GB2280184A - Fungicidal spiroheterocyclic compounds having a tetrahydropyrimidylamino substituent - Google Patents

Abstract

New plant fungicidal compounds have the formula I <IMAGE> or are acid addition salts thereof, in which R<1> or each R<1> independently represents an optionally substituted I alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, aryl, arakyl or aryloxy group or R<1> or each R<1>, together with the ring to which they are attached, represents an optionally substituted polycyclic hydrocarbyl group, R<2> represents a hydrogen atom or an optionally substituted alkyl, or aralkyl group or represents together with R<4> an alkylene group, R<3> or each R<3> independently represents an optionally substituted alkyl, aryl or aralkyl group, R<4> represents a hydrogen atom or represents together with R<2> an alkylene group, m represents zero or an integer from 1 to 6, n represents an integer from 1 to 3, o represents zero or an integer from 1 to 4, and p represents zero or one. New intermediates have the formula III <IMAGE>

Description

FUNGICIDAL SPIROHETEROCYCLIC COMPOUNDS HAVING A TETRAHYDROPYRIMIDYLAMINO SUBSTITUENT The present invention relates to certain new spiroheterocyclic compounds having fungicidal properties, processes for the preparation of these compounds, fungicidal compositions containing the compounds and the use of the compounds as fungicides for the control of phytopathogenic fungi.

In EP 281842, EP 349247, EP 413223 and WO 92/16518 fungicidal spiroheterocyclic compounds have been described. These known compounds contain a substituted cyclohexyl ring in spiro conjunction with a substituted heterocyclic five or six membered ring.

The substituents of the cyclohexyl ring are usually (substituted) (branched) alkyl or phenyl groups. The substituents of the heterocyclic ring are usually (substituted) (cyclo)alkyl- or dialkyl-amino-methyl or dialkyl-amino-polymethyl groups, including alkylene-amino-methyl or alkylene-amino-polymethyl groups. Other fungicidal spiroheterocyclic compounds have been described in EP 278352.

It has now been found that certain new spiroheterocyclic compounds show excellent fungicidal activity against certain phytopathogenic fungi, for instance against Plasmopora viticola, Botrytis cinerea, Erysiphe graminis, Pseudocercosporella herpotrichoides, Rhizoctonia solani and Venturia inaequalis.

The present invention therefore relates to compounds of the general formula I

or an acid addition salt thereof, in which R or each R independently represents an optionally substituted alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, aryl, aralkyl or aryloxy group or R or each R, together with the ring to which they are attached, represents an optionally substituted polycyclic hydrocarbyl group, 2 R represents a hydrogen atom or an optionally substituted alkyl or aralkyl group* or represent together with R4 an alkylene group, R3 or each R3 independantly represents an optionally substituted alkyl, aryl or aralkyl group, 2 R4 represents a hydrogen atom or represents together with R an alkylene group, m represents zero or an integer from 1 to 6, n represents an integer from 1 to 3, o represents zero or an integer from 1 to 4, and p represents zero or one.

The invention especially relates to compounds of the general formula I in which any alkyl part of any of the substituents R1 to R3 contains up to 12 carbon atoms, preferably up to 10 carbon atoms, more preferably up to 8 carbon atoms, any cycloalkyl part of any of the substituents R to R contains from 3 to 10 carbon atoms, preferably from 3 to 8 carbon atoms, more preferably from 3 to 6 carbon atoms, any alkylene chain contains from 1 to 8 chain members, preferably from 1 to 4 chain members, and any aryl part of any of the substituents R to R contains 6, 10 or 14 carbon atoms, preferably 6 or 10 carbon atoms, and in which each optionally substituted group independently is substituted by one or more halogen atoms or nitro, cyano, alkyl, preferably C16 alkyl, cycloalkyl, preferably C36 cycloalkyl, haloalkyl, preferably C16 haloalkyl, halocycloalkyl, preferably C36 halocycloalkyl, alkoxy, preferably C16 alkoxy, haloalkoxy, preferably C1 6 haloalkoxy, phenyl or halo- or dihalo-phenyl groups. Any alkyl group may be linear or branched. Preferred alkyl substituents are at least methyl, ethyl, propyl, butyl and pentyl. A halogen atom suitably denotes a fluorine, chlorine or bromine atom.

