5-Arylidene-3-aryl-pyrrolidine-2,4-diones with affinity to the N- methyl-D-aspartate (glycine site) receptor, Part I

Article abstract of DOI:10.1002/(SICI)1521-4184(199812)331:12<389::AID-ARDP389>3.0.CO;2-W

A series of new 5-arylidene 3-aryl-pyrrolidine-2,4-diones has been prepared. Their binding affinity toward the N-methyl-D-aspartate (glycine site) receptor has been measured as a basis for more detailed structure- activity relationship studies.

Full text of DOI:10.1002/(SICI)1521-4184(199812)331:12<389::AID-ARDP389>3.0.CO;2-W

5-Arylidene-3-aryl-pyrrolidine-2,4-diones
389
5-Arylidene-3-aryl-pyrrolidine-2,4-diones with Affinity to the
N-Methyl-D-aspartate (Glycine Site) Receptor, Part I
Hermann Poschenrieder, Georg Höfner, and Hans-Dietrich Stachel*
Institut für Pharmazie/Zentrum für Pharmaforschung der Universität München, Sophienstraße 10, D- 80333 München, Germany
Key Words: Diazotetramic acids; 3-aryltetramic acids; NMDA (glycine site) receptor affinity;
3
[ H]MDL 105,519 displacement
tribute to a more detailed understanding we have synthesized
a series of new tetramic acids of type 1.
Summary
A series of new 5-arylidene 3-aryl-pyrrolidine-2,4-diones has been
prepared. Their binding affinity toward the N-methyl-D-aspartate
(glycine site) receptor has been measured as a basis for more
detailed structure-activity relationship studies.
Introduction
The N-methyl-D-aspartate (NMDA) receptor is known to
mediate neuronal signalling and to affect gene expression as
well as the neuronal plasticity, outgrowth, and survival of
[1–4]
cells
. On the other hand, over-stimulation of the NMDA
subtype of central excitatory amino acid receptor may play a
role in the delayed neuronal loss following cerebral ischemia
[5]
and in the etiology of neurogenerative disorders
like
[6]
epilepsy . NMDA antagonists may therefore be therapeu-
[5, 7]
tically useful
but the intervention strategies demand
precise knowledge.
The NMDA receptor complex is postulated to be a cation-
2+
selective ligand gated ion channel permeable to Ca which
2+
is blocked by Mg in a voltage dependent manner. Various
recognition sites regulating the ion flux occurring through the
ion channel have been identified: A site sensitive to agonists
like L-glutamate or NMDA, a distinct site sensitive to ligands
like glycine and D-serine, often described as co-agonists, a
site sensitive to polyamines like spermine and spermidine
with stimulatory effects on channel opening, a site within the
channel sensitive to compounds like dizolipine (MK-801)
Scheme 1
2+
2+
Chemistry
and PCP, sites for Mg and Zn and possibly sites for
+ [8,9]
phosphorylation, redox agents and H
. A variety of
approaches for therapeutic interventions has been investi-
gated. Antagonists acting at the glycine site of the NMDA azlactone approach as previously described by us
In the synthesis of the arylidene tetramic acids we used the
[11]
. The
receptor show a pattern of pharmacological activity which 3-aryl group was introduced afterwards via the carbens
may offer some advantages over other NMDA receptor ant- generated thermally from the corresponding 3-diazopyrrolid-
[8]
[12]
agonists in terms of their side effect profile
.
ine-2,4-diones
.
[3]
Kynurenic acid and 5-alkylidene-3-phenyltetramic acids
of the general formula 1 have been recognized as full with dimethyl malonate and potassium tert-butoxide led to
Starting with the arylidene azlactones 2a–h the reaction
[10]
antagonists at the glycine site. Both types of compounds bear the corresponding N-benzoylated tetramic acids which with-
some similarity in terms of ionizable groups (pK ) and lipo- out isolation were debenzoylated by means of sodium
a
philicity, allowing the definition of a pharmacophore methoxide to furnish the tetramic acids 3 (Scheme 1). Com-
[10]
model
in order to explain the interactions of the glycine pounds 3a and 3d have been prepared previously by this
[11]
antagonist with the glycine receptor.
method
. With a small amount of water in ethyl acetate at
With respect to the tetramic acids the publicized results reflux temperature the tetramic acids 3 underwent de-alkoxy-
appear to reflect a limited knowledge of the role of substit- carbonylation to give the arylidene tetramic acids 4 in high
uents of the 3-phenyl substituent as well as the possible value yields. Compounds 4a and 4d have already been prepared in
[11]
of aryl groups with different substitution pattern in the alkyl- this way . All tetramic acids 4 showed keto-enol tautomer-
idene side chain including the E/Z isomers. In order to con- ism in their NMR spectra.
