Synthesis and antimalarial activity of 7-benzylamino-1-isoquinolinamines

Article abstract of DOI:10.1002/jhet.5570440319

(Chemical Equation Presented) Computer modelling suggests that 7-benzylamino-1-isoquinolinamines should mediate antimalarial effects by a mechanism distinct from that employed by existing antimalarial drugs. A series of these compounds was prepared in sev

Full text of DOI:10.1002/jhet.5570440319

May-Jun 2007
633
Synthesis and Antimalarial Activity of 7-Benzylamino-1-
Isoquinolinamines
Clare E. Gutteridge [a],* Marshall M. Hoffman [a], Apurba K. Bhattacharjee [b]
and Lucia Gerena [b].
[a] Department of Chemistry, United States Naval Academy, Annapolis, MD 21402.
[b] Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, MD 20910.
Received July 17, 2006
N
NH
O2N
N
N
N
H
H2N
NH2
NH2
Computer modelling suggests that 7-benzylamino-1-isoquinolinamines should mediate antimalarial
effects by a mechanism distinct from that employed by existing antimalarial drugs. A series of these
compounds was prepared in seven synthetic steps, via reductive amination of 1,7-isoquinolinediamine. In
vitro efficacy testing of the novel compounds against Plasmodium falciparum revealed them to be potent
antimalarial agents.
J. Heterocyclic Chem., 44, 633 (2007).
drug resistance [13]. Using the pharmacophore and
published data describing the structural requirements for
the inhibition of dihydrofolate reductase [14-16], we sought
to design compounds with minimal inhibition of
dihydrofolate reductase, instead possessing antimalarial
activity via the chalcone-mechanism.
7-Benzylamino-1-isoquinolinamines emerged as a class
in which these goals were potentially met. It was
anticipated that these compounds would be isolated as
hydrogen chloride salts (2a-e). Though not described in
detail, the synthesis of a potential precursor to these
compounds, 1,7-isoquinolinediamine (3), has been
outlined in the patent literature [17,18].
INTRODUCTION
Each year, more than 1 million people die from malaria.
The organism responsible for most of these deaths,
Plasmodium falciparum, has developed resistance to most
available drugs [1]. Thus, there is an urgent need for novel
and affordable therapeutics. The antimalarial activity of the
chalcone class of compounds (1,3-diphenyl-2-propen-1-
ones) is well established [2-10]. Several groups have
studied the relationship between the structure of substituted
2-propen-1-ones and their antimalarial activity. Since the
emerging relationship does not correlate with that between
structure and the inhibition of any known antimalarial
target, the mechanism by which the chalcones act appears
to be distinct from the established mechanisms [7-9].
During our investigation of the relationship between 1,3-
diaryl-2-propen-1-one structure and antimalarial activity
[10], we generated a computer model of the structural and
electronic features required in such compounds to
maximize in vitro antimalarial activity [11]. When this
pharmacophore was used to screen the collection of
compounds at the Walter Reed Army Institute of Research,
it was predicted that 6-(3'-bromobenzylamino)-2,4-
quinazolinediamine (1) should also mediate antimalarial
effects by this novel chalcone-mechanism. Such
quinazolinetriamines are known to be potent antimalarials
by their inhibition of dihydrofolate reductase [12], but are
also known to be susceptible to the rapid development of
2
N
NH2
7
6
3'
N
Br
N
N
H
N
H
1
4
R
2 HCl
NH2
NH2
(1)
(2a-e)
Figure 1
This study proposes a selective reductive amination of
the 7-amino group of 1,7-isoquinolinediamine (3) to
provide the target molecules [19]. Using benzaldehyde in
this reaction, 7-benzylamino-1-isoquinolinamine (2a)
would be the expected product. This paper describes the

634
C. E. Gutteridge, M. M. Hoffman, A. K. Bhattacharjee and L. Gerena
Vol 44
synthesis of this, and several benzyl-substituted analogs
(2b-e), along with their in vitro efficacy against a multi-
drug resistant strain of P. falciparum.
isoquinoline-2-oxide (7) [18]. Subsequent reaction with
p-toluenesulfonyl
chloride
gave
1-chloro-7-nitro-
isoquinoline (8), which in turn was reacted with
ethanolamine to provide 7-nitro-1-isoquinolinamine (9)
[18]. This was purified by alumina column chroma-
tography, and then hydrogenated to give 1,7-isoquino-
linediamine (3) [17]. Full experimental details are
provided for the steps from 1,2,3,4-tetrahydro-7-nitro-
isoquinoline hydrogen chloride (5) since they are
incomplete in the available literature [17,18].
