Aminoacetyl moiety as a potential surrogate for diacylhydrazine group of SC-51089, a potent PGE2 antagonist, and its analogs.

Article abstract of DOI:10.1021/jm950454k

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. During metabolism in cultured rat hepatocytes, SC-51089, which contains a diacylhydrazine moiety, has been shown to release hydrazine. Analogs of SC-51089, in which the diacylhydrazine functionality has been replaced by isosteric and isoelectronic groups, have been synthesized and have been shown to be analgesics and PGE2 antagonists of the EP1 subtype. This report discusses the structure-activity relationships within these series.

Full text of DOI:10.1021/jm950454k

J . Med. Chem. 1996, 39, 609-613
609
Am in oa cetyl Moiety a s a P oten tia l Su r r oga te for Dia cylh yd r a zin e Gr ou p of
SC-51089, a P oten t P GE2 An ta gon ist, a n d Its An a logs
E. Ann Hallinan,* Timothy J . Hagen, Sofya Tsymbalov, Robert K. Husa, Albert C. Lee, Awilda Stapelfeld, and
Michael A. Savage
Department of Chemistry, Searle, Skokie, Illinois 60077
Received J une 20, 1995X
8-Chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[1-oxo-3-(4-pyridinyl)propyl]hy-
drazide, monohydrochloride (1, SC-51089) is a functional PGE2 antagonist selective for the
EP1 receptor subtype with antinociceptive activity. During metabolism in cultured rat
hepatocytes, SC-51089, which contains a diacylhydrazine moiety, has been shown to release
hydrazine. Analogs of SC-51089, in which the diacylhydrazine functionality has been replaced
by isosteric and isoelectronic groups, have been synthesized and have been shown to be
analgesics and PGE2 antagonists of the EP1 subtype. This report discusses the structure-
activity relationships within these series.
In tr od u ction
effects including dyspepsia and heartburn.8 Chronic use
of NSAIDs often results in severe damage to gastric and
intestinal mucosa that can lead to frank bleeding
requiring emergency intervention.
The rationale of our analgesia program is based on
the hypothesis that PGE2-induced hyperalgesia occur-
ring in inflamed tissue would be attenuated by selective
blockade of PGE2 receptors.6,7 Analgesia based on PGE2
antagonism would preclude the problems associated
with inhibition of prostanoid biosynthesis.
Although research on the SC-51089 class of com-
pounds has exhaustively explored the extended chain1,9,10
and more recently the 8-chlorodibenzoxazepine,11 little
effort has been directed toward identifying an alterna-
tive for the diacylhydrazine functionality. Our initial
strategy examined the need for hydrogen-bonding prop-
erties of the diacylhydrazine group. This was ac-
complished by a systematic replacement of each nitro-
gen of hydrazine with a methylene. Although concep-
tually basic, this is key to understanding the require-
ment for the hydrogen bond acceptor-hydrogen bond
donor properties of the diacylhydrazine. Using the
extended chains of four exceedingly effective analgesic-
PGE2 antagonists,1,10,12 the diacylhydrazine group of
compounds 1-4 has been substituted by an aminoacetyl
moiety as illustrated by analogs 11-13, 15, 21, and 22.
SC-51089, a functional PGE2 antagonist with an
excellent analgesic profile,1,2 contains a diacylhydrazine
moiety, which, during metabolism in cultured rat hep-
atocytes, releases hydrazine.3 Although hydrazine was
known to be carcinogenic in rodents,4 its release had
not been seen in an earlier member of this structural
class, 4.3 This phenomenon necessitates identifying a
pharmacophore that can replace the diacylhydrazine
and, yet, will retain the desirable pharmacological
profile of SC-51089.
