Novel Thieno[2,3-d][1,3]oxazin-4-ones as HLE Inhibitors
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 10 1737
(2.55 g, 22.5 mmol) was added dropwise to a solution of
compound 1946 (4 g, 15 mmol) in CH2Cl2 (15 mL). The mixture
was stirred at room temperature for 5 h and acidified with 1
M HCl/EtOH, and the precipitate was collected by filtration
to yield 23 (5.5 g, 96%): mp 156-157 °C (EtOH); IR (KBr,
cm-1) 1648 (CdO); 1H NMR (CDCl3) δ 1.05-1.90 (m, 14H,
CH2), 1.38 (t, J ) 7.1 Hz, 3H, CH3), 2.59-2.80 (m, 4H, CH2),
3.18 (s, 3H, NCH3), 4.32 (q, J ) 7.1 Hz, 2H, OCH2), 4.91-5.08
(m, 1H, CH), 12.25 (s, 1H, NH). Anal. (C19H28N2O2S2) C, H,
N, S.
Eth yl 2-(3,3-Dieth ylth iou r eido)-4,5-dim eth ylth ioph en e-
3-ca r boxyla te (25). This compound was prepared from
isothiocyanate 2046 (3.6 g, 15 mmol) and diethylamine (1.65
g, 22.5 mmol) in 89% yield: mp 96-97 °C (EtOH/H2O); 1H
NMR (CDCl3) δ 1.32 (t, J ) 7.1 Hz, 6H, CH3), 1.39 (t, J ) 7.1
Hz, 3H, CH3), 2.24 (s, 6H, 4- and 5-CH3), 3.81 (q, J ) 7.1 Hz,
4H, NCH2), 4.34 (q, J ) 7.1 Hz, 2H, OCH2), 12.31 (s, 1H, NH).
Anal. (C14H22N2O2S2) C, H, N, S.
3.72 (m, 4H, NCH2), 3.84-3.88 (m, 4H, OCH2), 12.60 (s, 1H,
NH). Anal. (C12H16N2O3S2) C, H, N, S.
2-(3,3-Dieth ylth iou r eido)-4,5-dim eth ylth ioph en e-3-car -
boxylic Acid (37). Compound 37 was prepared from 31 in
1
84% yield: mp 144-145 °C (EtOH); H NMR (CDCl3) δ 1.33
(t, J ) 7.1 Hz, 6H, CH3), 2.26 (s, 6H, 4- and 5-CH3), 3.81 (q, J
) 7.1 Hz, 4H, NCH2), 12.15 (s, 1H, NH). Anal. (C12H18N2O2S2)
C, H, N; S: calcd, 22.39; found, 22.94.
2-(3-Cycloh e xyl-3-m e t h ylt h iou r e id o)-4,5-d im e t h yl-
th iop h en e-3-ca r boxylic Acid (38). Compound 38 was pre-
pared from 32 in 80% yield: mp 142-144 °C (EtOH); 1H NMR
(CDCl3) δ 1.05-1.86 (m, 10H, CH2), 2.26 and 2.27 (each s, 3H,
4- and 5-CH3), 3.23 (s, 3H, NCH3), 12.07 (s 1H, NH). Anal.
(C15H22N2O2S2) C, H, N, S.
2-Eth oxy-5,6,7,8-tetr a h yd r o-4H-[1]ben zoth ien o[2,3-d ]-
[1,3]oxa zin -4-on e (39): Gen er a l P r oced u r e for 2-Alk oxy-
th ien o[2,3-d ][1,3]oxa zin -4-on es 39-45. A mixture of trif-
luoroacetic acid (5 mL) and trifluoroacetic anhydride (1.47 g,
7 mmol) was stirred at 0 °C under argon atmosphere. Com-
pound 5 (1.63 g, 5 mmol) was added in portions over 30 min.
Stirring was continued at room temperature for 90 min. The
mixture was poured into chilled saturated aqueous NaHCO3
(75 mL). The precipitate was collected by filtration to yield
39 (1.1 g, 88%): mp 119-120 °C (hexane); IR (KBr, cm-1) 1775
(br, CdO); UV (EtOH) λmax (nm) (log ꢀ) 234 (4.26), 316 (3.77);
1H NMR (CDCl3) δ 1.43 (t, J ) 7.1 Hz, 3H, CH3), 1.77-1.92
(m, 4H, CH2), 2.66-2.89 (m, 4H, CH2), 4.47 (q, J ) 7.1 Hz,
2H, OCH2); 13C NMR (CDCl3) δ 14.05 (CH3), 22.06 and 23.05
(C-6 and C-7), 24.84 and 25.04 (C-5 and C-8), 66.33 (OCH2),
112.36 (C-4a), 130.72 and 131.41 (C-4b and C-8a), 154.44 (C-
9a), 156.71 (C-2), 165.35 (C-4). Anal. (C12H13NO3S) C, H, N,
S.
