Mixtures of 5-fluoro-4-imino-3-methyl-1-tosyl-3,4-dihydropyrimidin-2-one

Abstract

The present invention provides a mixture comprising flumetylsulforim and the compound 5-FC.

Description

[0001]

[0002] MIXTURES OF 5-FLUORO-4-IMINO-3-METHYL-l-TOSYL-3,4- DIHYDROPYRIMIDIN-2-ONE

[0003] Throughout this application various publications are referenced. The disclosures of these documents in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains.

[0004] This application claims the benefit of U.S. Provisional Application No. 63 / 765,156, filed February 28, 2025, the contents of which are hereby incorporated by reference.

[0005] BACKGROUND

[0006] Fungicides are compounds, of natural or synthetic origin, which act to protect plants against damage caused by fungi. Current methods of agriculture rely heavily on the use of fungicides. In fact, some crops cannot be grown usefully without the use of fungicides. Using fungicides allows a grower to increase the yield and the quality of the crop, and consequently, increase the value of the crop. In most situations, the increase in value of the crop is worth at least three times the cost of the use of the fungicide. 5 -fluoro-4-imino-3 -methyl- 1 -tosyl-3 ,4-dihydropyrimidin-2( I / / )-onc (flumetylsulforim) having the structure of a Formula I:

[0007]

[0008] Formula I

[0009] is a fungicide which provides control of a variety of pathogens in economically important crops including, but not limited to, the causal agent of leaf blotch in wheat, Septoria tritici, (SEPTTR) and diseases caused by fungi of the classes Ascomycetes and Basidiomycetes.SUMMARY

[0010] The present invention provides a mixture comprising flumetylsulforim, wherein 0.1% or less by weight of the mixture is 5 -Fluorocytosine (5 -FC):

[0011]

[0012] The present invention further provides a combination of (1) a mixture comprising flumetylsulforim, wherein 0.1% or less by weight of the mixture is the compound 5-FC, and (2) one or more carriers.

[0013] The present invention further provides a composition comprising (1) a mixture comprising flumetylsulforim, wherein 0.1% or less by weight of the mixture is the compound 5 -FC, and (2) at least one agriculture acceptable additive.

[0014] The present invention further provides a method for the control of fungal attack on a plant, the method comprising:

[0015] (1) obtaining a mixture of flumetylsulforim as described herein, (2) formulating the mixture, (3) diluting the formulated mixture in water and (4) applying the to a locus of the fungus, to a locus in which the infestation is to be prevented, and / or to the plant, so as to thereby control fungal attack on the plant.

[0016] The present invention provides a method of monitoring the stability of flumetylsulforim during storage, the method comprising periodically measuring the concentration of the compound 5 -FC formed in the flumetylsulforim technical or formulation, wherein an increase in the concentration of the compound 5 -FC indicates degradation of flumetylsulforim .

[0017] The present invention provides a method of monitoring the extent of degradation of flumetylsulforim during storage, the method comprising periodically measuring the concentration of the compound 5 -FC formed in the flumetylsulforim technical or formulation.

[0018] The present invention provides a method of monitoring the extent of degradation of flumetylsulforim during storage, the method comprising periodically measuring the concentration of the compound 5 -FC formed in the flumetylsulforim technical or formulation, wherein an increase in concentration of the compound 5 -FC indicates degradation of flumetylsulforim.The present invention provides a method of monitoring the rate of degradation of flumetylsulforim during storage, the method comprising periodically measuring the concentration of the compound 5 -FC formed in the flumetylsulforim technical or formulation.

[0019] The present invention provides a method of monitoring the rate of degradation of flumetylsulforim during storage, the method comprising periodically measuring the concentration of the compound 5 -FC formed in the flumetylsulforim technical or formulation, wherein an increase in the concentration of the compound 5-FC indicates degradation of flumetylsulforim.

[0020] The present invention provides a method for assessing the quality of a manufacturing process for flumetylsulforim, the method comprises determining the concentration of the compound 5-FC generated during said process.

[0021] The present invention provides a method for assessing the quality of a manufacturing process for flumetylsulforim, the method comprises determining the concentration of the compound 5-FC generated during said process, wherein an elevated concentration of the compound 5-FC is indicative of reduced process quality.