Pain on exposure to noxious stimuli is thought to
occur through the intermediacy of several autacoids,
among them prostaglandin E2 (PGE2), that are released
at the site of injury.5 Relief of mild to moderate pain is
attained with over-the-counter and prescription non-
steroidal antiinflammatory drugs (NSAIDs). The an-
tinociceptive action of NSAIDs is believed to occur
through the inhibition of the action of cyclooxygenase
on arachidonic acid.6 Ferreira suggested that the ef-
fectiveness of NSAIDs against the pain accompanying
inflammation and tissue injury is due specifically to the
inhibition of PGE2 formation from arachidonate.6b More
particularly, NSAIDs block the production of PGE2, a
prostanoid, which causes pain and hyperalgesia and
potentiates the action of bradykinin in pain transmis-
sion.6 Two decades of research by several research
groups have provided evidence supporting this view.7
While NSAIDs are considered generally safe, unto-
ward effects do accompany their administration. The
most notable and most prevalent are the gastric side
Syn th esis
Syntheses of the diamide analogs, where the nitrogen
proximal to the 8-chlorodibenzoxazepine ring is replaced
with a methylene, are illustrated in Schemes 1 and 2.
Acylation of 8-chlorodibenzoxazepine (5) with activated
Boc-Gly (e.g. symmetrical anhydride, mixed anhydride,
and carbodiimide with and without additives) was
unsuccessful. With Phth-Gly-Cl, acylation of 5 was
effected, yielding 7. Subsequent transformations of 7
including removal of the phthaloyl protecting group and
acylation of the resultant amine gave analogs 11-14.
Oxidation of 14 with H2O2 resulted in sulfone 15.
The methods for assembling the urea-ketone analogs,
in which the nitrogen distal to 8-chlorodibenzoxazepine
is replaced with methylene, are illustrated in Scheme
3. Installation of the aminoacetyl group was accom-
plished by acylating 5 with ethyl isocyanoacetate.
X Abstract published in Advance ACS Abstracts, December 15, 1995.
0022-2623/96/1839-0609$12.00/0 © 1996 American Chemical Society

610 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 2
Notes
Sch em e 1a
a
(a) toluene, TEA, ∆, 3h; (b) NH2NH2, EtOH, ∆, 4 h; (c) Me2N(CH2)3NdCdNCH2CH3, Et3N, DMF, 5-20 °C, 16 h; (d) HCl/EtOH or 1
N HCl.
Sch em e 2a
disappointingly is a significantly less efficacious anal-
gesic and PGE2 antagonist than its parent, 3.10 As with
13, uninteresting analgesic and PGE2 antagonism activ-
ity is noted with 11. None of the desirable properties
of its parent, 1, is seen with 11. Analog 12 parallels its
parent, 2, in its analgesic potency.1
Con clu sion
PGE2 antagonism is observed in all compounds of this
series that have been tested; however, this series of
compounds shows a trend toward attenuation of PGE2
antagonism. That PGE2 antagonism is observed sug-
gests that the hydrogen-bonding properties of the hy-
drazine NH’s are not essential in eliciting PGE2 an-
tagonism in this class of compounds.
Observing the desired analgesic activity in diamides
12 and 15 indicates that modification of the diacylhy-
drazine is allowed without a concomitant loss of anal-
gesic efficacy. However, methylene substitution for NH
is not universally tolerated as 11 and 13 are poorly
active.
a
(a) 8, AlMe3, toluene; (b) 8, TEA, DCM, 5 °C; (c) 30% H2O2,
HOAc, 72 °C.
Subsequent manipulations, including saponication of 16
and acylation of N,O-dimethylhydroxylamine with 17,
resulted in the Weinreb amide 18. Metalation of 18
with vinylmagnesium bromide yielded R,â-unsaturated
ketone, 19. Michael addition to 19 with ethyl mercap-
tan and furfuryl mercaptan produced 20 and 21. Oxi-
dation of 20 with H2O2 resulted in the sulfone 22.
