Quinolinone-3-aminoamides and R-Lipoic Acid Adducts
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 10 2455
CF3COOD): δ 10.47 (br s, 0.4H, CONH), 8.30 (dd, 1H, J5,6 ) 8.1
Hz, J5,7 ) 1.2 Hz, 5-H), 7.68-7.61 (m, 3H), 7.60-7.56 (m, 1H),
7.41 (pseudotriplet, 1H), 7.28-7.23 (m, 2H), 6.72 (d, 1H, J ) 8.7
Hz), 3.79 (br s, 2H, NH-CH2-), 3.39 (br s, 2H, -CH2NH2). 13C
NMR (CDCl3/CF3COOD): δ 173.4 (9-C), 172.6 (4-C), 163.3 (2-
C), 140.6 (8a-C), 136.0 (1′-C), 134.8 (7-C), 130.9, 130.2, 128.7,
125.6, 124.3, 116.8 (4a-C), 113.0 (8-C), 109.2 (3-C), 41.6 (10-C),
37.5 (11-C). Anal. (C18H17N3O3) C, H, N.
3.68 (s, 3H, N-CH3), 3.65-3.59 (m, 2H, -CONHCH2CH2-
NHCO-), 3.51-3.44 (m, 3H, -CONHCH2CH2NHCO- and 17-
H), 3.14-3.04 (m, 2H), 2.41 (sextet, 1H, J ) 6.3 Hz), 2.20 (m,
2H, -NHCOCH2CH2CH2CH2-), 1.86 (sextet, 1H, J ) 6.4 Hz),
1.65-1.61 (m, 4H, -NHCOCH2CH2CH2CH2-), 1.46-1.43 (m,
2H, -NHCOCH2CH2CH2CH2-). 13C NMR (CDCl3): δ 173.3 (9-
C), 172.3 (4-C), 171.9, 162.8 (2-C), 140.1 (8a-C), 134.1 (7-C), 125.6
(5-C), 122.6 (6-C), 116.2 (8-C), 114.4 (4a-C), 96.8 (3-C), 56.3,
40.3, 40.1, 38.5, 38.3, 36.4, 34.5, 29.1 (N-CH3), 28.7, 25.2. Anal.
(C21H27N3O4S2) C, H, N, S.
N-Hexylamino-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-3-quin-
olinecarboxamide (7). Compound 7 was prepared from quinolinone
3 and 1,6-hexamethylenediamine: yield 46% (Method A) and 69%
(Method B), white solid, mp 156-158 °C. 1H NMR (CDCl3/CD3-
N-(1,2-Dihydro-4-hydroxy-2-oxo-1-phenyl-3-quinolinecarbo-
nyl)-N′-(1,2-dithiolane-3-pentanoyl)-ethylenediamine (15). Com-
pound 15 was obtained by reaction of 6 with 13, as a white solid,
after purification with flash column chromatography (CH2Cl2/
MeOH, 97:3) and recrystallization from CHCl3/petroleum ether:
OD): δ 10.27 (br s, 1H, CONH), 8.12 (dd, 1H, J5,6 ) 8.1, J5,7
)
1.2 Hz, 5-H), 7.62 (pseudotriplet, 1H, 7-H), 7.32-7.21 (m, 2H,
6-H, 8-H), 3.59 (s, 3H, N-CH3), 3.37-3.30 (m, 2H, NH-CH2-),
2.56 (pseudotriplet, 2H, -CH2NH2), 1.58-1.29 (m, 8H, -(CH2)4-
). Anal. (C17H23N3O3) C, H, N.
