GB2160860A - Urea derivatives, their preparation and their use as fungicides - Google Patents

Abstract

The invention provides pyridylalkyl urea derivatives of formula <IMAGE> and acid-addition salts thereof, wherein n is 0 or 1, R is a halogen, C1-4 alkyl or C1-4 alkoxy moiety, R<1> represents a phenyl group substituted by at least one halogen atom, R<2> represents hydrogen or an optionally substituted alkyl, cycloalkyl or alkenyl group, and R<3> represents an optionally substituted alkyl, cycloalkyl or alkenyl group, or R<2> and R<3> together with the interjacent nitrogen atom form a 5- or 6-membered ring optionally containing a second heteroatom selected from oxygen and nitrogen, the ring being optionally substituted by one or two C1-4 alkyl groups; processes for their preparation; and their use as fungicides.

Description

SPECIFICATION Urea derivatives, their preparation and their use as fungicides This invention relates to urea derivatives, more particularly pyridylalkyl urea derivatives, to a process for their preparation, and to the use of such derivatives as fungicides.

UK Patent Specification No. 1,486,459 discloses a class of pyridylalkyl urea derivatives, and pyridyl Noxides and addition salts, having stimulant activity in the biosynthesis of endogenous prostagladins in mammals. The pyridylalkyl urea derivatives have the formula

wherein Rl and R2 are each hydrogen, halogen, hydrocarbyl of 1 to 6 carbon atoms, alkoxy, alkylthio, nitro, amino, alkylamino, dialkylamino, acylamino or trihalomethyl; R3 and R4 are each hydrogen, lower alkyl, lower cycloalkyl, aryl, aralkyl or aryl substituted with a member selected from halogen, lower alkoxy, nitro, aryloxy and hydrocarbyl, R5 is hydrogen, halogen, hydrocarbyl, alkoxy or halogen-substituted hydrocarbyl;R6 and R7 are each nitro, cyano, amino, acylamino, alkylamino, dialkylamino, alkylthio, aryloxy, arylthio or a group R5 as defined above, and n is 1 or 2, provided that when one of R5, R, and R7 is chlorine, the substituted -(CH2)n-group is attached at the 4-position of the pyridine ring and that when R, and R2 are both selected from hydrogen or alkyl, R4 is cycloalky, aryl, aralkyl or aryl substituted with a member selected from halogen, lower alkoxy, nitro, aryloxy and hydrocarbyl, or at least one of R5, R6 and R7 is cycloalkyl, aryl, aralkyl, alkenyl, cyano, amino, acylamino, alkylamino, dialkylamino, alkylthio, arylthio or aryloxy. The one specific example of a 3-pyridylmethylurea derivative is 1,1- diphenyl-3-(3-pyridylmethyl) urea, which is prepared by reaction of 3-aminomethylpyridine with diphenylcarbamoyl chloride.

An analogous class of 1-naphthyl-3-(pyridylalkyl)urea derivatives having similar activity is described in UK Patent Specification No. 1,498,629.

US Patent No. 3,128,280 discloses a class of 1-(alkoxylated/halogenated phenyl)-3-(pyridylmethyl)ureas wherein the 3-nitrogen atom bears either a hydrogen atom or an alkyl substituent. The compounds are stated to possess valuable pharmacological properties e.g. anti-inflammatory, anti-bacterial (8. sub tllis), anti-fungal (ringworm -Trichophyton menfagrophytes) and anorectic activity.Specific 3-pyridylmethyl urea derivatives exemplified are 1 -p-chlorophenyl-3-(3-pyridylmethyl)urea, 1 -o-chlorophenyl-3-methyl-(3- pyridylmethyl)urea, 1-(3,4,5- trimethoxyphenyl)-3-(3-pyridylmethyl)urea (and its hydrochloride salt), and 1p-ethoxyphenyl-3-methyl-3-(3-pyridylmethyl)urea, all of which are prepared by reacting the appropriate 3aminomethylpyridine with the appropriate substituted phenyl isocyanate.

US Patent No. 3,700,678 discloses a class of herbicidal 1- phenyl-3-(pyridylmethyl)ureas of formula

wherein X is nitro, methyl or trifluoromethyl and n is 1 or 2. Synthesis of these compounds is by reaction of the appropriate amine with the appropriate substituted phenyl isocyanate.

