Irosustat SAR
[D6]DMSO) d=0.90 (t, J~7 Hz, 3H, CH3), 1.39 (m, 4H), 1.51 (m, 2H),
1.59 (m, 2H), 1.75 (m, 2H), 1.86 (m, 2H), 2.93 (m, 2H), 3.12 (m, 2H),
4.33 (t, J=6.6 Hz, 2H, OCH2), 6.91 (dd, J=2.3 and 8.9 Hz, 1H,
C2-H), 6.97 (d, J=2.3 Hz, 1H, C4-H), 7.88 (d, J=8.9 Hz, 1H, C1-H)
and 9.81 ppm (brs, 1H, ex. with D2O, OH); MS (FAB+): m/z (%):
300.2 (100) [M+H]+, 230.1 (30); MS (FABꢀ) m/z (%) 452.2 (7)
[M+NBA]ꢀ, 298.2 (100) [MꢀH]ꢀ, 228.1(17); HRMS-FAB+: m/z [M+
H]+ calcd for C19H26NO2: 300.1964, found: 300.1962; Anal. calcd for
C19H25NO2: C 76.22, H 8.42, N 4.68, found: C 75.9, H 8.50, N, 4.66.
438.2433, found: 438.2423. Anal. calcd for C30H31NO2: C 82.35, H
7.14, N, 3.20, found: C 82.7, H 7.14, N 3.43.
3-Hydroxy-5-(3-phenylpropyl)-8,9,10,11-tetrahydro-5H-cyclohep-
ta[c]quinolin-6(7H)-one (22b).
A solution of 22a (300 mg,
686 mmol) in absolute EtOH (30 mL) was debenzylated by hydroge-
nation in similar manner to 18a in the presence of Pd/C (10%,
60 mg). The crude solid that resulted (205 mg, 590 mmol, 86%) was
recrystallised from toluene/hexane (8:3) to give 22b as creamy
crystals (150 mg): Rf =0.68 (CHCl3/EtOAc, 4:1), c.f. Rf =0.91 (22a);
mp: 182–1868C; 1H NMR (400 MHz, [D6]DMSO): d=1.45 (m, 2H),
1.56 (m, 2H), 1.81 (m, 2H), 1.90 (quintet, J=7.8 Hz, 2H,
NCH2CH2CH2Ph), 2.73 (t, J=7.8 Hz, 2H, CH2Ph), 2.88 (m, 2H), 2.96
(m, 2H), 4.18 (t, J=7 Hz, 2H, NCH2), 6.72 (dd, J=2.3 and 8.9 Hz,
1H, C2-H), 6.78 (d, J=2 Hz, 1H, C4-H), 7.25 (m, 5H, Ph), 7.76 (d, J=
8.9 Hz, 1H, C1-H) and 10.1 (brs, 1H, ex. with D2O, OH); MS (FAB+):
m/z (%): 348.3 (100) [M+H]+, 243.2 (18); MS (FABꢀ): m/z (%):
500.3(47) [M+NBA]ꢀ, 346.3 (100) [MꢀH]ꢀ; HRMS-FAB+: m/z
[M+H]+ calcd for C23H26NO2: 348.1964, found: 348.1964.
6-(Pentyloxy)-8,9,10,11-tetrahydro-7H-cyclohepta[c]quinolin-3-yl
sulfamate (21). Compound 21b (140 mg, 468 mmol) in anhydrous
DMF (10 mL) was sulfamoylated in a similar manner to 16a. The
crude light-brown syrup (175 mg) that was obtained was fractio-
nated on silica with EtOAc/hexane (1:3 ! 1:2). The second fraction
that was collected gave 21 as a yellow syrup that solidified to wax
upon standing at room temperature overnight (87 mg, 230 mmol,
49%): Rf =0.41 (EtOAc/hexane, 1:2), c.f. Rf =0.54 (21b); mp: 103–
1
1078C; H NMR (400 MHz, [D6]DMSO) d=0.92 (t, J=7 Hz, 3H, CH3),
1.41 (m, 4H), 1.54 (m, 2H), 1.61 (m, 2H), 1.78 (m, 2H), 1.89 (m, 2H),
3.01 (m, 2H), 3.22 (m, 2H), 4.40 (t, J=6.5 Hz, 2H, OCH2), 7.30 (dd,
J=2.3 and 8.9 Hz, 1H, C2-H), 7.59 (d, J=2.3 Hz, 1H, C4-H), 8.06 (s,
2H, ex. with D2O, OSO2NH2) and 8.17 ppm (d, J=9 Hz, 1H, C1-H);
MS (FAB+): m/z (%): 379.2 (100) [M+H]+, 300.2 (5) [M+
HꢀHNSO2]+; MS (FABꢀ): m/z (%): 377.1 (100) [MꢀH]ꢀ, 298.2 (11)
[MꢀH2NSO2]ꢀ, 77.9 (52); HRMS-FAB+: m/z [M+H]+ calcd for
C19H27N2O4S: 379.1692, found: 379.1691; Anal. calcd for
C19H26N2O4S: C 60.30, H 6.92, N 7.40, found: C 60.5, H 7.05, N 7.34.
