Cyclic depsipeptide compounds and their uses
Inventors
Fliri, Hans Georg • Ford, Rhonan Lee • Vong, Antonio Kuok Keong
Assignees
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Publication Number
US-9895412-B2
Publication Date
2018-02-20
Expiration Date
Abstract
The present invention relates to novel cycloundecadepsipeptide compounds and their analogues which bind and inhibit cyclophilins, have reduced immunosuppressive activity and improved physicochemical properties including water solubility. The present invention further relates to pharmaceutical compositions containing said depsipeptide compounds and their analogues for use in the treatment or prevention of diseases and pathologies which may be ameliorated by the inhibition of cyclophilin activity.
Core Innovation
The invention relates to cyclopeptide compounds of formula 1, including cycloundecadepsipeptide compounds and related cyclo-peptide embodiments provided as pharmaceutically acceptable salts, tautomers, or N-oxides. The compounds are defined by structural variables including L, Q, R1, R2, R3, R4, R5, R6, X, Ra, and Rb, with optional ring formation containing one or more nitrogen atoms and optionally substituted, optionally partially unsaturated chains linked in the overall formula 1 framework.
The disclosure describes cyclophilins, including cyclophilin-A and cyclophilin-D, as secreted peptidyl-prolyl cis/trans isomerases that act as extracellular receptors, including via the CD147 receptor. Cyclophilin-D is associated with mitochondrial permeability transition pore (MPTP), and cyclophilin/cyclophilin-D mediated cell death is discussed in the context of inflammatory disease mechanisms, including those involving cyclophilin/cyclosporin A/calcineurin ternary complexes.
Specific cyclopeptide variants are disclosed, including cyclo-[(3R,4R,5S)-1-benzocarbamoyl-3-methyl-5-methylamino-4-hydroxy-pentanoic acid-Thr-Sar-MeLeu-Leu-MeLeu-Ala-D-Hiv-MeLeu-Leu-MeVal] and cyclo-[(3R,4R,5S)-4-hydroxy-1-isopropylamino-3-methyl-5-methylamino-hexanoic acid-Thr-Sar-MeLeu-Leu-MeLeu-Ala-D-Hiv-MeLeu-Leu-MeVal], together with related cyclo-peptide variants. Exemplified substituent patterns include pyridinyl-linked groups, morpholine-linked groups, bicyclic aza-oxa substituents, thiomorpholine 1,1-dioxide substituents, difluoro-piperidine, fluoro-piperidine, oxa-aza bicyclic motifs, piperidin-4-yl methanol, pyrrolidinyl methanol, methylamino-propionitrile, and methyl-pyridinyl-amine substituents.
Claims Coverage
The consolidated claim coverage centers on a method of treating chronic and acute inflammatory disorders by administering an effective amount of a compound of formula 1, or a pharmaceutically acceptable salt, tautomer, or N-oxide thereof. Five inventive features are supported across the inputs: treatment with formula 1 compounds, linker moieties L and Q, broad substituent definitions for R1 and R2, additional substituent scope for X, Ra, and Rb, and selection of specific cyclo-peptide compounds from the provided chemical structures.
Treating chronic and acute inflammatory disorders with formula 1 compounds
A method of treating a disorder selected from chronic and acute inflammatory disorders by administering an effective amount of a compound of formula 1 to a subject in need thereof, or a pharmaceutically acceptable salt, tautomer, or N-oxide thereof.
Linker moieties L and Q enabling ring formation
L represents a bond or an optionally substituted, optionally partially unsaturated chain of 1-6 carbon atoms with optional additional heteroatoms, and Q represents a primary, secondary or tertiary covalent bond or a carbonyl group, with optional linking to R1 and optional ring formation containing one or more nitrogen atoms.
Substituent definitions for R1 and R2 with optional ring fusion
R1 and R2 may be absent or independently represent hydrogen, alkyl, substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or named carbonyl-, oxygen-, or nitrogen-containing substituent patterns, and may together with the nitrogen atom form a 4-7 membered aryl, cycloalkyl, or heterocyclic ring that may be further fused or optionally substituted.
Extended substitution framework for X, Ra, and Rb
X is H, OH, OC(=O)-alkyl, OC(=O)-substituted alkyl, O-alkyl, O-substituted alkyl, carbonyl, or imine where Y is —OR4 or —NR4R5; Ra is hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkylthio, substituted alkylthio, or optionally substituted alkylene; and Rb is hydrogen or is absent.
Selection of specific cyclo-peptide compounds from provided chemical structures
The method further includes selection of specific enumerated cyclo-peptide variants defined by the provided chemical structures.
Overall, the claims cover administering formula 1 cyclo-peptide compounds, or their salts, tautomers, or N-oxides, for treating chronic and acute inflammatory disorders, with scope defined by linker and ring-forming variables, broad substituent options, and selection of specific cyclo-peptide variants.
Stated Advantages
Reduced immunosuppressive activity.
Improved water solubility.
Documented Applications
Treating chronic and acute inflammatory disorders by administering the disclosed compounds to a subject in need thereof.
Treatment or prevention of diseases or pathologies ameliorated by cyclophilin inhibition, including chronic and acute inflammatory disorders.
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