Polycyclic N-heterocyclic compounds. Part 85: Synthesis and evaluation of antiplatelet aggregation activity of 2,4-disubstituted 5,6-dihydro[1]benzazepino[5,4-d]pyrimidine and related compounds

Article abstract of DOI:10.1002/jhet.2040

We have synthesized a large number of tricyclic 2-substituted 4-alkylamino-5,6-dihydro[1]benzazepino[5,4-d]pyrimidines as part of our research to develop new effective antiplatelet 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 antiplatelet candidates with potencies superior to aspirin.

Full text of DOI:10.1002/jhet.2040

8
88
Polycyclic N-Heterocyclic Compounds. Part 85: Synthesis and Evaluation
of Antiplatelet Aggregation Activity of 2,4-Disubstituted 5,6-Dihydro[1]
benzazepino[5,4-d]pyrimidine and Related Compounds
Vol 52
a
b
b
b
Kensuke Okuda, * Ying-Xue Zhang, Takashi Hirota, and Kenji Sasaki
a
Laboratory of Medicinal and Pharmaceutical Chemistry, Gifu Pharmaceutical University, Gifu 501-1196, Japan
Laboratory of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Okayama University, Kita-ku, Okayama
00-8530, Japan
b
7
*
E-mail:okuda@gifu-pu.ac.jp
Received March 24, 2013
DOI 10.1002/jhet.2040
Published online 11 June 2014 in Wiley Online Library (wileyonlinelibrary.com).
We have synthesized a large number of tricyclic 2-substituted 4-alkylamino-5,6-dihydro[1]benzazepino
[
5,4-d]pyrimidines as part of our research to develop new effective antiplatelet 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 antiplatelet candidates with
potencies superior to aspirin.
J. Heterocyclic Chem., 52, 888 (2015).
INTRODUCTION
tosylated with tosyl chloride in pyridine to afford N-tosyl-2-
aminobenzonitrile (5) (87%) (Scheme 1). The functionality
required for the construction of the benzazepine structure
was introduced by alkylation of 5 with 4-chlorobutyronitrile
and potassium iodide in the presence of potassium carbonate
in acetone to give 2-(N-tosyl-3-cyanopropylamino)
benzonitrile (6) (93%). Treatment of 6 with sodium hydride
in THF triggered a Thrope–Ziegler cyclization to give
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 antiplatelet
aggregation activity of these compounds, we discovered that
-substituted 4-(2-hydroxyethylamino)-5,6-dihydrobenzo[h]qui-
naozlines (1) [1] and 2-substituted 4-(2-hydroxyethylamino)-
,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 antiplatelet agent (Fig. 1) [3]. The most potent 1
2
6
5-amino-1-tosyl-2,3-dihydro-1H-[1]benzazepine-4-carbonitrile
(7) (82%). Next, 7 was allowed to react with Vilsmeier
reagents prepared from a series of N,N-dimethylamides and
phosphoryl chloride to give 4-chloro-7-tosyl-6,7-dihydro-
(
R=Ph) had six times the activity of aspirin, whereas the most
5H-pyrimido[5,4-d][1]benazepines (8a–d). Structures of
potent 2 (R=4-Cl-Ph) had four times the activity of aspirin.
Current antiplatelet drugs are important for the preven-
tion 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]. To develop more active
compounds derived from our hit compounds, we decided to
explore the structure–activity relationships of 2-substituted
8
a–d were supported by the disappearance of the enamine
and nitrile groups and the appearance of chlorine atoms in
their IR and MS spectra. In addition, the NMR spectra and
elemental analyses provided confirmation of these structures.
Next, intermediates 8a–d were hydrolyzed with concd HCl
and acetic acid to give 6,7-dihydro-5H-pyrimido[5,4-d][1]
benazepin-4(3H)-ones (9a–d). Concomitant hydrolysis at
4-position and removal of N-tosyl protecting group were
apparent by the disappearance of chlorine atoms and tosyl
group in their IR and MS spectra. In addition, the NMR
spectra provided confirmation of these structures.
Compounds 9a–d were converted to 10a–d by treatment
4-(2-hydroxyethylamino)-5,6-dihydro[1]benzazepino[5,4-
d]pyrimidines (3), the aza-analogues of 1 and 2. In this
report, we describe in detail the synthesis and evaluation
of these compounds.
with phosphoryl chloride.
Next, we employed 2-aminoethanol to carry out nucleo-
RESULTS AND DISCUSSION
philic substitution at the 4-position of 10a–d to give 3a–d
(63–75%, Scheme 2) as analogues of 1 and 2. Because we also
expected the 2-hydroxyethylamino substituent to influence
Chemistry.
We synthesized the target molecules by
the following method. First, 2-aminobenzonitrile (4) was
©
2014 HeteroCorporation

May 2015
Polycyclic N-Heterocyclic Compounds. Part 85: Synthesis and Evaluation of Antiplatelet Aggregation
Activity of 2,4-Disubstituted 5,6-Dihydro[1]benzazepino[5,4-d]pyrimidine and Related Compounds
889
Figure 1. Previous hit compounds (1 and 2) as antiplatelet agents and their analogues (3) prepared here.
Scheme 1. Preparation of 10.
bioactivity, to eliminate the hydrogen donor ability of amino
group, N-methyl-2-aminoethanol was also chosen to react
with 10a–d to give 11a–d (67–91%). Similarly, the reaction
of morpholine with 10a–d was carried out to give 12a–d
activity (IC ) of the compounds that showed significant
50
difference (P < 0.05) from the activity of aspirin at the
same concentration was determined. Among them, 12e
with the 2-unsusbituted 4-morpholino substituent is the
most potent, having 15 times more activity than aspirin and
having greater potency than the most potent 1 (R=Ph) [1]
and most potent 2 (R=4-Cl-Ph) [2]. The difference in the
potency observed for series 3 and 11 is quite interesting
because the only difference in the structures is the presence
of NH in the less active 3 and NMe in the more active 11.
A 2-methyl substituent is preferable for 11–13 in general.
Because our results suggest that the presence of a
secondary amino group of 3 decreases activity in this
series, we prepared compounds 14a–d (67–83%) by
dehydration of 3a–d and 14e (R=H) [14] from 3e to
examine the effects of an imine on activity (Scheme 3).
However, none of 14 showed any significant improvement
in potency over aspirin (data not shown). More detailed
examination will be needed to clarify structure–activity
relationships in this series of compounds.
(
61–89%), thus simultaneously eliminating the hydrogen
donor ability of the amino and hydroxy groups of the
-hydroxyethylamino substituent. Finally, the reaction of
2
piperidine with 10a–d gave 13a–d (70–78%) thereby elimi-
nating the influence of the hydrogen acceptor ability of the
ether group in the morpholine moiety. We had also prepared
each corresponding 2-unsubsituted derivatives (R=H) (3e
[14], 10e [14], 11e [15], 12e [15], and 13e [15]). All deriva-
tives 3 and 10–13 satisfy the Lipinski’s rule of five, and thus,
they are expected to have drug-like properties [16].
