# Patent

## Title
Methods and apparatus for cleaning or disinfecting a water delivery system

## Abstract

Methods for cleaning or disinfecting water delivery systems, self-cleaning or self-disinfecting water delivery systems, and inserts for use in cleaning or disinfecting water delivery systems utilize cationic steroidal antimicrobial (CSA) molecules to kill microbes and/or break up biofilms within water delivery systems. The methods and systems involve adding CSA molecules to water to form an aqueous CSA composition and passing the aqueous CSA composition through the water delivery system, such as a water storage vessel and/or water delivery line to clean or disinfect the water delivery system. CSA molecules can be added to a water storage vessel, water delivery line, or well, such as by a solid or liquid CSA composition. A CSA-eluting composition may provide CSA molecules to water to form an aqueous CSA composition that passes through or is stored within the water delivery system. CSA molecules provided to agricultural animals in drinking water may improve animal health.

## Background
CROSS-REFERENCE TO RELATED APPLICATIONS
This Application claims the benefit of U.S. Provisional Patent Application No. 61/986,435, filed Apr. 30, 2014, and also U.S. Provisional Patent Application No. 62/009,523, filed Jun. 9, 2014, the disclosures of which are incorporated herein in their entirety.


BACKGROUND OF THE INVENTION
1. The Field of the Invention
The invention relates to methods and apparatus for cleaning or disinfecting water delivery systems, such as water delivery lines or water storage vessels which provide drinking water to animals or humans.
2. the Relevant Technology
Clean and safe water for humans and animals is a valuable commodity. This is particularly true in the case of agricultural animals raised to provide food for human consumption. Unclean water can cause or spread disease, which can harm both animals and those who consume animal products, such as meat, dairy products, and eggs. Avoiding disease is especially important in the case of confined animal feed operations. To avoid disease and also to improve animal health generally and induce weight gain, agricultural animals are often fed antibiotics. Unfortunately, antibiotics can be found in animals and animal products, making them less safe for human consumption.
The United States and other industrialized nations have extensive water systems for delivering safe water to houses and business. Unfortunately, water for humans or animals is only as safe and clean as the storage vessels and water delivery lines that store and deliver such water. To prevent disease, culinary water is often treated with chemicals such as chlorine to inhibit growth of bacteria and parasitic organisms. Unfortunately, chlorine can impart a bad taste and is harmful or toxic to humans or animals at higher concentrations. In addition, chlorine may not be effective at preventing the formation of biofilms on interior surfaces of storage tanks and water lines. Nor does chlorine mitigate bad taste and potentially harmful effects of metals contained in water.
SUMMARY
Disclosed herein are methods for cleaning and disinfecting water delivery lines and systems using cationic steroidal antimicrobial (CSA) molecules. Also disclosed are self-cleaning or self-disinfecting water delivery systems that utilize CSA molecules and also CSA-eluting inserts for attachment to and cleaning or disinfecting of a water delivery system by releasing CSA molecules. The CSA molecules introduced into a water deliver system can kill microbes and/or break up biofilms that may contaminate a water delivery line or water storage vessel.
In some embodiments, a method for cleaning or disinfecting a water delivery line comprises: (1) adding cationic steroidal antimicrobial (CSA) molecules to water to form an aqueous CSA composition; and (2) passing the aqueous CSA composition through the water delivery line to clean or disinfect the water delivery line.
In some embodiments, a method for cleaning or disinfecting a water delivery system comprised of a water storage vessel or well and a water delivery line in fluid communication with the water storage vessel or well comprises: (1) adding cationic steroidal antimicrobial (CSA) molecules to water to form an aqueous CSA composition; and (2) passing the aqueous CSA composition through at least one of the water delivery line or water storage vessel.
In some embodiments, a self-cleaning or self-disinfecting water delivery system, comprises: (1) at least one of a water delivery line or a water storage vessel; and (2) a CSA-releasing composition on an interior surface of the water delivery line and/or within the water storage vessel, wherein the CSA-releasing composition is formulated to release CSA molecules into water in the water delivery line and/or water storage vessel.
In some embodiments, a CSA-releasing insert for attachment to and cleaning or disinfecting of a water delivery system, comprises: (1) an insert substrate for placement on or within a water storage vessel or water delivery line; and (2) a CSA-eluting composition on a surface of or impregnated in the insert substrate, wherein the CSA-eluting composition is formulated to release CSA molecules into water within a water storage vessel or water delivery line.
In some embodiments, the water delivery system provides drinking water to animals, such as agricultural animals, examples of which include cattle, horses, sheep, swine, turkeys, and chickens. In some embodiments, the animals may be located at a confined animal feed operation, and the CSA molecules are used to clean a water delivery system so as to prevent or slow the spread of disease. In addition to cleaning and disinfecting a water delivery system, CSA molecules, when ingested by animals, can improve the health of the animals. By way of example, not limitation, the CSA molecules can provide at least one of the following benefits: (1) reduced harmful bacteria in a digestive tract of an animal; (2) increased beneficial bacteria flora in the digestive tract of the animal; (3) improved feed conversion efficiency by the animal; (4) reduced morbity of the animal; (5) reduced mortality of the animal; or (6) harvested meat from the animal having a reduced content of harmful bacteria.
In some cases, the aqueous CSA composition is formulated to break up biofilms within the water line and/or form complexes with metal ions, metal compounds, or contaminants in water passing through the water line. In some embodiments, the aqueous CSA composition is periodically passed through the water line, and water without CSA molecules is also periodically passed through the water line.
In some embodiments, the water line may provide drinking water to humans. In some cases, the water line may form part of a culinary water system which includes a water storage vessel or well containing water and one or more water delivery lines in communication with the storage vessel or well that deliver water to one or more locations, such as homes or businesses. The one or more water delivery lines may comprise a plurality of pipes or conduits, such as pipes or conduits made of metal or a polymer. The CSA molecules can be added directly to water in the storage vessel or well and/or combined with water, liquid, or solid to form a concentrated CSA composition that is introduced into a storage vessel, well, and/or one or more water delivery lines.
In the case where CSA molecules form complexes with metal ions, metal compounds, or contaminants, it may be desirable to filter the water to remove at least a portion of such complexes in order to yield purified water. This can be accomplished using water filtration or purification systems known in the art.
Additional features and advantages will be set forth in part in the description that follows, and in part will be obvious from the description, or may be learned by practice of the embodiments disclosed herein. It is to be understood that both the foregoing brief summary and the following detailed description are exemplary and explanatory only and are not restrictive of the embodiments disclosed herein or as claimed.



BRIEF DESCRIPTION OF DRAWINGS
FIG. 1 schematically illustrates a self-cleaning or self-disinfecting water deliver system in which CSA molecules are introduced into a water delivery line that delivers water to a water storage vessel.
FIG. 2 schematically illustrates a self-cleaning water or self-disinfecting water deliver system in which CSA molecules are introduced into a water storage vessel or well in fluid communication with a plurality of water delivery lines.
FIG. 3 schematically illustrates a CSA-releasing insert comprised of an insert substrate and CSA molecules impregnated within the insert substrate.
FIG. 4 schematically illustrates a CSA-releasing insert comprised of an insert substrate and a CSA-eluting composition coated on a surface of the insert substrate.



