2-Substituted-4-aryl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,5] oxazocin-5-one as a structurally new NK1 antagonist

Article abstract of DOI:10.1016/j.bmcl.2004.12.089

The structurally novel pyrimido[4,5-b][1,5]oxazocine derivative 3, a hybrid compound of pyrido[4,3-b]- and [2,3-b]-1,5-oxazocine (1 and 2, respectively), was designed and synthesized. We examined the atropisomeric property and the NK₁ antagonis

Full text of DOI:10.1016/j.bmcl.2004.12.089

Bioorganic & Medicinal Chemistry Letters 15 (2005) 1485–1488
2-Substituted-4-aryl-6,7,8,9-tetrahydro-5H-pyrimido
[4,5-b][1,5]oxazocin-5-one as a structurally new NK1 antagonist
Shigeki Seto,* Asao Tanioka, Makoto Ikeda and Shigeru Izawa
Discovery Research Laboratories, Kyorin Pharmaceutical Co., Ltd, 2399-1, Nogi, Nogi-machi, Shimotsuga-gun,
Tochigi 329-0114, Japan
Received 6 December 2004; accepted 28 December 2004
Available online 29 January 2005
Abstract—The structurally novel pyrimido[4,5-b][1,5]oxazocine derivative 3, a hybrid compound of pyrido[4,3-b]- and [2,3-b]-1,5-
oxazocine (1 and 2, respectively), was designed and synthesized. We examined the atropisomeric property and the NK1 antagonist
activity of 3. Compound 3 was found to possess both a feature of 1, free rotation about the biaryl bond, and a feature of 2, potent
in vivo activity.
Ó 2005 Elsevier Ltd. All rights reserved.
Substance P (SP)1 elicits a wide variety of biological re-
sponses, both centrally and peripherally. The binding of
SP to NK1, receptors has been implicated in the trans-
mission of pain and stress signals, inflammation, and
the contraction of smooth muscle. Therefore, NK1
antagonists may be clinically useful in the treatment of
a wide range of diseases.
ryl bond. Possibly because of their different structures at
the 8-position (1, N; 2, CH), rotation about the biaryl
bond of 1 appeared to be free, whereas that of 2 was par-
tially restricted on the NMR time scale.2 This property of
2 might promote the stacking conformation that is
important for NK1 receptor recognition.3 However, in
order to avoid substantial analytical complications dur-
ing manufacture and drug development, it is necessary
to ensure either inseparable rapid interconversion of iso-
mers or a completely separable rigid conformation.
Recently, we reported the design and synthesis of the pyr-
ido[4,3-b]-1,5-oxazocine 1 and the pyrido[2,3-b]-1,5-oxa-
zocine 2 as potent NK1 antagonists.2 In that study, we
established that although compounds 1 and 2 exhibit sim-
ilar and potent NK1 antagonist activity in vitro, the in
vivo activity of 2 is superior to that of 1. These two com-
pounds differ structurally in the following two aspects: (1)
the position of the nitrogen atom on the pyridine ring,
and (2) the presence in 2 of atropisomerism about the bia-
On the basis of these results, we became interested in the
pyrimido[4,5-b][1,5]oxazocine 3 as a hybrid compound
of 1 and 2. Interestingly, the 6,7,8,9-tetrahydro-5H-
pyrimido[4,5-b][1,5]oxazocin-5-one skeleton constitutes
a novel ring system that to our knowledge has not pre-
viously been described (Fig. 1).
1
N
10
10
R1
R1
N
R1
O
O
O
R1 =
R2 =
1
1
10
9
9
8
2
N3
N
N
N8
4
N
7
N
N
7
CF3
O
R2
O
R2
O
R2
Me
Me
Me
CF3
1
2
3
Figure 1.
Keywords: Pyrimido[4,5-b][1,5]oxazocin-5-one; NK1 antagonist.
*
Corresponding author. Fax: +81 280 57 1293; e-mail: shigeki.seto@ mb.kyorin-pharm.co.jp
0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.12.089

