F. Herold et al. / European Journal of Medicinal Chemistry 44 (2009) 1710–1717
1715
7.1.4.2. 2-{4-[4-(5-Methoxy-1H-indol-3-yl)-piperidin-1-yl]-butyl}-
4-(4-methoxyphenyl)-pyrido[1,2-c]pyrimidine-1,3-dione (7b). Yield:
13C NMR (100 MHz)
d
: 24.8 (C-3x), 25.9 (C-2x), 33.3 (Cb, Cd),
33.8 (Cc), 42.8 (C-1x), 54.7 (Ca, Ce), 59.0 (C-4x), 103.8 (C-4), 111.0 (C-
7), 111.4 (C-700), 119.2 (C-500), 119.9 (C-200), 121.3 (C-5), 121.8 (C-300),
122.0 (C-600), 126.9 (C-300a), 128.4 (C-8), 129.2 (C-20, C-60), 131.6 (C-
10), 132.9 (C-30, C-50), 133.1 (C-6), 133.9 (C-40), 136.6 (C-700a), 143.8
(C-4a), 149.1 (C-1), 160.2 (C-3); IR v: 1635 (C]O), 1713 (C]O). Anal.
Calcd for C31H31N4O2Cl: C, 70.6; H, 5.9; N, 10.6. Found: C, 70.0; H,
6.2; N, 10.6.
58.8%; yellow crystals, m.p. 162–164 ꢁC; 1H NMR (400 MHz)
d: 1.64
(q, C-3 x H2), 2.03 (m, C-2 x H2, Cb,dHax), 2.03 (pd, Cb,dHeq), 2.44 (t,
3J ¼ 7.6 Hz, C-4 x H2), 2.77 (tt, CcH), 3.83 (s, OCH3), 3.86 (s, OC-
10H3), 4.19 (t, 3J ¼ 7.4 Hz, C-1 x H2), 6.35 (t, 3J ¼ 7.2 Hz, C-7H), 6.83
(dd, 3J ¼ 8.8 Hz, 4J ¼ 2.0 Hz, C-600H), 6.90 (m, C-5H, C-6H), 6.92 (s, C-
4
200H), 7.05 (d, J ¼ 1.6 Hz, C-400H), 7.05 (d, C-30H, C-50H), 7.21 (d,
3J ¼ 8.4 Hz, C-700H), 7.26 (d, 3J ¼ 8.4 Hz, C-20H, C-60H), 8.04 (bs, NH),
8.31 (d, 3J ¼ 7.2 Hz, C-8H).
7.1.4.6. 4-(4-Chloro-phenyl)-2-{4-[4-(5-methoxy-1H-indol-3-yl)-
piperidin-1-yl]-butyl}-pyrido[1,2-c]pyrimidine-1,3-dione (9b). Yield:
13C NMR (100 MHz)
d: 24.8 (C-3x), 25.9 (C-2x), 33.2 (Cb, Cd), 33.7
(Cc), 42.7 (C-1x), 54.7 (Ca, Ce), 55.6 (OCH3), 56.3 (OC-10H3), 59.1 (C-
4x), 101.3 (C-400), 104.8 (C-4), 110.8 (C-7), 112.1 (C-700), 112.2 (C-600),
114.5 (C-30, C-50), 121.8 (C-5), 125.1 (C-10), 127.3 (C-300a), 128.1 (C-8),
131.8 (C-700a),132.6 (C-20, C-60),143.7 (C-4a),149.2 (C-500),153.9 (C-1),
159.4 (C-40), 160.6 (C-3); IR v: 1647 (C]O), 1720 (C]O). Anal. Calcd
for C33H36N4O4: C, 71.7; H, 6.6; N, 10.1. Found: C, 71.1; H, 6.4; N, 10.0.
