4926 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 25
Halazy et al.
tected compound (634 mg, 94%). This intermediate was
deprotected under the conditions described for general method
A to give 4l (338 mg, 64%) isolated as the hydrochloride salt:
Celite, and the filtrate was concentrated. The crude product
was purified by chromatography (CH2Cl2/MeOH/NH4OH, 90/
9.5/0.5) to give 11 (1.68 g, 77%).
1
mp 140 °C; H NMR (DMSO-d6) δ 2.98 (br s, 8H, CH2), 3.40
P r epar ation of 2-[[3-(2-Am in oeth yl)-1H-in dol-5-yl]oxy]-
1-[4-[2-[[3-(2-a m in oeth yl)-1H-in d ol-5-yl]oxy]eth yl]p ip er -
a zin -1-yl]eth a n on e (4h ). A mixture of compound 11 (600
mg, 1.49 mmol), compound 8 (505 mg, 1.49 mmol), K2CO3 (618
mg, 4.47 mmol), and KI (25 mg, 0.15 mmol) in DMF (2 mL)
was heated at 90 °C for 48 h. The mixture was diluted with
EtOAC, washed with H2O and saturated NaCl, dried (Na2SO4),
and concentrated. The crude product was purified by chro-
matography (CH2Cl2/MeOH/NH4OH, 95/4.5/0.5) to give the
N-BOC-protected product (959 mg, 91%) which after depro-
tection afforded compound 4h (295 mg, 44%) isolated as the
hydrochloride salt: mp 187 °C; 1H NMR (DMSO-d6) δ 3.01 (br
s, 8H, CH2), 3.20-3.48 (m, 8H, CH2), 4.20-4.47 (m, 4H, CH2),
4.87 (s, 2H, OCH2CO), 6.76-6.85 (m, 2H, 6,6′-CH), 7.19-7.31
(m, 6H, Ar), 8.17 (br s, 6H, NH3+), 10.86 (d, 1H, J ) 2.0 Hz,
NH), 10.91 (d, 1H, J ) 2.0 Hz, NH), 11.65 (br s, 1H, NH+).
Anal. (C28H36N6O3‚3.4HCl‚1.3H2O) C, H, N, Cl.
(t, 4H, J ) 5.0 Hz, CH2), 3.93-3.99 (m, 4H, CH2), 6.74 (dd,
2H, J ) 2.1, 8.7 Hz, 6,6′-CH), 7.10 (d, 2H, J ) 2.0 Hz, 2,2′-
CH), 7.18 (d, 2H, J ) 2.1 Hz, 4,4′-CH), 7.24 (d, 2H, J ) 8.7
Hz, 7,7′-CH), 8.08 (br s, 6H, NH3+), 10.84 (d, 2H, J ) 2.0 Hz,
NH). Anal. (C25H34Cl2N6O3‚1H2O) C, H, N, Cl.
P r ep a r a tion of 4,4′-Bis[[[[6-[[3-(2-a m in oeth yl)-1H-in -
d ol-5-yl]oxy]h exyl]a m in o]su lfon yl]-1,1′-bip h en yl (4o). A
solution of intermediate 13 (1.0 g, 2.66 mmol) and Et3N (0.56
mL, 3.99 mmol) in anhydrous CH2Cl2 (15 mL) was treated at
0 °C with 4,4′-biphenyldisulfonyl chloride (470 mg, 1.33 mmol).
The mixture was stirred from 0 °C to room temperature for 1
h, diluted with CH2Cl2, washed with H2O and saturated NaCl,
dried (Na2SO4), and concentrated. The crude oil was purified
by chromatography (CH2Cl2/MeOH, 30/1) to give the N-BOC-
protected product (1.1 g, 80%). This intermediate (600 mg,
0.583 mmol) was deprotected under the conditions described
for general method A to give 4o (396 mg, 73%) isolated as the
hydrochloride salt: mp 140 °C; 1H NMR (DMSO-d6) δ 1.33 (br
s, 12H, CH2), 1.60-1.70 (m, 4H, CH2), 2.78 (m, 4H, CH2), 2.90-
3.00 (m, 8H, CH2), 3.91 (t, 4H, J ) 6.3 Hz, CH2O), 6.69 (dd,
2H, J ) 2.2, 8.6 Hz, 6,6′-CH), 7.04 (d, 2H, J ) 2.0 Hz, 2,2′-
CH), 7.16 (d, 2H, J ) 2.2 Hz, 4,4′-CH), 7.22 (d, 2H, J ) 8.6
Hz, 7,7′-CH), 7.73-7.97 (m, 14H, Ar, NH3+), 10.80 (d, 2H, J )
2.0 Hz, NH). Anal. (C44H56N6O6S2‚2HCl‚1.5H2O‚0.3EtOH) C,
H, N, Cl.
