Field of the invention

This invention relates to new derivatives of anthranilic acid useful as fungicides.

Prior Art

In GB 1 ,563,664 and Japanese Kokai 531 30655 and 53072825, there are disclosed fungicidal esters of anthranilic acid. We have found that certain novel anthranilic acid derivatives also have valuable fungicidal activity and also have advantages over compounds disclosed in these publications.

Disclosure of the invention According to the invention there is provided a compound of formula I

wherein

A is a 5 membered optionally substituted, heteroaryl group comprising at least one hetero atom selected from nitrogen, sulfur and oxygen, which is optionally substituted by one or more of the group R ² ;

R ¹ is alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, or amino, (each of which is optionally substituted), Y ¹ -X- _f halogen, cyano, nitro, acyl, optionally substituted heterocyclyl or optionally substituted phenyl; or two adjacent groups together with the carbon atoms to which they are attached can form an optionally substituted benzo ring;

R ² has the same meaning as R ¹ or two adjacent groups together with the carbon atoms to which they are attached can form an optionally substituted heterocyclic ring; Y is alkyl, cycloalkyl, cycloalkenyl, alkenyl or alkynyl, each of which is optionally substituted, hydrogen or acyl;

Y ¹ has the same meaning as Y or is optionally substituted phenyl or optionally substituted heterocyclyl;

Z is C( = X ¹ )-X ² -R ³ , cyano, nitro, amino, acyl, optionally substituted heterocyclyl,

-C(R ^s ) = N-OR ⁶ or -C.(R ⁵ ) = N-NR ⁶ R ⁷ ;

R ³ is alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, phenyl or heterocyclyl, each of which is optionally substituted, hydrogen or an inorganic or organic cationic group;

X ¹ and X ² , which may be the same or different, are 0 or S;

R ⁵ , R ^β and R ⁷ , which may be the same or different, are alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, phenyl or heterocyclyl, each of which is optionally substituted or hydrogen or R ⁶ and R ⁷ together with the atom(s) to which they are attached can form a ring; and n is 0 to 4, together with complexes with metal salts, as well as salts with bases of compounds which are acids and salts with acids of compounds which are bases, with the proviso that when Z is methoxycarbonyl and Y is hydrogen and ring A is furyl or thienyl, then either n is not 0 or ring A is substituted.

Examples of rings that A can be include, thiophene, furan, pyrrole, pyrazole, imidazole, thiazole, isothiazole, oxazole, isoxazole, thiadiazole, oxadiazole and triazole. When the ring comprises a sulfur atom this may be in an oxidised state either as sulfoxide or sulfone.

In a particularly preferred group of compounds Z is methoxycarbonyl.

Alkyl groups are preferably of 1 to 20, eg 1 to 6, carbon atoms. Alkenyl and alkynyl groups are generally of 3 to 6 carbon atoms. Cycloalkyl or cycloalkenyl groups are preferably of 3 to 8 carbon atoms.

Substituents, when present on any alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, alkoxy or alkylthio group, include halogen, cyano, alkoxy (e.g. of 1 to 4 carbon atoms, and which may be substituted, e.g. by halo), hydroxy, alkylthio, nitro, optionally substituted amino, carboxy, alkoxycarbonyl, acyl, acyloxy, heterocyclyl and aryl.

Cycloalkyl or cycloalkenyl groups may also be substituted by alkyl.

Aryl groups are usually phenyl, optionally substituted, e.g. by one or more of the same groups as defined for R ¹ .

The term heterocyclyl includes both aromatic and non-aromatic heterocyclyl groups. Heterocyclyl groups are generally 5, 6 or 7-membered rings containing up to 4 hetero atoms selected from nitrogen, oxygen and sulfur. Examples of heterocyclyl groups are furyl, thienyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, dioxolanyl, oxazolyl, thiazolyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyranyl, pyridyl, piperidinyl, dioxanyl, morpholino, dithianyl, thiomorpholino, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, triazinyl, thiazolinyl, benzimidazolyl, tetrazolyl, benzoxazolyl, imidazopyridinyl, 1 ,3-benzoxazinyl, 1 ,3-benzothiazinyl, oxazolopyridinyl, benzofuranyl, quinolinyl, quinazolinyl, quinoxalinyl, sulfolanyl, dihydroquinazolinyl, benzothiazolyl, phthalimido, benzofuranyl, azepinyl, oxazepinyl, thiazepinyl, diazepinyl and benzodiazepinyl. Heterocyclyl groups may themselves be substituted for example as for phenyl.

Amino groups may be substituted for example by one or two optionally substituted alkyl, acyl or sulfonyi groups, or two substituents can form a ring, preferably a 5 to 7-membered ring, which may be substituted and may contain other hetero atoms, for example morpholine, thiomorphoiine, or piperidine.

