Synthesis and configurational assignment of 1,2-dihydroimidazo[5,1-b] quinazoline-3,9-diones: Novel NMDA receptor antagonists

Article abstract of DOI:10.1016/j.tet.2012.09.086

NMDA receptors form a major subdivision of the ionotropic glutamate receptor family that mediates excitatory synaptic transmission in the brain. Series of 1-substituted 1,2-dihydroimidazo[5,1-b]quinazolinediones were synthesized and found to have potent nanomolar activity at the glycine site of the NMDA receptor. Imidazoquinazolinediones were prepared by cyclocondensation of 4-oxo-quinazoline-2-carboxamide with aldehydes and orthoesters with good yields. The formed enantiomers were separated by chiral HPLC. The absolute configuration of pure enantiomers is elucidated by combined CD/Quantumchemical time-dependent DFT calculation method (TDDFT).

Full text of DOI:10.1016/j.tet.2012.09.086

Tetrahedron 68 (2012) 10365e10371
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis and configurational assignment of 1,2-dihydroimidazo[5,1-b]
quinazoline-3,9-diones: novel NMDA receptor antagonists
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Andras Varadi , Peter Horvath , Tibor Kurtan , Attila Mandi , Gergo Toth , Andras Gergely ,
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Jozsef Kokosi
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Department of Pharmaceutical Chemistry, Semmelweis University, Hogyes E. u. 9, Budapest H-1092, Hungary
Department of Organic Chemistry, University of Debrecen, Egyetem ter 1, Debrecen H-4032, Hungary
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a r t i c l e i n f o
a b s t r a c t
Article history:
Received 31 May 2012
Received in revised form 30 August 2012
Accepted 17 September 2012
Available online 26 September 2012
NMDA receptors form a major subdivision of the ionotropic glutamate receptor family that mediates
excitatory synaptic transmission in the brain. Series of 1-substituted 1,2-dihydroimidazo[5,1-b]quina-
zolinediones were synthesized and found to have potent nanomolar activity at the glycine site of the
NMDA receptor. Imidazoquinazolinediones were prepared by cyclocondensation of 4-oxo-quinazoline-2-
carboxamide with aldehydes and orthoesters with good yields. The formed enantiomers were separated
by chiral HPLC. The absolute configuration of pure enantiomers is elucidated by combined CD/Quan-
tumchemical time-dependent DFT calculation method (TDDFT).
Keywords:
Quinazoline
HPLCeECD
Ó 2012 Elsevier Ltd. All rights reserved.
TDDFT ECD calculation
Absolute configuration
NMDA antagonist
1. Introduction
likely a modulatory, albeit critical, role. Competitive antagonists at
the glutamate site profoundly disturb synaptic transmission and
The excitatory amino acid neurotransmitter system is the key
component for rapid synaptic excitation in the central nervous
system of mammals.1 The glutamate transmitter system has cap-
tured worldwide attention because it not only mediates standard
fast excitatory synaptic transmission, but also participates in more
complex neuronal processes, such as development, learning and
memory, and even neuropathology.2,3 Glutamate receptors have
been implicated in various neurological diseases and conditions,
including epilepsy, stroke, Alzheimer’s disease, Parkinson’s disease,
Huntington’s disease.4 Selective modulation of glutamate receptor
subtypes is expected to have enormous therapeutic potential in
treatment of neurodegenerative disorders.5,6
are incompatible with most therapeutic interventions. Conversely,
glycine-site agonists and antagonists have been used with prom-
ising results in a variety of disorders.10,11
There is much interest in ligand molecules acting on various
subtypes of excitatory amino acid receptors and having the prop-
erties of partial agonists; the search for new ligands of NMDA re-
ceptors is therefore of current importance.
Various heterocyclic-fused chemical entities, including qui-
noxalines, quinolones, and quinazoline derivatives have been
shown to harbor effective NMDA or AMPA antagonist effect in the
glutaminergic system.12,13 Quinazoline is among ‘privileged’ struc-
tures; a wide variety of pharmacological effects can be achieved by
synthetic modifications on this bicyclic system.14,15 Structural var-
iants of heterocondensed quinazolines can afford new compounds
for evaluation against a variety of biological targets.16 Numerous
biological applications have been attributed to imidazoquinazo-
lines; and the group includes narcotic antagonists,17 antihyper-
tensives,18 blood platelet aggregation inhibitors,19,20 central
nervous system stimulants,21 tranquilizers,22 anti-tumor agents,23
PDE-5 inhibitors,24 and anticonvulsants (Fig. 1).25
The release of glutamate stimulates postsynaptic receptors for
excitatory amino acids, which are divided into two large groupsd
metabotropic and ionotropic receptors.7 Ionotropic receptors
include N-methyl-D-aspartic acid (NMDA), 2-amino-3-(3-hydroxy-
5-methyl-4-isoxazolyl)propionic acid (AMPA), and kainic acid re-
ceptors, which in turn include several subtypes.8,9 NMDA receptors
are glutamate-gated ion channels with high calcium permeability.
