2,4-Disubstituted oxazoles and thiazoles as latent pharmacophores for diacylhydrazine of SC-51089, a potent PGE2 antagonist

Article abstract of DOI:10.1016/S0968-0896(00)00229-7

8-Chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[1-oxo-3-(4-pyridinyl)propyl]hydrazide, monohydrochloride (1, SC-51089) is a functional PGE₂ antagonist selective for the EP₁ receptor subtype with antinociceptive activity. Analogues of SC-51089, in which the diacylhydrazine moiety has been replaced with 2,4-disubstituted-oxazoles and-thiazoles, are described.

Full text of DOI:10.1016/S0968-0896(00)00229-7

Bioorganic & Medicinal Chemistry 9 (2001) 1±6
2,4-Disubstituted Oxazoles and Thiazoles as Latent
Pharmacophores for Diacylhydrazine of SC-51089,
a Potent PGE2 Antagonist
E. Ann Hallinan,* Timothy J. Hagen, Sofya Tsymbalov, Awilda Stapelfeld
and Michael A. Savage
Department of Discovery Chemistry, Searle, Skokie, IL 60077, USA
Received 27 June 2000; accepted 7 July 2000
AbstractÐ8-Chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[1-oxo-3-(4-pyridinyl)propyl]hydrazide, monohydrochloride
(1, SC-51089) is a functional PGE2 antagonist selective for the EP1 receptor subtype with antinociceptive activity.1,2 Analogues of
SC-51089, in which the diacylhydrazine moiety has been replaced with 2,4-disubstituted-oxazoles and-thiazoles, are described.
# 2000 Published by Elsevier Science Ltd.
Introduction
an alternative for the diacylhydrazine group. The amino
acetyl moiety6 has been shown to have some promise as
a replacement for the diacylhydrazine. Having identi®ed
the pyridylpropionyl group, among others of the exten-
ded chain, and the 8-chlorodibenzoxazepine, 5, as desir-
able structural fragments in the PGE2 antagonist-
analgesics, this report describes research on identifying
possible pharmacophores for the diacylhydrazine moiety.
SC-51089 illustrated in Figure 1, a functional PGE2
antagonist with an excellent analgesic pro®le,1,2 con-
tains
a 1,2-diacylhydrazine moiety which releases
hydrazine during metabolism in cultured rat hepato-
cytes.3 Although hydrazine is known to be carcinogenic
in rodents,4 its release had not been seen in 4, an ear-
3
lier member of this structural class. It should be noted
that this phenomenon has not been seen in human
hepatocytes.3 Identifying a pharmacophore that could
replace the diacylhydrazine and, yet, would retain the
desirable analgesic-PGE2 antagonism pro®le of SC-
51089 became the focus of our research.
Earlier studies on the conformation of diacylhydrazines
by X-ray crystallography have shown that 1,2-diformyl-
hydrazine and 1,2-diacetylhydrazine are planar molecules
1
with Z-E-Z geometry.7 A series of H NMR studies by
Sutherland8 suggested that there was hindered rotation
about the N N bond of the diacylhydrazine in nonpolar
solvent. Anthoni et al.9 found monoacylhydrazines to
exist in an all trans conformation in nonpolar solvents.
However, with increasing solvent dielectric constant, iso-
merism shifted from all trans to a cis-trans/trans-trans
mixture. Bouchet et al.10 studied rotation about NCO
bonds of 1,2-diacylhydrazine and the in¯uences of solvent
on geometric isomerism. They found in polar solvents such
as dimethylsulfoxide-d6 (DMSO-d6) equilibrium shifts the
NCO bond from E to Z. The NMR studies on 4 reveal
two distinct conformers, the most stable having no
NOE interactions between the hydrazide hydrogens, the
less stable having complex interactions between these
hydrogens.11
As described in earlier reports,1,5,6 the rationale of our
analgesia program is based on the hypothesis that
PGE2-induced hyperalgesia occurring in in¯amed tissue
would be attenuated by selective blockade of PGE2
receptors. Analgesia based on PGE2 antagonism would
preclude the problems associated with inhibition of
prostanoid biosynthesis.
