Acaricidal agents

The present invention relates to novel acaricidal agents.
Ticks and mites which are parasitic on a variety of garden plants and domesticated animals have short life cycles and very high breeding capabilities. These characteristics demand a frequent application of control chemicals, which fosters in turn their readiness to acquire the resistance to such chemicals. It is for this reason that the efficacies of many of the control chemicals hitherto employed tend to diminish by degrees and that, accordingly, it has been desired to develop new control chemicals. Referring to the characteristic features that are particularly required of acaricidal agents, in view of the exceedingly high breeding capabilities of ticks and mites, such acaricidal agents will not only have to possess the acaricidal action but also develop the breeding suppressing activities such as egglaying inhibiting action and ovicidal property.
Under these circumstances, the present inventors, after the extensive screening work on a wide variety of chemicals for their acaricidal activities, found out that particular pyrroline compounds exhibited extremely potent controlling effect against ticks and mites, when applied on their body surfaces, hosts, etc. The finding was followed by further studies, which have culminated in the present invention.
Thus, the present invention relates to an acaricidal agent which contains, as an active ingredient, at least one member of the class of the compounds represented by the formula (I): ##STR2## wherein R.sup.1 and R.sup.2 are each hydrogen, halogen or lower (especially C.sub.1-3) alkyl; R.sup.3 is hydrogen or phenyl which may be substituted by halogen; R.sup.4 is hydrogen or lower (especially C.sub.2-4) alkanoyl; R.sup.5 is hydrogen or phenyl, or their acid addition salts.
Among the above-mentioned compounds (I), preferable compounds are those of the formula (II): ##STR3## wherein R.sup.1' is halogen and R.sup.2' is hydrogen, halogen or C.sub.1-3 alkyl or their acid addition salt, which are novel compounds.
The compounds represented by the above general formula (I) display the extremely high control activity against a variety of the bloodsucking ticks living on domestic animals such as cattle, horses, goats and sheep, and poultry such as barn-door fowls and turkeys, and against the so-called leaf-mites that live and feed on fruit-bearing trees such as apple, pear, orange and peach, various legumes, vegetables such as egg plant and cucumber, specialty crops such as hop, mulberry and tobacco, and ornamental flowers such as carnation and tulip, when such compounds are used for treatment of such parasite bodies or their hosts by spray, etc.
These compounds not only possess the acaricidal activity but also inhibit the oviposition of acari at lowered concentrations. More surprisingly, these compounds when applied to ticks not only exhibit the effect of inhibiting the blood-sucking act against ticks not having sucked the blood, but also block the blood-sucking behavior against ticks gorging on the blood of animals and detach them from the hosts, thereby causing them to die of incomplete growth. These compounds are also safe to man and easy to handle.
The followings are examples of the compounds represented by the formula (I). As shown herein by way of example, these compounds may be put into use as acid addition salts or in the form of free base. As examples of such acid addition salts, there may be mentioned inorganic acid salts such as hydrochlorides, sulfates, nitrates, etc., and organic acid salts such as p-toluenesulfonates, maleates, tartarates and oxalates.