Glutamate is the principal neurotransmitter; glycine has most
In spite of the interesting pharmacological properties of imidazo
[1,5-a]quinazolines, very few synthetic and pharmacological re-
ports have appeared in the literature on imidazo[5,1-b]quinazoline
derivatives until recently.26,27
* Corresponding author. Tel./fax: þ36 1 217 0891; e-mail address: varadi.andras@
ꢀ
pharma.semmelweis-univ.hu (A. Varadi).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.09.086

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A. Varadi et al. / Tetrahedron 68 (2012) 10365e10371
10366
Starting from anthranilamide 1 the condensation reaction was
performed with diethyl oxalate at 180 ꢀC for 5 h.35 The amidation of
the ethyl 4-oxo-3H-quinazoline-2-carboxylate 2 led to the 2-
carboxamide derivative 3, which was cyclized with different aro-
matic and heteroaromatic aldehydes to imidazoquinazoline-3,9-
diones 4aet in high yields. In the case of substituted-phenyl de-
rivatives the cyclization was performed at 170 ꢀC for 3 h. The ring
closure reactions with aldehydes having lower boiling points were
carried out at 130 ꢀC for 10 h in the presence of small amounts of
DMF. The yields, melting points, and HRMS data of the synthesized
1,2-saturated tricyclic compounds (4aet) are found in Table 1.
The 1H and 13C NMR spectra of synthesized derivatives were
completely assigned based on one, and homo- and heteronuclear
two dimensional NMR experiments (COSY, HSQC, and HMBC). For
numbering and detailed 1H and 13C NMR assignments, UV and IR
absorption data of 4aet see Fig. 2 and Tables 2e4.
The reaction of quinazoline-2-carboxamide 3 with formalde-
hyde was carried out under pressure in sealed tube at 80 ꢀC for 5 h
to yield imidazo[5,1-b]quinazoline-3,9(1H,2H)-dione 4u. Under the
same conditions the other aliphatic aldehydes gave intermediates,
which failed to cyclize. The use of acid or base catalysis did not
facilitate the cyclocondensation. The reaction of 3 with trimethyl
orthoacetate in the presence of sodium methoxide in methanol led
to the formation of 1-methyl-1-methoxy-imidazo[5,1-b]quinazo-
line-3,9(1H,2H)dione 5. Selective dehydration of 3 with excess
phosphorus pentoxide in xylene at 130 ꢀC for 3 h led to the 2-cyano
derivative36 6, which was treated with methanolic hydrochloric
acid solution at ambient temperature to afford the 2-iminoether
derivative 7. Imino group in compound 7 is a better nucleophile,
and therefore higher reactivity is expected in condensation re-
actions than that for 3. The 2-iminoether was easily cyclized to
compound 8 with acetaldehyde if the mixture was allowed to stand
in ethanol at ambient temperature for 12 h.
Fig 1. Linearly condensed imidazoquinazolinediones.
In addition, the ‘kynurenine pathway’, a cascade of enzymatic
steps generates several biologically active endogenous compounds,
including kynurenic acid,28 which in micromolar concentrations
may selectively antagonize NMDA receptors.29,30 Such compounds,
like imidazoquinazolones bearing modified functionality of
kynurenic acid have potential NMDA antagonist properties. The
angularly condensed imidazo[1,5-a]quinazolines have been re-
ported to show a promising anticonvulsant profile.31,25
Recently, we developed quinazolineealkyl-carboxylic acid de-
rivatives as a new class of antagonists, which modulate excitatory
synaptic transmission at the NMDA/AMPA receptor thus exhibiting
strong anticonvulsant and antiepileptic activities.32 In this paper
we report the synthesis, stereochemistry, chiral properties, and
glycine/NMDA affinities of imidazo[5,1-b]-quinazoline-3,9-diones
as ring constrained tricyclic analogues of quinazolineecarboxylic
acid derivatives.
2. Results and discussion
For the synthesis of imidazo[5,1-b]quinazolines two synthetic
approaches are known: (a) condensation of anthranilic acid de-
rivatives with substituted imidazolones27 and (b) ring closure of 2-
amino-alkyl-quinazolones.26 1-Dimethylamino-1,2-dihydro imi-
dazo[5,1-b]quinazoline-3,9-dione was described as an intermediate
for synthesis of aryl-substituted quinazolone-2-carboxamides
prepared by cyclization of quinazolone-2-carboxamide with mod-
ified Vilsmeier formylation using DMF/p-toluenesulfonylchloride
reagents at rt for 15 h. No structural characterization for the com-
pound was given.33 Earlier, we elaborated a synthetic method for
linearly condensed imidazo[5,1-b]quinazolines by condensation of
2-aminoethylquinazolones with aliphatic and aromatic alde-
hydes.34 Modification of this procedure was found suitable for the
preparation of imidazo[5,1-b]quinazolindiones.
The cyclization of 2-iminoether (7) derivative with benzalde-
hyde could be accomplished under milder reaction conditions by
heating the reaction mixture at 100 ꢀC for 3 h. After completion of
the reaction the product imidazoquinazolinedione 4k was sepa-
rated after the fast hydrolysis of the iminoether derivative upon
diluting the reaction mixture with water. Prolonged heating of
quinazoline-2-carboxamide 3 with trimethyl orthoformate pro-
vided 9.
2.1. Determination of the absolute configuration of 1-aryl-
imidazo[5,1-b]quinazoline-1,9(1H,2H)-diones
The synthetic routes to the prepared imidazoquinazolinediones
are outlined in Scheme 1.
The cyclization of quinazolin-2-carboxamide 3 with aromatic
aldehydes generates a new stereogenic center at C-1, and hence it
affords racemic mixtures. Since the stereochemistry of 1-aryl-imi-
dazo[5,1-b]quinazoline-3,9(1H,2H)-diones have not been studied
yet and there is no correlation reported between their stereo-
chemistry and the characteristic ECD transitions, chiral HPLCeECD
analysis and TDDFT ECD calculation were carried out on a selected
5
2
1
compound 4e. Chiral HPLC separation of 4e was achieved on b-
cyclodextrin stationary phase using H2O/MeOH 85:15 as eluent.
