Cationic steroidal antimicrobial compounds with endogenous groups

Abstract

Cationic steroidal antimicrobial (CSA) compounds having a structure of formula I, II, or III, wherein R1-R 18 At least one of them (e.g., R) 18 It includes terpene groups linked by ester or amide bonds, and R1-R 18 At least one of (e.g., R3, R7, and R) 12 ) are amino acids that are linked to the steroid backbone via ester or amide bonds. 18 It has the following structure: -R 19 -(C=O)-X-R 20 , where R 19 It is either omitted or alkyl, alkenyl, alkynyl, or aryl, X is oxygen or nitrogen, and R is... 20 It is a terpene group. R3, R7, and R 12 It has the following structure: R 22 R 23 N-R 21 -(C=O)-X-, where R 21 It is a substituted or unsubstituted alkyl group, X is oxygen or nitrogen, and R is... 22 and R 23 It can be hydrogen, alkyl, alkenyl, alkynyl or aryl independently.

Description

Technical Field

[0001] Cationic steroidal antimicrobial (CSA) compounds are disclosed, including CSA compounds having endogenous groups based on natural terpenes, amino acids and cholic acids or cholic acid derivatives, and a method for manufacturing CSA compounds having endogenous groups. Background Technology

[0002] Antimicrobial peptides have been found in organisms ranging from mammals and amphibians to insects and plants. The ubiquity of antimicrobial peptides has been used as evidence that these compounds are less likely to induce bacterial resistance. Furthermore, given the different sequences of antimicrobial peptides in different organisms, it is clear that they have evolved independently multiple times. Therefore, antimicrobial peptides appear to be one of the primary “natural” means of controlling bacterial growth. For example, endogenous antimicrobial peptides (such as human keselin-37) play a crucial role in innate immunity. LL-37 is present in airway mucus and is thought to play an important role in controlling bacterial growth in the lungs. However, significant challenges exist in the clinical application of antimicrobial peptides, including the relatively high cost of producing peptide-based therapeutics, the sensitivity of peptides to proteases produced by the host and bacterial pathogens, and the inactivation of antimicrobial peptides by proteins and DNA in the lung mucosa.

[0003] A worthwhile approach to utilizing the antimicrobial activity of antimicrobial peptides without the aforementioned problems is to develop non-peptide mimics of antimicrobial peptides that exhibit similar broad-spectrum antimicrobial activity through the same or similar mechanisms of action. Non-peptide mimics would offer lower synthetic costs and potentially increased stability against proteolytic degradation. Furthermore, control over water solubility and charge density could be used to control binding to proteins and DNA in the lung mucosa.

[0004] More than 1,600 examples of antimicrobial peptides are known, and they can be classified based on their common structural features. Although these peptides vary greatly in their primary sequences, the vast majority adopt similar morphologies. Those employing an α-helical conformation have hydrophobic side chains juxtaposed on one side of the helix, while cationic (positively charged) side chains are juxtaposed on the opposite side. A similar morphology has been found in antimicrobial peptides that form β-sheet structures: hydrophobic side chains on one side of the sheet, and cationic side chains on the other side.

[0005] Examples of small-molecule, non-peptide mimics of antimicrobial peptides include steroids called "ceragenins," such as "CSA-13" and "CSA-44," which reproduce the amphiphilic form of antimicrobial peptides. One remaining issue is that CSA compounds have side groups that form non-endogenous degradation products, which may be unsuitable for humans and / or not entirely safe at higher concentrations. Another issue is that the manufacture of CSA compounds typically requires a complex, multi-step reaction sequence. Each additional step in the CSA compound manufacturing process increases cost and reduces overall product yield. Summary of the Invention

[0006] This article discloses a new class of cationic steroidal antimicrobial (CSA) compounds that have endogenous groups linked to an endogenous sterol backbone. These CSA compounds are referred to as "endogenous CSA compounds".

[0007] The degradation products of endogenous CSA compounds are themselves endogenous, such as bile acids (common bile acids), amino acids such as β-alanine (an endogenous neurotransmitter and amino acid), and natural terpenes such as geraniol (a natural terpene found in higher organisms and some edible plants). Endogenous CSA compounds are relatively easy and inexpensive to produce, yet still possess the desired antimicrobial, anti-inflammatory, and other desirable properties.

[0008] The CSA compounds disclosed herein may have the structure of formula I, II or III or a salt thereof, having a steroidal skeleton, and wherein R1-R 18 At least one of them, preferably R 18 It may contain a terpenoid group, such as geraniol, at the C-24 position of the steroid skeleton, and R1-R 18 At least one of them, preferably R3, R7 and R 12 At least one of them may contain an amino acid linked to the sterol backbone via an ester bond at the C3, C7, and / or C12 position:

[0009]

[0010] In the implementation plan, R1-R 18 At least one of them, preferably R 18 It can have the following structures:

[0011] -R 19 -(C=O)-OR 20

[0012] Where R 19 The radical is omitted or selected from alkyl, alkenyl, ynyl, and aryl, and R 20It is the terpenoid group that forms a terpenoid ester, such as geraniol, which forms a natural terpene, such as geraniol, as a degradation product (e.g., through hydrolysis of the ester group at the C24 position). The terpenoid group can be attached to the C24 position (or other positions) by other bonds, such as a reverse ester bond (which forms another natural terpene, geraniol, as a degradation product), an amide bond, an ether bond, or an amine bond.

[0013] In the implementation plan, R1-R 18 At least one of them, preferably R3, R7 and R 12 At least one of them may have the following aminoalkyl carboxyl group structure:

[0014] R 22 R 23 NR 21 -(C=O)-O-

[0015] Where R 21 It is a substituted or unsubstituted alkyl group and R 22 and R 23 Independently selected from hydrogen, alkyl, alkenyl, alkynyl, and aryl. R3, R7, and R 12 At least one of them, preferably R3, R7 and R 12 Two or three of them are ester groups of amino acids (e.g., β-alanine), which form endogenous amino acids (e.g., β-alanine) as degradation products (e.g., through hydrolysis of ester groups at the C3, C7, and / or C12 positions). Alternatively, R3, R7, and R 12 At least one of the aminoalkyl groups can be attached to one or more of the C3, C7 and / or C12 positions (or other positions) via other bonds (e.g. amide or ether bonds).

[0016] Non-limiting examples of endogenous CSA compounds that form endogenous degradation products through ester hydrolysis are CSA-148 and its salts:

[0017]

[0018] The degradation products of CSA-148 and its salts are endogenous molecules:

[0019]

[0020] In the embodiments, a method for preparing an endogenous CSA compound having an ester bond includes: (1) reacting the C24 acid group of cholic acid with a terpene (e.g., geraniol) or a terpene derivative (e.g., geraniol bromide) having a leaving group in one or more steps to achieve a reaction in R 18(1) Forming a terpene ester (e.g., geraniol ester) at the C24 position of the cholic acid, and (2) in one or more steps forming an ester bond between at least one hydroxyl group at the C3, C7, and C12 positions of the cholic acid and an optionally protected amino acid (e.g., optionally protected β-alanine), the ester bond connecting R3, R7, and R... 12 At least one of them is attached to the sterol skeleton to produce the desired CSA compound.

[0021] The advantages of the endogenous CSA compounds disclosed herein include, but are not limited to, the formation of endogenous degradation products, such as bile acids, amino acids such as β-alanine, and natural terpenes such as geraniol, and providing comparable and / or improved antimicrobial activity, anti-inflammatory activity, and other desired properties compared to existing CSA compounds, and / or simplified synthesis of CSA compounds and / or intermediate CSA compounds compared to existing synthetic routes.

[0022] Additional features and advantages will be set forth in the following description, and in part will be obvious from the description or may be learned by practicing the embodiments disclosed herein. It should be understood that the foregoing brief overview and the following detailed description are exemplary and not intended to limit the embodiments disclosed herein or claimed. Detailed Implementation

[0023] This article discloses a new class of cationic steroidal antimicrobial (CSA) compounds that have endogenous groups linked to an endogenous sterol backbone. These CSA compounds are referred to as "endogenous CSA compounds".

[0024] The degradation products of endogenous CSA compounds are themselves endogenous, such as bile acids (common bile acids), amino acids like β-alanine (an endogenous neurotransmitter and amino acid), and natural terpenes like geraniol (a terpene found in higher organisms and some edible plants). Endogenous CSA compounds are relatively easy and inexpensive to produce, yet still possess the desired antimicrobial, anti-inflammatory, and other desirable properties.

[0025] definition

[0026] Any "R" group, such as, but 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 , represents a substituent that can be attached to the sterol skeleton. Unless otherwise stated, the R group can be substituted or unsubstituted.

[0027] A "ring" can be a heterocyclic or carbocyclic ring. "Saturated" refers to a ring in which each atom is hydrogenated or substituted such that the valence of each atom is filled. "Unsaturated" refers to a ring in which the valence of each atom cannot be filled by hydrogen or other substituents. For example, adjacent carbon atoms in a fused ring can be double-bonded together. Unsaturation can also include the deletion of at least one of the following pairs, where the valence of the ring carbon atoms is completed by double bonding at these deletion sites, such as R5 and R9, R8 and R... 10 and R 13 and R 14 .

