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CN-122028917-A - Compositions and methods for treating and preventing bacterial infections caused by gram positive bacteria

CN122028917ACN 122028917 ACN122028917 ACN 122028917ACN-122028917-A

Abstract

The present invention relates to photoactive compounds and compositions comprising the same, and their use in the treatment and prevention of infections caused by gram positive bacteria. In embodiments, the present invention relates to methods of administering compounds and compositions, and in particular topical compositions, for the treatment and prevention of bacterial infections caused by gram positive bacteria, including infections of diseases and conditions caused by gram positive bacteria, as well as skin lesions.

Inventors

  • Carrie Ambler
  • David Chizem

Assignees

  • 莱托克斯有限公司

Dates

Publication Date
20260512
Application Date
20240830
Priority Date
20230905

Claims (19)

  1. 1. A compound of formula I: Wherein R is a C 1 -C 4 alkyl group, The compounds of formula I are in free form or in salt form for use in the treatment or prophylaxis of infections caused by gram positive bacteria.
  2. 2. Compounds of formula I according to claim 1, wherein R is methyl or tert-butyl.
  3. 3. A compound of formula I according to claim 1 or claim 2, wherein the infection by a gram-positive bacterium is a disease or condition caused by a gram-positive bacterium or an infection of a skin lesion.
  4. 4. A compound of formula I according to any preceding claim in the form of a salt, wherein the salt is acetate, trifluoroacetate, triflate, hydrobromide or hydroiodide.
  5. 5. A pharmaceutical composition comprising a compound of formula I according to any preceding claim.
  6. 6. The pharmaceutical composition of claim 5, wherein the composition is in the form of an aqueous solution, suspension, emulsion, cream, foam, paste, ointment, gel, or hydrogel.
  7. 7. The pharmaceutical composition of claim 5 or claim 6, wherein the pharmaceutical composition is a topical composition.
  8. 8. A compound of formula I according to any one of claims 1 to 4 or a pharmaceutical composition according to any one of claims 5 to 7 for use in the treatment or prevention of infections caused by gram-positive bacteria, wherein the compound or composition is administered topically.
  9. 9. The compound or pharmaceutical composition of claim 8, wherein the compound or composition is administered topically and exposed to light.
  10. 10. The compound or pharmaceutical composition of claim 9, wherein the compound or composition is exposed to light having a wavelength between 365 nm-460 nm.
  11. 11. A dressing or patch comprising a compound of formula I according to any one of claims 1 to 4 or 8 to 10, or a pharmaceutical composition according to any one of claims 5 to 10.
  12. 12. The dressing or patch of claim 11, wherein at least a portion of the dressing or patch is transparent.
  13. 13. A compound of formula I according to any one of claims 1 to 4 or 8 to 10 or a pharmaceutical composition according to any one of claims 5 to 10 for use in the treatment or prevention of a disease or condition caused by gram-positive bacteria or an infection of skin lesions, wherein the disease or condition caused by gram-positive bacteria is selected from cellulitis, erysipelas, impetigo, folliculitis, carbuncles, furuncles, erythema, leprosy and tuberculosis of the skin, and wherein the infection of skin lesions is selected from ulcers, skin wounds, burns or gram-positive infection of insect bites.
  14. 14. A compound of formula I according to any one of claims 1 to 4 or 8 to 10 or a pharmaceutical composition according to any one of claims 5 to 10 for use in the treatment of an infection caused by gram positive bacteria, wherein the infection is caused by staphylococcus aureus (Staphylococcus aureus), methicillin-resistant staphylococcus aureus (METHICILLIN RESISTANT Staphylococcus aureus, MRSA), community acquired methicillin-resistant staphylococcus aureus (Community-Acquired METHICILLIN RESISTANT Staphylococcus aureus, CA-MRSA), staphylococcus epidermidis (Staphylococcus epidermidis), staphylococcus hemolyticus (Staphylococcus haemolyticus), micrococcus luteus (Micrococcus luteus), corynebacterium parvus (Corynebacterium minutissimum), enterococcus faecalis (Enterococcus faecalis), streptococcus group a (Group A Streptococcus), streptococcus group C, streptococcus group G, mycobacterium tuberculosis (Mycobacterium tuberculosis), mycobacterium bovis (Mycobacterium bovis), mycobacterium leprosy (Mycobacterium lepromatosis), mycobacterium marinus (Mycobacterium marinum) and mycobacterium ulcerans (Mycobacterium ulcerans).
  15. 15. A method of treating a patient suffering from a bacterial infection caused by gram-positive bacteria, the method comprising administering to the patient a therapeutically effective amount of a compound of formula I according to any one of claims 1 to 4 or a salt thereof.
  16. 16. The method of treatment of claim 15, wherein the administration is topical administration.
  17. 17. The method of treatment according to claim 15 or claim 16, wherein the method further comprises exposing the compound of formula I to light.
  18. 18. A compound of formula II: The compound of formula II is in free form or in salt form, wherein R is C 1 -C 3 alkyl.
  19. 19. A compound of formula II according to claim 18, wherein the salt is acetate, trifluoroacetate, triflate, hydrobromide or hydroiodide.

