Water Soluble Fluoroquinolones
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 19 4707
3.16 (4H, m), 3.23 (3H, s), 3.43 (4H, m), 6.88 (2H, d, J ) 9.0
Hz), 7.41 (2H, d, J ) 9.0 Hz), 7.90 (1H, d, J ) 12.0 Hz), 8.37
(1H, s), 9.30 (1H, br s), 9.60 (1H, br s), 9.98 (1H, s), 14.80 (1H,
br s); 13C NMR (125 MHz, DMSO-d6) δ 43.2, 46.9, 55.9, 61.9,
106.5, 106.6, 115.3, 121.7, 121.8, 126.3, 133.3, 136.2, 138.0,
138.1, 145.6, 151.4, 154.7, 157.1, 157.6, 165.4, 176.5; MS (ESI+)
413.6 (M + 1). Anal. Calcd for C21H20FN3O5‚1.7H2O‚1.2HCl:
C, 51.71; H, 5.08; N, 8.61; Cl, 8.72. Found: C, 51.82; H, 5.01;
N, 8.59; Cl, 8.78.
J ) 7.5 Hz), 7.51 (1H, d), 7.79 (1H, d, J ) 14.0 Hz), 8.32 (1H,
s), 8.37 (3H, s), 9.98 (1H, s), 15.08 (1H, s); 13C NMR (125 MHz,
DMSO-d6) δ 5.1, 13.5, 24.1, 25.4, 55.0, 55.3, 55.3, 55.9, 61.1,
64.8, 106.4, 106.6, 115.2, 117.8, 117.8, 125.4, 126.3, 133.8,
136.1, 136.3, 136.4, 140.5, 140.5, 151.0, 151.9, 154.4, 157.4,
165.7, 176.2; MS (APCI+) 440.0 (100%). Anal. Calcd for
C
23H22FN3O5‚1.3H2O‚1.5HCl: C, 53.38; H, 5.08; N, 8.12; Cl,
10.28. Found: C, 53.09; H, 4.96; N, 7.79; Cl, 10.07.
7-(3-Am in om eth yl-pyr r olidin -1-yl)-6-fluor o-1-(4-h ydr oxy-
p h en yl)-8-m eth oxy-4-oxo-1,4-d ih yd r oqu in olin e-3-ca r box-
6-F lu or o-1-(4-h yd r oxyp h en yl)-8-m et h oxy-7-(4-m et h -
ylp ip er a zin -1-yl)-4-oxo-1,4-d ih yd r oqu in olin e-3-ca r boxy-
1
ylic a cid HCl sa lt, 55: mp 215 °C (dec); H NMR (500 MHz,
1
lic a cid HCl sa lt, 49: mp 268 °C (dec); H NMR (500 MHz,
DMSO-d6) δ 1.68 (1H, m), 2.07 (1H, m), 2.48 (1H, m), 2.88 (2H,
m), 3.05 (3H, s), 3.32 (1H, m), 3.50-3.60 (3H, m), 6.88 (2H,
m), 7.40 (2H, m), 7.76 (1H, d, J ) 14.0 Hz), 8.11 (3H, br s),
8.30 (1H, s), 9.97 (1H, s), 15.14 (1H, br s); 13C NMR (125 MHz,
DMSO-d6) δ 28.9, 36.7, 40.6, 50.1, 54.2, 60.6, 106.2, 106.4,
115.3, 117.3, 117.4, 125.7, 126.1, 133.8, 136.5, 136.7, 140.5,
150.9, 152.2, 154.7, 157.4, 165.7, 176.1; MS (ESI+) 428.14 (M
+ 1). Anal. Calcd for C22H22FN3O5‚1.5H2O‚1.3HCl: C, 52.65;
H, 5.28; N, 8.37; Cl, 9.18. Found: C, 52.75; H, 5.02; N, 8.09;
Cl, 9.00.