Then online HPLCeECD spectra of the baseline-separated enan-
tiomers were recorded affording mirror image ECD curves. The
first-eluting enantiomer has a broad positive Cotton effect (CE) at
306 nm with distinct vibrational fine-structure, a positive CE at
240 nm and a negative one at 223 nm (Fig. 3).
4a-t
4u: R=H
6
3
For the configurational assignment, the solution TDDFT ECD
protocol has been pursued, which had been proved a powerful
method for the stereochemical study of synthetic37 and natural
derivatives.38,39 The MMFF conformational search of 4e provided
two initial conformers, the DFT reoptimization of which at the
B3LYP/6-31G(d) level resulted in two slightly different conformers
with 54 and 46% populations (Fig. 4).
9
7
8
Scheme 1. Synthesis of imidazoquinazolinediones.

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A. Varadi et al. / Tetrahedron 68 (2012) 10365e10371
10367
Table 1
Physical and receptor binding data for compounds 4aet
Nr.
1-Substituent
Mp [ꢀC]
Yield [%]
Formula
HRMS [MþH]þ (calcd)
Ki [nM]a
4a
4b
4c
4d
4e
4f
4g
4h
4i
4-N(CH3)2eC6H4
4-NHAceC6H4
2-OHeC6H4
3-OHeC6H4
4-OHeC6H4
4-OHe3-OMeeC6H3
4-OMeeC6H4
3,4-(OMe)2eC6H3
3,4,5-(OMe)3eC6H2
4-CH3eC6H4
C6H5
CH2C6H5
4-CleC6H4
4-CF3eC6H4
4-COOMeeC6H4
3-NO2eC6H4
2-Furyl
275e278
293e295
277e281
307e309
325e327
285e288
274e277
245e248
264e268
288e291
329e331
291e295
304e305
306e308
245e248
230e233
270 (dec)
285e287
302e305
292 (dec)
82
84
73
88
85
89
57
75
91
83
94
41
97
96
93
77
73
59
87
70
C18H16N4O2
C18H14N4O3
C16H11N3O3
C16H11N3O3
C16H11N3O3
C17H13N3O4
C17H13N3O3
C18H15N3O4
C19H17N3O5
C17H13N3O2
C16H11N3O2
C16H11N3O3
C16H10CIN3O2
C17H10F3N3O2
C18H13N3O4
C16H10N4O4
C14H10N4O2
C15H10N4O2
C15H10N4O2
C18H12N4O2
321.1343 (321.1346)
335.1135 (335.1139)
294.0877 (294.0873)
294.0880 (294.0873)
294.0876 (294.0873)
324.0983 (324.0979)
308.1024 (308.1030)
338.1134 (338.1135)
368.1237 (368.1241)
292.1079 (292.1081)
278.0919 (278.0924)
292.1077 (292.1081)
312.0533 (312.0534)
346.0794 (346.0798)
336.0982 (336.0979)
323.0778 (323.0775)
268.0720 (268.0717)
279.0879 (279.0877)
279.0878 (279.0877)
317.1039 (317.1034)
250
8
19
58
21
79
17
54
4j
4k
4l
32
4m
4n
4o
4p
4q
4r
4s
4t
11
89
15
2-Pyridyl
3-Pyridyl
3-Indolyl
a
Selected compounds.
The two conformers differed only in the orientation of the
hydroxyl hydrogen. TDDFT ECD calculations of both conformers
were performed using various functionals (B3LYP, BH&HLYP,
PBE0) and TZVP basis set, the Boltzmann-averaged spectra of
which reproduced well the experimental ECD spectrum with
BH&HLYP giving the best agreement. Since the BH&HLYP/TZVP
Boltzmann-weighted spectrum of (R)-4e was near identical with
the experimental HPLCeECD curve of the second-eluted enan-
tiomer (Fig. 3), the absolute configuration of the second-eluted
enantiomer was determined as (R). This correlation between the
chiroptical data and absolute configuration may serve as a refer-
ence to deduce the absolute configuration of analogous 1-aryl-
imidazo[5,1-b]quinazoline-3,9(1H,2H)-diones with similar sub-
stitution pattern.
5
8
3
11
12
13
5
8
6
7
3
2
11
6'
12
13
6
7
2
1
9
1
2'
9
1'
1'
3'
2'
4'
3'
5'
8'
5'
7'
4'
6'
Fig 2. Numbering of 1-aryl-imidazo[5,1-b]quinazoline-3,9(1H,2H)diones (4aet).
Table 2
1H NMR data for compounds 4aet
Substituent
Nr.
