Antifungal compounds
Inventors
Hoekstra, William J. • Yates, Christopher M. • Schotzinger, Robert J. • Loso, Michael R. • Gustafson, Gary D. • Sullenberger, Michael T. • Steward, Kimberly • Delgado, Javier • Wang, Xuelin
Assignees
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Publication Number
US-11051514-B2
Publication Date
2021-07-06
Expiration Date
Abstract
The present invention relates to compounds of Formula (I): wherein R1 is as defined herein, or an acceptable salt, solvate, prodrug or hydrate thereof. The compounds of Formula I are inhibitors of metalloenzymes, such as lanosterol demethylase (CYP51).
Core Innovation
The disclosed subject matter provides antifungal compounds as inhibitors of metalloenzymes, notably lanosterol demethylase (CYP51), including a Formula (I) scaffold with an R1 substituent selected from Formula (II) or Formula (III) attached via CH2, together with tautomers, isomers, acceptable salts, solvates, hydrates, and prodrugs. The compounds include fluorinated pyridine-ether benzonitrile intermediates and final triazole-thio/oxygen derivatives, with representative embodiments including Example 1 compound 1 and Example 2 compound 2.
The invention further describes compounds with improved fungicidal activity, including activity against Septoria tritici (leaf blotch of wheat), and reports physicochemical properties including water solubility and favorable Log D, determined via the CHI method. Selected compounds are compared with prior-art examples 5 and 45, and the disclosure supports the claimed scope with compound embodiments, intermediates A-D, B-D, and final compounds C and 1-2.
The disclosure includes agricultural composition concepts using excipients or carriers and application contexts such as plants, soil, foliage, and seeds, framing the compounds as useful in controlling plant fungal disease. It also describes a process that includes reacting a compound of Formula D with 1H-1,2,4-triazole to produce a compound of Formula 1.
Claims Coverage
The independent claims cover a Formula (I) compound and its agriculturally or pharmaceutically acceptable salt, solvate, or hydrate forms, an agricultural composition containing the claimed compound with excipients, and plant treatment methods for metalloenzyme-mediated disease, further restricted to plant fungal disease. An additional independent claim scope includes a defined process reacting a Formula D compound with 1H-1,2,4-triazole to produce a compound of Formula 1.
Formula (I) antifungal compound (with salt, solvate, or hydrate forms)
A compound of formula (I), or an agriculturally or pharmaceutically acceptable salt, solvate, or hydrate thereof.
Agricultural composition with excipients
An agricultural composition that includes a compound according to the Formula (I) compound definition, or an agriculturally or pharmaceutically acceptable salt, solvate, or hydrate of that compound, together with one or more agriculturally or phytologically acceptable excipients.
Plant treatment for metalloenzyme-mediated disease
A method to treat a metalloenzyme-mediated disease or disorder in a plant by applying a compound according to the Formula (I) compound definition, or an agricultural composition containing the compound.
Plant treatment for plant fungal disease
The method where the metalloenzyme-mediated disease or disorder is specifically a plant fungal disease or disorder.
Process to produce compound of Formula 1 from Formula D and 1H-1,2,4-triazole
A process that includes reacting a compound of Formula D with 1H-1,2,4-triazole using potassium carbonate in dimethylsulfoxide under inert atmosphere conditions to produce the compound of Formula 1.
Overall, the claim coverage centers on the Formula (I) metalloenzyme-inhibiting antifungal compounds, their formulation into agricultural compositions with excipients, and methods of applying them to plants to treat metalloenzyme-mediated disease, particularly plant fungal disease. A further claim scope defines a synthesis process to generate a compound of Formula 1 using a Formula D intermediate and 1H-1,2,4-triazole.
Stated Advantages
Improved fungicidal activity, including against Septoria tritici (leaf blotch of wheat).
Improved physicochemical properties including water solubility.
Favorable Log D.
Fungicidal activity is reported as % disease control against wheat leaf blotch caused by Septoria tritici (SEPTTR).
Selected compounds are reported with water solubility and LogD values (CHI method), and are presented as characterized properties versus prior-art examples.
Documented Applications
Agricultural use in compositions and applications to plants, soil, foliage, and seeds.
Use against plant fungal diseases including Septoria tritici (leaf blotch of wheat), with susceptible pathogen genera and species listed in the document such as Septoria and other enumerated genera.
Fungicidal testing against wheat leaf blotch caused by Septoria tritici (SEPTTR), including % disease control across multiple application rates.
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