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KR-20260065920-A - Bioreabsorbable cationic steroid antimicrobial compounds having glyceride bonds

KR20260065920AKR 20260065920 AKR20260065920 AKR 20260065920AKR-20260065920-A

Abstract

The following chemical formulas I, II, or III: In the above chemical formula, at least one of R1 - R18 (e.g., R18 ) comprises a mono- or diglyceride of a fatty acid attached via an ester bond, and at least one of R1 - R18 (e.g., R3 , R7 , and R12 ) is an amino acid connected to a steroid backbone via an ester or amide bond, wherein The above R 18 has the following structure: -R 19 -(C=O)-OC-CR 20 -CR 21 having, wherein R 19 is omitted or selected from alkyl, alkenyl, alkynyl, and aryl, and R 20 and R 21 are independently selected from hydroxy, alkylcarboxyl and aminoalkylcarboxyl, provided that at least one of R 20 or R 21 is alkylcarboxyl, R3 , R7 , and R12 have the following structure: R 24 R 23 NR 22 -(C=O)-X- having, wherein R 22 is a substituted or unsubstituted alkyl, X is oxygen or nitrogen, and R 23 and R 24 are independently hydrogen, alkyl, alkenyl, alkynyl, or aryl; A bioreabsorbable cationic steroidal antimicrobial (CSA) compound having the structure of, or a salt thereof.

Inventors

  • 새비지, 폴 비.

Assignees

  • 브라이엄 영 유니버시티

Dates

Publication Date
20260511
Application Date
20240904
Priority Date
20240903

Claims (20)

