Novel anti-acarid methods

Novel antiacaridal composition comprising an effective amount of at least one compound selected from the group consisting of cis and trans, racemic and optically active isomers of a compound of the formula ##STR1## wherein R.sub.1 is selected from the group consisting of hydrogen, halogen and alkyl of 1 to 8 carbon atoms, R.sub.2 is selected from the group consisting of hydrogen, halogen, alkyl of 1 to 8 carbon atoms and alkoxy carbonyl of 2 to 8 carbon atoms and R.sub.1 and R.sub.2 taken together with the carbon atom to which they are attached form a cycloalkyl of 3 to 6 carbon atoms and R is selected from the group consisting of ##STR2## and a pharmaceutical carrier and to a method of combatting acarids in warm-blooded animals.

OBJECTS OF THE INVENTION 
It is an object of the invention to provide novel antiacaridal compositions 
based on pyrethrinoids. 
It is a further object of the invention to provide a novel method of 
combatting acarids in warm-blooded animals. 
These and other objects and advantages of the invention will become obvious 
from the following detailed description. 
THE INVENTION 
The novel and antiacaridal compositions of the invention are comprised of 
an antiacaridally effective amount of at least one compound selected from 
the group consisting of cis and trans, racemic and optically active 
isomers of a compound of the formula 
##STR3## 
wherein R.sub.1 is selected from the group consisting of hydrogen, halogen 
and alkyl of 1 to 8 carbon atoms, R.sub.2 is selected from the group 
consisting of hydrogen, halogen, alkyl of 1 to 8 carbon atoms and alkoxy 
carbonyl of 2 to 8 carbon atoms and R.sub.1 and R.sub.2 taken together 
with the carbon atom to which they are attached form a cycloalkyl of 3 to 
6 carbon atoms and R is selected from the group consisting of 
##STR4## 
and a pharmaceutical carrier. 
When R.sub.1 and R.sub.2 are halogen, the are preferably chlorine or 
bromine and when they are alkyl, they are preferably methyl, ethyl, 
n-propyl or n-butyl. When R.sub.2 is alkoxy carbonyl, it is preferably 
methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl or butoxycarbonyl. When 
R.sub.1 and R.sub.2 and the carbon atom to which they are attached form a 
cycloalkyl, it is preferably cyclopropyl. 
Among the preferred compositions of the invention are those where R.sub.1 
and R.sub.2 are alkyl of 1 to 8 carbon atoms, those where R.sub.1 and 
R.sub.2 are chlorine, those where R.sub.1 and R.sub.2 are bromine and 
those where R.sub.1 and R.sub.2 together with the carbon atom to which 
they are attached are cycloalkyl of 3 to 6 carbon atoms. 
Among the preferred compositions of the invention are those containing at 
least one compound of formula I or mixtures thereof except for those 
compounds where R.sub.1 and R.sub.2 both represent chlorine or both 
represent methyl where R is 3-phenoxybenzyl or 
.alpha.-cyano-3-phenoxybenzyl, those compositions wherein R.sub.1 and 
R.sub.2 are alkyl of 1 to 8 carbon atoms but R.sub.1 and R.sub.2 are not 
both methyl where R is 3-phenoxybenzyl or .alpha.-cyano-3-phenoxybenzyl 
and those compositions wherein R.sub.1 and R.sub.2 are chlorine and R is 
other than 3-phenoxybenzyl or .alpha.-cyano-3-phenoxybenzyl. 
Among the preferred compositions of the invention are those containing 
compounds of formula I wherein R is 
##STR5## 
in cis or trans form, racemic mixtures or optically active isomers or 
mixtures thereof, or is 
##STR6## 
in cis or trans form, racemic mixtures or optically active isomers or 
mixtures thereof or is 
##STR7## 
in cis or trans form, racemic mixtures or optically active isomers or 
mixtures thereof. Especially preferred are the compounds of formula I 
wherein R is 3-phenoxybenzyl or .alpha.-cyano-3-phenoxybenzyl with the 
proviso that R.sub.1 and R.sub.2 are not both chlorine or both methyl. 
Another preferred group of compositions are those wherein R is 
##STR8## 
with a cis or trans form, racemic mixture or optically active isomer or 
mixtures thereof. 
The most preferred compositions contain as the active ingredient a compound 
selected from the group consisting of 3-phenoxybenzyl 
2,2-dimethyl-3S-(2',2'-dichlorovinyl)-cyclopropane-1R-carboxylate, (.+-.) 
.alpha.-cyano-3-phenoxybenzyl 
2,2-dimethyl-3R-(2',2'-dibromovinyl)-cyclopropane-1R-carboxylate, (.+-.) 
