Selective Noncovalent Thrombin Inhibitors
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 19 3671
H2O/CH3CN (1:9) in H2O/CH3CN (9:1) both containing 0.1%
TFA; flow rate 1.5 mL/min] indicated that the product was
95% pure.
5H-Th ia zolo[3,2-a ]p yr id in e-3-ca r boxa m id e, 6-Am in o-
N-[3-[[b is[[(1,1-d im et h ylet h oxy)ca r b on yl]a m in o]m et h -
ylen e]a m in o]p r op yl]-h exa h yd r o-5-oxo-, [3R-(3r,6r,8a r)]-
(9Cl) (22). This compound was prepared from 20 according
to the same procedure as 21. 22 (385 mg, 98%) was obtained
as a colorless oil: 1H NMR (DMSO) δ 1.41 (s, 9H, Boc), 1.50
(s, 9H, Boc), 1.58-1.72 (m, 4H, H7, H8, H13), 2.02-2.10 (m,
1H, H7 or H8), 2.24-2.35 (m, 1H, H7 or H8), 2.98-3.15 (m,
3H, H2, H12 or H14), 3.18-3.25 (m, 1H, H6), 3.26-3.35 (m,
3H, H2, H12 or H14), 4.80 (dd, 1H, J ) 6.5, 7.0 Hz, H3 or
H9), 4.90 (dd, 1H, J ) 5.5, 9.5 Hz, H3 or H9), 8.09 (t, 1H, J )
6.0 Hz, H-N15), 8.38 (t, 1H, J ) 6.0 Hz, H-N11), 11.45 (s, 1H,
H-N17); IR (neat) λmax 3326, 2978, 1722, 1641, 1135, 735; ESI-
MS 515 (M + H)+; C22H38N6O6S.
5H-Th ia zolo[3,2-a ]p yr id in e-3-ca r boxa m id e, 6-Am in o-
N-[3-[(a m in oim in om et h yl)a m in o]p r op yl]-h exa h yd r o-5-
oxo-, [3R-(3r,6â,8a r)]-(9Cl), Tr i(tr iflu or oa cetic a cid ) Sa lt
(26). This compound was prepared from 22 according to the
same procedure as 25. The trifluoroacetic acid salt of 26 (50
mg, 50%) was obtained as a colorless oil: 1H NMR (DMSO) δ
1.56-1.68 (m, 2H, H13), 1.80-2.00 (m, 2H, H7, H8), 2.18-
2.25 (m, 1H, H7 or H8), 2.35-2.44 (m, 1H, H7 or H8), 3.05
(dd, 1H, J ) 6.0, 12.0 Hz, H2), 3.07-3.20 (m, 4H, H12, H14),
3.42 (dd, 1H, J ) 9.5, 12.0 Hz, H2), 4.01 (m, 1H, H6), 4.83
(dd, 1H, J ) 6.5, 7.0 Hz, H3 or H9), 4.94 (dd, 1H, J ) 4.5, 11.5
Hz, H3 or H9), 7.15 (br, 3H, NH3+), 7.57 (t, 1H, J ) 6.0 Hz,
NH), 8.21 (t, 1H, J ) 6.0 Hz, NH), 8.33 (br s, 3H, NH3+); IR
(neat) λmax 3192, 1668, 1202, 1137, 723; ESI-MS 315 (M + H)+;
C12H22N6O2S. HPLC analysis [C18, isocratic; elution H2O/CH3-
CN (9:1) containing 0.1% TFA; flow rate 1.5 mL/min] indicated
that the product was >98%.
