Synthesis and biological activity of various derivatives of a novel class of potent, selective, and orally active prostaglandin D2 receptor antagonists. 2. 6,6-Dimethylbicyclo(3.1.1)heptane Derivatives


Mitsumori, S.; Tsuri, T.; Honma, T.; Hiramatsu, Y.; Okada, T.; Hashizume, H.; Kida, S.; Inagaki, M.; Arimura, A.; Yasui, K.; Asanuma, F.; Kishino, J.; Ohtani, M.

Journal of Medicinal Chemistry 46(12): 2446-2455

2003


In an earlier paper, we reported that novel prostaglandin D2 (PGD2) receptor antagonists having the bicyclo(2.2.1)heptane ring system as a prostaglandin skeleton were a potent new class of antiallergic agents and suppressed various allergic inflammatory responses such as those observed in conjunctivitis and asthma models. In the present study, we synthesized PGD2 receptor antagonists having the 6,6-dimethylbicyclo(3.1.1)heptane ring system. These derivatives have the amide moiety, in contrast to those with the bicyclo(2.2.1)heptane ring system, which have the sulfonamide group. The derivatives having the 6,6-dimethylbicyclo(3.1.1)heptane ring also exhibited strong activity in PGD2 receptor binding and cAMP formation assays. In in vivo assays such as allergic rhinitis, conjunctivitis, and asthma models, these series of derivatives showed excellent pharmacological profiles. In particular, compound 45 also effectively suppressed eosinophil infiltration in allergic rhinitis and asthma models. This compound (S-5751) is now being developed as a promising alternative antiallergic drug candidate.

2446
J.
Med.
Chem.
2003,
46,
2446-2455
Synthesis
and
Biological
Activity
of
Various
Derivatives
of
a
Novel
Class
of
Potent,
Selective,
and
Orally
Active
Prostaglandin
D2
Receptor
Antagonists.
2.
6,6-Dimethylbicyclo[3.1.1]heptane
Derivatives
Susumu
Mitsumori,
Tatsuo
Tsuri,*
Tsunetoshi
Honma,
Yoshiharu
Hiramatsu,
Toshihiko
Okada,
Hiroshi
Hashizume,
Shiro
Kida,
Masanao
Inagaki,
Akinori
Arimura,
Kiyoshi
Yasui,
Fujio
Asanuma,
Junji
Kishino,
and
Mitsuaki
Ohtani
Shionogi
Research
Laboratories,
Shionogi
&
Co.,
Ltd.,
12-4,
Sagisu
5-chome,
Fukushima-ku,
Osaka
553-0002,
Japan
Received
November
14,
2002
In
an
earlier
paper,
we
reported
that
novel
prostaglandin
D2
(PGD2)
receptor
antagonists
having
the
bicyclo[2.2.1]heptane
ring
system
as
a
prostaglandin
skeleton
were
a
potent
new
class
of
antiallergic
agents
and
suppressed
various
allergic
inflammatory
responses
such
as
those
observed
in
conjunctivitis
and
asthma
models.
In
the
present
study,
we
synthesized
PGD
2
receptor
antagonists
having
the
6,6-dimethylbicyclo[3.1.1]heptane
ring
system.
These
deriva-
tives
have
the
amide
moiety,
in
contrast
to
those
with
the
bicyclo[2.2.1]heptane
ring
system,
which
have
the
sulfonamide
group.
The
derivatives
having
the
6,6-dimethylbicyclo[3.1.1]heptane
ring
also
exhibited
strong
activity
in
PGD
2
receptor
binding
and
cAMP
formation
assays.
In
in
vivo
assays
such
as
allergic
rhinitis,
conjunctivitis,
and
asthma
models,
these
series
of
derivatives
showed
excellent
pharmacological
profiles.
In
particular,
compound
45
also
effectively
suppressed
eosinophil
infiltration
in
allergic
rhinitis
and
asthma
models.
This
compound
(45,
S-5751)
is
now
being
developed
as
a
promising
alternative
antiallergic
drug
candidate.
Introduction
In
an
earlier
paper,
1
we
reported
that
novel
prostag-
landin
D2
(PGD
2
)
receptor
antagonists
having
the
bicyclo[2.2.1]heptane
ring
system
as
a
prostaglandin
skeleton
were
synthesized
as
a
potential
new
class
of
antiallergic
agents.
These
compounds
exhibited
selective
antagonism
of
the
PGD
2
receptor
in
radioligand
binding
and
cAMP
formation
assays
with
IC
5
o
values
below
50
nM
and
exhibited
much
less
antagonism
of
TXA
2
and
PGI
2
receptors.
Furthermore,
they
suppressed
various
allergic
inflammatory
responses
such
as
those
in
rhini-
tis,
conjunctivitis,
and
asthma
models.
Clearly,
PGD
2
plays
an
important
role
in
the
pathogenesis
of
allergic
diseases,
1
'
2
and
support
for
this
comes
from
a
study
of
DP
knockout
mice
recently
reported
by
Narumiya
et
al.
3
We
have
been
trying
to
develop
PGD
2
receptor
an-
tagonists
having
other
prostaglandin
skeletons
in
order
to
enhance
the
biological
activities.
As
described
in
an
earlier
paper,la
the
bicyclo[2.2.1]heptane
ring
system
was
derived
from
a
TXA
2
receptor
antagonist.
4
At
that
time,
we
obtained
two
different
types
of
prostaglandin
(PG)
skeletons,
both
of
which
exhibited
strong
TXA2
antagonism.
One
(S-1452)
is
the
bicyclo[2.2.1]heptane
ring
system,
and
the
other
(S-6877)
is
the
6,6-dimethyl-
bicyclof3.1.11heptane
ring
systems
(Figure
1).
In
the
case
of
the
bicyclo[2.2.1]heptane
ring
system,
compounds
having
the
enantiomer
skeleton
of
S-1452,
which
is
a
strong
TXA
2
antagonist,
exhibited
strong
PGD
2
inhibi-
tory
activities.
This
suggested
that
6,6-dimethylbicyclo-
f3.1.11heptane
ring
derivatives
having
the
enantiomer
structure
of
S-6877,
which
also
displays
strong
TXA
2
*
To
whom
correspondence
should
be
addressed.
Phone:
+81-6-
6458-5861.
Fax:
+81-6-6458-0987.
E-mail:
tatsuo.tsuri@shionogi.co.jp.
TXA
2
antagonist
PGD
2
antagonist
[2.2.1]
CO
2
H
MeO
CO
2
H
NHSO
2
/
NHS0
2
S-1452
1
[3.1
]
CO2H
CO
2
H
N
HS0
2
Me
S-6877
/
NH
Ar
Figure
1.
Relation
between
TXA
2
and
PGD
2
antagonists.
antagonism,
would
have
PGD
2
inhibitory
activity.
How-
ever,
the
enantiomer
skeleton
of
S-6877
was
unsuitable
for
an
SAR,
study
and
as
a
drug
candidate
because
of
its
synthetic
difficulty.
We
have
therefore
tried
to
investigate
types
of
the
6,6-dimethylbicyclof3.1.11heptane
ring
system
that
are
regio-
and
stereoisomeric
to
S-6877
to
fi
nd
a
new
seed
compound
for
PGD
2
antagonists.
Examination
of
the
three
types
of
regio-
and
stereoiso-
mers
having
the
sulfonamide
moiety
(2,
5,
and
6)
showed
that
compound
2
with
a
(1R,2R,3S,5S)-6,6-
dimethylbicyclof3.1.11heptane
ring
skeleton
exhibited
PGD
2
antagonist
activity
(Table
1).
Several
sulfona-
mides
with
this
stereo
structure
were
synthesized
as
done
in
the
SAR,
study
on
the
bicyclof2.2.11heptane
ring
system,
but
no
better
results
were
obtained.
However,
evaluation
of
compounds
having
the
amide
moiety
revealed
that
the
simple
compound
7
having
the
benzoyl
group
and
its
analogues
of
the
w
-chain
(8
and
9)
showed
strong
activity
especially
in
the
in
vivo
assay.
No
improvement
of
the
antagonistic
activity
was
noted
for
the
other
regio-
and
stereoisomers
having
the
amide
moiety
(10
and
11),
despite
the
conversion
of
the
sulfonamide.
We
therefore
initiated
further
SAR,
studies
of
the
(1R,
2R,
3S,
5S)-6,6-dimethylbicyclo[3.1.1]heptane
10.1021/jm0205189
CCC:
$25.00
©
2003
American
Chemical
Society
Published
on
Web
05/10/2003
6,6'-Dimethylbicyclo[3.1.1]heptane
Derivatives
Journal
of
Medicinal
Chemistry,
2003,
Vol.
46,
No.
12
2447
Table
1.
Inhibition
of
PGD
2
Receptor
Binding,
Biological
Activity
in
Human
Platelets,
and
Antigen
-Induced
Nasal
Blockage
in
Guinea
Pigs
CO
2
1-1
ICs
0
(1-00
in
vivo
b
DP
(rhinitis
model)
Compd
A
X
binding
cAMP
inhibn
at
1
mg/kg
(iv)
2
p
-biphenyl
1.2
0.53
nd'
3
-SO2-
4-(phenylazo)benzene
1.3
>1.0
4
-SO
2
-
2-dibenzofurane
0.78
>1.0
ncr
5
-SO
2
-
p
-biphenyl
1.3
>1.0
6
p
-biphenyl
1.3
>1.0
nd'
7
-CO-
Ph
5.2
0.36
52+5'
8
-CO-
p
-biphenyl
0.047
0.47
308
9
-CO-
4-(phenylazo)benzene
0.54
0.38
60
10
b
10
-CO-
p
-biphenyl
5.1
>1.0
11
.
