Triazolopyrimidine derivatives

This invention relates to certain triazolopyrimidine derivatives, a process for their preparation, compositions containing such compounds and their use as fungicides.
EP-A-0071792 discloses compounds of the general formula ##STR2## in which R.sub.1 represents alkyl, halogen, alkoxy, cyano, cycloalkyl, aryl, aryloxy, arylthio, arylalkyl, arylalkyloxy or arylalkylthio each optionally substituted by halogen or alkoxy, or (R.sup.1).sub.n represents a benzene, indane or tetrahydronaphthalene ring fused with the phenyl ring, aromatic moieties in the above groups being optionally substituted by alkyl, alkoxy, halogen or cyano; n is 1 or 2; R.sub.2 and R.sub.3 are each hydrogen, alkyl or aryl, A represents a nitrogen atom or a CR.sub.4 group; and R.sub.4 is as R.sub.2 but can also be halogen, cyano or alkoxycarbonyl or together with R.sub.3 can form an alkylene chain containing up to 2 double bonds. The compounds are said to be active against various phytopathogenic fungi, especially those of the phycomycete class. However, evidence of fungicidal activity is only provided for 17 of the 80 disclosed compounds against Plasmopara viticola, a member of the phycomycete class of fungi.
A new class of triazolopyrimidine derivatives has now been discovered which exhibits a different spectrum of fungicidal activity, the new compounds being active against fungi which are members of the oomycota such as Venturia inaequalis, Botrytis cinerea and Alternaria solani, Erysiphe graminis, Leptosphaeria nodorum, Micronectriella nivalis, Monilinia fructigena, Mycopshaerella ligulicola, Mycosphaerella pinodes, Sclerotinia sclerotiorum, Uncinula necator, Cercospora beticola, Cladosporium herbarum, Helminthosporium tritici repentis, Pyricularia oryzae, Corticium rolfsii, Rhizoctonia solani and the like.
According to the invention there is provided a compound of formula I ##STR3## wherein R.sub.1 represents an optionally substituted alkyl, alkenyl, alkynyl, alkadienyl, cycloalkyl, bicycloalkyl or heterocyclyl group; R.sub.2 represents a hydrogen atom or an alkyl group; or R.sub.1 and R.sub.2 together with the interjacent nitrogen atom represent an optionally substituted heterocyclic ring; R.sub.3 represents an optionally substituted aryl group; and R.sub.4 represents a hydrogen or halogen atom or a group--NR.sub.5 R.sub.6 where R.sub.5 represents a hydrogen atom or an amino, alkyl, cycloalkyl or bicycloalkyl group and R.sub.6 represents a hydrogen atom or an alkyl group.
When the compounds of this invention contain an alkyl, alkenyl, alkynyl or alkadienyl substituent group, this may be linear or branched and may contain up to 12 , preferably up to 6 and especially up to 4, carbon atoms. A cycloalkyl group may contain from 3 to 8, preferably 3 to 6, carbon atoms. A bicycloalkyl group may contain from 4 to 12, preferably 4 to 8, carbon atoms. An aryl group may be any aromatic hydrocarbon group, especially a phenyl or naphthyl group. A heterocyclic ring may be any saturated or unsaturated ring system containing at least one heteroatom, 3- to 12-membered rings being preferred and 5- to 10-membered rings being more preferred. A heterocyclic ring may be a single ring, a bicyclic ring system or a system of annelated or spiro-fused rings. A heterocyclic ring may also contain one or more additional heteroatoms such as oxygen and/or sulfur atoms. Heterocyclic rings such as pyrrolidinyl, piperidyl, dihydropiperidyl, dihydropyridinyl, piperazinyl, morpholinyl, thiazinyl, azepanyl, azocanyl and dioxa-aza-spiro-decyl preferred.
When any of the foregoing substituents are designated as being optionally substituted, the substituent groups which are optionally present may be any one or more of those customarily employed in the development of pesticidal compounds and/or the modification of such compounds to influence their structure/activity, persistence, penetration or other property. Specific examples of such substituents include, for example, halogen atoms, nitro, cyano, thiocyanato, cyanato, hydroxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, formyl, alkoxycarbonyl, carboxyl, alkanoyl, alkylthio, alkylsulphinyl, alkylsulphonyl, carbamoyl, alkylamido, phenyl, phenoxy, benzyl, benzyloxy, heterocyclyl, especially furyl, and cycloalkyl, especially cyclopropyl, groups. Typically, 0-3 substituents may be present. When any of the foregoing substituents represents or contains an alkyl substituent group, this may be linear or branched and may contain up to 12, preferably up to 6, and especially up to 4, carbon atoms. When any of the foregoing substituents represents or contains an aryl or cycloalkyl moiety, the aryl or cycloalkyl moiety may itself be substituted by one or more halogen atoms, nitro, cyano, alkyl, haloalkyl, alkoxy or haloalkoxy groups. In the case of cycloalkyl and heterocyclyl groups, optional substituents also include groups which together with two adjacent carbon atoms of the cycloalkyl or heterocyclyl group form a saturated or unsaturated hydrocarbyl ring. In other words, a saturated or unsaturated hydrocarbyl ring may be optionally fused with the cycloalkyl or heterocyclyl group.
It is preferred that R.sub.1 represents a C.sub.1-12 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.4-12 alkadienyl, C.sub.3-8 cycloalkyl or C.sub.4-8 bicycloalkyl group or a 3- to 6-membered heterocyclic ring, each group or ring being optionally substituted by one or more substituents selected from halogen atoms, nitro, cyano, hydroxyl, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkoxy, amino, C.sub.1-4 alkylamino, di-C.sub.1-4 alkylamino, formyl, C.sub.1-4 alkoxycarbonyl, carboxyl, phenyl, C.sub.1-4 haloalkylphenyl, di-C.sub.1 -C.sub.4 alkoxyphenyl, furyl and dihalo-C.sub.3-6 cycloalkyl groups, or in the case where R.sub.1 represents a C.sub.3-8 cycloalkyl group or a 3- to 6-membered heterocyclic ring, optionally ortho-fused with a benzene ring.
More preferably, R.sub.1 represents a C.sub.1-12 alkyl, C.sub.2-6 alkenyl, alkenyl, C.sub.2-4 alkynyl, C.sub.4-8 alkadienyl, C.sub.3-8 cycloalkyl, C.sub.4-8 bicycloalkyl group or a 3- to 6-membered nitrogen-containing heterocyclic ring, each group or ring being optionally substituted by up to three substituents selected from halogen, especially chlorine, hydroxyl, C.sub.1-4 alkyl, alkyl, especially methyl, C.sub.1-4 haloalkyl, especially trifluoromethyl, C.sub.1-4 alkoxy, especially methoxy, C.sub.1-4 haloalkoxy, especially trifluoromethoxy, phenyl, C.sub.1-4 haloalkylphenyl, di-C.sub.1-4 alkoxyphenyl, furyl and dihalo C.sub.3-6 cycloalkyl groups or, in the case where R.sub.1 represents a C.sub.3-8 cycloalkyl group or a 3- to the 6-membered heterocyclic ring, optionally ortho-fused with a benzene ring.
Preferably, R.sub.2 represents a hydrogen atom or a C.sub.1-4 alkyl group.
More preferably, R.sub.1 and R.sub.2 together with the interjacent nitrogen atom, represent an optionally substituted 3- to 12-membered heterocyclic ring optionally substituted with one or more substituents selected from halogen atoms, nitro, C.sub.1-4 alkyl and C.sub.1-4 haloalkyl groups. Particularly preferred are those formula I compounds wherein R.sub.1 and R.sub.2 together with the interjacent nitrogen atom represent a 5- to 10-membered heterocyclic ring optionally substituted with one or more substituents selected from halogen atoms, C.sub.1-4 alkyl and C.sub.1-4 haloalkyl groups. The more preferred optionally substituted heterocyclic rings are C.sub.1-4 alkyl-substituted pyrrolidinyl, piperidyl, dihydropiperidyl, dihydropyridinyl, thiazanyl, azepanyl, azocanyl or dioxa-aza-spiro decyl
It is also preferred that R.sub.3 represents a phenyl or naphthyl group, each group being optionally substituted by one or more substituents selected from halogen atoms, nitro, cyano, hydroxyl, C.sub.1-12 alkyl, C.sub.1-12 haloalkyl, C.sub.1-12 -alkoxy, C.sub.1-12 haloalkoxy, amino, C.sub.1-4 alkylamino, di-C.sub.1-4 -alkylamino, formyl, C.sub.1-4 alkoxycarbonyl, carboxyl, phenyl, phenoxy and benzyloxy groups.
More preferably, R.sub.3 represents a phenyl group optionally substituted by up to three substituents selected from halogen atoms, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkoxy, phenyl, phenoxy and benzyloxy groups, or a naphthyl group.
Preferably, R.sub.4 represents a hydrogen or halogen atom or a group --NR.sub.5 R.sub.6 where R.sub.5 represents a hydrogen atom or an amino, C.sub.1-4 alkyl, especially methyl, C.sub.3-6 cycloalkyl or C.sub.4-8 bicycloalkyl group and R.sub.6 represents a hydrogen atom or a C.sub.1-4 alkyl, especially methyl, group.
A particularly preferred sub-group of compounds of formula I is that in which R.sub.1 represents a methyl, ethyl, propyl, heptyl, dodecyl, benzyl, dichlorocyclopropylmethyl, furylmethyl, trifluoromethylphenethyl, dimethoxyphenethyl, pentenyl, propynyl, dimethyloctadienyl, cyclopropyl, cyclopentyl, hydroxycyclopentyl, trimethylcyclopentyl, cyclohexyl, trimethylcyclohexyl, cyclooctyl, indanyl, bicycloheptyl, dichloroaziridinyl, pyrrolidinyl, morpholinyl or benzothiazolyl group; R.sub.2 represents a hydrogen atom, methyl or ethyl group; or R.sub.1 and R.sub.2 together with the interjacent nitrogen atom represent a phenylpiperidyl group; R.sub.3 represents a phenyl, fluorophenyl, chlorophenyl, bromophenyl, chlorofluorophenyl, methylphenyl, propylphenyl, trifluoromethylphenyl, methoxyphenyl, ethoxyphenyl, dimethoxyphenyl, trimethoxyphenyl, trifluoromethoxyphenyl, biphenylyl, phenoxyphenyl, benzyloxyphenyl or naphthyl group; and R.sub.4 represents a hydrogen, fluorine, chlorine, bromine, or iodine atom or an amino, methylamino, dimethylamino, hydrazino, cyclopentylamino or bicycloheptylamino group.
An especially preferred sub-group of compounds of formula I is that in which R.sub.1 and R.sub.2 together represent an optionally C.sub.1-4 -alkyl-substituted pyrrolidinyl, piperidyl, dihydropiperidyl dihydropyridinyl, thiazanyl, azepanyl, azocanyl or dioxa-aza-spiro decyl group; R.sub.3 represents a phenyl, fluorophenyl, chlorophenyl, bromophenyl, chlorofluorophenyl, difluorophenyl, dichlorophenyl, methylphenyl, trifluoromethylphenyl, tert-butylphenyl or chloronitrophenyl group; and R.sub.4 represents a hydrogen, fluorine, chlorine or bromine atom.
