Polycyclic N-heterocyclic compounds. Part 82: Synthesis and evaluation of anti-platelet aggregation activity of 2,4-disubstituted 5,6-dihydro[1] benzothiepino[5,4-d]pyrimidine and related compounds

Article abstract of DOI:10.1002/jhet.1741

We have synthesized a large number of tricyclic 2-substituted 4-alkylamino-5,6-dihydro[1]benzothiepino[5,4-d]pyrimidines as part of our research to develop new effective anti-platelet drugs. A variety of alkyl and aryl groups were used as substituents at the 2-position. Evaluation of the effects of the newly synthesized compounds on collagen-induced platelet aggregation revealed several promising anti-platelet candidates with potencies superior to aspirin.

Full text of DOI:10.1002/jhet.1741

July 2014
Polycyclic N-Heterocyclic Compounds. Part 82: Synthesis and Evaluation
of Anti-Platelet Aggregation Activity of 2,4-Disubstituted 5,6-Dihydro[1]
benzothiepino[5,4-d]pyrimidine and Related Compounds
911
a
b
b
*
Kensuke Okuda, Takashi Hirota, and Kenji Sasaki
aLaboratory of Medicinal and Pharmaceutical Chemistry, Gifu Pharmaceutical University, Gifu 501-1196, Japan
bLaboratory of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Okayama University, Kita-ku, Okayama
700-8530, Japan
*
E-mail: okuda@gifu-pu.ac.jp
Received April 6, 2012
DOI 10.1002/jhet.1741
Published online 9 December 2013 in Wiley Online Library (wileyonlinelibrary.com).
R1
N
N
R2
R1 = 4-MeO-Ph and R2 = Cl is the most potent.
S
We have synthesized a large number of tricyclic 2-substituted 4-alkylamino-5,6-dihydro[1]benzothiepino
[5,4-d]pyrimidines as part of our research to develop new effective anti-platelet drugs. A variety of alkyl and
aryl groups were used as substituents at the 2-position. Evaluation of the effects of the newly synthesized
compounds on collagen-induced platelet aggregation revealed several promising anti-platelet candidates
with potencies superior to aspirin.
J. Heterocyclic Chem, 51, 911 (2014).
INTRODUCTION
CHEMISTRY
We have been involved in research on the synthesis
and biological evaluation of a series of polycyclic
N-heterocyclic compounds. During our investigation of
the anti-platelet aggregation activity of these compounds,
we discovered that 2-substituted 4-(2-hydroxyethylamino)-
5,6-dihydrobenzo[h]quinazolines (1) [1] and 2-substituted
4-(2-hydroxyethylamino)-6,7-dihydro-5H-benzo[6,7]
cyclohepta[1,2-d]pyrimidines (2) [2] had stronger
inhibitory activities against collagen-induced aggregation
of rabbit platelets in vitro than aspirin, the well-known
anti-platelet agent (Figure 1) [3]. The most potent 1
(R═Ph) had six times the activity of aspirin, whereas
the most potent 2 (R═4-Cl─Ph) had four times the activity
of aspirin.
Current anti-platelet drugs are important for the pre-
vention and treatment of acute ischemic syndromes.
However, drugs in clinical use often have drawbacks
that include side effects and less than ideal efficacy
and thus there continues to be much research directed
to the development of new drugs in this class [4–13].
In order to develop more active compounds derived
from our hit compounds, we decided to explore the
structure–activity relationships of 2-substituted 4-(2-
hydroxyethylamino)-5,6-dihydro[1]benzothiepino[5,4-d]
pyrimidines (3), the thia-analogs of 1 and 2. In this report,
we describe in detail the synthesis and evaluation of these
compounds.
We synthesized the target molecules by the following
method. First, bicyclic enaminonitrile (5) was prepared
by reaction of 5-oxo-2,3,4,5-tetrahydrobenzo[b]thiepin-
4-carbonitrile (4) [14] with ammonia (Scheme 1). The
structure of 5 was supported by the characteristic amino
and cyano absorption in the IR spectrum. Next, 5 was
allowed to react with Vilsmeier reagents prepared from a
series of N,N-dimethylamides and phosphoryl chloride
to give 6a–i. Structures of 6a–i were supported by the
disappearance of the enamine and nitrile groups and
appearance of chlorine atoms in their IR and MS spectra.
In addition, the NMR spectra and elemental analyses
provided confirmation of these structures.
Next, we employed 2-aminoethanol to carry out nucleo-
philic substitution at the 4-position to give 3. An advantage
of the 2-hydroxyethylamino moiety comes from the
expected increase in aqueous solubility of the hydropho-
bic 5,6-dihydro[1]benzothiepino[5,4-d]pyrimidines 3a–i
(61–95%, Scheme 2). Because we also expected the 2-
hydroxyethylamino substituent to influence bioactivity, to
eliminate hydrogen donor ability of amino group, N-methyl-
2-aminoethanol was also chosen to react with 6a–i to
give 7a–i (47–84%). Similarly, reaction of dimethyla-
mine with 6a–i gave 8a–i (34–95%) thereby eliminating
the influence of the hydroxyethyl group of the N-methyl-
N-(2-hydroxyethyl) moiety. Finally, reaction of morpho-
line with 6a–i was carried out to give 9a–i (55–83%),
© 2013 HeteroCorporation

912
K. Okuda, T. Hirota, and K. Sasaki
Vol 51
R
R
R
OH
OH
N
N
N
N
N
N
N
N
OH
H
H
N
H
S
1
2
3
Figure 1. Previous hit compounds (1 and 2) as anti-platelet agents and their analogs (3) prepared here.
Scheme 1. Preparation of 6.
R
N
H2N
O
N
CN
CN
Cl
RCONMe2
POCl3
liq. NH3
S
S
S
4
5 (86%)
6a: R=Me (69%)
6b: R=Et (76%)
6c: R=cyclohexyl (71%)
6d: R=Ph (84%)
6e: R=4-F-Ph (76%)
6f: R=4-Cl-Ph (85%)
6g: R=4-Me-Ph (64%)
6h: R=4-MeO-Ph (71%)
6i: R=4-NO2-Ph (82%)
Lipinski’s rule of five, and thus they are expected to have
drug-like properties [15].
Scheme 2. Preparation of 3 and 7–9.
3a: R=Me (75%)
3b: R=Et (76%)
3c: R=cyclohexyl (67%)
3d: R=Ph (75%)
R
BIOLOGY
3e: R=4-F-Ph (61%)
3f: R=4-Cl-Ph (83%)
3g: R=4-Me-Ph (90%)
3h: R=4-MeO-Ph (88%)
3i: R=4-NO2-Ph (95%)
7a: R=Me (51%)
OH
N
N
N
The products prepared as described earlier were screened
for inhibitory activity against rabbit platelet aggregation by a
turbidimetric method using an aggregometer as described by
Born and Cross [16]. Platelet aggregation was induced by
the addition of collagen (final concentration 14.3 mg/mL).
A 10% solution of dimethylsulfoxide (DMSO, final concen-
tration 0.71%) or 60% N,N-dimethylformamide (DMF, final
concentration 4.3%, in the case of poor aqueous solubility)
was used as a cosolvent to dissolve drugs. The results are
shown in Table 1. Comparison of the inhibition potency of
test compounds with that of aspirin revealed that none of
8 and 9 showed any significant improvement in potency
over aspirin (data not shown). However, certain of the
substituted tricyclic compounds 3, 6, and 7 showed bioac-
tivity superior to aspirin. A detailed comparison of the
inhibitory activity (IC50) of the compounds that showed
significant difference (P < 0.01) from the activity of aspi-
rin at the same concentration was determined. Among
them, 6h with the 2-(4-methoxyphenyl)-4-Cl substituent,
is the most potent, having three times more activity than
aspirin. It is, however, less potent than either 1 (R═Ph)
or 2 (R═4-Cl─Ph), which were the most potent of
the 1 and 2 series, respectively. It seems that the substi-
tution of the 2-phenyl group of 6 had substantial effects
H
S
NH2CH2CH2OH
7b: R=Et (47%)
R
1,4-dioxane
7c: R=cyclohexyl (62%)
7d: R=Ph (84%)
OH
N
N
N
7e: R=4-F-Ph (73%)
7f: R=4-Cl-Ph (74%)
7g: R=4-Me-Ph (75%)
7h: R=4-MeO-Ph (68%)
7i: R=4-NO2-Ph (79%)
Me
MeNHCH2CH2OH
S
N
1,4-dioxane
Me2NH
6a i
8a: R=Me (85%)
8b: R=Et (94%)
8c: R=cyclohexyl (93%)
8d: R=Ph (95%)
8e: R=4-F-Ph (63%)
8f: R=4-Cl-Ph (73%)
8g: R=4-Me-Ph (79%)
8h: R=4-MeO-Ph (34%)
8i: R=4-NO2-Ph (76%)
R
H2O, Et2O
N
NMe2
morpholine
1,4-dioxane
S
9a: R=Me (74%)
R
9b: R=Et (65%)
9c: R=cyclohexyl (83%)
9d: R=Ph (83%)
N
N
N
9e: R=4-F-Ph (70%)
9f: R=4-Cl-Ph (55%)
9g: R=4-Me-Ph (58%)
9h: R=4-MeO-Ph (63%)
9i: R=4-NO2-Ph (64%)
O
S
thus simultaneously eliminating the hydrogen donor abil-
ity of the amino and hydroxy groups of the 2-hydroxyethy-
lamino substituent. All derivatives 3 and 6–9 satisfy
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2014
Synthesis and Evaluation of Anti-Platelet Aggregation Activity of 2,4-Disubstituted
913
5,6-Dihydro[1]benzothiepino[5,4-d]Pyrimidine and Related Compounds
Table 1
Effects of 3, 6, and 7 on rabbit platelet aggregation in vitro induced by collagen.
Compound
% inhibitiona
IC50 (mM)b
Compound
% inhibitiona
IC50 (mM)b
3ac
3bc
7.9 ꢁ 3.6
7.3 ꢁ 1.6
–
–
3fd
10.3 ꢁ 2.2
–
35.1
(28.4–46.0)
3gc
35.3 ꢁ 3.2*
3cc
45.6 ꢁ 5.0*
18.4
(10.5–30.4)
3hd
3id
6fd
14.0 ꢁ 1.7
18.9 ꢁ 3.2
40.7 ꢁ 0.5*
–
3dd
3ec
6ad
13.5 ꢁ 1.9
10.8 ꢁ 3.6
2.1 ꢁ 0.7
–
–
–
–
2.8
(1.4–5.0)
–
2.1
(0.8–4.3)
–
6bd
6cd
22.7 ꢁ 1.4
10.1 ꢁ 0.2
–
–
6gd
6hd
21.6 ꢁ 4.6
46.5 ꢁ 10.4*
6dd
6ed
7ac
7bc
10.1 ꢁ 8.6
9.5 ꢁ 1.0
–
–
–
55.4
6id
34.8 ꢁ 0.8
2.7 ꢁ 1.8
7fd
21.9 ꢁ 3.2
20.0 ꢁ 2.6
–
–
29.1 ꢁ 2.2*
7gd
(39.7–93.3)
7cd
22.1 ꢁ 2.9
9.5 ꢁ 3.3
–
–
–
7hd
7id
13.2 ꢁ 2.2
–
–
7dd
17.6 ꢁ 10.8
7ed
14.0 ꢁ 4.8
15.7 ꢁ 1.0
Aspirinc
48.0
(44.1–53.3)
Aspirind
26.1 ꢁ 1.7
6.5
(5.3–8.8)
aData represent % inhibition of the vehicle control group (Mean ꢁ SE of three experiments at least) at a final concentration of 25 mM (in the case of 10%
DMSO) or 2.5 mM (in the case of 60% DMF).
