Polycyclic N-heterocyclic compounds. Part 78: Synthesis of N-[2-([1,2,4]oxadiazol-5-yl)cyclohepten-1-yl]formamide oximes and their evaluation as inhibitors of platelet aggregation

Article abstract of DOI:10.1002/jhet.1628

N-[2-([1,2,4]Oxadiazol-5-yl)cyclohepten-1-yl]formamide oximes were synthesized by fusion of (6,7,8,9-tetrahydro-5H-cyclohepta[1,2-d]pyrimidin-4-yl) amidines with hydroxylamine hydrochloride through a subsequent rearrangement reaction. Effects of the products as well as the structurally related N-[4-([1,2,4]oxadiazol-5-yl)-2,3-dihydro[1]benzoxepin-5-yl]formamide oximes and N-[4-([1,2,4]oxadiazol-5-yl)-2,3-dihydro[1]benzothiepin-5-yl]formamide oximes on platelet aggregation were evaluated.

Full text of DOI:10.1002/jhet.1628

518
Polycyclic N-Heterocyclic Compounds. Part 78: Synthesis of N-[2-([1,2,4]
Oxadiazol-5-yl)cyclohepten-1-yl]formamide Oximes and Their Evaluation
as Inhibitors of Platelet Aggregation
Vol 51
a
b
b
b
*
Kensuke Okuda, Ying-Xue Zhang, 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, Okayama 700-8530, Japan
*
E-mail: okuda@gifu-pu.ac.jp
Received November 10, 2011
DOI 10.1002/jhet.1628
Published online 13 November 2013 in Wiley Online Library (wileyonlinelibrary.com).
N-[2-([1,2,4]Oxadiazol-5-yl)cyclohepten-1-yl]formamide oximes were synthesized by fusion of (6,7,8,
9-tetrahydro-5H-cyclohepta[1,2-d]pyrimidin-4-yl)amidines with hydroxylamine hydrochloride through a subsequent
rearrangement reaction. Effects of the products as well as the structurally related N-[4-([1,2,4]oxadiazol-5-yl)-2,
3-dihydro[1]benzoxepin-5-yl]formamide oximes and N-[4-([1,2,4]oxadiazol-5-yl)-2,3-dihydro[1]benzothiepin-5-yl]
formamide oximes on platelet aggregation were evaluated.
J. Heterocyclic Chem., 51, 518 (2014).
As part of our research to develop new bioactive
compounds, we have been investigating the syntheses
and biological evaluation of heterocycles that are
accessible by rearrangement reactions. Current anti-platelet
drugs are known to have certain detrimental side effects
and low efficacy, and thus, there continues to be much
research directed to the development of new drugs in
this class [1–7]. For these reasons, we have been
investigating the anti-platelet aggregation activity of our
new heterocyclic compounds that possess unique scaffolds.
During the course of this research, we have previously
reported that N-[2-(3-substituted [1,2,4]oxadiazol-5-yl)
cyclohexen-1-yl]formamide oximes (3, n = 2) are accessi-
ble by the reaction of N1,N1-dimethyl-N2-(5,6,7,8-
tetrahydroquinazolin-4-yl)amidines (1, n = 2, R═Ar) or their
amide oximes (2, n = 2, R═H, alkyl) with hydroxylamine
hydrochloride followed by pyrimidine ring cleavage
and 1,2,4-oxadiazole ring closure (Fig. 1). Similarly,
N-[2-(3-substituted [1,2,4]oxadiazol-5-yl)cyclopenten-1-yl]-
formamide oximes (3, n = 1) are accessible by the reac-
tion of N1,N1-dimethyl-N2-(6,7-dihydro-5H-cyclopenta[1,2-d]
pyrimidin-4-yl)amidines (1, n = 1, R═alkyl, Ar) or their
amide oximes (2, n = 1, R═H) with hydroxylamine
hydrochloride followed by pyrimidine ring cleavage and
1,2,4-oxadiazole ring closure. A study of biological
properties of these compounds revealed that series 3 (n = 1,
R═4-Cl–Ph, and n = 2, R═4-Cl–Ph) had considerable
activity as inhibitors of arachidonic acid-induced platelet
aggregation [8,9], whereas other phenyl or substituted
phenyl groups did not have activity. To develop more active
compounds in this series, we decided to explore the structure
activity relationships of the related compounds, N-[2-(3-
substituted [1,2,4]oxadiazol-5-yl)cyclohepten-1-yl]formamide
oximes (4). In this report, we describe in detail the
synthesis and evaluation of these compounds as well as
structure-related N-[4-([1,2,4]oxadiazol-5-yl)-2,3-dihydro[1]
benzoxepin-5-yl]formamide oximes (5) [10] and N-[4-
([1,2,4]oxadiazol-5-yl)-2,3-dihydro[1]benzothiepin-5-yl]
formamide oximes (6) [11].
