Patent Application
20200181117
The invention relates to the technical field of crop protection agents, in particular that of herbicides for the selective control of broad-leaved weeds and weed grasses in crops of useful plants.
Specifically, the present invention relates to substituted 3-heteroaryloxy-1H-pyrazoles and salts thereof, to processes for their preparation and to their use as herbicides.
In their application, crop protection agents known to date for the selective control of harmful plants in crops of useful plants or active compounds for controlling unwanted vegetation sometimes have disadvantages, be it (a) that they have no or else insufficient herbicidal activity against particular harmful plants, (b) that the spectrum of harmful plants which can be controlled with an active compound is not wide enough, (c) that their selectivity in crops of useful plants is too low and/or (d) that they have a toxicologically unfavorable profile. Furthermore, some active compounds which can be used as plant growth regulators for a number of useful plants cause unwanted reduced harvest yields in other useful plants or are not compatible with the crop plant, or only within a narrow application rate range. Some of the known active compounds cannot be produced economically on an industrial scale owing to precursors and reagents which are difficult to obtain, or they have only insufficient chemical stabilities. In the case of other active compounds, the activity is too highly dependent on environmental conditions, such as weather and soil conditions.
The herbicidal activity of these known compounds, in particular at low application rates, and/or their compatibility with crop plants remain in need of improvement.
Various documents describe substituted heteroaryloxypyrazoles. JP2002/348280 and J. Pestic. Sci. 2004, 29, 96-104 describe heteroaryloxypyrazoles as herbicides that are substituted by carbamoyl or acylamino radicals in the 4 position of the pyrazole. JP07285962 names heteroaryloxypyrazoles specifically substituted by hydrogen or halogen in the 3 position of the pyrazole and claims them as herbicides. WO2002/066439 names heteroaryloxypyrazoles specifically substituted by carbamoyl radicals in the 1 position of the pyrazole and claims them as herbicides. WO2016/124769 names heteroaryloxypyrazoles specifically substituted by alkynyl radicals in the 1 position of the pyrazole and claims them as nitrification inhibitors. WO2003/144309 names heteroaryloxypyrazoles specifically substituted by aminopyridines or aminopyrimidines in the 4 position of the pyrazole and claims them as protein kinase inhibitors with pharmaceutical uses. JP2000/095778 names heteroaryloxypyrazoles specifically substituted by imidazoles and 1,2,4-triazoles in the 4 position of the pyrazole and claims them as fungicides.
By contrast, there has been no description to date of substituted 3-heteroaryloxy-1H-pyrazoles or salts thereof as herbicidal active compounds.
It has now been found that, surprisingly, substituted 3-heteroaryloxy-1H-pyrazoles or salts thereof are particularly suitable as herbicidal active compounds.
The present invention thus provides substituted 3-heteroaryloxy-1H-pyrazoles of the general formula (I) or salts thereof
in which
The compounds of the general formula (I) can form salts by addition of a suitable inorganic or organic acid, for example mineral acids, for example HCl, HBr, H2SO4, H3PO4 or HNO3, or organic acids, for example carboxylic acids such as formic acid, acetic acid, propionic acid, oxalic acid, lactic acid or salicylic acid or sulfonic acids, for example p-toluenesulfonic acid, onto a basic group, for example amino, alkylamino, dialkylamino, piperidino, morpholino or pyridino. In such a case, these salts comprise the conjugated base of the acid as the anion. Suitable substituents in deprotonated form, for example sulfonic acids, particular sulfonamides or carboxylic acids, are capable of forming internal salts with groups, such as amino groups, which are themselves protonatable. Salts may also be formed by action of a base on compounds of the general formula (I). Suitable bases are, for example, organic amines such as trialkylamines, morpholine, piperidine and pyridine, and the hydroxides, carbonates and bicarbonates of ammonium, alkali metals or alkaline earth metals, especially sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate. These salts are compounds in which the acidic hydrogen is replaced by an agriculturally suitable cation, for example metal salts, especially alkali metal salts or alkaline earth metal salts, in particular sodium and potassium salts, or else ammonium salts, salts with organic amines or quaternary ammonium salts, for example with cations of the formula [NRaRbRcRd]+ in which Ra to Rd are each independently an organic radical, especially alkyl, aryl, arylalkyl or alkylaryl. Also suitable are alkylsulfonium and alkylsulfoxonium salts, such as (C1-C4)-trialkylsulfonium and (C1-C4)-trialkylsulfoxonium salts.
The inventive substituted arylpyrazoles of the general formula (I) can, depending on external conditions such as pH, solvent and temperature, be present in various tautomeric structures, all of which are embraced by the general formula (I).
The compounds of the formula (I) used in accordance with the invention and salts thereof are referred to hereinafter as “compounds of the general formula (I)”.
The invention preferably provides compounds of the general formula (I) in which
R1 represents hydrogen, (C1-C8)-alkyl, (C1-C8)-haloalkyl, (C1-C8)-cyanoalkyl, (C1-C8)-hydroxyalkyl, (C1-C6)-alkoxy-(C1-C6)-alkyl, (C1-C6)-haloalkoxy-(C1-C6)-alkyl, (C1-C6)-alkylthio-(C1-C6)-alkyl, (C1-C6)-alkylsulfinyl-(C1-C6)-alkyl, (C1-C6)-alkylsulfonyl-(C1-C6)-alkyl, (C1-C6)-cycloalkylthio-(C1-C6)-alkyl, (C1-C6)-cycloalkylsulfinyl-(C1-C6)-alkyl, (C1-C6)-cycloalkylsulfonyl-(C1-C6)-alkyl, aryl-(C1-C6)-alkyl, heteroaryl-(C1-C6)-alkyl, heterocyclyl-(C1-C6)-alkyl, (C3-C8)-cycloalkyl, (C3-C6)-cycloalkyl-(C1-C6)-alkyl, (C3-C6)-halocycloalkyl, (C3-C6)-halocycloalkyl-(C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-haloalkenyl, tris-[(C1-C6)-alkyl]silyl-(C2-C6)-alkynyl, carboxyl, carboxyl-(C1-C6)-alkyl, (C1-C8)-alkylcarbonyl, (C1-C8)-haloalkylcarbonyl, (C3-C8)-cycloalkylcarbonyl, (C1-C8)-alkoxycarbonyl, (C2-C8)-haloalkoxycarbonyl, (C3-C8)-cycloalkoxycarbonyl, (C2-C8)-alkylaminocarbonyl, (C3-C10)-dialkylaminocarbonyl, (C3-C10)-cycloalkylaminocarbonyl, (C1-C8)-alkoxycarbonyl-(C1-C6)-alkyl, (C2-C8)-haloalkoxycarbonyl-(C1-C6)-alkyl, (C3-C8)-cycloalkoxycarbonyl-(C1-C6)-alkyl, (C2-C8)-alkylaminocarbonyl-(C1-C6)-alkyl, (C3-C10)-dialkylaminocarbonyl-(C1-C6)-alkyl, (C3-C10)-cycloalkylaminocarbonyl-(C1-C6)-alkyl, (C1-C8)-alkylcarbonyloxy-(C1-C4)-alkyl, (C1-C8)-alkoxycarbonyloxy-(C1-C4)-alkyl, (C3-C6)-cycloalkoxycarbonyloxy-(C1-C4)-alkyl, (C1-C6)-alkylsulfonyl, (C1-C6)-haloalkylsulfonyl, arylsulfonyl, phthalimidomethyl,
The invention more preferably provides compounds of the general formula (I) in which
The invention likewise further preferably provides compounds of the general formula (I) in which
The invention most preferably provides compounds of the general formula (I) in which
The abovementioned general or preferred radical definitions apply both to the end products of the general formula (I) and, correspondingly, to the starting materials or the intermediates required in each case for the preparation. These radical definitions can be combined with one another as desired, i.e. including combinations between the given preferred ranges.
Primarily for reasons of higher herbicidal activity, better selectivity and/or better producibility, inventive compounds of the abovementioned general formula (I) or their salts or their use according to the invention are of particular interest in which individual radicals have one of the preferred meanings already specified or specified below, or in particular those in which one or more of the preferred meanings already specified or specified below occur in combination.
With regard to the compounds according to the invention, the terms used above and further below will be elucidated. These are familiar to the person skilled in the art and especially have the definitions elucidated hereinafter:
Unless defined differently, names of chemical groups are generally to be understood such that attachment to the skeleton or the remainder of the molecule is via the structural element mentioned last, i.e. for example in the case of (C2-C8)-alkenyloxy via the oxygen atom and in the case of heterocyclyl-(C1-C8)-alkyl or R12O(O)C—(C1-C8)-alkyl in each case via the carbon atom of the alkyl group.
According to the invention, “alkylsulfonyl”—alone or as part of a chemical group—refers to straight-chain or branched alkylsulfonyl, preferably having 1 to 8 or 1 to 6 carbon atoms, for example (but not limited to) (C1-C6)-alkylsulfonyl such as methylsulfonyl, ethylsulfonyl, propylsulfonyl, 1-methylethylsulfonyl, butylsulfonyl, 1-methylpropylsulfonyl, 2-methylpropylsulfonyl, 1,1-dimethylethylsulfonyl, pentylsulfonyl, 1-methylbutylsulfonyl, 2-methylbutylsulfonyl, 3-methylbutylsulfonyl, 1,1-dimethylpropylsulfonyl, 1,2-dimethylpropylsulfonyl, 2,2-dimethylpropylsulfonyl, 1-ethylpropylsulfonyl, hexylsulfonyl, 1-methylpentylsulfonyl, 2-methylpentylsulfonyl, 3-methylpentylsulfonyl, 4-methylpentylsulfonyl, 1,1-dimethylbutylsulfonyl, 1,2-dimethylbutylsulfonyl, 1,3-dimethylbutylsulfonyl, 2,2-dimethylbutylsulfonyl, 2,3-dimethylbutylsulfonyl, 3,3-dimethylbutylsulfonyl, 1-ethylbutylsulfonyl, 2-ethylbutylsulfonyl, 1,1,2-trimethylpropylsulfonyl, 1,2,2-trimethylpropylsulfonyl, 1-ethyl-1-methylpropylsulfonyl and 1-ethyl-2-methylpropylsulfonyl.
According to the invention, “heteroarylsulfonyl” denotes optionally substituted pyridylsulfonyl, pyrimidinylsulfonyl, pyrazinylsulfonyl or optionally substituted polycyclic heteroarylsulfonyl, here in particular optionally substituted quinolinylsulfonyl, for example substituted by fluorine, chlorine, bromine, iodine, cyano, nitro, alkyl, haloalkyl, haloalkoxy, amino, alkylamino, alkylcarbonylamino, dialkylamino or alkoxy groups.
According to the invention, “alkylthio”—alone or as part of a chemical group—denotes straight-chain or branched S-alkyl, preferably having 1 to 8 or 1 to 6 carbon atoms, such as (C1-C10)-, (C1-C6)- or (C1-C4)-alkylthio, for example (but not limited to) (C1-C6)-alkylthio such as methylthio, ethylthio, propylthio, 1-methylethylthio, butylthio, 1-methylpropylthio, 2-methylpropylthio, 1,1-dimethylethylthio, pentylthio, 1-methylbutylthio, 2-methylbutylthio, 3-methylbutylthio, 1,1-dimethylpropylthio, 1,2-dimethylpropylthio, 2,2-dimethylpropylthio, 1-ethylpropylthio, hexylthio, 1-methylpentylthio, 2-methylpentylthio, 3-methylpentylthio, 4-methylpentylthio, 1,1-dimethylbutylthio, 1,2-dimethylbutylthio, 1,3-dimethylbutylthio, 2,2-dimethylbutylthio, 2,3-dimethylbutylthio, 3,3-dimethylbutylthio, 1-ethylbutylthio, 2-ethylbutylthio, 1,1,2-trimethylpropylthio, 1,2,2-trimethylpropylthio, 1-ethyl-1-methylpropylthio and 1-ethyl-2-methylpropylthio.
According to the invention, “alkenylthio” denotes an alkenyl radical bonded via a sulfur atom, alkynylthio denotes an alkynyl radical bonded via a sulfur atom, cycloalkylthio denotes a cycloalkyl radical bonded via a sulfur atom, and cycloalkenylthio denotes a cycloalkenyl radical bonded via a sulfur atom.
According to the invention, “alkylsulfinyl (alkyl-S(═O)—)”, unless defined differently elsewhere, denotes alkyl radicals which are bonded to the skeleton via—S(═O)—, such as (C1-C10)-, (C1-C6)- or (C1-C4)-alkylsulfinyl, for example (but not limited to) (C1-C6)-alkylsulfinyl such as methylsulfinyl, ethylsulfinyl, propylsulfinyl, 1-methylethylsulfinyl, butylsulfinyl, 1-methylpropylsulfinyl, 2-methylpropylsulfinyl, 1,1-dimethylethylsulfinyl, pentylsulfinyl, 1-methylbutylsulfinyl, 2-methylbutylsulfinyl, 3-methylbutylsulfinyl, 1,1-dimethylpropylsulfinyl, 1,2-dimethylpropylsulfinyl, 2,2-dimethylpropylsulfinyl, 1-ethylpropylsulfinyl, hexylsulfinyl, 1-methylpentylsulfinyl, 2-methylpentylsulfinyl, 3-methylpentylsulfinyl, 4-methylpentylsulfinyl, 1,1-dimethylbutylsulfinyl, 1,2-dimethylbutylsulfinyl, 1,3-dimethylbutylsulfinyl, 2,2-dimethylbutylsulfinyl, 2,3-dimethylbutylsulfinyl, 3,3-dimethylbutylsulfinyl, 1-ethylbutylsulfinyl, 2-ethylbutylsulfinyl, 1,1,2-trimethylpropylsulfinyl, 1,2,2-trimethylpropylsulfinyl, 1-ethyl-1-methylpropylsulfinyl and 1-ethyl-2-methylpropylsulfinyl.
Analogously, “alkenylsulfinyl” and “alkynylsulfinyl” are defined in accordance with the invention respectively as alkenyl and alkynyl radicals bonded to the skeleton via —S(═O)—, such as (C2-C10)-, (C2-C6)- or (C2-C4)-alkenylsulfinyl or (C3-C10)-, (C3-C6)- or (C3-C4)-alkynylsulfinyl.
Analogously, “alkenylsulfonyl” and “alkynylsulfonyl” are defined in accordance with the invention respectively as alkenyl and alkynyl radicals bonded to the skeleton via —S(═O)2—, such as (C2-C10)-, (C2-C6)- or (C2-C4)-alkenylsulfonyl or (C3-C10)-, (C3-C6)- or (C3-C4)-alkynylsulfonyl.
“Alkoxy” denotes an alkyl radical bonded via an oxygen atom, for example (but not limited to) (C1-C6)-alkoxy such as methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, 1,1-dimethylethoxy, pentoxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, hexoxy, 1-methylpentoxy, 2-methylpentoxy, 3-methylpentoxy, 4-methylpentoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,2-dimethylbutoxy, 2,3-dimethylbutoxy, 3,3-dimethylbutoxy, 1-ethylbutoxy, 2-ethylbutoxy, 1,1,2-trimethylpropoxy, 1,2,2-trimethylpropoxy, 1-ethyl-1-methylpropoxy and 1-ethyl-2-methylpropoxy. Alkenyloxy denotes an alkenyl radical bonded via an oxygen atom, and alkynyloxy denotes an alkynyl radical bonded via an oxygen atom, such as (C2-C10)-, (C2-C6)- or (C2-C4)-alkenoxy and (C3-C10)-, (C3-C6)- or (C3-C4)-alkynoxy.
“Cycloalkyloxy” denotes a cycloalkyl radical bonded via an oxygen atom and cycloalkenyloxy denotes a cycloalkenyl radical bonded via an oxygen atom.
According to the invention, “alkylcarbonyl” (alkyl-C(═O)—), unless defined differently elsewhere, represents alkyl radicals bonded to the skeleton via —C(═O)—, such as (C1-C10)-, (C1-C6)- or (C1-C4)-alkylcarbonyl. Here, the number of the carbon atoms refers to the alkyl radical in the alkylcarbonyl group.
Analogously, “alkenylcarbonyl” and “alkynylcarbonyl”, unless defined differently elsewhere, in accordance with the invention, respectively represent alkenyl and alkynyl radicals bonded to the skeleton via —C(═O)—, such as (C2-C10)-, (C2-C6)- or (C2-C4)-alkenylcarbonyl and (C2-C10)-, (C2-C6)- and (C2-C4)-alkynylcarbonyl. Here, the number of the carbon atoms refers to the alkenyl or alkynyl radical in the alkenylcarbonyl or alkynylcarbonyl group.
“Alkoxycarbonyl (alkyl-O—C(═O)—),” unless defined differently elsewhere: alkyl radicals bonded to the skeleton via —O—C(═O)—, such as (C1-C10)-, (C1-C6)- or (C1-C4)-alkoxycarbonyl. Here, the number of the carbon atoms refers to the alkyl radical in the alkoxycarbonyl group. Analogously, “alkenyloxycarbonyl” and “alkynyloxycarbonyl”, unless defined differently elsewhere, in accordance with the invention, respectively represent alkenyl and alkynyl radicals bonded to the skeleton via —O—C(═O)—, such as (C2-C10)-, (C2-C6)- or (C2-C4)-alkenyloxycarbonyl or (C3-C10)-, (C3-C6)- or (C3-C4)-alkynyloxycarbonyl. Here, the number of the carbon atoms refers to the alkenyl or alkynyl radical in the alkenyloxycarbonyl or alkynyloxycarbonyl group.
According to the invention, the term “alkylcarbonyloxy” (alkyl-C(═O)—O—), unless defined differently elsewhere, represents alkyl radicals bonded to the skeleton via the oxygen of a carbonyloxy group (—C(═O)—O—), such as (C1-C10)-, (C1-C6)- or (C1-C4)-alkylcarbonyloxy. Here, the number of the carbon atoms refers to the alkyl radical in the alkylcarbonyloxy group.
