Development of Novel EDG3 Antagonists
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 21 4637
(ArC3), 142.35 (ArC3), 140.92 (ArC1), 138.75 (ArC1), 128.34
(ArC2), 128.24 (ArC5), 128.11 (ArC2) 127.56 (ArC5), 127.11
(ArC4), 126.84 (ArC4), 124.62 (ArC6), 124.31 (ArC6), 71.87
(C4), 71.24 (C4), 65.43 (C2), 64.88 (C2), 38.42 (C5), 37.95 (C5),
35.12 (C1′), 35.07 (C1′), 32.42, 31.27 (C2′), 30.98 (C2′), 28.98,
28.97, 28.86, 28.69, 22.09 (C8′), 13.95 (C9′). MS (ESI) m/z 336
(MH+). Anal. (C19H29NO2S) calcd: C, 68.02; H, 8.71; N, 4.17.
Found: C, 67.80; H, 8.51; N, 4.40.
filtered and washed with water and diethyl ether to give a
colorless powder. Recrystallization from boiling isopropyl
alcohol gave compound 8 as a colorless powder (611 mg, 2.23
mmol, 60%); mp 140-141 °C. 1H NMR (300 MHz, CD3OD):
4.67 (dd, J ) 8.81, 4.96 Hz, app 0.3H, 2-CH), 4.30 (dd, J )
10.09, 4.04 Hz, app 0.7H, 2-CH), 3.90 (t, J ) 4.59 Hz, app 0.3H,
4-CH), 3.51 (dd, J ) 12.66, 2.75 Hz, app 0.7H, 4-CH), 3.04
(app t, app 0.6H, 6-CH2), 2.86-2.80 (m, app 1.4H, 6-CH2),
2.75-2.63 (m, 2H, 5-CH2), 1.97-1.74 (m, 2H, 1′-CH2), 1.35-
1.28 (m, 14H, CH2), 0.89 (t, J ) 6.97 Hz, 3H, 9′-CH3). 13C NMR
(75 MHz, DMSO-d6): δ 173.36 (CdO), 61.22 (C4), 58.96 (C2),
38.67 (C6), 35.88 (C5), 31.28 (C1′), 28.91, 28.72, 28.68, 28.52,
27.49, 25.30, 22.09 (C8′), 13.94 (C9′). MS (ESI) m/z 274 (MH+).
Anal. (C14H27NO2S) calcd: C, 61.50; H, 9.95; N, 5.12. Found:
C, 61.47; H, 9.97; N, 5.29.
(2R*,4R*)- a n d (2S*,4R*)-2-Decyl-1,3-th ia zin a n e-4-ca r -
boxylic Acid (9). Compound 9 was prepared according to the
procedure described for 8 but using 1-undecanal instead of
1-decanal. Compound 9 was obtained as a colorless powder
(560 mg, 1.95 mmol, 53%); mp 148-149 °C. 1H NMR (300
MHz, CD3OD): 4.66 (dd, J ) 13.76, 4.96 Hz, app 0.3H, 2-CH),
4.31 (dd, J ) 9.91, 3.85 Hz, app 0.7H, 2-CH), 3.90 (t, J ) 4.58
Hz, app 0.3H, 4-CH), 3.49 (dd, J ) 12.66, 2.75 Hz, app 0.7H,
4-CH), 3.04 (app t, app 0.6H, 6-CH2), 2.86-2.81 (m, app 1.4H,
6-CH2), 2.73-2.58 (m, 2H, 5-CH2), 1.93-1.74 (m, 2H, 1′-CH2),
1.33-1.30 (m, 16H, CH2), 0.90 (t, J ) 6.79 Hz, 3H, 10′-CH3).
13C NMR (75 MHz, DMSO-d6): δ 173.34 (CdO), 61.20 (C4),
58.96 (C2), 38.67 (C6), 35.87 (C5), 31.30 (C1′), 28.98, 28.90,
28.71, 28.52, 27.49, 25.31, 22.10 (C9′), 13.95 (C10′). MS (ESI)
m/z 288 (MH+). Anal. (C15H29NO2S) calcd: C, 62.67; H, 10.17;
N, 4.87. Found: C, 62.65; H, 9.97; N, 5.05.