We initiated the synthetic efforts with the aliphatic seven-
membered ring-fused amidines 8. As shown in Scheme 1,
the amidines 8 we required as starting materials were synthe-
sized by the previously reported method [8,9]. Thus, amidine
8a was prepared in 68% yield by reaction of 4-amino-
6,7,8,9-tetrahydro-5H-cyclohepta[1,2-d]pyrimidine (7) with
commercially available N,N-dimethylformamide dimethyl
acetal in refluxing toluene. A similar reaction with N,N-
dimethylacetamide dimethyl acetal, however, does not give
a satisfactory result. It is possible that the corresponding
amidine was too unstable in this case. Other amidines 8b–f
were prepared by the reaction of compound 7 with
the Vilsmeier reagents prepared from the corresponding
N,N-dimethylamide and phosphoryl chloride.
When a hydrogen is attached to the amidine moiety
(R═H), the reaction of 8a with 1.2 equiv. of hydroxylamine
hydrochloride in methanol at room temperature gave the
amide oxime (9a) in 73% yield. However, conversion of
9a to the 1,2,4-oxadiazole derivative (4a) was not successful
in contrast to the case of 3 (R═H). Reaction with 6 equiv. of
hydroxylamine hydrochloride in refluxing methanol did lead
to almost complete consumption of 9a, but this procedure
produced a mixture of products, and we could not isolate
4a, although this may exist in the reaction mixture. Our
inability to isolate 4a was probably due to the fact that 4a
appears to be contaminated in the reaction mixture with
hydrolyzed 7, as judged by the 1H NMR spectrum.
© 2013 HeteroCorporation

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519
cyclohepten-1-yl]formamide Oximes and Their Evaluation as Inhibitors of Platelet Aggregation
of 4b, a characteristic formamide oxime one-proton doublet
(J = 9.8 Hz) appeared at 7.67 coupled with an adjacent NH
proton (J = 9.8 Hz). This NH is exchangeable and, accord-
ingly, the formamide oxime signal changed to a singlet in
the presence of deuterium oxide. The one-proton singlet at
8.52ppm (pyrimidine ring proton) present in 8b was
absent in the product 4b. These NMR data indicate that
pyrimidine ring cleavage occurred during reaction of 8b with
hydroxylamine hydrochloride and are consistent with the
structure of 4b. Structures also were supported by FAB-MS
and elemental analysis.
Other amidines 8c–f having an aryl group substituted in
the amidine moiety required 6–11 equiv. of hydroxylamine
hydrochloride to consume starting materials completely to
give the desired oxadiazoles 4c–f. These phenomena are in
full accord with previous examples [8,9].
Figure 1. Substrates (1 and 2) and rearranged products (3–6).
In a similar manner, we carried out the reaction of 8b
(R═Et) with hydroxylamine hydrochloride in methanol at
room temperature. In this case, 2 equiv. of hydroxylamine
hydrochloride was necessary to consume 8b, and the
reaction gave exclusively oxadiazole derivative 4b (54%)
instead of amide oxime 9b (R═Et). In the 1H NMR spectrum
The activities of 4b–f as well as 5b–f and 6b–f as inhibi-
tors of arachidonic acid-induced platelet aggregation were
assayed. This was carried out by a turbidimetric method
developed by Born and Cross [12] using an aggregometer.
As shown in Table 1, a comparison of the inhibition rate
at the final concentration of 30mmol/L with that of
Scheme 1. The synthesis of 4.
Table 1
Effects of 4b–f, 5b–f, and 6b–f on rabbit platelet aggregation in vitro.
