Synthesis of potential biologically active 1,2-benzothiazin-3-yl- quinazolin-4(3H)-ones

Article abstract of DOI:10.1248/cpb.54.1175

A series of potential biologically active 2-(4-hydroxy-1,1-dioxido-2H-1,2- benzothiazin-3-yl)quinazolin-4(3H)-ones was synthesized in a straight forward manner by condensation of respective 4-hydroxy-1,2-benzothiazine-1,1-dioxides with anthranilamide followed by simple and high throughput cyclization of N-[2-(aminocarbonyl) phenyl]-4-hydroxy-1,2-benzothiazine-3-carboxamide-1,1- dioxides. All the synthesized compounds were subjected to preliminary evaluation for their biological activity against Gram positive and Gram negative bacteria. Some of the assayed compounds showed marked activity against Bacillus subtilis.

Full text of DOI:10.1248/cpb.54.1175

August 2006
Chem. Pharm. Bull. 54(8) 1175—1178 (2006)
1175
Synthesis of Potential Biologically Active 1,2-Benzothiazin-3-yl-
quinazolin-4(3H)-ones
b
Muhammad ZIA-UR-REHMAN, ,a,b Jamil Anwar CHOUDARY,b Saeed AHMAD,a and Hamid Latif SIDDIQUI
*
a Applied Chemistry Research Center, PCSIR Laboratories Complex; Lahore–54600, Pakistan: and b Institute of Chemistry,
University of The Punjab; Lahore, 54590 Pakistan. Received April 18, 2006; accepted May 9, 2006
A series of potential biologically active 2-(4-hydroxy-1,1-dioxido-2H-1,2-benzothiazin-3-yl)quinazolin-4(3H)-
ones was synthesized in a straight forward manner by condensation of respective 4-hydroxy-1,2-benzothiazine-
1,1-dioxides with anthranilamide followed by simple and high throughput cyclization of N-[2-(aminocar-
bonyl)phenyl]-4-hydroxy-1,2-benzothiazine-3-carboxamide-1,1-dioxides. All the synthesized compounds were
subjected to preliminary evaluation for their biological activity against Gram positive and Gram negative
bacteria. Some of the assayed compounds showed marked activity against Bacillus subtilis.
Key words 1,2-benzothiazin-3-yl-quinazolin-4(3H)-one; anthranilamide; antibacterial agent; 1,2-benzothiazine-3-carboxamide;
potassium tertiary butoxide
Benzothiazine derivatives possess versatile type of biologi- their thermal instability, and the environmental issues, butyl
cal activities.1) Among these, 1,2-benzothiazine-3-carboxam- pyridinium tetrafluoroborate [BuPy]BF4, a room temperature
ide-1,1-dioxides such as piroxicam,2) ampiroxicam3) and ionic liquid (RTIL) was used as a catalyst for these transfor-
meloxicam4) are well known for their analgesic and anti-in- mations. It is environmentally benign, easy to use due to sim-
flammatory activities. Some of the 3,4-dihydro-1,2-benzoth- ple product isolation, high yields and is economically
iazine-3-carboxylate 1,1-dioxide a-ketomide5) and P(2)–P(3) friendly having potential for recyclization.24) In the next step,
peptide mimetic aldehyde6) compounds act as potent calpain 1,2-benzothiazine-1,1-dioxides, (1a—d) and (2a—d) were
I inhibitors, while 1,4-benzothiazines generally possess sig- reacted with anthranilamide via condensation reaction in an
nificant antifungal activities.7,8)
inert medium (toluene or xylene) using 4 Å molecular sieves
Similarly, 3H-quinazolin-4-ones and their derivatives are in a Soxhelt apparatus. It provided highly pure products in
found to be antihypertensive, antifibrillatory, choleretic, an- good yields to form respective N-[2-(aminocarbonyl)phenyl]-
tiphlogistic,9) antimitotic, anticancer, and anticonvulsant 4-hydroxy-1,2-benzothiazine-3-carboxamide-1,1-dioxides
agents.10) They have also been successfully tested as CNS de- (Chart 2). Intramolecular cyclization of N-[2-(aminocar-
pressants,11) muscle relaxants12) and for their antineoplastic bonyl)phenyl]-4-hydroxy-1,2-benzothiazine-3-carboxamide-
activity.13) Another interesting characteristic of quinazolines 1,1-dioxides was then effected by their reaction with a base
is their antimicrobial activity against different species of (NaOH) in the presence of hydrogen peroxide. Carboxam-
pathogenic Gram negative bacteria, Gram positive bacteria ides (3a—h) were added in aliquots to a mixture of aque-
and fungi.14—20)
ous sodium hydroxide, hydrogen peroxide and ethanol; the
Keeping in view the potential biological activities of 4-hy- contents were refluxed for three to four hours. Products [(1,2-
droxy-1,2-benzothiazine-1,1-dioxides and 3H-quinazolin-4- benzothiazin-3-yl-quinazolin-4(3H)-ones (4a—h)] were ob-
ones, it was perceived that if both the heterocyclic moieties tained by acidifying the mixtures with dilute hydrochloric
are synergized in a single nucleus, the new compounds ob- acid in cold followed by extraction with an organic solvent
tained were likely to possess significant biological activities. such as dichloromethane. However, the reaction was found
In this quest, novel 1,2-benzothiazin-3-yl-quinazolin-4(3H)- sensitive to the amount of sodium hydroxide used and the
ones (4a to h) were synthesized from various alkyl 4-hy- portion-wise addition of the reactants. Sometimes, an orange
droxy-1,2-benzothiazine-1,1-dioxides (1, 2a—d), prepared coloured impurity appeared in the product in small amounts,
by literature methods,21,22) from simple substituted toluenes perhaps due to the hydrolysis of the amides (3a—h) with
(Chart 1) and subjected to antibacterial activity.
