Synthesis, resolution and anticonvulsant activity of chiral N-1′-ethyl,N-3′-(1-phenylethyl)-(R,S)-2′H,3H, 5′H-spiro-(2-benzofuran-1,4′-imidazolidine)-2′,3, 5′-trione diastereomers

Article abstract of DOI:10.1016/j.bmcl.2012.02.005

Four new N-1′,N-3′-disubstituted-2′H,3H,5′H-spiro- (2-benzofuran-1,4′-imidazolidine)-2′,3,5′-triones bearing a chiral N-3′ substituent were synthesized, resolved and their anticonvulsant activity was obtained and determined that the activity was not stere

Full text of DOI:10.1016/j.bmcl.2012.02.005

Bioorganic & Medicinal Chemistry Letters 22 (2012) 2507–2509
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis, resolution and anticonvulsant activity of chiral
N-10-ethyl,N-30-(1-phenylethyl)-(R,S)-20H,3H,50H-spiro-
(2-benzofuran-1,40-imidazolidine)-20,3,50-trione diastereomers
Ishwar R. Sadarangani a, Souful Bhatia a, Daniel Amarante b, Istvan Lengyel c, Ralph A. Stephani a,c,
⇑
a Department of Pharmaceutical Sciences, St. John’s University, 8000 Utopia Parkway, Jamaica, NY 11439, USA
b Department of Chemistry and Biochemistry, College of Mount Saint Vincent, 6301 Riverdale Avenue, Riverdale, NY 10471, USA
c Department of Chemistry, St. John’s University, 8000 Utopia Parkway, Jamaica, NY 11439, USA
a r t i c l e i n f o
a b s t r a c t
Four new N-10,N-30-disubstituted-20H,3H,50H-spiro-(2-benzofuran-1,40-imidazolidine)-20,3,50-triones bearing
a chiral N-30 substituent were synthesized, resolved and their anticonvulsant activity was obtained
and determined that the activity was not stereoselective.
Article history:
Received 3 October 2011
Revised 1 February 2012
Accepted 2 February 2012
Available online 11 February 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Spirohydantoins
Anticonvulsant
Diastereomers
Stereoselective
Resolution
R1
Epilepsy is a neurological disorder that affects approximately 45
million people worldwide.1 It is a condition characterized by the
periodic and unpredictable occurrence of seizures. A seizure can
occur when there is an abnormal discharge of neurons in the cen-
tral nervous system specifically in the cerebral cortex of the brain.2
Symptoms may include any brief unusual behavior such as the loss
of consciousness, a stare, a short period of confusion, a recurring
thought, a peculiar feeling, an emotional outburst, a strange sensa-
tion, an odd posturing or uncontrolled movements.3 Several new
antiepileptic drugs (AEDs) have been introduced since 1990 such
as felbamate, levetiracetam, pregabalin, lamotrigine, gabapentin,
topiramate, tiagabine, oxcarbazepine, zonisamide and vigabatrin.
In comparison, each drug exhibits a different mechanism of action
from each other and also when compared to the traditional AEDs.
These drugs displayed good efficacy and tolerability in patients,
but also have a potential for developing serious side effects.4 As a
result, there is still a quest for designing new AEDs with improved
efficacy and fewer toxic effects. Compounds containing a hydan-
toin ring system, for example phenytoin have been shown to pos-
sess appreciable anticonvulsant activity and is one of the most
important drugs used in treating epileptic seizures.5–7 Since its
discovery, many hydantoin analogs have been shown to possess
O
O
R2
O
HN
O
HN NH
O
N
R3
2
1
R1, R2 = H, halogen
R3 = H, alkyl
Figure 1. Spirohydantoins with antiepileptic activity.
anticonvulsant activity. One type of analog, a 5,5-cyclic hydrocar-
bon hydantoin or spirohydantoin, was synthesized and its anticon-
vulsant activity was reported, Figure 1.5 Type 1 spirohydantoins
had similar or better efficacy than diphenylhydantoin and meth-
ylphenylhydantoin when subjected to a stimulus test.8 On the
other hand, sedation, hypnosis and anticonvulsant properties were
characteristic of the type 2 spirohydantoins.9
Previously in our group, several new N-10,N-30-disubstituted-
20H,3H,50H-spiro-[2-benzofuran-1,40-imidazolidine]-20,3,50-triones
were synthesized by the periodate oxidation of N-1,N-3-disubstituted
imidazolidinediones. All compounds were synthesized as racemates
⇑
Corresponding author.
