R. Slavik et al. / European Journal of Medicinal Chemistry 92 (2015) 554e564
561
J1 ¼ 1.4 Hz, J2 ¼ 8.1 Hz, 1H), 7.50 (t, J ¼ 8.1 Hz, 1H), 7.20 (dd,
5.3.13. 1-Butyl-N-(cyclopropylmethyl)-8-methoxy-4-oxo-1,4-
J1 ¼1.0 Hz, J2 ¼ 8.0 Hz, 1H), 4.76 (t, J ¼ 5.5 Hz, 1H), 4.65 (t, J ¼ 5.7 Hz,
1H), 4.72 (t, J ¼ 7.4 Hz, 2H), 4.52 (t, J ¼ 7.0 Hz, 2H), 4.09 (s, 3H),
dihydroquinoline-3-carboxamide (RS-008)
RS-008 was obtained in a similar way to RS-005 in 89% yield. 1H
2.30e2.18 (m, 2H). 13C NMR (100 MHz, DMSO-d6):
d
178.2, 154.1,
NMR (400 MHz, CDCl3): d 10.11 (s, 1H), 8.67 (s, 1H), 8.18 (dd,
126.5, 119.5, 115.3, 108.3, 81.3, 79.9, 72.0, 56.5, 52.9, 32.5. HRMS
calcd for C14H15FNO4 280.0985, found 280.0982.
J1 ¼1.4 Hz, J2 ¼ 8.2 Hz, 1H), 7.40 (t, J ¼ 8.0 Hz, 1H), 7.21e7.19 (m, 1H),
4.57 (t, J ¼ 7.3 Hz, 2H), 3.98 (s, 3H), 3.35e3.32 (m, 2H), 1.83e1.76 (m,
2H), 1.37 (m, J ¼ 7.5 Hz, 2H), 1.15e1.05 (m, 1H), 0.95 (s, J ¼ 7.4, 3H),
0.57e0.52 (m, 2H), 0.31e0.27 (m, 2H). 13C NMR (100 MHz, CDCl3):
5.3.9. Synthesis of 3-hydroxy-1-aminoadamantane (5)
To an ice-cooled mixture of sulfuric acid (96%, 12.33 mL,
231 mmol) and nitric acid (65%, 1.2 mL, 26.5 mmol) was added 1-
aminoadamantane hydrochloride (1 g, 6.61 mmol) portion wise.
The mixture was stirred at rt for 2 days, ice-water (6 mL) was added
to the reaction mixture. The solution was stirred in an ice-water
bath for 30 min; KOH (35 g, 0.62 mol) was added in small por-
tions over 1 h at such a rate to keep the temperature below 80 ꢁC.
The resulting white paste was mixed with CH2Cl2 (300 mL) and
vigorously stirred for 1 h. The solid was filtered off, and the mother
liquor was evaporated to dryness under reduced pressure to pro-
vide 5 (527 mg, 3.15 mmol) in 48% yield as a white solid. 1H NMR
d 150.0, 125.3, 119.3, 114.3, 59.7, 56.3, 44.0, 33.5, 19.8.13.7, 10.9, 3.5.
HRMS calcd for C19H25N2O3 329.1860, found 329.1859.
5.3.14. N-(tert-butyl)-1-(3-fluoropropyl)-8-methoxy-4-oxo-1,4-
dihydroquinoline-3-carboxamide (RS-011)
RS-011 was synthesized as an analogue of RS-005 in 81% yield.
1H NMR (400 MHz, CDCl3):
d 10.00 (s, 1H), 8.67 (s, 1H), 8.16 (dd,
J1 ¼ 1.4 Hz, J2 ¼ 8.1 Hz, 1H), 7.40 (t, J ¼ 8.0 Hz, 1H), 7.20 (dd,
J1 ¼1.3 Hz, J2 ¼ 8.0 Hz, 1H), 4.72 (t, J ¼ 7.4 Hz, 2H), 4.57 (t, J ¼ 5.5 Hz,
1H), 4.46 (t, J ¼ 5.5 Hz, 1H), 3.98 (s, 3H), 2.30e2.17 (m, 2H), 1.49 (s,
9H). 13C NMR (CDCl3):
d
¼ 149.8, 130.6, 125.4, 119.3, 114.2, 81.5, 79.9,
(400 MHz, DMSO-d6):
d
4.33 (s, 1H), 2.08 (s, 2H), 1.49e1.42 (m, 5H),
67.7, 54.0, 44.8,
56.2, 50.9, 32.5, 29.0. 19F NMR (CDCl3):
d
¼ ꢃ222.04 (m). HRMS
1.38e1.35 (m, 9H). 13C NMR (100 MHz, DMSO-d6):
d
calcd for C18H24FN2O3 335.1765, found 335.1763.