Biology. 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 [17]. Platelet aggregation was
induced by the addition of collagen (final concentration
14.3 mg/mL). A 10% solution of DMSO (final concentration
On the basis of the promising results reported herein, we
are currently exploring the development of additional
derivatives with antiplatelet aggregation activity.
0
.71%) or 60% 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 3 showed any
significant improvement in potency over aspirin.
Compound 10 did not show any superior potency to aspirin
either (data not shown). However, certain of the substituted
tricyclic compounds 11–13 showed a bioactivity superior
to that of aspirin. A detailed comparison of the inhibitory
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 EI-mass and
FAB-mass (m-nitrobenzyl alcohol was used as the matrix) were
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

8
90
K. Okuda, Y.-X. Zhang, T. Hirota, and K. Sasaki
Vol 52
Scheme 2. Preparation of 3 and 11–13.
obtained on a VG (UK) 70-SE mass spectrometer. The IR spectra
were recorded on a Japan Spectroscopic (Hachioji, Japan) diffrac-
tion grating A-102 spectrophotometer, and frequencies are
(DMSO-d
2.61 (br t, 2H, J = 8.0 Hz, CH
NCH ), 6.95–8.10 (m, 8H, Ar-H); FAB-mass m/z 340 (MH ).
Anal. Calcd for C18 S: C, 63.70; H, 5.05; N, 12.38.
Found: C, 63.70; H, 5.14; N, 12.45.
-Amino-1-tosyl-2,3-dihydro-1H-[1]-benzazepine-4-carbonitrile
7). A mixture of 6 (10.0 g, 29.5 mmol) and NaH (60%, 3.54 g,
6
): d 1.50–1.92 (m, 2H, NCH
2 2 2
CH CH ), 2.43 (s, 3H, Me),
2
CN), 3.65 (br t, 2H, J = 8.0 Hz,
+
2
ꢀ
1
1
expressed in cm . The H NMR spectra were recorded on a
Varian (Palo Alto, CA) VXR-200 instrument or a Hitachi (Tokyo,
Japan) R-1500 instrument with TMS 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 TLC to determine the
appropriate time for termination.
17 3 2
H N O
5
(
8
8.5 mmol, washed twice with ligroin) in dry THF (200 mL) was
ꢁ
heated at 45 C for 14 h under a nitrogen atmosphere. After the
removal of solvent in vacuo, ice water (150 mL) was added to
the residue slowly, and the resulting white precipitate was
filtered off, washed with water, and recrystallized from
ethanol–ethyl acetate to give 7 (8.20 g, 82%) as pale yellow
N-Tosyl-2-aminobenzonitrile (5).
To a solution of 2-
aminobenzonitrile (4, 25.0 g, 0.212 mol) in 150 mL of pyridine
ꢁ
ꢀ1
1
ꢁ
needles, mp 226–227.5 C; IR (potassium bromide) cm : 3450,
3
was added tosyl chloride (50.0 g, 0.262 mol) at 0 C, and the
350, 3250 (NH), 2190 (CN), 1340, 1150 (SO); H NMR
reaction mixture was stirred at rt for 2 days. After the
evaporation of solvent in vacuo, ice water (400 mL) was added,
and the resulting precipitate was filtered off then washed with
(
DMSO-d ): d 1.96 (br t, 2H, J = 7.0 Hz, H3), 2.41 (s, 3H, Me),
6
3
.87 (br t, 2H, J = 7.0 Hz, H2), 6.21 (s, 2H, deuterium oxide
exchangeable, NH ), 7.27–7.64 (m, 8H, Ar-H); FAB-mass
m/z 340 (MH ). Anal. Calcd for C H N O S: C, 63.70; H,
2
water. The solid was recrystallized from ethanol to give 5
+
ꢁ
18 17 3 2
(
50.0 g, 87%) as colorless plates, mp 133–135 C; IR (potassium
ꢀ
1
1
5.05; N, 12.38. Found: C, 64.09; H, 5.05; N, 12.41.
bromide) cm : 3160 (NH), 2200 (CN), 1320, 1145 (SO); H
NMR (DMSO-d ): d 2.38 (s, 3H, Me), 6.98–7.98 (m, 8H,
General procedure for the synthesis of 2-substituted 4-
6
chloro-7-tosyl-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepine
Ar-H), 10.5 (br, 1H, deuterium oxide exchangeable, NH);
(
8a–d). The Vilsmeier reagent was prepared by the reaction of
+
FAB-mass m/z 273 (MH ). Anal. Calcd for C H N O S: C,
1
4
12
2
2
the corresponding N,N-dimethylamide [18] (67.9 mmol) and
phosphoryl chloride (60 mL) under ice cooling for 1 h. The
enaminonitrile 7 (10.0 g, 29.5 mmol) was added, and the
6
1.75; H, 4.44; N, 10.29. Found: C, 61.74; H, 4.51; N, 10.21.
-(N-Tosyl-3-cyanopropylamino)benzonitrile (6). A mixture
2
of 5 (50.0 g, 0.184 mol), 4-chlorobutyronitrile (19.1 g, 0.184 mmol),
potassium carbonate (76.0 g, 0.550 mol), and potassium iodide
ꢁ
reaction was stirred at 75 C for 4 h. After the removal of excess
phosphoryl chloride, ice water (300 mL) was poured into the
residue, and the mixture was basified to pH 9 with sodium
carbonate. The resulting white solid precipitate was washed
with water and recrystallized from the appropriate solvent to
(10.0 g, 60.2 mmol) in dry acetone (500 mL) was refluxed for
1
week. After the removal of solvent in vacuo, ice water (500 mL)
was added to the resulting oily residue, and the mixture was
stirred for a couple of hours. The resulting precipitate was filtered
give 8.
off, washed with water, and recrystallized from methanol to give
4-Chloro-2-methyl-7-tosyl-6,7-dihydro-5H-pyrimido[5,4-d]
ꢁ
6
(58.0 g, 93%) as colorless plates, mp 86–88 C; IR (potassium
[1]benzazepine (8a).
methanol gave 8a (77%) as colorless prisms, mp 200–202 C;
Recrystallization of the solid from
ꢀ
1
1
ꢁ
bromide) cm : 2250 (CN), 1350, 1160 (SO); H NMR
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2015
Polycyclic N-Heterocyclic Compounds. Part 85: Synthesis and Evaluation of Antiplatelet Aggregation
Activity of 2,4-Disubstituted 5,6-Dihydro[1]benzazepino[5,4-d]pyrimidine and Related Compounds
891
Table 1
4-Chloro-2-(4-methoxyphenyl)-7-tosyl-6,7-dihydro-5H-
pyrimido[5,4-d][1]benzazepine (8c). Recrystallization of
the solid from acetone gave 8c (93%) as colorless prisms, mp
Effects of compounds 3 and 11–13 on rabbit platelet aggregation in vitro
induced by collagen.
