Calcitonin-Inducing Agents
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 6 1229
MHz on a Bruker DPX-300 spectrometer using tetramethyl-
silane (δ 0.0) as an internal standard. Infrared (IR) spectra
were obtained as KBr pellets. Combustion analyses were
obtained using a Perkin-Elmer series II 2400 CHNS/O ana-
lyzer. Mass spectra were obtained using a Micromass platform
electrospray ionization quadrapole mass spectrometer. Flash
chromatography was performed using EM Science 230-400
mesh silica gel. Thin-layer chromatography (TLC) was per-
formed in Analtech silica gel GHLF 250-µm prescored plates.
(s, 1H); IR (KBr, cm-1) 1710, 1668; MS 405 (MH)+. Anal.
C
19H24N4O4S: C, H, N.
1,3-Dib u t yl-7-(2-flu or ob en zen esu lfon yl)-3,7-d ih yd r o-
p u r in e-2,6-d ion e (13). Compound 13 was prepared according
to method B using 1,3-dibutyl-3,7-dihydropurine-2,6-dione and
(2-F)PhSO2Cl: yield 86%; mp 122-123 °C; 1H NMR (300 MHz,
CDCl3) δ 0.89 (t, J ) 7.5 Hz, 3H), 0.96 (t, J ) 7.5, 3H); 1.22-
1.43 (m, 4H), 1.45-1.54 (m, 2H), 1.72 (pent, J ) 7.5 Hz, 2H),
3.87 (t, J ) 7.5 Hz, 2H), 4.08 (t, J ) 7.4 Hz, 2H), 7.19 (t, J )
9.1 Hz, 1H), 7.44 (t, J ) 7.9 Hz, 1H), 7.68-7.78 (m, 1H), 8.37
(s, 1H), 8.44 (td, J ) 7.9, 1.7 Hz, 1H); IR (KBr, cm-1) 1713,
1665; MS 423 (MH)+. Anal. C19H23FN4O4S: C, H, N.
1,3-Dibu tyl-7-m eth a n esu lfon yl-3,7-d ih yd r op u r in e-2,6-
d ion e (7). Meth od A. To 500 mg (1.89 mmol) of 1,3-dibutyl-
3,7-dihydropurine-2,6-dione12 in 30 mL of acetone at 23 °C was
added 1.04 g (7.56 mmol) of K2CO3 followed by 0.15 mL (216
mg, 1.89 mmol) of MeSO2Cl. After stirring at 23 °C for 30 min,
the reaction mixture was filtered, and the filtrate collected and
evaporated to give a white solid. This solid was then triturated
with 30 mL of petroleum ether to give 500 mg (1.46 mmol, a
77% yield) of the title compound as a white crystalline solid:
2-(1,3-Dibu tyl-2,6-d ioxo-1,2,3,6-tetr a h yd r op u r in e-7-su l-
fon yl)ben zoic Acid Meth yl Ester (14). Compound 14 was
prepared according to method A using 1,3-dibutyl-3,7-dihy-
dropurine-2,6-dione and (2-CO2Me)PhSO2Cl: yield 60%; mp
1
106-109 °C; H NMR (300 MHz, CDCl3) δ 0.88-1.0 (m, 6H),
1.30-1.43 (m, 4H), 1.50-1.60 (m, 2H), 1.66-1.77 (m, 2H), 3.92
(t, J ) 7.6 Hz, 2H), 3.96 (s, 3H), 4.09 (t, J ) 7.6 Hz, 2H), 7.65-
1
mp 98-100 °C; H NMR (300 MHz, CDCl3) δ 0.93-0.99 (m,
7.81 (m, 3H), 8.32 (s, 1H), 8.86-8.94 (m, 1H); IR (KBr, cm-1
)
6H), 1.42-1.49 (m, 4H), 1.55-1.58 (m, 2H), 1.60-1.70 (m, 2H),
3.85 (s, 3H), 3.99-4.04 (m, 2H), 4.05-4.16 (t, 2H), 8.17 (s, 1H),
8.55; IR (KBr, cm-1) 1715, 1663, 1537, 1397, 1182; MS 343
(MH)+. Anal. C14H22N4O4S: C, H, N.
1711, 1668; MS 463 (MH)+. Anal. C21H26N4O6S: C, H, N.
1,3-Dibu tyl-7-(2,5-d im eth ylben zen esu lfon yl)-3,7-d ih y-
d r op u r in e-2,6-d ion e (15). Compound 15 was prepared ac-
cording to method A using 1,3-dibutyl-3,7-dihydropurine-2,6-
1,3-Dibu tyl-7-p r op a n esu lfon yl-3,7-d ih yd r op u r in e-2,6-
d ion e (8). Meth od B. To 412 mg (1.56 mmol) of 1,3-dibutyl-
3,7-dihydropurine-2,6-dione in 15 mL of CH2Cl2 at 23 °C were
added 0.41 mL (302 mg, 2.34 mmol) of i-Pr2NEt and 0.19 mL
(245 mg, 1.72 mmol) of n-PrSO2Cl. After stirring at 23 °C at
24 h, the reaction mixture as poured into 50 mL of brine and
extracted with 2 × 30 mL of EtOAc. The combined organics
were washed with 1 × 50 mL of H2O and 1 × 50 mL of brine,
dried over MgSO4, filtered and evaporated to a light yellow
oil. Flash chromatography on silica gel, eluting with CH2Cl2/
EtOAc (40/1), gave the title compound as an off-white solid.
