Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
~5~)Z80
This invention relates to benzimidazole-carbamates
endowed with anthelmintic activity; more particularly it
relates to new benzimidazole-carbamates substituted in position
5(6) by a diene chain bound to position 5(6) by an atom
of oxygen or of sulphur optionally oxidized, and the use thereof
as anthelminthes.
Benzimidazole-derivatives exist in tautomeric forms
such as
~ B~ -B
For nomemclature convention the substituent A which is in
position 5 in a tautomeric form, assumes position 6 in the
other tautomeric form~
So a benzimidazole-derivatives having a substituent
in the position corresponding to substituent A, is generally
defined as "5(6)-substituted".
Several benzimidazole-carbamates variously substituted
in position 5(6), as well as their anthelmintic action are
known (see for example German patent applications Nos. 2,029,637
and 2,164,690; French patents Nos. 1,556,824 and 2,052,988; US
patents Nos. 3,010,968, 3,915,986 and 4,002,640).
Anthelmintic benzimidazole-carbamates have been
described also in German patent applications Nos. 2,816,694 and
2,843,308 in the name of the Applications.
Many benzimidazole-carbamates substituted in position
5(6) have been put on the market, such as for example Albendazole,
Oxibendazole and Parbendazole produced by Smith Kline Co.;
Phenbendazole produced by Hoechst; Oxphendazole produced
by Syntex; Cambendazole and Thiabendazole produced by Merck,
- 1 - ~
z~
and Mebendazole produced by Janssen.
We have now found new benzimidazole-carbamates, which
constitute the object of the present invention, substituted in
position 5(6), having the general formula:
R2 R3R4
C=CH-l=C-CH2-X ~ N ~ (I)
Rl / ~ J ~ NH-COOR
,'
wherein:
R = alkyl Cl-C4;
Rl and R2 (like or unlike each other) = H, halogen, methyl
optionally substituted by one or more halogen atoms;
R3 and R4 (like or unlike each other) = H, Cl, CH3;
X = O, S, SO, S02.
The compounds of general formula I are endoxed with
an high anthelmintic activity and a wide action spectrum being
active against both gastrointestinal and broncho-pulmonary
parasites and against hepatic parasites of domestic and breeding
animals.
The synthesis of the compounds of general formula (I)
is carried out according to simple steps, as results from the
following scheme (wherein R, Rl, R2, R3 and R4 have the same
meanings indicated in general formula (I); Z and Z' = Cl, Br;
RS = H, CH3CO) :
Rl Z R3 R
I) C / (A)+CH2=C - C=CH2 (B) ___~
R2 z~
Rl . . R3 R4
,f CH2-C = c cH2z (c,
R Z'
-- 2 --
~ ~5~Z80
R \ IR3 Rl 4
II) C' bases ) R2/C=CH-C = C-CH2-Z (C) + HZ'
NH-R5
III) C + ~ P (E) + NaZ
1 1
X Na X-Y
RlR3 R
(X = O, S) (Y = C=CH-C = C-CH2-)
R2/
~H2
~ N02
IV) C ' +D --------~ ~J (E ' ) + NaZ
X-Y'
R \ R3 R
~y ' = C -CH2-C = C-CH2-3
V) E' bases_ > E
NH2
reducers ~ (F)
VI ) E ----~ J
S-CH3 X-Y
Vl I ) E + N = C - NH - COOR -----> ( I ) ~X=O, S_ 7
COOR _ 3 _
2~30
VI~ X=S ~ _~er_cldS~ X=SO, SO2_/
The first passage of the scheme of reaction for obtain-
ing the compounds of formula (I) (reaction I), i.e. the reaction
between a compound of fo~mula C ~whe~ein R1 and R2
have the meanings indicated in general formula (I), and Z and Z'
(like or unlike each other) are Cl, Br_/' and a diene of the
R3 R
type CH2=C - C=CH2 ~wherein R3 and R4 have the same meanings
specified in general formula (I) ~, is conducted by radical
intermediates in the presence of suitable catalysts such as
Redox-transfer systems, as for example copper salts and
amines, as described by B.M. Asscher et al. / J. Chem. Soc.
page 1887 ~1963) ~ , or in the presence of ruthenium complexes,
as more recently described by H. Matsumoto et al. /Chemistry
Letters, page 115 (1978) ~ for the reaction between CC14/(A),
IH3
Rl=R2=Z=Z'+Cl ~ and isoprene CH2=C - CH=CH2 / (B), R3=CH3,
R4=H / in the presence of dichloro-tris-triphenyl-phosphine-
ruthenium (Ru /P(c6Hs)3 ~ 3C12)
It is important to point out that reaction I, both
when conducted in the presence of Redox-transfer systems, and
when conducted in the presence of ruthenium complexes, is not
region-selective, wherefore when in compound B substituent R3
is different from R4, also mixtures of positional isomers,
besides mixtures of cis-trans isomers due the presence of
the double bond, are obtained.
For example, starting from CC14 and isoprene, mixtures
of the following compounds are obtained:
IH3 fH3
Cc13-CH2-C = CH-CH2Cl Ccl3-cH2-cEl=c - CH2Cl
-- 4
~5~80
/(C'), Rl=R =Z=Z'=Cl; R3=CH3, R4=H and R3=H, R4--C~13 7
Generally the mixture of the positional isomers is separable
into the individual isomers by fractionated distillation.
