GB2198127A - Benzothiopyranone derivatives used as rodenticides - Google Patents

Abstract

The invention provides compounds of general formula <IMAGE> wherein R<1> and R<2> are independently selected from hydrogen and halogen atoms; R<3> represents a hydrogen or halogen atom or a CN, CF3, OCF3 or NO2 group; and X represents an oxygen atom or a CH2 group; their preparation and their use as rodenticides.

Description

BENZOTHIOPYRANONE DERIUsTIVES This invention relates to 4-hydroxy-2H-l-benzothiopyran-2one compounds, to processes for their preparation, to rodenticidal compositions containing them and to their use as rodenticides.

In 1947, the first anti-coagulant rodenticide, Warfarin, was disclosed in US Patent 2,427,578. Warfarin is 3-( - acetonylbenzyl)-4-hydroxycoumarin.

Following the disclosure of Warfarin, two further 4-hydroxycoumarin anti-coagulant rodenticides, brodifacoum and difenacoum were disclosed in US Patent No. 3,957,824 (and the corresponding UK patent specification No. 1,458,679).

GB-A-2 126 578 (and the corresponding EP-A-98 629) disclosed a further class of 4-hydroxycoumarin anti-coagulant rodenticides.

A different class of anti-coagulant rodenticides, which comprises certain derivatives of 4 -hydroxy-2H-l-benzothiopyran2-one, was disclosed in EP-A-161 163 (and the corresponding US Patent 4,585,786). These compounds are represented by the formula

in which R can form with AR' a tetrahydronaphthyl cycle when RI is hydrogen; R and R1 may be a carbonyl group; R may be a hydroxyl group when RI is hydrogen; AR is a biphenyl or phenoxyphenyl group, which is substituted or non-substituted by a halogen; and AR' is a substituted or non-substituted phenyl group which may form with R a tetrahydronaphthyl cycle or a thienyl group.

Surprisingly, there has now been discovered a novel class of 4-hydroxy-2H-l-benzothiopyran-2-one derivatives having useful (anticoagulant) rodenticidal properties.

According to the present invention there are provided compounds of general formula

wherein R and R are independently selected from hydrogen and halogen atoms; R3 represents a hydrogen or halogen atom or a CN, CF3, OCF3 or N02 group; and X represents an oxygen atom or a CH2 group.

A halogen atom represented by R or R is preferably a fluorine, chlorine or bromine atom. However it is preferred that R1 and R2 are both hydrogen atoms.

Preferably X is an oxygen atom.

R preferably represents a hydrogen, fluorine, chlorine, chlorine or bromine atom or a CN or cF3 group. Advantageously R3 represents a CF3 group.

Those skilled in the art will appreciate that the compounds of formula I can exist in the form of individual isomers, mixtures of isomer pairs (e.g. "cis-" or "trans-" isomers) or mixtures of all possible isomers.

The invention also provides a process for preparing a compound of formula I as defined above which comprises thermally condensing 4-hydroxy-2H-l-benzothiopyran-2-one with a compound of the general formula

or the corresponding 1, 2-dihydronaphthalene, wherein R1, R2, R3 and X are as defined above, and L is a hydroxy group or a halogen atom, preferably a bromine atom. Preferred compounds of formula II are those where L is a hydroxy group.

4-Hydroxy-2H- l-benzothiopyran- a-one may be prepared according to the method of P.S. Jhewedbandi and S. Rajagopal, Achiv. der Pharmazie, 1967 300 561-6 or P.C. Rath and K.

Rajagopal, Ind. J. Chem. 1971 9(1) 91-3.

The compounds of formula II may be prepared according to the method described in GB-A-2,126 578 and EP-A-98629 referred to above.

4-Hydroxy-2H-1-benzothiopyran-2-one may conveniently be thermally condensed with the compound of formula II at a temperature in the range 500C to 1700C. Condensation may be effected with or without the use of a solvent. Thus the 4-hydroxy-2H-l-benzothiopyran-2-one and compound of formula II may be reacted directly with one another, in the absence of solvent, typically at temperatures in the range 160 to 170 0C.

If a solvent is present, reaction may generally be effected at temperatures from 500C to reflux temperature, in the presence of a catalyst, e.g. sulphuric acid or a sulphonic acid.