base. To avoid the difficulty, reaction was modified and con-
Chemistry N-Methylation of methyl 4-hydroxy-2H-1,2- ducted under anhydrous conditions; reaction was performed
benzothiazine-3-carboxylate-1,1-dioxides (1a—d) was car- by heating the amides (3a—h) with 1.2 equiv of potassium
ried by reaction with methyl iodide to get the corresponding
methylated compounds (2a—d). Usually for the alkylation of
such compounds, solvent such as DMF or DMSO is used in
the presence of strong bases such as NaH, metal alkoxides or
alkyl lithiums.23) Due to high boiling points of these solvents,
Chart 2. Synthesis of 2-(4-Hydroxy-1,1-dioxido-2H-1,2-benzothiazin-3-
Chart 1. N-Methylation of 1,2-Benzothiazine-3-carboxylate-1,1-dioxides
yl)quinazolin-4(3H)-ones
∗ To whom correspondence should be addressed. e-mail: rehman_pcsir@hotmail.com
© 2006 Pharmaceutical Society of Japan

1176
Vol. 54, No. 8
Table 1. Antibacterial Activity (MIC, mg mlꢀ1
Susceptible microorganisms
Bacillus subtilis Escherichia coli
20
)
tert-butoxide in anhydrous tert-butyl alcohol at 80 °C. By
conducting the cyclization under these conditions, the hy-
drolysis side products were avoided, and the reaction pro-
ceeded in very good isolated yields with no impurities de-
tected. Simple high throughput isolation was devised, in
which the reaction was diluted with water and acidified with
3 M hydrochloric acid to pH 5.5.
Antimicrobial Testing All the newly synthesized com-
pounds (dissolved in dimethylformamide) were subjected to
antimicrobial screening by determining the minimum in-
hibitory concentration (MIC) using the agar dilution tech-
nique.25)
The in vitro antimicrobial activity of the prepared com-
pounds (4a—h) against the Gram positive bacterium, Bacil-
lus subtilis and a Gram negative bacterium, Escherichia coli
was determined by preparing suspensions of each microor-
ganism to contain approximately 105—106 CFU (colony
forming units)/well. The test compounds were applied to
the wells at concentrations ranging from 200 to about
3.0 mg mlꢀ1 in dimethyl formamide solution, in addition to
the 0 (control), 1,2-benzothiazine-1,1-dioxides (1, 2a—d)
and the standard Tetracycline. The plates were incubated for
24 h at 37 °C and growth assessed by visual inspection. The
minimum inhibitory concentration (MIC) was defined as the
lowest concentration of inhibitor at which microbial growth
was not apparent disregarding a single colony or a faint haze
caused by the inoculums.
Compound
4a
—
4b
4c
4d
4e
4f
4g
4h
7
12
40
41
21
23
—
—
—
57
69
—
—
—
—
—
—
—
1a—d
2a—d
Tetracycline
0.25
0.35
Table 2. N-Methylation of 4-Hydroxy-2H-1,2-benzothiazine-3-carboxy-
late-1,1-dioxides
Entry
Reactant
Product
Reaction conditions Yield (%)a)
1
2
3
4
1a
1b
1c
1d
2a
2b
2c
2d
40 °C, 6 h
40 °C, 5 h
50 °C, 6 h
50 °C, 6 h
94
93
94
93
a) Isolated yields based on corresponding 4-hydroxy-2H-1,2-benzothiazine-3-car-
boxylate-1,1-dioxide.
