Synthesis of 1-(2-aminophenyl)isoquinolines and the biological activity of their cis-dichloro platinum(II) complexes

Article abstract of DOI:10.1021/jm980434t

The broad biological effects of isoquinolines prompted us to use them as chelating, nonleaving ligands in cis-platinum(II) antitumor complexes. The synthesis of several 1-(2-aminophenyl)isoquinoline derivatives with different levels of hydrogenation and v

Full text of DOI:10.1021/jm980434t

3478
J . Med. Chem. 1999, 42, 3478-3485
Syn th esis of 1-(2-Am in op h en yl)isoqu in olin es a n d th e Biologica l Activity of
Th eir cis-Dich lor o P la tin u m (II) Com p lexes
Franz von Nussbaum,† Bernhard Miller,‡ Stefan Wild,§ Christoph S. Hilger,† Susanne Schumann,†,|
Haralabos Zorbas,§ Wolfgang Beck,‡ and Wolfgang Steglich*,†
Institut fu¨r Organische Chemie der Universita¨t Mu¨nchen, Butenandtstrasse 5-13, D-81377 Mu¨nchen, Germany, Institut fu¨r
Anorganische Chemie der Universita¨t Mu¨nchen, Butenandtstrasse 5-13, D-81377 Mu¨nchen, Germany, Institut fu¨r Biochemie
der Universita¨t Mu¨nchen, Feodor-Lynen-Strasse 25, D-81377 Mu¨nchen, Germany
Received J uly 24, 1998
The broad biological effects of isoquinolines prompted us to use them as chelating, nonleaving
ligands in cis-platinum(II) antitumor complexes. The synthesis of several 1-(2-aminophenyl)-
isoquinoline derivatives with different levels of hydrogenation and varying substitution of the
phenyl ring is reported. These compounds constitute a new class of ligands for the synthesis
of oligocyclic platinum(II) complexes. In vitro cytotoxicity tests indicate that the most basic
amine ligands afford the most effective complexes. Two of the new complexes were more potent
against L1210 murine leukemia cells than the well-established antitumor compound cisplati-
num.
In tr od u ction
line and related ligands. However, these compounds
have not yet been used for chelate complexes.
In this paper we report on the synthesis and biological
evaluation of several new platinum(II) complexes with
1-(2-aminophenyl)isoquinoline ligands.
Since the discovery of the antitumor activity of cis-
diamminedichloroplatinum(II) by Rosenberg et al.,1 a
tremendous number of platinum(II) complexes have
been synthesized and their cytotoxicity examined. Sec-
ond generation platinum(II) antitumor complexes that
carry nonleaving groups other than simply ammonia are
of interest for their altered affinity to tissues (carrier
function, tumor specific accumulation) and their ability
to modulate drug metabolism (hydrolysis) and target
binding through steric and electronic effects on the
substitution mechanism.2
Knowledge of the relationship between the ligand
structure and the cytotoxicity of the complexes derived
therefrom is still limited.3 However, several rules are
apparent.4 A general assumption is, that in order to be
cytotoxic, the compounds must have two cis-coordinated
amine ligands as nonleaving groups, each carrying at
least one N-H bond. However, Farrell5 and others6 have
shown examples which do not follow this structure-
activity relationship. Apparently, polar substituents or
charged compounds also diminish the biological activ-
ity.7 The substitution of NH3 in cisplatinum by chelate
ligands such as trans-1,2-diaminocyclohexane,8 3-ami-
nohexahydroazepines,9 or aminomethylpiperidines10,11
yields bicyclic chelate platinum(II) complexes with an
altered spectrum of biological activity including cases
with reduced cross resistance. Thus far, only few plati-
num(II) complexes with amine ligands of different
basicity have been reported, e.g., complexes with a
mixed aromatic-aliphatic amine environment around
the metal. A recent case is cis-ammine-dichloro-picoline-
platinum(II).12 In addition, Bierbach13 and Farrell14
have prepared trans-platinum complexes with isoquino-
Ch em istr y
Syn th esis of th e Liga n d s. Since imines of ortho-
donor-substituted benzaldehydes are weak electrophiles
and may not be cyclized under classical Pictet-Spengler
conditions,15 all 1-(2-aminophenyl)-1,2,3,4-tetrahydroiso-
quinolines were synthesized on a highly efficient modi-
fied route. The dihydroisoquinolines16 were obtained by
Bischler-Napieralski reactions.
Condensation of 2-(trifluoroacetylamino)benzalde-
hydes 2 with homoveratrylamine (1) afforded the
imines 3 (Scheme 1). As indicated by the NH signal at
14.7 ppm and the X-ray crystal structure, compounds 3
are stabilized by a strong intramolecular hydrogen bond.
The Pictet-Spengler cyclization could therefore only be
achieved in a pressure tube with pure trifluoroacetic
acid anhydride (TFAA). Under less vigorous reaction
conditions, hydrolytic cleavage of the imines 3 was
observed. The resulting tetrahydroisoquinolines 4 were
then deprotected either with sodium borohydride17 or
concentrated hydrobromic acid to yield the ligands 5 or
6.
Dihydroisoquinolines 9 and 10 were synthesized by
Bischler-Napieralski cyclization of the nitro compounds
7 followed by selective reduction18 of the nitro group
with stannous chloride in ethyl acetate (Scheme 2).
Dehydration of the dihydroisoquinoline 8a yielded the
isoquinoline ligand precursor 11a (Scheme 3).
Syn th esis of th e P la tin u m (II) Com p lexes. The
platinum(II) complexes 12-15 (Chart 1) were prepared
by titration of the isoquinoline ligands in the presence
of equimolar amounts of K2PtCl4 in 0.05 M HCl (pH 2)
with 0.1 M NaOH to pH 6 at 60 °C. The complexes were
characterized by elemental analyses, IR, and NMR
techniques. Due to slow chloro-ligand-DMSO exchange,19
* To whom correspondence should be addressed. E-mail: wos@
cup.uni-muenchen.de. Fax: 49-89-21807756.
† Institut fu¨r Organische Chemie.
‡ Institut fu¨r Anorganische Chemie.
§ Institut fu¨r Biochemie.
| X-ray crystallography.
10.1021/jm980434t CCC: $18.00 © 1999 American Chemical Society
Published on Web 08/21/1999

Synthesis of 1-(2-Aminophenyl)isoquinolines
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 18 3479
Sch em e 1. Pictet-Spengler Route to 1-(2-Amino-
Ch a r t 1. Platinum(II) Complexes of
phenyl)-1,2,3,4-tetrahydroisoquinolinesa
1-(2-Aminophenyl)-1,2,3,4-tetrahydroisoquinolines,
1-(2-Aminophenyl)-3,4-dihydroisoquinolines, and
1-(2-Aminophenyl)isoquinolines
a
Reagents: (a) pyridine, 145 °C {>95%}; (b) TFAA, pressure
tube, 80 °C {72-86%}; (c) NaBH4, MeOH {71-89%}; (d) 48% HBr,
145 °C {71-73%}.
Ta ble 1. IC50 of Platinum(II) Complexes and Free Ligands 5
(Growth Inhibition during 48 h)
compound
solventa
IC50 ( SD (µM)
Sch em e 2. Bischler-Napieralski Route to 1-(2-Amino-
phenyl)-3,4-dihydroisoquinolinesa
12a
12b
cisplatinum
15
5a
5b
DMSO
DMSO
H2O
DMSO
H2O
0.88 ( 0.08
0.95 ( 0.16
1.4 ( 0.2
9.7 ( 0.6
141 ( 14
97 ( 9
H2O
DMSO
cisplatinum
>100
a
“DMSO” indicates that the compound has been dissolved in
DMSO and then diluted with water to a final DMSO concentration
of 0.5%.
a
Reagents: (a) POCl3, CH3CN, 80 °C {84-96%}; (b) SnCl2‚2H2O,
EtOAc, 80 °C, 5-18 h {74-88%}; (c) 48% HBr, 145 °C {67-91%}.
F igu r e 1. Growth inhibition by different platinum(II) com-
plexes and the free ligands 5.