1
yield 70%, mp 170-172 °C. H NMR (CDCl3): δ 16.92 (s, 1H,
OH), 10.38 (br, 1H, CONH-(CH2)2-), 8.24 (dd, 1H, J5,6 ) 8.1
Hz, J5,7 ) 1.5 Hz, 5-H), 7.66-7.53 (m, 3H), 7.48 (dtd, 1H, J )
1.8, 8.7, 7.2 Hz), 7.32-7.26 (m, 3H), 6.66 (d, 1H, J ) 8.4 Hz),
6.14 (br, 1H, -(CH2)2-NHCO), 3.60-3.42 (m, 5H), 3.15-3.02
(m, 2H), 2.42 (sextet, 1H, J ) 6.3 Hz), 2.17 (m, 2H, -NHCOCH2-
CH2CH2CH2-), 1.88 (sextet, 1H, J ) 6.4 Hz), 1.70-1.61 (m, 4H,
-NHCOCH2CH2CH2CH2-), 1.48-1.40 (m, 2H, -NHCOCH2-
CH2CH2CH2-). 13C NMR (CDCl3): δ 173.2 (9-C), 172.9 (4-C),
172.2, 163.1 (2-C), 141.0 (8a-C), 137.1, 133.7 (7-C), 130.5, 129.4,
129.0, 125.3 (5-C), 122.9 (6-C), 116.2 (8-C), 116.0 (4a-C), 96.7
(3-C), 56.3, 40.2, 40.1, 38.6, 38.3, 36.3, 34.5, 28.7, 25.2. Anal.
(C26H29N3O4S2) C, H, N, S.
N-o-Phenylamino-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-3-
quinolinecarboxamide (9). Compound 9 was prepared from
quinolinone 3 and 1,2-phenylenediamine, according to Method B:
yield 65%, light green solid, mp 230-232 °C (lit.60 mp 230-232
°C). 1H NMR (CDCl3): δ 16.61 (s, 1H, OH), 12.17 (s, 1H, CONH),
8.26 (dd, 1H, J5,6 ) 8.1, J5,7 ) 1.5 Hz, 5-H), 7.73 (dtd, 1H, J7,8
)
8.7 Hz, J7,6 ) 6.9 Hz, J7,5 ) 1.5 Hz, 7-H), 7.55 (dd, 1H, J ) 8.4,
1.8 Hz), 7.09 (ddd, 1H, J ) 9.3, 7.8, 1.5 Hz), 6.85 (pseudotriplet,
2H), 7.41 (d, J8,7 ) 9.0 Hz, 1H, 8-H), 7.35 (ddd, 1H, J6,5 ) 8.1
Hz, J6,7 ) 7.2 Hz, J6,8 ) 1.2 Hz, 6-H), 3.93 (br s, 2H, -NH2), 3.75
(s, 3H, N-CH3). 13C NMR (CDCl3): δ 169.7 (4-C), 159.9 (CONH),
155.0 (2-C), 140.3, 140.2 (8a-C), 134.2 (7-C), 127.1, 125.7, 125.2
(5-C), 122.7, 119.3, 117.3 (4a-C), 114.4 (8-C), 100.0 (3-C), 29.1
(N-CH3). Anal. (C17H15N3O3) C, H, N.
N-(1,2-Dihydro-4-hydroxy-1-methyl-2-oxo-3-quinolinecarbo-
nyl)-N′-(1,2-dithiolane-3-pentanoyl)-hexamethylenediamine (16).