Analogously, “alkenylcarbonyloxy” and “alkynylcarbonyloxy” are defined in accordance with the invention respectively as alkenyl and alkynyl radicals bonded to the skeleton via the oxygen of (—C(═O)—O—), such as (C2-C10)-, (C2-C6)- or (C2-C4)-alkenylcarbonyloxy or (C2-C10)-, (C2-C6)- or (C2-C4)-alkynylcarbonyloxy. Here, the number of the carbon atoms refers to the alkenyl or alkynyl radical in the alkenyl- or alkynylcarbonyloxy group respectively.
In short forms such as C(O)R12, C(O)OR12, OC(O)NR10R11 or C(O)NR10R11, the short form O shown in brackets represents an oxygen atom attached to the adjacent carbon atom via a double bond.
In short forms such as OC(S)OR12, OC(S)SR13, OC(S)NR10R11, the short form S shown in brackets represents a sulfur atom attached to the adjacent carbon atom via a double bond.
The term “aryl” denotes an optionally substituted mono-, bi- or polycyclic aromatic system having preferably 6 to 14, especially 6 to 10, ring carbon atoms, for example phenyl, naphthyl, anthryl, phenanthrenyl and the like, preferably phenyl.
The term “optionally substituted aryl” also embraces polycyclic systems, such as tetrahydronaphthyl, indenyl, indanyl, fluorenyl, biphenylyl, where the bonding site is on the aromatic system. In systematic terms, “aryl” is generally also encompassed by the term “optionally substituted phenyl”. Preferred aryl substituents here are, for example, hydrogen, halogen, alkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, halocycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, alkoxyalkyl, alkylthio, haloalkylthio, haloalkyl, alkoxy, haloalkoxy, cycloalkoxy, cycloalkylalkoxy, aryloxy, heteroraryloxy, alkoxyalkoxy, alkynylalkoxy, alkenyloxy, bisalkylaminoalkoxy, tris[alkyl]silyl, bis[alkyl]arylsilyl, bis[alkyl]alkylsilyl, tris[alkyl]silylalkynyl, arylalkynyl, heteroarylalkynyl, alkylalkynyl, cycloalkylalkynyl, haloalkylalkynyl, heterocyclyl-N-alkoxy, nitro, cyano, amino, alkylamino, bisalkylamino, alkylcarbonylamino, cycloalkylcarbonylamino, arylcarbonylamino, alkoxycarbonylamino, alkoxycarbonylalkylamino, arylalkoxycarbonylalkylamino, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, cycloalkylaminocarbonyl, bis-alkylaminocarbonyl, heteroarylalkoxy, arylalkoxy.
A heterocyclic radical (heterocyclyl) contains at least one heterocyclic ring (=carbocyclic ring in which at least one carbon atom has been replaced by a heteroatom, preferably by a heteroatom from the group of N, O, S, P) which is saturated, unsaturated, partially saturated or heteroaromatic and may be unsubstituted or substituted, in which case the bonding site is localized on a ring atom. If the heterocyclyl radical or the heterocyclic ring is optionally substituted, it may be fused to other carbocyclic or heterocyclic rings. In the case of optionally substituted heterocyclyl, polycyclic systems are also included, for example 8-azabicyclo[3.2.1]octanyl, 8-azabicyclo[2.2.2]octanyl or 1-azabicyclo[2.2.1]heptyl. Optionally substituted heterocyclyl also includes spirocyclic systems, such as, for example, 1-oxa-5-aza-spiro[2.3]hexyl. Unless defined otherwise, the heterocyclic ring preferably contains 3 to 9 ring atoms, in particular 3 to 6 ring atoms, and one or more, preferably 1 to 4, in particular 1, 2 or 3 heteroatoms in the heterocyclic ring, preferably from the group N, O and S, where, however, two oxygen atoms must not be directly adjacent to one another, for example having one heteroatom from the group consisting of N, O and S1- or 2- or 3-pyrrolidinyl, 3,4-dihydro-2H-pyrrol-2- or -3-yl, 2,3-dihydro-1H-pyrrol-1- or -2- or -3- or -4- or -5-yl; 2,5-dihydro-1H-pyrrol-1- or -2- or -3-yl, 1- or 2- or 3- or 4-piperidinyl; 2,3,4,5-tetrahydropyridin-2- or -3- or -4- or -5-yl or -6-yl; 1,2,3,6-tetrahydropyridin-1- or -2- or -3- or -4- or -5- or -6-yl; 1,2,3,4-tetrahydropyridin-1- or -2- or -3- or -4- or -5- or -6-yl; 1,4-dihydropyridin-1- or -2- or -3- or -4-yl; 2,3-dihydropyridin-2- or -3- or -4- or -5- or -6-yl; 2,5-dihydropyridin-2- or -3- or -4- or -5- or -6-yl, 1- or 2- or 3- or 4-azepanyl; 2,3,4,5-tetrahydro-1H-azepin-1- or -2- or -3- or -4- or -5- or -6- or -7-yl; 2,3,4,7-tetrahydro-1H-azepin-1- or -2- or -3- or -4- or -5- or -6- or -7-yl; 2,3,6,7-tetrahydro-1H-azepin-1- or -2- or -3- or -4-yl; 3,4,5,6-tetrahydro-2H-azepin-2- or -3- or -4- or -5- or -6- or -7-yl; 4,5-dihydro-1H-azepin-1- or -2- or -3- or -4-yl; 2,5-dihydro-1H-azepin-1- or -2- or -3- or -4- or -5- or -6- or -7-yl; 2,7-dihydro-1H-azepin-1- or -2- or -3- or -4-yl; 2,3-dihydro-1H-azepin-1- or -2- or -3- or -4- or -5- or -6- or -7-yl; 3,4-dihydro-2H-azepin-2- or -3- or -4- or -5- or -6- or -7-yl; 3,6-dihydro-2H-azepin-2- or -3- or -4- or -5- or -6- or -7-yl; 5,6-dihydro-2H-azepin-2- or -3- or -4- or -5- or -6- or -7-yl; 4,5-dihydro-3H-azepin-2- or -3- or -4- or -5- or -6- or -7-yl; 1H-azepin-1- or -2- or -3- or -4- or -5- or -6- or -7-yl; 2H-azepin-2- or -3- or -4- or -5- or -6- or -7-yl; 3H-azepin-2- or -3- or -4- or -5- or -6- or -7-yl; 4H-azepin-2- or -3- or -4- or -5- or -6- or -7-yl, 2- or 3-oxolanyl (=2- or 3-tetrahydrofuranyl); 2,3-dihydrofuran-2- or -3- or -4- or -5-yl; 2,5-dihydrofuran-2- or -3-yl, 2- or 3- or 4-oxanyl (=2- or 3- or 4-tetrahydropyranyl); 3,4-dihydro-2H-pyran-2- or -3- or -4- or -5- or -6-yl; 3,6-dihydro-2H-pyran-2- or -3- or -4- or -5- or -6-yl; 2H-pyran-2- or -3- or -4- or -5- or -6-yl; 4H-pyran-2- or -3- or -4-yl, 2- or -3- or -4-oxepanyl; 2,3,4,5-tetrahydrooxepin-2- or -3- or -4- or -5- or -6- or -7-yl; 2,3,4,7-tetrahydrooxepin-2- or -3- or -4- or -5- or -6- or -7-yl; 2,3,6,7-tetrahydrooxepin-2- or -3- or -4-yl; 2,3-dihydrooxepin-2- or -3- or -4- or -5- or -6- or -7-yl; 4,5-dihydrooxepin-2- or -3- or -4-yl; 2,5-dihydrooxepin-2- or -3- or -4- or -5- or -6- or -7-yl; oxepin-2- or -3- or -4- or -5- or -6- or -7-yl; 2- or 3-tetrahydrothiophenyl; 2,3-dihydrothiophen-2- or -3- or -4- or -5-yl; 2,5-dihydrothiophen-2- or -3-yl; tetrahydro-2H-thiopyran-2- or -3- or -4-yl; 3,4-dihydro-2H-thiopyran-2- or -3- or -4- or -5- or -6-yl; 3,6-dihydro-2H-thiopyran-2- or -3- or -4- or -5- or -6-yl; 2H-thiopyran-2- or -3- or -4- or -5- or -6-yl; 4H-thiopyran-2- or -3- or -4-yl. Preferred 3-membered and 4-membered heterocycles are, for example, 1- or 2-aziridinyl, oxiranyl, thiiranyl, 1- or 2- or 3-azetidinyl, 2- or 3-oxetanyl, 2- or 3-thietanyl, 1,3-dioxetan-2-yl. Further examples of “heterocyclyl” are a partly or fully hydrogenated heterocyclic radical having two heteroatoms from the group of N, O and S, for example 1- or 2- or 3- or 4-pyrazolidinyl; 4,5-dihydro-3H-pyrazol-3- or 4- or 5-yl; 4,5-dihydro-1H-pyrazol-1- or 3- or 4- or 5-yl; 2,3-dihydro-1H-pyrazol-1- or 2- or 3- or 4- or 5-yl; 1- or 2- or 3- or 4-imidazolidinyl; 2,3-dihydro-1H-imidazol-1- or 2- or 3- or 4-yl; 2,5-dihydro-1H-imidazol-1- or 2- or 4- or 5-yl; 4,5-dihydro-1H-imidazol-1- or 2- or 4- or 5-yl; hexahydropyridazin-1- or 2- or 3- or 4-yl; 1,2,3,4-tetrahydropyridazin-1- or 2- or 3- or 4- or 5- or 6-yl; 1,2,3,6-tetrahydropyridazin-1- or 2- or 3- or 4- or 5- or 6-yl; 1,4,5,6-tetrahydropyridazin-1- or 3- or 4- or 5- or 6-yl; 3,4,5,6-tetrahydropyridazin-3- or 4- or 5-yl; 4,5-dihydropyridazin-3- or 4-yl; 3,4-dihydropyridazin-3- or 4- or 5- or 6-yl; 3,6-dihydropyridazin-3- or 4-yl; 1,6-dihydropyridazin-1- or 3- or 4- or 5- or 6-yl; hexahydropyrimidin-1- or 2- or 3- or 4-yl; 1,4,5,6-tetrahydropyrimidin-1- or 2- or 4- or 5- or 6-yl; 1,2,5,6-tetrahydropyrimidin-1- or 2- or 4- or 5- or 6-yl; 1,2,3,4-tetrahydropyrimidin-1- or 2- or 3- or 4- or 5- or 6-yl; 1,6-dihydropyrimidin-1- or 2- or 4- or 5- or 6-yl; 1,2-dihydropyrimidin-1- or 2- or 4- or 5- or 6-yl; 2,5-dihydropyrimidin-2- or 4- or 5-yl; 4,5-dihydropyrimidin-4- or 5- or 6-yl; 1,4-dihydropyrimidin-1- or 2- or 4- or 5- or 6-yl; 1- or 2- or 3-piperazinyl; 1,2,3,6-tetrahydropyrazin-1- or 2- or 3- or 5- or 6-yl; 1,2,3,4-tetrahydropyrazin-1- or 2- or 3- or 4- or 5- or 6-yl; 1,2-dihydropyrazin-1- or 2- or 3- or 5- or 6-yl; 1,4-dihydropyrazin-1- or 2- or 3-yl; 2,3-dihydropyrazin-2- or 3- or 5- or 6-yl; 2,5-dihydropyrazin-2- or 3-yl; 1,3-dioxolan-2- or 4- or 5-yl; 1,3-dioxol-2- or 4-yl; 1,3-dioxan-2- or 4- or 5-yl; 4H-1,3-dioxin-2- or 4- or 5- or 6-yl; 1,4-dioxan-2- or 3- or 5- or 6-yl; 2,3-dihydro-1,4-dioxin-2- or 3- or 5- or 6-yl; 1,4-dioxin-2- or 3-yl; 1,2-dithiolan-3- or 4-yl; 3H-1,2-dithiol-3- or 4- or 5-yl; 1,3-dithiolan-2- or 4-yl; 1,3-dithiol-2- or 4-yl; 1,2-dithian-3- or 4-yl; 3,4-dihydro-1,2-dithiin-3- or 4- or 5- or 6-yl; 3,6-dihydro-1,2-dithiin-3- or 4-yl; 1,2-dithiin-3- or 4-yl; 1,3-dithian-2- or 4- or 5-yl; 4H-1,3-dithiin-2- or 4- or 5- or 6-yl; isoxazolidin-2- or 3- or 4- or 5-yl; 2,3-dihydroisoxazol-2- or 3- or 4- or 5-yl; 2,5-dihydroisoxazol-2- or 3- or 4- or 5-yl; 4,5-dihydroisoxazol-3- or 4- or 5-yl; 1,3-oxazolidin-2- or 3- or 4- or 5-yl; 2,3-dihydro-1,3-oxazol-2- or 3- or 4- or 5-yl; 2,5-dihydro-1,3-oxazol-2- or 4- or 5-yl; 4,5-dihydro-1,3-oxazol-2- or 4- or 5-yl; 1,2-oxazinan-2- or 3- or 4- or 5- or 6-yl; 3,4-dihydro-2H-1,2-oxazin-2- or 3- or 4- or 5- or 6-yl; 3,6-dihydro-2H-1,2-oxazin-2- or 3- or 4- or 5- or 6-yl; 5,6-dihydro-2H-1,2-oxazin-2- or 3- or 4- or 5- or 6-yl; 5,6-dihydro-4H-1,2-oxazin-3- or 4- or 5- or 6-yl; 2H-1,2-oxazin-2- or 3- or 4- or 5- or 6-yl; 6H-1,2-oxazin-3- or 4- or 5- or 6-yl; 4H-1,2-oxazin-3- or 4- or 5- or 6-yl; 1,3-oxazinan-2- or 3- or 4- or 5- or 6-yl; 3,4-dihydro-2H-1,3-oxazin-2- or 3- or 4- or 5- or 6-yl; 3,6-dihydro-2H-1,3-oxazin-2- or 3- or 4- or 5- or 6-yl; 5,6-dihydro-2H-1,3-oxazin-2- or 4- or 5- or 6-yl; 5,6-dihydro-4H-1,3-oxazin-2- or 4- or 5- or 6-yl; 2H-1,3-oxazin-2- or 4- or 5- or 6-yl; 6H-1,3-oxazin-2- or 4- or 5- or 6-yl; 4H-1,3-oxazin-2- or 4- or 5- or 6-yl; morpholin-2- or 3- or 4-yl; 3,4-dihydro-2H-1,4-oxazin-2- or 3- or 4- or 5- or 6-yl; 3,6-dihydro-2H-1,4-oxazin-2- or 3- or 5- or 6-yl; 2H-1,4-oxazin-2- or 3- or 5- or 6-yl; 4H-1,4-oxazin-2- or 3-yl; 1,2-oxazepan-2- or 3- or 4- or 5- or 6- or 7-yl; 2,3,4,5-tetrahydro-1,2-oxazepin-2- or 3- or 4- or 5- or 6- or 7-yl; 2,3,4,7-tetrahydro-1,2-oxazepin-2- or 3- or 4- or 5- or 6- or 7-yl; 2,3,6,7-tetrahydro-1,2-oxazepin-2- or 3- or 4- or 5- or 6- or 7-yl; 2,5,6,7-tetrahydro-1,2-oxazepin-2- or 3- or 4- or 5- or 6- or 7-yl; 4,5,6,7-tetrahydro-1,2-oxazepin-3- or 4- or 5- or 6- or 7-yl; 2,3-dihydro-1,2-oxazepin-2- or 3- or 4- or 5- or 6- or 7-yl; 2,5-dihydro-1,2-oxazepin-2- or 3- or 4- or 5- or 6- or 7-yl; 2,7-dihydro-1,2-oxazepin-2- or 3- or 4- or 5- or 6- or 7-yl; 4,5-dihydro-1,2-oxazepin-3- or 4- or 5- or 6- or 7-yl; 4,7-dihydro-1,2-oxazepin-3- or 4- or 5- or 6- or 7-yl; 6,7-dihydro-1,2-oxazepin-3- or 4- or 5- or 6- or 7-yl; 1,2-oxazepin-3- or 4- or 5- or 6- or 7-yl; 1,3-oxazepan-2- or 3- or 4- or 5- or 6- or 7-yl; 2,3,4,5-tetrahydro-1,3-oxazepin-2- or 3- or 4- or 5- or 6- or 7-yl; 2,3,4,7-tetrahydro-1,3-oxazepin-2- or 3- or 4- or 5- or 6- or 7-yl; 2,3,6,7-tetrahydro-1,3-oxazepin-2- or 3- or 4- or 5- or 6- or 7-yl; 2,5,6,7-tetrahydro-1,3-oxazepin-2- or 4- or 5- or 6- or 7-yl; 4,5,6,7-tetrahydro-1,3-oxazepin-2- or 4- or 5- or 6- or 7-yl; 2,3-dihydro-1,3-oxazepin-2- or 3- or 4- or 5- or 6- or 7-yl; 2,5-dihydro-1,3-oxazepin-2- or 4- or 5- or 6- or 7-yl; 2,7-dihydro-1,3-oxazepin-2- or 4- or 5- or 6- or 7-yl; 4,5-dihydro-1,3-oxazepin-2- or 4- or 5- or 6- or 7-yl; 4,7-dihydro-1,3-oxazepin-2- or 4- or 5- or 6- or 7-yl; 6,7-dihydro-1,3-oxazepin-2- or 4- or 5- or 6- or 7-yl; 1,3-oxazepin-2- or 4- or 5- or 6- or 7-yl; 1,4-oxazepan-2- or 3- or 5- or 6- or 7-yl; 2,3,4,5-tetrahydro-1,4-oxazepin-2- or 3- or 4- or 5- or 6- or 7-yl; 2,3,4,7-tetrahydro-1,4-oxazepin-2- or 3- or 4- or 5- or 6- or 7-yl; 2,3,6,7-tetrahydro-1,4-oxazepin-2- or 3- or 5- or 6- or 7-yl; 2,5,6,7-tetrahydro-1,4-oxazepin-2- or 3- or 5- or 6- or 7-yl; 4,5,6,7-tetrahydro-1,4-oxazepin-2- or 3- or 4- or 5- or 6- or 7-yl; 2,3-dihydro-1,4-oxazepin-2- or 3- or 5- or 6- or 7-yl; 2,5-dihydro-1,4-oxazepin-2- or 3- or 5- or 6- or 7-yl; 2,7-dihydro-1,4-oxazepin-2- or 3- or 5- or 6- or 7-yl; 4,5-dihydro-1,4-oxazepin-2- or 3- or 4- or 5- or 6- or 7-yl; 4,7-dihydro-1,4-oxazepin-2- or 3- or 4- or 5- or 6- or 7-yl; 6,7-dihydro-1,4-oxazepin-2- or 3- or 5- or 6- or 7-yl; 1,4-oxazepin-2- or 3- or 5- or 6- or 7-yl; isothiazolidin-2- or 3- or 4- or 5-yl; 2,3-dihydroisothiazol-2- or 3- or 4- or 5-yl; 2,5-dihydroisothiazol-2- or 3- or 4- or 5-yl; 4,5-dihydroisothiazol-3- or 4- or 5-yl; 1,3-thiazolidin-2- or 3- or 4- or 5-yl; 2,3-dihydro-1,3-thiazol-2- or 3- or 4- or 5-yl; 2,5-dihydro-1,3-thiazol-2- or 4- or 5-yl; 4,5-dihydro-1,3-thiazol-2- or 4- or 5-yl; 1,3-thiazinan-2- or 3- or 4- or 5- or 6-yl; 3,4-dihydro-2H-1,3-thiazin-2- or 3- or 4- or 5- or 6-yl; 3,6-dihydro-2H-1,3-thiazin-2- or 3- or 4- or 5- or 6-yl; 5,6-dihydro-2H-1,3-thiazin-2- or 4- or 5- or 6-yl; 5,6-dihydro-4H-1,3-thiazin-2- or 4- or 5- or 6-yl; 2H-1,3-thiazin-2- or 4- or 5- or 6-yl; 6H-1,3-thiazin-2- or 4- or 5- or 6-yl; 4H-1,3-thiazin-2- or 4- or 5- or 6-yl. Further examples of “heterocyclyl” are a partially or fully hydrogenated heterocyclic radical having 3 heteroatoms from the group of N, O and S, for example 1,4,2-dioxazolidin-2- or -3- or -5-yl; 1,4,2-dioxazol-3- or -5-yl; 1,4,2-dioxazinan-2- or -3- or -5- or -6-yl; 5,6-dihydro-1,4,2-dioxazin-3- or -5- or -6-yl; 1,4,2-dioxazin-3- or -5- or -6-yl; 1,4,2-dioxazepan-2- or -3- or -5- or -6- or -7-yl; 6,7-dihydro-5H-1,4,2-dioxazepin-3- or -5- or -6- or -7-yl; 2,3-dihydro-7H-1,4,2-dioxazepin-2- or -3- or -5- or -6- or -7-yl; 2,3-dihydro-5H-1,4,2-dioxazepin-2- or -3- or -5- or -6- or -7-yl; 5H-1,4,2-dioxazepin-3- or -5- or -6- or -7-yl; 7H-1,4,2-dioxazepin-3- or -5- or -6- or -7-yl. Structural examples of heterocycles which are optionally substituted further are also listed below:
The heterocycles listed above are preferably substituted, for example, by hydrogen, halogen, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkoxy, aryloxy, alkoxyalkyl, alkoxyalkoxy, cycloalkyl, halocycloalkyl, aryl, arylalkyl, heteroaryl, heterocyclyl, alkenyl, alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, hydroxycarbonyl, cycloalkoxycarbonyl, cycloalkylalkoxycarbonyl, alkoxycarbonylalkyl, arylalkoxycarbonyl, arylalkoxycarbonylalkyl, alkynyl, alkynylalkyl, alkylalkynyl, trisalkylsilylalkynyl, nitro, amino, cyano, haloalkoxy, haloalkylthio, alkylthio, hydrothio, hydroxyalkyl, oxo, heteroarylalkoxy, arylalkoxy, heterocyclylalkoxy, heterocyclylalkylthio, heterocyclyloxy, heterocyclylthio, heteroaryloxy, bisalkylamino, alkylamino, cycloalkylamino, hydroxycarbonylalkylamino, alkoxycarbonylalkylamino, arylalkoxycarbonylalkylamino, alkoxycarbonylalkyl(alkyl)amino, aminocarbonyl, alkylaminocarbonyl, bisalkylaminocarbonyl, cycloalkylaminocarbonyl, hydroxycarbonylalkylaminocarbonyl, alkoxycarbonylalkylaminocarbonyl, arylalkoxycarbonylalkylaminocarbonyl.
