Antimicrobial compounds, compositions, and uses thereof

Abstract

To provide novel antibacterial compounds, pharmaceutical compositions, and methods for treating bacterial infections in patients in need of such treatment.SOLUTION: Provided are antimicrobial compounds and compositions, such as those of Formula (I). [wherein A: a mono -, bi -, or tri-cyclic carbo - or hetero-cyclic moiety; R1 and R2 are C1 - C8 alkyl moieties, respectively] SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application Nos. 62 / 470,025 and 62 / 470,039, filed March 10, 2017, each of which is incorporated herein by reference in its entirety.

[0002] The present disclosure provides novel antimicrobial compounds and compositions and their uses. [Background technology]

[0003] Bisphosphocin® compounds have antibacterial activity. US Patent No. 7,868,162 discloses Bisphosphocin® compounds. Summary of the Invention

[0004] The present disclosure provides a compound having the formula: [ka] (In the formula, A is a monocyclic, bicyclic, or tricyclic carbocyclic or heterocyclic moiety; R1 and R2 are each a C1-C8 alkyl moiety. or a compound having Pharmaceutically acceptable salts thereof are provided.

[0005] In some embodiments, R1 and R2 are each butyl.

[0006] Another aspect of the disclosure is a compound having the formula: [ka] (In the formula, Q is oxygen or sulfur; W is an amino- or guanidino-substituted nitrogen-containing heterocyclic moiety; X and Z are endblocking groups; A is H, alkyl, halogen, alkoxy, alkyl-(O-alkyl), aryl, alkenyl, alkanol, or phenol. The present invention provides a compound having the formula:

[0007] Another aspect of the present disclosure provides a compound selected from any one of compounds 1 to 2520 set forth in Table 1 in the detailed description of the invention.

[0008] Another aspect of the disclosure is a compound having the formula: [ka] a compound having or a pharmaceutically acceptable salt thereof.

[0009] Another aspect of the present disclosure provides pharmaceutical compositions comprising a compound according to Formulas (I)-(III), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients, or diluents.

[0010] Another aspect of the present disclosure provides a method of treating a diabetic foot ulcer infection in a patient in need thereof, comprising administering to the patient an effective amount of a compound according to Formulae (I)-(III) or a pharmaceutically acceptable salt thereof.

[0011] Another aspect of the present disclosure provides a method of treating a complicated urinary tract infection in a patient in need thereof, comprising administering to the patient an effective amount of a compound of Formulae (I)-(III) or a pharmaceutically acceptable salt thereof.

[0012] Another aspect of the present disclosure provides a method of treating a pulmonary infection caused by cystic fibrosis in a patient in need thereof, comprising administering to the patient an effective amount of a compound of Formulae (I)-(III), or a pharmaceutically acceptable salt thereof.

[0013] Another aspect of the present disclosure provides a method of treating ventilator-acquired pneumonia in a patient in need thereof, comprising administering to the patient an effective amount of a compound of Formulae (I)-(III) or a pharmaceutically acceptable salt thereof.

[0014] Another aspect of the present disclosure provides a method of treating a burn infection in a patient in need thereof, comprising administering to the patient an effective amount of a compound of Formulae (I)-(III) or a pharmaceutically acceptable salt thereof.

[0015] Another aspect of the present disclosure provides a method of treating otitis externa in a patient in need thereof, comprising administering to the patient an effective amount of a compound of Formulae (I)-(III) or a pharmaceutically acceptable salt thereof.

[0016] Another aspect of the present disclosure provides a method of treating bacterial vaginosis in a patient in need thereof, comprising administering to the patient an effective amount of a compound of Formulae (I)-(III) or a pharmaceutically acceptable salt thereof.

[0017] Another aspect of the present disclosure provides a method of treating impetigo in a patient in need thereof, comprising administering to the patient an effective amount of a compound of Formulae (I)-(III) or a pharmaceutically acceptable salt thereof.

[0018] Another aspect of the present disclosure provides a compound according to Formulas (I)-(III) or a pharmaceutically acceptable salt thereof for use in therapy.

[0019] Another aspect of the present disclosure provides the use of a compound according to Formulas (I)-(III) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament.

[0020] In some embodiments, the compounds of Formulas (I)-(III) or pharmaceutically acceptable salts thereof possess certain surprising features and advantages that were not predictable prior to the present disclosure. One advantage of the compounds of Formulas (I)-(III) or pharmaceutically acceptable salts thereof according to some embodiments of the present disclosure is that such compounds and / or salts have a high level of biological activity when such compounds and / or salts are formulated at higher (less acidic) pH levels. Without being bound by theory, it is believed that, according to some embodiments, the free amino or guanidino groups of the compounds of Formulas (I)-(III) or pharmaceutically acceptable salts thereof provide the desired biological activity at higher pH levels. It has been discovered that the compounds of Formulas (I)-(III) or pharmaceutically acceptable salts thereof according to some embodiments of the present disclosure are unexpectedly more potent at pH levels above about pH 3. Thus, it is believed that the compounds of Formulas (I)-(III) or pharmaceutically acceptable salts thereof according to some embodiments are useful for indications where prolonged exposure to antimicrobial agents is beneficial, such as, for example, microbial infections. Unlike some drugs formulated at a pH below about 3, which produces unacceptable contact irritation via topical, inhalation, or intravesical routes of administration, the compounds of Formulas (I)-(III) or pharmaceutically acceptable salts thereof according to some embodiments are compatible with topical, inhalation, and intravesical routes of administration. Furthermore, according to some embodiments, the compounds of Formulas (I)-(III) or pharmaceutically acceptable salts thereof are effective against slow-growing bacteria because the compounds or salts thereof exhibit a high level of biological activity at higher pH for a short period of time (fast-acting antibacterial mechanism).

[0021] Additional aspects and embodiments will be apparent from the detailed description and claims. DETAILED DESCRIPTION OF THE INVENTION

[0022] The embodiments described below are not intended to be exhaustive or to limit the invention to the precise forms disclosed in the following detailed description. Rather, the embodiments are chosen and described so that others skilled in the art can appreciate and understand the principles and practices of the present disclosure.

[0023] The present disclosure provides a compound having the formula: [ka] (In the formula, A is a monocyclic, bicyclic, or tricyclic carbocyclic or heterocyclic moiety; R1 and R2 are each a C1-C8 alkyl moiety. or a compound having Pharmaceutically acceptable salts thereof are provided.

[0024] In some embodiments, R1 and R2 are each butyl, as shown below: [ka] or a pharmaceutically acceptable salt thereof.

[0025] The present disclosure provides a compound having the formula: [ka] (In the formula, Q is oxygen or sulfur; W is an amino- or guanidino-substituted nitrogen-containing heterocyclic moiety; X and Z are endblocking groups; A is H, alkyl, halogen, alkoxy, alkyl-(O-alkyl), aryl, alkenyl, alkanol, or phenol. Also provided is a compound having the formula:

[0026] As used herein, the term "terminal blocking group" refers to any chemical moiety that prevents substantial nuclease degradation, particularly exonuclease degradation, of a protonated compound. The terminal group can be any chemical moiety that allows for proper protonation of a compound of formula (II), including, but not limited to, H, OH, SH, NH, alkyl groups, alkanol groups, etc.

[0027] In some embodiments, A is alkyl. In some embodiments, alkyl is CH3- or CH3-CH2-. In some embodiments, A is halogen. In some embodiments, halogen is F-, Cl-, Br-, or I-. In some embodiments, A is alkoxy. In some embodiments, alkoxy is CH3-O-CH2- or CH3-CH2-O-CH2-. In some embodiments, A is alkyl-(O-alkyl). In some embodiments, alkyl-(O-alkyl) is CH3-O- or CH3-CH2-O-. In some embodiments, A is aryl. In some embodiments, aryl is: [ka]

[0028] In some embodiments, A is alkenyl. In some embodiments, alkenyl is: [ka]

[0029] In some embodiments, A is an alkanol. In some embodiments, the alkanol is —CH—OH or CH—CH—OH. In some embodiments, A is a phenol. In some embodiments, the phenol is: [ka]

[0030] In some embodiments, W is an amino-substituted aziridine as shown below: [ka]

[0031] In some embodiments, W is an amino-substituted azetidine, as shown below: [ka]

[0032] In some embodiments, W is an amino-substituted 1,3-azetidine, as shown below: [ka]

[0033] In some embodiments, W is an amino-substituted azetidin-2-one (β-lactam), as shown below: [ka]

[0034] In some embodiments, W is an amino-substituted pyrrolidine, as shown below: [ka]

[0035] In some embodiments, W is an amino-substituted 3-pyrroline, as shown below: [ka]

[0036] In some embodiments, W is an amino-substituted 2-pyrroline, as shown below: [ka]

[0037] In some embodiments, W is an amino-substituted 1H-pyrrole, as shown below: [ka]

[0038] In some embodiments, W is an amino-substituted pyrazolidine, as shown below: [ka]

[0039] In some embodiments, W is an amino-substituted imidazolidine, as shown below: [ka]

[0040] In some embodiments, W is an amino-substituted 2-pyrazoline, as shown below: [ka]

[0041] In some embodiments, W is an amino-substituted 2-imidazoline, as shown below: [ka]

[0042] In some embodiments, W is an amino-substituted succinimide, as shown below: [ka]

[0043] In some embodiments, W is an amino-substituted hydantoin, as shown below: [ka]

[0044] In some embodiments, W is an amino-substituted 2,4-thiazolidinedione, as shown below: [ka]

[0045] In some embodiments, W is an amino-substituted piperidine, as shown below: [ka]

[0046] In some embodiments, W is an amino-substituted piperazine, as shown below: [ka]

[0047] In some embodiments, W is an amino-substituted morpholine, as shown below: [ka]

[0048] In some embodiments, W is an amino-substituted 2H-1,2-oxazudine, as shown below: [ka]

[0049] In some embodiments, W is an amino-substituted 4H-1,4-oxazudine, as shown below: [ka]

[0050] In some embodiments, W is an amino-substituted thiomorpholine, as shown below: [ka]

[0051] In some embodiments, W is an amino-substituted 2H-1,2-thiazine, as shown below: [ka]

[0052] In some embodiments, W is an amino-substituted 4H-1,4-thiazine, as shown below: [ka]

[0053] In some embodiments, W is an amino-substituted thiomorpholine dioxide, as shown below: [ka]

[0054] In some embodiments, W is an amino-substituted 1,4,5,6-tetrahydrocyclopenta[b]pyrrole, as shown below: [ka]

[0055] In some embodiments, W is an amino-substituted 1,3a,4,6a-tetrahydropyrrolo-[3,2-b]pyrrole, as shown below: [ka]

[0056] In some embodiments, W is an amino-substituted 1,4-dihydropyrrolo-[3,2-b]pyrrole, as shown below: [ka]

[0057] In some embodiments, W is an amino-substituted 1,6-dihydropyrrolo-[2,3,-b]pyrrole, as shown below: [ka]

[0058] In some embodiments, W is an amino-substituted 6H-furo[2,3-b]pyrrole, as shown below: [ka]

[0059] In some embodiments, W is an amino-substituted 4H-furo[3,2-b]pyrrole, as shown below: [ka]

[0060] In some embodiments, W is an amino-substituted 6H-thieno[2,3-b]pyrrole, as shown below: [ka]

[0061] In some embodiments, W is an amino-substituted 4H-thieno[3,2-b]pyrrole, as shown below: [ka]

[0062] In some embodiments, W is an amino-substituted indoline, as shown below: [ka]

[0063] In some embodiments, W is an amino-substituted 1H-indole, as shown below: [ka]

[0064] In some embodiments, W is an amino-substituted 2H-isoindole, as shown below: [ka]

[0065] In some embodiments, W is an amino-substituted 1H-indazole, as shown below: [ka]

[0066] In some embodiments, W is an amino-substituted benzamidazole, as shown below: [ka]

[0067] In some embodiments, W is an amino-substituted 4-azaindole, as shown below: [ka]

[0068] In some embodiments, W is an amino-substituted 5-azaindole, as shown below: [ka]

[0069] In some embodiments, W is an amino-substituted 6-azaindole, as shown below: [ka]

[0070] In some embodiments, W is an amino-substituted 7-azaindole, as shown below: [ka]

[0071] In some embodiments, W is an amino-substituted 7-azaindazole, as shown below: [ka]

[0072] In some embodiments, W is an amino-substituted purine, as shown below: [ka]

[0073] In some embodiments, W is an amino-substituted 1,2-benzisothiazol-3(2H)-one, as shown below: [ka]

[0074] In some embodiments, W is an amino-substituted guanine, as shown below: [ka]

[0075] In some embodiments, W is an amino-substituted adenine, as shown below: [ka]

[0076] In some embodiments, W is an amino-substituted decahydroisoquinoline, as shown below: [ka]

[0077] In some embodiments, W is an amino-substituted decahydroquinoline, as shown below: [ka]

[0078] In some embodiments, W is an amino-substituted 1,2,3,4-tetrahydroquinoline, as shown below: [ka]

[0079] In some embodiments, W is an amino-substituted 1,2-dihydroquinoline, as shown below: [ka]

[0080] In some embodiments, W is an amino-substituted 1,2-dihydroisoquinoline, as shown below: [ka]

[0081] In some embodiments, W is an amino-substituted 2H-benzo-[e][1,2]oxazine, as shown below: [ka]

[0082] In some embodiments, W is an amino-substituted quinolin 2(1H)-one, as shown below: [ka]

[0083] In some embodiments, W is an amino-substituted isoquinolin 1(2H)-one, as shown below: [ka]

[0084] In some embodiments, W is an amino-substituted carbazole, as shown below: [ka]

[0085] In some embodiments, W is an amino-substituted phenoxazine, as shown below: [ka]

[0086] In some embodiments, W is an amino-substituted phenothiazine, as shown below: [ka]

[0087] In some embodiments, W is an amino-substituted 2-azaadamantane, as shown below: [ka]

[0088] In some embodiments, W is an amino-substituted 2,3-dihydroazepine, as shown below: [ka]

[0089] In some embodiments, W is an amino-substituted 2,5-dihydroazepine, as shown below: [ka]

[0090] In some embodiments, W is an amino-substituted azepine, as shown below: [ka]

[0091] In some embodiments, W is an amino-substituted 1,2-azepine, as shown below: [ka]

[0092] In some embodiments, W is an amino-substituted 1,3-azepine, as shown below: [ka]

[0093] In some embodiments, W is an amino-substituted 1,4-azepine, as shown below: [ka]

[0094] In some embodiments, W is an amino-substituted azocane, as shown below: [ka]

[0095] In some embodiments, W is a guanidino-substituted aziridine. In some embodiments, W is a guanidino-substituted azetidine. In some embodiments, W is a guanidino-substituted 1,3-azetidine. In some embodiments, W is a guanidino-substituted azetidin-2-one (β-lactam). In some embodiments, W is a guanidino-substituted pyrrolidine. In some embodiments, W is a guanidino-substituted 3-pyrroline. In some embodiments, W is a guanidino-substituted 2-pyrroline. In some embodiments, W is a guanidino-substituted 1H-pyrrole. In some embodiments, W is a guanidino-substituted pyrazolidine.

[0096] In some embodiments, W is a guanidino-substituted imidazolidine. In some embodiments, W is a guanidino-substituted 2-pyrazoline. In some embodiments, W is a guanidino-substituted 2-imidazoline. In some embodiments, W is a guanidino-substituted succinimide. In some embodiments, W is a guanidino-substituted hydantoin. In some embodiments, W is a guanidino-substituted 2,4-thiazolidinedione.

[0097] In some embodiments, W is a guanidino-substituted piperidine. In some embodiments, W is a guanidino-substituted piperazine. In some embodiments, W is a guanidino-substituted morpholine. In some embodiments, W is a guanidino-substituted 2H-1,2-oxazidine. In some embodiments, W is a guanidino-substituted 4H-1,4-oxazidine. In some embodiments, W is a guanidino-substituted thiomorpholine.

[0098] In some embodiments, W is a guanidino-substituted 2H-1,2-thiazine. In some embodiments, W is a guanidino-substituted 4H-1,4-thithiazine. In some embodiments, W is a guanidino-substituted thiomorpholine dioxide. In some embodiments, W is a guanidino-substituted 1,4,5,6-tetrahydrocyclopenta[b]pyrrole. In some embodiments, W is a guanidino-substituted 1,3a,4,6a-tetrahydropyrrolo-[3,2-b]pyrrole. In some embodiments, W is a guanidino-substituted 1,4-dihydropyrrolo-[3,2-b]pyrrole.

[0099] In some embodiments, W is a guanidino-substituted 1,6-dihydropyrrolo-[2,3,-b]pyrrole. In some embodiments, W is a guanidino-substituted 6H-furo[2,3-b]pyrrole. In some embodiments, W is a guanidino-substituted 4H-furo[3,2-b]pyrrole. In some embodiments, W is a guanidino-substituted 6H-thieno[2,3-b]pyrrole. In some embodiments, W is a guanidino-substituted 4H-thieno[3,2-b]pyrrole. In some embodiments, W is a guanidino-substituted indoline.

[0100] In some embodiments, W is a guanidino-substituted 1H-indole. In some embodiments, W is a guanidino-substituted 2H-isoindole. In some embodiments, W is a guanidino-substituted 1H-indazole. In some embodiments, W is a guanidino-substituted benzamidazole. In some embodiments, W is a guanidino-substituted 4-azaindole. In some embodiments, W is a guanidino-substituted 5-azaindole.

[0101] In some embodiments, W is a guanidino-substituted 6-azaindole. In some embodiments, W is a guanidino-substituted 7-azaindole. In some embodiments, W is a guanidino-substituted 7-azaindazole. In some embodiments, W is a guanidino-substituted purine. In some embodiments, W is a guanidino-substituted 1,2-benzisothiazol-3(2H)-one.

[0102] In some embodiments, W is a guanidino-substituted guanine. In some embodiments, W is a guanidino-substituted adenine. In some embodiments, W is a guanidino-substituted decahydroisoquinoline. In some embodiments, W is a guanidino-substituted decahydroquinoline. In some embodiments, W is a guanidino-substituted 1,2,3,4-tetrahydroquinoline. In some embodiments, W is a guanidino-substituted 1,2-dihydroquinoline.

[0103] In some embodiments, W is a guanidino-substituted 1,2-dihydroisoquinoline. In some embodiments, W is a guanidino-substituted 2H-benzo-[e][1,2]oxazine. In some embodiments, W is a guanidino-substituted quinolin 2(1H)-one. In some embodiments, W is a guanidino-substituted isoquinolin 1(2H)-one. In some embodiments, W is a guanidino-substituted carbazole. In some embodiments, W is a guanidino-substituted phenoxazine.

[0104] In some embodiments, W is a guanidino-substituted phenothiazine. In some embodiments, W is a guanidino-substituted 2-azaadamantane. In some embodiments, W is a guanidino-substituted 2,3-dihydroazepine. In some embodiments, W is a guanidino-substituted 2,5-dihydroazepine. In some embodiments, W is a guanidino-substituted azepine. In some embodiments, W is a guanidino-substituted 1,2-azepine.

[0105] In some embodiments, W is a guanidino-substituted 1,3-azepine. In some embodiments, W is a guanidino-substituted 1,4-azepine. In some embodiments, W is a guanidino-substituted azocane.

[0106] In some embodiments, X and / or Z are straight alkyl chains. In some embodiments, the straight alkyl chain is: [ka]

[0107] In some embodiments, X and / or Z are branched alkyl chains. In some embodiments, the branched alkyl chain is: [ka]

[0108] In some embodiments, X and / or Z are branched alkyl chains. In some embodiments, the branched alkyl chain is: [ka]

[0109] In some embodiments, X and / or Z is a cyclic alkyl. In some embodiments, the cyclic alkyl is: [ka]

[0110] In some embodiments, X and / or Z is a cyclic alkyl. In some embodiments, the cyclic alkyl is: [ka]

[0111] In some embodiments, X and / or Z is aryl. In some embodiments, aryl is: [ka]

[0112] In some embodiments, X and / or Z is benzyl. In some embodiments, benzyl is: [ka]

[0113] In some embodiments, X and / or Z are straight chain alkanols. In some embodiments, the straight chain alkanol is: [ka]

[0114] In some embodiments, X and / or Z are branched chain alkanols. In some embodiments, the branched chain alkanol is: [ka]

[0115] In some embodiments, X and / or Z are cyclic alkanols. In some embodiments, the cyclic alkanol is: [ka]

[0116] In some embodiments, X and / or Z are cyclic alkanols. In some embodiments, the cyclic alkanol is: [ka]

[0117] In some embodiments, X and / or Z are phenolic. In some embodiments, the phenolic is: [ka]

[0118] In some embodiments, X and / or Z is 4-hydroxybenzyl. In some embodiments, 4-hydroxybenzyl is: [ka]

[0119] The present disclosure also provides compounds set forth in Table 1. As used herein, the term "compound" refers to a compound of formula (II) or a pharmaceutically acceptable salt thereof, where W, X, Z, A, and Q are defined as W, X, Z, A, and Q in one of the rows of Table 1 labeled Compound 1 through Compound 2520. For example, in the present disclosure or claims, "Compound 1 set forth in Table 1" specifically refers to a compound of formula (II) or a pharmaceutically acceptable salt thereof, where W, X, Z, A, and Q of the compound of formula (II) or a pharmaceutically acceptable salt thereof are as follows: [ka]

[0120] Compounds 1-2520 can be made by reference to the compound of formula (II), Table 1, and the synthetic schemes described in Examples 1-3. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] Table 1-9 Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14 Table 1-15 Table 1-16 Table 1-17 Table 1-18 Table 1-19 Table 1-20 Table 1-21 Table 1-22 Table 1-23 Table 1-24 Table 1-25 Table 1-26 Table 1-27 Table 1-28 Table 1-29 Table 1-30 Table 1-31 Table 1-32 Table 1-33 Table 1-34 Table 1-35 Table 1-36 Table 1-37 Table 1-38 Table 1-39 Table 1-40 Table 1-41 Table 1-42 Table 1-43 Table 1-44 Table 1-45 Table 1-46 Table 1-47 Table 1-48 Table 1-49 Table 1-50 Table 1-51 Table 1-52 Table 1-53 Table 1-54 Table 1-55 Table 1-56 Table 1-57 Table 1-58 Table 1-59 Table 1-60 Table 1-61 Table 1-62 Table 1-63 Table 1-64 Table 1-65 Table 1-66 Table 1-67 Table 1-68 Table 1-69 Table 1-70 Table 1-71 Table 1-72 Table 1-73 Table 1-74 Table 1-75 Table 1-76 Table 1-77 Table 1-78 Table 1-79 Table 1-80 Table 1-81 Table 1-82 Table 1-83 Table 1-84 Table 1-85 Table 1-86 Table 1-87 Table 1-88 Table 1-89

Table 1-90

Table 1-97

Table 1-110

Table 1-120

Table 1-195

Table 1-201

Table 1-202

Table 1-204

Table 1-206

Table 1-210

Table 1-220

Table 1-234

Table 1-239

Table 1-285

Table 1-289

Table 1-290

Table 1-299

Table 1-300

Table 1-302

Table 1-309

Table 1-340

Table 1-342

Table 1-345

Table 1-347

Table 1-349

Table 1-350

Table 1-351

Table 1-357

Table 1-359

Table 1-360

Table 1-365

Table 1-368

Table 1-369

Table 1-373

Table 1-375

Table 1-379

Table 1-380

Table 1-381

Table 1-382

Table 1-387

Table 1-389

Table 1-390

Table 1-392

Table 1-397

Table 1-399

Table 1-400

Table 1-401

Table 1-402

Table 1-403

Table 1-404

Table 1-405

Table 1-406

Table 1-407

Table 1-408

Table 1-409

Table 1-415

Table 1-419

Table 1-420

Table 1-429

Table 1-432

Table 1-439

Table 1-440

Table 1-441

Table 1-443

Table 1-447

Table 1-450

Table 1-451

Table 1-452

Table 1-455

Table 1-459

Table 1-460

[0121] The present disclosure provides a compound having the formula: [ka] a compound having or a pharmaceutically acceptable salt thereof.