Table 3. Reaction of Methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxy-
late-1,1-dioxides with Anthranilamide
Results
The MICs of the active compounds against the susceptible
pathogenic organisms are presented in Table 1. It was found
that all the newly synthesized compounds except 4h have in-
hibitory activity against Bacillus subtilis. The compounds 4b
and c caused inhibition against Escherichia coli, while com-
pounds 4a, d, f, g and h were found inactive or presented a
MIC more than 200 mg mlꢀ1.
Compound 4b showed highest activity against both the
strains (MICꢁ7.0 mg mlꢀ1 and 57.0 mg mlꢀ1). An insight to
the activities of different compounds obtained reveals that
these are more active against Bacillus subtilis (a gram posi-
tive bacterium) than that of Escherichia coli. Only the two
compounds 4b and c showed some activity against the later.
Also it is evident that compounds 4a—d are relatively more
active against Bacillus subtilis than 4e—h (N-methyl deriva-
tives of 4a—d) and this higher activity may be attributed to
the presence of two NH groups. Further, it seems that incor-
poration of an electronegative halogen atom at 7-position of
benzothiazine nucleus enhances the antimicrobial activity;
chloro compound 4b showed maximum (MICꢁ7.0 mg mlꢀ1)
while electron donating methyl substituted compound 4h ex-
hibited no activity.
In conclusion, the present study revealed that synergism of
two different heterocyclic systems, 4-hydroxy-1,2-benzoth-
iazine-1,1-dioxide and quinazolin-4(3H)-one to a new system
2-(4-hydroxy-1,1-dioxido-2H-1,2-benzothiazin-3-yl)quina-
zolin-4(3H)-ones could be useful as a template for future de-
velopment through modification or derivatization to design a
more potent biologically active compounds. The new skele-
ton may also possess other biological activities of the parent
ring systems.2—20)
Entry
Reactant
Product
Reaction time Yield (%)a)
1
2
3
4
5
6
7
8
1a
1b
1c
1d
2a
2b
2c
2d
3a
3b
3c
3d
3e
3f
8 h
8 h
8 h
8 h
12 h
12 h
12 h
12 h
75
73
72
76
72
71
75
70
3g
3h
a) Isolated yield based on corresponding methyl 4-hydroxy-2H-1,2-benzothiazine-3-
carboxylate-1,1-dioxide.
Table 4. Synthesis of 2-(4-Hydroxy-1,1-dioxido-2H-1,2-benzothiazin-3-
yl)quinazoline-4(3H)-ones
Entry
Reactant
Product
Reaction time Yield (%)a)
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
4a
4b
4c
4d
4e
4f
2.5 h
2.5 h
2.5 h
2.5 h
3 h
3 h
3 h
3 h
93
92
90
94
92
90
92
90
3g
3h
4g
4h
a) Isolated yield based on corresponding N-[2-(aminocarbonyl)phenyl]-4-hydroxy-
1,2-benzothiazine-3-carboxamide-1,1-dioxide.
Experimental
Melting points were taken on Gallenkemp melting point apparatus and are
uncorrected. 1H-NMR spectra were taken on the Bruker DPX-400 NMR
spectrometer, and chemical shifts are given in ppm downfield from TMS as
the internal standard. IR spectra were recorded in the spectral range of
4000—400 cmꢀ1 on Hitachi spectrometer, model 270-30. Mass spectra were

August 2006
1177
taken on Jeol JMS-HX110 H spectrometer. All the chemicals were pur- (m, 3H, C6H3); 8.48 (s, 2H, CONH2), 8.61 (br s, 1H, CONH), 13.09 (s, 1H,
chased from E. Merck, BDH or Fluka and used without purification. How-
OH); MS m/z: 439 [Mꢃꢃ2], 437, [Mꢃ], 392.97 [MꢃꢀCONH2], 273.97
ever, solvents were purified through distillation. Butyl pyridinium tetrafluo- [MꢃꢀCONHC6H4CONH2]. Anal. Calcd for C16H12BrN3O5S: C, 43.85; H,
roborate was synthesized according to the method described by Owens et 2.76; N, 9.59; Found: C, 43.77; H, 2.75; N, 9.70.
al.26) while methyl 4-hydroxy-1,2-benzothiazine-3-carboxylate-1,1-dioxides
(1a—d) were synthesized according to procedures given in literature.21,22)
(Chart 1).