When a base structure is substituted “by one or more radicals” from a list of radicals (=group) or a generically defined group of radicals, this in each case includes simultaneous substitution by a plurality of identical and/or structurally different radicals.
In the case of a partially or fully saturated nitrogen heterocycle, this may be joined to the remainder of the molecule either via carbon or via the nitrogen.
Suitable substituents for a substituted heterocyclic radical are the substituents specified further down, and additionally also oxo and thioxo. The oxo group as a substituent on a ring carbon atom is then, for example, a carbonyl group in the heterocyclic ring. As a result, lactones and lactams are preferably also included. The oxo group may also occur on the ring heteroatoms, which may exist in different oxidation states, for example in the case of N and S, and in that case form, for example, the divalent —N(O)—, —S(O)— (also SO for short) and —S(O)2— (also SO2 for short) groups in the heterocyclic ring. In the case of —N(O)— and —S(O)— groups, both enantiomers in each case are included.
According to the invention, the expression “heteroaryl” refers to heteroaromatic compounds, i.e. fully unsaturated aromatic heterocyclic compounds, preferably 5- to 7-membered rings having 1 to 4, preferably 1 or 2, identical or different heteroatoms, preferably O, S or N. Inventive heteroaryls are, for example, 1H-pyrrol-1-yl; 1H-pyrrol-2-yl; 1H-pyrrol-3-yl; furan-2-yl; furan-3-yl; thien-2-yl; thien-3-yl, 1H-imidazol-1-yl; 1H-imidazol-2-yl; 1H-imidazol-4-yl; 1H-imidazol-5-yl; 1H-pyrazol-1-yl; 1H-pyrazol-3-yl; 1H-pyrazol-4-yl; 1H-pyrazol-5-yl, 1H-1,2,3-triazol-1-yl, 1H-1,2,3-triazol-4-yl, 1H-1,2,3-triazol-5-yl, 2H-1,2,3-triazol-2-yl, 2H-1,2,3-triazol-4-yl, 1H-1,2,4-triazol-1-yl, 1H-1,2,4-triazol-3-yl, 4H-1,2,4-triazol-4-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl, 1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl, 1,2,5-oxadiazol-3-yl, azepinyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrazin-2-yl, pyrazin-3-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyridazin-3-yl, pyridazin-4-yl, 1,3,5-triazin-2-yl, 1,2,4-triazin-3-yl, 1,2,4-triazin-5-yl, 1,2,4-triazin-6-yl, 1,2,3-triazin-4-yl, 1,2,3-triazin-5-yl, 1,2,4-, 1,3,2-, 1,3,6- and 1,2,6-oxazinyl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, 1,3-oxazol-2-yl, 1,3-oxazol-4-yl, 1,3-oxazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, 1,3-thiazol-2-yl, 1,3-thiazol-4-yl, 1,3-thiazol-5-yl, oxepinyl, thiepinyl, 1,2,4-triazolonyl and 1,2,4-diazepinyl, 2H-1,2,3,4-tetrazol-5-yl, 1H-1,2,3,4-tetrazol-5-yl, 1,2,3,4-oxatriazol-5-yl, 1,2,3,4-thiatriazol-5-yl, 1,2,3,5-oxatriazol-4-yl, 1,2,3,5-thiatriazol-4-yl. The heteroaryl groups according to the invention may also be substituted by one or more identical or different radicals. If two adjacent carbon atoms are part of a further aromatic ring, the systems are fused heteroaromatic systems, such as benzofused or polyannealed heteroaromatics. Preferred examples are quinolines (e.g. quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl); isoquinolines (e.g. isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin-4-yl, isoquinolin-5-yl, isoquinolin-6-yl, isoquinolin-7-yl, isoquinolin-8-yl); quinoxaline; quinazoline; cinnoline; 1,5-naphthyridine; 1,6-naphthyridine; 1,7-naphthyridine; 1,8-naphthyridine; 2,6-naphthyridine; 2,7-naphthyridine; phthalazine; pyridopyrazines; pyridopyrimidines; pyridopyridazines; pteridines; pyrimidopyrimidines. Examples of heteroaryl are also 5- or 6-membered benzofused rings from the group of 1H-indol-1-yl, 1H-indol-2-yl, 1H-indol-3-yl, 1H-indol-4-yl, 1H-indol-5-yl, 1H-indol-6-yl, 1H-indol-7-yl, 1-benzofuran-2-yl, 1-benzofuran-3-yl, 1-benzofuran-4-yl, 1-benzofuran-5-yl, 1-benzofuran-6-yl, 1-benzofuran-7-yl, 1-benzothiophen-2-yl, 1-benzothiophen-3-yl, 1-benzothiophen-4-yl, 1-benzothiophen-5-yl, 1-benzothiophen-6-yl, 1-benzothiophen-7-yl, 1H-indazol-1-yl, 1H-indazol-3-yl, 1H-indazol-4-yl, 1H-indazol-5-yl, 1H-indazol-6-yl, 1H-indazol-7-yl, 2H-indazol-2-yl, 2H-indazol-3-yl, 2H-indazol-4-yl, 2H-indazol-5-yl, 2H-indazol-6-yl, 2H-indazol-7-yl, 2H-isoindol-2-yl, 2H-isoindol-1-yl, 2H-isoindol-3-yl, 2H-isoindol-4-yl, 2H-isoindol-5-yl, 2H-isoindol-6-yl; 2H-isoindol-7-yl, 1H-benzimidazol-1-yl, 1H-benzimidazol-2-yl, 1H-benzimidazol-4-yl, 1H-benzimidazol-5-yl, 1H-benzimidazol-6-yl, 1H-benzimidazol-7-yl, 1,3-benzoxazol-2-yl, 1,3-benzoxazol-4-yl, 1,3-benzoxazol-5-yl, 1,3-benzoxazol-6-yl, 1,3-benzoxazol-7-yl, 1,3-benzothiazol-2-yl, 1,3-benzothiazol-4-yl, 1,3-benzothiazol-5-yl, 1,3-benzothiazol-6-yl, 1,3-benzothiazol-7-yl, 1,2-benzisoxazol-3-yl, 1,2-benzisoxazol-4-yl, 1,2-benzisoxazol-5-yl, 1,2-benzisoxazol-6-yl, 1,2-benzisoxazol-7-yl, 1,2-benzisothiazol-3-yl, 1,2-benzisothiazol-4-yl, 1,2-benzisothiazol-5-yl, 1,2-benzisothiazol-6-yl, 1,2-benzisothiazol-7-yl.
The term “halogen” denotes, for example, fluorine, chlorine, bromine or iodine. If the term is used for a radical, “halogen” denotes, for example, a fluorine, chlorine, bromine or iodine atom.
According to the invention, “alkyl” denotes a straight-chain or branched open-chain, saturated hydrocarbon radical which is optionally mono- or polysubstituted, and in the latter case is referred to as “substituted alkyl”. Preferred substituents are halogen atoms, alkoxy, haloalkoxy, cyano, alkylthio, haloalkylthio, amino or nitro groups, particular preference being given to methoxy, methyl, fluoroalkyl, cyano, nitro, fluorine, chlorine, bromine or iodine. The prefix “bis” also includes the combination of different alkyl radicals, e.g. methyl(ethyl) or ethyl(methyl).
“Haloalkyl”, “-alkenyl” and “-alkynyl” respectively denote alkyl, alkenyl and alkynyl partially or fully substituted by identical or different halogen atoms, for example monohaloalkyl such as CH2CH2Cl, CH2CH2Br, CHClCH3, CH2Cl, CH2F; perhaloalkyl such as CCl3, CClF2, CFCl2, CF2CClF2, CF2CClFCF3; polyhaloalkyl such as CH2CHFCl, CF2CClFH, CF2CBrFH, CH2CF3; the term perhaloalkyl also encompasses the term perfluoroalkyl.
“Partially fluorinated alkyl” denotes a straight-chain or branched, saturated hydrocarbon which is mono- or polysubstituted by fluorine, where the fluorine atoms in question may be present as substituents on one or more different carbon atoms of the straight-chain or branched hydrocarbon chain, for example CHFCH3, CH2CH2F, CH2CH2CF3, CHF2, CH2F, CHFCF2CF3.
“Partially fluorinated haloalkyl” denotes a straight-chain or branched, saturated hydrocarbon which is substituted by different halogen atoms with at least one fluorine atom, where any other halogen atoms optionally present are selected from the group consisting of fluorine, chlorine or bromine, iodine. The corresponding halogen atoms may be present as substituents on one or more different carbon atoms of the straight-chain or branched hydrocarbon chain. Partially fluorinated haloalkyl also includes full substitution of the straight or branched chain by halogen including at least one fluorine atom.
“Haloalkoxy” is, for example, OCF3, OCHF2, OCH2F, OCF2CF3, OCH2CF3 and OCH2CH2Cl; this applies correspondingly to haloalkenyl and other halogen-substituted radicals.
The expression “(C1-C4)-alkyl” mentioned here by way of example is a brief notation for straight-chain or branched alkyl having one to 4 carbon atoms according to the range stated for carbon atoms, i.e. encompasses the methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methylpropyl or tert-butyl radicals. General alkyl radicals with a larger specified range of carbon atoms, e.g. “(C1-C6)-alkyl”, correspondingly also encompass straight-chain or branched alkyl radicals with a greater number of carbon atoms, i.e. according to the example also the alkyl radicals having 5 and 6 carbon atoms.
Unless stated specifically, preference is given to the lower carbon skeletons, for example having from 1 to 6 carbon atoms, or having from 2 to 6 carbon atoms in the case of unsaturated groups, in the case of the hydrocarbyl radicals such as alkyl, alkenyl and alkynyl radicals, including in composite radicals. Alkyl radicals, including in composite radicals such as alkoxy, haloalkyl, etc., are, for example, methyl, ethyl, n-propyl or i-propyl, n-, i-, t- or 2-butyl, pentyls, hexyls such as n-hexyl, i-hexyl and 1,3-dimethylbutyl, heptyls such as n-heptyl, 1-methylhexyl and 1,4-dimethylpentyl; alkenyl and alkynyl radicals are defined as the possible unsaturated radicals corresponding to the alkyl radicals, where at least one double bond or triple bond is present. Preference is given to radicals having one double bond or triple bond.
The term “alkenyl” also includes, in particular, straight-chain or branched open-chain hydrocarbon radicals having more than one double bond, such as 1,3-butadienyl and 1,4-pentadienyl, but also allenyl or cumulenyl radicals having one or more cumulated double bonds, for example allenyl (1,2-propadienyl), 1,2-butadienyl and 1,2,3-pentatrienyl. Alkenyl denotes, for example, vinyl which may optionally be substituted by further alkyl radicals, for example (but not limited thereto) (C2-C6)-alkenyl such as ethenyl, 1-propenyl, 2-propenyl, 1-methylethenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 3-methyl-1-pentenyl, 4-methyl-1-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-1-butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-1-butenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-1-butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 3,3-dimethyl-1-butenyl, 3,3-dimethyl-2-butenyl, 1-ethyl-1-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl-1-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl, 1-ethyl-2-methyl-1-propenyl and 1-ethyl-2-methyl-2-propenyl.
The term “alkynyl” also includes, in particular, straight-chain or branched open-chain hydrocarbon radicals having more than one triple bond, or else having one or more triple bonds and one or more double bonds, for example 1,3-butatrienyl or 3-penten-1-yn-1-yl. (C2-C6)-Alkynyl denotes, for example, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-2-butynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 3-methyl-1-butynyl, 1,1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2-methyl-3-pentynyl, 2-methyl-4-pentynyl, 3-methyl-1-pentynyl, 3-methyl-4-pentynyl, 4-methyl-1-pentynyl, 4-methyl-2-pentynyl, 1,1-dimethyl-2-butynyl, 1,1-dimethyl-3-butynyl, 1,2-dimethyl-3-butynyl, 2,2-dimethyl-3-butynyl, 3,3-dimethyl-1-butynyl, 1-ethyl-2-butynyl, 1-ethyl-3-butynyl, 2-ethyl-3-butynyl and 1-ethyl-1-methyl-2-propynyl.
The term “cycloalkyl” denotes a carbocyclic saturated ring system having preferably 3-8 ring carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, which optionally has further substitution, preferably by hydrogen, alkyl, alkoxy, cyano, nitro, alkylthio, haloalkylthio, halogen, alkenyl, alkynyl, haloalkyl, amino, alkylamino, bisalkylamino, alkoxycarbonyl, hydroxycarbonyl, arylalkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, cycloalkylaminocarbonyl. In the case of optionally substituted cycloalkyl, cyclic systems with substituents are included, also including substituents with a double bond on the cycloalkyl radical, for example an alkylidene group such as methylidene. In the case of optionally substituted cycloalkyl, polycyclic aliphatic systems are also included, for example bicyclo[1.1.0]butan-1-yl, bicyclo[1.1.0]butan-2-yl, bicyclo[2.1.0]pentan-1-yl, bicyclo[1.1.1]pentan-1-yl, bicyclo[2.1.0]pentan-2-yl, bicyclo[2.1.0]pentan-5-yl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]hept-2-yl, bicyclo[2.2.2]octan-2-yl, bicyclo[3.2.1]octan-2-yl, bicyclo[3.2.2]nonan-2-yl, adamantan-1-yl and adamantan-2-yl, but also systems such as 1,1′-bi(cyclopropyl)-1-yl, 1,1′-bi(cyclopropyl)-2-yl, for example. The term “(C3-C7)-cycloalkyl” is a brief notation for cycloalkyl having three to 7 carbon atoms, corresponding to the range specified for carbon atoms.