[0122] The chemical name of the compound of formula (III) is sodium ((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-((butoxyoxidephosphoryl)oxy)tetrahydrofuran-2-yl)methylbutylphosphate. The molecular formula of the compound of formula (III) is C 17 H 29 N3Na2O 10 P2. The molecular weight of the compound of formula (III) is 543.11 Da. The compound of formula (III) is also referred to herein as Nu-8, compound (III), or compound 1, and these terms are used interchangeably herein. In some embodiments, Nu-8 comprises a ribose, two phosphate groups, two butyl groups, and a cytosine.

[0123] The compounds of the present disclosure are described with reference to the specific compounds shown herein. Furthermore, the compounds of the present disclosure may exist in any number of different forms or derivatives, all within the scope of the present disclosure. Alternative forms or derivatives include, for example, pharmaceutically acceptable salts, prodrugs and active metabolites, tautomers, and solid forms, including, but not limited to, different crystalline forms, polymorphs or amorphous solids, including hydrates and solvates thereof, and other forms.

[0124] Unless otherwise specified, the specification of the compounds of the present disclosure herein includes pharmaceutically acceptable salts of such compounds. Thus, the compounds of the present disclosure can be in the form of or formulated as pharmaceutically acceptable salts. Contemplated pharmaceutically acceptable salt forms of the present disclosure include, but are not limited to, mono-, bis-, tris-, tetrakis-, etc. The pharmaceutically acceptable salts of the present disclosure are non-toxic in the amounts and concentrations at which such pharmaceutically acceptable salts are administered. The preparation of such pharmaceutically acceptable salts of the present disclosure can facilitate pharmacological use by altering the physical properties of the compounds of the present disclosure without preventing them from exerting their physiological effects.

[0125] As used herein, the term "pharmaceutically acceptable" with respect to salts and formulation ingredients such as carriers, excipients, and diluents refers to those salts and ingredients that are not harmful to the patient and are compatible with other ingredients, active ingredients, salts, or ingredients. Pharmaceutically acceptable includes "veterinarily acceptable," and therefore includes both human and non-human mammalian use, independently.

[0126] As used herein, the term "pharmaceutically acceptable salt" refers to salts that are commonly used to form alkali metal salts and to form addition salts of free acids or free bases.Such salts include, for example, the physiologically acceptable salts listed in Handbook of Pharmaceutical Salts: Properties, Selection and Use, PH Stahl and CG Wermuth (eds.), Wiley-VCH, New York, 2002, which are known to those skilled in the art.Salt formation may occur at one or more positions that have labile protons.The pharmaceutically acceptable salts of the compounds of the present disclosure include both acid addition salts and base addition salts.

[0127] In some embodiments, suitable pharmaceutically acceptable acid addition salts of the compounds of the present disclosure can be prepared from inorganic or organic acids. Examples of such inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, sulfuric acid, and phosphoric acid. Suitable organic acids include, but are not limited to, organic acids from the aliphatic, alicyclic, aromatic, arylaliphatic, heterocyclic, carboxylic, and sulfonic acid classes, including, but not limited to, formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, maleic acid, embonic (pamoic) acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, pantothenic acid, benzenesulfonic acid, toluenesulfonic acid, sulfanilic acid, mesylic acid, cyclohexylaminosulfonic acid, stearic acid, algenic acid, beta-hydroxybutyric acid, malonic acid, galactaric acid, and galacturonic acid, to name a few. Pharmaceutically acceptable acid / anionic salts include acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camcyllerate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estrate, esylate, fumarate, glyceptate, gluconate, glutamate, glycolurilsanilate, hexylresorcinate, hydrobromide, hydrochloride, hydroxynaphthoate, Also included are iodide, isethionate, lactate, lactobionate, malate, maleate, malonate, mandelate, mesylate, methylsulfate, mucate, napsylate, nitrate, pamoate, pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, hydrogensulfate, tannate, tartrate, theocrate, tosylate, and triethiodide salts.

[0128] In some embodiments, suitable pharmaceutically acceptable base addition salts of the compounds of the present disclosure include, but are not limited to, metal salts made from aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc, or organic salts made from N,N'-dibenzylethylene-diamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, lysine, arginine, and procaine. All of these salts can be prepared by conventional means from the compounds of the present disclosure by treating the compounds with the appropriate acid or base. To give some examples, pharmaceutically acceptable basic / cationic salts also include diethanolamine, ammonium, ethanolamine, piperazine, and triethanolamine salts. In some embodiments, the pharmaceutically acceptable salts of the present disclosure contain a monovalent or divalent cation.

[0129] In some embodiments, the pharmaceutically acceptable salt of the present disclosure is selected from the group consisting of ammonium salts, calcium salts, sodium salts, potassium salts, magnesium salts, and cobalt salts. In some embodiments, the ammonium salt is ammonium ((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-((butoxyoxidephosphor-yl)oxy)tetrahydrofuran-2-yl)methylbutylphosphate. In some embodiments, the calcium salt is calcium ((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-((butoxyoxidephosphor-yl)oxy)tetrahydrofuran-2-yl)methylbutylphosphate. In some embodiments, the sodium salt is sodium ((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-((butoxyoxidephosphor-yl)oxy)tetrahydrofuran-2-yl)methylbutylphosphate. In some embodiments, the potassium salt is potassium ((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-((butoxyoxidephosphor-yl)oxy)tetrahydrofuran-2-yl)methylbutylphosphate. In some embodiments, the magnesium salt is magnesium ((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-((butoxyoxidephosphor-yl)oxy)tetrahydrofuran-2-yl)methylbutylphosphate. In some embodiments, the cobalt salt is cobalt ((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-((butoxyoxidephosphor-yl)oxy)tetrahydrofuran-2-yl)methylbutylphosphate.

[0130] Pharmaceutically acceptable salts of the present disclosure can be prepared by standard techniques known in the art to which the present disclosure pertains. For example, the free base form of a compound of the present disclosure can be isolated by dissolving it in a suitable solvent, such as an aqueous or aqueous alcoholic solution containing an appropriate acid, and then evaporating the solution. In another example, a salt can be prepared by reacting the free base with an acid in an organic solvent. If a particular compound is an acid, the desired pharmaceutically acceptable salt can be prepared by any suitable method, including, for example, treating the free acid with a suitable inorganic or organic base.

[0131] In addition to the compounds of the present disclosure, the present disclosure also includes prodrugs (eg, pharmaceutically acceptable prodrugs), active metabolic derivatives (active metabolites), and pharmaceutically acceptable salts thereof.

[0132] A prodrug is a compound or its pharmaceutically acceptable salt that, when metabolized under physiological conditions or converted by solvolysis, yields the desired active compound. Typically, prodrugs are inactive or less active than the active compound, but may offer one or more advantageous handling, administration, and / or metabolic properties. Some prodrugs are enzymatically activated to produce the active compound, or the compound may undergo further chemical reactions to produce the active compound. A prodrug may proceed from the prodrug form to the active form in a single form, or may have one or more intermediate forms, which may be active or inactive.

[0133] As described in *The Practice of Medicinal Chemistry*, Ch. 31-32 (Ed. Wermuth, Academic Press, San Diego, Calif., 2001), prodrugs can be conceptually divided into two non-exclusive categories: bioprecursor prodrugs and carrier prodrugs. Generally, bioprecursor prodrugs contain one or more protecting groups and are inactive or less active than the corresponding active drug compound that is converted to its active form by metabolism or solvolysis. Both the active drug form and the released metabolites should have acceptably low toxicity. Typically, the formation of an active drug compound involves one of the following types of metabolic processes or reactions:

[0134] Oxidation reaction: Exemplary oxidation reactions include, but are not limited to, reactions such as the oxidation of alcohol, carbonyl, and acid functional groups, hydroxylation of aliphatic carbons, hydroxylation of alicyclic carbon atoms, oxidation of aromatic carbon atoms, oxidation of carbon-carbon double bonds, oxidation of nitrogen-containing functional groups, oxidation of silicon, phosphorus, arsenic, and sulfur, oxidative N-dealkylation, oxidative O- and S-dealkylation, oxidative deamination, and other oxidation reactions.

[0135] Reduction reaction: Examples of reduction reactions include, but are not limited to, reactions such as reduction of carbonyl functional groups, reduction of alcohol functional groups and carbon-carbon double bonds, reduction of nitrogen-containing functional groups, and other reduction reactions.

[0136] Reactions that do not change oxidation state: Reactions that do not result in a change in oxidation state include, but are not limited to, reactions such as the hydrolysis of esters and ethers, hydrolytic cleavage of carbon-nitrogen single bonds, hydrolytic cleavage of non-aromatic heterocycles, hydration and dehydration at multiple bonds, dehydration reactions, hydrolytic dehalogenation, new atomic bonds resulting from the removal of a hydrogen halide molecule, and other such reactions.

[0137] Carrier prodrugs are drug compounds containing a transport moiety that, for example, improves uptake and / or localized delivery to the site of action. In such carrier prodrugs, the bond between the drug moiety and the transport moiety is covalent, the prodrug is desirably inactive or less active than the drug compound, and the prodrug and any release transport moiety are acceptably non-toxic. For prodrugs where the transport moiety is intended to enhance uptake, the transport moiety typically must release rapidly. In other cases, it is desirable to utilize a moiety that provides sustained release, such as certain polymers or other moieties such as cyclodextrins. Such carrier prodrugs are often advantageous for orally administered drugs. In some instances, the transport moiety provides targeted delivery of the drug. For example, the drug may be conjugated to an antibody or antibody fragment. Carrier prodrugs can be used, for example, to improve one or more of the following properties: increased lipophilicity, increased duration of pharmacological effect, increased site specificity, reduced toxicity and adverse reactions, and / or improved formulation (e.g., stability, water solubility, reduced undesirable organoleptic or physicochemical properties). For example, lipophilicity can be increased by esterification of hydroxyl groups with lipophilic carboxylic acids, or esterification of carboxylic acid groups with alcohols, such as aliphatic alcohols. Wermuth, supra.

[0138] Metabolites, such as active metabolites, overlap with the above-mentioned prodrugs, such as bioprecursor prodrugs. Thus, such metabolites are pharmacologically active compounds that are derivatives resulting from metabolic processes in the subject's body or compounds that are further metabolized to pharmacologically active compounds. Among these, active metabolites are such pharmacologically active derivative compounds. In the case of prodrugs, the prodrug compounds are generally inactive or less active than the metabolites. In the case of active metabolites, the parent compound may be an active compound or an inactive prodrug. For example, in some compounds, one or more alkoxy groups can be metabolized to hydroxyl groups and / or carboxyl groups can be esterified, e.g., glucuronidated, while retaining pharmacological activity. In some cases, multiple metabolites may exist when intermediate metabolites are further metabolized to provide active metabolites. For example, in some cases, derivative compounds resulting from metabolic glucuronidation may be inactive or less active and can be further metabolized to provide active metabolites.

[0139] Metabolites of compounds of the present disclosure may be identified using routine techniques known in the art, and their activities determined using tests such as those described in Bertolini et al., 1997, J. Med. Chem., 40:2011-2016; Shan et al., 1997, J Pharm Sci 86(7):756-757; Bagshawe, 1995, Drug Dev. Res., 34:220-230; Wermuth, supra.

[0140] It is understood by those skilled in the art that some compounds may exhibit tautomerism.In such cases, the formula provided herein expressly shows only one of possible tautomeric forms.Therefore, it should be understood that the compounds of the present disclosure are intended to represent any tautomeric form of the compound shown, and are not limited to the specific tautomeric form shown by the drawing of the compound.

[0141] For pharmaceutical agents that are solids, those skilled in the art will understand that compounds and salts may exist in different crystalline or polymorphic forms, may be formulated as co-crystals, may be amorphous, or may be any combination thereof (e.g., partially crystalline, partially amorphous, or a mixture of polymorphs), all of which are intended to be within the scope of this disclosure and the specific formula. While salts are formed by acid / base addition (i.e., the free base or free acid of the subject compound forms an acid / base reaction with the corresponding added base or added acid, respectively, resulting in an ionic charge interaction), co-crystals are new chemical species formed between neutral compounds, resulting in the compound and an additional molecular species within the same crystal structure.

[0142] In some examples, the compounds of the present disclosure are complexed with acids or bases, including, but not limited to, base addition salts such as ammonium, diethylamine, ethanolamine, ethylenediamine, diethanolamine, t-butylamine, piperazine, meglumine, and the like; acid addition salts such as acetate, acetylsalicylate, besylate, camcylate, citrate, formate, fumarate, glutarate, hydrochlorate, maleate, mesylate, nitrate, oxalate, phosphate, succinate, sulfate, tartrate, thiocyanate, and tosylate; and amino acids such as alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine.

[0143] Additionally, the compounds of the present disclosure are intended to encompass hydrated or solvated forms as well as unhydrated or unsolvated forms. Other examples of solvates include, but are not limited to, compounds of the present disclosure in combination with a suitable solvent such as isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, or ethanolamine.

[0144] In some embodiments, the compounds of the present disclosure are protonated compounds. As used herein, the term "protonated compound" refers to a compound of the present disclosure that is protonated by adding a proton (or a positively charged hydrogen ion) to the proton acceptor site of the compound of the present disclosure. In some embodiments, the proton acceptor site includes the phosphate group of the compound of the present disclosure, as well as any additional proton acceptor site of either the ribose or butyl group of the compound of the present disclosure.

[0145] The amount of protonation of a compound of the present disclosure can be determined by measuring the pH of the water solution after addition of the compound of the present disclosure, since the resulting pH when the compound of the present disclosure is dissolved in water having a pH of 7 decreases as the number of proton acceptor sites that are protonated on the compound of the present disclosure increases. pH indicates the hydrogen ion concentration of the solution. Solutions with a high concentration of hydrogen ions have a low pH and are therefore acidic, while solutions with a low concentration of hydrogen ions have a high pH and are therefore basic. In some embodiments, a compound of the present disclosure is protonated such that, when dissolved in water (pH 7), such compound forms an aqueous solution having a pH of less than about pH 7 to about pH 1. As used herein, the term "about," when used in conjunction with a numerical value, is intended to include the specified amount and variations of 20%, 10%, 5%, 1%, 0.5%, and 0.1% of the specified amount. In some embodiments, a compound of the present disclosure is a protonated compound that, when dissolved in water, has a pH of less than about pH 6 to about pH 1. In some embodiments, a compound of the present disclosure is a protonated compound that, when dissolved in water, has a pH of about pH 5 to about pH 1. In some embodiments, the compounds of the present disclosure are protonated compounds having a pH of about pH 4.5 to about pH 1 when dissolved in water. In some embodiments, the compounds of the present disclosure are protonated compounds having a pH of about pH 4 to about pH 1 when dissolved in water. In some embodiments, the compounds of the present disclosure are protonated compounds having a pH of about pH 3 to about pH 1 when dissolved in water. In some embodiments, the compounds of the present disclosure are protonated compounds having a pH of about pH 2 to about pH 1 when dissolved in water. In some embodiments, the compounds of the present disclosure are protonated compounds having a pH of about pH 3 to about pH 5 when dissolved in water. In some embodiments, the compounds of the present disclosure are protonated compounds having a pH of about pH 3 to about pH 4 when dissolved in water.

[0146] In some embodiments, protonation can be achieved by incubating a compound of the present disclosure in the presence of a strong acid. The compounds of the present disclosure can be protonated by adding a proton to a reactive site on the compound, although other modifications of the compounds of the present disclosure are possible and are intended to be encompassed by the term protonated compound as used herein. In some embodiments, protonated forms of the compounds of the present disclosure can be generated by subjecting purified, partially purified, or crude compounds to a low pH (e.g., acidic) environment. In some embodiments, purified or crude compounds can be protonated with acids including phosphoric acid, nitric acid, hydrochloric acid, and acetic acid.

[0147] Other procedures for preparing protonated compounds of the present disclosure that are known to those skilled in the art are equally considered within the scope of the present disclosure. In some embodiments, once a compound of the present disclosure is protonated, such a compound can be separated from any undesired components, such as excess acid. Those skilled in the art will recognize many methods for separating a compound from undesired components, including, but not limited to, the use of an H+-cation exchanger (e.g., H+-SCX). In some embodiments, a compound of the present disclosure can be subjected to chromatography after protonation. In some embodiments, a compound of the present disclosure can be run on a poly(styrene-divinylbenzene)-based resin (e.g., Hamilton's PRP-1 or 3 and Polymer Lab's PLRP) after protonation.

[0148] In some embodiments, the protonated compounds of the present disclosure can be used directly. In some embodiments, the protonated compounds of the present disclosure can be further processed to remove excess acid or salt, for example, by precipitation, reverse-phase chromatography, diafiltration, or gel filtration. In some embodiments, the protonated compounds of the present disclosure can be concentrated by lyophilization, solvent evaporation, or the like. In some embodiments, when suspended in water or saline, the compounds of the present disclosure generally exhibit a pH of about pH 3 to about pH 5, depending on the level of protonation / acidification, which is determined by the amount of acid used during the acidification process. In some embodiments, the compounds of the present disclosure can be protonated by passing them through a cation exchange column charged with hydrogen ions.

[0149] In some embodiments, the use of two butyl groups in the compounds of the present disclosure prevents or limits substantial nuclease degradation of the compounds of the present disclosure, including, but not limited to, exonuclease degradation. In some embodiments, the butyl groups are positioned to protect the ribose of the compounds of the present disclosure. The rate of acid degradation can be determined using analytical HPLC to assess loss of functional molecules or other suitable methods. Acid degradation is generally measured as a function of time. In some embodiments, the compounds of the present disclosure are also nuclease-resistant, allowing such compounds to maintain activity (e.g., pH stability) in an in vivo environment. The rate of degradation of the compounds of the present disclosure in a nuclease-containing environment can be determined by methods known to those of skill in the art, such as, for example, mass spectrometry. Nuclease degradation is generally measured as a function of time. In some embodiments, a reference compound is used in determining the extent or rate of acid or nuclease degradation. In some embodiments, compounds of the present disclosure are 10%, 20%, 30%, 40%, 50%, 70%, 90%, 100%, 150%, 200%, 300%, 500%, or 750% more stable than a reference compound.

[0150] The compounds of the present disclosure, according to some embodiments, are useful as antibacterial agents active against any microorganism. As used herein, terms such as "microorganism," "microorganism," and the like refer to bacteria, fungi, protozoa, viruses, yeast, and the like. As used herein, the term "antibacterial" refers to compounds of the present disclosure that have the ability to kill or inhibit the growth of microorganisms, or reduce the severity of microbial infections. A non-limiting list of bacteria against which the compounds of the present disclosure are effective includes, but is not limited to, gram-positive bacteria, gram-negative bacteria, slow-growing bacteria, and acid-fast bacteria, as well as any species within the following genera: Aerococcus, Listeria, Streptomyces, Chlamydia, Lactobacillus, Eubacteria, Burkholderia, Stenotrophomonas, Achromobacter, Arachnida, Mycobacterium, Peptosporium, and the like. Treptococcus, Staphylococcus, Corynebacterium, Erysipelothrix, Dermatophilus, Rhodococcus, Pseudomonas, Streptococcus, Bacillus, Peptococcus, Pneumococcus, Micrococcus, Neisseria, Klebsiella, Kurzia, Nocardia, Serratia, Rothia, Escherichia, Propionibacterium, Actinomyces, Helicobacter, Enterococcus, Shigella, Vibrio, Clostridium, Salmonella, Yersinia, and Haemophilus.

[0151] A non-limiting list of fungi against which the compounds of the present disclosure are effective includes, but is not limited to, Trichophyton, Epidermophyton, Microsporum, Candida albicans and other Candida species, Pityrosporum orbiculare, fungi, Mentagrophytes, Trichophyton rubrum, Epidermophyton floccosurn, and Trichophyton tonsurans. A non-limiting list of viruses against which the compounds of the present disclosure are effective includes, but is not limited to, human immunodeficiency virus (HIV), herpes simplex virus (HSV), cytomegalovirus (CMV), hepatitis B virus (HBV), hepatitis C virus (HCV), and influenza virus.

