The invention is the use of .alpha.-cyano-m-phenoxybenzyl C.sub.1 -C.sub.4 alkyl-2-naphthaleneacetates as systemic insecticidal and acaricidal agents for treatment of homothermic animals.

CROSS REFERENCE TO RELATED APPLICATIONS 
The co-pending Application Ser. No. 673,244, of Roger Williams Addor and 
Venkataraman Kameswaran, filed of even date discloses the compounds useful 
in my invention. 
BACKGROUND OF THE INVENTION 
1. Field of the Invention 
The field of the invention is systemic control of ectoparasites with 
.alpha.-cyano-m-phenoxybenzyl-.alpha.-C.sub.1 -C.sub.4 
-alkyl-2-naphthaleneacetates. 
2. The Prior art 
I am not familiar with any art, other than the application of R. W. Addor 
et al. referred to above and made of reference herein, that describes the 
compound of this invention for any use whatsoever. The closest art of 
which I am aware, is the pyrethroid art which decribes chemical compounds 
that contain the .alpha.-cyano-m-phenoxybenzyl substituents and are shown 
to possess insecticidal properties. My invention provides a process 
wherein .alpha.-cyano-m-phenoxybenzyl .alpha.-C.sub.1 -C.sub.4 
-alkyl-2-naphthaleneacetates are highly effective systemic insecticidal 
and acaricidal agents useful for the treatment of warm-blooded or 
homothermic animals. U.S. Pat. No. 3,835,176, issued Sept. 10, 1974 and 
assigned to Sumitomo Chemical Company Limited of Japan discloses 
alpha-cyanobenzylcyclopropanecarboxylates containing a m-phenoxy 
substituent, as insecticidal agents. There is, however, no disclosure of 
animal systemic insecticidal or acaricidal properties for the patentees 
compounds and the compounds are chemically distinct from those of the 
subject application. 
SUMMARY OF THE INVENTION 
The invention is a method for the systemic control of ectoparasites, 
particularly insects and acarina which parasitize homothermic animals 
which comprises admininstering to the animals a systemically effective 
amount against the pests of an .alpha.-cyano-m-phenoxybenzyl 
.alpha.-C.sub.1 -C.sub.4 -alkyl-2-naphthaleneacetate of the formula: 
##STR1## 
wherein R.sub.1 is alkyl C.sub.1 -C.sub.4. 
DETAILED DESCRIPTION 
The phenoxybenzyl-.alpha.-alkyl-2-naphthaleneacetates represented by 
formula I above, can be prepared by reaction of approximately equimolar 
amounts of a 2-naphthylacetyl halide (II) preferably the chloride, and a 
benzyl alcohol (III). The reaction is generally conducted in the presence 
of a hydrocarbon or halocarbon solvent such as heptane, toluene, xylene, 
ethylene chloride or the like, at a temperature between about 0.degree. C. 
and 30.degree. C., and preferably in the presence of an acid acceptor such 
as pyridine, triethylamine, or aqueous sodium hydroxide. 
Using pyridine as representative of the acid acceptor, the reaction may be 
illustrated as follows: 
##STR2## 
wherein R.sub.1 is alkyl C.sub.1 -C.sub.4 and X is halogen such as chloro 
or bromo. 
The formula (II) naphthaleneacetyl halide can be obtained by reaction of 
the appropriate alkylated-2-naphthaleneacetic acid with a thionyl halide 
such as thionyl chloride or thionyl bromide, or a phosphorus halide such 
as phosphorus trichloride, phosphorus tribromide or phosphorus 
pentachloride in the presence of an organic solvent such as toluene, 
methylene chloride, benzene or a benzene hexane mixture. The halide and 
the acid are employed in approximately equimolar amounts, although as much 
as two mole equivalents of the halide per mole of acid may be used, and 
the reaction is preferably conducted at about the refluxing temperature of 
the solvent, generally between about 40.degree. C. and 110.degree. C. This 
reaction may be graphically illustrated as follows: 
##STR3## 
wherein R.sub.1 and X are as previously described. 
The alkylated-2-naphthaleneacetic acid, employed in the above-illustrated 
reaction, can be prepared from the commercially available 
2-naphthaleneacetonitrile. The process involves reacting approximately 
equimolar amounts of 2-naphthaleneacetonitrile and an alkyl halide 
represented by the formula: R.sub.1 X, wherein R.sub.1 is alkyl C.sub.1 
-C.sub.4 as defined above and X is halogen, such as chloro, iodo or bromo. 
An excess of the alkyl halide may, of course, be used. This reaction is 
conducted in the presence of a base and ammonia an aprotic solvent such as 
toluene, xylene, diethylether or the like. The reaction yields the 
corresponding alkylated-2-naphthaleneacetonitrile which is then readily 
hydrolyzed to the alkylated-2-naphthaleneacetic acid. This reaction is 
conducted with a strong mineral acid and water at an elevated temperature, 
preferably a temperature between 120.degree. C. and 150.degree. C. The 
reactions can be graphically illustrated as follows: 
##STR4## 
wherein R.sub.1 and X are as described above. 
