Cholinergic compounds. IX. Cyclohexane analogs of Deoxa muscarine and derivatives


Angeli, P.; Melchiorre, C.; Giannella, M.; Pigini, M.

Journal of Medicinal Chemistry 20(3): 398-400

1977


The synthesis of some cyclohexane analogues of deoxamuscarine is reported. Stereochemical aspects are discussed on the basis of IR and NMR spectra. Muscarinic activity, measured on guinea pig ileum, shows a sharp drop when comparison is made with the cyclopentyl analogues.

398
Journal
of
Medicinal
Chemistry,
1977,
Vol.
20,
No.
3
Melchiorre
et
al.
Cholinergic
Compounds.
9.
Cyclohexane
Analogues
of
Deoxamuscarine
and
Derivatives'
Piero
Angeli,
Carlo
Melchiorre,*
Mario
Giannella,
Maria
Pigini,
Institute
of
Pharmaceutical
and
Organic
Chemistry,
University
of
Camerino,
62032
Camerino
(MC),
Italy
and
M.
L.
Cingolani
Laboratory
of
Pharmacology,
Institute
of
Experimental
and
Clinical
Medicine,
University
of
Ancona
Medical
School,
60100
Ancona,
Italy.
Received
June
25,
1976
The
synthesis
of
some
cyclohexane
analogues
of
deoxamuscarine
is
reported.
Stereochemical
aspects
are
discussed
on
the
basis
of
IR
and
NMR
spectra.
Muscarinic
activity,
measured
on
guinea
pig
ileum,
shows
a
sharp
drop
when
comparison
is
made
with
the
cyclopentyl
analogues.
In
order
to
better
understand
the
structure
—activity
relationships
within
the
deoxamuscarine
(16)
2
'
3
and
de-
oxamuscarone
(14)
4
series
of
agonists,
it
was
of
interest
to
extend
our
investigations
to
cyclohexane
analogues
1-3.
With
these
new
analogues
the
most
serious
structural
alteration
is
that
the
methyl
substituent
of
the
cyclopentyl
compounds
now
forms
part
of
the
enlarged
ring
and
finds
itself
at
the
end
of
the
"5
-atom
chain"
(which
is
important
for
cholinergic
activity).
5
Such
analogues
may
contribute
to
a
better
understanding
of
the
role
of
the
C-7
methyl
of
muscarine
analogues
and,
hence,
may
help
clarify
the
chemistry
of
the
cholinergic
receptor.
In
order
to
complete
our
SAR
studies
in
this
field,
6
the
methiodide
derivatives
4'
and
5
were
also
investigated.
2
5
6
1
OH
2
OH
3
4
5
R
=
CH,N'(CH,),I
-
;
spatial
position
is
referred
to
R
Chemistry.
Methiodide
derivatives
1-3
were
syn-
thesized
starting
from
the
lactone
of
3-hydroxycyclo-
hexane-1-carboxylic
acid
(6),
easily
prepared
by
reduction
of
3-hydroxybenzoic
acid
8
(Scheme
I).
Ketoamine
9
was
synthesized
by
oxidation
of
8
or
13
avoiding,
in
this
way,
protection
of
the
carbonyl
group
of
3-oxocyclohexane-1-carboxylic
acid
9
'
113
when
used
as
starting
material.
Besides,
the
synthesis
of
11
was
carried
out
through
inversion
at
position
3
of
7,
avoiding
the
tedious
separation
of
the
cis
and
trans
isomers
of
3-
hydroxycyclohexane-1-carboxylic
In
order
to
confirm
the
structure
of
12,
obtained
through
this
inversion
reaction,
cis-3-acetoxy-1-(N,N-dimethyl-
carboxamido)cyclohexane
was
synthesized
from
alcohol
7
by
treatment
with
acetic
anhydride.
Finally,
3-dimethylaminomethylcyclohex-1-ene
meth
-
iodide
(5)
was
obtained
starting
from
the
corresponding
dimethylamide
of
3-cyclohexene-l-carboxylic
acid.
12
Stereochemistry.