Sch em e
3. Dehydration
of
1-(2-Aminophenyl)-
3,4-dihydroisoquinoline 8a a
Biology
In Vitr o Cytotoxicity. The cytotoxicities of the
complexes and ligands were studied with L1210 cells.
The cytotoxicity of some complexes could not be tested
due to precipitation on dilution of the stock solutions
with water. The results are shown in Figure 1 as a log-
linear plot of concentration-inhibition. Table 1 sum-
marizes the L1210 data for the compounds assayed. The
complexes 12a and 12b may have a similar mode of
action, due to their close structural relationship. Both
species are roughly 2 times more effective than cisplati-
num. In contrast, the complex 15 shows a significantly
a
Reagents: (a) activated MnO2, PhH, 80 °C, 8-10 h {84-88%}.
all 1H NMR spectra, taken in (D6)DMSO, showed
multiple sets of signals. This exchange was observed
also in the 13C NMR spectra.

3480 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 18
von Nussbaum et al.
Ta ble 2. IC50 of Platinum(II) Complexes and Free Ligands 5
(Inhibition of DNA Synthesis during 48 h)
compound
solventa
IC50 ( SD (µM)
12a
DMSO
DMSO
H2O
DMSO
H2O
H2O
DMSO
1.4 ( 0.6
1.4 ( 0.5
1.7 ( 0.2
20 ( 0.6
90 ( 10
100 ( 10
>100
12b
cisplatinum
15
5a
5b
cisplatinum
a
“DMSO” indicates that the compound has been dissolved in
DMSO and then diluted with water to a final DMSO concentration
of 0.5%.
F igu r e 3. Structure analysis of the dihydroisoquinoline 9b
in the crystal.
All our platinum(II) complexes are soluble in DMSO.
A critical factor for the solubility of the complexes is
the exchange21 of one chloride ligand by a DMSO
molecule inducing a positive charge at the metal atom.
In the biological testing, the DMSO solutions were
therefore kept for 30 min at 40 °C to allow for the ligand
exchange before water was added. This procedure
revealed different degrees of solubility. The highest
solubility was observed for the methoxy substituted
tetrahydroisoquinoline complexes 12a and 12b, whereas
the complexes 14-15 showed a reduced solubility.
Obviously, ligands with stronger basicity, e.g., tetrahy-
droisoquinolines 5, favor the displacement of chloride
by DMSO.22 Surprisingly, the phenolic complex 13
showed only a low solubility.
In clinically administered cisplatinum, the chloride
is displaced by water giving an activated aqua form of
the drug,23 whereas substitution of a chloride by DMSO
results in severely reduced cytotoxicity.24 Despite the
chloride-DMSO exchange, our compounds display a 2
times higher biological activity, in terms of cytotoxicity
and inhibition of DNA synthesis, than cisplatinum
dissolved in water,25 and they are 2 orders of magnitude
more active than cisplatinum dissolved in DMSO. The
new diamine ligands form a rigid system enclosing the
six-membered metallacycle. The most basic ligands 5
afford the biologically most potent complexes 12.
F igu r e 2. Inhibition of DNA synthesis by different plati-
num(II) complexes and the free ligands 5.
reduced cytotoxicity, which was found to be about 10
times lower than that of cisplatinum. The free ligands
5 are about 100 times less cytotoxic than the corre-
sponding platinum(II) complexes 12a and 12b.
In h ibition of DNA Syn th esis. L1210 cells were
incubated with the platinum complexes for 48 h. During
the last 6 h, [6-3H]thymidine was added to examine
DNA synthesis. IC50 values were derived from log-linear
plots of concentration effects (Table 2, Figure 2). We
found a good correlation between the IC50 values derived
from the cytotoxicity tests and those from the inhibition
of DNA synthesis.
Discu ssion
Differences in structure, leaving groups, oxidation
state, or ligands are important for the development of
alternatives for cisplatinum. Carboplatinum, the second
clinically administered platinum complex, leads to the
formation of identical platinum-DNA adducts,7 since
both compounds differ only in their leaving groups.
Our 1-(2-aminophenyl)isoquinolines represent a novel
class of platinum(II) ligands, which combine an aniline
with an isoquinoline unit. The basicity of the isoquino-
line nitrogen depends significantly on the hydrogenation
state of the pyridine ring, whereas the basicity of the
aniline nitrogen differs only slightly due to substituent
effects. Three different types of isoquinoline substruc-
tures were synthesized: aromatic isoquinolines,
3,4-dihydroisoquinolines, and 1,2,3,4-tetrahydroisoquin-
olines. The aromatic isoquinolines are probably planar
due to the intramolecular NH-N hydrogen bond. In
contrast, the tetrahydroisoquinolines 5-6 and dihy-
droisoquinolines 9-10 have a twisted structure. For
example, in the crystal structure of tetrahydroisoquino-
line 4b the interplanar angle between the isoquinoline
ring and the aniline moiety is 85°, whereas it is only
52° in dihydroisoquinoline 9b due to the formation of
an intramolecular hydrogen bond (Figure 3).20
Exp er im en ta l Section
Silica gel 60 230-400 mesh (Merck, Germany) was used for
chromatography. 1H and 13C NMR spectra were recorded on
Bruker AMX 600, ARX 300, WH-90, and J EOL EX-400
instruments. 1H and 13C chemical shifts are given with respect
to TMS or the solvent as internal standard. 13C NMR signals
for the solvolysis products of the platinum complexes 12-15
are also given, if there was no certain assignment possible.
The symbols #, †, and ‡ indicate an interchangeable assign-
ment of NMR signals. IR spectra were measured on a Nicolet
520 FT-IR. An interchangeable assignment of IR absorption
is indicated by an asterisk (*). C, H, N, Br analyses were
performed by the microanalytical laboratories of our institutes.
X-ray structure analyses [measured with Enraf Nonius CAD4
MACH3; solution and refinement with SHELXS-86 and
SHELXL-93] are shown as ORTEP plots. The full data of the
X-ray crystal structures have been deposited at the Cambridge

Synthesis of 1-(2-Aminophenyl)isoquinolines
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 18 3481
2
Crystallographic Data Centre. Mass spectra were measured
with a Finnigan MAT 95Q sector mass spectrometer using EI
at 70 eV.
157.36 (q, J CF ) 36.8 Hz, COCF3); EI-MS m/z (%) ) 476 (33)
[M+], 380 (15), 379 (73), 365 (20), 364 (100), 288 (10); HR-EI-
MS calcd for C22H20F6N2O5 476.1171, found 476.1182. Anal.
(C21H18F6N2O4) C, H, N.