DETAILED DESCRIPTION
I. Introduction
Disclosed herein are methods, systems, and inserts for cleaning or disinfecting water delivery systems using cationic steroidal antimicrobial (CSA) molecules. Methods, systems, and inserts disclosed herein may beneficially clean or disinfect water delivery systems that provides drinking water to animals, such as agricultural animals, or humans. CSA molecules can be added to a water deliver line used to deliver water. CSA molecules can be added to a water storage vessel or well in communication with one or more water delivery lines. CSA molecules can be used to clean water delivery lines or vessels used to provide drinking water to animals, such as animals in a confined animal feed operation. CSA molecules can be used to clean or disinfect a culinary water system that delivers culinary water to one or more locations, such as homes or businesses. CSA molecules can used formulated to kill microbes and/or break up biofilms within water delivery lines or water storage vessels and/or form complexes with metal ions or metal compounds in water passing through water lines and/or contained in water storage vessels.
II. CSA Molecules and Compositions
Cationic steroidal anti-microbial (CSA) molecules, sometimes referred to as CSA compounds or ceragenin compounds, can include synthetically produced, small molecule chemical compounds that include a sterol backbone having various charged groups (e.g., amine and cationic groups) attached to the backbone. The sterol backbone can be used to orient amine or guanidine groups on a face or plane of the sterol backbone. CSAs are cationic and amphiphilic, based upon the functional groups attached to the backbone. They are facially amphiphilic with a hydrophobic face and a polycationic face.
Without wishing to be bound to theory, the CSA molecules described herein act as anti-microbial agents (e.g., anti-bacterial, anti-fungal, and anti-viral). It is believed, for example, that anti-microbial CSA molecules may act as an anti-microbial by binding to the cellular membrane of bacteria and other microbes and modifying the cell membrane, e.g., such as by forming a pore that allows the leakage of ions and cytoplasmic materials critical to the microbe's survival, and leading to the death of the affected microbe. In addition, anti-microbial CSA molecules may also act to sensitize bacteria to other antibiotics. For example, at concentrations of anti-microbial CSA molecules below the corresponding minimum bacteriostatic concentration (MIC), the CSA compound may cause bacteria to become more susceptible to other antibiotics by disrupting the cell membrane, such as by increasing membrane permeability. It is postulated that charged cationic groups may be responsible for disrupting the bacterial cellular membrane and imparting anti-microbial properties. CSA molecules may have similar membrane- or outer coating-disrupting effects on fungi and viruses.
CSA molecules can also form complexes with metal ions or other dissolved species contained within water, which can improve taste and/or reduce harmful effects of certains metals or other contaminates within water.
A. DEFINITIONS
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which these embodiments belong. The terminology used in the description herein is for describing particular embodiments only and is not intended to be limiting of the embodiments. As used in the specification and the appended claims, the singular forms “a,” “an,” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety.
Terms and phrases used in this application, and variations thereof, especially in the appended claims, unless otherwise expressly stated, should be construed as open ended as opposed to limiting. As examples of the foregoing, the term “including” should be read to mean “including, without limitation,” “including but not limited to,” or the like; the term “comprising” as used herein is synonymous with “including,” “containing,” or “characterized by,” and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps; the term “having” should be interpreted as “having at least”; the term “includes” should be interpreted as “includes but is not limited to”; the term “example” is used to provide exemplary instances of the item in discussion, not an exhaustive or limiting list thereof; and use of terms like “preferably,” “preferred,” “desired,” or “desirable,” and words of similar meaning should not be understood as implying that certain features are critical, essential, or even important to the structure or function of the invention, but instead as merely intended to highlight alternative or additional features that may or may not be utilized in a particular embodiment. In addition, the term “comprising” is to be interpreted synonymously with the phrases “having at least” or “including at least”. When used in the context of a process, the term “comprising” means that the process includes at least the recited steps, but may include additional steps. When used in the context of a compound, composition or device, the term “comprising” means that the compound, composition or device includes at least the recited features or components, but may also include additional features or components. Likewise, a group of items linked with the conjunction “and” should not be read as requiring that each and every one of those items be present in the grouping, but rather should be read as “and/or” unless expressly stated otherwise. Similarly, a group of items linked with the conjunction “or” should not be read as requiring mutual exclusivity among that group, but rather should be read as “and/or” unless expressly stated otherwise.
It is understood that, in any compound described herein having one or more chiral centers, if an absolute stereochemistry is not expressly indicated, then each center may independently be of R-configuration or S-configuration or a mixture thereof. Thus, the compounds provided herein may be enantiomerically pure, enantiomerically enriched, racemic mixture, diastereomerically pure, diastereomerically enriched, or a stereoisomeric mixture. In addition it is understood that, in any compound described herein having one or more double bond(s) generating geometrical isomers that can be defined as E or Z, each double bond may independently be E or Z a mixture thereof.
Likewise, it is understood that, in any compound described, all tautomeric forms are also intended to be included.
It is to be understood that where compounds disclosed herein have unfilled valencies, then the valencies are to be filled with hydrogens or isotopes thereof, e.g., hydrogen-1 (protium) and hydrogen-2 (deuterium).
It is understood that the compounds described herein can be labeled isotopically. Substitution with isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements. Each chemical element as represented in a compound structure may include any isotope of said element. For example, in a compound structure a hydrogen atom may be explicitly disclosed or understood to be present in the compound. At any position of the compound that a hydrogen atom may be present, the hydrogen atom can be any isotope of hydrogen, including but not limited to hydrogen-1 (protium) and hydrogen-2 (deuterium). Thus, reference herein to a compound encompasses all potential isotopic forms unless the context clearly dictates otherwise.
It is understood that the methods and combinations described herein include crystalline forms (also known as polymorphs, which include the different crystal packing arrangements of the same elemental composition of a compound), amorphous phases, salts, solvates, and hydrates. In some embodiments, the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water, ethanol, or the like. In other embodiments, the compounds described herein exist in unsolvated form. Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and may be formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, or the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.
Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present embodiments. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should be construed in light of the number of significant digits and ordinary rounding approaches.
Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the embodiments are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements. Every numerical range given throughout this specification and claims will include every narrower numerical range that falls within such broader numerical range, as if such narrower numerical ranges were all expressly written herein. Where a range of values is provided, it is understood that the upper and lower limit, and each intervening value between the upper and lower limit of the range is encompassed within the embodiments.
As used herein, any “R” group(s) such as, without limitation, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, and R18 represent substituents that can be attached to the indicated atom. Unless otherwise specified, an R group may be substituted or unsubstituted.
The term “ring” as used herein can be heterocyclic or carbocyclic. The term “saturated” used herein refers to a fused ring having each atom in the fused ring either hydrogenated or substituted such that the valency of each atom is filled. The term “unsaturated” used herein refers to a fused ring where the valency of each atom of the fused ring may not be filled with hydrogen or other substituents. For example, adjacent carbon atoms in the fused ring can be doubly bound to each other. Unsaturation can also include deleting at least one of the following pairs and completing the valence of the ring carbon atoms at these deleted positions with a double bond; such as R5 and R9; R8 and R10; and R13 and R14.
Whenever a group is described as being “substituted” that group may be substituted with one, two, three or more of the indicated substituents, which may be the same or different, each replacing a hydrogen atom. If no substituents are indicated, it is meant that the indicated “substituted” group may be substituted with one or more group(s) individually and independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, acylalkyl, alkoxyalkyl, aminoalkyl, amino acid, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, protected hydroxyl, alkoxy, aryloxy, acyl, mercapto, alkylthio, arylthio, cyano, halogen (e.g., F, Cl, Br, and I), thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, protected C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, oxo, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, an amino, a mono-substituted amino group and a di-substituted amino group, RaO(CH2)mO—, Rb(CH2)nO—, RcC(O)O(CH2)pO—, and protected derivatives thereof. The substituent may be attached to the group at more than one attachment point. For example, an aryl group may be substituted with a heteroaryl group at two attachment points to form a fused multicyclic aromatic ring system. Biphenyl and naphthalene are two examples of an aryl group that is substituted with a second aryl group.
As used herein, “Ca” or “Ca to Cb” in which “a” and “b” are integers refer to the number of carbon atoms in an alkyl, alkenyl or alkynyl group, or the number of carbon atoms in the ring of a cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl or heteroalicyclyl group. That is, the alkyl, alkenyl, alkynyl, ring of the cycloalkyl, ring of the cycloalkenyl, ring of the cycloalkynyl, ring of the aryl, ring of the heteroaryl or ring of the heteroalicyclyl can contain from “a” to “b”, inclusive, carbon atoms. Thus, for example, a “C1 to C4 alkyl” group refers to all alkyl groups having from 1 to 4 carbons, that is, CH3—, CH3CH2—, CH3CH2CH2—, (CH3)2CH—, CH3CH2CH2CH2—, CH3CH2CH(CH3)— and (CH3)3C—. If no “a” and “b” are designated with regard to an alkyl, alkenyl, alkynyl, cycloalkyl cycloalkenyl, cycloalkynyl, aryl, heteroaryl or heteroalicyclyl group, the broadest range described in these definitions is to be assumed.
As used herein, “alkyl” refers to a straight or branched hydrocarbon chain that comprises a fully saturated (no double or triple bonds) hydrocarbon group. The alkyl group may have 1 to 25 carbon atoms (whenever it appears herein, a numerical range such as “1 to 25” refers to each integer in the given range; e.g., “1 to 25 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 25 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated). The alkyl group may also be a medium size alkyl having 1 to 15 carbon atoms. The alkyl group could also be a lower alkyl having 1 to 6 carbon atoms. The alkyl group of the compounds may be designated as “C4” or “C1-C4 alkyl” or similar designations. By way of example only, “C1-C4 alkyl” indicates that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl and hexyl. The alkyl group may be substituted or unsubstituted.
As used herein, “alkenyl” refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more double bonds. The alkenyl group may have 2 to 25 carbon atoms (whenever it appears herein, a numerical range such as “2 to 25” refers to each integer in the given range; e.g., “2 to 25 carbon atoms” means that the alkenyl group may consist of 2 carbon atom, 3 carbon atoms, 4 carbon atoms, etc., up to and including 25 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated). The alkenyl group may also be a medium size alkenyl having 2 to 15 carbon atoms. The alkenyl group could also be a lower alkenyl having 1 to 6 carbon atoms. The alkenyl group of the compounds may be designated as “C4” or “C2-C4 alkenyl” or similar designations. An alkenyl group may be unsubstituted or substituted.
As used herein, “alkynyl” refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more triple bonds. The alkynyl group may have 2 to 25 carbon atoms (whenever it appears herein, a numerical range such as “2 to 25” refers to each integer in the given range; e.g., “2 to 25 carbon atoms” means that the alkynyl group may consist of 2 carbon atom, 3 carbon atoms, 4 carbon atoms, etc., up to and including 25 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated). The alkynyl group may also be a medium size alkynyl having 2 to 15 carbon atoms. The alkynyl group could also be a lower alkynyl having 2 to 6 carbon atoms. The alkynyl group of the compounds may be designated as “C4” or “C2-C4 alkynyl” or similar designations. An alkynyl group may be unsubstituted or substituted.
As used herein, “aryl” refers to a carbocyclic (all carbon) monocyclic or multicyclic aromatic ring system (including fused ring systems where two carbocyclic rings share a chemical bond) that has a fully delocalized pi-electron system throughout all the rings. The number of carbon atoms in an aryl group can vary. For example, the aryl group can be a C6-C14 aryl group, a C6-C10 aryl group, or a C6 aryl group (although the definition of C6-C10 aryl covers the occurrence of “aryl” when no numerical range is designated). Examples of aryl groups include, but are not limited to, benzene, naphthalene and azulene. An aryl group may be substituted or unsubstituted.
As used herein, “aralkyl” and “aryl(alkyl)” refer to an aryl group connected, as a substituent, via a lower alkylene group. The aralkyl group may have 6 to 20 carbon atoms (whenever it appears herein, a numerical range such as “6 to 20” refers to each integer in the given range; e.g., “6 to 20 carbon atoms” means that the aralkyl group may consist of 6 carbon atom, 7 carbon atoms, 8 carbon atoms, etc., up to and including 20 carbon atoms, although the present definition also covers the occurrence of the term “aralkyl” where no numerical range is designated). The lower alkylene and aryl group of an aralkyl may be substituted or unsubstituted. Examples include but are not limited to benzyl, 2-phenylalkyl, 3-phenylalkyl, and naphthylalkyl.
“Lower alkylene groups” refer to a C1-C25 straight-chained alkyl tethering groups, such as —CH2— tethering groups, forming bonds to connect molecular fragments via their terminal carbon atoms. Examples include but are not limited to methylene (—CH2—), ethylene (—CH2CH2—), propylene (—CH2CH2CH2—), and butylene (—CH2CH2CH2CH2—). A lower alkylene group can be substituted by replacing one or more hydrogen of the lower alkylene group with a substituent(s) listed under the definition of “substituted.”
As used herein, “cycloalkyl” refers to a completely saturated (no double or triple bonds) mono- or multi-cyclic hydrocarbon ring system. When composed of two or more rings, the rings may be joined together in a fused fashion. Cycloalkyl groups can contain 3 to 10 atoms in the ring(s) or 3 to 8 atoms in the ring(s). A cycloalkyl group may be unsubstituted or substituted. Typical cycloalkyl groups include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
As used herein, “cycloalkenyl” refers to a mono- or multi-cyclic hydrocarbon ring system that contains one or more double bonds in at least one ring; although, if there is more than one, the double bonds cannot form a fully delocalized pi-electron system throughout all the rings (otherwise the group would be “aryl,” as defined herein). When composed of two or more rings, the rings may be connected together in a fused fashion. A cycloalkenyl group may be unsubstituted or substituted.
As used herein, “cycloalkynyl” refers to a mono- or multi-cyclic hydrocarbon ring system that contains one or more triple bonds in at least one ring. If there is more than one triple bond, the triple bonds cannot form a fully delocalized pi-electron system throughout all the rings. When composed of two or more rings, the rings may be joined together in a fused fashion. A cycloalkynyl group may be unsubstituted or substituted.
As used herein, “alkoxy” or “alkyloxy” refers to the formula —OR wherein R is an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl or a cycloalkynyl as defined above. A non-limiting list of alkoxys includes methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy and tert-butoxy. An alkoxy may be substituted or unsubstituted.
As used herein, “acyl” refers to a hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl connected, as substituents, via a carbonyl group. Examples include formyl, acetyl, propanoyl, benzoyl, and acryl. An acyl may be substituted or unsubstituted.
As used herein, “alkoxyalkyl” or “alkyloxyalkyl” refers to an alkoxy group connected, as a substituent, via a lower alkylene group. Examples include alkyl-O-alkyl- and alkoxy-alkyl- with the terms alkyl and alkoxy defined herein.
As used herein, “hydroxyalkyl” refers to an alkyl group in which one or more of the hydrogen atoms are replaced by a hydroxy group. Exemplary hydroxyalkyl groups include but are not limited to, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, and 2,2-dihydroxyethyl. A hydroxyalkyl may be substituted or unsubstituted.
As used herein, “haloalkyl” refers to an alkyl group in which one or more of the hydrogen atoms are replaced by a halogen (e.g., mono-haloalkyl, di-haloalkyl and tri-haloalkyl). Such groups include but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl and 1-chloro-2-fluoromethyl, 2-fluoroisobutyl. A haloalkyl may be substituted or unsubstituted.
The term “amino” as used herein refers to a —NH2 group.
As used herein, the term “hydroxy” refers to a —OH group.
A “cyano” group refers to a “—CN” group.
A “carbonyl” or an “oxo” group refers to a C═O group.
The term “azido” as used herein refers to a —N3 group.
As used herein, “aminoalkyl” refers to an amino group connected, as a substituent, via a lower alkylene group. Examples include H2N-alkyl- with the term alkyl defined herein.
As used herein, “alkylcarboxyalkyl” refers to an alkyl group connected, as a substituent, to a carboxy group that is connected, as a substituent, to an alkyl group. Examples include alkyl-C(═O)O-alkyl- and alkyl-O—C(═O)-alkyl- with the term alkyl as defined herein.
As used herein, “C-carboxyalkyl” refers to a carboxy group connected, as a substituent, to an alkyl group. Examples include HO—(C═O)-alkyl, with the term alkyl as defined herein.
As used herein, “alkylaminoalkyl” refers to an alkyl group connected, as a substituent, to an amino group that is connected, as a substituent, to an alkyl group. Examples include alkyl-NH-alkyl-, with the term alkyl as defined herein.
As used herein, “dialkylaminoalkyl” or “di(alkyl)aminoalkyl” refers to two alkyl groups connected, each as a substituent, to an amino group that is connected, as a substituent, to an alkyl group. Examples include




