Catamphiphilic Reverters of MDR
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 10 1695
as a yellow-brown solid. Mp: 38-40 °C. IR (Nujol): ν 3400
added, and the mixture was heated to reflux for 6 h. The
reaction mixture was cooled to room temperature, and 10 mL
of H2O was added; after separation, the organic layer was dried
with Na2SO4 and removed under reduced pressure. Compound
41 (570 mg, 84% yield) was obtained as a thick oil. IR (neat):
1
(NH2) cm-1. H NMR (CDCl3): δ 1.75 (bs, 2H, NH2), 4.85 (s,
2H, CH2-N), 7.04-7.62 (m, 4H, aromatics), 8.05 (d, 2H,
aromatics), 8.25-8.48 (m, 3H, aromatics).
N-(9-F lu or en yl)tr iflu or oa ceta m id e (47). Trifluoroacetic
anhydride (1.5 mL, 11.2 mmol) was added to a solution of
9-aminofluorene (1.4 g, 7.73 mmol) in 50 mL of anhydrous
ethyl ether. The mixture was stirred for 1 h; then the solvent
was evaporated under reduced pressure to give 2.09 g (97%
yield) of a white solid. Mp: 250-252 °C. IR (Nujol): ν 1700
ν 1710 (CO) cm-1 1H NMR (CDCl3): δ 0.70 (d, J ) 6.6 Hz,
.
3H, CH3), 1.14 (d, J ) 6.6 Hz, 3H, CH3), 1.30-1.45 (m, 1H,
CH), 1.70-2.40 (m, 4H, 2CH2), 3.50-3.65 (m, 2H, CH2-N),
3.79 (s, 3H, OCH3), 3.83 (s, 3H, OCH3), 6.70-6.83 (m, 3H,
aromatics), 7.65-7.81 (m, 4H, aromatics). Anal. (C24H26N2O4)
C, H, N.
1
(CO) cm-1. H NMR (CDCl3): δ 1.54 (s, 1H, NH), 6.21 (s, 1H,
5-Am in o-2-(3,4-d im eth oxyp h en yl)-2-isop r op ylp en ta n e-
n itr ile (36). Hydrazine hydrate (0.5 mL, 10.3 mmol) was
added to a solution of compound 41 (570 mg, 1.40 mmol) in 3
mL of tetrahydrofuran and 2 mL of ethanol. The mixture was
stirred for 3 h at room temperature and the solid filtered off
and washed with tetrahydrofuran. The filtrate was evaporated
under reduced pressure and the resulting material purified
by column chromatography using CHCl3/MeOH (9:1) as eluting
system. Compound 36 (200 mg, 84% yield) was obtained as
CH), 7.35-7.75 (m, 8H, aromatics). Anal. (C15H10F3NO) C, H,
N.
9-(Meth yla m in o)flu or en e (48). Methyl iodide (2.26 mL,
35.5 mmol) was added to a solution of 47 (2.02 g, 7.29 mmol)
in 70 mL of anhydrous acetone. The mixture was stirred for
30 min, then the solvent was removed, and 25 mL of water
and KOH (1.65 g, 29.4 mmol) were added. The mixture was
heated to 80 °C for 8 h, then cooled, and extracted with
chloroform. The organic layer was dried over Na2SO4 and
evaporated under reduced pressure to give 750 mg (53% yield)
an oil. IR (neat): ν 2235 (CN) cm-1. H NMR (CDCl3): δ 0.76
1
of oily 48. IR (neat): ν 3400-3220 (NH) cm-1 1H NMR
.
(CDCl3): δ 2.10 (s, 1H, NH), 2.21 (s, 3H, N-CH3), 4.92 (s, 1H,
CH), 7.28-7.73 (m, 8H, aromatics).
(d, J ) 6.6 Hz, 3H, CH3), 1.16 (d, J ) 6.6 Hz, 3H, CH3), 1.39-
1.58 (m, 3H, CH and NH2), 1.70-1.90 (m, 2H, CH2), 1.99-
2.20 (m, 2H, CH2), 2.55-2.70 (m, 2H, CH2-N), 3.85 (s, 3H,
OCH3), 3.83 (s, 3H, OCH3), 6.79-6.92 (m, 3H, aromatics). Anal.
