Use of cationic steroidal antimicrobial compounds to inactivate coronaviruses

Abstract

Compositions and methods for inactivating coronaviruses are provided. [Solution] A method for inactivating coronavirus, comprising the steps of preparing an inactivating composition comprising one or more CSA compounds in a carrier, and administering the inactivating composition to a subject, wherein the inactivating composition inactivates coronavirus virions in the subject or that come into contact with the subject.

Description

[Technical Field]

[0001] [Background technology]

[0002] Coronaviruses are single-stranded, positive-sense RNA viruses that cause respiratory disease in mammals and birds. They are among the largest known RNA viruses, with genomes of approximately 26–32 kilobases. Coronaviruses have characteristic club-shaped spikes protruding from their enveloped surfaces. When coronavirus virions were first visualized under electron microscopy, these spikes formed an image reminiscent of the solar corona, hence the name of the virus.

[0003] There are several different types of coronaviruses capable of infecting humans. Some of these are relatively harmless and cause symptoms similar to those of the common cold. However, other types of coronaviruses can cause severe illness. Four human coronaviruses (OC43, HKU1, 229E, and NL63) are known to generally cause mild symptoms. These are constantly circulating in the human population and are thought to be responsible for approximately 15% of all common colds.

[0004] Three human coronaviruses that can potentially cause severe illness are severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome-related coronavirus (MERS-CoV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS first appeared in late 2002 and went on to infect more than 8,000 people with a case fatality rate of approximately 10%. MERS first appeared in mid-2012. MERS has a case fatality rate of approximately 35% but is not as easily transmitted from person to person as other coronaviruses.

[0005] In late 2019, a novel coronavirus, now known as SARS-CoV-2, was identified from a pneumonia outbreak in Wuhan, China. Infection with SARS-CoV-2 can result in coronavirus disease 2019 (COVID-19), with symptoms including fever, cough, fatigue, shortness of breath, organ damage, swelling and inflammation of the extremities, and loss of smell and taste. While most cases do not progress beyond these flu-like symptoms, some develop acute respiratory distress syndrome (ARDS), which can lead to septic shock, blood clots, and multiple organ failure. By early 2020, COVID-19 had become a global pandemic. SARS-CoV-2 does not have the same high mortality rate as SARS or MERS, but it is much more contagious. Several variants also exist, which may or may not evade existing immunity acquired through exposure to other viruses, such as other coronaviruses.

[0006] There are several recently developed vaccines and antiviral treatments of questionable efficacy against COVID-19. The vaccines are experimental and have not all passed FDA testing for safety and efficacy. The course of most viral infections involves exposure to the virus, the onset of symptoms, the development of a specific adaptive immune response, and the elimination of the virus from infected patients. Apart from a safe and effective vaccine, the most effective means of stopping the effects of a widespread virus is widespread exposure by the population, which leads to herd immunity. However, this can come at a great cost in terms of the morbidity required to achieve such herd immunity.

[0007] Innate immunity, on the other hand, provides continuous protection against pathogens ranging from bacteria to fungi to viruses. The continuity and breadth of innate immune activity is important due to constant exposure to a wide range of pathogens. In some patients, the pathogenesis of coronavirus infections, such as SARS-CoV-2 infection, may be attributed to a lack of innate immunity, because in such cases, broad innate protection is insufficient during the time required to develop a specific adaptive immune response.

[0008] Although vaccines exist, they are still highly disliked by many people because they are still experimental and have no proven long-term safety, which may require years of observation and retrospective analysis. Summary of the Invention [Problem to be solved by the invention]

[0009] Thus, there is a continuing need for compositions and methods capable of inactivating coronaviruses. Such compositions and methods should be capable of preventing, reducing, and / or treating coronavirus infections. [Means for solving the problem]

[0010] The present disclosure describes methods of administering one or more cationic steroidal antimicrobial (CSA) compounds to inactivate coronaviruses. The methods disclosed herein are capable of reducing or inhibiting coronavirus infection or pathogenesis in cells in vitro, ex vivo, or in vivo.

[0011] In one embodiment, a method for inactivating coronavirus includes (1) providing an inactivation composition comprising one or more CSA compounds and a carrier, (2) administering the inactivation composition to a subject in need thereof, and (3) wherein the inactivation composition inactivates coronavirus virions in the subject or that contact the subject. The method can thereby prevent, reduce, or suppress a coronavirus infection, such as COVID-19, in the subject.

[0012] The subject may be a mammal or a bird. The subject may be a human, a livestock animal, a pet, a laboratory animal, or a zoo animal. The carrier may be any suitable carrier in which one or more CSA compounds can be mixed. Examples include water, alcohol, other organic solvents, emulsions, or combinations thereof.

[0013] The inactivating composition may be administered via any suitable route of administration, including topically, orally, transdermally, via inhalation, or parenterally (e.g., via injection).

[0014] In one embodiment, a method for inactivating coronavirus includes (1) preparing an inactivating composition comprising one or more CSA compounds in a carrier; (2) applying the inactivating composition to a surface; and (3) the inactivating composition inactivates coronavirus virions on or in contact with the surface.

[0015] The surface may include any surface that is considered to be contaminated with coronavirus, or is susceptible to contamination by coronavirus, or is at risk of contamination by coronavirus, and is suitable for contact with the inactivating composition.

[0016] In some embodiments, the CSA liquid formulation is converted into a mist, which is used to spray barns, feedlots, or other animal enclosures or buildings that may be occupied by other mammals, including humans. Fogging of a room can cause allergies to the airborne particles in the room. The CSA compound is dispersed over a wide area so that it can contact exposed or accessible surfaces.In addition, it has been found that animals, including farm animals and other mammals, can safely breathe in the mist and are protected from contracting or spreading coronavirus disease.Nebulizers can be used to deliver the atomized liquid formulation of the CSA compound to subjects, including human subjects, as therapeutic or preventive treatment.

[0017] Any CSA compound described herein or any combination of such CSA compounds may be utilized in the therapeutic composition. Presently preferred CSA compounds include CSA-44, CSA-131, and / or structurally similar CSA compounds.

[0018] Additional features and advantages will be set forth in part in the detailed description that follows, and in part will be obvious from the detailed description, or may be learned by practice of the embodiments disclosed herein. It should be understood that both the foregoing summary and the following detailed description are illustrative and are not limitations of the embodiments disclosed or claimed herein.

[0019] To describe various features and concepts of the present disclosure, a more particular description of particular subject matter will be made by reference to specific embodiments that are illustrated in the accompanying drawings. Various embodiments will be described and explained with additional specificity and detail through the use of the accompanying drawings, with the understanding that these drawings merely depict example embodiments and are not to be considered limiting in scope. [Brief explanation of the drawings]

[0020] [Figure 1A-1] FIG. 1 shows examples of cationic steroidal antimicrobial compounds with ester or amide bonds at one or more of the R3, R7, and R12 positions. [Figure 1A-2] FIG. 1 shows examples of cationic steroidal antimicrobial compounds with ester or amide bonds at one or more of the R3, R7, and R12 positions. [Figure 1A-3] FIG. 1 shows examples of cationic steroidal antimicrobial compounds with ester or amide bonds at one or more of the R3, R7, and R12 positions. [Figure 1B-1] FIG. 1 shows examples of cationic steroidal antimicrobial compounds with ether linkages at one or more of the R3, R7, and R12 positions. [Figure 1B-2] FIG. 1 shows examples of cationic steroidal antimicrobial compounds with ether linkages at one or more of the R3, R7, and R12 positions. [Figure 1B-3] FIG. 1 shows examples of cationic steroidal antimicrobial compounds with ether linkages at one or more of the R3, R7, and R12 positions. [Figure 1B-4] FIG. 1 shows examples of cationic steroidal antimicrobial compounds with ether linkages at one or more of the R3, R7, and R12 positions. [Figure 1B-5] FIG. 1 shows examples of cationic steroidal antimicrobial compounds with ether linkages at one or more of the R3, R7, and R12 positions. [Figure 1B-6] FIG. 1 shows examples of cationic steroidal antimicrobial compounds with ether linkages at one or more of the R3, R7, and R12 positions. [Figure 1B-7] FIG. 1 shows examples of cationic steroidal antimicrobial compounds with ether linkages at one or more of the R3, R7, and R12 positions. [Figure 1B-8] FIG. 1 shows examples of cationic steroidal antimicrobial compounds with ether linkages at one or more of the R3, R7, and R12 positions. [Figure 1B-9] FIG. 1 shows examples of cationic steroidal antimicrobial compounds with ether linkages at one or more of the R3, R7, and R12 positions. [Figure 1B-10] FIG. 1 shows examples of cationic steroidal antimicrobial compounds with ether linkages at one or more of the R3, R7, and R12 positions. [Figure 1C] FIG. 1 shows examples of cationic steroidal antimicrobial compounds with an amide bond in the R18 group and ether or urethane bonds at the R3, R7, and R12 positions. DETAILED DESCRIPTION OF THE INVENTION

[0021] I. Overview of CSA Compounds Cationic steroidal antimicrobial (CSA) compounds, also referred to as "CSA compounds," "CSA," "CSA molecules," or "ceragenin" compounds, are synthetically produced small molecule compounds containing a sterol backbone with various charged groups (e.g., amine and cationic groups) attached to the backbone. The sterol backbone can be used to orient the amine or guanidine groups on one face or plane of the sterol backbone. CSAs are cationic and amphiphilic based on the functional groups attached to the backbone; they have a hydrophobic face and a polycationic face and are facially amphiphilic.

[0022] Without being bound to a particular theory, it is theorized that the CSA compounds described herein may act as antiviral agents by binding to and partially or completely inserting into the viral envelope and / or capsid, thereby forming pores resulting in leakage of internal virion material and / or causing disruption of host binding structures such as glycoproteins, preventing virions from binding to host cells.

