A. Tsotinis et al. / European Journal of Pharmaceutical Sciences 18 (2003) 297–304
301
Hz), 3.64 (d, 2H, CH2NH, J 5 5.8 Hz), 4.04 (t, 2H, 6-H,
2.1.5. 1-(6,7,8,9-Tetrahydropyrido[1,2-a]indol-10-yl)-
cyclobutanecarbonitrile (18)
J 5 6.2 Hz), 5.25 (br s, 1H, NH), 6.99–7.09 (m, 1H,
Harom), 7.10–7.19 (m, 1H, Harom), 7.25–7.29 (m, 1H,
Harom), 7.72–7.80 (m, 1H, Harom) ppm; 13C NMR, d 5
21.2, 23.4, 23.6, 24.0, 26.5, 35.7, 42.3, 48.9, 99.2, 108.7,
117.6, 119.3, 120.4, 127.9, 134.1, 136.0, 172.8 ppm. Anal.
Calc. for C18H24N2O (284.40): C, 76.02; H, 8.50; N, 9.85.
Found: C, 75.95; H, 8.45; N, 9.80.
A solution of the acetonitrile 10 (0.15 g, 0.71 mmol)
and 1,3-dibromopropane (143.4 mg, 0.71 mmol) in DMSO
(2 ml) was added dropwise at 0 8C to a stirred suspension
of sodium hydride (60% dispersion in mineral oil, 0.08 g,
2.13 mmol) in DMSO (2.5 ml). The reaction mixture was
then allowed to warm to room temperature. After stirring
for 18 h, the resulting suspension was treated with
saturated NH4Cl (5 ml) and extracted with AcOEt. The
extract was washed with H2O and brine, dried over
Na2SO4 and the solvent removed in vacuo. The crude
product formed was triturated with AcOEt to give the
desired compounds as a white solid: Yield, 27%; m.p.,
2.1.4.2. N-[2-(6,7,8,9-Tetrahydropyrido[1,2-a]indol-10-
yl)-2-methylpropyl]butyramide (16b)
1
Yield, 33%; m.p., 129–131 8C; H NMR, d 5 0.96 (t,
3H, CH2CH3, J 5 7.3 Hz), 1.51 (s, 6H, C(CH3)2), 1.58–
1.76 (sextet, 2H, CH2CH3, J 5 7.3 Hz), 1.78–1.92 (m, 2H,
8-H), 1.94–2.06 (m, 2H, 7-H), 2.41 (t, 2H, COCH2,
J 5 7.3 Hz), 3.09 (t, 2H, 9-H, J 5 6.2 Hz), 3.64 (d, 2H,
CH2NH, J 5 6.2 Hz), 4.03 (t, 2H, 6-H, J 5 6.2 Hz), 5.25
(br s, 1H, NH), 6.99–7.08 (m, 1H, Harom), 7.09–7.17 (m,
1H, Harom), 7.20–7.27 (m, 1H, Harom), 7.72–7.79 (m, 1H,
Harom) ppm; 13C NMR, d 5 13.7, 19.2, 21.5, 23.5, 24.3,
26.5, 35.7, 38.8, 42.3, 48.6, 97.5, 108.5, 117.4, 119.6,
120.1, 128.2, 136.3, 137.1, 173.0 ppm. Anal. Calc. for
C20H28N2O (312.45): C, 76.88; H, 9.03; N, 8.96. Found:
C, 76.80; H, 9.00; N, 8.90.
1
116-119 8C; H NMR, d 5 1.81–1.97 (m, 2H, 8-H), 1.98–
2.12 (m, 3H, 7-H11H cyclobut.), 2.43–2.70 (m, 1H,
cyclobut.), 2.73–2.83 (m, 1H, cyclobut.), 2.84–2.96 (m,
5H, 9-H13H cyclobut.), 4.03 (t, 2H, 6-H, J 5 6.2 Hz),
7.03–7.20 (m, 2H, Harom), 7.21–7.29 (m, 1H, Harom),
7.44–7.52 (m, 1H, Harom) ppm; 13C NMR, d 5 17.8, 21.3,
23.8, 33.8, 34.0, 42.5, 98.7, 108.8, 117.5, 119.7, 120.2,
128.0, 135.8, 136.6, 137.0 ppm. Anal. Calc. for C17H18N2
(250.34): C, 81.56; H, 7.25; N, 11.19. Found: C, 81.46; H,
7.20; N, 11.15.