Arch. Pharm. Pharm. Med. Chem.
© WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1998
0365-6233/98/1212/0389 $17.50 +.50/0

390
From the tetramic acids 4 the known diazoketone 5a
Poschenrieder, Höfner, and Stachel
[20]
and the new diazoketones 5b–5g were obtained using p-tolu-
enesulfonyl azide and triethylamine. Finally the aryltetramic
acids 7a–i resulted in moderate yields by thermal decompo-
sition of the diazo compounds 5 at 130°C in anisole or in
benzene in a sealed tube in presence of rhodium(II)-ace-
[13]
tate . In the same way the N-methylated aryltetramic acid
[20]
8h was obtained from diazoketone 6a
.
Scheme 3
The corresponding O-acetates 22a and 23a were obtained
from both these compounds by acetylation with acetic anhy-
dride and triethylamine. The acetyl groups showed up in the
1
H NMR spectra at around 1.5 ppm. UV irradiation of solu-
tions of each compound 22a or 23a in methylene chloride for
15 minutes led to a photostationary equilibrium of the E/Z
isomers at a ratio of 1:3 in both cases. The acetyl NMR signals
for the minor components were found at 2.4 ppm, correspond-
ing to the E isomers 22b or 23b, respectively, since a relative
upfield shift of the acetyl group absorption was to be expected
for the Z isomer due to the shielding effect of the aromatic
electrons. In order to control this method, we have prepared
the O-acetate 24a from the benzylidene tetramic acid 4a
Scheme 2
Stereochemically different from the arylidene tetramic
acids mentioned so far are the tetramic acids 9 and 10
The corresponding 3-aryl derivatives 13–15 were obtained
via the diazoketones 11 and 12 (Scheme 2). A proof of the
preservation of the Z configuration during this reaction se-
quence is given below. Finally, the diazoketone 17 generated
from the alkoxycarbonylalkylidene tetramic acid 16
converted to the 3-aryl derivative 18 by heating in anisole in
a stereochemically uniform way.
In addition to these 3-aryl tetramic acids we have prepared
[14]
.
whose Z configuration was previously established by NOE
[14]
experiments
. The acetyl signal of 24a showed up at
1
2.39 ppm in the H NMR spectrum. The E isomer 24b was
formed during UV irradiation of 24a and could be isolated in
20% yield by fractional crystallization. As expected, the
NMR signal of the acetyl group of the unstable isomer was
shifted distinctly to higher field. In addition the long range
[12]
was
coupling of the endocyclic vinyl proton with both the exocy-
the 3-benzoyl tetramic acid 20 by Fries rearrangement from
the 3-benzoyloxy compound 19
[16]
[19]
clic vinyl hydrogen and the NH group
, forming a
. The synthesis of 3-ben-
pseudotriplet, can be valued as an independent structure proof
of 24b. The Z acetate 24a could be regioselectively bromi-
nated to the above mentioned O-acetate 22a.
zyl tetramic acid 21 used in testing as a homolog of the
[15]
3-phenyl tetramic acid 7h has already been described
.
Stereochemistry
Pharmacological Results and Discussion
In some cases the configuration of the side chain of alkyl-
idene tetramic acids has been established spectroscopi-
cally . The O-methyl ethers of Z isomers showed a positive
NOE effect between the methoxy and the neighboring vinyl
protons. To prove the presumed Z configuration of the
methoxylated and brominated alkylidene tetramic acids 9 and
10 another procedure was developed (Scheme 3).