RESULTS AND DISCUSSION
Scheme 1 outlines the synthetic route developed in our
laboratory.
As previously reported, commercially
available 1,2,3,4-tetrahydroisoquinoline (4) underwent
selective nitration at C7 upon treatment with potassium
nitrate in aqueous sulfuric acid [20].
Though the
The isoquinolinediamine (3) was dissolved in acetic
acid and benzaldehyde added to generate an imine, which
was then reduced using sodium cyanoborohydride. When
the reaction was conducted using conditions described for
protonated amine would direct the electrophile to C5 or
C7, a peri hydrogen interaction at C5 ensures reaction
proceeds exclusively at C7 [21]. Purification of the
1,2,3,4-tetrahydro-7-nitro-isoquinoline was achieved by
recrystalization of the corresponding hydrogen chloride
salt (5).
Oxidation of the heterocycle to provide 7-nitro-
isoquinoline (6) was mediated by potassium nitro-
sodisulfonate in aqueous sodium carbonate [17].
Purification was by extraction of the reaction mixture into
chloroform. Depending upon the quality of the oxidizing
agent used, in some cases this extraction was followed by
alumina column chromatography. Attempts to purify the
crude product by crystallization as described in the
literature [22] were unsuccessful due to sparing
compound solubility in a range of solvents. The high cost
of the oxidant and the long reaction time required (7 days)
led us to explore the other procedure known to mediate
a
similar reaction (with 15 mole equivalents of
benzaldehyde and 30 of sodium cyanoborohydride [19])
NMR analysis of the crude product suggested a small
amount of dialkylation had occurred. When the quantity
of reagent was decreased (to 2 mole equivalents of
benzaldehyde and 3 of sodium cyanoborohydride) only
the desired 7-benzylamino-1-isoquinolinamine was
formed. Selective alkylation of the 7-amino over the 1-
amino group would be expected upon electronic grounds.
Preparation of the corresponding salt (2a) afforded
material which was easily handled.
Four other 7-benzylamino-1-isoquinolinamine salts
(2b-e), substituted on the benzyl group, were prepared
similarly from the corresponding substituted benzal-
dehydes. For this initial series halogen substituents, at
the 3- and 4- positions, were explored since such
substituents are potency enhancing in the chalcone
series [4]. The yield for the key reductive amination
step in each case is shown in Table 1. All are isolated
yields following alumina column chromatography,
which was performed in such a way to maximize purity
of isolated material, not yield. The yield of crude
this reaction.
Though reaction of the tetrahydro-
isoquinoline (5) with iodine and potassium acetate did
furnish 7-nitro-isoquinoline (6) [22], complete removal of
the side-products from the reaction mixture by alumina
column chromatography proved impossible.
Installation of the 1-amino group was carried out in
three synthetic steps. Treatment of 7-nitro-isoquinoline
(6) with m-chloroperbenzoic acid in acetone gave 7-nitro-
Scheme 1
[a]
[b]
[c]
N
N
NH
O2N
NH.HCl
O2N
O2N
O
(4)
(5)
(6)
(7)
[d]
[f]
[g]
[e]
N
N
N
N
N
H2N
O2N
O2N
R
H
2 HCl
NH2
NH2
NH2
Cl
(2a-e)
(3)
(9)
(8)
[a] KNO3, H2SO4, H2O; HCl, EtOH. [b] (KSO3)2NO, Na2CO3, H2O. [c] m-Chloroperbenzoic acid, acetone. [d] p-Toluenesulfonyl chloride,
pyridine. [e] Ethanolamine. [f] H2, Pd/C, MeOH. [g] R-C6H5CHO, acetic acid; NaBH3CN, tetrahydrofuran; HCl, ethanol. R = H (2a), 3-Cl (2b),
4-Cl (2c), 3-Br (2d), 3,4-Cl2 (2e).

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Synthesis and Antimalarial Activity of 7-Benzylamino-1-Isoquinolinamines
635
Table 1
Physical, Analytical and Biological Data for Compounds 2a-e
N
NH2
x H2O
N
R
H
2 HCl
Cmpd.