Especially good results in terms of control of phytopathogenic fungi are obtained by using, for example, the following compounds of formula I: 5-chloro-6-(2,6-dichlorophenyl)-7-(2-methyl-piperidin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidine; 5-chloro-6-(2,6-dichlorophenyl)-7-(2-methyl-pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidine; 5-chloro-6-(2,6-difluorophenyl)-7-(2-methyl-pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidine; 5-chloro-6-(2,6-difluorophenyl)-7-(2-methyl-pyrrolidin-1-yl)-[1,2,4]triazolo[1,5a]pyrimidine; 5-chloro-6-(2,6-difluorophenyl)-7-(4-methyl-pyrrolidin-1-yl)-[1,2,4]triazolo[1,5a]pyrimidine; 5-chloro-6-(2-chlor-6-fluorophenyl)-7-([1,4]thiazinan-4-yl)-[1,2,4]triazolo[1,5a]pyrimidine; 5-chloro-6-(2-chlor-6-fluorophenyl)-7-(1,4-dioxa-8-aza-spiro[4.5]dec-8yl)-[1,2,4]triazolo[1,5a]pyrimidine; 5-chloro-6-(2-chlor-6-fluorophenyl)-7-(3,6-dihydro-2H-pyridin-1-yl)-[1,2,4]triazolo[1,5a]pyrimidine; 5-chloro-6-(2-chloro-6-fluorophenyl)-7-(2-ethyl-piperidin-1-yl)-[1,2,4]triazolo[1,5a]pyrimidine; 5-chloro-6-(2-chloro-6-fluorophenyl)-7-(2-methyl-piperidin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidine; 5-chloro-6-(2-chloro-6-fluorophenyl)-7-(2-methyl-pyrrolidin-1-yl)-[1,2,4]-triazolo[1,5-a]pyrimidine; 5-chloro-6-(2-chloro-6-fluorophenyl)-7-(4-methyl-piperidin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidine; 5-chloro-6-(2-chlorophenyl)-7-(2-methyl-piperidin-1-yl)-[1,2,4]triazolo[1,5a]pyrimidine; 5-chloro-6-(2-chloro-phenyl)7-(2-methyl-pyrrolidin-1-yl )-[1,2,4]triazolo [1,5-a]pyrimidine; 5-chloro-6-(2-chloro-phenyl )-7-(4-methyl-piperidin-1-yl)-[1,2,4]triazolo[1,5a]pyrimidine; 5-chloro-6-(2-fluoro-phenyl)-7-(2-methyl-piperidin-1-yl)-[1,2,4]triazolo[1,5a]pyrimidine; 5-chloro-6-(2-fluoro-phenyl)-7-(2-methyl-pyrrolidin-1-yl)-[1,2,4]triazolo[1,5a]pyrimidine; 5-chloro-6-(3,4-difluorophenyl)-7-(2-methyl-piperidin-1-yl)-[1,2,4]triazolo[1,5a]pyrimidine; 7-azepan-1-yl-5-chloro-6-(2,6-difluorophenyl)-[1,2,4]triazolo[1,5a]pyrimidine; 7-azepan- 1-yl- 5-chloro-6-(2-chloro-6-fluorophenyl)-[1,2,4]triazolo[1,5a]pyrimidine; 7-azepan-1-yl-5-chloro-6-(2-chlorophenyl)-[1,2,4]triazolo[1,5a]pyrimidine; 7-azepan-1-yl-5-chloro-6-(2-fluorophenyl)-[1,2,4]triazolo[1,5-a]pyrimidine; 7-azepan-1-yl-5-chloro-6-(3,4-difluorophenyl)-[1,2,4]triazolo[1,5-a]pyrimidine; 7-azocan-1-yl-5-chloro-6-(2-chloro-6-fluorophenyl)-[1,2,4]triazolo[1,5a]pyrimidine.
It will be appreciated that certain of the compounds of the invention, for example those in which R.sub.3 is a 2-chloro-6-fluorophenyl group, can exist in different atropoisomeric forms. The present invention is to be understood to include all individual atropoisomeric forms of the compounds of formula I and mixtures thereof in whatever proportion. It will be further appreciated that one atropoisomer may have a greater activity than another atropoisomer of the same compound or than a mixture of the isomers.
The present invention also provides a process for the preparation of a compound of formula I as defined above which comprises
(a) reacting a compound of the general formula ##STR4## in which R.sub.3 is as defined above and Hal represents a chlorine or bromide atom with a compound of the general formula
HNR.sub.1 R.sub.2 (III)
in which R.sub.1 and R.sub.2 are as defined above, to produce a compound of formula I in which R.sub.4 represents a chlorine or bromine atom;
(b) if desired, reacting the compound of formula I formed in (a) with a fluorinating agent to produce a compound of formula I in which R.sub.4 represents a fluorine atom;
(c) if desired, reacting the compound of formula I formed in (a) with a reducing agent to produce a compound of formula I in which R.sub.4 represents a hydrogen atom;
(d) if desired, reacting the compound of formula I formed in (a) with a compound of the general formula
HNR.sub.5 R.sub.6 (IV)
in which R.sub.5 and R.sub.6 are as defined above, to produce a compound of formula I in which R.sub.4 represents a group --NR.sub.5 R.sub.6 ; and
(e) if desired, reacting a compound of formula I formed in (d) in which R.sub.5 and R.sub.6 both represent a hydrogen atom with diiodomethane in the presence of a diazotising agent to produce a compound of formula I in which R.sub.4 represents an iodine atom.
The process of step (a) is conveniently carried out in the presence of a solvent. Suitable solvents include ethers, such as dioxane, diethyl ether and, especially, tetrahydrofuran, halogenated hydrocarbons, such as dichloromethane, and toluene. The reaction is suitably carried out at a temperature in the range from 0.degree. C. to 70.degree. C., the preferred reaction temperature being from 10.degree. C. to 35.degree. C. It is also preferred that the reaction is carried out in the presence of a base. Suitable bases include tertiary amines, such as triethylamine, and inorganic bases, such as potassium carbonate or sodium carbonate. Alternatively, an excess of the compound of formula III may serve as a base.
The process of step (b) is conveniently carried out in the presence of a solvent. Suitable solvents include sulpholane, dimethylformamide or a mixture of acetonitrile and crown ether. If sulpholane or dimethylformamide is used as solvent, it is advantageous to use toluene as a co-solvent to aid dehydration of the fluorinating agent. The reaction is suitably carried out at a temperature in the range from room temperature (about 15.degree. C.) to the reflux temperature of the reaction mixture, the preferred reaction temperature being from 40.degree. C. to the reflux temperature of the reaction mixture. Suitable fluorinating agents include alkali metal fluorides, especially potassium fluoride, and antimony fluoride.
The reducing agent utilized in step (c) is conveniently a catalytic hydrogenating agent, that is, hydrogen gas used under elevated pressure in the presence of a catalyst. Preferably, the catalyst is palladium on charcoal. It is also preferred that this step is carried out in the presence of a base. Suitable bases include tertiary amines, such as triethylamine, and inorganic bases, such as sodium carbonate or, especially, sodium hydroxide. This step may also be conveniently carried out in the presence of a solvent. Suitable solvents include alcohols, such as methanol. The reaction is suitably carried out at a temperature in the range from 0.degree. C. to 70.degree. C., the preferred reaction temperature being from 10.degree. C. to 35.degree. C.
The process of step (d) is conveniently carried out in the presence of a solvent. Suitable solvents include ethers, such as dioxane, diethyl ether and tetrahydrofuran, halogenated hydrocarbons, such as dichloromethane, and, especially, toluene. The reaction is suitably carried out at a temperature in the range from 20.degree. C. to the reflux temperature of the reaction mixture, the preferred reaction temperature being from 40.degree. C. to the reflux temperature of the reaction mixture. It is also preferred that the reaction is carried out in the presence of a base. Suitable bases include tertiary amines, such as triethylamine, and inorganic bases, such as potassium carbonate or sodium carbonate. Alternatively, an excess of the compound of formula IV may serve as a base.
When R.sub.1 represents the same substituent as R.sub.5 and R.sub.2 represents the same substituent as R.sub.6 in the resultant compound of formula I, the compound of formula III will be the same as the compound of formula IV and steps (a) and (d) may therefore be performed as one step by using double the quantity of amine of formula III/IV.
The diazotising agent used in step (e) may be any alkyl ester of nitrous acid, isopentyl nitrite being especially preferred. If an alkyl ester of nitrous acid is used, this may also serve as a co-solvent with the diiodomethane. The reaction is suitably carried out at a temperature from 60.degree. C. to 120.degree. C., the preferred reaction temperature being from 70.degree. C. to 110.degree. C.
Compounds of formula II may be prepared by reacting a compound of the general formula ##STR5## in which R.sub.3 is as defined above, with a chlorinating or brominating agent, such as phosphorus oxychloride or phosphorus oxybromide.
Compounds of formula V can be prepared by reacting 3-amino-1,2,4-triazole with an appropriate malonic acid ester under alkaline conditions according to the method of Y. Makisumi, Chem. Pharm. Bull., 9, 801, (1961).
Compounds of formula III and IV are known compounds or can be prepared by processes analogous to known processes.
The inventive compounds of formula I are oils, gums, or predominantly crystalline solid materials. They are superior through their valuable fungicidal properties. For example, they can be used in agriculture or related fields for the control of phytopathogenic fungi such as Alternaria solani, Botrytis cinerea, Cercospora beticola, Cladosporium herbarum, Corticium rolfsii, Erysiphe graminis, Helminthoporium tritici repentis, Leptosphaeria nodorum, Micronectriella nivalis, Monilinia fructigena, Mycosphaerella ligulicola, Mycosphaerella pinodes, Rhizoctonia solani and Sclerotinia sclerotiorum. The compounds of formula I possess a high fungicidal activity within a wide concentration range and may be used in agriculture without any difficulties.
Accordingly, the invention further provides a fungicidal composition which comprises a carrier and, as active ingredient, a compound of formula I as defined above. A method of making such a composition is also provided which comprises bringing a compound of formula I as defined above into association with at least one carrier. Such a composition may contain a single compound or 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.
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 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 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 fertilizers, 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, kerosene 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 sulfphonic 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 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 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% wt/wt of active ingredient and usually contain in addition to solid inert carrier, 3-10% wt/wt of a dispersing agent and, where necessary, 0-10% wt/wt 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 0.5-10% wt/wt 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 0.5-75% wt/wt active ingredient and 0-10% wt/wt of additives such as stabilizers, surfactants, slow release modifiers and binding agents. 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 stabilizers, penetrants and corrosion inhibitors. Suspension concentrates are usually compounded so as to obtain a stable, non-sedimenting flowable product and usually contain 10-75% wt/wt active ingredient, 0.5-15% wt/wt of dispersing agents, 0.1-10% wt/wt of suspending agents such as protective colloids and thixotropic agents, 0-10% wt/wt of other additives such as defoamers, corrosion inhibitors, stabilizers, 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 other 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.
In general, the compositions of the invention may be in a concentrated form for the convenience of the end-user who employs diluted compositions. The compositions may be diluted to a concentration of as low as 0.001% of active ingredient (a.i.). The doses usually are in the range of about 0.01 to 10 kg a.i./ha.
The 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, and a method for combating fungus at a locus, which comprises treating the locus, which may be for example 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 compound or composition.
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, apples and tomatoes. The duration of protection is normally dependent on the individual compound selected, and also a variety of external factors, such as climate, the impact of which is normally mitigated by the use of a suitable formulation.

The invention is further illustrated by the following examples.