[14]
The 3-aryltetramic acids 7, 8, 13–15, and 18 as well as
compounds 20 and 21 have been evaluated for their potency
3
to inhibit [ H]MDL 105,519 binding at the NMDA receptor
associated glycine site in pig cortical brain membranes. The
results are summarized in Table 1.
Arch. Pharm. Pharm. Med. Chem. 331, 389–394 (1998)

5-Arylidene-3-aryl-pyrrolidine-2,4-diones
391
Table 1: Affinity of new ligands at the NMDA (glycine site) receptor.
Experimental Section
General
All melting points were determined with a Dr. Tottoli melting point
apparatus (Büchi) and are uncorrected. Infrared spectra were measured as
potassium bromide plates using an IR Spectrometer FT-IR 1600 Series
(Perkin Elmer). Ultraviolet spectra were determined in methanolic solutions
on Uvicon 810 Anacomp 220 (Kontron Analytik). 1H NMR spectra were
recorded using tetramethylsilane as internal standard on the spectrometers
A 60 A, EM 360 A (Varian) and JEOL GSX 400 (Jeol).
All new compounds gave correct elemental analyses which were carried
out applying an Analysator CHN-O-Rapid (Heraeus) or were done by
I. Beetz, Mikroanalytisches Laboratorium, Kronach, Germany. The melting
points and spectroscopic data of the new compounds are listed in Table 2.
——————————————————————————————
Compd.
X
R1
R2
Ki values (µM)
——————————————————————————————
7a
7b
7c
7d
7e
7f
H
H
H
H
H
H
H
H
H
H
Me
OMe
OMe
OMe
OMe
OMe
OMe
OMe
H
72.4 ± 11.5
27.4 ± 2.4
> 100
2-Cl
3-Cl
Chemistry
4-Cl
21.1 ± 3.2
> 100
2,3-di-Cl
2,4-di-Cl
2,6-di-Cl
H
General Procedure for the Synthesis of the Tetramic Acids 3
18.8 ± 2.5
16.1
20 mmol of the corresponding azlactone 2 was added to a solution of
20 mmol potassium dimethyl malonate (from 0.78 g potassium, 40 ml
tert-butanol and 2.64 g dimethyl malonate) and 15 ml dimethoxyethane.
After heating for 2 h at 85 °C the reaction mixture was stirred in an ice bath
for an additional 2 h. The precipitate was filtered off and washed with diethyl
ether. The crude product was refluxed in a solution of 0.46 g (20 mmol)
sodium in 100 ml methanol for 1 h. After cooling to room temp. the
precipitate was collected, suspended in water and acidified with 6 N HCl.
After stirring for 30 min the precipitate was collected, washed with water,
dried and recrystallized from methanol.
7g
7h
7i
43.0 ± 2.7
20.6
2,4-di-Cl
H
H
8h
H
> 10. m,0
——————————————————————————————
Compd.
13
Ki values (µM)
> 100
14
15
18
20
21
> 100
General Procedure for the Synthesis of the Tetramic Acids 4
> 100
The corresponding tetramic acids 3 were refluxed in ethyl acetate in the
presence of 2% water for 1 h. The solution was dried with Na2SO4 and after
filtration concentrated under reduced pressure to afford the pure product.
> 100
> 100
> 100
——————————————————————————————
General Procedure for the Synthesis of the Diazo Ketones 5, 11 and 12
To a cooled solution of 10 mmol of the corresponding arylidene-2,4-pyr-
rolidinedione (4, 9, 10) and 2 ml (14 mmol) triethylamine in 30 ml methanol
was added dropwise asolution2.8g(14mmol) p-toluenesulfonazide in 15 ml
methanol. The reaction mixture was allowed to stir while warming to room
temp. for 3 h. After cooling overnight the crude product was filtered off.
A small sample was purified by CC, eluting with dioxane to give the pure
compound for microanalysis.
3
The tetramic acid 7h inhibited [ H]MDL 105,519 binding
3
in the same order of magnitude as described for [ H]L
[10]
689,560 binding by Mawer et al.