R
Yield
% [a]
Mp
Molecular Formula
Analysis %
Mass of MH+
Inhibition of P.
(°C) [b]
Calcd./Found
H
Calcd./Found
falciparum [d]
(IC50 μM)
0.49
C
N
[c]
250
250
284
284
284
284
328
328
318
318
-
2a
2b
2c
2d
2e
H
86
49
60
22
49
-
160-165 dec.
176-181 dec.
170-175 dec.
207-215 dec.
200-205 dec.
-
C16H16ClN3 • 2 HCl • 0.3 H2O
C16H15Cl2N3 • 2 HCl • 0.65 H2O
C16H15Cl2N3 • 2 HCl • 0.37 H2O
C16H15BrClN3 • 2 HCl • 0.8 H2O
C16H14Cl3N3 • 2 HCl • 0.9 H2O
-
58.65
58.87
52.17
52.57
52.89
53.29
46.25
46.61
47.18
46.95
-
5.41
5.35
4.73
4.69
4.64
4.74
4.27
4.35
4.16
3.78
-
12.83
12.46
11.41
10.98
11.56
11.16
10.11
9.73
3-Cl
0.21
4-Cl
0.14
3-Br
3,4-Cl2
0.16
10.32
10.12
-
0.072
0.071
Chloroquine
[a] Of reductive amination step. [b] Precipitated from ethanolic hydrogen chloride solution. [c] Calcd. is molecular weight of MH+ for the free base
and Found is m/z for the molecular ion. [d] Inhibition of [3H] hypoxanthine uptake by P. falciparum TM91C235.
These compounds are potent enough to be considered
for further development if the mechanism by which they
act is found to be distinct from those employed by other
antimalarial agents. Future studies will use the synthetic
route described herein to prepare additional analogs. This
will allow continued exploration of the structure-activity
relationships for the 7-benzylamino-1-isoquinolinamines
against malaria. The most potent compounds will be
tested in an animal model of malaria. Determination of
the mechanism by which they act will be crucial to assess
their potential for development against drug-resistant
malaria. Measurement of their activity against a panel of
P falciparum strains resistant to standard antimalarial
drugs will provide some information in this area.
product in each case was significantly higher (especially
of 2b, d, e).
All the analytical and spectroscopic data obtained (ir,
nmr, ms) were in full agreement with the structures
targeted (Table 1). Elemental analysis showed that the
salts contain two equivalents of hydrogen chloride with
a variable amount of water [23].
Attempts to
completely dry the salts were unsuccessful:
discoloration occurred even upon moderate heating.
When this hydration is taken into account the elemental
analyses for carbon, hydrogen and nitrogen for all
analogs agree with the theoretical value to within 0.4%
except that the nitrogen content of the 3-chloro analog
(2b) agrees to 0.42%.
The in vitro antimalarial activity of the novel
compounds was determined using a standard assay which
measures the ability of the compound to inhibit the uptake
of [3H]-hypoxanthine by P. falciparium [4].
EXPERIMENTAL
Reagents were obtained from Acros and Aldrich. Analytical
TLC was performed using Basic Alumina Selectro Flexible-
Backed TLC plates (Fisher). Liquid chromatography was
performed using 50-200 μm activated neutral aluminum oxide
(Fisher). Visualization of the developed chromatogram was by
UV absorbance. Melting points were determined on an
Electrothermal Mel-Temp melting point apparatus and are
uncorrected. IR spectra were recorded on a Thermo Electron
Corporation IR100 Spectrometer. 1H NMR spectra were
The parasite used for this test was a multi-drug resistant
isolate from Southeast Asia, TM91C235.
All five
compounds were found to inhibit the parasite at
submicromolar concentrations, the best possessing
activity comparable to chloroquine (Table 1). The data
suggest that both the 3- and the 4-halo substituent on the
benzyl group contribute to this activity.

636
C. E. Gutteridge, M. M. Hoffman, A. K. Bhattacharjee and L. Gerena
Vol 44
recorded on a Jeol ECX 400 MHz spectrometer. Mass spectra
were recorded on a Shimadzu QP-2010S GC/MS or an Agilent
1100/Waters Micromass ZQ LC/MS fitted with a Waters Xterra
MS-C18 column, both operating in electrospray positive ion
mode. Combustion analyses were performed by Atlantic
Microlab, Inc. (Norcross, GA).
