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F. Lehmann et al. / Bioorg. Med. Chem. 13 (2005) 3057–3068
1H NMR (500 MHz) d 2.62–2.80 (m, 9H), 3.16–3.22
(m, 1H), 3.44–3.52 (m, 2H), 3.76 (s, 3H), 6.83 (d, 2H,
J = 8.2 Hz), 7.17 (d, 1H, J = 7.0 Hz), 7.25–7.29 (m,
2H), 7.30–7.34 (m, 1H), 7.47–7.50 (m, 1H), 8.01 (d,
1H, J = 8.1 Hz), 12.85 (br s, 1H). 13C NMR
(125 MHz) d 36.8, 39.6, 42.7, 44.2, 53.7, 55.4, 84.1,
114.7, 124.7, 126.3 (2 C:s), 127.8, 128.1 (2 C:s), 130.2,
131.7, 134.7, 136.9, 159.5, 164.7.
4.4.28. 3-(2-Dimethylaminoethyl)-3-(1-naphthyl)isochro-
man-1-one HCl (32). Compound 3a (1.3 g, 8.8 mmol)
and 2q (1.0 g, 4.4 mmol) yielded 140 mg (18%) of the ti-
tle compd. Mp > 250 ꢁC (decomp). 1H NMR (400 MHz)
d 2.54–2.98 (m, 8H), 3.13–3.34 (m, 2H), 3.75 (d, 1H,
2
2J = 16.5 Hz), 4.03 (d, 1H, J = 16.5 Hz), 7.09–7.32 (m,
4H), 7.44–7.52 (m, 3H), 7.61–7.65 (m, 1H), 7.74 (d,
1H, J = 8.1 Hz), 7.84 (d, 1H, J = 8.4 Hz), 7.96 (d, 1H,
J = 7.7 Hz), 12.85 (br s, 1H). 13C NMR (100 MHz) d
35.1, 37.9, 43.0, 43.3, 53.8, 85.7, 124.3, 124.5, 124.7,
125.7, 126.1, 127.2, 128.0, 130.0, 130.1, 130.4, 133.9,
134.0, 134.6, 135.0, 137.2, 137.6, 164.4. Anal. Calcd
for C23H24ClNO2H2O: C, 69.1; H, 6.5; N, 3.5. Found:
C, 69.0; H, 6.3; N, 3.9.
4.4.24.
3-(3-Chlorophenyl)-3-(2-dimethylaminoethyl)-
isochroman-1-one HCl (28). Compound 3a (1.2 g,
8.0 mmol) and 2m (0.83 g, 4.0 mmol) yielded 160 mg
(11%) of the title compound. Mp > 250 ꢁC (decomp).
1H NMR (400 MHz) d 2.66–2.83 (m, 9H), 3.16–3.23
(m, 1H), 3.44–3.54 (m, 2H), 7.19 (d, 1H, J = 7.2 Hz),
7.22–7.38 (m, 5H), 7.48–7.52 (m, 1H), 8.02 (d, 1H,
J = 7.6 Hz), 12.70 (s, 1H). 13C NMR (100 MHz) d
36.0, 39.0, 42.2, 43.8, 53.2, 83.5, 122.9, 124.2, 125.1,
127.9, 128.2, 128.8, 130.4, 130.7, 134.8, 135.5, 136.3,
142.2, 164.1. Anal. Calcd for C19H21Cl2NO2: C, 62.3;
H, 5.8; N, 3.8. Found: C, 62.1; H, 5.8; N, 3.8.
4.4.29. 3-(2-Dimethylaminoethyl)-3-(2-naphthyl)isochro-
man-1-one HCl (33). Compound 3a (1.3 g, 8.8 mmol)
and 2r (1.0 g, 4.4 mmol) yielded 400 mg (24%) of the ti-
tle compound. Mp > 250 ꢁC (decomp). 1H NMR
(400 MHz) d 2.61 (d, 3H, J = 4.8 Hz), 2.69–2.78 (m,
5H), 2.89–2.98 (m, 1H), 3.19–3.29 (m, 1H), 3.56 (s,
2H), 7.16 (d, 1H, J = 7.7 Hz), 7.26–7.30 (m, 1H), 7.42–
7.51 (m, 4H), 7.77–7.85 (m, 4H), 8.02 (d, 1H,
J = 7.7 Hz), 12.75 (s, 1H). 13C NMR (100 MHz) d
36.4, 39.4, 42.7, 44.1, 53.6, 84.0, 122.0, 124.5, 124.6,
126.9, 127.0, 127.7, 128.0, 128.1, 128.4, 129.7, 130.1,
132.7, 132.9, 134.7, 136.5, 137.0, 164.5. Anal. Calcd
for C23H24ClNO2 · 0.25 H2O: C, 71.5; H, 6.4; N, 3.6.
Found: C, 71.7; H, 6.4; N, 3.5.
4.4.25.
3-(2-Dimethylaminoethyl)-(3-methoxyphenyl)-
isochroman-1-one HCl (29). Compound 3a (0.92 g,
6.1 mmol) and 2n (0.63 g, 3.0 mmol) yielded 190 mg
(20%) of the title compound. Mp > 250 ꢁC (decomp).
1H NMR (400 MHz) d 2.66–2.82 (m, 9H), 3.13–3.23
(m, 1H), 3.44–3.52 (m, 2H), 3.76 (s, 3H), 6.74 (dd, 1H,
J = 2.2, 8.4 Hz), 6.86 (s, 1H), 6.89 (d, 1H, J = 7.7 Hz),
7.15–7.32 (m, 3H), 7.45–7.48 (m, 1H), 8.00 (d, 1H,
J = 8.8 Hz), 12.75 (br s, 1H). 13C NMR (100 MHz) d
36.3, 39.2, 42.4, 44.1, 53.3, 55.2, 83.8, 111.0, 113.5,
117.1, 124.5, 128.0, 128.1, 130.1, 130.4, 134.7, 136.7,
141.4, 160.1, 164.5. HRTofMS calcd for C20H24NO3
(M+H) m/z 326.1772, found 326.1756.