5H-Th ia zolo[3,2-a ]p yr id in e-3-ca r boxa m id e, N-[3-[[Bis-
[[(1,1-dim eth yleth oxy)car bon yl]am in o]m eth ylen e]am in o]-
pr opyl]-h exah ydr o-5-oxo-6-[[(ph en ylm eth yl)su lfon yl]am i-
n o]-, [3R-(3r,6r,8a r)]-(9Cl) (23). To a solution of 22 (103
mg, 0.2 mmol) in CH2Cl2 (5 mL) cooled to 0 °C was added Et3N
(43 µL, 0.3 mmol) and benzenesulfonyl chloride (42 mg, 0.22
mmol). The mixture was stirred overnight at room tempera-
ture and concentrated. The residue was purified by FCC
(AcOEt/EtOH/aqueous NH3, 80:18:2) to afford 23 (71 mg, 53%)
as a white foam: 1H NMR (DMSO) δ 1.40 (s, 9H, Boc), 1.48
(s, 9H, Boc), 1.61-1.69 (m, 2H, H13), 1.78-1.99 (m, 2H, H7,
H8), 2.05-2.15 (m, 1H, H7 or H8), 2.26-2.35 (m, 1H, H7 or
H8), 3.03-3.16 (m, 4H, H2, H12, H14), 3.27-3.41 (m, 2H, H2,
H12 or H14), 4.10 (m, 1H, H6), 4.49 (d, 1H, J ) 13.5 Hz,
-SO2CH2Ph), 4.55 (d, 1H, J ) 13.5 Hz, -SO2CH2Ph), 4.87 (dd,
1H, J ) 6.0, 6.5 Hz, H3 or H9), 4.92 (dd, 1H, J ) 4.5, 10.5 Hz,
H3 or H9), 7.28-7.44 (m, 5H, ArH), 7.49 (d, 1H, J ) 7.2 Hz,
-SO2NH-), 8.09 (t, 1H, J ) 6.0 Hz, H-N15), 8.38 (t, 1H, J )
6.0 Hz, H-N11), 11.45 (s, 1H, H-N17); IR (KBr) λmax 3331, 2978,
1723, 1642, 1329, 1134, 699; FAB-MS 669 (M + H)+, 469 (M
+ 2H - 2Boc)+; C29H44N6O8S2.
5H-Th iazolo[3,2-a ]pyr idin e-3-car boxam ide, N-[3-[(Am i-
n o im in o m e t h y l)a m in o ]p r o p y l]-h e x a h y d r o -5-o x o -6-
[[(p h en ylm eth yl)su lfon yl]a m in o]-, [3R-(3r,6r,8a r)]-(9Cl),
Di(tr iflu or oa cetic a cid ) Sa lt (27). This compound was
prepared from 23 according to the same procedure as 15. The
trifluoroacetic acid salt of 27 (30 mg, 82%) was obtained as a
colorless oil: 1H NMR (DMSO) δ 1.60-1.67 (m, 2H, H13),
1.79-1.98 (m, 2H, H7, H8), 2.08-2.16 (m, 1H, H7 or H8),
2.28-2.36 (m, 1H, H7 or H8), 3.05 (dd, 1H, J ) 6.0, 12.0 Hz,
H2), 3.08-3.18 (m, 4H, H12, H14), 3.39 (dd, 1H, J ) 6.5, 12.0
Hz, H2), 4.10 (m, 1H, H6), 4.49 (d, 1H, J ) 13.5 Hz, -SO2CH2-
Ph), 4.54 (d, 1H, J ) 13.5 Hz, -SO2CH2Ph), 4.86 (dd, 1H, J )
6.0, 6.5 Hz, H3 or H9), 4.92 (dd, 1H, J ) 4.5, 11.0 Hz, H3 or
H9), 7.25-7.47 (m, 5H, ArH), 7.49 (d, 1H, J ) 7.2 Hz, NH),
8.10 (t, 1H, J ) 6.0 Hz, NH); IR (neat) λmax 3351, 1668, 1203,
1131; FAB-MS 469 (M + H)+; C19H28N6O4S2. HPLC analysis
[C18, 20-min linear gradient; elution 0-100% H2O/CH3CN (1:
9) in H2O/CH3CN (9:1) both containing 0.1% TFA; flow rate
1.5 mL/min] indicated that the product was >98% pure.
