Substituted Naphthofurans as Hybrid Molecules
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 12 2141
J ) 8.5 Hz), 6.58 (d, 1, ArH, J ) 8.5 Hz), 7.30 (m, 5, ArH,
benzylic); CIMS m/z 296 (M + 1). Anal. (C19H21NO2‚HCl) C,
H, N.
mmol) of anti-naphthofuran 4a and 1.5 mL of 0.11 N Br2-
CHCl3 solution in 5 mL of CHCl3 gave 40 mg (69%) of 4c‚HBr
as a white solid that was purified by recrystallization from
1
methanol: mp 269-270 °C; H NMR (HBr salt in CD3OD) δ
The second band to elute from the Chromatotron was the
major product and was the syn isomer 12b, as confirmed by
subsequent NOESY NMR experiments. The free base was a
yellow oil weighing 0.84 g (63%). It was taken up into dry
ether and converted to its hydrochloride salt by the addition
of 1 N HCl in anhydrous ethanol. After solvent removal in
vacuo, the solid was crystallized from ethanol-ether to give
fine white crystals of 12b‚HCl: mp 269-270 °C; 1H NMR (free
base in CDCl3) δ 1.33 (q, 1, ArCHCH2CHN, J ) 11.1 Hz), 1.80
(bs, 1, NH), 2.29-2.39 (m, 2, a mixture of ArCHCH2CHN and
ArCH2CHN), 3.06-3.26 (m, a mixture of ArCH2CHN and
ArCH2CHN), 3.38 (m, 1, ArCH), 3.78 (s, 3, ArOCH3), 3.9-4.1
(a mixture of s, 2, a mixture of OCH2 and the benzylic
methylene), 4.73 (t, 1, OCH2, J ) 8.2 Hz), 6.53 (d, 1, ArH, J )
8.4 Hz), 6.57 (d, 1, ArH, J ) 8.4 Hz), 7.32 (m, 5, ArH, benzylic);
CIMS m/z 296 (M + 1). Anal. (C19H21NO2‚HCl) C, H, N.
a n ti-4-Am in o-6-m eth oxy-2a ,3,4,5-tetr a h yd r o-2H-n a p h -
th o[1,8-bc]fu r a n Hyd r och lor id e (4a ). To a suspension of
100 mg of 10% Pd-C in 100 mL of absolute methanol was
added 160 mg (0.48 mmol) of 12a ‚HCl in a Parr flask. The
mixture was shaken under 60 psi of H2 for 12 h and then
filtered through Celite. Removal of solvent under reduced
pressure gave a clean-white solid that was recrystallized from
methanol-ethyl acetate-ether to yield 97 mg (84%) of 4a ‚-
HCl as fine white crystals: mp 229 °C; 1H NMR (free base in
CDCl3) δ 1.35 (bs, 2, NH2), 1.45 (qd, 1, ArCHCH2CHN, J )
12.1, 2.9 Hz), 1.98 (dt, 1, ArCHCH2CHN, J ) 12.5, 4.5 Hz),
2.53 (d, 1, ArCH2CHN, J ) 18.2 Hz), 2.71 (dd, 1, ArCH2CHN,
J ) 18.2, 4.5 Hz), 3.59 (m, 1, ArCH), 3.62 (m, 1, ArCH2CHN),
3.69 (s, 3, ArOCH3), 3.9 (dd, 1, OCH2, J ) 12.3, 8.0 Hz), 4.70
(t, 1, OCH2, J ) 8.0 Hz), 6.45 (d, 1, ArH, J ) 8.5 Hz), 6.50 (d,
1, ArH, J ) 8.5 Hz); CIMS m/z 206 (M + 1), 189. Anal.
(C12H15NO2‚HCl) C, H, N.