In the case of substituted cycloalkyl, spirocyclic aliphatic systems are also included, for example spiro[2.2]pent-1-yl, spiro[2.3]hex-1-yl, spiro[2.3]hex-4-yl, 3-spiro[2.3]hex-5-yl, spiro[3.3]hept-1-yl, spiro[3.3]hept-2-yl.
“Cycloalkenyl” denotes a carbocyclic, nonaromatic, partially unsaturated ring system having preferably 4-8 carbon atoms, e.g. 1-cyclobutenyl, 2-cyclobutenyl, 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, or 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 1,3-cyclohexadienyl or 1,4-cyclohexadienyl, also including substituents with a double bond on the cycloalkenyl radical, for example an alkylidene group such as methylidene. In the case of optionally substituted cycloalkenyl, the elucidations for substituted cycloalkyl apply correspondingly.
The term “alkylidene”, also, for example, in the form (C1-C10)-alkylidene, means the radical of a straight-chain or branched open-chain hydrocarbon radical which is bonded via a double bond. Possible bonding sites for alkylidene are naturally only positions on the base structure where two hydrogen atoms can be replaced by the double bond; radicals are, for example, ═CH2, ═CH—CH3, ═C(CH3)—CH3, ═C(CH3)—C2H5 or ═C(C2H5)—C2H5. Cycloalkylidene denotes a carbocyclic radical bonded via a double bond.
“Cycloalkylalkyloxy” denotes a cycloalkylalkyl radical bonded via an oxygen atom and “arylalkyloxy” denotes an arylalkyl radical bonded via an oxygen atom.
“Alkoxyalkyl” represents an alkoxy radical bonded via an alkyl group and “alkoxyalkoxy” denotes an alkoxyalkyl radical bonded via an oxygen atom, for example (but not limited thereto) methoxymethoxy, methoxyethoxy, ethoxyethoxy, methoxy-n-propyloxy.
“Alkylthioalkyl” represents an alkylthio radical bonded via an alkyl group and “alkylthioalkylthio” denotes an alkylthioalkyl radical bonded via an oxygen atom.
“Arylalkoxyalkyl” represents an aryloxy radical bonded via an alkyl group and “heteroaryloxyalkyl” denotes a heteroaryloxy radical bonded via an alkyl group.
“Haloalkoxyalkyl” represents a haloalkoxy radical and “haloalkylthioalkyl” denotes a haloalkylthio radical, bonded via an alkyl group.
“Arylalkyl” represents an aryl radical bonded via an alkyl group, “heteroarylalkyl” denotes a heteroaryl radical bonded via an alkyl group, and “heterocyclylalkyl” denotes a heterocyclyl radical bonded via an alkyl group.
“Cycloalkylalkyl” represents a cycloalkyl radical bonded via an alkyl group, for example (but not limited thereto) cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 1-cyclopropyleth-1-yl, 2-cyclopropyleth-1-yl, 1-cyclopropylprop-1-yl, 3-cyclopropylprop-1-yl.
“Arylalkenyl” represents an aryl radical bonded via an alkenyl group, “heteroarylalkenyl” denotes a heteroaryl radical bonded via an alkenyl group, and “heterocyclylalkenyl” denotes a heterocyclyl radical bonded via an alkenyl group.
“Arylalkynyl” represents an aryl radical bonded via an alkynyl group, “heteroarylalkynyl” denotes a heteroaryl radical bonded via an alkynyl group, and “heterocyclylalkynyl” denotes a heterocyclyl radical bonded via an alkynyl group.
According to the invention, “haloalkylthio”—on its own or as constituent part of a chemical group—represents straight-chain or branched S-haloalkyl, preferably having 1 to 8, or having 1 to 6 carbon atoms, such as (C1-C8)-, (C1-C6)- or (C1-C4)-haloalkylthio, for example (but not limited thereto) trifluoromethylthio, pentafluoroethylthio, difluoromethyl, 2,2-difluoroeth-1-ylthio, 2,2,2-difluoroeth-1-ylthio, 3,3,3-prop-1-ylthio.
“Halocycloalkyl” and “halocycloalkenyl” denote cycloalkyl and cycloalkenyl, respectively, which are partially or fully substituted by identical or different halogen atoms, such as F, Cl and Br, or by haloalkyl, such as trifluoromethyl or difluoromethyl, for example 1-fluorocycloprop-1-yl, 2-fluorocycloprop-1-yl, 2,2-difluorocycloprop-1-yl, 1-fluorocyclobut-1-yl, 1-trifluoromethylcycloprop-1-yl, 2-trifluoromethylcycloprop-1-yl, 1-chlorocycloprop-1-yl, 2-chlorocycloprop-1-yl, 2,2-dichlorocycloprop-1-yl, 3,3-difluorocyclobutyl.
According to the invention, “trialkylsilyl”—on its own or as constituent part of a chemical group—represents straight-chain or branched Si-alkyl, preferably having 1 to 8, or having 1 to 6 carbon atoms, such as tri-[(C1-C8)-, (C1-C6)- or (C1-C4)-alkyl]silyl, for example (but not limited thereto) trimethylsilyl, triethylsilyl, tri(n-propyl)silyl, tri(isopropyl)silyl, tri(n-butyl)silyl, tri(1-methylprop-1-yl)silyl, tri(2-methylprop-1-yl)silyl, tri(1,1-dimethyleth-1-yl)silyl, tri(2,2-dimethyleth-1-yl)silyl.
“Trialkylsilylalkynyl” represents a trialkylsilyl radical bonded via an alkynyl group.
If the compounds can form, through a hydrogen shift, tautomers whose structure is not formally covered by the general formula (I), these tautomers are nevertheless covered by the definition of the inventive compounds of the general formula (I), unless a particular tautomer is under consideration. For example, many carbonyl compounds may be present both in the keto form and in the enol form, both forms being encompassed by the definition of the compound of the general formula (I).
Depending on the nature of the substituents and the manner in which they are attached, the compounds of the general formula (I) may be present as stereoisomers. The possible stereoisomers defined by the specific three-dimensional form thereof, such as enantiomers, diastereomers, Z and E isomers, are all encompassed by the general formula (I). If, for example, one or more alkenyl groups are present, diastereomers (Z and E isomers) may occur. If, for example, one or more asymmetric carbon atoms are present, enantiomers and diastereomers may occur. Stereoisomers can be obtained from the mixtures obtained in the preparation by customary separation methods. The chromatographic separation can be effected either on the analytical scale to find the enantiomeric excess or the diastereomeric excess, or else on the preparative scale to produce test specimens for biological testing. It is likewise possible to selectively prepare stereoisomers by using stereoselective reactions with use of optically active starting materials and/or auxiliaries. The invention thus also relates to all stereoisomers which are embraced by the general formula (I) but are not shown in their specific stereomeric form, and to mixtures thereof.
If the compounds are obtained as solids, the purification can also be carried out by recrystallization or digestion. If individual compounds (I) cannot be obtained in a satisfactory manner by the routes described below, they can be prepared by derivatization of other compounds (I).
Suitable isolation methods, purification methods and methods for separating stereoisomers of compounds of the general formula (I) are methods generally known to the person skilled in the art from analogous cases, for example by physical processes such as crystallization, chromatographic methods, in particular column chromatography and HPLC (high pressure liquid chromatography), distillation, optionally under reduced pressure, extraction and other methods, any mixtures that remain can generally be separated by chromatographic separation, for example on chiral solid phases. Suitable for preparative amounts or on an industrial scale are processes such as crystallization, for example of diastereomeric salts which can be obtained from the diastereomer mixtures using optically active acids and, if appropriate, provided that acidic groups are present, using optically active bases.
The present invention also claims processes for preparing the inventive compounds of the general formula (I).
The inventive compounds of the general formula (I) can be prepared proceeding from known processes inter alia. The synthesis routes used and examined proceed from commercially available or easily preparable building blocks. In the schemes which follow, the moieties Q1, Q2, A, R1, R2, n of the general formula (I) have the meanings defined above, unless exemplary, but not limiting, definitions are given.
Inventive compounds with R1 representing methyl and A representing O, S(O)n and CR3R4 can be prepared by the method specified in scheme 1.
The pyrazoles of the general formula (I) can be prepared via an alkylation of the pyrazolones (E-III) in the presence of bases, alkylating agents, for example Q2-X where X is a leaving group, and copper(I) salts. The base may be a carbonate salt of an alkali metal (for example sodium, potassium or cesium). The copper salts may be copper halides, for example copper(I) iodide. The reactions are generally conducted in an organic solvent, for example acetonitrile or dimethylformamide, at temperatures between 0° C. and the boiling point of the solvent.
The pyrazoles of the general formula (E-III) can be prepared via a dealkylation of the pyrazoles (E-II) in the presence of acids, for example hydrobromic acid. The reactions are generally conducted in an organic solvent, for example acetic acid, at temperatures between 0° C. and the boiling point of the solvent.
The pyrazoles of the general formula (E-II) can be prepared via a bisalkylation of the pyrazolones (E-I) in the presence of bases and alkylating agents, for example R1—X where X is a leaving group. The base may be a carbonate salt of an alkali metal (for example sodium, potassium or cesium). The reactions are generally conducted in an organic solvent, for example acetonitrile or tetrahydrofuran, at temperatures between 0° C. and the boiling point of the solvent.
Pyrazolones of the general formula (E-I) are known from the literature and can be prepared, for example, by the methods described in Eur. J. Med. Chem. 2009, 44, 3852-7, J. Heterocyclic Chem. 2011, 48, 323-330, Org. Lett. 2016, 18, 6388-91, WO 2016/066664 A1, WO 2011/039338 A2 and the like.
Inventive compounds with A representing O, S(O)n and CR3R4 can also be prepared by the method specified in scheme 2.
The pyrazoles of the general formula (I) can be prepared via an alkylation of the pyrazolones (Ia) in the presence of bases and alkylating agents, for example R1—X where X is a leaving group. The base may be a carbonate salt of an alkali metal (for example sodium, potassium or cesium), or an amine (for example triethylamine). The reactions are generally conducted in an organic solvent, for example acetonitrile, tetrahydrofuran or dimethylformamide, at temperatures between 0° C. and the boiling point of the solvent.
The pyrazoles of the general formula (Ia) can be prepared via a deprotection of the pyrazoles (E-VI) in the presence of acids, for example trifluoroacetic acid. The reactions are generally conducted in an organic solvent, for example dichloromethane, or in neat form, at temperatures between 0° C. and the boiling point of the solvent. As is known to the person skilled in the art, the NH-pyrazoles Ia may also be in their corresponding other tautomeric form.
The pyrazoles of the general formula (E-VI) can be prepared via an alkylation of the pyrazolones (E-V) in the presence of bases and alkylating agents, for example Q2-X where X is a leaving group. The base may be a carbonate salt of an alkali metal (for example sodium, potassium or cesium). The reactions are generally conducted in an organic solvent, for example butyronitrile, acetonitrile or dimethylformamide, at temperatures between 0° C. and the boiling point of the solvent.
The compounds of the general formula (E-V) can be obtained by reaction of the building blocks (E-IV) with hydrazines, for example NH2NH-PG where PG is a protecting group. The hydrazines used may be in free form or in the form of salts, for example of hydrochlorides. In the case of use of salts, it may be advantageous to add an organic or inorganic base to the reaction mixture, for example triethylamine. The protecting group PG may, for example, be benzyl or 4-methoxybenzyl. The reaction is generally conducted in an organic solvent, for example ethanol, at temperatures between 0° C. and the boiling point of the solvent.
Keto esters of the general formula (E-IV) are known from the literature and can be prepared, for example, by the methods described in Tetrahedron, 1982, 38, 85-91, J. Am. Chem. Soc. 2013, 135, 14556-14559 and the like. As is known to the person skilled in the art, the keto esters E-IV may also be in their corresponding other tautomeric form.
Inventive compounds can also be prepared, for example, by the method specified in scheme 3.
The pyrazoles of the general formula (Ib) can be prepared via a substitution reaction of the pyrazoles (E-IX) with sulfur nucleophiles, for example Q2-SH, in the presence of bases and copper(I) salts. The base may be a hydride salt of an alkali metal (for example sodium). The copper salts may be copper halides, for example copper(I) iodide. The reactions are generally conducted in an organic solvent, for example dimethylformamide, at temperatures between 0° C. and the boiling point of the solvent.
The pyrazoles of the general formula (E-IX) can be prepared via an iodination of the pyrazoles (E-VIII) with a suitable iodinating agent, for example iodine, in the presence of cerium ammonium nitrate. The reactions are generally conducted in an organic solvent, for example acetonitrile, at temperatures between 0° C. and the boiling point of the solvent.
The pyrazoles of the general formula (E-VIII) can be prepared via an alkylation of the pyrazolones (E-VII) in the presence of bases, alkylating agents, for example Q2-X where X is a leaving group, and copper(I) salts. The base may be a carbonate salt of an alkali metal (for example sodium, potassium or cesium). The copper salts may be copper halides, for example copper(I) iodide. The reactions are generally conducted in an organic solvent, for example acetonitrile or dimethylformamide, at temperatures between 0° C. and the boiling point of the solvent.
Pyrazoles of the general formula (E-VII) are known from the literature and can be prepared, for example, by the methods described in J. Org. Chem. 2015, 80, 6001-6011, WO2013/110643 A1, U.S. Pat. No. 5,663,365 A, WO2015/50989 A2, WO2015/095788 and the like. As is known to the person skilled in the art, the pyrazoles (E-VII) may also be in their corresponding other tautomeric form.
Inventive compounds can also be prepared, for example, by the method specified in scheme 4.
The pyrazoles of the general formula (Ic) can be prepared via a Suzuki reaction of the pyrazoles (E-IX) with boronic acids, for example Q2-B(OH)2, in the presence of bases and palladium catalysts (for example PdCl2(dppf)(CH2Cl2)). The base may be a carbonate salt of an alkali metal (for example sodium, potassium or cesium). The reactions are generally conducted in an organic solvent, for example dioxane, at temperatures between 0° C. and the boiling point of the solvent.
Inventive compounds can also be prepared, for example, by the method specified in scheme 5.
The pyrazoles of the general formula (Ie) can be prepared via an alkylation of the pyrazolones (Id) in the presence of bases and alkylating agents, for example R5—X where X is a leaving group. The base may be a hydride salt of an alkali metal (for example sodium). The reactions are generally conducted in an organic solvent, for example acetonitrile, tetrahydrofuran or dimethylformamide, at temperatures between 0° C. and the boiling point of the solvent.
The pyrazoles of the general formula (Id) can be prepared via a Buckwald-Hartwig coupling of the pyrazoles (E-XI) with aryl halide or aryl triflate, for example Q1-X, in the presence of bases, palladium catalysts (for example tris(dibenzylideneacetone)dipalladium(0)) and ligands (for example Xantphos). The base may be a phosphate salt of an alkali metal (for example sodium, potassium or cesium). The reactions are generally conducted in an organic solvent, for example toluene, at temperatures between 0° C. and the boiling point of the solvent.
The pyrazoles of the general formula (E-XI) can be prepared via a reduction of the pyrazoles (E-X). Such reactions are known to those skilled in the art and are described, for example, in WO2008/8375 A2 and WO2011/3065 A2.
The pyrazoles of the general formula (E-X) can be prepared via a nitration of the pyrazoles (E-VIII). Such reactions are known to those skilled in the art and are described, for example, in WO2005/99688 A2 and US2014/194452 A1.
Inventive compounds with n representing 1 and 2 can be prepared, for example, by the method specified in scheme 6.
The sulfones and sulfoxides of the general formula (If) can be prepared via an oxidation of the pyrazoles (Ib). Such reactions are known to the person skilled in the art and are described, for example, in Eur. J. Med. Chem. 2014, 71, 168-184 and Org. Lett. 2013, 15, 3994-3997.
Selected detailed synthesis examples for the inventive compounds of the general formula (I) are given below. The 1H NMR, 13C-NMR and 19F-NMR spectroscopy data reported for the chemical examples described in the sections which follow (400 MHz for 1H-NMR and 150 MHz for 13C-NMR and 375 MHz for 19F-NMR, solvent CDCl3, CD3OD or d6-DMSO, internal standard: tetramethylsilane δ=0.00 ppm), were obtained on a Bruker instrument, and the signals listed have the meanings given below: br=broad; s=singlet, d=doublet, t=triplet, dd=doublet of doublets, ddd=doublet of a doublet of doublets, m=multiplet, q=quartet, quint=quintet, sext=sextet, sept=septet, dq=doublet of quartets, dt=doublet of triplets. In the case of diastereomer mixtures, either the significant signals for each of the two diastereomers are reported or the characteristic signal of the main diastereomer is reported. The abbreviations used for chemical groups have, for example, the following meanings: Me=CH3, Et=CH2CH3, t-Hex=C(CH3)2CH(CH3)2, t-Bu=C(CH3)3, n-Bu=unbranched butyl, n-Pr=unbranched propyl, i-Pr=branched propyl, c-Pr=cyclopropyl, c-Hex=cyclohexyl.
5-Methyl-4-phenylsulfanyl-1,2-dihydropyrazol-3-one (7.46 g, 36.2 mmol, 1.0 equiv) was dissolved in acetonitrile (485 ml), and potassium carbonate (15.0 g, 109 mmol, 3.0 equiv) was added. Dimethyl sulfate (3.4 ml, 36.2 mmol, 1.0 equiv) was added to the resulting reaction mixture at 0° C., and it was stirred at 0° C. for 15 minutes and then at 70° C. for 45 minutes. Dimethyl sulfate (6.8 ml, 72.4 mmol, 2.0 equiv) was added once again to the resulting reaction mixture and it was stirred at 70° C. for a further 3 hours and then cooled down to room temperature, water and dichloromethane were added and the phases were subsequently separated. The aqueous phase was extracted repeatedly with dichloromethane, and then the combined organic phases were washed with water and saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. By final purification of the resulting crude product by column chromatography (ethyl acetate/heptane gradient), 3-methoxy-1,5-dimethyl-4-phenylsulfanylpyrazole was isolated in the form of a colorless solid (6.80 g, 80% of theory).
