4698 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 24
Norman et al.
and dried to give 1.15 g (27%) of the title compound as off-
white crystals. Mp: 231-234 °C. 1H NMR (DMSO-d6): δ 1.61
(m, 2), 1.76 (m, 2), 3.18-3.38 (m, 8), 3.57 (m, 2), 4.10 (m, 2),
7.47 (tm, 1, J ) 7.6), 7.61 (m, 2), 8.02 (m, 2), 8.12 (t, 2, J )
8.1), 8.65 (dt, 1, J ) 4.7, 1.2), 8.92 (t, 1, J ) 6.2), 10.30 (br s,
1). 13C NMR (DMSO-d6): δ 21.79, 27.54, 39.31, 47.51, 51.61,
56.32, 122.36, 123.02, 125.15, 125.78, 127.61, 128.10, 129.28,
138.94, 149.50, 151.16, 153.24, 163.37, 165.04. MS (CI/CH4,
50 mA/s): M + 1, base (396). Anal. (C21H25N5OS‚HCl) C, H,
N, S, Cl.
to stir at room temperature for 1 h. The resulting white
crystals were collected by filtration and dried in a vacuum oven
to give the corresponding hydrochloride salts.
3-Am in o-N-(4-(4-(1,2-ben zisoth iazol-3-yl)-1-piper azin yl)-
b u t yl)-2-p yr id in eca r b oxa m id e H yd r och lor id e (16).
TLC: silica gel, MeOH/CHCl3 (1:9), Rf ) 0.47. Mp: 238-240
°C. 1H NMR (DMSO-d6): δ 1.59 (m, 2), 1.74 (m, 2), 3.30 (m,
8), 3.58 (m, 2), 4.08 (m, 2), 6.84 (br s, 2), 7.15 (dd, 1, J ) 1.4,
8.4), 7.24 (dd, 1, J ) 4.2, 8.4), 7.47 (tm, 1, J ) 8.0), 7.60 (tm,
1, J ) 8.0), 7.79 (dd, 1, J ) 1.4, 4.2), 8.12 (t, 2, J ) 8.2), 8.69
(br t, 1, J ) 6.2), 10.40 (br s, 1). 13C NMR (DMSO-d6): δ 20.77,
26.55, 37.68, 46.47, 50.56, 55.29, 121.27, 124.07, 124.53,
124.70, 127.02, 127.24, 128.19, 128.91, 135.49, 146.32, 152.17,
162.28, 167.56. MS (CI/CH4, 50 mA/s): m/z M + 1 (411). Anal.
(C21H26N6OS‚HCl) C, H, N, S, Cl.
2-Am in o-N-(4-(4-(1,2-ben zisoth iazol-3-yl)-1-piper azin yl)-
b u t yl)-3-p yr id in eca r b oxa m id e H yd r och lor id e (19).
TLC: silica gel, MeOH/CHCl3 (1:9), Rf ) 0.25. Mp: 220-222
°C. 1H NMR (DMSO-d6): δ 1.59 (m, 2), 1.75 (m, 2), 3.32 (m,
8), 3.57 (m, 2), 4.08 (m, 2), 6.60 (dd, 1, J ) 4.8, 7.7), 7.10 (s, 2),
7.47 (t, 1, J ) 7.6), 7.60 (t, 1, J ) 7.5), 7.93 (dd, 1, J ) 0.8,
7.6), 8.07 (dd, 1, J ) 1.3, 4.7), 8.12 (t, 2, J ) 8.0), 8.54 (br t, 1,
J ) 5.5), 10.55 (br s, 1). 13C NMR (DMSO-d6): δ 20.84, 26.30,
38.45, 46.62, 50.71, 55.38, 110.97, 111.59, 121.51, 124.32,
124.94, 127.28, 128.45, 138.10, 149.18, 152.47, 158.05, 162.58,
167.33. MS (CI/CH4, 50 mA/s): M + 1 (411). Anal. (C21H26N6-
OS‚HCl) C, H, N, S, Cl.
