Triazole or imidazole and tetrahydrofuran compounds, their use as fungicides and preparation processes.

The present invention relates to new compounds, for phytosanitary use, with triazole or imidazole groups and _tetrahydrofuran. It also relates to the processes for the preparation of said compounds and the products which may be used as intermediates in the preparation processes. It then relates to the use as fungicides of these compounds, the fungicidal compositions based on these compounds and methods for combating fungal diseases of crops using these compounds.

Many products with triazole groups, in particular fungicides, are already known in particular from European patent application No. 151 084. This patent application effectively describes the compounds whose formula is indicated at the end of the description and their use as fungicide.

An object of the present invention is to provide compounds with improved properties in the treatment of fungal diseases.

Another object of the present invention is to provide compounds with a spectrum of use also improved in the field of fungal diseases.

It has now been found that these objects can be achieved with the products of the invention. These are characterized in that they correspond to formula (I) in which<ul id="ul0001" list-style="none"><li>A is the group (Y) n Ph- (CH₂) m where Ph is a phenylene ring and m = 0 or 1, preferably 0,</li><li>Y is a halogen atom or a cyano or nitro group, or an optionally halogenated alkyl or alkoxy group,</li><li>n is a positive or zero integer less than 6, the groups Y being able to be identical or different when n is greater than 1,</li><li>Tr represents a group 1, 2, 4-triazole 1-yl and Im represents a group 1,3-imidazole 1-yl,</li><li>R₁ at _R5, identical or different, represent the hydrogen atom or a lower alkyl, lower cycloalkyl, aryl (especially phenyl), aralkyl (especially benzyl), lower alkoxy, lower alkanoyl, aroyl (especially benzoyl) radical, these various radicals being able to be optionally substituted (for example by one or more atoms or radicals such as halogen atoms, and lower alkoxy radicals),</li><li>X₁, X₂, identical or different, represent the hydrogen atom, a halogen atom, a lower alkyl radical, a lower cycloalkyl radical, an aryl radical (in particular phenyl), or aralkyl (in particular benzyl), these various radicals possibly being similarly substituted for R groups₁ at R₅, a QR group₆ in which Q represents 0 or S, and R6 represents the hydrogen atom or a lower alkyl radical, a lower cycloalkyl, aryl (especially phenyl), aralkyl (especially benzyl), acyl, aroyl, or thioacyl, (especially benzoyl) radical , acetyl, thioacetyl, propionyl, thiopropionyl), alkyloxythioyl, aryloxythioyl or aralkyloxythioyl (the term thioyl corresponds to C - S (S)), these radicals being able to be similarly substituted for the R groups₁ at R₅ and may have identical or different meanings when X₁ and X₂ each correspond to OR₆ or SR₆, a group of formula -QR₇-Q- where Q has the same meaning as before and in which R₇ is a divalent hydrocarbon radical, comprising from 2 to 6 carbon atoms, one of these carbon atoms being able to be replaced by an oxygen or nitrogen atom, said single divalent radical being itself optionally substituted (for example by one or more halogen atoms or lower alkyl, lower alkoxy or hydroxy radicals, a group -NR₈R₉ in which R₈and R₉, identical or different, represent the hydrogen atom or a lower alkyl radical, a lower cycloalkyl, aryl (especially phenyl), aralkyl (especially benzyl) radical, these various radicals possibly being optionally substituted similarly to the R groups₁at _R5, or else R₈ and R₉ can form together a single divalent hydrocarbon radical, comprising from 2 to 6 carbon atoms, one of these carbon atoms being able to be replaced by an oxygen, sulfur or nitrogen atom, said single divalent radical being itself even optionally substituted (for example by one or more halogen atoms or lower alkyl, optionally halogenated lower alkoxy, hydroxy), a group = NR₁₀ in which R₁₀ corresponds to a lower alkyl radical, a lower cycloalkyl, aryl (especially phenyl), aralkyl (especially benzyl) radical, to a group of formula OR₁₁ in which R₁₁ is an alkyl or an aralkyl, aryloxy, these radicals being able to be substituted in a similar way to the groups R₁at R₅, to a hydroxy group an N group₃ provided that X₂ be different from N₃₀ X₁and X₂ can together constitute a ₀ ou = S, with the general condition that if X₁ is chosen from the list consisting of hydrogen, a lower alkyl radical, a lower cycloalkyl radical, an aryl radical or an aralkyl radical, X₂ cannot match any of the meanings on the same list.</li></ul>

The invention also relates to the salified forms of the compounds according to the invention. The salified forms are the forms acceptable in agriculture among which there may be mentioned: the hydrochloride, sulphate, oxalate, nitrate or arylsulphonate as well as the addition complexes of these compounds with metal salts, and in particular iron, chromium, copper salts , manganese, zinc, cobalt, tin, magnesium and aluminum.

For example, complexes with zinc can be obtained by reacting the compound of formula 1 with zinc chloride.

It should be noted that the claimed compounds are not described in European patent application No. 151,084.

For the purposes of this text, it is meant that the lower adjective, when it qualifies an organic radical, means that this radical contains at most six carbon atoms. This radical can be linear or branched.

The applicant wishes to emphasize that the additional plates cannot in any way be considered as drawings but as an integral part of the description of the invention.

The compounds of formula 1 and the compounds which may be used as intermediates in the preparation processes and which will be defined when describing these processes may exist in one or more forms of isomers depending on the number of asymmetric centers of the molecule. The invention therefore relates to all the optical isomers as well as their racemic mixtures and the corresponding diastereoisomers. The separation of the diastereoisomers and / or of the optical isomers can be carried out according to the methods known per se.

With a view to fungicidal applications it has been found that the invention preferably relates to the compounds of formula I in which Y is a halogen and n = 1, 2 or 3.

It has also been found that it is preferable to use the compounds of formula I in which n = 1 or 2, and Y is a halogen atom placed in ortho and / or para.

More preferably n = 2 and Y is a halogen atom, advantageously chlorine placed in ortho and para.

In view of the restrictions defined above, taken separately or in combinations, it has been found that it is preferable, because of the fungicidal properties, to use the triazole compounds of formula II in which R₁ in R correspond to a hydrogen atom, to a lower alkyl or cycloalkyl group, Y, n, m have the same meaning as in formula I with the preferred variants set out above, Hal corresponds to a halogen atom, preferably chlorine or bromine, X₁ is a halogen atom, preferably chlorine or bromine, or a hydrogen atom and advantageously the hydrogen atom.