1,2,3,4-Tetrahydro-7-nitro-isoquinoline hydrogen chloride
(5). Commercially available 1,2,3,4-tetrahydroisoquinoline (4)
was reacted with potassium nitrate in sulfuric acid [20] to
2.4, 9.2 Hz), 8.14 (d, 1H, 3-H, J = 5.6 Hz), 7.83 (d, 1H, 5-H, J =
9.2 Hz), 7.12 (d, 1H, 4-H, J = 5.6 Hz), 5.43 ppm (br, 2H, NH);
ms: m/z 190 (MH+).
1,7-Isoquinolinediamine (3). 10% Palladium on carbon
(105 mg) suspended in methanol (3 mL) was added to a
solution of compound (9) (260 mg, 1.38 mmol) in methanol
(100 mL) [17]. The flask was evacuated, and then connected
to
a
balloon containing hydrogen gas.
After stirring
vigorously for 15 h, the reaction mixture was filtered through
Celite®. Removal of the solvent by evaporation under
reduced pressure gave 1,7-isoquinolinediamine (3) as a pale
yellow solid (254 mg, quantitative), mp 191-195° dec.; ir:
3548, 3486, 3389, 3281, 1663, 1595, 1550 cm-1; 1H nmr
(deuteriochloroform): ꢀ 7.75 (d, 1H, 3-H, J = 6.0 Hz), 7.54 (d,
1H, 5-H, J = 8.8 Hz), 7.07 (dd, 1H, 6-H, J = 2.4, 8.8 Hz), 6.95
(d, 1H, 4-H, J = 5.6 Hz), 6.91 (d, 1H, 8-H, J = 2.4), 4.91 (br,
2H, NH), 3.93 ppm (br, 2H, NH); ms: m/z 160 (MH+).
General Procedure for the Reaction of Benzaldehydes
with 1,7-isoquinolinediamine (3) [19]. Compound (3) was
dissolved in acetic acid (1.65 mL), the requisite benzaldehyde
was added, and the reaction was allowed to stir at room
temperature for 30 min. Sodium cyanoborohydride (1.65 mL, 1
M THF solution) was added and the reaction stirred for 3 h. The
mixture was poured into ice water, the pH adjusted to 11 by
addition of 10% aqueous sodium hydroxide solution and then
extracted into ethyl acetate (3 x 100 mL). Alumina column
chromatography (eluting with 5% methanol in ethyl acetate)
afforded the corresponding 7-benzylamino-1-isoquinolinamine.
Following dissolution of this compound in ethanol, a saturated
ethanolic solution of hydrogen chloride (4 mL) was added.
After stirring for a few minutes the solvent was removed by
evaporation under reduced pressure to give the corresponding
hydrogen chloride salt (2a-e). Each salt was dried at 50°C under
reduced pressure for 24 h.
7-Benzylamino-1-isoquinolinamine•2HCl•0.3H2O (2a). The
general procedure described above was carried out beginning
with compound (3) (88 mg, 0.55 mmol) and using benzaldehyde
(112 μL, 1.10 mmol) to afford 7-benzylamino-1-isoquinolin-
amine•2HCl•0.3H2O (2a) as a yellow solid (135.3 mg, 86%), mp
160-165° dec.; ir: 3168, 2964, 2701, 2600, 2470, 1698, 1661,
1613, 1542 cm-1; 1H nmr (deuteriodimethylsufoxide): ꢀ 8.70
(2H, br); 7.61 (1H, d, J = 8.4 Hz); 7.40-7.18 (7H, m); 7.21 (1H,
m); 6.99 (1H, d, J = 7.2 Hz); 4.39 ppm (2H, s); ms: m/z 250
(MH+). Anal. Calcd. for C16H16ClN3•2HCl•0.3H2O: C, 58.65; H,
5.41; N, 12.83. Found: C, 58.87; H, 5.35; N, 12.46.
produce
1,2,3,4-tetrahydro-7-nitro-isoquinoline
hydrogen
chloride (5) as a white solid, mp 236-240° from methanol (lit.
214-216° [20]). Anal. Calcd. for C9H11ClN2O2: C, 50.36; H,
5.17; N, 13.05. Found: C, 50.44; H, 5.11; N, 13.10.
