IE44018B1 - Trinitro diphenylamines, their preparation and rodenticidal compositions - Google Patents

Description

The present invention relates to diphenylamine compounds having trinitro substitution on one ring and from 1 to 5 substituents of a defined class, particularly halogen atoms, on the other ring, which are useful rodenticides.

This invention belongs to the rodenticidal art and provides a new method and compositions for reducing populations of rats or mice.

It has long been known that rats and mice must be controlled. Rats and mice are known carriers of many diseases of which bubonic plague is the best known. The pestiferous animals also, when sharing the habitations of mankind, soil and contaminate the areas in which they live, and destroy buildings and their contents by their tunnelling and nest-building. The animals also consume foodstuffs, and contaminate what they do not consume. A colony of rats in a i grain-storage building can consume or destroy substantial amounts of food.

Many kinds of rodenticides have been, and still are, in use. Metallic poisons, such as arsenic and thallium compounds, are still in use, but obviously pose serious hazards to people and useful ) animals. Organic chemical poisons, of which warfarin is the best known, are in extremely wide use and have served well. However, rodents are developing resistance to such poisons.

Rodenticides are usually presented to rats or mice in the form of mixtures with foodstuffs. The concentration of rodenticide i in the mixture is adjusted so that the rodents consume an amount of the rodenticide which is either acutely or chronically lethal. - 3 It is advisable not to make the mixture so concentrated that the rodent dies immediately, or even soon after eating. Rodents, and especially rats, are intelligent enough to understand the casual relationship between feeding and death if the time interval is very short. Thus, the best practice is to adjust the concentration of the rodenticide so that the rodents will be poisoned over a number of feedings at the poison bait.

In special circumstances, rodenticides are sometimes mixed in drinking water, or prepared as tracking powders", which are deposited in runways used by the rodents. After the animals have walked through the loose poison powder, they lick their feet clean and thus ingest the rodenticide.

Compounds such as those used in the present invention have not previously been used for the control of rodents. The compounds are known to be fungicides and insecticides, however. Therefore, prior workers have made formulations which comprised the compounds dispersed in water and in finely powdered solids.

The present invention provides a rodenticidal composition which comprises a foodstuff and as active ingredient a diphenylamine compound of the formula NO, 4 5 6 7 R , R , R , R and R independently represent chloro, bromo, fluoro or hydrogen; provided that no more than two of *» - 4 R3, R4, R3, R^ and R7 represent hydrogen, and two such hydrogen atoms are not adjacent to each other; and provided that: when one and only one of R3, R4, R3, R6 and R7 -represents 3 5 7 fluoro, two or three of R , R and R represent chloro or bromo.

The invention also provides a method of reducing a population of rats or mice which comprises supplying to a locus frequented by the rats or mice a rodenticidally-e££ective amount of a rodenticidal composition comprising an inert carrier and as active ingredient a rodenticidally-effective concentration of a diphenylamine compound of fcrmula I wherein the symbols have the meanings stated above.

The invention further provides novel diphenylamine compounds of formula I wherein Q R represents methyl, ethyl or propyl; and R3, R4, R3, R3 and R7 independently represent chloro, bromo, 4 5 fluoro or hydrogen; provided that no more than two of R , R , R , R6 and R7 represent hydrogen, and that two such hydrogen atoms are 3 4 not adjacent to each other; and provided that, when one of R , R , R3, R3 and R7 represents fluoro, two or three of R3, R3 and R7 represent chloro or bromo.

All of the compounds below will Tse named as diphenylamines for the sake of consistency and clarity, even though some compounds may be named otherwise according to the rules of nomenclature.

All percentages and parts described hereafter refer to percentages and parts by weight.

The term halo refers to chloro, bromo, fluoro and iodo.

