D2R/D3R Receptor Ligands from a Tropine Framework
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 19 6105
cold acetone (0 °C, 3 × 1 mL) and dried over high vacuum to
yield fine white crystals (94 mg, 0.18 mmol; 39%): mp 131-134
°C dec (EtOH). Anal. (C22H23ClN2O·(COOH)2 ·1.5CH3CH2OH) C,
H, N.
converted to the oxalate salt using general procedure K except using
i-PrOH as solvent (0.16 g, 0.32 mmol, 50%): mp 145-149 °C dec
(i-PrOH). Anal. (C26H26N2O·(COOH)2 ·0.75H2O) C, H, N.
endo-8-(1H-Indol-3-ylmethyl)-3-(2-methoxyphenyl)-8-
azabicyclo[3.2.1]octan-3-ol (36). Gramine (0.91 g, 5.25 mmol) and
25 (1.29 g, 5.53 mmol) in pyridine (55 mL) were reacted according
to general procedure J, except the chromatographed material was
triturated with CHCl3 (5 mL) to yield white solid 36 (0.21 g, 0.58
endo-8-(1H-Indol-3-ylmethyl)-3-(3,4-dichlorophenyl)-8-
azabicyclo[3.2.1]octan-3-ol (32). Gramine (0.23 g, 1.30 mmol) and
24 (0.37 g, 1.36 mmol) in pyridine (13 mL) were reacted according
to general procedure J, yielding pure 32 (0.19 g, 0.48 mmol, 37%):
Rf(10% MeOH/CHCl3 + 1% NH4OH) ) 0.54; 1H NMR (400 MHz,
CDCl3) δ 1.57 (s, 1H, -OH), 1.76 (d, J ) 14.0 Hz, 2H), 2.13 (m,
2H), 2.23 (m, 2H), 2.35 (br d, J ) 12.8 Hz, 2H), 3.43 (br s, 2H),
3.82 (s, 2H), 7.15 (ddd, J ) 1.2, 7.2, 8.0 Hz, 1H), 7.21 (ddd, J )
1.2, 7.2, 8.4 Hz, 1H), 7.23 (obs br s, 1H), 7.30-7.33 (m, 1H), 7.36
(obs d, J ) 8.4 Hz, 1H), 7.37 (obs d, J ) 8.0 Hz, 1H), 7.61 (d, J
) 2.4 Hz, 1H), 7.83 (d, J ) 7.6 Hz, 1H), 8.22 (br s, 1H, -NH);
13C NMR (100 MHz, CDCl3) δ 25.8, 29.9, 46.6, 48.4, 58.9, 73.3,
111.4, 119.6, 119.7, 122.2, 123.6, 124.6, 127.3, 127.8, 130.2, 130.5,
132.3, 136.5, 150.9; IR (thin film) 3419, 3468 cm-1. The product
was converted to the oxalate salt using general procedure K (105
mg, 0.20 mmol, 42%): mp 166-170 °C dec (EtOH). Anal.
(C22H22Cl2N2O·0.5(COOH)2 ·1.5CH3CH2OH·0.25H2O) C, H, N.
endo-8-(1H-Indol-3-ylmethyl)-3-(2,3-dichlorophenyl)-8-
azabicyclo[3.2.1]octan-3-ol (33). Gramine (59 mg, 0.34 mmol) and
26 (102 mg, 0.37 mmol) in pyridine (4 mL) were reacted according
to general procedure J, then purified using preparative TLC (10%
MeOH/CHCl3 + 1% MeOH) to yield pure solid 33 (0.62 g, 0.16
mmol, 42%): Rf(3% MeOH/CHCl3 + 1% NH4OH) ) 0.25; 1H
NMR (400 MHz, CDCl3) δ 1.69 (d, J ) 13.6 Hz, 2H), 2.05 (br s,
1H, -OH), 2.12 (m, 2H), 2.20 (m, 2H), 2.93 (dd, J ) 4.0, 14.4
Hz, 2H), 3.44 (br s, 2H), 3.77 (s, 2H), 7.17 (m, 4H), 7.36 (obs d,
J ) 7.6 Hz, 1H), 7.39 (obs dd, J ) 1.6, 8.4 Hz, 1H), 7.64 (dd, J
) 1.6, 8.4 Hz, 1H), 7.87 (d, J ) 7.2 Hz, 1H), 8.10 (s, 1H, -NH);
13C NMR (100 MHz, CDCl3) δ 26.1, 43.6, 49.1, 59.2, 74.9, 111.2,
115.1, 119.4, 120.2, 122.2, 123.0, 125.4, 127.2, 127.8, 129.4, 129.8,
135.0, 136.7, 148.2; IR (thin film) 3413, 3544 cm-1. The product
was converted to the oxalate salt using general procedure K (52
mg, 0.10 mmol, 63%): mp 175-179 °C dec (EtOH). Anal.
