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colorless prisms. 1H NMR (400 MHz, DMSO-d6) d 1.76e1.84
7.1.12. 3-(4-Aminoindol-1-yl)-3-(3-pyridyl)
acrylic acid methyl ester (23)
(m, 2H, CH2), 2.63e2.73 (m, 2H, CH2), 2.88e2.98 (m, 2H,
CH2), 3.05e3.17 (m, 2H, CH2), 3.35e3.57 (m, 4H, 2CH2),
5.85e6.00 (m, 1H, CH), 6.17e6.21 (m, 1H, ArH), 6.42e6.55
(m, 1H, ArH), 6.60e6.62 (m, 1H, ArH), 6.85 (d, J ¼ 7.6, 1H,
ArH), 6.98e7.05 (m, 1H, ArH), 7.15e7.42 (m, 6H, ArH),
7.74 (br s, 1H, ArH); m/z 426 (M þ H)þ. HRMS (ESI) m/z
calcd for C27H27N3O2 425.21033, found 426.21254 (M þ Hþ).
Compound 23 was prepared from 22 and methyl 3-pyridyl-
propiolate using the procedure described for 19. Compound 23
1
was isolated (85%) as a E/Z mixture. H NMR (400 MHz,
CDCl3) d 3.62 (s, 2H, 2/3CH3), 3.69 (s, 1H, 1/3CH3), 6.28e
6.82 (m, 4H, 3ArH þ CH), 6.90 (t, J ¼ 8.2, 1H, ArH), 7.03
(d, J ¼ 3.6, 1H, ArH), 7.25e7.29 (m, 1H, ArH), 7.35e7.47
(m, 1H, ArH), 8.67e8.75 (m, 2H, ArH); m/z 294 (M þ H)þ.
7.1.9. 7-[2-[1-[2-Methoxycarbonyl-1-(3-pyridyl)vinyl]-1H-
indol-4-yl]vinyl]-3,4-dihydro-2H-[1,8]naphthyridine-1-
carboxylic acid tert-butyl ester (19)
7.1.13. 7-[[1-[2-Methoxycarbonyl-1-(3-pyridyl)
vinyl]-1H-indol-4-ylamino]methyl]-3,4-dihydro-
2H-[1,8]naphthyridine-1-carboxylic acid
Product 19 was prepared (84%) from 15 and methyl 3-pyr-
idylpropiolate using the procedure described for 16. Compound
19 was isolated as an E/Z mixture. 1H NMR (400 MHz, CDCl3)
d 1.61 (s, 9H, (CH3)3), 1.95e2.01 (m, 2H, CH2), 2.80 (t, 2H,
CH2), 3.62 (s, 2H, 2CH), 3.71 (s, 1H, 1CH), 3.82e3.85 (m,
2H, CH2), 6.35 (s, 1/3H, 1/3CH), 6.38 (s, 2/3H, 2/3CH),
6.79e7.47 (m, 10H, 8ArH þ 2CH), 8.04e8.1 (m, 1H, ArH),
8.69e8.72 (m, 2H, ArH); m/z 537 (M þ H)þ.
tert-butyl ester (24)
A mixture of 23 (200 mg, 0.68 mmol), 13 (215 mg, 0.82
mmol), sodium triacetoxyborohydride (260 mg, 1.2 mmol),
and acetic acid (47 mL, 0.82 mmol) in 1,2-dichloroethane was
stirred at room temperature for 12 h. After evaporation of the
solvent, the residue was purified by chromatography on silica
1
(AcOEt) yielded 24 (264 mg, 72%) as an E/Z mixture. H
NMR (400 MHz, CDCl3) d 1.56 (s, 9H, 3CH3), 1.95e2.01 (m,
2H, CH2), 2.77e2.82 (m, 2H, CH2), 3.26e3.43 (m, 2H, CH2),
3.61 (s, 2H, 2/3CH3), 3.92 (s, 1H, 1/3CH3), 3.79e3.86 (m,
2H, CH2), 4.55 (br s, 4/3H, 4/3CH2), 4.71 (br s, 2/3H,
2/3CH2), 6.28e6.35 (m, 2H, 1ArH þ 1CH), 6.80e7.06 (m, 4H,
ArH), 7.27e7.31 (m, 1H, ArH), 7.40 (d, J ¼ 7.6, 1H, ArH),
7.43e7.48 (m, 2H, ArH), 8.68e8.71 (m, 2H, ArH); m/z 540
(M þ H)þ.