ꢁ
ꢀ1
2
06–208 C; IR (potassium bromide) cm : 1330, 1155 (SO);
a
b
1
Compound
% inhibition
IC50 (mM)
H NMR (deuterochloroform): d 1.73 (s, 3H, Me), 2.85 (t, 2H,
J = 6.5 Hz, H5), 3.91 (s, 3H, OMe), 4.37 (t, 2H, J = 6.5 Hz, H6),
6
c
3
3
3
3
3
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
a
20.4 ꢃ 0.2
29.9 ꢃ 3.5
26.7 ꢃ 7.1
17.5 ꢃ 5.1
11.8 ꢃ 2.2
95.8 ꢃ 3.3*
—
—
—
—
—
0 0
.73–7.85 (m, 10H, Ar-H), 8.35 (d, 2H, J = 8.0 Hz, H2 and 6 );
d
b
+
+
d
EI-mass m/z 491 (M ), 493 (M + 2). Anal. Calcd for
22ClN S: C, 63.47; H, 4.51; N, 8.54. Found: C, 63.47;
H, 4.66; N, 8.62.
-Chloro-2-(4-chlorophenyl)-7-tosyl-6,7-dihydro-5H-pyrimido
c
d
C
26
H
3 3
O
d
c
e
c
4
1a
4.5 (1.1–7.1)
2.1 (1.3–3.0)
—
2.5 (1.9–3.5)
—
8.9 (3.9–13.3)
2.3 (1.4–3.7)
—
d
1b
56.5 ꢃ 11.3*
38.2 ꢃ 9.9
58.6 ꢃ 10.7*
39.2 ꢃ 9.2
92.7 ꢃ 4.1*
67.4 ꢃ 8.4*
24.2 ꢃ 1.5
11.7 ꢃ 8.1
83.9 ꢃ 4.4*
92.5 ꢃ 1.7*
19.5 ꢃ 1.7
10.3 ꢃ 2.7
29.6 ꢃ 4.4
72.3 ꢃ 7.4*
15.7 ꢃ 1.0
26.1 ꢃ 1.7
[5,4-d][1]benzazepine (8d). Recrystallization of the solid from
d
ꢁ
1c
ethyl acetate gave 8d (84%) as colorless prisms, mp 225–227 C;
d
ꢀ1
1
1d
1e
2a
IR (potassium bromide) cm : 1340, 1155 (SO); H NMR
deuterochloroform): d 1.72 (s, 3H, Me), 2.87 (t, 2H, J = 6.5 Hz,
H5), 4.40 (t, 2H, J = 6.5 Hz, H6), 6.75–7.88 (m, 10H, Ar-H), 8.34
c
(
c
d
2b
0 0
+
(
d, 2H, J = 8.5 Hz, H2 and 6 ); FAB-mass m/z 496 (MH ), 498
d
2c
+
d
(MH + 2). Anal. Calcd for C25
2 3 2
H19Cl N O S: C, 60.49; H, 3.86;
2d
2e
3a
—
c
N, 8.46. Found: C, 60.60; H, 3.93; N, 8.36.
General procedure for the synthesis of 2-substituted
6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-4(3H)-one
3.1 (1.1–5.6)
4.4 (0.5–7.7)
—
c
d
3b
d
(
9a–d).
A mixture of 8a–d (1.00 g) in concd hydrochloric acid
3c
—
—
d
3d
(30 mL) and acetic acid (15 mL) was refluxed for an appropriate
time. After the removal of volatile components in vacuo, ice water
c
3e
14.3 (11.0–21.4)
48.0 (44.1–53.3)
6.5 (5.3–8.8)
c
Aspirin
Aspirin
(50 mL) was poured into the residue, and the solution was adjusted
d
to pH 9 with sodium carbonate. The precipitated solid was washed
with water and recrystallized from a suitable solvent to give 9.
*
Means significantly different from aspirin at P < 0.05.
a
2
-Methyl-6,7-dihydro-5H-pyrimido[5.4-d][1]benzazepin-4
Data represent the % inhibition of the vehicle control group (mean ꢃ SE
of three experiments at least) at final concentration of 25 mM (in the case
of 10% DMSO) or 2.5 mM (in the case of 60% DMF).
Experiments were repeated at least three times each at final concentra-
tions of 5.0, 25, and 50 mM in the case of 10% DMSO; 25, 50, and
00 mM aspirin in the case of 10% DMSO; 1.0, 2.5, and 5.0 mM in the case
of 60% DMF; or 2.5, 5.0, and 10 mM aspirin in the case of 60% DMF.
Figures in parentheses represent the 95% confidence limits of IC50
0% DMSO was used as a cosolvent.
0% DMF was used as a cosolvent.
(3H)-one (9a). The reaction was refluxed for 30h, and the
product was recrystallized from ethyl acetate to give 9a (90%) as
b
ꢁ
ꢀ1
a yellow powder, mp 241–243 C; IR (potassium bromide) cm
:
1
3
340 (NH), 1650 (CO); H NMR (DMSO-d ): d 2.30 (s, 3H,
6
1
Me), 2.61–2.90 (m, 2H, H5), 3.20–3.51 (m, 3H, changed to 2H
with addition of deuterium oxide, H6, and NH), 6.45–8.06 (m,
4H, Ar-H), 12.30 (br, 1H, deuterium oxide exchangeable, NH);
.
c
1
6
d
+
FAB-mass m/z 228 (MH ) [19].
2
-Phenyl-6,7-dihydro-5H-pyrimido[5.4-d][1]benzazepin-4
(
3H)-one (9b). The reaction was refluxed for 24h, and the
Scheme 3. Preparation of 14.
product was recrystallized from 1,4-dioxane to give 9b (60%) as
ꢁ
ꢀ1
yellow prisms, mp 239–241 C; IR (potassium bromide) cm
:
1
3
6
450 (NH), 1630 (CO); H NMR (DMSO-d ): d 2.73–2.98 (m,
2
H, H5), 3.35–3.70 (m, 2H, H6), 6.35 (br, 1H, deuterium oxide
exchangeable, NH), 6.62–8.39 (m, 9H, Ar-H), 12.4 (br, 1H,
+
deuterium oxide exchangeable, NH); FAB-mass m/z 290 (MH ).
Anal. Calcd for C18
C, 74.61; H, 5.47; N, 14.89.
-(4-Methoxyphenyl)-6,7-dihydro-5H-pyrimido[5.4-d]
1]benzazepin-4(3H)-one (9c). The reaction was refluxed for
6h, and the product was recrystallized from 1,4-dioxane to give
15 3
H N O: C, 74.72; H, 5.23; N, 14.52. Found:
2
ꢀ
1
1
[
3
IR (potassium bromide) cm : 1327, 1160 (SO); H NMR
(
deuterochloroform): d 2.36, 2.55 (each s, each 3H, 2 ꢂ Me),
ꢁ
c (55%) as yellow prisms, mp 282–283 C; IR (potassium
1 1
9
2
6
(
.82 (t, 2H, J = 6.0 Hz, H5), 4.34 (t, 2H, J = 6.0 Hz, H6),
ꢀ
+
bromide) cm : 3420 (NH), 1610 (CO); H NMR (DMSO-d ): d
.85–7.81 (m, 8H, Ar-H); FAB-mass m/z 400 (MH ), 402
MH + 2). Anal. Calcd for C20
.54; N, 10.51. Found: C, 60.20; H, 4.55; N, 10.49.