The invention especially relates to compounds of the general formula I in which R or each R independently represents a C1-10 alkyl, C3-8 cycloalkyl, C3-8 cycloalkyl-Cl 6 alkyl, C1-10 alkoxy, 1 1 C1 10 alkoxy-Cl 6 alkyl, phenyl or benzyl group or R or each R together with the ring to which they are attached represents a C7 20 polycyclic group, preferably a C8 12 bicyclic, C9-14 tricyclic or C9-16 quadricyclic hydrocarbyl group, preferably a saturated hydrocarbyl group, each of the above groups optionally substituted by one or more halogen atoms, especially chlorine and/or fluorine atoms, or C14 alkyl, C1-4 haloalkyl or C14 alkoxy groups.

R1 preferably represents a C16 alkyl, C3-6 cycloalkyl, phenyl or benzyl group, each group optionally substituted by one or more chlorine and/or fluorine atoms or C1-4 alkyl, C1-4 haloalkyl or C1-4 alkoxy groups. R or each R independently more preferably represents a C16 alkyl or phenyl group, especially a branched alkyl group. Especially suitable are secondary and tertiary alkyl groups as isopropyl, secondary butyl, tertiary butyl and tertiary amyl or phenyl groups. More preferably R represents a t-butyl or t-amyl group. The invention also especially relates to compounds of the general formula I in which m is zero or represents an integer from 1 to 4, preferably m represents 1 or 2, more preferably 1.The group or groups R are preferably attached to the positions 3, 4 and/or 5 of the cyclohexyl ring, more preferably to the 4-position.

The invention also especially relates to compounds of the general formula I in which R represents a hydrogen atom or a methyl or ethyl group, optionally substituted by up to three chlorine or fluorine atoms, a phenyl or benzyl group or R together with R4 represents a methylene or ethylene group. Preferably R2 represents a hydrogen atom or a methyl or ethyl group or R2 together with R represents a methylene group.

The invention further especially relates to compounds of the general formula I in which R3 or each R3 independently represents a C1 10, preferably C1 8 alkyl, phenyl or benzyl group, each group optionally substituted by one or more halogen atoms, especially chlorine and/or fluorine atoms, or C1-4 alkyl, C1-4 haloalkyl or C1-4 alkoxy groups R or each R independently preferably represent a methyl, ethyl, propyl, butyl, pentyl, hexyl, phenyl or benzyl group, each group optionally substituted by up to five chlorine and/or fluorine atoms, especially three chlorine or fluorine atoms.

The invention especially relates to compounds of the general formula I in which n represents 1, o reoresents 0, 1 or 2 and p represents 1. The substituents R are preferably attached to the 4 and/or 6 position of the tetrahydropyrimidyl ring.

A particular preferred sub-group of compounds of the general formula I is that in which R represents a methyl, a propyl, especially i-propyl, a butyl, especially t-butyl, a pentyl, especially t-amyl, or a phenyl group. The groups are especially attached to the 4-position of the cyclohexyl group. Another preferred sub-group of compounds of the general formula I is that in which R or each R independently represents a methyl, propyl, butyl, especially i-butyl, or pentyl group. A further preferred sub-group of compounds of the general formula I is that in which R 4 and R4 both represent a hydrogen atom or together form a methylene group.

The present invention further provides a process for the preparation of compounds of the general formula I as defined in any of the preceding claims, which process comprises reacting a compound of the general formula II

in which R1 and m are as defined hereinbefore, with a compound of the general formula III

2 3 4 or an acid addition salt thereof, in which R , R , R4, n, o and p are as defined hereinbefore.

It will be appreciated that between the above indicated reaction steps additional chemical modifications can be made to the compounds obtained, e.g. introduction or amendment of certain substituents in the cycloalkyl or heteroaromatic ring.

The starting compounds with the general formula II are known in the literature, and many of them are commercially available.

Compounds of the general formula II are new compounds. These compounds form part of the present invention. These compounds may be prepared by oxidation of an alkene of the general formula IV

2 3 4 in which R , R , R , n and o are as defined hereinbefore, with a suitable oxidant, for instance with potassium permanganate or, especially, osmium tetroxide, especially a catalytic amount thereof together with a regeneration reagent, to give a compound of the general formula V

in which R2, R3, R4, n and o are as defined hereinbefore, followed by hydrogenation. The hydrogenation can be carried out according to literature methods. Very suitably hydrogen and a catalyst, for instance a noble metal catalyst as palladium or platinum, can be used.The alkenes of the general formula IV may be prepared by reaction of a (substituted) alkenylamine with a compound of the general formula VI

in which R and o are as defined hereinbefore and Z represents a leaving group. or by reaction of a (substituted) alkenylamine and a compound of the general formula VI

in which P represents a leaving group, followed by reaction with a compound of the general formula VIII

in which R represents hydrogen or is as defined above. Compounds of the general formulas VI, VII and VIII are known in the literature, or can be prepared in analogous ways. Alternatively, compounds of the general formula III can be prepared by reaction of a compound of the general formula V with a compound of the general formula IX

in which R2 and n are as defined hereinbefore followed by hydrogenation.