[0152] In some embodiments, the compounds of the present disclosure are useful for both therapeutic and non-therapeutic medical applications. In some embodiments, including non-therapeutic medical applications, the antimicrobial effect of the compounds of the present disclosure allows them to sterilize (e.g., sterilize the skin or surfaces of a patient, or an object such as a surgical instrument) or disinfect (e.g., clean the surface of an instrument to ensure that the surface does not contain undesirable concentrations of disease-causing microorganisms). In some embodiments, the compounds of the present disclosure are effective in combating microbial contamination of laboratory cultures, consumables (e.g., food or beverage preparations), medical devices, hospital equipment, or industrial processes. Therapeutic applications of the compounds of the present disclosure are described herein.

[0153] The present disclosure also provides pharmaceutical compositions. As used herein, the term "pharmaceutical composition" refers to a pharmaceutical formulation containing a compound of the present disclosure or a pharmaceutically acceptable salt thereof, suitable for administration to a patient for therapeutic purposes. As used herein, the term "patient" refers to an organism treated with a compound of the present disclosure, including, but not limited to, any mammal, such as a human, other primates (e.g., monkeys, chimpanzees, etc.), companion animals (e.g., dogs, cats, horses, etc.), farm animals (e.g., goats, sheep, pigs, cows, etc.), laboratory animals (e.g., mice, rats, etc.), and wild and zoo animals (e.g., wolves, bears, deer, etc.).

[0154] In some embodiments, the compositions may comprise at least one pharmaceutically acceptable component to provide improved formulations of the disclosed compounds, including, but not limited to, one or more pharmaceutically acceptable carriers, excipients, or diluents. The carriers, excipients, or diluents may take a wide variety of forms depending on the form of preparation desired for administration.

[0155] As used herein, the term "carrier" includes, but is not limited to, calcium carbonate, calcium phosphate, various sugars such as lactose, glucose, sucrose, types of starch, cellulose derivatives, gelatin, lipids, liposomes, nanoparticles, physiologically acceptable liquids as solvents or for suspension, including, for example, sterile water for injection (WFI), saline, dextrose solution, Hank's solution, Ringer's solution, vegetable oils, mineral oil, animal oils, polyethylene glycols, liquid paraffin, and the like.

[0156] As used herein, the term "excipient" generally includes, but is not limited to, fillers, binders, disintegrants, glidants, lubricants, complexing agents, solubilizers, stabilizers, preservatives, and surfactants, which may be selected to facilitate administration of a compound by a particular route. Suitable excipients include, for example, colloidal silicon dioxide, silica gel, talc, magnesium silicate, calcium silicate, sodium aluminosilicate, magnesium trisilicate, powdered cellulose, macrocrystalline cellulose, carboxymethylcellulose, cross-linked sodium carboxymethylcellulose, sodium benzoate, calcium carbonate, magnesium carbonate, stearic acid, aluminum stearate, calcium stearate, magnesium stearate, zinc stearate, sodium stearyl fumarate, syloid, stearate C, magnesium oxide, starch, sodium starch glycolate, glyceryl monostearate, glyceryl dibehenate, glyceryl palmitostearate, hydrogenated vegetable oil, hydrogenated cottonseed oil, castor oil, mineral oil, polyethylene glycol (e.g., PEG-10 stearate), PEG-10 stearate, ...4000-8000), polyoxyethylene glycol, poloxamer, povidone, crospovidone, croscarmellose sodium, alginic acid, casein, methacrylate divinylbenzene copolymer, docusate sodium, cyclodextrin (e.g., 2-hydroxypropyl-delta-cyclodextrin), polysorbate (e.g., polysorbate 80), cetrimide, TPGS (d-alpha-tocopheryl polyethylene glycol 1000 succinate), magnesium lauryl sulfate, sodium lauryl sulfate, polyethylene glycol ether, difatty acid ester of polyethylene glycol, or polyoxyalkylene sorbitan fatty acid ester (e.g., polyoxyethylene sorbitan ester Tween (registered trademark) Also included are sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, sorbitan fatty acid esters, e.g., from fatty acids such as oleic acid, stearic acid, or palmitic acid, mannitol, xylitol, sorbitol, maltose, lactose, lactose monohydrate, or spray-dried lactose, sucrose, fructose, calcium phosphate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, dextrates, dextran, dextrin, dextrose, cellulose acetate, maltodextrin, simethicone, polydextrin, chitosan, gelatin, HPMC (hydroxypropyl methylcellulose), HPC (hydroxypropyl cellulose), hydroxyethyl cellulose, and the like.

[0157] As one skilled in the art will appreciate, any diluent known in the art may be utilized in accordance with the present disclosure. In some embodiments of the present disclosure, the diluent is water-soluble. In some embodiments of the present disclosure, the diluent is water-insoluble. As used herein, the term "diluent" includes, but is not limited to, water, saline, phosphate buffered saline (PBS), dextrose, glycerol, ethanol, buffered sodium acetate or ammonium acetate solutions, and the like, and combinations thereof.

[0158] In some embodiments, the pharmaceutical composition of the present disclosure comprises at least one additional active ingredient. As used herein, the term "active ingredient" refers to a therapeutically active compound, as well as any prodrugs thereof, and pharmaceutically acceptable salts, hydrates, and solvates of the compound and prodrug. The additional active ingredient may be combined with the compound of the present disclosure, or may be administered separately or in the same pharmaceutical composition. The amount of the additional active ingredient to be administered can be determined by those skilled in the art based on the therapy with the compound of the present disclosure.

[0159] In some embodiments, the composition is a human pharmaceutical composition. As used herein, the term "human pharmaceutical composition" refers to a pharmaceutical composition intended for administration to a human.

[0160] The pharmaceutical compositions of the present disclosure are suitable for administration to a patient by any suitable means, including, but not limited to, those used to administer conventional antibacterial agents. The pharmaceutical compositions of the present disclosure may be administered using any applicable route conceivable by one of ordinary skill in the art, including, but not limited to, oral, intravenous ("IV") injection or infusion, intravesical, subcutaneous ("SC"), intramuscular ("IM"), intraperitoneal, intradermal, intraocular, inhalation (and intrapulmonary), intranasal, transdermal, epicutaneous, subcutaneous, topical, mucosal, nasal, ocular, skin impression, intravaginal, intrauterine, intrauterine, and rectal. Such dosage forms should enable the compounds of the present disclosure to reach target cells. Other factors are well known in the art and include considerations such as toxicity and dosage forms that delay the compound or composition from exerting its effect. Techniques and formulations may generally be found in Remington: The Science and Practice of Pharmacy, 21st edition, Lippincott, Williams and Wilkins, Philadelphia, Pa., 2005.

[0161] In some embodiments, the pharmaceutical compositions of the present disclosure are adapted for topical administration. As used herein, the term "topical administration" refers to administering a compound of the present disclosure to the skin surface of a patient so that the compound of the present disclosure passes through the skin layer. Transdermal administration and transmucosal administration are also encompassed by the term topical administration. As used herein, the term "transdermal" refers to the compound of the present disclosure passing through at least one skin layer of a patient. As used herein, "transmucosal" refers to the passage of a compound of the present disclosure across a patient's mucosa. Unless otherwise specified or implied, the terms "topical administration," "transdermal administration," and "transmucosal administration" are used interchangeably herein.

[0162] Various topical delivery systems for delivering bioactive compounds to a patient's microbiome are known in the art. Such systems include, but are not limited to, lotions, creams, gels, oils, ointments, solutions, suspensions, emulsions, and the like, with the appropriate carrier selected in the art. In some embodiments, the pharmaceutical composition is administered in the form of a gel containing a polyhydric alcohol.

[0163] Suitable carriers include, but are not limited to, vegetable or mineral oils, white petrolatum (e.g., white soft paraffin), branched-chain fats or oils, animal fats, and high molecular weight alcohols (e.g., greater than C12). In some embodiments, the carrier is selected so that the compound of the present disclosure is soluble. In some embodiments, emulsifiers, stabilizers, humectants, and antioxidants may also be included, as well as agents imparting color or fragrance, if desired. In some embodiments, organic solvents or cosolvents, such as ethanol or propanol, may be used in the pharmaceutical compositions of the present disclosure. In some embodiments, evaporation of the solvent leaves a residue on the treated surface, inhibiting reinfection. In some embodiments, a penetrating agent appropriate for the barrier to be penetrated is used. Such penetrating agents are generally known in the art and include, but are not limited to, bile salts and fusidic acid derivatives. In some embodiments, a detergent may be used to enhance penetration. In some embodiments, a cream for topical administration is formulated from a mixture of mineral oil, self-emulsifying beeswax, and water, to which a compound of the present disclosure dissolved in a small amount of solvent (e.g., oil) is mixed. The particular local delivery system used will depend on the location of the microorganism.

[0164] In some embodiments, other materials may be added to the topical pharmaceutical compositions of the present disclosure to provide additional moisturizing effects and improve the consistency of the pharmaceutical composition. Examples of such compounds include, but are not limited to, cetyl ester wax, stearyl alcohol, cetyl alcohol, glycerin, methylparaben, propylparaben, quaternium-15, humectants, volatile methylsiloxane fluids, and polydiorganosiloxane-polyoxyalkylenes. See, for example, U.S. Patent Nos. 5,153,230 and 4,421,769. In some embodiments, if it is desired that the pharmaceutical composition have additional cleansing effects, chemicals such as sodium lauryl sulfate or metal salts of carboxylic acids may be added.

[0165] In some embodiments, a wide variety of non-volatile emollients are useful in the pharmaceutical compositions of the present disclosure. Non-limiting examples of such non-volatile emollients are listed in McCutcheon's, Vol. 2 Functional Materials, North American Edition, (1992), pp. 137-168, and in the CTFA Cosmetic Ingredient Handbook, Second Edition (1992), which lists Skin-Conditioning Agents on pp. 572-575 and Skin Protectants on p. 580. In some embodiments, non-volatile emollients include silicones, hydrocarbons, esters, and mixtures thereof. In some embodiments, esters include esters of monofunctional and difunctional fatty acids esterified with alcohols and polyols (i.e., alcohols with two or more hydroxyl groups). In some embodiments, long-chain esters of long-chain fatty acids are utilized in the pharmaceutical compositions of the present disclosure (i.e., C10-40 fatty acids esterified with C10-40 fatty alcohols). Non-limiting examples of esters useful in the pharmaceutical compositions of the present disclosure include, but are not limited to, those selected from the group consisting of diisopropyl adipate, isopropyl myristate, isopropyl palmitate, myristyl propionate, ethylene glycol distearate, 2-ethylhexyl palmitate, isodecyl neopentanoate, C12-15 benzoic alcohol, di-2-ethylhexyl maleate, ceryl palmitate, myristyl myristate, stearyl stearate, cetyl stearate, behenyl behenate, and mixtures thereof.

[0166] Examples of silicone emollients useful in the pharmaceutical compositions of the present disclosure include, but are not limited to, polyalkylsiloxanes, cyclic polyalkylsiloxanes, and polyalkylarylsiloxanes. Suitable commercially available polyalkylsiloxanes include polydimethylsiloxanes, also known as dimethicones, non-limiting examples of which include the Vicasil™ series sold by General Electric Company and the Dow Corning™ 200 series sold by Dow Corning Corporation. Commercially available polyalkylsiloxanes include cyclomethicones (Dow Corning™ 244 Fluid, Dow Corning™ 344 Fluid, Dow Corning™ 245 Fluid, and Dow Corning™ 345), among others. A suitable commercially available trimethylsiloxysilicate is sold in a mixture with dimethicone as Dow Corning™ 593 Fluid. Also useful in the pharmaceutical compositions of the present disclosure is dimethiconol, a hydroxyl-terminated dimethyl silicone. Suitable commercially available dimethiconols are typically sold as mixtures with dimethicone or cyclomethicone (e.g., Dow Corning™ 1401, 1402, and 1403 fluids). Suitable commercially available polyalkylaryl siloxanes include SF1075 methylphenyl fluid (sold by General Electric Company) and 556 cosmetic grade phenyl trimethicone fluid (sold by Dow Corning Corporation).

[0167] Hydrocarbons suitable for use in the pharmaceutical compositions of the present disclosure include, but are not limited to, straight-chain and branched-chain hydrocarbons having from about 10 to about 30 carbon atoms. In some embodiments, the straight-chain and branched-chain hydrocarbons have from about 12 to about 24 carbon atoms. In some embodiments, the straight-chain and branched-chain hydrocarbons have from about 16 to about 22 carbon atoms. Non-limiting examples of such hydrocarbon materials include, among others, dodecane, squalane, cholesterol, pentahydrogenated polyisobutylene, docosane (i.e., a C22 hydrocarbon), hexadecane, and isohexadecane (a commercially available hydrocarbon sold as Permethyl™ 101A by Presperse, South Plainsfield, NJ).

[0168] In some embodiments, the topical pharmaceutical compositions of the present disclosure include propylene glycol. In some embodiments, propylene glycol acts as a surfactant, aiding in penetration, contact, and absorption of the compounds of the present disclosure. In some embodiments, propylene glycol functions as a preservative. In some embodiments, the pharmaceutical compositions of the present disclosure include a non-ionic surfactant, such as polysorbate. Such surfactants further reduce surface tension, thereby providing better surface contact between the pharmaceutical compositions of the present disclosure and mucous membranes (such as the vaginal mucosa).

[0169] The topical pharmaceutical compositions of the present disclosure may also optionally be formulated with a lipophilic phase, such as emulsions and liposomal dispersions. In some embodiments, liposomal formulations may extend the circulation time of the compounds of the present disclosure, increase their permeability, and improve the overall efficacy of the compounds of the present disclosure as antibacterial agents. In some embodiments, the compounds of the present disclosure may be combined with lipids, cationic lipids, or anionic lipids. In some embodiments, the resulting emulsions or liposomal suspensions, combined with the pH-stabilizing qualities of the compounds of the present disclosure, can effectively increase the in vivo half-life of the activity of the pharmaceutical compositions of the present disclosure. Examples of anionic lipids suitable for use with the pharmaceutical compositions of the present disclosure include, but are not limited to, anionic forms of cardiolipin, dimyristoyl, dipalmitoyl, dioleoylphosphatidylcholine, phosphatidylglycerol, palmitoyloleoylphosphatidylcholine, phosphatidylglycerol, phosphatidic acid, lysophosphatidic acid, phosphatidylserine, phosphatidylinositol, and cholesterol.

[0170] In some embodiments, the compounds of the present disclosure are incorporated into liposomes. In some embodiments, neutral lipids, cholesterol, and / or polyethylene glycol (PEG) are utilized in such liposomes. In some embodiments, the liposome composition is composed of partially hydrogenated soybean phosphatidylcholine (PHSC), cholesterol, methoxy-terminated PEG (mPEG), and / or distearoylphosphatidylethanolamine (DSPE). Liposomes can be prepared according to any suitable method known in the art.

[0171] In some embodiments, topical administration is via nasal spray or suppository (rectal or vaginal). Suppositories are prepared by mixing a compound of the present disclosure with a lipid vehicle such as theobroma oil, cocoa butter, glycerin, gelatin, or polyoxyethylene glycol. In some embodiments, topical administration involves a transdermal patch or dressing, such as a bandage, impregnated with a compound of the present disclosure and, optionally, one or more carriers, excipients, or diluents known in the art. In some embodiments, such dressings include, but are not limited to, semipermeable membranes, foams, hydrocolloids, and calcium alginate swabs. In some embodiments, the dosage regimen is continuous rather than intermittent throughout the entire dosage regimen.

[0172] In some embodiments, the pharmaceutical compositions of the present disclosure are adapted for oral administration. As used herein, the term "oral administration" refers to administration of a compound of the present disclosure to a patient's mouth for ingestion into the gastrointestinal tract. In some embodiments, the pharmaceutical compositions of the present disclosure can be formulated into conventional oral dosage forms, including, but not limited to, capsules, tablets, powders, and liquid preparations such as suspensions, solutions, elixirs, syrups, and concentrated drops. In some embodiments, the compounds of the present disclosure can be combined with solid excipients, optionally after adding suitable adjuvants, to obtain, for example, tablets, coated tablets, hard capsules, soft capsules, solutions (e.g., aqueous, alcoholic, or oily solutions), and the like, and the resulting mixture can be optionally milled and the resulting mixture can be optionally processed into granules. In some embodiments, excipients suitable for use in oral pharmaceutical compositions of the present disclosure include, but are not limited to, fillers such as sugars including lactose, glucose, sucrose, mannitol, or sorbitol; cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose (CMC), and / or polyvinylpyrrolidone (PVP or povidone); and oily excipients including vegetable and animal oils such as sunflower oil, olive oil, or cod liver oil. In some embodiments, the oral pharmaceutical compositions of the present disclosure may also contain disintegrating agents such as cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate; lubricants such as talc, talc, or magnesium stearate; plasticizers such as glycerol or sorbitol; sweeteners such as sucrose, fructose, lactose, aspartame, or natural or artificial flavoring agents such as peppermint, oil of wintergreen, or cherry flavor; or dyes or pigments, which can be used to identify or characterize different doses or combinations. In some embodiments, the oral pharmaceutical compositions of the present disclosure may also contain dragee cores with suitable coatings.In some embodiments, for example, gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, titanium dioxide, lacquer solutions, and concentrated sugar solutions that may optionally contain suitable organic solvents or solvent mixtures may be used.

[0173] In some embodiments, orally usable pharmaceutical compositions of the present disclosure include, but are not limited to, push-fit capsules ("gelcaps") made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. In some embodiments, the push-fit capsules may contain a compound of the present disclosure mixed with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and optionally, a stabilizer. In some embodiments comprising soft capsules, the active compound may be dissolved or suspended in a suitable liquid, such as fatty oils, liquid paraffin, or liquid polyethylene glycol.

[0174] In some embodiments, the pharmaceutical compositions of the present disclosure are adapted for inhalation administration. As used herein, the term "inhalation administration" refers to delivery of a compound of the present disclosure by passing through a patient's nose or mouth during inhalation and passage of the compound through the patient's lung walls. In some embodiments, pharmaceutical compositions of the present disclosure suitable for inhalation administration can be formulated as a dry powder or a suitable solution, suspension, or aerosol. In some embodiments, powders and solutions can be formulated with suitable additives known in the art. In some embodiments, powders can include a suitable powder base such as lactose or starch. In some embodiments, solutions can include propylene glycol, sterile water, ethanol, sodium chloride, and other additives such as acids, alkalis, and buffer salts. In some embodiments, such solutions or suspensions can be administered by inhalation via a spray, pump, atomizer, nebulizer, or the like. In some embodiments, pharmaceutical compositions of the present disclosure suitable for inhaled administration may also be used in combination with other inhaled therapies, including, but not limited to, corticosteroids such as, for example, fluticasone propionate, beclomethasone dipropionate, triamcinolone acetonide, budesonide, and mometasone furoate; beta-agonists such as, for example, albuterol, salmeterol, formoterol; anticholinergics such as, for example, ipratropium bromide or tiotropium; vasodilators such as, for example, treprostinal and iloprost; enzymes such as, for example, DNAase; therapeutic proteins; immunoglobulin antibodies; oligonucleotides such as, for example, single- or double-stranded DNA or RNA, siRNA; antibiotics such as, for example, tobramycin; muscarinic receptor antagonists; leukotriene antagonists; cytokine antagonists; protease inhibitors; cromolyn sodium; nedocryl sodium; and sodium cromoglycate.

[0175] In some embodiments, the pharmaceutical composition of the present disclosure is adapted for intravesical administration. As used herein, the term "intravesical administration" refers to delivering a compound of the present disclosure directly to a patient's bladder. In some embodiments, the pharmaceutical composition is administered via a catheter. In some embodiments, the catheter is a urethral catheter.

[0176] In some embodiments, the pharmaceutical compositions of the present disclosure are suitable for parenteral administration. As used herein, the term "parenteral administration" refers to a compound of the present disclosure injected or infused into a patient, including, but not limited to, intravenous, intramuscular, intraarterial, intrathecal, intraventricular, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, intradermal, intraarticular, subcapsular, intrathecal, intraspinal, and intrasternal injection and infusion. In some embodiments, pharmaceutical compositions of the present disclosure suitable for parenteral administration can be formulated in a sterile liquid solution, including, but not limited to, physiologically compatible buffers or solutions such as saline, Hank's solution, or Ringer's solution. In some embodiments, pharmaceutical compositions of the present disclosure suitable for parenteral administration can be prepared as a dispersion in a non-aqueous solution, such as, for example, glycerol, propylene glycol, ethanol, liquid polyethylene glycol, triacetin, vegetable oil, or the like. In some embodiments, the solution may contain a preservative, such as, for example, methylparaben, propylparaben, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. Additionally, pharmaceutical compositions of the present disclosure suitable for parenteral administration may be formulated in solid form, including, for example, lyophilized forms, and redissolved or suspended prior to use. In some embodiments, the pharmaceutical composition is administered via needle.

[0177] In some embodiments, the present disclosure provides methods and compositions for pretreating a catheter with a compound of the present disclosure, for example, to prevent infection after the catheter has been inserted into a patient. In some embodiments, the methods of the present disclosure include coating the catheter with a compound of the present disclosure before inserting the catheter into a patient. In some embodiments, the present disclosure provides compositions comprising a catheter coated with a compound of the present disclosure. In some embodiments, such methods and compositions can be used as a prophylactic treatment of infection in a patient.

[0178] The present disclosure also provides methods of treatment. As used herein, the terms "treat," "treatment," "therapy," and the like refer to the administration of a compound or pharmaceutical composition of the present disclosure in an amount effective to prevent, alleviate, or ameliorate one or more symptoms of a disease or condition (i.e., an indication) and / or prolong the survival of the patient being treated. In some embodiments, "treat," "treatment," "therapy," and similar terms also include, but are not limited to, reducing or eliminating an infection in a patient.

