5
486 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 17
Arafa et al.
‚0.25C OH
in toluene (10 mL) was added ethyl isothocyanatoformate (0.41
g, 3.1 mmol). The reaction mixture was heated at reflux for
19), 255 (100). Anal. Calcd for C27
(520.13): C, 63.50; H, 7.26; N, 16.15. Found: C, 63.20; H, 7.06;
N, 16.35.
H
36
N
6
O
4
2 5
H
1
0 h. After cooling to room temperature, the reaction mixture
was diluted with hexanes. The orange precipitate obtained was
2,7-Bis(N′-ethoxycarbonyl-N′′-methoxy)guanidino-9H-
fluorene (11f). With the general procedure and O-methylhy-
droxylamine hydrochloride, a tan white solid was obtained
filtered off and crystallized from aqueous EtOH (0.66 g, 98%):
mp >340 °C (dec); H NMR (DMSO-d
1
6
) δ 1.26 (t, J ) 7.2 Hz,
6
7
2
1
H), 4.22 (q, J ) 7.2 Hz, 4H), 7.69 (dd, J ) 8.1, 1.8 Hz, 2H),
.80 (d, J ) 8.1 Hz, 2H), 7.97 (d, J ) 1.8 Hz, 2H), 11.39 (s,
H), 11.60 (s, 2H); 13C NMR (DMSO-d
) δ 191.6, 178.7, 153.4,
40.8, 139.0, 133.8, 130.9, 121.2, 120.2, 62.0, 14.0. Anal. Calcd
‚H O (490.55): C, 51.41; H, 4.52. Found: C,
1
6
(0.55 g, 87%): mp 180-2 °C; H NMR (DMSO-d ) δ 0.92-0.95
(m, 6H), 1.20 (t, J ) 6.9 Hz, 6H), 3.67 (s, 6H), 3.69 (s, 6H),
3.73-3.86 (m, 8H), 4.10 (q, J ) 6.9 Hz, 4H), 6.99 (d, J ) 8.1
Hz, 2H), 7.16 (s, 2H), 7.35 (d, J ) 8.1 Hz, 2H), 7.55-7.62 (m,
6H), 8.34 (br s, 1H), 8.36 (br s, 1H), 8.70 (br s, 2H), 9.13 (br s,
6
for C21
1.27; H, 4.54.
Preparation of N-Substituted Carbamoyl Guanidines
General Procedure) (Scheme 2). 2,7-Bis(N′-ethoxycar-
H
20 4
N O
S
5 2
2
5
2H), 9.15 (br s, 2H); MS (ESI) m/z (rel intens) 485 (M + 1,
+
100).
(
2,7-Bis(N′-ethoxycarbonyl-N′′-isobutoxy)guanidino-
9H-fluorene (11g). Following the general procedure, O-
isobutylhydroxylamine hydrochloride was used to prepare the
target compound, which was obtained as creamy white crystals
bonyl)guanidino-9H-fluorene (11a). A stirred solution of
carbamoyl thiourea (10a) (0.58 g, 1.26 mmol), ammonia (0.5
M solution in dioxane) (10 mL, 5.05 mmol), and diisopropyl-
1
ethylamine (0.98 g, 7.56 mmol) in anhydrous CH
2
Cl
2
(10 mL)
(0.8 g, 93%): mp 122-5 °C; H NMR (DMSO-d ) δ 0.88-0.99
6
was cooled to 0 °C. EDCI (N-ethyl-N′-(3-dimethylaminopropyl)-
carbodiimide hydrochloride) (0.96 g, 5.05 mmol) was added,
and the solution was stirred at room temperature overnight.
The reaction mixture was washed with water (3×) followed
(m, 30H), 1.21 (t, J ) 7.2 Hz, 6H), 1.92-2.02 (m, 4H), 3.65 (d,
J ) 6.6 Hz, 8H), 3.74-3.78 (m, 4H), 3.85 (q, J ) 7.2 Hz, 4H),
4.11 (q, J ) 7.2 Hz, 4H), 7.00 (d, J ) 8.1 Hz, 2H), 7.17 (s, 2H),
7.35 (d, J ) 8.1 Hz, 2H), 7.55-7.62 (m, 6H), 8.19 (br s, 1H),
8.21 (br s, 1H), 8.67 (br s, 1H), 8.68 (br s, 1H), 9.01 (br s, 1H),
2 4
by brine and dried over anhydrous Na SO . The residue
1
3
remaining after removal of the solvent was crystallized from
9.02 (br s, 1H), 9.10 (br s, 1H), 9.11 (br s, 1H); C NMR
1
EtOH/water (0.45 g, 84%): mp >340 °C; H NMR (DMSO-d
δ 1.16 (t, J ) 7.2 Hz, 6H), 3.87 (s, 2H), 3.98 (q, J ) 7.2 Hz,
H), 7.33 (d, J ) 8.4 Hz, 2H), 7.54 (br s, 4H), 7.65 (s, 2H), 7.72
6
)
(DMSO-d ) δ 154.0, 153.9, 153.3, 143.4, 143.3, 143.1, 142.9,
6
142.9, 142.3, 142.2, 138.8, 138.6, 137.9, 137.7, 135.8, 135.6,
134.4, 134.2, 119.7, 119.4, 199.1, 118.8, 117.7, 117.6, 116.6,
114.5, 79.5, 79.3, 61.1, 60.4, 36.6, 36.5, 36.3, 27.3, 27.3, 19.3,
4
(
1
3
d, J ) 8.4 Hz, 2H), 9.13 (br s, 2H); C NMR (DMSO-d
6
) δ
63.1, 159.0, 143.4, 136.9, 136.3, 120.4, 119.4, 118.4, 59.4, 36.4,
4.4. Anal. Calcd for C21 ‚0.5C OH (447.48): C,
9.04; H, 6.08; N, 18.78. Found: C, 58.96; H, 5.74; N, 18.88.