The compounds of formula (C) or (C') are then reacted
with the sodium salt of 2-nitro-4-hydroxy-aniline (sodium phenate)
/ (D), X=O, R5=H~ or of 2-nitro-4-mercapto-aniline (sodium
mercaptate) ~ (D), X=S, R5=H~ according to reactions III and IV.
In some cases it is preferable ,to protect the amino
group of compounds (D) by acetylation starting then from the
corresponding N-acetyl-anilines ~ (D), R5=CH3CoJ ,
The acetyl group then can be easily removed by hydroli-
sis at the more convenient step of the process.
In this manner, nitro-aniline of formula (E) or ~E')
are obtained. The latter, when treated with bases, undergoes
a dehydrohalogenation on its side chain in position 4 respect to
the amino group (X-Y'), so providing the nitro-aniline indicated
by letter (E) (reaction V).
Nitro-aniline (E) is then reduced, for example, with
sodium hydrosulphite (Na2S2O4), so obtaining phenylenediamine
(F) (reaction VI).
Phenylenediamine F is then reacted with 1,3-bis-
alkoxycarbonyl-S-methyl-isothiourea, so obtaining benzimidazole-
carbamates of general formula (I), in which X = O or X = S
(reaction VII).
By reacting phenylenediamine F with 1,3-bis-methoxycar-
bonyl-S-methyl-isothiourea compounds of formula I in which R is
methyl are obtained.
In a similar manner by reacting phenylenediamine F with
1,3-bis-ethoxycarbonyl-S-methyl-isothiourea or 1,3-bis-
propoxycarbonyl-S-methyl-isothiourea or 1,3-bis-butoxycarbonyl-S-
methyl-isothiourea, benzimidazole-carbamates of formula I are
prepared in which R is either ethyl, propyl or butyl.
~5~2~30
Finally, from the benzimidazole-carbamates of formula
(I), in which X = S, it is possible to obtain, by oxidation
with peracids, the compounds of formula (I~ t in which X = SO
or SO2 (reaction VIII).
Reaction VIII is conveniently carried out by
dissolving the benzimidazole-carbamate of formula I (in which
X=S) in an inert solvent (or in a mixture of inert solvents)
and by adding at a temperature of from -30C to room temperature,
a peracid such as peracetic acid, perbenzoic acid or 3-chloro-
perbenzoic acid.
When it is desired to convert the thio group to its
corresponding sulphinyl group, equimolecular quantities of
peracids are used. While when it is desired to convert the
thio group to its corresponding sulphonyl group, or to convert
the sulphonyl group to its corresponding sulphonyl group, an
excess of peracid is used.
As examples of compounds of formula :
R \ / Z
C (A) the following may be cited:
R2 / \ z'
3 3, 4, CC14, CH3-CC13, CH3-CHCL2, CF3-CHBr
3 , F3 CFBr2~ CF3-CC13, CF2Cl-CFCl CF CB
CF Br CF Cl-CCl , CF3-CBr2-CF3 CH3-cclBr-cl~3-
As examples of compounds of formulal3 IR4
CH2= C=CH2 IB) the following may be cited:
~H3 fl fH3 IH3
CH2= --CH=CH2, CH2=CH-CH=CE~2, CH2=C-CH=CH2, CH2=C-- =CH2,
fl cll
CH2=C C=CH2.
Some of the compounds indicated by the letters C and
C' on scheme 1 are known compounds such as the afore mentioned
~S~280
adduct of carbon tetrachloride and isoprene or l-bromo-exa-2,4-
dienetsorbyl bromide) of formula CH3-CH=CH-CH=CH2Br
or 5-chloro-1,3-pentadiene of formula
cH2=cH-cH=cH-cH2cl
described in Russian Patent No 472,926 ~Chemical Abstract 83,
78559 x (1975)_/.
However in the course of the studies carried out on
the synthesis of the benzimidazole-carbamates of general
formula (I), it has been noticed that many of the intermediates
indicated by the letters C and C' on scheme 1 are compounds
previously unknown, wherefore the compounds having the general
formulae given hereinbelow are a further object of this inven-
tion:
R \ R3 R4
C-CH2-C = C-CH2Z (II) and
R,2, Z I
Rl' R3 R
\ C=CH-C = C-CH2Z (III)
R2~1/
wherein:
Rl = F, methyl substituted by one or more halogen atoms,
R2 = halogen, methyl substituted by one or more halogen
atoms,
Z and Z' (like or unlike each other) = Cl, Br,
R3 and R4 (like or unlike each other) = H, CH3.
Some of the compounds of general formulae II and III
can be prepared also by other methods.
For example, compounds in which R3 = H and R4 = CH3
can be prepared by reacting the corresponding compounds in
which z = H with N-halo imides (N-bromo-succinimide etc.) in the
presence of radical reaction promoters.
As already mentioned hereinbefore, the compounds of
~: .
~s~o
general formula (I) are endowed with a high enthelmintic activity
and a wide action range, these characteristics permitting to
successfully fight infestations in mammals and birds, for example
in the domestic and breeding animals.
Compounds of formula I are active against gastrointes-
tinal parasites such as Ostertaqia spp., T~ichostronqYlus ssp.,
StronqYloides ssp., Trichuris ssp., Oesophaqostum ssp.,Chabertia
., Nematodirus ssp., Moniezia ssp., Cooperia ssp., ~laemonchus
ssp., against broncho-pulmonary parasites such as Dictyocaulus
ssP.l and against hepatic parasites such as Fasciola ssp.
