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EP-4486753-B1 - BROAD SPECTRUM AMINOGLYCOSIDES AND USES THEREOF

EP4486753B1EP 4486753 B1EP4486753 B1EP 4486753B1EP-4486753-B1

Inventors

  • LOPEZ, Michael Steven
  • CIRZ, Ryan Thomas
  • CALABRESE, ANDREW ANTONY

Dates

Publication Date
20260513
Application Date
20230303

Claims (14)

  1. A compound having a structure: or a pharmaceutically acceptable salt or solvate thereof, wherein: R a is H or methyl; R b has a structure according to Formula (II): wherein: Q is NH, O, or S; n is an integer from 0 to 4; R 1 is hydrogen or C 1-3 alkyl; R 2 and R 3 are each selected independently for each occurrence from the group consisting of hydrogen, alkyl, halogen, and -OH; R 4 is H, C 1-3 alkyl, or -C(=NH)NR 4a R ab , wherein R 4a and R 4b are each independently selected from the group consisting of hydrogen and C 1-3 alkyl; or R 1 and R 4 , together with the atoms to which they are attached, form a heterocycloalkyl ring system comprising at least one N; and R 5 is H or methyl
  2. The compound of claim 1, wherein R a is H.
  3. The compound of claim 1, wherein R a is methyl.
  4. The compound of any one of claims 1-3, wherein R b is selected from the group consisting of:
  5. The compound of claim 4, wherein R b is selected from the group consisting of:
  6. The compound of any one of claims 1-5, wherein R 5 is methyl.
  7. The compound of claim 6, having a structure selected from the group consisting of:
  8. The compound of claim 7, having a structure selected from the group consisting of:
  9. The compound of any one of claims 1-5, wherein R 5 is H.
  10. The compound of claim 9, having a structure selected from the group consisting of:
  11. A pharmaceutical composition comprising the compound of any one of claims 1-10, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and at least one pharmaceutically acceptable excipient.
  12. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, or the pharmaceutical composition of claim 11, for use in treating a bacterial infection in a subject in need thereof.
  13. The compound or pharmaceutical composition for use according to claim 12, wherein the bacterial infection is with Gram-positive, Gram-negative, aerobic, or facultative anaerobic bacteria.
  14. The compound or pharmaceutical composition for use according to claim 13, wherein one or more of the following apply: the bacterial infection is with an Escherichia sp., a Klebsiella sp. a Proteus sp., a Citrobacter sp., a Morganella sp., a Providencia sp., a Yersinia sp., an Enterobacter sp., a Salmonella sp., or a Serratia sp.; the bacterial infection is with a Moraxella sp., a Pseudomonas sp., an Acinetobacter sp., a Mycobacterium sp., a Staphylococcus sp., a Bacillus sp., a Francisella sp., or a Burkholderia sp.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Provisional Patent Application No. 63/316,731, filed March 4, 2022. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with government support under Contract No. 75N93020C00018 awarded by the National Institutes of Health. The government has certain rights in this invention. TECHNICAL FIELD The present disclosure relates generally to aminoglycoside compounds having antibacterial activity, and to uses thereof in treatment of medical conditions associated with pathogenic microorganisms. BACKGROUND The rapid spread of antibiotic resistance has prompted a continuing search for new agents capable of antibacterial activity. Aminoglycosides (AGs) are highly potent, broad-spectrum antibiotics with many desirable properties for the treatment of life-threatening infections. AGs are used to treat a variety of diseases including, but not limited to, urinary tract infections, bloodstream infections, pneumonia and neonatal sepsis. Examples of AGs include tobramycin, gentamicin, and amikacin. AG antibiotics exert their antibacterial effects by binding to specific target sites in the bacterial ribosome. For the structurally related antibiotics neamine, ribostamycin, neomycin B, and paromomycin, the binding site has been localized to the A-site of the prokaryotic 16S ribosomal decoding region RNA (see Moazed, D.; Noller, H.F., Nature, 1987, 327, 389). Binding of AGs to this RNA target interferes with the fidelity of mRNA translation and results in miscoding and truncation, leading ultimately to bacterial cell death (see Alper et al., J. Am. Chem. Soc., 1998, 120, 1965). Over time, resistance to AGs has emerged in the clinic and degraded our antibacterial armamentarium. AG resistance (AG-R) can be categorized mechanistically into two primary types: (1) AG-modifying enzymes (AMEs), which modify and inactive the drug; and (2) enzymes called ribosomal methyltransferases (RMTs), which modify the drug target binding pocket. At present, the most common form of AG-R amongst clinical isolates is conferred by AMEs, which are diverse and widely distributed. RMTs, while less common than AMEs in some species, are a serious threat because they modify the 16S rRNA AG binding site and prevent AG target engagement, conferring high-level resistance to all clinically available parenteral AGs. As an additional concern, AME and RMT genes are typically located on plasmids or transposons together with genes encoding resistance to other classes of antibacterial agents, which leads to multidrug resistant isolates. Further, AGs can be toxic to the kidney (nephrotoxicity) and cochlea (ototoxicity). These are cumulative processes, with the likelihood of observing toxicity increasing with treatment duration. The nephrotoxic potential of AGs limits the dose and the length of treatment, making it challenging to achieve the systemic exposures required for efficacy against some infections. Quite often, but not always, the structure-activity relationships that lead to increased antibacterial potency are correlated with those that cause toxicity to human kidney cells. The origin of this toxicity is assumed to result from a combination of different factors and mechanisms such as interactions with phospholipids, inhibition of phospholipases and the formation of free radicals. WO2019/046126 A1 describes aminoglycoside compounds and their use in treating a bacterial infection in a subject, for example a Gram-negative bacterial infection. For the foregoing reasons, while progress has been made in this field, there is a need for new chemical entities that possess antibacterial activity against highly resistant organisms and an acceptable safety profile. SUMMARY The present disclosure relates to aminoglycoside compounds, including stereoisomers, tautomers, solvates, and pharmaceutically acceptable salts thereof, having antibacterial activity, and to uses thereof in, for example, treatment of medical conditions associated with a pathogenic microorganism, which are also referred to herein as "bacterial infections." According to a first aspect there is provided a compound as claimed in claim 1. In one embodiment, the compound is a compound having a structure according to Formula (I): or a pharmaceutically acceptable salt or solvate thereof, wherein: Ra is hydrogen (H) or methyl; andRb has a structure according to Formula (II): wherein: Q is NH, O, or S;n is an integer from 0 to 4;R1 is hydrogen or C1-3 alkyl;R2 and R3 are each selected independently for each occurrence from the group consisting of hydrogen, alkyl, halogen, and -OH; andR4 is H, C1-3 alkyl, or -C(=NH)NR4aR4 , wherein R4a and R4b are each independently selected from the group consisting of H and C1-3 alkyl; orR1 and R4, together with the atoms to which they are attached, form a heterocycloalkyl ring system comprising at least one N. In some embodiments, Ra is H. In so