Suitable solvents include, for example, acetic acid, formic acid and mixtures thereof, and liquid halogenated hydrocarbons having a boiling temperature of at least 500C, e.g. chlorinated alkanes such as C24 di- and trichloroalkanes. 1,2-dichloroethane (bp 830C to 840C) is very suitable, but other suitable chlorinated alkanes include 1,1,2-trichloroethane (bp 1130C to 114 C), l,l,l-trichloroethane (bp 740C to 750C), 1,1-dichloropropane (bp 870C), 1,2-dichloropropane (bp 950C to 96"C) and 1,3-dichloropropane (bp 1250C).

Examples of sulphonic acids include methane sulphonic acid, trifluoromethane sulphonic acid and aryl sulphonic acids such as benzenesulphonic acid and ptoluenesulphonic acid.

Further in accordance with the invention there are provided a rodenticidal composition comprising a carrier in combination with, as active ingredient, a compound of formula I defined above; a method of exterminating rodents which comprises providing at a locus such a composition; and use of a compound of formula I as defined above as a rodenticide.

Compositions in accordance with the invention may contain up to 50% active ingredient, e.g. 0.0005 to 50% active ingredient. They may be in the form of a bait concentrate (which in use may be diluted by mixing with appropriate quantities of bait base), loose grain bait, block bait, pellet bait, suspension concentrate (which may be used in the preparation of gel formulations or progressively diluted by mixing with appropriate amounts of bait base), gel, tracking dust, or water bait.

The carrier may, according to the nature of the specific composition comprise one or more of a bait base (e.g. wheat, barley, oats, rye, maize, rice, millet, sorghum or pulses), an inorganic solid (e.g. chalk, china clay, gypsum, amorphous silica or diatanaceous earth) or water. A warning dye will usually be included for safety reasons. Flavourings (e.g. salt, mono-sodium glutamate, sugar, or saccharin) may also be included. Other additives which may be present in rodenticidal compositions include surfactants, oils, waxes, thickeners (e.g.

polysaccharides), gums, and, if desired, chopped or minced vegetables or fruit.

The invention will be further understood frcan the following Examples.

EXAMPLE 1 Preparation of 4-hydroxy-3-(1,2,3,4-tetrahydro-3-(4-(4'-tri fluoromethylbenzyloxy) phenyl) -1-naphthyl) -2H-benzothiopyran- 2- one 1-Hydroxy-3-(4-(4'-trifluoromethylbenzyloxy)phenyl) -1,2,3,4- tetrahydronaphthalene (9.95g), 4-hydroxy-2H-l-benzo- thiopyran-2- one (8.9g) and 4-toluenesulphonic acid (5.0g) were heated under reflux in 1,2-dichloroethane (50ml) for 8 hrs, with azeotropic removal of water. After cooling, the reaction mixture was washed cautiously with sodium carbonate (5g) in water (40ml), the separated aqueous washes then being back-extracted with methylene chloride (2 x 5ml). The combined organics were washed with water (50ml), and stripped of solvent to give an oil (12.3g).The residue is purified by chromatography on silica using methylene chloride as eluant.

Crystallisation of the product using methanol (20ml) yielded the title compound 4.2g (31%) as a mixture of cis and trans isomers having a nelting range of 104-1110C.

Calc. for C33H25F3O3S: C: 70.96% H: 4.48% S: 5.75% Found: C: 71.3% H: 4.6% S: 6.0% The structure was confirmed by 1H and 13C nmr and by the observation of the protonated molecular ion at m/e 559 in chemical ionisation mass spectrometry.

EXAMPLE 2 The anticoagulant activity of test compounds was determined by measurement of the prothrombin time, which is a measure of blood-clotting properties and is a reliable indicator of efficacy for an anticoagulant rodenticide. The procedure for measurement of prothrombin time is based on Quick et al, Am. J.

Med. Sci., 190, 501 to 511, (1935).

Prothrombin tines were determined according to the following specific procedures. Test compounds were dissolved in a mixture of polyethylene glycol 200 (i.e. polyethylene glycol of average molar mass 200) and triethanolamine (9:lw/w) and serially diluted with the same solvent system to give concentrations of; 5.0, 2.5, 1.0, 0.9, 0.8, 0.7, 0.6, 0.5, 0.45, 0.40, 0.35, 0.30, 0.25, 0.2 and 0.1 milligrammes per millilitre (mg/ml).

As these concentrations represent a known number of milligrammes per millilitre, administration of any solution to the test animal at the rate of 1 millilitre per 1 kilogramme of bodyweight (eg. a 250g rat is administered 0.25ml) delivers a dose (in mg/kg) numerically equivalent to the concentration of that solution. In this instance the terms concentration and dose are synonymous.

Thus, appropriate doses were a range of at least three consecutive doses from the above series of concentrations which it was estimated would induce a range of prothrombin tine elevations between 0 to 100% such that a dose-response curve could be constructed for that analogue.