5H-Th ia zolo[3,2-a ]p yr id in e-3-ca r boxa m id e, N-[4-[[Bis-
[[(1,1-dim eth yleth oxy)car bon yl]am in o]m eth ylen e]am in o]-
b u t yl]-6-[[(9H -flu or e n -9-ylm e t h oxy)ca r b on yl]a m in o]-
h exa h yd r o-5-oxo-, [3R-(3r,6â,8a r)]-(9Cl) (19). To a solu-
tion of Fmoc-BTD20 (262 mg, 0.6 mmol) in CH2Cl2 (30 mL)
cooled to 0 °C were added sequentially EDCI (153 mg, 0.8
mmol), HOBT (108 mg, 0.8 mmol), and the amine 17 (255 mg,
0.77 mmol) dissolved in CH2Cl2 (5 mL). The mixture was
stirred overnight at room temperature and concentrated. The
residue was purified by FCC (AcOEt/hexane, 1:1) to afford 19
(200 mg, 44%) as a white foam: 1H NMR (DMSO) δ 1.38 (s,
9H, Boc), 1.46 (s, 9H, Boc), 1.35-1.45 (m, 4H, H13, H14), 1.72-
2.05 (m, 3H, H7, H8), 2.27 (m, 1H, H7 or H8), 3.01-3.14 (m,
3H, H2, H12 or H15), 3.18-3.31 (m, 3H, H2, H12 or H15),
3.93 (m, 1H, H6), 4.23 (t, 1H, J ) 6.0 Hz, -CHCH2O-), 4.32
(d, 2H, J ) 6.0 Hz, -CHCH2O-), 4.85 (dd, 1H, J ) 4.5, 10.5
Hz, H3 or H9), 4.97 (dd, 1H, J ) 6.0, 7.0 Hz, H3 or H9), 7.32
(m, 2H, ArH), 7.40 (m, 2H, ArH), 7.68 (m, 3H, ArH, NH), 7.88
(m, 3H, ArH, NH), 8.23 (t, 1H, J ) 6.0 Hz, H-N11), 11.47 (s,
1H, H-N18); IR (KBr) λmax 3338, 2960, 1721, 1641, 1134, 741;
ESI-MS 751 (M + H)+; C38H50N6O8S.
5H-Th ia zolo[3,2-a ]p yr id in e-3-ca r boxa m id e, 6-Am in o-
N-[4-[[b is[[(1,1-d im et h ylet h oxy)ca r b on yl]a m in o]m et h -
ylen e]a m in o]bu tyl]-h exa h yd r o-5-oxo-, [3R-(3r,6r,8a r)]-
(9Cl) (21). 19 (100 mg, 0.13 mmol) was dissolved in CH2Cl2/
piperidine (8:2) and stirred for 30 min. The mixture was
concentrated, and the residue was purified by FCC (AcOEt/
EtOH/aqueous NH3, 80:18:2) to afford 21 (48 mg, 68%) as a
colorless oil: 1H NMR (DMSO) δ 1.41 (s, 9H, Boc), 1.48 (s, 9H,
Boc), 1.40-1.51 (m, 4H, H13, H14), 1.65-1.74 (m, 2H, H7, H8),
2.03-2.07 (m, 1H, H7 or H8), 2.25-2.31 (m, 1H, H7 or H8),
2.98 (dd, 1H, J ) 6.0, 11.5 Hz, H2), 3.08 (m, 2H, H12 or H15),
3.23-3.34 (m, 4H, H2, H6, H12 or H15), 4.83 (dd, 1H, J )
6.0, 6.5 Hz, H3 or H9), 4.90 (dd, 1H, J ) 5.5, 9.0 Hz, H3 or
H9), 8.04 (t, 1H, J ) 6.0 Hz, H-N16), 8.28 (t, 1H, J ) 6.0 Hz,
H-N11), 11.47 (s, 1H, H-N18); IR (KBr) λmax 3337, 2935, 2979,
1722, 1641, 1134; ESI-MS 529 (M + H)+; C23H40N6O6S.
