Cholecystokinin-B Receptor
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 16 2499
3.05 (1H, m), 2.19 (2H, br s), 1.50 and 1.47 (9H, two s), 1.42-
1.24 (6H, m), 0.94-0.87 (6H, m); MS (CI) m/ z 415 (M+ + 1).
Gen er a l P r oced u r e for th e P r ep a r a tion of 3-Ur eid o-
ben zod ia zep in es 9a-g a n d 10a -d . N-[2,3-Dih yd r o-2-oxo-
5-[piper idin -2(R,S)-yl]-1-(1-pr opyl)-1H-1,4-ben zodiazepin -
3(R,S)-yl]-N′-(3-m eth ylp h en yl)u r ea Hyd r och lor id e Sa lt
(9b). To a stirred solution of 32 (370 mg, 0.92 mmol) in
anhydrous THF (10 mL) was added dropwise m-tolyl isocy-
anate (130 µL, 1.0 mmol) over 2 min, under nitrogen. After
the mixture was stirred at room temperature for 4.5 h, MeOH
(8 mL) was added and solvents were removed under vacuum.
The remaining residue was triturated with a mixture of
hexane (15 mL) and Et2O (10 mL) to give 432 mg (88%) of
N-[5-[1-(tert-butyloxycarbonyl)piperidin-2(R,S)-yl]-2,3-dihydro-
2-oxo-1-(1-propyl)-1H-1,4-benzodiazepin-3(R,S)-yl]-N′-(3-meth-
ylphenyl)urea as a white solid: mp 206-213 °C; 1H NMR
(CDCl3) δ 7.76-7.60 (7H, m), 6.86 (1H, br d, J ) 7.8 Hz), 6.62
(1H, br s), 6.35 (1H, br d, J ) 8.0 Hz), 5.50-5.38 (2H, m), 4.30-
4.20 (1H, m), 3.98-3.84 (1H, m), 3.66-3.52 (1H, m), 3.44-
3.22 (1H, br s), 2.31 (3H, s), 1.80-1.04 (17H, m), 0.86 (3H, t,
J ) 7.3 Hz); MS (CI) m/ z 533 (M-). Anal. (C30H39N5O4) C,
H, N.
m), 3.54-3.44 (1H, m), 3.12-2.90 (2H, m), 2.82-2.68 (4H, m),
2.00-1.87 (2H, m), 1.60-1.45 (1H, m), 1.34-1.10 (3H, m),
0.95-0.86 (4H, m and s), 0.73 (3H, t, J ) 7.4 Hz), 0.59 (3H, s),
0.48 (1H, t, J ) 13.5 Hz); MS (CI) m/ z 400 (M+ + 1). Anal.
(C29H37N5O2‚1.0HCl‚0.5H2O) C, H, N.
10a h yd r och lor id e: mp 174-184 °C dec; 1H NMR (DMSO-
d6) δ 9.33 (1H, br s), 9.27 (1H, s), 8.52 (1H, br s), 7.92 (1H, d,
J ) 7.6 Hz), 7.76-7.74 (2H, m), 7.52-7.46 (2H, m), 7.20-7.15
(2H, m), 7.09 (1H, t, J ) 7.7 Hz), 6.73 (1H, d, J ) 7.5 Hz),
5.21 (1H, d, J ) 8.3 Hz), 4.95 (1H, m), 4.22 (1H, m), 3.73 (1H,
m), 3.18 (2H, m), 2.22 (3H, s), 1.73-1.23 (8H, m), 0.92 (3H, s),
0.76 (3H, t, J ) 7.3 Hz); MS (CI) m/ z 476 (M+ + 1). Anal.
(C28H37N5O2‚1.0HCl‚0.7H2O) C, H, N.
10c h yd r och lor id e: mp 193-203 °C; 1H NMR (DMSO-d6)
δ 9.40 (1H, br m), 9.27 (1H, s), 8.49 (1H, br m), 7.92 (1H, dd),
7.77 (1H, dt), 7.65 (1H, dd), 7.48 (2H, m), 7.19-7.15 (2H, m),
7.09 (1H, t, J ) 7.6 Hz), 6.73 (1H, dd), 5.24 (1H, d, J ) 8.2
Hz), 4.94 (1H, m), 3.37 (3H, s), 3.18 (2H, m), 2.22 (3H, s), 1.74-
1.24 (6H, m), 0.91 (3H, s), 0.83 (3H, s); MS (CI) m/ z 448 (M+
+ 1). Anal. (C26H33N5O2‚1.0HCl‚0.4H2O) C, H, N.
