Journal of Medicinal Chemistry
Article
3
.93−4.06 (m, 1H, 8a-H ), 6.61 (d, J = 7.83 Hz, 1H, 4-H
phenothiazine), 133.28 (9a-C phenothiazine), 138.90 (2-C phenothia-
zine), 138.98 (4a-C phenothiazine), 140.97 (5a-C phenothiazine),
168.91 (CO−CH ). Anal. Calcd for C H BrN O S·0.25H O: C, 51.64;
ax
phenothiazine), 6.67 (t, J = 7.34 Hz, 1H, 3-H phenothiazine), 6.84−
6
8
.92 (m, 4H, 6,7,8,9-H phenothiazine), 7.35 (s, 1H, 1-H phenothiazine),
.71 (s, 1H, -NH phenothiazine), 9.84 (brs, 1H, NH). Anal. Calcd for
3
19 21
2
3
2
H, 4.91. Found: C, 51.52; H, 4.65.
C H BrN O S·3H O: C, 50.10; H, 5.00. Found: C, 50.16; H, 4.52.
3-(10-Acetyl-2-phenothiazinyl)-octahydro-1,4-pyrido[2,1-c]-
2
1
4
25
2
2
2
-Methyl-2-(10-methyl-2-phenothiazinyl)-morpholin-2-ol Hydro-
oxazin-3-ol Hydrobromide (8). White solid. Yield 40%. mp 136−
1
1
bromide (4). Green-yellow solid. Yield 51%. mp 183−185 °C. H NMR
139 °C. H NMR (400 MHz, DMSO-d ): δ 1.30−1.51 (m, 3H, 7,8,9-
6
(
1
400 MHz, CDCl ): δ 2.73 (ds, J = 4.69 Hz, 3H, N-CH ), 2.86−2.91 (m,
H ), 1.57 (s, 1H, −OH), 1.64−1.95 (m, 5H, 7,8,9-H and 2 × 6-H),
3
3
ax
eq
H, 5-H ), 3.01−3.13 (m, 1H, 5-H ), 3.28 (s, 3H, N-CH
2.06 (s, 3H, CO-CH ), 2.86−2.89 (m, 1H, 9a-H ), 3.11−3.20 (m, 1H,
ax
eq
3
3
ax
phenothiazine), 3.38−3.50 (m, 2H, 3-H and -OH), 3.69−4.20 (m,
2
4-H ), 3.46−3.73 (m, 2H, 4-H and 1-H ), 3.84−3.97 (m, 1H, 1-H ),
ax
ax
eq
eq
ax
H, 3-H και 6-H ), 4.55−4.73 (m, 1H, 6-H ), 6.65−6.76 (m, 1H, 4-H
7.25 (t, J = 7.53 Hz, 1H, 7-H phenothiazine), 7.34 (t, J = 7.44 Hz, 1H,
8-H phenothiazine), 7.41 (d, J = 8.03 Hz, 1H, 3-H phenothiazine), 7.50
(d, J = 6.82 Hz, 1H, 4-H phenothiazine), 7.56−7.59 (m, 2H, 6,9-H
phenothiazine), 7.69 (s, 1H, 1-H phenothiazine), 9.74 (brs, 1H, NH).
Anal. Calcd for C H BrN O S·H O: C, 53.33; H, 5.49. Found: C,
eq
eq
ax
phenothiazine), 6.80−6.89 (m, 1H, 3-H phenothiazine), 6.94−7.09 (m,
H, 6,7,8,9-H phenothiazine), 7.20 (s, 1H, 1-H phenothiazine), 9.97
brs, 1H, NH). Anal. Calcd for C H BrN O S: C, 52.81; H, 5.17.
4
(
18
21
2
2
Found: C, 53.20; H, 5.26.
22
25
2
3
2
3
-(10-Methyl-2-phenothiazinyl)-octahydro-1,4-pyrido[2,1-c]-
53.41; H, 5.61.
oxazin-3-ol Hydrobromide (5). White solid. Yield 96%. mp 218.5−
2-(10-Acetyl-2-phenothiazinyl)-4-methyl-octahydro-1,4-benzox-
1
2
19.5 °C. H NMR (400 MHz, CDCl ): δ 1.56−1.91 (m, 4H, 8,9-H
azin-2-ol Hydrobromide (9). White solid. Yield 40%. mp 118−121 °C.
