Inhibition of Sphingosine-1-Phosphate Lyase
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 13 3951
135.84, 134.08, 130.18, 129.67, 119.88, 73.11, 70.99, 65.16, 63.22.
MS (EI) m/z: 293 [M + H]+. HRMS calcd for C14H16N2O5 [M +
H]+ 293.1137, found 293.1162. HPLC (Sunfire C18 4.6 mm × 50
General Procedure D: (1R,2S,3R)-1-(2-(1H-1,2,4-Triazol-3-yl)-
1H-imidazol-4-yl)butane-1,2,3,4-tetraol (27). A solution of 26 (275
mg, 0.80 mmol) in methanol (10 mL) and 0.5 M aqueous HCl
(14 mL) was sparged with nitrogen for 10 min. Then, palladium
hydroxide on carbon (20% w/w, 100 mg) was added, and the
reaction vessel was charged with H2 (65 psi). After 18 h, the
reaction was sparged with nitrogen and then filtered over a pad
of celite and washed with methanol (10 mL). The solvent was
removed to give an off white solid which was then triturated
with ether:THF (1:1) to give the deprotected triazole 27 (180
mg, 100% yield) as an off white solid. 1H NMR (400 MHz,
MeOD) δ ppm 8.72 (s, 1 H), 7.54 (s, 1 H), 5.24 (d, J ) 1.3 Hz,
1 H), 3.78-3.88 (m, 2 H), 3.66-3.76 (m, 2 H). 13C NMR (100
MHz, 1.0 M DCl in D2O) δ ppm 148.04, 145.55, 135.49, 135.09,
117.08, 72.39, 70.40, 64.25, 62.57. MS (EI) m/z: 256 [M + H]+.
HRMS calcd for C16H20N5O4 [M + H]+ 256.1048, found
256.1033. HPLC (Zorbax C8 4.6 mm × 150 mm, 5-90%
MeCN:10 mM aq NH4OAc, 4 min gradient) tR ) 0.80 min, 99%
integrated area.
mm, 5-90% MeCN:10 mM aq NH4OAc, 3 min gradient) tR
)
0.80 min, 100% integrated area.
(1R,2S,3R)-1-(2-(2-Methylthiazol-4-yl)-1H-imidazol-4-yl)butane-
1,2,3,4-tetraol (22). Prepared according to the general procedure B
from fructosamine-HOAc 18 (1.00 g, 4.13 mmol) and 2-methylthi-
azole-4-carbonitrile (0.50 g, 4.13 mmol) to provide 22 (0.68 g, 58%
1
yield). H NMR (400 MHz, MeOD) δ ppm 7.40 (s, 1 H) 7.32 (d,
J ) 3.3 Hz, 1 H) 6.39 (dd, J ) 3.6, 0.9 Hz, 1 H) 3.76-3.89 (m,
2 H) 3.67-3.75 (m, 2 H) 2.46 (s, 3 H). 13C NMR (100 MHz, 1.0
M DCl in D2O) δ ppm 171.51, 138.56, 136.39, 134.69, 116.74,
108.40, 72.85, 70.85, 64.68, 62.98, 18.16. MS (EI) m/z: 286 [M +
H]+. HRMS calcd for C11H15N3O4S [M + H]+ 286.0862, found
286.0842. HPLC (Zorbax C8 4.6 mm × 150 mm, 5-90% MeCN:
10 mM aq NH4OAc, 3 min gradient) tR ) 1.76 min, 99% integrated
area.
(1R,2S,3R)-1-(2-(5-methylthiazol-4-yl)-1H-imidazol-4-yl)butane-
1,2,3,4-tetraol (23). Prepared according to the General procedure
B from fructosamine-HOAc 18 (2.00 g, 8.25 mmol) and 5-meth-
ylthiazole-4-carbonitrile35 (1.02 g, 8.25 mmol) to provide 23 (1.70
(1R,2S,3R)-1-(1H,1′H-2,2′-biimidazol-4-yl)butane-1,2,3,4-tetraol
(28). Prepared according to the general procedure B from
fructosamine-HOAc 18 (1.94 g, 8.37 mmol) and 1-benzyl-1H-
imidazole-2-carbonitrile (0.78 g, 8.37 mmol) to provide, after
hydrogenation by general procedure D, compound 28 (60 mg,
1
g, 72% yield). H NMR (400 MHz, MeOD) δ ppm 9.01 (s, 1 H)
1
7.55 (s, 1 H) 5.24 (d, J ) 1.3 Hz, 1 H) 3.78-3.89 (m, 2 H)
3.67-3.77 (m, 2 H) 2.77 (s, 3 H). 13C NMR (100 MHz, 1.0 M
DCl in D2O) δ ppm 155.22, 140.38, 137.84, 134.89, 133.71, 117.14,
72.84, 70.84, 64.63, 62.98, 11.52. MS (EI) m/z: 286 [M + H]+.