The latter characteristic can be dificulty found in
the known anthelminthes. The wide field of action of the
compounds of general formula (I) represents an important
characteristic as the administration of same to infested animals
causes a simultaneous liberation o the animal from gastrointes-
tinal, hepatic and broncho-pulmonary parasites.
Furthermore, compounds of formula I have been found to
be active against-other nematode parasites of the order of fila-
rioidea, including Bruqia Pahangi and Dirofilaria immitis.
The activity of compounds according to the present inven-
tion was determined in experiments conducted on naturally infested
sheeps or, in the case of Fasciola,on artificially infested sheeps.
The animals were divided into two groups, one of which
was treated with one dose of the product being tested (orally)
while the other untreated group was used as check. During 48-72
houes after treatment with the compound being tested, the
excrements of the animals were collected in order to determine
the number of parasites or of eggs; successively the animals
were killed to determine the reduction of the infestation in
comparison with the check.
For veterinary use, the administration of the
compounds of this invention to the animals to be treated can
be effected according to the usual veterinary techniques for
~15132130
the anthelmintic trea~ment, namely orally in the form of boil,
tablets, suspensions, etc., by injections in the form of an
injectable liquid or by absorption through the skin (spot on).
It is important to notice that the anthelmintic
compounds object oE the present invention are endowed, unlike
known anthelminthes, with a good solubility (about 20% by
weight) in N-methyl-2-pyrrolidone, an injectable liquid
employed in the veterinary technique.
The amounts to be given depend on various actors,
among which important are the weight oE the animal to be
treated, the nat~re and the severity of the infestation.
Suitable doses are at the discretion of the veterinary physician
but may be within the range of 0.5 tolOO mg of the compound of
formula I per Kg body weight of the host, preferably 1 to 10 mg/Kg.
Little animals need amounts of a few milligrams of
anthelmintic compound, while great animals, such as cattle,
sheep, etc., may need amounts of the order of grams per subject.
In practice, the active compound is usually formulated
with a vehicle agent (carrier) of veterinary use, or directly
in the food for the animal. The active compound may be mixed or
dispersed in one of the components of the food, or utilized
in the form of boil, tablets easily ingestable or capsules,
drenching, suspensions, powders, pastes, salt licks, block
licks, granules, pelIets feed premixes. The carrier may be
also a pharmaceutic diluent or excipient of the type generally
employed in the formulation of medicines; easily available
products are, for example, the following: maize starch, terra
alba, lactose, saccharose, calcium phosphate, gelatin, stearic
acid,magnesium stearate, dextrin, agar, pectines, vegetable
oils, injectable liquid carrier such as propylen glycol,
N-methyl-2-pyrrolidone, and so on.
If desired other active ingredients such as other
Z80
anthelmintics, food and mineral supplements may be included
in the formulation.
The way of administering may vary remarkably and
depends on the specific requirements.
With respect to anthelmintic activity, preferred
compounds are thio-derivatives ~X=S) and sulphinyl derivatives
(X=SO). Some of the samples tested for anthelmintic activity
were mixtures of positional isomers ~R3 different from R4).
However the anthelmintic activity of samples of
different composition is practically non-affected by the
relative positional isomers ratio (see example 21).
The following examples are given to better illustrate
the invention.
EXAMPLE 1
PreParation of 1,5,5-trichloro-3-methylhex-2-ene(A) and of
1,5,5-trichloro-2-methylhex-2-ene (B)
/Mixture No 1 7
In a "Pfaudler" type autoclave of 2.5 1 capacity the
following compounds were introduced under vacuum:
- l,l,l-trichloroethane (CH3-CC13) 1200 ml
CIH3
- isoprene (CH2=C=CH-CH2) 500 ml
- Ruthenium-tris-triphenylphosphine-dichloride Ru
(C6Hs)3p J 3C12
The content of the autoclave was then stirred and
heated up to 90C. At this temperature an exothermic reaction
began and the temperature raised to 130C.
The reaction was continued for 2 and half hours keeping
the temperature between 120 and 130C, then the autoclave was
left to cool at room temperature. The reaction mixture was
then concentrated by evaporation at reduced pressure (20 mmHg,
40C)-
_ 10 _
~5~3280
The residue of about 800 g was diluted with 1200 mlof petroleum ether. The ruthenium complex precipitated and
was quantitatively recovered by filtration. The filtrate
was again concentrated b~ evaporation and the residue was
distilled under reduced pressure. The fraction boiling between
- 82 and 85C at 5 mmHg was gathered (690 9).
Nuclear Magnetic Resonance (NMR) analysis revealed
that the collected fraction was a mixtur~ of compounds (A)
an^d (B) in a ratio of about 85:15
CH3
CH - CCl - CH2 - C = CH - CH2Cl (A)
(cis-trans)
`
CH3
CH3 CC12 CH2 C 2 (B)
(cis-trans)
EXAMPLE 2
By operating analogously with what described in
Example 1, the compounds or mixtures of compounds reported
on the following Table 1, were prepared.