*Means significantly different from aspirin at P < 0.01.
bExperiments were repeated at least three times each at final concentration of 5.0, 25, 50 mM (3 and 7 in the case of 10% DMSO), 25, 50, 100 mM (aspirin
in the case of 10% DMSO), 1.0, 2.5, 5.0 mM (3, 6, and 7 in the case of 60% DMF), or 2.5, 5.0, 10 mM (aspirin in the case of 60% DMF). Figures in
parentheses represent 95% confidence limits of IC50
.
c10% DMSO was used as a cosolvent.
d60% DMF was used as a cosolvent.
on activity (6d–6i). When the 4-substituent was either
the 2-hydroxyethylamino moiety (3) or N-methyl-N-(2-
hydroxyethylamino) moiety (7), the favored 2-substitution
is not 4-methoxyphenyl but rather cyclohexyl (3c), 4-tolyl
(3g), or ethyl (7b), although potencies of these compounds
were less than that of 6h.
We were also interested in the effect of the oxidation
state of the S atom on activity. Among the tested com-
pounds, 6h was the most potent. Therefore, sulfoxides 10
and sulfones 11 were prepared from sulfides 6 by the usual
procedures (Scheme 3). Thus, performic acid oxidation of
6a–i gave 10a–i (51–80%). Structures of 10 were verified
based on the appearance of the sulfoxide groups in their IR
spectra. In addition, the NMR and MS spectra and elemental
analyses supported these structures. Potassium permanga-
nate oxidation of 6a–i gave 11a–i (37–68%). Structures
of 11 were supported by the appearance of the sulfone
groups in their IR spectra. None of the compounds in series
10 and 11 showed any significant improvement in potency
over aspirin (data not shown). More detailed examination
will be needed to clarify this structure–activity relationship.
On the basis of the promising results reported herein, we
are currently exploring development of additional deriva-
tives with anti-platelet aggregation activity.
Scheme 3. Preparation of 10 and 11.
10a: R=Me (67%)
R
10b: R=Et (54%)
10c: R=cyclohexyl (51%)
10d: R=Ph (66%)
N
N
H2O2 aq.
HCO2H
Cl
10e: R=4-F-Ph (78%)
10f: R=4-Cl-Ph (79%)
10g: R=4-Me-Ph (80%)
10h: R=4-MeO-Ph (77%)
10i: R=4-NO2-Ph (64%)
EXPERIMENTAL
All melting points were determined on a Yanagimoto (Kyoto,
Japan) micro-melting point apparatus, and are uncorrected. Elemental
analyses were performed on a Yanagimoto (Kyoto, Japan) MT-5
CHN Corder elemental analyzer. The electron impact (EI)-mass and
fast atom bombardment (FAB)-mass (m-nitrobenzyl alcohol was
used as the matrix) were obtained on a VG (UK) 70-SE mass spec-
trometer. The IR spectra were recorded on a Japan Spectroscopic
(Hachioji, Japan) diffraction grating A-102 spectrophotometer, and
frequencies are expressed in cmꢀ1. The 1H NMR spectra were
recorded on a Varian (Palo Alto, CA) VXR-200 instrument or a
CH2Cl2
S
O
6a i
KMnO4
R
11a: R=Me (62%)
11b: R=Et (54%)
11c: R=cyclohexyl (37%)
11d: R=Ph (47%)
N
AcOH, H2O
N
Cl
11e: R=4-F-Ph (64%)
11f: R=4-Cl-Ph (55%)
11g: R=4-Me-Ph (57%)
11h: R=4-MeO-Ph (68%)
11i: R=4-NO2-Ph (56%)
S
O
O
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

914
K. Okuda, T. Hirota, and K. Sasaki
Vol 51
Hitachi (Tokyo, Japan) R-1500 instrument with tetramethylsilane as
an internal standard. Chemical shifts are given in parts per million
(d) and J values in Hertz, and the signals are designated as follows:
s, singlet; d, doublet; dd, double doublet; t, triplet; q, quartet; br,
broad; m, multiplet. Reactions were monitored by thin layer
chromatography to determine the appropriate time for termination.
5-Amino-2,3-dihydro-1-benzothiepin-4-carbonitrile (5).
Compound 4 (10.0 g, 49.2 mmol) and liquid ammonia (30 mL)
were heated at 150 ꢂC in a pressure reactor vessel equipped with
a manometer under 46 kg/cm2 for 40 h. After ice cooling, the
vessel was opened carefully in a fume food and ammonia was
removed. The residue was recrystallized from ethanol to give 5
(8.60 g, 86%) as colorless plates; mp 148–150 ꢂC; IR
(potassium bromide) cmꢀ1: 2180 (CN), 3440, 3340, 3240 (NH);
1H NMR (deuterochloroform): d 2.24 (t, 2H, J = 6.5 Hz, H3),
3.38 (t, 2H, J = 6.5 Hz, H2), 4.68 (br, 2H, deuterium oxide
exchangeable, NH2), 7.20–7.75 (m, 4H, H6, 7, 8, and 9); EIMS
m/z: 202 (M+). Anal. Calcd. for C11H10N2S: C, 65.31; H, 4.98;
N, 13.84. Found: C, 65.30; H, 5.01; N, 13.80.
H5), 3.50 (t, 2H, J= 6.0Hz, H6), 7.32–7.72 (m, 6H, H8, 9, 10 and
30, 40, 50), 7.85–7.99 (m, 1H, H11), 8.44–8.60 (m, 2H, H20 and 60);
EIMS m/z: 324 (M+), 326 (M+ +2). Anal. Calcd. for C18H13ClN2S:
C, 66.56; H, 4.03; N, 8.62. Found: C, 66.62; H, 4.23; N; 8.58.
4-Chloro-2-(4-fluorophenyl)-5,6-dihydro[1]benzothiepino[5,4-
d]pyrimidine (6e).
The product was recrystallized from ethyl
1
acetate to give 6e (76%) as colorless prisms, mp 191–192 ꢂC; H
NMR (deuterochloroform): d 3.00 (t, 2H, J = 6.4 Hz, H5), 3.49
(t, 2H, J = 6.4 Hz, H6), 7.00–7.97 (m, 6H, H8, 9, 10, 11 and 30,
50), 8.41–8.64 (m, 2H, H20 and 60); EIMS m/z: 342 (M+), 344
(M+ + 2). Anal. Calcd. for C18H12ClFN2S: C, 63.06; H, 3.53; N,
8.17. Found: C, 63.15; H, 3.74; N, 8.22.
4-Chloro-2-(4-chlorophenyl)-5,6-dihydro[1]benzothiepino[5,4-
d]pyrimidine (6f). The product was recrystallized from benzene-
ethyl acetate to give 6f (85%) as colorless prisms, mp 196–197 ꢂC;
1H NMR (deuterochloroform): d 2.99 (br t, 2H, J = 5.8Hz, H5),
3.50 (t, 2H, J =5.8 Hz, H6), 7.43 (br d, 2H, J = 8.8Hz, H30 and
50), 7.55–7.97 (m, 4H, H8, 9, 10, and 11), 8.46 (br d, 2H,
J = 8.8 Hz, H20 and 60); EIMS m/z: 358 (M+), 360 (M+ + 2), 362
(M+ + 4). Anal. Calcd. for C18H12Cl2N2S: C, 60.18; H, 3.37; N,
7.80. Found: C, 60.24; H, 3.54; N, 7.74.
2-Substituted 4-chloro-5,6-dihydro[1]benzothiepino[5,4-d]
pyrimidine (6a–i). General procedure.
To a Vilsmeier
reagent prepared from phosphoryl chloride (74.3 mmol) and
the corresponding N,N-dimethylamide [17–20] (24.8 mmol) by
stirring for 1 h under ice-water cooling was added compound 5
(1.00 g, 4.95 mmol), and the reaction was then refluxed for 0.5 h.
After evaporation of excess phosphoryl chloride in vacuo, ice
water (40 mL) was poured into the residue. The mixture was
neutralized with sodium hydrogen carbonate and was extracted
with chloroform (30 mL ꢃ 3). The organic layer was washed with
sat. brine, dried over anhydrous sodium sulfate, and evaporated in
vacuo. The residue was recrystallized from the appropriate solvent
to give 6a–i.
4-Chloro-2-(4-methylphenyl)-5,6-dihydro[1]benzothiepino
[5,4-d]pyrimidine (6g). The product was recrystallized from
acetonitrile to give 6g (64%) as colorless needles, mp 190–
191 ꢂC; 1H NMR (deuterochloroform): d 2.41 (s, 3H, CH3),
2.99 (t, 2H, J = 5.8 Hz, H5), 3.49 (t, 2H, J = 5.8Hz, H6), 7.28
(d, 2H, J = 8.2 Hz, H30 and 50), 7.39–7.94 (m, 4H, H8, 9, 10,
and 11), 8.41 (d, 2H, J = 8.2 Hz, H20 and 60); EIMS m/z: 338
(M+), 340 (M+ + 2). Anal. Calcd. for C19H15ClN2S: C, 67.35;
H, 4.46; N, 8.27. Found: C, 67.26; H, 4.56; N, 8.21.
4-Chloro-2-(4-methoxyphenyl)-5,6-dihydro[1]benzothiepino
[5,4-d]pyrimidine (6h).
The product was recrystallized from
4-Chloro-2-methyl-5,6-dihydro[1]benzothiepino[5,4-d]pyrimidine
(6a). The product was recrystallized from acetonitrile to give 6a
(69%) as colorless needles, mp 126–127 ꢂC; 1H NMR
(deuterochloroform): d 2.77 (s, 3H, CH3), 2.93 (t, 2H, J = 6.0 Hz,
H5), 3.44 (t, 2H, J = 6.0 Hz, H6), 7.40–7.85 (m, 4H, H8, 9, 10,
and 11); EIMS m/z: 262 (M+), 264 (M+ + 2). Anal. Calcd. for
C13H11ClN2S: C, 59.42; H, 4.22; N, 10.66. Found: C, 59.37; H,
4.32; N, 10.58.
ethyl acetate-acetonitrile to give 6h (71%) as colorless needles,
mp 188–190 ꢂC; 1H NMR (deuterochloroform): d 2.98 (t, 2H,
J = 6.0 Hz, H5), 3.48 (t, 2H, J = 6.0 Hz, H6), 3.88 (s, 3H,
OCH3), 6.98 (d, 2H, J = 9.0 Hz, 30 and 50), 7.43–7.93 (m, 4H,
H8, 9, 10, and 11), 8.47 (d, 2H, J = 9.0 Hz, H20 and 60); EIMS
m/z: 354 (M+), 356 (M+ + 2). Anal. Calcd. for C19H15ClN2OS:
C, 64.31; H, 4.26; N, 7.89. Found: C, 64.20; H, 4.39; N, 7.96.
