+

WO2013191550A1 - Diazotation régiosélective des aminoglycosides - Google Patents

Diazotation régiosélective des aminoglycosides Download PDF

Info

Publication number
WO2013191550A1
WO2013191550A1 PCT/NL2013/050440 NL2013050440W WO2013191550A1 WO 2013191550 A1 WO2013191550 A1 WO 2013191550A1 NL 2013050440 W NL2013050440 W NL 2013050440W WO 2013191550 A1 WO2013191550 A1 WO 2013191550A1
Authority
WO
WIPO (PCT)
Prior art keywords
derivative
azido
alkyl
aminoglycoside
amikacin
Prior art date
Application number
PCT/NL2013/050440
Other languages
English (en)
Inventor
Andreas Alexander BASTIAN
Andreas Hermann
Original Assignee
Rijksuniversiteit Groningen
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Rijksuniversiteit Groningen filed Critical Rijksuniversiteit Groningen
Publication of WO2013191550A1 publication Critical patent/WO2013191550A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/20—Carbocyclic rings
    • C07H15/22—Cyclohexane rings, substituted by nitrogen atoms
    • C07H15/222—Cyclohexane rings substituted by at least two nitrogen atoms
    • C07H15/224—Cyclohexane rings substituted by at least two nitrogen atoms with only one saccharide radical directly attached to the cyclohexyl radical, e.g. destomycin, fortimicin, neamine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/20—Carbocyclic rings
    • C07H15/22—Cyclohexane rings, substituted by nitrogen atoms
    • C07H15/222—Cyclohexane rings substituted by at least two nitrogen atoms
    • C07H15/226—Cyclohexane rings substituted by at least two nitrogen atoms with at least two saccharide radicals directly attached to the cyclohexane rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/20—Carbocyclic rings
    • C07H15/22—Cyclohexane rings, substituted by nitrogen atoms
    • C07H15/222—Cyclohexane rings substituted by at least two nitrogen atoms
    • C07H15/226—Cyclohexane rings substituted by at least two nitrogen atoms with at least two saccharide radicals directly attached to the cyclohexane rings
    • C07H15/228—Cyclohexane rings substituted by at least two nitrogen atoms with at least two saccharide radicals directly attached to the cyclohexane rings attached to adjacent ring-carbon atoms of the cyclohexane rings
    • C07H15/23—Cyclohexane rings substituted by at least two nitrogen atoms with at least two saccharide radicals directly attached to the cyclohexane rings attached to adjacent ring-carbon atoms of the cyclohexane rings with only two saccharide radicals in the molecule, e.g. ambutyrosin, butyrosin, xylostatin, ribostamycin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/20—Carbocyclic rings
    • C07H15/22—Cyclohexane rings, substituted by nitrogen atoms
    • C07H15/222—Cyclohexane rings substituted by at least two nitrogen atoms
    • C07H15/226—Cyclohexane rings substituted by at least two nitrogen atoms with at least two saccharide radicals directly attached to the cyclohexane rings
    • C07H15/234—Cyclohexane rings substituted by at least two nitrogen atoms with at least two saccharide radicals directly attached to the cyclohexane rings attached to non-adjacent ring carbon atoms of the cyclohexane rings, e.g. kanamycins, tobramycin, nebramycin, gentamicin A2