Although research on this class of compounds has
exhaustively explored the exocyclic chain appended to the
hydrazine1,5,6 and more recently the 8-chlorodibenz-
oxazepine (5), current e€orts have been directed towards
*Corresponding author at Searle-Pharmica, 4901 Searle Parkway,
Skokie, Illinois. Tel.: +1-847-982-7753; fax: +1-847-982-4714; e-mail:
ann.hallinan@monsanto.com
Since MM2 calculations12 and NMR data have indicated
that a number of low energy conformations are available
0968-0896/01/$ - see front matter # 2000 Published by Elsevier Science Ltd.
PII: S0968-0896(00)00229-7

2
E. A. Hallinan et al. / Bioorg. Med. Chem. 9 (2001) 1±6
Figure 1.
to the 1,2-diacylhydrazine, few structural constraints can
be imposed, a priori, on choices of isosteres (as seen in
Figure 3).
TXA2 antagonists, 6±8, and PGE2 antagonists-analgesics
as illustrated by 9 and 10 shown in Figure 4,6 suggested
2,4-substituted oxazoles as a potential pharmacophore
for the diacylhydrazine. Having surmised that ®ve-
membered aromatic heterocycles are possible pharma-
cophores, syntheses of 15±26 have been undertaken and
are illustrated below.
Thromboxane A2 (TXA2) antagonists described by
Squibb researchers as illustrated in Figure 2 suggested
possible insight into potential pharmacophores.13 An acyl
hydrazone functionality incorporated into the omega
chain of the thromboxane skeleton, 6, evolved into
amino acetyl group, 7, and, subsequently, 2,4-dis-
ubstituted-oxazole, 8.
Results
Ethyl 2-methyl-4-oxazolecarboxylate, 11, described by
Cornforth,14 is brominated using NBS catalyzed by
AIBN with or without light. Ethyl 2-bromomethyl-4-
oxazolecarboxylate, 13, as well as all possible combina-
tions of brominated products including ring bromina-
tion, are isolated. With minor modi®cations, a rhodium
catalyzed cycloaddition of ethyl 2-diazo-3-oxo-pro-
panoate to bromoacetonitrile as reported by Helquist15
was employed to generate 13. With 13 in hand, alkyla-
tion of 5 proceeds uneventfully to give 15 as illustrated
in Scheme 1. Hydrolysis of the ester provides inter-
mediate acid 17 that is coupled to the appropriate amine
or alcohol to obtain 19±21 as shown in Scheme 2.
Alternatively, amidation of 15 using Weinreb conditions
lead to 22±24 as illustrated in Scheme 2.
This observation begged the question as to whether an
analogy could be drawn between TXA2 antagonists and
the PGE2 antagonists-analgesics. A parallelism between
Figure 2.
Figure 3.

E. A. Hallinan et al. / Bioorg. Med. Chem. 9 (2001) 1±6
3
Figure 4.
Scheme 1. (a) NBS, CCl4, AlBN, hn, Á. (b) BrCH2CN, Rh2(OAc)4, 70 ꢀC. (c) 5, i-Pr2EtN, toluene, Á.
Scheme 2. (a) 15 or 16, 1 N NaOH, MeOH:THF (1:1). (b) i. 15, Me2N(CH2)3NˆCˆNCH2CH3, RNH2, Et3N, DMAc, 5±20 ꢀC, 16 h. ii. HCl/
dioxane, Et2O. (c) i. 15 or 16, H2NR, AlMe3, DCM, Á, 5 h. ii. 1 N HCl. (d) 16, H2NR, 110 ꢀC, 1 h.
