6-methoxy-3,3-dimethyl-2,3-dihydro-1H-benzo[c]pyrano[3,2- dazole (163 mg, 0.18 mmol) was added to a solution of 16 (65 mg,
h]acridine-2,7-diyle Dipropionate (20), and (ꢀ)-cis-6-Methoxy-3,3-di- 0.17 mmol) in dry 2-butanone (5 ml). The reaction mixture was refluxed for
methyl-2,3-dihydro-1H-benzo[c]pyrano[3,2-h]acridine-1,2,7-triyle
Tripropionate (21) Propionylation of 16 (180 mg, 0.45 mmol), under con-
ditions similar to those described for the preparation of 17 and 18, but using
propionic anhydride instead of acetic anhydride, afforded 19 (34 mg, 3%),
3 h under nitrogen, and then 5% aqueous NaHCO (5 ml) was added. The so-
lution was extracted with EtOAc (3ꢆ10 ml) and the combined organic layers
3
were dried over anhydrous Na CO , filtered, and evaporated under reduced
2
3
pressure. Column chromatography over silica gel (20—45 mm) (solvent:
2
0 (39 mg, 18%), and 21 (142 mg, 33%) as yellow amorphous solids.
CH Cl /MeOH 2 : 1) gave 22 (59 mg, 83%) as yellow crystals, mp 240 °C.
2
2
ꢃ1
(
ꢁ)-cis-1,2-Dihydroxy-6-methoxy-3,3-dimethyl-7-propioxy-2,3-dihydro- IR (KBr) cm : 3440, 2950, 1810, 1643, 1583, 1487, 1458, 1398, 1210,
ꢃ1
1
3
2
H-benzo[c]pyrano[3,2-h]acridine-7-yle Propionate (19): IR (KBr) cm
:
1160, 1084, 1032, 975. UV lmax (MeOH) nm (log e): 223 (4.12), 269 (4.83),
1
385, 3255, 1595, 1460, 1380, 1144, 1080. UV lmax (MeOH) nm (log e):
274 (4.87), 294 (3.68), 320 (3.34), 357 (3.31), 368 (3.28), 384 (3.27). H-
21 (3.80), 225 (3.78), 244 (3.32), 290 (4.80), 324 (3.21), 343 (3.28), 399 NMR (300 MHz, DMSO-d ) d: 1.13 (s, 3H, C3-(CH ) ), 1.41 (s, 3H, C3-
6
3 a
1
(3,24). H-NMR (300 MHz, CDCl ) d: 1.38 (s, 3H, C3-(CH ) ), 1.45 (t, 3H,
(CH ) ), 3.75 (d, 1H, Jꢀ5 Hz, C2-H), 3.78 (s, 3H, O-CH ), 5.29 (d, 1H,
3
3
a
3
b
3
Jꢀ8 Hz, CH -CH -CO-O-C7), 1.67 (s, 3H, C3-(CH ) ), 2.89 (q, 2H, Jꢀ5 Hz, C1-H), 6.01 (s, 1H, C5-H), 7.33 (d, 1H, Jꢀ9 Hz, C9-H), 7.57 (td,
3
2
3 b
Jꢀ8 Hz, CH -CH -CO-O-C7), 3.43 (dd, 1H, Jꢀ7, 4.5 Hz, C2-H), 3.96 (s,
1H, Jꢀ7, 2 Hz, C11-H), 7.59 (td, 1H, Jꢀ7, 2 Hz, C12-H), 7.86 (dd, 1H,
Jꢀ7, 2 Hz, C10-H), 8.15 (d, 1H, Jꢀ9 Hz, C8-H), 8.64 (dd, 1H, Jꢀ7, 2 Hz,
3
2
3
H, O-CH ), 4.07 (d, 1H, Jꢀ7 Hz, HO-C1), 5.68 (d, 1H, Jꢀ7 Hz, HO-C2),
3
1
3
6
.53 (s, 1H, C5-H), 7.75 (m, 3H, C1-H, C11-H, C12-H), 7.81 (d, 1H, C13-H), 12.07 (br s, 1H, D O exch., N-H). C-NMR (75 MHz, DMSO-d6)
