Control of parasitic mites with alkyl amines

Certain secondary and tertiary straight and branched chain amines and amides are found to be highly effective for controlling scabies mites and other parasitic mites.

BACKGROUND OF THE INVENTION 
1. Field of the Invention 
This invention relates to the control of scabies mites and other parasitic 
mites and more specifically to the control of these parasites with certain 
straight and branched-chain amines and amides. 
2. Description of the Art 
A particular shortcoming in the control of scabies mites in livestock is 
the fact that at present there are only four chemicals registered with the 
Environmental Protection Agency for use in the United States as dips on 
cattle and sheep. Although the four chemicals are effective in the control 
of scabies, their use presents certain disadvantages. Three of the 
chemicals, toxaphene, coumaphos, and phosmet, cannot be used on lactating 
dairy cattle and beef cattle treated with phosmet and toxaphene must be 
held 21 and 28 days, respectively, before slaughter to avoid pesticide 
residue problems. In fact, toxaphene, one of the most widely used 
agricultural insecticides in the world, has been found by the National 
Cancer Institute to cause liver cancer in male and female mice (Chemical 
and Engineering News, Volume 57, No. 12, March 19, 1979, page 20). The 
fourth chemical, lime-sulfur, which is used on lactating dairy cattle must 
be heated to 95.degree. to 105.degree. F. to be effective. 
Some of the compounds of the present invention are also useful in the 
control of nematodes and other helminths, U.S. Pat. No. 4,036,987 and No. 
4,073,939. 
SUMMARY OF THE INVENTION 
An object of this invention is to provide new chemicals useful in the 
control of scabies mites and other parasitic mites. 
Another object is to provide compounds that are lethal to scabies mites and 
other parasitic mites yet have relatively low vertebrate toxicities so 
that they are not toxic or harmful to the host. 
A further object is to provide compounds that are lethal to scabies mites 
and other parasitic mites at concentrations equivalent to or far below 
those required for most of the currently used chemicals. 
A still further object is to provide compounds that are economical to use 
for the control of scabies mites and other parasitic mites. 
In general, according to this invention certain secondary and tertiary 
straight and branched chain amines and amides having chain lengths of from 
8 to 24 carbon atoms are found to be highly effective for controlling 
scabies mites and other parasitic mites. Compounds found useful for the 
purpose of this invention are represented by the general formula 
##STR1## 
wherein A is selected from the group consisting of 
##STR2## 
R.sup.1 and R.sup.2 are individually H, lower alkyl, 
##STR3## 
or taken together with the N is 
##STR4## 
x is a number from 5 to 17, n is a number from 1 to 5, m and p are 
individually H or lower alkyl. 
More specifically, general formula 1 embodies the following types of 
compounds that have been found useful for the purposes of this invention 
##STR5## 
where R.sup.1 and R.sup.2 are the same as described under the general 
formula above and x is a number from 10 to 17; 
##STR6## 
wherein R.sup.1 and R.sup.2 are individually lower alkyl and x is a number 
from 8 to 12; and 
##STR7## 
wherein R.sup.1 and R.sup.2 are as described under the general formula 
above and R.sup.3, R.sup.4, and R.sup.5 are lower alkyl. 
The term "lower alkyl" in this application refers to straight and branched 
chain saturated aliphatic hydrocarbons having a chain length of not more 
than four carbon atoms.

DESCRIPTION OF THE INVENTION 
In 1975, parasitic mites causes an estimated $157 million loss to the 
United States livestock industry. Even though there were only 45 confirmed 
outbreaks of cattle scabies in the United States in 1975, approximately 
$65 million of this loss was due to psoroptic scabies in cattle. The 
problem has since increased in severity and in 1978 alone over 300 
outbreaks of psoroptic scabies were confirmed in the United States. 
Virtually all mammals including man suffer from parasitic mites and 
domestic animals, particularly livestock, are no exception. Psoroptic 
scabies of cattle are a universal problem; infestations have been and are 
today reported from all areas of the world. In recent years, following a 
violent outbreak in 1971, common scabies has become an ever increasing 
threat to the cattle industry and to animal health agencies in the United 
States. Consequently, in the United States, this disease must be reported 
to and is quarantined by the Veterinary Services of the Animal Plant 
Health Inspection Services of the U.S.D.A. With the distinct possibility 
that the use of certain of the more effective of these chemicals used for 
scabies mites control may be banned in the future, the need for new 
chemicals for control of scabies mites is even more urgent and critical. 
The difficulty in finding safe active chemicals is partially responsible 
for the low number of registered compounds for control of scabies mites. 