It is believed that the compounds useful in this invention are clearly described by the above generic formula. In order to - 5 ensure that those skilled in the art understand the invention, however, the following exemplary compounds, which are not intended to delineate the bounds of the invention, are named. 2,3,4,5,6 - pentachloro - N - methyl - 2^4^61 - trinitrodiphenylamine, 2,3,4,5,6 - pentabromo - N - ethyl - 2',4',6' - trinitrodiphenylamine , 2,3,4,5,6 - pentafluoro - 2',4',6' - trinitro - N‘propyldiphenylamine, N - methyl - 2,3,6 - trichloro - 4 - fluoro - 2^4^6^ trinitrodiphenylamine, 2.3.5 - tribromo - N - ethyl - 2',4',6' - trinitrodiphenylamine, U - ethyl - 2,6 - dibromo - 4 - fluoro - 2^4^61 - trinitrodiphenylamine, 3.4.5 - tribromo - 2',4',6' - trinitro - N - propyldiphenylamine, - fluoro - N - ethyl - 4,6 - dichloro - 2',4',6‘ - trinitrodiphenylamine , 2.4 - dibromo - N - ethyl - 6 - fluoro - 2^4^61 - trinitrodiphenylamine, 3.5 - dichloro - 2,6 - dibromo - N - methyl - 2*,4',6'trinitrodiphenylamine, - bromo - 2,6 - dichloro - N - methyl - 2^4^61 trinitrodiphenylamine, N - propyl - 3,4,5 - trichloro - 2^4^61 - trinitrodiphenylamine, - fluoro - 2,6 - dibromo - N - methyl - 2',4',6‘trinitrodiphenylamine, - 6 3.5 - dibromo - 2 - chloro - 2^4^61 - trinitro - Npropyldiphenylamine, 2.3.6 - trichloro - 4 - fluoro - N - methyl - 2',4*,6'trinitrodiphenylamine, H - ethyl - 2,3,4,5,6 - pentachloro - 2‘,4',6' - trinitrodiphenylamine , 2.3.4.5 - tetrachloro - N - ethyl - 2’,4',6' - trinitrodiphenylamine , 2,4 - dibromo - 6 - fluoro - 2',4',6' - trinitro - Npropyldiphenylamine, 3.4.5 - tribromo - U - ethyl - 2',4',6' - trinitrodiphenylamine, - bromo - 2,6 - dichloro - 2',4‘,6’ - trinitro - Npropyldiphenylamine, 2.3.4.5.6 - pentabromo - 2’,4',6' - trinitro - N - propyldiphenylamine, 2.3.5.6 - tetrachloro - N - propyl - 2',4’,6' - trinitrodiphenylamine, 4.6 - dichloro - N - ethyl - 2 - fluoro - 2',4',6' - trinitrodiphenylamine, 3.5 - dibromo - 2 - chloro - N - ethyl - 2',4',6'tr initr odiphenylamine, 2.3.5 - tribromo - 2^4^61 - trinitro - N - propyldipheny1 amine, 2.3.5.6 - tetrabromo - N - methyl - 2^4^61 - trinitrodiphenylamine, - bromo - 2,6 - dichloro - N - ethyl - 2',4',6'tr initrodiphenylamine, - fluoro - 4,6 - dichloro - 2^4^61 - trinitro - Npropyldiphenylamine, 3.4.5 - trichloro - N - methyl - 2',4',6' - trinitrodiphenylamine, - bromo - 4,6 - dichloro - N - propyl - 2',4',6'trinitrodiphenylamine. 2.4.6 - trichloro - N - methyl - 2',4',6' - trinitrodiphenylamine, 2,4,6 - tribromo - N - methyl - 2',4',6' - trinitrodiphenylamine , 2,4 - dinitro - 2',4',6' - trichloro - 6 - trifluoromethyldiphenylamine , 2,4,6 - trichloro - 2^4^61 - trinitrodiphenylamine, 2,4,6 - tribromo - 2*,4' - dinitro - 6' - trifluoromethyldiphenylamine .

The compounds used in the practice of this invention are easily synthesized by the reaction of a phenyl halide bearing trinitro substituents with an appropriate-substituted aniline.

The reaction is a simple amination and is readily accomplished according to the known methods. An acid scavenger, such as an inorganic base, a tertiary amine or excess of the aniline intermediate, is needed in the reaction mixture. In general, the most convenient reaction medium is dimethylformamide at about -10°C., and sodium hydride is the best acid scavenger.

The starting substituted anilines and phenyl halides are readily obtained by methods which are commonly known in the chemical literature.

It will be understood that the fluorinated aniline compounds are often prepared by first making a dizonium fluoroborate salt at the position where the fluorine atom is desired. The salt is then decomposed with heat to leave a fluorine atom at the desired posi44018 - 8 tion. Alternatively, it has recently been found that fluorine atoms may be inserted in phenyl rings with elemental fluorine at very low temperatures.

In some instances, it is convenient to use a starting aniline which lacks some or all of the halogen substituents of the desired product. The diphenylamine is formed by coupling the aniline with the appropriate phenyl halide, and the desired halogen substituents are added by the common methods, as with the elemental halogen in acetic acids or methylene chloride.

Iodination is best carried out with iodine monochloride as the reagent.

When a compound having no 4-substitUent is to be made, it will often be necessary to block the 4-position before halogenating. It is most convenient to use a sulfonic acid group as the blocking group, because it is readily added and readily removed.

