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WO2009058327A1 - Dérivés de cyclodextrine en tant que renforçateurs pour antibiotiques - Google Patents

Dérivés de cyclodextrine en tant que renforçateurs pour antibiotiques Download PDF

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Publication number
WO2009058327A1
WO2009058327A1 PCT/US2008/012313 US2008012313W WO2009058327A1 WO 2009058327 A1 WO2009058327 A1 WO 2009058327A1 US 2008012313 W US2008012313 W US 2008012313W WO 2009058327 A1 WO2009058327 A1 WO 2009058327A1
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Prior art keywords
compound
antibiotic
cyclodextrins
antibiotics
alkyl
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Ceased
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PCT/US2008/012313
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English (en)
Inventor
Sidney Hecht
Nour Eddine Fahmi
Larisa Dedkova
Sanjib Bera
Renata Kolanos
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Pinnacle Pharmaceuticals Inc
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Pinnacle Pharmaceuticals Inc
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Publication of WO2009058327A1 publication Critical patent/WO2009058327A1/fr
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention relates to cyclodextrin derivatives and their use as antibiotic and/or potentiators for antibiotics against pathogenic bacteria.
  • bacteria are known to cause diseases in humans. Among these bacteria are Enterococcus faecium, Eschericia coli, Pseudomonas aeruginosa, Bacillus atrophaeus, Staphylococcus aureus, Salmonella choleraesuis, Bacillus anthrasis, Pseudomonas aeruginosa, and many others. A disturbing recent trend has been the development of resistance to existing antibiotics in numerous pathogenic bacteria. [003] Conventional drugs consist of simple, fast-acting chemical compounds that are dispensed orally (as solid pills and liquids) or as injectables.
  • Drug delivery systems include soluble polymers, microparticles made of insoluble or biodegradable natural and synthetic polymers, microcapsules, lipoproteins, liposomes, micelles, etc.
  • Drug delivery systems are designed to alter the pharmacokinetics, pharmacodynamics, non-specific toxicity, immunogenicity, biorecognition, and efficacy of their associated drugs, or to function as drug reservoirs (i.e., as sustained release systems), or both.
  • Cyclodextrins are cyclic ( ⁇ -l ⁇ 4)-linked oligosaccharides of ⁇ -D- glucopyranose containing a relatively hydrophobic central cavity and a hydrophilic outer surface. Cyclodextrins are designated ⁇ , ⁇ and ⁇ corresponding to 6, 7 or 8 glycopyranose units, with cavity diameters of 4.7-5.3, 6.0-6.5 and 7.5-8.3 A, respectively ( Figure 1).
  • cyclodextrins Due to their unique ability to bind hydrophobic molecules within their cavity, cyclodextrins have been successfully applied in pharmaceutical formulations to enhance solubility, chemical stability and absorption of bioactive molecules. In addition, cyclodextrins are readily available at low cost, are not toxic, are nonimmunogenic, and exhibit an excellent pharmacokinetic profile.
  • the present invention involves the encapsulation of an antibiotic into a cyclodextrin derivative, thus permitting the facilitated transport of the antibiotic through bacterial cell membrane, and/or protection against degrading enzymes and efflux pumps.
  • Gram-negative bacterial infections are the cause of significant morbidity and mortality. Infections due to one such Gram negative organism, P. aeruginosa, are recognized by the medical community as particularly difficult to treat. For example chronic lung infection with Pseudomonas aeruginosa is responsible for the pulmonary deterioration and reduced life expectancy in patients with cystic fibrosis (CF). Once P. aeruginosa has taken residence in the CF lungs, it is rarely possible to eradicate it by antimicrobial chemotherapy.
  • CF cystic fibrosis
  • cyclodextrins are able to form inclusion complexes with a plethora of "guest” molecules, they can play a dual role in: i) increasing the stability of guest molecules, and ii) transporting drug molecules across membranes, due to their ability to recognize specific cellular receptors, such as lectins located on the bacterial cell surface. Moreover, recent studies showed that the inclusion of ampicillin in a cyclodextrin provided some protection against degradation by ⁇ -lactamase enzymes.