10d h yd r och lor id e: mp 171-175 °C; 1H NMR (DMSO-d6)
δ 9.41 (1H, m), 9.17 (1H, s), 8.47 (1H, m), 7.91 (1H, d, J ) 7.9
Hz), 7.76 (1H, t, J ) 7.8 Hz), 7.65 (1H, d, J ) 8.1 Hz), 7.48
(1H, t, J ) 7.6 Hz), 7.43 (1H, d, J ) 8.5 Hz), 7.26 (1H, s), 7.07
(2H, m), 5.25 (1H, d, J ) 8.4 Hz), 4.93 (1H, m), 3.37 (3H, s),
3.18 (2H, m), 2.76 (4H, q, J ) 6.9 Hz), 1.96 (2H, qn, J ) 7.3
Hz), 1.70-1.24 (6H, m), 0.91 (3H, s), 0.83 (3H, s); MS (CI) m/ z
473 (M-). Anal. (C28H35N5O2‚1.0HCl‚0.6H2O) C, H, N.
Gen er a l P r oced u r e for th e N-Meth yla tion of 9b a n d
10a . N-[2,3-Dih yd r o-5-[1-m et h ylp ip er id in -2(R,S)-yl]-2-
oxo-1-(1-p r op yl)-1H -1,4-b en zod ia zep in -3(R,S)-yl]-N′-(3-
m eth ylp h en yl)u r ea Hyd r och lor id e (9c). To a stirred
solution of 9b (100 mg, 0.23 mmol) in a mixture of MeOH (5
mL) and glacial AcOH (53 µL, 0.92 mmol) was added NaC-
NBH3 (15 mg, 0.23 mmol) followed by a solution of CH2O (38%
w/v aqueous solution; 23 µL) in MeOH (1 mL). After 40 min,
saturated aqueous K2CO3 (2 mL) was added, and the MeOH
was removed under vacuum. The residue was diluted with
water (15 mL), and the product was extracted with CH2Cl2 (2
× 40 mL), washed with brine (20 mL), dried, and concentrated.
Flash chromatography of the residue (CH2Cl2/MeOH, 90:10)
gave 96 mg of 9c as a white solid. The hydrochloride salt was
prepared from MeOH/Et2O; mp 180-187 °C; 1H NMR (DMSO-
d6) δ 9.62 (1H, br s), 9.30 (1H, s), 8.01 (1H, d, J ) 7.8 Hz),
7.82-7.72 (2H, m), 7.59 (1H, d, J ) 7.2 Hz), 7.51 (1H, br t, J
) 8.0 Hz), 7.22-7.06 (3H, m), 6.74 (1H, d, J ) 7.4 Hz), 5.08
(1H, d, J ) 7.2 Hz), 4.90-4.80 (1H, m), 4.30-4.21 (1H, m), 3.80-
3.69 (1H, m), 3.48-3.38 (1H, m), 3.28-3.10 (1H, m), 2.97 (3H,
br s), 2.22 (3H, s), 1.86-1.66 (4H, m), 1.56-1.18 (4H, m), 0.75
(3H, t, J ) 7.3 Hz); MS (CI) m/ z 447 (M-). Anal. (C26H33N5O2‚
1.0HCl‚1.0H2O) C, H, N.
A solution of the above product (80 mg) in a mixture of CH2-
Cl2 (4 mL) and TFA (2 mL) was allowed to stand at room
temperature for 20 min. Solvents were removed under
vacuum and the residue azeotroped with MeOH (2 × 15 mL)
before it was partitioned between 10% aqueous K2CO3 (5 mL)
and EtOAc (50 mL). The combined organic solutions were
dried and concentrated, and the residue was purified by flash
chromatography (CH2Cl2/MeOH, 90:10) to give 46 mg (71%)
of 9b free base. The hydrochloride salt was prepared and
recrystallized from MeOH/Et2O: mp 191-195 °C; 1H NMR
(CDCl3) δ 10.65 (1H, s), 9.27 (1H, br d), 9.02 (1H, d, J ) 8.6
Hz), 8.89 (1H, br q), 7.83 (1H, d, J ) 6.8 Hz), 7.54 (1H, t, J )
7.2 Hz), 7.40-7.24 (4H, m), 6.98 (1H, t, J ) 7.7 Hz), 6.67 (1H,
d, J ) 7.5 Hz), 5.39 (1H, d, J ) 8.6 Hz), 4.32-4.23 (1H, m),
3.96 (1H, br t), 3.54-3.42 (1H, m), 3.11 (1H, br d, J ) 12.6
Hz), 2.87 (1H, br q, J ) 11 Hz), 2.23 (3H, s), 1.92-1.76 (1H,
m), 1.70-1.44 (2H, m), 1.30-1.02 (4H, m), 0.77 (3H, t, J ) 7.3
Hz), 0.46-0.30 (1H, m); MS (CI) m/ z 433 (M-). Anal.
(C25H31N5O2‚1.0HCl‚0.7H2O) C, H, N.
1
9a h yd r och lor id e: H NMR (DMSO-d6) δ 9.34-9.22 (2H,
m), 7.76-7.46 (1H, br s), 7.80 (1H, d, J ) 7.9 Hz), 7.73 (1H,
dt, J ) 7.8 and 1.2 Hz), 7.64 (1H, d, J ) 7.8 Hz), 7.49 (1H, d,
J ) 8.2 Hz), 7.44 (1H, t, J ) 7.9 Hz), 7.19 (1H, s), 7.15-7.06
(2H, m), 6.73 (1H, d, J ) 7.3 Hz), 5.13 (1H, d, J ) 8.2 Hz),
4.50-4.38 (1H, br s), 3.88-3.74 (2H, m), 3.17 (1H, br d, J )
12.9 Hz), 3.04-2.90 (1H, br s), 2.41 (1H, br d, J ) 11 Hz),
2.22 (3H, s), 1.90-1.52 (6H, m), 0.86 (3H, t, J ) 7.3 Hz); MS
(CI) m/ z 433 (M-). Anal. (C25H31N5O2‚1.0HCl) C, H, N.