Other pyridylmethyl ureas preparable by reaction of 3-aminomethylpyridine with various aryl isocyanates are disclosed in UK Patent Specifications Nos. 1,456,269 and 1,503,004. It is stated of the compounds of UK Patent Specification No. 1,456,269 that they are biologically active and may be useful as bactericides, fungicides (especially for phytopathogenic fungi), insecticides, rodenticides and herbicides. However, the disclosure thereafter concentrates exclusively on the rodenticidal nature of the compounds and the only activity data presented is rodenticidal data. UK Patent Specification No. 1,503,004 mentions only rodenticidal activity for the compounds thereof.

There has now been discovered a novel class of pyridylalkyl urea derivatives having useful fungicidal activity.

According to the present invention there are provided pyridylalkyl urea derivatives of formula

and acid-addition salts thereof, wherein n is 0 or 1, R is a halogen, C,4alkyl or C1.4alkoxy moiety, R' represents a phenyl group substituted by at least one halogen atom, R2 represents hydrogen or an optionally substituted alkyl, cycloalkyl or alkenyl group, and R3 represents an optionally substituted alkyl, cycloalkyl or alkenyl group, or R2 and R3 together with the interjacent nitrogen atom form a 5-or 6- membered ring optionally containing a second heteroatom selected from oxygen and nitrogen, the ring being optionally substituted by one or two CIA alkyl groups.

Optional substituents include for exmaple halogen atoms and alkyl, alkoxy, haloalkyl, haloalkoxy, alkoxycarbonyl, phenyl, phenoxy, phenylthio, and alkylthio groups, any alkyl moiety present preferably having up to 4 carbon atoms.

Preferably n is 0.

Fl is preferably a phenyl group substituted by 1 to 3 halogen atoms and is more preferably a 4-halophenyl or 2,4-dihalophenyl group.Preferably the or each halogen atom is independently selected from chlorine and bromine. Examples or preferred Fl groups include 4-chlorophenyl, 2,4-dichlorophenyl and 2bromo- 4-chlorophenyl.

In respect of R2 and R3, conveniently an alkyl or alkenyl group may be linear or branched and may have up to 10 carbon atoms, and a cycloalkyl group 3 to 10 carbon atoms. R2 preferably represents hydrogen or a C,6alkyl group and R3 a C,6alkyl group. An alkyl group R2 and/or R3 is preferably C,4alkyl.When R2 and R3 together with the interjacent nitrogen atom form a ring, the ring is preferably a piperidino, pyrrolidino or morpholino group.

Pyridylalkyl urea derivatives of formula I may conveniently be prepared according to the invention by a process which comprises reacting an amine of formula

wherein n, R and R1 are as defined above, with an acid derivative of formula

or an isocyanate of formula R3-N=C=O, wherein R4 is R2 as defined above, other than hydrogen, R3 is as defined above and L is a leaving group, in the presence of an inert solvent.

The derivative of formula Ill is conveniently an acid halide, preferably an acid chloride, which may if desired by generated in situ by prior reaction of the appropriate secondary amine with phosgene.

Suitable inert solvents for the process include hydrocarbon solvents, especially aromatic hydrocarbons, such as xylene and toluene, and ethers, such as tetrahydrofuran. Reaction is conveniently effected in the presence of a base, for example a tetiary amine, such as triethylamine. Reaction temperatures in the range from ambient temperature to the reflux temperature of the reaction mixture may conveniently by employed.

The invention further provides a fungicial composition which comprises at least one carrier and, as active ingredient, a pyridylalkyl urea derivative of the invention.

A composition according to the invention preferably contains from 0.5 to 95% by weight of active ingredient.

A carrier in a composition according to the invention is any material with which the active ingedient is formulated to facilitate application to the locus to be treated, which may for example be a plant, seed or soil, or to facilitate storage, transport or handling.A carrier may be a solid or a liquid, including a material which is normally gaseous but which has been compressed to form a liquid, and any of the carriers normally used in formulating fungicidal compositions may be used.