[0179] In practicing the methods of the present disclosure, an effective amount of a compound of the present disclosure is administered to a patient in need of treatment. As used herein, the term "effective amount" in the context of administration refers to the amount of a compound or pharmaceutical composition of the present disclosure that, when administered to a patient, is sufficient to prevent, alleviate, or ameliorate one or more symptoms of a disease or condition (i.e., an indication) and / or prolong the survival of the patient during treatment. Such an amount should result in no or little adverse events in the treated patient. Similarly, such an amount should result in no or little toxic effects in the treated patient. As will be understood by one of ordinary skill in the art, the amount of a compound or pharmaceutical composition of the present disclosure will vary depending on many factors, including, but not limited to, the activity of the compound of the present disclosure (in vitro, e.g., compound-to-target, or in vivo activity in an animal efficacy model), pharmacokinetic results in animal models (e.g., biological half-life or bioavailability), the type of patient being treated, the patient's age, size, weight, and general physical condition, the disorder associated with the patient, and the dosing regimen used in the treatment.

[0180] In some embodiments of the present disclosure, the effective amount of a compound of the present disclosure delivered to a patient in need of treatment can be quantified by determining micrograms of a compound of the present disclosure per kilogram of the patient's body weight. In some embodiments, the amount of a compound of the present disclosure administered to a patient is about 0.1 to about 1000 milligrams (mg) of a compound of the present disclosure per kilogram (kg) of the patient's body weight. In some embodiments, the amount of a compound of the present disclosure administered to a patient is about 0.1 to about 500 mg of a compound of the present disclosure per kg of the patient's body weight. In some embodiments, the amount of a compound of the present disclosure administered to a patient is about 0.1 to about 300 mg of a compound of the present disclosure per kg of the patient's body weight. In some embodiments, the amount of a compound of the present disclosure administered to a patient is about 0.1 to about 200 mg of a compound of the present disclosure per kg of the patient's body weight. In some embodiments, the amount of a compound of the present disclosure administered to a patient is about 0.1 to about 100 mg of a compound of the present disclosure per kg of the patient's body weight. As one of ordinary skill in the art will appreciate, multiple doses may be used.

[0181] In some embodiments of the present disclosure, the compounds of the present disclosure are administered as a multiple dose regimen. As used herein, the term "multiple dose regimen" refers to a treatment period of two or more days. In some embodiments of the present disclosure, the multiple dose regimen is up to about two days in duration. In some embodiments of the present disclosure, the multiple dose regimen is up to about three days in duration. In some embodiments of the present disclosure, the multiple dose regimen is up to about four days in duration. In some embodiments of the present disclosure, the multiple dose regimen is up to about five days in duration. In some embodiments of the present disclosure, the multiple dose regimen is up to about six days in duration. In some embodiments of the present disclosure, the multiple dose regimen is up to about seven days in duration. In some embodiments of the present disclosure, the multiple dose regimen is up to about 14 days in duration. In some embodiments of the present disclosure, the multiple dose regimen is up to about one month in duration. In some embodiments of the present disclosure, the multiple dose regimen is up to about two months in duration. In some embodiments of the present disclosure, the multiple dose regimen is up to about three months in duration. In some embodiments of the present disclosure, the multiple dose regimen is for a period of up to about 4 months. In some embodiments of the present disclosure, the multiple dose regimen is for a period of up to about 5 months. In some embodiments of the present disclosure, the multiple dose regimen is for a period of up to about 6 months. Other periods may be used herein.

[0182] In some embodiments of the present disclosure, the compounds of the present disclosure are administered as part of a chronic treatment regimen. As used herein, the term "chronic treatment regimen" refers to treatment with a compound of the present disclosure for an extended period of time throughout the patient's life. In some embodiments, the chronic treatment is lifelong treatment.

[0183] In some embodiments of the present disclosure, the compound of the present disclosure is administered as a single dose. In some embodiments of the present disclosure, the compound of the present disclosure is administered as a single unit dose. As used herein, the term "unit dose" refers to a predetermined amount of the compound of the present disclosure. The amount of the compound of the present disclosure is generally equal to the dosage of the compound of the present disclosure administered to a patient, or a convenient fraction of such a dosage, such as half or one-third of such a dosage. According to the method of the present disclosure, the terms "single dose" and "single unit dose" include embodiments in which the composition can be administered as a single application or as multiple applications.

[0184] In some embodiments, the compounds of the present disclosure may also be used in combination with one or more additional active ingredients to treat the same disease or condition. In some embodiments, such combined use includes administering the compound of the present disclosure and one or more additional active ingredients at different times, or administering the compound of the present disclosure and one or more additional active ingredients simultaneously. In some embodiments, the dosage may be modified by methods known to those skilled in the art to reduce the amount administered of the compound of the present disclosure or one or more additional active ingredients used in combination, for example, the compound of the present disclosure or one or more additional active ingredients used alone. In some embodiments, simultaneous administration includes administering the compound of the present disclosure and the additional active ingredient(s) simultaneously in the same dosage form, administering the compound of the present disclosure and the additional active ingredient(s) simultaneously in separate dosage forms, and administering the compound of the present disclosure and the additional active ingredient(s) separately.

[0185] Use in combination is understood to include the use of one or more additional active ingredients or other medical procedures, rather than the compounds or pharmaceutical compositions of the present disclosure, with or simultaneously with one or more additional active ingredients or other medical procedures that may be administered at different times (e.g., within a short period of time, such as within a few hours (e.g., 1, 2, 3, 4 to 24 hours, etc.), or within a longer period of time (e.g., 1 to 2 days, 2 to 4 days, 4 to 7 days, 1 to 4 weeks, etc.)). Use in combination also includes the use of one or more additional active ingredients or other medical procedures that are administered once or infrequently, such as surgery, together with a compound or pharmaceutical composition of the present disclosure that is administered within a short or long period of time before or after the administration of the one or more additional active ingredients or completion of the other medical procedure.

[0186] In some embodiments, the present disclosure provides for the delivery of a compound or pharmaceutical composition of the present disclosure and one or more additional active ingredients delivered by different or the same route of administration. In some embodiments, the use of any combination of routes of administration includes the delivery of a compound or pharmaceutical composition of the present disclosure and one or more additional active ingredients delivered together by the same route of administration in any pharmaceutical composition, including pharmaceutical compositions in which the two compounds are chemically linked such that such compounds maintain their therapeutic activity when administered. In some embodiments, one or more additional active ingredients may be co-administered with a compound or pharmaceutical composition of the present disclosure. In some embodiments, the use of a combination by co-administration includes the administration of a co-formulation or formulation of chemically linked compounds administered by the same or different routes, or the administration of two or more compounds in separate formulations within a short time of each other (e.g., within 1 hour, 2 hours, 3 hours, up to 24 hours, etc.). In some embodiments, the co-administration of separate formulations includes co-administration via a single device, such as the same inhalation device, the same syringe, etc., or administration from separate devices within a short time of each other. In some embodiments, co-formulation of a compound or pharmaceutical composition of the present disclosure with one or more additional active ingredients delivered by the same route includes preparing the materials together so that they can be administered by a single device containing the separate combined compounds, or compounds that have been modified so that the compounds are chemically linked while retaining their biological activity. In some embodiments, such chemically linked compounds may have a linkage that is substantially maintained in vivo, or the linkage may be broken in vivo, separating the two active ingredients.

[0187] The present disclosure also provides methods for treating an infectious disease in a patient in need of treatment. In some embodiments, the methods comprise administering to the patient an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof. As used herein, the term "infectious disease" refers to any microbial infection of the patient's body. Infectious diseases include the invasion of the patient's body by a microorganism and subsequent proliferation within the patient's body.

[0188] The present disclosure also provides a method for treating a lower extremity ulcer infection in a patient in need of treatment. In some embodiments, the method comprises administering to the patient an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof. As used herein, the term "infection" refers to any microbial infection in a patient's body. Infection includes the invasion of a patient's body by a microorganism and subsequent proliferation within the patient's body. As used herein, the term "lower extremity" refers to an extremity in the lower half of a patient's body, including, but not limited to, the hip, thigh, leg, ankle, and foot. As used herein, the term "ulcer" refers to an open wound found anywhere on a patient's lower extremity.

[0189] In some embodiments, the present disclosure provides a method for treating a diabetic foot ulcer infection in a patient in need of treatment. In some embodiments, the method comprises administering to the patient an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof. In some embodiments, the patient has type I diabetes or type II diabetes. As used herein, the term "diabetic foot ulcer" refers to an open wound located anywhere on the patient's foot. In some embodiments, the wound is located in the heel, midfoot, and / or forefoot of the patient. As used herein, the term "treating" in the context of a diabetic foot ulcer also includes, but is not limited to, reducing or eliminating the infection in a patient, which in some embodiments results in: limiting the progression of the size, area, and / or depth of the foot ulcer; reducing the size, area, and / or depth of the foot ulcer; increasing the rate of healing and / or shortening the time to healing; healing of the foot ulcer (approximately 100% epithelialization without drainage); and / or reducing the incidence of or delaying the time to amputation.

[0190] In some embodiments, the patient is a human. In some embodiments, the administration is topical. In some embodiments, the administration is carried out using the compound or a pharmaceutically acceptable salt thereof in a lotion, paste, gel, cream, ointment, oil, or other viscous composition. In some embodiments, the patient is administered at least one additional active ingredient. In some embodiments, the administration is carried out as a multiple dose regimen. In some embodiments, the multiple dose regimen is for a period of up to about 1 month. In some embodiments of the present disclosure, the multiple dose regimen is for a period of up to about 2 months. In some embodiments of the present disclosure, the multiple dose regimen is for a period of up to about 3 months. In some embodiments of the present disclosure, the multiple dose regimen is for a period of up to about 4 months. Other periods may be used herein.

[0191] In some embodiments, administration is performed one or more times daily. In some embodiments, administration is performed once daily. In some embodiments, administration is performed twice daily. In some embodiments, administration is performed three times daily. In some embodiments, administration is performed four times daily.

[0192] The present disclosure also provides methods for treating a urinary tract infection in a patient in need thereof. In some embodiments, the method comprises administering to the patient an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof. As used herein, the term "urinary tract" refers to the organs of a patient's body that produce, store, and excrete urine, including, but not limited to, the kidneys, ureters, bladder, and urethra. As used herein, the term "urinary tract infection" refers to an infection of a patient's urinary tract, including, but not limited to, uncomplicated urinary tract infections and complicated urinary tract infections. As used herein, the term "uncomplicated urinary tract infection" refers to a microbial infection of a patient's structurally and functionally normal urinary tract. As used herein, the term "complicated urinary tract infection" refers to a microbial infection of a patient's abnormal structural and functional urinary tract. In some embodiments, the complicated urinary tract infection is a catheter-associated urinary tract infection. As used herein, the term "catheter-associated urinary tract infection" refers to a complicated urinary tract infection that occurs in a patient with an indwelling urinary catheter.

[0193] In some embodiments, the patient is human. In some embodiments, the administration is intravesical. In some embodiments, the administration is carried out using a compound of the present disclosure or a pharmaceutically acceptable salt thereof in a liquid solution or suspension. In some embodiments, the patient is administered at least one additional active ingredient. In some embodiments, the administration is carried out as a multiple dose regimen. In some embodiments of the present disclosure, the multiple dose regimen is for a period of up to about 2 days. In some embodiments of the present disclosure, the multiple dose regimen is for a period of up to about 3 days. In some embodiments of the present disclosure, the multiple dose regimen is for a period of up to about 4 days. In some embodiments of the present disclosure, the multiple dose regimen is for a period of up to about 5 days. In some embodiments of the present disclosure, the multiple dose regimen is for a period of up to about 6 days. In some embodiments of the present disclosure, the multiple dose regimen is for a period of up to about 7 days. In some embodiments of the present disclosure, the multiple dose regimen is for a period of up to about 14 days. In some embodiments of the present disclosure, the administration is carried out as a chronic treatment regimen. Other periods may be used herein.

[0194] In some embodiments, administration is performed one or more times daily. In some embodiments, administration is performed once daily. In some embodiments, administration is performed twice daily. In some embodiments, administration is performed three times daily. In some embodiments, administration is performed four times daily.

[0195] The present disclosure also provides methods of treating a pulmonary infection in a patient in need thereof. In some embodiments, the method comprises administering to the patient an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof. As used herein, the term "pulmonary infection" refers to an infection of one or both of the patient's lungs. In some embodiments, the pulmonary infection is caused by a pulmonary condition. As used herein, the term "pulmonary condition" refers to both infectious and non-infectious-induced diseases and dysfunctions of the respiratory system.

[0196] Non-limiting examples of pulmonary conditions include genetic conditions, acquired conditions, primary conditions, secondary conditions, asthma, chronic obstructive pulmonary disease, cystic fibrosis, bronchiolitis, pneumonia, bronchitis, emphysema, adult respiratory distress syndrome, allergies, lung cancer, small cell lung cancer, primary lung cancer, metastatic lung cancer, bronchiectasis, bronchopulmonary dysplasia, chronic bronchitis, chronic lower respiratory tract disease, croup, high altitude pulmonary edema, pulmonary fibrosis, interstitial lung disease, reactive airway disease, lymphangioleiomyoma, neonatal respiratory distress syndrome, parainfluenza, These include, but are not limited to, pleural effusion, pleuritis, pneumothorax, primary pulmonary hypertension, psittacosis, pulmonary edema secondary to various causes, pulmonary embolism, pulmonary hypertension secondary to various causes, respiratory failure secondary to various causes, sleep apnea, sarcoidosis, smoking, wheezing, acute respiratory distress syndrome, infectious diseases, SARS, tuberculosis, psittacosis infection, Q fever, parainfluenza, respiratory syncytial virus, combinations thereof, and conditions caused by any one or combination of the above.

[0197] In some embodiments of the present disclosure, a method of treating a lung infection caused by cystic fibrosis in a patient in need thereof is provided. In some embodiments, the method comprises administering to the patient an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof. As used herein, the term "cystic fibrosis" refers to a genetic disease that causes the production of abnormally thick mucus, leading to lung infections and damage to the lungs, digestive system, and other organs in the patient's body.

[0198] In some embodiments, the administration is by inhalation. In some embodiments, the patient is administered at least one additional active ingredient. In some embodiments, the patient is human. In some embodiments, the administration is carried out using a compound of the present disclosure or a pharmaceutically acceptable salt thereof in a liquid solution, suspension, or dry powder. In some embodiments, the administration is carried out as a multiple dose regimen. In some embodiments, the multiple dose regimen is for a period of up to about 1 month. In some embodiments of the present disclosure, the multiple dose regimen is for a period of up to about 2 months. In some embodiments of the present disclosure, the multiple dose regimen is for a period of up to about 3 months. In some embodiments of the present disclosure, the multiple dose regimen is for a period of up to about 4 months. In some embodiments of the present disclosure, the multiple dose regimen is for a period of up to about 5 months. In some embodiments of the present disclosure, the multiple dose regimen is for a period of up to about 6 months. In some embodiments of the present disclosure, the multiple dose regimen is for a period of up to about 7 months. In some embodiments of the present disclosure, the multiple dose regimen is for a period of up to about 8 months. Other periods may be used herein.

[0199] In some embodiments, administration is performed one or more times daily. In some embodiments, administration is performed once daily. In some embodiments, administration is performed twice daily. In some embodiments, administration is performed three times daily. In some embodiments, administration is performed four times daily.

[0200] In some embodiments of the present disclosure, a method of treating pneumonia in a patient in need thereof is provided. In some embodiments, the method comprises administering to the patient an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof. As used herein, the term "pneumonia" refers to a microbial infection of one or both lungs of a patient, resulting in inflammation of lung tissue. In some embodiments, the pneumonia is ventilator-acquired pneumonia. As used herein, the term "ventilator-acquired pneumonia" refers to pneumonia resulting from a patient being connected to a mechanical ventilator. Ventilator-acquired pneumonia includes pneumonia that occurs more than about 48 hours after the patient has been intubated and is receiving mechanical ventilation.

[0201] In some embodiments, the administration is by inhalation. In some embodiments, the patient is administered at least one additional active ingredient. In some embodiments, the patient is human. In some embodiments, the administration is carried out using a compound of the present disclosure or a pharmaceutically acceptable salt thereof in a liquid solution, suspension, or dry powder. In some embodiments, the administration is carried out as a multiple dose regimen. In some embodiments of the present disclosure, the multiple dose regimen is for a period of up to about 7 days. In some embodiments of the present disclosure, the multiple dose regimen is for a period of up to about 14 days. In some embodiments of the present disclosure, the multiple dose regimen is for a period of up to about 21 days. In some embodiments, the multiple dose regimen is for a period of up to about 1 month. In some embodiments of the present disclosure, the multiple dose regimen is for a period of up to about 2 months. Other periods may be used herein.

[0202] In some embodiments, administration is performed one or more times daily. In some embodiments, administration is performed once daily. In some embodiments, administration is performed twice daily. In some embodiments, administration is performed three times daily. In some embodiments, administration is performed four times daily.

[0203] The present disclosure also provides a method for treating a burn infection in a patient in need of treatment. In some embodiments, the method comprises administering to the patient an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof. As used herein, the term "burn" refers to thermal damage to the patient's body, involving damage to the patient's skin and possibly the tissues underlying the patient's skin. There are three major types of burn levels known to those skilled in the art, including, but not limited to, first-degree, second-degree, and third-degree burns. In some embodiments, the method for treating a burn infection contemplated by the present disclosure is used to treat first-degree, second-degree, and / or third-degree burns.

[0204] In some embodiments, the patient is a human. In some embodiments, the administration is topical. In some embodiments, the administration is carried out using a compound of the present disclosure or a pharmaceutically acceptable salt thereof in a lotion, gel, cream, ointment, oil, solution, suspension, emulsion, or other viscous composition. In some embodiments, the patient is administered at least one additional active ingredient. In some embodiments, the administration is carried out as a multiple dose regimen. In some embodiments of the present disclosure, the multiple dose regimen is up to about 2 days in duration. In some embodiments of the present disclosure, the multiple dose regimen is up to about 3 days in duration. In some embodiments of the present disclosure, the multiple dose regimen is up to about 4 days in duration. In some embodiments of the present disclosure, the multiple dose regimen is up to about 5 days in duration. In some embodiments of the present disclosure, the multiple dose regimen is up to about 6 days in duration. In some embodiments of the present disclosure, the multiple dose regimen is up to about 7 days in duration. In some embodiments of the present disclosure, the multiple dose regimen is up to about 14 days in duration. In some embodiments of the present disclosure, the multiple dose regimen is up to about 21 days in duration. In some embodiments, the multiple dose regimen is for a period of up to about 1 month. In some embodiments, the multiple dose regimen is for a period of up to about 2 months. Other periods may also be used herein.

[0205] In some embodiments, administration is performed one or more times daily. In some embodiments, administration is performed once daily. In some embodiments, administration is performed twice daily. In some embodiments, administration is performed three times daily. In some embodiments, administration is performed four times daily.

[0206] The present disclosure also provides methods of treating otitis externa in a patient in need thereof. In some embodiments, the methods comprise administering to the patient an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof. As used herein, the term "otitis externa" refers to an infection of the patient's ear canal.

[0207] In some embodiments, the patient is a human. In some embodiments, administration is by direct topical administration to the patient's ear canal. In some embodiments, administration is carried out using a compound of the present disclosure or a pharmaceutically acceptable salt thereof in a liquid solution, suspension, lotion, paste, gel, cream, ointment, oil, or other viscous composition. In some embodiments, the patient is administered at least one additional active ingredient. In some embodiments, administration is carried out as a multiple-dose regimen. In some embodiments of the present disclosure, the multiple-dose regimen is for a period of up to about 7 days. In some embodiments of the present disclosure, the multiple-dose regimen is for a period of up to about 14 days. In some embodiments of the present disclosure, the multiple-dose regimen is for a period of up to about 21 days. In some embodiments, the multiple-dose regimen is for a period of up to about 1 month. Other periods may be used herein.

[0208] In some embodiments, administration is performed one or more times daily. In some embodiments, administration is performed once daily. In some embodiments, administration is performed twice daily. In some embodiments, administration is performed three times daily. In some embodiments, administration is performed four times daily.

[0209] The present disclosure also provides methods for treating bacterial vaginosis in a patient in need thereof. In some embodiments, the methods comprise administering to the patient an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof. As used herein, the term "bacterial vaginosis" refers to an infection of the patient's vagina caused by an overgrowth of bacteria naturally found in the vagina.

[0210] In some embodiments, the patient is a female human. In some embodiments, administration is topical. In some embodiments, administration is carried out using a compound of the present disclosure or a pharmaceutically acceptable salt thereof in a lotion, gel, cream, ointment, oil, solution, suspension, emulsion, or other viscous composition. In some embodiments, the patient is administered at least one additional active ingredient. In some embodiments, administration is carried out as a multiple dose regimen. In some embodiments of the present disclosure, the multiple dose regimen is for a period of up to about 7 days. In some embodiments of the present disclosure, the multiple dose regimen is for a period of up to about 14 days. In some embodiments of the present disclosure, the multiple dose regimen is for a period of up to about 21 days. In some embodiments, the multiple dose regimen is for a period of up to about 1 month. Other periods may be used herein.

[0211] In some embodiments, administration is performed one or more times daily. In some embodiments, administration is performed once daily. In some embodiments, administration is performed twice daily. In some embodiments, administration is performed three times daily. In some embodiments, administration is performed four times daily.

[0212] The present disclosure also provides methods of treating impetigo in a patient in need thereof. In some embodiments, the methods comprise administering to the patient an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof. As used herein, the term "impetigo" refers to an infection of the patient's skin that results in vesicles, pustules, a yellowish crust, and the like.