Synthesis of the thiazole analogues requires the pivotal
intermediate, ethyl 2-methyl-4-thiazolecarboxylate, 12,
whichis synthesizedasdescribedpreviously.16 Bromination
using NBS proceeds in good yield to a€ord 14. Chemistry
analogous to that used to synthesize the oxazoles is
employed to assemble thiazole analogues 25 and 26.
these compounds.1 PGE2 antagonism was con®rmed in
PGE2-stimulated guinea pig ileum muscle strips assay.1
Discussion
In the oxazole series, 15, 17 and 19±24 are PGE2
antagonists with observed pA2's in the range of 6.1±7.4
(shown in Table 1). The analgesic activity seen among
The phenylbenzylquinone writhing assay in mouse was
used to evaluate the antinociceptive e€ectiveness of

4
E. A. Hallinan et al. / Bioorg. Med. Chem. 9 (2001) 1±6
Table 1. Phenylbenzoquinone writhing assay in mouse and PGE2
antagonism in guinea pig ileum for oxazolyl and thiazolyl analogues
with conditions described by Still.17 The hydrochloride
salts were made from 1 N HCl, HCl in ethanol (EtOH),
or 6 N HCl in dioxane. Thin layer chromatograms were
run on 0.25 mm EM precoated plates of silica gel 60
F254. High performance liquid chromatograms (HPLC)
were obtained from C-8 or C-18 reverse phase columns
which were obtained from several vendors. Analytical
samples were dried in an Abderhalden apparatus at
either 56 ꢀC or 78 ꢀC. H NMR spectra were obtained
1
from either General Electric QE-300 or Varian VXR
400 MHz spectrometers with tetramethylsilane as an
internal standard. 13C NMR spectra were obtained from
b
No.
X
Y
PBQ
writhing assaya
pA2
a
Varian spectrometer at 125.8 MHz with tetra-
15
17
19
23
20
22
21
24
16
18
25
26
O
O
O
O
O
O
O
O
S
OEt
OH
9/10
1/10
7/10
2/10
9/10
6/10
4/10
7/10
1/10
5/10
4/9
6.1
7.4Æ0.01
7.3Æ0.07
7.5Æ 0.01
7.4Æ0.17
ntc
methylsilane as an internal standard. Melting points
were obtained by di€erential scanning calorimetry on a
Dupont Model 9900 thermal analysis system.
HN(CH2)2-2-Pyridyl
HNCH2-2-Pyridyl
HNCH2-4-Pyridyl
HN(CH2)2-4-Pyridyl
OCH2-4-Pyridyl
HNCH2-2-Thienyl
OEt
OH
HNCH2-4-Pyridyl
HNCH2-2-Pyridyl
ntc
Ethyl 2-(bromomethyl)-4-oxazolecarboxylate (13). To 50
mL of bromoacetonitrile was added 0.12 g of Rh2
(OAc)4. A 50 mL bromoacetonitrile solution of ethyl 2-
diazo-3-oxo-propanoate18 (2.84 g, 20 mmol) was added
dropwise via syringe pump at a rate of 5 mL/h to the
stirring rhodium acetate solution, which had been
heated to 70 ꢀC. Once the addition was complete, the
reaction was maintained at 70 ꢀC for an additional 8 h.
The excess bromoacetonitrile was removed from the
reaction via vacuum distillation. The residue was ®ltered
through a pad of silica gel which was washed with hex-
anes and DCM. The solvent from the DCM wash was
removed in vacuo to yield 3.67 g (78%) of 13.
6.9Æ0.35
5.9Æ0.15
8.1Æ0.11
ntc
S
S
S
7/10
6.0Æ0.10
aThe initial screening dose of test compound is 30 mg/kg. The data are
reported as number of animals positively responding out of the ten
aminals tested.
bpA2 determined based on the dose ratio at 3 mM.
cNot tested.
the oxazoles does not correlate with its PGE2 antagon-
ism. Illustrative of this are 17 and 23, which are potent
PGE2 antagonists but have minimal analgesic activity,
while 15, 19, 20, 21 and 24 are both e€ective analgesics
and PGE2 antagonists.
Ethyl 2-[(8-chlorodibenz[b,f][1,4]oxazepin-10(11H)-yl)me-
thyl]-4-oxazole-carboxylic acid (15). To a stirring solu-
tion of 5 (1.16 g, 5 mmol) in 50 mL toluene were added
13
(1.17 g,
5 mmol),
N,N-diisopropylethylamine
(1.7 mL, 10 mmol), and NaI (5 mg). The reaction was
heated at re¯ux for 24 h. The reaction was poured
directly onto a column of silica gel and chromato-
graphed to yield 15, 1.38 g (72%). Anal. calcd for
C20H17N2O4Cl.0.2 H2O: C, 61.85; H, 4.52; N, 7.21.