Eth yl 2-(3-Cycloh exyl-3-m eth ylth iou r eid o)-4,5-d im eth -
ylth iop h en e-3-ca r boxyla te (26). Compound 20 was reacted
with N-methylcyclohexylamine. The crude product was re-
crystallized from EtOH to give 26 in 73% yield: mp 154-155
1
°C; H NMR (CDCl3) δ 1.05-1.89 (m, 10H, CH2), 1.39 (t, J )
7.1 Hz, 3H, CH3), 2.23 (s, 6H, 4- and 5-CH3), 3.17 (s, 3H,
NCH3), 4.34 (q, J ) 7.1 Hz, 2H, OCH2), 4.91-5.07 (m, 1H, CH),
12.28 (s, 1H, NH). Anal. (C17H26N2O2S2) C, H, N; S: calcd,
18.09; found, 18.79.
2-(N-Cycloh exyl-N-m et h yla m in o)-5,6,7,8-t et r a h yd r o-
4H-[1]ben zoth ien o[2,3-d ][1,3]th ia zin -4-on e (29): Gen er a l
P r oced u r e for Th ien o[2,3-d ][1,3]th ia zin -4-on es 27-32. A
mixture of compound 23 (5.7 g, 15 mmol) and concentrated
H2SO4 (30 mL) was kept at room temperature for 3 days and
poured into ice-water (800 mL). The precipitate was collected
by filtration, washed with H2O, dried, and recrystallized from
ethyl acetate/EtOH to yield 29 (2.6 g, 52%): mp 154-156 °C;
IR (KBr, cm-1) 1652 (CdO); 1H NMR (CDCl3) δ 1.04-1.90 (m,
14H, CH2), 2.61-2.90 (m, 4H, CH2), 3.03 (s, 3H, NCH3), 4.12-
4.28 (m, 1H, CH). Anal. (C17H22N2OS2) C, H, N, S.
2-P r opoxy-5,6,7,8-tetr ah ydr o-4H-[1]ben zoth ien o[2,3-d]-
[1,3]oxa zin -4-on e (40). Compound 40 was prepared from 6
and recrystallized from hexane: yield 32%; mp 70-71 °C; 1H
NMR (CDCl3) δ 1.03 (t, J ) 7.4 Hz, 3H, CH3), 1.76-1.91 (m,
6H, CH2), 2.68-2.89 (m, 4H, CH2), 4.37 (t, J ) 6.7 Hz, 2H,
OCH2). Anal. (C13H15NO3S) C, H, N, S.
2-Isobu toxy-5,6,7,8-tetr a h yd r o-4H-[1]ben zoth ien o[2,3-
d ][1,3]oxa zin -4-on e (41). Compound 41 was prepared from
7 and recrystallized from hexane: yield 42%; mp 64-66 °C;
1H NMR (CDCl3) δ 1.02 (d, J ) 6.9 Hz, 6H, CH3), 1.78-1.91
(m, 4H, CH2), 2.05-2.18 (m, 1H, CH), 2.67-2.89 (m, 4H, CH2),
4.19 (d, J ) 6.6 Hz, 2H, OCH2). Anal. (C14H17NO3S) C, H, N,
S.
2-E t h oxy-5,6-d im et h yl-4H -t h ien o[2,3-d ][1,3]oxa zin -4-
on e (42). Compound 42 was prepared from 8 in 93% yield:
mp 96-97 °C (hexane); 1H NMR (CDCl3) δ 1.43 (t, J ) 7.1 Hz,
3H, CH3), 2.33 and 2.35 (each s, 3H, 5- and 6-CH3), 4.46 (q, J
) 7.1 Hz, 2H, OCH2); 13C NMR (CDCl3) δ 12.73 and 12.79 (5-
and 6-CH3), 14.05 (CH3), 66.30 (OCH2), 113.36 (C-4a), 127.42
and 129.25 (C-5 and C-6), 154.73 (C-7a), 156.65 (C-2), 164.48
(C-4). Anal. (C10H11NO3S) C, H, N; S: calcd, 14.23; found,
14.83.
2-P r op oxy-5,6-d im eth yl-4H-th ien o[2,3-d ][1,3]oxa zin -4-
on e (43). Compound 43 was prepared from 9 in 92% yield:
mp 34.5-35.5 °C (hexane); 1H NMR (CDCl3) δ 1.03 (t, J ) 7.4
Hz, 3H, CH3), 1.76-1.89 (m, 2H, CH2), 2.34 and 2.36 (each s,
3H, 5- and 6-CH3), 4.36 (t, J ) 6.7 Hz, 2H, OCH2). Anal.
(C11H13NO3S) C, H, N, S.
