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Chemical modification and structure-activity relationship studies of piperine and its analogs: an example of drug development from folk medicine
QSAR and Drug Design - New Developments and Applications T. Fujita, editor 9 1995 Elsevier Science B.V. All rights reserved
CHEMICAL MODIFICATION STUDIES OF PIPERINE DEVELOPMENT FROM FOLK
321
AND STRUCTURE-ACTIVITY AND ITS ANALOGS: AN MEDICINE
RELATIONSHIP EXAMPLE OF DRUG
REN-LI LI and SHU-YU WANG
School of Pharmaceutical Sciences Beijing Medical University Beijing 100083 China
A folk medicine, the c o n s t i t u e n t s of w h i c h are w h i t e pepper and radish powders, has been used in the northern part of China in the treatment of epilepsy for m a n y years. Piperine(I) was shown to be the active ingredient of this recipe. Structure m o d i f i c a t i o n of p i p e r i n e r e s u l t e d in N - ( 3 , 4 - m e t h y l e n e d i o x y c i n n a m o y l ) - p i p e r i d i n e w h i c h was then used in clinics u n d e r the n a m e of a n t i e p i l e p s i r i n e ( I I ) . For the improvement of its a n t i c o n v u l s a n t a c t i v i t y , f u r t h e r s t r u c t u r a l m o d i f i c a t i o n s of (II) h a v e b e e n e x t e n s i v e l y s t u d i e d f o r e a c h of s t r u c t u r a l moieties in t h i s m o l e c u l e . Q S A R a n a l y s e s of N - c i n n a m o y l p i p e r i d i n e s and c i n n a m a m i d e s s h o w e d that +~, +~ s u b s t i t u e n t s w i t h s m a l l b u l k on the b e n z e n e r i n g f a v o r the a n t i c o n v u l s a n t activity. S u b s t i t u t i o n on the v i n y l e n e l i n k a g e d e m o n s t r a t e d that the s p e c i f i c m o l e c u l a r c o n f i g u r a t i o n and c o n f o r m a t i o n are crucial for the anticonvulsant activity. On the basis of these s t r u c t u r e - a c t i v i t y r e l a t i o n s h i p studies, the m o d e of r e c e p t o r binding of this kind of compound was suggested. ABSTRACT:
i.
INTRODUCTION
Discovery especially the m a i n
of
active
from h i g h e r
approaches
structure
of the
to
an optimized
a novel
drug on a large
natural
lead
lead coming
us with
brilliant
ingredients
plants,
paradigm
active
has
from
natural
been w i d e l y
used
generation.
Modifications
from natural
sources
compound which
scale.
the
one of
of p r o c a i n e
lead
of the
could provide
could be supplied
The d i s c o v e r y
of how to o p t i m i z e
generated
as
is a from
sources.
China has a long h i s t o r y treatment traditional
of d i s e a s e s . and
In this chapter,
The
folk medicines
in u s i n g h e r b a l m e d i c i n e s approach
to
is of great
lead
in the
generation
importance
from
in China.
we will present our research work as an example
of d e v e l o p i n g a novel drug from one of the Chinese recipes.
sources, as
folk medicine
322 2.
ANTIEPILEPTIC
Dry
powder
medicine
of w h i t e
recipe
University, recipe
FOLK MEDICINE
kept
which
was
pepper
by
in the n o r t h e r n
part
handed
on
of C h i n a
presumed
to be safe subjected
to h i m
was
of
from
a secret
Beijing his
body,
In 1970,
it was
Because
radish
so that
trials.
this
recipe was
effects were also studied with animals.
prescriptions
with
designed results
and
tested
showed
that,
of a n t i e p i l e p s y the
in
an equal
dose,
(2) .
Thus,
effect
as
white
white
pepper
Piperine(I) extract, results
was
hence
so
made
radish
it was
that
and
65.36
(2).
The P.I.
mg/kg
value
tablets in
Because plentiful,
was
of
the
be i s o l a t e d
bonds
that
the
showed the same
crude
of
(3).
of this crude in
rats.
The
a c t i v i t y with
seizure,
its LD50 was was
extract
trials
tested
electroshock
and
(LD50/ED50)
source
of
and in addition,
complicated
the were
348.6
MES)
in
(+ 49.65)
5.42.
2
(I)
OF A N T I E P I L E P S I R I N E
considered.
double
obvious
clinical
CH=CH--CH=CH -C--N DISCOVERY
results
in this recipe.
used
(maximum
and
possesses
piperine
ED50
effect
pepper,
Similar
synthetic
Its
could
therapeutic
showed that it shows potent a n t i c o n v u l s a n t
(+- 14.76)
was
The
as the m a j o r c o m p o n e n t
low t o x i c i t y .
3.
tests.
identified
rats was mg/kg
were
animal
extract of w h i t e p e p p e r
pepper,
were
Several
pepper
of w h i t e
(i).
the
white
the
without
effect
r a d i s h p o w d e r was only an e x c i p i e n t The crude a l c o h o l i c
and
the content
pepper
tests
of
clinics
therapeutic
in a n i m a l
ratios
with
of w h i t e
significant
obtained
with
increased
prescription
most
both
both are
In the m e a n w h i l e ,
pharmacological
different
This
of e p i l e p s y
is a kind of seasoning,
clinical
folk
Medical
family.
in the t r e a t m e n t
for m a n y years.
for the human to
radish
member
to the University.
and white pepper
directly
and
family
by the staff m e m b e r
is a v e g e t a b l e
PIPERINE
a staff
had been used by his
presented
AND
white
from w h i t e But,
and thus
the
pepper,
the
synthesis
it w o u l d
is e l i m i n a t e d
pepper
in
China
only 20 % of the content synthesis
of
piperine
be e x p e n s i v e .
from its
structure,
is
not
of piperine of p i p e r i n e is
rather
If one of the two synthesis
of the
323 resulting
molecule
vinylogy,
this
anticonvulsant prediction. named was
would
be
simple.
simplified
activity.
the
could
Pharmacological
principle also
tests
of
possess
verified
this
N-(3,4-methylenedioxy-cinnamoyl)-piperidine(II),
antiepilepsirine,
did exhibit
less potent than piperine.
(• 12.3) mg/kg
(mice)
(4).
The
anticonvulsant
Its ED50
and 98.6
LD50 doses were 132.6 (rats)
From
molecule
(• 14.3) mg/kg
(• 12.1) mg/kg
P.I.
values
activity
(rats)
(mice) and 177
were
but
(MES) values were
1.5
(mice)
88.5
(4).
The
(• 19) mg/kg
and
1.8
(rats)
which were not as high as those of piperine. O t i CH=CH ! I
A After systematic chronic subjected
to
B tests
clinical
broad
(4),
trials
observations
effective
C
pharmacological
toxicological
Clinical
(II)
-I I I
for
showed
spectrum
experiments
the
that
treatment agent,
At present,
4.
Compared clinics,
MODIFICATION
its
an
side is
have given various
OF ANTIEPILEPSIRINE
to the other antiepileptic
the anticonvulsant enough.
activity,
and
is
of its therapeutic effect.
STRUCTURAL
potent
epilepsy.
antiepilepsirine
still used in clinics in China but physicians evaluations
of
was
antiepilepsirine
antiepileptic
effects are relatively low (5).
and acute and
antiepilepsirine(II)
For
the
agents usually used in
activity of antiepilepsirine improvement
structural modifications
of
its
is not
anticonvulsant
have been extensively studied
according to the A, B, and C moieties of its structure(II). 4.1 Modifications
in the Aromatic Ring Moiety
4.1.1 V a r i a t i o n s substituted piperidine
benzene
of the A r o m a t i c
ring
is displaced
piperidine(III) markedly decreased
in
(ED50:200
Its
group,
N-(hexadienoyl)-
anticonvulsant
mg/kg)
activity
(6).
o (III)
W h e n the
N-(3,4-methylenedioxy-cinnamoyl)-
by the propenyl
resulted.
(A in II)
R i n g System:
9 (IV)
/-A
was
324 If
the
benzene
ring
was
replaced
furanacryloylpiperidine(IV), and all m i c e
Z(cis)
have
indicated
form
show
a CNS
form exerts
verified due
to
Tung
whether its
(9)
protons
Z(cis)
have on
NMR be
shown
are
spectrum
of
to
relationship cinnamic
hence
(7) that
the
cinnamamides
effect
of
whereas
the
It r e m a i n e d
to be
of
IV is
the
Rappe
(8)
coupling acids
than
IV, it
the
13,
derivatives
the
with
does
and
Speziale
E
of
while than
hold
for
the
Z
coupling
was
(6).
found
Thus,
the c o n f i g u r a t i o n
not
two
the
From the
constant form
of
the
13.
and
the
cinnamamides
coupling
takes
compound
constants
and
are all g r e a t e r
of the a c t i v i t y
acid
resulted
activity
smaller
compound
CNS
the
effect.
E forms
15,
forming
stimulating
cinnamic all
ring
stimulating
that
of
of their
close
CNS
of
depressing
configuration.
CH=CH
configuration constants
a CNS
the
furan
(6).
et al.
E(trans)
the
a stimulation
died of c o n v u l s i o n
Balsamo the
by
IH to the
observed
for
furanacryloyl
analogs. 4.1.2
Variations
of
Substituents
Cinnamoylpiperidines
with
various
ring w e r e
and
evaluated
results
synthesized
indicated
influenced
by
that
the
Table
1 (6).
these
compounds
The c o u p l i n g were
all
on
the
constants close
to
the
Benzene on
by the m o u s e
anticonvulsant
substituent
on
substituents
the
MES
activity
is
benzene
ring
test.
their
The
significantly as
of the two vinyl
15,
Ring: benzene
shown
in
protons
of
configuration
being
E.
TABLE
1
Substituted
No. i 2 3 4
X
ED50 (MES) mmol/kg
3,4-0CH20H 4-0Me 4-CI
For the
cinnamoylpiperidines
0.342 0.437 0.502 0.248
the p u r p o s e
anticonvulsant
No. 5 6 7 8
of rational activity
of
ED50 (MES) mmol/kg
X 4-Br 4-N02 3,4,5-(0Me) 3 4-0H, 3-0Me
drug
0.481 1.250 0.306 1.812
design,
compounds
of
the
comparison
Table
1 was
of
made
325 first
by
the
reference, benzene
ring
substituted tree, be
Topliss
(10).
was by
substituted
chlorine.
Taking
activity by
synthesized, 1
(ii).
but
was
Thus,
as
methoxy,
According
found the
compound
decreased
to
3,4-dichlorocinnamoylpiperidine(V)
Table and
method
the a n t i c o n v u l s a n t
less
but
the was
Compound
They were VII
piperidines
is
all more potent
the m o s t
potent
was
synthesized
the s t r u c t u r e - a c t i v i t y
relationships
among
Modifications moiety
in order
ethoxycarbonyl acid
ethyl
group
amide
group
of
b i n d i n g with
cinnamoyl-
to
cinnaclarify
4.3).
X : 3,4-CI2 X : 2,4-CI 2 X : 4-CF 3
resulting
(6).
This
cinnamamides
in
is
result
the a n t i c o n v u l s a n t
was
changed
to the
3,4-methylenedioxy-cinnamic
which
almost
led
would
0.282 0.217 0.120
(C in II)
antiepilepsirine(II)
ester(VIII),
anticonvulsant
i.
ED50 (MES) mmol/kg
in the A m i d e M o i e t y
C of
synthesized
the
(See section
V VI Vll
The
to
4 of
4 of Table
substituted
O
4.2
choice
compound
were
Meanwhile, extensively
when
2,4-dichloro-(VI),
compound
molecule
so far s y n t h e s i z e d .
moylpiperidines
than
the
decision
next
than
choice,
4-trifluoromethylcinnamoylpiperidine(VII)
(12,13).
increased
Topliss the
potent
second
2 as
if 4-H on the
be
us
to
inactive believe
indispensable
as
an
that
the
probably
for
receptor. O
II 0 ~ ~ " / - CH=CH---C-OEt
A
series
amides(X)
of
with
synthesized
3,4-methylenedioxy-(IX)
and
various
cyclic
(6).
isopropylamine
and
Cinnamoylpiperidines
We
found
and
that
4-chlorocinnam-
cinnamamides are
exhibit m o d e r a t e
c. c.-c-.
(IX)
aliphatic
sec-butylamine
O
o_%/?
(VIII)
among
the
amines
were
formed
with
most
potent.
activity.
R: NH 2, NHPr, NHPr(i), NHBu, NHBu(i), NHBu(s), NHPent, NHPent(i), NHHept, N(Me) 2, N(Et)2, N(Pr)2, N(i-Bu) 2, NHCH (CH2 )4' NHPh, NHPh (p-Me ), NHCH2Ph, N(CH2)4, N(CH2CH2)20, N(CH2)5
326 oII
CI
R: N. 2, NePr
CH=CH--C--R
'
NHPr(i)
(X)
Each of the p - c h l o r o c i n n a m a m i d e s ( X ) the
corresponding
obvious
that
NHBu
'
N.Bu(i)
'
'
NHBu(s),NHPent, NHHex, N(Me)2, N(Et)2, N(Bu)2, NHCH(CH 2)4, NHCH(CH 2)5, N(CH 2)4, N(CH2) 5 was m o r e p o t e n t
3,4-methylenedioxycinnamamide(IX).
the
anticonvulsant
activity
of
than
It was
cinnamamides
is
influenced by substituents not only on the benzene ring but also at the amide moiety. 4.3
Quantitative S t r u c t u r e - A c t i v i t y A n a l y s i s Derivatives
amine,
of c i n n a m o y l p i p e r i d i n e ,
of
cinnamoylisopropyl-
and cinnamoyl-sec-butylamine with various
the b e n z e n e three
ring w e r e
series
tested
(12,13).
of c i n n a m a m i d e s ,
quantitative
substituents on
On the b a s i s
the H a n s c h
structure-activity
C i n n a m a m i d e s
approach
relationship
of t h e s e
was
(QSAR)
used
in
studies
in
order to further optimize the structure. The QSAR of cinnamoylpiperidines(No. first
studied
equation
(14).
