Pyrrolidine-2,4-diones with affinity to the N-methyl-D-aspartate (glycine site) receptor. Part II: 5-Arylidene-pyrrolidine-2,3,4-trione 3- oximes as NMDA receptor antagonists

Article abstract of DOI:10.1002/(SICI)1521-4184(19999)332:9<309::AID-ARDP309>3.0.CO;2-N

A series of oximes deriving from 5-arylidene-pyrrolidine-2,3,4-triones and pyridine-2,3,4-triones has been prepared. The presence of the tautomeric nitrosoenol was proven in solutions of α-ketooxime 7a. The binding affinity of the new oximes toward the N-methyl-D-aspartate (glycine site) receptor has been measured as a basis for more detailed structure-activity relationship studies. Oxime 13b showed the highest binding potency acting as glycine antagonist in nanomolar concentration.

Full text of DOI:10.1002/(SICI)1521-4184(19999)332:9<309::AID-ARDP309>3.0.CO;2-N

5-Arylidene-pyrrolidine-2,3,4-trione 3-Oximes
309
[1]
Pyrrolidine-2,4-diones with Affinity to the N-Methyl-D-aspartate (Glycine Site) Receptor, Part II
5-Arylidene-pyrrolidine-2,3,4-trione 3-Oximes as NMDA Receptor
Antagonists
Hermann Poschenrieder, Georg Höfner, and Hans-Dietrich Stachel*
Institut für Pharmazie/Zentrum für Pharmaforschung der Universität München, Butenandtstraße 7, D-81377 München, Germany
Key Words: 3-Hydroxyiminopyrrolidine-2,4-diones; 3-hydroxyiminopyridine-2,4-diones; nitrosation; NMDA (glycine site)
3
receptor affinity; [ H]MDL 105,519 displacement
quinolone oximes 3 just mentioned, as is likewise the case for
the pair of active compounds 1 and 2.
Summary
A series of oximes deriving from 5-arylidene-pyrrolidine-2,3,4-
triones and pyridine-2,3,4-triones has been prepared. The presence
of the tautomeric nitrosoenol was proven in solutions of α-ke-
tooxime 7a. The binding affinity of the new oximes toward the
N-methyl-D-aspartate (glycine site) receptor has been measured as
a basis for more detailed structure-activity relationship studies.
Oxime 13b showed the highest binding potency acting as glycine
antagonist in nanomolar concentration.
Chemistry
The oximes 7 (Scheme 1) are derivatives of the known
tetramic acids 6
CH-acidic precursors 6 with nitrous acid. The NMR spectra
of the well crystallizing substances 7 showed duplication of
the NH- as well as the vinylic proton signals indicating the
existence of isomers, possibly the syn/anti isomers, in a ratio
of 2:1 in DMSO solution.
[1, 12]
and were formed by nitrosation of the
Another set of oximes was obtained starting with the known
[1, 12]
tetramic acids 5
. As reported earlier, compound 5a is
Introduction
[13]
easily transformed into lactam 9a
by bromination to
[14]
The function of L-glutamate as the primary excitatory trans- 8a
followed by saponification and decarboxylation. We
mitter in the mammalian central nervous system has been have ramified this reaction sequence in preparing the bromi-
generally accepted since the 1980s. It is now established that nated lactams 8b–f and 9b–d, f from compounds 5b–f. All
excessive stimulation by excitatory amino acids like gluta-
mate causes degeneration and death of neurons and that enol tautomers in a ratio of 1:1 in DMSO as judged from their
new tetramic acids 9 formed mixtures of the respective keto-
1
N-methyl-D-aspartate (NMDA) receptors, a subtype of iono-
H NMR spectra. Finally nitrosation of the tetramic acids 9
tropic glutamate receptors, plays a major role in this excito- afforded the oximes 10. According to their NMR spectra, all
[2]
toxicity of glutamate . It is also well known that glycine is these oximes formed equilibria of two isomers in a ratio of
[3, 4]
an obligatory co-agonist for NMDA receptor activation
.
2:1 when dissolved in DMSO.
Therefore the glycine site on NMDA receptors represents an
interesting target in the development of potential neuropro- of nucleophilic displacement of the vinylic halogen . With
It is known that the brominated tetramic acid 8a is capable
[13]
tective drugs.
