P. K. Baruah et al. / Bioorg. Med. Chem. 20 (2012) 3551–3564
3563
(3 ꢃ 25 mL). The organic layers were combined and dried (Na2SO4),
concentrated in vacuo, and purified by flash column chromatogra-
phy (SiO2; 3:97 MeOH/CH2Cl2) to give the desired product (67 mg,
52%) as a light yellow oil. Rf 0.21 (3:97 MeOH/ CH2Cl2). IR (nujol)
3296, 3067, 2922, 2864, 1662, 1524, 1450, 1360, 1244, 1079,
in full accordance with recommendations contained in the Guide
for the Care and Use of Laboratory Animals.59 Pharmacological
evaluation by UCB Pharma consisted of four assays using male
NMRI mice (ip): the MES test54 and the 6 Hz test55 to assess
anticonvulsant activity, the formalin test35 to assess neuropathic
pain attenuation, and the rotorod test57 to assess neurological
toxicity.
The compounds were administered ip. ED50 and TD50 values are
in mg/kg and were determined 30 min after ip administration. In
cases where the ED50 could not be determined, the lowest dose
that elicited activity (minimally active dose) or the percent reduc-
tion in activity from a single dose was given (see Tables 1 and 2 for
doses employed).
1029, 908, 847, 701 cmꢁ1 1H NMR (CDCl3) d 1.93 (s, 2H), 4.30–
.
4.46 (m, 2H), 4.80 (s, 1H), 6.29–6.96 (m, 1H), 7.05 (d, J = 3.6 Hz,
1H), 7.19–7.37 (m, 6H), 7.23–7.51 (br s, 1H). HRMS (ESI)
269.0726 [M+Na+] (calcd for C13H14N2OSNa+ 269.0725).
4.1.20. (R,S)-N-Benzyl 2-amino-2-(thiophen-2-yl)acetamide
hydrochloride (24ꢂHCl)
HCl in Et2O (0.60 mL, 0.0603 mmol) was cooled to 0 °C followed
by drop wise addition of (R,S)-24 (135 mg, 0.0548 mmol). The mix-
ture was warmed to room temperature, stirred for 20 min, and
then filtered. The solid was washed with anhydrous Et2O
(2 ꢃ 10 mL) and dried in vacuo to give the desired product
(110 mg, 71%) as a light yellow solid. IR (nujol) 3208, 3059, 2904,
1678, 1563, 1460, 1373, 1250, 1112, 1032, 852, 708, 609,
Acknowledgments
The project was supported by UCB Pharma (Braine-l’Alleud, Bel-
gium) with the assistance of Dr. Robert Kramer. Harold Kohn has a
royalty-stake position in (R)-2.
502 cmꢁ1 1H NMR (DMSO-d6) d 4.33 (d, J = 5.7 Hz, 2H), 5.38
.
(s, 1H), 7.08 (d, J = 3.6 Hz, 1H), 7.23–7.32 (m, 6H), 7.62 (dd, J = 3.6,
3.6 Hz, 1H), 8.67–9.01 (br s, 3H), 9.32 (t, J = 5.7 Hz, 1H). HRMS
(ESI) 269.0726 [M+Na+] (calcd for C13H14N2OSNa+ 269.0725). Anal.
Calcd for C13H14ClN2OS: 0.08H2O: C, 54.73; H, 5.33; Cl, 12.43; N,
9.82; S, 11.24. Found: C, 54.77; H, 5.48; Cl, 12.37; N, 9.52; S, 11.04.
Supplementary data
Supplementary data associated with this article can be found, in
References and notes
4.1.21. (R,S)-N-Benzyl 2-amino-2-(thiazol-2-yl)acetamide (25)
(R,S)-N-Benzyl N0-(benzyloxycarbonylamino)-2-(thiazol-2-yl)
acetamide (102) (183 mg, 0.480 mmol) was added to concen-
trated aqueous HCl (3 mL) and heated between 65–70 °C
(6.5 h). The reaction mixture was cooled to room temperature,
basified to pH ꢀ10 with aqueous 50% NaOH, and extracted with
CH2Cl2 (3 ꢃ 15 mL). The organic extracts were concentrated in
vacuo and purified by flash column chromatography (SiO2; 3:97
MeOH/CH2Cl2) to give the desired product (73 mg, 62%) as a light
yellow solid. Mp 83–84 °C. Rf 0.18 (3:97 MeOH/CH2Cl2). IR (nujol)
3468, 3157, 2957, 1652, 1563, 1456, 1374, 1311, 1237, 1182,
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1092, 938, 703 cmꢁ1 1H NMR (DMSO-d6) d 2.67 (s, 2H), 4.30–
.
4.46 (m, 2H), 4.76 (s, 1H), 7.21–7.32 (m, 5H), 7.62 (d, J = 3.0 Hz,
1H), 7.75 (d, J = 3.0 Hz, 1H), 8.73–8.77 (br t, 1H). HRMS (ESI)
270.0678 [M+Na+] (calcd for C12H13N3OSNa+ 270.0677). Anal.
Calcd for C12H13N3OS: C, 58.28; H, 5.30; N, 16.99; S, 12.97. Found:
C, 58.43; H, 5.29; N, 16.77; S, 12.92.
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(R,S)-N-Benzyl 2-(benzo[b]thiophen-2-yl)-2-(hydroxyimino)
acetamide (70) (206 mg, 0.664 mmol) was added to MeOH (3 mL)
followed by the addition of Zn dust (174 mg, 2.66 mmol) and
HC(O)ONH4 (167 mg, 2.65 mmol). The mixture was heated at 70 °C
(2–3 h). The reaction mixture was filtered hot and concentrated in
vacuo. The crude material was purified by flash column chromatog-
raphy (SiO2; 3:97 MeOH/CH2Cl2) to give the desired product
(100 mg, 51%) as a white solid. Mp 100–101 °C. Rf 0.29 (3:97
MeOH/CH2Cl2). IR (nujol) 3188, 2954, 2842, 1654, 1523, 1373,
1299, 1229, 1073, 939, 824, 738, 591 cmꢁ1 1H NMR (DMSO-d6) d
.
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2.49 (s, 2H), 4.36 (d, J = 6.0 Hz, 2H), 4.76 (s, 1H), 7.22–7.36 (m, 8H),
7.73 (d, J = 7.8 Hz, 1H), 7.87 (d, J = 7.8 Hz, 1H), 8.63–8.79 (br t, 1H).
HRMS (ESI) 297.1062 [M+H+] (calcd for C17H17N2OS+ 297.1062).
Anal. Calcd for C17H16N2OS: 0.06H2O: C, 68.40; H, 5.42; N, 9.38; S,
10.74. Found: C, 68.42; H, 5.44; N, 9.34; S, 10.69.
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4.2. Pharmacological evaluation
Compounds were screened under the auspices of UCB Pharma
(Braine L’Alleud, Belgium). Housing, handling, and feeding were