Hypo cholesteremic agents. II. Cyclohexane and indan derivatives


Villani, F.J.; Ellis, C.A.

Journal of Medicinal Chemistry 13(6): 1245-1246

1970


Maximum hypocholesteremic activity and minimal estrogenic potency was found in the dihydrostilbazole series containing lower alkyl substituents on both carbons of the ethylenic bridge. It was of interest to study the hypocholesteremic activity of compounds in which R and R1 are fused in a cyclohexane ring or are part of an indan structure.

NOTES
Journal
of
Medicinal
Chemistry,
1970,
Vol.
13,
No.
6
1245
31
-
,170-Diacetoxy-4-oxa-5a-androstane
(Ie).-Aeetylation
of
hemiacetal
Ia
(0.4
g)
was
repeated
(see
Id).
In
this
case
the
crude
product
weighed
0.45
g
and
melted
at
120-122°.
Re-
crystn
from
Me
2
CO-pentane
gave
needles
melting
at
141-144°.
Further
recrystn
from
the
same
solvent
provided
an
analytical
sample
of
diacetate
Ie,
mp
142-144°.
Anal.
(C22113405)
C,
H,
0.
Comparison
of
acetal
Id,
mp
141-143°,
with
diacetate
Ie,
mp
141-144°,
by
mixture
melting
point
determination
showed
a
depression
to
115°.
17/3-Acetoxy-4-oxa-2-androstene
(III).
-A
soln
of
acetal
Id
(0.2
g)
in
C
5
I1
6
(25
ml)
containing
p-Tos0H
(0.04
g)
was
heated
at
reflux
20
hr.
The
mixture
was
washed
successively
with
1120,
aq
NaHCO
3
,
and
H
2
0.
Following
removal
of
solvent,
the
residue
was
chromatographed
on
activated
alumina.
Elution
with
1:1
hexane
-C
6
11
6
led
to
0.14
g
of
III.
The
oily
product
crystd
from
l‘le0H
as
small
needles
melting
at
118-120°.
Recrystal-
lization
from
Me0H
gave
a
pure
sample,
mp
120-121°.
Anal.
(C20113003)
C,
H,
0.
Formation
of
III
was
monitored
by
tic
(1:1
C6H6-CHCl3,
mobile
phase)
and
extended
reaction
periods
(for
example,
66
hr)
were
shown
to
yield
a
series
of
products.
33
-
,17
(3-Bis
(dihydropyranyloxy
)-4-oxa-5a-androstane
(If
).-A
soln
prepared
from
C6116
(12
ml),
hemiacetal
Ia
(0.21
g),
dihy-
dropyran
(2
ml),
and
p-Tos0H
(0.05
g)
was
stirred
1
hr
at
room
temp.
The
soln
was
washed
with
aq
NaHCO
3
and
1120.
Re-
moval
of
solvent
in
vacuo
gave
a
semisolid
which
crystd
from
Me0H-Me2C0
as
small
needles
weighing
0.10
g,
mp
165-169°.
Recrystallization
from
the
same
solvent
afforded
thick
needle
clusters
melting
at
176-179°.
Anal.
(C28114606)
C,
H,
0.
3i
-
-Acetoxy-4-oxa-5a-cholestane
(IIb).-A
sample
(0.25
g)
of
3
-
-hydroxy-4-oxa-5a-cholestane
(IIa)
2
b
was
acetylated
as
sum-
marized
in
the
case
of
la
(see
le).
The
crude
acetate
crystd
from
pentane
as
thick
needles
melting
at
103-107°
(sintering
at
90°).
An
anal.
sample,
recrystd
from
pentane,
melted
at
105-108°
(sin
tering
at
95°
);
tic
1:2
C6116-CHC13.
Anal.
(C
28
H
48
0
2
)C,
11
,
0.
Oxidation
of
12«,15-Epoxy-12-nor-13i3-methy1-119,14a-abie-
tane
(IVa).
Method
A.
-A
soln
of
XXIa
(0.20
g)
4
in
glacial
AcOH
(6
ml)
was
treated
with
a
slight
excess
of
an
8
N
CO3
reagent'
at
60°.
Heating
was
continued
at
steam
bath
temp
for
10
min.
Excess
oxidizing
agent
was
removed
by
adding
Me0H.
