Use of cationic steroid antimicrobial compounds to inactivate coronavirus

Abstract

The present disclosure describes compositions and methods for inactivating coronaviruses. The methods include preparing an inactivation composition containing one or more CSA compounds and a carrier, administering the inactivation composition to a subject, and inactivating coronavirus virions in the subject or in contact with the subject. The methods can thereby prevent, reduce, or suppress coronavirus infections, such as COVID-19, in the subject.

Description

[Technical Field]

[0001] [Background technology]

[0002] Coronaviruses are single-stranded positive-sense RNA viruses that cause respiratory illness in mammals and birds. Coronaviruses are among the largest known RNA viruses, possessing a genome of approximately 26–32 kilobases. They have a distinctive, club-shaped spike protruding from their enveloped surface. When coronavirus virions were first visualized under electron microscopy, these spikes formed an image reminiscent of the solar corona, which led to the virus's naming.

[0003] There are several different types of coronaviruses that can infect humans. Some of them pose a relatively low risk and cause symptoms similar to the common cold. However, other types of coronaviruses can cause serious symptoms. Four types of human coronaviruses (OC43, HKU1, 229E, and NL63) are known to generally cause mild symptoms. They are constantly circulating in human populations and are thought to be responsible for about 15% of all common colds.

[0004] Three human coronaviruses that can potentially cause severe symptoms are Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV), Middle East Respiratory Syndrome-Associated Coronavirus (MERS-CoV), and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). SARS first appeared in late 2002 and has continued to infect more than 8,000 people, with a fatality rate of approximately 10%. MERS first appeared in mid-2012. MERS has a fatality rate of approximately 35%, but does not spread from person to person as easily as other coronaviruses.

[0005] In late 2019, a novel coronavirus was identified from a pneumonia outbreak in Wuhan, China, and is now known as SARS-CoV-2. Infection with SARS-CoV-2 can cause coronavirus disease 2019 (COVID-19), which includes symptoms such as fever, cough, fatigue, shortness of breath, organ damage, edema and inflammation of the extremities, and loss of smell and taste. While most cases do not progress beyond these flu-like symptoms, some cases progress to 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 is not as lethal as SARS or MERS, but it is far 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] Several recently developed vaccines and antiviral treatments of questionable effectiveness against COVID-19 exist. Vaccines are experimental and have not all passed FDA safety and efficacy tests. 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 the infected person. Apart from safe and effective vaccines, the most effective means of stopping the effects of a spreading virus is widespread exposure by the population, leading to herd immunity. However, this can come at a great cost in terms of the morbidity rate required to achieve such herd immunity.

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

[0008] While vaccines exist, they are still in an experimental stage and lack long-term safety evidence, which may require several years of observation and retrospective analysis, and are therefore still widely disliked. [Overview of the project] [Problems that the invention aims to solve]

[0009] Therefore, there is a continuing need for compositions and methods that have the ability to inactivate coronavirus. Such compositions and methods should have the ability to prevent, reduce, and / or treat coronavirus infection. [Means for solving the problem]

[0010] This disclosure describes a method for administering one or more cationic steroidal antimicrobial (CSA) compounds to inactivate coronaviruses. The methods disclosed herein have the ability to reduce or suppress coronavirus infection or pathogenesis in cells in vitro, ex vivo, or in vivo.

[0011] In one embodiment, a method for inactivating coronaviruses comprises (1) providing an inactivation composition comprising one or more CSA compounds and a carrier, (2) administering the inactivation composition to a subject requiring it, and (3) the inactivation composition inactivating coronavirus virions in the subject or coronavirus virions in contact with the subject. Thereafter, the method can prevent, reduce, or suppress coronavirus infections such as COVID-19 in the subject.

[0012] The subjects may be mammals or birds. The subjects may be humans, livestock, pets, laboratory animals, or zoo animals. 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 topical administration, oral administration, transdermal administration, administration by inhalation, or parenteral administration (e.g., administration by injection).

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

[0015] The surface may include all surfaces that are thought to be contaminated with coronavirus, susceptible to coronavirus contamination, or at risk of coronavirus contamination, and is suitable for contact with the inactivation composition.

[0016] In some embodiments, the CSA solution is converted into a mist, which is introduced into a room or building such as a barn, kennel, or other animal shed, or into a building that may be occupied by other mammals, including humans. Fogging of a room disperses the CSA compound over a wide area, allowing it to come into contact with any exposed or touchable surfaces within the room. In addition, it has been found that animals, including farm animals and other mammals, can breathe safely in the mist and are protected from contracting or spreading coronavirus disease. Nebulizers may be used to deliver the atomized solution of the CSA compound to subjects, including human subjects, as a therapeutic or prophylactic treatment.

[0017] Any CSA compound described herein, or any combination thereof, may be used in therapeutic compositions. Preferred CSA compounds at present include CSA-44, CSA-131, and / or structurally similar CSA compounds.

[0018] Additional features and advantages will be partially expressed in subsequent embodiments for carrying out the invention, partially revealed in embodiments for carrying out the invention, or acquired by practicing the embodiments disclosed herein. It should be understood that the above summary of the invention and the following embodiments for carrying out the invention are both illustrative and not limiting to the embodiments disclosed herein or claimed herein.

[0019] To describe the various features and concepts of this disclosure, a more detailed description of specific subject matter will be made by reference to the specific embodiments illustrated in the accompanying drawings. With the understanding that these drawings merely illustrate examples of embodiments and are not intended to limit the scope, various embodiments will be described and explained with additional specificity and detail through the use of the accompanying drawings. [Brief explanation of the drawing]

[0020] [Figure 1A] This figure shows examples of cationic steroidal antimicrobial compounds having an ester or amide bond at one or more of the R3, R7, and R12 positions. [Figure 1B] This figure shows examples of cationic steroidal antimicrobial compounds having an ether linkage at one or more of the R3, R7, and R12 positions. [Figure 1C] This figure shows examples of cationic steroid antimicrobial compounds that have an amide bond in the R18 group and ether or urethane bonds at the R3, R7, and R12 positions. [Modes for carrying out the invention]

[0021] I. Overview of CSA Compounds Cationic steroidal antimicrobial (CSA) compounds, also known as "CSA compounds," "CSA," "CSA molecules," or "selagenin" compounds, are low-molecular-weight compounds produced by synthesis. These compounds consist of a sterol skeleton with various charged groups (e.g., amines and cationic groups) bonded to it. The sterol skeleton can be used to orient amine or guanidine groups onto one face or plane of the sterol skeleton. Based on the functional groups bonded to its skeleton, CSAs are cationic and amphiphilic; they have hydrophobic and polycationic surfaces and are superficially amphiphilic.