EXAMPLE 1
Preparation of 5-chloro-6-(4-methylphenyl)-7-cyclopentylamino-1,2,4-triazolo[1,5-a]pyrimidine (R.sub.1 =cyclopentyl; R.sub.2 .dbd.H; R.sub.3 =4-methylphenyl; R.sub.4 .dbd.Cl)
5,7 Dichloro-6-(4-methylphenyl)-1,2,4-triazolo-[1,5-a]pyrimidine (1.8 g, 6 mmol) was dissolved in tetrahydrofuran. A solution of cyclopentylamine (0.51 g, 6 mmol) and triethylamine (0.61 g, 6 mmol) in tetrahydrofuran (2 ml) was then added with stirring and the stirring continued for a further 3 hours at ambient temperature (20.degree. C.). The reaction mixture was then evaporated in vacuo and the residue extracted with dichloromethane and water (100 ml each). The organic layer was dried over sodium sulphate and the solvent evaporated in vacuo. The residue was crystallized from ethyl acetate to give 1.7 g 5-chloro-6-(4-methylphenyl)-7-cyclopentylamino-1,2,4-triazolo[1,5-a]pyrimidine as yellowish crystals, m.pt. 158.degree. C. Yield: 87% of theoretical .sub.1 H-NMR: .delta.=1.3-1.75 (2 m, 8H); 2.43(s,1H); 3.73 (m,1H); 5.97 (d,1H); 7.25 (m,4H); 8.25(s,1H) ppm
EXAMPLE 2
Preparation of 5-bromo-6-phenyl-7-cyclopentylamino-1,2,4-triazolo-[1,5-a]pyrimidine (R.sub.1 =cyclopentyl; R.sub.2 .dbd.H; R.sub.3 =phenyl; R.sub.4 .dbd.Br)
5,7-Dibromo-6-phenyl-1,2,4-triazolo[1,5-a]-pyrimidine (2 g, 5.7 mmol) was dissolved in tetrahydrofuran (40 ml). A solution of triethylamine (0.61 g, 6 mmol) and cyclopentylamine (0.51, 6 mmol) in tetrahydrofuran (5 ml) was then added whilst stirring and the stirring continued for a further 2 hours at ambient temperature (20.degree. C.). The reaction mixture was then evaporated in vacuo and the residue extracted with ethyl acetate and water (100 ml each). The organic layer was dried over sodium sulphate and the solvent evaporated in vacuo. Column chromatography of the residue on a silica gel column (3.5.times.15 cm) using 3:7 ethyl acetate: petroleum ether as eluant gave 0. 6 g 5-bromo-6-phenyl-7-cyclopentylamino-1,2,4-triazolo-[1,5-a]pyrimidine as a yellowish oil.
Yield: 28% of theoretical.
.sub.1 H-NMR: .delta.=1.3-1.7 (2 m, 8H); 3.64 (m,1H); 6.05(d,1H); 7.34 (m,2H); 7.50 (m,3H); 8.26 (s,1H) ppm.
EXAMPLE 3
Preparation of 6-(4-methoxyphenyl)-7-cyclopentylamino1,2,4-triazolo[1,5-a]pyrimidine (R.sub.1 =cyclopentyl; R.sub.2 .dbd.H; R.sub.3 =4-methoxyphenyl; R.sub.4 .dbd.H)
5-Chloro-6-(4-methoxyphenyl)-7-cyclopentylamino1,2,4-triazolo[1,5-a]pyrimidine (5.1 g, 14.8 mmol), prepared by a method analogous to Example 1, was dissolved in a mixture of methanol (100 ml) and aqueous sodium hydroxide (1N, 15 ml), palladium (0.5 g; on charcoal, 5% E 10N) was added and the reaction mixture stirred for 3 hours under hydrogen (5 bar). The catalyst was removed by filtration and the filtrate evaporated in vacuo. Column chromatography of the residue on a silica gel column (3.5.times.15 cm) using 4:1 ethyl acetate: petroleum ether as eluant and evaporation of the solvent in vacuo gave 2.6 g 6-(4-methoxyphenyl)-7-cyclopentylamino-1,2,4-triazolo-[1,5-a]pyrimidine as colourless crystals, m.pt. 127.degree. C. Yield: 57% of theoretical .sub.1 H-NMR: .delta.=1.35-1.75 (2 m,8H); 3.88 (s,3H); 6.16 (d,1H); 7.00 (dd,2H); 7.34 (m,2H); 8.32 (s,1H); 8.34 (s,1H) ppm
EXAMPLE 4
Preparation of 5-methylamino-6-phenyl-7-cyclopentylamino-1,2,4-triazolo[1,5-a]pyrimidine (R.sub.1 =cyclopentyl; R.sub.2 .dbd.H; R.sub.3 =phenyl; R.sub.4 .dbd.NR.sub.5 R.sub.6 ;R.sub.5 .dbd.CH.sub.3 ; R.sub.6 .dbd.H)
A mixture of 5-chloro-6-phenyl-7-cyclopentylamino-1,2,4-triazolo[1,5-a]pyrimidine (3.1 g, 10 mmol) prepared by a method analogous to Example 2, methylamine (5 ml), triethylamine (5 ml) and toluene (50 ml) was refluxed for 10 hours. After cooling, the reaction mixture was washed with water (50 ml) and the organic layer separated, dried over sodium sulphate and evaporated. Recrystallization of the solid residue from diisopropyl ether gave 2.3 g 5-methylamino-6-phenyl-7-cyclopentylamino-1,2,4-triazolo[1,5-a]pyrimidine as colourless crystals, m.pt. 158.degree.-160.degree. C. Yield: 75% of theoretical .sub.1 H-NMR: .delta.=1.25-1.7 (mm, 8H); 2.95 (d,3H); 3.42 (m,1H); 4.48 (m,1H); 5.55 (d,1H); 7.3-7.5 (m,5H); 8.03 (s,1H)
EXAMPLE 5
Preparation of 5-fluoro-6-(4-methoxyphenyl)-7-cyclopentylamino-1,2,4-triazolo[1,5-a]pyrimidine (R.sub.1 =cyclopentyl; R.sub.2 .dbd.H; R.sub.3 =4-methoxyphenyl; R.sub.4 .dbd.F)
Potassium fluoride (3.1 g, 0.05 mol) was suspended in a mixture of dry sulpholane (60 ml) and toluene (20 ml) and the mixture was then refluxed for 6 hours over a water separator. 5-Chloro-6-(4 methoxyphenyl)-7-cyclopentylamino-1,2,4-triazolo[1,5-1]pyrimidine (8.5 g, 0.025 mol), obtained by a method analogous to that of Example 1 above, was added at room temperature and an azeotrope of sulpholane and toluene distilled off until the reaction temperature reached 200.degree. C. The reaction mixture was then kept at this temperature for 3 days before cooling to room temperature and then pouring into water (600 ml). The mixture was then filtered and the precipitate washed with water. The precipitate was then dissolved in dichloromethane, extracted twice with water, dried with sodium sulphate and the solvent was distilled off in vacuo. The residue was then washed twice with warm diethyl ether, the ether fraction was decanted off and then dried in vacuo. Flash column chromatography on silica gel using a mixture of petroleum ether and ethyl ethanoate as eluant yielded 4.5 g 5-fluoro-6-(4-methoxyphenyl)-7-cyclopentylamino-1,2,4-triazolo[1,5-1-]pyrimidine as a colourless crystalline solid, m.pt. 124.degree. C. Yield: 55% of theoretical.
EXAMPLE 6
Preparation of 5-iodo-6-(2-chlorophenyl)-7-cyclopentylamino-1,2,4-triazolo[1,5-a]pyrimidine (R.sub.1 =cyclopentyl; R.sub.2 .dbd.H; R.sub.3 =2-chlorophenyl; R.sub.4 .dbd.I)
5-Amino-6-(2-chlorophenyl)-7-cyclopentylamino 1,2,4-triazolo[1,5-a-]pyrimidine (3.3 g, 10 mmol), obtained by a method analogous to that of Example 4 above, and diiodomethane (50 ml)were mixed together. Isopentyl nitrite (20 ml) was added under nitrogen and the reaction mixture heated for 3 hours at 90.degree. C. The reaction mixture was then cooled to room temperature and filtered. The solvent was distilled off in vacuo and the residue was purified by flash column chromatography on silica gel using 7:3 petroleum ether:ethyl ethanoate as eluant to yield 1.33 g 5-iodo-6-(2-chlorophenyl)-7-cyclopentylamino1,2,4-triazolo-[1,5-a]pyrimidine as colourless crystals, m.pt. 150.degree. C. Yield: 30.3% of theoretical.
EXAMPLES 7 to 117
By processes similar to those described in Examples 1 to 6 above, 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. Melting point, NMR and C,H,N analysis data for the compounds of Examples 7 to 117 are given in Table IA below.
