Patent Application
20200345010
This invention relates to certain oxadiazoles, their N-oxides, salts and compositions, and methods of their use as fungicides.
The control of plant diseases caused by fungal plant pathogens is extremely important in achieving high crop efficiency. Plant disease damage to ornamental, vegetable, field, cereal, and fruit crops can cause significant reduction in productivity and thereby result in increased costs to the consumer. Many products are commercially available for these purposes, but the need continues for new compounds which are more effective, less costly, less toxic, environmentally safer or have different sites of action.
PCT Patent Publications WO 2018/080859, WO 2018/118781, WO 2018/187553 and WO 2019/010192 disclose trifluoromethyl-oxadiazole derivatives and their use in agriculture.
This invention is directed to compounds of Formula 1 (including all stereoisomers), N-oxides, and salts thereof, agricultural compositions containing them and their use as fungicides:
wherein
provided that:
More particularly, this invention pertains to a compound of Formula 1 (including all stereoisomers), an N-oxide or a salt thereof.
This invention also relates to a fungicidal composition comprising (a) a compound of the invention (i.e. in a fungicidally effective amount); and (b) at least one additional component selected from the group consisting of surfactants, solid diluents and liquid diluents.
This invention also relates to a fungicidal composition comprising (a) a compound of the invention; and (b) at least one other fungicide (e.g., at least one other fungicide having a different site of action).
This invention further relates to a method for controlling plant diseases caused by fungal plant pathogens comprising applying to the plant or portion thereof, or to the plant seed, a fungicidally effective amount of a compound of the invention (e.g., as a composition described herein).
This invention also relates to a composition comprising a compound of Formula 1, an N-oxide, or a salt thereof, and at least one invertebrate pest control compound or agent.
As used herein, the terms “comprises,” “comprising,” “includes,” “including,” “has,” “having,” “contains,” “containing,” “characterized by” or any other variation thereof, are intended to cover a non-exclusive inclusion, subject to any limitation explicitly indicated. For example, a composition, mixture, process, method, article, or apparatus that comprises a list of elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such composition, mixture, process, method, article, or apparatus.
The transitional phrase “consisting of” excludes any element, step, or ingredient not specified. If in the claim, such would close the claim to the inclusion of materials other than those recited except for impurities ordinarily associated therewith. When the phrase “consisting of” appears in a clause of the body of a claim, rather than immediately following the preamble, it limits only the element set forth in that clause; other elements are not excluded from the claim as a whole.
The transitional phrase “consisting essentially of” is used to define a composition, method or apparatus that includes materials, steps, features, components, or elements, in addition to those literally disclosed, provided that these additional materials, steps, features, components, or elements do not materially affect the basic and novel characteristic(s) of the claimed invention. The term “consisting essentially of” occupies a middle ground between “comprising” and “consisting of”.
Where applicants have defined an invention or a portion thereof with an open-ended term such as “comprising,” it should be readily understood that (unless otherwise stated) the description should be interpreted to also describe such an invention using the terms “consisting essentially of” or “consisting of.”
Further, unless expressly stated to the contrary, “or” refers to an inclusive or and not to an exclusive or. For example, a condition A or B is satisfied by any one of the following: A is true (or present) and B is false (or not present), A is false (or not present) and B is true (or present), and both A and B are true (or present).
Also, the indefinite articles “a” and “an” preceding an element or component of the invention are intended to be nonrestrictive regarding the number of instances (i.e. occurrences) of the element or component. Therefore “a” or “an” should be read to include one or at least one, and the singular word form of the element or component also includes the plural unless the number is obviously meant to be singular.
As referred to in the present disclosure and claims, “plant” includes members of Kingdom Plantae, particularly seed plants (Spermatopsida), at all life stages, including young plants (e.g., germinating seeds developing into seedlings) and mature, reproductive stages (e.g., plants producing flowers and seeds). Portions of plants include geotropic members typically growing beneath the surface of the growing medium (e.g., soil), such as roots, tubers, bulbs and corms, and also members growing above the growing medium, such as foliage (including stems and leaves), flowers, fruits and seeds.
As referred to herein, the term “seedling”, used either alone or in a combination of words means a young plant developing from the embryo of a seed.
As referred to herein, the term “broadleaf” used either alone or in words such as “broadleaf crop” means dicot or dicotyledon, a term used to describe a group of angiosperms characterized by embryos having two cotyledons.
As referred to in this disclosure, the terms “fungal pathogen” and “fungal plant pathogen” include pathogens in the Ascomycota, Basidiomycota and Zygomycota phyla classes, and the fungal-like Oomycota class that are the causal agents of a broad spectrum of plant diseases of economic importance, affecting ornamental, turf, vegetable, field, cereal and fruit crops. In the context of this disclosure, “protecting a plant from disease” or “control of a plant disease” includes preventative action (interruption of the fungal cycle of infection, colonization, symptom development and spore production) and/or curative action (inhibition of colonization of plant host tissues).
As used herein, the term “mode of action” (MOA) is as define by the Fungicide Resistance Action Committee (FRAC) and is used to distinguish fungicides according to their biochemical mode of action in the biosynthetic pathways of plant pathogens. FRAC-defined modes of actions include (A) nucleic acid synthesis, (B) mitosis and cell division, (C) respiration, (D) amino acid and protein synthesis, (E) signal transduction, (F) lipid synthesis and membrane integrity, (G) sterol biosynthesis in membranes, (H) cell wall biosynthesis, (I) melanin synthesis in cell wall, (P) host plant defense induction, (U) unknown mode of action, (NC) not classified and (M) multi-site contact activity. Each of these mode of action (letters A through M) contain one or more subgroups (e.g., A includes subgroups A1, A2, A3 and A4) based either on individual validated target sites of action, or in cases where the precise target site is unknown, based on cross resistance profiles within a group or in relation to other groups. Each of these subgroups (e.g., A1, A2, A3 and A4) is assigned a FRAC code (a number and/or letter). For example, the FRAC code for subgroup A1 is 4. Additional information on target sites and FRAC codes can be obtained from publicly available databases maintained, for example, by FRAC.
As used herein, the term “cross resistance” refers to the phenomenon that occurs when a pathogen develops resistance to one fungicide and simultaneously becomes resistant to one or more other fungicides. These other fungicides are typically, but not always, in the same chemical class or have the same target site of action or can be detoxified by the same mechanism.
Generally, when a molecular fragment (i.e. radical) is denoted by a series of atom symbols (e.g., C, H, N, O and S) the implicit point or points of attachment will be easily recognized by those skilled in the art. In some instances herein, particularly when alternative points of attachment are possible, the point or points of attachment may be explicitly indicated by a hyphen (“-”). For example, “—NCS” indicates that the point of attachment is the nitrogen atom (i.e. isothiocyanato, not thiocyanato).
As used herein, the term “alkylating agent” refers to a chemical compound in which a carbon-containing radical is bound through a carbon atom to a leaving group such as halide or sulfonate, which is displaceable by bonding of a nucleophile to said carbon atom. Unless otherwise indicated, the term “alkylating” does not limit the carbon-containing radical to alkyl; the carbon-containing radicals in alkylating agents include the variety of carbon-bound substituent radicals specified, for example, for R1 and R2.
In the above recitations, the term “alkyl”, used either alone or in compound words such as “haloalkyl” or “alkylsulfonyl” includes straight-chain or branched alkyl such as methyl, ethyl, n-propyl and i-propyl, or the different butyl isomers. “Alkenyl” includes straight-chain or branched alkenes such as ethenyl, 1-propenyl, 2-propenyl, and the different butenyl, pentenyl and hexenyl isomers. “Alkenyl” also includes polyenes such as 1,2-propadienyl and 2,4-hexadienyl. “Alkynyl” includes straight-chain or branched alkynes such as ethynyl, 1-propynyl, 2-propynyl and the different butynyl, pentynyl and hexynyl isomers. “Alkynyl” can also include moieties comprised of multiple triple bonds such as 2,5-hexadiynyl. “Alkylene” denotes a straight-chain or branched alkanediyl. Examples of “alkylene” include CH2, CH2CH2, CH(CH3), CH2CH2CH2, CH2CH(CH3), and the different butylene isomers. “Alkenylene” denotes a straight-chain or branched alkenediyl containing one olefinic bond. Examples of “alkenylene” include CH═CH, CH2CH═CH, CH═C(CH3) and the different butenylene isomers. “Alkynylene” denotes a straight-chain or branched alkynediyl containing one triple bond. Examples of “alkynylene” include CH2C≡C, C≡CCH2, and the different butynylene, pentynylene or hexynylene isomers. The term “cycloalkylene” denotes a cycloalkanediyl ring. Examples of “cycloalkylene” include cyclobutanediyl, cyclopentanediyl and cyclohexanediyl. The term “cycloalkenylene” denotes a cycloalkenediyl ring containing one olefinic bond. Examples of “cycloalkenylene” include cyclopropenediyl and cyclopentenediyl.
“Alkoxy” includes, for example, methoxy, ethoxy, n-propyloxy, i-propyloxy and the different butoxy isomers. “Alkoxyalkyl” denotes alkoxy substitution on alkyl. Examples of “alkoxyalkyl” include CH3OCH2, CH3CH2CH2, CH3CH2OCH2, CH3CH2CH2CH2OCH2 and CH3CH2OCH2CH2. “Alkenyloxy” includes straight-chain or branched alkenyl attached to and linked through an oxygen atom. Examples of “alkenyloxy” include H2C═CHCH2O, CH3CH═CHCH2, CH3CH═C(CH3)O and CH2═CHCH2CH2O. “Alkynyloxy” includes straight-chain or branched alkynyl attached to and linked through an oxygen atom. Examples of “alkynyloxy” include HC≡CCH2O and CH3C≡CCH2O. “Alkoxyalkoxy” denotes alkoxy substitution on another alkoxy moiety. Examples of “alkoxyalkoxy” include CH3OCH2O, CH3OCH2O and CH3CH2OCH2O. “Alkoxyalkoxyalkyl” denotes alkoxyalkoxy substitution on alkyl. Examples of “alkoxyalkoxyalkyl” include CH3CH2OCH2, CH3CH2OCH2CH2 and CH3CH2OCH2OCH2.
“Alkylsulfinyl” includes both enantiomers of an alkylsulfinyl group. Examples of “alkylsulfinyl” include CH3S(═O), CH3CH2S(═O), CH3CH2CH2S(═O), (CH3)2CHS(═O) and the different butylsulfinyl isomers. Examples of “alkylsulfonyl” include CH3S(═O)2, CH3CH2S(═O)2, CH3CH2CH2S(═O)2, (CH3)2CHS(═O)2 and the different butylsulfonyl, isomers. “Alkylsulfonylalkyl” denotes alkylsulfonyl substitution on alkyl. Examples of “alkylsulfonylalkyl” include CH3S(═O)2CH2, CH3S(═O)2CH2CH2, CH3CH2S(═O)2CH2 and CH3CH2S(═O)2CH2CH2. The term “alkylsulfonyloxy” denotes an alkylsulfonyl group bonded to an oxygen atom. Examples of “alkylsulfonyloxy” include CH3S(═O)2O, CH3CH2S(═O)2O, CH3CH2CH2S(═O)2O, (CH3)2CHS(═O)2O, and the different butylsulfonyloxyisomers.
“Alkylamino” includes an NH radical substituted with straight-chain or branched alkyl. Examples of “alkylamino” include CH3NH, CH3CH2NH, CH3CH2CH2NH and (CH3)2CHNH. Examples of “dialkylamino” include (CH3)2N, (CH3CH2)2N and CH3CH2(CH3)N. “Alkylaminoalkyl” denotes alkylamino substitution on alkyl. Examples of “alkylaminoalkyl” include CH3NHCH2, CH3NHCH2CH2, CH3CH2NHCH2, CH3CH2CH2CH2NHCH2 and CH3CH2NHCH2CH2. Examples of “dialkylaminoalkyl” include (CH3)2NCH2 and CH3CH2(CH3)NCH2.
“Alkylcarbonyl” denotes a straight-chain or branched alkyl group bonded to a C(═O) moiety. Examples of “alkylcarbonyl” include CH3C(═O), CH3CH2CH2C(═O) and (CH3)2CHC(═O). Examples of “alkoxycarbonyl” include CH3OC(═O), CH3CH2OC(═O), CH3CH2CH2OC(═O) and (CH3)2CHOC(═O). “Alkylaminocarbonyl” denotes a straight-chain or branched alkyl group bonded to a NHC(═O) moiety. Examples of “alkylaminocarbonyl” include CH3NHC(═O), CH3CH2NHC(═O), CH3CH2CH2NHC(═O), (CH3)2CHNHC(═O), and the different butylamino- and pentylaminocarbonyl isomers. Examples of “dialkylaminocarbonyl” include (CH3)2NC(═O), (CH3CH2)2NC(═O), CH3CH2(CH3)NC(═O), (CH3)2CH(CH3)NC(═O) and CH3CH2CH2(CH3)NC(═O).
The term “alkoxycarbonylalkyl” denotes alkoxycarbonyl substitution on alkyl. Examples of “alkoxycarbonylalkyl” include CH3CH2OC(═O)CH2, (CH3)2CHOC(═O)CH2 and CH3OC(═O)CH2CH2. The term “alkylaminocarbonylalkyl” denotes a straight-chain or branched alkylaminocarbonyl attached to alkyl. Examples of “alkylaminocarbonylalkyl” include (CH3)2CHCH2NHC(═O)CH2 and CH3CH2NHC(═O)CH2. Examples of “dialkylaminocarbonylalkyl” include CH3CH2CH2(CH3)NC(═O)CH2 and (CH3)2NC(═O)CH2.
The term “alkylcarbonyloxy” denotes a straight-chain or branched alkyl bonded to a C(═O)O moiety. Examples of “alkylcarbonyloxy” include CH3CH2C(═O)O and (CH3)2CHC(═O)O. The term “alkoxycarbonyloxy” denotes a straight-chain or branched alkoxy bonded to a C(═O)O moiety. Examples of “alkoxycarbonyloxy” include CH3CH2CH2OC(═O)O and (CH3)2CHOC(═O)O. The term “alkylaminocarbonyloxy” denotes a straight-chain or branched alkylaminocarbonyl attached to and linked through an oxygen atom. Examples of “alkylaminocarbonyloxy” include (CH3)2CHCH2NHC(═O)O and CH3CH2NHC(═O)O.
The term “alkylcarbonylamino” denotes a straight-chain or branched alkyl group bonded to a C(═O)NH moiety. Examples of “alkylcarbonylamino” include CH3CH2C(═O)NH and CH3CH2CH2C(═O)NH. The term “alkoxycarbonylamino” denotes alkoxy bonded to a C(═O)NH moiety. Examples of “alkoxycarbonylamino” include CH3OC(═O)NH and CH3CH2OC(═O)NH. The term “alkylaminocarbonylamino” denotes a straight-chain or branched alkyl group bonded to a NHC(═O)NH moiety. Examples of “alkylaminocarbonylamino” include CH3CH2NHC(═O)NH.
The term “cycloalkyl” denotes a saturated carbocyclic ring consisting of between 3 to 6 carbon atoms linked to one another by single bonds. Examples of “cycloalkyl” include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The term “cycloalkylalkyl” denotes cycloalkyl substitution on an alkyl group. Examples of “cycloalkylalkyl” include cyclopropylmethyl, cyclopentylethyl, and other cycloalkyl moieties bonded to straight-chain or branched alkyl groups.
The term “halogen”, either alone or in compound words such as “haloalkyl”, or when used in descriptions such as “alkyl substituted with halogen” includes fluorine, chlorine, bromine or iodine. Further, when used in compound words such as “haloalkyl”, or when used in descriptions such as “alkyl substituted with halogen” said alkyl may be partially or fully substituted with halogen atoms which may be the same or different. Examples of “haloalkyl” or “alkyl substituted with halogen” include F3C, ClCH2, CF3CH2 and CF3CCl2. The terms “haloalkoxy”, “haloalkenyl”, “haloalkynyl”, “haloalkylsulfonyl”, “halocycloalkyl”, and the like, are defined analogously to the term “haloalkyl”. Examples of “haloalkoxy” include CF3O, CCl3CH2O, F2CHCH2CH2O and CF3CH2O. Examples of “haloalkenyl” include Cl2C═CHCH2 and CF3CH2CH═CHCH2. Examples of “haloalkynyl” include HC≡CCHCl, CF3C≡C, CCl3C≡C and FCH2C≡CCH2. Examples of “haloalkylsulfonyl” include CF3S(═O)2, CCl3S(═O)2, CF3CH2S(═O)2 and CF3CF2S(═O)2. Examples of “halocycloalkyl” include 2-chlorocyclopropyl, 2-fluorocyclobutyl, 3-bromocyclopentyl and 4-chorocyclohexyl.
“Cyanoalkyl” denotes an alkyl group substituted with one cyano group. Examples of “cyanoalkyl” include NCCH2, NCCH2CH2 and CH3CH(CN)CH2. “Hydroxyalkyl” denotes an alkyl group substituted with one hydroxy group. Examples of “hydroxyalkyl” include HOCH2CH2, CH3CH2(OH)CH and HOCH2CH2CH2CH2. “Trialkylsilyl” includes 3 branched and/or straight-chain alkyl radicals attached to and linked through a silicon atom, such as trimethylsilyl, triethylsilyl and tert-butyldimethylsilyl.
The total number of carbon atoms in a substituent group is indicated by the “Ci-Cj” prefix where i and j are numbers from 1 to 9. For example, C1-C3 alkylsulfonyl designates methylsulfonyl through propylsulfonyl; C2 alkoxyalkyl designates CH3OCH2; C3 alkoxyalkyl designates, for example, CH3OCH2CH2 or CH3CH2OCH2; and C4 alkoxyalkyl designates the various isomers of an alkyl group substituted with an alkoxy group containing a total of four carbon atoms, examples including CH3CH2CH2OCH2 and CH3CH2OCH2CH2.
The term “unsubstituted” in connection with a group such as a ring means the group does not have any substituents other than its one or more attachments to the remainder of Formula 1. The term “optionally substituted” means that the number of substituents can be zero. Unless otherwise indicated, optionally substituted groups may be substituted with as many optional substituents as can be accommodated by replacing a hydrogen atom with a non-hydrogen substituent on any available carbon or nitrogen atom. Commonly, the number of optional substituents (when present) range from 1 to 3. As used herein, the term “optionally substituted” is used interchangeably with the phrase “substituted or unsubstituted” or with the term “(un)substituted.”
The number of optional substituents may be restricted by an expressed limitation. For example, the phrase “optionally substituted with up to 5 substituents independently selected from R5a” means that 0, 1, 2, 3, 4 or 5 substituents can be present.
When a compound is substituted with a substituent bearing a subscript that indicates the number of said substituents can vary (e.g., (R5a)x in Exhibit A wherein x is 0 to 5), then said substituents are independently selected from the group of defined substituents, unless otherwise indicated. When a variable group is shown to be optionally attached to a position, for example (R5a)x wherein x may be 0, then hydrogen may be at the position even if not recited in the definition of the variable group.
Naming of substituents in the present disclosure uses recognized terminology providing conciseness in precisely conveying to those skilled in the art the chemical structure. For sake of conciseness, locant descriptors may be omitted.
Unless otherwise indicated, a “ring” or “ring system” as a component of Formula 1 (e.g., R1b or R2b) is carbocyclic (e.g., phenyl) or heterocyclic (e.g., pyridinyl). The term “ring member” refers to an atom (e.g., C, O, N or S) or other moiety (e.g., C(═O), C(═S) or S(═O)2) forming the backbone of a ring or ring system. The term “ring system” denotes two or more connected rings. In a “fused bicyclic ring system” the common atoms are adjacent, and therefore the rings share two adjacent atoms and a bond connecting them. (e.g., quinazolinyl).
The term “aromatic” indicates that each ring atom is essentially in the same plane and has a p-orbital perpendicular to the ring plane, and that (4n+2) π electrons, where n is a positive integer, are associated with the ring to comply with Hückel's rule.
The term “carbocyclic ring” denotes a ring wherein the atoms forming the ring backbone are selected only from carbon. Unless otherwise indicated, a carbocyclic ring can be a saturated, partially unsaturated, or fully unsaturated ring. When a fully unsaturated carbocyclic ring satisfies Hückel's rule, then said ring is also called an “aromatic ring”. “Saturated carbocyclic” refers to a ring having a backbone consisting of carbon atoms linked to one another by single bonds; unless otherwise specified, the remaining carbon valences are occupied by hydrogen atoms.
As used herein, the terms “partially unsaturated ring” or “partially unsaturated heterocycle” refer to a ring which contain unsaturated ring atoms and one or more double bonds but is not aromatic. The term “nonaromatic” includes rings that are fully saturated as well as partially or fully unsaturated, provided that the rings are not aromatic.
The terms “heterocyclic ring”, “heterocycle” or “heteroaromatic bicyclic ring system” denote a ring wherein at least one of the atoms forming the ring backbone is other than carbon. Unless otherwise indicated, a heterocyclic ring can be a saturated, partially unsaturated, or fully unsaturated ring. When a fully unsaturated heterocyclic ring satisfies Hückel's rule, then said ring is also called a “heteroaromatic ring” or aromatic heterocyclic ring. “Saturated heterocyclic ring” refers to a heterocyclic ring containing only single bonds between ring members. The terms “heteroaromatic ring system” or “heteroaromatic bicyclic ring system” denote a ring wherein at least one of the atoms forming the ring backbone is other than carbon and at least one ring is aromatic. Unless otherwise indicated, heterocyclic rings and heteroaromatic ring systems can be attached through any available carbon or nitrogen atom by replacement of a hydrogen on said carbon or nitrogen atom.
In the context of the present invention when an instance of R1b or R2b comprises a phenyl or 6-membered heterocyclic ring (e.g., pyridinyl), the ortho, meta and para positions of each ring are relative to the connection of the ring to the remainder of Formula 1.
Compounds of this invention can exist as one or more stereoisomers. Stereoisomers are isomers of identical constitution but differing in the arrangement of their atoms in space and include enantiomers, diastereomers, cis- and trans-isomers (also known as geometric isomers) and atropisomers. Atropisomers result from restricted rotation about single bonds where the rotational barrier is high enough to permit isolation of the isomeric species. One skilled in the art will appreciate that one stereoisomer may be more active and/or may exhibit beneficial effects when enriched relative to the other stereoisomer(s) or when separated from the other stereoisomer(s). Additionally, the skilled artisan knows how to separate, enrich, and/or to selectively prepare said stereoisomers. For a comprehensive discussion of all aspects of stereoisomerism, see Ernest L. Eliel and Samuel H. Wilen, Stereochemistry of Organic Compounds, John Wiley & Sons, 1994.