~ ~5~80
~,
1 o ~ ~ ~ ~
~, .U' ~ CO
,c~ , ~
~. ~0'~ ~ ~ In ~
~ o O ~ l ~ r ~O'
~N_ _ ~_ H
C~ U ~~ ~ U ~ ~
~) C) 1:4~ ¢l
1~1 _ ~_, ~
~c m ~ m ~c m ~: m
o . ~I ~ ~ ~ ~ ~ ~
~ ~ m m m m m m
U) _ ~ S`l~ ~ ~ ~I C~ C~
~ ~ o
o 1 i 1 1 ~
~ ~ o
::c m m 5: m m ~
~ c~ m m mm u u ~ :
r~ ~ ~
o~ o ~- J ~. U o
H ¦ ~: X _ ~ t~) ~
~1 uz .. I
-- 12 --
-
2~0
.
.
_
u m o c~
_
~: m ~ m ~ m ~: m
_ _ _ _ _ _ _ _
5~ ~ ~ I: X X :~
m m ~ ~ o c~ o c~
_ l l l l ~ C~ _
:C ~ ~ ~ ~ ~
C~ C~~ O ~ C~ ~ C~5: U
m 1l :c 1l ~ I o m .
~ _ ~ ~ ~ ~ C~ 5: 1
C~ ~:~ ~ -- ~ --
~ ~ Y X ~ ~ ~ ~
-- ~ _ ~:: _ ~ ~ ~ ~::
~: o c~ o ~ ~ m
~ ~: :r: ~ c~l ~ ~ _
~ ~ ~ ~C ~C X ~ ~ ~ ~
I
:I: ~ ~ ~ ~ ~ ~ X
C~ ~ ~ ~ ~ ~ Y '~ ~
~ ~ ~ ~, ~ ~ C~
m m m l l l l ~ ~ u
m
~:
r~ ~ ~C~ ~ C~ U ~ ~ O
C~
-
.
, ~ In ~g I_ c~
m~ _
~ .....
3~81~
_~ _
~ ~ o
I
+ m ~ c~ m H H
u~ ~r ~r c~
m c~ m ~ ~ m
~ o ~ ~ U ~> C~
~: m ~ ~ ~ ~: m ~ â:~
__ .
U h _ _
m~ m ~ ~ m m m
:~ :C _ _
c~ ~ ~ m c~ ~: :c
~ ~ ~ ~: :~
uUl~mU~ ~ ml I mm~ ~ U~ ~ ~ I m~mU UU~mm
~ ~ ~ ~ ~ - ~J N ~I ~ t~l
O C~ r: ::~ ~ C~ ~ :C ~ ~:
U U ~) ~1 ~ l ~ (r) ~) '1
m m ,1 u ~ ~ ~ ~ u u
c~ ~ ~ V m
H _
~1 1~ L~ L~ ~ L~
E~
-- 14 --
Z8al
Notes to Table 1
(a) Mixture of cis and trans isomers
CH3
(b) I = isoprene (CH2=C-CH=CH2), B = butadiene ~CH2=CH-CH=CH2)
(c) Approximative ratio determined by NMR spectroscopy
(d) The preparation of MixtureNo lis described in Example 1
(e) Spectroscopic data of compound No 6
NMR (solvent CDC13, internal standard TMS) d, ppm:
3 1 (d-t., 2EI, JH H =5.66 Hz, JH,F
3.8-4 (m, 2H)
5.3-6.3 (m, 2H)
(d.t. = doublet of triplet, m = multiplet, J = coupling
constant)
(f) Mixture No 9 was isolated as pure (GLC) as residue after
distillation from the reactior. crude of unreacted CHC13
and isoprene.
(g) NMR spectroscopic data consistent with the assigned
structure.
(h) An analogous preparation has been described by J.Tanaka et
al. /Nippon Kagaku Zasshi 90, 803 (1969) ~ (100~ of
isomer A).
EXAMPLE 3
Preparation of 1,5,5,5-tetrachloro-3-methyl-pent-2-ene (A)
and of 1,5,5,5-tetrachloro-2-methyl-pent-2-ene (B) by redox-
transfer catalyst.
CuC12.2H2O (2g) was introduced in an enamelled
autoclave of 2.5 1 capacity.
The air was elimiriated from the autoclave and, under
vacuum, the following compounds were introduced:
- a solution of n.butyl-amine (n.C4Hg-NH2) (3.~5 g) in
acetonitrile (CH3C~) (300 ml)
- a mixture of carbon tetrachloride (CC14) (600 ml) and isoprene
(300 ml)
_ 15 _
280
- carbon tetrachloride (200 ml).
The autoclave was then heated at 90-130C in three
hours keeping the internal pressure a 7-8 atm by adding small
amounts of isoprene from a small cylinder.
Then the autoclave was leEt to cool at room tempera-
ture, and was opened. The content of the autoclave was
distilled at reduced presSue (about 20 mmHg) in order to
eliminate the volatile components from tpe reaction mixture
~isoprene, CC14 and CH3CN). The residue was distilled under
high vacuum collecting all the distilled material in a single
fraction which was then re-distilled collecting the fraction
(570 g) boiling at 65 C (1.3 mmHg). NMR analysis revealed
that the collected fraction was a mixture of compounds A and
B (97% pure by GLC) in a ratio of about 70:30. An analogous
preparation has been described by P. Piccardi et al. /Agric.
and Food Chem. ~ 1073 (1977)
EXAMPLE 4
Preparation of 1,1,5-trichloro-3-methyl-penta-1,3-diene (A)
and of l,1,5-trichloro-4-methyl-penta-1,3-diene (B)
~ Reaction II /
200 g of the mixture of compounds, prepared as
described in Example 3, were dissolved in benzene ~240 ml).
