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JEAN GUILLON ET AL
Figure 1. Structures of baclofen, saclofen, phaclofen and CGP-35348.
(CH2), 125Á3 (CF3), 128Á7 (C-20 and C-60), 129Á3
(C-30 and C-50), 133Á6 (C-40), 138Á2 (C-10), 170Á9
(CO), 179Á0 (CO). Calculated for C12H11ClF3NO3:
C, 46Á54; H, 3Á58; N, 4Á52. Found: C, 46Á66; H,
3Á65; N, 4Á46%.
and 70 mL hydrochloric acid (6 M) was re¯uxed for
3 h. After cooling, the reaction solution was deco-
lorized with animal charcoal, ®ltered and evapo-
rated to dryness under reduced pressure to give a
precipitate which was recrystallized in propanol-2
to give beige crystals (30%); mp 144ꢀC; IR (KBr)
1
1
n: 3090±2840 (NH3 ), 1720 cm (CO); H NMR
(d6-DMSO) d: 2Á75 (1H, dd, J 19Á25 and 3Á40, H-
2b), 2Á86 (1H, dd, J 19Á25 and 7Á35, H-2a), 2Á93
(1H, m, CH), 3Á39 (1H, m, CH), 3Á73 (1H, m, H-1),
7Á64 (1H, d, J 1Á85, H-4), 7Á77 (1H, dd, J 8Á20
and 1Á85, H-6), 7Á81 (1H, d, J 8Á20, H-7), 8Á23
3-(4-Chlorophenyl)-4-(2,2,2-tri¯uoroacetylamino)-
butyryl chloride (7)
A solution of 2 g (6Á45 mmol) 3-(4-chlorophenyl)4-
(2,2,2-tri¯uoroacetylamino)butyric acid (5) in
30 mL thionyl chloride was re¯uxed for 30 min and
evaporated to dryness under reduced pressure.
After cooling, the residue was washed with petro-
leum ether to give an orange oil (96%); IR (KBr) n:
(3H, s, NH3 ); 13C NMR (d6-DMSO) d: 36Á0 (CH),
41Á1 (CH2), 42Á6 (CH2), 122Á5 (C-4), 128Á3 (C-7),
133Á5 (C-5), 134Á6 (C-6), 138Á6 (C-7a), 152Á6 (C-
3a), 203Á0 (CO). Calculated for C10H11Cl2NO2: C,
51Á75; H, 4Á78; N, 6Á03. Found: C, 51Á80; H, 4Á75;
N, 5Á89%.
1
3335 (NH), 1805 and 1725 cm (CO).
N-(5-Chloro-3-oxoindan-1-ylmethyl)-2,2,2-tri¯uoro-
acetamide (8)
To a cooled solution of 1Á4 g (4Á2 mmol) 3-(4-
chlorophenyl) - 4 -(2,2,2-tri¯uoroacetylamino)buty-
ryl chloride (7) in 60 mL methylene chloride was
added portionwise 1Á42 g (10Á64 mmol) aluminium
chloride. The reaction mixture was re¯uxed for 4 h
and evaporated to dryness. The residue was tritu-
rated in ice and extracted with diethyl ether. The
organic layer was washed with an aqueous solution
of sodium hydrogencarbonate, dried over magne-
sium sulphate and evaporated to dryness to give
Pharmacology
Animals. OF-1 mice (Iffa Credo, France), 8±22 g,
were used. The animals were allowed free access to
food and water and were housed at room tem-
perature (20±22ꢀC). In the pre-screening and acti-
metry study, test compounds were administered via
intraperitoneal injection. In the hot-plate test the
drugs were given subcutaneously. Baclofen, CGP-
35348 and derivatives 1 and 9 were dissolved in
0Á9% saline; compounds 2 to 6 were dissolved in
0Á9% saline with PEG (one drop per mL).
Gross behavioural effects and acute toxicity in
mice. Morpugo's modi®cation (Morpugo 1971) of
Irwin's multidimensional screening procedure was
used on groups of four mice to evaluate drug-
induced behavioural effects. The test compounds
were administered in log-spaced doses, and
detailed observations of the mice were made at
30 min, 3 h and 24 h after treatment. Baclofen was
used for comparison. The approximate LD50 was
obtained from the mortality observed during a 48-h
period.
white crystals (79%); mp 98ꢀC; IR (KBr) n: 3330
1
(NH), 1730 and 1700 cm
(CO); 1H NMR
(CDCl3) d: 2Á48 (1H, dd, J 19Á10 and 2Á95, H-
2b), 2Á93 (1H, dd, J 19Á10 and 7Á65, H-2a), 3Á58
(1H, m, H-1), 3Á73 (1H, m, CH), 3Á80 (1H, m, CH),
6Á50 (1H, s, NH), 7Á50 (1H, d, J 8Á20, H-7), 7Á63
(1H, dd, J 8Á20 and 1Á90, H-6), 7Á75 (1H, d,
J 1Á90, H-4); 13C NMR (CDCl3) d: 37Á4 (CH),
41Á1 (CH2), 44Á1 (CH2), 115Á3 (CF3), 123Á8 (C-4),
127Á1 (C-7), 135Á1 (C-5), 135Á2 (C-6), 138Á5 (C-7a),
152Á2 (C-3a), 158Á1 (CO), 203Á4 (CO). Calculated
for C12H9ClF3NO2: C, 49Á42; H, 3Á11; N, 4Á80.
Found: C, 49Á51; H, 3Á37; N, 4Á85%.
5-Chloro-3-oxoindan-1-ylmethylammonium
chloride (9)
Locomotor activity. Locomotor activity was
recorded with a photocell activity meter for 15 min,
starting 60 min after administration of each test
A mixture of 2Á6 g (8Á9 mmol) N-(5-chloro-3-
oxoindan-1-ylmethyl)-2,2,2-tri¯uoroacetamide (8)