5-HT1D Receptor Agonists as Antimigraine Agents
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 4 703
The residue was partitioned between CH2Cl2 (100 mL) and
H2O (100 mL). The organic layer was separated and the
aqueous phase extracted with CH2Cl2 (50 mL). The combined
organic layers were dried (Na2SO4) and evaporated and the
residue chromatographed on silica gel (CH2Cl2:MeOH (90:10)).
The title compound (1.44 g, 30%) was isolated as a colorless
oil: 1H NMR (CDCl3) δ 1.44 (9H, s), 2.74 (2H, t, J ) 6.0 Hz),
2.79 (2H, m), 2.88 (2H, m), 3.19 (2H, m), 4.87 (1H, br s), 7.19-
7.22 (3H, m), 7.26-7.31 (2H, m). Anal. (C15H24N2O2‚0.2(H2O))
C, H, N.
1-(2-P h en yleth yl)p ip er a zin -2-on e (37). To a solution of
bromoacetyl bromide (0.25 mL, 2.9 mmol) in CH2Cl2 (10 mL)
at -10 °C was added a solution of 35 (0.7 g, 2.7 mmol) and
Et3N (0.41 mL, 2.9 mmol) in CH2Cl2 (10 mL). The mixture was
stirred at -10 °C for 30 min; then the solvent was removed in
vacuo. The residue was partitioned between EtOAc (30 mL)
and H2O (30 mL). The organic layer was separated, dried (Na2-
SO4), and evaporated. The residue was chromatographed on
silica gel (hexane:EtOAc (2:1)) to afford the amide 36 (0.81 g,
79%) as a colorless oil: 1H NMR (CDCl3) δ 1.44 (9H, s), 2.86-
2.94 (2H, m), 3.10-3.94 (8H, m), 4.59 and 4.92 (1H, br s), 7.15-
7.37 (5H, m); MS (ES+) 385/387 (M+).
Cl2 (100 mL) and H2O (100 mL). The organic layer was
separated, dried (Na2SO4), and evaporated. The residue was
chromatographed on silica gel (CH2Cl2:MeOH:NH3 (90:10:1))
to afford the title compound (0.42 g, 33%) as a pale-yellow oil:
1H NMR (CDCl3) δ 1.44 (9H, s), 1.84-1.96 (2H, m), 2.68-2.85
(6H, m), 3.16-3.26 (2H, m), 4.91 (1H, br s), 7.13-7.17 (2H,
m), 7.48 (1H, d, J ) 8.6 Hz), 7.56 (1H, d, J ) 2.1 Hz), 8.48
(2H, s), 8.53 (1H, br s). Anal. (C20H28N6O2‚1.2(H2O)) C, H, N.
Eth yl 2-[(P h en ylm eth yl)-(3-[5-(1,2,4-tr ia zol-4-yl)-1H-in -
d ol-3-yl]p r op yl)a m in o]eth yla m in oa ceta te (39). To a solu-
tion of 38 (0.42 g, 1.1 mmol) in MeOH (10 mL) at 0 °C were
added benzaldehyde (133 µL, 1.3 mmol), AcOH (189 µL, 3.3
mmol), and NaCNBH3 (137 mg, 2.2 mmol). The cooling bath
was removed and the mixture stirred at room temperature for
4 h. More benzaldehyde (220 µL, 2.2 mmol) was added and
the mixture stirred for an additional 18 h. The solvents were
evaporated, and the residue was partitioned between EtOAc
(50 mL) and H2O (50 mL). The organic layer was separated,
dried (Na2SO4), and evaporated. The residue was chromato-
graphed on silica gel (CH2Cl2:MeOH:NH3 (95:5:1)) to give
2-(phenylmethyl-(3-[5-(1,2,4-triazol-4-yl)-1H-indol-3-yl]propyl)-
amino)ethylcarbamic acid tert-butyl ester (0.44 g, 85%) as a
pale-yellow foam: 1H NMR (CDCl3) δ 1.41 (9H, s), 1.84-1.96
(2H, m), 2.52-2.58 (4H, m), 2.75 (2H, t, J ) 7.5 Hz), 3.12-
3.20 (2H, m), 3.58 (2H, s), 4.78 (1H, br s), 7.03 (1H, s), 7.14
(1H, dd, J ) 8.5 and 2.0 Hz), 7.21-7.36 (5H, m), 7.45 (1H, d,
J ) 8.5 Hz), 7.51 (1H, d, J ) 2.0 Hz), 8.29 (1H, br s), 8.45 (2H,
s); MS (ES+) 475 (M + 1).
