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BR-112024019620-B1 - DERIVATIVES OF 2-[(2-OXO-4-PHENYL-2H-CROMEN-7-YL)OXY]PROPANAMIDO, PHARMACEUTICAL COMPOSITIONS AND USES

BR112024019620B1BR 112024019620 B1BR112024019620 B1BR 112024019620B1BR-112024019620-B1

Abstract

DERIVATIVES OF 2-[(2-OXO-4-PHENYL-2H-CROMEN-7-YL)OXY]PROPANAMIDE. The present invention relates to derivatives of 2-[(2-Oxo-4-phenyl-2H-chromen-7-yl)oxy]propanamide, which can be used to target and eliminate cancerous stem cells and be used as therapeutic agents for the treatment of cancer, including reducing the likelihood and/or preventing tumor recurrence and metastasis. The compounds disclosed herein have demonstrated inhibition of the ability to form tumor spheres, migration, and signaling related to stem cell turnover in cancerous stem cells. These properties result from the selective inhibition of mitochondrial transcription directed at mitochondrial RNA polymerase (POLRMT) in cancerous cells.

Inventors

  • MICHAEL P. LISANTI
  • Federica Sotgia
  • Jussi Kangasmetsa
  • Filippo DI PISA

Assignees

  • LUNELLA BIOTECH, INC

Dates

Publication Date
20260310
Application Date
20230323
Priority Date
20220330

Claims (20)