53.8%; yellow crystals, m.p. 110–112 ꢁC; 1H NMR (400 MHz)
d: 1.64
(q, 3J ¼ 7.2 Hz, C-3 x H2), 1.77 (m, 4H, C-2 x H2, Cb,dHax), 2.03 (pd,
Cb,dHeq), 2.11 (pt, Ca,eHax), 2.44 (t, 3J ¼ 7.8 Hz, C-4 x H2), 2.77 (tt, 3JA–
3
¼ 12.0 Hz, JA–E ¼ 3.6 Hz, CcH), 3.04 (pd, Ca,eeq), 3.86 (s, OCH3),
A
4.19 (t, 3J ¼ 7.4 Hz, C-1 x H2), 6.40 (td, 3J ¼ 6.8 Hz, 4J ¼ 1.0 Hz, C-7H),
6.84 (dd, 3J ¼ 8.8 Hz, 4J ¼ 2.4 Hz, C-600H), 6.88 (d, 3J ¼ 9.6 Hz, C-5H),
6.94 (s, C-200H), 6.94 (td, 3J ¼ 7.8 Hz, 4J ¼ 0.8 Hz, C-6H), 7.06 (d,
3
7.1.4.3. 2-{4-[4-(1H-Indol-3-yl)-piperidin-1-yl]-butyl}-4-p-tolyl-
pyrido[1,2-c]pyrimidine-1,3-dione (8a). Yield: 50%; yellow crystals,
4J ¼ 2.4 Hz, C-400H), 7.23 (d, J ¼ 8.4 Hz, C-700H), 7.27 (d, C-30H, C-
3
50H), 7.42 (d, J ¼ 8.4 Hz, C-20H, C-60H), 7.94 (bs, NH), 8.35 (d,
m.p. 178–179 ꢁC; 1H NMR (400 MHz)
d
: 1.64 (q, 3J ¼ 7.6 Hz, C3 x H2),
3J ¼ 7.6 Hz, C-8H).
1.78 (m, 4H, C-2 x H2, Cb,dHax), 2.07 (m, 4H, Ca,eHax, Cb,dHeq), 2.38
(s, CH3), 2.43 (t, 3J ¼ 7.6 Hz, C-4 x H2), 2.82 (pt, CcH), 4.20 (t,
3J ¼ 7.4 Hz, C-1 x H2), 6.35 (td, 3J ¼ 6.0 Hz, 4J ¼ 0.8 Hz, C-7H), 6.88
(m, C-5H, C-6H), 6.93 (bs, C-200H), 7.08 (t, 3J ¼ 7.4 Hz, C-500H), 7.16 (t,
3J ¼ 7.6 Hz, C-600H), 7.20 (d, C-30H, C-50H), 7.25 (d, 3J ¼ 7.2 Hz, C-20H,
C-60H), 7.33 (d, 3J ¼ 8.0 Hz, C-700H), 7.63 (d, 3J ¼ 7.6 Hz, C-400H), 8.09
(bs, NH), 8.31 (d, 3J ¼ 7.2 Hz, C-8H).
13C NMR (100 MHz)
d: 24.5 (C-3x), 25.6 (C-2x), 32.9 (Cb, Cd),
33.5 (Cc), 42.5 (C-1x), 54.5 (Ca, Ce), 56.0 (OCH3), 58.8 (C-4x), 101.0
(C-400), 103.5 (C-4), 110.8 (C-7), 111.8 (C-700), 112.0 (C-600), 121.0 (C-5),
121.3 (C-300), 125.5 (C-300a), 128.1 (C-8), 129.0 (C-20, C-60), 131.2 (C-
10), 131.5 (C-700a), 132.7 (C-30, C-50), 132.9 (C-6), 133.7 (C-40), 143.6
(C-4a), 148.8 (C-500), 153.7 (C-1), 160.0 (C-3); IR v: 1624 (C]O), 1709
(C]O). Anal. Calcd for C32H33N4O3Cl: C, 69.0; H, 6.0; N, 10.1. Found:
C, 68.6; H, 6.1; N, 9.5.
13C NMR (100 MHz)
d: 21.5 (CH3), 24.8 (C-3x), 25.9 (C-2x), 33.3
(Cb, Cd), 33.8 (Cc), 42.7 (C-1x), 54.7 (Ca, Ce), 59.1 (C-4x), 105.2 (C-4),
110.8 (C-7), 111.4 (C-700), 119.2 (C-500), 119.3 (C-400), 119.7 (C-300), 119.9
(C-200), 121.8 (C-5), 122.0 (C-600), 126.9 (C-300a), 128.1 (C-8), 129.7 (C-
20, C-60), 129.9 (C-10), 131.3 (C-30, C-50), 132.3 (C-6), 136.6 (C-700a),
137.8 (C-40), 143.6 (C-4a), 149.2 (C-1), 160.5 (C-3); IR v: 1635 (C]O),
1709 (C]O). Anal. Calcd for C32H34N4O2: C, 75.8; H, 6.7; N, 11.0.