2
Jꢀ8 Hz, C9-H), 7.89 (dd, 1H, Jꢀ8, 2 Hz, C10-H), 9.17 (dd, 1H, Jꢀ8, 2 Hz,
d: 24.8 (q, C3-(CH ) ), 25.6 (q, C3-(CH ) ), 56.5 (q, O-CH ), 65.6 (d, C-1),
3 a 3 b 3
13
C13-H). C-NMR (75 MHz, CDCl ) d: 9.0 (q, CH -CH -CO-O-C7), 23.3
71.2 (s, C-3), 78.8 (d, C-2), 93.4 (d, C-5), 103.4 (s, C-14b), 110.0 (s, C-6a),
3
3
2
(
q, C3-(CH ) ), 24.4 (q, C3-(CH ) ), 27.6 (t, CH -CH -CO-O-C7), 56.2 (q,
119.3 ((s, C-7a)ꢄ(d, C-8)), 123.9 (d, C-9), 124.5 (d, C-13), 126.2 (d, C-11),
3
a
3
b
3
2
O-CH ), 64.5 (d, C-1), 70.5 (d, C-2), 78.8 (s, C-3), 99.3 (d, C-5), 105.5 (s, C- 128.5 (d, C-12), 128.6 (s, C-13a), 128.9 (d, C-10), 135.8 ((s, C-9a)ꢄ(s, C-
3
1
4b), 110.0 (s, C-6a), 116.8 (s, C-7a), 118.7 (d, C-8), 124.6 (d, C-9), 127.0 13b)), 143.3 (s, C-14a), 150.8 (s, CO), 155.1 (s, C-4a), 161.5 (s, C-6), 175.7
ꢄ
(
d, C-13), 127.6 (d, C-11), 128.2 (d, C-12), 129.6 (d, C-10), 129.8 (s, C-13a), (s, C7). DCI-MS m/z: 418 [MH] . Anal. Calcd for C H NO : C, 69.06; H,
24 19 6
1
34.4 (s, C-9a), 147.5 (s, C-13b), 150.2 (s, C-7), 152.4 (s, C-14a), 154.8 (s, 4.59; N, 3.36. Found: C, 65.97; H, 4.65; N, 3.46.
1-(6-Methoxyquinolin-8-ylamino)-2-naphthalenecarboxylic Acid (26)
C-4a), 155.8 (s, C-6), 172.1 (s, CH -CH -CO-O-C7). DCI-MS m/z: 448
3
2

December 2005
1545
6
-Methoxy-8-aminoquinoline (23) (280 mg, 1.61 mmol) and 1-bromo-2-
d ) d: 56.3 (q, O-CH ), 95.3 (d, C-6), 110.3 (s, C-6a), 122.3 (s, C-7a), 123.1
6
3
naphthalenecarboxylic acid (9) (404 mg, 1.61 mmol) were condensed under
(d, C-8), 123.5 (d, C-9), 123.6 (d, C-3), 123.8 (d, C-9), 126.6 (d, C-11),
conditions similar to those described for the preparation of 14. Purification 129.0 (d, C-13), 129.1 (d, C-10), 130.5 (s, C-4a), 135.0 (s, C-13a), 135.8 (d,
by flash chromatography (solvent: CH Cl /MeOH 97 : 3) gave 26 (264 mg,
C-4), 136.7 (s, C-14a), 139.2 (s, C-14b), 142.1 (s, C-9a), 145.6 (s, C-13b),
2
2
ꢃ1
ꢄ
4
2
(
8%) as yellow crystals from MeOH, mp 246 °C. IR (KBr) cm : 3200, 146.0 (d, C-2), 158.3 (s, C-6), 176.9 (s, C7). DCI-MS m/z: 327 [MH] .
942, 1620, 1270. UV l (MeOH) nm (log e): 270 (4.82), 313 (4.41), 372 Anal. Calcd for C H N O : C, 77.29; H, 4.32; N, 8.58. Found: C, 77.22; H,
max
21 14
2
2
1
3.65). H-NMR (300 MHz, DMSO-d ) d: 3.65 (s, 3H, O-CH ), 5.79 (d, 1H, 4.37; N, 8.66.