The
configuration
of
these
com-
pounds
was
clearly
established
by
the
reaction
sequences
shown
in
Scheme
I.
As
regards
the
more
stable
confor-
mations,
examination
of
relative
hindrance
13
'"
between
groups
at
positions
1
and
3
suggests
a
sharp
preference
for
chair
conformations
with
the
two
functional
groups
as-
suming
the
equatorial
orientation
in
the
cis
series
but
one
axial
(3
-OH)
and
one
equatorial
(position
1)
orientation
in
the
trans
series
(conformer
A).
Using
the
tosyl
de-
rivative
10
and
lactone
6
15
as
models,
the
NMR
spectra
Scheme
I
I
,37
6
OH
OTs
20
0
6
3
0
v
..di
cH
2
N(0H
3
)
2
.
:;
,,,A
CH
2
N(cH
3
)
2
9
OH
1
CON(
C
H
3
)
2
CON(C
H
3
)
2
7
10
OH
CH
2
N(CH
3
)
2
8
CON(CH
3
)
2
OR
11,
R
=
H
12,
R
=
COCH,
13
2
Table
I.
IR
and
NMR
Data
at
Position
3
of
Some
Compounds
of
the
Cyclohexyl
Series
Compd
V
3-
OH,
cm
-
'
'H
NMR,
3-H
Solvent
8,
PPm
W
i
l2
a
W
b
8
3330
CDCI,
3.88
19
30
3
3360
D
2
0
3.80
20
30c
13
3350
CDC1
3
4.28
11
18
2
3375
D
2
0
4.23
11
18
10
CDC1
3
4.50
22
40
'H
NMR,
1-H
6
CDC1,
4.68
13
23
a
Half
-height
width
in
hertz.
b
Base
width
in
hertz.
c
Signal
partially
obscured.
confirmed
these
conformations
as
judged
from
chemical
shift
data
and
line
width
of
the
proton
on
the
OH
-bearing
carbon
14
'
16
(Table
I).
Furthermore,
the
stretching
fre-
quency
of
the
OH
at
position
3
was
greater
for
the
trans
compound
than
for
the
corresponding
cis
isomer,''
as
would
be
expected.
Therefore,
it
is
possible
to
exclude
the
existence
of
skew
—boat
forms (conformer
B)
in
the
trans
series
and
of
conformers
like
C
in
the
cis
series.
However,
the
spatial
arrangement
of
the
OH
and
N
-
bearing
carbon
in
the
cyclopentyl
series
may
assume
pseudoequatorial
positions,
13
'
13-2
°
a
possibility
which
is
difficult
to
prove.
However,
the
difference
in
the
relative
positions
of
the
hydroxyl
and
the
side
chain
of
the
two
cyclic
systems
is
rather
small,
so
that
the
major
difference
Cyclohexane
Analogues
of
Deoxamuscarine
Journal
of
Medicinal
Chemistry,
1977,
Vol.
20,
No.
3
399
Table
II.
Comparative
Biological
Activity
of
Cyclohexyl
and
Cyclopentyl
Analogues
of
Muscarone,
Muscarine,
and
Derivatives
on
Guinea
Pig
Terminal
Ileuma
,
b
Cyclohexyl
series
Cyclopentyl
series
Compd
EPMRc
,
d
Compd
EPMR
Ref
1
507
14
0.5
4
2
2
897
15
50
5
3
>
10
000
16
9.8
3
4f
203
17
454
1
5
269
18
221e
5
19
500
23
20
100
23
21
3590e
5
22
100
2
23
16
6
24
30
6
25
11
6
a
Significance
of
the
EPMR's
averages
was
estimated
by
the
t
test
at
p
<
0.05
level.
b
More
details
on
these
ex-
periments
are
reported
in
cited
references.
C
EPMR
equipotent
molar
ratios:
average
number
of
molecules
of
compound
required
to
equal
at
50%
level
the
effects
ob-
tained
by
the
reference
(AcCh).
d
AcCh
(chloride
or
bro-
mide)
taken
equal
to
1.0.
e
Further
tests
have
shown
that
the
activity
previously
reported
was
incorrect.
f
This
compound
was
synthesized
according
to
Baumgarten
et
al.