E-mail address: stephanr@stjohns.edu (R.A. Stephani).
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2012.02.005

2508
I. R. Sadarangani et al. / Bioorg. Med. Chem. Lett. 22 (2012) 2507–2509
to the exclusion of any trans-product, thereby giving only two
O
stereoisomers. The two diastereomers of the optically active indeno-
[1,2-d]-imidazole intermediates were separated through a combi-
nation of recrystallization and chromatography. Recrystallization
of the intermediate bearing the (S)-1-phenylethyl group as the
substituent led to the selective crystallization of the dextrorotatory
isomer ((+)-7a) while the levorotatory isomer ((ꢀ)-7a) was ob-
tained from the filtrate by simple, achiral silica chromatography.
In contrast, recrystallization of the intermediate with the (R)-1-
phenylethyl substituent gave the levorotatory isomer ((ꢀ)-7b)
while the dextrorotatory isomer ((+)-7b) was also isolated from
the filtrate by achiral chromatography. For each diastereomer,
the configurations of the two chiral carbons bearing the two hydro-
xyl groups were assigned according to their X-ray structures,12–15
Table 1.
According to Scheme 1, the spirohydantoins are formed by oxi-
dation of the indeno-[1,2-d]-imidazole intermediates (7a,b) with
sodium periodate. The chiral carbon at the 40 position results in
two possible diastereomers for the oxidation product. Since previ-
ously prepared spirohydantoins were racemates, the isolated prod-
ucts were optically inactive.10 In the current work, when the
optically active diastereomeric mixture of the (S)- and the (R)-in-
deno-[1,2-d]-imidazole intermediates were oxidized, thin layer
chromatography showed that two corresponding spirohydantoins
were formed. The mixture of the two diastereomers was easily re-
solved by recrystallization or column chromatography. The struc-
tures of spirohydantoins (ꢀ)-3a and (+)-3b were confirmed by
their X-ray analyses16,17 and the configurations of the 40-spirocar-
bons were assigned, however, their absolute configurations could
not be determined. The X-ray structures of (+)-3a and (ꢀ)-3b could
not be obtained since they were isolated as ‘gums’ by the chro-
matographic separation. As a result, the configuration of the 40-spi-
rocarbons for (+)-3a and (ꢀ)-3b were deduced intuitively, namely
opposite to that of crystalline compounds (ꢀ)-3a and (+)-3b,
respectively, as indicated from their physical properties shown in
Table 2. In addition, the structures of all compounds were con-
O
R2
3'
N
O
R
1'
1 N
O
3
R1 = C2H5
R2 = CH(CH3)C6H5
Figure 2. General structure of N-10,N-30-disubstituted-20H,3H,50H-spiro-[2-benzo-
furan-1,40-imidazolidine]-20,3,50-triones.
and no attempts to resolve their enantiomers have been made to
date. These spirohydantoins were tested for their anticonvulsant
activities and were found to be active in the subcutaneous pentyl-
enetetrazol (scPTZ) test.10 In this research, we are reporting the
synthesis and resolution of four new N-10,N-30-disubstituted-
20H,3H,50H-spiro-[2-benzofuran-1,40-imidazolidine]-20,3,50-triones
containing a chiral substituent at the N-30 position, Figure 2.
The spirohydantoins were synthesized according to Scheme 1.