Exp er im en ta l Section 1
1,3-Dih yd r o-1,3-d ioxo-2H-isoin d ole-2-a cetyl Ch lor id e
(6). A solution of 1,3-dihydro-1,3-dioxo-2H-isoindole-2-acetic
acid (Phth-Gly) (7.00 g, 34.1 mmol) and thionyl chloride (12
mL, 165 mmol) was heated at reflux for 1 h. Thionyl chloride
was distilled from the reaction, and the resulting crude product
was further purified by distillation at 160-180 °C (10 Torr)
to yield 6.88 g (90%).
8-Ch lor o-10,11-d ih yd r o-10-[(1,3-d ih yd r o-1,3-d ioxo-2H-
isoin d ol-2-yl)a cetyl]d iben z[b,f] [1,4]oxa zep in e (7). After
heating 3 h at reflux, the reaction mixture of 5 (4.00 g, 17.9
mmol), 6 (4.16 g, 18.0 mmol), and triethylamine (TEA) (2.8
mL, 20.1 mmol) in toluene solution (100 mL) was poured onto
1 N HCl at 0 °C. The insoluble product was collected by
filtration, washed with toluene and Et2O, and dried in vacuo
to yield 6.36 g (85%) of shiny white crystals: mp 184-185 °C.
10-(Am in oacetyl)-8-ch lor o-10,11-dih ydr odiben z[b,f][1,4]-
oxa zep in e (8). After a solution of hydrazine monohydrate
(1.25 mL) and 7 (5.00 g, 11.9 mmol) in absolute ethanol (125
mL) was heated at reflux for 4 h, the reaction mixture was
filtered hot and rinsed with EtOH and then with hot DCM.
The filtrate and rinses were combined, evaporated in vacuo,
and purified by chromatography to give 2.91 g (84%) of a light
yellow solid: mp 110-112 °C.
P h a r m a cology
The phenylbenzoquinone (PBQ) writhing assay in
mouse was used to evaluate the antinociceptive ef-
fectiveness of these compounds.1 PGE2 antagonism was
confirmed in PGE2-stimulated guinea pig ileum muscle
strip assay.1
Resu lts a n d Discu ssion
As seen in Table 1, the urea-ketones, 21 and 22,
show a reduction in analgesic efficacy as compared to
parents, 3 and 4, respectively. A loss in PGE2 antago-
nism activity is also seen with 21. Given the uninter-
esting activity in these urea-ketones, no attempts were
made to synthesize the urea-ketone analogs of 1 and
2.
A disparate picture emerges with the diamide con-
geners of the PGE2 antagonists-analgesics as can be
seen in Table 1. Diamide 15 has a biological profile that
parallels its parent, 4, in that it has comparable
analgesic and PGE2 antagonism activity. Analog 13
3-(4-P yr id yl)p r op a n oic Acid (9). After stirring for 3 h
at ambient temperature, the reaction mixture of methyl 3-(4-
pyridyl)propanoate1 (1.00 g, 6.1 mmol) and sodium hydroxide

Notes
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 2 611
Sch em e 3a
a
(a) (i) 5, OCNCH2COOEt, toluene, ∆; (ii) 1 N NaOH, MeOH; (iii) 1,1′-carbonyldiimidazole, NH(OMe)Me‚HCl, TEA, THF, 5′-20 °C; (b)
CH2dCHMgBr, THF, -70 °C; (c) HSR, piperidine, BzlMe3N+OH-, DCM/MeOH (4:1); (d) 30% H2O2, HOAC, 60 °C.
Ta ble 1. Phenylbenzoquinone Writhing Assay in Mouse and PGE2 Antagonism in Guinea Ileum for Aminoacetyl Analogs
ED50 (mg/kg)a
pA2
no.
X
Y
ED50 (mg/kg)
pA2
b
no.
