BzR Agonist Ligands
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 14 2549
(m, 2H), 3.66 (m, 2H), 3.95 (m, 2H), 4.29 (m, 1H), 6.61 (m,
1H), 6.69 (m, 1H), 7.20 (m, 1H), 9.47 (s, 1H); MS (CI) m/e 460
(M+ + 1, 0), 418 (100), 385 (24), 315 (26). This material was
employed in a later step.
3.52 (s, 3H), 4.09 (t, 2H, J ) 6.5 Hz), 4.52 (q, 2H, J ) 7.1 Hz),
5.38 (s, 2H), 7.24 (dd, 1H, J ) 2.4, 8.9 Hz), 7.46 (d, 1H, J )
9.0 Hz), 7.80 (d, 1H, J ) 2.2 Hz), 8.62 (br s, 1H), 8.87 (s, 1H);
MS (CI) m/e 414 (M+ + 1, 100), 301 (10). Anal. (C24H32N2O4)
C, H, N.
6-(Octyloxy)-4-eth yl-3-(eth oxycar bon yl)-1,2,3,4-tetr ah y-
d r o-â-ca r bolin e-1-ca r boxylic Acid (19). The amino ethyl
ester 13 (1.24 g, 3.2 mmol) was treated as described in
procedure c to provide 19 as a mixture of diastereomers (1.29
g) in 91% yield. 19: mp >300 °C; IR (KBr) 2924, 2854, 1743
(CdO) cm-1; 1H NMR (CDCl3) δ 0.89 (t, 3H, J ) 6.2 Hz), 0.99
(m, 2H), 1.30 (m, 12H), 1.47 (m, 2H), 1.79 (m, 2H), 3.68 (m,
1H), 3.70 (m, 3H), 4.08 (m, 2H), 4.28 (m, 2H), 4.49 (m, 1H),
6.78 (m, 1H), 6.96 (m, 1H), 7.16 (m, 1H), 7.32 (s, 1H); MS (CI)
m/e 444 (M+ + 1, 3), 430 (20), 402 (100). This material was
employed in a later step.
6-(P r op yloxy)-4-(m eth oxym eth yl)-3-(eth oxyca r bon yl)-
1,2,3,4-tetr a h yd r o-â-ca r bolin e-1-ca r boxylic Acid (18). The
amino ethyl ester 12 (15 g, 4.5 mmol) was treated as described
in procedure c to provide the carboxylic acid 18 as a mixture
of diastereomers (10.2 g) in 90% yield. 18: mp 160-163 °C;
1H NMR (CDCl3) δ 3.27 (s, 3H), 3.73 (m, 2H), 3.90 (m, 2H),
4.0 (m, 2H), 6.77 (d, 1H), 6.92 (s, 1H), 6.96 (s, 1H), 7.04 (s,
1H), 7.07 (d, 1H), 7.23 (s, 1H), 9.12 (s, 1H); MS (CI) m/e 347
(M+ + 1, 100). This material was employed in a later step.
6-(Octyloxy)-4-eth yl-â-car bolin e-3-car boxylic Acid Eth -
yl Ester (25). The â-carboline 19 (3.89 g, 0.0085 mol) in
xylenes (50 mL) was heated at reflux, followed by oxidation
in DMSO (21 mL) with sulfur powder (0.55 g) as described in
procedure d. A wash column (silica gel, CH2Cl2) was run on
the black residue followed by crystallization from hot ethyl
acetate to provide 25 as light beige crystals (1.01 g, 30%). 25:
1
mp 163-165 °C; IR (KBr) 2931, 1701 (CdO) cm-1; H NMR
(CDCl3) δ 0.89 (t, 3H, J ) 6.9 Hz), 1.30-1.56 (m, 16H), 1.86
(m, 2H), 3.56 (q, 2H, J ) 7.3 Hz), 4.08 (t, 2H, J ) 6.5 Hz), 4.5
(q, 2H, J ) 7.1 Hz), 7.25 (dd, 1H, J ) 2.3, 8.9 Hz), 7.49 (d, 1H,
J ) 8.9 Hz), 7.71 (d, 1H, J ) 2.2 Hz), 8.82 (s, 1H), 8.95 (br s,
1H); MS (EI) m/e 396 (M+, 52), 367 (35), 350 (17), 255 (19),
238 (38), 211 (100), 181 (36). Anal. (C24H32N2O3) C, H, N.