A leaving group is any group that, under the reaction conditions appropriate for the reaction involved, will cleave from the starting material, thus enabling substitution at that specific site. The leaving group Z may suitably be a halogen atom, for example a bromine atom or, especially, a chlorine atom, an alkoxy group, suitably C14 alkoxy, especially methoxy, an alkyl- or arylsulphonium group, especially a C16 alkyl-, phenyl- or tolylsulphonium group, or an alkyl- or aryl-sulphonic acid group, especially a C16 alkyl-, phenyl- or tolyl-sulphonic acid group.

The leaving group P is suitably an alkoxy or alkylthio group, suitably a C1 -4 alkoxy or C14 alkylthio group, especially a methoxy or methylthio group.

The process of the present invention in which the heterocyclic spirocompound is formed is suitably carried out in the presence of an organic solvent, for example an alkane, an aromatic solvent, a chlorinated hydrocarbon or an ether. Especially suitable are those organic solvents which form an azeotrope with water, such as benzene, toluene, chloroform etc.

The process is suitably carried out at a temperature in the range of O to 15O0C, especially between 40 and 120 "C, preferably at the reflux temperature of the solvent, and suitably in the presence of a acid.

Suitably the reaction is carried out using substantially equimolar amounts of the reactants. However, it can be expedient to use one reactant in excess.

The invention also provides fungicidal compositions comprising at least one of the compounds according to general formula I or an acid addition salt thereof, as well as methods of combating fungi at a locus comprising treatment of the locus with a compound of formula I or an acid addition salt thereof as defined hereinbefore, or with a composition as defined in this specification. The locus to be treated especially comprises plants subject to or subjected to fungal attack, seeds of such plants or the medium in which the plants are growing or are to be grown.

The fungicidal composition comprises a carrier and, as active ingredient, a compound of the general formula I or an acid addition salt thereof.

A method of making such a composition is also provided, which comprises bringing a compound of the general formula I as defined above or an acid addition salt thereof into association with at least one carrier. Such a composition may contain a single compound or a mixture of several compounds of the present invention.

It is also envisaged that different isomers or mixtures of isomers may have different levels or spectra of activity and thus compositions may comprise individual isomers or mixtures of isomers.

The invention further relates to the use as a fungicide of a compound of formula I as defined hereinbefore or a composition as defined hereinbefore.

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 ingredient is formulated to facilitate-application to the locus t9 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 and synthetic clays and silicates, for example natural silicas such as diatomaceous earths; magnesium silicates, for example talcs; magnesium'aluminium silicates, for example attapulgites and vermiculites; aluminium silicates, for example kaolinites, montmorillonites and micas; calcium carbonate; calcium sulphate; ammonium 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 glycols; 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 the composition may contain at least two carriers, at least one of which is a surface-active agent.

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, sorbitol, sucrose or pentaerythritol; condensates of these with ethylene oxide and/or propylene oxide; condensation products of fatty alcohol or alkyl phenols, for example E-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 castor oil, and sodium alkylaryl sulphonates such as dodecylbenzene sulphonate; and polymers of ethylene oxide and copolymers of ethylene oxide and propylene oxide.

The compositions of the invention may for example be formulated 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, 3-108 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 h-10% w of active ingredient. Granules are usually prepared to have a size between 10 and 100 BS mesh (1.676 - 0.152 mm), and may be manufactured by agglomeration or impregnation techniques.

Generally, granules will contain h-75% w active ingredient and 0-10% w of additives such as stabilisers, surfactants, slow release modifiers and binding agents. The so-called "dry flowable powders" consist of relatively small granules having a relatively high concentration of active ingredient. 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 10-75% w active ingredient, 0.5-15% w of dispersing agents, 0.1-10% w of suspending agents such as protective colloids and thixotropic agents, 0-108 w of other additives such as defoamers, corrosion inhibitors, stabilisers, penetrants and stickers, and water or an organic liquid in which the active ingredient is substantially insoluble; certain organic solids or inorganic salts may be present dissolved in the formulation to assist in preventing sedimentation or as anti-freeze agents for water.

Aqueous dispersions 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 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 consistency.

The composition of the invention may also contain other ingredients, for example compounds possessing herbicidal, insecticidal or fungicidal properties.

Of particular interest in enhancing the duration of the protective 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.

The present invention still further provides the use as a fungicide of a compound of the general formula I as defined above or a composition as defined above.

