GB2044100A - Amidoamine eotoparasiticides - Google Patents

Abstract

Topical compositions for the control of ectoparasites or their ova, mosquito larva and aphids contain an alkyl or alkenyl amidopropyl dimethylamine of formula RCONH(CH2)3N(CH3)2 wherein R is C11 to C17 alkyl or alkenyl, or an acid addition salt thereof. The compositions are preferably in the form of liquids, powders, lotions, creams, gels, aerosols and foams.

Description

SPECIFICATION Amidoamine toxicants Background of the invention There are only a relatively few ectoparasiticides which are commercially available today. The most popular pediculicidal toxicants are Lindane (gamma benzene hexachloride), Malathion [(S-1,2-dicarbethoxyethyl)0,0-dimethyl phosphorodithioate], synergized pyrethrins and Cuprex (a combination of tetrahydronaphthalene, copper oleate and acetone, the acetone not asserted to be active). Sulphur and Lindane are the best known agents for scabies. Because of increased concern about the overall safety of some of the known ectoparasitic toxicants, the search for new, safe and effective ectoparasiticides has intensified recently.

Many species of insects encase their ova in protective sheaths which are impregnable to most toxicants.

The gestation period of the egg is often relatively long in comparison to the life cycle of the adult forms.

Thus, an agent effective only against adults must persistforthe lifetime of the developing ovum or must 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-toxic to the host. Few agents are, however, so active..

The toxicants can be used in 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 effects within a very 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 ectoparasites or their ova, mosquito larva and aphids. While it has been previously reported that certain partially acylated polyamines are suitable for destroying pests (see Hartmann U.S. Patent 1,968,341), the present amidoamides exhibit a surprising degree of toxicity against the ectoparasites or their ova, mosquito larva and aphids and such activity can be enhanced by the cojoint use of a lower alkanol.

Accordingly, it is the object of this invention to provide new, 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.

Summary ofthe invention 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 amidopropyl dimethylamines as toxicants for the ectoparasites and/or their ova, mosquito larvae and aphids and to toxicant compositions containing such amidoamines as toxicants.

Description ofthe invention The toxicants of the instant invention are certain alkyl or alkenyl amidopropyl dimethylamines of the formula R-C-NH-(CH2)3-N(CH3)2 0 wherein R is alkyl or alkenyl of 11 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 moiety in the above formula appears to substantially reduce activity. A decrease in activity is also noted when the propyl and methyl groups in the above formula 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 of 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 foam as the result of formulation with inert pharmaceutically acceptable carriers by procedures well known in the art.

Any pharmaceutically acceptable carrier, whether aqueous or non-aqueous, which is inert to the active ingredient can be employed. By inert is meant that the carrier does not have a substantial detrimental effect 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 is meant the amount which will cause at least 50% of the target organisms to die within 24 hours (or within two weeks in the case of the ova).

The minimum concentration of 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, concentrations 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 8.9 and exhibits maximum activity. Adjustment of the pH to 8.5 or lower results in diminishing of pediculicidal and ovicidal activity, but not larvacidal activity.Usually, the amidoamines of the present invention will be present in concentrations of about 1-25%, and most preferably in concentrations of about 1 0-20%.

The instant amidoamines can also be employed as adjuncttoxicants in a preparation which otherwise exhibits toxicant activity. In such preparations, the term "effective toxic dose" means that amount which will increase the mortality rate by at least about 20%.

The references to mortality herein have been made with regard to standard test procedures. When the ectoparasite is the human body louse, the standard mortality tests are the following two minute immersion tests: Pediculicidal activity: A 50 ml beaker is filled with tap water and allowed to come to room temperature (about 24 C). Ten young adult male and ten young adult female lice (Pediculus humanus corporis) of the same age group and from the same stock colony are placed on a 2 x 2 cm coarse mesh patch. The sample to be tested, maintained at room temperature, is shaken until homogeneous and placed into a 50 ml beaker.

The mesh patch is placed into the sample immediately after pouring, allowed to submerge, and after two 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 30"C holding chamber.

Ovicidal activity: 15 adult, 5 to 10 day old, female lice (Pediculus humanus corporisJ 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 30"C 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.Immediately, after the pouring, the mesh patch is placed into the beaker, allowed to submerge, and after two minutes is removed and immediately plunged into a 50 ml beaker containing tap water at room temperature (about 24 C). The patch is vigorously 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 30"C incubator. Fourteen days following treatment, the number of hatched eggs and the number of shriveled 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 (24"C) tap water substituted for the sample to be tested. The results of the tests reported are net results.

For determining miticidal activity, the following procedure is used: Into a one cubic foot chamber, held at room temperature, is placed a covered microscope depression slide containing ten adult mixed sex mites, Psoroptes equivar. cuniculi. The slide is positioned at a distance of ten inches horizontally and four inches below the activator of 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 twice, 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. For testing each concentration, 40 ml of the test solution is placed in a paper cup.

Ten mosquito larvae (third instar) of Aedes aegypti are transferred into the test solution by means of a piece of 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 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. 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 is allowed to settle, the petri dish containing the aphids is rotated 180 and the primed pump is depressed again. The mist is allowed to settle and the dish is removed and covered. This point of time is considered zero hours. The covered dish is held at room temperature for 24 hours and 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.

The pediculicidal and ovicidal activity of various toxicants of the instant invention were tested in the two minute immersion tests described above. The concentration of the amidoamines which caused 50% mortality (LC50) and which caused 99% mortality (LCg9) was determined in a system where the amidoamine was mixed with 25% of isopropanol, and water q.s. ad. 100%. For contrast, various amidoamines of similar stricture were also tested. The results are shown in the following Table 1.

