Benzoquinoliziniums as Activators of CFTR Channels
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 4 969
9-Ch lor o-6-h ydr oxyben zo[c]qu in olizin iu m ch lor ide (8b,
MP B-08): yellow powder; yield 0.36 g, 72%; 1H NMR (DMSO-
d6) δ 9.8 (d, J ) 8 Hz, 1H, 1-H), 9.0 (s, 1H, 10-H), 8.2-7.6 (m,
6H), 7.4 (bs, 1H, OH); IR (KBr) 3410, 3102, 3056, 2700, 2356
cm-1; FABMS calcd (C+, C13H9NO35Cl) 230.03727, found
230.0371. Anal. (C13H9NOCl2‚0.25H2O) C, H, N.
8-Ch lor o-6-h ydr oxyben zo[c]qu in olizin iu m ch lor ide (8c,
MP B-30): brown powder; yield 0.34 g, 68%; mp 210 °C (dec);
1H NMR (DMSO-d6) δ 9.8 (d, J ) 7 Hz, 1H, 1-H), 8.9 (d, J )
10 Hz, 1H), 8.2-7.9 (m, 6H), 7.4 (bs, 1H, OH); IR (KBr) 3383,
3200, 3090, 2455, 1903 cm-1; FABMS calcd (C+, C13H9NO35Cl)
230.03727, found 230.0371. Anal. (C13H9NOCl2‚0.5H2O) C, H, N.
7-Ch lor o-6-h ydr oxyben zo[c]qu in olizin iu m ch lor ide (8d,
MP B-27): yellow powder; yield 0.22 g, 45%; mp 210 °C (dec);
1H NMR (DMSO-d6) δ 9.8 (d, J ) 7 Hz, 1H, 1-H), 8.9 (m, 1H),
8.2-7.1 (m, 7H); IR (KBr) 3097, 3045, 2396 cm-1; FABMS calcd
(C+, C13H9NO35Cl) 230.03727, found 230.0372. Anal. (C13H9-
NOCl2) C, H, N.
10-F lu or o-6-h yd r oxyb en zo[c]q u in olizin iu m ch lor id e
(8e, MP B-80): yellow powder; yield 0.21 g, 43%; mp 186 °C;
1H NMR (CF3COOD) δ 10.0 (m, 1H, 1-H), 8.6 (m, 1H), 8.4-
7.7 (m, 6H), 7.6 (s, 1H, 5-H); 19F NMR (DMSO-d6) δ -113.4
(ddd, J F/9-H ) 16 Hz, J F/1-H ) 8.1 Hz and J F/8-H ) 4.7 Hz, 1F);
IR (KBr) 3164, 2467, 1885 cm-1; FABMS calcd (C+, C13H9NOF)
214.06682, found 214.0664. Anal. (C13H9NOClF‚H2O) C, H, N.
9-Flu or o-6-h ydr oxyben zo[c]qu in olizin iu m ch lor ide (8f,
MP B-29): beige powder; yield 0.32 g, 65%; 1H NMR (CF3-
COOD) δ 9.4 (d, J ) 7 Hz, 1H, 1-H), 8.9-8.6 (m, 1H), 8.5-8.1
(m, 3H), 8.0-7.6 (m, 3H), 7.5 (s, 1H, 5-H); 19F NMR (DMSO-
d6) δ -103.4 (td, J F/7-H ) J F/8-H ) 7 Hz and J F/10-H ) 11.6 Hz,
1F); IR (KBr) 3263, 3065, 2550, 2000 cm-1; FABMS calcd (C+,
from 2,6-difluorobenzoyle chloride (18 mmol), 0.52 g, 9%; mp
173 °C; 1H NMR (DMSO-d6) δ 9.0 (d, J ) 8 Hz, 1H, 1-H), 8.4-
6.8 (m, 7H), 4.2 (q, J ) 7 Hz, 2H), 1.3 (t, J ) 7 Hz, 3H); 19F
NMR (DMSO-d6) δ -112.3 (dd, J F/8-H ) 12.0 Hz and J F/9-H
)
5.6 Hz, 1F); IR (KBr) 3420, 3160, 3101, 3046, 2984, 1720 cm-1
;
FABMS calcd (C+, C16H13NO3F) 286.08795, found 286.0878.