The present invention is of wide applicability in the protection of crop plants against fungal attack. Typical crops which may be protected include cereals, especially wheat and barley, rice, vines, potatoes, tomatoes, top fruit, especially apples, and cucumber. The duration of protection is normally dependent 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 compounds of the present invention are especially suitable to combat Erysiphe graminis in cereals.

The invention is further illustrated by the following examples.

Example 1 8-Methyl-2-(cis-4,6-dimethyl-3,4,5,6-tetrahydropyrimid-2-ylamino- methyl)-1,4-dioxaspiro(4,5)decane hydrochloride (compound 1) (i) Preparation of 1(4, 6-dimethylpyrimid-2-ylamino) -prop-2-ene 4,6-dimethyl-2-rnethylsulfonylpyrimidine (93.0 g, 0.5 mol) and allylamine (250 ml) were heated to reflux for 1 hour. Excess allylamine was distilled off and water (800 ml) was added. The crystalline product was filtrated and washed with water. Drying in vacuum yields 76.2 g of yellowish crystals (m.p. 62-63"C).

(ii) Preparation of 3-(4,6-dimethylpyrimid-2-ylamino) propane-1,2-diol N-methylmorpholine-N-oxide (64.0 g, 0.47 mol) and osmiumtetroxide (0.7 g, 2.75 mmol) were dissolved in a mixture of 180 ml water and 100 ml acetone. l-(4,6-dimethylpyrimid-2ylamino)-prop-2-ene (73.5 g, 0.45 mol) in 100 ml acetone was added over a period of 15 minutes. The mixture was stirred at room temperature for 1 hour and then warmed to 500C for 2 hours. 10 ml aqueous saturated sodium hydrogensulphite was then added together with 40 g of diatomaceous earth. After filtration the reaction mixture was evaporated to dryness and the residue extracted with dioxane/ethanol 2:1 (700 ml). Filtration from insoluble material and concentration of the solution in vacuum caused crystallisation of the product. Addition of toluene completed product precipitation, which was isolated by filtration (83 g, m.p. 124-127"C).

(iii) Preparation of 3-(cis-4,6-dimethyl-3,4,5,6-tetrahydropyrimid- 2-ylamino) -propane-l , 2-diol -hydrochloride A mixture of 3-(4,6.dimethylpyrimid-2-ylamino) -propane-l,2- diol (19.7 g, 0.1 mol) and palladium on charcoal (5 g, 10%) in 200 ml ethanol and conc. hydrochloric acid (12 ml) was Parr hydrogenated at 50 psi/SOOC until hydrogen uptake ceased. The reacton mixture was then filtered through diatomeous earth and the solvent was evaporated in vacuo to afford 3-(cis-4,6-dimethyl 3,4,5,6-tetrahydropyrimid-2-ylamino)-propane-1,2-diol hydrochloride as a colourless resin.

(iv) Preparation of 8-Methyl-2-(cis-4,6-dimethyl-3,4,5,6-tetra- hydropyrimid-2-ylamino-methyl)-1,4-dioxaspiro(4,5)decane hydrochloride 3-(cis-4,6-Dimethyl-3,4,5,6-tetrahydropyrimid-2-ylamino)- propane-1,2-diol hydrochloride (1.2 g, 5 mmol), 4-methyl cyclohexanone (0.56 g, 5 mmol) and hydrochloric acid in diethylether (2 ml, 27%) in 50 ml chloroform were refluxed on a water trapp for 2 hours. The reaction mixture was washed twice with saturated aqueous sodium bicarbonate (50 ml), dried with magnesium sulphate and the solvent was evaporated in vacuum. The colourless residue was recrystallised from diisopropylether. Yield 0.83 g of colourless crystals (m.p. 105-115"C).

Examples 2 to 21 By processes similar to those described in Example 1, further compounds according to the invention were prepared as detailed in Table I below. In this table, the compounds are identified by reference to formula I in which p represents 1. The starting alkene for compound 9 was 3-pyrroline.