6-Oxo-5-(3-phenylpropyl)-6,7,8,9,10,11-hexahydro-5H-cyclohep-
ta[c]quinolin-3-yl sulfamate (22). Compound 22b (100 mg,
288 mmol) in anhydrous DMF (10 mL) was sulfamoylated in a simi-
lar manner to 16a. The crude light-yellow residue (122 mg) ob-
tained was fractionated on silica with CHCl3/EtOAc (8:1). The
second fraction that was collected gave a light-yellow syrup that
solidified on standing overnight to give 22 as a white solid (65 mg,
152 mmol, 53%). Recrystallisation from hot CHCl3/hexane (5:4) gave
22 as fine white crystals (39 mg): Rf =0.23 (CHCl3/EtOAc, 8:1), c.f.
Rf =0.43 (22b); mp: 176–1798C; IR (KBr) n˜ =3650–3000, 3000–
3-(Benzyloxy)-5-(3-phenylpropyl)-8,9,10,11-tetrahydro-5H-cyclo-
hepta[c]quinolin-6(7H)-one (22a) and 3-(benzyloxy)-6-(3-phenyl-
propoxy)-8,9,10,11-tetrahydro-7H-cyclohepta[c]quino-line (23a).
NaH (60% in mineral oil, 65 mg, 1.62 mmol) was added to a solu-
tion of 17 (500 mg, 1.57 mmol) in DMF (40 mL) at room tempera-
ture cautiously followed by 1-bromo-3-phenylpropane (0.25 mL,
1.65 mmol) 15 min later after the evolution of H2 had ceased. The
reaction mixture was heated at 1008C for 1 h and then concentrat-
ed in vacuo after cooling to room temperature. The crude material
that was obtained was dissolved in EtOAc (100 mL) and the result-
ing mixture was washed with brine (4ꢁ50 mL), dried (MgSO4), fil-
tered and evaporated to give a yellow syrup which was fractionat-
ed on silica eluting first with CHCl3/hexane (2:1 ! 4:1 gradient),
then CHCl3 followed by CHCl3/EtOAc (2:1 ! 1:2 gradient). The first
fraction that was collected upon evaporation gave 23a as a light-
yellow syrup (287 mg, 656 mmol, 42%): Rf =0.71 (CHCl3/hexane,
2:1), c.f. Rf <0.1 (17); 1H NMR (400 MHz, [D6]DMSO): d=1.57 (m,
4H), 2.09 (quintet, J=7 Hz, 2H, OCH2CH2CH2Ph), 2.77 (t, 2H,
CH2CH2Ph), 2.98 (m, 2H), 3.16 (m, 2H), 4.35 (t, J=6.3 Hz, 2H,
OCH2CH2), 5.23 (s, 2H, OCH2Ph), 7.09 (dd, J=2.5 and 9 Hz, 1H, C2-
H), 7.34 (m, 11H, C4-H and 2ꢁAr) and 7.98 ppm (d, J=9 Hz, 1H,
C1-H); MS (FAB+): m/z (%): 438.4 (20) [M+H]+, 319.3 (14) [M+H-
CH2CH2CH2Ph]+, 91.1 (45) [Bn]+, 73.1(100); HRMS-FAB+: m/z
[M+H]+ calcd for C30H32NO2: 438.2433, found: 438.2438. The
second fraction that was collected upon evaporation gave a clear
syrup (373 mg, 852 mmol, 55%) that was recrystallised from EtOAc/
hexane (1:15, ~32 mL) to give 22a as light-beige rod-shaped crys-
tals (240 mg): Rf =0.38 (CHCl3/hexane, 2:1), c.f. Rf <0.1 (17); mp:
120–1228C; 1H NMR (400 MHz, [D6]DMSO) d=1.45 (m, 2H), 1.56
