Mapping the Melatonin Receptor
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 4 465
7.14 (ddd, J ) 1.2, 7.0, 8.0 Hz), 7.23 (d, 1H, J ) 8.4 Hz), 7.49
(d, 1H, J ) 7.6 Hz); 13C NMR δ 9.6, 25.7, 25.8, 27.3, 29.5, 29.7,
30.5, 34.2, 42.9, 108.9, 113.2, 117.3, 119.0, 120.7, 128.1, 135.8,
138.7, 173.6; IR 3245, 2923, 1636, 1552, 735 cm-1; EIMS m/z
284, 211, 198, 107 (100), 84. Anal. (C18H24N2O) C, H, N.
N-Bu t a n oyl-10-(a m in om et h yl)-5-m et h yl-5,6,7,8,9,10-
h exa h yd r ocycloh ep t[b]in d ole (11c, R ) H, R1 ) P r ): 82%;
mp 131-132 °C; 1H NMR δ 0.84 (t, 3H, J ) 7.5 Hz), 1.51-
1.57 (m, 3H), 1.71-2.13 (m, 7H), 2.73-2.81 (m, 1H), 3.00 (ddd,
1H, J ) 2.4, 5.8, 15.8 Hz), 3.31 (ddd, 1H, J ) 4.2, 9.0, 12.7
Hz), 3.42-3.46 (m, 1H), 3.65 (s, 3H), 3.69 (dd, J ) 6.2, 12.6
Hz), 5.49 (br s, 1H), 7.06 (dd, 1H, J ) 7.2, 7.6 Hz), 7.13 (ddd,
1H, J ) 1.1, 7.6, 9.0 Hz), 7.23 (d, 1H, J ) 8.2 Hz), 7.49 (d, 1H,
J ) 7.9 Hz); 13C NMR δ 13.6, 18.9, 25.7, 25.8, 27.3, 29.5, 30.4,
34.3, 38.7, 42.8, 108.9, 113.2, 117.3, 119.0, 120.6, 128.1, 135.8,
138.8, 172.9; IR 3244, 2919, 1637, 1559, 732 cm-1; EIMS m/z
298, 211, 198, 159, 84 (100). Anal. (C19H26N2O) C, H, N.
N-P en t a n oyl-10-(a m in om et h yl)-5-m et h yl-5,6,7,8,9,10-
h exa h yd r ocycloh ep t[b]in d ole (11d , R ) H, R1 ) Bu ): 89%;
mp 130-132 °C; 1H NMR δ 0.83 (t, 3H, J ) 7.3 Hz), 1.19-
1.25 (m, 2H), 1.41-1.47 (m, 2H), 1.49-1.54 (m, 1H), 1.71-
2.13 (m, 7H), 2.77 (ddd, 1H, J ) 2.4, 12.1, 15.0 Hz), 3.00 (ddd,
1H, J ) 2.4, 5.8, 16.0 Hz), 3.30 (ddd, 1H, J ) 4.3, 9.3, 12.6
Hz), 3.41-3.46 (m, 1H), 3.66 (s, 3H), 3.69 (dd, 1H, J ) 6.5,
12.8 Hz), 5.43 (br s, 1H), 7.06 (dd, 1H, J ) 7.0, 7.9 Hz), 7.14
(ddd, 1H, J ) 1.1, 7.1, 7.9 Hz), 7.23 (d, 1H, J ) 8.3 Hz), 7.49
(d, 1H, J ) 7.6 Hz); 13C NMR δ 13.7, 22.3, 25.7, 25.8, 27.4,
27.6, 29.5, 30.5, 34.3, 36.5, 42.9, 109.0, 113.2, 117.4, 119.1,
120.6, 128.2, 135.8, 138.8, 173.0; IR 3248, 2924, 1634, 1547
cm-1; EIMS m/z 312, 211, 198 (100), 170. Anal. (C20H28N2O)
C, H, N.
3.83 (s, 3H), 5.45 (br s, 1H), 6.78 (dd, 1H, J ) 2.4, 8.8 Hz),
6.95 (d, 1H, J ) 2.3 Hz), 7.11 (d, 1H, J ) 8.7 Hz); 13C NMR δ
23.5, 25.8, 26.1, 27.4, 29.7, 30.6, 34.4, 43.2, 56.0, 99.4, 109.8,
110.7, 112.9, 128.5, 131.2, 139.5, 154.1, 170.1; IR 3332, 2920,
1639, 1531, 1233 cm-1; EIMS m/z 300, 241, 228 (100), 137,
122, 43. Anal. (C18H24N2O2) C, H, N.