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S. Seto et al. / Bioorg. Med. Chem. Lett. 15 (2005) 1485–1488
Ra
N
O
O
MeS
N
N
Rb
O
MeS
N
B(OH)2
N
N
+
N
N
N
R1
R2
N
O
R2
O
O
R2
R1
Cl
R1
3
4
5
6
MeS
N
Cl
R2
N
MeS
N
Cl
CO2H
HN
OH
N
OH
+
N
R2
Cl
O
Cl
7
8
9
Scheme 1.
The retrosynthesis of the skeleton 3 is shown in Scheme
1. Sulfide 4 may be converted to 3 by oxidation to the
corresponding sulfone and displacement with an amine
nucleophile. The formation of the biaryl bond of 4 could
be achieved by a Suzuki coupling reaction. The bicyclic
compound 5 could be constructed from the carboxylic
acid 8 by condensation with aminopropanol 9 and a
subsequent cyclization reaction using nucleophilic aro-
matic substitution (SNAr).
fide 12 with mCPBA and subsequent nucleophilic
amination with 4-(pyrrolidinyl)piperidine afforded tar-
get compound 3.5
The characteristic 1H NMR properties of compounds 1,
2, and 3 are summarized in Table 1.
The rotation about the biaryl bond of 3 was examined.
Although the NMR spectrum of 2 showed two pairs of
benzylic methylene protons, presumably as a result of
two-axial chirality,2 the NMR spectrum of 3 showed
one pair of benzylic methylene protons, similar to that
of 1. Consequently, rotation about the biaryl bond of
3 appears to be free on the NMR timescale at room
temperature.
The synthesis of the desired compound 3 is shown in
Scheme 2.
Compound 8,4 which was prepared from 4,6-dichloro-2-
(methylthio)pyrimidine, was treated with SOC12, fol-
lowed by condensation with 3-[[3,5-bis(trifluoro-
methyl)benzyl]amino]-l-propanol3a and intramolecular
cyclization using potassium carbonate to afford the bicy-
clic compound 11. Suzuki coupling reactions of 11 with
2-methylphenylboronic acids afforded the correspond-
ing biaryl compounds 12 in good yield. Oxidation of sul-
The interconversion about oxazocine ring of 3 was
examined. Compound 3 showed a distinct AB pattern
for the benzylic and ring methylene protons that might
indicate a slow interconversion about the oxazocine ring
on the NMR timescale at room temperature.3 Several
MeS
N
Cl
MeS
N
Cl
O
MeS
N
a
b
N
N
CF3
CF3
N
CO2H
N
Cl
Cl
Cl
O
10
8
11
N
O
O
MeS
Me
N
N
N
c
d, e
CF3
CF3
CF3
CF3
N
N
N
N
Me
O
O
12
3
Scheme 2. Reagents and conditions: (a) (1) LDA, THF, À78 °C, 5 h; (2) CO2, 1 h; (3) HCl, rt, 1 h, 58%; (b) (1) SOCl2, DMF, reflux, 2 h; (2) 3-[[3,5-
bis(trifluoromethyl)benzyl]amino]-1-propanol, THF, 0 °C, 1 h then rt, 3 h; (3) K2CO3, DMF, 80 °C, 1 h, 63%; (c) 2-methylphenylboronic acid,
10 mol % Pd(PPh3)4, 2 M Na2CO3, toluene, dioxane; reflux, 6 h, 95%; (d) mCPBA, THF, 0 °C, 0.5 h then rt, 3 h, 99%; (e) 4-(pyrrolidinyl)piperidine,
1,4-dioxane, diisopropylethylamine, reflux, 5 h, 64%.