The doses were injected into test animals (200 to 250g Wistar-strain male rats) by the interperitoneal route. Three days after injection, blood was withdrawn by cardiac puncture whilst the animals were held under "Halothane" anaesthesia.

Three rats were used in each test of a particular compound and three prothrombin tine determinations were carried out on each blood sample. Prothranbin tines were determined using the modified one-stage method of Quick. The percentage extension time of each prothrombin time was determined by assigning 0% extension tine to an arbitary prothrombin resting tine of 12 seconds, and 100% extension time to a prothrombin tine elevated to an arbitrary 212 seconds. Results were plotted on log-probability graph paper, the best - line fitted, and the prothrombin time ED read from the graph.

For some compounds, LD50 data has also been generated, as follows.

Compounds were dissolved in a mixture of polyethylene glycol 200 and triethanolamine (9:lw/w) and serially diluted with the same solvent system to give concentrations of: 10.0, 4.64, 2.15, 1.00, 0.464, 0.215, 0.10, milligrammes per millilitre (mg/ml).

As these concentrations represent a known number of milligrammes per millilitre, administration of any solution to the test animal at the rate of 1 millilitre per 1 kilogramme of bodyweight delivers a dose (in mg/kg) numerically equivalent to the concentration of that solution.

Thus appropriate doses were a range of four consecutive oral doses from the series of concentration sufficient to cause low group mortality at the lowest dose, and high group mortality at the highest dose. Acute oral LD50's were then determined by reference to the tables in Horns' paper "Simplified LD50 (or ED50) Calculations", Biometrics, 12, 311-322.

Results of these tests are given in the following table, which includes, as comparative data, values obtained for the commercial rodent icide s warfarin and difenacoum.

TABLE

Example 3-day ED50 (mg/kg) LD50 (mg/kg) 1 0.71 0.90 Warfarin 5.2 Difenacoum 0.56 1.80 The compound of Example 1 (active ingredient) may be incorporated in rodenticidal formulations as illustrated by the following composition examples.

(1) BAIT CONCENTRATES (Master mixes) Bait concentrates are prepared having the following compositions : %w (a) Active ingredient 50 Salt (NaCl) 10 Chalk 25 "Gasil" (amorphous silica) 5 Eurocert Indigo Carmine (warning dye) 10 %w (b) Active ingredient 0.05 Salt 10 Sugar 10 "Aerosil-200" (amorphous silica) 2 Eurocet Indigo Carmine (warning dye) 5 Milled barley (bait base) 72.95 The active ingredient, warning dye and other ingredients are mixed together, and in the case of (b), homogeneously combined with bait base.

For use in simple solid baits, the resulting bait concentrates are diluted by mixing with appropriate quantities of bait base.

(2) SOLID (LOOSE GRAIN) BAITS Solid, loose grain, baits are prepared having the following compositions : %w (c) Active ingredient 0.025 Sugar 10 "Silica HP21" (amorphous silica) 1 Helio Fast Blue (warning dye) 0.1 Soya bean oil 1 Pin-head oatmeal (bait base) 87.875 %w (d) Active ingredient 0.0005 Salt 0.1 Saccharin 0.1 "Silica HP21" (amorphous silica) 0.1 Helio Fast Blue (warning dye) 0.05 Mineral Oil 2.0 Whole wheat (bait base) 97.6495 The active ingredient, warning dye and other ingredients are mixed together and then combined homogeneously with the bait base.

3. SOLID (BLOCK AND PRTTFT) BAITS Solid, block and pellet, baits are prepared having the following compositions : %w (e) Active ingredient 0.025 Mono-sodium glutamate 0.5 Solvent Blue-A (warning dye) 0.15 "Syloid" (amorphous silica) 0.1 Fish meal (bait base) 10 Oat flour (bait base) 30 Rye (bait base) 29.225 Parafin wax 30 %w (f) Active ingredient 0.0005 Sugar 7.5 Lactose 15 Solvent Blue-A (warning dye) 0.15 Maize flour (bait) 20 Parafin wax 57.3495 The active ingredient, warning dye and other ingredients are mixed together, combined homogenously with the bait base (s) and parafin wax and either compressed into 20g water-resistant blocks in a mould, or extruded into pellets (4mn dia. x 7-15mn length).