Out of thousands of compounds tested in both government and industry 
evaluation programs, relatively few have been found to be both safe and 
effective against scabies mites and other parasitic mites. Consequently, 
it was very surprising and quite unexpected when we found that a number of 
N-substituted alkyl amines and amides of this invention displayed very 
high miticidal activity against scabies mites. 
The compounds of the invention were prepared in 60-80% yield according to 
the general method of reaction of the appropriate acid with thionyl 
chloride to give the respective acid chloride which when reacted with the 
respective low molecular weight amine or ammonia yielded the amide which 
was reduced to the long chain or branched chain amine with lithium 
aluminum hydride in tetrahydrofuran. The amines could be in most cases 
purified via formation of the amine hydrochlorides and by reconversion to 
the free amines or by column chromatography. The outline of synthesis 
according to general known method is presented below. 
##STR8## 
A typical preparation is illustrated by the following detailed example of 
the synthesis of N,N-dimethyldodecanamide [CH.sub.3 (CH.sub.2).sub.10 
CON(CH.sub.3).sub.2 ] and N,N-dimethyldodecanamine [CH.sub.3 
(CH.sub.2).sub.11 N(CH.sub.3).sub.2 ]. 
A mixture of 30 g of lauric acid (dodecanoic acid), 150 ml of dry benzene 
and 21.4 g (13.4 ml) of thionyl chloride was gently refluxed for about 16 
hours. The solvent and excess thionyl chloride was removed to yield 32.8 g 
of the crude acid chloride. To a mechanically stirred solution of the 
crude acid chloride in 20 ml of dry hexane chilled to 10.degree. C. was 
added 16 g of dimethylamine in 85 ml of hexane. The reaction mixture was 
removed from the ice bath, stirred for 2 hours at room temperature, and 
then filtered. The filtrate was concentrated to dryness under vacuum to 
give 32 g of crude N,N-dimethyldodecanamide, &gt;95% pure. Trace amounts of 
the impurity dimethylamine hydrochloride were removed by partitioning the 
crude dimethylamide between hexane and water. The hexane phase was then 
dried over sodium sulfate and concentrated to dryness under vacuum, 
yielding &gt;98% pure N,N-dimethyldodecanamide, N.sub.D 19 1.4610. 
Crude dimethylamide in 150 ml of dry tetrahydrofuran (THF) was added 
dropwise to a refluxing solution of 6 g of solid lithium aluminum hydride 
in 150 ml of THF, and the solution refluxed for about 16 hours, after 
which two drops of ethyl acetate were added to determine if an excess of 
lithium aluminum hydride was still present. The reaction mixture was 
chilled to 10.degree. C., 25 ml of water added dropwise with caution, and 
then sodium hydroxide, 25 l g in 20 ml of water, was added. Upon standing 
for about 2 hours with occasional stirring and shaking, a a gelatinous 
mass formed and separated from the THF phase. The THF phase was removed 
and the gelatinous mass rinsed with additional THF. The THF phases were 
combined and concentrated nearly to dryness under vacuum. The residue was 
dissolved in hexane and the hexane solution washed with dilute sodium 
hydroxide, and with water, and then dried over sodium hydroxide pellets. 
The hexane solution (ca. 300 ml) was treated with a slight excess of a 6 N 
solution of hydrogen chloride in isopropanol to precipitate out amine 
hydrochloride which was collected by filtration. The amine hydrochloride 
was treated with a 3 N sodium hydroxide solution and the amine extracted 
into hexane. The hexane phase was washed with water, and then dried over 
sodium hydroxide pellets. Removal of the hexane under vacuum gave 25 g 
(98%) of N,N-dimethyldodecanamine, n.sub.D 19 1.4463, &gt;99% pure. 
The compounds were tested in vitro on the rabbit ear mite, Psoroptes 
cuniculi, which has come to be used as the model biological system for 
testing candidate chemicals for miticidal activity against scabies mites 
such as the common scabies mite of cattle and sheep, Psoroptes ovis, and 
other parasitic mites. Groups of large mites (20 to 25 adults and nymphs) 
were exposed to the chemicals using a modification of the "tea bag" 
technique (J. Econ. Entomol. 65, 174, 1972), by dipping them for 30 
seconds in aqueous emulsions prepared from a 10% emulsifiable concentrate 
(10% test chemical, 85% ethanol and 5% Triton X-100) of the test chemical. 
