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F. Varano et al. / Il Farmaco 53 (1998) 752–757
(Na2SO4) and evaporated at reduced pressure to yield
an oil which solidified when treated with a mixture of
50% diethyl ether/40–60°C petroleum ether. The solid
was collected and recrystallized.
ture, the lithium diisopropylamide solution was again
cooled to 0°C and the benzothiazine 8 (0.85 mmol) was
added. The dark red resulting solution, still at 0°C and
under nitrogen atmosphere, was then added with a
solution of the suitable aralkyl chloride (0.85 mmol) in
anhydrous THF (4 ml). The solution was stirred for 2 h
at 0°C and for 2 h at room temperature, diluted with
water (20 ml), acidified with glacial acetic acid and then
extracted with diethyl ether (3×10 ml). The organic
phases were washed with a solution of sodium hydro-
gen carbonate (saturated solution, 10 ml), water (10
ml), dried (Na2SO4) and evaporated at reduced pressure
to yield an oily residue which became solid by treat-
ment with diethyl ether/40–60°C petroleum ether. The
solid was collected and recrystallized.
1
1a: m.p. 189–193°C (toluene), 50% yield. H NMR
(DMSO-d6): 3.31 (d, 2H, CH2, J=6.2 Hz), 5.22 (t, 1H,
CH, J=6.2 Hz), 7.13–7.26 (m, 6H, ar), 7.54 (d, 1H, ar,
J=1.5 Hz), 11.47 (s, 1H, NH). IR: 3200, 1710.
1
1b: m.p. 224–227°C (ethanol), 35% yield. H NMR
(DMSO-d6): 3.32 (d, 1H, CH2, J=6.2 Hz), 5.34 (t, 1H,
CH, J=6.2 Hz), 7.17–7.44 (m, 4H, ar), 7.52–7.57 (m,
2H, ar), 11.52 (s, 1H, NH). IR: 3220, 3150, 1700.
4.1.8. 2-Arylidene-6,8-dichloro-3,4-dihydro-3-oxo-
2H-1,4-benzothiazine-1,1-dioxides (Z or E isomer)
(2a-b)
11a: m.p. 185–187°C (75–120°C ligroin/ethyl ac-
1
A mixture of 9 (0.38 mmol) and the suitable aryl
aldehyde (1.88 mmol) was heated at 200°C for 30 min.
After cooling the mixture was treated with diethyl ether
to yield a solid which was collected and recrystallized.
2a: m.p. 269–271°C (acetonitrile), 50% yield. 1H
NMR (DMSO-d6): 7.27 (d, 1H, ar, J=2.0 Hz), 7.46–
7.60 (m, 4H, ar), 7.97 (d, 2H, ar, J=7.0 Hz), 8.11 (s,
1H, CH), 11.7 (s, 1H, NH). IR: 3200, 1690.
2b: m.p. 277–279°C (acetonitrile), 38% yield. 1H
NMR (DMSO-d6): 7.28 (s, 1H, ar), 7.45 (t, 1H, ar,
J=8.1 Hz), 7.59 (s, 1H, ar), 7.75 (d, 1H, ar, J=8.1
Hz), 7.89 (d, 1H, ar, J=8.1 Hz), 8.12 (s, 1H, ar/CH),
8.21 (s, 1H, CH/ar), 11.72 (s, 1H, NH). IR: 3210, 3140,
1690.
etate), 40% yield. H NMR (DMSO-d6): 2.79 (dd, 1H,
CH2, J=14.0, 9.0 Hz), 3.16 (dd, 1H, CH2, J=14.0, 5.8
Hz), 3.99 (dd, 1H CH, J=9.0, 5.8 Hz), 6.97 (d, 1H, ar,
J=2.0 Hz), 7.14–7.32 (m, 6H, ar), 10.96 (s, 1H, NH).
IR: 3200, 1675.
11b: m.p. 187–189°C (75–120°C ligroin/ethyl ac-
1
etate), 29% yield. H NMR (DMSO-d6): 2.81 (dd, 1H,
CH2, J=9.0, 2.5 Hz), 3.13 (dd, 1H, CH2, J=9.0, 6.2
Hz), 4.02 (dd, 1H, CH, J=6.2, 2.5 Hz), 6.98 (s, 1H,
ar), 7.19–7.40 (m, 5H, ar), 11.01 (s, 1H, NH). IR: 3200,
1670.
4.1.11. 2-Aralkyl-6,8-dichloro-3,4-dihydro-3-oxo-
2H-1,4-benzothiazine-1-oxides (mixture of
diastereomers) (4a-b)
4.1.9. (9)-2-Arylidene-6,8-dichloro-3,4-dihydro-3-
oxo-2H-1,4-benzothiazine-1-oxides (Z or E isomer)
(3a-b)
Compound 11a or 11b (0.46 mmol) was added to a
solution of m-CPBA (55%, 0.7 mmol) in chloroform
(20 ml). The solution was stirred at room temperature
for 1 h, extracted with a solution of sodium hydrogen
carbonate (saturated solution, 15 ml) and then with
water (2×10 ml). The organic phases were dried
(Na2SO4) and evaporated at reduced pressure to yield
an oily residue which became solid upon treatment with
diethyl ether. Attempts to separate the two
diastereomers were performed (i) by column chro-
matography, eluting system ethyl acetate/chloroform
(7:3) and then (ii) by recrystallization from
nitromethane.
Triethyl amine (0.8 mmol) and the suitable aryl alde-
hyde (1.6 mmol) were successively added to a suspen-
sion of 10 (0.8 mmol) in benzene (20 ml). The mixture
was refluxed for 4 h. Evaporation of the solvent at
reduced pressure yielded a yellow oil which became
solid upon treatment with a 50% mixture of diethyl
ether/40–60°C petroleum ether. The solid was collected
and recrystallized.
1
3a: m.p. 283–285°C (ethanol), 49% yield. H NMR
(DMSO-d6): 7.26 (d, 2H, ar, J=1.2 Hz), 7.53–7.73 (m,
6H, ar), 12.02 (s, 1H, NH). IR: 3200, 1680, 1650.
3b: m.p. 277–279°C (dimethylformamide/water),
1
4a: 38% yield. H NMR (DMSO-d6): 2.75–3.72 (m,
CH2), 4.45–4.62 (m, H-2), 7.15–7.55 (m, ar), 11.40 (br
1
43% yield. H NMR (DMSO-d6): 7.26–7.30 (m, 2H,
s, NH).
1
ar), 7.58–7.77 (m, 5H, ar), 12.02–12.09 (br s, 1H, NH).
IR: 3200, 1690.
4b: 40% yield. H NMR (DMSO-d6): 2.69–3.70 (m,
CH2), 4.53–4.65 (m, H-2), 7.13–7.58 (m, ar), 11.36
(br s, NH).
4.1.10. (9)-2-Aralkyl-6,8-dichloro-3,4-dihydro-2H-
1,4-benzothiazin-3-ones (11a-b)
4.2. Biochemistry
A solution of n-butyl lithium in hexane (1.6 M, 1.33
ml) was added, at 0°C and under nitrogen atmosphere,
to a stirred solution of diisopropylamine (1.7 mmol) in
anhydrous THF (4 ml). After 30 min at room tempera-
Crude synaptic membranes were prepared from cere-
bral cortices of male Sprague–Dawley rats (170–250
g). The tissue was homogenized in 20 vol. of ice-cold