Suitable solid carriers include natural silicas such as diatomaceous earths; magnesium silicates, for example talcs; magnesium aluminum silicates, for example attapulgites and vermiculites; aluminium silicates, for example kaolinites, montmorillonites and micas; calcium carbonate; calcium sulphate; synthetic hydrated silicon oxides and synthetic calcium or aluminium silicates; elements, for example carbon and sulphur; natural and synthetic resins, for example coumarone resins, polyvinyl chloride, and styrene polymers and copolymers; solid polychlorophenols; bitumen; waxes, for example beeswax, paraffin wax, and chlorinated mineral waxes; and solid fertilisers, for example superphosphates.

Suitable liquid carriers include water; alcohols, for example isopropanol and glycois; ketones, for example acetone, methyl ethyl ketone, methyl isobutyl ketone and cyclohexanone; ethers; aromatic or araliphatic hydrocarbons, for example benzene, toluene and xylene; petroleum fractions, for example kerosine and light mineral oils; chlorinated hydrocarbons, for example carbon tetrachloride, perchloroethylene and trichloroethane. Mixtures of different liquids are often suitable.

Fungicidal compositions are often formulated and transported in a concentrated form which is subsequently diluted by the user before application. The presence of small amounts of a carrier which is a surface-active agent facilitates this process of dilution. Thus preferably at least one carrier in a composition according to the invention is a surface-active agent. For example, a composition may contain at least two carriers, at least one of which is a surface-active agent.

Of particular interest in enhancing the duration of the protectant activity of the compounds of this invention is the use of a carrier which will provide a slow release of the fungicidal compounds into the environment of the plant which is to be protected. Such slow-release formulations could, for example, be inserted in the soil adjacent to the roots of a vine plant, or could include an adhesive component enabling them to be applied directly to the stem of a vine plant.

A surface-active agent may be an emulsifying agent, a dispersing agent or a wetting agent; it may be nonionic or ionic. Examples of suitable surface-active agents include the sodium or calcium salts of polyacrylic acids and lignin sulphonic acids; the condensation products of fatty acids or aliphatic amines or amides containing at least 12 carbon atoms in the molecule with ethylene oxide and/or propylene oxide; fatty acid esters of glycerol, sorbitan, sucrose or pentaerythritol; condensates of these with ethylene oxide and/or propylene oxide; condensation products of fatty alcohol or alkyl phenols, for example p-octylphenol or p-octylcresol, with ethylene oxide and/or propylene oxide; sulphates or sulphonates of these condensation products; alkali or alkaline earth metal salts, preferably sodium salts, of sulphuric or sulphonic acid esters containing at least 10 carbon atoms in the molecule, for example sodium lauryl sulphate, sodium secondary alkyl sulphates, sodium salts of sulphonated caster oil, and sodium alkylaryl sulphonates such as sodium copolymers of ethylene oxide and propylene oxide.

The compositions of the invention may for example be formualted as wettable powders, dusts, granules, solutions, emulsifiable concentrates, emulsions, suspension concentrates and aerosols. Wettable powders usually contain 25, 50 or 75%w of active ingredient and usually contain, in addition to solid inert carrier, 3-10%w of a dispersing agent and, where necessary, 0- 10%w of stabiliser(s) and/or other additives such as penetrants or stickers. Dusts are usually formulated as a dust concentrate having a similar composition to that of a wettable powder but without a dispersant, and may be diluted in the field with further solid carrier to give a composition usually containing -71-10%w of active ingredient. Granules are usually prepared to have a size between 10 and 100 BS mesh (1.676-0.152mm), and may be manufactured by agglomeration or impregnation techniques.

Generally, granules will contain 1/2-25%w active ingredient and 0-10%w of additives such as stabilisers, slow release modifiers and binding agents. Emulsifiable concentrates usually contain, in addition to a solvent and, when necessary, co-solvent, 1- 50%w/v active ingredient, 2-20%w/v emulsifiers and 0-20%w/ v of other additives such as stabilisers, penetrants and corrosion inhibitors.Suspension concentrates are usually compounded so as to obtain a stable, non-sedimenting flowable product and usually contain 1075%w of suspending agents such as protective colloids and thixotropic agents, 0-10%w of other additives such as defoamers, corrosion inhibitors, stabilisers, penetrants and stickers, and water on an organic liquid in which the active ingredient is substantially insoluble; certain organic solids or inorganic salts may be present dissolved in the formation to assist in preventing sedimentation or as antifreeze agents for water.

