Chloroquine Susceptibility in Plasmodium falciparum
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 15 3205
(m, 1H); 2.23 (d, J ) 1.8 Hz, 1H); 1.05 (d, J ) 6.5 Hz, 3H). 13
C
cis-9,10-Dih yd r o-N,N,N′,N′-tetr a m eth yl-9,10-eth a n oa n -
th r a cen e-11,12-d ica r boxa m id e (4). Yield, 81%; mp 205 °C.
1H NMR (CDCl3): 7.35 (m, 4H); 7.09 (m, 4H); 4.37 (s, 2H); 3.
72 (s, 2H); 3.23 (s, 6H); 2.92 (s, 6H). 13C NMR (CDCl3): 171.9
(s); 142.7 (s); 139.7 (s); 126.2 (d); 126.1 (d); 124.9 (d); 122.5
(d); 47.3 (d); 45.1 (d); 37.3 (q); 35.9 (q). Anal. (C22H24N2O2) C,
H, N.
Meth od C. A mixture of ester derivative 20 (16.5 mmol)
and KOH (16.5 mmol) in MeOH (45 mL) and in Et2O (50 mL)
was left at room temperature during 3 days. Solvents were
then eliminated under vacuum. A mixture of 11-carboxy-12-
carbomethoxy, 11,12-dicarbomethoxy, and 11,12-dicarboxy-9,-
10-dihydro-9,10-ethanoanthracene was obtained. Successive
extractions at variable pH separated the expected compounds
of the two other products. The 11-carboxy-12-carbomethoxy-
9,10-dihydro-9,10-ethanoanthracene was treated as an acid
derivative in method A to obtain the corresponding amide
derivative.
t r a n s-9,10-D ih y d r o -N ,N -d im e t h y l-9,10-e t h a n o a n -
th r a cen e-11-ca r boxa m id e-12-ca r boxylic Acid , Meth yl-
ester (21). Yield, 83%; mp 125-130 °C. 1H NMR (CDCl3): 7.31
(m, 3H), 7.12 (m, 5H); 4.76 (d, J ) 2.3 Hz, 1H); 4.32 (d, J )
2.1 Hz, 1H); 3.61 (br. s, 4H); 3.52 (dd, J ) 5.4, 2.1 Hz, 1H);
3.25 (s, 3H); 2.92 (s, 3H). 13C NMR (CDCl3): 173.5 (s); 171.3
(s); 142.7 (s); 142.1 (s); 140.6 (s); 139.4 (s); 126.4 (d); 126.3 (d);
126.2 (d); 124.9 (d); 124.6 (d); 123.4 (d); 122.9 (d); 52.1 (q); 48.1
NMR (CDCl3): 176.3 (s); 144.7 (s); 142.5 (s); 140.3 (s); 139.1
(s); 126.4 (d); 126.1 (d); 126.0 (d); 125.9 (d); 125.8 (d); 125.3
(d); 123.3 (d); 123.0(d); 54.4 (d); 50.8 (d); 47.5 (d); 38.9 (d); 21.1
(q). Anal. (C18H17NO) C, H, N.
9,10-Dih ydr o-N,N-12-tr im eth yl-9,10-eth an oan th r acen e-
11-ca r boxa m id e (8).12 Yield, 55%; mp 145-147 °C. 1H NMR
(CDCl3): 7.58 (m, 4H); 7.13 (m, 4H); 4.14 (d, J ) 1.8 Hz, 1H);
3.95 (d, J ) 2.1 Hz, 1H); 3.09 (br. s, 3H); 2.89 (br. s, 3H); 2.59
(m, 1H); 2.35 (dd, J ) 5.4, 2.0 Hz, 1H); 0.80 (d, J ) 6.9 Hz,
3H). 13C NMR (CDCl3): 172.3 (s); 144.3 (s); 142.8 (s); 141.3
(s); 138.6 (s); 126.1 (d); 125.9 (d); 125.7 (d); 125.6 (d); 125.5
(d); 124.6 (d); 122.8 (d); 122.4 (d); 50.8 (d); 49.9 (d); 47.8 (d);
37.3 (q); 36.8 (d); 36.0 (q); 20.7 (q).
9,10-Dih yd r o-12-m eth yl-N-2′-p yr id in yl-9,10-eth a n oa n -
th r a cen e-11-ca r boxa m id e (9). Yield, 30%; mp 221-222 °C.
1H NMR (CDCl3): 8.22 (d, J ) 4.9 Hz, 1H); 8.08 (d, J ) 8.4
Hz, 1H); 7.83 (br. s, 1H); 7.62 (m, 1H); 7.29 (m, 4H); 7.14 (m,
4H); 6.97 (m, 1H); 4.52 (m, 1H); 4.06 (d, J ) 1.8 Hz, 1H); 5.43
(td, J ) 6.6, 2.1 Hz, 1H); 2.23 (dd, J ) 2.1, 1.8 Hz, 1H); 0.97
(d, J ) 6.7 Hz, 3H). 13C NMR (CDCl3): 171.8 (s); 151.5 (s);
147.8 (d); 144.5 (s); 142.4 (s); 140.8 (s); 138.8 (s); 138.4 (d);
126.6 (d); 126.2 (d); 126.1 (d); 125.9 (d); 125.3 (d); 123.3 (d);
123.1 (d); 119.7 (d); 114.1 (d); 55.7 (d); 50.9 (d); 48.0 (d); 37.9
(d); 21.2 (q). Anal. (C23H20N2O) C, H, N.