TABLE 1______________________________________CompoundNo. Chemical Name______________________________________1 2-[N'-(2-chlorophenylhydrazino)]-1-pyrroline hydrochloride2 2-[N'-(2-methylphenylhydrazino)]-1-pyrroline hydrochloride3 2-[N'-(4-chlorophenylhydrazino]-1-pyrroline hydrochloride4 2-[N'-(4-methylphenylhydrazino)]-1-pyrroline hydrochloride5 2-[N'-(4-bromophenylhydrazino)]-1-pyrroline hydrochloride6 2-(N'-phenylhydrazino)-4-phenyl-1-pyrroline hydrochloride7 2-(N'-phenylhydrazino)-4-(4-chlorophenyl)-1- pyrroline hydrochloride8 2-(N'-phenylhydrazino)-1-pyrroline hydro- chloride9 2-(N,N'-diphenylhydrazino)-1-pyrroline10 2-(N,N'-diphenyl-N'-propionylhydrazino)-1- pyrroline hydrochloride11 2-[N'-(2,3-dichlorophenylhydrazino)]-1- pyrroline hydrochloride12 2-[N'-(3-chloro-2-methylphenylhydrazino)]-1- pyrroline hydrochloride13 2-[N'-(2,4-dichlorophenylhydrazino)]-1- pyrroline hydrochloride14 2-[N'-(4-chloro-2-methylphenylhydrazino)]-1- pyrroline hydrochloride15 2-[N'-(3-fluorophenylhydrazino)]-1-pyrroline hydrochloride16 2-[N'-(2-fluorophenylhydrazino)]-1-pyrroline hydrochloride17 2-[N'-(4-chloro-2-fluorophenylhydrazino)]-1- pyrroline hydrochloride18 2-[N'-(3-chlorophenylhydrazino)]-1-pyrroline hydrochloride19 2-[N'-(2-methylphenylhydrazino)]-4-(4- chlorophenyl)-1-pyrroline hydrochloride20 2-[N'-(2-bromophenylhydrazino)]-1-pyrroline hydrochloride21 2-[N'-(3-bromophenylhydrazino)]-1-pyrroline hydrochloride22 2-[N'-(2,5-dichlorophenylhydrazino)]-1- pyrroline hydrochloride23 2-[N'-(2,6-dichlorophenylhydrazino)]-1- pyrroline hydrochloride24 2-[N'-(3,4-dichlorophenylhydrazino)]-1- pyrroline hydrochloride25 2-[N'-(3,5-dichlorophenylhydrazino)]-1- pyrroline hydrochloride26 2-[N'-(2,4-difluorophenylhydrazino)]-1- pyrroline hydrochloride27 2-[N'-(2,6-difluorophenylhydrazino)]-1- pyrroline hydrochloride28 2-[N'-(2,4-dibromophenylhydrazino)]-1- pyrroline hydrochloride29 2-[N'-(2,5-dibromophenylhydrazino)]-1- pyrroline hydrochloride30 2-[N'-(2,6-dibromophenylhydrazino)]-1- pyrroline hydrochloride______________________________________
The compounds of the formula (I) may be easily synthesized in the manner shown in the following production examples or, for example, by the procedures described in West-German Published Unexamined Patent Application No. 1957783 and Bull. Soc. Chim. Fr., 3704 (1969).

PRODUCTION EXAMPLE 1
Synthesis of 2-[N'-(3-Chlorophenylhydrazino)]-1-Pyrroline Hydrochloride
In 5 ml of benzene was dissolved 2 g of 2-pyrrolidinone, and a solution of 1.5 g of phosphorus oxychloride in 3 ml of benzene was added dropwise to the solution with stirring under ice-cooling over a 10-minute period. After the dropwise addition was concluded, the solution was stirred at room temperature for 3 hours, followed by adding 4.5 g of 3-chlorophenylhydrazine sulfate and warming at 65.degree. C. for 3 hours. After cooling, the separated benzene layer was removed by decantation, and to the residue was added 50 ml of water and the PH of the mixture was adjusted to 10 with 1 N-NaOH and the mixture was extracted with three 50 ml portions of ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield 3.5 g of an oily material. The material was dissolved in 10 ml of ethanol and followed by addition of 2 ml of a 2 N HCl-ether solution to afford instantaneously crystals of 2-[N'-(3-chlorophenylhydrazino)]-1-pyrroline hydrochloride. The resulting crystals were collected by filtration and recrystallized from methanol-ether to yield 2.8 g of crystals. m.p., 242-243.degree. C.
Elementary analysis for C.sub.10 H.sub.12 N.sub.3.HCl: Calcd., C 48.80; H 5.32; N 17.07. Found, C 48.91; H 5.42; N 17.21.
Among the compounds obtained thus, physico-chemical data of the new compounds are tabulated in Table 2.
