Asymmetric synthesis of a neuroprotective and orally active N-methyl-D-aspartate receptor ion-channel blocker, CNS 5788

Article abstract of DOI:10.1016/S0957-4166(00)00328-1

Asymmetric synthesis of N-(2-chloro-5-methylthiophenyl)-N'-(3-methylsulfinylphenyl)-N'-methylguanidine (CNS 5788) was achieved in high enantiomeric excess through condensation of the cyanamide derivative, 6 and the sulfinylaniline hydrochloride, 5. The key step involved the asymmetric oxidation of N-methyl-3-methylthioaniline using a Davis reagent. Copyright (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(00)00328-1

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 11 (2000) 3455–3457
Asymmetric synthesis of a neuroprotective and orally active
N-methyl-
D
-aspartate receptor ion-channel blocker,
CNS 5788†
Seetharamaiyer Padmanabhan,* Ruth C. Lavin and Graham J. Durant
Cambridge NeuroScience, Inc., One Kendall Square, Cambridge, MA 02139, USA
Received 6 July 2000; accepted 31 July 2000
Abstract
Asymmetric synthesis of N-(2-chloro-5-methylthiophenyl)-N%-(3-methylsulfinylphenyl)-N%-methyl-
guanidine (CNS 5788) was achieved in high enantiomeric excess through condensation of the cyanamide
derivative, 6 and the sulfinylaniline hydrochloride, 5. The key step involved the asymmetric oxidation of
N-methyl-3-methylthioaniline using a Davis reagent. © 2000 Elsevier Science Ltd. All rights reserved.
A number of guanidine derivatives containing sulfoxide groups were synthesized to determine
whether the target sulfoxides afford neuroprotection with a potentially improved safety profile
over conventional NMDA (N-methyl- -aspartate) channel blockers. It was hypothesized that
D
sulfoxide derivatives could be preferentially reduced in the hypoxic environment of ischemic
tissue to generate a sulfide-containing potent NMDA ion-channel blocker. Among the com-
pounds studied, the racemic sulfoxide N-(2-chloro-5-methylthiophenyl)-N%-(3-methylsufin-
ylphenyl)-N%-methylguanidine 2 (CNS 5655), a sulfoxide derived from the potent NMDA
channel blocker CNS 51611 1, showed good activity in various animal models including the rat
middle cerebral artery occlusion (MCAO) model for stroke. In the rat MCAO model CNS 5655
showed good neuroprotection (32% at 4.5 mg/kg), and in the DBA/2 audiogenic mouse
antiseizure test showed good activity following oral administration (76% inhibition at 60 mg/kg,
p.o. compared to 72% at 20 mg/kg, i.p.). Both the enantiomers of CNS 5655, obtained through
preparative chiral resolution (Chiral Technologies, Exton, PA) of the racemic compound as the
free base, were evaluated in several animal models for neuroprotection and for side effects. The
(+)-enantiomer 82 (CNS 5788) was found to be at least as neuroprotective as the racemic
compound 2 whereas the (−)-enantiomer did not show significant neuroprotection (1% at 4.5
* Corresponding author. E-mail: padman@cambneuro.com
†
219th ACS meeting held at San Francisco, CA on March 25, 2000. Abstract of Papers, Medicinal Chemistry
Division, 095.
0957-4166/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00328-1

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S. Padmanabhan et al. / Tetrahedron: Asymmetry 11 (2000) 3455–3457
mg/kg) in the rat MCAO model. This good pharmacological profile combined with oral activity
led us to explore the asymmetric synthesis of CNS 5788, which is the focus of this report.
The absolute configuration of CNS 5788 as (R) was initially determined by NMR studies
following the method developed by the addition of (R)-(−)-2,2,2-trifluoro-1-(9-anthryl)ethanol3
and was unambiguously established through X-ray crystallography.4
Among the various methods reported, chiral oxidation of N-methyl-3-methylthioaniline1 3 for
the preparation of the key sulfoxide intermediate, 4 was pursued. Three different Davis oxidizing
agents, viz. (1R)-(−)-(10-camphorsulfonyloxaziridine),5 (1R)-(8,8-dichloro-10-camphorsulfonyl-
oxaziridine)6 (DCCSO) and (1R)-8,8-dimethoxy-10-camphorsulfonyloxaziridine)6 were studied
under various reactions conditions and in each case the enantiomeric excess of the resulting
sulfoxide was determined by NMR experiments involving the addition of the chiral shift reagent,
[(+)-Eu(hfc)3] [tris-3-(heptafluoropropylhydroxymethylene)-(+)-camphorato europium(III)]. Best
results were obtained using the Davis reagent DCCSO in carbon tetrachloride at room
temperature leading to the desired sulfoxide in ꢀ95% yield and in moderate enantiomeric excess
(ꢀ75% ee by NMR).
The chiral sulfoxide, 4 was converted to the hydrochloride salt 5 using methanolic hydrogen
chloride (1 M) using dichloromethane as solvent in almost quantitative yield. Subsequent
condensation of the chiral sulfoxide, 5, with 2-chloro-5-methylthiophenylcyanamide1 6 in a
mixture of dichloromethane and toluene (1:1) in an oil bath at 115–120°C for 90 min led to the
isolation of CNS 5788 as hydrochloride salt, 7, in 51% yield (72% ee by NMR).
The hydrochloride salt, 7 was converted to the free base 8 in 73% yield using aqueous sodium
hydroxide (1N) and the enantiomeric purity was determined by chiral HPLC as 76.5%. Chiral

S. Padmanabhan et al. / Tetrahedron: Asymmetry 11 (2000) 3455–3457
3457
HPLC analysis was carried out using a Chiralpak AD analytical column (4.6×250 mm) with
100% EtOH as the mobile phase using a Beckman system with a photodiode array (PDA)
detector (flow rate=0.4 mL/min; ambient temperature) with detection at 254 nm.
The enantiomeric purity of CNS 5788 was enhanced to 98% through two crystallizations of
the free base from a mixture of hexanes and dichloromethane in 31% yield (mp 122–124°C). The
specific rotation of CNS 5788 free base, [h]2D2=+74.87 (c 0.31, EtOH) was found to be in good
agreement with that of the preparative chiral HPLC sample, [h]2D2=+74.03 (c 0.31, EtOH).
In conclusion, asymmetric synthesis of CNS 5788, a good neuroprotective agent with oral
activity, was achieved in high enantiomeric purity following two crystallizations after the initial
asymmetric oxidation. This procedure was followed for synthesis of CNS 5788 in gram
quantities (ꢀ4 g) for further evaluation in various efficacy and safety animal models.
Acknowledgements
We wish to acknowledge M. E. Perlman, Deke Moore, Lu Zhang, Lang Yu, J. B. Fischer,
Dan Zhou, C. Chen, S. Wang, D. Berlove, W. F. Holt, C. Kirk, K. Burke-Howie, T. Wolcott,
D. Daly and Robert N. McBurney for their valuable contributions to the work. We also thank
B. M. Burkhart and W. L. Duax of Hauptman-Woodward Research Institute, Buffalo, NY, for
the X-ray crystallography and Professor Franklin A. Davis of Temple University, Philadelphia,
PA, for useful discussion during the course of this work.
References
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