TABLE I__________________________________________________________________________Ex.No. R.sup.1 R.sup.2 R.sup.3 R.sup.4__________________________________________________________________________ 7 cyclopentyl H 2-OCH.sub.3 phenyl Cl 8 " " 3-OCH.sub.3 phenyl " 9 " " 4-OC.sub.2 H.sub.5 phenyl "10 2-OH cyclopentyl " 4-OCH.sub.3 phenyl "11 2,4,4-(CH.sub.3).sub.3 " phenyl " cyclopentyl12 cyclooctyl " 4-OCH.sub.3 phenyl "13 4-phenylpiperidyl phenyl "14 2,4-(CH.sub.3).sub.2 pent-3-yl " "15 cyclopentyl " 4-OCH.sub.3 phenyl cyclo- pentyl amino16 " " " --NHCH.sub.317 --CH(CH.sub.3).sub.2 " 4-OC.sub.2 H.sub.5 phenyl Cl18 2,2,5-(CH.sub.3).sub.3 cyclohexyl " phenyl " cyclohexyl19 indan-2-yl " phenyl "20 --CH.sub.3 --CH.sub.3 3-Cl phenyl "21 --CH(CH.sub.3).sub.2 H 4-CH.sub.3 phenyl "22 cyclopentyl " 4-OCH.sub.3 phenyl "23 cyclohexyl " phenyl "24 C.sub.12 H.sub.25 " " "25 cyclopentyl " phenyl "26 cyclopropyl " " "27 cyclopentyl " 3-CF.sub.3 phenyl "28 " " 4-.sup.i C.sub.3 H.sub.7 phenyl "29 " " 4-OCF.sub.3 phenyl "30 " " naphth-2-yl "31 " " 3,4-(OCH.sub.3 ).sub.2 phenyl "32 cyclopentyl H 2-Cl phenyl Cl33 " " 4-F phenyl "34 " " 4-biphenylyl "35 --CH.sub.2 C H " phenyl "36 benzyl " " "37 cyclopentyl " 2-Br phenyl "38 --CH(CH.sub.3).sub.2 " " "39 bicyclo[2.2.1]hept-2-yl " " "40 cyclopentyl " 2-F phenyl "41 --CH(CH.sub.3).sub.2 " " "42 " " naphth-2-yl "43 " " 2-Cl phenyl "44 " " 4-F phenyl "45 --CH.sub.2 CH.dbd.C(CH.sub.3).sub.2 " phenyl "46 --CH.sub.3 --CH.sub.3 4-OCH.sub.3 phenyl "47 --CH.sub.2 CH.dbd.C(CH.sub.3)CH.sub.2 CH.sub.2 CH.dbd.C(CH.sub.3).sub.2 1 --H 4-CH.sub.3 phenyl "48 " " 4-OCH.sub.3 phenyl "49 --CH.sub.3 --CH.sub.3 " --N(CH.sub.3).sub.250 fur-2-ylmethyl --H phenyl --Cl51 benzothiazol-2-yl " " "52 morpholin-4-yl " " "53 2-OH cyclopentyl " " "54 cyclopentyl " 4-OC.sub.6 H.sub.5 phenyl "55 --CH(CH.sub.3).sub.2 " 3-CF.sub.3 phenyl "56 " " 4-.sup.i C.sub.3 H.sub.7 phenyl "57 " " 4-CF.sub.3 O phenyl "58 " " 4-OC.sub.6 H.sub.5 phenyl "59 " " 4-biphenylyl "60 " " 3,4-(OCH.sub.3).sub.2 phenyl "61 cyclopentyl " 4-OCH.sub.2 C.sub.6 H.sub.5 "henyl62 --CH(CH.sub.3).sub.2 --H 4-OCH.sub.2 C.sub.6 H.sub.5 --Clyl63 bicyclo[2.2.1]hept-2-yl " 4-OCH.sub.3 phenyl "64 " " 2-Cl phenyl "65 cyclopentyl " 4-Br phenyl "66 --CH(CH.sub.3).sub.2 " " "67 bicyclo[2.2.1]hept-2-yl " " "68 " " 3-Br phenyl "69 cyclopentyl " " "70 bicyclo[2.2.1]hept-2-yl " 2-F phenyl "71 cyclopentyl " 3-F phenyl "72 --CH(CH.sub.3).sub.2 " " "73 bicyclo[2.2.1]hept-2-yl " " "74 cyclopentyl " 2-OCH.sub.2 C.sub.6 H.sub.5 "henyl75 --CH(CH.sub.3).sub.2 " " "76 bicyclo[2.2.1]hept-2-yl " " "77 cyclopentyl " 2,3-(OCH.sub.3).sub.2 phenyl "78 --CH(CH.sub.3).sub.2 " " "79 bicyclo[2.2.1]hept-2-yl " " "80 --CH.sub.2 CH.sub.2 -(3-CF.sub.3 phenyl) " 4-OCH.sub.3 phenyl "81 " " 2-Cl phenyl "82 2,2-dichloroaziridin-1-yl " 4-OCH.sub.3 phenyl "83 " " 2-Cl phenyl "84 pyrrolidin-1-yl " " "85 bicyclo[2.2.1]hept-2-yl " 4-OCH.sub.3 phenyl --NH- bicyclo- [2.2.1]- hept- 2-yl86 " " 2-Cl phenyl --NH- bicyclo- [2.2.1]- hept- 2-yl87 " " 4-OCH.sub.3 phenyl H88 bicyclo[2.2.1]hept-2-yl --H 2-Cl phenyl H89 cyclopentyl " " --NH--NH.sub.290 cyclopentyl " 4-OCH.sub.3 phenyl --91 bicyclo[2.2.1]hept-2-yl " 2-Cl phenyl "92 2,2-dichlorocycloprop-1-yl " 3,4,5-(OCH.sub.3).sub.3 --Cl phenyl93 cyclopentyl " 2-F phenyl --NH--NH.sub.294 bicyclo[2.2.1]hept-2-yl " phenyl --Br95 --CH(CH.sub.3).sub.2 " " "96 2,2-dichlorocycloprop-1-yl " " "97 --CH.sub.3 " 2-Cl phenyl --Cl98 " --CH.sub.3 " "99 --C.sub.2 H.sub.5 --H " "100 --CH.sub.3 " 2-F phenyl "101 " --CH.sub.3 " "102 --C.sub.2 H.sub.5 --H " "103 cyclopentyl " 4-OCH.sub.3 phenyl --NH.sub.2104 " " 2-Cl phenyl "105 " " 2-Cl,6-F phenyl --Cl106 --CH(CH.sub.3).sub.2 " " "107 bicyclo[2.2.1]hept-2-yl " 2-Cl,6-F phenyl "108 --CH.sub.2 CH.sub.2 -(3,4-(OCH.sub.3).sub.2 phenyl) " " "109 --CH.sub.3 --CH.sub.3 " "110 bicyclo[2.2.1]hept-2-yl --H 2-Cl phenyl --NH.sub.2111 --C.sub.2 H.sub.5 --C.sub.2 H.sub.5 2-Cl,6-F phenyl --Cl112 " " 2-F phenyl "113 " " 2-Br phenyl "114 " " 2-Cl phenyl "115 " " 4-OCH.sub.3 phenyl "116 cyclopentyl --H " I117 bicyclo[2.2.1]hept-2-yl " 2-Cl phenyl "__________________________________________________________________________
TABLE IA__________________________________________________________________________ Elemental AnalysisEx. M. pt. C H NNo. .sup.1 H-NMR(ppm) (.degree.C.) Calc. Found Calc. Found Calc. Found__________________________________________________________________________ 7 1.3-1.7(m, 8H), 3.7 121 (m, 1H), 3.75(s, 3H), 6.1(d, 1H), 7.0 (m, 2H), 7.25(m, 1H), 7.48(dt, 1H), 8.25 (s, 1H) 8 1.35-1.78(m, 8H), 110 3.75(m, 1H), 3.85 (s, 3H), 6.05(d, 1H), 6.95(m, 3H), 7.88 (dt, 1H), 8.27(s, 1H) 9 1.3-1.8(2m, 8H), 118 1.45(t, 3H), 3.78 (m, 1H), 4.08(q, 2H), 6.05(d, 1H), 7.00 (m, 2H), 7.25(m, 2H), 8.25(s, 1H)10 1.3-2.03(3m, 6H), 148 3.25(m, 1H), 3.86 (s, 3H), 5.75(d, 1H), 7.02(m, 2H), 7.27 (dd, 1H), 7.44(dd, 1H), 8.20(s, 1H)11 0.5-1.8(mm, 13H), 124-130 6.06(d, 1H), 7.83 (m, 2H), 7.45(m, 3H), 8.28(s, 1H)12 1.1-1.75(m, 14H), 118 3.55(m, 1H), 3.9 (s, 3H), 6.05(d, 1H), 7.05(dd, 2H), 7.25 (dd, 2H)13 1.7-1.9(m, 4H), 2.6 168 (m, 1H), 2.75(m, 2H), 4.84(m, 2H), 7.1-7.5 (mm, 10H), 8.4(s, 1H)14 0.5-2.7(mm, 15H), oil 6.45(m, 1H), 7.2-7.6 (mm, 5H), 8.32(s, 1H)15 1.07-2.05(mm, 16H), oil 3.37(m, 1H), 3.86 (s, 3H), 4.30(d, 1H), 4.45(m, 1H), 4.97 (d, 1H), 7.0(dd, 2H), 7.28(dd, 2H), 8.0 (s, 1H)16 1.3-1.9(mm, 8H), 180 2.95(d, 3H), 3.87 (s, 3H), 4.40(d, 1H), 5.50(d, 1H), 7.00 m, 2H), 7.24(m, 2H), 8.03(s, 1H)17 1.03(2s, 6H), 1.46 122 (t, 3H), 3.67(m, 1H), 4.06(q, 2H), 5.85 (d, 1H), 7.0(d, 2H), 7.23(d, 2H), 8.26 (s, 1H)18 0.5-1.7(mm, 17H), 130 3.25(m, 1H), 5.95 (d, 1H), 7.34(m, 2H), 7.47(m, 3H), 8.28 (s, 1H)19 1.2-1.9(m, 1H), 2.1- oil 2.25(m, 1H), 2.55- 2.7(m, 1H), 2.86-2.96 (m, 1H), 5.05(s, 1H), 6.29(d, 1H), 7.12-7.57 (2m, 4H)20 177-179 50.66 50.60 3.59 3.83 22.72 22.6621 113 59.69 59.59 5.34 5.33 23.20 23.3322 1.3-1.8(2m, 8H), 140 59.38 59.42 5.27 5.39 20.37 20.39 3.8(m, 1H), 3.90 (s, 3H), 6.03(d, 1H), 6.98(dd, 2H), 7.28 (dd, 2H), 8.27(s, 1H)23 130-132 62.28 62.26 5.58 5.48 21.36 21.3124 92-94 66.76 66.74 7.79 7.78 16.91 16.7925 1.3-1.8(2m, 8H), 125 61.23 61.15 5.13 5.16 22.32 22.33 3.63(m, 1H), 6.08 (d, 1H), 7.35(m, 2H), 7.56(m, 3H), 8.30 (s, 1H)26 175 58.84 58.69 4.23 4.22 24.51 24.4727 1.05-1.86(m, 8H), 165 2.6(s, 1H), 3.4-3.7 (2m, 2H), 7.60-8.0 (m, 4H), 8.6(s, 1H)28 1.05-1.7(mm, 14H), 112 2.6(s, 2H), 3.05 (m, 1H), 3.46(m, 1H), 7.38-7.44(2m, 4H), 8.68(s, 1H)29 1.05-1.7(mm, 8H), oil 2.6(s, 1H), 3.6 (m, 1H), 7.60(dd, 2H), 7.68(dd, 2H), 8.62 s, 1H)30 1.0-1.7(mm, 8H), 107 2.6(m, 1H), 3.46 (s, 1H), 7.68(m, 3H), 8.1(m, 4H), 8.70 (s, 1H)31 1.1-1.8(mm, 8H), oil 3.48(s, 1H), 3.84 (d, 3H), 3.94(d, 3H), 6.9-7.35(m, 3H), 8.63(s, 1H)32 1.34-1.8(m, 8H), 145 3.55(m, 1H), 6.22 (d, 1H), 7.48-7.55 (m, 4H), 8.32(s, 1H)33 1.23-1.75(m, 8H), oil 3.46(s, 1H), 3.72 (m, 1H), 7.45(m, 2H), 7.65(m, 2H), 8.6534 1.05-1.8(m, 8H), 65 3.48(s, 1H), 3.74 (m, 1H), 7.48-8.0 (m, 9H), 8.68(s, 1H)35 126 59.26 59.48 3.55 3.78 24.68 24.6836 105 64.37 65.69 4.20 4.36 20.85 19.5037 16038 6039 14040 9741 14242 15043 12844 9945 9546 134 56.68 56.62 5.07 5.08 22.04 22.0347 (CDCl.sub.3): 1.4(s, 3H); 1.55(s, 3H); 1.7(s, 3H); 1.9(m, 2H); 2.4(s, 3H); 3.5(m, 2H); 5.0(m, 1H); 5.1(m, 1H); 6.0(m, 1H); 7.25(m, 4H); 8.3(s, 1H)48 (CDCl.sub.3): 1.4(s, 3H); 1.5(s, 3H); 1.6(s, 3H); 1.9(m, 2H); 3.5(m, 2H); 3.8(s, 3H); 5.0(m, 1H); 5.1(m, 1H); 5.9(t, 1H); 6.9(d, 2H); 7.2(d, 2H); 8.2(s, 1H)49 19450 10051 19852 (CDCl.sub.3): 2.3(m, 2H); 2.6(m, 4H); 3.5(m, 2H); 7.2(s, 1H); 7.25(m, 2H); 7.4(m, 3H); 8.4(s, 1H)53 162 (decomp)54 (dmso-d.sub.6): 1.2-1.4(m, 2H); 1.6-1.8(m, 6H); 3.7(m, 1H); 7.1-7.3 (m, 5H); 7.5-7.6 (m, 4H); 7.7(d, 1H); 8.6(s, 1H)55 13856 10057 10858 14559 65-7060 15061 13862 (dmso-d.sub.6): 1.1(d, 6H); 3.6(m, 1H); 5.3(s, 2H); 7.2(d, 1H); 7.4-7.6(m, 7H); 8.6(s, 1H)63 (acetone-d.sub.6): 0.5(m, 1H); 0.9 (m, 1H); 1.1(d, 1H); 1.2-1.6(m, 6H); 1.80(m, 1H); 2.2(m, 2H); 3.3(m, 1H);3.9(s, 3H); 6.3(d, 1H); 7.1(m, 2H); 7.4-7.5(m, 2H); 8.4(s, 1H)64 (acetone-d.sub.6): ppm: 0.2-0.4(m, 1H); 0.9(m, 1H); 1.1(m, 1H); 1.2-1.6(m, 5H); 2.20 (m, 2H); 3.2(m, 1H); 6.6(t, 1H); 7.5-7.8 (m, 4H); 8.4(s, 1H)65 16766 8067 18068 14069 15070 17471 13072 13073 17074 (dmso-d.sub.6): 1.3-1.5(m, 4H); 1.5-1.7(m, 4H); 3.7 (m, 1H); 5.1(s, 2H); 6.1(d, 1H); 7.05 (m, 2H); 7.3(m, 6H); 7.4(t, 1H); 8.3(s, 1H)75 (CDCl.sub.3): 1.1(m, 6H); 3.6(m, 1H); 5.1(s, 1H); 5.95(d, 1H); 7.3-7.3(m, 6H); 7.4 (t, 1H); 8.3(s, 1H)76 (CDCl.sub.3): 0.1(m, 1H); 0.7 (m, 1H); 