sodium methoxide mainly the methoxylated tetramic acid
A number of compounds from different classes have been
derivative 11a was formed, accompanied by the pyridone 14a
recognized as functional antagonists at the glycine site such as a by-product (Scheme 2). Analogously the treatment of
[5]
as kynurenic acid derivatives , certain 1,2,3,4-tetrahydro- brominated tetramic acids 8b–f with sodium methoxide led
[6]
quinoline-2-carboxylic acids , 4-hydroxyquinoline- to the substituted tetramic acids 11b–f as well as the pyri-
[7]
[8]
2(1H)ones 1 , quinazoline-2,4-diones , and aryl-sub- dones 14b, c, f with yields of the ring enlargement products
[1]
stituted 3-arylidene tetramic acids 2 . These compounds differring in a wide range. So in the reaction of the bro-
have in common certain steric and structural aspects includ- motetramic acid 8f the pyridone 14f was found to be the chief
ing the presence of an acid group, i.e. a carboxyl or β-dicar- component. In general, using potassium methoxide instead of
[9]
[7]
bonyl function , and a sufficient lipophilicity . An the sodium salt enhanced the amount of the ring enlargement
account of aspects of structure-activity relationships of com- products 14 at the expense of the substitution products 11.
pounds active at the glycine site of the NMDA receptor and However, in the reaction of 8a with potassium ethoxide or
possible therapeutic implications has been given by propoxide we observed only substitution of the halogen and
[10]
Dannhardt and Kohl
.
no ring enlargement at all. Since this reaction was accompa-
In a recent paper the high affinity of 1,2,3,4-tetrahydroquin- nied by transesterification, the corresponding tetramic acids
oline-2,3,4-trione 3-oximes 3 for the NMDA receptor glycine 17 or 18 were isolated as the sole products.
[11]
site has been stated
. These compounds, dubbed QTOs,
The tetramic acids 11, 17, and 18 were subjected to dealk-
seem to fit into the binding model proposed for this recep- oxycarbonylation forming the new tetramic acids 12, 19, and
[8, 9]
tor
. We have synthesized and tested a series of oximes 20 all of which showed keto-enol tautomerism in a ratio of
of the general formula 4. These pyrrolidine-2,3,4-trione 3:1 in DMSO. Compound 12a has been prepared previously
[13]
3-oximes, abbreviated as PTOs, bear a resemblance with the in this way
. In comparison it was less simple to accom-
Arch. Pharm. Pharm. Med. Chem.
© WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
0365-6233/99/0909/0309 $17.50 +.50/0

310
Poschenrieder, Höfner, and Stachel
Scheme 1
plish the removal of the ester group of pyridones 14 by
However, oxime 7a smoothly reacted with diazomethane
saponification and decarboxylation leading to the 3-unsubsti- forming a compound different from both the syn- or anti-
1
tuted pyridones 15. Compound 15a has been prepared in this oxime ethers 25 in nearly quantitative yield. The H NMR
[13]
1
way already
. According to the H NMR spectra pyridones spectrum revealed that the new isomer of 25 was uniform and
15 exist predominantly as enols in DMSO as solvent.
contained one methoxy group, the signal of which at 4.3 ppm
is in agreement with the expectation for the nitrosotetramic
acid derivative 24. The structure of 24 was finally established
Nitrosation of these new compounds 12, 15, 19, and 20 led
to the usually yellow or orange colored pyrrolidinetrione
oximes 13a–f, and 21/22 and to the yellow pyridinetrione
oximes 16a–c, f, respectively. Judging from the NMR spec-
tra, all but oxime 16 were 1:2 mixtures of two isomers.
These findings led to the question whether the observed
isomers ofthe tetramic acid oximes4 are the assumed syn/anti
isomers or the isomers resulting from an α-ketooxime-ni-
trosoenol tautomerism. We have examined this question in
the case of oxime 7a which may also exist as nitrosotetramic
acid 23. Informative was the synthesis of the oxime derivative
25 by reaction of the hitherto unknown pyrrolidinetrione 26
and O-methylhydroxylamine (Scheme 3) and the comparison
13
by the C NMR spectrum which was very similar to that of
the nitrotetramic acid 29 with two signals each for the car-
bonyl-C and the β-C atom between 172 and 150 ppm. The
nitro derivative was obtained by oxidation of 7a or by nitra-
tion of oxime 6a.
Compound 24 may be regarded as a formal ester of a
tetramic acid and was therefore expected to react with amines
forming tetramic acid amides. In this way, reaction of 24 with
benzylamine afforded compound 27, which also might be
seen as a vinylogous nitrosamine. We shall report on the
synthesis of other compounds of this type as well as on the
results of their pharmacological testing in the near future.
From the reaction of 7a with diazomethane it is apparent
13
of the C NMR spectra of 25 and 7a. We observed nearly
congruent signals of the corresponding C atoms. In both cases
the C=O signals were doubled. Evidently, 7a indeed was a that in ethereal solution the oxime is in equilibrium with the
mixture of the syn- and anti-oximes just as the oxime ether nitrosotetramic acid 23 to a small extent. The disfavored enol
25 is a mixture of syn/anti isomers.
is intercepted by diazomethane thus continually disturbing
Arch. Pharm. Pharm. Med. Chem. 332, 309–316 (1999)

5-Arylidene-pyrrolidine-2,3,4-trione 3-Oximes
311
Scheme 2
the certainly swift equilibrium. Most likely, all the oximes same type as depicted in general formula 30. Therefore we
mentioned above will react with diazomethane in the same
way. The scope of this reaction is currently under investiga-
tion. It is worth mentioning that a similar behavior as in the
see reason to include componds 27–29 and their derivatives
in further testing.