Compound
% Inhibition
Compound
% Inhibition
Compound
% Inhibition
4b
4c
4d
4e
ꢀ3.8 ꢁ 20.1
ꢀ5.4 ꢁ 6.4
28.1 ꢁ 13.8
37.4 ꢁ 9.3
1.5 ꢁ 41.2
96.5 ꢁ 1.3*
5b
5c
5d
5e
5f
ꢀ12.5 ꢁ 6.1
11.7 ꢁ 12.8
23.7 ꢁ 16.4
ꢀ0.2 ꢁ 2.0
ꢀ15.8 ꢁ 19.0
6b
6c
6d
6e
6f
ꢀ18.3 ꢁ 21.5
ꢀ2.5 ꢁ 2.2
ꢀ1.2 ꢁ 9.8
ꢀ0.9 ꢁ 7.2
ꢀ2.9 ꢁ 6.4
4f
Cilostazol
Data represent % inhibition of the vehicle control group (mean ꢁ SE of three experiments).
*Significantly different from the vehicle control group at P < 0.01 (Dunnett’s multiple range test).
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K. Okuda, Y.-X. Zhang, T. Hirota, and K. Sasaki
Vol 51
reaction mixture was refluxed for 50 h. The residue was purified
by column chromatography (ethyl acetate/n-hexane, 1:8) to
give 8b (830mg, 53%) as
Cilostazol [13] showed that none had potency comparable
with Cilostazol. Apparently, homologation of cycloalkene
ring to cycloheptene with 4-Cl–Ph (4d) diminished anti-
platelet aggregation activity compared with 3 (n = 1, R═4-
Cl–Ph and n = 2, R═4-Cl–Ph).
a
colorless oil. 1H NMR
(deuterochloroform): d 1.06 (t, 3H, J = 7.6 Hz, ꢀCH3), 1.51–1.73
(m, 4H, H6 and 7), 1.79–1.93 (m, 2H, H8), 2.46 (q, 2H,
J = 7.6Hz, ꢀCH2CH3), 2.75 (t, 2H, J = 5.5 Hz, H5), 2.93 (t, 2H,
J = 5.5Hz, H9), 3.09 (s, 6H, N(CH3)2), 8.52 (s, 1H, H2);
FAB-MS: m/z 247 (MH+). Anal. Calcd for C14H22N4ꢃ0.5H2O: C,
65.85; H, 9.08; N, 21.94. Found: C, 66.04; H, 8.76; N, 21.70.
N1,N1-Dimethyl-N2-(6,7,8,9-tetrahydro-5H-cyclohepta[1,2-d]
pyrimidin-4-yl)benzamidine (8c). To a dry chloroform solution of
7 (750 mg, 4.60mmol) were added N,N-dimethylbenzamide
(754 mg, 5.06 mmol), phosphoryl chloride (0.65 mL, 6.93mmol),
and triethylamine (1.80 mL, 12.9 mmol) sequentially, and the
reaction mixture was refluxed for 52h. The residue was
purified by column chromatography (ethyl acetate/n-hexane, 1:8)
and recrystallized from petroleum ether to give 8c (707 mg,
52%) as colorless fine crystals, mp 95–96ꢂC; 1H NMR
(deuterochloroform): d 1.44–1.70 (m, 4H, H6 and 7), 1.73–1.89
(m, 2H, H8), 2.75 (t, 2H, J= 5.5 Hz, H5), 2.84 (t, 2H, J=5.5Hz,
H9), 3.05 (br s, 6H, N(CH3)2), 7.12–7.30 (m, 5H, Ph), 8.26 (s, 1H,
H2); FAB-MS: m/z 295 (MH+). Anal. Calcd for C18H22N4:
C, 73.44; H, 7.53; N, 19.03. Found: C, 73.36; H, 7.54; N, 18.93.
N1,N1-Dimethyl-N2-(6,7,8,9-tetrahydro-5H-cyclohepta[1,2-d]
pyrimidin-4-yl)-4-chlorobenzamidine (8d). To a dry chloroform
solution of 7 (2.00 g, 12.3 mmol) were added N,N-dimethyl-4-
chlorobenzamide (2.48 g, 13.5 mmol), phosphoryl chloride
(1.75 mL, 18.65 mmol), and triethylamine (5.15 mL, 36.8 mmol)
sequentially, and the reaction mixture was refluxed for 52 h. The
residue was purified by column chromatography (ethyl acetate/
n-hexane, 1:8) to give 8d (890 mg, 20%) as a colorless oil.