[0213] In some embodiments, the patient is a human. In some embodiments, the administration is topical. In some embodiments, the administration is carried out using a compound of the present disclosure or a pharmaceutically acceptable salt thereof in a lotion, gel, cream, ointment, oil, solution, suspension, emulsion, or other viscous composition. In some embodiments, the patient is administered at least one additional active ingredient. In some embodiments, the administration is carried out as a multiple dose regimen. In some embodiments of the present disclosure, the multiple dose regimen is up to about 2 days in duration. In some embodiments of the present disclosure, the multiple dose regimen is up to about 3 days in duration. In some embodiments of the present disclosure, the multiple dose regimen is up to about 4 days in duration. In some embodiments of the present disclosure, the multiple dose regimen is up to about 5 days in duration. In some embodiments of the present disclosure, the multiple dose regimen is up to about 6 days in duration. In some embodiments of the present disclosure, the multiple dose regimen is up to about 7 days in duration. In some embodiments of the present disclosure, the multiple dose regimen is up to about 14 days in duration. In some embodiments of the present disclosure, the multiple dose regimen is up to about 21 days in duration. In some embodiments, the multiple dose regimen is for a period of up to about one month. Other periods may also be used herein.

[0214] In some embodiments, administration is performed one or more times daily. In some embodiments, administration is performed once daily. In some embodiments, administration is performed twice daily. In some embodiments, administration is performed three times daily. In some embodiments, administration is performed four times daily.

[0215] The present disclosure also provides kits. In some embodiments, the kit includes a compound according to the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the present disclosure. As used herein, the term "kit" refers to any manufactured article, such as a package, container, or the like, that contains a compound according to the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the present disclosure. In some embodiments, the compound according to the present disclosure or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to the present disclosure is packaged in a vial, bottle, tube, flask, or patch, which may be further packaged in a box, envelope, bag, or the like. In some embodiments, the compound according to the present disclosure or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to the present disclosure is approved by the U.S. Food and Drug Administration or a similar regulatory agency in the United States, or a jurisdiction or territory outside the United States, for administration to patients. In some embodiments, the kit includes instructions for use and / or other indications that the compound according to the present disclosure or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to the present disclosure is suitable for or approved for administration to patients. In some embodiments, the compounds or compositions of the disclosure are packaged in unit dose or single unit dose form, such as, for example, a single unit dose pill, capsule, etc. In some embodiments, the kit comprises a dispenser.

[0216] The present disclosure also provides the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof for the manufacture of a medicament. As used herein, the term "medicament" refers to a pharmaceutical composition according to the present disclosure. In some embodiments, the pharmaceutical composition is contained in any article of manufacture, such as, for example, a package, a container, etc.

[0217] In addition to the aspects and embodiments described and provided elsewhere in this disclosure, the following non-limiting list of embodiments is also contemplated.

[0218] 1. A compound having the formula: [ka] (In the formula, A is a monocyclic, bicyclic, or tricyclic carbocyclic or heterocyclic moiety; R1 and R2 are each a C1-C8 alkyl moiety. or a compound having and pharmaceutically acceptable salts thereof.

[0219] 2. The compound according to claim 1, wherein R1 and R2 are each butyl.

[0220] 3. A compound having the formula: [ka] (In the formula, Q is oxygen or sulfur; W is an amino- or guanidino-substituted nitrogen-containing heterocyclic moiety; X and Z are endblocking groups; A is H, alkyl, halogen, alkoxy, alkyl-(O-alkyl), aryl, alkenyl, alkanol, or phenol. A compound having the formula:

[0221] 4. The compound according to claim 3, wherein W is: [ka]

[0222] 5. The compound according to claim 3, wherein W is: [ka]

[0223] 6. The compound according to claim 3, wherein W is: [ka]

[0224] 7. The compound according to claim 3, wherein W is: [ka]

[0225] 8. The compound according to claim 3, wherein W is: [ka]

[0226] 9. The compound according to claim 3, wherein W is: [ka]

[0227] 10. The compound according to claim 3, wherein W is: [ka]

[0228] 11. The compound according to claim 3, wherein W is: [ka]

[0229] 12. The compound according to claim 3, wherein W is: [ka]

[0230] 13. The compound according to claim 3, wherein W is: [ka]

[0231] 14. The compound according to claim 3, wherein W is: [ka]

[0232] 15. The compound according to claim 3, wherein W is: [ka]

[0233] 16. The compound according to claim 3, wherein W is: [ka]

[0234] 17. The compound according to claim 3, wherein W is: [ka]

[0235] 18. The compound according to claim 3, wherein W is: [ka]

[0236] 19. The compound according to claim 3, wherein W is: [ka]

[0237] 20. The compound according to claim 3, wherein W is: [ka]

[0238] 21. The compound according to claim 3, wherein W is: [ka]

[0239] 22. The compound according to claim 3, wherein W is: [ka]

[0240] 23. The compound according to claim 3, wherein W is: [ka]

[0241] 24. The compound according to claim 3, wherein W is: [ka]

[0242] 25. The compound according to claim 3, wherein W is: [ka]

[0243] 26. The compound according to claim 3, wherein W is: [ka]

[0244] 27. The compound according to claim 3, wherein W is: [ka]

[0245] 28. The compound according to claim 3, wherein W is: [ka]

[0246] 29. The compound according to claim 3, wherein W is: [ka]

[0247] 30. The compound according to claim 3, wherein W is: [ka]

[0248] 31. The compound according to claim 3, wherein W is: [ka]

[0249] 32. The compound according to claim 3, wherein W is: [ka]

[0250] 33. The compound according to claim 3, wherein W is: [ka]

[0251] 34. The compound according to claim 3, wherein W is: [ka]

[0252] 35. The compound according to claim 3, wherein W is: [ka]

[0253] 36. The compound according to claim 3, wherein W is: [ka]

[0254] 37. The compound according to claim 3, wherein W is: [ka]

[0255] 38. The compound according to claim 3, wherein W is: [ka]

[0256] 39. The compound according to claim 3, wherein W is: [ka]

[0257] 40. The compound according to claim 3, wherein W is: [ka]

[0258] 41. The compound according to claim 3, wherein W is: [ka]

[0259] 42. The compound according to claim 3, wherein W is: [ka]

[0260] 43. The compound according to claim 3, wherein W is: [ka]

[0261] 44. The compound according to claim 3, wherein W is: [ka]

[0262] 45. The compound according to claim 3, wherein W is: [ka]

[0263] 46. ​​The compound according to claim 3, wherein W is: [ka]

[0264] 47. The compound according to claim 3, wherein W is: [ka]

[0265] 48. The compound according to claim 3, wherein W is: [ka]

[0266] 49. The compound according to claim 3, wherein W is: [ka]

[0267] 50. The compound according to claim 3, wherein W is: [ka]

[0268] 51. The compound according to claim 3, wherein W is: [ka]

[0269] 52. The compound according to claim 3, wherein W is: [ka]

[0270] 53. The compound according to claim 3, wherein W is: [ka]

[0271] 54. The compound according to claim 3, wherein W is: [ka]

[0272] 55. The compound according to claim 3, wherein W is: [ka]

[0273] 56. The compound according to claim 3, wherein W is: [ka]

[0274] 57. The compound according to claim 3, wherein W is: [ka]

[0275] 58. The compound according to claim 3, wherein W is: [ka]

[0276] 59. The compound according to claim 3, wherein W is: [ka]

[0277] 60. The compound according to claim 3, wherein W is: [ka]

[0278] 61. The compound according to claim 3, wherein W is: [ka]

[0279] 62. The compound according to claim 3, wherein W is: [ka]

[0280] 63. The compound according to claim 3, wherein W is: [ka]

[0281] 64. The compound according to claim 3, wherein W is: [ka]

[0282] 65. The compound according to claim 3, wherein W is: [ka]

[0283] 66. The compound according to claim 3, wherein W is: [ka]

[0284] 67. The compound according to claim 3, wherein W is: [ka]

[0285] 68. The compound according to claim 3, wherein W is: [ka]

[0286] 69. The compound according to claim 3, wherein W is a guanidino-substituted aziridine.

[0287] 70. The compound according to claim 3, wherein W is a guanidino-substituted azetidine.

[0288] 71. The compound according to claim 3, wherein W is a guanidino-substituted 1,3-azetidine.

[0289] 72. The compound according to claim 3, wherein W is a guanidino-substituted azetidin-2-one (β-lactam).

[0290] 73. The compound according to claim 3, wherein W is a guanidino-substituted pyrrolidine.

[0291] 74. The compound according to claim 3, wherein W is a guanidino-substituted 3-pyrroline.

[0292] 75. The compound according to claim 3, wherein W is a guanidino-substituted 2-pyrroline.

[0293] 76. The compound according to claim 3, wherein W is a guanidino-substituted 1H-pyrrole.

[0294] 77. The compound according to claim 3, wherein W is a guanidino-substituted pyrazolidine.

[0295] 78. The compound according to claim 3, wherein W is a guanidino-substituted imidazolidine.

[0296] 79. The compound according to claim 3, wherein W is a guanidino-substituted 2-pyrazoline.

[0297] 80. The compound according to claim 3, wherein W is a guanidino-substituted 2-imidazoline.

[0298] 81. The compound according to claim 3, wherein W is a guanidino-substituted succinimide.

[0299] 82. The compound according to claim 3, wherein W is a guanidino-substituted hydantoin.

[0300] 83. The compound according to claim 3, wherein W is a guanidino-substituted 2,4-thiazolidinedione.

[0301] 84. The compound according to claim 3, wherein W is a guanidino-substituted piperidine.

[0302] 85. The compound according to claim 3, wherein W is a guanidino-substituted piperazine.

[0303] 86. The compound according to claim 3, wherein W is a guanidino-substituted morpholine.

[0304] 87. The compound according to claim 3, wherein W is a guanidino-substituted 2H-1,2-oxazidine.

[0305] 88. The compound according to claim 3, wherein W is a guanidino-substituted 4H-1,4-oxazudine.

[0306] 89. The compound according to claim 3, wherein W is a guanidino-substituted thiomorpholine.

[0307] 90. The compound according to claim 3, wherein W is a guanidino-substituted 2H-1,2-thiazine.

[0308] 91. The compound according to claim 3, wherein W is a guanidino-substituted 4H-1,4-thithiazine.

[0309] 92. The compound according to claim 3, wherein W is a guanidino-substituted thiomorpholine dioxide.

[0310] 93. The compound according to claim 3, wherein W is a guanidino-substituted 1,4,5,6-tetrahydrocyclopenta[b]pyrrole.

[0311] 94. The compound according to claim 3, wherein W is a guanidino-substituted 1,3a,4,6a-tetrahydropyrrolo-[3,2-b]pyrrole.

[0312] 95. The compound according to claim 3, wherein W is a guanidino-substituted 1,4-dihydropyrrolo-[3,2-b]pyrrole.

[0313] 96. The compound according to claim 3, wherein W is a guanidino-substituted 1,6-dihydropyrrolo-[2,3,-b]pyrrole.

[0314] 97. The compound according to claim 3, wherein W is a guanidino-substituted 6H-furo[2,3-b]pyrrole.

[0315] 98. The compound according to claim 3, wherein W is a guanidino-substituted 4H-furo[3,2-b]pyrrole.

[0316] 99. The compound according to claim 3, wherein W is a guanidino-substituted 6H-thieno[2,3-b]pyrrole.

[0317] 100. The compound according to claim 3, wherein W is a guanidino-substituted 4H-thieno[3,2-b]pyrrole.

[0318] 101. The compound according to claim 3, wherein W is a guanidino-substituted indoline.

[0319] 102. The compound according to claim 3, wherein W is a guanidino-substituted 1H-indole.

[0320] 103. The compound according to claim 3, wherein W is a guanidino-substituted 2H-isoindole.

[0321] 104. The compound according to claim 3, wherein W is a guanidino-substituted 1H-indazole.

[0322] 105. The compound according to claim 3, wherein W is a guanidino-substituted benzamidazole.

[0323] 106. The compound according to claim 3, wherein W is a guanidino-substituted 4-azaindole.

[0324] 107. The compound according to claim 3, wherein W is a guanidino-substituted 5-azaindole.

[0325] 108. The compound according to claim 3, wherein W is a guanidino-substituted 6-azaindole.

[0326] 109. The compound according to claim 3, wherein W is a guanidino-substituted 7-azaindole.

[0327] 110. The compound according to claim 3, wherein W is a guanidino-substituted 7-azaindazole.

[0328] 111. The compound according to claim 3, wherein W is a guanidino-substituted purine.

[0329] 112. The compound according to claim 3, wherein W is a guanidino-substituted 1,2-benzisothiazol-3(2H)-one.

[0330] 113. The compound according to claim 3, wherein W is a guanidino-substituted guanine.

[0331] 114. The compound according to claim 3, wherein W is a guanidino-substituted adenine.

[0332] 115. The compound according to claim 3, wherein W is a guanidino-substituted decahydroisoquinoline.

[0333] 116. The compound according to claim 3, wherein W is a guanidino-substituted decahydroquinoline.

[0334] 117. The compound according to claim 3, wherein W is a guanidino-substituted 1,2,3,4-tetrahydro-quinoline.

[0335] 118. The compound according to claim 3, wherein W is a guanidino-substituted 1,2-dihydroquinoline.

[0336] 119. The compound according to claim 3, wherein W is a guanidino-substituted 1,2-dihydroisoquinoline.

[0337] 120. The compound according to claim 3, wherein W is a guanidino-substituted 2H-benzo-[e][1,2]oxazine.

[0338] 121. The compound according to claim 3, wherein W is a guanidino-substituted quinolin 2(1H)-one.

[0339] 122. The compound according to claim 3, wherein W is a guanidino-substituted isoquinolin 1(2H)-one.

[0340] 123. The compound according to claim 3, wherein W is a guanidino-substituted carbazole.

[0341] 124. The compound according to claim 3, wherein W is a guanidino-substituted phenoxazine.

[0342] 125. The compound according to claim 3, wherein W is a guanidino-substituted phenothiazine.

[0343] 126. The compound according to claim 3, wherein W is a guanidino-substituted 2-azaadamantane.

[0344] 127. The compound according to claim 3, wherein W is a guanidino-substituted 2,3-dihydroazepine.

[0345] 128. The compound according to claim 3, wherein W is a guanidino-substituted 2,5-dihydroazepine.

[0346] 129. The compound according to claim 3, wherein W is a guanidino-substituted azepine.

[0347] 130. The compound according to claim 3, wherein W is a guanidino-substituted 1,2-azepine.

[0348] 131. The compound according to claim 3, wherein W is a guanidino-substituted 1,3-azepine.

[0349] 132. The compound according to claim 3, wherein W is a guanidino-substituted 1,4-azepine.

[0350] 133. The compound according to claim 3, wherein W is a guanidino-substituted azocane.

[0351] 134. The compound according to any one of the above 3 to 133, wherein X is: [ka]

[0352] 135. The compound according to any one of the above 3 to 133, wherein X is: [ka]

[0353] 136. The compound according to any one of the above 3 to 133, wherein X is: [ka]

[0354] 137. The compound according to any one of the above 3 to 133, wherein X is: [ka]

[0355] 138. The compound according to any one of the above 3 to 133, wherein X is: [ka]

[0356] 139. The compound according to any one of the above 3 to 133, wherein X is: [ka]

[0357] 140. The compound according to any one of the above 3 to 133, wherein X is: [ka]

[0358] 141. The compound according to any one of the above 3 to 133, wherein X is: [ka]

[0359] 142. The compound according to any one of the above 3 to 133, wherein X is: [ka]

[0360] 143. The compound according to any one of the above 3 to 133, wherein X is: [ka]

[0361] 144. The compound according to any one of the above 3 to 133, wherein X is: [ka]

[0362] 145. The compound according to any one of the above 3 to 133, wherein X is: [ka]

[0363] 146. The compound according to any one of the above 3 to 133, wherein X is: [ka]

[0364] 147. The compound according to any one of the above 3 to 146, wherein Z is: [ka]

[0365] 148. The compound according to any one of the above 3 to 146, wherein Z is: [ka]

[0366] 149. The compound according to any one of the above 3 to 146, wherein Z is: [ka]

[0367] 150. The compound according to any one of the above 3 to 146, wherein Z is: [ka]

[0368] 151. The compound according to any one of the above 3 to 146, wherein Z is: [ka]

[0369] 152. The compound according to any one of the above 3 to 146, wherein Z is: [ka]

[0370] 153. The compound according to any one of the above 3 to 146, wherein Z is: [ka]

[0371] 154. The compound according to any one of the above 3 to 146, wherein Z is: [ka]

[0372] 155. The compound according to any one of the above 3 to 146, wherein Z is: [ka]

[0373] 156. The compound according to any one of the above 3 to 146, wherein Z is: [ka]

[0374] 157. The compound according to any one of the above 3 to 146, wherein Z is: [ka]

[0375] 158. The compound according to any one of the above 3 to 146, wherein Z is: [ka]

[0376] 159. The compound according to any one of the above 3 to 146, wherein Z is: [ka]

[0377] 160. A compound selected from any one of compounds 1 to 2,520 listed in Table 1.

[0378] 161. Compound 1 listed in Table 1.

[0379] 162. A pharmaceutically acceptable salt of the compound according to claim 160 selected from the group consisting of ammonium, calcium, sodium, potassium, magnesium, and cobalt salts.

[0380] 163. The pharmaceutically acceptable salt according to claim 162, wherein the ammonium salt is ammonium ((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-((butoxyoxidephosphoryl)-yl)oxy)tetrahydrofuran-2-yl)methylbutylphosphate.

[0381] 164. The pharmaceutically acceptable salt according to claim 162, wherein the calcium salt is calcium ((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-((butoxyoxidephosphoryl)-yl)oxy)tetrahydrofuran-2-yl)methylbutylphosphate.

[0382] 165. The pharmaceutically acceptable salt according to claim 162, wherein the sodium salt is sodium ((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-((butoxyoxidephosphoryl)-yl)oxy)tetrahydrofuran-2-yl)methylbutylphosphate.

[0383] 166. The pharmaceutically acceptable salt according to claim 162, wherein the potassium salt is potassium ((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-((butoxyoxidephosphoryl)-yl)oxy)tetrahydrofuran-2-yl)methylbutylphosphate.

[0384] 167. The pharmaceutically acceptable salt according to claim 162, wherein the magnesium salt is magnesium ((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-((butoxyoxidephosphoryl)-yl)oxy)tetrahydrofuran-2-yl)methylbutylphosphate.

[0385] 168. The pharmaceutically acceptable salt according to claim 162, wherein the cobalt salt is cobalt ((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-((butoxyoxidephosphoryl)-yl)oxy)tetrahydrofuran-2-yl)methylbutylphosphate.

[0386] 169. The compound or pharmaceutically acceptable salt thereof according to the above 160, which is a protonated compound having a pH of about pH 3 to about pH 5 when dissolved in water.

[0387] 170. The compound or pharmaceutically acceptable salt thereof according to the above 160, which is a protonated compound having a pH of about pH 3 to about pH 4 when dissolved in water.

[0388] 171. A pharmaceutical composition comprising a compound according to 160 above or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients, or diluents.

[0389] 172. The pharmaceutical composition according to claim 171, wherein the pharmaceutical composition comprises at least one additional active ingredient.

[0390] 173. The pharmaceutical composition according to claim 171 or 172, wherein the pharmaceutical composition is a human pharmaceutical composition.

[0391] 174. The pharmaceutical composition according to any one of the above 171 to 173, wherein the pharmaceutical composition is adapted for topical administration.

[0392] 175. The pharmaceutical composition according to any one of 171 to 174 above, wherein the pharmaceutical composition is administered in the form of a lotion, gel, cream, ointment, oil, solution, suspension, emulsion, or other viscous composition.

[0393] 176. The pharmaceutical composition according to any one of the above 171 to 175, wherein the pharmaceutical composition is administered in the form of a gel containing a polyhydric alcohol.

[0394] 177. A pharmaceutical composition according to any one of the above 171 to 173, wherein the pharmaceutical composition is adapted for oral administration.

[0395] 178. The pharmaceutical composition according to claim 177, wherein the pharmaceutical composition is administered in the form of a capsule, tablet, powder, liquid suspension, solution, elixir, syrup, or concentrated drop.

[0396] 179. A pharmaceutical composition according to any one of the above 171 to 173, wherein the pharmaceutical composition is adapted for administration by inhalation.

[0397] 180. The pharmaceutical composition according to claim 179, wherein the pharmaceutical composition is administered in the form of a dry powder, a solution, a suspension, or an aerosol.

[0398] 181. The pharmaceutical composition according to any one of the above 171 to 173, wherein the pharmaceutical composition is adapted for intravesical administration.

[0399] 182. The pharmaceutical composition according to claim 181, wherein the pharmaceutical composition is administered via a catheter.

[0400] 183. The pharmaceutical composition according to any one of the above 171 to 173, wherein the pharmaceutical composition is adapted for parenteral administration.

[0401] 184. The pharmaceutical composition according to claim 183, wherein the pharmaceutical composition is administered through a needle.

[0402] 185. A method for treating a diabetic foot ulcer infection in a patient in need thereof, comprising administering to the patient an effective amount of a compound according to claim 160 or a pharmaceutically acceptable salt thereof.

[0403] 186. The method according to claim 185, wherein the administration is topical administration.

[0404] 187. The method according to claim 185 or 186, wherein the administration is carried out using the compound or a pharmaceutically acceptable salt thereof in a lotion, paste, gel, cream, ointment, oil, or other viscous composition.

[0405] 188. The method according to any one of 185 to 187 above, wherein the administration is carried out using the compound or a pharmaceutically acceptable salt thereof in a gel.

[0406] 189. The method according to any one of 185 to 188 above, wherein the patient is administered at least one additional active ingredient.

[0407] 190. The method according to any one of 185 to 189 above, wherein the patient is a human.

[0408] 191. The method according to any one of 185 to 190 above, wherein the administration is carried out as a multiple dose regimen.

[0409] 192. The method according to claim 191, wherein the multiple dose regimen is for a period of up to about one month.

[0410] 193. The method according to claim 191, wherein the multiple dose regimen is for a maximum of about 2 months.