N-[2-(3,4-Dim et h oxyp h en yl)et h yl]-2-(t r iflu or oa cet yl-
am in o)ben zyliden im in e (3a). A mixture of 2-(trifluoroacetyl-
amino)benzaldehyde (2a )26 (2.17 g, 10.0 mmol), homoveratryl-
amine (1) (1.81 g, 10.0 mmol), molecular sieve 4 Å (1.0 g), and
pyridine (15 mL) was refluxed for 36 h. After filtration, the
filtrate was concentrated under reduced pressure and the
resulting residue subjected to flash chromatography (SiO2;
EtOAc/hexanes, 2:3) to yield imine 3a (3.65 g, 96%) as a yellow
solid. Recrystallization from EtOH afforded 3.00 g (78%) of
yellow needles: mp 116.5 °C; IR (KBr) 2940 (m), 2850 (m),
1720 (s), 1650 (s), 1620 (s), 1600 (s), 1560 (s), 1520 (s), 1480
(s), 1430 (w), 1350 (w), 1300 (m), 1270 (m), 1240 (m), 1150
6,7-Dim eth oxy-1-[5-m eth oxy-2-(tr iflu or oa cetyla m in o)-
p h e n yl]-2-t r iflu or oa ce t yl-1,2,3,4-t e t r a h yd r oisoq u in o-
lin e (4b). Isoquinoline 4b was prepared from benzylidenimine
3b (1.80 g, 4.45 mmol) according to the procedure described
for 4a . Flash chromatography (SiO2; EtOAc/hexanes, 1:1) gave
4b (1.94 g, 86%) as a yellow solid: mp 156 °C; IR (KBr) 3441
(s br), 1726 (s), 1700 (m), 1676 (s), 1521 (s), 1465 (m), 1368
(m), 1281 (m), 1255 (s), 1219 (s), 1179 (m), 1154 (s), 1121 (m)
cm-1; 1H NMR (300 MHz, CDCl3) δ 2.89 (dd, J ) 16.3, 2.4 Hz,
1H, 4-HR), 3.10 (ddd, J ) 17.1, 12.4, 5.3 Hz, 1H, 4-Hâ), 3.71
(ddd, 1H, 3-HR), 3.70 (s, 3H, OCH3), 3.73 (s, 3H, OCH3), 3.89
(s, 3H, OCH3), 4.08 (dd, J ) 14.8, 4.5 Hz, 1H, 3-Hâ), 6.22 (s,
1H, 5-H#), 6.46 (s, 1H, 1-H), 6.54 (d, J ) 3.2 Hz, 1H, 6′-H),
6.64 (s, 1H, 8-H#), 6.94 (dd, J ) 8.8, 3.0 Hz, 1H, 4′-H), 7.85 (d,
J ) 8.8 Hz, 1H, 3-H), 10.47 (s, 1H, NHCOCF3); 13C NMR (151
MHz, CDCl3) δ 28.48 (C-4), 39.74 (C-3), 53.01 (C-1), 55.53
(OCH3), 55.98 (OCH3), 56.16 (OCH3), 110.72 (C-8#), 110.74 (C-
1
(m), 880 (w) cm-1; H NMR (300 MHz, CDCl3) δ 2.97 (t, J )
7.1 Hz, 2H, ArCH2), 3.78 (s, 3H, OCH3), 3.82 (s, 3H, OCH3),
3.85 (td, J ) 7.1, 1.1 Hz, 2H, CH2N), 6.66 (d, J ) 1.9 Hz, 1H,
2′-H), 6.70 (dd, J ) 8.1, 1.9 Hz, 1H, 6′-H), 6.76 (d, J ) 8.1 Hz,
1H, 5′-H), 7.19 (ddd, J ) 8.2, 7.4, 1.1 Hz, 1H, 5-H), 7.30 (dd,
J ) 7.7, 1.7 Hz, 1H, 6-H), 7.43 (ddd, J ) 8.2, 7.7, 1.9 Hz, 1H,
4-H), 8.16 (s, 1H, CHdN), 8.63 (d, J ) 8.4 Hz, 1H, 3-H), 14.35
(s, 1H, NHCOCF3); 13C NMR (76 MHz, CDCl3) δ 36.65 (ArCH2),
55.68 (OCH3), 55.84 (OCH3), 62.45 (CH2N), 111.31, 112.09,
5#), 113.34 (CH), 116.23 (q, J CF ) 288.3 Hz, CF3), 116.38 (q,
1
1J CF ) 287.5 Hz, CF3), 117.35 (CH), 124.57 (C), 124.98 (C),
126.53 (CH), 126.69 (C), 134.25 (C-2′), 148.75 (C-7†), 148.90
1
2
2
116.01 (q, J CF ) 288.9 Hz, CF3), 120.25, 120.68, 121.52,
(C-6†), 156.51 (q, J CF ) 37.0 Hz, COCF3), 157.29 (q, J CF
)
124.58, 131.56, 131.64, 132.91, 137.75, 147.56, 148.80, 155.68
(q, 2J CF ) 37.6 Hz, COCF3), 164.20 (CdN); FAB-MS m/z (%) )
381 (100) [M+ + H], 380 (50), 289 (14). Anal. (C19H19F3N2O3)
C, H, N.
37.1 Hz, COCF3), 157.79 (C-5′); EI-MS m/z (%) ) 506 (24) [M+],
409 (50) [M+ - CF3 - CO], 394 (100) [M+ - NHCOCF3], 288
(6); HR-EI-MS calcd for C22H20F6N2O5 506.1276, found 506.1270.
Anal. (C22H20F6N2O5) C, H, N.
5-Meth oxy-N-[2-(3,4-dim eth oxyph en yl)eth yl]-2-(tr iflu o-
r oa cetyla m in o)ben zylid en im in e (3b). Imine 3b was pre-
pared from 5-methoxy-2-(trifluoroacetylamino)benzaldehyde
(2b) (1.49 g, 6.03 mmol) according to the procedure described
for 3a . Flash chromatography (SiO2; EtOAc/hexanes, 1:2)
afforded imine 3b (2.36 g, 95%) as a yellow solid: mp 115-
115.5 °C; IR (KBr) 3450 (m), 1715 (s, CdO), 1641 (m), 1554
(s), 1519 (s), 1468 (m), 1456 (m), 1283 (s), 1260 (s), 1239 (s),
1163 (s), 1148 (s), 1123 (m), 804 (m) cm-1; 1H NMR (300 MHz,
CDCl3) δ 2.98 (t, J ) 7.0 Hz, 2H, ArCH2), 3.79 (s, 3H, OCH3),
3.80 (s, 3H, OCH3), 3.86 (s, 3H, OCH3), 3.86 (t, J ) 6.8 Hz,
2H, CH2N), 6.67 (d, J ≈ 1.3 Hz, 1H, 2′-H), 6.71 (dd, J ) 8.3,
1.7 Hz, 1H, 6′-H), 6.78 (d, J ) 7.9 Hz, 1H, 5′-H), 6.82 (d, J )
2.9 Hz, 1H, 6-H), 6.96 (dd, J ) 9.1, 2.9 Hz, 1H, 4-H), 8.12 (s,
1H, CHdN), 8.58 (d, J ) 9.2 Hz, 1H, 3-H), 14.07 (s, 1H,
NHCOCF3); 13C NMR (75 MHz, CDCl3) δ 36.57 (ArCH2), 55.48
(OCH3), 55.63 (OCH3), 55.80 (OCH3), 62.45 (CH2N), 111.25,
1-(2-Am in oph en yl)-6,7-dim eth oxy-1,2,3,4-tetr ah ydr oiso-
qu in olin e (5a ).27 To a stirred solution of 4a (2.38 g, 5.00
mmol) in dry EtOH (25 mL) NaBH4 (1.15 g, 40.0 mmol) was
added in portions.17 After the gas evolution had ceased, the
mixture was stirred for another hour. The white precipitate
was filtered off under Ar, washed with H2O and dried in vacuo
(0.95 g of 5a , 67%, colorless solid). After the addition of acetone
(30 mL) and H2O (30 mL), the filtrate was partitioned between
H2O (150 mL) and EtOAc (150 mL). The aqueous phase was
extracted with EtOAc (2 × 150 mL), and the combined organic
layers were washed with brine (100 mL) and dried (MgSO4).
The solvent was evaporated in vacuo and the residue recrys-
tallized from MeOH to yield 5a as yellow crystals (0.31 g, 22%);
all-over yield of 5a was 1.26 g, 89%: mp 157 °C; IR (KBr) 3406
(s), 3324 (m), 3003 (w), 2948 (m), 2934 (m), 2832 (w), 1612 (s),
1580 (w), 1514 (s), 1494 (s), 1458 (s), 1406 (w), 1360 (m), 1325
(w), 1312 (m), 1260 (s), 1233 (s), 1215 (s), 1170 (w), 1154 (w),
1115 (s), 1100 (s), 1065 (w), 1032 (m), 1013 (m), 940 (w), 903
(w), 874 (w), 858 (m), 835 (m), 797 (s), 771 (s), 759 (s), 723 (m)
1
112.04, 116.18 (q, J CF ) 289.0 Hz, CF3), 116.30, 118.18,
120.63, 121.64, 122.66, 131.03, 131.50, 147.51, 148.76, 155.01
2
1
(q, J CF ) 37.2 Hz, COCF3), 156.19, 163.91 (CHdN); EI-MS
cm-1; H NMR (300 MHz, CDCl3, TMS) δ 2.71 (dt, J ) 15.7,
m/z (%) ) 410 (43) [M+], 341 (31) [M+ - CF3], 259 (24), 232
(7), 165 (20), 151 (100), 146 (12); HR-EI-MS calcd for
C20H21F3N2O4 410.1453, found 410.1453. Anal. (C20H21F3N2O4)
C, H, N.
