SEQUENCE LISTING SUBMISSION VIA EFS-WEB

A computer readable text file, entitled “SequenceListing.txt,” created on or about Jan. 15, 2021 with a file size of about 2 kb contains the sequence listing for this application and is hereby incorporated by reference in its entirety.

BACKGROUND OF THE INVENTION

In susceptible individuals, certain Gram-negative bacteria can cause serious complications and infections, such as pneumonia, urinary tract infections, wound infections, ear infections, eye infections, intra-abdominal infections, oral bacterial overgrowth and sepsis. The treatment of serious bacterial infections in clinical practice can be complicated by antibiotic resistance. Recent years have seen a rise in infections by Gram-negative bacteria that are resistant to many types of antimicrobials, including broad-spectrum antibiotics such as aminoglycosides, cephalosporins and even carbapenems. This alarming trend highlights the need to identify new antimicrobials that are effective against Gram-negative bacteria, in particular against multidrug-resistant Gram-negative bacteria.

Polymyxins are a class of antibiotics produced by the Gram-positive bacteriumBacillus polymyxa. First identified in the late 1940s, polymyxins, particularly polymyxin B and polymyxin E (colistin), were once used in the treatment of Gram-negative infections. However, these antibiotics exhibited side effects such as nephrotoxicity. Consequently, their use in therapy has been limited to treatments of last resort.

SUMMARY OF THE INVENTION

The present invention pertains to a novel compound and its analogues, which exhibit excellent antimicrobial activity—particularly against Gram-negative pathogens. Pharmaceutical compositions containing the novel compound and its analogues are useful for the treatment of prevention of various infectious disease including skin and skin structure infections, respiratory infections, septicemia, bacteremia, and inflammatory bowel diseases (IBD). Embodiments of the invention also relate to treating or preventing a bacterial infection.

In one aspect, the present invention comprises, consists essentially of or consists of a novel compound represented by the following Formula (II):


and/or pharmaceutically acceptable salts, stereoisomers (including enantiomers), tautomers, or hydrates thereof, as well as analogues Formula (II) (hereinafter, collectively, “Formula (II) compounds”). The present invention also includes pharmaceutical compositions comprising or consisting essentially of Formula (II) compounds, the use of Formula (II) compounds, and method for treating or preventing a bacterial infection with one or more of the Formula (II) compounds.

In another aspect, the present invention comprises, consists essentially of or consists of a novel compound represented by the following Formula (I):


wherein:

R1, R2, R3, R4, R5, and R6are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, hydroxyl, hydroxyalkyl, halogen, —CN, —O-alkyl, —C(O)-alkyl, —C(O)O-alkyl, —C(O)OH, —C(O)NH2, —C(O)NH-alkyl, —NH2, —NO2, —CF3, —NH-alkyl, —N-(alkyl)2, —NHC(O)-alkyl and aryl, wherein said alkyl, alkenyl, alkynyl and aryl are each optionally substituted,

R7and R8are each independently selected from the group consisting of hydrogen, straight or branched C1-C5 alkyl, straight or branched C2-C6 alkenyl, straight or branched C2-C6 alkynyl; wherein said alkyl, alkenyl and alkynyl are each optionally substituted;

R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19and R20are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, haloalkyl, hydroxyl, hydroxyalkyl, halogen, —CN, —O-alkyl, —C(O)-alkyl, —C(O)O-alkyl, —C(O)OH, —C(O)NH2, —C(O)NH-alkyl, —NH2, —NO2, —CF3, —NH-alkyl, —NHC(O)-alkyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, haloalkyl are each optionally substituted;

A is a bond or —(CH2)n—, wherein n is an integer between 0 and 10;

X is —C(O)—, —CH2—, —C(OH)—, —C(O)O-alkyl, —C((O)alkyl)- and/or pharmaceutically acceptable salts, stereoisomers (including enantiomers), tautomers, or hydrates thereof, as well as analogues Formula (I) (hereinafter, collectively, “Formula (I) compounds”). The present invention also includes pharmaceutical compositions comprising or consisting essentially of Formula (I) compounds, the use of Formula (I) compounds, and method for treating or preventing a bacterial infection with one or more of the Formula (I) compounds.

Formula (I) compounds, prodrugs, pharmaceutically acceptable salts, enantiomers, stereoisomers, rotamers, tautomers, diastreomers, and racemates thereof exhibit advantageous antibacterial activity against various Gram-negative bacteria, and is useful for the treatment or prevention of various infectious diseases induced by various bacteria in human and other animals.

The compound of Formula (I) includes the following Formula (Ia):


wherein:

R3, R4, R5, R6, R7and R8are as defined in the above.

and/or pharmaceutically acceptable salts, stereoisomers (including enantiomers), tautomers, or hydrates thereof, as well as analogues Formula (Ia) (hereinafter, collectively, “Formula (Ia) compounds”). The present invention also includes pharmaceutical compositions comprising or consisting essentially of Formula (Ia) compounds, the use of Formula (Ia) compounds, and method for treating or preventing a bacterial infection with one or more of the Formula (Ia) compounds.

Another aspect of the invention relates to a pharmaceutical composition for treating infections in an animal caused by Gram-negative bacteria. In various embodiments, the pharmaceutical composition comprises a therapeutically effective amount of one or more the Formula (I), (Ia) or (II) compounds, or a pharmaceutically acceptable salt thereof, and one or more additional components selected from the group consisting of pharmaceutically acceptable carriers, surfactants, solid diluents, and liquid diluents. The Formula (I), (Ia) or (II) compounds may optionally be present in the form of a pharmaceutically acceptable solvate such as a hydrate.

In general, as used herein, the term “substantially” means±10%, and in some embodiments, ±5% In addition, reference throughout this specification to “one example,” “an example,” “one embodiment,” or “an embodiment” means that a particular feature, structure, or characteristic described in connection with the example is included in at least one example of the present technology. Thus, the occurrences of the phrases “in one example,” “in an example,” “one embodiment,” or “an embodiment” in various places throughout this specification are not necessarily all referring to the same example. Furthermore, the particular features, structures, routines, steps, or characteristics may be combined in any suitable manner in one or more examples of the technology. The headings provided herein are for convenience only and are not intended to limit or interpret the scope or meaning of the claimed technology.