Description

Compositions and methods for treating and preventing bacterial infections caused by gram positive bacteria The present invention relates to compounds and compositions, and their use in the treatment and prevention of infections caused by gram positive bacteria. In embodiments, the present invention relates to methods of administering compounds and compositions, and in particular topical compositions (topical composition), for the treatment and prevention of bacterial infections caused by gram-positive bacteria, including infections of diseases and conditions caused by gram-positive bacteria, as well as skin lesions. The discovery and introduction of antibiotics into clinical care can be said to be one of the biggest breakthroughs in medicine in the 20 th century. The discovery of penicillin in the 20 th century marks the beginning of the golden age of antimicrobial discovery, which continues with the rapid discovery of various classes of natural antibiotics during a relatively dense period of time up to the 60 th century. This age also has seen widespread antibiotic use and overuse, providing selective pressure for the acquisition and spread of antimicrobial resistance (AMR) across multiple species, leading to global health problems, commonly referred to as "silent epidemics (SILENT PANDEMIC)". AMR was responsible for about 130 tens of thousands of deaths worldwide only in 2019. In addition, there is clear evidence that bacteria become increasingly resistant to existing antibiotics. However, since the rate of development of drug resistance exceeds the discovery of new antibiotics, other treatments for microbial infections are urgently needed. Photoactivated cytotoxic compounds that can be used to trigger cell killing capability when exposed to light are advantageous in minimizing off-target toxicity in humans. Photoactive cytotoxic activity, generally the photoactive cytotoxic activity via the production of reactive oxygen species (reactive oxygen species, ROS), is a promising area of research, as bacteria are understood to be unable to develop resistance to ROS. However, a major obstacle to the use of photoactive compounds in therapy is the photosensitizer itself. Among other problems, most known photoactive compounds are high molecular weight porphyrin-based structures that are often insoluble or poorly soluble, making it difficult to formulate them into useful therapeutic forms. Among other properties, known compounds also exhibit poor or inadequate pharmacokinetic characteristics, limited or no ability to penetrate bacterial cells, and limited selectivity between cell types. In combination, these difficulties limit the use of such compounds in antimicrobial therapy. Accordingly, it would be advantageous to provide compounds that alleviate one or more of these drawbacks and that can be used as antibacterial agents in the treatment of bacterial infections caused by gram-positive bacteria. Compounds having good physical properties such as good solubility in commonly used formulation solvents in addition to an effective antibacterial effect against gram-positive bacteria would be useful. Compositions comprising such compounds may also be beneficial. Summary of The Invention The present invention therefore relates generally to compounds of formula I, in free form or in salt form, for use in the treatment and prophylaxis of infections caused by gram-positive bacteria, Wherein R is a C 1-C4 alkyl group. Throughout this specification, the term "alkyl" refers to a fully saturated, branched, unbranched or cyclic hydrocarbon moiety, i.e. primary, secondary or tertiary alkyl, or where appropriate cycloalkyl or alkyl substituted by cycloalkyl. Without further indication, the alkyl group comprises 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, or more preferably 1 to 4 carbon atoms. Representative examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2-dimethylpentyl, 2, 3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl. In formula I, R is C 1-C4 alkyl. R may be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl. In embodiments, R is methyl or butyl. In embodiments, R is methyl or tert-butyl. In embodiments, R is methyl or tert-butyl. In embodiments, R is tert-butyl. Unless otherwise stated, compounds useful in the present invention include salts thereof, and reference to a compound of formula I is intended to include reference to salts thereof. Suitable salts include, for example, acid salts with inorganic and/or organic acids, basic salts with inorganic and/or organic bases, and zwitterionic ("inner salts") salts that may be formed and are included in the term "salt" as used herein. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts may be useful in some instances. Exemplar