[0022] While not bound by any particular theory, the CSA compounds described herein are theorized to act as antiviral agents by binding to the viral envelope and / or capsid, and partially or completely inserting therein, thereby forming pores that lead to leakage of internal virion material and / or causing the breakdown of host-binding structures such as glycoproteins, thereby preventing virions from binding to host cells.

[0023] An example of a CSA compound is shown below as formula I. As will be explained in more detail below, the R group of formula I can have a variety of different functionalities, thus forming a given selagenin compound with uniquely different properties. In addition, as will be understood by those skilled in the art, the sterol skeleton can be formed from a 5-membered ring and / or a 6-membered ring, so p, q, m, and n may independently be 1 (forming a 6-membered ring) or 0 (forming a 5-membered ring). Typically, the A, B, and C rings are 6-membered rings, while the D ring is a 5-membered ring.

[0024] [ka]

[0025] CSA compounds may have the structure of formula II, formula III, or formula IV.

[0026] [ka]

[0027] The definition of the R group is as follows: Formula II is a subset of Formula I, where rings A, B, C, and D are 6-membered rings. Formula III is a subset of Formula I, where rings A, B, and C are 6-membered rings and D is a 5-membered ring. Formula IV has a defined stereochemistry and includes R3, R7, and R 12 , and R 18 This is a subset of formula III in which the other R groups are defined as either hydrogen or methyl.

[0028] Some examples of CSA compounds of formulas I, II, III, and IV that can be used to stimulate stem cells are illustrated in Figures 1A–1C. Typically, the CSAs used herein are of two types: (1) CSAs having cationic groups bonded to a sterol skeleton using hydrolyzable bonds, and (2) CSAs having cationic groups bonded to a sterol skeleton 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 coupling the cationic group to the sterol skeleton, 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 shown 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 shown in Figure 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 shown in Figure 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 the coronavirus includes CSA compounds such as CSA-44, CSA-131, CSA-148, CSA-255, structurally similar CSA compounds, or combinations thereof.

[0033] In equations I, II, III, and IV, R3, R7, or R 12 At least two of these may independently contain cationic moieties attached to their sterol skeleton via hydrolyzable (e.g., ester) or hydrolyzable (e.g., ether) bonds. The tail moiety is R 18This is typically coupled to formula I. This tail portion may be, for example, charged, uncharged, polar, nonpolar, hydrophobic, or amphiphilic, and can be selected to modulate the properties of the CSA and / or to bring about desired properties.

[0034] The activity of a CSA compound can be influenced by the orientation of substituents attached to the skeletal structure. In one embodiment, substituents attached to the skeletal structure are oriented on a single plane of the CSA compound. Therefore, R3, R7, and R 12 Each of these may be arranged on a single plane of Equation I, Equation II, Equation III, and Equation IV. In addition, R 18 They may also be arranged on the same single surface. II. Inactivation of coronavirus using CSA compounds While CSAs are known to provide effective antimicrobial activity against various bacteria, fungi, and several types of viruses, it was unknown whether CSA compounds possessed any ability to inactivate coronaviruses. In particular, CSA compounds are known to derive antiviral activity against poxviruses, herpesviruses, influenza viruses, and HIV viruses. However, each of these viruses has characteristics that are quite different from coronaviruses. These differences include variations in envelope structure, capsid morphology, glycoprotein composition, size, and nucleic acid replication classification.

[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 have an envelope and a complex capsid structure that is usually brick-shaped or oval. Poxviruses are relatively large (approximately 200 nm × 300 nm). Poxviruses have their genome in single-stranded, linear, and double-stranded DNA segments. The poxvirus genome also encodes its own RNA polymerase, which replicates in the cytoplasm of infected cells, which is more likely than delivery to the nucleus of the infected cell.

[0036] CSA compounds have also been shown to be effective against herpesviruses, as described in U.S. Patent No. 8,211,879. Like poxviruses, herpesviruses are dsDNA viruses belonging to Group I of the Baltimore virus classification system. Herpesviruses have an envelope and an icosahedral capsid, and the virion has a diameter of approximately 225 nm due to the presence of multiple glycoprotein spikes extending from it.

[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 belonging to group V of the Baltimore virus classification system. Influenza viruses have an envelope, and their virions are typically elliptical, with a diameter of approximately 80–120 nm. Some virions can take on spherical and filamentous forms, with filamentous virions reaching 20 μm in length. Approximately 500 surface spikes extend from their envelope.

[0038] CSA compounds have also been shown to be effective against the human immunodeficiency (HIV) virus, as described in International Patent Application No. 2007 / 089907. The HIV virus is a retrovirus, including single-stranded (+-strand or sense) RNA viruses ((+)ssRNA-RT viruses) that use reverse transcriptase on DNA intermediates in their life cycle, and belongs to group VI of the Baltimore virus classification system. The HIV virus has an envelope and is nearly spherical with a diameter of about 120 nm. The capsid is conical and contains its 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 (+-strand 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 envelope, are nearly spherical, and possess a 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 virion-protruding spikes are approximately 20 nm long.

[0040] Given the overall complexity and diversity of various virus types, and especially the structural / morphological, compositional, and replication characteristics of coronaviruses, which are quite different from other types of viruses known to be susceptible to CSA compounds, it was unpredictable whether CSA compounds would also provide sufficient antiviral activity against coronaviruses. However, despite these distinctive characteristics of coronaviruses, CSA compounds have now been found to be surprisingly effective in inactivating coronaviruses such as SARS-CoV-2.

[0041] In one embodiment, a method for inactivating coronaviruses comprises (1) providing an inactivation composition comprising one or more CSA compounds and a carrier, (2) administering the inactivation composition to a subject requiring it, and (3) the inactivation composition inactivates coronavirus virions associated with the subject or coronavirus virions in contact with the subject. Thereafter, the method can prevent, reduce, or suppress coronavirus infections such as COVID-19 in the subject.

[0042] The subjects may be mammals or birds. For example, the subjects may be humans, livestock, pets, laboratory animals, or zoo animals. 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 by inhalation, or administration by injection. A few currently preferred embodiments are briefly described, but additional details regarding carriers, pharmaceutical compositions, and routes of administration are provided in separate sections below.

[0043] In some embodiments, the composition is formulated as a cream, liniment, ointment, lotion, liquid, spray, soap, or other such formulation that can be easily administered by topical application. Topical administration can beneficially provide effective and long-lasting protection against viral transmission via skin contact. This may include direct inoculation (e.g., if a subject's hands are contaminated and the subject touches their face), diffusion of virions from skin to surface (e.g., a doorknob), and diffusion of virions from one person's skin to another's skin (e.g., during a handshake).

