Metalloenzyme inhibitor compounds
Inventors
Hoekstra, William J. • Schotzinger, Robert J. • Rafferty, Stephen W.
Assignees
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Publication Number
US-10526312-B2
Publication Date
2020-01-07
Expiration Date
Abstract
The instant invention describes compounds having metalloenzyme modulating activity, and methods of treating diseases, disorders or symptoms thereof mediated by such metalloenzymes.
Core Innovation
The invention provides compounds of Formula I, or salts thereof, having MBG defined as tetrazolyl. The substituent framework specifies that R1 and R2 are halo or fluoro, and that R3 is independently halo, haloalkoxy, haloalkoxyalkyl, or hydroxyl. The remaining substituents are defined by R4 as aryl, optionally substituted with 0, 1, 2 or 3 independent R3, and by R5 as H or —P(O)(OH)2, while R6 is H or halo, with n being 0, 1, 2 or 3.
Further compound definitions refine the Formula I scaffold by constraining the substituent sets to particular halogen and fluorinated groups, including embodiments where R1 and R2 are fluoro and where R3 is specifically selected from fluorinated haloalkoxy or haloalkoxyalkyl options. The document includes specific fluorinated heteroaryl-containing compounds illustrated with detailed chemical structures showing variations in substituents on the aryl and side-chain groups, within the Formula I framework.
The disclosed embodiments support coverage of the Formula I scaffold by presenting concrete examples with halogenated aryl patterns and fluorinated side-chain substituents. The disclosure also includes examples of salt or ester formation such as hydrochloride salts and aminoacetate hydrochloride, together with analytical characterization for selected chiral compounds.
Claims Coverage
Three independent claims are present. Collectively, they define Formula I compounds centered on a tetrazolyl MBG, with defined halo/fluoro substitution patterns at R1–R4, specified hydrogen or phosphonic acid status at R5, specified hydrogen or halo status at R6, and n set to 0, 1, 2, or 3, with one claim also extending to salt, solvate, hydrate, or prodrug forms and fixing n to 1.
Formula I compound with tetrazolyl MBG and halo/fluoro substitution pattern
A compound of Formula I, or salt thereof, wherein MBG is tetrazolyl; R1 is halo; R2 is halo; R3 is independently halo, haloalkoxy, haloalkoxyalkyl, or hydroxyl; R4 is aryl, optionally substituted with 0, 1, 2 or 3 independent R3; R5 is H or —P(O)(OH)2; R6 is H or halo; and n is 0, 1, 2 or 3.
Formula I compound with tetrazolyl MBG and phosphonic acid with R6 hydrogen
A compound of Formula I, or salt thereof, wherein MBG is tetrazolyl; R1 is halo; R2 is halo; R3 is independently halo, haloalkoxy, or haloalkoxyalkyl; R4 is aryl, optionally substituted with 0, 1, 2 or 3 independent R3; R5 is —P(O)(OH)2; R6 is hydrogen; and n is 0, 1, 2 or 3.
Formula I compound with fixed fluoro substitution, haloalkoxy at R3, and n equal to 1
A compound of Formula I, or salt, solvate, hydrate or prodrug thereof, wherein MBG is tetrazolyl; R1 is fluoro; R2 is fluoro; R3 is haloalkoxy or haloalkoxyalkyl; R4 is phenyl substituted with 1, 2, or 3 fluoro; R5 is hydrogen; R6 is hydrogen; and n is 1.
Across the independent claims, the inventive coverage is centered on the Formula I scaffold with MBG as tetrazolyl, combined with defined halo/fluoro patterns for R1–R4 and with either phosphonic acid (—P(O)(OH)2) at R5 or hydrogen at R5, and with R6 specified as either hydrogen or halo depending on the claim. One independent claim additionally fixes R1 and R2 to fluoro, fixes n to 1, and extends coverage to salts, solvates, hydrates, and prodrugs.
Stated Advantages
Balance potency and selectivity and reduce off-target toxicity.
Selectivity over off-target enzymes such as CYP2C9, CYP2C19, and CYP3A4 using provided activity thresholds.
Inhibition of metalloenzymes, notably lanosterol demethylase (CYP51).
Documented Applications
Treatment of disease or disorder involving metalloenzymes, including metalloenzyme-mediated disease indications.
Treatment of fungal infections, including compounds intended to inhibit lanosterol demethylase (CYP51).
A pharmaceutical composition including the compound, or its salt, solvate, hydrate, or prodrug, with a pharmaceutically acceptable carrier.
A method for inhibiting the activity of lanosterol demethylase (CYP51) metalloenzymes by contacting them with the compound or one of its salts, solvates, hydrates, or prodrugs.
The disclosed examples include metalloenzyme activity testing involving Candida albicans MIC.
The disclosed examples assess selectivity against liver cytochrome P450 enzymes using IC50 determinations for CYP3A4, CYP2C9, and CYP2C19.
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