N-P r op a n oyl-10-(a m in om et h yl)-2-m et h oxy-5-m et h yl-
5,6,7,8,9,10-h exa h yd r ocycloh ep t[b]in d ole (11i, R ) OMe,
R ) Et): 91%; mp 125-127 °C; 1H NMR δ 1.00 (t, 3H, J ) 7.7
Hz), 1.49-1.52 (m, 1H), 1.72-2.15 (m, 7H), 2.73-2.77 (m, 1H),
2.94-2.99 (m, 1H), 3.26-3.30 (m, 1H), 3.35-3.40 (m, 1H), 3.62
(s, 3H), 3.64-3.73 (m, 1H), 3.82 (s, 3H), 5.40 (br s, 1H), 6.78
(dd, 1H, J ) 2.3, 8.7 Hz), 6.94 (d, 1H, J ) 2.0 Hz), 7.11 (d, 1H,
J ) 8.8 Hz); 13C NMR δ 9.7, 25.8, 26.0, 27.4, 29.6, 29.8, 30.6,
34.3, 42.9, 55.9, 99.4, 109.7, 110.6, 112.9, 128.4, 131.1, 139.5,
154.0, 173.6; IR 3338, 2917, 1640, 1524, 1229 cm-1; EIMS m/z
314, 241, 228 (100), 137, 122, 43. Anal. (C19H26N2O2) C, H,
N.
N-Bu t a n oyl-10-(a m in om et h yl)-2-m et h oxy-5-m et h yl-
5,6,7,8,9,10-h exa h yd r ocycloh ep t[b]in d ole (11j, R ) OMe,
1
R1 ) P r ): 83%; mp 58-60 °C; H NMR δ 0.82 (t, 3H, J ) 7.4
Hz), 1.48-1.56 (m, 3H), 1.63-2.11 (m, 5H), 2.00 (t, 2H, J )
6.9 Hz), 2.69-2.77 (m, 1H), 2.93-2.98 (m, 1H), 3.28 (ddd, 1H,
J ) 4.0, 9.3, 12.1 Hz), 3.34-3.38 (m, 1H), 3.61 (s, 3H), 3.33
(ddd, 1H, J ) 6.0, 7.4, 12.7 Hz), 3.82 (s, 3H), 5.47 (br s, 1H),
6.78 (dd, 1H, J ) 2.4, 8.8 Hz), 6.95 (d, 1H, J ) 2.2 Hz), 7.10
(d, 1H, J ) 8.1 Hz); 13C NMR δ 13.7, 19.0, 25.7, 25.9, 27.4,
29.6, 30.5, 34.4, 38.7, 42.8, 56.0, 99.5, 109.7, 110.5, 112.9, 128.3,
131.2, 139.5, 154.0, 172.9; IR 3340, 2923, 1641, 1530, 1234
cm-1; EIMS m/z 328, 241, 228 (100), 137, 122, 43 (100). Anal.
(C20H28N2O2) C, H, N.
N -C y c lo p r o p a n o y l-10-(a m i n o m e t h y l)-5-m e t h y l-
5,6,7,8,9,10-h exa h yd r ocycloh ep t[b]in d ole (11e, R ) H, R1
) c-C3H5): 75%; mp 130-132 °C; 1H NMR δ 0.58-0.67 (m,
2H), 0.84-0.97 (m, 2H), 1.07-1.12 (m, 1H), 1.52-1.56 (m, 1H),
1.72-2.14 (m, 5H), 2.77 (ddd, 1H, J ) 2.6, 6.5, 12.1 Hz), 3.01
(ddd, 1H, J ) 2.4, 5.8, 12.0 Hz), 3.31 (ddd, 1H, J ) 4.5, 8.7,
15.5 Hz), 3.44-3.48 (m, 1H), 3.66 (s, 3H), 3.67-3.74 (m, 1H),
5.63 (br s, 1H), 7.06 (ddd, 1H, J ) 1.0, 7.0, 7.8 Hz), 7.13 (dd,
1H, J ) 7.0, 8.0 Hz), 7.23 (d, 1H, J ) 8.1 Hz), 7.52 (d, 1H, J
) 7.7 Hz); 13C NMR δ 6.9, 14.8, 25.7, 25.8, 27.4, 29.5, 30.5,
34.4, 43.3, 108.9, 113.3, 117.5, 119.1, 120.6, 128.2, 135.9, 138.8,
173.5; IR 3248, 2913, 1630, 1556, 739 cm-1; EIMS m/z 296,
211, 198 (100), 170, 41. Anal. (C19H24N2O) C, H, N.