Follow-
ing
diln
with
11
2
0
and
extraction
with
Et
2
0
containing
CHC1
3
,
the
extract
was
washed
well
with
11
2
0,
aq
NaHCO
3
,
and
H
2
0.
Removal
of
solvent
gave
0.17
g
of
solid
which
was
chromato-
graphed
in
pentane
on
activated
alumina.
Elution
with
pentane
removed
0.03
g
of
starting
material.
A
fraction
eluted
by
1:1
pentane
-C6116
provided
0.12
g
of
dihydroabietic
y-lactone
(IVb)
4
melting
at
125-127°.
Recrystallization
from
l‘1e0H
gave
long
needles
melting
at
126-128°.
Method
B.
-Oxidation
of
IVa
(1.1
g)
3
was
repeated
in
a
soln
composed
of
glacial
AcOH
(16
ml),
C
6
11
6
(6
ml),
and
Na2Cr207.
211
2
0
(2.1
g).
5
The
soln
was
stirred
and
maintained
at
approx
75°
for
30
hr.
The
product
was
isolated
and
purified
as
noted
directly
above.
In
this
case,
0.87
g
of
starting
ether
IVa
was
recovered
and
0.26
g
of
lactone
IVb
was
isolated.
Acknowledgment.
-This
investigation
was
supported
by
Public
Health
Service
Research
Grants
CA
-04074-06
and
CA
-10115-01
from
the
National
Cancer
Institute.
(4)
G.
R.
Pettit,
B.
Green,
T.
R.
liasturi,
and
U.
R.
Ghatak,
Tetrahedron,
18,
953
(1962).
(5)
L.
F.
Fieser,
J.
Amer.
Chem.
Soc.,
75,
4386
(1953).
Hypocholesteremic
Agents.
2.
Cyclohexane
and
Indan
Derivatives
FRANK
J.
VILLANI*
AND
CLAIRE
A.
ELLIS
Medicinal
Chemical
Research
Department,
Schering
Corporation,
Bloomfield,
New
Jersey
07003
Received
May
29,
1970
Maximum
hypocholesteremic
activity
and
minimal
estrogenic
potency
was
found
in
the
dihydrostilbazole
series
containing
lower
alkyl
substituents
on
both
car-
*
To
whom
correspondence
should
be
addressed.
bons
of
the
ethylenic
bridge
(1).
1
It
was
of
interest
to
study
the
hypocholesteremic
activity
of
compounds
in
which
R
and
R
1
are
fused
in
a
cyclohexane
ring
(2)
or
are
part
of
an
indan
structure
(3).
p•CI
-
130C6114
2-(C
5
H
4
N)
p-CH
3
0C
5
1
-
1
4
CHRCHR'.2-(C
5
H
4
N)
1
2
7
Et
CE1,0
Et
2
(C,H
4
N)
3
Compounds
of
formulas
2
and
3
were
prepared
by
treating
the
appropriately
substituted
cyclic
ketone
with
pyridyllithium,
followed
by
dehydration
of
the
tertiary
carbinol
and
hydrogenation
of
the
resulting
double
bond.
2-p-Methoxypheny1-1-(2-pyridy1)-1-cy-
clohexanol
having
OH
on
C
a
to
2-pyridyl,
as
in
the
cases
previously
reported,'
resisted
dehydration
by
the
usual
acid
dehydrating
agents.
However,
fusion
of
this
carbinol
with
potassium
pyrosulfate
gave
a
mixture
of
the
1,2-
and
2,3-cyclohexenes
(4)."
The
addition
of
2-pyridyllithium
to
6
gave
the
tertiary
carbinol
which
was
converted
into
the
indene
derivative
8a
by
heating
with
H3PO4.
In
contrast,
the
addition
of
3-pyridyllithium
to
6
gave
the
unsaturated
compound
8b
directly
and
provides
further
evidence
for
the
sta-
bility
of
the
2-pyridyl
carbinol
moiety.
At
the
screening
dose
of
50
mg/kg
orally
and
10
mg/kg
subcutaneously,'
these
compounds
were
in-
effective
in
lowering
the
serum
cholesterol
levels
in
both
male
and
female
rats.
The
compounds
were
devoid
of
estrogenic
activity
even
at
higher
doses.
Previous
investigators'a.b
have
shown
that
1,2-bis(p-
methoxyphenyl)cyclohexane
has
definite
but
weak
es-
trogenic
activity.