The term acyl includes the residue of sulfur and phosphorus-containing acids as well as carboxylic acids. Examples of acyl groups are thus -COR ⁵ , -COOR ⁵ , -CXNR ⁵ R ^β , -CON(R ⁵ )OR ⁶ , -COONR ⁵ R ^e , -CON(R ⁵ )NR ^β R ⁷ , -COSR ⁵ , -CSSR ⁵ , -S(0) _p R ⁵ , -S(0) ₂ OR ⁵ , -S(0) _p NR ⁵ R ⁶ , -P( = X)(OR ⁵ )(OR ⁶ ), -CO-COOR ⁵ , where R ⁵ , R ^β and R ⁷ are as defined previously, or R ^δ and R ⁷ together with the atom(s) to which they are attached can form a ring, p is 1 or 2 and X is 0 or S.

Complexes of compounds of the invention are usually formed from a salt of formula An ₂ , in which is a divalent metal cation, e.g. copper, manganese, cobalt, nickel, iron or zinc and An is an anion, e.g. chloride, nitrate or sulfate.

The compounds of the invention have activity against a wide range of pathogens of Deuteromycete, Ascomycete, Phycomycete and Basidiomycete origin, and especially against fungal diseases of plants, e.g. mildews and particularly cereal powdery mildew (Erysiphe graminis) and vine downy mildew (Plasmopara vtticola), rice blast (Pyricularia oryzae), rice sheath blight (Pellicularia sasakii), apple scab

(Ventυria inaequalis). grey mould (Botrytis cmerea) and glume blotch

(Leptosphaeria nodorum).

The compounds of the invention are generally formulated in conventional compositions used for fungicides. These compositions can contain one or more additional pesticides, for example compounds known to possess herbicidal, fungicidal, insecticidal, acancidal or nematicidal properties.

The diluent or carrier in the composition of the invention can be a solid or a liquid optionally in association with a surface-active agent, for example a dispersing agent, emulsifying agent or wetting agent. Suitable surface-active agents include anionic compounds such as a carboxylate, for example a metal carboxylate of a long chain fatty acid; an N-acylsarcosinate; mono- or di-esters of phosphoric acid with fatty alcohol ethoxylates or salts of such esters; fatty alcohol sulfates such as sodium dodecyl sulfate, sodium octadecyl sulfate or sodium cetyl sulfate; ethoxylated fatty alcohol sulfates; ethoxylated alkylphenol sulfates; lignin sulfonates; petroleum sulfonates; alkyl-aryl sulfonates such as alkyl-benzene sulfonates or lower alkylnaphthalene suifonates, e.g. butyl-naphthalene sulfonate; salts of sulfonated naphthalene-formaldehyde condensates; salts of sulfonated phenol-formaldehyde condensates; or more complex sulfonates such as the amide sulfonates, e.g. the sulfonated condensation product of oleic acid and N-methyl taunne or the dialkyl sulfosuccinates, e.g. the sodium sulfonate of dioctyl succinate. Nonionic agents include condensation products of fatty acid esters, fatty alcohols, fatty acid amides or fatty-alkyl- or alkenyl-substituted phenols with ethylene oxide, fatty esters of polyhydric alcohol ethers, e.g. sorbitan fatty acid esters, condensation products of such esters with ethylene oxide, e.g. polyoxyethylene sorbitan fatty acid esters, block copolymers of ethylene oxide and propylene oxide, acetylenic glycols such as 2,4,7,9-tetramethyl-

5-decyne-4,7-diol, or ethoxylated acetylenic glycols. Examples of a cationic surface-active agent include, for instance, an aliphatic mono-, di-, or polyamine as an acetate, naphtheπate or oleate; an oxygen-containing amine such as an amine oxide or polyoxyethylene alkylamine; an amide-linked amine prepared by the condensation of a carboxylic acid with a di- or polyamine; or a quaternary ammonium salt.

The compositions of the invention can take any form known in the art for the formulation of agrochemicals, for example, a solution, a dispersion, an aqueous emulsion, a dusting powder, a seed dressing, a fumigant, a smoke, a dispersible powder, an emulsifiable concentrate or granules. Moreover it can be in a suitable form for direct application or as a concentrate or primary composition which requires dilution with a suitable quantity of water or other diluent before application.

As a dispersion, the composition comprises a compound of the invention dispersed in a liquid medium, preferably water. It is often convenient to supply the consumer with a primary composition which can be diluted with water to form a dispersion having the desired concentration. The primary composition can be provided in any one of the following forms. It can be a dispersible solution which comprises a compound of the invention dissolved in a water-miscible solvent with the addition of a dispersing agent. A further alternative comprises a compound of the invention in the form of a finely ground powder in association with a dispersing agent and intimately mixed with water to give a paste or cream which can if desired be added to an emulsion of oil in water to give a dispersion of active ingredient in an aqueous oil emulsion.