(C22H22Cl2N2O·(COOH)2 ·0.5CH3CH2OH) C, H, N.
endo-8-(1H-Indol-3-ylmethyl)-3-(4-fluorophenyl)-8-
azabicyclo[3.2.1]octan-3-ol (34). Gramine (97 mg, 0.56 mmol) and
27 (0.15 g, 0.70 mmol) in pyridine (6 mL) were reacted according
to general procedure J to yield pure 34 (0.11 g, 0.32 mmol, 57%);
Rf(10% MeOH/CHCl3 + 1% NH4OH) ) 0.15; 1H NMR (400 MHz,
CD3OH) δ 1.82 (d, J ) 14.4 Hz, 2H), 2.19 (m, 2H), 2.25 (dd, J )
3.6, 14.8 Hz, 2H), 2.38 (m, J ) 13.6 Hz, 2H), 3.46 (br s, 2H), 3.81
(s, 2H), 6.97 (m, J ) 8.8 Hz, 2H), 7.04 (t, J ) 7.4 Hz, 1H), 7.11
(t, J ) 7.4 Hz, 1H), 7.31 (s, 1H), 7.36 (d, J ) 8.4 Hz, 1H), 7.54
(m, J ) 2.0 Hz, 2H), 7.68 (d, J ) 7.6 Hz, 1H); 13C NMR (100
MHz, CD3OH) δ 26.3, 46.5, 48.1, 60.4, 73.6, 112.3, 112.4, 115.3
(d, J ) 21.1 Hz), 119.4, 120.0, 122.4, 125.8, 127.8 (d, J ) 7.5
Hz), 129.2, 137.8, 147.9 (d, J ) 2.5 Hz), 162.8 (d, J ) 241.1 Hz);
19F NMR (376 MHz, CDCl3/CFCl3) δ -118.0 (m); IR (thin film)
3292, 3407 cm-1. The product was converted to the oxalate salt
using general procedure K (79 mg, 0.16 mmol, 51%): mp 162-165
°C dec (acetone). Anal. (C22H23FN2O·0.66(COOH)2 ·H2O·(CH3)2-
CO) C, H, N.
1
mmol, 11%): Rf(10% MeOH/CHCl3 + 1% NH4OH) ) 0.46; H
NMR (400 MHz, DMSO-d6) δ 1.36 (d, J ) 12.8 Hz, 2H), 1.90 (br
m, 2H), 2.19 (m, 2H), 2.61 (br dd, J ) 3.4, 13.4 Hz, 2H), 3.18 (br
s, 2H), 3.75 (s, 2H), 3.87 (s, 3H), 4.52 (s, 1H, -OH), 6.89 (dt, J
) 1.2, 7.6 Hz, 1H), 6.94 (dd, J ) 0.8, 8.0 Hz, 1H), 6.99 (dt, J )
0.8, 7.6 Hz, 1H), 7.06 (dt, J ) 1.2, 7.6 Hz, 1H), 7.17 (obs dt, J )
2.0, 8.0 Hz, 1H), 7.20 (obs d, J ) 2.4 Hz, 1H), 7.33 (d, J ) 8.0
Hz, 1H), 7.57 (dd, J ) 2.0, 7.6 Hz, 1H), 7.92 (d, J ) 7.6 Hz, 1H),
10.79 (s, 1H, -NH); 13C NMR (100 MHz, DMSO-d6) δ 26.0, 41.6,
47.8, 55.0, 58.0, 71.9, 111.3, 111.4, 113.6, 118.0, 119.8, 120.0,
120.9, 123.4, 126.7, 127.5, 127.6, 136.6, 138.4, 155.8; IR (thin film)
3438 cm-1. Because of low solubility, the oxalate salt could not
be
generated:
mp
209-212
°C
(CHCl3).
