Substituted 2-Carboxyindole Derivatives
57
yield, 62/38 mixture of isomers of unassigned stereochemistry) as a white
solid. IR (nujol) ν = 1736 and 1718 (C=O) cm–1.– 1H-NMR (CDCl3): Major
isomer δ = 8.04 (m, 2H), 8.01 (d, 1H), 8.00 (s, 1H), 7.65 (tt, 1H), 7.55 (td,
2H), 7.28 (d, 1H), 4.41 (q, 2H), 1.56 (s, 9H), 1.37 (t, 3H); minor isomer: 8.09
(m, 2H), 8.0 (d, 1H), 7.55 (td, 2H), 4.41 (q, 2H), 1.37 (t, 3H).– m/z 558 [M
+ H]+.
4,6-Dichloro-3-(naphthalen-1-ylcarbamoylethynyl)indole-2-carboxylic
Acid Sodium Salt (2b)
98% yield from the corresponding ester as a granular yellow solid,
mp 280 °C. IR (Nujol) ν = 3400–3153 cm–1(NH).– 1H NMR ([D6]DMSO):
δ = 8.24 (bs, 1H), 7.95–7.92 (m, 1H), 7.83–7.76 (m, 2H), 7.58–7.48 (m, 3H),
7.43 (bs, 1H), 7.20 (bs, 1H).– m/z 445 [M + H]+.
E- and Z-1-Benzenesulfonyl-3-(2-carboxy-2-chlorovinyl)-4,6-dichloro-
indole-2-carboxylic Acid Ethyl Ester (6)
3-(Benzylcarbamoylethynyl)-4,6-dichloroindole-2-carboxylic Acid Sodium
Salt (2c)
A suspension of 5 (5.42 mmol) in formic acid (150 ml) was stirred over-
night at room temperature. After evaporation of the formic acid, product 4
(100% yield, mixture of E- and Z-isomers) was obtained as a white solid. The
product can be purified further, if desired, by trituration with diethyl ether to
give pure Z-isomer. Pure E-isomer can be obtained by evaporating the mother
liquor (enriched in E-isomer) to dryness and re-triturating the resulting solid
with diethyl ether. The same process is repeated several times on the mother
liquor to give pure E-isomer as a white solid. Subsequent reactions could be
carried out on either the pure isomers or on the mixture. Z-isomer: mp
229.5–232.1 °C. Z-isomer: IR (nujol) ν = 2900–2790 (OH), 1736 (C=O)
cm–1.– 1H-NMR ([D6]DMSO): δ = 8.09 (m, 2H), 8.06 (s, 1H), 8.04 (d, 1H),
7.82 (m, 1H), 7.71 (m, 2H), 7.65 (d, 1H), 4.34 (q, 2H), 1.23 (t, 3H).–
72% yield from the corresponding ester as a white solid, mp >250 °C.– IR
(Nujol) ν = 3400–3150 (NH), 1616 (C=O) cm–1.– 1H NMR (([D6]DMSO),
mixture of two rotamers in ratio 80/20*): δ = 8.79 (m, 1H), 8.28* (m, 1H),
7.42–7.16 (m, 6H), 7.08 (d, 1H), 7.06* (d, 1H), 4.81* (d, 1H), 4.32 (d, 1H).–
m/z 409 [M + H]+.
3-[2′-(3-cyclohexylcarbamoyl)ethynyl]-4,6-dichloroindole -2-carboxylic
Acid Sodium Salt (2d)
97% yield from the corresponding ester as a creamy solid, mp > 250 °C.–
NMR studies revealed the presence of a rotational isomer* 30% in mol IR
(Nujol) ν = 3445 and 3227, (NH), 1715, 1680, and 1603 (C=O) cm–1.–
1H-NMR (([D6]DMSO), 8.44 (m, 1H), 8.09* (m), 7.477* (d), 7.45 (d, 1H),
7.356* (d), 7.31 (d, 1H), 3.87* (m), 3.6 (m, 1H), 1.85–1.0 (m, 10H).–
13C-NMR (([D6]DMSO), 160.74, 151.71, 136.56, 133.62, 129.63, 127.55,
123.61, 122.03, 111.86, 98.14, 90.39, 77.02, 51.21 and 48.19*, 33.73 and
32.03*, 25.09, 24.69 and 24.59*.– m/z 379 [M + H]+.
1
E-isomer: IR (Film) ν = 3600–2500 (OH), 1732 (C=O) cm–1.– H NMR
([D6]DMSO): δ = 8.10–8.00 (m, 2H), 7.93 (d, 1H), 7.84–7.60 (m, 3H), 7.59
(d, 1H), 7.52 (s, 1H), 4.29 (m, 2H), 1.24 (m, 3H).– m/z 502 [M + H]+.
General Procedure for Amidation Reaction
To a solution of 6 in dry THF were added 2,2′-dipyridyl disulfide
(2.3 mmol) and triphenyl phosphine (2.3 mmol) and the resulting yellow
solution was stirred at room temperature for 2.5 h. The desired amine (a–h)
(2.7 mmol) was added and the mixture heated at reflux for 24 h, then 1N
hydrochloric acid was added and the mixture extracted with EtOAc. The
combined organic phase was washed with brine, dried and concentrated
under reduced pressure. The resulting residue was adsorbed onto silica and
purified by flash chromatography to give single isomers of 7(a–h).
