Peptide Mimetic Aldehyde Calpain I Inhibitos
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 21 3499
N-(2-Ben zyl-3,4-dih ydr o-6,7-dim eth oxy-2H-1,2-ben zoth i-
a zin e-3-ca r bon yl)-L-p h en yla la n in a l 1,1-Dioxid e (15e) (R6
) R7 ) OCH3; R1 ) Bn ; Y ) NBn ), Isom er 2. From 14e (25
mg, 0.05 mmol), the title compound (23 mg, 82%) was obtained.
NMR (CDCl3, δ): 2.88 (1H, dd), 3.02 1H, dd), 3.25 (2H, m),
3.95 (3H, s), 3.97 (3H, s), 4.35 (4H, m), 6.8-7.4 (12H, m), 9.39
(1H, s). MS m/z: 509 (M + H)+, 531 (M + Na)+. FAB-HRMS
(m/z): (M + H)+ calcd for C27H29N2O6S, 509.1746; found,
509.1744.
mg, 0.06 mmol), the title compound (21 mg, 84%) was obtained
as an off-white solid. NMR (CDCl3, δ): 2.61 (3H, s), 2.9-3.5
(4H, m), 4.10 (1H, dd), 4.18 (1H, m), 4.75 (1H, dd), 7.2-7.5
(7H, m), 7.75 (1H, d), 9.65 (1H, s). MS m/z: 405, 407 (M +
H)+. Anal. (C19H19N2O4SCl‚0.8H2O‚0.25CH2Cl2) C, H, N.
N-(3,4-Dih yd r o-6-(4-m or p h olin o)-2-m eth yl-2H-1,2-ben -
zoth iazin e-3-car bon yl)-L-ph en ylalan in al 1,1-Dioxide (15k)
(R6 ) Mor p h olin o; R1 ) Bn ; Y ) NCH3), Isom er 1. From
14k (102 mg, 0.22 mmol), the title compound (91 mg, 89%)
was obtained. NMR (CDCl3, δ): 2.52 (3H, s), 3.0-3.3 (8H, m),
3.86 (4H, m), 4.05 (1H, t), 4.73 (1H, m), 6.75, (1H, s), 6.86 (1H,
d), 7.25 (5H, m), 7.67 (1H, d), 9.66 (1H, s). MS m/z: 458 (M +
H)+. Anal. (C23H27N3O5S‚0.25CH2Cl2) C, H; N, calcd 8.78; found
8.16.
N-(3,4-Dih yd r o-6-(4-m or p h olin o)-2-m eth yl-2H-1,2-ben -
zoth iazin e-3-car bon yl)-L-ph en ylalan in al 1,1-Dioxide (15k)
(R6 ) Mor p h olin o; R1 ) Bn ; Y ) NCH3), Isom er 2. From
14k (63 mg, 0.14 mmol), the title compound (56 mg, 89%) was
obtained. NMR (CDCl3, δ): 2.58 (3H, s), 3.0-3.3 (8H, m), 3.84
(4H, m), 4.12 (1H, dd), 4.71 (1H, dd), 6.72, (1H, s), 6.83 (1H,
d), 7.25 (5H, m), 7.66 (1H, d), 9.63 (1H, s). MS m/z: 458 (M +
H)+. Anal. (C23H27N3O5S‚0.35CH2Cl2) C, H; N, calcd 8.62; found
7.86.
N-(3,4-Dih ydr o-6,7-eth ylen ed ioxy-2-m eth yl-2H-1,2-ben -
zoth ia zin e-3-ca r bon yl)-L-ph en ylalan in al 1,1-Dioxide (15l)
(R6 + R7 ) OCH2CH2O; R1 ) Bn ; Y ) NCH3). From 13l (100
mg, 0.23 mmol), the title compound (67 mg, 67%) was obtained
as a buff-white solid. NMR (DMSO-d6, δ): 2.35 (1.5H, s), 2.55
(1.5H, s), 2.8-3.4 (4H, m), 4.31 (4H, br. s), 4.50 (2H, m), 6.97
(1H, s), 7.15 (1H, s), 7.25 (5H, m), 8.69 (1H, dd), 9.57 (1H, s).