5H-Th ia zolo[3,2-a ]p yr id in e-3-ca r boxa m id e, 6-Am in o-
N-[4-[(a m in oim in om et h yl)a m in o]b u t yl]-h exa h yd r o-5-
oxo-, [3R-(3r,6â,8a r)]-(9Cl), Tr i(tr iflu or oa cetic a cid ) Sa lt
(25). This compound was prepared from 21 according to the
same procedure as described for 13. The trifluoroacetic acid
salt of 25 (87 mg, 81%) was obtained as a white foam: 1H NMR
(DMSO) δ 1.38-1.51 (m, 4H, H13, H14), 1.78-2.00 (m, 2H,
H7, H8), 2.15-2.25 (m, 1H, H7 or H8), 2.33-2.43 (m, 1H, H7
or H8), 2.97-3.18 (m, 6H, H2, H12, H15), 4.00 (m, 1H, H6),
4.85 (dd, 1H, J ) 6.0, 7.0 Hz, H3 or H9), 4.92 (dd, 1H, J ) 4.5,
11.0 Hz, H3 or H9), 7.58 (t, 1H, J ) 5.5 Hz, H-N16), 8.18 (t,
1H, J ) 5.5 Hz, H-N11), 8.35 (br, 3H, NH3+); IR (neat) λmax
3200 (br), 1651, 1176, 1135; FAB-MS 329 (M + H)+; C13H24
-
N6O2S. HPLC analysis [C18, isocratic; elution H2O/CH3CN
(9:1) containing 0.1% TFA; flow rate 1.5 mL/min] indicated
that the product was >98% pure.
5H-Th ia zolo[3,2-a ]p yr id in e-3-ca r boxa m id e, N-[3-[[Bis-
[[(1,1-dim eth yleth oxy)car bon yl]am in o]m eth ylen e]am in o]-
p r op yl]-6-[[(9H-flu or en -9-ylm eth oxy)ca r bon yl]-a m in o]-
h exa h yd r o-5-oxo-, [3R-(3r,6r,8a r)]-(9Cl) (20). This com-
pound was prepared from Fmoc-BTD according to the same
procedure as 19, except that the amine 17 was replaced by
the amine 18. 20 (480 mg, 41%) was obtained as a white foam:
1H NMR (DMSO) δ 1.40 (s, 9H, Boc), 1.46 (s, 9H, Boc), 1.58-
1.68 (m, 2H, H13), 1.75-2.06 (m, 3H, H7, H8), 2.23-2.34 (m,
1H, H7 or H8), 3.03-3.15 (m, 3H, H2, H12 or H14), 3.27-
3.38 (m, 3H, H2, H12 or H14), 3.96 (m, 1H, H6), 4.23 (t, 1H,
J ) 6.0 Hz, -CHCH2O-), 4.33 (d, 2H, J ) 6.0 Hz, -CHCH2O-),
4.88-4.96 (m, 2H, H3, H9), 7.31 (m, 2H, ArH), 7.42 (t, 2H, J
) 6.5 Hz, ArH), 7.70 (d, 2H, J ) 6.5 Hz, ArH), 7.78-7.86 (m,
2H, NH, H-N15), 7.90 (d, 2H, J ) 6.5 Hz, ArH), 8.35 (t, 1H, J
) 6.0 Hz, H-N11), 11.47 (s, 1H, H-N17); IR (KBr) λmax 3336,
2980, 1722, 1641, 1134, 741;ESI-MS 737 (M +H)+;C37H48N6O8S.
5H-Th ia zolo[3,2-a ]p yr id in e-3-ca r boxa m id e, N-[3-[[Bis-
[[(1,1-dim eth yleth oxy)car bon yl]am in o]m eth ylen e]am in o]-
p r op yl]-h exa h yd r o-6-[[(1-n a p h t h yl)su lfon yl]a m in o]-5-