(m, 2H), 1.83 (m, 4H), 2.71 (t, J=7.4 Hz, 2H, CH2CH2Ph), 2.89 (m,
2H), 2.98 (m, 2H), 4.22 (t, J=7.6 Hz, 2H, NCH2), 5.17 (s, 2H,
OCH2Ph), 6.83 (d, J=2.3 Hz, 1H, C4-H), 6.93 (dd, J=2.3 and 8 Hz,
1H, C2-H), 7.34 (m, 10H, Ar) and 7.86 ppm (d, J=9 Hz, 1H, C1-H);
MS (FAB+): m/z (%): 438.4 (100) [M+H]+, 346.3 (20) [MꢀBn]+, 91.1
(62) [Bn]+; HRMS-FAB+: m/z [M+H]+ calcd for C30H32NO2:
1
2800, 1610, 1560, 1380, 1190 cmꢀ1; H NMR (400 MHz, [D6]DMSO)
d=1.45 (m, 2H), 1.56 (m, 2H), 1.83 (m, 2H), 1.91 (m, 2H), 2.71 (t,
J=7.7 Hz, 2H, CH2Ph), 2.92 (m, 2H), 3.03 (m, 2H), 4.24 (t, J=7.7 Hz,
2H, CH2N), 7.22 (m, 6H, C2-H and Ar), 7.35 (d, J=2.2 Hz, 1H, C4-H),
8.03 (d, J=8.8 Hz, 1H, C1-H) and 8.08 ppm (brs, 2H, ex. with D2O,
OSO2NH2); MS (FAB+): m/z (%): 427.2 (100) [M+H]+, 346.2 (25)
[MꢀH2NSO2]+; MS (FABꢀ): m/z (%): 425.1(100) [MꢀH]ꢀ, 346.2 (19)
[MꢀH2NSO2]ꢀ; HRMS-FAB+: m/z [M+H]+ calcd for C23H27N2O4S:
427.1620, found 427.1695. Anal. calcd for C23H26N2O4S: C 64.77, H
6.14, N 6.57, found: C 64.2, H 6.13, N 6.65.
6-(3-Phenylpropoxy)-8,9,10,11-tetrahydro-7H-cyclohepta[c]qui-
nolin-3-ol (23b). A solution of 23a (255 mg, 583 mmol) in a mix-
ture of absolute EtOH (30 mL) and THF (10 mL) was debenzylated
by hydrogenation in similar manner to 18a in the presence of Pd/
C (10%, 51 mg). The crude yellow syrup that was obtained solidi-
fied on standing overnight to give 23b as a yellow wax (182 mg,
524 mmol, 90%): Rf =0.61 (CHCl3/EtOAc, 4:1), c.f. Rf =0.88 (23a);
mp: ~1358C; IR (KBr) n˜ =3700–2500, 3000–2800, 1615, 1590, 1420,
1330, 1200 cmꢀ1 1H NMR (400 MHz, [D6]DMSO) d=1.57 (m, 4H),
;
1.86 (m, 2H), 2.08 (m, 2H, CH2CH2CH2Ph), 2.77 (t, J=7.5 Hz, 2H,
CH2Ph),2.95 (m, 2H), 3.13 (m, 2H), 4.33 (t, J=6.4 Hz, 2H, OCH2),
6.91 (dd, J=2.7 and 8.9 Hz, 1H, C2-H), 6.95 (d, J=2.3 Hz, 1H, C4-
H), 7.25 (m, 5H, Ar), 7.88 (d, J=8.9 Hz, 1H, C1-H) and 9.82 (brs, 1H,
ex. with D2O, OH); MS (FAB+): m/z (%): 348.3 (100) [M+H]+, 229.3
(40) [M+HꢀCH2CH2CH2Ph]+; MS (FABꢀ): m/z (%): 346.3 (100)
[MꢀH]ꢀ, 275.2 (40), 181.2 (50); HRMS-FAB+: m/z [M+H]+ calcd for
C23H26NO2: 348.1964, found: 348.1969.
6-(3-Phenylpropoxy)-8,9,10,11-tetrahydro-7H-cyclohepta[c]qui-
nolin-3-yl sulfamate (23). Compound 23b (135 mg, 389 mmol) in
anhydrous DMF (10 mL) was sulfamoylated in a similar manner to
16a. The crude light-brown syrup (175 mg) that obtained was frac-
tionated on silica with EtOAc/hexane (1:3 ! 1:2). The second frac-
tion that was collected gave 23 as a yellow syrup that solidified to
ChemMedChem 2011, 6, 2019 – 2034
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2033