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

[0045] The therapeutic composition may be administered using any suitable inhalation route, including routes via the use of metered-dose inhalers, nebulizers, and / or dry powder dispersion devices. These types of devices generally include a mouthpiece or face mask that allows for the transfer of the atomized / atomized medicine 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 those associated with delivery by inhalation, comprises physiological saline. The carrier may contain 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 oligosaccharides and polysaccharides (e.g., dextran, cyclodextrin), etc.), alcohols and polyhydric alcohols (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 for inactivating coronavirus comprises (1) preparing an inactivation composition comprising one or more CSA compounds in a carrier, (2) applying the inactivation composition to a surface, and (3) the inactivation composition inactivates coronavirus virions on the surface or coronavirus virions in contact with the surface.

[0048] The surface may include all surfaces that are thought to be contaminated with coronavirus, susceptible to coronavirus contamination, or at risk of coronavirus contamination, and is suitable for contact with the inactivation composition.

[0049] For example, the surface may be located in a medical environment such as a hospital, clinic, medical office, laboratory, quarantine facility, or similar. The surface may be located in a home environment, a workplace environment (e.g., an office, factory), a meeting place (e.g., a cinema, arena, stadium, classroom, church), or a business establishment (e.g., a retail store, restaurant). The surface may be located in an environment where mammals and / or birds are raised and / or processed, such as a farm, dairy farm, pasture, stable, livestock barn, poultry farm, meat processing facility, slaughterhouse, butcher shop, or animal market.

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

[0051] In other embodiments, the inactivating composition is applied more continuously over a longer period. For example, the inactivating composition may be applied prophylactically to at-risk subjects, such as healthcare workers, 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 evening), once a day, once a week, or at a frequency appropriate to provide adequate protection to the subject.

[0052] A method of application to a surface and / or object involves providing an inactivating composition in a form suitable for filling a mist. The environment being treated (such as any of the exemplary environments described above) may be exposed to this mist, thereby exposing surfaces within this environment to the inactivating composition.

[0053] In some applications, one or more subjects may be present in the environment while the mist is filling or immediately thereafter, and may inhale the inactivating composition. This method may be particularly useful in animal facilities, for example, as a method of administering the inactivating composition to animals within the facility at the same time as applying the inactivating composition to a surface.

[0054] In some embodiments, one or more CSA compounds are included in the inactivation composition in amounts of about 0.01% by weight, 0.1% by weight, 0.2% by weight, 0.3% by weight, 0.5% by weight, 1% by weight, 2% by weight, 3% by weight, 5% by weight, 10% by weight, 15% by weight, 20% by weight, 25% by weight, or 30% by weight, or within the range defined by any two of the aforementioned percentage values ​​based on weight. In some embodiments, one or more CSA compounds are included at concentrations 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 within the range defined by any two of the aforementioned concentration values.

[0055] It will be understood that the upper limit of concentration in the aforementioned example does not necessarily represent a lack of efficacy at CSA concentrations above that upper limit. Rather, the upper limit defines a range in which effective activity may be obtained without the need for additional CSA compounds, thereby providing efficient use of the CSA compound, which would incur associated formulation costs. In some implementations, one or more CSA compounds may be included at concentrations higher than the aforementioned range, where the cost is less important than obtaining stronger activity.

[0056] Any CSA compound described herein, or any combination thereof, may be used in the inactivation composition. In some circumstances, it may be preferable to administer one or more CSA compounds having hydrolyzable bonds. 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, in particular CSA-44, CSA-142, CSA-144, and CSA-148. These compounds are likely to be hydrolyzed more rapidly than CSA compounds with non-hydrolyzable bonds, and therefore the risk of them remaining as active substances in or on the surface of the target organ system for too long is considered low.

[0057] On the other hand, in certain situations where longer-term protection is desired and / or where the risks associated with longer-term protection are low, such as when an inactivating composition is applied to a surface for disinfection purposes, it may be preferable to use one or more CSA compounds having 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. [Examples]

[0058] 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 illustrates that CSA compounds were capable of significantly reducing the virus compared to the control. Concentrations of 25 ppm and above showed efficacy comparable to 35% ethanol. Some efficacy, though lower, was also observed at a lower concentration of 5 ppm. Given the current lack of a reliable treatment for Covid-19, these results are unexpected and surprising. IV. Additional Details of Pharmaceutical Compositions The CSA compounds described herein may be administered alone, but it is preferable to formulate the compounds as pharmaceutical compositions (i.e., formulations). A pharmaceutical composition is any composition that may be administered to a subject in vitro, in vivo, or both, to treat or improve a condition. In a preferred embodiment, the pharmaceutical composition may be administered in vivo. The subject may 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 may be a human or a primate. Mammals include, in non-limiting examples, any mammal such as a cow, a pig, a sheep, a goat, a horse, a camel, a buffalo, a bison, a cat, a dog, a rat, a mouse, a bat, a pangolin, and a human.

[0061] "Pharmacologically acceptable" and "physiologically acceptable" mean a biocompatible formulation, gas, liquid, or solid, or mixture thereof, suitable for one or more routes of administration, in vivo delivery, or contact. The formulation is suitable in that it does not impair the activity of its active ingredient (e.g., a CSA compound) and does not cause any adverse side effects that far outweigh any preventive or therapeutic effects or benefits.

[0062] The pharmaceutical composition may be formulated with pharmaceutically acceptable excipients such as carriers, solvents, stabilizers, adjuvants, and diluents, depending on the specific mode of administration and dosage form. The pharmaceutical composition may be formulated to obtain a physiologically suitable pH, depending on its formulation and route of administration, and the pH may be in the range of about 3 to 11, preferably about 3 to 7. In alternative embodiments, the pH is adjusted to about 5 to 8. The pharmaceutical composition may contain at least one of the compounds described herein in a therapeutically or prophylactically effective amount, together with one or more pharmaceutically acceptable excipients.

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

[0064] The composition can be formulated as a coating agent for medical devices, for example. In the embodiment, the coating agent is for medical devices. Formulations for parenteral or oral administration may be solid, liquid, emulsion, or suspension formulations. Inhalable formulations for pulmonary administration may be liquid or powder formulations. Pharmaceutical compositions may be formulated as lyophilized solids that are reconstituted before administration using physiologically compatible solvents. Alternative pharmaceutical compositions may be formulated as syrups, creams, ointments, tablets, etc.