6
3
Jꢀ2 Hz, C7ꢂ-H), 6.72 (d, 1H, Jꢀ2 Hz, C5ꢂ-H), 7.49 (td, 1H, Jꢀ8, 1.5 Hz,
C6-H), 7.54 (dd, 1H, Jꢀ8, 5 Hz, C3ꢂ-H), 7.61 (td, 1H, Jꢀ8, 1.5 Hz, C7-H),
Naphtho[1,2-b][1,10]-phenanthrolin-7(14H)-one (30) 1-(Quinolin-8-
ylamino)-naphthalene-2-carboxylic acid 27 (400 mg, 1.27 mmol), treated
under conditions similar to those described for the preparation of 29 from
7
.83 (d, 1H, Jꢀ9 Hz, C4-H), 7.92 (dd, 1H, Jꢀ8, 1.5 Hz, C5-H), 7.98 (d, 1H,
Jꢀ9 Hz, C3-H), 8.06 (dd, 1H, Jꢀ8, 1.5 Hz, C8-H), 8.19 (dd, 1H, Jꢀ8, 2 Hz,
26, gave 30 (150 mg, 40%) which crystallized in MeOH as yellow crystals,
ꢃ1
C4ꢂ-H), 8.75 (dd, 1H, Jꢀ5, 2 Hz, C2ꢂ-H), 8.92 (br s, 1H, D O exch., NH), mp 287 °C. IR (KBr) cm : 3000, 2850, 1670. UV l (MeOH) nm (log e):
2
max
1
3
1
1
0.03 (br s, 1H, D O exch., COOH). C-NMR (75 MHz, DMSO-d ) d: 56.1 263 (3.98), 278 (4.52), 348 (4.39). H-NMR (300 MHz, DMSO-d ) d: 7.59
6
2
6
(q, O-CH ), 96.7 (d, C-7ꢂ), 102.5 (d, C-5ꢂ), 122.3 (s, C-2), 123.5 (d, C-3ꢂ), (d, 1H, Jꢀ9 Hz, C5-H), 7.62 (dd, 1H, Jꢀ8, 5 Hz, C3-H), 7.70 (d, 1H,
3
1
1
8
25.4 (d, C-4), 126.9 (d, C-6), 127.3 (s, C-8a), 127.6 (d, C-5), 129.3 (d, C-3), Jꢀ9 Hz, C9-H), 7.72 (td, 1H, Jꢀ8, 2 Hz, C11-H), 7.74 (td, 1H, Jꢀ8, 2 Hz,
29.6 (d, C-8), 130.3 (d, C-7), 130.6 (s, C-4ꢂa), 136.0 (d, C-4ꢂ), 136.3 (s, C-
C12-H), 7.98 (dd, 1H, Jꢀ8, 2 Hz, C10-H), 8.24 (dd, 1H, Jꢀ8, 2 Hz, C4-H),
ꢂ), 136.7 (s, C-4a), 141.9 (s, C-8ꢂa), 142.7 (d, C-2ꢂ), 144.6 (s, C-1), 158.7 8.47 dd, 1H, Jꢀ8, 2 Hz, C13-H), 8.49 (d, 1H, Jꢀ9 Hz, C6-H), 8.52 (d, 1H,
ꢄ
(s, C-6ꢂ), 169.6 (s, COOH). DCI-MS m/z: 345 [MH] . Anal. Calcd for
Jꢀ9 Hz, C8-H), 8.98 (dd, 1H, Jꢀ5, 2 Hz, C2-H), 11.25 (br s, 1H, D O exch.,
2
1
3
C H N O : C, 73.24; H, 4.68; N, 8.13. Found: C, 73.22; H, 4.64; N, 8.16.
NH). C-NMR (75 MHz, DMSO-d ) d: 119.9 (s, C-6a), 120.1 (s, C-7a),
120.4 (d, C-8), 120.6 (d, C-5), 122.9 (d, C-6), 123.0 (d, C-3), 123.4 ((d, C-
21
16
2
3
6
1-(Quinolin-8-ylamino)-2-naphthalenecarboxylic Acid (27) 8-Ami-
noquinoline (24) (172 mg, 1.19 mmol) and 1-bromo-2-naphthalenecarbox- 9)ꢄ(d, C-13)), 126.6 (d, C-11), 128.8 (d, C-12), 129.1 (d, C-10), 130.8 (s, C-
ylic acid (9) (300 mg, 1.19 mmol) were condensed under conditions similar
4a), 135.4 ((d, C-4)ꢄ(s, C-13a)), 141.2 (s, C-14a), 142.0 (s, C-9a), 143.8 (s,
to those described for the preparation of 14. Flash chromatography (solvent: C-14b), 147.2 (s, C-13b), 148.6 (d, C-2), 177.5 (s, C7). DCI-MS m/z: 297
ꢄ
CH Cl /MeOH 97 : 3) afforded 27 (153 mg, 41% yield) as yellow crystals [MH] . Anal. Calcd for C H N O: C, 81.07; H, 4.08; N, 9.45. Found: C,
2
2
20 12
2
ꢃ1
from MeOH, mp 252—253 °C. IR (KBr) cm : 3200, 2990, 1670, 1595. UV 80.94; H, 4.07; N, 9.46.