,7-Bis(N′-ethoxycarbonyl)guanidinofluoren-9-one
+
1
1
5
14.4; MS (ESI) m/z (rel intens) 569 (M + 1, 100).
H
24
N
O
6 4
2 5
H
Preparation of N-Substituted Guanidines (General
Procedure) (Scheme 2). 2,7-Bis(N′-methyl)guanidino-9H-
fluorene (12a). The substituted guanidine 11c (0.5 g, 1.1
mmol) was suspended in EtOH (5 mL), and 1 N KOH (11 mL,
11 mmol) was then added. The reaction mixture was kept
stirring for 10 h, maintaining the temperature at 50 °C. The
solvent was evaporated, and the residue was washed multiple
times with water and crystallized from aqueous EtOH to give
2
1
(
11b). Brick-red solid (0.35 g, 75%), mp >340 °C; H NMR
DMSO-d ) δ 1.17 (t, J ) 6.9 Hz, 6H), 4.00 (q, J ) 6.9 Hz, 4H),
.47 (dd, J ) 8.1, 1.8 Hz, 2H), 7.59 (d, J ) 8.1 Hz, 2H), 7.77
(
6
7
(
1
3
d, J ) 1.8 Hz, 2H), 9.31 (br s, 2H); C NMR (DMSO-d
6
) δ
92.9, 162.6, 158.6, 139.6, 138.4, 134.1, 126.5, 120.8, 116.7,
9.9, 14.6. Anal. Calcd for C21 ‚0.15C OH‚0.5H
1
5
1
H
22
N
O
6 5
2
H
5
2
O
a light-orange solid (0.24 g, 70%): mp 240-2 °C (dec); H NMR
(
454.35): C, 56.30; H, 5.30; N, 18.49. Found: C, 56.54; H, 5.10;
6
(DMSO-d ) δ 2.66 (s, 6H), 3.69 (s, 2H), 4.96 (br s, 4H), 5.34 (br
N, 18.47.
s, 2H), 6.70 (d, J ) 8.1 Hz, 2H), 6.90 (s, 2H), 7.50 (d, J ) 8.1
2
,7-Bis(N′-ethoxycarbonyl-N′′-methyl)guanidino-9H-
Hz, 2H).
fluorene (11c). With the same procedure for preparation of
For preparation of the HCl salt, a solution of the free base
in dry EtOH (20 mL) chilled in an ice bath was treated with
dry HCl gas for 10 min. The reaction mixture was concentrated
under reduced pressure and then diluted with ether. The
1
1a, methylamine (2 M solution in THF) was used for the
transformation of the thiourea compound (10a) into the
N-substituted guanidine 11c. The reaction yielded an off-white
1
solid (0.53 g, 93%): mp 157-8 °C; H NMR (DMSO-d
6
) δ 1.15
precipitate formed was collected by filtration to give an orange
1
(
t, J ) 7.2 Hz, 6H), 2.83 (s, 6H), 3.90 (s, 2H), 3.94 (q, J ) 7.2
solid (0.16 g): mp 276-8 °C; H NMR (DMSO-d
6
) δ 2.84 (s,
Hz, 4H), 7.32 (d, J ) 8.1 Hz, 2H), 7.54 (s, 2H), 7.83 (d, J ) 8.1
6H), 3.96 (s, 2H), 7.25 (d, J ) 8.4 Hz, 2H), 7.46 (s, 2H), 7.77
(br s, 2H), 7.89 (br s, 2H), 7.95 (d, J ) 8.4 Hz, 2H), 10.01 (br
s, 2H); C NMR (DMSO-d ) δ 155.7, 144.5, 138.6, 134.2, 123.5,
6
121.5, 120.9, 36.6, 28.3; MS (ESI) m/z (rel intens) 309 (M
1, 100), 155 (9). Anal. Calcd for C17 ‚2HCl‚0.25C OH‚
0.75H O (406.33): C, 51.73; H, 6.20; N, 20.68. Found: C, 51.77;
H, 6.24; N, 20.48.