(4) SUSPENSION CONCENTRATES Suspension concentrates are prepared having the following compositions : %w (g) Active ingredient 50 Lignin sulphonate 3 Polyethylene polypropylene glycol 15 Polysaccharide 0.5 Bentonite 7.5 Mcnoethylene glycol 2.5 Diphenyl Brilliant Blue (warning dye) 0.1 Water to 100 %w (h) Active ingredient 1 Saccharin 5 Lignin sulphonate 2.5 Polymethyacrylate 3 Bentonite 5 Diphenyl Brilliant Blue (warning dye) 0.1 Water to 100 The lignin sulphonate and bentonite are dispersed in the bulk of the water, the active ingredient is added to the resulting dispersion and the mixture is ground in a wet mill, before addition of the remaining ingredients and water to 100t and blending until homogeneous.

Suspension concentrates may be used in the preparation of gel formulations. Alternatively, for use in simple solid baits, the resulting suspension concentrates can be mixed with quantities of bait base and the resulting solid concentrates homogeneously mixed with further appropriate quantities of bait base.

(5) GELS Gels are prepared having the following compositions: %w (i) Active ingredient 5 Sodium alginate 10 Calcium sulphate 10 Carboxypolymethylene 5 Carboxypolymethyl ene 5 Polysaccharide 5 Sodium stearate 2 Polypropylene glycol 5 "Aerosil-200" (amorphous silica) 20 Chloramine Sky Blue (warning dye) - 0.5 Water to 100 %w (j) Active ingredient 0.005 Polypropylene glycol 20 "Aerosil-200" (amorphous silica) 30 Chloramine Sky Blue (warning dye) 0.05 Polyethylene glycol 40 Carboxycellulose 9.945 Surfactants components are mixed (where appropriate) with some of the water, the active ingredient is added, with grinding in a wet mill, and retraining ingredients are added and the gel blended until homogeneous.

Gels are injected into burrows and laid in rodent runs.

(6) TRACKING DUSTS Tracking dusts are prepared having the following compositions : %w (k) Active ingredient 5 Direct Blue (warning dye) 2.5 "Sipernat 17" (amorphous silica) 1 Gypsum (dust) 91.5 %w (l) Active ingredient 0.05 Direct Blue (warning dye) 0.1 "Sipernat 17" (amorphous silica) 0.5 Basic slag (dust) 99.35 The active ingredient, warning dye and amorphous silica are homogeneously dispersed in the inorganic dust.

Tracking dusts are blown into rodent burrows or laid in patches 1 to 2rtrn deep in rodent runs.

(7) WATER BAITS Water baits are prepared having the following ccmpositions:- (m) Active ingredient 0.025 Sugar 5 Acacia gum 10 Sodium cellulose glycolate 5 Paper Blue Dye (warning dye) 0.025 Water to 100 %w (n) Active ingredient 0.0005 Glycerol 5 Sorbitol 5 Triethanolamine 0.05 Carboxyttethylce liulose 2.5 Polyoxyethylene sorbitan monolaurate 2 Water to 100 The active ingredient is mixed with other ingredients to form a concentrate which is diluted with the water.

Water baits are most frequently used in dry environments such as warehouses and deep litter chicken houses, where rodents require a supply of drinking water.

Claims (11)

1. A compound of general formula

wherein R1 and R2 are independently selected from hydrogen and halogen atoms; R3 represents a hydrogen or halogen atom or a CN, CF3, OCF3 or NO2 group; and X represents an oxygen atom or a CH2 group.

2. A compound as claimed in Claim 1 wherein R1 and R2 are both hydrogen atoms.

3. A compound as claimed in Claim 1 or 2 wherein X is an oxygen atom.

4. A compound as claimed in Claim 1,2 or 3 wherein R3 represents a hydrogen, fluorine, chlorine or bromine atom or a cN or CF3 group. 3

5. A compound as claimed in Claim 4 wherein R3 represents a CF3 group.

6. A compound of formula I as defined in claim 1 substantially as hereinbefore described with reference to Example 1.

7. A process for preparing a compound of formula I as defined in any of claims 1 to 6 which comprises thermally condensing 4-hydroxy-2H-l-benzothiopyran-2-one with a compound of the general formula

or the corresponding dihydronaphthalene where R11 R2, R3 and X are as defined in Claim 1, and L is a hydroxy group or a halogen atom.

8. A process according to claim 7 substantially as hereinbefore described with reference to Example 1.

9. A rodenticidal composition comprising a carrier in combination with, as active ingredient, a compound of formula I as claimed in any of Claims 1 to 6.

10. A method of exterminating rodents which comprises providing at a locus a composition according to Claim 9.

11. Use of a compound of formula I as defined in any of Claims 1 to 6 as a rodenticide.