[0022] The present invention provides a method for assessing the quality of the formulation process for flumetylsulforim, the method comprises determining the concentration of the compound 5-FC generated during said process.

[0023] The present invention provides a method for assessing the quality of the formulation process for flumetylsulforim, the method comprises determining the concentration of the compound 5-FC generated during said process, wherein an elevated concentration of the compound 5-FC is indicative of reduced process quality.

[0024] The present invention provides use of the compound 5-FC for monitoring the stability of flumetylsulforim during storage, wherein an increase in the concentration of the compound 5-FC indicates degradation of flumetylsulforim.

[0025] The present invention provides use of the compound 5-FC for assessing the quality of a manufacturing process for flumetylsulforim, wherein an elevated concentration of the compound 5-FC is indicative of reduced process quality.DETAILED DESCRIPTION OF THE INVENTION

[0026] Definitions

[0027] Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by persons of ordinary skill in the art to which this subject matter pertains.

[0028] The term “a” or “an” as used herein includes the singular and the plural, unless specifically stated otherwise. Therefore, the terms “a,” “an,” or “at least one” can be used interchangeably in this application.

[0029] As used herein, the term “about” when used in connection with a numerical value includes ±10% from the indicated value. In addition, all ranges directed to the same component or property herein are inclusive of the endpoints, are independently combinable, and include all intermediate points and ranges. It is understood that where a parameter range is provided, all integers within that range, and tenths thereof, are also provided by the invention. For example, “0.1-80%” includes 0.1%, 0.2%, 0.3%, etc. up to 80%.

[0030] As used herein the term "plant" or “crop” includes reference to whole plants, plant organs (e.g. leaves, stems, twigs, roots, trunks, limbs, shoots, fruits etc.), plant cells, or plant seeds. This term also encompasses plant crops such as fruits. In yet another embodiment, the term “plant” may include the propagation material thereof, which may include all the generative parts of the plant such as seeds and vegetative plant material such as cuttings and tubers, which can be used for the multiplication of the plant. This includes seeds, tubers, spores, corms, bulbs, rhizomes, sprouts basal shoots, stolons, and buds and other parts of plants, including seedlings and young plants, which are to be transplanted after germination or after emergence from soil.

[0031] As used herein, the term "locus" includes not only areas in which the infestation is to be controlled, but also areas in which the infestation is to be prevented and also to areas under cultivation.

[0032] As used herein, the term “combination” refers, but is not limited, to a combination in any physical form, e.g., blend, solution, alloy, or the like.

[0033] As used herein, the term "effective amount" refers to an amount of the compound that, when applied, is sufficient to achieve a good level of control.

[0034] As used herein, the phrase "agrochemically acceptable" means which is known and accepted in the art for use in agricultural / pesticidal use.As used herein, the term “adjuvant” is broadly defined as any substance that itself is not a fungicide, but which enhances or is intended to enhance the effectiveness of the fungicide with which it is used. Adjuvants may be understood to include, but are not limited to, spreading agents, penetrants, compatibility agents, and drift retardants. As used herein, the term "additive" is defined as any substance that itself is not a fungicide but is added to the composition such as sticking agents, surfactants, synergists, buffers, acidifiers, defoaming agents and thickeners.

[0035] As used herein, the term “tank mix” means that at least one pesticide and / or additive and / or adjuvant are mixed in the spray tank prior to the application or at the time of spray application.

[0036] As used herein, the phrase "agriculturally acceptable carrier" means carriers which are known and accepted in the art for the formation of compositions for agricultural or horticultural use.

[0037] As used herein, the term “w / w” means percentage by weight based on the total weight of the solid or mixture.

[0038] Fungicidal mixture

[0039] The present invention provides a mixture comprising flumetylsulforim, wherein 0.1% or less by weight of the mixture is the compound 5-FC.