1H-NMR (400 MHz, CDCl3 δ, ppm) 7.22-7.18 (m, 2H), 7.10-7.05 (m, 3H), 3.93 (s, 3H), 3.72 (s, 3H), 2.23 (s, 3H).
3-Methoxy-1,5-dimethyl-4-phenylsulfanylpyrazole (6.80 g, 29.0 mmol, 1.0 equiv) was dissolved in acetic acid (95 ml), and a solution of 45% hydrobromic acid in acetic acid (35.0 ml, 290 mmol, 10 equiv) was added. The resulting reaction mixture was stirred at 90° C. for 18 hours and then cooled down to room temperature and concentrated. The resulting solids were dissolved in ethyl acetate, and the solution was washed with water and saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. By final recrystallization (1:1 ethyl acetate:methanol) of the resulting crude product, 1,5-dimethyl-4-phenylsulfanylpyrazol-3-ol was isolated in the form of a colorless solid (3.12 g, 49% of theory).
1H-NMR (400 MHz, d6-DMSO δ, ppm) 10.04 (s, 1H), 7.26-7.22 (m, 2H), 7.10-7.06 (m, 1H), 7.00-6.98 (m, 2H), 3.60 (s, 3H), 2.15 (s, 3H).
Under argon, 1,5-dimethyl-4-phenylsulfanylpyrazol-3-ol (300 mg, 1.36 mmol, 1.0 equiv) and 2-chloropyrimidine (156 mg, 1.36 mmol, 1.0 equiv) were dissolved in anhydrous dimethylformamide (5 ml), and cesium carbonate (890 mg, 2.72 mmol, 2.0 equiv) and copper(I) iodide (25.9 mg, 0.136 mmol, 0.1 equiv) were added. The resulting reaction mixture was stirred at 100° C. for 6 hours and then cooled down to room temperature, ethyl acetate and water were added and the phases were subsequently separated. The aqueous phase was extracted repeatedly with ethyl acetate, and then the combined organic phases were washed with water (×3) and saturated sodium chloride solution (×1), dried over magnesium sulfate, filtered and concentrated. By final purification of the resulting crude product by column chromatography (ethyl acetate/heptane gradient), 2-(1,5-dimethyl-4-phenylsulfanylpyrazol-3-yl)oxypyrimidine was isolated in the form of a yellow oil (170 mg, 43% of theory).
1H-NMR (400 MHz, CDCl3 δ, ppm) 8.44 (d, 2H), 7.17-7.13 (m, 2H), 7.09-7.04 (m, 3H), 6.96 (t, 1H), 3.83 (s, 3H), 2.30 (s, 3H).
Analogously to the synthesis of 3-methoxy-1,5-dimethyl-4-phenylsulfanylpyrazole, 5.37 g of 4-(2,4-difluorophenoxy)-5-methyl-1,2-dihydropyrazol-3-one was used to obtain 2.35 g (39%) of 4-(2,4-difluorophenoxy)-3-methoxy-1,5-dimethylpyrazole.
1H-NMR (400 MHz, CDCl3 δ, ppm) 7.11-7.05 (m, 1H), 6.88-6.83 (m, 1H), 6.76-6.70 (m, 1H), 3.34 (s, 3H), 3.17 (s, 3H), 2.14 (s, 3H).
Analogously to the synthesis of 1,5-dimethyl-4-phenylsulfanylpyrazol-3-ol, 2.35 g of 4-(2,4-difluorophenoxy)-3-methoxy-1,5-dimethylpyrazole was used to obtain 2.93 g of 4-(2,4-difluorophenoxy)-1,5-dimethylpyrazol-3-ol with a little acetic acid.
1H-NMR (400 MHz, CDCl3 δ, ppm) 6.98-6.84 (m, 2H), 6.77-6.70 (m, 1H), 3.56 (s, 3H), 2.12 (s, 3H).
Analogously to the synthesis of 2-(1,5-dimethyl-4-phenylsulfanylpyrazol-3-yl)oxypyrimidine, 150 mg of 4-(2,4-difluorophenoxy)-1,5-dimethylpyrazol-3-ol was used to obtain 97 mg (46%) of 2-[4-(2,4-difluorophenoxy)-1,5-dimethylpyrazol-3-yl]oxy-5-fluoropyrimidine.
1H-NMR (400 MHz, CDCl3 δ, ppm) 8.34 (s, 2H), 6.97-6.93 (m, 1H), 6.80-6.77 (m, 1H), 6.69-6.66 (m, 1H), 3.76 (s, 3H), 2.21 (s, 3H).
4-[(4-Fluorophenyl)methyl]-5-methyl-1,2-dihydropyrazol-3-one (7.60 g, 37.0 mmol, 1.0 equiv) was dissolved in acetonitrile (220 ml), and potassium carbonate (12.8 g, 92.9 mmol, 2.4 equiv) was added. The resulting reaction mixture was cooled down to a temperature of 0° C., dimethyl sulfate (5.49 ml, 58.1 mmol, 1.5 equiv) was added and then the reaction mixture was stirred at 0° C. for 30 minutes and then at room temperature for 18 hours. Water was added, the aqueous phase was extracted repeatedly with dichloromethane, and the combined organic phases were then dried over magnesium sulfate, filtered and concentrated. By final purification of the resulting crude product by column chromatography (ethyl acetate/heptane gradient), 4-[(4-fluorophenyl)methyl]-3-methoxy-1,5-dimethylpyrazole was isolated (720 mg, 8% of theory).
1H-NMR (400 MHz, CDCl3 δ, ppm) 7.13-7.10 (m, 2H), 6.94-6.90 (m, 2H), 3.88 (s, 3H), 3.62 (s, 3H), 3.60 (s, 2H), 2.06 (s, 3H).
4-[(4-Fluorophenyl)methyl]-3-methoxy-1,5-dimethylpyrazole (710 mg, 3.03 mmol, 1.0 equiv) was dissolved in acetic acid (9 ml), and a solution of 45% hydrobromic acid in acetic acid (3.7 ml, 30.3 mmol, 10 equiv) was added. The resulting reaction mixture was stirred at 140° C. for 8 hours and then cooled down to room temperature and concentrated. The resulting solids were dissolved in ethyl acetate, and the solution was washed with water and saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. In this way, 4-[(4-fluorophenyl)methyl]-1,5-dimethylpyrazol-3-ol is obtained (450 mg, 67% of theory).
1H-NMR (400 MHz, CDCl3 δ, ppm) 7.18-7.15 (m, 2H), 6.96-6.91 (m, 2H), 3.65 (s, 2H), 3.62 (s, 3H), 2.07 (s, 3H).
Analogously to the synthesis of 2-(1,5-dimethyl-4-phenylsulfanylpyrazol-3-yl)oxypyrimidine, 145 mg of 4-[(4-fluorophenyl)methyl]-1,5-dimethylpyrazol-3-ol was used to obtain 93 mg (45%) of 5-fluoro-2-[4-[(4-fluorophenyl)methyl]-1,5-dimethylpyrazol-3-yl]oxypyrimidine.
1H-NMR (400 MHz, CDCl3 δ, ppm) 8.32 (s, 2H), 7.06-7.03 (m, 2H), 6.87-6.82 (m, 2H), 3.74 (s, 3H), 3.59 (s, 2H), 2.16 (s, 3H).
Ethyl (E)-3-hydroxy-2-phenylsulfanylbut-2-enoate (9.16 g, 38.4 mmol, 1.0 equiv) was dissolved in ethanol (65 ml), and (4-methoxyphenyl)hydrazine (7.96 g, 57.6 mmol, 1.5 equiv) was added. The resulting reaction mixture was stirred at 90° C. for 2 hours and then cooled down to room temperature and concentrated, and water and ethyl acetate were added. The resulting solids were filtered off and washed with water and ethyl acetate. In this way, 2-[(4-methoxyphenyl)methyl]-5-methyl-4-phenylsulfanylpyrazol-3-ol (9.30 g, 74% of theory) was obtained in the form of a colorless solid.
1H-NMR (400 MHz, d6-DMSO δ, ppm) 7.27-7.23 (m, 2H), 7.16-7.07 (m, 3H), 6.99-6.89 (m, 4H), 4.99 (s, 2H), 3.73 (s, 3H), 1.98 (s, 3H).
2-[(4-Methoxyphenyl)methyl]-5-methyl-4-phenylsulfanylpyrazol-3-ol (4.45 g, 13.6 mmol, 1.0 equiv) was dissolved in butyronitrile (45 ml), and 2-chloropyrimidine (3.12 g, 27.3 mmol, 2.0 equiv) and cesium carbonate (7.55 g, 23.2 mmol, 1.7 equiv) were added. The resulting reaction mixture was stirred at 160° C. for 8 hours and then cooled down to room temperature and concentrated, and water was added. The aqueous phase was extracted repeatedly with ethyl acetate, and the combined organic phases were then dried over magnesium sulfate, filtered and concentrated. By final purification of the resulting crude product by column chromatography (ethyl acetate/heptane gradient), 2-[2-[(4-methoxyphenyl)methyl]-5-methyl-4-phenylsulfanylpyrazol-3-yl]oxypyrimidine was isolated (5.23 g, 95% of theory).
1H-NMR (400 MHz, CDCl3 δ, ppm) 8.37 (d, 2H), 7.20-7.12 (m, 4H), 7.06-6.98 (m, 4H), 6.77-6.75 (m, 2H), 5.15 (s, 2H), 3.75 (s, 3H), 2.22 (s, 3H).
2-[2-[(4-Methoxyphenyl)methyl]-5-methyl-4-phenylsulfanylpyrazol-3-yl]oxypyrimidine (5.59 g, 13.8 mmol, 1.0 equiv) was dissolved in trifluoroacetic acid (37 ml), stirred at 50° C. for 2 hours and then cooled down to room temperature and concentrated. By final purification of the resulting crude product by column chromatography (ethyl acetate/heptane gradient), 2-[(5-methyl-4-phenylsulfanyl-1H-pyrazol-3-yl)oxy]pyrimidine was isolated (3.61 g, 90% of theory).
1H-NMR (400 MHz, CDCl3 δ, ppm) 8.45 (d, 2H), 7.17-7.13 (m, 2H), 7.07-7.03 (m, 3H), 6.98 (t, 1H), 2.29 (s, 3H).
2-[(5-Methyl-4-phenylsulfanyl-1H-pyrazol-3-yl)oxy]pyrimidine (150 mg, 0.53 mmol, 1.0 equiv) was dissolved in acetonitrile (3 ml), and cesium carbonate (206 mg, 0.63 mmol, 1.2 equiv) and iodoethane (166 mg, 1.06 mmol, 2.0 equiv) were added. The resulting reaction mixture was stirred at room temperature for 1 hour and then 2 M aqueous ammonia was added. The aqueous phase was extracted repeatedly with ethyl acetate, and then the combined organic phases were washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. By final purification of the resulting crude product by column chromatography (ethyl acetate/heptane gradient), 2-(1-ethyl-5-methyl-4-phenylsulfanylpyrazol-3-yl)oxypyrimidine was isolated (106 mg, 64% of theory).
1H-NMR (400 MHz, CDCl3 δ, ppm) 8.43 (d, 2H), 7.17-7.13 (m, 2H), 7.08-7.03 (m, 3H), 6.95 (t, 1H), 4.13 (q, 2H), 2.31 (s, 3H), 1.48 (t, 3H).
2-[(5-Methyl-4-phenylsulfanyl-1H-pyrazol-3-yl)oxy]pyrimidine (150 mg, 0.53 mmol, 1.0 equiv) was dissolved in tetrahydrofuran (3 ml), and di-tert-butyl dicarbonate (138 mg, 0.63 mmol, 1.2 equiv) and triethylamine (0.11 ml, 0.79 mmol, 1.5 equiv) were added. The resultant reaction mixture was stirred at room temperature for 18 hours and then diluted with ethyl acetate, washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. By final purification of the resulting crude product by column chromatography (ethyl acetate/heptane gradient), tert-butyl 5-methyl-4-phenylsulfanyl-3-pyrimidin-2-yloxypyrazole-1-carboxylate was isolated (171 mg, 84% of theory).
1H-NMR (400 MHz, CDCl3 δ, ppm) 8.42 (d, 2H), 7.19-7.15 (m, 2H), 7.11-7.06 (m, 3H), 6.98 (t, 1H), 2.63 (s, 3H), 1.65 (s, 9H).
Under argon, 2-[(5-methyl-4-phenylsulfanyl-1H-pyrazol-3-yl)oxy]pyrimidine (150 mg, 0.53 mmol, 1.0 equiv) was dissolved in anhydrous dimethylformamide (2 ml), and ethyl 2-chloro-2,2-difluoroacetate (100 mg, 0.63 mmol, 1.2 equiv) and potassium carbonate (146 mg, 1.06 mmol, 2.0 equiv) were added. The resulting reaction mixture was stirred at 60° C. for 12 hours and then at 140° C. for 6 hours and then cooled down to room temperature, and water was added. The aqueous phase was extracted repeatedly with dichloromethane, and the combined organic phases were then dried over magnesium sulfate, filtered and concentrated. By final purification of the resulting crude product by column chromatography (ethyl acetate/heptane gradient), 2-[1-(difluoromethyl)-5-methyl-4-phenylsulfanylpyrazol-3-yl]oxypyrimidine was isolated (17 mg, 10% of theory).
1H-NMR (400 MHz, CDCl3 δ, ppm) 8.43 (d, 2H), 7.21-7.07 (m, 6H), 7.00 (t, 1H), 2.52 (s, 3H).
1,5-Dimethyl-1H-pyrazol-3-ol hydrochloride (3.68 g, 24.8 mmol, 1.0 equiv) was dissolved in acetonitrile (100 ml), and 2-chloropyrimidine (2.84 g, 24.8 mmol, 1.0 equiv), cesium carbonate (28.2 g, 86.7 mmol, 3.5 equiv) and copper(I) iodide (0.36 g, 4.95 mmol, 0.2 equiv) were added. The resulting reaction mixture was stirred at 80° C. for 3 hours and then cooled down to room temperature, filtered and concentrated. By final purification of the resulting crude product by column chromatography (ethyl acetate/heptane gradient), 2-(1,5-dimethylpyrazol-3-yl)oxypyrimidine in the form of a brown oil was isolated (2.68 g, 55% of theory).
1H-NMR (400 MHz, CDCl3 δ, ppm) 8.59 (d, 2H), 7.04 (t, 1H), 5.83 (s, 1H), 3.74 (s, 3H), 2.29 (s, 3H).
2-(1,5-Dimethylpyrazol-3-yl)oxypyrimidine (4.00 g, 21.0 mmol, 1.0 equiv) was dissolved in acetonitrile (120 ml), and iodine (3.20 g, 12.6 mmol, 0.6 equiv) and ammonium cerium(IV) nitrate (6.92 g, 12.6 mmol, 0.6 equiv) were added. The resulting reaction mixture was stirred at room temperature for 3 hours and then concentrated. The resulting oil was dissolved in dichloromethane, and the solution was washed with 10% aqueous sodium thiosulfate, dried over magnesium sulfate, filtered and concentrated. In this way, 2-(4-iodo-1,5-dimethylpyrazol-3-yl)oxypyrimidine (5.92 g, 85% of theory) is obtained in the form of a brown oil.
1H-NMR (400 MHz, CDCl3 δ, ppm) 8.60 (d, 2H), 7.07 (t, 1H), 3.83 (s, 3H), 2.33 (s, 3H).
Under argon, 2,4-difluorothiophenol (104 mg, 0.71 mmol, 1.5 equiv) was dissolved in anhydrous dimethylformamide (4 ml) and cooled down to a temperature of 0° C., and sodium hydride (60% in oil, 28 mg, 0.71 mmol, 1.5 equiv) was added. The resulting reaction mixture was stirred at 0° C. for 10 minutes, and then 2-(4-iodo-1,5-dimethylpyrazol-3-yl)oxypyrimidine (150 mg, 0.48 mmol, 1.0 equiv) and copper(I) iodide (90 mg, 0.48 mmol, 1.0 equiv) were added. The resulting reaction mixture was stirred at 80° C. for 6 hours and then cooled down to room temperature, and water was added. The aqueous phase was extracted repeatedly with dichloromethane, and the combined organic phases were then dried over magnesium sulfate, filtered and concentrated. By final purification of the resulting crude product by column chromatography (ethyl acetate/heptane gradient), 2-[4-(2,4-difluorophenyl)sulfanyl-1,5-dimethylpyrazol-3-yl]oxypyrimidine was isolated in the form of a yellow oil (124 mg, 74% of theory).
1H-NMR (400 MHz, CDCl3 δ, ppm) 8.50 (d, 2H), 7.09-7.01 (m, 2H), 6.74-6.67 (m, 2H), 3.82 (s, 3H), 2.35 (s, 3H).
Methyl 3-hydroxy-1-methyl-1H-pyrazole-5-carboxylate (1.50 g, 9.61 mmol, 1.0 equiv) was dissolved in dimethylformamide (48 ml), and 2-chloropyrimidine (1.10 g, 9.61 mmol, 1.0 equiv), cesium carbonate (6.26 g, 19.2 mmol, 2.0 equiv) and copper(I) iodide (140 mg, 1.92 mmol, 0.2 equiv) were added. The resulting reaction mixture was stirred at 80° C. for 3 hours and then cooled down to room temperature, and ethyl acetate was added. The organic phase was washed with water, dried over magnesium sulfate, filtered and concentrated. The resulting solids were suspended in heptane, stirred and then filtered. In this way, methyl 1-methyl-3-(pyrimidin-2-yloxy)-1H-pyrazole-5-carboxylate is obtained (1.00 g, 44% of theory).
1H-NMR (400 MHz, CDCl3 δ, ppm) 8.60 (d, 2H), 7.09 (t, 1H), 6.65 (s, 1H), 4.16 (s, 3H), 3.89 (s, 3H).