In view of the restrictions defined above, taken separately or in combinations, it has been found that it is preferable, because of the fungicidal properties, to use the triazole compounds of formula III in which R₁ at R_s correspond to a hydrogen atom, to a lower alkyl or cycloalkyl group, Y, n, m have the same meaning as in formula I with the preferred variants stated above, X₁ corresponds to a hydrogen atom, to a lower alkyl or cycloalkyl group, Q has the same meaning as in formula I, _R⁶ corresponds to a hydrogen atom, to a lower alkyl or cycloalkyl group.

The preferred triazole compounds of formula II are those in which the groups R₁ at R₅ correspond to a hydrogen atom.

The preferred triazole compounds of formula III are those in which the groups R₁ at R₅ correspond to a hydrogen atom where X₁ corresponds to the hydrogen atom or lower alkyl or cycloalkyl, and where R₆ corresponds to an alkyl, lower cycloalkyl group and preferably Q = 0.

The present invention also relates to processes for the preparation of the compounds according to the invention.

In case the group X₂ corresponds to a halogen atom, (compound of formula II), a preparation process consists of the following stages:<ul id="ul0002" list-style="none"><li>Step a) A halogenoketone of formula IIa obtained is reacted by a known method, in which Y, n, R₅ have the same meaning as that given for the compounds of formula I and Z corresponds to a halogen atom, with an organometallic of formula IIb, in which _R1at _R49 X₁, have the same meaning as above and M corresponds to an alkali metal or to a magnesian (Mg Hal) or to a zincic (Zn Hal) for example, in a solvent, preferably chosen from ethers, such as diethyl ether or tetrahydrofuran, aliphatic, alicyclic or aromatic hydrocarbons such as hexane, toluene at a temperature chosen between -50 ° C and the reflux of the solvent considered and in a molar ratio II a: II b preferably between 1.1 and 0.2. The reaction leads to the compound of formula IIc after neutralization of the reaction medium.</li><li>Step b) The compound of formula IIc is then reacted with an imidazole or an unsubstituted triazole in the presence of an organic or inorganic base, for example pyridine, triethylamine, sodium hydroxide, potassium hydroxide, carbonates and bicarbonates of alkali or alkali metals earthy and in a suitable solvent such as, for example, alcohols, ketones, amides, nitriles, aromatic hydrocarbons optionally halogenated at a temperature between 80 ° and the reflux of the solvent and in a molar ratio IIc: imidazole or triazole preferably between 1.1 and 0.2, which leads to the compound of formula IId. The reaction generally passes through an epoxy intermediate of formula IIh which can optionally be isolated or prepared separately by methods known to those skilled in the art.</li><li>Step c) A compound of halogen or mixed halogen in an inert solvent such as saturated or aromatic hydrocarbons, optionally halogenated, is added to the compound IId, preferably mole to mole, which leads to the compound IIe.</li><li>Step d) Compound II is preferably obtained at room temperature by cyclization of compound IIe in the presence of an organic or inorganic base indicated in b in a molar ratio of compound II: base preferably between 1.1 and 0.66. The reaction can be carried out in a protic or aprotic solvent medium (water, alcohol, ketone, nitrile, ester, saturated or aromatic hydrocarbon optionally halogenated, dimethylsulfoxide, amide such as dimethylformamide).</li></ul>

A second process for the preparation of the compounds where the group X₂ is a halogen consists in placing step b) of grafting the imidazole or triazole nucleus after step d) using the same procedure for the different steps. Thus a compound of halogen or halogen halide (mixed halogen) is added to compound IIc to give compound IIf, the latter then being cyclized to give compound IIg, which is then provided with a triazole group. or imidazole to give compound II.

Of course, other preparation methods may also be suitable.

In case the group X₂ corresponds to QR₆, and X₁ is different from Hal, (compounds of formula III), a preparation process consists in reacting a compound of formula II with a heteroatomic nucleophile of formula R₆-QE, in which R₆ and Q have the same meaning as in formula 1 and E is a cation, for example an alkali or alkaline earth metal or a quaternary ammonium. The reaction is carried out in an appropriate solvent in the presence of a base and optionally a phase transfer catalyst and at reaction temperatures generally between -30 ° C. and the reflux of the solvent used and in a molar ratio III: R_6Q E preferably between 1.2 and 0.1.

Another method consists in reacting compound IIg under the same conditions with the same heteroatomic nucleophile to obtain a compound IIIa to which the triazole or imidazole nucleus is then fixed as described above.

It is also possible to reach the compounds in the formula of which R₆ is a lower alkyl group optionally mono- or polyhalogenated, by reacting the compounds III or IIIa in the formula of which R₆ corresponds to the hydrogen atom with an alkyl halide (optionally mono- or polyhalogenated) in a molar ratio III or IIIa: halide preferably between 1.1 and 0.2, in the presence of an organic base or mineral. If one started from compound IIIa, a triazole or imidazole nucleus is then fixed.

In case X₂ corresponds to a hydroxyl group (compounds of formula III in which Q corresponds to the oxygen atom and R₆ with the hydrogen atom) it is also possible to react in the optional presence of an inert organic solvent at a temperature between -30 ° and the reflux of the solvent for the compounds of formula IIg or II with a hydroperoxide, a hydroxide, a alkali, alkaline earth or metallic oxide or superoxide, in a molar ratio preferably of between 1.1 and 0.2, then fix, in the case where the compound IIg is the starting compound, an imidazole or triazole ring.

In case X₂ corresponds to N₃ compounds IIg or II are reacted with an alkali metal or ammonium azide in a molar ratio preferably of between 1.1 and 0.2, preferably in an aprotic solvent, at a temperature of between -30 ° and the reflux of the solvent, then reacting, if we started from compound IIg, the azidured compound with an imidazole or triazole ring. In case X₂ corresponds to an alkyloxy- or aryloxy- or aralkyloxythioyl group, compounds IIg or II are reacted with an alkali metal or ammonium xanthogenate.

In case X₂ corresponds to a hydroxyl group; it is also possible to react the compounds IIc or IId with a peroxide in order to obtain the epoxy compounds of formula IIIb for IIc, and IIIc for the compound IId. These epoxides can then be hydrated to triol respectively IIId, IIIe in a well known manner. Cyclization is carried out in the presence of a dehydrating agent such as hydrochloric, hydrobromic, sulfuric or sulphonic acids, optionally in a protic or aprotic solvent. Which leads to compound IIIa in which QR₆ corresponds to OH to which a triazole or imidazole ring is then attached, or to compound III in the case of compound IIIe. Optionally, if necessary, the alcohol function can be protected in a manner known per se for the compounds IIId and IIIe.