[0023] An example of a CSA compound is shown below as Formula I. As described in more detail below, the R group in Formula I can have a variety of different functionalities, thus forming a given ceragenin compound with unique and different properties. Additionally, as will be understood by those skilled in the art, the sterol backbone can be formed from five-membered and / or six-membered rings, so p, q, m, and n can independently be 1 (forming a six-membered ring) or 0 (forming a five-membered ring). Typically, the A, B, and C rings are six-membered rings, while the D ring is a five-membered ring.

[0024] [ka]

[0025] The CSA compound can have the structure of Formula II, Formula III, or Formula IV.

[0026] [ka]

[0027] The definitions of the R groups are specified below. Formula II is a subset of Formula I in which rings A, B, C, and D are six-membered rings. Formula III is a subset of Formula I in which rings A, B, and C are six-membered rings and D is a five-membered ring. Formula IV has a defined stereochemistry and is defined by R3, R7, R 12 , and R 18 The R groups other than are defined as either hydrogen or methyl. is a subset of Formula III.

[0028] Some examples of CSA compounds of Formula I, Formula II, Formula III, and Formula IV that can be utilized to stimulate stem cells are illustrated in Figures 1A-1C. Typically, CSAs used herein are of two types: (1) CSAs having cationic groups attached to the sterol backbone using hydrolyzable bonds, and (2) CSAs having cationic groups attached to the sterol backbone using non-hydrolyzable bonds. For example, one type of hydrolyzable bond is an ester bond, and one type of non-hydrolyzable bond is an ether bond. The first type of CSA can be "inactivated" by hydrolysis of the bond connecting the cationic group to the sterol backbone, while the second type of CSA is more resistant to degradation and inactivation.

[0029] Some examples of CSA compounds that may be used in the embodiments described herein are illustrated in Figures 1A-1C. Non-limiting examples of CSAs having hydrolyzable bonds are identified in Figure 1A and include CSA-27, CSA-28, CSA-30, CSA-31, CSA-32, CSA-33, CSA-34, CSA-35, CSA-36, CSA-37, CSA-41, CSA-42, CSA-43, CSA-44, CSA-45, CSA-47, CSA-49, CSA-50, CSA-51, CSA-52, CSA-56, CSA-61, CSA-141, CSA-142, CSA-144, CSA-145, CSA-146, and CSA-148.

[0030] Non-limiting examples of CSAs with non-hydrolyzable bonds are set forth in FIG. 1B and include CSA-13, CSA-90, CSA-131, CSA-136, CSA-137, and CSA-138.

[0031] Non-limiting examples of CSAs having both hydrolyzable and non-hydrolyzable bonds are set forth in FIG. 1C and include CSA-190, CSA-191, CSA-192, CSA-255, CSA-256, and CSA-257.

[0032] In a currently preferred embodiment, the composition used to inactivate coronaviruses comprises a CSA compound such as CSA-44, CSA-131, CSA-148, CSA-255, a structurally similar CSA compound, or a combination thereof.

[0033] In Formula I, Formula II, Formula III, and Formula IV, R3, R7, or R 12 At least two of R may independently comprise a cationic moiety attached to its sterol backbone via a hydrolyzable (e.g., ester) or non-hydrolyzable (e.g., ether) bond. 18is typically attached to Formula I. This tail portion can be, for example, charged, uncharged, polar, non-polar, hydrophobic, or amphipathic, and can be selected to thereby tailor the properties of the CSA and / or to provide desired characteristics.

[0034] The activity of the CSA compound can be influenced by the orientation of the substituents attached to the backbone structure. In one embodiment, the substituents attached to the backbone structure are oriented on a single face of the CSA compound. Thus, R3, R7, and R 12 may be located on a single face of Formula I, Formula II, Formula III, and Formula IV. 18 may also be arranged on the same single surface. II. Inactivation of Coronaviruses with CSA Compounds Although CSA is known to provide effective antimicrobial activity against a variety of bacteria, fungi, and several viruses, it was not known whether CSA compounds had any ability to inactivate coronaviruses. In particular, CSA compounds have been shown to be effective against poxviruses. Coronaviruses are known to exert antiviral activity against flu, herpes, influenza, and HIV viruses. However, each of these viruses has properties that are quite different from coronaviruses. These differences include differences in envelope structure, capsid morphology, glycoprotein composition, size, and nucleic acid replication.

[0035] CSA compounds have been shown to be effective against poxviruses, as described in U.S. Patent No. 7,754,705. Poxviruses are double-stranded DNA (dsDNA) viruses and belong to Group I of the Baltimore virus classification system. Poxviruses are enveloped and have a complex capsid structure that is usually brick- or ovoid-shaped. Poxviruses are relatively large (approximately 200 nm x 300 nm). Poxviruses have their genomes in single-stranded, linear, and double-stranded segments of DNA. Poxvirus genomes also encode their own RNA polymerase and replicate in the cytoplasm of infected cells, potentially rather than requiring delivery to the nucleus of the infected cell.

[0036] CSA compounds have also been shown to be effective against herpes viruses, as described in U.S. Patent No. 8,211,879. Like poxviruses, herpes viruses are dsDNA viruses in Group I of the Baltimore virus classification system. Herpes viruses are enveloped, have icosahedral capsids, and have multiple glycoprotein spikes extending from the virion, giving the virion a diameter of approximately 225 nm.

[0037] CSA compounds have also been shown to be effective against influenza viruses, as described in U.S. Patent Application Publication No. 2007 / 0191322. Influenza viruses are antisense single-stranded RNA ((-)ssRNA) viruses and belong to Group V of the Baltimore virus classification system. Influenza viruses have an envelope, and virions are typically oval in shape, measuring approximately 80-120 nm in diameter. Some virions can be spherical or filamentous, with the filamentous form having a length of up to 20 μm. Approximately 500 surface spikes extend from the envelope.

[0038] CSA compounds have also been shown to be effective against the human immunodeficiency virus (HIV), as described in International Patent Application Publication No. 2007 / 089907. The HIV virus is a retrovirus containing a single-stranded (positive or sense) RNA virus ((+)ssRNA-RT virus) that uses reverse transcriptase on a DNA intermediate in its life cycle, and belongs to Group VI of the Baltimore virus classification system. The HIV virus has an envelope and is roughly spherical, with a diameter of approximately 120 nm. The capsid is cone-shaped and contains the RNA along with enzymes necessary for the development of the virion, including reverse transcriptase and integrase.

[0039] Unlike the aforementioned types of viruses, coronaviruses are single-stranded (positive or sense) RNA viruses ((+)ssRNA viruses) that do not utilize reverse transcriptase and belong to Group IV of the Baltimore virus classification system. Coronaviruses have an enveloped, roughly spherical, helically symmetric capsid. Coronaviruses have characteristic club-like spikes protruding from their surface. The lipid bilayer of the envelope contains envelope (E), spike (S), and membrane (M) structural proteins in an E:S:M ratio of approximately 1:20:300. The diameter of the envelope is approximately 85 nm, while the protruding spikes of the virion are approximately 20 nm long.

[0040] The general complexity and diversity of various types of viruses and the impact of CSA compounds in particular Given the very different structural / morphological, compositional, and replicative properties of coronaviruses compared to other types of viruses known to be susceptible to HIV, it was not predicted that CSA compounds would also provide sufficient antiviral activity against coronaviruses. However, despite these distinctive features of coronaviruses, CSA compounds have now surprisingly been found to be effective in inactivating coronaviruses such as SARS-CoV-2.

[0041] In one embodiment, a method for inactivating coronavirus includes (1) providing an inactivation composition comprising one or more CSA compounds and a carrier, (2) administering the inactivation composition to a subject in need thereof, and (3) inactivating coronavirus virions associated with or contacting the subject, thereby preventing, reducing, or suppressing a coronavirus infection, such as COVID-19, in the subject.

[0042] The subject may be a mammal or a bird. The subject may be, for example, a human, a livestock animal, a pet, a laboratory animal, or a zoo animal. The carrier may be any suitable carrier in which one or more CSA compounds can be mixed. Examples include water, alcohol and / or other organic solvents, emulsions, excipients, or combinations thereof. The inactivating composition may be administered via any suitable route of administration, including topical administration, oral administration, transdermal administration, administration via inhalation, or administration via injection. A few currently preferred embodiments will be briefly described, but additional details regarding carriers, pharmaceutical compositions, and administration routes are provided in separate sections below.

[0043] In some embodiments, the composition is formulated as a cream, liniment, salve, lotion, liquid, spray, soap, or other such formulation that can be easily administered topically.Topical administration can advantageously provide effective and long-lasting protection against the transmission of viruses through skin contact.This can include direct inoculation (for example, when a subject's hands are contaminated and the subject touches their face), the spread of virions from skin to surfaces (for example, door handles), and the spread of virions from one person's skin to another person's skin (for example, during a handshake).

[0044] In some embodiments, the composition is formulated as an aqueous solution that can be atomized by a nebulizer, a powder that can be delivered via an inhaler, or any other form suitable for delivery via inhalation. Inhalation of the inactivated composition can beneficially prevent or reduce viral infection of cells in the respiratory tract, such as epithelial cells. Inhalation can also beneficially treat the respiratory system of a subject already infected with coronavirus by inactivating virions already present in the subject's respiratory system and / or reducing the ability of virions to multiply and infect other cells in the subject's respiratory system.

[0045] The therapeutic composition may be administered by any suitable inhalation route, including via the use of a metered dose inhaler, a nebulizer, and / or a dry powder dispersion device. These types of devices generally include a mouthpiece or face mask that allows the delivery of nebulized / atomized medication to the patient. The nebulizer may be, for example, an ultrasonic nebulizer, a jet nebulizer, a vibrating mesh nebulizer, or a soft mist inhaler.

