Synthesis and Some Pharmacological Properties of Elatidine Derivatives
481
TABLE 2. Acute Toxicity of Elatidine Derivatives in Mice
Anthranoyl elatidine, or [18-(2-aminobenzoyloxy)-7,8-
methylenebisoxy-1a,6b,14a,16b-tetramethoxy-20-ethylaco-
nitane] (IV). A mixture of 2.53 g (5.27 mmole) elatidine
(VI), 0.119 g (0.95 mmole) DMAP, 2.13 g (14.5 mmole)
isatoic anhydride, and 6.4 ml DMF was heated with stirring
to 100°C and the resulting solution was kept at this tempera-
ture for 9 h. Upon cooling, to this reaction mixture was
added with stirring 30 ml of a saturated aqueous NaCl solu-
tion, and the product was extracted with diethyl ether
(3 ´ 15 ml). Then the solvent was removed from the com-
bined extracts and the residue dried in vacuum (3 Torr) at
50°C. The resulting amorphous powder was dissolved in
10 ml of tert-butyl methyl ether and purified by preparative
TLC on Al2O3 (grade TU 6-09-3916–75; particle size frac-
tion, 50 – 250 mm; activity degree II) with K-35 luminophor
additive (1% w/w). The sorbent band with Rf = 0.54 (blue lu-
minescence under UV irradiation) was cut and the target
product was eluted with tert-butyl methyl ether. Finally the
solvent was distilled off from the eluate and the residue was
dried in vacuum (3 Torr) at 50°C to obtain 2.99 g (95%) of
anthranoyl elatidine (IV) in the form of an amorphous pow-
LD50, mg/kg;
I × HCl IV × 2HCl VII × HCl X × 4HCl
Way of intro-
duction
Ditylin
10
Subcutaneous
Intraperitoneal
20
56
65
60
170
215
198
in vacuum. The residue was dried in vacuum (3 Torr) at
100°C to obtain 44 mg (95%) of compound V in the form of
20
an amorphous powder; [a] , +10.8° (c, 1.5; MeOH).
578
Compound V, high-resolution mass spectrum, m/z:
1
640.3353 [M]+; C35H48N2O9; H NMR spectrum (d, ppm; J,
Hz): 1.04 (t, 3H, J 7, NCH2CH3), 2.19 (s, 3H, NHCOCH3),
3.28, 3.34, 3.35, 3.40 (4s, 3H, 1-, 6-, 14-, and 16-OCH3),
4.11 (s, 2H, CH-18), 5.04 (s, 2H, OCH2O), 7.06 (t, 1H, J 7.5,
CH-5¢), 7.51 (td, 1H, J 8.5 and 1.5, CH-4¢), 7.94 (dd, 1H, J
8.5 and 1.5, CH-6¢), 8.70 (d, 1H, J 8.5, CH-3¢), 10.96 (bs, 1H,
NH); IR spectrum in KBr (nmax, cm – 1): 758, 1089, 1123,
1164, 1238, 1262, 1297, 1449, 1528, 1590, 1606, 1688
(C=O), 2889, 2931, 2973; UV spectrum in EtOH, lmax, nm
(log e): 223 (4.34), 252 (4.08), 310 (3.65).
20
der; [a] , +13.3° (c, 4.2; CH OH).
578
3
Compound IV, high-resolution mass spectrum, m/z:
1
Benzoyl elatidine, or [18-benzoyloxy-7,8-methylene-
bisoxy-1a6b,14a,16b-tetramethoxy-20-ethylaconitane]
(VII).3 To a solution of 1.22 g (8.64 mmole) of benzoyl chlo-
ride in 12.8 ml of anhydrous pyridine was introduced with
stirring 3.60 g (7.5 mmole) of elatidine and the mixture was
kept for 16 h at 20°C. To this reaction mixture was added
dropwise with stirring 39 ml of water and 30 ml of CHCl3.
Then the chloroform layer was separated and the aqueous
layer was washed with CHCl3 (2 ´ 10 ml). After removal of
chloroform from the combined extracts, the residue was
dried in vacuum (3 Torr) at 40°C. The resulting viscous oil
was dissolved in 15 ml of CHCl3 and purified on an column
with 51 g of Al2O3 (activity degree II according to Brock-
man) eluted with chloroform. Finally, the solvent was dis-
tilled off from the eluate and the residue was dried at a re-
duced pressure (20 Torr) at 40°C. The target product was ex-
598.3296 [M]+; C33H46N2O8; H NMR spectrum (d, ppm; J,
Hz): 1.04 (t, 3H, J 7, NCH2CH3), 3.24 (s, 3H), 3.31 (s, 6H),
3.40 (s, 3H) (1-, 6-, 14-, and 16-OCH3); 4.07 (s, 2H, CH-18),
5.04 (s, 2H, OCH2O), 5.70 (broad signal, 2H, NH2),
6.57 – 6,66 (m, 2H, CH-3¢,5¢), 7.24 (td, 1H, J 8 and 1.5,
CH-4¢), 7.80 (dd, 1H, J 8 and 1.5); IR spectrum in KBr (nmax
,
cm – 1): 752, 963, 1091, 1161, 1196, 1245, 1295, 1385, 1456,
1487, 1591, 1619, 1690 (C=O), 2818, 2878, 2933, 2973; UV
spectrum in EtOH, lmax, nm (log e): 220 (4.32), 249
(3.84), 341 (3.71). Hydrochloride (IV × 2HCl), m.p.,
153 – 155°C (decomp.); C33H46N2O8 × 2HCl.
N-Acetylanthranoyl elatidine, or [18-(2-acetylamino-
benzoyloxy)-7,8-methylenebisoxy-1a,6b,14a,16b-tetrame
thoxy-20-ethylaconitane] (V).
A mixture of 43 mg
(0.072 mmole) of compound IV and 28 mg (0.275 mmole) of
AcO2 was heated at 100°C for 4 h. The excess AcO2 together
with acetic acid formed during the reaction were distilled off
3
This compound was synthesized with the participation of E. N. Nankova.
TABLE 3. Effect of Elatidine Derivatives (15 mg/kg, s.c.) on the Motor Activity of Mice
Parameter
Control
I × HCl
IV × 2HCl
VII × HCl
X × 4HCl
Total number of general movements
for 120 sec
79.0 ± 0.8
86.0 ± 1.8*
63.0 ± 0.9
79.0 ± 0.7
70.0 ± 1.2
Time required for performing
general movements, sec
91.75 ± 2.1
474.7 ± 4.1
26.0 ± 0.8
80.75 ± 1.5*
430.7 ± 2.5*
3.0 ± 0.08*
98.75 ± 1.3
621.4 ± 3.3*
42.0 ± 1.9*
87.75 ± 1.4
537.7 ± 3.4*
53.0 ± 0.7*
97.75 ± 1.8
508.8 ± 2.8*
25.0 ± 1.1
Distance traveled for 120 sec, cm
Total number of research reactions
Time for performing research
actions (sec)
7.75 ± 0.5
0.75 ± 0.06*
9.25 ± 1.5
7.5 ± 0.5
9.5 ± 0.8
*
Differences from control are reliable for P < 0.05.