A solution of the preceding N-benzylated derivative (440 mg,
0.93 mmol) and TFA (3 mL) in CH2Cl2 (20 mL) was stirred at
room temperature for 5 h. After this time the solvent was
evaporated and the residue partitioned between CH2Cl2 (30
mL) and K2CO3 (10% (w/v), 20 mL). The organic layer was
separated and the aqueous phase extracted with CH2Cl2 (2 ×
30 mL). The combined organic layers were dried (Na2SO4) and
evaporated. N-(Phenylmethyl)-N-(3-[5-(1,2,4-triazol-4-yl)-1H-
indol-3-yl]propyl)-1,2-diaminoethane (287 mg, 83%) was iso-
lated as a colorless foam and used without further purifica-
tion: 1H NMR (CDCl3 + MeOH-d4) δ 1.83-1.99 (2H, m), 2.44-
2.59 (4H, m), 2.61-2.79 (4H, m), 3.58 (2H, s), 7.07 (1H, s), 7.11
(1H, dd, J ) 8.6 and 2.1 Hz), 7.20-7.32 (5H, m), 7.48 (1H, d,
J ) 8.6 Hz), 7.51 (1H, d, J ) 2.1 Hz), 8.49 (2H, s); HRMS
calcd: C22H26N6 375.2219 [M + H]+, found 375.2307.
To a mixture of the preceding diamine (125 mg, 0.33 mmol)
and K2CO3 (46 mg, 0.33 mmol) in DMF (10 mL) was added
ethyl bromoacetate (37 µL, 0.33 mmol) at 0 °C. The mixture
was stirred at 0 °C for 4 h, then the solvent was evaporated,
and the residue was partitioned between CH2Cl2 (20 mL) and
H2O (20 mL). The organic layer was separated and the aqueous
phase extracted further with CH2Cl2 (30 mL). The combined
organic layers were dried (Na2SO4) and evaporated, and the
residue was chromatographed on silica gel (CH2Cl2:MeOH (90:
10)). The ester (94 mg, 62%) was isolated as a colorless oil:
1H NMR (CDCl3) δ 1.23 (3H, t, J ) 7.2 Hz), 1.84-1.99 (2H,
m), 2.52-2.80 (6H, m), 3.31 (2H, s), 3.60 (2H, s), 4.15 (2H, q,
J ) 7.2 Hz), 7.01 (1H, s), 7.14 (1H, dd, J ) 8.5 and 2.1 Hz),
7.21-7.30 (5H, m), 7.45 (1H, d, J ) 8.5 Hz), 7.58 (1H, d, J )
2.1 Hz), 8.35 (1H, br s), 8.48 (2H, s); MS (ES+) 461 (M + 1).
A solution of 36 (0.81 g, 2.1 mmol) and TFA (2.5 mL) in
CH2Cl2 (25 mL) was stirred at room temperature for 1 h. The
solvent was removed in vacuo; the resultant amine trifluoro-
acetate dissolved in EtOH (50 mL) and K2CO3 (0.58 g, 4.2
mmol) was added. The mixture was heated at reflux for 20 h,
cooled to room temperature, and filtered. The filtrate was
evaporated and the residue partitioned between CH2Cl2 (30
mL) and H2O (30 mL). The organic phase was separated and
the aqueous layer extracted with CH2Cl2 (3 × 30 mL). The
combined organic layers were dried (Na2SO4) and evaporated,
and the residue was chromatographed on silica gel (CH2Cl2:
MeOH:NH3 (90:10:1)). The piperazinone 37 (0.36 g, 84%) was
1
isolated as a colorless solid: mp 75-78 °C; H NMR (CDCl3)
δ 2.89 (2H, t, J ) 7.1 Hz), 2.97 (2H, m), 3.14 (2H, m), 3.51
(2H, s), 3.59 (2H, t, J ) 7.2 Hz), 7.19-7.33 (5H, m). Anal.
(C12H16N2O) C, H, N.