-Chloro-2-phenyl-7-tosyl-6,7-dihydro-5H-pyrimido[5,4-d]
1]benzazepine (8b). Recrystallization of the solid from
benzene gave 8b (62%) as colorless prisms, mp 139–141 C; IR
6
+
2
.75–2.93 (m, 2H, H5), 3.35–3.60 (m, 2H, H6), 3.85 (s, 3H,
H
18ClN
3
O
2
S: C, 60.07; H,
OMe), 6.64–8.28 (m, 9H, changed to 8H after addition of
4
deuterium oxide, Ar-H, and NH), 12.4 (br, 1H, deuterium oxide
4
+
exchangeable, NH); FAB-mass m/z 320 (MH ). Anal. Calcd for
[
ꢁ
C H N O : C, 71.46; H, 5.37; N, 13.16. Found: C, 71.39; H,
19 17 3 2
ꢀ
1
1
5
.46; N, 13.17.
-(4-Chlorophenyl)-6,7-dihydro-5H-pyrimido[5.4-d][1]
(potassium bromide) cm
:
1346, 1162 (SO);
H NMR
2
(
deuterochloroform): d 1.66 (s, 3H, Me), 2.87 (t, 2H, J = 6.0Hz,
benzazepin-4(3H)-one (9d). The reaction was refluxed for 72 h,
H5), 4.40 (t, 2H, J = 6.0Hz, H6), 6.65–7.82 (m, 11H, Ar-H),
0 0
+
and the product was recrystallized from 1,4-dioxane to give 9d
8
(
.23–8.47 (m, 2H, H2 and 6 ); FAB-mass m/z 462 (MH ), 464
+
ꢁ
(
50%) as yellow prisms, mp 285–287 C; IR (potassium bromide)
MH + 2). Anal. Calcd for C25
N, 9.10. Found: C, 65.37; H, 4.53; N, 9.00.
3 2
H20ClN O S: C, 65.00; H, 4.36;
ꢀ
1
1
6
cm : 3340 (NH), 1620 (CO); H NMR (DMSO-d ): d 2.84
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K. Okuda, Y.-X. Zhang, T. Hirota, and K. Sasaki
Vol 52
(
t, 2H, J = 7.1Hz, H5), 3.47 (t, 2H, J = 7.1 Hz, H6), 6.46 (br, 1H,
deuterium oxide exchangeable, NH), 6.63–8.32 (m, 8H, Ar-H),
2.59 (br, 1H, deuterium oxide exchangeable, NH); FAB-mass
4-(2-Hydroxyethylamino)-2-methyl-6,7-dihydro-5H-pyrimido
[5,4-d][1]benzazepine (3a). The solution was refluxed for 7 h,
and the solid was recrystallized from ethyl acetate to give 3a
1
+
+
ꢁ
m/z 324 (MH ), 326 (MH + 2). Anal. Calcd for C18
C, 66.77; H, 4.36; N, 12.98. Found: C, 66.57; H, 4.64; N, 13.05.
H
14ClN
3
O:
(69%) as pale brown needles, mp 217–219 C; IR (potassium
ꢀ
1
1
bromide) cm : 3300, 3250, 3150 (NH, OH); H NMR
General procedure for the synthesis of 2-substituted
-chloro-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepine (10a–d).
(DMSO-d ): d 2.52 (s, 3H, Me), 2.78–2.91 (m, 2H, H5), 3.25–
6
4
3.70 (m, 6H, H6 and NCH CH O), 4.93, 6.31 (each br, each
2
2
Compounds 9a–d (1.00 g) and phosphoryl chloride (10 mL)
were heated at 100 C for an appropriate time with stirring.
1H, deuterium oxide exchangeable, NH or OH), 6.75–7.64 (m,
ꢁ
4H, Ar-H), 8.31 (br, 1H, deuterium oxide exchangeable, NH or
+
After the evaporation of excess phosphoryl chloride in vacuo,
ice water (80 mL) was added to the residue, and the solution
was adjusted to pH 10 with sodium carbonate to precipitate a
yellow solid. The solid was purified by silica gel column
chromatography using n-hexane-ethyl acetate as an eluent
solvent and purified by recrystallization from 1,4-dioxane to
give 10.
OH); FAB-mass m/z 271 (MH ). Anal. Calcd for C H N O:
1
5 18 4
C, 66.64; H, 6.71; N, 20.73. Found: C, 66.26; H, 6.73; N, 20.42.
4-(2-Hydroxyethylamino)-2-phenyl-6,7-dihydro-5H-pyrimido
[5,4-d][1]benzazepine (3b). The solution was refluxed for 24 h,
and the solid was recrystallized from ethyl acetate to give 3b
ꢁ
(
75%) as colorless needles, mp 192–194 C; IR (potassium
ꢀ
1
1
bromide) cm : 3420, 3320, 3190 (NH, OH); H NMR
DMSO-d ): d 2.80 (br t, 2H, J = 5.5 Hz, H5), 3.34–3.60 (m,
H, H6, NCH CH O), 4.65, 6.20, 6.85 (each br, each 1H,
deuterium oxide exchangeable, NH and OH), 7.01–8.45 (m,
H, Ar-H); FAB-mass m/z 333 (MH ); Anal. Calcd for C20
C, 72.27; H, 6.06; N, 16.86. Found: C, 72.25; H, 6.14; N, 16.67.
-(2-Hydroxyethylamino)-2-(4-methoxyphenyl)-6,7-dihydro-
H-pyrimido[5,4-d][1]benzazepine (3c). The solution was
4
-Chloro-2-methyl-6,7-dihydro-5H-pyrimido[5,4-d][1]
(
6
6
benzazepine (10a). The reaction was heated for 2 h, and the
2
2
product was eluted with n-hexane-ethyl acetate (5:2) to give 10a
ꢁ
(
73%) as yellow fine crystals, mp 140–143 C; IR (potassium
+
9
20 4
H N O:
ꢀ
1
1
bromide) cm : 3300 (NH); H NMR (deuterochloroform): d
.73 (s, 3H, Me), 3.10 (t, 2H, J = 6.0 Hz, H5), 3.76 (t, 2H,
2
4
J = 6.0 Hz, H6), 3.98 (br, 1H, deuterium oxide exchangeable,
5
+
NH), 6.63–8.15 (m, 4H, Ar-H); FAB-mass m/z 246 (MH ), 248
refluxed for 48 h, and the solid was recrystallized from benzene
+
(
MH + 2). Anal. Calcd for C H ClN : C, 63.55; H, 4.92; N,
ꢁ
1
3
12
3
to give 3c (65%) as a pale yellow powder, mp 152–153 C; IR
1
7.10. Found: C, 63.41; H, 5.18; N, 17.03.
-Chloro-2-phenyl-6,7-dihydro-5H-pyrimido[5,4-d][1]
benzazepine (10b). The reaction was heated for 15 min,
ꢀ1
1
(
potassium bromide) cm : 3380, 3300, 3180 (NH, OH);
H
4
NMR (DMSO-d ): d 2.73 (br t, 2H, J = 5.0 Hz, H5), 3.40–3.75
6
(
m, 6H, H6 and NCH CH O), 3.82 (s, 3H, OMe), 4.74, 5.89
2 2
and the product was eluted with n-hexane-ethyl acetate (5:1)
(
6
each br, each 1H, deuterium oxide exchangeable, NH or OH),
.62–8.45 (m, 9H, changed to 8H with addition of deuterium
ꢁ
to give 10b (95%) as yellow fine crystals, mp 123–125 C;
ꢀ
1
1
IR (potassium bromide) cm
:
3400 (NH);
H
NMR
+
oxide, Ar-H, and NH or OH); FAB-mass m/z 363 (MH ); Anal.
