Phenylimidazo[1,2-a]pyridines as Ligands for PBR
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 19 3939
N,N-Di-n -pr opyl-[2-(4-ch lor oph en yl)-8-m eth oxyim idazo-
[1,2-a ]p yr id in -3-yl]a ceta m id e (24): IR (KBr) 1630 cm-1; 1H
NMR (CDCl3) δ 0.66 (t, J ) 2.5 Hz, 3H, CH3), 0.80 (t, J ) 2.5
Hz, 3H, CH3), 1.3-1.6 (m, 4H, CH2), 3.03 (t, J ) 2.5 Hz, 2H,
CH2-N), 3.24(t, J ) 0.5 Hz, 2H, CH2-N), 4.00 (s, 3H, OCH3),
4.10 (s, 2H, CH2CO), 6.4-6.5 (m, 1H, Ar), 6.7-6.8 (m, 1H, Ar),
7.3-7.4 (m, 2H, Ar), 7.6-7.7 (m, 2H, Ar), 7.85 (dd, J ) 2 and
1H, NH), 6.8-7.7 (m, 7H, Ar), 8.05 (d, J ) 2.3 Hz, 1H, Ar);
MS m/z 327 (M+, 24), 241 (base). Anal. (C18H18ClN3O) C, H,
N.
N-n -Bu tyl-(2-ph en yl-6,8-dich lor oim idazo[1,2-a ]pyr idin -
3-yl)a ceta m id e (40): IR (KBr) 3270, 1640 cm-1 1H NMR
;
(CDCl3) δ 0.84 (t, J ) 2.5 Hz, 3H, CH3), 1.1-1.3 (m, 2H, CH2),
1.3-1.4 (m, 2H, CH2), 3.21 (q, J ) 4.5 Hz, 2H, CH2-NH), 3.87
(s, 2H, CH2CO), 5.93 (br s, 1H, NH), 7.3-7.7 (m, 6H, Ar), 8.08
(d, J ) 0.5 Hz, 1H, Ar); MS m/z 375 (M+, 11), 275 (base). Anal.
(C19H19Cl2N3O) C, H, N.
Gen er a l P r oced u r e for P r ep a r a tion of (8-Am in oim i-
d a zo[1,2-a ]p yr id in -3-yl)a ceta m id es 27 a n d 28. A mixture
of (8-nitroimidazo[1,2-a]pyridin-3-yl)acetamide 21 or 22 (7.9
mmol) and 10% palladium on carbon in ethanol (30 mL) was
shaken on a hydrogenation apparatus at 24 atm of hydrogen.
The progress of reaction was monitored by TLC. Then the
catalyst was filtered, and the filtrate was concentrated in
vacuo. The residue was purified by silica gel column chroma-
tography [light petroleum ether/ethyl acetate 8/2 (v/v) as
eluent] to give the amide 27 or 28, respectively.
5 Hz, 1H, Ar); MS m/z 399 (M+, 13), 271 (base). Anal. (C22H26
-
ClN3O2) C, H, N.
N,N-Di-n -p r op yl-(2-p h en yl-8-ch lor oim id a zo[1,2-a ]p y-
r id in -3-yl)a ceta m id e (25): IR (KBr) 1620 cm-1 1H NMR
;
(CDCl3) δ 0.53 (t, J ) 9 Hz, 3H, CH3), 0.73 (t, J ) 9 Hz, 3H,
CH3), 1.1-1.6 (m, 4H, CH2), 2.93 (t, J ) 9 Hz, 2H, CH2-N),
3.23 (t, J ) 9 Hz, 2H, CH2-N), 4.07 (s, 2H, CH2CO), 6.5-7.8
(m, 7H, Ar), 8.27 (d, J ) 8 Hz, 1H, Ar); MS m/z 369 (M+, 23),
241 (base). Anal. (C21H24ClN3O) C, H, N.