Definitions

  • the invention relates to the field of chemical derivatization.
  • it relates to modified aminoglycosides, such as aminoglycosidic antibiotics, and methods for producing them.
  • Aminoglycosides represent one of the largest classes of antibacterials with activity against both Gram negative and Gram positive bacteria. These antibiotics exert their antibacterial activity by binding to the decoding site (A-site) in 16S rRNA. However, the increased bacterial resistance against aminoglycoside antibiotics gained the interest in modification of these to obtain new active compounds since four decades. Especially the neamine moiety of these antibiotics received major attention, since the main resistance is caused by enzymatic modifications at ring I and II. The introduction of negative charge at ring II by 3'-phosphotranferase (APH-3'), and erasing positive charges at ring II and I by acetyltransferases (ACCs) reduces their biological activity 8 .
  • APH-3' 3'-phosphotranferase
  • ACCs acetyltransferases
  • the present inventors set out to develop a simple, non-enzymatic method for regioselective derivatization of the 3-N position of the 2-desoxy-streptamine ring.
  • the method is cost-efficient, high scalable method and does not require any protection- or deprotection steps.
  • the reaction is preferably performed in an aqueous solution.
  • the invention relates to a method for the regioselective diazotation of a desoxy-streptamine-substituted aminoglycoside, comprising contacting the aminoglycoside with imidazole- 1-sulfonyl azide hydrochloride under neutral pH conditions to allow for the conversion of the single amine group at the 3-C position of the desoxy-streptamine ring into an azide group.
  • Azides have proven to be useful precursors to amines in organic syntheses.
  • the diazotransfer reaction followed by regioselective azide reduction of compounds containing multiple azides has been disclosed in the art.
  • Nyffeler et at. J. Am Chem. Soc. 2002, 124, 10773-107778
  • Azides were then reduced with good regioselectivity in moderate yields by a modification of the Staudinger reaction using trimethylphosphine at low temperatures.
  • the diazo-transfer reagent used in the present invention has been recently introduced as a shelf-stable, non-explosive and water soluble reagent. 20
  • a further advantage of this reagent is that is has got a good functional group tolerance and is even reactive without catalyst, such as Cu(II), Ni(II) or Zn(II).
  • This reagent has proven to be a straightforward way to convert free amines into azides via an aqueous diazo-transfer (Scheme la). Hence, in one embodiment, the diazotation is performed in an aqueous solution.
  • the other reaction conditions for the diazotation can be determined by routine optimization.
  • Any suitable solvent may be used.
  • it is water or an aqueous buffer, like a phosphate buffer.
  • the diazotransfer reagent imidazole- 1-sulfonyl azide hydrochloride can be added as an aqueous solution, e.g. 10- 100 mM, preferably adjusted to about pH 7.5- 8.5.
  • the diazotransfer reagent may be prepared by methods known in the art, see Goddard-Borger, E. D., Stick, R. V. Org. Lett. 2007, 9, 3797. For example, it comprises treating sulfuryl chloride with sodium azide in acetonitrile, followed by the addition of excess imidazole.
  • the hydrochloride salt can be precipitated using ethanolic hydrochloric acid.
  • an excess amount of the diazotransfer reagent like 5-20 equivalents, are used relative to the aminoglycoside in a method of the invention.
  • the reaction is suitably performed at room temperature. However, any temperature in the range of about 10-40 °C, preferably 15 -30°C can be used. Incubation periods can vary between about 6 and 48 hours.
  • the reaction mixture is preferably stirred. Good results are obtained with overnight (about 14- 18h) incubations.
  • the reaction may thereafter be quenched, e.g. by adding an aqueous ethylamine solution.
  • diazotation is preferably performed in the absence of a Cu(II) catalyst, more in particular in the absence of a Cu(II) sulphate catalyst.
  • the invention provides a method for the regioselective diazotation of the amine at the 3-C position of the desoxy-streptamine ring of any aminoglycoside.
  • An aminoglycoside is a molecule or a portion of a molecule composed of amino-modified sugars.
  • Several aminoglycosides function as antibiotics that are effective against certain types of bacteria.
  • the invention provides a method for the regioselective diazotation of an aminoglycoside antibiotic. They include amikacin, arbekacin, neomycin, paromomycin, and apramycin.
  • the aminoglycoside is a neamine-based aminoglycoside antibiotic, for instance selected from the group consisting of neomycin, apramycin, neamin, amikacin, paromomycin, ribostamycin, framycetin and isepamecin.
  • neamin-based aminoglycosides wherein the amine at the 3-C position of the desoxy-streptamine ring is transformed into an azide, obtainable by a method of the invention.
  • An azide -derivative of a neamine-based aminoglycoside is characterized by an azide at 3-C position of the desoxy-streptamine ring and the absence of any protective groups at the other amine-moieties.
  • Exemplary compounds include C-3-azido neomycin B, C-3-azido paromomycin, C-3- azido ribostamycin, C-3-azido neamine, C-3-azido amikacin and C-3-azido apramycin.
  • the invention provides a compound according to any one of the following structures,
  • An azide- derivative according to the invention is advantageously used in the manufacture of an aminoglycoside antibiotic having antimicrobial activity and showing increased resistance against bacterial aminoglycoside modifying enzymes (AMEs).
  • AMEs bacterial aminoglycoside modifying enzymes
  • it can serve as intermediate in an approach to provide an analog which is protected against a bacterial enzyme having aminoglycoside acetyltransferase (AAC) activity and capable of N-acetylation, hence erasing a positive charge at the 3-position of ring I.
  • AAC aminoglycoside acetyltransferase
  • Selective transformation of the amino group at the 3-position of ring I into an azide, followed by azide modification into a moiety which can not be N-acetylated by AAC is a powerful tool to protect against AMEs.
  • the invention therefore also provides for the regioselective diazotation of the amine at the 3-C position of the desoxy-streptamine ring of an aminoglycoside, comprising contacting the aminoglycoside with imidazole- 1-sulfonyl azide
  • hydrochloride under neutral pH (pH 6.5-7.5) conditions to allow for the conversion of a single amine group into an azide group, further comprising chemical modification of the azide group.
  • an aminoglycoside antibiotic derivative wherein the 3-C position of the desoxy-streptamine ring carries a moiety which is not recognized as a substrate by a bacterial acetyl transferase (AAC) enzyme, i.e. wherein the moiety is an alkylated amine, a quaternized amine or amide, obtainable by a method of the invention.