1, w h e r e
The best
C is
1 - 20 of Table 2) was
correlation
equivalent
with
represented
as
ED50(MES ) mmol/kg
was
in
mice. log I/C = -0.248 n = 19, Equation series value
r = 0.875,
1 shows
of
(P b e i n g
of
that
compounds
The electronic 0.i)
(log p)2 + 1.885
the
contributions
the a c t i v i t y
s = 0.158,
l-octanol/water
parameter
to variations withdrawing
of
related
the
benzene
ring
of
and a small
The n e g a t i v e
did not
was 6-fold more potent than the predicted value.
P
significant
Substituents
of steric hindrance
2) w h i c h
log
compounds.
size will
and the c o r r e s p o n d i n g
9 of Table
limited
the
(MR scaled by
make
in the activity.
effect
this
with
c oefficient)
of c i n n a m o y l p i p e r i d i n e .
(No.
activity
(~) and steric parameter
on
ring s u b s t i t u e n t s
compound
(log P)opt = 3.80
anticonvulsant
of ZMR 2 3 4 shows the existence
One
[i]
is p a r a b o l i c a l l y
substituents
an e l e c t r o n
benzene
(log P) + 0.150 Za
0.285 EMR2,3, 4 - 2.664
-
with
increase
coefficient between
receptor
the
site.
fit e q u a t i o n
i,
327
TABLE
2
Parameters
used
in
the
derivation
--CH=CH---
of
equations
2 and
3
% R
log I/C No
X
1 2 3 4 5 6 7
Ra
3-Ci 3-F 4-F 4-Br 2,4-Ci 2 3,4-Ci 2 4-Ci 3,4-OCH20d 3,4,5-(0Me)3 e 4-NO 2 3-NO 2 3-CF 3 2-CF 3 4-CF 3 3-OH,4-OMe 4-OMe 3-I 4-OEt 4-OPr(n) 4-OBu(n) 3-CI 3-F 4-F 4-Br 2,4-Ci 2 3,4-Ci 2 4-CI 4-CF 3 3-CF 3 3-C~ 3-F 4-F 4-Br 2,4-CI 2 4-CI 3,4-Ci 2 4-CF 3 3-CF 3
8
9 i0 ii 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38
a. c. d. e.
N(CH2) 5 N(CH2) 5 N(CH2) 5 N(CH2) 5 N(CH2) 5 N(CH2) 5 N(CH2) 5 N(CH2) 5 N(CH2) 5 N(CH2) 5 N(CH2) 5 N(CH2) 5 N(CH2) 5 N(CH2) 5 N(CH2) 5 N(CH2) 5 N(CH2) 5 N(CH2) 5 N(CH2) 5 N(CH2) 5 NHBu(s) NHBu(s) NHBu(s) NHBu(s) NHBu(s) NHBu(s) NHBu(s) NHBu(s) NHBu(s) NHPr(i) NHPr(i) NHPr(i) NHPr(i) NHPr(i) NHPr(i) NHPr(i) NHPr(i) NHPr(i)
0.788 0.578 0.458 0.314 0.664 0.550 0.606 0.564 0.793 0.268 0.324 0.921 0.723 0.921 -0.272 0.218 0.320 0.500 0.290 0.180 0.410 0.495 0.495 0.540 0.735 0.977 0.714 0.772 0.989 0.620 0.301 0.288 0.580 0.600 0.801 0.498 0.899 0.924
calcd b
0.658 0.572 0.499 0.582 0.673 0.709 0.621 0.116 0.037 0.292 0.274 0.744 0.772 0.772
-0.263 0.152 0.525 0.252 0.285 0.196 0.717 0.674 0.602 0.633 0.680 0.716 0.681 0.819 0.790 0.628 0.674 0.452 0.559 0.665 0.592 0.701 0.747
0.719
IAI
log P
0.130 0.006 0.041 0.268 0.009 0.159 0.015 0.448 0.756 0.024 0.050 0.177 0.049 0.149 0.009 0.066 0.205 0.248 0.005 0.016 0.307 0.179 0.107 0.093 0.055 0.211 0.033 0.047 0.199 0.008 0.373 0.164 0.021 0.065 0.209 0.203 0.152 0.205
3.42 2.86 2.86 3.57
4.14 4.14 3.43 2.66 2.66 2.44 2.44 3.60 3.60 3.60 2.05 2.70 3.84 3.19 3.77 4.27 3.67 3.10 3.10 3.82 4.38 4.38 3.67 3.84 3.84 3.33 3.10 2.76 3.48 4.04 3.33 4.04 3.50 3.50
EMR2,3,4 c
Z~
0.37 0.34 0.06 0.23 0.46 0.60 0.23 -0.32 0.07 0.78 0.71 0.43 0.54 0.54 -0.15 -0.27 0.35 -0.24 -0.25 -0.32 0.37 0.34 0.06 0.23 0.46 0.60 0.23 0.54 0.43 0.37 0.34 0.06 0.23 0.46 0.23 0.60 0.54 0.43
0.80 0.29 0.29 1.09 1.30 1.30 0.80 1.00 1.68 0.94 0.94 0.70 0.70 0.70 1.17 0.99 1.60 1.45 1.91 2.37 0.80 0.29 0.29 1.09 1.30 1.30 0.80 0.70 0.70 0.80 0.29 0.29 1.09 1.30 0.80 1.30 0.70 0.70
N(CH2)5: piperidinyl, b. Calculated using eq. 2. MR(H): 0.I0 was accounted. Not used in the derivation of eq. 2. Not used in the derivation of eqs. i and 2. When
were
obsd
cinnamoylisopropylamines
included
in
the
analysis,
and an
cinnamoyl-sec-butylamines
almost
identical
correlation
328
was o b t a i n e d
as shown in equation
log i/C = -0.155
n = 35, The
value)
binding
obtained
of
the
except
for
included
amide
are
moiety 2
did
Compounds compound
is
8 and
broad
fit 9 were
31 w a s
1/2.4
not
less
to
of
log
and
and
potent
than
effect
in equation
P.
8,
hence
5.7-fold
Topliss
The
This
variations
Compounds
2
potent results
the
reflected
term
enough.
2.8-
with
4.1.2).
9,
was
in the
and
were
more
the
optimum
generate
structural
equation
with
the
ring
according
the
the
to and the
ring
(with
than
The role
accord
(see Section
in
fact that
not
not
+~
in
syntheses
mentioned
that
to the
benzene
on the b e n z e n e This
higher
large.
of compounds
that
in the amide m o i e t y was
attributable
somewhat
is not
substituted 2 shows
design
as p r e v i o u s l y
Table
the
activity.
from
2 is
the transport
+~ s u b s t i t u e n t s
of v a r i a t i o n s 2,
equation
Equation
anticonvulsant
scheme
includes
site.
and
of
(log P)opt = 4.35
i, but the d i f f e r e n c e
of log P p r o b a b l y
receptor
[2]
s = 0.156,
log P v a l u e
of e q u a t i o n
hydrophobic
Z~
ZMR2,3, 4 - 2.032
r = 0.844,
optimum
that
(log p)2 + 1.305 log P + 0.257
0.264
-
2 (14).
31 of
dropped.
potent,
predicted,
while
the
reason
b e i n g obscure. Hopfinger's applied Twenty
to five
molecular
examine
the m o l e c u l a r
volume, area
shape p a r a m e t e r s log I/C = 2.298
In e q u a t i o n lengths,
the
4.4.2).
this
The
log P - 0.301
of
(15) w a s compound
chosen
overlapping
quantitative
gave equation
(MSA)
series
arbitrarily
surface area,
(So).
r = 0.917, 3, A is
volume
(16).
(Vo), and
using
structure
(log p)2 + 0.202 So [3]
of
of the t r i a n g l e
These
bond
by the MO
3 indicates
that
of c i n n a m a m i d e s
is p a r a b o l i c a l l y
the o v e r l a p p i n g
area
(So)
the
(So)opt = 33.67
product
optimized
Equation
these
3 as of the best quality.
the area
group.
next
for c o m p u t i n g
analysis
(log P)opt = 3.82,
the
reflecting
0 and N of the a m i d e by
of
were
analysis
0.003 So 2 + 9.222A - 22.218
n = 25,
bond
QSAR
cinnamamides
overlapping
-
the
shape
values
of
lengths
C=O
were
calculation
related
with and
C-N
by C,
estimated
(see
the a n t i c o n v u l s a n t
of the m o l e c u l e
and
defined
Section activity
log P as well linearly
as
related
329
with
A.
The
to t h a t amide
are
ring
reflection
shown
character
single
bond
the
C=O
character
closer
aspects: an
the
one
ethylene
or
substitution 4.4.1 Methylene
unit
of m o i e t y
diverse
results TABLE
3
are
shown
of
group
Anticonvulsant
1 2 3 4 5 6
R H H H 3,4-0CH20 3,4-0CH20 3,4-0CH20
Except
X
bond
to
donating
increase the
since
bond
length.
electron
overweighs
Structure
linkage
the
the
effect
of
N-substituents
(B in II)
of
includes
the v i n y l e n e
and
the
Vinylene
with
of the d o u b l e moiety
other
moiety is
the
in
the
Ethylene
or
activity
ED50(MES) mmol/kg
CH=CH 0.437 (CH2) 2 0.747 CH 2 >0.985 CH=CH 0.342 (CH2)2 0.237 CH 2 inactive
for the u n s u b s t i t u t e d
and
deletion
respectively.
anticonvulsant
3 and Table
an
bond
of c i n n a m a m i d e s
and p h e n y l a c e t a m i d e s ,
activity.
result They The
4 (17).
of p h e n y l a c y l p i p e r i d i n e s
o
No.
activity
double
B of a n t i e p i l e p s i r i n e
from the v i n y l e n e
in Table
the
the
the
the
bond.
Saturation
variations
for
moiety
replacement
methylene
in p h e n y l p r o p i o n a m i d e s
the
Electron
C=O group.
is the
Replacement
that
is r e a s o n a b l e
in the L i n k a g e
on the d o u b l e
Linkage:
of a c a r b o n
gave
C=O
to the amide
Modifications
with
of the
A is a c t u a l l y
lower
amide
of the the
enhance
to
mean
the
C-N
on
favorable
leading
and
is close
substituents
substituents.
ring
of
of C=O in
probably
could
3.82 w h i c h
so that
these
the
This
The m o d i f i c a t i o n two
of
bond
A term
lengths
nitrogen,
on
N-substituents
3 is
variations
2 would
substituents.
are m u c h 4.4
amide
bond
effects
positive
of
ring
the
the
equation
of
effect
the
The with
substituents
in
the
2.
varied
and of
withdrawing
Thus,
log P of e q u a t i o n
of e q u a t i o n
group
benzene
as
optimum
r-x
No.
7 8 9 i0 ii 12
R
4-Ci 4-CI 4-CI 4-NO 2 4-NO 2 4-NO 2
X
ED50(MES) mmol/kg
CH=CH 0.248 (CH2)2 0.234 CH 2 0.638 CH=CH 1.250 (CH2)2 0.901 CH 2 inactive
derivative(compound
2) in Table
330
3,
the
was
activity
close
However, less in
of
to that
all
substituted
of t h e i r
the s u b s t i t u t e d
potent
Table
than
4.
their
For
the
than
indicate
their
activity
that
the removal is,
unsaturated
double
bond
Anticonvulsant
1 2 3 4 5 6
X
H H H 3,4-0CH20 3,4-0CH20 3,4-0CH20
the
to
EDs0 (MES) mmol /kg
No. 7 8 9 I0 ii 12
of
postulation
bond b e t w e e n
the
group.
But,
postulate. position
could
effect the
The
carbonyl
of the ring
results
anticonvulsant
of
introduction
activity
pionylpiperidine
respectively,
not
results group
necessarily
of The
indis-
EDs0 (MES) mmol /kg
X
4-ci 4-Ci 4-Ci 4-N02 4-N02 4-N02
CH=CH (CH2)2 CH 2 CH=CH (CH2)2 CH 2
0.158 0.546 0.441 0.359 inactive inactive
is to e l e c t r o n i c a l l y
be tenable,
of the b e n z e n e
anticonvulsant
These
less
to the a c t i v i t y .
group
of
the
amide
saturation
Table
3 did
1.76-fold,
activity
was
by i n t r o d u c t i o n
the
whereas activity
enhanced
not atom
interrupt
support into
that
enhanced
into
and
of a m e t h y l e n e d i o x y
this
the p a r a the
phenylpro-
3.19-fold.