(2R*,4R*)- a n d (2S*,4R*)-2-Un d ecyl-1,3-t h ia zin a n e-4-
ca r boxylic a cid (10). Compound 10 was prepared according
to the procedure described for 8 but using 1-dodecanal instead
of 1-decanal. Compound 10 was obtained as a colorless powder
(792 mg, 2.63 mmol, 71%); mp 150-151 °C. 1H NMR (300
MHz, CD3OD): 4.68 (dd, J ) 8.63, 4.95 Hz, app 0.3H, 2-CH),
4.31 (dd, J ) 9.91, 4.04 Hz, app 0.7H, 2-CH), 3.90 (t, J ) 4.77
Hz, app 0.3H, 4-CH), 3.49 (dd, J ) 12.66, 2.75 Hz, app 0.7H,
4-CH), 3.04 (app t, app 0.6H, 6-CH2), 2.86-2.81 (m, app 1.4H,
6-CH2), 2.72-2.60 (m, 2H, 5-CH2), 1.93-1.77 (m, 2H, 1′-CH2),
1.33-1.29 (m, 18H, CH2), 0.90 (t, J ) 6.97 Hz, 3H, 11′-CH3).
13C NMR (75 MHz, DMSO-d6): δ 173.34 (CdO), 61.20 (C4),
58.96 (C2), 38.67 (C6), 35.87 (C5), 31.30 (C1′), 29.01, 28.97,
28.91, 28.72, 28.52, 27.49, 25.31, 22.10 (C10′), 13.94 (C11′).
MS (ESI) m/z 302 (MH+). Anal. (C16H31NO2S) calcd: C, 63.74;
H, 10.36; N, 4.65. Found: C, 63.78; H, 10.15; N, 4.83.
(2R,4R)- a n d (2S,4R)-2-(p-P en tylp h en yl)th ia zolid in e-
4-ca r boxylic Acid (22). Compound 22 was prepared accord-
ing to the procedure described for 1 but using p-pentylben-
zaldehyde 16 instead of 1-undecanal. Compound 22 was
obtained as a colorless powder (182 mg, 0.65 mmol, 60%); mp
159-160 °C. 1H NMR (300 MHz, CD3OD): 7.46 (dd, J ) 8.07,
3.30 Hz, 2H, ArH), 7.21 (dd, J ) 3.30, 8.07 Hz, 2H, ArH), 5.73
(s, app 0.5H, 2-CH), 5.55 (s, app 0.5H, 2-CH), 4.40 (dd, J )
12.84, 4.96 Hz, app 0.5H, 4-CH), 4.07 (t, J ) 7.34 Hz, app 0.5H,
4-CH), 3.54-3.48 (m, app 1H, 5-CH2), 3.40 (dd, J ) 11.02, 4.96
Hz, app 1H, 5-CH2), 2.62 (t, J ) 8.81 Hz, 2H, 1′-CH2), 1.64-
1.62 (m, 2H, 2′-CH2), 1.34-1.31 (m, 4H, CH2), 0.89 (t, J ) 7.16
Hz, 3H, 5′-CH3). 13C NMR (75 MHz, DMSO-d6): δ 173.02 (Cd
O), 172.24 (CdO), 142.54 (ArC4), 142.80 (ArC4), 138.24 (ArC1),
136.09 (ArC1), 128.36 (ArC2, 6), 128.11 (ArC2, 6), 127.18
(ArC3, 5) 126.91 (ArC3, 5), 71.71 (C4), 71.10 (C4), 65.36 (C2),
64.84 (C2), 38.45 (C5), 37.93 (C5), 34.77 (C1′), 34.74 (C1′), 30.86
(C3′), 30.62 (C2′), 30.59 (C2′), 21.94 (C4′), 13.91 (C5′). MS (ESI)
m/z 280 (MH+). Anal. (C15H21NO2S) calcd: C, 64.48; H, 7.58;
N, 5.01. Found: C, 64.27; H, 7.59; N, 5.21.