I The above two-step process is often particularly convenient for making the N-alkyl compounds. In such cases, one of the starting compounds is an N-alkylaniline, which is coupled with a trinitrophenyl halide to form the desired N-aIkyldiphenylamine lacking some or all of the halogen substituents of the desired product. Halogenation produces the desired N-alkyldiphenylamine. Alternatively, in other instances it is convenient to form the N—H diphenylamine, and then to alkylate with an agent such as a dialkylsulfate or an alkyl halide .

The typical preparations below are shewn to assure that organic chemists can obtain any of the compounds used in this invention.

Example 1 2,4,6 - trichloro - N - methyl - 2^4^61 - trinitrodiphenylamine Three g. of sodium hydride as a 50% dispersion in oil was - 9 dispersed in 50 ml. of dry dimethylformamide, and the suspension was cooled to -10° under nitrogen. The temperature was maintained approximately constant throughout the process. A solution of 10 g. of N-methylaniline in 50 ml. of dimethylformamide was then added over a period of 16 minutes. After the mixture had been stirred for 1-1/2 hours, a solution of 23.1 g. of piczyl chloride in 75 ml. of dimethylformamide was added over a 25-minute period. The mixture was stirred and allowed to warm to room temperature overnight.

The reaction mixture was then poured over a large amount of crushed ice, and the aqueous mixture acidified with hydrochloric acid and allowed to stand overnight. The mixture was then filtered, and the solids were recrystallized from denatured ethanol to produce 10.2 g. of N - methyl - 2,4,6 - trinitrodiphenylamine, m.p. 104—105°C.

A 2.3 g. portion of the above intermediate was suspended in 30 ml. of acetic acid, and the mixture was saturated with gaseous chlorine with stirring at room temperature. After 3 hours of constant stirring with slow addition of chlorine, the reaction mixture was poured into water and the resulting yellow precipitate was filtered out of the mixture, the filtrate was stirred with magnesium sulfate and charcoal, filtered and evaporated to dryness. The residue was taken up in diethyl etherpetroleum ether, and the insoluble portions were removed by filtration. Recrystallization of the product by evaporation of the solvents produced 0.48 g. of 2,4,6 - trichloro - N - methyl - 2',4',6' - trinitrodipheftyl- amine, m.p. 178—179.5°C. Theoretical Found C 37.04% 37.24% H 1.67 1.87 N 13.29 13.42 Cl 25.23 24.99 - 10 Similarly, the Example below illustrates the use of two stages of halogenation.

Example 2 2,4 - dibromo - 6 - chloro - N - methyl - 2',4,6' - trinitrodiphenylamine a 1.3 g. portion of the diphenylamine intermediate of Example 36 was suspended in 10 ml. of acetic acid and stirred at room temperature for 2 hours with 1 ml. of elemental bromine. The mixture was then poured into water and filtered. The solids were taken up in 20 ml. of acetic acid, warmed slightly and saturated with chlorine. After 1-1/2 hours of stirring with occasional addition of chlorine, a light yellow precipitate formed, which was separated by filtration. The solids were identified as 0.72 g. of 2,4 - dibromo - 6 - chloro - N - methyl - 2^4^61 - trinitrodiphenylamine, m.p. 199—200°C.

Theoretical Found c 30.59% 30,74% E 1.38 1.51 N 10.98 10.75 Cl 6.95 6.99 The following additional compounds are typical of those most readily prepared by the processes typified by Examples 36 and 37. Example 3 2,4,6 - trichloro - M - ethyl - 2',4',6' - trinitrodiphenyl- amine, m.p. 138—140°C., yield 60%. Theoretical Found C 38.60% 38.90% H 2.08 2.03 N 12.86 13.10 0 24.42 24.71 Cl 22.04 21.94 The utility of this invention has been investigated by administering the compounds to rats in laboratory tests. The following reports of typical tests illustrate the outstanding rodenticidal efficacy of the compounds of formula I.

The tests were performed by mixing the compounds with an animal feed of cereal origin, and presenting the treated feeds to male albino rats of the Sprague-Dawley strain.

The tables below report the concentration of the compound in the feed, in parts per million parts of feed (ppm.), the number of days after starting the rats on treated feed when each rat died, and the weight change, positive or negative, of each rat during the 10-day experiment.

Juvenile rats weighing 50—60 g. were used in some tests, and older rats up to about 250 g. were used in others. The weight gains of the untreated control rats varied widely from experiment to experiment, because of the varying ages and sizes of the rats. In all instances, however, controls made weight gains in the vicinity of 40 to 60 g. per animal during the experimental period.

Compound of Example 1, 25 ppm.

Day of Weight No. Death Change Rat No. -8 g. -19 g. -18 g. -24 g. -20 g.