Compounds of this invention can exist as one or more conformational isomers due to restricted rotation about an amide bond (e.g., C(═O)—N) in Formula 1. This invention comprises mixtures of conformational isomers. In addition, this invention includes compounds that are enriched in one conformer relative to others.
This invention comprises all stereoisomers, conformational isomers and mixtures thereof in all proportions as well as isotopic forms such as deuterated compounds.
One skilled in the art will appreciate that not all nitrogen containing heterocycles can form N-oxides since the nitrogen requires an available lone pair for oxidation to the oxide; one skilled in the art will recognize those nitrogen-containing heterocycles which can form N-oxides. One skilled in the art will also recognize that tertiary amines can form N-oxides. Synthetic methods for the preparation of N-oxides of heterocycles and tertiary amines are very well known by one skilled in the art including the oxidation of heterocycles and tertiary amines with peroxy acids such as peracetic and m-chloroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as t-butyl hydroperoxide, sodium perborate, and dioxiranes such as dimethyldioxirane. These methods for the preparation of N-oxides have been extensively described and reviewed in the literature, see for example: T. L. gilchrist in Comprehensive Organic Synthesis, vol. 7, pp 748-750, S. V. Ley, Ed., Pergamon Press; M. Tisler and B. Stanovnik in Comprehensive Heterocyclic Chemistry, vol. 3, pp 18-20, A. J. Boulton and A. McKillop, Eds., Pergamon Press; M. R. grimmett and B. R. T. Keene in Advances in Heterocyclic Chemistry, vol. 43, pp 149-161, A. R. Katritzky, Ed., Academic Press; M. Tisler and B. Stanovnik in Advances in Heterocyclic Chemistry, vol. 9, pp 285-291, A. R. Katritzky and A. J. Boulton, Eds., Academic Press; and G. W. H. Cheeseman and E. S. g. Werstiuk in Advances in Heterocyclic Chemistry, vol. 22, pp 390-392, A. R. Katritzky and A. J. Boulton, Eds., Academic Press.
One skilled in the art recognizes that because in the environment and under physiological conditions salts of chemical compounds are in equilibrium with their corresponding nonsalt forms, salts share the biological utility of the nonsalt forms. Thus, a wide variety of salts of the compounds of Formula 1 are useful for control of plant diseases caused by fungal plant pathogens (i.e. are agriculturally suitable). The salts of the compounds of Formula 1 include acid-addition salts with inorganic or organic acids such as hydrobromic, hydrochloric, nitric, phosphoric, sulfuric, acetic, butyric, fumaric, lactic, maleic, malonic, oxalic, propionic, salicylic, tartaric, 4-toluenesulfonic or valeric acids. When a compound of Formula 1 contains an acidic moiety such as a carboxylic acid, salts also include those formed with organic or inorganic bases such as pyridine, triethylamine or ammonia, or amides, hydrides, hydroxides or carbonates of sodium, potassium, lithium, calcium, magnesium or barium. Accordingly, the present invention comprises compounds selected from Formula 1, N-oxides and agriculturally suitable salts thereof.
Compounds selected from Formula 1, stereoisomers, N-oxides, and salts thereof, typically exist in more than one form, therefore Formula 1 includes all crystalline and non-crystalline forms of the compounds that Formula 1 represents. Non-crystalline forms include embodiments which are solids such as waxes and gums as well as embodiments which are liquids such as solutions and melts. Crystalline forms include embodiments which represent essentially a single crystal type and embodiments which represent a mixture of polymorphs (i.e. different crystalline types). The term “polymorph” refers to a particular crystalline form of a chemical compound that can crystallize in different crystalline forms, these forms having different arrangements and/or conformations of the molecules in the crystal lattice. Although polymorphs can have the same chemical composition, they can also differ in composition due to the presence or absence of co-crystallized water or other molecules, which can be weakly or strongly bound in the lattice. Polymorphs can differ in such chemical, physical and biological properties as crystal shape, density, hardness, color, chemical stability, melting point, hygroscopicity, suspensibility, dissolution rate and biological availability. One skilled in the art will appreciate that a polymorph of a compound represented by Formula 1 can exhibit beneficial effects (e.g., suitability for preparation of useful formulations, improved biological performance) relative to another polymorph or a mixture of polymorphs of the same compound represented by Formula 1. Preparation and isolation of a particular polymorph of a compound represented by Formula 1 can be achieved by methods known to those skilled in the art including, for example, crystallization using selected solvents and temperatures.
Embodiments of the present invention as described in the Summary of the Invention include those described below. In the following Embodiments, Formula 1 includes stereoisomers, N-oxides and salts thereof, and reference to “a compound of Formula 1” includes the definitions of substituents specified in the Summary of the Invention unless further defined in the Embodiments.
A compound of Formula 1 wherein A is S(═O) or S(═NR3).
A compound of Embodiment 1 wherein A is S(═O).
A compound of Embodiment 1 wherein A is S(═NR3).
A compound of Formula 1 wherein A is S.
A compound of Formula 1 or Embodiments 1 and 3 wherein R3 is H, cyano, C1-C2 alkyl, C2-C3 alkylcarbonyl or C2-C3 haloalkylcarbonyl.
A compound of Embodiment 5 wherein R3 is H, cyano or C1-C2 alkyl.
A compound of Embodiment 6 wherein R3 is H, cyano or methyl.
A compound of Embodiment 7 wherein R3 is H.
A compound of Formula 1 or any one of Embodiments 1 through 8 wherein R1 is R1aZ1a—.
A compound of Formula 1 or any one of Embodiments 1 through 8 wherein R1 is R1bZ1b—.
A compound of Formula 1 or any one of Embodiments 1 through 10 wherein R2 is R2aZ2a—.
A compound of Formula 1 or any one of Embodiments 1 through 10 wherein R2 is R2bZ2b—.
A compound of Formula 1 or any one of Embodiments 1 through 12 wherein R1 is R1aZ1a— or R1bZ1b— and R2 is R2aZ2a—.
A compound of Embodiment 13 wherein R1 is R1bZ1b— and R2 is R2aZ2a—.
A compound of Embodiment 13 wherein R1 is R1aZ1a— and R2 is R2aZ2a—.
A compound of Formula 1 or Embodiments 1 through 12 wherein R1 is R1bZ1b and R2 is R2bZ2b.
A compound of Formula 1 or any one of Embodiments 1 through 16 wherein when R1 and R2 are taken together with the sulfur atom to which they are attached to form a 4- to 6-membered fully saturated heterocyclic ring, then said ring contains ring members, in addition to the connecting sulfur atom, selected from carbon atoms and up to 1 heteroatom selected from up to 1 O and up to 1 N atom, each ring optionally substituted with up to 2 substituents independently selected from halogen and methyl on carbon atom ring members and C2-C4 alkylcarbonyl and C2-C4 alkoxycarbonyl on the nitrogen atom ring member.
A compound of Embodiment 17 wherein R1 and R2 are taken together with the sulfur atom to which they are attached to form a 5 to 6-membered fully saturated heterocyclic ring containing ring members, in addition to the connecting sulfur atom, selected from carbon atoms and up to 1 heteroatom selected from up to 1 O and up to 1 N atom, each ring optionally substituted with up to 2 substituents independently selected from halogen and methyl on carbon atom ring members and C2-C4 alkylcarbonyl and C2-C4 alkoxycarbonyl on the nitrogen atom ring member.
A compound of Embodiment 18 wherein R1 and R2 are taken together with the sulfur atom to which they are attached to form a 5 to 6-membered fully saturated heterocyclic ring containing ring members, in addition to the connecting sulfur atom, selected from carbon atoms and up to 1 heteroatom selected from up to 1 O and up to 1 N atom, each ring optionally substituted with up to 2 substituents independently selected from methyl on carbon atom ring members and methylcarbonyl and methoxycarbonyl on the nitrogen atom ring member.
A compound of Embodiment 19 wherein R1 and R2 are taken together with the sulfur atom to which they are attached to form a 5 to 6-membered fully saturated heterocyclic ring containing ring members, in addition to the connecting sulfur atom, selected from carbon atoms and up to 1 heteroatom selected from up to 1 O and up to 1 N atom.
A compound of Embodiment 20 wherein R1 and R2 are taken together with the sulfur atom to which they are attached to form a 5 to 6-membered fully saturated heterocyclic ring containing ring members, in addition to the connecting sulfur atom, selected from carbon atoms.
A compound of Embodiment 20 wherein R1 and R2 are taken together as —CH2CH2OCH2CH2—, —CH2CH2NCH2CH2—, —CH2CH2CH2CH2CH2— or —CH2CH2CH2CH2—.
A compound of Embodiment 22 wherein R1 and R2 are taken together as —CH2CH2OCH2CH2—, —CH2CH2CH2CH2CH2— or —CH2CH2CH2CH2—.
A compound of Embodiment 23 wherein R1 and R2 are taken together as —CH2CH2CH2CH2CH2— or —CH2CH2CH2CH2—.
A compound of Formula 1 or any one of Embodiments 1 through 24 wherein R1a and R2a are each independently C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C1-C6 hydroxyalkyl, C2-C6 cyanoalkyl, C2-C6 alkoxyalkyl, C2-C6 haloalkoxyalkyl, C3-C8 alkoxyalkoxyalkyl, C2-C6 alkylsulfonylalkyl, C3-C8 alkylcarbonylalkyl, C3-C8 haloalkylcarbonylalkyl, C3-C8 alkoxycarbonylalkyl, C3-C8 haloalkoxycarbonylalkyl, C3-C8 alkylcarbonyloxyalkyl or C3-C8 haloalkylcarbonyloxyalkyl.
A compound of Embodiment 25 wherein R1a and R2a are each independently C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkoxyalkyl, C2-C6 haloalkoxyalkyl, C3-C8 alkoxyalkoxyalkyl, C3-C8 alkylcarbonylalkyl, C3-C8 haloalkylcarbonylalkyl, C3-C8 alkoxycarbonylalkyl or C3-C8 haloalkoxycarbonylalkyl.
A compound of Embodiment 26 wherein R1a and R2a are each independently C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkoxyalkyl, C2-C6 haloalkoxyalkyl, C3-C8 alkylcarbonylalkyl, C3-C8 haloalkylcarbonylalkyl or C3-C8 alkoxycarbonylalkyl.
A compound of Embodiment 27 wherein R1a and R2a are each independently C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkoxyalkyl, C3-C8 alkylcarbonylalkyl or C3-C8 alkoxycarbonylalkyl.
A compound of Embodiment 28 wherein R1a and R2a are each independently C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkoxyalkyl or C3-C8 alkoxycarbonylalkyl.
A compound of Embodiment 29 wherein R1a and R2a are each independently C1-C3 alkyl, C1-C3 haloalkyl, C2-C3 alkenyl, C2-C3 alkoxyalkyl or C3-C4 alkoxycarbonylalkyl.
A compound of Embodiment 30 wherein R1a and R2a are each independently C1-C3 alkyl or C2-C3 alkenyl.
A compound of Embodiment 31 wherein R1a and R2a are each independently C1-C3 alkyl.
A compound of Embodiment 32 wherein R1a and R2a are each independently C1-C2 alkyl.
A compound of Embodiment 33 wherein R1a and R2a are each methyl.
A compound of Formula 1 or any one of Embodiments 1 through 34 wherein Z1a and Z2a are each a direct bond.
A compound of Formula 1 or any one of Embodiments 1 through 34 wherein Z1a is NR4a.
A compound of Formula 1 or any one of Embodiments 1 through 34 wherein Z2a is NR4a.
A compound of Formula 1 or any one of Embodiments 1 through 37 wherein R1b and R2b are each independently selected from G-1 through G-66 as shown in Exhibit A Exhibit A
A compound of Embodiment 38 wherein G is selected from G-1, G-2, G-3, G-4, G-7, G-16, G-18, G-19, G-22, G-27, G-28, G-46, G-47, G-48, G-53, G-54, G-55. G-56 and G-57.
A compound of Embodiment 39 wherein G is selected from G-1, G-2, G-3, G-4, G-16, G-22, G-27, G-28, G-46, G-47, G-48, G-53, G-54, G-55, G-56 and G-57.
A compound of Embodiment 40 wherein G is selected from G-1, G-2, G-3, G-4, G-16, G-22, G-46, G-47, G-54, G-55 and G-57.
A compound of Embodiment 41 wherein G is selected from G-3, G-16, G-46, G-47, G-54, G-55 and G-57.
A compound of Embodiment 42 wherein G is selected from G-3 and G-55.
A compound of Embodiment 43 wherein G is G-3.
A compound of Embodiment 43 wherein G is G-55.
A compound of any one of Embodiments 38 through 45 wherein G-3 is connected at its 2-position to Formula 1.
A compound of any one of Embodiments 38 through 45 wherein G-3 is connected at its 3-position to Formula 1.
A compound of Formula 1 or any one of Embodiments 38 through 47 wherein x is 0, 1, 2 or 3.
A compound of Embodiment 48 wherein x is 0, 1 or 2.
A compound of Embodiment 49 wherein x is 0 or 1.
A compound of Embodiment 50 wherein x is 0.
A compound of Formula 1 or any one of Embodiments 1 through 51 wherein Z1b and Z2b are each independently a direct bond or (CR6aR6b)m.
A compound of Embodiment 52 wherein Z1b and Z2b are each independently a direct bond, CH2 or CH2CH2.
A compound of Embodiment 53 wherein Z1b and Z2b are each independently a direct bond or CH2.
A compound of Embodiment 54 wherein Z1b and Z2b are each a direct bond.
A compound of Embodiment 54 wherein Z1b and Z2b are each CH2.
A compound of Formula 1 or any one of Embodiments 1 through 51 wherein Z1b is NR4b.
A compound of Formula 1 or any one of Embodiments 1 through 51 wherein Z2b is NR4b.
A compound of Formula 1 or any one of Embodiments 1 through 52 wherein m is 1.
A compound of Formula 1 or any one of Embodiments 1 through 52 wherein m is 2.
A compound of Formula 1 or any one of Embodiments 1 through 60 wherein R4a and R4b are each independently H, methyl or halomethyl.
A compound of Embodiment 61 wherein R4a and R4b are each independently H or methyl.
A compound of Embodiment 62 wherein R4a and R4b are each H.
A compound of Formula 1 or any one of Embodiments 1 through 63 wherein when R1a and R4a are taken together with the nitrogen atom to which they are attached to form a 4- to 6-membered fully saturated heterocyclic ring, then said ring contains ring members, in addition to the connecting nitrogen atom, selected from carbon atoms and up to 1 heteroatom selected from up to 1 O and up to 1 N atom, each ring optionally substituted with up to 2 substituents independently selected from halogen and methyl on carbon atom ring members and methylcarbonyl and methoxycarbonyl on the nitrogen atom ring member.
A compound of Embodiment 64 wherein R1a and R4a are taken together with the nitrogen atom to which they are attached to form a 5 to 6-membered fully saturated heterocyclic ring containing ring members, in addition to the connecting nitrogen atom, selected from carbon atoms and up to 1 heteroatom selected from up to 1 O and up to 1 N atom, each ring optionally substituted with up to 2 substituents independently selected from halogen and methyl on carbon atom ring members and methylcarbonyl and methoxycarbonyl on the nitrogen atom ring member.
A compound of Embodiment 65 wherein R1a and R4a are taken together with the nitrogen atom to which they are attached to form a 5 to 6-membered fully saturated heterocyclic ring containing ring members, in addition to the connecting nitrogen atom, selected from carbon atoms and up to 1 heteroatom selected from up to 1 O and up to 1 N atom.
A compound of Embodiment 66 wherein R1a and R4a are taken together with the nitrogen atom to which they are attached to form a 5 to 6-membered fully saturated heterocyclic ring containing ring members, in addition to the connecting nitrogen atom, selected from carbon atoms.
A compound of Formula 1 or any one of Embodiments 1 through 67 wherein each R6a and R6b is independently H, halogen, methyl or halomethyl.
A compound of Embodiment 68 wherein each R6a and R6b is independently H, halogen or methyl.
A compound of Embodiment 69 wherein each R6a and R6b is H.
A compound of Formula 1 or any one of Embodiments 1 through 70 wherein L is CH, CH(CH3) or CH2CH2.
A compound of Embodiment 71 wherein L is CH2 or CH(CH3).
A compound of Embodiment 72 wherein L is CH2.
A compound of Formula 1 or any one of Embodiments 1 through 70 wherein each R7a and R7b is independently H, cyano, halogen, methyl or halomethyl.
A compound of Embodiment 74 wherein each R7a and R7b is independently H, cyano, halogen or methyl.
A compound of Embodiment 75 wherein each R7a and R7b is independently H, halogen or methyl.
A compound of Embodiment 76 wherein each R7a and R7b is independently H or methyl.
A compound of Embodiment 77 wherein each R7a and R7b is H.
A compound of Formula 1 or any one of Embodiments 1 through 78 wherein n is 0, 1 or 2.
A compound of Embodiment 79 wherein n is 0 or 1.
A compound of Embodiment 80 wherein n is 0.
A compound of Embodiment 81 wherein n is 1.
A compound of Formula 1 or any one of Embodiments 1 through 82 wherein J is J-1 through J-3, J-6 through J-10 or J-14.
A compound of Embodiment 83 wherein J is J-1, J-2, J-3, J-6 or J-14.
A compound of Embodiment 84 wherein J is J-1, J-2, J-3 or J-14.
A compound of Embodiment 85 wherein J is J-1 or J-14.
A compound of Embodiment 86 wherein J is J-1.
A compound of Formula 1 or any one of Embodiments 1 through 87 wherein each R8 is independently F, 0 or methyl.
A compound of Embodiment 88 wherein each R8 is methyl.
A compound of Formula 1 or any one of Embodiments 1 through 89 wherein q is 0 or 1.
A compound of Embodiment 90 wherein q is 0.
A compound of Formula 1 or any one of Embodiments 1 through 91 wherein each R5a is independently cyano, halogen, NR9aR9b, C(═O)NR9aR9b, C(R10)═NR11 or —U—V-Q; or C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, C2-C4 alkenyloxy, C2-C4 alkynyloxy, C1-C4 alkylsulfonyl, C1-C4 alkylsulfonyloxy, C2-C5 alkylcarbonyl, C2-C5 alkoxycarbonyl, C2-C5 alkylcarbonyloxy, C2-C5 alkoxycarbonyloxy, C2-C5 alkylaminocarbonyloxy, C2-C5 alkylcarbonylamino, C2-C5 alkoxycarbonylamino or C2-C5 alkylaminocarbonylamino, each optionally substituted with up to 3 substituents independently selected from R12.
A compound of Embodiment 92 wherein each R5a is independently cyano, halogen, C(═O)NR9aR9b, C(R10)═NR11 or —U—V-Q; or C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, C2-C4 alkenyloxy, C2-C4 alkynyloxy, C1-C4 alkylsulfonyl, C1-C4 alkylsulfonyloxy, C2-C5 alkylcarbonyl, C2-C5 alkoxycarbonyl or C2-C5 alkoxycarbonyloxy, each optionally substituted with up to 3 substituents independently selected from R12.
A compound of Embodiment 93 wherein each R5a is independently cyano, halogen, C(═O)NR9aR9b or —U—V-Q; or C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, C2-C4 alkenyloxy, C2-C4 alkynyloxy, C1-C4 alkylsulfonyl, C1-C4 alkylsulfonyloxy, C2-C5 alkylcarbonyl, C2-C5 alkoxycarbonyl or C2-C5 alkoxycarbonyloxy, each optionally substituted with up to 3 substituents independently selected from R12.
A compound of Embodiment 94 wherein each R5a is independently cyano, halogen, C(═O)NR9aR9b or —U—V-Q; or C1-C4 alkyl, C1-C4 alkoxy, C2-C5 alkoxycarbonyl or C2-C5 alkoxycarbonyloxy, each optionally substituted with up to 3 substituents independently selected from R12.
A compound of Embodiment 95 wherein each R5a independently cyano, halogen, C1-C2 alkyl, C1-C4 alkoxy or C2-C4 alkoxycarbonyl, each optionally substituted with up to 2 substituents independently selected from R12.
A compound of Embodiment 96 wherein each R5a independently cyano, halogen, methyl or methoxy.
A compound of Formula 1 or any one of Embodiments 1 through 97 wherein when each R9a is separate (i.e. not taken together with R9b), then each R9a is independently H, cyano, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, C2-C4 haloalkenyl, C2-C4 alkynyl, C2-C4 haloalkynyl, C2-C4 alkylcarbonyl, C2-C4 alkoxycarbonyl, C2-C4 alkylaminocarbonyl or C3-C5 dialkylaminocarbonyl.
A compound of Embodiment 98 wherein each R9a is independently H, cyano, C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 alkylcarbonyl, C2-C4 alkoxycarbonyl, C2-C4 alkylaminocarbonyl or C3-C5 dialkylaminocarbonyl.
A compound of Embodiment 99 wherein each R9a independently H, C1-C2 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 alkylcarbonyl or C2-C4 alkoxycarbonyl.
A compound of Formula 1 or any one of Embodiments 1 through 100 wherein when each R bis separate (i.e. not taken together with R9a), then each R9b is independently H, C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, C2-C4 haloalkenyl, C2-C4 alkynyl, C2-C4 haloalkynyl, C2-C4 alkoxyalkyl, C2-C4 haloalkoxyalkyl, C2-C4 alkylsulfonylalkyl, C2-C4 alkylaminoalkyl or C3-C5 dialkylaminoalkyl, each optionally substituted with up to 1 substituent selected from cyano, hydroxy, nitro, C2-C4 alkylcarbonyl, C2-C4 alkoxycarbonyl, C3-C9 trialkylsilyl and C3-C9 halotrialkylsilyl.
A compound of Embodiment 101 wherein each R bis independently H, C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, C2-C4 haloalkenyl, C2-C4 alkynyl, C2-C4 alkoxyalkyl, C2-C4 haloalkoxyalkyl, C2-C4 alkylaminoalkyl or C3-C5 dialkylaminoalkyl.
A compound of Embodiment 102 wherein each R bis independently H, C1-C3 alkyl, C1-C3 haloalkyl, C2-C4 alkenyl, C2-C4 haloalkenyl, C2-C4 alkynyl, C2-C4 alkoxyalkyl or C2-C4 alkylaminoalkyl.
A compound of Embodiment 103 wherein each R bis independently H, C1-C3 alkyl, C1-C3 haloalkyl, C2-C4 alkenyl, C2-C4 alkynyl or C2-C4 alkoxyalkyl.
