Studies on quinazolines and 1,2,4-benzothiadiazine 1,1-dioxides. 8. Synthesis and pharmacological evaluation of tricyclic fused quinazolines and 1,2,4-benzothiadiazine 1,1-dioxides as potential α1-adrenoceptor antagonists

Article abstract of DOI:10.1021/jm970159v

A series of 2-substituted methyl 2,3-dihydroimidazo[1,2-c]quinazolin- 5(6H)-ones (4), 3-substituted methyl 2,3-dihydroimidazo[1,2-c]quinazolin- 5(6H)-ones (5), 3-substituted methyl 2,3-dihydro-5H-thiazolo[2,3- b]quinazolin-5-ones (15a,b), 3-substituted methyl 2,3-dihydroimidazo[2,1- b]quinazolin-5(1H)-ones (16a,b), 3-substituted methyl 2,3-dihydro-1H- imidazo[1,2-b][1,2,4]benzothiadiazine 5,5-dioxides (33a,b), 2-substituted methyl imidazo[1,2-c]quinazolin-5(6H)-ones (42-45a,b), 3-substituted methyl imidazo[1,2-c]quinazolin-5(6H)-ones (50-53a,b), 3-substituted methyl 5H- thiazolo[2,3-b]quinazolin-5-ones (55-56a,b), and 3-substituted methyl 5- (methylthio)-2,3-dihydroimidazo[1,2-c]quinazoline (57) were synthesized as compound 1 conformational rigid congeners for pharmacological evaluation as potential α₁-adrenoceptor antagonists. Compounds 4, 5, 33a,b, 44a,b, 45a,b, 52a,b, 53a,b, and 57 were found to possess high affinity for the α₁- adrenoceptor. Compounds 5 and 57 were the most highly selective and potent α₁ antagonists with K(i) = 0.21 ± 0.02 and 0.90 ± 0.08 nM, respectively. The S-enantiomers of these two compounds (K(i) = 0.13 ± 0.01 nM for (S)-(- )-5; K(i) = 1.0 ± 0.2 nM for (S)-(+)-57) were 144-200-fold more potent than the R-enantiomers (K(i) = 26 ± 8 nM for (R)-(+)-5; K(i) = 144 ± 23 nM for (R)-(-)-57). Compound 4 showed 8-fold higher affinity to α1A-AR better than α1B-AR. These compounds possessed weak to no activity against the 5-HT1A receptor.

Full text of DOI:10.1021/jm970159v

3128
J . Med. Chem. 1998, 41, 3128-3141
Articles
Stu d ies on Qu in a zolin es a n d 1,2,4-Ben zoth ia d ia zin e 1,1-Dioxid es. 8.1,2
Syn th esis a n d P h a r m a cologica l Eva lu a tion of Tr icyclic F u sed Qu in a zolin es a n d
1,2,4-Ben zoth ia d ia zin e 1,1-Dioxid es a s P oten tia l r1-Ad r en ocep tor An ta gon ists
J i-Wang Chern,*,† Pao-Luh Tao, Kuang-Chao Wang, Alexander Gutcait,§ Shiou-Wen Liu,† Mao-Hsiung Yen,
Shu-Lan Chien,‡ and J iann-Kuo Rong
School of Pharmacy, College of Medicine, National Taiwan University, No. 1, Section 1, J en-Ai Road, Taipei 100,
Taiwan, Republic of China, and Department of Pharmacology and Institute of Pharmacy, National Defense Medical Center,
Taipei 100, Taiwan, Republic of China
Received March 11, 1997
A series of 2-substituted methyl 2,3-dihydroimidazo[1,2-c]quinazolin-5(6H)-ones (4), 3-substi-
tuted methyl 2,3-dihydroimidazo[1,2-c]quinazolin-5(6H)-ones (5), 3-substituted methyl 2,3-
dihydro-5H-thiazolo[2,3-b]quinazolin-5-ones (15a ,b), 3-substituted methyl 2,3-dihydroimidazo-
[2,1-b]quinazolin-5(1H)-ones (16a ,b ), 3-substituted methyl 2,3-dihydro-1H-imidazo[1,2-
b][1,2,4]benzothiadiazine 5,5-dioxides (33a ,b), 2-substituted methyl imidazo[1,2-c]quinazolin-
5(6H)-ones (42-45a ,b), 3-substituted methyl imidazo[1,2-c]quinazolin-5(6H)-ones (50-53a ,b),
3-substituted methyl 5H-thiazolo[2,3-b]quinazolin-5-ones (55-56a ,b), and 3-substituted methyl
5-(methylthio)-2,3-dihydroimidazo[1,2-c]quinazoline (57) were synthesized as compound 1
conformational rigid congeners for pharmacological evaluation as potential R1-adrenoceptor
antagonists. Compounds 4, 5, 33a ,b, 44a ,b, 45a ,b, 52a ,b, 53a ,b, and 57 were found to possess
high affinity for the R1-adrenoceptor. Compounds 5 and 57 were the most highly selective
and potent R1 antagonists with Ki ) 0.21 ( 0.02 and 0.90 ( 0.08 nM, respectively. The
S-enantiomers of these two compounds (Ki ) 0.13 ( 0.01 nM for (S)-(-)-5; Ki ) 1.0 ( 0.2 nM
for (S)-(+)-57) were 144-200-fold more potent than the R-enantiomers (Ki ) 26 ( 8 nM for
(R)-(+)-5; Ki ) 144 ( 23 nM for (R)-(-)-57). Compound 4 showed 8-fold higher affinity to
R1A-AR better than R1B-AR. These compounds possessed weak to no activity against the
5-HT1A receptor.
In tr od u ction
fectively lower blood pressure by antagonizing the R1-
adrenoceptor. Our laboratories are interested in preparing
unique cardiovascular agents based on the quinazoline
ring system.9 Addition of a (2-methoxyphenyl)pipera-
zine side chain at the 2- or 3-position of the angular
tricyclic 2,3-dihydroimidazo[1,2-c]quinazoline ring sys-
tem of SGB-1534 resulted in the formation of potent
antihypertensive agents such as 2-[[4-(2-methoxyphe-
nyl)piperazin-1-yl]methyl]-2,3-dihydroimidazo[1,2-c]-
quinazolin-5(6H)-one (4) and 3-[[4-(2-methoxyphenyl)-
piper a zin -1-yl]m et h yl]-2,3-dih ydr oim ida zo[1,2-c]-
quinazolin-5(6H)-one (5) that selectively antagonized
the R1-adrenoceptor.9 However, the stereochemical
effect of the substituent in compounds 4 and 5 on the
binding affinity to the R1-adrenoceptor has not been
studied. Furthermore, 2-[[4-(2-methoxyphenyl)piper-
azin-1-yl]ethyl]-1,2,4-benzothiadiazin-3(4H)-one 1,1-
dioxide (6),10 a bioisostere formed by replacing the
quinazoline ring system with 1,2,4-benzothiadiazine 1,1-
dioxide, was synthesized and characterized as a potent
antihypertensive agent. On the basis of these active
molecules, we presumed that the 1-arylpiperazine side
chain might be an essential moiety for lowering blood
pressure.11 Thus, the conformational effects of 2,3-
dihydroimidazo[1,2-c]quinazoline derivatives such as
Blocking the action of adrenergic neurotransmitters
on the R1-adrenoceptor is a well-known approach for the
clinical treatment of hypertension.3 It was recently
reported that the antihypertensive effects of several R1-
adrenoceptor antagonists were associated with favorable
changes in serum cholesterol profiles,4 and there are
several R1-antagonists currently being studied for the
treatment of dysuria secondary to benign prostatic
hypertrophy.5 The quinazoline-2,4-dione derivative 1,6
which possesses a ((2-methoxyphenyl)piperazinyl)ethyl
side chain at the 3-position, is a potent antihypertensive
agent that acts via the R1-adrenoceptor. A literature
survey revealed that the addition of a (2-methoxyphe-
nyl)piperazine side chain onto different heterocycles,
such as thienopyrimidinediones (2)7 and pyrimido[5,4-
b]indole (3) derivatives,8 provides compounds that ef-
* Corresponding author address: Prof. J i-Wang Chern, School of
Pharmacy, National Taiwan University, No. 1, Section 1, J en-Ai Road,
Taipei, Taiwan 100, ROC. Tel: 886-2-2393-9462. Fax: 886-2-2393-
4221. E-mail: chern@jwc.mc.ntu.edu.tw.
† Department of Pharmacology.
‡ Institute of Pharmacy.
§ On leave from Department of Organic Chemistry, Faculty of
Chemical Engineering, Riga Technical University, Azenes st. 14/24,
Riga, LV 1048, Latvia.
S0022-2623(97)00159-3 CCC: $15.00 © 1998 American Chemical Society
Published on Web 07/21/1998

Quinazolines and 1,2,4-Benzothiadiazine 1,1-Dioxides
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 17 3129
Sch em e 1a
a
(i) CS2, NaOH, ethanol/water (5/1), reflux, 24 h, 86%; (ii) CH3I, H2O, rt, 76%; (iii) 60% mCPBA, CHCl3, rt, 1 h, 85%; (iv) allyl bromide,
NaOH, H2O, rt, 30 min, 98% for 11; (v) allylamine hydrochloride, NaHCO3, CH3CN, reflux, 1 h, 78% for 12; (vi) NBS, THF, rt, 30 min,
96% for 13, 93% for 14; (vii) 4-(2-substituted phenyl)-1-piperazine HCl, NaHCO3, reflux, 48 h, 16% for 15a and 70% for 17, 50% for 16a
and 8.4% for 18, 21% for 16b and 48% for 18; (viii) H2SO4, 45 °C, 20 min, 98%.
compounds 4 and 5 on the R1-adrenoceptor were exam-
ined. In addition, the rigid coplanar tricyclic congeners
of compounds 4 and 5 were also synthesized for phar-
macological study in an attempt to reduce the freedom
of the side chain on compounds 4 and 5. This paper
describes the synthesis and biological activity of these
novel tricyclic compounds.
Ch em istr y
The preparation of tricyclic fused quinazolines and
1,2,4-benzothiadiazine 1,1-dioxides containing an arylpip-
erazine side chain was accomplished by the synthetic
sequence depicted in Schemes 1 and 2. The key
intermediates, 2-(allylthio)-4(3H)quinazolinones (11),
2-(allylamino)-4(3H)quinazolinones (12), 3-(allylthio)-
4H-1,2,4-benzothiadiazine 1,1-dioxide (25), and 3-(ally-
lamino)-4H-1,2,4-benzothiadiazine 1,1-dioxide (27) were
first synthesized. It was reasoned that the bromocy-
clization of compounds 11, 12, 25, and 27 with N-
bromosuccinimide would follow Baldwin’s rules12 in
which 5-exo-trig ring closure would provide the tricyclic
quinazolinone or 1,2,4-benzothiadiazine 1,1-dioxide de-
rivatives (13, 14, 28, and 30) for the subsequent
substitution reaction with arylpiperazines.
NBS at room temperature to furnish 3-(bromomethyl)-
2,3-dihydro-5H-thiazolo[2,3-b]quinazolin-5-one (13) in
96% yield. Treatment of 13 with 4-(2-methoxyphenyl)-
1-piperazine in the presence of sodium bicarbonate at
50 °C afforded the desired product 3-[[4-(2-methoxyphe-
nyl)piperazin-1-yl]methyl]-2,3-dihydro-5H-thiazolo[2,3-
b]quinazolin-5-one (15) in 16% yield and also produced
The starting material, 2-thioxo-1H,3H-quinazolin-4-
one (8), which was prepared by condensation of anthra-
nilamide (7) with carbon disulfide,13 was treated with
allyl bromide in aqueous sodium hydroxide solution to
afford 2-(allylthio)-4(3H)-quinazolinone (11) in 98%
yield. Compound 11 was subsequently reacted with

3130 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 17
Chern et al.
Sch em e 2a
a
(i) CS2, NaHCO3, ethanol/water (5/1), reflux, 24 h, 94%; (ii) CH3I, Na3CO3, 99%; (iii) 30% H2O2, acetic acid, rt, 24 h, 79%; (iv) allyl
bromide, NaOH, water, rt, 20 min, 93% for 25; (v) allyl isothiocyanate, 2-propanol, rt, 48 h, 80%; (vi) NaHCO3, reflux, 24 h, 51% for 27;
(vii) allylamine hydrochloride, K2CO3, CH3CN, reflux, 1 h, 94% for 27; (viii) NBS, THF, rt, 30 min, 71% for 28, 72% for 30; (ix) 4-(2-
substituted phenyl)-1-piperazine HCl, NaHCO3, reflux, 48 h, 46% for 33a , 50% for 33b; (x) H2SO4, 45 °C, 20 min, 90%.
3-methylene-2,3-dihydro-5H-thiazolo[2,3-b]quinazolin-
5-one (17) in 48% yield. Compound 17 was also pre-
pared in 88% yield by refluxing 11 with 2 equiv of
potassium carbonate in MIBK. The proton-catalyzed
isomerization of 17 with sulfuric acid yielded 3-methyl-
5H-thiazolo[2,3-b]quinazolin-5-one (19).
ylimidazo[2,1-b]quinazolin-5(1H)-one (20) under acidic
conditions was unsuccessful.
For the synthesis of tricyclic fused 4H-1,2,4-ben-
zothiadiazine 1,1-dioxide derivatives, the starting mate-
rial, 3-mercapto-4H-1,2,4-benzothiadiazine 1,1-dioxide
(22),14 obtained by condensation of 2-aminobenzene-
sulfonamide with carbon disulfide, was reacted with
allyl bromide to produce 3-(allylthio)-4H-1,2,4-benzothi-
adiazine 1,1-dioxide (25) in 93% yield. Treatment of 25
with NBS afforded the linear 3-(bromomethyl)-2,3-
dihydrothiazolo[3,2-b][1,2,4]benzothiadiazine 5,5-diox-
ide (28) in 71% yield instead of the angular 29. The
structural assignment of compound 28 was primarily
based on 13C NMR spectral data. The original 13C NMR
spectroscopic studies on the 3-substituted 1,2,4-ben-
zothiadiazine 1,1-dioxides by J akobsen and Trep-
pendahl15 provided a critical tool to distinguish between
compounds alkylated at the C-2 and C-4 positions by
examination of the chemical shift of C-4a in the ben-
zothiadiazine 1,1-dioxide ring. For example, the chemi-
cal shift of C-4a in the 2-alkylated derivatives was found
around 143 ppm, while that in the 4-alkylated com-
pounds appeared between 135 and 138 ppm. The same
phenomenon was applicable to the angular tricycles
such as 2,4-dihydro-1H-imidazo[2,1-c][1,2,4]benzothia-
diazine 5,5-dioxide, 2,3-dihydro-1H,5H-pyrimido[2,1-c]-
[1,2,4]benzothiadiazine 6,6-dioxide,16 and 2,3-dihydrox-
azolo[3,2-b][1,2,4]benzothiadiazine 5,5-dioxide10 and the
linear tricyclic ring systems such as in 2,3-dihydro-1H-
An attempt to prepare 2-(allylamino)-4(3H)-quinazoli-
none (12) by treatment of 3-(methylthio)-4(3H)-quinazoli-
none (9)14 with allylamine was unsuccessful; 2,4(1H,3H)-
quinazolinedione was isolated as the sole product. This
was probably due to the poor nucleophilicity of ally-
lamine with the methylthio moiety serving as the
leaving group. Oxidation of compound 9 in acetic acid
with 30% hydrogen peroxide furnished 2,4(1H,3H)-
quinazolinedione instead of 3-(methylsulfinyl)quinazo-
lin-4(3H)-one (10). However, compound 10 was ob-
tained in 85% yield when 9 was treated with m-chloro-
perbenzoic acid (mCPBA). Subsequent reaction of 10
with allylamine afforded compound 12 in 78% yield.
Treatment of compound 12 with NBS in THF at room
temperature gave 3-(bromomethyl)-2,3-dihydroimidazo-
[2,1-b]quinazolin-5(1H)-one (14) in 93% yield. An analo-
gous treatment of 14 with 4-(2-methoxyphenyl)-1-
piperazine under identical conditions gave 3-[[4-(2-
methoxyphenyl)piperzin-1-yl]methyl]-2,3-dihydroimidazo-
[2,1-b]quinazolin-5(1H)-one (16a ) in 50% yield and
3-methylene-2,3-dihydroimidazo[2,1-b]quinazolin-5(1H)-
one (18) in 8.4% yield. Isomerization of 18 to 3-meth-

