Design and synthesis of 6-amino-1,4-oxazepane-3,5-dione derivatives as novel broad spectrum anticonvulsants

Article abstract of DOI:10.1016/j.bmcl.2008.04.067

Based on the structural estimations of the typical anticonvulsant drugs, a series of 6-amino-1,4-oxazepane-3,5-dione derivatives, novel structures of 7-membered heterocyclic imides, which were hybridized with pharmacophores such as cyclic imide and N-CO-C

Full text of DOI:10.1016/j.bmcl.2008.04.067

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry Letters 18 (2008) 3188–3191
Design and synthesis of 6-amino-1,4-oxazepane-3,5-dione
derivatives as novel broad spectrum anticonvulsants
Gitalee Sharma, Jin Yup Park and Min Soo Park*
College of Pharmacy, Kyungsung University, 110-1 Daeyeon-Dong, Nam-Gu, Busan 608-736, Republic of Korea
Received 18 March 2008; revised 23 April 2008; accepted 26 April 2008
Available online 1 May 2008
Abstract—Based on the structural estimations of the typical anticonvulsant drugs, a series of 6-amino-1,4-oxazepane-3,5-dione
derivatives, novel structures of 7-membered heterocyclic imides, which were hybridized with pharmacophores such as cyclic imide
and N-CO-C-N group in their molecule were designed and synthesized. Their anticonvulsant activities were evaluated by the max-
imal electroshock induced seizure (MES) and subcutaneous pentylenetetrazole (PTZ) tests. Almost all the designed compounds
except 1c and 1f showed comparable anticonvulsant activities in at least one of the anticonvulsant tests. Moreover, some of the
tested compounds exhibited moderate anticonvulsant activities in both MES and PTZ tests. From these results, 6-amino-1,4-oxa-
zepane-3,5-dione derivatives could be recommended as novel structures of broad spectrum anticonvulsants.
Ó 2008 Elsevier Ltd. All rights reserved.
About 1% of the population worldwide is affected by
epilepsy, convulsive disease.1 20–40% of epileptic pa-
tients fail to experience significant seizure control with
the drugs in clinical use.2 Clinically, epilepsy consists
of various forms of seizure. Therefore, combination of
various antiepileptic drugs (AEDs) is used for the treat-
ment of epilepsy.3 Owing to the limitations of currently
used AEDs, there is still need for the development of
new AEDs of broader spectrum.
O
N
O
O
Oxazolidinedione
O
O
O
O
N
H
N
Recently, there have been various trials for the develop-
ment of new anticonvulsants, including derivatives of
amino acids,4,5 structural modification of conventional
AEDs,6,7 GABA related compounds,8,9 and NMDA
antagonists.10
N
N
HN
R
O
O
O
O
Hydantoin
R
Succinimides
6-amino-1,4-oxazepane-3,5-diones
In view of the development of new anticonvulsant drugs,
we examined the structural characteristics of typical
anticonvulsant compounds, such as hydantoins,3 oxazo-
lidinediones,3 succinimides,3 and N-acyl-a-amino acid
amide.4,5 The structural inspection showed that these
compounds included cyclic imides or N-CO-C-N moiety
in their molecules as shown in Figure 1. Thus, these
groups such as cyclic imide and N-CO-C-N play an
O
HN
NHR
O
R
N-acyl amide
Figure 1. Structural characteristics of 6-amino-1,4-oxazepane-3,5-
diones.
Keywords: Anticonvulsant; 6-Amino-1,4-oxazepane-3,5-dione; MES
test; PTZ test.
important role on their anticonvulsant activities as phar-
macophores. Interestingly, hydantoins and N-acyl-a-
amino acid amide, which are used for the generalized
*
Corresponding author. Tel./fax: +82 51 620 4884; e-mail addresses:
mspark@ks.ac.kr; mspark4884@hanmail.net
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.04.067

G. Sharma et al. / Bioorg. Med. Chem. Lett. 18 (2008) 3188–3191
3189
seizure, have N-CO-C-N group, and oxazolidinedione
and succinimide, having cyclic imide in their molecules,
are used for the absence seizure in clinical practice.3–5
evaluation of their anticonvulsant spectrum.3,12 There-
fore, the anticonvulsant evaluation for the tested com-
pounds was carried out by both the MES and PTZ
tests according to the protocol of the antiepileptic Drug
Development program, National Institute of Neurolog-
ical Disorder and Stroke.12
Based on these structural characteristics, it was assumed
that the compound which hybridized both cyclic imide
and N-CO-C-N moiety in a single molecule could be a
broad spectrum anticonvulsant. In view of this struc-
tural estimation, the 6-amino-1,4-oxazepane-3,5-dione
derivatives, which are 7-membered heterocyclic imides
and also include N-CO-C-N moiety in their molecule,
were designed as novel structure of broad spectrum anti-
convulsants. The structural characteristics and similari-
ties of 6-amino-1,4-oxazepane-3,5-diones to some
anticonvulsants are shown in Figure 1.