[0028] When a group is "substituted," it can be substituted by one, two, three, or more specified substituents, which can be the same or different, each substituting for a hydrogen atom. If no substituents are specified, the specified "substituted" group can be substituted by one or more groups individually and independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, acylalkyl, alkoxyalkyl, aminoalkyl, amino, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroarylalkyl, (heteroalicyclyl)alkyl, hydroxyl, protected hydroxyl, alkoxy, aryloxy, acyl, mercapto, alkylthio, arylthio, cyano, halogen (e.g., F, Cl, Br, and I), thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amide, N-amide, S-sulfonamide, N-sulfonamide, C-carboxyl, protected C-carboxyl, O-carboxyl, isocyanate, cyanothio, isothiocyanate, nitro, oxo, silyl, oxothio, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonylamino, amino, monosubstituted and disubstituted amino, R a O(CH2) m O, R b (CH2) n O, R c C(O)O(CH2) p O and its protected derivatives. Substituents can be attached to a group at more than one linkage site. For example, an aryl group can be replaced by a heteroaryl group at two linkage sites, forming a fused polycyclic aromatic ring system. Biphenyl and naphthalene are two examples of aryl groups substituted with a second aryl group. Groups not specifically labeled as substituted or unsubstituted can be considered substituted or unsubstituted.

[0029] Term "C" a "or "C a To C bThe symbol “C1 to C4 alkyl” indicates the number of carbon atoms in an alkyl, alkenyl, or alkynyl group, or in a cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, or heteroalicyclic ring. In other words, the rings of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, or heteroalicyclic groups can contain “a” to “b” (inclusive) carbon atoms. Therefore, for example, “C1 to C4 alkyl”. This refers to all alkyl groups having 1 to 4 carbons, namely CH3, CH3CH2, CH3CH2CH2, (CH3)2CH, CH3CH2CH2CH2, CH3CH2CH(CH3), (CH3)2CHCH2, and (CH3)3C. If "a" and "b" are not specified for alkyl, alkenyl, ynyl, cycloalkyl, cycloalkenyl, cycloynyl, aryl, heteroaryl, or heterocycloalkenyl, the broadest range described in these definitions is assumed.

[0030] “Alkyl” refers to a straight-chain or branched hydrocarbon chain containing a fully saturated (without double or triple bonds) hydrocarbon group. An alkyl group can have 1 to 25 carbon atoms (wherever it appears in this document, a numerical range such as “1 to 25” refers to each integer within the given range; for example, “1 to 25 carbon atoms” means that an alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 25 carbon atoms, although this definition also covers the case where the term “alkyl” is not specified with a numerical range). An alkyl group can also be a medium-sized alkyl group having 1 to 15 carbon atoms. An alkyl group can also be a lower-order alkyl group having 1 to 6 carbon atoms. The alkyl group of a compound can be specified as “C4” or “C1-C4 alkyl” or similar names. By way of example only, “C1-C4 alkyl” means 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 tert-butyl. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, and hexyl. Alkyl groups can be substituted or unsubstituted.

[0031] "Alkenyl" refers to an alkyl group containing one or more double bonds in a straight-chain or branched hydrocarbon chain. An alkenyl group can 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 an alkenyl group can consist of 2, 3, or 4 carbon atoms, etc., up to and including 25 carbon atoms, although this definition also covers cases where the term "alkenyl" is not specified with a numerical range). An alkenyl group can also be of medium size, having 2 to 15 carbon atoms. An alkenyl group can also be of lower alkenyl groups, having 1 to 6 carbon atoms. The alkenyl group of the compound may be designated as "C4" or "C2-C4 alkenyl" or similar names. An alkenyl group can be unsubstituted or substituted.

[0032] "Alynyl" refers to an alkyl group containing one or more triple bonds in a straight-chain or branched hydrocarbon chain. An alkynyl group can 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 an alkynyl group can consist of 2, 3, or 4 carbon atoms, etc., up to and including 25 carbon atoms, although this definition also covers cases where the term "alkynyl" is not specified within a numerical range). An alkynyl group can also be of medium size, having 2 to 15 carbon atoms. An alkynyl group can also be of lower alkynyl groups, having 2 to 6 carbon atoms. The alkynyl group of the compound may be designated as "C4" or "C2-C4 alkynyl" or similar names. An alkynyl group can be unsubstituted or substituted.

[0033] "Aryl" refers to a monocyclic or polycyclic aromatic ring system (including fused ring systems where two carbon rings share a single chemical bond) with completely delocalized π electrons in all rings. The number of carbon atoms in an aryl group can vary. For example, an aryl group can be C6-C. 14 Aryl, C6-C 10 aryl or C6 aryl (although C6-C 10 The definition of aryl covers cases where no numerical range is specified for "aryl". Examples of aryl groups include, but are not limited to, benzene, naphthalene, and azulene. Aryl groups can be substituted or unsubstituted.

[0034] "Aranyl" and "aryl (alkyl)" refer to an aryl group linked by a lower alkylene group as a substituent. An aranyl group can have 6 to 20 carbon atoms (wherever it appears herein, a numerical range such as "6 to 20" refers to each integer within a given range; for example, "6 to 20 carbon atoms" means that an aranyl group can consist of 6, 7, 8, etc., up to and including 20 carbon atoms, although this definition also covers the case where the term "aranyl" is used without a specified numerical range). The lower alkylene group and the aryl group of an aranyl group can be substituted or unsubstituted. Examples include, but are not limited to, benzyl, 2-phenylalkyl, 3-phenylalkyl, and naphthylalkyl.

[0035] "Lower alkylene" refers to C1-C 25 Straight-chain alkyl tethering groups, such as -CH2- tethering groups, form bonds that link molecular segments through their terminal carbon atoms. Examples include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), and butylene (-CH2CH2CH2CH2-). Lower alkylene groups can be substituted by replacing one or more hydrogen atoms of the lower alkylene group with substituents listed below by the definition of "substituted".

[0036] "Cycloalkyl" refers to a fully saturated (without double or triple bonds) monocyclic or polycyclic hydrocarbon ring system. When composed of two or more rings, these rings can be fused together. A cycloalkyl group can accommodate 3 to 10 atoms in one or more rings, or 3 to 8 atoms in one or more rings. Cycloalkyl groups can be unsubstituted or substituted. Typical cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0037] "Cycloalkenyl" refers to a monocyclic or polycyclic hydrocarbon ring system containing one or more double bonds in at least one ring; however, if more than one double bond is present, the double bonds cannot form a fully delocalized π-electron system in all rings (otherwise the group would be "aryl," as defined herein). When composed of two or more rings, these rings can be joined together in a fused manner. Cycloalkenyl groups can be unsubstituted or substituted.

[0038] A "cycloalkynyl" group refers to a monocyclic or polycyclic hydrocarbon ring system containing one or more triple bonds in at least one ring. If more than one triple bond is present, the triple bonds cannot form a fully delocalized π-electron system in any of the rings. When composed of two or more rings, these rings can be connected together in a fused manner. Cycloalkynyl groups can be unsubstituted or substituted.

[0039] "Alkoxy" refers to the formula -OR, where R is an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, or cycloalkynyl group as defined above. A non-limiting list of alkoxy groups includes methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, isobutoxy, sec-butoxy, and tert-butoxy. Alkoxy groups can be substituted or unsubstituted.

[0040] "Acyl" refers to a hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl group that is linked as a substituent via a carbonyl group, such as -(C=O)-R. Examples include formyl, acetyl, propionyl, benzoyl, and acryloyl. The acyl group can be substituted or unsubstituted.

[0041] "alkoxyalkyl" refers to an alkoxy group linked by a lower alkylene group as a substituent. Examples include alkyl-O-alkyl- and alkoxy-alkyl-, wherein the terms alkyl and alkoxy are as defined herein.

[0042] "Hydroxyalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by hydroxyl groups. 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.

[0043] "Haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by a halogen (e.g., monohaloalkyl, dihaloalkyl, and trihaloalkyl). Examples include chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, and 1-chloro-2-fluoromethyl, 2-fluoroisobutyl. Haloalkyl can be substituted or unsubstituted.

[0044] "Amino" refers to "-NH2".

[0045] "Hydroxy group" refers to "-OH".

[0046] "Cyano" refers to "-CN".

[0047] "Carbonyl" or "oxo" refers to "-C=O".

[0048] "Azide group" refers to "-N3".

[0049] "Aminoalkyl" refers to an amino group linked by a lower alkylene group as a substituent. Examples include H2N-alkyl-, and the term alkyl is as defined herein.

[0050] "alkyl-carboxyalkyl" refers to an alkyl group that is attached to a carboxyl group as a substituent. Examples include alkyl-(C=O)-O-alkyl and alkyl-O-(C=O)-alkyl, and the term alkyl is as defined herein.

[0051] "alkylaminoalkyl" refers to an alkyl group attached to an amino group as a substituent. Examples include alkyl-NH-alkyl-, and the term alkyl is as defined herein.