Table I

R1 R2 R4 R3 m no 1. 4CH3 -H -H -4,6-(CH3)2 1 1 2 2. -4-t-C H -H -H -4,6-(CH3)2 1 1 2 3. -4-i-C H H -H -4,6-(CH3)2 1 1 2 4. -4-C H -H -H -4,6-(CH3)2 1 1 2 5. -3,5-(CH3)2 -H -H -4,6-(CH3)2 2 1 2 6. -H -H -4,6-(CH3)2 0 1 2 7. -4-t-C H -H -H -4,6-(CH3)2 1 1 2 8. -3,4-(CH2)4 -H -H -4,6-(CH3)2 2 1 2 9. -4-t-C H -CH2- -4,6-(CH3)2 1 1 2 10. -4-t-C H -H -H -4-(CH3) 1 1 1 11. -4-t-C5H11 -H -H -4-(CH3) 1 1 1 12. -4-t-C5H11 -H -H - 1 1 0 13. -4-t-C4H9 -H -H - 1 1 0 14. -4-C H -H -H - 1 1 0 15. -4-t-C H -H -H -4-(CH3)-6-n-C5H11 1 1 2 16. -4-t-C5Hll -H -H -4-(CH3)-6-n-C5H11 1 1 2 17. -4-C H -H -H -4-(CH3)-6-n-C5H11 1 1 2 18. -4-t-C4Hg -H -H -4-(CH3)-6-i-C4H9 1 1 2 19. -4-t-C5H11 -H -H -4-(CH3)-6-i-C4H9 1 1 2 20. -4-t-C H -CH3 -H -4,6-(CH3)2 1 1 2 21. -4-t-C5H11 -CH3 -H -4,6-(CH3)2 1 1 2 Physical data for the above compounds are set out in Tables II, III and IV below.

Table II Elemental Analysis (%) Compound C H N No. Calc. Found Calc. Found Calc. Found 15 64.24 63.52 10.31 10.93 9.77 9.61 16 64.91 63.82 10.44 10.37 9.36 9.36 17 77.72 64.25 8.96 8.84 9.31 9.29 18 63.67 61.28 9.96 10.12 9.80 8.98 19 64.20 63.30 10.30 10.80 9.80 9.80 20 61.90 56.80 9.90 11.10 10.80 11.20 21 62.70 58.70 10.00 9.50 10.50 10.20 Table III Melting point ( C) Compound No.

1 105-115 2 178-192 3 139-146 4 128-137 6 123-127 7 190-215 8 109-119 9 250-258 (dec.) Table IV 1H NMR-data (DMSO-D@) Compound 5: 8.10(s(br.), 2H); 7.60(m,1H); 4.25(mm,1H); 4.10(m,1H); 3.75(dd,lH); 3.57(m,3H); 3.36(m,1H); 2.13(m,1H); 1.80(m,6H) 1.30(d, 6H); 1.05(m,2H); 0.95(m,6H); 0.65 (m,1H).

Compound 10: 8.10(d(br.),1H); 7.96(d(br.),lH); 7.50(m(br.),lH); 4.15 m.1H); 4.0(m.1H); 3.63(m,1H); 3.40-3.10(m,5H); 1.92(m,1H); 1.85-1.60(m,4H); 1.50(m,2H); 1.30(m,3H); 1.10(d,3H); 1.03(m,1H); 0.85(s,9H).

Compound 11: 8.12(s(br.),lH); 7.95(d(br.),1H), 7.53(s(br.), 1H); 4.15(m,1H); 3.98(m,1H); 3.63(m,1H); 3.52(m,1H); 3.27(m,4H); 1.92(m,1H); 1.83-1.08(m,15H); 0.78(m,9H).

Compound 12: 7.95(d(br.),2H); 7.50(m(br.),lH); 4.15(m,1H); 3.98 (m,lH); 3.63(m,lH); 3.30-3.10(m,6H); 1.85-1.08(m,13H); 0.77(m,9H).

Compound 13: 8.05(d(br.), 2H), 7.65(m(br.), 1H); 4.15(m,1H); 4.0 (m,lH); 3.63(m,lH); 3.40-3.10(m,6H); 1.87-0.93(m,llH); 0.85(s,9H).

Compound 14: 8.10(d(br.), 2H); 7.73(m(br.),lH); 7.23(m,5H); 4.20 (m,1H); 4.05(m,1H); 3.68(m,1H); 3.37(m,2H); 3.24(m,4H); 2.56(m,1H); 1.90-1.50(m,10H).

Compound 21: 7.70(m(br.),2H); 4.28(m,lH); 4.04(m,1H); 3.75-3.43(m,5H); 3.03(s,3H); 2.03(m,1H); 1.75(m,2H); 1.60(m,3H); 1.40-1.08(m,13H); 0.78(s,9H).

Fungicidal activity The fungicidal activity of compounds of the invention was investigated by means of the following tests.

(a) Antisporulant activity against vine downy mildew (Plasmopara viticola; PVA) The test is a direct antisporulant one using a foliar spray.