1)
' (
-CO-
p-biphenvl
3.6
>1.0
PGD
2
receptor
(DP)
assay.'
Inhibition
of
[
3
H]PGD
2
specific
binding
to
human
platelet
membranes
1
'
and
cAMP
formation
evoked
by
PGD
2
in
human
platelets.
25
IC
50
represents
the
mean
value
of
two
or
three
measurements.
b
Inhibition
of
antigen
-
induced
increase
in
intranasal
pressure
in
actively
sensitized
guinea
pigs.
Compounds
were
administered
iv
10
min
before
the
antigen
challenge.
Values
represent
the
mean
±
SEM.
Not
done.
d
Significantly
different
from
each
control;
p
<
0.01
(Student's
t
-test).
ring
system
having
the
amide
moiety.
The
results
revealed
that
the
compound
with
the
benzothiophene-
3-carbonyl
moiety
as
the
w
-chain
exhibited
fairly
strong
antagonistic
activity
against
the
PGD
2
receptor.
In
this
paper,
we
describe
the
synthesis
and
development
of
a
new
class
of
PGD
2
receptor
antagonists
with
the
6,6-
dimethylbicyclo[3.1.1]heptane
ring
system
having
the
benzothiophene-3-carbonyl
moiety.
Synthetic
Chemistry
(
1R
,2R
,3S,5S)-(5Z)-7-(2
-Amino
-6
,6
-dime
thylbicyclo-
[3.1.1]hept-3-yl)hept-5-enoic
acid
methyl
ester
(48)
was
prepared
by
methods
described
in
the
literature.
5
a
Most
of
the
target
compounds
were
synthesized
in
the
fol-
lowing
manner.
Coupling
of
amine
48
with
the
readily
prepared
sulfonyl
and
acyl
chloride
or
carboxylic
acid
by
using
Et
3
N
or
water-soluble
carbodiimide
(WSCD)
produced
the
desired
ester
in
good
yield.
6
Hydrolysis
of
the
corresponding
ester
using
aqueous
potassium
hy-
droxide
in
methanol
produced
the
target
molecule
in
almost
quantitative
yield
(Scheme
1).
Other
regio-
and
Scheme
la
a,b
NH2
48
,b
NHS0
2
-R
1
2-4
CO
2
H
NH
O
R
1
7-9,
12-26,
30-36,
39-46
Reagents:
(a)
R
1
CO
2
H,
WSCD,
HOBt,
THF;
or
R
1
C0C1,
Et
3
N;
(b)
KOH;
(c)
R
1
S0
2
C1,
Et
3
N.
Scheme
2a
Br
-h..
1,.„-0O2
Me
a,
b
Me0-
I L
S
.
S
31a:
4-
32a:
5-
R
3
,
CO2R2
c,
b
R
3
R
4
NH
2
R
2
=
Me
or
Et
CO
2
H
CO
2
H
R
4
33a:
R
3
=
Ph,
R
4
=
Me
34a:
R
3
,
R
4
=
-(CH
2
)
4
.-
35a:
R
3
=
H,
R
4
=
Me
36a:
R
3
=
H,
R
4
=
Ph
a
Reagents:
(a)
(1)
NaOMe,
NaI,
CuO,
Me0H,
(2)
CH
2
N
2
,
Et
2
O;
(b)
NaOH;
(c)
(1)
NaNO
2
,
HC1,
(2)
1
-
13P02.
Scheme
3a
R
5
a,b
SH
41a:
R
5
=
2-CO
2
H
40b:
=
H
44a:
R
5
=
4-F
41b:
R
5
=
7-CO
2
H
41
45a:
R
5
=
4
-Br
c
44b:
R
5
=
5-F
46a:
R
5
=
3
-Br
45b:
R
5
=
5
-Br
46b:
R
5
=
6
-Br
CO
2
H
CO
2
H
s
-
40c:
R
5
=
H
g,h
40
44c:
R
5
-
5
F
g,h
44
HO-
45c:
R
5
=
5
-Br
46c:
R
5
=
6
-Br
45d:
R
5
-
5
g,h
45
46d:
R
5
-
6
-
46
a
Reagents:
(a)
BrCH
2
CH(OMe)
2
,
NaOMe;
(b)
PPA,
PhCl;
(c)
(1)
AcC1,
SnC1
4
,
(2)
Na0C1
or
NaOBr;
(d)
NaOMe,
CuBr,
Cu;
(e)
CH2N2;
(1
.
)
BBr3;
(g)
48,
WSCD,
HOBt,
THF;
(h)
KOH.
stereoisomers
(5,
6,
10,
and
11)
were
also
synthesized,
as
done
for
the
(1R,2R,3S,5S)-isomer.
5
The
substituted
thiophene
or
benzothiophene
carboxylic
acids
were
prepared
from
the
appropriately
substituted
compounds
as
shown
in
Schemes
2-4.
Briefly,
reaction
of
the
substituted
thiophene
with
NaNO
2
or
NaOMe,
deami-
nation
7
or
methoxy
substitution,
8
followed
by
suitable
treatment
afforded
the
corresponding
3
-substituted
2448
Journal
of
Medicinal
Chemistry,
2003,
Vol.
46,
No.
12
Mitsumori
et
al.
Scheme
4a
0
2
N
dE
0
2
N
a
47a
0
R
6
47c:
R
6
=
NO2,
R
7
=
CH
2
OH
r
47d:
R
6
=
NHBoc,
R
7
=
CH
2
OH
g,►f
c
1
-0-
e
47e:
R
6
=
NHBoc,
R
7
=
CO
2
H
47
a
Reagents:
(a)
H
2
0
2
,
HCO
2
H;
(b)
(1)
dioxane,
reflux,
(2)
p-TsOH,
H
2
O;
(c)
(1)
NaOC1,
TEMPO,
(2)
H202,
NaC1O
2
;
(d)
(1)
SnC1
2
,
EtOH,
H
2
O,
(2)
Boc
2
O,
K2CO3;
(e)
48,
WSCD,
HOBt;
(0
aqueous
NaOH;
(g)
(1)
TFA,
(2)
MsC1,
Et
3
N.
47b
carboxylic
acids
such
as
31a
-36a
(Scheme
2).
Ben-
zothiophene
carboxylic
acid,
which
is
an
important
synthon
because
of
expression
of
the
fairly
good
inhibi-
tory
activity
as
the
w
-chain,
can
be
synthesized
from
the
substituted
benzenethiol
by
two
synthetic
routes.
One
is
the
cyclization
of
(2,2-dimethoxyethylsulfanyl)-
benzene
in
the
presence
of
polyphosphoric
acid
(PPA),
which
readily
gave
the
desired
benzothiophene
in
good
yield.
9
Friedel-Crafts
acylation
of
benzothiophene
de-
rivatives
using
SnC1
4
followed
by
oxidation
with
Na0C1
1
°
produced
the
target
molecules
(40c,
44c,
45d,
and
46d)
11
in
moderate
yields
(Scheme
3).
47e
was
prepared
by
the
other
method:
tandem
[2,31/[3,31
thio-Claisen
rearrangement
12
of
propargyl
sulfoxide
and
cyclization
to
hydroxymethylbenzothiophene
(Scheme
4).
Propar-
gylphenylsulfoxide
(47b)
prepared
by
the
oxidation
of
47a
with
H202/HCO2H
gave
the
3-hydroxymethylben-
zothiophene
derivative
47c
on
application
of
heat
in
1,4-
dioxane
and
successive
treatment
with
p-Ts0H.
12
c
The
obtained
3-hydroxymethylbenzothiophene
(47d)
was
oxidized
to
the
corresponding
carboxylic
acid
in
two
steps;
that
is,
the
hydroxymethyl
substituent
was
changed
to
an
aldehyde
using
the
2,2,6,6-tetrameth-
ylpiperidine
1
-oxide
(TEMPO)
catalyst,
13
and
the
result-
ing
aldehyde
was
further
oxidized
to
the
desired
ben-
zothiophene
carboxylic
acid
by
a
general
method.
14
This
synthetic
route
involving
oxidation
steps
can
be
used
for
industrial
-scale
synthesis
for
its
safety
and
efficiency.
The
modifications
of
the
a
-chain
at
the
prostaglandin
skeleton
containing
methanesulfonamide
and
tetrazole
moieties
are
presented
in
Scheme
5.
Compound
20
was
reacted
with
C1CO
2
Et
to
give
the
corresponding
mixed
anhydride.
Methanesulfonamide
or
ammonia
was
coupled
with
this
acyl
chloride
to
afford
27
15
or
49,
respectively.
Compound
49
was
further
treated
with
thionyl
choride
to
give
the
corresponding
nitrile,
16
which
was
converted
into
the
tetrazole
derivative
by
reaction
with
TMSN
3
.
17
5-Ketoheptanoic
acid
derivative
29
was
synthesized
from
29a
protected
by
the
2,4-dimethoxybenzyl
moiety.