[0052] "Dialkylaminoalkyl" and "di(alkyl)aminoalkyl" refer to two alkyl groups, each acting as a substituent attached to an amino group. Examples include... The term alkyl is as defined herein.

[0053] "alkylamino" refers to an alkyl group attached to an amino group as a substituent. Examples include alkyl-NH- and alkyl-NH-, and the term alkyl is as defined herein.

[0054] "alkylaminoalkylaminoalkylamino" refers to an alkyl group attached as a substituent to an amino group, wherein the amino group is attached as a substituent to an alkyl group attached as a substituent to the alkyl group. Examples include alkyl-NH-alkyl-NH-alkyl-, and the term alkyl is as defined herein.

[0055] "Arylaminoalkyl" refers to an aryl group attached as a substituent to an amino group, which in turn is attached as a substituent to an alkyl group. Examples include aryl-NH-alkyl-, and the terms aryl and alkyl are as defined herein.

[0056] "Aminoalkoxy" refers to an amino group that is attached to an alkoxy group as a substituent. Examples include H2N-alkyl-O- and H2N-alkoxy-, the terms alkyl and alkoxy as defined herein.

[0057] "Aminoalkoxyalkyl" refers to an amino group that is attached as a substituent to an alkoxy group, with the amino group being attached to the alkyl group as a substituent. Examples include H2N-alkyl-O-alkyl- and H2N-alkoxy-alkyl-, the terms alkyl and alkoxy as defined herein.

[0058] "Aminoalkylcarboxyl" refers to an amino group that is attached as a substituent to an alkyl group, which is attached as a substituent to a carboxyl group. Examples include H2N-alkyl-(C=O)-O- and H2N-alkyl-O-(C=O)-, and the term alkyl is as defined herein.

[0059] "Aminoalkylaminocarbonyl" refers to an amino group that is attached as a substituent to an alkyl group, where the alkyl group is attached as a substituent to the amino group. Examples include H₂N-alkyl-NH-(C=O)-, and the term alkyl is as defined herein.

[0060] "Aminoalkylformamide" refers to an amino group attached as a substituent to an alkyl group, which is then attached as a substituent to a carbonyl group, which in turn is attached as a substituent to the amino group. Examples include H2N-alkyl-(C=O)-NH- and H2N-alkyl-NH-(C=O)-, where the term alkyl is as defined herein.

[0061] "Azide-alkoxy" refers to an azide group attached as a substituent to an alkoxy group. Examples include N3-alkyl- and N3-alkoxy-, the terms alkyl and alkoxy as defined herein.

[0062] "Cyanoalkoxy" refers to a cyano group attached as a substituent to an alkoxy group. Examples include NC-alkyl-O- and NC-alkoxy-, the terms alkyl and alkoxy as defined herein.

[0063] "Thio" refers to "-SR", where R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heterocycloalkyl, aralkyl, or (heterocycloalkyl)alkyl. The thio group can be substituted or unsubstituted.

[0064] "Sylenyl group" refers to "-(S=O)-R", where R can be the same as defined for sulfinyl group. The sulfinyl group can be substituted or unsubstituted.

[0065] "Sulfonyl" refers to "-(S=O)-OR", where R can be the same as the definition for a thio group. The sulfonyl group can be substituted or unsubstituted.

[0066] “O-carboxyl” refers to “R-(C=O)-O-”, where R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heterocycloalkyl, aralkyl, or (heterocycloalkyl)alkyl, as defined herein. The O-carboxyl group can be substituted or unsubstituted.

[0067] "Ester" and "C-carboxyl" refer to "-(C=O)-OR", where R can be the same as the definition for O-carboxyl. Esters and C-carboxyl groups can be substituted or unsubstituted.

[0068] "Thiocarbonyl" refers to "-(C=S)-R", where R can be the same as the definition of an O-carboxyl group. Thiocarbonyl groups can be substituted or unsubstituted.

[0069] "Trihalomethanesulfonyl" refers to "X3CSO2-", where X is a halogen.

[0070] "S-sulfonamide group" refers to "-SO2N(RARB)", where RA and RB can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heterocycloalkyl, aralkyl, or (heterocycloalkyl)alkyl. The S-sulfonamide group can be substituted or unsubstituted.

[0071] "N-sulfonamide" refers to "RSO2N(RA)-", where R and RA can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heterocyclocycloyl, aralkyl, or (heterocyclocycloyl)alkyl. The N-sulfonamide group can be substituted or unsubstituted.

[0072] "O-carbamoyl" and "carbamate" refer to "-O-(C=O)-N(RARB)", where RA and RB can independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heterocyclocycloyl, aralkyl, or (heterocyclocycloyl)alkyl. The O-carbamoyl or carbamate group can be substituted or unsubstituted.

[0073] "N-Carbamoyl" refers to "RO-(C=O)-N(RA)-", where R and RA can independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heterocyclocycloyl, aralkyl, or (heterocyclocycloyl)alkyl. N-Carbamoyl can be substituted or unsubstituted.

[0074] "O-Thiocarbamoyl" refers to "-O-(C=S)-N(RARB)", where RA and RB can independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heterocyclocycloyl, aralkyl, or (heterocyclocycloyl)alkyl. O-Thiocarbamoyl can be substituted or unsubstituted.

[0075] "N-Thiocarbamoyl" refers to "RO-(C=S)-N(RA)-", where R and RA can independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heterocyclocycloyl, aralkyl, or (heterocyclocycloyl)alkyl. N-Thiocarbamoyl can be substituted or unsubstituted.

[0076] "C-amide group" refers to "-(C=O)-N(RARB)", where RA and RB can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heterocyclocycloyl, aralkyl, or (heterocyclocycloyl)alkyl. The C-amide group can be substituted or unsubstituted.

[0077] "N-Amide group" refers to "R-(C=O)-N(RA)-", where R and RA can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heterocyclocycloyl, aralkyl, or (heterocyclocycloyl)alkyl. The N-amide group can be substituted or unsubstituted.

[0078] "Guidinylalkoxy" refers to a guanidinyl group attached as a substituent to an alkoxy group. Examples include... The terms alkyl and alkoxy are as defined herein.

[0079] "Guidinylalkylcarboxyl" refers to a guanidinyl group attached as a substituent to an alkyl group, where the alkyl group acts as a substituent linked to the carboxyl group. Examples include... The term alkyl is as defined herein.

[0080] "Quaternary ammonium alkyl carboxyl group" refers to a quaternized amino group attached as a substituent to an alkyl group, where the alkyl group acts as a substituent linked to the carboxyl group. Examples include... The term alkyl is as defined herein.

[0081] "Halogen atom" and "halogen" refer to any radioactive stable atom in column 7 of the periodic table, such as fluorine, chlorine, bromine, and iodine.

[0082] When the number of substituents is not specified (e.g., in the case of haloalkyl), one or more substituents may be present. For example, "haloalkyl" may include one or more of the same or different halogens.

[0083] "Amino acid" refers to any amino acid (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. Other examples of suitable amino acids include, but are not limited to, ornithine, homolysine, 2-aminoisobutyric acid, dehydroalanine, γ-aminobutyric acid, citrulline, β-alanine, α-ethylglycine, α-propylglycine, and leucine.

[0084] A linker group is a divalent moiety used to attach one steroid to another. In embodiments, the linker group is used to link a first CSA and a second CSA (which may be the same or different). Examples of linker groups are (C1-C...). 10 )alkoxy-(C1-C 10 )alkyl.

[0085] "PG" or "protecting group" or "multiple protecting groups" refers to any atom or group of atoms added to a molecule to prevent unwanted chemical reactions of existing groups in the molecule. Examples of partial protecting groups are described in TW Greene and PGM Uts, *Protective Groups in Organic Synthesis*, 3. Ed. John Wiley & Sons, 1999, and JFW McOmie, *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 groups can be selected in such a way that they are stable to certain reaction conditions and can be readily removed at a convenient stage using methods known in the art. The non-limiting list of protecting groups includes benzyl, substituted benzyl, alkyl carbonyl and alkoxy carbonyl (e.g., t-butoxycarbonyl (BOC), acetyl or isobutyryl), aralkyl carbonyl and aralkyloxy carbonyl (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), esters (such as benzoates), carbonates (such as methoxymethyl carbonate), sulfonates (such as p-toluenesulfonate or methanesulfonate), acyclic ketals (such as dimethylacetal), 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 acetals, Hemiacetals, cyclic dithioketals (e.g., 1,3-dithiaran or 1,3-dithiopentane), orthoesters (e.g., those described herein), and triphenylmethyl groups (e.g., triphenylmethylol, monomethoxytriphenylmethyl (MMTr), 4,4'-dimethoxytriphenylmethyl (DMTr), 4,4',4"-trimethoxytriphenylmethyl (TMTr), and those described herein). Amino protecting groups are known to those skilled in the art. Generally, the type of protecting group is not critical, provided that it is stable to the conditions of any subsequent reactions at other positions of the compound and can be removed when appropriate without adversely affecting the rest of the molecule. Furthermore, after a substantial synthetic transformation, one protecting group can be substituted by another. Clearly, if a compound differs from those disclosed herein solely in that one or more protecting groups of the disclosed compound are substituted with different protecting groups, then that compound is within the scope of this disclosure.