DMSO-d6) δ 2.80 (3H, s), 3.23 (3H, s), 3.05-3.60 (8H, m), 6.88
(2H, m), 7.42 (2H, m), 7.90 (1H, d, J ) 12.0 Hz), 8.37 (1H, s),
9.97 (1H, s), 10.85 (1H, br s), 14.8 (1H, br s); 13C NMR (125
MHz, DMSO-d6) δ 42.2, 46.9, 46.9, 48.5, 52.8, 61.9, 106.5,
106.6, 115.2, 121.8, 121.9, 126.3, 133.3, 136.2, 137.6, 137.7,
145.6, 151.4, 154.8, 156.8, 157.5, 165.4, 176.5; MS (ESI+)
428.16 (M + 1). Anal. Calcd for C22H22FN3O5‚0.6H2O‚HCl: C,
55.66; H, 5.14; N, 8.85; Cl, 7.47. Found: C, 55.77; H, 5.21; N,
8.42; Cl, 7.62.
7-(3,5-Dim eth ylp ip er a zin -1-yl)-6-flu or o-1-(4-h yd r oxy-
p h en yl)-8-m eth oxy-4-oxo-1,4-d ih yd r oqu in olin e-3-ca r box-
ylic a cid , 50: mp 265 °C (dec); 1H NMR (500 MHz, DMSO-d6)
δ 0.93 (6H, d, J ) 6.5 Hz), 2.60 (2H, m), 2.85 (2H, m), 3.12
(2H, m), 3.16 (3H, s), 3.29 (1H, m), 6.87 (2H, m), 7.40 (2H, m),
7.82 (1H, d, J ) 12.0 Hz), 8.32 (1H, s), 9.85 (1H, br s); 13C
NMR (125 MHz, DMSO-d6) δ 19.0, 50.6, 50.9, 56.7, 61.6, 106.2,
106.5, 115.2, 120.5, 126.3, 133.5, 136.5, 139.1, 144.9, 151.0,
154.7, 157.2, 157.3, 165.6, 176.4; MS (ESI+) 442.2 (M + 1).
Anal. Calcd for C23H24FN3O5‚0.7H2O: C, 60.84; H, 5.64; N,
9.25. Found: C, 60.96; H, 5.57; N, 9.00.
7-(3-Am in op yr r olid in -1-yl)-6-flu or o-1-(4-h yd r oxyp h en -
yl)-8-m et h oxy-4-oxo-1,4-d ih yd r oq u in olin e-3-ca r b oxylic
a cid HCl sa lt, 51: mp 213 °C (dec); 1H NMR (500 MHz,
DMSO-d6) δ 2.00 (1H, m), 2.25 (1H, m), 3.06 (3H, s), 3.40-
3.90 (4H, m), 4.35 (1H, m), 6.87 (2H, d, J ) 9.0 Hz), 7.42 (2H,
m), 7.80 (1H, d, J ) 14.0 Hz), 8.17 (3H, br s), 8.33 (1H, s),
9.91 (1H, s), 15.05 (1H, br s); 13C NMR (125 MHz, DMSO-d6)
δ 18.5, 29.3, 48.9, 54.0, 55.9, 61.0, 106.3, 106.5, 115.3, 117.8,
117.8, 125.8, 126.0, 133.8, 136.1, 136.2, 136.5, 140.7, 150.9,
152.0, 154.5, 157.4, 165.7, 176.2; MS (ESI+) 414.1 (M + 1).
Anal. Calcd for C21H20FN3O5‚H2O‚HCl: C, 53.91; H, 4.95; N,
8.98; Cl, 7.58. Found: C, 54.17; H, 4.71; N, 8.76; Cl, 7.37.
7-[(3S*,4S*)-3-Am in o-4-m eth yl-pyr r olidin -1-yl]-6-flu or o-
1-(4-h yd r oxyp h en yl)-8-m eth oxy-4-oxo-1,4-d ih yd r oqu in o-
lin e-3-ca r boxylic a cid HCl sa lt , 56: mp 226 °C (dec); 1H
NMR (500 MHz, DMSO-d6) δ 1.07 (5H, m), 3.42 (7H, m, J )
7.0 Hz), 3.71 (2H, m), 6.89 (2H, m), 7.32 (1H, m), 7.45 (1H,
m), 7.78 (1H, d, J ) 14.0 Hz), 8.27 (2H, br s), 9.94 (1H, s),
15.10 (1H, s); 13C NMR (125 MHz, DMSO-d6) δ 11.6, 25.4, 34.3,
51.9, 54.2, 55.3, 55.4, 55.9, 61.1, 61.9, 106.3, 106.6, 115.3, 117.5,
117.5, 125.7, 126.1, 126.9, 133.8, 136.3, 136.4, 136.4, 140.1,
140.2, 150.9, 151.7, 154.2, 157.4, 165.7, 176.2, 176.2; MS
(APCI+) 428.1. Anal. Calcd for C22H22FN3O5‚1.4H2O‚HCl: C,
54.02; H, 5.32; N, 8.59; Cl, 7.25. Found: C, 54.09; H, 5.16; N,
7.60; Cl, 7.27.