(C16H24N2O2) C, H, N.
N-Meth ylflu or en e-9-ca r boxa m id e (49). 9-Fluorenecar-
boxylic acid (5.4 g, 25 mmol) was converted into the corre-
sponding acyl chloride using SOCl2 (32 mL) in 50 mL of
anhydrous benzene at 60 °C for 2 h. After removal of the
solvent the crude acyl chloride was dissolved in 50 mL of
anhydrous tetrahydrofuran and cooled to 0 °C; then methyl-
amine (40% solution in water) (78.2 mL) was slowly added.
The mixture was stirred for 30 min and then extracted with
CH2Cl2. The organic layer was washed twice with water, dried
over Na2SO4, and evaporated under reduced pressure to give
a white solid purified by column chromatography using CH2-
Cl2/MeOH (97:3) as eluting system. Compound 49 was ob-
tained as a white solid (2 g, 25% yield). Mp: 233-235 °C. IR
N-[5-Cya n o-5-(3,4-d im et h oxyp h en yl)-6-m et h yl-2-h ep -
tyn yl]p h th a lim id e (42). Following the procedure described
for 41, starting from 6-chloro-2-(3,4-dimethoxyphenyl)-2-iso-
propyl-4-hexynenitrile (38) (500 mg, 1.67 mmol), compound 42
(560 mg, 89% yield) was obtained as a thick oil. IR (neat): ν
1
1710 (CO) cm-1. H NMR (CDCl3): δ 0.83 (d, J ) 6.6 Hz, 3H,
CH3), 1.14 (d, J ) 6.6 Hz, 3H, CH3), 2.30-2.42 (m, 1H, CH),
2.80-2.90 (m, 2H, CH2), 3.79 (s, 3H, OCH3), 3.84 (s, 3H, OCH3),
4.36 (s, 2H, CH2-N), 6.71-6.76 (m, 1H, aromatic), 6.94-6.99
(m, 2H, aromatics), 7.72-7.78 (m, 2H, aromatics), 7.85-7.89
(m, 2H, aromatics). Anal. (C25H24N2O2) C, H, N.
1
(Nujol): ν 1648 (CO) cm-1. H NMR (DMSO): δ 2.10 (s, 1H,
6-Am in o-2-(3,4-d im et h oxyp h en yl)-2-isop r op yl-4-h ex-
yn en itr ile (39). Following the procedure described for 36,
starting from 42 (570 mg, 1.45 mmol), compound 39 (280 mg,
NH), 2.66-3.00 (d, 3H, NCH3), 4.81 (s, 1H, CH), 7.29-7.80
(m, 8H, aromatics). Anal. (C15H13NO) C, H, N.
85% yield) was obtained as an oil. IR (neat): ν 2230 (CN) cm-1
.
N-Meth yl-9-(a m in om eth yl)flu or en e (50). Borane-tet-
rahydrofuran complex (1.0 M in tetrahydrofuran; 24 mL, 24
mmol) was added to a solution of 49 (2 g, 8.96 mmol) in 20
mL of anhydrous tetrahydrofuran cooled to -18 °C. The
mixture was stirred for 30 min then heated to reflux for 1 h;
the solvent was removed, and 6 mL of 6 N HCl was added.
The mixture was heated to reflux for 5 h, then, after cooling,
neutralized with 10% NaOH solution, and extracted with ethyl
ether. The organic layer was dried over Na2SO4 and evaporated
under reduced pressure to give a residue that was purified by
flash chromatography using CHCl3/MeOH/CH3COOH (90:5:
5) as eluting system. Compound 50 was obtained as the acetate
salt which was treated with 10% solution of NaOH to give 600
mg of the oily free base (32% yield). IR (neat): ν 3400-3220
1H NMR (CDCl3): δ 0.82 (d, J ) 6.6 Hz, 3H, CH3), 1.14 (d, J
) 6.6 Hz, 3H, CH3), 1.70 (bs, 2H, NH2), 2.26-2.38 (m, 1H, CH),
2.70-3.00 (m, 2H, CH2), 3.29 (s, 2H, CH2-N), 3.85 (s, 3H,
OCH3), 3.87 (s, 3H, OCH3), 6.79-7.01 (m, 3H, aromatics). Anal.