2-Isobu toxy-5,6-d im eth yl-4H-th ien o[2,3-d ][1,3]oxa zin -
4-on e (44). Compound 44 was prepared from 10 and recrys-
tallized from hexane: yield 38%; mp 61-62 °C; 1H NMR
(CDCl3) δ 1.02 (d, J ) 6.8 Hz, 6H, CH3), 2.04-2.19 (m, 1H,
CH), 2.33 and 2.35 (each s, 3H, 5- and 6-CH3), 4.17 (d, J ) 6.6
Hz, 2H, OCH2). Anal. (C12H15NO3S) C, H, N, S.
2-(Diet h yla m in o)-5,6-d im et h yl-4H -t h ien o[2,3-d ][1,3]-
th ia zin -4-on e (31). Compound 31 was prepared from 25 in
90% yield: mp 136-136.5 °C (EtOH); 1H NMR (CDCl3) δ 1.24
(t, J ) 7.1 Hz, 6H, CH3), 2.26 and 2.35 (each s, 3H, 5- and
6-CH3), 3.57 (q, J ) 7.1 Hz, 4H, NCH2). Anal. (C12H16N2OS2)
C, H, N, S.
2-(N -Cycloh e xyl-N -m e t h yla m in o)-5,6-d im e t h yl-4H -
th ien o[2,3-d ][1,3]th ia zin -4-on e (32). Compound 32 was
prepared from 26 in 68% yield: mp 154-155 °C (ethyl acetate/
EtOH); 1H NMR (CDCl3) δ 1.05-1.90 (m, 10H, CH2), 2.29 and
2.35 (each s, 3H, 5- and 6-CH3), 3.03 (s, 3H, NCH3), 4.10-
4.25 (m, 1H, CH). Anal. (C15H20N2OS2) H, N, S; C: calcd,
58.41; found, 57.98
2-(3,3-Diet h ylt h iou r eid o)-4,5,6,7-t et r a h yd r oben zo[b]-
th iop h en e-3-ca r boxylic Acid (34): Gen er a l P r oced u r e
for Th iou r ea s 33-38. A mixture of compound 2835 (2.94 g,
10 mmol), 3 M NaOH (40 mL), and dioxane (80 mL) was
refluxed for 80 min. After cooling, 1 M HCl (200 mL) was
added, and the precipitate was collected by filtration to yield
34 (2.71 g, 87%): mp 144-144.5 °C; IR (KBr, cm-1) 1630
(CdO); 1H NMR (CDCl3) δ 1.33 (t, J ) 7.1 Hz, 6H, CH3), 1.72-
1.85 (m, 4H, CH2), 2.60-2.82 (m, 4H, CH2), 3.81 (q, J ) 7.1
Hz, 4H, NCH2), 12.11 (s, 1H, NH). Anal. (C14H20N2O2S2) C,
H, N; S: calcd, 20.52; found, 19.88.
2-(3-Cycloh exyl-3-m et h ylt h iou r eid o)-4,5,6,7-t et r a h y-
d r oben zo[b]th iop h en e-3-ca r boxylic Acid (35). Compound
35 was prepared from 29. The mixture was refluxed for 160
1
min: yield 66%; mp 158-160 °C (EtOH); H NMR (CDCl3) δ
2-E t h oxy-5-isop r op yl-4H -t h ien o[2,3-d ][1,3]oxa zin -4-
on e (45). Compound 45 was prepared from 11 in 97% yield:
mp 71-73 °C (hexane); 1H NMR (CDCl3) δ 1.28 (d, J ) 6.8
Hz, 6H, CH3), 1.45 (t, J ) 7.1 Hz, 3H, CH3), 3.48 (sept, J )
6.8 Hz, 1H, CH), 4.50 (q, J ) 7.1 Hz, 2H, OCH2), 6.65 (s, 1H,
H-6). Anal. (C11H13NO3S) C, H, N, S.
1.04-1.99 (m, 14H, CH2), 2.60-2.83 (m, 4H, CH2), 3.23 (s, 3H,
NCH3), 4.63-4.79 (m, 1H, CH), 12.05 (s, 1H, NH). Anal.
(C17H24N2O2S2) C, H, N, S.
2-[(Mor p h olin ot h ioca r b on yl)a m in o]-4,5-d im e t h yl-
th iop h en e-3-ca r boxylic Acid (36). Compound 36 was pre-
pared from 3035 in 63% yield: mp 172-173 °C (ethyl acetate/
EtOH); 1H NMR (DMSO-d6) δ 2.20 (s, 6H, 4- and 5-CH3), 3.68-
2-(Meth ylth io)-5,6,7,8-tetr a h yd r o-4H-[1]ben zoth ien o-
[2,3-d ][1,3]oxa zin -4-on e (46): Gen er a l P r oced u r e for