Substituted phenazines and methods of treating cancer and bacterial diseases
Inventors
Rongved, Pål • ÅSTRAND, Ove Alexander Høgmoen • VIKTORSSON, Elvar Ørn • SAMUELSON, Ørjan • Heikal, Adam • LØCHEN ØKSTAD, Ole Andreas • KILDAHL-ANDERSEN, Geir
Assignees
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Publication Number
US-11046678-B2
Publication Date
2021-06-29
Expiration Date
Abstract
Compounds of formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, pharmaceutical compositions comprising the compounds, and methods of treatment using the compounds.
Core Innovation
The disclosure relates to substituted phenazines and phenazine 5,10-dioxide derivatives, including phenazine-related compounds, iodinin-analog structures, myxin, and substituted analogs of 1-hydroxyphenazine 5,10-dioxide. The compounds are defined by formulae (IIIa), (IIIb), (IV), and related embodiments, with substituent options for R7, R8, R, R′, R3, R11, and R12, and may include pharmaceutically acceptable salts.
The subject matter further includes phenazine/quinoxaline building blocks and extended formulae, together with optional formation of substituted 5- or 6-membered heterocyclyl groups containing ring heteroatoms or heteroatomic groups selected from N, NH, O, and S. The document also describes N-oxide-containing aromatic or azaaromatic compounds and N-oxide-functionalized heterocycles bearing a hydrolytically and/or enzymatically cleavable Z group, with optional targeting groups.
The disclosed compounds are evaluated in AML cell lines, in membrane permeability assessment using PAMPA with LogPeff categorization, and in antibacterial activity evaluation in a microbroth dilution assay context. The document also states anti-neoplastic and anti-infective applications, including treatment-related use claims directed to neoplastic disease, acute myeloid leukemia, and bacterial or fungal infection.
Claims Coverage
The claims coverage centers on structurally defined compound families of formula (IIIa)/(IIIb) and formula (IV), together with related formula-based embodiments including IV′/IV and V/Va/Vb, each with extensive substituent-defined scope and pharmaceutically acceptable salts. Dependent claims further add pharmaceutical composition, combination-product, targeting-vector, and method-of-use contexts.
Compound of formula (IIIa) or formula (IIIb)
A compound of formula (IIIa) or formula (IIIb), or a pharmaceutically acceptable salt thereof, wherein R7 and R8 are selected from H, halogen, lower alkyl, B(OH)2, C(O)OH, P(O)(OH)2, S(O)2OH, or aryl; R′ is selected from H, C1-6 alkyl, (CH2)nC(O)OR3, C(O)C1-6 alkyl, C(O)NR11R12, or C(O)OR3; R is selected from C(O)NR11R12 or C(O)OR3; R3 is H or C1-6 alkyl; R11 is H, lower alkyl, or aryl; R12 is H, lower alkyl, or aryl; or R11 and R12 together with the nitrogen atom form a 5- or 6-membered heterocyclyl comprising ring heteroatoms or heteroatomic groups independently selected from N, NH, O, and S, optionally substituted with lower alkyl and aryl; and n is 1, 2, or 3.
Compound of formula (IV)
A compound of formula (IV), or a pharmaceutically acceptable salt thereof, wherein R7 and R8 are selected from H, halogen, lower alkyl, B(OH)2, C(O)OH, P(O)(OH)2, S(O)2OH, or aryl; R is selected from C(O)NR11R12 or C(O)OR3; R3 is H or C1-6 alkyl; R11 is H, lower alkyl, or aryl; and R12 is H, lower alkyl, or aryl; or R11 and R12 together with the nitrogen atom form a 5- or 6-membered heterocyclyl comprising ring heteroatoms or heteroatomic groups independently selected from N, NH, O, and S, optionally substituted with lower alkyl and aryl.
N-oxide-containing aromatic/azaaromatic quaternary ammonium compounds
Compounds defined by general formulae including IV′, IV, Va, and Vb, with substituent-defined aromatic/azaaromatic quaternary ammonium scope, including lower alkyl, aryl, and heteroatom-containing groups such as B(OH)2, C(O)OH, P(O)(OH)2, and S(O)2OH, and pharmaceutically acceptable salts such as HCl, sulphuric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, maleic acid, ascorbic acid, and other salt-forming agents.