N-(2-Carbamoylphenyl)-4-hydroxy-7-methyl-2H-1,2-benzothiazine-3-car-
boxamide-1,1-dioxide (3d): Yellow crystalline solid, mp 280—281 °C de-
1
comp; IR (KBr): 3367, 1673, 1337, 1178 cmꢀ1. H-NMR (CDCl3), d: 2.34
General Procedure of N-Methylation of Methyl 4-Hydroxy-2H-1,2- (s, 3H, ArCH3), 2.90 (s, 1H, NH), 7.21—7.63 (m, 4H, anthranilamide ring),
benzothiazine-3-carboxylate-1,1-dioxides Methyl 4-hydroxy-2H-1,2- 7.83—8.10 (m, 3H, C6H3); 8.46 (s, 2H, CONH2), 8.61 (br s, 1H, CONH),
benzothiazine-3-carboxylate-1,1-dioxide (10.0 mmol) and KOH (1.12 g; 13.08 (s, 1H, OH); MS m/z: 373 [Mꢃ], 329 [MꢃꢀCONH2], 210
20.0 mmol) was added to butyl pyridinium tetrafluoroborate (6.0 ml), and the [MꢃꢀCONHC6H4CONH2]. Anal. Calcd for C17H15N3O5S: C, 54.68; H,
mixture was stirred magnetically for 5 min. Then, methyl iodide (20.0 mmol) 4.05; N, 11.25; Found: C, 54.75; H, 3.96; N, 11.19.
was added in a single portion and stirring continued for 2—3 h (for reaction
conditions, see Table 2). After completion of the reaction, product was ex- boxamide-1,1-dioxide (3e): White crystalline solid, mp 250—252 °C. IR
tracted with chloroform (3ꢂ25 ml). The combined organic phases were (KBr): 3376, 1669, 1330, 1169 cmꢀ1 1H-NMR (CDCl3), d: 2.72 (s, 3H,
evaporated under reduced pressure to get the crude product which was crys- NCH3); 7.37—7.74 (m, 4H, anthranilamide ring), 7.79—8.03 (m, 4H,
N-(2-Carbamoylphenyl)-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-car-
.
tallized from methanol. After isolation of the product, remainder of the ionic C6H4); 8.41 (s, 2H, CONH2), 8.60 (br s, 1H, CONH), 13.10 (s, 1H, OH); MS
liquid was recovered by drying at vacuum followed by filtration of the sus- m/z: 373 [Mꢃ], 315 [MꢃꢀCONH2], 196 [MꢃꢀCONHC6H4CONH2]. Anal.
pension to remove the residual KOH and the formed potassium iodide.
Calcd for C17H15N3O5S: C, 54.68; H, 4.05; N, 11.25; Found: C, 54.70; H,
Methyl 4-Hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate-1,1- 3.95; N, 11.20.
dioxide (2a): White crystalline solid; mp 165 °C. IR (KBr): 3439, 1667,
N-(2-Carbamoylphenyl)-7-chloro-4-hydroxy-2-methyl-2H-1,2-benzo-
1319, 1160 cmꢀ1
.
1H-NMR (CDCl3), d: 2.95, (s, 3H, NCH3), 3.95 (s, 3H, thiazine-3-carboxamide-1,1-dioxide (3f): Pale yellow crystalline solid, mp
OCH3), 7.75—8.12 (m, 4H, ArH), 12.09 (s, 1H, OH). MS m/z: 269 [Mꢃ], 277 °C. IR (KBr): 3344, 1668, 1335, 1140, 1051 cmꢀ1. H-NMR (CDCl3),
1
254 [MꢃꢀCH3], 238 [MꢃꢀOCH3]. Anal. Calcd for C11H11NO5S: C, 49.06; d: 3.21 (s, 3H, NCH3); 7.32—7.71 (m, 4H, anthranilamide ring), 7.87—8.18
H, 4.12; N, 5.20; Found: C, 49.21; H, 4.24; N, 4.99.
Methyl 7-Chloro-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxy- OH); MS m/z: 409 [Mꢃꢃ2], 407 [Mꢃ], 363 [MꢃꢀCONH2], 244
late-1,1-dioxide (2b): White crystalline solid; mp 295—296 °C. IR (KBr):
[MꢃꢀCONHC6H4CONH2]. Anal. Calcd for C17H14ClN3O5S: C, 50.07; H,
3450, 1678, 1329, 1160, 1074 cmꢀ1
(m, 3H, C6H3); 8.42 (s, 2H, CONH2), 8.58 (br s, 1H, NH), 13.07 (s, 1H,
.
1H-NMR (CDCl3), d: 3.16, (s, 3H, 3.46; N, 10.30; Found: C, 50.14; H, 3.38; N, 10.36.
NCH3), 4.08 (s, 3H, OCH3), 7.89—8.34 (m, 3H, ArH), 12.17 (s, 1H, OH).