. Variation of the substit-
1
2
uents R , R and X markedly affected the affinity for the
glycine site. Replacing the hydrogen in position 1 by a methyl
group (compound 8h) as well as changing from Z to E
configuration (compounds 13–15) or spacing the 3-phenyl
substituent by a methylene or carbonyl group from the
tetramic acid moiety (compounds 20 and 21) or exchanging
the arylidene group by a methoxycarbonylmethylene side
chain likewise resulted in a loss of binding activity. The
4-methoxyphenyl compound 7a showed slightly decreased
General Procedure for the Synthesis of the 3-[4-Methoxy-phenyl]tetramic
Acids 7a-f, 13, 15, and 18
1 mmol of the corresponding diazo ketone (5, 11, 12, 17) was heated in
20 ml anisole with a small portion of rhodium(II)-acetate for 10 min at
120 °C. After cooling the precipitate was filtered off and washed with diethyl
ether.
3
inhibition of [ H]MDL 105,519 binding in comparison with
General Procedure for the Synthesis of the 3-Phenyltetramic Acids 7g-h, 8h,
and 14
the 3-phenyltetramic acid 7h.
According to the literature, introduction of chloro substit-
uents in definite positions of the phenyl moiety of kynurenic
acid and indole-2-carboxylic acid structures enhanced the
affinity for the glycine site more than two orders ofmagnitude
1 mmole of the corresponding diazo ketone (5, 12) was heated in 50 ml
benzene with a small portion of rhodium(II)-acetate for 1 h in a sealed tube
at 120 °C. The volatile products were removed and the residue was purified
by CC on silica gel eluting with diethyl ether/petroleum ether (1:1).
and indicated strict spatial requirements of the phenyl moiety
[3, 4, 8]
binding pocket
. The same is true with the compounds
3-Benzoyl-2-benzylidene-4-hydroxy-2-pyrrolone (20)
under study here bearing chlorinated benzylidene groups.
Ortho and para-chloro substitution enhanced the affinity to
the glycine site in comparison with the benzylidene tetramic
acids 7a and 7h, whereas the meta-chloro derivative of 7a
was inactive at concentrations up to 100 µM.
1.45 g (5 mmol) of compound 19 [19] and 1.0 g potassium carbonate were
refluxed in 80 ml ethyl acetate. After 4 h the suspension was extracted with
water and the aqueous phase after filtration acidified with 2 N HCl. The
precipitate was filtered off, washed with water, and recrystallized from ethyl
acetate.
Arch. Pharm. Pharm. Med. Chem. 331, 389–394 (1998)

392
Poschenrieder, Höfner, and Stachel
Table 2: Chemical and physical data.
—————————————————————————————————————————————————————————————
Compd
Analysis