.alpha.-cyano-3-phenoxybenzyl 
2,2-dimethyl-3R-(2',2'-dichlorovinyl)-cyclopropane-1R-carboxylate, 
5-benzyl-3-furylmethyl 
2,2-dimethyl-3R-cyclopentylidenemethyl-cyclopropane-1R-carboxylate or 
mixtures of the said compounds, as well as racemic or optically active 
isomer, cis or trans 5-benzyl-3-furylmethyl chrysanthemates or mixtures 
thereof or 5-benzyl-3-furylmethyl d-trans-chrysanthemate. 
Among the mixtures of d-trans and d-cis or dl-trans and dl-cis 
5-benzyl-3-furylmethyl chrysanthemate are mentioned particularly those 
containing 5 to 95% of d-trans or dl-trans 5-benzyl-3-furylmethyl 
chrysanthemate and 95 to 5% of d-cis or dl-cis 5-benzyl-3-furylmethyl 
chrysanthemate. 
Also a preferred embodiment of the invention are the compositions 
containing as the active ingredient (-) .alpha.-cyano-3-phenoxybenzyl 
2,2-dimethyl-3R-(2',2'-dibromovinyl)-cyclopropane-1R-carboxylate or 
(S)-allethrolone d-transchrysanthemate or neopynaminol 
d-trans-chrysanthemate. 
The compounds of formula I are known compounds and may be prepared by the 
process of French Patent No. 1,503,260. They are known for their 
insecticidal activity and are frequently used to combat insects such as 
flies, beetles and cockchafers. 
It has now been discovered that the composition of the invention possess 
antiacaridal activity and can be used more especially in veterinary 
medicine to combat particularly all sorts of mange such as sarcoptic 
mange, psoroptic mange and chorioptic mange while ensuring a rapid 
disappearance of pruritus and healing of lesions. The compositions are 
also useful against ticks, such as Boophilus species, Hyalomma species, 
Amblyomma species and Rhipicephalus species. The compositions have an 
excellent cutaneous and general tolerance. It is particularly possible to 
treat a great number of animals in the same stable without any 
inconvenience. 
The preferred compositions of the invention possess besides the compound of 
formula I a synergist such as 
.alpha.-[2-(2-butoxyethoxy)-ethoxy]-4,5-methylene dioxy-2-propyltoluene or 
piperonyl butoxide, or the 2,3-dicarboximide of N-(2-ethylbenzyl)-bicyclo 
(2,2,1)-hepta-5-ene-anhydrophthalic acid preferably in a weight ratio of 
synergist to compound of formula I of 2 to 15:1, most preferably 3 to 7:1. 
The compositions may be prepared in the usual form of veterinary products. 
For local application, for example, the compositions may be in the form of 
solutions emulsifible with water for dilution at the time of use. 
Generally, they contain 1/500 to 1/5 by weight of the active principle, 
preferably 1/100 to 1/10. The solutions can also contain a quantity of 
synergist agent for pyrethrinoids as indicated above such as one part by 
weight of the compound of formula I per 2 to 15 parts, preferably 3 to 7 
parts by weight of piperonyl butoxide. 
The compositions usually also contain an emulsifier such as Tween or Span. 
Preferably, nonionic emulsifiers such as Polysorbate 80 or Triton X-100 
are used and the emulsifiers act in the role of aiding wetting and 
penetration of the active compound in the lesions of the skin. The amount 
of emulsifier is preferably 1 part by weight of active compound per 2 to 
20, preferably 5 to 10, parts by weight of emulsifier. The compositions 
may also contain an antioxidant agent soluble in organic solvents such as 
Tocopherol acetate. 
The active ingredient and the other ingredients such as synergists, 
emulsifiers and antioxidants are generally in solution in an alcohol such 
as ethanol or a mixture of ethanol and isopropanol or a mixture of 
ethanol, isopropanol and ethyl acetate. 
The dosage for external use will vary with the animal being treated and the 
parasites carried thereby. For example, 5-benzyl-3-furylmethyl d-trans 
chrysanthemate is advantageously used in solution at a concentration of 
1/1000 and (-) .alpha.-cyano-3-phenoxybenzyl 
2,2-dimethyl-3R-(2',2'-dichlorovinyl)-cyclopropane-1R-carboxylate is 
preferably used at a concentration of 1/10,000. 
For subcutaneous or intramuscular use, the compounds of formula I may be 
used in solution with a conventional excipient such as a mixture of benzyl 
benzoate and arachide oil. Injectable solutions can equally contain 
.alpha.-tocopherol acetate and piperonyl butoxide. For oral use, the 
compositions may be in the form of capsules. 