A compound of Formula 1 or any one of Embodiments 1 through 104 wherein when R9a and R9b are taken together with the nitrogen atom to which they are attached to form a 4- to 6-membered fully saturated heterocyclic ring, then said ring contains ring members, in addition to the connecting nitrogen atom, selected from carbon atoms and up to 1 heteroatom selected from up to 10, up to 1 S and up to 1 N atom, each ring optionally substituted with up to 2 methyl groups.
A compound of Embodiment 105 wherein R9a and R9b are taken together with the nitrogen atom to which they are attached to form an azetidinyl, morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl or thiomorpholinyl ring, each ring optionally substituted with up to 2 methyl groups.
A compound of Formula 1 or any one of Embodiments 1 through 106 wherein each R10 is independently H, cyano, halogen, methyl or methoxy.
A compound of Embodiment 107 wherein each R10 is independently H or methyl.
A compound of Formula 1 or any one of Embodiments 1 through 108 wherein each R11 is independently hydroxy, NR13aR13b, C1-C2 alkyl, C1-C2 alkoxy, C2-C4 alkenyloxy, C2-C4 alkylcarbonyloxy or C2-C4 alkoxycarbonyloxy.
A compound of Embodiment 109 wherein each R11 is independently hydroxy, NR13aR13b, C1-C2 alkyl or C1-C2 alkoxy.
A compound of Embodiment 110 wherein each R11 is independently hydroxy, NR13aR13b, methyl or methoxy.
A compound of Embodiment 111 wherein each R11 is hydroxy.
A compound of Formula 1 or any one of Embodiments 1 through 113 wherein each R12 is independently cyano, halogen, hydroxy, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C2-C3 alkoxyalkoxy, C1-C3 alkylsulfonyl, C1-C3 haloalkylsulfonyl, C2-C3 alkylcarbonyl, C2-C3 haloalkylcarbonyl, C2-C3 alkoxycarbonyl, C2-C3 alkylaminocarbonyl, C3-C5 dialkylaminocarbonyl, C(R14)═NOR15 or C(R16)═NR17.
A compound of Embodiment 113 wherein each R12 is independently cyano, halogen, hydroxy, C1-C2 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy, C1-C2 haloalkoxy, C1-C2 alkylsulfonyl, C1-C2 haloalkylsulfonyl, C2-C3 alkylcarbonyl, C2-C3 haloalkylcarbonyl, C2-C3 alkoxycarbonyl, C2-C3 alkylaminocarbonyl or C3-C5 dialkylaminocarbonyl.
A compound of Embodiment 114 wherein each R12 is independently halogen, C1-C2 alkyl or C1-C2 haloalkyl.
A compound of Embodiment 115 wherein each R12 is independently halogen.
A compound of Formula 1 or any one of Embodiments 1 through 116 wherein each U is independently a direct bond, C(═O)O or C(═O)N(R18).
A compound of Embodiment 117 wherein each U is a direct bond.
A compound of Embodiment 117 wherein each U is independently C(═O)O or C(═O)N(R18).
A compound of Formula 1 or any one of Embodiments 1 through 119 wherein each V is independently a direct bond; or C1-C6 alkylene, C2-C6 alkenylene or C3-C6 alkynylene, each optionally substituted with up to 2 substituents independently selected from halogen, cyano, nitro, hydroxy, C1-C2 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy and C1-C2 haloalkoxy.
A compound of Embodiment 120 wherein each V is independently a direct bond; or C1-C3 alkylene, C2-C4 alkenylene or C3-C4 alkynylene, each optionally substituted with up to 2 substituents independently selected from halogen, hydroxy, C1-C2 alkyl, C1-C2 alkoxy and C1-C2 haloalkoxy.
A compound of Embodiment 121 wherein each V is independently a direct bond, C1-C3 alkylene, C2-C4 alkenylene or C3-C4 alkynylene.
A compound of Embodiment 122 wherein each V is independently a direct bond, C1-C3 alkylene or C2-C4 alkenylene.
A compound of Embodiment 123 wherein each V is a direct bond.
A compound of Embodiment 124 wherein each V is independently C1-C3 alkylene.
A compound of Formula 1 or any one of Embodiments 1 through 125 wherein each Q is independently phenyl optionally substituted with up to 2 substituents independently selected from R20; or a 5- to 6-membered heteroaromatic ring, each ring containing ring members selected from carbon atoms and 1 to 4 heteroatoms independently selected from up to 2 O, up to 2 S and up to 3 N atoms, each ring optionally substituted with up to 2 substituents independently selected from R20; or a 3- to 7-membered nonaromatic heterocyclic ring, each ring containing ring members selected from carbon atoms and 1 to 4 heteroatoms independently selected from up to 2 O, up to 2 S and up to 3 N atoms, wherein up to 2 ring members are independently selected from C(═O), C(═S), S(═O) and S(═O)2, each ring optionally substituted with up to 2 substituents independently selected from R20.
A compound of Embodiment 126 wherein each Q is independently phenyl optionally substituted with up to 2 substituents independently selected from R20; or pyridinyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, thienyl, isoxazolinyl, piperidinyl, morpholinyl or piperazinyl, each optionally substituted with up to 2 substituents independently selected from R20.
A compound of Embodiment 127 wherein each Q is independently phenyl optionally substituted with up to 2 substituents independently selected from R20; or pyridinyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl or oxazolyl, each optionally substituted with up to 2 substituents independently selected from R20.
A compound of Embodiment 128 wherein each Q is independently phenyl optionally substituted with up to 2 substituents independently selected from R20; or pyridinyl or pyrazolyl, each optionally substituted with up to 2 substituents independently selected from R20.
A compound of Formula 1 or any one of Embodiments 1 through 129 wherein when each R13a is separate (i.e. not taken together with R13b), then each R13a is independently H, methyl or methylcarbonyl.
A compound of Embodiment 130 wherein each R13a is independently H or methyl.
A compound of Formula 1 or any one of Embodiments 1 through 131 wherein when each R13b is separate (i.e. not taken together with R13a), then each R13b is independently H, cyano, methyl, methylcarbonyl, methoxycarbonyl, methoxycarbonylmethyl, methylaminocarbonyl or dimethylaminocarbonyl.
A compound of Embodiment 132 wherein each R13b is independently H, cyano or methyl.
A compound of Formula 1 or any one of Embodiments 1 through 133 wherein when R13a and R13b are taken together with the nitrogen atom to which they are attached to form a 5- to 6-membered fully saturated heterocyclic ring, then said ring contains ring members, in addition to the connecting nitrogen atom, selected from carbon atoms and up to 1 heteroatom selected from up to 10, up to 1 S and up to 1 N atom, each ring optionally substituted with up to 2 methyl groups.
A compound of Embodiment 134 wherein R13a and R13b are taken together with the nitrogen atom to which they are attached to form an azetidinyl, morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl or thiomorpholinyl ring, each ring optionally substituted with up to 2 methyl groups.
A compound of Formula 1 or any one of Embodiments 1 through 135 wherein each R14 and R16 is independently H, cyano, halogen, methyl or methoxy.
A compound of Formula 1 or any one of Embodiments 1 through 136 wherein each R15 is independently H, C1-C3 alkyl, C1-C3 haloalkyl, C2-C3 alkylcarbonyl or C2-C3 alkoxycarbonyl; or phenyl optionally substituted with up to 2 substituents independently selected halogen and methyl; or a 5- to 6-membered fully saturated heterocyclic ring, each ring containing ring members selected from carbon atoms and up to 2 heteroatoms independently selected from up to 2 O, up to 2 S and up to 2 N atoms, each ring optionally substituted with up to 2 substituents independently selected from halogen and methyl.
A compound of Embodiment 137 wherein each R15 is independently H or C1-C2 alkyl.
A compound of Formula 1 or any one of Embodiments 1 through 138 wherein each R17 is independently H, cyano or C1-C2 alkyl.
A compound of Formula 1 or any one of Embodiments 1 through 139 wherein each R18 and R19 is independently H, cyano, hydroxy, C1-C4 alkyl or C1-C4 haloalkyl.
A compound of Embodiment 140 wherein each R18 and R19 is independently H, cyano, hydroxy or C1-C2 alkyl.
A compound of Formula 1 or any one of Embodiments 1 through 141 wherein each R20 is independently halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl or C1-C4 alkoxy.
A compound of Embodiment 142 wherein each R20 is independently halogen, cyano, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 alkoxy.
A compound of Embodiment 143 wherein each R20 is independently halogen, cyano, C1-C2 alkyl, C1-C2 haloalkyl or C1-C2 alkoxy.
A compound of Embodiment 144 wherein each R20 is independently halogen, methyl or methoxy.
Embodiments of this invention, including Embodiments 1-145 above as well as any other embodiments described herein, can be combined in any manner, and the descriptions of variables in the embodiments pertain not only to the compounds of Formula 1 but also to the starting compounds and intermediate compounds useful for preparing the compounds of Formula 1. In addition, embodiments of this invention, including Embodiments 1-145 above as well as any other embodiments described herein, and any combination thereof, pertain to the compositions and methods of the present invention.
Combinations of Embodiments 1-145 are illustrated by:
A compound of Formula 1 wherein
A compound of Embodiment A wherein
A compound of Embodiment B wherein
A compound of Embodiment C wherein
A compound of Embodiment D wherein
This invention provides a fungicidal composition comprising a compound of Formula 1 (including all stereoisomers, N-oxides, and salts thereof), and at least one other fungicide. Of note as embodiments of such compositions are compositions comprising a compound corresponding to any of the compound embodiments described above.
This invention provides a fungicidal composition comprising a compound of Formula 1 (including all stereoisomers, N-oxides, and salts thereof) (i.e. in a fungicidally effective amount), and at least one additional component selected from the group consisting of surfactants, solid diluents and liquid diluents. Of note as embodiments of such compositions are compositions comprising a compound corresponding to any of the compound embodiments described above.
This invention provides a method for controlling plant diseases caused by fungal plant pathogens comprising applying to the plant or portion thereof, or to the plant seed, a fungicidally effective amount of a compound of Formula 1 (including all stereoisomers, N-oxides, and salts thereof). Of note as embodiments of such methods are methods comprising applying a fungicidally effective amount of a compound corresponding to any of the compound embodiments describe above. Of particular note are embodiments where the compounds are applied as compositions of this invention.
One or more of the following methods and variations as described in Schemes 1-17 can be used to prepare the compounds of Formula 1. The definitions of R1, R2, A, L and J in the compounds of Formulae 1-15 below are as defined above in the Summary of the Invention unless otherwise noted. Compounds of Formula 1a are various subsets of Formula 1, and all substituents for Formula 1a are as defined above for Formula 1 unless otherwise indicated. Compounds of Formula 3a are a subset of Formula 3, Formulae 4a-4d are a subset of Formula 4, Compounds of Formula 6a are a subset of Formula 6, and Compounds of Formula 7a are a subset of Formula 7.
As shown in Scheme 1, compounds of Formula 1 can be prepared by reacting amidoximes of Formula 2 with trifluoroacetic anhydride (TFAA) or an equivalent. The reaction can be carried out without solvent other than the compounds of Formula 2 and TFAA. More typically the reaction is conducted in a liquid phase with a solvent such as tetrahydrofuran, toluene, acetonitrile or dichloromethane at a temperature between about 0 to 100° C., and optionally in the presence of a base such as pyridine or trimethylamine. Preparation of oxadiazole rings by this method and others are known in the art; see, for example, Comprehensive Heterocyclic Chemistry, Vol. 6, Part 4B, pages 365-391, Kevin T. Potts editor, Pergamon Press, New York, 1984, and Tetrahedron Letters 2014, 55(9), 1557-1560. The method of Scheme 1 is also illustrated in present Example 3, Step D, and Example 4, Step D.
As shown in Scheme 2, amidoximes of Formula 2 can be prepared from corresponding nitriles of Formula 3 and hydroxylamine or a hydroxylamine salt (e.g., hydroxylamine hydrochloride) in a solvent such as ethanol or methanol at a temperature ranging from about 0 to 80° C. The hydroxylamine may be used in the form of a solution in water or, alternatively, the hydroxylamine can be generated in situ by treating an acid salt of hydroxylamine with a base. Suitable bases for liberating the hydroxylamine from its salt include, but are not limited to, sodium hydroxide, sodium bicarbonate, sodium carbonate, potassium carbonate, pyridine or triethylamine. Hydroxylamine salts include salts which hydroxylamine forms with inorganic acids such as sulfuric acid, hydrochloric acid, nitric acid and phosphoric acid or with organic acids such as formic acid, acetic acid, propionic acid and sulfonic acids. The preparation of amidoximes is known in the art; see, for example, Science of Synthesis 2005, 22, 489-563 and Organic Letters 2014, 16(3), 892-895. The method of Scheme 2 is also illustrated in present Example 3, Step C and Example 4, Step C.
As shown in Scheme 3, nitriles of Formula 3 can be prepared from compounds of Formulae 4 and 5 wherein Y1 is a suitable functional group which under the appropriate reaction conditions will allow for the construction of the L group. Suitable functional groups include, but are not limited to, aldehyde, alkyl halide, carboxyl acid, acid chloride, and the like. Suitable reaction conditions include metal-catalyzed coupling, alkylation, reductive amination and acylation/reduction. For example, compounds of Formula 3 wherein L is CH2 can be prepared by reacting a compound of Formula 4 with a base such as potassium carbonate or sodium hydride, followed by treatment with a compound of Formula 5 wherein Y1 is a methyl halide (e.g., BrCH2—). Alternatively, a two-step acylation/reduction protocol can be used when Y1 is an acid chloride. The synthetic literature describes many general methods for forming a saturated chain containing 1- to 3-atoms consisting of (optionally substituted) carbon atoms such as the L groups of the present invention; see, for example, Tetrahedron 2014, 70, 6613-6622; Comprehensive Organic Functional Group Transformations, Vols. 1, 2, 3 and 5, A. R. Katritzky editor, Pergamon Press, New York, 1995; Vogel's Textbook of Practical Organic Chemistry, 5th Ed., pp 470-823, Longman Group, London, 1989; and Advanced Organic Chemistry, 4th Ed. Jerry March, Wiley, New York 1992.
One skilled in the art will recognize that the method of Scheme 3 can also be performed when the substituent —C≡N in Formula 5 is replaced with 5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl (i.e. Formula 6 below) thus providing a compound of Formula 1 as illustrated in Scheme 4.
Scheme 5 illustrates a specific example of the general method of Scheme 4 for the preparation of a compound of Formula 1a (i.e. Formula 1 wherein L is CH2 and J is phenyl). In this method the compound of Formula 6a (i.e. Formula 6 wherein J is phenyl and Y1 is BrCH2—) is reacted with a compound of Formula 4 in the presence of a base such as sodium or potassium hydroxide, sodium hydride or sodium bicarbonate in a solvent such as tetrahydrofuran, N,N-dimethylformamide, ethanol or acetonitrile typically at a temperature between about 0 to 80° C. Present Example 1, Step E, Example 2 and Example 5, Step D illustrate the method of Scheme 5.
As shown in Scheme 6, nitriles of Formula 3 where L is a direct bond can be prepared via a palladium-catalyzed cross-coupling reaction of compounds of Formulae 4 and 7 wherein X1 is bromine, iodine or triflate. These reactions are typically run in the presence of a base, a catalyst (e.g., Pd(0) or Pd(II)) and a suitable ligand. Suitable bases for this transformation are potassium carbonate, cesium carbonate or sodium tert-butoxide, while Pd(II) salts such as palladium(II) acetate, palladium(II) acetate or palladium(II) chloride are used in conjunction with ligands such as triphenylphosphine, 1,1′-bis(diphenylphosphino)ferrocene (dppf), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (xantphos), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (xphos), 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (BINAP) or 2,2′-bis[(di-4-tolyl)phosphino]]-1,1′-binaphthyl (tol-BINAP). Palladium-catalyzed C—N coupling reactions are reported in a variety of published chemistry references; see, for example, Chemical Reviews 2002, 102, 1359-1469, Angewandte Chemie International Edition 2008, 47, 6338-6361 and Chemical Science 2010, 1, 13-31.
Scheme 7 illustrates a specific example of the general method of Scheme 6 for the preparation of a compound of Formula 3a (i.e. Formula 3 wherein J is phenyl and L is a direct bond). In this method the compound of Formula 7a (i.e. Formula 7 wherein J is phenyl and X is Br) is reacted with a compound of Formula 4 in the presence of cesium carbonate, palladium(II) acetate and 2,2′-bis(di-4-tolylphosphino)-1,1′-binaphthyl (tol-BINAP) in toluene as illustrated in present Example 3, Step B.
Alternatively, as shown in Scheme 8, nitriles of Formula 3 can be prepared by reacting a compound of Formula 8 wherein X2 is halogen (e.g., I, Br or Cl) with a cyanating reagent such as zinc cyanide, sodium cyanide, potassium cyanide, potassium hexacyanoferrate(II) or sodium hexacyanoferrate(II). There are a variety of conditions published in the chemistry literature which can be used for converting an aryl halide to a nitrile including palladium-catalyzed conditions employing tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3) or palladium(II) acetate Pd(OAc)2 as the palladium catalyst and a phosphine ligand such as 1,1′-bis(diphenylphosphino)ferrocene (dppf). For references see, for example, Journal of the American Chemical Society 2003, 125, 2890-2891, Synlett 2007, 4, 555-558 and Chemistry—A European Journal 2007, 13, 6249-6254. The method of Scheme 8 is also illustrated in Example 4, Step B.
Intermediates of Formula 8 can be prepared analogous to the method of Scheme 3. For reaction conditions see present Example 4. Step A.
Compounds of Formula 4 are commercially available and can be prepared by variety general methods described in the chemical literature. For example, as shown in Scheme 9, sulfoximines of Formula 4a (i.e. Formula 4 wherein A is S(═O)) can be prepared by transfer of an NH group to a sulfoxide of Formula 9 using ammonium salts or ammonia as the nitrogen source (e.g., ammonium carbamate, ammonia in methanol or ammonium acetate) mediated by a hypervalent iodine(III) reagent such as (diacetoxyiodo)benzene PhI(OAc)2. For reaction conditions see Angewandte Chemie International Edition 2016, 55, 7203-7207
Compounds of Formula 4a (i.e. Formula 4 wherein A is S(═O)) can also are prepared directly from sulfides through a one-pot oxidation and NH-transfer reaction, as illustrated in Scheme 10. Reaction conditions are essentially the same as Scheme 9, i.e. a nitrogen source such as ammonium carbamate or ammonium carbonate and an oxidant such as (diacetoxyiodo) benzene (PhI(OAc)2). For reaction conditions see, Chemical Communications 2017, 53, 348-351 and Chemistry Select 2017, 2(4), 1620-1624. The method of Scheme 10 is also illustrated in present Example 1, Step D.
As shown in Scheme 11, compounds of Formula 4a (i.e. Formula 4 wherein A is S(═O)) can also be prepared via a metal-catalyzed imination reaction of sulfoxides of Formula 9. Typical conditions involve reacting a sulfoxide of Formula 9 with an imitating agent such as O-(2,4-dinitrophenyl)hydroxylamine (DPH) or O-pivaloylhydroxylamine trifluoromethane-sulfonate (also known as O-pivaloylhydroxylamine triflate salt or PivONH3OTf) in the presence of a rhodium(II) or iron(II) catalyst such as Rh2(esp)2, Rh2(OAc)4 or FeSO4 in a solvent such as methanol, 2,2,2-trifluoroethanol, acetonitrile or toluene at ambient temperature. For relevant references, Chemical Communications 2014, 50, 9687-9689 and Angewandte Chemie International Edition 2018, 57, 324-327.
Sulfoxides of Formula 9 can be prepared from the oxidation of commercially available sulfides. Reaction conditions for oxidizing sulfides to sulfoxides are well-known in the art; see, for example, The Synthesis of Sulphones, Sulphoxides and Cyclic Sulphides, Eds. S. Patai and Z. Rappoport, John Wiley & Sons, New York, 1994.
Sulfilimines of Formula 4b (i.e. Formula 4 wherein A is S) can be prepared by a variety of methods well-document in the chemistry literature. Depending on the nature of the R1 and R2 groups attached to the sulfur atom, it is often useful to prepare sulfilimines as N-protected derivatives, which can be deprotected to the desired free-NH compounds and used directly for preparing compounds of Formula 3. For example, as shown in Scheme 12, sulfilimines of Formula 4b (i.e. Formula 4 wherein A is S) can be prepared by reacting sulfides of Formula 10 with amines of Formula 11, followed by treatment with an acid. Particularly useful amines for this method include O-(mesitylenesulfonyl)hydroxylamine, hydroxylamine-O-sulfonic acid and N-chloro-4-methylbenzenesulfonamide sodium salt (also known as chloramine-T). Reaction conditions are described in Journal of Organic Chemistry 1976, 41(10), 1728-1732, Chemical Reviews 1977, 77(3), 409-435 and Journal of Organic Chemistry 1973, 38(25), 4324-4328.
As shown in Scheme 13, sulfilimines of Formula 4b (i.e. Formula 4 wherein A is S) can also be prepared by reacting sulfides of Formula 10 with [N-(p-nitrobenzene-sulfonyl)imino]phenyliodane (NsN═IPh) in the presence of a rhodium(II)-catalyst (e.g. rhodium(II) acetate) followed by reductive cleavage of the p-nitrobenzenesulfonyl group to obtain the free-NH compound of Formula 4b. This method can also be used to be prepare sulfoximines of Formula 4a starting from the corresponding sulfoxides. For reaction conditions, see Organic Letter 2004, 6(8), 1305-1307.
Alternatively, imidation of sulfides to the corresponding sulfilimines can be carried out with N-tert-butyloxycarbonyl azide. For example, as shown in Scheme 14, reacting sulfides of Formula 10 with N-tert-butyloxycarbonyl azide (BocN3) in the presence of an iron(II)-catalyst (e.g. iron(II) chloride) followed by removal of the N-Boc protecting group provides compounds of Formula 4b. The method of Scheme 14 is described in European Journal of Organic Chemistry 1999, 1033-1039 and Tetrahedron Letters 1998, 39, 5015-5016.
Sulfondiimines of Formula 4c (i.e. Formula 4 wherein S(═NR3)) can be prepared by oxidative imination of the corresponding sulfiliminium salt of Formula 12 in the presence of N-chlorosuccinimide (NCS) as described in Angewandte Chemie International Edition 2012, 51, 4440-4443. The sulfiliminium salts of Formula 12 can be prepared by the method of Scheme 11.
As illustrated in Scheme 16, sulfonimidamides of Formula 4d (i.e. Formula 4 wherein A is S(═O) and R2 is R2aNR4a) can be prepared by reacting amines of Formula 13 with N-alkanesulfonimidoyl chlorides of Formula 14 followed by removal of tosyl group under acidic conditions. Present Example 5 (Steps B and C) illustrates the method of Scheme 16 for the preparation of a compound of Formula 4d wherein R1 is methyl using N-tosylmethanesulfonimidoylchloride.
