Tetrahydroquinoline-Based Shank3 PDZ Domain Inhibitors
113.3 (C, aryl C-6), 110.7 (CH, aryl C-8), 61.1 (CH2, ethyl CH2), 53.7
(CH, C-4), 52.2 (CH3, methyl CH3), 42.3 (CH, C-9b), 39.2 (CH, C-3a),
32.3 (CH2, C-3), 13.9 ppm (CH3, ethyl CH3); HR-ESI-MS: [M+H]+
calcd for C17H19N2O6: 348.1269, found: 348.1272.
lution remained, followed by stirring for 2 h at room temperature.
Amberliteꢄ IR-120 hydrogen form was used to neutralize the reac-
tion mixture. The resin was filtered off and washed with H2O
(20 mL). Lyophilization of the filtrate yielded the pure product. Col-
orless solid (224 mg, 99%); mp: 1158C (dec.); 1H NMR (300 MHz,
[D6]DMSO): d=7.55 (s, 1H, 9), 7.47 (dd, J=8.5 Hz, J=1.9 Hz, 1H, 7),
6.82 (d, J=8.5 Hz, 1H, 6), 6.18 (s, 1H, 5), 5.83 (dd, J=5.0 Hz, J=
2.3 Hz, 1H, 1), 5.62 (d, J=5.0 Hz, 1H, 2), 4.07 (d, J=3.5 Hz, 1H, 4),
4.03 (d, J=9.0 Hz, 1H, 9b), 3.74 (s, 3H, methyl CH3), 3.16 (m, 1H,
3a), 2.34–2.17 ppm (m, 2H, 3); 13C NMR (75 MHz, [D6]DMSO): d=
172.5 (C, methyl ester C=O), 166.2 (C, carboxylate C=O), 149.4 (C,
aryl C-5a), 134.7 (CH, C-1), 130.1 (CH, aryl C-9), 129.4 (CH, C-2),
127.6 (CH, aryl C-7), 123.7 (C, aryl C-9a), 117.6 (C, aryl C-8), 114.6
(CH, aryl C-6), 54.4 (CH, C-4), 51.2 (CH3, methyl CH3), 44.8 (CH, C-
9b), 40.2 (CH, C-3a), 32.0 ppm (CH2, C-3); HR-ESI-MS: [M+H]+ calcd
for C15H16NO4: 274.1074, found: 274.1070.
3a,4,5,9b-Tetrahydro-3H-cyclopenta[c]quinoline-4,8-dicarboxylic
acid 4-ethyl ester 8-methyl ester (24): Aniline derivative: 4-
Amino-benzoic acid methyl ester (11, 325 mg, 2.15 mmol). Column
chromatography: n-hexane/EtOAc=1:1. Colorless solid (346 mg,
1
54%); mp: 1148C (dec.); H NMR (300 MHz, [D6]DMSO): d=7.57 (d,
J=2.3 Hz, 1H, 9), 7.49 (dd, J=8.5 Hz, J=2.3 Hz, 1H, 7), 6.82 (d, J=
8.5 Hz, 1H, 6), 6.31 (s, 1H, 5), 5.84 (dd, J=5.4 Hz, J=2.3 Hz, 1H, 1),
5.62 (d, J=5.4 Hz, 1H, 2), 4.25–4.12 (m, 3H, ethyl CH2, 4), 4.78 (d,
J=8.7 Hz, 1H, 9b), 3.75 (s, 3H, methyl CH3), 3.13 (m, 1H, 3a), 2.34–
2.15 (m, 2H, 3), 1.23 ppm (t, J=7.1 Hz, 3H, ethyl CH3); 13C NMR
(75 MHz, [D6]DMSO): d=171.0 (C, ethyl ester C=O), 166.1 (C,
methyl ester C=O), 149.1 (C, aryl C-5a), 134.7 (CH, C-1), 130.1 (CH,
aryl C-9), 129.2 (CH, C-2), 127.6 (CH, aryl C-7), 123.5 (C, aryl C-9a),
117.9 (C, aryl C-8), 114.7 (CH, aryl C-6), 60.5 (CH2, ethyl CH2), 54.3
(CH, C-4), 51.2 (CH3, methyl CH3), 44.6 (CH, C-9b), 40.1 (CH, C-3a),
32.0 (CH2, C-3), 14.0 ppm (CH3, ethyl CH3); HR-ESI-MS: [M+H]+
calcd for C17H20NO4: 302.1387, found: 302.1384.