It is convenient for veterinary use to use the compounds of formula I in 
admixture with balanced feeds for the animal which feed components for the 
animals are constituted of a balanced feed for animals which contain one 
or more of the compounds of formula I. Examples of suitable feeds are 
those containing 0.004 to 0.2% by weight of (-) 
.alpha.-cyano-3-phenoxybenzyl 
2,2-dimethyl-3R-(2',2'-dibromovinyl)-cyclopropane-1R-carboxylate or 0.04 
to 10% by weight of 5-benzyl-3-furylmethyl d-trans-chrysanthemate or 0.04 
to 0.3% by weight of (S) allethrolone d-trans chrysanthemate or 0.03 to 
7.5% by weight of neopynaminol d-trans-chrysanthemate. The animal feeds 
may also contain a synergist. The novel method of combatting acaridal 
infections in warm-blooded animals comprises administering to warm-blooded 
animals an antiacaridally effective amount of at least one compound of 
formula I, preferably with a synergist, most preferably with piperonyl 
butoxide. The compounds may be administered particularly to farm animals 
such as bovines, sheep, pigs and poultry parenterally, orally, rectally or 
topically. The dosage will vary depending on the parasite and the product. 
For example, to attack mange in bovines by oral administration, the dosage 
may be 0.20 to 0.80 g/kg of body weight of 5-benzyl-3-furylmethyl d-trans 
chrysanthemate, 0.003 to 0.013 g/kg of body weight of (-) 
.alpha.-cyano-3-phenoxybenzyl 
2,2-dimethyl-3R-(2',2'-dibromovinyl)-cyclopropane-1R-carboxylate, 0.02 to 
0.08 g/kg of body weight of (S)-allethrolone d-trans chrysanthemate or 0.4 
to 3 g/kg of body weight of neopynaminol d-trans chrysanthemate. 
Chronic toxicity studies on rats show that at these doses there is no 
danger to the animals. Orally administered doses to rats of 2 g/kg of body 
weight of 5-benzyl-3-furylmethyl d-trans-chrysanthemate, of 0.010 g/kg of 
body weight of (-) .alpha.-cyano-3-phenoxybenzyl 2,2-dimethyl 
-3R-(2',2'-dibromovinyl)-cyclopropane-1R-carboxylate, of 0.075 g/kg of 
body weight of (S) allethrolone d-trans chrysanthemate and of 2 g/kg of 
body weight of neopynaminol d-trans chrysanthemate were well tolerated in 
chronic toxicity tests. 
The method of the invention is particularly directed to treating farm 
animals for psoroptic mange with (-) .alpha.-cyano-3-phenoxybenzyl 
2,2-dimethyl-3R-(2',2'-dibromovinyl)-cyclopropane-1R-carboxylate or 
5-benzyl-3-furylmethyl d-trans chrysanthemate or (S) allethrolone d-trans 
chrysanthemate or neopynaminol d-trans chrysanthemate or mixtures thereof. 
The said compounds may be administered topically, parenterally, or orally. 
In the following examples there are described several preferred embodiments 
to illustrate the invention. However, it should be understood that the 
invention is not intended to be limited to the specific embodiments.

EXAMPLE 1 
A solution was prepared with 5 g of 5-benzyl-3-furylmethyl d-trans 
chrysanthemate, 25 g of piperonyl butoxide, 10 g of Polysorbate 80 
[polyoxyethylene (20) sorbitan monooleate], 25 g of Triton X-100 
[condensation of ethylene oxide-octylphenol], 1 g of tocopherol acetate 
and sufficient ethanol for 100 ml and the concentrate was diluted with 5 
liters of water just before use. 
EXAMPLE 2 
A solution was prepared with 0.5 g of (-).alpha.-cyano -3-phenoxybenzyl 
2,2-dimethyl-3R-(2',2'-dibromovinyl)cyclopropane-1R-carboxylate, 2.5 g of 
piperonyl butoxide, 10 g of Polysorbate 80, 25 g of Triton X-100, 1 g of 
tocopherol acetate and sufficient ethanol for 100 ml and the concentrate 
was diluted with 5 liters of water just before use. 
EXAMPLE 3 
A solution was prepared with 2 g of 3-phenoxybenzyl 
2,2-dimethyl-3R-(2',2'-dibromovinyl)-cyclopropane-1R-carboxylate, 10 g of 
piperonyl butoxide, 10 g of Polysorbate 80, 25 g of Triton X 100, 0.4 g of 
tocopherol acetate, 0.4 g of citric acid and sufficient ethanol to obtain 
100 ml and the concentrate was diluted with water before use. 