with the term alkyl as defined herein.

As used herein, “alkylaminoalkylamino” refers to an alkyl group connected, as a substituent, to an amino group that is connected, as a substituent, to an alkyl group that is connected, as a substituent, to an amino group. Examples include alkyl-NH-alkyl-NH—, with the term alkyl as defined herein.
As used herein, “alkylaminoalkylaminoalkylamino” refers to an alkyl group connected, as a substituent, to an amino group that is connected, as a substituent, to an alkyl group that is connected, as a substituent, to an amino group that is connected, as a substituent, to an alkyl group. Examples include alkyl-NH-alkyl-NH-alkyl-, with the term alkyl as defined herein.
As used herein, “arylaminoalkyl” refers to an aryl group connected, as a substituent, to an amino group that is connected, as a substituent, to an alkyl group. Examples include aryl-NH-alkyl-, with the terms aryl and alkyl as defined herein.
As used herein, “aminoalkyloxy” refers to an amino group connected, as a substituent, to an alkyloxy group. Examples include H2N-alkyl-O— and H2N-alkoxy- with the terms alkyl and alkoxy as defined herein.
As used herein, “aminoalkyloxyalkyl” refers to an amino group connected, as a substituent, to an alkyloxy group connected, as a substituent, to an alkyl group. Examples include H2N-alkyl-O-alkyl- and H2N-alkoxy-alkyl- with the terms alkyl and alkoxy as defined herein.
As used herein, “aminoalkylcarboxy” refers to an amino group connected, as a substituent, to an alkyl group connected, as a substituent, to a carboxy group. Examples include H2N-alkyl-C(═O)O— and H2N-alkyl-O—C(═O)— with the term alkyl as defined herein.
As used herein, “aminoalkylaminocarbonyl” refers to an amino group connected, as a substituent, to an alkyl group connected, as a substituent, to an amino group connected, as a substituent, to a carbonyl group. Examples include H2N-alkyl-NH—C(═O)— with the term alkyl as defined herein.
As used herein, “aminoalkylcarboxamido” refers to an amino group connected, as a substituent, to an alkyl group connected, as a substituent, to a carbonyl group connected, as a substituent to an amino group. Examples include H2N-alkyl-C(═O)—NH— with the term alkyl as defined herein.
As used herein, “azidoalkyloxy” refers to an azido group connected as a substituent, to an alkyloxy group. Examples include N3-alkyl-O— and N3-alkoxy- with the terms alkyl and alkoxy as defined herein.
As used herein, “cyanoalkyloxy” refers to a cyano group connected as a substituent, to an alkyloxy group. Examples include NC-alkyl-O— and NC-alkoxy- with the terms alkyl and alkoxy as defined herein.
As used herein, “guanidinoalkyloxy” refers to a guanidinyl group connected, as a substituent, to an alkyloxy group. Examples include




with the terms “alkyl” and “alkoxy” as defined herein.

As used herein, “guanidinoalkylcarboxy” refers to a guanidinyl group connected, as a substituent, to an alkyl group connected, as a substituent, to a carboxy group. Examples include




with the term “alkyl” as defined herein.

As used herein, “quaternaryammoniumalkylcarboxy” refers to a quaternized amino group connected, as a substituent, to an alkyl group connected, as a substituent, to a carboxy group. Examples include




with the term “alkyl” as defined herein.

The term “halogen atom” or “halogen” as used herein, means any one of the radio-stable atoms of column 7 of the Periodic Table of the Elements, such as, fluorine, chlorine, bromine and iodine.
Where the numbers of substituents is not specified (e.g. haloalkyl), there may be one or more substituents present. For example “haloalkyl” may include one or more of the same or different halogens.
As used herein, the term “amino acid” refers to any amino acid (both standard and non-standard amino acids), including, but not limited to, α-amino acids, β-amino acids, γ-amino acids and δ-amino acids. Examples of suitable amino acids include, but are not limited to, alanine, asparagine, aspartate, cysteine, glutamate, glutamine, glycine, proline, serine, tyrosine, arginine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan and valine. Additional examples of suitable amino acids include, but are not limited to, ornithine, hypusine, 2-aminoisobutyric acid, dehydroalanine, gamma-aminobutyric acid, citrulline, beta-alanine, alpha-ethyl-glycine, alpha-propyl-glycine and norleucine.
A linking group is a divalent moiety used to link one steroid to another steroid. In some embodiments, the linking group is used to link a first CSA with a second CSA (which may be the same or different). An example of a linking group is (C1-C10) alkyloxy-(C1-C10) alkyl.
The terms “P.G.” or “protecting group” or “protecting groups” as used herein refer to any atom or group of atoms that is added to a molecule in order to prevent existing groups in the molecule from undergoing unwanted chemical reactions. Examples of protecting group moieties are described in T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3. Ed. John Wiley & Sons, 1999, and in J. F. W. McOmie, Protective Groups in Organic Chemistry Plenum Press, 1973, both of which are hereby incorporated by reference for the limited purpose of disclosing suitable protecting groups. The protecting group moiety may be chosen in such a way, that they are stable to certain reaction conditions and readily removed at a convenient stage using methodology known from the art. A non-limiting list of protecting groups include benzyl; substituted benzyl; alkylcarbonyls and alkoxycarbonyls (e.g., t-butoxycarbonyl (BOC), acetyl, or isobutyryl); arylalkylcarbonyls and arylalkoxycarbonyls (e.g., benzyloxycarbonyl); substituted methyl ether (e.g. methoxymethyl ether); substituted ethyl ether; a substituted benzyl ether; tetrahydropyranyl ether; silyls (e.g., trimethylsilyl, triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl, tri-iso-propylsilyloxymethyl, [2-(trimethylsilyl)ethoxy]methyl or t-butyldiphenylsilyl); esters (e.g. benzoate ester); carbonates (e.g. methoxymethyl-carbonate); sulfonates (e.g. tosylate or mesylate); acyclic ketal (e.g. dimethyl acetal); cyclic ketals (e.g., 1,3-dioxane, 1,3-dioxolanes, and those described herein); acyclic acetal; cyclic acetal (e.g., those described herein); acyclic hemiacetal; cyclic hemiacetal; cyclic dithioketals (e.g., 1,3-dithiane or 1,3-dithiolane); orthoesters (e.g., those described herein) and triarylmethyl groups (e.g., trityl; monomethoxytrityl (MMTr); 4,4′-dimethoxytrityl (DMTr); 4,4′,4′′-trimethoxytrityl (TMTr); and those described herein). Amino-protecting groups are known to those skilled in the art. In general, the species of protecting group is not critical, provided that it is stable to the conditions of any subsequent reaction(s) on other positions of the compound and can be removed at the appropriate point without adversely affecting the remainder of the molecule. In addition, a protecting group may be substituted for another after substantive synthetic transformations are complete. Clearly, where a CSA compound differs from a compound disclosed herein only in that one or more protecting groups of the disclosed compound has been substituted with a different protecting group, that compound is within the disclosure
Anti-microbial CSA compounds may also include a tether or “tail moiety” attached to the sterol backbone. The tail moiety may have variable chain length or size and may be one of charged, uncharged, polar, non-polar, hydrophobic, amphipathic, and the like. In various embodiments, a tail moiety may be attached at R17. A tail moiety may include the heteroatom (O or N) covalently coupled to the sterol backbone. The tail moiety may, for example, be configured to alter the hydrophobicity/hydrophilicity of the CSA compound. CSA compounds of the present disclosure having different degrees of hydrophobicity/hydrophilicity may, for example, have different rates of uptake into different target microbes. Likewise, altering the hydrophobicity and/or hydrophilicity of the CSA compounds described herein can affect the retention of the CSA compounds in certain media.
B. CSA COMPOUNDS OR MOLECULES
CSA compounds (also referred to herein as “CSA molecules”) useful in accordance with this disclosure are described herein, both generically and with particularity, and in U.S. Pat. Nos. 6,350,738, 6,486,148, 6,767,904, 7,598,234, 7,754,705, U.S. Application Ser. Nos. 61/786,301, 13/288,892, 61/642,431, 13/554,930, 61/572,714, 13/594,608, 61/576,903, 13/594,612, 13/288,902, 61/605,639, 13/783,131, 61/605,642, 13/783,007, 61/132,361, 13/000,010, 61/534,185, 13/615,244, 61/534,194, 13/615,324, 61/534,205, 61/637,402, 13/841,549, 61/715,277, PCT/US13/37615, 61/749,800, 61/794,721, and 61/814,816, which are incorporated herein by reference. Additional molecules or compounds are generally and specifically described in relation to the methods discussed herein. The skilled artisan will recognize the compounds within the generic formulae set forth herein and understand their preparation in view of the references cited herein and the Examples.
In some embodiments, the CSA is a compound of Formula (I) or a salt thereof:




wherein:

rings A, B, C, and D are independently saturated, or are fully or partially unsaturated, provided that at least two of rings A, B, C, and D are saturated;
m, n, p, and q are independently 0 or 1;
R1 through R4, R6, R7, R11, R12, R15, R16, and R18 are independently selected from the group consisting of hydrogen, hydroxyl, a substituted or unsubstituted alkyl, a substituted or unsubstituted hydroxyalkyl, a substituted or unsubstituted alkyloxyalkyl, a substituted or unsubstituted alkylcarboxyalkyl, a substituted or unsubstituted alkylaminoalkyl, a substituted or unsubstituted alkylaminoalkylamino, a substituted or unsubstituted alkylaminoalkylaminoalkylamino, a substituted or unsubstituted aminoalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted arylaminoalkyl, a substituted or unsubstituted haloalkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, oxo, a linking group attached to a second steroid, a substituted or unsubstituted aminoalkyloxy, a substituted or unsubstituted aminoalkyloxyalkyl, a substituted or unsubstituted aminoalkylcarboxy, a substituted or unsubstituted aminoalkylaminocarbonyl, a substituted or unsubstituted aminoalkylcarboxamido, a substituted or unsubstituted di(alkyl)aminoalkyl, H2N—HC(Q5)-C(O)—O—, H2N—HC(Q5)-C(O)—N(H)—, a substituted or unsubstituted azidoalkyloxy, a substituted or unsubstituted cyanoalkyloxy, P.G.-HN—HC(Q5)-C(O)—O—, a substituted or unsubstituted guanidinoalkyloxy, a substituted or unsubstituted quaternaryammoniumalkylcarboxy, and a substituted or unsubstituted guanidinoalkyl carboxy, where Q5 is a side chain of any amino acid (including a side chain of glycine, i.e., H), and P.G. is an amino protecting group; and
R5, R8, R9, R10, R13, R14 and R17 are independently deleted when one of rings A, B, C, or D is unsaturated so as to complete the valency of the carbon atom at that site, or R5, R8, R9, R10, R13, and R14 are independently selected from the group consisting of hydrogen, hydroxyl, a substituted or unsubstituted alkyl, a substituted or unsubstituted hydroxyalkyl, a substituted or unsubstituted alkyloxyalkyl, a substituted or unsubstituted aminoalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted haloalkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, oxo, a linking group attached to a second steroid, a substituted or unsubstituted aminoalkyloxy, a substituted or unsubstituted aminoalkylcarboxy, a substituted or unsubstituted aminoalkylaminocarbonyl, a substituted or unsubstituted di(alkyl)aminoalkyl, H2N—HC(Q5)-C(O)—O—, H2N—HC(Q5)-C(O)—N(H)—, azidoalkyloxy, cyanoalkyloxy, P.G.-HN—HC(Q5)-C(O)—O—, guanidinoalkyloxy, and guanidinoalkylcarboxy, where Q5 is a side chain of any amino acid, P.G. is an amino protecting group,
provided that at least two or three of R1-4, R6, R7, R11, R12, R15, R16, R17, and R18 are independently selected from the group consisting of a substituted or unsubstituted aminoalkyl, a substituted or unsubstituted aminoalkyloxy, a substituted or unsubstituted alkylcarboxyalkyl, a substituted or unsubstituted alkylaminoalkylamino, a substituted or unsubstituted alkylaminoalkylaminoalkylamino, a substituted or unsubstituted aminoalkylcarboxy, a substituted or unsubstituted arylaminoalkyl, a substituted or unsubstituted aminoalkyloxyaminoalkylaminocarbonyl, a substituted or unsubstituted aminoalkylaminocarbonyl, a substituted or unsubstituted aminoalkylcarboxyamido, a quaternaryammoniumalkylcarboxy, a substituted or unsubstituted di(alkyl)aminoalkyl, H2N—HC(Q5)-C(O)—O—, H2N—HC(Q5)-C(O)—N(H)—, azidoalkyloxy, cyanoalkyloxy, P.G.-HN—HC(Q5)-C(O)—O—, a substituted or unsubstituted guanidine-alkyloxy, and a substituted or unsubstituted guanidinoalkylcarboxy.
In some embodiments, R1 through R4, R6, R7, R11, R12, R15, R16, and R18 are independently selected from the group consisting of hydrogen, hydroxyl, a substituted or unsubstituted (C1-C22) alkyl, a substituted or unsubstituted (C1-C22) hydroxyalkyl, a substituted or unsubstituted (C1-C22) alkyloxy-(C1-C22) alkyl, a substituted or unsubstituted (C1-C22) alkylcarboxy-(C1-C22) alkyl, a substituted or unsubstituted (C1-C22) alkylamino-(C1-C22) alkyl, a substituted or unsubstituted (C1-C22) alkylamino-(C1-C22) alkylamino, a substituted or unsubstituted (C1-C22) alkylamino-(C1-C22) alkylamino-(C1-C22) alkylamino, a substituted or unsubstituted (C1-C22) aminoalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted arylamino-(C1-C22) alkyl, a substituted or unsubstituted (C1-C22) haloalkyl, a substituted or unsubstituted C2-C6 alkenyl, a substituted or unsubstituted C2-C6 alkynyl, oxo, a linking group attached to a second steroid, a substituted or unsubstituted (C1-C22) aminoalkyloxy, a substituted or unsubstituted (C1-C22) aminoalkyloxy-(C1-C22) alkyl, a substituted or unsubstituted (C1-C22) aminoalkylcarboxy, a substituted or unsubstituted (C1-C22) aminoalkylaminocarbonyl, a substituted or unsubstituted (C1-C22) aminoalkylcarboxamido, a substituted or unsubstituted di(C1-C22 alkyl)aminoalkyl, H2N—HC(Q5)-C(O)—O—, H2N—HC(Q5)-C(O)—N(H)—, a substituted or unsubstituted (C1-C22) azidoalkyloxy, a substituted or unsubstituted (C1-C22) cyanoalkyloxy, P.G.-HN—HC(Q5)-C(O)—O—, a substituted or unsubstituted (C1-C22) guanidinoalkyloxy, a substituted or unsubstituted (C1-C22) quaternaryammoniumalkylcarboxy, and a substituted or unsubstituted (C1-C22) guanidinoalkyl carboxy, where Q5 is a side chain of any amino acid (including a side chain of glycine, i.e., H), and P.G. is an amino protecting group.
R5, R8, R9, R10, R13, R14 and R17 are independently deleted when one of rings A, B, C, or D is unsaturated so as to complete the valency of the carbon atom at that site, or R5, R8, R9, R10, R13, and R14 are independently selected from the group consisting of hydrogen, hydroxyl, a substituted or unsubstituted (C1-C22) alkyl, a substituted or unsubstituted (C1-C22) hydroxyalkyl, a substituted or unsubstituted (C1-C22) alkyloxy-(C1-C22) alkyl, a substituted or unsubstituted (C1-C22) aminoalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted (C1-C22) haloalkyl, a substituted or unsubstituted (C2-C6) alkenyl, a substituted or unsubstituted (C2-C6) alkynyl, oxo, a linking group attached to a second steroid, a substituted or unsubstituted (C1-C22) aminoalkyloxy, a substituted or unsubstituted (C1-C22) aminoalkylcarboxy, a substituted or unsubstituted (C1-C22) aminoalkylaminocarbonyl, a substituted or unsubstituted di(C1-C22 alkyl)aminoalkyl, H2N—HC(Q5)-C(O)—O—, H2N—HC(Q5)-C(O)—N(H)—, a substituted or unsubstituted (C1-C22) azidoalkyloxy, a substituted or unsubstituted (C1-C22) cyanoalkyloxy, P.G.-HN—HC(Q5)-C(O)—O—, a substituted or unsubstituted (C1-C22) guanidinoalkyloxy, and (C1-C22) guanidinoalkylcarboxy, where Q5 is a side chain of any amino acid, and P.G. is an amino protecting group; provided that at least two or three of R1-4, R6, R7, R11, R12, R15, R16, R17, and R18 are independently selected from the group consisting of a substituted or unsubstituted (C1-C22) aminoalkyl, a substituted or unsubstituted (C1-C22) aminoalkyloxy, a substituted or unsubstituted (C1-C22) alkylcarboxy-(C1-C22) alkyl, a substituted or unsubstituted (C1-C22) alkylamino-(C1-C22) alkylamino, a substituted or unsubstituted (C1-C22) alkylamino-(C1-C22) alkylamino (C1-C22) alkylamino, a substituted or unsubstituted (C1-C22) aminoalkylcarboxy, a substituted or unsubstituted arylamino (C1-C22) alkyl, a substituted or unsubstituted (C1-C22) aminoalkyloxy (C1-C22) aminoalkylaminocarbonyl, a substituted or unsubstituted (C1-C22) aminoalkylaminocarbonyl, a substituted or unsubstituted (C1-C22) aminoalkylcarboxyamido, a substituted or unsubstituted (C1-C22) quaternary ammonium alkylcarboxy, a substituted or unsubstituted di(C1-C22 alkyl)aminoalkyl, H2N—HC(Q5)-C(O)—O—, H2N—HC(Q5)-C(O)—N(H)—, a substituted or unsubstituted (C1-C22) azidoalkyloxy, a substituted or unsubstituted (C1-C22) cyanoalkyloxy, P.G.-HN—HC(Q5)-C(O)—O—, a substituted or unsubstituted (C1-C22) guanidinoalkyloxy, and a substituted or unsubstituted (C1-C22) guanidinoalkylcarboxy.
In some embodiments, R1 through R4, R6, R7, R11, R12, R15, R16, and R18 are independently selected from the group consisting of hydrogen, hydroxyl, an unsubstituted (C1-C18) alkyl, unsubstituted (C1-C18) hydroxyalkyl, unsubstituted (C1-C18) alkyloxy-(C1-C18) alkyl, unsubstituted (C1-C18) alkylcarboxy-(C1-C18) alkyl, unsubstituted (C1-C18) alkylamino-(C1-C18)alkyl, unsubstituted (C1-C18) alkylamino-(C1-C18) alkylamino, (C1-C18) alkylamino-(C1-C18) alkylamino-(C1-C18) alkylamino, an unsubstituted (C1-C18) aminoalkyl, an unsubstituted aryl, an unsubstituted arylamino-(C1-C18) alkyl, oxo, an unsubstituted (C1-C18) aminoalkyloxy, an unsubstituted (C1-C18) aminoalkyloxy-(C1-C18) alkyl, an unsubstituted (C1-C18) aminoalkylcarboxy, an unsubstituted (C1-C18) aminoalkylaminocarbonyl, an unsubstituted (C1-C18) aminoalkylcarboxamido, an unsubstituted di(C1-C18 alkyl)aminoalkyl, unsubstituted (C1-C18) guanidinoalkyloxy, unsubstituted (C1-C18) quaternary ammonium alkylcarboxy, and unsubstituted (C1-C18) guanidinoalkyl carboxy; R5, R8, R9, R10, R13, R14 and R17 are independently deleted when one of rings A, B, C, or D is unsaturated so as to complete the valency of the carbon atom at that site, or R5, R8, R9, R10, R13, and R14 are independently selected from the group consisting of hydrogen, hydroxyl, an unsubstituted (C1-C18) alkyl, unsubstituted (C1-C18) hydroxyalkyl, unsubstituted (C1-C18) alkyloxy-(C1-C18) alkyl, unsubstituted (C1-C18) alkylcarboxy-(C1-C18) alkyl, unsubstituted (C1-C18) alkylamino-(C1-C18)alkyl, (C1-C18) alkylamino-(C1-C18) alkylamino, unsubstituted (C1-C18) alkylamino-(C1-C18) alkylamino-(C1-C18) alkylamino, an unsubstituted (C1-C18) aminoalkyl, an unsubstituted aryl, an unsubstituted arylamino-(C1-C18) alkyl, oxo, an unsubstituted (C1-C18) aminoalkyloxy, an unsubstituted (C1-C18) aminoalkyloxy-(C1-C18) alkyl, an unsubstituted (C1-C18) aminoalkylcarboxy, an unsubstituted (C1-C18) aminoalkylaminocarbonyl, an unsubstituted (C1-C18) aminoalkylcarboxamido, an unsubstituted di(C1-C18 alkyl)aminoalkyl, unsubstituted (C1-C18) guanidinoalkyloxy, unsubstituted (C1-C18) quaternaryammoniumalkylcarboxy, and unsubstituted (C1-C18) guanidinoalkyl carboxy; provided that at least two or three of R1-4, R6, R7, R11, R12, R15, R16, R17, and R18 are independently selected from the group consisting of hydrogen, hydroxyl, an unsubstituted (C1-C18) alkyl, unsubstituted (C1-C18) hydroxyalkyl, unsubstituted (C1-C18) alkyloxy-(C1-C18) alkyl, unsubstituted (C1-C18) alkylcarboxy-(C1-C18) alkyl, unsubstituted (C1-C18) alkylamino-(C1-C18) alkyl, unsubstituted (C1-C18) alkylamino-(C1-C18) alkylamino, unsubstituted (C1-C18) alkylamino-(C1-C18) alkylamino-(C1-C18) alkylamino, an unsubstituted (C1-C18) aminoalkyl, an unsubstituted aryl, an unsubstituted arylamino-(C1-C18) alkyl, oxo, an unsubstituted (C1-C18) aminoalkyloxy, an unsubstituted (C1-C18) aminoalkyloxy-(C1-C18) alkyl, an unsubstituted (C1-C18) aminoalkylcarboxy, an unsubstituted (C1-C18) aminoalkylaminocarbonyl, an unsubstituted (C1-C18) aminoalkylcarboxamido, an unsubstituted di(C1-C18 alkyl) amino alkyl, unsubstituted (C1-C18) guanidinoalkyloxy, unsubstituted (C1-C18) quaternaryammoniumalkylcarboxy, and unsubstituted (C1-C18) guanidinoalkyl carboxy.
In some embodiments, the CSA, or a salt thereof, is selected from the compound of Formula (IA), which is a subgenus of Formula (I) in that R15 is omitted:




In some embodiments, rings A, B, C, and D are independently saturated.
In some embodiments, one or more of rings A, B, C, and D are heterocyclic.
In some embodiments, rings A, B, C, and D are non-heterocyclic.
In some embodiments, R3, R7, R12, and R18 are independently selected from the group consisting of hydrogen, an unsubstituted (C1-C18) alkyl, unsubstituted (C1-C18) hydroxyalkyl, unsubstituted (C1-C18) alkyloxy-(C1-C18) alkyl, unsubstituted (C1-C18) alkylcarboxy-(C1-C18) alkyl, unsubstituted (C1-C18) alkylamino-(C1-C18)alkyl, unsubstituted (C1-C18) alkylamino-(C1-C18) alkylamino, unsubstituted (C1-C18) alkylamino-(C1-C18) alkylamino-(C1-C18) alkylamino, an unsubstituted (C1-C18) aminoalkyl, an unsubstituted arylamino-(C1-C18) alkyl, an unsubstituted (C1-C18) aminoalkyloxy, an unsubstituted (C1-C18) aminoalkyloxy-(C1-C18) alkyl, an unsubstituted (C1-C18) aminoalkylcarboxy, an unsubstituted (C1-C18) aminoalkylaminocarbonyl, an unsubstituted (C1-C18) aminoalkylcarboxamido, an unsubstituted di(C1-C18 alkyl) amino alkyl, unsubstituted (C1-C18) guanidinoalkyloxy, unsubstituted (C1-C18) quaternary ammonium alkylcarboxy, and unsubstituted (C1-C18) guanidinoalkyl carboxy; and R1, R2, R4, R5, R6, R8, R9, R10, R11, R13, R14, R15, R16, and R17 are independently selected from the group consisting of hydrogen and unsubstituted (C1-C6) alkyl.
In some embodiments, R3, R7, R12, and R18 are independently selected from the group consisting of hydrogen, an unsubstituted (C1-C6) alkyl, unsubstituted (C1-C6) hydroxyalkyl, unsubstituted (C1-C16) alkyloxy-(C1-C5) alkyl, unsubstituted (C1-C16) alkylcarboxy-(C1-C5) alkyl, unsubstituted (C1-C16) alkylamino-(C1-C5)alkyl, unsubstituted (C1-C16) alkylamino-(C1-C5) alkylamino, unsubstituted (C1-C16) alkylamino-(C1-C16) alkylamino-(C1-C5) alkylamino, an unsubstituted (C1-C16) aminoalkyl, an unsubstituted arylamino-(C1-C5) alkyl, an unsubstituted (C1-C5) aminoalkyloxy, an unsubstituted (C1-C16) aminoalkyloxy-(C1-C5) alkyl, an unsubstituted (C1-C5) aminoalkylcarboxy, an unsubstituted (C1-C5) aminoalkylaminocarbonyl, an unsubstituted (C1-C5) aminoalkylcarboxamido, an unsubstituted di(C1-C5 alkyl)amino-(C1-C5) alkyl, unsubstituted (C1-C5) guanidinoalkyloxy, unsubstituted (C1-C16) quaternaryammoniumalkylcarboxy, and unsubstituted (C1-C16) guanidinoalkylcarboxy.
In some embodiments, R1, R2, R4, R5, R6, R8, R10, R11, R14, R16, and R17 are each hydrogen; and R9 and R13 are each methyl.
In some embodiments, R3, R7, R12, and R18 are independently selected from the group consisting of aminoalkyloxy; aminoalkylcarboxy; alkylaminoalkyl; alkoxycarbonylalkyl; alkylcarbonylalkyl; di(alkyl)aminoalkyl; alkylcarboxyalkyl; and hydroxyalkyl.
In some embodiments, R3, R7, and R12 are independently selected from the group consisting of aminoalkyloxy and aminoalkylcarboxy; and R18 is selected from the group consisting of alkylaminoalkyl; alkoxycarbonylalkyl; alkylcarbonyloxyalkyl; di(alkyl)aminoalkyl; alkylaminoalkyl; alkyoxycarbonylalkyl; alkylcarboxyalkyl; and hydroxyalkyl.
In some embodiments, R3, R7, and R12 are the same. In some embodiments, R3, R7, and R12 are aminoalkyloxy. In some embodiments, R3, R7, and R12 are aminoalkylcarboxy. In some embodiments, R18 is alkylaminoalkyl. In some embodiments, R18 is alkoxycarbonylalkyl. In some embodiments, R18 is di(alkyl)aminoalkyl. In some embodiments, R18 is alkylcarboxyalkyl. In some embodiments, R18 is hydroxyalkyl.
In some embodiments, R3, R7, R12, and R18 are independently selected from the group consisting of amino-C3-alkyloxy; amino-C3-alkyl-carboxy; C8-alkylamino-C5-alkyl; C8-alkoxy-carbonyl-C4-alkyl; C8-alkyl-carbonyl-C4-alkyl; di-(C5-alkyl)amino-C5-alkyl; C13-alkylamino-C5-alkyl; C6-alkoxy-carbonyl-C4-alkyl; C6-alkyl-carboxy-C4-alkyl; and C16-alkylamino-C5-alkyl.
In some embodiments, at least two, or at least three, of m, n, p, and q are 1. In some embodiments, m, n, and p are each 1 and q is 0.
In some embodiments, the CSA, or a salt thereof, is selected from the compound of Formula (IB), which is a subgenus of Formula (IA):




In some embodiments, the CSA, or a salt thereof of the compound of Formula (IB), is selected from the group consisting of:







and salts thereof.