(ref
7
).
Ye
Xa
a
Re
Xe''
H
Ha
a
Re
Xe
Ya
C
a
e
A
8,
R
=
CH,N(CH
3
)
2
;
X
=
H;
Y
=
OH
3,
R
=
CH,N+(CH,),;
X
=
H;
Y
=
OH
13,
R
=
CH,N(CH,),;
X
=
OH;
Y
=
H
2,
R
=
CH
2
N
4-
(CH,),;
X
=
OH;
Y
=
H
10,
R
=
CON(CH,),;
X
=
H;
Y
=
p-CH,C
6
1-1,S0,
-
lies
in
the
relative
arrangements
about
carbon
7
[4
-methyl
in
the
cyclopentyl
and
methylene
(position
4)
in
the
cy-
clohexyl
series].
Pharmacological
Results
and
Discussion.
Com-
pounds
1-5
were
assayed
on
the
guinea
pig
ileum
prep-
aration.
The
potency
ratios,
relative
to
AcCh,
are
as-
sembled
in
Table
II.
The
large
drop
in
activity,
with
these
substances
when
compared
with
the
corresponding
cy-
clopentyl
analogues
14-25,
shows
that
the
cyclopentane
0
3
2
R
X
^^"
,,
R
7
OH
1
4,
X
=
CH,
1
6,
X
=
CH„
cis
(deoxamuscarone)
(deoxamuscarine)
1
5,
X
=
H
17,
X
=
CH,,
trans
(epi-allo-deoxamuscarine)
1
8,
X
=
H
HO
X
19,
X
=
CH„
cis
(epi-deoxamuscarine
)
20,
X
=
CH„
trans
(al/o-deoxamuscarine
)
21,
X
=
H
X
22,
X
=
CH,
23,
X
=
H
24,
X
=
CH,
25,
X
=
H
R
=
CH,N*(CH,),I
-
;
spatial
position
is
referred
to
R
nucleus
is
a
better
carrier
of
activity
than
the
cyclohexane
ring.
Furthermore,
the
observation
that
the
quaternary
ammonium
group
and
the
oxygenated
functions
in
these
two
series
of
compounds
are
in
almost
identical
positions
further
confirms
the
importance
of
the
C-7
methyl
for
muscarinic
activity.'
In
fact,
by
comparing
the
EPMR's
of
compounds
1-3
with
that
of
the
corresponding
demethyl
derivatives
15,18,
and
21,
it
can
be
concluded
that
the
ring
methylene
of
the
cyclohexane
ring
is
unable
to
contribute
significantly
to
the
biological
activity.
Compounds
of
the
cyclohexyl
series,
as
well
as
those
of
the
cyclopentane
series,
6
lacking
an
oxygenated
function
in
3,
merit
special
consideration.
Thus,
compounds
4
and
5
are
the
most
active
of
the
series
and
their
potency
does
not
drop
dramatically
when
compared
to
the
corresponding
cyclopentane
derivatives
22-25,
in
contrast
to
the
pre-
ceding
cases.
This
result
seems
to
confirm
Triggle's
statement,
21
particularly
for
n-pentyltrimethylammonium
iodide,
22
that
cholinergic
compounds
lacking
an
oxygenated
function
interact
at
the
receptor
level
with
an
accessory
receptor
site
of
reduced
polarity.
Comparison
of
the
EPMR's
supports
the
reduced
specificity
of
this
site
as
compared
to
the
polar
recognition
site.
Experimental
Section
All
melting
points
were
taken
in
sealed
capillaries
on
a
Buchi
apparatus
and
are
uncorrected.
Infrared
spectra
were
recorded
with
a
Perkin-Elmer
257
spectrophotometer
in
Nujol
mull
for
solids
and
neat
for
liquids.
NMR
spectra
were
measured
on
a
Jeol
C-60
HL
spectrometer
using
Me
4
Si
or
DSS
as
internal
standards.
Chromatographic
separations
were
performed
on
a
silica
gel
column
(Kieselgel
40,
0.063-0.200
mm,
Merck).