4-Chloro-2-(4-nitrophenyl)-5,6-dihydro[1]benzothiepino[5,4-
4-Chloro-2-ethyl-5,6-dihydro[1]benzothiepino[5,4-d]pyrimidine
(6b). The product was recrystallized from acetonitrile to give
6b (76%) as colorless plates, mp 86–89 ꢂC; 1H NMR
(deuterochloroform): d 1.41 (t, 3H, J = 7.5 Hz, CH3), 2.96 (t,
2H, J = 6.5 Hz, H5), 3.02 (q, 2H, J = 7.5 Hz, CH2CH3), 3.45 (t,
2H, J = 6.5 Hz, H6), 7.44, 7.52 (each ddd, each 1H, each
J = 8.0, 7.0, 1.0 Hz, H9 and 10), 7.64 (br d, 1H, J = 8.0 Hz, H8),
7.77 (dd, 1H, J = 8.0, 1.0 Hz, H11); EIMS m/z: 276 (M+), 278
(M+ + 2). Anal. Calcd. for C14H13ClN2S: C, 60.75; H, 4.73; N,
10.12. Found: C, 60.97; H, 4.90; N, 9.94.
4-Chloro-2-cyclohexyl-5,6-dihydro[1]benzothiepino[5,4-d]
pyrimidine (6c). The product was recrystallized from ethanol to
give 6c (71%) as colorless prisms, mp 128–129 ꢂC; 1H NMR
(deuterochloroform): d 1.23–2.16 (m, 10H, cyclohexyl-H), 2.93
(t, 2H, J = 5.8 Hz, H5), 2.65–3.03 (m, 1H, H10), 3.45 (t, 2H,
J = 5.8 Hz, H6), 7.37–7.82 (m, 4H, H8, 9, 10, and 11); EIMS m/z:
330 (M+), 332 (M+ + 2). Anal. Calcd. for C18H19ClN2S: C, 65.34;
H, 5.79; N, 8.47. Found: C, 65.44; H, 5.78; N, 8.46.
d]pyrimidine (6i).
The product was recrystallized from ethyl
acetate-acetonitrile to give 6i (82%) as colorless needles, mp 221–
1
222 ꢂC; H NMR (deuterochloroform): d 3.05 (t, 2H, J=6.0Hz,
H5), 3.53 (t, 2H, J = 6.0Hz, H6), 7.47–7.99 (m, 4H, H8, 9, 10, and
11), 8.31 (d, 2H, J =8.8Hz, H30 and 50), 8.71 (d, 2H, J=8.8Hz,
H20 and 60); EIMS m/z: 369 (M+), 371 (M+ +2). Anal. Calcd. for
C18H12ClN3O2S: C, 58.46; H, 3.27; N, 11.36. Found: C, 58.44; H,
3.47; N, 11.29.
2-Substituted 4-(2-hydroxyethylamino)-5,6-dihydro[1]
benzothiepino[5,4-d]pyrimidine (3a–i). General procedure.
A mixture of 6a–i (400 mg) and 2-aminoethanol (10 eq. of 6a–i)
in dry 1,4-dioxane (8.0 mL) was refluxed for the appropriate time.
After removal of solvent in vacuo, ice water (40 mL) was poured
into the residue. The resulting crystalline precipitate was
collected by filtration and then recrystallized from a suitable
solvent to give 3a–i.
4-(2-Hydroxyethylamino)-2-methyl-5,6-dihydro[1]benzothiepino
[5,4-d]pyrimidine (3a). The reaction was refluxed for 34 h, and
the product was recrystallized from acetonitrile to give 3a (75%)
as colorless prisms, mp 198–199 ꢂC; IR (potassium bromide)
cmꢀ1: 3370, 3200, 3130 (NH, OH); 1H NMR (DMSO-d6): d 2.41
(s, 3H, CH3), 2.59 (t, 2H, J = 6.0 Hz, H5), 3.31–3.69 (m, 6H, H6
4-Chloro-2-phenyl-5,6-dihydro[1]benzothiepino[5,4-d]
pyrimidine (6d).
The product was recrystallized from ethyl
acetate-acetonitrile to give 6d (84%) as colorless needles, mp 161–
1
163 ꢂC; H NMR (deuterochloroform): d 3.01 (t, 2H, J=6.0Hz,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2014
Synthesis and Evaluation of Anti-Platelet Aggregation Activity of 2,4-Disubstituted
915
5,6-Dihydro[1]benzothiepino[5,4-d]Pyrimidine and Related Compounds
and NCH2CH2O), 4.75 and 7.09 (each br, each 1H, each deuterium
oxide exchangeable, NH and OH), 7.33–7.75 (m, 4H, H8, 9, 10, and
11); EIMS m/z: 287 (M+). Anal. Calcd. for C15H17N3OS: C, 62.69;
H, 5.96; N, 14.62. Found: C, 62.47; H, 6.00; N, 14.62.
to 4H (br s) with addition of deuterium oxide, NCH2CH2O and NH
or OH), 5.38 (br, 1H, deuterium oxide exchangeable, NH or OH),
7.32–7.70 (m, 5H, H8, 9, 10 and 30, 50), 7.81–7.97 (m, 1H, H11),
8.27–8.45 (m, 2H, H20 and 60); FAB MS m/z: 384 (MH+), 386
(MH+ +2). Anal. Calcd. for C20H18ClN3OS: C, 62.57; H, 4.73; N,
10.95. Found: C, 62.78; H, 4.87; N, 10.99.
2-Ethyl-4-(2-hydroxyethylamino)-5,6-dihydro[1]benzothiepino
[5,4-d]pyrimidine (3b). The reaction was refluxed for 32h, and
the product was recrystallized from acetonitrile to give 3b (76%)
as colorless needles, mp 143–145 ꢂC; IR (potassium bromide)
cmꢀ1: 3300, 3130 (NH, OH); 1H NMR (deuterochloroform): d
1.35 (t, 3H, J = 7.6 Hz, CH3), 2.58 (t, 2H, J = 6.4 Hz, H5), 2.84
(q, J = 7.6 Hz, 2H, CH2CH3), 3.48 (t, 2H, J = 6.4 Hz, H6), 3.58–
3.97 (m, 5H, changed to 4H with addition of deuterium oxide,
NCH2CH2O and NH or OH), 5.36 (br, 1H, deuterium oxide
exchangeable, NH or OH), 7.34–7.84 (m, 4H, H8, 9, 10, and 11);
FAB MS m/z: 302 (MH+). Anal. Calcd. for C16H19N3OS: C,
63.76; H, 6.35; N, 13.94. Found: C, 63.57; H, 6.29; N, 13.86.
2-Cyclohexyl-4-(2-hydroxyethylamino)-5,6-dihydro[1]
4-(Hydroxyethylamino)-2-(4-methylphenyl)-5,6-dihydro[1]
benzothiepino[5,4-d]pyrimidine (3g).
The reaction was
refluxed for 46h, and the product was recrystallized from benzene
to give 3g (90%) as colorless needles, mp 172–174 ꢂC; IR
(potassium bromide) cmꢀ1: 3310, 3250 (NH, OH); 1H NMR
(deuterochloroform): d 2.37 (s, 3H, CH3), 2.58 (t, 2H, J = 6.5 Hz,
H5), 3.37 (t, 2H, J = 6.5 Hz, H6), 3.81 (br s, 5H, changed to 4H
(br s) with addition of deuterium oxide, NCH2CH2O and NH or
OH), 5.36 (br, 1H, deuterium oxide exchangeable, NH or OH),
7.23 (d, 2H, J = 8.2 Hz, H30 and 50), 7.35–7.65 (m, 3H, 8, 9, and
10), 7.83–7.98 (m, 1H, H11), 8.30 (d, 2H, J = 8.2 Hz, H20 and
60);. FAB MS m/z: 364 (MH+). Anal. Calcd. for C21H21N3OS: C,
69.39; H, 5.82; N, 11.56. Found: C, 69.66; H, 6.00; N, 11.28.
4-(2-Hydroxyethylamino)-2-(4-methoxyphenyl)-5,6-dihydro[1]
benzothiepino[5,4-d]pyrimidine (3h). The reaction was refluxed
for 48h, and the product was recrystallized from benzene to give 3h
(88%) as colorless plates, mp 103–107 ꢂC; IR (potassium bromide)
cmꢀ1: 3440, 3330 (NH, OH); 1H NMR (deuterochloroform): d 2.61
(t, 2H, J = 6.4 Hz, H5), 3.40 (t, 2H, J = 6.4 Hz, H6), 3.82 (br s, 8H,
changed to 7H (br s) with addition of deuterium oxide, OCH3,
NCH2CH2O, and NH or OH), 5.33 (br, 1H, deuterium oxide
exchangeable, NH or OH), 6.94 (d, 2H, J = 9.4 Hz, H30 and 50),
7.35–7.65 (m, 3H, H8, 9, and 10), 7.82–7.92 (m, 1H, H11), 8.38
(d, 2H, J = 9.4 Hz, H20 and 60); FAB MS m/z: 380 (MH+). Anal.
Calcd. for C21H21N3O2S: C, 66.47; H, 5.58; N, 11.07. Found: C,
66.40; H, 5.65; N, 11.26.
benzothiepino[5,4-d]pyrimidine (3c).
The reaction was
refluxed for 45 h, and the product was recrystallized from
acetonitrile to give 3c (67%) as colorless prisms, mp 168–170 ꢂC;
IR (potassium bromide) cmꢀ1: 3430 (sh.), 3300, 3130 (NH, OH);
1H NMR (deuterochloroform): d 1.27–2.17 (m, 10H, cyclohexyl-
H), 2.59 (t, 2H, J = 6.4 Hz, H5), 2.56–3.00 (m, 1H, H10), 3.40
(t, 2H, J = 6.4 Hz, H6), 3.68–3.91 (m, 5H, changed to 4H with
addition of deuterium oxide, NCH2CH2O and NH or OH), 5.33
(br, 1H, deuterium oxide exchangeable, NH or OH), 7.36–7.85
(m, 4H, H8, 9, 10, and 11); EIMS m/z: 355 (M+). Anal. Calcd. for
C20H25N3OS: C, 67.57; H, 7.09; N, 11.82. Found: C, 67.41; H,
6.99; N, 11.77.
4-(2-Hydroxyethylamino)-2-phenyl-5,6-dihydro[1]benzothiepino
[5,4-d]pyrimidine (3d). The reaction was refluxed for 30 h, and the
product was recrystallized from acetonitrile to give 3d (75%)ꢀa1s
colorless needles, mp 207–208 ꢂC; IR (potassium bromide) cm
:
4-(2-Hydroxyethylamino)-2-(4-nitrophenyl)-5,6-dihydro[1]
3350, 3240 (sh.), 3140 (NH, OH); 1H NMR (deuterochloroform): d
2.69 (t, 2H, J=6.5Hz, H5), 3.46 (t, 2H, J=6.5Hz, H6), 3.67
(br, 1H, deuterium oxide exchangeable, NH or OH), 3.82–3.97 (m,
4H, NCH2CH2O), 5.34 (br, 1H, deuterium oxide exchangeable, NH
or OH), 7.35–7.65 (m, 6H, H8, 9, 10 and 30, 40, 50), 7.92 (dd, 1H,
J=7.5, 1.4Hz, H11), 8.41–8.46 (m, 2H, H20 and 60); FAB MS m/z:
350 (MH+). Anal. Calcd. for C20H19N3OS: C, 68.74; H, 5.48; N,
12.02. Found: C, 68.75; H, 5.57; N, 12.07.
benzothiepino[5,4-d]pyrimidine (3i).