  • AAC bacterial acetyl transferase
  • azide modification comprises reduction to amine, followed by alkylation.
  • the AAC enzymes are not able to acylate this position anymore and with this antibacterial resistance can be overcome.
  • the azide is converted into a NR2 or ⁇ 13 ⁇ 4 + moiety, wherein R is C1-C5 alkyl, preferably C1-C3 alkyl.
  • the alkyl can be linear, branched, substituted or unsubstituted. Linear, unsubstituted alkyls are preferred.
  • R is methyl, ethyl or propyl.
  • the azide is converted into a carbamate, a primary amine or amide.
  • the azide is converted to a substituted or unsubstituted triazole moiety, referring to either one of a pair of isomeric chemical compounds with molecular formula C2H3N3, having a five-membered ring of two carbon atoms and three nitrogen atoms.
  • Substituted 1,2,3-triazoles can be produced using click chemistry, e.g. via the azide alkyne Huisgen cyclo addition, in which an azide and an alkyne undergo a 1,3-dipolar cycloaddition reaction.
  • the invention also provides a novel antibacterial aminoglycoside compound according to the general formula II, Formula III, Formula IV, or a salt thereof.
  • R a linear or branched lower alkyl, preferably C1-C5 alkyl, such as C1-C.3 alkyl;
  • Ri, R2 H, or any carbohydrate conjugates at CI position;
  • R4 acyl residue, preferably a-hydroxy,y-amino butyrate.
  • Gentamicin C1 a Gentamicin C1 Gentamicin C2 derivative derivative derivative
  • Gentamicin C1 a Gentamicin C1 Gentamicin C2 derivative derivative derivative
  • R is methyl, ethyl, propyl, butyl, pentyl or hexyl
  • R 1 H, 2-L-hydroxy-gamma-amino butyryl or gamma-amino butyryl;
  • Formula III above depicts the desoxy-streptamine ring of a neamine antibiotic such that the invention provides a di- or tri-alkylated neamine antibiotic.
  • exemplary compounds include 3-N,N-di-alkyl neomycin B, 3-N,N-tri-alkyl neomycin B, 3-N,N-di-alkyl paromomycin, 3-N,N-tri-alkyl paromomycin, 3-N,N-di- alkyl ribostamycin, 3-N,N-tri-alkyl ribostamycin, 3-N,N-di-alkyl neamine, 3-N,N-tri- alkyl neamine, 3-N,N-di-alkyl amikacin, 3-N,N-tri-alkyl amikacin, 3-N,N-di-alkyl apramycin and 3-N,N-tri-alkyl apramycin.
  • alkyl is methyl, ethyl n
  • Gentamicin C1 a Gentamicin C1 Gentamicin C2 derivative derivative derivative
  • R is methyl, ethyl, propyl, butyl, pentyl or hexyl
  • R 1 is H, 2-L-hydroxy-gamma-amino butyryl or gamma-amino butyryl
  • n 1-5.
  • the N- l position of ring I is modified.
  • the hydroxyl- group at the 3-position of ring II is (be it chemically or enzymatically) derivatized to protect against introduction of a positive charge by a bacterial 3'- phosp ho transferase (APH-3') activity.
  • the additional derivatization comprises selective oxidation of the hydroxyl- group at the 3-position of ring II by contacting the aminoglycoside in the presence of a transition metal catalyst complex with an oxidizing agent.
  • the transition metal catalyst complex may comprise Pd2+, Rh3+, Ir3+, Ru3+, Pt2+ or Cu2+, preferably palladium.
  • the transition metal catalyst complex is a palladium phenanthroline complex
  • Suitable protecting groups for hydroxyl include trialkylsilyl or diarylalkylsilyl (for example, t-butyldimethylsilyl, t- butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, and the like.
  • Suitable protecting groups for amino, amidino and guanidino include t-butoxycarbonyl, benzyloxycarbonyl, and the like.
  • Suitable protecting groups for mercapto include - C(0)-R" (where R" is alkyl, aryl or arylalkyl), p-methoxybenzyl, trityl and the like.
  • Suitable protecting groups for carboxylic acid include alkyl, aryl or arylalkyl esters. Protecting groups may be added or removed in accordance with standard techniques, which are known to one skilled in the art and as described herein.
  • an antibacterial aminoglycoside compound disclosed herein may not possess pharmacological activity as such, they may be administered to a mammal and thereafter metabolized in the body to form an antibacterial aminoglycoside compound which is pharmacologically active. Such derivatives may therefore be described as "prodrugs”. All prodrugs of antibacterial aminoglycoside compounds disclosed herein are included within the scope of the invention.
  • antibacterial aminoglycoside compounds disclosed herein which exist in free base or acid form can be converted to their pharmaceutically acceptable salts by treatment with the appropriate inorganic or organic base or acid by methods known to one skilled in the art.
  • Salts of the antibacterial aminoglycoside compounds disclosed herein can be converted to their free base or acid form by standard techniques.
  • aminoglycoside-lipid conjugate comprises at least two guanidino groups attached to a primary or secondary carbon atom of the aminoglycoside group.
  • a further aspect of the invention relates to drug discovery, more specifically to the screening for novel antibacterial compounds that are based on or derived from an azide- derivative obtained by regioselective diazotation.
  • the invention provides a method for identifying an aminoglycoside antibiotic, comprising the steps of (i) providing at least one candidate compound using the regioselective diazotation of the amine at the 3-C position of the desoxy-streptamine ring of an aminoglycoside according to the invention, (ii) determining whether the candidate compound has antimicrobial activity.
  • Step (i) preferably comprising providing a desoxy-streptamine-substituted aminoglycoside wherein the amine at the C-3 position is transformed into an azide by contacting the aminoglycoside with imidazole- 1- sulfonyl azide hydrochloride at a pH in the range of 6.5-7.5 under neutral pH conditions, and wherein the azide is further chemically modified, preferably by reduction to amine followed by alkylation and acylation.
  • acylation is suitably used to provide a compound according to Formula IV.
  • one or more candidate compounds are provided wherein the C-3 azide is converted into a NR2 or NR3 + moiety, wherein each of R is independently Ci- C5 alkyl, e.g. C1-C3 alkyl. to allow for the conversion of the single amine group at the 3-C position of the desoxy-streptamine ring into an azide group.
  • the candidate compound is obtained by chemical modification of C-3-azido neomycin B, C-3-azido paromomycin, C-3-azido ribostamycin, C-3-azido neamine, C-3-azido amikacin or C-3-azido apramycin.
  • Antimicrobial activity is suitably assessed using methods known in the art, e.g. in a double dilution method against E. coli and B. subtilis (Green et al. Antimicr. Agents and Chemother. 2011, p. 3207-3213).
  • MICs minimum inhibitory concentrations
  • Antibiotic MICs can be obtained using the broth microdilution method according to approved guidelines.
  • Candidate compounds can be evaluated using a panel of strains that do not possess known aminoglycoside resistance mechanisms, for example ATCC strains of Escherichia coli (ATCC 25922), Staphylococcus aureus (ATCC 29213), Klebsiella pneumonia (ATCC 43816),