The results of anticonvulsant activities for these tested
compounds are summarized in Table 1.
As seen in Table 1, 1a, 1b, 1d, 1e, 1g, 1h, and 1l com-
pounds among the tested compounds exhibited consid-
erable anticonvulsant activities in the MES test, and
Table 1. The anticonvulsant activities of 6-amino-1,4-oxazepane-3,5-
dione derivatives (1a–l)
The present work focuses on the design, synthesis and
anticonvulsant evaluation of 6-amino-1,4-oxazepane-
3,5-dione derivatives.
Compound
R
ED50 (mg/kg)a
MESb
PTZc
A series of 6-amino-1,4-oxazepane-3,5-dione derivatives
1a–l were designed and prepared from (S)-N-Cbz-serine
2 by usual synthetic procedure. The synthetic procedures
are outlined in Scheme 1.
1a
1b
1c
1d
1e
1f
H
CH3
81.25
68.75
>100
87.5
55.08
41.02
>100
26.97
34.77
>100
37.11
35.56
64.06
53.91
n-C3H7
Cyclopropyl
n-C4H9
Isobutyl
Allyl
93.75
>100
70.31
87.5
The general synthetic procedures are as follows:
1g
1h
1i
n-C6H11
Benzyl
4-Fluorobenzyl
The methyl ester of (S)-N-Cbz-serine 3 was obtained by
usual acid catalyzed esterification. Compound 4 was
prepared by O-alkylation of compound 3 with ethyl bro-
moacetate and NaH in acetonitrile in good yields. A ser-
ies of tested compounds 1a–l could be afforded by
treating the corresponding amine with compound 4.
All the tested compounds 1a–l gave satisfactory spectral
data11 and were submitted for the following anticonvul-
sant evaluation.
>100
>100
1j
1k
>100
64.06
CH2
O
1l
OH
93.75
9.5
42.6
96.88
—
Diphenylhydantoind
Methosuximided
Valproic acidd
Trimethadioned
34.5
148.6
250.5
271.1
704.2
The anticonvulsant activities are usually evaluated by
both the MES and PTZ tests.12 The MES test is related
to the generalized tonic–clonic seizure and PTZ test to
the absence seizure.2,3,12 Thus, these two kinds of anti-
convulsant tests are meaningful for the clinical predic-
tion of the anticonvulsant drug candidates and
a All compounds were administered ip to ICR male mice and all
anticonvulsant tests were performed in groups of four mice 30 min
after test compound administration.
b Maximal electric shock seizure test: 50 mA, 60 Hz, ac, 0.2 s.
c Subcutaneous pentylenetetrazole (80 mg/kg) induced seizure test.
d Ref. 13.
O
OH
OH
O
OC2H5
ii)
i)
iii)
HN
CO2H
HN
CO2CH3
OCH2Ph
HN
CO2CH3
OCH2Ph
O
OCH2Ph
2
O
O
4
3
1a, R = H
O
1b, R = CH3
1c, R = -C3H7
1d, R = cyclopropyl
1e, R = -C4H9
n
O
n
N
HN
1f, R = isobutyl
1g, R = allyl
1h, R = n-C6H11
1i , R = benzyl
1j , R = 4-fluorobenzyl
1k, R =
i) H+ / CH3OH, reflux, 5hrs, 98%
R
ii) NaH / BrCH2CO2C2H5 / CH3CN, 0 °C, 3-4 hrs, 70%
RNH2 (1.5-2 eq.) / CH3OH, rt, 7-8 hrs, 80-100%
O
O
OCH2Ph
iii)
1a-l
CH2
O
1l, R = OH
Scheme 1. The preparation of 6-amino-1,4-oxazepane-3,5-diones derivatives (1a–l).