The reaction was
refluxed for 6 h, and the product was recrystallized from
benzene to give 3i (95%) as yellow needles, mp 211–213 ꢂC;
IR (potassium bromide) cmꢀ1: 3400 (br, NH and OH); 1H
NMR (deuterochloroform): d 2.72 (t, 2H, J = 6.0 Hz, H5), 3.48
(t, 2H, J = 6.0 Hz, H6), 3.85–3.98 (m, 5H, changed to 4H (m)
with addition of deuterium oxide, NCH2CH2O, and NH
or OH), 5.43 (br, 1H, deuterium oxide exchangeable, NH or
OH), 7.42 (ddd, 1H, J = 7.5, 7.0, 1.5 Hz, H9), 7.56 (ddd, 1H,
J = 7.5, 7.0, 1.4 Hz, H10), 7.65 (dd, 1H, J = 7.5, 1.4 Hz, H8), 7.98
(dd, 1H, J = 7.5, 1.5 Hz, H11), 8.29 (d, 2H, J = 9.0 Hz, H30 and
50), 8.63 (d, 2H, J = 9.0 Hz, H20 and 60); FAB MS m/z: 395
(MH+). Anal. Calcd. for C20H18N4O3S: C, 60.90; H, 4.60; N,
14.20. Found: C, 60.97; H, 4.68; N, 13.92.
2-Substituted 4-(N-methyl-2-hydroxyethylamino)-5,6-dihydro
[1]benzothiepino[5,4-d]pyrimidine (7a–i). General procedure.
A mixture of compound 6a–i (400 mg) and 2-methylaminoethanol
(10 eq. of 6a–i) in 1,4-dioxane (8.0 mL) was refluxed for the
appropriate time. After removal of solvent in vacuo, ice water
(40 mL) was poured into the residue. In the case of 7a–c, the
mixture was extracted with benzene (30 mL ꢃ 3). The combined
organic layer was washed with sat. brine, dried over anhydrous
sodium sulfate, and then evaporated in vacuo. The residue was
purified by recrystallization or column chromatography. In the case
of 7d–i, the precipitate that formed was collected by filtration and
recrystallized from the appropriate solvent to give 7d–i.
2-(4-Fluorophenyl)-4-(2-hydroxyethylamino)-5,6-dihydro[1]
benzothiepino[5,4-d]pyrimidine (3e).
The reaction was
refluxed for 24 h, and the product was recrystallized from ethyl
acetate to give 3e (61%) as colorless needles, mp 186–189 ꢂC;
1
IR (potassium bromide) cmꢀ1: 3450, 3340, 3140 (NH, OH); H
NMR (deuterochloroform): d 2.68 (t, 2H, J = 6.3 Hz, H5), 3.45
(br t, 3H, J = 6.3 Hz, changed to 2H (br t, J = 6.3 Hz) with
addition of deuterium oxide, H6, NH or OH), 3.81–3.94 (m, 4H,
NCH2CH2O), 5.34 (br, 1H, deuterium oxide exchangeable, NH or
OH), 7.06–7.16 (m, 2H, H30 and 50), 7.39 (ddd, 1H, J = 7.5, 7.4,
1.7 Hz, H9), 7.54 (ddd, 1H, J = 7.6, 7.5, 1.4 Hz, H10), 7.63
(dd, 1H, J = 7.4, 1.4 Hz, H8), 7.89 (dd, 1H, J = 7.6, 1.7 Hz, H11),
8.41–8.48 (m, 2H, H20 and 60); EIMS m/z: 367 (M+). Anal. Calcd.
for C20H18FN3OS: C, 65.38; H, 4.94; N, 11.44. Found: C, 65.41;
H, 5.06; N, 11.42.
2-(4-Chlorophenyl)-4-(2-hydroxyethylamino)-5,6-dihydro[1]
benzothiepino[5,4-d]pyrimidine (3f). The reaction was refluxed for
24 h, and the product was recrystallized from benzene to give 3f (83ꢀ%1)
as colorless needles, mp 162–165 ꢂC; IR (potassium bromide) cm
:
2-Methyl-4-(N-methyl-2-hydroxyethylamino)-5,6-dihydro[1]
benzothiepino[5,4-d]pyrimidine (7a). The reaction was refluxed
for 12h, and the product was recrystallized from n-hexane to give
3300, 3250 (NH, OH); 1H NMR (deuterochloroform): d 2.63 (t, 2H,
J= 6.5 Hz, H5), 3.42 (t, 2H, J= 6.5 Hz, H6), 3.86 (br s, 5H, changed
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

916
K. Okuda, T. Hirota, and K. Sasaki
Vol 51
7a (51%) as colorless plates, mp 129–130 ꢂC; IR (potassium
bromide) cmꢀ1: 3150 (OH); 1H NMR (deuterochloroform): d
2.60 (s, 3H, 2-CH3), 2.75 (t, 2H, J = 6.0 Hz, H5), 3.25 (s, 3H,
NCH3), 3.49 (t, 2H, J= 6.0Hz, H6), 3.66–3.97 (m, 4H,
NCH2CH2O), 7.37–7.73 (m, 4H, H8, 9, 10, and 11); FAB MS m/z:
302 (MH+), High resolution FAB MS m/z: Calcd. for
C16H20N3OS: 302.1327. Found: 302.1334 (MH+). Anal. Calcd. for
C16H19N3OSꢄ4/5H2O: C, 60.85; H, 6.57; N, 13.31. Found: C,
60.45; H, 6.12; N, 13.11.
2-Ethyl-4-(N-methyl-2-hydroxyethylamino)-5,6-dihydro[1]
benzothiepino[5,4-d]pyrimidine (7b). The reaction was refluxed
for 11h, and the product was recrystallized from acetonitrile to give
7b (47%) as colorless plates, mp 143–145 ꢂC; IR (potassium
bromide) cmꢀ1: 3210 (OH); 1H NMR (deuterochloroform): d
1.36 (t, 3H, J = 7.6Hz, CH2CH3), 2.75 (t, 2H, J = 6.4 Hz, H5),
2.86 (q, 2H, J = 7.6 Hz, CH2CH3), 3.25 (s, 3H, NCH3), 3.50
(t, 2H, J = 6.4Hz, H6), 3.72–3.96 (m, 4H, NCH2CH2O), 6.04
(br, 1H, deuterium oxide exchangeable, OH), 7.36–7.88 (m, 4H,
H8, 9, 10, and 11); FAB MS m/z: 316 (MH+). Anal. Calcd. for
C17H21N3OS: C, 64.73; H, 6.71; N, 13.32. Found: C, 64.68; H,
6.64; N, 13.29.
2-Cyclohexyl-4-(N-methyl-2-hydroxyethylamino)-5,6-dihydro[1]
benzothiepino[5,4-d]pyrimidine (7c). The reaction was refluxed
for 12 h, and the crude product was chromatographed on silica gel.
The eluate of benzene-ethyl acetate (1:4) was evaporated in vacuo
to give 7c (62%) as a viscous oil. IR (CHCl3) cmꢀ1: 3200 (OH);
1H NMR (deuterochloroform): d 1.22–2.17 (m, 10H, cyclohexyl-
H), 2.75 (t, 2H, J = 6.0Hz, H5), 2.78–3.00 (m, 1H, H10), 3.26 (s,
3H, CH3), 3.51 (d, 2H, J = 6.0 Hz, H6), 3.55–4.02 (m, 4H,
NCH2CH2O), 7.31–7.86 (m, 4H, H8, 9, 10, and 11); FAB MS
m/z: 370 (MH+). Anal. Calcd. for C21H27N3OSꢄ1/2H2O: C,
66.63; H, 7.46; N, 11.10. Found: C, 66.83; H, 7.17; N, 10.99.
4-(N-Methyl-2-hydroxyethylamino)-2-phenyl-5,6-dihydro[1]
CH3), 3.54 (t, 2H, J=6.0Hz, H6), 3.76–4.13 (m, 4H, NCH2CH2O),
4.54 (br, 1H, deuterium oxide exchangeable, OH), 7.41–7.71
(m, 3H, H8, 9, and 10), 7.42 (d, 2H, J = 8.8 Hz, H30 and 50),
7.86–8.01 (m, 1H, H11), 8.36 (d, 2H, J = 8.8 Hz, H20 and 60);
FAB MS m/z: 398 (MH+), 400 (MH+ + 2). Anal. Calcd. for
C21H20ClN3OS: C, 63.39; H, 5.07; N, 10.56. Found: C, 63.56;
H, 5.20; N, 10.58.
4-(N-Methyl-2-hydroxyethylamino)-2-(4-methylphenyl)-5,6-
dihydro[1]benzothiepino[5,4-d]pyrimidine (7g). The reaction
was refluxed for 9 h, and the product was recrystallized from
cyclohexane to give 7g (75%) as colorless needles, mp 143–
144 ꢂC; IR (potassium bromide) cmꢀ1: 3380 (OH); 1H NMR
(deuterochloroform): d 2.39 (s, 3H, tolyl-CH3), 2.81 (t, 2H,
J = 6.4 Hz, H5), 3.29 (s, 3H, NCH3), 3.53 (t, 2H, J = 6.4 Hz,
H6), 3.84–4.04 (m, 4H, NCH2CH2O), 4.95 (br, 1H, deuterium
oxide exchangeable, OH), 7.26 (d, 2H, J = 8.2 Hz, H30 and 50),
7.40–7.70 (m, 3H, H8, 9, and 10), 7.87–7.98 (m, 1H, H11),
8.30 (d, 2H, J = 8.2 Hz, H20 and 60); FAB MS m/z: 378 (MH+).
Anal. Calcd. for C22H23N3OS: C, 70.00; H, 6.14; N, 11.13.
Found: C, 69.94; H, 6.12; N, 11.14.
2-(4-Methoxyphenyl)-4-(N-methyl-2-hydroxyethylamino)-5,6-
dihydro[1]benzothiepino[5,4-d]pyrimidine (7h). The reaction
was refluxed for 10 h, and the product was recrystallized from
benzene-cyclohexane to give 7h (68%) as colorless needles, mp
152–154 ꢂC; IR (potassium bromide) cmꢀ1: 3200 (OH); 1H
NMR (deuterochloroform): d 2.81 (t, 2H, J = 6.0 Hz, H5), 3.29
(s, 3H, NCH3), 3.53 (t, 2H, J = 6.0 Hz, H6), 3.76–4.09 (m, 4H,
NCH2CH2O), 3.86 (s, 3H, OCH3), 5.06 (br, 1H, deuterium oxide
exchangeable, OH), 6.98 (d, 2H, J = 8.8 Hz, H30 and 50), 7.36–
7.75 (m, 3H, H8, 9, and 10), 7.82–7.97 (m, 1H, H11), 8.38
(d, 2H, J = 8.8 Hz, H20 and 60); FAB MS m/z: 394 (MH+). Anal.
