CA1125655A - Amidoamine toxicants - Google Patents

Abstract

AMIDOAMINE TOXICANTS

ABSTRACT OF THE DISCLOSURE

Ectoparasites or their ova, mosquito larva and aphids are controlled through the use of an alkyl or alkenyl amidopropyl dimethylamine.

Description

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AMIDOAMINE TOXICANTS

~ACKGROUND OF THE INVENTION

There are only a relatively few ectoparasiticides which are commercially available today. The most popular pediculicidal toxicants are Lindane ~gamma ~enzene he~a-chloride), Malathion [~S-l,2-dicarbethoxyethyl)-0,0-di-methyl phosphorodithioate], synergized pyrethrins and Cupre~ (a combination of tetrahydronaphthalene~ copper oleate and acetone, the acetone not asserted to be active).
Sulphur and Lindane are the bes1 known agents for scabies.
Because o-f increased concern about the overall safety of some o the known ectoparasitic toxicants, the search for new, safe and e~fective ectoparasiticides has intensified recently.
Many species of insects encase their ova in protective sheaths which are impregnable to most to~icants.
The gestation period of the egg is often relatively lo~g in comparison to the life c~cle of the adult forms. Thus, an agent effective only against adults must persist for the lifetime of the developing ovum or mus~ be reapplied as successive hatchings occur. The ideal agent for treatment of ectoparasites should be active against the ova as well as the adult and nymphal forms, and should be relatively ` non-to~ic to the host. Fe~ agents are, however, so active.

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The t.oxicants can be used în the form of shampoos or body washes. In contrast to agents used by inunction, compositions designed to be used as shampoos or body washes must fulfill certain criteria. For example, they must either exert their parasiticidal and/or ovicidal ef~ec*s ~ithin a ~ery short time or must resist washing off during the course of ablutions.
It has now been discovered that a small group of amidoamines are quite effective as toxicants for ecto-parasites or their ova, mosquito larva and aphids.While it has been previously reported that certain partially acylated polyamines are suita~le for destroying pests (see Hartmann U.S. Patent 1,96~,341), the present amidoamides exhibit a surprising degree of toxicity against the ecto-parasites or their ova, mosquito larva and aphids andsuch activity can be enhanced by the cojoint use o~ a lo~er alkanol.
Accordingly, it is the ob~ect of this invention to provide ne~, safe and effective toxicants for use against ectoparasites and their ova, mosquito larvae or aphids.
This and other objects of the invention will become apparent to those skilled in this art from the following detailed description.

SUM~RY OP THE INVENTION
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This invention relates to ectoparasiticidal toxicants and a method for controlling ectoparasites, mosquito larve or aphids. More particularly, the invention relates to the use of certain amidoprop~l dimethylamines as toxicants for the ectoparasites and/or their ova, mosquito larvae and aphids and to toxicant compositions containing ~ such amidoamines as toxicants.
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: :.. , DESCRIPTION OF THE INVENTION

The toxicants of the instant invention are certain alkyl or alkeny:L amidopropyl dimethylamines of the formula R-C-NH-~CH2)3-N(CH322 wherein R is alkyl or alkenyl of 11 O
to 17 carbon atoms. Typical examples of the amidoamines of the present invention thus include lauramidopropyl dimethylamine, cocamidopropyl dimethylamine, oleamidopropyl dimethylamine and the like. In general, toxicant activity increases with increasing chain length. However, closely related amidoamines do not have the same toxicant activity as those of the present invention. Thus, the presence of a hydroxyl moiet~ in the above formula appears to sub-stantially reduce activity. A decrease in activity is also noted when the propyl and methyl groups ;n the above ormula are ethyl groups. The toxicants of the present invention can be used as such or in the form of their non-toxic acid addition salts such as the hydrochloride.
One or more of the amidoamines o-f the present invention can be incorporated into an active toxicant composition which can be in the forM of a liquid, powder, lotion, cream, gel or aerosol spray, or oam as the result of formulation with inert pharmaceutically acceptable carriers by procedures well known in the art. Any pharma-ceutically acceptable carrier, whether aqueous or non-aqueous, which is ineTt to ~he active ingredient can be employed. By inert is meant that the carrier does not have a substantial detrimental ef-fect on the toxicant activity of the active ingredient. Aqueous pharmaceutically acceptable carriers are preferred.
The active amidoamine toxicants are incorporated into the toxicant compositions used to treat the animal or human host in need of such treatment, believed to be in need of such treatment, or desired to be prophylactically protected in an effective toxicant amount. By such amount ~ .