4-Carbamoyl-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-
carboxylic acid methyl ester (52): To a suspension of 51 (150 mg,
0.55 mmol), Boc2O (132 mg, 0.60 mmol) and NH4HCO3 (260 mg,
3.29 mmol) in dry dioxane (4 mL), pyridine (44 mL, 1.21 mmol) was
added under nitrogen atmosphere. After stirring at room tempera-
ture for 18 h, the reaction mixture was diluted with EtOAc (15 mL)
and washed with H2O (1ꢂ20 mL) and 5% HCl (2ꢂ20 mL). The or-
ganic phase was dried over Na2SO4 and evaporated. Recrystalliza-
tion from EtOAc and n-hexane yielded the title compound. Off-
white solid (54 mg, 36%); mp: 2288C (dec.); 1H NMR (300 MHz,
[D6]DMSO): d=7.55 (s, 1H, 9), 7.48–7.45 (m, 2H, 7, 1ꢂNH2), 7,23 (s,
1H, 1ꢂNH2), 6.78 (d, J=8.5 Hz, 1H, 6), 6.13 (s, 1H, 5), 5.84 (dd, J=
5.2 Hz, J=2.2 Hz, 1H, 1), 5.63 (d, J=5.2 Hz, 1H, 2), 3.99 (d, J=
8.7 Hz, 1H, 9b), 3.93 (d, J=3.6 Hz, 1H, 4), 3.74 (s, 3H, methyl CH3),
3.16 (m, 1H, 3a), 2.36–2.26 (m, 1H, 1ꢂ3, 2.18–2.10 ppm (m, 1H, 1ꢂ
3); 13C NMR (75 MHz, [D6]DMSO): d=172.3 (C, amide C=O), 166.2
(C, methyl ester C=O), 149.4 (C, aryl C-5a), 134.5 (CH, C-1), 130.1
(CH, aryl C-9), 129.6 (CH, C-2), 127.6 (CH, aryl C-7), 123.6 (C, aryl C-
9b), 117.5 (CH, aryl C-6), 114.6 (C, aryl C-8), 54.9 (CH, C-4), 51.2 (CH3,
methyl CH3), 44.7 (CH, C-9b), 40.8 (CH, C-3a), 32.5 ppm (CH2, C-3);
HR-ESI-MS: [M+H]+ calcd for C15H17N2O3: 273.1234, found:
273.1228.
2-Chloro-4-hydroxy-1-nitro-5,6a,7,11b-tetrahydro-6H-indeno[2,1-
c]quinoline-6-carboxylic acid ethyl ester (33): Aniline derivative:
9
(405 mg; 2.15 mmol). Column chromatography: n-hexane/
EtOAc=2:1!1:1. Yellow solid (372 mg, 45%); mp: 2228C (dec.);
1H NMR (300 MHz, [D6]DMSO): d=11.00 (s, 1H, OH), 7.17 (d, J=
7.0 Hz, 1H, 11), 7.11 (dd, J=7.0 Hz, J=7.8 Hz, 1H, 10), 7.05 (ddd,
J=7.4 Hz, J=7.8 Hz, J=1.2 Hz, 1H, 9), 6.90 (d, J=7.4 Hz, 1H, 8),
6.77 (s, 1H, 3), 5.65 (bs, 1H, 5), 4.71 (d, J=7.3 Hz, 1H, 11b), 4.07 (d,
J=4.9 Hz, J=1.8 Hz, 1H, 6), 3.69 (q, J=7.1 Hz, 2H, ethyl CH2), 3.25
(m, 1H, 6a), 3.09–2.94 (m, 2H, 7), 1.07 ppm (t, J=7.1 Hz, 3H, ethyl
CH3); 13C NMR (75 MHz, [D6]DMSO): d=170.9 (C, non-aromatic C=
O), 146.4 (C, aryl C-4), 143.0 and 141.7 (2ꢂC, aryl C-7a and aryl C-
11b), 141.4 (C, aryl C-1), 133.8 (C, aryl C-4a), 126.9 (CH, aryl C-10),
126.2 (CH, aryl C-9), 124.8 (CH, aryl C-11), 123.9 (CH, aryl C-8), 115.0
(C, aryl C-11c), 112.1 (C, aryl C-2), 111.8 (CH, aryl C-3), 60.4 (CH2,
ethyl CH2), 53.7 (CH, C-6), 41.8 (CH, C-11b), 40.7 (CH, C-6a), 32.9
(CH2, C-7), 13.7 ppm (CH3, ethyl CH3); HR-ESI-MS: [M+H]+ calcd for
C19H18ClN2O5: 389.0899, found: 389.0906.
4-Hydroxymethyl-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quino-
line-8-carboxylic acid methyl ester (53): 51 (150 mg, 0.55 mmol)
was dissolved in 1,2-dimethoxyethane (7.5 mL), and 4-methylmor-
pholine (61 mL, 0.55 mmol) and isobutyl chloroformate (75 mL,
0.55 mmol) were added at ꢀ158C under nitrogen atmosphere.