3
ax
1
and 2 × 7-H), 1.94−2.07 (m, 2H, 8-H and -OH), 2.32−2.43 (m, 1H,
H NMR (400 MHz, DMSO-d ): δ 1.24−1.39 (m, 4H, 5,8-H and 2 ×
eq
6
ax
9
-H ), 2.60−2.71 (m, 1H, 6-H , 2.79−2.85 (m, 1H, 6-H ), 3.16−3.24
7-H), 1.55−1.71 (m, 4H, 2 × 6-H and 5,8-H ), 1.85 (t, J = 12.91 Hz,
eq
ax)
eq
eq
(
(
4
m, 1H, 9a-H ), 3.33 (s, 3H, N-CH ), 3.40−3.43 (m, 1H, 4-H ), 3.82
1H, 4a-H ), 2.06 (s, 3H, CO-CH ), 2.50 (s, 1H, -OH), 2.67 (ds, J = 4.11
ax
3
ax
ax
3
dd, J = 3.13 Hz, J = 13.30 Hz, 1H, 1-H ), 4.16 (d, J = 8.81 Hz, 1H,
Hz, 3H, N-CH ), 3.00−3.14 (m, 1H, 3-H ), 3.51−3.64 (m, 1H, 3-H ),
1
2
eq
3
ax
eq
-H ), 4.44 (m, 1H, 1-H ), 6.77 (d, J = 8.02 Hz, 4-H, 1-H
3.98−4.04 (m, 1H, 8a-H ), 7.24 (t, J = 7.54 Hz, 1H, 7-H
eq
ax
ax
phenothiazine), 6.87 (dd, J1 = 1.50 Hz, J2 = 7.24 Hz, 1H, 3-H
phenothiazine), 7.04−7.13 (m, 5H, 1,6,7,8,9-H phenothiazine), 11.41
phenothiazine), 7.33 (t, J = 7.63 Hz, 1H, 8-H phenothiazine), 7.41 (d,
J = 8.02 Hz, 1H, 3-H phenothiazine), 7.50 (d, J = 6.46 Hz, 1H, 4-H
phenothiazine), 7.55−7.60 (m, 2H, 6,9-H phenothiazine), 7.68 (s, 1H,
1-H phenothiazine), 9.92 (brs, 1H, NH). Anal. Calcd for
C H BrN O S: C, 56.21; H, 5.54. Found: C, 56.55; H, 5.51.
(
brs, 1H, NH). 13C NMR (200 MHz, DMSO-d ): δ 21.69 (8-C
6
oxazine), 22.06 (7-C oxazine), 23.85 (9-C oxazine), 35.72 (N−CH ),
3
53.79 (6-C oxazine), 59.61 (4-C oxazine), 61.20 (9a-C oxazine), 61.85
2
3
27
2
3
(
(
1-C oxazine), 94.50 (3-C oxazine), 112.51 (9-C phenothiazine), 115.18
4a,5a-C phenothiazine), 120.29 (3-C phenothiazine), 122.23 (1-C
4-Methyl-2-(2-phenothiazinyl)-3,4-dihydro-2H-1,4-benzoxazin-2-ol
22
(10). To a solution of 2-methylaminophenol (2.03 mmol) in dry DMF
phenothiazine), 123.15 (7-C phenothiazine), 123.55 (6-C phenothia-
zine), 126.85 (8-C phenothiazine), 127.30 (4-C phenothiazine), 128.38
were added NaHCO (2.13 mmol) and 2-bromoacetyl-phenothiazine b
3
(2.23 mmol). After stirring at room temperature overnight, dichloro-
methane was added, and the mixture was washed with water and brine,
dried, and concentrated in vacuum. The residue was purified by flash
column chromatography on silica gel (ethyl acetate/petroleum ether
(
2-C phenothiazine), 141.27 (10a-C phenothiazine), 145.58 (9a-C
phenothiazine). Anal. Calcd for C H BrN O S·0.25H O: C, 55.56; H,
21
25
2
2
2
5.62. Found: C, 55.28; H, 5.73.
1
4
-Methyl-2-(10-methyl-2-phenothiazinyl)-octahydro-1,4-benzox-
1:10) to give 10 (31%) as a deep red semisolid. H NMR (400 MHz,
azin-2-ol Hydrobromide (6). Yellow solid. Yield 74%. mp 149−150 °C.
