1512
G. Ronsisvalle et al. / Bioorg. Med. Chem. 8 (2000) 1503±1513
(dd, 1H, J=4.0, 9.1 Hz), 1.50±2.00 (m, 14H), 2.08±2.25
(m, 4H), 3.14 (dd, 1H, J=7.2, 12.1 Hz), 3.53 (dd, 1H,
J=5.4, 12.1 Hz), 3.61 (s, 3H), 5.5 (br s, 2H), 7.27±7.45
(m, 5H); 13C NMR (DMSO-d6) d 20.58, 23.31, 27.98,
34.50, 35.66, 38.40, 45.91, 51.02, 60.92, 126.33, 128.03,
131.00, 139.02, 166.48, 172.20; MS: m/z 339 [M]+; anal.
20.47, 24.57, 28.72, 34.18, 35.38, 36.93, 37.88, 56.68,
60.50, 127.39, 130.41, 139.80, 164.48, 171.95; MS: m/z
+
.
353 [M] ; anal. (C23H31NO2 H2C2O4) C, H, N.
(Æ)-cis-{2-[(1-Adamantylamino)methyl]-1-phenylcyclopro-
pyl}methanol (24). (0.18 g 76%); mp 282±283 ꢀC; 1H
NMR (DMSO-d6) d 1.05 (dd, 1H, J=5.0, 8.6 Hz), 1.11
(dd, 1H, J=5.5, 8.6 Hz), 1.46 (m, 1H) 1.58 (m, 6H), 1.87
(m, 6H), 2.14 (m, 3H), 3.11 (dd, 1H, J=6.4, 12.2 Hz),
3.29 (dd, 1H, J=5.1, 12.2 Hz), 3.53 (d, 1H, J=11.6 Hz),
4.10 (d, 1H, J=11.6 Hz), 5.60 (br s, 3H), 7.15±7.45
(m, 5H); 13C NMR (DMSO-d6) d 17.51, 20.28, 28.42,
.
(C22H29NO2 0.6H2C2O4) C, H, N.
Methyl (+)-(1R,2S)-2-[(1-adamantylamino)methyl]-1-
phenylcyclopropanecdarboxylate [(+)-18]. (80 mg, 18%);
20
mp 105±112 ꢀC; a +49ꢀ; 1H NMR (DMSO-d6) d
1.47 (dd, 1H, J=4.1, 9.1 Hz), 1.50±2.00 (m, 14H), 2.08±
2.25 (m, 4H), 3.14 (dd, 1H, J=7.2, 12.1 Hz), 3.50 (dd,
1H, J=5.4, 12.1 Hz), 3.59 (s, 3H), 6.2 (br s, 2H), 7.28±
7.50 (m, 5H); 13C NMR (DMSO-d6) d 19.98, 23.10,
28.01, 33.98, 35.00, 39.65, 46.00, 51.32, 61.22, 126.15,
31.72, 35.21, 37.79, 40.12, 55.94, 64.74, 126.29, 128.01,
+
.
128.72, 143.93; MS: m/z 311 [M] ; anal. (C21H29NO2
.
HCl 0.2H2O) C, H, N.
128.32, 131.50, 139.10, 165.98, 172.50; MS: m/z 339
+
(Æ)-cis-{2-[(1-Adamantylamino)methyl]-1-phenylcyclopro-
pyl}methyl acetate (25). (97 mg, 28%); mp 210±211 ꢀC;
1H NMR (DMSO-d6) d 1.09 (dd, 1H, J=7.6, 8.2 Hz),
1.25 (dd, 1H, J=7.4, 8.2 Hz), 1.41 (m, 1H), 1.50±1.78
(m, 6H), 1.80±1.95 (m, 6H), 1.97 (s, 3H) 2.05±2.22 (m,
3H), 2.90 (dd, 1H, J=5.6, 12.5 Hz), 3.42 (dd, 1H,
J=8.7, 12.5 Hz), 4.30 (d, 1H, J=12.4 Hz), 4.38 (d, 1H,
J=12.4 Hz), 5.00 (br s, 3H), 7.18±7.41 (m, 5H); 13C
NMR (DMSO-d6) d 17.66, 21.10, 21.50, 28.78, 29.51,
35.43, 37.88, 40.91, 56.71, 67.52, 127.16, 128.69, 128.75,
142.94, 165.19, 170.92; MS: m/z 353 [M]+; anal. (C23
.
[M] ; anal. (C22H29NO2 0.7H2C2O4 2H2O) C, H, N.
.
Methyl (Æ)-cis-2-{[(1-adamantylmethyl)amino]methyl}-
1-phenylcyclopropanecarboxylate (20). (120 mg, 57%);
mp 210±212 ꢀC; H NMR (DMSO-d6) d 1.41 (dd, 1H,
1
J=4.6, 8.7 Hz), 1.46±1.80 (m, 13H), 1.82±2.10 (m, 4H),
2,6 (s, 2H) 3.22 (dd, 1H, J=5.0, 12.6 Hz), 3.45 (dd, 1H,
J=9.0, 12.6 Hz), 3.60 (s, 3H), 5.8 (br s, 3H), 7.27±7.45
(m, 5H); 13C NMR (DMSO-d6) d 19.80, 23.71, 27.08,
35.95, 37.80, 39.45, 44.71, 45.80, 52.75, 60.97, 127.44,
.
.
