Imidazolylbenzodiazepines as FT Inhibitors
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 25 5251
[2,3,4,5-Tet r a h yd r o-1-(1H -im id a zol-4-ylm et h yl)-4-(1-
n a p h t h a len ylca r b on yl)-1H -1,4-b en zod ia zep in -8-yl]ca r -
ba m ic a cid , cycloh exyl ester , d ih yd r och lor id e (23): 1H
NMR (270 MHz, CD3OD) δ 8.0-6.9 (m, 11H), 6.81 (d, 0.5H, J
) 8 Hz), 5.85 (d, 0.5H, J ) 9 Hz), 5.85 (m, 1H), 4.4-4.0 (m,
3H), 3.9-3.7 (m, 0.5H), 3.4-3.1 (m, 1.5H), 2.88 (m, 1H), 2.0-
1.2 (m, 12H); MS (M + H)+ 524.
in CH2Cl2) to give the crude alcohol (80 mg) as well as a 25%
yield of 30. TFA (3 mL) was added to the crude alcohol (40
mg) in CH2Cl2 (15 mL) at -78 °C. The resulting blue solution
was treated with solid NaBH4 (0.7 g, 18.5 mmol). The mixture
was warmed to room temperature, quenched with NH4OH (10
mL), diluted with CH2Cl2 (20 mL), and washed with aqueous
NaOH (1 N, 10 mL) and brine (10 mL). Drying over Na2SO4
and evaporation of solvent gave a solid which was converted
to its HCl salt by lyophilization from 1 M HCl to provide 30
as a yellow solid (30 mg): 1H NMR (CD3OD) δ 1.50-2.40 (m,
10H), 2.89 (m, 1H), 3.20 (m, 2H), 4.00 (br s, 1H), 4.20 (br s,
1H), 4.40 (br d, 1H), 4.50 (br s, 1H), 4.65 (s, 1H), 4.95 (s, 1H),
6.15 (d, 1H), 7.19-8.10 (m, 11H), 8.85 (s, 1H), 8.95 (s, 1H):
MS (M + H+) 465.
N-[2,3,4,5-Tetr a h yd r o-1-(1H-im id a zol-4-ylm eth yl)-4-(1-
n a p h th a len ylca r bon yl)-1H-1,4-ben zod ia zep in -8-yl]ben -
za m id e, d ih yd r och lor id e (24): 1H NMR (270 MHz, CD3OD)
δ 8.83 (d, 1H, J ) 20 Hz), 8.06-7.82 (m, 4H), 7.8-7.19 (m,
11H), 6.81 (d, 0.5H, J ) 8 Hz), 5.92 (d, 0.5H, J ) 8 Hz), 4.95
(m, 1H), 4.6 (s, 1H), 4.52-4.35 (m, 2H), 4.3-4.15 (d, 1H, J )
0.02 Hz), 3.96 (br s, 0.5H), 3.45 (m, 1.5H), 2.96-2.92 (d, 1H, J
) 0.16 Hz); IR (KBr) 3434, 2930, 1611, 1508, 1424, 1263 cm-1
;
2,3,4,5-Tetr a h yd r o-1-(1H-im id a zol-4-ylm eth yl)-7-(4-p y-
r id in yl)-4-[2-(tr iflu or om eth oxy)ben zoyl]-1H-1,4-ben zod i-
a zep in e, tr ih yd r och lor id e (36): prepared from 7-bromo-1H-
1,4-benzodiazepine by EDC/HOBt-mediated coupling with
2-trifluoromethoxybenzoic acid, trifluoroacetylation of N-1 with
trifluoroacetic acid, coupling with 4-(tributylstannyl)pyridine
using Pd(PPh3)4 catalysis as described for 21, deprotection
MS (M + H)+ 502.
N-Cycloh exyl-N′-[2,3,4,5-tetr a h yd r o-1-(1H-im id a zol-4-
ylm eth yl)-4-(1-n a p h th a len ylca r bon yl)-1H-1,4-ben zod ia z-
1
ep in -8-yl]u r ea , d ih yd r och lor id e (25): H NMR (270 MHz,
CD3OD) δ 8.83 (d, 1H, J ) 19 Hz), 8.0-7.89 (m, 2.5H), 7.63-
7.3 (m, 6.5H), 7.23 (d, 0.5H, J ) 7 Hz), 6.8 (d, 0.5H, J ) 8 Hz),
6.31 (d, 0.5H, J ) 7 Hz), 5.83 (d, 0.5H, J ) 8 Hz), 4.8 (s, 1H),
4.6-3.8 (m, 4H), 3.6-3.5 (m, 1H), 3.45-3.3 (m, 2H), 3.0-2.8
(m, 1H), 1.9-1.58 (m, 5H), 1.48-1.13 (m, 5H); MS (M + H)+
523.