X
1
2
3
NHNH
NHNH
NHNH
6.8c
9.1c
0.9d
6.5c
7.5c
8.1d
11
12
13
21
15
22
CH2NH
CH2NH
CH2NH
NHCH2
CH2NH
NHCH2
(CH2)2-4-pyridyl
5/10
5.7 ( 0.05
ntf
7.4 ( 0.13
7.2 ( 0.10
5.7 ( 0.12
5.6 ( 0.10
CF2CHOH-2-pyridyl
(CH2)2SCH2-2-furanyl
(CH2)2SCH2-2-furanyl
(CH2)2SO2CH2CH3
(CH2)2SO2CH2CH3
8.1 (0.88-29.6)
13.5 (4.7-199)
5/10
5.9 (3.9-16.6)
5/10
4
NHNH
7.4e
5.8e
a
The initial screening dose of test compound is 30 mg/kg. ED50’s are determined for compounds in which seven out of ten animals
b
respond. Values in parentheses are confidence limits determined at 95% (p < 0.05). pA2’s are determined based on the dose ratio at 3
µM.9a,13 c Reference 1. Reference 10. e Reference 11. f Not tested.
d
(0.42g, 10.5 mmol) in 8 mL of methanol-H2O (5:3) was treated
with 6 N HCl. After the reaction mixture was concentrated,
the residue was treated with absolute EtOH (10 mL), heated
at reflux, filtered, and rinsed with hot EtOH. The filtrates
were evaporated in vacuo. The residue was treated with Et2O,
and the product was collected by filtration, washed with Et2O,
and dried in vacuo to yield 0.52 g (46%) of a white solid: mp
204-207 °C.
r,r-Diflu or o-â-h yd r oxy-3-(2-p yr id yl)p r op a n oic Acid
(10). 10 was synthesized in a similar manner to 9 on a 17
mmol scale starting with ethyl R,R-difluoro-â-hydroxy-3-(2-
pyridinyl)propanoate1 to give a quantitative yield of a pale
yellow solid.
J ) 7.3 Hz), 2.56 (t, 2H, J ) 7.3 Hz). Anal. (C23H20ClN3O3‚
HCl) C, H, N, Cl.
N-[2-(8-Ch lor od ib en z[b,f][1,4]oxa zep in -10(11H )-yl)-2-
oxoeth yl]-r,r-d iflu or o-â-h yd r oxyp yr id in e-2-p r op a n a m -
id e, Mon oh yd r och lor id e (12). 12 was synthesized in a
manner similar to 11 on a 3.8 mmol scale starting with 8 and
10 to give 1.40 g (78%) of the free base which was treated with
1 N HCl to give a white solid hydrochloride salt: 1H NMR
(DMSO-d6) δ 8.69 (d, 1H, J ) 4.6 Hz), 8.29 (dt, 1H, J ) 1.6,
7.9 Hz), 7.87 (d, 1H, J ) 8.0 Hz), 7.76-7.80 (m, 2H), 7.52 (br
d, 1H), 7.44 (br d, 1H), 7.27-7.31 (m, 2H), 7.21 (d, 1H, J ) 1.1
Hz), 7.19 (d, 1H, J ) 1.1 Hz), 7.11 (t, 1H, J ) 7.3 Hz), 5.43
(dd, 1H, J ) 8.0, 15.2 Hz). Anal. (C23H18ClN3O3F2‚HCl) C,
H, N, Cl.