Calcd. for C22H23N3O2S: C, 67.15; H, 5.89; N, 10.68. Found: C,
67.06; H, 5.91; N, 10.53.
benzothiepino[5,4-d]pyrimidine (7d).
The reaction was
4-(N-Methyl-2-hydroxyethylamino)-2-(4-nitrophenyl)-5,6-
refluxed for 8 h, and the product was recrystallized from
benzene-cyclohexane to give 7d (84%) as colorless needles, mp
122–124 ꢂC; IR (potassium bromide) cmꢀ1: 3350 (OH); 1H
NMR (deuterochloroform): d 2.82 (t, 2H, J = 6.5 Hz, H5), 3.30
(s, 3H, CH3), 3.53 (t, 2H, J = 6.5 Hz, H6), 3.77–4.10 (m, 4H,
NCH2CH2O), 4.84 (br, 1H, deuterium oxide exchangeable,
OH), 7.40–7.75 (m, 6H, H8, 9, 10 and 30, 40, 50), 7.91–8.04
(m, 1H, H11), 8.34–8.50 (m, 2H, H20 and 60); FAB MS m/z:
364 (MH+). Anal. Calcd. for C21H21N3OS: C, 69.39; H, 5.82;
N, 11.56. Found: C, 69.18; H, 5.75; N, 11.40.
2-(4-Fluorophenyl)-4-(N-methyl-2-hydroxyethylamino)-5,6-
dihydro[1]benzothiepino[5,4-d]pyrimidine (7e). The reaction
was refluxed for 13 h, and the product was recrystallized from
benzene-cyclohexane to give 7e (73%) as colorless needles, mp
161–163 ꢂC; IR (potassium bromide) cmꢀ1: 3200 (OH); 1H
NMR (deuterochloroform): d 2.82 (t, 2H, J = 5.8 Hz, H5), 3.30
(s, 3H, CH3), 3.53 (t, 2H, J = 5.8 Hz, H6), 3.84–4.05 (m, 4H,
NCH2CH2O), 4.69 (br, 1H, deuterium oxide exchangeable,
OH), 6.97–7.65 (m, 5H, H8, 9, 10 and 30, 50), 7.86–7.97
(m, 1H, H11), 8.30–8.55 (m, 2H, H20 and 60); FAB MS m/z:
382 (MH+). Anal. Calcd. for C21H20FN3OS: C, 66.12; H, 5.28;
N, 11.02. Found: C, 66.28; H, 5.38, N, 10.77.
dihydro[1]benzothiepino[5,4-d]pyrimidine (7i).
The reaction
was refluxed for 2 h, and the product was recrystallized from
benzene-cyclohexane to give 7i (79%) as yellow needles, mp
148–150 ꢂC; IR (potassium bromide) cmꢀ1: 3400 (OH); 1H NMR
(deuterochloroform): d 2.86 (t, 2H, J = 6.0 Hz, H5), 3.34 (s, 3H,
NCH3), 3.56 (t, 2H, J = 6.0 Hz, H6), 3.76–4.16 (m, 5H, changed
to 4H with addition of deuterium oxide, OH and NCH2CH2O),
7.39–7.78 (m, 3H, H8, 9, and 10), 7.88–8.01 (m, 1H, H11), 8.26
(d, 2H, J = .9.0 Hz, H30 and 50), 8.60 (d, 2H, J = 9.0 Hz, H20 and
60); FAB MS m/z: 409 (MH+). Anal. Calcd. for C21H20N4O3S: C,
61.75; H, 4.94; N, 13.72. Found: C, 61.45; H, 4.96; N, 13.60.
2-Substituted 4-dimethylamino-5,6-dihydro[1]benzothieno
[5,4-d]pyrimidine (8a–i). General procedure. A mixture of
compound 6a–i (100 mg), 50% aqueous dimethylamine (2.0mL)
and diethyl ether (2.0mL) was stirred at room temperature for the
appropriate time. The reaction mixture was evaporated in vacuo,
and ice water (30 mL) was poured into the residue. The mixture
was extracted with chloroform (30mLꢃ 3). The combined
organic layer was washed with sat. brine, dried over anhydrous
sodium sulfate, and evaporated in vacuo. The residue was
recrystallized from a suitable solvent or purified by silica gel
column chromatography.
2-(4-Chlorophenyl)-4-(N-methyl-2-hydroxyethylamino)-5,6-
dihydro[1]benzothiepino[5,4-d]pyrimidine (7f). The reaction
was refluxed for 6 h, and the product was recrystallized from
benzene to give 7f (74%) as colorless needles, mp 155–157 ꢂC;
2-Methyl-4-dimethylamino-5,6-dihydro[1]benzothiepino[5,4-
d]pyrimidine (8a). The reaction was stirred for 1 h, and the
product was recrystallized from acetonitrile to give 8a (85%) as
1
colorless needles, mp 94–97 ꢂC; H NMR (deuterochloroform):
IR (potassium bromide) cmꢀ1
:
3290 (OH); 1H NMR
d 2.60 (s, 3H, 2-CH3), 2.73 (t, 2H, J = 8.0 Hz, H5), 3.13 (s, 6H,
N(CH3)2), 3.50 (t, 2H, J = 8.0 Hz, H6), 7.35–7.51 (m, 4H, H8,
(deuterochloroform): d 2.82 (t, 2H, J = 6.0 Hz, H5), 3.31 (s, 3H,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2014
Synthesis and Evaluation of Anti-Platelet Aggregation Activity of 2,4-Disubstituted
917
5,6-Dihydro[1]benzothiepino[5,4-d]Pyrimidine and Related Compounds
9, 10, and 11); EIMS m/z: 271 (M+). Anal. Calcd. for C15H17N3S:
C, 66.39; H, 6.31; N, 15.48. Found: C, 66.61; H, 6.38; N, 15.46.
2-Ethyl-4-dimethylamino-5,6-dihydro[1]benzothiepino[5,4-d]
4-Dimethylamino-2-(4-methoxyphenyl)-5,6-dihydro[1]
benzothiepino[5,4-d]pyrimidine (8h). The reaction was stirred
for 6 h, and the product was recrystallized from n-hexane to give
8h (34%) as colorless plates, mp 138–140 ꢂC; 1H NMR
(deuterochloroform): d 2.78 (t, 2H, J = 7.0 Hz, H5), 3.21 (s, 6H, N
(CH3)2), 3.53 (t, 2H, J = 7.0 Hz, H6), 3.87 (s, 3H, OCH3), 6.96
(d, 2H, J = 9.0 Hz, H30 and 50), 7.39–7.68 (m, 3H, H8, 9, and 10),
7.88–8.02 (m, 1H, H11), 8.48 (d, 2H, J = 9.0 Hz, H20 and 60);
EIMS m/z: 363 (M+). Anal. Calcd. for C21H21N3OS: C, 69.39; H,
5.82; N, 11.56. Found: C, 69.58; H, 5.85; N, 11.64.
4-Dimethylamino-2-(4-nitrophenyl)-5,6-dihydro[1]benzothiepino
[5,4-d]pyrimidine (8i). The reaction was stirred for 1 h, and the
product was recrystallized from ethyl acetate to give 8i (76%) as
yellow needles, mp 213–215 ꢂC; 1H NMR (deuterochloroform): d
2.83 (t, 2H, J = 6.0 Hz, H5), 3.26 (s, 6H, N(CH3)2), 3.56 (t, 2H,
J = 6.0Hz, H6), 7.42–7.77 (m, 3H, H8, 9, and 10), 7.87–8.02
(m, 1H, H11), 8.27 (d, 2H, J = 8.8 Hz, H30 and 50), 8.69 (d, 2H,
J = 8.8Hz, H20 and 60); FAB MS m/z: 379 (MH+). Anal. Calcd.
for C20H18N4O2S: C, 63.47; H, 4.79; N, 14.80. Found: C, 63.46;
H, 4.75; N, 14.62.
2-Substituted 4-morpholino-5,6-dihydro[1]benzothiepino[5,4-
d]pyrimidine (9a–i). General procedure. To a mixture of 6a–i
(100 mg) in dry 1,4-dioxane (2.0mL) was added morpholine
(10 eq. of 6a–i), and the reaction mixture was refluxed for the
appropriate time. Ice water (30mL) was poured into the reaction
mixture, and the resulting solid (except for 9c) was collected on a
filter. The precipitate was recrystallized from a suitable solvent to
give 9a–i.
2-Methyl-4-morpholino-5,6-dihydro[1]benzothiepino[5,4-d]
pyrimidine (9a). The reaction mixture was refluxed for 24 h,
and the product was recrystallized from cyclohexane to give
9a (74%) as colorless prisms, mp 180–182 ꢂC; 1H NMR
(deuterochloroform): d 2.65 (s, 3H, CH3), 2.74 (t, 2H, J = 6.4 Hz,
H5), 3.35–3.54 (m, 6H, H6 and 30, 50), 3.78–3.93 (m, 4H, H20
and 60), 7.32–7.83 (m, 4H, H8, 9, 10, and 11); EIMS m/z: 313
(M+). Anal. Calcd. for C17H19N3OS: C, 65.15; H, 6.11; N, 13.41.
Found: C, 64.92; H, 6.01; N, 13.16.
pyrimidine (8b).
The reaction was stirred for 2 h, and the
product was chromatographed on silica gel. The eluate of
benzene-ethyl acetate (9:1) was evaporated in vacuo to give 8b
(94%) as a colorless viscous oil. 1H NMR (deuterochloroform): d
1.37 (t, 3H, J = 7.0 Hz, CH2CH3), 2.66–2.80 (q, 2H, J = 7.0 Hz,
CH2CH3), 2.83 (t, 2H, J = 5.8 Hz, H5), 3.14 (s, 6H, N(CH3)2),
3.49 (t, 2H, J = 5.8 Hz, H6), 7.40–7.73 (m, 4H, H8, 9, 10, and
11); EIMS m/z: 285 (M+). Anal. Calcd. for C16H19N3S: C, 67.33;
H, 6.71; N, 14.72. Found: C, 67.58; H, 6.69; N, 14.63.
2-Cyclohexyl-4-dimethylamino-5,6-dihydro[1]benzothiepino
[5,4-d]pyrimidine (8c). The reaction was stirred for 6 h, and
the product was chromatographed on silica gel. The eluate of
benzene was evaporated in vacuo to give 8c (93%) as a colorless
1
viscous oil. H NMR (deuterochloroform): d 1.26–2.29 (m, 10H,
cyclohexyl-H), 2.73 (t, 2H, J = 6.4 Hz, H5), 2.58–2.90 (m, 1H,
H10), 3.14 (s, 6H, N(CH3)2), 3.50 (t, 2H, J = 6.4 Hz, H6), 7.32–
7.90 (m, 4H, H8, 9, 10, and 11); EIMS m/z: 339 (M+). Anal.
Calcd. for C20H25N3S: C, 70.76; H, 7.42; N, 12.38. Found: C, 70.
88; H, 7.38; N, 12.41.