0.8-1.3(m, 7H); 2.0 (m, 1H); 3.0(m, 1H); 4.9(s, 1H); 5.9(m, 1H); 6.8-6.9(m, 2H); 7.0-7.15(m, 6H); 7.25(m, 1H); 8.05(s, 1H)77 16278 14179 73 (amorph.)80 14082 (CDCl.sub.3): 112 1.2(t, 1H); 1.6 (t, 1H); 1.8(m, 1H); 3.1(m, 1H); 3.8(m, 1H); 3.9(s, 3H); 6.25(t, 1H); 7.0(d, 2H); 7.3(d, 2H);83 68-78 (amorph)84 24085 25886 17087 (CDCl.sub.3): 0.3(m, 1H); 0.9(m, 1H); 1.1(d, 1H); 1.2-1.6 (m, 5H); 1.7(m, 1H); 2.2(m, 1H); 3.4(m, 1H); 3.9(s, 3H); 7.0 (d, 1H); 7.2(d, 2H); 7.5(d, 2H); 8.3 (s, 1H); 8.6(s, 1H)88 (dmso-d.sub.6): 122 0.0(m, 1H); 0.7(m, 1H); 0.8-1.7(m, 7H); 3.1(m, 1H); 6.9(d, 1H); 7.4(m, 2H); 7.6(m, 2H); 8.2(s, 1H); 8.5(s, 1H)89 (dmso-d.sub.6): 1.2-1.4(m, 2H); 1.4-1.7(m, 6H); 3.4(m, 1H); 4.4(m, 2H); 5.8(m, 1H); 6.5(d, 1H); 6.9(m, 1H); 7.6(m, 3H); 7.8(d, 1H); 8.3(s, 1H)90 12191 (dmso-d.sub.6): 0-0.2(m, 1H); 0.8(m, 1H); 1.0-1.6(m, 6H); 2.0(m, 1H); 2.2(m, 1H); 2.7(m, 1H); 6.1(d, 1H); 7.5(m, 3H); 7.6((d, 1H); 8.2(s, 1H)92 20593 (dmso-d.sub.6): 1.1-1.3(m, 2H); 1.4-1.7(m, 6H); 3.4(m, 1H); 4.0-4.6 (broad, 2H); 6.4 (d, 1H); 7.0(broad, 1H); 7.2(m, 1H); 7.3-7.5(m, 2H); 7.6(m, 1H); 8.2(s, 1H)94 (dmso-d.sub.6): 0.1(m, 1H); 0.7 (m, 1H); 1(m, 1H); 1.1-1.6(m, 5H); 2.0(m, 1H); 2.1 (m, 1H); 3.0(m, 1H); 6.9(d, 1H); 7.4- 7.6(m, 5H); 8.6 (s, 1H)95 14896 11697 11298 15099 154100 210101 163102 160103 213104 230105 102106 140107 185108 143109 138110 275111 163112 150113 (dmso-d.sub.6): 1.0(t, 6H); 3.2(m, 2H); 3.5(m, 2H); 7.6(m, 2H); 7.9(d, 1H); 8.6(s, 1H)114 (dmso-d.sub.6): 1.0(t, 6H); 3.2(q, 4H); 7.3(m, 2H); 7.5(m, 2H); 8.6(s, 1H)115 (dmso-d.sub.6): 1.0(t, 6H); 3.2(q, 4H); 3.8(s, 1H); 7.1(d, 2H); 7.4(d, 2H); 8.6(s, 1H)116 200117 84 (amorph.)__________________________________________________________________________
EXAMPLE 118
Preparation of 7-azepan-1-yl-5-chloro-6-(2-chloro-6-fluoro-phenyl)-1,2,4-triazolo[1,5-a]pyrimidine R.sub.1 R.sub.2 azepan-1-yl, R.sub.3 =2-chloro-6-fluoro-phenyl, R.sub.4 =chloro)
5,7-dichloro-6-(2-chloro-6-fluoro-phenyl)-1,2,4-triazolo[1,5-a]pyrimidine (16 g, 0.05 mol) is suspended in dichloromethane (100 ml). Azepane (4.9 g, 0.05 mol) is added under stirring, followed by triethylamine (5.5 g, 0.055 mol). The reaction temperature (30.degree.-35.degree. C.) is maintained with the aid of an ice bath. Then the reaction mixture is stirred for 3 h at ambient temperature, subsequently washed two times with 1N hydrochloric acid and once with water. The organic layer is separated, dried with anhydrous sodium sulphate and the solvent is evaporated under reduced pressure. Treatment of the resulting light brown oil with t-butyl methyl ether (50 ml) yields beige crystals (16.1 g, 85% of th.) having a melting point of 152.degree.-154.degree. C.
EXAMPLES 119-218
The following examples (structures, Table IIA; physical data, Table IIB) are synthesized analogously to Example 118.
TABLE IIA______________________________________ ##STR6## (I)Ex.No. R.sub.1 R.sub.2 R.sub.3 R.sub.4______________________________________119 4-methylpiperid-1-yl 2,6-difluorophenyl Cl120 3-methylpiperid-1-yl 2,6-difluorophenyl Cl121 2-methylpiperid-1-yl 2,6-difluorophenyl Cl122 piperid-1-yl 2-bromophenyl Cl123 piperid-1-yl 3-methylphenyl Cl124 piperid-1-yl 3-fluorophenyl Cl125 piperid-1-yl 2,6-difluorophenyl Cl126 piperid-1-yl 2-fluorophenyl Cl127 piperid-1-yl 2-chloro-5-nitrophenyl Cl128 piperid-1-yl 2,6-dichlorophenyl Cl129 piperid-1-yl 2-chloro-6-fluorophenyl Cl130 pyrrolidin-1-yl 2-chloro-6-fluorophenyl Cl131 morpholin-4-yl 2-chloro-6-fluorophenyl Cl132 pyrrolidin-1-yl 2-chlorophenyl Cl133 piperid-1-yl 2-chlorophenyl Cl134 azepan-1-yl 2-chlorophenyl Cl135 3-methylpiperid-1-yl 2-chlorophenyl Cl136 4-methylpiperid-1-yl 2-chlorophenyl Cl137 2-methylpiperid-1-yl 2-chlorophenyl Cl138 3-methylpiperid-1-yl 2-chloro-6-fluorophenyl Cl139 4-methylpiperid-1-yl 2-chloro-6-fluorophenyl Cl140 2-methylpiperid-1-yl 2-chloro-6-fluorophenyl Cl141 3,5-dimethylpiperid-1- 2-chloro-6-fluorophenyl Cl yl142 3,5-dimethylpiperid-1- 2-chlorophenyl Cl yl143 azepan-1-yl 2-bromophenyl Cl144 azepan-1-yl 2-chloro-5-nitrophenyl Cl145 azepan-1-yl 2,6-dichlorophenyl Cl146 azepan-1-yl 3-chlorophenyl Cl147 azepan-1-yl phenyl Cl148 azepan-1-yl 3-trifluoromethylphenyl Cl149 azepan-1-yl 4-tert-butylphenyl Cl150 azepan-1-yl 2-fluorophenyl Cl151 azepan-1-yl 2,6-difluorophenyl Cl152 azepan-1-yl 3-fluorophenyl Cl153 azepan-1-yl 3-methylphenyl Cl154 3,4-dihydro-2H-pyridin- 2-chloro-6-fluorophenyl Cl 1-yl155 3,3,5-trimethylazepan- 2-chloro-6-fluorophenyl Cl 1-yl156 azocan-1-yl 2-chloro-6-fluorophenyl Cl157 decahydroquinolin-1-yl 2-chloro-6-fluorophenyl Cl158 piperazin-1-yl 2-chloro-6-fluorophenyl Cl159 3,5-methylpiperazin-1-yl 2-chloro-6-fluorophenyl Cl160 3,5-dimethylpiperazin- 2-chloro-6-fluorophenyl Cl 1-yl161 4-ethylpiperazin-1-yl 2-chloro-6-fluorophenyl Cl162 4-methylpiperid-1-yl 2,6-difluorophenyl Br163 azepan-1-yl 2,6-difluorophenyl Br164 4-methylpiperid-1-yl 2-chloro-6-fluorophenyl Br165 azepan-1-yl 2-chloro-6-fluorophenyl Br166 2-hydroxyiminoazepan-1- 2-chloro-6-fluorophenyl Cl yl167 3,3-dimethylpiperid-1- 2-chloro-6-fluorophenyl Cl yl168 triazol-1-yl 2-chloro-6-fluorophenyl Cl169 4-hydroxypiperid-1-yl 2-chloro-6-fluorophenyl Cl170 4-formylaminopiperid-1- 2-chloro-6-fluorophenyl Cl yl171 1,4-dioxa-8-aza- 2-chloro-6-fluorophenyl Cl spiro[4.5]dec-8-yl172 2-ethylpiperid-1-yl 2-chloro-6-fluorophenyl Cl173 4-benzylpiperid-1-yl 2-chloro-6-fluorophenyl Cl174 4-formylpiperazin-1-yl 2-chloro-6-fluorophenyl Cl175 [1,4]thiazinan-4-yl 2-chloro-6-fluorophenyl Cl176 4-cyclopentylpiperazin- 2-chloro-6-fluorophenyl Cl 1-yl177 2,4-dimethylpiperid-1- 2-chloro-6-fluorophenyl Cl yl178 2- 2-chloro-6-fluorophenyl Cl carbomethoxypyrrolidin- 1-yl179 3-methylpiperid-1-yl 4-tert-butylphenyl "180 3-methylpiperid-1-yl 3-trifluoromethylphenyl Cl181 3-methylpiperid-1-yl 3-chlorophenyl Cl182 3-methylpiperid-1-yl phenyl Cl183 3-methylpiperid-1-yl 2-methylphenyl Cl184 3-methylpiperid-1-yl 4-methoxyphenyl Cl185 3-methylpiperid-1-yl 4-bromophenyl Cl186 2-methylpiperid-1-yl 3,4-difluorophenyl Cl187 3-methylpiperid-1-yl 3,4-difluorophenyl Cl188 4-methylpiperid-1-yl 3,4-difluorophenyl Cl189 azepan-1-yl 3,4-difluorophenyl Cl190 2-methylpiperid-1-yl 2,6-dichlorophenyl Cl191 3-methylpiperid-1-yl 2,6-dichlorophenyl Cl192 4-methylpiperid-1-yl 2,6-dichlorophenyl Cl193 2-methylpyrrolidin-1-yl 2-chloro-6-fluorophenyl Cl194 2-methylpyrrolidin-1-yl 2,6-difluorophenyl Cl195 2-methylpyrrolidin-1-yl 2,6-dichlorophenyl Cl196 2-methylpyrrolidin-1-yl 2-chlorophenyl Cl197 2-methylpyrrolidin-1-yl 2-methylphenyl Cl198 2-methylpyrrolidin-1-yl 2-fluorophenyl Cl199 2-methylpyrrolidin-1-yl 3-fluorophenyl Cl200 2-methylpiperid-1-yl 2-fluorophenyl Cl201 2-methylpiperid-1-yl 3-fluorophenyl Cl202 2-methylpiperid-1-yl 3-methylphenyl Cl203 azepan-1-yl 3-chloro-4-methoxyphenyl Cl204 4-methylpiperid-1-yl 3-chloro-4-methoxyphenyl Cl205 3-methylpiperid-1-yl 3-chloro-4-methoxyphenyl Cl206 pyrrolidin-1-yl 3-chloro-4-methoxyphenyl Cl207 2-methylpiperid-1-yl 3-chloro-4-methoxyphenyl Cl208 2-methylpiperid-1-yl 4-tert-butylphenyl Cl209 2-methylpiperid-1-yl 3-trifluoromethylphenyl Cl210 2-methylpiperid-1-yl 2-chlorophenyl Cl211 2-methylpiperid-1-yl phenyl Cl212 2-methylpiperid-1-yl 4-methoxyphenyl Cl213 2-methylpiperid-1-yl 2-chloro-6-fluorophenyl Cl214 4-(prop-2-yl)piperid-1- 2-chloro-6-fluorophenyl Cl yl215 4-methylpiperid-1-yl 2-chloro-6-nitrophenyl Cl216 azepan-1-yl 2-chloro-6-nitrophenyl Cl217 2-methylpyrrolidin-1-yl 2-chloro-6-nitrophenyl Cl218 piperid-1-yl 2-chloro-6-nitrophenyl Cl______________________________________
TABLE IIB______________________________________Ex. No. mp [.degree.C.] Ex. No. mp [.degree.C.]______________________________________119 164 147 134120 160 148 180121 141 149 157122 192 150 130123 173-174 151 150124 194-199 152 170125 184-185 153 155126 180-181 154 149-150127 185-187 155 175128 141-150 156 137-140129 185-188 157 179-182130 173-176 158 128-131131 249-251 159 168-169132 168-172 160 228-230133 186-189 161 129-130134 174-176 162 145-147135 152-154 163 161-164136 213-215 164 152-155137 165-170 165 138-139138 169-171 166 184 dec139 153-155 167 162-164140 147-150 168 211-215141 196-200 169 157-161142 200-204 170 216-219143 176 171 173-176144 172-177 172 121-123145 145-150 173 133-137146 177 174 80 dec175 158-159 197 169176 178-180 198 176177 156 199 178178 62-66 200 169179 145-146 201 199-202180 191 202 221-222181 192-194 203 203-206182 152-154 204 159-156183 125 205 170-175184 152 206 218-210185 186 207 147-148186 185-190 208 126-129187 180 209 207-209188 176 210 234-239189 187 211 172-173190 184-186 212 186-187191 156-158 213 202-205192 148 214 139193 179 215 203-206194 190 216 89-95195 195 217 114 dec196 165 218 173-175______________________________________