7-Bromo-N-(2-carbamoylphenyl)-4-hydroxy-2-methyl-2H-1,2-benzo-
MS m/z: 305 [Mꢃꢃ2], 303 [Mꢃ], 288 [MꢃꢀCH3], 272 [MꢃꢀOCH3]. Anal.
thiazine-3-carboxamide-1,1-dioxide (3g): Light yellow crystalline solid, mp
Calcd for C11H10ClNO5S: C, 43.50; H, 3.32; N, 4.61; Found: C, 43.39; H, 269 °C. IR (KBr): 3408, 1673, 1332, 1125, 1035 cmꢀ1. H-NMR (CDCl3),
1
3.35; N, 4.78.
Methyl 7-Bromo-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxy- (m, 3H, C6H3); 8.39 (s, 2H, CONH2), 8.64 (br s, 1H, NH), 13.17 (s, 1H,
late-1,1-dioxide (2c): White crystalline solid; mp 189—190 °C. IR (KBr):
OH); MS m/z: 453 [Mꢃꢃ2], 451 [Mꢃ], 407 [MꢃꢀCONH2], 288
3447, 1680, 1325, 1162, 1053 cmꢀ1 1H-NMR (CDCl3), d: 3.09, (s, 3H, [MꢃꢀCONHC6H4CONH2]. Anal. Calcd for C17H14BrN3O5S: C, 45.15; H,
d: 3.12 (s, 3H, NCH3); 7.35—7.70 (m, 4H, anthranilamide ring), 7.91—8.21
.
NCH3), 3.98 (s, 3H, OCH3), 7.81—8.22 (m, 3H, ArH), 12.22 (s, 1H, OH). 3.12; N, 9.29; Found: C, 45.06; H, 3.05; N, 9.37.
MS m/z: 349 [Mꢃꢃ2], 347 [Mꢃ], 332 [MꢃꢀCH3], 316 [MꢃꢀOCH3]. Anal.
N-(2-Carbamoylphenyl)-4-hydroxy-2,7-dimethyl-2H-1,2-benzothiazine-3-
Calcd for C11H10BrNO5S: C, 37.95; H, 2.89; N, 4.02; Found: C, 38.06; H, carboxamide-1,1-dioxide (3h): White crystalline solid, mp 264 °C. IR (KBr):
3.01; N, 4.11.
Methyl 4-Hydroxy-2,7-dimethyl-2H-1,2-benzothiazine-3-carboxylate-1,1- 2.95 (s, 3H, NCH3); 7.36—7.73 (m, 4H, anthranilamide ring), 7.77—8.10
3360, 1666, 1328, 1149 cmꢀ1 1H-NMR (CDCl3), d: 2.49 (s, 3H, ArCH3),
.
dioxide (2d): White crystalline solid; mp 141 °C. IR (KBr): 3393, 1675,
(m, 3H, C6H3); 8.44 (s, 2H, CONH2), 8.58 (br s, 1H, CONH), 13.15
1
1322, 1157 cmꢀ1. H-NMR (CDCl3), d: 2.44 (s, 3H, ArCH3), 3.26, (s, 3H, (s, 1H, OH); MS m/z: 387 [Mꢃ], 343 [MꢃꢀCONH2], 224 [Mꢃꢀ
NCH3), 3.93 (s, 3H, OCH3), 7.71—7.96 (m, 3H, ArH), 12.13 (s, 1H, OH). CONHC6H4CONH2]. Anal. Calcd for C18H17N3O5S: C, 55.80; H, 4.42; N,
MS m/z: 283 [Mꢃ], 268 [MꢃꢀCH3], 252 [MꢃꢀOCH3]. Anal. Calcd for 10.85; Found: C, 55.71; H, 4.48; N, 10.91.
C12H13NO5S: C, 50.87; H, 4.63; N, 4.94; Found: C, 50.88; H, 4.57; N, 4.88.
General Procedure of Synthesis of 2-(4-Hydroxy-1,1-dioxido-2H-
General Procedure of Synthesis of N-(2-Carbamoylphenyl)-4-hy- 1,2-benzothiazin-3-yl)quinazolin-4(3H)-ones. A. Using H2O2 N-[2-
droxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxides A mixture of (Aminocarbonyl)phenyl]-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide-
methyl 4-hydroxy-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide (8.51 g; 1,1-dioxide (6.76 mmol) was added portion-wise to a solution of sodium hy-
33.33 mmol), anthranilamide (5.0 g; 36.72 mmol) and xylene (250 ml) was
droxide (0.54 g; 13.5 mmol) and hydrogen peroxide solution (2.5 ml; 30%)
refluxed (for reaction conditions, see Table 3) under nitrogen atmosphere in in water (20 ml). Ethanol (7.0 ml) was added and the resulting mixture was
a Soxhlet apparatus having Linde type 4 Å molecular sieves. Three fourth of heated under reflux for 3 h, cooled and evaporated under vacuum. The re-
the xylene was then distilled off and the remaining contents were allowed to sulted solid was treated with 2 N hydrochloric acid (4.0 ml) followed by ex-
stand overnight at room temperature. Crystals were filtered off, washed with traction with dichloromethane (3ꢂ15 ml). The combined organic extracts
diethyl ether and recrystallized from ethanol to get the required compound.