7.1.10. 7-[2-[1-[2-Carboxy-1-(3-pyridyl)ethyl]-1H-indol-
4-yl]ethyl]-3,4-dihydro-2H-[1,8]naphthyridine-1-
carboxylic acid tert-butyl ester (20)
A solution of 19 (600 mg, 1.12 mmol), LiOH$H2O (85 mg,
2.03 mmol) and 10% Pd/C (600 mg) in THF (10 mL), MeOH
(5 mL), and H2O (1 mL) was stirred for 2 h at 25 ꢂC. Then, the
mixture was shaken in a hydrogenation apparatus under atmo-
spheric pressure of H2 at room temperature for 24 h. The cat-
alyst was removed by filtration, washed with methanol and the
filtrate was concentrated to dryness. Then, the residue was par-
titioned between ice-cold water (30 mL) and AcOEt (20 mL).
The aqueous layer was acidified to pH ¼ 4 with diluted AcOH,
then extracted twice with additional AcOEt (2 ꢀ 50 mL) and
dried (Na2SO4). After evaporation of the solvent, the residue
was triturated in ether and filtered to give 20 (483 mg,
7.1.14. 7-[[1-[2-Carboxy-1-(3-pyridyl)ethyl]-1H-indol-4-
ylamino]methyl]-3,4-dihydro-2H-[1,8]naphthyridine-1-
carboxylic acid tert-butyl ester (25)
Compound 25 was prepared (73%) from 24 using the pro-
1
cedure described for 20. H NMR (400 MHz, CDCl3) d 1.55
(s, 9H, 3CH3), 1.92e2.00 (m, 2H, CH2), 2.74e2.80 (m, 2H,
CH2), 3.26e3.43 (m, 2H, CH2), 3.79e3.86 (m, 2H, CH2),
4.35 (dd, J ¼ 16.4, J ¼ 32.0, 2H, CH2), 6.12e6.15 (m, 2H,
1ArH þ 1CH), 6.69 (d, J ¼ 3.2, 1H, ArH), 6.72 (d, J ¼ 8.8,
1H, ArH), 6.96e7.03 (m, 2H, ArH), 7.22e7.24 (m, 2H,
ArH), 7.36e7.41 (m, 2H, ArH), 8.46 (d, J ¼ 4.4, 1H, ArH),
8.60 (s, 1H, ArH); m/z 528 (M þ H)þ.
1
82%). H NMR (400 MHz, CDCl3) d 1.57 (s, 9H, (CH3)3),
1.95 (quint., 2H, CH2), 2.76 (t, 2H, CH2), 3.08e3.44 (m,
6H, 3CH2), 3.78e3.82 (m, 2H, CH2), 6.16 (t, 1H, CH), 6.64
(d, 1H, ArH), 6.82 (d, 1H, ArH), 6.95 (d, 1H, ArH), 7.08e
7.42 (m, 6H, ArH), 8.46e8.47 (m, 1H, ArH), 8.61 (d, 1H,
ArH); m/z 427 (M ꢁ (t-BOC) þ H)þ.
7.1.11. 3-Pyridin-3-yl-3-[4-[2-(5,6,7,8-tetrahydro
[1,8]naphthyridin-2-yl)ethyl]indol-1-yl]
propionic acid (21)
7.1.15. 3-(3-Pyridyl)-3-[4-[[(5,6,7,8)-tetrahydro
[1,8]naphthyridin-2-yl methyl]amino]
indol-1-yl]propionic acid (26)
Compound 26 was prepared from 25 using the procedure
1
described for 21. H NMR (400 MHz, MeOD4) d 1.70e1.85
(m, 2H, CH2), 2.61e2.70 (m, 2H, CH2), 3.17e3.30 (m, 2H,
CH2), 4.27 (dd, J ¼ 16.4, J ¼ 31.6, 2H, CH2), 5.97 (d,
J ¼ 7.6, 1H, ArH), 6.11 (t, J ¼ 4.4, 1H, CH), 6.59 (d, 1H,
ArH), 6.66e7.42 (m, 6H, ArH), 7.64e7.67 (m, 1H, ArH),
8.36 (d, J ¼ 2.4, 2H, ArH); m/z 428 (M þ H)þ. HRMS (ESI)
m/z calcd for C25H25N5O2 427.20083, found 428.20875
(M þ Hþ).
Compound 21 was prepared (48%) from 20 using the pro-
cedure described for 18. 1H NMR (400 MHz, CDCl3) d 1.85e
1.89 (m, 2H, CH2), 2.40e2.82 (m, 6H, 3CH2), 3.16e3.37 (m,
2H, CH2), 3.44e3.46 (m, 2H, CH2), 5.85e6.00 (m, 1H, CH),
6.17e6.21 (m, 1H, CH), 6.32e6.55 (m, 1H, ArH), 6.92 (t,
J ¼ 7.2, 1H, ArH), 7.02e7.53 (m, 6H, ArH), 8.45e8.48 (m,
2H, ArH), 10.96 (br s, 1H, NH); m/z 427 (M þ H)þ. HRMS
(ESI) m/z calcd for C26H26N4O2 426.20558, found
427.20594 (M þ Hþ).