1-Ar
H-5a
H-6b
H-7c
H-8d
Other protons
2-NHe
1-CHf
p-N(CH3)2
p-NHAcePh
o-OH
m-OH
p-OH
m-OMe-p-OH 4f
p-OMe
3,4-(OMe)2
3,4,5-(OMe)3
p-Me
Ph
Benzyl
p-ClePh
p-CF3
p-COOMe
m-NO2
Fur-2-yl
Pyridine-2-yl
Pyridine-3-yl
Indol-3-yl
4a
4b
4c
4d
4e
7.23, d, 2H; 6.69, d, 2H
7.59, d, 2H; 7.38, d, 2H
7.89
7.91
7.89
7.92
7.89
7.89
7.91
7.89
7.89
7.90
7.92
7.76
7.91
7.93
7.92
7.91
7.91
7.92
7.92
7.92
7.62
7.63
7.63
7.64
7.62
7.62
7.63
7.62
7.63
7.63
7.63
7.68
7.64
7.64
7.66
7.64
7.65
7.64
7.64
7.61
7.91
7.93
7.92
7.94
7.92
7.92
7.93
7.92
7.92
7.92
7.93
7.91
7.93
7.95
7.94
7.94
7.95
7.95
7.95
7.92
8.10
8.11
8.12
8.13
8.10
8.11
8.11
8.11
8.12
8.10
8.11
8.32
8.11
8.11
8.11
8.11
8.16
8.12
8.12
8.07
2.89, s, CH3
10.04, s, NHeAc; 2.03, s, CH3
9.78, s, OH
9.57, s, OH
9.69, s, OH
9.25, s, OH; 3.73, s, CH3
3.75, s, CH3
3.75, s, CH3; 3.65, s, CH3
3.74, s, CH3ꢁ2; 3.65, s, CH3
2.30, s, CH3
10.49
10.56
10.35
10.62
10.52
10.51
10.56
10.53
10.52
10.59
10.64
10.35
10.62
10.68
10.69
10.69
10.65
10.63
10.63
10.56
6.53
6.57
6.64
6.55
6.54
6.53
6.59
6.57
6.55
6.59
6.64
6.06
6.65
6.74
6.71
6.85
6.78
6.75
6.71
6.94
7.35, d, 1H; 7.20, t, 1H; 6.84, t, 1H; 6.73, d, 1H
7.20, t, 1H; 6.86, d, 1H; 6.78, d, 1H 6.76, s, 1H
7.26, d, 2H; 6.77, d, 2H
7.02, s, 1H; 6.85, d, 1H; 6.77, d, 1H;
7.39, d, 2H; 6.94, d, 2H
7.06, d, 1H; 7.00, dd, 1H; 6.95, d, 1H;
6.82, s, 2H
7.33, d, 2H; 7.21, d, 2H
7.48, m, 2H; 7.40, m, 3H
7.12, m, 3H; 6.96, m, 2H
7.53, d, 2H; 7.46, d, 2H
7.78, d, 2H; 7.75, d, 2H
4g
4h
4i
4j
4k
41
4
4n
4o
4p
4q
4r
4s
4t
3.68, dd, CH2(a); 3.24, dd, CH2(b)
3.86,s, CH3
7.98, d, 2H; 7.65, d, 2H
8.49, s, 1H; 8.27, d, 1H; 8.00, d, 1H; 7.70, t, 1H
7.67, d, 1H; 6.85, d, 1H; 6.51, m, 1H;
8.51, dd, 1H; 7.94, m, 1H; 7.78, d, 1H; 7.42, dd, 1H
8.82, d, 1H; 8.61, dd, 1H; 7.89, m, 1H; 7.42, dd, 1H
7.77, d, 1H; 7.41, d, 1H; 7.07, t, 1H; 7.02, d, 1H; 6.91, t, 1H
11.36, s, NH
a
d, J5e6z7.8 Hz, 1H.
dd, J6e7z7.0 Hz, 1H.
d, J7e8z8.0 Hz, 1H.
d, 1H.
b
c
d
e
f
s, 1H.
s, 1H except for 4l; t, J¼3.2 Hz, 1H.

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A. Varadi et al. / Tetrahedron 68 (2012) 10365e10371
10368
Table 3
13C NMR data for compounds 4aet
Nr.
1
3
5
6
7
8
9
10
12
13
10
20
30
40
50
60
Other carbons
4a
69.1 159.2 128.4 128.1 134.8 125.9 157.8 121.8 121.8 148.5 121.4 128.2 111.9
151.1 111.9
127.9 118.9
130.5 119.0
116.4 129.8
158.8 115.3
147.6 115.3
160.1 114.0
149.7 111.6
138.2 153.0
139.0 129.2
128.7 128.7
128.1 128.1
129.5 128.7
128.2 40.0, N(CH3)2
129.2 168.4, C(O)CH3; 24.0, C(O)CH3
130.3
117.7
4b 68.8 159.2 128.5 128.1 134.9 125.9 157.8 121.8 121.8 148.5 140.3 127.9 118.9
4c 67.6 160.0 128.4 127.9 134.8 125.9 157.7 121.6 121.6 148.6 120.1 155.6 116.0
4d 68.8 159.2 128.5 128.2 135.0 126.0 157.6 121.7 121.7 148.4 136.5 113.6 157.7
4e
4f
68.9 159.2 128.5 128.1 134.9 125.9 157.8 121.8 121.8 148.5 125.0 128.8 115.3
69.2 159.2 128.4 128.1 134.8 125.9 157.9 121.9 121.9 148.5 125.5 111.4 147.7
68.7 159.2 128.5 128.1 134.9 125.9 157.8 121.8 121.8 148.5 126.6 128.8 114.0
128.8
120.3 55.8, OCH3
128.8 55.2, OCH3
120.2 55.7, 30-OCH3; 55.6, 40-OCH3
104.9 60.0, 40-OCH3; 56.1, 30,50-OCH3ꢁ2
127.3 20.8, CH3
127.4
130.0 35.7, CH2
134.1
4g
4h 69.1 159.2 128.4 128.1 134.8 125.9 157.9 121.8 121.8 148.5 127.1 110.8 148.7
4i
4j