Conclusions
2,4-Substituted-oxazoles as potential isosteres for di-
acylhydrazines have been identi®ed. However, a one to
one correlation does not seem to exist between the PGE2
antagonism and analgesia in the oxazole and thiazole ser-
ies. At present, it is unknown whether this is due to bio-
availability, metabolism, or a separation of activity in this
structural class. On a larger issue, we do not know at this
time whether or not there has been a dissociation of PGE2
antagonism and analgesia or the lack of analgesic action is
due to metabolism or bioavailability.
1
Found: C, 61.55; H, 4.50; N, 7.19. H NMR (DMSO-
d6) 8.78 (s, 1H), 7.30±7.33 (m, 2H), 7.09±7.14 (m, 3H),
6.92 (d, 1H, J=2.4 Hz), 6.74 (dd, 1H, 2.4, 8.5), 4.74 (s,
2H), 4.61 (s, 2H), 4.28 (q, 2H, 7.1), 1.28 (t, 3H, 7.1).
2-[(8-Chlorodibenz[b,f][1,4]oxazepin-10(11H)-yl)methyl]-
4-oxazolecarboxylic acid (17). To a stirring solution of
15 (0.56 g, 1.5 mmol) in 10 mL MeOH:THF (1:1) was
added 4.5 mL of 1 N NaOH. After 1 h, the reaction was
adjusted to pH 3. The organic solvents were removed in
vacuo. A white precipitate was ®ltered, washed with
H2O, and dried to yield 0.48 g (89%) of 17. Anal. calcd
for C18H13N2O4Cl: C, 60.60; H, 3.67; N, 7.85. Found:
C, 60.13; H, 4.00; N, 7.82. 1H NMR (DMSO-d6) 8.66 (s,
1H), 7.30±7.33 (m, 2H), 7.19 (d, 1H, J=7.4 Hz), 7.09±
7.15 (m, 2H), 6.91 (d, 1H, J=2.0), 6.73 (dd, 1H, J=2.5,
8.5), 4.72 (s, 2H), 4.62 (s, 2H).
Experimental
All experiments were performed under either dry nitro-
gen or argon. All solvents and reagents were used with-
out further puri®cation unless otherwise noted. The
routine work up of the reactions involved the addition
of the reaction mixture to a mixture of either neutral, or
acidic, or basic aqueous solutions and organic solvent.
The aqueous layer was extracted n times (Â) with the
indicated organic solvent. The combined organic
extracts were washed n times (Â) with the indicated
aqueous solutions, dried over anhydrous Na2SO4, ®l-
tered, concentrated in vacuo, and puri®ed as indicated.
Separations by column chromatography were achieved
2-[(8-Chlorodibenz[b,f][1,4]oxazepin-10(11H)-yl)methyl]-
N-[2-(2-pyridinyl)-ethyl]-4-oxazolecarboxamide, hydro-
chloride (19). To a stirring solution of 17 (0.47 g,
1.3 mmol), 2-(2-ethylamino)pyridine (0.17 g, 1.6 mmol),
hydroxybenzotriazole (0.22 g, 1.6 mmol), and triethyl-

E. A. Hallinan et al. / Bioorg. Med. Chem. 9 (2001) 1±6
5
.
.
amine (0.23 mL, 1.6 mmol) in 5 mL dimethylacetamide
(DMAc) at 5 ꢀC was added N,N-dimethylaminopropyl-
ethylcarbodiimide hydrochloride (0.31 g, 1.6 mmol).
