Orally Bioavailable Thrombin Inhibitors
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 23 4473
ch lor id e (14). A mixture of 11 (4.0 g, 30.0 mmol) and 10%
Pd/C (3.08 g) in ethanol (80 mL), methanol (30 mL), concen-
trated HCl (6 mL), and water (10 mL) was shaken on a Parr
apparatus at 60 psi for 25 h. The reaction was filtered through
Celite, rinsing with 1:1 ethanol/methanol, and was evaporated
in vacuo to a solid, which was triturated with 5:1 ethyl acetate/
ethanol to give the title compound (5.95 g, 94%): 1H NMR
(CD3OD) δ 2.58 (s, 3 H), 4.12 (s, 2 H), 6.92 (d, J ) 9.2 Hz, 1
H), 7.93 (d, J ) 9.2 Hz, 1 H).
CONHCH2), 4.71 (d, J ) 16.5 Hz, 1 H, CHaHbCO), 4.76 (d, J
) 16.5 Hz, 1 H, CHaHbCO), 6.45 (s, 1 H, pyrazinone H-5), 6.85
(d, J ) 9.2 Hz, 1 H, pyridine H-3), 7.18-7.30 (m, 5 H, Ph),
7.86 (d, J ) 9.2 Hz, 1 H, pyridine H-4), 8.87 (br t, 1 H, CONH);
HRMS (FAB) calcd C23H29N6O2 (M + 1) 421.2352, found
421.2351. Anal. (C28H28N6O2‚2HCl‚1.2H2O‚0.3EtOAc) C, H,
N.
(S)-3-(1-P h en yl-2-p r op yla m in o)-6-m eth yl-1-(2-a m in o-6-
m e t h y l -5 -m e t h y l c a r b o x a m i d o m e t h y l p y r i d i n y l )-
p yr a zin on e (32). The title compound was prepared as an
amorphous bis-HCl salt starting from 26 and (S)-1-phenyl-2-
propylamine: HPLC retention times 5.13 min (99%, system
A) and 16.26 min (96% and 96% at 235 and 320 nm,
respectively, system B); HRMS (FAB) calcd C23H29N6O2 (M +
1) 421.2352, found 421.2344.
3-(1-P h en yl-2-m et h yl-2-p r op yla m in o)-6-m et h yl-1-(2-
a m in o-6-m eth yl-5-m eth ylca r boxa m id om eth ylp yr id in yl)-
p yr a zin on e (33). The title compound was prepared as an
amorphous bis-HCl salt from 26 and 1-phenyl-2-methyl-2-
propylamine: 1H NMR (CD3OD) δ 1.53 (s, 6 H, C(CH3)2), 2.22
(s, 3 H, CH3), 2.53 (s, 3 H, CH3), 3.13 (s, 2 H, PhCH2), 4.34 (d,
J ) 5.5 Hz, 2H, CONHCH2), 4.78 (s, 2 H, CH2CO), 6.62 (s, 1
H, pyrazinone H-5), 6.84 (d, J ) 9.2 Hz, 1 H, pyridine H-3),
7.24-7.34 (m, 5 H, Ph), 7.86 (d, J ) 9.2 Hz, 1 H, pyridine H-4),
8.89 (br t, 1 H, CONH); HPLC retention times 7.81 min (99%,
system A) and 18.91 min (93% and 92% at 235 and 320 nm,
respectively, system B); HRMS (FAB) calcd C24H31N6O2 (M +
1) 435.2506, found 435.2501.
3-(2-P h en et h yla m in o)-6-m et h yl-1-(2-a m in o-6-m et h yl-
5-m eth ylen ecar boxam idom eth ylpyr idin yl)pyr azin on e Di-
h yd r och lor id e (3). N-Methylmorpholine (15.08 mL, 0.137
mol) was added to a stirred mixture of 28 (8.33 g, 29.0 mmol),
14 (6.09 g, 29.0 mmol), HOBT‚H2O (5.09 g, 37.7 mmol), and
EDC‚HCl (7.23 g, 37.7 mmol) in dry DMF (100 mL) at 0 °C,
and after 5 min the reaction mixture was warmed to room
temperature. After 4 h, the volume of the reaction was
reduced by one-half by evaporation in vacuo, and the residual
slurry was partitioned between methylene chloride (100 mL)
and 0.2 M HCl solution (500 mL). The aqueous layer was
adjusted to pH 7-8 with saturated sodium hydrogen carbonate
solution, and the voluminous precipitate was collected by
filtration, washing with water and ethanol, and dried to give
the title compound (11.0 g) as the free base. This was crushed
to a fine powder and stirred as a suspension in ethanol (20
mL). Ethanolic HCl (9.9 M, 5.47 mL, 54.2 mmol) was added
rapidly to give a solution. After 30 min the mixture was cooled
to 0 °C, and after a further 30 min the bis-HCl salt was
collected by filtration, washing with ethanol (100 mL). The
product was resuspended in ethanol (100 mL), heated to reflux,
cooled, collected by filtration washing with ethanol (50 mL),
and dried for 16 h at 50 °C, 0.5 mmHg, to give the title
compound (12.79 g, 88%): mp >200 °C;1H NMR (DMSO-d6) δ
2.10 (s, 3 H, CH3), 2.45 (s, 3 H, CH3), 2.91 (t, J ) 7.6 Hz, 2 H,
PhCH2), 3.63 (br q, 2 H, PhCH2CH2), 4.16 (d, J ) 5.5 Hz, 2 H,
CONHCH2), 4.62 (s, 2 H, CH2CO), 6.68 (s, 1 H, pyrazinone
H-5), 6.82 (d, J ) 9.0 Hz, 1 H, pyridine H-3), 7.21-7.31 (m, 5
H, Ph), 7.76 (d, J ) 9.0 Hz, 1 H, pyridine H-4), 7.77 (s, 1 H,
NH), 8.81 (br t, 1 H, NH); HRMS (FAB) calcd C22H27N6O2 (M
+ 1) 407.2195, found 407.2189. Anal. (C22H26N6O2‚2HCl‚
1.1H2O) C, H, N.