(C17H22N2O2) C, H, N.
N-(10,11-Dih yd r o-5H -d ib en zo[a ,c]cycloh ep t en -5-yl)-
p h th a lim id e (43). Following the procedure described for 41,
starting from commercially available 5-chlorodibenzosuberane
(460 mg, 2 mmol), compound 43 (670 mg, 99% yield) was
obtained as a pink solid. Mp: 193-195 °C. IR (Nujol): ν 1710
(CO) cm-1. 1H NMR (CDCl3): δ 2.95-3.15 (m, 2H, CH2), 3.55-
3.75 (m, 2H, CH2), 6.75 (s, 1H, CH), 7.10-7.30 (m, 6H,
aromatics), 7.32-7.43 (m, 2H, aromatics), 7.62-7.80 (m, 4H,
aromatics). Anal. (C23H17NO2) C, H, N.
1
(NH) cm-1. H NMR (CDCl3): δ 2.53 (s, 3H, NCH3), 3.13 (d, J
5-Am in o-10,11-d ih yd r o-5H -d ib en zo[a ,c]cycloh ep t en e
(44). Following the procedure described for 36, starting from
43 (670 mg, 1.97 mmol), compound 44 was obtained as a white
solid. Recrystallizations from 2-propanol gave 90 mg (22%
yield). Mp: 90-91 °C (lit.47 mp 91-92 °C). IR (Nujol): ν 3400-
3220 (NH) cm-1. 1H NMR (CDCl3): δ 2.15 (bs, 2H, NH2), 3.10-
3.30 (m, 2H, CH2), 3.30-3.50 (m, 2H, CH2), 5.45 (s, 1H, CH),
7.08-7.23 (m, 6H, aromatics), 7.35-7.45 (m, 2H, aromatics).
N-(9-An th r a n ylm eth yl)p h th a lim id e (45). Following the
procedure described for 41, starting from 9-(chloromethyl)-
anthracene (500 mg, 2.2 mmol), compound 45 (730 mg, 98%
yield) was obtained as a yellow solid. Mp: 240-242 °C. IR
) 6.4 Hz, 2H, CH2), 4.15 (t, J ) 6.4 Hz, 1H, CH), 7.36-7.50
(m, 4H, aromatics), 7.64-7.68 (m, 2H, aromatics), 7.82-7.86
(m, 2H, aromatics). Anal. (C15H15N) C, H, N.
QSAR Ca lcu la tion s. Volume, van der Waals surface, and
Connolly surface were calculated using the MSI package
Insight II (v. 2.3.0/95.0) (MSI, San Diego, CA) implemented
on a Risc IBM. The molecules were first generated using the
Builder module and minimized with Discover (v. 2.9.7/95.0)
using the cvff force field and the conjugate gradient algorithm.
The log P and molecular refractivity values of the molecules
were calculated using the software package ClogP 2.0 (Biobyte
Corp., Claremont, CA) implemented on a Pentium 200. It is
known that, in general, accuracy decreases as molecular mass
and complexity increase; in this respect, log P values for 20,
21, and 23 (g 7.00) are signaled by the software as very high
and unrealistic. Molecular weight was calculated as the sum
of the individual weights of the atoms comprising the molecule
(values are exact). Statistical analysis was performed with the
aid of the software package CA-Cricket Graph III (v. 1.0)
(Nujol): ν 1700 (CO) cm-1 1H NMR (CDCl3): δ 5.85 (s, 2H,
.
CH2-N), 7.40-7.80 (m, 8H, aromatics), 8.02 (d, J ) 8.5 Hz,
2H, aromatics), 8.46 (s, 1H, aromatic), 8.65 (d, J ) 8.5 Hz,
2H, aromatics). Anal. (C23H15NO2) C, H, N.
9-(Am in om eth yl)a n th r a cen e (46). Following the proce-
dure described for 36, starting from compound 45 (410 mg,
1.21 mmol), compound 46 (200 mg, 80% yield) was obtained