[0411] 194. The method of claim 191, wherein the multiple dose regimen is for a maximum of about 3 months.

[0412] 195. The method of claim 191, wherein the multiple dose regimen is for a maximum of about 4 months.

[0413] 196. The method of any one of paragraphs 185 to 195, wherein administration is performed once a day.

[0414] 197. A method for treating a complicated urinary tract infection in a patient in need thereof, comprising administering to the patient an effective amount of a compound according to claim 160 or a pharmaceutically acceptable salt thereof.

[0415] 198. The method according to claim 197, wherein the urinary tract infection is a catheter-associated urinary tract infection.

[0416] 199. The method according to claim 197 or 198, wherein the administration is intravesical administration.

[0417] 200. The method according to any one of claims 197 to 199, wherein the administration is carried out using the compound or a pharmaceutically acceptable salt thereof in a liquid solution or suspension.

[0418] 201. The method according to any one of claims 197 to 200, wherein the patient is administered at least one additional active ingredient.

[0419] 202. A method according to any one of 197 to 201 above, wherein the patient is a human.

[0420] 203. The method according to any one of 197 to 202 above, wherein the administration is carried out as a multiple dose regimen.

[0421] 204. The method according to claim 203, wherein the multiple dose regimen is for a maximum of about 2 days.

[0422] 205. The method according to claim 203, wherein the multiple dose regimen is for a maximum of about 3 days.

[0423] 206. The method according to claim 203, wherein the multiple dose regimen is for a maximum of about 4 days.

[0424] 207. The method of claim 203, wherein the multiple dose regimen is for a maximum of about 5 days.

[0425] 208. The method of claim 203, wherein the multiple dose regimen is for a maximum of about 6 days.

[0426] 209. The method of claim 203, wherein the multiple dose regimen is for a maximum of about 7 days.

[0427] 210. The method of claim 203, wherein the multiple dose regimen is for a maximum of about 14 days.

[0428] 211. The method according to any one of claims 197 to 202, wherein the administration is carried out as a chronic treatment regimen.

[0429] 212. The method according to any one of claims 197 to 211, wherein administration is carried out once a day.

[0430] 213. A method for treating a pulmonary infection caused by cystic fibrosis in a patient in need thereof, comprising administering to the patient an effective amount of a compound described in 160 above or a pharmaceutically acceptable salt thereof.

[0431] 214. The method according to claim 213, wherein the administration is by inhalation.

[0432] 215. The method according to claim 213 or 214, wherein the administration is carried out using the compound or a pharmaceutically acceptable salt thereof in a dry powder, solution, suspension, or aerosol.

[0433] 216. The method according to any one of 213 to 215 above, wherein the patient is administered at least one additional active ingredient.

[0434] 217. A method according to any one of 213 to 216 above, wherein the patient is a human.

[0435] 218. The method according to any one of 213 to 217 above, wherein the administration is carried out as a multiple dose regimen.

[0436] 219. The method according to any one of claims 213 to 218, wherein the multiple dose regimen is for a maximum period of about one month.

[0437] 220. The method according to claim 218, wherein the multiple dose regimen is for a maximum period of about 2 months.

[0438] 221. The method of claim 218, wherein the multiple dose regimen is for a maximum of about 3 months.

[0439] 222. The method of claim 218, wherein the multiple dose regimen is for a maximum of about 4 months.

[0440] 223. The method of claim 218, wherein the multiple dose regimen is for a maximum of about 5 months.

[0441] 224. The method of claim 218, wherein the multiple dose regimen is for a maximum of about 6 months.

[0442] 225. The method of claim 218, wherein the multiple dose regimen is for a duration of up to about 7 months.

[0443] 226. The method of claim 218, wherein the multiple dose regimen is for a maximum of about 8 months.

[0444] 227. The method according to any one of 213 to 217 above, wherein administration is carried out once a day.

[0445] 228. A method for treating ventilator-acquired pneumonia in a patient in need thereof, comprising administering to the patient an effective amount of a compound described in 160 above or a pharmaceutically acceptable salt thereof.

[0446] 229. The method according to claim 228, wherein the administration is by inhalation.

[0447] 230. The method according to claim 228 or 229, wherein the administration is carried out using the compound or a pharmaceutically acceptable salt thereof in a liquid solution, suspension, or dry powder.

[0448] 231. The method according to any one of 228 to 230 above, wherein the patient is administered at least one additional active ingredient.

[0449] 232. A method according to any one of 228 to 231 above, wherein the patient is a human.

[0450] 233. The method according to any one of claims 228 to 232, wherein the administration is carried out as a multiple dose regimen.

[0451] 234. The method of claim 233, wherein the multiple dose regimen is for a maximum of about 7 days.

[0452] 235. The method of claim 233, wherein the multiple dose regimen is for a maximum of about 14 days.

[0453] 236. The method of claim 233, wherein the multiple dose regimen is for a maximum of about 21 days.

[0454] 237. The method of claim 233, wherein the multiple dose regimen is for a maximum of about one month.

[0455] 238. The method according to any one of 228 to 237 above, wherein administration is carried out once a day.

[0456] 239. A method for treating a burn infection in a patient in need thereof, comprising administering to the patient an effective amount of a compound according to claim 160 or a pharmaceutically acceptable salt thereof.

[0457] 240. The method according to claim 239, wherein the administration is topical.

[0458] 241. The method according to claim 239 or 240, wherein the administration is carried out using the compound in a lotion, gel, cream, ointment, oil, solution, suspension, emulsion, or other viscous composition.

[0459] 242. The method according to any one of claims 239 to 241, wherein the patient is administered at least one additional active ingredient.

[0460] 243. A method according to any one of 239 to 242 above, wherein the patient is a human.

[0461] 244. The method according to any one of claims 239 to 243, wherein the administration is carried out as a multiple dose regimen.

[0462] 245. The method of claim 244, wherein the multiple dose regimen is for a maximum of about 2 days.

[0463] 246. The method of claim 244, wherein the multiple dose regimen is for a maximum of about 3 days.

[0464] 247. The method of claim 244, wherein the multiple dose regimen is for a maximum of about 4 days.

[0465] 248. The method of claim 244, wherein the multiple dose regimen is for a maximum of about 5 days.

[0466] 249. The method of claim 244, wherein the multiple dose regimen is for a maximum of about 6 days.

[0467] 250. The method of claim 244, wherein the multiple dose regimen is for a maximum of about 7 days.

[0468] 251. The method of claim 244, wherein the multiple dose regimen is for a maximum of about 14 days.

[0469] 252. The method of claim 244, wherein the multiple dose regimen is for a maximum of about 21 days.

[0470] 253. The method of claim 244, wherein the multiple dose regimen is for a period of up to about one month.

[0471] 254. The method according to any one of 239 to 253 above, wherein administration is carried out one or more times a day.

[0472] 255. The method according to any one of 239 to 253 above, wherein administration is carried out once a day.

[0473] 256. The method according to any one of 239 to 253 above, wherein administration is carried out twice a day.

[0474] 257. The method according to any one of 239 to 253 above, wherein administration is performed three times a day.

[0475] 258. The method according to any one of 239 to 253 above, wherein administration is carried out four times a day.

[0476] 259. A method for treating otitis externa in a patient in need thereof, comprising administering to the patient an effective amount of a compound according to claim 160 or a pharmaceutically acceptable salt thereof.

[0477] 260. The method of claim 259, wherein the administration is local administration directly to the patient's ear canal.

[0478] 261. The method according to claim 259 or 260, wherein the administration is carried out using the compound in a lotion, gel, cream, ointment, oil, solution, suspension, emulsion, or other viscous composition.

[0479] 262. The method according to any one of claims 259 to 261, wherein the patient is administered at least one additional active ingredient.

[0480] 263. A method according to any one of 259 to 262 above, wherein the patient is a human.

[0481] 264. The method according to any one of 259 to 263 above, wherein the administration is carried out as a multiple dose regimen.

[0482] 265. The method of claim 264, wherein the multiple dose regimen is for a maximum of about 7 days.

[0483] 266. The method of claim 264, wherein the multiple dose regimen is for a maximum of about 14 days.

[0484] 267. The method of claim 264, wherein the multiple dose regimen is for a maximum of about 21 days.

[0485] 268. The method of claim 264, wherein the multiple dose regimen is for a period of up to about one month.

[0486] 269. The method according to any one of 259 to 268 above, wherein administration is carried out one or more times a day.

[0487] 270. The method according to any one of 259 to 268 above, wherein administration is carried out once a day.

[0488] 271. The method according to any one of claims 259 to 268, wherein administration is performed twice a day.

[0489] 272. The method according to any one of claims 259 to 268, wherein administration is performed three times a day.

[0490] 273. A method for treating bacterial vaginosis in a patient in need thereof, comprising administering to the patient an effective amount of a compound according to claim 160 or a pharmaceutically acceptable salt thereof.

[0491] 274. The method according to claim 273, wherein the administration is topical.

[0492] 275. The method according to claim 273 or 274, wherein the administration is carried out using the compound in a lotion, gel, cream, ointment, oil, solution, suspension, emulsion, or other viscous composition.

[0493] 276. A method according to any one of claims 273 to 275, wherein administration is carried out using a gel.

[0494] 277. The method according to any one of 273 to 276 above, wherein the patient is administered at least one additional active ingredient.

[0495] 278. A method according to any one of 273 to 277 above, wherein the patient is a female human.

[0496] 279. The method according to any one of claims 273 to 278, wherein the administration is carried out as a multiple dose regimen.

[0497] 280. The method of claim 279, wherein the multiple dose regimen is for a maximum of about 7 days.

[0498] 281. The method of claim 279, wherein the multiple dose regimen is for a maximum of about 14 days.

[0499] 282. The method of claim 279, wherein the multiple dose regimen is for a maximum of about 21 days.

[0500] 283. The method according to any one of 273 to 282 above, wherein administration is carried out one or more times a day.

[0501] 284. The method according to any one of claims 273 to 282, wherein administration is performed once a day.

[0502] 285. A method for treating impetigo in a patient in need thereof, comprising administering to the patient an effective amount of a compound according to claim 160 or a pharmaceutically acceptable salt thereof.

[0503] 286. The method according to claim 285, wherein the administration is topical.

[0504] 287. The method according to claim 285 or 286, wherein the administration is carried out using the compound in a lotion, gel, cream, ointment, oil, solution, suspension, emulsion, or other viscous composition.

[0505] 288. A method according to any one of claims 285 to 287, wherein the administration is carried out using a gel.

[0506] 289. The method according to any one of 285 to 288 above, wherein the patient is administered at least one additional active ingredient.

[0507] 290. The method according to any one of 285 to 289 above, wherein the patient is a human.

[0508] 291. The method according to any one of claims 285 to 290, wherein the administration is carried out as a multiple dose regimen.

[0509] 292. The method of claim 291, wherein the multiple dose regimen is for a maximum of about 2 days.

[0510] 293. The method of claim 291, wherein the multiple dose regimen is for a maximum of about 3 days.

[0511] 294. The method of claim 291, wherein the multiple dose regimen is for a maximum of about 4 days.

[0512] 295. The method of claim 291, wherein the multiple dose regimen is for a maximum of about 5 days.

[0513] 296. The method of claim 291, wherein the multiple dose regimen is for a maximum of about 6 days.

[0514] 297. The method of claim 291, wherein the multiple dose regimen is for a maximum of about 7 days.

[0515] 298. The method of claim 291, wherein the multiple dose regimen is for a maximum of about 14 days.

[0516] 299. The method of claim 291, wherein the multiple dose regimen is for a duration of up to about 21 days.

[0517] 300. The method according to any one of 285 to 299 above, wherein administration is carried out one or more times a day.

[0518] 301. The method according to any one of claims 285 to 299, wherein administration is performed once a day.

[0519] 302. The method according to any one of claims 285 to 299, wherein administration is performed twice a day.

[0520] 303. A kit comprising the compound described in 160 above or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described in any one of 171 to 184 above.

[0521] 304. A compound according to claim 160 or a pharmaceutically acceptable salt thereof for use in therapy.

[0522] 305. A compound according to claim 160 or a pharmaceutically acceptable salt thereof for use in the treatment of infection of a diabetic foot ulcer.

[0523] 306. A compound according to claim 160 or a pharmaceutically acceptable salt thereof for use in the treatment of complicated urinary tract infections.

[0524] 307. A compound according to claim 160 or a pharmaceutically acceptable salt thereof for use in the treatment of pulmonary infections caused by cystic fibrosis.

[0525] 308. A compound according to claim 160 or a pharmaceutically acceptable salt thereof for use in the treatment of ventilator-acquired pneumonia.

[0526] 309. A compound according to claim 160 or a pharmaceutically acceptable salt thereof for use in treating infections in burns.

[0527] 310. The compound according to 160 or a pharmaceutically acceptable salt thereof for use in the treatment of otitis externa.

[0528] 311. A compound according to 160 above or a pharmaceutically acceptable salt thereof for use in the treatment of bacterial vaginosis.

[0529] 312. A compound according to 160 above or a pharmaceutically acceptable salt thereof for use in the treatment of impetigo.

[0530] 313. Use of a compound according to 160 above or a pharmaceutically acceptable salt thereof for the manufacture of a medicament.

[0531] 314. A method for coating a catheter with a compound or a pharmaceutically acceptable salt thereof according to claim 160, comprising coating the catheter with the compound or a pharmaceutically acceptable salt thereof before inserting the catheter into a patient.

[0532] 315. A composition comprising a catheter coated with the compound according to 160 above or a pharmaceutically acceptable salt thereof.

[0533] example The following examples are provided for the present invention. In most cases, alternative techniques can be used. The examples are intended to be illustrative and are not intended to limit or restrict the scope of the invention as set forth in the claims.

[0534] Example 1 General synthetic scheme for compounds of formula (II) having an amino-substituted nitrogen containing heterocyclic moiety

[0535] Step 1. Protection of the amino-substituted nitrogen containing heterocycle. [ka] An amino-substituted nitrogen-containing heterocycle is treated with di-tert-butyl dicarbonate ((BOC)2O) in the presence of a base such as 4-(dimethylamino)pyridine (DMAP) in an organic solvent such as methanol to provide Boc protection at the exocyclic amine nitrogen.

[0536] Step 2. Glycosylation of nucleobases [ka] The Boc-protected amino-substituted nitrogen-containing heterocycle prepared in step 1 is coupled to an electrophilic acetyl-protected ribose / deoxyribose derivative at the anomeric carbon under thermal conditions.

[0537] Step 3. Deprotection of acetyl groups [ka] The glycosylated nucleobase prepared in step 2 is treated with NaOH, MeOH, and HO to deprotect the acetyl protecting groups and provide primary and secondary hydroxy groups.

[0538] Step 4. Preparation of phosphorylation reagent [ka] Step 4 can be carried out as a precursor to Step 5 and is an independent process of Steps 1 to 3. The alcohol reacts with the phosphine amide in THF in the presence of N,N-diisopoylethylamine (DIEA) using tartrazole as a catalyst.

[0539] Step-5. Phosphorylation [ka] The Boc-protected nucleobase prepared in step 3 is bisphosphinylated with the phosphitylation reagent prepared in step 4 and tartrazole as a catalyst in dichloromethane (DCM).

[0540] Step 6. Oxidation [ka] The bisphosphonate is generated by oxidation of the bisphosphinylated compound prepared in step 5 with tert-butyl hydroperoxide (TBTH) in the presence of decane.

[0541] Step-7. Deprotection of amino substituted nitrogen containing heterocycle. [ka] Removal of the Boc protecting group on the amino-substituted nitrogen containing heterocycle prepared in step 6 is accomplished in DCM in the presence of trifluoroacetic acid (TFA).

[0542] Step 8. Deprotection of phosphodiester [ka] Hydrolysis of the β-cyanoethyl protecting group of the phosphodiester prepared in step 7 with methanolic ammonium hydroxide (NH 4 OH, MeOH) affords the target compound.

[0543] Example 2 Synthesis of Nu-8 [ka]

[0544] Step 1. Protection of amine (building block key intermediate) The nitrogen atom of cytidine 2a is protected by adding hexamethyldisilazane (HMDS), 4-(dimethylamino)pyridine (DMAP), trimethylsilyl trifluoromethanesulfonate, and di-tert-butyl dicarbonate ((BOC)2O) to generate the BOC-protected compound Int-2.

[0545] Step 2. Preparation of phosphorylation reagents (building block key intermediates) n-Butanol is reacted with phosphinamide 1 in THF in the presence of N,N-diisopoylethylamine (DIEA) and tartrazole as a catalyst. The crude product is chromatographed on neutral alumina eluting with hexane, then 2% ethyl acetate in hexane. Pure fractions are combined (by TLC) and evaporated in vacuo to a residue.

[0546] Step-3. Coupling of key intermediates The BOC-protected species Int-2 is bisphosphinylated with reagent 2 and tartrazole as a catalyst in dichloromethane (DCM) / dimethylformamide (DMF) solvent to produce 3. The reaction mixture is concentrated to a residue, and the crude product is immediately oxidized in the next step.

[0547] Steps 4 and 5. Oxidation and Amino Deprotection The crude product 3 is oxidized with tert-butyl hydroperoxide (TBTH) in the presence of decane to give the bisphosphonate species 4. Removal of the BOC group is achieved with DCM in the presence of trifluoroacetic acid (TFA) to give 5. The crude product is chromatographed on silica gel eluting with ethyl acetate. Pure fractions (by TLC) are combined and evaporated in vacuo to give a residue.

[0548] Step 6. Deprotection of phosphodiester Hydrolysis of 5 with methanolic ammonium hydroxide (NHOH, MeOH) gives crude (I) ammonium salt (6).

[0549] Steps 7 and 8. Purification Purification of 6 by preparative HPLC and conversion to the free acid on Dowex 50WX8-200 resin is carried out. Evaporation of the aqueous eluate provides (I), which is diluted with purified water to give a 20% solution at ambient pH.

[0550] Example 3 Synthesis of Nu-8 sodium salt [ka]

[0551] Synthesis of Compound-2 To a solution of compound-1 (1.0 kg, 3.3222 mol) in THF (6 L) is added DIEA (1.370 mL, 8.3055 mol) and tetrazole (230 g, 3.3222 mol), followed by the dropwise addition of n-butanol (275 mL, 2.99 mol) in THF (6 L) at 0° C. for 12 hours. The reaction mixture is stirred at room temperature for 24 hours. The progress of the reaction is monitored by TLC, and after completion of the reaction, the solid is filtered off. The filtrate is evaporated under reduced pressure at 40° C. to obtain the crude compound. The crude compound is dissolved in ethyl acetate (5 L). The organic layer is washed with water (3 L) and brine (2 L). The organic layer is dried over anhydrous NaSO, filtered, and the solvent is evaporated under reduced pressure to obtain the crude compound. The crude compound was purified by column chromatography on basic lumina (Al2O3) and eluted with 0-2% EtOAc in petroleum ether to obtain compound-2 (700 g, 76.92%) as a pale yellow liquid. H-NMR (400 MHz, chloroform-d) δ 4.18-4.07 (m, 1H), 4.02 (q, J = 6.6 Hz, 1H), 3.93-3.74 (m, 4H), 2.65 (td, J = 6.5, 3.6 Hz, 2H), 1.31-1.23 (m, 4H), 1.18 (dd, J = 6.8, 3.8 Hz, 12H), 0.93 (td, J = 7.4, 3.1 Hz, 3H). LC-MS: 275 (M+H).

[0552] Synthesis of Compound-4 To a solution of compound-3 (300 g, 1.321 mol) in hexamethyldisilazane (638 g, 3.964 mol), DMAP (16.11 g, 0.132 mol) was added, followed by TMSOTf (7.22 g, 0.039 mol) at 0 °C, and the resulting reaction mixture was stirred at room temperature for 1 hour. After the starting material was removed, Boc anhydride (1.4 L, 6.605 mol) was added at 0 °C for 1 hour, and the reaction mixture was stirred at room temperature for 16 hours. Methanol (3 L) was added to the reaction mixture, followed by triethylamine (1.5 L) at 0 °C for 1 hour, and the reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude compound. The crude compound was diluted with ethyl acetate (3 L) and washed with water (1.0 L) and brine (1.0 L) solution; the organic layer was dried over anhydrous NaSO, filtered, and the solvent was evaporated under reduced pressure to obtain the crude compound. The crude compound is purified by column chromatography silica gel (100-200 mesh) eluted with 0-3% MeOH in DCM to give compound-4 (180 g, 31.89%) as an off-white solid. H-NMR(300MHz,DMSO-d6) δ 8.41(d,J=7.5Hz,1H),6.84(d,J=7.5Hz,1H),6.06(t,J=6.2Hz,1H),5.28(d,J=4.3Hz,1H),5.07(q,J=4.6,4.0Hz,1H),4.21(q,J= 4.1Hz,1H),3.87(q,J=3.7Hz,1H),3.71-3.49(m,2H),2.32(m,1H),2.03(dt,J=13.0,6.2Hz,1H),1.49(s,18H),LC-MS:275(M+H).

[0553] Synthesis of Compound-6 To a stirred solution of compound-4 (180 g, 0.421 mol) in THF (1.0 L) is added DIEA (348 mL, 2.105 mol) and tetrazole (176 g, 2.526 mol) at 0 °C. To the resulting reaction mixture, a solution of compound-2 (519 g, 1.896 mol) in THF (800 mL) is added dropwise at 0 °C for 1 h. The reaction mixture is stirred at room temperature for 16 h. After completion of the reaction, tert-butyl peroxide (505 mL, 5 M) in decane is added dropwise at 0 °C, and the reaction mixture is stirred at room temperature for 6 h. The reaction is monitored by TLC. After completion of the reaction, the reaction mixture is concentrated at 40 °C, diluted with ethyl acetate (3 L), and washed with water (1 L) and brine (1 L) solutions. The organic layer is dried over anhydrous NaSO, filtered, and the solvent is evaporated under reduced pressure to give crude compound (crude 350 g). The crude compound is purified by column chromatography on a silica gel (100-200 mesh) column eluted with 0-5% MeOH in DCM. All collected pure fractions are concentrated to obtain pure compound-6 (220 g, 64.83%) as a wine-red liquid. H-NMR(300MHz,DMSO-d6) δ 8.19(dd,J=7.6,1.3Hz,1H),6.88(d,J=7.5Hz,1H),6.13(t,J=10.5Hz,1H),4.99(s,1H),4.44(s,1H),4.26-3.96(m,10H),3.00 -2.84(m,4H),2.57-2.79(m,2H),1.70-1.54(m,4H),1.50(s,18H),1.35(m,4H),0.88(qd,J=7.5,2.5Hz,6H);LC-MS:806(M+H).