S. Seto et al. / Bioorg. Med. Chem. Lett. 15 (2005) 1485–1488
Table 1. 1H NMR properties and NK1 antagonist activities of 1–3
1487
N
O
N
Y
CF3
CF3
X
N
Me
O
Compd
X
Y
1H NMRa ppm, d (Hz)
(benzylic methylene protons)
NK1 antagonist activityb
KB (nM)
Effective bladder
capacity increasing
ratio (%) (0.3 mg/kg iv)c
1
N
CH
N
3.93, 5.34 (each 1H, d, J = 15.3 Hz)
3.94, 3.95, 5.36, 5.39 (each 0.5H, d, J = 15.3 Hz)
3.84, 5.32 (each 1H, d, J = 15.3 Hz)
0.339
0.210
0.166
0.270
3.97
24.2
33.4
12.0
2
CH
N
3
TAK-637
N
a In CDCI3; d = doublet.
b Compounds were screened for antagonist activity on guinea pig ileum as described in the text.
c Effective bladder capacity was measured as the volume of saline injected into spinalized guinea pigs. The increasing effects of the test compounds
were expressed as the ratio of the increase in effective bladder capacity compared with the predrug values.
groups have reported on separable amido-base atrop-
isomerism.3,6 However, not all the atropisomers detect-
able by NMR spectroscopy can be physically
separated by experimental procedures.7 We were unable
to separate the atropisomers of 3 by high-performance
liquid chromatography with a chiral column. To investi-
gate the possibility of separation of the atropisomers
arising from oxazocine ring inversion, the effect of tem-
perature on the degree of coalescence of the AB pattern
was examined by NMR in dimethyl sulfoxide-d6.7 The
AB pattern for the benzylic methylene protons of 3 dete-
riorated to very broad peaks at 100 °C and collapsed to
singlet peaks at 150 °C. In addition, each pair of oxazo-
cine ring methylene protons showed one peak with dis-
tinct fission patterns at 150 °C. From these results, we
predict that the barrier for inversion is too low to allow
isolation of the enantiomers about the oxazocine ring,
since rapid interconversion would occur at room
temperature.7
the biaryl bond (a feature of 1) and N-1 (numbering
for 3) is important for potent in vivo activity (a feature
of 2).
In conclusion, we have succeeded in the design and syn-
thesis of the novel pyrimido[4,5-b][1,5]oxazocine deriva-
tive 3, which shows potent NK1 antagonist activity in
vitro as well as potent activity on the effective bladder
capacity of guinea pigs in vivo. In addition, we found
that 3 had a property independent of restricted biaryl
bond rotation from an NMR study, therefore, of which
chemical property would be preferable as a development
candidate. Further pharmacological investigations on 3
are in progress.
Acknowledgements
The authors wish to thank Dr. H. Miyachi, presently at
the University of Tokyo, for many valuable suggestions
and for encouragement, and also Dr. T. Ishizaki, Dr. Y.
Fukuda, Dr. Y. Takano and Dr. M. Segawa of Kyorin
Pharmaceutical Co., Ltd., for helpful discussion.
We evaluated the NK1 antagonist activity of 3 in com-
parison with that of a representative antagonist, TAK-
637 (Table 1). The NK1 receptor antagonist activity
towards guinea pig ileum was evaluated by the previ-
ously described method8 with slight modification. The
activity was expressed as KB values, as determined by
the Schild method.9 The effective bladder capacity was
measured by injection of saline into spinalized guinea
pigs according to the method previously described.10
References and notes
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Compound 3 showed potent NK1 antagonist activity in
vitro, similar to that of compounds 1, 2, and TAK-637.
Interestingly, compound 3, like compound 2, showed
potent in vivo activity on the effective bladder capacity
of guinea pigs following iv administration.
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S. Seto et al. / Bioorg. Med. Chem. Lett. 15 (2005) 1485–1488
1
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2.90–3.01 (2H, m), 3.23–3.32 (1H, m), 3.76–3.89 (1H, m),
3.84 (1H, d, J = 15.3 Hz), 4.27–4.41 (2H, m), 4.67–4.80 (1H,
m), 5.32 (1H, d, J = 15.3 Hz), 6.92–6.98 (1H, m), 7.02–7.08
(1H, m), 7.18–7.25 (2H, m), 7.57 (2H, s), 7.80 (1H, s).
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