  • porins Many antibiotics enter the Gram negative outer membrane through channel-forming proteins called porins. These are essential also for the uptake of hydrophilic molecules and nutrients across lipid bilayer membranes in Gram negative and some Gram positive bacteria.
  • the porin superfamily contains a number of homotrimeric, transmembrane proteins that form water-filled pores across the outer cell membranes of gram-negative bacteria. A number of porins in their active form have been isolated and had their crystal structures determined.
  • a maltoporin known as the LamB porin. It is responsible for the guided diffusion of maltose and maltodextrins into E. coli cells. Antibacterial resistance resulting from loss of a porin or from a mutation that lead to a narrowing of the porin channel have been reported.
  • Cym transport system a specific transport system for cyclodextrins in the bacterial cell wall
  • CymA encodes a "cycloporin", enabling cyclodextrins to penetrate the bacterial cell outer membrane.
  • Cyclodextrins have also been shown to reversibly enter and modify the pore properties of CymA bacterial porin and fully block the ionic conductance of CymA pores.
  • Figure 1 represents the structures of ⁇ , ⁇ and ⁇ cyclodextrins.
  • Figure 2 represents partial 1 H NMR spectra of free doxycycline, free Compound No.
  • Figure 3 represents a partial NOESY spectrum of Compound No. 141 :doxycycline
  • Figure 4 represents the HPLC profile of Compound No. 106.
  • Figure 5 represents the HPLC profile of a Compound No. 106 Iosmer.
  • Figure 6 represents the HPLC profile of a Compound No. 106 Isomer.
  • Figure 7 represents the HPLC profile of a Compound No. 138 Isomer.
  • the invention relates to cyclodextrins as potentiators of known antibiotics against pathogenic bacteria, particularly those bacteria that have developed resistance to known antibiotics.
  • the cyclodextrins are derivatives of ⁇ , ⁇ , or ⁇ cyclodextrins.
  • the cyclodextrins of the present invention are ⁇ -cyclodextrins ( ⁇ -CD), which are cyclic molecules comprising seven D-glucose units.
  • ⁇ -CD derivatives are represented by General Formula 1.
  • R 2 is independently H, OH, OAc, OMe, 0-lower alkyl, or 0(CH 2 CH 2 O) n ;
  • R 3 is independently H, OH, OAc, OMe, O-lower alkyl, OSO 3 Na, or NH 2 ;
  • R 6 is independently H, NH 2 , S(CH 2 ) m NH 2 , N 3 , 1, SH, lower-alkyl, S-alkylguanidyl, O-alkylguanidyl, S- alkylphthalimido, S-aralkylphthalimido, S-alkyl, S-aryl, S-arylalkyl, S-heterocyclic, S- heterocylic alkyl, S-aminoalkyl, O-aminoalkyl, aminoalkyl, 0-lower alkyl, aralkyl, aryl, heterocyclic ring(s), OSO 3 Na or N which is mono
  • R 6 is an ornthine, aminoalkyl, aryl amino, aminoamide, thioureido, S-aminoalkyl or an N 3 group.
  • lower alkyl means an alkyl group from 1 to 7 carbon atoms.
  • alkyl and aryl include alkyl or aryl groups which may be substituted or unsubstituted. Preferred substitutions include, without limitation, substitution with nitrogen containing moieties, including amino groups, which may be mono or disubstituted, preferably with alkyl or aryl groups.
  • alkyl includes chains of 1-7 atoms with one or more nitrogen atoms and the remainder carbon atoms.
  • Table 1 depicts several non-limiting examples of ⁇ -CD derivatives according to the invention.
  • Table 2 depicts antibacterial and/or antibiotic potention properties of several of the ⁇ -CD derivatives disclosed herein.