TABLE 2______________________________________ Elementary analysis (%)Com- Theoretical values arepound M.P. in parenthesesNo. (.degree.C.) Molecular formula C H N______________________________________2 258-262 C.sub.11 H.sub.15 N.sub.3 . HCl 58.75 7.28 18.65 (58.53) (7.15) (18.62)4 260-263 C.sub.11 H.sub.15 N.sub.3 . HCl 58.61 7.24 18.69 (58.53) (7.15) (18.62)6 240-245 C.sub.16 H.sub.17 N.sub.3 . HCl 66.63 6.11 15.06 (66.77) (6.30) (14.60)7 245-250 C.sub.16 H.sub.16 N.sub.3 Cl . HCl 59.31 5.27 13.44 (59.60) (5.32) (13.04)9 139-140 C.sub.16 H.sub.17 N.sub.3 76.19 6.70 16.50 (76.46) (6.82) (16.72)10 217-221 C.sub.19 H.sub.21 N.sub.3 O . HCl . 64.42 6.63 11.74 1/2 H.sub.2 0 (64.66) (6.57) (11.91)11 274-277 C.sub.10 H.sub.11 N.sub.3 Cl.sub.2 . HCl 42.50 4.33 14.88 (42.78) (4.28) (14.97)12 158-162 C.sub.11 H.sub.14 N.sub.3 Cl . HCl 49.55 5.43 15.75 (50.76) (5.77) (16.15)13 272-277 C.sub.10 H.sub.11 N.sub.3 Cl.sub.2 . HCl 42.75 4.31 15.06 (42.78) (4.28) (14.97)14 273-278 C.sub.11 H.sub.14 N.sub.3 Cl . HCl 50.71 5.81 16.16 (50.76) (5.77) (16.15)15 265-275 C.sub.10 H.sub.12 N.sub.3 F . HCl 52.26 5.67 18.23 (52.28) (5.72) (18.30)16 241-243 C.sub.10 H.sub.12 N.sub.3 F . HCl 51.95 5.67 18.19 (52.28) (5.72) (18.30)17 263-266 C.sub.10 H.sub.11 N.sub.3 FCl . HCl 45.39 4.33 15.80 (45.47) (4.59) (15.91)18 242-243 C.sub.10 H.sub.12 N.sub.3 Cl . HCl 48.91 5.42 17.21 (48.80) (5.32) (17.07)19 257-260 C.sub.17 H.sub.18 N.sub.3 Cl . HCl 60.28 5.57 12.53 (60.72) (5.69) (12.50)______________________________________
Given below are examples of the experiment on the controlling effects of the representative compounds (I).
EXPERIMENT EXAMPLE 1
Egg-laying Inhibitory Activity Upon Completely Engorged (Blood Saturated) Female Adults of Haemaphysalis longicornis
A suitable amount of each of the compounds indicated in Table 3 was dissolved in methanol to prepare a test solution of the desired application concentration.
By means of a micropipet, this test solution was applied by dropping onto a group composed for each concentration of five or ten female adults of Haemaphysalis longicornis immediately after having gorged fully on the blood and dropped off from the host at the rate of 5 .mu.l per each group. After the solvent has been air-dried, the ticks were transferred to a dish and held in a constant-temperature, constant-humidity chamber at 25.degree. C. and 95% R.H. for 3 weeks. Then, the egg-laying inhibition effect of each compound was determined by comparing the weight of eggs laid by the ticks treated with 30 .mu.g and 300 .mu.g of the compound per body weight (gram) respectively with the weight of eggs laid by control ticks treated with the solvent alone and by calculating the egg-laying inhibition rate according to the equation given below. That is to say, 100% of the egg-laying inhibition rate means that no egg was laid, while 0% means that there took place the egg-laying equal to the control reference.
Egg-laying inhibition rate (%)=100-W/W.sub.o .times.100
where;
W=the weight of eggs laid by treated ticks
W.sub.o =the weight of eggs laid by control ticks
TABLE 3______________________________________Egg-laying inhibitory activity upon completely en-gorged (blood saturated) female adults of Haemaphysalislongicornis (the egg-laying inhibition rates found whentreated with 300 .mu.g and 30 .mu.g of compound per gram bodyweight, respectively, %) Egg-laying inhibition rate (%)Compound (treatment concentration)No. 300 .mu.g/g 30 .mu.g/g______________________________________1 100 682 93 163 32 04 20 05 13 08 100 829 46 711 100 10012 100 6713 100 1915 100 8416 100 6617 89 2918 100 90______________________________________
EXPERIMENT EXAMPLE 2
Blood-sucking Inhibitory Activity Upon Female Adult Ticks While Engorging
A suitable amount of each of the compounds indicated in Table 4 was dissolved in methanol to prepare a test solution of the desired application concentration. About 50 unengorged adults of Haemaphysalis longicornis were deposited on the auricles of a rabbit for each test solution and, after it was confirmed that they had attached properly to the host and were gorging on the blood three days later, each of the above test solutions was sprayed by means of a small-sized sprayer at the rate of 3 ml per ear.