(2R,4R)- a n d (2S,4R)-2-(p-Hep tylp h en yl)th ia zolid in e-
4-ca r boxylic Acid (23). Compound 23 was prepared accord-
ing to the procedure described for 1 but using p-heptylben-
zaldehyde 17 instead of 1-undecanal. Compound 23 was
obtained as a colorless powder (158 mg, 0.51 mmol, 77%); mp
154-156 °C. 1H NMR (300 MHz, CD3OD): 7.47 (dd, J ) 8.07,
3.30 Hz, 2H, ArH), 7.21 (dd, J ) 3.30, 8.07 Hz, 2H, ArH), 5.73
(s, app 0.5H, 2-CH), 5.56 (s, app 0.5H, 2-CH), 4.40 (dd, J )
7.34, 4.77 Hz, app 0.5H, 4-CH), 4.09 (t, J ) 7.34 Hz, app 0.5H,
4-CH), 3.55-3.50 (m, app 1H, 5-CH2), 3.45 (dd, J ) 16.88, 4.77
Hz, app 1H, 5-CH2), 2.61 (t, J ) 7.16 Hz, 2H, 1′-CH2), 1.63-
1.61 (m, 2H, 2′-CH2), 1.32-1.29 (m, 8H, CH2), 0.89 (t, J ) 6.97
Hz, 3H, 7′-CH3). 13C NMR (75 MHz, DMSO-d6): δ 172.92 (Cd
O), 172.15 (CdO), 142.45 (ArC4), 141.69 (ArC4), 138.15 (ArC1),
136.00 (ArC1), 128.26 (ArC2, 6), 128.01 (ArC2, 6), 127.08
(ArC3, 5) 126.81 (ArC3, 5), 71.62 (C4), 71.00 (C4), 65.27 (C2),
64.75 (C2), 38.36 (C5), 37.83 (C5), 34.71 (C1′), 34.68 (C1′),
31.15, 30.86 (C2′), 30.83 (C2′), 28.52, 28.42, 21.98 (C6′), 13.85
(C7′). MS (ESI) m/z 308 (MH+). Anal. (C17H25NO2S) calcd: C,
66.41; H, 8.20; N, 4.56. Found: C, 66.25; H, 8.16; N, 4.76.
(2R*,4R*)- a n d (2S*,4R*)-2-Dod ecyl-1,3-th ia zin a n e-4-
ca r boxylic Acid (11). Compound 11 was prepared according
to the procedure described for 8 but using 1-tridecanal instead
of 1-decanal. Compound 11 was obtained as a colorless powder
(831 mg, 2.63 mmol, 71%); mp 146-147 °C. 1H NMR (300
MHz, CD3OD): 4.67 (dd, J ) 8.49, 5.51 Hz, app 0.3H, 2-CH),
4.31 (dd, J ) 9.91, 4.04 Hz, app 0.7H, 2-CH), 3.90 (t, J ) 4.77
Hz, app 0.3H, 4-CH), 3.50 (dd, J ) 12.66, 2.75 Hz, app 0.7H,
4-CH), 3.04 (app t, app 0.6H, 6-CH2), 2.86-2.81 (m, app 1.4H,
6-CH2), 2.75-2.60 (m, 2H, 5-CH2), 1.94-1.73 (m, 2H, 1′-CH2),
1.35-1.29 (m, 16H, CH2), 0.90 (t, J ) 7.16 Hz, 3H, 10′-CH3).
13C NMR (75 MHz, DMSO-d6): δ 173.37 (CdO), 61.23 (C4),
58.92 (C2), 38.67 (C6), 35.91 (C5), 31.27 (C1′), 28.99, 28.93,
28.88, 28.69, 28.50, 27.48, 25.29, 22.08 (C11′), 13.93 (C12′).