Found: C, 75.3; H, 6.7; N, 11.1.
7.1.4.7. 4-(4-Fluoro-phenyl)-2-{4-[4-(1H-indol-3-yl)-piperidin-1-yl]-
butyl}-pyrido[1,2-c]pyrimidine-1,3-dione (10a). Yield: 56.5%; yellow
crystals, m.p. 182–183 ꢁC; 1H NMR (400 MHz)
d: 1.64 (q, C-3 x H2),
1.79 (m, 4H, C-2 x H2, Cb,dHax), 2.02 (pd, Cb,dHeq), 2.10 (pt, Ca,eHax),
2.44 (t, 3J ¼ 7.6 Hz, C-4 x H2), 2.83 (tt, CcH), 3.05 (pd, Ca,eHeq), 4.19 (t,
3J ¼ 7.4 Hz, C-1 x H2), 6.39 (t, 3J ¼ 6.8 Hz, 4J ¼ 0.8 Hz, C-7H), 6.86 (d,
3
3J ¼ 9.2 Hz, C-5H), 6.92 (t, J ¼ 6.0 Hz, C-6H), 6.95 (s, C-200H), 7.05–
7.1.4.4. 2-{4-[4-(5-Methoxy-1H-indol-3-yl)-piperidin-1-yl]-butyl}-4-
p-tolyl-pyrido[1,2-c]pyrimidine-1,3-dione (8b). Yield: 78%; yellow
7.23 (m, C-500H, C-600H), 7.27–7.33 (m, C-20H, C-60H), 7.34 (d,
3J ¼ 8.4 Hz, C-700H), 7.64 (d, 3J ¼ 7.6 Hz, C-400H), 8.02 (bs, NH), 8.34 (d,
3J ¼ 7.6 Hz, C-8H).
crystals, m.p. 110–112 ꢁC; 1H NMR (400 MHz)
d: 1.67 (q, C3 x H2),
1.79 (m, C-2 x H2, Cb,dHax), 2.03 (pd, Cb,dHeq), 2.15 (pt, Ca,eHax),
2.39 (s, CH3), 2.46 (t, 3J ¼ 7.8 Hz, C-4 x H2), 2.78 (pt, CcH), 3.06 (pd,
Ca,eeq), 3.87 (s, OCH3), 4.19 (t, 3J ¼ 7.2 Hz, C-1 x H2), 6.39 (m, C-7H),
6.83 (dd, 3J ¼ 8.8 Hz, 4J ¼ 2.4 Hz, C-600H), 6.91 (bps, C-50H, C-6H), 7.07
13C NMR (100 MHz)
d: 24.8 (C-3x), 25.9 (C-2x), 33.3 (Cb, Cd),
33.7 (Cc), 42.8 (C-1x), 54.7 (Ca, Ce), 59.0 (C-4x), 104.0 (C-4), 110.9
2
(C-7), 111.3 (C-700), 116.0 (d^, J ¼ 21.4 Hz, C-30, C-50), 119.2 (C-500),
119.3 (C-400), 119.7 (C-300), 119.8 (C-200), 121.4 (C-5), 122.1 (C-600),
4
3
4
(t, J ¼ 2.0 Hz, C-400H), 7.20 (d, J ¼ 8.0 Hz, C-30H, C-5 H), 7.22–7.31
126.9 (C-300a), 128.3 (C-8), 128.9 (d^, J ¼ 3.1 Hz, C-10), 132.9 (C-6),
3
3
(m, C-20H, C-60H, C-700H), 7.33 (d, J ¼ 8.0 Hz, C-700H), 8.32 (d,
133.2 (d^, J ¼ 8.0 Hz, C-20, C-60), 136.5 (C-700a), 143.9 (C-4a), 149.1
3J ¼ 7.2 Hz, C-8H), 8.40 (bs, NH).
(C-1), 160.4 (C-3), 162.5 (d^, 1J ¼ 246.9 Hz, C-40); IR v: 1643 (C]O),
1720 (C]O). Anal. Calcd for C31H31N4O2F: C, 72.8; H, 6.1; N, 11.0.
Found: C, 72.3; H, 6.1; N, 10.8.