Where
analyses
are
indicated
using
symbols,
the
analytical
results
are
within
±0.4%
of
the
theoretical
values.
cis-3-Hydroxy-1-(N,N-dimethylcarboxamido)cyclohexane
(7).
3-Oxo-2-oxabicyclo[3.2.1]octane
(6,
8
8.0
g)
and
dimethylamine
(20
ml)
were
heated
in
a
sealed
tube
for
24
h
at
80
°C.
Work
-up
of
the
mixture
23
gave
pure
7
as
a
pale
yellow
oil
that
was
used
without
further
purification:
85%
yield;
IR
3380
(OH)
and
1625
cm'
(CO);
NMR
(CDC1
3
)
5
1.00-2.30
(m,
8,
cyclohexane
protons),
2.73
(m,
1,
1-H),
3.05
(s,
3,
NCH
3
),
3.17
(s,
3,
NCH
3
),
3.73
(m,
2,
3-H
and
3
-OH,
W
112
=
20
Hz).
Anal.
(C
9
H
i7
NO
2
)
C,
H,
N.
cis-3-Hydroxy-1-(N,N-dimethylaminomethyl)cyclohexane
(8).
A
solution
of
7
(3.6
g)
in
dry
ether
(100
ml)
was
added
to
a
stirred
and
cooled
(ice
-water
bath)
suspension
of
LiA1H
4
(2.0
g)
in
dry
ether
(100
ml)
and
then
refluxed
for
4
h.
When
cooled,
the
excess
LiA1H
4
was
decomposed
with
EtOAc
(50
ml)
and
water
(5
ml).
The
solution
was
decanted,
the
white
solid
was
washed
with
EtOAc
(2
X
50
ml),
and
the
organic
layer
dried
over
Na
2
SO
4
.
Evaporation
of
solvent
gave
8
which
was
distilled:
70%
yield;
bp
96-100
°C
(8
mm);
IR
3330
crn
-
'
(OH);
NMR
(CDC1
3
)
0.50-2.30
(m,
11,
cyclohexane
and
1-CH
2
protons),
2.48
[s,
6,
N(CH3)2],
3.88
(m,
1,
3-H),
4.28
(s,
1,
OH).
Anal.
(C
9
H
39
NO)
C,
H,
N.
trans-3-Hydroxy-1-(N,N-dimethylaminomethyl)cyclo-
hexane
(13).
13
was
obtained,
as
described
for
8
starting
from
11
or
12,
as
a
colorless
oil:
70-75%
yield;
IR
3350
cm
-1
(OH);
NMR
(CC1
4
)
1
1.00-2.80
(m,
11,
cyclohexane
and
1-CH
2
protons),
2.40
[s,
6,
N(CH
3
)
2
],
3.96
(s,
1,
3
-OH),
4.28
(m,
1,
3-H).
Anal.
(C
9
H
19
N0)
C,
H.
3-0xo-1-(N,N-dimethylaminomethyl)cyclohexane
(9).
A
solution
of
Cr0
3
(1.08
g)
in
4.5
M
H
2
SO
4
(50
ml)
was
slowly
added
to
a
stirred
solution
of
8
or
13
(1.7
g)
in
4.5
M
H
2
SO
4
(5
ml).
After
standing
at
room
temperature
overnight,
the
solution
was
con-
centrated
in
vacuo,
made
basic
with
5
N
NaOH,
and
extracted
with
CH
2
C1
2
.
Evaporation
of
the
dried
(Na
2
SO
4
)
extract
gave
9
which
was
distilled:
73%
yield;
bp
98-100
°C
(10
mm);
IR
1715
cm'
(CO);
NMR
(CC1
4
)
51.00-3.00
(m,
11,
cyclohexane
and
1-CH2
protons),
2.15
[s,
6,
N(CH
3
)
2
].
Anal.
(C
9
H,,NO)
C,
H,
N.
cis-3-Hydroxy-1-(N,N-dimethylcarboxamido)cyclohexane
p-Toluenesulfonate
(10).
Tosyl
chloride
(8.75
g)
was
added
to
a
stirred
and
cooled
(ice
bath)
solution
of
compound
7
(4.0
g)
in
pyridine
(40
m1).