4.4 Hz, 1H, 4-HR), 2.89-3.09 (m, 2H, 4-Hâ, 3-HR), 3.22 (dt, J
) 11.9, 5.2 Hz, 1H, 3-Hâ), 3.64 (s, 3H, OCH3), 3.86 (s, 3H,
OCH3), 4.54 (br, 2H, NH2), 5.06 (s, 1H, 1-H), 6.32 (s, 1H, 5-H#),
6.62-6.71 (m, 3H, 8-H#, 2 ArH), 6.94 (dd, J ) 7.4, 1.4 Hz, 1H),
7.10 (dt, J ) 7.6, ∼0.6 Hz, 1H); 13C NMR (75 MHz, CDCl3,
TMS) δ 29.22 (C-4), 42.52 (C-3), 55.80 (2C, 2 OCH3), 60.76 (C-
1), 109.95 (C-5#), 111.51 (C-8#), 116.65 (CH), 117.42 (CH),
127.23 (C-4R†), 127.37 (C-8R†), 128.41 (CH), 129.22 (C-1′), 130.75
(CH), 146.18 (C-2′‡), 147.28 (C-6‡), 147.70 (C-7‡); EI-MS m/z
(%) ) 284 (100) [M+], 283 (48) [M+ - H], 269 (41) [M+ - CH3],
6,7-Dim eth oxy-2-(tr iflu or oa cetyl)-1-[2-(tr iflu or oa cetyl-
am in o)ph en yl]-1,2,3,4-tetr ah ydr oisoqu in olin e (4a). A mix-
ture of benzylidenimine 3a (1.0 g, 2.63 mmol) and trifluoro-
acetic anhydride (3.0 mL, 21.4 mmol) was heated to 80 °C for
24 h. After removal of the volatiles in vacuo, flash chroma-
tography (SiO2; EtOAc/hexanes, 1:2) yielded 4a (900 mg, 72%)
as a yellow solid: mp 74.5 °C; IR (CHCl3) 3250 (s.br), 1740
(s), 1680 (s), 1615 (m), 1520 (s), 1460 (m), 1280 (m), 1260 (s),
267 (45) [M+ - NH3], 253 (16) [M+ - CH3O], 192 (36) [M+
C6H4NH2]. Anal. (C17H20N2O2) C, H, N.
-
1
1200 (s), 1160 (s), 1125 (s) cm-1; H NMR (300 MHz, CDCl3,
1-(2-Am in o-5-m et h oxyp h en yl)-6,7-d im et h oxy-1,2,3,4-
tetr a h yd r oisoqu in olin e (5b). Tetrahydroisoquinoline 4b
(240 mg, 0.474 mmol) was deprotected with NaBH4 as de-
scribed above to yield 5b (106 mg, 71%) as a yellow solid: mp
163 °C; IR (KBr) 3443 (s br, NH2), 2960 (m), 2925 (s), 2853
(m, OCH3), 1635 (s.br), 1578 (s), 1559 (m), 1504 (s), 1463 (m),
TMS) δ 2.91 (dd, J ) 16.6, 3.0 Hz, 1H, 4-HR#), 3.13 (ddd, J )
17.6, 12.3, 5.3 Hz, 1H, 4-Hâ#), 3.69 (s, 3H, OCH3), 3.69 (td, J
) 13.5, 3.3 Hz, 1H, 3-Hâ†), 3.89 (s, 3H, OCH3), 4.08 (dd, J )
14.3, 4.7 Hz, 1H, 3-HR†), 6.21 (s, 1H, 1-H‡), 6.52 (s, 1H, 5-H‡),
6.66 (s, 1H, 8-H‡), 7.03 (d, J ) 7.6 Hz, 1H), 7.17 (t, J ) 7.7 Hz,
1H), 7.42 (t, J ) 7.6 Hz, 1H), 7.99 (d, J ) 8.3 Hz, 1H), 10.74
(s, 1H, NHCOCF3); 13C NMR (75.5 MHz, CDCl3) δ 28.46 (C-
4), 39.59 (C-3), 52.98 (C-1), 55.92 (OCH3), 56.12 (OCH3), 110.63
(2C, C-5, C-8), 116.08 (q, 1J CF ) 288.0 Hz, CF3), 116.34 (q, 1J CF
) 287.6 Hz, CF3), 124.68 (C-4R#), 124.79 (CH), 125.03 (C-8R#),
126.54 (CH), 129.52 (CH), 130.74 (CH), 132.02 (C), 133.90 (C),
148.62 (C-7†), 148.80 (C-6†), 156.43 (q, 2J CF ) 37.8 Hz, COCF3),
1283 (m), 1214 (m), 1121 (m), 1036 (m), 1025 (m) cm-1 1H
;
NMR (400 MHz, CDCl3) δ 2.71 (m, 1H, 4-HR#), 2.86-2.94 (m,
1H, 4-Hâ#), 3.00-3.06 (m, 1H, 3-HR†), 3.14-3.20 (m, 1H, 3-Hâ†),
3.65 (s, 3H, OCH3), 3.69 (s, 3H, OCH3), 3.85 (s, 3H, OCH3),
5.07 (s, 1H, 1-H), 6.33 (s, 1H, 8-H‡), 6.52 (d, J ) 2.0 Hz, 1H,
6′-H), 6.59-6.61 (m, 2H, 5-H‡, 3′-H), 6.68 (dd, J ) 8.4, 2.4 Hz,
4′-H); 13C NMR (100 MHz, CDCl3) δ 28.87 (C-4), 41.93 (C-3),

3482 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 18
von Nussbaum et al.
55.73 (OCH3), 55.78 (OCH3), 55.83 (OCH3), 59.90 (C-1), 109.97
(CH), 111.46 (CH), 113.27, 117.18, 127.08, 128.45, 128.91,
139.60, 147.30 (C), 147.78 (C), 147.78 (C), 152.01 (C); EI-MS
NMR (23 MHz, CDCl3) δ 25.5 (C-4), 47.7 (C-3), 56.1 (OCH3),
56.2 (OCH3), 109.6 (CH), 110.7 (CH), 121.5 (C), 124.5 (CH),
129.8 (CH), 131.2 (CH), 131.7 (C), 133.5 (CH), 134.7 (C), 147.7
(C), 148.7 (C), 151.7 (C), 164.6 (C).
m/z (%) ) 314 (56) [M+], 313 (41) [M+ - H], 299 (38) [M+
-
CH3], 297 (44) [M+ - NH3], 283 (23) [M+ - CH3O], 266 (30),
192 (36) [M+ - CH3O(C6H3)NH2]. Anal. (C18H22N2O3) C, N; H:
calcd, 7.05; found, 6.46.
6,7-Dim et h oxy-1-(5-m et h oxy-2-n it r op h en yl)-3,4-d ih y-
d r oisoqu in olin e (8b).16 The title compound was prepared
from amide 7b16 (64.0 g, 178 mmol) according to the general
procedure B. Recrystallization of the crude product from
acetone/hexanes/MeOH yielded a yellow powder (56.9 g,
93%): mp 138-139 °C; IR (KBr) 3035 (w), 1605 (m), 1588 (s),
1570 (m), 1515 (s), 1405 (m), 1335 (s), 1295 (m), 1265 (m), 1242
Gen er a l P r oced u r e A. A suspension of the 6,7-dimethoxy-
isoquinoline 4 or 9 (10 mmol) in 48% aqueous hydrobromic
acid (3 mL) was refluxed until TLC showed no starting
material (approximately 4-8 h). The reaction mixture was
slowly cooled to 5 °C and stirred at this temperature for
additional 12 h. The resulting yellow precipitate was filtered
under Ar, immediately washed with Et2O (3 × 5 mL) and then
dried in vacuo.