3-Am in o-N-(4-(4-(1,2-ben zisoth iazol-3-yl)-1-piper azin yl)-
bu tyl)-4-p yr id in eca r boxa m id e Dih yd r och lor id e Hyd r a te
(18) a n d 4-Am in o-N-(4-(4-(1,2-ben zisoth ia zol-3-yl)-1-p ip -
er a zin yl)bu tyl)-3-p yr id in eca r boxa m id e Dih yd r och lor id e
(17). A 1:1 mixture of 4-azaisatoic anhydride (11) and 5-aza-
isatoic anhydride (12) (4.71 g, 28.7 mmol) was added to a
stirred solution of 3-(4-(4-aminobutyl)-1-piperazinyl)-1,2-benz-
isothiazole (8.33 g, 28.7 mmol, 1.0 equiv) in anhydrous THF
(40 mL). The reaction mixture was allowed to stir under N2
at room temperature for 1 h. The solvent was removed with
a rotary evaporator, and the resulting crude residue was
purified by flash chromatography (2×) on silica gel, once with
5:95 MeOH-CH2Cl2 and 0.1% triethylamine as eluant and
once with 3:97 MeOH-CH2Cl2 and 0.1% triethylamine as
eluant, to give 3.11 g (26%) of 3-amino-N-(4-(4-(1,2-benz-
isothiazol-3-yl)-1-piperazinyl)butyl)-4-pyridinecarboxamide as
a tan powder (TLC: silica gel, MeOH/CH2Cl2 (5:95), Rf ) 0.44)
and 2.99 g (24%) of 4-amino-N-(4-(4-(1,2-benzisothiazol-3-yl)-
1-piperazinyl)butyl)-3-pyridinecarboxamide as an orange solid
(TLC: silica gel, MeOH/CH2Cl2 (5:95), Rf ) 0.32). The
hydrochloride salts of each isomer were prepared independ-
ently by treatment with 1 N ethereal HCl. The salts were
recrystallized from either EtOH/Et2O or 95% EtOH/Et2O/
hexanes and dried in a vacuum oven.
4-Am in o-N-(4-(4-(1,2-ben zisoth iazol-3-yl)-1-piper azin yl)-
b u t yl)-3-p yr id in eca r b oxa m id e Dih yd r och lor id e (17).
Mp: 122-130 °C (effervesces). 1H NMR (DMSO-d6): δ 1.64
(m, 2), 1.79 (m, 2), 3.07 (m, 2), 3.30 (m, 8), 3.74 (br s, 2), 6.93
(d, 1, J ) 6.6), 7.48 (t, 1, J ) 7.5), 7.61 (t, 1, J ) 8.7), 8.12 (m,
1), 8.44 (br d, J ) 2), 8.74 (s, 1), 8.97 (br t, 1, J ) 5.6), 12.40
(br s, 1). 13C NMR (DMSO-d6): δ 21.12, 26.07, 38.30, 46.95,
50.83, 55.51, 111.05, 111.14, 121.22, 124.07, 124.64, 127.06,
128.13, 141.52, 142.36, 152.11, 157.68, 162.50, 165.22. Anal.
(C21H26N6OS‚2HCl) C, H, N.
N-(4-(4-(1,2-Ben zisoth ia zol-3-yl)-1-p ip er a zin yl)bu tyl)-
3-p yr id in eca r boxa m id e Hyd r och lor id e (14). Nicotinoyl
chloride hydrochloride (5) (1.1 g, 6.1 mmol) was added por-
tionwise to an ice-cold, stirred solution of 3-(4-(4-aminobutyl)-
1-piperazinyl)-1,2-benzisothiazole (1.8 g, 6.0 mmol) and tri-
ethylamine (2.5 mL, 17.9 mmol, 3.0 equiv) in CH2Cl2 (25.0 mL).
The resulting suspension was allowed to stir at 0 °C for 0.5 h
and at room temperature for 2 h. The cloudy reaction mixture
was diluted with CH2Cl2 (25.0 mL) and washed with saturated
aqueous NaHCO3 (2 × 50 mL). The organic layer was
separated, dried over Na2SO4, filtered, and concentrated with
a rotary evaporator to give an off-white foam. The crude
material was dissolved in 2-propanol (20.0 mL), chilled with
an ice-water bath, and treated dropwise with HCl (6.0 mL of
a 1 N solution in Et2O) with swirling. The mixture was diluted
with Et2O (40.0 mL), and the resulting off-white solid was
filtered and washed with Et2O (3 × 10 mL). The salt was
recrystallized from 95% EtOH to give 1.47 g (57%) of the title
compound as off-white crystals. Mp: 229-231 °C. 1H NMR
(DMSO-d6): δ 1.64 (m, 2), 1.81 (m, 2), 3.27 (m, 4), 3.47 (m, 2),
3.62 (br d, 2, J ) 11.5), 4.10 (br d, 2, J ) 13.1), 7.56 (m, 2),
7.62 (t, 1, J ) 7.6), 8.14 (t, 2, J ) 6.8), 8.23 (d, 1, J ) 6.2), 8.73
(d, 1, J ) 4.5), 8.81 (br t, 1, J ) 6.2), 9.05 (s, 1), 10.82 (br s, 1).
13C NMR (DMSO-d6): δ 21.76, 27.33, 39.58, 47.53, 51.61, 56.25,
122.35, 124.57, 125.16, 125.78, 128.11, 129.28, 131.10, 136.15,
149.55, 152.88, 153.26, 163.39, 165.92. MS (CI/CH4, 50 mA/
s): M + 1 (396). Anal. (C21H25N5OS‚HCl) C, H, N, S, Cl.