18
Swern
oxidation
of
29a
gave
an
aldehyde
29b,
which
was
successively
oxidized
by
Jones
reagent,
19
followed
by
coupling
with
the
corresponding
a
-chain
Grignard
reagent
to
give
the
N
-protected
5-keto
derivative
29c.
Deprotection
of
29c
occurred
smoothly
in
the
presence
of
m-dimethoxybenzene
by
treatment
of
TFA
to
give
29
(Scheme
6).
Scheme
5a
NH
j
27:
R
8
=
CONHSO
2
Me
20:
R
8
=
CO
2
H
7
a,
c
a,
b
49:
R
8
=
CONH
2
d
50:
R
8
=
CN
e
L
N
-N
28:
R
8
=
----
N
,
n
N
H
a
Reagents:
(a)
C1CO
2
Et,
Et
3
N;
(b)
aqueous
NH
3
;
(c)
MeS02N112,
DBU;
(d)
SOC1
2
;
(e)
TMSN
3
,
Bu
2
SnO.
Scheme
6a
OH
O
29a
C
6
H
3
-(2,4-0Me)
U
CO2H
NH
I
j
29
's
s'
\
CHO
C
6
H
3
-(2,4-0Me)
a
0
29b
j
b
O
29c
CO
2
H
C
6
H
3
-(2,4-OMe)
a
Reagents:
(a)
(1)
(C0C1)
2
,
DMSO
then
Et
3
N;
(b) (1)
TBDMSO-
(CH2)5MgBr,
(2)
Jones
oxidation;
(c)
TFA,
m-dimethoxybenzene.
Biological
Results
and
Discussion
As
reported
before,
novel
PGD
2
receptor
antagonists
having
the
bicyclo[2.2.1]heptane
ring
system
showed
promise
as
a
potential
new
class
of
antiallergic
agents.
In
the
present
study,
we
tried
to
synthesize
another
series
ofPGD
2
antagonists
having
the
6,6-dimethylbicyclo-
[3.1.1]heptane
ring
system
as
a
PG
skeleton.
Study
of
several
isomers
of
the
6,6-dimethylbicyclo[3.1.1]heptane
ring
system
as
a
PG
skeleton
revealed
that
only
the
(1R,2R,
3S,
5S)-6,6-dimethylbicyclo[3.1.1]heptane
deriva-
tive
exhibited
moderate
antagonistic
activity
in
the
cAMP
assay.
At
first,
many
kinds
of
sulfonamide
derivatives
(2-4)
were
synthesized
and
studied,
as
was
done
for
the
bicyclo[2.2.1]heptane
ring
system,la
but
similar
modifications
of
the
w
-chain,
which
led
to
strong
activity
in
the
case
of
the
bicyclo[2.2.1]heptane
ring
system,
did
not
improve
the
inhibitory
activity
(Table
1).
We
next
tried
to
fi
nd
other
types
of
w
-chains
having
the
amide
instead
of
the
sulfonamide
moiety.
To
our
surprise,
it
turned
out
that
the
very
simple
amide
7
having
the
benzoyl
group
exhibited
fairly
strong
activity
in
the
in
vivo
assay
rather
than
the
sulfonamide
ones,
which
exhibited
some
activity
in
vitro.
Other
amide
derivatives
(8
and
9)
also
had
fairly
good
activities
similar
to
the
activity
of
7.
Strong
activity
was
exhibited
by
compound
9
in
the
in
vivo
assay,
but
the
azo
structure
is
thought
to
be
unsuitable
for
a
drug
candi-
date
because
of
the
possibility
of
pharmacological
in-
stability
and
toxicology.
Thus,
benzoyl
derivative
8,
which
is
thought
to
be
pharmacologically
stable
and
6,6'-Dimethylbicyclo[3.1.1]heptane
Derivatives
Journal
of
Medicinal
Chemistry,
2003,
Vol.
46,
No.
12
2449
Table
2.
Inhibition
of
PGD
2
Receptor
Binding,
Biological
Activity
in
Human
Platelets,
and
Antigen
-Induced
Nasal
Blockage
in
Guinea
Pigs
CO
2
H
NH
c
5
0
(
m
compd
DP
binding
cAMP
12
13
14
15
4
-NO2
-C6144
4-MeO-C
6
H
4
2-MeO-C
6
H
4
4.4
3.9
4.6
3.4
0.11
0.19
0.32
0.24
16
\/
0
2.1
0.17
17
'hexyl
>10
>1.0
18
benzyl
>10
>1.0
19
2-thienyl
3.3
0.015
20
3-thienyl
1.6
0.038
21
3-furfuryl
0.56
0.017
22
2-pyrrolyl
nd
b
0.037
23
N-methyl-3-pyrrolyl
0.42
0.11
24
3-pyridyl
0.33
nd
b
25
5-thiazolyl
>10
0.50
26
2-naphthyl
nd
b
0.073
PGD
2
receptor
(DP)
assay.'
Inhibition
of
[
3
H]PGD
2
specific
binding
to
human
platelet
membranes
4
'
and
cAMP
formation
evoked
by
PGD
2
in
human
platelets.
25
IC
H
represents
the
mean
value
of
two
or
three
measurements.
b
Not
done.
fl
exible
for
modification,
was
selected
for
the
lead
compound
to
be
further
modified.
Study
of
the
biological
activities
of
the
compounds
by
introducing
various
kinds
of
substituents
to
the
phenyl
ring
and
other
types
of
aromatics
or
alkyl
moieties
(12-
26)
showed
that
derivatives
replacing
the
phenyl
group
with
other
aromatic
rings,
such
as
2-
or
3-thienyl,
3-furfuryl,
and
2-pyrrolyl
(19-22),
gave
fairly
good
activity
in
the
cAMP
assay
(Table
2).
In
particular,
compound
20,
having
the
3-thienyl
group
as
a
benzene
ring
equivalent,
effectively
inhibited
the
antigen
-
induced
increase
in
intranasal
pressure
in
actively
sensitized
guinea
pigs,
with
the
percent
inhibition
at
1
mg/kg
(iv)
being
77%
(p
<
0.01).
On
the
other
hand,
compound
19
having
the
2-thienyl
group
exhibited
weak
activity
in
vivo,
with
the
percent
inhibition
at
1
mg/kg
(iv)
being
38%.
Thus,
further
evaluation
was
performed
with
20
as
the
next
lead
compound
to
obtain
more
favorable
derivatives
for
drug
candidates.
At
this
stage,
a
-chain
modification
was
performed
for
compound
20
having
the
3-thienyl
group
as
the
co
-chain
as
shown
in
Table
3.
However,
these
transformations
dramatically
decreased
the
inhibitory
activity
in
com-
Table
3.
Inhibition
of
PGD
2
Receptor
Binding
and
Biological
Activity
in
Human
Platelets
NH
O
s
10
50
(1M)'
compd
DP
Z
binding
cAMP
27
'''
'
'=CONHS0
2
1VIe
6.0
0.41
28
'N
nd
b
0.093
HN
-
N
29
lCO2H
>10
>1.0
PGD
2
receptor
(DP)
assay.'
Inhibition
of
[
3
H]PGD
2
specific
binding
to
human
platelet
membranes
4
c
and
cAMP
formation
evoked
by
PGD
2
in
human
platelets.
25
IC
50
represents
the
mean
value
of
two
or
three
measurements.
b
Not
done.
parison
with
the
normal
w
-chain
except
for
28,
which
has
a
tetrazole
moiety
as
the
bioisoster
of
the
carboxylic
acid
group.
This
suggested
that
the
spatial
position
and
acidity
of
the
carboxylic
acid
are
very
important
for
the
inhibitory
activity
(27-29)
and
the
normal
type
of
w
-chain,
the
heptenoic
acid
structure,
is
the
most
suitable
for
expression
of
the
biological
activity.
Methylation
of
the
amide
moiety
of
compounds
7
and
20
significantly
diminished
the
activity
(37
and
38),
indicating
that
the
acidic
proton
of
the
amide
moiety
played
an
important
role
in
the
PGD
2
inhibitory
activity
in
the
case
of
the
6,6-dimethylbicyclo[3.1.1]heptane
ring
system
as
well
as
the
bicyclo[2.2.1]heptane
derivativesia
,2
°
and
the
introduction
of
methyl,
methoxy,
and
phenyl
groups
at
the
5
-position
in
the
thiophene
moiety
(32-
36)
tended
to
enhance
the
activity
in
comparison
with
other
transformations
(Table
4).
In
our
previous
report,la
we
suggested
that
a
rigid
and
planar
conformation
of
the
w
-chain
would
be
important
for
strong
PGD
2
an-
tagonism,
so
we
linked
each
aromatic
ring
of
36
as
a
benzothiopene
moiety
in
order
to
further
enhance
the
activity.
In
accord
with
our
expectation,
compound
40
showed
very
good
activity
in
in
vitro
and
in
vivo
assays
(Table
5).
The
substitution
patterns
of
the
benzothoiphene
derivaives
(39-41)
indicated
fairly
good
results,
but
replacement
of
the
sulfur
atom
of
the
benzothiophene
moiety
with
a
nitrogen
or
oxygen
atom
considerably
decreased
the
inhibitory
activity
(42
and
43).
Study
of
the
substitution
groups
in
the
ben-
zothiophene-3-carbonyl
derivative
showed
that
intro-
duction
of
a
hydroxyl
or
fl
uoro
substituent
at
the
5
-position
(44
and
45)
increased
the
inhibitory
activities
of
PGD
2
receptor
binding
and
cAMP
assay
about
1
or
more
orders
of
magnitude
over
the
compound
40.