Alternatively, sulfonimidamides of Formula 4d (i.e. Formula 4 wherein A is S(═O) and R2 is R2aNR4a) can be prepared from sulfonamides of Formula 15 with ammonium carbamate in the presence of (diacetoxyiodo)benzene (PhI(OAc)2) in a solvent such as methanol, as shown in Scheme 17. One skilled in the art will recognize that the method of Scheme 16 can also be performed when the substituent R2 is R2bNR4b, or when R1 is R1aNR4a or R1 is R1bNR4b. Reaction conditions are described in Chemistry—A European Journal 2017, 23(60), 15189-15193.
It is recognized that some reagents and reaction conditions described above for preparing compounds of Formula 1 may not be compatible with certain functionalities present in the intermediates. In these instances, the incorporation of protection/deprotection sequences or functional group interconversions into the synthesis will aid in obtaining the desired products. The use and choice of the protecting groups will be apparent to one skilled in chemical synthesis (see, for example, T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd ed.; Wiley: New York, 1991). One skilled in the art will recognize that, in some cases, after the introduction of a given reagent as it is depicted in any individual scheme, it may be necessary to perform additional routine synthetic steps not described in detail to complete the synthesis of compounds of Formula 1. One skilled in the art will also recognize that it may be necessary to perform a combination of the steps illustrated in the above schemes in an order other than that implied by the particular sequence presented to prepare the compounds of Formula 1.
One skilled in the art will also recognize that compounds of Formula 1 and the intermediates described herein can be subjected to various electrophilic, nucleophilic, radical, organometallic, oxidation, and reduction reactions to add substituents or modify existing substituents.
Without further elaboration, it is believed that one skilled in the art using the preceding description can utilize the present invention to its fullest extent. The following examples are, therefore, to be construed as merely illustrative, and not limiting of the disclosure in any way whatsoever. Steps in the following examples illustrate a procedure for each step in an overall synthetic transformation, and the starting material for each step may not have necessarily been prepared by a particular preparative run whose procedure is described in other examples or steps. Percentages are by weight except for chromatographic solvent mixtures or where otherwise indicated. Parts and percentages for chromatographic solvent mixtures are by volume unless otherwise indicated. 1H NMR spectra are reported in ppm downfield from tetramethylsilane; “s” means singlet, “d” means doublet, “t” means triplet, “m” means multiplet, “br s” means broad singlet and “dd” means doublet of doublets. Mass spectra are reported as the molecular weight of the highest isotopic abundance parent ion (M+1) formed by addition of H+(molecular weight of 1) to the molecule, or (M−1) formed by the loss of H+(molecular weight of 1) from the molecule, observed by using liquid chromatography coupled to a mass spectrometer (LCMS) using either atmospheric pressure chemical ionization (AP+) or electrospray ionization (ESI+), where “amu” stands for atomic mass units.
To a stirred solution of 4-methylbenzonitrile (50 g, 0.43 mol) in ethanol (220 mL) and water (410 mL) was added hydroxylamine hydrochloride (59 g, 0.85 mol). The reaction mixture was cooled to 5° C. and potassium carbonate (94 g, 0.68 mol) was added portionwise followed by 8-hydroxyquinoline (0.31 g, 0.002 mol). The reaction mixture was heated at 80° C. for 6 h, cooled to room temperature and concentrated under reduced pressure to remove ethanol. The resulting material was cooled to 5° C. and the pH was adjusted to 8 using 2N hydrochloric acid. The resulting solid precipitate was collected by filtration, washed with water and dried to provide the title product as an off-white solid (56 g).
1H NMR (CDC3, 400 MHz) δ 9.53 (s, 1H), 7.54 (d, 2H), 7.17 (d, 2H), 5.74 (br s, 2H), 2.30 (s, 3H).
LCMS m/z: 151.1 [M+H]+.
To a solution of N-hydroxy-4-methyl-benzenecarboximidamide (i.e. the product of Step A) (56 g, 0.37 mol) in 2-methyltetrahydrofuran (560 mL) at 0° C. was added trifluoroacetic anhydride (63 mL, 0.45 mol). The reaction mixture was stirred at 0° C. for 3 h, warmed to room temperature and stirred for an additional 16 h. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic extract was washed with saturated aqueous sodium bicarbonate solution followed by saturated aqueous sodium chloride solution. The extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting material was purified by silica gel column chromatography (eluting with petroleum ether) to provide the title compound as an oil (76 g).
1H NMR (CDCl3, 400 MHz) δ 7.99 (d, 2H), 7.31 (d, 2H), 2.43 (s, 3H).
To a solution of 3-(4-methylphenyl)-5-(trifluoromethyl)-1,2,4-oxadiazole (i.e. the product of Step B) (76 g, 0.33 mol) in carbon tetrachloride (300 mL) at room temperature was added N-bromosuccinimide (62 g, 0.35 mol) followed by 2,2′-azobis(2-methylpropionitrile) (5.47 g, 0.033 mol). The reaction mixture was stirred at 65° C. for 16 h, cooled to room temperature, and then filtered through Celite® diatomaceous earth filter aid. The resulting filtrate was diluted with dichloromethane, washed with water, followed by saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting material was purified by silica gel column chromatography (eluting with petroleum ether) to provide the title compound as an oil (48 g).
1H NMR (CDC3, 400 MHz) δ 8.09 (d, 2H), 7.54 (d, 2H), 4.53 (s, 2H).
To a solution of 2-methoxyethyl phenyl sulfide (0.50 g, 2.97 mmol) in methanol (20 mL) was added ammonium carbonate (0.42 g, 4.45 mmol) and (diacetoxyiodo)benzene (2.20 g, 6.83 mmol). The reaction mixture was stirred at room temperature for 16 h and then concentrated under reduced pressure. The resulting material was purified by neutral alumina column chromatography (eluting with 30% ethyl acetate in petroleum ether) to provide the title compound as a pale-yellow oil (0.50 g).
1H NMR (CDC3, 400 MHz) δ 7.98 (d, 2H), 7.60 (t, 1H), 7.53 (t, 2H), 3.83-3.73 (m, 2H), 3.40 (t, 2H), 3.24 (s, 3H), 2.84 (br s, 1H).
LCMS m/z: 200.1 [M+H]+.
To a solution of S-(2-methoxyethyl)-S-phenylsulfoximine (i.e. product of Step D) (0.50 g, 2.51 mmol) in acetonitrile (20 mL) was added 3-[4-(bromomethyl)phenyl]-5-(trifluoromethyl)-1,2,4-oxadiazole (i.e. product of Step C) (0.77 g, 2.51 mmol) and sodium bicarbonate (0.31 g, 3.76 mmol). The reaction mixture at reflux for 16 h, cooled to room temperature and filtered. The resulting filtrate was concentrated under reduced pressure. The resulting material was purified by neutral alumina column chromatography (eluting with 30% ethyl acetate in petroleum ether) to provide the title compound, a compound the present invention, as a colorless oil (0.15 g).
1H NMR (CDC3, 400 MHz) δ 8.05 (d, 2H), 7.89 (dd, 2H), 7.65-7.62 (m, 1H), 7.61-7.52 (m, 4H), 4.27 (d, 1H), 4.08 (d, 1H), 3.83-3.77 (m, 2H), 3.50 (t, 2H), 3.22 (s, 3H).
LCMS m/z: 426 [M+H]+.
A mixture of S-methyl-S-(phenylmethyl)sulfoximine (7.20 g, 0.043 mol), 3-[4-(bromo-methyl)phenyl]-5-(trifluoromethyl)-1,2,4-oxadiazole (i.e. product of Example 1 Step C) (10.18 g, 0.033 mol), sodium bicarbonate (15.41 g, 0.18 mol) and acetonitrile (80 mL) was stirred overnight at 80° C. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting material was purified by silica gel column chromatography (eluting with a gradient of 0 to 100% ethyl acetate in hexane) to yield a white solid (6.12 g) that was further purified by recrystallization from ethanol to provide the title compound, a compound of the present invention, as a white solid (4.15 g).
1H NMR (CDC3, 500 MHz) δ 8.06 (d, 2H), 7.52 (d, 2H), 7.40 (s, 5H), 4.43-4.32 (m, 4H), 2.79 (s, 3H).
LCMS m/z: 396.2 [M+H]+.
To a solution of 3-(methylthio)thiophene (0.50 g, 3.8 mmol) in methanol (20 mL) was added ammonium carbonate (0.47 g, 4.92 mmol) and (diacetoxyiodo)benzene (2.43 g, 7.55 mmol). The reaction mixture was stirred at room temperature for 16 h and then concentrated under reduced pressure. The resulting material was purified by neutral alumina column chromatography (eluting with 30% ethyl acetate in petroleum ether) to provide the title compound as an off-white solid (0.46 g).
1H NMR (DMSO-d6, 400 MHz) δ 8.18-8.17 (m, 1H), 7.72-7.70 (m, 1H), 7.42-7.41 (m, 1H), 3.11 (s, 3H).
LCMS m/z: 162.1 [M+H]+.
A mixture of S-methyl-S-3-thienylsulfoximine (i.e. the product from Step A) (0.46 g, 2.87 mmol), 4-bromobenzonitrile (0.43 g, 2.3 mmol), cesium carbonate (1.12 g, 3.44 mmol), palladium(II) acetate (trimeric form) (77 mg, 0.11 mmol), 2,2′-bis[(di-4-tolyl)phosphino]]-1,1′-binaphthyl (0.12 g, 0.17 mmol) and toluene (10 mL) was stirred at 100° C. for 4 h. The reaction mixture was cooled to room temperature, filtered through Celite® diatomaceous earth filter aid and concentrated under reduced pressure. The resulting material was purified by silica gel chromatography (eluting with 30% ethyl acetate in petroleum ether) to give the title compound as an off-white solid (0.55 g).
1H NMR (DMSO-d6, 400 MHz) δ 8.42-8.41 (m, 1H), 7.80-7.78 (m, 1H), 7.52 (d, 2H), 7.39 (d, 1H), 6.94 (d, 2H), 3.51 (s, 3H).
LCMS m/z: 262.9 [M+H]+.
To a solution of 4-[(methyloxido-3-thienyl-λ4-sulfanylidene)amino]benzonitrile (i.e. the product of Step B) (0.45 g, 1.72 mmol) in ethanol (30 mL) was added hydroxylamine hydrochloride (0.30 g, 4.29 mmol) and sodium bicarbonate (0.43 g, 5.1 mmol). The reaction mixture was heated at 80° C. for 16 h, cooled to room temperature, and then filtered through Celite® diatomaceous earth filter aid. The resulting filtrate was concentrated under reduced pressure to provide the title product as an off-white solid (0.55 g).
1H NMR (DMSO-d6, 400 MHz) δ 9.35 (br s, 1H), 8.34-8.33 (m, 1H), 7.75-7.73 (m, 1H), 7.40-7.38 (m, 3H), 6.83 (d, 2H), 5.58 (br s, 2H), 3.42 (s, 3H).
LCMS m/z: 296.27 [M+H]+.
To a solution of N-hydroxy-4-[(methyloxido-3-thienyl-λ4-sulfanylidene)amino]-benzenecarboximidamide (i.e. the product of Step C) (0.50 g) in dichloromethane (20 mL) at 0° C. was added trifluoroacetic anhydride (0.70 mL, 5.08 mmol). The reaction mixture was heated at 50° C. for 3 h, cooled to room temperature, and then concentrated under reduced pressure. The resulting material was and purified by silica gel chromatography (eluting with 30% ethyl acetate in petroleum ether) to provide the title compound, a compound of the present invention, as an off-white solid (0.16 g).
1H NMR (DMSO-d6, 400 MHz) δ 8.40 (m, 1H), 7.81-7.76 (m, 3H), 7.41 (d, 1H), 7.03 (d, 2H), 3.51 (s, 3H).
LCMS m/z: 373.8 [M+H]+.
A mixture of 1-bromo-4-(2-bromoethyl)benzene (2.50 g, 9.5 mmol), S,S-dimethyl-sulfoximine (0.98 g, 10.5 mmol), potassium carbonate (1.6 g, 11.5 mmol), potassium iodide (0.32 g, 1.9 mmol) and acetonitrile (8 mL) was heated at reflux for 18 h, cooled to room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure and the resulting material was purified by silica gel chromatography (eluting with a gradient of 10 to 100% ethyl acetate in hexanes followed by a gradient of 0 to 25% methanol in ethyl acetate) to provide the title compound as a white solid (0.35 g).
1H NMR (CDC3, 500 MHz) δ 7.40 (d, 2H), 7.11 (d, 2H), 3.28 (t, 2H), 2.92 (s, 6H), 2.81 (t, 2H).
A solution of N,N-dimethylacetamide (5 mL) was sparged with nitrogen for 10 minutes, and then a mixture of 4-bromo-N-(dimethyloxido-λ4-sulfanylidene)benzeneethanamine (i. e. the product from Step A) (0.14 g, 0.51 mmol), zinc cyanide (0.12 g, 1.02 mmol), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (32 mg, 0.035 mmol), 1,1′-bis(diphenylphosphino)ferrocene (66 mg, 0.12 mmol) and zinc dust (0.032 g, 0.49 mmol) was added under a nitrogen atmosphere. The reaction mixture was stirred overnight at 120° C., cooled to room temperature, and then concentrated under reduced pressure. The resulting material was purified by silica gel chromatography (eluting with a gradient of 0 to 100% ethyl acetate in hexanes followed by a gradient of 0 to 30% methanol in ethyl acetate) to provide the title product as a yellow solid (0.14 g).
1H NMR (CDCl3, 500 MHz) δ 7.58 (d, J=8.04 Hz, 2H), 7.36 (d, J=8.04 Hz, 2H), 3.34 (t, J=7.25 Hz, 2H), 3.00-2.91 (m, 8H).
A mixture of 4-[2-[(dimethyloxido-λ4-sulfanylidene)amino]ethyl]benzonitrile (i.e. the product of Step B) (0.14 g, 0.62 mmol) and hydroxylamine (50% aqueous solution, 0.12 g, 1.82 mmol) in ethanol (5 mL) was stirred at room temperature for 72 h. The reaction mixture was concentrated under reduced pressure to provide the title, which was used directly in Step D.
To a solution of N-hydroxy4-[2-[(dimethyloxido-λ4-sulfanylidene)amino]ethyl]-benzenecarboximidamide (i.e. the product of Step C) in acetonitrile (6 mL) at 0° C. was added pyridine (0.26 mL, 1.87 mmol) followed by trifluoroacetic anhydride (0.15 mL, 1.85 mmol). The reaction mixture was heated at 70° C. for 3 h, cooled to room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure. The resulting material was purified by silica gel chromatography (eluting with a gradient of 0 to 100% ethyl acetate in hexanes followed by a gradient of 0 to 30% methanol in ethyl acetate) to provide the title compound, a compound of the present invention, as a white solid (11 mg).
1H NMR (CDC3, 500 MHz) δ 8.04 (d, J=8.51 Hz, 2H), 7.40 (d, J=8.35 Hz, 2H), 3.35 (t, J=7.41 Hz, 2H), 3.00-2.80 (m, 8H), 2.03 (s, 2H).
LCMS m/z: 334.0 [M+H]+.
To a solution of dimethyl disulfide (20 g, 212 mmol) in acetic acid (25 ml), at −20° C. was added sulfuryl chloride (51.5 ml, 638 mmol) dropwise. The reaction mixture was stirred at −20° C. for 1 h, warmed to room temperature and stirred for 2 h. The reaction mixture was concentrated under reduced pressure to provide the intermediate compound methanesulfinyl chloride as a pale-yellow oil (20.5 g).
To a solution of N,N-dichloro-4-methylbenzenesulfonamide (50 g, 209 mmol) in chloroform (400 ml) at to 0° C. was added dropwise a solution of methanesulfinyl chloride (20.5 g, 209 mmol) in chloroform (50 ml). The reaction mixture was stirred at room temperature for 16 h, concentrated under reduced pressure and purified by silica gel column chromatography (eluting with 35% ethyl acetate in petroleum ether) to provide the title compound as off-white solid (14 g).
1H NMR (CDC3, 400 MHz) δ 7.88 (d, 2H), 7.33 (2H), 3.77 (s, 3H), 2.44 (s, 3H).
LCMS m/z: 266 [M−H]−.
To a solution of N-[(4-methylphenyl)sulfonyl]methanesulfonimidoyl chloride (i.e. the product of Step A) (3.0 g, 11.2 mmol) in dichloromethane (30 ml) at 0° C. was added dimethylamine (2 M in tetrahydrofuran, 11.2 ml, 22.4 mmol) dropwise. The reaction mixture was stirred at room temperature for 16 h, concentrated under reduced pressure and purified by silica gel column chromatography (eluting with 50% ethyl acetate in petroleum ether) to provide the title product as an off-white solid (1.7 g).
1H NMR (CDC3, 400 MHz) δ 7.84 (d, 2H), 7.26 (d, 2H), 3.06 (s, 3H), 2.95 (s, 6H), 2.40 (s, 3H).
LCMS m/z: 277 [M+H]+.
Concentrated sulfuric acid (7.5 ml) was added dropwise to N-[(dimethylamino)methyl-oxido-4-sulfanylidene]-4-methylbenzenesulfonamide (i.e. the product of Step B) (1.5 g, 5.4 mmol) while maintaining the reaction temperature at 0° C. The reaction mixture was warmed to room temperature and stirred for 16 h, and then poured into ice water (20 ml). Sodium hydroxide (50% aqueous solution) was added to the aqueous mixed to bring the pH 10. The resulting material was concentrated under reduced pressure, diluted methanol and dichloromethane (1:10, 20 ml), stirred for 10 minutes and filtered. The resulting filtrate was concentrated under reduced pressure, diluted with chloroform (20 ml), stirred for 10 minutes and filtered. The resulting filtrate was concentrated to provide the title compound as a pale brown semisolid (500 mg).
1H NMR (CDCl3, 400 MHz) δ 2.87 (s, 6H), 2.80 (s, 3H).
To a solution of N,N-dimethylmethanesulfonimidamide (i.e. the product of Step C) (500 mg, 4.03 mmol) in acetonitrile (8 ml) was added 3-[4-(bromomethyl)phenyl]-5-(trifluoromethyl)-1,2,4-oxadiazole (i.e. product of Example 1 Step C) (1.13 g, 3.68 mmol) and sodium bicarbonate (500 mg, 6.04 mmol). The reaction mixture was stirred at 80° C. for 3 h, diluted with water (10 ml) and extracted with dichloromethane (10 ml×2). The combined extracts were washed with water (10 ml) and saturated aqueous sodium chloride solution (5 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting material was purified by silica gel column (eluting with 25% ethyl acetate in petroleum ether) to provide the title compound, a compound of the present invention, as a pale brown solid (200 mg).
1H NMR (CDC3, 400 MHz) δ 8.04 (d, 2H), 7.53 (d, 2H), 4.36 (d, 1H), 4.11 (d, 1H), 2.86 (s, 3H), 2.84 (s, 6H).
LCMS m/z: 349 [M+H]+.
A compound of Formula 1 of this invention (including N-oxides, hydrates, and salts thereof) will generally be used as a fungicidal active ingredient in a composition, i.e. formulation, with at least one additional component selected from the group consisting of surfactants, solid diluents and liquid diluents, which serve as a carrier. The formulation or composition ingredients are selected to be consistent with the physical properties of the active ingredient, mode of application and environmental factors such as soil type, moisture and temperature.
Useful formulations include both liquid and solid compositions. Liquid compositions include solutions (including emulsifiable concentrates), suspensions, emulsions (including microemulsions and/or suspoemulsions) and the like, which optionally can be thickened into gels. The general types of aqueous liquid compositions are soluble concentrate, suspension concentrate, capsule suspension, concentrated emulsion, microemulsion and suspo-emulsion. The general types of nonaqueous liquid compositions are emulsifiable concentrate, microemulsifiable concentrate, dispersible concentrate and oil dispersion.
The general types of solid compositions are dusts, powders, granules, pellets, pills, pastilles, tablets, filled films (including seed coatings) and the like, which can be water-dispersible (“wettable”) or water-soluble. Films and coatings formed from film-forming solutions or flowable suspensions are particularly useful for seed treatment. Active ingredient can be (micro)encapsulated and further formed into a suspension or solid formulation; alternatively the entire formulation of active ingredient can be encapsulated (or “overcoated”). Encapsulation can control or delay release of the active ingredient. An emulsifiable granule combines the advantages of both an emulsifiable concentrate formulation and a dry granular formulation. High-strength compositions are primarily used as intermediates for further formulation.
Sprayable formulations are typically extended in a suitable medium before spraying. Such liquid and solid formulations are formulated to be readily diluted in the spray medium, usually water, but occasionally another suitable medium like an aromatic or paraffinic hydrocarbon or vegetable oil. Spray volumes can range from about one to several thousand liters per hectare, but more typically are in the range from about ten to several hundred liters per hectare. Sprayable formulations can be tank mixed with water or another suitable medium for foliar treatment by aerial or ground application, or for application to the growing medium of the plant. Liquid and dry formulations can be metered directly into drip irrigation systems or metered into the furrow during planting. Liquid and solid formulations can be applied onto seeds of crops and other desirable vegetation as seed treatments before planting to protect developing roots and other subterranean plant parts and/or foliage through systemic uptake.
The formulations will typically contain effective amounts of active ingredient, diluent and surfactant within the following approximate ranges which add up to 100 percent by weight.
Solid diluents include, for example, clays such as bentonite, montmorillonite, attapulgite and kaolin, gypsum, cellulose, titanium dioxide, zinc oxide, starch, dextrin, sugars (e.g., lactose, sucrose), silica, talc, mica, diatomaceous earth, urea, calcium carbonate, sodium carbonate and bicarbonate, and sodium sulfate. Typical solid diluents are described in Watkins et al., Handbook of Insecticide Dust Diluents and Carriers, 2nd Ed., Dorland Books, Caldwell, N.J.