The solution was added to a solution of NaOH ~162 g) in the
presence of tetrabutylammonium iodide (n.C4H9)4N J (1.2 g).
The reaction mixture was maintained under intense stirring
at 25-30C for 5 hours.
The organic layer was separated and the aqueous
layer, after neutralization with hydrochloric acid, was extracted
with diethylether (2 x 100 ml). The organic phases were
reunited and anhydrified on anhydrous Na2SO4. The solvents
were evaporated under vacuum, the residue was distilled and
the fraction boiling at 50-52C (0.7 mmHg) was collected. NMR
_ 16 -
~5~80
analysis revealed that the collected fraction was a mixture of
compounds A and B in a ratio of about 60:40 (pure at 93% by
GLC).
EXAMPLE 5
Preparation of 1,1- dichloro-4-methyl-S-bromo-penta-1,3-diene
ccl2=cH-cH=f-cH2Br (A)
CH3
By a procedure analogous to thé one described in
Example 1, CC14 (243 ml) was additioned to isopentene
CH2=CH-CH(CH3)2 (66 g) in the presence of RuII/(C6H5)3P ~ 3C12
(1.8 g) obtaining 1,1,1,3-tetrachloro-4-methyl-pentane (45 g)
'CCl --CH2-CH-CH-CH3
Cl C~13
The product thus obtained was dehydrohalogenated
by treatment with (C2H5)3N (41.4 9) in DMF at reflux temperature
- for 10 hours.
The reaction mixture was then poured in H2O (100 ml)
and extracted by ethyl ether.
The organic solution was distilled and the fraction
boiling at 44C (4 mmHg) consisting of 1,1-dichloro-4-methyl-
penta-1,3-diene was collected (NMR consistent with the
assigned structure CC12=CH-CH=f-CH3)
CH3
16.3 g of the product thus obtained were dissolved in
CC14 (50 ml) and additioned with N-bromosuccinimide (19.3 g)
in the presence of azobis-isobutyronitrile (100 my).
The reaction mixture was refluxed for 8 hours.
The succinimide was filtered, the solvent was
eliminated under vacuum and the residue was distilled.
The fraction boiling at 93-96C/2 mmHg (14.6 g)
was collected. NMR data are consistent with the structure
_ 17
~15~280
assigned to compound A.
EXAMPLE 6
By operating as described in Example 5 and starting
from 2,5-dimethyl-hexa-2,4-diene the compound 1-bromo-2,5-
dimethyl-hexa-2,4-diene was obtained (NMR consistent with the
assigned structure)
H3C / CH2Br
/ C=CH-CH=C ~
H3C CH3
EXAMPLE 7
By operating analogously to what described in Example
4, the compounds (or mixtures of compounds) reported in the
follbwing Table 2, were prepared.
~S~280
_ .
o ~ o ~ o ~
., ~ m .. ..
~ ~ ~ ~ o C~
.,1 ~ ~ ~ ~D I_
o ~ _, .
.
~ r In ~'
P~
, ~0'~ l ,~ er
~ 0 o
o~ ~ o
a~ o ~ ~ .
U~
Co o~ ~ ~
~ ~ ~ ,. ~ P~ ~
~ o a~ ~ ~ e
~ XX
~1 e t
-- 19
~5~)280
~_
'un. c. .
I N ~1
~J t~1
. 4~--
_ _ _ _
~: m ~ m
.
~ m~ :q ~ ~ m~
c~ a O u N _
_ 11 D~~r) ~_
$~ :~C U U ~C
y U V 5~ ::~ $ .
m ::c ~ Y u
~ ~ u u ~ ~ ~)~
Y ~ u-m y--m ~1~ _
~ ". ~ ~ ~ ~c
~ ~ u ~ u u
u . .,
'l ~ .~ ~ i
m~
_ 20 _
Z80
Notes to Table 2
(a) Mixture of cis and trans isomers
(b) Approximative ratio determined by NMR spectroscopy
(c) The preparation is described in Example 4
(d) Compounds of mixture No 20 decompose when distilled,
Mass-spectroscopic data (M /e)
248 (10%), 246 (10%), 167 (80~), 147 (56%), 127 (60~),
69 (30%), 53 (100%)
(e) Compounds of mixture No 21 decompose when distilled
Mass-spectroscopic data (M /e)
310 (8%), 30B (16%), 306 (8~), 229 (50%), 227 (50%),
148 (45%), 147 (90~), 127 (100~).
(f) The preparation is described in Example 5.
(g) The preparation is described in Example 6.
EXAMPLE 8
Preparation of 4-/(5,5-dichloro-3-methyl-penta-2,4-dien-1-yl)-
-thio 7-2-nitro-aniline (A) and of 4- /(5,5-dichloro-2-methyl-
-penta-2,4-dien-1-yl)-thio 7-2-nitro-aniline (B)
~ Reaction III, X = S, R5 - H 7.
A solution of 10 g (51.2 m.moles) of 2-nitro-4-thio-
cyano-aniline in 25 ml of dimethylformamide was added to a
solution of 2. 26 g (51 m.moles) of sodium-boron-hydride in
25 ml of dimethylformamide. The reaction mixture was maintained
under stirring at room temperature for 1 hour, whereupon
60 m.moles of the mixture of the products obtained as described
in Example 3 were added.
