Phosphoramidate alkylator prodrugs
Inventors
Matteucci, Mark • Duan, Jian-Xin • Jiao, Hailong • Kaizerman, Jacob
Assignees
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Publication Number
US-8507464-B2
Publication Date
2013-08-13
Expiration Date
Abstract
Phosphoramidate alkylator prodrugs can be used to treat cancer when administered alone or in combination with one or more anti-neoplastic agents.
Core Innovation
The disclosure relates to phosphoramidate alkylator prodrugs defined by formula (I) in which a Trigger, T, is incorporated as R1 = L-Z3 and linked to a phosphorus-containing framework with variable heteroatoms and substituents. The compounds include broad variability for Y1, Y2, Y3, Y4, Z1, Z2, R6, R7, R8, X1, and X2, and the Trigger is selected from specified linker structures with bioreductive group Z3.
The invention includes hypoxia activated phosphoramidate alkylator prodrugs and deuterated phosphoramidate alkylator prodrugs, together with embodiments describing trigger linkage motifs, bioreductive trigger activation, and glucose/glucose analog or aromatic/heteroaromatic trigger-linked families. The disclosure also includes specific structural families, excluded phosphoramidate structures, and enumerated compounds.
The hypoxia-driven activation mechanism is described in terms of activation in hypoxic tumor zones and release of a phosphoramidate alkylator. The document also describes related nitroimidazole derivative preparation and phosphoramidate alkylator prodrug contexts, including continuation to further defined compounds and biological testing contexts.
Claims Coverage
The claim coverage centers on independent claim clm-00001, which defines compounds of formula (I) with a phosphorus-containing Trigger T having the formula L-Z3 and broad structural variability across the formula scaffold. Additional claim scope includes therapeutic use, formulation, and making the compound in the disclosed claim sets. The inventive features are captured in three merged feature groups.
Phosphoramidate alkylator prodrug compound of formula (I) with trigger L-Z3
A compound of formula (I) wherein R1 is a Trigger, T, having the formula L-Z3, with L selected from specified structural options and Z3 selected from defined bioreductive group motifs, and with broad substitution defined for Y1/Y2/Y3/Y4, Z1/Z2, R6/R7/R8, and X1/X2.
Defined substituent scope and provisos
The formula (I) scaffold includes defined selections for Y3, Y4, Z1, Z2, X1, and X2, and in some claim sets the proviso requires NR2R3 is NHR3 and NR4R5 is NHR5, with R3 and R5 independently selected from 2-haloalkyl, 2-alkylsulfonyloxyalkyl, heteroalkylsulfonyloxyalkyl, 2-arylsulfonyloxyalkyl, and 2-heteroarylsulfonyloxyalkyl, including stereoisomer and salt/solvate/hydrate options.
Therapeutic use and making the compound
Independent and dependent claim coverage includes methods for treating cancer in a patient by administering a pharmaceutical formulation, methods of treating pancreatic cancer, lung cancer, or colorectal cancer, and methods of making the claimed compound by reacting a phosphorus-containing precursor with an R1-Y2-H component.
Across the claims, the core coverage is a phosphoramidate alkylator prodrug scaffold of formula (I) with Trigger T defined as L-Z3 and broad variable substituent space, together with specific provisos on amine-related substituents in some claim sets. The claim coverage also includes explicit therapeutic use, pharmaceutical formulation, and making the compound.
Stated Advantages
More stable against oxidative metabolism, especially in liver.
Provides pharmacokinetic improvement over known prodrugs.
Hypoxic cytotoxicity is increased, with reported hypoxia IC50/GI50 values down to the 0.01 nM range.
Lower toxicity in normoxic cells relative to hypoxic cells, with reported up to about 10^3-10^6 fold reductions and higher hypoxia cytotoxicity ratios.
Selectivity improvements are stated, including reduced normoxic toxicity and improvements related to solubility and stability.
Retains cytotoxicity against hypoxic tumor tissue.
Enables more efficient detection in vivo by nuclear magnetic resonance (NMR) for pharmacokinetic/pharmacodynamic use.
Provides hypoxia-selective activation.
Is safer than conventional alkylator prodrugs by reduced or absent acrolein production and lower chloro/bromo/acetaldehyde byproduct formation.
Reduced reaction volume for diazonium ion formation compared with prior aqueous sulfuric acid diazonium formation.
Improved stirring for diazonium ion formation compared with prior aqueous sulfuric acid diazonium formation.
Documented Applications
Methods of treating cancer by administering a pharmaceutical formulation, including pancreatic cancer, lung cancer, or colorectal cancer.
Treatment of cancer and hyperproliferative disease using the hypoxia-activated phosphoramidate alkylator prodrugs.
Combination with other anti-cancer agents.
Pharmacokinetic/pharmacodynamic use enabled by in vivo nuclear magnetic resonance (NMR) detection.
Subsequent biological testing contexts for related prodrugs after formation of Compound 119.
Use of bioreductive trigger activation to form modified trigger/linker species with a bystander effect associated with diffusion into nearby tumor zones in hypoxic tumor tissue.
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