Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
  • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents

Definitions

• Pleuromutilins having the principle ring structure of Pleuromutilin and being substituted at the primary hydroxy group have been developed, e.g. as antibacterials. Due to their pronounced antibacterial activity, a group of Pleuromutilin derivatives, aminohydroxy-substituted cyclohexylsulfanylacetylmutilins, as disclosed in WO 2008/113089, have been found to be of particular interest. As described in WO 2008/113089 14-O- ⁇ [(4-Amino-2- hydroxy-cyclohexyl)-sulfanyl]-acetyl ⁇ -mutilins are particularly useful compounds because of their activity against Gram-positive and Gram-negative bacteria.
• Valnemulin (compound of formula (C), approved as Econor®) and Tiamulin (compound of formula (D), approved as Denagard®) are two other semi-synthetic Pleuromutilin derivatives which have been used systemically as antibiotics in veterinary medicine for many years.
• Approved semisynthetic compounds derived from Pleuromutilin have shown excellent activity against bacterial organisms which include inter alia Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus (including MRS A), Moraxella catarrhalis, Legionella pneumophila, Chlamydophila pneumoniae and Mycoplasma pneumoniae.
• Tularemia is an infectious disease caused by the bacterium Francisella tularensis (F. tularensis).
• the infectious disease of human is zoonotic as the pathogen circulates in wild animal hosts transmitted for example by parasites.
• the frequency of infections with F. tularensis in humans is rather low (rare disease) and the occurrence characterized by local outbreaks.
• Tularemia may result from aerosolized F. tularensis and the bacterium is highly infective. Therefore, the causative agent, the bacterium Francisella tularensis, is regarded as a viable biological warfare agent, i.e. is regarded as a biothreat.
• WO 2007/062333, WO 2007/062334, and WO 2007/062335 refer to specific pleuromutilin compounds with an O-acyl-carbamate linker and mention activity of individual compounds against several bacteria including F. tularensis. However, the application discloses no microbiological data such as minimum inhibitory concentration (MIC).
• MIC minimum inhibitory concentration
• the Pleuromutilin derivatives disclosed in WO 2008/113089A1 show antimicrobial activity against the biothreat bacteria F. tularensis.
• the Pleuromutilin derivatives, in particular Lefamulin are active in vitro and in vivo against strains of the bacterium known to cause tularemia in humans. Therefore, in a first aspect, the present invention relates to a compound as defined in claims 1 to 6, in particular Lefamulin, or any pharmaceutically acceptable salt, solvate, ester of metabolite thereof, for the specific use in the treatment or prevention of a bacterial infection mediated by F. tularensis.
• the present invention relates to a method of treatment or prevention of a bacterial infection mediated by F. tularensis comprising administering a compound as defined in any of claims 1 to 6, in particular Lefamulin, or a pharmaceutically acceptable salt, solvate, ester of metabolite thereof to a subject in need of such treatment.
• Fig. 1 shows the probability of survival over time as a result of an in vivo study with mice challenged with an aerosol of F. tularensis subsp. tularensis SchuS4 for Lefamulin (Lef) at different oral dose regimes compared with the untreated control and treatment with ciprofloxacin (cipro).
• Francisella tularensis is a Gram-negative, facultative intracellular bacterium, able to survive and grow within eukaryotic cells including macrophages. Francisella tularensis is currently divided into four subspecies (abbreviated as subsp. / ssp.):
• Type A strains are more virulent and found exclusively in North America and Mexico and cause the most severe form of human disease.
• Type B is found throughout the Northern Hemisphere and is less pathogenic in humans than Type A and F. tularensis subsp. mediasiatica found in Central Asia (Champion MD et al., PLoS Pathog. 2009, 5(5): el000459, DOI: 10.1371/journal.ppat.1000459).
• Debate continues on whether subsp. novicida is a fourth subspecies of F. tularensis or a separate species and is sometimes classified as a separate species “F. novicida’” due to its aquatic reservoir and very low virulence in humans (Kingry LC, Petersen JM, Front Cell Infect Microbiol 2014, 4:35, DOI:
• the bacterial infection is mediated by a subspecies of F. tularensis selected from the group of F. tularensis subsp. tularensis (Type A), F. tularensis subsp. holarctica (Type B), F. tularensis subsp. mediasiatica and tularensis subsp. novicida, preferably a subspecies of F. tularensis selected from the group of F. tularensis subsp. tularensis (Type A), F. tularensis subsp. holarctica (Type B), and F. tularensis subsp. novicida.
• F. tularensis selected from the group of F. tularensis subsp. tularensis (Type A), F. tularensis subsp. holarctica (Type B), and F. tularensis subsp
• Tularemia is the common term for an infectious disease, i.e. a bacterial infection mediated by F. tularensis.
• infectious disease i.e. a bacterial infection mediated by F. tularensis.
• non-medical synonyms to tularemia such as rabbit fever or deer fly fever are used.
• the bacterial infection mediated by F. tularensis is tularemia.

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• Health & Medical Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Veterinary Medicine (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Public Health (AREA)
• Communicable Diseases (AREA)
• Emergency Medicine (AREA)
• Epidemiology (AREA)
• Oncology (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Organic Chemistry (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

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• 2022
  • 2022-09-27 EP EP22198179.8A patent/EP4338732A1/de not_active Ceased
• 2023
  • 2023-09-15 WO PCT/EP2023/075431 patent/WO2024056858A1/en not_active Ceased
  • 2023-09-15 JP JP2025516277A patent/JP2025529559A/ja active Pending
  • 2023-09-15 EP EP23777157.1A patent/EP4587009A1/de active Pending

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