1
3
Hz, 2H); C NMR (DMSO-d
6
) δ 161.9, 157.9, 143.7, 137.7,
13
1
(
35.9, 123.1, 121.1, 119.9, 59.9, 36.5, 28.3, 14.5; MS (ESI) m/z
+
+
rel intens) 453 (M + 1, 100), 407 (39), 323 (15). Anal. Calcd
for C23 ‚H O (470.52): C, 58.71; H, 6.42; N, 17.86.
Found: C, 58.81; H, 6.39; N, 17.71.
,7-Bis(N′-ethoxycarbonyl-N′′-ethyl)guanidino-9H-flu-
orene (11d). Following the general procedure, starting with
0a and utilizing ethylamine hydrochloride, the target com-
pound was obtained as a beige solid (0.79 g, 96%): mp 220-2
+
H
28
6
N O
4
2
H
20
N
6
2 5
H
2
2
2,7-Bis(N′-ethyl)guanidino-9H-fluorene (12b). Free
1
Base. Starting with 11d and following the general procedure,
a beige solid was obtained (0.24 g, 85%): mp 155-7 °C (dec);
1
1
°
C; H NMR (DMSO-d
6
) δ 1.12-1.19 (m, 12H), 3.32 (t, J ) 6.9
6
H NMR (DMSO-d ) δ 1.07 (t, J ) 7.2 Hz, 6H), 3.14 (q, J )
Hz, 4H), 3.89 (s, 2H), 3.95 (q, J ) 6.9 Hz, 4H), 7.31 (d, J ) 8.1
7.2 Hz, 4H), 3.68 (s, 2H), 5.00 (br s, 6H), 6.68 (d, J ) 8.1 Hz,
1
3
13
Hz, 2H), 7.51 (s, 2H), 7.81 (d, J ) 8.1 Hz, 2H); C NMR
DMSO-d ) δ 163.3, 158.1, 143.7, 137.5, 136.0, 123.1, 121.1,
20.0, 59.7, 36.5, 35.7, 14.8, 14.6; MS (ESI) m/z (rel intens)
2H), 6.88 (s, 2H), 7.49 (d, J ) 8.1 Hz, 2H); C NMR (DMSO-
(
1
4
6
6
d ) δ 151.2, 148.9, 143.3, 134.3, 121.4, 119.6, 118.9, 36.2, 35.1,
+
15.0; MS (ESI) m/z (rel intens) 337 (M + 1, 90), 292 (60), 205
+
81 (M , 80), 435 (20), 364 (10), 339 (12), 241 (100). Anal. Calcd
‚0.25H O (485.06): C, 61.90; H, 6.75; N, 17.32.
Found: C, 61.66; H, 6.79; N, 17.37.
(50), 169 (100).
for C25
H
32
N
6
O
4
2
Dihydrochloride Salt. Bright-yellow solid, mp 193-5 °C
1
(dec); H NMR (DMSO-d ) δ 1.14 (t, J ) 7.2 Hz, 6H), 3.28 (q,
6
2
,7-Bis(N′-ethoxycarbonyl-N′′-isopropyl)guanidino-9H-
J ) 7.2 Hz, 4H), 3.95 (s, 2H), 7.24 (d, J ) 8.1 Hz, 2H), 7.44 (s,
2H), 7.74 (br s, 4H), 7.95 (d, J ) 8.1 Hz, 2H), 8.03 (br s, 2H),
fluorene (11e). With isopropylamine and the same synthetic
steps used for preparing 11a, a beige solid was obtained (0.39
24 6 2 2 5
9.96 (br s, 2H). Anal. Calcd for C19H N ‚2HCl‚1.75H O‚0.2C H -
1
OH (450.09): C, 51.76; H, 6.87; N, 18.67. Found: C, 51.86; H,
6.64; N, 18.68.
6
g, 88%): mp 142-4 °C; H NMR (DMSO-d ) δ 0.84 (t, J ) 7.2
Hz, 6H), 1.10-1.23 (m, 12H), 3.88 (s, 2H), 3.93 (q, J ) 7.2 Hz,
4
7
1
3
H), 4.10-4.21 (m, 2H), 7.31 (d, J ) 8.4 Hz, 2H), 7.52 (s, 2H),
2,7-Bis(N′-isopropyl)guanidino-9H-fluorene (12c). Free
13
6
.80 (d, J ) 8.4 Hz, 2H); C NMR (DMSO-d ) δ 163.42, 157.38,
Base. Starting with (11e) and following the general procedure,
43.54, 137.36, 136.25, 122.93, 120.93, 119.72, 59.60, 42.35,
a salmon-orange solid was obtained (0.17 g, 79%): mp 247-9
6.47, 22.53, 14.57; MS (ESI) m/z (rel intens) 509 (M+ + 1,
°C (dec); H NMR (DMSO-d
1
6
) δ 1.11 (d, J ) 5.4 Hz, 12H), 3.68