N,N-Di-n -p r op yl-[2-(4-ch lor op h en yl)-8-ch lor oim id a zo-
[1,2-a ]p yr id in -3-yl]a ceta m id e (26): IR (KBr) 1630 cm-1; 1H
NMR (CDCl3) δ 0.73 (t, J ) 9 Hz, 3H, CH3), 0.86 (t, J ) 9 Hz,
3H, CH3), 1.3-1.6 (m, 4H, CH2), 3.10 (t, J ) 9 Hz, 2H, CH2-
N), 3.30 (t, J ) 9 Hz, 2H, CH2-N), 4.10 (s, 2H, CH2CO), 6.8-
7.7 (m, 6H, Ar), 8.20 (d, J ) 9 Hz, 1H, Ar); MS m/z 403 (M+,
22), 275 (base). Anal. (C21H23Cl2N3O) C, H, N.
Alternatively, the title compounds were prepared according
to the following procedure. A mixture of (8-nitroimidazo[1,2-
a]pyridin-3-yl)acetamide 21 or 22 (4.8 mmol) in concentrated
HCl (10 mL) and granular tin (0.40 g, 3.37 mmol) was heated
at 100 °C for 2 h. After cooling at room temperature, the
mixture was made alkaline with NaOH and the organic phase
extracted with CHCl3 (3 × 20 mL), washed, and dried (Na2-
SO4). Evaporation of the solvent gave a residue which was
purified by silica gel column chromatography [light petroleum
ether/ethyl acetate 8/2 (v/v) as eluent] to give the amide 27 or
28, respectively. Physical data are summarized in Table 1.
N,N-Di-n -p r op yl-(2-p h en yl-8-a m in oim id a zo[1,2-a ]p yr i-
N,N-Dieth yl-(2-p h en ylim id a zo[1,2-a ]p yr id in -3-yl)a ce-
1
ta m id e (32): IR (Nujol) 1650 cm-1; H NMR (CDCl3) δ 0.90
(t, J ) 6 Hz, 3H, CH3), 1.10 (t, J ) 6 Hz, 3H, CH3), 3.13 (q, J
) 9 Hz, 2H, CH2), 3.33 (q, J ) 9 Hz, 2H, CH2), 4.13 (s, 2H,
CH2CO), 6.7-7.7 (m, 8H, Ar), 8.30 (d, J ) 9 Hz, 1H, Ar); MS
m/z 307 (M+, 22), 207 (base). Anal. (C19H21N3O) C, H, N.
N,N-Di-n -p r op yl-[2-(4-ch lor op h en yl)im id a zo[1,2-a ]p y-
r id in -3-yl]a ceta m id e (33): IR (KBr) 1620 cm-1 1H NMR
;
(CDCl3) δ 0.68 (t, J ) 2.5 Hz, 3H, CH3), 0.81 (t, J ) 2.5 Hz,
3H, CH3), 1.4-1.5 (m, 4H, CH2), 3.06 (t, J ) 0.5 Hz, 2H, CH2-
N), 3.25 (t, J ) 0.5 Hz, 2H, CH2-N), 4.08 (s, 2H, CH2CO), 6.8-
7.6 (m, 7H, Ar), 8.23 (dd, J ) 2 and 3 Hz, 1H, Ar); MS m/z 369
(M+, 26), 241 (base). Anal. (C21H24ClN3O) C, H, N.
N,N-Di-n -b u t yl-(2-p h en ylim id a zo[1,2-a ]p yr id in -3-yl)-
a ceta m id e (34): IR (KBr) 1620 cm-1; 1H NMR (CDCl3) δ 0.83
(t, J ) 4.5 Hz, 3H, CH3), 0.90 (t, J ) 4.5 Hz, 3H, CH3), 1.1-
1.6 (m, 8H, CH2), 3.10 (t, J ) 6 Hz, 2H, CH2-N), 3.33 (t, J )
6 Hz, 2H, CH2-N), 4.16 (s, 2H, CH2CO), 6.8-7.8 (m, 8H, Ar),
8.40 (d, J ) 9 Hz, 1H, Ar); MS m/z 363 (M+, 22), 207 (base).