3190
G. Sharma et al. / Bioorg. Med. Chem. Lett. 18 (2008) 3188–3191
4. Kohn, H.; Sawhney, K. N.; LeGall, D.; Leader, J. D.
J. Med. Chem. 1991, 34, 2444.
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J. Med. Chem. 1990, 33, 919.
6. Brouillette, W. J.; Jeskov, V. P.; Brown, M. L.; Akhatar,
M. S.; DeLorey, T. M.; Brown, G. B. J. Med. Chem. 1994,
37.
7. Kown, C. H.; Iqbal, M. T.; Eurpel, J. N. D. J. Med.
Chem. 1991, 34, 1845.
8. Andersen, K. E.; Braestrup, C.; Gronwald, F. C.; Jorgen-
sen, A. S.; Nielsen, E. B.; Sonnewald, U.; Sorensen, P. O.;
Suzdak, P. D.; Knutsen, L. J. S. J. Med. Chem. 1993, 36,
1716.
9. Bruke, J. R.; Silvermann, R. B. J. Am. Chem. Soc. 1991,
113, 9329.
their ED50 values were 68.75–93.75 mg/kg. These phar-
macological results were comparable to those of anti-
convulsants in clinical use. The most active compound
among the tested compounds was N-methylated com-
pound 1b (ED50 = 68.75 mg/kg). As evaluated from the
ED50, 1b was 3.9 times more active than valproic acid,
typical antiepileptic drug of broad spectrum in clinical
practice. The order of anticonvulsant activities as judged
from ED50 values is 1b > 1g > 1a > 1d = 1h > 1e = 1l. In
the case of PTZ test, all the tested compounds except 1c
and 1f showed moderate anticonvulsant activities, and
their ED50 values were 26.97–96.88 mg/kg. These results
were also comparable to those of clinically used antiep-
ileptic drugs. The most active compound in the PTZ test
was N-cyclopropylated compound 1d (ED50 = 26.97).
Compound 1d was 5.5 times more active than valproic
acid as evaluated from ED50. The order of anticonvul-
sant activities in the PTZ test as judged from ED50 val-
ues is 1d > 1e > 1h > 1g > 1b > 1j > 1a > 1i = 1k > 1l.
Especially, 1a, 1b, 1d, 1e, 1g, 1h, and 1l exhibited signif-
icant anticonvulsant activities in both the MES and PTZ
tests. As mentioned above, this result, showing anticon-
vulsant activities against these two kinds of tests, sug-
gested that the designed compounds could be
recommended to develop as anticonvulsant drug candi-
dates of broad spectrum.
10. Pook, P. C.; Jane, D. E.; Watkins, J. C. J. Med. Chem.
1994, 37, 4288.
11. The spectral data and physical properties for the com-
pounds 1a–l are given below. 1a: White solid. Yield: 100%;
mp: 97–99 °C; Rf: 0.3 [ethyl acetate/hexane (1:2)]; IR
(KBr) cmÀ1: 1215, 1402, 1438, 1666, 1703, 1739, 3000; 1H
NMR (400 MHz, CDCl3): d 3.77 (d, 2H, CH2), 4.13 (d,
1H, J = 3.12, CH2), 4.32 (d, 1H, J = 3.12, CH2), 5.01 (m,
1H, CH), 5.20 (s, 2H, CH2), 7.32 (s, 1H, NH), 7.35 (s, 5H,
Ph), 7.46 (s, 1H, NH). 13C NMR (CDCl3): d 59.9, 65.9,
71.1, 81.0, 127.2, 127.7, 129.0, 141.2, 156.0, 170.7, 175.2.