The reaction mixture was heated to 100C for 1 hour,
then it was allowed to cool down and was poured into 200 ml
of H2O-
It was extracted with chloroform (3 x 100 ml). The
organic extracts were reunited, anhydrified with anhydrous
Na2SO4, and the solvent was removed under vacuum.
_ 21 _
~15~80
A crude product (11.9 g) was obtained, which consisted
of compounds A and B in a ratio of about 55:45 (NMR) and
resulted sufficiently pure for the successive step (Example 9).
EXAMPLE 9
Preparation of 4-/(5,5-dichloro-3-methyl-penta-2,4-dien-1-yl)
thio 7-1,2-phenylenediamine (A) and of 4-~ (5,5-dichloro-2-
methylpenta-2,4-dien-1-yl)-thioJ -1,2-phenylendiamine (B).
Reaction VI~
11.7 g of the crude product obtained as describecl
in example 8 were added to a mixture of 200 ml of H2O and 200 ml
of Cll3OH containing 45 g of Na2S2O4.
The reaction mixture was heated to 80C for 15
minutes, whereupon the inorganic salts were filtered and a
methanol portion was removed under vacuum.
After extraction with chloroform (3 x 100 ml), the
organic phases were reunited, anhydrified with anhydrous Na2SO4,
and the solvent was removed, so obtaining a brown viscous oil
composed by products A and B in a ratio of about 55:45 (NMR~.
EXAMPLE 10
Preparation of 5(6)-/(5,5-dichloro-3-methyl-penta-2,4-dien-1-
-
yl)-thio 7-benzimidazole-2-methylcarbamate (A) and of 5(6)-
-
(5,5-dichloro-2-methyl-penta-2,4-dien-1-yl)-thio ~-benzimi-
dazole-2-methylcarbamate (2)
Reaction VII 7
_
8.5 g (29.4 m.moles) of the raw oil obtained as
described in Example 9 were dissolved in a mixture of 35 ml of
H2O, 35 ml of ethanol, 2 ml of acetic acid and 6.05 g
(29.4 m.moles) of 1,3-bis-methoxycarbonyl-S-methyl-isothiourea.
The reaction mixture was heated at reflux for 2 hours.
A solid formed, which was separated by filtration
and was re-crystallized by methanol and chloroform (1:1).
7 g of a mixture of compounds A and B in a ratio of
- 22 -
~15~28()
about 55:45 (NMR) (melting point 169-170C with decomposition)
were obtained.
EXAMPLE 1 1
Preparation of 5(6)-~ (5,5-dichloro-3-methyl-penta-2,4-dien-1-
-
yl)-sulphinyl 7-benzimidazole-2-methylcarbamate (A) and of
-
5(6)- (5 5-dichloro-2-methyl-penta-2,4-dien-1-yl)-sulphinyl/-
benzimidazole-2-methylcarbamate (B)
eaction VIII 7
10.1 m.moles of 3-chloro-perbenzoic acid were rapidly
added, under intense stirring, to a solution of 4 g (10.7 m.moles)
of the mixture of products obtained as described in example 10,
in 400 ml of chloroform, 200 ml of ethanol and 1.5 ml of
acetic acid.
The reaction mixture was left at room temperature
for 1 hour, then it was treated with an aqueous solution of
NaHCO3 and successively with water until a neutral pH was
attained. The organic solution was anhydrified with anhydrous
Na2SO4 and the solvent was evaporated under vacuum.
The residual oil was washed with methanol and ethyl
ether, and the resulting solid was re-crystallized by methanol
so obtaining 3.5 g of a mixture of products A and B in a ratio
of about 55:45 (melting point = 134-135C with decomposition).
EXAMPLE 12
Preparation of 4-/ (5,6,6,6-tetrafluoro-3-methyl-hexa-2,4-
. .
dien-l-yl)-thio /-2-nitro-aniline (A) and of 4-/ (5,6,6,6-
tetrafluoro-2-methyl-hexa-2,4-dien-1-yl)-thio /-2-nitro-
aniline (~)
/ Reaction IV and V 7.
A solution of 10.5 g of NaBN4 in 15 ml of dimethyl-
3 formamide was added, at room temperature, to a solution of 5 g
of 2-nitro-4-thiocyano-aniline (25.6 m.molesl in 15 ml of
dimethylformamide.
_ 23 _
~5~280
The reaction mixture was maintained under stirring
at room temperature for 1 hour, whereupon 8.85 g (27 m.moles)
of mixture No 2 (see Table 1), were added.
The reaction mixture was heated to 100C for 1 hour.
After cooling 4.9 ml (35 m.moles) of triethylamine were
added, then it was heated to 100C for 2 hours.
The mixture was cooled and then diluted with 300 ml
of H2O and extracted with chloroform (4 x 100 ml). The organic
phase was anhydrified with anhydrous Na2SO4, concentrated under
vacuum and was chromatographied on silica gel (eluent: ethyl
ether - petroleum ether 1:1).
5.~ g (red oil) of a mixture of compounds A and B
in ratio of about 1:1 (NMR) were obtained.