After stirring for 10 min at ꢀ158C and 10 min at room tempera-
ture, the precipitate was filtered off. The filtrate was cooled to
ꢀ158C, and a solution of NaBH4 (31 mg, 0.824 mmol) in H2O
(300 mL) was added. Stirring was continued for 1 min, then H2O
(14 mL) was added. The reaction mixture was extracted with
CH2Cl2 (3ꢂ20 mL). Drying the combined organic phases over
Na2SO4 and evaporation yielded the crude product, which was pu-
rified by column chromatography (EtOAc/n-hexane=4:1). Colorless
4-(4-Methoxycarbonylphenylcarbamoyl)-3a,4,5,9b-tetrahydro-
3H-cyclopenta[c]quinoline-8-carboxylic acid methyl ester (50):
Aniline derivative: 4-Amino-benzoic acid methyl ester (11, 325 mg,
2.15 mmol). Column chromatography: n-hexane/EtOAc=1:1. Off-
white solid (96 mg, 11%); mp: 2448C (dec.); 1H NMR (300 MHz,
CDCl3): d=8.04 (d, J=8.5 Hz, 1H, 3’), 7.75 (bs, 1H, 9), 7.71 (dd, J=
8.3 Hz, J=1.3 Hz, 1H, 7), 7.65 (d, J=8.5 Hz, 1H, 2’), 6.71 (d, J=
8.3 Hz, 1H, 6), 5.94 (bs, 1H, 1), 5.70 (d, J=5.1 Hz, 1H, 2), 4.28 (d,
J=3.3 Hz, 1H, 4), 4.09 (bd, J=8.9 Hz, 1H, 9b), 3.91 and 3.87 (2ꢂs,
2ꢂ3H, 2ꢂmethyl CH3), 3.24 (m, 1H, 3a), 2.54 (m, 1H, 3A), 2.32 (m,
1H, 3B) ppm; 13C NMR (75 MHz, [D6]DMSO): d=170.1 (C, amide C=
O), 166.2 (C, benzoic acid ester C=O), 165.7 (C, aromatic quinoline
carbocylic acid ester C=O), 149.3 (C, aryl C-5a), 143.1 (C, aryl C-1’),
134.4 (CH, C-1), 130.1 (2ꢂCH, aryl C-9 and aryl C-3’), 129.5 (CH, C-
2), 127.7 ( aryl CH, C-7), 124.1 (C, aryl C-4’), 123.5 (C, aryl C-8), 118.8
(CH, aryl C-2’), 117.8 (C, aryl C-9a), 114.7 (CH, aryl C-6), 56.1 (CH, C-
4), 51.8 and 51.2 (2ꢂCH3, 2ꢂmethyl CH3), 44.7 (CH, C-9b), 40.9 (CH,
C-3a), 31.4 ppm (CH2, C-3); HR-ESI-MS: [M+H]+ calcd for
C23H23N2O5: 407.1601, found: 407.1595.
1
oil (91 mg, 64%); H NMR (300 MHz, [D6]DMSO): d=7.53 (s, 1H, 9),
7.46 (dd, J=8.5 Hz, J=1.9 Hz, 1H, 7), 6.69 (d, J=8.5 Hz, 1H, 6),
5.91–5.88 (m, 2H, 5, 1), 5.65 (d, J=5.2 Hz, 1H, 2), 3.91 (d, J=8.6 Hz,
1H, 9b), 3.74 (s, 3H, methyl CH3), 3.52–3.41 (m, 3H, 4, hydroxy-
methyl CH2), 2.78 (m, 1H, 3a), 2.31–2.12 ppm (m, 2H, 3); 13C NMR
(75 MHz, [D6]DMSO): d=166.2 (C, methyl ester C=O), 150.3 (C, aryl
C-5a), 134.6 (CH, C-1), 130.4 (CH, aryl C-9), 129.7 (CH, C-2), 127.5
(CH, aryl C-7), 124.1 (C, aryl C-8), 117.3 (C, aryl C-9a), 114.4 (CH, aryl
C-6), 63.1 (CH2, hydroxymethyl CH2), 53.8 (CH, C-4), 51.1 (CH3,
methyl CH3), 44.6 (CH, C-9b), 39.5 (CH, C-3a), 30.6 ppm (CH2, C-3);
3a,4,5,9b-Tetrahydro-3H-cyclopenta[c]quinoline-4,8-dicarboxylic
acid 8-methyl ester (51): 24 (400 mg, 1.24 mmol) was suspended
in 0.1m aq. NaOH solution (15 mL). THF was added until a clear so-
ChemMedChem 2011, 6, 1411 – 1422
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1419