The lower surfaces of leaves of whole vine plants (cv Cabernet Sauvignon), approximately 8 cm high, are inoculated by spraying with an aqueous suspension containing 5 x 104 zoosporangia/ml. The inoculated plants are kept for 24 hours at 21"C in a high humidity compartment, then 24 hours at glasshouse ambient temperature and humidity. Infected leaves are sprayed on their lower surfaces with a solution of active material in 1:1 water/acetone containing 0.04% "TWEEN 20" (Trade Mark; a polyoxyethylene sorbitan ester surfactant). Plants are treated using an automated sprayline with an atomising nozzle.The concentration of the compound is 600 ppm, and the spray volume is 750 1/aha. After spraying, the plants are returned to normal glasshouse conditions for 96 hours and are then transferred to the high humidity compartment for 24 hours to induce sporulation. Assessment is based on the percentage of the leaf area covered by sporulation compared with that on control leaves.

(b) Activity against tomato early blight (Alternaria solani; AS) This test measures the contact prophylactic activity of test compounds applied as a foliar spray. Tomato seedlings (cv Outdoor Girl) are grown to the stage at which the second true leaf is expanded. The plants are treated using an automated sprayline as described under (a). Test compounds are applied as solutions or suspensions in a mixture of acetone and water (50:50 v/v) containing 0.04% surfactant ("TWEEN 20" - Trade Mark). After drying the plants are kept for 24 hours in a glasshouse at 20 C and 40% R.H., followed by inoculaton of the leaf upper surfaces with a suspension of A. solani conidia containing 10 spores/ml. For 4 days after inoculation plants are kept moist in a humidity compartment at 210C. Disease is assessed 4 days after inoculation, based on the percentage of leaf surface area covered by lesions when compared with control plants.

(c) Direct protectant activity against broad bean grey mould (Botrytis cinerea; BCB) The test is a direct protectant foliar spray. The upper surfaces of leaves of broad bean plants with two leaf pairs (cv The Sutton) are sprayed with the test compound at a dosage of 600 ppm using an automated sprayline as described under (a). 24 hours after spraying the leaves are inoculated with an aqueous suspension containing 106 conidia/ml. For 4 days after inoculation plants are kept in a high humidity compartment at 220 C. Disease is assessed 4 days after inoculation, based on the percentage of leaf surface area covered by lesions.

(d) Activity against wheat leafspot (Leptosphaeria nodorum; LN.) The test is a direct therapeutic foliar spray. Leaves of wheat plants (cv Norman). at the single leaf stage, are inoculated by spraying with an aqueous suspension containing 1.5 x 106 conidia/ml. The inoculated plants are kept for 24 hours in a high humidity compartment prior to treatment. The plants are sprayed with a solution of the test compound at a dosage of 600 ppm using an automated sprayline as described under (a). After drying, the plants are kept for 6-8 days at 220C and moderate humidity (70%).

Assessment is based on the density of lesions per leaf compared with that on leaves of control plants.

(e) Activity against barley powdery mildew (Erysiphe graminis f.sp. hordei; EGT) The test is a direct therapeutic foliar spray. Leaves of barley seedlings, (cv. Golden Promise) at the single leaf stage 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 (18"C) and humidity (40%) prior to treatment. The plants are sprayed with the test compound at a dosage of 600 ppm using an automated sprayline as described under (a). After drying, plants are returned to a compartment at 18"C and 40% humidity for up to 7 days. Assessment is based on the percentage of leaf area covered by sporulation compared with that on leaves of control plants.

(f) Direct protectant activity against barley powdery mildew (Erysiphe graminis f.sp. hordei; EGP) The test is a direct protectant foliar spray. Leaves of barley seedlings (cv Golden Promise) at the single leaf stage are sprayed with the test compound as described under (a). After drying, the plants are kept for 24 hours in a glasshouse at 18"C and 40% R.H. Then the plants are inoculated by dusting with mildew conidia and kept at 180C and 40% R.H. for to 8 days. Assessment is based on the percentage of leaf area covered by sporulation compared with that on leaves of control plants.

(g) Direct protectant activity against tomato late blight (Phytophthora infestants: PIP) The test is a direct protectant foliar spray. Tomato plants with two expanded leaves (cv First in the Field) are sprayed with the test compound as described under (a). After drying, the plants are kept for 24 hours in the glasshouse at 200C and 40% R.H. Then, the upper surfaces of the leaves are inoculated with an aqueous suspension containing 2 x 105 zoosporangia/ml. The inoculated plants are kept for 24 hours at 18 C in a high humidity cabinet and 5 days at 15"C and 80% R.H. in a growth chamber with 14 hours light/day. The assessment is based on the percentage of diseased leaf area compared with that on control leaves.