Analogously to the synthesis of 2-(4-iodo-1,5-dimethylpyrazol-3-yl)oxypyrimidine, 1.00 g of methyl 1-methyl-3-(pyrimidin-2-yloxy)-1H-pyrazole-5-carboxylate was used to obtain 1.55 g (100%) of methyl 4-iodo-1-methyl-3-(pyrimidin-2-yloxy)-1H-pyrazole-5-carboxylate.
1H-NMR (400 MHz, CDCl3 δ, ppm) 8.60 (d, 2H), 7.11 (t, 1H), 4.20 (s, 3H), 3.95 (s, 3H).
Analogously to the synthesis of 2-[4-(2,4-difluorophenyl)sulfanyl-1,5-dimethylpyrazol-3-yl]oxypyrimidine, 150 mg of methyl 4-iodo-1-methyl-3-(pyrimidin-2-yloxy)-1H-pyrazole-5-carboxylate was used to obtain 45 mg (28%) of methyl 4-[(4-fluorophenyl)sulfanyl]-1-methyl-3-(pyrimidin-2-yloxy)-1H-pyrazole-5-carboxylate.
1H-NMR (400 MHz, CDCl3 δ, ppm) 8.47 (d, 2H), 7.22-7.19 (m, 2H), 7.02 (t, 1H), 6.86-6.82 (m, 2H), 4.17 (s, 3H), 3.86 (s, 3H).
Under argon, 2-(4-iodo-1,5-dimethylpyrazol-3-yl)oxypyrimidine (150 mg, 0.48 mmol, 1.0 equiv) was dissolved in dioxane (4 ml), and 3,5-difluorophenylboronic acid (165 mg, 1.04 mmol, 2.2 equiv), PdCl2(dppf)(CH2Cl2) (58 mg, 0.071 mmol, 0.15 equiv), cesium carbonate (464 mg, 1.42 mmol, 3.0 equiv) and water (1 ml) were added successively. The resulting reaction mixture was stirred in a microwave at 130° C. for 1 hour and then cooled down to room temperature, and saturated sodium hydrogencarbonate solution was added. The aqueous phase was extracted repeatedly with dichloromethane, and the combined organic phases were then dried over magnesium sulfate, filtered and concentrated. By final purification of the resulting crude product by column chromatography (ethyl acetate/heptane gradient), 2-[4-(3,5-difluorophenyl)-1,5-dimethylpyrazol-3-yl]oxypyrimidine was isolated in the form of a yellow solid (111 mg, 74% of theory).
1H-NMR (400 MHz, CDCl3 δ, ppm) 8.53 (d, 2H), 7.00 (t, 1H), 6.88-6.86 (m, 2H), 6.64-6.60 (m, 1H), 3.82 (s, 3H), 2.38 (s, 3H).
2-(1,5-Dimethylpyrazol-3-yl)oxypyrimidine (1.20 g, 6.30 mmol, 1.0 equiv) was dissolved in trifluoroacetic acid (10 ml), and trifluoroacetic anhydride (6.24 ml, 9.28 mmol, 7.0 equiv) was added. The resulting reaction mixture was cooled down to a temperature of 0° C., ammonium nitrate (530 mg, 6.62 mmol, 1.05 equiv) was added in portions and then the reaction mixture was stirred at room temperature for 2.5 hours. Water was added, the aqueous phase was extracted repeatedly with dichloromethane, and the combined organic phases were then dried over magnesium sulfate, filtered and concentrated. By final purification of the resulting crude product by column chromatography (ethyl acetate/heptane gradient), 2-(1,5-dimethyl-4-nitropyrazol-3-yl)oxypyrimidine was isolated (980 mg, 66% of theory).
1H-NMR (400 MHz, CDCl3 δ, ppm) 8.57 (d, 2H), 7.11 (t, 1H), 3.84 (s, 3H), 2.69 (s, 3H).
2-(1,5-Dimethyl-4-nitropyrazol-3-yl)oxypyrimidine (5.00 g, 21.3 mmol, 1.0 equiv) was dissolved in ethanol (200 ml) and water (50 ml), and iron (3.56 g, 63.8 mmol, 3.0 equiv) and ammonium chloride (1.14 g, 21.3 mmol, 1.0 equiv) were added. The resulting reaction mixture was stirred at 80° C. for 6 hours and then cooled down to room temperature, filtered through kieselguhr and concentrated. In this way, 1,5-dimethyl-3-pyrimidin-2-yloxypyrazol-4-amine (4.07 g, 93% of theory) was obtained in the form of a brown solid.
1H-NMR (400 MHz, CDCl3 δ, ppm) 8.60 (d, 2H), 7.05 (t, 1H), 3.70 (s, 3H), 2.21 (s, 3H).
1,5-Dimethyl-3-pyrimidin-2-yloxypyrazol-4-amine (220 mg, 1.07 mmol, 1.0 equiv) and 1-bromo-2,4-difluorobenzene (290 mg, 1.50 mmol, 1.4 equiv) were dissolved in toluene (6 ml), and tris(dibenzylideneacetone)dipalladium(0) (49 mg, 0.054 mmol, 0.05 equiv), Xantphos (62 mg, 0.11 mmol, 0.1 equiv) and potassium phosphate (455 mg, 2.14 mmol, 2.0 equiv) were added. The resulting reaction mixture was degassed with argon and stirred at 120° C. for 2 hours and then cooled down to room temperature, diluted with dichloromethane, filtered and concentrated. By final purification of the resulting crude product by column chromatography (ethyl acetate/heptane gradient), N-(2,4-difluorophenyl)-1,5-dimethyl-3-(pyrimidin-2-yloxy)-1H-pyrazol-4-amine was isolated (120 mg, 34% of theory).
1H-NMR (400 MHz, CDCl3 δ, ppm) 8.50 (d, 2H), 7.00 (t, 1H), 6.70-6.61 (m, 2H), 6.57-6.53 (m, 1H), 3.78 (s, 3H), 2.18 (s, 3H).
Under argon, N-(2,4-difluorophenyl)-1,5-dimethyl-3-(pyrimidin-2-yloxy)-1H-pyrazol-4-amine (60 mg, 0.19 mmol, 1.0 equiv) was dissolved in anhydrous dimethylformamide (3 ml) and cooled down to a temperature of 0° C., and sodium hydride (60% in oil, 9 mg, 0.23 mmol, 1.2 equiv) was added. The resulting reaction mixture was stirred at 0° C. for 10 minutes, and then iodomethane (13 μl, 0.21 mmol, 1.1 equiv) was added. The resulting reaction mixture was stirred at room temperature for 6 hours, and then water was added. The aqueous phase was extracted repeatedly with dichloromethane, and the combined organic phases were then dried over magnesium sulfate, filtered and concentrated. By final purification of the resulting crude product by column chromatography (ethyl acetate/heptane gradient), N-(2,4-difluorophenyl)-N, 1,5-trimethyl-3-(pyrimidin-2-yloxy)-1H-pyrazol-4-amine was isolated (42 mg, 67% of theory).
1H-NMR (400 MHz, CDCl3 δ, ppm) 8.43 (d, 2H), 6.93 (t, 1H), 6.79-6.75 (m, 1H), 6.65-6.59 (m, 1H), 6.54-6.53 (m, 1H), 3.74 (s, 3H), 3.10 (s, 3H), 2.17 (s, 3H).
In analogy to the preparation examples cited above and recited at the appropriate point, and taking account of the general information relating to the preparation of substituted (het)arylpyrazolamides, the compounds of the general formula (I) specified hereinafter and shown in table I are obtained.
In analogy to the preparation examples cited above and recited at the appropriate point, and taking account of the general information relating to the preparation of substituted (het)arylpyrazolamides, the intermediates of the general formula (II) specified hereinafter and shown in table II are obtained.
NMR Data of Selected Examples (End Products and Intermediates)
NMR Peak List Method
The 1H-NMR data of selected examples are noted in the form of 1H-NMR peak lists. For each signal peak, first the δ value in ppm and then the signal intensity in round brackets are listed. The δ value-signal intensity number pairs for different signal peaks are listed with separation from one another by semicolons.
The peak list for one example therefore takes the form of:
δ1 (intensity1); δ2 (intensity2); . . . ; δi (intensityi); . . . ; δn (intensityn)
The intensity of sharp signals correlates with the height of the signals in a printed example of an NMR spectrum in cm and shows the true ratios of the signal intensities. In the case of broad signals, several peaks or the middle of the signal and the relative intensity thereof may be shown in comparison to the most intense signal in the spectrum.
For calibration of the chemical shift of 1H NMR spectra we use tetramethylsilane and/or the chemical shift of the solvent, particularly in the case of spectra measured in DMSO. Therefore, the tetramethylsilane peak may but need not occur in NMR peak lists.
The lists of the 1H NMR peaks are similar to the conventional 1H NMR printouts and thus usually contain all peaks listed in a conventional NMR interpretation.
In addition, like conventional 1H NMR printouts, they may show solvent signals, signals of stereoisomers of the target compounds, which likewise form part of the subject-matter of the invention, and/or peaks of impurities.
In the reporting of compound signals in the delta range of solvents and/or water, our lists of 1H NMR peaks show the usual solvent peaks, for example peaks of DMSO in DMSO-D6 and the peak of water, which usually have a high intensity on average.
The peaks of stereoisomers of the target compounds and/or peaks of impurities usually have a lower intensity on average than the peaks of the target compounds (for example with a purity of >90%).
Such stereoisomers and/or impurities may be typical of the particular preparation process. Their peaks can thus help in identifying reproduction of our preparation process with reference to “by-product fingerprints”.
An expert calculating the peaks of the target compounds by known methods (MestreC, ACD simulation, but also with empirically evaluated expected values) can, if required, isolate the peaks of the target compounds, optionally using additional intensity filters. This isolation would be similar to the relevant peak picking in conventional 1H NMR interpretation.
Further details of 1H NMR peak lists can be found in the Research Disclosure Database Number 564025.
NMR Data of the End Products (Peak List)
NMR Data of Selected Intermediates (Peak List)
NMR Data of Selected Intermediates (Manual Evaluation)
1H-NMR (400 MHz, CDCl3): δ = 8.26 (s, 2H), 5.81 (s, 1H), 3.87 (s, 3H), 3.72 (s, 3H),
1H-NMR (400 MHz, CDCl3): δ = 8.46 (d, 1H), 7.93 (dd, 1H), 7.13 (d, 1H), 3.83 (s, 3H),
1H-NMR (400 MHz, CDCl3): δ = 8.83 (s, 2H), 3.84 (s, 3H), 2.35 (s, 3H)
1H-NMR (400 MHz, CDCl3): δ = 8.25 (s, 2H), 3.88 (s, 3H), 3.82 (s, 3H), 2.32 (s, 3H)
1H-NMR (400 MHz, CDCl3): δ = 7.26-7.14 (m, 5H), 3.88 (s, 3H), 3.64 (s, 2H), 3.62 (s, 3H),
1H-NMR (400 MHz, CDCl3): δ = 7.29-7.24 (m, 2H), 7.01-6.92 (m, 3H), 3.87 (s, 3H), 3.64
1H-NMR (400 MHz, CDCl3): δ = 7.30-7.26 (m, 2H), 7.01-6.98 (m. 3H), 3.57 (s, 3H), 2.07
1H-NMR (400 MHz, d6-DMSO): δ = 7.28-7.24 (m, 1H), 7.04-7.00 (m, 1H), 6.84-6.78 (m,
1H-NMR (400 MHz, d6-DMSO): δ = 7.49-7.46 (m, 2H), 7.31-7.29 (m, 2H), 3.62 (s, 3H),
1H-NMR (400 MHz, d6-DMSO): δ = 7.28-7.26 (m, 1H), 7.16-7.14 (m, 1H), 7.00-6.95 (m,
1H-NMR (400 MHz, d6-DMSO): δ = 7.42-7.38 (m, 1H), 7.09-7.05 (m, 1H), 6.91-6.87 (m,
1H-NMR (400 MHz, CDCl3): δ = 7.26-6.99 (m, 5H), 3.83 (s, 3H), 1.64-1.60 (m, 1H),
1H-NMR (400 MHz, d6-DMSO): δ = 7.29-7.25 (m, 1H), 7.14 (d, 1H), 6.96-6.92 (m, 2H),
1H-NMR (400 MHz, d6-DMSO): δ = 7.37-7.30 (m, 1H), 7.01-6.96 (m, 1H), 6.81-6.78 (m,
1H-NMR (400 MHz, CDCl3): δ = 7.32-7.30 (m, 3H), 7.20-7.19 (m, 1H), 3.92 (s, 3H),
1H-NMR (400 MHz, CDCl3): δ = 7.01-6.99 (m, 1H), 6.85-6.79 (m, 2H), 3.92 (s, 3H),
1H-NMR (400 MHz, CDCl3): δ = 7.14-7.10 (m, 1H), 7.05-7.02 (m, 1H), 6.99-6.93
1H-NMR (400 MHz, CDCl3): δ = 6.89-6.86 (m, 1H), 6.79-6.73 (m, 2H), 3.92 (s, 3H),
1H-NMR (400 MHz, CDCl3): δ = 7.21-7.18 (m, 2H), 7.08-7.03 (m, 3H), 3.90 (s, 3H),
1H-NMR (400 MHz, d6-DMSO): δ = 8.83 (s, 2H), 4.07 (s, 3H), 3.88 (s, 3H)
The present invention further provides for the use of one or more compounds of the general formula (I) and/or salts thereof, as defined above, preferably in one of the embodiments identified as preferred or particularly preferred, in particular one or more compounds of the formulae (I-001) to (I-240) and/or salts thereof, in each case as defined above, as herbicide and/or plant growth regulator, preferably in crops of useful plants and/or ornamentals.
The present invention further provides a method for controlling harmful plants and/or for regulating the growth of plants, characterized in that an effective amount
The present invention also provides a method for controlling unwanted plants, preferably in crops of useful plants, characterized in that an effective amount
The present invention also further provides methods for controlling regulating the growth of plants, preferably of useful plants, characterized in that an effective amount
In this context, the compounds according to the invention or the compositions according to the invention can be applied for example by pre-sowing (if appropriate also by incorporation into the soil), pre-emergence and/or post-emergence processes. Specific examples of some representatives of the monocotyledonous and dicotyledonous weed flora which can be controlled by the compounds according to the invention are as follows, though there is no intention to restrict the enumeration to particular species.
In a method according to the invention for controlling harmful plants or for regulating the growth of plants, one or more compounds of the general formula (I) and/or salts thereof are preferably employed for controlling harmful plants or for regulating growth in crops of useful plants or ornamental plants, where in a preferred embodiment the useful plants or ornamental plants are transgenic plants.
The inventive compounds of the general formula (I) and/or their salts are suitable for controlling the following genera of monocotyledonous and dicotyledonous harmful plants:
Monocotyledonous Harmful Plants of the Genera:
Aegilops, Agropyron, Agrostis, Alopecurus, Apera, Avena, Brachiaria, Bromus, Cenchrus, Commelina, Cynodon, Cyperus, Dactyloctenium, Digitaria, Echinochloa, Eleocharis, Eleusine, Eragrostis, Eriochloa, Festuca, Fimbristylis, Heteranthera, Imperata, Ischaemum, Leptochloa, Lolium, Monochoria, Panicum, Paspalum, Phalaris, Phleum, Poa, Rottboellia, Sagittaria, Scirpus, Setaria, Sorghum.
Dicotyledonous Harmful Plants of the Genera:
Abutilon, Amaranthus, Ambrosia, Anoda, Anthemis, Aphanes, Artemisia, Atriplex, Bellis, Bidens, Capsella, Carduus, Cassia, Centaurea, Chenopodium, Cirsium, Convolvulus, Datura, Desmodium, Emex, Erysimum, Euphorbia, Galeopsis, Galinsoga, Galium, Hibiscus, Ipomoea, Kochia, Lamium, Lepidium, Lindernia, Matricaria, Mentha, Mercurialis, Mullugo, Myosotis, Papaver, Pharbitis, Plantago, Polygonum, Portulaca, Ranunculus, Raphanus, Rorippa, Rotala, Rumex, Salsola, Senecio, Sesbania, Sida, Sinapis, Solanum, Sonchus, Sphenoclea, Stellaria, Taraxacum, Thlaspi, Trifolium, Urtica, Veronica, Viola, Xanthium.
When the inventive compounds of the general formula (I) are applied to the soil surface before germination of the harmful plants (weed grasses and/or broad-leaved weeds) (pre-emergence method), either the seedlings of the weed grasses or broad-leaved weeds are prevented completely from emerging or they grow until they have reached the cotyledon stage, but then stop growing and eventually, after three to four weeks have elapsed, die completely.
If the active compounds of the general formula (I) are applied post-emergence to the green parts of the plants, growth stops after the treatment, and the harmful plants remain at the growth stage at the time of application, or they die completely after a certain time, so that in this manner competition by the weeds, which is harmful to the crop plants, is eliminated very early and in a sustained manner.
Although the inventive compounds of the general formula (I) display outstanding herbicidal activity against monocotyledonous and dicotyledonous weeds, crop plants of economically important crops, for example dicotyledonous crops of the genera Arachis, Beta, Brassica, Cucumis, Cucurbita, Helianthus, Daucus, Glycine, Gossypium, Ipomoea, Lactuca, Linum, Lycopersicon, Miscanthus, Nicotiana, Phaseolus, Pisum, Solanum, Vicia, or monocotyledonous crops of the genera Allium, Ananas, Asparagus, Avena, Hordeum, Oryza, Panicum, Saccharum, Secale, Sorghum, triticale, triticum, Zea, are damaged only to an insignificant extent, or not at all, depending on the structure of the respective compound according to the invention and its application rate. For these reasons, the present compounds are very suitable for selective control of unwanted plant growth in plant crops such as agriculturally useful plants or ornamental plants.