7-(3-Am in o-4-m et h ylp yr r olid in -1-yl)-6-flu or o-1-(4-h y-
d r oxyp h en yl)-8-m eth oxy-4-oxo-1,4-d ih yd r oqu in olin e-3-
ca r boxylic a cid HCl sa lt, 57: mp 208 °C (dec); 1H NMR (500
MHz, DMSO-d6) δ 1.12 (3H, d, J ) 7.0 Hz), 2.38 (1H, m), 3.06
(3H, s), 3.43 (3H, m), 3.61 (1H, m), 3.68 (1H, m), 3.74 (2H, m),
6.89 (2H, t, J ) 9.5 Hz), 7.31 (1H, d, J ) 8.0 Hz), 7.48 (1H, d,
J ) 8.0 Hz), 7.78 (1H, d, J ) 14.0 Hz), 8.32 (1H, s), 8.56 (3H,
s), 10.02 (1H, s), 15.07 (1H, s); 13C NMR (125 MHz, DMSO-d6)
δ 15.1, 25.4, 36.5, 53.8, 54.3, 56.3, 56.4, 61.0, 61.9, 106.3, 106.6,
115.2, 115.4, 117.7, 117.8, 125.5, 126.3, 133.8, 136.0, 136.1,
136.4, 140.6, 140.7, 151.0, 152.0, 154.5, 157.5, 165.7, 176.2,
176.2; MS (ESI+) 428.1 (100%) Anal. Calcd for C22H22FN3O5‚
3.3H2O‚2.1HCl: C, 46.90; H, 5.49; N, 7.46; Cl, 13.21. Found:
C, 46.78; H, 4.81; N, 6.61; Cl, 13.22.
7-(2,5-Dia za b icyclo[2.2.1]h ep t -2-yl)-6-flu or o-1-(4-h y-
d r oxyp h en yl)-8-m eth oxy-4-oxo-1,4-d ih yd r oqu in olin e-3-
ca r boxylic a cid HCl sa lt, 52: mp 223 °C (dec); 1H NMR (500
MHz, DMSO-d6) δ 1.95 (1H, m), 2.06 (1H, m), 3.03 (3H, s),
3.30-3.40 (3H, m), 3.67 (1H, m), 4.35 (1H, m), 4.74 (1H, m),
6.85 (1H, m), 6.91 (1H, m), 7.22 (1H, m), 7.54 (1H, m), 7.85
(1H, d, J ) 14.0 Hz), 8.32 (1H, s), 9.97 (1H, s), 9.00-9.80 (1H,
br s); 13C NMR (125 MHz, DMSO-d6) δ 35.6, 51.3, 55.3, 56.8,
59.4, 60.0, 106.4, 106.8, 107.0 115.2, 115.3, 117.5, 117.6, 125.4,
126.5, 133.6, 135.5, 135.6, 136.3, 139.6, 150.1, 151.1, 152.5,
157.4, 165.6, 176.2; MS (ESI+) 426.16 (M + 1). Anal. Calcd for
6-F lu or o-1-(4-h yd r oxyp h en yl)-8-m et h oxy-7-(oct a h y-
dr opyr r olo[3,4-b]pyr idin -6-yl)-4-oxo-1,4-dih ydr oqu in olin e-
1
3-ca r boxylic a cid HCl sa lt, 58: mp 220 °C (dec); H NMR
(500 MHz, DMSO-d6) δ 1.60-1.80 (4H, m), 2.54 (1H, m), 2.92
(1H, m), 3.07 (3H, s), 3.14 (1H, m), 3.50 (1H, m), 3.65 (1H, m),
3.75 (2H, m), 3.85 (1H, m), 6.80 (2H, m), 7.27 (1H, m), 7.52
(1H, m), 7.79 (1H, d, J ) 14.0 Hz), 8.32 (1H, s), 8.65 (1H, br
s), 9.67 (1H, br s), 9.94 (1H, s), 15.13 (1H, s); 13C NMR (125
MHz, DMSO-d6) δ 17.5, 20.4, 33.9, 41.3, 51.7, 51.8, 53.8, 54.0,
61.1, 106.3, 106.6, 115.3, 117.2, 117.2, 125.4, 126.3, 133.8,
136.5, 136.6, 139.5, 139.6, 150.9, 151.4, 153.9, 157.4, 165.7,
176.1; MS (ESI+) 454.1 (M + 1). Anal. Calcd for C24H24FN3O5‚
1.6H2O‚1.07HCl: C, 55.30; H, 5.47; N, 8.06; Cl, 7.28. Found:
C, 55.29; H, 5.19; N, 7.89; Cl, 7.15.