[0086] CSA compounds

[0087] Cationic steroidal antimicrobial (CSA) compounds, also known as “CSA compounds,” “CSAs,” CSA molecules, or “ceragenin” compounds, are synthetically produced small molecule compounds comprising a sterol backbone to which various charged groups (e.g., amines and cationic groups) are attached. The sterol backbone can be used to orient amine or guanidine groups on its facets or planes. Based on the functional groups attached to the backbone, CSAs are cationic and amphiphilic. They are amphiphilic on the surface, having a hydrophobic side and a polycationic side.

[0088] Not wishing to be limited by theory, the CSA molecules described herein are considered as antimicrobial agents (e.g., antibacterial, antifungal, and antiviral). It is believed, for example, that antimicrobial CSA molecules can act as antimicrobial agents by binding to and modifying the cell membranes of bacteria and other microorganisms, for example, by forming pores that allow leakage of ions and cytoplasmic material essential for microbial survival, leading to the death of affected microorganisms. Furthermore, antimicrobial CSA molecules can also susceptible bacteria to other antibiotics. For example, at concentrations below the corresponding minimum inhibitory concentration (MIC), CSA compounds can make bacteria more susceptible to other antibiotics by disrupting the cell membrane, for example, by increasing membrane permeability. It is speculated that the charged cationic groups may be the cause of the disruption of bacterial cell membranes and the conferral of antimicrobial properties. CSA molecules may have similar membrane or capsid disrupting effects on fungi and viruses.

[0089] For background, exemplary CSA compounds and methods of their manufacture are described 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 Publications Nos. 2016 / 0311850 and 2017 / 0210776, and U.S. Provisional Application No. 63 / 025,255, which are incorporated herein by reference. Those skilled in the art will recognize the compounds within the general formulas listed herein and understand their preparation based on the references and examples cited herein.

[0090] The compounds and compositions disclosed herein are optionally prepared as salts, which advantageously make them cations when one or more amine groups are protonated. The term "salt" as used herein is a broad term and is given the usual and customary meaning to those skilled in the art (and is not limited to a particular or customary meaning), referring to a salt of a compound, but not limited to that of a particular compound. In embodiments, the salt is an acid addition salt of the compound. Salts can be obtained by reacting the compound with inorganic acids such as hydrohalic acids (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid, phosphoric acid, and phosphonic acids. Salts can also be obtained by reacting the compound with an organic acid, such as aliphatic or aromatic carboxylic acids or sulfonic acids, sulfinic acids, 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, mucilage, 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. Salts can also be obtained by reacting a compound with a base to form a salt, such as ammonium salts, alkali metal salts (e.g., lithium, sodium, or potassium salts), alkaline earth metal salts (e.g., calcium, magnesium, or aluminum salts), organic base salts (e.g., dicyclohexylamine, N-methyl-D-glucosamine, tri(hydroxymethyl)methylamine, C1-C7 alkylamines, cyclohexylamine, dicyclohexylamine, triethanolamine, ethylenediamine, ethanolamine, diethanolamine, triethanolamine, tromethamine), and salts containing an amino group (e.g., arginine and lysine) or salts of inorganic bases (e.g., aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, etc.).

[0091] In the embodiments, the salt is a hydrochloride salt. In the embodiments, the salt is a monohydrochloride, dihydrochloride, trihydrochloride, or tetrahydrochloride salt. Other examples of salts include sulfuric acid addition salts, sulfonic acid addition salts, disulfonic acid addition salts, 1,5-naphthalenedisulfonic acid addition salts, sulfates, and hydrogen sulfates.

[0092] The CSA compounds disclosed herein may have the structure of formula I, II or III, or a salt thereof, have a steroidal skeleton, and wherein R1-R 18 At least one of them, preferably R 18 It may include terpenoid groups, such as geraniol at the C24 position of the steroid skeleton, and R1-R 18 At least one of them, preferably R3, R7 and R 12 At least one of them may include an amino acid linked to the sterol backbone via an ester bond at the C3, C7, and / or C12 position:

[0093]

[0094] In the implementation plan, R1-R 18At least one of them, preferably R 18 It can have the following structures:

[0095] -R 19 -(C=O)-OR 20

[0096] Where R 19 The radical is omitted or selected from alkyl, alkenyl, ynyl, and aryl, and R 20 It is the terpenoid group that forms a terpenoid ester, such as geraniol, which forms a natural terpene as a degradation product, such as geraniol (e.g., through hydrolysis of the ester group at the C24 position). Geraniol has the empirical formula C... 10 H 18 O, its chemical structure is:

[0097]

[0098] The use of other terpene groups, such as isomers, analogs, and derivatives of geraniol that form natural terpenes as degradation products, is also within the scope of this invention. Below are examples of terpene-based R groups. 20 Examples of other alcohol terpenes.

[0099] Nerolimol is the cis isomer of geraniol (trans isomer), and it has the empirical formula C1. 10 H 18 O and chemical structure:

[0100]

[0101] 8-Hydroxygeraniol has the empirical formula C 10 H 18 O2 and its chemical structure:

[0102]

[0103] Farnesol has an empirical C 15 H 26 O and chemical structure:

[0104]

[0105] Geraniol has the empirical formula C 20 H 34 O and chemical structure:

[0106]

[0107] Geranium foliol has empirical C 25 H 42 O and chemical structure:

[0108]

[0109] Isopentenol has the empirical formula C5H 10 O, its chemical structure is as follows, and it has the general formula H-[CH2CCH3=CHCH2). n The structural blocks of polypentenols with -OH groups, such as geranialdehyde, farnesol, geraniylgeraniol, and geraniyl farnesol mentioned above:

[0110]

[0111] Agarol has empirical C 10 H 18 O and chemical structure:

[0112]

[0113] Nerolidols, including trans-nerolidol and cis-nerolidol, have the empirical formula C 15 H 26 O and chemical structure:

[0114]

[0115] L-citronellol has the empirical formula C 10 H 20 O and chemical structure:

[0116]

[0117] Phytosterol has an empirical C 20 H 40 O and chemical structure:

[0118]

[0119] Isophytol has an empirical C 20 H 40 O and chemical structure:

[0120]

[0121] Phytotriol has the empirical formula C 20 H 40 O and chemical structure:

[0122]

[0123] Citronellol, including (+)-citronellol and (–)-citronellol, has the empirical formula C 10 H 20 O and the following chemical structures:

[0124]

[0125] α-Bisabolol has the empirical formula C 15 H 26 O and chemical structure:

[0126]

[0127] Retinol (vitamin A) has an empirical formula C 20 H 30 O and chemical structure:

[0128]

[0129] Terpineol, including α-terpineol, β-terpineol, γ-terpineol, δ-terpineol, and 4-terpineol, has the empirical formula C 10 H 18 O and chemical structure:

[0130]

[0131] Natural menthol, (-)-menthol and its isomers, have the empirical formula C 10 H 20 O and chemical structure:

[0132]

[0133] Anethole has empirical formula C 10 H 18 O and chemical structure:

[0134]

[0135] Coffee alcohol has empirical C 20 H 28 O3 and its chemical structure:

[0136]

[0137] Coffee bean mellowness has empirical C 20 H 26 O3 and its chemical structure:

[0138]

[0139] Terpenoid groups can be attached to the sterol skeleton via bonds other than ester bonds as defined above, such as reverse ester bonds (where the terpenoid group is attached to the carbonyl group and forms a terpenic acid, such as geraniic acid (a natural terpene compound) as a degradation product), amide bonds, ether bonds, or amine bonds, for example, where R 18 It has one of the following optional structures:

[0140] -R 19 -O-(C=O)-R 20(Reverse ester)

[0141] -R 19 -(C=O)-NX-R 20 (amide)

[0142] -R 19 -OR 20 (ether)

[0143] -R 19 -NX-R 20 (amine)

[0144] Where R 19 and R 20 As defined above, X is selected from hydrogen, alkyl, alkenyl, alkynyl, or aryl.

[0145] In the implementation plan, R1-R 18 At least one of them, preferably R3, R7 and R 12 At least one, such as two or three, may have the following aminoalkyl carboxyl group structure:

[0146] R 22 R 23 NR 21 -(C=O)-O-

[0147] Where R 21 It is a substituted or unsubstituted alkyl group, R 22 and R 23 Independently selected from hydrogen, alkyl, alkenyl, alkynyl, and aryl. R3, R7, and R 12 At least one of them, preferably R3, R7 and R 12 Two or three of them are aminoalkyl ester groups (e.g., β-alanine esters) that form endogenous amino acids (e.g., β-alanine) as degradation products (e.g., via R3, R7, and / or R at the C3, C7, and / or C12 positions of the sterol skeleton). 12 (Hydrolysis of aminoalkyl ester groups).