Ethyl isocyanate was reacted separately with (S)-(ꢀ)- and (R)-(+)-
1-phenylethylamine to yield the corresponding optically active
disubstituted ureas ((S)-(ꢀ)-6a and (R)-(+)-6b). When the (S)-
(ꢀ)- and (R)-(+)-disubstituted ureas were refluxed with ninhydrin
in benzene for 1 h, an indeno-[1,2-d]-imidazole intermediate was
formed as a mixture of two diastereomers. Previously synthesized
indeno-[1,2-d]-imidazole intermediates displayed only one major
product (by tlc) since they were obtained as racemic mixtures,
and have not been resolved into their enantiomers to date.10 There
are two asymmetric carbons present in this intermediate, specifi-
cally the carbons of the indane ring bonded to the two hydroxyl
groups. Theoretically, four stereoisomers should be possible for
this intermediate, however, X-ray crystallography11 shows that
both hydroxyl groups are in the cis-conformation to each other,
R1
N
C O
O
O
R1
OH
N
O
4
i
ii
iii
O
R1
N
H
N
H
R2
R2
O
+
N
N
HO
O
R2
N
R2 NH2
R1
O
6a-b
5
7a-b
3a-b
Scheme 1. The synthesis of 3a–b. Reagents and conditions: (i) Dry THF, 25 °C; (ii) ninhydrin, C6H6, 1 h; (iii) NaIO4, MeOH, 2 h.
Table 1
Physical properties and assigned configurations of the optically active indeno-[1,2-d]-imidazole intermediates
O
R1
OH
3a
8a
N
*
*
O
N
HO
R2
7a-b
Compound
R1
R2
Mp (°C)
[a]
(°)
Assigned configurations
D
of carbons 3a,8a
(+)-7a
(ꢀ)-7a
(ꢀ)-7b
(+)-7b
C2H5
C2H5
C2H5
C2H5
(S)-CH(CH3)C6H5
(S)-CH(CH3)C6H5
(R)-CH(CH3)C6H5
(R)-CH(CH3)C6H5
192–195
182–184
198–201
188–190
+110.8
ꢀ81.5
ꢀ105.1
+77.0
S,R
R,S
S,R
R,S

I. R. Sadarangani et al. / Bioorg. Med. Chem. Lett. 22 (2012) 2507–2509
2509
Table 2
Physical properties, assigned configurations and anticonvulsant test results (ED50) of the optically active spirohydantoins
O
O
R2
*
4'
3' N
O
N1'
R1
O
3a-b
Compound
R1
R2
Mp
[
a]
D
(°)
Assigned configuration
of carbon 40
ED50ascPTZ
(ꢀ)-3a
C2H5
C2H5
C2H5
C2H5
(S)-CH(CH3)C6H5
(S)-CH(CH3)C6H5
(R)-CH(CH3)C6H5
(R)-CH(CH3)C6H5
149–150 °C
ꢀ137.70
+32.8
+133.7
ꢀ34.4
S
R
R
S
300
b
c
(+)-3a
d
c
(+)-3b
148–149 °C
b
(ꢀ)-3b
Phenobarbital
25e (16)f
a
b
c
d
e
f
ED50 values are in mg/kg of test drug delivered intraperitoneally and measured at 0.5 h. The time of peak effect was not determined.
Isolated as a ‘gum’.
Not active up to 300 mg/kg.
Active at 300 mg/kg, ED50 value not determined.
Experimental ED50 value.
Literature ED50 value.10
firmed by their infrared, NMR and mass spectra as well as elemen-
tal analyses.
include MOL files and InChiKeys of the most important compounds
described in this article.
The anticonvulsant activities of these four spirohydantoins
were determined by assessing their ability to decrease convulsions
in mice induced by the drug, pentylenetetrazol (PTZ).18,19 Pheno-
barbital was used in the scPTZ model as the reference compound.
