Phosphoramidate alkylator prodrugs
Inventors
Matteucci, Mark • Duan, Jian-Xin • Jiao, Hailong
Assignees
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Publication Number
US-8664204-B2
Publication Date
2014-03-04
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 hypoxia-activated phosphoramidate alkylator prodrugs and triggerable compounds having formulas (I), (II), (III), (IV)–(XXIII), with a Trigger (T) group linked through a phosphoramidate or phosphorodiamidate scaffold. The trigger linker is described as L-Z3, where Z3 is a bioreductive group, and the compounds are designed to generate an alkylator at hypoxic sites while reducing formation of toxic byproducts such as acrolein and reduced chloroacetaldehyde.
Z3 includes nitro-containing bioreductive groups, including nitroimidazole, nitrothiophene, nitrofuran, and related nitro-containing ring structures, as well as indole quinones and glucose or glucose analog groups in the broader substituent set. The disclosure describes reduction of the bioreductive group under hypoxic tumor conditions to release the alkylator for DNA alkylation, and it states less toxicity in normoxic tissue with hypoxia cytotoxicity in hypoxic tissue.
The released alkylator includes an aziridinium or aziridine electrophile for DNA alkylation, and trigger and modified trigger variants are described to tune hypoxia activation behavior. The disclosure also describes a bystander effect in which cytotoxic alkylation extends beyond hypoxic activation zones by diffusion from hypoxic activation zones, and it includes deuterated phosphoramidate alkylators/prodrugs, including octadeuterated examples.
The document further describes phosphoramidate alkylator prodrugs and related intermediates in which a T-OH compound is reacted with a tri-substituted phosphine, a compound of the formula T, and a dialkyl azodicarboxylate to yield a compound of formula I, including pharmaceutically acceptable salts. The synthetic scheme includes formation of phosphoramidate intermediates and related intermediates, and also describes an oxime-phosphoramidate conjugate, an enzymatic hydrolysis product, and improved NMR-based in vivo detection using the deuterated phosphoramidate alkylators/prodrugs.
Claims Coverage
The provided claim content identifies one independent claim for a method of synthesizing a compound of formula I, or a pharmaceutically acceptable salt thereof. The merged claim coverage centers on four reaction components and dependent refinements that narrow X4, the tri-substituted phosphine options, the dialkyl azodicarboxylate options, and the preparation route for the formula T intermediate.
Method to synthesize formula I phosphoramidate alkylator compounds
A method comprising reacting a compound having the formula T-OH, a tri-substituted phosphine, a compound of the formula T, and a dialkyl azodicarboxylate to yield a compound of formula I, or a pharmaceutically acceptable salt thereof.
Halo identity at X4
Each X4 is halo, with dependent content specifying chloro in some items.
Defined tri-substituted phosphine selection
The tri-substituted phosphine is constrained by listed substituent classes and by named options including triphenylphosphine, tributylphosphine, tripropylphosphine, triethylphosphine, trimethylphosphine, and tributylphosphite.
Dialkyl azodicarboxylate selection
The dialkyl azodicarboxylate is diethyl azodicarboxylate or diisopropyl azodicarboxylate.
Preparation of the formula T intermediate
The compound of the formula T is prepared by reacting bromoethylammonium bromide, phosphoryl chloride, and triethyl amine.
The claim coverage centers on synthesizing formula I compounds, or pharmaceutically acceptable salts, by reacting T-OH with a tri-substituted phosphine, a formula T intermediate, and a dialkyl azodicarboxylate, with dependent limitations on X4, phosphine identity, azodicarboxylate identity, and the preparation of the formula T intermediate.
Stated Advantages
Less toxicity in normoxic tissue while targeting hypoxia.
Hypoxia cytotoxicity in hypoxic tissue is maintained.
Reduced formation of toxic byproducts, including reduced or absent acrolein and reduced chloroacetaldehyde.
Improved detection in vivo via NMR using deuterated phosphoramidate alkylators/prodrugs.
Enhanced hypoxic cytotoxicity (IC50/GI50 under hypoxia).
Markedly reduced normoxic toxicity.
Very high hypoxia cytotoxicity ratios (HCR).
Improved solubility.
Controlled activation selectivity versus normoxia.
Bystander effect supported by trigger modification and diffusion under hypoxic conditions.
Improves hypoxia selectivity and safety versus parent alkylators.
Enables bystander killing via diffusion from hypoxic activation zones.
Documented Applications
Hypoxia-targeted activation of phosphoramidate alkylator prodrugs and resulting effects in hypoxic tumor tissue, contrasted with toxicity in normoxic tissue.
In vivo detection using NMR with deuterated phosphoramidate alkylators/prodrugs.
Treating cancer using hypoxia-activated trigger phosphoramidate alkylator prodrugs, including resistant and metastatic cancer cases.
Combination therapy in the context of the hypoxia-activated anticancer prodrugs.
Pharmaceutical formulation for treating cancer with the described prodrugs.
Preparation of phosphorus-based prodrug/toxin conjugates, including compounds such as Compound 35 and downstream compounds.
Synthesis routes to compounds listed in the examples, including Compounds 7, 6, 15, 23/26/36, 1, and expanded scope compounds 37–105.
Trigger-modified intermediate activation framework to support hypoxia-associated therapeutic effects including bystander effect.
Use of hypoxia-activated phosphoramidate alkylator prodrugs for hypoxic activation with a bystander effect enabled by diffusion from hypoxic activation zones.
Cancer therapy of hypoxic tumor regions using the disclosed prodrugs.
Combination therapy with various chemotherapeutics and radiotherapy.
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