The compositions may also contain other ingredients, for example other compounds possessing pesticidal, especially insecticidal, acaricidal, herbicidal or fungicidal, properties.

Aqueous disperions and emulsions, for example compositions obtained by diluting a wettable powder or a concentrate according to the invention with water, also lie within the scope of the present invention.

The said emulsions may be of the water- in-oil or of the oil-in-water type, and may have a thick 'mayonnaise'-like consistancy.

The invention still further provides the use as a fungicide of a derivative of the general formula I or a salt or an ester thereof as defined above, and a method for combating fungus at a locus, which comprises treating the locus, which may for example be plants subject to or subjected to fungal attack, seeds of such plants or the medium in which such plants are growing or are to be grown, with such a derivative.

The present invention is of wide applicability in the protection of crop plants against fungal attack.

Typical crops which may be protected include vines, grain crops such as wheat and barley, and apples.

The duration of protection is normally dependant on the individual compound selected, and also a variety of external factors, such as climate, whose impact is normally mitigated by the use of a suitable formulation.

The invention will be further understood from the following Examples.

Example 1 Preparation of N-2,4dichlorophenyl-N-3-pyridylmethyl-N'N'- dimethyl urea N-3-pyridylmethyl-2,4-dichloroaniline (7.599, 0.03mol) and N,N- dimethylcarbamoyl chloride (6.459, 0.06mol) were dissolved in xylene (100ml) and the resulting solution was treated with triethylamine (6.06g, 0.06mol) in xylene (35ml) at ambient temperature (206C). The mixture was stirred for 5 minutes at ambient temperature and then for 60 hours under reflux. The resulting mixture was cooled to ambient temperature, washed with 5%w/v aqueous sodium bicarbonate and with water (3 times), dried (MgSO4) and volatiles were then evaporated off.The residue was purified by chromatography on a silica column using 4% methanolidichloromethane as eluant to give the title product as an oil (8.69, 88%).

Examples 2 to 4 A further four compounds of general formula I wherein n is 0 were prepared by processes similar to that employed in Example 1.

Example 5 Preparation of N-2,4-dichlorophen yl-N-(3-p yridylmethyl)- N'-n-butyl-N'-methylurea A solution of N-methyl-N-nbutylamine (6.19, 0.07 mol) in dry xylene (70ml) was stirred, warmed to 40"C, and saturated with phosgene. Excess phosgene was removed with nitrogen, and the resulting solution treated with dry triethylamine (7.079, 0.07mol) and 2,4-dichloro-N-(3'-pyridylmethyl)-aniline (7.599, 0.03 mol) in dry xylene (70 ml). After 5 minutes, the reaction mixture was heated to 145-150"C, and stirred at this temperature for 40 hours.After cooling, the reaction mixture was washed with 5% w/v aqueous sodium bicarbonate, then with water (X2) and dried (MgSO4). After filtration, solvent was removed in vacuo, and the residual oil subjected to column chromatography (silica gel/ethylacetate, then silica gel/4% w/v methanol in dich(oromethane), to yield N-2,4-dichlorophenyl- N-(3-pyridylmethyl)-N'-nbutyl-N'-methylurea as an oil.

Example 6 Preparation of N-2,4-dichlorophenyl-N-(3-pyridylmethyl)- N'-n-butylurea To a stirred solution of N-(3-pyridylmethyl)-2,4-dichloroaniline (7.599, 0.03 mol) in dry xylene (70 ml) was added a solution of n-butylisocyanate (6.3g, 0.06 mol) in dry xylene (35 ml) followed by dry triethylamine (2ml.). The reaction mixture was stirred at ambient temperature (20"C) for 1/2 hour, then at 145 150"C for 14 days. The mixture was cooled, washed with water (X3), and the organic solution dried (MgSO4). After filtration, solvent was removed in vacuo and the residue subjected to column chromatography on silica gel, eluting with 4% w/v methanol in dichloromethane, to yield N-2,4-dichlorophenyl- N (3-pyridylemthyl)-N'-n-butylurea as an oil.