It is also possible to react the compounds of formula II or IIg with the carboxylate (acylic, cyclic, saturated, unsaturated or aromatic) of an alkali or alkaline earth metal (in particular sodium benzoate) in the presence of a transfer catalyst. phase optionally in the presence of an inert or polar aprotic solvent, optionally in the presence of water and at temperatures between 0 ° and the reflux of solvent considered.

In case X₁ and X₂ together correspond to an oxygen atom doubly linked to tetrahydrofuran (compounds of formula IV where X₁ corresponds to the oxygen atom), a preparation process consists in operating from a compound of formula III to or III in which QR₆ corresponds to hydroxyl and X₁ with hydrogen, with an oxidant well known for obtaining a compound IV or IVa to which an imidazole or triazole nucleus is grafted.

We prepare the halogenated gem (X₁= X₂- Hal) by action of phosphorus pentachloride on the ketone (compound of formula IV where X₁ corresponds to the oxygen atom), optionally in the presence of an inert aprotic solvent and optionally of a quaternary ammonium halide, preferably at room temperature.

To achieve thioketone function (compound of formula IV or X₁ corresponds to the sulfur atom) a thionation of the ketone function is carried out by reacting the compounds IV or IVa for example with H₂S or P₂S₅ in a molar ratio preferably between 1.1 and 0.2 in the presence of an inert organic solvent (pyridine or hydrocarbon for example) at a temperature between 20 ° and reflux.

In case X₁ and X₂correspond simultaneously to QR₆ (compound of formula V) reacting the compounds of formula (IV) or (IVa) in which X₁ (or X₂) corresponds to an oxygen or sulfur atom doubly linked to tetrahydrofuran with a compound of formula _HQR6 or _Q corresponds to 0 or S in a molar ratio preferably between 1.1 and 0.2 in the presence of an acid catalyst and in an appropriate solvent, which may be alcohol or thiol itself, or an inert solvent such as hydrocarbons or alcohols. If we started from the compound of formula IVa we obtain the compound of formula Va, we then graft on the compound of formula Va an imidazole or triazole ring.

In case X₁ and X₂ correspond to QR₇-Q and R₇ forming a single divalent radical as defined above, the compounds of formula (IV) or (IVa) are reacted with an HQ-R compound₇-QH under the same conditions as for monoalcohols or monothiols. If we started from compound IVa, we obtain compound Vb to which an imidazole or triazole is attached under the same conditions as above.

In the case where X₂ corresponds to NR₈R₉, a preparation process consists in reacting a compound of formula II or of formula IIg with an amine of formula HN R₈R₉in a molar ratio of between 1.1 and 0.2, optionally in the presence of another organic or mineral base. This leads to the compound of formula VI in the case where one started from the compound of formula II and to compound VIa to which a imidazole or triazole nucleus is subsequently fixed in the case where one started from the compound of formula IIg.

In case X₁ (or X₂) corresponds to grouping = NR₁₀ (compound of formula VII), a compound of formula IV or IVa is reacted with an amine of formula R₁₀-NH₂or a salt thereof in a molar ratio preferably between 1.1 and 0.2 in an inert organic solvent. In the case of compound IVa, compound VIIa is obtained to which an imidazole or triazole ring is then added.

It is also possible to react the compound of formula VII in which R₁₀ corresponds to hydroxyl with an alkylating agent of formula R₁₁ D where R₁₁ is a lower alkyl or an optionally substituted aralkyl and in which D corresponds to a sulfonium, ammonium, sulfonate or sulfate group in the presence of an organic or inorganic base in order to obtain the substituted oxime on oxygen.

A subject of the invention is also the compounds which may be used as intermediates in the preparation processes described above and of formula II, IIc, IId, IIe, IIf, IIg, IIh, III, IIIa, IIIb, IIIc, IIId, IIIe, IV, IVa, V, Va, Vb, VI, VIa, VII, VIIa in which R_I at R₆₃ Y, Tr, Im, m, n, X₁, X₂, Q, Hal, Z have any of the meanings given in the description above.

The present invention also relates to the use of the compounds of formula 1 as fungicides.

The compounds according to the invention can be used for the preventive as well as curative fight against fungi, in particular of the basidiomycetes, ascomycetes, adelomycetes or fungi-imperfecti type, in particular rusts, powdery mildew, foot-rot, fusarioses, helminthosporioses, septorioses, rhizoctones of plants and plants in general and in particular of cereals such as wheat, barley, rye, oats and their hybrids and also rice and corn. The compounds according to the invention are active in particular against fungi, in particular of the basidiomycetes, ascomycetes, adelomycetes or fungi-imperfecti type such as Botrytis cinerea, Erysiphe graminis, Puccinia recondita, Piricularia oryzae, Cercospora beticola, Puccinia striiformis, Erysiphe cichoracearum (Fusarium oxarium melonis), Pyrenophora avenae, Septoria tritici, Venturia inaequalis, Whetzelinia sclerotiorum, Monilia laxa, Mycosphaerella fijiensis, Marssonina panettoniana, Alternaria solani, Aspergillus niger, Cercospora arachidicola, Cladosporium herbarum, Helminthosporium oryzae, Penicillium expansum, Pestalozzia sp, Phialophora cinerescens, Phoma betae, Phoma foveata, Phoma lingam, Ustilago maydis, Verticillium dia. , Sclerotinia sclerotiorum, Sclerotinia minor, Coryneum cardinale, Rhizoctonia solani.

They are also and still active against the following fungi: Acrostalagmus koningi, Alternaria, Colletotrichum, Corticium rolfsii, Diplodia natalensis, Gaeumannomyces graminis, Gibberella fujikuroi, Hormodendron cladosporioides, Lentinus degener or tigrinus, Lenzites quercina, Memnoniella echinata, Myrothiia phinusus Pichinusus Pichinus, Porcinusus puminus, Porcinius echinata, Myrothieaus pucinus, Porcinusus puminus, Porcinius echinata, Myrothius pucinusus, Porcinusus, Porciusea, etc. Poria vaporaria, Sclerotium rolfsii, Stachybotris atra, Stereum, Stilbum sp. Trametes trabea, Trichoderma pseudokoningi, Trichothecium roseum.