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is meant the amount which will cause at least 50% of the target organisms to die within Z4 hours ~or within two weeks in the case of the ova). The minimum concentration o-f amidoamine required to provide an effective toxic amount varies considerably depending on the particular amidoamine, the particular inert pharmaceutically acceptable carrier being employed and~any other ingredients which are present.
Thus, in one case, a 0.1% concentration may suffice, while in other cases~ concentra~ions as high as 30% may be required to obtain an effective toxic dose. The toxicant activity of these compounds is also dependent upon the pH
of the formulation. For example, oleamidopropyl dimethylamine at a 15 weight percent concentration in 25% isopropanol and 60% water, results in~a pH of 8.~ and exhibits maximum activity.
Adjustment of the pH to S.5 or lo~er results in diminish-ing of pediculicidal and ovicidal activity, but not larvacidal activity. IJsually, the amidoamines of the present invention will be present in concentrations of about 1-25%, and m~st preferably in concentrations of about 10-20~.
The instant amidoamlnes can also be employed as adjunct toxicants in a preparation which otherwise exhibits toxicant activity. In such preparations, the term "effective toxic dose" means that amount ~hich will increase the mortality rate by at least about 20~.
The re~erences to mortality herein have been made ~ith regard to standard test procedures. IYhen the ecto-parasite is the human body louse, the standard mortality tests are the following ~wo minute immersion tests:
Pediculicidal activity: ~ 50 ml beaker is filled with tap water and allowed to come to room temperature ~about 24C~. Ten young adult male and ten young adult female lice (Pediculus humanus corporis? o~ the same age group and from the same stock colony are placed on a 2 ~ 2 cm coarse mesh patch. The sample to be tested, maintained at room temperature, is shaken until homogeneous and placed in~o a 50 ml beaker. The mesh patch is placed into the .

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" ' '''' '':''' ` '~''' ' `~'`` ' ' sample immediately after pouring9 allowed to submerge~ and af~er ~wo minutes is removed and immediately plunged into the beaker containing the tap water. The patch is vigorously agitated every ten seconds and after one minute the patch is removed and placed on paper toweling. The lice are then transferred to a 4 x 4 cm black corduroy cloth patch and this point of time is considered zero hours. Thereafter, the corduroy patch is placed in a petri dish which is covered and stored in a 3aC holding chamber.
- 10 Ovicidal activity: 15 adult, 5 to 10 day old, female lice CPediculus humanus corporis~ are placed on a 2 x 2 cm . .
nylon mesh patch which is placed in a petri dish, covered and maintained in an incubator at 30C for 24 hours. The adult lice are then removed and the number of plump, viable eggs and shriveled non-fertile eggs on the patch are recorded. The sample to be tested, maintained at room temperature, is shaken until homogeneous and poured into a 50 ml beaker. Immediatel~, a~ter the pouring, the mesh pa$ch is placed into the beaker, allowed to submerge, and after-two minutes is removed and immediately plunged into a 50 ml beaker containing tap ~ater at room temperature ~about ~4C2. The patch is vigorousl~ agitated every ten seconds and after one minute, the patch is removed and placed on paper toweling for one minute. The patch is then placed in a petri dish which is covered and stored in the 3QC incubator. Fourteen days following treatment, ; the number o~ hatched eggs and the number of s~riveled or unhatched eggs is noted.
In both the pediculicidal and ovicidal two minute immersion tests, controls are run in the identical manner to that described, with room temperature ~24C) tap water substi~uted for the sample to be tested. The results of the tests reported are net results.
For determining miticidal activity, the follo~ing procedure lS used:

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Into a one cubic foot cllamber, held at room temperature, is placed a covered microscope d~pression slide containing ten adult mixed sex mites, Psoro~tes equi var.
cuniculi. The slide is positioned at a distance of ten inches horizontally and four inches belo-~ the activator o a mechanical spray device and uncovered. The mechanical pump spray device delivers 50 milligrams of sample per depression of the activator. The sample to be tested, maintained at room temperature, is shaken until homogeneous and placed in the mechanical pump spray device. The primed activator is depressed t~ice, releasing 100 milligrams of spray mist into the closed chamber. The mist is allowed to settle and the slide containing the mites is removed and covered. This point of time is considered zero hours. The covered slide is then held at room temperature for 24 hours. Microscopic observations are noted at 0, 1, and 24 hours post treatment. Controls are run in an identical manner as that described using water, and net mortality results are reported.
In order to determine larvicidal activity, the compound to be tested is dissolved in water at 100~ 10 and 5 ppm concentration levels. ~or testing each concentration, ~0 ml of the test solution is placed in a paper cup. Ten mosquito larvae (third instar) o~ Aedes aegypti are transferred into the test solution by means of a piece o~
fine wire mesh. Four replications of ten mosquito larvae are used for each concentration of the test compound.
Mortality observations are noted at 1, 6, 24 and 48 hours and controls are run in the identical manner using water ; 30 alone.
Aphicidal activity is determined as follows:
Into a 1 cubic foot chamber held at room temperature is placed a covered petri dish containing ten adult mixed sex aphids, Macrosiphum euphorbiae. The dish is positioned at a distance of ten inches horizontally and four inches below the tip of a mechanical spray device and uncovered.