[0046] In some embodiments, the carrier, such as that associated with delivery via inhalation, comprises saline. The carrier may include one or more excipients suitable for use in inhalation applications. Suitable excipients include, for example, inhalable bulking powders, carbohydrates (monosaccharides (e.g., glucose, arabinose), disaccharides (e.g., lactose, sucrose, maltose), and the like. and oligo- and polysaccharides (e.g., dextran, cyclodextrin), alcohols and polyalcohols (e.g., ethanol, sorbitol, mannitol, xylitol), salts (e.g., sodium chloride, calcium carbonate, carboxylates, fatty acid salts), amino acids (e.g., glycine), buffers (e.g., citrates, phosphates, acetates), or combinations thereof.

[0047] In another embodiment, a method of inactivating coronavirus includes (1) preparing an inactivating composition comprising one or more CSA compounds in a carrier; (2) applying the inactivating composition to a surface; and (3) the inactivating composition inactivates coronavirus virions on or in contact with the surface.

[0048] The surface may include any surface that is considered to be contaminated with coronavirus, or is susceptible to contamination by coronavirus, or is at risk of contamination by coronavirus, and is suitable for contact with the inactivating composition.

[0049] For example, the surface may be located in a healthcare environment such as a hospital, doctor's office, clinic, laboratory, quarantine facility, or the like. The surface may be located, for example, in a home environment, a work environment (e.g., office, factory), a public gathering place (e.g., movie theater, arena, stadium, classroom, church), or a place of business (e.g., retail store, restaurant). The surface may be located in an environment where mammals and / or birds are raised and / or processed, such as, for example, a farm, dairy farm, ranch, stable, livestock pen, poultry farm, meat processing facility, slaughterhouse, butcher shop, or animal market.

[0050] In embodiments, the inactivating composition is applied in a relatively short-term or temporary regimen until the subject has sufficiently recovered from the infection or is no longer considered at risk of contracting the infection.

[0051] In other embodiments, the inactivating composition is applied continuously for a longer period of time. For example, the inactivating composition may be applied prophylactically to at-risk subjects, such as medical personnel, or subjects known to have come into contact with infected individuals. In such situations, the inactivating composition may be administered multiple times a day (e.g., morning and night), once a day, once a week, or as frequently as appropriate to provide sufficient protection to the subject.

[0052] One method of application to surfaces and / or objects involves providing the passivating composition in a form suitable for filling a mist, which the environment to be treated (such as any of the exemplary environments described above) can be exposed to, thereby exposing surfaces within the environment to the passivating composition.

[0053] In some applications, one or more subjects may be present in the environment during or shortly after the mist filling and may breathe in the inactivating composition. This method may be particularly useful in animal facilities, for example, as a method of administering the inactivating composition to animals in the facility simultaneously with applying the inactivating composition to surfaces.

[0054] In some embodiments, the one or more CSA compounds are present in the inactivating composition at about 0.01%, 0.1%, 0.2%, 0.3%, 0.5%, 1%, 2%, 3%, 5%, 10%, 15%, 20%, 25%, or 30% by weight, or within a range defined by any two of the foregoing percentage values ​​by weight. In some embodiments, the one or more CSA compounds are present at a concentration of about 1 μg / mL, 5 μg / mL, 10 μg / mL, 25 μg / mL, 50 μg / mL, 100 μg / mL, 150 μg / mL, or 200 μg / mL. or at a concentration within a range defined by any two of the foregoing concentration values.

[0055] It will be understood that the upper concentration endpoints in the foregoing examples do not necessarily represent a lack of efficacy at CSA concentrations above that upper endpoint. Rather, the upper range endpoints define ranges within which effective activity may be obtained without the need for additional CSA compounds, thereby providing efficient use of CSA compounds with associated formulation costs. In some implementations where cost is less important than providing stronger activity, one or more CSA compounds may be included at concentrations higher than the aforementioned ranges.

[0056] Any CSA compound described herein or any combination of such CSA compounds may be utilized in the inactivation composition. In some situations, it may be preferable to administer one or more CSA compounds having a hydrolyzable bond. Exemplary compounds include CSA-27, CSA-28, CSA-29, CSA-30, CSA-31, CSA-32, CSA-33, CSA-34, CSA-35, CSA-36, CSA-37, CSA-41, CSA-42, CSA-43, CSA-44, CSA-45, CSA-47, CSA-49, CSA-50, CSA-51, CSA-52, CSA-56, CSA-61, CSA-141, CSA-142, CSA-144, CSA-145, CSA-146, and CSA-148, particularly CSA-44, CSA-142, CSA-144, and CSA-148. They will be hydrolyzed more rapidly than CSA compounds with non-hydrolyzable bonds and therefore will likely have less risk of remaining active in or on the surface of a subject for too long.

[0057] On the other hand, in certain situations where longer-term protection is desired and / or where longer-term protection poses lower risks, such as when the deactivating composition is applied to a surface for disinfection purposes, it may be preferable to utilize one or more CSA compounds with non-hydrolyzable bonds. Exemplary compounds include CSA-1, CSA-26, CSA-38, CSA-40, CSA-46, CSA-48, CSA-53, CSA-55, CSA-57, CSA-60, CSA-90, CSA-107, CSA-109, CSA-110, CSA-112, CSA-113, CSA-118, CSA-124, CSA-130, CSA-131, CSA-139, CSA-190, CSA-191, CSA-192, and CSA-255. [Example]

[0058] III. Working Examples The virucidal activity of CSA-44 and CSA-131 was tested against SARS-CoV-2 after 30 minutes of contact at 22 ± 2°C. The results are shown in Table 1.

[0059] [Table 1]

[0060] This data demonstrates that the CSA compound was able to produce a significant reduction in virus compared to the control. Concentrations of 25 ppm and above were as effective as 35% ethanol. Some efficacy, albeit lower, was also demonstrated at the lower 5 ppm concentration. Given the current lack of a reliable treatment for Covid-19, these results are unexpected and surprising. IV. Additional Details of Pharmaceutical Compositions While the CSA compounds described herein can be administered alone, it may be preferable to formulate the compounds as pharmaceutical compositions (i.e., formulations). A pharmaceutical composition is any composition that can be administered to a subject in vitro, in vivo, or both, to treat or ameliorate a condition. In preferred embodiments, the pharmaceutical composition can be administered in vivo. The subject can include one or more cells or tissues, or organisms. In exemplary embodiments, the subject is an animal. In embodiments, the animal is a mammal. In some embodiments, the mammal can be a human or a primate. Mammals include any mammal, such as, by way of non-limiting example, cows, pigs, sheep, goats, horses, camels, buffalo, bison, cats, dogs, rats, mice, bats, pangolins, and humans.

[0061] "Pharmaceutically acceptable" and "physiologically acceptable" refer to a biologically compatible formulation, gas, liquid, or solid, or mixture thereof, that is suitable for one or more routes of administration, delivery, or contact in vivo. A formulation is suitable in that it does not impair the activity of the active ingredient (e.g., a CSA compound) therein or cause adverse side effects that far outweigh any prophylactic or therapeutic effects or benefits.

[0062] Pharmaceutical compositions may be formulated with pharmaceutically acceptable excipients such as carriers, solvents, stabilizers, adjuvants, diluents, etc., depending on the particular mode of administration and dosage form. Depending on the formulation and route of administration, the pharmaceutical composition may be formulated to obtain a physiologically compatible pH, which may range from about 3 to 11, preferably about 3 to 7. In an alternative embodiment, the pH is adjusted to about 5 to 8. The pharmaceutical composition may be used for therapeutic or prophylactic purposes. It may comprise an effective amount of at least one compound described herein together with one or more pharmaceutically acceptable excipients.

[0063] The pharmaceutical compositions may include a combination of compounds described herein and / or may include a second active ingredient (e.g., an antibacterial or antimicrobial agent) useful in the treatment or prevention of bacterial infections.

[0064] The composition may be formulated as a coating, such as for a medical device. In embodiments, the coating is for a medical instrument. The formulation for parenteral or oral administration can be solid, liquid, emulsion, or suspension.The inhalable formulation for pulmonary administration can be liquid or powder.The pharmaceutical composition can be formulated as a lyophilized solid that is reconstituted before administration with a physiologically compatible solvent.Alternatively, the pharmaceutical composition can be formulated as a syrup, cream, ointment, tablet, etc.

[0065] The composition may contain one or more excipients. Pharmaceutically acceptable excipients are determined in part by the specific composition to be administered, and also by the specific method used to administer the composition. There are a wide variety of suitable formulations of pharmaceutical compositions (see, for example, Remington's Pharmaceutical Sciences).

[0066] Suitable excipients may be carrier molecules, including large, slowly metabolized macromolecules such as proteins, polysaccharides, polylactic acids, polyglycolic acids, polymeric amino acids, amino acid copolymers, and inactive virus particles. Other exemplary excipients include antioxidants such as ascorbic acid, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid, liquids such as oils, water, saline, glycerol, and ethanol, wetting or emulsifying agents, pH buffering substances, etc. Liposomes are pharmaceutically acceptable excipients.

[0067] Pharmaceutical compositions may be formulated into any form suitable for the intended administration method.For example, for oral use, tablets, troches, lozenges, aqueous or oily suspensions, non-aqueous liquids, dispersible powders or granules (including micronized particles or nanoparticles), emulsions, hard or soft capsules, syrups, or elixirs may be prepared.Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents, including sweeteners, flavoring agents, coloring agents, and preservatives, to form a palatable preparation.