HRMS calcd for C11H15N3O4S [M + H]+ 286.0862, found
286.0864. HPLC (Luna Phenyl-hexyl 4.6 mm × 50 mm, 5-90%
MeCN:10 mM aq NH4OAc, 3 min gradient) tR ) 0.93 min, 100%
integrated area.
3% yield) as a white solid. H NMR (400 MHz, MeOD) δ ppm
7.14 (d, J ) 4.3 Hz, 3 H), 5.02 (s, 1 H), 3.73-3.89 (m, 3 H),
3.66 (br s, 1 H). 13C NMR (100 MHz, 1.0 M DCl in D2O) δ
ppm 138.20, 127.82, 122.98, 119.80, 72.87, 70.78, 64.77, 63.02.
MS (EI) m/z: 255 [M + H]+. HRMS calcd for C10H15N4O4 [M
+ H]+ 255.1092, found 255.1085. HPLC (HILIC Silica 4.6 mm
× 50 mm, 100-80% MeCN:10 mM aq NH4OAc, 3 min gradient)
tR ) 2.23 min, 99% integrated area.
(1R,2S,3R)-1-(2-(pyrimidin-2-yl)-1H-imidazol-4-yl)butane-1,2,3,4-
tetraol (29). Prepared according to the general procedure B from
fructosamine-HOAc 18 (2.39 g, 10.00 mmol) and pyrimidine-
2-carbonitrile (1.05 g, 10.00 mmol) to provide 29 (0.68 g, 26%
(1R,2S,3R)-1-(2-(Thiazol-4-yl)-1H-imidazol-4-yl)butane-1,2,3,4-
tetraol (24). Prepared according to the general procedure B from
fructosamine-HOAc 18 (0.93 g, 3.88 mmol) and 5-methylthi-
azole-4-carbonitrile (0.43 g, 3.88 mmol) to provide 24 (95 mg,
1
1
yield). H NMR (400 MHz, DMSO-d6) δ ppm 8.82 (d, J ) 4.8
9% yield). H NMR (400 MHz, 1.0 M DCl in D2O) δ ppm 9.01
Hz, 2 H), 7.39 (t, J ) 4.9 Hz, 1 H), 7.14 (s, 1 H), 4.80 (d, J )
1.5 Hz, 1 H), 3.61 (dd, J ) 10.7, 3.1 Hz, 2 H), 3.40 (dd, J )
10.8, 5.8 Hz, 2 H). 13C NMR (100 MHz, 1.0 M DCl in D2O) δ
ppm 158.25, 151.04, 140.91, 136.18, 122.70, 118.04, 72.43,
70.45, 64.41, 62.62. MS (EI) m/z: 267 [M + H]+. HRMS calcd
for C11H14N4O4 [M + H]+ 267.1093, found 267.1079. HPLC
(Zorbax C8 4.6 mm × 150 mm, 5% MeCN:10 mM aq NH4OAc,
4 min isocratic) tR ) 1.01 min, 100% integrated area.
(1R,2S,3R)-1-(2-(Pyrazin-2-yl)-1H-imidazol-4-yl)butane-1,2,3,4-
tetraol (30). Prepared according to the general procedure B from
fructosamine-HOAc 18 (1.62 g, 7.00 mmol) and pyrazine-2-
carbonitrile (0.74 g, 7.00 mmol) to provide 30 (0.72 g, 39% yield).
1H NMR (300 MHz, deuterium oxide) δ ppm 8.96 (d, J ) 1.5 Hz,
1 H), 8.52 (dd, J ) 2.7, 1.5 Hz, 1 H), 8.42 (d, J ) 2.7 Hz, 1 H),
7.22 (br s, 1 H), 4.91 (br s, 1 H), 3.78 (dd, J ) 7.1, 3.6 Hz, 1 H),
3.59-3.75 (m, 2 H), 3.47-3.58 (m, 1 H). 13C NMR (100 MHz,
1.0 M DCl in D2O) δ ppm 146.28, 145.98, 141.42, 140.38, 138.82,
136.66, 118.52, 72.84, 70.85, 64.82, 63.02. MS (EI) m/z: 267 [M
+ H]+. HRMS calcd for C11H14N4O4 [M + H]+ 267.1093, found
267.1091. HPLC (HILIC Silica 4.6 mm × 50 mm, 100-40%
MeCN:10 mM aq NH4OAc, 3 min gradient) tR ) 1.47 min, 99%
integrated area.