[0065] The composition may contain one or more excipients. The pharmaceutically acceptable excipients are determined to some extent by the specific composition being administered, and similarly by the specific method used to administer the composition. A wide variety of suitable formulations of pharmaceutical compositions exist (see, for example, Remington's Pharmaceutical Sciences).

[0066] Suitable excipients may include carrier molecules containing large, slowly metabolized polymers such as proteins, polysaccharides, polylactic acid, polyglycolic acid, 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, and stearic acid, liquids such as oils, water, saline, glycerol, and ethanol, wetting or emulsifying agents, and pH buffers. Liposomes are pharmaceutically acceptable excipients.

[0067] Pharmaceutical compositions may be formulated into any form suitable for the intended method of administration. For example, for oral use, tablets, lozenges, aqueous or oily suspensions, non-aqueous liquids, dispersible powders or granules (including finely ground 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 relating to 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 with tablets include, for example, inert diluents such as cellulose, calcium carbonate or sodium carbonate, lactose, calcium phosphate or sodium phosphate; disintegrants such as cross-linked povidone, corn starch or alginate; binders such as povidone, starch, gelatin or acacia gum; and lubricants such as magnesium stearate, stearic acid or talc.

[0069] The tablets may be uncoated or coated by known techniques, including microencapsulation, to delay disintegration and adsorption in the gastrointestinal tract, thereby providing a sustained effect over a longer period. For example, time-delaying agents such as glyceryl monostearate or glyceryl distearate may be used alone or in combination with 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 medium such as glycerin, propylene glycol, polyethylene glycol, peanut oil, liquid paraffin, or olive oil.

[0071] The pharmaceutical composition may be formulated as a suspension containing a CSA compound mixed with at least one pharmaceutically acceptable excipient suitable for the preparation of a suspension. The pharmaceutical composition can be formulated as a dispersible powder or granule suitable for preparing a suspension by adding appropriate excipients.

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

[0073] The pharmaceutical composition may be in the form of an oil-in-water emulsion. This 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 soy lecithin, fatty acid-derived esters or partial esters, hexitol anhydrides such as sorbitan monooleate, and condensates of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may contain sweeteners and flavorings. Syrups and elixirs may be formulated with sweeteners such as glycerol, sorbitol, or sucrose. Such formulations may contain lubricants, preservatives, flavorings, or colorings.

[0074] The pharmaceutical composition may be in the form of a sterile injectable preparation, such as a sterile aqueous emulsion or oily suspension for injection. This emulsion or suspension may be formulated using the above-mentioned suitable dispersants or wetting agents and suspending agents 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 employed include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile non-volatile oils may be employed as solvents or suspensions. For this purpose, any non-irritating non-volatile oil, including synthetic monoglycerides or diglycerides, may be employed. Furthermore, fatty acids such as oleic acid may also be used in the preparation of injectable preparations.

[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 a 0.3 M succinic acid solution, or more preferably, in an aqueous solution of an organic or inorganic acid such as citric acid. If a soluble salt form is not available, the compound may be dissolved in a suitable co-solvent or combination of co-solvents. Examples of suitable co-solvents include alcohol, propylene glycol, polyethylene glycol 300, polysorbate 80, and glycerin, in 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 also be in the form of a liquid formulation of the active ingredient in salt form in water or a suitable aqueous vehicle such as isotonic saline or dextrose solution. Compounds modified by substitution or addition of chemical or biochemical moieties to make the compound more suitable for delivery (e.g., increased solubility, enhanced bioactivity, enhanced palatability, reduced adverse reactions), such as esterification, glycosylation, pegylation, and complex formation, may also be considered.

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

[0078] With respect to CSA therapeutics, the biochemical portion for complex formation can 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 within a range delimited by any two of the aforementioned numbers, or around any of the aforementioned numbers. In embodiments, the weight ratio of albumin to CSA is about 9:1 or less and about 18:1 or less. In embodiments, CSA is coated with albumin.

[0079] Non-biochemical compounds may be added to pharmaceutical compositions to reduce the toxicity of the therapeutic agent and / or improve its half-life. Appropriate amounts and proportions of toxicity-reducing adducts may be determined via cell assays. With respect to CSA therapeutic agents, toxicity-reducing compounds 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 within a range separated 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 the embodiment, the compound that reduces toxicity is allantoin.

[0080] In some embodiments, the CSA composition is prepared using one or more surfactants. In certain embodiments, the CSA is compounded with one or more poloxamer surfactants. A poloxamer surfactant is a nonionic triblock copolymer consisting of a central hydrophobic chain, polyoxypropylene (poly(propylene oxide)), flanked on both sides by two hydrophilic chains, polyoxyethylene (poly(ethylene oxide)). In some embodiments, the poloxamer is a liquid, paste, or flake (solid). Suitable examples of poloxamers include those traded as Synperonic, Pluronic, or Kolliphor. In some embodiments, one or more of the poloxamer surfactants in the composition are flake poloxamers. In some embodiments, one or more of the poloxamer surfactants in the composition have a molecular weight of about 3600 g / mol with respect to their central hydrophobic chain, polyoxypropylene, and have a polyoxyethylene content of about 70%. In embodiments, the ratio of one or more poloxamers to CSA is between approximately 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 approximately 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 approximately 50:1 and 1:50. In embodiments, the ratio of one or more poloxamers to CSA is between approximately 30:1 and 3:1. In some embodiments, the poloxamer is Pluronic F127.

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

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

[0083] A pharmaceutical composition may contain a therapeutically or prophylactically effective amount of one of the compounds described herein, together with at least one pharmaceutically acceptable excipient selected from the group consisting of medium-chain fatty acids or their propylene glycol esters (e.g., propylene glycol esters of edible fatty acids such as caprylic and caprin fatty acids) and a pharmaceutically acceptable surfactant such as polyoxyl 40 hydrogenated castor oil.

[0084] In embodiments, cyclodextrins may be added as water solubility enhancers. Preferred cyclodextrins include hydroxypropyl, hydroxyethyl, glucosyl, maltosyl, and maltotriosyl derivatives of α-, β-, and γ-cyclodextrins. 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 water solubility properties of the compounds of the embodiments. In one embodiment, the composition contains about 0.1% to about 20% hydroxypropyl-o-cyclodextrin, more preferably about 1% to about 15% hydroxypropyl-o-cyclodextrin, and even more preferably about 2.5% to about 10% hydroxypropyl-o-cyclodextrin. The amount of solubility enhancer used will depend on the amount of the compounds of the embodiments in the composition. Additional details on V.CSA compounds Exemplary CSA compounds and methods for their production are designated by 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, and 10. These are described in U.S. Patent Publications 155,788, 10,227,376, 10,370,403, and 10,626,139, U.S. Patent Publications 2016 / 0311850 and 2017 / 0210776, and U.S. Provisional Patent Applications 63 / 025,255 and 63 / 028,249, which are incorporated herein by reference. Those skilled in the art will recognize compounds within the range of general formulas expressed herein and will understand their preparation by considering the references and examples cited herein.