[0040] In some embodiments, less than 0.1% by weight of the mixture is the compound 5-FC. In some embodiments, 0.09% or less by weight of the mixture is the compound 5-FC. In some embodiments, 0.08% or less by weight of the mixture is the compound 5-FC. In some embodiments, 0.07% or less by weight of the mixture is the compound 5-FC. In some embodiments, 0.06% or less by weight of the mixture is the compound 5-FC. In some embodiments, 0.05% or less by weight of the mixture is the compound 5-FC. In some embodiments, 0.04% or less by weight of the mixture is the compound 5-FC. In some embodiments, 0.03% or less by weight of the mixture is the compound 5-FC. In some embodiments, 0.02% or less by weight of the mixture is the compound 5-FC. In some embodiments, 0.01% or less by weight of the mixture is the compound 5-FC. In some embodiments, the mixture comprises 0.001%-0.1% by weight of the compound 5-FC.

[0041] In some embodiments, the mixture is solid form of flumetylsulforim.In some embodiments, the mixture comprising flumetylsulforim is mixed with at least one excipient.

[0042] Fungicidal combination

[0043] The present invention provides a combination of (1) a mixture comprising flumetylsulforim, wherein 0.1% or less by weight of the mixture is the compound 5-FC as disclosed herein, and (2) one or more carriers.

[0044] In some embodiments, the combination is composition.

[0045] In some embodiments, the composition is a storable composition. In some embodiments, the composition is a diluted composition.

[0046] In some embodiments, the combination is a tank mix.

[0047] The present invention provides a composition comprising (1) a mixture comprising flumetylsulforim, wherein 0.1% or less by weight of the mixture is the compound 5-FC as disclosed herein, and (2) at least on agriculture acceptable additive.

[0048] In some embodiments, the agriculture acceptable additive is a dispersant.

[0049] In some embodiments, the fungicidal combination is mixed with at least one additional fungicide.

[0050] In some embodiments, the fungicidal combination comprises at least one additional fungicide.

[0051] In some embodiments, the additional fungicide and the flumetylsulforim of the present invention, are mixed together in tank and / or are applied separately.

[0052] In some embodiments, the additional fungicide(s) and the flumetylsulforim of the present invention are applied separately.

[0053] In some embodiments, the additional fungicide(s) and the flumetylsulforim of the present invention are applied simultaneously.

[0054] In some embodiments, the additional fungicide(s) and the flumetylsulforim of the present invention are formulated together in a single composition.

[0055] In some embodiments, the additional fungicide(s) and the flumetylsulforim of the present invention are applied in separate compositions.In some embodiments, the mixture of the present invention and the additional fungicide(s) are applied as tank mix.

[0056] In some embodiments, the composition or fungicidal composition of the present invention is a solid composition.

[0057] In some embodiments, the composition or fungicidal composition of the present invention is a liquid composition.

[0058] The composition may be employed or prepared in any conventional form, for example, as wettable powders (WP), emulsion concentrates (EC), microemulsion concentrates (MEC), water-soluble powders (SP), water-soluble concentrates (SL), suspoemulsion (SE), oil dispersions (OD), concentrated emulsions (BW) such as oil-in-water and water-in-oil emulsions, sprayable solutions or emulsions, capsule suspensions (CS), suspension concentrates (SC), suspension concentrates, dusts (DP), oil-miscible solutions (OL), a mixed formulation of CS and SC (ZC), a mixed heterogeneous formulation of CS and SE (ZE), a mixed heterogeneous formulation CS and EW (ZW), seed-dressing products, granules (GR) in the form of microgranules, spray granules, coated granules and absorption granules, granules for soil application or broadcasting, water-soluble granules (SG), water-dispersible granules (WDG), ULV formulations, microcapsules or waxes. These individual formulation types are known in the art. In some embodiments, the at least one additional fungicide is a fungicidal sterol biosynthesis inhibitor.

[0059] In some embodiments, the sterol biosynthesis inhibitor is selected from the group consisting of prothioconazole, epoxiconazole, cyproconazole, myclobutanil, prochloraz, metconazole, difenoconazole, tebuconazole, tetraconazole, fenbuconazole, propiconazole, fluquinconazole, flusilazole, flutriafol, and fenpropimorph.