This
suggests
the
existence
of
a
hydrogen
bonding
site
at
the
5
-position.
These
compounds
also
exhibited
strong
inhibitory
activity
in
vivo
at
3
mg/kg
(po),
and
we
now
had
two
highly
active
compounds
as
drug
candidates
against
allergic
diseases.
2450
Journal
of
Medicinal
Chemistry,
2003,
Vol.
46,
No.
12
Mitsumori
et
al.
Table
4.
Inhibition
of
PGD
2
Receptor
Binding,
Biological
Activity
in
Human
Platelets,
and
Antigen
-Induced
Nasal
Blockage
in
Guinea
Pigs
‘-
CO
2
H
N
-X
0
R
I
IC
50
titMia
DP
compd
X
R
1
binding
cAMP
30
H
2-Me-3-thienyl
0.18
0.02
31
H
4-Me0-3-thienyl
4.5
0.23
32
H
5-Me0-3-thienyl
0.52
0.056
33
H
5-Me-4-Ph-3-thienyl
0.59
0.074
34
H
0.15
0.035
35
H
5-Me-3-thienyl
0.013
0.025
36
H
5-Ph-3-thienyl
0.042
0.10
37
Me
Ph
>10
>1.0
38
Me
3-thienyl
>10
>1.0
PGD
2
receptor
(DP)
assay.'
Inhibition
of
[
3
H]PGD
2
specific
binding
to
human
platelet
membranes
4
'
and
cAMP
formation
evoked
by
PGD
2
in
human
platelets.
25
IC
H
represents
the
mean
value
of
two
or
three
measurements.
Table
5.
Inhibition
of
PGD
2
Receptor
Binding,
Biological
Activity
in
Human
Platelets,
and
Antigen
-Induced
Nasal
Blockage
in
Guinea
Pigs
NH
3
I II
R
5
5
CO
2
H
compd
position
Y
R
5
IC50
(ttAll)
DP
binding
cAMP
39
2
S
0.019
0.39
40
3
S
0.032
0.022
41
7
S
0.026
0.0056
42
3
NH
0.52
0.11
43
2
0
0.69
0.076
44
3
S
5-F
0.00042
0.0032
45
3
S
5
-OH
0.0019 0.0009
46
3
S
6
-OH
0.0022
0.018
47
3
S
5-NHMs
7.5
0.030
PGD
2
receptor
(DP)
assay.'
Inhibition
of
[
3
H]PGD
2
specific
binding
to
human
platelet
membranes
4
'
and
cAMP
formation
evoked
by
PGD
2
in
human
platelets.
25
IC
H
represents
the
mean
value
of
two
or
three
measurements.
b
Inhibition
of
antigen
-
induced
increase
in
intranasal
pressure
in
actively
sensitized
guinea
pigs.
Compounds
were
administrated
po
10
min
before
the
antigen
challenge.
Not
done.
d
Significantly
different
from
each
control;
p
<
0.01
(Student's
t
-test).
e
%
inhibition
at
10
mg/kg
(po).
1%
inhibition
at
3
mg/kg
(po).
g
Na
salt
was
used.
Further
evaluation
was
performed
for
the
selected
compounds
(20,
44,
and
45)
that
markedly
inhibited
PGD
2
-
and
antigen
-induced
increase
in
conjunctival
microvascular
permeability
(Table
6).
In
the
asthma
in
vivob
(rhinitis
model)
%
inhibition
ncic
82
±
70
±
6
e4e
ncr
ncic
ncic
(86
±
8'40
96
±
5d'
(64
±
7'
4
0
88
±
ncic
Table
6.
Effect
of
Orally
Administered
DP
Antagonists
on
PGD
2
-
and
Antigen
-Induced
Increase
in
Vascular
Permeability
in
Conjunctiva
and
Antigen
-Induced
Increase
in
Airway
Resistance
in
Guinea
Pigs
conjunctivitis
model
ED
50
(mg/kg)
compd
PGD2
antigen
asthma
model
%
inhibition
at
10
mg/kgb
antigen
20
3.5
9.5
15
±
21
44
3.5
8.9
69
±
9'
45
0.12
2.0
70
±
5'
Dose
required
to
inhibit
50%
of
conjunctival
microvascular
permeability
caused
by
topical
application
of
0.1%
PGD
2
or
antigen
in
guinea
pigs.
b
Inhibition
of
increase
in
specific
airway
resistance
by
antigen
inhalation
in
conscious
guinea
pigs.
All
antagonists
were
administered
po
1
h
before
the
challenge.
Values
represent
the
mean
±
SEM.
Significantly
different
from
each
control;
p
<
0.01
(Student's
t
-test).
model,
compounds
44
and
45
also
inhibited
antigen
-
induced
increase
in
specific
airway
resistance
at
10
mg/
kg
(po).
Since
PGD
2
has
been
thought
to
exert
a
contractile
response
of
airway
smooth
muscle
by
directly
acting
on
the
TXA
2
receptor
not
via
the
PGD
2
receptor,
21
there
is
a
possibility
that
the
antiasthmatic
activity
of
these
compounds
arises
from
their
TXA
2
receptor
an-
tagonistic
activity.
However,
this
possibility
was
ruled
out
by
our
fi
nding
that
none
of
these
three
compounds
had
a
significant
effect
on
the
bronchoconstriction
induced
by
intravenous
injection
of
U-46619,
a
TXA
2
mimic,
at
10
mg/kg
(po)
in
the
guinea
pig
model.lb
,21
b
Thus,
the
PGD
2
receptor
mediated
component
may
have
a
role
in
the
antigen
-induced
increase
in
specific
airway
resistance.
2
a
,3,22
We
also
evaluated
the
effect
of
com-
pound
45
on
antigen
-induced
eosinophil
infiltration
in
allergic
rhinitis
and
asthma
models.
Compound
45
effectively
reduced
the
increase
in
the
eosinophil
num-
ber
in
nasal
lavage
fl
uid
at
5
h
after
intranasal
antigen
challenge
in
actively
sensitized
guinea
pig2b,23
and
in
bronchoalveolar
lavage
fl
uid
at
72
h
after
inhalation
of
aerosol
antigen,
22
the
percent
inhibition
at
10
mg/kg
(po)
being
80%
(p
<
0.01)
and
43%
(p
<
0.05),
respectively.
Conclusion
We
have
described
here
novel
PGD
2
receptor
antago-
nists
containing
the
6,6-dimethylbicyclo[3.1.1]heptane
ring
system
with
the
characteristic
carbonylamino
group,
which
were
originally
synthesized
in
our
labo-
ratories.
Although
there
have
been
several
reports
on
the
contribution
of
PGD
2
to
the
pathogenesis
of
allergic
diseases
on
the
basis
of
local
production
of
PGD
2
after
antigen
challenge,
3,24
only
a
small
number
of
PGD
2
antagonists
have
been
synthesized,
even
as
experimen-
tal
agents.
In
this
study,
we
obtained
PGD
2
antagonists
that
were
effective
in
rhinitis,
conjunctive,
and
asthma
models
in
the
guinea
pig.
Among
them,
compound
45,
designated
as
S-5751,
was
considered
to
be
a
promising
candidate
for
development
as
a
drug
against
diseases
caused
by
excess
PGD
2
production.
It
is
now
being
developed
as
an
alternative
antiallergic
drug.
Experimental
Section
Chemistry.
Melting
points
were
uncorrected.
'H
NMR
spectra
were
taken
with
a
Varian
VXR-200
or
Gemini
-200,
300
FT-NMR
spectrometer
using
tetramethylsilane
as
an
internal
standard.
IR
spectra
were
recorded
on
a
Nicolet
20SXB
FT-
6,6'-Dimethylbicyclo[3.1.1]heptane
Derivatives
Journal
of
Medicinal
Chemistry,
2003,
Vol.
46,
No.
12
2451
IR
spectrometer.
Mass
spectra
were
measured
on
a
JEOL
JMS-SX/S102A
or
a
HITACHI
M-90
mass
spectrometer.
Unless
otherwise
stated,
all
reactions
were
carried
out
under
a
nitrogen
atmosphere
with
commercial
grade
solvents
that
had
been
dried
over
type
4A
molecular
sieves.
Drying
of
organic
extracts
over
anhydrous
sodium
sulfate
is
simply
indicated
by
the
word
"dried".
Column
chromatography
using
Merck
silica
gel
60
(70-230
or
230-400
mesh)
or
a
Merck
Lobar
column
is
referred
to
as
"chromatography
on
silica
gel".
Typical
Procedures.
(1R,2R,3S,5S)-(5Z)-(6,6-Dimethy1-
2-((thiophene-3-carbonyl)amino)bicyclo[3.1.1]hept-3-y1)-
hept-5-enoic
Acid
Methyl
Ester.
A
mixture
of
0.256
g
(2.00
mmol)
of
3-thiophene
carboxylic
acid,
one
drop
of
DMF,
and
0.43
mL
(6
mmol)
of
SOC1
2
in
4
mL
of
toluene
was
refluxed
for
1
h.
The
reaction
mixture
was
concentrated
in
vacuo
to
obtain
the
corresponding
acid
chloride.