EXAMPLE 13
Preparation of 4-/ (5,6,6,6-tetrafluoro-3-methyl-hexa-2,4-
dien-l-yl)-thio 7-1,2-phenylenediamine (A) and of 4-/ (5,6,6,6-
tetrafluoro-2-methyl-hexa-2,4-dien-1-yl)-thio 7-1,2-phenylene-
diamine (B)
~ Reaction VI ~
Starting from 5.7 g of the mixture of the 2-nitro-
anilines obtained as described in Example 12 and operating
as described in Example 9, 4.6 g of an intensely coloured oil,
consisting of a mixture of compounds A and B in a ratio of
about 1:1 (NMR), were obtained.
EXAMPLE 14
Preparation of S (6) -/ (5, 6, 5, 6-tetrafluoro-3-methyl-hexa-2,4-
dien-l-yl)-thio 7-benzimidazole-2-methylcarbamate (A) and
of 5(6)-~ (5,6,6,6-tetrafluoro-2-methyl-hexa-2,4-dien-1-yl)-
thio 7-benzimidazole-2-methylcarbamate (B)
.
~ Reaction VII 7 .
4.6 g (1.5 m.moles) of the mixture of compounds
obtained as described in Example 13 were dissolved in a mixture
_ 24 _
~q3Z80
of 20 ml of H2O, 20 ml of ethanol and 0.5 ml of acetic acid
containing 3.1 g (1.5 m.moles) of 1,3-bis-methoxycarbonyl-S-
methyl-isothiourea. The reaction mixture was heated at reflux
for 2 hours, then it was allowed to cool. A solid formed, which
was separated by filtration and crystallized by methano-
chloroform (1:1), so obtaining 3.7 g of a mixture of compounds
A and B in a ratio of about 1:1 (melting point: 167-170 C).
EXAMPLE 15
Preparation of 5~6)-~ (5,6,6,6-tetrafluoro-3-methyl-hexa-
2,4-dien-1-yl)-sulphinyl 7-benzimidazole-2-methylcarbamate (A)
_
and of 5(6)-~ (5,6,6,6-tetrafluoro-3-methyl-hexa-2,4-dien-
l-yl)-sulphinyl ~-benzimidazole-2-methylcarbamate (B)
_ _
Reaction VIII_ 7 .
Starting from 1.3 g (3.34 m.moles) of the mixture of
benzimidazole carbamates obtained as described in Example 14
and operating as described in Example 11, it was possible to
obtain 0.95 g of a mixture of compounds A and B in a ratio of
about 1:1 (NMR) (melting point : 147-139C~.
EXAMPLE 16
Preparation of 4-/ (5,5-dichloro-3-methyl-penta-2,4-dien-1-yl)-
oxy 7-2-nitro-aniline (A) and of 4-~ (5,5-dichloro-2-methyl-
_
penta-2,4-dien-1-yl)-oxy 7-2-nitro-aniline (B)
_ .
/ Reaction III, X = O, R5 = CH3CO /.
A mixture of 10.2 g (52 m.moles) of 3-nitro-4-acetamino-
phenol, 20 g of Na2CO3, 11.12 g ~60 m.moles) of the mixture No 18
(see Table 2) and 60 ml of acetone was heated at reflux for
48 hours. The reaction mixture was then allowed to cool, the
inorganic salts were filtered and a part of the solvent was
removed.
The resulting crude product was subjected to chromato-
graphied on silica gel (eluent: ethyl ether - petroleum ether
1:1); 7.8 g of a brown crystalline solid consisting of a
- ~15~Z80
mixture of compounds A and B in a ratio of about 3:2 (NMR)
were obtained.
EXAMPLE 17
Preparation of 4-~ (5,5-dichloro-3-methyl-penta-2,4-dien-1-yl)-
oxy 7-1,2-phenylenediamine (A) and of 4-~ (5,5-dichloro-2-
methyl-penta-2,4-dien-1-yl)-oxy 7-1,2-phenylenediamine (B)
-
Reaction VI~ .
Starting from 7.5 g of the mix~ure of compounds
obtained as described in Example 16 and operating as illustrated
in Example 9 it was possible to obtain 6.2 g of a thick brown
oil consisting of a mixture of compounds A and s in a ratio
of about 3:2.
EXAMPLE 18
Preparation of 5(6)-~ (5,5-dichloro-3-methyl-penta-2,4-dien-1-
yl)-oxy /-benzimidazole-2-methylcarbamate (A) and of 5(6)-
.
(5,5-dichloro-2-methyl-penta-2,4-dien-1-yl)-oxy_7-benzimidazole-
2-methyl-carbamate (B)
Reaction VI / .
4.6 g of 1,3-bis-methoxycarbonyl-S-methyl-isothiourea
were added to a solution of 6.2 g (22.7 m.moles) of the mixture
of products obtained as described in Example 17, in 30 ml of
H2O, 30 ml of ethanol and 0.8 ml of acetic acid. The reaction
mixture was heated at reflux for 2 hours, whereupon it was
allowed to cool. A solid formed, which was filtered and crystal-
lized by methanol-chloroform, so obtaining 5.6 9 of a mixture
of compounds A and B in a ratio of about 3,2 (NMR) (melting
point: 183:185C).
EXAMPLE 19
On the following Table 3 benzimidazole-carbamates of
general formula I are reported, together with their character-
istics and the synthesis procedure.