Details of the compounds of Examples 1 to 6, including analytical data are given in Table 1 following: TABLE 1 Example RI R2 R3 Yield (%) mp pC) Analysis (calculated) (found) 1 2,4-dichlorophenyl methyl methyl 88 oil 55.6 C, 4.6 H, 13.0 N 1 55.3 C, 4.6 H, 12.7 N 2 4-chlorophenyl methyl methyl 75 98-9 62.3 C, 5.5 H, 14.5 N 62.1 C, 5.6 H, 14.5 N 3 2-bromo-4-chloro- methyl methyl 68 oil 48.9 C, 4.1 H, 11.4 N phenyl 48.3 C, 4.2 H, 10.7 N 4, 2,4-dichlorophenyl ethyl ethyl 71 oil 58.0 C, 5.4 H, 11.9 N 58.1 C, 5.5 H, 11.9 N 5 2,4-dichlorophenyl methyl n-butyl 11 ' oil 59.0 C, 5.7 H, 11.5 N 59.0 C, 6.2 H, 11.1 N 6 2,4-dichlorophenyl H n-butyl 5 oil 58.0 C, 5.4 H, 11.9 N 58.3 C, 5.5 H, 11.4N Example 7 The fungicidal activity of compounds of the invention was investigated by means of the following tests.

(a) Direct protectant activity against vine downy mildew rPlasmopara viticola; P.v.pJ The test is a direct protectant one, using a foiar spray. The lower surfaces of leaves of whole vine plants (cv Cabernet Sauvignon) are sprayed with a solution of active material in 1:1w/v water/acetone containing 0.04%w/v "Triton X-155" (trade mark) surfactant, at a dosage of 1 kilogram of active material per hectare using a track sprayer which delivers 620 1/ha, and after a subsequent 24 hours under normal glasshouse conditions the lower surfaces of the leaves are iiioculated by spraying with an aqueous solution containing 104 zoosporangia/ml. The inoculated plants are kept for 24 hours in a high humidity compartment, 5 days under normal glasshouse conditions and then returned for a further 24 hours to high humidity.Assessment is based on the percentage of leaf area covered by sporulation compared with that on control leaves.

(b) Activity against wheat leafspot (Leptosphaeria nodorum; Ln.) The test is a direct antisporulant one, using a folair spray. Leaves of wheat plants (cv Mardler), at the single leaf stage, are inoculated by spraying with an aqueous suspension containing 8 x 105 spores/ ml.The inoculated plants are kept for 24 hours in a high humidity compartment prior to treatment. The plants are sprayed at a dosage of 1 kg. of active material per hectare using a track sprayer as described under (a). After drying, the plants are kept for 5 days under normal glasshouse conditions, followed by assessment. Assessment is based on the percentage of leaf area covered by sporulation compared with that on leaves of control plants.

(c) Activity against barley powdery mildew {Erysiphe graminis f.sp. hordei; Eg.J The test is a direct antisporulant one, using a folair spray. Leaves of barley seedlings, cultivar Golden Promise, are inoculated by dusting with mildew conidia one day prior to treatment with the test compound. The inoculated plants are kept overnight at glasshouse ambient temperature and humidity prior to treatment. The plants are sprayed at a dosage of 1kg. of active material per hectare using a track sprayer as described under (a). After drying, plants are returned to a compartment at ambient temperature and humidity for up to 7 days, followed by assessment. Assessment is based on the percentage of leaf area covered by sporulation compared with that on leaves of control plants.

(d) Activity against apple powdery mildew (Podosphaera leucotricha; P. I.J The test is a direct anti-sporulant one using a folair spray. The upper surfaces of leaves of whole apple seedlings are inoculated by spraying with an aqueous suspension containing 105 conidia/ml 2 days prior to treatment with the test compound. The inoculated plants are immediately dried and kept at glasshouse ambient temperatures and humidity prior to treatment. The plants are sprayed at a dosage of 1 kilogram of active material per hectare using a track sprayer as described under (a). After drying the plants are returned to a compartment at ambient temperature and humidity for up to 9 days, followed by assessment. Assessment is based on the percentage of the leaf area covered by sporulation compared with that on leaves of control plants.