[0085] CSA compounds may have structures of formula I, formula II, formula III, and / or formula IV. Formula III is R 15By omitting the ring carbon to which it is attached, it is different from Formulas I and II. Formula IV more specifically defines Formula III with respect to all R groups other than stereochemistry and R3, R7, R 12 , and R 18 .

[0086] [Chemical formula]

[0087] In embodiments of Formula I, Formula II, Formula III, and Formula IV, at least two of R3, R7, and R 12 may independently include a cationic moiety (e.g., an amino group or a guanidino group) attached to its sterol backbone structure via a hydrolyzable or non-hydrolyzable bond. For embodiments of the present disclosure, the bond is preferably hydrolyzable, stable under sterilization and storage conditions, and hydrolyzable under physiological conditions. Such a cationic functional group (e.g., an amino group or a guanidino group) may be separated from the backbone by at least 1, 2, 3, 4 or more atoms.

[0088] The tail portion may be attached to the sterol backbone at R 18 , may have a variable chain length or size, and may be charged, uncharged, polar, nonpolar, 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 uptake rates into different target microorganisms.

[0089] The "R" groups described herein may be substituted or unsubstituted unless otherwise specified. For the CSA compounds of Formulas I, II, and III (when not yet specified for Formula IV): Each of the fused rings A, B, C, and D may be independently saturated, completely, or partially unsaturated if 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, such as compounds having skeletons with five-membered fused rings and / or combinations of five and six-membered rings, may also be used; R1 to R 18 This includes hydrogen, hydroxyl, alkyl, hydroxyalkyl, alkyloxyalkyl, alkylcarboxyalkyl, terpenylcarboxyalkyl, terpenylcarbonyloxyalkyl, terpenylamidealkyl, 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, A group independently selected from the group consisting of aminoalkyloxy, aminoalkylcarboxy, aminoalkyloxyalkyl, aminoalkylaminocarbonyl, aminoalkylcarboxyamide, di(alkyl)aminoalkyl, H2N-HC(Q5)-(C=O)-O-, H2N-HC(Q5)-(C=O)-NH-, azidoalkyloxy, cyanoalkyloxy, PG-HN-HC(Q5)-(C=O)-O-, guanidinoalkyloxy, quaternary ammonium alkylcarboxy, and guanidinoalkylcarboxy (wherein Q5 is the side chain of any amino acid (the side chain of glycine, i.e., containing 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 18If at least one, sometimes two, three, or four of the following are independently selected from the group consisting of aminoalkyl, aminoalkyloxy, aminoalkylcarboxyalkyl, alkylaminoalkyl, alkylamino-alkylamino, alkylaminoalkylaminoalkylamino, aminoalkylcarboxy, aryl-aminoalkyl, aminoalkyloxyamino, alkylaminocarbonyl, aminoalkylaminocarbonyl, aminoalkyl-carboxyamide, di(alkyl)aminoalkyl, aminoalkyluretanyl, aminoalkenyl-uretanyl, aminoalkynyluretanyl, aminoaryluretanyl, H2N-HC(Q5)-C(O)-O-, H2N-HC(Q5)-C(O)-N(H)-, azidoalkyloxy, cyanoalkyloxy, PG-HN-HC(Q5)-C(O)-O-, guanidinoalkyloxy, quaternary ammonium alkylcarboxy, and guanidinoalkylcarboxy, then R5, R8, R9, R 10 , R 13 , R 14 , and R 17 If any of rings A, B, C, or D is unsaturated to satisfy the valence of all carbon atoms in that region, it is removed independently.

[0090] In one embodiment, R 1~4 R6, R7, R 11 , R 12 , R 15 , R 16 , R 17 , and R 18 At least two or three of these are (C1~C 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-carboxyamide, quaternary ammonium (C1~C 22 ) Alkylcarboxy, di(C1~C 22 Alkyl)amino-(C1~C 22 ) alkyl, (C1~C 22 ) Aminoalkyluretanyl, (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 )Cyanazoleoxy, PG-HN-HC(Q5)-C(O)-O-, (C1~C 22 ) Guanidinoalkyl oxy, and (C1~C 22 ) When independently selected from the group consisting of guanidinoalkylcarboxy, R1 to R4, R6, R7, R 11 , R 12 , R 15 , R 16 , and R 18 This refers to 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~C 25)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 bonded to a second steroid, substituted or unsubstituted (C1-C 22 )Aminoalkyluretanil, substituted or unsubstituted (C2-C 22 )Aminoalkenyluretanil, substituted or unsubstituted (C2-C 22 )Aminoalkynyluretanil, substituted or unsubstituted aminoaryluretanil, 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-amino carbonyl, substituted or unsubstituted (C1-C 22)Aminoalkyl carboxamide, 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, P.G.-HN-HC(Q5)-(C=O)-O-, substituted or unsubstituted (C1-C 22 )guanidinoalkyloxy, substituted or unsubstituted quaternary ammonium (C1-C 22 )alkyl carboxy, and substituted or unsubstituted (C1-C 22 )guanidinoalkyl carboxy (wherein Q5 is the side chain of an amino acid (including the side chain of glycine, i.e., H), and P.G. is a protecting group for an amino group), independently selected from the group consisting of; and R5, R8, R9, R 10 , R 13 , R 14 , and R 17 are independently deleted when one of rings A, B, C, or D is unsaturated to satisfy all valences of carbon atoms at that site, or R5, R8, R9, R 10 , R 13 , and R 14 are 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 bonded to a second steroid, (C1-C 22 )aminoalkyloxy, (C1-C 22 )aminoalkyl carboxy, (C1-C 22 )aminoalkyl aminocarbonyl, di(C1-C 22 alkyl)amino-(C1-C 22)alkyl, H2N-HC(Q5)-C(O)-O-, H2N-HC(Q5)-C(O)-N(H)-, (C1~C 22 ) Azidoalkyloxy, (C1~C 22 )Cyanazoleoxy, PG-HN-HC(Q5)-C(O)-O-, (C1~C 22 ) Guanidinoalkyl oxy, and (C1~C 22 ) Independently selected from the group consisting of guanidinoalkylcarboxy (wherein Q5 is the side chain of an amino acid and PG is the protecting group of the amino group).

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

[0092] In this embodiment, R1, R2, R4, R5, R6, R8, R 10 , R 11 , R 14 , R 16 , and R 17 These are hydrogen, and R9 and R 13 These are methyl compounds.

[0093] In this embodiment, R3, R7, R 12 , and R 18 These are 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 )Terpenylcarboxamide-(C1~C5)alkyl, (C5~C 25 )Terpenylamino-(C1~C5)alkyl, (C5~C 25 )Terpenyl oxo-(C1~C5)alkyl, (C1~C6)aminoalkyluretanyl, (C2~C6)aminoalkenyluretanyl, (C2~C6)aminoalkynyluretanyl, aminoaryluretanyl, (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)aminoalkylcarboxyamide, di(C1~C5alkyl)amino-(C1~C5)alkyl, (C1~C5)guanidino-alkyloxy, quaternary ammonium (C1~C 16 ) alkylcarboxy and unsubstituted (C1~C 16 ) Independently selected from the group consisting of guanidinoalkylcarboxy.

[0094] In this embodiment, R1, R2, R4, R5, R6, R8, R 10 , R 11 , R 14 , R 16 , and R 17 These are hydrogen, and R9 and R 13 These are methyl compounds.

[0095] In this embodiment, R3, R7, R 12 , and R 18The following are independently selected from the group consisting of aminoalkyloxy, aminoalkylcarboxy, alkylaminoalkyl, alkoxycarbonylalkyl, alkylcarbonylalkyl, di(alkyl)aminoalkyl, alkylcarboxyalkyl, hydroxyalkyl, terpenylcarboxyalkyl, terpenylcarbonyloxyalkyl, terpenylcarboxyamide-alkyl, terpenylamino-alkyl, terpenyloxoalkyl, aminoalkyluretanyl, aminoalkenyluretanyl, aminoalkynyluretanyl, and aminoaryluretanyl.

[0096] In this embodiment, R3, R7, and R 12 The aminoalkyloxy, aminoalkylcarboxy, aminoalkyluretanyl, aminoalkenyluretanyl, aminoalkynyluretanyl, and aminoaryluretanyl are independently selected from the group consisting of aminoalkyloxy, aminoalkylcarboxy, aminoalkyluretanyl, aminoalkenyluretanyl, aminoalkynyluretanyl, and aminoaryluretanyl.

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

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

[0099] The compounds and compositions disclosed herein are optionally prepared as salts, thereby conveniently becoming cationic when one or more amine groups are protonated. As used herein, “salt” is a broad term and should be given its ordinary and conventional meaning to those skilled in the art (not limited to a specific or specialized meaning), referring non-limitingly to a salt of a compound. In embodiments, the salt is an acid addition salt of the compound. Salts can be obtained by reacting the compound with an inorganic acid such as a hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid, phosphoric acid, and phosphonic acid. Salts can also be obtained by reacting the compound with an aliphatic or aromatic carboxylic acid or sulfonic acid, sulfinic acid, such as 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 an organic acid such as 1,5-naphthalenedisulfonic acid (NDSA). Salts can also be obtained by reaction of 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, cyclohexylamines, 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, and sodium hydroxide.

[0100] In embodiments, the salt is a hydrochloride salt. In embodiments, the salt is a mono-hydrochloride, di-hydrochloride, tri-hydrochloride, or tetra-hydrochloride salt. Examples of additional salts include sulfates, sulfonicates, disulfonicates, 1,5-naphthalenedisulfonicates, sulfates, and bisulfates.

[0101] These are 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 The "R" group, as shown above, indicates a substituent that can be attached to the sterol skeleton. Unless otherwise specified, the R group may be substituted or unsubstituted.

[0102] A "ring" can be a heterocyclic or carbocyclic ring. "Saturated" means a ring in which each atom 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 may not be satisfied by hydrogen or other substituents. For example, adjacent carbon atoms in a fused ring may be double-bonded to each other. Unsaturated rings include R5 and R9, R8 and R 10 , and R 13 and R 14 This involves removing at least one of the following combinations, and ensuring that the valences of the ring carbon atoms at these removed positions are all filled with double bonds.

[0103] If a group is “substituted,” it may be substituted with one, two, three, or more of the suggested substituents, which may be the same or different, each replacing a hydrogen atom. If 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) , 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, isocyanic acid, thiocyanic acid, isothiocyanic acid, 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 substituents may be substituted with one or more groups individually and independently selected from O- and its protected derivatives. The substituents may be bonded to the group at two or more bond points. For example, an aryl group may be substituted with a heteroaryl group at two bond points to form a condensed polycyclic aromatic ring system. Biphenyl and naphthalene are two examples of aryl groups substituted with a second aryl group. Groups not specifically marked as substituted or unsubstituted may be considered either substituted or unsubstituted.

[0104] "C a " or "C a ~C bThe term "C1-C4 alkyl" refers to the number of carbon atoms in an alkyl, alkenyl, or alkynyl group, or the number of carbon atoms in a cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, or heteroalicyclic ring, 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 "a" to "b" carbon atoms. For example, a "C1-C4 alkyl" group refers to all alkyl groups having 1 to 4 carbon atoms, i.e., CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)-, (CH3)2CHCH2-, and (CH3)3C-. If "a" and "b" are not specified for alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, or heteroalicyclic groups, the broadest range described in those definitions should be assumed.

[0105] "Alkyl" means a linear or branched hydrocarbon chain containing a fully saturated (no double or triple bonds) hydrocarbon group. Alkyl groups can have 1 to 25 carbon atoms (wherever they appear herein, numerical ranges such as "1 to 25" refer to each integer within a given range; for example, "1 to 25 carbon atoms" means that the alkyl group may consist of 25 or fewer carbon atoms, such as 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., but this definition also takes into account appearances of the term "alkyl" where no numerical range is specified). Alkyl groups may be medium-sized alkyl groups having 1 to 15 carbon atoms. Alkyl groups may also be lower alkyl groups having 1 to 6 carbon atoms. The alkyl group of a compound may be designated as "C4" or "C1-C4 alkyl" or similar names. As an example, "C1-C4 alkyl" suggests that the alkyl chain contains 1 to 4 carbon atoms, 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 not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, and hexyl. Alkyl groups may be substituted or unsubstituted.