Liquid diluents include, for example, water, N,N-dimethylalkanamides (e.g., N,N-dimethylformamide), limonene, dimethyl sulfoxide, N-alkylpyrrolidones (e.g., N-methylpyrrolidinone), alkyl phosphates (e.g., triethyl phosphate), ethylene glycol, triethylene glycol, propylene glycol, dipropylene glycol, polypropylene glycol, propylene carbonate, butylene carbonate, paraffins (e.g., white mineral oils, normal paraffins, isoparaffins), alkylbenzenes, alkylnaphthalenes, glycerine, glycerol triacetate, sorbitol, aromatic hydrocarbons, dearomatized aliphatics, alkylbenzenes, alkylnaphthalenes, ketones such as cyclohexanone, 2-heptanone, isophorone and 4-hydroxy-4-methyl-2-pentanone, acetates such as isoamyl acetate, hexyl acetate, heptyl acetate, octyl acetate, nonyl acetate, tridecyl acetate and isobornyl acetate, other esters such as alkylated lactate esters, dibasic esters, alkyl and aryl benzoates and γ-butyrolactone, and alcohols, which can be linear, branched, saturated or unsaturated, such as methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol, isobutyl alcohol, n-hexanol, 2-ethylhexanol, n-octanol, decanol, isodecyl alcohol, isooctadecanol, cetyl alcohol, lauryl alcohol, tridecyl alcohol, oleyl alcohol, cyclohexanol, tetrahydrofurfuryl alcohol, diacetone alcohol, cresol and benzyl alcohol. Liquid diluents also include glycerol esters of saturated and unsaturated fatty acids (typically C6-C22), such as plant seed and fruit oils (e.g., oils of olive, castor, linseed, sesame, corn (maize), peanut, sunflower, grapeseed, safflower, cottonseed, soybean, rapeseed, coconut and palm kernel), animal-sourced fats (e.g., beef tallow, pork tallow, lard, cod liver oil, fish oil), and mixtures thereof. Liquid diluents also include alkylated fatty acids (e.g., methylated, ethylated, butylated) wherein the fatty acids may be obtained by hydrolysis of glycerol esters from plant and animal sources, and can be purified by distillation. Typical liquid diluents are described in Marsden, Solvents guide, 2nd Ed., Interscience, New York, 1950.
The solid and liquid compositions of the present invention often include one or more surfactants. When added to a liquid, surfactants (also known as “surface-active agents”) generally modify, most often reduce, the surface tension of the liquid. Depending on the nature of the hydrophilic and lipophilic groups in a surfactant molecule, surfactants can be useful as wetting agents, dispersants, emulsifiers or defoaming agents.
Surfactants can be classified as nonionic, anionic or cationic. Nonionic surfactants useful for the present compositions include, but are not limited to: alcohol alkoxylates such as alcohol alkoxylates based on natural and synthetic alcohols (which may be branched or linear) and prepared from the alcohols and ethylene oxide, propylene oxide, butylene oxide or mixtures thereof; amine ethoxylates, alkanolamides and ethoxylated alkanolamides; alkoxylated triglycerides such as ethoxylated soybean, castor and rapeseed oils; alkylphenol alkoxylates such as octylphenol ethoxylates, nonylphenol ethoxylates, dinonyl phenol ethoxylates and dodecyl phenol ethoxylates (prepared from the phenols and ethylene oxide, propylene oxide, butylene oxide or mixtures thereof); block polymers prepared from ethylene oxide or propylene oxide and reverse block polymers where the terminal blocks are prepared from propylene oxide; ethoxylated fatty acids; ethoxylated fatty esters and oils; ethoxylated methyl esters; ethoxylated tristyrylphenol (including those prepared from ethylene oxide, propylene oxide, butylene oxide or mixtures thereof); fatty acid esters, glycerol esters, lanolin-based derivatives, polyethoxylate esters such as polyethoxylated sorbitan fatty acid esters, polyethoxylated sorbitol fatty acid esters and polyethoxylated glycerol fatty acid esters; other sorbitan derivatives such as sorbitan esters; polymeric surfactants such as random copolymers, block copolymers, alkyl peg (polyethylene glycol) resins, graft or comb polymers and star polymers; polyethylene glycols (pegs); polyethylene glycol fatty acid esters; silicone-based surfactants; and sugar-derivatives such as sucrose esters, alkyl polyglycosides and alkyl polysaccharides.
Useful anionic surfactants include, but are not limited to: alkylaryl sulfonic acids and their salts; carboxylated alcohol or alkylphenol ethoxylates; diphenyl sulfonate derivatives; lignin and lignin derivatives such as lignosulfonates; maleic or succinic acids or their anhydrides; olefin sulfonates; phosphate esters such as phosphate esters of alcohol alkoxylates, phosphate esters of alkylphenol alkoxylates and phosphate esters of styryl phenol ethoxylates; protein-based surfactants; sarcosine derivatives; styryl phenol ether sulfate; sulfates and sulfonates of oils and fatty acids; sulfates and sulfonates of ethoxylated alkylphenols; sulfates of alcohols; sulfates of ethoxylated alcohols; sulfonates of amines and amides such as N,N-alkyltaurates; sulfonates of benzene, cumene, toluene, xylene, and dodecyl and tridecylbenzenes; sulfonates of condensed naphthalenes; sulfonates of naphthalene and alkyl naphthalene; sulfonates of fractionated petroleum; sulfosuccinamates; and sulfosuccinates and their derivatives such as dialkyl sulfosuccinate salts.
Useful cationic surfactants include, but are not limited to: amides and ethoxylated amides; amines such as N-alkyl propanediamines, tripropylenetriamines and dipropylenetetramines, and ethoxylated amines, ethoxylated diamines and propoxylated amines (prepared from the amines and ethylene oxide, propylene oxide, butylene oxide or mixtures thereof); amine salts such as amine acetates and diamine salts; quaternary ammonium salts such as quaternary salts, ethoxylated quaternary salts and diquaternary salts; and amine oxides such as alkyldimethylamine oxides and bis-(2-hydroxyethyl)-alkylamine oxides.
Also useful for the present compositions are mixtures of nonionic and anionic surfactants or mixtures of nonionic and cationic surfactants. Nonionic, anionic and cationic surfactants and their recommended uses are disclosed in a variety of published references including McCutcheon's Emulsifiers and Detergents, annual American and International Editions published by McCutcheon's Division, The Manufacturing Confectioner Publishing Co.; Sisely and Wood, Encyclopedia of Surface Active Agents, Chemical Publ. Co., Inc., New York, 1964; and A. S. Davidson and B. Milwidsky, Synthetic Detergents, Seventh Edition, John Wiley and Sons, New York, 1987.
Compositions of this invention may also contain formulation auxiliaries and additives, known to those skilled in the art as formulation aids. Such formulation auxiliaries and additives may control: pH (buffers), foaming during processing (antifoams such polyorganosiloxanes (e.g., Rhodorsil® 416)), sedimentation of active ingredients (suspending agents), viscosity (thixotropic thickeners), in-container microbial growth (antimicrobials), product freezing (antifreezes), color (dyes/pigment dispersions (e.g., Pro-lzed® Colorant Red)), wash-off (film formers or stickers), evaporation (evaporation retardants), and other formulation attributes. Film formers include, for example, polyvinyl acetates, polyvinyl acetate copolymers, polyvinylpyrrolidone-vinyl acetate copolymer, polyvinyl alcohols, polyvinyl alcohol copolymers and waxes. Examples of formulation auxiliaries and additives include those listed in McCutcheon's Volume 2: Functional Materials, annual International and North American editions published by McCutcheon's Division, The Manufacturing Confectioner Publishing Co.; and PCT Publication WO 03/024222.
The compound of Formula 1 and any other active ingredients are typically incorporated into the present compositions by dissolving the active ingredient in a solvent or by grinding in a liquid or dry diluent. Solutions, including emulsifiable concentrates, can be prepared by simply mixing the ingredients. If the solvent of a liquid composition intended for use as an emulsifiable concentrate is water-immiscible, an emulsifier is typically added to emulsify the active-containing solvent upon dilution with water. Active ingredient slurries, with particle diameters of up to 2,000 μm can be wet milled using media mills to obtain particles with average diameters below 3 μm. Aqueous slurries can be made into finished suspension concentrates (see, for example, U.S. Pat. No. 3,060,084) or further processed by spray drying to form water-dispersible granules. Dry formulations usually require dry milling processes, which produce average particle diameters in the 2 to 10 μm range. Dusts and powders can be prepared by blending and usually grinding (such as with a hammer mill or fluid-energy mill). Granules and pellets can be prepared by spraying the active material upon preformed granular carriers or by agglomeration techniques. See Browning, “Agglomeration”, Chemical Engineering, Dec. 4, 1967, pp 147-48, Perry's Chemical Engineer's Handbook, 4th Ed., McGraw-Hill, New York, 1963, pp 8-57 and following, and WO 91/13546. Pellets can be prepared as described in U.S. Pat. No. 4,172,714. Water-dispersible and water-soluble granules can be prepared as taught in U.S. Pat. Nos. 4,144,050, 3,920,442 and DE 3,246,493. Tablets can be prepared as taught in U.S. Pat. Nos. 5,180,587, 5,232,701 and 5,208,030. Films can be prepared as taught in gB 2,095,558 and U.S. Pat. No. 3,299,566.
One embodiment of the present invention relates to a method for controlling fungal pathogens, comprising diluting the fungicidal composition of the present invention (a compound of Formula 1 formulated with surfactants, solid diluents and liquid diluents or a formulated mixture of a compound of Formula 1 and at least one other fungicide) with water, and optionally adding an adjuvant to form a diluted composition, and contacting the fungal pathogen or its environment with an effective amount of said diluted composition.
Although a spray composition formed by diluting with water a sufficient concentration of the present fungicidal composition can provide sufficient efficacy for controlling fungal pathogens, separately formulated adjuvant products can also be added to spray tank mixtures. These additional adjuvants are commonly known as “spray adjuvants” or “tank-mix adjuvants”, and include any substance mixed in a spray tank to improve the performance of a pesticide or alter the physical properties of the spray mixture. Adjuvants can be anionic or nonionic surfactants, emulsifying agents, petroleum-based crop oils, crop-derived seed oils, acidifiers, buffers, thickeners or defoaming agents. Adjuvants are used to enhancing efficacy (e.g., biological availability, adhesion, penetration, uniformity of coverage and durability of protection), or minimizing or eliminating spray application problems associated with incompatibility, foaming, drift, evaporation, volatilization and degradation. To obtain optimal performance, adjuvants are selected with regard to the properties of the active ingredient, formulation and target (e.g., crops, insect pests).
The amount of adjuvants added to spray mixtures is generally in the range of about 2.5% to 0.1% by volume. The application rates of adjuvants added to spray mixtures are typically between about 1 to 5 L per hectare. Representative examples of spray adjuvants include: Adigor® (Syngenta) 47% methylated rapeseed oil in liquid hydrocarbons, Silwet® (Helena Chemical Company) polyalkyleneoxide modified heptamethyltrisiloxane and Assist® (BASF) 17% surfactant blend in 83% paraffin based mineral oil.
One method of seed treatment is by spraying or dusting the seed with a compound of the invention (i.e. as a formulated composition) before sowing the seeds. Compositions formulated for seed treatment generally comprise a film former or adhesive agent. Therefore, typically a seed coating composition of the present invention comprises a biologically effective amount of a compound of Formula 1 and a film former or adhesive agent. Seeds can be coated by spraying a flowable suspension concentrate directly into a tumbling bed of seeds and then drying the seeds. Alternatively, other formulation types such as wetted powders, solutions, suspoemulsions, emulsifiable concentrates and emulsions in water can be sprayed on the seed. This process is particularly useful for applying film coatings on seeds. Various coating machines and processes are available to one skilled in the art. Suitable processes include those listed in P. Kosters et al., Seed Treatment: Progress and Prospects, 1994 BCPC Mongraph No. 57, and references listed therein.
For further information regarding the art of formulation, see T. S. Woods, “The Formulator's Toolbox—Product Forms for Modern Agriculture” in Pesticide Chemistry and Bioscience, The Food-Environment Challenge, T. Brooks and T. R. Roberts, Eds., Proceedings of the 9th International Congress on Pesticide Chemistry, The Royal Society of Chemistry, Cambridge, 1999, pp. 120-133. See also U.S. Pat. No. 3,235,361, Col. 6, line 16 through Col. 7, line 19 and Examples 10-41; U.S. Pat. No. 3,309,192, Col. 5, line 43 through Col. 7, line 62 and Examples 8, 12, 15, 39, 41, 52, 53, 58, 132, 138-140, 162-164, 166, 167 and 169-182; U.S. Pat. No. 2,891,855, Col. 3, line 66 through Col. 5, line 17 and Examples 1-4; Klingman, Weed Control as a Science, John Wiley and Sons, Inc., New York, 1961, pp 81-96; Hance et al., Weed Control Handbook, 8th Ed., Blackwell Scientific Publications, Oxford, 1989; and Developments in formulation technology, PJB Publications, Richmond, U K, 2000.
In the following Examples, all percentages are by weight and all formulations are prepared in conventional ways. Compound numbers refer to compounds in Index Tables A-C. Without further elaboration, it is believed that one skilled in the art using the preceding description can utilize the present invention to its fullest extent. The following Examples are, therefore, to be constructed as merely illustrative, and not limiting of the disclosure in any way whatsoever.
High Strength Concentrate
Wettable Powder
Granule
Extruded Pellet
Emulsifiable Concentrate
Microemulsion
Seed Treatment
Fertilizer Stick
Suspension Concentrate
Emulsion in Water
Oil Dispersion
Suspoemulsion
Water-soluble and water-dispersible formulations are typically diluted with water to form aqueous compositions before application. Aqueous compositions for direct applications to the plant or portion thereof (e.g., spray tank compositions) typically contain at least about 1 ppm or more (e.g., from 1 ppm to 100 ppm) of the compound(s) of this invention.
Seed is normally treated at a rate of from about 0.001 g (more typically about 0.1 g) to about 10 g per kilogram of seed (i.e. from about 0.0001 to 1% by weight of the seed before treatment). A flowable suspension formulated for seed treatment typically comprises from about 0.5 to about 70% of the active ingredient, from about 0.5 to about 30% of a film-forming adhesive, from about 0.5 to about 20% of a dispersing agent, from 0 to about 5% of a thickener, from 0 to about 5% of a pigment and/or dye, from 0 to about 2% of an antifoaming agent, from 0 to about 1% of a preservative, and from 0 to about 75% of a volatile liquid diluent.
The compounds of this invention are useful as plant disease control agents. The present invention therefore further comprises a method for controlling plant diseases caused by fungal plant pathogens comprising applying to the plant or portion thereof to be protected, or to the plant seed to be protected, an effective amount of a compound of the invention or a fungicidal composition containing said compound. The compounds and/or compositions of this invention provide control of diseases caused by a broad spectrum of fungal plant pathogens in the Ascomycota, Basidiomycota, Zygomycota phyla, and the fungal-like Oomycata class. They are effective in controlling a broad spectrum of plant diseases, particularly foliar pathogens of ornamental, turf, vegetable, field, cereal, and fruit crops. These pathogens include but are not limited to those listed in Table 1-1. For Ascomycetes and Basidiomycetes, names for both the sexual/teleomorph/perfect stage as well as names for the asexual/anamorph/imperfect stage (in parentheses) are listed where known. Synonymous names for pathogens are indicated by an equal sign. For example, the sexual/teleomorph/perfect stage name Phaeosphaeria nodorumis followed by the corresponding asexual/anamorph/imperfect stage name Stagnospora nodorum and the synonymous older name Septoria nodorum.
Guignardia bidwellii, Venturia inaequalis, Pyrenophora tritici-repentis (Dreschlera tritici-repentis =
Helminthosporium tritici-repentis) and Pyrenophora teres (Dreschlera teres =
Helminthosporium teres), Corynespora cassiicola, Phaeosphaeria nodorum (Stagonospora
nodorum = Septoria nodorum), Cochliobolus carbonum and C. heterostrophus, Leptosphaeria
biglobosa and L. maculans;
tritici = Septoria tritici), M. berkeleyi (Cercosporidium personatum), M. arachidis (Cercospora
arachidicola), Passalora sojina (Cercospora sojina), Cercospora zeae-maydis and C. beticola;
tritici and Blumeria graminis f.sp. hordei, Elysiphe polygoni, E. necator (= Uncinula necator),
Podosphaera fuliginea (= Sphaerotheca fuliginea), and Podosphaera leucotricha (= Sphaerotheca
fuliginea);
yallundae (= Tapesia yallundae; anamorph Helgardia herpotrichoides = Pseudocercosporella
hopetrichoides), Monilinia fructicola,Sclerotinia sclerotiorum, Sclerotinia minor, and Sclerotinia
homoeocarpa;
monoliformis (Fusarium moniliforme), Fusarium solani and Verticillium dahliae;
Phomopsis longicolla, and Diaporthe phaseolorum;
Rhynchosporium secalis, and anthracnose pathogens such as Glomerella acutata (Colletotrichum
acutatum), G. graminicola (C. graminicola) and G. lagenaria (C. orbiculare);
Puccinia hordei, P. graminis and P. arachidis), Hemileia vastatrix and Phakopsora pachyrhizi;
solani) and Ceratobasidium oryzae-sativae (Rhizoctonia oryzae);
P. sojae, P. cinnamomi and P. capsici, and Pythium pathogens such as Pythium aphanidermatum,
P. graminicola, P. irregulare, P. ultimum and P. dissoticum;
hyoscyami (= Peronospora tabacina), P. manshurica, Hyaloperonospora parasitica (= Peronospora
parasitica), Pseudoperonospora cubensis and Bremia lactucae;
In addition to their fungicidal activity, the compositions or combinations also have activity against bacteria such as Erwinia amylovora, Xanthomonas campestris, Pseudomonas syringae, and other related species. By controlling harmful microorganisms, the compounds of the invention are useful for improving (i.e. increasing) the ratio of beneficial to harmful microorganisms in contact with crop plants or their propagules (e.g., seeds, corms, bulbs, tubers, cuttings) or in the agronomic environment of the crop plants or their propagules.
Compounds of the invention are useful in treating all plants, plant parts and seeds. Plant and seed varieties and cultivars can be obtained by conventional propagation and breeding methods or by genetic engineering methods. Genetically modified plants or seeds (transgenic plants or seeds) are those in which a heterologous gene (transgene) has been stably integrated into the plant's or seed's genome. A transgene that is defined by its particular location in the plant genome is called a transformation or transgenic event.
Genetically modified plant cultivars which can be treated according to the invention include those that are resistant against one or more biotic stresses (pests such as nematodes, insects, mites, fungi, etc.) or abiotic stresses (drought, cold temperature, soil salinity, etc.), or that contain other desirable characteristics. Plants can be genetically modified to exhibit traits of, for example, herbicide tolerance, insect-resistance, modified oil profiles or drought tolerance.
Treatment of genetically modified plants and seeds with compounds of the invention may result in super-additive or synergistic effects. For example, reduction in application rates, broadening of the activity spectrum, increased tolerance to biotic/abiotic stresses or enhanced storage stability may be greater than expected from just simple additive effects of the application of compounds of the invention on genetically modified plants and seeds.
Compounds of this invention are useful in seed treatments for protecting seeds from plant diseases. In the context of the present disclosure and claims, treating a seed means contacting the seed with a biologically effective amount of a compound of this invention, which is typically formulated as a composition of the invention. This seed treatment protects the seed from soil-borne disease pathogens and generally can also protect roots and other plant parts in contact with the soil of the seedling developing from the germinating seed. The seed treatment may also provide protection of foliage by translocation of the compound of this invention or a second active ingredient within the developing plant. Seed treatments can be applied to all types of seeds, including those from which plants genetically transformed to express specialized traits will germinate. Representative examples include those expressing proteins toxic to invertebrate pests, such as Bacillus thuringiensis toxin or those expressing herbicide resistance such as glyphosate acetyltransferase, which provides resistance to glyphosate. Seed treatments with compounds of this invention can also increase vigor of plants growing from the seed.
Compounds of this invention and their compositions, both alone and in combination with other fungicides, nematicides and insecticides, are particularly useful in seed treatment for crops including, but not limited to, maize or corn, soybeans, cotton, cereal (e.g., wheat, oats, barley, rye and rice), potatoes, vegetables and oilseed rape.
Furthermore, the compounds of this invention are useful in treating postharvest diseases of fruits and vegetables caused by fungi and bacteria. These infections can occur before, during and after harvest. For example, infections can occur before harvest and then remain dormant until some point during ripening (e.g., host begins tissue changes in such a way that infection can progress); also infections can arise from surface wounds created by mechanical or insect injury. In this respect, the compounds of this invention can reduce losses (i.e. losses resulting from quantity and quality) due to postharvest diseases which may occur at any time from harvest to consumption. Treatment of postharvest diseases with compounds of the invention can increase the period of time during which perishable edible plant parts (e.g., fruits, seeds, foliage, stems, bulbs, tubers) can be stored refrigerated or un-refrigerated after harvest, and remain edible and free from noticeable or harmful degradation or contamination by fungi or other microorganisms. Treatment of edible plant parts before or after harvest with compounds of the invention can also decrease the formation of toxic metabolites of fungi or other microorganisms, for example, mycotoxins such as aflatoxins.
Plant disease control is ordinarily accomplished by applying an effective amount of a compound of this invention either pre- or post-infection, to the portion of the plant to be protected such as the roots, stems, foliage, fruits, seeds, tubers or bulbs, or to the media (soil or sand) in which the plants to be protected are growing. The compounds can also be applied to seeds to protect the seeds and seedlings developing from the seeds. The compounds can also be applied through irrigation water to treat plants. Control of postharvest pathogens which infect the produce before harvest is typically accomplished by field application of a compound of this invention, and in cases where infection occurs after harvest the compounds can be applied to the harvested crop as dips, sprays, fumigants, treated wraps and box liners.
Rates of application for these compounds (i.e. a fungicidally effective amount) can be influenced by factors such as the plant diseases to be controlled, the plant species to be protected, ambient moisture and temperature and should be determined under actual use conditions. One skilled in the art can easily determine through simple experimentation the fungicidally effective amount necessary for the desired level of plant disease control. Foliage can normally be protected when treated at a rate of from less than about 1 g/ha to about 5,000 g/ha of active ingredient. Seed and seedlings can normally be protected when seed is treated at a rate of from about 0.001 g (more typically about 0.1 g) to about 10 g per kilogram of seed.
Compounds of this invention can also be mixed with one or more other biologically active compounds or agents including fungicides, insecticides, nematocides, bactericides, acaricides, herbicides, herbicide safeners, growth regulators such as insect molting inhibitors and rooting stimulants, chemosterilants, semiochemicals, repellents, attractants, pheromones, feeding stimulants, plant nutrients, other biologically active compounds or entomopathogenic bacteria, virus or fungi to form a multi-component pesticide giving an even broader spectrum of agricultural protection. Thus the present invention also pertains to a composition comprising a compound of Formula 1 (in a fungicidally effective amount) and at least one additional biologically active compound or agent (in a biologically effective amount) and can further comprise at least one of a surfactant, a solid diluent or a liquid diluent. The other biologically active compounds or agents can be formulated in compositions comprising at least one of a surfactant, solid or liquid diluent. For mixtures of the present invention, one or more other biologically active compounds or agents can be formulated together with a compound of Formula 1, to form a premix, or one or more other biologically active compounds or agents can be formulated separately from the compound of Formula 1, and the formulations combined together before application (e.g., in a spray tank) or, alternatively, applied in succession.