  • the cyclodextrins according to the present invention are ⁇ or ⁇ cyclodextrins, which have 6 or 8 D-glucose units, respectively. These cyclodextrins are represented by General Formulas 2 and 3:
  • R 2 , R 3 , and R 6 are as defined in General Formula 1.
  • the invention additionally provides methods for potentiating the activity of antibiotics to inhibit the growth of a bacterium which are resistant to clinically used antibiotics, to treat or prevent an infection by these bacteria.
  • the methods according to this aspect of the invention comprise contacting the bacterium with said antibiotic and one or more members of the compound of General Formulas 1, 2, or 3.
  • the cyclodextrin derivatives of the present invention are effective in potentiating the activity of vancomycin against
  • VRE Vanocomycin-resistant Enterococci
  • MRSA Methicillin-resistant Staphylococcus aureus
  • resistant or “resistance” to a bacterium or bacterial infection to an antibiotic includes a complete resistance to the antibiotic or a partial resistance which is defined herein as a circumstance in which the minimum inhibitory concentration (MIC) of an antibiotic toward the organism in question has increased or renders the antibiotic clinically inoperative due to lack of effectiveness or excessive side effects.
  • MIC minimum inhibitory concentration
  • Examples of increased MIC include, but are not limited to, situations where the MIC has increased by 25%, 50%, or 100% and increments therein.
  • potentiation may be defined as a circumstance in which a compound substantially lowers the MIC of an antibacterial agent toward one or more organisms. It includes the case in which it effectively restores the therapeutic utility of an antibacterial agent whose utility has been compromised by bacterial resistance.
  • the invention provides pharmaceutical compositions. These compositions comprise one or more members of the compounds of the invention, a known antibiotic, and a physiologically acceptable carrier.
  • physiologically acceptable refers to a material that does not interfere with the effectiveness of the compounds of the first or third aspects of the invention and is compatible with a biological system such as a cell, cell culture, tissue, or organism.
  • the biological system is a living organism, such as a mammal.
  • the mammal is a human.
  • carrier encompasses any excipient, diluent, filler, salt, buffer, stabilizer, solubilizer, lipid, or other material well known in the art for use in pharmaceutical formulations. It will be understood that the characteristics of the carrier, excipient, or diluent will depend on the route of administration for a particular application. The preparation of pharmaceutically acceptable formulations containing these materials is described in, e.g., Remington's Pharmaceutical Sciences, 18th Edition, ed. A. Gennaro, Mack Publishing Co., Easton, PA, 1990, ISBN: 0-912734-04-3.
  • the invention provides methods for treating a bacterial infection.
  • the method according to this embodiment of the invention comprises administering to a mammal with a bacterial infection one or more members of the compound of General Formulas 1, 2, or 3, in conjunction with a known antibiotic.
  • the invention provides methods for preventing a bacterial infection.
  • the method according to this embodiment of the invention comprises administering to a mammal susceptible to a bacterial infection one or more members of the compound of General Formulas 1, 2, or 3 in conjunction with a known antibiotic.
  • the cyclodextrins may be used to potentiate the activity of known antibiotics, such as those approved by the FDA or other regulatory agencies for the treatment of bacterial infections.
  • Antibiotics useful in the present invention include, but are not limited to, glycopeptides, aminoglycosides, beta-lactams, quinolones, sulfonamides, rifampins, monobactams, carbepenems, macrolides, lincosamines, fluoroquinolones, penicillins, oxazolidinones, and tetracyclines.
  • the bacteria is in a mammal.
  • the mammal is a human.
  • administration of the compound can be by any suitable route, including, without limitation, parenteral, oral, sublingual, transdermal, topical, intranasal, aerosol, intraocular, intratracheal, intrarectal or vaginal.
  • Administration of the therapeutic compositions can be carried out using known procedures at dosages and for periods of time effective to reduce symptoms or surrogate markers of the infection.
  • a doctor can determine the appropriate dose to administer or therapeutic protocol useful for preventing or preventing a bacterial infection. It may be desirable to administer simultaneously, or sequentially a therapeutically effective amount of one or more of the therapeutic compositions of the invention to an individual as a single treatment episode.