44.1, 34.8, 30.5. HRMS calcd for C10H18NO 168.1383, found 168.1380.
5.3.15. N-(1-adamantyl)-1-(2-ethoxyethyl)-8-methoxy-4-oxo-1,4-
dihydroquinoline-3-carboxamide (RS-016)
5.3.10. Representative procedure for amide formation. Synthesis of
N-(1-adamantyl)-1-butyl-8-methoxy-4-oxo-1,4-dihydroquinoline-
3-carboxamide (RS-005)
RS-016 was prepared in the same way as RS-005 in 75% yield. 1H
NMR (400 MHz, CHCl3):
d 9.91 (s, 1H), 8.66 (s, 1H), 8.17 (dd,
To a suspension of 3a (206 mg, 0.748 mmol) in DMF (10 mL) was
added DIPEA (0.392 mL, 2.245 mmol) and the solution was stirred
at rt for 30 min. HBTU (568 mg, 1.497 mmol) was added portion
wise, followed by the addition of 1-aminoadamantane (0.136 g,
0.898 mmol). The mixture was stirred at rt for 4 h and diluted with
EtOAc (60 mL), washed with water (3 x 10 mL), HCl (0.5 M, 10 mL),
water (10 mL) and brine (15 mL). Solvents were removed under
reduced pressure and the residue was purified with flash chro-
matography using hexane:EtOAc (10:1 to 2:1) to give RS-005
J1 ¼ 1.4 Hz, J2 ¼ 8.2 Hz, 1H), 7.38 (t, J1 ¼ 8.0 Hz), 7.18 (t, J1 ¼ 1.2 Hz,
J2 ¼ 8.0 Hz, 1H), 4.73 (t, J ¼ 5.5 Hz, 2H), 3.96 (s, 3H), 3.75 (t,
J ¼ 5.5 Hz, 2H), 3.41 (q, J ¼ 7.0 Hz, 2H), 2.18 (s, 6H), 2.11 (s, 3H),
1.77e1.68 (m, 6H), 1.11 (t, J ¼ 7.0 Hz, 3H). 13C NMR (100 MHz,
CDCl3):
d 151.1, 125.2, 119.6, 114.4, 69.7, 66.9, 59.0, 56.5, 42.0, 36.8,
29.7. HRMS calcd for C25H34N2O4 425.2436, found 425.2436.
5.3.16. 1-(2-Ethoxyethyl)-8-methoxy-4-oxo-N-phenethyl-1,4-
dihydroquinoline-3-carboxamide (RS-022)
(263 mg, 0.644 mmol, 86% yield). 1H NMR (400 MHz, CDCl3):
d
9.95
RS-022 was obtained in a similar way as RS-005 in 69% yield. 1H
(s, 1H), 8.63 (s, 1H), 8.16 (dd, J1 ¼ 1.4 Hz, J2 ¼ 8.2 Hz, 1H), 7.38 (t,
J ¼ 8.0 Hz, 1H), 7.18 (dd, J1 ¼ 1.3 Hz, J2 ¼ 8.0 Hz, 1H), 4.54 (t,
J ¼ 7.6 Hz, 2H), 3.98 (s, 3H), 2.19e2.11 (m, 9H), 1.83e1.68 (m, 8H),
1.37 (m, J ¼ 7.5 Hz, 2H), 0.95 (t, J ¼ 7.4 Hz, 3H). 13C NMR (100 MHz,
NMR (400 MHz, DMSO-d6):
d
9.96 (t, J ¼ 5.7 Hz, 1H), 8.61 (s, 1H),
7.98e7.93 (m, 1H), 7.49e7.44 (m, 2H), 7.32e7.26 8 (m, 4H),
7.23e7.18 (m, 1H), 4.82 (t, J ¼ 4.8 Hz, 2H), 3.95 (s, 3H), 3.69 (t,
J ¼ 4.8 Hz, 2H), 3.60e3.55 (m, 2H), 3.35 (q, J ¼ 7.0 Hz, 2H), 2.85 (t,
J ¼ 7.2 Hz, 2H), 0.97 (t, J ¼ 7.0 Hz, 3H). 13C NMR (100 MHz, DMSO-
CDCl3):
d 149.8, 125.1, 119.3, 114.1, 59.7, 56.3, 51.6, 41.8, 36.6, 33.5,
29.6, 19.8, 13.7. HRMS calcd for C25H33N2O3 409.2486, found
409.2492.
d6): d 151.2, 128.6, 128.3, 126.1, 125.5, 118.1, 115.4, 68.7, 65.5, 58.3,
56.7, 35.4, 14.9. HRMS calcd for C23H27N2O4 395.1965, found
395.1964.