4-Dimethylamino-2-phenyl-5,6-dihydro[1]benzothiepino[5,4-d]
pyrimidine (8d). The reaction was stirred for 3 h, and the product
was recrystallized from cyclohexane to give 8d (95%) as colorless
needles, mp 133–136 ꢂC; 1H NMR (deuterochloroform): d 2.79
(t, 2H, J = 6.0 Hz, H5), 3.22 (s, 6H, N(CH3)2), 3.53 (t, 2H,
J = 6.0 Hz, H6), 7.18–7.74 (m, 6H, H8, 9, 10 and 30, 40, 50), 7.89–
8.04 (m, 1H, H11), 8.45–8.60 (m, 2H, H20 and 60); EIMS m/z: 333
(M+). Anal. Calcd. for C20H19N3S: C, 72.04; H, 5.74; N, 12.60.
Found: C, 72.15; H, 5.84; N, 12.72.
2-(4-Fluorophenyl)-4-dimethylamino-5,6-dihydro[1]
benzothiepino[5,4-d]pyrimidine (8e). The reaction was stirred
for 2 h, and the product was recrystallized from cyclohexane to
give 8e (63%) as colorless plates, mp 137–139 ꢂC; 1H NMR
(deuterochloroform): d 2.79 (t, 2H, J = 7.0 Hz, H5), 3.22 (s, 6H,
N(CH3)2), 3.53 (t, 2H, J = 7.0 Hz, H6), 6.96–7.74 (m, 5H, H8,
9, 10 and 30, 50), 7.85–8.02 (m, 1H, H11), 8.40–8.64 (m, 2H,
H20 and 60); EIMS m/z: 351 (M+). Anal. Calcd. for
C20H18FN3S: C, 68.35; H, 5.16; N, 11.96. Found: C, 68.55; H,
5.44; N, 11.96.
2-Ethyl-4-morpholino-5,6-dihydro[1]benzothiepino[5,4-d]
pyrimidine (9b).
The reaction was refluxed for 24h, and the
product was recrystallized from methanol to give 9b (65%) as
colorless plates, mp 152–154 ꢂC; 1H NMR (deuterochloroform): d
1.37 (t, 3H, J = 7.6 Hz, CH3), 2.63–3.10 (m, 4H, H5 and
CH2CH3), 3.35–3.55 (m, 6H, H6 and 30, 50), 3.79–3.94 (m, 4H,
H20 and 60), 7.32–7.85 (m, 4H, H8, 9, 10, and 11); EIMS m/z:
327 (M+). Anal. Calcd. for C18H21N3OS: C, 66.02; H, 6.46; N,
12.83. Found: C, 65.74; H, 6.37; N, 12.78.
2-(4-Chlorophenyl)-4-dimethylamino-5,6-dihydro[1]
benzothiepino[5,4-d]pyrimidine (8f).
The reaction was
stirred for 2 h, and the product was recrystallized from
acetonitrile to give 8f (73%) as colorless plates, mp 143–
145 ꢂC; 1H NMR (deuterochloroform):
d 2.80 (t, 2H,
J = 5.8 Hz, H5), 3.22 (s, 6H, N(CH3)2), 3.53 (t, 2H, J = 5.8 Hz,
H6), 7.40 (d, 2H, J = 8.2 Hz, H30 and 50), 7.47–7.65 (m, 3H,
H8, 9, and 10), 7.85–7.97 (m, 1H, H11), 8.47 (d, 2H,
J = 8.2 Hz, H20 and 60); EIMS m/z: 367 (M+), 369 (M+ + 2).
Anal. Calcd. for C20H18ClN3S: C, 65.29; H, 4.93; N, 11.42.
Found: C, 65.49; H, 5.12; N, 11.37.
4-Dimethylamino-2-(4-methylphenyl)-5,6-dihydro[1]benzothiepino
[5,4-d]pyrimidine (8g). The reaction was stirred for 5 h, and
the product was recrystallized from ethyl acetate to give
8g (79%) as colorless prisms, mp 159–161 ꢂC; 1H NMR
(deuterochloroform): d 2.40 (s, 3H, CH3), 2.79 (t, 2H, J = 5.8 Hz,
H5), 3.21 (s, 6H, N(CH3)2), 3.52 (t, 2H, J = 5.8 Hz, H6), 7.25
(d, 2H, J = 8.0 Hz, H30 and 50), 7.44–7.69 (m, 3H, H8, 9, and 10),
7.87–8.03 (m, 1H, H11), 8.39 (d, 2H, J = 8.0 Hz, H20 and 60);
EIMS m/z: 347 (M+). Anal. Calcd. for C21H21N3S: C, 72.59; H,
6.09; N, 12.09. Found: C, 72.73; H, 6.10; N, 12.11.
2-Cyclohexyl-4-morpholino-5,6-dihydro[1]benzothiepino[5,4-
d]pyrimidine (9c). The reaction was refluxed for 24 h. In this
case, the resulting oily residue was chromatographed on silica gel.
The eluate of benzene-ethyl acetate (19:1) was evaporated in
vacuo to give 9c (83%) as a colorless viscous oil, 1H NMR
(deuterochloroform): d 1.26–2.17 (m, 10H, cyclohexyl-H), 2.73
(t, 2H, J = 6.4 Hz, H5), 2.65–3.05 (m, 1H, H10), 3.36–3.56
(m, 6H, H6 and morpholino-30, 50), 3.78–3.94 (m, 4H, morpholino-20
and 60), 7.36–7.82 (m, 4H, H8, 9, 10, and 11); EIMS m/z: 381
(M+). Anal. Calcd. for C22H27N3OSꢄ1/4H2O: C, 68.45; H, 7.18; N,
10.88. Found: C, 68.74; H, 7.17; N, 10.72.
4-Morpholino-2-phenyl-5,6-dihydro[1]benzothiepino[5,4-d]
pyrimidine (9d).
The reaction was refluxed for 24h, and the
product was recrystallized from ethanol to give 9d (83%) as
colorless needles, mp 191–192 ꢂC; 1H NMR (deuterochloroform):
d 2.82 (t, 2H, J = 6.4 Hz, H5), 3.40–3.65 (m, 6H, H6 and
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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K. Okuda, T. Hirota, and K. Sasaki
Vol 51
morpholino-30, 50), 3.84–3.98 (m, 4H, morpholino-20 and 60), 7.39–
7.69 (m, 6H, H8, 9, 10 and phenyl-30, 40, 50), 7.85–8.00 (m, 1H,
H11), 8.44–8.59 (m, 2H, phenyl-20 and 60); EIMS m/z: 375 (M+).
Anal. Calcd. for C22H21N3OS: C, 70.37; H, 5.64; N, 11.19.
Found: C, 70.27; H, 5.75; N, 10.94.
formic acid (4.0 eq. of 6a–i), and the reaction was then stirred at
room temperature for the appropriate time. Water (40 mL) was
added and the mixture was extracted with dichloromethane
(30 mL ꢃ 3). The combined organic layer was washed with sat.
brine, dried over anhydrous sodium sulfate, and evaporated in
vacuo. The residue was chromatographed on silica gel. The eluate
of benzene-ethyl acetate (1:1) was evaporated in vacuo. The
residue was recrystallized from a suitable solvent to give 10a–i.
4-Chloro-2-methyl-5,6-dihydro[1]benzothiepino[5,4-d]pyrimidine
7-oxide (10a). The reaction was stirred for 8 h, and the product
was recrystallized from benzene-cyclohexane to give 10a (67%)
as colorless plates, mp 210–211 ꢂC; IR (potassium bromide)
2-(4-Fluorophenyl)-4-morpholino-5,6-dihydro[1]benzothiepino
[5,4-d]pyrimidine (9e). The reaction was refluxed for 24 h, and
the product was recrystallized from ethanol-ethyl acetate to give
9e (70%) as colorless prisms, mp 234–235 ꢂC; 1H NMR
(deuterochloroform): d 2.81 (t, 2H, J=6.4 Hz, H5), 3.40–3.63 (m,
6H, H6 and morpholino-30, 50), 3.84–3.98 (m, 4H, morpholino-20
and 60), 6.97–7.76 (m, 5H, H8, 9, 10 and fluorophenyl-30, 50),
7.83–7.97 (m, 1H, H11), 8.39–8.63 (m, 2H, fluorophenyl-20 and
60); EIMS m/z: 393 (M+). Anal. Calcd. for C22H20FN3OS: C,
67.15; H, 5.12; N, 10.68. Found: C, 67.16; H, 5.24; N, 10.60.
2-(4-Chlorophenyl)-4-morpholino-5,6-dihydro[1]benzothiepino
[5,4-d]pyrimidine (9f). The reaction was refluxed for 9 h, and the
product was recrystallized from ethyl acetate to give 9f (55%) as
1
cmꢀ1: 1030 (SO); H NMR (deuterochloroform): d 2.77 (s, 3H,
CH3), 2.72–3.37 (m, 3H, H5 and one of H6), 4.03–4.54 (m, 1H,
one of H6), 7.73–8.12 (m, 4H, H8, 9, 10, and 11); FAB MS m/z:
279 (MH+), 281 (MH+ + 2). Anal. Calcd. for C13H11ClN2OS: C,
56.01; H, 3.98; N, 10.05. Found: C, 55.94; H, 4.04; N, 10.00.
4-Chloro-2-ethyl-5,6-dihydro[1]benzothiepino[5,4-d]pyrimidine
7-oxide (10b). The reaction was stirred for 5h, and the product
was recrystallized from cyclohexane to give 10b (54%) as colorless
prisms, mp 136–137 ꢂC; IR (potassium bromide) cmꢀ1: 1030 (SO);
1H NMR (deuterochloroform): d 1.43 (t, 3H, J=7.6Hz, CH3),
2.70–2.77 (m, 1H, one of H5), 3.03 (q, 2H, J=7.6Hz, CH2CH3),
3.18–3.22 (m, 1H, one of H5), 3.29–3.33 (m, 1H, one of
H6), 4.25–4.31 (m, 1H, one of H6), 7.71 (dd, 1H, J= 7.6, 7.6 Hz,
H10), 7.80 (dd, 1H, J= 7.6, 7.5Hz, H9), 7.86 (d, 1H, J=7.5Hz,
H8), 8.03 (d, 1H, J=7.6Hz, H11); FAB MS m/z: 293 (MH+), 295
(MH+ +2). Anal. Calcd. for C14H13ClN2OS: C, 57.43; H, 4.48; N,
9.57. Found: C, 57.53; H, 4.50; N, 9.61.
1
colorless prisms, mp 226–228 ꢂC; H NMR (deuterochloroform):
d 2.82 (t, 2H, J =6.4Hz, H5), 3.41–3.64 (m, 6H, H6 and
morpholino-30, 50), 3.84–3.94 (m, 4H, morpholino-20 and 60),
7.34–7.76 (m, 5H, H8, 9, 10 and chlorophenyl-30, 50), 7.83–7.99
(m, 1H, H11), 8.46 (d, 2H, J = 8.1 Hz, chlorophenyl-20 and 60);
EIMS m/z: 409 (M+), 411 (M+ + 2). Anal. Calcd. for
C22H20ClN3OS: C, 64.46; H, 4.92; N, 10.25. Found: C, 64.37; H,
5.08; N, 10.12.