[0068] Pharmaceutically acceptable excipients particularly suitable for use in connection with tablets include, for example, inert diluents such as cellulose, calcium or sodium carbonate, lactose, calcium or sodium phosphate; disintegrating agents such as cross-linked povidone, corn starch, or alginic acid; binding agents such as povidone, starch, gelatin, or acacia; and lubricating agents such as magnesium stearate, stearic acid, or talc.

[0069] Tablets may be uncoated or they may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period, for example, by employing a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax.

[0070] Formulations for oral use may be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, such as cellulose, lactose, calcium phosphate, or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with a non-aqueous or oily vehicle such as glycerin, propylene glycol, polyethylene glycol, peanut oil, liquid paraffin, or olive oil.

[0071] Pharmaceutical compositions may be formulated as suspensions containing the CSA compound in admixture with at least one pharmaceutically acceptable excipient suitable for the manufacture of suspensions. Pharmaceutical compositions may be formulated as dispersible powders and granules suitable for preparation of a suspension by the addition of suitable excipients.

[0072] Excipients suitable for use in connection with suspensions include suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, gum acacia; dispersing or wetting agents such as naturally occurring phospholipids (e.g., lecithin), condensates of alkylene oxides with fatty acids (e.g., polyoxyethylene stearate), condensates of ethylene oxide with long-chain aliphatic alcohols (e.g., heptadecaethyleneoxyethanol), condensates of ethylene oxide with fatty acids and partial esters derived from hexitol anhydrides (e.g., polyoxyethylene sorbitan monooleate); polysaccharides and polysaccharide-like compounds (e.g., dextran sulfate), glycosaminoglycans and glycosaminoglycan-like compounds (e.g., hyaluronic acid); and thickening agents such as carbomer, beeswax, hard paraffin, or cetyl alcohol. The suspension may also contain one or more preservatives, such as acetic acid, methyl and / or n-propyl p-hydroxy-benzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

[0073] The pharmaceutical composition may be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil such as olive oil or peanut oil, a mineral oil such as liquid paraffin, or a mixture thereof. Suitable emulsifiers include naturally occurring gums such as acacia gum and tragacanth gum, naturally occurring phospholipids such as soybean lecithin, esters or partial esters derived from fatty acids, hexitol anhydrides such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. Emulsions may contain sweeteners and flavoring agents. Syrups and elixirs may be formulated with sweeteners such as glycerol, sorbitol, or sucrose. Such formulations may contain demulcents, preservatives, flavorings, or coloring agents.

[0074] The pharmaceutical compositions may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous emulsion or oily suspension. The emulsion or suspension may be formulated using the appropriate dispersing or wetting agent and suspending agent described above according to the known art. The sterile injectable preparation may be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a 1,2-propanediol solution.

[0075] Sterile injectable preparations may be prepared as lyophilized powders.Acceptable vehicles and solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution.In addition, sterile fixed oils may be used as solvents or suspending media.For this purpose, any non-irritating fixed oil may be used, including synthetic monoglycerides or diglycerides.In addition, fatty acids such as oleic acid may also be used in the preparation of injectables.

[0076] To obtain a stable, water-soluble dosage form of the pharmaceutical composition, pharmaceutically acceptable salts of the compounds described herein may be dissolved in an aqueous solution of an organic or inorganic acid, such as 0.3 M succinic acid solution, or more preferably, citric acid solution. If a soluble salt form is not available, the compound may be dissolved in a suitable cosolvent or combination of cosolvents. Examples of suitable cosolvents include alcohol, propylene glycol, polyethylene glycol 300, polysorbate 80, glycerin, etc., at concentrations ranging from about 0 to 60% of the total volume. In one embodiment, the active compound is dissolved in DMSO and diluted with water. The pharmaceutical composition may be in the form of a solution of the active ingredient in salt form in a suitable aqueous vehicle, such as water or isotonic saline or dextrose solution. Compounds modified by substitution or addition of chemical or biochemical moieties, such as esterification, glycosylation, pegylation, and complexation, that make the compound more suitable for delivery (e.g., increased solubility, enhanced biological activity, enhanced palatability, reduced adverse reactions, etc.) are also contemplated.

[0077] Many therapeutic agents have undesirably short half-lives and / or undesirable toxicity. Therefore, the concept of improving half-life or toxicity is applicable to a variety of treatments and settings. However, pharmaceutical compositions can be prepared by conjugating therapeutic agents with biochemical moieties to improve these undesirable properties. Proteins are particular biochemical moieties that may be conjugated to CSA for administration in a wide variety of applications. In some embodiments, one or more CSAs are conjugated to proteins. In some embodiments, one or more CSAs are conjugated to proteins to extend the half-life of the CSA. In other embodiments, one or more CSAs are conjugated to proteins to reduce the toxicity of the CSA. Albumin is a particularly preferred protein for conjugation with CSA. In some embodiments, the albumin is non-fat albumin.

[0078] For CSA therapeutics, the biochemical moiety for complexation may be added to the pharmaceutical composition as 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 10, 20, 50, or 100 weight equivalents, or a range bounded by any two of the foregoing numbers, or around any of the foregoing numbers. In embodiments, the weight ratio of albumin to CSA is about 18:1 or less, such as about 9:1 or less. In embodiments, CSA is coated with albumin.

[0079] Non-biochemical compounds can be added to pharmaceutical compositions to reduce the toxicity of therapeutic agents and / or improve their half-life. Appropriate amounts and ratios of toxicity-reducing additives can be determined via cellular assays. For CSA therapeutic agents, the toxicity-reducing compound can be added to the pharmaceutical composition at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 10, 20, 50, or 100 weight equivalents, or a range bounded by any two of the aforementioned numbers, or around any of the aforementioned numbers. In embodiments, the toxicity-reducing compound is cocoamphodiacetic acid, such as Miranol® (disodium cocoamphodiacetate). In embodiments, the toxicity-reducing compound is an amphoteric surfactant. In embodiments, the toxicity-reducing compound is a surfactant. In embodiments, the molar ratio of cocoamphodiacetic acid to CSA is between about 8:1 and 1:1, preferably about 4:1. In an embodiment, the toxicity-reducing compound is allantoin.

[0080] In embodiments, CSA compositions are prepared utilizing one or more surfactants. In certain embodiments, CSA is complexed with one or more poloxamer surfactants. Poloxamer surfactants consist of a central hydrophobic chain, polyoxypropylene, flanked on either side by two hydrophilic chains, polyoxyethylene (poly(ethylene oxide)). Poloxamers are nonionic triblock copolymers composed of propylene (poly(propylene oxide)). In some embodiments, the poloxamer is a liquid, paste, or flake (solid). Examples of suitable poloxamers include those sold under the trade names Synperonic, Pluronic, or Kolliphor. In some embodiments, one or more of the poloxamer surfactants in the composition are flake poloxamers. In embodiments, the one or more poloxamer surfactants in the composition have a molecular weight of about 3600 g / mol for their central hydrophobic polyoxypropylene chain and a polyoxyethylene content of about 70%. In embodiments, the ratio of one or more poloxamers to CSA is between about 50:1, about 40:1, about 30:1, about 20:1, about 10:1, about 5:1, about 1:1, about 1:10, about 1:20, about 1:30, about 1:40, or about 1:50. In embodiments, the ratio of one or more poloxamers to CSA is between 50:1, 40:1, 30:1, 20:1, 10:1, 5:1, 1:1, 1:10, 1:20, 1:30, 1:40, or 1:50. In embodiments, the ratio of one or more poloxamers to CSA is between about 50:1 and about 1:50. In embodiments, the ratio of one or more poloxamers to CSA is between about 30:1 and about 3:1. In some embodiments, the poloxamer is Pluronic F127.

[0081] The amount of poloxamer may be based on a weight percentage of the composition. In embodiments, the amount of poloxamer is about 10%, 15%, 20%, 25%, 30%, 35%, 40% of the formulation, around any of the aforementioned figures, or a range bounded by any two of the aforementioned figures. In embodiments, the one or more poloxamers are between about 10% and about 40% by weight of the formulation administered to a patient. In some embodiments, the one or more poloxamers are between about 20% and about 30% by weight of the formulation. In embodiments, the formulation contains less than about 50%, 40%, 30%, 20%, 10%, 5%, or 1% CSA. In embodiments, the formulation contains less than about 20% by weight CSA. The above-described poloxamer formulations are particularly suitable for therapeutic methods, device coatings, the preparation of unit dosage forms (i.e., solutions, mouthwashes, injectables), and the like.

[0082] In embodiments, the compounds described herein may be formulated for oral administration in lipid-based formulations suitable for low-solubility compounds, which can generally improve the oral bioavailability of such compounds.

[0083] The pharmaceutical compositions may comprise a therapeutically or prophylactically effective amount of a compound described herein together with at least one pharmaceutically acceptable excipient selected from the group consisting of medium chain fatty acids or propylene glycol esters thereof (e.g., propylene glycol esters of edible fatty acids such as caprylic fatty acid and capric fatty acid) and a pharmaceutically acceptable surfactant such as polyoxyl 40 hydrogenated castor oil.

[0084] In embodiments, cyclodextrin may be added as an aqueous solubility enhancer. Preferred cyclodextrins include hydroxypropyl, hydroxyethyl, glucosyl, maltosyl, and maltotriosyl derivatives of α-, β-, and γ-cyclodextrin. A particularly preferred cyclodextrin solubility enhancer is hydroxypropyl-o-cyclodextrin (BPBC), which may be added to any of the above compositions to further improve the aqueous solubility characteristics of the compound of the embodiments. In one embodiment, the composition comprises about 0.1% to about 20% hydroxypropyl-o-cyclodextrin, more preferably about 1% to about 15%, and even more preferably about 2.5% to about 10% hydroxypropyl-o-cyclodextrin. The amount of solubility enhancer employed will depend on the amount of the compound of the embodiments in the composition. Additional details on V.CSA compounds Exemplary CSA compounds and methods for their production are disclosed in U.S. Patent Nos. 6,350,738, 6,486,148, 6,767,904, 7,598,234, 7,754,705, 8,691,252, 8,975,310, 9,434,759, 9,527,883, 9,943,614, 10, 155,788, 10,227,376, 10,370,403, and 10,626,139, U.S. Patent Publication Nos. 2016 / 0311850 and 2017 / 0210776, and U.S. Provisional Patent Application Nos. 63 / 025,255 and 63 / 028,249, which are incorporated herein by reference. Those skilled in the art will recognize compounds within the scope of the general formulas set forth herein and will understand their preparation in light of the references and examples cited herein.