were washed successively with saturated aqueous sodium bicarbonate solu-
N-(2-Carbamoylphenyl)-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide-
tion (3ꢂ10 ml) and brine (5 ml) followed by drying with magnesium sul-
1,1-dioxide (3a): Bright yellow crystalline solid, mp 265 °C. IR (KBr): 3358, phate and evaporation of solvent under vacuum. Recrystallization from chlo-
1666, 1344, 1180 cmꢀ1. 1H-NMR (CDCl3), d: 2.88 (s, 1H, NH); 7.20—7.64 roform afforded light yellow product.
(m, 4H, anthranilamide ring), 7.84—8.10 (m, 4H, C6H4); 8.47 (s,
B. Using KOBut/tBuOH N-[2-(Aminocarbonyl)phenyl]-4-hydroxy-
2H, CONH2), 8.58 ( br s, 1H, NH), 13.12 (s,1H, OH); MS m/z: 359 [Mꢃ], 2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide (5.0 mmol) was sus-
315 [MꢃꢀCONH2], 196 [MꢃꢀCONHC6H4CONH2]. Anal. Calcd for pended in tert-butyl alcohol (10.0 ml) followed by addition of potassium
C16H13N3O5S: C, 53.48; H, 3.65; N, 11.69; Found: C, 53.51; H, 3.58; N, tert-butoxide (6.0 mmol). The resulting mixture was heated at reflux for a
11.73.
time till completion (given in Table 4). Water (15 ml) was added after cool-
N-(2-Carbamoylphenyl)-7-chloro-4-hydroxy-2H-1,2-benzothiazine-3-car- ing the mixture and subsequently the contents were acidified by adding di-
boxamide-1,1-dioxide (3b): Light yellow crystalline solid, mp 289—290 °C. lute HCl to Congo Red. Precipitates were washed with water and dried in
1
IR (KBr): 3358, 1670, 1341, 1181, 1078 cmꢀ1. H-NMR (CDCl3), d: 2.92 vacuum to get the crystalline product.
(s, 1H, NH); 7.19—7.66 (m, 4H, anthranilamide ring), 7.81—8.14
2-(4-Hydroxy-1,1-dioxido-2H-1,2-benzothiazin-3-yl)quinazolin-4(3H)-
(m, 3H, C6H3); 8.44 (s, 2H, CONH2), 8.57 (br s, 1H, CONH), 12.98 (s, 1H, one (4a): Yellow crystalline solid, mp 263—265 °C. IR (KBr): 3398, 1668,
OH); MS m/z: 395 [Mꢃꢃ2], 393 [Mꢃ], 349 [MꢃꢀCONH2], 230 1331, 1170 cmꢀ1 1H-NMR (CDCl3), d: 2.91 (s, 1H, NH); 7.42—7.92 (m,
.
[MꢃꢀCONHC6H4CONH2]. Anal. Calcd for C16H12ClN2O5S: C, 48.80; H, 8H, ArH); 9.02 (br s, CONH), 13.07 (s, 1H, OH). MS m/z: 341 [Mꢃ], 196
3.07; N, 10.67; Found: C, 48.73; H, 3.13; N, 10.77.
7-Bromo-N-(2-carbamoylphenyl)-4-hydroxy-2H-1,2-benzothiazine-3-car-
[Mꢃꢀquinazolin-4(3H)-one]. Anal. Calcd for C16H11N3O4S: C, 50.07; H,
3.46; N, 10.30; Found: C, 50.11; H, 3.38; N, 10.24.
boxamide-1,1-dioxide (3c): Cream coloured crystalline solid, mp 271—
2-(7-Chloro-4-hydroxy-1,1-dioxido-2H-1,2-benzothiazin-3-yl)quinazolin-
1
273 °C. IR (KBr): 3275, 1676, 1337, 1184, 1039 cmꢀ1. H-NMR (CDCl3), 4(3H)-one (4b): Light yellow crystalline solid, mp 249—254 °C. IR (KBr):
d: 2.95 (br s, 1H, NH); 7.21—7.72 (m, 4H, anthranilamide ring), 7.78—8.19
3408, 1671, 1321, 1165, 1057 cmꢀ1. 1H-NMR (CDCl3), d: 2.99 (s, 1H, NH);

1178
Vol. 54, No. 8
7.51—7.95 (m, 7H, ArH); 9.08 (br s, CONH), 13.10 (s, 1H, OH). MS m/z: References
377 [Mꢃꢃ2], 375 [Mꢃ], 229.96 [Mꢃꢀquinazolin-4(3H)-one]. Anal. Calcd
for C16H10ClN3O4S: C, 51.14; H, 2.68; N, 11.18; Found: C, 50.99; H, 2.74;
N, 11.07.