1
(s), 1122 (m), 1080 (s), 1000 (w), 752 (w) cm-1; H NMR (90
MHz, CDCl3) δ 2.83 (t, J ) 6.6 Hz, 2H), 3.58 (s, 3H, OCH3),
3.82 (t, J ) 6.6 Hz, 2H), 3.87 (s, 6H, OCH3), 6.32 (s, 1H), 6.77
(s, 1H), 6.91-7.11 (m, 2H), 8.08 (d, J ) 9.6 Hz, 1H); 13C NMR
(23 MHz, CDCl3) δ 25.5 (C-4), 46.8 (C-3), 56.2 (OCH3), 56.3
(2C, OCH3), 109.5 (CH), 110.7 (CH), 115.5 (CH), 115.7 (CH),
121.2 (C), 127.2 (CH), 131.9 (C), 136.2 (C), 141.1 (C), 147.8
(C), 152.3 (C), 163.9 (C), 165.8 (C); EI-MS m/z (%) ) 342 (100)
[M+], 312 (26), 299 (26), 281 (30), 269 (21). Anal. (C18H18N2O5)
C, H, N.
Gen er a l P r oced u r e C. A suspension of the (nitrophenyl)-
isoquinoline 8 or 11 (20.0 mmol) and SnCl2‚2H2O (120 mmol)
in dry EtOAc (250 mL)18 was refluxed until completion of the
reaction was indicated by TLC (18-36 h). To this mixture were
added with stirring H2O (60 mL) and 10 N NaOH (18 mL),
and the resulting solution was cautiously poured into satu-
rated aqueous NaHCO3 (500 mL). After extraction with EtOAc
(3 × 200 mL), the combined organic layers were filtered, dried
over MgSO4, and evaporated in vacuo.
1-(2-Am in oph en yl)-6,7-dih ydr oxy-1,2,3,4-tetr ah ydr oiso-
qu in olin e Dih yd r obr om id e (6a ). The title compound (3.09
g, 73%) was prepared from tetrahydroisoquinoline 4a (4.84 g,
10.2 mmol) according to the general procedure A: mp 274 °C
(dec); IR (KBr) 3435 (s br), 1618 (s), 1495 (s), 1457 (s), 1274
(s), 754 (m) cm-1; UV/vis (H2O): λmax (lg ꢀ) ) 227 (sh, 4.03),
287 nm (3.64); 1H NMR (600 MHz, CD3OD) δ 3.09 (dt, J )
17.4, 4.8 Hz, 1H, 4-HR), 3.25-3.31 (m, 1H, 4-Hâ), 3.62-3.65
(m, 2H, 3-HR, 3-Hâ), 5.95 (s, 1H, 1-H), 6.21, 6.77 (2 s, each 1H,
5-H, 8-H), 7.39 (dd, J ) 7.9, 1.0 Hz, 1H, 6′-H), 7.54-7.57 (m,
2H, 3′-H, 5′-H#), 7.67 (ddd, J ) 7.3, 7.1, 1.3 Hz, 1H, 4′-H#); 13
C
NMR (151 MHz, CD3OD) δ 25.68 (C-4), 42.80 (C-3), 55.71 (C-
1), 115.67 (CH), 116.33 (CH), 122.61 (C), 125.18 (C), 125.35
(CH), 130.33 (CH), 131.45 (C), 133.11 (CH), 133.37 (CH),
134.00 (br, C), 146.41 (C-6#), 147.81 (C-7#); FAB-MS m/z (%)
) 257 (7) [M+ + H]; HR-FAB-MS calcd for C15H17N2O2
257.1290, found 257.1283. Anal. (C15H18Br2N2O2) C, H, N, Br.
1-(2-Am in op h en yl)-6,7-d im eth oxy-3,4-d ih yd r oisoqu in -
olin e (9a ).28 The title compound was prepared from dihy-
droisoquinoline 8a (6.3 g, 20.0 mmol) according to the general
procedure C. The foamy crude product (4.95 g, 88%) was
recrystallized from EtOAc, providing yellow crystals: mp 129
°C; IR (KBr) 3423 (s), 2942 (m), 2927 (m), 2832 (w), 1613 (s),
1573 (m), 1557 (s), 1513 (s), 1491 (m), 1454 (m), 1358 (s), 1320
(m), 1298 (m), 1278 (s), 1256 (m), 1234 (w), 1208 (s), 1162 (w),
1111 (s) cm-1; UV/vis (CH3OH) λmax (lg ꢀ) ) 232 (4.48), 284
1-(2-Am in o-5-h yd r oxyp h en yl)-6,7-d ih yd r oxy-1,2,3,4-
tetr a h yd r oisoqu in olin e Dih yd r obr om id e (6b). The title
compound (612 mg, 71%) was prepared from tetrahydroiso-
quinoline 4b (1.00 g, 1.98 mmol) following the general proce-
dure A: mp 247 °C (dec); IR (KBr) 3388 (s br), 1608 (m), 1506
(m), 1451 (m), 1366 (m), 1275 (m), 1193 (m), 1105 (m), 868
1
(m) cm-1; H NMR (300 MHz, D2O) δ 2.95 (dt, J ) 17.4, 5.7
Hz, 1H, 4-HR#), 3.05-3.15 (m, 1H, 4-Hâ#), 3.37-3.46 (m, 1H,
3-HR†), 3.54 (dt, J ) 12.7, 6.1 Hz, 1H, 3-Hâ†), 5.66 (s, 1H, 1-H),
6.18 (s, 1H, 5-H‡), 6.61 (d, J ) 2.9 Hz, 1H, 6′-H), 6.74 (s, 1H,
8-H‡), 6.97 (dd, J ) 8.8, 2.7 Hz, 1H, 4′-H), 7.33 (d, J ) 8.7 Hz,
1H, 3′-H); 13C NMR (75 MHz, D2O) δ 25.03 (C-4), 41.58 (C-3),
54.56 (C-1), 116.06 (C-8), 116.87 (C-5), 119.43 (C-4′#), 119.93
(C-6′#), 122.85 (2C, C-4R†, C-2′), 126.13 (C-8R†), 127.53 (C-3′),
132.54 (C-1′), 144.45 (C-7‡), 145.96 (C-6‡), 158.03 (C-5′); EI-
MS m/z (%) ) 272 (1) [M+], 269 (4) [M+ - 3 H], 153 (12), 124
(49), 82 (96) [H81Br+], 81 (32) [81Br+], 80 (100) [H79Br+], 79 (31)
[79Br+]; HR-EI-MS calcd for C15H16N2O3 272.1161, found
272.1160. Anal. (C15H18Br2N2O3‚11/2H2O) C, H, N.
1
(3.92), 311 nm (3.93); H NMR (300 MHz, CDCl3) δ 2.70 (t, J
) 7.3 Hz, 2H, ArCH2), 3.73 (s, 3H, OCH3), 3.81 (t, J ) 7.3 Hz,
2H, CH2N), 3.95 (s, 3H, OCH3), 5.12 (br, 2H, NH2), 6.67-6.78
(m, 2H), 6.75 (s, 1H), 6.82 (s, 1H), 7.15 (dd, J ) 8.1, 1.5 Hz,
1H), 7.17 (dd, J ) 6.4, 1.5 Hz, 1H); 13C NMR (76 MHz, CDCl3)
δ 25.90 (C-4), 47.14 (C-3), 56.01 (OCH3), 56.13 (OCH3), 110.13
(CH), 111.85 (CH), 116.64 (CH), 116.80 (CH), 121.61 (C),
121.99 (C), 129.83 (CH), 131.02 (CH), 132.61 (C), 146.99 (C),
147.00 (C), 150.78 (C), 166.93 (C-1); GC/EI-MS m/z (%) ) 282
(31) [M+], 281 (100) [M+ - H], 266 (12) [M+ - NH2], 251 (36)
[M+ - CH3O]; FAB-MS m/z (%) ) 283 (100) [M+ + H]; HR-
EI-MS calcd for C17H18N2O2 282.1368, found 282.1329. Anal.
(C17H18N2O2) C, H, N.