Mp (°C) UV (methanol, nm):
IR (KBr, cm-1): ν
1H NMR ([D6]DMSO): δ
Mol. mass
Yield(%) λmax (log )
—————————————————————————————————————————————————————————————
3b
3c
3e
3f
C13H10ClNO4
279.68
235
70
336 (1.274)
3209, 1725,
1657, 1614
9.93 (s, 1H), 7.73 -7.55 (m, 4H),
6.60 (s, 1H), 3.71 (s, 3H)
C13H10ClNO4
279.68
238
57
336 (1.366)
3206, 1715,
1657, 1613
10.04 (s, 1H), 7.69-7.33 (m, 4H),
6.43 (s, 1H), 3.71 (s, 3H)
C13H9Cl2NO4
314.12
268
64
205 (4.365),
314 (4.275)
3200, 1720,
1657, 1614
7.64-7.34 (m, 3H),
6.55 (s, 1H), 3.70 (s, 3H)
C13H9Cl2NO4
314.12
265
80
335 (4.345)
3187, 1719,
1659, 1613
9.91 (s, 1H), 7.71-7.41 (m, 3H ),
6.50 (s, 1H), 3.70 (s, 3H)
3g
4b
C13H9Cl2NO4
314.12
160
75
205 (4.369),
296 (4.250)
3417, 3210, 1729,
1709, 1685, 1613
9.62 (s, 1H), 7.50-7.34 (m, 3H),
3.70 (s, 3H)
C11H8ClNO2
221.64
137
73
307 (1.184)
3442, 1752,
1719, 1638
11.90, 11.07 and 9.53 (3s, 1,6H),
7.70-7.27 (m, 4 H), 6.40 and 6.34
(2s, 1H), 5.02 (s, 0.6 H), 3.22 and
3.17 (2s, 0.8 H)
4c
4e
4f
C11H8ClNO2
221.64
169
82
235 (0.995),
318 (1.353)
3210, 1746,
1722, 1638
11.82, 11.16 and 9.62 (3s, 1.6 H),
7.69-7.28 (m, 4H), 6.23 and 6.14
(2s, 1H), 4.99 (s, 0.6 H),
3.20 (s, 0.8 H)
C11H7Cl2NO2
256.09
200
88
206 (4.225),
240 (3.988),
306 (4.221)
3201, 1756,
1721, 1651
12.06, 11.134 and 9.58 (3s, 1.6 H),
7.66-7.36 (m, 3H), 6.39 and 6.35
(2s, 1H), 5.06 (s, 0.6H),
3.26 (s, 0.8H)
C11H7Cl2NO2
256.09
190
80
317 (1.298)
3427, 1726, 1660,
1637, 1595
12.84, 11.12 and 9.58 (3s, 1.6 H),
7.69-7.29 (m, 3H), 6.31 and 6.26
(2s, 1H), 5.03 (s, 0.6 H),
3.22 (s, 0.8 H)
4g
C11H7Cl2NO2
256.09
181
75
205 (4.239),
287 (4.203)
3158, 1767,
1726, 1655
11.82, 10.75 and 9.16 (3s, 1.6 H),
7.49-7.34 (m, 3H), 6.12 and 6.00
(2s, 1H), 4.96 (s, 0.6 H)
5b
5c
5d
5e
5f
C11H6ClN3O2
247.64
210
90
258 (4.241),
331 (3.827)
3180, 2169,
1703, 1650
10.78 (s, 1H), 7.68-7.53 (m, 4H ),
6.58 (s, 1H)
C11H6ClN3O2
247.64
231
90
260 (4.291), 286 (4.265),
329 (4.140)
3255, 2138,
1694, 1641
10.84 (s, 1H), 7.71-7.37 (m, 4H ),
6.44 (s, 1H)
C11H6ClN3O2
247.64
240
85
231 (4.246), 263 (4.268),
288 (4.272), 336 (4.178)
3218, 2134,
1696, 1633
10.71 (s, 1H), 7.64 -7.46 (m, 4H ),
6.46 (s, 1H)
C11H5Cl2N3O2
282.09
239
75
205 (4.246), 224 (4.277),
251 (4.118)
3184, 2162,
1702, 1653
10.35 (s, 1H), 7.73-7.27
(m, 3H), 6.56 (s, 1H)
C11H5Cl2N3O2
282.09
243
90
232 (4.266), 261 (4.274),
287 (4.256), 334 (4.163)
3213, 2145,
1697, 1637
10.83 (s, 1H), 7.72-6.50 (m, 3H )
5g
7a
7b
7c
7d
7e
7f
C11H5Cl2N3O2
282.09
185
70
225 (4.338),
249 (4.381)
3263, 2158, 1777,
1711, 1651
10.49 (s, 1H), 7.5-7.31 (m, 3H),
6.31 s, 1H)