1H NMR (deuterochloroform): d 1.46–1.71 (m, 4H, H6 and 7),
1.75–1.90 (m, 2H, H8), 2.77 (t, 2H, J = 5.5 Hz, H5), 2.89 (t, 2H,
J = 5.5 Hz, H9), 3.06 (br s, 6H, N(CH3)2), 7.13 (br d, 2H,
J = 8.4 Hz, Ph-30 and 50), 7.29 (br d, 2H, J = 8.4 Hz, Ph-20 and
60), 8.26 (s, 1H, H2); FAB-MS: m/z 329 (MH+), 331 (MH+ + 2).
Anal. Calcd for C18H21ClN4ꢃ1/3AcOEt: C, 64.82; H, 6.66; N,
15.64. Found: C, 64.56; H, 6.69; N, 16.02.
In summary, we have synthesized
a series of
N-[2-(3-substituted [1,2,4]oxadiazol-5-yl)cyclohepten-1-yl]
formamide oximes (4) through the reaction of N-(6,7,8,9-
tetrahydro-5H-cyclohepta[1,2-d]pyrimidin-4-yl)amidines (8)
with hydroxylamine hydrochloride. The reaction involves
ring cleavage of the pyrimidine component accompanied
by a ring closure to the 1,2,4-oxadiazole. None of the
compounds in this new series showed significant inhibitory
activity against platelet aggregation [14].
EXPERIMENTAL
All melting points were determined on a Yanagimoto micro-
melting point apparatus and were uncorrected. Elemental analyses
were performed on a Yanagimoto MT-5 CHN Corder elemental
analyzer. The FAB-mass spectra were obtained on a VG70-SE mass
spectrometer, and m-nitrobenzyl alcohol was used as the matrix.
The IR spectra were recorded on a Japan spectroscopic FT/IR-200
spectrophotometer with potassium bromide, and frequencies were
expressed in centimeters (cmꢀ1). The 1H NMR spectra were
recorded on a Varian VXR-200 instrument operating at 200 MHz
with tetramethylsilane as an internal standard. Chemical shifts were
given in ppm (d) and J values in hertz (Hz). The signals were
designated as follows: s, singlet; d, doublet; dd, double doublet; t,
triplet; q, quartet; br, broad; m, multiplet. Column chromatography
was performed on aluminum oxide active neutral (Merck). TLC
was carried out on Kieselgel 60F254 (Merck).
N1,N1-Dimethyl-N2-(6,7,8,9-tetrahydro-5H-cyclohepta[1,2-d]
pyrimidin-4-yl)formamidine (8a). A mixture of 4-amino-6,7,8,9-
tetrahydro-5H-cyclohepta[1,2-d]pyrimidine (7, 1.63 g, 9.99mmol)
and N,N-dimethylformamide dimethyl acetal (1.79g, 15.0mmol)
in dry toluene (40mL) was refluxed for 19h. After removal of the
solvent in vacuo, the residue was recrystallized from n-hexane to
give 8a (1.485 g, 68%) as colorless fine crystals; mp 68–69ꢂC; 1H
NMR (deuterochloroform): d 1.60 (m, 2H, H7), 1.71, 1.88 (each
m, each 2H, H6 and 8), 3.04 (m, 4H, H5 and 9), 3.17, 3.19 (each
s, each 3H, N(CH3)2), 8.50 (s, 1H, H2), 8.62 (s, 1H, CHN(CH3)2).
FAB-MS: m/z 219 (MH+). FAB-HRMS m/z: 219.1556 (Calcd for
C12H19N4: 219.1610).