[0148] The use of other amino acid derivatives that form other naturally occurring amino acids as degradation products is also within the scope of this invention, such as D-alanine, L-alanine, L-asparagine, D-aspartic acid, L-aspartic acid, L-cysteine, L-glutamic acid, L-glutamine, glycine, L-proline, D-serine, L-serine, L-tyrosine, L-arginine, L-histidine, L-isoleucine, L-leucine, L-lysine, D-methionine, L-methionine, L-phenylalanine, L-threonine, L-lysine, D-methionine, L-methionine, L-phenylalanine, L-threonine, L-tryptophan, D-valine, L-valine, L-ornithine, homolysine, 2-aminoisobutyric acid, dehydroalanine, γ-aminobutyric acid, L-citrulline, α-ethylglycine, α-propylglycine, and L-leucine.

[0149] R3, R7 and R 12 At least one (e.g., one or two) of the aminoalkyl groups can be attached to the sterol skeleton by other bonds (e.g., amide or ether bonds), for example, where R 18 It has one of the following alternative structures:

[0150] R 22 R 23 NR 21 -(C=O)-N-(amide)

[0151] R 22 R 23 NR 21 -O-(ether)

[0152] Where R 21 R 22 and R 23 As defined above.

[0153] Referring again to Formulas I, II, and III, when the CSA compound has the structure of Formula I, m, n, p, and q are 0 or 1, respectively.

[0154] When the CSA compound has the structure of formula I or II

[0155] Rings A, B, C, and D are independently saturated, or completely or partially unsaturated, provided that at least two of rings A, B, C, and D are saturated.

[0156] R1 to R 18Independently selected from the group consisting of: hydrogen, hydroxyl, alkyl, hydroxyalkyl, alkoxyalkyl, alkylcarboxylalkyl, terpenylcarboxylalkyl, terpenylcarbonyloxyalkyl, terpenylaminoalkyl, terpenylamidoalkyl, terpenyloxyalkyl, alkylaminoalkyl, alkylaminoalkylamino, alkylaminoalkylaminoalkylamino, aminoalkyl, aryl, arylaminoalkyl, haloalkyl, alkenyl, alkynyl, oxo, linking group attached to a second steroid, aminoalkylcarbamate, aminoalkenylcarbamate, aminoalkynylcarbamate, aminoaryl. The following groups are included: carbamate group, aminoalkoxy group, aminoalkylcarboxyl group, aminoalkoxyalkyl group, aminoalkylcarbonyl group, aminoalkylformamido group, di(alkyl)aminoalkyl group, H2N-HC(Q5)-(C=O)-O-, H2N-HC(Q5)-(C=O)-NH-, azidoalkoxy group, cyanoalkoxy group, PG-HN-HC(Q5)-(C=O)-O-, guanidinoalkoxy group, quaternary ammonium alkylcarboxyl group, and guanidinoalkylcarboxyl group, wherein Q5 is the side chain of any amino acid (including the side chain of glycine, i.e., H), and PG is an amino protecting group; and

[0157] When one of rings A, B, C, or D is unsaturated, R5, R8, R9, R 10 R 13 R 14 and R 17 It is deleted independently to complete the valence of the carbon atom at that position.

[0158] The conditions are R1 to R4, R6, R7, R 11 R 12 R 15 R 16 and R 18 At least one of them, preferably R 18 This includes terpenoid groups (e.g., geraniol) linked to the sterol skeleton (e.g., at the C24 position) via ester, amide, ether, or amine bonds, and

[0159] The conditions are R1 to R4, R6, R7, R 11 R 12 R 15 R 16 and R 18 At least one of them, preferably R3, R7 and R 12 One, two, or three of them, including amino acids linked to the sterol backbone (e.g., at the C3, C7, and / or C12 positions) via ester or amide bonds.

[0160] In the implementation plan, R1 to R 18 Independently selected from the group consisting of: hydrogen, hydroxyl, substituted or unsubstituted (C1-C2) 22)alkyl, substituted or unsubstituted (C1-C 22 )hydroxyalkyl, substituted or unsubstituted (C1-C 22 )alkoxy-(C1-C 22 )alkyl, substituted or unsubstituted (C1-C 22 )alkylcarboxyl-(C1-C 22 )alkyl, substituted or unsubstituted (C5-C 25 )terpenoid carboxyl-(C1-C 22 )alkyl, substituted or unsubstituted (C5-C 25 )terpenoid carbonyloxy-(C1-C 22 )alkyl, substituted or unsubstituted (C5-C 22 )terpenoid formamido-(C1-C 22 )alkyl, substituted or unsubstituted (C5-C 25 )terpenoid amino-(C1-C 22 )alkyl, (C5-C 25 )terpenoid oxygen-(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, linking group attached to the second steroid, substituted or unsubstituted (C1-C6) 22 )aminoalkyl carbamate group, substituted or unsubstituted (C2-C 22 Amino-alkenyl carbamate group, substituted or unsubstituted (C2-C) 22 Amino-alkynyl carbamate group, substituted or unsubstituted amino-aryl carbamate group, substituted or unsubstituted (C1-C2) 22 Aminoalkoxy, substituted or unsubstituted (C1-C) 22 )aminoalkylcarboxyl, substituted or unsubstituted (C1-C 22 )aminoalkoxy-(C1-C 22)alkyl, substituted or unsubstituted (C1-C 22 )aminoalkyl-aminocarbonyl, substituted or unsubstituted (C1-C 22 )aminoalkylformamide, substituted or unsubstituted di(C1-C1) 22 )alkylamino-(C1-C 22 Alkyl, H2N-HC(Q5)-(C=O)-O-, H2N-HC(Q5)-(C=O)-NH-, substituted or unsubstituted (C1-C 22 )Azide alkoxy, substituted or unsubstituted (C1-C 22 ) cyanokineoxy, PG-HN-HC(Q5)-(C=O)-O-, substituted or unsubstituted (C1-C 22 ) guanidinoalkoxy, substituted or unsubstituted quaternary ammonium (C1-C4) 22 ) alkyl carboxyl groups and substituted or unsubstituted guanidinoalkyl carboxyl groups; wherein Q5 is a side chain of an amino acid (including the side chain of glycine, i.e., H), and PG is an amino protecting group; and

[0161] When one of rings A, B, C, or D is unsaturated, R5, R8, R9, R 10 R 13 R 14 and R 17 It is deleted independently to complete the valence of the carbon atom at that position.

[0162] The conditions are R1 to R4, R6, R7, R 11 R 12 R 15 R 16 and R 18 At least one of them, preferably R 18 This includes (C5-C) bonds that are attached to the sterol skeleton (e.g., at the C24 position) via ester, amide, ether, or amine bonds. 25 )terpenoids (e.g., geraniol), and

[0163] The conditions are R1 to R4, R6, R7, R 11 R 12 R 15 R 16 and R 18 At least one of them, preferably R3, R7 and R 12 One, two, or three of them, including amino acids linked to the sterol backbone (e.g., at the C3, C7, and / or C12 positions) via ester or amide bonds.

[0164] In the implementation plan, R1, R2, R4, R5, R6, R8, R9, R 10 R 11 R13 R 14 R 15 R 16 and R 17 The group consisting of hydrogen and unsubstituted (C1-C6) alkyl groups is selected independently.

[0165] In the implementation plan, R1, R2, R4, R5, R6, R8, R 10 R 11 R 14 R 16 and R 17 Each is hydrogen, and R9 and R 13 Each is a methyl group.

[0166] In the implementation scheme, one or more of rings A, B, C, and D are heterocyclic rings.

[0167] In the implementation scheme, rings A, B, C, and D are non-heterocyclic.

[0168] In the embodiments, the CSA compound is a compound of formula III, which is a subgenus of formulas I and II having specific stereochemistry, wherein R1, R2, R4, R5, R6, R8, R 10 R 11 R 14 and R 16 It is hydrogen or methyl, as shown in the figure, R 15 Omitted:

[0169]

[0170] Among them, R3, R7, R 12 and R 18 As defined above for equations I and II, for example:

[0171] R 18 It has the following structure:

[0172] -R 19 -(C=O)-OR 20

[0173] Where R 19 and R 20 As defined above for equations I and II, and

[0174] R3, R7 and R 12 At least one, preferably two or three, of the following have an aminoalkyl carboxyl group structure:

[0175] R 22 R 23 NR 21 -(C=O)-O-

[0176] Where R 21 R 22 and R 23 As defined above for equations I and II.

[0177] In the implementation plan, R3, R7 and R 12 One or both of them independently have an aminoalkyl carboxyl group structure as defined herein, R3, R7 and R 12 One or two of them are independently selected from the following groups: hydrogen, (C1-C2) 22 )alkyl, (C1-C 22 )hydroxyalkyl, (C1-C 22 )alkoxy-(C1-C 22 )alkyl, (C1-C 22 )alkylcarboxyl-(C1-C 22 )alkyl, (C1-C 22 )alkylamino-(C1-C 22 )alkyl, (C1-C 22 )alkylamino-(C1-C 22 )alkylamino, (C1-C 22 )alkylamino-(C1-C 22 )alkylamino-(C1-C 18 )alkylamino, (C1-C 22 )aminoalkyl, arylamino-(C1-C 22 )alkyl, (C1-C 22 )aminoalkoxy, (C1-C 22 )aminoalkylcarboxyl, (C1-C 22 )aminoalkoxycarbonyl, (C1-C 22 )aminoalkoxy-(C1-C 22 )alkyl, (C1-C 22 )aminoalkylcarbonyl, (C1-C 22 )aminoalkyl-carboxamide group, di(C1-C 22 )alkylaminoalkyl, (C1-C 22 ) guanidinoalkoxy, quaternary ammonium (C1-C 22 )alkyl carboxyl group, and (C1-C 22 Guanidinyl alkyl carboxyl group.