[0060] In some embodiments, the sterol biosynthesis inhibitor is selected from the group consisting of epoxiconazole, cyproconazole, myclobutanil, metconazole, propiconazole, prothioconazole, fluquinconazole, flutriafol, and difenoconazole. In some embodiments, the at least one additional fungicide is a succinate dehydrogenase inhibitor.

[0061] In some embodiments, the succinate dehydrogenase inhibitor is selected from the group consisting of fluxapyroxad, benzovindiflupyr, penthiopyrad, isopyrazam, bixafen, boscalid, penflufen, and fluopyram.In some embodiments, the succinate dehydrogenase inhibitor is selected from the group consisting of fluxapyroxad, benzovindiflupyr, penthiopyrad, isopyrazam, boscalid, and fluopyram.

[0062] In some embodiments, the at least one additional fungicide is a strobilurin fungicide. In some embodiments, the strobilurin fungicide is selected from the group consisting of pyraclostrobin, fluoxastrobin, azoxystrobin, trifloxystrobin, picoxystrobin, and kresoxim-methyl.

[0063] In some embodiments, the at least one additional fungicide is a fungicidal multisite inhibitor.

[0064] In some embodiments, the fungicidal multisite inhibitor is selected from a group consisting of chlorothalonil, mancozeb, folpet, and captan.

[0065] In some embodiments, the fungicidal multisite inhibitor is folpet or captan.

[0066] In some embodiments, the mixture of the present invention alone, or in combination with at least one additional fungicide provides control of a fungal pathogen and the fungal pathogen is one of Leaf Blotch of Wheat (Mycosphaerella graminicola; anamorph: Septoria tritici) , Wheat Brown Rust (Puccinia triticina) , Stripe Rust (Puccinia striiformis f. sp. tritici) , Scab of Apple (Venturia inaequalis) , Blister Smut of Maize (Ustilago maydis) , Powdery Mildew of Grapevine (Uncinula necator) , Barley scald (Rhynchosporium secalis) , Blast of Rice (Magnaporthe grisea) , Rust of Soybean (Phakopsora pachyrhizi) , Glume Blotch of Wheat (Leptosphaeria nodorum) , Powdery Mildew of Wheat (Blumeria graminis f. sp. tritici), Powdery Mildew of Barley (Blumeria graminis f. sp. hordei) , Powdery Mildew of Cucurbits (Erysiphe cichoracearum) , Anthracnose of Cucurbits (Glomerella lagenarium) , Leaf Spot of Beet (Cercospora beticola) , Early Blight of Tomato (Altemaria solani) , and Net Blotch of Barley (Pyrenophora teres).

[0067] In some embodiments, the fungus is one of Leaf Blotch of Wheat(Mycosphaerella graminicola; anamorph: Septoria tritici), Wheat Brown Rust (Puccinia triticina) , Stripe Rust (Puccinia striiformis f. sp. tritici) , Scab of Apple (Venturia inaequalis) , Blister Smut of Maize(Ustilago maydis) , Powdery Mildew of Grapevine (Uncinula necator) , Barley scald (Rhynchosporium secalis) , Blast of Rice (Magnaporthe grisea) , Rust of Soybean (Phakopsora pachyrhizi) , Glume Blotch of Wheat(Leptosphaeria nodorum) , Powdery Mildew of Wheat (Blumeria graminis f. sp. tritici), Powdery Mildew of Barley (Blumeria graminis f. sp. hordei) , Powdery Mildew of Cucurbits (Erysiphe cichoracearum) , Anthracnose of Cucurbits (Glomerella lagenarium) , Leaf Spot ofBeet(Cercospora beticola) , Early Blight of Tomato (Altemaria solani) , and Net Blotch of Barley (Pyrenophora teres).

[0068] Method for controlling a fungal attack

[0069] The present invention further provides a method for the control of fungal attack on a plant, the method comprising:

[0070] (1) obtaining a mixture of flumetylsulforim of the present invention, (2) formulating the mixture, (3) diluting the formulated mixture in water and) applying the to a locus of the fungus, to a locus in which the infestation is to be prevented, and / or to the plant, so as to thereby control fungal attack on the plant.

[0071] Uses

[0072] The present invention provides use of the compound 5 -FC as a reference standard to test for its presence and / or quantity in a composition.