Compound of Example 2, 30 ppm. Rat No. Day of Death Weight Change 1 6 -19 g. 2 5 -13 g. 3 4 -12 g. 4 3 -12 g. 5 4 -10 g. Compound of Example 3, 25 ppm. Rat No. Day of Death Weight Change 1 7 -86 g. 2 7 -60 g. 3 5 -46 g. 4 5 -46 g. 5 5 -35 g.

The excellent rodenticidal results produced by the compounds are obvious from the data. It will be observed that the compounds are effective at very low concentrations. Further, it is most significant fhat the compounds kill the rats with certainty, but not immediately. As has been explained, a good rodenticide allows time for many or all of the rats or mice of a colony to consume the poison bait before animals begin to die.

It is clear that the compounds of formula I when used in proper concentrations, work in the desired sure, but delayed, manner.

In its most broad description, this invention provides a I method of reducing a population of rats or mice which comprises supplying to a locus frequented by the rats or mice a rodenticidally-effective amount of a rodenticidal composition which comprises an effective rodenticidal concentration of a compound described above. The invention also provides the rodentical compositions which comprise inert carriers and effective rodenti cidal concentrations of the compounds described above.

The details of the method, such as the times and places in which the rodenticidal compositions are supplied, and the carriers of the rodenticidal compositions, are common to the rodenticidal art. Sone explanation of the various ways in which the method is carried out will be presented.

The method is effective in the control of rats and mice in general. For example, such pestiferous species as the following are controlled by the proper use of the present invention.

House mouse (Mus musculus) Norway rat (Rattus norvegicus) Black rat (R. rattus rattus) Roof rat (R. r.. fruqivorus) White-footed mouse (Peromyscus leucopus) Pack rat (Neotoma cinerea) Meadow mouse (Microtus pennsylvanicus) Those skilled in the rodenticidal art will understand that the present invention can also be used for the control of rodents other than rats and mice. Since rodents other than rats and mice are frequently beneficial, the control of such other rodents is not contemplated as a regular part of the benefit of this invention. However, should the control of other rodents be desirable in particular circumstances, the invention can be used therefor.

This invention effectively controls rats and mice by both acute and chronic toxicity techniques. Proper adjustment of the concentration of the compound in the rodenticidal composition, as those of skill in the art will understand, allows the invention to reduce a population of rats or mice either by immediately poisoning the animals, or by chronically poisoning them over a number of feedings.

As has been explained, however, the delayed lethal effect of the compounds taught herein is an important factor in their rodenticidal usefulness. The maximum benefit of this invention is obtained by supplying to the locus of the rats or mice a rodenticidal composition which contains a concentration of the compound which is not acutely lethal in a single feeding, but which contributes to a lethal effect in the course of at least two feedings, and preferably a larger number Of feedings. Accordingly it is also preferred to supply a sufficiently large amount of the rodenticidal composition to allow all the members of the population to feed on the composition two or more times.

A rat consumes about 5 to 50 grains of feed per day; a mouse consumes about 1 to 5 grams per day, depending in each case on the animal's age, size, and state of health. A pest control specialist can estimate the number of animals in a colony, and can supply to the locus of the animals appropriate quantities of treated feed, or otter compositions, to provide an effective amount for each animal.

A preferred embodiment of the invention is, therefore, a method for reducing a population of rats or mice which comprises supplying to a locus frequented by the rats or mice a sufficient quantity for two or more feedings, of a rodentical composition which comprises a sufficient concentration of a compound described above to be effectively rodenticidal upon two or more feedings. Another preferred embodiment of the invention is the rodenticidal composition just described.

Although the invention is described herein in terms of feedings, the invention is also used by supplying rodenticidal compositions in the forms of tracking powders and drinking water compositions. It will be understood that such compositions are used in the same way as compositions based on foodstuffs, making 4 018 appropriate adjustments to accommodate for the difference in the way the rodents ingest the compositions. The concentrations of the compounds in preferred drinking water or tracking powder compositions are effectively rodenticidal upon two or more water5 ings or cleanings, respectively. The term feeding is used herein to include watering and cleaning.

Rodenticidal compositions are based on inert carriers which include foodstuffs, drinking water and finely powdered solids. Compositions based on foodstuffs, which are the preferred inert carriers, may comprise any edible substance, since rats and mice are omnivorous. For example, such compositions may comprise cereals, meat by-products or fats. Cereal foodstuffs which can be used in rodenticidal compositions include such substances as oatmeal, ground or cracked corn, soybean products, wheat and wheat byproducts and waste rice. Any grain can be the basis of such compositions. Sweetening and flavor-enhancing agents, can also be added to increase the attraction of the bait.

