REACTION OF METHYL 5(6)-(4-AMINOPHENYLTHIO)-2-BENZIMIDAZOLYLCARBAMATE
1295
phenyl isocyanate derivatives IId and IIId. Mixed
derivative IVa proved to be as potent helminthocide
as aminobenzimidazole I. The most active derivatives
(compounds IIe, IIIe, IIIf, and IVa) were tested for
embriotropic activity in pregnant rats in critical days,
and they all proved to act as embriotropic agents in
therapeutic doses.
Table 2. Biologic properties of compounds II IV
Toxicity Antihelminth activity
Comp.
no. dose,
deaths
of enimals,
%
quantity of
nematodes tiveness,
effec-
dose,
mg/kg
mg/kg
per heada
%
The fact that compounds IIe, IIIe, IIIf, and IVa
exhibit embriotoxicity and lack total toxicity can be
explained in terms of faster metabolism in embryos
and the resulting faster release of the parent amino-
benzimidazole compared with adult animals. Thus,
these compounds can be used as helmintocides only
in mixtures with special additives we developed for
suppression of their embriotropic activity.
I
IIa
IIb 1000
IIc 1000
IIc 1000
IIe 1000
IIf
IIIa
IIIb 1000
40
100
100
50
0
0
0
0
0
25
0
20
100
100
100
100
100
100
25
6.1
16.0
30.6
31.6
16.0
15.6
11.2
17.2
37.8
22.4
22.4
28.0
19
85.0
60.0
23.0
21.0
60.0
61.2
72.2
59.0
10.0
44.0
44.0
30.0
54.0
96.0
94.0
98.0
67.0
1000
100
25
EXPERIMENTAL
100
100
100
25
100
100
25
IIIc 1000
IIId 1000
IIIe 1000
0
0
0
Methyl 5(6)-(4-aminophenylthio)-2-benzimidazolyl-
carbamate I and its derivatives II IV were analyzed
by HPLC on Ultrasphere-ODS in the following
eluents (vol%): (1) acetonitrile:water, 70:30, with
5% of DMF and (2) methanol:water:DMF, 67.5:29:
3.5, plus 4 ml/l tetrabutylammonium phosphate (0.5 g
1.0
1.6
0.84
13.9
IIIf 1000
IVa 1000
IVb 1000
0
0
0
25
per 20 ml of water), UV detectection at
254 nm.
max
a
Monocarbamoyl derivatives IIa IIf. To a
solution of 0.05 mol of aminobenzimidazole I in
60 ml of DMSO, 0.05 mol of corresponding iso-
cyanate was added. The mixture was left to stand for
16 18 h at room temperature and then poured into
water. The precipitate was filtered off, washed with
water, and dried.
The quantity of nematodes per head in the control group was
40.2.
Biological tests. Toxicity tests were performed
with mice 18 20 g in weight. Samples as suspensions
were introduced orally in one portion in doses of 100
to 1000 mg/ kg. The animals were observed over the
course of 5 days, keeping a record of deaths.
Dicarbamoyl derivatives IIIa IIIf. To a solu-
tion of 0.05 mol of aminobenzimidazole I in 60 ml of
DMSO, 0.11 mol of isocyanate was added. The mix-
ture was heated for 3 h at 70 80 C and then cooled
and poured into water. The precipitate was filtered off,
washed with water, and dried.
Nematocide activity tests were performed with rats
50 60 g in weight experimentally infected with
nippostrongilus larvae (300 350 per head). Samples
as suspensions were introduced orally in doses of 10
to 100 mg/kg eight days after infection. For each dose,
five infected and five control rats were used. After
5-day exposure the animals were killed. The effi-
ciency of the preparations was judged about by data
of helminthological examination of thin intestines for
tested and control groups.
Mixed carbamoyl derivatives IVa IVi. To a
solution of 0.05 mol of compound II in 100 ml of
DMSO, 0.055 mol of corresponding isocyanate was
added. The reaction mixture was stirred for 3 h at
70 80 C and then cooled and poured into water. The
precipitate was filtered off, washed with water, and
dried.
REFERENCES
For analysis the products were dissolved in DMSO,
the solution was poured into methanol, the precipitate
was filtered off, washed with methanol, and dried.
1. DE Patent 2332343, Ref. Zh. Khim., 1975, 17 O 130.
2. DE Patent 2332398, Ref. Zh. Khim., 1975, 16 O 185.
3. DE Patent 2332486, Ref. Zh. Khim., 1975, 23 O 165.
4. DE Patent 2332487, Ref. Zh. Khim., 1975, 17 O 131.
5. DE Patent 2348104, Ref. Zh. Khim., 1975, 24 O 112.
6. DE Patent 2348120, Ref. Zh. Khim., 1975, 24 O 111.
Most isocyanates used were prepared by reactions
of excess phosgene with primary amine hydrochlo-
rides. The reactions were performed at elevated
temperatures according to the procedures in [13 17].
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 73 No. 8 2003