EXAMPLE 219
Fungicidal activity against Venturia inaequalis on Malus sp.
Apple cuttings of the variety Morgenduft, which are about 6 weeks old, were treated with a solution of the test compound (400 ppm) in water/acetone/Triton X or water/methanol/Triton X. After 24 hours, the plants were infected with a conidia suspension of Venturia inaequalis (about 50,000 conidia/ml), incubated in a dark climatic chamber at a relative humidity of 100% for 48 hours and then kept at a relative humidity of 95-99% and temperature of 18.degree.-20.degree. C. during the day and 13.degree. C. during the night for about 14 days. The extent of infection was assessed according to the following scheme:
0=no infection
1=1-10% infection
2=11-40% infection
3=41-100% infection
The results of these tests are set out in Table II below:
TABLE II______________________________________Example No. Activity Example No. Activity______________________________________1 1 28 2.32 0 29 1.83 2.5 30 1.34 2.3 31 2.37 1.8 32 08 1 33 09 1 34 1.511 2.8 37 1.312 1.3 38 013 2.3 39 1.014 2 40 1.015 2.7 41 016 2.7 43 017 0 46 1.019 2.4 47 2.820 3 48 2.921 1.4 49 2.922 0 50 2.923 2.5 51 2.524 3 52 2.825 1 55 2.5*27 2.5 56 1.5*57 1.5* 80 0.858 2.3* 81 2.359 1.8* 82 2.360 1.5* 83 1.661 0 86 1.362 0 87 063 0 88 064 0 91 2.070 0 105 071 1.3 106 073 2.8 107 0______________________________________ *signifies concentration of test compound = 200 ppm.
EXAMPLE 220
Determination of MIC-Values of compounds against various phytopathogenic fungi
The MIC (Minimum Inhibition Concentration)-values were determined by serial dilution tests using 48-well microtitre plates. The dilution of the test compounds in the nutrient solution and the distribution to the wells were carried out by a TECAN RSP 5000 robotic processor.
The compounds were diluted to the following concentrations: 100, 50, 25, 12.5, 6.25, 3.13, 1.56, 0.78, 0.39, 0.20, 0.10 and 0.05 .mu.g/ml.
For preparation of the nutrient solution, V8 juice (Trade Mark) was neutralized with calcium carbonate and centrifuged. The supernatant was diluted with distilled water (1:5) to the final concentration.
The fungi (Alternaria solani, Botrytis cinerea, Septoria nodorum) were added into the wells as a droplet of spore suspension. The microtitre plates were then incubated at 20.degree. C. for 6-8 days. This MIC-value was determined by visual inspection of the plates. In the case of Alternaria solani and Botrytis cinerea, the lowest concentration in the dilution series without mycelial growth was defined to be the MIC-value. For Spetoria nodorum, no MIC-value but only a strong inhibition of growth was regularly observed.
The results of these tests are set out in Table III below:
TABLE III______________________________________ MIC-value (.mu.g/ml)Example Botrytis Alternaria SeptoriaNo. cinerea solani nodorum______________________________________1 12.5 1.566 6.25 3.137 25.08 6.259 3.1310 12.518 >100.019 50.0 >100.020 100.0 100.021 12.5 25.022 1.56 0.39 >12.524 >100.025 6.25 0.78 >3.1326 50.028 >12.529 >3.1332 0.78 0.39 >0.3933 6.25 1.56 >3.1335 50.036 >100.037 0.7838 12.50 25.0039 25.00 0.3940 3.13 0.7841 25.00 12.5043 6.25 12.5046 12.50 12.5063 6.25 0.0564 3.13 0.0565 3.1370 3.13 0.2071 3.1373 1.5682 12.50 3.1383 6.25 1.5685 6.2586 25.00 1.5687 12.5088 12.5091 12.5094 1.5698 25.0099 12.50103 25.00104 25.00105 1.56 0.39106 3.13 3.13107 3.13 0.39110 25.00 12.50111 0.39 3.13112 3.13113 3.13114 1.56 12.50115 12.50 12.50116 25.00 3.13117 6.25 3.13______________________________________
EXAMPLE 221
The fungicidal activity of compounds of the invention was investigated by means of the following tests.
(a) Direct protectant activity against tomato late blight (Phytophthora infestans: PIP)
The test is a direct protectant one using a foliar spray. The upper leaf surfaces of tomato plants with two expanded leaves (cv. First in the field) are sprayed with a solution of test compound 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 atomizing nozzle. The concentration of the compound is 1000 ppm, and the spray volume is 700 1/ha. After a subsequent period of 24 hours under normal glasshouse conditions, the upper surfaces of the leaves are inoculated by spraying with an aqueous suspension containing 2.times.10.sup.5 zoospores/ml. The inoculated plants are kept for 24 hours in a high humidity cabinet and 5 days under growth chamber conditions. The assessment is based on the percentage of diseased leaf area compared with that on control leaves.
(b) Direct protectant activity against vine downy mildew (Plasmopara viticola: PVP)
The test is a direct protectant one using a foliar spray. The lower surface of leaves of whole vine plants (cv Cabernet Sauvignon) are sprayed with the test compound at a dosage of 1000 ppm using an automated sprayline as described under (a), and after a subsequent period of 24 hours under normal glasshouse conditions the lower surfaces of the leaves are inoculated by spraying with an aqueous suspension containing 2.5.times.10.sup.4 zoosporangia/ml. The inoculated plants are kept for 24 hours in a high humidity cabinet, 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.
(c) 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). One day after treatment the seedlings are inoculated by spraying the leaf upper surfaces with a suspension of A. solani conidia containing 10.sup.4 spores/ml. For 4 days after inoculation plants are kept moist in a humidity compartment at 21.degree. C. Disease is assessed 4 days after inoculation, based on the percentage of leaf surface area covered by lesions.
(d) Direct protectant activity against broad bean grey mould (Botrytis cinerea; BCB)
The test is a direct protectant one using a foliar spray. The upper surfaces of leaves of broad bean plants (cv The Sutton) are sprayed with the test compound at a dosage of 1000 ppm using an automated sprayline as described under (a). 24 hours after spraying the leaves are inoculated with an aqueous suspension containing 10.sup.5 conidia/ml. For 4 days after inoculation plants are kept moist in a humidity compartment at 21.degree. C. Disease is assessed 4 days after inoculation, based on the percentage of leaf surface area covered by lesions.
(e) Activity against wheat leafspot (Leptosphaeria nodorum; LN.)
The test is a direct therapeutic one, using a foliar spray. Leaves of wheat plants (cv Norman), at the single leaf stage, are inoculated by spraying with an aqueous suspension containing 1.times.10.sup.6 spores/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 1000 ppm using an automated sprayline as described under (a). After drying, the plants are kept for 6-8 days at 22.degree. C. and moderate humidity, followed by assessment. Assessment is based on the density of lesions per leaf compared with that on leaves of control plants.
(f) Activity against wheat brown rust (Puccinia recondita; PR)
The test is a direct protectant one using a foliar spray. Wheat seedlings (cv Avalon) are grown to the 1-1 1/2 leaf stage. The plants are then sprayed with the test compound at a dosage of 1000 ppm 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). 18-24 hours after treatment, the seedlings are inoculated by spraying the plants from all sides with an aqueous spore suspension containing about 10.sup.5 spores/ml. For 18 hours after inoculation, the plants are kept in high humidity conditions at a temperature of 20.degree.-22.degree. C. Thereafter, the plants are kept in ambient glasshouse conditions, that is, in moderate relative humidity and at a temperature of 20.degree.C. The disease is assessed 10 days after inoculation on the basis of the percentage of the plant covered by sporulating pustules compared with that on the control plants.
g) Activity against barley powdery mildew (Erysiphe graminis f.sp hordei; EG)
The test is a direct therapeutic one, using a foliar spray. Leaves of barley seedlings, (cv. 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 with the test compound at a dosage of 1000 ppm using an automated sprayline as described under (a). After drying, plants are returned to a compartment at 20.degree.-25.degree. C. and moderate 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.