With warming to ambient temperature, the reaction
mixture was stirred for 18 h. The reaction was worked
up in the usual manner to yield 0.51 g (85%) of the free
base. The residue was dissolved in 100 mL Et2O to which
was added 2 mL 6.8 N HCl/dioxane. The precipitate was
®ltered, washed with Et2O, and dried. Anal. calcd for
C25H21N4O3Cl 1.2 HCl 0.3 H2O: C, 58.78; H, 4.51; N,
10.98; Cl, 15.29. Found: C, 58.50; H, 4.44; N, 10.66; Cl,
14.87. 1H NMR (DMSO-d6) 8.80 (dd, 1H, J=1.5,
6.6 Hz), 8.53 (s, 1H), 8.49 (t, 1H, J=6.1 Hz), 8.43 (dt, 1H,
J=1.6, 7.9 Hz), 7.86±7.89 (m, 2H), 7.28±7.34 (m, 2H),
7.21 (d, 1H, J=7.9), 7.10±7.14 (m, 2H), 6.89 (d, 1H,
J=2.5 Hz), 6.75 (dd, 1H, J=2.4, 8.5), 4.69 (s, 2H), 4.60
(s, 2H), 3.71 (dd, 2H, J=6.6, 6.9), 3.28 (t, 2H, J=6.6).
Anal. calcd for C24H19N4O3Cl 0.9 HCl 0.5 H2O: C, 58.98;
H, 4.31; N, 11.46; Cl, 13.78. Found: C, 59.13; H, 4.27; N,
11.44; Cl, 13.73. 1H NMR (DMSO-d6) 9.02 (t, 1H,
J=5.9Hz), 8.73±8.75 (m, 1H), 8.65 (s, 1H), 8.29 (dt, 1H,
J=1.3, 7.8 Hz), 7.72±7.75 (m, 2H), 7.30±7.34 (m, 2H),
7.10±7.15 (m, 2H), 6.93 (d, 1H, J=2.3Hz), 6.75 (dd, 1H,
J=2.4, 8.5 Hz), 4.73±4.75 (m, 4H), 4.64 (s, 2H).
2-[(8-Chlorodibenz[b,f][1,4]oxazepin-10(11H)-yl)methyl]-
N-(2-thienylmethyl)-4-oxazolecarboxamide (24). Com-
pound 24 was prepared in the same manner as described
in example 22 starting with 2-aminomethylthiophene
(0.06 g, 0.5 mmol) to yield 0.10 g (45%). Anal. calcd for
C23H18N3O3ClS: C, 61.13; H, 4.01; N, 9.30. Found: C,
.
.
1
60.81; H, 3.93; N, 9.10. H NMR (DMSO-d6) 8.18 (s,
1H), 7.15±7.28 (m, 3H), 7.13 (dd, 2H, J=1.2, 3.3 Hz),
7.03±7.06 (m, 3H), 6.98 (dd, 1H, J=3.5, 5.1 Hz), 6.91
(d, 1H, J=2.4 Hz), 6.77 (dd, 1H, J=2.5, 8.5 Hz), 4.78
(d, 2H, J=5.9 Hz), 4.47 (s, 2H), 4.38 (s, 2H).
2-[(8-Chlorodibenz[b,f][1,4]oxazepin-10(11H)-yl)methyl]-
N-(4-pyridinylmethyl)-4-oxazolecarboxamide, monohy-
drochloride (20). Compound 20 was prepared in the
manner described in example 19 starting with 4-amino-
methylpyridine (0.67 mmol) to yield 0.14 g (56%). Anal.
2-Bromomethyl-4-carboxyethyl-thiazole (14). To a stir-
ring solution of 4-carboxyethyl-2-methyl-thiazole
(30.3 g, 179 mmol) in CCl4 (1L) were added NBS (37.7 g,
212 mmol) and AIBN (2.2 g). The resulting mixture was
re¯uxed and irradiated with sun lamp light for 4 h. The
mixture was cooled to room temperature and ®ltered.
The solution was chromatographed to yield 36.6 g
(95%) of a red oil. This material was used without fur-
ther puri®cation.
.
.
calcd for C24H19N4O3Cl HCl 1.5 H2O: C, 56.48; H,
4.54; N, 10.98; Cl, 13.89. Found: C, 56.79; H, 4.54; N,
10.70; Cl, 13.59.