Anal.
(C23H26N2O2 ·0.5H2O) C, H, N.
endo-8-(1H-Indol-3-ylmethyl)-3-(4-(methylthio)phenyl)-8-
azabicyclo[3.2.1]octan-3-ol (37). Gramine (92 mg, 0.53 mmol) and
30 (0.15 g, 0.59 mmol) in pyridine (6 mL) were reacted according
to general procedure J and purified using preparative TLC (10%
MeOH/CHCl3 + 1% NH4OH) to yield pure 37 (0.13 g, 0.34 mmol,
64%); Rf(10% MeOH/CHCl3 + 1% NH4OH) ) 0.26; 1H NMR
(400 MHz, CD3OD) δ 1.82 (d, J ) 14.4 Hz, 2H), 2.21 (br m, 2H),
2.26 (br dd, J ) 3.2, 14.8 Hz, 2H), 2.39 (m, 2H), 2.42 (s, 3H,
-SCH3), 3.49 (br s, 2H), 3.85 (s, 2H), 7.05 (dt, J ) 0.8, 7.2 Hz,
1H), 7.11 (dt, J ) 0.8, 7.2 Hz, 1H), 7.18 (dt, J ) 1.4, 8.0 Hz, 2H),
7.33 (s, 1H), 7.36 (d, J ) 8.0 Hz, 1H), 7.46 (dt, J ) 2.0, 8.4 Hz,
2H), 7.68 (d, J ) 8.0 Hz, 1H); 13C NMR (100 MHz, CD3OD) δ
15.9, 26.3, 46.3, 48.1, 60.5, 73.6, 112.2, 112.3, 119.4, 120.0, 122.4,
125.9, 126.5, 127.3, 129.2, 137.6, 137.8, 148.9; IR (thin film) 3391
(br) cm-1. The product was converted to the oxalate salt using
general procedure K except using i-PrOH as solvent (0.11 g, 0.23
mmol, 70%): mp 135-143 °C dec (i-PrOH); Anal.
(C23H26N2OS·(COOH)2 ·0.5CH3OH) C, H, N.
endo-8-(1H-Indazol-3-ylmethyl)-3-(4-chlorophenyl)-8-
azabicyclo[3.2.1]octan-3-ol (38). 3-(Dimethylaminomethyl)inda-
zole43 (0.20 g, 1.13 mmol) and 23 (0.30 g, 1.26 mmol) in pyridine
(3 mL) were reacted according to general procedure J, yielding
pure 38 (0.27 g, 0.73 mmol, 64%): mp 90-95 °C (CHCl3); Rf(3%
MeOH/CHCl3 + 1% NH4OH) ) 0.30; 1H NMR (400 MHz,
DMSO-d6) δ 1.71 (d, J ) 13.2 Hz, 2H), 1.97 (m, 2H), 2.06 (br dd,
J ) 2.8, 14.0 Hz, 2H), 2.34 (m, 2H), 3.25 (br s, 2H), 3.91 (s, 2H),
4.83 (s, 1H, -OH), 7.10 (t, J ) 7.2 Hz, 1H), 7.32 (obs dt, J ) 0.8,
8.4 Hz, 1H), 7.33 (obs d, J ) 8.4 Hz, 2H), 7.43 (d, J ) 8.4 Hz,
2H), 7.48 (d, J ) 8.4 Hz, 1H), 8.02 (d, J ) 8.4 Hz, 1H), 12.75 (s,
1H, -NH); 13C NMR (100 MHz, DMSO-d6) δ 25.5, 45.1, 49.4,
58.5, 71.5, 110.1, 119.6, 121.1, 122.0, 125.9, 126.8, 127.6, 130.5,
141.1, 143.8, 150.8; IR (thin film) 3227 (br) cm-1. The product
was converted to the oxalate salt using general procedure K (0.17
g, 0.36 mmol, 49%): mp 171-174 °C (EtOH). Anal. (C21H22-
ClN3O·(COOH)2 ·0.25H2O) C, H, N.