N1,N1-Dimethyl-N2-(6,7,8,9-tetrahydro-5H-cyclohepta[1,2-d]
pyrimidin-4-yl)-4-fluorobenzamidine (8e). To a dry chloroform
solution of 7 (1.10 g, 6.74 mmol) were added N,N-dimethyl-4-
fluorobenzamide (1.24 g, 7.42mmol), phosphoryl chloride
(0.95 mL, 10.1 mmol), and triethylamine (2.85 mL, 20.4 mmol)
sequentially, and the reaction mixture was refluxed for 50h. The
residue was purified by column chromatography (ethyl acetate/
n-hexane, 1:8) and recrystallized from petroleum ether to give 8e
(860 mg, 41%) as colorless prisms, mp 73–74ꢂC; 1H NMR
(deuterochloroform): d 1.42–1.68 (m, 4H, H6 and 7), 1.74–1.89
(m, 2H, H8), 2.71 (t, 2H, J = 5.5 Hz, H5), 2.80 (t, 2H, J = 5.5 Hz,
H9), 3.02 (br s, 6H, N(CH3)2), 6.94 (br t, 2H, J=8.7Hz, Ph-30 and
50), 7.11–7.21 (m, 2H, Ph-20 and 60), 8.29 (s, 1H, H2); FAB-MS:
m/z 313 (MH+). Anal. Calcd for C18H21FN4: C, 69.21; H, 6.78; N,
17.94. Found: C, 69.46; H, 6.70; N, 17.88.
General procedure for the reaction of
6 with N,N-
dimethylamide to give 8b–f. To a solution of 7 in dry
chloroform (ca 20 mL) were added N,N-dimethylamide,
phosphoryl chloride, and triethylamine sequentially, and the
mixture was refluxed for the appropriate time. Water was added to
quench the reaction, and the mixture was basified with sat.
sodium bicarbonate aq. and then extracted with chloroform. The
organic phase was washed with sat. brine, dried over anhydrous
sodium sulfate, and then evaporated in vacuo. The residue was
purified by column chromatography and recrystallization to give 8.
N1,N1-Dimethyl-N2-(6,7,8,9-tetrahydro-5H-cyclohepta[1,2-d]
pyrimidin-4-yl)propionamidine (8b). To a dry chloroform solution
of 7 (1.00 g, 6.13mmol) were added N,N-dimethylpropionamide
(680mg, 6.75mmol), phosphoryl chloride (0.85 mL, 9.06mmol),
and triethylamine (4.30 mL, 30.7mmol) sequentially, and the
N1,N1-Dimethyl-N2-(6,7,8,9-tetrahydro-5H-cyclohepta[1,2-d]
pyrimidin-4-yl)-3-methylbenzamidine (8f). To a dry chloroform
solution of 7 (1.00 g, 6.13 mmol) were added N,N-dimethyl-3-
methylbenzamide (1.10g, 6.74mmol), phosphoryl chloride
(0.90 mL, 9.59 mmol), and triethylamine (3.10 mL, 22.1 mmol)
sequentially, and the reaction mixture was refluxed for 28h. The
residue was purified by column chromatography (ethyl acetate/
n-hexane, 1:8) to give 8f (350mg, 18%) as a colorless oil.
1H NMR (deuterochloroform): d 1.42–1.67 (m, 4H, H6 and 7),
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1.73–1.88 (m, 2H, H8), 2.26 (s, 3H, ꢀCH3), 2.74 (t, 2H, J = 5.5 Hz,
H5), 2.82 (t, 2H, J = 5.5 Hz, H9), 3.03 (br s, 6H, N(CH3)2),
6.92–7.17 (m, 4H, Ph), 8.28 (s, 1H, H2); FAB-MS: m/z 309
(MH+). Anal. Calcd for C19H24N4ꢃ0.5H2O: C, 71.89; H, 7.94; N,
17.65. Found: C, 71.61; H, 7.78; N, 17.32.
7.51mmol) in dry methanol (10 mL) for 21 h. Compound
4d (175.9 mg, 73%) was obtained as colorless needles; mp
189–191ꢂC; IR (potassium bromide): 3430, 3160 (br, NH or
1
OH) cmꢀ1; H NMR (DMSO-d6): d 1.48–1.69 (m, 4H, H4 and 5),
1.70–1.84 (m, 2H, H6), 2.68–2.80 (m, 2H, H7), 2.81–2.92 (m, 2H,
H-3), 7.57 (br d, 2H, J=8.5Hz, Ph-30 and 50), 7.81 (d, 1H,
J= 9.8 Hz, changed to singlet after addition of deuterium oxide,
NCH═NO), 8.13 (d, 2H, J=8.5Hz, Ph-20 and 60), 10.79 (s, 1H,
deuterium oxide exchangeable, OH), 11.84 (d, 1H, J=9.8Hz,
deuterium oxide exchangeable, NH); FAB-MS: m/z 333 (MH+),
335 (MH+ +2). Anal. Calcd for C16H17ClN4O2ꢃ0.5CH3OH: C,
56.82; H, 5.49; N, 16.06. Found: C, 56.81; H, 5.56; N, 16.12.