  1. As a bioresorbable cationic steroidal antimicrobial (CSA) compound, or a salt thereof, Chemical formula I or II below: In the above chemical formula, m, n, p, and q are independently 0 or 1; 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; R1 to R18 are independently hydrogen, hydroxyl, alkyl, hydroxyalkyl, alkyloxyalkyl, alkylcarboxyalkyl, terphenylcarboxyalkyl, terphenylcarbonyloxyalkyl, terphenylamidoalkyl, terphenylaminoalkyl, terphenyloxyalkyloxyalkyl, alkylaminoalkyl, alkylamino-alkylamino, alkylaminoalkylaminoalkylamino, aminoalkyl, aryl, arylaminoalkyl, haloalkyl, alkenyl, alkynyl, oxo, a linking group attached to a second steroid, aminoalkyluretanyl, aminoalkenyluretanyl, aminoalkynyluretanyl, aminoaryluretanyl, aminoalkyloxy, aminoalkylcarboxy, aminoalkyloxyalkyl, aminoalkylaminocarbonyl, aminoalkylcarboxymido, di(alkyl)aminoalkyl, H₂N -HC( Q₅ )-(C=O)-O-, H₂N -HC(Q₅ ) Selected from the group consisting of )- (C=O)-NH-, azidoalkyloxy, cyanoalkyloxy, PG-HN-HC(Q 5 )-(C=O)-O-, guanidinoalkyloxy, quaternary ammonium alkylcarboxy, and guanidinoalkylcarboxy, wherein Q 5 is a side chain of any amino acid (a side chain of glycine, i.e., containing H), and PG is an amino protecting group; R5 , R8 , R9 , R10 , R13 , R14 , and R17 are independently removed to complete the valence of the carbon atom at that site when any of rings A, B, C, or D are unsaturated, but, However, at least one of R1 to R4 , R6 , R7 , R11 , R12 , R15 , R16 , and R18 , preferably R18 comprises a glyceride of a fatty acid attached to a sterol skeleton by an ester linkage or an amide linkage, and However, at least one of R1 to R4 , R6 , R7 , R11 , R12 , R15 , R16 , and R18 , preferably one, two, or three of R3 , R7 , and R12, comprises an amino acid attached to a sterol backbone by an ester bond, an amide bond, or an ether bond. A bioreabsorbable CSA compound having the structure of
  2. In Article 1, The above CSA compound is the following chemical formula III: (III), In the above chemical formula, R 15 is omitted, A bioreabsorbable CSA compound having the structure of
  3. In Article 1 or Article 2, At least one of the above R1 - R18 , preferably R18 , has the following structure: -R 19 -(C=O)-OC-CR 20 -CR 21 In the above formula, R19 is omitted or selected from alkyl, alkenyl, alkynyl, and aryl, and R20 and R21 are independently selected from hydroxy and ( C2 - C22 )alkylcarboxyl, provided that at least one of R20 or R21 is ( C2 - C22 )alkylcarboxyl. A bioreabsorbable CSA compound having
  4. In Article 1 or Article 2, The above R 18 has the following structure: -R 19 -(C=O)-OC-CR 20 -CR 21 In the above chemical formula, R19 is omitted or selected from alkyl, alkenyl, alkynyl, and aryl, R20 is a ( C2 - C22 )alkylcarboxyl and R21 is the following aminoalkylcarboxyl structure: R 24 R 23 NR 22 -(C=O)-O- having, wherein R 22 is a substituted or unsubstituted alkyl and R 23 and R 24 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, and aryl, A bioreabsorbable CSA compound having
  5. In any one of paragraphs 1 to 4, At least one of the above R1 - R18 , preferably one, two, or three of R3 , R7 , and R12, is R 24 R 23 NR 22 -(C=O)-O-, R 24 R 23 NR 22 -(C=O)-N-, and R 24 R 23 NR 22 -O- In the above chemical formula, R 22 is a substituted or unsubstituted alkyl, and R 23 and R 24 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, and aryl, Bioreabsorbable CSA compound having a structure selected from.
  6. In any one of paragraphs 1 to 5, The above R1 to R18 are independently hydrogen, hydroxyl, substituted or unsubstituted ( C1 - C22 )alkyl, substituted or unsubstituted ( C1 - C22 )hydroxyalkyl, substituted or unsubstituted ( C1 - C22 )alkyloxy-( C1 - C22 )alkyl, substituted or unsubstituted ( C1 - C22 )alkylcarboxy-( C1 - C22 )alkyl, substituted or unsubstituted ( C5 - C25 )terphenylcarboxy-( C1 - C22 )alkyl, substituted or unsubstituted ( C5 - C25 )terphenylcarbonyloxy-( C1 - C22)alkyl, substituted or unsubstituted (C5-C25 ) terphenylcarboxymido- ( C1 - C22 )alkyl, substituted or unsubstituted ( C5 - C25 )terphenylamino-( C1 - C22 )alkyl, (C5-C25)terphenyloxyo-( C1 - C22 )alkyl, substituted or unsubstituted ( C1 - C22 )alkylamino-( C1 - C22 )alkyl, substituted or unsubstituted ( C1 - C22 )alkylamino-( C1 - C22 )alkylamino, substituted or unsubstituted ( C1 -C22)alkylamino-(C1 - C22 ) alkylamino, substituted or unsubstituted ( C1 - C22 )aminoalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylamino-( C1 - C22 )alkyl, substituted or unsubstituted ( C1 - C22 )haloalkyl, Substituted or unsubstituted ( C2 - C6 )alkenyl, substituted or unsubstituted ( C2 - C6 )alkynyl, oxo, linker attached to a second steroid, substituted or unsubstituted ( C1 - C22 )aminoalkynyluretanyl, substituted or unsubstituted ( C2 - C22 )aminoalkenyluretanyl, substituted or unsubstituted ( C2 - C22 )aminoalkynyluretanyl, substituted or unsubstituted aminoaryluretanyl, substituted or unsubstituted ( C1 - C22 )aminoalkyloxy, substituted or unsubstituted ( C1 - C22 )aminoalkylcarboxy, substituted or unsubstituted ( C1 - C22 )aminoalkyloxy-( C1 - C22 )alkyl, substituted or unsubstituted ( C1 - C22 )aminoalkyl-aminocarbonyl, substituted or unsubstituted ( C1 - C22 )aminoalkylcarboxymid, substituted or unsubstituted di( C1 - C22 )alkylamino-( C1 - C22 )alkyl, H2N -HC( Q5 )-(C=O)-O-, H2N -HC( Q5 )-(C=O)-NH-, substituted or unsubstituted ( C1 - C22 )azidoalkyloxy, substituted or unsubstituted ( C1 - C22 )cyanoalkyloxy, PG-HN-HC( Q5 )-(C=O)-O-, substituted or unsubstituted ( C1 - C22 )guanidinoalkyloxy, substituted or unsubstituted quaternary ammonium ( C1 -C22)alkylcarboxy, and substituted or unsubstituted ( C1 - C 22 ) Selected from the group consisting of guanidinoalkylcarboxyl, wherein Q5 is a side chain of an amino acid (a side chain of glycine, i.e., containing H), and PG is an amino protecting group; R5 , R8 , R9 , R10 , R13 , R14 , and R17 are independently removed to complete the valence of the carbon atom at that site when any of rings A, B, C, or D are unsaturated, but, However, at least one of R1 to R4 , R6 , R7 , R11 , R12 , R15 , R16 , and R18 , preferably R18 comprises a glyceride of a ( C2 - C22 ) fatty acid attached to a sterol backbone by an ester bond, wherein However, at least one of R1 to R4 , R6 , R7 , R11 , R12 , R15 , R16 , and R18 , preferably one, two, or three of R3 , R7 , and R12, comprises an amino acid attached to a sterol backbone by an ester bond or an amide bond. Bioreabsorbable CSA compound.
  7. In any one of paragraphs 1 to 6, The above R 18 is a bioreabsorbable CSA compound comprising a mono- or diglyceride of a (C 2 -C 22 ) fatty acid attached to a sterol backbone at the C24 position by an ester bond.
  8. In any one of paragraphs 1 through 7, A bioreabsorbable CSA compound in which two or three of the above R3 , R7 , and R12 are amino acids attached to a sterol backbone by ester bonds.
  9. In any one of paragraphs 1 through 8, The above fatty acid is a bioreabsorbable CSA compound selected from the group consisting of butyric acid, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, and combinations thereof.
  10. In any one of paragraphs 1 through 9, The above amino acids are selected from the group consisting of D-alanine, L-alanine, beta-alanine, L-asparagine, D-aspartic acid, L-aspartic acid, L-cysteine, L-glutamine, glycine, L-proline, D-serine, L-serine, L-tyrosine, L-histidine, L-isoleucine, L-leucine, L-lysine, D-methionine, L-methionine, L-phenylalanine, L-threonine, L-tryptophan, D-valine, L-valine, L-ornithine, L-arginine, hypsine, 2-aminoisobutyric acid, dehydroalanine, γ-aminobutyric acid, L-citrulline, α-ethyl-glycine, α-propyl-glycine, and L-norleucine, biocompatible Reabsorbable CSA compound.
  11. In any one of Articles 1 to 10, The above amino acid is a bioreabsorbable CSA compound containing beta-alanine.
  12. In any one of paragraphs 1 to 11, The above R1 , R2 , R4 , R5 , R6 , R8 , R9 , R10 , R11 , R13 , R14 , R15 , R16 , and R17 are bioreabsorbable CSA compounds independently selected from the group consisting of hydrogen and unsubstituted ( C1 - C6 )alkyl groups.
  13. In any one of paragraphs 1 to 12, The above R3 , R7 , and R12 are bioreabsorbable CSA compounds containing the same amino acid ester group.
  14. In any one of paragraphs 1 to 13, The above R 18 is a bioreabsorbable CSA compound comprising a mixed diglyceride containing an alkyl carboxyl group and an amino alkyl carboxyl group.
  15. In any one of paragraphs 1 through 14, The above CSA compound is: (CSA-4108), (CSA-4110), (CSA-4110R), (CSA-4110S), (CSA-4112), (CSA-4114), (CSA-4204), (CSA-4206), (CSA-4208), (CSA-4210), (CSA-4310), A bioabsorbable CSA compound selected from the group consisting of and their salts.
  16. As a pharmaceutical composition, A pharmaceutical composition comprising a bioreabsorbable CSA compound of any one of claims 1 to 15 and a pharmaceutically acceptable excipient selected from a carrier, solvent, stabilizer, adjuvant, and diluent.
  17. A method for producing a bioreabsorbable CSA compound according to any one of claims 1 to 16, A step of reacting cholic acid with a protecting agent in a polar aprotic solvent in the presence of a base to form protected cholic acid having a protected carboxyl group at the C24 position; A step of reacting the above-mentioned protected cholic acid with an N-protected amino acid to form a first intermediate compound having an N-protected aminoalkylcarboxylic ester group at one or more of the C3, C7, and C12 positions of a sterol backbone and a protected carboxyl group at the C24 position; A step of deprotecting the carboxyl group of the first intermediate compound at the C24 position to form a second intermediate compound having an unprotected carboxyl group at the C24 position; A step of reacting the second intermediate compound with (i) a monoglyceride of a fatty acid, (ii) a diglyceride of a fatty acid, or (iii) a mixed diglyceride of a fatty acid and an N-protected amino acid to form a third intermediate compound having a glyceride ester at the C24 position; and A step of obtaining a bioreabsorbable CSA compound or an intermediate thereof by deprotecting the above N-protected aminoalkylcarboxy ester group(s); A method including
  18. In Article 17, A method comprising the step of deprotecting the above N-protected aminoalkylcarboxyl group(s) by treating with an acid (e.g., hydrochloric acid) to form an acid addition salt of a bioreabsorbable CSA compound or its intermediate.
  19. In Article 18, A method further comprising the step of neutralizing the acid addition salt of the bioreabsorbable CSA compound or its intermediate with a base, and recovering the free base of the bioreabsorbable CSA compound or its intermediate.
  20. In Article 19, A method further comprising the step of acidifying the free base of the bioreabsorbable CSA compound or its intermediate with an acid to form a second acid addition salt of the bioreabsorbable CSA compound or its intermediate (e.g., 1,5-naphthalenedisulfonic acid di-addition salt).