After
3
h
at
0
°C,
the
solution
was
left
at
room
temperature
overnight.
After
the
usual
work
-up'
10
was
obtained
as
a
white
solid
which
was
purified
by
recrystallization
from
EtOAcc-petroleum
ether:
75%
yield;
mp
119-120
°C;
IR
1635
cm
-
'
(CO);
NMR
(CDC1
3
)
5
1.00-2.20
(m,
8,
cyclohexane
protons),
2.20-2.80
(m,
1,
1-H),
2.45
(s,
3,
PhCH
3
),
2.90
(s,
3,
NCH
3
),
2.99
400
Journal
of
Medicinal
Chemistry,
1977,
Vol.
20,
No.
3
Melchiorre
et
al.
(s,
3,
NCH
3
),
4.50
(m,
1,
3-H,
W
1/2
=
22
Hz),
7.20-8.00
(m,
4,
aromatics).
Anal.
(C
16
H
23
N0
4
S)
C,
H,
N.
trans-3-Hydroxy-1-(N,N-dimethylcarboxamido)cyclo-
hexane
(11)
and
trans-3-Acetoxy-1-(N,N-dimethylcarbox-
amido)cyclohexane
(12).
Compound
10
(2.0
g)
and
potassium
acetate
(2.94
g)
were
heated
under
reflux
for
20
h
in
dimethyl-
formamide
(75
ml)
containing
water
(2.5
ml).
The
solution
was
then
evaporated
in
vacuo
to
dryness;
the
residue
was
treated
with
a
saturated
solution
(2
ml)
of
NaHCO
3
and
extracted
several
times
with
CH
2
C1
2
.
After
evaporation
of
the
solvent,
an
oil
was
obtained
which
was
separated
into
three
main
fractions
by
column
chromatography
using
ethyl
acetate
as
the
eluting
phase.
The
first
fraction
was
an
unidentified
product
of
elimination
(28%
yield).
The
second
fraction
was
12
obtained
as
a
colorless
oil:
35%
yield;
IR
1735
(ester
CO)
and
1640
cm
-1
(amide
CO);
NMR
(CDCI
3
)
6
1.00-2.50
(m,
8,
cyclohexane
protons),
2.12
(s,
3,
CH
3
),
2.50-3.40
(m,
1,
1-H),
3.10
[s,
6,
N(CH
3
)
2
],
5.18
(m,
1,
3-H,
W112
=
9
Hz).
Anal.
(C
11
H
19
NO
3
)
C,
H.
The
third
fraction,
recovered
by
washing
the
column
with
methanol,
was
11
obtained
as
a
colorless
oil:
30%
yield;
IR
3390
(OH)
and
1635
cm
-1
(CO);
NMR
(CDC1
3
)
1
1.10-2.20
(m,
8,
cyclohexane
protons),
2.60-3.40
(m,
1,
1-H),
3.10
(s,
3,
NCH
3
),
3.25
(s,
3,
NCH
3
),
4.32
(m,
1,
3-H,
W
1/2
=
9
Hz).
Anal.
(C
9
H
17
NO
2
)
C,
H.
cis-3-Acetoxy-1-(N,N-dimethylcarboxamido)cyclohexane.
Compound
7
(0.5
g)
and
acetic
anhydride
(5
ml)
were
left
at
room
temperature
overnight.
The
solution
was
then
decomposed
with
water
and
extracted
with
ether
to
give
a
colorless
oil
which
was
used
without
further
purification:
90%
yield;
IR
1730
(ester
CO)
and
1640
cm
-1
(amide
CO);
NMR
(CDC1
3
)
6
1.10-2.20
(m,
8,
cyclohexane
protons),
2.10
(s,
3,
CH
3
),
2.65
(m,
1,
1-H),
2.98
(s,
3,
NCH
3
),
3.10
(s,
3,
NCH
3
),
4.78
(m,
1,
3-H,
W
112
=
19
Hz).
Anal.
(C
11
H19NO3)
C,
H.
3-
(N,N-Dimet
hylaminomethyl)cyclohex-
1-ene.