6-(P r op yloxy)-4-(m et h oxym et h yl)-â-ca r b olin e-3-ca r -
boxylic Acid Eth yl Ester (24). The carboxylic acid 18 (1.2
g, 2.98 mmol) was suspended in xylenes, and the mixture was
heated to reflux under an atmosphere of N2 for 1 h. Then 10%
Pd/C (1.33 g) was added to the yellow solution and the mixture
heated to reflux for 3 h. The mixture was filtered and the
catalyst washed with hot xylenes (100 mL). The xylenes were
combined and removed under reduced pressure to provide a
crude solid. Flash chromatography provided the â-carboline
24 (512 mg) in 54% yield. 24: mp 250-251 °C; (IR (KBr) 2936,
6-(Ben zyloxy)-4-(m eth oxym eth yl)-3-(eth oxyca r bon yl)-
1,2,3,4-tetr a h yd r o-â-ca r bolin e-1-ca r boxylic Acid (21). The
amino ethyl ester 15 (2.9 g, 7.6 mmol) was treated as described
in procedure c to provide the carboxylic acid 21 as a mixture
of diastereomers (2.7 g) in 87% yield. 21: mp 156-157 °C;
MS (CI) m/e 395 (M+ - 44, 100). This material was employed
in a later step without further characterization.
1
1706 (CdO) cm-1; H NMR (G.E. 500 MHz, CDCl3) δ 1.06 (t,
3H, J ) 7 Hz), 1.32 (t, 3H, J ) 7.4 Hz), 1.85 (sextet, 2H, J )
6.6, 7.4 Hz), 3.52 (s, 3H), 4.02 (t, 2H, J ) 6.6 Hz), 4.43 (q, 2H,
J ) 7 Hz), 5.37 (s, 2H), 7.19 (dd, 1H, J ) 1.5, 9 Hz), 7.41 (d,
1H, J ) 9 Hz), 7.75 (s, 1H), 8.74 (s, 1H), 10.2 (s, 1H); HRMS
m/e 342.1581 (C19H22N2O4 requires 342.1579). Anal.
(C19H22N2O4) C, H, N.
6-(1-Na p h th ylm eth yloxy)-4-(m eth oxym eth yl)-â-ca r bo-
lin e-3-ca r boxylic Acid Eth yl Ester (29) (P r oced u r e d ).
Into a 100 mL round-bottom flask were added carboxylic acid
23 (3.23 g, 6.61 mmol) and a mixture of xylenes (65 mL). The
solution was heated at reflux for 1 h and the solvent removed
under reduced pressure. The residue was dissolved in DMSO
(18 mL), followed by the addition of sulfur powder (0.47 g),
and this mixture was stirred at a bath temperature of 144 °C
for 1.5 h. The DMSO was removed by high vacuum distilla-
tion, followed by a wash column (silica gel, EtOAc), and then
purification by flash chromatography (silica gel, EtOAc/hex-
anes, 80:20) provided â-carboline 29 (642 mg) in 22% yield.
6-(Ben zyloxy)-4-(m et h oxym et h yl)-â-ca r b olin e-3-ca r -
boxylic Acid Eth yl Ester (27). The â-carboline 21 (3.05 g,
6.97 mmol) in xylenes (200 mL) at reflux was subjected to
decarboxylation, followed by oxidation in DMSO (100 mL) with
sulfur powder (0.56 g) as described in procedure d. Flash
chromatography of the black residue (silica gel, 9:1 CHCl3:
MeOH) followed by crystallization from ethyl acetate/ether
furnished the â-carboline 27 (1.45 g) in 31% yield whose
spectral properties were identical to those previously pub-
lished.27,28 27: mp 187 °C (lit.27,28 mp 187 °C).
29: mp 174-176 °C; IR (KBr) 2931, 1694 (CdO) cm-1 1H
;
NMR (DMSO-d6) δ 1.33 (t, 3H, J ) 7.1 Hz), 3.27 (s, 3H), 4.34
(q, 2H, J ) 7.1 Hz), 5.10 (s, 2H), 5.65 (s, 2H), 7.39 (dd, 1H, J
) 2.3, 8.9 Hz), 7.48-7.62 (m, 4H), 7.71 (d, 1H, J ) 6.7 Hz),
7.85 (s, 1H), 7.95 (m, 2H), 8.17 (d, 1H, J ) 8.2 Hz), 8.85 (s,
1H); MS (CI) m/e 440 (M+ + 1, 100), 299 (33), 143 (30) 111
(16). Anal. (C27H24N2O4) C, H, N.