4.4.30.
3-(2-Dimethylaminoethyl)-3-(2-thienyl)isochro-
man-1-one HCl (34). Compound 3a (1.5 g, 9.8 mmol)
and 2s (0.9 g, 4.9 mmol) yielded 200 mg (12%) of the ti-
tle compound. Mp > 250 ꢁC (decomp). 1H NMR
(400 MHz) d 2.71–2.82 (m, 8H), 2.89–2.97 (m, 1H),
3.25–3.34 (m, 1H), 3.43–3.59 (m, 2H), 6.86 (dd, 1H,
J = 4.0, 8.8 Hz), 6.97 (dd, 1H, J = 1.0, 4.4 Hz), 7.17–
7.22 (m, 2H), 7.31–7.34 (m, 1H), 7.48–7.52 (m, 1H),
8.00 (dd, 1H, J = 1.5, 8.0 Hz), 12.70 (s, 1H). 13C NMR
(100 MHz) d 37.6, 40.3, 42.8, 43.8, 53.4, 82.7, 124.2,
125.4, 125.9, 127.5, 128.1, 128.2, 130.3, 134.6, 136.5,
143.8, 163.7. Anal. Calcd for C17H20ClNO2S: C, 60.4;
H, 6.0; N, 4.1. Found: C, 60.1; H, 6.0; N, 4.1.
4.4.26.
3-(2-Dimethylaminoethyl)-3-(3-fluorophenyl)-
isochroman-1-one HCl (30). Compound 3a (0.3 g,
2.0 mmol) and 2o (0.2 g, 1.0 mmol) yielded 60 mg
(17%) of the title compound. Mp > 250 ꢁC (decomp).
1H NMR (400 MHz) d 2.60–2.84 (m, 9H), 3.16–3.22
(m, 1H), 3.44–3.53 (m, 2H), 6.90–7.47 (m, 7H), 7.97
(d, 1H, J = 8.7 Hz), 12.50 (br s, 1H). 13C NMR
(100 MHz) d 36.4, 38.9, 42.7, 43.9, 53.3, 83.5, 112.5 (d,
2
2JCF = 36.7 Hz), 115.4 (d, JCF = 29.8 Hz), 120.6,
4.4.31.
3-(4-Chlorophenyl)-3-(dimethylaminomethyl)-
3
124.3, 127.9, 128.1, 130.2, 131.1 (d, JCF = 9.9 Hz),
isochroman-1-one HCl (35). Compound 3a (1 g,
6.7 mmol) and 2t (0.66 g, 3.4 mmol) yielded 175 mg
(16%) of the title compound. Mp > 250 ꢁC (decomp).
1H NMR (500 MHz) d 2.88 (s, 3H), 3.13 (s, 3H), 3.50
(d, 1H, J = 14.5 Hz), 3.74 (d, 1H, J = 14.5 Hz), 3.94
(d, 1H, J = 16.5 Hz), 4.30 (d, 1H, J = 16.5 Hz), 7.24–
7.29 (m, 4H), 7.42–7.48 (m, 3H), 7.91 (d, 1H,
J = 7.0 Hz), 12.4 (s, 1H). 13C NMR (125 MHz) d 35.1,
44.5, 46.7, 65.2, 83.2, 124.0, 127.1 (2 C:s), 128.0, 128.2,
129.5 (2 C:s), 130.1, 134.8, 135.2, 136.4, 137.1, 163.2.
Anal. Calcd for C18H19Cl2NO2: C, 61.4; H, 5.5; N,
4.0. Found: C, 61.5; H, 5.5; N, 3.9.
3
134.7, 136.3, 142.7 (d, JCF = 9.9 Hz), 163.3 (d,
3JCF = 275 Hz),
C19H20FNO2 (M+H) m/z 314.1556, found 314.1563.
164.1.
HRTofMS
calcd
for
4.4.27. 3-(2-Dimethylaminoethyl)-3-(2-methoxyphenyl)-
isochroman-1-one HCl (31). Compound 3a (0.6 g,
4.1 mmol) and 2p (0.43 g, 2.0 mmol) yielded 100 mg
(15%) of the title compound. Mp > 250 ꢁC (decomp).
1H NMR (500 MHz) d 2.52–2.74 (m, 8H), 3.17–3.27
(m, 2H), 3.44–3.47 (m, 2H), 3.96 (s, 3H), 6.81–6.88 (m,
2H), 7.09–7.28 (m, 4H), 7.41–7.44 (m, 1H), 7.98 (d,
1H, J = 7.5 Hz), 12.45 (br s, 1H). 13C NMR
(125 MHz) 33.2, 36.7, 42.3, 43.9, 53.7, 55.8, 84.2,
111.8, 120.7, 124.4, 126.6, 127.3, 127.6, 127.8, 129.4,
129.9, 134.3, 137.4, 155.1, 164.7. Anal. Calcd for
C20H24ClNO3 · 0.5 H2O: C, 64.8; H, 6.8; N, 3.8. Found:
C, 64.9; H, 6.9; N, 3.9.
4.4.32. 3-(4-Chlorophenyl)-3-(3-dimethylaminopropyl)-
isochroman-1-one HCl (36). Compound 3a (0.7 g,
4.7 mmol) and 2u (0.53 g, 2.4 mmol) yielded 250 mg
(27%) of the title compound. Mp > 250 ꢁC (decomp).
1H NMR (400 MHz) d 1.76–1.83 (m, 1H), 1.90–1.99