7-Nitro-isoquinoline (6). Compound (5) (2.16 g, 10 mmol)
was added to a solution of potassium nitrosodisulfonate (30.1 g,
112 mmol) in 4% aqueous sodium carbonate solution (450 mL)
[17]. The dark purple reaction mixture was allowed to stir for 7
d, and then extracted with chloroform (3 x 500 mL). The
combined organic layers were washed with saturated aqueous
sodium chloride solution (200 mL) and dried over anhydrous
sodium sulfate. Following filtration, the solvent was removed
by evaporation under reduced pressure. The residue was
purified by alumina column chromatography (eluting with 10%
v/v hexane in ethyl acetate) to give 7-nitro-isoquinoline (6) as an
off-white solid (0.532 g, 30%), mp 168-169° (lit. 176-177°
1
[22]); ir: 1625, 1581, 1516, 1328 cm-1; H nmr (deuteriochloro-
form): ꢀ 9.48 (br, 1H, 1-H), 8.95 (br, 1H, 8-H), 8.75 (d, 1H, 3-H,
J = 5.6 Hz), 8.48 (dd, 1H, 6-H, J = 2.4, 9.2 Hz), 8.00 (d, 1H, 5-
H, J = 9.2 Hz), 7.79 ppm (d, 1H, 4-H, J = 5.6 Hz) [24]; ms: m/z
174 (M+), 128, 116, 101, 75.
7-Nitro-1-isoquinolinamine (9). m-Chloroperoxy-benzoic
acid (4.04 g of 70-75%, 16 mmol) was added to a solution of
compound (6) (1.7 g, 9.8 mmol) in acetone (70 mL) [18]. The
reaction was allowed to stir for 21 h, during which time a yellow
solid formed. The solvent was then removed by evaporation
under reduced pressure then the residual solid was dissolved in
dichloromethane (300 mL). This solution was washed with 5%
aqueous sodium hydroxide solution (300 mL), saturated aqueous
sodium chloride solution (150 mL), and then dried over
anhydrous magnesium sulfate. Following filtration, the solvent
was removed by evaporation under reduced pressure to give 7-
nitro-isoquinoline-2-oxide (7) as a bright yellow solid, which
was used without further purification.
Pyridine (70 mL) was added to compound (7) followed by p-
toluenesulfonyl chloride (2.24 g, 11.7 mmol) [18]. The resulting
orange solution was stirred at room temperature for 2 h. The
solvent was then removed by evaporation under reduced
pressure yielding 1-chloro-7-nitro-isoquinoline (8) as a viscous
brown oil, which was used without further purification.
Ethanolamine (150 mL) was added to compound (8) and the
resulting dark solution was stirred at room temperature for 18 h
[18]. The mixture was extracted with dichloromethane (2 x 600
mL). The combined organic layers were washed with water (2 x
500 mL) and saturated aqueous sodium chloride solution (100
mL) then dried over anhydrous magnesium sulfate. Following
filtration, the solvent was then removed by evaporation under
reduced pressure. The residue was purified by alumina column
chromatography (eluting with 1% methanol in ethyl acetate) to
give 7-nitro-1-isoquinolinamine (9) as an orange solid (280 mg,
15% yield from compound (6)), mp 225-233° dec.; ir: 3446,
3340, 3056, 1666, 1610, 1463 cm-1; 1H nmr (deuterio-
chloroform): ꢀ 8.81 (d, 1H, 8-H, J = 1.6), 8.39 (dd, 1H, 6-H, J =
7-(3'-Chlorobenzylamino)-1-isoquinolinamine•2HCl•0.65H2O
(2b). The general procedure described above was carried out
beginning with compound (3) (86 mg, 0.54 mmol) and using 3-
chlorobenzaldehyde (123 μL, 1.08 mmol) to afford 7-(3'-
chlorobenzylamino)-1-isoquinolinamine•2HCl•0.65H2O (2b) as
a yellow solid (84.5 mg, 49%), mp 176-181° dec.; ir: 3404,
1
3165, 2704, 2597, 2463, 2366, 1695, 1613, 1549 cm-1; H nmr
(deuteriodimethylsufoxide): ꢀ 8.77 (2H, br); 7.62 (1H, d, J = 8.8
Hz); 7.47 (1H, s); 7.43-7.24 (6H, m); 6.99 (1H, d, J = 6.8 Hz);
4.39 ppm (2H, s); ms: m/z 286 (MH+), 284 (MH+). Anal. Calcd.
for C16H15Cl2N3•2HCl•0.65 H2O: C, 52.17; H, 4.73; N, 11.41.