[0085] The CSA compound may have the structure of Formula I, Formula II, Formula III, and / or Formula IV. Formula III is represented by the formula: R 15and the ring carbon to which it is attached. Formula IV differs from Formulas I and II by omitting the stereochemistry and R3, R7, R 12 , and R 18 Formula III is more specifically defined with respect to all R groups other than

[0086] [ka]

[0087] In the embodiments of Formula I, Formula II, Formula III, and Formula IV, R3, R7, and R 12 At least two of the groups may independently contain a cationic moiety (e.g., an amino group or a guanidino group) linked to the sterol backbone structure via a hydrolyzable or non-hydrolyzable bond. For embodiments of the present disclosure, the bond is preferably hydrolyzable, but stable under sterilization and storage conditions, and hydrolyzable under physiological conditions. Such cationic functional groups (e.g., an amino group or a guanidino group) may be separated from the backbone by at least one, two, three, four, or more atoms.

[0088] The tail part is R 18 The sterol backbone may be attached by a hydroxyl group, may have variable chain length or size, and may be charged, uncharged, polar, non-polar, hydrophobic, or amphiphilic. The tail portion may be used to select the hydrophobicity / hydrophilicity of the ceragenin compound. CSA compounds with different degrees of hydrophobicity / hydrophilicity may have different rates of uptake into different target microorganisms.

[0089] The "R" groups described herein can be substituted or unsubstituted, unless otherwise specified. For CSA compounds of formula I, II, and III (for formula IV, if not already specified): Each of the fused rings A, B, C, and D may independently be saturated, or fully or partially unsaturated, provided that at least two of A, B, C, and D are saturated (wherein rings A, B, C, and D form a ring system). Other ring systems may also be used, e.g., compounds with backbones having five-membered fused rings and / or combinations of five- and six-membered rings; R1 to R 18 is hydrogen, hydroxyl, alkyl, hydroxyalkyl, alkyloxyalkyl, alkylcarboxyalkyl, terpenylcarboxyalkyl, terpenylcarbonyloxyalkyl, terpenylamidoalkyl, terpenylaminoalkyl, terpenyloxoalkyl, alkylaminoalkyl, alkylamino-alkylamino, alkylaminoalkylaminoalkylamino, aminoalkyl, aryl, arylaminoalkyl, haloalkyl, alkenyl, alkynyl, oxo, a linking group attached to a second steroid, aminoalkyluretanyl, aminoalkenyluretanyl, aminoalkynyluretanyl, aminoaryluretanyl, are independently selected from the group consisting of aminoalkyloxy, aminoalkylcarboxy, aminoalkyloxyalkyl, aminoalkylaminocarbonyl, aminoalkylcarboxamide, di(alkyl)aminoalkyl, HN—HC(Q5)—(C═O)—O—, HN—HC(Q5)—(C═O)—NH—, azidoalkyloxy, cyanoalkyloxy, PG-HN—HC(Q5)—(C═O)—O—, guanidinoalkyloxy, quaternary ammonium alkylcarboxy, and guanidinoalkylcarboxy, where Q5 is the side chain of any amino acid (including the side chain of glycine, i.e., H), and PG is a protecting group for the amino group; and R 1~4 , R6, R7, R 11 , R 12 , R 15 , R 16 , R 17 , and R 18R, R, R, R are independently selected from the group consisting of aminoalkyl, aminoalkyloxy, aminoalkylcarboxyalkyl, alkylaminoalkyl, alkylamino-alkylamino, alkylaminoalkylaminoalkylamino, aminoalkylcarboxy, aryl-aminoalkyl, aminoalkyloxyamino, alkylaminocarbonyl, aminoalkylaminocarbonyl, aminoalkyl-carboxyamido, di(alkyl)aminoalkyl, aminoalkyluretanyl, aminoalkenyl-uretanyl, aminoalkynyluretanyl, aminoaryluretanyl, HN—HC(Q5)—C(O)—O—, HN—HC(Q5)—C(O)—N(H)—, azidoalkyloxy, cyanoalkyloxy, PG-HN—HC(Q5)—C(O)—O—, guanidinoalkyloxy, quaternary ammonium alkylcarboxy, and guanidinoalkylcarboxy. 10 , R 13 , R 14 , and R 17 is independently deleted if one of rings A, B, C, or D is unsaturated to satisfy all the valences of the carbon atoms at that site.

[0090] In embodiments, R 1~4 , R6, R7, R 11 , R 12 , R 15 , R 16 , R 17 , and R 18 At least two or three of the 22 ) aminoalkyl, (C1-C 22 ) aminoalkyloxy, (C1-C 22 ) Alkylcarboxy-(C1-C 22 ) alkyl, (C1-C 22 ) Alkylamino-(C1-C 22 ) alkylamino, (C1-C 22 ) Alkylamino-(C1-C 22 ) Alkylamino-(C1-C 22 ) alkylamino, (C1-C 22) Aminoalkylcarboxy, arylamino- (C1~C 22 ) alkyl, (C1-C 22 ) Aminoalkyloxy (C1-C 22 ) aminoalkylaminocarbonyl, (C1-C 22 ) aminoalkylaminocarbonyl, (C1-C 22 ) Aminoalkyl-carboxamide, Quaternary ammonium (C1-C 22 ) Alkyl carboxy, di(C1-C 22 Alkyl)amino-(C1-C 22 ) alkyl, (C1-C 22 ) Aminoalkyl uretanyl, (C2-C 22 ) Aminoalkenyluretanyl, (C2-C 22 ) Amino-alkynyluretanyl, aminoaryluretanyl, H2N-HC(Q5)-C(O)-O-, H2N-HC(Q5)-C(O)-N(H)-, (C1-C 22 ) Azidoalkyloxy, (C1-C 22 ) cyanoalkyloxy, PG-HN-HC(Q5)-C(O)-O-, (C1-C 22 ) guanidinoalkyloxy, and (C1-C 22 ) guanidinoalkylcarboxy, R1 to R4, R6, R7, R 11 , R 12 , R 15 , R 16 , and R 18 is hydrogen, hydroxyl, substituted or unsubstituted (C1-C 22 ) alkyl, substituted or unsubstituted (C1-C 22 ) hydroxyalkyl, substituted or unsubstituted (C1-C 22 )Alkyloxy-(C1-C 22 ) alkyl, substituted or unsubstituted (C1-C 22 ) Alkylcarboxy-(C1-C 22 ) alkyl, substituted or unsubstituted (C5-C 25 ) Terpenyl-carboxy-(C1-C 22 ) alkyl, substituted or unsubstituted (C5-C25 ) Terpenylcarbonyloxy-(C1-C 22 ) alkyl, substituted or unsubstituted (C5-C 25 ) Terpenylcarboxamide-(C1-C 22 ) alkyl, substituted or unsubstituted (C5-C 25 ) Terpenylamino-(C1-C 22 ) Alkyl, (C5-C 25 ) Terpenyloxo-(C1-C 22 ) alkyl, substituted or unsubstituted (C1-C 22 ) Alkylamino-(C1-C 22 ) alkyl, substituted or unsubstituted (C1-C 22 ) Alkylamino-(C1-C 22 ) alkylamino, substituted or unsubstituted (C1-C 22 ) Alkylamino-(C1-C 22 ) Alkylamino-(C1-C 22 ) alkylamino, substituted or unsubstituted (C1-C 22 )aminoalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylamino-(C1-C 22 ) alkyl, substituted or unsubstituted (C1-C 22 ) haloalkyl, substituted or unsubstituted (C2-C6) alkenyl, substituted or unsubstituted (C2-C6) alkynyl, oxo, a linking group attached to a second steroid, substituted or unsubstituted (C1-C 22 ) Aminoalkyluretanyl, substituted or unsubstituted (C2-C 22 ) aminoalkenyluretanyl, substituted or unsubstituted (C2-C 22 ) aminoalkynyluretanyl, substituted or unsubstituted aminoaryluretanyl, substituted or unsubstituted (C1-C 22 )aminoalkyloxy, substituted or unsubstituted (C1-C 22 ) aminoalkylcarboxy, substituted or unsubstituted (C1-C 22 ) Aminoalkyloxy-(C1-C 22 ) alkyl, substituted or unsubstituted (C1-C 22 )aminoalkyl-aminocarbonyl, substituted or unsubstituted (C1-C 22) aminoalkylcarboxamide, substituted or unsubstituted di(C1-C 22 ) Alkylamino-(C1-C 22 ) alkyl, H2N-HC(Q5)-(C=O)-O-, H2N-HC(Q5)-(C=O)-NH-, substituted or unsubstituted (C1-C 22 ) azidoalkyloxy, substituted or unsubstituted (C1-C 22 ) cyanoalkyloxy, PG-HN-HC(Q5)-(C=O)-O-, substituted or unsubstituted (C1-C 22 ) guanidinoalkyloxy, substituted or unsubstituted quaternary ammonium (C1-C 22 ) alkylcarboxy, and substituted or unsubstituted (C1-C 22 ) guanidinoalkylcarboxy (wherein Q5 is the side chain of an amino acid (the side chain of glycine, i.e., containing H), and PG is a protecting group for the amino group); and R5, R8, R9, R 10 , R 13 , R 14 , and R 17 is independently deleted if one of rings A, B, C, or D is unsaturated to satisfy all valences of the carbon atoms at that site, or R5, R8, R9, R 10 , R 13 , and R 14 is hydrogen, hydroxyl, (C1-C 22 ) alkyl, (C1-C 22 ) hydroxyalkyl, (C1-C 22 )Alkyloxy-(C1-C 22 ) alkyl, (C1-C 22 ) Aminoalkyl, aryl, (C1-C 22 ) haloalkyl, (C2-C6) alkenyl, (C2-C6)alkynyl, oxo, a linking group attached to a second steroid, (C1-C 22 ) aminoalkyloxy, (C1-C 22 ) aminoalkylcarboxy, (C1-C 22 )aminoalkylaminocarbonyl, di(C1-C 22 Alkyl)amino-(C1-C22 ) alkyl, H2N-HC(Q5)-C(O)-O-, H2N-HC(Q5)-C(O)-N(H)-, (C1-C 22 ) Azidoalkyloxy, (C1-C 22 ) cyanoalkyloxy, PG-HN-HC(Q5)-C(O)-O-, (C1-C 22 ) guanidinoalkyloxy, and (C1-C 22 ) guanidinoalkylcarboxy (wherein Q5 is the side chain of an amino acid and PG is a protecting group for the amino group).