  • Preferred methods of administration include parenteral (IV, IM, SC), intranasal, ocular (eye) delivery, and oral administration (as tablet, solution, capsule, etc.).
  • Triphenylphosphine (54.1 g, 0.2 mol) was dissolved with stirring in 210 rtiL of anhydrous DMF. To this solution was added 51 g (0.2 mol) of iodine over a 15 min. period with evolution of heat. Dry ⁇ -cyclodextrin (10.41 g, 9.65 mmol) was added to the dark brown solution and the mixture stirred at 70 oC for 20 h. The solution was then concentrated to about one-half the volume ( ⁇ 100 mL). 3 M NaOMe in MeOH (57 niL) was prepared by adding 3.78 g of sodium to cooled (0 °C) dry methanol (57 mL) under argon.
  • per-6-bromo-6-deoxy- ⁇ -CD may be synthesized according to the procedure set forth below.
  • Per-6-amino-6-deoxy- ⁇ -cyclodextrin was obtained as a white solid: yield 8.2 g (95%). To allow characterization by NMR, a small amount of per-6-amino-6-deoxy- ⁇ -CD was converted to its hydrochloride salt.
  • n 3, propyl: colorless foam, yield 0.372 g (59%); 1 H NMR (CDCl 3 ) ⁇ 1.91 (m, 2H),
  • n 6, hexyl: colorless foam, yield 0.462 g (67%); 13 C NMR (acetone-d 6 ) ⁇ 20.96,
  • n 10, decyl: yellow foam, yield 0.530 g (69%); 13 C NMR (acetone-d 6 ) ⁇ 20.35,
  • the crude product was dissolved in 24 mL of pyridine and 36 mL OfAc 2 O, 20 mg of dimethylaminopyridine were added and the mixture stirred at 23 oC for 48 h under argon.
  • the reaction was quenched by slow addition of 35 mL of MeOH and the solvent was concentrated under diminished pressure.
  • the residue was partitioned between 75 mL of water and 65 mL of EtOAc.
  • the organic layer was dried (MgSO 4 ) and concentrated under diminished pressure.
  • the crude product was purified on a silica gel column (4 x 20 cm), eluting with 1 :4 hexane-EtOAc then EtOAc.
  • nteta isomer yellow foam, yield 0.584 g (51%); 13 C NMR (acetone-d 6 ) ⁇ 20.40,
  • N ⁇ -Boc-N ⁇ -benzyloxy-L-ornithine (0.587 g, 1.60 mmol) was dissolved in 10 mL of dry DMF.
  • HOBt 0.249 g, 1.63 mmol
  • DCC 0.330 g, 1.60 mmol
  • the reaction mixture was stirred at 0 oC for 1 h.
  • the reaction mixture was allowed to warm to room temperature and was stirred for an additional 1 h.
  • To the reaction vessel was added 250 mg (0.22 mmol) of per-6-amino- ⁇ - cyclodextrin and 0.2 mL of N-methylmorpholine.
  • Example 12 Inclusion complex of Compound No. 141 and doxycycline
  • NMR techniques including two-dimensional NOE spectroscopy are commonly used to study inclusion complexes of cyclodextrins.
  • the chemical shifts of the protons of Compound No. 141 : doxycycline inclusion complex were shifted in the 1 H NMR spectrum.
  • the largest chemical shifts occurred between those of the aromatic protons on the cyclodextrin and the antibiotic.
  • the ⁇ H values of four protons shifted upfield from ⁇ H
  • the 13 C NMR spectrum of the inclusion complex showed some up/down-shifts for the ⁇ c values compared with those of their free forms.
  • the assignments of protons and carbons of the inclusion complex were confirmed through COSY, HMQC, HMBC, and NOESY spectral analyses.