1
l
(
(MeOH) nm (log e): 273 (3.21), 344 (4.47), 352 (4.32). H-NMR
Naphtho[1,2-b][1,7]-phenanthrolin-7(14H)-one (31) 1-(Quinolin-5-
ylamino)-naphthalene-2-carboxylic acid 28 (100 mg, 0.32 mmol), treated
Jꢀ8 Hz, C6ꢂ-H), 7.33 (dd, 1H, Jꢀ8, 2 Hz, C5ꢂ-H), 7.55 (td, 1H, Jꢀ8, under conditions similar to those described for the preparation of 29 from
.5 Hz, C6-H), 7.61 (dd, 1H, Jꢀ8, 5 Hz, C3ꢂ-H), 7.64 (td, 1H, Jꢀ8, 1.5 Hz, 26, gave 31 (44 mg, 46%) which crystallized in EtOH as yellow crystals, mp
max
300 MHz, DMSO-d ) d: 6.25 (dd, 1H, Jꢀ8, 2 Hz, C7ꢂ-H), 7.18 (t, 1H,
6
1
ꢃ1
C7-H), 7.80 (d, 1H, Jꢀ9 Hz, C4-H), 7.89 (dd, 1H, Jꢀ8, 1.5 Hz, C5-H), 7.99
d, 1H, Jꢀ9 Hz, C3-H), 8.06 (dd, 1H, Jꢀ8, 1.5 Hz, C8-H), 8.32 (dd, 1H,
Jꢀ8, 2 Hz, C4ꢂ-H), 8.95 (dd, 1H, Jꢀ5, 2 Hz, C2ꢂ-H), 10.10 (br s, 1H, D O (d, 1H, Jꢀ9 Hz, C5-H), 7.64 (dd, 1H, Jꢀ8, 5 Hz, C2-H), 7.73 (d, 1H,
265 °C. IR (KBr) cm : 3150, 2900, 1620. UV l
(MeOH) nm (log e):
max
1
(
254 (3.97), 280 (3.43), 347 (4.22). H-NMR (300 MHz, DMSO-d ) d: 7.39
6
2
1
3
exch., NH), 11.75 (br s, 1H, D O exch., COOH). C-NMR (75 MHz,
Jꢀ9 Hz, C9-H), 7.76 (td, 1H, Jꢀ8, 2 Hz, C11-H), 7.79 (td, 1H, Jꢀ8, 2 Hz,
2
DMSO-d ) d: 110.6 (d, C-7ꢂ), 118.7 (d, C-5ꢂ), 121.5 (s, C-2), 123.2 (d, C- C12-H), 8.04 (dd, 1H, Jꢀ8, 2 Hz, C10-H), 8.43 (d, 1H, Jꢀ9 Hz, C6-H), 8.63
6
3
1
4
ꢂ), 125.0 (d, C4), 127.2 ((d, C-6)ꢄ(s, C8a)), 127.3 (d, C-5), 127.7 (d, C-3),
27.8 (d, C-8), 129.2 (s, C-4ꢂa), 129.4 (d, C-6ꢂ), 129.6 (d, C-7), 136.8 (s, C-
(d, 1H, Jꢀ9 Hz, C8-H), 8.55 (dd, 1H, Jꢀ8, 2 Hz, C13-H), 8.85 (dd, 1H,
Jꢀ5, 2 Hz, C3-H), 9.42 (dd, 1H, Jꢀ8, 2 Hz, C1-H), 12.63 (br s, 1H, D O
2
1
3
a), 137.3 (d, C-4ꢂ), 139.5 (s, C-8ꢂ), 142.6 (s, C-8ꢂa), 143.4 (s, C-1), 149.4 exch., NH). C-NMR (75 MHz, DMSO-d ) d: 116.3 (s, C-14b), 117.4 (s, C-
6
ꢄ
(d, C-2ꢂ), 169.8 (s, COOH). DCI-MS m/z: 315 [MH] . Anal. Calcd for 6a), 121.4 (s, C-7a), 122.0 (d, C-8), 122.8 (d, C2), 123.6 (d, C-5), 124.2 (d,
C H N O : C, 76.42; H, 4.49; N, 8.91. Found: C, 76.31; H, 4.43; N, 8.97.