EXAMPLE 4 
A solution was prepared with 5 g of neopynaminol d-trans chrysanthemate, 25 
g of piperonyl butoxide, 15 g of Polysorbate 80, 20 g of Triton X-100, 1 g 
of tocopherol acetate and sufficient ethanol to obtain 100 ml and the 
concentrate was diluted before use with water. 
EXAMPLE 5 
A solution was prepared with 5 g of (S) allethrolone d-trans 
chrysanthemate, 25 g of piperonyl butoxide, 10 g of Polysorbate 80, 25 g 
of Triton X-100, 1 g of tocopherol acetate and sufficient ethanol for 100 
ml. 
EXAMPLE 6 
An injectable solution was prepared with 2 g of 5-benzyl-3-furylmethyl 
d-trans chrysanthemate, 6.65 g of piperonyl butoxide, 6.33 g of 
.alpha.-tocopherol acetate, 29 g of benzyl benzoate and sufficient 
arachide oil to obtain 100 ml. 
EXAMPLE 7 
An injectable solution was prepared with 0.03 g of (-) 
.alpha.-cyano-3-phenoxybenzyl 
2,2-dimethyl-3R-(2',2'-dibromovinyl)-cyclopropane-1R-carboxylate, 1 g of 
piperonyl butoxide, 0.15 g of .alpha.-tocopherol acetate, 29 g of benzyl 
benzoate and sufficient arachide oil for 100 ml. 
EXAMPLE 8 
An injectable solution was prepared with 0.2 g of (S) allethrolone d-trans 
chrysanthemate, 0.6 g of piperonyl butoxide, 0.25 g of .alpha.-tocopherol 
acetate, 29 g of benzyl benzoate and sufficient arachide oil for 100 ml. 
EXAMPLE 9 
An injectable solution was prepared with 4 g of neopynaminol d-trans 
chrysanthemate, 12 g of piperonyl butoxide, 1 g of .alpha.-tocopherol, 29 
g of benzyl benzoate and sufficient arachide oil for 100 ml. 
EXAMPLE 10 
Capsules were prepared containing 1 g of (-) .alpha.-cyano-3-phenoxybenzyl 
2,2-dimethyl-3R-(2',2'-dibromovinyl)-cyclopropane-1R-carboxylate and 
excipient. 
EXAMPLE 11 
A balanced feed base comprising corn, dehydrated alfalfa, wheat stalks, 
palmiste molasses cake, urea and a mineral vitamin condiment contained a 
minimum of 11% raw protein material (2.8% apportional to urea) and 2.5% of 
fatty material and a maximum of 15% of celullosic material, 6% of mineral 
material and 13% of moisture. The said feed base corresponded to 82 forage 
units per 100 kilos and contained 910,000 I.U. of vitamin A, 91,000 I.U. 
of vitamin D.sub.3, 156 mg of vitamin E and 150 mg of vitamin C per 100 
kilos, 0.3 kg of 5-benzyl-3-furylmethyl d-trans chrysanthemate was 
incorporated to make 100 kg of the feed in all. 
EXAMPLE 12 
Using the feed base of Example 11, there was incorporated to make 100 kg of 
the feed in all either 0.04 kg of (-) .alpha.-cyano-3-phenoxybenzyl 
2,2-dimethyl-3R-(2',2'-dibromovinyl)-cyclopropane-1R-carboxylate or 0.2 kg 
of (S) allethrolone d-trans chrysanthemate or 0.25 kg of neopynaminol 
d-trans chrysanthemate. 
EXAMPLE 13 
Clinical study of cattle attacked by psoroptic mange 
50 bull-calves weighing between 550 to 600 kg were attacked by psoroptic 
mange and samples were taken by scraping until rose blood at several 
points to gauge the lesions before the treatment and then 5, 15 and 25 
days after the first treatment. A solution of Example 1 was diluted with 5 
liters of water to obtain a concentration of 5-benzyl-3-furylmethyl 
d-trans chrysanthemate of 1 part per 1000 and the solution was applied to 
the lesions three times at 10 days intervals on days Day 0, Day 10 and Day 
20. Before treatment, 25 samples were positive as noted by the presence 
of living psoroptes and on the 5th day after the first treatment, the 
pruritis of all the animals disappeared, the skin began to assume a normal 
aspect and only 3 cows out of the 50 showed the parasites in the lesions. 
15 and 25 days after the start of treatment, there were no living 
psoroptes and the cutaneous tolerance was very good. The conclusion is 
that 5-benzyl-3-furylmethyl d-trans chrysanthemate when applied locally in 
solution at a concentration of 1/1000 was effective against mange. 