1.28-
If
on the c a r b o n y l
ring of c i n n a m o y l p i p e r i d i n e
enhanced
function,
the double
ring will
substituents
of a c h l o r i n e
of
on
influence
a c t i v i t y of compounds.
the
the amide group and the b e n z e n e
the e l e c t r o n i c
but
were
from the vinyl
R
and hence to alter the a n t i c o n v u l s a n t this
all
4),
that the role of s u b s t i t u e n t s
of c i n n a m a m i d e s
polarization
be
shown
a c t i v i t y of p h e n y l a c y l i s o p r o p y l a m i n e s
we p o s t u l a t e d
ring
as
activity.
CH=CH 0.760 (CH2) 2 0.977 CH 2 0.590 CH=CH 0.265 (CH2)2 0.602 CH 2 >1.449
Originally, the b e n z e n e
Table
cinnamamides.
seems
TABLE 4
R
3 of
unfavorable
to the a n t i c o n v u l s a n t
were all
analogs
phenylacetamides,
of one carbon
in general,
pensable
No.
of
cinnamoyl
(compound
corresponding
cinnamamides
cinnamoylpiperidines.
phenylpropionylisopropylamines corresponding
phenylacetylisopropylamine potent
phenylpropionylpiperidines
corresponding
The
3.15-fold,
group into the
331
3,4-position
of
the
benzene
ring
These
results
propionylpiperidines. substituents effect
on
on
interaction
then
the
amide
the b i n d i n g
the vinyl Me,
this
group
CI,
larger
OMe,
and
the
(18).
convulsants
Double
or less
TABLE 5 Anticonvulsant sec-butylamines
the
was
located
s-hydrogen
of as
whereas
Also,
influenced
the
where
on o p p o s i t e and the
linkage
substitutents
increased,
compounds
the
anticonvulsant
the
activity.
drastically
are
in
Cinnamoyl-sec-
small
the
that
electronic
(17).
Bond:
When
activity
anticonvulsant
potent
an
on the v i n y l e n e
such
Z configuration moiety
exert
5 shows
by
phenyl-
to m e a n
participate
compounds.
the
compounds
bond were
only
also
Table
of
decreased
the
amide
of the d o u b l e
on t h e
SMe,
and
believed
site of the r e c e p t o r
substituted
and
of
activities:
ring
was
not
but
cinnamoyl-
were
s-substitutions
series
substituents
configuration CNS
various
synthesized of
ring
group
s-Substitution with
activities
F,
benzene
with
4.4.2 butylamines were
the
of
the
the
type
of
benzene
sides(trans)
E(cis)
forms w e r e
anticonvulsants.
activities
of s - s u b s t i t u t e d
cinnamoyl-
NH --sec-Bu
No. i 2 3 4 5 6 7 8 9 i0
a.
After of
the
number
Me Et Bu-n PhCH 2 Ph F CI(E) CI(Z) Br(E) Br(Z)
that
0.314 1.054 0.950 >1.365 0.461 0.289 a 0.472 a 1.003
realizing bond
Z(trans)
bromo-cinnamamides show
No. ii 12 13 14 15 16 17 18 19
ED50 (MES) mmol/kg
R OMe(E) OMe(Z) OEt SMe SEt SPh NHCOMe NHCOPh H
0.662 0.348 0.525 0.219 1.073 0.536 0.419 1.755 0.621
convulsant effect.
double of
ED50 (MES) mmol/kg
R
that
of
small
substituents
cinnamamides
and were
E(cis)
may
isomeric
synthesized
on
enhance pairs
(19
the
s-position activity,
of ~ - c h l o r o
- 21).
N-(~-halo-cinnamoyl)-sec-butylamines
the
Tables are more
a
and ~6 and
7
potent
332 than
the
cinnamamides
substituent
on
the
formed
benzene
with
ring.
other For
chloro-cinnamoyl-sec-butylamines, or
bromo
the
atom
into
anticonvulsant
derivatives, decreased note
more
to
in
Tables
the
for
(X)-cinnamamides TABLE
6
X
1
7 8 9
i0 ii 12 13 14 15
16 17 18 19 20 21 22
2,4-C12 2,4-C12 2,4-C12 3,4-CI 2
3,4-Cl 2 3,4-Ci 2
3,4-C12 2-Cl 2-Cl
MES
s-Bu s-Bu i-Pr i-Pr s-Bu s-Bu i-Pr i-Pr s-Bu s-Bu i-Pr i-Pr s-Bu s-Bu i-Pr i-Pr s-Bu s-Bu i-Pr i-Pr i-Pr i-Pr
of
Z E Z E Z E Z E Z E Z E Z E Z E Z E Z E Z E
is
Z(trans)
why
X
27
8.23 7.06 8.22 7.06 8.25 7.07 8.25 7.08 8.23 7.06 8.23 7.08 8.33 7.47 8.32 7.45 8.20 7.01 8.19 7.02 8.38 7.36
of
activity
ED50 (MES) mmol/kg
0.076 0.517 0.234 0.485 0.098 0.606 0.180 1.178 0.195 0.195 0.814 0.857 0.202 0.463 1.332 0.417 0.311 0.351 0.636 1.461 1.135 0.576
u-halo
(22).
Br
6.56 5.54 6.55 5.56 6.56 5.62 6.59 5.62 6.62 5.56 6.60 5.49 6.60 5.60 6.55 5.64 6.63 5.53 6.59 5.67 6.63 5.54
are
Speculation
CONHR
NH
to of
activity, isomers
E-isomer
8ppm
atom
pairs
\c=c' / \
UV IHNMR MeOH X max(nm) ~-H
other
interesting
of ~ - b r o m o c i n n a m a m i d e s
H
282.5 267.5 283.0 268.0 281.5 264.5 281.5 266.5 272.5 257.0 272.5 257.5 273.0 268.0 273.0 268.5 278.0 267.5 278.5 267.5 265.0 258.0
for
bromo
isomers. the
3-
chloro
increased
anticonvulsant the
same
and a
But, or
the
anticonvulsant
~ONHR
Configuration
It
E(cis) of
activity
Br
R
4-Br 4-Br 4-Br 4-Br 4-CI 4-CI 4-CI 4-CI 3-CI 3-Ci 3-C1 3-Ci 2,4-Ci 2
possesses
\c=c" I \
H
2 3 4 5 6
Most
of
linkage
fold.
all
the
4-bromo,
chloro
of
7 exhibit
explanation
and
a
degrees.
corresponding
also
vinylene
1.2-1.6
isomers
with
introduction
of
various E
6 and
the
Structure
No.
about
extents.
than
made
to
and
various
potent been
activity Z
cinnamamides
of
introduction
both
4-chloro,
the
u-position
activity
the
the
that
though
has
the
amines
333
The
dipole
the
role
some
of of
~-C-X
C=O
of
in
the
E-isomer
Z-s-halo
E-~-halo-cinnamamides
position The
of
steric
dihedral side
the
hindrance angle
with
benzene
ring
of
between
are
ortho the
could
probably
cinnamamides.
More
substituents
more
potent
on
than
substituents
supplement interesting,
would benzene
the
the
ortho
Z-isomers.
influence
planes
of
the
ring
activity
of
~-chlorocinnamamides
and
chain.
TABLE
7
Structure
and
X
C!
1 2 3 4 5 6 7 8 9 i0 Ii 12 13 14 15 16 17 18 19 20 21
R
22
23 24 25 26 27 28
29 30 31 32
4-CI 4-CI 4-Ci 4-CI 4-Ci 4-Ci 4-Br 4-Br 4-Br 4-Br 3-CI 3-CI 3-Ci 3-Ci 3-Ci 3-Ci
3,4-Cl 2 3,4-CI 2 3,4-CI 2
3,4-C12 2-Ci 2-CI 2-Ci 2-Ci 2-Ci 2-CI
2,4-Cl 2 2,4-Cl 2 2,4-Ci 2
2,4-C12 2,4-C12 2,4-C12
X
\c=c' H'
No.
MES
s-Bu s-Bu i-Pr i-Pr CH(CH2) A ~ CH(CH2) & ~ s-Bu s-Bu i-Pr i-Pr s-Bu s-Bu i-Pr i-Pr CH(CH2) A ~ CH(CH2) n ~ i-Pr i-Pr CH(CH2)&i CH(CH2) & i s-Bu s-Bu i-Pr i-Pr CH(CH2) ~ CH(CH2) & ~ s-Bu s-Bu i-Pr i-Pr CH(CH2) n ~ CH(CH2)._.~
\CONHR
CONHR
\c=c' / n
Configuration
UV MeOH I max(nm)
Z E Z E Z E Z E Z E Z E Z E Z E Z E Z E Z E Z E Z E Z E Z E Z E
280.0 264.0 281.0 265.0 281.0 265.0 282.0 266.5 282.5 266.5 272.0 259.5 272.0 259.5 272.0 259.0 277.5 265.5 278.5 265.5 267.5 256.5 268.0 258.0 268.0 256.5 274.5 264.5 274.0 265.5 275.0 264.0
\Cl IHNMR ~-H
7.96 6.93 7.96 6.93 7.96 6.93 7.95 6.92 7.94 6.91 7.95 6.88 7.94 6.89 7.95 6.90 7.91 6.87 7.90 6.88 8.19 7.12 8.19 7.13 8.20 7.27 8.14 7.07 8.14 7.08 8.13 7.08
8ppm
EDs0 (MES)
NH
mmol/kg
6.51 5.76 6.60 5.75 6.74 5.85 6.61 5.73 6.68 5.96 6.52 5.73 6.58 5.76 6.74 5.81 6.63 5.83 6.65 5.86 6.50 5.86 6.53 5.74 6.67 5.79 6.46 5.87 6.58 5.83 6.61 5.95
0.113 0.358 0.294 0.488 0.887 0.222 0.079 0.251 0.152 0.431 0. 211 0.845 0.775 0.435 0.887 0.534 0.684 0.171 0.249 0.440 0.735 0.825 1.550 1.096 1.226 0.704 0.518 0.416 1.352 0.609 1.056 0.528
the the
334
The
configurations
assigned and of
by the
the m o l a r steric the
the
benzene
side
6ma x is
of
shift
of
form
and
shows
and
in Tables
listed of
are w i t h i n E and
81,
by
between
of the E isomer was
on
the
are all w i t h i n
of
shifts
by
on
same of
the
in the
where
the
~-
chemical
nitrogen
shifts
longer
of
the
of the E Z form
is
of the NH proton
5.49-5.95
and those
of Z
2,4-dichloro-~-bromocinnamoylIH NMR s p e c t r o s c o p y
crystallography
the b e n z e n e
ring
46.4 ~ , w h i l e
TABLE 8 Anticonvulsant cinnamoyl-sec-butylamines
the
grades
(23).
by the X max and
X-ray
located
7, the ~ - p r o t o n
The chemical
6.46-6.74
assigned
and
is
were (Xmax)
isomer
configuration
distinguished
6 and
lower
isomer
E(cis)
are
proton
6.88-7.47
Z isomers
confirmed
angle,
the
of 7.91-8.38.
isopropylamine also
also
~-proton
the
The
maximum
of the
Z(trans)
of
group
(23).
was
of E - ~ - h a l o - c i n n a m a m i d e s
The
of the
amido
bond
cinnamamides
absorption
Because
those
As shifts
in the range
isomers
Xmax
cinnamamides
the
of the
than
the
double
group.
s-substituted
(6max).
the
greater
ring
the
substituted
amido
absorptivity
distortion,
and
of
UV w a v e l e n g t h
(23).
and v i n y l e n e
that of the
activity
of
The
linkage
Z isomer was
~-substituted
were
dihedral planes 27.8 ~ .
4-chloro-
R
HI
No.
the
that
ED50(MES) mmol/kg
No.
0.240 0.073 0.070 0.655 0.348 0.144 0.217
8 9 i0 ii 12 13 14
1 2 3 4 5 6 7
Me Et n-Pr i-Pr Ph CI Br
a.
With convulsant effect.
4.4.3 on
R
double
smaller
~-Substitution bond
NH --sec-Bu
gave
substituents
ED50(MES) mmol/kg
R
NH 2 0.244 NHMe 0.713 NHEt 0.635 NHPr(i) 0.524 NHPr 1.358 a NHBu(i) >1.314 NHBu >1.314
on the D o u b l e
results
similar
enhance
the
Bond:
~-Substitution
to s - s u b s t i t u t i o n ,
anticonvulsant
so
activity
335
and larger substituents Table
m a r k e d l y decrease
It is interesting of compound only
group
n-propyl
compound benzene
of
4 has greater
that
3.
distortion
of
to o b t a i n
4.4.4
a suitable
Table
angle
planes
(81)
planes
(82) were
and
between
above
the
benzene
the
amide
on the opposite
side
analogs,
(trans)
however,
82 is not w i t h i n
30 ~ a n d
-64 ~ , t h e
amide
linkage.
of compounds
on c o m p o u n d
vinyl
group
and
vinyl
group
with
activity
seem
to
in Table
do
not
additional be
9.
the
is a l m o s t
show
factors
crucial
to
the
of
the
range
between
anticonvulsant
2, 4, 6, 8, 10 and In this
perpendicular
The conformations of the receptor.