1b: White solid. Yield: 100%; mp: 107–109 °C; Rf: 0.5
[ethyl acetate/hexane (1:2)]; IR (KBr) cmÀ1: 1214, 1346,
1403, 1438, 1667, 1703, 1739; 1H NMR (400 MHz,
CDCl3): d 2.98 (s, 3H, CH3), 3.73 (m, 2H, CH2), 4.28 (d,
1H, J = 3.12, CH2), 4.32 (d, 1H, J = 3.12, CH2), 5.05 (m,
1H, CH), 5.18 (s, 2H, CH2), 7.34 (s, 1H, NH), 7.35 (s, 5H,
Ph). 13C NMR (CDCl3): d 27.3, 57.4, 65.9, 71.4, 78.5,
127.2, 127.7, 129.0, 141.2, 156.0, 174.6, 176.6. 1c: Light
yellow viscous product. Yield: 100%; Rf: 0.55 [ethyl
acetate/hexane (1:2)]; IR (KBr) cmÀ1: 1217, 1342, 1400,
1436, 1654, 1706, 1740; 1H NMR (400 MHz, CDCl3): d
0.88 (t, 3H, CH3), 1.51 (m, 2H, CH2), 3.21 (t, 2H, CH2),
3.70 (m, 2H, CH2), 4.24 (d, 1H, J = 3.12, CH2), 4.28 (d,
1H, J = 3.12, CH2), 5.00 (m, 1H, CH), 5.18 (s, 2H, CH2),
7.32 (s, 1H, NH), 7.35 (s, 5H, Ph). 13C NMR (CDCl3): d
11.2, 20.5, 42.1, 57.7, 65.9, 71.4, 78.8, 127.2, 127.7, 129.0,
141.2, 156.0, 174.3, 176.3. 1d: Light yellow viscous
product. Yield: 100%; Rf: 0.6 [ethyl acetate/hexane (1:2)];
IR (KBr) cmÀ1: 1209, 1311, 1406, 1671, 1705, 1743; 1H
NMR (400 MHz,CDCl3): d 0.52 (m, 1H, CH2), 0.65 (m,
1H, CH2), 0.77 (m, 1H, CH2), 0.91(m, 1H, CH2), 2.67 (m,
1H, CH), 3.76 (d, 2H, CH2), 4.12 (d, 1H, J = 3.12, CH2),
4.23 (d, 1H, J = 3.12, CH2), 5.00 (m, 1H, CH), 5.19 (s, 2H,
CH2), 7.33 (s, 1H, NH), 7.36 (s, 5H, Ph). 13C NMR
(CDCl3): d 4.9, 26.0, 58.0, 65.9, 71.4, 79.1, 127.2, 127.7,
129.0, 141.2, 156.0, 174.0, 176.0. 1e: Light yellow viscous
product. Yield: 100%; Rf: 0.6 [ethyl acetate/hexane (1:2)];
IR (KBr) cmÀ1: 1217, 1275, 1342, 1400, 1436, 1655, 1706,
In conclusion, a series of 6-amino-1,4-oxazepane-3,5-
dione derivatives, novel structures of 7-membered het-
erocyclic imides, were designed, synthesized, and their
anticonvulsant activities were evaluated by both the
MES and PTZ tests. The 6-amino-1,4-oxazepane-3,5-
diones were designed as broad spectrum anticonvulsant
by hybridizing important pharmacophores such as cyclic
imide and N-CO-C-N group in a single molecule. This
was based on the inspection of the structural character-
istics in typical anticonvulsants in clinical practice. The
ED50 values for the designed compounds were compara-
ble to clinically used antiepileptic drugs. Moreover,
some of the designed compounds in this study exhibited
considerable anticonvulsant activities in both the MES
and PTZ tests. These pharmacological activities were
sufficient for them to develop as Broad Spectrum Anti-
convulsants. Therefore, it was concluded that 6-amino-
1,4-oxazepane-3,5-dione derivatives were recommended
as novel structures of broad spectrum anticonvulsants.
Acknowledgment
1
1740; H NMR (400 MHz, CDCl3): d 0.93 (t, 3H, CH3),
1.26 (m, 2H, CH2), 1.46 (m, 2H, CH2), 3.50 (m, 2H, CH2),
3.68 (d, 2H, CH2), 4.14 (d, 1H, J = 3.12, CH2), 4.28 (d,
1H, J = 3.12, CH2), 5.00 (m, 1H, CH), 5.18 (s, 2H, CH2),
7.32 (s, 1H, NH), 7.35 (s, 5H, Ph). 13C NMR (CDCl3): d
13.8, 19.9, 29.6, 39.6, 57.7, 65.9, 71.4, 78.8, 127.2, 127.7,
129.0, 141.2, 156.0, 174.3, 176.3. 1f: White solid. Yield:
100%; mp: 73–75 °C; Rf: 0.4 [ethyl acetate/hexane (1:2)];
IR (KBr) cmÀ1: 1213, 1294, 1403, 1666, 1703, 1742; 1H
NMR (400 MHz,CDCl3): d 0.88 (dd, 6H, CH3), 3.09 (m,
1H, CH), 3.34 (m, 2H, CH2), 3.75 (d, 2H, CH2), 4.18(d,
1H, J = 8.96, CH2), 4.30(d, 1H, J = 8.96, CH2), 5.00 (m,
1H, CH), 5.19 (s, 2H, CH2), 7.34 (s, 1H, NH), 7.38 (s, 5H,
Ph). 13C NMR (CDCl3): d 20.3, 26.0, 48.7, 57.7, 65.9, 71.4,
78.8, 127.2, 127.7, 129.0, 141.2, 156.0, 174.3, 176.3. 1g:
This work was supported by Kyungsung University Re-
search Grant in 2006.