Quinazolines and 1,2,4-Benzothiadiazine 1,1-Dioxides
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 17 3131
Sch em e 3a
imidazo[1,2-b][1,2,4]benzothiadiazine 5,5-dioxide.2,17 In
fact, the chemical shift of C-9a (142.3 ppm) in the 13C
NMR spectrum of 28 is in good agreement with previ-
ously reported data of the 4-alkylated product and
tricyclic fused 4H-2,4-benzothiadiazine 1,1-dioxide de-
rivatives.2,15 Compound 28 was reacted with 4-(2-
methoxyphenyl)-1-piperazine to furnish 3-methylene-
2,3-dihydrothiazolo[3,2-b][1,2,4]benzothiadiazine 5,5-
dioxide (34) in 86% yield. The reaction failed to give
the desired 3-[[4-(2-methoxyphenyl)piperazin-1-yl]meth-
yl]-2,3-dihydrothiazolo[3,2-b][1,2,4]benzothiadiazine 5,5-
dioxide (32a ). The proton-catalyzed isomerization of
compound 34 afforded 3-methylthiazolo[3,2-b][1,2,4]ben-
zothiadiazine 5,5-dioxide (36) in 90% yield (Scheme 1).
3-(Methylthio)-4H-1,2,4-benzothiadiazine 1,1-dioxide
(23) was obtained in 99% yield by treatment of 22 with
methyl iodide in the presence of aqueous sodium hy-
droxide. Unlike the oxidation of compound 9, oxidation
of compound 23 with 30% hydrogen peroxide produced
a precipitate of 3-(methylsulfinyl)-4H-1,2,4-benzothia-
diazine 1,1-dioxide (24) in 79% yield on the basis of the
1H NMR spectral data and elemental analysis. Com-
pound 24 was treated with allylamine to afford com-
pound 27 in 94% yield. Since we have previously
reported that the reaction of 2-aminobenzenesulfona-
mide (21) with alkyl or aryl isothiocyanate led to the
formation of 3-substituted amino-4H-1,2,4-benzothia-
diazine 1,1-dioxide via elimination of hydrogen sulfide,18
compound 27 was alternatively prepared by condensa-
tion of 21 with allyl isothiocyante in 2-propanol followed
by ring closure of the resulting 2-(3-allylthioureido)-
benzenesulfonamide (26) under basic conditions. Com-
pound 27 was then subjected to bromocyclization with
NBS to afford 3-(bromomethyl)-2,3-dihydro-1H-imidazo-
[1,2-b][1,2,4]benzothiadiazine 5,5-dioxide (30) in 72%
yield. The chemical shift of C-9a (145.4 ppm) in the 13C
NMR spectrum of compound 30 was in good agreement
with the previously reported data2,17 of the 2,3-dihydro-
1H-imidazo[1,2-b][1,2,4]benzothiadiazine 5,5-dioxide ring
system. Treatment of 30 with 4-(2-methoxyphenyl)-1-
piperazine afforded 3-[[4-(2-methoxyphenyl)piperazin-
1-yl]m et h yl]-2,3-dih ydr o-1H -im ida zo[1,2-b][1,2,4]-
benzothiadiazine 5,5-dioxide (33a ) in 46% yield and
3-[[4-(2-methoxyphenyl)piperazin-1-yl]methyl]-2,3-dihy-
dro-1H-imidazo[1,2-b][1,2,4]benzothiadiazine 5,5-diox-
ide (35) in 24% yield. Similarly, the elimination of
hydrogen bromide from compound 30 also yielded large
amounts of 3-methylene-2,3-dihydro-1H-imidazo[1,2-b]-
[1,2,4]benzothiadiazine 5,5-dioxide (35). However, com-
pound 35 did not undergo acid-catalyzed isomerization
of the exocyclic double bond (Scheme 2).
a
(i) K2CO3, DMF, reflux, 88%; (ii) Br2, CCl4, rt, 85%; (iii) NBS,
AIBN, dichloroethane/CCl4, rt, 2 days, 91.6%; (iv) 4-substituted
piperazine hydrochloride, NaHCO3, CH3CN, reflux, 42a (59%), 42b
(44.7%); (v) H2, Pd/C, DMF, 44a (63%), 44b (80%); (vi) NaH, CH3I,
DMF, rt, 45a (61%), 45b (56%), 43a (65%), 43b (52%).
tained in 91.6% yield when 39 was treated at room
temperature with NBS in the presence of AIBN in
dichloroethane and carbon tetrachloride. Recrystalli-
zation of the crude product in ethanol allowed the
isolation of 2-(ethoxymethyl)-3-bromoimidazo[1,2-c]-
quinazolin-5(6H)-one in 40% yield. Compound 41 was
subsequently treated with (2-substituted phenyl)pip-
erazine hydrochloride in the presence of sodium bicar-
bonate in CH3CN at reflux to afford 3-bromo-2-[[4-(2-
substituted phenyl)piperazin-1-yl]methyl]imidazo[1,2-
c]quinazolin-5(6H)-one (42) in good yield. The reductive
debromination of 42 was performed with a catalytic
amount of Pd/C under hydrogen to give 2-[[4-(2-
substituted phenyl)piperazin-1-yl]methyl]imidazo[1,2-
c]quinazolin-5(6H)-one (44). Compounds 43 and 45
were obtained in good yields by treatment of 42 and 44
with methyl iodide under basic conditions, respectively
(Scheme 3).
2-(Bromomethyl)-3-bromo-5-(methylthio)imidazo[1,2-
c]quinazoline (49) was obtained by an analogous reac-
tion in which 2-(bromomethyl)-5-(methylthio)imidazo-
[1,2-c]quinazoline (46)9 was treated with (2-substituted
phenyl)piperazine, followed by reductive debromination
with Pd/C under hydrogen and subsequent methylation
with methyl iodide to give compounds 50-53, respec-
tively (Scheme 4). By starting from compound 19,
compounds 54-56 were prepared by the same reaction
sequence (Scheme 5). Compounds (S)-(-)-5 and (R)-
(+)-5 were obtained in 94% and 98% yield by treatment
of (S)-(+)-5719 and (R)-(-)-5719 with aqueous sodium
hydroxide (Scheme 6).
To study the pharmacological effect of inserting a
double bond between C-2 and C-3 in compounds 4 and
5, the key intermediates 2-methylimidazo[1,2-c]quinazo-
lin-5(6H)-one (39) and 3-methylimidazo[1,2-c]quinazo-
lin-5(6H)-one (47) were synthesized. 2-(Bromomethyl)-
5-(methylthio)imidazo[1,2-c]quinazoline (38),9 prepared
according to a previously reported procedure, was re-
fluxed with potassium carbonate in DMF to give 39 in
good yield. When 39 was treated with bromine in
carbon tetrachloride at room temperature, only 2-meth-
yl-3-bromoimidazo[1,2-c]quinazolin-5(6H)-one (40) was
obtained in 85% yield. However, 2-(bromomethyl)-3-
bromoimidazo[1,2-c]quinazolin-5(6H)-one (41) was ob-
Resu lts a n d Discu ssion
Tables 1-5 list the R1-adrenoceptor binding affinity
of various heterocycles containing a (2-substituted phe-

3132 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 17
Chern et al.
Sch em e 4a
Sch em e 6a
a
(i) Aq NaOH, reflux, 17 h, then HCl.
Ta ble 1. R1- and R2-Adrenergic Receptor Binding Affinities for
3-[[4-(2-Substituted phenyl)piperazin-1-yl]methyl]-5H-
2,3-dihydrothiazolo[2,3-b]quinazolin-5-ones
a
(i) K2CO3, DMF, reflux, 67%; (ii) Br2, CCl4, rt, 55%; (iii) NBS,
AIBN, dichloroethane/CCl4, rt, 2 days, 90%; (iv) 4-substituted
piperazine hydrochloride, NaHCO3, CH3CN, reflux, 50a (53%), 50b
(28.7%); (v) H2, Pd/C, DMF, 52a (81.6%), 52b (70%); (vi) NaH,
CH3I, DMF, rt, 51a (57%), 51b (50%), 53a (72.7%), 53b (31%).
Ki,a nM
no.
X
Y
R
R1-AR
R2-AR
NDb
NDb
R2/R1
15a
16a
33a
33b
CdO
CdO NH
SO2
SO2
S
OCH3 >10000
OCH3 186
ND
ND
93
Sch em e 5a
NH
NH
OCH3 4.95 ( 0.19 460 ( 17
Cl 11.8 ( 1.0 2290 ( 12
194
a
The Ki binding data were calculated as described in the
Experimental Section. Values are means ((SEM) of three to six
b
separate experiments. ND, not determined.
Ta ble 2. R1- and R2-Adrenergic Receptor Binding Affinities for
2-[[4-(2-Substituted phenyl)piperazin-1-yl]methyl]imidazo-
[1,2-c]quinazolin-5(6H)-ones
a
(i) NBS, AIBN, dichloroethane/CCl4, rt, 61%; (ii) 4-substituted
piperazine, NaHCO3, CH3CN, reflux, 55a (67%), 55b (57%); (iii)
H2, Pd/C, DMF, 56a (60%), 56b (51%).
nyl)piperazine moiety. Some selective compounds with
high affinity for the R1-adrenoceptor were identified. The
most active structural feature for receptor binding
appears to be the 3-methyl-2,3-dihydroimidazo[1,2-c]-
quinazolin-5(6H)-one ring system.
Ki,a nM
no.
R
R1
R2
R1-AR
R2-AR
NDb
ND
ND
R2/R1
42a
42b
43a
43b
44a
44b
45a
45b
OCH3
Cl
OCH3
Cl
OCH3
Cl
OCH3
Cl
Br
Br
Br
Br
H
H
H
H
H
H
CH3
CH3
H
H
CH3
CH3
>10000
>10000
>10000
>10000
6.53 ( 1.33
9.29 ( 0.94
6.5
ND
ND
ND
ND
1034
486
499
36
Synthesis of the constrained analogue of 1 to map the
active site of the receptor led to the discovery that
angular tricyclic compounds are potent and selective R1-
adrenoceptor antagonists. To further define the recep-
tor, linear tricycles were synthesized by changing the
2,3-dihydroimidazo[1,2-c]quinazoline ring system to 2,3-
dihydrothiazolo[2,3-b]quinazolin-5-one (15a ), 2,3-dihy-
droimidazo[2,1-b]quinazolin-5-one (16a ), and 2,3-dihy-
droimidazo[1,2-b][1,2,4]benzothiadiazine 5,5-dioxide
(33a ,b). The effects of attaching the phenylpiperazine
side chain to different heterocycles on R1- and R2-
adrenoceptor binding affinities are summarized in Table
1. Surprisingly, only those compounds containing a
built-in guanidino moiety such as compounds 16a and
ND
6760 ( 440
4510
3250
513
14.1
a
The Ki binding data were calculated as described in the
Experimental Section. Values are means ((SEM) of three to six
separate experiments. ND, not determined.
b
33a ,b antagonized the R1-adrenoceptor. Compound 33a
was the most potent antagonist in this series with 38-
fold greater potency than 16a . When the o-methoxy
group was replaced by o-chloro (33b), the affinity
decreased 2.4-fold, in agreement with reports8,9 showing
that the introduction of these two substituents to the