Gen er a l P r oced u r e for th e P r ep a r a tion of P ip er a zi-
n on es 31 a n d 32 a n d Th iop ip er a zin on e 34. 1-(P h en ylm -
et h yl)-4-(3-[5-(1,2,4-t r ia zol-4-yl)-1H -in d ol-3-yl]p r op yl)-
p ip er a zin e-2-th ion e (34). To a suspension of 25 (150 mg, 0.62
mmol) in THF (80 mL) were added Et3N (172 µL, 1.24 mmol)
and methanesulfonyl chloride (96 µL, 1.24 mmol). The mixture
was stirred for 90 min; then more Et3N (86 µL, 0.62 mmol)
and methanesulfonyl chloride (48 µL, 0.62 mmol) were added.
The mixture was stirred for a further 1 h and then filtered
and the filtrate evaporated. The resultant crude mesylate was
treated with 30 (255 mg, 1.24 mmol), K2CO3 (257 mg, 1.9
mmol), and NaI (93 mg, 0.62 mmol) in isopropanol (20 mL)
and the mixture heated at reflux for 20 h. The mixture was
then cooled to room temperature and filtered and the filtrate
evaporated. The residue was partitioned between CH2Cl2 (50
mL) and H2O (50 mL). The organic phase was separated and
the aqueous layer extracted with CH2Cl2 (50 mL). The com-
bined organic layers were dried (Na2SO4) and evaporated, and
the residue was chromatographed on silica gel (CH2Cl2:MeOH:
NH3 (95:5:1)). The title piperazine (47 mg, 18%) was isolated
as a colorless solid: mp (MeOH) 201-203 °C; 1H NMR (DMSO-
d6) δ 1.81-1.92 (2H, m), 2.42 (2H, t, J ) 7.1 Hz), 2.70-2.76
(4H, m), 3.37-3.42 (2H, m), 3.61 (2H, s), 5.24 (2H, s), 7.27-
7.38 (7H, m), 7.47 (1H, d, 8.6 Hz), 7.77 (1H, s), 9.01 (2H, s),
11.07 (1H, br s). Anal. (C24H26N6S‚0.3(H2O)) C, H, N.
2-[3-[5-(1,2,4-Tr ia zol-4-yl)-1H-in d ol-3-yl]p r op yla m in o]-
eth ylca r ba m ic Acid ter t-Bu tyl Ester (38). To a suspension
of 25 (0.8 g, 3.3 mmol) in THF (250 mL) were added Et3N (0.51
mL, 6.6 mmol) and methanesulfonyl chloride (0.92 mL, 6.6
mmol). The mixture was stirred for 90 min, then filtered, and
evaporated. The crude mesylate was dissolved in 2-propanol
(130 mL), and K2CO3 (1.4 g, 9.9 mmol), NaI (0.5 g, 3.3 mmol),
and 2-aminoethylcarbamic acid tert-butyl ester (1.3 g, 8.3
mmol) were added. The mixture was heated at reflux in the
dark for 9 h. After cooling the mixture was filtered and the
filtrate evaporated. The residue was partitioned between CH2-
1(H )-4-(3-[5-(1,2,4-Tr ia zol-4-yl)-1H -in d ol-3-yl]p r op yl)-
p ip er a zin -3-on e (40). A solution of 39 (94 mg, 0.25 mmol)
and 1 M HCl (2 mL) in EtOH (20 mL) was hydrogenated at
40 psi for 3 h in the presence of palladium on carbon (10%,
121 mg). The catalyst was removed by filtration and the filtrate
evaporated and azeotroped with EtOH (20 mL) The resultant
foam was dissolved in EtOH (8 mL), K2CO3 (56 mg, 0.41 mmol)
added, and the mixture heated at reflux for 2 h. The solvent
was evaporated and the residue partitioned between CH2Cl2
(20 mL) and H2O (20 mL). The organic layer was separated
and the aqueous layer extracted with BuOH (3 × 15 mL). The
combined BuOH layers were evaporated, and the residue was
chromatographed on silica gel (CH2Cl2:MeOH:NH3 (60:8:1)) to
give the piperazinone (42 mg, 40%) as a colorless oil: 1H NMR
(CDCl3) δ 1.94-2.07 (2H, m), 2.80 (2H, t, J ) 7.2 Hz), 3.02
(2H, t, J ) 5.7 Hz), 3.31-3.37 (2H, m), 3.41-3.45 (4H, m),