N-P en t a n oyl-10-(a m in om et h yl)-2-m et h oxy-5-m et h yl-
5,6,7,8,9,10-h exa h yd r ocycloh ep t[b]in d ole (11k , R ) OMe,
R1 ) C4H9): 76%; mp 78-82 °C; 1H NMR δ 0.81 (t, H, J ) 7.3
Hz), 1.17-1.23 (m, 2H), 1.40-1.54 (m, 3H), 1.69-2.11 (m, 5H),
2.00 (t, 2H, J ) 7.9 Hz), 2.69-2.77 (m, 1H), 2.94 (ddd, 1H, J
) 2.5, 5.6, 13.3 Hz), 3.26-3.35 (m, 1H), 3.37-3.38 (m, 1H),
3.61 (s, 3H), 3.63-3.70 (m, 1H), 3.82 (s, 3H), 5.47 (br s, 1H),
6.78 (dd, 1H, J ) 2.5, 9.0 Hz), 6.94 (d, 1H, J ) 2.5 Hz), 7.10
(d, 1H, J ) 8.9 Hz); 13C NMR δ 13.7, 22.3, 25.7, 25.9, 27.4,
27.6, 29.6, 30.5, 34.3, 36.6, 42.8, 55.9, 99.5, 109.7, 110.5, 112.8,
128.3, 131.2, 139.5, 154.0, 173.1; IR 3337, 2929, 1636, 1230;
EIMS m/z 342, 241, 228 (100), 137, 122, 43. Anal. (C21H30N2O2)
C, H, N.
N -C y c l o b u t a n o y l -1 0 -(a m i n o m e t h y l )-5 -m e t h y l -
5,6,7,8,9,10-h exa h yd r ocycloh ep t[b]in d ole (11f, R ) H, R1
) c-C4H7): 68%; mp 177-179 °C; 1H NMR δ 1.51-1.57 (m,
1H), 1.69-2.22 (m, 12H), 2.73-2.81 (m, 2H), 3.01 (ddd, 1H, J
) 2.0, 5.5, 10.2 Hz), 3.29 (ddd, 1H, J ) 4.0, 8.7, 11.5 Hz), 3.40-
3.45 (m, 1H), 3.65 (s, 3H), 3.63-3.71 (m, 1H), 5.35 (br s, 1H),
7.06 (ddd, 1H, J ) 1.0, 6.9, 7.8 Hz), 7.13 (ddd, 1H, J ) 1.1,
7.1, 8.1 Hz), 7.22 (d, 1H, J ) 8.2 Hz), 7.47 (d, 1H, J ) 7.7 Hz);
13C NMR δ 17.9, 25.1, 25.2, 25.7, 25.8, 27.3, 29.5, 30.5, 34.3,
39.9, 42.9, 108.9, 113.2, 117.4, 119.0, 120.6, 128.2, 135.8, 138.7,
174.8; IR 3245, 2919, 1634, 1557, 742; EIMS m/z 310, 211,
198 (100), 170, 41. Anal. (C20H26N2O) C, H, N.
N -Cyclop r op a n oyl-10-(a m in om e t h yl)-2-m e t h oxy-5-
m eth yl-5,6,7,8,9,10-h exa h yd r ocycloh ep t[b]in d ole (11l, R
) OMe, R1 ) c-C3H5): 92%; mp 160-161 °C; 1H NMR δ 0.58-
0.68 (m, 2H), 0.83-0.88 (m, 1H), 0.92-0.98 (m, 1H), 1.11-
1.14 (m, 1H), 1.50-1.53 (m, 1H), 1.73-2.14 (m, 5H), 2.71-
2.78 (m, 1H), 2.97 (ddd, 1H, J ) 3.8, 5.4, 12.1 Hz), 3.28 (ddd,
1H, J ) 3.7, 9.1, 12.8 Hz), 3.36-3.41 (m, 1H), 3.62 (s, 3H),
3.33 (m, 1H), 3.83 (s, 3H), 5.71 (br s, 1H), 6.78 (dd, 1H, J )
2.3, 8.8 Hz), 6.98 (d, 1H, J ) 2.1 Hz), 7.11 (d, 1H, J ) 8.7 Hz);
13C NMR δ 6.7, 14.7, 25.7, 26.0, 27.3, 29.6, 30.6, 34.5, 43.2,
55.9, 99.5, 109.7, 110.6, 113.0, 128.4, 131.1, 139.4, 154.0, 173.3;
IR 3327, 2924, 1636, 1542, 1236 cm-1; EIMS m/z 326, 241, 228
(100), 69, 41. Anal. (C20H26N2O2) C, H, N.