References and notes
1. Bell, G. S.; Sandler, J. W. In The Epidermiology: The Size
of the Problem (Suppl. A), pp 306–314.
2. Swinyard, E. A. Antiepileptic Drug, 2nd ed.; Ravan: New
York, 1982, p 5.
3. Williams, D. A.; Lemke, T. L. Foye’s Principles of
Medicinal Chemistry, 5th ed.; Lippincott Williams &
Wilkins: Philadelphia, 2002, Chapter 16.

G. Sharma et al. / Bioorg. Med. Chem. Lett. 18 (2008) 3188–3191
3191
White solid. Yield: 100%; mp: 56–58 °C; Rf: 0.5 [ethyl
acetate/hexane (1:2)]; IR (KBr) cmÀ1: 1214, 1348, 1403,
1438, 1663, 1703, 1741; 1H NMR (400 MHz,CDCl3): d
3.67 (d, 2H, CH2), 4.13(d, 2H, CH2), 4.30(d, 2H, CH2),
5.00 (m, 1H, CH), 5.20 (s, 2H, CH2), 5.22 (d, 1H, J = 2.88,
CH), 5.24 (d, 1H, J = 2.88, CH), 5.67 (m, 1H, CH), 7.34 (s,
1H, NH), 7.38 (s, 5H, Ph). 13C NMR (CDCl3): d 41.0,
57.8, 65.9, 71.4, 78.9, 127.2, 127.7, 129.0, 134.3, 141.2,
156.0, 174.3, 176.3. 1h: White solid. Yield: 100%; mp: 48–
50 °C; Rf: 0.75 [ethyl acetate/hexane (1:2)]; IR (KBr)
cmÀ1: 1211, 1346, 1403, 1437, 1665, 1702, 1742; 1H NMR
(400 MHz,CDCl3): d 0.87 (t, 3H, CH3), 1.24 (m, 2H,
CH2), 1.26 (m, 2H, CH2), 1.28 (m, 2H, CH2), 1.48 (m, 2H,
CH2), 3.48 (m, 2H, CH2), 3.70 (d, 2H, CH2), 4.14 (d, 1H,
J = 3.12, CH2), 4.29 (d, 1H, J = 3.12, CH2), 5.01 (m, 1H,
CH), 5.20 (s, 2H, CH2), 7.32 (s, 1H, NH), 7.35 (s, 5H, Ph).
13C NMR (CDCl3): d 14.1, 22.8, 26.5, 27.4, 31.6, 39.9,
57.7, 65.9, 71.4, 78.8, 127.2, 127.7, 129.0, 141.2, 156.0,
174.3, 176.3. 1i: White solid. Yield: 100%; mp: 113–115 °C;
Rf: 0.5 [ethyl acetate/hexane (1:2)]; IR (KBr) cmÀ1: 1211,
1348, 1404, 1437, 1665, 1702, 1742; 1H NMR
(400 MHz,CDCl3): d 3.51 (d, 2H, CH2), 4.29 (m, 1H,
CH2), 4.89 (s, 2H, CH2), 4.93 (m, 1H, CH), 5.19 (s, 2H,
CH2), 7.27 (dd, 1H, Ph), 7.30 (d, 2H, Ph), 7.31 (d, 2H, Ph),
7.33 (s, 1H, NH), 7.37 (s, 5H, Ph). 13C NMR (CDCl3): d
42.4, 57.7, 65.9, 71.4, 78.8, 126.8, 127.0, 127.2, 127.7,
128.6, 129.0, 141.2, 156.0, 174.6, 176.6. 1j: Yellow solid.