3 and 5 of the
of have
In spite the
from -90 ~ to -115 ~ .
group
fit the requirement
activities
82,
for compounds
in the range
plane of vinylene do not
cinnamamides
82 values
the
and
of the double bond.
such
if
of
next
ring and the amide m o i e t y
configuration,
fall
were
and
for anticonvulsant
E(trans)
9
of
(25). (4.1.1),
shown
plane
Because
bond on the
conformation
and
the
data
group
for the stable
81
Table
3 for X-
a c t i v i t y of this
ring
as
The
why
by the EHMO method.
angles,
activity.
of
it was
configuration
activity
anticonvulsant
Bond:
compounds
were m a d e
the benzene
For ~ , ~ - d i s u b s t i t u t e d torsion
of c o m p o u n d
on the d o u b l e
that
the
between
energy
cinnamamides,
to be g e n e r a l l y
is p r o b a b l y
for the anticonvulsant
estimated
As m e n t i o n e d
crystal
~,~-disubstituted
calculations
that
m i n i m u m potential
This
Unfortunately,
From the c r y s t a l l o g r a p h y
chemical
torsion
of
of the
The existence
on the Double
9 shows
are crucial
of compounds.
6, q u a n t u m
the planes
80 ~ .
ring.
of s u b s t i t u e n t s
activity,
(22).
conformation
than
study.
effect
anticonvulsant
hindrance
of the vinyl m o i e t y caused
decreased.
~,~-Disubstitution
the i m p o r t a n t
the
benzene
The the
is
crystallography
the angle between
dramatically
ray crystallographic
studied
the
steric
X-ray
group at the ~-position
3.
that
compounds
ring and the side chain is about
not p o s s i b l e
simple
two
compound
showed
its a c t i v i t y was
as
(see
activity
i/i0 that of compound
these
of compound
4 (24)
drastic
class
8 is about
between
group
the isopropyl
The
(24)
to note that the anticonvulsant
4 of Table
difference
isopropyl the
the a c t i v i t y
8).
Z(cis)
16 in range,
with
the
of these compounds The anticonvulsant configuration
are
336 probably these
to
a
molecules
dipole role
of of
Z(cis) only the
due
and
the the
similarity
amide
difference
about
of
but
between
42 ~ , which
ii
and
bond
carbonyl
8 I.
cyano
compounds
s-C-halogen
configuration,
value
of
should
the
cyano take
Compound
7
not
to
be
be
and a
a
is
and
the
of
the
in
the
part also
compounds
for
In
activity.
critical
exceeded
groups. group
convulsant
compound
seems
carbonyl
probably
possesses
this
There
13,
could
group. it
and
3
and
value
the
The
for
5
is
81
of
anticonvulsant
activity. TABLE 9 Configurations, torsion activities of ~,~-disubstituted butylamines
01
angles, and anticonvulsant 4-chlorocinnamoyl-sec-
02
D
No.
RI
R2
i 2 3 4 5 6 7
H Me Me Et Et n-Pr n-Pr i-Pr i-Pr Br Br Cl Cl Me Me n-Pr Et Me
CN CN CN CN CN CN CN CN CN Br Br Cl C1 Et Et Et Me Me
8
9 I0 ii 12 13 14 15 16 17 18
a.
In Balsamo
and
activities show
CNS
Configuration
to
the
coworkers
Torsion Angle 8 8 1 2
E(trans) E(trans) Z(cis) E(trans) Z(cis) E(trans) Z(cis) E(trans) Z(cis) E(trans) Z(cis) E(trans) Z(cis) E(trans) Z(cis) E(trans) E(trans) E(trans)
6.08 5.46 6.00 5.36 6.01 5.36 6.04 5.38 5.75 5.34 5.90 5.70 5.50 4.72
With convulsive
addition
dimethyl
IHNMR NH(ppm)
14 ~ 21 ~ 17 ~ 40 ~ 34 ~ 47 ~ 44 ~ 54 ~ 52 ~ 20 ~ 20 ~ 17 ~ 17 ~ 9~ i0 ~ 52 ~ 42 ~ ii ~
the
depressant
ED50(MES) mmol/kg
- 31 ~ -105 ~ 103 ~ -107 ~ i00 ~ -105 ~ 105 ~ -115 ~ i00 ~ _ 90 ~ 81 ~ - 64 ~ 104 ~ - 31 ~ 30 ~ _ 95 ~ - 45 ~ 34 ~
0.417 0.362 a 0.148 a 0.344 a 0.188 0.082 a 1.314 a 0.146 a 1.314 a 0.253 a 0.146 0.223 0.532 0.506 0.716 a 0.593 a 0.197 0.113
action.
results (7)
have
described
central
that
display
nervous
activity,
above
indicated
cinnamoyl-monoalkylamines on
u
system
whereas
the
(Section the
E-
quite
(CNS). Z
isomers
4.1.1),
and
Z-~,~-
different The
E
cause
forms CNS
337 stimulation.
Results
are c o n s i s t e n t not.
with
The convulsant
drastic
The
but that
of
the
benzene
for c o m p o u n d
ring
and
amide
of ~ , ~ - d i s u b s t i t u t e d
by the chemical
group
cinnamamides
shifts of the NH proton.
field and that of the Z isomer
higher
field,
in Table
X-ray
was
That of the E
is in the lower
9 (22).
planes
linkage.
isomer
as shown
is in the
crystallography
of E - N - ( ~ - c y a n o - ~ - n - p r o p y l - 4 - c h l o r o - c i n n a m o y l ) - s - b u t y l a m i n e showed
that
opposite 5.
the
benzene
ring
and
sides of the vinylene
RECEPTOR
In
9
16 is
16 is p r o b a b l y due to the
and ethyl groups on the vinylene
configuration
assigned
14, 15, 17 and 18 in Table
results,
effect of compound
distorsion
caused by propyl
for compounds their
the
linkage
amide
group
are
also on
the
(25).
MAPPING
summary
relationships
of
of
the
structure-anticonvulsant
cinnamamides,
we
can
come
to
activity the
following
conclusions: (i)
The
compounds
lipophilicity adjusted
by
should
possess
(log P = 3.82 ~ 4.35). substituents
on
the
comparatively
high
Their l i p o p h i l i c i t y benzene
ring
can be
and/or
amide
nitrogen. (2) The bulk,
substituents
comparatively
on the b e n z e n e
hydrophobic
and
ring
should
be small
electron-withdrawing
in in
nature. (3) The the
product
amide
moiety
activity.
This
of the values
of C=O and C-N bond
significantly
leads
influences
to the consideration
the
lengths
of
anticonvulsant
that
the amide
group
binds with the receptor. (4)
The
opposite least
benzene sides
two
distorted On
the
basis
for
possessing
and
of the double
carbon too much
receptor
ring
atoms.
of
the
above
compounds
interaction this
ring
should
conclusions, almost
sites.
binds,
the
from the hydrophobic
the
available
area, space
must
on
the
by at
not
be
linkage. hypothetical
a planar
structure
There is a hydrophobic which might also exert
with the substituted
hydrophobic
be
be separated
moieties
to the benzene moiety,
In the
of
two
has
at least three binding
region
group
bond and should These
a charge-transfer
benzene
amide
from the plane of the vinylene
these
area c o r r e s p o n d i n g
Apart
the
where is
benzene
the
somewhat
area at a proper distance,
ring.
substituted narrow.
there is a
338 binding
site w h i c h
carbonyl there
group
is
hydrogen
exerts
of the
a site
ligand.
which
bonding.
a dipole-dipole
can
Close
bind
to this
with
These situations
interaction
the
with
dipolar
amide
the
region,
nitrogen
are illustrated
in Fig.
by i.
dipol~ Fig. The
I.
Model of c i n n a m a m i d e - r e c e p t o r
halogen
atom
of
E-~-halo-cinnamamides
interact with the dipolar carbonyl
group
cinnamamides 6.
This
is probably
show anticonvulsant
fact
that
not known
piperine
can
in place of the
the reason why
E-s-halo-
activity.
before
possesses
the active
folk m e d i c i n e was discovered, cinnamamides generate designed
knowing
piperidine
studies
the
antiepileptic activity of
of piperine
anticonvulsant
to was
activity
of
We found this out only during a
literature
just b e f o r e
the
structural
N-(3,4-methylenedioxycinnamoyl)-
of the structure
substituent
vinylene
revealed
configuration Among 12,
14,
6, and
than
29,
compounds
than
antiepilepsirine.
them
is n o w
under
and
200
ring.
have
reached
effect
of
on the
on the a n t i c o n v u l s a n t synthesized,
2, c o m p o u n d s
7 in T a b l e
studies.
extensively
Substitutions
cinnamamides
From the economic
studies
been
we quickly
crucial
38 in Table
1 and
preclinical
relationship
the
and c o n f o r m a t i o n
more 26,
has
approach,
for the benzene
linkage
activity.
of N - ( 3 , 4 - m e t h y l e n e d i o x y -
(antiepilepsirine)
By the aid of the Hansch
the optimum
activity
that
of
cinnamoyl)-piperidine
in T a b l e
activity
were started.
The m o d i f i c a t i o n
compounds
of this
The m o d i f i c a t i o n
had been reported. r e v i e w of the
modification
molecular
component
but the anticonvulsant
had been reported.
without
systematic
studied.
anticonvulsant
N-(3,4-methylenedioxy-cinnamoyl)-piperidine
cinnamamides
the
probably
region of the receptor
CONCLUSION
The was
(22).
interaction
point
of view,
Moreoever,
provided
1 and 5
7 are m o r e
potent one of
structure-
us w i t h
a better
339
understanding
of the interaction
between cinnamamide
and its
receptor. REFERENCES
1 Epilepsy Clinics, People's Hospital. Beijing Medical College Affiliated Hospital, Journal of Beijing Medical College, 1974, 6: 214. 2 Faculty of Pharmacology, School of Basic Medicine, J. Beijing Medical College, 1974, 6; 217. 3 Pharmaceutical Factory of Beijing Medical College, J. Beijing Medical College, 1974, 6: 221. 4 Yin-quan Pei, Jia-shan Li, Zhi-ji Cai, Bao-heng Zhang, Cheng Tao, Bao-shan Ku, J. Beijing Medical College, 1977, 9: 234. 5 Epilepsy Clinics, People's Hospital, Beijing Medical College Affiliated Hospital, Chinese J. Internal Medicine, 1977 (new), 2: 321. 6 Xiao-hui Zhang, Ren-li Li, Meng-shen Cai, J. Beijing Medical College, 1980, 12: 83. 7 A. Balsamo, P.L. Barili, P. Crotti, B. Macchia, F. Macchia, A. Pecchia, A. Cuttica, and N. Passerini, J. Med. Chem., 1975, 18: 843. 8 C. Rappe, Acta Chem. Scand. 1964, 18: 818. 9 A.J. Speziale and C.C. Tung, J. Org. Chem., 1963, 28: 1353. I0 J.G. Topliss, J. Med. Chem., 1972, 15: 1007. ii Shu-yu Wang, and Ji-cang Zhou, J. Beijing Medical College, 1982, 14: 65. 12 Shu-yu Wang, Ren-li Li, Wei-qin Liu, Ping Liu, Jing-mei Song, Yin-quan Pei, Hai-yan Yao, Xue-min Gao, Acta Pharmaceutica Sinica, 1986, 21: 542. 13 An-liang Li, Wei-qin Liu, Yin-quan Pei, Shu-rong Zhang, and Chen Xu, Acta Pharmaceutica Sinica, 1984, 19: 888. 14 Ren-li Li, and Shu-yu Wang, Acta Pharmaceutica Sinica, 1986, 21: 580. 15 A.J. Hopfinger, J. Am. Chem. Soc., 1980, 102: 7196. 16 Shu-yu Wang, Ren-li Li, Wei-qin Liu, Xiao-jie Xu, Yue Guan, Chinese J. Org. Chem., 1988, 8: 217. 17 Xiao-hui Zhang and Ren-li Li, J. Beijing Medical College, 1985, 17: 225. 18 Wei-qin Liu, Ji-cang Zhou, An-liang Li, Cheng Bi, J. Beijing Medical College, 1984, 16: 62. 19 Shu-yu Wang, Gui-qi Wang, Gao-yun Hu, Song-jing Cai, Jingmei Song, Wei-chin Liu, Cheng Tao, Acta Pharm. Sinica, 1987, 22: 420. 20 Shu-yu Wang, Wei-qin Liu, Ren-li Li, Chemical J. Chinese University, 1987, 8: 813. 2 1 S h u - y u Wang, Wei-qin Liu, Yin-fen Wang, Jing-min Song, Cheng Tao, Xiang-fang Zhou, J. Beijing Medical University, 1988, 20: 297. 22 Shi-qi Peng, Wei-qin Liu, Yin-quan Pei, Su-ming Chen and Fang Guo, Acta Pharm. Sinica, 1986, 21: 20. 23 Shu-yu Wang, Dong Wang, Liang Qiao, Ying-fen wang, Ji-hai Pang, Wei-qin Liu, Ren-li Li, Chinese J. of Microwave and Radiofrequency Spectroscopy, 1987, 4: 355. 24 Wei-qin Liu, Ji-cang Zhou, and Xiao-ping Lei, Acta. Pharm. Sinica, 1983, 18: 912. 25 Ji-cang Zhou, Shi-qi Peng, and Wei-qin Liu, J. Mol. Sci. (Wuhan, China), 1986, 4: 187.