EXAMPLE 14 
Microcapsules containing 20 ml of a solution of 5-benzyl-3-furylmethyl 
d-trans chrysanthemate diluted as in Example 1 were injected 
subcutaneously to calves at the base of the ear and the animals were 
observed for 15 days during which there was no reddening, no pruritis, no 
depilation and no fever. This means that the composition was perfectly 
tolerated. 
EXAMPLE 15 
6 young bovines of charolaise race were attacked by psoroptic mange and 
were treated regularly for 4 months with commercially available 
ixodicides. In spite of the treatments, the bovines were very heavily 
infected with parasites at the end of the 4 months. It was ascertained 
that the animals were attacked generally by mange with zones of scaly 
dermitis and thickening of the skin (rhinoceros skin) and a serious 
inflammation of the skin and epidermic placard peeling off was observed. 
In certain places, the skin was literally destroyed, excorticated, oozing 
and bleeding. All animals were subjected to a very important thinness and 
samples taken from the depth of the mange lesions showed the presence of a 
very large number of acarids of the Posropte genus. 
Each of the bovines were sprayed with 11/2 liters of aqueous solution of 
(-) .alpha.-cyano-3-phenoxybenzyl 
2,2-dimethyl-3R-(2',2'-dibromovinyl)-cyclopropane-1R-carboxylate at a 
concentration of 1/10,000. After 12 days, it was ascertained that there 
was a clear improvement of the level of the skin and disappearance of 
pruritis. The samples from the lesions showed that there existed in two 
thirds of the animals living Psoroptes. A second treatment was effected on 
the 14th day after the first treatment and after another 12 days or on the 
26th day after the first treatment, the skin showed normal redevelopment, 
the hair covered over the old lesions and pruritis had definitely 
disappeared. The animals were clinically cured and samples did not show 
any evidence of acariens. 
EXAMPLE 16 
3 cows of Maine-Anjou race were attacked by mange on the tail, thigh and 
loins and the bovines showed a scally dermitis, certain portions of the 
skin excorticated, oozing and bleeding and also noted was the presence of 
abundant crusts. Parasitic examination before treatment of the 3 bovines 
showed the presence of acariens of Psoroptes genus. Treatment on Day 0 
with a preparation containing 1 ppm of (S) allethrolone d-trans 
chrysanthemate was effected by energetically brushing onto the mange 
lesions of the said preparation and local tolerance of the solution was 
excellent. After 48 hours of the treatment, there was noted a clear 
clinical amelioration of the mange lesions and pruritis disappeared. 
Parasitic examination on day 7 showed only one bovine (more attacked) had 
living Psoroptes. 
Cutaneous samples of the bovines were examined with a binocular magnifying 
glass, the following results were obtained 
______________________________________ 
Animal Before Treatment 
8th Day 
______________________________________ 
1 +++ + 
2 + - 
3 + - 
______________________________________ 
The results of the Table show that the tested compound has good acaracidal 
activity against Sarcopte mange in bovines. 
EXAMPLE 17 
The semichronic toxicity of (S) allethrolone d-trans chrysanthemate was 
determined on rats for a duration of 3 weeks and at a dose of 75 mg/kg of 
body weight, the product was perfectly well tolerated. 
EXAMPLE 18 
A bull, a heifer and a cow of the Maine-Anjou race were generally attacked 
by mange with zones of scaly dermitis and thickening skin and a grave 
inflammation of the skin and epidermic placard peeling off with the horns 
and rear members is observed. An examination of epidermic debris showed 
mange lesions before treatment of the 3 bovines with a presence of living 
acariens of Psoroptes genus. The treatment was applied on day 0 with a 
vigorous brushing using 1 liter of a solution containing 1 ppm of 
neopynaminol d-trans chrysanthemate for each bovine with an overflow 
largely around the lesions. The tolerance to the preparation was excellent 
and after 48 hours, the bovines showed the beginning of clinical healing 
with disappearance of pruritis and a clear amelioration of the mange 
lesions. Parasitic examination on day 7 showed no evidence of living 
psoroptes. Examination of Cutaneous samples of the bovines with a 
binocular magnifying glass showed the following results. 
______________________________________ 
No. of Animal 
Before Treatment 
7th Day 
______________________________________ 
1 + - 
2 ++ - 
3 +++ - 
______________________________________ 
The data of the Table shows that the tested compound possessed good 
acaricidal activity against Sarcoptes of mange in bovines. 
Various modifications of the compositions and method of the invention may 
be made without departing from the spirit or scope thereof and it is to be 
understood that the invention is intended to be limited only as defined in 
the appended claims.