Anal. (C23H29N3O) C, H, N.
d in -3-yl)a ceta m id e (27): IR (KBr) 1620 cm-1 1H NMR
;
(CDCl3) δ 0.59 (t, J ) 2.5 Hz, 3H, CH3), 0.79 (t, J ) 2.5 Hz,
3H, CH3), 1.4-1.5 (m, 4H, CH2), 3.00 (t, J ) 2.5 Hz, 2H, CH2-
N), 3.23 (t, J ) 2.5 Hz, 2H, CH2-N), 4.05 (s, 2H, CH2CO), 4.59
(s, 2H, NH2), 6.3-7.8 (m, 8H, Ar); MS m/z 350 (M+, 25), 222
(base). Anal. (C21H26N4O) C, H, N.
N,N-Di-n -p r op yl-[2-(4-ch lor op h en yl)-8-a m in oim id a zo-
[1,2-a ]p yr id in -3-yl]a ceta m id e (28): IR (KBr) 1630 cm-1; 1H
NMR (CDCl3) δ 0.69 (t, J ) 2.5 Hz, 3H, CH3), 0.81 (t, J ) 2.5
Hz, 3H, CH3), 1.3-1.6 (m, 4H, CH2), 3.06 (t, J ) 2.5 Hz, 2H,
CH2-N), 3.25 (t, J ) 0.5 Hz, 2H, CH2-N), 4.02 (s, 2H, CH2-
CO), 4.50 (s, 2H, NH2), 6.3-7.9 (m, 7H, Ar); MS m/z 384 (M+,
23), 256 (base). Anal. (C21H25ClN4O) C, H, N.
N,N-Di-n -bu tyl-[2-(4-ch lor op h en yl)im id a zo[1,2-a ]p yr i-
d in -3-yl]a ceta m id e (35): IR (KBr) 1620 cm-1 1H NMR
;
P r ep a r a tion of N,N-Di-n -p r op yl-[2-(4-ch lor op h en yl)-
8-m eth ylam in oim idazo[1,2-a ]pyr idin -3-yl]acetam ide (29).
To a mixture of (8-aminoimidazo[1,2-a]pyridin-3-yl)acetamide
28 (0.30 g, 0.78 mmol) and NaHCO3 (0.24 g, 2.90 mmol) in
water/methanol (8/2, 50 mL) was dropwise added dimethyl
sulfate (0.33 g, 2.6 mmol) maintaining the reaction tempera-
ture at 18-20 °C with a water bath. The reaction mixture was
stirred at room temperature for 1 h, heated at 60 °C for 15
min, and then diluted with water. To the stirred and ice-cooled
mixture was added ethanolamine (2 mL); the stirring was
prolonged overnight, and then the mixture was extracted with
CHCl3 (3 × 50 mL) to give an oil which solidified on standing
(CDCl3) δ 0.70 (t, J ) 3 Hz, 6H, CH3), 0.9-1.4 (m, 8H, CH2),
3.10 (t, J ) 9 Hz, 2H, CH2-N), 3.30 (t, J ) 9 Hz, 2H, CH2-
N), 4.10 (s, 2H, CH2CO), 6.7-7.8 (m, 7H, Ar), 8.20 (d, J ) 6
Hz, 1H, Ar); MS m/z 397 (M+, 24), 241 (base). Anal. (C23H28
-
ClN3O) C, H, N.