[0091] In an embodiment, R1, R2, R4, R5, R6, R8, R9, R 10 , R 11 , R 13 , R 14 , R 15 , R 16 , and R 17 are independently selected from the group consisting of hydrogen and unsubstituted (C1-C6) alkyl.

[0092] In an embodiment, R1, R2, R4, R5, R6, R8, R 10 , R 11 , R 14 , R 16 , and R 17 are hydrogen, and R and R 13 are methyl, respectively.

[0093] In embodiments, R, R, R 12 , and R 18 is hydrogen, (C1-C6) alkyl, (C1-C6) hydroxyalkyl, (C1-C 16 ) alkyloxy-(C1-C5) alkyl, (C1-C 16 ) alkylcarboxy-(C1-C5) alkyl, (C1-C 16 ) alkylamino-(C1-C5) alkyl, (C1-C 16 ) alkylamino-(C1-C5) alkylamino, (C1-C 16 ) Alkylamino-(C1-C 16) alkylamino-(C1-C5) alkylamino, (C5-C 25 ) terpenylcarboxy-(C1-C5) alkyl, (C5-C 25 ) terpenylcarbonyloxy-(C1-C5) alkyl, (C5-C 25 ) terpenylcarboxamido-(C1-C5) alkyl, (C5-C 25 ) terpenylamino-(C1-C5) alkyl, (C5-C 25 ) terpenyloxo-(C1-C5) alkyl, (C1-C6) aminoalkyl uretanyl, (C2-C6) aminoalkenyl uretanyl, (C2-C6) aminoalkynyl uretanyl, aminoaryl uretanyl, (C1-C 16 )aminoalkyl, arylamino-(C1-C5)alkyl, (C1-C5)aminoalkyloxy, (C1-C 16 )aminoalkyl-oxy-(C1-C5) alkyl, (C1-C5)aminoalkylcarboxy, (C1-C5)aminoalkyl-aminocarbonyl, (C1-C5)aminoalkylcarboxy-amido, di(C1-C5 alkyl)amino-(C1-C5) alkyl, (C1-C5)guanidino-alkyloxy, quaternary ammonium (C1-C 16 ) alkylcarboxy, and unsubstituted (C1-C 16 ) guanidinoalkylcarboxy.

[0094] In an embodiment, R1, R2, R4, R5, R6, R8, R 10 , R 11 , R 14 , R 16 , and R 17 are hydrogen, and R and R 13 are methyl, respectively.

[0095] In embodiments, R, R, R 12 , and R 18is independently selected from the group consisting of aminoalkyloxy, aminoalkylcarboxy, alkylaminoalkyl, alkoxycarbonylalkyl, alkylcarbonylalkyl, di(alkyl)aminoalkyl, alkylcarboxyalkyl, hydroxyalkyl, terpenylcarboxyalkyl, terpenylcarbonyloxyalkyl, terpenylcarboxamido-alkyl, terpenylamino-alkyl, terpenyloxoalkyl, aminoalkyluretanyl, aminoalkenyluretanyl, aminoalkynyluretanyl, and aminoaryluretanyl.

[0096] In embodiments, R3, R7, and R 12 is independently selected from the group consisting of aminoalkyloxy, aminoalkylcarboxy, aminoalkyluretanyl, aminoalkenyl-uretanyl, aminoalkynyluretanyl, and aminoaryluretanyl.

[0097] In embodiments, R 18 is independently selected from the group consisting of alkylaminoalkyl, alkoxycarbonylalkyl, alkylcarbonyloxyalkyl, alkylcarbonylalkyl, di(alkyl)aminoalkyl, alkylcarboxyalkyl, hydroxyalkyl, terpenylcarboxyalkyl, terpenylcarbonyloxyalkyl, terpenylcarboxamido-alkyl, terpenylaminoalkyl, and terpenyloxoalkyl.

[0098] In embodiments, one or more of rings A, B, C, and D is heterocyclic. In an embodiment, rings A, B, C, and D are non-heterocyclic.

[0099] The compounds and compositions disclosed herein can be optionally prepared as salts, whereby when one or more amine groups are protonated, these compounds and compositions are advantageously cationic.As used herein, " salt " is a broad term and should be given its usual and customary meaning for those skilled in the art (it should not be limited to any specific or special meaning), and refers to the salt of a compound without limitation.In embodiments, the salt is the acid addition salt of the compound.Salt can be obtained by reacting a compound with inorganic acid such as hydrohalic acid (for example, hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid, phosphoric acid, and phosphonic acid. Salts may also be obtained by reaction of the compound with an organic acid such as an aliphatic or aromatic carboxylic acid or a sulfonic acid, a sulfinic acid, 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 1,5-naphthalenedisulfonic acid (NDSA). Salts may also be obtained by reacting the compounds with bases to form salts such as ammonium salts; alkali metal salts such as lithium, sodium, or potassium salts; alkaline earth metal salts such as calcium, magnesium, or aluminum salts; salts of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C1-C7 alkylamines, cyclohexylamine, dicyclohexylamine, triethanolamine, ethylenediamine, ethanolamine, diethanolamine, triethanolamine, tromethamine; salts with amino acids such as arginine and lysine; or salts of inorganic bases such as aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.

[0100] In embodiments, the salt is a hydrochloride salt. In embodiments, the salt is a mono-, di-, tri-, or tetra-hydrochloride salt. Additional examples of salts include sulfate addition salts, sulfonic acid addition salts, disulfonic acid addition salts, 1,5-naphthalenedisulfonic acid addition salts, sulfate salts, and bisulfate salts.

[0101] These include, but are not limited to, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and R 18 An "R" group such as: denotes a substituent that may be attached to the sterol backbone. The R group can be substituted or unsubstituted.

[0102] The "ring" can be heterocyclic or carbocyclic. "Saturated" means a ring in which each atom in the ring is either hydrogenated or substituted so that the valence of each atom is satisfied. "Unsaturated" means a ring in which the valence of each atom in the ring may not be satisfied with hydrogen or other substituents. For example, adjacent carbon atoms in a fused ring may be doubly bonded to each other. Unsaturation can occur when R5 and R9, R8 and R9 are bonded together. 10 , and R 13 and R 14 and satisfying all of the valences of the ring carbon atoms at the positions of the deletions with double bonds.

[0103] When a group is "substituted," the group may be substituted with one, two, three, or more of the indicated substituents, which may be the same or different and each replace a hydrogen atom. When no substituents are suggested, the suggested "substituted" group is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, acylalkyl, alkoxyalkyl, aminoalkyl, amino acid, aryl, heteroaryl, heteroalicyclic, aralkyl, heteroaralkyl, (heteroalicyclic)alkyl, hydroxy, protected hydroxyl, alkoxy, aryloxy, acyl, mercapto, alkylthio, arylthio, cyano, halogen (e.g., F, Cl, Br), or the like. , and I), thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amide, N-amide, S-sulfonamide, N-sulfonamide, C-carboxy, protected C-carboxy, O-carboxy, isocyanate, thiocyanate, isothiocyanate, nitro, oxo, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamide, amino, monosubstituted amino group, disubstituted amino group, R a O(CH2) m O-, R b (CH2) n O-, R c C(O)O(CH2) p The aryl group may be substituted with one or more groups individually and independently selected from O- and protected derivatives thereof. The substituent may be attached to the group at two or more attachment points. For example, an aryl group may be substituted with a heteroaryl group at two attachment points to form a fused polycyclic aromatic ring system. Biphenyl and naphthalene are two examples of an aryl group substituted with a second aryl group. Groups not specifically designated as substituted or unsubstituted may be considered to be either substituted or unsubstituted.

[0104] "C a " or "C a ~C bThe term "a" refers to the number of carbon atoms in an alkyl, alkenyl, or alkynyl group, or the number of carbon atoms in a ring of a cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, or heteroalicyclic group, where "a" and "b" are integers. That is, an alkyl, alkenyl, alkynyl, cycloalkyl ring, cycloalkenyl ring, cycloalkynyl ring, aryl ring, heteroaryl ring, or heteroalicyclic ring can contain from "a" to "b" carbon atoms. Thus, for example, a "C1-C4 alkyl" group refers to all alkyl groups having one to four carbons, i.e., CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)-, (CH3)2CHCH2-, and (CH3)3C-. When "a" and "b" are not specified for an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, or heteroalicyclic group, the broadest range described in those definitions is to be assumed.