syn -4-Am in o-6-m eth oxy-2a ,3,4,5-tetr a h yd r o-2H-n a p h -
th o[1,8-bc]fu r a n Hyd r och lor id e (4b). In a method identical
to that for the preparation of the anti isomer 4a ‚HCl above,
550 mg (1.66 mmol) of 12b‚HCl was added to a suspension of
150 mg of 10% Pd-C in 100 mL of absolute methanol and
shaken under 60 psi of H2 for 12 h. Filtration through Celite
and removal of solvent under reduced pressure gave a clean-
white solid that was recrystallized from methanol-ethyl
acetate-ether to yield 381 mg (95%) of 4b‚HCl as fine white
crystals: mp >310 °C; 1H NMR (free base in CDCl3) δ 1.19 (q,
1, ArCHCH2CHN, J ) 11.6 Hz), 1.42 (bs, 2, NH2), 2.09 (dt, 1,
ArCHCH2CHN, J ) 11.6, 3.9 Hz), 2.18 (dd, 1, ArCH2CHN, J
) 17.3, 11.9 Hz), 3.01 (dd, 1, ArCH2CHN, J ) 17.4, 6.3 Hz),
3.21 (m, 1, ArCH2CHN), 3.38 (m, 1, ArCH), 3.69 (s, 3, ArOCH3),
3.9 (dd, 1, OCH2, J ) 12.3, 8.3 Hz), 4.70 (t, 1, OCH2, J ) 8.2
Hz), 6.45 (d, 1, ArH, J ) 8.5 Hz), 6.49 (d, 1, ArH, J ) 8.5 Hz);
CIMS m/z 206 (M + 1), 189. Anal. (C12H15NO2‚HCl) C, H, N.
1.65 (ddd, 1, ArCHCH2CHN, J ) 15.9, 12.4, 3.6 Hz), 2.30 (dt,
1, ArCHCH2CHN, J ) 14, 4.4 Hz), 2.65 (d, 1, ArCH2CHN, J
) 19.0 Hz), 2.92 (ddd, 1, ArCH2CHN, J ) 19, 6.5, 1.8 Hz),
3.45-3.65 (m, 1, ArCH), 3.68 (s, 3, ArOCH3), 3.92 (m, 1,
ArCH2CHN), 4.0 (dd, 1, OCH2, J ) 11.8, 8.4 Hz), 4.82 (t, 1,
OCH2, J ) 8.4 Hz), 6.70 (s, 1, ArH); CIMS m/z 284, 286 (M +
1), 206. Anal. (C12H14BrNO2‚HBr) C, H, N.
syn -N,N-Dim eth yl-4-a m in o-6-m eth oxy-2a ,3,4,5-tetr a h y-
d r o-2H-n a p h th o[1,8-bc]fu r a n (4e). Sodium cyanoborohy-
dride, 78 mg (1.24 mmol), was added to a stirred mixture of
70 mg (0.31 mmol) of 4b‚HCl in 5 mL of methanol and 0.5 mL
of 37% aqueous formaldehyde under N2. The clear mixture
was stirred at room temperature for 26 h, and the methanol
was removed under reduced pressure. The aqueous residue
was diluted with 2.5 N NaOH and extracted with 4 × 15 mL
of CH2Cl2. The extracts were combined, washed with 2 × 15
mL of 5% NaHCO3 solution and 25 mL of brine, dried over
MgSO4, and filtered through Celite. Removal of the solvent
on the rotary evaporator gave a yellow oil that was purified
by applying it to a 1-mm Chromatotron plate and eluting with
CH2Cl2 under a N2-NH3 atmosphere. This gave 36 mg (50%)
of the free base 4e as a pale-yellow oil. The oxalate salt was
formed by dissolving the base in ether and adding 1 equiv of
oxalic acid that had been dissolved in a small amount of ether.
The precipitated salt was collected on a Bu¨chner funnel and
washed well with ether to yield 48 mg (49%) of 4e‚C2H2O4 as
1
a white solid: mp 186-187 °C; H NMR (free base in CDCl3)
δ 1.35 (q, 1, ArCHCH2CHN, J ) 11.4 Hz), 2.24 (ddd, 1,
ArCHCH2CHN, J ) 11.3, 4.2, 3 Hz), 2.40 (s, 6, N(CH3)2), 2.52
(dd, 1, ArCH2CHN, J ) 15.8, 10.6 Hz), 2.9-3.1 (m, 2, a mixture
of ArCH2CHN and ArCH2CHN), 3.40 (m, 1, ArCH), 3.77 (s, 3,
ArOCH3), 4.0 (dd, 1, OCH2, J ) 12.1, 8.2 Hz), 4.82 (t, 1, OCH2,
J ) 8.2 Hz), 6.52 (d, 1, ArH, J ) 8.6 Hz), 6.56 (d, 1, ArH, J )
8.6 Hz); CIMS m/z 234 (M + 1), 205, 162. Anal. (C14H19
NO2‚C2H2O4) C, H, N.