CHEMICAL MODIFICATION STUDIES OF PIPERINE DEVELOPMENT FROM FOLK
321
AND STRUCTURE-ACTIVITY AND ITS ANALOGS: AN MEDICINE
RELATIONSHIP EXAMPLE OF DRUG
REN-LI LI and SHU-YU WANG
School of Pharmaceutical Sciences Beijing Medical University Beijing 100083 China
A folk medicine, the c o n s t i t u e n t s of w h i c h are w h i t e pepper and radish powders, has been used in the northern part of China in the treatment of epilepsy for m a n y years. Piperine(I) was shown to be the active ingredient of this recipe. Structure m o d i f i c a t i o n of p i p e r i n e r e s u l t e d in N - ( 3 , 4 - m e t h y l e n e d i o x y c i n n a m o y l ) - p i p e r i d i n e w h i c h was then used in clinics u n d e r the n a m e of a n t i e p i l e p s i r i n e ( I I ) . For the improvement of its a n t i c o n v u l s a n t a c t i v i t y , f u r t h e r s t r u c t u r a l m o d i f i c a t i o n s of (II) h a v e b e e n e x t e n s i v e l y s t u d i e d f o r e a c h of s t r u c t u r a l moieties in t h i s m o l e c u l e . Q S A R a n a l y s e s of N - c i n n a m o y l p i p e r i d i n e s and c i n n a m a m i d e s s h o w e d that +~, +~ s u b s t i t u e n t s w i t h s m a l l b u l k on the b e n z e n e r i n g f a v o r the a n t i c o n v u l s a n t activity. S u b s t i t u t i o n on the v i n y l e n e l i n k a g e d e m o n s t r a t e d that the s p e c i f i c m o l e c u l a r c o n f i g u r a t i o n and c o n f o r m a t i o n are crucial for the anticonvulsant activity. On the basis of these s t r u c t u r e - a c t i v i t y r e l a t i o n s h i p studies, the m o d e of r e c e p t o r binding of this kind of compound was suggested. ABSTRACT:
i.
INTRODUCTION
Discovery especially the m a i n
of
active
from h i g h e r
approaches
structure
of the
to
an optimized
a novel
drug on a large
natural
lead
lead coming
us with
brilliant
ingredients
plants,
paradigm
active
has
from
natural
been w i d e l y
used
generation.
Modifications
from natural
sources
compound which
scale.
the
one of
of p r o c a i n e
lead
of the
could provide
could be supplied
The d i s c o v e r y
of how to o p t i m i z e
generated
as
is a from
sources.
China has a long h i s t o r y treatment traditional
of d i s e a s e s . and
In this chapter,
The
folk medicines
in u s i n g h e r b a l m e d i c i n e s approach
to
is of great
lead
in the
generation
importance
from
in China.
we will present our research work as an example
of d e v e l o p i n g a novel drug from one of the Chinese recipes.
sources, as
folk medicine
322 2.
ANTIEPILEPTIC
Dry
powder
medicine
of w h i t e
recipe
University, recipe
FOLK MEDICINE
kept
which
was
pepper
by
in the n o r t h e r n
part
handed
on
of C h i n a
presumed
to be safe subjected
to h i m
was
of
from
a secret
Beijing his
body,
In 1970,
it was
Because
radish
so that
trials.
this
recipe was
effects were also studied with animals.
prescriptions
with
designed results
and
tested
showed
that,
of a n t i e p i l e p s y the
in
an equal
dose,
(2) .
Thus,
effect
as
white
white
pepper
Piperine(I) extract, results
was
hence
so
made
radish
it was
that
and
65.36
(2).
The P.I.
mg/kg
value
tablets in
Because plentiful,
was
of
the
be i s o l a t e d
bonds
that
the
showed the same
crude
of
(3).
of this crude in
rats.
The
a c t i v i t y with
seizure,
its LD50 was was
extract
trials
tested
electroshock
and
(LD50/ED50)
source
of
and in addition,
complicated
the were
348.6
MES)
in
(+ 49.65)
5.42.
2
(I)
OF A N T I E P I L E P S I R I N E
considered.
double
obvious
clinical
CH=CH--CH=CH -C--N DISCOVERY
results
in this recipe.
used
(maximum
and
possesses
piperine
ED50
effect
pepper,
Similar
synthetic
Its
could
therapeutic
showed that it shows potent a n t i c o n v u l s a n t
(+- 14.76)
was
The
as the m a j o r c o m p o n e n t
low t o x i c i t y .
3.
tests.
identified
rats was mg/kg
were
animal
extract of w h i t e p e p p e r
pepper,
were
Several
pepper
of w h i t e
(i).
the
white
the
without
effect
r a d i s h p o w d e r was only an e x c i p i e n t The crude a l c o h o l i c
and
the content
pepper
tests
of
clinics
therapeutic
in a n i m a l
ratios
with
of w h i t e
significant
obtained
with
increased
prescription
most
both
both are
In the m e a n w h i l e ,
pharmacological
different
This
of e p i l e p s y
is a kind of seasoning,
clinical
folk
Medical
family.
in the t r e a t m e n t
for m a n y years.
for the human to
radish
member
to the University.
and white pepper
directly
and
family
by the staff m e m b e r
is a v e g e t a b l e
PIPERINE
a staff
had been used by his
presented
AND
white
from w h i t e But,
and thus
the
pepper,
the
synthesis
it w o u l d
is e l i m i n a t e d
pepper
in
China
only 20 % of the content synthesis
of
piperine
be e x p e n s i v e .
from its
structure,
is
not
of piperine of p i p e r i n e is
rather
If one of the two synthesis
of the
323 resulting
molecule
vinylogy,
this
anticonvulsant prediction. named was
would
be
simple.
simplified
activity.
the
could
Pharmacological
principle also
tests
of
possess
verified
this
N-(3,4-methylenedioxy-cinnamoyl)-piperidine(II),
antiepilepsirine,
did exhibit
less potent than piperine.
(• 12.3) mg/kg
(mice)
(4).
The
anticonvulsant
Its ED50
and 98.6
LD50 doses were 132.6 (rats)
From
molecule
(• 14.3) mg/kg
(• 12.1) mg/kg
P.I.
values
activity
(rats)
(mice) and 177
were
but
(MES) values were
1.5
(mice)
88.5
(4).
The
(• 19) mg/kg
and
1.8
(rats)
which were not as high as those of piperine. O t i CH=CH ! I
A After systematic chronic subjected
to
B tests
clinical
broad
(4),
trials
observations
effective
C
pharmacological
toxicological
Clinical
(II)
-I I I
for
showed
spectrum
experiments
the
that
treatment agent,
At present,
4.
Compared clinics,
MODIFICATION
its
an
side is
have given various
OF ANTIEPILEPSIRINE
to the other antiepileptic
the anticonvulsant enough.
activity,
and
is
of its therapeutic effect.
STRUCTURAL
potent
epilepsy.
antiepilepsirine
still used in clinics in China but physicians evaluations
of
was
antiepilepsirine
antiepileptic
effects are relatively low (5).
and acute and
antiepilepsirine(II)
For
the
agents usually used in
activity of antiepilepsirine improvement
structural modifications
of
its
is not
anticonvulsant
have been extensively studied
according to the A, B, and C moieties of its structure(II). 4.1 Modifications
in the Aromatic Ring Moiety
4.1.1 V a r i a t i o n s substituted piperidine
benzene
of the A r o m a t i c
ring
is displaced
piperidine(III) markedly decreased
in
(ED50:200
Its
group,
N-(hexadienoyl)-
anticonvulsant
mg/kg)
activity
(6).
o (III)
W h e n the
N-(3,4-methylenedioxy-cinnamoyl)-
by the propenyl
resulted.
(A in II)
R i n g System:
9 (IV)
/-A
was
324 If
the
benzene
ring
was
replaced
furanacryloylpiperidine(IV), and all m i c e
Z(cis)
have
indicated
form
show
a CNS
form exerts
verified due
to
Tung
whether its
(9)
protons
Z(cis)
have on
NMR be
shown
are
spectrum
of
to
relationship cinnamic
hence
(7) that
the
cinnamamides
effect
of
whereas
the
It r e m a i n e d
to be
of
IV is
the
Rappe
(8)
coupling acids
than
IV, it
the
13,
derivatives
the
with
does
and
Speziale
E
of
while than
hold
for
the
Z
coupling
was
(6).
found
Thus,
the c o n f i g u r a t i o n
not
two
the
From the
constant form
of
the
13.
and
the
cinnamamides
coupling
takes
compound
constants
and
are all g r e a t e r
of the a c t i v i t y
acid
resulted
activity
smaller
compound
CNS
the
effect.
E forms
15,
forming
stimulating
cinnamic all
ring
stimulating
that
of
of their
close
CNS
of
depressing
configuration.
CH=CH
configuration constants
a CNS
the
furan
(6).
et al.
E(trans)
the
a stimulation
died of c o n v u l s i o n
Balsamo the
by
IH to the
observed
for
furanacryloyl
analogs. 4.1.2
Variations
of
Substituents
Cinnamoylpiperidines
with
various
ring w e r e
and
evaluated
results
synthesized
indicated
influenced
by
that
the
Table
1 (6).
these
compounds
The c o u p l i n g were
all
on
the
constants close
to
the
Benzene on
by the m o u s e
anticonvulsant
substituent
on
substituents
the
MES
activity
is
benzene
ring
test.
their
The
significantly as
of the two vinyl
15,
Ring: benzene
shown
in
protons
of
configuration
being
E.
TABLE
1
Substituted
No. i 2 3 4
X
ED50 (MES) mmol/kg
3,4-0CH20H 4-0Me 4-CI
For the
cinnamoylpiperidines
0.342 0.437 0.502 0.248
the p u r p o s e
anticonvulsant
No. 5 6 7 8
of rational activity
of
ED50 (MES) mmol/kg
X 4-Br 4-N02 3,4,5-(0Me) 3 4-0H, 3-0Me
drug
0.481 1.250 0.306 1.812
design,
compounds
of
the
comparison
Table
1 was
of
made
325 first
by
the
reference, benzene
ring
substituted tree, be
Topliss
(10).
was by
substituted
chlorine.
Taking
activity by
synthesized, 1
(ii).
but
was
Thus,
as
methoxy,
According
found the
compound
decreased
to
3,4-dichlorocinnamoylpiperidine(V)
Table and
method
the a n t i c o n v u l s a n t
less
but
the was
Compound
They were VII
piperidines
is
all more potent
the m o s t
potent
was
synthesized
the s t r u c t u r e - a c t i v i t y
relationships
among
Modifications moiety
in order
ethoxycarbonyl acid
ethyl
group
amide
group
of
b i n d i n g with
cinnamoyl-
to
cinnaclarify
4.3).
X : 3,4-CI2 X : 2,4-CI 2 X : 4-CF 3
resulting
(6).
This
cinnamamides
in
is
result
the a n t i c o n v u l s a n t
was
changed
to the
3,4-methylenedioxy-cinnamic
which
almost
led
would
0.282 0.217 0.120
(C in II)
antiepilepsirine(II)
ester(VIII),
anticonvulsant
i.
ED50 (MES) mmol/kg
in the A m i d e M o i e t y
C of
synthesized
the
(See section
V VI Vll
The
to
4 of
4 of Table
substituted
O
4.2
choice
compound
were
Meanwhile, extensively
when
2,4-dichloro-(VI),
compound
molecule
so far s y n t h e s i z e d .
moylpiperidines
than
the
decision
next
than
choice,
4-trifluoromethylcinnamoylpiperidine(VII)
(12,13).
increased
Topliss the
potent
second
2 as
if 4-H on the
be
us
to
inactive believe
indispensable
as
an
that
the
probably
for
receptor. O
II 0 ~ ~ " / - CH=CH---C-OEt
A
series
amides(X)
of
with
synthesized
3,4-methylenedioxy-(IX)
and
various
cyclic
(6).
isopropylamine
and
Cinnamoylpiperidines
We
found
and
that
4-chlorocinnam-
cinnamamides are
exhibit m o d e r a t e
c. c.-c-.
(IX)
aliphatic
sec-butylamine
O
o_%/?
(VIII)
among
the
amines
were
formed
with
most
potent.
activity.
R: NH 2, NHPr, NHPr(i), NHBu, NHBu(i), NHBu(s), NHPent, NHPent(i), NHHept, N(Me) 2, N(Et)2, N(Pr)2, N(i-Bu) 2, NHCH (CH2 )4' NHPh, NHPh (p-Me ), NHCH2Ph, N(CH2)4, N(CH2CH2)20, N(CH2)5
326 oII
CI
R: N. 2, NePr
CH=CH--C--R
'
NHPr(i)
(X)
Each of the p - c h l o r o c i n n a m a m i d e s ( X ) the
corresponding
obvious
that
NHBu
'
N.Bu(i)
'
'
NHBu(s),NHPent, NHHex, N(Me)2, N(Et)2, N(Bu)2, NHCH(CH 2)4, NHCH(CH 2)5, N(CH 2)4, N(CH2) 5 was m o r e p o t e n t
3,4-methylenedioxycinnamamide(IX).
the
anticonvulsant
activity
of
than
It was
cinnamamides
is
influenced by substituents not only on the benzene ring but also at the amide moiety. 4.3
Quantitative S t r u c t u r e - A c t i v i t y A n a l y s i s Derivatives
amine,
of c i n n a m o y l p i p e r i d i n e ,
of
cinnamoylisopropyl-
and cinnamoyl-sec-butylamine with various
the b e n z e n e three
ring w e r e
series
tested
(12,13).
of c i n n a m a m i d e s ,
quantitative
substituents on
On the b a s i s
the H a n s c h
structure-activity
C i n n a m a m i d e s
approach
relationship
of t h e s e
was
(QSAR)
used
in
studies
in
order to further optimize the structure. The QSAR of cinnamoylpiperidines(No. first
studied
equation
(14).