Quinazolines and 1,2,4-Benzothiadiazine 1,1-Dioxides
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 17 3133
Ta ble 3. R1- and R2-Adrenergic Receptor Binding Affinities for
3-[[4-(2-Substituted phenyl)piperazin-1-yl]methyl]imidazo-
[1,2-c]quinazolin-5(6H)-one Derivatives
51a ,b with a bromine atom at either the 3- or 2-position
are key intermediates for the synthesis of the corre-
sponding target compounds 44a ,b, 45a ,b, 52a ,b, and
53a ,b, respectively. Surprisingly, none of the interme-
diates was active against either R1- or R2-adrenoceptors.
Introduction of a bromo atom into the benzene ring of
the 2,3-imidazo[1,2-c]quinazolin-5(6H)-one ring system
was detrimental, producing inactive compounds. How-
ever, compounds 44a ,b and 45a ,b demonstrated potent
and selective affinity toward the R1-adrenoceptor in the
6.5-14.1 nM range. Similarly, compounds 52a ,b and
53a ,b were potent and selective R1-antagonists in the
4.28-7.12 nM range. Compound 52a (Ki ) 5.06 nM)
and compound 44a (Ki ) 6.53 nM) had similar potencies,
in agreement with a report9 showing that substitution
at the 3-position increased the affinity of compound 5
toward R1-adrenoceptors more than compound 4. There
were no significant differences between the R1-adreno-
ceptor binding affinities of the 6-alkylated derivatives
(45a ,b, 53a ,b) and the corresponding parent compounds
(44a ,b, 52a ,b), whereas compounds with a (2-methox-
yphenyl)piperazine side chain (44a , 45a , 52a ) exhibited
slightly higher affinities than compounds with a (2-
chlorophenyl)piperazine side chain (44b, 45b, 52b)
withe the exception of compounds 53a ,b. All these
compounds (44a ,b, 45a ,b, 52a ,b, 53a ,b) displayed lower
affinity for R2-adrenoceptors. Most compounds dis-
played high R2/R1 ratios but were not better than the
parent compound 5 with an R2/R1 ratio of 2823. Addi-
tion of a (2-substituted phenyl)piperazine side chain at
the 3-position of the 5H-thiazolo[2,3-b]quinazolin-5-one
ring system blocked R1-adrenoceptor activity (Table 4).
Ki,a nM
no.
R
R1
R2
R1-AR
R2-AR
NDb
ND
ND
R2/R1
50a
50b
51a
51b
52a
52b
53a
53b
OCH3
Cl
OCH3
Cl
OCH3
Cl
OCH3
Cl
Br
Br
Br
Br
H
H
H
H
H
H
CH3
CH3
H
H
CH3
CH3
>10000
ND
ND
ND
ND
1550
382
506
123
>10000
>10000
>10000
ND
5.06 ( 0.34
7.12 ( 1.39
6.1 ( 0.9
4.28 ( 0.34
7830 ( 8.8
2720 ( 690
3090 ( 63
525 ( 65
a
The Ki binding data were calculated as described in the
Experimental Section. Values are means ((SEM) of three to six
b
separate experiments. ND, not determined.
Ta ble 4. R1- and R2-Adrenergic Receptor Binding Affinities for
3-[[4-(2-Substituted phenyl)piperazin-1-yl]methyl]-5H-thiazolo-
[2,3-b]quinazolin-5-ones
Ki,a nM
no.
R
R1
R1-AR
R2-AR
R2/R1
To further elucidate the stereochemical requirements
for pharmacological activity, the enantiomers of com-
pounds 5 and 57 were prepared and examined in the
R1-adrenoceptor binding assay (Table 5). The affinity
of enantiomer (S)-(+)-57 for R1-adrenoceptors (Ki ) 1.0
( 0.2 nM) was 144-fold greater than that of enantiomer
(R)-(-)-57 (Ki ) 144 ( 23 nM), whereas racemic 57 had
a Ki value of 0.90 ( 0.08 nM. The affinity of enantiomer
(S)-(-)-5 with Ki ) 0.13 ( 0.01 nM was 200-fold greater
than that of (R)-(+)-5 (Ki ) 26 ( 8 nM). The Ki value
of racemic 5 was 0.21 ( 0.02 nM.
Three subtypes of the human R1 receptor have been
cloned and expressed: R1a, R1b, and R1d.20 The R1-
adrenoceptor has recently received much attention
because the antagonist blockade of norepinephrine- or
phenylephedrine-induced contraction of human prostate
tissue has been found to correlate with affinity for the
R1a subtype.21 Radioligand binding assays of selected
compounds 4, 5, and 57 and their chiral compounds
revealed that only compound 4 demonstrated approxi-
mately 8-fold selectivity for R1A binding sites vs R1B
sites (Table 5). There were no significant difference
between the R1A and R1B binding affinities of com-
pounds (S)-(-)-5 and (S)-(+)-57. Radioligand binding
assays were performed essentially as reported.23 The
compounds active against the R1 sites ((S)-(-)-5 and (S)-
(+)-57) were poor ligands for the R2a and R2B sites.
55a
55b
56c
56d
OCH3
Cl
OCH3
Cl
Br
Br
H
>10000
>10000
>10000
>10000
NDb
ND
ND
ND
ND
ND
ND
ND
H
a
The Ki binding data were calculated as described in the
Experimental Section. Values are means ((SEM) of three to six
b
separate experiments. ND, not determined.
ortho position of the phenyl ring of the phenylpiperazine
side chain may produce potent R1-adrenoceptor antago-
nists. Compounds 33a ,b also displayed lower affinity
for R2-adrenoceptors than for R1-adrenoceptors. The R2/
R1-selectivity ratio of 33b was higher than that of 33a .
Compounds containing built-in pseudothiourea, such as
15a and 32a , were inactive for both R1- and R2-
adrenoceptors.
Previous studies on conformational modifications of
1 found that compounds 4 and 5 were potent R1-
antagonists.9 However, these are chiral compounds that
possess an asymmetric carbon. Neither R- nor S-form
enatiomers exist in an extended form as demonstrated
by an initial examination simple stick-ball molecular
structure model. We presumed that insertion of a
double bond between the 2- and 3-positions of com-
pounds 4 and 5 might provide improved conformations
for binding to the receptor. The effects of introducing
a double bond in compounds 4 and 5 on R1- and
R2-adrenoceptor binding affinity are shown in Tables 2
and 3. Comparison of the R1-antagonizing activity of
compounds 42a and 50a with the corresponding parent
compounds 4 and 5 illustrates that the coplanarity of
compounds 42a and 50a did not increase receptor
binding affinity. Compounds 42a ,b, 43a ,b, 50a ,b, and
The affinity of compounds 4, 5, 44a , 52a ,b, and 57
and their chiral compounds for a large number of
receptors was 3 orders of magnitude less than their
affinity to the R1-adrenoceptors (Table 6). Compounds
with a 4-(2-methoxyphenyl)-1-piperazine side chain

3134 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 17
Chern et al.
Ta ble 5. R1- and R2-Adrenergic Receptor Binding Affinities for Compounds 1, 4, 5, and 57 and the Corresponding Chiral Compounds
Ki,a-c nM
compd
R1-AR
R1A-AR
0.5
0.65 ( 0.12
0.26 ( 0.02
0.23 ( 0.04
55 ( 9
0.93 ( 0.04
1.5 ( 0.2
122 ( 15
R1B-AR
1.1
R2-AR
R
2a-AR
R2B-AR
56
253 ( 26
ND
116 ( 17
9300 ( 1200
ND
376
ND
R2/R1
1
4
5
0.25 ( 0.06d
0.93 ( 0.13
0.21 ( 0.02
0.13 ( 0.01
26 ( 8
0.90 ( 0.08
1.0 ( 0.2
144 ( 23
1599 ( 324d
230 ( 47
593 ( 6
183 ( 32
>10000
970 ( 2
3500 ( 800
9000 ( 1500
1811
547 ( 63
NDe
444 ( 89
ND
ND
872
3000
6396
247
5.5 ( 0.4
0.67 ( 0.05
0.42 ( 0.05
123 ( 28
3.9 ( 0.3
1.4 ( 0.1
667 ( 20
2823
1407
>384
1078
3500
62.5
(S)-(-)-5
(R)-(+)-5
57
(S)-(+)-57
(R)-(-)-57
a
The Ki binding data were calculated as described in the Experimental Section. Values are means ((SEM) of three to six separate
experiments. The following radioligands were used: [3H]prazosin for R1, R1A, and R1B assays; [3H]clonidine for R2 assays; [3H]MK912
b
for R2a assays; [3H]yohimbine for R2B assays. c Radioligand studies against R1A, R1B, R2a, and R2B sites were performed by Pan Lab,
Inc.22 Data were taken from ref 9. e ND, not determined.
d
Ta ble 6. Affinity of Compounds 1, 4, 5, 44a , 52a ,b, and 57 for Different Receptors
Ki,a nM
assay
5-HT1
5-HT1A
5-HT2
ligand
[3H]-5-HT
source
1
4
5
44a
52a
52b
57
b
rat brain cortex
rat brain cortex
rat brain
guinea pig brain
rat brain
CHO cells
CHO cells
CHO cells
guinea pig lung
rat brain
1510
16
180
-
2500
238
369
4000
-
-
-
-
-
-
-
1839
237
168
451
-
[3H]-8-OH-DPAT
[3H]ketanserin
[3H]pentazocine
[3H]ifenprodil
[3H]spiperone
[3H]spiperone
[3H]spiperone
[3H]pyrilamine
[3H]batrachotoxin
155
377
6270
-
158
239
985
2320
-
4000
514
6520
-
3580
743
4880
-
114
1500
3050
-
σ
σ 2
-
D2
32
132
73
685
3680
-
-
449
-
rhD2
rhD3
H1
-
-
-
-
2200
961
-
-
-
-
-
-
-
-
-
sodium channel
4810
5380
2460
404
a
b
Inhibition constants (Ki) for in vitro inhibition by the compounds were studied by Pan Lab, Inc.22 A dash (-) indicates that the
inhibition percentage was below 50% at the concentration of 10 µM for each compound.
were reported to be potent 5-HT1A agents.11 Com-
on either a J EOL FX-100 or a J EOL J NM-EX400 spectrometer
at the National Taiwan Normal University or on a Bruker
model AM 300 spectrometer at the National Taiwan Univer-
pounds 4, 5, and 57, which are the most potent R1-AR
binders, were also ligands for the 5-HT1A receptor with
sity, Taipei, and are reported in parts per million with DMSO-
Ki ) 238, 155, and 237 nM, respectively. However, the
d6 as internal standard on a δ scale. EI mass spectra were
insertion of a double bond into compounds 4 and 5
recorded on a J EOL J MS-D100 mass spectrometer at the
between positions 2 and 3 (compounds 44a , 52a ,b)
decreased or totally abrogated binding to the 5-HT1A
receptor and D2 site. However, compound 1 was not
only a potent R1-AR antagonist but also a potent ligand
for 5-HT1A (Ki ) 16 nM) and D2 (Ki ) 32 nM), although
it was a weak ligand at H1 (Ki ) 685 nM). It should be
noted that compound 57 was also a weak ligand for the
sodium channel with Ki ) 404 nM.
Compounds (S)-(-)-5 and (R)-(+)-5 were evaluated for
blood pressure-lowering activity in anesthetized spon-
taneously hypertensive rats (SHR) by intravenous ad-
ministration (Figure 1A,B). Administration of (S)-(-)-
5 (0.005, 0.01, and 0.05 mg/kg, iv bolus) and (R)-(+)-5
(0.05, 0.1, and 0.2 mg/kg, iv bolus) produced a dose-
dependent reduction of mean arterial pressure (MAP)
which reached a maximal effect after 5 min and
persisted for over 3 h (Figure 1). (S)-(-)-5 was ap-
proximately 3-fold more potent than (R)-(+)-5 based on
the peak effect at the same dose. Neither (S)-(-)-5 nor
(R)-(+)-5 significantly affected the heart rate (Figure 2).
In summary, this investigation demonstrated that the
S-forms of 3-substituted 2,3-dihydroimidazo[1,2-c]-
quinazoline derivatives are more active than the R-
forms for antagonism of the R1-adrenoceptor. The
S-form might provide a better conformational fit to the
R1-adrenoceptor.
National Taiwan University. Elemental analyses for C, H, and
N were carried out either on a Heraeus elemental analyzer in
the Cheng-Kong University, Tainan, or on a Perkin-Elmer 240
elemental analyzer in the National Taiwan University, Taipei,
and were within (0.4% of the theoretical values.
3-(Meth ylsu lfin yl)qu in a zolin -4(3H)-on e (10). To a mix-
ture of 9 (2.0 g, 10.4 mmol) in chloroform (50 mL) was added
dropwise 60% 3-chloroperoxybenzoic acid (4.0 g, 23.2 mmol)
in chloroform (10 mL) under ice bath. After the mixture was
stirred at room temperature for 1 h, to the mixture was added
saturated sodium bicarbonate solution (50 mL). The organic
layer was collected and evaporated to dryness. The solid was
collected and recrystallized from water to furnish 10 (1.82 g,
1
85%): mp 144 °C dec; H NMR (100 MHz, DMSO_d6) δ 2.99
(s, 3 H, CH3), 7.50-7.95 (m, 3 H, Ar-H), 8.14 (d, 1 H, J ) 8.6
Hz, Ar-H), 12.13 (br, 1 H, NH); 13C NMR (75 MHz, DMSO-
d6) δ 121.9, 126.3, 127.9, 135.0, 146.8, 160.0, 161.2; MS m/z
208 (M+), 192 (M+ - 16), 177 (M+ - 31). Anal. (C9H8N2O2S2)
C, H, N.
2-(Allylth io)qu in a zolin -4(3H)-on e (11). To a solution of
8 (3.0 g, 16.85 mmol) and sodium hydroxide (0.67 g, 16.9 mmol)
in water (150 mL) was added allyl bromide (1.5 mL, 17.36
mmol). The mixture was stirred at room temperature for 30
min before being neutralized with acetic acid to give a white
solid which was collected by filtration and recrystallized from
ethanol and water (9:1) to afford 11 (3.6 g, 98%): mp 184 °C
dec; 1H NMR (100 MHz, DMSO-d6) δ 3.87 (d, 2 H, J ) 7.7 Hz,
CH2), 5.07-5.42 (m, 2 H, CH2), 5.84-6.01 (m, 1H, CH), 7.31-
7.55 (m, 2 H, Ar-H), 7.66-7.82 (m, 1 H, Ar-H), 7.97-8.05
(m, 1 H, Ar-H), 12.43 (br s, 1 H, NH); 13C NMR (25 MHz,
DMSO-d6) δ 32.3, 118.4, 119.8, 125.5, 125.7, 125.80, 133.1,
134.4, 148.0, 154.8, 161.0; MS m/z 218 (M+). Anal. (C11H10N2-
OS) C, H, N.
Exp er im en ta l Section
Ch em istr y. Gen er a l Meth od s. Melting points were
obtained on an Electrothermal apparatus and are uncorrected.
1H and 13C nuclear magnetic resonance spectra were recorded
2-(Allyla m in o)qu in a zolin -4(3H)-on e (12). To a mixture
of 10 (0.96 g, 4.42 mmol) and sodium bicarbonate (1.2 g, 8.84