N,N-Di-n -h exyl-(2-p h en ylim id a zo[1,2-a ]p yr id in -3-yl)-
a ceta m id e (36): IR (neat) 1630 cm-1; 1H NMR (CDCl3) δ 0.86
(t, J ) 6 Hz, 6H, CH3), 1.0-1.5 (m, 16H, CH2), 3.03 (t, J ) 6
Hz, 2H, CH2-N), 3.26 (t, J ) 6 Hz, 2H, CH2-N), 4.13 (s, 2H,
CH2CO), 6.7-7.8 (m, 8H, Ar), 8.33 (d, J ) 8 Hz, 1H, Ar); MS
m/z 419 (M+, 15), 207 (base). Anal. (C27H37N3O) C, H, N.
and was identified as compound 29: IR (KBr) 3410, 1625 cm-1
;
N,N-Di-n -h exyl-[2-(4-ch lor op h en yl)im id a zo[1,2-a ]p yr i-
d in -3-yl]a ceta m id e (37): IR (KBr) 1630 cm-1 1H NMR
;
1H NMR (CDCl3) δ 0.68 (t, J ) 2.5 Hz, 3H, CH3), 0.81 (t, J )
2.5 Hz, 3H, CH3), 1.3-1.5 (m, 4H, CH2), 2.96 (d, J ) 1 Hz,
3H, CH3), 3.06 (t, J ) 2.6 Hz, 2H, CH2-N), 3.25 (t, J ) 2.5
Hz, 2H, CH2-N), 4.01 (s, 2H, CH2CO), 5.24 (br s, 1H, NH),
6.09 (d, J ) 2.5 Hz, 1H, Ar), 6.70 (t, J ) 2.4 Hz, 1H, Ar), 7.3-
(CDCl3) δ 0.90 (t, J ) 3 Hz, 6H, CH3), 1.0-1.7 (m, 16H, CH2),
3.10 (t, J ) 6 Hz, 2H, CH2-N), 3.30 (t, J ) 6 Hz, 2H, CH2-
N), 4.10 (s, 2H, CH2CO), 6.8-7.8 (m, 7H, Ar), 8.20 (d, J ) 8
Hz, 1H, Ar); MS m/z 453 (M+, 20), 241 (base). Anal. (C27H36
-
7.6 (m, 5H, Ar); MS m/z 398 (M+, 19), 270 (base). Anal. (C22H27
-
ClN3O) C, H, N.
N-n -P r op yl-(2-p h en ylim id a zo[1,2-a ]p yr id in -3-yl)a ceta -
m id e (38): IR (KBr) 3225, 1630 cm-1; 1H NMR (CDCl3) δ 0.76
(t, J ) 2.5 Hz, 3H, CH3), 1.3-1.5 (m, 2H, CH2), 3.1-3.2 (m,
2H, CH2-NH), 3.99 (s, 2H, CH2CO), 5.77 (br s, 1H, NH), 6.8-
7.7 (m, 8H, Ar), 8.03 (dd, J ) 0.3 and 0.6 Hz, 1H, Ar); MS m/z
293 (M+, 23), 207 (base). Anal. (C18H19N3O) C, H, N.
ClN4O) C, H, N.
Gen er a l P r oced u r e for P r ep a r a tion of (8-Aceta m i-
d oim id a zo[1,2-a ]p yr id in -3-yl)a ceta m id es 30 a n d 31. A
mixture of (8-aminoimidazo[1,2-a]pyridin-3-yl)acetamide 27 or
28 (0.86 mmol) in acetic anhydride (25 mL) was stirred at room
temperature overnight. The solvent was evaporated under
reduced pressure, and the residue was purified by silica gel
column chromatography [light petroleum ether/ethyl acetate
1/1 (v/v) as eluent] to give the amide 30 or 31, respectively.
Physical data are summarized in Table 1.
N-n -P r op yl-[2-(4-ch lor op h en yl)im id a zo[1,2-a ]p yr id in -
3-yl]a ceta m id e (39): IR (KBr) 3230, 1635 cm-1 1H NMR
;
(CDCl3) δ 0.78 (t, J ) 2.5 Hz, 3H, CH3), 1.3-1.5 (m, 2H, CH2),
3.1-3.2 (m, 2H, CH2-NH), 3.98 (s, 2H, CH2CO), 5.84 (br s,