CDCl ): δ 3.13 (s, 3H, N-CH ), 3.46 (d, J = 11.74 Hz, 1H, 3-H
3
3
1
H NMR (400 MHz, CDCl ): δ 1.28−1.46 (m, 4H, 5,8-H and 2 × 7-
benzoxazine), 3.65 (d, J = 11.93 Hz, 1H, 3-H benzoxazine), 4.11 (s, 1H,
-OH), 5.61 (s, 1H, -NH), 6.66 (d, J = 7.63 Hz, 1H, 5-H benzoxazine),
6.84−6.90 (m, 2H, 1,3-H phenothiazine), 6.93 (d, J = 8.02 Hz, 1H, 4-H
phenothiazine), 6.98−7.04 (m, 3H, 6,7,8-H benzoxazine), 6.08−7.16
(m, 4H, 6,7,8,9-H phenothiazine). Anal. Calcd for C H N O S·H O:
3
ax
H), 1.77−1.84 (m, 1H, 6-H ), 1.90−1.96 (m, 2H, 6-H and -OH),
ax
eq
2
.02−2.11 (m, 1H, 8-H ), 2.16−2.22 (m, 1H, 5-H ), 2.72 (s, 3H,
eq
eq
N-CH ), 2.87−2.96 (m, 1H, 4a-H ), 3.32 (s, 3H, N-CH
3
ax
3
phenothiazine), 3.38−3.44 (m, 1H, 3-H ), 3.53 (d, J = 12.13 Hz, 1H,
ax
21 18
2
2
2
3
-H ), 4.41 (dt, J = 4.31 Hz, J = 9.59 Hz, 1H, 8a-H ), 6.77 (d, J = 8.22
C, 66.29; H, 5.31. Found: C, 66.36; H, 5.33.
eq
1
2
ax
Hz, 1-H phenothiazine), 6.84−6.89 (m, 1H, 3-H phenothiazine), 7.01−
4-Methyl-2-(2-phenothiazinyl)-3,4-dihydro-2H-1,4-benzothiazin-
2-ol (11). Benzothiazine derivative g (1 mmol) was dissolved in
7
.13 (m, 5H, 2,6,7,8,9-H phenothiazine), 11.48 (brs, 1H, NH). 13
C
NMR (200 MHz, DMSO-d ): δ 23.80 (6,7-C oxazine), 24.37 (5-C
anhydrous THF under argon, and BH /THF (1M, 7 mL) was added
3
6
oxazine), 24.66 (8-C oxazine), 31.02 (N−CH ), 35.69 (N−CH
dropwise. After stirring at room temperature for 1 h, water was added,
and the mixture was extracted with dichloromethane, washed with water
3
3
phenothiazine), 61.21 (3-C oxazine), 66.17 (4a-C oxazine), 70.38
(
1
(
8a-C oxazine), 94.12 (2-C oxazine), 112.51 (9-C phenothiazine),
15.21 (4a,5a-C phenothiazine), 120.27 (3-C phenothiazine), 122.26
1-C phenothiazine), 123.16 (7-C phenothiazine), 123.61 (6-C
and saturated NaHCO solution, and dried, and the solvent was distilled
off. The residue was purified by flash column chromatography on silica
3
gel (dichloromethane/petroleum ether 1:4) to give 11 (63%) as a brown
1
phenothiazine), 126.85 (8-C phenothiazine), 127.31 (4-C phenothia-
zine), 128.38 (2-C phenothiazine), 141.27 (10a-C phenothiazine),
1
0
solid. mp 128.5−129.5 °C. H NMR (400 MHz, CDCl
3
): δ 3.00 (s, 3H,
N−CH ), 3.11 (d, J = 11.74 Hz, 1H, 3-H benzothiazine), 3.41 (d, J =
3
45.61 (9a-C phenothiazine). Anal. Calcd for C H BrN O S·
11.93 Hz, 1H, 3-H benzothiazine), 3.87 (s, 1H, -OH), 5.81 (s, 1H,
-NH), 6.46 (d, J = 7.63 Hz, 1H, 5-H benzothiazine), 6.74−6.80 (m, 2H,
1,3-H phenothiazine), 6.83 (d, J = 8.02 Hz, 1H, 4-H phenothiazine),
6.88−6.94 (m, 3H, 6,7,8-H benzothiazine), 6.98−7.06 (m, 4H, 6,7,8,9-
H phenothiazine). 13C NMR (200 MHz, CDCl ): δ 40.74 (N-CH ),
2
2
27
2
2
.75H O: C, 55.40; H, 5.71. Found: C, 55.25; H, 5.62.