N-[2-(8-Ch lor o-10,11-d ih yd r od iben z[b,f][1,4]oxa zep in -
10-yl)-2-oxoeth yl]-4-p yr id in ep r op a n a m id e, Mon oh yd r o-
ch lor id e (11). To a stirring solution of 8 (0.77 g, 2.7 mmol),
9 (0.50 g, 2.7 mmol), and TEA (0.8 mL, 5.8 mmol) in 10 mL of
dimethylformamide (DMF) at 5 °C was added 1-(3-(dimethyl-
amino)propyl)-3-ethylcarbodiimide hydrochloride (0.56 g, 2.9
mmol). After stirring at room temperature for 60 h, the
reaction was partitioned between saturated NaHCO3 solution
(100 mL) and EtOAc (75 mL) and filtered. The filtrate was
separated, and the aqueous layer was extracted with EtOAc
(2 × 50 mL). The combined organic extracts were washed with
saturated NaHCO3 solution (2 × 100 mL), H2O (100 mL), and
brine (100 mL) and worked up in the routine manner. The
crude product was purified by chromatography. The purified
product was taken up in EtOAc and treated with HCl in
ethanol. The product was collected by filtration and dried in
vacuo to yield 0.23 g (19%) of a white solid: 1H NMR (DMSO-
d6) δ 8.74 (d, 2H, J ) 6.6 Hz), 8.25 (t, 1H, J ) 5.4 Hz), 7.84 (d,
2H, J ) 6.6 Hz), 7.49-7.51 (m, 1H), 7.41 (d, 1H, J ) 8.5 Hz),
7.17-7.30 (m, 3H), 7.11 (dt, 1H, J ) 0.9, 7.7 Hz), 3.03 (t, 2H,
N-[2-(8-Ch lor o-10,11-d ih yd r od iben z[b,f][1,4]oxa zep in -
10-yl)-2-oxoet h yl]-3-[(2-fu r a n ylm et h yl)t h io]p r op a n a m -
id e (13). Trimethylaluminum (2.0 M in toluene; 4.6 mL) was
added dropwise to a stirring solution of methyl 3-[(2-furanyl-
methyl)thio]propanoate (0.75 g, 3.7 mmol) and 8 (1.00 g, 3.5
mmol) in toluene (30 mL) at room temperature. After stirring
for 5 h, the reaction was quenched with methanol (14 mL).
After concentrating in vacuo, the resulting orange residue was
partitioned between chloroform (50 mL) and 1 N NaOH (50
mL). The aqueous layer was extracted with chloroform (50
mL). The combined chloroform extracts were washed with 1
N NaOH (50 mL), 1 N HCl (2 × 50 mL), and brine (50 mL)
and worked up in the usual manner. The crude product was
purified by chromatography followed by recrystallization from
cyclohexane/EtOAc to yield 0.63 g (40%) of a tan solid: mp
90-95 °C. Anal. (C23H21ClN2O4S) C, H, N, Cl, S.
N-[2-(8-Ch lor o-10,11-d ih yd r od iben z[b,f][1,4]oxa zep in -
10-yl)-2-oxoeth yl]-3-(eth ylth io)p r op a n a m id e (14). To a
stirring solution of 8 (1.50 g, 5.2 mmol) and triethylamine (0.84

612 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 2
Notes
mL, 5.7 mmol) in DCM (40 mL) at 5 °C was added dropwise
3-(ethylthio)propanoyl chloride (0.87 g, 5.9 mmol) in DCM (10
mL). After stirring for 3 h at ambient temperature, the
reaction was diluted with DCM (50 mL) and washed with 50
mL each of 1 N HCl, saturated NaHCO3 solution, and brine.
The organic layer was worked up in the usual manner to yield
1.90 g (90%): mp 148-151 °C.
3.07 (q, 2H, J ) 7.5 Hz), 2.84 (t, 2H, J ) 7.4 Hz); mp 140-142
°C. Anal. (C20H21ClN2O5S) C, H, N, S.
8-Ch lor o-N -[4-[(2-fu r a n ylm e t h yl)t h io]-2-oxob u t yl]-
diben z[b,f][1,4]oxazepin e-10(11H)-car boxam ide (21). Con-
ditions described for 20 repeated on a 2.2 mmol scale to yield
21, a colorless oil: 1H NMR (DMSO-d6) δ 7.57 (dd, 1H, J )
0.9, 1.8 Hz), 7.47 (d, 1H, J ) 2.4 Hz), 7.32-7.41 (m, 2H), 7.15-
7.27 (m, 3H), 7.05 (dt, 1H, J ) 1.3, 7.4 Hz), 6.72 (t, 1H, J )
5.6), 6.37 (dd, 1H, J ) 1.9, 3.2 Hz), 6.24 (dd, 1H, J ) 0.8, 3.2
Hz), 4.83 (s, 2H), 3.76 (d, 2H, J ) 5.5 Hz), 3.74 (s, 2H), 2.50-
2.64 (m, 4H). Anal. (C23H21ClN2O4S) H, N, Cl, S; C: calcd,
60.46; found, 59.94.