The preparation of .alpha.-tert-butyl-2-naphthaleneacetonitrile is carried 
out using 2-naphthaldehyde by the following sequence of reactions (1) 
reaction with t-butyl magnesium chloride, (2) conversion of the neopentyl 
alcohol to the chloride using thionyl chloride, (3) preparation of the 
Grignard reagent with magnesium in tetrahydrofuran, and, (4) carboxylation 
with carbon dioxide. 
Typical aprotic solvents which can be employed in the alkylation of 
2-naphthaleneacetonitrile include, toluene, xylenes, benzene, 
methylcyclohexane, dimethoxyethane and the like. 
The above alkylation can be conducted using commercially available sodium 
amide or an alkali amide prepared in situ from sodium or potassium metal 
in liquid ammonia. Following removal of excess ammonia, the alkylation 
proceeds in the presence of an aprotic solvent preferably at a temperature 
between 50.degree. C. and 120.degree. C. 
An alternate route to the alkylation of 2-naphthaleneacetonitrile and one 
which is preferred in large-scale reactions is to use R.sub.1 X as the 
alkylating agent in the presence of aqueous alkali, e.g. 50% aqueous 
sodium hydroxide, as the base. The reaction is promoted by phase-transfer 
catalysts, such catalysts being of the quaternary ammonium or quaternary 
phosphonium salt or crown ether types. Suitable quaternary ammonium or 
phosphonium salts include benzyltriethylammonium chloride, 
tetrabutylammonium hydrogen sulfate, cetyltrimethylammonium chloride, 
tricaprylmethylammonium chloride, hexadecyltributylphosphonium bromide, 
and the like. These salts may be incorporated to the extent of about 0.5 
to 100 mole percent based on the moles of starting acetonitrile used. 
Suitable crown ethers include 18-crown-6, dibenzo-18-crown-6, and 
dicyclohexyl-18-crown-6. Crown ethers are used in the range of 0.5 to 5 
mole percent based on the moles of alkylating agent used. 
Typical acids which can be employed in the conversion of the 
alkylated-2-naphthaleneacetonitrile to the corresponding acid, are 
sulfuric acid, hydrochloric acid, phosphoric acid, and mixtures thereof. 
For the conversion, the presence of water in the reaction mixture is 
essential and it has been found that the reaction appears to proceed 
satisfactorily only at elevated temperatures and preferably between 
120.degree. C. and 150.degree. C. Somewhat higher or lower temperatures 
may be used, but excessive temperatures causing charring of the reaction 
mixture and at low temperatures the reaction does not proceed at an 
acceptable rate. 
Further examples of the preparation of compounds useful in my invention are 
disclosed in the co-pending application of R. W. Addor et al. 
cross-referenced above, compounds useful in this invention include the 
following: 
.alpha.-cyano-m-phenoxybenzyl .alpha.-n-butyl-2-naphthaleneacetate; 
.alpha.-cyano-m-phenoxybenzyl .alpha.-t-butyl-2-naphthaleneacetate; 
.alpha.-cyano-m-phenoxybenzyl .alpha.-ethyl-2-naphthaleneacetate; 
.alpha.-cyano-m-phenoxybenzyl .alpha.-n-propyl-2-naphthaleneacetate; 
.alpha.-cyano-m-phenoxybenzyl .alpha.-sec-butyl-2-naphthaleneacetate; 
.alpha.-cyano-m-phenoxybenzyl .alpha.-isobutyl-2-naphthaleneacetate; 
.alpha.-cyano-m-phenoxybenzyl .alpha.-methyl-2-naphthaleneacetate; 
.alpha.-cyano-m-phenoxybenzyl .alpha.-isopropyl-2-naphthaleneacetate. 
The compounds can be administered to the animal host orally, topically or 
parenterally, for use as animal systemic insecticidal and acaricidal 
agents. When given orally, it may be in any convenient form designed for 
oral administration such as a bolus, capsule, tablet or as an oral drench. 
The active agent may also be incorporated in an edible animal feedstuff 
such as a nutritionally balanced diet containing from 0.001% to 3.0%, and 
preferably 0.001% to 1.5% by weight of feed of the active compound. 
When the active compound is administered as a single oral dose, generally 
about 25 mg to 1000 mg of compound per kg of animal body weight, and 
preferably 100 to 500 mg of compound per kg of animal body weight is used. 
If desired, the systemic insecticidal and acaricidial agent may be 
introduced into the body of the animal by subcutaneous, intramuscular or 
intraperitioneal injection, such that it may be distributed through the 
animal's body by the action of the animal's circulatory system. In 
practice, the systemic agent may be dissolved or dispersed in a 
pharmaceutically acceptable carrier such as water, propylene glycol, 
vegetable oil, glycerol formal, or the like, for administration. 