2
2
-(10-Acetyl-2-phenothiazinyl)-4-methylmorpholin-2-ol Hydro-
1
bromide (7). White solid. Yield 20%. mp 140−142 °C. H NMR (400
MHz, DMSO-d ): δ 2.06 (s, 3H, CO-CH ), 2.69 (s, 3H, N-CH ), 2.87
6
3
3
3
3
(
s, 1H, -OH), 3.03 (t, J = 10.47 Hz, 1H, 5-H ), 3.10−3.23 (m, 1H,
64.03 (3-C benzothiazine), 81.75 (2-C benzothiazine), 112.11 (5-C
benzothiazine), 112.27 (4a-C phenothiazine), 113.39 (9-C phenothia-
zine), 114.53 (3-C phenothiazine), 115.58 (5a-C phenothiazine),
119.94 (1-C phenothiazine), 120.10 (7-C benzothiazine), 120.43 (8a-
C benzothiazine), 122.74 (7-C phenothiazine), 125.43 (6-C benzothia-
zine), 126.63 (6-C phenothiazine), 126.72 (8-C phenothiazine), 126.82
(4-C phenothiazine), 127.46 (8-C benzothiazine), 129.02 (2-C
phenothiazine), 130.08 (9a-C phenothiazine), 140.16 (10a-C pheno-
thiazine), 143.18 (4a-C benzothiazine). Anal. Calcd for C H N OS ·
ax
5
1
7
-H ), 3.30 (d, J = 7.04 Hz, 2H, 2 × 3-H), 3.94 (dd, J = 3.13 Hz, J =
eq 1 2
2.71 Hz, 1H, 6-H ), 4.19 (dt, J = 2.36 Hz, J = 11.74 Hz, 1H, 6-H ),
eq
1
2
ax
.23−7.30 (m, 1H, 1-H phenothiazine), 7.34 (t, J = 8.02 Hz, 1H, 7-H
phenothiazine), 7.39 (d, J = 8.60 Hz, 1H, 3-H phenothiazine), 7.50 (d,
J = 7.63 Hz, 1H, 4-H phenothiazine), 7.55−7.62 (m, 2H, 6,8-H
phenothiazine), 7.68 (s, 1H, 9-H phenothiazine), 9.84 (brs, 1H, NH).
1
3
C NMR (200 MHz, DMSO-d ): δ 23.04 (COCH ), 43.42 (N−CH ),
6
3
3
5
(
1.92 (5-C oxazine), 57.46 (6-C oxazine), 59.44 (3-C oxazine), 93.86
2-C oxazine), 124.79 (1-C phenothiazine), 125.37 (3-C phenothia-
zine), 127.63 (7-C phenothiazine), 127.92 (6,9-C phenothiazine),
28.13 (8-C phenothiazine), 128.42 (4-C phenothiazine), 132.28 (10a-C
2
1
18
2
2
CH Cl : C, 56.35; H, 4.31. Found: C, 56.36; H, 4.08.
2 2
3.3. In Vitro Microsomal Lipid Peroxidation. Heat-inactivated
hepatic microsomes from untreated rats were prepared as described
1
2
578
dx.doi.org/10.1021/jm401842e | J. Med. Chem. 2014, 57, 2568−2581