Gen er a l P r oced u r e B. POCl3 (128 mL) was added drop-
wise to a stirred solution of N-phenylethyl-2-nitrobenzamide
7 (200 mmol) in dry CH3CN (800 mL), and the stirring was
continued for 1 h at room temperature. The resulting mixture
was refluxed for approximately 5 h until all starting material
had been consumed (TLC monitoring). After removal of the
solvent in vacuo, CHCl3 (400 mL) and H2O (400 mL) were
added, and the aqueous phase was adjusted with aqueous 10
N NaOH to pH 12. The organic layer was washed with
saturated aqueous NaHCO3 (4 × 100 mL), dried over anhy-
drous Na2SO4, and concentrated under reduced pressure. The
isoquinolines 13 precipitate on addition of Et2O.
6,7-Dim eth oxy-1-(2-n itr op h en yl)-3,4-d ih yd r oisoqu in o-
lin e (8a ).28 The title compound was prepared from amide 7a 29
(66.1 g, 200 mmol) according to general procedure B. Recrys-
tallization of the crude product from acetone/hexanes yielded
8a as a yellow solid (60.2 g, 96%): mp 117-118 °C; IR (KBr)
3000 (w), 1618 (m), 1575 (s), 1540 (s), 1470 (m), 1360 (s), 1330
(m), 1290 (s), 1275 (s), 1240 (w), 1210 (s), 1130 (s), 1090 (w),
1030 (m), 995 (w), 720 (w), 702 (w), 693 (w), 616 (w) cm-1; 1H
NMR (90 MHz, CDCl3) δ 2.79 (t, J ) 7.8 Hz, 2H), 3.62 (s, 3H,
OCH3), 3.83 (t, J ) 7.8 Hz, 2H), 3.88 (s, 3H, OCH3), 6.33 (s,
1H), 6.77 (s, 1H), 7.43-7.83 (m, 3H), 7.97-8.17 (m, 1H); 13C
1-(2-Am in o-5-m eth oxyp h en yl)-6,7-d im eth oxy-3,4-d ih y-
d r oisoqu in olin e (9b). The title compound (5.12 g, 94%) was
prepared from dihydroisoquinoline 8b (6.0 g, 17.5 mmol)
according to the general procedure C. Flash chromatography
(SiO2; CHCl3/MeOH, 10:1) of the crude product afforded 9b
(4.03 g, 74%) as an orange solid, which yielded yellow crystals
on recrystallization from EtOAc: mp 108 °C; UV/vis (MeOH)
λmax (lg ꢀ) ) 233 (4.48), 286 (3.86), 314 nm (3.94); IR (KBr)
3402 (br), 2999 (w), 2931 (m), 2832 (w), 1602 (s), 1557 (s), 1511
(s), 1498 (s), 1467 (m), 1414 (w), 1357 (s), 1319 (m), 1280 (s),
1229 (s), 1206 (s), 1166 (m), 1110 (s), 1043 (m), 1003 (w), 956
(w), 870 (m), 820 (w), 802 (w), 756 (w), 676 (w), 643 (w) 622
1
(w), cm-1; H NMR (300 MHz, [D6]DMSO) δ 2.63 (t, J ) 7.3
Hz, 2H, ArCH2), 3.58 (s, 3H, OCH3), 3.60 (s, 3H, OCH3), 3.68
(t, J ) 7.1 Hz, 2H, CH2N), 3.82 (s, 3H, OCH3), 5.33 (s, 2H,
NH2), 6.63-6.79 (m, 4H), 6.95 (s, 1H); 13C NMR (75 MHz, [D6]-
DMSO) δ 25.28 (C-4), 46.90 (C-3), 55.60 (OCH3), 55.89 (OCH3),
55.90 (OCH3), 111.10 (C-5#), 111.57 (C-8#), 114.75, 116.95,
117.46 (3 × 1C, C-3′, C-4′, C-6′), 121.15 (C), 121.30 (C), 132.46
(C), 141.89 (C), 146.79 (C), 149.72 (C), 150.87 (C), 165.62 (C-
1); GC/EI-MS m/z (%) ) 312 (43) [M+], 311 (100) [M+ - H],
296 (12) [M+ - NH2], 281 (28) [M+ - OCH3], 267 (8), 238 (3);

Synthesis of 1-(2-Aminophenyl)isoquinolines
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 18 3483
HR-EI-MS calcd for C18H20N2O3 282.1368, found 282.1329.
Anal. (C18H20N2O3) C, H, N.
1220 (m), 1197 (m), 1156 (m), 1113 (m), 914 (w), 879 (m) cm-1
1H NMR (300 MHz, CD3OD) δ 3.29 (m, 2H, 4-HR, 4-Hâ), 4.08-
4.13 (m, 2H, 3-HR, 3-Hâ), 6.73 (s, 1H, 5-H), 7.00 (s, 1H, 8-H),
7.14 (d, J ) 2.8 Hz, 1H, 6′-H), 7.28 (dd, J ) 8.8, 2.8 Hz, 1H,
4′-H), 7.54 (d, J ) 8.8 Hz, 1H, 3′-H); 13C NMR (75 MHz, [D6]-
DMSO) δ 25.89 (C-4), 43.52 (C-3), 117.39 (CH), 117.96 (C),
119.32 (CH), 120.19 (CH), 121.12 (C), 121.75 (CH), 128.02 (C),
128.23 (C), 136.35 (C), 147.17 (C), 158.73 (C), 159.81 (C),
;
Gen er a l P r oced u r e D. To a refluxing solution of the
dihydroisoquinoline 8 (10.0 mmol) in dry benzene was added
every 30-50 min a portion of activated MnO2 (1.0 g) (Dean-
Stark apparatus). After TLC indicated the completion of the
reaction (8-10 h), the hot reaction mixture was filtered, and
the filter cake was washed with hot CHCl3 (5 × 100 mL). The
combined filtrates were dried (Na2SO4) and the remaining
particles of MnO2 removed by filtration over Celite. Evapora-
tion of the solvent yielded the isoquinolines 11 as yellow oils
that crystallized on addition of Et2O.
170.75 (C-1); EI-MS m/z (%) ) 270 (28) [M+], 269 (100) [M+
-
H], 253 (15) [M+ - NH3]; HR-EI-MS calcd for C15H14N2O3
270.1004, found 270.0996.
Gen er a l P r oced u r e E. The amines used as ligands were
dissolved at 60 °C in 0.05 M HCl (5 mL). Hydrobromide 6a
was used directly as H2O solution. After addition of the
equimolar amount of K2PtCl4, the mixture was neutralized
slowly with 1 M NaOH to pH 6. The complexes precipitated
out, were washed twice with H2O and once with EtOH, and
were dried.
6,7-Dim eth oxy-1-(2-n itr oph en yl)isoqu in olin e (11a). The
title compound was prepared from isoquinoline 7a (50 g, 160
mmol) by the general procedure D. Recrystallization of the
crude product from Et2O/acetone/hexanes provided 11a (43.87
g, 88%) as a colorless solid: mp 170-171 °C; IR (KBr) 3050
(w), 2980 (w), 2870 (w), 1635 (m), 1575 (s), 1540 (s), 1518 (s),
1503 (m), 1490 (s), 1443 (s), 1430 (s), 1375 (s), 1360 (m), 1300
[1-(2-Am in oph en yl)-6,7-dim eth oxy-1,2,3,4-tetr ah ydr oiso-
qu in olin e]d ich lor op la tin u m (II) (12a ). The title compound
(148 mg, 68%) was prepared from tetrahydroisoquinoline 5a
(100 mg, 0.396 mmol), 1 M HCl (0.80 mL), K2PtCl4 (168 mg,
0.396 mmol), and 1 M NaOH (0.80 mL) according to the
general procedure E: mp > 200 °C (dec); IR (KBr) 3477 (br,
υ-NH2), 3228 (m), 3197 (m), 3158 (m), 3107 (m), 3072 (sh), 2963
(m), 2932 (m), 2835 (m, OCH3), 1613 (s), 1516 (s, NH), 1498
(m), 1458 (s), 1365 (m), 1323 (m), 1260 (s), 1237 (s), 1221 (m),
1119 (m), 1010 (m), 877 (m, F-NH2), 813 (m), 779 (sh), 768 (m),
(m), 1265 (s), 1243 (s), 1230 (s), 1145 (s), 870 (s), 753 (s) cm-1
;
1H NMR (90 MHz, CDCl3) δ 3.76 (s, 3H, OCH3), 3.97 (s, 3H,
OCH3), 6.86 (s, 1H), 7.12 (s, 1H), 7.42-7.85 (m, 4H), 8.00-
8.25 (m, 1H), 8.40 (d, J ) 6.0 Hz, 1H); 13C NMR (23 MHz,
CDCl3) δ 55.9 (OCH3), 56.2 (OCH3), 103.8 (CH), 105.4 (CH),
119.6 (CH), 122.8 (C), 124.7 (CH), 129.5 (CH), 132.2 (CH),
133.1 (CH), 133.4 (C), 135.1 (C), 141.4 (CH), 149.4 (C), 150.7
(C), 153.1 (C), 154.7 (C); EI-MS m/z (%) ) 311 (19) [M+ + 1],
310 (100) [M+], 279 (6), 264 (15), 249 (31), 220 (14), 191 (8);
HR-EI-MS calcd for C17H14N2O4 310.0954, found 310.0927.