C-9), 124.7 (d, C-13), 126.3 (d, C-11), 128.1 (d, C-6), 129.1 (d, C-12), 129.8
(d, C-10), 133.0 (d, C-1), 136.0 (s, C-13a), 140.1 (s, C-14a), 142.5 (s, C-9a),
20
14
2
2
1-(Quinolin-5-ylamino)-2-naphthalenecarboxylic Acid (28) 5-Ami-
noquinoline (25) (172 mg, 1.19 mmol) and 1-bromo-2-naphthalenecarbox- 146.7 (s, C-13b), 152.6 (s, C-4a), 154.9 (d, C-3), 177.4 (s, C7). DCI-MS
ꢄ
ylic acid (9) (300 mg, 1.19 mmol) were condensed under conditions similar
m/z: 297 [MH] . Anal. Calcd for C H N O: C, C, 81.07; H, 4.08; N, 9.45.
20 12 2
to those described for the preparation of 14. Flash chromatography (solvent: Found: C, 81.13; H, 4.16; N, 9.37.
CH Cl /MeOH 97 : 3) afforded 28 (183 mg, 49% yield) as yellow crystals
6-Methoxy-14-methylnaphtho[1,2-b][1,10]-phenanthrolin-7(14H)-one
from MeOH, mp 237—238 °C. IR (KBr) cm : 3260, 3000, 1670, 1600. UV (6) Methyl iodide (0.045 ml, 0.72 mmol) was added to a solution of 29
2
2
ꢃ1
1
l
(
(MeOH) nm (log e): 269 (3.56), 332 (4.21), 347 (4.67). H-NMR (125 mg, 0.38 mmol), benzyltriethylammonium chloride (330 mg, 1.45
max
300 MHz, DMSO-d ) d: 6.24 (dd, 1H, Jꢀ8, 1 Hz, C6ꢂ-H), 7.34 (t, 1H,
mmol), and 50% aqueous NaOH (3 ml) in 2-butanone (5 ml). The reaction
Jꢀ8 Hz, C7ꢂ-H), 7.36 (dd, 1H, Jꢀ8, 1 Hz, C5ꢂ-H), 7.55 (td, 1H, Jꢀ8, mixture was stirred and refluxed for 3 h. The cooled solution was diluted
6
1
.5 Hz, C6-H), 7.62 (dd, 1H, Jꢀ8, 5 Hz, C3ꢂ-H), 7.68 (td, 1H, Jꢀ8, 1.5 Hz, with a mixture of CH Cl (10 ml) and H O (5 ml). The aqueous phase was
2 2 2
C7-H), 7.83 (d, 1H, Jꢀ9 Hz, C4-H), 7.90 (dd, 1H, Jꢀ8, 1.5 Hz, C5-H), 7.98
extracted with CH Cl (2ꢆ20 ml). The organic layer was dried over anhy-
2 2
(d, 1H, Jꢀ9 Hz, C3-H), 8.02 (dd, 1H, Jꢀ8, 1.5 Hz, C8-H), 8.37 (dd, 1H,
drous Na SO , filtered, and evaporated under reduced pressure. Crystalliza-
2 4
Jꢀ8, 2 Hz, C4ꢂ-H), 8.91 (dd, 1H, Jꢀ5, 2 Hz, C2ꢂ-H), 8.95 (br s, 1H, D O tion from EtOAc gave 6 (44 mg, 34%) as a yellow crystals, mp 295—
2
1
3
ꢃ1
exch., NH), 9.62 (br s, 1H, D O exch., COOH). C-NMR (75 MHz, DMSO-
296 °C. IR (KBr) cm : 3220, 2990, 1610, 1490, 1250, 760. UV l
2
max
1
d ) d: 113.0 (d, C-6ꢂ), 120.5 (s, C-2), 122.0 (s, C-4ꢂa), 122.4 (d, C-8ꢂ), 124.7 (MeOH) nm (log e): 266 (3.32), 282 (4.53), 342 (4.61). H-NMR (300 MHz,
6
(
(d, C3ꢂ)ꢄ(d, C-4)), 126.8 (d, C-6), 127.3 (d, C-5), 127.8 (d, C-3), 128.8 (s, DMSO-d ) d: 4.27 (s, 3H, N-CH ), 4.46 (s, 3H, O-CH ), 6.89 (s, 1H, C5-H),
6
3