(
DMSO-d ): d 2.93–3.13 (m, 2H, H5), 3.70–3.91 (m, 2H,
6
Calcd for C H N O : C, 69.59; H, 6.12; N, 15.46. Found: C,
21 22 4 2
H6), 4.51 (br, 1H, deuterium oxide exchangeable, NH),
6
9.69; H, 6.23; N, 15.81.
-(4-Chlorophenyl)-4-(2-hydroxyethylamino)-6,7-dihydro-
H-pyrimido[5,4-d][1]benzazepine (3d). The solution was
+
7
(
.42–8.56 (m, 9H, Ar-H); FAB-mass m/z 308 (MH ), 310
2
+
MH + 2). Anal. Calcd for C18
N, 13.65. Found: C, 70.46; H, 4.78; N, 13.76.
-Chloro-2-(4-methoxyphenyl)-6,7-dihydro-5H-pyrimido
5,4-d][1]benzazepine (10c). The reaction was heated for
h, and the product was eluted with n-hexane-ethyl acetate
5:1) to give 10c (56%) as yellow fine crystals, mp 109–
3
H14ClN : C, 70.24; H, 4.58;
5
refluxed for 24 h, and the solid was recrystallized from
cyclohexane to give 3d (63%) as colorless needles, mp 103–
4
[
6
(
1
ꢁ
ꢀ1
1
05 C; IR (potassium oxide) cm : 3420, 3350, 3200 (NH,
1
OH); H NMR (deuterochloroform): d 2.70 (t, 2H, J = 6.0 Hz,
H5), 3.24 (br, 2H, deuterium oxide exchangeable, NH or OH),
ꢁ
ꢀ1
1
10 C. IR (potassium bromide) cm : 3420 (NH); H NMR
): d 2.85–3.14 (m, 2H, H5), 3.53–3.85 (m, 2H, H6),
.86 (s, 3H, OMe), 4.05 (br, 1H, deuterium oxide
3
.53–3.99 (m, 6H, H6 and NCH CH O), 5.28 (br, 1H,
2 2
(
DMSO-d
6
deuterium oxide exchangeable, NH or OH), 6.62–8.52 (m,
3
+
8
C
H, Ar-H); FAB-mass m/z 367 (MH ); Anal. Calcd for
19ClN O: C, 65.48; H, 5.22; N, 15.27. Found: C, 65.44;
exchangeable, NH), 6.95–8.49 (m, 8H, Ar-H); FAB ms m/z
20
H
4
+
+
3
38 (MH ), 340 (MH + 2) [19].
-Chloro-2-(4-chlorophenyl)-6,7-dihydro-5H-pyrimido[5,4-
H, 5.45; N, 15.39.
4
General procedure for the synthesis of 2-substituted 4-(N-
d][1]benzazepine (10d). The reaction was heated for 1 h, and
the product was eluted with n-hexane-ethyl acetate (5:1) to give
methyl-2-hydroxyethylamino)-6,7-dihydro-5H-pyrimido[5,4-
d][1]benzazepine (11a–d). A mixture of 10a–d (1.00 mmol)
and 2-(N-methylamino)ethanol (751 mg, 10.0 mmol) in dry 1,4-
dioxane (5.0mL) was refluxed for an appropriate time. The
reaction mixture was evaporated to dryness in vacuo, ice water
ꢁ
1
0d (56%) as yellow fine crystals, mp 120–122 C; IR (potassium
ꢀ
1
1
bromide) cm : 3420 (NH); H NMR (DMDO-d
m, 2H, H5), 3.64–3.92 (m, 2H, H6), 4.16 (br, 1H, deuterium
oxide exchangeable, NH), 7.18–8.53 (m, 8H, Ar-H); FAB-mass
6
): d 2.95–3.15
(
(
50 mL) was added to the residue, and the precipitated solid was
+
+
m/z 342 (MH ), 344 (MH + 2). Anal. Calcd for C H Cl N : C,
1
8
13
2
3
filtered off and washed with water. The solid was purified by
column chromatography on silica gel and/or recrystallization to
6
3.17; H, 3.83; N, 12.28. Found: C, 63.32; H, 4.10; N, 12.03.
General procedure for the synthesis of 2-substituted 4-
2-hydroxyethylamino)-6,7-dihydro-5H-pyrimido[5,4-d][1]
benzazepine (3a–d). A mixture of 10a–d (1.00 mmol) and 2-
give 11.
(
2-Methyl-4-(N-methyl-2-hydroxyethylamino)-6,7-dihydro-
5H-pyrimido[5,4-d][1]benzazepine (11a). The mixture was
refluxed for 30h, and the crude product was chromatographed on
silica gel. The eluate of n-hexane-ethyl acetate (1:1) was
evaporated in vacuo to give 11a (67%) as yellow needles, mp
aminoethanol (611 mg, 10.0mmol) in dry 1,4-dioxane (5.0 mL) was
refluxed for an appropriate time. The reaction mixture was
evaporated in vacuo, and ice water (5.0mL) was added to the
residue. The resulting solid was collected on a filter, washed with
water, and recrystallized to give 3.
ꢁ
ꢀ1
176–178 C; IR (potassium bromide) cm : 3260, 3180 (NH,
1
OH); H NMR (deuterochloroform): d 2.58 (s, 3H, 2-Me), 2.81
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2015
Polycyclic N-Heterocyclic Compounds. Part 85: Synthesis and Evaluation of Antiplatelet Aggregation
Activity of 2,4-Disubstituted 5,6-Dihydro[1]benzazepino[5,4-d]pyrimidine and Related Compounds
893
+
(
t, 2H, J = 6.0 Hz, H5), 3.14 (s, 3H, NMe), 3.50–4.22 (m, 7H,
changed to 6H with addition of deuterium oxide, H6,
NCH CH O, and NH or OH), 5.90 (br, 1H, deuterium oxide
exchangeable, NH or OH), 6.65–8.08 (m, 4H, Ar-H); FAB-
m/z 297 (MH ). Anal. Calcd for C H N O: C, 68.89; H, 6.80;
17 20 4
N, 18.90. Found: C, 68.77; H, 6.87; N, 18.93.
4-Morpholino-2-phenyl-6,7-dihydro-5H-pyrimido[5,4-d][1]
benzazepine (12b). Compound 12b (81%) was obtained as a
white powder, mp 175–176 C; IR (potassium bromide) cm
3340, 3400 (NH); H NMR (deuterochloroform): d 2.91 (br t,
2
2
+
ꢁ
ꢀ1
mass m/z 285 (MH ). Anal. Calcd for C16
.09; N, 19.70. Found: C, 67.42; H, 7.18; N, 19.55.