endo-8-(1H-Indol-3-ylmethyl)-3-(2-naphthyl)-8-
azabicyclo[3.2.1]octan-3-ol (35). Gramine (0.16 g, 0.91 mmol) and
29 (0.24 g, 0.94 mmol) in pyridine (9 mL) were reacted according
to general procedure J, yielding pure 35 (0.25 g, 0.65 mmol, 71%);
Rf(3% MeOH/CHCl3 + 1% NH4OH) ) 0.25; 1H NMR (400 MHz,
CDCl3) δ 1.59 (s, 1H, -OH), 1.85 (d, J ) 14.0 Hz, 2H), 2.15 (m,
2H), 2.31 (m, 2H), 2.56 (br d, J ) 13.2 Hz, 2H), 3.47 (br s, 2H),
3.87 (s, 2H), 7.17 (dt, J ) 1.0, 7.0 Hz, 1H), 7.22 (dt, J ) 1.0, 7.0
Hz, 1H), 7.26 (obs br s, 1H), 7.38 (d, J ) 8.0 Hz, 1H), 7.46 (m,
2H), 7.63 (d, J ) 8.0 Hz, 1H), 7.81 (obs m, 1H), 7.81 (obs s, 1H),
7.83 (obs s, 1H), 7.88 (d, J ) 8.0 Hz, 1H), 7.95 (d, J ) 1.6 Hz,
1H), 8.14 (br s, 1H, -NH); 13C NMR (100 MHz, CDCl3) δ 25.9,
46.3, 48.3, 59.0, 73.8, 111.4, 114.0, 119.5, 119.7, 122.1, 122.6,
123.6, 124.1, 125.9, 126.2, 127.5, 127.9, 128.1, 128.4, 132.3, 133.1,
136.5, 147.7; IR (thin film) 3297, 3417 cm-1. The product was
endo-8-(5-Methoxy-1H-indol-3-ylmethyl)-3-(4-chlorophenyl)-
8-azabicyclo[3.2.1]octan-3-ol (39). 5-Methoxygramine (79 mg,
0.38 mmol) and 23 (96 mg, 0.40 mmol) in pyridine (4 mL) were
reacted according to general procedure J and purified using
preparative TLC (10% MeOH/CHCl3 + 1% NH4OH) to yield pure
solid 39 (0.10 g, 0.25 mmol, 66%); Rf(10% MeOH/CHCl3 + 1%
1
NH4OH) ) 0.20; H NMR (400 MHz, CDCl3) δ 1.50 (br s, 1H,
-OH), 1.77 (d, J ) 14.0 Hz, 2H), 2.11 (br m, 2H), 2.25 (br m,
2H), 2.38 (br d, J ) 13.6 Hz, 2H), 3.41 (br s, 2H), 3.79 (s, 2H),
3.87 (s, 3H), 6.86 (dd, J ) 2.4, 8.4 Hz, 1H), 7.18 (br s, 1H), 7.24
(obs d, J ) 8.8 Hz, 2H), 7.26 (obs d, J ) 8.8 Hz, 1H), 7.32 (d, J
) 2.0 Hz, 1H), 7.42 (d, J ) 8.8 Hz, 2H), 8.10 (br s, 1H, -NH);
13C NMR (100 MHz, CDCl3) δ 25.9, 46.9, 48.7, 56.1, 58.9, 73.6,
101.9, 112.0, 112.4, 112.5, 124.1, 126.4, 128.3, 128.4, 131.8, 132.5,