[0554] Synthesis of Compound-7 To a solution of compound-6 (220 g, 0.273 mol) in DCM (4.4 L) was added TFA (210 mL, 2.732 mol) dropwise at 0 °C. The reaction mixture was stirred at room temperature for 24 h. The reaction was monitored by TLC. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude compound. The crude compound was purified by column chromatography on silica gel (230-400 mesh). The compound was eluted with 0-10% MeOH in DCM. All collected pure fractions were concentrated to obtain pure compound-7 (170 g, 84.67%) as a pale yellow liquid. H-NMR(300MHz,DMSO-d6) δ 7.61(d,J=7.5Hz,1H),7.27(d,J=13.9Hz,2H),6.19(t,J=6.9Hz,1H),5.74(d,J=7.4Hz,1H),4.96(s,1H),4.10-3.93(m,11H),2.93( q,J=6.2Hz,4H),2.29(d,J=13.1Hz,2H),1.61(h,J=7.1Hz,4H),1.35(p,J=7.3Hz,4H),0.89(dq,J=7.9,4.2Hz,6H);LC-MS:606(M+H).

[0555] Synthesis of Nu-8 To a stirred solution of compound-7 (720 g, 1.1900 mol) in MeOH (5.0 L) is added aqueous ammonia (600 mL) at 0° C. The reaction mixture is stirred at room temperature for 4 hours. The reaction is monitored by TLC. After completion of the reaction, MeOH is evaporated under reduced pressure and the aqueous layer is washed with DCM (1.5 L). The aqueous layer is purified by Dowex-H + Pass through the resin. Remove water under reduced pressure to give Nu-8 (260 g, 43.84%) as an off-white solid. H-NMR(300MHz,DMSO-d6) δ 8.94(s,1H),8.49(s,1H),7.97(d,J=7.8Hz,1H),6.08(t,J=6.1Hz,1H),5.95(d,J=7.7Hz,1H),4.76(q,J=5.8Hz,1H),4.15(q,J=4.1Hz ,1H),4.08(s,1H),3.83(m,6H),2.43(t,J=5.6Hz,2H),1.67-1.44(m,4H),1.44-1.26(m,4H),0.95-0.82(m,6H),LC-MS:500.15(M+H).

[0556] Synthesis of Nu-8 sodium salt To a stirred aqueous solution (2.6 L) of Compound-Nu-8 (260 g, 0.478 mol), 1N NaOH (950 mL) is added dropwise at 0° C. The reaction mixture is stirred at room temperature for 2 hours. The reaction is monitored by TLC. After completion of the reaction, the aqueous layer is washed with DCM (1.5 L). The aqueous layer is evaporated under reduced pressure to give Nu-8 sodium salt (265 g, 93%) as an off-white solid. H-NMR(300MHz,DMSO-d6) δ 7.81(d,J=7.2Hz,1H),7.2(bs,1H),7.0(bs,1H),6.16(t,J=4Hz,1H),5.71(d,J=7.6Hz,1H),4.69(bs,1H),3.75(m,1H), 3.71(m,1H),3.8(m,4H),2.2(q,1H),1.89-1.96-1.44(m,1H),1.49-1.39(m,4H),1.34-1.23(m,4H),0.88-0.84(m,6H).

[0557] Example 4 Comparative Study of the Physical Properties of Bisphosphocin® Compounds Nu-2, Nu-4, Nu-5, and the Compound of Formula (I) The structures of known Bisphosphocin® compounds Nu-2, Nu-4, and Nu-5 are shown below: [ka] [ka] [ka]

[0558] A pH study was performed to demonstrate the pH of Nu-8 compared to the Bisphosphocin® compounds Nu-2, Nu-4, and Nu-5. A 20 mg / mL Nu-2 solution was prepared by diluting 2 mL of a 250 mg / mL Nu-2 solution with 23 mL of DI water. 20 mg / mL Nu-4 and Nu-5 solutions were also prepared in the same manner. 401.65 mg of Nu-8 was weighed into a 5 mL volumetric flask and diluted to volume with DI water. A 20 mg / mL Nu-8 solution was prepared by diluting 5 mL of an 80.3 mg / mL Nu-8 solution with 15 mL of DI water. The pH values ​​of the four Nu-2, Nu-4, Nu-5, and Nu-8 compounds at 20 mg / mL were measured with a calibrated pH meter. The results are shown in Table 2. Table 2 also provides a summary of other physical properties of the compounds of formula (I) and reference compounds Nu-2, Nu-4, and Nu-5. [Table 2]

[0559] Nu-8 prepared in a 2% aqueous solution provides the most basic (highest pH) solution compared to the reference compounds Nu-2, Nu-4, and Nu-5. Without wishing to be bound by any particular theory, it is believed that the presence of a free exocyclic amino group in the structure of Nu-8 alters the pH of Nu-8 in solution, making it more rapidly acting and more potent at higher pH levels than Bisphosphocin® Nu-2, Nu-4, and Nu-5.

[0560] Furthermore, pKa measurements indicate that Nu-8 has the lowest acid dissociation constant compared to Bisphosphocin® Nu-2, Nu-4, and Nu-5, which is a measure of the dissociation of a molecule into hydrogen ions and the corresponding conjugate base. While not wishing to be bound by theory, it is believed that Nu-8 does not have as many acidic protons in its structure that can dissociate into solution as hydrogen ions, compared to the number of acidic protons present in the reference Bisphosphocin® compounds Nu-2, Nu-4, and Nu-5. The reference Bisphosphocin® compounds have acidic protons, such as hydroxyl protons and methyl ester protons, that can dissociate into solution.

[0561] In summary, Nu-8, prepared in a 2% aqueous solution, provides the most basic (highest pH) solution and is faster acting and more potent at higher pH levels compared to the reference compounds Nu-2, Nu-4, and Nu-5.

[0562] Example 5 Use of Nu-8 in treating Helicobacter pylori in mice

[0563] animal The mouse strain used in this study was C57 / BL6, ranging in age from 5-6 weeks and weight from 18-22 grams. Mice were housed five per cage and provided with free access to food and water according to NIH guidelines.

[0564] Bacterial strains A bacterial strain of H. pylori SS1 (CagA+, VacA+) from a human clinical isolate was adapted to a mouse model and validated in this infection model.

[0565] infection Six days prior to infection, streak the frozen stock onto one or two Columbia 5% sheep blood agar plates and incubate the plates microaerobically at 37°C for 72 hours. After 72 hours, subculture the plate growth onto five Columbia 5% sheep blood agar plates and incubate as before. After another 72 hours of incubation, remove the plates and suspend the plate growth in sterile 0.9% saline to an OD of 1.5-2.0 at 530 nm. This OD is approximately equal to 1.0e+09 CFU / mL and is used to orally infect mice on all three infection days. To infect mice, orally administer 0.25 mL of 1.0e+09 CFU / mL via a 20-22G gavage needle. Mice only need to fast prior to the first infection.

[0566] treatment One week after infection, mice are treated with Nu-8. Multiple-dose antibiotic therapy is administered orally at 0.2 mL / dose. Antibiotics are administered twice daily for 7 days. A control group receives vehicle only.

[0567] sampling Food was removed from cages 18 hours before euthanasia, and each cage was clearly labeled as experimentally fasted. Mice were euthanized (CO2 and cervical dislocation). After euthanasia, each stomach was removed by dissecting the esophagus from the upper part of the stomach and the duodenum from the pylorus. The excised stomach was placed in a sterile Petri dish, and the luminal contents were flushed out with sterile 1X PBS. Each rinsed stomach was placed in a 14 mL Falcon tube containing 2 mL of 1X PBS and stored on ice. Each stomach was homogenized, serially diluted 10-fold in 1X PBS, and spot-plated onto Columbia agar containing 3.5% lake horse blood ± DENT selective antibiotic supplement and incubated microaerobically at 37°C for 5 days. Colonies were then counted.

[0568] Dose response Nu-8 was administered orally twice daily for 7 days at various doses (mg / kg). The formulation, concentration, and dose volume for treatment were established prior to administration. The positive control group consisted of a triple therapy regimen (omeprazole, amoxicillin, and clarithromycin). The negative control used a drug-free dosing solution. The implementation schedule is shown in Table 3. The inoculation and treatment schedule is shown in Table 4. [Table 3] [Table 4]

[0569] result Mice were cultured at 6.16, 6.6, and 6.37 days on day 3. log10 Infected with an inoculum of 100 CFU. One week after the last infection (day 0 - start of treatment) the mean gastric titer was 6.74 log10 CFU. Counts remained consistent over the next two weeks, with mean titers in the untreated control group of 6.86 and 6.66 on days 7 and 14, respectively. log10 CFU (see Table 5, showing the mean bacterial stomach titers of H. pylori SS1 in mice after treatment with Nu-8 and Prevpac). Nu-8 had 5.62, 5.21, and 4.74 CFU at day 7 and 6.2, 5.67, and 5.81 CFU at day 14 for the 1, 5, and 10 mg / mL dose solutions, respectively. log10 Figure 1 shows the dose response of bacterial stomach layer CFU. Prevpac (e.g., clarithromycin, omeprazole, and amoxicillin) reduced bacterial titers to 3.22 on day 7. log10 CFU was reduced to 6.19 by day 14. log10 Although treatment with Nu-8 was less effective than the triple therapy regimen at day 7, Nu-8 resulted in less recovery by day 14 (7 days after the last administered dose) than Prevpac, with lower counts in the 5 and 10 mg / mL dose groups (see Table 5). In summary, these results support the use of Nu-8 as a long-term treatment for H. pylori infection, and such results are expected for other Gram-negative bacteria. [Table 5]

[0570] Example 6 Bacterial Cytological Profiling to Evaluate the Structure-Activity Relationship of Nu-8 Compared to Bisphosphocin® Compounds Nu-3, Nu-4, and Nu-5 The structure of the known Bisphosphocin® compound Nu-3 is shown below: [ka]

[0571] Methods and Materials This bacterial cytological profiling (BCP) study uses methods and materials previously described by Nonejuie, P., Burkart, M., Poglianoa, K., Pogiano, J. (2013). Bacterial cytological profiling rapidly identifies cellular pathways targeted by antimicrobial molecules. Proc. Natl. Acad. Sci. USA 110(40):16169-16174. doi:10.1073 / pnas.1311066110.

[0572] The wild-type strains of Escherichia coli ATCC25922 or Pseudomonas aeruginosa K2732 reached an OD of 30°C. 600 Grow in rich medium (unbuffered 2x lysogeny broth [LB]) until the OD of the culture is ~0.4. Then, split these cultures and mix each sample with the appropriate concentration of Nu-8 in unbuffered LB or buffered LB (final mixture OD 600 Treat with 0.1% Nu-8. Exposed cells without Nu-8 are buffered to pH 4 with phosphate.

[0573] BCP is performed in LB medium buffered to pH 4. The minimum inhibitory concentration (MIC) is measured for Nu-3, Nu-4, Nu-5, and Nu-8 against each bacterial strain. As understood by those skilled in the art, the minimum inhibitory concentration is the lowest concentration of an antimicrobial agent that inhibits visible growth of a microorganism after overnight incubation. Cells are treated with Nu-3, Nu-4, Nu-5, and Nu-8 at three different concentrations (1, 0.5, and 0.25xMIC), respectively, and samples are collected for imaging at 30 minutes, 2 hours, and 4 hours. Cell viability is assayed at three time points (5 minutes, 4 hours, and 24 hours after the start of treatment).

[0574] For imaging of E. coli, treated cells are stained with 1 μg / mL FM4-64, 2 μg / mL DAPI, and 0.5 μM SYTOX Green (Molecular Probes / Invitrogen), while P. aeruginosa samples are stained with 0.5 μM SYTOX Green, 28 μg / mL DAPI, and 4.5 μg / mL FM4-64. Transfer cells to agarose pads (20% LB, 1% agarose) for imaging as described in Pogliano, J., Osborne, N., Sharp, M.D., Abanes-De Mello, A., Perez, A., Sun, Y.-L., and Pogliano, K. (1999). A vital stain for studying membrane dynamics in bacteria: a novel mechanism controlling septation during Bacillus subtilis sporulation. Molecular Microbiology, 31:1149-1159. doi:10.1046 / j.1365-2958.1999.01255.x.

[0575] result BCP results show that Nu-3, Nu-4, Nu-5, and Nu-8 each affect the cell envelope of both E. coli (ATCC 25922) and P. aeruginosa (K2732). Treatment with Nu-3, Nu-4, Nu-5, and Nu-8 results in DNA condensation at higher treatment concentrations (buffered pH 4) in E. coli (ATCC 25922). Nu-4, Nu-5, and Nu-8 increase cell membrane permeability (buffered pH 4 or unbuffered LB) in both E. coli (ATCC 25922) and P. aeruginosa (K2732), whereas Nu-3, Nu-4, and Nu-5 cause cell wall deformation (unbuffered LB) in E. coli (ATCC 25922). Treatment with Nu-8 results in a rapid and significant decrease in cell viability, more effectively than Nu-3, Nu-4, and Nu-5. Specifically, Nu-8 is 10 9 From initial CFU / mL to cell viability of <10 within minutes 2 Nu-3, Nu-4, and Nu-5 reduced CFU / mL at a slower rate to <10 within hours. 2-3 to reduce it to.

[0576] In summary, these results support the use of Nu-8 in the treatment of infections where a fast-acting antibacterial mechanism is preferred, such as, for example, bacterial infections associated with urinary tract infections and diabetic foot ulcers, among others.

[0577] Example 7 The antibacterial efficacy of Bisphosphocin® compounds Nu-3, Nu-5 and Nu-8 at increasing pH increases against E. coli and P. aeruginosa. MIC testing is performed using the broth (Mueller Hinton Broth) microdilution procedure associated with each organism group established by the Clinical and Laboratory Standards Institute (CLSI; 3-7). MIC plates are prepared according to CLSI (3-7). To prepare the test plates, automated liquid handlers are used to perform serial dilutions and liquid transfers. Automated liquid handlers utilized in this study include the Multidrop 384 (Labsystems, Helsinki, Finland) and the Biomek 2000 (Beckman Coulter, Fullerton, CA). Solutions are diluted to the desired pH using 1 M citric acid or 1 M NaOH buffer. A standardized inoculum of each test organism is prepared according to CLSI methods (3, 5-7) to equal a 0.5 McFarland standard in the appropriate medium, followed by a further 1:20 dilution (1:10 for anaerobic bacteria).

[0578] Plates were then inoculated with 10 μL of the diluted 0.5 McFarland suspension using a Biomek 2000 from low to high drug concentrations, yielding approximately 5x10 cells per well. 5 A final concentration of CFU / mL is obtained. Uninoculated plates are incubated to assess drug solubility in the test medium. Plates are stacked 3-4 high, covered with a sterile lid on the top plate, and incubated for 18-24 hours according to CLSI. The MIC is recorded as the lowest concentration of each compound that inhibited visible growth of the organism.

[0579] As shown in Table 6, the efficacy of Nu-8 MIC is superior to the Bisphosphocin® compounds Nu-3 and Nu-5 against E. coli and P. aeruginosa at comparable pHs. Specifically, Nu-8 antibacterial activity is superior to Nu-3 and Nu-5 across the pH range (pH 3-4), which may be important for clinical use over several routes of administration, e.g., topical, inhaled, and intravesical. [Table 6]

[0580] Example 8 Bacterial cytological profiling of Nu-3 versus Nu-8 against Gram-negative and Gram-positive bacteria at pH 4, 5.5, and 7

[0581] Methods and Materials This bacterial cytological profiling (BCP) study uses methods and materials previously described by Nonejuie, P., Burkart, M., Poglianoa, K., Pogiano, J. (2013). Bacterial cytological profiling rapidly identifies cellular pathways targeted by antimicrobial molecules. Proc. Natl. Acad. Sci. USA 110(40):16169-16174. doi:10.1073 / pnas.1311066110.

[0582] For viable cell counts, measure the cells at OD 600 The cells are grown to a pH of approximately 0.4 and diluted 1:1 with buffered or unbuffered medium containing various compound concentrations. Samples are then collected and serially diluted (1:10) in a 96-well plate. Five microliters from each well is spotted onto an LB plate, incubated at 30°C, and viable cells are counted the next day.

[0583] Samples were collected at 10, 30, 120, and 240 minutes of exposure for viable cell count and imaging. For imaging of E. coli and S. aureus, 200 μL of treated cells per time point were stained with 0.8 μg / mL FM4-64, 1.5 μg / mL DAPI, and 0.4 μM SYTOX Green (Molecular Probes / Invitrogen). P. aeruginosa samples were stained with 0.4 μM SYTOX Green, 28 μg / mL DAPI, and 1 μg / mL FM4-64. Cells were transferred to agarose pads (20% LB, 1% agarose) for imaging.

[0584] For Nu-3 and Nu-8 stocks (pH 4, 5.5, and 7), the stock concentration is 500 mg / mL. For pH 4, stocks are prepared by dissolving Nu-3 in 25 mM citrate buffer and Nu-8 in 350 mM citric acid. For pH 5.5, stocks are prepared by dissolving Nu-3 in 25 mM citrate phosphate and Nu-8 in 25 mM criterion. For pH 7, stocks are prepared by dissolving Nu-3 and Nu-8 in 25 mM Sorensen phosphate buffer. 2XLB (Soluble Stock) solutions are prepared in 50 mM citrate buffer for pH 4, 50 mM citrate phosphate buffer for pH 5.5, and 50 mM Sorensen phosphate buffer for pH 7.

[0585] result Under experimental conditions for BCP procedures performed at pH levels above 4, Nu-8 is more effective than Nu-3 (at equimolar concentrations) against wild-type E. coli (ATCC 25922), wild-type P. aeruginosa (PAO1; K2732), and methicillin-susceptible Staphylococcus aureus (ATCC 29213) in terms of exposure time, concentration, and rapid changes in cell viability, cell growth, and cell permeability in buffered media (Linnaeus Bioscience 10-2-2017 Report). E. coli cultured without treatment at pH levels of 4, 5.5, and 7 is unaffected. E. coli cell growth, cell viability, and cell permeability for up to 24 hours remain consistent compared to similar parameters assayed at neutral pH. At pH 4, Nu-8 is more effective than Nu-3 at similar concentrations (112.5 and 225 mg / mL), resulting in a significant decrease in cell viability within 10 minutes of treatment (log10 cell viability). 7 From CFU / mL <log10 3 CFU / mL), whereas 112.5 mg / mL Nu-3 delayed cell growth during 240 min of treatment and reduced cell viability at 24 h (the cell growth delay was up to 10 at 240 min). 7 CFR / mL [pH 4 only, cell growth 10 8 CFU / mL] in 24 hours was 10 4.5CFU / mL), and at 225 mg / mL, cell viability decreased within 240 minutes (<10 3 CFU / mL). Cell viability occurs before a clear change in cell permeability is detected 10 minutes after treatment. At pH 5.5 and 7, Nu-8 alters E. coli cell permeability and reduces cell viability and cell growth, whereas Nu-3 is ineffective.

[0586] P. aeruginosa is rapidly affected at pH 4 alone, with a decrease in cell growth and viability and an increase in cell permeability of up to 100% (within 10-30 minutes of treatment). At pH 5.5 and 7 alone, cell growth and viability, as well as cell permeability, are unaffected (relative to similar parameters assayed at neutral pH). Nu-3 and Nu-8 at pH 4 generally decrease cell viability, effectively additive to that observed at pH 4 alone. Nu-8 at 56.5 mg / mL reduces cell viability (<10%) within 30 minutes relative to Nu-3 at twice the concentration (112.5 mg / mL). 3 CFU / mL), which reduces cell viability within 120 minutes (<10 3 At 112.5 mg / mL, Nu-8 outperformed the similar Nu-3 treatment and only pH 4 (approximately 10 CFU / mL by 10 min). 6 CFU / mL) within 10 min. 3 CFU / mL). Also, at pH 5.5 and 7, 112.5 mg / mL Nu-8 was more active, increasing cell permeability by <20% and decreasing cell proliferation relative to 112.5 mg / mL Nu-3, which barely changed cell permeability (<6%) and had no effect on cell proliferation. At pH 7, only Nu-8 (225 mg / mL) increased cell permeability (~37% at 10 min), but this did not persist thereafter, and cell proliferation was slightly lower than at pH 7 alone.

[0587] S. aureus shows a decrease in cell growth and cell viability and a slight increase in cell permeability (<8%) at pH 4 alone. At pH 5.5 alone, cell growth is inhibited up to 240 min and then recovers by 24 h, and cell permeability is unaffected. At pH 7, all cellular parameters are unaffected. At pH 4, 125 mg / mL Nu-8 inhibits cell growth at pH 4 alone (~10 at 240 min). 7 CFU / mL, 10 in 24 hours 4 CFU / mL) at the start of the study, slightly increased cell permeability (<4.3%) and enhanced killing activity. 7.5 CFU / mL to 10 by 240 min 3 CFU / mL, <10 in 24 hours 3 CFU / mLh). Nu-3 at 125 mg / mL is poorly cell permeable (<10%), resulting in a slight decrease in cell growth similar to that seen with pH 4 alone. At 250 mg / mL, Nu-8 reduces cell viability within 10 minutes (approximately 10 4 CFU / mL), and then did not recover (<10 3 CFU / mL) and increased cell permeability (approximately 60%). Nu-3 at 250 mg / mL has low activity, resulting in a slight increase in cell permeability (<10%) and a decrease in cell viability within 24 hours (<10%). 3 At pH 5.5 and 7, both Nu-3 and Nu-8 (125 mg / mL and 250 mg / mL) slightly reduced cell proliferation (<5%) for up to 24 h, with minimal effect on cell permeability.