3
C-8a), 129.4 (d, C-8), 129.6 (d, C-7), 130.7 (d, C-7ꢂ), 131.8 (d, C-4ꢂ), 137.2 7.60 (dd, 1H, Jꢀ8, 5 Hz, C3-H), 7.74 (td, 1H, Jꢀ8, 2 Hz, C11-H), 7.81 (td,
s, C-4a), 144.1 (s, C-8ꢂ), 144.4 (s, C-1), 149.8 (s, C-8ꢂa), 151.8 (d, C-2ꢂ), 1H, Jꢀ8, 2 Hz, C12-H), 7.83 (d, 1H, Jꢀ9 Hz, C9-H), 8.00 (dd, 1H, Jꢀ8,
(
ꢄ
1
70.7 (s, COOH). DCI-MS m/z: 315 [MH] . Anal. Calcd for C H N O : C,
2 Hz, C10-H), 8.68 (dd, 1H, Jꢀ8, 2 Hz, C4-H), 8.70 (d, 1H, Jꢀ9 Hz, C8-H),
8.72 (dd, 1H, Jꢀ8, 2 Hz, C13-H), 8.96 (dd, 1H, Jꢀ5, 2 Hz, C2-H). C-NMR
(75 MHz, DMSO-d ) d: 43.4 (q, N-CH ), 56.5 (q, O-CH ), 96.4 (d, C-6),
111.2 (s, C-6a), 123.1 (d, C-3), 124.8 (d, C-8), 125.0 (d, C-9), 125.4 (d, C-
13), 126.2 (s, C-7a), 127.2 (d, C-11), 128.6 (d, C-12), 129.1 (d, C-10), 130.7
(s, C-4a), 134.0 (d, C-4), 135.9 (s, C-13a), 138.2 (s, C-14a), 142.2 (s, C-
2
0
14
2
2
13
7
6.42; H, 4.49; N, 8.91. Found: C, 76.40; H, 4.53; N, 9.01.
-Methoxynaphtho[1,2-b][1,10]-phenanthrolin-7(14H)-one
6
(29) A
6
3
3
solution of 26 (200 mg, 0.58 mmol) in concentrated sulfuric acid (5 ml) was
heated at 100 °C for 5 h. The cooled solution was poured on ice-water, fil-
tered, and the precipitate was partitioned between CH Cl (150 ml) and 10 M
2
2
aqueous NaOH (100 ml). The organic layer was dried over anhydrous 14b), 142.7 (s, C-9a), 143.7 (d, C-2), 148.3 (s, C-13b), 159.8 (s, C-6), 177.1
ꢄ
Na SO , filtered, and evaporated under reduced pressure. Crystallization
(s, C7). DCI-MS m/z: 341 [MH] . Anal. Calcd for C H N O : C, 77.63; H,
2
4
22 16 2 2
from EtOH gave 29 (81 mg, 43%) as yellow crystals, mp 270 °C. IR (KBr)
4.74; N, 8.23. Found: C, 77.72; H, 4.79; N, 8.15.
14-Methylnaphtho[1,2-b][1,10]-phenanthrolin-7(14H)-one (7) Naph-
4.61), 352 (3.74). H-NMR (300 MHz, DMSO-d ) d: 4.09 (s, 3H, O-CH ), tho[1,2-b][1,10]-phenanthrolin-7(14H)-one (30) (113 mg, 0.38 mmol),
ꢃ1
cm : 3280, 2980, 1642. UV l
(MeOH) nm (log e): 263 (4.73), 284
max
1
(
6
3
6
.83 (s, 1H, C5-H), 7.52 (dd, 1H, Jꢀ8, 5 Hz, C3-H), 7.67 (d, 1H, Jꢀ9 Hz, treated under conditions similar to those described for the preparation of 6
from 29, afforded 7 (42 mg, 48%) as yellow crystals, mp 291 °C. IR (KBr)
C9-H), 7.74 (td, 1H, Jꢀ8, 2 Hz, C11-H), 7.80 (td, 1H, Jꢀ8, 2 Hz, C12-H),
ꢃ1
7
1
2
.98 (dd, 1H, Jꢀ8, 2 Hz, C10-H), 8.49 (dd, 1H, Jꢀ8, 2 Hz, C13-H), 8.64 (d,
cm : 3200—2950, 1645, 1300, 750. UV l
(MeOH) nm (log e): 252
max
1
