Antifungal agents
Inventors
Greenlee, Mark L. • Wilkening, Robert • Apgar, James • Sperbeck, Donald • Wildonger, Kenneth J. • Meng, DongFang • Parker, JR., Dann L. • Mamai, Ahmed
Assignees
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Publication Number
US-8722727-B2
Publication Date
2014-05-13
Expiration Date
Abstract
Novel derivatives of enfumafungin are disclosed herein, along with' their pharmaceutically acceptable salts, hydrates and prodrugs. Also disclosed are compositions comprising such compounds, methods of preparing such compounds and method of using such compounds as antifungal agents and/or inhibitors of (1,3)-β-D-glucan synthase. The disclosed compounds, their pharmaceutically acceptable salts, hydrates and prodrugs, as well as compositions comprising such compounds, salts, hydrates and prodrugs, are useful for treating and/or preventing fungal infections and associated diseases and conditions.
Core Innovation
The invention concerns compounds of Formula (I), or pharmaceutically acceptable salts thereof, with substituent variables R1 and R2 defined through detailed structural and functional-group selections. The variables W, X′, Y, and Z in the R1-containing structure are independently selected from N and CR^3, with only one of W, X′, Y and Z being CR^3, and the scope is further constrained by the allowed definitions of Rf and Rg, including options that may be optionally taken together with the attached nitrogen atom to form defined ring systems.
The definition of R2 is provided as a multi-parameter substituent framework, including integer selections m, n, and p, together with choices for T and the allowed forms of R5, R6, and R7. The patent specifies optional ring formation between R6 and R7, between R6 and R5, and between R8 and R9, with 4- to 7-membered or 3- to 7-membered saturated, unsaturated, or aromatic rings and 0 or 1 additional heteroatoms selected from N, O, and S.
The core structural concept is therefore a constrained chemical space: Formula (I) compounds whose substituent groups and heteroatom-bearing ring options are limited to specific families of amide, carbonyl, oxy, thio, sulfonyl, cyano, and aryl/heteroaryl/heterocyclyl substituents as defined for Re, Rf, Rg, R8, R9, and R10. The partial content additionally indicates tetrazole-containing derivatives of a tetrazole-containing phenanthro[1,2-c]pyran-7-carboxylic acid scaffold, with characterization data including LC/MS and 1H NMR identifiers.
Claims Coverage
Across the provided material, claim coverage is anchored in the independent claim for a compound of Formula (I) or a pharmaceutically acceptable salt thereof. The main inventive features are the constrained Formula (I) scaffold, the enumerated and ring-forming architecture of R2, the terminal functional-group definition of R3 through R14/R15 choices, and the explicit identity restrictions for X and the substituent group R0.
Formula (I) compound with constrained scaffold substituents
A compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R1 is defined by specified structural options including W, X′, Y and Z selected from N and CR^3, with only one of W, X′, Y and Z being CR^3, and wherein Rf and Rg are defined by the listed categories.
Defined R2 ring and functional-group architecture
A compound of Formula (I) wherein R2 is a group defined with m, n and p each independently selected from 0 or 1, T selected as NR6R7 or OR10, and with R5, R6, R7, R8 and R9 constrained to the enumerated group sets, including optional ring formation between R6 and R7, between R6 and R5, and between R8 and R9 under specified heteroatom-count and substitution constraints.
Defined R3 terminal functional group selection
A compound of Formula (I) wherein R3 is C(O)R14, and R14 is selected from OH, OR15, or N(R0)2, with R15 selected as C1-C6 alkyl optionally substituted with phenyl-bearing OR0 groups as specified.
Substituent identity restrictions for R0 and X
A compound of Formula (I) wherein X is selected from O or H, and each R0 is independently selected from H, C1-C6 alkyl, C3-C6 cycloalkyl or benzyl, thereby constraining the allowed substituent identity set used throughout the Formula (I) definitions.
Coverage centers on Formula (I) compounds with tightly constrained substituent definitions for R1 and R2, including optional ring formation rules and explicit limits on which atoms and substituent classes can be present within the defined ring systems. The claim set also narrows the scaffold through the R3 functional-group definition and the explicit identity restrictions for X and R0.
Stated Advantages
The compounds inhibit fungal (1,3)-β-D-glucan synthase.
The compounds are evaluated for antifungal activity in relation to (1,3)-β-D-glucan synthase inhibitory activity.
Reported IC50 values and susceptibility testing outcomes are described.
Used for treatment or prevention of a wide range of mycotic infections, including systemic and superficial infections.
In vivo anti-Candida results are measured as kidney CFU outcomes.
Documented Applications
Treatment of fungal infections in a patient by administering an effective amount of the compound or a pharmaceutically acceptable salt thereof.
Treatment or prevention of mycotic infections, including systemic and superficial infections caused by fungal pathogens.
In vivo anti-Candida evaluation.
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