Quinazolines and 1,2,4-Benzothiadiazine 1,1-Dioxides
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 17 3135
F igu r e 1. Time course of the depressor effect of (R)-(+)-5 (A)
and (S)-(-)-5 (B) on spontaneously hypertensive rats.
F igu r e 2. Time course of heart rate changes after an
intravenously administered series of doses of (R)-(+)-5 (A) and
(S)-(-)-5 (B) on spontaneously hypertensive rats.
mmol) in acetonitrile (20 mL) was added allylamine hydro-
chloride (0.65 g, 6.95 mmol). The mixture was refluxed for 1
h, and the hot mixture was then vacuum-filtered to remove
solids. The filtrate was cooled to room temperature, and the
precipitate was collected by filtration to afford crystals. The
solid was recrystallized from a mixture of DMF and water (3:
3-(Br om om eth yl)-2,3-dih ydr oim idazo[2,1-b]qu in azolin -
5(1H)-on e (14). A solution of 12 (0.6 g, 3.14 mmol) and NBS
(0.7 g, 3.9 mmol) in THF (20 mL) was stirred at room
temperature for 30 min. The solvent was removed in vacuo
to dryness. To the residue was added water (10 mL), and the
solid was then collected by filtration. The crude product was
recrystallized from DMF and methanol (3:1) to furnish 14 (0.8
g, 93%): mp 235-237 °C; 1H NMR (100 MHz, DMSO-d6) δ
3.48-3.60 (m, 2 H, CH2), 3.78-4.02 (m, 2 H, CH2), 5.13-5.25
(m, 1 H, CH), 7.15-7.38 (m, 2 H, Ar-H), 7.54-7.70 (m, 1 H,
Ar-H), 7.89-7.97 (m, 1 H, Ar-H), 8.24 (br s, 1 H, NH); 13C
NMR (25 MHz, DMSO-d6) δ 35.0, 44.8, 55.1, 113.0, 117.3,
122.5, 127.6, 132.8, 138.0, 158.2, 168.1; MS m/z 280 (M+), 200
(M+ - 80). Anal. (C11H10N3BrO) C, H, N.
3-[[4-(2-Meth oxyp h en yl)p ip er a zin -1-yl]m eth yl]-2,3-d i-
h yd r o-5H -t h ia zolo[2,3-b]q u in a zolin -5-on e (15a ) a n d 3-
Met h ylen e-2,3-d ih yd r o-5H -t h ia zolo[2,3-b]q u in a zolin -5-
on e (17). These were prepared by a similar approach which
afforded 16a . Compound 15: Rf ) 0.62, chloroform/ethyl
acetate ) 9/1; yield 16%, mp 261-264 °C; 1H NMR (300 MHz,
DMSO-d6) δ 2.49-2.58 (m, 6 H, 3 CH2), 2.73-2.95 (m, 6 H, 3
CH2), 3.76 (s, 3 H, CH3), 5.49 (m, 1 H, CH), 6.86-6.92 (m, 4
H, Ar-H), 7.42-7.54 (m, 2 H, Ar-H), 7.79-8.04 (m, 2 H, Ar-
H); MS m/z 408 (M+). Anal. (C22H24N4SO2) C, H, N.
1
1) to furnish 12 (0.69 g, 78%): mp 185 °C dec; H NMR (100
MHz, DMSO-d6) δ 3.99 (t, 2 H, CH2), 5.05-5.31 (m, 2 H,
dCH2), 5.77-6.10 (m, 1 H, CH), 7.03 (br s, 1 H, NH), 7.04-
7.26 (m, 2 H, Ar-H), 7.44-7.56 (m, 1 H, Ar-H), 7.86-7.93
(m, 1 H, Ar-H), 11.06 (br s, 1 H, NH); 13C NMR (75 MHz,
DMSO-d6) δ 42.3, 115.3, 117.4, 121.6, 125.9, 126.9, 134.0,
134.8, 135.1, 140.8, 150.6; MS m/z 200 (M+). Anal. (C11H10N3O‚
1/2H2O) C, H, N.
3-(B r o m o m e t h y l)-2,3-d ih y d r o -5H -t h ia zo lo [2,3-b ]-
qu in a zolin -5-on e (13). A solution of 11 (2.9 g, 13.3 mmol)
and NBS (2.4 g, 13.48 mmol) in THF was stirred at room
temperature for 30 min. The mixture was then concentrated
in vacuo to dryness. To the resulting residue was added water
(5 mL), and the solid was then collected by filtration to give
4.1 g of the crude product which was recrystallized from
1
ethanol to furnish 13 (3.8 g, 96%): mp 235-237 °C; H NMR
(300 MHz, DMSO-d6) δ 3.50-3.83 (m, 2 H, CH2), 3.91-4.01
(m, 2 H, CH2), 5.72 (t, 1 H, J ) 6.5 Hz, CH), 7.45 (t, 1 H, J )
7.6 Hz, Ar-H), 7.59 (d, 1 H, J ) 6.0 Hz, Ar-H), 7.79 (t, 1 H,
J ) 7.8 Hz, Ar-H), 8.02 (d, 1 H, J ) 7.7 Hz, Ar-H); 13C NMR
(75 MHz, DMSO-d6) δ 30.2, 32.0, 61.2, 115.9, 117.5, 125.5,
Compound 17: Rf ) 0.66, chloroform/ethyl acetate ) 9/1;
1
yield 70%, mp 205 °C dec; H NMR (100 MHz, DMSO-d6) δ
127.8, 134.2, 138.0, 166.0, 168.6; MS m/z 297 (M+), 217 (M+
80). Anal. (C11H9N2BrOS) C, H, N.
-
4.24 (s, 2 H, CH2), 5.38 (s, 1 H, dC-H), 5.57 (s, 1 H, dC-H),
7.58-8.07 (m, 4 H, Ar-H); 13C NMR (25 MHz, DMSO-d6) δ

3136 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 17
Chern et al.
32.5, 101.5, 116.3, 117.9, 125.8, 127.9, 133.6, 137.3, 141.2,
168.0, 169.6; MS m/z 216 (M+). Anal. (C11H8N2OS) C, H, N.
3-[[4-(2-Meth oxyp h en yl)p ip er a zin -1-yl]m eth yl]-2,3-d i-
h yd r oim id a zo[2,1-b]qu in a zolin -5(1H)-on e (16a ). A sus-
pension of 14 (0.5 g, 1.78 mmol), (2-methoxyphenyl)piperazine
hydrochloride (0.82 g, 3.57 mmol), and sodium hydrocarbonate
(0.3 g, 3.57 mmol) in acetonitrile (70 mL) was refluxed for 2
days. The white solid was then collected by filtration and
recrystallized from DMF to give 16a (0.5 g, 50%): mp 293-
294 °C; 1H NMR (300 MHz, DMSO-d6) δ 2.55-2.96 (m, 10 H,
5 CH2), 3.60-3.79 (m, 2 H, CH2), 3.76 (s, 3 H, -OCH3), 4.96
(m, 1H, CH), 6.85-6.92 (m, 4 H, Ar-H), 7.18-7.30 (m, 2 H,
Ar-H), 7.62-7.64 (m, 1 H, Ar-H), 7.90-7.93 (m, 1 H, Ar-
H), 8.17 (s, 1 H, NH); 13C NMR (75 MHz, DMSO-d6) δ 44.4,
50.0, 53.5, 53.8, 55.3, 57.6, 111.9, 113.6, 117.4, 117.9, 120.8,
122.3, 127.6, 132.8, 138.3, 141.1, 151.9, 158.5, 168.8. Anal.
(C22H25N5O2) C, H, N.
in water was added allyl bromide (0.9 mL, 10 mmol). The
mixture was stirred at room temperature for 20 min. The solid
was collected by filtration and recrystallized from water to
furnish 25 (2.2 g, 93%): mp 135-136 °C; 1H NMR (100 MHz,
DMSO-d6) δ 3.34 (t, 2 H, J ) 5.0 Hz, CH2), 5.10-5.29 (m, 2 H,
CH2), 5.80 (m, 1 H, CH), 7.20-7.70 (m, 4 H, Ar-H), 10.61 (br
s, 1 H, NH); 13C NMR (25 MHz, DMSO-d6) δ 32.3, 115.7, 116.4,
122.5, 125.5, 132.2, 133.1, 148.0, 154.8, 161.0; MS m/z 254
(M+). Anal. (C10H10N2S2O2) C, H, N.
2-(3-Allylth iou r eid o)ben zen esu lfon a m id e (26). To a
solution of 2-aminobenzenesulfonamide (21; 5.0 g, 29 mmol)
in 2-propanol (50 mL) was added allyl isothiocyanate (4 mL,
41 mmol). The mixture was stirred at room temperature for
48 h. The white solid was collected by filtration and recrystal-
lized from ethanol to furnish compound 26 (6.3 g, 80%): mp
133-134 °C; 1H NMR (100 MHz, DMSO-d6) δ 4.16 (t, 2 H,
CH2), 5.09-5.30 (m, 2 H, dCH2), 5.74-6.08 (m, 1 H, CH),
7.29-7.84 (m, 6 H, Ar-H and NH), 8.28 (s, 1 H, NH, D2O
exchangeable), 8.70 (t, 1 H, NH, D2O exchangeable); 13C NMR
(25 MHz, DMSO-d6) δ 46.6, 116.0, 124.4, 127.1, 128.2, 131.6,
134.1,134.4,136.7,180.9;MS m/z271 (M+). Anal. (C10H13N3O2S2)
C, H, N.
The mother liquid was subjected to column chromatography
(silica gel, 15 g; solvent system, CHCl3/MeOH ) 95/5), and the
Rf ) 0.22 fraction was collected and concentrated in vacuo to
1
give 18 (30 mg, 8.4%): mp >300 °C (ethanol); H NMR (300
MHz, DMSO-d6) 4.35 (s, 2 H, CH2), 4.83 (d, 1 H, J ) 2.5 Hz,
dC-H), 5.46 (d, 1 H, J ) 2.9 Hz, dC-H), 7.32-8.01 (m, 4 H,
Ar-H); 13C NMR (75 MHz, DMSO-d6) δ 29.4, 40.7, 46.4, 50.4,
92.0, 114.7, 124.3, 128.4, 133.7, 137.5, 140.5; MS m/z 198 (M+
- 1). Anal. (C11H9N3O) C, H, N.
3-(Allyla m in o)-4H-1,2,4-ben zoth ia d ia zin e 1,1-Dioxid e
(27). Meth od A: A mixture of 26 (0.8 g, 2.95 mmol) and
sodium hydrocarbonate (0.3 g, 3.57 mmol) in methanol (15 mL)
was refluxed for 24 h. The mixture was cooled to room
temperature, and the white solid was collected by filtration.
The solid was suspended in water (20 mL) and neutralized
with acetic acid (0.32 g, 51%). The filtrate was concentrated
in vacuo to an oily residue. To the residue was added water
(10 mL), and the whole was neutralized with acetic acid to
pH 7. The resulting white solid was collected by filtration and
recrystallized from water to give 27 (0.3 g, 43%): mp 151-
3-Meth ylen e-2,3-d ih yd r o-5H-th ia zolo[2,3-b]qu in a zolin -
5-on e (17). A mixture of 13 (2.1 g, 7.1 mmol) and potassium
carbonate (2.0 g, 14.5 mmol) in methyl isobutyl ketone (30 mL)
was refluxed for 1 h. The solid was filtered off, and the filtrate
was cooled to room temperature. The crystal needles were
collected by filtration to furnish 17 (1.43 g, 88%), mp 203-
204 °C. The analytical data was in agreement with the above
data.
1
152 °C; H NMR (100 MHz, DMSO-d6) δ 3.87 (t, 2 H, J ) 5.0
3-Meth yl-5H-th ia zolo[2,3-b]qu in a zolin -5-on e (19).
A
Hz, CH2), 5.09-5.29 (m, 2 H, CH2), 5.74-6.08 (m, 1 H, CH),
7.17-7.31 (m, 2 H, Ar-H), 7.46-7.62 (m, 2 H, Ar-H), 10.61
(br s, 1 H, NH, D2O exchangeable); 13C NMR (25 MHz, DMSO-
d6) δ 42.7, 115.6, 116.4, 122.5, 122.7, 123.6, 132.2, 134.4, 135.5,
150.9; MS m/z 237 (M+). Anal. (C10H11N3O2S) C, H, N.
mixture of 17 (0.75 g, 3.45 mmol) in concentrated sulfuric acid
(10 mL) was heated at 45 °C for 20 min. The solution was
then neutralized with 10% sodium hydroxide solution to pH
7. The white solid was collected and recrystallized from
ethanol to afford 19 (0.73 g, 98%): mp >300 °C; 1H NMR (300
MHz, DMSO-d6) δ 2.84 (s, 3 H, CH3), 7.02 (s, 1 H, dC-H),
7.60-7.65 (m, 2 H, Ar-H), 7.80-7.86 (m, 2 H, Ar-H); 13C
NMR (75 MHz, DMSO-d6) δ 19.4, 105.5, 116.9, 124.2, 125.2,
126.9, 128.2, 132.92, 133.7, 134.6, 168.2; MS m/z 216 (M+).
Anal. (C11H8N2OS) C, H, N.
1,2,4-Ben zoth ia d ia zin e-3(4H)-th ion e (22). To a mixture
of 2-aminobenzenesulfonamide (4.5 g, 29 mmol) in ethanol (50
mL) were added sodium hydrocarbonate (4.0 g, 48 mmol) in
water (10 mL) and carbon disulfide (15 mL, 0.25 mol). The
mixture was refluxed for 24 h, cooled to room temperature,
and neutralized with acetic acid to pH 6.5. The white solid
was then collected by filtration and recrystallized from ethanol
to give 22 (6.6 g, 94%).
3-(Meth ylth io)-4H-1,2,4-ben zoth ia d ia zin e 1,1-Dioxid e
(23). This was prepared in 99% yield by a similar approach
which afforded 9. An analytical sample was recrystallized
from water: mp 220 °C dec; 1H NMR (100 MHz, DMSO-d6) δ
2.53 (s, 3 H, CH3), 7.10-7.80 (m, 4 H, Ar-H), 12.30 (br s, 1 H,
NH); 13C NMR (25 MHz, DMSO-d6) δ 13.4, 116.7, 121.5, 123.2,
125.8, 133.1, 135.4, 160.7;MS m/z228 (M+). Anal. (C8H8N2O2S2)
C, H, N.
3-(Met h ylsu lfin yl)-4H -1,2,4-b en zot h ia d ia zin e 1,1-Di-
oxid e (24). To a solution of 23 (0.5 g, 2.2 mmol) in acetic acid
(20 mL) was added 30% hydrogen peroxide (2 mL). The
mixture was stirred at room temperature for 24 h, and the
white solid was then collected by filtration. The crude product
was recrystallized from ethanol to give 24 (0.42 g, 79%): mp
267-268 °C; 1H NMR (100 MHz, DMSO-d6) δ 2.99 (s, 3 H,
CH3), 7.66-8.18 (m, 4 H, Ar-H), 12.52 (br s, 1 H, NH); 13C
NMR (25 MHz, DMSO-d6) δ 121.7, 126.1, 126.9, 127.7, 134.8,
146.6, 159.7, 160.9; MS m/z 244 (M+), 228 (M+ - 16), 213 (M+
- 31). Anal. (C8H8N2O3S2) C, H, N.
Meth od B: A mixture of 24 (1.0 g, 3.85 mmol), allylamine
hydrochloride, and potassium carbonate (0.8 g, 5.79 mmol) in
acetonitrile (50 mL) was refluxed for 1 h. The solvent was
then removed in vacuo to dryness. To the residue was added
water (20 mL), and the whole was neutralized with acetic acid
to pH 7. The white solid was collected by filtration and
recrystallized from water to afford 27 (0.86 g, 94%), mp 150-
151 °C. The analyical data was in agreement with that
described above.
3-(Br om om e t h yl)-2,3-d ih yd r ot h ia zolo[3,2-b][1,2,4]-
ben zoth ia d ia zin e 5,5-Dioxid e (28). To a mixture of 25 (1.0
g, 3.9 mmol) in THF (20 mL) was added NBS (0.7 g, 4.0 mmol).
The mixture was stirred at room temperature for 30 min, and
the solvent was then removed in vacuo at 60 °C. The oily
residue was mixed with water (20 mL) to produce a solid which
was collected by filtration. The crude product was recrystal-
lized from methanol and water (1:1) to furnish 28 (0.92 g,
71%): mp 151-152 °C; 1H NMR (100 MHz, DMSO-d6) δ 3.45-
3.56 (m, 2 H, CH2), 3.77-4.05 (m, 2 H, CH2), 5.61-5.81 (m, 1
H, CH), 7.45-7.92 (m, 4 H, Ar-H); 13C NMR (25 MHz, DMSO-
d6) δ 31.3, 34.4, 59.0, 121.4, 124.4, 126.3, 126.4, 134.6, 142.3,
160.7; MS m/z 333 (M+), 253 (M+ - 80), 239 (M+ - 94). Anal.
(C10H9N2BrS2O2) C, H, N.
3-(Br om om eth yl)-2,3-d ih yd r o-1H-im id a zo[1,2-b][1,2,4]-
ben zoth ia d ia zin e 5,5-Dioxid e (30). To a mixture of 27 (0.63
g, 2.67 mmol) in THF was added NBS (0.5 g, 2.8 mmol). The
mixture was stirred at room temperature, and the solvent was
then removed in vacuo. The oily residue was mixed with CH3-
CN (20 mL) to form a solid which was collected by filtration
and recrystallized from methanol to furnish 30 (0.16 g, 72%):
1
mp 271-273 °C; H NMR (100 MHz, DMSO-d6) δ 3.63 (m, 2
H, CH2), 3.86 (m, 2 H, CH2), 5.06 (m, 1 H, CH), 7.19 (t, 2 H, J
) 7.1 Hz, Ar-H), 7.52-7.81 (m, 2 H, Ar-H), 8.14 (br s, 1 H,
NH); 13C NMR (25 MHz, DMSO-d6) δ 35.9, 44.1, 53.7, 121.4,
3-(Allylth io)-4H-1,2,4-ben zoth iadiazin e 1,1-Dioxide (25).
To a solution of 22 (2.0 g, 9.35 mmol) and sodium hydroxide