TABLE 1 Pediculicidal Ovicidal Activity Activity Compound LC50 LC99 LC50 LCg9 Lauramidopropyl Dimethylamine 7.9 > 15.0 0.28 0.51 Cocamidopropyl Dimethylamine 6.2 > 15.0 0.16 0.60 Oleamidopropyl Dimethylamine 3.1 9.5 0.15 0.22 Ricinoleamidopropyl Dimethylamine > 15.0 - > 15.0 > 15.0 Stearamidoethyl Dimethylamine > 15.0 - 7.1 9.4 Stearamidoethyl Ethanolamine > 15.0 - - The miticidal activity in isopropanol was determined against an ectoparasitic mite, Psoroptes equivar.

cuniculi. The oleamidopropyl dimethylamine exhibited an LC50 of 4.1 and an LC99 of 5.3 Lauramidopropyl dimethylamine, cocamidopropyl dimethylamine, ricinoleamidopropyl dimethylamine and stearamidoethyl dimethylamine all exhibited LC50's in excess of 25 weight percent.

The miticidal activity of a 1 weight percent solution of oleamidopropyl dimethylamine in 50% aqueous ethanol was determined against a n an agricultural mite, Bryobiapraetiosa. The results are shown in the following Table 2.

TABLE 2 % Morbidity % Mortality 5 min. 10 min. 15 min. 1 hr. 24 hr.

Oleamidopropyl Dimethylamine 80 100 100 100 100 (1 gram spray) Control 0 0 0 0 0 (1.06 gram spray) Using the larvicidal test procedure heretofore set forth, oleamidopropyl dimethylamine as the free base and as the hydrochloride salt were tested as mosquito larvicides. The test results are shown in Table 3.

TABLE 3 % Mortality Compound Concinppm 1 her 6hr 24 hr 48 hr Oleamidopropyl Dimethylamine 100 70.0 97.5 100 10 7.5 35.5 35.0 55.0 5 0.0 30.0 30.0 32.5 Oleamidopropyl Dimethylamine 100 40 97.5 100 Hydrochloride 10 2.5 20.0 30.0 42.5 5 0.0 2.5 22.5 32.5 Control 0.0 0.0 0.6 0.6 The aphicidal activity of 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 LC99 was found to be 0.99 weight percent.

The data in Table 4 demonstrates the adjunctive miticidal or pediculicidal activity of the instant amidoamines: TABLE 4 % Mortality % WIW Pediculicidal Miticidal Isopropyl Myristate 15 100 10 Isopropyl Alcohol 25 Water 60 Oleamidopropyl Dimethylamine 4 100 100 Isopropyl Myristate 15 Isopropyl Alcohol 25 Water 56 PhenylDimethicone 10 100 10 (22.5 centistokes) Isopropyl Alcohol 25 Water 65 Oleamidopropyl Dimethylamine 4 100 100 Phenyl Dimethicone 10 (22.5 centistokes) Isopropyl Alcohol 25 Water 61 Phenyl Dimethicone 1* 45 (22.5 centistokes Isopropanol 25 Water 74 Oleamidopropyl Dimethylamine 5* 100 Phenyl Dimethicone 1* (22.5 centistokes) Isopropanol 25 Water 69 *sublethal concentration As noted above, various end use formulations can be prepared.Some typical formulations are set forth below and the amounts recited are percentages by weight: Shampoo Triethanolamine lauryl sulfate 20.0 Lauramidopropyl dimethylamine 15.0 Isopropanol 14.0 Sorbitan monooleate 1.5 Water 49.5 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 36.0 Isobutane 8.0 Stick Oleamidopropyl dimethylamine 10.0 Sodium stearate 8.0 Sorbitol 3.5 Isopropanol 25.0 Ethanol 39.0 Water 14.5 Various 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 purpose of illustration only and were not intended to limit the invention. Unless otherwise specified, all temperatures have been in degrees Centigrade and all parts and percentages by weight throughout this specification and claims.

Claims (12)

1. An alkyl- or alkenyl- amidopropyldimethylamine ofthe general formula RCONH(CH2)3N(CH3)2 wherein R is alkyl or alkenyl of 11 to 17 carbon atoms, or an acid addition salt thereof, for use in a method of treatment of the human or animal body by surgery or therapy.

2. Oleamidopropyldimethylamine or an acid addition salt thereof, for use in a method of treatment of the human or animal body by surgery or therapy.

3. Lauramidopropyldimethylamine or cocamidopropyldimethylamine, or an acid salt of either, for use in a method of treatment of the human or animal body by surgery ortherapy.

4. A composition for use in a method oftreatment of the human or animal body by surgery or therapy, the composition comprising at least one alkyl- or alkenyl- amidopropyldimethylamine of the general formula RCONH(CH2)3N(CH3)2 wherein R is alkyl or alkenyl of 11 to 17 carbon atoms, or an acid addition salt thereof, together with a carrier.

5. A composition according to Claim 4 in the form of a liquid, powder, lotion, cream, gel, aerosol spray, foam or other get-up suited for topical administration.

6. A composition according to Claim 4 or 5, which contains oleamidopropyldimethylamine or an acid addition salt thereof.

7. A composition according to Claim 4, 5 or 6, which contains lau ramidopropyldimethylami ne or cocamidopropyldimethylamine or an acid addition salt thereof.

8. A composition according to any of Claims 4 to 7, wherein the carrier is aqueous.

9. A composition according to any of Claims 4 to 8, which also contains a lower aliphatic alcohol.

10. A composition according to Claim 9, wherein the alcohol is isopropanol.

11. A composition according to any of Claims 4 to 10, which contains a compound known to be toxic against insects, their larvae or ova.

12. A method of treatment of a substrate for control, prevention or removal of insects, their larvae or ova, which method comprises application of a compound or composition as claimed in any of Claims 1 to 3 or 4 to 11, respectively.