N-oxide-functionalized heterocycle with cleavable Z group
N-oxide-functionalized heterocycles bearing a hydrolytically and/or enzymatically cleavable Z group, with X being N-oxide (N+-O−) or CH, and with optional targeting groups and variable ring substituents defined in the disclosed formulae.
Pharmaceutical composition with pharmaceutically acceptable carrier, excipient, or antioxidant
A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt together with at least one pharmaceutically acceptable carrier, excipient, or antioxidant, or combinations thereof.
Combination pharmaceutical product with specified antibiotic classes
A combination pharmaceutical product comprising the compound or pharmaceutically acceptable salt together with at least one additional active agent selected from specified antibiotic classes including penicillin, carbapenem, cephalosporin, fluoroquinolone, polymyxin, macrolide, sulphonamide, aminoglycoside, tetracycline, and oxazolidinone.
Cancer treatment for selected named cancer types
A method of treating cancer selected from a specified group of named cancer types including acute lymphocytic leukemia, acute myeloid leukemia, adrenal cancer, bile duct cancer, bladder cancer, bone cancer, breast cancer, central nervous system tumor, cervical cancer, chronic lymphocytic leukemia, chronic myeloid leukemia, colon cancer, endometrial cancer, esophagus cancer, gallbladder cancer, gastrointestinal tumor, glioblastoma, Hodgkin's disease, hypopharyngeal cancer, Kaposi sarcoma, kidney cancer, laryngeal cancer, liver cancer, lung cancer, lymphoma, malignant mesothelioma, melanoma, multiple myeloma, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, osteosarcoma, ovarian cancer, pancreatic cancer, pituitary tumor, prostate cancer, rectum cancer, retinoblastoma, small intestine cancer, stomach cancer, testicular cancer, thymus cancer, thyroid cancer, and uterine sarcoma.
Treating infections caused by selected pathogens
A method for treating a bacterial or fungal infection caused by a selected pathogen chosen from an explicit list of bacteria and fungi including Acetobacter aurantius, Acinetobacter bitumen, Actinomyces israelii, Agrobacterium radiobacter, Agrobacterium tumefaciens, Anaplasma phagocytophilum, Azorhizobium caulinodans, Azotobacter vinelandii, Bacillus anthracis, Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Streptococcus pneumoniae, and Mycobacterium tuberculosis, among others enumerated in the list.
Overall, the claim coverage is directed to formula-defined substituted compound families with specific R7/R8, R/R′/R3, and R11/R12 limitations, optional 5- or 6-membered heterocyclyl formation, and pharmaceutically acceptable salts. The coverage also extends to composition, combination-product, targeting-vector, and method-of-use contexts tied to the named indications and agents.
Stated Advantages
Improved solubility for desired use conditions as compared to prior phenazine derivatives described as having low aqueous solubility for intravenous use.
Improved membrane penetration as stated in the invention overview.
Controlled regeneration of functional groups via hydrolytically and/or enzymatically cleavable Z group.
Anti-neoplastic activity, including treatment of acute myeloid leukemia (AML).
Anti-infective activity against a broad set of bacterial and fungal pathogens.
Combination therapy with conventional antibiotics.
Documented Applications
Biological evaluation of iodinin analogs in AML cell lines (MOLM-13 and IPC-81) using WST-1/IC50 values.
Membrane permeability assessment of iodinin analogs using PAMPA with LogPeff categorization.
Antibacterial activity evaluation in a microbroth dilution assay context, with MIC values reported for multiple named bacteria.
Therapeutic and diagnostic use claims directed to anti-neoplastic and anti-infective applications.
Use in combination with conventional antibiotics, including β-lactams, carbapenems, cephalosporins, and fluoroquinolones.
Attachment to targeting vectors, including monoclonal antibodies and related AML targets.
Pharmaceutical compositions comprising the claimed compound and a pharmaceutically acceptable carrier, excipient, and/or antioxidant.
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