  1. 1. Compound, characterized by the fact that it has the chemical structure or their pharmaceutically acceptable salts, wherein: • R1 and R2 may be the same or different and are selected from a halogen, CF2H, -CF3, -OCF2H, -OCF3, substituted or unsubstituted C5-C18 carboxyl, substituted or unsubstituted C5-C18 alkane, substituted or unsubstituted C5-C18 alkene, substituted or unsubstituted C5-C18 cyclic alkene, substituted or unsubstituted C5-C18 alkyne, substituted or unsubstituted C5-C18 ketone, substituted or unsubstituted C5-C18 aldehyde, substituted or unsubstituted C5-C18 ether, substituted or unsubstituted C5-C18 ester, substituted or unsubstituted C5-C18 amine, substituted or unsubstituted C5-C18 amide, substituted or unsubstituted C5-C18 alkylamide, phenol or benzoic acid; • R3 and R4 may be the same or different and are selected from hydrogen, substituted or unsubstituted C2-C18 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted pyridine, substituted or unsubstituted C2-C18 carboxyl, substituted or unsubstituted C2-C18 alkene, substituted or unsubstituted C2-C18 alkyne, substituted or unsubstituted C2-C18 ketone, substituted or unsubstituted C2-C18 aldehyde, substituted or unsubstituted C2-C18 ether, substituted or unsubstituted C2-C18 ester, substituted or unsubstituted C2-C18 amine, substituted or unsubstituted C2-C18 amide, substituted or unsubstituted C2-C18 alkylamide, substituted or unsubstituted phenol, or benzoic acid, or one of R3 and R4 is the group and the other is an H or a C2-C5 alkyl; or R3 and R4 form a substituted or unsubstituted C5 or C6 heterocycle; or R3 and R4 form the group or NR3R4 is OH; provided that R1 or R2 or R1 and R2 is a substituted or unsubstituted C5-C18 amide, or R3 or R4 or R3 and R4 is the group , and the other is either hydrogen or a C2-C5 alkyl group.
  2. 2. Compound according to claim 1, characterized in that it has the following structure: or a pharmaceutically acceptable salt thereof.
  3. 3. Compound according to claim 1, characterized in that it has the following structure: or a pharmaceutically acceptable salt thereof.
  4. 4. Compound according to claim 1, characterized in that it has the following structure: or a pharmaceutically acceptable salt thereof.
  5. 5. Compound according to claim 1, characterized in that it has the following structure: or a pharmaceutically acceptable salt thereof.
  6. 6. Compound according to claim 1, characterized in that one of R1 and R2 is a halogen.
  7. 7. Compound according to claim 1, characterized in that one of R3 and R4 is the group and the other is a C2-C5 alkyl.
  8. 8. Compound according to claim 1, characterized in that one of R3 and R4 is the group and the other is a C2-C5 alkyl.
  9. 9. Compound according to claim 1, characterized in that R3 and R4 form the group
  10. 10. Compound according to claim 1, characterized in that it has the following structure: or a pharmaceutically acceptable salt thereof.
  11. 11. Compound according to claim 1, characterized in that it has the following structure: or a pharmaceutically acceptable salt thereof.
  12. 12. Compound according to claim 1, characterized in that it has the following structure: or a pharmaceutically acceptable salt thereof.
  13. 13. Compound according to claim 1, characterized in that it has the following structure: or a pharmaceutically acceptable salt thereof
  14. 14. Compound according to claim 1, characterized in that it has the following structure: or a pharmaceutically acceptable salt thereof.
  15. 15. Compound characterized by having the following chemical structure: or a pharmaceutically acceptable salt thereof, wherein • R1 and R2 may be the same or different and are selected from a halogen, CF2H, -CF3, -OCF2H, -OCF3, substituted or unsubstituted C5-C18 carboxyl, substituted or unsubstituted C5-C18 alkane, substituted or unsubstituted C5-C18 alkene, substituted or unsubstituted C5-C18 cyclic alkene, substituted or unsubstituted C5-C18 alkyne, substituted or unsubstituted C5-C18 ketone, substituted or unsubstituted C5-C18 aldehyde, substituted or unsubstituted C5-C18 ether, substituted or unsubstituted C5-C18 ester, substituted or unsubstituted C5-C18 amine, substituted or unsubstituted C5-C18 amide, substituted or unsubstituted C5-C18 alkylamide, phenol or benzoic acid; and • R5 and R6 may be the same or different and are selected from hydrogen, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted pyridine, substituted or unsubstituted C2-C10 carboxyl, substituted or unsubstituted C2-C10 alkene, substituted or unsubstituted C2-C10 alkyne, substituted or unsubstituted C2-C10 ketone, substituted or unsubstituted C2-C10 aldehyde, substituted or unsubstituted C2-C10 ether, substituted or unsubstituted C2-C10 ester, substituted or unsubstituted C2-C10 amine, substituted or unsubstituted C2-C10 amide, substituted or unsubstituted C2-C10 alkylamide, substituted or unsubstituted phenol or benzoic acid, and • R3 and R4 may be the same or different and are selected from hydrogen, substituted or unsubstituted C2-C18 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, Substituted or unsubstituted pyridine, substituted or unsubstituted C2-C18 carboxyl, substituted or unsubstituted C2-C18 alkene, substituted or unsubstituted C2-C18 alkyne, substituted or unsubstituted C2-C18 ketone, substituted or unsubstituted C2-C18 aldehyde, substituted or unsubstituted C2-C18 ether, substituted or unsubstituted C2-C18 ester, substituted or unsubstituted C2-C18 amine, substituted or unsubstituted C2-C18 amide, substituted or unsubstituted C2-C18 alkylamide, substituted or unsubstituted phenol, or benzoic acid, or one of R3 and R4 is the group and the other is an H or a C2-C5 alkyl group; or R3 and R4 form a substituted or unsubstituted C5 or C6 heterocycle; or R3 and R4 form the group or NR3R4 is OH; provided that R1 or R2 or R1 and R2 is a substituted or unsubstituted C5-C18 amide, or R3 or R4 or R3 and R4 is the group , and the other is either hydrogen or a C2-C5 alkyl group.
  16. 16. Compound according to claim 15, characterized in that it has the structure or a pharmaceutically acceptable salt thereof.
  17. 17. Compound according to claim 15, characterized in that R5 and R6 are selected from the group consisting of:
  18. 18. Pharmaceutical composition, characterized in that it comprises the compound, as defined in any one of claims 1 to 17, and a pharmaceutically acceptable carrier.
  19. 19. Use of a compound, as defined in any one of claims 1 to 17, characterized in that it is in the preparation of a composition and/or a product and/or medicament for treating or preventing tumor recurrence and/or metastasis.
  20. 20. Use of a compound, as defined in any one of claims 1 to 17, characterized in that it is in the preparation of a composition and/or a product and/or medicament for the treatment of cancer.