4-Pyridinylmethyl 2-[(8-chlorodibenz[b,f][1,4]oxazepin-10
(11H) - yl)methyl] - 4 - oxazolecarboxylate, hydrochloride
(21). Compound 21 was prepared in the same manner
as 19 starting with 4-hydroxymethylpyridine (0.45 g,
Ethyl 2-[(8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-yl)-
methyl]-4-thiazolecarboxylate (16). Compound 16 was
prepared in the same manner as described for 15 from
14 and 5 on a 17 mmol scale to yield 6.46 g of the crude
product as a yellow solid after chromatography. The
product was then recrystallized from ethanol to yield
3.4 g of a white solid. Anal. calcd for C20H17N2O3SCl:
C, 59.92; H, 4.27; N, 6.99; Cl, 8.84; S, 8.00. Fouꢀnd: C,
59.78; H, 4.29; N, 6.95; Cl, 8.78; S, 8.63. Mp 151.3 C. 1H
NMR (CDCl3) 8.14 (s, 1H), 7.29 (dt, 1H, J=1.9, 7.8 Hz),
7.06±7.19 (m, 4H), 6.78±6.81 (m, 2H), 4.65 (s, 2H), 4.48
(s, 2H), 4.45 (q, 2H, J=7.1 Hz), 1.43 (t, 3H, J=7.1 Hz).
.
.
0.45 mmol). Anal. calcd for C24H18N3O4Cl 1.6 HCl 0.4
H2O: C, 56.15; H, 4.00; N, 8.18. Found: C, 55.99; H,
1
4.11; N, 8.07. H NMR (DMSO-d6) 9.03 (s, 1H), 8.89
(d, 2H, J=6.6 Hz), 7.99 (d, 2H, J=6.6 Hz), 7.30±7.34
(m, 2H), 7.20 (dd, 1H, J=1.2, 8.5 Hz), 7.10±7.15 (m,
2H), 6.95 (d, 1H, J=2.4 Hz), 6.74 (dd, 1H, J=2.4,
8.5 Hz), 5.61 (s, 2H), 4.79 (s, 2H), 4.64 (s, 2H).
2-[(8-Chlorodibenz[b,f][1,4]oxazepin-10(11H)-yl)methyl]-
N-[2-(4-pyridinyl)ethyl]-4-oxazolecarboxamide, hydro-
chloride, acetate (22). To a stirring solution of 15
(0.19 g, 0.5 mmol) in 5 mL DCM was added 4-(2-ami-
noethyl)pyridine (0.065 g, 0.6 mmol) and trimethylalu-
minum (0.3 mL of 2 M solution in toluene). After
heating the reaction at re¯ux for 5 h, the reaction mix-
ture was quenched with MeOH then worked up in the
usual manner. The free base was dissolved in acetic acid,
treated with 1 N HCl, and lyophilized to yield 0.06 g
2-[(8-Chlorodibenz[b,f][1,4]oxazepin-10(11H)-yl)methyl]-
4-thiazolecarboxylic acid, sodium salt (18). Compound
18 was synthesized from 16 using the same conditions
described for 17 to give its sodium salt as a white solid.
Anal. calcd for C18H12N2O3SClNa 0.75 H2O: C, 52.95;
H, 3.33; N, 6.86; Cl, 8.68; S, 7.85. Found: C, 53.29; H,
3.11; N, 6.85; Cl, 8.59; S, 7.37.
.
.
.
.
(26%) of 22. Anal. calcd for C25H21N4O3Cl 1.5 HCl 1.5
.
H2O 0.6 HOAc: C, 54.38; H, 4.86; N, 9.68; Cl, 15.32.
Found: C, 54.78; H, 4.65; N, 9.33; Cl, 15.01. H NMR
1
2-[(8-Chlorodibenz[b,f][1,4]oxazepin-10(11H)-yl)methyl]-
N-(4-pyridinylmethyl)-4-thiazolecarboxamide, acetate,
hydrochloride (25). Compound 25 was synthesized in the
same manner and scale as described for 22 to give a white
foam. Anal. calcd for C24H19N4O2SCl 1.66 HCl 1 HO
.
Ac 0.33 H2O: C, 52.97; H, 4.33; N, 9.50; Cl, 16.00; S, 5.44.
Found: C, 52.69; H, 4.14; N, 9.45; Cl, 15.81; S, 5.78.