[0588] In summary, this study demonstrates that Nu-8 outperforms Nu-3 in the pH range of 3 to 4 planned for clinical use.

[0589] Example 9 Nu-8 antibacterial activity against commonly associated strains of bacteria Bacterial strains evaluated in this study include Escherichia coli, Klebsiella spp., Serratia marcescens, Proteus mirabilis / vulgaris, Citrobacter spp., Providencia spp., Proteus morganii, Pseudomonas aeruginosa, Staphylococcus aureus (MRSA only), and Enterococcus faecalis. The Nu-8 test solution is adjusted to pH 3.5 with citric acid and MCI is assessed according to the CLSI method in Mueller-Hinton broth supplemented to promote the growth of specific strains.

[0590] The MICs of Nu-8 at pH 3.5 were determined in human and mouse urine and are comparable to the MICs of Nu-8 in Mueller-Hinton broth under similar conditions. Table 7 demonstrates the Nu-8 MICs for the bacterial strains identified therein. [Table 7]

[0591] The MIC is also determined using lysogeny broth (LB) as the growth medium at pH 4. Under these conditions, Nu-8 is active against E. coli and P. aeruginosa, with MICs of 54 and 27 mg / mL, respectively.

[0592] In summary, these results demonstrate that Nu-8 is effective against Gram-negative and Gram-positive bacteria, which may be important for clinical use by several routes of administration, e.g., topical, inhaled, and intravesical.

[0593] Example 10 Initial efficacy evaluation of Nu-8 against Escherichia coli in a BALB / c mouse urinary tract infection model Female BALB / c mice (20-22 g) ordered from Envigo were acclimated to the housing conditions and handled in accordance with Animal Use Protocol (AUP) No. TP-08. Animals were fed irradiated Teklad Global 29 18 rodent chow and water ad libitum. Mice were housed six per cage in static cages with irradiated 1 / 8-inch Teklad Cone Bedding 7902 in a bioBubble® cleanroom, which provides a bubble environment with HEPA-filtered air at 100 complete air changes per hour. The environment was controlled at a temperature range of 74° ± 4°F and a humidity range of 30-70%. All procedures performed in this experiment complied with National Institutes of Health laws, regulations, and guidelines and were approved by the TransPharm Preclinical Solutions Animal Care and Use Committee.

[0594] A clinical isolate of E. coli (strain CFT073, TPPS1041) will be procured from the University of Michigan.

[0595] Organisms are grown overnight at 37°C in ambient air on trypticase soy agar plates supplemented with 5% sheep blood cells. The culture is aseptically wiped off and transferred to a tube of trypticase soy broth. Optical density is determined at 600 nm. The culture is diluted to provide an inoculum of approximately 7.5 log10 CFU per mouse in a volume of 30 μL. The instillation of the bacterial challenge constituted time 0 for the study. The inoculum size is estimated by optical density before inoculation and confirmed by dilution and back-calculation after inoculation.

[0596] One hour before bacterial challenge, remove water from the animal's cage. At time 0 on day 0, anesthetize the mouse using isoflurane and drain urine from the bladder by applying gentle pressure to the abdomen with the thumb. Infect the mouse with bacteria via transurethral injection in a volume of 30 μL. Return water to the cage immediately after challenge. The challenge is performed in the BL2 operating room. Final count of the challenge inoculum demonstrated a delivered burden of 7.8 log10 organisms per mouse.

[0597] Nu-8 (test article) is prepared immediately before each dose. Nu-8 is dissolved in sterile saline and adjusted to pH 3.5 with phosphoric acid. 23 hours after challenge, water is removed from the animal's cage. One hour later, mice are anesthetized using isoflurane and residual urine is drained from the bladder. Mice are treated with test article or control via transurethral administration in a volume of 30 μL according to Table 8 (showing the animal challenge and treatment schedule). Harvest time is the time when mouse organs are processed. All treatments are administered in a BSL2 operating room. Immediately after treatment administration, the urethral opening is occluded using cyanoacrylate tissue adhesive. [Table 8]

[0598] The primary endpoint used to assess infection progression is the mean bacterial load per gram of bladder tissue. Sixty or 20 minutes after treatment administration and urethral obstruction, mice are euthanized by CO2 asphyxiation. Bladders are aseptically removed, weighed, and homogenized in 1 mL of TSB using a mini-bead beater. The resulting homogenate is serially diluted (neat to 10) and grown overnight at 37°C on ambient atmosphere trypticase soy agar plates supplemented with 5% sheep blood cells. Colony-forming units (CFU) are enumerated, and the total bacterial load per gram of bladder tissue homogenate is calculated.

[0599] Geometric mean CFU along with standard error of the mean (SEM) are calculated using Microsoft Excel, and bar graphs of the data are prepared using GraphPad Prism v.7.0. Statistical comparisons between groups are performed by comparing the geometric means of bacteria in different treatment groups in Excel using Student's t-test assuming unequal variances. A two-tailed P value ≤ 0.05 is considered significant.

[0600] At 60 minutes after treatment, vehicle-treated mice in Group 1 demonstrated a mean bladder CFU burden of 5.3 log10, while gentamicin-treated animals in Group 2 showed 6.1 log10 CFU. At 20 minutes after treatment, mice treated with Nu-8 showed a significant decrease (2.9 log10) in mean bladder CFU burden compared to the vehicle-treated control group. At 60 minutes, these mice showed a burden of 3.7 log10 CFU.

[0601] In summary, Nu-8 demonstrated a statistically significant reduction in E. coli in the animals' bladders 20 minutes after treatment, thereby confirming that Nu-8 is effective against E. coli in an animal model of urinary tract infection. These results are predictive for human therapy.

[0602] Example 11 Confirmatory efficacy evaluation of Nu-8 against Escherichia coli in a BALB / c mouse urinary tract infection model Female BALB / c mice (20-22 g) ordered from Envigo were acclimated to the housing conditions and handled in accordance with Animal Use Protocol (AUP) No. TP-08. Animals were fed irradiated Teklad Global 29 18 rodent chow and water ad libitum. Mice were housed six per cage in static cages with irradiated 1 / 8-inch Teklad Cone Bedding 7902 in a bioBubble® cleanroom, which provides a bubble environment with HEPA-filtered air at 100 complete air changes per hour. The environment was controlled at a temperature range of 74° ± 4°F and a humidity range of 30-70%. All procedures performed in this experiment complied with National Institutes of Health laws, regulations, and guidelines and were approved by the TransPharm Preclinical Solutions Animal Care and Use Committee.

[0603] A clinical isolate of E. coli (strain CFT073, TPPS1041) will be procured from the University of Michigan.

[0604] Organisms are grown overnight at 37°C in ambient air on trypticase soy agar plates supplemented with 5% sheep blood cells. The culture is aseptically wiped off and transferred to a tube of trypticase soy broth. Optical density is determined at 600 nm. The culture is diluted to provide an inoculum of approximately 7.5 log10 CFU per mouse in a volume of 30 μL. The instillation of the bacterial challenge constituted time 0 for the study. The inoculum size is estimated by optical density before inoculation and confirmed by dilution and back-calculation after inoculation.

[0605] One hour before bacterial challenge, remove water from the animal's cage. At time 0 on day 0, anesthetize the mouse using isoflurane and drain urine from the bladder by applying gentle pressure to the abdomen with the thumb. Infect the mouse with bacteria via transurethral injection in a volume of 30 μL. Return water to the cage immediately after challenge. The challenge is performed in the BL2 operating room. Final count of the challenge inoculum demonstrated a delivered burden of 7.8 log10 organisms per mouse.

[0606] Nu-8 (test article) is prepared immediately before each dosing. Nu-8 is dissolved in sterile saline and adjusted to pH 3.5 with phosphoric acid. 23 hours after challenge, water is removed from the animals' cages. One hour later, mice are anesthetized using isoflurane and residual urine is drained from the bladder. Mice are treated with test article or control via transurethral administration in a volume of 30 μL according to Table 9 (showing the animal challenge and treatment schedule). All treatments are administered in a BSL2 operating room.

[0607] Immediately after treatment administration, use Loctite Gel Super Glue to seal the urethral opening. Place one drop of glue at the urethral opening and use tissue forceps to hold the opening together for 5-10 seconds to allow the urethral opening to be sealed and the glue to dry. The animal remained under anesthesia after urethral occlusion. While under anesthesia, rotate the mouse (front to back) every 5 minutes. [Table 9]

[0608] The primary endpoint used to assess infection progression is the average bacterial load per gram of bladder tissue. Ten or 20 minutes after treatment administration and urethral obstruction, mice are euthanized by CO2 asphyxiation. The abdominal cavity is incised to expose the bladder, and the urethra is clamped close to the bladder to prevent urine leakage. Care is taken to prevent urine from leaving the bladder during removal by cutting the urethra distal to the ramp. The bladder (containing urine) is aseptically removed and transferred to a pre-weighed vial of 1 mL TSB. The bladder is then cut to release the urine into the vial along with the tissue. The tissue is weighed and homogenized using a mini-bead beater. The resulting homogenate is serially diluted (neat to 10-7), plated in 5 µL duplicate spots, and grown overnight at 37 °C in ambient atmosphere on trypticase soy agar plates supplemented with 5% sheep blood cells. Plate undiluted (neat) homogenate in a volume of 100 µL per sample. Enumerate colony-forming units (CFU) and calculate the total bacterial load per gram of bladder tissue homogenate.

[0609] Geometric mean CFU along with standard error of the mean (SEM) are calculated using Microsoft Excel, and bar graphs of the data are prepared using GraphPad Prism v.7.0. Statistical comparisons between groups are performed by comparing the geometric means of bacteria in different treatment groups in Excel using Student's t-test assuming unequal variances. A two-tailed P value ≤ 0.05 is considered significant.

[0610] At 10 minutes post-treatment, animals treated with 820 mg / kg Nu-8 exhibited a mean bladder CFU burden of 6.3 log10.

[0611] At 20 minutes post-treatment, vehicle-treated mice in Group 1 demonstrated an average of 6.8 log10 CFU / g tissue. Mice receiving Nu-8 at 205, 410, and 820 mg / kg exhibited bacterial loads of 6.5, 5.0, and 5.4 log10, respectively.

[0612] In summary, Nu-8 demonstrated a reduction in E. coli in the bladder of animals 20 minutes after treatment, confirming that Nu-8 is effective against E. coli in an animal model of urinary tract infection. These results are predictive for human therapy.

[0613] Example 12 A rat urinary tract infection (UTI) model induced by Escherichia coli via transurethral treatment Female Sprague-Dawley rats (n=6 / group) are infected intraurethrally with a predetermined inoculum of E. coli. At the designated time postinfection (according to the in vivo growth curve), animals are anesthetized (ketamine / xylazine) and treated transurethrally with neutral saline (Group 1), phosphate-adjusted saline pH 3.5 (Group 2), or test compound Nu-8 pH 3.5 at 103 and 207 mg / kg (Groups 3 and 4, respectively). When adjusting the pH, the amount of phosphate added is monitored, and the final concentration of the pH-adjusted dose solution is then determined. The goal is to ensure that the final concentration after pH adjustment is within 10% of the desired dose and to report the final concentration after pH adjustment. The dose volume will be 300 μL. Table 10 (Animal Challenge and Treatment Schedule) summarizes the study groups. [Table 10]

[0614] Two hours before each infection, animals were deprived of water. Each animal was infected twice, 24 hours apart, with 300 μL of bacterial suspension administered intraurethrally under mild ketamine and xylazine anesthesia. Before infection, urine was expelled by manual pressure, and a cannula was gently inserted into the bladder via the urethra, followed by the insertion of 300 μL of bacterial suspension. After gently removing the infection cannula, the animal was held upside down for 1 minute and then placed in its cage.

[0615] Animals from all groups are sacrificed by exsanguination with K2EDTA anticoagulant (under ketamine / xylazine anesthesia) 60 minutes after treatment and urine collected under sterile conditions for CFU determination.

[0616] The mean CFU log10 per mL of bladder tissue (tissue and urine) per group was 5.67, 5.53, and 4.60 Log10 CFU / mL bladder tissue for the 103 mg / kg and 207 mg / kg Nu-8 doses at 60 minutes, respectively, in a pH 3.5 saline solution. The Log10 CFU / mL bladder tissue for the pH 7 saline control was 5.51. A statistically significant decrease in CFU count was observed in the group treated with Nu-8 at a dose of 207 mg / kg BW compared to the saline pH 3.5 control group. There was no statistically significant difference in CFU count between the Nu-8-treated group and the saline pH 7 control group.

[0617] In summary, this rat study confirms the mouse studies presented in Examples 10 and 11, all of which demonstrate that Nu-8 produces a statistically significant reduction in E. coli in the animal bladders 20 minutes after treatment. The results of this study again confirm that Nu-8 is effective against E. coli in an animal model of urinary tract infection. These results are predictive of human therapy.

[0618] Example 13 Nu-8 treatment of human patients with complicated urinary tract infections A human patient is identified as having a complicated urinary tract infection. A pharmaceutical composition in the form of a liquid solution containing an effective amount of Nu-8 is administered intravesically to the patient via a catheter. The patient is monitored until symptoms are alleviated or improved, and the pharmaceutical composition may be administered one or more additional times if such administration is determined to be necessary or beneficial for treatment.

[0619] Example 14 Nu-8 treatment of human patients with pulmonary infections caused by cystic fibrosis A human patient is identified as having a pulmonary infection caused by cystic fibrosis. A pharmaceutical composition in the form of a liquid solution containing an effective amount of Nu-8 is administered to the patient by inhalation via a nebulizer. The patient is monitored until symptoms are alleviated or improved, and the pharmaceutical composition may be administered one or more additional times if such administration is determined to be necessary or beneficial for treatment.

[0620] Example 15 Nu-8 treatment of human patients with infected diabetic foot ulcers A human patient is identified as having a diabetic foot ulcer. A pharmaceutical composition in the form of a gel containing an effective amount of Nu-8 is administered topically to the patient at the site of the diabetic foot ulcer. The patient is monitored until symptoms are alleviated or improved, and the pharmaceutical composition may be administered one or more additional times if such administration is determined to be necessary or helpful for treatment.

[0621] Example 16 Nu-8 Treatment of Patients with Ventilator-Acquired Pneumonia A human patient is identified as having ventilator-acquired pneumonia. A pharmaceutical composition in the form of a liquid solution containing an effective amount of Nu-8 is administered to the patient by inhalation via a nebulizer. The patient is monitored until symptoms are alleviated or improved, and the pharmaceutical composition may be administered one or more additional times if such administration is determined to be necessary or beneficial for treatment.

[0622] Example 17 Nu-8 treatment of human patients with burn wound infections A human patient is identified as having an infected burn. A pharmaceutical composition in the form of a gel containing an effective amount of Nu-8 is administered topically to the patient at the site of the burn. The patient is monitored until symptoms are alleviated or improved, and the pharmaceutical composition may be administered one or more additional times if such administration is determined to be necessary or helpful for treatment.

[0623] Example 18 Nu-8 treatment of human patients with impetigo A human patient is identified as having impetigo. A pharmaceutical composition in the form of a gel containing an effective amount of Nu-8 is topically administered to the patient at the location of the vesicles, pustules, and / or yellowish crusts. The patient is monitored until symptoms are alleviated or improved, and the pharmaceutical composition may be administered one or more additional times if such administration is determined to be necessary or helpful for treatment.

[0624] Example 19 Nu-8 treatment of human patients with otitis externa A human patient is identified as having otitis externa. A pharmaceutical composition in the form of a liquid solution containing an effective amount of Nu-8 is administered topically directly to the patient's ear canal. The patient is monitored until symptoms are alleviated or improved, and the pharmaceutical composition may be administered one or more additional times if such administration is determined to be necessary or helpful for treatment.

[0625] Example 20 Nu-8 Treatment of Female Human Patients with Bacterial Vaginosis A female human patient is identified as having bacterial vaginosis. A pharmaceutical composition in the form of a gel containing an effective amount of Nu-8 is topically administered onto or into the patient's vagina. The patient is monitored until symptoms are alleviated or improved, and the pharmaceutical composition may be administered one or more additional times if such administration is determined to be necessary or helpful for treatment.

[0626] While embodiments have been disclosed, the invention is not limited to the disclosed embodiments. Instead, this application is intended to cover any variations, uses, or adaptations of the invention using its general principles. Further, this application is intended to cover such departures from the present disclosure as come within known or customary practice in the art to which this invention pertains and which fall within the limits of the appended claims.

[0627] [Claim 1] A compound having the formula: [ka] (In the formula, A is a monocyclic, bicyclic, or tricyclic carbocyclic or heterocyclic moiety; R1 and R2 are each a C1-C8 alkyl moiety. or Pharmaceutically acceptable salts thereof. [Claim 2] 2. The compound of claim 1, wherein R1 and R2 are both butyl. [Claim 3] A compound having the formula: [ka] (In the formula, Q is oxygen or sulfur; W is an amino- or guanidino-substituted nitrogen-containing heterocyclic moiety; X and Z are endblocking groups; A is H, alkyl, halogen, alkoxy, alkyl-(O-alkyl), aryl, alkenyl, alkanol, or phenol). [Claim 4] A compound selected from any one of compounds 1 to 2,520 listed in Table 1. [Claim 5] A compound having the formula: [ka] or a pharmaceutically acceptable salt thereof. [Claim 6] 10. A pharmaceutical composition comprising the compound of claim 4 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients, or diluents. [Claim 7] 10. A method for treating a diabetic foot ulcer infection in a patient in need thereof, comprising administering to the patient an effective amount of the compound of claim 4 or a pharmaceutically acceptable salt thereof. [Claim 8] 10. A method of treating a complicated urinary tract infection in a patient in need thereof, comprising administering to the patient an effective amount of the compound of claim 4 or a pharmaceutically acceptable salt thereof. [Claim 9] 10. A method of treating a pulmonary infection caused by cystic fibrosis in a patient in need thereof, comprising administering to the patient an effective amount of the compound of claim 4 or a pharmaceutically acceptable salt thereof. [Claim 10] 10. A method of treating ventilator-acquired pneumonia in a patient in need thereof, comprising administering to the patient an effective amount of the compound of claim 4 or a pharmaceutically acceptable salt thereof. [Claim 11] 10. A method of treating a burn infection in a patient in need thereof, comprising administering to the patient an effective amount of the compound of claim 4 or a pharmaceutically acceptable salt thereof. [Claim 12] 10. A method of treating otitis externa in a patient in need thereof, comprising administering to the patient an effective amount of the compound of claim 4 or a pharmaceutically acceptable salt thereof. [Claim 13] 10. A method of treating bacterial vaginosis in a patient in need thereof, comprising administering to the patient an effective amount of the compound of claim 4 or a pharmaceutically acceptable salt thereof. [Claim 14] 10. A method of treating impetigo in a patient in need thereof, comprising administering to said patient an effective amount of the compound of claim 4 or a pharmaceutically acceptable salt thereof. [Claim 15] 10. A compound according to claim 4 or a pharmaceutically acceptable salt thereof for use in therapy. [Claim 16] 10. Use of the compound of claim 4 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament.

Claims

1. A compound having the formula: 【Chemistry 1】 (In the formula, A is a monocyclic, bicyclic, or tricyclic carbocyclic or heterocyclic moiety; R １ and R ２ are C １ -C ８ alkyl moiety) or Pharmaceutically acceptable salts thereof.

2. R １ and R ２ The compound of claim 1 , wherein both are butyl.

3. A compound having the formula: 【Chemistry 2】 (In the formula, Q is oxygen or sulfur; W is an amino- or guanidino-substituted nitrogen-containing heterocyclic moiety; X and Z are endblocking groups; A is H, alkyl, halogen, alkoxy, alkyl-(O-alkyl), aryl, alkenyl, alkanol, or phenol.

4. A compound selected from any one of compounds 1 to 2,520 listed in Table 1.

5. A compound having the formula: 【Transformation 3】 or a pharmaceutically acceptable salt thereof.

6. 10. A pharmaceutical composition comprising a compound of claim 4 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients, or diluents.

7. 10. A method for treating a diabetic foot ulcer infection in a patient in need thereof, comprising administering to the patient an effective amount of a compound of claim 4 or a pharmaceutically acceptable salt thereof.

8. 10. A method of treating a complicated urinary tract infection in a patient in need thereof, comprising administering to said patient an effective amount of a compound of claim 4 or a pharmaceutically acceptable salt thereof.

9. 10. A method of treating a pulmonary infection caused by cystic fibrosis in a patient in need thereof, comprising administering to the patient an effective amount of a compound of claim 4 or a pharmaceutically acceptable salt thereof.

10. 10. A method of treating ventilator-acquired pneumonia in a patient in need thereof, comprising administering to said patient an effective amount of a compound of claim 4 or a pharmaceutically acceptable salt thereof.

11. 10. A method of treating a burn infection in a patient in need thereof, comprising administering to said patient an effective amount of a compound of claim 4 or a pharmaceutically acceptable salt thereof.

12. 10. A method of treating otitis externa in a patient in need thereof, comprising administering to said patient an effective amount of a compound of claim 4 or a pharmaceutically acceptable salt thereof.

13. 10. A method for treating bacterial vaginosis in a patient in need thereof, comprising administering to the patient an effective amount of a compound of claim 4 or a pharmaceutically acceptable salt thereof.

14. 10. A method of treating impetigo in a patient in need thereof, comprising administering to said patient an effective amount of a compound of claim 4 or a pharmaceutically acceptable salt thereof.

15. 10. A compound according to claim 4 or a pharmaceutically acceptable salt thereof for use in therapy.

16. 10. Use of a compound according to claim 4 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament.

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