-(N-Methyl-2-hydroxyethylamino)-2-phenyl-6,7-dihydro-5H-
H
20
N
4
O: C, 67.58; H,
:
1
7
0
0
0
0
4
2H, J = 5.0 Hz, H5), 3.32–4.02 (m, 10H, H6, 2 , 3 , 5 , and 6 ),
pyrimido[5,4-d][1]benzazepine (11b). The mixture was refluxed
for 25 h, and the crude product was chromatographed on silica gel.
The eluate of n-hexane-ethyl acetate (2:1) was evaporated in
vacuo, and the product was recrystallized from n-hexane to
4.80 (br, 1H, deuterium oxide exchangeable, NH), 6.64–8.65
(m, 9H, Ar-H); FAB-mass m/z 359 (MH ). Anal. Calcd for
+
C H N O ꢄ 1/2 H O: C, 71.91; H, 6.31; N, 15.25. Found: C,
2
2
22
4
2
71.62; H, 6.20; N, 15.61.
ꢁ
give 11b (75%) as yellow needles, mp 96–98 C; IR
2-(4-Methoxyphenyl)-4-morpholino-6,7-dihydro-5H-pyrimido
ꢀ
1
1
(
potassium bromide) cm : 3400, 3300 (NH, OH); H NMR
[5,4-d][1]benzazepine (12c).
Compound 12c (67%) was
ꢁ
(
deuterochloroform): d 2.88 (t, 2H, J = 6.0 Hz, H5), 3.16 (s,
obtained as yellow plates, mp 163–164 C; IR (potassium
ꢀ
1
1
3
H, NMe), 3.55–4.20 (m, 6H, H6 and NCH CH O), 5.90
bromide) cm : 3360, 3440 (NH); H NMR (deuterochloroform):
2
2
0 0
(
(
br, 1H, deuterium oxide exchangeable, NH or OH), 6.71–8.57
d 2.88 (br t, 2H, J = 6.0 Hz, H5), 3.27–4.02 (m, 10H, H6, 2 , 3 ,
0
0
m, 9H, Ar-H), 8.66 (br, 1H, deuterium oxide exchangeable,
5 , and 6 ), 3.87 (s, 3H, OMe), 4.30 (br, 1H, deuterium oxide
+
NH or OH); FAB-mass m/z 347 (MH ). Anal. Calcd for
exchangeable, NH), 6.60–8.60 (m, 8H, Ar-H); FAB-mass m/z
+
C
7
21
H
22
N
4
O ꢄ 1/2 H
1.28; H, 6.58; N, 15.61.
-(4-Methoxyphenyl)-4-(N-methyl-2-hydroxyethylamino)-
,7-dihydro-5H-pyrimido[5,4-d][1]benzazepine (11c). The
2
O: C, 70.96; H, 6.52; N, 15.76. Found: C,
389 (MH ). Anal. Calcd for C23
H N O : C, 71.11; H, 6.23; N,
24 4 2
14.42. Found: C, 71.35; H, 6.37; N, 14.49.
2-(4-Chlorophenyl)-4-morpholino-6,7-dihydro-5H-pyrimido
2
6
[5,4-d][1]benzazepine (12d).
Compound 12d (89%) was
ꢁ
mixture was refluxed for 34 h, and the product was
obtained as a white powder, mp 168–170 C; IR (potassium
ꢀ
1
1
recrystallized from ethyl acetate to give 11c (70%) as yellow
bromide)
cm
:
3310,
3430
(NH);
H
NMR
ꢁ
needles, mp 151–152 C; IR (potassium bromide) 3430, 3300
(
(deuterochloroform): d 2.91 (t, 2H, J = 5.0 Hz, H5), 3.34–4.04
1
0
0
0
0
NH, OH); H NMR (deuterochloroform): d 2.87 (t, 2H,
(m, 10H, H6, 2 , 3 , 5 , and 6 ), 4.24 (br, 1H, deuterium oxide
J = 6.5 Hz, H5), 3.15 (s, 3H, NMe), 3.64–4.10 (m, 9H, OMe,
exchangeable, NH), 6.62–8.60 (m, 8H, Ar-H); FAB-mass m/z
+
+
H6, and NCH CH O), 5.30 (br, 1H, deuterium oxide
2
2
393 (MH ), 395 (MH + 2). Anal. Calcd for C22H21ClN O: C,
4
exchangeable, NH or OH), 6.68–8.54 (m, 9H, changed to 8H
67.26; H, 5.39; N, 14.26. Found: C, 66.99; H, 5.47; N, 13.89.
General procedure for the synthesis of 2-substituted 4-
piperidino-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepine
with addition of deuterium oxide, Ar-H, NH or OH); FAB-
+
mass m/z 377 (MH ). Anal. Calcd for C22
H
24
N
4
O
2
ꢄ 1/3 H
2
O:
C, 69.09; H, 6.50; N, 14.65. Found: C, 69.01; H, 6.38; N,
4.63.
-(4-Chlorophenyl)-4-(N-methyl-2-hydroxyethylamino)-6,7-
(13a–d).
A mixture of 10a–d (1.00 mmol) and piperidine
1
(852 mg, 10.0 mmol) in dry 1,4-dioxane (5.0 mL) was refluxed
for 1 day. After the evaporation of solvent in vacuo, ice water
(50 mL) was poured into the residue, and the mixture was
extracted with ethyl acetate (25 mL ꢂ 3). The combined organic
layer was washed with saturated brine, dried over anhydrous
sodium sulfate, and evaporated in vacuo. The resulted yellow
viscous oil was purified by recrystallization to give 13.
2
dihydro-5H-pyrimido[5,4-d][1]benzazepine (11d). The
mixture was refluxed for 24h, and the crude product was
chromatographed on silica gel. The eluate of n-hexane-ethyl
acetate (2:1) was evaporated in vacuo to give 11d (91%) as
ꢁ
ꢀ1
yellow needles, mp 115–117 C; IR (potassium bromide) cm
3
:
1
420, 3300 (NH, OH); H NMR (deuterochloroform): d 2.89
2-Methyl-4-piperidino-6,7-dihydro-5H-pyrimido[5,4-d][1]
(
t, 2H, J = 6.0Hz, H5), 3.17 (s, 3H, NMe), 3.61–4.06 (m, 7H,
changed to 6H, with addition of deuterium oxide, H6,
NCH CH O, and NH or OH), 4.68 (br, 1H, deuterium oxide
exchangeable, NH or OH), 6.69–8.50 (m, 8H, Ar-H); FAB-
benzazepine (13a).
benzene to give 13a (73%) as colorless needles, mp 176–178 C;
IR (potassium bromide) cm
(deuterochloroform): d 1.66 (br s, 6H, 3 , 4 , and 5 ), 2.61 (s, 3H,
The residue was recrystallized from
ꢁ
ꢀ
1
1
:
3280 (NH);
H
NMR
2
2
0
0
0
+
+
0
0
mass m/z 381 (MH ), 383 (MH + 2). Anal. Calcd for
21ClN O: C, 66.22; H, 5.56; N, 14.71. Found: C, 66.02;
Me), 2.79 (t, 2H, J = 5.5 Hz, H5), 3.05–3.43 (m, 4H, H2 and 6 ),
3.73 (t, 2H, J = 5.5Hz, H6), 3.98 (br, 1H, deuterium oxide
exchangeable, NH), 6.61–8.10 (m, 4H, Ar-H); EI-mass m/z 294
21
C H
4
H, 5.77; N, 14.51.