  • test compounds Pseudomonas aeruginosa (ATCC 27853) and Acinetobacter baumannii (ATCC 19606). These strains are routinely used as a reference to provide the quality control for antibiotic ranges. Activity of the test compounds is preferably determined using QC strains and strains with known aminoglycoside resistance mechanisms.
  • the identification method also comprises determining resistance of the aminoglycoside against N-acylation, for instance using recombinant AAC enzyme, preferably AAC(3)-IV.
  • AAC enzyme preferably AAC(3)-IV.
  • the enzyme may be part of a cell lysate or it may be (partially) purified.
  • Aminoglycosides have several potential antibiotic mechanisms, some as protein synthesis inhibitors, although their exact mechanism of action is not fully known. They interfere with the proofreading process, causing increased rate of error in synthesis with premature termination. Also, there is evidence of inhibition of ribosomal translocation where the peptidyl-tRNA moves from the A-site to the P-site. They can also disrupt the integrity of bacterial cell membrane and they bind to the bacterial 30S ribosomal subunit.
  • a pharmaceutical composition may comprise, for example, an aminoglycoside-analog according to the invention in a pharmaceutically acceptable formulation.
  • the aminoglycoside-analog as disclosed herein may be used in methods of treatment.
  • the invention provides a method of treating a bacterial infection in a subject comprising administering to the subject an effective amount of an
  • the bacterium causing the bacterial infection may be a multidrug resistant bacterium.
  • the bacterial infection may be caused by, for example, a Gram-positive bacterium.
  • Gram-positive bacteria include Staphylococcus aureus methicillin-resistant Staphylococcus aureus (MRSA), Staphylococcus epidermidis, methicillin-resistant S. epidermidis (MRSE), Enterococcus faecalis, Enterococcus faecium, and Streptococcus pneumoniae.
  • MRSA Staphylococcus aureus methicillin-resistant Staphylococcus aureus
  • MRSE methicillin-resistant S. epidermidis
  • Enterococcus faecalis Enterococcus faecium
  • Streptococcus pneumoniae Alternatively, the bacterial infection may be caused by, for example, a Gram-negative bacterium.
  • Gram-negative bacteria include E. coli, gentamicin-resistant E. coli or amikacin-resistant E. coli, P.
  • concentration of the aminoglycoside antibiotic-analog is ⁇ 64 ⁇ g/mL. Certain methods contemplate an additional step comprising administration of a second antibacterial agent.
  • the bacterial infection is a urinary tract infection.
  • methods of the present invention may further comprise diagnosing a subject as needing treatment for a bacterial infection prior to
  • methods of the present invention may further comprise administering treatment to a subject who has been identified as needing treatment for a bacterial infection.
  • Also contemplated are methods of preventing a bacterial infection in a subject comprising administering to the subject an effective amount of an aminoglycoside antibiotic analog. Such methods may further comprise diagnosing the subject as needing preventative treatment for the bacterial infection prior to administering the aminoglycoside antibiotic.
  • a combination can include an aminoglycoside compound, composition, pharmaceutical composition described herein with an additional medicament.
  • additional medicaments include an antibacterial agent, antifungal agent, an antiviral agent, an anti-inflammatory agent and an anti-allergic agent.
  • additional antibacterial agents include chloramphenicol, tetracyclines, synthetic and semi- synthetic penicillins, beta-lactams, quinolones, fluoroquinolnes, macrolide antibiotics, peptide antibiotics, and cyclosporines.
  • antifungal agents examples include azoles, diazoles, triazoles, miconazole, fluconazole, ketoconazole, clotrimazole, itraconazole griseofulvin, ciclopirox, amorolfine, terbinafine, amphotericin B, potassium iodide, and flucytosine (5FC).
  • antifungal agents examples include vidarabine, acyclovir, gancyclovir, nucleoside- analog reverse transcriptase inhibitors, AZT (zidovudine), ddl (didanosine), ddC (zalcitabine), d4T (stavudine), 3TC (lamivudine), non-nucleoside reverse transcriptase inhibitors, nevirapine, delavirdine, protease Inhibitors, saquinavir, ritonavir, indinavir, nelfinavir, ribavirin, amantadine, rimantadine and interferon
  • anti-inflammatory and/or anti-allergic agents include corticosteroids, non-steroidal antiinflammatory drugs, anti- histamines, immunomodulating agents, and immuno suppressants.
  • Administration of the antibacterial aminoglycoside compounds disclosed herein, or their pharmaceutically acceptable salts, in pure form or in an appropriate pharmaceutical composition can be carried out via any of the accepted modes of administration of agents for serving similar utilities.
  • the pharmaceutical composition can be carried out via any of the accepted modes of administration of agents for serving similar utilities.
  • compositions of the invention can be prepared by combining an antibacterial aminoglycoside compound disclosed herein with an appropriate pharmaceutically acceptable carrier, diluent or excipient, and may be formulated into preparations in solid, semi-solid, liquid or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres, and aerosols.
  • Typical routes of administering such pharmaceutical compositions include, without limitation, oral, topical, transdermal, inhalation, parenteral, sublingual, buccal, rectal, vaginal, and intranasal.
  • parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.
  • Pharmaceutical compositions of the invention are formulated so as to allow the active ingredients contained therein to be bioavailable upon
  • compositions that will be
  • compositions to be administered take the form of one or more dosage units, where for example, a tablet may be a single dosage unit, and a container of a compound in aerosol form may hold a plurality of dosage units. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art.
  • the composition to be administered will, in any event, contain a therapeutically effective amount of an antibacterial aminoglycoside compounds disclosed herein, or a pharmaceutically acceptable salt thereof, for treatment of a urinary tract infection in accordance with the teachings of this invention.
  • a pharmaceutical composition of the invention may be in the form of a solid or liquid.
  • the carrier(s) are particulate, so that the compositions are, for example, in tablet or powder form.
  • the carrier(s) may be liquid, with the compositions being, for example, an oral syrup, injectable liquid or an aerosol, which is useful in, for example, inhalatory
  • the pharmaceutical composition is preferably in either solid or liquid form, where semi-solid, semi-liquid, suspension and gel forms are included within the forms considered herein as either solid or liquid.