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3~Z~55 The mechanical spray pump device delivers 50 milligrams of sample per depression of the actuator. The sample to be tested, maintained at room temperature, is shaken until homogeneous and placed in the mechanical pump spray device. The primed pump is depressed once, the mist ic allo~ed to settle, the petri dish containing the aphids is rotated 180 and the primed pump is depressed again.
The mist is allol~ed to settle and the dish is removed and covered. This point o~ time is considered zero hours.
The covered dish is held at room temperature ~or 24 hours and o~servations are noted at 0, 1 and 24 hour~ post treatment. Controls are run in an identical manner as that described using water and net mortality results are reported.
The pediculicidal and ovicidal activity of various to~icants of the instant invention were tested in the two minute immersion tests described above. The concentration o~ the am.idoamines which caused 50% mortality (LC5Q) and which caused 99% mortality ~LC99) was determined in a ~yste~ where the amidoamine was mixed with 25~ o-~isopropanol, and ~ater q.s. ad. 100%. Por contrast, various amidoamines of similar structure were also tested.
The results are shown in the ~oLlo~ing Ta~le 1.
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; TA~LE 1 Pediculicidal Ovicidal Activity Activity Com~ound LC50 LCg9 LC50 LCg9 . _ Lauramidopropyl Dimethylamine 7.9~150 00. 28 0.51 Cocamidopropyl Dimethylamine 6.2>15.00.16 0.60 Oleamidopropyl Dimethylamine 3.19.5 0.15 Q.22 Ricinoleamidopropyl Dimethylamine ~15.0 - ~15.0 ~15.0 -~ Stearamidoethyl Dimethylamine ~15.0 - 7.1 9.
Stearamidoethyl Ethanolamine - >15.0 -.25~5~i The miticidal activity in isopropanol was de~ermined against an ectoparasitic mite, Psoroptes equi var. cuniculi. The oleamidopropyl dimethylamine exhibited = ~ . . . .
an LC50 of 4.1 and an LC99 of 5.3. Lauramidopropyl dimethylamine, cocamidopropyl dimethylamine, ricinole-amidopropyl dimethylamine and stearamidoethyl dimethyl-amine all exhibited LC50's in excess of 25 weigh~ percen~.
The miticidal activity of a 1 weight percent solution of oleamidopropyl dimethylamine in 50% aqueous ethanol was determined against an agricultural mite~
Bryobia praetiosa. The results are shown in the following -Table 2.

% Morbidity % Mortality 5 min. lO m n. 15 min. 1 hr. 24 hr.
Oleamidopropyl Dimethylamine 8Q 100 100 100 100 ~1 gram spray~ -Control Cl. 06 gram spray~ o o o o 4 Using the larvicidal test procedure hereto~ore set forth, oleamidopropyl dimethylamine as the free base and as the hydrochloride salt were tested as mosquito larvicides.
The test results are shol~n in Table 3.

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% Mortality Co~pound Conc in ppm 1 hr 6 hr 24 hr 48 hr Oleamidopropyl Dimethylamine 100 70.0 97.5 100 :~ . . .
7.5 35.5 3s.0 55.0 0.0 30.0 30.0 32.5 `' ~'` ' .
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Oleamidopropyl Dimethylamine 100 40 97.5 100 Hydrochloride 10 2.520.0 30.0 42.5 0.02.5 22.5 32.5 Control 0.00.0 0.6 0.6 .
The aphicidal activity o~ the oleamidopropyl dimethylamine in a solution containing 24% isopropanol and aqueous q.s. ad. 100 was determined. The LC50 was found be 0.75 weight percent and the LCg9 was found to be 0.99 weight percent.
The data in Table 4 demonstrates the adjunctive miticidal or pediculicidal activity of the ins~ant amidoamines:
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I'ABLE 4 % Mortality lS % ~ Pediculicidal Miticidal Isopropyl Myristate 15 100 10 Isopropyl Alcohol25 ~ater 6Q