Recrystallization from hot hexanes/EtOAc gave 156 mg (0.42
1
dione and (2,5-Me2)PhSO2Cl: yield 73%; mp 120-122 °C; H
NMR (300 MHz, CDCl3) δ 0.89 (t, J ) 7.3 Hz, 3H), 0.96 (t, J
) 7.4 Hz, 3H), 1.23-1.43 (m, 4H), 1.46-1.56 (m, 2H), 1.63-
1.78 (m, 2H), 2.46 (s, 6H), 3.88 (t, J ) 7.5 Hz, 2H), 4.08 (t, J
) 7.5 Hz, 2H), 7.17 (d, J ) 7.8 Hz, 1H), 7.37 (dd, J ) 1.9, 7.8
Hz, 1H), 8.32 (d, J ) 2.0 Hz, 1H), 8.35 (s, 1H); IR (KBr, cm-1
)
1712, 1666; MS 433 (MH)+. Anal. C21H28N4O4S: C, H, N.
1,3-Dibu tyl-7-(5-flu or o-2-m eth ylben zen esu lfon yl)-3,7-
d ih yd r op u r in e-2,6-d ion e (16). Compound 16 was prepared
according to method A using 1,3-dibutyl-3,7-dihydropurine-
2,6-dione and (5-F,2-Me)PhSO2Cl: yield 84%; mp 88-90 °C;
1H NMR (300 MHz, CDCl3) δ 0.90 (t, J ) 7.3 Hz, 3H), 0.96 (t,
J ) 7.4 Hz, 3H), 1.26-1.46 (m, 4H), 1.48-1.56 (m, 2H), 1.68-
1.74 (m, 2H), 2.48 (s, 3H), 3.88 (t, J ) 7.6 Hz, 2H), 4.08 (t, J
) 7.6 Hz, 2H), 7.26-7,33 (m, 2H), 8.24 (dd, J ) 2.2, 8.0 Hz,
1H), 8.35 (s, 1H); IR (KBr, cm-1) 1711, 1667; MS 437 (MH)+.
Anal. C20H25FN4O4S: C, H, N.
1
mmol, a 27% yield) of 8 as a white solid: mp 73-74 °C; H
NMR (300 MHz, CDCl3) δ 0.92-1.01 (m, 6H), 1.11 (t, J ) 7.4
Hz, 3H), 1.32-1.48 (m, 4H), 1.60-1.79 (m, 4H), 1.92 (hex, J
) 7.6 Hz, 2H), 3.96-4.06 (m, 4H), 4.12 (t, J ) 7.6 Hz, 2H),
8.15 (s, 1H); IR (KBr, cm-1) 1699, 1667, 1376; MS 371 (MH)+.
Anal. C16H26N4O4S: C, H, N.
1,3-Dibu tyl-7-(4-m eth oxyben zen esu lfon yl)-3,7-dih ydr o-
p u r in e-2,6-d ion e (17). Compound 17 was prepared according
to method A using 1,3-dibutyl-3,7-dihydropurine-2,6-dione and
(4-OMe)PhSO2Cl: yield 80%; mp 68-70 °C; 1H NMR (300
MHz, CDCl3) δ 0.91-0.99 (m, 6H), 1.38 (m, 4H), 1.53-1.75
(m, 4H), 3.89 (s, 3H), 3.94 (t, J ) 7.5 Hz, 2H), 4.06 (t, J ) 7.5
Hz, 2H), 7.03 (d, J ) 8.1 Hz, 2H), 8.24 (d, J ) 8.1 Hz, 2H),
8.27 (s, 1H); IR (KBr, cm-1) 1714, 1667, 1167; MS 435 (MH)+.
Anal. C20H26N4O5S: C, H, N.
1,3-Dib u t yl-7-(3-ch lor op r op a n e-1-su lfon yl)-3,7-d ih y-
d r op u r in e-2,6-d ion e (9). Compound 9 was prepared accord-
ing to method B using 1,3-dibutyl-3,7-dihydropurine-2,6-dione
1
and Cl(CH2)3SO2Cl: yield 90%; mp 71-73 °C; H NMR (300
MHz, CDCl3) δ 0.90-1.01 (m, 6H), 1.32-1.49 (m, 4H), 1.56-
1.80 (m, 4H), 2.30-2.42 (m, 4H), 3.69 (t, J ) 6.1 Hz, 2H), 4.01
(t, J ) 7.6 Hz, 2H), 4.12 (t, J ) 7.4 Hz, 2H), 4.23 (t, J ) 7.6
Hz, 2H), 8.15 (s, 1H); IR (KBr, cm-1) 1704, 1670, 1385; MS
406 (MH)+. Anal. C16H25ClN4O4S: C, H, N.