2.1.6. 1-(6,7,8,9-Tetrahydropyrido[1,2-a]indol-10-yl)-
cyclohexanecarbonitrile (19)
2.1.4.3. N-[2-(2-Methoxy-6,7,8,9-tetrahydropyrido[1,2-a]-
indol-10-yl)-2-methylpropyl]acetamide (17a)
1
A solution of the acetonitrile 10 (0.24 g, 1.14 mmol)
and 1,5-dibromopropane (315 mg, 1.37 mmol) in a mix-
ture of Et2O (1 ml) and DMSO (1 ml) was added dropwise
at 0 8C to a stirred suspension of sodium hydride (60%
dispersion in mineral oil, 0.14 g, 3.42 mmol) in DMSO (3
ml). The reaction mixture was then allowed to warm to
room temperature. After stirring for 18 h, the suspension
was treated with saturated NH4Cl (5 ml) and extracted
with AcOEt. The extract was washed with H2O and brine,
dried over Na2SO4 and the solvent removed in vacuo. The
crude product formed was triturated with AcOEt to give
the desired compound as a white solid. Yield, 45%; m.p.,
Yield, 35%; m.p., 136–137 8C; H NMR, d 5 0.84 (t,
3H, CH2CH3, J 5 7.3 Hz), 1.50 (s, 6H, C(CH3)2), 1.77–
1.92 (m, 5H, 8-H1COCH3), 1.93–2.08 (m, 2H, 7-H), 3.07
(t, 2H, 9-H, J 5 6.2 Hz), 3.63 (d, 2H, CH2NH, J 5 5.8
Hz), 3.83 (s, 3H, OCH3), 4.00 (t, 2H, 6-H, J 5 6.2 Hz),
5.26 (br s, 1H, NH), 6.81 (dd, 1H, 3-H, J 5 8.8, 2.2 Hz),
7.14 (d, 1H, 4-H, J 5 8.8 Hz), 7.23 (d, 1H, 1-H, J 5 2.2
Hz) ppm; 13C NMR, d 5 21.3, 23.5, 23.7, 24.1, 26.7, 35.8,
42.4, 49.0, 55.8, 98.8, 108.6, 117.5, 119.4, 128.0, 134.3,
136.1, 153.3, 172.5 ppm. Anal. Calc. for C19H26N2O2
(314.43): C, 72.58; H, 8.33; N, 8.91. Found: C, 72.48; H,
8.30; N, 8.90.
1
118–119 8C; H NMR, d 5 1.28–1.39 (m, 2H, cyclohex.),
1.56–1.63 (m, 1H, cyclohex.), 1.79–1.95 (m, 9H, 8-H17H
cyclohex.), 2.00–2.08 (m, 2H, 7-H), 3.20 (t, 2H, 9-H,
J 5 6.2 Hz), 4.04 (t, 2H, 6-H, J 5 6.2 Hz), 7.05–7.11 (m,
1H, Harom), 7.12–7.17 (m, 1H, Harom), 7.23–7.26 (m, 1H,
Harom), 7.78–7.82 (m, 1H, Harom) ppm; 13C NMR, d 5
21.6, 23.5, 23.7, 24.4, 25.3, 37.4, 42.3, 44.3, 99.1, 108.5,
117.3, 119.4, 121.7, 128.2, 136.4, 137.2 ppm. Anal. Calc.
for C19H22N2 (278.40): C, 81.97; H, 7.96; N, 10.06.
Found: C, 81.87; H, 7.86; N, 10.00.
2.1.4.4. N-[2-(2-Methoxy-6,7,8,9-tetrahydropyrido[1,2-a]-
indol-10-yl)-2-methylpropyl]butyramide (17b)
1
Yield, 24%; m.p., 123–124 8C; H NMR, d 5 1.50 (s,
6H, C(CH3)2), 1.53–1.62 (m, 2H, CH2CH3), 1.81–1.89
(m, 2H, 8-H), 1.96–2.05 (m, 4H, 7-H1COCH2), 3.07 (t,
2H, 9-H, J 5 6.2 Hz), 3.63 (d, 2H, CH2NH, J 5 5.8 Hz),
3.83 (s, 3H, OCH3), 4.00 (t, 2H, 6-H, J 5 6.2 Hz), 5.25 (br
s, 1H, NH), 6.81 (dd, 1H, 3-H, J 5 8.8, 2.2 Hz), 7.14 (d,
1H, 4-H, J 5 8.8 Hz), 7.23 (d, 1H, 1-H, J 5 2.2 Hz) ppm;
13C NMR, d 5 13.5, 19.1, 21.4, 23.6, 24.4, 26.6, 35.8,
38.7, 42.2, 48.5, 55.5, 97.8, 108.4, 117.5, 119.5, 128.1,
136.4, 137.2, 154.0, 172.9 ppm. Anal. Calc. for
C21H30N2O2 (342.48): C, 73.65; H, 8.83; N, 8.18. Found:
C, 73.55; H, 8.80; N, 8.10.
2.1.7. 1-(6,7,8,9-Tetrahydropyrido[1,2-a]indol-10-yl)-
cyclobutylmethylamine (20)
This amine was prepared by the general method de-
scribed for amines 14 and 15. Yellow oil, yield 78%.