1-Benzopyran-4-ones as Aldose Reductase Inhibitors
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 11 1889
8.50), 7.90 (4H, m), 7.50 (3H, m), 6.98 (1H, dd, J ) 8.50, J )
2.40), 6.82 (1H, d, J ) 2.40), 6.18 (1H, s), 4.10 (2H, s), 3.88
(3H, s).
NMR 9.91 (1H, s), 9.34 (1H, s), 7.45 (1H, d, J ) 8.94), 7.28
(1H, d, J ) 2.94), 7.16 (3H, m), 6.76 (2H, m), 6.08 (1H, s), 3.87
(2H, s). C16H12O4: C, H.
6-Met h oxy-2-(4′-h yd r oxyb en zyl)-4H -1-b en zop yr a n -4-
on e (13b): from 12a ; yield 61%; mp 148-50 °C (acetone); 1H
NMR 9.39 (1H, s), 7.54 (1H, m), 7.37 (2H, m), 7.18 (2H, m),
6.76 (2H, m), 6.15 (1H, s), 3.89 (2H, s), 3.84 (3H, s). C17H14O4:
C, H.
7-H yd r oxy-2-(4′-h yd r oxyb en zyl)-4H -1-b en zop yr a n -4-
on e (13c): from 12b; yield 83%; mp 258-60 °C (acetone/
petroleum ether); 1H NMR 10.70 (1H, s), 9.34 (1H, s), 7.84 (1H,
d, J ) 8.71), 7.16 (2H, m), 6.88 (1H, dd, J ) 8.71, J ) 2.30),
6.76 (3H, m), 6.00 (1H, s), 3.84 (2H, s). C16H12O4: C, H.
7-Met h oxy-2-(4′-h yd r oxyb en zyl)-4H -1-b en zop yr a n -4-
on e (13d ): from 12b; yield 14%; mp 188-90 °C (acetone); 1H
NMR 9.34 (1H, s), 7.88 (1H, d, J ) 8.60), 7.17 (2H, m), 7.05
(2H, m), 6.78 (2H, m), 6.09 (1H, s), 3.90 (3H, s), 3.87 (2H, s).
7-Met h oxy-2-(4′-m et h oxyb en zyl)-3-b en zyl-4H -1-b en -
zop yr a n -4-on e (12h ) was synthesized by reaction between
2′-hydroxy-4′-methoxydihydrochalcone (4e)32 and methyl 4-meth-
oxyphenylacetate: yield 25%; mp 108-10 °C; 1H NMR (CDCl3)
8.17 (1H, d, J ) 8.77), 7.40 (5H, m), 7.15 (2H, m), 6.95 (1H,
dd, J ) 8.77, J ) 2.25), 6.86 (2H, m), 6.80 (1H, d, J ) 2.25),
4.09 (2H, s), 4.02 (2H, s), 3.91 (3H, s), 3.80 (3H, s).
7-Meth oxy-2-(4′-m eth oxyben zyl)-3-[(1,1′-bip h en yl-4-yl)-
m eth yl]-4H-1-ben zop yr a n -4-on e (12i) was synthesized by
reaction between 2′-hydroxy-4′-methoxy-4-phenyldihydroch-
alcone (4f) (prepared starting from biphenylcarboxaldehyde
and 2-hydroxy-4-methoxyacetophenone following the general
procedure described32) and methyl 4-methoxyphenylacetate:
yield 7%; mp 101-2 °C; 1H NMR (CDCl3) 8.16 (1H, d, J ) 8.89),
7.10 (15H, m), 4.07 (2H, s), 3.98 (2H, s), 3.89 (3H, s), 3.81 (3H,
s).
C
17H14O4: C, H.
7-Hyd r oxy-2-[(4′-h yd r oxyp h en yl)eth yl]-4H-1-ben zop y-
r a n -4-on e (13e): from 12c; yield 61%; mp 200-3 °C (acetone/
petroleum ether); 1H NMR 10.69 (1H, s), 9.15 (1H, s), 7.83 (1H,
d, J ) 8.65), 7.05 (2H, m), 6.89 (1H, dd, J ) 8.65, J ) 2.24),
6.82 (1H, d, J ) 2.24), 6.68 (2H, m), 6.04 (1H, s), 2.88 (4H, s).
7-H yd r oxy-2-(4′-m et h oxyb en zyl)-4H -1-b en zop yr a n -4-
on e (12l) was synthesized by reaction between 2-hydroxy-4-
(2-tetrahydropyranyloxy)acetophenone (4g)49 and methyl
1
4-methoxyphenylacetate: yield 32%; mp 171-4 °C; H NMR
C
17H14O4: C, H.