Fatty rodenticidal bait compositions are regularly made in inert ingredients such as peanut butter, other nut butters, milk solids, animal fats and vegetable oils. Rodenticidal compositions are also sometimes based on animal products such as bone meal and on meat products including animal by-products.

Tracking powders are composed of rodenticidal compounds dispersed in powdered solids. Virtually any powder can be used, including talc, chalk, ground clays flour, nut shell flour and the powdered stone.

Rodenticidal compositions in drinking water comprise suspensions or dispersiohs of the compounds. The compounds are quite water-insoluble, and it is therefore normally necessary to grind the compound to a fine particle size and Suspend it. - 16 Suspending agents are commonly used in the pharmaceutical art, and are Chosen from among the thickeners, such as carboxymethylcellulose, polyvinylpyrrolidone, gelatin and the alginates, and the surfactants such as lecithin, alkylphenol polyethylene oxide adducts, alkyl sulfates, naphthalenesulfonates, alkylbenzenesulfonates and the polyoxyethylene sorbitan esters. It is sometimes also possible to use silicone antifoams, glycols, sorbitol and sugars as suspending agents.

The time when a rodenticidal composition of this invention is supplied to the locus of a colony of rats or mice is not critical. There are no seasons when a rodent colony is particularly susceptible, or relatively immune, to the use of rodenticides. It is usually advantageous first to pre-bait the colony with an untreated composition. Preferably, sufficient of the treated composition should be supplied to last for the time during which the members of the colony feed at least twice.

The concentration of the compound in the composition depends on the identity of the compound chosen, since they are of different potencies, upon the rapidity with which the population is ) desired to be reduced, and upon other factors as well. For example, if the population can be isolated, so that its only food or water source is a rodenticidal composition, the concentration obviously should be lower than if a variety of food sources are available. In general, rodenticidal compositions should con> tain concentrations from 5 to 2000 parts per million parts of the composition (ppm). More preferably, concentrations from 10 to 500 ppm, should be used, although It will be understood that amounts both above and below the named range will be.effective and even desirable in.unusual circumstances.

It will be understood that additives and attractants can be usefully included in rodenticidal compositions of this invention. - 17 Such additives as, for example, odorants, sex hormones and flavoring agents are regularly used in rodenticidal compositions, and can usefully be used in the compositions of this invention to assist in breaking down the suspicion of the rodents.

Claims (11)

1. A rodenticidal composition which comprises a foodstuff and as active ingredient a diphenylamine compound of the formula propyl; andR 3 , r 4 , R 5 , R 6 and R 7 independently represent chloro, bromo, fluoro or hydrogen} provided that no more than two of R 3 , R 4 , R 5 , R 6 and R 7 represent hydrogen, and two such hydrogen atoms are not adjacent to each other; and provided that when one and only 3 4 5 6 7 one of R , R , R , R and R represents fluoro, two or three of 3 5 7 R , R and R represent chloro or bromo.

2. The composition of Claim 1, wherein the concentration of the active ingredients is rodenticidally effective upon two or more feedings.

3. The composition of Claim 1 or 2, wherein the concentratioh of the active ingredient is from 5 to 2000 ppm.

4. The composition of Claim 3, wherein the concentration of the active ingredient is from 10 to 500 ppm.

5. The composition as claimed in Claim 1, wherein the active ingredient is 2,4,6 - trichloro - N - methyl - 2',4‘,6'trinitrodiphenylamine.

6. The composition as claimed in Claim 1, wherein the active ingredient is 2,4 - dibromo - 6 - chloro - N - methy12',4‘,6' - trinitrodiphenylamine.

7. A method of reducing a population of rats or mice which comprises supplying to a locus frequented by the rats or mice a rodenticidal composition as claimed in any of Claims 1 to 23.

8. A diphenylamine of the formula g wherein R represents methyl, ethyl or propyl; and R 3 , R 4 , R 3 , R 3 and R 7 independently represent chloro, bromo, fluoro or hydrogen; provided that no more than two of R 3 , R 4 , R 3 , R 3 and R 7 represent hydrogen, and two such hydrogen atoms are not adjacent to each other; and provided that, when one and only one of R 3 , R 4 , R 3 , R 3 and R 7 represents 3 5 7 fluoro, two or three of R , R and R represent chloro or bromo.

9. A diphenylamine as claimed in Claim 8 , substantially as hereinbefore described with particular reference to any one of Examples 1, 2 and 3.

10. A method of reducing a population of rats or mice substantially as nereinbefore described.

11. A rodenticidal composition substantially as hereinbefore described.