As mentioned in the Summary of the Invention, one aspect of the present invention is a fungicidal composition comprising (i.e. a mixture or combination of) a compound of Formula 1, an N-oxide, or a salt thereof (i.e. component a), and at least one other fungicide (i.e. component b). Of note is such a combination where the other fungicidal active ingredient has different site of action from the compound of Formula 1. In certain instances, a combination with at least one other fungicidal active ingredient having a similar spectrum of control but a different site of action will be particularly advantageous for resistance management. Thus, a composition of the present invention can further comprise a fungicidally effective amount of at least one additional fungicidal active ingredient having a similar spectrum of control but a different site of action.
Of note is a composition which in addition to the Formula 1 compound of component (a), includes as component (b) at least one fungicidal compound selected from the group consisting of the FRAC-defined mode of action (MOA) classes (A) nucleic acid synthesis, (B) mitosis and cell division, (C) respiration, (D) amino acid and protein synthesis, (E) signal transduction, (F) lipid synthesis and membrane integrity, (G) sterol biosynthesis in membranes, (H) cell wall biosynthesis in membranes, (I) melanin synthesis in cell wall, (P) host plant defense induction, multi-site contact activity and unknown mode of action.
FRAC-recognized or proposed target sites of action along with their FRAC target site codes belonging to the above MOA classes are (A1) RNA polymerase I, (A2) adenosine deaminase, (A3) DNA/RNA synthesis (proposed), (A4) DNA topoisomerase, (B1-B3) β-tubulin assembly in mitosis, (B4) cell division (proposed), (B5) delocalization of spectrin-like proteins, (C1) complex I NADH odxido-reductase, (C2) complex II: succinate dehydrogenase, (C3) complex III: cytochrome bc1 (ubiquinol oxidase) at Qo site, (C4) complex III: cytochrome bc1 (ubiquinone reductase) at Qi site, (C) uncouplers of oxidative phosphorylation, (C6) inhibitors of oxidative phosphorylation, ATP synthase, (7) ATP production (proposed), (C8) complex III: cytochrome bc1 (ubiquinone reductase) at Qx (unknown) site, (D) methionine biosynthesis (proposed), (D2-D5) protein synthesis, (E1) signal transduction (mechanism unknown), (E2-E3) MAP/histidine kinase in osmotic signal transduction, (F2) phospholipid biosynthesis, methyl transferase, (F3) lipid peroxidation (proposed), (F4) cell membrane permeability, fatty acids (proposed), (F6) microbial disrupters of pathogen cell membranes, (F7) cell membrane disruption (proposed), (G1) C14-demethylase in sterol biosynthesis, (G2) Δ14-reductase and Δ8→Δ7-isomerase in sterol biosynthesis, (G3) 3-keto reductase, C4-demethylation, (G4) squalene epoxidase in sterol biosynthesis, (H3) trehalase and inositol biosynthesis, (H4) chitin synthase, (H5) cellulose synthase, (I1) reductase in melanin biosynthesis and (I2) dehydratase in melanin biosynthesis.
Of particular note is a composition which in addition to the Formula 1 compound of component (a), includes as component (b) at least one fungicidal compound selected from the group consisting of the classes (b1) methyl benzimidazole carbamate (MBC) fungicides; (b2) dicarboximide fungicides; (b3) demethylation inhibitor (DMI) fungicides; (b4) phenylamide fungicides; (b5) amine/morpholine fungicides; (b6) phospholipid biosynthesis inhibitor fungicides; (b7) succinate dehydrogenase inhibitor fungicides; (b8) hydroxy(2-amino-)pyrimidine fungicides; (b9) anilinopyrimidine fungicides; (b10) N-phenyl carbamate fungicides; (b11) quinone outside inhibitor (QoI) fungicides; (b12) phenylpyrrole fungicides; (b13) azanaphthalene fungicides; (b14) lipid peroxidation inhibitor fungicides; (b15) melanin biosynthesis inhibitor-reductase (MBI-R) fungicides; (b16) melanin biosynthesis inhibitor-dehydratase (MBI-D) fungicides; (b17) sterol biosynthesis inhibitor (SBI): Class III fungicides; (b18) squalene-epoxidase inhibitor fungicides; (b19) polyoxin fungicides; (b20) phenylurea fungicides; (b21) quinone inside inhibitor (QiI) fungicides; (b22) benzamide and thiazole carboxamide fungicides; (b23) enopyranuronic acid antibiotic fungicides; (b24) hexopyranosyl antibiotic fungicides; (b25) glucopyranosyl antibiotic: protein synthesis fungicides; (b26) glucopyranosyl antibiotic: trehalase and inositol biosynthesis fungicides; (b27) cyanoacetamideoxime fungicides; (b28) carbamate fungicides; (b29) oxidative phosphorylation uncoupling fungicides; (b30) organo tin fungicides; (b31) carboxylic acid fungicides; (b32) heteroaromatic fungicides; (b33) phosphonate fungicides; (b34) phthalamic acid fungicides; (b35) benzotriazine fungicides; (b36) benzene-sulfonamide fungicides; (b37) pyridazinone fungicides; (b38) thiophene-carboxamide fungicides; (b39) complex I NADH oxidoreductase inhibitor fungicides; (b40) carboxylic acid amide (CAA) fungicides; (b41) tetracycline antibiotic fungicides; (b42) thiocarbamate fungicides; (b43) benzamide fungicides; (b44) microbial fungicides; (b45) QXI fungicides; (b46) plant extract fungicides; (b47) host plant defense induction fungicides; (b48) multi-site contact activity fungicides; (b49) fungicides other than fungicides of classes (b1) through (b48); and salts of compounds of classes (b1) through (b48).
Further descriptions of these classes of fungicidal compounds are provided below.
(b1) “Methyl benzimidazole carbamate (MBC) fungicides” (FRAC code 1) inhibit mitosis by binding to β-tubulin during microtubule assembly. Inhibition of microtubule assembly can disrupt cell division, transport within the cell and cell structure. Methyl benzimidazole carbamate fungicides include benzimidazole and thiophanate fungicides. The benzimidazoles include benomyl, carbendazim, fuberidazole and thiabendazole. The thiophanates include thiophanate and thiophanate-methyl.
(b2) “Dicarboximide fungicides” (FRAC code 2) inhibit a MAP/histidine kinase in osmotic signal transduction. Examples include chlozolinate, iprodione, procymidone and vinclozolin.
(b3) “Demethylation inhibitor (DMI) fungicides” (FRAC code 3) (Sterol Biosynthesis Inhibitors (SBI): Class I) inhibit C14-demethylase, which plays a role in sterol production. Sterols, such as ergosterol, are needed for membrane structure and function, making them essential for the development of functional cell walls. Therefore, exposure to these fungicides results in abnormal growth and eventually death of sensitive fungi. DMI fungicides are divided between several chemical classes: azoles (including triazoles and imidazoles), pyrimidines, piperazines, pyridines and triazolinthiones. The triazoles include azaconazole, bitertanol, bromuconazole, cyproconazole, difenoconazole, diniconazole (including diniconazole-M), epoxiconazole, etaconazole, fenbuconazole, fluquinconazole, flusilazole, flutriafol, hexaconazole, imibenconazole, ipconazole, metconazole, myclobutanil, penconazole, propiconazole, quinconazole, simeconazole, tebuconazole, tetraconazole, triadimefon, triadimenol, triticonazole, uniconazole, uniconazole-P, α-(1-chlorocyclopropyl)-α-[2-(2,2-dichlorocyclopropyl)ethyl]-1H-1,2,4-triazole-1-ethanol, rel-1-[[(2R,3S)-3-(2-chlorophenyl)-2-(2,4-difluorophenyl)-2-oxiranyl]methyl]-1H-1,2,4-triazole, rel-2-[[(2R,3S)-3-(2-chlorophenyl)-2-(2,4-difluorophenyl)-2-oxiranyl]methyl]-1,2-dihydro-3H-1,2,4-triazole-3-thione, and rel-1-[[(2R,3S)-3-(2-chlorophenyl)-2-(2,4-difluorophenyl)-2-oxiranyl]methyl]-5-(2-propen-1-ylthio)-1H-1,2,4-triazole. The imidazoles include econazole, imazalil, oxpoconazole, prochloraz, pefurazoate and triflumizole. The pyrimidines include fenarimol, nuarimol and triarimol. The piperazines include triforine. The pyridines include buthiobate, pyrifenox, pyrisoxazole (3-[(3R)-5-(4-chlorophenyl)-2,3-dimethyl3-isoxazolidinyl]pyridine, mixture of 3R,5R- and 3R,5S-isomers) and (αS)-[3-(4-chloro-2-fluorophenyl)5-(2,4-difluorophenyl)-4-isoxazolyl]-3-pyridinemethanol. The triazolinthiones include prothioconazole and 2-[2-(1-chlorocyclopropyl)-4-(2,2-dichlorocyclopropyl)-2-hydroxybutyl]-1,2-dihydro-3H-1,2,4-triazole-3-thione. Biochemical investigations have shown that all of the above mentioned fungicides are DMI fungicides as described by K. H. Kuck et al. in Modern Selective Fungicides—Properties, Applications and Mechanisms of Action, H. Lyr (Ed.), Gustav Fischer Verlag: New York, 1995, 205-258.
(b4) “Phenylamide fungicides” (FRAC code 4) are specific inhibitors of RNA polymerase in Oomycete fungi. Sensitive fungi exposed to these fungicides show a reduced capacity to incorporate uridine into rRNA. Growth and development in sensitive fungi is prevented by exposure to this class of fungicide. Phenylamide fungicides include acylalanine, oxazolidinone and butyrolactone fungicides. The acylalanines include benalaxyl, benalaxyl-M (also known as kiralaxyl), furalaxyl, metalaxyl and metalaxyl-M (also known as mefenoxam). The oxazolidinones include oxadixyl. The butyrolactones include ofurace.
(b5) “Amine/morpholine fungicides” (FRAC code 5) (SBI: Class II) inhibit two target sites within the sterol biosynthetic pathway, Δ8→Δ7 isomerase and Δ14 reductase. Sterols, such as ergosterol, are needed for membrane structure and function, making them essential for the development of functional cell walls. Therefore, exposure to these fungicides results in abnormal growth and eventually death of sensitive fungi. Amine/morpholine fungicides (also known as non-DMI sterol biosynthesis inhibitors) include morpholine, piperidine and spiroketal-amine fungicides. The morpholines include aldimorph, dodemorph, fenpropimorph, tridemorph and trimorphamide. The piperidines include fenpropidin and piperalin. The spiroketal-amines include spiroxamine.
(b6) “Phospholipid biosynthesis inhibitor fungicides” (FRAC code 6) inhibit growth of fungi by affecting phospholipid biosynthesis. Phospholipid biosynthesis fungicides include phophorothiolate and dithiolane fungicides. The phosphorothiolates include edifenphos, iprobenfos and pyrazophos. The dithiolanes include isoprothiolane.
(b7) “Succinate dehydrogenase inhibitor (SDHI) fungicides” (FRAC code 7) inhibit Complex II fungal respiration by disrupting a key enzyme in the Krebs Cycle (TCA cycle) named succinate dehydrogenase. Inhibiting respiration prevents the fungus from making ATP, and thus inhibits growth and reproduction. SDHI fungicides include phenylbenzamide, furan carboxamide, oxathiin carboxamide, thiazole carboxamide, pyrazole-4-carboxamide, pyridine carboxamide, phenyl oxoethyl thiophene amides and pyridinylethyl benzamides. The benzamides include benodanil, flutolanil and mepronil. The furan carboxamides include fenfuram. The oxathiin carboxamides include carboxin and oxycarboxin. The thiazole carboxamides include thifluzamide. The pyrazole-4-carboxamides include benzovindiflupyr (N-[9-(dichloromethylene)-1,2,3,4-tetrahydro-1,4-methanonaphthalen-5-yl]-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamide), bixafen, fluxapyroxad (3-(difluoromethyl)-1-methyl-N-(3′,4′,5′-trifluoro[1,1′-biphenyl]-2-yl)-1H-pyrazole-4-carboxamide), furametpyr, isopyrazam (3-(difluoromethyl)-1-methyl-N-[1,2,3,4-tetrahydro9-(1-methylethyl)-1,4-methanonaphthalen-5-yl]-1H-pyrazole-4-carboxamide), penflufen (N-[2-(1,3-dimethylbutyl)phenyl]-5-fluoro-1,3-dimethyl-1H-pyrazole-4-carboxamide), penthiopyrad, sedaxane (N-[2-[1,1′-bicyclopropyl]-2-ylphenyl]-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamide), N-[2-(1S,2R)-[1,1′-bicyclopropyl]-2-ylphenyl]-3-(difluoro-methyl)-1-methyl-1H-pyrazole-4-carboxamide, 3-(difluoromethyl)-N-(2,3-dihydro-1,1,3-trimethyl-1H-inden-4-yl)-1-methyl-1H-pyrazole-4-carboxamide, N-[2-(2,4-dichlorophenyl)2-methoxy-1-methylethyl]-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamide and N-cyclopropyl-3-(difluoromethyl)-5-fluoro-1-methyl-N-[[2-(1-methylethyl)phenyl]methyl]-1H-pyrazole-4-carboxamide. The pyridine carboxamides include boscalid. The phenyl oxoethyl thiophene amides include isofetamid (N-[1,1-dimethyl-2-[2-methyl-4-(1-methylethoxy)phenyl]-2-oxoethyl]-3-methyl-2-thiophenecarboxamide). The pyridinylethyl benzamides include fluopyram.
(b8) “Hydroxy-(2-amino-)pyrimidine fungicides” (FRAC code 8) inhibit nucleic acid synthesis by interfering with adenosine deaminase. Examples include bupirimate, dimethirimol and ethirimol.
(b9) “Anilinopyrimidine fungicides” (FRAC code 9) are proposed to inhibit biosynthesis of the amino acid methionine and to disrupt the secretion of hydrolytic enzymes that lyse plant cells during infection. Examples include cyprodinil, mepanipyrim and pyrimethanil.
(b10) “N-Phenyl carbamate fungicides” (FRAC code 10) inhibit mitosis by binding to β-tubulin and disrupting microtubule assembly. Inhibition of microtubule assembly can disrupt cell division, transport within the cell and cell structure. Examples include diethofencarb.
(b11) “Quinone outside inhibitor (QoI) fungicides” (FRAC code 11) inhibit Complex III mitochondrial respiration in fungi by affecting ubiquinol oxidase. Oxidation of ubiquinol is blocked at the “quinone outside” (QO) site of the cytochrome bc complex, which is located in the inner mitochondrial membrane of fungi. Inhibiting mitochondrial respiration prevents normal fungal growth and development. Quinone outside inhibitor fungicides include methoxyacrylate, methoxycarbamate, oximinoacetate, oximinoacetamide and dihydrodioxazine fungicides (collectively also known as strobilurin fungicides), and oxazolidinedione, imidazolinone and benzylcarbamate fungicides. The methoxyacrylates include azoxystrobin, coumoxystrobin (methyl (αE)-2-[[(3-butyl-4-methyl-2-oxo-2H-1-benzopyran-7-yl)oxy]methyl]-α-(methoxymethylene)benzeneacetate), enoxastrobin (methyl (αE)-2-[[[(E)-[(2E)-3-(4-chlorophenyl)-1-methyl-2-propen-1-ylidene]amino]oxy]methyl]-α-(methoxymethylene)benzeneaceate) (also known as enestroburin), flufenoxystrobin (methyl (αE)-2-[[2-chloro-4-(trifluoromethyl)phenoxy]methyl]-α-(methoxymethylene)benzeneacetate), picoxystrobin, and pyraoxystrobin (methyl (αE)-2-[[[3-(4-chlorophenyl)-1-methyl-1H-pyrazol-5-yl]oxy]methyl]-α-(methoxymethylene)benzeneacetate). The methoxy-carbamates include pyraclostrobin, pyrametostrobin (methyl N-[2-[[(1,4-dimethyl-3-phenyl-1H-pyrazol-5-yl)oxy]methyl]phenyl]-N-methoxycarbamate) and triclopyricarb (methyl N-methoxy-N-[2-[[(3,5,6-trichloro-2-pyridinyl)oxy]methyl]phenyl]carbamate). The oximino-acetates include kresoxim-methyl, and trifloxystrobin. The oximinoacetamides include dimoxystrobin, fenaminstrobin ((αE)-2-[[[(E)-[(2E)-3-(2,6-dichlorophenyl)-1-methyl-2-propen-1-ylidene]amino]oxy]methyl]-α-(methoxyimino)-N-methylbenzeneacetamide), metominostrobin, orysastrobin and α-[methoxyimino]-N-methyl-2-[[[1-[3-(trifluoro-methyl)phenyl]ethoxy]imino]methyl]benzeneacetamide. The dihydrodioxazines include fluoxastrobin. The oxazolidinediones include famoxadone. The imidazolinones include fenamidone. The benzylcarbamates include pyribencarb. Class (b11) also includes mandestrobin (2-[(2,5-dimethylphenoxy)methyl]-α-methoxy-N-benzeneacetamide).
(b12) “Phenylpyrrole fungicides” (FRAC code 12) inhibit a MAP/histidine kinase associated with osmotic signal transduction in fungi. Fenpiclonil and fludioxonil are examples of this fungicide class.
(b13) “Azanaphthalene fungicides” (FRAC code 13) are proposed to inhibit signal transduction by a mechanism which is as yet unknown. They have been shown to interfere with germination and/or appressorium formation in fungi that cause powdery mildew diseases. Azanaphthalene fungicides include aryloxyquinolines and quinazolinones. The aryloxyquinolines include quinoxyfen. The quinazolinones include proquinazid.
(b14) “Lipid peroxidation inhibitor fungicides” (FRAC code 14) are proposed to inhibit lipid peroxidation which affects membrane synthesis in fungi. Members of this class, such as etridiazole, may also affect other biological processes such as respiration and melanin biosynthesis. Lipid peroxidation fungicides include aromatic hydrocarbon and 1,2,4-thiadiazole fungicides. The aromatic hydrocarboncarbon fungicides include biphenyl, chloroneb, dicloran, quintozene, tecnazene and tolclofos-methyl. The 1,2,4-thiadiazoles include etridiazole.
(b15) “Melanin biosynthesis inhibitors-reductase (MBI-R) fungicides” (FRAC code 16.1) inhibit the naphthal reduction step in melanin biosynthesis. Melanin is required for host plant infection by some fungi. Melanin biosynthesis inhibitors-reductase fungicides include isobenzofuranone, pyrroloquinolinone and triazolobenzothiazole fungicides. The isobenzofuranones include fthalide. The pyrroloquinolinones include pyroquilon. The triazolobenzothiazoles include tricyclazole.
(b16) “Melanin biosynthesis inhibitors-dehydratase (MBI-D) fungicides” (FRAC code 16.2) inhibit scytalone dehydratase in melanin biosynthesis. Melanin in required for host plant infection by some fungi. Melanin biosynthesis inhibitors-dehydratase fungicides include cyclopropanecarboxamide, carboxamide and propionamide fungicides. The cyclopropanecarboxamides include carpropamid. The carboxamides include diclocymet. The propionamides include fenoxanil.
(b17) “Sterol Biosynthesis Inhibitor (SBI): Class III fungicides (FRAC code 17) inhibit 3-ketoreductase during C4-demethylation in sterol production. SBI: Class III inhibitors include hydroxyanilide fungicides and amino-pyrazolinone fungicides. Hydroxyanilides include fenhexamid. Amino-pyrazolinones include fenpyrazamine (S-2-propen-1-yl 5-amino-2,3-dihydro-2-(1-methylethyl)-4-(2-methylphenyl)-3-oxo-1H-pyrazole-1-carbothioate).
(b18) “Squalene-epoxidase inhibitor fungicides” (FRAC code 18) (SBI: Class IV) inhibit squalene-epoxidase in the sterol biosynthesis pathway. Sterols such as ergosterol are needed for membrane structure and function, making them essential for the development of functional cell walls. Therefore, exposure to these fungicides results in abnormal growth and eventually death of sensitive fungi. Squalene-epoxidase inhibitor fungicides include thiocarbamate and allylamine fungicides. The thiocarbamates include pyributicarb. The allylamines include naftifine and terbinafine.
(b19) “Polyoxin fungicides” (FRAC code 19) inhibit chitin synthase. Examples include polyoxin.
(b20) “Phenylurea fungicides” (FRAC code 20) are proposed to affect cell division. Examples include pencycuron.
(b21) “Quinone inside inhibitor (QiI) fungicides” (FRAC code 21) inhibit Complex III mitochondrial respiration in fungi by affecting ubiquinone reductase. Reduction of ubiquinone is blocked at the “quinone inside” (Qi) site of the cytochrome bc1 complex, which is located in the inner mitochondrial membrane of fungi. Inhibiting mitochondrial respiration prevents normal fungal growth and development. Quinone inside inhibitor fungicides include cyanoimidazole and sulfamoyltriazole fungicides. The cyanoimidazoles include cyazofamid. The sulfamoyltriazoles include amisulbrom.
(b22) “Benzamide and thiazole carboxamide fungicides” (FRAC code 22) inhibit mitosis by binding to β-tubulin and disrupting microtubule assembly. Inhibition of microtubule assembly can disrupt cell division, transport within the cell and cell structure. The benzamides include zoxamide. The thiazole carboxamides include ethaboxam.
(b23) “Enopyranuronic acid antibiotic fungicides” (FRAC code 23) inhibit growth of fungi by affecting protein biosynthesis. Examples include blasticidin-S.
(b24) “Hexopyranosyl antibiotic fungicides” (FRAC code 24) inhibit growth of fungi by affecting protein biosynthesis. Examples include kasugamycin.
(b25) “Glucopyranosyl antibiotic: protein synthesis fungicides” (FRAC code 25) inhibit growth of fungi by affecting protein biosynthesis. Examples include streptomycin.
(b26) “Glucopyranosyl antibiotic: trehalase and inositol biosynthesis fungicides” (FRAC code 26) inhibit trehalase and inositol biosynthesis. Examples include validamycin.
(b27) “Cyanoacetamideoxime fungicides (FRAC code 27) include cymoxanil.
(b28) “Carbamate fungicides” (FRAC code 28) are considered multi-site inhibitors of fungal growth. They are proposed to interfere with the synthesis of fatty acids in cell membranes, which then disrupts cell membrane permeability. Propamacarb, iodocarb, and prothiocarb are examples of this fungicide class.