The
prepared
acid
chloride
was
dissolved
in
2
mL
of
THF
and
added
to
a
stirred
solution
of
0.279
g
(1.00
mmol)
of
48
and
0.50
mL
(0.360
mmol)
of
triethylamine
in
3
mL
of
THF.
After
being
stirred
for
2
h,
the
reaction
mixture
was
diluted
with
water
and
extracted
with
AcOEt.
The
organic
layer
was
washed
with
1
N
HC1,
water,
and
a
saturated
NaHCO
3
solution,
dried
over
MgSO
4
,
and
evaporated.
The
residue
was
purified
by
column
chroma-
tography
on
silica
gel
to
give
the
title
compound
(0.362
g,
93%).
(1R,2R,3S,5S)-(5Z)-(6,6-Dimethy1-2-((thiophene-3-car-
bonyl)amino)bicyclo
[3.1.1]
hept-3-yl)hept-5-enoic
Acid
(20).
To
a
solution
of
0.224
g
(0.575
mmol)
of
the
methyl
ester
prepared
above
in
2.5
mL
of
methanol
was
added
0.36
mL
(1.45
mmol)
of
4
N
NaOH,
and
the
mixture
was
stirred
for
6
h.
The
reaction
mixture
was
neutralized
with
1
N
HC1
and
extracted
with
AcOEt.
The
organic
layer
was
washed
with
water,
dried
over
MgSO
4
,
and
evaporated.
The
residue
was
dissolved
in
a
small
amount
of
AcOEt
and
diluted
with
hexane.
The
resulting
precipitate
was
filtered
with
glass
filter
and
dried
to
give
20
(0.206
g,
95%)
as
a
colorless
solid.
Mp
87-88
°C.
1
H
NMR
(CDC13):
d
0.96
(d,
J
=
10.5
Hz,
1H),
1.11
(s,
3H),
1.23(s,
3H),
1.52-2.46
(m,
14H),
4.25
(m,
1H),
5.34-5.56
(m,
2H),
6.14
(d,
J
=
8.7
Hz,
1H),
7.34
(d,
J
=
2.0
Hz,
2H),
7.85
(t,
J
=
2.0
Hz,
1H).
IR
(CHC1
3
):
3452, 3114,
3030, 3013,
2925,
2870,
1708,
1649, 1535, 1498,
1471
cm
-1
.
[0,]
24
D
+51.6°
(c
1.01,
Me0H).
Anal.
(C211129NO3S)
C,
H,
N,
S.
(1R,2R,3S,5S)-(5Z)-7-(24(Benzo
lb]
thiophene-3-carbo-
nyl)amino)-6,6-dimethylbicyclo
[3.1.1]
hept-3-yl)hept-5-
enoic
Acid
(40).
To
a
mixture
of
1.00
g
(3.36
mmol)
of
48,
0.718
g
(4.03
mmol)
of
3-benzothiophene
carboxylic
acid
(40c),
and
45
mg
(0.336
mmol)
of
HOBT
in
6
mL
of
THF
was
added
0.678
g
(4.37
mmol)
of
WSCD
in
4
mL
of
THF.
After
being
stirred
for
14
h
at
room
temperature,
the
mixture
was
poured
into
10
mL
of
water,
treated
with
5
mL
of
1
N
HC1,
and
extracted
with
Et
2
O
twice.
The
organic
layer
was
washed
with
water
and
saturated
NaHCO
3
solution,
dried
over
MgSO
4
,
and
evaporated.
The
residue
was
purified
by
column
chromatog-
raphy
on
silica
gel
to
give
1.718
g
of
the
ester
compound.
This
compound
was
dissolved
with
8
mL
of
Me0H
and
4
mL
of
THF,
and
2.0
mL
(8
mmol)
of
4
N
NaOH
solution
was
added.
After
being
stirred
for
3
h,
the
mixture
was
concentrated
in
vacuo
and
the
residue
was
dissolved
with
25
mL
of
H
2
O.
The
mixture
was
treated
with
1
N
HC1
and
extracted
with
Et
2
O.
The
organic
layer
was
washed
with
water,
dried
over
MgSO
4
,
and
evaporated.
The
residue
was
crystallized
from
a
small
portion
of
Et
2
O
and
washed
with
hexane
to
give
a
colorless
solid
(1.36
g,
98%).
Mp
112-113
°C.
1
H
NMR
(CDC1
3
):
d
0.99
(d,
J
=
10.2
Hz,
1H),
1.11
(s,
3H),
1.24
(s,
3H),
1.52-2.53
(m,
14H),
4.34
(m,
1H),
5.33-5.57
(m,
2H),
6.21
(d,
J
=
8.6
Hz,
1H),
7.35-7.50
(m,
2H),
7.83
(s,
1H),
7.86
(m,
1H),
8.31
(m,
1H).
IR
(CHC1
3
):
3443, 3067, 3013,
2925,
2870, 2665,
1708, 1651, 1515,
1493
cm
-1
.
[0]
23
D
+58.1°
(c
1.01,
Me0H).
Anal.
(C
25
H
3I
NO
3
S)
C
,
H,
N,
S.
Thiophene-3-carboxylic
Acid
R1R,2R,3S,5S)-34(Z)-6-
Carbamoyl-hex-2-eny1)-6,6-dimethylbicyclo[3.1.1]hept-2-
yl]
amide
(49).
To
a
mixture
of
0.376
g
(1.00
mmol)
of
20
and
0.146
mL
(1.05
mmol)
of
Et
3
N
in
1.5
mL
of
THF
was
added
0.10
mL
(1.05
mmol)
of
C1CO
2
Et
at
0
°C.
After
being
stirred
for
30
min,
this
solution
was
poured
into
0.7
mL
(5.00
mmol)
of
28%
NH
4
OH
in
6
mL
of
THF
and
allowed
to
warm
to
ambient
temperature.
The
mixture
was
stirred
for
1
h,
poured
into
water,
and
extracted
with
AcOEt.
The
organic
layer
was
washed
with
water
and
brine,
dried
over
MgSO
4
,
and
evapo-
rated.
The
residue
was
purified
by
column
chromatography
on
silica
gel
to
give
the
title
compound
(0.32
g,
89%)
as
an
amorphous
compound.
1
H
NMR
(CDC1
3
):
d
0.96
(d,
J
=
10.2
Hz,
1H),
1.12
(s,
3H),
1.22
(s,
3H),
1.54-2.44
(m,
14H),
4.20
(m,
1H),
5.26
(br,
1H),
5.34-5.50
(m,
2H),
6.21
(d,
J
=
8.7
Hz,
1H), 6.43
(br,
1H),
7.34-7.35
(m,
2H),
7.83
(dd,
J
=
2.1
and
1.8
Hz,
1H).
IR
(CHC1
3
):
3523, 3451, 3407,
3375, 3198,
2940,
1677, 1645, 1603,
1598,
1538, 1500, 1471,
1386,
1320
cm
-1
.
[a1
26
D
+57.2°
(c
1.02,
Me0H).
Anal.
(C
21
H
30
N
2
O
2
S•0.3H
2
O)
C,
H,
N,
S.
Thiophene-3-carboxylic
Acid
R1R,2R,3S,5S)-3-((Z)-6-
Cyanohex-2-enyl)
-
6,6
-dimethylbicyclo
[3.1.1]
hept
-2
-yl]
a-
mide
(50).
To
a
mixture
of
0.595
g
(1.59
mmol)
of
49
in
13
mL
of
toluene
and
6.5
mL
of
THF
was
added
0.173
mL
(2.39
mmol)
of
thionyl
chloride,
and
this
solution
was
heated
at
75
°C.
After
being
stirred
for
2.5
h,
the
mixture
was
poured
into
ice/water
and
extracted
with
AcOEt.
The
organic
layer
was
washed
with
water,
2
N
NaOH,
and
brine,
dried
over
Na
2
SO
4
,
and
evaporated.
The
residue
was
purified
by
column
chroma-
tography
on
silica
gel
to
give
50
(0.565
g,
99%)
as
an
amorphous
compound.
1
H
NMR
(CDC1
3
):
d
0.85
(d,
J
=
10.2
Hz,
1H),
1.10
(s,
3H),
1.23
(s,
3H),
1.57-2.28
(m,
11H),
2.35
(t,
J
=
7.2
Hz,
1H),
2.51
(m,
1H),
4.27
(m,
1H),
5.30-5.60
(m,
2H),
6.12
(d,
J
=
8.7
Hz,
1H),
7.34-7.35
(m,
2H),
7.83
(m,
1H).
IR
(CHC1
3
):
3678, 3452, 3012,
2922,
2244,
1647, 1533,
1497,
1470
cm
-1
.
Thiophene-3-carboxylic
Acid
{(1R,2R,3S,5S)-6,6-Dim-
ethy1-34(Z)-6-(1H-tetrazol-5-y1)hex-2-enyl]bicyclo[3.1.1]-
hept-2-yllamide
(28).
To
a
solution
of
0.327
g
(0.917
mmol)
of
50
in
1.8
mL
of
toluene
were
added
0.243
mL
(1.83
mmol)
of
TMSN
3
and
23
mg
(0.092
mmol)
of
Bu
2
SnO,
and
this
mixture
was
heated
at
110
°C.
After
being
stirred
for
45
h,
the
mixture
was
evaporated
and
the
residue
was
purified
by
column
chromatography
on
silica
gel
to
give
28
(0.315
g,
86%)
as
an
amorphous
compound.