(h) Activity against wheat eyespot in-vitro (Pseudocercosporella herpotrichoides; PHI) This test measures the in vitro activity of compounds against the fungus causing wheat eyespot. The test compound is dissolved or suspended in acetone and is added into 4 ml aliquots of half strength Potato Dextrose Broth (PDB) dispended in 25-compartment petri dishes to give a final concentration of 10ppm. The fungal inoculum consists of mycelial fragments of P. herpotrichoides grown in half strength PDB in shaken flasks and added to the broth to 4 provide 5 x 10 fragmentsiml broth. Petri dishes are incubated at 20 C for 10 days until the assessment of mycelial growth.

(i) Activity against Rhizoctonia in-vitro (Rhizoctonia solani: RSI) This test measures the in-vitro activity of compounds against R. solani that causes stem and root rots. The test compound in acetone is added into 4 ml aliquots of half strength Potato Dextrose Broth dispensed in 25-compartment petri dishes to give final concentratons of 10 ppm. The fungal inoculum consists of mycelial fragments of r. solani growth in half strength PDB in shaken culture flasks and added to the broth to provide 5 x 104 fragments/ml broth. Petri dishes are incubated at 20"C for 10 days until the assessment of mycelial growth.

(j) Activity against apple scab in-vitro (Venturia inaequalis: VII) This test measures the in-vitro activity of compounds against V. inaequalis that causes apple scab. The test compound in acetone is added into 4 ml aliquots of half strength Potato Dextrose Broth dispensed in 25-compartment petri dishes to give final concentrations of 10 ppm. The fungal inoculum consists of mycelial fragments and spores of V. inaequalis grown on malt agar and added to the broth to provide 5 x 104 propagules/ml broth. Petri dishes are incubated at 20 C for 10 days until the assessment of mycelial growth.

(k) Activity against rice leaf blast (Pyricularia oryzae; PO) The test is a direct therapeutic foliar spray. The leaves of rice seedlings (cv Aichiaishi - about 30 seedlings per pot) at the stage of the second leaf beginning to bend are sprayed with an aqueous suspension containing 105 spores/ml 24 hours prior to treatment with the test compound. The inoculated plants are kept overnight in high humidity and then allowed to dry before spraying with the test compound at a dosage of 600 ppm using an automated sprayline as described under (a). After treatment the plants are kept in a rice compartment at 25-300C and high humidity. Assessments are made 4-5 days after treatment and are based on the density of necrotic lesions per leaf when compared with control plants.

The extent of disease control in all the above tests is expressed as a rating compared with either an untreated control or a diluent-sprayed-control, according to the criteria:0 - less than 50% disease control 1about 50-80% disease control 2 = greater than 80% disease control The results of the tests are set out in Table V below.

TABLE V Comp. PVA AS BCB LN EGT EGP PIP PHI RSI VII PO 1 0 1 1 0 2 - 0 0 0 1 0 2 1 0 2 0 2 - 0 2 1 2 0 3 0 0 2 0 2 - 0 1 0 2 0 4 0 0 0 0 2 - 0 2 0 2 0 5 0 0 1 0 0 - 0 0 0 1 0 6 0 1 0 0 0 - 0 0 0 1 0 7 2 0 0 0 2 2 2 2 0 1 0 8 0 1 0 0 0 - 0 0 0 0 0 9 0 2 2 0 1 . 0 0 0 2 0 10 0 0 2 0 2 2 0 0 0 1 0 11 0 0 0 0 2 2 0 0 0 2 0 12 0 0 1 0 2 2 0 0 0 2 0 13 0 0 0 0 2 2 0 0 0 2 0 14 0 0 0 0 2 2 2 0 0 2 0 15 - - - - 2 2 - - - - 16 - - - - 2 2 - - - - 17 - - - - 2 2 - - - - 18 - - - - 2 2 - - - - 19 - - - - 2 2 - - - - 20 0 0 1 0 2 2 2 0 0 2 0 21 0 0 1 1 2 2 2 0 0 2 0

Claims (26)