9d h yd r och lor id e: mp 181-183 °C (MeOH/Et2O); 1H NMR
(CDCl3) δ 10.63 (1H, s), 9.10 (1H, br d), 9.02 (1H, d, J ) 8.6
Hz), 8.62 (1H, br q), 7.83 (1H, dd, J ) 7.9 and 1.2 Hz), 7.55
(1H, dt, J ) 7.1 and 1.3 Hz), 7.38-7.24 (4H, m), 6.99 (1H, t, J
) 7.7 Hz), 6.69 (1H, d, J ) 7.5 Hz), 5.42 (1H, d, J ) 8.6 Hz),
4.35-4.21 (2H, m), 3.54-3.43 (1H, m), 3.15-2.93 (2H, m), 2.25
(3H, s), 1.62-1.50 (1H, m), 1.32-1.04 (3H, m), 0.95-0.86 (4H,
m and s), 0.73 (3H, t, J ) 7.3 Hz), 0.64 (3H, s), 0.44 (1H, t, J
) 13.3 Hz); MS (CI) m/ z 461 (M-). Anal. (C27H35N5O2‚
1.0HCl‚0.2H2O) C, H, N.
10b h yd r och lor id e: mp 160-167 °C; 1H NMR (DMSO-d6)
δ 9.33 (1H, s), 9.15 (1H, br m), 7.97 (1H, d, J ) 7.6 Hz), 7.82-
7.73 (2H, m), 7.56-7.49 (2H, m), 7.19-7.15 (1H, m), 7.09 (1H,
t, J ) 7.7 Hz), 6.73 (1H, d, J ) 7.2 Hz), 5.13 (1H, d, J ) 7.5
Hz), 5.03 (1H, m), 4.18 (1H, m), 3.75 (1H, m), 3.40 (2H, m),
2.98 and 2.97 (3H, two s), 2.22 (3H, s), 1.76-1.24 (8H, m), 0.92
(3H, s), 0.83 (3H, s), 0.78 (3H, t, J ) 7.3 Hz); MS (CI) m/ z 490
(M+ + 1). Anal. (C29H39N5O2‚1.0 HCl‚1.8H2O) C, H, N.
Molecu la r Mod elin g. Structures were built for the sim-
plified analogues of 5, 10a , and 9d (37, 38, and 39, respec-
tively) from the fragments in the Sybyl23 fragment library and/
or, where available, based on X-ray crystal structures of
analogous compounds. The conformation of 37 was chosen
based on comparison with X-ray crystallographic data while
conformations for the other two models were generated using
Sybyl randomsearch method,24 using 1000 attempts and
energy cutoffs of 30 kcal/mol higher than the energy of the
initial structure. Chirality was checked on carbons only. This
process produced 58 conformations of 39 and 84 conformations
of 38. All of those structures generated with molecular
mechanics energy (Tripos forcefield) within 3.2 kcal/mol of the
best minimum found (11 for 39, and 15 for 38) were submitted
to further optimization by eigenvector following using the AM1
Hamiltonian with PRECISE convergence criteria in the semiem-
pirical SCF-MO package MOPAC.25 The lowest-energy con-
The enantiomers of this compound were separated by HPLC
using a DNBL column (250 × 20 mm i.d.; 5 µm particle size)
and eluting with hexane/EtOH (70:30; flow 20 mL/min; detec-
tion at 230 nm) to afford (+)-9d (retention time 16.1 min) and
(-)-9d (retention time 23.5 min). The enantiomeric purity of
these compounds was shown to be >99% ee for (+)-9d and
97.7% ee for (-)-9d , using an analytical DNBL column (250
× 4.6 mm i.d.; 5 µm particle size) and eluting with a mixture
of MeOH, 1-chlorobutane, and AcOH (10:89:1) (retention times
4.9 and 6.8 min, respectively). (-)-9d : [R]D -6.0 (c ) 0.55,
MeOH).
9e h yd r och lor id e: mp 170 °C (dec; CH2Cl2/Et2O); 1H NMR
(CDCl3) δ 10.51 (1H, s), 9.14-9.02 (2H, m), 8.76-8.60 (1H,
m), 7.84 (1H, dd, J ) 7.9 and 1.2 Hz), 7.54 (1H, dt, J ) 7.2
and 1.4 Hz), 7.35 (1H, d, J ) 8.2 Hz), 7.32-7.22 (3H, m), 6.94
(1H, d, J ) 8.0 Hz), 5.42 (1H, d, J ) 8.6 Hz), 4.36-4.20 (2H,