Anal. (C16H13NO3ClF‚0.5H2O) C, H, N.
10-Ch lor o-6-h yd r oxy-5-p h en ylben zo[c]qu in olizin iu m
ch lor id e (8q, MP B-67): yellow powder; yield 0.05 g, 9%; mp
187 °C (dec); 1H NMR (DMSO-d6) δ 9.5 (d, J ) 7 Hz, 1H, 1-H),
8.8 (d, J ) 6 Hz, 1H), 8.5-7.2 (m, 10H), 4.8 (s, 1H, OH); IR
(KBr) 3445, 3062, 3021 cm-1; FABMS calcd (C+, C19H13NO35Cl)
306.06857, found 306.0685. Anal. (C19H13NOCl2) C, H, N.
10-Ch lor o-6-h yd r oxy-5-m eth ylben zo[c]qu in olizin iu m
ch lor id e (8r , MP B-94): beige powder; yield 0.02 g, 4%; mp
160 °C; 1H NMR (CDCl3) δ 9.8 (d, J ) 7 Hz, 1H, 1-H), 9.4-8.6
(m, 2H), 8.2-7.2 (m, 5H), 2.8 (s, 3H); IR (KBr) 3256, 3142 cm-1
;
FABMS calcd (C+, C14H11NO35Cl) 244.05292, found 244.0525.
Anal. (C14H11NOCl2‚2H2O) C, H, N.
10-Ch lor o-6-h yd r oxy-5-p r op ylb en zo[c]q u in olizin iu m
ch lor id e (8s, MP B-96): cream powder; yield 0.11 g, 23%; mp
187 °C (dec); 1H NMR (DMSO-d6) δ 9.4 (d, J ) 7 Hz, 1H, 1-H),
8.5 (d, J ) 7 Hz, 1H), 8.2-7.2 (m, 6H), 3.0 (t, J ) 6 Hz, 2H),
1.8-1.2 (m, 2H), 1.0 (t, J ) 6 Hz, 3H); IR (KBr) 2963, 2915,
2870, 2464 cm-1; FABMS calcd (C+, C16H15NO35Cl) 272.08422,
found 272.0839. Anal. (C16H15NOCl2) C, H, N.
5-Bu t yl-10-ch lor o-6-h yd r oxyb e n zo[c]q u in olizin iu m
ch lor id e (8t, MP B-91): cream powder; yield 0.3 g, 60%; mp
186 °C (dec); 1H NMR (DMSO-d6) δ 9.3 (d, J ) 7 Hz, 1H, 1-H),
8.5 (d, J ) 7 Hz, 1H), 8.1-6.9 (m, 6H), 2.9 (t, J ) 4 Hz, 2H),
1.5-1.3 (m, 4H), 0.9 (t, J ) 5 Hz, 3H); IR (KBr) 2951, 2923,
2895, 2863, 2450 cm-1; MS (ESI) 286 (M+ - HCl); FABMS
calcd (C+, C17H17NO35Cl) 286.09987, found 286.0999. Anal.
(C17H17NOCl2) C, H, N.
C
13H9NOF) 214.06682, found 214.0666. Anal. (C13H9NOClF‚
0.5H2O) C, H, N.