1) Vidal A., Madelmont J. C., Mounetou E., Synthesis, 2006, 591—594
(2006).
2) Lombardino J. G., Wiseman E. H., Mclamore W., J. Med. Chem., 14,
1171—1175 (1971).
3) Marfat A., Annual Drug Report, 1987, 202; US Patent, 4551452
(1985).
4) Turck D., Busch U., Heinzel G., Narjes H., Nehmiz G., Clin. Pharma-
col., 36, 79—84 (1996).
2-(7-Bromo-4-hydroxy-1,1-dioxido-2H-1,2-benzothiazin-3-yl)quinazolin-
4(3H)-one (4c): Off white crystalline solid, mp 245—248 °C. IR (KBr):
3395, 2934, 1666, 1328, 1160, 1032 cmꢀ1 1H-NMR (CDCl3), d: 2.91 (s,
.
1H, NH); 7.32—8.08 (m, 7H, ArH); 9.16 (br s, CONH), 13.14 (s, 1H, OH).
MS m/z: 421 [Mꢃꢃ2], 419 [Mꢃ], 273.92 [Mꢃꢀquinazolin-4(3H)-one].
Anal. Calcd for C16H10BrN3O4S: C, 45.73; H, 2.40; N, 10.00; Found: C,
45.65; H, 2.49; N, 9.92.
5) Bihovsky R., Tao M., Mallamo J. P., Wells G. J., Bioorg. Med. Chem.
Lett., 14, 1035—1038 (2004).
2-(4-Hydroxy-7-methyl-1,1-dioxido-2H-1,2-benzothiazin-3-yl)quina-
zolin-4(3H)-one (4d): Off white crystalline solid, mp 254 °C. IR (KBr):
6) Bihovsky R., Tao M., Mallamo J. P., Wells G. J., J. Med. Chem., 44,
3488—3503 (2001).
7) Baruffini A., Pagani G., Amoretti L., Il Farmaco, 22, 528—534
(1967).
8) Fringuelli R., Schiaffella F., Vecchiarelli A., J. Chemother., 13, 9—14
(2001).
9) Bekhit A. A., Habbib N. S., Bekhit A. El., Boll. Chim. Farm., 140,
297—301 (2001).
3390, 1670, 1328, 1166 cmꢀ1
.
1H-NMR (CDCl3), d: 2.38 (s, 3H, ArCH3),
2.94 (s, 1H, NH); 7.47—7.87 (m, 7H, ArH); 8.98 (br s, CONH), 13.00 (s,
1H, OH). MS m/z: 355 [Mꢃ], 210 [Mꢃꢀquinazolin-4(3H)-one]. Anal. Calcd
for C17H13N3O4S: C, 57.46; H, 3.69; N, 11.82; Found: C, 57.39; H, 3.77; N,
11.86.
2-(4-Hydroxy-2-methyl-1,1-dioxido-2H-1,2-benzothiazin-3-yl)quina-
zolin-4(3H)-one (4e): White crystalline solid, mp 320 °C decomp. IR (KBr):
10) Jiang J. B., Hesson D. P., Dusak B. A., Dexter D. L., Kang G. T., J.
Med. Chem., 33, 1721—1728 (1990).
3406, 2927, 1678, 1332, 1169 cmꢀ1 1H-NMR (CDCl3), d: 2.63 (s, 1H,
.
NCH3), 3.07 (s, 1H, NH); 7.44—7.89 (m, 8H, ArH), 9.09 (br s, CONH), 11) Tani J., Yamada Y., Oine T., Ochiai T., Ishida R., Inoue I., J. Med.
13.11 (s, 1H, OH). MS m/z: 355 [Mꢃ], 210 [Mꢃꢀquinazolin-4(3H)-one].
Chem., 22, 95—99 (1979).
Anal. Calcd for C17H13N3O4S: C, 57.46; H, 3.69; N, 11.82; Found: C, 57.39; 12) Ochiai T., Ishida R., Jpn. J. Pharmacol., 32, 427—438 (1982).
H, 3.76; N, 11.90.
13) Raffa D., Daidone G., Schillaci D., Maggio B., Plescia F., Pharmazie,
54, 251—254 (1999).