Experimental
Section
6
0-Ethyl-p-methoxycinnamic
Acid.
-The
Reformatsky
ester
(160
g),
bp
125-155°
(1
mm),
obtained
from
164
g
(1
mole)
of
p-methoxypropiophenone,
167
g
of
ethyl
bromoacetate,
and
85
g
of
Zn
(20
mesh)
was
saponified
with
160
g
of
KOH
in
1600
ml
of
Et0H
and
800
ml
of
H
2
O
to
give
the
trans
acid,
mp
132-134,
and
cis
acid,
mp
68-70°.
Anal.
(C1
2
11140
3
)
C,
H.
/3-Ethyl-p-methoxyhydrocinnamic
Acid
(7).
-In
4
portions
a
solution
of
84
g
of
the
above
acids
in
1
1.
of
EtOH
was
reduced
in
a
Parr
hydrogenator
in
presence
of
20
g
of
5%
Pd
-C.
The
catalyst
was
fi
ltered,
the
solvent
removed
in
vacuo,
and
the
resi-
due
triturated
with
pet
ether.
The
product
was
crystd
from
hexane:
yield
73
g;
mp
81-83°.
Anal.
(C12111603)
C,
H.
3-Ethyl-6-methoxyindan-1-one
(5).
-Acid
7
(35
g)
and
1700
g
of
polyphosphoric
acid
were
heated
with
stirring
on
the
steam
(1)
F.
J.
Villani,
C.
A.
Ellis,
R,
F.
Tavares,
M.
Steinberg,
and
S.
Tolks-
dorf,
J.
Med.
Chem.,
13,
359
(1970).
(2)
The
mixture
was
not
separated
into
its
components
but
was
used
di-
rectly
in
the
hydrogenation.
(3)
The
composition
of
the
mixture
was
determined
by
nmr
and
contained
approximately
equal
amounts
of
both
isomers.
We
are
indebted
to
Mr.
James
Morton
of
the
Physical
Analytical
Department
of
the
Schering
Corp.
for
his
interpretations
of
the
nmr
spectrum.
(4)
The
authors
are
indebted
to
Drs.
S.
Tolksdorf
and
M.
Steinberg
of
the
Department
of
Endocrinology
of
the
Schering
Corp.
for
the
biological
data.
(5)
(a)
G.
P.
Mueller
and
D.
Pickens,
J.
Amer.
Chem.
Soc.,
72,
3626
(1950);
(b)
G.
P.
Mueller
and
R.
May,
ibtd.,
71,
3313
(1949).
(6)
Melting
point
are
uncorrected
and
were
obtained
on
a
Thomas
Hoover
open
capillary
melting
point
apparatus.
Where
analyses
are
indi-
cated
only
by
the
symbols
of
the
elements,
analytical
values
are
within
0.4%
of
the
theoretical
values.
1246
Journal
of
Medicinal
Chemistry,
1970,
Vol.
13,
Na.
Commusim
bath
for
3.5
hr,
poured
into
ice,
and
extracted
with
Et
2
O.
The
extracts
were
washed
and
distd
to
give
20.5
g
(63.5%)
of
an
oil:
bp
130-133°
(1
mm);
n
21
14
1.5548;
ir,
strong
band
at
5.85
A.
2,3-Diethyl-6-methoxyindan-l-one
(6).
--To
70
g
of
Nist)Ale
was
added
with
stirring
SO
g
(0.42
mole)
of
5.
With
cooling
400
g
of
ELI
was
added
rapidly
and
the
mixture
was
stirred
for
30
min
and
then
heated
on
the
steam
hark
for
3
hr.
Excess
Ell
was
removed
by
distir,
II
2
0
added,
and
the
mixture
extracted
(Fit
2
0).
The
solvent
was
evapd
after
drying
(Na
2
SO
4
)
and
the
residue
was
distd;
yield
74.5
g
(81(1):
bp
155-160°
(1
nun
):
n
25
0
1.5393.
Anal.
(C
[4
11
1
,0•
)
C,
11.
Pyridyllithium
Reactions.
2-!
p-Methoxypheny1)-1-(
2-pyridyl
)-
cyclohexanol.-
--To
an
El
2
(1soln
(400
ml)
of
13aLi
prepared
under
N2
at,
-10'
from
4.