9,10-Dih yd r o-12-m eth yl-N-3′-p yr id in yl-9,10-eth a n oa n -
th r a cen e-11-ca r boxa m id e (10). Yield, 38%; mp 222-223.5
°C. 1H NMR (DMSO-d6): 10.30 (s, 1H); 8.68 (d, J ) 2.1 Hz,
1H); 8.23 (dd, J ) 4.5, 1.0 Hz, 1H); 7.95 (ddd, J ) 8.3, 2.5, 1.5
Hz, 1H); 7.41-7.37 (m, 1H); 7.35-7.26 (m, 3H); 7.15 (m, 3H);
7.07-7.0 (m, 2H); 4.58 (d, J ) 1.9 Hz, 1H); 4.10 (d, J ) 1.9
Hz, 1H); 2.42 (m, 1H); 2.26 (dd, J ) 5.2, 2.0 Hz, 1H); 0.79 (d,
J ) 6.9 Hz, 3H). 13C NMR (DMSO-d6): 171.6 (s); 144.9 (s);
144.3 (d); 143.1 (s); 141.5 (s); 141.1 (d); 139.7 (s); 136.3 (s);
126.5 (d); 125.9 (d); 125.7 (d); 125.0(d); 123.9 (d); 123.5 (d);
123.2 (d); 54.1 (d); 50.0 (d); 48.3 (d); 35.8 (d); 20.8 (q). Anal.
(C23H20N2O) C, H, N.
9,10-Dih yd r o-12-m eth yl-N-4′-p yr id in yl-9,10-eth a n oa n -
th r a cen e-11-ca r boxa m id e (11). Yield, 74%; mp 275-276 °C.
1H NMR (DMSO-d6): 10.49 (s, 1H); 8.38 (d, J ) 5.5 Hz, 2H);
7.50 (d, J ) 5.5 Hz, 2H); 7.39 (m, 1H); 7.31 (m, 2H); 7.15-
7.09 (m, 3H); 7.10 (m, 2H); 4.56 (s, 1H); 4.10 (d, J ) 1.3 Hz,
1H); 2.42 (m, 1H); 2.27 (dd, J ) 5.1, 1.3 Hz, 1H); 0.78 (d, J )
6.8 Hz, 3H). 13C NMR (DMSO-d6): 172.2 (s); 150.5 (d); 146.3
(s); 144.9 (s); 143.0 (s); 141.5 (s); 139.5 (s); 126.0 (d); 125.9 (d);
125.7 (d); 125.0 (d); 123.6 (d); 123.2 (d); 113.5 (d); 54.4 (d); 50.0
(d); 48.2 (d); 35.7 (d); 20.7 (q). Anal. (C23H20N2O) C, H, N.
tr a n s-9,10-Dih yd r o-9,10-et h a n oa n t h r a cen e-11,12-d i-
ca r boxa m id e (16).10 Yield, 79%; mp 305-306 °C. 1H NMR
(DMSO-d6): 7.64 (s, 2H); 7.28 (m, 2H); 7.18 (m, 2H); 7.03 (m,
4H); 6.85 (s, 2H); 4.66 (s, 2H); 3.14 (s, 2H). 13C NMR (DMSO-
d6): 173.5 (s); 143.5 (s); 141.0 (s); 125.4 (d); 124.5 (d); 123.2
(d); 47.2 (d); 46.7 (d).
(d); 47.2 (d); 46.5 (d); 45.1 (d); 37.4 (q); 36.2 (q). Anal. (C21H21
NO3) C, H, N.
-
Meth od D. Ester derivative (40 mmol) and NaOH (0.16
mol) in H2O (48 mL) and MeOH (32 mL) were stirred under
reflux during 3 days. The corresponding acid obtained was
purified as in method B and treated as in method A, or after
acid chloride was obtained, it was treated with decanediamine
(7.5 mmol) and triethylamine (TEA, 15 mmol) in CH2Cl2 and
stirred for 1 day at room temperature. The amide derivative
obtained was purified as in method A.
9,10-Dih yd r o-N,N-d im eth yl-9,10-eth en oa n th r a cen e-11-
ca r b oxa m id e (29).16 Yield, 81%; mp 115 °C. 1H NMR
(CDCl3): 7.32 (m, 4H); 7.12 (dd, J ) 6.1, 1.9 Hz, 1H); 6.97 (m,
4H); 5.37 (d, J ) 1.7 Hz, 1H); 5.21 (d, J ) 6.0 Hz, 1H); 2.91 (s,
6H). 13C NMR (CDCl3): 168.9 (s); 146.8(s); 145.3 (s); 145.0 (s);
140.6 (d); 124.8 (d); 124.7 (d); 123.4 (d); 123.1 (d); 53.0 (d); 51.0
(d).