3-((±)-Bicyclo[2.2.1]hept-2-ylcarbamoyl)ethynyl-4,6-dichloroindole-
2-carboxylic acid sodium salt (2e)
100% yield from the corresponding ester as a yellow solid, mp >250 °C.–
IR (Nujol) ν = 3175 (NH), 1612 (C=O).– 1H NMR (([D6]DMSO), mixture
of two rotamers the less abundant, present in 14%, is designated by *): δ =
8.33 (bd, 1H), 7.81* (d, 1H), 7.36* (d, 1H), 7.33 (d, 1H), 7.04 (bs, 1H), 3.54
(m, 1H), 2.14 (m, 2H), 1.6–1.0 (m, 8H).– m/z 413 [M + H]+.
General Procedure for the Formation of the Triple Bond
3-(2′-(1-Adamantylcarbamoyl)ethynyl)-4,6-dichloroindole-2-carboxylic
Acid Sodium Salt (2f)
A solution of 7(a–h) (0.92 mmol) in dry THF (10.3 ml) was cooled to
–78 °C and LHMDS (3 mmol) was added dropwise. The reaction was stirred
at this temperature for 5 h then warmed to 10 °C over 3 h. Saturated NH4Cl
(10 ml) was added and extracted with EtOAc (3 × 30 ml). The combined
extracts were washed with brine, dried and concentrated under reduced
pressure. The resulting residue was purified by flash chromatography afford-
ing the desired solid 8(a–h).
88% yield from the corresponding ester. IR (Nujol) ν = 2230 (C=C), 1618
(C=O) .– 1H NMR ([D6]DMSO): δ = 12.10 (br, 1H), 7.79 (s, 1H), 7.39 (s,
1H), 7.14 (s, 1H), 2.002 (m, 9H), 1.6 (m, 6H).– m/z 453 [M + H]+.
3-(Adamantan-1-ylmethylcarbamoylethynyl)-4,6-dichloroindole-
2-carboxylic Acid Sodium Salt (2g)
General Procedure for the Removal of the Protecting Group
67% yield from the corresponding ester as a white solid, mp >250 °C.– IR
(nujol) ν = 3383–3200 (NH), 1616 (C=O) cm–1.– 1H NMR ([D6]DMSO): δ
8.22 (m, 1H), 7.38 (s, 1H), 7.13 (s, 1H), 2.84 (d, 2H), 1.92 (m, 3H), 1.7–1.4
(m, 12H).– m/z 467 [M + H.
A solution of 8(a–h) (1.0 mmol) in dry THF (10 ml) was cooled to –15 °C
and LHMDS (3.0 mmol) was added dropwise. The solution was warmed to
room temperature, stirred for 1 h then further LHMDS (2.0 mmol) was added
twice over 4 h. The reaction was quenched with saturated NH4Cl, extracted
with EtOAc, washed with brine, dried, and evaporated. Final purification by
flash chromatography gave the desired products 9(a–h) as solids.
3-(Cyclopropylmethylcarbamoylethynyl)-4,6-dichloroindole-2-carboxylic
Acid Sodium Salt (2h)
General Procedure for the Hydrolysis of the Ethyl Ester
72% yield from the corresponding ester as a white solid, mp >250 °C.– IR
(nujol) ν = 3200 (NH), 1616 (C=O) cm–1.– 1H NMR ([D6]DMSO): δ 8.46
(bt, 1H), 7.38 (s, 1H), 7.10 (s, 1H), 2.99 (t, 2H), 0.95 (m, 1H), 0.40 (m, 2H),
0.17 (m, 2HH).– m/z 373 [M + H]+.
Product 9(a–h) (0.52 mmol) was suspended in isopropanol (10 ml) and
NaOH (2.1 mmol) was added. The resulting solution was heated at 60 °C for
1 h, then cooled; water (15 ml) was added and the organic solvent was
evaporated in vacuo. The precipitate formed was filtered and washed with
more water, then dried to give the desired product 2(a–h) as a solid.
In vitro binding assay: NCEs (new chemical entities) were dissolved at
concentration of 5 mM in 100% DMSO and tested at seven different concen-
trations (from 0.1 nM to 100 µM). Affinity to the glycine binding site was
assessed in duplicate by inhibition of the binding of [3H]-glycine to crude
synaptic membranes prepared from adult rat cerebral cortex as decribed by
Kishimoto[7]. Incubation (20 min, 4 °C) was carried out in 50 mM Tris/citrate
(pH 7.10) using 20 nM [3H]-glycine. Data from displacement experiments,
performed to determinate the inhibition constants (Ki) were analysed using
4,6-Dichloro-3-phenylcarbamoylethynyl-indole-2-carboxylic Acid Sodium
Salt (2a)
85% yield from the corresponding ester as a pale yellow solid,
mp > 200 °C.– IR (Nujol) ν = 3300 (NH), 1657 and 1649 cm–1.– 1H-NMR
([D6]DMSO): δ = 12.00 (br, 1H), 10.74 (bs, 1H), 7.67 (d, 2H), 7.38 (d, 1H),
7.32 (t, 2H), 7.15 (d, 1H), 7.06 (t, 1H).– m/z 397 [M + H]+.
the non linear curve-fitting software program LIGAND[10]
.
Arch. Pharm. Pharm. Med. Chem. 332, 55–58 (1999)