Quinazolines and 1,2,4-Benzothiadiazine 1,1-Dioxides
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 17 3137
122.1, 123.2, 124.6, 134.2, 145.4, 153.5; MS m/z 316 (M+), 236
(M+ - 80). Anal. (C10H10N3BrO2S) C, H, N.
2-Me t h yl-3-b r om oim id a zo[1,2-c]q u in a zolin -5(6H )-
on e (40). To a suspension of 39 (0.6 g, 3.01 mmol) in carbon
tetrachloride (30 mL) was dropwise added bromine (0.3 mL,
5.92 mmol). The mixture was stirred at room temperature
for 24 h. The solvent was then removed in vacuo, and to the
residue was added acetone (20 mL). The solvent was then
removed by rotavaporatoration to get a white solid which was
recrystallized from CH3CN to yield 40 (0.71 g, 85%): mp 253-
3-[[4-(2-Meth oxyp h en yl)p ip er a zin -1-yl]m eth yl]-2,3-d i-
h yd r o-1H-im id a zo[1,2-b][1,2,4]ben zoth ia d ia zin e 5,5-Di-
oxid e (33a ) a n d 3-Meth ylen e-2,3-d ih yd r o-1H-im id a zo[1,2-
b][1,2,4]ben zoth ia d ia zin e 5,5-Dioxid e (35). Compound 33a
was prepared in 46% yield using a procedure similar to that
which afforded 16a . An analytical sample was recrystallized
from DMF and ethanol: mp 232-233 °C; 1H NMR (300 MHz,
DMSO-d6) δ 2.50-2.56 (m, 4 H, 2 CH2), 2.68-2.78 (m, 2 H,
CH2), 2.93 (br s, 4 H, 2 CH2), 3.46 (t, 1 H, J ) 6.8 Hz, Ar-H),
3.76 (s, 3 H, -OCH3), 3.79 (t, 1 H, J ) 9.3 Hz, Ar-H), 4.82
(m, 1 H, CH), 6.86-6.95 (m, 4 H, Ar-H), 7.14-7.20 (m, 2 H,
Ar-H), 7.58 (t, 1 H, J ) 7.0 Hz, Ar-H), 7.76 (d, 1 H, J ) 7.9
Hz, Ar-H), 8.29 (s, 1 H, NH); 13C NMR (75 MHz, DMSO-d6)
δ 44.0, 50.0, 53.2, 53.6, 55.3, 60.3, 111.9, 117.9, 120.8, 121.6,
122.0, 122.4, 123.4, 124.7, 134.2, 141.1, 146.1, 151.9, 154.1;
MS m/z 427 (M+). Anal. (C21H25N5O3S) C, H, N.
1
255 °C; H NMR (100 MHz, DMSO-d6) δ 2.58 (s, 3 H, CH3),
7.27-7.68 (m, 3 H, Ar-H), 8.09 (d, 1 H, J ) 8.4 Hz, Ar-H),
11.84 (s, 1 H, NH); 13C NMR (25 MHz, DMSO-d6) δ 11.4, 111.5,
115.4, 118.8, 122.3, 123.2, 130.3, 145.3; MS m/z 278 (M+). Anal.
(C11H8N3BrO) C, H, N.
2-(Br om om et h yl)-3-b r om oim id a zo[1,2-c]q u in a zolin -
5(6H)-on e (41). To a suspension of 39 (2.1 g, 10.3 mmol) in
a mixture of dichloroethane and carbon tetrachloride (2:1, 60
mL) were added AIBN (3.4 g, 20.68 mmol) and NBS (3.68 g,
20.68 mmol). The resulting mixture was stirred at room
temperature for 2 days. The solid was collected by filtration
and dried at 60 °C for 24 h. The crude product was purified
by column chromatography (silica gel, 4.1 × 22.3 cm, 70-230
mesh; solvent system, CHCl3/MeOH ) 97:3). The desired
portion (Rf ) 0.56, solvent system, CHCl3/MeOH ) 97:3) was
collected, and the solvent was then removed in vacuo. The
residue was recrystallized from DMF and acetonitrile to give
Compound 35: 24% yield, mp 252 °C dec; 1H NMR (200
MHz, DMSO-d6) δ 4.26 (s, 2 H, CH2), 4.85 (s, 1 H, dC-H),
5.30 (s, 1 H, dC-H), 7.22 (t, 2 H, J ) 8 Hz, Ar-H), 7.62 (t, 1
H, J ) 8 Hz, Ar-H), 7.83 (d, 1 H, J ) 8 Hz, Ar-H), 8.60 (br
s, 1 H, NH); MS m/z 235 (M+). Anal. (C9H9N3O2S) C, H, N.
3-[[4-(2-Ch lor op h en yl)p ip er a zin -1-yl]m eth yl]-2,3-d ih y-
d r o-1H-im id a zo[1,2-b][1,2,4]ben zoth ia d ia zin e 5,5-Diox-
id e (33b). Compound 33b was prepared in 50% yield using a
procedure similar to that which afforded 16a . An analytical
sample was recrystallized from DMF and water: mp 225-
226 °C; 1H NMR (300 MHz, DMSO-d6) δ 2.52-2.93 (m, 6 H, 3
CH2), 2.96 (br s, 4 H, 2 CH2), 3.43-3.49 (m, 1 H, -CH-), 3.80
(t, 1 H, J ) 9.2 Hz, -CH-), 4.82-4.86 (m, 1 H, -CH-), 7.00-
7.05 (dt, 1 H, J ) 1.5, 8.3 Hz, Ar-H), 7.13-7.20 (m, 3 H, Ar-
H), 7.25-7.31 (dt, 1 H, J ) 1.5, 8.5 Hz, Ar-H), 8.38-7.40 (dd,
1 H, J ) 1.4, 7.9 Hz, Ar-H), 7.58 (t, 1 H, J ) 6.9 Hz, Ar-H),
7.78 (d, 1 H, J ) 7.83 Hz, Ar-H), 8.32 (br s, 1 H, NH, D2O
exchangeable); 13C NMR (75 MHz, DMSO-d6) δ 44.4, 51.1, 53.4,
53.8, 60.6, 121.2, 122.0, 122.5, 123.7, 124.3, 125.1, 128.0, 128.5,
130.7, 134.6, 146.2, 149.3, 154.5; MS m/z 431 (M+, 70%), 432
(M+ + 1), 433 (M+ + 2), 434 (M+ + 3), 209 (M+ - 222, 100%).
Anal. (C20H22N5SO2Cl) C, H, N.
1
3.38 g of 41 in 91.6% yield: mp 236 °C; H NMR (300 MHz,
DMSO-d6) δ 4.67 (s, 2 H, CH2), 7.29 (t, 2 H, J ) 6.6 Hz, Ar-
H), 7.54 (t, 1 H, J ) 7.8 Hz, Ar-H), 8.06 (d, 1 H, J ) 7.2 Hz,
Ar-H), 11.98 (s, 1 H, NH); 13C NMR (75 MHz, DMSO-d6) δ
26.1, 98.9, 112.3, 116.0, 123.0, 123.8, 131.5, 135.7, 140.3, 145.1,
145.2; MS m/z 407 (M+). Anal. HREIMS (exact mass HREMS)
calcd for C11H7ON3Br2 m/e 354.8956, found 354.8956.
2-[[4-(2-Meth oxyp h en yl)p ip er a zin -1-yl]m eth yl]-3-br o-
m oim id a zo[1,2-c]qu in a zolin -5(6H)-on e (42a ). To a sus-
pension of 41 (1.0 g, 2.8 mmol) in acetonitrile (50 mL) were
added 1-(2-methoxyphenyl)piperazine hydrochloride (0.83 g,
5.36 mmol) and sodium bicarbonate (1.0 g, 11.1 mol). The
mixture was refluxed for 24 h. The solid was the collected,
and filtrate was moved to the refrigerator. The resulting
precipitate was collected, and the combined crude product was
purified by column chromatography (silica gel, 2.3 × 22.5 cm,
70-230 mesh; solvent system, CHCl3/CH3OH ) 98:2). The
desired portion (Rf ) 0.3, solvent system, CHCl3/CH3OH ) 98:
2) was collected, and the solvent was removed in vacuo. The
residue was recrystallized from methanol with a small amount
of chloroform to give 0.74 g of 42a in 59% yield: mp 230 °C
dec; 1H NMR (300 MHz, DMSO-d6) δ 2.64 (s, 4 H, 2 CH2), 2.90
(s, 4 H, 2 CH2), 3.75 (s, 3 H, OCH3), 4.01 (s, 2 H, CH2), 6.88
(m, 4 H, Ar-H), 7.28-7.35 (m, 2 H, Ar-H), 7.56 (t, 1 H, J )
8.4 Hz, Ar-H), 8.08 (d, 1 H, J ) 6.7 Hz, Ar-H), 11.93 (s, 1 H,
Ar-H); 13C NMR (75 MHz, DMSO-d6) δ 50.5, 50.5, 53.0, 55.7,
111.7, 112.2, 116.0, 118.3, 121.2, 122.7, 122.9, 123.2, 123.9,
124.6, 131.2, 135.8, 141.6, 144.4 145.3, 152.3; MS m/z 467 (M+
- 1). Anal. (C22H22N5O2Br‚1/2H2O) C, H, N.
3-Met h ylen e-2,3-d ih yd r ot h ia zolo[3,2-b][1,2,4]b en zo-
th ia d ia zin e 5,5-Dioxid e (34). This was prepared in 93%
yield by a similar approach which afforded compound 17. An
analytical sample was recrystallized from methanol: mp 194-
1
195 °C; H NMR (400 MHz, DMSO-d6) δ 4.28 (s, 2 H, CH2),
5.14 (s, 1 H, dCH), 5.50 (s, 1 H, dCH), 7.48 (d, 1 H, J ) 8.3
Hz, Ar-H), 7.54 (t, 1 H, J ) 7.3 Hz, Ar-H), 7.81 (t, 1 H, J )
8.3 Hz, Ar-H), 8.03 (d, 1 H, J ) 7.3 Hz, Ar-H); 13C NMR
(100.4 MHz, DMSO-d6) δ 31.2, 99.3, 122.2, 124.3, 126.5, 126.9,
135.3,138.7,141.7,159.0;MS m/z252 (M+). Anal. (C10H8N2O2S2)
C, H, N.
3-Met h ylt h ia zolo[3,2-b][1,2,4]b en zot h ia d ia zin e 5,5-
Dioxid e (36). Compound 36 was prepared in 90% yield using
a procedure similar to that which afforded 19: mp 179-180
1
2-[[4-(2-Ch lor op h en yl)p ip er a zin -1-yl]m et h yl]-3-b r o-
m oim id a zo[1,2-c]qu in a zolin -5(6H)-on e (42b). This was
prepared in 44.7% yield by a similar approach which afforded
42a . The crude product was isolated by column chromatog-
raphy (solvent system, CHCl3/EtOAc/n-hexane ) 1:2:2, Rf )
0.21) and recrystallized from MeOH with a small amount of
°C; H NMR (100 MHz, DMSO-d6) δ 2.85 (s, 3 H, CH3), 7.03
(s, 1 H, dCH), 7.53-7.89 (m, 2 H, Ar-H), 8.19-8.35 (m, 2 H,
Ar-H); 13C NMR (25 MHz, DMSO-d6) δ 17.8, 105.4, 119.5,
123.8, 124.2, 128.3, 132.4, 133.6, 135.0, 167.9; MS m/z 252
(M+). Anal. (C10H8N2O2S2) C, H, N.
2-Meth ylim id a zo[1,2-c]qu in a zolin -5(6H)-on e (39).
A
1
DMF: mp 250 °C; H NMR (300 MHz, DMSO-d6) δ 2.67 (s, 4
mixture of 38 (6.24 g, 22.3 mmol) and potassium carbonate
(7.7 g, 0.06 mol) in DMF (100 mL) was heated at 90 °C for 2
h. The solid was removed by filtration, and the filtrate was
rotatory-evaporated to dryness. The residue was purified by
column chromatography (silica gel, 4.6 × 20 cm, 70-230 mesh;
solvent system, n-hexane/EtOAc/EtOH ) 2:7:1). The desired
fraction (Rf ) 0.61) was collected, and the solvent was then
removed in vacuo. The solid was recrystallized from ethanol
to give 39 (3.92 g, 88%): mp 273-274 °C; 1H NMR (100 MHz,
DMSO-d6) δ 2.31 (s, 3 H, CH3), 7.19-7.57 (m, 4 H, Ar-H),
8.05 (d, 1 H, J ) 7.8 Hz, Ar-H), 11.89 (s, 1 H, NH); 13C NMR
(25 MHz, DMSO-d6) δ 13.8, 109.7, 111.9, 115.6, 122.4, 123.1,
129.9, 134.8, 140.5, 142.4, 144.5; MS m/z 199 (M+). Anal.
(C11H9N3O) C, H, N.
H, 2 CH2), 2.92 (s, 4H, 2 CH2), 7.01 (t, 1 H, J ) 9.7 Hz, Ar-
H), 7.10 (d, 1 H, J ) 8.3 Hz, Ar-H), 7.23-7.39 (m, 4 H, Ar-
H), 7.56 (t, 1 H, J ) 7.0 Hz, Ar-H), 8.07 (d, 1 H, J ) 8.3 Hz,
Ar-H), 11.94 (s, 1 H, NH); 13C NMR (75 MHz, DMSO-d6) δ
50.5, 51.2, 52.8, 111.7, 116.0, 121.2, 122.9, 123.2, 123.9, 124.2,
124.5, 128.4, 130.6, 131.4, 135.8, 144.4, 145.3, 149.4; MS m/z
473 (M+). Anal. (C21H19N5BrClO) C, H, N.
2-[[4-(2-Meth oxyph en yl)piper azin -1-yl]m eth yl]-3-br om o-
6-m eth ylim id a zo[1,2-c]qu in a zolin -5(6H)-on e (43a ). To a
mixture of 42a (0.3 g, 0.64 mmol) in DMF (20 mL) was added
sodium hydride (0.05 g, 2.1 mmol). The mixture was stirred
at room temperature for 15 min. Methyl iodide (0.056 mL,
0.79 mmol) was added, and the solution was further stirred