2-(4-Methylphenyl)-4-morpholino-5,6-dihydro[1]benzothiepino
[5,4-d]pyrimidine (9g). The reaction was refluxed for 47 h, and
the product was recrystallized from ethanol to give 9g (58%) as
1
colorless needles, mp 176–178 ꢂC; H NMR (deuterochloroform):
4-Chloro-2-cyclohexyl-5,6-dihydro[1]benzothiepino[5,4-d]
pyrimidine 7-oxide (10c). The reaction was stirred for 5 h, and
the product was recrystallized from n-hexane to give 10c (51%)ꢀa1s
d 2.41 (s, 3H, CH3), 2.81 (t, 2H, J= 6.4Hz, H5), 3.39–3.63 (m,
6H, H6 and morpholino-30, 50), 3.83–3.97 (m, 4H, morpholino-20
and 60), 7.26 (d, 2H, J=8.2 Hz, tolyl-30 and 50), 7.39–7.65 (m, 3H,
H8, 9, and 10), 7.84–7.99 (m, 1H, H11), 8.40 (d, 2H,
J= 8.2Hz, tolyl-20 and 60); EIMS m/z: 389 (M+). Anal. Calcd. for
C23H23N3OS: C, 70.92; H, 5.95; N, 10.79. Found: C, 71.14; H,
5.97; N, 10.80.
2-(4-Methoxyphenyl)-4-morpholino-5,6-dihydro[1]benzothiepino
[5,4-d]pyrimidine (9h). The reaction was refluxed for 24h, and
the product was recrystallized from ethanol to give 9h (63%) as
colorless needles, mp 167–168 ꢂC; 1H NMR (deuterochloroform):
d 2.80 (t, 2H, J = 6.4 Hz, H5), 3.38–3.63 (m, 6H, H6 and
morpholino-30, 50), 3.84–3.97 (m, 7H, OCH3 and morpholino-20,
60), 6.97 (d, 2H, J = 8.8 Hz, methoxyphenyl-30 and 50), 7.45–7.82
(m, 4H, H8, 9, 10, and 11), 8.46 (d, 2H, J = 8.8 Hz,
methoxyphenyl-20 and 60); EIMS m/z: 405 (M+). Anal. Calcd. for
C23H23N3O2S: C, 68.12; H, 5.72; N, 10.36. Found: C, 67.96; H,
5.89; N, 10.30.
colorless needles, mp 160–161 ꢂC; IR (potassium bromide) cm
:
1
1035 (SO); H NMR (deuterochloroform): d 1.20–2.39 (m, 10H,
cyclohexyl-H), 2.70–3.60 (m, 4H, H5, one of H6, and H10), 4.08–
4.44 (m, 1H, one of H6), 7.69–8.12 (m, 4H, H8, 9, 10, and 11);
FAB MS m/z: 347 (MH+), 349 (MH+ + 2); High resolution FAB
MS m/z: Calcd. for C18H20ClN2OS: 347.0985. Found: 347.0936
(MH+). Anal. Calcd. for C18H19ClN2OSꢄ1/6n-hexane: C, 63.18;
H, 5.94; N, 7.76. Found: C, 63.53; H, 5.99; N, 8.16.
4-Chloro-2-phenyl-5,6-dihydro[1]benzothiepino[5,4-d]
pyrimidine 7-oxide (10d). The reaction was stirred for 7 h, and
the product was recrystallized from benzene-cyclohexane to give
10d (66%) as colorless needles, mp 201–203 ꢂC; IR (potassium
bromide) cmꢀ1: 1035 (SO); 1H NMR (deuterochloroform): d
2.59–3.54 (m, 3H, H5 and one of H6), 4.08–4.53 (m, 1H, one of
H6), 7.45–7.56 (m, 3H, H30, 40, and 50), 7.70–8.15 (m, 4H, H8, 9,
10, and 11), 8.36–8.59 (m, 2H, H20 and 60); FAB MS m/z: 341
(MH+), 343 (MH+ + 2). Anal. Calcd. for C18H13ClN2OS: C,
63.43; H, 3.84; N, 8.22. Found: C, 63.18; H, 3.90; N; 8.06.
4-Chloro-2-(4-fluorophenyl)-5,6-dihydro[1]benzothiepino[5,4-
d]pyrimidine 7-oxide (10e). The reaction was stirred for 8 h, and
the product was recrystallized from benzene-cyclohexane to give
10e (78%) as colorless needles, mp 217–218 ꢂC; IR (potassium
bromide) cmꢀ1: 1035 (SO); 1H NMR (deuterochloroform): d
2.71–3.88 (m, 3H, H5 and one of H6), 4.07–4.37 (m, 1H, one of
H6), 7.02–7.31 (m, 2H, H30 and 50), 7.73–8.15 (m, 4H, H8, 9, 10,
and 11), 8.40–8.64 (m, 2H, H20 and 60); FAB MS m/z: 359
(MH+), 361 (MH+ + 2). Anal. Calcd. for H18H12ClFN2OS: C,
60.25; H, 3.37; N, 7.81. Found: C, 60.12; H, 3.51; N, 7.74.
4-Chloro-2-(4-chlorophenyl)-5,6-dihydro[1]benzothiepino[5,4-
d]pyrimidine 7-oxide (10f). The reaction was stirred for 6 h, and
4-Morpholino-2-(4-nitrophenyl)-5,6-dihydro[1]benzothiepino
[5,4-d]pyrimidine (9i). The reaction was refluxed for 5 h, and
the product was recrystallized from benzene to give 9i (64%) as
1
yellow needles, mp 274–276 ꢂC; H NMR (deuterochloroform):
d 2.85 (t, 2H, J = 6.4 Hz, H5), 3.42–3.68 (m, 6H, H6 and
morpholino-30, 50), 3.86–4.01 (m, 4H, morpholino-20 and 60),
7.49–7.85 (m, 4H, H8, 9, 10, and 11), 8.28 (d, 2H, J = 9.3 Hz,
nitrophenyl-30 and 50), 8.68 (d, 2H, J = 9.3 Hz, nitrophenyl-20 and
60); EIMS m/z: 420 (M+). Anal. Calcd. for C22H20N4O3S: C,
62.84; H, 4.79; N, 13.32. Found: C, 62.57; H, 4.90; N, 13.13.
2-Substituted 4-chloro-5,6-dihydro[1]benzothiepino[5,4-d]
pyrimidine 7-oxide (10a–i). General procedure. To a solution
of compound 6a–i (100mg) in dichloromethane (2.0mL) were
added 31% aqueous hydrogen peroxide (1.2 eq. of 6a–i) and
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2014
Synthesis and Evaluation of Anti-Platelet Aggregation Activity of 2,4-Disubstituted
919
5,6-Dihydro[1]benzothiepino[5,4-d]Pyrimidine and Related Compounds
the product was recrystallized from benzene-cyclohexane to give
10f (79%) as colorless needles, mp 216–218 ꢂC; IR (potassium
bromide) cmꢀ1: 1035 (SO); 1H NMR (deuterochloroform): d
2.83–3.53 (m, 3H, H5 and one of H6), 4.25–4.44 (m, 1H, one of
H6), 7.46 (d, 2H, J = 8.8Hz, H30 and 50), 7.69–8.15 (m, 4H, H8,
9, 10, and 11), 8.45 (d, 2H, J = 8.8 Hz, H20 and 60); FAB MS m/z:
375 (MH+), 377 (MH+ +2), 379 (MH+ +4). Anal. Calcd. for
C18H12Cl2N2OS: C, 57.61; H, 3.22; N, 7.46. Found: C, 57.38; H,
3.34; N, 7.48.
4-Chloro-2-(4-methylphenyl)-5,6-dihydro[1]benzothiepino[5,4-
d]pyrimidine 7-oxide (10g). The reaction was stirred for 9 h, and
the product was recrystallized from benzene-cyclohexane to give
10g (80%) as colorless needles, mp 213–214ꢂC; IR (potassium
bromide) cmꢀ1: 1035 (SO); 1H NMR (deuterochloroform): d 2.43
(s, 3H, CH3), 2.66–3.52 (m, 3H, H5 and one of H6), 4.07–4.45
(m, 1H, one of H6), 7.30 (d, 2H, J = 8.2 Hz, H30 and 50), 7.70–
8.10 (m, 4H, H8, 9, 10, and 11), 8.39 (d, 2H, J = 8.2 Hz, H20 and
60); FAB MS m/z: 355 (MH+), 357 (MH+ +2). Anal. Calcd. for
C19H15ClN2OS: C, 64.31; H, 4.26; N, 7.89. Found: C, 64.26; H,
4.30; N, 7.79.
4-Chloro-2-ethyl-5,6-dihydro[1]benzothiepino[5,4-d]pyrimidine
7,7-dioxide (11b).
The reaction was stirred for 2 h, and the
product was recrystallized from ethanol to give 11b (54%) as
colorless plates, mp 158–159 ꢂC; IR (potassium bromide)
1
cmꢀ1: 1305, 1150 (SO2); H NMR (deuterochloroform): d 1.41
(t, 3H, J = 7.7 Hz, CH3), 3.04 (q, 2H, J = 7.7 Hz, CH2CH3), 3.18
(t, 2H, J = 6.6 Hz, H5), 3.84 (t, 2H, J = 6.6 Hz, H6), 7.72 (ddd,
1H, J = 7.5, 7.4, 1.6 Hz, H10), 7.85 (ddd, 1H, J = 7.6, 7.5,
1.4 Hz, H9), 7.94 (dd, 1H, J= 7.6, 1.6 Hz, H8), 8.16 (dd, 1H,
J=7.4, 1.4Hz, H11); FAB MS m/z: 309 (MH+), 311 (MH+ +2).
Anal. Calcd. for C14H13ClN2O2S: C, 54.46; H, 4.24; N, 9.07.
Found: C, 54.64; H, 4.26; N, 9.10.
4-Chloro-2-cyclohexyl-5,6-dihydro[1]benzothiepino[5,4-d]
pyrimidine 7,7-dioxide (11c). The reaction was stirred for 2 h,
and the product was recrystallized from ethanol to give 11c (37%)
as colorless plates, mp 185–187 ꢂC; IR (potassium bromide)
1
cmꢀ1: 1310, 1150 (SO2); H NMR (deuterochloroform): d 1.26–
2.28 (m, 10H, cyclohexyl-H), 2.70–3.38 (m, 3H, H5 and 10), 3.83
(t, 2H, J = 7.0 Hz, H6), 7.77–8.00 (m, 3H, H8, 9, and 10), 8.09–
8.24 (m, 1H, H11); FAB MS m/z: 363 (MH+), 365 (MH+ + 2).
Anal. Calcd. for C18H19ClN2O2S: C, 59.58; H, 5.28; N, 7.72.
Found: C, 59.74; H, 5.30; N, 7.73.
4-Chloro-2-(4-methoxyphenyl)-5,6-dihydro[1]benzothiepino
[5,4-d]pyrimidine 7-oxide (10h). The reaction was stirred for
5 h, and the product was recrystallized from benzene-cyclohexane to
give 10h (77%) as colorless needles, mp 203–205 ꢂC; IR (potassium
4-Chloro-2-phenyl-5,6-dihydro[1]benzothiepino[5,4-d]pyrimidine
7,7-dioxide (11d).