From Table 2, it can be seen that the anticonvulsant activity is
not stereoselective. Spirohydantoin (ꢀ)-3a which contains the
(S)-1-phenylethyl substituent at the N-30 position with an assigned
configuration of (S) at the 40-spirocarbon was the most active hav-
ing an ED50 value of 300 mg/kg. Compound (+)-3b, which is the
enantiomer of (ꢀ)-3a, has an assigned configuration of (R) at the
40-spirocarbon, but bears the (R)-1-phenylethyl substituent at the
N-30 position was active at a dose of 300 mg/kg, however, its
ED50 value could not be determined. Similary, spirohydantoins
(+)-3a and (ꢀ)-3b are also enantiomers, but these two compounds
did not display any anticonvulsant activity even at a dose of
300 mg/kg.
References and notes
1. French, J. A.; Pedley, T. A. N. Eng. J. Med. 2008, 359, 166.
2. McNamara, J. O. In Goodman and Gilman’s: The Pharmacological Basis of
Therapeutics; Hardman, J. G., Limbird, L. E., Eds., 10th ed.; McGraw Hill: New
York, 2001; pp 521–547.
3. Svoboda, W. B. Learning About Epilepsy; University Park Press: Baltimore, 1980.
p 9.
4. Vajda, F. J. E. J. Clin. Neurosci. 2000, 7, 88.
5. Vida, J. A. In Anticonvulsants in Medicinal Chemistry; Academic Press, 1977; Vol.
15, pp 58, 59, 68, 69, 73, 74, 152, 155.
6. Brodie, M. J. Epilepsy Res. 2001, 45, 3.
7. Kung, C.; Wurpel, J.; Kwon, C. Drug Dev. Res. 1999, 47, 17.
8. Arnold, H.; Kuehas, E.; Brock, N. DE 1,135,915, Chem. Abstr. 1962, 58, 20770.
9. Brimelow, H.C.; Vasey, C. H. GB 807,676 and 807,678, Chem. Abstr. 1959, 53,
67757.
10. Patel, H. J.; Sarra, J.; Caruso, F.; Rossi, M.; Doshi, U.; Stephani, R. A. Bioorg. Med.
Chem. Lett. 2006, 16, 4644.
11. Naredelli, M. Gazz. Chim. Ital. 1987, 117, 731.
12. X-ray coordinates of compound (+)-7a have been deposited with the
Cambridge Crystallographic Data Centre and the deposition number is CCDC
860806.
13. X-ray coordinates of compound (ꢀ)-7a have been deposited with the
Cambridge Crystallographic Data Centre and the deposition number is CCDC
860803.
14. X-ray coordinates of compound (ꢀ)-7b have been deposited with the
Cambridge Crystallographic Data Centre and the deposition number is CCDC
860804.
15. X-ray coordinates of compound (+)-7b have been deposited with the
Cambridge Crystallographic Data Centre and the deposition number is CCDC
860807.
16. X-ray coordinates of compound (ꢀ)-3a have been deposited with the
Cambridge Crystallographic Data Centre and the deposition number is CCDC
860802.
17. X-ray coordinates of compound (+)-3b have been deposited with the
Cambridge Crystallographic Data Centre and the deposition number is CCDC
860805.
In conclusion, four new optically active N-10,N-30-disubstituted-
20H,3H,50H-spiro-(2-benzofuran-1,40-imidazolidine)-20,3,50-triones
were synthesized and resolved. The anticonvulsive activity of all
four compounds was obtained, but the activity was shown not to
be stereoselective.
Acknowledgments
The authors thank Nagaraju Annreddy for assisting with the
anticonvulsant testing.
This research was supported by the St. John’s University Re-
search Fund.
Supplementary data
18. Swinyard, E. A.; Brown, W. C.; Goodman, L. S. J. Pharmacol. Exp. Ther. 1952, 102,
319.
19. Sarra, J.; Stephani, R. A. Res. Commun. Biol. Psychol. Psychiat. 1998, 23, 73.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2012.02.005. These data