Anal. (C17H14N2O4) C, H, N.
748 (sh), 328 (m, υ-Pt-Cl) cm-1 1H NMR (400 MHz, [D6]-
;
DMSO) δ 2.60 (m, 1H, 4-HR), 2.84-2.89 (m, 1H, 4-Hâ), 3.53-
3.68 (m, 2H, 3-HR, 3-Hâ), 3.77 (s, 6H, 2 OCH3), 5.42 (s, 1H,
1-H), 6.10 (d, J ) 6.8 Hz, 1H, 5-H#), 6.26-6.35 (m, 2H, NH2),
6.82 (s, 2H, ArH), 7.31 (t, J ) 7.2 Hz, 2H, ArH), 7.50 (d, J )
7.6 Hz, 1H, ArH); 13C NMR (100 MHz, [D6]DMSO) δ 27.97 (C-
4), 44.87 (C-3), 56.04 (2C, OCH3), 58.85 (C-1), 110.98 (C-5#),
112.59 (C-8#), 122.35 (C), 124.72 (C), 125.86 (CH), 126.76 (CH),
129.70 (C), 130.13 (CH), 131.57 (CH), 147.89 (C-2′‡), 148.99
(C-6‡), 149.50 (C-7‡). Anal. (C17H20Cl2N2O2Pt) C, H, N.
1-(2-Am in op h en yl)-6,7-d im eth oxyisoqu in olin e (Liga n d
of 15). The title compound was prepared from isoquinoline
11a (6.51 g, 21.0 mmol) according to the general procedure C.
Flash chromatography (SiO2; CHCl3/MeOH, 20:1) of the crude
product yielded 1-(2-aminophenyl)-6,7-dimethoxyisoquinoline
(3.25 g, 55%) as a colorless solid: mp 163-167 °C; IR (KBr)
3468 (m), 1620 (s), 1558 (m), 1508 (s), 1496 (s), 1433 (m), 1417
(m), 1350 (w), 1313 (w), 1255 (s), 1235 (s), 1120 (m), 1034 (w),
1
1008 (w), 865 (m), 749 (m) cm-1; H NMR (400 MHz, CDCl3)
[1-(2-Am in o-5-m eth oxyp h en yl)-6,7-d im eth oxy-1,2,3,4-
tetr a h yd r oisoqu in olin e]d ich lor op la tin u m (II) (12b). The
title compound (144 mg, 78%) was prepared from tetrahy-
droisoquinoline 5b (100 mg, 0.318 mmol), 1 M HCl (0.64 mL),
K2PtCl4 (132 mg, 0.318 mmol), and 1 M NaOH (0.64 mL)
according to the general procedure E: mp > 200 °C (dec); IR
(KBr) 3466 (s br, υ-NH2), 3205 (s), 3131 (s), 3006 (s), 2934 (s),
2835 (s, OCH3), 1610 (s), 1516 (s, δ-NH2), 1503 (s), 1463 (s),
1434 (s), 1366 (m), 1288 (s), 1267 (s), 1260 (s), 1234 (s), 1216
(s), 1187 (s), 1165 (s), 1031 (s), 1009 (s), 862 (m, F-NH2), 825
(m), 780 (s), 335 (m, υ-Pt-Cl*), 325 (sh, υ-Pt-N*) cm-1; 1H NMR
(400 MHz, [D6]DMSO) δ 2.60-2.53 (m, 1H, 4-HR), 2.85-2.65
(m, 1H, 4-Hâ), 3.50-3.75 (m, 2H, 3-HR, 3-Hâ), 3.76 (s, 6H, 2
OCH3), 5.36 (s, 1H, 1-H), 6.0-5.8 (m, 1H, NH), 6.4-6.1 (m,
1H, NH), 8.4-6.6 (m, CH), 10.2-9.2 (m, 1H, NH); 13C NMR
(100 MHz, [D6]DMSO) δ 28.00 (C-4), 44.95 (C-3), 56.08 (OCH3),
56.09 (OCH3), 56.18 (OCH3), 58.95 (C-1), 110.94, 111.62,
112.01, 112.60, 113.40, 116.46, 118.83, 123.63, 124.62, 125.70,
125.82, 126.39, 130.25, 134.50, 147.58, 147.91, 148.05, 149.04,
149.15, 149.53, 149.58, 157.25, 157.44. Anal. (C18H22Cl2N2O3-
Pt) C, H, N.
[1-(2-Am in oph en yl)-6,7-dih ydr oxy-1,2,3,4-tetr ah ydr oiso-
qu in olin e]d ich lor op la tin u m (II) (13). The title compound
(76 mg, 61%) was prepared from tetrahydroisoquinoline di-
hydrobromide 6a (100 mg, 0.239 mmol), K2PtCl4 (100 mg,
0.239 mmol), and 1 M NaOH (0.44 mL) according to the
general procedure E: IR (KBr) 3637 (m, OH), 3467 (sh, OH),
3434 (s, υ-NH2), 3252 (s), 3172 (s), 3111 (s), 2957 (s), 2888 (sh),
2844 sh), 1620 (s), 1604 (s), 1592 (sh), 1521 (s, δ-NH), 1498
(s), 1461 (s), 1448 (s), 1360 (s), 1286 (s), 1274 (s), 1236 (s), 1225
(s), 1189 (s), 1169 (s), 1151 (s), 1114 (m), 1090 (m), 1038 (m),
869 (m, F-NH2), 857 (m), 818 (m), 787 (m), 763 (m), 328 (m.br,
υ-Pt-Cl) cm-1; 1H NMR (400 MHz, [D6]DMSO) δ 2.14 (m, 1H,
4-HR), 2.39 (m, 1H, 4-Hâ), 2.77 (m, 2H, 3-H), 5.29 (s, 1H, 1-H),
6.64-6.20 (m, 3H, NH), 7.01-7.79 (m, 6H), 8.86-9.14 (m, 2H,
OH); 13C NMR (100 MHz, [D6]DMSO) δ 27.72 (C-4), 44.93 (C-
δ 3.76 (s, 3H, OCH3), 3.94 (s, 3H, OCH3), 4.23 (s br, 2H, NH2),
7.00-7.05 (m, 2H), 7.02 (s, 1H), 7.17 (ddd, J ) 8.0, 7.2, 1.3
Hz, 1H), 7.22 (s, 1H), 7.25 (dd, J ) 7.9, 1.6 Hz, 1H), 7.41 (d, J
) 5.7 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 55.64 (OCH3),
55.83 (OCH3), 104.72, 105.54, 116.60, 117.56, 118.53, 122.96,
123.86, 129.27, 130.81, 133.95, 140.77, 145.11, 149.75, 152.59,
156.83; EI-MS m/z (%) ) 280 (54) [M+], 279 (100) [M+ - H],
264 (12), 249 (9), 246 (11), 234 (16). Anal. (C17H16N2O2‚1/4CH3-
OH) C, H, N.