[0178] Preferably, in R3, R7 and R 12 When one or both of them independently have an aminoalkyl carboxyl group structure as defined herein, R3, R7 and R 12 One or two of them are independently selected from the group consisting of: hydrogen, (C1-C6)alkyl, (C1-C6)hydroxy ... 16)alkoxy-(C1-C5)alkyl, (C1-C 16 )alkylcarboxyl-(C1-C5)alkyl, (C1-C 16 )alkylamino-(C1-C5)alkyl, (C1-C 16 )alkylamino-(C1-C 16 )alkylamino-(C1-C5)alkylamino, (C1-C 16 Aminoalkyl, arylamino-(C1-C5)alkyl, (C1-C5)aminoalkoxy, (C1-C5)aminoalkyl 16 Aminoalkoxy-(C1-C5)alkyl, (C1-C5)aminoalkylcarboxyl, (C1-C5)aminoalkoxycarbonyl, (C1-C5)aminoalkylaminocarbonyl, (C1-C5)aminoalkylcarboxamide, di(C1-C5)alkylamino-(C1-C5)alkyl, (C1-C5)guanidinylalkoxy, quaternary ammonium (C1-C5) 16 )alkyl carboxyl group, and (C1-C 16 The group consisting of guanidinoalkylcarboxyl groups.

[0179] In some implementations, R3, R7, and R 12 They are the same aminoalkyl carboxyl groups.

[0180] In some implementations, R3, R7, and R 12 They are the same aminoalkylformamide group.

[0181] In some implementations, R3, R7, and R 12 One or both of them are aminoalkoxy groups.

[0182] In some implementations, R3, R7, and R 12 One or both of them are aminoalkylcarboxyl groups.

[0183] Non-limiting examples of endogenous CSA compounds that form endogenous degradation products through ester hydrolysis are CSA-148 and its salts:

[0184]

[0185] In other implementation schemes, R 18 The geranyl group at the C24 position can be replaced by any other terpene group, such as those based on the example terpenes described herein.

[0186] In other implementations, R3, R7, and R 12 The amino acid ester group can be replaced by any other amino acid ester group, such as those based on the example amino acids described herein.

[0187] Pharmaceutical Composition

[0188] While the CSA compounds described herein can be administered alone, it is preferred to formulate the compounds into pharmaceutical compositions (i.e., formulations). A pharmaceutical composition is any composition that can be administered to a subject in vitro or in vivo, or in both ways, to treat or improve a condition. In a preferred embodiment, the pharmaceutical composition can be administered in vivo. The subject may include one or more cells or tissues, or an organism. In an exemplary embodiment, 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 any mammal, such as, but not limited to, cattle, pigs, sheep, goats, horses, camels, buffalo, cats, dogs, rats, mice, and humans.

[0189] "Pharmaceutically acceptable" and "physiologically acceptable" refer to biocompatible formulations, gases, liquids, or solids, or mixtures thereof, suitable for one or more routes of administration, in vivo delivery, or contact. The compatibility of a formulation is due to its non-degradation of the activity of the active ingredient therein (e.g., a CSA compound) or its non-induction of adverse side effects far outweighing any preventative or therapeutic effect or benefit.

[0190] The pharmaceutical composition may be formulated with pharmaceutically acceptable excipients (e.g., carriers, solvents, stabilizers, adjuvants, diluents, etc.), depending on the specific route of administration and dosage form. The pharmaceutical composition may be formulated to achieve physiological compatibility at a pH in the range of about 3 to 11, preferably about 3 to 7, depending on the formulation and route of administration. In an alternative embodiment, the pH is adjusted to about 5 to 8. The pharmaceutical composition may comprise a therapeutically or preventively effective amount of at least one of the compounds described herein, and one or more pharmaceutically acceptable excipients.

[0191] The pharmaceutical composition may comprise a combination of the compounds described herein and / or may comprise a second active ingredient (e.g., an antibacterial agent or antimicrobial agent) for the treatment or prevention of bacterial infections.

[0192] This composition can be formulated into a coating, such as a coating on a medical device. In an embodiment, the coating is located on a medical device.

[0193] Preparations intended for parenteral or oral administration may be solids, liquid solutions, emulsions, or suspensions. Inhalable preparations intended for pulmonary administration may be liquids or powders. Pharmaceutical compositions may be formulated as lyophilized solids, which are reconstituted with physiologically compatible solvents prior to administration. Optional pharmaceutical compositions may be formulated as syrups, creams, ointments, tablets, etc.

[0194] The composition may contain one or more excipients. Pharmaceutically acceptable excipients depend in part on the specific composition being administered and the specific method of administration. A wide variety of suitable formulations of pharmaceutical compositions exist (see, for example, Remington's Pharmaceutical Sciences).

[0195] Suitable excipients can be carrier molecules comprising large, slowly metabolizing macromolecules, such as proteins, polysaccharides, polylactic acid, polyglycolic acid, polymeric amino acids, amino acid copolymers, and inactive viral particles. Other exemplary excipients include antioxidants (such as ascorbic acid), chelating agents (such as EDTA), carbohydrates (such as dextrin, hydroxyalkyl cellulose, hydroxyalkyl methyl cellulose, stearic acid), liquids (such as oils, water, saline, glycerol, and ethanol), wetting agents or emulsifiers, pH buffers, and so on. Liposomes are pharmaceutically acceptable excipients.

[0196] Pharmaceutical compositions can be formulated in any form suitable for the intended method of administration. When intended for oral administration, they can be prepared, for example, into tablets, lozenges, throat lozenges, aqueous or oil suspensions, non-aqueous solutions, dispersible powders or granules (including microparticles or nanoparticles), emulsions, hard or soft capsules, syrups, or elixirs. Compositions for oral administration can be prepared according to any method of manufacturing pharmaceutical compositions known in the art, and such compositions may contain one or more adjuvants, including sweeteners, flavoring agents, coloring agents, and preservatives, to provide a palatable formulation.

[0197] Pharmaceutically acceptable excipients particularly suitable for use in combination with tablets include, for example, inert diluents such as cellulose, calcium carbonate or sodium carbonate, lactose, calcium phosphate or sodium phosphate; disintegrants such as crospovidone, corn starch or alginate; binders such as povidone, starch, gelatin or gum arabic; and lubricants such as magnesium stearate, stearic acid or talc.

[0198] Tablets may be uncoated or coated using known techniques, including microencapsulation, to delay disintegration and absorption in the gastrointestinal tract, thereby providing a longer duration of action. For example, delaying materials, such as glyceryl monostearate or glyceryl distearate, may be used alone or in combination with waxes.

[0199] Oral formulations may also exist in the form of hard gelatin capsules, in which the active ingredient is mixed with an inert solid diluent (such as cellulose, lactose, calcium phosphate or kaolin), or in the form of 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).

[0200] Pharmaceutical compositions can be formulated into suspensions comprising a CSA compound mixed with at least one pharmaceutically acceptable excipient suitable for preparing a suspension.

[0201] By adding appropriate excipients, pharmaceutical compositions can be formulated into dispersible powders and granules suitable for preparing suspensions.

[0202] Excipients suitable for suspensions include suspending agents such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinylpyrrolidone, gum arabic, gum arabic, dispersants or wetting agents such as natural phospholipids (e.g., lecithin), condensation products of ethylene oxide and fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxide and long-chain fatty alcohols (e.g., heptadecanoyl alcohol), condensation products of ethylene oxide and esters derived from fatty acids and hexyl 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 thickeners (e.g., carbomer, beeswax, hard paraffin, or cetyl alcohol). Suspensions may also contain one or more preservatives (e.g., acetic acid, methyl and / or n-propylparaben), one or more colorants, one or more flavoring agents, and one or more sweeteners (e.g., sucrose or saccharin).

[0203] Pharmaceutical compositions may be in the form of oil-in-water emulsions. The oil phase may be vegetable oils (such as olive oil or peanut oil), mineral oils (such as liquid paraffin), or mixtures thereof. Suitable emulsifiers include naturally occurring gums (such as gum arabic and tragacanth), naturally occurring phospholipids (such as soybean lecithin), esters or metaesters derived from fatty acids, hexitanic anhydrides (such as sorbitan monooleate), and condensation products of these metaesters with ethylene oxide (such as polyoxyethylene sorbitan monooleate). Emulsions may also contain sweeteners and flavoring agents. Syrups and elixirs may be formulated with sweeteners such as glycerin, sorbitol, or sucrose. Such formulations may also contain modifiers, preservatives, flavoring agents, or coloring agents.