As mentioned before, the pyridinetrione oxime 16a exists
1
case of oxime 7a with respect to tautomerism and the reaction
as a single isomer as judged from the H NMR spectrum. It
[15]
with diazomethane was observed earlier
with the for-
13
had to be the oxime because the C NMR spectrum is
myltetramic acid 28.
dissimilar to that of the corresponding nitro derivative 31
which was obtained by oxidation of 16a or directly by nitra-
tion of 15a. Oxime 16a was found to be a markedly stronger
acid than the oxime 7a derived from a tetramic acid as shown
All the oximes are acidic compounds. The pK values
a
measured by potentiometric titration of selected PTOs in
aqueous dioxane (Table 1) showed a marked dependence on
the substituents in the benzene ring aswell as in the side chain.
The values range from 6.25 to 4.74. As to be expected, the
nitrotetramic acid 29 showed a considerable higher acidity.
Compounds 7a and 27–29 may form mesomeric anions of the
by the respective pK values of 4.20 and 5.75.
a
Table 1: pKa values of selected PTOs and 29 in dioxane-water (1:5).
Pharmacological Results and Discussion
——————————————————————————————
Compd.
pKa
Compd.
pKa
The tetramic acid derived oximes (PTOs) 7a–g, 10a–d,f,
13a–f, and 21/22 as well as the pyridinetrione oximes16a–c,f
have been evaluated for their potency to inhibit [ H]MDL
105,519 binding at the NMDA receptor associated glycine
site in pig cortical brain membranes. The results are summa-
rized in Table 2.
——————————————————————————————
3
7a
5.75
4.75
4.75
13a
16a
29
6.25
4.20
2.75
7b
10a
——————————————————————————————
Arch. Pharm. Pharm. Med. Chem. 332, 309–316 (1999)

312
Poschenrieder, Höfner, and Stachel
Scheme 3
Table 2: Affinity of new ligands at the NMDA (glycine site) receptor.
—————————————————————————————————————————————————————————————–
Ki values (µM).
Compd.
(X)
7
10
13
16
21
22
—————————————————————————————————————————————————————————————–
a (H)
19.4 ± 1.9
42.8 ± 8.8
36.2 ± 3.7
0.257 ± 0.033
0.265 ± 0.081
10.95
0.280 ± 0.017
0.0935 ± 0.0132 >100
13 36.6
0.215 ± 0.013
>100
0.318 ± 0.039
19
0.603 ± 0.053
2.9 ± 0.28
b (2-Cl)
c (4-Cl)
d (2,3-Cl)
e (2,4-Cl)
f (2,6-Cl)
g (3-Cl)
>100
88.9
>100
>100
1.372 ± 0.349
13.9 ± 1.45
0.481 ± 0.016
—————————————————————————————————————————————————————————————–
3
The PTOs 7a as well as oxime 16a inhibited [ H]MDL derivatives of 10a were less potent with the sole exception of
105,519 binding in the same order of magnitude in the micro- 10b. On the other hand, halogenated derivatives of 13a partly
molar range. Their halogenated derivatives showed reduced showed improved binding. The highest potency of the com-
potency. A higher binding affinity in the nanomolar range pounds under investigation was found for 13b bearing a
was observed with the PTOs 10a and 13a. Again, halogenated 2-chlorophenyl group.
Arch. Pharm. Pharm. Med. Chem. 332, 309–316 (1999)

5-Arylidene-pyrrolidine-2,3,4-trione 3-Oximes
313
Table 3: Inhibition of [3H]MK-801 binding.
to remain at room temp. for 0.5 h and than, irrespective ofa new precipitation,
brought to dryness in vacuo. The residue was purified by crystallization from
ethanol. Yellow or orange crystals.
——————————————————————————————
5-Benzylidene-3-hydroxyimino-pyrrolidine-2,4-dione (7a): 13C NMR
([D6]DMSO): δ = 182.3, 175.0, 161.8, 156.7, 140.0, 132.8 – 128.3 (split
signals), 107.3, 106.9.
Compd. IC50 values (µM)
Compd. IC50 values (µM)
——————————————————————————————
10a
10b
5.31 ± 1.36
3.62 ± 0.97
13a
13b
4.52 ± 1.00
1.82 ± 0.40
General Procedure for the Synthesis of Tetramic acids 8b–f
——————————————————————————————
Bromine (1.1 ml, 22 mmol) was added to a suspension of compounds
5b–f (20 mmol) [1, 12], respectively, in acetic acid (50 ml). The resulting
solution was allowed to stand at room temp. for 1 h and than brought to
dryness in vacuo. The yellow residue was crystallized from methanol.