Triton X-100 is octylphenoxy polyethoxy ethanol, a nonionic surfactant 
containing an average of 8.5 ethylene oxide groups. Each compound was 
tested at a range of concentrations. At 24 hours after dipping, the mites 
were examined with the aid of a dissecting microscope, and those mites 
that showed absolutely no movement or that were able to move their legs 
but were unable to walk were judged as dead. Under these test conditions 
the range of concentrations required to kill 100% of the mites with three 
commercial miticide formulations used for scabies control, coumaphos, 
phosmet and toxaphene, are &gt;0.1%, 0.005-0.01%, and 0.00005-0.0001% 
respectively. As shown in Table I, a surprisingly large number of the 
straight chain amines and amides of this invention were more active than 
the miticides that are currently registered for the control of the common 
scabies mite of cattle and sheep, with the exception of toxaphene, when 
tested against the rabbit ear mite Psoroptes cuniculi. Compounds 7,18 and 
27 were the most active causing complete lethality at concentrations of 
0.0005-1.001%, thus approaching the effectiveness of toxaphene. In 
addition, a number of other chemicals, including Compounds 
5,6,8,9,14,15,19,20,22,24,28,31,32,33,34,35,36,41 and 42 were also highly 
effective and killed 100% of the rabbit ear mites in the dipping test at 
the 0.001-0.005% concentration range. 
In addition to the straight chain amides and amines in Table I, a number of 
branched-chain amides and amines were also quite active. For example, 
N,N-dimethyl-3,7,11-trimethyl-dodecanamine caused 100% mortality on rabbit 
ear mites at concentrations of 0.005 to 0.01% in "tea bag" dipping tests. 
Seven of the more active compounds listed in Table I were further tested in 
the "tea bag" dipping test against the common scabies mite of cattle and 
sheep, Psoroptes ovis, which is the most economically important scabies 
mite of domestic animals. As shown in Table II all seven chemicals were 
highly effective against the common scabies mite of cattle and sheep and 
killed 100% of the mites in the dipping test at the 0.001-0.005% 
concentration range. Five of the test chemicals, compounds 6,8,15,20, and 
22, were equally active against the common scabies mite and the rabbit ear 
mite while compounds 7 and 18 l were only slightly less active. 
A number of amines were tested in vivo at a range of concentrations for 
miticidal activity against scabies mites and other parasitic mites using 
rabbits infested in both ears with the rabbit ear mite Psoroptes cuniculi. 
Both ears of each of the infested rabbit were treated with aqueous 
emulsions containing from 0.2% to 1.0% of the test compound prepared from 
a 10% emulsifiable concentrate (10% test compound, 85% ethanol, and 5% 
Triton X-100) of the test compound. Approximately 10-12.5 ml of the 
emulsion was poured into each ear of the rabbit and massaged into the 
scabs for 1 minute. The rabbits were examined with an otoscope at regular 
intervals after treatment to determine the effectiveness of the compounds 
and the examinations were terminated at 41 to 44 days after treatment. The 
results of the treatments were classified as follows: A=No reduction in 
number of mites or amount of scab, B=Initial reduction in number of mites 
or scab but mite population soon builds back up, C=Near complete 
elimination of mites and scab; mites not found until end of test, 
D=Complete elimination of mites and scabs. The results of these in vivo 
tests are shown in Table III. All the test chemicals showed some degree of 
miticidal activity against the ear canker mites at the concentrations 
tested, and only Compounds 1,9, and 16 did not cause complete elimination 
of the mites and scabs at 1.0%, the highest concentration used. Compound 3 
was highly active and completely eliminated mites and scabs at a 
concentration of 0.50%. Compounds 4,5,7, and 8 were completely effective 
at a concentration of 0.75% and Compounds 2 and 6 completely eliminated 
the infestations at a concentration of 1.0%. 
TABLE I 
__________________________________________________________________________ 
Range of concentrations of N-substituted amines and amides 
required to kill 100% of nymphs and/or adults of the 
rabbit ear mite (Psoroptes cuniculi) exposed for 30 
seconds in "tea bag" dipping tests. 