Yield: 100%; mp: 68–70 °C; Rf: 0.4 [ethyl acetate/hexane
2H, CH2) 5.00 (m, 1H, CH), 5.19 (s, 2H, CH2), 6.29 (d,
1H, J = 0.92, CH), 6.33 (d, 1H, J = 0.92, CH), 7.26 (d, 1H,
CH), 7.34 (s, 1H, NH), 7.36 (s, 5H, Ph). 13C NMR
(CDCl3): d 42.1, 57.7, 65.9, 71.4, 78.8, 106.7, 110.6, 127.2,
127.7, 129.0, 141.2, 142.1, 148.8, 156.0, 174.3, 176.3. 1l:
Oily product. Yield: 80%; Rf: 0.3 [ethyl acetate/hexane
(1:2)]; IR (KBr) cmÀ1: 1214, 1348, 1403, 1663, 1703, 1741,
3300; 1H NMR (400 MHz,CDCl3): d 2.04 (s, 1H, OH),
3.72 (d, 2H, CH2), 4.10 (m, 2H, CH2), 4.87 (m, 1H, CH),
5.14 (s, 2H, CH2), 7.32 (s, 1H, NH), 7.34 (s, 5H, Ph).; 13
C
NMR (CDCl3): d 53.7, 71.4, 74.8, 127.2, 127.7, 129.0,
141.2, 156.0, 164.0, 168.5.
12. Krall, R. L.; Penry, J. K.; White, B. G.; Kapferberg, H. J.;
Swinyard, E. A. Epilepsia 1978, 19, 409. The Pharmaco-
logical tests were carried out as follows: All tested
compounds were dissolved in polyethylene glycol 400
and administered ip to ICR male mice at dose of 25, 50,
75, and 100 mg/kg, and anticonvulsant test was performed
30 min after the administration in groups of four mice. We
also determined the lowest dose that with which all the
tested animals could be induced with a seizure at the stage
of preliminary screening. The seizure was artificially
induced by either electric shock or pentylenetetrazole.
The maximal electroshock seizure (MES) test was elicited
with a 60-cycle a.c. of 50 mA intensity delivered for 0.2 s
via corneal electrodes with ECT unit (UGO Baseline,
Italy). A drop of 0.9% saline was instilled in the eye prior
to application of electrodes. Protection in this test was
defined as the abolition of the hind limb tonic extension
component of the seizure. The pentylenetetrazole induced
seizure (PTZ) test entailed the subcutaneous administra-
tion of 80 mg/kg of pentylenetetrazole as a 0.5% solution
in the posterior midline of the mice, and the animal was
observed for 30 min. Protection was defined as the failure
to observe even a threshold seizure (single episode of
clonic spasms of at least 5 s duration). The ED50 was
estimated from the dose–response data.
1
(1:2)]; IR (KBr) cmÀ1: 1214, 1403, 1662, 1704, 1739; H
NMR (400 MHz, CDCl3): d 3.53 (d, 2H, CH2), 4.26 (m,
1H, CH2), 4.81 (s, 2H, CH2), 4.96 (m, 1H, CH), 5.19 (s,
2H, CH2), 7.02 (d, 1H, CH), 7.20 (d, 1H, CH), 7.36 (s, 1H,
NH), 7.37 (s, 5H, Ph). 13C NMR (CDCl3): d 42.4, 57.7,
65.9, 71.4, 78.8, 115.3, 127.2, 127.7, 128.6, 129.0, 137.3,
141.2, 156.0, 160.9, 174.6, 176.6. 1k: White solid. Yield:
100%; mp: 97–99 °C; Rf: 0.5 [ethyl acetate/hexane (1:2)];
IR (KBr) cmÀ1: 1214, 1347, 1403, 1438, 1665, 1703, 1742;
1H NMR (400 MHz, CDCl3): d 3.65 (d, 2H, CH2), 4.15 (d,
1H, J = 3.12, CH2), 4.30(d, 1H, J = 3.12, CH2), 4.53 (m,
13. Witak, D. T.; Seth, S. K.; Baizman, E. R.; Wirdel, S. L.;
Wolf, H. H. J. Med. Chem. 1972, 15, 1117.