General procedure for the synthesis of 2-substituted 4-
morpholino-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepine
+
(M ). Anal. Calcd for C H N : C, 73.44; H, 7.53; N, 19.03.
18 22 4
Found: C, 73.30; H, 7.56; N, 18.75.
(
12a–d).
A mixture of 10a–d (1.00 mmol) and morpholine
2-Phenyl-4-piperidino-6,7-dihydro-5H-pyrimido[5,4-d][1]
(
871 mg, 10.0 mmol) in dry 1,4-dioxane (5.0 mL) was refluxed
benzazepine (13b).
cyclohexane to give 13b (70%) as yellow prisms, mp 150–151 C;
IR (potassium bromide) cm
(deuterochloroform): d 1.70 (br s, 6H, H3 , 4 , and 5 ), 2.87 (t,
The residue was recrystallized from
ꢁ
for 1 day. After the evaporation of solvent in vacuo, ice water
60 mL) was poured into the residue. The precipitated solid was
ꢀ
1
1
(
:
3420 (NH);
H
NMR
0
0
0
collected on a filter and was recrystallized from cyclohexane to
give 12a–d.
0
0
2H, J = 5.5 Hz, H5), 3.16–3.59 (m, 4H, H2 and 6 ), 3.74 (t, 2H,
2
-Methyl-4-morpholino-6,7-dihydro-5H-pyrimido[5,4-d][1]
J = 5.5Hz, H6), 4.21 (br, 1H, deuterium oxide exchangeable,
NH), 6.65–8.76 (m, 9H, Ar-H); FAB-mass m/z 357 (MH ). Anal.
Calcd for C23H N : C, 77.50; H, 6.79; N, 15.72. Found: C,
24 4
77.18; H, 6.79; N, 15.78.
+
benzazepine (12a). Compound 12a (61%) was obtained as a
white powder, mp 161–162 C; IR (potassium bromide) cm
280 (NH); H NMR (deuterochloroform): d 2.63 (s, 3H, Me),
.82 (t, 2H, J = 5.0 Hz, H5), 3.25–3.51 (m, 4H, 3 and 4 ),
ꢁ
ꢀ1
:
1
3
2
3
0
0
2-(4-Methoxyphenyl)-4-piperidino-6,7-dihydro-5H-pyrimido
0
0
.60–4.02 (m, 6H, H6, 2 , and 6 ), 4.14 (br, 1H, deuterium
[5,4-d][1]benzazepine (13c).
The residue was recrystallized
oxide exchangeable, NH), 6.62–8.16 (m, 4H, Ar-H); FAB ms
from cyclohexane to give 13c (74%) as a white powder, mp
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

8
94
K. Okuda, Y.-X. Zhang, T. Hirota, and K. Sasaki
Vol 52
ꢁ
ꢀ1
1
ꢁ
ꢀ1
1
61–163 C; IR (potassium bromide) cm : 3340 (NH); H NMR
needles, mp 127–130 C; IR (potassium bromide) cm : 3400
0
0
0
1
(
(
(
deuterochloroform): d 1.50–1.94 (m, 6H, H3 , 4 , and 5 ), 2.87
br t, 2H, J = 5.0 Hz, H5), 3.18–3.55 (m, 4H, H2 and 6 ), 3.74
br t, 2H, J = 5.0 Hz, H6), 3.87 (s, 3H, OMe), 4.23 (br, 1H,
(NH); H NMR (deuterochloroform): d 2.73–3.02 (m, 2H, H4),
3.56–4.37 (m, 9H, OMe, H1, 2, and 5), 6.60–8.32 (m, 9H,
changed to 8H with addition of deuterium oxide, Ar-H, and
NH); FAB-mass m/z 345 (MH ). Elemental analysis was
0
0
+
deuterium oxide exchangeable, NH), 6.62–8.63 (m, 8H,
+
Ar-H); FAB-mass m/z 387 (MH ). Anal. Calcd for
performed for the hydrochloride prepared as described earlier;
C H N O; C, 74.58; H, 6.78; N, 14.50. Found: C, 74.83;
Anal. Calcd for C H N O ꢄ 2HCl ꢄ 2.5H O: C, 54.55; H, 5.89;
2
4
26
4
21 20
4
2
H, 6.87; N, 14.70.
-(4-Chlorophenyl)-4-piperidino-6,7-dihydro-5H-pyrimido
5,4-d][1]benzazepine (13d). The residue was recrystallized
from cyclohexane to give 13d (78%) as a white powder, mp
N, 12.12. Found: C, 54.33; H, 5.49; N, 12.11.
0
0
2
12-(4-Chlorophenyl)-1,2,5,6-tetrahydro-4H-imidazo[1 ,2 :1,6]
pyrimido[5,4-d][1]benzazepine (14d). According to the general
procedure, free amine 14d (67%) was obtained from 3d as yellow
[
ꢁ
ꢀ1
1
ꢁ
ꢀ1
1
70–172 C; IR (potassium bromide) cm : 3410 (NH);
H
needles, mp 201–203 C; IR (potassium bromide) cm : 3340
0
0
0
0
1
NMR (deuterochloroform): d 1.72 (br s, 6H, H3 , 4 , and 5 ),
.91 (br t, 2H, J = 5.0 Hz, H5), 3.25–4.59 (m, 4H, H2 and 6 ),
6
(NH); H NMR (DMSO-d ): d 2.74 (t, 2H, J = 5.0 Hz, H4),
0
2
3.30–3.56 (m, 2H, H5), 3.82, 4.10 (each t, each 2H, J = 9.0 Hz,
3
.76 (br t, 2H, J = 5.0 Hz, H6), 3.94 (br, 1H, deuterium oxide
H1 and 2), 6.28 (br s, 1H, deuterium oxide exchangeable,
+
exchangeable, NH), 6.62–8.61 (m, 8H, Ar-H); FAB-mass m/z
3
7
NH), 6.60–8.07 (m, 8H, Ar-H); FAB-mass m/z 349 (MH ),
+
+
+
91 (MH ), 393 (MH + 2). Anal. Calcd for C23
H
23ClN
4
: C,
351 (MH + 2). Elemental analysis was performed for the
0.67; H, 5.93; N, 14.33. Found: C, 71.02; H, 6.05; N, 14.01.
hydrochloride prepared as described earlier; Anal. Calcd for
C H ClN ꢄ 2HClꢄ 8/3H O: C, 51.35; H, 4.81; N, 11.98.