This
compound
was
obtained
as
described
for
the
case
of
8
starting
from
3-(N,N-dimethylcarboxamido)cyclohex-1-ene:
12
72%
yield;
NMR
(CC1
4
)
1
1.00-2.30
(m,
9,
cyclohexane
and
1-CH
2
protons),
2.13
[s,
6,
N(CH
3
)
2
],
5.57
(m,
2,
CH=CH).
Anal.
(C
9
1
-1
17
N)
C,
H.
3-0xo-l-dimethylaminomethylcyclohexane
Methiodide
(1),
trans-3-Hydroxy-1-dimethylaminomethylcyclohexane
Methiodide
(2),
cis-3-Hydroxy-l-dimethylaminomethyl-
cyclohexane
Methiodide
(3),
and
3-Dimethylamino-
methylcyclohex-1-ene
Methiodide
(5).
The
general
procedure,
described
for
1,
was
as
follows.
An
excess
of
CH
3
I
(5
ml)
was
added
to
a
solution
of
9
(1.5
g)
in
ether
(50
ml).
After
standing
at
room
temperature
overnight
a
white
solid
was
obtained
which
was
recrystallized
from
anhydrous
Et0H-Et
2
0:
90%
yield;
mp
200-202
°C;
IR
1710
cm
-1
(CO);
NMR
(D
2
0)
6
1.10-2.80
(m,
9,
cyclohexane
protons),
3.30
[s,
9,
+
N(CH
3
)
3
],
3.55
(m,
2,
1-CH
2
).
Anal.
(C
1o
H
20
IN0)
C,
H,
N.
Methiodides
2,
3,
and
5
were
obtained
similarly
starting
from
13,
8,
and
3-(N,N-dimethylaminomethyl)cyclohex-1-ene,
re-
spectively,
and
recrystallized
from
the
same
solvent.
Compound
2:
93%
yield;
mp
166-168
°C;
IR
3370
cm
-1
(OH);
NMR
(D
2
0)
1
1.00-2.20
(m,
9,
cyclohexane
protons),
3.33
[s,
9,
+
N(CH
3
)
3
],
3.45
(d,
2,
1-CH
2
),
4.23
(m,
1,
3-H).
Anal.
(C1oH22IN0)
C,
H,
N.
Compound
3:
95%
yield;
mp
204-206
°C;
IR
3360
cm
-1
(OH);
NMR
(D
2
0)
5
0.80-2.30
(m,
9,
cyclohexane
protons),
3.13
[s,
9,
+
N(CH
3
)
3
],
3.23
(d,
2,
1-CH
2
),
3.80
(m,
1,
3-H).
Anal.
(C
10
H
20
IN0)
C,
H,
N.
Compound
5:
92%
yield;
mp
235-237
°C;
NMR
(D
2
0)
I
1.30-2.50
(m,
7,
cyclohexane
protons),
3.15
[s,
9,
+N(CH
3
)
3
],
3.30
(d,
2,
1-CH
2
),
5.73
(m,
2,
CH=CH).
Anal.
(C
1
oH
20
IN)
C,
H,
N.
Pharmacological
testing
was
carried
out
on
guinea
pig
ileum
as
previously
described.
13-6
'
23
In
order
to
allow
a
general
com-
parison
of
the
results,
the
techniques
and
the
statistical
evaluation
of
the
bioassays
were
kept
uniform.
Each
value
of
the
potency
ratio
represents
the
average
of
a
minimum
of
four
determinations
with
AcCh
and
the
experimental
compounds.
Acknowledgment.
The
authors
thank
Professor
F.
Gualtieri
of
the
University
of
Palermo
for
valuable
dis-
cussions
and
suggestions
during
this
research.
References
and
Notes
(1)
(2)
(3)
(4)
(5)
(6)
(7)
(8)
(9)
(10)
(11)
(12)
(13)
(14)
(15)
(16)
(17)
(18)
(19)
(20)
(21)
(22)
(23)
For
paper
8,
see
C.
Melchiorre,
P.
Angeli,
M.
Giannella,
M.
Pigini,
M.
L.
Cingolani,
G.
Gamba,
and
P.
Pigini,
Farmaco,
Ed.