N-(4-(4-(1,2-Ben zisoth ia zol-3-yl)-1-p ip er a zin yl)bu tyl)-
4-p yr id in eca r boxa m id e Hyd r och lor id e (15). This com-
pound was prepared according to the method described for
compound 14, by employing isonicotinoyl chloride hydrochlo-
ride (6) (1.1 g, 6.1 mmol), 3-(4-(4-aminobutyl)-1-piperazinyl)-
1,2-benzisothiazole (1.8 g, 6.0 mmol), and triethylamine (2.5
mL, 17.9 mmol, 3.0 equiv) in CH2Cl2 (25.0 mL). The crude
hydrochloride salt was recrystallized from 95% EtOH to give
1.20 g (46%) of the title compound as off-white crystals. Mp:
238-240 °C. 1H NMR (DMSO-d6): δ 1.64 (m, 2), 1.80 (m, 2),
3.29 (m, 4), 3.46 (m, 2), 3.61 (br d, 2, J ) 10.5), 4.10 (br d, 2,
J ) 10.5), 7.49 (t, 1, J ) 7.6), 7.62 (t, 1, J ) 7.6), 7.80 (d, 2, J
) 5.8), 8.15 (t, 2, J ) 6.7), 8.75 (d, 2, J ) 5.8), 8.90 (br t, 1, J
) 5.5), 10.80 (br s, 1). 13C NMR (DMSO-d6): δ 21.76, 27.24,
39.68, 47.53, 51.61, 56.24, 122.36, 122.45, 125.17, 125.78,
128.11, 129.28, 142.56, 151.30, 153.26, 163.39, 165.78. MS (CI/
CH4, 50 mA/s): M + 1 (396). Anal. (C21H25N5OS‚HCl) C, H,
N, S, Cl.
2-Am in o-N-(4-(4-(1,2-ben zisoth iazol-3-yl)-1-piper azin yl)-
bu tyl)-3-p yr id in eca r boxa m id e Hyd r och lor id e (19) a n d
3-Am in o-N-(4-(4-(1,2-ben zisoth ia zol-3-yl)-1-p ip er a zin yl)-
bu tyl)-2-p yr id in eca r boxa m id e Hyd r och lor id e (16). A 2:1
mixture of 3-azaisatoic anhydride (9) and 6-azaisatoic anhy-
dride (10) (1.0 g, 6.1 mmol) was added to a stirred solution of
3-(4-(4-aminobutyl)-1-piperazinyl)-1,2-benzisothiazole (1.8 g,
6.0 mmol) in THF (20.0 mL). The reaction mixture was
allowed to stir under nitrogen at room temperature for 0.5 h.
The solvent was removed with a rotary evaporator, and the
resulting crude residue was purified by flash chromatography
on silica gel with a gradient eluant of CH2Cl2 (100%)/CH2Cl2-
MeOH (98.5:1.5)/CH2Cl2-MeOH (97:3)/CH2Cl2-MeOH (93:7)
to give 1.48 g (91%) of 2-amino-N-(4-(4-(1,2-benzisothiazol-3-
yl)-1-piperazinyl)butyl)-3-pyridinecarboxamide (19) as a foam
and 0.54 g (66%) of 3-amino-N-(4-(4-(1,2-benzisothiazol-3-yl)-
1-piperazinyl)butyl)-2-pyridinecarboxamide (16) as a foam. The
hydrochloride salts of each isomer were prepared independ-
ently by dissolving the free amine in CH2Cl2 (20.0 mL),
filtering, and treating the filtrate with 1 N ethereal HCl (1
equiv). The solutions were diluted with EtOAc and allowed
3-Am in o-N-(4-(4-(1,2-ben zisoth iazol-3-yl)-1-piper azin yl)-
bu tyl)-4-p yr id in eca r boxa m id e Dih yd r och lor id e Hyd r a te
(18). Mp: 229-231 °C. 1H NMR (DMSO-d6): δ 1.61 (m, 2),
1.83 (m, 2), 3.25 (m, 6), 3.55 (m, 4), 4.06 (br d, 2, J ) 13.2),
7.46 (t, 1, J ) 7.6), 7.59 (dt, 1, J ) 8.1, 0.8), 8.04 (s, 2), 8.12 (t,
1, J ) 8.1), 8.31 (s, 1), 9.24 (br t, 1, J ) 4.4), 11.45 (br s, 1).
13C NMR (DMSO-d6): δ 20.73, 26.05, 38.47, 46.54, 50.64, 55.26,
121.51, 124.32, 124.93, 126.48, 126.40, 127.02, 127.28, 128.44,
130.62, 146.83, 152.46, 162.59, 165.43. Anal. (C21H26N6OS‚
2HCl‚0.5H2O) C, H, N, Cl, H2O.
Meth yl 4-((ter t-Bu toxyca r bon yl)a m in o)-3-th iop h en e-
ca r boxyla t e (22). Methyl 4-aminothiophene-3-carboxylate
hydrochloride (21) (6.57 g, 33.9 mmol), 1,4-dioxane (25 mL),
and 5% aqueous Na2CO3 (25 mL) were combined in a 500 mL,
round-bottomed flask, and the mixture was cooled in an ice-