For systemic control of insects and acarina which attack homothermic 
animals, the active .alpha.-cyano-m-phenoxybenzyl .alpha.-C.sub.1 -C.sub.4 
-alkyl-2-naphthaleneacetate may also be administered to the animal in the 
form of a pour-on formulation. Such formulation is applied generally to 
the back of the animal such that the active ingredient is permitted to 
come in contact with the animals skin. The active ingredient penetrates 
through the skin, is picked up by the body fluids and is circulated 
through the animals body affording it the protection of the active 
ingredient. 
Pour-on formulations generally contain from about 7% to about 35% and 
preferably 10% to 15% by weight of the active ingredient dispersed in a 
diluent composition comprising a vegetable oil, aromatic solvent and a 
ketone. A typical formulation which is useful in the practice of the 
present invention is as follows: .alpha.-cyano-m-phenoxybenzyl 
.alpha.-C.sub.1 -C.sub.4 -alkyl-2-naphthaleneacetate 13% by weight, 25% by 
weight of cyclohexanone, 46% by weight of xylene and 16% by weight of corn 
oil. 
Surprisingly, it has been found that in addition to the systemic control of 
ectoparasites which attack warm-blooded animals, administering the 
.alpha.-cyano-m-phenoxybenzyl .alpha.-C.sub.1 -C.sub.4 
alkyl-2-naphthaleneacetate to homothermic animals has the advantage that a 
portion of the active material passes through the treated animal and 
controls fly larvae feeding in the manure eliminated by the treated 
animal. 
Advantageously, the systemic agents of this invention have relatively low 
mammalian toxicity and are effective for protecting a variety of animals, 
particularly livestock and domestic animals such as cattle, sheep, horses, 
dogs, cats, zoo and laboratory animals and the like, from attack by fleas, 
mosquitoes, flies, ticks, and the like.

The invention is further demonstrated by the examples provided below. 
EXAMPLE 1 
Systemic Control of Stable Flies on Mice 
To determine the effectiveness of the compounds of the present invention as 
animal systemic insecticidal agents, test compounds are mixed in 10% 
acetone-90% sesame oil and administered orally (by gavage) to two 20 g 
Swiss-Webster white female mice at 100 and 400 mg/kg. Mice are dosed with 
10% acetone/90% corn oil and used as a controls. 
One hour after treatment, 10 stable flies (Stomoxys calcitrans) are placed 
in a cage with each mouse and allowed 18 hours to feed. Mortality counts 
are made at 24 hours and data obtained are reported in the table below. 
Table I 
__________________________________________________________________________ 
Systemic Insecticidal Activity of Test Compounds 
Dose 
No. Mice 
No. % Mortality of Flies 
Compound mg/kg 
Treated 
Flies/Mouse 
Feeding on Treated Mice 
__________________________________________________________________________ 
.alpha.-Cyano-m-phenoxybenzyl .alpha.-methyl- 
400 3 10 73 
2-naphthaleneacetate 
100 3 10 33 
.alpha.-Cyano-m-phenoxybenzyl .alpha.-sec- 
400 3 10 100 
butyl-2-naphthaleacetate 
100 3 10 13 
.alpha.-Cyano-m-phenoxybenzyl .alpha.-iso- 
400 3 10 26 
butyl-2-naphthaleneacetate 
100 3 10 0 
.alpha.-Cyano-m-phenoxybenzyl .alpha.-ethyl- 
400 3 10 100 
2-naphthaleneacetate 
100 3 10 13 
Control -- 3 10 3 
__________________________________________________________________________ 
EXAMPLE 2 
The systemic activity of .alpha.-cyano-m-phenoxybenzyl 
.alpha.-isopropyl-2-naphthaleneacetate is determined using the procedure 
of Example 1, excepting that 25, 100 and 400 mg of compound per kg of 
animal body weight is used. In one test 100 and 400 mg/kg of test compound 
is evaluated against controls and in a second test 25 and 100 mg/kg of 
test compound is evaluated. Results are reported in Table II below. 
Table II 
__________________________________________________________________________ 
Systemic Insecticidal Activity of Test Compounds 
Dose 
No. Mice 
No. % Mortality of Flies 
Compound mg/kg 
Treated 
Flies/Mouse 
Feeding on Treated Mice 
__________________________________________________________________________ 
.alpha.-Cyano-m-phenoxybenzyl .alpha.-iso- 
400 4 10 100 
propyl-2-naphthaleneacetate 
100 4 10 85 
Control -- 4 10 17 
.alpha.-Cyano-m-phenoxybenzyl .alpha.-iso- 
100 3 10 100 
propyl-2-naphthaleneacetate 
25 3 10 93 
Control -- 3 10 0 
__________________________________________________________________________