(h) Activity against rice leaf blast (Pyricularia oryzae; PO)
The test is a direct therapeutic one using a foliar spray. The leaves of rice seedlings (cv Aichiaishi--about 30 seedlings per pot) are sprayed with an aqueous suspension containing 10.sup.5 spores/ml 20-24 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 1000 ppm using an automated sprayline as described under (a). After treatment the plants are kept in a rice compartment at 25.degree.-30.degree. C. 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.
(i) 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 dispensed in 25-compartment petri dishes to give a final concentration of 50 ppm compound and 2.5% acetone. Each compartment is inoculated with a 6 mm diameter plug of agar/mycelium taken from a 14 day old culture of P. herpotrichoides.
Plates are incubated at 20.degree. C. for 12 days until the assessment of mycelial growth.
(j) Activity against Fusarium in-vitro (Fusarium culmorum; FSI)
This test measures the in vitro activity of compounds against a species of Fusarium that causes stem and root rots. The test compound is dissolved or suspended in acetone and added to molten half strength Potato Dextrose Agar to give a final concentration of 50 ppm compound and 2.5% acetone. After agar has set, plates are inoculated with 6 mm diameter plugs of agar and mycelium taken from a 7 day old culture of Fusarium sp. Plates are incubated at 20.degree. C. for 5 days and radial growth from the plug is measured.
(k) Activity against Rhizoctonia in vitro (Rhizoctonia solani: RSI)
This test measures the in vitro activity of compounds against Rhizoctonia solani, a fungus that causes stem and root rot. The test compound is dissolved or suspended in acetone and added into aliquots of 4 ml half strength Potato Dextrose Broth dispensed in 25-compartment petri dishes to give a final concentration of 50 ppm compound and 2.5% acetone.
The fungal inoculum consists of mycelial fragments of R. solani grown in shaken culture flasks and added to the broth to provide 2.times.10.sup.3 fragments/ml broth.
Plates are incubated at 20.degree. C. for 10 days until the assessment of mycelial growth.
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
1=about 50-80% disease control
2=greater than 80% disease control
The results of these tests are set out in Table IV below:
TABLE IV__________________________________________________________________________Ex. Fungicidal ActivityNo. PIP PVP AS BCB LN PR EG PO PHI FSI RSI__________________________________________________________________________10 1 2 1 134 237 2 2 1 138 1 2 2 2 139 1 2 240 2 2 2 1 241 2 2 2 2 2 1 242 2 1 143 2 2 1 2 2 144 2 1 153 1 2 154 165 2 166 2 1 1 1 167 2 268 2 269 170 2 2 1 2 171 2 1 2 1 272 273 274 175 176 177 2 1 178 2 2 179 1 182 2 2 2 284 185 2 1 186 1 1__________________________________________________________________________
EXAMPLE 222
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 surface of leaves of vine plants (cv. Cabernet Sauvignon), approximately 8 cm high, are inoculated with an aqueous suspension containing 5.times.10.sup.4 zoosporangia/ml. The inoculated plants are kept for 24 hours at 21.degree. C. in a high humidity cabinet, then for 24 hours in a glasshouse at 20.degree. C. and 40% relative humidity. Infected leaves are sprayed on their lower surfaces with a solution of the test compound in 1:1 water/acetone containing 0.04% "TWEEN 20" (Trade Mark; a polyoxyethylene sorbitan ester surfactant). Plants are sprayed using a track sprayer equipped with 2 air-atomizing nozzles. The concentration of the compound is 600 ppm and the spray volume is 750 l/ha. After drying, the plants are returned to the glasshouse at 20.degree. C. and 40% relative humidity for 96 hours and are then transferred to the high humidity cabinet 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) Direct protectant activity against tomato late blight (Phytophthora infestans; PIP)
The test is a direct protectant one using a foliar spray. Tomato plants with two expanded leaves (cv. First in the Field) are sprayed with the test compound at a dosage of 600 ppm as described under (a). After drying, the plants are kept for 24 hours in a glasshouse at 20.degree. C. and 40% relative humidity. The upper surfaces of the leaves are then inoculated with an aqueous suspension containing 2.times.10.sup.5 zoosporangia/ml. The inoculated plants are kept for 24 hours at 18.degree. C. in a high humidity cabinet and then for 5 days in a growth chamber at 15.degree. C. and 80% relative humidity with 14 hours light/day. The assessment is based on the percentage of diseased leaf area compared with that on control leaves.
(c) Activity against tomato early blight (Alternaria solani; AS)
The test is a direct prophylactic one using a foliar spray. Tomato seedlings (cv Outdoor Girl), at the stage at which the second leaf is expanded, are sprayed with the test compound at a dosage of 600 ppm as described under (a). After drying, the plants are kept for 24 hours in a glasshouse at 20.degree. C. and 40% relative humidity followed by inoculation of the leaf upper surfaces with an aqueous suspension of A. solani conidia containing 1.times.10 conidia/ml. After 4 days in a high humidity cabinet at 21.degree. C., disease is assessed based on the percentage of leaf surface area covered by lesions when compared with control plants.
(d) Direct protectant activity against broad bean grey mould (Botrytis cinerea; BCB)
The test is a direct protectant one using a foliar spray. Broad bean plants (cv The Sutton) with two leaf pairs are sprayed with the test compound at a dosage of 600 ppm as described under (a). After drying, the plants are kept for 24 hours in a glasshouse at 20.degree. C. and 40% relative humidity. The upper surface of the leaves are then inoculated with an aqueous suspension containing 1.times.10.sup.6 conidia/ml. Plants are kept for 4 days at 22.degree. C. in a high humidity cabinet. The assessment is based on the percentage of diseased leaf area compared with that on control leaves.
(e) Activity against barley Powdery mildew (Erysiphe graminis f.sp. hordei: EG)
The test is a direct therapeutic one using a foliar spray. Leaves of barley seedlings (cv Golden Promise) at the single leaf stage are inoculated by dusting with mildew conidia and kept in the glasshouse at 18.degree. C. and 40% relative humidity for 24 hours. Plants are then sprayed with the test compound at a dosage of 600 ppm as described under (a). After drying, plants are returned to the glasshouse at 18.degree. C. and 40% relative 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) Activity against rice leaf blast (Pyricularia oryzae; PO)
The test is a direct therapeutic one using a foliar spray. The leaves of rice seedlings at the stage of the second leaf beginning to bend (cv Aichiaishi) are inoculated with an aqueous suspension containing 10.sup.5 spores/ml. The inoculated plants are kept for 24 hours at 18.degree. C. in a high humidity cabinet and then sprayed with the test compound at a dosage of 600 ppm as described under (a). Treated plants are kept for 8-9 days in the glasshouse at 22.degree. C. and 90% relative humidity. Assessment is based on the density of necrotic lesions when compared with control plants.
(g) 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 dispensed in 25-compartment petri dishes to give a final concentration of 10 ppm test compound and 0.825% acetone. The fungal inoculum consists of mycelial fragments of P. herpotrichoides grown in half strength Potato Dextrose Broth in shaken flasks and added to the broth to provide 5.times.10.sup.4 mycelial fragments/ml broth. Petri dishes are incubated at 20.degree. C. for 10 days until the assessment of mycelial growth.
h) Activity against Rhizoctonia in vitro (Rhizoctonia solani: RSI)
The test measures the in vitro activity of compounds against Rhizoctonia solani which causes stem and root rot. The test compound is dissolved or suspended in acetone and added into 4 ml aliquots of half strength Potato Dextrose Broth dispensed in 25-compartment petri dishes to give a final concentration of 10 ppm compound and 0.825% acetone. The fungal inoculum consists of mycelial fragments of R. solani grown in half strength Potato Dextrose Broth in shaken culture flasks and added to the broth to provide 5.times.10.sup.4 fragments/ml broth. Petri dishes are incubated at 20.degree. C. for 10 days until the assessment of mycelial growth.
(i) Activity against apple scab in vitro (Venturia inaequalis; VII)
This test measures the in vitro activity of compounds against Venturia inaequalis which causes apple scab. The test compound is dissolved or suspended in acetone and added into 4 ml aliquots of half strength Potato Dextrose Broth dispensed in 25-compartment petri dishes to give a final concentration of 10 ppm compound and 0.825% acetone. The fungal inoculum consists of mycelial fragments and spores of V. inaequalis grown on malt agar and added to the broth to provide 5.times.10.sup.4 propagules/ml broth. Petri dishes are incubated at 20.degree. C. for 10 days until the assessment of mycelial growth.
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
1=50-80% disease control
2=greater than 80% disease control
The results of these tests are set out in Table V below:
TABLE V______________________________________Ex-ample Fungicidal ActivityNo. PVA PIP AS BCB EG PO PHI RSI VII______________________________________45 2**89 1 1 1*90 1 2 1*92 1 193 294 2 1 295 2 1 296 2 297 298 2 2 1 1 199 2 2 2 1 2 2100 2101 2 1102 2 2 1 1 2106 2 2 2 2 1 1 2 1107 2 2 2 2 1 2 1108 2109 2 2 2 1 2______________________________________ *signifies dosage of test compound = 30 ppm **signifies dosage of test compound = 3 ppm
Example 223
Determination of Effective Dose for >90% Inhibition by Test Compounds in the Serial Dilution Test with Various Phytopathogenic Fungi
The ED>90 (Effective lose >90%)-value is determined by serial dilution tests using Microtiter plates with 24 or 48 wells per plate. The dilution of the test compounds in the nutrient solution and the distribution to the wells is carried out by a TECAN RSP 5000 Robotic Sample Processor. The following test compound concentrations are used: 0.05, 0.10, 0.20, 0.39, 0.78, 1.56, 3.13, 6.25, 12.50, 25.00, 50.00 and 100.00 mg/ml. For preparation of the nutrient solution, V8 vegetable juice (333 ml) is mixed with calcium carbonate (4.95 g), centrifuged, the supernatant (200 ml) diluted with water (800 ml) and autoclaved at 121.degree. C. for 30 min.
The respective inocula (Alternaria solani, ALTESO; Botrytis cinerea, BOTRICI; Cercospora beticola, CERCBE; Cladosporium herbarum, MYCOTA; Corticium rolfsii, SCLORO; Helminthosporium tritici repentis, PYRNTR; Leptosphaeria nodorum, LEPTNO; Micronectriella nivalis, MICNI; Monilinia fructigena, MONIFG; Mycosphaerella ligulicola, MYCOLG; Mycosphaerella pinodes, MYCOPI; Rhizoctonia solani, RHYZSO; Sclerotinia sclerotiorum, SCLESC) are added into the wells as spore suspensions (50 ml; 5.times.10.sup.5 ml) or agar slices (6 mm) of an agar culture of the fungus.
After 6-12 days incubation at suitable temperatures (18.degree.-25.degree. C.), the ED>90 values are determined by visual inspection of the plates. The lowest concentration in the dilution series with mycelial growth of less than 10% is defined to be the ED>90 value (Table VIA-C).