C. SALTS
The compounds and compositions disclosed herein are optionally prepared as salts. The term “salt” as used herein is a broad term, and is to be given its ordinary and customary meaning to a skilled artisan (and is not to be limited to a special or customized meaning), and refers without limitation to a salt of a compound. In some embodiments, the salt is an acid addition salt of the compound. Salts can be obtained by reacting a compound with inorganic acids such as hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid, and phosphoric acid. Salts can also be obtained by reacting a compound with an organic acid such as aliphatic or aromatic carboxylic or sulfonic acids, for example formic acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, malonic acid, maleic acid, fumaric acid, trifluoroacetic acid, benzoic acid, cinnamic acid, mandelic acid, succinic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, nicotinic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, muconic acid, butyric acid, phenylacetic acid, phenylbutyric acid, valproic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, or naphthalenesulfonic acid. Salts can also be obtained by reacting a compound with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a lithium, sodium or a potassium salt, an alkaline earth metal salt, such as a calcium, magnesium or aluminum salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C1-C7 alkylamine, cyclohexylamine, dicyclohexylamine, triethanolamine, ethylenediamine, ethanolamine, diethanolamine, triethanolamine, tromethamine, and salts with amino acids such as arginine and lysine; or a salt of an inorganic base, such as aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, or the like.
In some embodiments, the salt is a hydrochloride salt. In some embodiments, the salt is a mono-hydrochloride salt, a di-hydrochloride salt, a tri-hydrochloride salt, or a tetra-hydrochloride salt. Additional examples of salts include sulfuric acid addition salts and sulfonic acid addition salts. 1,5-naphthalenedisulfonic acid is a particularly useful sulfonic acid addition salt.
III. Methods for Cleaning or Disinfecting a Water Deliver System
According to some embodiments, a method for cleaning or disinfecting a water delivery system, such as a water delivery line comprises: (1) adding cationic steroidal antimicrobial (CSA) molecules to water to form an aqueous CSA composition; and (2) passing the aqueous CSA composition through the water delivery line in order to clean or disinfect the water delivery line. For example, a method for cleaning or disinfecting a water delivery line that delivers drinking water to animals comprises: (1) adding cationic steroidal antimicrobial (CSA) molecules to the water delivery line to form an aqueous CSA composition; and (2) passing the aqueous CSA composition through the water delivery line in order to clean or disinfect the water line.
In some embodiments, a method for cleaning or disinfecting a water delivery system comprised of a water storage vessel or well and a water delivery line in fluid communication with the water storage vessel or well comprises: (1) adding cationic steroidal antimicrobial (CSA) molecules to water to form an aqueous CSA composition; and (2) passing the aqueous CSA composition through at least one of the water delivery line or water storage vessel. The aqueous CSA composition can be periodically passed through a water delivery line, followed by periodically passing water without CSA molecules through the water delivery line.
The aqueous CSA compositions used to clean or disinfect a water delivery system can be prepared in any desired manner. In some embodiments, CSA molecules are added directly to at least one of a water delivery line, well, or storage vessel. The CSA molecules can also be combined with a liquid or solid to form a CSA delivery composition, which can be contacted with water in order to provide CSA molecules to one or more components of a water delivery system. CSA molecules can be mixed with water to form a concentrated CSA composition that is introduced into at least one of a water delivery line, well, or storage vessel to form an aqueous CSA composition. The CSA delivery composition can be a CSA-containing table, powder, CSA-eluting composition, or CSA-eluting device. The method may comprise placing a CSA-containing tablet, powder, or eluting device into a storage vessel upstream from the water delivery line. A CSA-eluting insert can be positioned within or form part of a water delivery line or water storage vessel.
In some embodiments, a CSA-eluting composition is applied to an interior surface of a water delivery line and/or a water storage vessel. The CSA-eluting composition releases CSA molecules into water over time, thereby providing at least a portion of the CSA molecules added to water to form an aqueous CSA composition. The water storage vessel may be positioned upstream from a water delivery line, wherein the CSA-eluting composition releases at least a portion of the CSA molecules added to water to form an aqueous CSA composition. The water storage vessel may be positioned so as to receive water from a water delivery line (e.g., can be an animal watering trough or vessel).
The aqueous CSA compositions used to clean or disinfect a water delivery system can have a concentration of CSA molecules that is able to kill microbes and/or break up biofilms located within the water delivery system. The optimal concentration may depend on several factors, such as the type of CSA molecules, the contact time of the aqueous CSA compositions and interior surfaces within the water delivery system, the amount of microbes or biofilms within the water delivery system, and the intended use of the cleaned or disinfected water. Suitable concentrations of CSA molecules in the aqueous CSA compositions can be at least 0.00005%, 0.0001%, 0.0005%, 0.001%, 0.005%, 0.01%, 0.05%, 0.1%, 0.5%, or 1% by weight and/or less than 5%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% by weight and/or within a concentration range defined by the any of the foregoing as lower and upper range endpoints. In some embodiments, the concentration may be at least 0.5 ppm, 1 ppm, 2 ppm, 5 ppm, 10 ppm, 50 ppm, 100 ppm, 500 ppm, or 1000 ppm and/or less than 5000 ppm, 1000 ppm, 500 ppm, 100 ppm, 50 ppm, or 10 ppm and/or within a concentration range defined by the any of the foregoing as lower and upper range endpoints.
In some embodiments, the methods involve cleaning or disinfecting a water delivery line and/or water storage vessel which provides drinking water to animals, including but not limited to, at least one of cattle, horses, sheep, swine, or poultry (e.g., turkeys or chickens). Such methods are particularly advantageous in the case of confined animal feed operations, where diseases can be more easily spread and/or where infections can occur rapidly when animals are given contaminated water.
In addition to helping prevent infections and/or spread of infections among animals, feeding animals with a quantity of CSA molecules can, in some cases, improve the health of the animals. By way of example, CSA molecules, when ingested by an animal, may provide one or more of the following benefits: (1) reduced harmful bacteria in a digestive tract of the animal; (2) increased beneficial bacteria flora in the digestive tract of the animal; (3) improved feed conversion efficiency by the animal; (4) reduced morbity of the animal; (5) reduced mortality of the animal; or (6) harvested meat from the animal having a reduced content of harmful bacteria.
In some embodiments, the water delivery system provides drinking water to humans. The water delivery system may comprise a water storage vessel or well and one or more water lines in fluid communication with the water storage vessel or well that are configured to transport or deliver water to one or more locations, such as house or buildings. The one or more water lines may comprise a plurality of pipes or conduits, such as pipes or conduits made of metal or polymers.
In addition to cleaning or disinfecting the water delivery system, such as by killing microbes and/or breaking up biofilms, the CSA molecules may also form complexes with metal ions, metal compounds, or contaminants in water passing through the water delivery line. In some embodiments, it may be desirable to remove at least a portion of the CSA molecules or CSA complexes in culinary water prior to ingestion by humans, such as by filtration systems and methods known in the art.
IV. Water Deliver Systems
Water delivery systems for use with the disclosed methods and/or which are self-cleaning or self-disinfecting include structures known in the arts and/or means for performing the disclosed methods and/or method steps.
Example water delivery systems may include one or more water storage vessels having a capacity of at least 1 liter, 5 liters, 10 liters, 50 liters, 100 liters, 500 liters, 1000 liters, 5000 liters, 10,000 liters, 100,000 liters, or 1,000,000 liters. The water delivery systems may include one or more water delivery lines having a length of at least 0.5 meter, 1 meter, 5 meters, 10 meters, 25 meters, 50 meters, 100 meters, 1000 meters, 5 kilometers, 10 kilometers, or 100 kilometers. The water storage vessels and/or water delivery lines may have walls constructed from one or more materials selected from metals, wood, polymers, composites, concrete, or ceramics.
Water delivery systems can be used to deliver water for many different uses, including, but not limited to, culinary uses and industrial uses. Water delivery systems exclude dental unit water lines and other tubing and connection products that form a part of, or an integral connection to, a medical device (such as dialysate delivery systems and water purifications systems for hemodialysis).
Referring now to the drawings, FIG. 1 schematically illustrates a water cleaning or disinfecting system 100 for use in cleaning or disinfecting a water delivery line 102. Water delivery line 102 may be used for any desired purpose, such as for delivering water 104 to a water storage vessel 106, which may be used to provide drinking water to an animal or human. CSA molecules added to water delivery line 102 and/or water storage vessel 106 may advantageously kill microbes and/or break up biofilms that may be present within water delivery line 102 and/or water storage vessel 106. A water storage vessel or well (not shown) can be positioned upstream from water delivery line 102 in order to provide a source of water passing through water delivery line 102.
A CSA dispensing vessel 110 is positioned upstream from water delivery line 102 and can be configured to provide a metered quantity of CSA molecules to water passing through water delivery line 102. A conduit 112 fluidly couples dispensing vessel 110 with water delivery line 102. The CSA dispensing vessel 110 may include a concentrated CSA composition, such as an aqueous or other liquid CSA containing composition. A metering pump 114 positioned along or in fluid communication with conduit 112 can be configures to provide a metered quantity of CSA composition to water delivery line 102. A valve 116 positioned along conduit 112 can be selectively opened or closed in order to periodically provide CSA composition to water delivery line 102 and/or provide a desired quantity of CSA composition.
For example, it may be desirable to periodically flush water delivery line 102 with a relatively high concentration of CSA molecules in order to rapidly clean or disinfect water delivery line 102 and/or water storage vessel 106. Thereafter, a smaller concentration of CSA molecules or water without CSA molecules can be periodically passed through water delivery line 102 in order to provide drinking water to humans or animals that contain no CSA molecules or a smaller concentration of CSA molecules.
FIG. 2 schematically illustrates a water cleaning or disinfecting system 200 for use in cleaning or disinfecting a water storage vessel 214 and/or one or more water delivery lines 216 in fluid communication with water storage vessel 214. A CSA dispensing vessel 210 positioned upstream from water storage vessel 214 is configured to provide a constant and/or metered quantity of CSA molecules via one or more conduits 212 to water storage vessel 214. For example, a plurality of conduits 212a and 212b may be individually actuated as desired to control the amount of CSA composition or molecules delivered to water storage vessel 214. For example, conduits 212a and 212b may provide different flow rates and/or concentrations of CSA molecules.
A plurality of water delivery lines, such as illustrated lines 216a, 216b, and 216c, can be used to transport or deliver water from water storage vessel 214 to different locations, such as houses, buildings, or confined animal feed operations. CSA molecules added to water storage vessel 214 may advantageously kill microbes and/or break up biofilms that may be present within water storage vessel 214 and/or water delivery lines 216 and/or water storage vessels (not shown) downstream from water delivery lines 216.
FIG. 3 schematically illustrates a CSA-releasing insert 300 that may be positioned within and/or form part of a water delivery system, such as within or part of a water storage vessel or water delivery line. CSA-releasing insert 300 includes an insert substrate 302, which is formed from an appropriate CSA-eluting polymer or material, and CSA molecules 304 impregnated within insert substrate 302. The CSA-eluting polymer or material of insert substrate 302 is configured to release CSA molecules into water or other liquid in contact with insert 300. In some embodiments, insert substrate 302 may be sized and configured for temporary attachment to an interior surface or region of a water storage vessel or water delivery line. CSA-releasing insert 300 may comprise a pipe configured to temporarily or permanently form part of a water delivery line or water storage vessel. If CSA-releasing insert 300 becomes spent and no longer releases a desired minimum quantity of CSA molecules, it can be augmented or replaced within another CSA-releasing insert 300.
FIG. 4 schematically illustrates a CSA-releasing insert 400 that may be positioned within and/or form part of a water delivery system, such as within or part of a water storage vessel or water delivery line. CSA-releasing insert 400 includes an insert substrate 402, which is formed from an appropriate polymer or other material, and a CSA-eluting composition 404 coated on a surface of insert substrate 402. CSA-eluting composition 404 is configured to release CSA molecules into water or other liquid in contact with insert 400. In some embodiments, insert 402 may be sized and configured for temporary attachment to an interior surface or region of a water storage vessel or water delivery line. CSA-releasing insert 400 may comprise a pipe configured to temporarily or permanently form part of a water delivery line or water storage vessel. If the CSA-releasing insert becomes spent and no longer releases a desired minimum quantity of CSA molecules, it can be augmented or replaced within another CSA-releasing insert.
The present invention may be embodied in other specific forms without departing from its spirit or essential characteristics. The described embodiments are to be considered in all respects only as illustrative and not restrictive. The scope of the invention is, therefore, indicated by the appended claims rather than by the foregoing description. All changes which come within the meaning and range of equivalency of the claims are to be embraced within their scope.