H, Jꢀ9 Hz, C8-H), 8.67 (dd, 1H, Jꢀ8, 2 Hz, C4-H), 8.83 (dd, 1H, Jꢀ5, (4.23), 282 (4.55), 344 (3.97), 367 (3.81). H-NMR (300 MHz, DMSO-d )
6
1
3
Hz, C2-H), 10.93 (br s, 1H, D O exch., NH). C-NMR (75 MHz, DMSO-
d: 4.43 (s, 1H, N-CH ), 7.58 (dd, 1H, Jꢀ8, 5 Hz, C3-H), 7.70 (m, 2H, C11-
3
2

1
546
Vol. 53, No. 12
H, C12-H), 7.72 (d, 1H, Jꢀ9 Hz, C5-H), 7.77 (d, 1H, Jꢀ9 Hz, C9-H), 7.98
dd, 1H, Jꢀ8, 2 Hz, C10-H), 8.26 (dd, 1H, Jꢀ8, 2 Hz, C4-H), 8.44 (d, 1H,
Jꢀ9 Hz, C6-H), 8.55 (d, 1H, Jꢀ9 Hz, C8-H), 8.74 dd, 1H, Jꢀ8, 2 Hz, C13-
6) Scarffe J. H., Beaumont A. R., Gowther D., Cancer Treat. Rep., 67,
93—94 (1983).
7) Brum-Bousquet M., Mitaku S., Skaltsounis A.-L., Tillequin F., Koch
M., Planta Med., 54, 470—471 (1988).
8) Elomri A., Mitaku S., Michel S., Skaltsounis A.-L., Tillequin F., Koch
M., Pierré A., Guilbaud N., Léonce S., Kraus-Berthier L., Rolland Y.,
Atassi Gh., J. Med. Chem., 39, 4762—4766 (1996).
(
1
3
H), 9.02 (dd, 1H, Jꢀ5, 2 Hz, C2-H). C-NMR (75 MHz, DMSO-d ) d: 51.9
6
(
q, N-CH ), 122.7 (d, C-5), 122.0 (d, C-8), 123.0 (d, C-6), 123.4 (d, C-3),
3
1
1
24.4 (d, C-9), 125.2 (s, C-6a), 125.4 (d, C-13), 125.8 (s, C-7a), 127.6 (d, C-
1), 128.3 (d, C-12), 128.8 (d, C-10), 131.7 (s, C-4a), 136.4 (d, C-4), 136.9
(
2
s, C-13a)), 142.4 (s, C-9a), 146.6 (s, C-14a), 147.8 (s, C-14b), 147.9 (d, C-
), 150.3 (s, C-13b), 178.3 (s, C7). DCI-MS m/z: 311 [MH] . Anal. Calcd
9) Costes N., Le Deit H., Michel S., Tillequin F., Koch M., Pfeiffer B.,
Renard P., Leonce S., Guilbaud N., Kraus-Berthier L., Pierré A.,
Atassi Gh., J. Med. Chem., 43, 2395—2402 (2000).
ꢄ
for C H N O: C, 81.27; H, 4.55; N, 9.03. Found: C, 81.34; H, 4.47; N,
21
14
2
9
.12.
4-Methylnaphtho[1,2-b][1,7]-phenanthrolin-7(14H)-one (8) Naph-
10) David-Cordonnier M.-H., Laine W., Lansiaux A., Kouach M., Briand
G., Pierré A., Hickman J. A., Bailly C., Biochemistry, 41, 9911—9920
(2002).
1
tho[1,2-b][1,7]-phenanthrolin-7(14H)-one (31) (90 mg, 0.30 mmol), treated
under conditions similar to those described for the preparation of 6 from 29,
gave 8 (48 mg, 52% yield) as yellow crystals from EtOAc, mp 279—280 °C.
IR (KBr) cm : 3100, 3000, 1670, 1300, 750. UV lmax (MeOH) nm (log e):
2
11) Doan Thi Mai H., Gaslonde T., Michel S., Tillequin F., Koch M.,
Bongui J.-B., Elomri A., Seguin E., Pfeiffer B., Renard P., David-Cor-
donnier M.-H., Laine W., Bailly C., Kraus-Berthier L., Léonce S.,
Hickman J. A., Pierré A., J. Med. Chem., 46, 3072—3082 (2003).