C18H15NO3
293.32
195
30
230 (4.233),
330 (4.517)
3240, 1626,
1609, 1516
9.65 (s, 1H), 7.89-6.94 (m, 9H),
6.47 (s, 1H), 3.77 (s, 1H)
C18H14ClNO3
327.77
218
45
238 (4.200),
327 (4.476)
3298, 1638,
1600, 1511
9.67 (s, 1H), 7.82-6.95 (m, 8H),
6.63 (s, 1H), 3.77 (s, 3H)
C18H14ClNO3
327.77
212
50
237 (4.242), 321 (4.480),
332 (4.489)
3435, 1654,
1606, 1513
9.84 (s, 1H), 7.86-6.95 (m, 8H),
6.42 (s, 1H), 3.77 (s, 3H)
C18H14ClNO3
327.77
248C
57
233 (4.287),
334 (4.517)
3274, 1628,
1602, 1512
9.71 (s, 1H), 7.88-6.94 (m, 8H),
6.44 (s, 1H), 3.77 (s, 3H)
C18H13Cl2NO3
362.21
210
40
205 (4.470),
320 (4.387)
3196, 1697,
1654, 1605
9.72 (s, 1H), 7.91-6.98 (m, 7H),
6.65 (s, 1H), 3.80 (s, 3H)
C18H13Cl2NO3
362.21
232
40
234 (4.236),
327 (4.469)
3219, 1684,
1636, 1607
11.20 (s, 1H), 9.78 (s, 1H),
7.87-6.91 (m, 7H), 6.57 (s, 1H),
3.77 (s, 3H)
7g
7h
7i
C17H11Cl2NO2
332.18
206
35
205 (4.394),
298 (4.324)
3023, 1665,
1639
11.40 (s, 1H), 9.50 (s, 1H),
7.92-7.21 (m, 8H), 6,42 (s, 1H)
C17H13NO2
263.29
224
15
225 (4.181),
329 (4.443)
3435, 3048,
1654
9.72 (s, 1H), 7.92-7.23 (m, 10 H),
6.51 (s, 1H)
C17H11Cl2NO2
332.18
210
40
230 (4.133),
327 (4.399)
3226, 1681,
1632
11.44 (s, 1H), 9.80 (s, 1H),
7.87-7.23 (m, 8H), 6.62 (s, 1H)
—————————————————————————————————————————————————————————————
Arch. Pharm. Pharm. Med. Chem. 331, 389–394 (1998)

5-Arylidene-3-aryl-pyrrolidine-2,4-diones
393
Table 2: Continued
—————————————————————————————————————————————————————————————
Compd
Analysis
Mp (°C) UV (methanol, nm):
IR (KBr, cm-1): ν
1H NMR ([D6]DMSO): δ
Mol. mass
Yield(%) λmax (log )
—————————————————————————————————————————————————————————————
8h
C18H15NO2
277.33
205
15
230 (4.126),
317 (4.367)
3232, 1666,
1630
11.45 (s, 1H), 8.01-7.87 (m, 2H),
7.43-7.33 (m, 8H), 6.82 (s, 1H),
2.82 (s, 3H)
11
12
C11H6BrN3O2
292.09
193
80
250 (4.358)
3162, 2143,
1705, 1633
C12H9N3O3
243.22
176
70
259 (4.139),
282 (4.084)
3142, 2141,
1715, 1690, 1668,
1618
10.14 (s, 1H), 7.45-7,41 (m, 5H),
3.42 (s, 3H)
13
14
15
C18H14BrNO3
372.22
182
45
313 (4.321)
3432, 1653,
1637, 1597, 1512
3218, 1648,
1593
9.50 (s, 1H), 7.47-6.90 (m, 9H),
3.75 (s, 3H)
C18H13NO3
293.32
185
10
229 (4.072),
324 (4.421)
237 (4.094),
327 (4.390)
10.03 (s, 1H), 9.38 (s, 1H),
7.57-7.12 (m, 10 H), 3.40 (s, 3H)
9.81 (s, 1H), 9.33 (s, 1H),
C19H17NO4
323.35
196
50
3192, 1643,
1599, 1510
7.53-6.90 (m, 9H), 3.74 (s, 3H),
3.39 (s, 3H)
18
C14H13NO3
275.26
205
35
246 (4.033), 314 (4.376),
384 (3.649)
3380, 1697,
1670, 1639
9.41 (s, 1H), 7.89-7.85 (m, 2H),
6.99-6.95 (m, 2H), 5.77 (s, 1H),
3.69 (s, 3H).