1
g
(0.6
mole;
of
Li
and
41
.
1
g
(0.3
mole)
of
BuBr
was
added
at
--
r',
47.4
g
10.3
mole
1
of
2-bromopyridi11e
in
200
ml
of
Et
2
0.
After
1
hr.
a
soh]
of
30.6
g
(0.15
mole)
of
2-(p-methoxyphenyl)cyclohexanone
4
in
500
nil
of
I.:1,0
was
added
dropwise
with
stirring
told
the
mixture
was
allowed
to
warns
to
room
temp.
Stirring
was
continued
for
6
hr.
.H
2
0
was
cautiously
added,
the
organic
layer
was
sepd
and
combined
with
an
additional
Et),
;
(
/
extract.
The
combine('
Et2()
solo
were
extracted
with
10%
HC1
and,
actor
preliminary
washing
(lit20),
the
acid
sole
was
basified
(NII
4
011)
and
extracted
(CHC1
3
).
The
CHC1
3
sole
was
washed
(II2t
)))
and
coned
on
the
steam
bath
to
an
oil
which
was
trit
mated
with
pet
ether
(hp
30-60°)
and
recrystd
from
hexane;
yield
24.7
g
(58
1
(i
)
,
nip
74
.7:5°.
The
ir
spectrum
showed
a
typical
()II
hand
at
3
a,
Anal.
Cid],
NO,
C,
11,
N.
1-(2-Pyridy1)-2,3-diethyl-6-methoxy-indan-l-ol
was
prepared
by
a
similar
procedure:
yield
74
1
,
-
,
;
by
183-189'
(1
mat);
nun
1
.5722;
strong
OH
in
ir
at
3.0
Anal.
iC1if323NO2)C,
11.
N.
1-
(3-Pyridy1)-2,3-diethy1-6-methoxy
-1
-indene
(8b).
-This
compound
was
At:anted
Irons
3-bromopyridine
by
the,
above
pro-
cedure
in
61%
yield:
bp
180-185°
(1
intu),
it"ii
1.5923;
log
elliS„,µ
4.05.
Anal.
(,c,,H„No)
C,
11,
N.
Dehydration
Procedure
(Mixture
4).
A
mixture
of
III
g
(0.035
mole)
of
2-(p-methoxypheny1)-1,-(2-pyridyl)cyclohexatiol
and
40
g
of
powdered
potassium
pyrosulfate
was
placed
in
a
bath
at
240°
and
the
temp
raised
to
240-200°
with
manual.
stirring
until
the
fusion
was
completed
and
held
at
this
temp
for
1
min.
The
mixture
was
allowed
I
to
eta)l
somewhat.
and
poured
into
ice.
made
basic
(N11
4
0H),
and
extracted
(C1
-1C1
4
),
trashed,
and
distd:
by
172-175°
(2.5
min);
yield
5.8
g
(
.
63
4
,)
)
:
,1
5
1
1.0063.
Anal.
(C
18
1I
19
1\TO)
C,
11
,
N.
1-(2-Pyridy1)-2,3-diethyl-6-methoxy-l-indene
(8.a).•
A
inix-
ture
of
the
2-pyridyl
carbinol
(I()
g)
and
7
nil
of
85%
115104
was
heated
tinder
reflux
for
0
hr
and
poured
into
ice.
The
solution
was
made
basic
(NaOH)
and
extracted
(ClIC13).
The
solvent
was
removed
and
the
residue
was
distil;
yield
7
g
(70%):
by
173-178°
(I
runt
)
:
n"ti
1
.5838;
log
e.26.
4
„,,
4.08.
Ana/.
;C,
11,,,NO)
C,
p-Methoxypheny1-2-(2-pyridyl)cyclohexane
i2).
--A
sol
ii
of
5.))
g
(0.019
mole)
of
mixture
4
in
250
ml
of
Et(R1
was
hydro-
genated
in
a
Parr
hvdrogenator
in
presence
of
0.5
g
of
Pt(
i
t
.
The
reduction
required
20-22
hr.
Th,,
catalyst
was
filtered
and
the
residue
after
removal
of
the
solvent
was
distil:
yield
4.3
g
(85%);
by
190-192°
;3
nun):
n'
2
0
1
.5766.
Areal.
[C1‘11))1NO
C,
II,
N.
1-(2-Pyridyl)-2,3-diethyl-6-methoxyindane
(3).