MS (ESI) m/z 316 (MH+). Anal. (C17H33NO2S) calcd: C, 64.71;
H, 10.54; N, 4.44. Found: C, 64.64; H, 10.36; N, 4.63.
(2R,4R)- a n d (2S,4R)-2-(p-Non ylp h en yl)th ia zolid in e-4-
ca r boxylic Acid (24). Compound 24 was prepared according
to the procedure described for 1 but using p-nonylbenzaldehyde
18 instead of 1-undecanal. Compound 24 was obtained as a
colorless powder (135 mg, 0.40 mmol, 45%); mp 130-131 °C.
1H NMR (300 MHz, CD3OD): 7.46 (dd, J ) 8.02, 3.30 Hz, 2H,
ArH), 7.20 (dd, J ) 3.30, 8.02 Hz, 2H, ArH), 5.74 (s, app 0.5H,
2-CH), 5.57 (s, app 0.5H, 2-CH), 4.41 (dd, J ) 7.34, 4.95 Hz,
app 0.5H, 4-CH), 4.10 (t, J ) 7.34 Hz, app 0.5H, 4-CH), 3.55-
3.50 (m, app 1H, 5-CH2), 3.45 (dd, J ) 16.88, 4.95 Hz, app
1H, 5-CH2), 2.62 (t, J ) 6.61 Hz, 2H, 1′-CH2), 1.63-1.61 (m,
2H, 2′-CH2), 1.32-1.89 (m, 12H, CH2), 0.89 (t, J ) 6.42 Hz,
3H, 9′-CH3). 13C NMR (75 MHz, DMSO-d6): δ 173.00 (CdO),
172.23 (CdO), 142.53 (ArC4), 141.77 (ArC4), 138.25 (ArC1),
136.08 (ArC1), 128.34 (ArC2, 6), 128.08 (ArC2, 6), 127.15
(ArC3, 5) 126.88 (ArC3, 5), 71.71 (C4), 71.07 (C4), 65.37 (C2),
64.83 (C2), 38.46 (C5), 37.91 (C5), 34.79 (C1′), 34.75 (C1′),
31.24, 30.92 (C2′), 30.89 (C2′), 28.93, 28.84, 28.66, 28.62, 22.06
(C8′), 13.93 (C9′). MS (ESI) m/z 336 (MH+). Anal. (C19H29NO2S)
calcd: C, 68.02; H, 8.71; N, 4.17. Found: C, 67.87; H, 8.48; N,
4.39.
(2R*,4R*)- a n d (2S*,4R*)-2-Tr id ecyl-1,3-th ia zin a n e-4-
ca r boxylic Acid (12). Compound 12 was prepared according
to the procedure described for 8 but using 1-tetradecanal
instead of 1-decanal. Compound 12 was obtained as a colorless
1
powder (408 mg, 1.24 mmol, 56%); mp 136-137 °C. H NMR
(300 MHz, CD3OD): 4.70-4.66 (m, app 0.3H, 2-CH), 4.32 (dd,
J ) 9.91, 4.04 Hz, app 0.7H, 2-CH), 3.90 (app t, app 0.3H,
4-CH), 3.47 (dd, J ) 12.66, 2.94 Hz, app 0.7H, 4-CH), 3.04
(app t, app 0.6H, 6-CH2), 2.86-2.81 (m, app 1.4H, 6-CH2),
2.63-2.59 (m, 2H, 5-CH2), 1.92-1.77 (m, 2H, 1′-CH2), 1.35-
1.26 (m, 22H, CH2), 0.90 (t, J ) 6.98 Hz, 3H, 13′-CH3). 13C
(2R*,4R*)- a n d (2S*,4R*)-2-Non yl-1,3-th ia zin a n e-4-ca r -
boxylic Acid (8). 1-Decanal (500 mg, 3.69 mmol) was added
to a stirred DL-homocysteine (500 mg, 3.69 mmol) in aqueous
ethanol (75%, 100 mL). The reaction was refluxed for 12 h.
After it was cooled to room temperature, the precipitate was