9-Meth yl-6-(1-n aph th ylm eth yloxy)-4-(m eth oxym eth yl)-
â-ca r bolin e-3-ca r boxylic Acid Eth yl Ester (35) (P r oce-
d u r e e). Into a 50 mL flame-dried round-bottom flask was
added â-carboline 29 (126 mg, 0.285 mmol) in dry DMF (12
mL). To this solution were added 2.5 equiv of iodomethane
and sodium hydride (16 mg, 60% dispersion in mineral oil, 0.39
mmol), and the solution was stirred at room temperature for
12 h under an atmosphere of N2. The DMF was removed by
heating in vacuo and the residue taken up in CHCl3 and
washed with water. The aqueous layer was extracted with
CHCl3 (3 × 25 mL). The combined organic layers were washed
with brine and dried (K2CO3), and the solvent was removed
under reduced pressure. A wash column (silica gel, ethyl
acetate) provided 35 as an off-white solid (77 mg, 60%). 35:
6-(1-Naph th ylm eth yloxy)-4-eth yl-â-car bolin e-3-car box-
ylic Acid Eth yl Ester (28). The â-carboline 22 (3.12 g, 6.61
mmol) in xylenes at reflux was subjected to decarboxylation,
followed by oxidation in DMSO (7 mL) with sulfur powder
(0.156 g) as described in procedure d. The black residue was
purified using flash chromatography (silica gel, EtOAc/hex-
anes, 80:20) to provide 28 (456 mg) in 16% yield. 28: mp
195.3-196.5 °C; IR (KBr) 2973, 1694 (CdO) cm-1 1H NMR
;
(DMSO-d6) δ 1.18 (t, 3H, J ) 7.3 Hz), 1.29 (t, 3H, J ) 7.1 Hz),
3.24 (q, 2H, J ) 7.3 Hz), 4.29 (q, 2H, J ) 7.1 Hz), 5.64 (s, 2H),
7.36 (dd, 1H, J ) 2.2, 9.0 Hz), 7.43-7.69 (m, 6H), 7.92 (m,
2H), 8.18 (d, 1H, J ) 7.6 Hz), 8.69 (s, 1H); MS (EI) m/e 424
(M+, 0.9), 141 (100). Anal. (C27H24N2O3) C, H, N.
1
mp 138-140 °C; IR (KBr) 2931, 1708 (CdO) cm-1; H NMR
(DMSO-d6) δ 1.32 (t, 3H, J ) 7.1 Hz), 3.25 (s, 3H), 3.98 (s,
3H), 4.33 (q, 2H, J ) 7.1 Hz), 5.09 (s, 2H), 5.66 (s, 2H), 7.43-
7.58 (m, 5H), 7.64 (m, 2H), 7.92 (m, 2H), 7,15 (d, 1H, J ) 7.7
Hz), 8.97 (s, 1H); MS (EI) m/e 454 (M+, 21), 141 (100), 115
(17). Anal. (C28H26N2O4) C, H, N.
6-(Octyloxy)-4-(m eth oxym eth yl)-â-ca r bolin e-3-ca r box-
ylic Acid Eth yl Ester (26). The â-carboline 20 (2.40 g,
0.0052 mol) in xylenes (28 mL) at reflux was subjected to
decarboxylation, followed by oxidation in DMSO (13 mL) with
sulfur powder (0.33 g) as described in procedure d. The DMSO
was removed by high vacuum distillation, and a wash column
(silica gel, CH2Cl2) was run on the black residue. Crystalliza-
tion from hot ethyl acetate provided the fully aromatic â-car-
boline 26 (820 mg) in 38% yield. 26: mp 147.3-149 °C; IR
(KBr) 3198 (NH), 2931, 1701 (CdO) cm-1; 1H NMR (CDCl3) δ
0.89 (t, 2H, J ) 6.9 Hz), 1.29-1.57 (m, 16H), 1.84 (m, 2H),
9-Meth yl-6-(1-n a p h th ylm eth yloxy)-4-eth yl-â-ca r bolin e-
3-ca r boxylic Acid Eth yl Ester (34). A solution of â-carbo-
line 28 (350 mg, 0.824 mmol) in dry DMF (18 mL) was
methylated as described in procedure e to provide 34 (306 mg,
84%) as a white solid. 34: mp 153-156 °C; IR (KBr) 2980,
1
1715 (CdO) cm-1; H NMR (DMSO-d6) δ 1.24 (t, 3H, J ) 7.0
Hz), 1.33 (t, 3H, J ) 7.1 Hz), 3.23 (q, 2H, J ) 6.5 Hz), 3.97 (s,
3H), 4.33 (q, 2H, J ) 7.6 Hz), 5.71 (s, 2H), 7.46-7.62 (m, 4H),