69.4 159.3 128.4 128.0 134.8 126.0 158.1 121.8 121.8 148.5 130.6 104.9 153.0
68.9 159.2 128.5 128.1 134.9 125.9 157.7 121.7 121.7 148.5 132.1 127.3 129.2
4k 69.0 159.3 128.5 128.2 134.9 125.9 157.8 121.7 121.7 148.5 135.2 127.4 128.7
4l 67.2 159.2 128.4 128.2 135.0 126.1 158.7 121.2 121.2 148.1 132.4 130.0 128.1
4m 68.3 159.3 128.5 128.2 135.0 125.9 157.9 121.7 121.7 148.5 134.2 129.5 128.7
4n 68.3 159.4 128.6 128.3 135.1 126.0 157.9 121.7 121.7 148.5 139.8 128.5 125.6a 129.9 125.6b 128.5 123.9,c CF3
4o 68.4 159.3 128.6 127.9 135.0 126.0 157.9 121.7 121.7 148.5 140.2 127.9 129.5
4p 67.9 159.5 128.5 128.2 134.9 125.9 158.0 121.7 121.7 148.5 137.4 123.0 147.8
4q 62.3 159.3 128.0 127.8 134.2 125.3 157.2 121.5 121.5 148.5 136.9 110.7 110.5
130.6 129.5
124.4 130.3
143.3
127.9 165.7, COOCH3; 52.3, COOCH3
134.1
4r
4s
4t
68.9 159.8 128.6 128.2 135.1 125.9 157.6 121.6 121.6 148.6 153.4
67.1 159.4 128.5 128.2 134.9 125.9 158.0 121.7 121.7 148.5 130.9 149.5
64.8 159.3 128.5 128.1 134.8 125.9 157.8 121.8 121.8 148.4 124.1 107.4 127.3
150.0
124.6 137.4
150.6 135.0
119.5 121.5
123.9
123.8
121.5 136.5 (80), 112.2 (70)
a
q, J13C-19F¼3.6 Hz.
q, J13Ce19F¼31.8 Hz.
q, J13C-19F¼272.4 Hz.
b
c
Table 4
UV and IR absorption data for compounds 4aet
Nr.
UV absorption
IR absorption
2NH
lmax [nm], (log
3 )
3C]O
9C]O
Other
4a
4b
4c
4d
4e
4f
4g
4h
4i
322 (3.75), 304 (3.96), 296 (4.06), 288 (3.99), 231 (4.55)
321 (3.73), 303 (3.95), 294 (4.02), 285 (3.97), 231 (4.48)
319 (3.71), 302 (3.93), 293 (3.97), 286 (3.96), 230 (4.44)
318 (3.76), 303 (3.95), 294 (3.98), 285 (3.95), 232 (4.43)
319 (3.72), 303 (3.94), 294 (3.99), 285 (3.98), 231 (4.46)
320 (3.72), 304 (3.94), 295 (4.01), 284 (3.97), 231(4.47)
318 (3.78), 293 (4.04), 286 (4.03), 230 (4.56)
319 (3.77), 293 (4.01), 286 (3.99), 230 (4.59)
319 (3.80), 293 (4.03), 286 (4.01), 230 (4.61)
319 (3.82), 304 (4.04), 294 (4.08), 229 (4.49)
319 (3.85), 303i (4.06), 294.5 (4.11), 229 (4.48)
318 (3.81), 303 (4.07), 295 (4.05), 231 (4.39)
319 (3.72), 303 (3.92), 294 (3.99), 285 (3.95), 234 (4.36)
317 (3.76), 305 (3.94), 296 (4.04), 235 (4.51)
321 (3.84), 306 (4.04), 297.5 (4.10), 239 (4.54)
320 (3.71), 303 (3.89), 295 (3.95), 234 (4.67)
319 (3.74), 302i (4.03), 294 (4.11), 226 (4.36)
316 (3.71), 301 (3.86), 292 (3.99), 228 (4.41)
317 (3.85), 303 (4.06), 293 (4.05), 229 (4.53)
3224
3187
3215
3281
3246
3230
3253
3278
3212
3219
3210
3243
3274
3321
3337
3348
3213
3306
3312
3246
1715
1718
1705
1720
1708
1697
1706
1700
1703
1708
1720
1692
1723
1728
1721
1722
1695
1716
1713
1719
1676
1678
1679
1680
1681
1675
1678
1681
1677
1678
1680
1673
1681
1688
1687
1690
1672
1680
1684
1670
1645 COCH3
3287 OH
3445 OH
3392 OH
3435 OH
4j
4k
4l
4m
4n
4o
4p
4q
4r
4s
4t
1743 COOMe
319 (3.70), 303 (3.91), 294 (3.98), 287 (3.95), 233(4.36)
2.2. NMDA antagonist properties
3. Experimental
3.1. General
Preliminary pharmacological testing of selected 1-aryl-imidazo-
quinazolinediones suggests that the compounds are highly
potent antagonists with nanomolar affinity in the [3H]5,7-
dichlorokynurenic acid binding assay40 for NMDA receptors (Table 1).
The most active compounds of the series were the 4-
substituted-aryl derivatives. The size of the functional group had
no marked effect on the activity profile.