The reaction was stirred for 1 h, and the
1
bromide) cmꢀ1: 1035 (SO); H NMR (deuterochloroform): d 2.97–
product was recrystallized from ethanol to give 11d (47%)ꢀa1s
3.51 (m, 3H, H5 and one of H6), 3.89 (s, 3H, OCH3), 4.07–4.38
(m, 1H, one of H6), 6.98 (d, 2H, J=9.0Hz, H30 and 50), 7.67–8.15
(m, 4H, H8, 9, 10, and 11), 8.45 (d, 2H, J=9.0Hz, H20 and 60);
FAB MS m/z: 371 (MH+), 373 (MH+ +2). Anal. Calcd. for
C19H15ClN2O2S: C, 61.53; H, 4.08; N, 7.55. Found: C, 61.42; H,
4.15; N, 7.52.
colorless needles, mp 223–225 ꢂC; IR (potassium bromide) cm
:
1
1312, 1155 (SO2); H NMR (deuterochloroform): d 3.21 (t, 2H,
J = 6.4 Hz, H5), 3.87 (t, 2H, J = 6.4 Hz, H6), 7.50–8.23 (m, 7H,
H8, 9, 10, 11, and 30, 40, 50), 8.44–8.56 (m, 2H, H20 and 60);
FAB MS m/z: 357 (MH+), 359 (MH+ + 2). Anal. Calcd. for
C18H13ClN2O2S: C, 60.59; H, 3.67; N, 7.85. Found: C, 60.82; H,
3.77; N; 7.86.
4-Chloro-2-(4-nitrophenyl)-5,6-dihydro[1]benzothiepino[5,4-
d]pyrimidine 7-oxide (10i).
The reaction was stirred for 5 h,
4-Chloro-2-(4-fluorophenyl)-5,6-dihydro[1]benzothiepino
[5,4-d]pyrimidine 7,7-dioxide (11e). The reaction was stirred for
4 h, and the product was recrystallized from ethanol to give 11e
(64%) as colorless needles, mp 237–239 ꢂC; IR (potassium
bromide) cmꢀ1: 1312, 1150 (SO2); 1H NMR (deuterochloroform):
d 3.22 (t, 2H, J = 6.5 Hz, H5), 3.87 (t, 2H, J = 6.5Hz, H6), 7.01–
7.31 (m, 2H, H30 and 50), 7.73–7.98 (m, 3H, H8, 9, and 10),
8.12–8.22 (m, 1H, H11), 8.41–8.65 (m, 2H, H20 and 60); FAB
MS m/z: 375 (MH+), 377 (MH+ + 2). Anal. Calcd. for
C18H12ClFN2O2S: C, 57.68; H, 3.23; N, 7.47. Found: C, 57.64;
H, 3.48; N, 7.39.
and the product was recrystallized from benzene to give 11i
(64%) as yellow needles, mp 236–238 ꢂC; IR (potassium
bromide) cmꢀ1: 1035 (SO); 1H NMR (deuterochloroform): d
2.78–3.60 (m, 3H, H5 and one of H6), 4.07–4.57 (m, 1H, one
of H6), 7.72–8.15 (m, 4H, H8, 9, 10, and 11), 8.32 (d, 2H,
J = 9.0 Hz, H30 and 50), 8.71 (d, 2H, J = 9.0 Hz, H20 and 60);
FAB MS m/z: 386 (MH+), 388 (MH+ + 2). Anal. Calcd. for
C18H12ClN3O3S: C, 56.03; H, 3.13; N, 10.89. Found: C, 55.86;
H, 3.27; N, 10.78.
2-Substituted 4-chloro-5,6-dihydro[1]benzothiepino[5,4-d]
pyrimidine 7,7-dioxide (11a–i). General procedure.
To a
4-Chloro-2-(4-chlorophenyl)-5,6-dihydro[1]benzothiepino[5,4-
solution of potassium permanganate (2.7 eq. of 6a–i) in acetic
acid (6.0 mL) and water (1.0 mL) was added 6a–i (100 mg), and
the reaction mixture was stirred at room temperature for
the appropriate time. Sat. sodium hydrogen sulfite aq. was
added to the reaction mixture under cooling to dissolve
generated manganese dioxide. The crystalline precipitate was
collected by filtration and recrystallized from a suitable solvent
to give 11a–i.
d]pyrimidine 7,7-dioxide (11f).
The reaction was stirred for
12h, and the product was recrystallized from ethyl acetate to
give 11f (55%) as colorless prisms, mp 100–102 ꢂC; IR
:
(potassium bromide) cmꢀ1 1312, 1152 (SO2); 1H NMR
(deuterochloroform): d 3.24 (t, 2H, J = 6.6Hz, H5), 3.88 (t, 2H,
J = 6.6 Hz, H6), 7.46 (d, 2H, J = 9.0 Hz, H30 and 50), 7.76 (ddd,
1H, J =7.8, 7.7, 1.5 Hz, H10), 7.89 (ddd, 1H, J = 7.8, 7.4,
1.4 Hz, H9), 8.04 (dd, 1H, J = 7.4, 1.5Hz, H8), 8.19 (dd, 1H,
J = 7.7, 1.4 Hz, H11), 8.46 (d, 2H, J = 9.0Hz, H20 and 60);
FAB MS m/z: 391 (MH+), 393 (MH+ + 2), 395 (MH+ + 4).
Anal. Calcd. for C18H12Cl2N2O2S: C, 55.25; H, 3.09; N, 7.16.
Found: C, 55.31; H, 3.22; N, 7.16.
4-Chloro-2-methyl-5,6-dihydro[1]benzothiepino[5,4-d]pyrimidine
7,7-dioxide (11a).
The reaction was stirred for 2 h, and the
product was recrystallized from ethanol to give 11a (62%) as
colorless plates, mp 219–221 ꢂC; IR (potassium bromide)
1
cmꢀ1: 1308, 1151 (SO2); H NMR (deuterochloroform): d 2.78
4-Chloro-2-(4-methylphenyl)-5,6-dihydro[1]benzothiepino[5,4-
d]pyrimidine 7,7-dioxide (11g). The reaction was stirred for 2 h,
and the product was recrystallized from ethanol to give 11g (57%) as
(s, 3H, CH3), 3.16 (t, 2H, J = 5.8 Hz, H5), 3.84 (t, 2H,
J = 5.8 Hz, H6), 7.75–7.96 (m, 3H, H8, 9, and 10), 8.11–8.22
(m, 1H, H11); FAB MS m/z: 295 (MH+), 297 (MH+ + 2). Anal.
Calcd. for C13H11ClN2O2S: C, 52.97; H, 3.76; N, 9.50. Found:
C, 53.13; H, 3.80; N, 9.50.
colorless needles, mp 272–274ꢂC; IR (potassium bromide) cmꢀ1
:
1
1312, 1155 (SO2); H NMR (deuterochloroform): d 2.43 (s, 3H,
CH3), 3.20–3.32 (m, 2H, H5), 3.76–4.03 (m, 2H, H6), 7.29
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

920
K. Okuda, T. Hirota, and K. Sasaki
Vol 51
(d, 2H, J= 7.6 Hz, H30 and 50), 7.79–8.24 (m, 4H, H8, 9, 10, and 11),
8.40 (d, 2H, J =7.6Hz, H20 and 60); FAB MS m/z: 371 (MH+), 373
(MH+ +2). Anal. Calcd. for C19H15ClN2O2S: C, 61.53; H, 4.08; N,
7.55. Found: C, 61.40; H, 4.14; N, 7.51.
Acknowledgments. The authors are grateful to the SC-NMR
Laboratory of Okayama University for 200MHz 1H NMR
experiments. They also thank Mr. Hiroyuki Kohmoto (Laboratory
of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences,
Okayama University) for his experimental assistance, and Dr. K.
L. Kirk (NIDDK, NIH) for helpful comments on the manuscript.
4-Chloro-2-(4-methoxyphenyl)-5,6-dihydro[1]benzothiepino
[5,4-d]pyrimidine 7,7-dioxide (11h). The reaction was stirred
for 1 h, and the product was recrystallized from ethanol to give 11h
(68%) as colorless needles, mp 235–237 ꢂC; IR (potassium
bromide) cmꢀ1: 1305, 1150 (SO2); 1H NMR (deuterochloroform):
d 3.15–3.28 (m, 2H, H5), 3.73–3.95 (m, 2H, H6), 3.89 (s, 3H,
OCH3), 6.99 (d, 2H, J = 8.8 Hz, H30 and 50), 7.86–8.16 (m, 4H,
H8, 9, 10, and 11), 8.47 (d, 2H, J = 8.8 Hz, H20 and 60); FAB
MS m/z: 387 (MH+), 389 (MH+ + 2). Anal. Calcd. for
C19H15ClN2O3S: C, 58.99; H, 3.91; N, 7.24. Found: C, 58.70;
H, 4.06; N, 7.33.
REFERENCES AND NOTES
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4-Chloro-2-(4-nitrophenyl)-5,6-dihydro[1]benzothiepino[5,4-
d]pyrimidine 7,7-dioxide (11i). The reaction was stirred for
1 h, and the product was recrystallized from ethyl acetate to
give 11i (56%) as colorless needles, mp >300 ꢂC; IR
(potassium bromide) cmꢀ1: 1315, 1160 (SO2); 1H NMR
(deuterochloroform): d 3.28 (t, 2H, J = 7.0 Hz, H5), 3.90 (t, 2H,
J = 7.0 Hz, H6), 7.79 (ddd, 1H, J = 8.0, 7.6, 1.5 Hz, H10), 7.92
(ddd, 1H, J = 7.7, 7.6, 1.4 Hz, H9), 8.05 (dd, 1H, J = 7.7,
1.5 Hz, H8), 8.21 (dd, 1H, J = 8.0, 1.4 Hz, H11), 8.34 (d, 2H,
J = 9.0 Hz, H30 and 50), 8.71 (d, 2H, J = 9.0 Hz, H20 and 60);
FAB MS m/z: 402 (MH+), 404 (MH+ + 2). Anal. Calcd. for
C18H12ClN3O4S: C, 53.80; H, 3.01; N, 10.46. Found: C, 53.65;
H, 3.13; N, 10.35.
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Measurement of platelet aggregation.
Preparation of
platelet rich plasma was carried out according to the
method described previously [21]. The platelet rich plasma
described earlier, 250 mL, synthetic compounds 3 and 6–11,
25 mL (10% DMSO solution or 60% DMF solution), and 1 M
Tris–HCl buffer (pH 7.4) 25 mL were mixed and pre-
incubated at 37 ꢂC, followed 2 min later by addition of 50 mL
aggregating agent (collagen, final concentration 14.3 mg/mL).
Platelet aggregation was measured by continuous recording of
light transmission at 650 nm through plasma for 10–15 min
using an aggregometer (Aggrecoder II PA-3220, Kyoto
Daiichi Kagaku Co. Ltd., Kyoto, Japan). Aspirin was used as
a positive control. The inhibition rate was calculated from an
aggregation response according to the method already
described [21].
[18] Davenport, A. J.; Hallett, D. J.; Corsi, M. In PCT Int Appl,
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[21] Hirota, T.; Sasaki, K.; Ohtomo, H.; Uehara, A.; Nakayama, T.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet