Benzyl amine-containing heterocyclic compounds and compositions useful against mycobacterial infection
Inventors
Miller, Marvin J. • Moraski, Garrett C.
Assignees
Publication Number
US-11820767-B2
Publication Date
2023-11-21
Expiration Date
2036-09-19
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Abstract
Described herein are compounds and compositions, and methods of making and their use as effective agents against mycobacterial infections.
Core Innovation
The invention provides benzyl amine-containing heterocyclic compounds and compositions, with methods of making and using them as agents against mycobacterial infections. These compounds are described by specific formulas incorporating various substituents such as alkyl, halogen, and substituted cyclic amines, and are capable of existing in multiple forms, including salts and resonance forms. The core chemical structures are carefully defined, and methods for their synthesis are detailed, including processes for forming heterocyclic scaffolds and coupling with amines.
The background identifies an urgent need for new treatments for mycobacterial infections, particularly due to pathogens such as Mycobacterium tuberculosis (Mtb) and Mycobacterium avium (MAC), which pose significant health threats due to drug resistance and high morbidity. Current treatments are described as only modestly effective and costly, especially against drug-resistant strains. The invention addresses this unmet medical need by offering new compounds that are considered effective against both drug-sensitive and drug-resistant strains, either as single agents or in combination therapy.
The invention encompasses compositions containing these compounds with physiologically acceptable carriers, as well as methods involving administering the compounds to subjects in need of treatment. Various formulations and routes of administration are disclosed, aimed at treating mycobacterial infections in humans and animals. The patent also details the broad applicability of these compounds to a range of mycobacteria, including both tuberculous and non-tuberculous species.
Claims Coverage
There is one independent claim in this patent, which defines the main inventive feature relating to a method of treating non-tuberculous mycobacterial infectious disease by administering a specific class of compounds.
Method of treating non-tuberculous mycobacterial infectious disease with specific heterocyclic compounds
The invention covers a method for treating non-tuberculous mycobacterial infectious disease in a subject by administering a compound defined by a particular formula. This formula specifies: - R1 is selected from halogen or alkyl groups; - R2 is an alkyl group; - R3 is a substituted cyclic amine; - R4 is hydrogen or halogen. The method includes administering this compound, its resonance form, salt, or salt of resonance form, optionally in combination with a physiologically acceptable carrier, to a subject requiring treatment for non-tuberculous mycobacterial infection. The claim further details the utility for subjects needing treatment related to a defined set of mycobacterial strains.
The claim coverage centers on the therapeutic method using the defined class of benzyl amine-containing heterocyclic compounds for non-tuberculous mycobacterial infectious diseases.
Stated Advantages
The compounds display great potency, with some examples showing nanomolar-range in vitro activity against mycobacteria.
Lead compounds demonstrate high in vivo safety and reduced toxicity, with maximum tolerated doses ≥250 mg/kg in mice and no observed signs of distress or weight loss.
The compounds are effective against both drug-sensitive and drug-resistant mycobacterial strains, including mono-drug resistant, multi-drug resistant (MDR), and extensively drug resistant (XDR) Mtb.
Lead compounds show no toxicity to mammalian cell lines at concentrations IC50 >50 μM.
When tested in combination with rifampicin, the compounds provide statistically supported improvement in efficacy in clearing bacteria from infected organs compared to rifampicin alone.
Documented Applications
Treatment and/or prevention of diseases and disorders characterized by mycobacterial activity or infection, including both tuberculous and non-tuberculous mycobacteria such as M. tuberculosis, M. avium, M. intracellularae, and M. kansasii.
Use in the treatment of mycobacterial infections in humans (immunocompetent or immunocompromised) and animals, including livestock.
Killing or inhibiting growth of populations of pathogenic and non-pathogenic mycobacteria by contacting the population with the compound or composition.
Treatment as a single agent or in combination therapy with other antimicrobials such as rifampicin, clarithromycin, and other standard drugs for mycobacterial infections.
Treatment of subjects for maladies related to a broad list of non-tuberculous mycobacterial infections, as explicitly listed in the patent.
Use in the treatment of inflammatory diseases such as asthma, lung inflammation, chronic granulomatous diseases (including tuberculosis and leprosy), and other related inflammatory or infectious conditions.
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