  • the pharmaceutical composition may be formulated into a powder, granule, compressed tablet, pill, capsule, chewing gum, wafer or the like form.
  • a solid composition will typically contain one or more inert diluents or edible carriers.
  • binders such as carboxymethylcellulose, ethyl cellulose, microcrystalline cellulose, gum tragacanth or gelatin; excipients such as starch, lactose or dextrins, disintegrating agents such as alginic acid, sodium alginate, Primogel, corn starch and the like; lubricants such as magnesium stearate or Sterotex; glidants such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin; a flavoring agent such as peppermint, methyl salicylate or orange flavoring; and a coloring agent.
  • a liquid carrier such as polyethylene glycol or oil.
  • the pharmaceutical composition may be in the form of a liquid, for example, an elixir, syrup, solution, emulsion or suspension.
  • the liquid may be for oral administration or for delivery by injection, as two examples.
  • preferred composition contain, in addition to an antibacterial aminoglycoside compound, one or more of a sweetening agent, preservatives, dye/colorant and flavor enhancer.
  • a surfactant, preservative, wetting agent, dispersing agent, suspending agent, buffer, stabilizer and isotonic agent may be included.
  • the liquid pharmaceutical compositions of the invention may include one or more of the following adjuvants: sterile diluents such as water for injection, saline solution, preferably physiological saline, Ringer's solution, isotonic sodium chloride, fixed oils such as synthetic mono or diglycerides which may serve as the solvent or suspending medium, polyethylene glycols, glycerin, propylene glycol or other solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • the parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
  • Physiological saline is a preferred adjuvant.
  • a liquid pharmaceutical composition of the invention intended for either parenteral or oral administration should contain an amount of an antibacterial aminoglycoside compound disclosed herein such that a suitable dosage will be obtained.
  • the pharmaceutical composition of the invention may be intended for topical
  • the carrier may suitably comprise a solution, emulsion, ointment or gel base.
  • the base may comprise one or more of the following: petrolatum, lanolin, polyethylene glycols, bee wax, mineral oil, diluents such as water and alcohol, and emulsifiers and stabilizers.
  • Thickening agents may be present in a pharmaceutical composition for topical administration. If intended for transdermal administration, the composition may include a transdermal patch or iontophoresis device.
  • the pharmaceutical composition of the invention may be intended for rectal administration, in the form, for example, of a suppository, which will melt in the rectum and release the drug.
  • the composition for rectal administration may contain an oleaginous base as a suitable nonirritating excipient.
  • bases include, without limitation, lanolin, cocoa butter and polyethylene glycol.
  • the pharmaceutical composition of the invention may include various materials, which modify the physical form of a solid or liquid dosage unit.
  • the composition may include materials that form a coating shell around the active ingredients.
  • the materials that form the coating shell are typically inert, and may be selected from, for example, sugar, shellac, and other enteric coating agents.
  • the active ingredients may be encased in a gelatin capsule.
  • the pharmaceutical composition of the invention in solid or liquid form may include an agent that binds to an antibacterial aminoglycoside compound disclosed herein and thereby assists in the delivery of the compound.
  • Suitable agents that may act in this capacity include a monoclonal or polyclonal antibody, a protein or a liposome.
  • the pharmaceutical composition of the invention may consist of dosage units that can be administered as an aerosol.
  • aerosol is used to denote a variety of systems ranging from those of colloidal nature to systems consisting of pressurized packages. Delivery may be by a liquefied or compressed gas or by a suitable pump system that dispenses the active ingredients. Aerosols of antibacterial aminoglycoside compounds disclosed herein may be delivered in single phase, bi-phasic, or tri-phasic systems in order to deliver the active ingredient(s). Delivery of the aerosol includes the necessary container, activators, valves, subcontainers, and the like, which together may form a kit. One skilled in the art, without undue experimentation may determine preferred aerosols. EXPERIMENTAL SECTION General
  • ⁇ -NMR- and heteronuclear single- quantum correlation (HSQC) spectra as well as attached proton test (ATP) were recorded on a Varian Unity Inova (500 MHz and 600 MHz) NMR spectrometer at 25 °C.
  • HRMS High resolution mass spectrometry
  • EI+ electron impact ionization in positive ion mode
  • HPLC high performance liquid chromatography
  • DGU- 14A3 Online Vacuum-Degasser two LC-20 AT pumps, SIL-20A auto sampler, CTP-20 A column oven, RID- 10 refractive detector, FRC-10 A fraction collector and Shimadzu LCsolution software.
  • HPLC purification was performed with a Waters Spherisorb ODS-2 Cis analytical (250 x 4.6 mm) and semi- preparative column (250 x 10mm) (spherical particles of 5 ⁇ and 80 A pore size) using isocratic elution at 40 °C.
  • a pH-meter (Hanna Instruments pH 209) equipped with a glass combination electrode was used for pH adjustments of the reaction buffers.
  • Neomycin B trisulfate x hydrate (VETRANAL ® ), paromomycin sulfate salt (98%), ribostamycin sulfate salt, aparmycin sulfate, amikacin sulfate, sulfuryl chloride (97%), sodium azide (95%), acetonitril (99.8%), imodazole (99%) and methanolic 3N HC1 solution were purchased from Sigma Aldrich and used as received.
  • HFBA heptafluorobutyric acid
  • Neomycin B derivative 1 was obtained as a white solid.
  • ⁇ -NMR 400 MHz, D2O, 25 °C, TMS
  • Neomycin B derivative 2a was obtained as a white solid.
  • Neomycin B derivative 2b was obtained as a white solid.
  • Neomycin B derivative 2c was obtained as a white solid.
  • MICs minimal inhibitory concentrations
  • Enzyme ACC-3 catalyses the acetylation reaction of the amino group in C-3 position at the 2-desoxystrepamine (2-DOS) ring in aminoglycoside antibiotics resulting in deactivation of the drug in resistant bacteria.
  • 2-DOS 2-desoxystrepamine
  • Table 1 all synthesized derivatives show antibacterial activity in resistant and not resistant E. coli strains. However, these compounds exhibit lower antibacterial activity compared to the unmodified antibiotic neomycin B against the E. coli strain not expressing enzyme ACC-3.
  • the modification at the C-3 position results in lower affinity to the ribosomal unit 30S in E. coli bacteria.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Saccharide Compounds (AREA)