3138 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 17
Chern et al.
at room temperature for 20 min. The solvent was removed in
vacuo, and water (20 mL) was added with stirring. The solid
that was formed was collected by filtration. The crude product
was dried at 60 °C for 12 h and then was recrystallized from
EtOH to afford 0.2 g of 43a in 65% yield: mp 242-243 °C; 1H
NMR (300 MHz, CDCl3) δ 2.87 (s, 4 H, 2 CH2), 3.81 (s, 4 H, 2
CH2), 3.74 (s, 3 H, OCH3), 3.86 (s, 3 H, CH3), 4.14 (s, 2 H,
CH2), 6.91 (m, 4 H, Ar-H), 7.31 (m, 2 H, Ar-H), 7.58 (t, 1 H,
J ) 7.2 Hz, Ar-H), 8.36 (d, 1 H, J ) 7.8 Hz, Ar-H); 13C NMR
(75 MHz, CDCl3) δ 31.6, 51.1, 51.6, 53.8, 55.9, 111.7, 113.4,
114.8, 118.8, 121.5, 123.4, 124.3, 124.5, 124.8, 125.4, 131.8,
137.1, 142.0, 144.2, 146.4, 152.9. Anal. (C23H24N5BrO2‚1/4H2O)
C, H, N.
2-[[4-(2-Ch lor op h en yl)p ip er a zin -1-yl]m eth yl]-3-br om o-
6-m eth ylim id a zo[1,2-c]qu in a zolin -5(6H)-on e (43b). This
was prepared in 52% yield by a similar approach which
afforded 43a . An analytical sample was recrystallized from
methanol and chloroform: mp 237-238 °C; 1H NMR (300
MHz, CDCl3) δ 2.85 (s, 4 H, 2 CH2), 3.07 (s, 4 H, 2 CH2), 3.75
(s, 3 H, CH3), 4.13 (s, 2 H, CH2), 6.94 (t, 1 H, J ) 7.6 Hz, Ar-
H), 7.00 (d, 1 H, J ) 7.6 Hz, Ar-H), 7.19 (t, 1 H, J ) 7.5 Hz,
Ar-H), 7.34 (m, 3 H, Ar-H), 7.58 (t, 1 H, J ) 7.2 Hz, Ar-H),
8.36 (dd, 1 H, J ) 1.59, 8.1 Hz, Ar-H); 13C NMR (75 MHz,
CDCl3) δ 31.6, 51.6, 51.7, 53.8, 113.4, 114.8, 121.0, 124.1, 124.2,
124.5, 124.8, 125.5, 128.1, 129.4, 131.2, 131.8, 137.1, 144.2,
146.4, 150.0; MS m/z 487 (M+). Anal. (C22H21N5BrClO‚1/2H2O)
C, H, N.
pared in 56% yield by a similar approach which afforded 43a :
mp 197-199 °C; H NMR (200 MHz, DMSO-d6) δ 2.66 (m, 4
1
H, 2 CH2), 2.96 (m, 4 H, 2 CH2), 3.65 (s, 3 H, NCH3), 4.10 (s,
2 H, CH2), 7.00-7.62 (m, 8 H, Ar-H), 8.20 (d, 1 H, J ) 7.3
Hz, Ar-H). Anal. HREIMS (exact mass HREMS) calcd for
C
22H22ON5Cl m/z 407.1513, found 407.1516.
3-Meth ylim id a zo[1,2-c]qu in a zolin -5(6H)-on e (47). This
was prepared in 67% yield by a similar approach which
afforded 39. An analytical sample was recrystallized from
ethanol: mp 262-264 °C; 1H NMR (300 MHz, DMSO-d6) δ
2.60 (s, 3 H, CH3), 7.07 (s, 1 H, Ar-H), 7.22-7.34 (m, 2 H,
Ar-H), 7.44-7.57 (m, 1 H, Ar-H), 8.04 (d, 1 H, J ) 11 Hz,
Ar-H); 13C NMR (75 MHz, DMSO-d6) δ 11.8, 112.8, 115.4,
122.4, 123.2, 126.5, 129.7, 129.9, 135.1, 143.3, 146.7; MS m/z
199 (M+). Anal. (C11H9N3O) C, H, N.
2-Br om o-3-m e t h ylim id a zo[1,2-c]q u in a zolin -5(6H )-
on e (48). This was prepared in 55% yield by a similar
approach which afforded 40. An analytical sample was
recrystallized from CH3CN: mp 255 °C dec; 1H NMR (300
MHz, DMSO-d6) δ 2.25 (s, 3 H, CH3), 7.25-7.31 (m, 2 H, Ar-
H), 7.51 (t, 1 H, J ) 6.9 Hz, Ar-H), 8.04 (d, 1 H, J ) 8.1 Hz,
Ar-H), 11.87 (s, 1 H, NH); 13C NMR (75 MHz, DMSO-d6) δ
12.8, 112.0, 115.5, 122.3, 123.3, 130.5, 135.0, 140.3, 144.8.
Anal. (C11H8N3BrO) C, H, N.
2-Br om o-3-(b r om om et h yl)im id a zo[1,2-c]q u in a zolin -
5(6H)-on e (49). This was obtained in 90% yield using a
procedure similar to that which afforded 41. An analytical
sample was recrystallized from chloroform: mp 217 °C; 1H
NMR (300 MHz, DMSO-d6) δ 4.67 (s, 2 H, CH2), 7.30 (m, 2 H,
Ar-H), 7.55 (t, 1 H, J ) 7.7 Hz, Ar-H), 8.07 (d, 1 H, J ) 7.1
Hz, Ar-H), 11.98 (s, 1 H, NH); 13C NMR (75 MHz, DMSO-d6)
δ 26.1, 98.9, 112.3, 116.0, 123.0, 123.8, 131.5, 131.5, 140.3,
145.2; MS m/z 357 (M+). Anal. (C11H7N3Br2O) C, H, N.
2-Br om o-3-[[4-(2-m eth oxyp h en yl)p ip er a zin -1-yl]m eth -
yl]im id a zo[1,2-c]qu in a zolin -5(6H)-on e (50a ). This was
prepared in 53% yield by a similar approach which afforded
42a . Compound 50a (Rf ) 0.33, CHCl3/MeOH ) 98:2, silica
gel) was isolated by column chromatography. An analytical
sample was recrystallized from DMF: mp 244-245 °C; 1H
NMR (300 MHz, DMSO-d6) δ 2.64 (s, 4 H, CH2), 2.91 (m, 4 H,
CH2), 3.76 (s, 3 H, OCH3), 4.01 (s, 2 H, CH2), 6.89 (m, 4 H,
Ar-H), 7.32 (q, 2 H, J ) 6.4 Hz, Ar-H), 7.56 (t, 1 H, J ) 7.6
Hz, Ar-H), 8.08 (d, 1 H, J ) 7.6 Hz, Ar-H); 13C NMR (75
MHz, DMSO-d6) δ 50.1, 52.5, 55.3, 111.3, 111.8, 115.6, 117.9,
120.8, 122.3, 122.4, 122.7, 123.5, 124.2, 131.0, 135.4, 141.2,
144.0, 144.9, 152.0; MS m/z 467 (M+ - 1). Anal. (C22H22N5-
BrO2) C, H, N.
2-[[4-(2-Meth oxyph en yl)piper azin -1-yl]m eth yl]im idazo-
[1,2-c]qu in a zolin -5(6H)-on e (44a ). To a solution of 42a
(0.32 g, 0.68 mmol) in DMF (30 mL) under nitrogen was added
10% Pd/C (0.1 g). A Fisher-Porter bottle was degassed three
to four times on the vacuum line and then pressurized to 40
psi with hydrogen. The reaction mixture was shaken at room
temperature for 20 h and was then filtered through a bed of
Celite. The solvent was removed in vacuo, and acetone (10
mL) was added to the oily residue. The solid was collected by
filtration and was recrystallized from CH3CN and H2O (20 mL,
1:1) with 3 drops of triethylamine to give 0.17 g of 44a in 63%
1
yield: mp 212 °C; H NMR (300 MHz, DMSO-d6) δ 2.63 (s, 4
H, 2 CH2), 2.95 (s, 4 H, 2 CH2), 3.74 (s, 3 H, OCH3), 4.10 (s, 2
H, CH2), 6.80-6.94 (m, 4 H, Ar-H), 7.27 (t, 2 H, J ) 7.5 Hz,
Ar-H), 7.32 (s, 1 H, CH), 7.49 (t, 1 H, J ) 7.3 Hz, Ar-H),
8.08 (d, 1 H, J ) 7.8 Hz, Ar-H), 11.77 (s, 1 H, NH); 13C NMR
(75 MHz, DMSO-d6) δ 50.1, 51.8, 52.5, 55.2, 111.9, 112.5, 115.4,
117.9, 120.8, 122.3, 122.5, 123.2, 127.3, 130.2, 135.1, 141.2,
144.0, 146.3, 152.0. Anal. (C22H23N5O2) C, H, N.
2-[[4-(2-Ch lor op h en yl)p ip er a zin -1-yl]m eth yl]im id a zo-
[1,2-c]qu in a zolin -5(6H)-on e (44b). This was prepared in
80% yield by a similar approach which afforded 44a . An
analytical sample was recrystallized from CH3CN: mp 210 °C
dec; 1H NMR (300 MHz, DMSO-d6) δ 2.67 (s, 4 H, 2 CH2), 2.98
(s, 4 H, 2 CH2), 4.13 (s, 2 H, CH2), 7.02 (t, 1 H, J ) 7.7 Hz,
Ar-H), 7.15 (d, 1 H, J ) 7.0 Hz, Ar-H), 7.30 (m, 4 H, Ar-H),
7.51 (t, 1 H, J ) 7.7 Hz, Ar-H), 8.10 (d, 1 H, J ) 7.8 Hz, Ar-
H), 11.79 (s, 1 H, NH); 13C NMR (100 MHz, DMSO-d6) δ 50.9,
51.7, 52.4, 112.5, 115.5, 120.8, 122.6, 123.3, 123.8, 127.3, 127.6,
128.0, 130.2, 131.6, 135.1, 146.3, 149.0. Anal. HREIMS (exact
mass HREMS) calcd for C21H20N5OCl m/z 393.1352, found
393.1357.
2-Br om o-3-[[4-(2-ch lor op h en yl)p ip er a zin -1-yl]m eth yl]-
im id a zo[1,2-c]qu in a zolin -5(6H)-on e (50b). This was pre-
pared in 28.7% yield by a similar approach which afforded 42a .
An analytical sample was recrystallized from ethanol: mp
1
223-224 °C; H NMR (300 MHz, DMSO-d6) δ 2.68 (s, 4 H, 2
CH2), 2.92 (s, 4 H, 2 CH2), 4.03 (s, 2 H, CH2), 7.01 (t, 1 H, J )
7.5 Hz, Ar-H), 7.10 (d, 1 H, J ) 8.3 Hz, Ar-H), 7.31 (m, 4 H,
Ar-H), 7.56 (t, 1 H, J ) 7.0 Hz, Ar-H), 8.08 (d, 1 H, J ) 6.7
Hz, Ar-H), 11.91 (s, 1 H, NH); 13C NMR (75 MHz, DMSO-d6)
δ 50.5, 51.3, 52.8, 111.7, 116.0, 121.2, 122.9, 123.2, 123.9, 124.2,
124.6, 128.0, 128.4, 130.6, 131.4, 135.8, 144.5, 145.3, 149.4;
MS m/z 473 (M+). Anal. (C21H19N5BrClO) C, H, N.
2-[[4-(2-Me t h o x y p h e n y l)p ip e r a zin -1-y l]m e t h y l]-6-
m eth ylim id a zo[1,2-c]qu in a zolin -5(6H)-on e (45a ). This
was prepared in 61% yield by a similar approach which
afforded 43a . An analytical sample was recrystallized from
CH3CN and water (1:1, 20 mL) with 3 drops of triethylamine:
mp 176 °C; 1H NMR (300 MHz, CDCl3) δ 2.83 (s, 4 H, 2 CH2),
3.13 (s, 4 H, 2 CH2), 3.74 (s, 3 H, OCH3), 3.86 (s, 3 H, CH3),
4.20 (s, 2 H, CH2), 6.84-6.96 (m, 4 H, Ar-H), 7.31 (m, 3 H,
Ar-H), 7.55 (t, 1 H, J ) 8.1 Hz, Ar-H), 8.36 (dd, 1 H, J ) 1.5,
6.3 Hz, Ar-H); 13C NMR (75 MHz, CDCl3) δ 31.3, 51.2, 53.5,
53.9, 55.9, 111.7, 111.6, 114.8, 118.8, 121.5, 123.4, 124.4, 124.5,
128.7, 131.1, 132.8, 136.9, 141.9, 144.6, 147.8, 152.8; MS m/z
403 (M+). Anal. (C23H25N5O2‚1/4H2O) C, H, N.
2-Br om o-3-[[4-(2-m eth oxyp h en yl)p ip er a zin -1-yl]m eth -
yl]-6-m eth ylim idazo[1,2-c]qu in azolin -5(6H)-on e (51a). This
was prepared in 57% yield by a similar approach which
afforded 43a . An analytical sample was recrystallized from
ethanol and DMF: mp 242-245 °C; 1H NMR (300 MHz,
CDCl3) δ 2.86 (s, 4 H, 2 CH2), 3.08 (s, 4 H, 2 CH2), 3.74 (s, 3
H, OCH3), 3.86 (s, 3 H, CH3), 4.13 (s, 2 H, CH2), 6.91 (m, 4 H,
Ar-H), 7.31 (m, 2 H, Ar-H), 7.58 (t, 1 H, J ) 8.7 Hz, Ar-H),
8.35 (dd, 1 H, J ) 1.4, 7.9 Hz, Ar-H); 13C NMR (75 MHz,
CDCl3) δ 31.6, 51.1, 51.6, 53.8, 55.9, 111.7, 113.4, 114.8, 118.8,
121.5, 123.4, 124.3, 124.5, 124.6, 124.8, 131.8, 137.1, 141.9,
144.2, 152.9; MS m/z 481 (M+ - 1). Anal. (C23H24N5O2Br) C,
H, N.
2-[[4-(2-Ch lor op h en yl)p ip er a zin -1-yl]m eth yl]-6-m eth -
ylim id a zo[1,2-c]qu in a zolin -5(6H)-on e (45b). This was pre-
2-Br om o-3-[[4-(2-ch lor op h en yl)p ip er a zin -1-yl]m eth yl]-
6-m eth ylim id a zo[1,2-c]qu in a zolin -5(6H)-on e (51b). This