  • the NOESY spectrum of the complex Compound No. 141 doxycycline clearly showed cross peaks between the two aromatic protons at ⁇ 6.880 (Ha), and 6.624 (Hb) on the cyclodextrin, and the antibiotic, respectively (Figure 4).
  • Bacteria form liquid stocks (10-20 ⁇ L) were placed on the corresponding agar plates and grown at 37 oC during 16-18 h. One colony was picked from the agar plate and transferred to 3 mL of Mueller-Hinton or Brain Heart) infusion media (for Enterococcus strains) and permitted to grow for 3-4 h at 37 oC in a thermostated shaker. To standardize the concentration of bacteria in the prepared cultures McFarland standard was used. All cultures were used at concentrations of about 10 8 per mL. One hundred ⁇ L of each standardized culture was inoculated in 20 mL of corresponding media and assayed in the presence of eleven 2-fold dilutions of tested compounds.
  • the MIC of antibacterial agents was determined for different bacterial strains in the absence and in the presence of selected cyclodextrins (10-20 ⁇ g/mL).
  • the antimicrobial agents were mixed with cyclodextrins (normally 1 : 1 molar ratio) and MICs were estimated for antibacterial agent alone, cyclodextrins alone and mixture.
  • the protocol for MIC determination described above was used in both assays.
  • a library of- 150 individual cyclodextrin derivatives were synthesized and surveyed for their ability to potentiate known antibiotics against four bacterial strains. A number of derivatives which increased the activity of these antibiotics have been identified from this survey. In particular, Pseudomonas aeruginosa was more sensitive to doxycylin when this antibiotic was combined with cyclodextrins bearing a lysinamide group (Compound No. 29), an aminoalkylthio group (Compound Nos. 4, 5, 27and 28) or aminobenzylthio group (Compound Nos .115, 116and 141) at the primary position. The activity of doxycycline increased 16-fold compared to doxycycline alone.
  • cyclodextrin HP- ⁇ - cyclodextrin did not have any effect on the activity of doxycycline. The activity was completely lost when doxycycline was tested with 2,6-DMCD and 2,3,6-TMCD. These cyclodextrins are more water soluble and are often used to increase the water solubility of drugs.
  • the activity of norfloxacin was also potentiated by the same cyclodextrins ⁇ See Table 1 for potentiation against P. aeruginosa) and increased 4-fold compared to norfloxacin alone.
  • a panel of cyclodextrins was selected and screened for their ability to potentiate the antibacterial activity of four known antibiotics: one aminoglycoside (tobramycin), one cephalosporin (ceftriaxone), one quinolone (norflaxocin) and one tetracycline (doxycycline), against P. aeruginosa (Table 3).
  • Table 4 summarizes the potentiating effect of a series of cyclodextrin derivatives on aminoglycosides against an aminoglycoside resistant strain of P. Aeruginosa. From a library of -150 cyclodextrins , nine derivatives were able to lower the MICs of aminoglycosides when mixed in a 1 :1 molar ratio. HP- ⁇ - cyclodextrin did not have any noticeable effect on the antibacterial activities of aminoglycosides, as was also true for the methylated cyclodextrins. A slight potentiating effect was detected for Compound Nos. 16, 74 and 75 and 106 while a 4-fold decrease in MIC 90 was noted for tobramycin.
  • Compound Nos. 74 and 75 slightly potentiate the activities neomycin and gentamycin. A more pronounced potentiating affect was observed with cyclodextrin derivatives possessing an alkylamino and arylamino group on the primary position.
  • Compound Nos. 1 15, 1 16and 141 can increase the activity of the aminoglycosides up to 30-fold, as observed in the case of neomycin and streptomycin.
  • MRSA Methicillin-resistant Staphylococcus aureus
  • MRSA strains represent a worldwide threat because of their virulence and broad distribution in the hospital setting and community. See Michel, M., Gutmann, L. Lancet 1997, 349, 1901-1906.
  • the MRSA strains are often resistant not only to ⁇ -lactam antibiotics but also to fluoroquinolones, chloramphenicol, clindamycin, tetracycline and aminoglycosides.