In conclusion, we synthesized 1-substituted derivatives of imi-
dazoquinazolindione by thermal cyclocondensation of 4-oxo-qui-
nazoline-2-carboxamide with a series of aldehydes. Absolute
configuration of separated enantiomers was determined by com-
parison of the online HPLCeECD spectra with the computed TDDFT
ECD spectra. Such promising compounds may act as lead molecules
for future investigations of novel NMDA receptor subsite selective
drugs.
All chemicals were purchased from SigmaeAldrich Chemicals
(Darmstadt, Germany) and were used without further purification.
1H and 13C NMR spectra were recorded on a Varian VNMRS nuclear
magnetic resonance spectrometer (600 MHz for 1H, 150.9 MHz for
13C) equipped with a dual 5-mm inverse-detection gradient (IDPFG)
probehead. Spectra were recorded in DMSO-d6 or CDCl3 at
25.0ꢂ0.1 ꢀC and referenced to internal standard Me4Si. NMR spectra
were processed with both VNMRJ 2.2C and MestReNova software
(ver. 6.1.1.). The structure of the compounds was confirmed by 1D
(1H, 13C) and 2D NMR (HSQC, HMBC, COSY) spectra. Melting points
were taken on a Stuart SMP-3 apparatus. The high-resolution ac-
curate masses (HRMS) were determined with an Agilent 6230 time-
of-flight mass spectrometer. Samples were introduced by the

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A. Varadi et al. / Tetrahedron 68 (2012) 10365e10371
10369
for water. Geometry reoptimizations at B3LYP/6-31G(d) level of
theory followed by TDDFT calculations using various functionals
(B3LYP, BH&HLYP, PBE0) and TZVP basis set were performed by
the Gaussian 03 package.42 Boltzmann distributions were esti-
mated from the ZPVE corrected B3LYP/6-31G(d) energies. ECD
spectra were generated as the sum of Gaussians43 with 3000 cmꢃ1
half-height width (corresponding to ca. 17 nm at 240 nm), using
dipole-velocity computed rotational strengths. The MOLEKEL44
software package was used for visualization of the results.
3.3. Chemical synthesis
3.3.1. Ethyl-4(3H)-oxo-quinazoline-2-carboxylate (2). A mixture of
anthranilamide 1 (50 g) and diethyl oxalate (110 mL) was refluxed
in oil bath at 185e186 ꢀC for 4.5 h. The reaction mixture exhibited
a yellowish green fluorescence. Excess of diethyl oxalate was re-
moved by distillation under reduced pressure. The brownish resi-
due was triturated with cold ethanol, filtered, dried, and
crystallized from ethanol to give 63 g (78%) of 2 as colorless crystals,
mp 192e194 ꢀC, lit. 189 ꢀC.35
Fig 3. Online HPLCeECD spectra of the first- (black) and second-eluting (gray) enan-
tiomers of 4e in H2O/MeOH 85:15 compared with the Boltzmann-weighted BH&HLYP/
TZVP spectrum (blue) calculated for the two lowest-energy conformers of the
(R)-enantiomer. Bars indicate the calculated rotatory strengths of conformer A.
3.3.2. 4(3H)-Oxo-quinazoline-2-carboxamide (3). A suspension of
40 g (0.18 mol) of 2 in 25%. NH4OH (200 mL) was heated at 70 ꢀC for
2 h. The reaction mixture was allowed to stand at room tempera-
ture overnight. The pH of the mixture was set to neutral with acetic
acid and the precipitated crystals were filtered and washed with
water and cold ethanol to give 34 g (98%) of 3 as colorless powder,
mp 231e233 ꢀC, lit. 230 ꢀC.45
3.3.3. General procedure for preparation of 1-aryl-imidazo[5,1-b]
quinazoline-3,9(1H,2H)diones
(4aet). The
well-homogenized
equimolar mixture of 3 and the appropriate aromatic aldehyde
was heated at 170 ꢀC for 3 h. After completion of the reaction (TLC
control, silica gel; benzene/methanol 4:1), the semisolid waxy
residue was suspended in 3 mL ethanol, and sonicated for 1 h at
60 ꢀC. The resulting precipitate was filtered and washed with eth-
anol. The crude products were recrystallized from DMF/ethyl ace-
tate (Tables 1e4).
Fig 4. DFT optimized geometries and populations of the two low-energy conformers of
(R)-4e.
Agilent 1260 Infinity LC system, the mass spectrometer was oper-
ated in conjunction with a Jet Stream electrospray ion source in
positive ion mode. Reference masses of m/z 121.050873 and
922.009798 were used to calibrate the mass axis during analysis.
Mass spectra were processed using Agilent MassHunter B.02.00
software. UV spectra were recorded on Jasco V-550 spectrometer
with 1 cm cuvettes in ethanol solution at 25 ꢀC. IR spectra were
recorded from KBr discs on a. Perkin-Elmer 1600 FTIR instrument.
ECD spectra were recorded on Jasco J-720 instrument. The liquid
chromatograph consisted of a Jasco PU-980 Intelligent HPLC pump
with a Rheodyne 7725i injector (Cotati, CA, USA), and a Jasco UV-
975 Intelligent UV/VIS detector. For the chiroptical detection of
the resolved enantiomers a cylindrical, focusable flow through cell
was applied in to the spectropolarimeter sample compartment. The
3.3.3.1. 1-Phenyl-imidazo[5,1-b]quinazoline-3,9(1H,2H)dione
(4k). To a stirred suspension of 7 hydrochloride (0.5 g, 2 mmol) in
dioxane (5 mL) was added benzaldehyde (0.2 mL, 2 mmol). The
reaction mixture was then heated at 100 ꢀC for 3 h. The solvent was
evaporated, the residue diluted with 5% hydrochloric acid (5 mL),
and stirred for 30 min. The precipitated product was filtered and
washed with water. The crude product was crystallized from eth-
anol to give 4k as colorless crystals (0.35 g, 64%) (Tables 1e4).