-
syn -N,N-Dip r op yl-4-a m in o-6-m eth oxy-2a ,3,4,5-tetr a h y-
d r o-2H-n a p h th o[1,8-bc]fu r a n (4f). Sodium cyanoborohy-
dride, 130 mg (2.07 mmol), was added to a stirred mixture of
100 mg of 4b‚HCl in 3 mL of methanol and 0.3 mL (4.14 mmol)
of propionaldehyde under N2. The white slurry was stirred
at room temperature for 72 h, and the methanol was removed
under reduced pressure. The residue was diluted with 2.5 N
NaOH and extracted with 4 × 15 mL of CH2Cl2. The extracts
were combined, washed with 2 × 15 mL of 5% NaHCO3
solution and 25 mL of brine, dried over MgSO4, and filtered
through Celite. Removal of solvent on the rotary evaporator
gave an oil that was purified by applying it to a 1-mm
Chromatotron plate and eluting with CH2Cl2 under a N2-NH3
atmosphere. Concentration of the eluted fractions gave a
quantitative yield of the free base as a yellow oil. Several
attempts were made to crystallize the product as its hydro-
chloride or methanesulfonate salt, but these formed gumlike
solids that could not be induced to crystallize. The product
finally was precipitated as its oxalate salt and recrystallized
from ethyl acetate-ether-hexane to give 4f‚C2H2O4 as a white
granular solid: mp 132-133 °C; 1H NMR (oxalate in CD3OD)
δ 1.01 (t, 6, N(CH2CH2CH3)2, J ) 7.4 Hz), 1.7 (q, 1, ArCHCH2-
CHN, J ) 11.4 Hz), 1.73 (m, 4, N(CH2CH2CH3)2) 2.45 (dt, 1,
ArCHCH2CHN, J ) 10.9, 3.8 Hz), 2.78 (dd, 1, ArCH2CHN, J
) 17.3, 11.8 Hz), 3.1-3.26 (m, 5, a mixture of ArCH2CHN and
N(CH2CH2CH3)2), 3.5 (m, 1, ArCH2CHN), 3.77 (s, 3, ArOCH3),
4.01 (m, 1, ArCH and OCH2), 4.78 (t, 1, OCH2, J ) 8.2 Hz),
6.54 (d, 1, ArH, J ) 8.5 Hz), 6.63 (d, 1, ArH, J ) 8.5 Hz); CIMS
m/z 290 (M + 1). Anal. (C18H27NO2‚C2H2O4) C, H, N.
syn -4-Am in o-8-b r om o-6-m et h oxy-2a ,3,4,5-t et r a h yd r o-
2H-n a p h th o[1,8-bc]fu r a n (4d ). To an ice-bath-cooled solu-
tion of 85 mg (0.41 mmol) of the naphthofuran 4b in 5 mL of
CHCl3 was slowly added via syringe through a septum 2.1 mL
of a 0.20 N solution of Br2 in CHCl3. The mixture was stirred
for 30 min, during which time the solution turned orange and
a white precipitate formed. Ether was added, and the solid
was collected by suction filtration, rinsing well with ether on
the filter to afford 119 mg (79%) of 4d ‚HBr as a pristine-white
solid. The solid was recrystallized from methanol to give fine
1
white crystals: mp 277-278 °C; H NMR (HBr salt in CD3-
OD) δ 1.45 (q, 1, ArCHCH2CHN, J ) 11.7 Hz), 2.35 (m, 1,
ArCHCH2CHN), 2.40 (ddd, 1, ArCH2CHN, J ) 17.4, 10.3, 1.9
Hz), 3.1 (dd, 1, ArCH2CHN, J ) 17.4, 6.6 Hz), 3.55 (m, 2, a
mixture of ArCH and ArCH2CHN), 3.70 (s, 3, ArOCH3), 3.95
(dd, 1, OCH2, J ) 12.2, 8.4 Hz), 4.82 (t, 1, OCH2, J ) 8.4 Hz),
6.68 (s, 1, ArH); CIMS m/z 284, 286 (M + 1), 206. Anal.
(C12H14BrNO2‚HBr) C, H, N.
P h ar m acological Meth ods. Dr u g Discr im in ation Stu d-
ies. The procedures for the drug discrimination assays were
essentially as described in previous reports.10,29-31 Twenty
male Sprague-Dawley rats (Harlan Laboratories, Indianapo-
lis, IN), weighing 200-220 g at the beginning of the study,
were trained to discriminate LSD tartrate from saline. None
a n ti-4-Am in o-8-br om o-6-m eth oxy-2a ,3,4,5-tetr a h yd r o-
2H-n a p h th o[1,8-bc]fu r a n (4c). In a manner identical to that
for the preparation of the syn isomer 4d above, 30 mg (0.16