N -(T r i flu o r o a c e t y l)-10-(a m i n o m e t h y l)-5-m e t h y l-
5,6,7,8,9,10-h exa h yd r ocycloh ep t[b]in d ole (11g, R ) H, R1
N-Cyclobu tan oyl-10-(am in om eth yl)-2-m eth oxy-5-m eth -
yl-5,6,7,8,9,10-h exa h yd r ocycloh ep t[b]in d ole (11m , R )
1
) CF 3): 77%; mp 157-159 °C; H NMR δ 1.41-1.50 (m, 1H),
1
1.75-1.79 (m, 2H), 1.97-2.08 (m, 3H), 2.73 (dd, 1H, J ) 2.4,
11.2 Hz), 2.94-3.07 (m, 3H), 3.53-3.55 (m, 1H), 3.65 (s, 3H),
5.67 (br s, 1H), 6.98-7.00 (m, 2H), 7.15 (d, 1H, J ) 9.0 Hz),
7.40 (br s, 1H), 7.51 (d, 1H, J ) 8.9 Hz); 13C NMR δ 25.5, 25.7,
27.2, 29.6, 29.8, 32.5, 42.7, 109.2, 110.1, 117.3, 117.9, 119.5,
120.8, 127.8, 135.9, 140.0, 161.8; IR 3323, 2930, 1690, 1187,
1159, 740 cm-1; EIMS m/z 324, 228, 211, 198 (100), 170, 128.
Anal. (C17H19N2OF3) Calcd: C, 62.95; H, 5.91; N, 8.63.
Found: C, 62.49; H, 5.88; N, 8.57.
OMe, R1 ) c-C4H7): 69%; mp 119-121 °C; H NMR δ 1.48-
1.52 (m, 1H), 1.70-2.14 (m, 11H), 2.70-2.80 (m, 2H), 2.97
(ddd, 1H, J ) 2.3, 5.7, 13.2 Hz), 3.28 (ddd, 1H, J ) 4.0, 9.6,
12.3 Hz), 3.33 (ddd, 1H, J ) 5.8, 7.5 Hz, 12.4 Hz), 3.34-3.38
(m, 1H), 3.62 (s, 3H), 3.82 (s, 3H), 5.33 (br s, 1H), 6.78 (dd,
1H, J ) 2.4, 8.8 Hz), 6.93 (d, 1H, J ) 2.4 Hz), 7.10 (d, 1H, J
) 8.7 Hz); 13C NMR δ 18.0, 25.3, 25.9, 26.1, 27.5, 29.7, 30.7,
34.5, 40.1, 42.9, 56.1, 99.6, 109.8, 110.6, 113.0, 128.5, 131.2,
139.6, 154.1, 174.9; IR 3331, 2920, 1638, 1537, 1232 cm-1
;
EIMS m/z 340, 241, 228 (100), 69, 41. Anal. (C20H26N2O2)
Calcd: C, 74.08; H, 8.29; N, 8.23. Found: C, 73.56; H, 8.13;
N, 8.23.
Sep a r a t ion of E n a n t iom er s: Tet r a h yd r oca r b a zoles.
The racemic mixture (0.250 g of 9g; 1.20 g of 9a ) was dissolved
in ethanol (10 mg/mL) and injected in 0.5 mL aliquots onto a
N -Ac e t y l-10-(a m in o m e t h y l)-2-m e t h o x y -5-m e t h y l-
5,6,7,8,9,10-h exa h yd r ocycloh ep t[b]in d ole (11h , R ) OMe,
R1 ) Me): 69%; mp 132-134 °C; 1H NMR δ 1.49-1.53 (m,
1H), 1.72-2.12 (m, 5H), 1.82 (s, 3H), 2.69-2.77 (m, 1H), 2.95
(ddd, 1H, J ) 2.4, 5.7, 12.6 Hz), 3.25 (ddd, 1H, J ) 4.0, 9.4,
12.4 Hz), 3.35-3.40 (m, 1H), 3.62 (s, 3H), 3.65-3.72 (m, 1H),