N-{2-[3-(4-Fluorophenyl)[1,2,4]oxadiazol-5-yl]cyclohepten-1-yl}
formamide oxime (4e). Compound 8e (360.2 mg, 1.15 mmol) was
allowed to react with hydroxylamine hydrochloride (481 mg, 6.92
mmol) in dry methanol (10 mL) for 20 h. Compound 4e ꢂ(306.7
mg, 84%) was obtained as colorless needles, mp 185–188 C; IR
N-(6,7,8,9-Tetrahydro-5H-cyclohepta[1,2-d]pyrimidin-4-yl)
formamide oxime (9a). To a solution of 8a (1.09 g, 4.99mmol) in
dry methanol (6.0 mL) was added hydroxylamine hydrochloride
(4.17 g, 6.00 mmol), and the reaction was then stirred at room
temperature for 2 h. Water was added, and the mixture was
basified with sat. sodium bicarbonate aq. The resulting precipitate
was filtered and washed with water, and the solid was
recrystallized from methanol to give 9a (800mg, 73%) as a white
powder; mp 181ꢂC; IR (potassium bromide): 3440, 3280 (NH or
OH) cmꢀ1; 1H NMR (DMSO-d6): d 1.58 (m, 4H, H6 and 7), 1.81
(m, 2H, H8), 2.69 (m, 2H, H5), 2.87 (m, 2H, H9), 7.94 (d, 1H,
J = 9.2 Hz, changed to singlet after addition of deuterium oxide,
NCH═NO), 8.41 (s, 1H, H2), 8.41 (d, 1H, J = 9.2 Hz, deuterium
oxide exchangable, NH), 10.58 (s, 1H, deuterium oxide
exchangeable, OH); FAB-MS: m/z 207 (MH+). Anal. Calcd for
C10H14N4Oꢃ0.4CH3OH: C, 57.02; H, 7.18; N, 25.58. Found: C,
56.68; H, 7.15; N, 25.74.
General procedure for the reaction of 8b–f with
hydroxylamine hydrochloride to give 4b–f. A solution of
amidine (8) in dry methanol was added with hydroxylamine
hydrochloride, and the mixture was stirred at room temperature
for the appropriate time. Water was added, and the mixture was
basified with sat. sodium bicarbonate aq. The precipitate was
filtered and washed with water, and the solid was recrystallized
from methanol to give 4.
1
(potassium bromide): 3450, 3140 (br, NH or OH) cm-1; H NMR
(DMSO-d6): d 1.50–1.69 (m, 4H, H4 and 5), 1.70–1.87 (m, 2H,
H6), 2.68–2.78 (m, 2H, H7), 2.80–2.91 (m, 2H, H3), 7.35 (t, 2H,
J = 8.9 Hz, Ph-3’ and 5’), 7.80 (d, 1H, J = 9.8 Hz, changed to
singlet after addition of deuterium oxide, NCH= NO), 8.12–8.26
(m, 2H, Ph-2’ and 6’), 10.77 (s, 1H, deuterium oxide
exchangeable, OH), 11.83 (d, 1H, J = 9.8 Hz, deuterium oxide
exchangeable, NH); FAB-MS: m/z 317 (MH+). Anal. Calcd for
C16H17FN4O2: C, 60.75; H, 5.42; N, 17.71. Found: C, 60.72; H,
5.55; N, 17.80.