3.3.3.2. Imidazo[5,1-b]quinazoline-3,9(1H,2H)-dione (4u). A mix-
ture of 3 (1.89 g, 0.01 mol), paraformaldehyde (0.36 g, 0.012 mol),
and triethylamine (two drops) in dimethylformamide (3 mL) was
stirred in a sealed tube at room temperature for 2 h, then heated for
8 h until the disappearance of amide (checked by TLC). The reaction
mixture was diluted with water (20 mL). The separated solid was
filtered and washed with water. The crude product was dissolved in
chloroform (20 mL), the insoluble material was filtered, and the
solution washed with 5% sodium carbonate solution (2ꢁ10 mL) and
water (10 mL), then dried over sodium sulfate. The solvent was
evaporated and the residue was crystallized from isopropanol to give
4u as colorless crystals (1.14 g, 56%), mp: 251e252 ꢀC (decomp.).
Found: C 9.74; H 3.50; N 20.85. C10H7N3O2 requires: C 9.70; H 3.51; N
b
-cyclodextrin column (250ꢁ4.6 mm; 5 mm) was purchased from
ChiroQuest (Budapest, Hungary). The mobile phase contained 15 v/
v% methanol and 85 v/v% purified water. The eluent components
were degassed before mixing and have been sonicated for 10 min
after mixing. The eluent flow was set to 0.8 mL/min. TLC was carried
out on TLC aluminum sheets, Kieselgel 60 F254 (Merck KGaA,
Darmstadt, Germany). In silico calculations were carried out on an
Intel Core i7-950 PC by using MMFF force-field method in Macro-
model, and B3LYP/6-31G(d), B3LYP/TZVP, BH&HLYP, and PBE0/TZVP
methods in the Gaussian 03 program package.
3.2. Computational section
20.89%; UV (EtOH): lmax (log
231 (4.24) nm; IR (KBr): nmax¼3163 (NH), 1702 (C]O), 1673 (C]O)
cmꢃ1
dH (600 MHz, CDCl3) 8.11 (1H, dd, J 8.1, 1.1 Hz), 7.93 (1H, dd, J
8.1, 1.1 Hz), 7.87 (1H, ddd, J 8.0, 7.1, 1.2 Hz), 7.63 (1H, dt, J 7.8, 0.9 Hz),
5.86 (1H, d, J 13.1 Hz), 5.31 (1H, d, J 13.1 Hz); dC (150 MHz, CDCl3)
3
)¼315 (3.80), 301 (4.01), 295 (3.95),
Mixed torsional/low mode conformational searches were car-
ried out by means of the Macromodel 9.7.21141 software using
Merck Molecular Force Field (MMFF) with implicit solvent model
;

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A. Varadi et al. / Tetrahedron 68 (2012) 10365e10371
10370
161.6,159.2,150.7,145.7,134.3,130.5,128.2,126.1,124.2, 48.3; HRMS:
(5 mL) was added excess acetaldehyde (0.22 mL, 4 mmol). The re-
action mixture was then stirred at room temperature overnight.
The solvent was evaporated, the residue diluted with 5% hydro-
chloric acid (5 mL), and stirred for 30 min. The mixture was neu-
tralized with 10% sodium carbonate solution and extracted with
chloroform (3ꢁ10 mL). The combined organic phase was washed
with water, decolorized by charcoal, dried over sodium sulfate, and
evaporated. The solid residue was crystallized from ethyl acetate to
give 8 as colorless crystals (0.27 g, 63%), mp 233e234 ꢀC. Found: C
61.44; H 4.19; N 19.45. C11H9N3O2 requires: C 61.39; H 4.22; N
[MþH]þ, found: 201.0538. C10H7N3O2 requires: 201.0548.
3.3.4. 1-Methyl-1-methoxy-imidazo[5,1-b]quinazoline-3,9(1H,2H)di-
one (5). Compound 3 (1.89 g, 0.01 mol) was suspended in a solu-
tion of sodium methoxide (8.3%) in methanol (20 mL) under
efficient stirring at room temperature. Then a mixture of 10 mL
methanol and 2.50 mL (0.02 mol) methyl orthoacetate was added
drop-wise into this suspension for 1 h, and the mixture was stirred
for another 1 h. Then the reaction mixture was refluxed for 10 h.
HCl (36%) was used to adjust the pH to 4 and the temperature was
kept below 30 ꢀC. Then the mixture was filtrated and the solvent
was evaporated to obtain a colorless powder, which was then
refluxed in 10 mL methanol for 20 min. Insoluble residue was re-
moved by filtration and the filtrate was kept in the refrigerator for
12 h to obtain 1.25 g (51%) of 5 as colorless crystals, mp 204e206 ꢀC.
