Pegylated carfilzomib compounds

#The present invention relates to pegylated carfilzomib compounds, pharmaceutical compositions comprising the compounds, and methods and uses thereof for treating cancer, including hematologic malignancies such as multiple myeloma, and solid tumors.

#Cancer is one of the most widespread diseases and a leading cause of death worldwide. In the United States alone, cancer is the second leading cause of death, surpassed only by heart disease. Cancer is often characterized by deregulation of normal cellular processes or unregulated cell proliferation.

#Multiple myeloma (MM) is a progressive and malignant neoplastic type of cancer originating from plasma cells. It is characterized by abnormal accumulation of malignant plasma cells within bone marrow, and it accounts for approximately 13% of all hematologic cancers (Palumbo and Anderson, 2011). In 2015, about 26,850 new cases were expected to be diagnosed with MM, and about 11,240 people were expected to die from the disease in the United States (ACS, 2015). The incidence of MM has increased steadily due to increased life expectancy of the general population in the United States (Warren et al., 2013). The disease most commonly affects the elderly population, with the median age of incidence around 69 years old (Howlander et al., 2013; ACS, 2015).

#FIG. 1 is a graph of curves generated by rates of conversion of several exemplified pegylated compounds of carfilzomib to free carfilzomib in human plasma (representative of human pK);

#FIG. 2 is a graph reflecting the pK of representative pegylated compounds of carfilzomib in rat plasma;

#FIG. 3 is a graphic illustration of the effects of carfilzomib and compound Example 1 on chymotrypsin-like proteasome activity in the blood, adrenal gland, heart and liver tissues;

#The present invention provides novel pegylated carfilzomib compounds, pharmaceutical compositions comprising the compounds, methods of making the compounds, and uses of the compounds and compositions including the compounds for the treatment of cancer, including treatment of hematologic malignancies such as multiple myeloma, lymphoma, leukemia, and treatment of other cancers such as solid tumors. Specifically, the polymeric units of polyethylene glycol (PEG) linked carfilzomib possess various pharmacokinetic (pK) and/or pharmacodynamics (PD) properties comparable to or improved over that of the currently approved IV administered Kyprolis® (carfilzomib).

#Carfilzomib is an epoxy ketone protease inhibitor described in U.S. Pat. Nos. 7,417,042 and 7,737,112, among others. The pegylated carfilzomib compounds described in the present invention (i) generally confer enhanced solubility, permeability, pK and/or PD properties relative to free drug carfilzomib not containing such PEG moieties; and (ii) can be cleaved in vivo thereby releasing the freely active drug carfilzomib. In the embodiments presented by the invention, the N-terminal “cap” of the carflizomib (e.g., the morpholino cap) is converted to a quaternary salt (e.g., by the addition of a N-acyloxyphenylmethyl group). In some embodiments, the quaternary salt contains a PEG moiety. In some embodiments, the pegylated compounds are cleavable by pH change and/or enzymes such as, but not limited to, esterases, cytochrome P450, phosphodiesterase, phosphoamidase, phosphatase, and DT-diaphorase, or any combination thereof. In some embodiments, the PEG is a linear PEG. In some embodiments, the PEG is a bifunctional PEG that can conjugate 1-2 compounds per PEG In some embodiments, the PEG is a four-arm PEG that can conjugate 1-4 compounds per PEG. In some embodiments, the PEG is an eight-arm PEG with a hexaglycerin core that can conjugate 1-8 compounds per PEG. In some embodiments, the PEG is an eight-arm PEG with a tripentaerythritol core that can conjugate 1-8 compounds per PEG. In some embodiments, the PEG is a branched two-arm PEG. In some embodiments, the PEG is a branched four-arm PEG. In addition, the compounds can further include solubilizers, permeability enhancers, masking agents, macromolecular carriers, targeting moieties, and biologics to improve half-life and disease specificity that are attached directly to the compound or indirectly attached via a spacer moiety.

#The terms “aspect” and embodiment” are used interchangeably herein.