An emulsifiable concentrate comprises a compound of the invention dissolved in a water-immiscible solvent together with an emulsifying agent and which is formed into an emulsion on mixing with water.

A dusting powder comprises a compound of the invention intimately mixed with a solid pulverulent diluent, for example, kaolin.

A granular solid comprises a compound of the invention associated with similar diluents to those which may be employed in dusting powders, but the mixture is granulated by known methods. Alternatively it comprises the active ingredient adsorbed or absorbed on a pre-granular diluent, for example. Fuller's earth, attapulgite or limestone grit.

A wettable powder usually comprises the active ingredient in admixture with a suitable surfactant and an inert powder diluent such as china clay.

Another suitable concentrate, particularly when the product is a solid, is a flowable suspension concentrate which is formed by grinding the compound with water, a wetting agent and a suspending agent.

The concentration of the active ingredient in the composition of the present invention is preferably within the range of 1 to 30 per cent by weight, especially 5 to 30 per cent by weight. In a primary composition the amount of active ingredient can vary widely and can be, for example, from 5 to 95 per cent by weight of the composition.

The compounds of the invention may be prepared in known manner, for example by reacting a compound of formula II

with a compound of formula III

O

II

Q— C— A (III) where Q is a leaving group, preferably a halogen and especially chlorine, to give a compound of formula I, where X is 0 and Y is hydrogen, and if desired modifying this compound in known manner to give other compounds where X and/or Y have other desired values, and if desired modifying compounds of formula I in known manner to give compounds where R ¹ has other values.

The reaction between compounds II and III is generally carried out in the presence of a base, e.g. an organic tertiary amine and preferably in the presence of a solvent, e.g. an ether.

The compounds of formula II and III are either known or can be prepared in known manner.

Where A is a sulfur containing ring, the sulfur can be oxidised in known manner.

The invention is illustrated in the following examples. Structures of isolated novel compounds were confirmed by elemental and/or other appropriate analyses. Temperatures are in °C.

Example 1

A stirred mixture of 5-bromo-2-furancarboxyiic acid (5 g) in dry toluene was treated with phosphoryl chloride (2.9 ml) and the mixture stirred at room temperature overnight. Methyl anthranilate (3.93 g) and triethylamine (3.63 ml) were added dropwise with ice-bath Cooling and the mixture stirred at room temperature overnight. Ethyl acetate was added and the mixture partitioned with water. The organic layer was washed with aqueous sodium hydrogen carbonate and brine, dried and evaporated. The residue was washed with light petroleum and recrystallised from acetonitrile to give methyl N-(5-bromo-2-furancarbonyl)- anthranilate, m.p. 1 70-1 .5 °. (compound 1 )

Example 2 A solution of methyl anthranilate (4.3 g) and triethylamine (3.93 ml) in tetrahydrofuran was added dropwise with ice-bath cooling and stirring to a solution of 5-nitro-2-furancarbonyl chloride (5 g) in tetrahydrofuran. The mixture was stirred for 5 hours, and evaporated under reduced pressure. The residue was washed with water, dissolved in dichloromethane and the organic extract washed with aqueous sodium hydrogen carbonate and brine, dried and evaporated. The residue was washed with light petroleum to give methyl N-(5-nitro-2-furan- carbonyDanthranilate, m.p. 1 79-81 ° . (compound 2)

Example 3

Compound 1 from Example 2 (1 g) was treated with methanolic sodium methoxide under reflux. The mixture was cooled, poured into water acidified with acetic acid and extracted with ethyl acetate. The extract was washed in turn with water and brine, dried over magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography to give methyl N-(5-methoxy-2-furan- carbonyDanthranilate, m.p. 109-10.5 °. (compound 3)

Example 4 A stirred mixture of 4-methoxy-5-methoxycarbonyl-2-thiophenecarboxylic acid (1 g) and thionyl chloride (5 ml) was heated under reflux for 9 minutes. The mixture was cooled, evaporated and the residue (comprising crude 4-methoxy- 5-ethoxycarbonyl-2-furancarbonyl chloride) was treated with methyl anthranilate and triethylamine in a similar manner to Example 1 . The reaction mixture was poured into water and the precipitate collected, washed with water and dried to give methyl N-(4-methoxy-5-methoxycarbonyl-2-thiophenecarbonyl)anthranil ate, m.p. 1 76-9°. (compound 4)

Example 5 A mixture of 2-methoxy-1 -methyl-5-imidazolecarboxylic acid (1 g) and 2-chloro-