8-Flu or o-6-h ydr oxyben zo[c]qu in olizin iu m ch lor ide (8g,
MP B-79): yellow powder; yield 0.30 g, 60%; mp 250 °C; 1H
NMR (DMSO-d6) δ 10.0 (d, J ) 7 Hz, 1H, 1-H), 9.4-9.0 (m,
1H), 8.4-8.2 (d, 2H), 8.0 (s, 1H), 7.9-7.6 (m, 3H), 7.2 (bs, OH
5-Bu tyl-7-ch lor o-6-h ydr oxyben zo[c]qu in olizin iu m ch lo-
r id e (8u , MP B-104): yellow powder; yield 0.3 g, 60%; mp 190
1
°C; H NMR (DMSO-d6) δ 9.4 (d, J ) 7 Hz, 1H, 1-H), 8.7 (m,
+ H2O); 19F NMR (DMSO-d6) δ -109.9 (td, J F/7-H ) J F/9-H
)
1H), 8.0-7.7 (m, 5H), 7.4-7.1 (m, 1H), 2.9 (t, J ) 5 Hz, 2H),
1.7-1.3 (m, 4H), 1.0 (t, J ) 5 Hz, 3H); IR (KBr) 3100, 3060,
2951, 2925, 2868, 2853 cm-1; FABMS calcd (C+, C17H17NO35Cl)
286.09987, found 286.0999. Anal. (C17H17NOCl2‚0.2H2O) C, H,
N.
8.2 Hz and J F/10-H ) 4.2 Hz, 1F); IR (KBr) 3274, 3102, 3062,
2362 cm-1; FABMS calcd (C+, C13H9NOF) 214.06682, found
214.0671. Anal. (C13H9NOClF) C, H, N.
7-Flu or o-6-h ydr oxyben zo[c]qu in olizin iu m ch lor ide (8h ,
MP B-78): beige powder; yield 0.22 g, 45%; 1H NMR (DMSO-
d6) δ 9.9 (d, J ) 9 Hz, 1H, 1-H), 8.9 (d, J ) 9 Hz, 1H), 8.3-8.1
(m, 2H), 8.0-7.6 (m, 5H); 19F NMR (DMSO-d6) δ -107.9
(dd, J F/8-H ) 11.3 Hz and J F/9-H ) 5.6 Hz, 1F); IR (KBr) 3247,
3107, 3056, 2679, 2401 cm-1; FABMS calcd (C+, C13H9NOF)
214.06682, found 214.0669. Anal. (C13H9NOClF) C, H, N.
5-Ca r beth oxy-10-flu or o-6-h yd r oxyben zo[c]qu in olizin -
iu m ch lor id e (8j, MP B-77): beige powder; yield reported from
2,6-difluorobenzoyl chloride (18 mmol), 0.43 g, 7%; mp 134 °C;
1H NMR (DMSO-d6) δ 8.9 (bd, 1H, 1-H), 8.2-6.9 (m, 6H), 6.3
(s, 1H, OH), 4.3 (q, J ) 7 Hz, 2H), 1.3 (t, J ) 7 Hz, 3H); 19F
NMR (DMSO-d6) δ -116.7 (td, J F/8-H ) J F/1-H ) 5.0 Hz and
J F/9-H ) 15 Hz, 1F); IR (KBr) 3420, 3171, 3080, 2973, 1718
cm-1; FABMS calcd (C+, C16H13NO3F) 286.08795, found
286.0878. Anal. (C16H13NO3ClF‚H2O) C, H, N.
10-Ch lor o-6-h yd r oxy-5-p en t ylb en zo[c]q u in olizin iu m
ch lor id e (8v, MP B-97): cream powder; yield 0.04 g, 8%; mp
177 °C (dec); 1H NMR (DMSO-d6) δ 9.6 (d, J ) 7 Hz, 1H, 1-H),
8.6 (d, J ) 7 Hz, 1H), 8.3-7.1 (m, 6H), 3.3 (t, J ) 4 Hz, 2H),
1.6-1.2 (m, 6H), 1.0 (t, J ) 5 Hz, 3H); IR (KBr) 2958, 2925,
2850 cm-1; FABMS calcd (C+, C18H19NO35Cl) 300.11552, found
300.1155. Anal. (C18H19NOCl2) C, H, N.
10-Ch lor o-6-h yd r oxy-5-isobu tylben zo[c]qu in olizin iu m
ch lor id e (8w , MP B-95): cream powder; yield 0.28 g, 55%; mp
185 °C (dec); 1H NMR (DMSO-d6) δ 9.3 (d, J ) 7 Hz, 1H, 1-H),
8.6 (d, J ) 7 Hz, 1H), 8.2-7.2 (m, 6H), 3.0 (d, J ) 6 Hz, 2H),
2.2-1.3 (m, 1H), 1.0 (d, J ) 6 Hz, 6H); IR (KBr) 3083, 3042,
2958, 2863, 2550 cm-1; FABMS calcd (C+, C17H17NO35Cl)
286.09987, found 286.0997. Anal. (C17H17NOCl2) C, H, N.