N-[2,3,4,5-Tetr a h yd r o-1-(1H-im id a zol-4-ylm eth yl)-4-(1-
n a p h th a len ylca r bon yl)-1H-1,4-ben zod ia zep in -8-yl]a ceta -
m id e, d ih yd r och lor id e (28): 1H NMR (270 MHz, DMSO-
d6) 2.00-2.09 (m, 3H), 3.15-3.40 (m, 4H), 4.32 (s, 1H), 4.48
(s, 1H), 4.83 (s, 2H), 5.85 (m, 1H), 6.75 (m, 1H), 7.15-7.70 (m,
6H), 7.90-8.05 (m, 4H), 9.05, 9.10 (s, 1H); MS (M + H)+ 440.
N-[2,3,4,5-Tet r a h yd r o-1-(1H -im id a zol-4-ylm et h yl)-4-
(1-naphthalen ylcar bonyl)-1H-1,4-ben zodiazepin -8-yl]ph en-
ylsu lfon a m id e, d ih yd r och lor id e (32): 1H NMR (270 MHz,
CD3OD) δ 8.8 (d, 1H, J ) 20 Hz), 7.23-8.1 (m, 13H), 7.1 (d,
0.5H, J ) 8 Hz), 7.0 (d, 0.5H, J ) 8 Hz), 6.9 (d, 0.5H, J ) 8
Hz), 6.62 (d, 0.5H, J ) 8 Hz), 6.12 (d, 0.5H, J ) 8 Hz), 5.71 (d,
0.5H, J ) 8 Hz), 4.55 (m, 1H), 4.55-3.9 (m, 3H), 3.45-3.25
(m, 2H), 3.0-2.8 (m, 2H); MS (M + H)+ 538.
1
using aq NaOH, and reductive alkylation; H NMR (CD3OD)
δ 3.40 (m, 1H), 3.65 (m, 2H), 3.95 (m, 1H), 4.20 (m, 1H), 4.5-
5.0 (m, 3H), 5.1 (d, 1H, J ) 10 Hz), 7.05-7.70 (m, 7H), 7.95
(dd, 1H, J ) 1 Hz, 9 Hz), 8.10 (s, 1H), 8.39 (d, 1H, J ) 6 Hz),
8.75 (dd, 2H, J ) 5 Hz, 10 Hz), 8.94 (d, 2H, J ) 10 Hz); MS
(M + H)+ 494.
2,3,4,5-Tetr a h yd r o-1-(1H-im id a zol-4-ylm eth yl)-4-[2-(4-
m eth oxyp h en yl)-1,2-d ioxoeth yl]-7-p h en yl-1H-1,4-ben zo-
d ia zep in e, h yd r och lor id e (38): prepared from 4-(methoxy-
phenyl)-2-oxoacetic acid and 51b (R1 ) 7-phenyl) using stan-
dard 1-hydroxy-7-azotriazole (HOAt)/diisopropylcarbodiimide
(DIC)-mediated coupling; 1H NMR (CD3OD) δ 3.12 (m, 1H),
3.27 (m, 1H), 3.39-3.45 (m, 2H), 3.74, 3.87 (s, 3H), 4.49-4.58
(m, 3H), 4.87 (m, 1H), 6.78-778 (m, 13H), 9.09-9.11 (m, 1
H); MS (M + H+) 467.
2,3,4,5-Tetr a h yd r o-1-(1H-im id a zol-4-ylm eth yl)-7-p h en -
yl-4-[(1,2,3,4-t et r a h yd r o-1-q u in olin yl)ca r b on yl]-1H -1,4-
ben zod ia zep in e, m on oh yd r och lor id e (40): prepared from
47b by reaction with N-(tetrahydroquinolinyl)carbonyl chloride
in methylene chloride/1 N NaOH followed by reductive alky-
2,3,4,5-Te t r a h yd r o-1-(1H -im id a zol-4-ylm e t h yl)-4-(1-
n a p h t h a le n y lc a r b o n y l)-7-p h e n y l-1H -1,4-b e n zo d ia z-
ep in e, H yd r och lor id e (26). A solution of 7-bromo-1,4-
benzodiazepine-2,5-dione (0.834 g, 3.1 mmol; prepared from
6-bromoisatoic anhydride as described for 8) in DMF (10 mL)/
THF (10 mL) was degassed with nitrogen. Tetrakis(triphen-
ylphosphine)palladium (10 mol %) was added. After 30 min,
anhydrous sodium cabonate (0.37 g, 3.5 mmol) in water (6 mL)
and phenylboronic acid (1.00 g, 8.3 mmol) were added. The
suspension was stirred at room temperature overnight, then
at 80-90 °C for 2 days. The resulting dark suspension was
filtered. The solid was washed with water and then ethyl
acetate to give 7-phenyl-1,4-benzodiazepine-2,5-dione (66) as
a slightly gray solid (0.65 g, 84%): MS (M + H) 253. Reduction
to 7-phenyl-1,4-benzodiazepine (47b, R1 ) 7-phenyl) was
accomplished by LAH reduction as described for 8. Compound
26 was prepared from this material as described for 8: mp
1
lation as described for 8; mp 143-148 °C dec; H NMR (400
MHz, CD3OD) δ 1.87 (m, 2H, C-CH2-C), 2.77 (m, 2H, Ar-
CH2-C), 3.22 (m, 2H, N-CH2), 3.52 (m, 4H, 2 N-CH2), 4.54
(br s, 2H, N-CH2), 4.58 (br s, 2H, N-CH2), 6.9-7.6 (m, 13 H,
12 aromatics + 1 imidazole), 8.90 (s, 1H, 1 imidazole); MS (M
+ H+) 464.