Ack n ow led gm en t. The authors wish to thank Elis-
abeth Dupeyron for preparing the manuscript.
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P r ep a r a tion of 2-[5-[2-[[3-(2-Am in oeth yl)-1H-in d ol-5-
yl]oxy]eth oxy]-1H-in d ol-3-yl]eth yla m in e (4a ). A solution
of compound 5 (1.5 g, 5.43 mmol) in dry DMF (15 mL) was
treated at room temperature by NaH (60% in oil) (217 mg,
5.43 mmol) for 1 h. Compound 7 (1.8 g, 5.43 mmol) was added,
and the mixture was heated at 80 °C overnight. The reaction
mixture was diluted with EtOAc, washed with H2O and
saturated NaCl, dried (Na2SO4), and concentrated. The crude
product was purified by chromatography (CH2Cl2/MeOH/NH4-
OH, 97.75/2/0.25 to 96.5/3/0.5) to give the N-BOC-protected
product (1.7 g, 54%). This intermediate (8.61 mg, 1.49 mmol)
was then deprotected to give 4a (275 mg, 49%) isolated as the
(3) (a) Saudou, F.; Hen, R. 5-HT receptor subtypes: Molecular and
functional diversity. Med. Chem. Res. 1994, 4, 16-84. (b)
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contraction in bovine cerebral arteries: a model for human
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1
hydrocholoride salt: mp 270 °C; H NMR (DMSO-d6) δ 3.00
(br s, 8H, CH2), 4.34 (s, 4H, CH2), 6.77 (dd, 2H, J ) 2.1, 8.7
Hz, 6,6′-CH), 7.18-7.29 (m, 6H, Ar), 8.14 (br s, 6H, NH3+),
10.86 (d, 2H, J ) 2.0 Hz, NH). Anal. (C22H28Cl2N4O2‚1H2O)
C, H, N, Cl.
P r ep a r a tion of 2-[5-[2-[4-[2-[[3-(2-Am in oeth yl)-1H-in -
d ol-5-yl]oxy]eth yl]p ip er a zin -1-yl]eth oxy]-1H-in d ol-3-yl]-
eth yla m in e (4i). A mixture of compound 7 (1.5 g, 4.43 mmol),
K2CO3 (1.8 g, 13.2 mmol), KI (73 mg, 0.44 mmol), and
piperazine (191 mg, 2.21 mmol) in DMF (4 mL) was heated at
90 °C for 48 h. The reaction mixture was then diluted with
EtOAC, washed with H2O and NaCl, dried (Na2SO4), and
concentrated. The crude product was purified by chromatog-
raphy (CH2Cl2/MeOH/NH4OH, 95/4.5/0.5) to give the N-BOC-
protected product (986 mg, 64%) which, after deprotection,
afforded 4i (638 mg, 91%) isolated as the hydrochloride salt:
mp 182 °C; 1H NMR (DMSO-d6) δ 3.02 (br s, 8H, CH2), 3.65-
3.86 (m, 12H, CH2), 4.47 (br s, 4H, CH2O), 6.85 (dd, 2H, J )
2.1, 8.6 Hz, 6,6′-CH), 7.22-7.32 (m, 6H, Ar), 8.21 (br s, 6H,
NH3+), 10.95 (d, 2H, J ) 2.0 Hz, NH). Anal. (C28H42
Cl4N6O2‚2.1H2O) C, H, N.
-
P r epar ation of 2-[[3-(2-Am in oeth yl)-1H-in dol-5-yl]oxy]-
1-p ip er a zin -1-yleth a n on e (11). A mixture of compound 10
(2.0 g, 5.98 mmol) and N-methylmorpholine (0.98 mL, 8.97
mmol) in CH2Cl2 (100 mL) was treated, at -15 °C and under
nitrogen, with ethyl chloroformate (0.74 mL, 7.77 mmol). The
reaction mixture was stirred at -15 °C for 0.5 h, and then
benzylpiperazine (2.6 mL, 15 mmol) was added. The reaction
mixture was allowed to stir from -15 °C to room temperature
for 1 h and then diluted with CH2Cl2, washed with NaHCO3
and H2O, dried (NaSO4), and concentrated. The crude product
was purified by chromatography (CH2Cl2/MeOH/NH4OH, 95/
4.5/0.5) to give the pure intermediate (2.66 g, 90%). This
product was hydrogenated over Pd/C (10%) (∼250 mg, 0.27
mmol) in MeOH (160 mL), under 1 atm of H2, at room
temperature for 4 days. The mixture was filtered through