1, w h e r e
The best
C is
1 - 20 of Table 2) was
correlation
equivalent
with
represented
as
ED50(MES ) mmol/kg
was
in
mice. log I/C = -0.248 n = 19, Equation series value
r = 0.875,
1 shows
of
(P b e i n g
of
that
compounds
The electronic 0.i)
(log p)2 + 1.885
the
contributions
the a c t i v i t y
s = 0.158,
l-octanol/water
parameter
to variations withdrawing
of
related
the
benzene
ring
of
and a small
The n e g a t i v e
did not
was 6-fold more potent than the predicted value.
P
significant
Substituents
of steric hindrance
2) w h i c h
log
compounds.
size will
and the c o r r e s p o n d i n g
9 of Table
limited
the
(MR scaled by
make
in the activity.
effect
this
with
c oefficient)
of c i n n a m o y l p i p e r i d i n e .
(No.
activity
(~) and steric parameter
on
ring s u b s t i t u e n t s
compound
(log P)opt = 3.80
anticonvulsant
of ZMR 2 3 4 shows the existence
One
[i]
is p a r a b o l i c a l l y
substituents
an e l e c t r o n
benzene
(log P) + 0.150 Za
0.285 EMR2,3, 4 - 2.664
-
with
increase
coefficient between
receptor
the
site.
fit e q u a t i o n
i,
327
TABLE
2
Parameters
used
in
the
derivation
--CH=CH---
of
equations
2 and
3
% R
log I/C No
X
1 2 3 4 5 6 7
Ra
3-Ci 3-F 4-F 4-Br 2,4-Ci 2 3,4-Ci 2 4-Ci 3,4-OCH20d 3,4,5-(0Me)3 e 4-NO 2 3-NO 2 3-CF 3 2-CF 3 4-CF 3 3-OH,4-OMe 4-OMe 3-I 4-OEt 4-OPr(n) 4-OBu(n) 3-CI 3-F 4-F 4-Br 2,4-Ci 2 3,4-Ci 2 4-CI 4-CF 3 3-CF 3 3-C~ 3-F 4-F 4-Br 2,4-CI 2 4-CI 3,4-Ci 2 4-CF 3 3-CF 3
8
9 i0 ii 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38
a. c. d. e.
N(CH2) 5 N(CH2) 5 N(CH2) 5 N(CH2) 5 N(CH2) 5 N(CH2) 5 N(CH2) 5 N(CH2) 5 N(CH2) 5 N(CH2) 5 N(CH2) 5 N(CH2) 5 N(CH2) 5 N(CH2) 5 N(CH2) 5 N(CH2) 5 N(CH2) 5 N(CH2) 5 N(CH2) 5 N(CH2) 5 NHBu(s) NHBu(s) NHBu(s) NHBu(s) NHBu(s) NHBu(s) NHBu(s) NHBu(s) NHBu(s) NHPr(i) NHPr(i) NHPr(i) NHPr(i) NHPr(i) NHPr(i) NHPr(i) NHPr(i) NHPr(i)
0.788 0.578 0.458 0.314 0.664 0.550 0.606 0.564 0.793 0.268 0.324 0.921 0.723 0.921 -0.272 0.218 0.320 0.500 0.290 0.180 0.410 0.495 0.495 0.540 0.735 0.977 0.714 0.772 0.989 0.620 0.301 0.288 0.580 0.600 0.801 0.498 0.899 0.924
calcd b
0.658 0.572 0.499 0.582 0.673 0.709 0.621 0.116 0.037 0.292 0.274 0.744 0.772 0.772
-0.263 0.152 0.525 0.252 0.285 0.196 0.717 0.674 0.602 0.633 0.680 0.716 0.681 0.819 0.790 0.628 0.674 0.452 0.559 0.665 0.592 0.701 0.747
0.719
IAI
log P
0.130 0.006 0.041 0.268 0.009 0.159 0.015 0.448 0.756 0.024 0.050 0.177 0.049 0.149 0.009 0.066 0.205 0.248 0.005 0.016 0.307 0.179 0.107 0.093 0.055 0.211 0.033 0.047 0.199 0.008 0.373 0.164 0.021 0.065 0.209 0.203 0.152 0.205
3.42 2.86 2.86 3.57
4.14 4.14 3.43 2.66 2.66 2.44 2.44 3.60 3.60 3.60 2.05 2.70 3.84 3.19 3.77 4.27 3.67 3.10 3.10 3.82 4.38 4.38 3.67 3.84 3.84 3.33 3.10 2.76 3.48 4.04 3.33 4.04 3.50 3.50
EMR2,3,4 c
Z~
0.37 0.34 0.06 0.23 0.46 0.60 0.23 -0.32 0.07 0.78 0.71 0.43 0.54 0.54 -0.15 -0.27 0.35 -0.24 -0.25 -0.32 0.37 0.34 0.06 0.23 0.46 0.60 0.23 0.54 0.43 0.37 0.34 0.06 0.23 0.46 0.23 0.60 0.54 0.43
0.80 0.29 0.29 1.09 1.30 1.30 0.80 1.00 1.68 0.94 0.94 0.70 0.70 0.70 1.17 0.99 1.60 1.45 1.91 2.37 0.80 0.29 0.29 1.09 1.30 1.30 0.80 0.70 0.70 0.80 0.29 0.29 1.09 1.30 0.80 1.30 0.70 0.70
N(CH2)5: piperidinyl, b. Calculated using eq. 2. MR(H): 0.I0 was accounted. Not used in the derivation of eq. 2. Not used in the derivation of eqs. i and 2. When
were
obsd
cinnamoylisopropylamines
included
in
the
analysis,
and an
cinnamoyl-sec-butylamines
almost
identical
correlation
328
was o b t a i n e d
as shown in equation
log i/C = -0.155
n = 35, The
value)
binding
obtained
of
the
except
for
included
amide
are
moiety 2
did
Compounds compound
is
8 and
broad
fit 9 were
31 w a s
1/2.4
not
less
to
of
log
and
and
potent
than
effect
in equation
P.
8,
hence
5.7-fold
Topliss
The
This
variations
Compounds
2
potent results
the
reflected
term
enough.
2.8-
with
4.1.2).
9,
was
in the
and
were
more
the
optimum
generate
structural
equation
with
the
ring
according
the
the
to and the
ring
(with
than
The role
accord
(see Section
in
fact that
not
not
+~
in
syntheses
mentioned
that
to the
benzene
on the b e n z e n e This
higher
large.
of compounds
that
in the amide m o i e t y was
attributable
somewhat
is not
substituted 2 shows
design
as p r e v i o u s l y
Table
the
activity.
from
2 is
the transport
+~ s u b s t i t u e n t s
of v a r i a t i o n s 2,
equation
Equation
anticonvulsant
scheme
includes
site.
and
of
(log P)opt = 4.35
i, but the d i f f e r e n c e
of log P p r o b a b l y
receptor
[2]
s = 0.156,
log P v a l u e
of e q u a t i o n
hydrophobic
Z~
ZMR2,3, 4 - 2.032
r = 0.844,
optimum
that
(log p)2 + 1.305 log P + 0.257
0.264
-
2 (14).
31 of
dropped.
potent,
predicted,
while
the
reason
b e i n g obscure. Hopfinger's applied Twenty
to five
molecular
examine
the m o l e c u l a r
volume, area
shape p a r a m e t e r s log I/C = 2.298
In e q u a t i o n lengths,
the
4.4.2).
this
The
log P - 0.301
of
(15) w a s compound
chosen
overlapping
quantitative
gave equation
(MSA)
series
arbitrarily
surface area,
(So).
r = 0.917, 3, A is
volume
(16).
(Vo), and
using
structure
(log p)2 + 0.202 So [3]
of
of the t r i a n g l e
These
bond
by the MO
3 indicates
that
of c i n n a m a m i d e s
is p a r a b o l i c a l l y
the o v e r l a p p i n g
area
(So)
the
(So)opt = 33.67
product
optimized
Equation
these
3 as of the best quality.
the area
group.
next
for c o m p u t i n g
analysis
(log P)opt = 3.82,
the
reflecting
0 and N of the a m i d e by
of
were
analysis
0.003 So 2 + 9.222A - 22.218
n = 25,
bond
QSAR
cinnamamides
overlapping
-
the
shape
values
of
lengths
C=O
were
calculation
related
with and
C-N
by C,
estimated
(see
the a n t i c o n v u l s a n t
of the m o l e c u l e
and
defined
Section activity
log P as well linearly
as
related
329
with
A.
The
to t h a t amide
are
ring
reflection
shown
character
single
bond
the
C=O
character
closer
aspects: an
the
one
ethylene
or
substitution 4.4.1 Methylene
unit
of m o i e t y
diverse
results TABLE
3
are
shown
of
group
Anticonvulsant
1 2 3 4 5 6
R H H H 3,4-0CH20 3,4-0CH20 3,4-0CH20
Except
X
bond
to
donating
increase the
since
bond
length.
electron
overweighs
Structure
linkage
the
the
effect
of
N-substituents
(B in II)
of
includes
the v i n y l e n e
and
the
Vinylene
with
of the d o u b l e moiety
other
moiety is
the
in
the
Ethylene
or
activity
ED50(MES) mmol/kg
CH=CH 0.437 (CH2) 2 0.747 CH 2 >0.985 CH=CH 0.342 (CH2)2 0.237 CH 2 inactive
for the u n s u b s t i t u t e d
and
deletion
respectively.
anticonvulsant
3 and Table
an
bond
of c i n n a m a m i d e s
and p h e n y l a c e t a m i d e s ,
activity.
result They The
4 (17).
of p h e n y l a c y l p i p e r i d i n e s
o
No.
activity
double
B of a n t i e p i l e p s i r i n e
from the v i n y l e n e
in Table
the
the
the
the
bond.
Saturation
variations
for
moiety
replacement
methylene
in p h e n y l p r o p i o n a m i d e s
the
Electron
C=O group.
is the
Replacement
that
is r e a s o n a b l e
in the L i n k a g e
on the d o u b l e
Linkage:
of a c a r b o n
gave
C=O
to the amide
Modifications
with
of the
A is a c t u a l l y
lower
amide
of the the
enhance
to
mean
the
C-N
on
favorable
leading
and
is close
substituents
substituents.
ring
of
of C=O in
probably
could
3.82 w h i c h
so that
these
the
This
The m o d i f i c a t i o n two
of
bond
A term
lengths
nitrogen,
on
N-substituents
3 is
variations
2 would
substituents.
are m u c h 4.4
amide
bond
effects
positive
of
ring
the
the
equation
of
effect
the
The with
substituents
in
the
2.
varied
and of
withdrawing
Thus,
log P of e q u a t i o n
of e q u a t i o n
group
benzene
as
optimum
r-x
No.
7 8 9 i0 ii 12
R
4-Ci 4-CI 4-CI 4-NO 2 4-NO 2 4-NO 2
X
ED50(MES) mmol/kg
CH=CH 0.248 (CH2)2 0.234 CH 2 0.638 CH=CH 1.250 (CH2)2 0.901 CH 2 inactive
derivative(compound
2) in Table
330
3,
the
was
activity
close
However, less in
of
to that
all
substituted
of t h e i r
the s u b s t i t u t e d
potent
Table
than
4.
their
For
the
than
indicate
their
activity
that
the removal is,
unsaturated
double
bond
Anticonvulsant
1 2 3 4 5 6
X
H H H 3,4-0CH20 3,4-0CH20 3,4-0CH20
the
to
EDs0 (MES) mmol /kg
No. 7 8 9 I0 ii 12
of
postulation
bond b e t w e e n
the
group.
But,
postulate. position
could
effect the
The
carbonyl
of the ring
results
anticonvulsant
of
introduction
activity
pionylpiperidine
respectively,
not
results group
necessarily
of The
indis-
EDs0 (MES) mmol /kg
X
4-ci 4-Ci 4-Ci 4-N02 4-N02 4-N02
CH=CH (CH2)2 CH 2 CH=CH (CH2)2 CH 2
0.158 0.546 0.441 0.359 inactive inactive
is to e l e c t r o n i c a l l y
be tenable,
of the b e n z e n e
anticonvulsant
These
less
to the a c t i v i t y .
group
of
the
amide
saturation
Table
3 did
1.76-fold,
activity
was
by i n t r o d u c t i o n
the
whereas activity
enhanced
not atom
interrupt
support into
that
enhanced
into
and
of a m e t h y l e n e d i o x y
this
the p a r a the
phenylpro-
3.19-fold.