13C NMR (100 MHz)
d: 21.4 (CH3), 24.3 (C-3x), 25.8 (C-2x), 32.8
(Cb, Cd), 33.6 (Cc), 42.6 (C-1x), 54.5 (Ca, Ce), 56.2 (OCH3), 58.9 (C-
4x),101.2 (C-400), 105.1 (C-4), 110.9 (C-7), 112.0 (C-600, C-700), 120.8 (C-
200), 120.9 (C-300), 121.8 (C-5), 127.0 (C-300a), 128.0 (C-8), 129.6 (C-20,
C-600), 129.7 (C-10), 131.2 (C-700a), 132.5 (C-6), 137.8 (C-40), 143.8 (C-
4a), 149.1 (C-500), 153.7 (C-1), 160.6 (C-3); IR v: 1620 (C]O), 1709
(C]O). Anal. Calcd for C33H36N4O3: C, 73.9; H, 6.8; N,10.4. Found: C,
73.3; H, 6.8; N, 10.3.
7.1.4.8. 4-(4-Fluoro-phenyl)-2-{4-[4-(5-methoxy-1H-indol-3-yl)-
piperidin-1-yl]-butyl}-pyrido[1,2-c]pyrimidine-1,3-dione (10b).
Yield: 78.7%; yellow crystals, m.p. 151–152 ꢁC; 1H NMR
(400 MHz)
d: 1.82 (ps, 4H, C-3 x H2, Cb,Hax, CdHax), 2.08 (ps,
C2 x H2, CbHeq, CdHeq), 2.41 (bps, C-4 x H2), 2.72 (ps, CaHax
,
CeHax), 2.86 (ps, CcH), 3.26 (ps, Ca,Heq, CeHeq), 3.88 (s, OCH3),
4.20 (t, C-1 x H2), 6.41 (t, 3J ¼ 6.4 Hz, C-7H), 6.86 (m, C-5H, C-
600H), 6.94 (m, C-6H), 6.97 (s, C-200H), 7.06 (d, 4J ¼ 1.6 Hz, C-400H),
7,14 (t, C-30H, C-50H), 7.27 (m, C-20H, C-60H, C-700H), 8.08 (bs,
NH), 8.35 (t, 3J ¼ 7.6 Hz, C-8H).
7.1.4.5. 4-(4-Chloro-phenyl)-2-{4-[4-(1H-indol-3-yl)-piperidin-1-yl]-
butyl}-pyrido[1,2-c]pyrimidine-1,3-dione (9a). Yield: 75.5%; yellow
crystals, m.p. 173–174 ꢁC; 1H NMR (400 MHz)
d: 1.69 (q, C-3 x H2),
1.78 (m, 4H, C-2 x H2, Cb,dHax), 2.01 (pd, Cb,dHeq), 2.43 (t,
3J ¼ 7.6 Hz, C-4 x H2), 2.82 (tt, CcH), 4.19 (t, 3J ¼ 7.4 Hz, C-1 x H2),
6.39 (td, 3J ¼ 6.8 Hz, 4J ¼ 0.8 Hz, C-7H), 6.87 (d, 3J ¼ 9.2 Hz, C-5H),
13C NMR (100 MHz)
d: 25.4 (C-3x), 25.5 (C-2x), 36.0 (Cb, Cd),
54.2 (Ca, Ce), 56.4 (OCH3), 101.14 (C-400), 103.9 (C-4), 111.1 (C-7),
112.2 (C-700), 112.4 (C-600), 116.1 (d^, 2J ¼ 21.4 Hz, C-30, C-50), 119.4 (C-
300), 121.1 (C-200), 121.4 (C-5), 127.0 (C-300a), 128.3 (C-8), 128.9 (d^,
4J ¼ 3.0 Hz, C-10), 132.1 (C-6), 133.2 (d^, 3J ¼ 8.2 Hz, C-20, C-60), 131.7
(C-700a), 144.1 (C-4a), 154.1 (C-1), 160.5 (C-3); IR v: 1635 (C]O),
3
6.93 (t, C-6H), 6.93 (s, C-200H), 7.08 (t, J ¼ 7.2 Hz, C-500H), 7.16 (t,
3J ¼ 7.2 Hz, C-600H), 7.26 (d, C-30H, C-50H), 7.33 (d, 3J ¼ 8.0 Hz, C-
700H), 7.41 (d, 3J ¼ 8.4 Hz, C-20H, C-60H), 7.64 (d, 3J ¼ 8.0 Hz, C-400H),
8.11 (bs, NH), 8.34 (d, 3J ¼ 7.2 Hz, C-8H).