Found: C 58.77; H 4.52; N 17.13. C12H11N3O3 requires C 58.77, H
19.52%; UV (EtOH): lmax (log
3
)¼317 (3.85), 305 (4.06), 295 (4.11),
231 (4.43) nm; IR (KBr): nmax¼3225 (NH), 1705 (C]O), 1678 (C]O);
dH (600 MHz, CDCl3) 8.16 (1H, dd, J 8.15, 1.10 Hz), 7.95 (1H, dd, J 8.15,
1.10 Hz), 7.88 (1H, ddd, J 8.0, 7.1, 1.2 Hz), 7.67 (1H, dt, J 7.8, 0.9 Hz),
6.28 (1H, q, J 7.2 Hz),1.83 (3H, d, J 7.8 Hz); dC (150 MHz, CDCl3) 161.7,
159.3, 150.7, 145.7, 134.3, 130.5, 128.2, 126.2, 124.2, 58.5, 18.3;
HRMS: [MþH]þ, found: 215.2093. C11H9N3O2 requires: 215.2091.
4.52, N 17.13%; UV (EtOH): lmax (log
(4.01), 233 (4.39) nm; IR (KBr) nmax¼3260 (NeH), 1678 (C]O), 1615
(C]N) cmꢃ1
dH (600 MHz, CDCl3) 8.23 (1H, dd, J 8.0, 1.2 Hz), 7.95
3 )¼317 (3.80), 302 (4.06), 294
3.3.8. Imidazo[5,1-b]quinazoline-3,9-dione(9). Compound 3 (0.01 mol)
of 1.89 g was suspended in excess of trimethyl orthoformate (10 mL)
and heated at 150 ꢀC for 5 h. The reaction mixture was concentrated in
vacuo, and the residue was diluted with 5% sodium hydroxide (20 mL)
and extracted with chloroform (3ꢁ20 mL). The combined organic
layers were washed with 5% acetic acid water solution (2ꢁ10 mL) and
with water (2ꢁ10 mL), dried over sodium sulfate and then evaporated
in vacuo. The crude solid was crystallized from ethanol to give 1.5 g
(75%) of 9 as a colorless product, mp 154e157 ꢀC. Found: C 60.28; H
2.52; N 21.22. C10H5N3O2 requires: C 60.31; H 2.53; N 21.10%; UV
;
(1H, dd, J 8.0, 0.9 Hz), 7.87 (1H, ddd, J 8.0, 7.1, 1.2 Hz), 7.63(1H, dt, J
7.8, 0.9 Hz), 3.32 (3H, s), 1.71 (3H, s); dC (150 MHz, CDCl3) 159.8,
158.5, 151.7, 148.2, 134.5, 131.4, 128.5, 126.2, 123.6, 88.7, 51.3, 18.5;
HRMS: [MþH]þ, found: 245.0798. C12H11N3O3 requires: 245.0800.
3.3.5. 4(3H)-Oxo-quinazoline-2-carbonitrile (6). To a suspension of
3 (1.89 g, 0.01 mol) in toluene (10 mL) was added excess phos-
phorus pentoxide (4.23 g, 0.03 mol) and the mixture was stirred at
110 ꢀC for 3 h. The solvent was evaporated in vacuo, the residue
suspended in water (20 mL), and neutralized with sodium car-
bonate. The water layer was extracted with chloroform (3ꢁ10 mL).
The combined organic phases were washed with water (2ꢁ10 mL)
dried over sodium sulfate, decolorized by charcoal, and evaporated.
The residue was crystallized from ethyl acetate/hexane to give 636
1.60 g (84%), mp>240 ꢀC (decomp.). Found: C 63.19; H 2.92; N
24.58. C9H5N3O requires: C 63.16; H 2.94; N 24.55%; UV (EtOH):
(EtOH): lmax (log
3
)¼228 (4.45), 246 (4.38), 255 (4.25), 328 (3.98) nm;
IR (KBr): nmax¼1668 (C]O), 1618 (C]N); dH (600 MHz, CDCl3) 8.66
(1H, s) 8.18 (1H, dd, J 8.1, 1.1 Hz), 7.95 (1H, dd, J 8.1, 0.9 Hz), 7.87 (1H,
ddd, J 8.0, 7.1, 1.2 Hz), 7.63 (1H, dt, J 7.8, 0.9 Hz); dC (150 MHz, CDCl3)
162.4, 158.4, 151.9, 148.2, 144.8, 134.6, 131.4, 128.6, 126.3, 124.0; HRMS:
[MþH]þ, found 199.1793. C10H5N3O2 requires: 199.1877.
Acknowledgements
lmax (log
3
)¼227 (4.14), 238 (4.20), 253 (4.05), 312 (3.81) nm; IR
(KBr): nmax¼3317 (NeH), 2237 (CN), 1686 (C]O) cmꢃ1
; dH
T.K. and A.M. thank the HURO/0901/274/2.2.2 project for support
(websites:www.huro-cbc.eu and www.hungary-romania-cbc.eu).
(600 MHz, DMSO-d6) 8.18 (1H, dd, J 7.96 Hz), 7.59 (1H, m), 7.52 (1H,
m), 7.36 (1H, m); dC (150 MHz, DMSO-d6) 171.2, 150.7, 143.6, 126.5,
126.0 (2ꢁ), 132.4, 123.8, 118.1; HRMS: [MþH]þ, found: 171.0430.
C9H5N3O requires: 171.0433.
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(1H, dd, J 7.9, 1.2 Hz), 7.62 (1H, ddd, J 8.2, 7.0, 1.5 Hz), 7.53 (1H, dd, J
8.2, 0.8 Hz), 7.38 (1H, dt, J 7.7, 0.8 Hz), 4.48 (2H, q, J 7.1 Hz), 1.51 (3H,
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