[0204] The pharmaceutical composition may be in the form of a sterile injectable formulation, such as a sterile injectable aqueous emulsion or oil suspension. Emulsions or suspensions may be formulated using suitable dispersants or wetting agents and suspending agents already mentioned above, according to known techniques. Sterile injectable formulations may also be sterile injectable solutions or suspensions in non-toxic, parenteral-acceptable diluents or solvents, such as solutions in 1,2-propanediol.

[0205] Sterile injectable formulations can also be formulated as lyophilized powders. Acceptable carriers and solvents that can be used are water, Ringer's solution, and isotonic sodium chloride solution. Furthermore, sterile non-volatile oils can be used as solvents or suspension media. For this purpose, any mild non-volatile oil can be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid can also be used in the preparation of injectable formulations.

[0206] To obtain a stable, water-soluble dosage form of the pharmaceutical composition, a pharmaceutically acceptable salt of the compound described herein may be dissolved in an aqueous solution of an organic or inorganic acid, such as a 0.3 M succinic acid solution, or more preferably a citric acid solution. 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 ethanol, propylene glycol, polyethylene glycol 300, polysorbate 80, glycerol, etc., at concentrations ranging from about 0-60% of the total volume. In one embodiment, the active compound is dissolved in DMSO and diluted with water.

[0207] Pharmaceutical compositions may also be in the form of a salt solution of the active ingredient in a suitable aqueous carrier (such as water or isotonic saline or glucose solution). Compounds that have been modified by substitution or addition of chemical or biochemical components, making them more suitable for delivery (e.g., increasing solubility, bioactivity, palatability, reducing adverse reactions, etc.), for example, through esterification, glycosylation, polyethylene glycolation, and complexation.

[0208] Many therapeutic agents have undesirable short half-lives and / or undesirable toxicities. Therefore, the concept of improving half-life or toxicity is applicable to a wide range of therapies and fields. However, pharmaceutical compositions can be prepared by conjugating the therapeutic agent with a biochemical moiety to improve this undesirable property. Proteins are a special type of biochemical moiety that can be conjugated with CSAs for administration in a variety of applications. In some embodiments, one or more CSAs are conjugated with a protein. In some embodiments, one or more CSAs are conjugated with a protein to increase the half-life of the CSA. In other embodiments, one or more CSAs are conjugated with a protein to reduce the toxicity of the CSA. Albumin is a particularly preferred protein for conjugation with CSAs. In some embodiments, the albumin is fat-free albumin.

[0209] For CSA therapeutic agents, the biochemical component used for chelation may be added to the pharmaceutical composition in weight equivalents of 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 10, 20, 50, or 100, or within a range bounded by any two of the above figures or approximately any of these figures. In an embodiment, the weight ratio of albumin to CSA is about 18:1 or less, for example, about 9:1 or less. In an embodiment, the CSA is coated with albumin.

[0210] Non-biochemical compounds may be added to the pharmaceutical composition to reduce the toxicity of the therapeutic agent and / or increase its half-life. The appropriate amount and proportion of the toxicity-reducing additive can be determined by cell analysis. For CSA therapeutic agents, the toxicity-reducing compound may be added to the pharmaceutical composition in amounts of 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 defined by any two of the above figures or approximately any of the figures. In an embodiment, the toxicity-reducing compound is cocoamphoacetate, for example... (Disodium cocoamphodiacetate). In an embodiment, the toxicity-reducing compound is an amphoteric surfactant. In an embodiment, the toxicity-reducing compound is a surfactant. In an embodiment, the molar ratio of cocoamphodiacetate to CSA is about 8:1 to 1:1, preferably about 4:1. In an embodiment, the toxicity-reducing compound is allantoin.

[0211] In some embodiments, CSA compositions are prepared using one or more surfactants. In a specific embodiment, the CSA is compounded with one or more poloxamer surfactants. Poloxamer surfactants are nonionic triblock copolymers consisting of a central hydrophobic chain of poly(propylene oxide) and two hydrophilic chains of polyethylene oxide. In some embodiments, the poloxamer is a liquid, paste, or sheet (solid). Suitable examples of poloxamers include those traded under the names Synperonics, Pluronics, or Kolliphor. In some embodiments, one or more poloxamer surfactants in the composition are sheet-like poloxamers. In some embodiments, the one or more poloxamer surfactants in the composition have a central hydrophobic chain of polypropylene with a molecular weight of about 3600 g / mol and a polyoxyethylene content of about 70%. In the embodiments, the ratio of one or more poloxamers to CSA is between approximately 50 and 1, approximately 40 and 1, approximately 30 and 1, approximately 20 and 1, approximately 10 and 1, approximately 5 and 1, approximately 1 and 1, approximately 1 and 10, approximately 1 and 20, approximately 1 and 30, approximately 1 and 40, or approximately 1 and 50. In the embodiments, the ratio of one or more poloxamers to CSA is between 50 and 1, 40 and 1, 30 and 1, 20 and 1, 10 and 1, 5 and 1, 1 and 1, 1 and 10, 1 and 20, 1 and 30, 1 and 40, or 1 and 50. In the embodiments, the ratio of one or more poloxamers to CSA is between approximately 50 and 1 and approximately 1 and 50. In the embodiments, the ratio of one or more poloxamers to CSA is between approximately 30 and 1 and approximately 3 and 1. In some implementations, poloxamer is Pluronic F127.

[0212] The amount of poloxamer can be based on a weight percentage of the composition. In embodiments, the amount of poloxamer is about 10%, 15%, 20%, 25%, 30%, 35%, 40%, approximately any of the above values, or a range defined by any two of the above values ​​or the formulation. In embodiments, one or more poloxamers constitute about 10% to about 40% by weight of the formulation administered to the patient. In some embodiments, one or more poloxamers constitute about 20% to 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 the preparation of treatment methods, device coatings, unit dosage forms (i.e., solutions, mouthwashes, injections), etc.

[0213] In the embodiments, the compounds described herein can be formulated into lipid-based formulations suitable for oral administration of compounds with low solubility. Lipid-based formulations generally improve the oral bioavailability of such compounds.

[0214] The pharmaceutical composition may contain a therapeutically or preventively effective amount of the compound described herein, and 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 acid and capric acid) and pharmaceutically acceptable surfactants (such as polyoxyethylene 40 hydrogenated castor oil).

[0215] In this embodiment, cyclodextrin may be added as a water-soluble enhancer. Preferred cyclodextrins include hydroxypropyl, hydroxyethyl, glucosyl, maltose-based, and maltotriose-based derivatives of α-, β-, and γ-cyclodextrins. A particularly preferred cyclodextrin solubilizer is hydroxypropyl-o-cyclodextrin (BPBC), which may be added to any of the above compositions to further improve the water-soluble properties of the compounds 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% hydroxypropyl-o-cyclodextrin, and even more preferably about 2.5% to about 10% hydroxypropyl-o-cyclodextrin. The amount of solubilizer used will depend on the amount of the compounds of the embodiments in the composition.

[0216] synthesis

[0217] The methods disclosed herein may be as described below, or modifications thereof. Modifications include, in particular, temperature, solvents, reagents, etc., known to those skilled in the art. Typically, in any of the preparations disclosed herein, it may be necessary and / or desirable to protect any sensitive or reactive groups on the relevant molecules. This can be achieved with conventional protecting groups, such as those described in *Protective Groups in Organic Chemistry* (ed. J.F.W. McOmie, Plenum Press, 1973) and *Protecting Groups in Organic Synthesis* (3rd ed.), Wiley, New York (1999), both of which are incorporated herein by reference in their entirety. Protecting groups may be removed at a convenient subsequent stage using methods known in the art. Synthetic chemical transformations useful for synthesizing applicable compounds are known in the art and include, for example, those described in R. Larock, *Comprehensive Organic Transformations*, VCH Publishers, 1989, or L. Paquette, ed., *Encyclopedia of Reagents for Organic Synthesis*, John Wiley and Sons, 1995, both of which are incorporated herein by reference in their entirety. The routes shown and described herein are illustrative only and are not intended, nor should they be construed, as limiting the scope of the claims in any way. Those skilled in the art will be able to recognize modifications to the disclosed synthesis methods and to design alternative routes based on the disclosure herein; all such modifications and alternative routes are within the scope of the claims.

[0218] Exemplary but non-limiting general synthetic schemes for the preparation of compounds of formulas I, II and III are shown in Scheme A. Unless otherwise stated, variables are defined as above for formulas I, II and / or III.

[0219] Option A

[0220]

[0221] Cholic acid (1) is treated with a terpenoid halide (e.g., geranylacetyl bromide) in a polar aprotic solvent (e.g., tetrahydrofuran) in the presence of a base (e.g., potassium carbonate) to produce a terpenoid cholate intermediate compound (2), such as geranylacetylcholate. The ester may optionally be modified, reduced, or protected before or after any further step to achieve the desired effect in R... 18 The required terpene group bond is generated at the location.