N-{2-[3-(3-Methylphenyl)[1,2,4]oxadiazol-5-yl]cyclohepten-1-yl}
formamide oxime (4f). Compound 8f (219.0 mg, 0.690 mmol) was
allowed to react with hydroxylamine hydrochloride (494 mg, 7.11
mmol) in dry methanol (8.0 mL) for 9 h. Compound 4f (148.3 mg,
68%) was obtained as colorless needles, mp 165–168 ꢂC; IR
N-[2-(3-Ethyl[1,2,4]oxadiazol-5-yl)cyclohepten-1-yl]formamide
oxime (4b). Compound 8b (237.5 mg, 0.930mmol) was allowed to
react with hydroxylamine hydrochloride (135 mg, 1.94 mmol) in
dry methanol (5.0mL) for 24 h. Compound 4b (126.2 mg, 54%)
was obtained as colorless needles; mp 164–165ꢂC; IR (potassium
1
(potassium bromide): 3450, 3160 (br, NH or OH) cm-1; H NMR
(DMSO-d6): d 1.50–1.69 (m, 4H, H4 and 5), 1.70–1.88 (m, 2H,
H6), 2.40 (s, 3H, ꢀCH3), 2.68–2.78 (m, 2H, H7), 2.80–2.92 (m, 2H,
H3), 7.35–7.46 (m, 2H, Ph-4’ and 5’), 7.80 (d, 1H, J=9.9 Hz,
changed to singlet after addition of deuterium oxide, NCH = NO),
7.87–7.95 (m, 1H, Ph-6’), 7.98 (br s, 1H, Ph-2’), 10.84 (s, 1H,
deuterium oxide exchangeable, OH), 11.84 (d, 1H, J=9.9 Hz,
deuterium oxide exchangeable, NH); FAB-MS: m/z 313 (MH+).
Anal. Calcd for C17H20N4O2•0.25H2O: C, 64.44; H, 6.52; N, 17.68.
Found: C, 64.45; H, 6.48; N, 17.88.
1
bromide): 3450, 3140 (br, NH or OH) cmꢀ1; H NMR (DMSO-
d6): d 1.26 (t, 3H, J = 7.5 Hz, ꢀCH3), 1.45–1.66 (m, 4H, H4 and
5), 1.70–1.83 (m, 2H, H6), 2.61–2.74 (m, 4H, H7, and
ꢀCH2CH3), 2.75–2.84 (m, 2H, H3), 7.67 (d, 1H, J = 9.8 Hz,
changed to singlet after addition of deuterium oxide, NCH═NO),
10.45 (s, 1H, deuterium oxide exchangeable, OH), 11.45
(d, 1H, J = 9.8Hz, deuterium oxide exchangeable, NH); FAB-MS:
m/z 251 (MH+). Anal. Calcd for C12H18N4O2: C, 57.58; H, 7.25;
N, 22.38. Found: C, 57.46; H, 7.16; N, 22.45.
Measurement of platelet aggregation.
Preparation of
platelet and measurement of platelet aggregation were
performed according to the method described previously [8].
N-[2-(3-Phenyl[1,2,4]oxadiazol-5-yl)cyclohepten-1-yl]formamide
oxime (4c). Compound 8c (175 mg, 0.594mmol) was allowed to
react with hydroxylamine hydrochloride (414 mg, 5.95 mmol) in
dry methanol (8.0mL) for 22 h. Compound 4c (108 mg, 61%)
was obtained as colorless needles; mp 170–173ꢂC; IR (potassium
Acknowledgments. The authors are grateful to the SC-NMR
Laboratory of Okayama University for the 200 MHz 1H NMR
experiments. We also thank Ms Hiromi Ohtomo (Laboratory of
Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences,
Okayama University) for her experimental assistance and Dr K. L.
Kirk (NIDDK, NIH) for his helpful comments on the manuscript.
1
bromide): 3400, 3200 (br, NH or OH) cmꢀ1; H NMR (DMSO-
d6): d 1.51–1.69 (m, 4H, H4 and 5), 1.71–1.84 (m, 2H, H6),
2.70–2.80 (m, 2H, H-7), 2.81–2.92 (m, 2H, H3), 7.46–7.65
(m, 3H, Ph-30, 40, and 50), 7.79 (d, 1H, J = 10.0Hz, changed to
singlet after addition of deuterium oxide, NCH═NO), 8.14
(dd, 2H, J = 8.0, 1.8 Hz, Ph-20 and 60), 10.78 (s, 1H, deuterium
oxide exchangeable, OH), 11.84 (d, 1H, J = 10.0 Hz, deuterium
oxide exchangeable, NH); FAB-MS: m/z 299 (MH+). Anal. Calcd
for C16H18N4O2: C, 64.41; H, 6.08; N, 18.78. Found: C, 64.24;
H, 6.19; N, 18.67.
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K. Okuda, Y.-X. Zhang, T. Hirota, and K. Sasaki
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