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The formation of the d-homocyclopamine ring system in IPI-926 is the key step in its semisynthesis and proceeds via a chemoselective cyclopropanation followed by a stereoselective acid-catalyzed carbocation rearrangement. In order to perform large-scale cyclopropanation reactions, we developed new iodomethylzinc bis(aryl)phosphate reagents that were found to be both effective and safe. These soluble reagents can be prepared under mild conditions and are stable during the course of the reaction. Importantly, they have favorable energetics relative to other cyclopropanating agents such as EtZnCH2I. Herein, we describe the process optimization studies that led to successful large-scale production of the d-homocyclopamine core necessary for IPI-926.

A design of experiments (DoE) approach was taken to optimize purity and reaction yield of the final debenzylation and hydrochloride salt formation of IPI-926. The study involved a careful dissection of the different process steps to enable an independent investigation of these steps while ensuring that process streams were representative. The results enabled a streamlined process from the final chemical transformation to the salting and isolation and led to the elimination of variability in the process as well as a robust control of impurities. The optimized process was applied to production and demonstrated on the kilogram scale.

IPI-504 (retaspimycin hydrochloride) is an Hsp90 inhibitor that is the subject of multiple clinical trials for the treatment of cancer. IPI-504 is an aqueous soluble (>200 mg/ml) hydroquinone hydrochloride salt of 17-(allylamino)-17-demethoxygeldanamycin (17-AAG), a quinone derivative also undergoing clinical evaluation, albeit with suboptimal formulations that address its inferior aqueous solubility (∼50 µg/ml). IPI-504 interconverts with 17-AAG in vivo through oxidation-reduction reactions that result in a dynamic redox equilibrium. The development challenges associated with redox active molecules are significant due to the pH, oxygen, and temperature sensitivities associated with such chemotypes. The API and sterile drug product manufacturing processes thus warrant the monitoring and control of these key variables. Furthermore, the pharmaceutical development challenges associated with cancer agents that are often fast-tracked due to unmet medical needs mandate a rapid development cycle with associated regulatory hurdles. Drug Dev Res 71: 429–438, 2010. © 2010 Wiley-Liss, Inc.

Recent evidence suggests that blocking aberrant hedgehog pathway signaling may be a promising therapeutic strategy for the treatment of several types of cancer. Cyclopamine, a plant Veratrum alkaloid, is a natural product antagonist of the hedgehog pathway. In a previous report, a seven-membered D-ring semisynthetic analogue of cyclopamine, IPI-269609 (2), was shown to have greater acid stability and better aqueous solubility compared to cyclopamine. Further modifications of the A-ring system generated three series of analogues with improved potency and/or solubility. Lead compounds from each series were characterized in vitro and evaluated in vivo for biological activity and pharmacokinetic properties. These studies led to the discovery of IPI-926 (compound 28), a novel semisynthetic cyclopamine analogue with substantially improved pharmaceutical properties and potency and a favorable pharmacokinetic profile relative to cyclopamine and compound 2. As a result, complete tumor regression was observed in a Hh-dependent medulloblastoma allograft model after daily oral administration of 40 mg/kg of compound 28.