TH-302 solid forms and methods related thereto
Inventors
Duan, Jian-Xin • Matteucci, Mark • Davar, Nipun • Andersen, Denise
Assignees
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Publication Number
US-10654876-B2
Publication Date
2020-05-19
Expiration Date
Abstract
The present invention provides a new method for making TH-302 and solid forms thereof. The compound in its solid form is an effective anti-cancer agent and may be used in various pharmaceutical compositions, and are particularly effective for the treatment of cancer. The invention also provides a method for preparing such compounds and forms and for treating cancer in a mammal comprising the step of administering a therapeutically effective amount of a solid form of TH-302 thereof.
Core Innovation
TH-302 is defined as a hypoxia-activated prodrug and is disclosed in terms of pharmaceutically acceptable salts and solid forms. The document also defines crystalline solid forms and polymorphs associated with TH-302.
A crystalline solid form A of TH-302 is identified and characterized using DSC, XRPD, Raman spectroscopy, and an infra-red spectrum. The document reports that the crystalline solid form A has an anhydrous stability to humidity and provides analytical characterizations including key DSC and XRPD peaks, as well as solvent systems for crystallization.
The process and solid form work are tied to manufacturing approaches for TH-302 involving intermediate and API preparation, including impurity reduction and purity improvement during intermediate and API preparation, with analytical characterization. The document further discloses treatment of cancer in mammals via administration of solid TH-302, optionally in combination with other anti-cancer agents.
Claims Coverage
The relevant portion includes one independent process claim (clm-00001). Across the dependent claims in this family, multiple inventive processing features refine the core two-step sequence for producing a compound of Formula V and include specific reagent choices and purification constraints.
Reducing a compound of Formula II in a base, acid addition to provide Formula III
Reacting a compound of Formula II with a reducing agent in a base followed by adding an acid to provide a compound of Formula III.
Phosphorus-mediated coupling using trisubstituted phosphine, oxidizing agent, and Formula IV phosphorus compound
Reacting a compound of Formula III with a trisubstituted phosphine, an oxidizing agent and a phosphorus containing compound having the formula IV to provide a compound of Formula V.
Oxidizing agent specification for the Formula III-to-Formula V step
Using diisopropyl azodicarboxylate as the oxidizing agent.
Purifying Formula V by filtering through a solid filtration aid using a selected solvent
Purifying the compound of Formula V by filtering it through a solid filtration aid using a selected solvent from a listed group.
Processing parameter ranges for the reduction step
Using a ratio of the compound of Formula II to sodium borohydride of about 1:1.1 to about 1:1.5 and a NaOH concentration of about 0.01 M to about 0.05 M.
Recrystallizing Formula V from ethyl acetate for purification
Purifying the compound of Formula V by recrystallizing it from ethyl acetate.
Water-content constraint for preparing the Formula IV phosphorus compound
Preparing the compound of formula IV by reacting POBr3 with 2-bromoethylamine (or its salt) in a solvent with water content no more than about 0.02% v/v.
The claim set centers on a two-stage process converting a Formula II compound to Formula III via reduction in a base followed by acid addition, and then converting Formula III to Formula V via reaction with a trisubstituted phosphine, an oxidizing agent, and a Formula IV phosphorus-containing compound. Dependent features specify particular reagent selections, define constrained conditions such as water content for Formula IV preparation, and refine purification and processing parameters for the Formula V product.
Stated Advantages
Impurity reduction and purity improvement during intermediate and API preparation.
Anhydrous stability to humidity for the crystalline solid form A.
Documented Applications
Treatment of cancer in mammals via administration of solid TH-302.
Administration of solid TH-302 optionally in combination with other anti-cancer agents.
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