Ack n ow led gm en t. We thank Carl Homnick for
assistance with the HPLC analysis, the analytical
chemistry and mass spectroscopy groups for chemical
characterization, Ying Li for assistance with the cocrys-
tallization procedures, and Mary Becker for help pre-
paring the manuscript.
Su p p or tin g In for m a tion Ava ila ble: Procedures for the
Ki determinations, the APTT assay, the rat thrombosis model,
the conscious dog and monkey bioavailability studies, and the
X-ray crystallography (4 pages). Ordering information is given
on any current masthead page.
By the same procedures, the following compounds were
prepared.
Refer en ces
3-(2-P h en eth ylam in o)-6-m eth yl-1-(2-am in o-4,6-dim eth yl-
5-m eth ylca r boxa m id om eth ylp yr id in yl)p yr a zin on e (29).
The title compound was prepared as the bis-HCl salt from 28
and 2-amino-5-aminomethyl-4,6-dimethylpyridine dihydro-
chloride:10 mp >200 °C; 1H NMR (CD3OD) δ 2.19 (s, 3 H, CH3),
2.45 (s, 3 H, CH3), 2.56 (s, 3 H, CH3), 3.01 (t, J ) 7.5 Hz, 2 H,
PhCH2), 3.68 (t, J ) 7.5 Hz, 2 H, PhCH2CH2), 4.38 (s, 2 H,
CONHCH2), 4.73 (s, 2 H, CH2CO), 6.55 (s, 1 H, pyrazinone
H-5), 6.71 (s, 1 H, pyridine H-3), 7.23-7.33 (m, 5 H, Ph); HPLC
retention times 5.01 min (100%, system A) and 15.51 min (99%
and 97% at 235 and 320 nm, respectively, system B); HRMS
(FAB) C23H29N6O2 calcd 421.2352 (M + 1), found 421.2349.
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3-(2-P h en et h yla m in o)-6-m et h yl-1-(2-a m in o-5-m et h yl-
ca r boxa m id om eth ylp yr id in yl)p yr a zin on e (30). The title
compound was prepared as the bis-HCl salt from 28 and
2-amino-5-aminomethylpyridine dihydrochloride:10 mp >220
1
°C; H NMR (DMSO-d6) δ 2.11 (s, 3 H, CH3), 2.92 (t, J ) 7.6
Hz, 2 H, PhCH2), 3.65 (br q, 2 H, PhCH2CH2), 4.19 (d, J ) 5.7
Hz, 2 H, CONHCH2), 4.65 (s, 2 H, CH2CO), 6.69 (s, 1 H,
pyrazinone H-5), 7.00 (d, J ) 9.9 Hz, 1 H, pyridine H-3), 7.21-
7.30 (m, 5 H, Ph), 7.82 (obscured d, 1 H, pyridine H-4), 7.83
(s, 1 H, pyridine H-6), 8.10 (br s, 2 H, NH2), 8.86 (br t, 1 H,
NH); HRMS (FAB) C21H25N6O2 calcd 393.2033 (M + 1), found
393.2024. Anal. (C21H24N6O2‚2HCl‚0.5H2O) C, H, N.
(R)-3-(1-P h en yl-2-p r op yla m in o)-6-m et h yl-1-(2-a m in o-
6-m e t h y l-5-m e t h y lc a r b o x a m i d o m e t h y lp y r i d i n y l)-
p yr a zin on e (31). The title compound was prepared as an
amorphous bis-HCl salt starting from 26 and (R)-1-phenyl-2-
propylamine: 1H NMR (CD3OD) δ 1.36 (d, J ) 6.4 Hz, 3 H,
CHCH3), 2.15 (s, 3 H, CH3), 2.53 (s, 3 H, CH3), 3.00 (m, 2 H,
PhCH2), 4.11 (m, 1 H, CHCH3), 4.33 (d, J ) 5.5 Hz, 2 H,