1
H
NMR
(CDC1
3
):
d
0.85
(d,
J
=
10.2
Hz,
1H),
1.14
(s,
3H),
1.26
(s,
3H),
1.61
(m,
1H),
1.83
(m,
1H),
1.91-2.14
(m,
5H),
2.20-2.38
(m,
5H),
2.90-3.10
(m,
2H),
4.09
(m,
1H),
5.46
(m,
2H),
6.29
(d,
J
=
8.7
Hz,
1H),
7.35-
7.42
(m,
2H),
7.94
(dd,
J
=
1.5
and
3.0
Hz,
1H).
IR
(CHC1
3
):
3451, 3117,
2925, 2871, 2753, 2621,
1631, 1538, 1500, 1471,
1415, 1386,
1367,
1320,
1260,
1236,
1078,
1058,
988
cm
-1
.
[a]
26
o
+60.6°
(c
1.01,
Me0H).
Anal.
(C21H29N5OS•0.2H2O)
C,
H,
N,
S.
Thiophene-3-carboxylic
Acid
(2,4-Dimethoxybenzy1)-
R1R,2R,3R,5S)-6,6-dimethy1-3-(2-oxo-ethyl)bicyclo[3.1.1]-
hept-2-yl]
amide
(29b).
To
a
solution
of
0.274
mL
(3.87
mmol)
of
DMSO
in
1.3
mL
of
CH
2
C1
2
was
added
0.162
mL
(1.81
mmol)
of
(COC1)
2
in
3.8
mL
of
CH2C12
over
a
period
of
30
min
at
—78
°C.
After
being
stirred
for
30
min,
0.536
g
(1.21
mmol)
of
29a
in
2
mL
of
CH
2
C1
2
was
added
dropwise
to
the
mixture,
the
mixture
was
stirred
for
40
min
at
—50
°C,
then
1.13
mL
(8.09
mmol)
of
Et
3
N
was
added,
and
the
mixture
was
allowed
to
reach
ambient
temperature.
After
being
stirred
for
1
h,
the
mixture
was
poured
into
ice/water
and
extracted
with
AcOEt.
The
organic
layer
was
washed
with
water
and
brine,
dried
over
Na
2
SO
4
,
and
evaporated
to
give
29b
(0.564
g,
100%)
as
an
amorphous
compound.
1
H
NMR
(CDC1
3
):
d
0.90
(m,
1H),
1.06
(s,
3H),
1.17
(s,
3H),
1.82
(m,
1H),
2.18-2.89
(m,
7H),
3.77
(s,
3H),
3.79
(s,
3H),
4.56-4.65
(m,
3H),
6.40
(d,
J
=
2.4
Hz,
1H),
6.44
(dd,
J
=
8.4
and
2.4
Hz,
1H),
7.10
(d,
J
=
8.4
Hz,
1H),
7.16
(dd,
J
=
1.2
and
5.1
Hz,
1H),
7.23
(m,
1H),
7.42
(dd,
J
=
1.2
and
3.0
Hz,
1H),
9.61
(s,
1H).
(1R,2R,3R,5S)-R2,4-Dimethoxybenzyl)
(1-thiophen-3-
yl-met
hanoyl)
amino]
dimet
hylbicyclo
[3.1
.1]
hept
-3-y1
-
oxoheptanoic
Acid
(29c).
To
a
mixture
of
44
mg
(1.81
mmol)
of
magnesium
turnings
and
a
catalytic
amount
of
I
2
in
0.2
mL
of
dry
Et
2
O
was
added
dropwise
0.544
g
(1.93
mmol)
of
5-bromo-1-(tert-butyldimethylsiloxy)pentane
in
2
mL
of
Et
2
O
with
gentle
refluxing.
After
being
stirred
for
2
h,
the
mixture
was
cooled
to
0
°C
and
0.564
g
(1.21
mmol)
of
29b
was
added.
2452
Journal
of
Medicinal
Chemistry,
2003,
Vol.
46,
No.
12
Mitsumori
et
al.
This
reaction
mixture
was
allowed
to
reach
ambient
temper-
ature,
stirred
for
18
h,
poured
into
saturated
NH
4
C1
solution,
and
extracted
with
AcOEt.
The
organic
layer
was
washed
with
water
and
brine,
dried
over
Na
2
SO
4
,
and
evaporated.
The
residue
was
purified
by
column
chromatography
on
silica
gel
to
give
0.597
g
(0.826
mmol)
of
an
alcohol
derivative.
This
compound
was
successively
dissolved
with
12
mL
of
acetone
and
0.96
mL
(27.81
mmol)
of
Jones
reagent
at
0
°C.
The
reaction
mixture
was
allowed
to
reach
ambient
temperature,
stirred
for
1.5
h,
and
quenched
with
several
drops
of
Me0H.
The
mixture
was
poured
into
ice/water
and
extracted
with
AcOEt.
The
organic
layer
was
washed
with
water
and
brine,
dried
over
Na
2
SO
4
,
and
evaporated
to
give
29c
(0.450
g,
69%)
as
an
amorphous
compond.
1
11
NMR
(CDC1
3
):
d
0.10
(s,
3H),
0.91
(s,
3H),
1.32
(m,
1H),
1.88
(m,
1H),
2.17-2.62
(m,
13H),
2.79
(m,
2H),
3.76
(s,
3H),
3.78
(s,
3H),
4.51-4.77
(m,
3H),
6.39
(s,
1H),
6.42
(m,
1H),
7.06-7.22
(m,
3H),
7.43
(s,
1H).
IR
(CHC13):
3664,
3572, 3010,
2924, 2852,
1710, 1613, 1503, 1462,
1418,
1300, 1283,
1254
cm
-1
.
7-{(1R,2R,3R,5S)-6,6-Dimethy1-24(1-thiophen-3-ylme-
thanoyflaminoThicyclo[3.1.1]hept-3-y11-6-oxoheptanoic
Acid
(29).
To
a
solution
of
0.450
g
(0.83
mmol)
of
29c
and
0.218
mL
(1.66
mmol)
of
1.3-dimethoxybenzene
in
4
mL
of
CH
2
-
C1
2
was
added
1.92
mL
(24.9
mmol)
of
trifluoroaceetic
acid
at
0
°C.
After
being
stirred
for
15
h,
the
mixture
was
poured
into
water
and
extracted
with
AcOEt.
The
organic
layer
was
washed
with
water
and
brine,
dried
over
Na
2
SO
4
,
and
evapo-
rated.
The
residue
was
purified
by
column
chromatography
on
silica
gel
to
give
29
(0.188
g,
58%).
1
11
NMR
(CDC1
3
):
0.93
(d,
J
=
10.2
Hz,
1H),
1.15
(s,
3H),
1.24
(s,
3H),
1.36
(m,
1H),
1.56-1.62
(m,
3H),
1.99
(m,
1H),
2.17
(m,
1H),
2.30-2.65
(m,
9H),
3.00
(dd,
J
=
4.2
and
16.8
Hz,
1H),
4.19
(m,
1H),
6.19
(d,
J
=
8.4
Hz,
1H),
7.31-7.36
(m,
2H),
7.84
(dd,
J
=
1.5
and
2.7
Hz,
1H).
IR
(CHC1
3
):
3452,
2925,
1710, 1649, 1535,
1498,
1471, 1412, 1387,
1367, 1284, 1267, 1159, 1133, 1096, 1017,
874,
841
cm'.
[0,]
25
D
+20.7°
(c
1.01,
Me0H).
Anal.
(C21H29-
NO
4
S•0.2H
2
O)
C,
H,
N,
S.
4,5,6,7-Tetrahydrobenzo[b]thiophene-3-carboxylic
Acid
(34a).
To
a
solution
of
4.00
g
(17.75
mmol)
of
ethyl
2-amino-
4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate
in
20
mL
of
1,4-dioxane
and
14
mL
of
concentrated
HC1
solution
was
slowly
added
1.35
g
(19.53
mmol)
of
NaNO
2
in
2.0
mL
of
water
at
0
°C.
The
reaction
mixture
was
stirred
for
15
min
at
—5
°C
and
then
added
portionwise
to
36
mL
of
50%
H
3
PO
4
solution
and
36
mL
of
Et
2
O
at
0
°C
with
vigorous
stirring.
After
being
stirred
for
30
min,
the
mixture
was
poured
into
ice/water
and
extracted
with
Et
2
O.
The
organic
layer
was
washed
with
saturated
NaHCO
3
solution
and
brine,
dried
over
Na
2
SO
4
,
and
evaporated.
The
residue
was
purified
by
column
chromatog-
raphy
on
silica
gel
to
give
an
ester
(2.00
g,
54%).
This
compound
(2.00
g,
9.51
mmol)
was
dissolved
with
21
mL
of
EtOH
and
21
mL
of
1
N
NaOH
and
refluxed.
After
being
stirred
for
30
min,
the
mixture
was
cooled
to
ambient
tem-
perature
and
treated
with
4.2
mL
of
5
N
HC1.
The
precipitate
was
collected
with
a
glass
filter
and
dried
under
reduced
pressure
to
give
34a
(1.68
g,
97%)
as
a
colorless
solid.
Mp
181-
183
°C.
1
11
NMR
(CDC1
3
):
d
1.80-1.86
(m,
4H),
2.71-2.96
(m,
4H),
8.06
(s,
1H).
4-Methoxythiophene-3-carboxylic
Acid
(31a).