(d, J ) 1.8 Hz, 1 H), 7.94 (d, J ) 1.8 Hz, 1 H), 7.19 (s, 1 H),
4.95 (d, J ) 3.8 Hz, 1 H), 3.84 (dd, J ) 7.0, 3.8 Hz, 1 H),
3.67-3.80 (m, 2 H), 3.59 (dd, J ) 11.5, 6.5 Hz, 1 H). 13C NMR
(100 MHz, 1.0 M DCl in D2O) δ ppm 157.72, 139.06, 138.58,
134.67, 123.70, 116.73, 72.85, 70.85, 64.69, 62.98. MS (EI) m/z:
272 [M + H]+. HRMS calcd for C10H13N3O4S [M + H]+
271.0627, found 272.0693. HPLC (HILIC Silica 4.6 mm × 50
mm, 97-40% MeCN:10 mM aq NH4OAc, 3 min gradient) tR )
1.21, 100% integrated area.
(1R,2S,3R)-1-(2-(Oxazol-4-yl)-1H-imidazol-4-yl)butane-1,2,3,4-
tetraol (25). Prepared according to the general procedure B from
fructosamine-HOAc 18 (510 mg, 2.13 mmol) and oxazole-4-
carbonitrile (200 mg, 2.13 mmol) to provide 29 (64 mg, 12% yield).
1H NMR (400 MHz, MeOD) δ ppm 8.29 (s, 1 H), 8.22 (s, 1 H),
7.12 (br s, 1 H), 5.01 (br s, 1 H), 3.71-3.88 (m, 3 H), 3.56-3.71
(m, 1 H). 13C NMR (100 MHz, 1.0 M DCl in D2O) δ ppm 154.05,
140.93, 136.68, 134.86, 125.27, 116.84, 72.85, 70.83, 64.66, 62.98.
MS (EI) m/z: 256 [M + H]+. HRMS calcd for C10H13N3O5 [M +
H]+ 256.0933, found 256.0936. HPLC (Sunfire C18 4.6 mm × 50
mm, 10-90% MeCN:10 mM aq NH4OAc, 2 min gradient) tR
0.30 min, 100% integrated area.
)
(1R,2S,3R)-1-(2-(1-Benzyl-1H-1,2,4-triazol-3-yl)-1H-imidazol-4-
yl)butane-1,2,3,4-tetraol (26). Prepared according to the general
procedure B from fructosamine-HOAc (2.73 g, 11.40 mmol) and
1-benzyl-1H-1,2,4-triazole-3-carbonitrile36 (2.1 g, 11.40 mmol)
(1R,2S,3R)-1-(2-(1,2,4-Oxadiazol-3-yl)-1H-imidazol-4-yl)butane-
1,2,3,4-tetraol (31). Prepared according to the general procedure B
from fructosamine-HOAc 18 (478 mg, 2.00 mmol) and 1,2,4-
oxadiazole-3-carbonitrile (512 mg, 2.00 mmol) to provide 31 (205
1
1
to provide 26 (3.21 g, 81% yield). H NMR (400 MHz, MeOD)
mg, 40% yield). H NMR (400 MHz, 1.0 M DCl in D2O) δ ppm
δ ppm 8.80 (s, 1 H), 7.51 (s, 1 H), 7.33-7.45 (m, 5 H), 5.58 (s,
2 H), 5.21 (d, J ) 1.3 Hz, 1 H), 3.76-3.86 (m, 2 H), 3.66-3.73
(m, 2 H). MS (EI) m/z: 346 [M + H]+. HRMS calcd for
C16H20N5O4 [M + H]+ 346.1515, found 346.1501. HPLC (Sunfire
C18 4.6 mm × 50 mm, 5-90% [methanol/water/TFA (95/5/
0.1)]:water with 0.1% TFA, 3 min gradient) tR ) 1.89 min, 99%
integrated area.
9.43 (s, 1 H), 7.64 (s, 1 H), 5.24 (s, 1 H), 3.72-3.84 (m, 3 H),
3.61-3.68 (m, J ) 13.1, 6.8 Hz, 1 H).13C NMR (100 MHz, 1.0 M
DCl in D2O) δ ppm 169.3, 157.4, 138.6, 132.8, 119.9, 73.8, 71.6,
65.8, 63.8. MS (EI) m/z: 257 [M + H]+. HRMS calcd for
C9H12N4O5 [M + H]+ 257.0886, found 257.0870. HPLC (Luna
Phenyl-hexyl 4.6 mm × 50 mm, 5% [methanol/water/TFA (95/5/
0.1)]:water, isocratic) tR ) 2.41 min, 100% integrated area.