Tentatively, two conclusions can be drawn from these re-
3
sults in the [ H]MDL 105,519 displacement assay. Firstly,
that the acid strength of the ligand molecules is playing only
a modest role, as shown by the same receptor affinity
(260 nM) of oximes 10a and 13a despite a considerable
General Procedure of the Synthesis of Tetramic acids 9b–d, f, 12b–f, 19, 20
A solution of the corresponding tetramic acids 8, 11, 17, 18 (2 mmol) in
ethyl acetate (50 ml) was refluxed for 1 h in presence of 1 ml of water. The
solution was dried over Na2SO4 and concentrated under reduced pressure to
afford the pure product.
difference in acidity (pK = 4.75 and 6.25, repectively). And
a
secondly, that the electronic properties of the substituted
benzene ring and/or sidechain have little effect on the po-
tency, as illustrated by the same receptor affinity of oximes
10a and 13a in spite of the different character of their substi-
tuents. The sole exception in this line is 2-chloro-13a. The
increase in binding potency in comparison with the parent
substance may be attributed to the difference in lipophilicity.
On the other hand, the stereochemistry of the compounds
investigated appear to be highly significant. This assumption
is supported, for instance, by the decrease in activity observed
after replacement of the side-chain methoxy group in 13a by
an ethoxy- or propoxy group (20, 21). The binding affinity of
21, however, still is higher than the binding of the parent
General Procedure of the Synthesis of Tetramic Acids 11b–f
A solution of the corresponding tetramic acid 8 (10 mmol) and sodium
methoxide (1.6 g, 30 mmol) or potassium methoxide (2.1 g, 30 mmol) in
methanol (70 ml) was heated to 150 °C for 1.5 h in a sealed tube. The solution
was than brought to dryness in vacuo and the residue dissolved inwater. After
acidification the solution was extracted with dichloromethane, the organic
phase evaporated and the dry residue extracted twice with ethyl acetate. The
product remained undissolved and was crystallized from methanol if neces-
sary. The solution was retained for isolation of the respective compounds 14.
The use of potassium methoxide usually changed the ratio of compounds 11
and 14 in favor of the pyridones 14.
compound 7a, both of which differ in the position of the
[1]
General Procedure for the Synthesis of Pyridones 14b, c, f
sidechain aryl substituent
.
Ligands acting as agonists or antagonists at the NMDA
The mother lie obtained in the preparation of the corresponding tetramic
acids 11 was refluxed after addition of a small amount of water. The product
separated on cooling.
receptor associated glycine site can be recorded by enhance-
3
ment or inhibition of [ H]MK-801 binding performed under
[16, 17]
non-equilibrium conditions
. Compounds 10a, 10b,
3
General Procedure for the Synthesis of Pyridones 15b, c, f
13a, and 13b reduced [ H]MK-801 binding to the level of
non-specific binding and can therefore be classified as gly-
cine antagonists. The potencies in reduction of [ H]MK-801
The corresponding pyridones 14 (2 mmol) were refluxed with 3 N KOH
solution (30 ml). The product precipitated upon acidification.
3
binding (Table 3) correlated with the results observed in
[ H]MDL 105,519 displacement assays.
3
Ethyl 5-(α-ethoxybenzylidene)-2-oxo-3-pyrroline-3-carboxylate (17)
The compound was prepared from 8a (3.2 g, 10 mmol) [13] and potassium
ethoxide (2.5 g, 30 mmol) in ethanol (70 ml) analogously to the synthesis of
compounds 11.
Experimental Section
General
Propyl 5-(α-propoxybenzylidene)-2-oxo-3-pyrroline-3-carboxylate (18)
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 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 spectrometer 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 spectroscopical data of the new compounds are listed in Table 4.
The compound was prepared from 8a (3.2 g, 10 mmol) [13] and potassium
propoxide (3.0 g, 30 mmol) in propanol (70 ml) analogously to the synthesis
of compounds 11.
5-Benzylidene-4-methoxy-3-nitroso-pyrrolin-2-one (24)
A suspension of compound 7a (0.42 g, 2 mmol) in methanol (5 ml) was
treated with an excess of an ethereal solution of diazomethane. After the
vigorous evolution of N2 had ceased the solution was evaporated to dryness
in vacuo. Orange crystals from methanol.– 13C NMR ([D6]DMSO): δ =
166.6, 147.4, 133.8, 130.1, 129.6, 129.2, 128.7, 128.5, 127.6, 107.6, 103.8,
56.1.
Chemistry
5-Benzylidene-3-methoxyimino-pyrrolidine-2,4-dione (25)
General Procedure for the Synthesis of Oximes 7, 10, 13, 16
A solution of trione 26 (0.30 g, 1.5 mmol) and of O-methylhydroxylamine
hydrochloride (0.17 g, 2 mmol) in methanol (15 ml) was refluxed in the
presence of 1 ml triethylamine for 2 h. The product precipitated in pure state.