1. CLAIMS 1. A compound of the general formula I

   or an acid addition salt thereof, in which R or each R independently represents an optionally substituted alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, aryl, aralkyl or aryloxy group, or R or each R, together with the ring to which they are attached, represents an optionally substituted polycyclic hydrocarbyl group, R represents a hydrogen atom or an optionally substituted alkyl or aralkyl group or represents together with R4 an alkylene group, R3 or each R3 independently represents an optionally substituted alkyl, aryl or aralkyl group, R4 represents a hydrogen atom or represents together with R an alkylene group, m represents zero or an integer from 1 to 6, n represents an integer from 1 to 3, o represents zero or an integer from 1 to 4, and p represents zero or one.
2. 2. A compound according to claim 1, in which any alkyl part of any of the substituents R to R contains up to 10 carbon atoms, any cycloalkyl part of any of the substituents R to R contains from 3 to 8 carbon atoms, any alkylene chain contains from 1 to 8 chain members and any aryl part of any of the substituents R to R contains 6 to 10 carbon atoms and in which each optionally substituted group independently is substituted by one or more halogen atoms or nitrro, cyano, C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, C3-6 halocycloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, phenyl or halo- or dihalo-phenyl groups.
3. 3. A compound according to claim 1 or 2, in which R or each R independently represents a C1-10 alkyl, C3-8 cycl, C3-8 cycloalkyl-C1-6 alkyl, C1-10 alkoxy, C1-10 alkoxy-C1-6 alkyl, phenyl or benzyl group or R or each R together with the ring to which they are attached represents a C7 20 polycyclic group, especially a C8 12 bicyclic, C9-14 tricyclic or C9-16 quadricyclic saturated hydrocarbyl group, each of the above groups optionally substituted by one or more halogen atoms or C1-4 alkyl, C1-4 haloalkyl or C1-4 alkoxy groups.
4. 4. A compound according to any of claim 1 to 3, in which R1 or each R1 independently represents a C1-6 alkyl, C3-6 cycloalkyl, phenyl or benzyl group, each group optionally substituted by one or more chlorine and/or fluorine atoms or C1-4 alkyl, C1-4 haloalkyl or C1-4 alkoxy groups.
5. 5. A compound according to claim 4, in which R or each R independently represents a secondary or tertiary C1-6 alkyl group or a phenyl group.
6. 6. A compound according to claim 5, in which R1 represents an iso-propyl, secondary butyl, tertiary butyl, tertiary amyl or phenyl group attached to the 4-position of the cycloalkyl ring.
7. 7. A compound according to any of claims 1 to 6, in which m represents 0, 1 or 2.
8. 8. A compound according to any of claims 1 to 7, in which R represents a hydrogen atom or a methyl or ethyl group, optionally substituted by up to three chlorine or fluorine atoms, a phenyl or benzyl group or R together with R4 represents a methylene or ethylene group.
9. 9. A compound according to claim 8, in which R represents a hydrogen atom or a methyl or ethyl group or R2 together with R4 represents a methylene group.
10. 10. A compound according to any of claims 1 to 9, in which R3 or each R3 independently represents a C1-10 alkyl, phenyl or benzyl group, each group optionally substituted by one or more halogen atoms or C14 alkyl, C1-4 haloalkyl or C14 alkoxy groups.
11. 11. A compound according to claim 10, in which R3 or each R3 independently represents a C16 alkyl, phenyl or benzyl group.
12. 12. A compound according to any of claims 1 to 11, in which o is 0, 1 or 2.
13. 13. A compound according to any of claims 1 to 12, in which n is 1.
14. 14. A compound according to any of claims 1 to 13, in which p is 1.
15. 15. A compound according to any of claims 1 to 14, in which o is 1 or 2, p is 1 and the substituents R3 are at the 4 and/or 6 position of the tetrahydropyrimidyl ring.
16. 16. A compound substantially as described hereinbefore with reference to the Examples.
17. 17. A process for the preparation of a compound of the general formula I as defined in any of the preceding claims, which process comprises reacting a compound of the general formula II

    in which R1 and m are as defined in any of the preceding claims, with a compound of the general formula III

    in which R2, R3, R4, n, o and p are as defined in any of the preceding claims.
18. 18. A process according to claim 17 substantially as described hereinbefore with reference to the Examples.
19. 19. A fungicidal composition which comprises a carrier and, as active ingredient, a compound of the general formula I or an acid addition salt thereof as defined in any one of claims 1 to 16.
20. 20. A composition according to claim 19, which composition comprises at least two carriers, at least one of them being a surface active agent.
21. 21. A method of combating fungi at a locus which comprises treating the locus with a compound of the general formula I or an acid addition salt thereof as defined in any one of claims 1 to 16.
22. 22. A method according to claim 21, in which the locus comprises plants subject to or subjected to fungal attack, seeds of such plants or the medium in which the plants are to be grown.
23. 23. The use as a fungicide of a compound of the general formula I or an acid addition salt thereof as defined in any of claims 1 to 16 or a composition as defined in claims 19 or 20.
24. 24. The use according to claim 23 against fungicidal diseases in cereals.
25. 25. A compound of the general formula III

    in which R2, R3, R4, n and o are as defined in any one of claims 1 to 16 and p is 1.
26. 26. A process for the preparation of a compound of the general formula III as defined in claim 25, which comprises oxidation of a compound of the general formula IV

    2 3 4 in which R , R , R , n and o are as defined in claim 25, with a suitable dihydroxylation reagent, followed by hydrogenation.