Sci.,
in
press.
K.
G.
R.
Sundelin,
R.
A.
Wiley,
R.
S.
Givens,
and
D.
R.
Rademacher,
J.
Med.
Chem.,
16,
235
(1973).
C.
Melchiorre,
F.
Gualtieri,
M.
Giannella,
M.
Pigini,
M.
L.
Cingolani,
G.
Gamba,
P.
Pigini,
and
L.
Rossini,
Farmaco,
Ed.
Sci.,
30,
300
(1975).
F.
Gualtieri,
M.
Giannella,
C.
Melchiorre,
and
M.
Pigini,
J.
Med.
Chem.,
17,
455
(1974).
C.
Melchiorre,
F.
Gualtieri,
M.
Giannella,
M.
Pigini,
M.
L.
Cingolani,
G.
Gamba,
P.
Pigini,
and
L.
Rossini,
Farmaco,
Ed.
Sci.,
30,
287
(1975).
C.
Melchiorre,
F.
Gualtieri,
M.
Giannella,
M.
Pigini,
M.
L.
Cingolani,
G.
Gamba,
P.
Pigini,
L.
Re,
and
L.
Rossini,
Farmaco,
Ed.
Sci.,
31,
218
(1976).
H.
E.
Baumgarten,
F.
A.
Bower,
and
T.
T.
Okamoto,
J.
Am.
Chem
Soc.,
79,
3145
(1957).
P.
B.
LeVine
and
J.
E.
Gearien,
J.
Org.
Chem.,
26,
4060
(1961).
M.
P.
Mertes,
A.
A.
Ramsey,
P.
E.
Hanna,
and
D. D.
Miller,
J.
Med.
Chem.,
13,
789
(1970).
G.
Stork
and
J.
Ficini,
J.
Am.
Chem.
Soc.,
83,
4678
(1961).
H.
0.
House,
H.
Babad,
R.
B.
Toothill,
and
A.
W.
Noltes,
J.
Org.
Chem.,
27,
4141
(1962).
E.
I.
du
Pont
de
Nemours
&
Co.,
Wm.
F.
Gresham,
British
Patent
628659
(Sept
1,
1949);
Chem.
Abstr.,
44,
8364i
(1950).
E. L.
Eliel,
N.
L.
Allinger,
S.
J.
Angyal,
and
G.
A.
Morrison,
"Conformational
Analysis",
Wiley-Interscience,
New
York,
N.Y.,
1965,
Chapter
2.
A.
F.
Casy,
E.
S.
C.
Wu,
and
B.
D.
Whelton,
Can.
J.
Chem.,
50,
3998
(1972).
The
induced
deformation
by
the
lactone
ring
is
not
taken
into
account.
A.
Hassner
and
C.
Heathcock,
J.
Org.
Chem.,
29,
1350
(1964).
H.
S.
Aaron,
C.
P.
Ferguson,
and
C.
P.
Rader,
J.
Am.
Chem.
Soc.,
89,
1431
(1967).
The
examination
has
been
limited
only
to
those
"envelope"
and
"half
-chair"
conformations
in
which
the
-CH
2
N
+
(CH
3
)
3
group
assumes
the
more
stable
spatial
arrangements
(equatorial,
pseudoequatorial,
or
bisectional).
R.
L.
Lipnick,
J.
Am.
Chem.
Soc.,
96,
2941
(1974).
H.
Baumann,
N.
C.
Franklin,
and
H.
Mohrle,
Tetrahedron,
23,
4331
(1967).
D.
J.
Triggle,
"Neurotransmitter
-Receptor
Interactions
Academic
Press,
New
York,
N.Y.,
1971,
Chapter
IV.
(a)
B.
Belleau,
J.
Med.
Chem.,
7,
776
(1964);
(b)
B.
Belleau,
Ado.
Drug
Res.,
2,
89
(1965).
F.
Gualtieri,
M.
Giannella,
C.
Melchiorre,
M.
Pigini,
M.
L.
Cingolani,
G.
Gamba,
P.
Pigini,
and
L.
Rossini,
Farmaco,
Ed.
Sci.,
30,
223
(1975).