7-F lu or o-6-h yd oxyb e n zo[c]cyclop e n t a n o[i,j]q u in o-
lizin iu m ch lor id e (8x, MP B-92): beige powder; yield re-
ported from methyl 2,6-difluorobenzoate (10 mmol), 0.05 g, 2%;
5-Ca r b et h oxy-9-flu or o-6-h yd r oxyb en zo[c]q u in olizin -
iu m ch lor id e (8k , MP B-86): yellow powder; yield reported
from 2,5-difluorobenzoyle chloride (18 mmol), 2.02 g, 35%; mp
154 °C; 1H NMR (DMSO-d6) δ 9.2 (d, J ) 8 Hz, 1H, 1-H), 8.7-
7.1 (m, 6H), 5.7 (s, 1H, OH), 4.3 (q, J ) 7 Hz, 2H), 1.3 (t, J )
7 Hz, 3H); 19F NMR (DMSO-d6) δ -105.7, (td, J F/7-H ) J F/8-H
) 8 Hz and J F/10-H ) 12 Hz, 1F); IR (KBr) 3454, 3104, 3047,
3016, 2960, 1727 cm-1; FABMS calcd (C+, C16H13NO3F)
286.08795, found 286.0877. Anal. (C16H13NO3ClF) C, H, N.
5-Ca r b et h oxy-8-flu or o-6-h yd r oxyb en zo[c]q u in olizin -
iu m ch lor id e (8l, MP B-75): yellow powder; yield 0.09 g, 18%;
1
mp 245 °C; H NMR (CF3COOD) δ 11.3 (bs, 1H, OH), 9.3 (d,
J ) 6 Hz, 1H, 1-H), 8.6 (d, J ) 8 Hz, 1H), 8.2-7.4 (m, 4H), 3.6
(s, 4H); IR (KBr) 3418, 3100, 3055, 2927, 2367 cm-1; FABMS
calcd (C+, C15H11NOF) 240.08247, found 240.0824. Anal.
(C15H11NOClF‚0.25H2O) C, H, N.
Syn th esis of Com p ou n d s 9. Heating compounds 6j-m ,
6q-r , and 6x led to compounds 9. When chromatographed on
an Alumine or Florisil column, compounds 8a and 8s-w were
converted into 9. All products 9 could also be purified by
column chromatography on silica gel (elution with CH2Cl2).
10-Ch lor oben zo[c]qu in olizin -6-on e (9a , MP B-70): yel-
low powder; yield 80%; mp 144 °C; 1H NMR (CDCl3) δ 8.9 and
8.5 (2d, J ) 7 Hz, 1H each), 7.8-7.4 (m, 2H), 7.2-7.0 (m, 2H,),
6.6-6.3 (m, 2H); IR (KBr) 3126, 3046, 1680 cm-1. Anal. (C13H8-
NOCl) C, H, N.
1
mp 168 °C; H NMR (DMSO-d6) δ 9.4 (d, J ) 9 Hz, 1H, 1-H),
8.9-8.7 (m, 1H), 8.2-7.0 (m, 5H), 6.0 (s, 1H, OH), 4.3 (q, J )
8 Hz, 2H), 1.3 (t, J ) 8 Hz, 3H); IR (KBr) 3500, 3157, 3049,
2960, 1670 cm-1. Anal. (C16H13NO3ClF) C, H, N.
5-Ca r b et h oxy-7-flu or o-6-h yd r oxyb en zo[c]q u in olizin -
iu m ch lor id e (8m , MP B-73): beige powder; yield reported