[0106] "Alkenyl" refers to an alkyl group containing one or more double bonds in a linear or branched hydrocarbon chain. An alkenyl group may have 2 to 25 carbon atoms (wherever it appears herein, a numerical range such as "2 to 25" refers to each integer within a given range; for example, "2 to 25 carbon atoms" means that the alkenyl group may consist of 25 or fewer carbon atoms, such as 2, 3, or 4 carbon atoms, but this definition also takes into account the appearance of the term "alkenyl" without a specified numerical range). An alkenyl group may be a medium-sized alkenyl having 2 to 15 carbon atoms. An alkenyl group may also be a lower alkenyl having 1 to 6 carbon atoms. The alkenyl group of a compound may be designated as "C4" or "C2-C4 alkenyl" or a similar name. The alkenyl group may be unsubstituted or substituted.

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

[0108] "Aryl" refers to a carbocyclic (all carbon), monocyclic, or polycyclic aromatic ring system (including fused ring systems where two carbocyclics share a chemical bond) that has a completely delocalized pi-electron system throughout its entire ring. The number of carbon atoms in an aryl group can vary. For example, an aryl group may have C6~C 14 Aryl group, C6~C 10 It can be an aryl group or a C6 aryl group (however, C6~C 10 The definition of aryl takes into account the occurrence of "aryl" when no numerical range is specified. Examples of aryl groups include, but are not limited to, benzene, naphthalene, and azulene. Aryl groups may be substituted or unsubstituted.

[0109] "Aralkyl" and "aryl(alkyl)" refer to aryl groups linked via lower alkylene groups as substituents. Aralkyl groups may have 6 to 20 carbon atoms (wherever they appear herein, numerical ranges such as "6 to 20" refer to each integer within a given range; for example, "6 to 20 carbon atoms" means that an aralkyl group may consist of 20 or fewer carbon atoms, such as 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, etc., but this definition also takes into account the appearance of the term "aralkyl" without specifying a numerical range). The lower alkylene and aryl groups of aralkyl may be substituted or unsubstituted. Examples include, but are not limited to, benzyl, 2-phenylalkyl, 3-phenylalkyl, and naphthylalkyl groups.

[0110] A "lower alkylene group" is a C1-C group that forms a bond to link molecular fragments via its terminal carbon atoms, such as a -CH2-tethering group. 25This refers to a linear alkyl tethering group. Examples include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), and butylene (-CH2CH2CH2CH2-). Lower alkylene groups may be substituted by replacing one or more hydrogens of the lower alkylene group with substituents listed under the definition of "substituted".

[0111] "Cycloalkyl" refers to a monocyclic or polycyclic hydrocarbon ring system that is completely saturated (having no double or triple bonds). If it consists of two or more rings, these rings may be linked in a condensed manner. A cycloalkyl group may contain 3 to 10 atoms or 3 to 8 atoms in the ring. A cycloalkyl group may be unsubstituted or substituted. Typical cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0112] "Cycloalkenyl" means a monocyclic or polycyclic hydrocarbon ring system containing one or more double bonds in at least one ring, but if there are two or more, the double bonds cannot form a completely delocalized pi-electron system throughout the entire ring (otherwise the group would be "aryl" as defined herein). If it consists of two or more rings, these rings may be linked in a condensation manner. The cycloalkenyl group may 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, these triple bonds cannot form a completely delocalized pi-electron system throughout the entire ring. If it consists of two or more rings, these rings may be bonded in a condensation manner. The cycloalkynyl group may be unsubstituted or substituted.

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

[0115] "Acyl" refers to a substituent consisting of a hydrogen atom, alkyl, alkenyl, alkynyl, aryl, or heteroaryl group linked via a carbonyl group such as -(C=O)-R. Examples include formyl, acetyl, propanoyl, benzoyl, and acrylic. Acyls may be substituted or unsubstituted.

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

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

[0118] "Haloalkyl" refers to an alkyl group in which one or more of its hydrogen atoms are replaced by a halogen (e.g., mono-haloalkyl, di-haloalkyl, and tri-haloalkyl). Examples include chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, and 1-chloro-2-fluoromethyl and 2-fluoroisobutyl. Haloalkyls may be substituted or unsubstituted.

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

[0120] "Carbonyl" or "oxo" means "-C=O". "Azid" means "-N3". "Aminoalkyl" refers to an amino group linked via a lower alkylene group as a substituent. Examples include H2N-alkyl-, using the term alkyl as defined herein.

[0121] "Alkylcarboxyalkyl" means an alkyl group that is substituted for an alkyl group, and an alkyl group that is substituted for a carboxyl group that is substituted for an alkyl group. Examples include alkyl-(C=O)-O-alkyl- and alkyl-O-(C=O)-alkyl-, using the term alkyl as defined herein.

[0122] "Alkylaminoalkyl" refers to an alkyl group that is substituted for an amino group that is substituted for an alkyl group. Examples include alkyl-NH-alkyl-, which uses the term alkyl as defined herein.

[0123] "Dialkylaminoalkyl" and "di(alkyl)aminoalkyl" refer to two alkyl groups, each substituted for an alkyl group and an amino group, respectively. The terms alkyl as defined herein are used in the examples.

[0124] [ka]

[0125] It includes. "Alkylaminoalkylamino" means an amino group to which an alkyl group is substituted, and an amino group to which an alkyl group is substituted, and an alkyl group is substituted, and an alkyl group is substituted, and an amino group is substituted, and an alkyl group is substituted, and an alkyl group is substituted, and an alkyl group is substituted, and an alkyl group is substituted, and an alkyl group is substituted, and an alkyl group is substituted, and an alkyl group is substituted, and an alkyl group is substituted, and an alkyl group is substituted, and an alkyl group is substituted, and an amino alkyl group is substituted, and an amino group is substituted, and an alkyl group is substituted, and an alkyl group is substituted, and an alkyl group is substituted, and an alkyl group is substituted, and an alkyl group is substituted, and an alkyl group is substituted, and an alkyl group is substituted, and an alkyl group is substituted, and an alkyl group is substituted, and an alkyl group is substituted, and an alkyl group is substituted, and an alkyl group is substituted, and an alkyl group is substituted, and an alkyl group is substituted, and an alkyl group is substituted, and an alkyl group is substituted, and an alkyl group is substituted, and an alkyl group is

[0126] "Alkylaminoalkylaminoalkylamino" means an alkyl group that is substituted for an amino group that is substituted for an alkyl group that is substituted for an alkyl group that is substituted for an amino group that is substituted for an alkyl group that is substituted for an amino group that is substituted for an alkyl group. Examples include alkyl-NH-alkyl-NH-alkyl-, which use the term alkyl as defined herein.

[0127] "Arylaminoalkyl" means an aryl group that is substituted for an amino group that is substituted for an alkyl group. Examples include aryl-NH-alkyl-, using the terms aryl and alkyl as defined herein.