- -
The
indetat
8a
(5.5
g,
0.02
mole)
in
150
ml
of
Et()11
was
reduced
for
20
hr
itt
a
Parr
hydrogeriator
using
Raney
Ni
catalyst.
The
catalyst
was
removed
and
the
product
was
distil:
yield
3.8
g
(83
(
:);.);
by
1.85-190°
(1
non
a
;
.0
6
1.)
15696.
Anti/.
iC,
1
11
23
N0)HN,
calcd;
found)
(:,
80.68.
New
Compounds
1-Dodecylpyridinium
Dodecyl
Sulfate
C
NTHER
S.
FON
KEN
AND
FoitansT
A.
Al
AcKEni-til
The
Upjohn
Company,
Kalamazoo,
.11
iehigan
40001
Received
April
18,
1970
When
a
mixture
of
1-decanol
and
N-bromoacetamide
in
pyridine
is
treated
with
SO
2
under
the
conditions
described
for
the
dehydration
of
certain
steroid
alco-
hols
1
an
excellent
yield
of
1-dodecylpyridinium
dodecyl
sulfate
is
obtained.
The
same
compound
is
obtained
when
didodecyl
sulfate
is
reacted
with
pyridine.
Evi-
dently
this
fact
had
been
observed
some
years
ago
by
Sementsov,
et
al.,
2
but
their
"S
-containing
salt
of
pyridine"
had
not
been
characterized.
Experimental
Section'
A
solution
of
15.6
g
of
1-dodecanol
and
27.6
g
of
AT-bromo-
acetamide
(NBA)
in
160
ml
of
pyridine
was
treated
with
SO
2
at
about
25°
until
all
of
the
NBA
had
been
destroyed.
Upon
pour-
ing
the
solution
into
an
ice
-water
slurry,
20.23
g
of
1-dodecyl-
pyridinium
dodecyl
sulfate,
mp
68-90°,
precipitated.
Re
-
(1)
See
L.
F.
Fieser
and
M.
Fieser,
"Reagents
for
Organic
Synthesis."
Wiley,
New
York,
N.
V.,
1967,
p
75.
(2)
A.
Sementsov,
R.
J.
Kiesel,
M.
E.
MeOreal,
and
W.
F.
Hart,
./.
Org.
Chem.,
23,
2020
(1958).
(3)
Melting
points
are
uncorrected.
Where
analyses
are
indicated
only
Icy
the
symbols
for
the
elements,
analytical
results
obtained
for
those
ele-
ments
were
within
of
the
theoretical
values.
crystallization
front
EtOAc
gave
an
analytical
sample,
nip
90-
90.5°.
Jr
and
mar
spectra
supported
the
structure.
Anal.
(C25F
L3NO4S1)
C,
H,
N,
S.
The
sample
prepared
by
dissolving
didodecyl
sulfate
in
pyri-
dine,
followed
by
addition
to
11
2
()),
had
nip
91-02°
and
spectral
properties
identical
with
those
of
the
material
prepared
by
thi)
other'
route.
Sit
Analog
of
the
Estrogen
llexestrol
1.Ans
T1.111,N11.'s
Deaartnunt
M
.
Pharmacology,
University
of
Uppsala,
Uppsala,
Sweden
Received
April
4,
1970
The
synthetic
estrogen
me8o-liexestrol
(1)
is
fre-
quently
used
in
the
clinic.
A
great
number
of
anal-
ogous
compounds
have
been
prepared.'
The
thio-
phenol
isostere
II
should
at
least
be
useful
in
making
decisions
about
bonding
forces
in
estrogen
-receptor
complexes'
and
could
be
expected
to
show
some
inter-
esting
biological
properties.
The
synthesis
of
II
by
a
method
similar
to
one
previously
described'
is
reported.
Biological
Activity.
The
thiophenol
analog
II
was
(1)
U.
V.
Sulmssen.
Chun,
Her.
,
37,
481
(1945);
J.
Grundy,
ibid.,
57,
281
(1957).
(2)
11.
G.
Mautner,
Pim
m.
Rer.,
19,
107
(1967).
(3)
S.
F.
Torf
and
N.
V.
Khromov-Burisov,
Zh.
Otcchch.
Khi,,,„
31,
2102
(1961).
They
report
11
to
have
rep
155-157'.