Orange crystals.– 13C NMR ([D6]DMSO): δ = 181.3, 175.1, 160.7, 156.3,
140.5, 132.7 – 128.4 (split signals), 107.7, 107.5, 65.9, 65.8.
An aqueous solution of sodium nitrite (0.075 g, 1.1 mmol) was added
dropwise to a stirred and cooled suspension of the corresponding tetramic
acids 6 (2 mmol) [1, 12], 9a [13], 9b–d, f, 12a [13], and 12b–f or the pyridones
15a [13] and 15b, c, f in 5 ml acetic acid. The resulting solution was allowed
Arch. Pharm. Pharm. Med. Chem. 332, 309–316 (1999)

314
Poschenrieder, Höfner, and Stachel
Table 4. Chemical and physical data.
—————————————————————————————————————————————————————————————–
Compd.Analysis
Mol. mass
Mp (°C)
UV (methanol, nm): IR (KBr, cm–1): ν
1H NMR ([D6]DMSO): δ
Yield (%)
λmax (log ε)
—————————————————————————————————————————————————————————————–
7a
7b
7c
7d
C11H8N2O3
216.19
C11H7ClN2O3
250.64
C11H7ClN2O3
250.64
C11H6Cl2N2O3
285.09
C11H6Cl2N2O3
285.09
C11H6Cl2N2O3
285.09
205 (dec.)
65
176
60
190
50
180
55
176
45
232
65
295 (4.489)
305 (4.267)
301 (4.354)
3435, 3200, 1738,
1715, 1635
3478, 1745, 1718,
1642
3230, 1739, 1718,
1639, 1587
3433, 3181, 1743,
1721, 1638
3435, 1745, 1723,
1646
3230, 1742, 1710,
1662
14.66 (s, 1H), 11.25 (s, 0.66H), 11.18 (s, 0.33H),
7.64–7.31 (m, 5H), 6.42 (s, 0.33H), 6.36 (s, 0.66H)
11.40 (s, 0.66H), 11.34 (s, 0.33H), 7.46–7.21 (m, 4H),
6.52 (s, 0.33H), 6.47 (s, 0.66H)
11,35 (s, 0.66H), 11,28 (s, 0.33H), 7.67–7.64 (m, 2H),
7,45–7.35 (m, 2H), 6.40 (s, 0.33H), 6.35 (s, 0.66H).
11.43 (s, 0.66H), 11.37 (s, 0.33H), 7.63–7.37 (m, 3H),
6.50 (s, 0.33H), 6.45 (s, 0.66H)
11.38 (s, 0.66H), 11.32 (s, 0.33H), 7.68–7.65 (m, 2H),
7.45–7.43 (m, 1H), 6.42 (s, 0.33H), 6.36 (s, 0.66H)
11.12 (s, 0.66H), 11.08 (s, 0.33H), 7.50–7.48 (m, 2H),
7.39–7.35 (m, 1H), 6.27 (s, 0.33H), 6.22 (s, 0.66H)
221 (4.157),
290 (4.292)
300 (4.297)
7e
7f
221 (4.277),
267 (4.392)
7g
C11H7ClN2O3
250.64
185
50
293 (4.369)
3473, 1735, 1709,
1638
14.69 (s, 0.66H), 14.53 (s, 0.33H), 11.47 (s, 0.66H),
11.40 (s, 0.33H), 7.72–7.20 (m, 4H), 6.38 (s, 0.33H),
6.33 (s, 0.66H).
8b
8c
C13H9BrClNO4
358.57
C13H9BrClNO4
358.57
C13H8BrCl2NO4
393.02
C13H8BrCl2NO4
393.02
215 (dec)
60
195
55
220
70
220 (dec.)