10.69 (1H, s), 7.83 (1H d, J ) 8.72), 7.31 (2H, m), 6.90 (3H,
m), 6.78 (1H, d, J ) 2.20), 6.03 (1H, s), 3.90 (2H, s), 3.76 (3H,
s). C17H14O4: C, H.
7-Hydr oxy-2-[(4′-h ydr oxyph en yl)pr opyl]-4H-1-ben zopy-
r a n -4-on e (13f): from 12d ; yield 61%; mp 210-12 °C (acetone/
petroleum ether); 1H NMR 10.67 (1H, s), 9.11 (1H, s), 7.85 (1H,
d, J ) 8.67), 7.03 (2H, m), 6.89 (1H, dd, J ) 8.66, J ) 2.22),
6.83 (1H, d, J ) 2.09), 6.82 (2H, m), 6.08 (1H, s), 2.57 (4H, m),
1.94 (2H, m). C18H16O4: C, H.
7-Hyd r oxy-2-ben zyl-4H-1-ben zop yr a n -4-on e (12m ) was
synthesized by reaction between 2-hydroxy-4-(2-tetrahydro-
pyranyloxy)acetophenone (4g)49 and methyl phenylacetate:
yield 40%; mp 167-9 °C; 1H NMR (CDCl3) 10.69 (1H, s), 7.84
(1H, d, 8.71), 7.32 (5H, m), 6.89 (1H, dd, J ) 8.70, J ) 2.25),
6.77 (1H, d, J ) 2.18), 6.07 (1H, s), 3.98 (2H, s). C16H12O3: C,
H.
7-Br om o-2-(4′-m e t h oxyb e n zyl)-4H -1-b e n zop yr a n -4-
on e (12n ) was synthesized by reaction between 4-bromo-2-
hydroxyacetophenone (4h )50 and methyl 4-methoxyphenylac-
etate: yield 56%; mp 93-5 °C; 1H NMR 7.92 (2H, m), 7.65
(1H, dd, J ) 1.80, J ) 8.49), 7.30 (2H, m), 6.92 (2H, m), 6.22
(1H, s), 3.96 (2H, s), 3.75 (3H, s).
7-Hyd r oxy-2-(3′,4′-d ih yd r oxyben zyl)-4H-1-ben zop yr a n -
4-on e (13g): from 12e; yield 55%; mp 235-7 °C (acetone/
petroleum ether); 1H NMR 10.65 (1H, s), 8.80 (1H, s), 7.84 (1H,
d, J ) 8.70), 6.89 (1H, dd, J ) 8.71, J ) 2.25), 6.78 (1H, d, J
) 2.22), 6.72 (2H, m), 6.60 (1H, m), 6.03 (1H, s), 3.78 (2H, s).
C
16H12O5: C, H.
7-H yd r oxy-2-(d ip h e n ylm e t h yl)-4H -1-b e n zop yr a n -4-
1
on e (13h ): from 12f; yield 53%; mp 255-8 °C (acetone); H
NMR 10.70 (1H, s), 7.87 (1H, d, J ) 8.71), 7.36 (10H, m), 6.91
(1H, dd, J ) 8.79, J ) 2.18), 6.73 (1H, d, J ) 2.25), 5.61 (1H,
s). C22H16O3: C, H.
7-[(Dim eth yla m in o)m eth yl]-2-(4′-m eth oxyben zyl)-4H-
1-ben zop yr a n -4-on e (12o). A solution of 1-(4-[(dimethylami-
no)methyl]-2-hydroxyphenyl)ethanone (4i)51 (2.80 g, 14.5 mmol)
and 4-methoxyphenylacetic acid methyl ester (2.88 g, 16.0
mmol) in anhydrous pyridine (8 mL) was added under stirring
to a suspension of NaH (60% dispersion in mineral oil (2.08 g,
52.0 mmol) in anhydrous pyridine (5 mL). The reaction
mixture was warmed to 100 °C for 20 min and then cooled,
and anhydrous ether was added; the yellow precipitate was
then collected and washed with diethyl ether. The solid was
dissolved in acetic acid (30 mL), and concentrated HCl was
added (1.5 mL). The resulting mixture was heated to 100 °C
for 1 h; after cooling, the solvent was removed under reduced
pressure and the resulting mixture was brought to pH 10.0
with NaOH, 5 N; the mixture was extracted with ethyl acetate
(3 × 30 mL); the organic layers were dried (Na2SO4), and the
solvent was removed under reduced pressure to afford an oil:
7-Hyd r oxy-2-[(2-n a p h th yl)m eth yl]-4H-1-ben zop yr a n -4-
1
on e (13i): from 12g; yield 26%; mp 225-8 °C (acetone); H
NMR 10.67 (1H, s), 7.89 (5H, m), 7.53 (3H, m), 6.90 (1H, dd,
J ) 8.71, J ) 2.25), 6.78 (1H, d, J ) 2.16), 6.15 (1H, s), 3.29
(2H, s). C20H14O3: C, H.