[0105] "Alkyl" means a straight or branched hydrocarbon chain containing a hydrocarbon group that is fully saturated (no double or triple bonds). An alkyl group can have from 1 to 25 carbon atoms (wherever it appears herein, a numerical range such as "1 to 25" refers to each integer in the given range; for example, "1 to 25 carbon atoms" means that the alkyl group has 1 carbon atom). (This definition also takes into account appearances of the term "alkyl" where no numerical range is specified.) An alkyl group may be a medium-sized alkyl having 1 to 15 carbon atoms. An alkyl group may also be a lower alkyl having 1 to 6 carbon atoms. The alkyl group of a compound may be designated as "C4" or "C1-C4 alkyl" or similar designation. By way of example only, "C1-C4 alkyl" indicates that there are 1 to 4 carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and t-butyl. Typically, alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, and hexyl. An alkyl group may be substituted or unsubstituted.

[0106] "Alkenyl" refers to an alkyl group containing one or more double bonds in a straight or branched hydrocarbon chain. An alkenyl group can have 2 to 25 carbon atoms. (Whenever it appears herein, a numerical range such as "2 to 25" refers to each integer in the range; for example, "2 to 25 carbon atoms" means that the alkenyl group can be composed of up to 25 carbon atoms, such as 2, 3, or 4 carbon atoms, although this definition also takes into account appearances of the term "alkenyl" where no numerical range is specified.) An alkenyl group can also be a medium-sized alkenyl having 2 to 15 carbon atoms. An alkenyl group can also be a lower alkenyl having 1 to 6 carbon atoms. The alkenyl group of a compound can be designated as "C4" or "C2-C4 alkenyl" or similar designations. An alkenyl group can be unsubstituted or substituted.

[0107] "Alkynyl" refers to an alkyl group containing one or more triple bonds in its linear or branched hydrocarbon chain. An alkynyl group can have 2 to 25 carbon atoms. (Whenever it appears herein, a numerical range such as "2 to 25" refers to each integer in the range; for example, "2 to 25 carbon atoms" means that the alkynyl group can be composed of up to 25 carbon atoms, such as 2, 3, or 4 carbon atoms, although this definition also takes into account appearances of the term "alkynyl" without a specified numerical range.) An alkynyl group can also be a medium-sized alkynyl having 2 to 15 carbon atoms. An alkynyl group can also be a lower alkynyl having 2 to 6 carbon atoms. The alkynyl group of a compound can be designated as "C4" or "C2-C4 alkynyl" or similar designations. An alkynyl group can be unsubstituted or substituted.

[0108] "Aryl" means a carbocyclic (all carbon) monocyclic or polycyclic aromatic ring system (including fused ring systems in which two carbon rings share a chemical bond) having a completely delocalized pi-electron system throughout all of its rings. The number of carbon atoms in an aryl group can vary. For example, an aryl group can be C6 to C8. 14 Aryl groups, C6-C 10 It may be an aryl group, or a C6 aryl group (but not C6 to C 10 The definition of aryl reflects the appearance of "aryl" when no numerical range is specified. Examples of aryl groups include, but are not limited to, benzene, naphthalene, and azulene. Aryl groups can be substituted or unsubstituted.

[0109] "Aralkyl" and "aryl(alkyl)" refer to an aryl group linked, as a substituent, via a lower alkylene group. The aralkyl group may have 6 to 20 carbon atoms (wherever it appears herein, a numerical range such as "6 to 20" refers to each integer in the range; for example, "6 to 20 carbon atoms" means that the aralkyl group may be composed of 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, etc., or up to 20 carbon atoms, but this definition does not apply to "aralkyl" groups where a numerical range is not specified). (This also reflects the appearance of the term "aralkyl" in the context of the term "aryl"). The lower alkylene and aryl groups of an aralkyl can be substituted or unsubstituted. Examples include, but are not limited to, benzyl, 2-phenylalkyl, 3-phenylalkyl, and naphthylalkyl.

[0110] A "lower alkylene group" is a C1-C2 alkylene group that forms a bond to link molecular fragments through its terminal carbon atoms, such as a -CH2- tethering group. 25 "" means a straight-chain alkyl tethering group. Examples include, but are not limited to, methylene (-CH-), ethylene (-CHCH-), propylene (-CHCHCH-), and butylene (-CHCHCHCHCH-). A lower alkylene group can be substituted by replacing one or more hydrogens of the lower alkylene group with a substituent listed under the definition of "substituted."

[0111] "Cycloalkyl" means a monocyclic or polycyclic hydrocarbon ring system that is fully saturated (no double or triple bonds). When composed of more than one ring, the rings may be joined in a fused fashion. A cycloalkyl group can contain 3 to 10 atoms in the ring or 3 to 8 atoms in the ring. A cycloalkyl group can be unsubstituted or substituted. Exemplary cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0112] "Cycloalkenyl" refers to a monocyclic or polycyclic hydrocarbon ring system containing one or more double bonds in at least one ring, but if there are more than one, the double bonds cannot form a completely delocalized pi-electron system throughout all of the rings (otherwise the group would be "aryl" as defined herein). When composed of more than one ring, the rings may be connected in a fused manner. Cycloalkenyl groups can be unsubstituted or substituted.

[0113] "Cycloalkynyl" refers to a monocyclic or polycyclic hydrocarbon ring system containing one or more triple bonds in at least one ring. If there are two or more triple bonds, the triple bonds cannot form a completely delocalized pi-electron system throughout all of the rings. If two or more rings are composed, the rings may be connected in a fused manner. A cycloalkynyl group may be unsubstituted or substituted.

[0114] "Alkoxy" or "alkyloxy" means a group of the formula -OR, where R is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, or cycloalkynyl as defined above. Examples of alkoxy are methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, and tert-butoxy. An alkoxy can be substituted or unsubstituted.

[0115] "Acyl" means, as a substituent, hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl linked through a carbonyl group, such as -(C=O)-R. Examples include formyl, acetyl, propanoyl, benzoyl, and acryl. Acyl can be substituted or unsubstituted.

[0116] "Alkoxyalkyl" or "alkyloxyalkyl" means, as a substituent, an alkoxy group linked via a lower alkylene group. Examples include alkyl-O-alkyl- and alkoxy-alkyl-, with the terms alkyl and alkoxy defined herein.

[0117] "Hydroxyalkyl" means an alkyl group in which one or more of its hydrogen atoms has been replaced by a hydroxy group. Exemplary hydroxyalkyl groups include, but are not limited to, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, and 2,2-dihydroxyethyl. Hydroxyalkyl can be substituted or unsubstituted.

[0118] "Haloalkyl" means an alkyl group in which one or more of its hydrogen atoms has been replaced with a halogen (e.g., mono-haloalkyl, di-haloalkyl, and tri-haloalkyl). Examples include chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, and 1-chloro-2-fluoromethyl, 2-fluoroisobutyl. A haloalkyl can be substituted or unsubstituted.

[0119] "Amino" means "-NH2". "Hydroxy" means "-OH". "Cyano" means "-CN".

[0120] "Carbonyl" or "oxo" means "-C=O". "Azido" means "-N3". "Aminoalkyl" means, as a substituent, an amino group linked via a lower alkylene group. Examples include HN-alkyl-, with the term alkyl as defined herein.

[0121] "Alkylcarboxyalkyl" means an alkyl group linked as a substituent to a carboxy group which is linked as a substituent to an alkyl group. Examples include alkyl-(C=O)-O-alkyl- and alkyl-O-(C=O)-alkyl-, with the term alkyl being defined herein.

[0122] "Alkylaminoalkyl" means an alkyl group linked as a substituent to an amino group which is linked as a substituent to an alkyl group. Examples include alkyl-NH-alkyl-, with the term alkyl being defined herein.

[0123] "Dialkylaminoalkyl" and "di(alkyl)aminoalkyl" refer to two alkyl groups linked as substituents to an amino group, which is linked as a substituent to an alkyl group, respectively. Examples include alkyl groups as defined herein.

[0124] [ka]

[0125] Includes: "Alkylaminoalkylamino" means an alkyl group linked as a substituent to an amino group which is linked as a substituent to an alkyl group which is linked as a substituent to an amino group. Examples include alkyl-NH-alkyl-NH-, with the term alkyl being defined herein.

[0126] "Alkylaminoalkylaminoalkylamino" means an alkyl group linked as a substituent to an amino group which is linked as a substituent to an alkyl group which is linked as a substituent to an alkyl group. Examples include alkyl-NH-alkyl-NH-alkyl-, with the term alkyl being defined herein.

[0127] "Arylaminoalkyl" means an aryl group linked as a substituent to an amino group which is linked as a substituent to an alkyl group. Examples include aryl-NH-alkyl-, with the terms aryl and alkyl being defined herein.

[0128] "Aminoalkyloxy" means an amino group linked, as a substituent, to an alkyloxy group. Examples include HN-alkyl-O- and HN-alkoxy-, with the terms alkyl and alkoxy defined herein.

[0129] "Aminoalkyloxyalkyl" means an amino group linked as a substituent to an alkyloxy group which is linked as a substituent to an alkyl group. Examples include HN-alkyl-O-alkyl- and HN-alkoxy-alkyl-, with the terms alkyl and alkoxy defined herein.

[0130] "Aminoalkylcarboxy" means an amino group linked as a substituent to an alkyl group which is linked as a substituent to a carboxy group. Examples include HN-alkyl-(C=O)-O- and HN-alkyl-O-(C=O)-, with the term alkyl being defined herein.

[0131] "Aminoalkylaminocarbonyl" means an amino group linked as a substituent to an alkyl group which is linked as a substituent to an amino group which is linked as a substituent to a carbonyl group. Examples include HN-alkyl-NH-(C=O)-, with the term alkyl being defined herein.