Quinazolines and 1,2,4-Benzothiadiazine 1,1-Dioxides
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 17 3139
was prepared in 50% yield by a similar approach which
afforded 43a . An analytical sample was recrystallized from
methanol and chloroform: mp 232-233 °C; 1H NMR (300
MHz, CDCl3) δ 2.85 (s, 4 H, 2 CH2), 3.07 (s, 4 H, 2 CH2), 3.75
(s, 3 H, CH3), 4.13 (s, 2 H, CH2), 6.97 (t, 1 H, J ) 7.7 Hz, Ar-
H), 7.01 (d, 1 H, J ) 6.7 Hz, Ar-H), 7.19 (t, 1 H, J ) 6.9 Hz,
Ar-H), 7.33 (m, 3 H, Ar-H), 7.59 (t, 1 H, J ) 7.2 Hz, Ar-H),
8.37 (d, 1 H, J ) 7.8 Hz, Ar-H); 13C NMR (75 MHz, CDCl3) δ
31.6, 51.6, 51.6, 53.8, 113.4, 114.8, 121.0, 124.1, 124.3, 124.6,
124.8, 125.4, 128.1, 129.4, 131.2, 131.8, 137.1, 144.2, 146.4,
149.9; MS m/z 486.9 (M+). Anal. (C22H21N5BrClO) C, H, N.
3-[[4-(2-Meth oxyph en yl)piper azin -1-yl]m eth yl]im idazo-
[1,2-c]qu in a zolin -5(6H)-on e (52a ). This was prepared in
81.6% yield by a similar approach which afforded 44a . An
analytical sample was recrystallized from CH3CN: mp 214-
215 °C; 1H NMR (300 MHz, DMSO-d6) δ 2.63 (s, 4 H, 2 CH2),
2.95 (s, 4 H, 2 CH2), 3.74 (s, 3 H, OCH3), 4.10 (s, 2 H, CH2),
6.82-6.92 (m, 4 H, Ar-H), 7.27 (t, 2 H, J ) 7.5 Hz, Ar-H),
7.32 (s, 1 H, dCH-), 7.49 (t, 1 H, J ) 8.5 HZ, Ar-H), 8.08 (d,
1 H, J ) 7.7 Hz, Ar-H), 11.75 (s, 1 H, NH); 13C NMR (75 MHz,
DMSO-d6) δ 50.1, 51.8, 52.5, 55.2, 111.9, 112.5, 115.4, 117.9,
120.8, 122.3, 122.5, 123.2, 127.3, 130.2, 131.5, 135.1, 141.2,
144.0, 146.3, 152.0. Anal. HREIMS (exact mass HREMS)
calcd for C22H23O2N5 m/z 390.1932, found 390.1933.
DMSO-d6) δ 2.82 (s, 4 H, 2 CH2), 2.99 (s, 4 H, 2 CH2), 3.79 (s,
3 H, OCH3), 3.95 (s, 2 H, CH2), 6.85-6.94 (m, 4 H, Ar-H),
7.64 (m, 1 H, Ar-H), 7.86 (m, 1 H, Ar-H), 8.21 (m, 1 H, Ar-
H), 8.75 (d, 1 H, J ) 8.67 Hz, Ar-H); 13C NMR (75 MHz,
DMSO-d6) δ 50.5, 52.3, 54.2, 55.7, 101.9, 112.3, 118.4, 119.4,
119.5, 121.2, 123.0, 127.6, 128.1, 133.6, 133.9, 138.6, 141.3,
152.4, 166.7; MS m/z 485 (M+). Anal. (C22H21N4O2SBr) C, H,
N.
3-[[4-(2-Ch lor op h en yl)p ip er a zin -1-yl]m eth yl]-2-br om o-
5H-th ia zolo[2,3-b]qu in a zolin -5-on e (55b). Compound 55b
was prepared in 57% yield using a procedure similar to that
which afforded 42a . An analytical sample was recrystallized
1
from ethanol: mp 242-244 °C; H NMR (300 MHz, DMSO-
d6) δ 2.84 (s, 4 H, 2 CH2), 3.00 (s, 4 H, 2 CH2), 3.97 (s, 2 H,
CH2), 7.04 (t, 1 H, J ) 6.96 Hz, Ar-H), 7.14 (d, 1 H, J ) 6.69
Hz, Ar-H), 7.28 (t, 1 H, J ) 7.0 Hz, Ar-H), 7.41 (d, 1 H, J )
7.86 Hz, Ar-H), 7.64 (t, 1 H, J ) 7.5 Hz, Ar-H), 7.89 (t, 1 H,
J ) 7.1 Hz, Ar-H), 8.21 (dd, 1 H, J ) 1.53, 6.33 Hz, Ar-H),
8.73 (d, 1 H, J ) 8.79 Hz, Ar-H); 13C NMR (75 MHz, DMSO-
d6) δ 51.7, 52.9, 54.8, 103.4, 119.0, 120.2, 121.0, 124.7, 128.1,
128.2, 129.4, 129.7, 131.3, 133.5, 133.7, 139.0, 149.3, 169.1;
MS m/z 489 (M+). Anal. (C21H18N4OBrClS) C, H, N.
3-[[4-(2-Meth oxyph en yl)piper azin -1-yl]m eth yl]-5H-th ia-
zolo[2,3-b]qu in a zolin -5-on e (56a ). Compound 56a was
prepared in 60% yield using a procedure similar to that which
afforded 44a . An analytical sample was recrystallized from
ethanol: mp 243-244 °C; 1H NMR (300 MHz, DMSO-d6) δ
2.73 (s, 4 H, 2 CH2), 2.97 (d, 4 H, 2 CH2), 3.78 (s, 3 H, OCH3),
3.93 (s, 2 H, CH2), 6.86 (m, 4 H, Ar-H), 7.35 (s, 1 H, dC-H),
7.62 (t, 1 H, J ) 7.5 Hz, Ar-H), 7.86 (t, 1 H, J ) 7.02 Hz,
Ar-H), 8.21 (d, 1 H, J ) 7.86 Hz, Ar-H), 8.58 (d, 1 H, J )
8.49 Hz, Ar-H); 13C NMR (75 MHz, CDCl3) δ 51.0, 53.3, 56.0,
58.3, 110.7, 111.8, 118.7, 118.8, 119.8, 121.6, 123.9, 127.9,
129.6, 133.4, 136.0, 138.8, 141.3, 152.8, 168.9; MS m/z 406
(M+). Anal. (C22H22N4O2S‚1/4H2O) C, H, N.
3-[[4-(2-Ch lor op h en yl)p ip er a zin -1-yl]m eth yl]-5H-th ia -
zolo[2,3-b]qu in a zolin -5-on e (56b). Compound 56b was
prepared in 51% yield using a procedure similar to that which
afforded 44a . An analytical sample was recrystallized from
ethanol: mp 253-255 °C; 1H NMR (300 MHz, DMSO-d6) δ
2.75 (s, 4 H, 2 CH2), 2.99 (s, 4 H, 2 CH2), 3.97 (s, 2 H, CH2),
7.03 (t, 1 H, J ) 8.3 Hz, Ar-H), 7.13 (d, 1 H, J ) 6.7 Hz, Ar-
H), 7.28 (t, 1 H, J ) 8.0 Hz, Ar-H), 7.37 (s, 1 H, dCH), 7.40
(d, 1 H, J ) 8.0 Hz, Ar-H), 7.63 (t, 1 H, J ) 7.5 Hz, Ar-H),
7.87 (t, 1 H, J ) 8.8 Hz, Ar-H), 8.22 (dd, 1 H, J ) 1.7, 7.9 Hz,
Ar-H), 8.58 (d, 1 H, J ) 8.5 Hz, Ar-H); 13C NMR (75 MHz,
DMSO-d6) δ 51.2, 52.3, 56.7, 111.2, 119.1, 119.3, 121.3, 124.4,
127.4, 128.0, 128.1, 128.5, 130.7, 133.3, 135.7, 138.4, 149.2,
164.8, 168.7; MS m/z 410 (M+). Anal. (C21H19N4OSCl)
C, H, N.
3-[[4-(2-Ch lor op h en yl)p ip er a zin -1-yl]m eth yl]im id a zo-
[1,2-c]qu in a zolin -5(6H)-on e (52b). This was prepared in
70% yield by a similar approach which afforded 44a . An
analytical sample was recrystallized from CH3CN: mp 221-
1
222 °C; H NMR (300 MHz, DMSO-d6) δ 2.65 (s, 4 H, CH2),
2.97 (s, 4 H, CH2), 4.10 (m, 2 H, CH2), 6.74-7.52 (m, 8 H, Ar-
H), 8.08 (d, 1 H, J ) 7.8 Hz, Ar-H), 11.76 (s, 1 H, NH); 13C
NMR (75 MHz, DMSO-d6) δ 50.9, 51.7, 52.4, 112.5, 115.5,
120.8, 122.6, 123.3, 123.8, 127.3, 127.6, 128.0, 130.2, 131.6,
135.1, 144.1, 146.3, 149.0. Anal. HREIMS (exact mass
HREMS) calcd for C21H20N5ClO m/z 393.1352, found 393.1352.
3-[[4-(2-Me t h o x y p h e n y l)p ip e r a zin -1-y l]m e t h y l]-6-
m eth ylim id a zo[1,2-c]qu in a zolin -5(6H)-on e (53a ). This
was prepared in 72.7% yield by a similar approach which
afforded 43a . An analytical sample was recrystallized from
1
methanol: mp 174-175 °C; H NMR (300 MHz, DMSO-d6) δ
2.64 (s, 4 H, 2 CH2), 2.95 (s, 4 H, 2 CH2), 3.65 (s, 3 H, CH3),
3.75 (s, 3 H, OCH3), 4.08 (s, 2 H, CH2), 6.89 (m, 4 H, Ar-H),
7.30 (s, 1 H, Ar-H), 7.37 (t, 1 H, J ) 7.14 Hz, Ar-H), 7.53 (d,
1 H, J ) 7.86 Hz, Ar-H), 7.61 (t, 1 H, J ) 7.2 Hz, Ar-H),
8.19 (d, 1 H, J ) 6.4 Hz, Ar-H); 13C NMR (75 MHz, DMSO-
d6) δ 31.0, 50.5, 52.5, 53.0, 55.7, 112.2, 113.7, 115.7, 118.3,
121.2, 122.7, 123.2, 123.9, 128.0, 130.9, 132.2, 136.6, 141.6,
143.6, 146.9, 152.4; MS m/z 403 (M+). Anal. (C23H25N5O2) C,
H, N.
3-[[4-(2-Ch lor op h en yl)p ip er a zin -1-yl]m eth yl]-6-m eth -
ylim id a zo[1,2-c]qu in a zolin -5(6H)-on e (53b). This was pre-
pared in 31% yield by a similar approach which afforded 43a .
An analytical sample was recrystallized from ethanol: mp
200-201 °C; 1H NMR (300 MHz, CDCl3) δ 2.82 (s, 4 H, 2 CH2),
3.11 (s, 4 H, 2 CH2), 3.74 (s, 3 H, CH3), 4.20 (s, 2 H, CH2), 6.95
(t, 1 H, J ) 6.7 Hz, Ar-H), 7.04 (d, 1 H, J ) 8.0 Hz, Ar-H),
7.19 (d, 1 H, J ) 7.1 Hz, Ar-H), 7.31 (m, 4 H, Ar-H), 8.36 (d,
1 H, J ) 7.9 Hz, Ar-H); 13C NMR (300 MHz, CDCl3) δ 31.3,
51.7, 53.4, 53.8, 114.8, 116.6, 121.0, 124.2, 124.4, 124.5, 128.1,
128.7, 129.3, 129.6, 131.1, 131.2, 132.9, 136.9, 144.6, 149.9;
MS m/z 407 (M+). Anal. (C22H22N5ClO) C, H, N.
(S)-(+)-3-[[4-(2-Meth oxyp h en yl)p ip er a zin -1-yl]m eth yl]-
5-(m eth ylth io)-2,3-dih ydr oim idazo[1,2-c]qu in azolin e ((S)-
(+)-57) a n d (R)-(-)-3-[[4-(2-Meth oxyp h en yl)p ip er a zin -
1-yl]m e t h yl]-5-(m e t h ylt h io)-2,3-d ih yd r oim id a zo[1,2-
c]qu in a zolin e ((R)-(-)-57). These were prepared according
to previous published procedures.19
(S)-(-)-3-[[4-(2-Meth oxyp h en yl)p ip er a zin -1-yl]m eth yl]-
2,3-d ih yd r oim id a zo[1,2-c]qu in a zolin -5(6H)-on e ((S)-(-)-
5). A solution of (S)-(+)-57 (1.2 g, 2.85 mmol) and NaOH (5.69
g, 142 mmol) in methanol (60 mL) and water (35 mL) was
refluxed for 17 h. Concentrated HCl (6.0 mL, 68 mmol) was
added to the cooled solution, and the methanol was evaporated
in vacuo. After addition of water (60 mL) the mixture was
extracted with dichloromethane (3 × 60 mL). The organic
solutions were dried over Na2SO4 (5 g), and solvent was
evaporated in vacuo. The residue was purified by column
chromatography (eluent EtOAc/CH3OH ) 10:1) to give 1.05 g
3-(Br om om eth yl)-2-br om o-5H-th ia zolo[2,3-b]qu in a zo-
lin -5-on e (54). Compound 54 was prepared in 61% yield using
a procedure similar to that which afforded 41. An analytical
sample was recrystallized from CH3CN and CHCl3: mp 221-
1
222 °C; H NMR (300 MHz, DMSO-d6) δ 5.16 (s, 2 H, CH2),
7.68 (t, 1 H, J ) 7.32 Hz, Ar-H), 7.93 (m, 1 H, Ar-H), 8.22-
8.26 (m, 2 H, Ar-H); 13C NMR (75 MHz, DMSO-d6) δ 27.0,
106.2, 117.4, 119.4, 127.9, 128.8, 134.1, 134.2, 137.7, 166.3.
Anal. HREIMS (exact mass HREMS) calcd for C11H6ON2-
SCBr2 m/e 381.8568, found 381.8570.
(94.0%) of (S)-(-)-5 as a colorless foam: [R]25 -33.0 (c 1.342,
D
CHCl3); 1H NMR (CDCl3) δ 9.65 (br s, 1 H, NH), 7.97 (dd, 1 H,
J ) 9.2, 1.3 Hz, ArH), 7.47 (t, 1 H, J ) 7.5 Hz, ArH), 7.13 (1
H, t, J ) 7.2 Hz, ArH), 7.01-6.85 (m, 5 H, ArH), 4.68-4.56
(m, 1 H, (S)-CH), 4.25-4.09 (m, 2 H, dNCH2), 3.86 (s, 3 H,
OCH3), 3.08-3.03 (m, 5 H), 2.85-2.83 (m, 2 H), 2.73-2.71 (m,
1 H); 13C NMR (CDCl3) δ 154.0, 152.8, 150.3, 141.9, 139.6,
3-[[4-(2-Meth oxyph en yl)piper azin -1-yl]m eth yl]-2-br om o-
5H-th ia zolo[2,3-b]qu in a zolin -5-on e (55a ). Compound 55a
was prepared in 67% yield using a procedure similar to that
which afforded 42a : mp 231 °C dec; 1H NMR (300 MHz,