[0073] In some embodiments, the composition is a composition comprising flumetylsulforim. The present invention provides use of the compound 5 -FC as a reference standard to test for its presence and / or quantity at a locus where flumetylsulforim was applied. The amount of the compound 5 -FC at a locus may be used as an indicator of whether a desirable amount of flumetylsulforim was applied.

[0074] The present invention provides use of the compound 5 -FC as a reference standard to test for its presence and / or quantity in a plant to which flumetylsulforim was applied. The amount of the compound 5 -FC in a plant may be used as an indicator of whether a desirable amount of flumetylsulforim was applied.

[0075] The present invention provides use of the compound 5-FC as reference standard for determining purity and optionally metabolite profde of flumetylsulforim.

[0076] The present invention provides use of the compound 5-FC as reference standard for determining purity of composition comprising flumetylsulforim.

[0077] The present invention provides use of the compound 5-FC as a reference standard for screening a batch of flumetylsulforim. The amount of the compound 5-FC may be used to determine whether the batch of flumetylsulforim should be released for commercial use.The present invention provides a method of monitoring the stability of flumetylsulforim during storage, the method comprising periodically measuring the concentration of the compound 5 -FC formed in the flumetylsulforim technical or formulation, wherein an increase in the concentration of the compound 5 -FC indicates degradation of flumetylsulforim .

[0078] The present invention provides a method of monitoring the extent of degradation of flumetylsulforim during storage, the method comprising periodically measuring the concentration of the compound 5 -FC formed in the flumetylsulforim technical or formulation.

[0079] The present invention provides a method of monitoring the extent of degradation of flumetylsulforim during storage, the method comprising periodically measuring the concentration of the compound 5 -FC formed in the flumetylsulforim technical or formulation, wherein an increase in concentration of the compound 5 -FC indicates degradation of flumetylsulforim.

[0080] The present invention provides a method of monitoring the rate of degradation of flumetylsulforim during storage, the method comprising periodically measuring the concentration of the compound 5 -FC formed in the flumetylsulforim technical or formulation.

[0081] The present invention provides a method of monitoring the rate of degradation of flumetylsulforim during storage, the method comprising periodically measuring the concentration of the compound 5 -FC formed in the flumetylsulforim technical or formulation, wherein an increase in the concentration of the compound 5-FC indicates degradation of flumetylsulforim.

[0082] In one embodiment, “periodically measuring” comprises measuring at intervals selected from hourly, daily, weekly, biweekly, monthly, or quarterly intervals.

[0083] In another embodiment, the measuring interval is from 1 hour to 36 months.

[0084] In a further embodiment, the measuring interval is selected based on expected storage stability of flumetylsulforim.

[0085] In one embodiment, the concentration profde of the compound 5-FC is used as a diagnostic parameter for assessing degradation of flumetylsulforim.In another embodiment, an increase of at least 1%, 3%, 5%, 7%, 10%, 20%, or 50% in the concentration of the compound 5 -FC relative to the initial concentration is correlated with degradation.

[0086] In a further embodiment, degradation is determined by comparing measured impurity levels to a reference impurity profde.

[0087] In a further embodiment, the extent of degradation is determined by calculating the difference between the measured concentration of the compound 5 -FC and its initial concentration in the technical material or formulation.

[0088] In some embodiment, the storage conditions include one or more of: 4°C, 25 °C, 40°C accelerated storage, or 54°C oven-trial conditions.

[0089] In some embodiment, storage includes ambient warehouse storage and / or transport storage.

[0090] The present invention provides a method for assessing the quality of a manufacturing process for flumetylsulforim, the method comprises determining the concentration of the compound 5-FC generated during said process.

[0091] The present invention provides a method for assessing the quality of a manufacturing process for flumetylsulforim, the method comprises determining the concentration of the compound 5-FC generated during said process, wherein an elevated concentration of the compound 5-FC is indicative of reduced process quality.

[0092] In one embodiment, “process quality” refers to compliance with a predetermined impurity specification for the compound 5-FC.

[0093] In another embodiment, the quality is assessed by determining whether impurity levels fall within acceptable regulatory or internal specification limits.