Found: C, 52.57; H, 4.69; N, 10.98.
7-(4'-Chlorobenzylamino)-1-isoquinolinamine•2HCl•0.37H2O
(2c). The general procedure described above was carried out
beginning with compound (3) (71 mg, 0.45 mmol) and using 4-
chlorobenzaldehyde (129 mg, 0.88 mol) to afford 7-(4'-
chlorobenzylamino)-1-isoquinolinamine•2HCl•0.37H2O (2c) as

May-Jun 2007
Synthesis and Antimalarial Activity of 7-Benzylamino-1-Isoquinolinamines
637
a yellow solid (85.4 mg, 60%), mp 170-175° dec.; ir: 3362,
3178, 2958, 2699, 2604, 2469, 2365, 1698, 1662, 1543 cm-1; 1H
nmr (deuteriodimethylsufoxide): ꢀ 8.78 (2H, br); 7.68 (1H, d, J
= 8.8 Hz); 7.50-7.38 (7H, m); 7.06 (1H, d, J = 6.8 Hz); 4.46 ppm
(2H, s); ms: m/z 286 (MH+), 284 (MH+). Anal. Calcd. for
C16H15Cl2N3 · 2HCl · 0.37 H2O: C, 52.89; H, 4.64; N, 11.56.
Found: C, 53.29; H, 4.74; N, 11.16.
REFERENCES AND NOTES
[1] Greenwood, B.; Mutabingwa, T. Nature 2002, 415, 670.
[2] Chen, M.; Theander, T. G.; Christensen, S. B.; Hviid, L.;
Zhai, L.; Kharazmi, A. Antimicrob. Agents Chemother. 1994, 37, 1470.
[3] Chen, M.; Christensen, S. B.; Zhai, L.; Rasmussen, R.;
Theander, T. G.; Frokjaer, S.; Steffansen, B.; Davidsen, J.; Kharazmi, A.
J. of Infectious Diseases 1997, 176, 1327.
[4] Li, R.; Kenyon, G. L.; Cohen, F. E.; Chen, X.; Gong, B.;
Dominguez, J. N.; Davidson, E.; Kurzban, G.; Miller, R. E.; Nuzum, E.
O.; Rosenthal, P. J.; McKerrow, J. H. J. Med. Chem. 1995, 38, 5031.
[5] Liu, M.; Wilairat, P.; Go, M.-L. J. Med. Chem. 2001, 44,
4443.
[6] Dominguez, J. N.; Charris, J. E.; Lobo, G.; Gamboa de
Dominguez, N.; Moreno, M. M.; Riggione, F.; Sanchez, E.; Olsen, J.;
Rosenthal, P. J. Eur. J. Med. Chem. 2001, 36, 555.
[7] Go, M.-L.; Liu, M.; Wilairat, P.; Rosenthal, P. J.; Saliba, K.
J.; Kirk, K. Antimicrob. Agents Chemother. 2004, 48, 3241.
[8] Ziegler, H. L.; Hansen, H. S.; Staerk, D.; Christensen, S. B.;
Hägerstrand, H.; Jaroszewski, J. W. Antimicrob. Agents Chemother.
2004, 48, 4067.
7-(3'-Bromobenzylamino)-1-isoquinolinamine•2HCl•0.8H2O
(2d). The general procedure described above was carried out
beginning with compound (3) (88 mg, 0.55 mmol) and using 3-
bromobenzaldehyde (123 μL, 1.05 mmol) to afford 7-(3'-
bromobenzylamino)-1-isoquinolinamine•2HCl•0.8 H2O (2d) as
a yellow solid (44.5 mg, 22%), mp 207-215° dec.; ir: 3463,
3164, 2704, 2600, 2465, 1693, 1611, 1548 cm-1; 1H nmr
(deuteriodimethylsufoxide): ꢀ 8.75 (2H, br); 7.66-7.58 (2H, m);
7.42-7.22 (6H, m); 6.99 (1H, d, J = 6.8 Hz); 4.42 ppm (2H, s);
ms: m/z 330 (MH+), 328 (MH+). Anal. Calcd. for
C16H15BrClN3•2HCl•0.8H2O: C, 46.25; H, 4.27; N, 10.11.
Found: C, 46.61; H, 4.35; N, 9.73.