1.28-
If
on the c a r b o n y l
ring of c i n n a m o y l p i p e r i d i n e
enhanced
function,
the double
ring will
substituents
of a c h l o r i n e
of
on
influence
a c t i v i t y of compounds.
the
the amide group and the b e n z e n e
the e l e c t r o n i c
but
were
from the vinyl
R
and hence to alter the a n t i c o n v u l s a n t this
all
4),
that the role of s u b s t i t u e n t s
of c i n n a m a m i d e s
polarization
be
shown
a c t i v i t y of p h e n y l a c y l i s o p r o p y l a m i n e s
we p o s t u l a t e d
ring
as
activity.
CH=CH 0.760 (CH2) 2 0.977 CH 2 0.590 CH=CH 0.265 (CH2)2 0.602 CH 2 >1.449
Originally, the b e n z e n e
Table
cinnamamides.
seems
TABLE 4
R
3 of
unfavorable
to the a n t i c o n v u l s a n t
were all
analogs
phenylacetamides,
of one carbon
in general,
pensable
No.
of
cinnamoyl
(compound
corresponding
cinnamamides
cinnamoylpiperidines.
phenylpropionylisopropylamines corresponding
phenylacetylisopropylamine potent
phenylpropionylpiperidines
corresponding
The
3.15-fold,
group into the
331
3,4-position
of
the
benzene
ring
These
results
propionylpiperidines. substituents effect
on
on
interaction
then
the
amide
the b i n d i n g
the vinyl Me,
this
group
CI,
larger
OMe,
and
the
(18).
convulsants
Double
or less
TABLE 5 Anticonvulsant sec-butylamines
the
was
located
s-hydrogen
of as
whereas
Also,
influenced
the
where
on o p p o s i t e and the
linkage
substitutents
increased,
compounds
the
anticonvulsant
the
activity.
drastically
are
in
Cinnamoyl-sec-
small
the
that
electronic
(17).
Bond:
When
activity
anticonvulsant
potent
an
on the v i n y l e n e
such
Z configuration moiety
exert
5 shows
by
phenyl-
to m e a n
participate
compounds.
the
compounds
bond were
only
also
Table
of
decreased
the
amide
of the d o u b l e
on t h e
SMe,
and
believed
site of the r e c e p t o r
substituted
and
of
activities:
ring
was
not
but
cinnamoyl-
were
s-substitutions
series
substituents
configuration CNS
various
synthesized of
ring
group
s-Substitution with
activities
F,
benzene
with
4.4.2 butylamines were
the
of
the
the
type
of
benzene
sides(trans)
E(cis)
forms w e r e
anticonvulsants.
activities
of s - s u b s t i t u t e d
cinnamoyl-
NH --sec-Bu
No. i 2 3 4 5 6 7 8 9 i0
a.
After of
the
number
Me Et Bu-n PhCH 2 Ph F CI(E) CI(Z) Br(E) Br(Z)
that
0.314 1.054 0.950 >1.365 0.461 0.289 a 0.472 a 1.003
realizing bond
Z(trans)
bromo-cinnamamides show
No. ii 12 13 14 15 16 17 18 19
ED50 (MES) mmol/kg
R OMe(E) OMe(Z) OEt SMe SEt SPh NHCOMe NHCOPh H
0.662 0.348 0.525 0.219 1.073 0.536 0.419 1.755 0.621
convulsant effect.
double of
ED50 (MES) mmol/kg
R
that
of
small
substituents
cinnamamides
and were
E(cis)
may
isomeric
synthesized
on
enhance pairs
(19
the
s-position activity,
of ~ - c h l o r o
- 21).
N-(~-halo-cinnamoyl)-sec-butylamines
the
Tables are more
a
and ~6 and
7
potent
332 than
the
cinnamamides
substituent
on
the
formed
benzene
with
ring.
other For
chloro-cinnamoyl-sec-butylamines, or
bromo
the
atom
into
anticonvulsant
derivatives, decreased note
more
to
in
Tables
the
for
(X)-cinnamamides TABLE
6
X
1
7 8 9
i0 ii 12 13 14 15
16 17 18 19 20 21 22
2,4-C12 2,4-C12 2,4-C12 3,4-CI 2
3,4-Cl 2 3,4-Ci 2
3,4-C12 2-Cl 2-Cl
MES
s-Bu s-Bu i-Pr i-Pr s-Bu s-Bu i-Pr i-Pr s-Bu s-Bu i-Pr i-Pr s-Bu s-Bu i-Pr i-Pr s-Bu s-Bu i-Pr i-Pr i-Pr i-Pr
of
Z E Z E Z E Z E Z E Z E Z E Z E Z E Z E Z E
is
Z(trans)
why
X
27
8.23 7.06 8.22 7.06 8.25 7.07 8.25 7.08 8.23 7.06 8.23 7.08 8.33 7.47 8.32 7.45 8.20 7.01 8.19 7.02 8.38 7.36
of
activity
ED50 (MES) mmol/kg
0.076 0.517 0.234 0.485 0.098 0.606 0.180 1.178 0.195 0.195 0.814 0.857 0.202 0.463 1.332 0.417 0.311 0.351 0.636 1.461 1.135 0.576
u-halo
(22).
Br
6.56 5.54 6.55 5.56 6.56 5.62 6.59 5.62 6.62 5.56 6.60 5.49 6.60 5.60 6.55 5.64 6.63 5.53 6.59 5.67 6.63 5.54
are
Speculation
CONHR
NH
to of
activity, isomers
E-isomer
8ppm
atom
pairs
\c=c' / \
UV IHNMR MeOH X max(nm) ~-H
other
interesting
of ~ - b r o m o c i n n a m a m i d e s
H
282.5 267.5 283.0 268.0 281.5 264.5 281.5 266.5 272.5 257.0 272.5 257.5 273.0 268.0 273.0 268.5 278.0 267.5 278.5 267.5 265.0 258.0
for
bromo
isomers. the
3-
chloro
increased
anticonvulsant the
same
and a
But, or
the
anticonvulsant
~ONHR
Configuration
It
E(cis) of
activity
Br
R
4-Br 4-Br 4-Br 4-Br 4-CI 4-CI 4-CI 4-CI 3-CI 3-Ci 3-C1 3-Ci 2,4-Ci 2
possesses
\c=c" I \
H
2 3 4 5 6
Most
of
linkage
fold.
all
the
4-bromo,
chloro
of
7 exhibit
explanation
and
a
degrees.
corresponding
also
vinylene
1.2-1.6
isomers
with
introduction
of
various E
6 and
the
Structure
No.
about
extents.
than
made
to
and
various
potent been
activity Z
cinnamamides
of
introduction
both
4-chloro,
the
u-position
activity
the
the
that
though
has
the
amines
333
The
dipole
the
role
some
of of
~-C-X
C=O
of
in
the
E-isomer
Z-s-halo
E-~-halo-cinnamamides
position The
of
steric
dihedral side
the
hindrance angle
with
benzene
ring
of
between
are
ortho the
could
probably
cinnamamides.
More
substituents
more
potent
on
than
substituents
supplement interesting,
would benzene
the
the
ortho
Z-isomers.
influence
planes
of
the
ring
activity
of
~-chlorocinnamamides
and
chain.
TABLE
7
Structure
and
X
C!
1 2 3 4 5 6 7 8 9 i0 Ii 12 13 14 15 16 17 18 19 20 21
R
22
23 24 25 26 27 28
29 30 31 32
4-CI 4-CI 4-Ci 4-CI 4-Ci 4-Ci 4-Br 4-Br 4-Br 4-Br 3-CI 3-CI 3-Ci 3-Ci 3-Ci 3-Ci
3,4-Cl 2 3,4-CI 2 3,4-CI 2
3,4-C12 2-Ci 2-CI 2-Ci 2-Ci 2-Ci 2-CI
2,4-Cl 2 2,4-Cl 2 2,4-Ci 2
2,4-C12 2,4-C12 2,4-C12
X
\c=c' H'
No.
MES
s-Bu s-Bu i-Pr i-Pr CH(CH2) A ~ CH(CH2) & ~ s-Bu s-Bu i-Pr i-Pr s-Bu s-Bu i-Pr i-Pr CH(CH2) A ~ CH(CH2) n ~ i-Pr i-Pr CH(CH2)&i CH(CH2) & i s-Bu s-Bu i-Pr i-Pr CH(CH2) ~ CH(CH2) & ~ s-Bu s-Bu i-Pr i-Pr CH(CH2) n ~ CH(CH2)._.~
\CONHR
CONHR
\c=c' / n
Configuration
UV MeOH I max(nm)
Z E Z E Z E Z E Z E Z E Z E Z E Z E Z E Z E Z E Z E Z E Z E Z E
280.0 264.0 281.0 265.0 281.0 265.0 282.0 266.5 282.5 266.5 272.0 259.5 272.0 259.5 272.0 259.0 277.5 265.5 278.5 265.5 267.5 256.5 268.0 258.0 268.0 256.5 274.5 264.5 274.0 265.5 275.0 264.0
\Cl IHNMR ~-H
7.96 6.93 7.96 6.93 7.96 6.93 7.95 6.92 7.94 6.91 7.95 6.88 7.94 6.89 7.95 6.90 7.91 6.87 7.90 6.88 8.19 7.12 8.19 7.13 8.20 7.27 8.14 7.07 8.14 7.08 8.13 7.08
8ppm
EDs0 (MES)
NH
mmol/kg
6.51 5.76 6.60 5.75 6.74 5.85 6.61 5.73 6.68 5.96 6.52 5.73 6.58 5.76 6.74 5.81 6.63 5.83 6.65 5.86 6.50 5.86 6.53 5.74 6.67 5.79 6.46 5.87 6.58 5.83 6.61 5.95
0.113 0.358 0.294 0.488 0.887 0.222 0.079 0.251 0.152 0.431 0. 211 0.845 0.775 0.435 0.887 0.534 0.684 0.171 0.249 0.440 0.735 0.825 1.550 1.096 1.226 0.704 0.518 0.416 1.352 0.609 1.056 0.528
the the
334
The
configurations
assigned and of
by the
the m o l a r steric the
the
benzene
side
6ma x is
of
shift
of
form
and
shows
and
in Tables
listed of
are w i t h i n E and
81,
by
between
of the E isomer was
on
the
are all w i t h i n
of
shifts
by
on
same of
the
in the
where
the
~-
chemical
nitrogen
shifts
longer
of
the
of the E Z form
is
of the NH proton
5.49-5.95
and those
of Z
2,4-dichloro-~-bromocinnamoylIH NMR s p e c t r o s c o p y
crystallography
the b e n z e n e
ring
46.4 ~ , w h i l e
TABLE 8 Anticonvulsant cinnamoyl-sec-butylamines
the
grades
(23).
by the X max and
X-ray
located
7, the ~ - p r o t o n
The chemical
6.46-6.74
assigned
and
is
were (Xmax)
isomer
configuration
distinguished
6 and
lower
isomer
E(cis)
are
proton
6.88-7.47
Z isomers
confirmed
angle,
the
of 7.91-8.38.
isopropylamine also
also
~-proton
the
The
maximum
of the
Z(trans)
of
group
(23).
was
of E - ~ - h a l o - c i n n a m a m i d e s
The
of the
amido
bond
cinnamamides
absorption
Because
those
As shifts
in the range
isomers
Xmax
cinnamamides
the
of the
than
the
double
group.
s-substituted
(6max).
the
greater
ring
the
substituted
amido
absorptivity
distortion,
and
of
UV w a v e l e n g t h
(23).
and v i n y l e n e
that of the
activity
of
The
linkage
Z isomer was
~-substituted
were
dihedral planes 27.8 ~ .
4-chloro-
R
HI
No.
the
that
ED50(MES) mmol/kg
No.
0.240 0.073 0.070 0.655 0.348 0.144 0.217
8 9 i0 ii 12 13 14
1 2 3 4 5 6 7
Me Et n-Pr i-Pr Ph CI Br
a.
With convulsant effect.
4.4.3 on
R
double
smaller
~-Substitution bond
NH --sec-Bu
gave
substituents
ED50(MES) mmol/kg
R
NH 2 0.244 NHMe 0.713 NHEt 0.635 NHPr(i) 0.524 NHPr 1.358 a NHBu(i) >1.314 NHBu >1.314
on the D o u b l e
results
similar
enhance
the
Bond:
~-Substitution
to s - s u b s t i t u t i o n ,
anticonvulsant
so
activity
335
and larger substituents Table
m a r k e d l y decrease
It is interesting of compound only
group
n-propyl
compound benzene
of
4 has greater
that
3.
distortion
of
to o b t a i n
4.4.4
a suitable
Table
angle
planes
(81)
planes
(82) were
and
between
above
the
benzene
the
amide
on the opposite
side
analogs,
(trans)
however,
82 is not w i t h i n
30 ~ a n d
-64 ~ , t h e
amide
linkage.
of compounds
on c o m p o u n d
vinyl
group
and
vinyl
group
with
activity
seem
to
in Table
do
not
additional be
9.
the
is a l m o s t
show
factors
crucial
to
the
of
the
range
between
anticonvulsant
2, 4, 6, 8, 10 and In this
perpendicular
The conformations of the receptor.