(b29) “Oxidative phosphorylation uncoupling fungicides” (FRAC code 29) inhibit fungal respiration by uncoupling oxidative phosphorylation. Inhibiting respiration prevents normal fungal growth and development. This class includes 2,6-dinitroanilines such as fluazinam, and dinitrophenyl crotonates such as dinocap, meptyldinocap and binapacryl.
(b30) “Organo tin fungicides” (FRAC code 30) inhibit adenosine triphosphate (ATP) synthase in oxidative phosphorylation pathway. Examples include fentin acetate, fentin chloride and fentin hydroxide.
(b31) “Carboxylic acid fungicides” (FRAC code 31) inhibit growth of fungi by affecting deoxyribonucleic acid (DNA) topoisomerase type II (gyrase). Examples include oxolinic acid.
(b32) “Heteroaromatic fungicides” (Fungicide Resistance Action Committee (FRAC) code 32) are proposed to affect DNA/ribonucleic acid (RNA) synthesis. Heteroaromatic fungicides include isoxazoles and isothiazolones. The isoxazoles include hymexazole and the isothiazolones include octhilinone.
(b33) “Phosphonate fungicides” (FRAC code 33) include phosphorous acid and its various salts, including fosetyl-aluminum.
(b34) “Phthalamic acid fungicides” (FRAC code 34) include teclofthalam.
(b35) “Benzotriazine fungicides” (FRAC code 35) include triazoxide.
(b36) “Benzene-sulfonamide fungicides” (FRAC code 36) include flusulfamide.
(b37) “Pyridazinone fungicides” (FRAC code 37) include diclomezine.
(b38) “Thiophene-carboxamide fungicides” (FRAC code 38) are proposed to affect ATP production. Examples include silthiofam.
(b39) “Complex I NADH oxidoreductase inhibitor fungicides” (FRAC code 39) inhibit electron transport in mitochondria and include pyrimidinamines such as diflumetorim, and pyrazole-5-carboxamides such as tolfenpyrad.
(b40) “Carboxylic acid amide (CAA) fungicides” (FRAC code 40) inhibit cellulose synthase which prevents growth and leads to death of the target fungus. Carboxylic acid amide fungicides include cinnamic acid amide, valinamide and other carbamate, and mandelic acid amide fungicides. The cinnamic acid amides include dimethomorph, flumorph and pyrimorph (3-(2-chloro-4-pyridinyl)-3-[4-(1,1-dimethylethyl)phenyl]-1-(4-morpholinyl)-2-propene-1-one). The valinamide and other carbamates include benthiavalicarb, benthiavalicarb-isopropyl, iprovalicarb, tolprocarb (2,2,2-trifluoroethyl N-[(1S)-2-methyl-1-[[(4-methylbenzoyl)amino]methyl]propyl]carbamate) and valifenalate (methyl N-[(1-methylethoxy)carbonyl]-
(b41) “Tetracycline antibiotic fungicides” (FRAC code 41) inhibit growth of fungi by affecting protein synthesis. Examples include oxytetracycline.
(b42) “Thiocarbamate fungicides” (FRAC code 42) include methasulfocarb.
(b43) “Benzamide fungicides” (FRAC code 43) inhibit growth of fungi by delocalization of spectrin-like proteins. Examples include pyridinylmethyl benzamide fungicides such as fluopicolide (now FRAC code 7, pyridinylethyl benzamides).
(b44) “Microbial fungicides” (FRAC code 44) disrupt fungal pathogen cell membranes. Microbial fungicides include Bacillus species such as Bacillus amyloliquefaciens strains QST 713, FZB24, MB1600, D747 and the fungicidal lipopeptides which they produce.
(b45) “QXI fungicides” (FRAC code 45) inhibit Complex III mitochondrial respiration in fungi by affecting ubiquinone reductase at an unknown (QX) site of the cytochrome bc1 complex. Inhibiting mitochondrial respiration prevents normal fungal growth and development. QXI fungicides include triazolopyrimidylamines such as ametoctradin (5-ethyl-6-octyl[1,2,4]triazolo[1,5-α]pyrimidin-7-amine).
(b46) “Plant extract fungicides” are proposed to act by cell membrane disruption. Plant extract fungicides include terpene hydrocarbons and terpene alcohols such as the extract from Melaleuca alternifolia (tea tree).
(b47) “Host plant defense induction fungicides” (FRAC code P) induce host plant defense mechanisms. Host plant defense induction fungicides include benzothiadiazoles, benzisothiazole and thiadiazole-carboxamide fungicides. The benzothiadiazoles include acibenzolar-S-methyl. The benzisothiazoles include probenazole. The thiadiazole-carboxamides include tiadinil and isotianil.
(b48) “Multi-site contact fungicides” inhibit fungal growth through multiple sites of action and have contact/preventive activity. This class of fungicides includes: (b48.1) “copper fungicides” (FRAC code M1)”, (b48.2) “sulfur fungicides” (FRAC code M2), (b48.3) “dithiocarbamate fungicides” (FRAC code M3), (b48.4) “phthalimide fungicides” (FRAC code M4), (b48.5) “chloronitrile fungicides” (FRAC code M5), (b48.6) “sulfamide fungicides” (FRAC code M6), (b48.7) multi-site contact “guanidine fungicides” (FRAC code M7), (b48.8) “triazine fungicides” (FRAC code M8), (b48.9) “quinone fungicides” (FRAC code M9), (b48.10) “quinoxaline fungicides” (FRAC code M10) and (b48.11) “maleimide fungicides” (FRAC code M11). “Copper fungicides” are inorganic compounds containing copper, typically in the copper(II) oxidation state; examples include copper oxychloride, copper sulfate and copper hydroxide, including compositions such as Bordeaux mixture (tribasic copper sulfate). “Sulfur fungicides” are inorganic chemicals containing rings or chains of sulfur atoms; examples include elemental sulfur. “Dithiocarbamate fungicides” contain a dithiocarbamate molecular moiety; examples include mancozeb, metiram, propineb, ferbam, maneb, thiram, zineb and ziram. “Phthalimide fungicides” contain a phthalimide molecular moiety; examples include folpet, captan and captafol. “Chloronitrile fungicides” contain an aromatic ring substituted with chloro and cyano; examples include chlorothalonil. “Sulfamide fungicides” include dichlofluanid and tolyfluanid. Multi-site contact “guanidine fungicides” include, guazatine, iminoctadine albesilate and iminoctadine triacetate. “Triazine fungicides” include anilazine. “Quinone fungicides” include dithianon. “Quinoxaline fungicides” include quinomethionate (also known as chinomethionate). “Maleimide fungicides” include fluoroimide.
(b49) “Fungicides other than fungicides of classes (b1) through (b48)” include certain fungicides whose mode of action may be unknown. These include: (b49.1), “phenyl-acetamide fungicides” (FRAC code U6), (b49.2) “aryl-phenyl-ketone fungicides” (FRAC code U8), (b49.3) “guanidine fungicides” (FRAC code U12), (b49.4) “thiazolidine fungicides” (FRAC code U13), (b49.5) “pyrimidinone-hydrazone fungicides” (FRAC code U14) and (b49.6) compounds that bind to oxysterol-binding protein as described in PCT Patent Publication WO 2013/009971. The phenyl-acetamides include cyflufenamid and N-[[(cyclopropylmethoxy)amino][6-(difluoromethoxy)-2,3-difluorophenyl]-methylene]-benzeneacetamide. The aryl-phenyl ketones include benzophenones such as metrafenone, and benzoylpyridines such as pyriofenone (5-chloro-2-methoxy-4-methyl-3-pyridinyl)(2,3,4-trimethoxy-6-methylphenyl)methanone). The quanidines include dodine. The thiazolidines include flutianil ((2Z)-2-[[2-fluoro-5-(trifluoromethyl)phenyl]thio]-2-[3-(2-methoxyphenyl)-2-thiazolidinylidene]acetonitrile). The pyrimidinonehydrazones include ferimzone. The (b49.6) class includes oxathiapiprolin (1-[4-[4-[5-(2,6-difluorophenyl)-4,5-dihydro-3-isoxazolyl]-2-thiazolyl]-1-piperidinyl]-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone) and its R-enantiomer which is 1-[4-[4-[5R-(2,6-difluorophenyl)-4,5-dihydro-3-isoxazolyl]-2-thiazolyl]-1-piperidinyl]-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]-ethanone (Registry Number 1003319-79-6). The (b49) class also includes bethoxazin, flometoquin (2-ethyl-3,7-dimethyl-6-[4-(trifluoromethoxy)phenoxy]-4-quinolinyl methyl carbonate), fluoroimide, neo-asozin (ferric methanearsonate), picarbutrazox (1,1-dimethylethyl N-[6-[[[[((Z)1-methyl-1H-tetrazol-5-yl)phenylmethylene]amino]oxy]methyl]-2-pyridinyl]carbamate), pyrrolnitrin, quinomethionate, tebufloquin (6-(1,1-dimethylethyl)-8-fluoro-2,3-dimethyl-4-quinolinyl acetate), tolnifanide (N-(4-chloro-2-nitrophenyl)-N-ethyl-4-methylbenzenesulfonamide), 2-butoxy-6-iodo-3-propyl-4H-1-benzopyran-4-one, 3-butyn-1-yl N-[6-[[[[(1-methyl-H-tetrazol-5-yl)phenylmethylene]amino]oxy]methyl]-2-pyridinyl]-carbamate, (N-(4-chloro-2-nitrophenyl)-N-ethyl-4-methylbenzenesulfonamide), N-[4-[4-chloro-3-(trifluoromethyl)phenoxy]-2,5-dimethylphenyl]-N-ethyl-N-methylmethanimidamide, N-[[(cyclopropylmethoxy)amino][6-(difluoromethoxy)-2,3-difluorophenyl]-methylene]benzeneacetamide, 2,6-dimethyl-1H,5H-[1,4]dithiino[2,3-c:5,6-c′]dipyrrole-1,3,5,7(2H,6H)-tetrone, 5-fluoro-2-[(4-methylphenyl)methoxy]-4-pyrimidinamine, 5-fluoro-2-[(4-fluorophenyl)methoxy]-4-pyrimidinamine and 4-fluorophenyl N-[1-[[[1-(4-cyano-phenyl)ethyl]sulfonyl]methyl]propyl]carbamate, pentyl N-[6-[[[[(1-methyl-1H-tetrazol-5-yl)-phenylmethylene]amino]oxy]methyl]-2-pyridinyl]carbamate, pentyl N-[4-[[[[(1-methyl-1H-tetrazol-5-yl)phenylmethylene]amino]oxy]methyl]-2-thiazolyl]carbamate and pentyl N-[6-[[[[(Z)-(1-methyl-1H-tetrazol-5-yl)phenylmethylene]amino]oxy]methyl]-2-pyridinyl]-carbamate. The (b46) class further includes mitosis- and cell division-inhibiting fungicides besides those of the particular classes described above (e.g., (b1), (b10) and (b22)).
Additional “Fungicides other than fungicides of classes (1) through (46)” whose mode of action may be unknown, or may not yet be classified include a fungicidal compound selected from components (b49.7) through (b49.12), as shown below.
Component (b49.7) relates to a compound of Formula b49.7
wherein Rb1 is
Examples of a compound of Formula b49.7 include (b49.7a) (2-chloro-6-fluorophenyl)methyl 2-[1-[2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinyl]-4-thiazolecarboxylate (Registry Number 1299409-40-7) and (b49.7b) (1R)-1,2,3,4-tetrahydro-1-naphthalenyl 2-[1-[2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinyl]-4-thiazolecarboxylate (Registry Number 1299409-42-9). Methods for preparing compounds of Formula b46.2 are described in PCT Patent Publications WO 2009/132785 and WO 2011/051243.
Component (b49.8) relates to a compound of Formula b49.8
Examples of a compound of Formula b49.8 include (b49.8a) 1-[4-[4-[5-[(2,6-difluorophenoxy)methyl]-4,5-dihydro-3-isoxazolyl]-2-thiazolyl]-1-piperdinyl]-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone. Methods for preparing compounds of Formula b49.8 are described in PCT Patent Application PCT/US11/64324.
Component (b4799) relates to a compound of Formula b49.9
wherein Rb5 is —CH2OC(O)CH(CH3)2, —C(O)CH3, —CH2OC(O)CH3.
Examples of a compound of Formula b49.9 include (b49.9a) [[4-methoxy-2-[[[(3S,7R,8R,9S)-9-methyl-8-(2-methyl-1-oxopropoxy)-2,6-dioxo-7-(phenylmethyl)-1,5-dioxonan-3-yl]-amino]carbonyl]-3-pyridinyl]oxy]methyl 2-methylpropanoate (also known as fenpicoxamid) (Registry Number 517875-34-2), (b49.9b) (3S,6S,7R,8R)-3-[[[3-(acetyloxy)-4-methoxy-2-pyridinyl]carbonyl]amino]-6-methyl-4,9-dioxo-8-(phenylmethyl)-1,5-dioxonan-7-yl 2-methylpropanoate (Registry Number 234112-93-7), (b49.9c) (3S,6S,7R,8R)-3-[[[3[(acetyloxy)-methoxy]-4-methoxy-2-pyridinyl]carbonyl]amino]-6-methyl-4,9-dioxo-8-(phenylmethyl)-1,5-dioxonan-7-yl 2-methylpropanoate (Registry Number 517875-31-9), (b49.9d) (3S,6S,7R,8R)-3-[[[4-methoxy-3-[[(2-methylpropoxy)carbonyl]oxy]-2-pyridinyl]carbonyl]-amino]6-methyl-4,9-dioxo-8-(phenylmethyl)-1,5-dioxonan-7-yl 2-methylpropanoate (Registry Number 328256-72-0), and (b49.9e) N-[[3-(1,3-benzodioxol-5-ylmethoxy)-4-methoxy-2-pyridinyl]carbonyl]-O-[2,5-dideoxy-3-O-(2-methyl-1-oxopropyl)-2-(phenyl-methyl)
Component (b49.10) relates to a compound of Formula b49.10
wherein Rb6 is H or F, and Rb7 is —CF2CHFCF3 or —CF2CF2H. Examples of a compound of Formula b49.10 are (b49.10a) 3-(difluoromethyl)-N-[4-fluoro-2-(1,1,2,3,3,3-hexafluoro-propoxy)phenyl]-1-methyl-1H-pyrazole-4-carboxamide (Registry Number 1172611-40-3) and (b49.10b) 3-(difluoromethyl)-1-methyl-N-[2-(1,1,2,2-tetrafluoroethoxy)phenyl]-1H-pyrazole-4-carboxamide (Registry Number 923953-98-4). Compounds of Formula 49.10 can be prepared by methods described in PCT Patent Publication WO 2007/017450.
Component b49.11 relates a compound of Formula b49.11
wherein
Component 49.12 relates to N′-[4-[[3-[(4-chlorophenyl)methyl]-1,2,4-thiadiazol-5-yl]oxy]-2,5-dimethylphenyl]-N-ethyl-N-methylmethanimidamide, which is believed to inhibit C24-methyl transferase involved in the biosynthesis of sterols.
Therefore of note is a mixture (i.e. composition) comprising a compound of Formula 1 and at least one fungicidal compound selected from the group consisting of the aforedescribed classes (1) through (49). Also of note is a composition comprising said mixture (in fungicidally effective amount) and further comprising at least one additional component selected from the group consisting of surfactants, solid diluents and liquid diluents. Of particular note is a mixture (i.e. composition) comprising a compound of Formula 1 and at least one fungicidal compound selected from the group of specific compounds listed above in connection with classes (1) through (49). Also of particular note is a composition comprising said mixture (in fungicidally effective amount) and further comprising at least one additional surfactant selected from the group consisting of surfactants, solid diluents and liquid diluents.
Examples of component (b) fungicides include acibenzolar-S-methyl, aldimorph, ametoctradin, amisulbrom, anilazine, azaconazole, azoxystrobin, benalaxyl (including benalaxyl-M), benodanil, benomyl, benthiavalicarb (including benthiavalicarb-isopropyl), benzovindiflupyr, bethoxazin, binapacryl, biphenyl, bitertanol, bixafen, blasticidin-S, boscalid, bromuconazole, bupirimate, buthiobate, captafol, captan, carbendazim, carboxin, carpropamid, chloroneb, chlorothalonil, chlozolinate, clotrimazole, copper hydroxide, copper oxychloride, copper sulfate, coumoxystrobin, cyazofamid, cyflufenamid, cymoxanil, cyproconazole, cyprodinil, dichlofluanid, diclocymet, diclomezine, dicloran, diethofencarb, difenoconazole, diflumetorim, dimethirimol, dimethomorph, dimoxystrobin, diniconazole (including diniconazole-M), dinocap, dithianon, dithiolanes, dodemorph, dodine, econazole, edifenphos, enoxastrobin (also known as enestroburin), epoxiconazole, etaconazole, ethaboxam, ethirimol, etridiazole, famoxadone, fenamidone, fenarimol, fenaminstrobin, fenbuconazole, fenfuram, fenhexamid, fenoxanil, fenpiclonil, fenpropidin, fenpropimorph, fenpyrazamine, fentin acetate, fentin chloride, fentin hydroxide, ferbam, ferimzone, flometoquin, fluazinam, fludioxonil, flufenoxystrobin, flumorph, fluopicolide, fluopyram, flouroimide, fluoxastrobin, fluquinconazole, flusilazole, flusulfamide, flutianil, flutolanil, flutriafol, fluxapyroxad, folpet, fthalide, fuberidazole, furalaxyl, furametpyr, guazatine, hexaconazole, hymexazole, imazalil, imibenconazole, iminoctadine albesilate, iminoctadine triacetate, iodocarb, ipconazole, iprobenfos, iprodione, iprovalicarb, isoconazole, isofetamid, isoprothiolane, isopyrazam, isotianil, kasugamycin, kresoxim-methyl, mancozeb, mandepropamid, mandestrobin, maneb, mepanipyrim, mepronil, meptyldinocap, metalaxyl (including metalaxyl-M/mefenoxam), metconazole, methasulfocarb, metiram, metominostrobin, metrafenone, miconazole, myclobutanil, naftifine, neo-asozin, nuarimol, octhilinone, ofurace, orysastrobin, oxadixyl, oxathiapiprolin, oxolinic acid, oxpoconazole, oxycarboxin, oxytetracycline, pefurazoate, penconazole, pencycuron, penflufen, penthiopyrad, phosphorous acid (including salts thereof, e.g., fosetyl-aluminum), picarbutrazox, picoxystrobin, piperalin, polyoxin, probenazole, prochloraz, procymidone, propamacarb, propiconazole, propineb, proquinazid, prothiocarb, prothioconazole, pyraclostrobin, pyrametostrobin, pyraoxystrobin, pyrazophos, pyribencarb, pyributicarb, pyrifenox, pyrimethanil, pyriofenone, pyrisoxazole, pyroquilon, pyrrolnitrin, quinconazole, quinomethionate, quinoxyfen, quintozene, sedaxane, silthiofam, simeconazole, spiroxamine, streptomycin, sulfur, tebuconazole, tebufloquin, teclofthalam, tecnazene, terbinafine, tetraconazole, thiabendazole, thifluzamide, thiophanate, thiophanate-methyl, thiram, tiadinil, tolclofos-methyl, tolnifanide, tolprocarb, tolyfluanid, triadimefon, triadimenol, triarimol, triticonazole, triazoxide, tribasic copper sulfate, tricyclazole, triclopyricarb, tridemorph, trifloxystrobin, triflumizole, triforine, trimorphamide, uniconazole, uniconazole-P, validamycin, valifenalate (also known as valiphenal), vinclozolin, zineb, ziram, zoxamide, (3S,6S,7R,8R)-3-[[[3-[(acetyloxy)methoxy]-4-methoxy-2-pyridinyl]carbonyl]amino]-6-methyl-4,9-dioxo-8-(phenylmethyl)-1,5-dioxonan-7-yl 2-methylpropanoate, (3S,6S,7R,8R)-3-[[[3-(acetyloxy)-4-methoxy-2-pyridinyl]carbonyl]amino]-6-methyl-4,9-dioxo-8-(phenylmethyl)-1,5-dioxonan-7-yl 2-methylpropanoate, N-[[3-(1,3-benzodioxol-5-ylmethoxy)-4-methoxy-2-pyridinyl]carbonyl]-O-[2,5-dideoxy-3-O-(2-methyl-1-oxopropyl)-2-(phenylmethyl)-L-arabinonoyl]-L-serine, (1→4′)-lactone, N-[2-(1S,2R)-[1,1′-bicyclopropyl]-2-ylphenyl]-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamide, 2-[(3-bromo-6-quinolinyl)oxy]-N-(1,1-dimethyl-2-butyn-1-yl)-2-(methylthio)acetamide, 2-[(3-bromo-6-quinolinyl)oxy]-N-(1,1-dimethylethyl)butanamide, 2-[(3-bromo-8-methyl-6-quinolinyl)oxy]-N-(1,1-dimethyl-2-propyn-1-yl)-2-(methylthio)acetamide, 2-butoxy-6-iodo-3-propyl-4H-1-benzopyran-4-one, 3-butyn-1-yl N-[6-[[[[(1-methyl-1H-tetrazol-5-yl)phenylmethylene]-amino]oxy]methyl]-2-pyridinyl]carbamate, α-(1-chlorocyclopropyl)-α-[2-(2,2-dichloro-cyclopropyl)ethyl]-1H-1,2,4-triazole-1-ethanol, 2-[2-(1-chlorocyclopropyl)-4-(2,2-dichloro-cyclopropyl)-2-hydroxybutyl]-1,2-dihydro-3H-1,2,4-triazole-3-thione, (αS)-[3-(4-chloro-2-fluorophenyl)-5-(2,4-difluorophenyl)-4-isoxazolyl]-3-pyridinemethanol, rel-1-[[(2R,3S)-3-(2-chlorophenyl)-2-(2,4-difluorophenyl)-2-oxiranyl]methyl]-1H-1,2,4-triazole, rel-2-[[(2R,3S)-3-(2-chlorophenyl)-2-(2,4-difluorophenyl)-2-oxiranyl]methyl]-1,2-dihydro-3H-1,2,4-triazole-3-thione, rel-1-[[(2R,3S)-3-(2-chlorophenyl)-2-(2,4-difluorophenyl)-2-oxiranyl]methyl]-5-(2-propen-1-ylthio)-1H-1,2,4-triazole, 3-[5-(4-chlorophenyl)-2,3-dimethyl-3-isoxazolidinyl]pyridine, (2-chloro-6-fluorophenyl)methyl 2-[1-[2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinyl]-4-thiazolecarboxylate, N-[4-[[3-[(4-chloro-phenyl)methyl]-1,2,4-thiadiazol-5-yl]oxy]-2,5-dimethylphenyl]-N-ethyl-N-methylmethanimidamide, N-[2-[4-[[3-(4-chlorophenyl)-2-propyn-1-yl]oxy]-3-methoxyphenyl]-ethyl]-3-methyl-2-[(methylsulfonyl)amino]butanamide, N-[2-[4-[[3-(4-chlorophenyl)-2-propyn-1-yl]oxy]-3-methoxyphenyl]ethyl]-3-methyl-2-[(ethylsulfonyl)amino]butanamide, N-[4-[4-chloro-3-(trifluoromethyl)phenoxy]-2,5-dimethylphenyl]-N-ethyl-N-methylmethanimidamide, N-cyclopropyl-3-(difluoromethyl)-5-fluoro-1-methyl-N-[[2-(1-methyl-ethyl)phenyl]methyl]-1H-pyrazole-4-carboxamide, N-[[(cyclopropylmethoxy)amino][6-(difluoromethoxy)-2,3-difluorophenyl]methylene]benzeneacetamide, N-[2-(2,4-dichloro-phenyl)-2-methoxy-1-methylethyl]-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamide, N-(3′,4′-difluoro[1,1′-biphenyl]-2-yl)-3-(trifluoromethyl)-2-pyrazinecarbox-amide, 3-(difluoromethyl)-N-(2,3-dihydro-1,1,3-trimethyl-1H-inden-4-yl)-1-methyl-1H-pyrazole-4-carboxamide, 3-(difluoromethyl)-N-[4-fluoro-2-(1,1,2,3,3,3-hexafluoropropoxy)-phenyl]-1-methyl-1H-pyrazole-4-carboxamide, 5,8-difluoro-N-[2-[3-methoxy-4-[[4-(tri-fluoromethyl)-2-pyridinyl]oxy]phenyl]ethyl]-4-quinazolinamine, 3-(difluoromethyl)-1-methyl-N-[2-(1,1,2,2-tetrafluoroethoxy)phenyl]-1H-pyrazole-4-carboxamide, 1-[4-[4-[5R-[(2,6-difluorophenoxy)methyl]-4,5-dihydro-3-isoxazolyl]-2-thiazolyl]-1-piperdinyl]-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone, N-(1,1-dimethyl-2-butyn-1-yl)-2-[(3-ethynyl-6-quinolinyl)oxy]-2-(methylthio)acetamide, 2,6-dimethyl-1H,5H-[1,4]dithiino[2,3-c:5,6-c′]dipyrrole-1,3,5,7(2H,6H)-tetrone, 2-[(3-ethynyl-6-quinolinyl)oxy]-N-[1-(hydroxy-methyl)-1-methyl-2-propyn-1-yl]-2-(methylthio)acetamide, 4-fluorophenyl N-[1-[[[1-(4-cyanophenyl)ethyl]sulfonyl]methyl]propyl]carbamate, 5-fluoro-2-[(4-fluorophenyl)methoxy]-4-pyrimidinamine, 5-fluoro-2-[(4-methylphenyl)methoxy]-4-pyrimidinamine, (3S,6S,7R,8R)-3-[[[4-methoxy-3-[[(2-methylpropoxy)carbonyl]oxy]-2-pyridinyl]carbonyl]amino]-6-methyl-4,9-dioxo-8-(phenylmethyl)-1,5-dioxonan-7-yl-2-methylpropanoate, α-(methoxyimino)-N-methyl-2-[[[1-[3-(trifluoromethyl)phenyl]ethoxy]imino]methyl]benzeneacetamide, [[4-methoxy-2-[[[(3S,7R,8R,9S)-9-methyl-8-(2-methyl-1-oxopropoxy)-2,6-dioxo-7-(phenylmethyl)-1,5-dioxonan-3-yl]amino]carbonyl]-3-pyridinyl]oxy]methyl 2-methylpropanoate, pentyl N-[6-[[[[(1-methyl-1H-tetrazol-5-yl)phenylmethylene]amino]oxy]methyl]-2-pyridinyl]carbamate, pentyl N-[4-[[[[(1-methyl-1H-tetrazol-5-yl)phenylmethylene]amino]oxy]methyl]-2-thiazolyl]carbamate, and pentyl N-[6-[[[[(Z)-(1-methyl-1H-tetrazol-5-yl)phenylmethylene]amino]oxy]methyl]-2-pyridinyl]carbamate and (1R)-1,2,3,4-tetrahydro-1-naphthalenyl 2-[1-[2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinyl]-4-thiazolecarboxylate. Therefore of note is a fungicidal composition comprising as component (a) a compound of Formula 1 (or an N-oxide or salt thereof) and as component (b) at least one fungicide selected from the preceding list.