[0132] "Aminoalkylcarboxamido" means an amino group linked as a substituent to an alkyl group linked as a substituent to a carbonyl group linked as a substituent to an amino group. Examples include HN-alkyl-(C=O)-NH- and HN-alkyl-NH-(C=O)-, with the term alkyl being defined herein.

[0133] "Azidoalkyloxy" means an azido group linked as a substituent to an alkyloxy group. Examples include N-alkyl-O- and N-alkoxy-, with the terms alkyl and alkoxy defined herein.

[0134] "Cyanoalkyloxy" means a cyano group linked as a substituent to an alkyloxy group. Examples include N-C-alkyl-O- and N-C-alkoxy-, with the terms alkyl and alkoxy defined herein.

[0135] "Sulfenyl" means "-SR," where R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclic, aralkyl, or (heteroalicyclic)alkyl. Sulfenyl can be substituted or unsubstituted.

[0136] "Sulfinyl" refers to "-(S=O)-R" where R is as defined for sulfenyl. The term "-(S=O)-R" refers to a group that may be the same as defined above. Sulfinyl may be substituted or unsubstituted.

[0137] "Sulfonyl" means "-(S=O)-OR" where R can be the same as defined for sulfenyl. Sulfonyl can be substituted or unsubstituted.

[0138] "O-carboxy" means "R-(C=O)-O-", where R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclic, aralkyl, or (heteroalicyclic)alkyl, as defined herein. O-carboxy can be substituted or unsubstituted.

[0139] "Ester" and "C-carboxy" mean "-(C=O)-OR" where R can be the same as defined for O-carboxy. Ester and C-carboxy can be substituted or unsubstituted.

[0140] "Thiocarbonyl" means "-(C=S)-R" where R can be the same as defined for O-carboxy. Thiocarbonyl can be substituted or unsubstituted.

[0141] "Trihalomethanesulfonyl" means "X3CSO2-" where X is a halogen. "S-sulfonamide" means "-SON(RARB)" where R and R can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclic, aralkyl, or (heteroalicyclic)alkyl. S-sulfonamide can be substituted or unsubstituted.

[0142] "N-sulfonamide" means "RSON(RA)-", where R and R can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclic, aralkyl, or (heteroalicyclic)alkyl. N-sulfonamide can be substituted or unsubstituted.

[0143] "O-carbamyl" and "uretanyl" refer to "-O-(C=O)-N(RARB)," where R and R can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclic, aralkyl, or (heteroalicyclic)alkyl. The O-carbamyl or uretanyl can be substituted or unsubstituted.

[0144] "N-carbamyl" means "RO-(C=O)-N(RA)-", where R and R can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclic, aralkyl, or (heteroalicyclic)alkyl. N-carbamyl can be substituted or unsubstituted.

[0145] "O-thiocarbamyl" is "-O-(C=S)-N(RARB)" and and R can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclic, aralkyl, or (heteroalicyclic)alkyl. O-thiocarbamyl can be substituted or unsubstituted.

[0146] "N-thiocarbamyl" means "RO-(C=S)-N(RA)-", where R and R can independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclic, aralkyl, or (heteroalicyclic)alkyl. N-thiocarbamyl can be substituted or unsubstituted.

[0147] "C-amido" means "-(C=O)-N(RARB)" where R and R are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclic, aralkyl, or (heteroalicyclic)alkyl. C-amido can be substituted or unsubstituted.

[0148] "N-amido" means "R-(C=O)-N(RA)-", where R and R are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclic, aralkyl, or (heteroalicyclic)alkyl. N-amido can be substituted or unsubstituted.

[0149] "Guanidinoalkyloxy" means a guanidinyl group linked as a substituent to an alkyloxy group. Examples include alkyl and alkoxy groups, as defined herein.

[0150] [ka]

[0151] is. "Guanidinoalkylcarboxy" means a guanidinyl group linked as a substituent to an alkyl group which is linked as a substituent to a carboxy group. Examples include alkyl groups as defined herein.

[0152] [ka]

[0153] is. "Quaternary ammonium alkylcarboxy" refers to a quaternary ammonium alkyl group linked as a substituent to a carboxy group. The term "quaternized amino group" refers to a quaternized amino group attached as a substituent to an alkyl group that is also substituted with the term "alkyl" as defined herein.

[0154] [ka]

[0155] is. "Halogen atom" and "halogen" refer to any one of the radioactive-stable atoms in column 7 of the periodic table, such as fluorine, chlorine, bromine, and iodine. Where the number of substituents is not specified (e.g., haloalkyl), one or more substituents may be present. For example, "haloalkyl" may include one or more of the same or different halogens.

[0156] "Amino acid" refers to any amino acid (both standard and non-standard), 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, aspartic acid, cysteine, glutamic acid, 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, γ-aminobutyric acid, citrulline, β-alanine, α-ethyl-glycine, α-propyl-glycine, and norleucine.

[0157] A "linking group" is a divalent moiety used to connect one steroid to another. In embodiments, a linking group is used to connect a first CSA to a second CSA (which may be the same or different). Examples of linking groups include (C1-C 10 )Alkyloxy-(C1-C 10 ) alkyl.

[0158] "PG" or "protecting group" or "protecting groups" means any atom or group of atoms added to a molecule to prevent an existing group in the molecule from undergoing an undesired chemical reaction. Examples of protecting group moieties are described in T.W. Greene and P.G.M. Buts, Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, 1999, and J.F.W.M. Comie, Protective Groups in Organic Chemistry, Plenum Press, 1973, both of which are incorporated herein by reference for the limited purpose of disclosing suitable protecting groups. Protecting group moieties may be selected so that they are stable to the particular reaction conditions and are easily removed at a convenient stage using methodologies known in the art. A non-limiting list of protecting groups includes benzyl; substituted benzyl; alkylcarbonyl and alkoxycarbonyl (e.g., t-butoxycarbonyl (BOC), acetyl, or isobutyryl); arylalkylcarbonyl and arylalkoxycarbonyl (e.g., benzyloxycarbonyl); substituted methyl ethers (e.g., methoxymethyl ether); substituted ethyl ethers; substituted benzyl ethers; tetrahydropyranyl ethers; silyl (e.g., trimethylsilyl, triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl, tri- Isopropylsilyloxymethyl, [2-(trimethylsilyl)ethoxy]methyl, or t-butyldiphenylsilyl; esters (e.g., benzoic acid esters); carbonates (e.g., methoxymethyl carbonate); sulfonates (e.g., tosylates or mesylates); acyclic ketals (e.g., dimethyl acetal); cyclic ketals (e.g., 1,3-dioxane, 1,3-dioxolane, and those described herein); acyclic acetals; cyclic acetals (e.g., those described herein); acyclic hemiacetals; cyclic hemiacetals; 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. Generally, the chemical species of the protecting group is not important, as long as the protecting group is stable to the conditions of all subsequent reactions at other positions of the compound and can be removed at an appropriate time without adversely affecting the remainder of the molecule. Furthermore, the protecting group may be replaced with another one after substantial synthetic transformation is completed. Obviously, if a compound differs from the compounds disclosed herein only in that one or more protecting groups of the compounds disclosed herein are replaced with different protecting groups, the compound is within the scope of the present disclosure.

[0159] 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 that come within the meaning and range of equivalency of the claims are to be embraced within the scope of the invention.

Claims

1. 1. A method for inactivating coronavirus, comprising: providing an inactivation composition comprising one or more CSA compounds in a carrier; administering the inactivating composition to a subject; The method, wherein the inactivating composition inactivates coronavirus virions in the subject or that contact the subject.

2. 10. The method of claim 1, wherein the subject is a human, a livestock animal, poultry, a pet, a laboratory animal, or a zoo animal.

3. 3. The method of claim 1 or 2, wherein the inactivating composition is administered topically.

4. 4. The method of any one of claims 1 to 3, wherein the inactivating composition is provided in the form of a liniment, salve, lotion, ointment, cream, powder, soap, cleanser, or spray.

5. 3. The method of claim 1 or 2, wherein the inactivating composition is administered via inhalation.

6. 6. The method of claim 5, wherein the inactivating composition is provided as a nebulizable aqueous solution.

7. 7. The method of claim 5 or 6, wherein the inactivated composition is administered using a metered dose inhaler, a nebulizer, and / or a dry powder dispersion device.

8. 8. The method of any one of claims 5 to 7, wherein the carrier comprises one or more of saline, a bulking powder, a carbohydrate, a di-, oligo- or polysaccharide, an alcohol or polyalcohol, a salt, an amino acid, a buffering agent, or a combination thereof.

9. 3. The method of claim 1 or 2, wherein the inactivating composition is administered orally or parenterally.

10. 1. A method for inactivating coronavirus, comprising: providing an inactivation composition comprising one or more CSA compounds in a carrier; applying the deactivating composition to a surface; The method, wherein the inactivating composition inactivates coronavirus virions on or in contact with a surface.

11. The method of claim 10 , wherein the surface is in a medical environment.

12. The method of claim 10 or 11, wherein the surface comprises at least a portion of a medical device.

13. The method of claim 12, wherein the medical device is an endotracheal tube.

14. 11. The method of claim 10, wherein the surface is in a home environment, a work environment, a place of business, or a gathering place.

15. The method of claim 10 , wherein the surface is in a vivarium.

16. The carrier may be water, alcohol, other organic solvents, emulsions, or combinations thereof.

16. The method of any one of claims 1 to 15, comprising one or more of:

17. 17. The method of any one of claims 1 to 16, wherein the inactivating composition is delivered by misting the environment.

18. 18. The method of claim 17, wherein the object is present in the environment.

19. 20. The method of claim 18, wherein the subject is an animal.

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