5.3.11. N-(tert-butyl)-1-butyl-8-methoxy-4-oxo-1,4-
dihydroquinoline-3-carboxamide (RS-006)
5.3.17. 1-(2-Ethoxyethyl)-N-(3-hydroxyadamantan-1-yl)-8-
methoxy-4-oxo-1,4-dihydroquinoline-3-carboxamide (RS-028)
RS-028 was prepared in a similar way as RS-005 in 84% yield. 1H
RS-006 was prepared in the same way as RS-005 in 92% yield. 1H
NMR (400 MHz, CDCl3):
d 10.05 (s, 1H), 8.64 (s, 1H), 8.14 (dd,
J1 ¼1.4 Hz, J2 ¼ 8.2 Hz, 1H), 7.37 (t, J ¼ 7.9 Hz, 1H), 7.18e7.17 (m, 1H),
NMR (400 MHz, CDCl3):
d
10.04 (s, 1H), 8.64 (s, 1H), 8.16 (dd, J1
¼
4.53 (t, J ¼ 6.3 Hz, 2H), 3.96 (s, 3H),1.79 (m, 2H),1.48 (s, 9H),1.36 (m,
1.4 Hz, J2 ¼ 8.1 Hz, 1H), 7.39 (t, J ¼ 8.0 Hz, 1H), 7.19 (dd, J1 ¼ 1.2 Hz,
J2 ¼ 8.0 Hz, 1H), 4.74 (t, J ¼ 5.4 Hz, 2H), 3.97 (s, 3H), 3.75 (t,
J ¼ 5.4 Hz, 2H), 3.42 (q, J ¼ 7.0 Hz, 2H), 2.31e2.04 (m, 9H), 1.78e1.62
(m, 5H), 1.42 (s, 1H), 1.11 (t, J ¼ 7.0 Hz, 3H). 13C NMR (100 MHz,
2H), 0.94 (t, J ¼ 7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3):
d 149.8,
125.2, 119.2, 114.2, 59.7, 56.3, 33.5, 29.0, 19.8, 13.7. HRMS calcd for
C
19H27N2O3 331.2016, found 331.2018.
CDCl3):
d 150.9, 114.3, 69.5, 59.0, 56.3, 49.3, 44.2, 40.5, 35.1, 30.7.
5.3.12. 1-Butyl-N-cyclopentyl-8-methoxy-4-oxo-1,4-
dihydroquinoline-3-carboxamide (RS-007)
HRMS calcd for C25H33N2O5 441.2384, found 441.2382.
RS-007 was obtained in the same way as RS-005 in 90% yield. 1H
5.3.18. Synthesis of N-(1-adamantyl)-1-(2-ethoxyethyl)-8-hydroxy-
4-oxo-1,4-dihydroquinoline-3-carboxamide (6)
NMR (400 MHz, CDCl3):
d 10.00 (s, 1H), 8.67 (s, 1H), 8.13 (dd,
J1 ¼1.4 Hz, J2 ¼ 8.2 Hz, 1H), 7.39 (t, J ¼ 8.0 Hz,1H), 7.20e7.18 (m, 1H),
4.56 (t, J ¼ 7.5 Hz, 2H), 4.40 (m, J ¼ 6.8 Hz, 1H), 3.96 (s, 3H),
2.07e1.98 (m, 2H), 1.81e1.73 (m, 4H), 1.64e1.57 (m, 4H), 1.36 (m,
J ¼ 7.5 Hz, 2H), 0.93 (t, J ¼ 7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3):
To a solution of RS-016 (202 mg, 0.476 mmol) in DMF (5 mL) was
added lithium chloride (303 mg, 7.14 mmol). The mixture was
heated to reflux and stirred overnight, then cooled to rt. Ethyl ac-
etate (EtOAc, 60 mL) was added and the mixture was washed with
HCl (0.2 M, 3 x 10 mL) and brine (15 mL). The organic layer was
dried over MgSO4 and solvent was removed under reduced pres-
sure. The residue was purified by HPLC with a C18 column using
d
150.1, 149.8, 130.3, 125.4, 119.1, 114.4, 59.8, 56.3, 50.9, 33.5, 33.2,
23.9, 19.7, 13.7. HRMS calcd for C20H27N2O3 343.2016, found
343.2016.