Of particular note are combinations of compounds of Formula 1 (or an N-oxide or salt thereof) (i.e. Component (a) in compositions) with azoxystrobin, benzovindiflupyr, bixafen, captan, carpropamid, chlorothalonil, copper hydroxide, copper oxychloride, copper sulfate, cymoxanil, cyproconazole, cyprodinil, diethofencarb, difenoconazole, dimethomorph, epoxiconazole, ethaboxam, fenarimol, fenhexamid, fluazinam, fludioxonil, fluopyram, flusilazole, flutianil, flutriafol, fluxapyroxad, folpet, iprodione, isofetamid, isopyrazam, kresoxim-methyl, mancozeb, mandestrobin, meptyldinocap, metalaxyl (including metalaxyl-M/mefenoxam), metconazole, metrafenone, myclobutanil, oxathiapiprolin, penflufen, penthiopyrad, phosphorous acid (including salts thereof, e.g., fosetyl-aluminum), picoxystrobin, propiconazole, proquinazid, prothioconazole, pyraclostrobin, pyrimethanil, sedaxane spiroxamine, sulfur, tebuconazole, thiophanate-methyl, trifloxystrobin, zoxamide, α-(1-chlorocyclopropyl)-α-[2-(2,2-dichlorocyclopropyl)ethyl]-1H-1,2,4-triazole-1-ethanol, 2-[2-(1chlorocyclopropyl)-4-(2,2-dichlorocyclopropyl)-2-hydroxybutyl]-1,2-dihydro-3H-1,2,4-triazole-3-thione, N-[2-(2,4-dichlorophenyl)-2-methoxy-1-methylethyl]-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamide, 3-(difluoromethyl)-N-(2,3-dihydro-1,1,3-trimethyl-1H-inden-4-yl)-1-methyl-1H-pyrazole-4-carboxamide, 1-[4-[4-[5R-(2,6-difluorophenyl)-4,5-di-hydro-3-isoxazolyl]-2-thiazolyl]-1-piperidinyl]-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone, 1,1-dimethylethyl N-[6-[[[[(1-methyl-1H-tetrazol-5-yl)phenylmethylene]amino]oxy]methyl]-2-pyridinyl]carbamate, 2,6-dimethyl-1H,5H-[1,4]dithiino[2,3-c:5,6-c′]dipyrrole-1,3,5,7(2H,6H)-tetrone, 5-fluoro-2-[(4-fluorophenyl)-methoxy]-4-pyrimidinamine, 5-fluoro-2-[(4-methylphenyl)methoxy]-4-pyrimidinamine, (αS)-[3-(4-chloro-2-fluorophenyl)-5-(2,4-difluorophenyl)-4-isoxazolyl]-3-pyridinemethanol, rel-1-[[(2R,3S)-3-(2-chlorophenyl)-2-(2,4-difluorophenyl)-2-oxiranyl]methyl]-1H-1,2,4-triazole, rel-2-[[(2R,3S)-3-(2-chlorophenyl)-2-(2,4-difluorophenyl)-2-oxiranyl]methyl]-1,2-dihydro-3H-1,2,4-triazole-3-thione, and rel-1-[[(2R,3S)-3-(2-chlorophenyl)-2-(2,4-difluorophenyl)-2-oxiranyl]methyl]-5-(2-propen-1-ylthio)-1H-1,2,4-triazole (i.e. as Component (b) in compositions).
Examples of other biologically active compounds or agents with which compounds of this invention can be formulated are: invertebrate pest control compounds or agents such as abamectin, acephate, acetamiprid, acrinathrin, afidopyropen ([(3S,4R,4aR,6S,6aS,12R,12aS,12bS)-3-[(cyclopropylcarbonyl)oxy]-1,3,4,4a,5,6,6a,12,12a,12b-decahydro-6,12-dihydroxy-4,6a,12b-trimethyl-11-oxo-9-(3-pyridinyl)-2H,11H-naphtho[2,1-b]pyrano[3,4-e]pyran-4-yl]methylcyclopropanecarboxylate), amidoflumet (S-1955), avermectin, azadirachtin, azinphos-methyl, bifenthrin, bifenazate, buprofezin, carbofuran, cartap, chlorantraniliprole, chlorfenapyr, chlorfluazuron, chlorpyrifos, chlorpyrifos-methyl, chromafenozide, clothianidin, cyantraniliprole (3-bromo-1-(3-chloro-2-pyridinyl)-N-[4-cyano-2-methyl-6-[(methylamino)carbonyl]phenyl]-1H-pyrazole-5-carboxamide), cyclaniliprole (3-bromo-N-[2-bromo-4-chloro-6-[[(1-cyclopropylethyl)-amino]carbonyl]phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide), cycloxaprid ((5S,8R)-1-[(6-chloro-3-pyridinyl)methyl]-2,3,5,6,7,8-hexahydro-9-nitro-5,8-epoxy-1H-imidazo[1,2-α]azepine), cyflumetofen, cyfluthrin, beta-cyfluthrin, cyhalothrin, lambda-cyhalothrin, cypermethrin, cyromazine, deltamethrin, diafenthiuron, diazinon, dieldrin, diflubenzuron, dimefluthrin, dimethoate, dinotefuran, diofenolan, emamectin, endosulfan, esfenvalerate, ethiprole, fenothiocarb, fenoxycarb, fenpropathrin, fenvalerate, fipronil, flonicamid, flubendiamide, flucythrinate, flufenoxystrobin (methyl (αE)-2-[[2-chloro-4-(trifluoromethyl)phenoxy]methyl]-α-(methoxymethylene)benzeneacetate), flufensulfone (5-chloro-2-[(3,4,4-trifluoro-3-buten-1-yl)sulfonyl]thiazole), flupiprole (1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-5-[(2-methyl-2-propen-1-yl)amino]-4-[(trifluoromethyl)sulfinyl]-1H-pyrazole-3-carbonitrile), flupyradifurone (4-[[(6-chloro-3-pyridinyl)methyl](2,2-difluoroethyl)amino]-2(5H)-furanone), tau-fluvalinate, flufenerim (UR-50701), flufenoxuron, fonophos, halofenozide, heptafluthrin ([2,3,5,6-tetrafluoro-4-(methoxymethyl)phenyl]methyl 2,2-dimethyl-3-[(1Z)-3,3,3-trifluoro-1-propen-1-yl]cyclopropanecarboxylate), hexaflumuron, hydramethylnon, imidacloprid, indoxacarb, isofenphos, lufenuron, malathion, meperfluthrin ([2,3,5,6-tetrafluoro-4-(methoxymethyl)phenyl]methyl (1R,3S)-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarboxylate), metaflumizone, metaldehyde, methamidophos, methidathion, methomyl, methoprene, methoxychlor, methoxyfenozide, metofluthrin, milbemycin oxime, momfluorothrin ([2,3,5,6-tetrafluoro-4-(methoxymethyl)phenyl]methyl-3-(2-cyano-1-propen-1-yl)-2,2-dimethylcyclopropanecarboxylate), monocrotophos, nicotine, nitenpyram, nithiazine, novaluron, noviflumuron (XDE-007), oxamyl, pyflubumide (1,3,5-trimethyl-N-(2-methyl-1-oxopropyl)-N-[3-(2-methylpropyl)-4-[2,2,2-trifluoro-1-methoxy-1-(trifluoromethyl)ethyl]phenyl]-1H-pyrazole-4-carboxamide), parathion, parathion-methyl, permethrin, phorate, phosalone, phosmet, phosphamidon, pirimicarb, profenofos, profluthrin, pymetrozine, pyrafluprole, pyrethrin, pyridalyl, pyrifluquinazon, pyriminostrobin (methyl (αE)-2-[[[2-[(2,4-dichlorophenyl)amino]-6-(trifluoromethyl)-4-pyrimidinyl]oxy]methyl]-α-(methoxymethylene)benzeneacetate), pyriprole, pyriproxyfen, rotenone, ryanodine, spinetoram, spinosad, spirodiclofen, spiromesifen (BSN 2060), spirotetramat, sulfoxaflor, sulprofos, tebufenozide, teflubenzuron, tefluthrin, terbufos, tetrachlorvinphos, tetramethylfluthrin, thiacloprid, thiamethoxam, thiodicarb, thiosultap-sodium, tolfenpyrad, tralomethrin, triazamate, trichlorfon and triflumuron; and biological agents including entomopathogenic bacteria, such as Bacillus thuringiensis subsp. aizawai, Bacillus thuringiensis subsp. kurstaki, and the encapsulated delta-endotoxins of Bacillus thuringiensis (e.g., Cellcap, MPV, MPVII); entomopathogenic fungi, such as green muscardine fungus; and entomopathogenic virus including baculovirus, nucleopolyhedro virus (NPV) such as HzNPV, AfNPV; and granulosis virus (GV) such as CpGV.
Compounds of this invention and compositions thereof can be applied to plants genetically transformed to express proteins toxic to invertebrate pests (such as Bacillus thuringiensis delta-endotoxins). The effect of the exogenously applied fungicidal compounds of this invention may be synergistic with the expressed toxin proteins.
General references for agricultural protectants (i.e. insecticides, fungicides, nematocides, acaricides, herbicides and biological agents) include The Pesticide Manual, 13th Edition, C. D. S. Tomlin, Ed., British Crop Protection Council, Farnham, Surrey, U. K., 2003 and The BioPesticide Manual, 2nd Edition, L. G. Copping, Ed., British Crop Protection Council, Farnham, Surrey, U. K., 2001.
For embodiments where one or more of these various mixing partners are used, the weight ratio of these various mixing partners (in total) to the compound of Formula 1 is typically between about 1:3000 and about 3000:1. Of note are weight ratios between about 1:300 and about 300:1 (for example ratios between about 1:30 and about 30:1). One skilled in the art can easily determine through simple experimentation the biologically effective amounts of active ingredients necessary for the desired spectrum of biological activity. It will be evident that including these additional components may expand the spectrum of diseases controlled beyond the spectrum controlled by the compound of Formula 1 alone.
In certain instances, combinations of a compound of this invention with other biologically active (particularly fungicidal) compounds or agents (i.e. active ingredients) can result in a greater-than-additive (i.e. synergistic) effect. Reducing the quantity of active ingredients released in the environment while ensuring effective pest control is always desirable. When synergism of fungicidal active ingredients occurs at application rates giving agronomically satisfactory levels of fungal control, such combinations can be advantageous for reducing crop production cost and decreasing environmental load.
Also in certain instances, combinations of a compound of the invention with other biologically active compounds or agents can result in a less-than-additive (i.e. safening) effect on organisms beneficial to the agronomic environment. For example, a compound of the invention may safen a herbicide on crop plants or protect a beneficial insect species (e.g., insect predators, pollinators such as bees) from an insecticide.
Fungicides of note for formulation with compounds of Formula 1 to provide mixtures useful in seed treatment include but are not limited to amisulbrom, azoxystrobin, boscalid, carbendazim, carboxin, cymoxanil, cyproconazole, difenoconazole, dimethomorph, fluazinam, fludioxonil, flufenoxystrobin, fluquinconazole, fluopicolide, fluoxastrobin, flutriafol, fluxapyroxad, ipconazole, iprodione, metalaxyl, mefenoxam, metconazole, myclobutanil, paclobutrazole, penflufen, picoxystrobin, prothioconazole, pyraclostrobin, sedaxane, silthiofam, tebuconazole, thiabendazole, thiophanate-methyl, thiram, trifloxystrobin and triticonazole.
Invertebrate pest control compounds or agents with which compounds of Formula 1 can be formulated to provide mixtures useful in seed treatment include but are not limited to abamectin, acetamiprid, acrinathrin, afidopyropen, amitraz, avermectin, azadirachtin, bensultap, bifenthrin, buprofezin, cadusafos, carbaryl, carbofuran, cartap, chlorantraniliprole, chlorfenapyr, chlorpyrifos, clothianidin, cyantraniliprole, cyclaniliprole, cyfluthrin, beta-cyfluthrin, cyhalothrin, gamma-cyhalothrin, lambda-cyhalothrin, cypermethrin, alpha-cypermethrin, zeta-cypermethrin, cyromazine, deltamethrin, dieldrin, dinotefuran, diofenolan, emamectin, endosulfan, esfenvalerate, ethiprole, etofenprox, etoxazole, fenothiocarb, fenoxycarb, fenvalerate, fipronil, flonicamid, flubendiamide, fluensulfone, flufenoxuron, flufiprole, flupyradifurone, fluvalinate, formetanate, fosthiazate, heptafluthrin, hexaflumuron, hydramethylnon, imidacloprid, indoxacarb, lufenuron, meperfluthrin, metaflumizone, methiocarb, methomyl, methoprene, methoxyfenozide, momfluorothrin, nitenpyram, nithiazine, novaluron, oxamyl, pyflubumide, pymetrozine, pyrethrin, pyridaben, pyriminostrobin, pyridalyl, pyriproxyfen, ryanodine, spinetoram, spinosad, spirodiclofen, spiromesifen, spirotetramat, sulfoxaflor, tebufenozide, tetramethrin, tetramethylfluthrin, thiacloprid, thiamethoxam, thiodicarb, thiosultap-sodium, tralomethrin, triazamate, triflumuron, Bacillus thuringiensis delta-endotoxins, strains of Bacillus thuringiensis and strains of Nucleo polyhydrosis viruses.
Compositions comprising compounds of Formula 1 useful for seed treatment can further comprise bacteria and fungi that have the ability to provide protection from the harmful effects of plant pathogenic fungi or bacteria and/or soil born animals such as nematodes. Bacteria exhibiting nematicidal properties may include but are not limited to Bacillus firmus, Bacillus cereus, Bacillus subtilis and Pasteuria penetrans. A suitable Bacillus firmus strain is strain CNCM I-1582 (GB-126) which is commercially available as BioNem™. A suitable Bacillus cereus strain is strain NCMM I-1592. Both Bacillus strains are disclosed in U.S. Pat. No. 6,406,690. Other suitable bacteria exhibiting nematicidal activity are B. amyloliquefaciens IN937a and B. subtilis strain GB03. Bacteria exhibiting fungicidal properties may include but are not limited to B. pumilus strain GB34. Fungal species exhibiting nematicidal properties may include but are not limited to Myrothecium verrucaria, Paecilomyces lilacinus and Purpureocillium lilacinum.
Seed treatments can also include one or more nematicidal agents of natural origin such as the elicitor protein called harpin which is isolated from certain bacterial plant pathogens such as Erwinia amylovora. An example is the Harpin-N-Tek seed treatment technology available as N-Hibit™ Gold CST.
Seed treatments can also include one or more species of legume-root nodulating bacteria such as the microsymbiotic nitrogen-fixing bacteria Bradyrhizobium japonicum. These inocculants can optionally include one or more lipo-chitooligosaccharides (LCOs), which are nodulation (Nod) factors produced by rhizobia bacteria during the initiation of nodule formation on the roots of legumes. For example, the Optimize® brand seed treatment technology incorporates LCO Promoter Technology™ in combination with an inocculant.
Seed treatments can also include one or more isoflavones which can increase the level of root colonization by mycorrhizal fungi. Mycorrhizal fungi improve plant growth by enhancing the root uptake of nutrients such as water, sulfates, nitrates, phosphates and metals. Examples of isoflavones include, but are not limited to, genistein, biochanin A, formononetin, daidzein, glycitein, hesperetin, naringenin and pratensein. Formononetin is available as an active ingredient in mycorrhizal inocculant products such as PHC Colonize® AG.
Seed treatments can also include one or more plant activators that induce systemic acquired resistance in plants following contact by a pathogen. An example of a plant activator which induces such protective mechanisms is acibenzolar-S-methyl.
of this invention on specific pathogens. The pathogen control protection afforded by the compounds is not limited, however, to these species. See Index Tables A-C below for compound descriptions. The following abbreviations are used in Index Tables A-C: Me means methyl, c-Pr means cyclopropyl, —CN means cyano, and Ph means phenyl. The abbreviation “Cmpd.” stands for “Compound”, and the abbreviation “Ex.” Stands for “Example” and is followed by a number indicating in which example the compound is prepared. The numerical value reported in the column “AP+ (M+1)”, is the molecular weight of the observed molecular ion formed by addition of H+ (molecular weight of 1) to the molecule having the greatest isotopic abundance (i.e. M). The presence of molecular ions containing one or more higher atomic weight isotopes of lower abundance (e.g., 37Cl, 81Br) is not reported. The reported M+1 peaks were observed by mass spectrometry using electrospray ionization (ESI) or atmospheric pressure chemical ionization (APCI).
General protocol for preparing test suspensions for Tests A-C: the test compounds were first dissolved in acetone in an amount equal to 3% of the final volume and then suspended at the desired concentration (in ppm) in acetone and purified water (50/50 mix by volume) containing 250 ppm of the surfactant PEG400 (polyhydric alcohol esters). The resulting test suspensions were then used in Tests A-C.
The test solution was sprayed to the point of run-off on soybean seedlings. The following day the seedlings were inoculated with a spore suspension of Phakopsora pachyrhizi (the causal agent of Asian soybean rust) and incubated in a saturated atmosphere at 22° C. for 24 h, and then moved to a growth chamber at 22° C. for 8 days, after which time visual disease ratings were made.
The test solution was sprayed to the point of run-off on wheat seedlings. The following day the seedlings were inoculated with a spore suspension of Zymoseptoria tritici (the causal agent of wheat leaf blotch) and incubated in a saturated atmosphere at 24° C. for 48 h, and then moved to a growth chamber at 20° C. for 17 days, after which time disease ratings were made.
The test solution was sprayed to the point of run-off on wheat seedlings. The following day the seedlings were inoculated with a spore suspension of Puccinia recondita f. sp. tritici (the causal agent of wheat leaf rust) and incubated in a saturated atmosphere at 20° C. for 24 h, and then moved to a growth chamber at 20° C. for 7 days, after which time disease ratings were made.
Results for Tests A-C are given in Table A below. A rating of 100 indicates 100% disease control and a rating of 0 indicates no disease control (relative to the controls). A dash (-) indicates the compound was not tested.
| Number | Date | Country | |
|---|---|---|---|
| 62840529 | Apr 2019 | US |