TABLE VIA______________________________________Ex. MY-No. ALTESO BOTRCI CERCBE COTA PYRNTR______________________________________118 0.05 0.15 0.10 0.05 0.39119 1.56 0.39120 0.78 3.13 0.78 50.00 6.25121 0.39 0.78 0.78 0.78 3.13122 0.20 12.50123 12.50 >100124 50.00 50.00125 0.20 3.13126 0.39 12.50127 3.13 6.25129 0.39 0.78130 3.13 3.13131 3.13 6.25132 1.56 1.56133 0.20 0.88134 0.10 0.30 1.56 1.56135 0.65 1.45 6.25 >100 100.00136 0.12 1.43 0.20 >100137 0.52 0.78 3.13 1.56 100.00138 0.59 0.59 3.13 >100 100.00139 0.05 0.15 0.78 0.05 0.39140 0.25 0.25 3.13 0.39 1.56141 >100 3.13142 6.25 25.00143 0.20 1.17 3.13 25.00144 3.52 >100 >100145 0.10 3.13147 2.35 18.75 1.56 >100 25.00148 100.00 >100149 >100 >100150 0.78 0.78151 0.15 0.49 0.78 0.20 3.13152 6.25 12.50153 >100 >100154 0.10 0.39155 0.78 100.00156 0.20 0.39157 >100 1.56158 >100 >100159 3.13 100.00160 50.00 >100161 3.13 50.00162 0.10 0.39163 0.20 0.20164 0.05 0.20165 0.10 0.20166 >100 >100167 0.78 50.00168 >100 >100169 6.25 25.00170 50.00 >100171 0.20 1.56172 0.20 0.05173 >100 >100174 3.13 50.00175 0.05 0.39176 12.50 >100177 0.05 0.20178 12.50 12.50179 >100 >100180 >100 >100181 >100 >100182 25.00 >100183 3.13 25.00184 1.56 >100185 >100 >100186 >100 >100187 >100 >100188 0.78 >100189 0.78 >100190 0.20 0.39191 0.78 >100192 0.20 0.78193 0.39 0.39194 0.39 1.56195 >100 >100196 1.56 3.13197 3.13 6.25198 1.56 6 .25199 25.00 3.13200 1.56 12.50201 >100 >100202 >100 >100203 >100 >100204 3.13 25.00205 >100 >100206 >100 >100208 >100 >100209 >100 >100210 >100 >100211 >100 >100212 3.13 3.13213 0.78 >100214 0.39 3.13215 3.13 6.25______________________________________
TABLE VIB__________________________________________________________________________Ex.No. LEPTNO MICNNI MONIFG MYCOLG MYCOPI SCLSCE__________________________________________________________________________118 0.78 0.78 0.10 0.05 >100 100.00120 3.13 3.13 1.56 0.39 3.13 100.00121 25.00 0.20 0.39 0.78 0.39 3.13134 >100 3.13 0.39 0.39 3.13 25.00135 3.13 6.15 1.56 3.13 12.50 50.00136 25.00 12.50 0.78 0.20 25.00 >100137 0.78 6.25 0.78 1.56 3.13 100.00138 3.13 0.20 0.78 0.78 3.13 >100139 0.78 3.13 0.20 0.10 0.78 1.56140 1.56 1.56 0.39 0.39 0.05 25.00143 50.00 100.00 3.13 3.13 3.13 6.25144 >100 >100 >100147 50.00 100.00 3.13 3.13 3.13 >100151 0.78 3.13 0.20 0.39 0.78 >100213 6.25 6.25__________________________________________________________________________
TABLE VIC______________________________________Ex. Ex.No. RHIZSO SCLORO No. RHIZSO SCLORO______________________________________118 1.67 0.39 147 >100 25.00120 25.00 3.13 148 >100121 0.78 3.13 149 >100122 >100 151 1.56 0.39123 >100 154 0.39124 >100 155 >100125 0.78 156 3.13126 12.50 157 >100127 >100 158 >100129 3.13 159 100.00130 6.25 160 >100131 >100 161 >100132 12.50 162 3.13133 >100 163 3.13134 3.13 1.56 164 6.25135 >100 6.25 165 1.56136 >100 >100 166 >100137 37.50 25.00 167 >100138 >100 100.00 168 >100139 1.17 0.39 169 >100140 0.59 1.56 170 >100141 >100 171 12.50142 >100 172 0.78143 >100 3.13 173 >100144 >100 174 >100145 1.56 175 6.25176 >100 196 12.50177 3.13 197 12.50178 >100 198 25.00179 >100 199 6.25180 >100 200 >100181 >100 201 >100182 >100 202 >100183 >100 203 >100184 >100 204 >100185 >100 205 >100186 >100 206 >100187 >100 207 >100188 >100 208 >100189 >100 209 >100190 3.13 210 >100191 >100 211 >100192 >100 212 >100193 3.13 213 >100194 0.78 214 >100195 >100 215 >100______________________________________
EXAMPLE 224
Determination of Activity of Test Compounds Against Cereal Powdery Mildew
This test measures the prophylactic activity of test compounds applied as a foliar spray. Cereal seedlings (barley, cv Golden promise; wheat, cv Kormoran) are grown to the 1 leaf stage. The plants are then sprayed with a solution of active material in water, made up from a 5000 ppm stock solution in acetone containing 5000 ppm of TRITON.TM. X 155 (a non-ionic polyoxyethylene ether surfactant). Plants are treated using an automated sprayline with an atomising nozzle. The spray volume is 20 ml. 24 hours after treatment the seedlings are inoculated with powdery mildew by shaking stock culture plants with sporulating pathogen (barley--Erysiphe graminis f.sp. hordei; wheat--Erysiphe graminis f.sp. tritici) over them. Thereafter, the plants are kept for 3 h without air movement in order to allow the spores to settle on the leaves. The plants are then kept in the greenhouse until symptoms occur. Assessment is based on the percentage of diseased leaf area compared with that on control leaves (Table VII).
TABLE VII______________________________________ Activity [%] Barley WheatEx. No. 100 ppm 100 ppm______________________________________118 100 91139 100 100140 100 44______________________________________
EXAMPLE 225
Determination of Activity of Test Compounds Against Rice Blast (Pyricularia oryzae)
This test measures the protectant activity of test compounds upon foliar application. Rice seedlings (Oryza sativa L. "M-9") are grown in the greenhouse. Approximately two weeks after seeding, the plants are sprayed with a solution of active material (200 ppm) in a solvent/surfactant system containing 5% aceton and 0.05% TWEEN.TM. 20 (a polyoxy-ethylenesorbitan monolaurate surfactant) in deionized water. All foliar surfaces of the plants are sprayed to the point of run-off, and the plants are allowed to air-dry 2-5 hours prior to inoculation. The inoculate is prepared from Pyricularia oryzae Cavara (culture FD 7, FD 190) (PYRIOR) grown on oatmeal agar plates, of which the conidia are washed off with a solution of 0.05% TWEEN 20 in deionized water. Then the conidia concentration is adjusted to 1,000,000 conidia/ml. This solution is used for inoculating the foliage, including the clams, by spraying the conidia suspension onto the plants. Thereafter the plants are kept in a moisture chamber (18.degree.-28.degree. C., 100% rel. humidity) for 24-48 hours. Thereafter, the plants are placed in th greenhouse for 8-10 days. Assessment is based on the percentage of diseased leaf area compared with that on leaves of control plants. The activity is expressed as percentage of disease control using the rating scale shown below.
______________________________________RATING SCALERating % Disease Control______________________________________0 01 1-142 15-293 30-444 45-595 60-746 75-897 90-958 96-999 100______________________________________
TABLE VIII______________________________________Ex. No. PYRIOR Ex. No. PYRIOR______________________________________118 0 130 0119 8 131 0120 8 132 0121 9 133 4122 0 134 0124 0 135 0125 7 136 0126 0 137 7127 5 138 5128 3 139 8129 0 140 6141 0 171 7142 0 172 8143 3 173 0144 6 174 0145 2 175 3147 0 176 0148 5 177 7149 0 178 7150 7 179 2151 0 180 0152 6 181 0153 3 184 5154 7 185 0155 0 186 0156 0 187 0157 5 188 4158 0 189 3159 0 190 4160 0 191 4161 0 192 4162 5 193 7163 7 194 7164 0 195 0165 0 196 6166 0 197 5167 2 198 6168 0 199 4169 3 214 2170 0 215 4______________________________________
Example 226
Determination of Activity of Test Compounds in Field Trials Against Rice Blast
This test measures the curative effect of the test compounds. Rice (Oryza sativa var. Koshihikari) is grown in field plots (1 m.times.1 m; 1 m.sup.2). The plants are sprayed with the test compounds 8 and 20 days after inoculation with rice leaf blast (Pyricularia oryzae) and additional transplanting of infected seedlings. The spray volume is 0.1 l/plot, equivalent to 1,000 l/ha. Assessments of the results are carried out 11 days after the first (11 DAT1) and 15 days after the second application (15 DAT2). They are based on the percentage of diseased leaf area compared with that on leaves of control plants. The activity is expressed as percentage of disease control (Table IX).
TABLE IX______________________________________Ex. Dose % ControlNo. [ppm] 11 DAT1 15 DAT2______________________________________118 200 73 80 400 68 80139 200 72 64 400 64 59______________________________________
Example 227
Activity Against Grapevine Powdery Mildew (Uncinula necator)
This test measures the direct protectant activity of test compositions and test compounds applied as foliar spray. Cuttings of grapevine (cv M uller-Thurgau) are grown to the 6-8 leaf stage and then cut back to 4 equally sized leaves. The plants are sprayed to run-off in a spray cabinet with a solution (20 ml, 200 ppm) of active material in water made up from a 5000 ppm stock solution in acetone containing 5000 ppm of TRITON.RTM. X 155. 48 hours after treatment the cuttings are inoculated with conidia of Uncinula necator (UNCINE) in a special spore setting tower. The spores are blown from freshly sporulating grape leaves (U. necator stock culture) into the upper hole of the settling tower and are allowed to settle on the leaves for 5 min. Then the plants are kept in a phytotron at 18.degree. C. night and 22.degree. C. day temperature at an interval of 12 h night and 12 h day. Illumination is accomplished by fluorescent tubes at 11,200 lux. Assessment is carried out after 21d by visual inspection and based on the percentage of the diseased leaf area of the three youngest leaves compared with that on control plants.
The results of the tests are set out in Table X below, in which the compounds are identified by reference to the preceding Example Nos. and to above. Absence of a numerical indicates that none of the tests described above is carried out. A rating 0 indicates disease as untreated control, a rating 100 indicates no infection.
Fungicidal activity against Venturia inaequalis on Malus sp.
Apple seedlings of the varieties Morgenduft or Macintosh, which are about 6 weeks old, are treated with a solution of the respective test compound (100 ppm) in water/aceton/TRITON X or water/methanol/TRITON X. After 72 hours, the plants are infected with a conidia suspension of Venturia inaequalis (c. 50,000 conidia/ml) (VENTIN), incubated in a dark climatic chamber at a relative humidity of 100% for 48 h and, then, kept at a relative humidity of 95-99% and temperatures of 18.degree.-20.degree. C. during the day and 13.degree. C. during the night for about 14 days.
The results of the tests are set out in Table X below, in which the compounds are identified by reference to the preceding Example Nos. and to above. Absence of a numerical indicates that none of the tests described above is carried out. A rating 0 indicates disease as untreated control, a rating 100 indicates no infection.
TABLE X______________________________________ % Disease ControlEx. No. UNCINE VENTIN______________________________________118 100 94119 100 96120 83 86125 91 48129 72130 77131 61134 100137 100 80138 97 36139 100 88140 100 60143 76147 57151 68152 42154 74162 37163 36164 91165 89167 36171 89174 54175 66177 89______________________________________

Number	Name	Date
4036840	OBrien et al.	Jul 1977
4189483	Snowling	Feb 1980
4199584	Cox et al.	Apr 1980
4567263	Eicken et al.	Jan 1986
4617303	Eicken et al.	Oct 1986
5250530	Giencke et al.	Oct 1993

Number	Date	Country
0071792	Feb 1983	EPX
550113	Jul 1993	EPX
1148629	Apr 1969	GBX
94-20501	Sep 1996	WOX

Triazolopyrimidine derivatives

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