Mou se Wr ith in g Assa y.1 The phenylbenzoquinone (PBQ)
writhing assay in mouse was used to evaluate the antinoci-
ceptive activity.1
P GE 2 An t a gon ism Assa y Ut ilizin g t h e Gu in ea P ig
Ileu m .1 PGE2 antagonism was assessed in PGE2-stimulated
guinea pig ileum muscle strip assay.1
N-[2-(8-Ch lor o-10,11-d ih yd r od iben z[b,f][1,4]oxa zep in -
10-yl)-2-oxoeth yl]-3-(eth ylsu lfon yl)p r op a n a m id e (15). To
a stirring solution of 14 (1.50 g, 3.7 mmol) in acetic acid (11
mL) at 58 °C was added dropwise H2O2 (30 wt % in water;
1.19 mL). After 1 h, the temperature of the oil bath was raised
to 72 °C, and additional H2O2 (0.8 mL) was added. After 3 h,
the reaction was concentrated. The residue was taken up in
EtOAc (50 mL) and washed with saturated NaHCO3 solution.
The aqueous wash was extracted with EtOAc (50 mL), and
the organic extracts were combined and washed with 50 mL
each of saturated NaHCO3 solution. The organic layers were
worked up in the routine manner and chromatographed. The
product was recrystallized from ethanol (3A) to yield 1.30 g
(80%) of shiny white crystals: 1H NMR (DMSO-d6) δ 8.36 (t,
1H, J ) 5.7 Hz), 7.83 (br s, 1H), 7.49-7.51 (m, 1H), 7.41 (d,
1H, J ) 8.7 Hz), 7.26-7.29 (m, 2H), 7.19 (d, 1H, J ) 7.4 Hz),
7.09 (t, 1H, J ) 7.4 Hz), 3.21 (t, 2H, J ) 7.5 Hz), 3.05 (q, 2H,
J ) 7.3 Hz), 2.56 (t, 2H, J ) 7.5 Hz), 1.17 (t, 2H, J ) 7.5 Hz);
mp 167-168 °C. Anal. (C20H21ClN2O5S) C, H, N, Cl, S.
Eth yl [[(8-Ch lor o-10,11-dih ydr odiben z[b,f][1,4]oxaepin -
10-yl)ca r bon yl]a m in o]a ceta te (16). After 5 (5.00 g, 21.6
mmol) and ethyl isocyanoacetate (3.07 g, 27.1 mmol) in 50 mL
of toluene were heated at reflux for 4 h, additional ethyl
isocyanoacetate (1.00 g, 7.7 mmol) was added. The reaction
mixture was heated for 16 h. The reaction was worked up in
the usual manner to give 7.12 g (91%) of a yellowish oil which
solidified on standing.
Ack n ow led gm en t. 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 me-
dicinal chemistry and pharmacology; Dr. Richard Bit-
man for his assistance in the statistics calculations of
the bioassays; and Dr. Michael F. Rafferty for his
support of this project. E.A.H. would particularly like
to thank Dr. Barnett S. Pitzele for his many helpful
ideas and thoughts on this project.