6-F lu or o-1-(4-h yd r oxyp h en yl)-8-m eth oxy-7-(1-m eth yl-
h exa h yd r o-p yr r olo[3,4-b]p yr r ol-5-yl)-4-oxo-1,4-d ih yd r o-
qu in olin e-3-ca r boxylic a cid HCl sa lt, 59: mp 230 °C (dec);
1H NMR (500 MHz, DMSO-d6) δ 1.78 (1H, m), 2.34 (1H, m),
2.80 (3H, d, J ) 4.5 Hz), 3.05-3.15 (2H, m), 3.16 (3H, s), 3.30
(1H, m), 3.48 (1H, m), 3.60-3.75 (2H, m), 3.85 (1H, m), 4.03
(1H, m), 6.91 (2H, m), 7.23 (1H, m), 7.55 (1H, m), 7.83 (1H, d,
J ) 13.0 Hz), 8.34 (1H, s), 10.12 (1H, s), 11.08 (1H, br s), 14.99
(1H, br s); 13C NMR (125 MHz, DMSO-d6) δ 28.9, 41.0, 51.9,
55.3, 55.8, 62.0, 70.9, 106.4, 106.5, 106.6, 115.2, 115.4, 119.6,
125.3, 126.5, 133.5, 135.9, 136.0, 136.2, 142.9, 151.2, 153.1,
155.5, 157.5, 165.6, 176.3; MS (ESI+) 454.25 (M + 1).
C
22H20FN3O5‚1.5H2O‚1.2HCl: C, 53.25; H, 4.92; N, 8.47; Cl,
8.57. Found: C, 53.12; H, 4.54; N, 8.21; Cl, 8.45.
7-(6-Am in o-3-a za b icyclo[3.1.0]h ex-3-yl)-6-flu or o-1-(4-
h yd r oxyp h en yl)-8-m eth oxy-4-oxo-1,4-d ih yd r oqu in olin e-
1
3-ca r boxylic a cid HCl sa lt, 53: mp 206 °C (dec); H NMR
(500 MHz, DMSO-d6) δ 1.98 (2H, m), 2.40 (1H, m), 3.03
(3H, s), 3.48 (2H, m), 3.58 (2H, m), 6.87 (2H, d, J ) 8.5 Hz),
7.40 (2H, d, J ) 8.5 Hz), 7.81 (1H, d, J ) 13.0 Hz), 8.25 (3H,
br s), 8.34 (1H, s), 9.91 (1H, s), 15 (1H, br s); 13C NMR (125
MHz, DMSO-d6) δ 20.5, 29.4, 50.8, 61.4, 106.2, 106.5, 106.5,
115.3, 119.7, 119.7, 126.1, 133.6, 135.7, 135.8, 136.4, 143.8,
151.1, 153.6, 156.1, 157.4, 165.6, 176.4; MS (ESI+) 426.13
(M + 1).
7-[(7R*)-7-Am in o-5-a za -sp ir o[2.4]h ep t-5-yl]-6-flu or o-1-
(4-h ydr oxyph en yl)-8-m eth oxy-4-oxo-1,4-dih ydr oqu in olin e-
1
3-ca r boxylic a cid HCl sa lt, 54: mp 242 °C (dec); H NMR
(500 MHz, DMSO-d6) δ 0.70 (1H, m), 0.76 (2H, m), 1.11 (2H,
m), 3.09 (3H, s), 3.18 (1H, d, J ) 10.0 Hz), 3.59 (1H, d, J )
11.5 Hz), 4.05 (2H, m), 6.88 (2H, d, J ) 16.0 Hz), 7.27 (1H, d,