In addition, the inventive compounds of the general formula (I) (depending on their particular structure and the application rate deployed) have outstanding growth-regulating properties in crop plants. They intervene in the plants' own metabolism with regulatory effect, and can thus be used for the controlled influencing of plant constituents and to facilitate harvesting, for example by triggering desiccation and stunted growth. Furthermore, they are also suitable for the general control and inhibition of unwanted vegetative growth without killing the plants in the process. Inhibition of vegetative growth plays a major role for many mono- and dicotyledonous crops since, for example, this can reduce or completely prevent lodging.
By virtue of their herbicidal and plant growth regulatory properties, the active compounds of the general formula (I) can also be used to control harmful plants in crops of genetically modified plants or plants modified by conventional mutagenesis. In general, the transgenic plants are characterized by particular advantageous properties, for example by resistances to certain pesticides, in particular certain herbicides, resistances to plant diseases or pathogens of plant diseases, such as certain insects or microorganisms such as fungi, bacteria or viruses. Other specific characteristics relate, for example, to the harvested material with regard to quantity, quality, storability, composition and specific constituents. For instance, there are known transgenic plants with an elevated starch content or altered starch quality, or those with a different fatty acid composition in the harvested material.
It is preferred with a view to transgenic crops to use the inventive compounds of the general formula (I) and/or their salts in economically important transgenic crops of useful plants and ornamentals, for example of cereals such as wheat, barley, rye, oats, millet, rice and corn or else crops of sugar beet, cotton, soybean, oilseed rape, potato, tomato, peas and other vegetables.
It is preferable to employ the inventive compounds of the general formula (I) also as herbicides in crops of useful plants which are resistant, or have been made resistant by recombinant means, to the phytotoxic effects of the herbicides.
By virtue of their herbicidal and plant growth regulatory properties, the inventive compounds of the general formula (I) can also be used to control harmful plants in crops of genetically modified plants which are known or are yet to be developed. In general, the transgenic plants are characterized by particular advantageous properties, for example by resistances to certain pesticides, in particular certain herbicides, resistances to plant diseases or pathogens of plant diseases, such as certain insects or microorganisms such as fungi, bacteria or viruses. Other specific characteristics relate, for example, to the harvested material with regard to quantity, quality, storability, composition and specific constituents.
For instance, there are known transgenic plants with an elevated starch content or altered starch quality, or those with a different fatty acid composition in the harvested material. Further special properties may be tolerance or resistance to abiotic stressors, for example heat, cold, drought, salinity and ultraviolet radiation.
Preference is given to the use of the inventive compounds of the general formula (I) or salts thereof in economically important transgenic crops of useful plants and ornamentals, for example of cereals such as wheat, barley, rye, oats, triticale, millet, rice, cassava and corn, or else crops of sugar beet, cotton, soybean, oilseed rape, potatoes, tomatoes, peas and other vegetables.
It is preferable to employ the compounds of the general formula (I) as herbicides in crops of useful plants which are resistant, or have been made resistant by recombinant means, to the phytotoxic effects of the herbicides.
Conventional ways of producing novel plants which have modified properties in comparison to existing plants consist, for example, in traditional cultivation methods and the generation of mutants. Alternatively, novel plants with altered properties can be generated with the aid of recombinant methods.
A large number of molecular-biological techniques by means of which novel transgenic plants with modified properties can be generated are known to the person skilled in the art. For such genetic manipulations, nucleic acid molecules which allow mutagenesis or sequence alteration by recombination of DNA sequences can be introduced into plasmids. With the aid of standard methods, it is possible, for example, to undertake base exchanges, remove part sequences or add natural or synthetic sequences. To connect the DNA fragments to each other, adapters or linkers may be added to the fragments.
For example, the generation of plant cells with a reduced activity of a gene product can be achieved by expressing at least one corresponding antisense RNA, a sense RNA for achieving a cosuppression effect, or by expressing at least one suitably constructed ribozyme which specifically cleaves transcripts of the abovementioned gene product.
To this end, it is firstly possible to use DNA molecules which encompass the entire coding sequence of a gene product inclusive of any flanking sequences which may be present, and also DNA molecules which only encompass portions of the coding sequence, in which case it is necessary for these portions to be long enough to have an antisense effect in the cells. It is also possible to use DNA sequences which have a high degree of homology to the coding sequences of a gene product, but are not completely identical to them.
When expressing nucleic acid molecules in plants, the protein synthesized may be localized in any desired compartment of the plant cell. However, to achieve localization in a particular compartment, it is possible, for example, to join the coding region to DNA sequences which ensure localization in a particular compartment. Such sequences are known to those skilled in the art (see, for example, Braun et al., EMBO J. 11 (1992), 3219-3227). The nucleic acid molecules can also be expressed in the organelles of the plant cells.
The transgenic plant cells can be regenerated by known techniques to give rise to entire plants. In principle, the transgenic plants may be plants of any desired plant species, i.e. not only monocotyledonous but also dicotyledonous plants.
Thus, transgenic plants can be obtained whose properties are altered by overexpression, suppression or inhibition of homologous (=natural) genes or gene sequences or expression of heterologous (=foreign) genes or gene sequences.
It is preferred to employ the inventive compounds of the general formula (I) in transgenic crops which are resistant to growth regulators such as, for example, dicamba, or to herbicides which inhibit essential plant enzymes, for example acetolactate synthases (ALS), EPSP synthases, glutamine synthases (GS) or hydroxyphenylpyruvate dioxygenases (HPPD), or to herbicides from the group of the sulfonylureas, glyphosate, glufosinate or benzoylisoxazoles and analogous active compounds.
When the inventive compounds of the general formula (I) are employed in transgenic crops, not only do the effects toward harmful plants observed in other crops occur, but frequently also effects which are specific to application in the particular transgenic crop, for example an altered or specifically widened spectrum of weeds which can be controlled, altered application rates which can be used for the application, preferably good combinability with the herbicides to which the transgenic crop is resistant, and influencing of growth and yield of the transgenic crop plants.
The invention therefore also relates to the use of the inventive compounds of the general formula (I) and/or their salts as herbicides for controlling harmful plants in crops of useful plants or ornamentals, optionally in transgenic crop plants.
Preference is given to the use of compounds of the general formula (I) in cereals, here preferably corn, wheat, barley, rye, oats, millet or rice, by the pre- or post-emergence method.
Preference is also given to the use of compounds of the general formula (I) in soybean by the pre-emergence or post-emergence method.
The use of inventive compounds of the formula (I) for the control of harmful plants or for growth regulation of plants also includes the case in which a compound of the general formula (I) or its salt is not formed from a precursor substance (“prodrug”) until after application on the plant, in the plant or in the soil.
The invention also provides the use of one or more compounds of the general formula (I) or salts thereof or of a composition according to the invention (as defined below) (in a method) for controlling harmful plants or for regulating the growth of plants which comprises applying an effective amount of one or more compounds of the general formula (I) or salts thereof onto the plants (harmful plants, if appropriate together with the useful plants), plant seeds, the soil in which or on which the plants grow or the area under cultivation.
The invention also provides a herbicidal and/or plant growth-regulating composition, characterized in that the composition comprises
(a) one or more compounds of the general formula (I) and/or salts thereof, as defined above, preferably in one of the embodiments identified as preferred or particularly preferred, in particular one or more compounds of the formulae
(I-001) to (I-240) and/or salts thereof, in each case as defined above,
and
(b) one or more further substances selected from groups (i) and/or (ii):
Here, the further agrochemically active substances of component (i) of a composition according to the invention are preferably selected from the group of substances mentioned in “The Pesticide Manual”, 16th edition, The British Crop Protection Council and the Royal Soc. of Chemistry, 2012.
A herbicidal or plant growth-regulating composition according to the invention comprises preferably one, two, three or more formulation auxiliaries (ii) customary in crop protection selected from the group consisting of surfactants, emulsifiers, dispersants, film-formers, thickeners, inorganic salts, dusting agents, carriers solid at 25° C. and 1013 mbar, preferably adsorbant granulated inert materials, wetting agents, antioxidants, stabilizers, buffer substances, antifoam agents, water, organic solvents, preferably organic solvents miscible with water in any ratio at 25° C. and 1013 mbar.
The inventive compounds of the general formula (I) can be used in the form of wettable powders, emulsifiable concentrates, sprayable solutions, dusting products or granules in the customary formulations. The invention therefore also provides herbicidal and plant growth-regulating compositions which comprise compounds of the general formula (I) and/or salts thereof.
The inventive compounds of the general formula (I) and/or salts thereof can be formulated in various ways according to which biological and/or physicochemical parameters are specified. Possible formulations include, for example: wettable powders (WP), water-soluble powders (SP), water-soluble concentrates, emulsifiable concentrates (EC), emulsions (EW), such as oil-in-water and water-in-oil emulsions, sprayable solutions, suspension concentrates (SC), dispersions based on oil or water, oil-miscible solutions, capsule suspensions (CS), dusting products (DP), dressings, granules for scattering and soil application, granules (GR) in the form of microgranules, spray granules, absorption and adsorption granules, water-dispersible granules (WG), water-soluble granules (SG), ULV formulations, microcapsules and waxes.
These individual formulation types and the formulation assistants, such as inert materials, surfactants, solvents and further additives, are known to the person skilled in the art and are described, for example, in: Watkins, “Handbook of Insecticide Dust Diluents and Carriers”, 2nd Ed., Darland Books, Caldwell N.J.; H. v. Olphen, “Introduction to Clay Colloid Chemistry”, 2nd ed., J. Wiley & Sons, N.Y.; C. Marsden, “Solvents Guide”, 2nd ed., Interscience, N.Y. 1963; McCutcheon's “Detergents and Emulsifiers Annual”, MC Publ. Corp., Ridgewood N.J.; Sisley and Wood, “Encyclopedia of Surface Active Agents”, Chem. Publ. Co. Inc., N.Y. 1964; Schinfeldt, “Grenzflichenaktive Athylenoxidaddukte” [Interface-active Ethylene Oxide Adducts], Wiss. Verlagsgesellschaft, Stuttgart 1976; Winnacker-Kiichler, “Chemische Technologie” [Chemical Technology], volume 7, C. Hanser Verlag Munich, 4th Ed. 1986.
Wettable powders are preparations which can be dispersed uniformly in water and, in addition to the active compound, apart from a diluent or inert substance, also comprise surfactants of the ionic and/or nonionic type (wetting agents, dispersants), for example polyoxyethylated alkylphenols, polyoxyethylated fatty alcohols, polyoxyethylated fatty amines, fatty alcohol polyglycol ether sulfates, alkanesulfonates, alkylbenzenesulfonates, sodium lignosulfonate, sodium 2,2′-dinaphthylmethane-6,6′-disulfonate, sodium dibutylnaphthalenesulfonate or else sodium oleoylmethyltaurate. To produce the wettable powders, the herbicidally active compounds are finely ground, for example in customary apparatuses such as hammer mills, blower mills and air-jet mills, and simultaneously or subsequently mixed with the formulation auxiliaries.
Emulsifiable concentrates are produced by dissolving the active compound in an organic solvent, for example butanol, cyclohexanone, dimethylformamide, xylene, or else relatively high-boiling aromatics or hydrocarbons or mixtures of the organic solvents, with addition of one or more ionic and/or nonionic surfactants (emulsifiers). Examples of emulsifiers which may be used are: calcium alkylarylsulfonates such as calcium dodecylbenzenesulfonate, or nonionic emulsifiers such as fatty acid polyglycol esters, alkylaryl polyglycol ethers, fatty alcohol polyglycol ethers, propylene oxide-ethylene oxide condensation products, alkyl polyethers, sorbitan esters, for example sorbitan fatty acid esters, or polyoxyethylene sorbitan esters, for example polyoxyethylene sorbitan fatty acid esters.
Dusting products are obtained by grinding the active compound with finely distributed solids, for example talc, natural clays, such as kaolin, bentonite and pyrophyllite, or diatomaceous earth.
Suspension concentrates may be water- or oil-based. They may be prepared, for example, by wet-grinding by means of commercial bead mills and optional addition of surfactants as have, for example, already been listed above for the other formulation types.
Emulsions, for example oil-in-water emulsions (EW), can be produced, for example, by means of stirrers, colloid mills and/or static mixers using aqueous organic solvents and optionally surfactants as already listed above, for example, for the other formulation types.
Granules can be produced either by spraying the active compound onto adsorptive granular inert material or by applying active compound concentrates to the surface of carriers, such as sand, kaolinites or granular inert material, by means of adhesives, for example polyvinyl alcohol, sodium polyacrylate or else mineral oils. Suitable active compounds can also be granulated in the manner customary for the production of fertilizer granules—if desired as a mixture with fertilizers.
Water-dispersible granules are produced generally by the customary processes such as spray-drying, fluidized-bed granulation, pan granulation, mixing with high-speed mixers and extrusion without solid inert material.
For the production of pan, fluidized-bed, extruder and spray granules, see e.g. processes in “Spray Drying Handbook” 3rd Ed. 1979, G. Goodwin Ltd., London, J. E. Browning, “Agglomeration”, Chemical and Engineering 1967, pages 147 ff; “Perry's Chemical Engineer's Handbook”, 5th Ed., McGraw Hill, New York 1973, p. 8-57.
For further details regarding the formulation of crop protection compositions, see, for example, G. C. Klingman, “Weed Control as a Science”, John Wiley and Sons, Inc., New York, 1961, pages 81-96 and J. D. Freyer, S. A. Evans, “Weed Control Handbook”, 5th Ed., Blackwell Scientific Publications, Oxford, 1968, pages 101-103.
The agrochemical preparations, preferably herbicidal or plant growth-regulating compositions, of the present invention preferably comprise a total amount of from 0.1 to 99% by weight, preferably 0.5 to 95% by weight, particularly preferably 1 to 90% by weight, especially preferably 2 to 80% by weight, of active compounds of the general formula (I) and their salts.
In wettable powders, the active compound concentration is, for example, about 10 to 90% by weight, the remainder to 100% by weight consisting of customary formulation constituents. In emulsifiable concentrates, the active compound concentration may be about 1% to 90% and preferably 5% to 80% by weight. Formulations in the form of dusts comprise 1% to 30% by weight of active compound, preferably usually 5% to 20% by weight of active compound; sprayable solutions contain about 0.05% to 80% by weight, preferably 2% to 50% by weight of active compound. In the case of water-dispersible granules, the active compound content depends partially on whether the active compound is in liquid or solid form and on which granulation auxiliaries, fillers, etc., are used. In the water-dispersible granules, the content of active compound is, for example, between 1% and 95% by weight, preferably between 10% and 80% by weight.
In addition, the active compound formulations mentioned optionally comprise the respective customary stickers, wetters, dispersants, emulsifiers, penetrants, preservatives, antifreeze agents and solvents, fillers, carriers and dyes, defoamers, evaporation inhibitors and agents which influence the pH and the viscosity. Examples of formulation auxiliaries are described inter alia in “Chemistry and Technology of Agrochemical Formulations”, ed. D. A. Knowles, Kluwer Academic Publishers (1998).
The inventive compounds of the general formula (I) or salts thereof can be used as such or in the form of their preparations (formulations) in a combination with other pesticidally active substances, for example insecticides, acaricides, nematicides, herbicides, fungicides, safeners, fertilizers and/or growth regulators, for example in the form of a finished formulation or of a tank mix. The combination formulations can be prepared on the basis of the abovementioned formulations, while taking account of the physical properties and stabilities of the active compounds to be combined.
Active compounds which can be employed in combination with the inventive compounds of the general formula (I) in mixture formulations or in a tank mix are, for example, known active compounds based on inhibition of, for example, acetolactate synthase, acetyl-CoA carboxylase, cellulose synthase, enolpyruvylshikimate-3-phosphate synthase, glutamine synthetase, p-hydroxyphenylpyruvate dioxygenase, phytoendesaturase, photosystem I, photosystem II, protoporphyrinogen oxidase, as described, for example, in Weed Research 26 (1986) 441-445 or “The Pesticide Manual”, 16th edition, The British Crop Protection Council and the Royal Soc. of Chemistry, 2012 and literature cited therein.
Of particular interest is the selective control of harmful plants in crops of useful plants and ornamentals. Although the inventive compounds of the general formula (I) have already demonstrated very good to adequate selectivity in a large number of crops, in principle, in some crops and in particular also in the case of mixtures with other, less selective herbicides, phytotoxicities on the crop plants may occur. In this connection, combinations of inventive compounds of the general formula (I) that are of particular interest are those which comprise the compounds of the general formula (I) or their combinations with other herbicides or pesticides and safeners. The safeners, which are used in an antidotically effective amount, reduce the phytotoxic side effects of the herbicides/pesticides employed, for example in economically important crops, such as cereals (wheat, barley, rye, corn, rice, millet), sugarbeet, sugarcane, oilseed rape, cotton and soybeans, preferably cereals.
The weight ratios of herbicide (mixture) to safener depend generally on the herbicide application rate and the efficacy of the safener in question and may vary within wide limits, for example in the range from 200:1 to 1:200, preferably 100:1 to 1:100, in particular 20:1 to 1:20. Analogously to the compounds of the general formula (I) or mixtures thereof, the safeners can be formulated with further herbicides/pesticides and be provided and employed as a finished formulation or tank mix with the herbicides.
For application, the herbicide or herbicide/safener formulations present in commercial form are, if appropriate, diluted in a customary manner, for example in the case of wettable powders, emulsifiable concentrates, dispersions and water-dispersible granules with water. Dust-type preparations, granules for soil application or granules for scattering and sprayable solutions are not normally diluted further with other inert substances prior to application.
The application rate of the compounds of the general formula (I) and/or their salts is affected to a certain extent by external conditions such as temperature, humidity, etc. Here, the application rate may vary within wide limits. For the application as a herbicide for controlling harmful plants, the total amount of compounds of the general formula (I) and their salts is preferably in the range from 0.001 to 10.0 kg/ha, with preference in the range from 0.005 to 5 kg/ha, more preferably in the range from 0.01 to 1.5 kg/ha, in particular in the range from 0.05 to 1 kg/ha. This applies both to the pre-emergence and the post-emergence application.