[[8-Ch lor o-10,11-d ih yd r od iben z[b,f][1,4]oxa ep in -10-yl)-
ca r bon yl]a m in o]a cetic Acid (17). After stirring for 16 h,
a solution of 16 (6.77 g, 18.8 mmol) in methanol (350 mL) and
1 N NaOH (25 mL) was concentrated. The residue taken up
in water (300 mL). The solution was washed with Et2O (2 ×
300 mL), acidified with 1 N HCl, and extracted with Et2O (2
× 350 mL). The combined etheral extracts were worked up
in the usual manner to yield 6.29 g (100%).
2-[[(8-Ch lor o-10,11-d ih yd r od ib en z[b,f][1,4]oxa zep in -
10-yl)ca r b on yl]a m in o]-N-m et h oxy-N-m et h yla cet a m id e
(18). To a stirring solution of 1,1′-carbonyldiimidazole (2.12
g, 14.3 mmol) in THF (60 mL) at 5 °C was added dropwise 17
(4.00 g, 13.7 mmol) in THF (20 mL). After stirring for 1 h at
5 °C and 4 h at room temperature, TEA (1.9 mL, 13.7 mmol)
and N,O-dimethylhydroxylamine hydrochloride (1.30 g, 13.3
mmol) were added. After 48 h, the reaction was concentrated
and worked up in the usual manner to yield 3.20 g (71%).
8-Ch lor o-N-(2-oxo-3-bu ten yl)d iben z[b,f][1,4]oxa zep in e-
10(11H)-ca r boxa m id e (19). To a stirring solution of 18 (3.2
g, 8.5 mmol) in THF (35 mL) at -70 °C was added dropwise a
solution of vinylmagnesium bromide (1.0 M THF, 28 mL) in
15 mL of THF. The ice bath was removed, and the reaction
mixture was stirred to room temperature for 1 h. The reaction
was worked up in the usual manner to yield 2.25 g (77%) of a
colorless glass.
8-Ch lor o-N-[4-(eth ylth io)-2-oxobu tyl]d iben z[b,f][1,4]-
oxa zep in e-10(11H)-ca r boxa m id e (20). A solution of 19
(1.00 g, 2.9 mmol), ethanethiol (0.23 mL, 3.1 mmol), piperidine
(0.092 mL), and N-benzyltrimethylammonium hydroxide (0.092
mL) in 20 mL of DCM:MeOH (4:1) was stirred for 5 h. The
reaction was worked up in the usual manner to yield 0.38 g
(32%) of a colorless oil.
8-Ch lor o-N-[4-(et h ylsu lfon yl)-2-oxob u t yl]d ib en z[b,f]-
[1,4]oxa zep in e-10(11H)-ca r boxa m id e (22). To a stirring
solution of 20 (0.38 g, 0.9 mmol) in HOAc (3 mL) at 60 °C was
added 30% H2O2 (0.3 mL). After 1 h, an additional 0.1 mL of
H2O2 was added, and the the reaction was heated for additional
1 h. The reaction mixture was concentrated and worked up
in the usual manner to give 0.16 g (39%) of a white solid: 1H
NMR (DMSO-d6) δ 7.47 (d, 1H, J ) 2.5 Hz), 7.15-7.42 (m,
5H), 7.06 (dt, 1H, J ) 1.1, 7.4 Hz), 6.79 (t, 1H, J ) 5.4 Hz),
4.84 (s, 2H), 3.83 (d, 2H, J ) 5.5 Hz), 3.23 (t, 2H, J ) 7.5 Hz),
Refer en ces
(1) Hallinan, E. A.; Hagen, T. J .; Husa, R. K.; Tsymbalov, S.; Rao,
S. N.; vanHoeck, J .-P.; Rafferty, M. F.; Stapelfeld, A.; Savage,
M. A.; Reichman, M. N-Substituted Dibenzoxazepines as Anal-
gesic PGE2 Antagonists. J . Med. Chem. 1993, 36, 3293-3299.
(2) Malmberg, A. B.; Rafferty, M. F.; Yaksh, T. L. Antinociceptive
Effect of Spinally Delivered Prostaglandin E Receptor Antago-
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