Description

Bioreabsorbable cationic steroid antimicrobial compounds having glyceride bonds A cationic steroidal antimicrobial (CSA) compound, more particularly a bioresorbable CSA compound having a glyceride linkage, more particularly mono- and diglycerides of a CSA compound and a fatty acid, and a method for preparing a bioresorbable glyceride of a CSA compound are disclosed. Hospital-acquired infections (HAIs) are a subset of infections that cause over 98,000 deaths annually worldwide. Seventy percent of all HAIs are associated with inhabiting medical devices and are collectively reported as Device-associated Infections (DRIs). The costs associated with treating DRIs are substantial, and reducing DRIs will not only decrease mortality from HAIs but also save billions of dollars spent on early eradication. DRIs are generally associated with bacterial and/or fungal biofilms growing on medical devices. Microbial biofilms are communities of organisms that are often polymicrobial, where organisms can be highly resistant and sterile to most antimicrobial agents. Furthermore, the proximity of organisms within biofilms facilitates gene transfer that leads to the exchange of drug-resistance mechanisms. The development of medical devices capable of preventing microorganisms from growing on their surfaces will inevitably improve patient outcomes. An attractive approach to preventing microbial biofilm formation on medical devices involves the leaching of antimicrobial agents from the device surface. Potential problems with the leaching of antimicrobial agents from medical device surfaces are local toxicity to host cells and systemic exposure to the antimicrobial agents. As antimicrobial agents enter systemic distribution, the natural flora is disturbed, and resistance may develop with repeated exposure to the antimicrobial agents. A possible means to avoid these problems would be broad-spectrum antimicrobial agents that act on or near the surface of medical devices while rapidly degrading into endogenous compounds upon leaching from the device. Bioreabsorbable materials are already commonly used in medical care and degrade slowly in the presence of water. Generally, these materials degrade spontaneously to produce endogenous compounds or compounds that can be converted into endogenous compounds through enzymatic activity. Bioreabsorbable materials with broad-spectrum antimicrobial effects at low concentrations have not been developed. Most tissues in higher organisms continuously produce natural antimicrobial compounds, including antimicrobial peptides (AMPs), as a means of controlling microbial growth. Providing similar protection for medical devices would be an attractive goal. AMPs are bioreabsorbable and are reabsorbed after proteolytic cleavage. Although bacteria and fungi have been exposed to AMPs over time, they generally retained susceptibility to AMPs and did not develop tolerance. In humans, AMP LL-37 (a member of the cathelicidin family) is well-characterized as an antimicrobial agent with activity against Gram-positive and Gram-negative bacteria, fungi, and lipid-enveloped viruses. LL-37 is found in most human tissues, including the skin, gastrointestinal lining, lungs, and even the surface of the eyes. Cathelicidin LL-37 selectively associates with microbial membranes and causes increased membrane permeability, leading to microbial cell death. AMP resistance is infrequent and requires bacteria and other microorganisms to alter their membrane structures. The ubiquity of AMPs has been used as evidence that these compounds do not easily lead to bacterial resistance. Furthermore, considering the diverse sequences of antimicrobial peptides across various organisms, it is evident that they evolve independently multiple times. Therefore, antimicrobial peptides appear to be one of the primary means of controlling bacterial growth. For example, endogenous antimicrobial peptides, such as human cathelicidin LL-37, play a significant role in innate immunity. LL-37 is found in airway mucus and is considered important for regulating bacterial growth in the lungs. However, the clinical use of AMPs presents significant challenges, including the high cost of producing peptide-based therapeutics, the susceptibility of peptides to proteases produced by hosts and bacterial pathogens, and the inactivation of antimicrobial peptides by proteins and DNA in the lung mucosa. An attractive method for utilizing the antibacterial activity of antimicrobial peptides without the problems described above is to develop non-peptide mimics of the antimicrobial peptides that exhibit similar broad-spectrum antibacterial activity using the same or similar mechanisms of action. Non-peptide mimics will provide lower-cost synthesis and potentially increased stability against proteolytic degradation. Furthermore, control of water solubility and charge density can be used to control association with proteins and DNA in the lung mucosa. With over 1,600 known e