MS m/z: 431 (M + H)+, 453 (M + Na)+. Anal. (C21H22N2O6S‚
0.75H2O) C, H, N.
N-(3,4-Dih yd r o-6,7-eth ylen ed ioxy-2-eth yl-2H-1,2-ben -
zoth iazin e-3-car bon yl)-L-ph en ylalan in al 1,1-Dioxide (15m )
(R6 + R7 ) OCH2CH2O; R1 ) Bn ; Y ) NEt), Isom er 1. From
14m (30 mg, 0.07 mmol, Rf 0.3 isomer), the title compound
(25 mg, 83%) was obtained as a white amorphous solid. NMR
(CDCl3, δ): 0.92 (3H, t), 2.86 (2H, dt), 3.0-3.3 (4H, m), 3.74
(1H, dd), 4.28 (4H, s), 4.73 (1H, dd), 6.80 (1H, s), 7.24 (6H, m),
9.64 (1H, s). MS m/z: 445 (M + H)+, 467 (M + Na)+. Anal.
(C22H24N2O6S) C, H, N.
N-(3,4-Dih yd r o-6,7-eth ylen ed ioxy-2-eth yl-2H-1,2-ben -
zoth iazin e-3-car bon yl)-L-ph en ylalan in al 1,1-Dioxide (15m )
(R6 + R7 ) OCH2CH2O; R1 ) Bn ; Y ) NEt), Isom er 2. From
14m (30 mg, 0.07 mmol, Rf 0.4 isomer), the title compound
(27 mg, 90%) was obtained as a white amorphous solid. NMR
(CDCl3, δ): 0.78 (3H, t), 2.82 (2H, dt), 3.0-3.3 (4H, m), 3.80
(1H, dd), 4.27 (4H, s), 4.62 (1H, dd), 6.81 (1H, s), 7.25 (6H, m),
9.61 (1H, s). MS m/z: 445 (M + H)+, 467 (M + Na)+. Anal.
(C22H24N2O6S‚0.2CH2Cl2) C, H, N.
N-(3,4-Dih yd r o-6,7-eth ylen ed ioxy-2-isop r op yl-2H-1,2-
ben zoth ia zin e-3-ca r bon yl)-L-p h en yla la n in a l 1,1-Dioxid e
(15n ) (R6 + R7 ) OCH2CH2O; R1 ) Bn ; Y ) N-i-P r ). From
14n (78 mg, 0.17 mmol), the title compound (63 mg, 81%) was
obtained as a white solid. NMR (DMSO-d6, δ): 0.42 (3H, m),
0.85 (1.5H, d), 0.92 (1.5H, d), 2.8-3.3 (3H, m), 3.95 (1H, m),
4.25 (4H, br. s), 4.46 (1H, m), 7.0-7.3 (7H, m), 8.22 (1H, d),
9.46 (0.5H, s), 9.48 (0.5H, s). MS m/z: 459 (M + H)+. Anal.
(C23H26N2O6S‚1.0H2O) C, H, N.
N-(3,4-Dih yd r o-6,7-eth ylen ed ioxy-2-eth yl-2H-1,2-ben -
zoth ia zin e-3-ca r bon yl)-L-leu cin a l 1,1-Dioxid e (15o) (R6 +
R7 ) OCH2CH2O; R1 ) i-Bu ; Y ) NEt), Isom er 1. From 13o
(155 mg, 0.32 mmol), the title compound (118 mg, 89%) was
obtained as a white solid. NMR (CDCl3, δ): 0.95 (t, J ) 7 Hz,
6H), 1.07 (t, J ) 7 Hz, 3H), 1.20 (m, 1H), 1.73 (m, 2H), 2.99
(m, 1H), 3.16-3.45 (m, 3H), 3.83 (m, 1H), 4.29 (br, 4H), 4.57
(m, 1H), 6.83 (s, 1H), 7.25 (br, 1H), 7.34 (s, 1H), 9.57 (s, 1H).