9,10-Dih yd r o-N-m eth yl-9,10-eth en oa n th r a cen e-11-ca r -
boxa m id e (30). Yield, 60%; mp 118-121 °C. 1H NMR (DMSO-
d6): 7.34 (m, 5H); 6.97 (m, 4H); 5.78 (m, 1H); 5.69 (d, J ) 1.8
Hz, 1H); 5.16 (d, J ) 6.08 Hz, 1H); 2.79 (d, J ) 4.90 Hz, 3H).
13C NMR (DMSO-d6): 165.7 (s); 147.9 (s); 145.3 (s); 144.7 (s);
141.4 (d); 124.9 (d); 124.7 (d); 123.7 (d); 123.2 (d); 51.0 (d); 50.6
(d); 26.3 (q). Anal. (C18H15NO) C, H, N.
N,N′-1,10-Deca n ed iylbis[9′,10′-d ih yd r o-9′,10′-eth en oa n -
th r a cen e-11′-ca r boxa m id e] (31). Yield, 25%; mp 190 °C. 1H
NMR (CDCl3): 7.36 (m, 10H); 6.99 (m, 8H); 5.94 (m, 2H); 5.72
(d, J ) 1.2 Hz, 2H); 5.16 (d, J ) 6.1 Hz, 2H); 3.21 (m, 4H);
1.42 (m, 4H); 1.22 (s, 12H). 13C NMR (CDCl3): 164.9 (s); 148.1
(s); 145.4 (s); 144.7 (s); 141.1 (d); 124.9 (d); 124.6 (d); 123.7
(d); 123.2 (d); 51.0 (d); 50.6 (d); 39.6 (t); 29.4 (t); 29.1 (t); 29.0
(t); 26.7 (t). Anal. (C44H44N2O2) C, H, N.
9,10-Dih yd r o-N-ben zyl-9,10-eth en oa n th r a cen e-11-ca r -
b oxa m id e (32). Yield, 60%; mp 187-189 °C. 1H NMR
(CDCl3): 7.34 (m, 10H); 6.98 (m, 4H); 5.95 (br. s, 1H); 5.75 (s,
1H); 5.19 (d, J ) 6.0 Hz, 1H); 4.45 (d, J ) 5.6 Hz, 2H). 13C
NMR (CDCl3): 164.7 (s); 147.8 (s); 145.2 (s); 144.5 (s); 141.4
(d); 128.6 (d); 127.8 (d); 127.5 (d); 124.9 (d); 124.6 (d); 123.7
(d); 123.1 (d); 51.0 (d); 50.5 (d); 43.7 (t). Anal. (C24H19NO) C,
H, N.
P r ep a r a tion of Am in e Der iva tives. Meth od E. Amide
or maleimide derivative (22 mmol) was added to a slurry of
LiAlH4 (110 mmol) in anhydrous THF (100 mL). After 1 day
at room temperature, H2O (4.2 mL), NaOH 1.25 N (4.2 mL),
and H2O (8.4 mL) were successively added. The suspension
was filtered over Celite. The filtrates were concentrated. The
residue was extracted with ethyl acetate/H2O (pH 1). The
aqueous phase was basified (pH 10) and extracted with CH2-
tr a n s-9,10-Dih yd r o-N,N,N′,N′-t et r a m et h yl-9,10-et h a -
n oa n th r a cen e-11,12-d ica r boxa m id e (17).12 Yield, 78%; mp
161-163 °C. 1H NMR (CDCl3): 7.32 (m, 4H); 7.10 (m, 4H);
4.34 (s, 2H); 3.69 (s, 2H); 3.21 (s, 6H); 2.90 (s, 6H). 13C NMR
(CDCl3): 172.0 (s); 142.7 (s); 139.7 (s); 126.2 (d); 126.1 (d);
125.0(d); 122.5 (d); 47.4 (d); 45.2 (d); 37.4 (q); 36.0(q).
(RR) Com p ou n d 17. [R]20 ) -129.75° (c 2 dioxan).
D
(SS) Com p ou n d 17. [R]20 ) +135.5° (c 2 dioxan).
D
9,10-Dih yd r o-N ,N ,N ′,N ′-t e t r a m e t h yl-9,10-e t h e n oa n -
th r a cen e-11,12-d ica r boxa m id e (36).17 Yield, 78%; mp 172
°C. 1H NMR (CDCl3): 7.35 (m, 4H); 6.99 (m, 4H); 5.20 (s, 2H);
2.92 (s, 6H); 2.59 (s, 6H). 13C NMR (CDCl3): 168.4 (s); 144.2
(s); 143.5 (s); 125.1 (d); 124.8 (d); 123.6 (d); 123.3 (d); 53.1 (d);
37.9 (q); 34.9 (q).
Meth od B. Anhydride derivative (36 mmol) was saponified
with KOH (0.9 mol) in H2O (120 mL) under reflux during 3
days. At room temperature, the mixture was filtered and the
solution obtained was acidified with HCl 10 N. The acid
obtained was filtered and then dried. The corresponding acid
chloride and the corresponding amide were prepared as in
method A.