7-(3',4'-Dichlorobenzylamino)-1-isoquinolinamine•2HCl
•0.9H2O (2e). The general procedure described above was
carried out beginning with compound (3) (70 mg, 0.44 mmol)
and using 3',4'-dichloro benzaldehyde (159.3 mg, 0.91 mmol)
to afford 7-(3',4'-dichlorobenzylamino)-1-isoquinolinamine
•2HCl•0.9H2O (2e) as a yellow solid (78.7 mg, 49%), mp 200-
205° dec.; ir: 3431, 2994, 2465, 1667, 1567 cm-1; 1H nmr
(deuteriodimethylsufoxide): ꢀ 8.66 (2H, br); 7.68-7.62 (2H, m);
7.56 (1H, d, J = 8.4 Hz); 7.35-7.25 (4H, m); 6.94 (1H, d, J = 6.8
Hz); 4.37 ppm (2H, s); ms: m/z 322 (MH+), 320 (MH+), 318
(MH+). Anal. Calcd. for C16H14Cl3N3•2HCl•0.9 H2O : C, 47.18;
H, 4.16; N, 10.32. Found: C, 46.95; H, 3.78; N, 10.12.
[9] Dominguez, J. N.; Leon, C.; Rodrigues, J.; Gamboa de
Dominguez, N.; Gut, J.; Rosenthal, P. J. J. Med. Chem. 2005, 48, 3654.
[10] Gutteridge, C. E.; Nichols, D. A.; Curtis, S. M.; Thota, D. S.; Vo,
J. V.; Gerena, L.; Montip, G.; Asher, C. O.; Diaz, D. S.; DiTusa, C. A.;
Smith, K. S.; Bhattacharjee, A. K. Bioorg. Med. Chem. Lett. 2006, 16, 5682.
[11] Bhattacharjee, A. K.; Nichols, D. A.; Gerena, L.; Gutteridge,
C. E. Medicinal Chemistry 2007 manuscript in press.
[12] Davoll, J.; Johnson, A. M.; Davies, H. J.; Bird, O. D.; Clarke,
J.; Elslager, E. F. J. Med. Chem. 1972, 15, 812.
[13] Schmidt, L. H. Am. J. Trop. Med. Hyg. 1979, 28, 793.
[14] Roth, B.; Cheng, C. C. Prog. Med. Chem. 1982, 19, 269.
[15] Ghose, A. K.; Crippen, G. M. J. Med. Chem. 1984, 27, 901.
[16] Rydon, H. N.; Undheim, K. J. Chem. Soc. 1962, 4689.
[17] Shinkai, H.; Ito, T.; Yamada, H. Worldwide Patent
WO9948492, 1999; Chem. Abstr. 1999, 131, 257447.
[18] Zhu, B.-Y.; Su, T.; Zhaozhong, J. J.; Scarborough, R. M.
Worldwide Patent WO0071507, 2000; Chem. Abstr. 2000, 134, 29203.
[19] Gunzenhauser, S.; Balli, H. Helv. Chim. Acta 1989, 72, 1186.
[20] Ajao, J. F.; Bird, C. W. J. Heterocycl. Chem. 1985, 22, 329.
[21] Grunewald, G. L.; Dahanukar, V. H.; Jalluri, R. K.;
Criscione, K. R. J. Med. Chem. 1999, 42, 118.
Acknowledgements. The authors gratefully acknowledge
support of this work by the Military Infectious Diseases
Research Program, the Office of Naval Research (Grant
N0001406WR20137 to M.M.H.) and the United States Naval
Academy.
Material has been reviewed by the Walter Reed Army
Institute of Research. There is no objection to its presentation
and/or publication. The opinions or assertions contained herein
are the private views of the authors and are not to be construed
as official, or reflecting true views of the Department of the
Army or the Department of Defense.
[22] Potter, M. D.; Taylor, E. P. J. Chem. Soc. 1953, 1320.
[23] This was seen in
a structurally-related series of 2,4-
quinazolinediamines, Werbel, L. M.; Elslager, E. F.; Newton, L. S. J.
Heterocycl. Chem. 1987, 24, 345.
C.E.G. and M.M.H. are grateful to Sean M. Curtis for
assistance in the laboratory.
[24] Armarego, W. L. F.; Batterham, T. J. J. Chem. Soc., Section
B 1966, 750.