85
297 (4.222)
3190, 1724, 1673,
1659, 1600
3170, 1720, 1656,
1598
3420, 1724, 1659,
1597
3187, 1716, 1673,
1658, 1598, 1581
3432, 3184, 1718,
1657, 1602
3197, 1764, 1714,
1640
3147, 1755, 1712,
1624, 1589
9.79 (s, 1H), 7.54–7.38 (m, 4H), 3.61 (s, 3H)
9.67 (s, 1H), 7.49–7.46 (m, 4H), 3.64 (s, 3H)
9.82 (s, 1H), 7.70–7.44 (m, 3H), 3.63 (s, 3H)
9.79 (s, 1H), 7.78–7.51 (m, 3H), 3.65 (s, 3H)
9.65 (s, 1H), 7.59–7.45 (m, 3H), 3.60 (s, 3H)
225 (4.204),
313 (4.239)
8d
8e
299 (4.177)
298 (4.250)
289 (4.049)
288 (4.170)
8f
C13H8BrCl2NO4
393.02
224
9b
9c
C
11H7BrClNO2
178
70
187
75
11.48, 10.90, 9.38 (3s, 1.5H), 7.49–7.35 (m, 4H),
4.96 (d, 0.5H, J = 2Hz), 3.34 (s, 1H)
10.75, 9.29 (2s, 1H), 7.42–7.40 (m, 4H),
5.01 (d, 0.5H, J = 2Hz), 3.24 (s, 1H)
300.54
C11H7BrClNO2
300.54
228 (4.174),
306 (4.166)
9d
9f
C11H6BrCl2NO2
334.99
C11H6BrCl2NO2
334.98
C11H7BrNO3
295.09
C11H6BrClN2O3
329.54
C11H6BrClN2O3
329.54
C11H5BrCl2N2O3
363.98
C11H5BrCl2N2O3
363.98
193
90
235 (dec)
80
158
65
215
60
208
40
188
45
195
60
288 (4.351)
283 (4.038)
266 (4.250)
263 (4.276)
265 (4.297)
262 (4.320)
264 (4.324)
3178, 1760, 1722,
1637
3134, 1762, 1724,
1647
3430, 3221, 2866,
1743, 1725, 1616
3177, 2887, 1747,
1726, 1646
3208, 1750, 1725,
1608
3179, 2892, 1747,
1728, 1649
3545, 3180, 1741,
1718, 1643
11.56, 10.97, 9.46 (3s, 1.5H), 7.65–7.34 (m, 3H),
4.96 (d, 0.5H, J=2Hz), 3.27 (s, 1H)
11.60, 11.07 (2s, 1H), 7.54–7.34 (m, 3H),
4.95 (d, 0.5H, J=2Hz), 3.37 (s, 1H)
14.46 (s, 1H), 11.06 (s, 0. 70H), 11.00 (s, 0.30H),
7.40–7.26 (m, 5H)
1195 (s, 1H), 11.26 (s, 0.66H), 11.20 (s, 0.33H),
7.52–7.30 (m, 4H)
11.10 (s, 0.66H), 11.04 (s, 0.33H),
7.45–7.44 (m, 4H)
11.98 (s, 1H), 11.36 (s, 0.66H), 11.30 (s, 0.33H),
7.69–7.66 (m, 1H), 7.40–7.38 (m, 2H)
10a
10b
10c
10d
10f
11.49 (s, 0.66H), 11.43 (s, 0.33H), 7.56–7.43 (m, 3H)
11b
11c
11d
11e
11f
C14H12ClNO5
309.70
C14H12ClNO5
309.70
C14H11Cl2NO5
314.15
C14H11Cl2NO5
344.15
C14H11Cl2NO5
344.15
C12H10ClNO3
251.67
C12H10ClNO3
251.67
C12H9Cl2NO3
286.11
183 (dec.)
40
192
30
179
80
208 (dec.)
60
202
15
181
75
200
65
195
50
234 (4.009),
325 (4.258)
236 (4.133),
332 (4.286)
326 (4.162)
325 (4.273)
307 (4.103)
306 (4.156)
3357, 1713, 1674,
1624, 1584
3352, 1708, 1167,
1622, 1578
3380, 1705, 1675,
1640, 1586
3342, 1709, 1672,
1623, 1578
3430, 1734, 1675,
1644
3434, 3176, 1706,
1680, 1639, 1608
3212, 1707, 1642,
1552
3124, 1740, 1707,
1638
9.58 (s, 1H), 8.30 (s, 1H), 7.58–7.50 (m, 4H),
3.63 (s, 3H), 3.40 (s, 3H)
9.88 (s, 1H), 9.61 (s, 1H), 7.64–7.44 (m, 4H),
3.66 (s, 3H), 3.44 (s, 3H)
9.63 (s, 1H), 7.79–7.46 (m, 3H), 3.62 (s, 3H),
3.42 (s, 3H)
9.72 (s, 1H), 7.90–7.62 (m, 3H), 3.71 (s, 3H),
3.51 (s, 3H)
12.18 (s, 1H), 9.66 (s, 1H), 7.65–7.57 (m, 3H),
3.62 (s, 3H), 3.45 (s, 3H)
10.37, 8.99 (2s, 1H), 7.54–7.38 (m, 4H),
4.74 (d, 0.25 H, J = 2Hz), 3.34 (s, 3H), 3.05 (s, 1.5 H)
10.98, 10.38, 9.04 (3s, 1.25H), 7.49–7.40 (m, 4H),
4.87 (d, 0.25H, J=2Hz), 3.41 (s, 3H), 3.08 (s, 1.5H)
12b
12c
12d
12e
239 (4.043),
319 (4.149)
305 (4.108)
10.87, 10.43, 9.07 (3s, 1.25H), 7.76–7.38 (m, 3H),
4.76 (d, 0.25H, J=2Hz), 3.38 (s, 3H), 3.07 (s, 1.5H)
10.85, 10.43, 9.08 (3s, 1.25H), 7.53–7.42 (m, 3H),
4.77 (d, J=2Hz, 0.25H), 3.38 (s, 3H), 3.08 (s, 1.5H)
C12H9Cl2NO3
286.11
168
60
308 (4.114)
3428, 1691, 1633,
1610
—————————————————————————————————————————————————————————————–
Arch. Pharm. Pharm. Med. Chem. 332, 309–316 (1999)

5-Arylidene-pyrrolidine-2,3,4-trione 3-Oximes
315
Table 4. Continued.