7-Hydr oxy-2-(4′-h ydr oxyben zyl)-3-ben zyl-4H-1-ben zopy-
r a n -4-on e (13l): from 12h ; yield 11%; mp 178-80 °C (acetone/
petroleum ether); 1H NMR 10.62 (1H, s), 9.26 (1H, s), 7.88 (1H,
d, J ) 8.78), 7.25 (5H, m), 7.01 (2H, m), 6.97 (1H, dd, J )
8.78, J ) 2.20), 6.74 (1H, d, J ) 2.20) 6.69 (2H, m), 3.94 (2H,
s), 3.93 (2H, s). C23H18O4: C, H.
7-Hyd r oxy-2-(4′-h yd r oxyben zyl)-3-[(1,1′-bip h en yl-4-yl)-
m eth yl]-4H-1-ben zop yr a n -4-on e (13m ): from 12i; yield
31%; mp 210-3 °C (acetone/petroleum ether); 1H NMR 10.70
(1H, s), 9.25 (1H, s), 7.90 (1H, d, J ) 8.75), 7.50 (9H, m), 7.00
(2H, m), 6.88 (1H, dd, J ) 8.75), 6.75 (1H, d, J ) 2.24), 6.66
(2H, m), 3.98 (4H, s). C29H22O4: C, H.
7-Cya n o-2-(4′-m e t h oxyb e n zyl)-4H -1-b e n zop yr a n -4-
on e (14a ). To a solution of 12n (1.60 g, 4.64 mmol) in
anhydrous DMF (10 mL) was added CuCN (0.45 g, 5.10 mmol).
The reaction mixture was then heated at 150 °C for 3 h. After
cooling, the reaction mixture was added to a solution of FeCl3
(2.0 g) in water (40 mL) and the resulting mixture extracted
with CHCl3. Column chromatography (cyclohexane:AcOEt, 70:
30) afforded 0.72 g (53%) of 14a : mp 98 °C; 1H NMR 8.30 (1H,
d, J ) 1.50), 8.11 (1H, d, J ) 8.14), 7.85 (1H, dd, J ) J ) 1.50.
J ) 8.14), 7.35 (2H, m), 6.95 (2H, m), 6.30 (1H, s), 4.00 (2H,
s), 3.76 (3H, s).
7-Cya n o-2-(4′-h yd r oxyb e n zyl)-4H -1-b e n zop yr a n -4-
on e (14b). A solution of 14a (0.66 g, 2.24 mmol) in methylene
chloride (40 mL) at 0 °C was treated with BBr3 (1 M solution
in CH2Cl2) (11 mL, 11 mmol). The resulting solution was
stirred at room temperature for 3 h and cooled at 0 °C, water
1
yield 1.85 g (39.5%); H NMR (CDCl3) 8.12 (1H, d, J ) 8.05),
7.42 (1H, d, J ) 1.0), 7.35 (1H, dd, J ) 8.05, J ) 1.0), 7.40
(2H, m), 6.90 (2H, m), 6.13 (1H, s), 3.87 (2H, s), 3.83 (3H, s),
3.54 (2H, s), 2.29 (6H, s).
Gen er a l P r oced u r e for th e Syn th esis of Com p ou n d s
13a -m . To a stirred solution of 12a -i (1.35 mmol) in
anhydrous methylene chloride (30 mL) at 0 °C under N2
atmosphere was added a BBr3 solution in methylene chloride
(4 equiv for 12f,g, 5 equiv for 12a -d ,h ,i, 6 equiv for 12e); the
solution was left to stand at room temperature for 24h, then
it was cooled again to 0 °C, and water and ice were added.
The resulting precipitate was collected and washed with water,
then purified by column chromatography (methylene chloride:
methanol, 96:4), and crystallized as described. Shortening the
reaction time (3 h instead of 24 h) afforded compounds 13b,d
from 12a ,b, respectively.
6-H yd r oxy-2-(4′-h yd r oxyb en zyl)-4H -1-b en zop yr a n -4-
on e (13a ): from 12a ; yield 83%; mp 218-20 °C (acetone); 1H