[0128] "Aminoalkyloxy" refers to an amino group attached as a substituent to an alkyloxy group. Examples include H2N-alkyl-O- and H2N-alkoxy-, using the terms alkyl and alkoxy as defined herein.

[0129] "Aminoalkyloxyalkyl" means an amino group that is substituted for an alkyloxy group that is substituted for an alkyl group. Examples include H2N-alkyl-O-alkyl- and H2N-alkoxy-alkyl-, using the terms alkyl and alkoxy as defined herein.

[0130] "Aminoalkylcarboxy" means an amino group that is substituted for an alkyl group that is substituted for a carboxyl group. Examples include H2N-alkyl-(C=O)-O- and H2N-alkyl-O-(C=O)-, using the term alkyl as defined herein.

[0131] "Aminoalkylaminocarbonyl" means an amino group that is substituted for an amino group that is substituted for an alkyl group that is substituted for an amino

[0132] "Aminoalkylcarboxamide" means an amino group that is substituted for an alkyl group that is substituted for an amino group that is substituted for a carbonyl group that is substituted for an amino group. Examples include H2N-alkyl-(C=O)-NH- and H2N-alkyl-NH-(C=O)-, using the term alkyl as defined herein.

[0133] "Azidoalkyloxy" refers to an azide group attached as a substituent to an alkyloxy group. Examples include N3-alkyl-O- and N3-alkoxy-, using the terms alkyl and alkoxy as defined herein.

[0134] "Cyanoalkyloxy" refers to a cyano group attached as a substituent to an alkyloxy group. Examples include NC-alkyl-O- and NC-alkoxy-, using the terms alkyl and alkoxy as 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 may be substituted or unsubstituted.

[0136] "Sulfinyl" means "-(S=O)-R", where R can be the same as the one defined for sulfenyl. Sulfinyl may or may not be substituted.

[0137] "Sulfonyl" means "-(S=O)-OR," where R can be the same as defined for sulfenyl. Sulfonyl may or may not be substituted.

[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. The O-carboxy may be substituted or unsubstituted.

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

[0140] "Thiocaunal" means "-(C=S)-R", where R can be the same as the one defined for O-carboxyl. Thiocaunal may be substituted or unsubstituted.

[0141] "Trihalomethanesulfonyl" means "X3CSO2-" (where X is a halogen). "S-sulfonamide" means "-SO2N(RARB)" where RA and RB can independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclic, aralkyl, or (heteroalicyclic)alkyl. S-sulfonamide may be substituted or unsubstituted.

[0142] "N-sulfonamide" means "RSO2N(RA)-" where R and RA can independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclic, aralkyl, or (heteroalicyclic)alkyl. N-sulfonamide may be substituted or unsubstituted.

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

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

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

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

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

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

[0149] "Guanidinoalkyloxy" refers to a guanidinyl group attached as a substituent to an alkyloxy group. Examples use the terms alkyl and alkoxy as defined herein.

[0150] [ka]

[0151] That is the case. "Guanidinoalkylcarboxy" means a guaidinyl group that is substituted for an alkyl group that is substituted for a carboxyl group. Examples use the term alkyl as defined herein.

[0152] [ka]

[0153] That is the case. "Quaternary ammonium alkylcarboxy" means a quaternary amino group that is substituted for an alkyl group that is substituted for a carboxyl group. Examples use the term alkyl as defined herein.

[0154] [ka]

[0155] That is the case. "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. If the number of substituents is not specified (e.g., haloalkyl), one or more substituents may be present. For example, "haloalkyl" may contain one or more of the same or different halogens.

[0156] "Amino acids" means any amino acids (both standard and non-standard amino acids), including α-amino acids, β-amino acids, γ-amino acids, and δ-amino acids, but are not limited to those listed below. 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, hypsin, 2-aminoisobutyric acid, dehydroalanine, γ-aminobutyric acid, citrulline, β-alanine, α-ethylglycine, α-propylglycine, and norleucine.

[0157] A "linking group" is a divalent portion used to link one steroid to another. In embodiments, a linking group is used to link a first CSA to a second CSA (which may be the same or different). An example of a linking group is (C1~C 10 )Alkyloxy-(C1~C 10 It is alkyl.

[0158] "PG" or "protecting group" refers to any atom or group of atoms added to a molecule to prevent an existing group in the molecule from undergoing an undesirable chemical reaction. Examples of protecting group moieties are described in TW Greene and PGMWuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, 1999, and JFWMcOmie, Protective Groups in Organic Chemistry, Plenum Press, 1973, both of which are incorporated herein by reference for the limited purpose of disclosing appropriate protecting groups. Protecting group moieties may be selected to be stable under specific reaction conditions and to be readily removed at a convenient stage using methodologies known from the art.A non-restrictive list of protecting groups includes: benzyl; substituted benzyl; alkylcarbonyl and alkoxycarbonyl (e.g., t-butoxycarbonyl (BOC), acetyl, or isobutyryl); allylalkylcarbonyl and allylalkoxycarbonyl (e.g., benzyloxycarbonyl); substituted methyl ether (e.g., methoxymethyl ether); substituted ethyl ether; substituted benzyl ether; tetrahydropyranyl ether; silyl (e.g., trimethylsilyl, triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl, triisopropylsilyloxymethyl, [2-(trimethylsilyl)ethoxy]methyl, or t-butyldiphenylsilyl); ester (e.g., benzoic acid ester); carbonate (e.g., methyl methylsilyl); This includes toxymethyl carbonates; sulfonates (e.g., tosylates or mesylates); acyclic ketals (e.g., dimethyl acetals); 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), as well as 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 species of the protecting group is not important if the protecting group is stable to the conditions of all subsequent reactions at other positions of the compound and can be removed at appropriate time without adversely affecting the remainder of the molecule. Furthermore, the protecting group may be replaced with another after the substantial synthetic transformation is complete. Clearly, if a compound differs from a compound disclosed herein only in that one or more protecting groups of that compound are replaced with a different protecting group, then that compound is within the scope of the disclosure.

[0159] The present invention may be embodied in other specific forms without departing from its spirit or essential characteristics. The embodiments described herein should be considered in all respects to be merely illustrative and not limiting. For this reason, the scope of the invention is indicated not by the foregoing description but by the appended claims. All modifications that fall within the meaning and scope equivalent to the claims should be included 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. 16. The method of any one of claims 1 to 15, wherein the carrier comprises one or more of water, an alcohol, another organic solvent, an emulsion, or a combination thereof.

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.