3140 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 17
Chern et al.
133.9, 126.9, 123.7, 123.5, 121.5, 118.8, 115.7, 112.7, 111.7,
60.5, 59.9, 55.9, 55.0, 54.6, 51.2; MS m/z 391 (M+). Anal.
(C22H25N5O2‚H2O) C, H, N.
Refer en ces
(1) For the previous paper in this series, see: Chern, J .-W.; Chen,
H.-T.; Lai, N.-Y.; Wu, K.-R.; Chern, Y.-C. Studies on Quinazo-
lines: 7. Reactions of Anthranilamide with â-Diketones; New
Approaches toward the Synthesis of Tetrahydropyrido[2,1-b]-
quinazolin-11-one Derivatives. Chem Pharm. Bull. 1998, 46, in
press.
(2) For the previous paper in this series, see: Chern, J .-W.; Liaw,
Y.-C.; Chen, C.-S.; Rong, J .-G.; Huang, C.-L.; Chan, C.-H.; Wang,
A. H.-J . Studies on 1,2,4-Benzothiadiazine 1,1-Dioxides VII and
Quinazolinones IV: Synthesis of Novel Built-in Hydroxyguani-
dine Tricycles as Potential Anticancer Agents. Heterocycles 1993,
36, 1091-1103.
(R)-(+)-3-[[4-(2-Meth oxyph en yl)piper azin -1-yl]m eth yl]-
2,3-d ih yd r oim id a zo[1,2-c]qu in a zolin -5(6H)-on e ((R)-(+)-
5). This was obtained in 98% yield from (R)-(-)-57 using the
similar procedure which yielded in (S)-(-)-5: [R]25 +30.9 (c
D
1
3.178, CHCl3); H NMR (CDCl3) δ 9.67 (br s, 1 H, NH), 7.89
(d, 1 H, J ) 8.8 Hz, ArH), 7.37 (t, 1 H, J ) 7.7 Hz, ArH), 7.03
(1 H, t, J ) 7.5 Hz, ArH), 6.91-6.75 (m, 5 H, ArH), 4.54-4.49
(m, 1 H, (S)-CH), 4.14-4.00 (m, 2 H, dNCH2), 3.86 (s, 3 H,
OCH3), 3.00-2.94 (m, 5 H), 2.82-2.75 (m, 2 H), 2.73-2.71 (m,
1H), 2.51-2.46 (m, 1 H); 13C NMR (CDCl3) δ 153.5, 152.2,
149.7, 141.3, 139.0, 133.3, 126.3, 123.2, 122.9, 121.0, 118.2,
115.1, 112.1, 111.2, 59.9, 59.3, 55.3, 54.4, 54.0, 50.6; MS m/z
391 (M+). Anal. (C22H25N5O2‚0.75H2O) C, H, N.
Meth od s of Bin d in g Stu d ies. 1. P r ep a r a tion of Mem -
br a n es for Bin d in g Stu d ies. Rat brain cortex membranes
were prepared for R1-adrenergic recpetor or R2-adrenergic
receptor binding; rat submaxillary gland members were
prepared for R1A binding; rat liver members were prepared
for R1B binding; members (BSR-2AH) encoding the human
adrenergic R2a receptor were prepared for R2a binding. Tissues
were homogenized in 0.32 M sucrose buffered with 50 mM Tris
buffer (pH 7.4) in a tissue/buffer ratio of 1:10. After the
removal of nuclei by centrifugation at 1000g for 10 min, P2
membranes were pelleted by centrifuging the supernatant at
22000g for 20 min. After two rounds of centrifugation at
22000g and resuspension in fresh buffer, the membrane
suspension (about 2 mg/mL protein) was ready for use.
(3) (a) Timmermans, B. M. W. M.; van Zwieten, P. A. R-Adrenoceptor
Agonists and Antagonists. Drugs Future 1984, 9, 41-55. (b)
Campbell, S. F.; Davey, M. Doxazosin, A Case History. J . Drug
Des. Deliv. 1986, 1, 83-89.
(4) Ames, R. P.; Kiyasu, J . Y. R1-Adrenoceptor Blockade with
Doxazosin in Hypertension: Effects on Blood Pressure and
Lipoproteins. J . Clin. Pharmacol. 1989, 29, 123-127.
(5) (a) Koga, T.; Shiraki, Y.; Sakai, K. Characterization of a Novel
R1-Adrenoceptor Antagonist, SGB-1534, in Contractile Response
of Isolated Canine Arterial and Venous Smooth Muscle to
Exogenous Noradrenaline: Comparison with Prazosin, Phento-
lamine and Yohimbine. J pn. J . Pharmacol. 1989, 50, 185-193.
(b) Seki, N.; Nishiye, E.; Itoh, T.; Susuki, H.; Kuriyama, H.
Electrical and Mechanical Properties of the Capsular Smooth
Muscles of the Rabbit Prostate in Relation to the Actions of the
R1-Adrenoceptor Blocker, YM-12617. Br. J . Pharmacol. 1988, 93,
702-714.
(6) (a) Nagano, H.; et al. Eur. Pat. 89 065, 1983, Chugai Pharma-
ceutical Co., Ltd.; Chem. Abstr. 1984, 100, 6547p. (b) Imagawa,
J .; Sakai, K. Further Evaluation of the Selectivity of a Novel
Antihypertensive Agent, SGB-1534, for Peripheral R1-adreno-
ceptors in the Spinally Anesthetized dog. Eur. J . Pharmacol.
1986, 131, 257-264.
2. Bin d in g Assa ys. Adrenergic R1, R1A, and R1B receptor
competition binding assays (in triplicate) were carried out with
0.2-0.25 nM [3H]prazosin and in a final volume of 1.0 mL of
Tris buffer at pH 7.4 for 30 min at room temperature, using
10 µM phentolamine to determine nonspecific binding. The
concentrations of each compound for competition binding were
in the range of 0.1-200 nM. R2-Adrenergic receptor competi-
tion binding assays (in triplicate) were carried out with 1 nM
[3H]clonidine in the presence of 10 mM MgCl2 in a final volume
of 1.0 mL of Tris buffer at pH 7.4 for 30 min at room
temperature, using 10 µM clonidine to determine nonspecific
binding. The concentrations of each compound for competition
binding were in the range of 1-100 µM. After binding had
reached equilibrium, incubations were terminated by collecting
the membranes on Whatman GF/B filters; the filters were
washed twice with 5 mL of 50 mM Tris buffer (pH 7.4) at 4
°C. The amount of membrane protein used in each assay was
in the range of 300-400 µg, as determined by the method of
Lowry.24
(7) Russell, R. K.; Press, J . B.; Rampulla, R. A.; McNally, J . J .;
Falotico, R.; Keiser, J . A.; Bright, D. A.; Tobia, A. Thiophene
Systems. 9. Thienopyrimidinedione Derivatives as Potential
Antihypertensive Agents. J . Med. Chem. 1988, 31, 1786-1793.
(8) Russo, F.; Romeo, G.; Guccione, S.; De Blasi, A. Pyrimido[5,4-
b]indole Derivatives: A New Class of Potent and Selective R1-
Adrenoceptor Ligands. J . Med. Chem. 1991, 34, 1850-1854.
(9) Chern, J .-W.; Yen, M.-H.; Lu, G.-Y.; Shiau, C.-Y.; Lai, Y.-J .;
Chan, C.-H. Studies on Quinazolines. 5. 2,3-Dihydroimidazo[1,2-
c]quinazoline Derivatives: A Novel Class of Potent and Selective
R1-Adrenoceptor Antagonists and Antihypertensive Agents. J .
Med. Chem. 1993, 36, 2196-2207.
(10) Chern, J .-W.; Tseng, C.-J .; Yen, M.-H.; Ferng, L.-J .; Ho, C.-P.;
Rong, J .-G.; Wu, K.-R. 1,2,4-Benzothiadiazine 1,1-Dioxide. Part
VI: Synthesis and Antihypertensive Activity of Dioxothia-
analogues of SGB-1534 and Ketanserin. Chin. J . Pharm. 1992,
44, 113-123.
(11) (a) Huff, J . R.; King, S. W.; Saari, W. S.; Springer, J . P.; Martin,
G. E.; Williams, M. Bioactive Conformation of 1-Arylpiperazines
at Central Serotonin Receptors. J . Med. Chem. 1985, 28, 945-
948. (b) Cliffe, I. A.; Brightwell, C. I.; Fletcher, A.; Forster, E.
A.; Mansell, H. L.; Reilly, Y.; Routledge, C.; White, A. C. (S)-N-
tert-Butyl-3-(4-(2-methoxyphenyl)piperazin-1-yl)-2-phenylpro-
panamide [(S)-WAY-100135]: A Selective Antagonist at Pre-
synaptic 5-HT1A Receptors. J . Med. Chem. 1993, 36, 1509-1510.
(12) Baldwin, J . E. Rules for Ring Closure. J . Chem. Soc., Chem.
Commun. 1976, 734.
(13) Liu, K.-C.; Tuan, J . Y.; Shih, B. J . Darstellun von 2-Methoxy-
carbomethoxyliden-1H-perimido[2,1-b]thiazolidinon. Arch. Pharm.
(Weinheim) 1976, 309, 928.
(14) DiBella, M.; Gamberini, G.; Tait, A.; Fabio, U.; Quaglio, G. P.
Synthesis and Antimicrobial Activity of Monoalkylcarbamic Acid
and Thiocarbamaic Esters of 3-Mercapto-1,2,4-benzothiadiazine
1,1-Dioxide and of its Bz-derivatives. Farmaco Ed. Sci. 1983,
38, 466-472.
(15) J akobsen, P.; Treppendahl, S. The Structure of 1,2,4-Benzothia-
diazine 1,1-Dioxides. Tetrahedron 1979, 35, 2151-2153.
(16) Chern, J .-W.; Shiau, C.-Y.; Wu, Y.-H. 2H-1,2,4-Benzothiadiazine
1,1-Dioxides IV: Mitsunobu Reactions of 3-Hydroxyalkylamino-
and 3-Mercaptoalkylamino-2H-1,2,4-Benzothiadiazine-3(4H)-one
1,1-Dioxides- A Convenient Synthesis of Built-in Guanidine
Tricycles and Disulfide. Synthesis 1991, 159-161.
(17) Chern, J .-W.; Rong, J .-G. 1,2,4-Benzothiadiazine 1,1-Dioxide.
V.: Synthesis of Built-in Hydroxyguanidine Tricycles as Poten-
tial Anticancer Agents. Tetrahedron Lett. 1991, 32, 2935-2938.
(18) Chern, J .-W.; Wu, Y.-H.; Liu, K.-C. 2H-1,2,4-Benzothiadiazine
1,1-Dioxides 2. A Condensation of 2-Aminobenzenesulfonamide
with Chloroalkyl Isothiocyanates. J . Heterocycl. Chem. 1990, 27,
1485-1488.
The competition binding assays were analyzed with the
McPherson program,25 which is a modification of the LIGAND
progam originally written by Munson and Rodbard.26 Ki value
(the equilibrium dissociation constant of tested compound) was
obtained by this analysis.
3. An tih yp er ten sive Activity. Male 16-week old spon-
taneously hypertensive rats (SHR) weighing 250-300 g were
anesthetized with urethane (0.6 g/kg, ip) and chloral hydrate
(0.4 g/kg, ip). The left femoral artery and vein were cannulated
for the measurement of blood pressure (BP) and intravenous
administration of drugs, respectively. The catheter for BP
measurement was connected to a pressure transducer (Statham
P23 ID, Gould), and the arterial BP was continuously recorded
on a biotechometer (RS 3400, Gould). The heart rate (HR)
was triggered from the arterial pressure through a tachometer
(Grass model).
Ack n ow led gm en t. These investigations were sup-
ported by research grants from the National Science
Council of the Republic of China (Grants NSC84-2622-
B016-001 and NSC85-2622-B002-009 to J .-W.C.).

Quinazolines and 1,2,4-Benzothiadiazine 1,1-Dioxides
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 17 3141
(19) Gutcait, A.; Wang, K.-C.; Liu, H.-W.; Chern, J .-W. Studies on
Quinazolines. 6. Asymmetric Synthesis of (S)-(+)- and (R)-(-
)-3-[[4-(2-methoxyphenyl)piperazin-1-yl]methyl]-5-methylthio-
2,3-dihydro-imidazo[1,2-c]quinazolines. Tetrahedron: Asymme-
try 1996, 7, 1641-1648.
(20) Price, D. T.; Schwinn, D. A.; Lomasney, J . W.; Allen, L. F.; Caron,
M. G.; Lefkowitz, R. J . Identification, Quantitation, and Local-
ization of mRNA for Three Distinct R1 adrenergic Subtypes in
Human Prostate. J . Urol. 1993, 150, 546-551.
(21) (a) Marshall, I.; Burt, R. P.; Chapple, C. R. Noradrenaline
Contraction of Human Prostate Mediated by R1A-(R1C)-adreno-
ceptor Subtype. Br. J . Pharmacol. 1995, 115, 781-786. (b)
Kenny, B.; Ballard, S.; Blagg, J .; Fox, D. Pharmacological Option
in the Treatment of Benign Prostatic Hyperplasia. J . Med. Chem.
1997, 40, 1293-1315.
(22) Pan Labs Taiwan, Ltd., P.O. Box 26-127, Taipei, Taiwan.
(23) (a) Michel, A. D.; Loury, D. N.; Whiting, R. L. Identification of
a Single R1A-adrenergic Corresponding to the R1A-subtype in rat
submaxillary gland. Br. J . Pharmacol. 1989, 98, 883-889. (b)
Garcia-Sainz, J . A.; Romero-Avila, M. T.; Hernandez, R. A.;
Macias-Silva, M.; Olivares-Reyes, A.; Gonzalez-Espinosa, C.
Species Heterogeneity of Hepatic R1-adrenoceptors: R1A-, R1B-,
and R1C-subtypes. Biochem. Biophys. Res. Commun. 1992, 186,
760-767.
(24) Lowry, H. I.; Hurst, R.; Hruby, V. J .; Gee, K.; Randall, R. J .
Protein Measurement with Folin Phenol Reagents. J . Biol.
Chem. 1951, 193, 265-275.
(25) McPherson, G. A. A Practical Computer-based Approach to the
Analysis of Radioligand Binding Experiments. Comput. Pro.
Biomed. 1983, 17, 107.
(26) Munson, P. J .; Rodbard, D. LIGAND: A Versatile Computerized
Approach for Characterization of Ligand Binding Systems. Anal.
Biochem. 1980, 107, 220.
J M970159V