Oleamidopropyl Di4 lO0 100 methylamine Isopropyl Myristate 15 Isopropyl Alcohol25 Water 56 .
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- 10 ~ ~S~5 Phenyl Dimet~icone 10 100 10 (22.5 centisto~es) Isopropyl ~lcohol 25 I~ra~er 65 Oleamidoprop~l Di- 4 100 100 methylamine Phenyl Dimethicone 10 ~22.5 centisto~es~
Isopropyl Alcohol. ` 25 lYater 61 .
Phenyl Dimethicone ~Z2.5 centisto~es)1* 45 ~sopropanol 25 l~a~er 74 1~ Oleamidopropyl Di-. ~ . 100 _ -methylamine.
Phenyl Dimethicone l*
(22.5 ~entisto~es) ~ Isopropanol 25 l~Ja~er 69 nc~ntration A~ noted above, various end use *ormulatio~s ca~
be prepared Some typical ~ormulations are set for-th belo~
and the amounts ~ecited are perGentages by wei~h~: -. ~ . . . . .
Shampoo -.
: Triethanolamine lau~yl sulate 20.~
Lauramidopropyl dimethylamine 15.0 : . Isopropanol . . 14;0 Sorbitan monooleate . 1.~
l~Tater 49~5 . :
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Lotion Stearic acid 4.0 Cetyl alcohol 1.5 Glyceryl monostearate 4.0 Sorbitan monostearate 3.0 Isopropanol - 30.0 Cocamidopropyl dimethylamine 15.0 Triethanolamine 3.5 Water 39.0 Aerosol Spray Oleamidopropyl dimethylamine 10.0 Isopropanol 35.0 Triethanolamine 2.0 Water - - 40.0 Isobutane 13.0 Ovicidal Aerosol Foam . Oleamidopropyl dimethylamine 15.0 Isopropanol 30.0 Mono and diglycerides of edible fats 8.0 Glycerine 3.0 Water 36. a Isobutane 8.0 ; Stick Oleamidopropyl dimethylamine 10.0 Sodium stearate 8.0 Sorbitol 3.5 Isopropanol 25.0 - E*hanol 39.0 ~ater 14.5 ~arious changes and modifications can be made in the present invention without departing from the spirit and scope thereof. The various embodiments described herein were for the purposè of illustration only and were not intended to limit the invention. Unless other~ise specified, :'` `, ' ': ' :; -'~ .

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all temperatures have been in degrees Centigrade and all par~s and. percentages by weight throughout this specification and clalms.

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Claims (15)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE PROPERTY
OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A method of controlling insects or their larva which comprises applying to a human or animal believed in need of such control, an effective toxic amount of at least one amidoamine of the formula R-?-NH-(CH2)-N(CH3)2 wherein R is alkyl or alkenyl of 11 to 17 carbon atoms.

2. The method of claim 1 wherein said amidoamine is oleamidopropyl dimethylamine.

3. The method of claim 1 wherein said amidoamine is selected from the group consisting of lauramidopropyl dimethylamine and cocamidopropyl dimethylamine.

4. The method of claim 1 wherein said amidoamine is employed in combination with an inert pharmaceutically acceptable carrier.

5. The method of claim 4 wherein said carrier is aqueous.

6. The method of claim 1 wherein said amidoamine is employed in combination with a lower aliphatic alcohol.

7. The method of claim 6 wherein said lower aliphatic alcohol is isopropanol.

8. The method of claim 1 wherein said insects or their larva are ectoparasites or their ova, mosquito larvae or aphids.

9. In an insecticidal or larvicidal toxicant composition comprising an active toxicant and an inert pharmaceutically acceptable carrier therefor, the improve-ment which comprises employing at least one amidoamine of the formula R-?-NH-(CH2)3-N(CH3)2 wherein R is alkyl or alkenyl of 11-17 carbon atoms as at least a part o-f the active toxicant therein.

10. The composition of claim 9 wherein said amidoamine is oleamidopropyl dimethylamine.

11. The composition of claim 9 wherein said amidoamine is selected from the group consisting of lauramidopropyl dimethylamine and cocamidopropyl di-methylamine.

12. The composition of claim 9 wherein said carrier is aqueous.

13. The composition of claim 9 wherein said composition includes a lower aliphatic alcohol.

14. The composition of claim 13 wherein said lower aliphatic alcohol is isopropanol.

15. The composition of claim 14 wherein said amidoamine is oleamidopropyl dimethylamine and said carrier is aqueous.