## Claims

1. A method for cleaning or disinfecting a water delivery system, including breaking up biofilms, used in providing a supply of drinking water to a human or animal, comprising:
adding cationic steroidal antimicrobial (CSA) molecules to water to form an aqueous CSA composition; and
passing the aqueous CSA composition through a water delivery line of the water delivery system to break up biofilms in the water delivery line.

2. A method as in claim 1, wherein the water delivery line provides drinking water to animals.

3. A method as in claim 2, wherein the water delivery line provides drinking water to at least one of cattle, horses, sheep, swine, or poultry.

4. A method as in claim 2, wherein the water delivery line provides drinking water to at least one of turkeys or chickens.

5. A method as in claim 2, wherein the drinking water provides a quantity of CSA molecules in order to improve the health of the animals.

6. A method as in claim 1, wherein the water delivery line provides drinking water to humans.

7. A method as in claim 1, wherein the CSA molecules form complexes with metal ions or metal compounds in water passing through the water delivery line.

8. A method as in claim 1, further comprising combining the CSA molecules with a liquid or solid to form a CSA delivery composition and contacting the CSA delivery composition with water in the water delivery line to form the aqueous CSA composition.

9. A method as in claim 1, wherein the water delivery line forms part of a water delivery system comprised of a water storage vessel or well and one or more water lines in fluid communication with the water storage vessel or well that transport water to one or more locations.

10. A method as in claim 9, wherein the one or more water lines comprise a plurality of pipes or conduits.

11. A method as in claim 10, wherein the pipes or conduits are made of metal.

12. A method as in claim 9, wherein the CSA molecules are added to water in the storage vessel or well.

13. A method as in claim 9, further comprising mixing the CSA molecules with water to form a concentrated CSA composition and introducing the concentrated CSA composition into at least one of the storage vessel, well, or one or more water lines.

14. A method as in claim 1, wherein the aqueous CSA composition is periodically passed through the water delivery line, and wherein water without the CSA molecules is periodically passed through the water delivery line.

15. A method as in claim 1, further comprising applying a CSA-eluting composition to an interior surface of the water delivery line, the CSA-eluting composition releasing at least a portion of the CSA molecules added to the water to form the aqueous CSA composition.

16. A method as in claim 1, further comprising applying a CSA-eluting composition to an interior surface of a water storage vessel upstream from the water delivery line, the CSA-eluting composition releasing at least a portion of the CSA molecules added to the water to form the aqueous CSA composition.

17. A method as in claim 1, wherein at least a portion of the CSA molecules are provided by a CSA-containing tablet, powder, or eluting device.

18. A method as in claim 17, the method comprising placing the CSA-containing tablet, powder, or eluting device into a storage vessel upstream from the water delivery line.

19. A method as in claim 1, wherein the water delivery line has a length of at least 1 meter, 5 meters, 10 meters, 25 meters, 50 meters, 100 meters, 1000 meters, or 5 kilometers.

20. A method as in claim 1, wherein the water delivery system comprises a water storage vessel having a capacity of at least 10 liters, 50 liters, 100 liters, 500 liters, 1000 liters, 5000 liters, 10,000 liters, or 100,000 liters.

21. A method as in claim 1, wherein the water delivery system comprises at least one water storage vessel of a confined animal feed operation.

22. A method as in claim 1, wherein the water delivery system comprises at least one water storage vessel that provides drinking water to at least one of a house, building, or human.

23. A method for cleaning or disinfecting a water delivery line, including breaking up biofilms, that delivers drinking water to animals, comprising:
adding cationic steroidal antimicrobial (CSA) molecules to the water delivery line to form an aqueous CSA composition; and
passing the aqueous CSA composition through the water delivery line to break up biofilms in the water delivery line and provide water that is safe for animals to drink.

24. A method as in claim 23, further comprising introducing water from the water delivery line to a drinking trough or vessel from which one or more animals drink.

25. A method as in claim 23, wherein the aqueous CSA composition provides a quantity of CSA molecules that, when ingested by the animals, improves the health of the animals.

26. A method as in claim 23, wherein the animals are located in a confined animal feed operation.

27. A method as in claim 23, wherein the animals are selected from the group of cattle, horses, sheep, swine, poultry, and combinations thereof.

28. A method as in claim 23, wherein the CSA molecules provide at least one of the following:
reduced harmful bacteria in a digestive tract of an animal;
increased beneficial bacteria flora in the digestive tract of the animal;
improved feed conversion efficiency by the animal;
reduced morbidity of the animal;
reduced mortality of the animal; or
harvested meat from the animal having a reduced content of harmful bacteria.

29. A method for cleaning or disinfecting a water delivery system, including breaking up biofilms, comprised of a water storage vessel or well and a water delivery line in fluid communication with the water storage vessel or well, the method comprising:
adding cationic steroidal antimicrobial (CSA) molecules to water to form an aqueous CSA composition having a concentration of CSA molecules in a range of 0.5 ppm to 5000 ppm; and
passing the aqueous CSA composition through at least one of the water delivery line or the water storage vessel or well to break up biofilms within the at least one of the water delivery line or the water storage vessel or well.

30. A method as in claim 29, wherein the water delivery system provides drinking water to animals or humans.

31. A method as in claim 29, wherein the water delivery system is configured to deliver water to houses and buildings.

32. A method as in claim 29, wherein the water delivery system comprises the well, and wherein adding the CSA molecules to water to form the aqueous CSA composition comprises introducing the CSA molecules into the well.

33. A method as in claim 29, wherein the water delivery system comprises the water storage vessel, and wherein adding the CSA molecules to water to form the aqueous CSA composition comprises introducing the CSA molecules into the water storage vessel.

34. A method as in claim 33, wherein the water storage vessel comprises a drinking trough or vessel from which one or more animals drink.

35. A method as in claim 34, wherein the one or more animals are located in a confined animal feed operation.

36. A method as in claim 34, wherein the one or more animals are selected from the group of cattle, horses, sheep, swine, poultry, and combinations thereof.

37. A method as in claim 29, wherein the cationic steroidal antimicrobial (CSA) molecules include one or more compounds according to Formula (I), or a salt thereof:



wherein
rings A, B, C, and D are independently saturated, or are fully or partially unsaturated, provided that at least two of rings A, B, C, and D are saturated;
m, n, p, and q are independently 0 or 1;
R1-R18 are substituent groups attached to one of rings A, B, C, or D; wherein R1-R18 are independently selected from the group consisting of hydrogen, hydroxyl, a substituted or unsubstituted alkyl, a substituted or unsubstituted hydroxyalkyl, a substituted or unsubstituted alkyloxyalkyl, a substituted or unsubstituted alkylcarboxyalkyl, a substituted or unsubstituted alkylaminoalkyl, a substituted or unsubstituted alkylaminoalkylamino, a substituted or unsubstituted alkylaminoalkylaminoalkylamino, a substituted or unsubstituted aminoalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted arylaminoalkyl, a substituted or unsubstituted haloalkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, oxo, a linking group attached to a second steroid, a substituted or unsubstituted aminoalkyloxy, a substituted or unsubstituted aminoalkyloxyalkyl, a substituted or unsubstituted aminoalkylcarboxy, a substituted or unsubstituted aminoalkylaminocarbonyl, a substituted or unsubstituted aminoalkyl-carboxamido, a substituted or unsubstituted di(alkyl)aminoalkyl, a substituted or unsubstituted C-carboxyalkyl; H2N—HC(Q5)-C(O)—O—, H2NHC(Q5)-C(O)—N(H)—, a substituted or unsubstituted azidoalkyloxy, a substituted or unsubstituted cyanoalkyloxy, P.G.-HN—HC(Q5)-C(O)—O—, a substituted or unsubstituted guanidinoalkyloxy, a substituted or unsubstituted quaternary ammonium alkylcarboxy, and a substituted or unsubstituted guanidinoalkyl carboxy, where Q5 is a side chain of an amino acid, and P.G. is an amino protecting group.

