IMIDAZOLE HETEROCYCLE BASED COMPOUNDS AND METHODS OF TREATING CANCER

The patent relates to imidazole heterocycle-based compounds, a pharmaceutical composition containing the compounds, and a method for treating cancer
with the compounds.

Colorectal cancer (CRC) is the third most common cancer and the second leading cause of mortality. Prognostic biomarkers help in determining the benefits of adjuvant chemotherapy. Despite the increasingly detailed molecular mapping of CRC, only a few markers have shown promise in clinical practice in terms of their ability to predict the disease course, such as amplification of oncogenes, including epidermal growth factor receptor (EGFR), ERBB2, CCND1, MET, and MYC, mutations within KRAS, BRAF proto-oncogenes and deletions of tumor suppressors, including, tumor protein 53 (TP53) and SMAD4.

5-Fluorouracil (5-FU) is one of the most widely used antimetabolite drugs for the first-line therapy of CRC. The standard treatment for locally advanced CRC cancer is surgical resection followed by adjuvant treatment with 5-FU and leucovorin. 5-FU is a pyrimidine analog and inhibitor of thymidylate synthase, which inhibits DNA synthesis and causes cell death. Several studies have shown chemoresistance to 5-FU for CRC patients with loss of SMAD4 expression. In addition, molecular-targeted drugs, including EGFR antagonists and angiogenesis inhibitors, have been introduced for the management of metastatic CRC. For example, cetuximab, a monoclonal antibody against the extracellular binding domain of EGFR, the first-line treatment with cetuximab plus FOLFIRI reduced the risk of progression of metastatic CRC when compared with FOLFIRI alone; however, the benefit of cetuximab was limited in patients with KRAS wild-type tumors. The addition of cetuximab to FOLFIRI has been shown to increase the median progression-free survival of patients with previously untreated RAS wild-type metastatic disease by approximately three months. However, most patients either have a poor initial response to treatment or develop secondary resistance to standard therapies. Therefore, there exists a need to identify new therapeutic compounds with anti-cancer activities.

Acute myeloid leukemia (AML) is a cancer of the blood forming myeloid cells. It is an aggressive cancer which requires appropriate diagnosis and immediate intervention. Conventional chemotherapy, allogeneic stem cell transplantation, and in some cases targeted therapies are the current standard of care for AML. A major concern in AML therapy is the poor outcome of the disease. More than 60% of AML patients treated with standard chemotherapy across all age groups eventually relapse. The 5-year survival rates following standard intensive chemotherapy is 30-35% in patients up to the age of 60 years, however, in patients over 60 years the 5-year survival rates are <10-15%. Treatment related mortality and multidrug resistance are believed to be the main reasons for the failure of current AML treatments. Using a combination of drugs that simultaneously inhibits multiple oncogenic targets is an alternative strategy for targeting AML. However, combination therapies are often hindered by complex drug-drug interactions and unclear pharmacokinetic profiles. In contrast, single agents that target multiple members of the oncogenic signaling pathway are expected to overcome the drawbacks associated with use of single-target inhibitors and drug combinations.

In a previous study, compound KIM-161, possessing a 5-arylidene-1,4-dihydro-4H-imidazol-5-one scaffold, was discovered as an inhibitor of proliferation of a variety of cancer cell lines (Khayat, M. T.; Omar, A. M.; Ahmed, F.; Khan, M. I.; Ibrahim, S. M.; Muhammad, Y. A.; Malebari, A. M.; Neamatallah, T.; El-Araby, M. E. Insights on Cancer Cell Inhibition, Subcellular Activities, and Kinase Profile of Phenylacetamides Pending 1H-Imidazol-5-One Variants. Front. Pharmacol. 2022, 12, referred to throughout as Khayat, et. al., and is incorporated herein by reference in its entirety). KIM-161 (depicted in FIG. 1) had good cytotoxic activity against solid tumor cells: PC3 prostate cancer (IC50 2.135 μM), MCF7 breast cancer (IC50 1.141 μM), and HCT116 CRC cells (IC50 0.294 μM). The compound's antiproliferative effect on NB4, HL60, and KG1a leukemia cell lines was higher with IC50 values of 0.275-0.893 μM. Furthermore, a concentration of 1 μM of KIM-161 caused cell cycle arrest at pre-G and G2/M phases of cell cycle, and it promoted apoptosis through activation of caspase-3. According to the in silico physicochemical profiling, KIM-161 demonstrated acceptable properties such as maximum aqueous solubility (19.9 μM), microsomal stability, as well as plasma stability. Additionally, the compound was not a substrate for the major CYP450 metabolizing enzymes (3A4, 2D6, and 2C9). Nonetheless, the presence of 4-methoxyphenyl as the 5-arylidene moiety poses a challenge in solubilizing the compound in the different dosage forms, especially for IV administration, for in vivo studies.

In view of the forgoing, it is one object of the present disclosure to design a derivative of KIM-161 with improved aqueous solubility to facilitate compound administration and a method for treating cancer with the compounds.