—————————————————————————————————————————————————————————————–
Compd.Analysis
Mol. mass
Mp (°C)
Yield (%)
UV (methanol, nm): IR (KBr, cm–1): ν
λmax (log ε)
1H NMR ([D6]DMSO): δ
—————————————————————————————————————————————————————————————–
12f
C12H9Cl2NO3
286.11
C12H10N2O4
246.22
C12H9ClN2O4
280.67
C12H9ClN2O4
280.67
C12H8Cl2N2O4
315.11
C12H8Cl2N2O4
315.11
206
55
174
60
171
55
193
60
152
40
150 (dec.)
35
304 (4.054)
278 (4.269)
270 (4.239)
289 (4.181)
267 (4.221)
267 (4.251)
3434, 1712, 1648,
1559
3433, 1734, 1714,
1627
3202, 2941, 1738,
1717, 1642
3244, 1733, 1716,
1622
3205, 2944, 1738,
1720, 1645
3186, 2940, 1738,
1715, 1634, 1586
10.81, 10.47, 9.72 (3s, 1.25H), 7.61–7.53 (m, 3H),
4.72 (d, 0.25H, J=2Hz), 3.56 (s, 3H), 3.11 (s, 1.5H)
11.95 (s, 1H), 10.74 (s, 0.66H), 10.71 (s, 0.33H),
7.46–7.42 (m, 5H), 3.42 (s, 1H), 3.41 (s, 2H)
10.83 (s, 0.66H), 10.79 (s, 0.33H),
7.60–7.43 (m, 4H), 3.45 (s, 1H), 3.40 (s, 2H)
13a
13b
13c
13d
13e
10.80 (s, 0.66H), 10.76 (s, 0.33H),
7.51–7.43 (m, 4H), 3.44 (s, 1H), 3.43 (s, 2H)
10.87 (s, 0.66H), 10.84 (s, 0.33H),
7.79–7.43 (m, 3H), 3.42 (t, 3H)
10.78 (s, 0.66H), 10.74 (s, 0.33H),
7.79–7.78 (m, 1H), 7.53–7.45 (m, 2H),
3.42 (s, 1H), 3.41 (s, 2H)
13f
C12H8Cl2N2O4
315.11
151
45
269 (4.174)
3210, 2944, 1737,
1713, 1639
10.95 (s, 0.66H), 10.91 (s, 0.33H),
7.65–7.56 (m, 3H), 3.57 (s, 1H), 3.46 (s, 2H)
14b
C14H12ClNO5
309.70
209
15
228 (4.214),
329 (3.960)
2952, 2771, 1644,
1562
11.54 (s, 1H), 7.60–7.47 (m, 4H), 3.82 (s, 3H),
3.40 (s, 3H)
14c
14f
15b
15c
15f
16a
16b
C14H12ClNO5
309.70
C14H11Cl2NO5
344.15
C12H10ClNO3
251.67
C12H10ClNO3
251.67
C12H9Cl2NO3
286.11
C12H10N2O4
246.22
C12H9ClN2O4
280.67
218 (dec)
25
303
15
240 (dec)
90
280 (dec)
75
256
70
192
70
204 (dec)
60
233 (4.247),
338 (4.091)
219 (4.333), )
328 (3.923
298 (3.832)
312 (4.009)
297 (3.853)
280 (3.995)
342 (3.832)
3058, 2953, 1668,
1642, 1497
2950, 2771, 1656,
1560
2927, 1646, 1614,
1587
2933, 1644, 1602,
1561
2930, 1648, 1613,
1562
3437,1700, 1684,
1602, 1524
7.65–7.52 (m, 4H), 3.82 (s, 3H), 3.44 (s, 3H)
11.60 (s, 1H), 7.62–7.53 (m, 3H), 3.81 (s, 3H),
3.47 (s, 3H)
11.00 (s, 1H), 7.56–7.42 (m, 4H), 5.72 (s, 1H),
3.39 (s, 3H)
10.81 (s, 1H), 7.64–7.49 (m, 4H), 5.76 (s, 1H),
3.44 (s, 3H)
10.94 (s, 1H), 7.58–7.50 (m, 3H), 5.76 (s, 1H),
3.46 (s, 3H)
10.92 (s, 1H), 7.56–7.50 (m, 5H), 3.48 (s, 3H)
3422, 1647, 1582
9.62 ((s, 1H), 8.30 (s, 1H), 7.54–7.34 (m, 4H),
3.55 (s, 3H)
16c
16f
17
C12H9ClN2O4
280.67
C12H8Cl2N2O4
315.11
C16H17NO5
303.31
230 (dec)
50
222
45
216
40
300 (3.948)
343 (3.924)
3077, 2934, 1698,
1644, 1600
3425, 1648, 1585
10.94 (s, 1H), 7.64–7.49 (m, 4H), 3.49 (s, 3H)