1 -methylpyridinium chloride (1 .8 g) in acetonitrile was stirred at room temperature for 1 5 minutes. Triethylamine ( 1 .4 g was added and the mixture stirred at room temperature for 4 hours to give crude 2-[2-methoxy- 1 -methyl-5-imidazole- carbonyl)-1 -methylpyridinium chloride. Methyl anthranilate (0.97 g) was added and the mixture heated under reflux for 1 8 hours. It was evaporated under reduced pressure and the residue dissolved in dichloromethane and the organic extract washed with water, aqueous sodium hydrogen carbonate, water, dried and evaporated. The residue was washed triturated with light petroleum and the resultant oil treated with ether and filtered. The ether solution was evaporated and the residue purified by silica gel chronmatography to give methyl N-(2-methoxy-1 -methyl-5-imidazolecarbonyl)anthranilate, m.p. 1 1 2-3 ° . (compound 5)

Example 6

Sodium hydride (0J 6 g of a 60% dispersion in oil) was added with stirring at room temperature to a solution of the compound 13 (see later) (1 .04 g) in dry tetrahydrofuran (30 ml). The mixture was stirred for 1 5 minutes and then methyl iodide (0.5 ml) was added. The mixture was stirred at room temperature for 3 hours, left to stand overnight and poured into brine. It was then extracted with ethyl acetate. The extract was washed in turn with water and brine, dried over magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography to give methyl N-(3-methoxy-5-isoxazolecarbonyl)- N-methylanthranilate, m.p. 61 -3 °. (compound 6)

Example 7

In a similar manner to one of the previous Examples the following compounds were obtained

121-4

Example 8

A mixture of compound 48 ( 1 g) dichloromethane (20 ml), trifluoroacetic acid

(10 ml) and hydrogen peroxide (2 ml; 30%) was stirred at room temperature for two days. The mixture was partitioned between water and dichloromethane and the water phase extracted with dichloromethane. The dichloromethane extracts were washed with aqueous sodium sulphite and brine, dried, filtered and evaporated under reduced pressure. The residue was recrystallised from ethyl acetate to give methyl N-(5-bromo-2-thienylcarbonyl)anthranilate S,S-dioxide, m.p. 142-4°. (Compound 8a)

In a similar manner the following were obtained:

(i) methyl N-(5-chloro-2-thieπylcarbonyl)anthranιlate S,S-dioxide, m.p. 46-8 ° .

(Compound 8b) (ii) methyl N-(4,5-dibromo-2-thienylcarbonyl)anthraniiate S,S-dioxide, m.p. 1 65-6 ° . (Compound 8c)

(iii) methyl N-(2,5-dichloro-3-thienylcarbonyl)anthranilate S,S-dioxide, m.p. 140-2 °. (Compound 8d) (iv) methyl N-(5-methoxybenzofb]thiophen-2-ylcarbonyl)anthranilate S,S-dioxide, m.p. 1 27-9 ° . (Compound 8e)

Test Example

Compounds are assessed for activity against one or more of the following: Phytophthora infestans: late tomato blight P/asmopara viticola: vine downy mildew Erysiphe graminis: barley powdery mildew

Pyricularia oryzae: rice blast Pellicularia sasakii: rice sheath blight (PS) Botrytis cinerea: grey mould Venturia inaequalis: apple scab Leptosphaeria nodorum: glume blotch

Aqueous solutions or dispersions of the compounds at the desired concentration, including a wetting agent, were applied by spray or by drenching the stem base of the test plants, as appropriate. Plants or plant parts were then inoculated with appropriate test pathogens and kept under controlled environment conditions

suitable for maintaining plant growth and development of the disease. After an appropriate time, the degree of infection of the affected part of the plant was visually estimated. Compounds were considered active if they gave greater than

50% control of the disease at a concentration of 500 ppm (w/v) or less.

Compounds 43, 45, 94 and 100 showed activity against Phytophthora infestans;

Compounds 2, 4, 9, 10, 12, 18, 20, 28, 29, 30, 32-38, 40, 42, 44, 46, 49, 54,

55, 61, 65, 66, 70, 73, 79, 81, 83-8, 90, 91-7, 100, 103-6, 110-3, 115-20,

123 and 125-7, showed activity against Plasmopara viticola; Compounds 3, 17, 20, 41, 43, 48, 50, 51, 53, 56, 57, 68, 70, 71, 74, 80, 81, 89, 94, 96, 98, 99, 102, 120, 121, 122 and 127 showed activity against Erysiphe graminis;

Compounds 6, 16, 22, 23, 31, 64, 69, 72, 81 and 84 showed activity against Pyricularia oryzae Compounds 58 and 74 showed activity Botrytis cinerea;

Compounds 3, 8, 9, 15, 33, 46, 56, 58, 70, 78, 80, 82, 89, 94, 107, 108, 109, 114, 118, 119 and126 showed activity against Venturia inaequalis, and Compounds 16, 33, 113 showed activity against Leptosphaeria nodorum.