20
C18H13NO3
291.31
209
80
321 (4.583)
3200, 1695,
1605
10.70 (s, 1H), 10.36 (s, 1H),
8.30-8.00 (m, 2H), 7.80-7.30
(m, 8H), 6.56 (s, 1H)
22a
22b
C14H13NO4
259.26
173
50
242 (3.567),
323 (4.352)
3154, 1772, 1670,
1654, 1595
(CDCl3) 7.48-7.38 (m, 5H),
5.93 (d, 1H, J = 2 Hz), 3.50
(s, 3H), 1.56 (s, 3H)
(CDCl3) 7.48-7.38 (m, 5H),
5.94 (d, 1H, J = 2 Hz), 3.53
(s, 3H), 2.34 (s, 3H)
23a
23b
24a
C13H10BrNO3
308.13
144
65
317 (4.144)
3174, 1794,
1688, 1587
(CDCl3) 7.37 (m, 5H), 6.13
(d, 1H, J = 2 Hz), 1.52 (s, 3H)
(CDCl3) 7.43-7.30 (m, 5H),
6.27 (d, 1H, J = 2 Hz), 2.37 (s, 3H)
C13H11NO3
229.24
183
70
227 (3.891),
332 (4.294)
3210, 1785,
1683, 1588
(CDCl3) 7.65 (s, 1H), 7.42
(m, 5H), 6.36 (s, 1H), 6.23
(d, 1H, J = 2 Hz), 2.39 (s, 3H)
24b
C13H11NO3
229.24
147
234 (3.904),
328 (4.301)
3170, 1791,
1686, 1583
(CDCl3) 8.07 (s, 1H),
7.43-7.30 (m, 5H), 6.58
(d, 1H, J = 2 Hz), 6.20
(t, 1H, J = 2 Hz), 1.85 (s, 3H)
—————————————————————————————————————————————————————————————
(E)-4-Acetoxy-5-benzylidene-3-pyrrolin-2-one (24b)
(Z)-4-Acetoxy-5-(α-methoxybenzylidene)-3-pyrrolin-2-one (22a)
To a solution of 0.43g (2 mmol) of compound 10 [14] in 20 ml CHCl3 were
added 1 ml triethylamine and 1 ml acetic anhydride. After stirring at room
temperature for 12 h the volatile fraction was removed and the residue
recrystallized from methanol. UV irradiation of a solution in methylene
chloride during 15 min led to an equilibrium of the Z and the not isolated E
isomer at a ratio of 3:1.
A solution of 0.46 g (2 mmol) 24a in 80 ml dichloromethane was irradiated
with a low-pressure Hg lamp (250 watt) for 30 min under N2. The volatile
was evaporated and the residue dissolved in the necessary amount of hot
methanol. After 3 h the precipitate of 24a was filtered off (yield: 0.32 g,
70 %). The resulting solution was concentrated to half of the original volume
and then stored in the refrigerator for 12 h. The yield of 24b was 0.09 g
(19 %).
(Z)-4-Acetoxy-5-(α-bromobenzylidene)-3-pyrrolin-2-one (23a)
Pharmacology
1. The compound was prepared in the same manner as compound 22a from
0.53 g (2 mmol) of compound 9 [14]
.
[3H]MDL 105,519 binding to pig cortical brain membranes was performed
as previously described 17. Test compounds insoluble in water were dissolved
by addition of DMSO. The total amount of DMSO in the assay did not exceed
1 % and inhibited binding only negligibly.
Ki values for test compounds were calculated from competition experi-
ments with at least 6 concentrations of test compounds using InPlot 4.0
2. To a solution of 0.46 g (2 mmol) of compound 24a in 15 ml acetic acid
were added 0.1 ml (2 mmol) of bromine. After 5 min at room temp. the
volatile was removed and the residue recrystallized from methanol. UV
irradiation of a solution in methylene chloride during 15 min led to an
equilibrium of the Z and the not isolated E isomer at a ratio of 3:1.
(GraphPad Software, San Diego, CA). The KD value used in the Cheng
(Z)-4-Acetoxy-5-benzylidene-3-pyrrolin-2-one (24a)
[18]
Prusoff
equation was determined in saturation experiments as 3.73 ±
0.43 nM for [3H]MDL 105,519. If not stated otherwise, data are expressed
The compound was prepared in the same manner as compound 22a from
0.36 g (2 mmol) of compound 4a [11]
.
as means ± SEM of three experiments, each carried out in triplicate.
Arch. Pharm. Pharm. Med. Chem. 331, 389–394 (1998)

394
Poschenrieder, Höfner, and Stachel
[11] H.-D. Stachel, K. K. Harigel, H. Poschenrieder, H. Burghard, J. Het-
erocycl. Chem. 1980, 17, 1195–1199.
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Received: September 3, 1998 [FP330]
Arch. Pharm. Pharm. Med. Chem. 331, 389–394 (1998)