1,3-Dibu tyl-7-(3-n itr oben zen esu lfon yl)-3,7-d ih yd r op u -
r in e-2,6-d ion e (18). Compound 18 was prepared according
to method B using 1,3-dibutyl-3,7-dihydropurine-2,6-dione and
1,3-Dibu tyl-7-bu ta n esu lfon yl-3,7-d ih yd r op u r in e-2,6-d i-
on e (10). Compound 10 was prepared according to method A
using 1,3-dibutyl-3,7-dihydropurine-2,6-dione and n-BuSO2-
Cl: yield 82%; mp 185-187 °C; 1H NMR (300 MHz, CDCl3) δ
0.93-0.99 (m, 9H), 1.39-1.88 (m, 11H), 3.98-4.09 (m, 6H),
4.10-4.19 (m, 4H), 8.14 (s, 1H); IR (KBr, cm-1) 1717, 1672,
1466, 1194; MS 385 (MH)+. Anal. C17H28N4O4S: C, H, N.
1
(3-NO2)PhSO2Cl: yield 79%; mp 178-179 °C; H NMR (300
MHz, CDCl3) δ 0.88-0.99 (m, 6H), 1.28-1.43 (m, 4H), 1.50-
1.62 (m, 2H), 1.62-1.75 (m, 2H), 3.93 (t, J ) 7.5 Hz, 2H), 4.10
(t, J ) 7.5 Hz, 2H), 7.86 (t, J ) 8.1 Hz, 1H), 8.34 (s, 1H), 8.56
(dd, J ) 2.0, 8.1 Hz, 1H), 8.77 (d, J ) 8.0 Hz, 1H), 9.01 (t, J )
2.0 Hz, 1H); IR (KBr, cm-1) 1717, 1661, 1538; MS 450 (MH)+.
Anal. C19H23N5O6S: C, H, N.
1,3-Dibu tyl-7-octa n esu lfon yl-3,7-d ih yd r op u r in e-2,6-d i-
on e (11). Compound 11 was prepared according to method B
using 1,3-dibutyl-3,7-dihydropurine-2,6-dione and n-octylSO2-
Cl: yield 98%; mp 59-60 °C; 1H NMR (300 MHz, CDCl3) δ
0.89 (t, J ) 7.5 Hz, 3H), 0.92-1.00 (m, 6H), 1.20-1.32 (m, 8
H), 1.34-1.49 (m, 6H), 1.57-1.68 (m, 2H), 1.70-1.79 (m, 2H),
1.79-1.89 (m, 2H), 3.97-4.05 (m, 4H), 4.12 (t, J ) 7.5 Hz, 2H),
8.14 (s, 1H); IR (KBr, cm-1) 1708, 1667, 1373, 1178; MS 441
(MH)+. Anal. C21H36N4O4S: C, H, N.
1,3-Dib u t yl-7-(3,4-d im et h oxyb en zen esu lfon yl)-3,7-d i-
h yd r op u r in e-2,6-d ion e (19). Compound 19 was prepared
according to method B using 1,3-dibutyl-3,7-dihydropurine-
2,6-dione and (3,4-OMe)PhSO2Cl: yield 81%; mp 134-135 °C;
1H NMR (300 MHz, CDCl3) δ 0.88-0.99 (m, 6H), 1.30-1.43
(m, 4H), 1.50-1.62 (m, 2H), 1.63-1.76 (m, 2H), 3.91-4.00 (m,
2H), 3.95 (s, 3H), 3.99 (s, 3H), 4.09 (t, J ) 7.5 Hz, 2H), 6.98 (d,
J ) 8.7 Hz, 1H), 7.86 (dd, J ) 2.3, 8.7 Hz, 1H), 7.97 (d, J )
2.3 Hz, 1H), 8.25 (s, 1H); IR (KBr, cm-1) 1713, 1668, 1513,
1273; MS 465 (MH)+. Anal. C21H28N4O6S: C, H, N.
7-Ben zen esu lfon yl-1,3-d ibu tyl-3,7-d ih yd r op u r in e-2,6-
d ion e (12). Compound 12 was prepared according to method
A using 1,3-dibutyl-3,7-dihydropurine-2,6-dione and PhSO2-
Cl: yield 61%; mp 144-146 °C; 1H NMR (300 MHz, CDCl3) δ
0.92 (t, J ) 7.5 Hz, 6H), 1.31-1.43 (m, 4H), 1.51-1.75 (m, 4H),
3.96 (t, J ) 7.5 Hz, 2H), 4.03 (t, J ) 7.5 Hz, 2H), 7.60 (t, J )
8.2 Hz, 2H), 7.68-7.76 (m, 1H), 8.29 (d, J ) 8.1 Hz, 2H), 8.29
7-(4-Bu toxyben zen esu lfon yl)-1,3-d ibu tyl-3,7-d ih yd r o-
p u r in e-2,6-d ion e (20). Compound 20 was prepared according
to method B using 1,3-dibutyl-3,7-dihydropurine-2,6-dione and
1
(4-n-OBu)PhSO2Cl: yield 88%; mp 84-86 °C; H NMR (300