38. A method as in claim 37, wherein:
R1 through R4, R6, R7, R11, R12, R15, R16, and R18 are independently selected from the group consisting of hydrogen, hydroxyl, a substituted or unsubstituted alkyl, a substituted or unsubstituted hydroxyalkyl, a substituted or unsubstituted alkyloxyalkyl, a substituted or unsubstituted alkylcarboxyalkyl, a substituted or unsubstituted alkylaminoalkyl, a substituted or unsubstituted alkylaminoalkylamino, a substituted or unsubstituted alkylaminoalkyl-aminoalkylamino, a substituted or unsubstituted aminoalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted arylaminoalkyl, a substituted or unsubstituted haloalkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, oxo, a linking group attached to a second steroid, a substituted or unsubstituted aminoalkyloxy, a substituted or unsubstituted aminoalkyloxyalkyl, a substituted or unsubstituted aminoalkylcarboxy, a substituted or unsubstituted aminoalkylaminocarbonyl, a substituted or unsubstituted aminoalkylcarboxamido, a substituted or unsubstituted di(alkyl)aminoalkyl, H2N—HC(Q5)-C(O)—O—, H2N—HC(Q5)-C(O)—N(H)—, a substituted or unsubstituted azidoalkyloxy, a substituted or unsubstituted cyanoalkyloxy, P.G.-HN—HC(Q5)-C(O)—O—, a substituted or unsubstituted guanidinoalkyloxy, a substituted or unsubstituted quaternary ammonium alkylcarboxy, and a substituted or unsubstituted guanidinoalkyl carboxy, where Q5 is a side chain of an amino acid, and P.G. is an amino protecting group; and
R5, R8, R9, R10, R13, R14 and R17 are independently deleted when one of rings A, B, C, or D is unsaturated so as to complete the valency of the carbon atom at that site, or R5, R8, R9, R10, R13, and R14 are independently selected from the group consisting of hydrogen, hydroxyl, a substituted or unsubstituted alkyl, a substituted or unsubstituted hydroxyalkyl, a substituted or unsubstituted alkyloxyalkyl, a substituted or unsubstituted aminoalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted haloalkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, oxo, a linking group attached to a second steroid, a substituted or unsubstituted aminoalkyloxy, a substituted or unsubstituted aminoalkylcarboxy, a substituted or unsubstituted aminoalkylaminocarbonyl, a substituted or unsubstituted di(alkyl)aminoalkyl, H2N—HC(Q5)-C(O)—O—, H2N—HC(Q5)-C(O)—N(H)—, azidoalkyloxy, cyanoalkyloxy, P.G.-HN—HC(Q5)-C(O)—O—, guanidinoalkyloxy, and guanidinoalkylcarboxy, where Q5 is a side chain of an amino acid, P.G. is an amino protecting group,
provided that at least two of R1-4, R6, R7, R11, R12, R15, R16, R17, and R18 are independently selected from the group consisting of a substituted or unsubstituted aminoalkyl, a substituted or unsubstituted aminoalkyloxy, a substituted or unsubstituted alkylcarboxyalkyl, a substituted or unsubstituted alkylaminoalkylamino, a substituted or unsubstituted alkyl aminoalkyl-aminoalkyl amino, a substituted or unsubstituted aminoalkylcarboxy, a substituted or unsubstituted arylaminoalkyl, a substituted or unsubstituted aminoalkyloxyaminoalkylaminocarbonyl, a substituted or unsubstituted aminoalkylaminocarbonyl, a substituted or unsubstituted aminoalkyl-carboxyamido, a quaternary ammonium alkylcarboxy, a substituted or unsubstituted di(alkyl)aminoalkyl, H2N—HC(Q5)-C(O)—O—, H2N—HC(Q5)-C(O)—N(H)—, azidoalkyloxy, cyanoalkyloxy, P.G.-HN—HC(Q5)-C(O)—O—, a substituted or unsubstituted guanidinoalkyloxy, and a substituted or unsubstituted guanidinoalkylcarboxy.

39. A method as in claim 37, wherein
R1 through R4, R6, R7, R11, R12, R15, R16, and R18 are independently selected from the group consisting of hydrogen, hydroxyl, a substituted or unsubstituted (C1-C18) alkyl, a substituted or unsubstituted (C1-C18) hydroxyalkyl, a substituted or unsubstituted (C1-C18) alkyloxy-(C1-C18) alkyl, a substituted or unsubstituted (C1-C18) alkylcarboxy-(C1-C18) alkyl, a substituted or unsubstituted (C1-C18) alkylamino-(C1-C18)alkyl, a substituted or unsubstituted (C1-C18) alkylamino-(C1-C18) alkylamino, a substituted or unsubstituted (C1-C18) alkylamino-(C1-C18) alkylamino-(C1-C18) alkylamino, a substituted or unsubstituted (C1-C18) aminoalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted arylamino-(C1-C18) alkyl, a substituted or unsubstituted (C1-C18) haloalkyl, a substituted or unsubstituted C2-C6 alkenyl, a substituted or unsubstituted C2-C6 alkynyl, oxo, a linking group attached to a second steroid, a substituted or unsubstituted (C1-C18) aminoalkyloxy, a substituted or unsubstituted (C1-C18) aminoalkyloxy-(C1-C18) alkyl, a substituted or unsubstituted aminoalkylcarboxy, a substituted or unsubstituted (C1-C18) aminoalkylaminocarbonyl, a substituted or unsubstituted (C1-C18) aminoalkylcarboxamido, a substituted or unsubstituted di(C1-C18 alkyl)aminoalkyl, H2N—HC(Q5)-C(O)—O—, H2N—HC(Q5)-C(O)—N(H)—, a substituted or unsubstituted (C1-C18) azidoalkyloxy, a substituted or unsubstituted (C1-C18) cyanoalkyloxy, P.G.-HN—HC(Q5)-C(O)—O—, a substituted or unsubstituted (C1-C18) guanidinoalkyloxy, a substituted or unsubstituted (C1-C18) quaternary ammonium alkylcarboxy, and a substituted or unsubstituted (C1-C18) guanidinoalkyl carboxy, where Q5 is a side chain of an amino acid, and P.G. is an amino protecting group;
R5, R8, R9, R10, R13, R14 and R17 are independently deleted when one of rings A, B, C, or D is unsaturated so as to complete the valency of the carbon atom at that site, or R5, R8, R9, R10, R13, and R14 are independently selected from the group consisting of hydrogen, hydroxyl, a substituted or unsubstituted (C1-C18) alkyl, a substituted or unsubstituted (C1-C18) hydroxyalkyl, a substituted or unsubstituted (C1-C18) alkyloxy-(C1-C18) alkyl, a substituted or unsubstituted (C1-C18) aminoalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted (C1-C18) haloalkyl, a substituted or unsubstituted (C2-C6) alkenyl, a substituted or unsubstituted (C2-C6) alkynyl, oxo, a linking group attached to a second steroid, a substituted or unsubstituted (C1-C18) aminoalkyloxy, a substituted or unsubstituted (C1-C18) aminoalkylcarboxy, a substituted or unsubstituted (C1-C18) aminoalkylaminocarbonyl, a substituted or unsubstituted di(C1-C18 alkyl)aminoalkyl, H2N—HC(Q5)-C(O)—O—, H2N—HC(Q5)-C(O)—N(H)—, a substituted or unsubstituted (C1-C18) azidoalkyloxy, a substituted or unsubstituted (C1-C18) cyanoalkyloxy, P.G.-HN—HC(Q5)-C(O)—O—, a substituted or unsubstituted (C1-C18) guanidinoalkyloxy, and (C1-C18) guanidinoalkylcarboxy, where Q5 is a side chain of an amino acid, and P.G. is an amino protecting group;
provided that at least three of R1-4, R6, R7, R11, R12, R15, R16, R17, and R18 are independently selected from the group consisting of a substituted or unsubstituted (C1-C18) aminoalkyl, a substituted or unsubstituted (C1-C18) aminoalkyloxy, a substituted or unsubstituted (C1-C18) alkylcarboxy-(C1-C18) alkyl, a substituted or unsubstituted (C1-C18) alkylamino-(C1-C18) alkylamino, a substituted or unsubstituted (C1-C18) alkylamino-(C1-C18) alkylamino (C1-C18) alkylamino, a substituted or unsubstituted (C1-C18) aminoalkylcarboxy, a substituted or unsubstituted arylamino (C1-C18) alkyl, a substituted or unsubstituted (C1-C18) aminoalkyloxy (C1-C18) aminoalkylaminocarbonyl, a substituted or unsubstituted (C1-C18) aminoalkylaminocarbonyl, a substituted or unsubstituted (C1-C18) aminoalkylcarboxyamido, a substituted or unsubstituted (C1-C18) quaternary ammonium alkylcarboxy, a substituted or unsubstituted di(C1-C18 alkyl)aminoalkyl, H2N—HC(Q5)-C(O)—O—, H2N—HC(Q5)-C(O)—N(H)—, a substituted or unsubstituted (C1-C18) azidoalkyloxy, a substituted or unsubstituted cyanoalkyloxy, P.G.-HN—HC(Q5)-C(O)—O—, a substituted or unsubstituted guanidinoalkyloxy, and a substituted or unsubstituted (C1-C18) guanidinoalkylcarboxy.

40. A method as in claim 37, wherein the one or more compounds of Formula (I) or salt thereof comprise a compound of Formula (IB):

41. A method as in claim 40, wherein R3, R7, and R12 are each independently aminoalkyloxy or aminoalkylcarboxy.

42. A method as in claim 41, wherein Rig is selected from the group consisting of: alkylaminoalkyl, di(alkyl)aminoalkyl, alkoxycarbonylalkyl, alkylcarboxyalkyl, and C-carboxyalkyl.

43. A method as in claim 37, wherein the CSA molecules are selected from the group consisting of:







and salts thereof.

44. A self-cleaning or self-disinfecting water delivery system configured to break up biofilms in the water delivery system and provide a supply of drinking water to a human or animal, comprising:
at least one of a water delivery line or a water storage vessel configured to provide a supply of drinking water to a human or animal; and
a cationic steroidal antimicrobial (CSA)-eluting composition positioned on an interior surface of the water delivery line and/or placed within the water storage vessel, wherein the CSA-eluting composition is formulated to release CSA molecules into water in the water delivery line and/or water storage vessel over time and in a concentration in order for the water delivery system to break up biofilms forming on an interior surface of the at least one of the water delivery line or the water storage vessel.

45. A self-cleaning or self-disinfecting water delivery system as in claim 44, wherein the CSA-eluting composition comprises a CSA-eluting composition positioned on an interior surface of the water delivery line and/or water storage vessel.

46. A self-cleaning or self-disinfecting water delivery system as in claim 44, wherein the CSA-eluting composition comprises a CSA-releasing tablet, CSA-releasing powder, or CSA-eluting device.

47. A self-cleaning or self-disinfecting water delivery system as in claim 44, wherein the water delivery system includes one or more water tanks positionable upstream of one or more water lines.

48. A self-cleaning or self-disinfecting water delivery system as in claim 44, wherein the water storage vessel is an animal drinking trough or vessel.

49. A self-cleaning or self-disinfecting water delivery system as in claim 44, wherein the water storage vessel is configured to provide drinking water to one or more animals in a confined animal feed operation.

50. A self-cleaning or self-disinfecting water delivery system as in claim 44, wherein the water storage vessel is configured to provide drinking water to one or more of cattle, horses, sheep, swine, or poultry.

51. A cationic steroidal antimicrobial (CSA)-releasing insert for attachment to and cleaning or disinfecting of a water delivery system and for breaking up biofilms in the water delivery system, the CSA-releasing insert comprising:
an insert substrate for placement on or within a water storage vessel or water delivery line; and
a CSA-eluting composition on a surface of or impregnated in the insert substrate, wherein the CSA-eluting composition is formulated to release CSA molecules into water within a water storage vessel or water delivery line and form an aqueous CSA composition having a concentration of CSA molecules in a range of 0.00005% to 5% by weight of the aqueous CSA composition, wherein the concentration of CSA molecules released by the CSA-eluting composition acts to break up biofilms in the water delivery system when in use.

52. A CSA-releasing insert as in claim 51, wherein the insert comprises a pipe configured to temporarily or permanently form part of the water delivery line.

53. A CSA-releasing insert as in claim 51, wherein the insert substrate is sized and configured for attachment to an interior surface or region of the water storage vessel or water delivery line.