To
a
mix-
ture
of
2.16
g
(93.9
mmol)
of
Na
in
40
mL
of
Me0H
was
added
2.00
g
(9.05
mmol)
of
methyl
3-bromo-4-thiophenecarboxylate,
0.51
g
(3.40
mmol)
of
NaI,
and
0.31
g
(3.90
mmol)
of
CuO,
and
the
mixture
was
refluxed.
After
being
stirred
for
68
h,
the
mixture
was
filtered
through
Hyflo
Super
-Cell
and
evaporated.
The
residue
was
treated
with
2
N
HC1
and
extracted
with
AcOEt.
The
organic
layer
was
washed
with
water
and
brine,
dried
over
Na
2
SO
4
,
and
evaporated.
The
residue
was
dissolved
with
Et
2
O,
and
25
mL
of
CH
2
N
2
in
Et
2
O
solution
(ca.
0.5
M)
was
added
at
0
°C.
The
mixture
was
quenched
with
AcOH
and
evaporated.
The
residue
was
purified
by
column
chromatog-
raphy
on
silica
gel
to
give
methyl
4-methoxy-3-thiophenecar-
boxylate
(1.30
g,
83%).
This
compound
was
dissolved
in
15
mL
of
Me0H,
15
mL
of
1
N
NaOH
was
added,
and
the
mixture
was
refluxed.
After
being
stirred
for
15
min,
the
mixture
was
concentrated
in
vacuo,
treated
with
2
N
HC1,
and
diluted
with
water.
The
precipitate
was
collected
with
a
glass
filter
and
dried
under
reduced
pressure
to
give
31a
(1.05
g,
81%)
as
a
colorless
solid.
Mp
100-105
°C.
1
11
NMR
(CDC1
3
):
d
4.00
(s,
3H),
6.41
(d,
J
=
3.6
Hz,
1H),
8.20
(d,
J
=
3.6
Hz,
1H).
IR
(Nujol):
3514, 3398,
1705, 1666, 1554, 1467, 1294, 1208, 1181,
1081
cm
-1
.
Anal.
(C
6
H
6
O
3
S•1.0H
2
O)
C,
H,
S.
5-Bromobenzo[b]thiophene
(45b).
To
a
solution
of
9.99
g
(0.434
mmol)
of
Na
in
250
mL
of
Me0H
was
added
50.95
g
(0.269
mmol)
of
4-bromothiophenol
and
35
mL
(0.296
mmol)
of
bromoacetoaldehyde
dimethylacetal
at
0
°C,
and
the
mixture
was
refluxed.
After
being
stirred
for
3.5
h,
the
mixture
was
evaporated
and
cool
water
was
added
to
the
residue.
The
aqueous
layer
was
extracted
with
Et
2
O,
and
the
combined
organic
layer
was
washed
with
water
and
brine,
dried
over
Na
2
SO
4
,
and
evaporated.
The
residue
was
distilled
under
reduced
pressure
to
give
a
thioether
(bp
o
5
118-123
°C).
To
a
mixture
of
140
g
of
PPA
and
600
mL
of
chlorobenzene
was
slowly
added
70.0
g
(0.253
mmol)
of
this
crude
material
with
gentle
refluxing.
After
being
stirred
for
15
h,
the
supernatant
of
the
reaction
mixture
was
separated
and
the
residue
was
washed
with
toluene.
The
combined
organic
phase
was
evapo-
rated,
and
the
residue
was
purified
by
column
chromatography
on
silica
gel
to
give
45b
(42.35
g,
79%)
as
a
colorless
solid.
Mp
45-46
°C.
1
11
NMR
(CDC1
3
):
d
7.27
(d,
J
=
5.0
Hz,
1H),
7.41-
7.49
(m,
2H),
7.74
(d,
J
=
8.6
Hz,
1H),
7.96
(d,
J
=
1.6
Hz,
1H).
5-Bromobenzo[b]thiophene-3-carboxylic
Acid
(45c).
To
a
solution
of
20.0
g
(93.9
mmol)
of
45b
and
8.0
mL
(0.113
mol)
of
acetyl
chloride
in
200
mL
of
1,2-dichloroethane
was
slowly
added
13.0
mL
(0.113
mol)
of
SnC1
4
in
30
mL
of
1,2-dichloro-
ethane
at
0
°C,
and
the
mixture
was
allowed
to
reach
ambient
temperature.
After
being
stirred
for
20
h,
the
mixture
was
poured
into
ice/water
and
extracted
with
CHC1
3
.
The
organic
layer
was
washed
with
saturated
NaHCO
3
solution,
water,
and
brine,
dried
over
Na
2
SO
4
,
and
evaporated.
The
residue
was
purified
by
column
chromatography
on
silica
gel
to
give
3-acetyl-5-bromobenzo[b]thiophene
(21.52
g,
90%).
To
a
solu-
tion
of
29.4
g
(0.734
mol)
of
NaOH
in
200
mL
of
water
was
slowly
added
15.2
mL
(0.295
mol)
of
Br
2
at
0
°C.
After
the
mixture
was
stirred
for
15
min,
21.52
g
(84.3
mmol)
of
an
acetyl
derivative
in
160
mL
of
1,4-dioxane
was
added
dropwise,
and
the
mixture
was
allowed
to
reach
ambient
temperature
and
stirred
for
1.5
h.
The
reaction
mixture
was
quenched
with
10.0
g
(96.1
mmol)
of
NaHSO
3
and
19
mL
of
concentrated
HC1.
The
precipitate
was
collected
with
a
glass
filter,
washed
with
water,
and
dried
to
give
45c
(16.6
g,
77%)
as
a
colorless
solid.
Mp
292-293
°C.
1
1-1
NMR
(DMSO-d6):
d
7.61
(dd,
J
=
8.6
and
2.0
Hz,
1H),
8.09
(d,
J
=
8.6
Hz,
1H),
8.66
(d,
J
=
2.0
Hz,
1H),
8.72
(s,
1H).
5-Hydroxybenzo[b]thiophene-3-carboxylic
Acid
(45d).
To
a
solution
of
4.37
g
(0.19
mol)
of
Na
in
100
mL
of
Me0H
was
added
5.00
g
(19.5
mmol)
of
45c
and
0.279
g
(1.95
mmol)
of
CuBr,
and
the
mixture
was
refluxed.
After
the
mixture
was
stirred
for
2
h,
0.124
g
(19.5
mmol)
of
Cu
was
added
and
the
mixture
was
stirred
for
42
h.
The
reaction
mixture
was
filtered
through
Hyflo
Super
-Cell
and
evaporated.
To
the
residue
was
added
ice/water,
and
the
mixture
was
treated
with
concen-
trated
HC1
solution
and
extracted
with
Et
2
O.
The
organic
layer
was
washed
with
water
and
brine,
and
20
mL
(ca.
20.0
mmol)
of
CH
2
N
2
solution
was
added
at
0
°C.
After
being
stirred
for
30
min,
the
mixture
was
quenched
with
AcOH
and
water
and
extracted
with
AcOEt.
The
organic
layer
was
washed
with
water
and
saturated
NaHCO
3
solution,
dried
over
MgSO
4
,
and
evaporated
to
give
a
methyl
ester
(4.53
g,
71%).
A
portion
of
the
methyl
ester
(2.06
g,
9.27
mmol)
was
dissolved
with
20
mL
of
CH2C12,
and
2.0
mL
(21.2
mmol)
of
BBr
3
in
5
mL
of
CH2-
C1
2
was
added
at
0
°C
under
N2.
After
being
stirred
for
20
min,
the
mixture
was
allowed
to
reach
ambient
temperature
and
was
stirred
for
another
3.5
h.
The
reaction
mixture
was
poured
into
ice/water,
and
the
precipitate
was
collected
with
a
glass
filter
and
dried.
To
the
obtained
solid
was
added
22
mL
(22.0
mmol)
of
1
N
NaOH,
and
the
mixture
was
heated
at
100
°C.
After
being
stirred
for
20
min,
the
mixture
was
cooled
to
room
6,6'-Dimethylbicyclo[3.1.1]heptane
Derivatives
Journal
of
Medicinal
Chemistry,
2003,
Vol.
46,
No.
12
2453
temperature,
treated
with
2
N
HC1,
and
extracted
with
AcOEt.
The
organic
layer
was
washed
with
water
and
brine,
dried
over
MgSO
4
,
and
evaporated
to
give
45d
(1.64
g,
91%)
as
a
colorless
solid.
Mp
264-265
°C.
'El
NMR
(DMSO-d
6
):
d
6.93
(dd,
J
=
2.6
and
8.6
Hz,
1H),
7.83
(d,
J
=
8.6
Hz,
1H),
7.93
(d,
J
=
2.6
Hz,
1H),
8.55
(s,
1H),
9.59
(br,
1H),
12.80
(br,
1H).
Compounds
40c,"a
41b,
1
b
44c,"a
and
46d
11
c
were
prepared
by
procedures
similar
to
those
used
for
45b
—d.
Nitro-4-prop-2-ynylsulfanylbenzene
(47b).
To
a
solution
of
28.23
g
(0.146
mmol)
of
47a
in
168
mL
of
HCO
2
H
and
9.2
mL
of
water
was
slowly
added
15.3
mL
(0.148
mmol)
of
30%
H
2
0
2
at
0
°C,
and
the
mixture
was
allowed
to
reach
room
temperature.