When the inventive compounds of the general formula (I) and/or their salts are used as plant growth regulator, for example as culm stabilizer for crop plants like those mentioned above, preferably cereal plants, such as wheat, barley, rye, triticale, millet, rice or corn, the total application rate is preferably in the range of from 0.001 to 2 kg/ha, preferably in the range of from 0.005 to 1 kg/ha, in particular in the range of from 10 to 500 g/ha, very particularly in the range from 20 to 250 g/ha. This applies both to the pre-emergence and the post-emergence application.
The application as culm stabilizer may take place at various stages of the growth of the plants. Preferred is, for example, the application after the tillering phase, at the beginning of the longitudinal growth.
As an alternative, application as plant growth regulator is also possible by treating the seed, which includes various techniques for dressing and coating seed. Here, the application rate depends on the particular techniques and can be determined in preliminary tests.
Active compounds which can be employed in combination with the inventive compounds of the general formula (I) in compositions according to the invention (for example in mixed formulations or in the tank mix) are, for example, known active compounds which are based on the inhibition of, for example, acetolactate synthase, acetyl-CoA carboxylase, cellulose synthase, enolpyruvylshikimate-3-phosphate synthase, glutamine synthetase, p-hydroxyphenylpyruvate dioxygenase, phytoene desaturase, photosystem I, photosystem II or protoporphyrinogen oxidase, as are described in, for example, Weed Research 26 (1986) 441-445 or “The Pesticide Manual”, 16th edition, The British Crop Protection Council and the Royal Soc. of Chemistry, 2012 and the literature cited therein. Known herbicides or plant growth regulators which can be combined with the compounds according to the invention are, for example, the following active compounds, where said compounds are designated either with their “common name” in accordance with the International Organization for Standardization (ISO) or with the chemical name or with the code number. They always encompass all of the application forms such as, for example, acids, salts, esters and also all isomeric forms such as stereoisomers and optical isomers, even if not explicitly mentioned.
Examples of such herbicidal mixing partners are:
acetochlor, acifluorfen, acifluorfen-sodium, aclonifen, alachlor, allidochlor, alloxydim, alloxydim-sodium, ametryn, amicarbazone, amidochlor, amidosulfuron, 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methylphenyl)-5-fluoropyridine-2-carboxylic acid, aminocyclopyrachlor, aminocyclopyrachlor-potassium, aminocyclopyrachlor-methyl, aminopyralid, amitrole, ammoniumsulfamate, anilofos, asulam, atrazine, azafenidin, azimsulfuron, beflubutamid, benazolin, benazolin-ethyl, benfluralin, benfuresate, bensulfuron, bensulfuron-methyl, bensulide, bentazone, benzobicyclon, benzofenap, bicyclopyron, bifenox, bilanafos, bilanafos-sodium, bispyribac, bispyribac-sodium, bromacil, bromobutide, bromofenoxim, bromoxynil, bromoxynil-butyrate, -potassium, -heptanoate and -octanoate, busoxinone, butachlor, butafenacil, butamifos, butenachlor, butralin, butroxydim, butylate, cafenstrole, carbetamide, carfentrazone, carfentrazone-ethyl, chloramben, chlorbromuron, chlorfenac, chlorfenac-sodium, chlorfenprop, chlorflurenol, chlorflurenol-methyl, chloridazon, chlorimuron, chlorimuron-ethyl, chlorophthalim, chlorotoluron, chlorthal-dimethyl, chlorsulfuron, cinidon, cinidon-ethyl, cinmethylin, cinosulfuron, clacyfos, clethodim, clodinafop, clodinafop-propargyl, clomazone, clomeprop, clopyralid, cloransulam, cloransulam-methyl, cumyluron, cyanamide, cyanazine, cycloate, cyclopyrimorate, cyclosulfamuron, cycloxydim, cyhalofop, cyhalofop-butyl, cyprazine, 2,4-D, 2,4-D-butotyl, -butyl, -dimethylammonium, -diolamin, -ethyl, 2-ethylhexyl, -isobutyl, -isooctyl, -isopropylammonium, -potassium, -triisopropanolammonium and -trolamine, 2,4-DB, 2,4-DB-butyl, -dimethylammonium, isooctyl, -potassium and -sodium, daimuron (dymron), dalapon, dazomet, n-decanol, desmedipham, detosyl-pyrazolate (DTP), dicamba, dichlobenil, 2-(2,4-dichlorobenzyl)-4,4-dimethyl-1,2-oxazolidin-3-one, 2-(2,5-dichlorobenzyl)-4,4-dimethyl-1,2-oxazolidin-3-one, dichlorprop, dichlorprop-P, diclofop, diclofop-methyl, diclofop-P-methyl, diclosulam, difenzoquat, diflufenican, diflufenzopyr, diflufenzopyr-sodium, dimefuron, dimepiperate, dimethachlor, dimethametryn, dimethenamid, dimethenamid-P, dimetrasulfuron, dinitramine, dinoterb, diphenamid, diquat, diquat-dibromide, dithiopyr, diuron, DNOC, endothal, EPTC, esprocarb, ethalfluralin, ethametsulfuron, ethametsulfuron-methyl, ethiozin, ethofumesate, ethoxyfen, ethoxyfen-ethyl, ethoxysulfuron, etobenzanid, F-9600, F-5231, i.e. N-[2-chloro-4-fluoro-5-[4-(3-fluoropropyl)-4,5-dihydro-5-oxo-1H-tetrazol-1-yl]phenyl]ethanesulfonamide, F-7967, i.e. 3-[7-chloro-5-fluoro-2-(trifluoromethyl)-1H-benzimidazol-4-yl]-1-methyl-6-(trifluoromethyl)pyrimidine-2,4(1H,3H)-dione, fenoxaprop, fenoxaprop-P, fenoxaprop-ethyl, fenoxaprop-P-ethyl, fenoxasulfone, fenquinotrione, fentrazamide, flamprop, flamprop-M-isopropyl, flamprop-M-methyl, flazasulfuron, florasulam, fluazifop, fluazifop-P, fluazifop-butyl, fluazifop-P-butyl, flucarbazone, flucarbazone-sodium, flucetosulfuron, fluchloralin, flufenacet, flufenpyr, flufenpyr-ethyl, flumetsulam, flumiclorac, flumiclorac-pentyl, flumioxazin, fluometuron, flurenol, flurenol-butyl, -dimethylammonium and -methyl, fluoroglycofen, fluoroglycofen-ethyl, flupropanate, flupyrsulfuron, flupyrsulfuron-methyl-sodium, fluridone, flurochloridone, fluroxypyr, fluroxypyr-meptyl, flurtamone, fluthiacet, fluthiacet-methyl, fomesafen, fomesafen-sodium, foramsulfuron, fosamine, glufosinate, glufosinate-ammonium, glufosinate-P-sodium, glufosinate-P-ammonium, glufosinate-P-sodium, glyphosate, glyphosate-ammonium, -isopropylammonium, -diammonium, -dimethylammonium, -potassium, -sodium and -trimesium, H-9201, i.e. O-2,4-dimethyl-6-nitrophenyl O-ethyl isopropylphosphoramidothioate, halauxifen, halauxifen-methyl, halosafen, halosulfuron, halosulfuron-methyl, haloxyfop, haloxyfop-P, haloxyfop-ethoxyethyl, haloxyfop-P-ethoxyethyl, haloxyfop-methyl, haloxyfop-P-methyl, hexazinone, HW-02, i.e. 1-dimethoxyphosphorylethyl 2,4-dichlorophenoxyacetate, imazamethabenz, imazamethabenz-methyl, imazamox, imazamox-ammonium, imazapic, imazapic-ammonium, imazapyr, imazapyr-isopropylammonium, imazaquin, imazaquin-ammonium, imazethapyr, imazethapyr-immonium, imazosulfuron, indanofan, indaziflam, iodosulfuron, iodosulfuron-methyl-sodium, ioxynil, ioxynil-octanoate, -potassium and -sodium, ipfencarbazone, isoproturon, isouron, isoxaben, isoxaflutole, karbutilate, KUH-043, i.e. 3-({[5-(difluoromethyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]methyl}sulfonyl)-5,5-dimethyl-4,5-dihydro-1,2-oxazole, ketospiradox, lactofen, lenacil, linuron, MCPA, MCPA-butotyl, -dimethylammonium, -2-ethylhexyl, -isopropylammonium, -potassium and -sodium, MCPB, MCPB-methyl, -ethyl and -sodium, mecoprop, mecoprop-sodium, and -butotyl, mecoprop-P, mecoprop-P-butotyl, -dimethylammonium, -2-ethylhexyl and -potassium, mefenacet, mefluidide, mesosulfuron, mesosulfuron-methyl, mesotrione, methabenzthiazuron, metam, metamifop, metamitron, metazachlor, metazosulfuron, methabenzthiazuron, methiopyrsulfuron, methiozolin, methyl isothiocyanate, metobromuron, metolachlor, S-metolachlor, metosulam, metoxuron, metribuzin, metsulfuron, metsulfuron-methyl, molinate, monolinuron, monosulfuron, monosulfuron-ester, MT-5950, i.e. N-[3-chloro-4-(1-methylethyl)-phenyl]-2-methylpentanamide, NGGC-011, napropamide, NC-310, i.e. 4-(2,4-dichlorobenzoyl)-1-methyl-5-benzyloxypyrazole, neburon, nicosulfuron, nonanoic acid (pelargonic acid), norflurazon, oleic acid (fatty acids), orbencarb, orthosulfamuron, oryzalin, oxadiargyl, oxadiazon, oxasulfuron, oxaziclomefon, oxyfluorfen, paraquat, paraquat dichloride, pebulate, pendimethalin, penoxsulam, pentachlorphenol, pentoxazone, pethoxamid, petroleum oils, phenmedipham, picloram, picolinafen, pinoxaden, piperophos, pretilachlor, primisulfuron, primisulfuron-methyl, prodiamine, profoxydim, prometon, prometryn, propachlor, propanil, propaquizafop, propazine, propham, propisochlor, propoxycarbazone, propoxycarbazone-sodium, propyrisulfuron, propyzamide, prosulfocarb, prosulfuron, pyraclonil, pyraflufen, pyraflufen-ethyl, pyrasulfotole, pyrazolynate (pyrazolate), pyrazosulfuron, pyrazosulfuron-ethyl, pyrazoxyfen, pyribambenz, pyribambenz-isopropyl, pyribambenz-propyl, pyribenzoxim, pyributicarb, pyridafol, pyridate, pyriftalid, pyriminobac, pyriminobac-methyl, pyrimisulfan, pyrithiobac, pyrithiobac-sodium, pyroxasulfone, pyroxsulam, quinclorac, quinmerac, quinoclamine, quizalofop, quizalofop-ethyl, quizalofop-P, quizalofop-P-ethyl, quizalofop-P-tefuryl, rimsulfuron, saflufenacil, sethoxydim, siduron, simazine, simetryn, SL-261, sulcotrion, sulfentrazone, sulfometuron, sulfometuron-methyl, sulfosulfuron, SYN-523, SYP-249, i.e. 1-ethoxy-3-methyl-1-oxobut-3-en-2-yl 5-[2-chloro-4-(trifluoromethyl)phenoxy]-2-nitrobenzoate, SYP-300, i.e. 1-[7-fluoro-3-oxo-4-(prop-2-yn-1-yl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]-3-propyl-2-thioxoimidazolidine-4,5-dione, 2,3,6-TBA, TCA (trichloroacetic acid), TCA-sodium, tebuthiuron, tefuryltrione, tembotrione, tepraloxydim, terbacil, terbucarb, terbumeton, terbuthylazin, terbutryn, thenylchlor, thiazopyr, thiencarbazone, thiencarbazone-methyl, thifensulfuron, thifensulfuron-methyl, thiobencarb, tiafenacil, tolpyralate, topramezone, tralkoxydim, triafamone, tri-allate, triasulfuron, triaziflam, tribenuron, tribenuron-methyl, triclopyr, trietazine, trifloxysulfuron, trifloxysulfuron-sodium, trifludimoxazin, trifluralin, triflusulfuron, triflusulfuron-methyl, tritosulfuron, urea sulfate, vernolate, XDE-848, ZJ-0862, i.e. 3,4-dichloro-N-{2-[(4,6-dimethoxypyrimidin-2-yl)oxy]benzyl} aniline, and also the following compounds:
Examples of plant growth regulators as possible mixing partners are:
acibenzolar, acibenzolar-S-methyl, 5-aminolevulinic acid, ancymidol, 6-benzylaminopurine, brassinolide, catechol, chlormequat chloride, cloprop, cyclanilide, 3-(cycloprop-1-enyl)propionic acid, daminozide, dazomet, n-decanol, dikegulac, dikegulac-sodium, endothal, endothal-dipotassium, -disodium, and mono(N,N-dimethylalkylammonium), ethephon, flumetralin, flurenol, flurenol-butyl, flurprimidol, forchlorfenuron, gibberellic acid, inabenfide, indole-3-acetic acid (IAA), 4-indol-3-ylbutyric acid, isoprothiolane, probenazole, jasmonic acid, jasmonic acid methyl ester, maleic hydrazide, mepiquat chloride, 1-methylcyclopropene, 2-(1-naphthyl)acetamide, 1-naphthylacetic acid, 2-naphthyloxyacetic acid, nitrophenoxide mixture, 4-oxo-4[(2-phenylethyl)amino]butyric acid, paclobutrazole, N-phenylphthalamic acid, prohexadione, prohexadione-calcium, prohydrojasmone, salicylic acid, strigolactone, tecnazene, thidiazuron, triacontanol, trinexapac, trinexapac-ethyl, tsitodef, uniconazole, uniconazole-P.
Useful combination partners for the inventive compounds of the general formula (I) also include, for example, the following safeners:
in which the symbols and indices are defined as follows:
in which
Preferred safeners in combination with the inventive compounds of the general formula (I) and/or salts thereof, in particular with the compounds of the formulae (I-1) to (I-240) and/or salts thereof, are: cloquintocet-mexyl, cyprosulfamide, fenchlorazole-ethyl, isoxadifen-ethyl, mefenpyr-diethyl, fenclorim, cumyluron, S4-1 and S4-5, and particularly preferred safeners are: cloquintocet-mexyl, cyprosulfamide, isoxadifen-ethyl and mefenpyr-diethyl.
A. Post-Emergence Herbicidal Action and Crop Plant Compatibility
Seeds of monocotyledonous and dicotyledonous weeds and crop plants were placed in sandy loam in plastic or wood-fiber pots, covered with soil and cultivated in a greenhouse under controlled growth conditions. 2 to 3 weeks after sowing, the test plants were treated at the one-leaf stage. The compounds of the invention, formulated in the form of wettable powders (WP) or as emulsion concentrates (EC), were then sprayed onto the green parts of the plants as aqueous suspension or emulsion with addition of 0.5% additive at a water application rate of 600 l/ha (converted). After the test plants had been kept in the greenhouse under optimum growth conditions for about 3 weeks, the activity of the preparations was rated visually in comparison to untreated controls. For example, 100% activity=the plants have died, 0% activity=like control plants.
Tables B1 to B15 below show the effects of selected compounds of the general formula (I) according to Table I on various harmful plants and an application rate corresponding to 1280 g/ha, which were obtained by the experimental procedure mentioned above.
Alopecurus myosuroides
Echinochloa crus-galli
Setaria viridis
Abutilon theophrasti
Amaranthus retroflexus
Polygonum convolvulus
Stellaria media
Viola tricolor
Ipomoea purpurea
Veronica persica
Avena fatua
Lolium rigidum
Matricaria inodora
Pharbitis purpurea
Hordeum murinum
The trial results demonstrate that inventive compounds of the general formula (I), in the case of post-emergence treatment, have good herbicidal efficacy against selected harmful plants, for example Alopecurus myosuroides, Echinochloa crus-galli, Setaria viridis, Abutilon theophrasti, Amaranthus retroflexus, Polygonum convolvulus, Stellaria media, Viola tricolor, Ipomoea purpurea, Veronica persica, Avena fatua, Hordeum murinum, Lolium rigidum, Matricaria inodora, Pharbitis purpurea, at a respective application rate of 1280 g of active substance per hectare.
Pre-Emergence Herbicidal Action and Crop Plant Compatibility
Seeds of monocotyledonous and dicotyledonous weed plants and crop plants were placed in plastic or wood fiber pots and covered with soil. The compounds of the invention, formulated in the form of wettable powders (WP) or as emulsion concentrates (EC), were then applied onto the surface of the covering soil as aqueous suspension or emulsion with addition of 0.5% additive at a water application rate of 600 l/ha (converted). After the treatment, the pots were placed in a greenhouse and kept under good growth conditions for the test plants. After about 3 weeks, the effect of the preparations was scored visually in comparison with untreated controls as percentages. For example, 100% activity=the plants have died, 0% activity=like control plants.
Tables C1 to C14 below show the effects of selected compounds of the general formula (I) according to Table I on various harmful plants and an application rate corresponding to 1280 g/ha, which were obtained by the experimental procedure mentioned above.
Alopecurus myosuroides
Setaria viridis
Abutilon theophrasti
Amaranthus retroflexus
Matricaria inodora
Stellaria media
Viola tricolor
Polygonum convolvulus
Veronica persica
Avena fatua
Echinochloa crus-galli
Lolium rigidum
Pharbitis purpurea
Hordeum murinum
The trial results demonstrate that inventive compounds of the general formula (I), in the case of pre-emergence treatment, have good herbicidal efficacy against selected harmful plants, for example Alopecurus myosuroides, Setaria viridis, Abutilon theophrasti, Amaranthus retroflexus, Matricaria inodora, Stellaria media, Viola tricolor, Polygonum convolvulus, Veronica persica, Avena fatua, Echinochloa crus-galli, Hordeum murinum, Lolium rigidum, Pharbitis purpurea, at an application rate of 1280 g of active substance per hectare.
| Number | Date | Country | Kind |
|---|---|---|---|
| 17181821.4 | Jul 2017 | EP | regional |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/EP2018/068959 | 7/12/2018 | WO | 00 |