Description

[001] The present invention relates to derivatives of 2-[(2-oxo-4-phenyl-2H-chromen-7-yl)oxy]propanamido, which inhibit the propagation of cancerous stem cells (CSCs) and senescent cells. BACKGROUND [002] The biological process of aging continues to receive significant attention in the scientific and medical research communities. Physiological aging is related, at least in part, to an increased rate of oxidative damage to cellular components, including DNA, lipids, proteins, and the like. Increased oxidative damage creates an imbalance that disrupts self-regulation processes at the cellular level. Furthermore, aging correlates with an accumulation of lipofuscin in the neuronal cytoplasm. Modern research also indicates that aging is a consequence of natural DNA damage, resulting in abnormal DNA alterations that accumulate over time. Both mitochondrial and nuclear DNA damage can contribute to aging, indirectly through increased apoptosis and cellular senescence, and directly through increased cellular dysfunction. Accumulated DNA damage can lead to cell loss and, in surviving cells, loss of gene expression and mutation—effects that, in cells that do not frequently divide, produce signs of aging. Cellular senescence occurs when aged cells cease cell division, believed to occur after various detrimental environmental events, abnormal cell growth, autophagy, and oxidative stress, among other factors. The Senescence-Associated Secretory Phenotype ("SASP") is a characteristic of senescent cells and leads to a proteotoxic impairment of healthy cellular function, including inflammatory or anti-inflammatory and tumoral or anti-tumor effects, depending on a number of factors. The impact of chronic inflammation related to SASP affects the normal ability of the immune system to remove senescent cells, and cells that provide immune function can be recruited by SASP into senescent cells. Biomarkers of cellular senescence have been found to accumulate as mammals age and contribute to a wide range of age-related diseases, including Alzheimer's, amyotrophic lateral sclerosis, and type 2 diabetes. And with regard to frequent cell division, the accumulated DNA damage can become a prominent cause of cancer. [003] Aging, therefore, increases the likelihood of developing cancer, and researchers have struggled to develop anti-cancer and anti-aging or senolytic treatments. Conventional cancer therapies (e.g., irradiation, alkylating agents such as cyclophosphamide, and antimetabolites such as 5-fluorouracil) have attempted to selectively detect and eradicate rapidly growing cancer cells by interfering with cellular mechanisms involved in cell growth and DNA replication. Other cancer therapies have used immunotherapies that selectively bind to mutant tumor antigens in rapidly growing cancer cells (e.g., monoclonal antibodies). Unfortunately, tumors often recur after these therapies in the same or different locations, indicating that not all cancer cells have been eradicated. Cancer stem cells, in particular, survive for various reasons and lead to treatment failure. Recurrence may be due to insufficient chemotherapy dosage and/or the emergence of therapy-resistant cancer clones. Therefore, new cancer treatment strategies are needed that overcome the shortcomings of conventional therapies. [004] Advances in mutational analysis have allowed for an in-depth study of the genetic mutations that occur during cancer development. Despite knowledge of the genomic landscape, modern oncology has difficulty identifying primary driver mutations in cancer subtypes. The harsh reality seems to be that each patient's tumor is unique, and a single tumor may contain several divergent cell clones. What is needed, then, is a new approach that emphasizes the similarities between different types of cancer. Targeting the metabolic differences between tumor and normal cells is promising as a new cancer treatment strategy. An analysis of transcriptional profile data from human breast cancer samples showed more than 95 elevated mRNA transcripts associated with mitochondrial biogenesis and/or mitochondrial translation. Sotgia et al., Cell Cycle, 11(23):4390-4401 (2012). Furthermore, more than 35 of the 95 positively regulated mRNAs encode mitochondrial ribosomal proteins (MRPs). Proteomic analysis of human breast cancer stem cells also revealed significant overexpression of several mitoribosomal proteins, as well as other proteins associated with mitochondrial biogenesis. Lamb et al., Oncotarget, 5(22):11029-11037 (2014). [005] The mitochondrial metabolism of cancer cells has been the target of recent exploratory research, both in terms of the search for anticancer therapeutic targets and senolytic therapeutic targets. Mitochondria are extremely dynamic organelles in constant division, elongation, and connection to each other to form tubular networks or fragmented granules in order to meet the needs of the cell and adapt to the cellular microenvironment. The b