(DMSO-d6) 8.76 (br s, 2H), 8.51 (s, 1H), 8.41 (t, 1H,
J=5.7), 7.85 (d, 2H, J=5.8 Hz), 7.10±7.34 (m, 5H), 6.89
(d, 1H, J=2.4), 6.75 (dd, 1H, J=2.5, 8.4), 4.69 (s, 2H),
4.61 (s, 2H), 3.61 (dd, 2H, J=6.7, 6.9), 3.12 (t, 2H,
J=6.6 Hz).
.
.
2-[(8-Chlorodibenz[b,f][1,4]oxazepin-10(11H)-yl)methyl]-
N-(2-pyridinylmethyl)-4-oxazolecarboxamide, monohy-
drochloride (23). Compound 23 was prepared in the
same manner as example 22 using 2-aminomethylpyr-
idine (0.073 g, 0.67 mmol). The yield of 23 was 58%.
2-[(8-Chlorodibenz[b,f][1,4]oxazepin-10(11H)-yl)methyl]-
N - (2 - pyridinylmethyl) - 4 - thiazolecarboxamide (26). A
mixture of 16 (0.50 g, 1.2 mmol) and 2-aminomethyl-
pyridine (2 mL, 19.5 mmol) was heated at 120 ꢀC for 1 h.

6
E. A. Hallinan et al. / Bioorg. Med. Chem. 9 (2001) 1±6
The mixture was cooled to ambient temperature and
chromatographed to yield 0.38 g of a yellow foam. Anal.
calcd for C24H19N4O2SCl: C, 62.26; H, 4.14; N, 12.10;
Cl, 7.66. Found: C, 62.11; H, 4.52; N, 11.80; Cl, 7.65.
1H NMR (DMSO-d6) 9.32 (m, 1H), 8.86 (d, 2H,
J=6.7 Hz), 8.26 (s, 1H), 7.96 (d, 2H, J=2.4 Hz), 7.33±
7.38 (m, 2H), 7.24 (d, 1H, J=8.0 Hz), 7.14±7.18 (m,
2H), 6.84 (d, 1H, J=2.4), 6.79 (dd, 1H, J=2.4, 8.5 Hz),
4.88 (s, 2H), 4.74 (d, 2H, J=6.1), 4.71 (s, 2H).
3. Lee, K.; Vandenberghe, Y. L.; Herin, M. F.; Cavalier, R.;
Beck, D.; Li, A.; Verbeke, N.; Lesne, M. L.; Roba, J. Com-
parative metabolism of SC-42867 and SC-51089, two PGE2
antagonists, in rat and human hepatocyte cultures. Xenobio-
tica 1994, 24, 25.
4. IARC Monographs 1974, 4, 127.
5. Hallinan, E. A.; Stapelfeld, A.; Savage, M. A.; Reichmann,
M. 8-Chlorodibenz[b,f][1,4]oxazepine-10(11H)carboxylic acid, 2-
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Mouse writhing assay1
The phenylbenzoquinone (PBQ) writhing test was used
to assess analgesic ecacy.
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PGE2 antagonism assay utilizing the guinea pig ileum1
Evaluation of PGE2 antagonism was performed as
described previously.
Acknowledgements
10. Bouchet, P.; Elguero, J.; Jaquier, R.; Pereillo, J.-M. Etude
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The authors would like to thank Professor Peter Beak
of the University of Illinois, Urbana and Professor A.
G. M. Barrett of Imperial College for their many useful
conversations about organic chemistry, Professor Lester
Mitscher of the University of Kansas for his thoughts
concerning medicinal chemistry and pharmacology and
Dr Richard Bitman for his assistance in the statistics of
the bioassays. EAH would particularly like to thank Dr
Barnett S. Pitzele for his many helpful ideas and
thoughts on this project.
11. Unpublished data, Bible Jr., R. H.
12. Unpublished data, Spangler, D. P.
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References and Notes
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1. Hallinan, E. A.; Hagen, T. J.; Husa, R. K.; Tsymbalov, S.;
Rao, S. N.; vanHoeck, J.-P.; Ra€erty, M. F.; Stapelfeld, A.;
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