[0222] In dimethylaminopyridine (DMAP) and methyl tert-butyl ether (MTBE), carbodiimide coupling is performed by using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) or alternatively, N,N′-dicyclohexylcarbodiimide (DCC), and the intermediate terpenoid (e.g., geranyl) cholate (2) or its analogue is treated with an N-protected amino acid, for example, protected with tert-butoxycarbonyl (Boc), fluorenyl-methoxycarbonyl (Fmoc) or benzyl chloroformate (Cbz) (e.g., Boc-β-alanine).

[0223] The intermediate compound (3) or its analogues are deprotected and acidified in dioxane with hydrochloric acid to form an acid addition salt of the CSA compound (e.g., CSA-148HCl).

[0224] In some implementations, some or all of the aforementioned steps can be carried out in a one-pot reaction without the need to purify the intermediate compound.

[0225] In some embodiments, intermediate compound (2) is purified before being used to manufacture intermediate compound (3), and intermediate compound (3) is purified and then treated with hydrochloric acid in dioxane to deprotect the amine and form a hydrochloric acid addition salt.

[0226] CSA salts formed by the acid addition of HCl can be purified, optionally neutralized with a base, and then separated (e.g., by two-phase liquid extraction followed by evaporation of the organic solvent) to obtain purified free base. The free base can be used as is or acidified with any desired acid to form an acid addition salt.

[0227] An exemplary acid addition salt is 1,5-naphthalenedisulfonate (1,5-NDSA salt, such as a diaddition salt), which is highly insoluble and therefore can be used as a coating, such as for implantable medical devices. In some cases, the NDSA salt is ground into submicron-sized particles and incorporated into the coating in particulate form. NDSA salts are insoluble in ethylene oxide, which is commonly used to sterilize medical devices, thus remaining a stable coating even after multiple sterilization cycles.

[0228] Making CSA compounds ionic, for example by exchanging the NDSA moiety with other anions, such as chloride ions from hydrochloric acid, sodium chloride, etc., leads to accelerated first-order release kinetics under acidic conditions.

[0229] One advantage of the disclosed CSA compounds is that they can be degraded into endogenous compounds such as bile acids, amino acids, and terpenes.

[0230] Example

[0231] The antibacterial activity of CSA-148 was determined in comparison with CSA-44, a known CSA compound with high antibacterial activity compared to other CSAs. The microorganisms used for the comparative tests were Candida albicans 90028, methicillin-resistant Staphylococcus aureus (MRSA) BAA-41, and Pseudomonas aeruginosa (PA0147085). The measured minimum inhibitory concentrations (MICs) are listed in Table 1.

[0232] Table 1

[0233]

[0234]

[0235] The MIC measured for Candida albicans 90028 was based on 100% growth inhibition (i.e., no cloudiness). Judging from a 50% inhibition rate is more difficult but typical for fungal MICs; the MIC of CSA-44 relative to Candida albicans can be extrapolated to 4 μg / ml, while the MIC of CSA-148 relative to Candida albicans can be extrapolated to 2 μg / ml.

[0236] Surprisingly, CSA compounds within the scope of this invention can perform the same or better in killing microorganisms as known and used CSAs for many years, even though the known CSAs contain side groups with endogenous compounds.

[0237] The invention may be embodied in other specific forms without departing from its spirit or essential characteristics. The described embodiments should be considered in all respects as illustrative only, and not restrictive. Therefore, the scope of the invention is defined by the appended claims rather than by the foregoing description. All variations falling within the meaning and scope of the claims should be included within their scope.

Claims

1. A cationic steroidal antimicrobial compound having the structure of Formula III, or a salt thereof: (III) in, R3, R7 and R 12 The amino acid is independently selected from hydrogen, hydroxyl, amino acid attached to the sterol backbone via ester or amide bond, or aminoalkyl group attached to the sterol backbone via ether bond, provided that R3, R7, and R 12 One or more of these include an amino acid linked to the sterol backbone via an ester or amide bond, or an aminoalkyl group linked to the sterol backbone via an ether bond; and R 18 It has a structure selected from the following: -R 19 -(C=O)-O-R 20 、 -R 19 -O-(C=O)-R 20 、 -R 19 -(C=O)-NX-R 20 、 -R 19 -OR 20 or -R 19 -NX-R 20 , Where R 19 The R group is omitted or selected from alkyl, alkenyl, ynyl, or aryl. 20 X is a terpenoid group, and X is selected from hydrogen, alkyl, alkenyl, alkynyl, or aryl, wherein the terpenoid group is formed from terpenes selected from the following: (geraniol) (Neroliol) (hydroxygeraniol), (Acacia alcohol) (geranyl geraniol) (Fragrant Leaf Foundation Albizia Extract) (Isoprenol) (Agaric alcohol) (trans-nerolidol), (cis-nerolidol) or (Coffee bean alcohol).

2. The CSA compound according to claim 1, wherein R3, R7, and R 12 At least one of them has a structure selected from the following: R 22 R 23 N-R 21 -(C=O)-O-、 R 22 R 23 NR 21 -(C=O)-N- or R 22 R 23 N-R 21 -O-, Where R 21 It is a substituted or unsubstituted alkyl group, and R 22 and R 23 Each is independently selected from hydrogen, alkyl, alkenyl, alkynyl or aryl.

3. The CSA compound according to claim 1 or 2, wherein R3, R7, and R 12 Two or three of the amino acids in the sterol backbone are linked to the sterol backbone via ester or amide bonds.

4. The CSA compound according to claim 1 or 2, wherein R 18 It has a structure selected from the following: -R 19 -(C=O)-O-R 20 、 -R 19 -O-(C=O)-R 20 or -R 19 -(C=O)-NX-R 20 , Where R 19 The R group is omitted or selected from alkyl, alkenyl, ynyl, or aryl. 20 It is C5-C 25 Terpenoid, and X is selected from hydrogen, alkyl, alkenyl, alkynyl or aryl.

5. The CSA compound according to claim 1 or 2, wherein R3, R7 and R 12 It has a structure selected from the following: R 22 R 23 NR 21 -(C=O)-O- or R 22 R 23 N-R 21 -(C=O)-N-, Where R 21 R 22 and R 23 It is the aminoalkyl moiety of one or more naturally occurring amino acids.

6. The CSA compound according to claim 1 or 2, wherein the amino acid is selected from: D-alanine, L-alanine, L-asparagine, D-aspartic acid, L-aspartic acid, L-cysteine, L-glutamic acid, L-glutamine, glycine, L-proline, D-serine, L-serine, L-tyrosine, L-arginine, L-histidine, L-isoleucine, L-leucine, L-lysine, D-methionine, L-methionine, L-phenylalanine, L-threonine, L-tryptophan, D-valine, L-valine, L-ornithine, high-lysine, 2-aminoisobutyric acid, dehydroalanine, γ-aminobutyric acid, L-citrulline, α-ethylglycine, α-propylglycine, and L-leucine.

7. The CSA compound according to claim 1 or 2, wherein the terpene group is a geraniol group.

8. The CSA compound according to claim 1 or 2, wherein the amino acid is β-alanine.

9. The CSA compound according to claim 1 or 2, wherein R3, R7 and R 12 They are the same aminoalkyl carboxyl groups.

10. The CSA compound according to claim 1 or 2, wherein the CSA compound is selected from CSA-148 and its salts: (CSA-148)。 11. A pharmaceutical composition comprising a CSA compound according to any one of claims 1 to 10 and a pharmaceutically acceptable excipient selected from carriers.

12. A pharmaceutical composition comprising a CSA compound according to any one of claims 1 to 10 and a pharmaceutically acceptable excipient selected from solvents, stabilizers, adjuvants and diluents.

13. A method for manufacturing a CSA compound according to any one of claims 1 to 10, comprising: In polar aprotic solvents, in the presence of a base, cholic acid is treated with terpenoid compounds to form terpenoid cholate esters or terpenoid cholate amide intermediates, which have a terpenoid group linked to a C24 carbonyl group via an ester or amide bond. Treating terpenoid cholate or terpenoid cholate amide intermediates with N-protected amino acids yields a second intermediate compound having a protected aminoalkyl carboxyl group or a protected aminoalkyl formamide group at the C3, C7, and C12 positions of the terpenoid cholate or terpenoid cholate amide. Optionally reduce the C24 carbonyl group to produce for R 18 The ether or amine bond of the terpene group; and The aminoalkylcarboxyl group or aminoalkylformamide group is deprotected to obtain the CSA compound.

14. The method of claim 13, wherein deprotecting the aminoalkylcarboxyl group or aminoalkylformamide comprises treating with an acid to form an acid addition salt of the CSA compound.

15. The method of claim 14, wherein the acid is hydrochloric acid.

16. The method according to claim 14 or 15, further comprising neutralizing the acid addition salt of the CSA compound with a base and recovering the free base of the CSA compound.

17. The method of claim 16, further comprising acidifying the free base of the CSA compound with an acid to form a second acid addition salt of the CSA compound.

18. The method of claim 17, wherein the second acid addition salt of the CSA compound is a 1,5-naphthalenedisulfonic acid diaddition salt.

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