- 26 -
0280
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~3 5~280
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-- 29
115~1280
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-- 30 --
~5~Z80
Notes to Table 3
(a) Mixture of cis and trans isomers
(b) Products 1-17 and 18-24 are reported on Table 1 and
Table 2 respectively
(c) Melting points have not been corrected.
dec. = decomposition, n.d. = not determined
(d) Approximative ratio determined by NMR spectroscopy
(e) Structures confirmed by the performed analysis
NMR = Nuclear Magnetic Resonance spectroscopy
IR = Infra-red spectroscopy
MS = Mass spectroscopy
EA = Elemental analysis
(f) Prepared by a procedure analogous to the one described in
Example 11, by using two equivalents of 3-chloro-perbenzoic
acid.
(g) Mixture 28/3 is described in Example No 21
EXAMPLE 20
Compounds of general formula I were tested for
anthelmintic activity acc~rding to the procedure described at
page 11.
Samples No 25, 26, 28, 29, 30, 31, 32, 33, 34, 35,
36, 37, 39, 40, 44, 45 and 47 (see Table 3) tested against
Gut-nematodes in infested sheeps, proved to be completely
effective (90-100~ reduction of infestation) at the dose of
5 mg/Kg of body weight.
Samples No 28, 29, 35 and 40 tested against Flukes
(Fasciola) in infested sheeps, proved to be completely effective
(90-100% reduction oE infestation) at the dose of 5 ~g/Kg of
body weight.
Samples No 32 and 44 tested against Lungworms
(Dictyocaulus) in infested sheeps, proved to be completely
effective (90-100% reduction of infestation) at the dose of
31 ~
l~S~Z80
5 and 2.5 mg/Kg of body weight respectively.
EXAMPLE 21
Anthelmintic activity of positional isomers mixtures
having different isomeric composition.
Sample No 28 (see Table 3) is a mixture of compound A
and compound B in the ratio A/B = 55:45
CC12=CH-C(CH3)=CH-cH2-s ~ NH-coocH3 (A)
H
CC12=CH-CH=C(CH3)-CH2-S ~ O X ~ NH-COOCH3 (B)
~, N
Sample No 48 (see Table 3) is compound B (100%).
A mixture consisting of compounds a and b in the
ratio a/b = 75:25 (NMR)
CC12=CH-C(CH3)=CH-CH2Cl (a)
CC12=CH-CH=C(CH3)-CH2Cl (b)
was distilled at reduced pressure.
The following fractions were collected:
Fraction B.p. Composition
No (C/mmHg) a/b (NMR)
,
1 50-54/0.5 90:10
2 54-57/0.5 80:20
3 5?/0.5 70:30
From fractions 1 and 3 independently and by operating
as described in Examples 8-10, the corresponding benzimidazole-
carbamate derivatives (Samples 28/1 and 28/3) were prepared.
32
Z80
Sample 28/1 A/B = 90:10 (NMR) m.p. = 163-5 C
Sample 28/3 AJB = 70:30 (NMR) m.p. = 160-5 C
Samples 28, 28/1, 28/3 and 48 were separately tested
for anthelmintic activity against Gut-nematodes in infested
sheeps.
The obtained activity data are reported on tne
following Table 4 and are expressed according to the following
scale of values:
O O-10~ reduction o infestation
1 Il-25% reduction
2 26-60~ reduction
3 61-90% reduction
4 91-100% reduction
- TABLE 4
Sample Compositions dose
Activity
No of Sample (~) (mg/Kg) l
28 A=55, B=45 5 4
28/1 A=90, B=10 5 4
- 28/3 A=70, B=30 5 4
48 A=0 , B=100 3
- 33 -
Z80
SUPPL~;M~;~TARY DISCLOSVRE
Example 22
Activity against ~rugia pahangi (Filarioidea)
n vivo Brugia pahangi adult worm transplant
screen.
Young male adult birds were infested with large
numbers of larvae by the intraperitoneal route. 60 days
later adult worm were rec~vered, washed, sexed and counted into
groups of 10 female and 5 male. These were then transplanted
into the peritoneal cavities of naive (normal) birds. Following
a recovery period, the compound to be tested was administered
at 100 mg/kg for 5 consecutiye days by subcutaneous injection.
The compound was formulated in 1~ Tween 80 (trademark).
Each compound was tested in two animals. If the
compound was inactive a worm recovery of 85-90% was expected;
this was then considered to be a pseudo-control. In this way
control~> groups of 20 or more animals can be used, against which
active compounds were compared. The selection of pseudo-controls
is thus subjective but the hypothesis tha~t a compound i8 inactive
was tested by the <sF test. If the variances of the pseudo-con-
trols were homogeneous, then the active compounds were tested
against thi~group by the <~student t test.
At autopsy (32 days after administration of the
final dose of compound), the peritoneal fluid was also examined
for the presence of microfilariae.
When these were absent, present in only small
numbers, or abnorma~, the adult worms were examlned to determine
if the compound has effected em~ryogenesis and/or spermetogenesis.
Reference to the F test and <~student t test
maybefound in Snedecor and Cochran, Statistical Methods,
published by Iowa State University Press at pages 258-268.
- _ 34 _
llSV~30
The following scores were allocated according
to the pe~ce~tage worm reduc~ion observed.
Percentage worm reduction . Score
0 - 10% 0
11 - 25%
26 - 60% 2
61- 90% 3
91 -100% 4
^ Samples n~ 25, 29, 35, 44 and 45 (see Table 3'
reported ~ereinafter) tested against Brugia ~ahangi according to
the above reported procedure proved to be completely effective
(91-100~ reduct~on o~ infes~ion, score 4). - -
z80
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