128.29, 130.41, 139.61, 164.27, 172.09; MS: m/z 353
+
H31NO2 H2C2O4 0.4H2O) C, H, N.
.
[M] ; anal. (C23H31NO2 H2C2O4 0.2H2O) C, H, N.
.
(Æ)-cis-(2-{[1-Adamantyl(methyl)amino]methyl}-1-phenyl-
cyclopropyl)methyl acetate (26). (110 mg, 15%); mp
132±133 ꢀC; 1H NMR (DMSO-d6) d 1.10 (dd, 1H,
J=7.3, 8.3 Hz), 1.28 (dd, 1H, J=7.0, 8.3 Hz), 1.40 (m,
1H), 1.50±1.90 (m, 12H), 1.99 (s, 3H), 2.10±2.32 (m,
3H), 2.73 (s, 3H), 2.92 (dd, 1H, J=5.8, 12.8 Hz), 3.44
(dd, 1H, J=8.5, 12.8 Hz), 4.33 (d, 1H, J=12.7 Hz), 4.41
(d, 1H, J=12.7 Hz), 5.50 (br s, 3H), 7.20±7.44 (m, 5H);
13C NMR (DMSO-d6) d 17.36, 20.98, 21.32, 28.80,
29.32, 32.00, 35.27, 36.90, 40.05, 55.80, 68.52, 127.51,
Methyl (Æ)-cis-2-({[1-(1-adamantyl)ethyl]amino}methyl)-
1-phenylcyclopropanecarboxylate (21). (125 mg, 66%);
mp 190±191 ꢀC; 1H NMR (DMSO-d6) (1:1 diastereo-
isomeric mixture) d 1.14 (d, 3H, J=6.6 Hz), 1.16 (d, 3H,
J=6.6 Hz), 1.40 (dd, 1H, J=4.0, 8.8 Hz) 1.45±1.80 (m,
13H), 1.84±2.10 (m, 4H), 2.83 (q, 1H, J=6.6 Hz), 3.10±
3.30 (m, 1H), 3.35±3.45 (m, 1H), 3.57 (s, 3H), 3.58 (s,
3H), 5.4 (br s, 3H), 7.20±7.45 (m, 5H); 13C NMR
(DMSO-d6) (1:1 diastereoisomeric mixture) d 10.28,
10.57, 20.06, 21.23, 23.68, 24.07, 2752, 33.20, 34.21,
34.81, 34.87, 36.11, 36.92, 43.96, 44.91, 52.57, 52.58,
61.59, 62.47, 127.31, 128.05, 128.18, 129.95, 130.26,
139.43, 139.54, 164.53, 172.01; MS: m/z 367 [M]+; anal.
128.44, 128.81, 141.09, 164.12, 171.32; MS: m/z 367
+
.
[M] ; anal. (C24H33NO2 H2C2O4 1.5H2O) C, H, N.
.
.
(C22H29NO2 H2C2O4) C, H, N.
Biological Evaluation
Methyl (Æ)-cis-2-{[1-adamantyl(methyl)amino]methyl}-
1-phenylcyclopropanecarboxylate (22). (135 mg, 42%);
Radioligand binding assays
mp 181±184 ꢀC; H NMR (DMSO-d6) d 1.51 (dd, 1H,
Sigma1 binding assays were carried out on guinea pig
brain membranes prepared by the method described by
Matsumoto et al.31 and the protein content was eval-
uated.32 The binding assay was performed as described
by DeHaven et al.33 Each tube contained 500 mg of
membrane protein, 3 nM [3H]-pentazocine (31.6 Ci/
mmol; the value of the apparent dissociation constant
(Kd) was 4.3Æ0.8 nM, n=3). Non-speci®c binding was
determined by addition of 10 mM haloperidol. The
reaction was performed for 150 min at 37 ꢀC and termi-
nated by ®ltering the solution through Whatman GF/B
glass ®lters that were presoaked in a 0.5% polyethyl-
enimine solution.
1
J=4.1, 8.8 Hz), 1.60±1.78 (m, 7H), 1.82±2.23 (m, 10H),
2.75 (s, 3H), 3.25±3.50 (m, 2H), 3.58 (s, 3H), 5.40 (br s,
2H), 7.22±7.45 (m, 5H); 13C NMR (DMSO-d6) d 20.65,
23.75, 28.92, 32.38, 34.10, 35.07, 35.52, 46.81, 52.62,
62.97, 127.31, 128.19, 130.07, 139.31, 164.63, 172.04;
+
.
MS: m/z 353 [M] ; anal. (C23H31NO2 0.5H2C2O4
1.5H2O) C, H, N.
.
Ethyl (Æ)-cis-2-[(1-adamantylamino)methyl]-1-phenyl-
cyclopropanecarboxylate (23). (98 mg, 35%); mp 210±
ꢀ
1
212 C; H NMR (DMSO-d6) d 1.07 (t, 3H, J=7 Hz),
1.49 (dd, 1H, J=4.0, 8.8 Hz), 1.54±2.00 (m, 13H), 2.10±
2.22 (m, 4H), 3.12 (dd, 1H, J=7.4, 12.7 Hz), 3.46 (dd,
1H, J=5.8, 12.7 Hz), 4.00 (q, 2H, J=7 Hz), 5.00 (br s,
3H), 7.20±7.42 (m, 5H); 13C NMR (DMSO-d6) d 14.26,
Sigma2 binding assays were carried out on guinea pig
brain membranes prepared as described by Mach et al.34