The compounds of the invention are especially advantageous by their broad spectrum in terms of cereal diseases (powdery mildew, rust, black mold, helminthosporiasis, septoria and fusarium wilt). They are also of great interest because of their activity on gray mold (Botrytis) and Sigatoka, and, therefore, they can be applied to crops as varied as vines, market gardening and arboriculture and tropical crops such as peanut, banana, coffee, pecan and others.

In addition to the applications already described above, the products according to the invention also exhibit excellent biocidal activity with regard to many other varieties of microorganisms among which mention may be made, without limitation, of fungi such as those of the genera:<ul id="ul0003" list-style="none"><li>- Pullularia like the species P. pullulans',</li><li>- Chaetomium such as C. globosum,</li><li>- Aspergillus like the Aspergillus niger species,</li><li>- Coniophora like the species C. puteana.</li></ul>

Because of their biocidal activity, the products of the invention make it possible to effectively combat microorganisms whose proliferation creates many problems in the agricultural and industrial fields. To this end, they are particularly suitable for protecting plants or industrial products such as wood, leather, paints, paper, ropes, plastics, industrial water circuits.

They are particularly well suited for the protection of lignocellulosic products and in particular wood, whether it is furniture wood, framework or wood exposed to the weather such as fence wood, vine stakes, railway sleepers.

The compounds according to the invention used alone or in the form of compositions as defined above in wood treatments, are generally used with organic solvents and can be optionally combined with one or more known biocidal products such as pentachlorophenol, metal salts, in particular of copper, manganese, cobalt, chromium, zinc derived from mineral or carboxylic acids (heptanoic, octanoic, naphthenic acids); organic tin complexes, mercaptobenzothiazole, insecticides such as pyrethroids or organochlorines.

Finally, they exhibit excellent selectivity with regard to crops.

They advantageously apply at doses of 0.005 to 5 kg / ha, and more specifically from 0.01 to 0.5 kg / ha.

For their practical use, the compounds according to the invention are rarely used alone. Most often they are part of compositions. These compositions, which can be used for protecting plants against fungal diseases, or in compositions which regulate plant growth, contain as active material a compound according to the invention as described above in combination with solid or liquid carriers, acceptable in agriculture and / or surfactants also acceptable in agriculture. In particular, the usual inert supports and the usual surfactants can be used.

By the term "support", in the present description, is meant an organic or mineral, natural or synthetic material, with which the active material is associated to facilitate its application on the plant, on seeds or on the soil. This support is therefore generally inert and it must be acceptable in agriculture, in particular on the treated plant. The support can be solid (clays, natural or synthetic silicates, silica, resins, waxes, solid fertilizers, etc.) or liquid (water, alcohols, ketones, petroleum fractions, aromatic or paraffinic hydrocarbons, chlorinated hydrocarbons, liquefied gases , etc ...).

The surfactant can be an emulsifying, dispersing or wetting agent of ionic or nonionic type. Mention may be made, for example, of salts of polyacrylic acids, salts of lignosulfonic acids, salts of phenolsulfonic or naphthalene sulfonic acids, polycondensates of ethylene oxide on fatty alcohols or on fatty acids or on fatty amines , substituted phenols (in particular alkylphenols or arylphenols), ester salts of sulfosuccinic acids, taurine derivatives (in particular alkyltaurates), phosphoric esters of polyoxyethylated alcohols or phenols. The presence of at least one surfactant is generally essential when the active material and / or the inert support are not soluble in water and the vector agent for the application is water.

For their application, the compounds of formula (I) are therefore generally in the form of compositions; these compositions according to the invention are themselves in fairly diverse forms, solid or liquid.

As forms of solid compositions, mention may be made of powders for dusting or dispersion (with a content of compound of formula (1) which can range up to 100%) and granules, in particular those obtained by extrusion, by compacting, by impregnation of a granulated support, by granulation from a powder (the content of compound of formula (1) in these granules being between 1 and 80% for the latter cases).

As forms of liquid compositions or intended to constitute liquid compositions during application, mention may be made of solutions, in particular water-soluble concentrates, emulsifiable concentrates, emulsions, concentrated suspensions, aerosols, powders wettable (or powder spray), pasta.

The emulsifiable or soluble concentrates most often comprise 10 to 80% of active material, the emulsions or solutions ready for application containing, for their part, 0.01 to 20% of active material.

These compositions can also contain all kinds of other ingredients such as, for example, protective colloids, adhesives, thickeners, thixotropic agents, penetrating agents, stabilizers, sequestering agents, etc. other known active ingredients with pesticidal properties (in particular insecticides or fungicides) or with properties which promote plant growth (in particular fertilizers) or with properties which regulate plant growth. More generally, the compounds according to the invention can be combined with all the solid or liquid additives corresponding to the usual techniques of formulation.

For example, in addition to the solvent, emulsifiable concentrates can contain, when necessary, 2 to 20% of suitable additives such as stabilizers, surfactants, penetrating agents, corrosion inhibitors, dyes or the previously mentioned adhesives.

The doses of use in the case of use as fungicides of the compounds according to the invention can vary within wide limits, in particular according to the virulence of the fungi and the climatic conditions.

In general, compositions containing 0.5 to 5000 ppm of activa substance are very suitable; these values ​​are indicated for the compositions ready for application. Ppm means "part per million". The 0.5 to 5000 ppm zone corresponds to a 5x10 zone^-5 at 0.5% (weight percentages).

As regards the compositions suitable for storage and transport, they more advantageously contain from 0.5 to 95% (by weight) of active substance.

Thus, the compositions for agricultural use according to the invention can contain the active materials according to the invention within very wide limits, ranging from 5.10^-5% to 95% (by weight).

As an example, here is the composition of some concentrates:

Example F (formulation) 1

<tables id="tabl0001" num="0001"><img file="EP0246982A2_D0001.tif" /></tables>

According to another formula of emulsifiable concentrate, the following are used:

Example F 2:

<tables id="tabl0002" num="0002"><img file="EP0246982A2_D0002.tif" /></tables>

From these concentrates, emulsions with any desired concentration can be obtained by dilution with water, which are particularly suitable for application to the leaves.

The concentrated suspensions, also applicable in spraying, are prepared so as to obtain a stable fluid product which does not deposit and they usually contain from 10 to 75% of active material, from 0.5 to 15% of surfactants, from 0 , 1 to 10% of thixotropic agents, from 0 to 10% of suitable additives, such as defoamers, corrosion inhibitors, stabilizers, penetrating agents and adhesives and, as a support, water or an organic liquid in which the active ingredient is sparingly or not very soluble: certain organic solids or mineral salts can be dissolved in the support to help prevent sedimentation or as antifreeze for water.

Wettable powders (or spray powder) are usually prepared in such a way that they contain 20 to 95% of active ingredient, and they usually contain, in addition to the solid support, 0 to 5% of a wetting agent, 3 10% of a dispersing agent, and, when necessary, 0 to 10% of one or more stabilizers and / or other additives, such as penetrating agents, adhesives, or anti-caking agents, coloring agents, etc ...

As an example, here are various compositions of wettable powders:

Example F 3:

<tables id="tabl0003" num="0003"><img file="EP0246982A2_D0003.tif" /></tables>

Another 70% spray powder composition uses the following constituents:

Example F 4:

<tables id="tabl0004" num="0004"><img file="EP0246982A2_D0004.tif" /></tables>

Another 40% spray powder composition uses the following constituents:

Example F 5:

<tables id="tabl0005" num="0005"><img file="EP0246982A2_D0005.tif" /></tables>

Another 25% spray powder composition uses the following constituents:

Example F 6:

<tables id="tabl0006" num="0006"><img file="EP0246982A2_D0006.tif" /></tables><tables id="tabl0007" num="0007"><img file="EP0246982A2_D0007.tif" /></tables>

Another 25% spray powder composition uses the following constituents:

Example F 7:

<tables id="tabl0008" num="0008"><img file="EP0246982A2_D0008.tif" /></tables>

Another 10% spray powder composition uses the following constituents:

Example F 8:

<tables id="tabl0009" num="0009"><img file="EP0246982A2_D0009.tif" /></tables>

To obtain these sprayable powders or wettable powders, the active materials are intimately mixed in appropriate mixers with the additional substances and ground with mills or other suitable grinders. This gives spraying powders whose wettability and suspension are advantageous; they can be suspended with water at any desired concentration and these suspensions can be used very advantageously in particular for application to the leaves of plants.

Instead of wettable powders, pasta can be made. The conditions and methods of making and using these pastes are similar to those of wettable powders or spraying powders.

As has already been said, aqueous dispersions and emulsions, for example the compositions obtained by diluting with water a wettable powder or an emulsifiable concentrate according to the invention, are included in the general scope of the present invention. The emulsions can be of the water-in-oil or oil-in-water type and they can have a thick consistency like that of a "mayonnaise".

The granules intended to be placed on the ground are usually prepared so that they have dimensions of between 0.1 and 2 mm and they can be manufactured by agglomeration or impregnation. In general, the granules contain 0.5 to 25% of active material and 0 to 10% of additives such as stabilizers, slow release modifiers, binders and solvents.

According to an example of a granule composition, the following constituents are used:

Example F 9:

<tables id="tabl0010" num="0010"><img file="EP0246982A2_D0010.tif" /></tables>

In this particular case, the active ingredient is mixed with epichlorohydrin and dissolved with 60 g of acetone; the polyethylene glycol and the cetyl ether of polyglycol are then added. The kaolin is sprayed with the solution obtained and the acetone is then evaporated under vacuum. Advantageously, such a microgranulate is used to combat soil fungi.

The compounds of formula (I) can also be used in the form of powders for dusting; one can also use a composition comprising 50 g of active material and 950 g of talc; one can also use a composition comprising 20 g of active material, 10 g of finely divided silica and 970 g of talc; these constituents are mixed and ground and the mixture is applied by dusting.

Examples I to VII illustrate particular modes of preparation of compounds according to the invention as well as these compounds themselves. The nomenclature of the compounds has been indicated according to French standards apart from the fact that the numbering of the substituents has been put before the substituents themselves.

Example 1: Preparation of 1- [4-bromo 2- (2,4-dichlorophenyl) tetrahydro 2-furanylmethyl] 1 H 1,2,4-triazole. Compounds n ° la, lb and 1a + 1b Step a) Preparation of 1-chloro 2- (2,4-dichlorophenyl)

4-pentene 2-ol:<ul id="ul0004" list-style="none"><li>An organomagnesium derivative is prepared by adding a solution of allyl bromide (110 ml) in ethyl ether (700 ml) and tetrahydrofuran (200 ml) with magnesium (110 g) between 15 and 20 ° C. three hours. The mixture is refluxed for 30 min, decanted and the residue washed with ether.</li></ul>

To this organic phase, at -30 ° C, is added a solution of trichloro-alpha, 2,4 acetophenone (175 g) in tetrahydrofuran (250 g), neutralized with acetic acid. Washed with water, dried over sodium sulfate, concentrated then distilled under vacuum. A colorless oil is obtained (205 g). Boiling point (3 10²mmHg) = 140-142 ° C.

_Estep b) Preparation of 1- [2- (2,4-dichlorophenyl) 2-hydroxy 4-pentenyl] 1 H 1,2,4-triazole

A mixture of product obtained in step a) (106 g), triazole (55 g) and potassium carbonate (160 g) is heated for four hours at 120 ° in dimethylformamide (600 ml). The insolubles are filtered, washed with dimethylformamide and the reaction mixture is concentrated under vacuum. The residue, dissolved in methylene chloride, is washed with water and then concentrated. The product is obtained by crystallization from ethyl acetate after dilution with heptane. A pale pink solid (97 g) is isolated, melting at 101 °.

Step c) Preparation of compounds n ° la and n ° 1b

The compound obtained in step b (35 g) in chloroform (200 ml) is treated at 0 ° with bromine. After discoloration, the solvent is evaporated and the residue redissolved in methanol. An aqueous solution of potassium hydroxide is then added until a basic pH is obtained. After evaporation of the medium under vacuum, the residue is extracted with ethyl acetate, washed with water and concentrated. The oil obtained (40 g) consists of a mixture of two diastereoisomers in substantially equal proportions. By chromatography on silica, the least polar isomer n ° la is successively isolated: white crystals melting at 83 °, then the most polar isomer n ° lb: white crystals melting at 94 °. After recrystallization, the melt is obtained at 96 ° and lb the melt at 104 °. The 50/50 mixture of la and lb melts at 74 °.

In the same way, the following compounds were prepared from the appropriate raw materials: 1- [4-bromo 2- (4-chlorophenyl) tetrahydro 2-furanylmethyl] 1H 1,2,4-triazole 1C F = 74 ° Id F = 78 ° Ic + d F = 69 °.

Example II - Preparation of 1- [2- (2,4-dichlorophenyl) 4-hydroxy tetrahydro 2-furanylmethyl] 1 H 1,2,4-triazole. Compounds # 2a and # 2b.

10 g of the isomer la of Example I, which is the least polar isomer, dissolved in 30 ml of chlorobenzene, is heated at reflux for 48 h in the presence of 20 g of sodium benzoate, in 30 ml of water, and 1 g of phase transfer catalyst "ADOGEN 464" methyltrialkylammonium chloride.

After dilution with ether, the organic phase is washed with water and reduced under vacuum. The residue is then treated at reflux for 3 hours in methanol (100 ml) in the presence of potassium hydroxide (7 g). 0n cooled, diluted with water, extracted with ethyl acetate, washed to neutrality and purified by chromatography the crude product obtained after concentration under vacuum. Alcohol 2a is isolated in the form of a white powder (2.8 g) melting at 193 °.

By proceeding in the same way from the most polar isomer 1b obtained according to Example I, the optically active alcohol 2b is obtained which is in the form of a white powder melting at 162 ° C. The 50/50 mixture 2a and 2b is an oil.

Example III - Preparation of 1- [2- (2,4-dichlorophenyl) 4-ethoxy tetrahydro 2-furanylmethyl] 1H 1,2,4-triazole. Compounds # 3a and # 3b.

The alcohol 2a (2.2 g) dissolved in dimethyl sulfoxide (12 ml) is treated successively with 80% sodium hydride (0.42 g) then ethyl iodide (1.15 ml). After 15 minutes the medium is diluted with water and extracted with ethyl acetate. After washing with water, the solvent is evaporated and the residue purified by chromatography on silica to give a colorless huit which is the 3a isomer which crystallizes by trituration with pentane melting at 90 °; similarly from 2b we obtain the 3b isomer white powder melting at 63 °. The 50/50 mixture of 3a + 3b is an oil. In the same way, the compounds of formula VIII obtained in the following table were obtained using the appropriate alcohols:<tables id="tabl0011" num="0011"><img file="EP0246982A2_D0011.tif" /></tables>

Example IV - Preparation of 1- [2- (2,4-dichlorophenyl) 4-ethylthio tetrahydro 2-furanylmethyl] 1H 1,2,4-triazole. Compounds # 7a and # 7b

The bromide la (3.8 g) dissolved in dimethyl sulfoxide (38 ml) containing water (2 ml) is treated with sodium hydrogen sulfide (2.8 g) for 2 hours. Powdered potash (3.3 g) is then added followed by ethyl iodide (4 ml). After 10 minutes of stirring, the medium is diluted with water and extracted with ether. After drying and evaporation, the isomer 7a is obtained, which is a yellow oil (3.9 g), melting at 88 °.

By proceeding in the same manner from lb, 7b is obtained in the form of a pale yellow powder melting at 64 °. The mixture of isomers is an oil. In the same way, the compounds of formula VIII obtained in the following table were obtained using the appropriate thiols:<tables id="tabl0012" num="0012"><img file="EP0246982A2_D0012.tif" /></tables>

Example V - Preparation of 1- [7- (2,4-dichloro phenyl) 1,4,6-trioxo spiro [4,41 7-nonanyl methyl] 1 H 1,2,4-triazole. Compound # 13

Step a) Preparation of 1-chloro 2- (2,4-dichlorophenyl) 3,4,5-pentanetriol.

The chlorohydrin obtained in step a) of Example 1 (91 g) is epoxidized in 1,2-dichloroethane (125 ml) in the presence of vanadyl acetylacetonate (5 g) and tert-butyl peroxide at 70 % (200 ml) by reflux heating for 48 hours. The cooled medium is diluted with water, washed several times with a sodium bisulfite solution and then concentrated. The residue is then converted into triol by heating in water (200 ml) and dioxane (200 ml) in the presence of perchloric acid (5 ml) for 3 hours. After dilution with water, the medium is extracted with toluene (300 ml) and then concentrated.

Step b) Preparation of 2- (2,4-dichlorophenyl) 2-chloromethyl tetrahydro 4-furanone

The oily residue obtained in step a) is then heated in toluene (100 ml) and butanol (200 ml) in the presence of paratoluenesulfonic acid (0.5 g) with separation of the water formed. After evaporation of the reaction medium, the residue is chromatographed on silica (eluent ethyl acetate / heptane 40:60) to give a colorless oil (14.5 g) corresponding to a mixture of alcohol diastereoisomers which is 2- ( 2,4-dichlorophenyl) 4-hydroxy 2-chloromethyl tetrahydrofuran. This product is directly oxidized by chromic anhydride in acetic acid to give furanone, after purification by chromatography on silica, in the form of white crystals melting at 99 ° C.

E

step c) Preparation of 7-chloromethyl 7- (2,4-dichlorophenyl) 1,4,6-trioxa spiro [4,4] nonane.

The furanone obtained in step b) (4.2 g), in toluene (50 ml) is heated to reflux in the presence of ethylene glycol (6.5 ml) and ptoluene sulfonic acid (0.1 g ) with separation of the water formed until disappearance of the starting product.

The medium is washed with sodium hydroxide and then diluted with water, extracted with ether and concentrated. A white solid (5.1 g) is obtained, melting at 99 °.

Step d) Preparation of compound 13

The halide of step c) (5 g) in dimethylsulfoxide (20 ml) is heated to 170 ° in the presence of triazolylsodium (2.75 g) for 6 hours. The medium is poured into water, extracted with ethyl acetate, concentrated and purified by chromatography on silica. Pale yellow crystals (3.6 g) are isolated, which melt at 123 ° after recrystallization from an ethyl acetate / heptane mixture.

Example VI - Preparation of 1- [4-chloro 2- (2,4-dichlorophenyl) tetrahydro 2-furanylmethyl] 1 H 1,2,4-triazole. Compounds # 14a and # 14b

Step a) Preparation of 2- (2,4-dichlorophenyl) 1,4,5-trichloro 2-pentanol.

The chlorohydrin obtained in step a) of Example I in solution in dichloromethane (150 ml) is treated with chlorine gas (13.4 g) at -15 °. The medium is then treated with a 37% sodium bisulfite solution (15 ml) washed with water and dried and then evaporated. A crude product is obtained in the form of a colorless oil (49.7 g) containing approximately 70% of the desired product in the form of a mixture of two diastereoisomers.

Step b) Preparation of 1- (2,4-dichlorophenyl) 1- (2,3-dichloro 1-propanyl) oxirane

A first method consists in putting the crude hydrochlorine (10.3 g) obtained in step a) above in solution in methanol (30 ml) and in treating it with a methanolic potassium hydroxide solution grading 2.55 - 10^-3 moles / 1 (12 ml) at room temperature. The precipitate is filtered and the methanolic solution evaporated in vacuo. The residue is purified by chromatography on silica. A colorless oil is obtained (7.4 g).

A second method consists in putting the hydrochlorine (19.9 g) obtained in step a of Example I in solution in methanol (75 ml) and in treating it with a potassium hydroxide solution (4.9 g) in methanol (20 ml) at room temperature. After filtration of the insolubles and evaporation, the epoxide (17.1 g) is obtained in the form of a yellow oil. This epoxide is treated with chlorine until the yellow color (10.1 g) persists at -15 ° C. The medium is then washed with a solution of sodium bisulfite, water and then evaporated in vacuo.

A yellow oil (20.8 g) consisting of a mixture of two diastereoisomers in a 45/55 ratio is obtained.

Step c) Preparation of 1- [4-chloro 2- (2,4-dichlorophenyl) tetrahydro 2-furanylmethyl] 1 H 1,2,4-triazole

The epoxide obtained in step b) (61.7 g) in butanol-1 (0.5 1) is heated at 90 ° for 6 hours in the presence of triazolylsodium (18.6 g). The mineral precipitate is filtered and the butanol evaporated. The residue is purified by chromatography on silica (eluent 48% ethyl acetate 48% heptane 4% methanol) to successively give the first diastereomer 14a melting at 113 ° then the 2nd diastereomer 14b melting at 97 °. The 50/50 mixture 14a + 14b melts at 90 °.

Example VII

Preparation of 1- [4-oxo 2- (2,4-dichlorophenyl) tetrahydro 2-furanylmethyl] 1H 1,2,4 triazole compound 15

Alcohol 2a (37.7 g) is added at -60 ° to a solution of dimethyl sulfoxide (17 ml), in dichloromethane (120 ml), treated at -60 ° with a solution of trifluoroacetic anhydride (25.4 ml) in dichloromethane (60 ml). After half an hour at -60 °, it is allowed to return to room temperature and then triethylamine (48 ml) is added. The medium is poured into water, extracted with dichloromethane and evaporated. A white powder melting at 91 ° is isolated by crystallization from ether.

Example VIII

Preparation of 1- [4,4-dichloro 2- (2,4 dichlorophenyl) tetrahydro 2-furanylmethyl] 1H 1,2,4-triazole, compound No. 20

A mixture of ketone 15 (3.1 g), phosphorus pentachloride (2.3 g), dichloromethane (30 ml) containing triethylbenzylammonium chloride (0.25 g) is stirred for 2 hours at room temperature until disappearance of the starting material. The medium is evaporated, diluted with water (100 ml), neutralized with sodium bicarbonate and extracted with ether. After drying and evaporation, the oily residue is recrystallized from isopropyl ether (2 times). A white powder (0.6 g) is obtained, melting at 138 °.

Example IX - Preparation of 1- [4-dimethylamino

2- (2,4-dichlorophenyl) tetrahydro 2-furanylmethyl] 1 H 1,2,4-triazole compound 16

To a solution of potassium hydroxide (0.24 g) and of dimethylamine hydrochloride (1.05 g) in methanol is added successively the ketone of Example III, then sodium cyanoborohydride (0.24 g). After 15 hours, the medium is diluted with water, extracted with ether. The desired product is then extracted from the organic phase with 6N hydrochloric acid (3 x 20 ml). After neutralization, extraction and chromatography on silica, 5 (1.6 g) are isolated in the form of a pale yellow oil (50/50 mixture of 2 isomers).

Example X - Preparation of 1- [4-methoximino

2- (2,4-dichlorophenyl) tetrahydro 2-furanylmethyl] 1H 1,2,4-triazole compound 17.

The ketone of Example III (2g) in ethanol (30 ml) is heated to reflux in the presence of methoxylamine hydrochloride (5.8 ml of a 25% solution in water) for 2 hours. The medium is diluted with water, extracted with dichloromethane and evaporated. The product is isolated by crystallization from a mixture of diisopropyl ether and heptane in the form of a white powder melting at 108 ° (mixture of two geometric isomers).

In the same way, the compounds where R have been prepared₁₁ = H (4-hydroxymino) F - 195 ° 18 R₁₁ =<img file="EP0246982A2_D0013.tif" /> (4-isopropoxyimino) oil 19.

Examples XI and following illustrate the fungicidal applications of the compounds according to the invention. in these examples, the spraying of solutions or suspensions of active materials is carried out under conditions such that the spraying of a solution or suspension of concentration equal to 1 g / 1 corresponds on average to the application of approximately 2 micrograms of material active per cm² of plant leaf.

Under the conditions of Examples X and following, the illustrated compounds did not exhibit phytotoxicity.

In these examples, it is considered that a product exerts total protection against a fungal disease when the protection is at least 95%; protection is considered good when it is at least 80% (but less than 95%), as fairly good when it is at least 70% (but less than 80%), as average when is at least 50% (but less than 70%).

In the present description, the percentages are, unless otherwise indicated and except those relating to yields, percentages by weight. In the case where the percentages are expressed relative to the stoichiometry, these are molar percentages. Regarding the concentrations, some of them are expressed in ppm (parts per million) which corresponds to mg / 1.

EXAMPLE XI In Vivo Test on Botrytis Cinerea on Tomato

An aqueous emulsion of the active ingredient to be tested having the following composition is prepared by fine grinding:<ul id="ul0005" list-style="none"><li>- active ingredient to be tested: 60 mg</li><li>- Tween 80 (surfactant) consisting of an oleate of polyéxyethylene derivative of sorbitan) diluted to 10% in water: 0.3 ml</li><li>- make up to 60 ml of water.</li></ul>

This aqueous emulsion is then diluted with water to obtain the desired concentration.

Tomatoes grown in a greenhouse (Marmande variety) aged 30 to 40 days are treated by spraying with aqueous emulsions (called boiled) as defined above and at various concentrations of the test compound. The test is repeated twice with each concentration.

After 24 or 48 hours, the leaves are cut and placed in 2 Petri dishes (diameter 14 cm), the bottom of which has previously been lined with a disc of wet filter paper (5 leaflets per dish).

The inoculum is then brought using a syringe by depositing drops (3 drops per leaflet) of a suspension of spores. This suspension of Botrytis cinerea spores was obtained from a 15-day culture, then suspended in a nutritive solution (100,000 units / cm³).

The control is done at 3 and 6 days after the contamination by comparison with an untreated control.

Under these conditions, at the dose of 1 g / 1, good or total protection is observed with the compounds la, lb, la + lb, 3b, 5b, 6b, 8b, 9b, 12b, 14a, 14b, 14a + 14b , 17.

EXAMPLE XII In Vivo Test on Erysiphe Graminis on Barley (Barley Powdery mildew)

Barley, in pots, sown in loam, is treated at the 10 cm high stage by spraying with an aqueous emulsion (called slurry) at the concentration indicated below. The test is repeated twice. After 24 hours, the barley plants are dusted with Erysiphe graminis spores, the dusting being carried out using diseased plants.

The reading is done 8 to 14 days after contamination.

Under these conditions, the following results are observed: at the dose of 1 g / 1, good or total protection with the compounds la, lb, la + lb, 2a, 2b, 3a, 3b, 3a + 3b, 4a, 4b, 5a, 5b, 6a, 6b, 7a + 7b, 8a, 8b, 13, 14a, 14b, 14a + 14b, 15, 17, 19, 20.

Example XIII In Vivo Test on "Puccina Recondita" responsible for Wheat Rust

Wheat, in pots, sown in loam, is treated at the 10 cm high stage by spraying with aqueous emulsions (called boiled) of the same composition as that described in Example VIII and at various concentrations of the test compound . The test is repeated twice with each concentration.

After 24 hours, an aqueous suspension of spores (50,000 sp / cm) is sprayed onto the wheat; this suspension was obtained from contaminated plants. The wheat is then placed for 48 hours in an incubation cell at approximately 18 ° C. and at 100% relative humidity.

After these 2 days, the relative humidity is reduced to 60%. The condition of the plants is checked between the 11th and 15th day after contamination by comparison with the untreated control.

At a dose of 1 g / 1, good or total protection with the compounds la, lb, la + lb, 3a, 3b, 3a + 3b, 5b, 6b, 7a, 7a + 7b, 8b, 12b, 13, 14a, 14b, 14a + 14b, 17, 19, 20.

Example XIV - In Vivo Test on "Piricularia Oryzae"

responsible for Rice Blast

Rice, in pots, sown in a 50/50 mixture of enriched peat and pozzolan, is treated at the 10 cm high stage by spraying with an aqueous emulsion (called slurry) defined above with the concentration indicated below. The test is repeated twice. After 48 hours, treatment is carried out by application to the leaves, with a suspension of spores obtained in pure culture.

Reading is done 8 days after contamination. Under these conditions, the following results are observed: at a dose of 1 g / 1, good or total protection with the compounds la, 1b, la + lb, 3a, 3b, 6a, 8a, 8b, 9a, 9b, 10b, lla, llb, 12a, 12b, 14a, 14b, 14a + 14b, 15, 20.

Example XV - In Vitro Test on Seed Mushrooms and

soil mushrooms

The action of the compounds according to the invention on the following fungi responsible for cereal and other plant diseases is studied:<ul id="ul0006" list-style="none"><li>1) Pyrenophorae avenae</li><li>2) Septoria nodorum</li><li>3) Helminthosporium teres</li><li>4) Fusarium roseum</li><li>5) Fusarium nivale</li><li>6) Fusarium culmorum</li><li>7) Rhizoctonia cerealis</li><li>8) Septoria tritici</li><li>9) Botrytis cinerea sensitive to carbendazim and cyclic imides</li><li>10) Botrytis cinerea resistant to carbendazim and cyclic imides</li><li>11) Pseudocercosporella herpotrichoïdes</li><li>12) Fusarium oxysporum F.sp melonis</li><li>13) Rhizoctonia solani</li><li>14) Helminthosporium gramineum</li></ul>

The figures before the names will be used to represent these mushrooms in Table (II).

For each test, the procedure is as follows: a nutritive medium consisting of potato, glucose and gelose (PDA medium) is introduced by supercooling into a series of Petri dishes (20 ml per dish) after sterilization with autoclave at 120 ° C.

During the filling of the boxes, an acetone solution of the active material is injected into the supercooling medium to obtain the desired final concentration.

We take as a petri dish similar to the previous ones, into which are poured similar amounts of a nutritive medium containing no active material.

After 24 or 48 h each dish is seeded by depositing a fragment of mycelium from a previous culture of the same fungus.

The boxes are kept for 2 to 10 days (depending on the fungus tested) at 22 ° C and the growth of the fungus in the boxes containing the active ingredient to be tested is then compared to that of the same fungus in the box used as a control.

The inhibition rate of the fungus considered for a dose of 30 ppm is thus determined for each compound tested. The results are shown in the table below.<tables id="tabl0013" num="0013"><img file="EP0246982A2_D0014.tif" /></tables><tables id="tabl0014" num="0014"><img file="EP0246982A2_D0015.tif" /></tables><tables id="tabl0015" num="0015"><img file="EP0246982A2_D0016.tif" /></tables><tables id="tabl0016" num="0016"><img file="EP0246982A2_D0017.tif" /></tables><chemistry id="chem0001" num="0001"><img file="EP0246982A2_D0018.tif" /></chemistry><chemistry id="chem0002" num="0002"><img file="EP0246982A2_D0019.tif" /></chemistry><chemistry id="chem0003" num="0003"><img file="EP0246982A2_D0020.tif" /></chemistry><chemistry id="chem0004" num="0004"><img file="EP0246982A2_D0021.tif" /></chemistry><chemistry id="chem0005" num="0005"><img file="EP0246982A2_D0022.tif" /></chemistry><chemistry id="chem0006" num="0006"><img file="EP0246982A2_D0023.tif" /></chemistry><chemistry id="chem0007" num="0007"><img file="EP0246982A2_D0024.tif" /></chemistry><chemistry id="chem0008" num="0008"><img file="EP0246982A2_D0025.tif" /></chemistry><chemistry id="chem0009" num="0009"><img file="EP0246982A2_D0026.tif" /></chemistry>