3 and 5 of the
of have
In spite the
from -90 ~ to -115 ~ .
group
fit the requirement
activities
82,
for compounds
in the range
plane of vinylene do not
cinnamamides
82 values
the
and
of the double bond.
such
if
of
next
ring and the amide m o i e t y
configuration,
fall
were
and
for anticonvulsant
E(trans)
9
of
(25). (4.1.1),
shown
plane
Because
bond on the
conformation
and
the
data
group
for the stable
81
Table
3 for X-
a c t i v i t y of this
ring
as
The
why
by the EHMO method.
angles,
activity.
of
it was
configuration
activity
anticonvulsant
Bond:
compounds
were m a d e
the benzene
For ~ , ~ - d i s u b s t i t u t e d torsion
of c o m p o u n d
on the d o u b l e
that
the
between
energy
cinnamamides,
to be g e n e r a l l y
is p r o b a b l y
for the anticonvulsant
estimated
As m e n t i o n e d
crystal
~,~-disubstituted
calculations
that
m i n i m u m potential
This
Unfortunately,
From the c r y s t a l l o g r a p h y
chemical
torsion
of
of the
The existence
on the Double
9 shows
are crucial
of compounds.
6, q u a n t u m
the planes
80 ~ .
ring.
of s u b s t i t u e n t s
activity,
(22).
conformation
than
study.
effect
anticonvulsant
hindrance
of the vinyl m o i e t y caused
decreased.
~,~-Disubstitution
the i m p o r t a n t
the
benzene
The the
is
crystallography
the angle between
dramatically
ray crystallographic
studied
the
steric
X-ray
group at the ~-position
3.
that
compounds
ring and the side chain is about
not p o s s i b l e
simple
two
compound
showed
its a c t i v i t y was
as
(see
activity
i/i0 that of compound
these
of compound
4 (24)
drastic
class
8 is about
between
group
the isopropyl
The
(24)
to note that the anticonvulsant
4 of Table
difference
isopropyl the
the a c t i v i t y
8).
Z(cis)
16 in range,
with
the
of these compounds The anticonvulsant configuration
are
336 probably these
to
a
molecules
dipole role
of of
Z(cis) only the
due
and
the the
similarity
amide
difference
about
of
but
between
42 ~ , which
ii
and
bond
carbonyl
8 I.
cyano
compounds
s-C-halogen
configuration,
value
of
should
the
cyano take
Compound
7
not
to
be
be
and a
a
is
and
the
of
the
in
the
part also
compounds
for
In
activity.
critical
exceeded
groups. group
convulsant
compound
seems
carbonyl
probably
possesses
this
There
13,
could
group. it
and
3
and
value
the
The
for
5
is
81
of
anticonvulsant
activity. TABLE 9 Configurations, torsion activities of ~,~-disubstituted butylamines
01
angles, and anticonvulsant 4-chlorocinnamoyl-sec-
02
D
No.
RI
R2
i 2 3 4 5 6 7
H Me Me Et Et n-Pr n-Pr i-Pr i-Pr Br Br Cl Cl Me Me n-Pr Et Me
CN CN CN CN CN CN CN CN CN Br Br Cl C1 Et Et Et Me Me
8
9 I0 ii 12 13 14 15 16 17 18
a.
In Balsamo
and
activities show
CNS
Configuration
to
the
coworkers
Torsion Angle 8 8 1 2
E(trans) E(trans) Z(cis) E(trans) Z(cis) E(trans) Z(cis) E(trans) Z(cis) E(trans) Z(cis) E(trans) Z(cis) E(trans) Z(cis) E(trans) E(trans) E(trans)
6.08 5.46 6.00 5.36 6.01 5.36 6.04 5.38 5.75 5.34 5.90 5.70 5.50 4.72
With convulsive
addition
dimethyl
IHNMR NH(ppm)
14 ~ 21 ~ 17 ~ 40 ~ 34 ~ 47 ~ 44 ~ 54 ~ 52 ~ 20 ~ 20 ~ 17 ~ 17 ~ 9~ i0 ~ 52 ~ 42 ~ ii ~
the
depressant
ED50(MES) mmol/kg
- 31 ~ -105 ~ 103 ~ -107 ~ i00 ~ -105 ~ 105 ~ -115 ~ i00 ~ _ 90 ~ 81 ~ - 64 ~ 104 ~ - 31 ~ 30 ~ _ 95 ~ - 45 ~ 34 ~
0.417 0.362 a 0.148 a 0.344 a 0.188 0.082 a 1.314 a 0.146 a 1.314 a 0.253 a 0.146 0.223 0.532 0.506 0.716 a 0.593 a 0.197 0.113
action.
results (7)
have
described
central
that
display
nervous
activity,
above
indicated
cinnamoyl-monoalkylamines on
u
system
whereas
the
(Section the
E-
quite
(CNS). Z
isomers
4.1.1),
and
Z-~,~-
different The
E
cause
forms CNS
337 stimulation.
Results
are c o n s i s t e n t not.
with
The convulsant
drastic
The
but that
of
the
benzene
for c o m p o u n d
ring
and
amide
of ~ , ~ - d i s u b s t i t u t e d
by the chemical
group
cinnamamides
shifts of the NH proton.
field and that of the Z isomer
higher
field,
in Table
X-ray
was
That of the E
is in the lower
9 (22).
planes
linkage.
isomer
as shown
is in the
crystallography
of E - N - ( ~ - c y a n o - ~ - n - p r o p y l - 4 - c h l o r o - c i n n a m o y l ) - s - b u t y l a m i n e showed
that
opposite 5.
the
benzene
ring
and
sides of the vinylene
RECEPTOR
In
9
16 is
16 is p r o b a b l y due to the
and ethyl groups on the vinylene
configuration
assigned
14, 15, 17 and 18 in Table
results,
effect of compound
distorsion
caused by propyl
for compounds their
the
linkage
amide
group
are
also on
the
(25).
MAPPING
summary
relationships
of
of
the
structure-anticonvulsant
cinnamamides,
we
can
come
to
activity the
following
conclusions: (i)
The
compounds
lipophilicity adjusted
by
should
possess
(log P = 3.82 ~ 4.35). substituents
on
the
comparatively
high
Their l i p o p h i l i c i t y benzene
ring
can be
and/or
amide
nitrogen. (2) The bulk,
substituents
comparatively
on the b e n z e n e
hydrophobic
and
ring
should
be small
electron-withdrawing
in in
nature. (3) The the
product
amide
moiety
activity.
This
of the values
of C=O and C-N bond
significantly
leads
influences
to the consideration
the
lengths
of
anticonvulsant
that
the amide
group
binds with the receptor. (4)
The
opposite least
benzene sides
two
distorted On
the
basis
for
possessing
and
of the double
carbon too much
receptor
ring
atoms.
of
the
above
compounds
interaction this
ring
should
conclusions, almost
sites.
binds,
the
from the hydrophobic
the
available
area, space
must
on
the
by at
not
be
linkage. hypothetical
a planar
structure
There is a hydrophobic which might also exert
with the substituted
hydrophobic
be
be separated
moieties
to the benzene moiety,
In the
of
two
has
at least three binding
region
group
bond and should These
a charge-transfer
benzene
amide
from the plane of the vinylene
these
area c o r r e s p o n d i n g
Apart
the
where is
benzene
the
somewhat
area at a proper distance,
ring.
substituted narrow.
there is a
338 binding
site w h i c h
carbonyl there
group
is
hydrogen
exerts
of the
a site
ligand.
which
bonding.
a dipole-dipole
can
Close
bind
to this
with
These situations
interaction
the
with
dipolar
amide
the
region,
nitrogen
are illustrated
in Fig.
by i.
dipol~ Fig. The
I.
Model of c i n n a m a m i d e - r e c e p t o r
halogen
atom
of
E-~-halo-cinnamamides
interact with the dipolar carbonyl
group
cinnamamides 6.
This
is probably
show anticonvulsant
fact
that
not known
piperine
can
in place of the
the reason why
E-s-halo-
activity.
before
possesses
the active
folk m e d i c i n e was discovered, cinnamamides generate designed
knowing
piperidine
studies
the
antiepileptic activity of
of piperine
anticonvulsant
to was
activity
of
We found this out only during a
literature
just b e f o r e
the
structural
N-(3,4-methylenedioxycinnamoyl)-
of the structure
substituent
vinylene
revealed
configuration Among 12,
14,
6, and
than
29,
compounds
than
antiepilepsirine.
them
is n o w
under
and
200
ring.
have
reached
effect
of
on the
on the a n t i c o n v u l s a n t synthesized,
2, c o m p o u n d s
7 in T a b l e
studies.
extensively
Substitutions
cinnamamides
From the economic
studies
been
we quickly
crucial
38 in Table
1 and
preclinical
relationship
the
and c o n f o r m a t i o n
more 26,
has
approach,
for the benzene
linkage
activity.
of N - ( 3 , 4 - m e t h y l e n e d i o x y -
(antiepilepsirine)
By the aid of the Hansch
the optimum
activity
that
of
cinnamoyl)-piperidine
in T a b l e
activity
were started.
The m o d i f i c a t i o n
compounds
of this
The m o d i f i c a t i o n
had been reported. r e v i e w of the
modification
molecular
component
but the anticonvulsant
had been reported.
without
systematic
studied.
anticonvulsant
N-(3,4-methylenedioxy-cinnamoyl)-piperidine
cinnamamides
the
probably
region of the receptor
CONCLUSION
The was
(22).
interaction
point
of view,
Moreoever,
provided
1 and 5
7 are m o r e
potent one of
structure-
us w i t h
a better
339
understanding
of the interaction
between cinnamamide
and its
receptor. REFERENCES
1 Epilepsy Clinics, People's Hospital. Beijing Medical College Affiliated Hospital, Journal of Beijing Medical College, 1974, 6: 214. 2 Faculty of Pharmacology, School of Basic Medicine, J. Beijing Medical College, 1974, 6; 217. 3 Pharmaceutical Factory of Beijing Medical College, J. Beijing Medical College, 1974, 6: 221. 4 Yin-quan Pei, Jia-shan Li, Zhi-ji Cai, Bao-heng Zhang, Cheng Tao, Bao-shan Ku, J. Beijing Medical College, 1977, 9: 234. 5 Epilepsy Clinics, People's Hospital, Beijing Medical College Affiliated Hospital, Chinese J. Internal Medicine, 1977 (new), 2: 321. 6 Xiao-hui Zhang, Ren-li Li, Meng-shen Cai, J. Beijing Medical College, 1980, 12: 83. 7 A. Balsamo, P.L. Barili, P. Crotti, B. Macchia, F. Macchia, A. Pecchia, A. Cuttica, and N. Passerini, J. Med. Chem., 1975, 18: 843. 8 C. Rappe, Acta Chem. Scand. 1964, 18: 818. 9 A.J. Speziale and C.C. Tung, J. Org. Chem., 1963, 28: 1353. I0 J.G. Topliss, J. Med. Chem., 1972, 15: 1007. ii Shu-yu Wang, and Ji-cang Zhou, J. Beijing Medical College, 1982, 14: 65. 12 Shu-yu Wang, Ren-li Li, Wei-qin Liu, Ping Liu, Jing-mei Song, Yin-quan Pei, Hai-yan Yao, Xue-min Gao, Acta Pharmaceutica Sinica, 1986, 21: 542. 13 An-liang Li, Wei-qin Liu, Yin-quan Pei, Shu-rong Zhang, and Chen Xu, Acta Pharmaceutica Sinica, 1984, 19: 888. 14 Ren-li Li, and Shu-yu Wang, Acta Pharmaceutica Sinica, 1986, 21: 580. 15 A.J. Hopfinger, J. Am. Chem. Soc., 1980, 102: 7196. 16 Shu-yu Wang, Ren-li Li, Wei-qin Liu, Xiao-jie Xu, Yue Guan, Chinese J. Org. Chem., 1988, 8: 217. 17 Xiao-hui Zhang and Ren-li Li, J. Beijing Medical College, 1985, 17: 225. 18 Wei-qin Liu, Ji-cang Zhou, An-liang Li, Cheng Bi, J. Beijing Medical College, 1984, 16: 62. 19 Shu-yu Wang, Gui-qi Wang, Gao-yun Hu, Song-jing Cai, Jingmei Song, Wei-chin Liu, Cheng Tao, Acta Pharm. Sinica, 1987, 22: 420. 20 Shu-yu Wang, Wei-qin Liu, Ren-li Li, Chemical J. Chinese University, 1987, 8: 813. 2 1 S h u - y u Wang, Wei-qin Liu, Yin-fen Wang, Jing-min Song, Cheng Tao, Xiang-fang Zhou, J. Beijing Medical University, 1988, 20: 297. 22 Shi-qi Peng, Wei-qin Liu, Yin-quan Pei, Su-ming Chen and Fang Guo, Acta Pharm. Sinica, 1986, 21: 20. 23 Shu-yu Wang, Dong Wang, Liang Qiao, Ying-fen wang, Ji-hai Pang, Wei-qin Liu, Ren-li Li, Chinese J. of Microwave and Radiofrequency Spectroscopy, 1987, 4: 355. 24 Wei-qin Liu, Ji-cang Zhou, and Xiao-ping Lei, Acta. Pharm. Sinica, 1983, 18: 912. 25 Ji-cang Zhou, Shi-qi Peng, and Wei-qin Liu, J. Mol. Sci. (Wuhan, China), 1986, 4: 187.