[0094] The present invention provides a method for assessing the quality of the formulation process for flumetylsulforim, the method comprises determining the concentration of the compound 5-FC generated during said process.

[0095] The present invention provides a method for assessing the quality of the formulation process for flumetylsulforim, the method comprises determining the concentration of the compound 5-FC generated during said process, wherein an elevated concentration of the compound 5-FC is indicative of reduced process quality.The present invention provides use of the compound 5 -FC for monitoring the stability of flumetylsulforim during storage.

[0096] The present invention provides use of the compound 5 -FC for monitoring the stability of flumetylsulforim during storage, wherein an increase in the concentration of the compound 5 -FC indicates degradation of flumetylsulforim.

[0097] The present invention provides use of the compound 5-FC for assessing the quality of a manufacturing process for flumetylsulforim.

[0098] The present invention provides use of the compound 5-FC for assessing the quality of a manufacturing process for flumetylsulforim, wherein an elevated concentration of the compound 5-FC is indicative of reduced process quality.

[0099] In some embodiments, the composition and / or method of the present invention may further comprise other solid form of flumetylsulforim as disclosed in WO2019 / 038583 and WO2022 / 234487, the content of which is hereby incorporated by reference. All publications, patents and patent applications mentioned in this specification are herein incorporated in their entirety by reference into the specification, to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated herein by reference.

[0100] The compound 5-FC and mixtures thereof with flumetylsulforim may be prepared using any process for preparing flumetylsulforim.

Claims

Claims1. A mixture comprising flumetylsulforim, wherein 0.1% or less by weight of the mixture is 5 -FC.

2. The mixture of claim 1, comprising at least one excipient.

3. A combination of (1) a mixture comprising flumetylsulforim, wherein 0.1% or less by weight of the mixture is 5-FC, and (2) one or more carriers.

4. A composition comprising (1) a mixture comprising flumetylsulforim, wherein 0.1% or less by weight of the mixture is 5-FC, and (2) at least one agriculture acceptable additive.

5. The composition of claim 4, comprising at least one additional fungicide.

6. A method for the control of fungal attack on a plant, the method comprising:(1) obtaining a mixture of flumetylsulforim as described herein, (2) formulating the mixture, (3) diluting the formulated mixture in water and (4) applying the to a locus of the fungus, to a locus in which the infestation is to be prevented, and / or to the plant, so as to thereby control fungal attack on the plant.

7. Use of 5-FC as a reference standard to test for its presence and / or quantity in a composition.

8. The use of claim 7, wherein the composition is a composition comprising flumetylsulforim.

9. Use of 5-FC as a reference standard to test for its presence and / or quantity at a locus where flumetylsulforim was applied.

10. Use of 5-FC as a reference standard to test for its presence and / or quantity in a plant to which flumetylsulforim was applied.

11. Use of 5-FC as reference standard for determining purity and optionally metabolite profile of flumetylsulforim.

12. Use of 5-FC as reference standard for determining purity of composition comprising flumetylsulforim.

14. A method of monitoring the stability of flumetylsulforim during storage, the method comprising periodically measuring the concentration of 5-FC formed in the flumetylsulforim technical or formulation, wherein an increase in the concentration of 5-FC indicates degradation of flumetylsulforim.

15. A method for assessing the quality of a manufacturing process for flumetylsulforim, the method comprises determining the concentration of 5-FC generated during said process.

16. A method for assessing the quality of the formulation process for flumetylsulforim, the method comprises determining the concentration of 5-FC generated during said process.

17. A method of monitoring the extent of degradation of flumetylsulforim during storage, the method comprising periodically measuring the concentration of 5-FC formed in the flumetylsulforim technical or formulation.

18. A method of monitoring the rate of degradation of flumetylsulforim during storage, the method comprising periodically measuring the concentration of 5-FC formed in the flumetylsulforim technical or formulation.

19. Use of 5-FC for monitoring the stability of flumetylsulforim during storage, wherein an increase in the concentration of 5-FC indicates degradation of flumetylsulforim.

20. Use of 5-FC for assessing the quality of a manufacturing process for flumetylsulforim, wherein an elevated concentration of 5-FC is indicative of reduced process quality.

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