  • anti-staphylococcus agents such as the oxazolidinone-type antibiotics has emerged. See Meka, V. G.; Gold, H. S. Clin. Infect. Dis. 2004, 39(7), 1010-1015.
  • Enterococci are normal colonizers of the human gastrointestinal tract and are organisms with relatively low virulence.
  • VRE vancomycin
  • the lipophilic cyclodextrins 74 and 75 (entries 8 and 9) were effective in decreasing the MICs of all 4 antibiotics tested, at least 16 fold. The same effect was noted with Compound Nos. 138, 106 and 110 (entries 15, 16 and 18). 5. Potentiation activity of antibiotics by ⁇ -cyclodextrin derivatives against Klebsiella. [0098] Initial studies with Klebsiella were carried out using a highly resistant strain (700603) available from ATCC. Klebsiella infections are presently treated clinically with either a monobactam (Aztreonam) or penicillin (Piperacillin) derivative.
  • ATCC700603 (Table 1 1).
  • CDs selected as antibacterials in concentration less then 10 ⁇ g/mL

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Abstract

L'invention concerne une nouvelle classe d'antibiotiques dérivés de la cyclodextrine, qui est une molécule cyclique comprenant des unités D-glucose. En outre, l'invention concerne un procédé de renforcement de l'activité des antibiotiques destiné à inhiber la croissance d'une bactérie qui est résistante audit antibiotique, les dérivés de cyclodextrine étant administrés avec un antibiotique.
PCT/US2008/012313 2007-10-30 2008-10-30 Dérivés de cyclodextrine en tant que renforçateurs pour antibiotiques Ceased WO2009058327A1 (fr)

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US60/983,864 2007-10-30

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8106111B2 (en) 2009-05-15 2012-01-31 Eastman Chemical Company Antimicrobial effect of cycloaliphatic diol antimicrobial agents in coating compositions
CN104870464A (zh) * 2012-07-24 2015-08-26 国家科研中心 多聚甘露糖苷及其制备方法和它们作为药物的用途
US9963518B2 (en) 2011-08-22 2018-05-08 Oxford University Innovation Limited Cyclic oligosaccharides for use in the treatment and prevention of bacterial infection
WO2024031162A1 (fr) * 2022-08-08 2024-02-15 DA SILVA, Tasso Pereira Compositions antimicrobiennes sporicides et leurs utilisations
WO2024105648A1 (fr) * 2022-11-17 2024-05-23 Silva Renata Moises Iwamizu Composition antivirale contenant des composés d'inclusion de cyclodextrines en tant que modulateurs d'activité et agents actifs antiseptiques et leurs utilisations

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060199785A1 (en) * 2005-01-28 2006-09-07 Pinnacle Pharmaceuticals Beta-cyclodextrin derivatives as antibacterial agents

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060199785A1 (en) * 2005-01-28 2006-09-07 Pinnacle Pharmaceuticals Beta-cyclodextrin derivatives as antibacterial agents

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8106111B2 (en) 2009-05-15 2012-01-31 Eastman Chemical Company Antimicrobial effect of cycloaliphatic diol antimicrobial agents in coating compositions
US9963518B2 (en) 2011-08-22 2018-05-08 Oxford University Innovation Limited Cyclic oligosaccharides for use in the treatment and prevention of bacterial infection
CN104870464A (zh) * 2012-07-24 2015-08-26 国家科研中心 多聚甘露糖苷及其制备方法和它们作为药物的用途
WO2024031162A1 (fr) * 2022-08-08 2024-02-15 DA SILVA, Tasso Pereira Compositions antimicrobiennes sporicides et leurs utilisations
WO2024105648A1 (fr) * 2022-11-17 2024-05-23 Silva Renata Moises Iwamizu Composition antivirale contenant des composés d'inclusion de cyclodextrines en tant que modulateurs d'activité et agents actifs antiseptiques et leurs utilisations

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