After
being
stirred
for
5
h,
the
mixture
was
poured
into
water
and
extracted
with
AcOEt.
The
organic
layer
was
washed
with
water
and
saturated
NaHCO
3
solution,
dried
over
Na
2
SO
4
,
and
evaporated
to
give
47b
(27.96
g,
91%)
as
a
pale
-yellow
solid.
Mp
139-140
°C.
41
NMR
(CDC1
3
):
d
2.40
(dd,
J
=
2.4
and
2.7
Hz,
1H),
3.72
(d,
J
=
2.4
Hz,
1H),
3.74
(d,
J
=
2.7
Hz,
1H),
7.92
(d,
J
=
8.4
Hz,
2H),
8.40
(d,
J
=
8.4
Hz,
2H).
1-Nitro-4-(prop-2-yne-1-sulfinyl)benzene
(47c).
A
solu-
tion
of
27
67
g
(0.132
mmol)
of
47b
in
810
mL
of
1,4-dioxane
was
refluxed.
After
the
mixture
was
stirred
for
3
h,
7.54
g
(39.68
mmol)
of
p-Ts011.11
2
0
and
75
mL
of
water
were
added,
followed
by
refluxing
for
a
further
2
h.
The
mixture
was
cooled
to
ambient
temperature
and
evaporated.
The
residue
was
treated
with
saturated
NaHCO
3
solution
and
extracted
with
AcOEt.
The
organic
layer
was
washed
with
water
and
brine,
dried
over
Na
2
SO
4
,
and
evaporated.
The
residue
was
purified
by
column
chromatography
on
silica
gel
to
give
47c
(20.0
g,
72%)
as
a
pale
-yellow
solid.
Mp
155-156
°C.
41
NMR
(CDC1
3
):
d
1.87
(t,
J
=
5.4
Hz,
1H),
5.02
(d,
J
=
5.1
Hz,
2H),
7.60
(s,
1H),
7.97
(d,
J
=
9.0
Hz,
1H),
8.22
(dd,
J
=
2.4
and
9.0
Hz,
1H),
8.77
(d,
J
=
2.4
Hz,
1H).
(5-Nitrobenzo[b]thiophen-3-yl)methanol
(47d).
To
a
solution
of
10.0
g
(47.85
mmol)
of
47c
in
100
mL
of
EtOH
was
added
64.59
g
(0.287
mmol)
of
SnC1
2
.11
2
0,
and
the
mixture
was
heated
at
80
°C.
After
being
stirred
for
40
min,
the
mixture
was
treated
with
2
N
NaOH
solution
and
extracted
with
AcOEt.
The
organic
layer
was
washed
with
water
and
brine,
dried
over
Na
2
SO
4
,
and
evaporated.
The
residue
was
purified
by
column
chromatography
on
silica
gel
to
give
an
amine
compound
(6.55
g,
76%).
To
a
solution
of
6.55
g
(36.59
mmol)
of
amine
in
66
mL
of
THF
and
6.6
mL
of
water
were
added
10.6
g
(76.70
mmol)
of
K
2
CO
3
and
15.95
g
(73.17
mmol)
of
Boc
2
O.
After
being
stirred
for
19
h,
the
mixture
was
poured
into
ice/water
and
extracted
with
AcOEt.
The
organic
layer
was
washed
with
water
and
brine,
dried
over
Na
2
SO
4
,
and
evaporated.
The
residue
was
purified
by
column
chromatog-
raphy
on
silica
gel
to
give
47d
(8.88
g,
87%)
as
a
colorless
solid.
Mp
124-126
°C.
41
NMR
(CDC1
3
):
d
1.54
(s,
9H),
1.58
(br,
1H),
4.92
(s,
2H),
6.58
(br,
1H),
7.30
(dd,
J
=
2.1
and
9.0
Hz,
1H),
7.40
(s,
1H),
7.74
(d,
J
=
9.0
Hz,
1H),
7.95
(d,
J
=
2.1
Hz,
1H).
5-tert-ButoxycarbonylaminobenzoWthiophene-3-car-
boxylic
Acid
(47e).
To
a
solution
of
8.88
g
(31.83
mmol)
of
47d
and
49.7
mg
(0.319
mmol)
of
2,2,6,6-tetramethylpiperidine
1
-oxide
(TEMPO)
in
266
mL
of
MeCN
was
added
dropwise
60
mL
(37.98
mmol)
of
0.633
N
NaC10
solution
at
0
°C.
After
the
mixture
was
stirred
for
30
min,
5.44
g
(47.75
mmol)
of
79%
NaC10
2
and
4.34
mL
(43.53
mmol)
of
31%
H
2
0
2
solution
were
added,
and
the
reaction
mixture
was
allowed
to
reach
ambient
temperature.
After
being
stirred
for
1
h,
the
mixture
was
diluted
with
water
and
the
precipitated
solid
was
collected.
The
precipitate
was
washed
with
water
and
dried
under
reduced
pressure
to
give
47e
(5.28
g,
57%)
as
a
colorless
solid.
Mp
203-205
°C.
41
NMR
(DMSO-d
6
):
d
1.50
(s,
9H),
7.47
(dd,
J
=
2.1
and
9.0
Hz,
1H),
7.91
(d,
J
=
9.0
Hz,
1H),
8.58
(s,
1H),
8.74
(d,
J
=
2.1
Hz,
1H),
9.48
(s,
1H),
12.82
(br,
1H).
(Z)-74(1R,2R,3S,5S)-2-{[1-(5-Methoxysulfinylaminoben-
zo
[b]
thiophen-3-yl)methanoyl]
amino
}
-6,6-dimethylbi-
cyclo[3.1.1]
hept-3-y1)
hept-5-enoic
Acid
(47).
To
a
solution
of
0.558
g
(2.00
mmol)
of
48
and
0.586
g
(2.00
mmol)
of
47e
in
6
mL
of
THF
was
added
27
mg
(0.20
mmol)
of
HOBT
and
0.403
g
(2.60
mmol)
of
WSCD
in
2
mL
of
THF,
and
the
mixture
was
stirred
at
room
temperature.
After
being
stirred
for
19
h,
the
mixture
was
poured
into
1
N
HC1
and
extracted
with
toluene.
The
combined
organic
layer
was
washed
with
saturated
NaHCO
3
solution
and
brine,
dried
over
Na
2
SO
4
,
and
evapo-
rated.
The
residue
was
purified
by
column
chromatography
on
silica
gel
to
give
the
crude
product
(1.03
g,
93%).
A
portion
of
this
compound
(0.768
g,
1.39 mmol)
was
dissolved
with
CH
2
-
C1
2
,
and
1.07
mL
(13.9
mmol)
of
TFA
was
added
at
room
temperature.
After
being
stirred
for
6
h,
the
mixture
was
evaporated,
treated
with
saturated
NaHCO
3
solution,
and
extracted
with
AcOEt.
The
organic
layer
was
washed
with
brine,
dried
over
Na
2
SO
4
,
and
evaporated
to
afford
the
amine
product
(0.628
g,
100%).
To
a
solution
of
this
amine
product
(0.178
g,
0.392
mol)
in
1.7
mL
of
pyridine
was
added
36
pt
(0.470
mmol)
of
methanesulfonyl
chloride
at
0
°C,
and
this
mixture
was
allowed
to
reach
ambient
temperature.
After
being
stirred
for
1
h,
the
mixture
was
quenched
with
1
N
HC1
and
extracted
with
AcOEt.
The
organic
layer
was
washed
with
water
and
brine,
dried
over
Na
2
SO
4
,
and
evaporated.
The
residue
was
purified
by
column
chromatography
on
silica
gel
and
hydrolyzed
by
4
N
NaOH
in
Me0H
at
room
temperature
to
afford
47
(0.184
g,
91%)
as
an
amorphous
compound.
1
11
NMR
(CDC1
3
):
d
1.12
(m,
1H),
1.22-1.33
(m,
2H),
1.42-1.54
(m,
2H),
1.61-1.76
(m,
4H),
2.01-2.33
(m,
5H),
2.40
(t,
J
=
7.2
Hz,
2H),
2.57
(m,
1H),
2.96
(s,
3H),
3.91
(m,
1H),
5.31-
5.47
(m,
2H),
6.19
(d,
J
=
7.2
Hz,
1H),
7.51
(dd,
J
=
2.4
and
9.0
Hz,
1H),
7.81
(d,
J
=
9.0
Hz,
1H),
7.88
(s,
1H),
8.20
(d,
J
=
2.4
Hz,
1H).
IR
(CHC1
3
):
3509, 3438,
3366,
3223, 3100, 3031,
3023, 3017, 3012,
2955, 2876,
1709, 1645, 1606, 1518, 1475,
1329
cm
-1
.
[a]
23
D
+37.8°
(c
1.01,
Me0H).
Anal.
(C26H34N205S2•
0.2H
2
0)
C,
H,
N,
S.
Acknowledgment.
The
authors
thank
Drs.
Hitoshi
Arita
and
Kenji
Kawada
for
their
encouragement
and
helpful
discussions
throughout
this
study.
We
also
thank
Ms.
Yoko
Furue
and
Ms.
Maki
Hattori
for
their
technical
support.
Supporting
Information
Available:
Experimental
de-
tails
with
spectral
data.
This
material
is
available
free
of
charge
via
the
Internet
at
http://pubs.acs.org.
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JM0205189