General procedure for the synthesis of 12-substituted
20
17
4
2
0
0
1
,2,5,6-tetrahydro-4H-imidazo[1 ,2 :1,6]pyrimido[5,4-d][1]
A mixture of 3a–d (100 mg) and
phosphoryl chloride (3.0mL) was refluxed for 1 h, and ice water
50mL) was added to the oily product. The solution was adjusted
Found: C, 50.98; H, 5.23; N, 11.90.
benzazepine (14a–d).
Measurement of platelet aggregation.
Preparation of
platelet-rich plasma was performed according to the method
described previously [20]. The platelet-rich plasma described
earlier, 250 mL, synthetic compounds 3 and 10–14, 25 mL (10%
DMSO solution or 60% DMF solution), and 1M Tris–HCl
(
to pH 11–12 with aq 10% potassium hydroxide and then
extracted with ethyl acetate (20 mLꢂ 3). The combined organic
phase was washed with saturated brine, dried over anhydrous
sodium sulfate, and evaporated in vacuo. The residue was
recrystallized from ethyl acetate to give crystalline 14 as a free
base. As a free base, 14 did not give satisfactory elemental
analytical data, possibly because of its hygroscopic nature, so an
analytical sample for elemental analysis was prepared as the
hydrochloride as follows: To a solution of 14 in ethanol (15mL)
was added concd hydrochloric acid (2.0mL) to pH 1–2 followed
by evaporation under reduced pressure. The resulting residue
was recrystallized from ethanol–ethyl acetate to give 14
as the hydrochloride.
ꢁ
buffer (pH 7.4) 25 mL were mixed and preincubated at 37 C,
followed 2 min later by addition of 50-mL aggregating agent
(collagen, final concentration 14.3 mg/mL) with stirring
(1000 rpm). 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 [20].
0
0
1
2-Methyl-1,2,5,6-tetrahydro-4H-imidazo[1 ,2 :1,6]pyrimido
5,4-d][1]benzazepine (14a). According to the general
procedure, free amine 14a (77%) was obtained from 3a as yellow
Acknowledgments. The authors are grateful to the SC-NMR
[
1
Laboratory of Okayama University for the 200-MHz H NMR
ꢁ
ꢀ1
experiments. They also thank Dr. K. L. Kirk (NIDDK, NIH)
for helpful comments on the manuscript.
prisms, mp 208–211 C; IR (potassium bromide) cm : 3260,
3
2
1
450 (sh) (NH); H NMR (DMSO-d ): d 2.23 (s, 3H, Me),
6
.63–2.82 (m, 2H, H4), 3.24–3.55 (m, 2H, H5), 3.78–4.12
(
m, 4H, H1 and 2), 6.11 (br, 1H, deuterium oxide exchangeable,
REFERENCES AND NOTES
NH), 6.47–8.06 (m, 4H, Ar-H); FAB-mass m/z 253. Elemental
analysis was performed for the hydrochloride prepared as
described earlier; Anal. Calcd for C H N ꢄ 2HClꢄ H O: C,
[
1] Sasaki, K.; Arichi, T.; Ohtomo, H.; Nakayama, T.; Hirota, T. J
Heterocycl Chem 1996, 33, 1663.
[2] Okuda, K.; Hirota, T.; Sasaki, K. J Heterocycl Chem in press.
DOI: 10.1002/jhet.1714
1
5
16
4
2
5
2.49; H, 5.87; N, 16.32. Found: C, 52.31; H, 5.74; N, 16.39.
0
0
1
2-Phenyl-1,2,5,6-tetrahydro-4H-imidazo[1 ,2 :1,6]pyrimido
[
3] Rafferty, M.; Walters, R., Dawson, M., J. Curr Med Chem
010, 17, 4578.
4] Cheng, S.; Zhang, X.; Wang, W.; Zhao, M.; Zheng, M.;
Chang, H. W.; Wu, J.; Peng, S. Eur J Med Chem 2009, 44, 4904.
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9] Yao, K.; Zhao, M.; Zhang, X.; Wang, Y.; Li, L.; Zheng, M.;
[
5,4-d][1]benzazepine (14b). According to the general
2
procedure, free amine 14b (83%) was obtained from 3b as
yellow prisms, mp 114–116 C; IR (potassium bromide) cm
3
J = 5.5 Hz, H4), 3.73 (t, 2H, J = 5.5 Hz, H5), 4.04 (br s, 4H, H1
and 2), 6.60–8.23 (m, 10H, changed to 9H with addition of
deuterium oxide, Ar-H, NH); FAB-mass m/z 315 (MH ).
Elemental analysis was performed for the hydrochloride
prepared
ꢀ1
[
ꢁ
:
1
350 (NH); H NMR (deuterochloroform): d 2.89 (t, 2H,
[
+
[
4
as
described
earlier;
Anal.
Calcd
for
[
C H N ꢄ 2HCl ꢄ 2/3H O: 60.16; H, 5.38; N, 14.03. Found: C,
2
0
18
4
2
5
9.95; H, 5.43; N, 13.86.
2-(4-Methoxyphenyl)-1,2,5,6-tetrahydro-4H-imidazo[1 ,2 :1,6]
[
0
0
1
Peng, S. Eur J Med Chem 2011, 46, 3237.
pyrimido[5,4-d][1]benzazepine (14c). According to the general
procedure, free amine 14c (81%) was obtained from 3c as yellow
[10] Liu, G.; Xu, J.; Park, K. C.; Chen, N.; Zhang, S.; Ding, Z.;
Wang, F.; Du, H. Tetrahedron 2011, 67, 5156.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2015
Polycyclic N-Heterocyclic Compounds. Part 85: Synthesis and Evaluation of Antiplatelet Aggregation
Activity of 2,4-Disubstituted 5,6-Dihydro[1]benzazepino[5,4-d]pyrimidine and Related Compounds
895
[11] Li, C.; Zhang, X.; Zhao, M.; Wang, Y.; Wu, J.; Liu, J.; Zheng,
[16] Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J
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Adv Drug Del Rev 1997, 23, 3.
[
[
12] Chen, H.; Li, G.; Zhan, P.; Liu, X. Eur J Med Chem 2011, 46, 5609.
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[17] Born, G. V. R.; Cross, M. J. J Physiol 1963, 168, 178.
[18] Sunada, Y.; Kawakami, H.; Imaoka, T.; Motoyama, Y.;
Nagashima, H. Angew Chem Int Ed Engl 2009, 48, 9511.
[19] Intermediate compounds 9a and 10c did not give satisfactory
elemental analytical data.
S. Med. Chem. Comm 2012, 3, 102.
14] Hirota, T.; Fukumoto, M.; Sasaki, K.; Namba, T.; Hayakawa,
S. Heterocycles 1986, 24, 143.
15] Nagamatsu, T.; Hantani, Y.; Yamada, M.; Sasaki, K.; Ohtomo,
H.; Nakayama, T.; Hirota, T. J Heterocycl Chem 1993, 30, 193.
[
[
[20] Hirota, T.; Sasaki, K.; Ohtomo, H.; Uehara, A.; Nakayama, T.
Heterocycles 1990, 31, 153.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet