Patent Application
20110218188
The present invention relates to substituted (pyridyl)-azinylamino derivatives, their process of preparation, preparation intermediate compounds, their use as fungicide active agents, particularly in the form of fungicide compositions, and methods for the control of phytopathogenic fungi, notably of plants, using these compounds or compositions.
WO 2007/003525 discloses N-Phenyl-triazinylamine derivatives useful as inhibitors of enzymes treating disease or disease symptoms. However, this reference does not relate to fungicidal applications of such derivatives. Additionally, WO 2005/019211 and WO 2005/033095 disclose a method of protecting plants against attack by phytopathogenic organisms using aminopyridinyl substituted N-Phenyl-triazinylamine derivatives. However, the said chemical structure of these compounds of the prior art is different from the compounds of the present invention.
It is always of high-interest in agriculture to use novel pesticide compounds in order to avoid or to control the development of resistant strains to the active ingredients. It is also of high-interest to use novel compounds being more active than those already known, with the aim of decreasing the amounts of active compound to be used, whilst at the same time maintaining effectiveness at least equivalent to the already known compounds. We have now found a new family of compounds which possess the above mentioned effects or advantages.
Accordingly, the present invention provides N-substituted (pyridyl)-azinyl-amino derivatives of formula (I)
wherein
In another particular embodiment of the invention, compounds of formula (I) according to the invention are those wherein W represents a saturated or unsaturated, aromatic or non-aromatic 4-, 5-, 6- or 7-membered heterocycle comprising up to four heteroatoms which may be the same or different.
A compound of formula (I) according to the invention is then represented by a compound of the Formula (III):
wherein
In another particular embodiment of the invention, compounds of formula (III) according to the invention are those wherein A represents a nitrogen atom.
A compound of formula (I) according to the invention is then represented by a compound of the Formula (III1):
wherein
In another particular embodiment of the invention, compounds of formula (III) according to the invention are those wherein A represents a carbon atom.
A compound of formula (I) according to the invention is then represented by a compound of the Formula (III2)
wherein
Any of the compounds according to the present invention may exist in one or more optical or chiral isomeric form depending on the number of asymmetric centres in the compound. The invention thus relates equally to all optical isomers and to any racemic or scalemic mixtures thereof (the term “scalemic” denotes a mixture of enantiomers in different proportions), and to the mixtures of any potential stereoisomers, in any proportion. Diastereoisomers or optical isomers can be separated according to any methods known per se by the man ordinary skilled in the art.
Any of the compounds according to the present invention may also exist in one or more geometric isomeric form depending on the number of double bond within the compound. The invention thus equally relates to any geometric isomer and to any possible mixtures thereof, in any proportion. Geometric isomers can be separated according to any method known per se by the man ordinary skilled in the art.
Any compound of formulas (I, II, III, III1, III2) according to the invention wherein L2Q2 represents a hydroxy group, a sulfanyl group or an amino group can exist in a tautomeric form resulting from the shift of the proton of said hydroxy group, sulfanyl group or amino group respectively. Such tautomeric forms are also part of the present invention. Generally, any tautomeric form of a compound of formulas (I, II, III, III1, III2) according to the invention wherein L2Q2 represents a hydroxy group, a sulfanyl group or an amino group, as well as the tautomeric forms of the compounds which can optionally be used as intermediates in the preparation processes according to the invention are also part of the present invention.
According to the invention, the following generic terms are generally used with the following meanings:
Preferred compounds of formula (I) according to the invention are those wherein W represents phenyl.
Other preferred compounds of formula (I) according to the invention are those wherein W represents a saturated or unsaturated, aromatic or non-aromatic heterocycle selected in the list consisting of:
Other preferred compounds of formula (I) according to the invention are those wherein Q1 represents a halogen atom, a nitro group, a hydroxy group, a cyano group, an amino group, a sulfanyl group, a pentafluoro-λ6-sulfanyl group, a formyl group, a formyloxy group, a formylamino group, a (hydroxyimino)-C1-C6-alkyl group, a C1-C8-alkyl, a tri(C1-C8-alkyl)silyl-C1-C8-alkyl, C1-C8-cycloalkyl, a C1-C8-halogenoalkyl having 1 to 5 halogen atoms, a C2-C8-alkenyl, a C2-C8-alkynyl, a C1-C8-alkylamino, a di-C1-C8-alkylamino, a C1-C8-alkoxy, a C1-C8-halogenoalkoxy having 1 to 5 halogen atoms, a C1-C8-alkylsulfanyl, a C1-C8-halogenoalkylsulfanyl having 1 to 5 halogen atoms, a C1-C8-alkylcarbonyl, a C1-C8-halogenoalkylcarbonyl having 1 to 5 halogen atoms, a C1-C8-alkoxycarbonyl, a C1-C8-halogenoalkoxycarbonyl having 1 to 5 halogen atoms, a C1-C8-alkylcarbonylamino, a C1-C8-halogenoalkylcarbonylamino having 1 to 5 halogen atoms, a C1-C8-alkylaminocarbonyloxy, a C1-C8-alkylsulphenyl, a C1-C8-halogenoalkylsulphenyl having 1 to 5 halogen atoms, a C1-C8-alkylsulphinyl, a C1-C8-halogenoalkylsulphinyl having 1 to 5 halogen atoms, a (C1-C6-alkoxyimino)-C1-C6-alkyl, C1-C8-alkoxyalkyl, C1-C8-halogenoalkoxyalkyl having 1 to 5 halogen atoms; it being possible for each of these groups or substituents to be substituted when chemically possible.
Other preferred compounds of formula (I) according to the invention are those wherein p represents 0, 1, 2, or 3. More preferably, p represents 0 or 1. Even more preferably p represents 1.
Other preferred compounds of formula (I) according to the invention are those wherein Ra represents a hydrogen atom or a substituted or non substituted C1-C8-cycloalkyl.
Other preferred compounds of formula (I) according to the invention are those wherein Rb and Rc independently represent a hydrogen atom, a halogen atom, a cyano, a C1-C8-halogenoalkyl having 1 to 5 halogen atoms, a C1-C8-halogenocycloalkyl having 1 to 5 halogen atoms. More preferably, Rb and Rc independently represent a hydrogen atom or a halogen atom.
Other preferred compounds of formula (I) according to the invention are those wherein L1 is selected in the list consisting of:
wherein
More preferred compounds of formula (I) according to the invention are those wherein L1 represents
wherein
Even more preferred compounds of formula (I) according to the invention are those wherein L1 represents
Other preferred compounds of formula (I) according to the invention are those wherein Q2 represents a hydrogen atom, a halogen atom, a hydroxy group, a cyano group, an amino group, a sulfanyl group, a formyl group, a formyloxy group, a formylamino group, a carbamoyl group, a N-hydroxycarbamoyl group, a carbamate group, (hydroxyimino)-C1-C6-alkyl group, C1-C8-alkyl, C1-C8-cycloalkyl, C1-C8-halogenoalkyl having 1 to 5 halogen atoms, a C2-C8-alkenyl, C2-C8-alkynyl, C1-C8-alkylamino, di-C1-C8-alkylamino, C1-C8-alkoxy, C1-C8-halogenoalkoxy having 1 to 5 halogen atoms, C1-C8-alkylsulfanyl, C1-C8-alkylcarbonyl, C1-C8-halogenoalkylcarbonyl having 1 to 5 halogen atoms, C1-C8-halogenoalkoxycarbonyl having 1 to 5 halogen atoms, C1-C8-alkylcarbonylamino, C1-C8-halogenoalkylcarbonylamino having 1 to 5 halogen atoms, (C1-C6-alkoxyimino)-C1-C6-alkyl, (C1-C6-alkenyloxyimino)-C1-C6-alkyl, (C1-C6-alkynyloxyimino)-C1-C6-alkyl, (2-oxopyrrolidin-1-yl) C1-C8-alkyl, (2-oxopyrrolidin-1-yl) C1-C8-halogenoalkyl having to 5 halogen atoms, (2-oxopiperidin-1-yl) C1-C8-alkyl, (2-oxopiperidin-1-yl) C1-C8-halogenoalkyl having 1 to 5 halogen atoms, (2-oxoazepan-1-yl) C1-C8-alkyl, (2-oxoazepan-1-yl) C1-C8-halogenoalkyl having 1 to 5 halogen atoms, (benzyloxyimino)-C1-C6-alkyl, C1-C8-alkoxyalkyl, C1-C8-halogenoalkoxyalkyl having 1 to 5 halogen atoms, benzyloxy, benzylsulfanyl, benzylamino, phenoxy, phenylsulfanyl, phenylamino, a 4-, 5-, 6- or 7-membered heterocycle comprising up to 4 heteroatoms selected in the list consisting of N, O, S, or a (4-, 5-, 6- or 7-membered heterocyclyl) C1-C6-alkyl comprising up to 4 heteroatoms selected in the list of consisting of N, O, S; it being possible for each of these groups or substituents to be substituted when chemically possible;
When L2 and Q2 form together a, 4-, 5-, 6- or 7-membered heterocycle comprising up to 4 heteroatoms selected in the list consisting of N, O, S, preferred resulting heterocycles are non-aromatic. More preferred heterocycles are pyrrolidine, piperidine, morpholine.
Other preferred compounds of formula (I) according to the invention are those wherein Rd to Ri independently represent a hydrogen atom, a halogen atom, a nitro group, a cyano group, a hydroxy group, an amino group, a sulfanyl group, a formyl group, a formyloxy group, a formylamino group, (hydroxyimino)-C1-C6-alkyl group, C1-C8-alkyl, tri(C1-C8-alkyl)silyl, tri(C1-C8-alkyl)silyl-C1-C8-alkyl, C1-C8-cycloalkyl, C1-C8-halogenoalkyl having 1 to 5 halogen atoms, C1-C8-halogenocycloalkyl having 1 to 5 halogen atoms a C2-C8-alkenyl, C2-C8-alkynyl, C1-C8-alkylamino, di-C1-C8-alkylamino, C1-C8-alkoxy, C1-C8-halogenoalkoxy having 1 to 5 halogen atoms, C2-C8-alkenyloxy, C2-C8-alkynyloxy, C1-C8-alkylsulfanyl, C1-C8-halogenoalkylsulfanyl having 1 to 5 halogen atoms, C1-C8-alkylcarbonyl, C1-C8-halogenoalkylcarbonyl having 1 to 5 halogen atoms, C1-C8-alkoxycarbonyl, C1-C8-halogenoalkoxycarbonyl having 1 to 5 halogen atoms, C1-C8-alkylcarbonyloxy, C1-C8-halogenoalkylcarbonyloxy having 1 to 5 halogen atoms, C1-C8-alkylcarbonylamino, C1-C8-halogenoalkylcarbonylamino having 1 to 5 halogen atoms, C1-C8-alkylaminocarbonyloxy, di-C1-C8-alkylaminocarbonyloxy, C1-C8-alkyloxycarbonyloxy, C1-C8-alkylsulphenyl, C1-C8-halogenoalkylsulphenyl having 1 to 5 halogen atoms, (C1-C6-alkoxyimino)-C1-C6-alkyl, (C1-C6-alkenyloxyimino)-C1-C6-alkyl, (C1-C6-alkynyloxyimino)-C1-C6-alkyl, (2-oxopyrrolidin-1-yl) C1-C8-alkyl, (2-oxopyrrolidin-1-yl) C1-C8-halogenoalkyl having 1 to 5 halogen atoms, (2-oxopiperidin-1-yl) C1-C8-alkyl, (2-oxopiperidin-1-yl) C1-C8-halogenoalkyl having 1 to 5 halogen atoms, (2-oxoazepan-1-yl) C1-C8-alkyl, (2-oxoazepan-1-yl) C1-C8-halogenoalkyl having 1 to 5 halogen atoms, (benzyloxyimino)-C1-C6-alkyl, phenylamino, phenyl hetarylamino or a 4-, 5-, 6- or 7-membered heterocycle comprising up to 4 heteroatoms selected in the list consisting of N, O, S; it being possible for each of these groups or substituents to be substituted when chemically possible.
Other more preferred compounds of formula (I) according to the invention are those wherein Rd represents H, (methoxycarbonyl)amino, (4-chlorophenyl)amino, [3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino, (2-ethoxy-2-oxoethyl)amino, (2,2,2-trifluoroethyl)amino, (2-cyanoethyl)amino, methylamino, (2-methylpropanoyl)oxy, (3-methylbut-2-enoyl)oxy, (3-methylbutanoyl)oxy, butanoyloxy, propanoyloxy, (methoxyacetyl)oxy, acetyloxy, cyclopentyloxy, dicyclopropylmethoxy, 1-cyclopropylethoxy, but-3-yn-2-yloxy, hex-2-yn-1-yloxy, but-2-yn-1-yloxy, prop-2-yn-1-yloxy, 2,2,2-trifluoroethoxy, (2,6-dichlorobenzyl)oxy, (4-chlorobenzyl)oxy, (4-methoxybenzyl)oxy, benzyloxy, cyclopropylmethoxy, 2-methylpropoxy, prop-2-en-1-yloxy, propoxy, 2-(dimethylamino)ethoxy, ethoxy, methoxy, hydroxyl, phenylamino, or phenyl hetarylamino.
Other more preferred compounds of formula (I) according to the invention are those wherein Rg represents Hydrogen, prop-2-en-1-yl, hexyl, butyl, propyl, 2-hydroxyethyl, ethyl, methyl.
Other more preferred compounds of formula (I) according to the invention are those wherein Q2 represents (2R)-2-(methoxymethyl)pyrrolidin-1-yl, (2S)-1-methoxypropan-2-yl, 1-(diethylamino)propan-2-yl, 1-(dimethylamino)propan-2-yl, 1,1-dioxidotetrahydrothiophen-3-yl, 1,3-dimethoxypropan-2-yl, 1-cyanobutan-2-yl, 1-cyclopropyl-2-methoxyethyl, 1-ethylpiperidin-3-yl, 1-methoxybutan-2-yl, 1-methoxypropan-2-yl, 2-(hydroxymethyl)piperidin-1-yl, 2-(morpholin-4-yl)ethyl, 2,2,2-trifluoroethyl, 2,3-dimethylpiperidin-1-yl, 2,5-dimethylpyrrolidin-1-yl, 2,6-dimethylmorpholin-4-yl, 2-cyanoethyl, 2-ethylpiperidin-1-yl, 2-hydroxy-2-methylpropyl, 2-hydroxyethyl, 2-methoxyethyl, 2-methylpiperidin-1-yl, 2-methylprop-2-en-1-yl, 2-methylpropyl, 2-methylpyrrolidin-1-yl, 3-(2-oxoazepan-1-yl)propyl, 3-(2-oxopyrrolidin-1-yl)propyl, 3-(formylamino)propyl, 3-(hydroxymethyl)piperidin-1-yl, 3,3,3-trifluoropropyl, 3,3-dimethylpiperidin-1-yl, 3,5-dimethylpiperidin-1-yl, 3,6-dihydropyridin-1(2H)-yl, 3-hydroxypiperidin-1-yl, 3-hydroxypropyl, 3-hydroxypyrrolidin-1-yl, 3-methoxybutan-2-yl, 3-methoxypiperidin-1-yl, 3-methoxypropyl, 3-methylbut-2-en-1-yl, 3-methylbutan-2-yl, 3-methylbutyl, 3-methylpiperidin-1-yl, 4-(2-oxopyrrolidin-1-yl)butyl, 4-(trifluoromethyl)piperidin-1-yl, 4-cyanopiperidin-1-yl, 4-ethoxycyclohexyl, 4-formylpiperazin-1-yl, 4-hydroxypiperidin-1-yl, 4-methoxypiperidin-1-yl, 4-methylpiperazin-1-yl, 4-methylpiperidin-1-yl, 4-oxoimidazolidin-1-yl, azepan-1-yl, butan-2-yl, butyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopropyl, cyclopropylmethyl, ethyl, hydrogen, hexyl, hydroxy, methoxy, methyl, morpholin-4-yl, oxetan-3-yl, pentan-2-yl, pentan-3-yl, pentyl, piperidin-1-yl, prop-2-en-1-yl, propan-2-yl, propyl, pyrrolidin-1-yl, tert-butyl, tetrahydrofuran-2-ylmethyl, thiomorpholin-4-yl.
The above mentioned preferences with regard to the substituents of the compounds of formula (I) according to the invention can be combined in various manners, either individually, partially or entirely. These combinations of preferred features thus provide sub-classes of compounds according to the invention. Examples of such sub-classes of preferred compounds according to the invention can combine:
In these combinations of preferred features of the substituents of the compounds according to the invention, the said preferred features can also be selected among the more preferred features of each of W, Q1 and p, Ra to Ri, L1, Y, L2 and Q2 so as to form most preferred subclasses of compounds according to the invention.
The preferred features of the other substituents of the compounds according to the invention can also be part of such sub-classes of preferred compounds according to the invention, notably the groups of substituents W, Q1 and p, Ra to Ri, L1, Y, L2 and Q2.
The present invention also relates to a process for the preparation of compounds of formula (I). Thus according to a further aspect of the present invention, there is provided a process P1 for the preparation of a compound of formula (I) as herein-defined, as illustrated by the following reaction scheme:
wherein
Advantageously, process P1 according to the invention can be simplified, allowing the direct preparation of certain compounds of formula (I) starting from a compound of formula (VI). Accordingly, the present invention provides an improved process P1A for the preparation of a compound of formula (I), as illustrated by the following reaction scheme:
wherein
The process according to the invention also allows the preparation of compounds of formula (I) according to the invention using other compounds of formula (I) according to the invention as starting material.
Thus according to a further aspect of the present invention, there is provided a process P2 for the preparation of a compound of formula (I) wherein Y represents a NRd group, L2 represents CRhRi; A, W, Q1, p, Ra, Rb, Rc, Rd, Rh, Ri, L1, Q2 being as herein defined;
that comprises reacting a different compound of formula (I) wherein Y represents an oxygen atom and L2 represents CRhRi; A, W, Q1, p, Ra, Rb, Rc, Rh, Ri, L1, Q2 being as herein-defined; with a compound of formula RdNH or one of its salts, wherein Rd is as herein-defined, optionally in the presence of a dehydrating agent such as molecular sieves, anhydrous metal salts, such as magnesium sulphate, sodium sulphate, or metal oxides such as barium oxide, calcium oxide, optionally in the presence of a base such as an inorganic or an organic base; notably an alkaline earth metal or an alkali metal hydride, hydroxide, amide, alcoholate, acetate, carbonate or hydrogen carbonate, such as sodium hydride, sodium amide, lithiium diisopropylamide, sodium methanolate, sodium ethanolate, potassium tert-butanolate, sodium acetate, potassium acetate, calcium acetate, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, potassium bicarbonate, sodium bicarbonate, cesium carbonate or ammonium carbonate; and also tertiary amines, such as trimethylamine, triethylamine (TEA), tributylamine, N,N-dimethylaniline, N,N-dimethyl-benzylamine, N,N-diisopropyl-ethylamine (DIPEA), pyridine, N-methylpiperidine, N-methylmorpholine, N,N-dimethylaminopyridine, diazabicyclooctane (DABCO), diazabicyclononene (DBN) or diazabicycloundecene (DBU), optionally in the presence of an acid such as a Lewis acid; notably metal or metalloïd halides such as aluminium trichloride, zinc dichloride, magnesium bromide, boron tribromide; or such as a Brönstedt acid; notably a mineral acid such as sulphuric acid, chlorhydric acid, ammonium chloride, phosphoric acid, or an organic acid, such as acetic acid, para-toluenesulphonic acid.
According to a further aspect of the present invention, there is provided a process P3 for the preparation of a compound of formula (I) wherein Y represents a CReRf group, L2 represents an oxygen atom and Q2 represents a formyl group, a (hydroxyimino)-C1-C6-alkyl group, C1-C8-alkyl, tri(C1-C8-alkyl)silyl-C1-C8-alkyl, C1-C8-cycloalkyl, tri(C1-C8-alkyl)silyl-C1-C8-cycloalkyl, C1-C8-halogenoalkyl having 1 to 5 halogen atoms, C1-C8-halogenocycloalkyl having 1 to 5 halogen atoms a C2-C8-alkenyl, C2-C8-alkynyl, C1-C8-alkylcarbonyl, C1-C8-halogenoalkylcarbonyl having 1 to 5 halogen atoms, C1-C8-alkylcarbamoyl, di-C1-C8-alkylcarbamoyl, N—C1-C8-alkyloxycarbamoyl, C1-C8-alkoxycarbamoyl, N—C1-C8-alkyl-C1-C8-alkoxycarbamoyl, C1-C8-alkoxycarbonyl, C1-C8-halogenoalkoxycarbonyl having 1 to 5 halogen atoms, C1-C8-alkylsulphinyl, C1-C8-halogenoalkylsulphinyl having 1 to 5 halogen atoms, C1-C8-alkylsulphonyl, C1-C8-halogenoalkylsulphonyl having 1 to 5 halogen atoms, (C1-C6-alkoxyimino)-C1-C6-alkyl, (C1-C6-alkenyloxyimino)-C1-C6-alkyl, (C1-C6-alkynyloxyimino)-C1-C6-alkyl, (2-oxopyrrolidin-1-yl) C1-C8-alkyl, (2-oxopyrrolidin-1-yl) C1-C8-halogenoalkyl having 1 to 5 halogen atoms, (2-oxopiperidin-1-yl) C1-C8-alkyl, (2-oxopiperidin-1-yl) C1-C8-halogenoalkyl having 1 to 5 halogen atoms, (2-oxoazepan-1-yl) C1-C8-alkyl, (2-oxoazepan-1-yl) C1-C8-halogenoalkyl having 1 to 5 halogen atoms, (benzyloxyimino)-C1-C6-alkyl, C1-C8-alkoxyalkyl, a or a 4-, 5-, 6- or 7-membered heterocycle comprising up to 4 heteroatoms selected in the list consisting of N, O, S; A, W, Q1, p, Ra, Rb, Rc, Rh, Ri, L1, being as herein defined;
that comprises reacting a different compound of formula (I) wherein Y represents an oxygen atom, L2 represents CRhR1 and Q2 represents a hydrogen atom; A, W, Q1, p, Ra, Rb, Rc, Rh, Ri, L1, being as herein-defined;
with a compound of formula Q2T wherein T represents a leaving group such as a halogen atom, a C1-C6 alkylsulfonate, a C1-C6 haloalkylsulfonate and Q2 represents a formyl group, a (hydroxyimino)-C1-C6-alkyl group, C1-C8-alkyl, tri(C1-C8-alkyl)silyl-C1-C8-alkyl, C1-C8-cycloalkyl, tri(C1-C8-alkyl)silyl-C1-C8-cycloalkyl, C1-C8-halogenoalkyl having 1 to 5 halogen atoms, C1-C8-halogenocycloalkyl having 1 to 5 halogen atoms a C2-C8-alkenyl, C2-C8-alkynyl, C1-C8-alkylcarbonyl, C1-C8-halogenoalkylcarbonyl having 1 to 5 halogen atoms, C1-C8-alkylcarbamoyl, di-C1-C8-alkylcarbamoyl, N—C1-C8-alkyloxycarbamoyl, C1-C8-alkoxycarbamoyl, N—C1-C8-alkyl-C1-C8-alkoxycarbamoyl, C1-C8-alkoxycarbonyl, C1-C8-halogenoalkoxycarbonyl having 1 to 5 halogen atoms, C1-C8-alkylsulphinyl, C1-C8-halogenoalkylsulphinyl having 1 to 5 halogen atoms, C1-C8-alkylsulphonyl, C1-C8-halogenoalkylsulphonyl having 1 to 5 halogen atoms, (C1-C8-alkoxyimino)-C1-C8-alkyl, (C1-C8-alkenyloxyimino)-C1-C8-alkyl, (C1-C8-alkynyloxyimino)-C1-C8-alkyl, (2-oxopyrrolidin-1-yl) C1-C8-alkyl, (2-oxopyrrolidin-1-yl) C1-C8-halogenoalkyl having 1 to 5 halogen atoms, (2-oxopiperidin-1-yl) C1-C8-alkyl, (2-oxopiperidin-1-yl) C1-C8-halogenoalkyl having 1 to 5 halogen atoms, (2-oxoazepan-1-yl) C1-C8-alkyl, (2-oxoazepan-1-yl) C1-C8-halogenoalkyl having 1 to 5 halogen atoms, (benzyloxyimino)-C1-C6-alkyl, C1-C8-alkoxyalkyl, a or a 4-, 5-, 6- or 7-membered heterocycle comprising up to 4 heteroatoms selected in the list consisting of N, O, S; optionally in the presence of a base such as an inorganic or an organic base; preferably an alkaline earth metal or alkali metal hydride, hydroxide, amide, alcoholate, acetate, carbonate or hydrogen carbonate, such as sodium hydride, sodium amide, lithiium diisopropylamide, sodium methanolate, sodium ethanolate, potassium tert-butanolate, sodium acetate, potassium acetate, calcium acetate, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, potassium bicarbonate, sodium bicarbonate, cesium carbonate or ammonium carbonate; and also tertiary amine, such as trimethylamine, triethylamine (TEA), tributylamine, N,N-dimethylaniline, N,N-dimethyl-benzylamine, N,N-diisopropyl-ethylamine (DIPEA), pyridine, N-methylpiperidine, N-methylmorpholine, N,N-dimethylaminopyridine, diazabicyclooctane (DABCO), diazabicyclononene (DBN) or diazabicycloundecene (DBU).
According to a further aspect of the present invention, there is provided a process P4 for the preparation of a compound of formula (I) wherein Y represents a NRd group, L2 represents a direct bond and Q2 represents a hydrogen atom; A, W, Q1, p, Ra, Rb, Rc, Rd, L1 being as herein defined,
and that comprises reacting a different compound of formula (I) wherein Y represents an oxygen atom, L2 represents a direct bond and Q2 represents a hydrogen atom; A, W, Q1, p, Ra, Rb, Rc, L1 being as herein-defined;
with a compound of formula RdNH or one of its salts, Rd being as herein-defined, optionally in the presence of dehydrating agent such as molecular sieves, anhydrous metal salts, such as magnesium sulphate, sodium sulphate, or metal oxides such as barium oxide, calcium oxide, optionally in the presence of a base such as an inorganic or an organic base; notably an alkaline earth metal or an alkali metal hydride, hydroxide, amide, alcoholate, acetate, carbonate or hydrogen carbonate, such as sodium hydride, sodium amide, lithiium diisopropylamide, sodium methanolate, sodium ethanolate, potassium tert-butanolate, sodium acetate, potassium acetate, calcium acetate, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, potassium bicarbonate, sodium bicarbonate, cesium carbonate or ammonium carbonate; and also tertiary amines, such as trimethylamine, triethylamine (TEA), tributylamine, N,N-dimethylaniline, N,N-dimethyl-benzylamine, N,N-diisopropyl-ethylamine (DIPEA), pyridine, N-methylpiperidine, N-methylmorpholine, N,N-dimethylaminopyridine, diazabicyclooctane (DABCO), diazabicyclononene (DBN) or diazabicycloundecene (DBU), optionally in the presence of an acid such as a Lewis acid; notably metal or metalloïd halides such as aluminium trichloride, zinc dichloride, magnesium bromide, boron tribromide; or such as a Brönstedt acid; notably a mineral acid such as sulphuric acid, chlorhydric acid, ammonium chloride, phosphoric acid, or an organic acid, such as acetic acid, para-toluenesulphonic acid.
According to a further aspect of the present invention, there is provided a process P5 for the to preparation of a compound of formula (I) wherein Y represents a CReRf group, L2 represents a direct bond and Q2 represents a hydrogen atom; A, W, Q1, p, Ra, Rb, Rc, L1 being as herein defined
and that comprises reacting a different compound of formula (I) wherein Y represents an oxygen atom, L2 represents a direct bond and Q2 represents a hydrogen atom; A, W, Q1, p, Ra, Rb, Rc, L1 being as herein-defined;
with a compound of formula CHUReRf, wherein U represents a hydrogen atom, a phosphonium group, a di-(C1-C6)-alkylphosphonate, Re, Rf being as herein-defined, or one of its salts, a tri-(C1-C6)-alkylsilyl, optionally in the presence of a base such as an inorganic or an organic base; notably an alkaline earth metal or an alkali metal hydride, hydroxide, amide, alcoholate, acetate, carbonate or hydrogen carbonate, such as sodium hydride, sodium amide, lithiium diisopropylamide, sodium methanolate, sodium ethanolate, potassium tert-butanolate, sodium acetate, potassium acetate, calcium acetate, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, potassium bicarbonate, sodium bicarbonate, cesium carbonate or ammonium carbonate; and also tertiary amines, such as trimethylamine, triethylamine (TEA), tributylamine, N,N-dimethylaniline, N,N-dimethyl-benzylamine, N,N-diisopropyl-ethylamine (DIPEA), pyridine, N-methylpiperidine, N-methylmorpholine, N,N-dimethylaminopyridine, diazabicyclooctane (DABCO), diazabicyclononene (DBN) or diazabicycloundecene (DBU), optionally in the presence of an acid such as a Lewis acid; notably metal or metalloïd halides such as aluminium trichloride, zinc dichloride, magnesium bromide, boron tribromide; or such as a Brönstedt acid; notably a mineral acid such as sulphuric acid, chlorhydric acid, ammonium chloride, phosphoric acid, or an organic acid, such as acetic acid, para-toluenesulphonic acid.
According to a further aspect of the present invention, there is provided a process P6 for the preparation of a compound of formula (I) wherein Y represents a CReRf group, L2 represents CRhRi and A, W, Q1, p, Ra, Rb, Rc, Re, Rf, Ri, L1, Q2 being as herein-defined;
and that comprises reacting a different compound of formula (I) wherein Y represents an oxygen atom and, L2 represents CRhRi; A, W, Q1, p, Ra, Rb, Rc, Re, Rf, Rh, Ri, L1, Q2 being as herein-defined;
with a compound of formula CHUReRf wherein U represents a hydrogen atom, a tri-(phenyl)-phosphonium group, a di-(C1-C6)-alkylphosphonate, Re, Rf being as herein-defined, or one of its salts, a tri-(C1-C6)-alkylsilyl, optionally in the presence of a base such as an inorganic or an organic base; notably an alkaline earth metal or an alkali metal hydride, hydroxide, amide, alcoholate, acetate, carbonate or hydrogen carbonate, such as sodium hydride, sodium amide, lithiium diisopropylamide, sodium methanolate, sodium ethanolate, potassium tert-butanolate, sodium acetate, potassium acetate, calcium acetate, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, potassium bicarbonate, sodium bicarbonate, cesium carbonate or ammonium carbonate; and also tertiary amines, such as trimethylamine, triethylamine (TEA), tributylamine, N,N-dimethylaniline, N,N-dimethyl-benzylamine, N,N-diisopropyl-ethylamine (DIPEA), pyridine, N-methylpiperidine, N-methylmorpholine, N,N-dimethylaminopyridine, diazabicyclooctane (DABCO), diazabicyclononene (DBN) or diazabicycloundecene (DBU), optionally in the presence of an acid such as a Lewis acid; notably metal or metalloïd halides such as aluminium trichloride, zinc dichloride, magnesium bromide, boron tribromide; or such as a Brönstedt acid; notably a mineral acid such as sulphuric acid, chlorhydric acid, ammonium chloride, phosphoric acid, or an organic acid, such as acetic acid, para-toluenesulphonic acid.
According to a further aspect of the present invention, there is provided a process P7 for the preparation of a compound of formula (I) wherein Y represents a NRd group, L2 represents an oxygen atom a sulphur atom or a NRg group wherein Rg represents a hydrogen atom, a formyl group, a formyloxy group, a formylamino group, a carbamoyl group, (hydroxyimino)-C1-C6-alkyl group, C1-C8-alkyl, tri(C1-C8-alkyl)silyl-C1-C8-alkyl, C1-C8-cycloalkyl, tri(C1-C8-alkyl)silyl-C1-C8-cycloalkyl, C1-C8-halogenoalkyl having 1 to 5 halogen atoms, C1-C8-halogenocycloalkyl having 1 to 5 halogen atoms a C2-C8-alkenyl, C2-C8-alkynyl, C1-C8-alkylamino, di-C1-C8-alkylamino, C1-C8-alkoxy, C1-C8-halogenoalkoxy having 1 to 5 halogen atoms, C2-C8-alkenyloxy, C2-C8-alkynyloxy, C1-C8-alkylsulfanyl, C1-C8-halogenoalkylsulfanyl having 1 to 5 halogen atoms, C2-C8-alkenyloxy, C2-C8-halogenoalkenyloxy having 1 to 5 halogen atoms, C3-C8-alkynyloxy, C3-C8-halogenoalkynyloxy having 1 to 5 halogen atoms, C1-C8-alkylcarbonyl, C1-C8-halogenoalkylcarbonyl having 1 to 5 halogen atoms, C1-C8-alkylcarbamoyl, di-C1-C8-alkylcarbamoyl, N—C1-C8-alkyloxycarbamoyl, C1-C8-alkoxycarbamoyl, N—C1-C8-alkyl-C1-C8-alkoxycarbamoyl, C1-C8-alkoxycarbonyl, C1-C8-halogenoalkoxycarbonyl having 1 to 5 halogen atoms, C1-C8-alkylcarbonyloxy, C1-C8-halogenoalkylcarbonyloxy having 1 to 5 halogen atoms, C1-C8-alkylcarbonylamino, C1-C8-halogenoalkylcarbonylamino having 1 to 5 halogen atoms, C1-C8-alkylaminocarbonyloxy, di-C1-C8-alkylaminocarbonyloxy, C1-C8-alkyloxycarbonyloxy, C1-C8-alkylsulphenyl, C1-C8-halogenoalkylsulphenyl having 1 to 5 halogen atoms, C1-C8-alkylsulphinyl, C1-C8-halogenoalkylsulphinyl having 1 to 5 halogen atoms, C1-C8-alkylsulphonyl, C1-C8-halogenoalkylsulphonyl having 1 to 5 halogen atoms, C1-C8-alkylaminosulfamoyl, di-C1-C8-alkylaminosulfamoyl, (C1-C8-alkoxyimino)-C1-C8-alkyl, (C1-C8-alkenyloxyimino)-C1-C8-alkyl, (C1-C6-alkynyloxyimino)-C1-C6-alkyl, (2-oxopyrrolidin-1-yl) C1-C8-alkyl, (2-oxopyrrolidin-1-yl) C1-C8-halogenoalkyl having 1 to 5 halogen atoms, (2-oxopiperidin-1-yl) C1-C8-alkyl, (2-oxopiperidin-1-yl) C1-C8-halogenoalkyl having 1 to 5 halogen atoms, (2-oxoazepan-1-yl) C1-C8-alkyl, (2-oxoazepan-1-yl) C1-C8-halogenoalkyl having 1 to 5 halogen atoms, (benzyloxyimino)-C1-C8-alkyl, C1-C8-alkoxyalkyl, C1-C8-halogenoalkoxyalkyl having 1 to 5 halogen atoms or a 4-, 5-, 6- or 7-membered heterocycle comprising up to 4 heteroatoms selected in the list consisting of N, O, S; Q2 represents a formyl group, a (hydroxyimino)-C1-C6-alkyl group, C1-C8-alkyl, tri(C1-C8-alkyl)silyl-C1-C8-alkyl, C1-C8-cycloalkyl, tri(C1-C8-alkyl)silyl-C1-C8-cycloalkyl, C1-C8-halogenoalkyl having 1 to 5 halogen atoms, C1-C8-halogenocycloalkyl having 1 to 5 halogen atoms a C2-C8-alkenyl, C2-C8-alkynyl, C1-C8-alkylcarbonyl, C1-C8-halogenoalkylcarbonyl having 1 to 5 halogen atoms, C1-C8-alkylcarbamoyl, di-C1-C8-alkylcarbamoyl, N—C1-C8-alkyloxycarbamoyl, C1-C8-alkoxycarbamoyl, N—C1-C8-alkyl-C1-C8-alkoxycarbamoyl, C1-C8-alkoxycarbonyl, C1-C8-halogenoalkoxycarbonyl having 1 to 5 halogen atoms, C1-C8-alkylsulphinyl, C1-C8-halogenoalkylsulphinyl having 1 to 5 halogen atoms, C1-C8-alkylsulphonyl, C1-C8-halogenoalkylsulphonyl having 1 to 5 halogen atoms, (C1-C6-alkoxyimino)-C1-C6-alkyl, (C1-C8-alkenyloxyimino)-C1-C8-alkyl, (C1-C8-alkynyloxyimino)-C1-C8-alkyl, (2-oxopyrrolidin-1-yl) C1-C8-alkyl, (2-oxopyrrolidin-1-yl) C1-C8-halogenoalkyl having 1 to 5 halogen atoms, (2-oxopiperidin-1-yl) C1-C8-alkyl, (2-oxopiperidin-1-yl) C1-C8-halogenoalkyl having 1 to 5 halogen atoms, (2-oxoazepan-1-yl) C1-C8-alkyl, (2-oxoazepan-1-yl) C1-C8-halogenoalkyl having 1 to 5 halogen atoms, (benzyloxyimino)-C1-C6-alkyl, C1-C8-alkoxyalkyl, a or a 4-, 5-, 6- or 7-membered heterocycle comprising up to 4 heteroatoms selected in the list consisting of N, O, S; and A, W, Q1, p, Ra, Rb, Rc, Rd, L1 being as herein-defined;
and that comprises reacting a different compound of formula (I) wherein Y represents a NRd group, L2 represents an oxygen atom, a sulphur atom or a NRg group wherein Rg represents a hydrogen atom, a formyl group, a formyloxy group, a formylamino group, a carbamoyl group, (hydroxyimino)-C1-C6-alkyl group, C1-C8-alkyl, tri(C1-C8-alkyl)silyl-C1-C8-alkyl, C1-C8-cycloalkyl, tri(C1-C8-alkyl)silyl-C1-C8-cycloalkyl, C1-C8-halogenoalkyl having 1 to 5 halogen atoms, C1-C8-halogenocycloalkyl having 1 to 5 halogen atoms a C2-C8-alkenyl, C2-C8-alkynyl, C1-C8-alkylamino, di-C1-C8-alkylamino, C1-C8-alkoxy, C1-C8-halogenoalkoxy having 1 to 5 halogen atoms, C2-C8-alkenyloxy, C2-C8-alkynyloxy, C1-C8-alkylsulfanyl, C1-C8-halogenoalkylsulfanyl having 1 to 5 halogen atoms, C2-C8-alkenyloxy, C2-C8-halogenoalkenyloxy having 1 to 5 halogen atoms, C3-C8-alkynyloxy, C3-C8-halogenoalkynyloxy having 1 to 5 halogen atoms, C1-C8-alkylcarbonyl, C1-C8-halogenoalkylcarbonyl having 1 to 5 halogen atoms, C1-C8-alkylcarbamoyl, di-C1-C8-alkylcarbamoyl, N—C1-C8-alkyloxycarbamoyl, C1-C8-alkoxycarbamoyl, N—C1-C8-alkyl-C1-C8-alkoxycarbamoyl, C1-C8-alkoxycarbonyl, C1-C8-halogenoalkoxycarbonyl having 1 to 5 halogen atoms, C1-C8-alkylcarbonyloxy, C1-C8-halogenoalkylcarbonyloxy having 1 to 5 halogen atoms, C1-C8-alkylcarbonylamino, C1-C8-halogenoalkylcarbonylamino having 1 to 5 halogen atoms, C1-C8-alkylaminocarbonyloxy, di-C1-C8-alkylaminocarbonyloxy, C1-C8-alkyloxycarbonyloxy, C1-C8-alkylsulphenyl, C1-C8-halogenoalkylsulphenyl having 1 to 5 halogen atoms, C1-C8-alkylsulphinyl, C1-C8-halogenoalkylsulphinyl having 1 to 5 halogen atoms, C1-C8-alkylsulphonyl, C1-C8-halogenoalkylsulphonyl having 1 to 5 halogen atoms, C1-C8-alkylaminosulfamoyl, di-C1-C8-alkylaminosulfamoyl, (C1-C6-alkoxyimino)-C1-C6-alkyl, (C1-C6-alkenyloxyimino)-C1-C6-alkyl, (C1-C6-alkynyloxyimino)-C1-C6-alkyl, (2-oxopyrrolidin-1-yl) C1-C8-alkyl, (2-oxopyrrolidin-1-yl) C1-C8-halogenoalkyl having 1 to 5 halogen atoms, (2-oxopiperidin-1-yl) C1-C8-alkyl, (2-oxopiperidin-1-yl) C1-C8-halogenoalkyl having 1 to 5 halogen atoms, (2-oxoazepan-1-yl) C1-C8-alkyl, (2-oxoazepan-1-yl) C1-C8-halogenoalkyl having 1 to 5 halogen atoms, (benzyloxyimino)-C1-C6-alkyl, C1-C8-alkoxyalkyl, C1-C8-halogenoalkoxyalkyl having 1 to 5 halogen atoms or a 4-, 5-, 6- or 7-membered heterocycle comprising up to 4 heteroatoms selected in the list consisting of N, O, S; Q2 represents a hydrogen atom; A, W, Q1, p, Ra, Rb, Rc, Rd, L1, being as herein-defined;
with a compound of formula Q2T wherein T represents a leaving group such as a halogen atom, a C1-C6 alkylsulfonate, a C1-C6 haloalkylsulfonate and Q2 represents a formyl group, a (hydroxyimino)-C1-C6-alkyl group, C1-C8-alkyl, tri(C1-C8-alkyl)silyl-C1-C8-alkyl, C1-C8-cycloalkyl, tri(C1-C8-alkyl)silyl-C1-C8-cycloalkyl, C1-C8-halogenoalkyl having 1 to 5 halogen atoms, C1-C8-halogenocycloalkyl having 1 to 5 halogen atoms a C2-C8-alkenyl, C2-C8-alkynyl, C1-C8-alkylcarbonyl, C1-C8-halogenoalkylcarbonyl having 1 to 5 halogen atoms, C1-C8-alkylcarbamoyl, di-C1-C8-alkylcarbamoyl, N—C1-C8-alkyloxycarbamoyl, C1-C8-alkoxycarbamoyl, N—C1-C8-alkyl-C1-C8-alkoxycarbamoyl, C1-C8-alkoxycarbonyl, C1-C8-halogenoalkoxycarbonyl having 1 to 5 halogen atoms, C1-C8-alkylsulphinyl, C1-C8-halogenoalkylsulphinyl having 1 to 5 halogen atoms, C1-C8-alkylsulphonyl, C1-C8-halogenoalkylsulphonyl having 1 to 5 halogen atoms, (C1-C6-alkoxyimino)-C1-C6-alkyl, (C1-C6-alkenyloxyimino)-C1-C6-alkyl, (C1-C6-alkynyloxyimino)-C1-C6-alkyl, (2-oxopyrrolidin-1-yl) C1-C8-alkyl, (2-oxopyrrolidin-1-yl) C1-C8-halogenoalkyl having 1 to 5 halogen atoms, (2-oxopiperidin-1-yl) C1-C8-alkyl, (2-oxopiperidin-1-yl) C1-C8-halogenoalkyl having 1 to 5 halogen atoms, (2-oxoazepan-1-yl) C1-C8-alkyl, (2-oxoazepan-1-yl) C1-C8-halogenoalkyl having 1 to 5 halogen atoms, (benzyloxyimino)-C1-C6-alkyl, C1-C8-alkoxyalkyl, a or a 4-, 5-, 6-, or 7-membered heterocycle comprising up to 4 heteroatoms selected in the list consisting of N, O, S; optionally in the presence of a base such as an inorganic or an organic base; notably an alkaline earth metal or an alkali metal hydride, hydroxide, amide, alcoholate, acetate, carbonate or hydrogen carbonate, such as sodium hydride, sodium amide, lithiium diisopropylamide, sodium methanolate, sodium ethanolate, potassium tert-butanolate, sodium acetate, potassium acetate, calcium acetate, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, potassium bicarbonate, sodium bicarbonate, cesium carbonate or ammonium carbonate; and also tertiary amines, such as trimethylamine, triethylamine (TEA), tributylamine, N,N-dimethylaniline, N,N-dimethyl-benzylamine, N,N-diisopropyl-ethylamine (DIPEA), pyridine, N-methylpiperidine, N-methylmorpholine, N,N-dimethylaminopyridine, diazabicyclooctane (DABCO), diazabicyclononene (DBN) or diazabicycloundecene (DBU), optionally in the presence of an acid such as a Lewis acid; notably metal or metalloïd halides such as aluminium trichloride, zinc dichloride, magnesium bromide, boron tribromide; or such as a Brönstedt acid; notably a mineral acid such as sulphuric acid, chlorhydric acid, ammonium chloride, phosphoric acid, or an organic acid, such as acetic acid, para-toluenesulphonic acid, optionally in the presence of a condensing agent such as acid halide former, notably phosgene, phosphorous tribromide, phosphorous trichloride, phosphorous pentachloride, phosphorous trichloride oxide or thionyl chloride; such as an anhydride former, notably ethyl chloroformate, methyl chloroformate, isopropyl chloroformate, isobutyl chloroformate, 2,2,-dimethylpropionyl chloride or methanesulfonyl chloride; notably carbodiimides, such as N,N′-dicyclohexylcarbodiimide (DCC) or such as other customary condensing agents, notably phosphorous pentoxide, polyphosphoric acid, N,N′-carbonyldiimidazole, 2-ethoxy-N-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), triphenylphosphine/tetrachloromethane or bromo-tripyrrolidinophosphonium-hexafluorophosphate, optionally in the presence of a catalyst notably a transition metal catalyst, such as palladium salts or complexes for example palladium (II) chloride, palladium (II) acetate, tetrakis-(triphenylphosphine) palladium(0), bis-(triphenylphosphine) palladium dichloride (II), tris(dibenzylideneacetone) dipalladium(0), bis(dibenzylideneacetone) palladium(0), or 1,1′-bis(diphenylphosphino)ferrocene-palladium (II) chloride. As an alternative the palladium complex is directly generated in the reaction mixture by separately adding to the reaction mixture a palladium salt and a complex ligand such as a phosphine, for example triethylphosphine, tri-tert-butylphosphine, tricyclohexylphosphine, 2-(dicyclohexylphosphine)biphenyl, 2-(di-tert-butylphosphin)biphenyl, 2-(dicyclohexylphosphine)-2′-(N,N-dimethylamino)-biphenyl, triphenylphosphine, tris-(o-tolyl)phosphine, sodium 3-(diphenylphosphino)benzolsulfonate, tris-2-(methoxyphenyl)phosphine, 2,2′-bis-(diphenylphosphine)-1,1′-binaphthyl, 1,4-bis-(diphenylphosphine)butane, 1,2-bis-(diphenylphosphine)ethane, 1,4-bis-(dicyclohexylphosphine)butane, 1,2-bis-(dicyclohexylphosphine)ethane, 2-(dicyclohexylphosphine)-2′-(N,N-dimethylamino)-biphenyl, bis(diphenylphosphino)ferrocene, tris-(2,4-tert-butylphenyl)-phosphite, (R)-(−)-1-[(S)-2-(diphenylphosphino)ferrocenyl]ethyldi-tert-butylphosphine, (S)-(+)-1-[(R)-2-(diphenylphosphino)ferrocenyl]ethyldicyclohexylphosphine, (R)-(+1-[(S)-2-(diphenylphosphino)ferrocenyl]ethyldicyclohexylphosphine, (S)-(+)-1-[(R)-2-(diphenylphosphino)ferrocenyl]ethyldi-t-butylphosphine.
According to a further aspect of the present invention, there is provided a process P8 for the preparation of a compound of formula (I) wherein Y represents a NRd group wherein Rd represents a formyloxy group, a formylamino group, C1-C8-alkyl amino, C1-C8-cycloalkylamino, di-C1-C8-alkylamino, C1-C8-alkoxy, C1-C8-halogenoalkoxy having 1 to 5 halogen atoms, C2-C8-alkenyloxy, C2-C8-alkynyloxy, C2-C8-halogenoalkenyloxy having 1 to 5 halogen atoms, C3-C8-halogenoalkynyloxy having 1 to 5 halogen atoms, C1-C8-alkylcarbonyloxy, C1-C8-halogenoalkylcarbonyloxy having 1 to 5 halogen atoms, C1-C8-alkylcarbonylamino, C1-C8-halogenoalkylcarbonylamino having 1 to 5 halogen atoms, C1-C8-alkylaminocarbonyloxy, di-C1-C8-alkylaminocarbonyloxy, C1-C8-alkyloxycarbonyloxy, C1-C8-alkoxycarbonylamino, C1-C8-halogenoalkoxycarbonylamino having 1 to 5 halogen atoms, C1-C8-alkoxycarbonyloxy, C1-C8-halogenoalkoxycarbonyloxy having 1 to 5 halogen atoms; L2 represents an oxygen atom, a sulphur atom or a NRg group; Q2 represents a hydrogen atom; and A, W, Q1, p, Ra, Rb, Rc, Rg, L1, being as herein-defined,
and that comprises reacting a different compound of formula (I) wherein Y represents a NRd group wherein Rd represents an amino group, a hydroxy group C1-C8-alkylamino, C1-C8-cycloalkylamino, L2 represents an oxygen atom, a sulphur atom or a NRg group; Q2 represents a hydrogen atom; A, W, Q1, p, Ra, Rb, Rc, Rg, L1, being as herein-defined;
with a compound of formula Q2T wherein T represents a leaving group such as a halogen atom, a C1-C6 alkylsulfonate, a C1-C6 haloalkylsulfonate and Q2 represents a formyl group, C1-C8-cycloalkyl, C1-C8-halogenoalkyl having 1 to 5 halogen atoms, C1-C8-halogenocycloalkyl having 1 to 5 halogen atoms a C2-C8-alkenyl, C2-C8-alkynyl, C2-C8-halogenoalkenyl having 1 to 5 halogen atoms, C3-C8-halogenoalkynyl having 1 to 5 halogen atoms, C1-C8-alkylcarbonyl, C1-C8-halogenoalkylcarbonyl having 1 to 5 halogen atoms, C1-C8-alkylcarbamoyl, di-C1-C8-alkylcarbamoyl, C1-C8-alkoxycarbonyl, C1-C8-halogenoalkoxycarbonyl having 1 to 5 halogen atoms; optionally in the presence of a base such as an inorganic or an organic base; notably an alkaline earth metal or an alkali metal hydride, hydroxide, amide, alcoholate, acetate, carbonate or hydrogen carbonate, such as sodium hydride, sodium amide, lithiium diisopropylamide, sodium methanolate, sodium ethanolate, potassium tert-butanolate, sodium acetate, potassium acetate, calcium acetate, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, potassium bicarbonate, sodium bicarbonate, cesium carbonate or ammonium carbonate; and also tertiary amines, such as trimethylamine, triethylamine (TEA), tributylamine, N,N-dimethylaniline, N,N-dimethyl-benzylamine, N,N-diisopropyl-ethylamine (DIPEA), pyridine, N-methylpiperidine, N-methylmorpholine, N,N-dimethylaminopyridine, diazabicyclooctane (DABCO), diazabicyclononene (DBN) or diazabicycloundecene (DBU), optionally in the presence of an acid such as a Lewis acid; notably metal or metalloïd halides such as aluminium trichloride, zinc dichloride, magnesium bromide, boron tribromide; or such as a Brönstedt acid; notably a mineral acid such as sulphuric acid, chlorhydric acid, ammonium chloride, phosphoric acid, or an organic acid, such as acetic acid, para-toluenesulphonic acid, optionally in the presence of a condensing agent such as acid halide former, notably phosgene, phosphorous tribromide, phosphorous trichloride, phosphorous pentachloride, phosphorous trichloride oxide or thionyl chloride; such as an anhydride former, notably ethyl chloroformate, methyl chloroformate, isopropyl chloroformate, isobutyl chloroformate, 2,2-dimethylpropionyl chloride or methanesulfonyl chloride; notably carbodiimides, such as N,N′-dicyclohexylcarbodiimide (DCC) or such as other customary condensing agents, notably phosphorous pentoxide, polyphosphoric acid, N,N′-carbonyldiimidazole, 2-ethoxy-N-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), triphenylphosphine/tetrachloromethane or bromo-tripyrrolidinophosphonium-hexafluorophosphate, optionally in the presence of a catalyst notably a transition metal catalyst, such as palladium salts or complexes for example palladium (II) chloride, palladium (II) acetate, tetrakis-(triphenylphosphine) palladium(0), bis-(triphenylphosphine) palladium dichloride (II), tris(dibenzylideneacetone) dipalladium(0), bis(dibenzylideneacetone) palladium(0), or 1,1′-bis(diphenylphosphino)ferrocene-palladium (II) chloride. As an alternative the palladium complex is directly generated in the reaction mixture by separately adding to the reaction mixture a palladium salt and a complex ligand such as a phosphine, for example triethylphosphine, tri-tert-butylphosphine, tricyclohexylphosphine, 2-(dicyclohexylphosphine)biphenyl, 2-(di-tert-butylphosphin)biphenyl, 2-(dicyclohexylphosphine)-2′-(N,N-dimethylamino)-biphenyl, triphenylphosphine, tris-(o-tolyl)phosphine, sodium 3-(diphenylphosphino)benzolsulfonate, tris-2-(methoxyphenyl)phosphine, 2,2′-bis-(diphenylphosphine)-1,1′-binaphthyl, 1,4-bis-(diphenylphosphine)butane, 1,2-bis-(diphenylphosphine)ethane, 1,4-bis-(dicyclohexylphosphine)butane, 1,2-bis-(dicyclohexylphosphine)ethane, 2-(dicyclohexylphosphine)-2′-(N,N-dimethylamino)-biphenyl, bis(diphenylphosphino)ferrocene, tris-(2,4-tert-butylphenyl)-phosphite, (R)-(+1-[(S)-2-(diphenylphosphino)ferrocenyl]ethyldi-tert-butylphosphine, (S)-(+)-1-[(R)-2-(diphenylphosphino)ferrocenyl]ethyldicyclohexylphosphine, (R)-(+1-[(S)-2-(diphenylphosphino)ferrocenyl]ethyldicyclohexylphosphine, (S)-(+)-1-[(R)-2-(diphenylphosphino)ferrocenyl]ethyldi-t-butylphosphine.
According to a further aspect of the present invention, there is provided a process P9 for the preparation of a compound of formula (I) wherein Y represents an oxygen atom, L2 represents an oxygen atom, a NRg group; A, W, Q1, p, Ra, Rb, Rc, Rg, L1, Q2, being as herein defined;
and that comprises reacting a different compound of formula (I) wherein Y represents an oxygen atom, L2 represents an oxygen atom and Q2 represents a hydrogen atom, a formyl group, a (hydroxyimino)-C1-C6-alkyl group, C1-C8-alkyl, C1-C8-cycloalkyl, C1-C8-halogenoalkyl having 1 to 5 halogen atoms, C1-C8-halogenocycloalkyl having 1 to 5 halogen atoms a C2-C8-alkenyl, C2-C8-alkynyl, C1-C8-alkylcarbonyl, C1-C8-halogenoalkylcarbonyl having 1 to 5 halogen atoms, C1-C8-alkylcarbamoyl, di-C1-C8-alkylcarbamoyl, N—C1-C8-alkyloxycarbamoyl, C1-C8-alkoxycarbamoyl, N—C1-C8-alkyl-C1-C8-alkoxycarbamoyl, C1-C8-alkoxycarbonyl, C1-C8-halogenoalkoxycarbonyl having 1 to 5 halogen atoms, C1-C8-alkylsulphinyl, C1-C8-halogenoalkylsulphinyl having 1 to 5 halogen atoms, C1-C8-alkylsulphonyl, C1-C8-halogenoalkylsulphonyl having 1 to 5 halogen atoms, (C1-C6-alkoxyimino)-C1-C6-alkyl, (C1-C6-alkenyloxyimino)-C1-C6-alkyl, (C1-C6-alkynyloxyimino)-C1-C6-alkyl, (2-oxopyrrolidin-1-yl) C1-C8-alkyl, (2-oxopyrrolidin-1-yl) C1-C8-halogenoalkyl having 1 to 5 halogen atoms, (2-oxopiperidin-1-yl) C1-C8-alkyl, (2-oxopiperidin-1-yl) C1-C8-halogenoalkyl having 1 to 5 halogen atoms, (2-oxoazepan-1-yl) C1-C8-alkyl, (2-oxoazepan-1-yl) C1-C8-halogenoalkyl having 1 to 5 halogen atoms, (benzyloxyimino)-C1-C6-alkyl, C1-C8-alkoxyalkyl, a or a 4-, 5-, 6- or 7-membered heterocycle comprising up to 4 heteroatoms selected in the list consisting of N, O, S; A, W, Q1, p, Ra, Rb, Rc, L1, being as herein defined;
with a compound of formula Q2L2H wherein Q2 being as herein defined and L2 represents an oxygen atom, a NRg group,
optionally in the presence of a base such as an inorganic or an organic base; notably an alkaline earth metal or an alkali metal hydride, hydroxide, amide, alcoholate, acetate, carbonate or hydrogen carbonate, such as sodium hydride, sodium amide, lithiium diisopropylamide, sodium methanolate, sodium ethanolate, potassium tert-butanolate, sodium acetate, potassium acetate, calcium acetate, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, potassium bicarbonate, sodium bicarbonate, cesium carbonate or ammonium carbonate; and also tertiary amines, such as trimethylamine, triethylamine (TEA), tributylamine, N,N-dimethylaniline, N,N-dimethyl-benzylamine, N,N-diisopropyl-ethylamine (DIPEA), pyridine, N-methylpiperidine, N-methylmorpholine, N,N-dimethylaminopyridine, diazabicyclooctane (DABCO), diazabicyclononene (DBN) or diazabicycloundecene (DBU), optionally in the presence of an acid such as a Lewis acid; notably metal or metalloïd halides such as aluminium trichloride, zinc dichloride, magnesium bromide, boron tribromide; or such as a Brönstedt acid; notably a mineral acid such as sulphuric acid, chlorhydric acid, ammonium chloride, phosphoric acid, or an organic acid, such as acetic acid, para-toluenesulphonic acid, optionally in the presence of a condensing agent such as acid halide former, notably phosgene, phosphorous tribromide, phosphorous trichloride, phosphorous pentachloride, phosphorous trichloride oxide or thionyl chloride; such as an anhydride former, notably ethyl chloroformate, methyl chloroformate, isopropyl chloroformate, isobutyl chloroformate, 2,2-dimethylpropionyl chloride or methanesulfonyl chloride; notably carbodiimides, such as N,N′-dicyclohexylcarbodiimide (DCC) or such as other customary condensing agents, notably phosphorous pentoxide, polyphosphoric acid, N,N′-carbonyldiimidazole, 2-ethoxy-N-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), triphenylphosphine/tetrachloromethane or bromo-tripyrrolidinophosphonium-hexafluorophosphate, optionally in the presence of a catalyst notably a transition metal catalyst, such as palladium salts or complexes for example palladium (II) chloride, palladium (II) acetate, tetrakis-(triphenylphosphine) palladium(0), bis-(triphenylphosphine) palladium dichloride (II), tris(dibenzylideneacetone) dipalladium(0), bis(dibenzylideneacetone) palladium(0), or 1,1′-bis(diphenylphosphino)ferrocene-palladium (II) chloride. As an alternative the palladium complex is directly generated in the reaction mixture by separately adding to the reaction mixture a palladium salt and a complex ligand such as a phosphine, for example triethylphosphine, tri-tert-butylphosphine, tricyclohexylphosphine, 2-(dicyclohexylphosphine)biphenyl, 2-(di-tert-butylphosphin)biphenyl, 2-(dicyclohexylphosphine)-2′-(N,N-dimethylamino)-biphenyl, triphenylphosphine, tris-(o-tolyl)phosphine, sodium 3-(diphenylphosphino)benzolsu lfonate, tris-2-(methoxyphenyl)phosphine, 2,2′-bis-(diphenylphosphine)-1,1′-binaphthyl, 1,4-bis-(diphenylphosphine)butane, 1,2-bis-(diphenylphosphine)ethane, 1,4-bis-(dicyclohexylphosphine)butane, 1,2-bis-(dicyclohexylphosphine)ethane, 2-(dicyclohexylphosphine)-2′-(N,N-dimethylamino)-biphenyl, bis(diphenylphosphino)ferrocene, tris-(2,4-tert-butylphenyl)-phosphite, (R)-(−)-1-[(S)-2-(diphenylphosphino)ferrocenyl]ethyldi-tert-butylphosphine, (S)-(+)-1-[(R)-2-(diphenylphosphino)ferrocenyl]ethyldicyclohexylphosphine, (R)-(+1-[(S)-2-(diphenylphosphino)ferrocenyl]ethyldicyclohexylphosphine, (S)-(+)-1-[(R)-2-(diphenylphosphino)ferrocenyl]ethyldi-t-butylphosphine; in one or a different-pot conditions.
According to the present invention, the compounds of formula (I) useful as starting material within the processes P2 to P9 can be prepared according to process P1 according to the invention.
According to a further aspect of the present invention, there is provided a process P10 for the preparation of a compound of formula (I) wherein Y represents a sulphur atom, L2 represents an oxygen atom, a NRg group and A, W, Q1, p, Ra, Rb, Rc, Rg, L1, Q2 being as herein defined; and that comprises reacting a different compound of formula (I) wherein Y represents an oxygen atom, L2 represents an oxygen atom, a NRg group and A, W, Q1, p, Ra, Rb, Rc, Rg, L1, Q2 being as herein defined;
with a thiocarbonylation agent such as 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide, phosphorus pentasulfide, sulphur.
According to a further aspect of the present invention, there is provided a process P11 for the preparation of a compound of formula (I) wherein Y represents a NRd group or an oxygen atom, L2 represents a NRg group and Rg represents a hydrogen atom, a nitro group, a cyano group, a hydroxy group, an amino group, a formyloxy group, a formylamino group, (hydroxyimino)-C1-C6-alkyl group, C1-C8-alkyl, C1-C8-cycloalkyl, C1-C8-halogenoalkyl having 1 to 5 halogen atoms, C1-C8-halogenocycloalkyl having 1 to 5 halogen atoms a C2-C8-alkenyl, C2-C8-alkynyl, C1-C8-alkylamino, di-C1-C8-alkylamino, C1-C8-alkoxy, C1-C8-halogenoalkoxy having 1 to 5 halogen atoms, C2-C8-alkenyloxy, C2-C8-alkynyloxy, C2-C8-alkenyloxy, C2-C8-halogenoalkenyloxy having 1 to 5 halogen atoms, C3-C8-alkynyloxy, C3-C8-halogenoalkynyloxy having 1 to 5 halogen atoms, C1-C8-alkylcarbonyloxy, C1-C8-halogenoalkylcarbonyloxy having 1 to 5 halogen atoms, C1-C8-alkylcarbonylamino, C1-C8-halogenoalkylcarbonylamino having 1 to 5 halogen atoms, C1-C8-alkylaminocarbonyloxy, di-C1-C8-alkylaminocarbonyloxy, (C1-C6-alkoxyimino)-C1-C6-alkyl, (C1-C6-alkenyloxyimino)-C1-C6-alkyl, (C1-C6-alkynyloxyimino)-C1-C6-alkyl, (2-oxopyrrolidin-1-yl) C1-C8-alkyl, (2-oxopyrrolidin-1-yl) C1-C8-halogenoalkyl having 1 to 5 halogen atoms, (2-oxopiperidin-1-yl) C1-C8-alkyl, (2-oxopiperidin-1-yl) C1-C8-halogenoalkyl having 1 to 5 halogen atoms, (2-oxoazepan-1-yl) C1-C8-alkyl, (2-oxoazepan-1-yl) C1-C8-halogenoalkyl having 1 to 5 halogen atoms, (benzyloxyimino)-C1-C6-alkyl, or a 4-, 5-, 6- or 7-membered heterocycle comprising up to 4 heteroatoms selected in the list consisting of N, O, S; A, W, Q1, p, Ra, Rb, Rc, Rd, L1, Q2 being as herein defined;
and that comprises reacting a different compound of formula (I) wherein Y represents a NRd group or an oxygen atom, L2 represents an oxygen atom, a sulphur atom; Q2 represents a formyl group, C1-C8-cycloalkyl, C1-C8-halogenoalkyl having 1 to 5 halogen atoms, C1-C8-halogenocycloalkyl having 1 to 5 halogen atoms a C2-C8-alkenyl, C2-C8-alkynyl, C2-C8-halogenoalkenyl having 1 to 5 halogen atoms, C3-C8-halogenoalkynyl having 1 to 5 halogen atoms, C1-C8-alkylcarbonyl, C1-C8-halogenoalkylcarbonyl having 1 to 5 halogen atoms, C1-C8-alkylcarbamoyl, di-C1-C8-alkylcarbamoyl, C1-C8-alkoxycarbonyl, C1-C8-halogenoalkoxycarbonyl having 1 to 5 halogen atoms and A, W, Q1, p, Ra, Rb, Rc, Rd, L1 being as herein defined;
with a compound of formula RgNH wherein Rg being as herein defined;
optionally in the presence of a base such as an inorganic or an organic base; notably an alkaline earth metal or an alkali metal hydride, hydroxide, amide, alcoholate, acetate, carbonate or hydrogen carbonate, such as sodium hydride, sodium amide, lithiium diisopropylamide, sodium methanolate, sodium ethanolate, potassium tert-butanolate, sodium acetate, potassium acetate, calcium acetate, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, potassium bicarbonate, sodium bicarbonate, cesium carbonate or ammonium carbonate; and also tertiary amines, such as trimethylamine, triethylamine (TEA), tributylamine, N,N-dimethylaniline, N,N-dimethyl-benzylamine, N,N-diisopropyl-ethylamine (DIPEA), pyridine, N-methylpiperidine, N-methylmorpholine, N,N-dimethylaminopyridine, diazabicyclooctane (DABCO), diazabicyclononene (DBN) or diazabicycloundecene (DBU), optionally in the presence of an acid such as a Lewis acid; notably metal or metalloïd halides such as aluminium trichloride, zinc dichloride, magnesium bromide, boron tribromide; or such as a Brönstedt acid; notably a mineral acid such as sulphuric acid, chlorhydric acid, ammonium chloride, phosphoric acid, or an organic acid, such as acetic acid, para-toluenesulphonic acid, optionally in the presence of a condensing agent such as acid halide former, notably phosgene, phosphorous tribromide, phosphorous trichloride, phosphorous pentachloride, phosphorous trichloride oxide or thionyl chloride; such as an anhydride former, notably ethyl chloroformate, methyl chloroformate, isopropyl chloroformate, isobutyl chloroformate, 2,2-dimethylpropionyl chloride or methanesulfonyl chloride; notably carbodiimides, such as N,N′-dicyclohexylcarbodiimide (DCC) or such as other customary condensing agents, notably phosphorous pentoxide, polyphosphoric acid, N,N′-carbonyld iimidazole, 2-ethoxy-N-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), triphenylphosphine/tetrachloromethane or bromo-tripyrrolidinophosphonium-hexafluorophosphate, optionally in the presence of a catalyst notably a transition metal catalyst, such as palladium salts or complexes for example palladium (II) chloride, palladium (II) acetate, tetrakis-(triphenylphosphine) palladiu m(0), bis-(triphenylphosphine) palladium dichloride (II), tris(dibenzylideneacetone) dipalladium(0), bis(dibenzylideneacetone) palladium(0), or 1,1′-bis(diphenylphosphino)ferrocene-palladium (II) chloride. As an alternative the palladium complex is directly generated in the reaction mixture by separately adding to the reaction mixture a palladium salt and a complex ligand such as a phosphine, for example triethylphosphine, tri-tert-butylphosphine, tricyclohexylphosphine, 2-(dicyclohexylphosphine)biphenyl, 2-(di-tert-butylphosphin)biphenyl, 2-(dicyclohexylphosphine)-2′-(N,N-dimethylamino)-biphenyl, triphenylphosphine, tris-(o-tolyl)phosphine, sodium 3-(diphenylphosphino)benzolsulfonate, tris-2-(methoxyphenyl)phosphine, 2,2′-bis-(diphenylphosphine)-1,1′-binaphthyl, 1,4-bis-(diphenylphosphine)butane, 1,2-bis-(diphenylphosphine)ethane, 1,4-bis-(dicyclohexylphosphine)butane, 1,2-bis-(dicyclohexylphosphine)ethane, 2-(dicyclohexylphosphine)-2′-(N,N-dimethylamino)-biphenyl, bis(diphenylphosphino)ferrocene, tris-(2,4-tert-butylphenyl)-phosphite, (R)-(+1-[(S)-2-(diphenylphosphino)ferrocenyl]ethyldi-tert-butylphosphine, (S)-(+)-1-[(R)-2-(diphenylphosphino)ferrocenyl]ethyldicyclohexylphosphine, (R)-(+1-[(S)-2-(diphenylphosphino)ferrocenyl]ethyldicyclohexylphosphine, (S)-(+)-1-[(R)-2-(diphenylphosphino)ferrocenyl]ethyldi-t-butylphosphine; in one or a different-pot conditions.
According to the present invention, the compounds of formula (I) useful as starting material within the processes P10 to P11 can be prepared according to process P1 to P9 according to the invention.
Thus according to a further aspect of the present invention, there is provided a process P12 for the preparation of a compound of formula (I) as illustrated by the following reaction scheme:
wherein
Suitable solvents for carrying out process P1 to P12 according to the invention are in each case all customary inert organic solvents. Preference is given to using optionally halogenated aliphatic, alicyclic or aromatic hydrocarbons, such as petroleum ether, hexane, heptane, cyclohexane, methylcyclohexane, benzene, toluene, xylene or decalin; chlorobenzene, dichlorobenzene, dichloromethane, chloroform, carbon tetrachloride, dichlorethane or trichlorethane; ethers, such as diethyl ether, diisopropyl ether, methyl t-butyl ether, methyl t-amyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxyethane, 1,2-diethoxyethane or anisole; nitriles, such as acetonitrile, propionitrile, n- or i-butyronitrile or benzonitrile; amides, such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylformanilide, N-methylpyrrolidone or hexamethylphosphoric triamide; esters, such as methyl acetate or ethyl acetate, sulphoxides, such as dimethyl sulphoxide, or sulphones, such as sulpholane.
When carrying out process P1 to P12 according to the invention, the reaction temperatures can independently be varied within a relatively wide range. Generally, processes according to the invention are carried out at temperatures between −80° C. and 250° C.
Process P1 to P12 according to the invention is generally independently carried out under atmospheric pressure. However, in each case, it is also possible to operate under elevated or reduced pressure.
Work-up is carried out by customary methods. Generally, the reaction mixture is treated with water and the organic phase is separated off and, after drying, concentrated under reduced pressure. If appropriate, the remaining residue can be freed by customary methods, such as chromatography or recrystallization, from any impurities that may still be present.
Compounds according to the invention can be prepared according to the above described process. It will nevertheless be understood that, on the basis of his general knowledge and of available publications, the skilled worker will be able to adapt these processes according to the specifics of each of the compounds according to the invention that is desired to be synthesized.
Still in a further aspect, the present invention relates to compounds of formula (V) useful as to intermediate compounds or materials for the process of preparation according to the invention. The present invention thus provides compounds of formula (V)
wherein A, W, Q1, p, Ra, Rb, Rc, L1 are as herein-defined.
Still in a further aspect, the present invention relates to compounds of formula (VI) useful as intermediate compounds or materials for the process of preparation according to the invention. The present invention thus provides compounds of formula (VI)
Preferred compounds of formula (VI) according to the invention are those wherein T is a chlorine atom.
More preferred compounds of formula (VI) according to the invention are those selected from the group constituted of 4-(2-chloropyridin-4-yl)-N-(pyridin-3-yl)pyrimidin-2-amine, 4-(2-chloropyridin-4-yl)-N-(6-methoxypyridin-3-yl)-1,3,5-triazin-2-amine, 4-(2-chloropyridin-4-yl)-N-(3,4,5-trimethoxyphenyl)-1,3,5-triazin-2-amine, 3-{[4-(2-chloropyridin-4-yl)-1,3,5-triazin-2-yl]amino}benzoic acid, 4-(2-chloropyridin-4-yl)-N-(6-chloropyridin-2-yl)pyrimidin-2-amine, N,4-bis(2-chloropyridin-4-yl)pyrimidin-2-amine, N4-[4-(2-chloropyridin-4-yl)pyrimidin-2-yl]-N2-(1-methoxybutan-2-yl)pyridine-2,4-diamine, N-(3-chloro-4-fluorophenyl)-4-(2-chloropyridin-4-yl)-1,3,5-triazin-2-amine, 4-(2-chloropyridin-4-yl)-N-[3-(methylsulfanyl)phenyl]-1,3,5-triazin-2-amine, N-(3-chloro-4-methylphenyl)-4-(2-chloropyridin-4-yl)-1,3,5-triazin-2-amine, N4-[4-(2-chloropyridin-4-yl)pyrimidin-2-yl]-N2-cyclobutylpyridine-2,4-diamine, N4-[4-(2-chloropyridin-4-yl)pyrimidin-2-yl]-N2-(3-methylbutan-2-yl)pyridine-2,4-diamine, N4-[4-(2-chloropyridin-4-yl)pyrimidin-2-yl]-N2-(pentan-3-yl)pyridine-2,4-diamine, 4-(2-chloropyridin-4-yl)-N-(pyridin-4-yl)-1,3,5-triazin-2-amine, methyl 3-{[4-(2-chloropyridin-4-yl)-1,3,5-triazin-2-yl}amino]thiophene-2-carboxylate, ethyl 2-{[4-(2-chloropyridin-4-yl)-1,3,5-triazin-2-yl]amino}-4-methyl-1,3-thiazole-5-carboxylate, 4-(2-chloropyridin-4-yl)-N-(4-methyl-1,3-thiazol-2-yl)-1,3,5-triazin-2-amine, 4-(2-chloropyridin-4-yl)-N-(5-methyl-1,3-thiazol-2-yl)-1,3,5-triazin-2-amine, 4-(2-chloropyridin-4-yl)-N-(2-methylpyridin-4-yl)pyrimidin-2-amine, N-(2-bromopyridin-4-yl)-4-(2-chloropyridin-4-yl)pyrim din-2-amine, N-(5-bromopyridin-3-yl)-4-(2-chloropyridin-4-yl)pyrimidin-2-amine, 4-(2-chloropyridin-4-yl)-N[2-(trifluoromethyl)pyridin-4-yl]pyrimidin-2-amine, 2-{[4-(2-chloropyridin-4-yl)-1,3,5-triazin-2-yl]amino}thiophene-3-carbonitrile, N-(5-chloro-3-methylpyridin-2-yl)-4-(2-chloropyridin-4-yl)-1,3,5-triazin-2-amine, 4-(2-chloropyridin-4-yl)-N-(4-chloropyridin-3-yl)-1,3,5-triazin-2-amine, 4-(2-chloropyridin-4-yl)-N-(2-methylpyridin-4-yl)-1,3,5-triazin-2-amine, N,4-bis(2-chloropyridin-4-yl)-N-(methoxymethyl)pyrimidin-2-amine, 4-(2-chloropyridin-4-yl)-N-(2,5-difluorophenyl)-1,3,5-triazin-2-amine, 4-(2-chloropyridin-4-yl)-N-(3-fluorophenyl)-1,3,5-triazin-2-amine, 4-(2-chloropyridin-4-yl)-N-[3-(methoxymethyl)phenyl]-1,3,5-triazin-2-amine, 4-(2-chloropyridin-4-yl)-N-(thiophen-3-yl)-1,3,5-triazin-2-amine, 4-(2-chloropyridin-4-yl)-N-[3-(trifluoromethyl)phenyl]-1,3,5-triazin-2-amine, 4-(2-chloropyridin-4-yl)-N-[3-(propan-2-yl)phenyl]-1,3,5-triazin-2-amine, 4-(2-chloropyridin-4-yl)-N-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-1,3,5-triazin-2-amine, 4-(2-chloropyridin-4-yl)-N-[3-(trifluoromethoxy)phenyl]-1,3,5-triazin-2-amine, 4-(2-chloropyridin-4-yl)-N-[3-(pentafluoro-lambda6-sulfanyl)phenyl]-1,3,5-triazin-2-amine, 4-(2-chloropyridin-4-yl)-N-(3-ethoxyphenyl)-1,3,5-triazin-2-amine, 4-(2-chloropyridin-4-yl)-N-(3-methoxyphenyl)-1,3,5-triazin-2-amine, 4-(2-chloropyridin-4-yl)-N-phenyl-1,3,5-triazin-2-amine, 4-(2-chloropyridin-4-yl)-N-(4-fluorophenyl)-1,3,5-triazin-2-amine, 4-(2-chloropyridin-4-yl)-N-[3-(difluoromethoxy)phenyl]-1,3,5-triazin-2-amine, N-(3-{[4-(2-chloropyridin-4-yl)-1,3,5-triazin-2-yl]amino}phenyl)acetamide, and 4-(2-chloropyridin-4-yl)-N-[3-(difluoromethyl)phenyl]-1,3,5-triazin-2-amine, 4-(2-chloropyridin-4-yl)-N-[3-(difluoromethyl)-4-fluorophenyl]-1,3,5-triazin-2-amine and N-[4-chloro-3-(difluoromethyl)phenyl]-4-(2-chloropyridin-4-yl)-1,3,5-triazin-2-amine
Compounds of formula (VI) useful as intermediates for the process of preparation of compounds to of formula (I) or formula (V) may be prepared by various processes. Accordingly, there is provided a process A according to the invention for the preparation of a compound of formula (VI) wherein
wherein
Alternatively, there is provided a process B according to the invention for the preparation of a compound of formula (VI) wherein A, W, Q1, p, Ra, Rb, Rc, L1, T being as herein-defined; and comprising
wherein
Alternatively, there is provided a process C according to the invention for the preparation of a compound of formula (VI) wherein A, W, Q1, p, Ra, Rb, Rc, L1, T, being as herein-defined; and comprising
wherein
In a further aspect, the present invention also relates to a fungicide composition comprising an effective and non-phytotoxic amount of an active compound of formula (I).
The expression “effective and non-phytotoxic amount” means an amount of composition according to the invention which is sufficient to control or destroy the fungi present or liable to appear on the crops, and which does not entail any appreciable symptom of phytotoxicity for the said crops. Such an amount can vary within a wide range depending on the fungus to be controlled, the type of crop, the climatic conditions and the compounds included in the fungicide composition according to the invention. This amount can be determined by systematic field trials, which are within the capabilities of a person skilled in the art.
Thus, according to the invention, there is provided a fungicide composition comprising, as an active ingredient, an effective amount of a compound of formula (I) as herein defined and an agriculturally acceptable support, carrier or filler.
According to the invention, the term “support” denotes a natural or synthetic, organic or inorganic compound with which the active compound of formula (I) is combined or associated to make it easier to apply, notably to the parts of the plant. This support is thus generally inert and should be agriculturally acceptable. The support may be a solid or a liquid. Examples of suitable supports include clays, natural or synthetic silicates, silica, resins, waxes, solid fertilisers, water, alcohols, in particular butanol, organic solvents, mineral and plant oils and derivatives thereof. Mixtures of such supports may also be used.
The composition according to the invention may also comprise additional components. In particular, the composition may further comprise a surfactant. The surfactant can be an emulsifier, a dispersing agent or a wetting agent of ionic or non-ionic type or a mixture of such surfactants. Mention may be made, for example, of polyacrylic acid salts, lignosulphonic acid salts, phenolsulphonic or naphthalenesulphonic acid salts, polycondensates of ethylene oxide with fatty alcohols or with fatty acids or with fatty amines, substituted phenols (in particular alkylphenols or arylphenols), salts of sulphosuccinic acid esters, taurine derivatives (in particular alkyl taurates), phosphoric esters of polyoxyethylated alcohols or phenols, fatty acid esters of polyols, and derivatives of the above compounds containing sulphate, sulphonate and phosphate functions. The presence of at least one surfactant is generally essential when the active compound and/or the inert support are water-insoluble and when the vector agent for the application is water. Preferably, surfactant content may be comprised from 5% to 40% by weight of the composition.
Optionally, additional components may also be included, e.g. protective colloids, adhesives, thickeners, thixotropic agents, penetration agents, stabilisers, sequestering agents. More generally, the active compounds can be combined with any solid or liquid additive, which complies with the usual formulation techniques.
In general, the composition according to the invention may contain from 0.05 to 99% by weight of active compound, preferably 10 to 70% by weight.
Compositions according to the invention can be used in various forms such as aerosol dispenser, capsule suspension, cold fogging concentrate, dustable powder, emulsifiable concentrate, emulsion oil in water, emulsion water in oil, encapsulated granule, fine granule, flowable concentrate for seed treatment, gas (under pressure), gas generating product, granule, hot fogging concentrate, macrogranule, microgranule, oil dispersible powder, oil miscible flowable concentrate, oil miscible liquid, paste, plant rodlet, powder for dry seed treatment, seed to coated with a pesticide, soluble concentrate, soluble powder, solution for seed treatment, suspension concentrate (flowable concentrate), ultra low volume (ULV) liquid, ultra low volume (ULV) suspension, water dispersible granules or tablets, water dispersible powder for slurry treatment, water soluble granules or tablets, water soluble powder for seed treatment and wettable powder. These compositions include not only compositions which are ready to be applied to the plant or seed to be treated by means of a suitable device, such as a spraying or dusting device, but also concentrated commercial compositions which must be diluted before application to the crop.
The compounds according to the invention can also be mixed with one or more insecticide, fungicide, bactericide, attractant, acaricide or pheromone active substance or other compounds with biological activity. The mixtures thus obtained have normally a broadened spectrum of activity. The mixtures with other fungicide compounds are particularly advantageous.
Examples of suitable fungicide mixing partners may be selected in the following lists:
(1) Inhibitors of the nucleic acid synthesis, for example benalaxyl, benalaxyl-M, bupirimate, clozylacon, dimethirimol, ethirimol, furalaxyl, hymexazol, metalaxyl, metalaxyl-M, ofurace, oxadixyl and oxolinic acid.
(2) Inhibitors of the mitosis and cell division, for example benomyl, carbendazim, chlorfenazole, diethofencarb, ethaboxam, fuberidazole, pencycuron, thiabendazole, thiophanate, thiophanate-methyl and zoxamide.
(3) Inhibitors of the respiration, for example diflumetorim as C1-respiration inhibitor; bixafen, boscalid, carboxin, fenfuram, flutolanil, fluopyram, furametpyr, furmecyclox, isopyrazam (mixture of syn-epimeric racemate 1RS,4SR,9RS and anti-epimeric racemate 1RS,4SR,9SR), isopyrazam (syn epimeric racemate 1R,4SR,9RS), isopyrazam (syn-epimeric enantiomer 1R,4S,9R), isopyrazam (syn-epimeric enantiomer 1S,4R,9S), isopyrazam (anti-epimeric racemate 1RS,4SR,9SR), isopyrazam (anti-epimeric enantiomer 1R,4S,9S), isopyrazam (anti-epimeric enantiomer 1S,4R,9R), mepronil, oxycarboxin, penflufen, penthiopyrad, sedaxane, thifluzamide as CII-respiration inhibitor; amisulbrom, azoxystrobin, cyazofamid, dimoxystrobin, enestroburin, famoxadone, fenamidone, fluoxastrobin, kresoxim-methyl, metominostrobin, orysastrobin, picoxystrobin, pyraclostrobin, pyraoxystrobin, pyrametostrobin, pyribencarb, trifloxystrobin as CIII-respiration inhibitor.
(4) Compounds capable to act as an uncoupler, like for example binapacryl, dinocap, fluazinam to and meptyldinocap.
(5) Inhibitors of the ATP production, for example fentin acetate, fentin chloride, fentin hydroxide, and silthiofam.
(6) Inhibitors of the amino acid and/or protein biosynthesis, for example andoprim, blasticidin-S, cyprodinil, kasugamycin, kasugamycin hydrochloride hydrate, mepanipyrim and pyrimethanil.
(7) Inhibitors of the signal transduction, for example fenpiclonil, fludioxonil and quinoxyfen.
(8) Inhibitors of the lipid and membrane synthesis, for example biphenyl, chlozolinate, edifenphos, etridiazole, iodocarb, iprobenfos, iprodione, isoprothiolane, procymidone, propamocarb, propamocarb hydrochloride, pyrazophos, tolclofos-methyl and vinclozolin.
(9) Inhibitors of the ergosterol biosynthesis, for example aldimorph, azaconazole, bitertanol, bromuconazole, cyproconazole, diclobutrazole, difenoconazole, diniconazole, diniconazole-M, dodemorph, dodemorph acetate, epoxiconazole, etaconazole, fenarimol, fenbuconazole, fenhexamid, fenpropidin, fenpropimorph, fluquinconazole, flurprimidol, flusilazole, flutriafol, furconazole, furconazole-cis, hexaconazole, imazalil, imazalil sulfate, imibenconazole, ipconazole, metconazole, myclobutanil, naftifine, nuarimol, oxpoconazole, paclobutrazol, pefurazoate, penconazole, piperalin, prochloraz, propiconazole, prothioconazole, pyributicarb, pyrifenox, quinconazole, simeconazole, spiroxamine, tebuconazole, terbinafine, tetraconazole, triadimefon, triadimenol, tridemorph, triflumizole, triforine, triticonazole, uniconazole, uniconazole-p, viniconazole and voriconazole.
(10) Inhibitors of the cell wall synthesis, for example benthiavalicarb, dimethomorph, flumorph, iprovalicarb, mandipropamid, polyoxins, polyoxorim, prothiocarb, validamycin A, and valifenalate.
(11) Inhibitors of the melanine biosynthesis, for example carpropamid, diclocymet, fenoxanil, phthalide, pyroquilon and tricyclazole.
(12) Compounds capable to induce a host defence, like for example acibenzolar-S-methyl, probenazole, and tiadinil.
(13) Compounds capable to have a multisite action, like for example bordeaux mixture, captafol, captan, chlorothalonil, copper naphthenate, copper oxide, copper oxychloride, copper preparations such as copper hydroxide, copper sulphate, dichlofluanid, dithianon, dodine, dodine free base, ferbam, fluorofolpet, folpet, guazatine, guazatine acetate, iminoctadine, iminoctadine albesilate, iminoctadine triacetate, mancopper, mancozeb, maneb, metiram, metiram zinc, oxine-copper, propamidine, propineb, sulphur and sulphur preparations including calcium polysulphide, thiram, tolylfluanid, zineb and ziram.
(14) Further compounds like for example 2,3-dibutyl-6-chlorothieno[2,3-d]pyrimidin-4(3H)-one, ethyl (2Z)-3-amino-2-cyano-3-phenylprop-2-enoate, N-[2-(1,3-dimethylbutyl)phenyl]-5-fluoro-1,3-dimethyl-1H-pyrazole-4-carboxamide, 3-(difluoromethyl)-1-methyl-N-(3′,4′,5′-trifluorobiphenyl-2-yl)-1H-pyrazole-4-carboxamide, 3-(difluoromethyl)-N-[4-fluoro-2-(1,1,2,3,3,3-hexafluoropropoxy)phenyl]-1-methyl-1H-pyrazole-4-carboxamide, (2E)-2-(2-{[6-(3-chloro-2-methylphenoxy)-5-fluoropyrimidin-4-yl]oxy}phenyl)-2-(methoxyimino)-N-methylethanamide, (2E)-2-{2-[({[(2E,3E)-4-(2,6-dichlorophenyl)but-3-en-2-ylidene]amino}oxy)methyl]phenyl}-2-(methoxyimino)-N-methylethanamide, 2-chloro-N-(1,1,3-trimethyl-2,3-dihydro-1H-inden-4-yl)pyridine-3-carboxamide, N-(3-ethyl-3,5,5-trimethylcyclohexyl)-3-(formylamino)-2-hydroxybenzamide, 5-methoxy-2-methyl-4-(2-{[({(1E)-1-[3-(trifluoromethyl)phenyl]ethylidene}amino)oxy]methyl}phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one, (2E)-2-(methoxyimino)-N-methyl-2-(2-{[({(1E)-1-[3-(trifluoromethyl)phenyl]ethylidene}amino)oxy]methyl}phenyl)ethanamide, (2E)-2-(methoxyimino)-N-methyl-2-{2-[(E)-({1-[3-(trifluoromethyl)phenyl]ethoxy}imino)methyl]phenyl}ethanamide, (2E)-2-{2-[({[(1E)-1-(3-{[(E)-1-fluoro-2-phenylethenyl]oxy}phenyl)ethylidene]amino}oxy)methyl]phenyl}-2-(methoxyimino)-N-methylethanamide, 1-(4-chlorophenyl)-2-(1H-1,2,4-triazol-1-yl)cycloheptanol, methyl 1-(2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)-1H-imidazole-5-carboxylate, N-ethyl-N-methyl-N′-{2-methyl-5-(trifluoromethyl)-4-[3-(trimethylsilyl)propoxy]phenyl}imidoformamide, N′-{5-(difluoromethyl)-2-methyl-4-[3-(trimethylsily)propoxy]phenyl}-N-ethyl-N-methylimidoformamide, O-{1-[(4-methoxyphenoxy)methyl]-2,2-dimethylpropyl}1H-imidazole-1-carbothioate, N-[2-(4-{[3-(4-chlorophenyl)prop-2-yn-1-yl]oxy}-3-methoxyphenyl)ethyl]-N2-(methylsulfonyl)valinamide, 5-chloro-7-(4-methylpiperidin-1-yl)-6-(2,4,6-trifluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidine, 5-amino-1,3,4-thiadiazole-2-thiol, propamocarb-fosetyl, 1-[(4-methoxyphenoxy)methyl]-2,2-dimethylpropyl 1H-imidazole-1-carboxylate, 1-methyl-N-[2-(1,1,2,2-tetrafluoroethoxy)phenyl]-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide, 2,3,5,6-tetrachloro-4-(methylsulfonyl)pyridine, 2-butoxy-6-iodo-3-propyl-4H-chromen-4-one, 2-phenylphenol and salts, 3-(difluoromethyl)-1-methyl-N-[2-(1,1,2,2-tetrafluoroethoxy)phenyl]-1H-pyrazole-4-carboxamide, 3,4,5-trichloropyridine-2,6-dicarbonitrile, 3-[5-(4-chlorophenyl)-2,3-dimethylisoxazolidin-3-yl]pyridine, 3-chloro-5-(4-chlorophenyl)-4-(2,6-difluorophenyl)-6-methylpyridazine, 4-(4-chlorophenyl)-5-(2,6-difluorophenyl)-3,6-dimethylpyridazine, quinolin-8-ol, quinolin-8-ol sulfate (2:1) (salt), tebufloquin, 5-methyl-6-octyl-3,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-7-amine, 5-ethyl-6-octyl-3,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-7-amine, ametoctradin, benthiazole, bethoxazin, capsimycin, carvone, chinomethionat, chloroneb, cufraneb, cyflufenamid, cymoxanil, cyprosulfamide, dazomet, debacarb, dichlorophen, diclomezine, dicloran, difenzoquat, difenzoquat methylsulphate, diphenylamine, ecomate, ferimzone, flumetover, fluopicolide, fluoroimide, flusulfamide, flutianil, fosetyl-aluminium, fosetyl-calcium, fosetyl-sodium, hexachlorobenzene, irumamycin, isotianil, methasulfocarb, methyl (2E)-2-{2-[({cyclopropyl[(4-methoxyphenyl)imino]methyl}thio)methyl]phenyl}-3-methoxyacrylate, methyl isothiocyanate, metrafenone, (5-chloro-2-methoxy-4-methylpyridin-3-yl)(2,3,4-trimethoxy-6-methylphenyl)methanone, mildiomycin, tolnifanide, N-(4-chlorobenzyl)-3-[3-methoxy-4-(prop-2-yn-1-yloxy)phenyl]propanamide, N-[(4-chlorophenyl)(cyano)methyl]-3-[3-methoxy-4-(prop-2-yn-1-yloxy)phenyl]propanamide, N-[(5-bromo-3-chloropyridin-2-yl)methyl]-2,4-dichloropyridine-3-carboxamide, N-[1-(5-bromo-3-chloropyridin-2-yl)ethyl]-2,4-dichloropyridine-3-carboxamide, N-[1-(5-bromo-3-chloropyridin-2-yl)ethyl]-2-fluoro-4-iodopyridine-3-carboxamide, N-{(Z)-[(cyclopropylmethoxy)imino][6-(difluoromethoxy)-2,3-difluorophenyl]methyl}-2-phenylacetamide, N-{(E)-[(cyclopropylmethoxy)imino][6-(difluoromethoxy)-2,3-difluorophenyl]methyl}-2-phenylacetamide, natamycin, nickel dimethyldithiocarbamate, nitrothal-isopropyl, octhilinone, oxamocarb, oxyfenthiin, pentachlorophenol and salts, phenazine-1-carboxylic acid, phenothrin, phosphorous acid and its salts, propamocarb fosetylate, propanosine-sodium, proquinazid, pyrroInitrine, quintozene, S-prop-2-en-1-yl 5-amino-2-(1-methylethyl)-4-(2-methylphenyl)-3-oxo-2,3-dihydro-1H-pyrazole-1-carbothioate, tecloftalam, tecnazene, triazoxide, trichlamide, 5-chloro-N′-phenyl-N′-prop-2-yn-1-ylthiophene-2-sulfonohydrazide, zarilamid, N-methyl-2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-N-[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]-1,3-thiazole-4-carboxamide, N-methyl-2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1,3-thiazole-4-carboxamide, 3-(difluoromethyl)-N-[4-fluoro-2-(1,1,2,3,3,3-hexafluoropropoxy)phenyl]-1-methyl-1H-pyrazole-4-carboxamide and pentyl {6-[({[(1-methyl-1H-tetrazol-5-yl)(phenyl)methylidene]amino}oxy)methyl]pyridin-2-yl}carbamate.
The composition according to the invention comprising a mixture of a compound of formula (I) with a bactericide compound may also be particularly advantageous. Examples of suitable bactericide mixing partners may be selected in the following list: bronopol, dichlorophen, nitrapyrin, nickel dimethyldithiocarbamate, kasugamycin, octhilinone, furancarboxylic acid, oxytetracycline, probenazole, streptomycin, tecloftalam, copper sulphate and other copper preparations.
The compounds of formula (I) and the fungicide composition according to the invention can be used to curatively or preventively control the phytopathogenic fungi of plants or crops.
Thus, according to a further aspect of the invention, there is provided a method for curatively or preventively controlling the phytopathogenic fungi of plants or crops characterised in that a compound of formula (I) or a fungicide composition according to the invention is applied to the seed, the plant or to the fruit of the plant or to the soil wherein the plant is growing or wherein it is desired to grow.
The method of treatment according to the invention may also be useful to treat propagation material such as tubers or rhizomes, but also seeds, seedlings or seedlings pricking out and plants or plants pricking out. This method of treatment can also be useful to treat roots. The method of treatment according to the invention can also be useful to treat the over ground parts of the plant such as trunks, stems or stalks, leaves, flowers and fruit of the concerned plant.
Among the plants that can be protected by the method according to the invention, mention may be made of cotton; flax; vine; fruit or vegetable crops such as Rosaceae sp. (for instance pip fruit such as apples and pears, but also stone fruit such as apricots, almonds and peaches), Ribesioidae sp., Juglandaceae sp., Betulaceae sp., Anacardiaceae sp., Fagaceae sp., Moraceae sp., Oleaceae sp., Actimidaceae sp., Lauraceae sp., Musaceae sp. (for instance banana trees and plantins), Rubiaceae sp., Theaceae sp., Sterculiceae sp., Rutaceae sp. (for instance lemons, oranges and grapefruit); Solanaceae sp. (for instance tomatoes), Liliaceae sp., Asteraceae sp. (for instance lettuces), Umbelliferae sp., Cruciferae sp., Chenopodiaceae sp., Cucurbitaceae sp., Papilionaceae sp. (for instance peas), Rosaceae sp. (for instance strawberries); major crops such as Graminae sp. (for instance maize, lawn or cereals such as wheat, rice, barley and triticale), Asteraceae sp. (for instance sunflower), Cruciferae sp. (for instance colza), Fabacae sp. (for instance peanuts), Papilionaceae sp. (for instance soybean), Solanaceae sp. (for instance potatoes), Chenopodiaceae sp. (for instance beetroots); horticultural and forest crops; as well as genetically modified homologues of these crops.
Among the diseases of plants or crops that can be controlled by the method according to the invention, mention may be made of:
The fungicide composition according to the invention may also be used against fungal diseases liable to grow on or inside timber. The term “timber” means all types of species of wood, and all types of working of this wood intended for construction, for example solid wood, high-density wood, laminated wood, and plywood. The method for treating timber according to the invention mainly consists in contacting one or more compounds according to the invention, or a composition according to the invention; this includes for example direct application, spraying, dipping, injection or any other suitable means.
The dose of active compound usually applied in the method of treatment according to the to invention is generally and advantageously from 10 to 800 g/ha, preferably from 50 to 300 g/ha for applications in foliar treatment. The dose of active substance applied is generally and advantageously from 2 to 200 g per 100 kg of seed, preferably from 3 to 150 g per 100 kg of seed in the case of seed treatment.
It is clearly understood that the doses indicated herein are given as illustrative examples of the method according to the invention. A person skilled in the art will know how to adapt the application doses, notably according to the nature of the plant or crop to be treated.
The method of treatment according to the invention can be used in the treatment of genetically modified organisms (GMOs), e.g. plants or seeds. Genetically modified plants (or transgenic plants) are plants in which a heterologous gene has been stably integrated into the genome. The expression “heterologous gene” essentially means a gene which is provided or assembled outside the plant and when introduced in the nuclear, chloroplastic or mitochondrial genome gives the transformed plant new or improved agronomic or other properties by expressing a protein or polypeptide of interest or by downregulating or silencing other gene(s) which are present in the plant (using for example, antisense technology, co suppression technology or RNA interference—RNAi-technology). A heterologous gene that is located in the genome is also called a transgene. A transgene that is defined by its particular location in the plant genome is called a transformation or transgenic event.
Depending on the plant species or plant cultivars, their location and growth conditions (soils, climate, vegetation period, diet), the treatment according to the invention may also result in superadditive (“synergistic”) effects. Thus, for example, reduced application rates and/or a widening of the activity spectrum and/or an increase in the activity of the active compounds and compositions which can be used according to the invention, better plant growth, increased tolerance to high or low temperatures, increased tolerance to drought or to water or soil salt content, increased flowering performance, easier harvesting, accelerated maturation, higher harvest yields, bigger fruits, larger plant height, greener leaf color, earlier flowering, higher quality and/or a higher nutritional value of the harvested products, higher sugar concentration within the fruits, better storage stability and/or processability of the harvested products are possible, which exceed the effects which were actually to be expected.
At certain application rates, the active compound combinations according to the invention may also have a strengthening effect in plants. Accordingly, they are also suitable for mobilizing the defense system of the plant against attack by unwanted phytopathogenic fungi and/or microorganisms and/or viruses. This may, if appropriate, be one of the reasons of the enhanced activity of the combinations according to the invention, for example against fungi. Plant-strengthening (resistance-inducing) substances are to be understood as meaning, in the present context, those substances or combinations of substances which are capable of stimulating the defense system of plants in such a way that, when subsequently inoculated with unwanted phytopathogenic fungi and/or microorganisms and/or viruses, the treated plants display a substantial degree of resistance to these unwanted phytopathogenic fungi and/or microorganisms and/or viruses. In the present case, unwanted phytopathogenic fungi and/or microorganisms and/or viruses are to be understood as meaning phytopathogenic fungi, bacteria and viruses. Thus, the substances according to the invention can be employed for protecting plants against attack by the abovementioned pathogens within a certain period of time after the treatment. The period of time within which protection is effected generally extends from 1 to 10 days, preferably 1 to 7 days, after the treatment of the plants with the active compounds.
Plants and plant cultivars which are preferably to be treated according to the invention include all plants which have genetic material which impart particularly advantageous, useful traits to these plants (whether obtained by breeding and/or biotechnological means).
Plants and plant cultivars which are also preferably to be treated according to the invention are resistant against one or more biotic stresses, i.e. said plants show a better defense against animal and microbial pests, such as against nematodes, insects, mites, phytopathogenic fungi, bacteria, viruses and/or viroids.
Plants and plant cultivars which may also be treated according to the invention are those plants which are resistant to one or more abiotic stresses. Abiotic stress conditions may include, for example, drought, cold temperature exposure, heat exposure, osmotic stress, flooding, increased soil salinity, increased mineral exposure, ozon exposure, high light exposure, limited availability of nitrogen nutrients, limited availability of phosphorus nutrients, shade avoidance.
Plants and plant cultivars which may also be treated according to the invention, are those plants characterized by enhanced yield characteristics. Increased yield in said plants can be the result of, for example, improved plant physiology, growth and development, such as water use efficiency, water retention efficiency, improved nitrogen use, enhanced carbon assimilation, improved photosynthesis, increased germination efficiency and accelerated maturation. Yield can furthermore be affected by improved plant architecture (under stress and non-stress conditions), including but not limited to, early flowering, flowering control for hybrid seed production, seedling vigor, plant size, internode number and distance, root growth, seed size, fruit size, pod size, pod or ear number, seed number per pod or ear, seed mass, enhanced to seed filling, reduced seed dispersal, reduced pod dehiscence and lodging resistance. Further yield traits include seed composition, such as carbohydrate content, protein content, oil content and composition, nutritional value, reduction in anti-nutritional compounds, improved processability and better storage stability.
Plants that may be treated according to the invention are hybrid plants that already express the characteristic of heterosis or hybrid vigor which results in generally higher yield, vigor, health and resistance towards biotic and abiotic stress factors. Such plants are typically made by crossing an inbred male-sterile parent line (the female parent) with another inbred male-fertile parent line (the male parent). Hybrid seed is typically harvested from the male sterile plants and sold to growers. Male sterile plants can sometimes (e.g. in corn) be produced by detasseling, i.e. the mechanical removal of the male reproductive organs (or males flowers) but, more typically, male sterility is the result of genetic determinants in the plant genome. In that case, and especially when seed is the desired product to be harvested from the hybrid plants it is typically useful to ensure that male fertility in the hybrid plants is fully restored. This can be accomplished by ensuring that the male parents have appropriate fertility restorer genes which are capable of restoring the male fertility in hybrid plants that contain the genetic determinants responsible for male-sterility. Genetic determinants for male sterility may be located in the cytoplasm. Examples of cytoplasmic male sterility (CMS) were for instance described in Brassica species (WO 1992/005251, WO 1995/009910, WO 1998/27806, WO 2005/002324, WO 2006/021972 and U.S. Pat. No. 6,229,072). However, genetic determinants for male sterility can also be located in the nuclear genome. Male sterile plants can also be obtained by plant biotechnology methods such as genetic engineering. A particularly useful means of obtaining male-sterile plants is described in WO 1989/10396 in which, for example, a ribonuclease such as barnase is selectively expressed in the tapetum cells in the stamens. Fertility can then be restored by expression in the tapetum cells of a ribonuclease inhibitor such as barstar (e.g. WO 1991/002069).
Plants or plant cultivars (obtained by plant biotechnology methods such as genetic engineering) which may be treated according to the invention are herbicide-tolerant plants, i.e. plants made tolerant to one or more given herbicides. Such plants can be obtained either by genetic transformation, or by selection of plants containing a mutation imparting such herbicide tolerance.
Herbicide-tolerant plants are for example glyphosate-tolerant plants, i.e. plants made tolerant to the herbicide glyphosate or salts thereof. Plants can be made tolerant to glyphosate through different means. For example, glyphosate-tolerant plants can be obtained by transforming the plant with a gene encoding the enzyme 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS). Examples of such EPSPS genes are the AroA gene (mutant CT7) of the bacterium Salmonella typhimurium (Comai et al., Science (1983), 221, 370-371), the CP4 gene of the bacterium Agrobacterium sp. (Barry et al., Curr. Topics Plant Physiol. (1992), 7, 139-145), the genes encoding a Petunia EPSPS (Shah et al., Science (1986), 233, 478-481), a Tomato EPSPS (Gasser et al., J. Biol. Chem. (1988), 263, 4280-4289), or an Eleusine EPSPS (WO 2001/66704). It can also be a mutated EPSPS as described in for example EP-A 0837944, WO 2000/066746, WO 2000/066747 or WO 2002/026995. Glyphosate-tolerant plants can also be obtained by expressing a gene that encodes a glyphosate oxido-reductase enzyme as described in U.S. Pat. No. 5,776,760 and U.S. Pat. No. 5,463,175. Glyphosate-tolerant plants can also be obtained by expressing a gene that encodes a glyphosate acetyl transferase enzyme as described in for example WO 2002/036782, WO 2003/092360, WO 2005/012515 and WO 2007/024782. Glyphosate-tolerant plants can also be obtained by selecting plants containing naturally-occurring mutations of the above-mentioned genes, as described in for example WO 2001/024615 or WO 2003/013226. Other herbicide resistant plants are for example plants that are made tolerant to herbicides inhibiting the enzyme glutamine synthase, such as bialaphos, phosphinothricin or glufosinate. Such plants can be obtained by expressing an enzyme detoxifying the herbicide or a mutant glutamine synthase enzyme that is resistant to inhibition. One such efficient detoxifying enzyme is an enzyme encoding a phosphinothricin acetyltransferase (such as the bar or pat protein from Streptomyces species). Plants expressing an exogenous phosphinothricin acetyltransferase are for example described in U.S. Pat. No. 5,561,236; U.S. Pat. No. 5,648,477; U.S. Pat. No. 5,646,024; U.S. Pat. No. 5,273,894; U.S. Pat. No. 5,637,489; U.S. Pat. No. 5,276,268; U.S. Pat. No. 5,739,082; U.S. Pat. No. 5,908,810 and U.S. Pat. No. 7,112,665. Further herbicide-tolerant plants are also plants that are made tolerant to the herbicides inhibiting the enzyme hydroxyphenylpyruvated ioxygenase (HPPD). Hydroxyphenylpyruvatedioxygenases are enzymes that catalyze the reaction in which para-hydroxyphenylpyruvate (HPP) is transformed into homogentisate. Plants tolerant to HPPD-inhibitors can be transformed with a gene encoding a naturally-occurring resistant HPPD enzyme, or a gene encoding a mutated HPPD enzyme as described in WO 1996/038567, WO 1999/024585 and WO 1999/024586. Tolerance to HPPD-inhibitors can also be obtained by transforming plants with genes encoding certain enzymes enabling the formation of homogentisate despite the inhibition of the native HPPD enzyme by the HPPD-inhibitor. Such plants and genes are described in WO 1999/034008 and WO 2002/36787. Tolerance of plants to HPPD inhibitors can also be improved by transforming plants with a gene encoding an enzyme prephenate dehydrogenase in addition to a gene encoding an HPPD-tolerant enzyme, as described in WO 2004/024928.
Still further herbicide resistant plants are plants that are made tolerant to acetolactate synthase
(ALS) inhibitors. Known ALS-inhibitors include, for example, sulfonylurea, imidazolinone, triazolopyrimidines, pyrimidinyloxy(thio)benzoates, and/or sulfonylaminocarbonyltriazolinone herbicides. Different mutations in the ALS enzyme (also known as acetohydroxyacid synthase, AHAS) are known to confer tolerance to different herbicides and groups of herbicides, as described for example in Tranel and Wright, Weed Science (2002), 50, 700-712, but also, in U.S. Pat. No. 5,605,011, U.S. Pat. No. 5,378,824, U.S. Pat. No. 5,141,870, and U.S. Pat. No. 5,013,659. The production of sulfonylurea-tolerant plants and imidazolinone-tolerant plants is described in U.S. Pat. No. 5,605,011; U.S. Pat. No. 5,013,659; U.S. Pat. No. 5,141,870; U.S. Pat. No. 5,767,361; U.S. Pat. No. 5,731,180; U.S. Pat. No. 5,304,732; U.S. Pat. No. 4,761,373; U.S. Pat. No. 5,331,107; U.S. Pat. No. 5,928,937; and U.S. Pat. No. 5,378,824; and international publication WO 1996/033270. Other imidazolinone-tolerant plants are also described in for example WO 2004/040012, WO 2004/106529, WO 2005/020673, WO 2005/093093, WO 2006/007373, WO 2006/015376, WO 2006/024351, and WO 2006/060634. Further sulfonylurea- and imidazolinone-tolerant plants are also described in for example WO 2007/024782.
Other plants tolerant to imidazolinone and/or sulfonylurea can be obtained by induced mutagenesis, selection in cell cultures in the presence of the herbicide or mutation breeding as described for example for soybeans in U.S. Pat. No. 5,084,082, for rice in WO 1997/41218, for sugar beet in U.S. Pat. No. 5,773,702 and WO 1999/057965, for lettuce in U.S. Pat. No. 5,198,599, or for sunflower in WO 2001/065922.
Plants or plant cultivars (obtained by plant biotechnology methods such as genetic engineering) which may also be treated according to the invention are insect-resistant transgenic plants, i.e. plants made resistant to attack by certain target insects. Such plants can be obtained by genetic transformation, or by selection of plants containing a mutation imparting such insect resistance. An “insect-resistant transgenic plant”, as used herein, includes any plant containing at least one transgene comprising a coding sequence encoding:
Of course, an insect-resistant transgenic plant, as used herein, also includes any plant comprising a combination of genes encoding the proteins of any one of the above classes 1 to 8. In one embodiment, an insect-resistant plant contains more than one transgene encoding a protein of any one of the above classes 1 to 8, to expand the range of target insect species affected when using different proteins directed at different target insect species, or to delay insect resistance development to the plants by using different proteins insecticidal to the same target insect species but having a different mode of action, such as binding to different receptor binding sites in the insect.
Plants or plant cultivars (obtained by plant biotechnology methods such as genetic engineering) which may also be treated according to the invention are tolerant to abiotic stresses. Such plants can be obtained by genetic transformation, or by selection of plants containing a mutation imparting such stress resistance. Particularly useful stress tolerance plants include:
Plants or plant cultivars (obtained by plant biotechnology methods such as genetic engineering) which may also be treated according to the invention show altered quantity, quality and/or storage-stability of the harvested product and/or altered properties of specific ingredients of the harvested product such as:
Plants or plant cultivars (that can be obtained by plant biotechnology methods such as genetic engineering) which may also be treated according to the invention are plants, such as cotton plants, with altered fiber characteristics. Such plants can be obtained by genetic transformation, or by selection of plants contain a mutation imparting such altered fiber characteristics and include:
Plants or plant cultivars (that can be obtained by plant biotechnology methods such as genetic engineering) which may also be treated according to the invention are plants, such as oilseed rape or related Brassica plants, with altered oil profile characteristics. Such plants can be obtained by genetic transformation or by selection of plants contain a mutation imparting such altered oil characteristics and include:
Particularly useful transgenic plants which may be treated according to the invention are plants which comprise one or more genes which encode one or more toxins, such as the following which are sold under the trade names YIELD GARD3 (for example maize, cotton, soya beans), KnockOut3 (for example maize), BiteGard3 (for example maize), Bt-Xtra3 (for example maize), StarLink3 (for example maize), Bollgard3 (cotton), Nucotn3 (cotton), Nucotn 33B® (cotton), NatureGard3 (for example maize), Protecta3 and NewLeaf3 (potato). Examples of herbicide-tolerant plants which may be mentioned are maize varieties, cotton varieties and soya bean varieties which are sold under the trade names Roundup Ready3 (tolerance to glyphosate, for example maize, cotton, soya bean), Liberty Link3 (tolerance to phosphinotricin, for example oilseed rape), IMI3 (tolerance to imidazolinones) and STS3 (tolerance to sulphonylureas, for example maize). Herbicide-resistant plants (plants bred in a conventional manner for herbicide tolerance) which may be mentioned include the varieties sold under the name Clearfield3 (for example maize).
Particularly useful transgenic plants which may be treated according to the invention are plants containing transformation events, or combination of transformation events, that are listed for example in the databases from various national or regional regulatory agencies (see for example http://dmoinfo.irc.it/gmp_browse.aspx and http://www.agbios.com/dbase.php).
The compounds or mixtures according to the invention may also be used for the preparation of composition useful to curatively or preventively treat human or animal fungal diseases such as, for example, mycoses, dermatoses, trichophyton diseases and candidiases or diseases caused by Aspergillus spp., for example Aspergillus fumigatus.
Furthermore compounds according to the invention may also be used to reduce the contents of mycotoxins in plants and the harvested plant material and therefore in foods and animal feed stuff made therefrom.
Method of combating phytopathogenic and mycotoxin producing fungi characterized in that compounds according to the invention are applied to these fungi and/or their habitat.
Especially but not exclusively the following mycotoxins can be specified:
Deoxynivalenole (DON), Nivalenole, 15-Ac-DON, 3-Ac-DON, T2- and HT2-Toxins, Fumonisines, Zearalenone Moniliformine, Fusarine, Diaceotoxyscirpenole (DAS), Beauvericine, Enniatine, Fusaroproliferine, Fusarenole, Ochratoxines, Patuline, Ergotalkaloides and Aflatoxines, which are caused for example by the following fungal diseases: Fusarium spec., like Fusarium acuminatum, F. avenaceum, F. crookwellense, F. culmorum, F. graminearum (Gibberella zeae), F. equiseti, F. fujikoroi, F. musarum, F. oxysporum, F. proliferatum, F. poae, F. pseudograminearum, F. sambucinum, F. scirpi, F. semitectum, F. solani, F. sporotrichoides, F. langsethiae, F. subglutinans, F. tricinctum, F. verticillioides and others but also by Aspergillus spec., Penicillium spec., Claviceps purpurea, Stachybotrys spec. and others.
The various aspects of the invention will now be illustrated with reference to the following tables I, II and III of compound examples and the following preparation or efficacy examples.
The following tables I, II and III illustrate in a non-limiting manner examples of compounds according to the invention.
In the following tables, M+H (or M−H) means the molecular ion peak, plus or minus 1 a.m.u. (atomic mass unit) respectively, as observed in mass spectroscopy and M (Apcl+) means the molecular ion peak as it was found via positive atmospheric pressure chemical ionisation in mass spectroscopy.
[b]Measurement was done at pH 2.3 with 0.1% phosphoric acid and acetonitrile as eluent.
[c]Measurement with LC-MS was done at pH 7.8 with 0.001 molar ammonium hydrogen carbonate solution in water as eluent with a linear
The double bond geometry of C═Y of the following compounds of table II is double bond either (a mixture of E, Z-isomers or double bond geometry not specified):
[b]Measurement was done at pH 2.3 with 0.1% phosphoric acid and acetonitrile as eluent.
[c]Measurement with LC-MS was done at pH 7.8 with 0.001 molar ammonium hydrogen carbonate solution in water as eluent with a linear gradient from 10% acetonitrile to 95 % acetonitrile.
Formula (III1) Whereas W represents a saturated or unsaturated, aromatic or non-aromatic 4-, 5-, 6- or 7-membered heterocycle comprising up to four heteroatoms which may be the same or different
[b]Measurement was done at pH 2.3 with 0.1% phosphoric acid and acetonitrile as eluent.
[c]Measurement with LC-MS was done at pH 7.8 with 0.001 molar ammonium hydrogen carbonate solution in water as eluent with a linear gradient from 10% acetonitrile to 95% acetonitrile.
The following examples illustrate in a non-limiting manner the preparation and efficacy of the compounds of formulas (II) to (IV) according to the invention.
150 mg of ethyl 3-[3-(dimethylamino)prop-2-enoyl]pyridine-2-carboxylate (0.6 mmol), 138 mg of 1-(6-methoxypyridin-3-yl)guanidine nitrate (0.6 mmol) and 64 mg of sodium carbonate (0.6 mmol) were stirred for 8 hours at reflux in 3.38 ml of 2-methoxyethanol. After cooling water was added and the precipitate was filtered and dried to yield 65 mg of ethyl 4-{2-[(6-methoxypyridin-3-yl)amino]-pyrimidin-4-yl}pyridine-2-carboxylate (yield=53%) [M+1]=352.
20.22 g (0.157 mol) of 4-amino-2-chloropyridine were diluted in triethylamine (67 ml) and dichloromethane (600 ml) at 0-5° C. 47 g of Mercury(II) chloride (0.173 mol) and 50.24 g (0.173 mol) of N,N′-bis(boc)-S-methyl-isothiourea were added to the reaction mixture, which was then stirred at room temperature for 4 days, filtered on a fritted funnel, concentrated in vacuo and chromatographed on silica (Heptane90/AcOEt10) to yield 43.67 g of di-tert-butyl {(Z)-[(2-chloropyridin-4-yl)amino]methylylidene}biscarbamate (yield=71%). [M+1]=371
To a solution of 43.67 g (0.117 mol) of di-tert-butyl {(Z)-[(2-chloropyridin-4-yl)amino]methylylidene}biscarbamate in dichloromethane (800 ml) at room temperature were added 81.64 ml of trifluoroacetic acid (1.06 mol). The reaction mixture was stirred at room temperature for 2 days, concentrated in vacuo, triturated with 100 ml of pentane, and upon standing crystallized to yield 51.68 g of 1-(2-chloropyridin-4-yl)guanidine bis(trifluoroacetate) (yield=99%). [M+1-2*CF3CO2H]=171
To a solution of 6.32 g of 1-(2-chloropyridin-4-yl)-3-(dimethylamino)prop-2-en-1-one (30 mmol) in 60 ml of 2-Propanol was added 2.52 g of sodium hydroxide (63 mmol) and 11.96 g of 1-(2-chloropyridin-4-yl)guanidine bis(trifluoroacetate) (30 mmol). The reaction mixture was heated to reflux under stirring for 20 h. After filtration, the precipitate was washed with 100 ml of n-butanol and 120 ml of i-Pr2O and then air-dried to yield 4.69 g of N,4-bis(2-chloropyridin-4-yl)pyrimidin-2-amine (yield=37%). [M+1]=318
200 mg of N,4-bis(2-chloropyridin-4-yl)pyrimidin-2-amine (0.63 mmol), 111 mg of N-Methyl-N-ethylamine (1.89 mmol), 166 mg of molybdenum hexacarbonyl (0.631 mmol), 0.282 ml of 1,8-Diazabicyclo(5.4.0)undec-7-ene (1.89 mmol) and 72.9 mg (0.063 mmol) of Tetrakis(triphenylphosphine)palladium(0) were diluted in 5 ml of N,N-dimethylformamide. The reaction mixture was stirred at 100° C. for 5 hours. After cooling, 10 ml of a saturated NH4Cl was added and the mixture was extracted with 5 ml of dichloromethane. After evaporation of the solvent the crude product was chromatographed on silica (dichloromethane/ethanol) to yield 58 mg of 4-{2-[(2-chloropyridin-4-yl)amino]pyrimidin-4-yl}-N-ethyl-N-methylpyridine-2-carboxamide (yield=22%) [M+1]=479 and 130 mg of N-ethyl-4-[2-({2-[ethyl(methyl)carbamoyl]pyridin-4-yl}amino)pyrimidin-4-yl]-N-methylpyridine-2-carboxamide (yield=44%) [M+1]=420.
To a solution of 24.5 g (93.4 mmol) 4-iodopyridine-2-carboxylic acid in 600 ml dichloromethane was added under an argon atmosphere 34 ml (197 mmol) N,N-diisopropylethylamine. After cooling to 0° C. 12.7 ml (103 mmol) 2,2-dimethylpropionylchloride was added dropwise and stirred for 1 h at ° C. followed by the dropwise addition of 20.3 ml (197 mmol) diethylamine. Stirring was continued for 1 hour at 0° C. and 1 hour at room temperature. Then 300 ml water was added and the aqueous phase extracted additional two times with 100 ml dichloromethane. The combined organic layers were dried and the solvent was removed in vacuo. The crude product was purified by chromatography on silica (heptane/ethyl acetate) to yield 23.4 g N,N-diethyl-4-iodopyridine-2-carboxamide (yield=72%) [M+1]=305.
5 g (16.44 mmol) of N,N-diethyl-4-iodopyridine-2-carboxamide (obtained from step 1) was dissolved under an argon atmosphere in 40 ml of 1,4-dioxane followed by the addition of 19.075 g (32.88 mmol) hexabutylditin and 0.577 g (0.822 mmol) dichlorobis(triphenylphosphine)palladium(II). The mixture was refluxed for 3 hours. After cooling the suspension was passed through a 10 g silica cartridge, the cartridge was rinsed with 10 ml 1,4-dioxane and the solvent was removed in vacuo. The crude product was purified by chromatography on silica (heptane/ethyl acetate) to yield 4.27 g of N,N-diethyl-4-(tributylstannyl)pyridine-2-carboxamide (yield=55%) [M+1]=468.
A solution of 2.5 g (5.35 mmol) N,N-diethyl-4-(tributylstannyl)pyridine-2-carboxamide (obtained from step 2) in 18 ml 1,4-dioxane was placed in a 20 ml microwave tube followed by the addition of 1.03 g (7 mmol) 2,4-dichloropyrimidine and 0.62 g (0.535 mmol) Tetrakis(triphenylphosphine)palladium(0). The mixture was microwaved in a Biotage Optimizer at 150° C. for 20 minutes. After cooling 20 ml of dichloromethane was added, the resulting suspension was filtrated and the filtrate was concentrated in vacuo. To the obtained residue was added 50 ml of saturated potassium fluoride solution and stirred for 15 min followed by the extraction with ethyl acetate. The combined organic layers were dried, evaporated and the crude product was purified by chromatography on silica (heptane/ethyl acetate) followed by chromatography on silica (dichloromethane/acetone) to yield 400 mg 4-(2-chloropyrimidin-4-yl)-N,N-diethylpyridine-2-carboxamide (yield=25%). [M+1]=291.
Under an argon atmosphere 1 g (5.4 mmol) 5-tert-butylthiophene-2-carboxylic acid was dissolved in 10 ml of tert-butanol. After the addition of 1.54 g (5.4 mmol) diphenylphosphoroazidate and of 0.76 ml (5.4 mmol) triethylamine the resulting mixture was refluxed for 6 hours followed by stirring at 50° C. for 16 hours. After cooling 50 ml of water was added and the mixture was extracted 3 times with 10 ml of ethyl acetate. The combined organic layers were dried and after evaporation of the solvent the crude product was purified by chromatography on silica (heptane/ethyl acetate) to yield 415 mg of tert-butyl (5-tert-butyl-2-thienyl)carbamate (yield=30%).
To a solution of 105 mg (0.41 mmol) tert-butyl (5-tert-butyl-2-thienyl)carbamate (obtained from step 4) in 3 ml of 1,4-dioxane were added 100 mg (0.34 mmol) 4-(2-chloropyrimidin-4-yl)-N,N-diethylpyridine-2-carboxamide (obtained from step 3) and 98 mg (0.51 mmol) 4-toluenesulfonic acid monohydrate and refluxed for 20 hourss. After cooling 3 ml of water was added and the mixture was extracted 3 times with 3 ml of dichloromethane. The combined organic layers were dried and after evaporation of the solvent the crude product was purified by chromatography on silica to yield 60 mg of 4-{2-[(5-tert-butyl-2-thienyl)amino]pyrimidin-4-yl}-N,N-diethylpyridine-2-carboxamide (yield=41%) [M+1]=410.
A solution of 1 g (2.05 mmol) N,N-diethyl-4-(tributylstannyl)pyridine-2-carboxamide (obtained from step 2 compound A-39) in 8 ml 1,4-dioxane was placed in a 10 ml microwave tube followed by the addition of 435 mg (2.67 mmol) 2,4-dichloro-5-methylpyrimidine and 0.23 g (0.2 mmol) Tetrakis(triphenylphosphine)palladium(0). The mixture was microwaved in a Biotage Optimizer at 150° C. for 20 minutes. After cooling 10 ml of dichloromethane was added, the resulting suspension was filtrated and the filtrate was concentrated in vacuo. To the obtained residue was added 20 ml of saturated potassium fluoride solution and stirred for 15 min followed by the extraction with ethyl acetate. The combined organic layers were dried, evaporated and the crude product was purified by chromatography on silica (heptane/ethyl acetate) to yield 400 mg of 4-(2-chloro-5-methylpyrimidin-4-yl)-N,N-diethylpyridine-2-carboxamide (yield=30%) [M+1]=306.
To a solution of 60 mg (0.2 mmol) 4-(2-chloro-5-methylpyrimidin-4-yl)-N,N-diethylpyridine-2-carboxamide (obtained from step 1) in 3 ml of 1,4-dioxane were added 144 mg (0.76 mmol) thiophen-3-ylamine oxalic acid salt and 21 mg (0.11 mmol) 4-toluenesulfonic acid monohydrate and refluxed for 10 days. After cooling 3 ml of water was added and the mixture was extracted 3 times with 3 ml of dichloromethane. The combined organic layers were washed succesively with 2 ml of 1M NaOH, 2 ml of 1M HCl and brine. After evaporation of the solvent the crude product was purified by prep hplc to yield 3 mg of N,N-diethyl-4-[5-methyl-2-(3-thienylamino)pyrimidin-4-yl]pyridine-2-carboxamide (yield=4%) [M+1]=368.
To a solution of 70 g of N-(3-chlorophenyl)-4-(2-chloropyridin-4-yl)-1,3,5-triazin-2-amine (prepared as described in WO 2005/033095) in 350 ml of N,N-dimethylformamide were added under argon 38.75 g (330 mmol) zink cyanide and 50.85 g (44 mmol) Tetrakis(triphenylphosphine)palladium(0). The mixture was heated for 3 hours at 100° C. After cooling the resulting slurry was filtered, the precipitate was washed with N,N-dimethylformamide and the combined filtrates were evaporated. The remaining solid was recrystallized from dichloromethane yielding 54.39 g of 4-{4-[(3-chlorophenyl)amino]-1,3,5-triazin-2-yl}pyridine-2-carbonitrile (yield=80%) [M+1]=310.
To 130 ml of tetrahydrofuran was added 26 ml of a 3 M solution of methylmagnesium bromide in toluene and cooled to 0° C. Then 8 g (26 mmol) of 4-{4-[(3-chlorophenyl)amino]-1,3,5-triazin-2-yl}pyridine-2-carbonitrile was added in small portions and stirring was continued for 3 hours at 0° C. After warming to room temperature stirring was continued for 4 hours. Then 120 ml of 1N HCl was added and the mixture was extracted with ethyl acetate. The combined organic phases were dried and evaporated to yield 8.13 g of 1-(4-{4-[(3-chlorophenyl)amino]-1,3,5-triazin-2-yl}pyridin-2-yl)ethanone (yield=96%) [M+1]=327.
50 mg (0.15 mmol) of 1-(4-{4-[(3-chlorophenyl)amino]-1,3,5-triazin-2-yl}pyridin-2-yl)ethanone, 26 mg (0.3 mmol) of O-methylhydroxylamine hydrochloride and 26 mg (0.31 mmol) sodium acetate dissolved in 3 ml ethanol were stirred at reflux for 6 hours. After cooling the solvent was evaporated in vacuo and 5 ml of water was added. The solid was filtrated, washed with water and dried to yield 21 mg of N-(3-chlorophenyl)-4-{2-[(1E)-N-methoxyethanimidoyl]pyridin-4-yl}-1,3,5-triazin-2-amine (yield=35%) [M+1]=356.
To a solution of 200 mg (0.62 mmol) 1-(4-{4-[(3-chlorophenyl)amino]-1,3,5-triazin-2-yl}pyridin-2-yl)ethanone, 0.028 ml (0.49 mmol) acetic acid and 51 mg (0.62 mmol) sodium acetate in 2 ml methanol was added 52 mg (0.62 mmol) of 3-hydrazinylpropanenitrile dissolved in 2 ml of methanol and stirred at reflux for 2 hours and at room temperature overnight. The solvent was evaporated in vacuo and 30 ml of water was added. The mixture was extracted with dichloromethane, the combined organic phases were dried and evaporated to yield 1280 mg of 3-{2-[1-(4-{4-[(3-chlorophenyl)amino]-1,3,5-triazin-2-yl}pyridin-2-yl)ethylidene]hydrazinyl}propanenitrile (yield=53%) [M+1]=394.
A solution of 1.5 g (4.86 mmol) of 4-{4-[(3-chlorophenyl)amino]-1,3,5-triazin-2-yl}pyridine-2-carbonitrile, 675 mg (9.7 mmol) hydroxylamine hydrochloride and 1.34 g (9.7 mmol) potassium carbonate dissolved in 20 ml ethanol was stirred at room temperature for 5 hours. After evaporation of the solvent water was added and the remaining solid was filtered and dried to yield 1.566 g of 4-{4-[(3-chlorophenyl)amino]-1,3,5-triazin-2-yl}-N′-hydroxypyridine-2-carboximidamide (yield=94%) [M+1]=343.
A solution of 200 mg (0.58 mmol) of 4-{4-[(3-chlorophenyl)amino]-1,3,5-triazin-2-yl}-N′-hydroxypyridine-2-carboximidamide, 63 mg (0.58 mmol) methoxyacetyl chloride and 49 mg (0.58 mmol) sodium bicarbonate dissolved in 5 ml acetone was stirred at room temperature for 16 hours. After evaporation of the solvent 30 ml of water was added and the remaining solid was filtered and dried to yield 145 mg of 4-{4-[(3-chlorophenyl)amino]-1,3,5-triazin-2-yl}-N′-[(methoxyacetyl)oxy]pyridine-2-carboximidamide (yield=60%) [M+1]=415.
A solution of 200 mg (0.65 mmol) 4-{4-[(3-chlorophenyl)amino]-1,3,5-triazin-2-yl}pyridine-2-carbonitrile, 126 mg (1.3 mmol) O-ethylhydroxylamine hydrochloride and 179 mg 1.3 mmol) potassium carbonate dissolved in 20 ml ethanol was stirred at 70° C. for 5 hours. After cooling and evaporation of the solvent water was added and the remaining solid was filtered and dried to yield 178 mg of 4-{4-[(3-chlorophenyl)amino]-1,3,5-triazin-2-yl}pyridine-2-carboximidoate (yield=74%) [M+1]=356.
To a solution of 3 g (9.7 mmol) of 4-{4-[(3-chlorophenyl)amino]-1,3,5-triazin-2-yl}pyridine-2-carbonitrile in 60 ml of ethanol was added 1.166 g (29.1 mmol) sodium hydroxide dissolved in 35 ml water. The mixture was heated at reflux for 2 hours. After cooling water was added and the mixture acidified with 1 N HCl. The precipitate which formed was filtered, washed with water and dried to yield 2.6 g of 4-{4-[(3-chlorophenyl)amino]-1,3,5-triazin-2-yl}pyridine-2-carboxylic acid (yield=81%) [M+1]=329
To a solution of 500 mg (1.53 mmol) of 4-{4-[(3-chlorophenyl)amino]-1,3,5-triazin-2-yl}pyridine-2-carboxylic acid dissolved in 6 ml of dimethylformamide were added 463 mg (4.58 mmol) triethylamine, 212 mg (3.05 mmol) hydroxylamine hydrochloride and 696 mg (1.83 mmol) O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetra-methyluronium hexafluorophosphate. The mixture was stirred at room temperature for 16 hours. After addition of water the mixture was extracted with dichloromethane and the organic layer was washed successively with 1 N HCl, saturated sodium bicarbonate and saturated lithium chloride solution. After evaporation of the solvent the residue was stirred with methanol, filtered and dried to yield 165 mg of 4-{4-[(3-chlorophenyl)amino]-1,3,5-triazin-2-yl}-N-hydroxypyridine-2-carboxamide (yield=29%) [M+1]=344.
To 130 mg (0.28 mmol) of N-ethyl-N-methyl-4-(4-{[3-(pentafluoro-lambda6-sulfanyl)phenyl]amino}-1,3,5-triazin-2-yl)pyridine-2-carboxamide dissolved in 5 ml of toluene was added 31.4 mg (0.14 mmol) of phosphorous pentasulfide. The reaction mixture was stirred under reflux for two hours, then 2 ml of water were added and the reaction mixture was stirred at 100° C. for one hour. After cooling, water was removed by filtration on solid-phase extraction cartridge. After rinsing of the cartridge with 3 ml of toluene, the filtrate was purified by chromatography on silica (dichloromethane/ethanol) to yield 55 mg of N-ethyl-N-methyl-4-(4-{[3-(pentafluoro-lambda6-sulfanyl)phenyl]amino}-1,3,5-triazin-2-yl)pyridine-2-carbothioamide (yield=41%) [M+1]=477.
118 mg (0.71 mmol) of lithium hexamethyldisilazane were added to 263 mg (0.64 mmol) of 4-(4-anilino-1,3,5-triazin-2-yl)-N-(cyclopropylmethyl)-N-methylpyridine-2-carbothioamide (prepared analogously to compound B-253) dissolved in 5 ml anhydrous tetrahydrofuran. After stirring for 30 minutes 55 mg (0.71 mmol) of acetyl chloride was added and stirring continued for 20 hours. 5 ml of water were then added and the organic phase is filtered through a Chemelute cartridge. Dichloromethane ifollowed by ethyl acetate were used to rinse the cartridge and the concentrated organic phases are purified on a silica gel column (ethyl acetate/dichloromethane) followed by prep rp-hplc to give 110 mg of N-(4-{2-[(cyclopropylmethyl)(methyl)carbamothioyl]pyridin-4-yl}-1,3,5-triazin-2-yl)-N-phenylacetamide (yield=39%) [M+1]=419.
371 mg (2.22 mmol) of lithium hexamethyldisilazane were added to 400 mg (1.11 mmol) of 4-(4-anilino-1,3,5-triazin-2-yl)-N-(cyclopropylmethyl)-N-methylpyridine-2-carboxamide (prepared analogously to compound C-2) dissolved in 5 ml anhydrous tetrahydrofuran. After stirring for 30 minutes 330 mg (2.22 mmol) of 3-bromoprop-1-yne was added and stirring continued for 20 hours. 4 ml of water were then added and the organic phase is filtered through a Chemelute cartridge. Dichloromethane is used to rinse the cartridge and the concentrated organic phases are purified on a silica gel column (ethyl acetate/dichloromethane) to give 180 mg of N-(cyclopropylmethyl)-N-methyl-4-{4-[phenyl(prop-2-yn-1-yl)amino]-1,3,5-triazin-2-yl}pyridine-2-carboxamide (yield=26%) [M+1]=399.
To a solution of 3.406 g (15 mmol) of 2-chloro-4-(2-chloropyridin-4-yl)-1,3,5-triazine (prepared as described in WO 2001/25220) and of 1.862 g (15 mmol) 6-methoxypyridin-3-amine in 250 ml of acetonitrile was added 2.073 g (15 mmol) of potassium carbonate. The reaction mixture was stirred for 3 days. After evaporation of the solvent the residue was treated with water, filtrated and dried to yield 4.0 g of 4-(2-chloropyridin-4-yl)-N-(6-methoxypyridin-3-yl)-1,3,5-triazin-2-amine (yield=84%) [M+1]=316.