2,3,4,5-Te t r a h yd r o-1-(1H -im id a zol-4-ylm e t h yl)-4-(1-
n a p h t h a le n y ls u lfo n y l)-7-p h e n y l-1H -1,4-b e n zo d ia z-
ep in e, m on oh yd r och lor id e (41): prepared from 47b by
reaction with 1-naphthalenesulfonyl chloride followed by
reductive alkylation; 1H NMR (CD3OD, 270 MHz) δ 8.83 (1H,
s), 8.5 (1H, m), 8.24 (1H, d, J ) 8 Hz), 8.11 (1H, J ) 8 Hz),
7.94 (1H, m), 7.61-7.25 (9H, m), 7.02 (1H, d, J ) 8 Hz). 4.61
(2H, s), 4.41 (2H, s) 3.52 (2H, m), 3.09 (2H, m); MS (M + H+)
415.
1
158-160 °C; H NMR (CD3OD, 300 MHz) δ 2.95 (br m, 1H),
3.30 (m, 1H), 4.00 (br s, 1H), 4.20 (br s, 1H), 4.40 (br d, 1H),
4.60 (m, 1H), 4.65 (m, 1H), 5.05 (s, 1H), 6.05 (d, 1H), 7.00 (d,
1H), 7.15-8.10 (m, 14H), 8.85 (s, 1H), 8.95 (s, 1H); 13C NMR
(CD3OD, 300 MHz) 48, 50, 52, 54.2, 55.0, 56.0 (CH2), 120-
142 (25C, Ar-C), 150, 172/172.5 ppm (CdO); MS (M + H)+
459.
2,3,4,5-Tetr a h yd r o-1-(1H-im id a zol-4-ylm eth yl)-7-p h en -
yl-4-(1-p h en yl-1H -t et r a zol-5-yl)-1H -1,4-b en zod ia zep in e,
Mon oh yd r och lor id e (42). To a solution of 47b (100 mg, 0.45
mmol) and potassium carbonate (60 mg) in DMF (2 mL) was
added 5-chloro-1-phenyltetrazole (100 mg, 0.55 mmol). The
mixture was stirred at 60 °C for 18 h and partitioned between
ethyl acetate and satd. NH4Cl. The organic layer was washed
with satd. NaHCO3, dried, and concentrated. The residue was
purified by column chromatography to give 2,3,4,5-tetrahydro-
7-phenyl-4-(1-phenyl-1H-tetrazol-5-yl)-1H-1,4-benzodiaz-
epine as a white solid (75 mg, 45%): mp 150-151 °C. Anal.
C,H,N. Reductive alkylation to form 42 was performed as
described for 8: mp 158 °C. 1H NMR (CD3OD) δ 3.40 (br s,
2H), 3.75 (br s, 2H), 4.55 (br s, 2H), 4.65 (br s, 2H), 6.75 (s,
1H), 7.15 (s, 1H), 7.30-7.75 (m, 10H), 9.00 (s, 1H); MS (M +
H+) 449.
2,3,4,5-Te t r a h yd r o-1-(1H -im id a zol-4-ylm e t h yl)-4-(1-
n a p h t h a len ylca r b on yl)-7-cycloh exyl-1H-1,4-b en zod ia z-
ep in e, 2.5 Hyd r och lor id e (30). n-BuLi (2.5 M in THF, 1.4
mL, 3.5 mmol) was added to a solution of 31 (0.68 g, 1.4 mmol)
in THF (15 mL) at -78 °C. The resulting brown solution was
stirred for 5 min at -78 °C and cyclohexanone (1.5 mL, 14.4
mmol) was added. After stirring at -78 °C for 10 min,
saturated NH4Cl (3 mL) was added followed by saturated
NaHCO3 (10 mL). The aqueous solution was extracted with
CH2Cl2. The organic phase was dried (Na2SO4) and evaporated.
The residue was chromatographed (10% CH3OH, 0.5% AcOH