7.55–7.43 (m, 3H), 3.47 (s, 3H)
236 (4.010),
338 (4.295)
3174, 1687, 1646,
1566
9.55 (s, 1H), 7.51–7.46 (m, 5H), 4.18 (q, 2H),
3.67 (q, 2H), 1.23–1.14 (2t, 6H)
18
C18H21NO5
331.37
169
52
235 (4.043),
338 (4.259)
3178, 2967, 1682,
1563
9.50 (s, 1H), 7.49–7.46 (m, 5H), 4.08 (t, 2H),
3.55 (t, 2H), 1.64–1.57 (sext. 4H), 0.90–0.81 (2t, 6H)
19
C13H13NO3
231.25
129
45
236 (3.952),
318 (4.088)
3176, 1706, 1651,
1616, 1559
10.29 and 8.95 (2s, 1H), 7.40–7.38 (m, 5H),
4.85 (d, 0.25H, J=2Hz), 3.63 and 3.60 (2q, 2H),
3.09 (s, 1.5H), 1.16 and 1.14 (2t, 3H)
20
C14H15NO3
245.28
127
55
237 (3.925),
316 (4.130)
3170, 2963, 1740,
1700, 1631
10.81, 10.25, 8.88 (3s, 1,25H), 7.42–7.37 (m, 5H),
4.83 (d, 0.25H, J=2Hz), 3.52–3.45 (2t, 2H),
3.07 (s, 1.5H), 1.61–1.54 (sext, 2H), 0.83–0.80 (2t, 3H)
21
22
C13H12N2O4
260.25
C14H14N2O4
274.27
142
55
147
45
282 (4.199)
281 (4.098)
3433, 1739, 1717,
1634
3244, 1739, 1715,
1623
10.70 (s, 0.66H), 10.66 (s, 0.33H),
7.44–7.41 (m, 5H), 3.67–3.62 (2q, 2H), 1.16 (t, 3H)
10.72 (s, 0.66H), 10.68 (s, 0.33H),
7.65–7.35 (m, 5H), 3.50 (2t, 2H), 1.64–1.48
(1 sext., 2H), 0.83 (t, 3H)
24
25
26
27
C12H10N2O3
230.22
C12H10N2O3
230.22
C11H7NO3
201.18
C18H15N3O2
305.34
172
90
230 (dec)
45
140 (dec)
80
220 (dec)
60
322 (4.51)
3190, 1718, 1697,
1636
3207, 1741, 1720,
1639
3336, 1755, 1718,
1636
3194, 1696, 1618
11.16 (s, 1H), 7.66–7.33 (m, 5H), 6.42 (s, 1H),
4.34 (s, 3H)
11.33 (s, 1H), 7.64–7.31 (m, 5H), 6.44 (s, 0.25H),
6.38 (s, 0.75H), 4.25 (s, 2.25H), 4.24 (s, 0.75H)
292 (4.392),
382 (3.300)
259 (3.998),
330 (4.066)
304 (4.402),
390 (4.223),
542 (3.921)
11.10 (s, 1H), 7.63–7.34 (m, 5H), 6.40 (s, 1H)
10.06 (s, 1H), 8.09 (s, 1H), 7.57–7.23 (m, 10H),
6.09 (s, 1H), 4.06 (s, 2H)
29
31
C12H8N2O4
232.19
C12H10N2O5
262.22
250(dec)
60
238 (dec)
46
232 (4.010),
324 (4.484)
319 (3.759),
377 (3.777)
3361, 1704, 1650
3065, 2953, 1676
9.30 (s, 1H), 7.54–7.18 (m, 5H), 6.14 (s, 1H)
11.89 (s, 1H), 7.61–7.50 (m, 5H), 3.32 (s, 3H)
—————————————————————————————————————————————————————————————–
Arch. Pharm. Pharm. Med. Chem. 332, 309–316 (1999)

316
Poschenrieder, Höfner, and Stachel
5-Benzylidene-pyrrolidine-2,3,4-trione (26)
References
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the presence of soluble starch until a faint blue color appeared. The solution
was extracted twice with ethyl acetate, the organic phase dried over Na2SO4.
The volatile was removed in vacuo and the residue purified. Colorless
crystals (from dichloromethane).
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Received: April 4, 1999 [FP383]
Arch. Pharm. Pharm. Med. Chem. 332, 309–316 (1999)