(e) Systemic activity against barley powdery mildew {Erysiphe graminis, Eg.S) The test is a sytemic protectant one using a soil drench. Active material is applied at a rate of 10 kg/ha by pouring a soil drench (concentration 0.36 g/l active material in 12% v/v actone/water) evenly over soil in pots. Seeds (25 per 6 cm square pot) are scattered on the surface of the treated soil and covered with untreated soil to a depth of 1 cm. The pots are then transferred to glasshouse and sub-irrigated. Seven days after planting, when the seeds have germinated, the seedlings are dusted with mildew conidia and kept at glasshouse ambient temperature and humidity for five days, followed by assessment. Assessment is based on the percentage of leaf area covered by sporulation compared that on leaves of control plants.

The extent of disease control in all the above tests is expressed as a rating compared with a diluent sprayed control according to the criteria: 0 = less than 50% disease control 1 = about 50-80% disease control 2 = greater than 80% disease control Results of the above tests are given in Table II following; wherein Comparative A denotes N-2,4-dichlorophenyl-N-3-pyridylmethyl-N',N'-diphenyl urea, a compound prepared by reaction of diphenylcarbamoyl chloride with the appropriate 3-aminomethylpyridine similarly to the procedure of Example 1 of UK Patent Specification No. 1,486,459.

TABLE II Compound Example Fungicidal activity Pvp Ln Eg Pl Eg. S 1 1 2 2 2 1 2 3 2 2 2 4, 1 1 2 5 1 1 2 6 1 2 1 Comparative A 1 -

Claims (15)

1. A pyridylalkyl urea derivative of formula

or an acid-addition salt thereof, wherein n is 0 or 1, R is a halogen, C,4alkyl or C14alkoxy moiety, R' represents a phenyl group substituted by at least one halogen atom, R2 represents hydrogen or an optionally substituted alkyl, cycloalkyl or alkenyl group, and R3 represents an optionally substituted alkyl, cycloalkyl or alkenyl group, or R2 and R3 together with the interjacent nitrogen atom form a 5-or 6- membered ring optionally containing a second heteroatom selected from oxygen and nitrogen, the ring optionally substituted by one or two C,4alkyl groups

2. A derivative according to Claim 1 wherein n is 0.

3. A derivative according to Claim 1 or 2 wherein R' represents a phenyl group substituted by 1 to 3 halogen atoms.

4. A derivative according to Claim 1 or 2 wherein R1 represents a 4-halophenyl or 2,4-dihalophenyl group.

5. A derivative according to any of Claims 1 to 4 wherein the or each halogen atom is independently selected from chlorine and bromine.

6. A derivative according to any of Claims 1 to 5 wherein R2 represents hydrogen or a C1.6alkyl group and R3 represents a C,,alkyl group.

7. A derivative according to Claim 1 substantially as described in any one of Examples 1 to 5.

8. A process for the preparation of a derivative of formula I as defined in any of Claims 1 to 7 which comprises reacting an amine of formula

wherein n, R and R1 are as defined in Claim 1, with an acid derivative of formula

or an isocyanate of formula R3-N=C=O, wherein R4 is R2 as defined above, other than hydrogen and R3 are as defined in Claim 1 and L is a leaving group, in the presence of an inert solvent.

9. A process according to Claim 8 wherein L is a halogen atom.

10. A process according to Claim 8 substantially as hereinbefore described with reference to any one of Examples 1 to 6.

11. A fungicidal composition which comprises at least one carrier and, as active ingredient, a derivative according to any of Claims 1 to 7.

12. A composition according to Claim 11 which includes at least two carriers, at least one of which is a surface-active agent.

13. A method of combating fungus at a locus, which comprises treating the locus with a derivative according to any of Claims 1 to 7.

14. A method according to Claim 13 wherein the locus comprises plants subject or subjected to fungal attack, seeds of such plants, or the medium in which the plants are growing or are to be grown.

15. The use as fungicide of a derivative of formula I or an acid-addition salt thereof as defined in any of Claims 1 to 7.