For the control experiment, fenitrothion, an organophosphorus insecticidal and acaricidal agent, was dissolved in methanol to the desired concentration to spray in the same manner as the test solution. Over four days after spraying, the number of ticks remaining attached to the hosts was investigated for each group of the experiments inclusive of the control experiment, and the blood-sucking inhibition effect of each compound was compared by determining the blood-sucking inhibition rate as calculated according to the equation given below:
Blood-sucking inhibition rate (%)=(q.sub.o -q)/q.sub.o .times.100
where;
q.sub.o =ratio of ticks attached in non-treated control experiment
q=ratio of ticks attached in a treated experiment
TABLE 4______________________________________Blood-sucking inhibitory effect upon female adultticks while engorging Blood-sucking inhibition rate up to 4 days after spraying, (%)Compound (treatment concentration)No. 1000 ppm 3000 ppm______________________________________ 1 78 10011 98 10018 100 100Controlchemical 0 35(fenitro-thion)______________________________________
EXPERIMENT EXAMPLE 3
Acaricidal Action Upon Unengorged Larval Ticks
A suitable amount of each of the compounds indicated in Table 5 was dissolved in methanol to prepare a test solution of the desired application concentration. Each test solution was dropped in the filter-paper side of a bag (which comprised of a Toyo filter paper No. 2 manufactured by Toyo filter paper Ltd., Japan of 5.times.5 cm in size heat-sealed with a 0.1 mm thick, clear polyethylene film) and, after the solvent had been air-dried, about 100 unengorged larvae of Haemaphysalis longicornis two to four weeks after hatching from eggs were placed in the bag, followed by sealing it. 0.4 ml of water was dropped on the filter-paper side for the purpose of prevention of drying, and the bag was transferred to a dish of 7 cm in diameter and protected under the conditions of 25.degree. C. and 95% R.H. 14 days later, the filter paper bag was taken out of the dish, and the number of dead ticks was investigated to calculate the LC.sub.50 (50% lethal concentration) according to the probit method by BLISS.
TABLE 5______________________________________Acaricidal effect upon unengorged larval ticks.CompoundNo. 50% lethal concentration (ppm)______________________________________1 18.311 9.8318 6.38______________________________________
EXPERIMENT EXAMPLE 4
Control Effect Upon Leaf-Mites
Female adults of Tetranychus urticae were allowed to feed on the seedlings of kidney bean (first leaf-unfolding stage), water cultured in a polyethylene cup of 6 cm diameter, a seedling per cup, at a rate of 10 mites per cup, and 20 ml of water containing 500 ppm of each of the compounds shown in Table 6 was sprayed to them on the following day by means of a spraying apparatus held at a distance of about 80 cm from each cup. The treated plants were held in a greenhouse of 28.degree. C., and the number of survived mites were counted two days later. The test was repeated three times, and the average percent decrease was calculated by the following equation: ##EQU1##
The results are shown in Table 6, whereby the acaricidal activity of 0 means that the average percent decrease of mites was not more than 20%; the activity of 1 means that the average percent decrease of mites was within the range of 21 to 50%; the activity of 2 means that the average percent decrease was in the range of 51 to 89%; and the activity of 3 means the average percent decrease of not less than 90%.
TABLE 6______________________________________Acaricidal activity upon leaf-mitesCompound Acaricidal Compound AcaricidalNo. activity No. activity______________________________________1 3 11 32 3 12 33 3 13 34 3 14 25 3 15 26 1 16 37 1 17 38 -- 18 39 1 19 210 3 Control 0 (water)______________________________________ Remarks: the symbol, "--", means that no test was performed.
In putting into actual use the compounds of the formula (I), each of them may be employed as it is but normally it is previously admixed with a suitable vehicle or adjuvant and processed into such application forms as powder, microgranules, solution, emulsifiable concentrate and wettable powder, so as to apply these forms or dilute them with water or a suitable organic solvent (e.g., tetrahydrofuran, dimethylsulfoxide, acetone, methanol, ethanol, machine oil, etc.). Examples of the emulsifying or dispersing agents being usable may include nonionic substances such as the condensation products of ethylene oxide with aliphatic alcohols, amines or carboxylic acids having long-chain hydrocarbon groups of 10 to 20 carbon atoms, e.g. the condensate of octadecyl alcohol with 25 to 30 mole equivalents of ethylene oxide or the commercially available condensate of oleylamine with 12 mole equivalents of ethylene oxide or the condensate of dodecylmercaptan with 12 mole equivalents of ethylene oxide; anionic emulsifiers such as the sodium salt of dodecyl alcohol sulfate, the sodium salt of dodecylbenzene sulfonate, the potassium or triethanolamine salt of oleic acid or abietic acid or their mixture and the sodium salts of petroleum-based sulfonic acids; and cationic substances such as cetyl pyridinium bromide and dihydroxyethylbenzyldodecylammonium chloride. These premixed composition for diluted solution or diluted mixture are usually formed at a concentration of 5% to 70% W/W.