MS m/z: 411 (M + H)+. FAB-HRMS (m/z): (M + H)+ calcd
for C19H26N2O6S, 411.1590; found, 411.1595.
N-(3,4-Dih yd r o-6,7-eth ylen ed ioxy-2-eth yl-2H-1,2-ben -
zoth ia zin e-3-ca r bon yl)-L-leu cin a l 1,1-Dioxid e (15o) (R6 +
R7 ) OCH2CH2O; R1 ) i-Bu ; Y ) NEt), Isom er 2. From 13o
(158 mg, 0.32 mmol), the title compound (119 mg, 89%) was
obtained as a white solid. NMR (CDCl3, δ): 0.96 (t, J ) 7 Hz,
N-(3,4-Dih yd r o-2-m et h yl-2H -1,2-b en zot h ia zin e-3-ca r -
bon yl)-L-p h en yla la n in a l 1,1-Dioxid e (15f) (R6 ) H; R7
)
H; R1 ) Bn ; Y ) NCH3), Isom er 1. From 14f (107 mg, 0.29
mmol), the title compound (84 mg, 79%) was obtained. NMR
(DMSO-d6, δ): 2.35 (3H, s), 2.8-3.4 (4H, m), 4.55 (2H, m), 7.3-
7.8 (8H, m), 8.70 (1H, d), 9.58 (1H, s). MS m/z: 373 (M + H)+.
Anal. (C19H20N2O4S‚1.1H2O) C, H, N.
N-(3,4-Dih yd r o-2-m et h yl-2H -1,2-b en zot h ia zin e-3-ca r -
bon yl)-L-p h en yla la n in a l 1,1-Dioxid e (15f) (R6 ) H; R7
)
H; R1 ) Bn ; Y ) NCH3), Isom er 2. From 14f (76 mg, 0.20
mmol), the title compound (64 mg, 84%) was obtained. NMR
(DMSO-d6, δ): 2.60 (3H, s), 2.9-3.3 (4H, m), 4.49 (1H, m), 4.59
(1H, dd), 7.3-7.8 (8H, m), 8.73 (1H, d), 9.58 (1H, s). MS m/z:
373 (M + H)+. Anal. (C19H20N2O4S‚1.0H2O) C, H, N.
N-(3,4-Dih ydr o-2-m eth yl-6-flu or o-2H-1,2-ben zoth iazin e-
3-ca r bon yl)-L-p h en yla la n in a l 1,1-Dioxid e (15g) (R6 ) F ;
R7 ) H; R1 ) Bn ; Y ) NCH3). From 14g (41 mg, 0.10 mmol),
the title compound (33 mg, 83%) was obtained as a white solid.
(DMSO-d6, δ): 2.4-3.4 (7H, m), 4.55 (2H, m), 7.2-7.8 (7H,
m), 8.75 (1H, d), 9.58 (1H, s). MS m/z: 391 (M + H)+. FAB-
HRMS (m/z) (M + H)+ calcd for C19H19N2O4SF, 391.1128;
found, 391.1140.
N-(3,4-Dih yd r o-6,7-d ich lor o-2-m eth yl-2H-1,2-ben zoth i-
a zin e-3-ca r bon yl)-L-p h en yla la n in a l 1,1-Dioxid e (15h ) (R6
) R7 ) Cl; R1 ) Bn ; Y ) NCH3), Isom er 1. From 14h (50
mg, 0.11 mmol), the title compound (45 mg, 90%) was obtained.
NMR (CDCl3, δ): 2.55 (3H, S), 3.0-3.4 (4H, m), 4.11 (1H, m),
4.78 (1H, m), 7.1-7.4 (5H, m), 7.46 (1H, s), 7.89 (1H, s), 9.68
(1H, s). MS m/z: 441, 443, 445 (M + H)+, Cl2 isotope pattern.