Compound 16 was obtained by reaction of 7 with 13, as a yellowish
solid, after purification with flash column chromatography (CH2-
N-p-Phenylamino-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-3-
quinolinecarboxamide (11). Compound 11 was prepared from
quinolinone 3 and 1,4-phenylenediamine, according to Method B:
1
Cl2/MeOH, 97:3): yield 60%, mp 93-95 °C. H NMR (CDCl3):
δ 17.19 (s, 1H, OH), 10.30 (br, 1H, CONH-(CH2)6-), 8.18 (dd,
1H, J5,6 ) 8.1 Hz, J5,7 ) 1.5 Hz, 5-H), 7.71 (ddd, 1H, J7,8 ) 8.4
Hz, J7,6 ) 7.5 Hz, J7,5 ) 1.8 Hz, 7-H), 7.35-7.25 (m, 2H, 6-H,
8-H), 5.68 (br, 1H, -(CH2)6-NHCO), 3.65 (s, 3H, N-CH3), 3.54
(quintet, 1H, J ) 6.6 Hz), 3.42 (q, 2H, J ) 6.6 Hz, CONH-
CH2(CH2)4CH2-NHCO-), 3.22 (q, 2H, J ) 6.9 Hz, CONH-CH2-
(CH2)4CH2-NHCO-), 3.17-3.30 (m, 2H), 2.42 (sextet, 1H, J )
6.6 Hz), 2.15 (m, 2H, -NHCOCH2CH2CH2CH2-), 1.87 (sextet,
1H, J ) 6.0 Hz), 1.70-1.30 (m, 14H). 13C NMR (CDCl3): δ 172.8
(9-C), 172.0 (4-C), 171.1, 162.8 (2-C), 139.9 (8a-C), 133.7 (7-C),
125.5 (5-C), 122.4 (6-C), 116.3 (8-C), 114.2 (4a-C), 96.7 (3-C),
56.3, 40.1, 39.2, 38.7, 38.3, 36.4, 34.5, 29.3 (N-CH3), 29.0, 28.8,
26.4, 26.3, 25.3. Anal. (C25H35N3O4S2) C, H, N, S.
1
yield 97%, green solid, mp 228 °C (dec). H NMR (CDCl3/CF3-
COOD): δ 8.34 (dd, 1H, J5,6 ) 7.8, J5,7 ) 1.5 Hz, 5-H), 7.90-
7.77 (m, 3H), 7.63-7.43 (m, 5H), 3.82 (s, 3H, N-CH3). 13C NMR
(CDCl3/CF3COOD): δ 172.7 (9-C), 169.8 (4-C), 164.0 (2-C), 139.7,
138.2 (8a-C), 135.8, 130.6 (7-C), 126.3 (5-C), 123.9 (6-C), 120.2,
116.5, 115.4 (4a-C), 112.7 (8-C), 108.9 (3-C), 30.8 (N-CH3). Anal.
(C17H15N3O3) C, H, N.
N-p-Phenylamino-1,2-dihydro-4-hydroxy-2-oxo-1-phenyl-3-
quinolinecarboxamide (12). Compound 12 was prepared from
quinolinone 4 and 1,4-phenylenediamine, according to Method B:
yield 99%, light green solid, mp > 280 °C (dec). 1H NMR (CDCl3/
CF3COOD): δ 8.37 (dd, 1H, J5,6 ) 8.1, J5,7 ) 1.5 Hz, 5-H), 7.75-
7.62 (m, 6H), 7.45 (pseudotriplet, 3H), 7.34-7.31 (m, 2H), 6.78
(d, 1H, J ) 8.7 Hz). 13C NMR (CDCl3/CF3COOD): δ 173.8 (9-
C), 169.8 (4-C), 163.9 (2-C), 140.8, 138.2 (8a-C), 135.9, 135.5,
131.3 (7-C), 130.8, 128.9, 125.8, 125.7 (5-C), 124.5, 124.0 (6-C),
120.3, 117.3 (4a-C), 116.5, 112.8 (8-C), 109.0 (3-C). Anal.
(C22H17N3O3) C, H, N.
General Procedure for the Synthesis of Compounds 14-18.
Quinolinone 3-aminocarboxamides 5-8 or 10 (0.46 mmol) were
mixed with N-(lipoyloxy)succinimide (13; 0.14 g, 0.46 mmol) in
dichloromethane (3 mL), and drops of DMF were added to facilitate
dissolution of the reactants. The mixture was stirred and light-
protected overnight. H2O (10 mL) was added to the mixture and
afterward it was extracted with dichloromethane (3 × 10 mL) and
washed repeatedly with H2O. The organic extracts were combined,
dried (Na2SO4), and concentrated in vacuo to afford the final
compounds, which were triturated with diethylether and filtered
off.