300 mg of 4-(2-chloropyridin-4-yl)-N-(6-methoxypyridin-3-yl)-1,3,5-triazin-2-amine (0.95 mmol), 243 mg of piperidine (2.86 mmol), 252 mg of molybdenum hexacarbonyl (0.95 mmol), 0.427 ml of 1,8-Diazabicyclo(5.4.0)undec-7-ene (2.86 mmol) and 110 mg (0.095 mmol) of Tetrakis(triphenylphosphine)palladium(0) were diluted in 8 ml of N,N-dimethylformamide. The reaction mixture was stirred at 80° C. for 5 hours. After cooling, 10 ml of a saturated ammonium chloride solution was added and the mixture was extracted with 5 ml of dichloromethane. After evaporation of the solvent the crude product was chromatographed on silica (dichloromethane/ethanol) to yield 99 mg of (4-{4-[(6-methoxypyridin-3-yl)amino]-1,3,5-triazin-2-yl}pyridin-2-yl)(piperidin-1-yl)-methanone (yield=26%) [M+1]=393.
To a solution of 5 g (20 mmol) of methyl 4-(4-chloro-1,3,5-triazin-2-yl)pyridine-2-carboxylate (prepared as described in WO 2007/003525) and of 7.55 g (40 mmol) thiophen-3-ylamine oxalic acid salt in 150 ml of acetonitrile was added 5.5 g (40 mmol) of potassium carbonate. The reaction mixture was stirred for 7 hours at room temperature. The resulting suspension was filtered, the precipitate was washed with water followed by acetonitrile and finally diisopropylether to yield 3.7 g of methyl 4-[4-(3-thienylamino)-1,3,5-triazin-2-yl]pyridine-2-carboxylate (yield=58%) [M+1]=314.
2 g (6.38 mmol) of (methyl 4-[4-(3-thienylamino)-1,3,5-triazin-2-yl]pyridine-2-carboxylate
(obtained from step 1) was suspended in 20 ml tetrahydrofuran followed by the addition of 19 ml 1M lithium hydroxide. The mixture was stirred at room temperature for 30 minutes and then the tetrahydrofuran was evaporated. The resulting aqueous solution was kept overnight whereas a precipitate was formed which was removed by filtration. The filtrate was acidified to pH 2 with 2 N HCl. The precipitate formed was filtrated and dried to yield 1.9 g of 4-[4-(3-thienylamino)-1,3,5-triazin-2-yl]pyridine-2-carboxylic acid (yield=97%) [M+1]=300.
To a solution of 200 mg (0.67 mmol) of 4-[4-(3-thienylamino)-1,3,5-triazin-2-yl]pyridine-2-carboxylic acid (obtained from step 2) dissolved in 7 ml of dimethylformamide were added 203 mg (2 mmol) triethylamine, 130 mg (1.34 mmol) N,O-dimethylhydroxylamine hydrochloride and 305 mg (0.8 mmol) 0-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetra-methyluronium hexafluorophosphate. The mixture was stirred at room temperature for 22 hours. After addition of water the mixture was extracted with dichloromethane and the organic layer was washed successively with 1 N HCl, saturated sodium bicarbonate and brine. After drying the solvent was to evaporated to yield 195 mg of N-methoxy-N-methyl-4-[4-(3-thienylamino)-1,3,5-triazin-2-yl]pyridine-2-carboxamide (yield=81%) [M+1]=343.
The active ingredients tested are prepared by homogenization in a mixture of acetone/Tween/DMSO, then diluted with water to obtain the desired active material concentration.
Cabbage plants (Eminence variety) in starter cups, sown on a 50/50 peat soil-pozzolana substrate and grown at 18-20° C., are treated at the cotyledon stage by spraying with the aqueous suspension described above.
Plants, used as controls, are treated with an aqueous solution not containing the active material. After 24 hours, the plants are contaminated by spraying them with an aqueous suspension of Peronospora parasitica spores (50 000 spores per ml). The spores are collected from infected plant.
The contaminated cabbage plants are incubated for 5 days at 20° C., under a humid atmosphere. Grading is carried out 5 days after the contamination, in comparison with the control plants. Under these conditions, good (at least 70%) or total protection is observed at a dose of 500 ppm with the following compounds: A5, All, B2, B6, B20, B27, B64, B76, B111, B116, B119, B123, B127, B129, B130, B132, B133, B134, B135, B139, B150, B151, B152, B156, B157, B158, B162, B163, B164, B165, B169, B170, B172, B173, B179, B180, B181, B186, B222, B236, B238, B239, B244, B254, B256, B258, B260, B268, B316, C2, C16.
The active ingredients tested are prepared by homogenization in a mixture of acetone/Tween/DMSO, then diluted with water to obtain the desired active material Gherkin plants (Vert petit de Paris variety), sown on a 50/50 peat soil-pozzolana substrate in starter cups and grown at 18-20° C., are treated at the cotyledon Z11 stage by spraying with the active ingredient prepared as described above.
Plants, used as controls, are treated with an aqueous solution not containing the active material. After 24 hours, the plants are contaminated by depositing drops of an aqueous suspension of Botrytis cinerea spores (150,000 spores per ml) on upper surface of the leaves. The spores are collected from a 15-day-old culture and are suspended in a nutrient solution composed of:
The contaminated cucumber plants are settled for 5/7 days in a climatic room at 15-11° C. (day/night) and at 80% relative humidity.
Grading is carried out 5/7 days after the contamination, in comparison with the control plants. Under these conditions, good (at least 70%) or total protection is observed at a dose of 500 ppm with the following compounds: A13, A15, A25, A26, A27, A29, A30, A31, A32, B1, B2, B6, B7, B20, B64, B115, B123, B124, B125, B127, B130, B131, B132, B133, B134, B135, B141, B143, B144, B146, B147, B148, B149, B150, B151, B152, B153, B155, B156, B157, B160, B161, B162, B163, B165, B169, B179, B186, B222, B236, B237, B238, B244, B254, B260, B268, B316, C5, C9, C11, C12, C16.
The active ingredients tested are prepared by homogenization in a mixture of acetone/tween/DMSO, then diluted with water to obtain the desired active material.
Radish plants (Pernot variety), sown on a 50/50 peat soil-pozzolana substrate in starter cups and grown at 18-20° C., are treated at the cotyledon stage by spraying with the active ingredient prepared as described above.
Plants, used as controls, are treated with the mixture of acetone/tween/water not containing the active material.
After 24 hours, the plants are contaminated by spraying them with an aqueous suspension of Alternaria brassicae spores (40,000 spores per cm3). The spores are collected from a 12 to 13 days-old culture.
The contaminated radish plants are incubated for 6-7 days at about 18° C., under a humid atmosphere.
Grading is carried out 6 to 7 days after the contamination, in comparison with the control plants. Under these conditions, good protection (at least 70%) is observed at a dose of 500 ppm with the following compounds: B54, B55, B64, B91, B93, B94, B97, B115, B123, B124, B125, B127, B130, B131, B132, B133, B134, B135, B137, B138, B141, B142, B143, B144, B146, B148, B151, B152, B153, B156, B158, B159, B160, B161, B162, B165, B166, B167, B169, B171, B183, B184, B186.
The active ingredients tested are prepared by homogenization in a mixture of acetone/tween/DMSO, then diluted with water to obtain the desired active material.
Gherkin plants (Vert petit de Paris variety) in starter cups, sown on a 50/50 peat soil-pozzolana substrate and grown at 20° C./23° C., are treated at the cotyledon Z10 stage by spraying with the aqueous suspension described above. Plants, used as controls, are treated with an aqueous solution not containing the active material.
After 24 hours, the plants are contaminated by spraying them with an aqueous suspension of Sphaerotheca fuliginea spores (100 000 spores per ml). The spores are collected from a contaminated plants. The contaminated gherkin plants are incubated at about 20° C./25° C. and at 60/70% relative humidity.
Grading (% of efficacy) is carried out 12 days after the contamination, in comparison with the control plants.
Under these conditions, good (at least 70%) or total protection is observed at a dose of 500 ppm with the following compounds: A5, A18, A24, A26, A27, A29, A30, A32, B2, B6, B7, B20, B123, B127, B222, B225, B236, B239, B244, B254, B256, B258, B260, B268, C5, C10.
The active ingredients tested are prepared by homogenization in a mixture of acetone/Tween/DMSO, then diluted with water to obtain the desired active material concentration.
Barley plants (Express variety), sown on a 50/50 peat soil-pozzolana substrate in starter cups and grown at 12° C., are treated at the 1-leaf stage (10 cm tall) by spraying with the active ingredient prepared as described above.
Plants, used as controls, are treated with an aqueous solution not containing the active material. After 24 hours, the plants are contaminated by spraying them with an aqueous suspension of Pyrenophora teres spores (12,000 spores per ml). The spores are collected from a 12-day-old culture. The contaminated barley plants are incubated for 24 hours at about 20° C. and at 100% relative humidity, and then for 12 days at 80% relative humidity.
Grading is carried out 12 days after the contamination, in comparison with the control plants.
Under these conditions, good (at least 70%) is observed at a dose of 500 ppm with the following compounds: A2, All, A17, A29, A30, A32, B1, B2, B6, B7, B20, B34, B36, B37, B38, B40, B41, B43, B45, B74, B75, B76, B77, B81, B82, B85, B105, B110, B111, B113, B115, B116, B123, B124, B125, B126, B127, B128, B129, B130, B131, B132, B133, B134, B135, B137, B139, B140, B141, B142, B143, B144, B145, B146, B147, B148, B149, B150, B151, B152, B153, B155, B156, B157, B158, B159, B160, B161, B162, B163, B164, B165, B166, B167, B169, B170, B171, B172, B173, B179, B180, B181, B183, B184, B186, B192, B207, B222, B237, B238, B239, B244, B252, B254, B256, B258, B260, B268, B316, C2, C4, C5, C7, C8, C9, C10, C11, C12, C16.
The active ingredients tested are prepared by homogenization in a mixture of acetone/tween/DMSO, then diluted with water to obtain the desired active material. Wheat plants (Scipion variety) sown on 50/50 peat soil-pozzolana substrate in starter cups and grown at 12° C., are treated at the 1-leaf stage (10 cm tall) by spraying with the aqueous suspension described above.
Plants, used as controls, are treated with an aqueous solution not containing the active material.
After 24 hours, the plants are contaminated by spraying the leaves with an aqueous suspension of Puccinia recondita spores (100,000 spores per ml). The spores are collected from a 10-day-old contaminated wheat and are suspended in water containing 2.5 ml/l of tween 80 10%. The contaminated wheat plants are incubated for 24 hours at 20° C. and at 100% relative humidity, and then for 10 days at 20° C. and at 70% relative humidity.
Grading is carried out 10 days after the contamination, in comparison with the control plants. Under these conditions, good (at least 70%) or total protection is observed at a dose of 500 ppm with the following compounds: A5, A7, A17, A18, A25, A32, B1, B2, B6, B7, B111, B127, B129, B130, B132, B133, B146, B150, B151, B152, B157, B158, B159, B160, B161, B162, B163, B164, B165, B169, B170, B172, B186, B236, B237, B256, B316, C4, C5, C8, C9, C10, C11, C12, C16.
The active ingredients tested are prepared by homogenization in a mixture of acetone/tween/DMSO, then diluted with water to obtain the desired active material concentration.
Wheat plants (Scipion variety), sown on a 50/50 peat soil-pozzolana substrate in starter cups and grown at 12° C., are treated at the 1-leaf stage (10 cm tall) by spraying with the aqueous suspension described above. Plants, used as controls, are treated with an aqueous solution not containing the active material.
After 24 hours, the plants are contaminated by spraying them with an aqueous suspension of Mycosphaerella graminicola spores (500 000 spores per ml). The spores are collected from a 7-day-old culture. The contaminated wheat plants are incubated for 72 hours at 18° C. and at 100% relative humidity, and then for 21 to 28 days at 90% relative humidity.
Grading (% of efficacy) is carried out 21 to 28 days after the contamination, in comparison with the control plants.
Under these conditions, good (at least 70%) or total protection is observed at a dose of 500 ppm with the following compounds: B1, B2, B33, B45, B46, B48, B64, B75, B76, B81, B85, B95, B113, B114, B116, B118, B123, B124, B125, B126, B127, B129, B132, B133, B134, B135, B137, B146, B151, B157, B166, B186, B192, B194, B195, B197, B226, B227, C12.
To produce a suitable preparation of active compound, 1 part by weight of active compound is mixed with the stated amounts of solvent and emulsifier, and the concentrate is diluted with water to the desired concentration.
To test for preventive activity, young plants are sprayed with a preparation of active compound at the stated rate of application. One day after this treatment, the plants are inoculated with an aqueous spore suspension of Leptosphaeria nodorum. The plants remain for 48 hours in an incubation cabinet at 22° C. and a relative atmospheric humidity of 100%. Then the plants are placed in a greenhouse at a temperature of approximately 22° C. and a relative atmospheric humidity of approximately 90%.
The test is evaluated 7-9 days after the inoculation. 0% means an efficacy which corresponds to that of the control, while an efficacy of 100% means that no disease is observed.
In this test the following compounds according to the invention showed efficacy of 70% or even higher at a concentration of 500 ppm of active ingredient:
To produce a suitable preparation of active compound, 1 part by weight of active compound is mixed with the stated amounts of solvent and emulsifier, and the concentrate is diluted with water to the desired concentration.
To test for protective activity, young plants are sprayed with the preparation of active compound at the stated rate of application. After the spray coating has dried on, the plants are inoculated with an aqueous conidia suspension of the causal agent of apple scab (Venturia inaequalis) and then remain for 1 day in an incubation cabinet at approximately 20° C. and a relative atmospheric humidity of 100%.
The plants are then placed in a greenhouse at approximately 21° C. and a relative atmospheric humidity of approximately 90%.
The test is evaluated 10 days after the inoculation. 0% means an efficacy which corresponds to that of the control, while an efficacy of 100% means that no disease is observed.
In this test the following compounds according to the invention showed efficacy of 70% or even higher at a concentration of 100 ppm of active ingredient:
To produce a suitable preparation of active compound, 1 part by weight of active compound is mixed with the stated amounts of solvent and emulsifier, and the concentrate is diluted with water to the desired concentration.
To test for protective activity, young plants are sprayed with the preparation of active compound at the stated rate of application. After the spray coating has dried on, the plants are inoculated with an aqueous spore suspension of the causal agent of bean rust (Uromyces appendiculatus) and then remain for 1 day in an incubation cabinet at approximately 20° C. and a relative atmospheric humidity of 100%.
The plants are then placed in a greenhouse at approximately 21° C. and a relative atmospheric humidity of approximately 90%.
The test is evaluated 10 days after the inoculation. 0% means an efficacy which corresponds to that of the control, while an efficacy of 100% means that no disease is observed.
In this test the following compounds according to the invention showed efficacy of 70% or even higher at a concentration of 100 ppm of active ingredient:
To produce a suitable preparation of active compound, 1 part by weight of active compound is mixed with the stated amounts of solvent and emulsifier, and the concentrate is diluted with water to the desired concentration.
To test for protective activity, young plants are sprayed with the preparation of active compound at the stated rate of application. One day after spraying, the plants are inoculated with an aqueous spore suspension of the causal agent of rice blast (Pyricularia oryzae). The plants are then placed in an incubator at approximately 25° C. and a relative atmospheric humidity of approximately 100% for 1 day.
The test is evaluated 5 days after the inoculation. 0% means an efficacy which corresponds to that of the control, while an efficacy of 100% means that no disease is observed.
In this test the following compounds according to the invention showed efficacy of 80% or even higher at a concentration of 250 ppm of active ingredient:
To produce a suitable preparation of active compound, 1 part by weight of active compound is mixed with the stated amounts of solvent and emulsifier, and the concentrate is diluted with water to the desired concentration.
To test for protective activity, young plants are sprayed with the preparation of active compound at the stated rate of application. One day after spraying, the plants are inoculated with a hypha of the causal agent of rice sheath blight (Rhizoctonia solani). The plants are then placed in an incubator at approximately 25° C. and a relative atmospheric humidity of approximately 100%.
The test is evaluated 4 days after the inoculation. 0% means an efficacy which corresponds to that of the control, while an efficacy of 100% means that no disease is observed.
In this test the compounds according to the invention of the following structures showed efficacy of 80% or even higher at a concentration of 250 ppm of active ingredient:
To produce a suitable preparation of active compound, 1 part by weight of active compound is mixed with the stated amounts of solvent and emulsifier, and the concentrate is diluted with water to the desired concentration.
To test for protective activity, young plants are sprayed with the preparation of active compound at the stated rate of application. One day after spraying, the plants are inoculated with an aqueous spore suspension of the causal agent of rice brown spot (Cochliobolus miyabeanus). The plants are then placed in an incubator at approximately 25° C. and a relative atmospheric humidity of approximately 100% for 1 day.
The test is evaluated 4 days after the inoculation. 0% means an efficacy which corresponds to that of the control, while an efficacy of 100% means that no disease is observed.
In this test the following compounds according to the showed efficacy of 80% or even higher at a concentration of 250 ppm of active ingredient:
To produce a suitable preparation of active compound, 1 part by weight of active compound is mixed with the stated amounts of solvent and emulsifier, and the concentrate is diluted with water to the desired concentration.
To test for protective activity, young plants are sprayed with the preparation of active compound at the stated rate of application. One day after spraying, the plants are inoculated with an aqueous spore suspension of the causal agent of soybean rust (Phakopsora pachyrhizi). The plants are then placed in a greenhouse at approximately 20° C. and a relative atmospheric humidity of approximately 80%.
The test is evaluated 11 days after the inoculation. 0% means an efficacy which corresponds to that of the control, while an efficacy of 100% means that no disease is observed.
In this test the following compounds according to the showed efficacy of 80% or even higher at a concentration of 500 ppm of active ingredient:
To produce a suitable preparation of active compound, 1 part by weight of active compound or active compound combination is mixed with the stated amounts of solvent and emulsifier, and the concentrate is diluted with water to the desired concentration.
To test for preventive activity, young plants are sprayed with the preparation of active compound or active compound combination at the stated rate of application. After the spray coating has dried on, the plants are sprayed with a spore suspension of Fusarium nivale (var. majus). The plants are placed in a greenhouse under translucent incubation cloches at a temperature of approximately 10° C. and a relative atmospheric humidity of approximately 100%.
The test is evaluated 5 days after the inoculation. 0% means an efficacy which corresponds to that of the control, while an efficacy of 100% means that no disease is observed.
In this test the following compounds according to the invention showed an efficacy of 70% or even higher at a concentration of 1000 ppm of active ingredient:
To produce a suitable preparation of active compound, 1 part by weight of active compound or active compound combination is mixed with the stated amounts of solvent and emulsifier, and the concentrate is diluted with water to the desired concentration.
To test for preventive activity, young plants are sprayed with the preparation of active compound or active compound combination at the stated rate of application. After the spray coating has dried on, the plants are sprayed with a spore suspension of Puccinia triticina. The plants remain for 48 hours in an incubation cabinet at approximately 20° C. and a relative atmospheric humidity of approximately 100%. The plants are placed in a greenhouse at a temperature of approximately 20° C. and a relative atmospheric humidity of approximately 80%.
The test is evaluated 8 days after the inoculation. 0% means an efficacy which corresponds to that of the control, while an efficacy of 100% means that no disease is observed.
In this test the following compounds according to the invention showed an efficacy of 70% or even higher at a concentration of 1000 ppm of active ingredient:
| Number | Date | Country | Kind |
|---|---|---|---|
| 08356139.9 | Nov 2008 | EP | regional |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/EP09/65018 | 11/12/2009 | WO | 00 | 5/12/2011 |