As to the vehicles or carriers for dusts and microgranules, there may be mentioned, for example, substances of mineral origin such as talc, kaoline, bentonite, powdered silica and calcium phosphate, and substances of biological origin such as lactose, cork powder and wood meal.
If necessary, fatty acids, casein or alginates, etc. may be further added so as to improve the dispersability, adhesiveness or penetration.
The present acaricidal agent may be employed in mixture or conjunction with other suitable agricultural chemicals, disinfectants, detergents and so forth, unless they deteriorate its effect. For example, by using the acaricidal agent in admixture or as a mixed formulation with various organophosphorus insecticides or carbamate based insecticides, or a variety of fungicides and bactericides, one can realize the improved control effects or labor-savings in the control work through the synergism to be developed therefrom.
The present acaricidal agent is used by dusting or spraying it inside or outside the breeding buildings for domestic animals and poultry intended to be cared for, or by bathing or immersing their bodies in it. In addition, the acaricidal agent is dusted over ranches, orchards, flower gardens, vegetable farms, etc. The application rate varies with the form of preparations, application method, species or kinds or sizes of useful animals and plants, species and breeding extent of acari, environmental factors, etc., and, in applying it directly to the bodies of animals in the form of a solution by a bathing or spraying method, it is desirable to use a diluted solution of 0.001% to 5% W/W (10 to 50,000 ppm) preferably 0.005% to 0.5% W/W (50 to 5,000 ppm). And, in applying it in a form of dust, it is desirable to use at a concentration of 0.1% to 30% W/W, preferably 0.5% to 5% W/W. In cases in which dusts, solution, etc. are applied in ranches or quarters inside or outside breeding buildings, further, it is dusted directly as it is or after being suitably diluted at the application rate of 5 to 250 g per 10 a. When dusts, aqueous solution, solutions, etc, are applied onto fruit trees, vegetables, specialty crops, ornamental flowers, etc., moreover, the acaricidal agent is dusted or sprayed directly onto them or applied for soil treatment, as it is or after being suitably diluted, at the application rate of 10 to 300 g per 10 a so as to achieve the exceedingly high control effects.
Below given are some examples of the present acaricidal agent, which are not intended to limit the scope of the present invention.
EXAMPLE 1
Wettable Powder
______________________________________2-[N'-(2-chlorophenylhydrazino)]-1-pyrroline hydrochloride 50 partsNeogen (produced by Dai-ichi KogyoSeiyaku Co., Ltd., Japan 5 partsPhosphoric acid 0.5 partKaoline 44.5 parts______________________________________
The above ingredients were mixed and pulverized to produce a wettable powder.
EXAMPLE 2
Dusts
______________________________________2-[N'-(3-chlorophenylhydrazino)]-1-pyrroline hydrochloride 2 partsHighly dispersable silicic acid 1 partKaoline 97 parts______________________________________
The above ingredients were mixed and pulverized to prepare dusts.
EXAMPLE 3
Soluble Powder
______________________________________2-(N'-phenylhydrazino)-1-pyrrolinehydrochloride 50 partsNeogen (produced by Dai-ichi KogyoSeiyaku Co., Ltd., Japan) 5 partsLactose 45 parts______________________________________
The above ingredients were mixed and pulverized to obtain a soluble powder.
EXAMPLE 4
Solution
______________________________________2-[N'-(3-chlorophenylhydrazino)]-1-pyrroline hydrochloride 10 partsNeogen (produced by Dai-ichi KogyoSeiyaku Co., Ltd., Japan) 5 partsEriogreen B-400 (produced by SumitomoChemical Co., Ltd., Japan) 0.01 part______________________________________
The above ingredients were mixed and dissolved in 84.99 parts of water to obtain a solution.
EXAMPLE 5
Emulsion
______________________________________ 2-[N'-(2,3-dichlorophenylhydrazino)]-1-pyrroline 10 partsNonipol (produced by Sanyo ChemicalIndustries, Ltd., Japan) 20 partsXylene 70 parts______________________________________
The above ingredients were mixed to obtain an emulsion.

Acaricidal agents

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Derwent Abstract (35571S-B) of German Offenlegungsschrift 1957783; 5/19/71.
Current Abstracts of Chemistry & Index Chemicus, 1-14-70, vol. 36(2), Issue 320, Abstract 126803.