2-(7-Chloro-4-hydroxy-2-methyl-1,1-dioxido-2H-1,2-benzothiazin-3-
yl)quinazolin-4(3H)-one (4f): Pale yellow crystalline solid, mp 300 °C de- 14) Robert J. A., Russell H. E., J. Med. Chem., 15, 335—336 (1972).
comp. IR (KBr): 3395, 2939, 1678, 1342, 1175, 1071 cmꢀ1 1H-NMR 15) Jantova S., Greif G., Spirkova K., Stankovsky S., Oravcova M., Folia
.
(CDCl3), d: 2.69 (s, 3H, NCH3), 7.51—8.13 (m, 7H, ArH), 9.09 (br s,
Microbiol. (Praha), 45, 133—137 (2000).
CONH), 13.12 (s, 1H, OH). MS m/z: 391 [Mꢃꢃ2], 389 [Mꢃ], 244 16) Guersoy A., Illhan N., Farmaco, 50, 559—562 (1995).
[Mꢃꢀquinazolin-4(3H)-one]. Anal. Calcd for C17H12ClN3O4S: C, 52.38; H, 17) Pandeya S. N., Sriram D., Nath G., DeClereq E., Pharm. Acta Helv.,
3.10; N, 10.78; Found: C, 52.47; H, 3.04; N, 10.85.
74, 11—17 (1999).
2-(7-Bromo-4-hydroxy-2-methyl-1,1-dioxido-2H-1,2-benzothiazin-3-
yl)quinazolin-4(3H)-one (4g): Yellow crystalline solid, mp 290—293 °C. IR
18) Caroll S. S., Stahlhut M., Greb J., Olsen D. B., J. Biol. Sci., 269,
32351—32359 (1994).
(KBr): 3403, 2937, 1675, 1339, 1175, 1028 cmꢀ1 1H-NMR (CDCl3), d: 19) Lopez S. E., Rosales M. E., Canelon C. E., Valverode E. A., Narvaez
.
2.70 (s, 3H, NCH3), 7.48—8.08 (m, 7H, ArH), 9.17 (br s, CONH), 13.08 (s,
R. C., Charris J. E., Giannini F. A., Enriz R. D., Carrasco M., Zacchino
S., Hetrocycl. Commun., 7, 473—480 (2000).
1H, OH). MS m/z: 499 [Mꢃꢃ2], 497 [Mꢃ], 288 [Mꢃꢀquinazolin-4(3H)-
one]. Anal. Calcd for C17H12BrN3O4S: C, 47.02; H, 2.79; N, 9.68; Found: C, 20) Farghaly A. O., Moharram A. M., Boll. Chim. Farm., 138, 280—289
46.94; H, 2.86; N, 9.75. (1999).
2-(4-Hydroxy-2,7-dimethyl-1,1-dioxido-2H-1,2-benzothiazin-3-yl)quina- 21) Kwon S. K., Park M. S., Arzneium-Forsch./Drug Res., 46, 966—971
zolin-4(3H)-one (4h): White crystalline solid, mp 280 °C decomp. IR (KBr): (1996).
3391, 2930, 1662, 1336, 1174 cmꢀ1 1H-NMR (CDCl3), d: 2.38 (s, 3H, 22) Rehman M. Z., Anwar J., Ahmad S., Bull. Korean Chem. Soc., 26,
ArCH3), 2.74 (s, 3H, NCH3), 7.46—7.95 (m, 7H, ArH), 8.99 (br s, CONH), 1771—1775 (2005).
13.04 (s, 1H, OH). MS m/z: 369 [Mꢃ], 224 [Mꢃꢀquinazolin-4(3H)-one]. 23) Nunomoto S., Kawakami Y., Yamashita Y., Takeuchi H., Eguchi S., J.
.
Anal. Calcd for C18H15N3O4S: C, 58.53; H, 4.09; N, 11.38; Found: C, 58.46;
H, 4.16; N, 11.47.
Chem. Soc., Perkin Trans. 1, 1990, 111—114 (1990).
24) Le Z. G., Chen Z. C., Hu Y., Zheng Q. G., Synthesis, 2004, 208—212
(2004).
Acknowledgements The authors greatly appreciate HEJ Research Insti- 25) Colle J. G., Duguid J. P., Fraser A. G., Marmion B. P., “Practical Med-
tute, Karachi and Department of Chemistry, Loughborough University,
LE11 3TU, Loughborough, Leicestershire for the analysis of compounds.
ical Biology,” 13th ed., ed. by Mackie T. J., McCartney J. E., Churchill
Livingstone, London, UK, 1989.
We are also grateful to Mr. Asrar Ahmad Kazi (PSO) and Mr. Karimullah 26) Owens G. S., Abu-Omer M. M., J. Mol. Catal. A: Chem., 187, 215—
(JTO) for their cooperation at PCSIR Laboratories. 221 (2002).