12) David-Cordonnier M.-H., Laine W., Joubert A., Tardy C., Goossens J.-
F., Kouach M., Briand G., Doan Thi Mai H., Michel S., Tillequin F.,
Koch M., Léonce S., Pierré A., Bailly C., Eur. J. Biochem., 270,
2848—2859 (2003).
ꢃ1
1
61 (3.70), 301 (4.21), 352 (4.47). H-NMR (300 MHz, DMSO-d ) d: 4.38
6
(s, 1H, N-CH ), 7.52 (dd, 1H, Jꢀ8, 5 Hz, C2-H), 7.59 (d, 1H, Jꢀ9 Hz, C5-
3
H), 7.69 (td, 1H, Jꢀ8, 2 Hz, C11-H), 7.72 (td, 1H, Jꢀ8, 2 Hz, C12-H), 7.80
d, 1H, Jꢀ9 Hz, C9-H), 8.02 (dd, 1H, Jꢀ8, 2 Hz, C10-H), 8.52 (d, 1H,
Jꢀ9 Hz, C6-H), 8.71 (dd, 1H, Jꢀ8, 2 Hz, C13-H), 8.75 (dd, 1H, Jꢀ5, 2 Hz,
(
1
3
C3-H), 8.78 (d, 1H, Jꢀ9 Hz, C8-H), 9.07 (dd, 1H, Jꢀ8, 2 Hz, C1-H). C- 13) David-Cordonnier M.-H., Laine W., Kouach M., Briand G., Vezin H.,
NMR (75 MHz, DMSO-d ) d: 44.9 (s, N-CH ), 118.3 (s, C-14b), 120.3 (d,
Gaslonde T., Michel S., Doan Thi Mai H., Tillequin F., Koch M.,
Léonce S., Pierré A., Bailly C., Bioorg. Med. Chem., 12, 23—29
(2004).
6
3
C2), 122.3 (s, C-6a), 123.4 (s, C-7a), 124.9 (d, C-8), 125.1 (d, C-13), 125.5
d, C-9), 126.1 (d, C-5), 126.3 (d, C-11), 127.8 (d, C-6), 129.0 (d, C-12),
30.1 (d, C-10), 134.2 (d, C-1), 136.8 (s, C-13a), 142.3 (s, C-9a), 145.2 (s,
C-14a), 149.9 (s, C-13b), 153.1 (d, C-3), 154.7 (s, C-4a), 177.8 (s, C7). DCI-
(
1
14) Michel S., Gaslonde T., Tillequin F., Eur. J. Med. Chem., 39, 649—655
(2004).
ꢄ
MS m/z: 311 [MH] . Anal. Calcd for C H N O: C, 81.27; H, 4.55; N, 9.03. 15) Kolokythas G., Kostakis I. K., Pouli N., Marakos P., Kletsas D., Pratsi-
2
1
14
2
Found: C, 81.14; H, 4.51; N, 9.07.
nis H., Bioorg. Med. Chem., 11, 4591—4598 (2003).
Pharmacology Cytotoxicity: Murine leukemia L1210 cells from the 16) Costes N., Elomri A., Dufat H., Michel S., Seguin E., Koch M., Tille-
American Type Culture Collection (Rockville Pike, MD, U.S.A.) were
grown in RPMI medium 1640 supplemented with 10% fetal calf serum, L-
glutamine 2 mM, penicillin 100 U/ml, streptomycin 100 mg/ml, and HEPES
buffer 10 mM (pH 7.4). The cytotoxicity was measured using the microcul-
quin F., Pfeiffer B., Renard P., Léonce S., Pierré A., Oncol. Res., 13,
191—197 (2003).
17) Michel S., Seguin E., Tillequin F., Curr. Med. Chem., 9, 1689—1700
(2002).
25)
ture tetrazolium assay essentially as described. Cells were exposed for 18) Loughhead D. G., J. Org. Chem., 55, 2245—2246 (1990).
48 h to nine graded concentrations in triplicate of the test drug. Results are
19) Elomri A., Michel S., Tillequin F., Koch M., Heterocycles, 34, 799—
expressed as IC50 values (mean, nꢀ3), which are defined as the drug con-
806 (1992).
centration inhibiting the absorbance by 50% with respect to that of untreated 20) Ullmann F., Ber. Dtsch. Chem. Ges., 36, 2382—2384 (1903).
cells.
21) Blechert S., Fichter K.-E., Winterfeldt E., Chem. Ber., 111, 439—450
1978).
(
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