Compound Concentration 
Number 
Formula (%) 
__________________________________________________________________________ 
1 CH.sub.3 (CH.sub.2).sub.8 CH.sub.2 N(CH.sub.3).sub.2 
0.01-0.05 
2 CH.sub.3 (CH.sub.2).sub.9 CH.sub.2 N(CH.sub.3).sub.2 
0.01-0.05 
3 CH.sub.3 (CH.sub.2).sub.10 CH.sub.2 N(CH.sub.3).sub.2 
0.005-0.01 
4 CH.sub.3 (CH.sub.2).sub.11 CH.sub.2 N(CH.sub.3).sub.2 
0.005-0.01 
5 CH.sub.3 (CH.sub.2).sub.12 CH.sub.2 N(CH.sub.3).sub.2 
0.001-0.005 
6 CH.sub.3 (CH.sub.2).sub.13 CH.sub.2 N(CH.sub.3).sub.2 
0.001-0.005 
7 CH.sub.3 (CH.sub.2).sub.14 CH.sub.2 N(CH.sub.3).sub.2 
0.0005-0.001 
8 CH.sub.3 (CH.sub.2).sub.15 CH.sub.2 N(CH.sub.3).sub.2 
0.001-0.005 
9 CH.sub.3 (CH.sub.2).sub.16 CH.sub.2 N(CH.sub.3).sub.2 
0.001-0.005 
10 CH.sub.3 (CH.sub. 2).sub.8 CON(CH.sub.3).sub.2 
0.05-0.1 
11 CH.sub.3 (CH.sub.2).sub.9 CON(CH.sub.3).sub.2 
0.01-0.05 
12 CH.sub.3 (CH.sub.2).sub.10 CON(CH.sub.3).sub.2 
0.005-0.01 
13 CH.sub.3 (CH.sub.2).sub.11 CON(CH.sub.3).sub.2 
0.005-0.01 
14 CH.sub.3 (CH.sub.2).sub.12 CON(CH.sub.3).sub.2 
0.001-0.005 
15 CH.sub.3 (CH.sub.2).sub.15 N(CH.sub.3)C.sub.2 H.sub.5 
0.001-0.005 
16 CH.sub.3 (CH.sub.2).sub.14 NHC.sub.2 H.sub.5 
0.005-0.01 
17 CH.sub.3 (CH.sub.2).sub.15 NHC.sub.2 H.sub.5 
0.01-0.05 
18 
##STR9## 0.0005-0.001 
19 
##STR10## 0.001-0.005 
20 CH.sub.3 (CH.sub.2).sub.11 N(CH.sub.3)C.sub.3 H.sub.7 
0.001-0.005 
21 CH.sub.3 (CH.sub.2).sub.9 N(CH.sub.3)C.sub.4 H.sub.9 
0.005-0.01 
22 CH.sub.3 (CH.sub.2).sub.10 N(CH.sub.3)C.sub.4 H.sub.9 
0.001-0.005 
23 CH.sub.3 (CH.sub.2).sub.10 CH.sub.2 NHCH(CH.sub.3).sub.2 
0.01-0.05 
24 CH.sub.3 (CH.sub.2).sub.10 CH.sub.2 N(CH.sub.3)CH(CH.sub.3).sub.2 
0.001-0.005 
25 
##STR11## 0.005-0.01 
26 
##STR12## 0.005-0.01 
27 
##STR13## 0.0005-0.001 
28 
##STR14## 0.001-0.005 
29 
##STR15## 0.01-0.05 
30 
##STR16## 0.005-0.01 
31 
##STR17## 0.001-0.005 
32 
##STR18## 0.001-0.005 
33 
##STR19## 0.001-0.005 
34 
##STR20## 0.001-0.005 
35 
##STR21## 0.001-0.005 
36 
##STR22## 0.001-0.005 
37 
##STR23## 0.01-0.05 
38 
##STR24## 0.01-0.05 
39 
##STR25## 0.01-0.05 
40 
##STR26## 0.01-0.05 
41 
##STR27## 0.001-0.005 
42 
##STR28## 0.001-0.005 
43 
##STR29## 0.01-0.05 
__________________________________________________________________________ 
TABLE II 
______________________________________ 
Range of concentrations of N-substituted amines required 
to kill 100% of nymphs and/or adults of the common 
scabies mite of cattle and sheep (Psoroptes ovis) 
exposed for 30 seconds in "tea bag" dipping tests. 
Compound Concentration 
Number (%) 
______________________________________ 
6 0.001-0.005 
7 0.001-0.005 
8 0.001-0.005 
15 0.001-0.005 
18 0.001-0.005 
20 0.001-0.005 
22 0.001-0.005 
______________________________________ 
TABLE III 
______________________________________ 
Effects of N-substituted amines on the elimination of 
mites and scabs from the ears of rabbits infested with 
rabbit ear mites (Psoroptes cuniculi). 
Effect of Treatment 
Concentration 
% 
Compound 0.20 0.50 0.75 1.0 
______________________________________ 
1 B -- -- C 
2 -- -- B D 
3 B D D D 
4 -- -- D D 
5 B C D D 
6 -- -- B D 
7 B C D D 
8 -- -- D D 
9 -- B B B 
16 -- B C B 
______________________________________