1-(2-Am in op h en yl)-6,7-d ih yd r oxy-3,4-d ih yd r oisoqu in -
olin e Dih yd r obr om id e (10a ). The title compound (1.38 g,
91%) was prepared from dihydroisoquinoline 9a (1.0 g, 3.54
mmol) according to general procedure A: mp 212-220 °C; UV/
vis (H2O) λmax ) 236 (4.01), 313 (3.80), 368 nm (3.80); IR (KBr)
3457 (s.br), 2851 (s), 2571 (m), 1634 (m), 1615 (m), 1574 (s),
1538 (m), 1494 (m), 1473 (m), 1453 (m), 1387 (w), 1333 (s),
1307 (s), 1252 (m), 1230 (m), 1198 (m), 1154 (m), 915 (m), 618
(m), 451 (m), 424 (w) cm-1; 1H NMR (300 MHz, D2O) δ 2.98 (t,
J ) 6.5 Hz, 2 H, 4-HR, 4-Hâ), 3.80 (t, J ) 6.5 Hz, 2H, 3-HR,
3-Hâ), 6.66 (s, 1H, 5-H), 6.81 (s, 1H, 8-H), 7.05 (d, J ) 8.5 Hz,
1H, 3′-H#), 7.08 (t, J ) 7.4 Hz, 1H, 5′-H†), 7.26 (d, J ) 7.8 Hz,
1H, 6′-H#), 7.47 (t, J ) 8.2 Hz, 1H, 4′-H†); 13C NMR (75 MHz,
D2O/CD3OD [25:1]) δ 25.54 (C-4), 42.62 (C-3), 117.11 (CH),
117.83 (C), 120.46 (C), 120.74 (CH), 121.61 (CH), 123.99 (CH),
132.02 (CH), 135.44 (CH), 136.14 (C), 140.50 (C), 145.17 (C),
156.00 (C), 172.91 (C-1); FAB-MS m/z (%) ) 255 (34) [M+
+
H]; HR-FAB-MS calcd for C15H15N2O2 255.1134, found 255.1153.
Anal. (C15H16Br2N2O2‚H2O) C, H, N, Br.
1-(2-Am in o-5-h yd r oxyp h en yl)-6,7-d ih yd r oxy-3,4-d ih y-
d r oisoqu in olin e Dih yd r obr om id e (10b). The title com-
pound (191 mg, 67%) was prepared from dihydroisoquinoline
9b (205 mg, 0.656 mmol) according to general procedure A:
mp >272 °C (dec); IR (KBr) 3428 (s br), 3120 (m br), 3040 (w),
2576 (w), 1628 (m), 1603 (m), 1615 (m), 1571 (s), 1503 (m),
1470 (m), 1435 (m), 1387 (w), 1342 (m), 1328 (m), 1305 (s),

3484 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 18
von Nussbaum et al.
3), 58.71 (C-1), 114.84 (CH), 116.12 (2C, C-5, C-8), 122.22 (C),
123.18 (C), 123.91 (CH), 124.95 (CH), 130.14 (CH), 131.72 (C),
nontreated control. The complex concentration causing 50%
growth inhibition (IC50) was derived by interpolation from a
log-linear plot of concentration-inhibition outcomes. All com-
pounds were at least tested in two independent duplicates.
Exa m in a tion of In h ibition of DNA Syn th esis. The effect
of platinum complexes upon cellular DNA synthesis was
measured as changes in thymidine incorporation. Experiments
were performed with logarithmic growth phase L1210 cells as
described above. After 42 h a solution of [6-3H]thymidine [0.5
µCi] in 20 µL of DMEM was added. Following 6 h of further
incubation, cells were harvested onto glass fiber filters and
washed two times with distilled H2O. Radioactivity on the
filters was measured using a Wallac 1450 Microbeta liquid
scintillation counter. All the data were derived from at least
two independent triplicates.
144.56 (C-2′‡), 145.76 (C-6‡), 146.67 (C-7‡). Anal. (C15H16
Cl2N2O2Pt‚2H2O) C, N; H: calcd, 3.04; found, 3.61.
-
[1-(2-Am in oph en yl)-6,7-d im eth oxy-3,4-d ih yd r oisoqu in -
olin e]d ich lor op la tin u m (II) (14a ). The title compound (124
mg, 64%) was prepared from dihydroisoquinoline 9a (100 mg,
0.354 mmol), 1 M HCl (0.387 mL), K2PtCl4 (161 mg, 0.354
mmol), and 1 M NaOH (0.387 mL) according to the general
procedure E: mp > 200 °C (dec); IR (KBr) 3580 (sh), 3481 (s),
3452 (s, υ-NH2), 3284 (m), 3159 (m), 3089 (s), 3030 (s), 2963
(s), 2912 s), 2834 (m, OCH3), 1604 (s, CdN), 1579 (sh), 1541
(s, δ-NH), 1517 (s), 1496 (m), 1463 (s), 1453 (s), 1368 (s), 1327
(s), 1285 (s), 1273 (sh), 1215 (s), 1176 (m), 1136 (s), 1092 (m),
1040 (m), 1022 (m), 991 (m), 970 (m), 876 (m, F-NH2), 865 (sh),
803 (m), 773 (m), 483 (m), 452 (m), 332 (sh, υ-Pt-N*), 328 (m,
Ack n ow led gm en t. We thank B. Czermin for excel-
lent technical help and S. Dannhauser-Riedl for an
introduction into cell culture and invaluable advice. We
thank the Degussa AG for the donation of chemicals.
Support from the Deutsche Forschungsgemeinschaft
(SFB 369; Zo 59/4-2, -3) and the Fonds der Chemischen
Industrie is gratefully acknowledged.
1
υ-Pt-Cl*) cm-1; H NMR (400 MHz, [D6]DMSO) δ 2.90-2.74
(m, 4H, 4-H, 3-H), 3.61 (s, 3H, OCH3), 3.88 (s, 3H, OCH3), 6.68
(s, 1H, CH), 7.09 (s, 1H, CH), 7.32 (t, J ) 7.6 Hz, 1H, CH),
7.41 (d, J ) 7.5 Hz, 1H, CH), 7.49 (d, J ) 7.8 Hz, 1H, CH),
7.59 (t, J ) 7.5 Hz, 1H, CH); 13C NMR (100 MHz, [D6]DMSO)
δ 26.54 (C-4), 53.14 (C-3), 56.37 (OCH3), 56.55 (OCH3), 111.43
(C-5#), 114.21 (C-8#), 120.31, 120.58, 125.33, 131.33, 132.47,
133.22, 133.83 (7 aromat. C), 140.65 (C-2′‡), 147.34 (C-6‡),
153.19 (C-7‡), 165.38 (C-1). Anal. (C17H18Cl2N2O2Pt‚1/2H2O) C,
H, N.
Su p p or tin g In for m a tion Ava ila ble: X-ray crystallo-
graphic data. This material is available free of charge via the
Internet at http://pubs.acs.org.
[1-(2-Am in o-5-m et h oxyp h en yl)-6,7-d im et h oxy-3,4-d i-
h yd r oisoqu in olin e]d ich lor op la tin u m (II) (14b). The title
compound (161 mg, 87%) was prepared from dihydroisoquino-
line 9b (100 mg, 0.320 mmol), 1 M HCl (0.6 mL), K2PtCl4 (132.9
mg, 0.320 mmol), and 1 M NaOH (0.6 mL) according to the
general procedure E: mp >200 °C (dec); IR (KBr, PE) 3578
(s), 3484 (s, υ-NH2), 3006 (s), 2934 (s), 2846 (s, OCH3), 1605
(s, CdN), 1534 (s, δ-NH), 1516 (s), 1502 (s), 1464 (s), 1422 (s),
1410 (s), 1368 (s), 1326 (s), 1285 (s), 1269 (s), 1238 (s), 1214
(s), 1189 (m), 1166 (s), 1137 (m), 1096 (s), 1032 (s), 999 (m),
972 (m), 876 (m, F-NH2), 848 (m), 838 (m), 804 (m), 331 (m,
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(m.br, υ-Pt-Cl) cm-1; H NMR (400 MHz, [D6]DMSO) δ 3.78
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