Abstract

La présente invention concerne le domaine de dérivation chimique. En particulier, elle concerne des aminoglycosides modifiés, tels que des antibiotiques, et leurs procédés de production. L'invention concerne un procédé de diazotation régiosélective d'un aminoglycoside à substitution de désoxy-streptamine, comprenant la mise en contact de l'aminoglycoside avec du chlorhydrate d'imidazole sulfonyle azide dans des conditions de pH neutre pour permettre la conversion du groupe amine simple à la position 3C du cycle désoxy-streptamine en un groupe azide. L'invention concerne également de nouveaux composés antibiotiques.
PCT/NL2013/050440 2012-06-20 2013-06-20 Diazotation régiosélective des aminoglycosides WO2013191550A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP12172790 2012-06-20
EP12172790.3 2012-06-20
US201261671839P 2012-07-16 2012-07-16
US61/671,839 2012-07-16

Publications (1)

Publication Number Publication Date
WO2013191550A1 true WO2013191550A1 (fr) 2013-12-27

Family

ID=49769059

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/NL2013/050440 WO2013191550A1 (fr) 2012-06-20 2013-06-20 Diazotation régiosélective des aminoglycosides

Country Status (1)

Country Link
WO (1) WO2013191550A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017018528A1 (fr) * 2015-07-30 2017-02-02 公益財団法人 微生物化学研究会 Nouvel antibiotique aminoglycosidique efficace contre les bactéries résistantes à plusieurs médicaments
CN106554374A (zh) * 2016-11-29 2017-04-05 无锡福祈制药有限公司 一种从核糖霉素发酵液中提纯制备核糖霉素硫酸盐的方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012004684A2 (fr) 2010-03-05 2012-01-12 University Of Manitoba Conjugués aminoglycoside-lipide guanidinylés

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012004684A2 (fr) 2010-03-05 2012-01-12 University Of Manitoba Conjugués aminoglycoside-lipide guanidinylés

Non-Patent Citations (37)

* Cited by examiner, † Cited by third party
Title
ALPER, P. B.; HENDRIX, M.; SEARS, P.; WONG, C. H., J. AM. CHEM. SOC., vol. 120, 1998, pages 1965
ARIZA, X.; URPI, F.; VILARRASA, J., TERAHEDRON LETT., vol. 40, 1999, pages 7515
BOTTO, R. E.; COXON, B., J. AM. CHEM. SOC., vol. 105, 1983, pages 1021
COHEN, M. A, SCIENCE, vol. 257, 1992, pages 1050
DAVIS, J., SCIENCE, vol. 264, 1994, pages 375
DENA L. BOXLER ET AL: "Semisynthetic aminoglycoside antibacterials. Part 9. Synthesis of novel 1- and 3-substituted and 1- and 3-epi-substituted derivatives of sisomicin and gentamicin from the 1- and 3-oxo-derivatives", JOURNAL OF THE CHEMICAL SOCIETY, PERKIN TRANSACTIONS 1, 1 January 1981 (1981-01-01), pages 2168, XP055074918, ISSN: 0300-922X, DOI: 10.1039/p19810002168 *
ETHAN D. GODDARD-BORGER ET AL: "An Efficient, Inexpensive, and Shelf-Stable Diazotransfer Reagent: Imidazole-1-sulfonyl Azide Hydrochloride", ORGANIC LETTERS, vol. 9, no. 19, 1 September 2007 (2007-09-01), pages 3797 - 3800, XP055042292, ISSN: 1523-7060, DOI: 10.1021/ol701581g *
FOURMY, D.; RECHT, M. I.; BLANCHARD, S. C.; PUGLISI, J. D., SCIENCE, vol. 274, 1996, pages 1367
GODDARD-BORGER, E. D.; STICK, R. V., ORG. LETT., vol. 9, 2007, pages 3797
GREEN ET AL., ANTIMICR. AGENTS AND CHEMOTHER., 2011, pages 3207 - 3213
GREEN, K. D.; CHEN, W.; GARNEAU-TSODIKOVA, S., ANTIMICROB. AGENTS CHEMOTHER., vol. 55, 2011, pages 3207
HADDAD, J.; VAKULENKO, S.; MOBASHERY, S., J. AM. CHEM. SOC., vol. 121, 1999, pages 11922
HANESSIAN, S.; KORNIENKO, A.; SWAYZE, E. E., TETRAHEDRON, vol. 59, 2003, pages 995
IGARASHI K ET AL: "Novel synthesis of 1- and 3-epi-tobramycin and 1-epi-kanamycin A", CARBOHYDRATE RESEARCH, PERGAMON, GB, vol. 109, 1 November 1982 (1982-11-01), pages 73 - 88, XP026638125, ISSN: 0008-6215, [retrieved on 19821101], DOI: 10.1016/0008-6215(82)84032-9 *
IGOR NUDELMAN ET AL: "Combined Chemical-Enzymatic Assembly of Aminoglycoside Derivatives with N-1-AHB Side Chain", ADVANCED SYNTHESIS & CATALYSIS, vol. 350, no. 11-12, 4 August 2008 (2008-08-04), pages 1682 - 1688, XP055017947, ISSN: 1615-4150, DOI: 10.1002/adsc.200800229 *
IGOR NUDELMAN ET AL: "Development of Novel Aminoglycoside (NB54) with Reduced Toxicity and Enhanced Suppression of Disease-Causing Premature Stop Mutations", JOURNAL OF MEDICINAL CHEMISTRY, vol. 52, no. 9, 14 May 2009 (2009-05-14), pages 2836 - 2845, XP055042341, ISSN: 0022-2623, DOI: 10.1021/jm801640k *
IGOR NUDELMAN ET AL: "Repairing faulty genes by aminoglycosides: Development of new derivatives of geneticin (G418) with enhanced suppression of diseases-causing nonsense mutations", BIOORGANIC & MEDICINAL CHEMISTRY, vol. 18, no. 11, 1 June 2010 (2010-06-01), pages 3735 - 3746, XP055017979, ISSN: 0968-0896, DOI: 10.1016/j.bmc.2010.03.060 *
J. J. WRIGHT: "Synthesis of 1-N-ethylsisomicin: a broad-spectrum semisynthetic aminoglycoside antibiotic", JOURNAL OF THE CHEMICAL SOCIETY, CHEMICAL COMMUNICATIONS, no. 6, 1 January 1976 (1976-01-01), pages 206, XP055074919, ISSN: 0022-4936, DOI: 10.1039/c39760000206 *
JIE LI ET AL: "Investigation of the Regioselectivity for the Staudinger Reaction and Its Application for the Synthesis of Aminoglycosides with N-1 Modification", JOURNAL OF ORGANIC CHEMISTRY, ACS, US, vol. 72, no. 11, 25 May 2007 (2007-05-25), pages 4055 - 4066, XP008142327, ISSN: 0022-3263, [retrieved on 20070428], DOI: 10.1021/JO062588J *
LEE, S. H.; CHEONG, C. S., TETRAHEDRON, vol. 57, 2001, pages 4801
LI, J.; CHIANG, F.-I; CHEN, H.-N.; CHANG, C.-W. T., J. ORG. CHEM., vol. 72, 2007, pages 4055
MOAZED, D.; NOLLER, H. F., NATURE, vol. 327, 1987, pages 389
NYFFELER ET AL., J. AM CHEM. SOC., vol. 124, 2002, pages 10773 - 10778
OULETTE, M.; KUNDIG, C., INT. J. ANTIMICROB. AGENTS, vol. 8, 1997, pages 179
PATHAK, R.; PREZE-FERNANDEZ, D.; NANDURDIKAR, R.; KALAPALA, S. K.; B6TTGER, E. C.; VASELLA, A., HELVETIKA CHIMICA ACTA, vol. 91, 2008, pages 1533
ROESTAMADJI, J.; GRAPSAS., I.; MOBASHERY, S., J. AM. CHEM. SOC., vol. 117, 1995, pages 11060
ROESTAMADJI, J.; MOBASHERY, S., BIOORG. MED. CHEM. LETT., vol. 8, 1998, pages 3483
SAMANTARAY, S.; MARATHE, U.; DASGUPTA, S.; NANDICOORI, V. K.; ROY, R. P., J. AM. CHE. SOC., vol. 130, 2008, pages 2132
SANNE SCHOFFELEN ET AL: "Metal-free and pH-controlled introduction of azides in proteins", CHEMICAL SCIENCE, vol. 2, no. 4, 1 January 2011 (2011-01-01), pages 701, XP055042384, ISSN: 2041-6520, DOI: 10.1039/c0sc00562b *
SATOSHI HORII ET AL: "A new method for selective N-acylation of aminoglycoside antibiotics", CARBOHYDRATE RESEARCH, vol. 60, no. 2, 1 February 1978 (1978-02-01), pages 275 - 288, XP055074905, ISSN: 0008-6215, DOI: 10.1016/S0008-6215(78)80035-4 *
SAWA, M.; HSU, T.-L.; ITOH, T.; SUGIYAMA, M.; HANSON, S. R.; VOGT, P. K.; WONG, C.-H, PROC. NATL. ACAD. SCI. U.S.A., vol. 103, 2006, pages 12371
SCHOFFELEN ET AL., CHEM. SCI., vol. 2, 2001, pages 701
SCHOFFELEN, S.; VAN ELDIJK, M. B.; ROOIJAKKERS, B.; RAIJMAKERS, R.; HECK, A. J. R.; HEST, J. C. M., CHEM. SCI., vol. 2, 2011, pages 701
VOCADLO, D. J.; BERTOZZI, C. R., ANGEW. CHEM. INT. ED., vol. 43, 2004, pages 5338
WRIGHT, G. D.; BERGHUIS, A. A.; MOBASHERY, S.: "Aminoglycoside Antibiotics: Structure and Resistance", 1998, PLENUM PRESS, pages: 27 - 69
YOSHIZAWA, S.; FOURMY, D.; PUGLISI, J. D., SCIENCE, vol. 285, 1999, pages 1722
ZHOU, J.; WANG, G.; ZHANG, L.-H.; YE, X.-S., MED. RES. REV., vol. 3, 2007, pages 279

