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New Antibiotic Ammonium Compounds for Treating Resistant Infections

Introduction

The rise of antibiotic-resistant bacterial infections is one of the most pressing public health challenges of our time. Traditional antibiotics are becoming less effective as bacteria evolve to withstand these treatments, leaving healthcare providers with limited options for fighting severe infections. Our patented antibiotic ammonium compounds offer a fresh solution to this critical issue. Designed to target resistant bacterial strains, these compounds represent a new frontier in the fight against drug-resistant infections.

The Urgent Need for Novel Antibiotics

Infections caused by multidrug-resistant bacteria are on the rise, causing complications in hospitals and healthcare facilities worldwide. Common infections like pneumonia, urinary tract infections, and bloodstream infections have become increasingly difficult to treat due to bacteria’s ability to develop resistance to commonly used antibiotics. With fewer treatment options available, the risk of severe complications and mortality increases, especially for immunocompromised patients or those undergoing surgeries.

For pharmaceutical companies and healthcare providers, the development of new antibiotics capable of combating resistant bacterial strains is crucial. The discovery of new compounds that can bypass these resistance mechanisms is key to overcoming the global health threat posed by antibiotic-resistant infections.

A New Approach with Ammonium-Based Antibiotics

Our patented antibiotic ammonium compounds introduce a novel mechanism of action, making them particularly effective against bacteria that have developed resistance to existing antibiotics. These compounds are designed to target bacterial cell membranes, disrupting essential cellular processes and leading to the death of the bacteria. Importantly, the ammonium-based structure of these compounds offers a unique pathway for overcoming bacterial resistance mechanisms, making them valuable in treating infections that no longer respond to traditional antibiotics.

These compounds can be applied to a wide range of bacterial infections, from common hospital-acquired infections to severe drug-resistant pathogens. They are also versatile enough to be developed into various forms, such as topical treatments, oral medications, or injectables, allowing for flexibility in addressing different types of infections and clinical scenarios.

Key Benefits

  • Effective Against Resistant Bacteria: Specifically targets bacterial strains that have developed resistance to traditional antibiotics.
  • New Mechanism of Action: Offers a fresh approach to antibiotic therapy, reducing the risk of bacterial resistance development.
  • Broad Application: Can be used for a variety of bacterial infections, including those acquired in hospitals and other healthcare settings.
  • Versatile Formulations: The compounds can be formulated into oral, topical, or injectable treatments, providing flexibility in clinical use.

A Critical Step Forward in Infection Control

Licensing this antibiotic ammonium compound technology offers pharmaceutical companies the chance to develop cutting-edge treatments for antibiotic-resistant infections. As bacterial resistance continues to rise, these compounds represent a critical tool in expanding the arsenal of effective antibiotics for healthcare providers worldwide.

Please see terms and conditions
The present disclosure provides ammonium compounds, e.g., compounds according to Formula I as set forth herein, which are useful as antimicrobial agents. Methods for the treatment of bacterial infections and associated conditions, e.g., gastrointestinal conditions, are also described, as well as methods for altering the microbiome of subjects such as humans.

What is claimed is:

1. A compound according to Formula I:
Figure US11952330-20240409-C00127
wherein
A is a pharmaceutically acceptable anion;
Y is selected from the group consisting of —NR7SO2—, —OC(O)—, and —NR7C(O)—;
Z is C1-6 alkylene;
R1 is selected from the group consisting of C1-18 alkyl, C3-8 cycloalkyl, C6-10 aryl, 3- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, and -L1-R1a;
L1 is C1-6 alkylene;
R1a is selected from the group consisting of C3-8 cycloalkyl, C6-10 aryl, 3- to 10-membered heterocyclyl, and 5- to 10-membered heteroaryl;
R2 is selected from the group consisting of H, C1-18 alkyl, C3-8 cycloalkyl, C6-10 aryl, 3- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, and -L2-R2a;
R3 is selected from the group consisting of H, C1-18 alkyl, C3-8 cycloalkyl, C6-10 aryl, 3- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, and -L2-R2a;
L2 is C1-6 alkylene;
R2a is selected from the group consisting of C3-8 cycloalkyl, C6-10 aryl, 3- to 10-membered heterocyclyl, and 5- to 10-membered heteroaryl;
R2 and R3 are optionally taken together with the nitrogen to which they are attached to form 3- to 10-membered heterocyclyl;
one of R2 and R3 is optionally taken together with the nitrogen to which it is attached and Y or Z to form 3- to 10-membered heterocyclyl;
R4a is selected from the group consisting of H, C1-18 alkoxy, C1-18 alkyl, C1-18 haloalkyl, C1-18 alkenyl, halogen, —OH, —COOH, —N(R7)2, —NO2, —SO3, —SO2N(R7)2, and -L4-R4x;
R4c is selected from the group consisting of halogen, H, C1-18 alkoxy, C1-18 alkyl, C1-18 haloalkyl, C1-18 alkenyl, —OH, —COOH, —N(R7)2, —NO2, —SO3, —SO2N(R7)2, and -L4-R4x;
R4b, R4d, and R4c are independently selected from the group consisting of H, C1-18 alkoxy, C1-18 alkyl, C1-18 haloalkyl, C1-18 alkenyl, halogen, —OH, —COOH, —N(R7)2, —NO2, —SO3, —SO2N(R7)2, and -L4-R4x;
L4 is selected from the group consisting of C1-6 alkylene, 2- to 6-membered heteroalkylene, and —O—;
R4x is selected from the group consisting of C3-8 cycloalkyl, C6-10 aryl, 3- to 10-membered heterocyclyl, and 5- to 10-membered heteroaryl;
R5a and R5b are independently selected from the group consisting of H, C1-18 alkoxy, C1-18 alkyl, C1-18 haloalkyl, C1-18 alkenyl, halogen, —OH, —COOH, —N(R7)2, —NO2, —SO3, —SO2N(R7)2, and -L5-R5x;
L5 is selected from the group consisting of C1-6 alkylene, 2- to 6-membered heteroalkylene, and —O—;
R5x is selected from the group consisting of C3-8 cycloalkyl, C6-10 aryl, 3- to 10-membered heterocyclyl, and 5- to 10-membered heteroaryl;
R6 is selected from the group consisting of H, C1-6 alkyl, and C2-7 acyl;
R6 is optionally taken together with R4a or R4c to form a 5-to- 8-membered ring;
each R7 is independently selected from the group consisting of H, C1-6 alkyl, and C2-7 acyl;
each C3-8 cycloalkyl, C6-10 aryl, 3- to 10-membered heterocyclyl, and 5- to 10-membered heteroaryl is optionally and independently substituted with one or more substituents selected from the group consisting of C1-18 alkyl, C1-18 haloalkyl, C1-18 alkenyl, C1-18 alkoxy, halogen, —OH, —C(O)R8, —C(O)N(R7)2, —N(R7)2, —NO2, —SO3, and —SO2N(R7)2; and
each R8 is independently selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, and —OH;
provided that at least one of R4a, R4b, R4c, R4d, and R4c is C7-18 alkoxy or C4-6 alkoxy;
provided that if Y is —OC(O)—, Z is ethylene (—(CH2)2—), R1 is methyl, and R2 and R3 are ethyl, then at least two of R4a, R4b, R4c, R4d, and R4c are other than H; and
provided that the compound is other than:
an N,N-diethyl-N-methyl-2-(4-(2-(octyloxy)benzamido)benzamido)ethan-1-aminium species,
an N,N,N-trimethyl-2-((4-(2-(octyloxy)benzamido)benzoyl)oxy)ethan-1-aminium species,
an N,N,N-trimethyl-2-((4-(4-(isopentyloxy)benzamido)benzoyl)oxy)ethan-1-aminium species,
an N,N,N-trimethyl-2-((4-(4-(isopentyloxy)benzamido)benzoyl)oxy)propan-1-aminium species,
an 1-methyl-1-(2-4-(2-(octyloxy)benzamido)benzoyl)oxy)ethyl)piperidin-1-ium species, or
4-methyl-4-(2-((4-(2-(octyloxy)benzamido)benzoyl)oxy)ethyl)morpholin-4-ium bromide.
2. The compound of claim 1, wherein at least one of R4a and R4c is C4-18 alkoxy.
3. The compound of claim 1, wherein at least one of R4a, R4b, R4c, R4d, and R4c is halogen.
4. The compound of claim 1, wherein R5a and R5b are independently selected from the group consisting of H and halogen.
5. The compound of claim 1, which is a compound according to Formula Ia:
Figure US11952330-20240409-C00128
6. The compound of claim 1, wherein R1 is selected from the group consisting of C3-8 alkyl and -L1-R1a.
7. The compound of claim 6, wherein R1a is selected from the group consisting of C3-8 cycloalkyl and C6-10 aryl.
8. The compound of claim 1, wherein:

R2 and R3 re each C1-6 alkyl;
R2 and R3 are taken together with the nitrogen to which they are attached to form 3- to 10-membered heterocyclyl; or
R2 is taken together with the nitrogen to which it is attached and Z to form 3- to 10-membered heterocyclyl.
9. The compound of claim 8, wherein R1 is C1-6 alkyl.
10. The compound of claim 1, wherein Y is —NR7SO2—.
11. The compound of claim 1, wherein Y is selected from the group consisting of —OC(O)— and —NR7C(O)—.
12. The compound of claim 1, wherein A is bromide.
13. The compound of claim 1, which is selected from the group consisting of:
Figure US11952330-20240409-C00129
Figure US11952330-20240409-C00130
Figure US11952330-20240409-C00131
Figure US11952330-20240409-C00132
Figure US11952330-20240409-C00133
Figure US11952330-20240409-C00134
14. The compound of claim 1, which is selected from the group consisting of:
Figure US11952330-20240409-C00135
Figure US11952330-20240409-C00136
Figure US11952330-20240409-C00137
Figure US11952330-20240409-C00138
15. The compound of claim 1, which is selected from the group consisting of:
Figure US11952330-20240409-C00139
Figure US11952330-20240409-C00140
16. A compound selected from the group consisting of:
Figure US11952330-20240409-C00141
Figure US11952330-20240409-C00142
17. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable excipient.
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Title

Antibiotic ammonium compounds and methods for the treatment of bacterial infections

Inventor(s)

Bryan DAVIES, Stanton McHardy, Ashley Cunningham, Hua-Yu WANG

Assignee(s)

University of Texas System

Patent #

11952330

Patent Date

April 9, 2024

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