N-(1,2-Dihydro-4-hydroxy-1-methyl-2-oxo-3-quinolinecarbo-
nyl)-N′-(1,2-dithiolane-3-pentanoyl)-ethylenediamine (14). Com-
pound 14 was obtained by reaction of 5 with 13, as a yellowish
solid, after purification with flash column chromatography (CH2-
Cl2/MeOH, 97:3): yield 69%, mp 146-148 °C. 1H NMR
(CDCl3): δ 16.71 (s, 1H, OH), 10.57 (br, 1H, CONH-(CH2)2-),
8.22 (d, 1H, J5,6 ) 8.1 Hz, 5-H), 7.71 (pseudotriplet, 1H, 7-H),
7.39-7.26 (m, 2H, 6-H, 8-H), 6.19 (br, 1H, -(CH2)2-NHCO),
N-(1,2-Dihydro-4-hydroxy-2-oxo-1-phenyl-3-quinolinecarbo-
nyl)-N′-(1,2-dithiolane-3-pentanoyl)-hexamethylenediamine (17).
Compound 17 was obtained by reaction of 8 with 13, as a yellowish
solid, after purification with flash column chromatography (CH2-
Cl2/MeOH, 97:3): yield 72%, mp 110-112 °C. 1H NMR
(CDCl3): δ 17.47 (s, 1H, OH), 10.11 (br, 1H, CONH-(CH2)6-),
8.22 (dd, 1H, J5,6 ) 8.1 Hz, J5,7 ) 1.5 Hz, 5-H), 7.64-7.54 (m,
3H), 7.44 (dtd, 1H, J ) 1.5, 8.4, 7.5 Hz), 7.28-7.24 (m, 3H), 6.62
(d, 1H, J ) 8.4 Hz), 5.63 (br, 1H, -(CH2)6-NHCO), 3.54 (quintet,
1H, J ) 6.6 Hz), 3.39 (q, 2H, J ) 6.9 Hz, CONH-CH2(CH2)4-
CH2-NHCO-), 3.19 (q, 2H, J ) 6.6 Hz, CONH-CH2(CH2)4CH2-
NHCO-), 3.16-3.04 (m, 2H), 2.43 (sextet, 1H, J ) 6.6 Hz), 2.12
(m, 2H, -NHCOCH2CH2CH2CH2-), 1.88 (sextet, 1H, J ) 6.9 Hz),
1.71-1.31 (m, 14H). 13C NMR (CDCl3): δ 173.2 (9-C), 172.9 (4-
C), 171.1, 163.3 (2-C), 141.0 (8a-C), 137.3, 133.4 (7-C), 130.5,
129.3, 129.1, 125.3 (5-C), 122.7 (6-C), 116.1 (8-C), 100.0 (4a-C),
96.7 (3-C), 56.4, 40.2, 39.2, 38.8, 38.4, 36.4, 34.5, 32.5, 29.3, 28.8,
26.3, 25.3. Anal. (C30H37N3O4S2) C, H, N, S.
N-(1,2-Dihydro-4-hydroxy-2-oxo-1-phenyl-3-quinolinecarbo-
nyl)-N′-(1,2-dithiolane-3-pentanoyl)-1,2-phenylenediamine (18).
Compound 18 was obtained by reaction of 10 with 13, as a green
solid, after purification with flash column chromatography (CH2-
Cl2/MeOH, 99:1): yield 68%, mp 196-198 °C. 1H NMR
(CDCl3): δ 16.81 (s, 1H, OH), 11.88 (s, 1H, CONHC6H4-), 8.27
(dd, 1H, J5,6 ) 7.9 Hz, J5,7 ) 1.2 Hz, 5-H), 7.66-7.57 (m, 3H),