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017018528A1 (fr) * 2015-07-30 2017-02-02 公益財団法人 微生物化学研究会 Nouvel antibiotique aminoglycosidique efficace contre les bactéries résistantes à plusieurs médicaments
CN108026133A (zh) * 2015-07-30 2018-05-11 公益财团法人微生物化学研究会 有效对抗多药耐药细菌的新的氨基糖苷抗生素
JPWO2017018528A1 (ja) * 2015-07-30 2018-05-17 公益財団法人微生物化学研究会 多剤耐性菌に有効な新規アミノグリコシド抗生物質
US10617704B2 (en) 2015-07-30 2020-04-14 Microbial Chemistry Research Foundation Effective aminoglycoside antibiotic for multidrug-resistant bacteria
CN108026133B (zh) * 2015-07-30 2021-05-07 公益财团法人微生物化学研究会 有效对抗多药耐药细菌的新的氨基糖苷抗生素
RU2751634C2 (ru) * 2015-07-30 2021-07-15 Майкробиал Кемистри Рисерч Фаундейшн Новый эффективный аминогликозидный антибиотик против бактерий с множественной лекарственной резистентностью
US11135234B2 (en) 2015-07-30 2021-10-05 Microbial Chemistry Research Foundation Effective aminoglycoside antibiotic for multidrug-resistant bacteria
CN106554374A (zh) * 2016-11-29 2017-04-05 无锡福祈制药有限公司 一种从核糖霉素发酵液中提纯制备核糖霉素硫酸盐的方法

Similar Documents

Publication Publication Date Title
USRE47741E1 (en) Antibacterial aminoglycoside analogs
TWI425947B (zh) 抗菌性胺基糖苷類似物
US8481502B2 (en) Antibacterial aminoglycoside analogs
US20080300199A1 (en) Antibacterial 1,4,5-substituted aminoglycoside analogs
US8653042B2 (en) Antibacterial aminoglycoside analogs
US8524675B2 (en) Antibacterial aminoglycoside analogs
US8658606B2 (en) Antibacterial aminoglycoside analogs
US8524689B2 (en) Antibacterial aminoglycoside analogs
CN106905386B (zh) 氨基糖苷衍生物
US20120283207A1 (en) Antibacterial aminoglycoside analogs
US20120283208A1 (en) Antibacterial aminoglycoside analogs
WO2011044502A1 (fr) Analogues d'aminoglycoside antibactériens
RU2751634C2 (ru) Новый эффективный аминогликозидный антибиотик против бактерий с множественной лекарственной резистентностью
WO2007142150A1 (fr) Nouvel antibiotique de type aminoglycoside
WO2013191550A1 (fr) Diazotation régiosélective des aminoglycosides
WO2018139599A1 (fr) Nouvel antibiotique aminoglycoside efficace pour de multiples bactéries résistantes aux médicaments
FI56388C (fi) Foerfarande foer framstaellning av en ny terapeutiskt anvaendbar 1-n-ny-amino-alfa-hydroxibutyryl-substituerad kanamycin(a eller b)-foerening

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 13734864

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 13734864

Country of ref document: EP

Kind code of ref document: A1

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载