Broad-spectrum carbapenems
Inventors
Burns, Christopher J. • Chu, Guo-Hua • HAMRICK, Jodie • Boyd, Steven A. • Condon, Stephen M.
Assignees
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Publication Number
US-12084445-B2
Publication Date
2024-09-10
Expiration Date
Abstract
The present disclosure provides broad-spectrum carbapenem derivatives and pharmaceutical compositions useful in the treatment of bacterial infections and methods for treating such infections using such derivatives and/or compositions.
Core Innovation
The disclosed subject matter provides representative chemical structures of disclosed compounds, including permitted forms defined by geometric isomers and chiral centers in R/S configurations. The disclosure further includes enantiomers, diastereomers, epimers, mixtures thereof, isotopically labeled compounds, and compounds labeled by fluorophore and/or chromophore moieties, together with pharmaceutically acceptable salt, solvate, stereoisomer, hydrate, alcoholate, and tautomer forms.
The compounds are described in a pharmaceutical-composition and combination-therapy context for treating bacterial infections. In that context, the disclosed compounds are used with antibiotics, including beta-lactam antibiotics and beta-lactamase inhibitors, and the disclosure also states that the compounds inhibit growth of beta-lactam-resistant bacteria.
The disclosure further includes compounds of Formula (IVa-1), Formula (IIa-1), and Formula (IIIa-1), and a selected group of compounds, with Ring A fixed as cyclohexyl and substituent patterns constrained through R5, R6, L, R60, R61, R62, R63, and discrete indices including v6, w6, n, m, p, q, and z. The provided content also references pharmaceutical compositions with excipients and synthetic and analytical context through examples, schemes, and ESI-MS characterization.
The invention also relates to broad-spectrum carbapenem derivatives and carbapenem compounds of Formula (I), together with related embodiments including Formula (Ia), Formula (Ia-1), and Formula (II)/(III), and definitions for substituent and variable groups such as L, Y, and X. The disclosed compounds are provided as carbapenem compounds including pharmaceutically acceptable salts, solvates, and stereoisomers, in a therapeutic administration context with or without a beta-lactamase inhibitor for bacterial infections.
Claims Coverage
The consolidated content includes independent claims directed to four compound/formulation claim sets: Formula (IVa-1), Formula (IIa-1), Formula (IIIa-1), and a selected group of compounds, with one additional pharmaceutical composition claim element. Across these claims, coverage centers on cyclohexyl Ring A, tightly constrained substituent patterns, and discrete variable ranges for v6, w6, n, m, p, q, and z. The carbapenem content does not provide explicit claims coverage in the input.
Cyclohexyl ring A and Formula (IVa-1) substituent constraints
A compound of Formula (IVa-1), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is cyclohexyl; R5 is hydrogen; each R6 is independently selected from the listed amine/heteroatom-containing forms; each R60 and R61 is independently selected from hydrogen and C1-C6 alkyl; each R62 and R63 is independently selected from hydrogen, halogen, and C1-C6 alkyl; v6 is 1 or 2; w6 is 2; n is 0 or 1; m is 0 or 1; p is 1; and q is 1 or 2.
Cyclohexyl ring A and Formula (IIa-1) substituent constraints
A compound of Formula (IIa-1), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is cyclohexyl; L is —(CR8R9)z—; each R8 and R9 is independently hydrogen or C1-C6 alkyl; R5 is hydrogen; each R6 is independently selected from the listed amine/heteroatom-containing forms; each R60 and R61 is independently selected from hydrogen and C1-C6 alkyl; each R62 and R63 is independently selected from hydrogen, halogen, and C1-C6 alkyl; v6 is 1 or 2; w6 is 2; n is 1; m is 0 or 1; p is 1; q is 1 or 2; and z is 1 or 2.
Cyclohexyl ring A and Formula (IIIa-1) substituent constraints
A compound of Formula (IIIa-1), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is cyclohexyl; L is —(CR8R9)z—; each R8 and R9 is independently hydrogen or C1-C6 alkyl; R5 is hydrogen; each R6 is independently selected from the listed amine/heteroatom-containing forms; each R60 and R61 is independently selected from hydrogen and C1-C6 alkyl; each R62 and R63 is independently selected from hydrogen, halogen, and C1-C6 alkyl; v6 is 1 or 2; w6 is 2; n is 0 or 1; m is 0 or 1; p is 1; q is 1 or 2; and z is 1 or 2.
Selected group of compounds
A compound selected from the group consisting of the listed compounds, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
Pharmaceutical composition including the claimed compound and a pharmaceutically acceptable excipient
A pharmaceutical composition including the compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, together with a pharmaceutically acceptable excipient.
Across the independent claims, coverage is directed to cyclohexyl-containing compounds defined by formulas (IVa-1), (IIa-1), and (IIIa-1), together with a selected group of compounds, all with constrained substituent forms and discrete parameter values. The claim set also includes a pharmaceutical composition variant including a pharmaceutically acceptable excipient.
Stated Advantages
The compounds inhibit growth of beta-lactam-resistant bacteria.
The compounds are used in combination therapy with beta-lactams and beta-lactamase inhibitors.
Broad-spectrum activity against Gram-positive bacteria and Gram-negative bacteria.
Activity against multi drug resistant (MDR) organisms.
Coverage against carbapenem-resistant Enterobacteriaceae (CRE).
Addresses beta-lactamase-driven resistance, including Ambler class A/D carbapenemases and Ambler class B metallo-carbapenemases.
Includes treatment of bacterial infection by administering effective amounts of the carbapenem compounds, including in combination with a beta-lactamase inhibitor.
Documented Applications
Combination treatment for bacterial infections using antibiotics, including beta-lactam antibiotics and beta-lactamase inhibitors.
Pharmaceutical compositions for administration via oral, parenteral, intranasal, topical, and other routes.
Therapeutic use of isotopically labeled compounds.
Tissue distribution assays using isotopically labeled compounds.
In vitro antibacterial activity measured by broth microdilution MIC assays across specified bacterial strains.
Treating bacterial infections by administering carbapenem compounds, including for infections involving Gram-positive bacteria, Gram-negative bacteria, MDR organisms, and CRE.
Use of carbapenem compounds in pharmaceutical compositions for treating bacterial infection with or without a beta-lactamase inhibitor.
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