Anal. (C19H20N2O4SCl2‚0.8H2O) C, H, N.
N-(3,4-Dih yd r o-6,7-d ich lor o-2-m eth yl-2H-1,2-ben zoth i-
a zin e-3-ca r bon yl)-L-p h en yla la n in a l 1,1-Dioxid e (15h ) (R6
) R7 ) Cl; R1 ) Bn ; Y ) NCH3), Isom er 2. From 14h (32
mg, 0.07 mmol), the title compound (27 mg, 84%) was obtained.
NMR (CDCl3, δ): 2.63 (3H, s), 3.0-3.4 (4H, m), 4.18 (1H, dd),
4.76 (1H, dd), 7.1-7.4 (5H, m), 7.46 (1H, s), 7.89 (1H, s), 9.66
(1H, s). MS m/z: 441, 443, 445 (M + H)+, Cl2 isotope pattern.
Anal. (C19H20N2O4SCl2‚0.8H2O) C, H, N.
N-(3,4-Dih yd r o-6-ch lor o-2-isobu tyl-2H-1,2-ben zoth ia z-
in e-3-ca r bon yl)-L-p h en yla la n in a l 1,1-Dioxid e (15i) (R6
)
Cl; R7 ) H; R1 ) Bn ; Y ) N-i-Bu ), Isom er 1. From 14i (41
mg, 0.09 mmol), the title compound (36 mg, 88%) was obtained.
NMR (CDCl3, δ): 0.72 (3H, d), 0.80 (3H, d), 2.29 (2H, m), 3.0-
3.4 (4H, m), 3.77 (1H, t), 4.77 (1H, m), 7.1-7.4 (7H, m), 7.73
(1H, d), 9.64 (1H, s). MS m/z: 449, 451 (M + H)+, Cl isotope
pattern. Anal. (C22H25N2O4SCl‚0.5H2O) C, H, N.
N-(3,4-Dih yd r o-6-ch lor o-2-isobu tyl-2H-1,2-ben zoth ia z-
in e-3-ca r bon yl)-L-p h en yla la n in a l 1,1-Dioxid e (15i) (R6
)
Cl; R7 ) H; R1 ) Bn ; Y ) N-i-Bu ), Isom er 2. From 14i (41
mg, 0.09 mmol), the title compound (37 mg, 90%) was obtained.
NMR (CDCl3, δ): 0.65 (6H, m), 2.29 (2H, m), 2.9-3.4 (4H, m),
3.79 (1H, t), 4.65 (1H, dd), 7.1-7.4 (7H, m), 7.73 (1H, d), 9.63
(1H, s). MS m/z: 449, 451 (M + H)+, Cl isotope pattern. Anal.
(C22H25N2O4SCl‚0.85CH2Cl2) C, H; N, calcd 5.32; found 4.83.
N-(6-Ch lor o-3,4-d ih yd r o-2-m et h yl-2H -1,2-b en zot h ia z-
in e-3-ca r bon yl)-L-p h en yla la n in a l 1,1-Dioxid e (15j) (R 6
)
Cl; R7 ) H; R1 ) Bn ; Y ) NCH3), Isom er 1. From 14j (25
mg, 0.06 mmol), the title compound (19 mg, 76%) was obtained
as an off-white solid. NMR (CDCl3, δ): 2.61 (3H, s), 2.9-3.5
(4H, m), 4.10 (1H, dd), 4.18 (1H, m), 4.75 (1H, dd), 7.2-7.5
(7H, m), 7.75 (1H, d), 9.65 (1H, s). MS m/z: 405, 407 (M +
H)+. Anal. (C19H19N2O4SCl‚0.8H2O) C, H, N.
N-(6-Ch lor o-3,4-d ih yd r o-2-m et h yl-2H -1,2-b en zot h ia z-
in e-3-ca r bon yl)-L-p h en yla la n in a l 1,1-Dioxid e (15j) (R 6
)
Cl; R7 ) H; R1 ) Bn ; Y ) NCH3), Isom er 2. From 14j (25