Aminoglycosides and uses thereof
Inventors
ANDREWS, Logan • Calabrese, Andrew • Kane, Timothy Robert • Cirz, Ryan • Cohen, Frederick • Lopez, Michael • Knox, John • Evdokimov, Nikolai
Assignees
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Publication Number
US-11414450-B1
Publication Date
2022-08-16
Expiration Date
Abstract
Provided herein are aminoglycoside compounds, such as compounds of formula (I), (II), (III), (IV), (IVa), (V), (VI), (VIIa), or (VIIb) or pharmaceutically acceptable salts, solvates, stereoisomers, or tautomers of any of the foregoing, useful as therapeutic or prophylactic agents. Also provided herein are methods for their preparation. The compounds may be useful in treating a bacterial infection in a subject, for example a Gram-negative bacterial infection.
Core Innovation
The invention relates to compounds of formula (IV) and pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer forms, as valence and stability permit. The compounds are defined by extensive substituent-variable rules for R1 through R8 and additional variables including Q1, n, and R35 through R52, with R1 as —OR9 or —NR10R11 and R9, R10, and R11 independently H or C1-C6 alkyl optionally substituted with one or more —OH. The structure further includes constraints on R2 and R3, additional substituent groups such as R4, R5, R6, R5a, and R6a, and multiple conditional constraints tying substituent presence or absence to other variable choices.
A central structural theme is the conditional formation of ring systems from substituent pairing. The rules state that R1 and R2, together with the atom to which they are attached, form a heterocycloalkyl group comprising at least one heteroatom selected from N and O, and that R2 and R3 together with the attached atom form a cycloalkyl group or a heterocycloalkyl group. The disclosed structures also permit oxo-group formation from paired substituents, and include provisos that restrict when specific OR substitutions may be present under defined R2 and R3 conditions.
The disclosure further describes embodiment-specific compound selections and ring assignments shown in formula variants and illustrated structures. The partial content includes Ring A, Ring B, Ring C, and Ring D depictions in some embodiments, together with selected compound examples, stereochemical designations, and structural variants such as formula (IV-X) and formula (IVa-X). These embodiments ground the variable-substituent framework in specific illustrated members of the compound set.
Claims Coverage
Two independent claims are identified, directed to compounds of formula (IV) with extensive substituent-definition rules and conditional provisos. The independent claims collectively define multiple inventive features within the formula-level scope, including variable R1 substitution, ring formation from substituent pairs, constrained substitution at R4 through R8, and provisos tied to whether R2 and R3 are both H.
Formula (IV) compound with defined R1 substituent options
A compound of formula (IV) (or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof) wherein, as valence and stability permit, R1 is —OR9 or —NR10R11, and R9, R10, and R11 are independently H or C1-C6 alkyl optionally substituted with one or more —OH.
Substituted R2 and R3 framework with ring formation options
R2 and R3 are independently H, alkyl, cycloalkyl, or aryl, where the alkyl, cycloalkyl, or aryl is unsubstituted or substituted with groups including halogen, cyano, —SR, —SO2R, —OSF2NRR, NRR, and —OR. R1 and R2 can form a heterocycloalkyl group comprising at least one heteroatom selected from N and O, and R2 and R3 can form a cycloalkyl group or a heterocycloalkyl group.
R4 through R8 substitution rules and oxo-group formation
R4 is H or absent; R5 and R6 are independently H, —OR27, —NR28R29, halogen, or alkyl with defined optional substituents; R5a and R6a are independently absent or H, —OR53, —NR54R55, halogen, or alkyl with analogous restrictions; and R5 and R5a can form an oxo group or R6 and R6a can form an oxo group, subject to provisos that restrict corresponding OR substitutions.
Conditional provisos when R2 and R3 are both H
If R2 and R3 are both H, then at least one of R41, R42, R43, R44, or R44a is not H; and if R2 and R3 are both H and one of R44 or R44a is —OH, then at least one of R41, R42, or R43 is not H.
Formula variant and Ring A selection
Dependent refinements specify formula variants such as formula (IV-X) or formula (IVa-X), and select Ring A from illustrated alternative ring structures, thereby narrowing the structural scope within the formula (IV) framework.
Across the independent claims, the inventive coverage centers on formula (IV) compounds defined by extensive substituent-variable rules, optional heterocycloalkyl and cycloalkyl ring formation, oxo-group pairing options for substituted positions, and conditional provisos that constrain substitution patterns when R2 and R3 are both H. Dependent refinements further narrow the structure through formula-variant selection and Ring A choices.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Treating bacterial infection in a subject using a pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier, including Gram-negative bacterial infection.
Use in manufacture of medicament for treating bacterial infection.
Methods of treating bacterial infection, including Gram-positive and Gram-negative bacteria and susceptible organisms listed in the disclosure.
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