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WO2012051663A1 - Composés antimicrobiens - Google Patents

Composés antimicrobiens Download PDF

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Publication number
WO2012051663A1
WO2012051663A1 PCT/AU2011/001340 AU2011001340W WO2012051663A1 WO 2012051663 A1 WO2012051663 A1 WO 2012051663A1 AU 2011001340 W AU2011001340 W AU 2011001340W WO 2012051663 A1 WO2012051663 A1 WO 2012051663A1
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Prior art keywords
atoms
peptide
distal
sequential
carbon atom
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Inventor
Jian Li
Tony Velkov
Roger L Nation
Philip E Thompson
Kade D Roberts
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Monash University
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Monash University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/50—Cyclic peptides containing at least one abnormal peptide link
    • C07K7/54—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring
    • C07K7/60—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring the cyclisation occurring through the 4-amino group of 2,4-diamino-butanoic acid
    • C07K7/62—Polymyxins; Related peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • 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 present invention relates to antimicrobial compounds and their uses, and in particular to peptide antibiotics which may be used in the treatment of bacterial infections such as Gram-negative bacterial infections, particularly those caused by multidrug-resistant (MDR) pathogens.
  • MDR multidrug-resistant
  • Gram-negative bacteria Representative genera of Gram-negative bacteria are: Acinetobacter; Actinobacillus; Bartonella; Bordetella; Brucella; Burkholderia; Campylobacter; Cyanobacteria; Enterobacter; Erwinia; Escherichia; Francisella; Helicobacter; Hemophilus; Klebsiella; Legionella; Moraxella; Morganella; Neisseria; Pasteurella; Proteus; Providencia; Pseudomonas; Salmonella; Serratia; Shigella; Stenotrophomonas; Treponema; Vibrio; and Yersinia.
  • Gram-positive bacteria are: Actinobacteria; Bacillus; Clostridium; Corynebacterium; Enterococcus; Listeria; Nocardia; Staphylococcus; and Streptococcus.
  • IDSA Infectious Diseases Society of America
  • Polymyxins belong to a class of peptides which was discovered more than 50 years ago.
  • the structures of representative polymyxins are shown below:
  • Polymyxins are produced by nonribosomal biosynthetic enzymes from the secondary metabolic pathways of Bacillus polymyxa. There are two polymyxins clinically available, colistin (polymyxin E) and polymyxin B, and cross resistance exists between these two polymyxins. The efficacy of polymyxins in treating certain Gram-negative bacterial infections has been demonstrated by recent clinical studies. Parenteral administration of colistin and polymyxin B can be potentially nephrotoxic and/or neurotoxic. Polymyxins are now being used as last-line antibiotics in patients where all other available antibiotics are inactive. Although the incidence of resistance to polymyxins is currently relatively low, it has been demonstrated that resistance can emerge in vitro in P.
  • polymyxin analogs are effective against Gram-negative bacteria, including both polymyxin-susceptible and -resistant MDR Gram-negative bacteria. Some of these polymyxin analogs may also have activity against Gram-positive bacteria, such as methicillin-resistant and vancomycin-resistant Gram-positive bacteria.
  • Ri is a lipophilic group comprising five or more carbon atoms and optionally comprising one or more O, N or S atoms, wherein the or each carbon atom in R ⁇ that is distal to the peptide backbone is conjugated to the peptide backbone by five or more sequential atoms, and the one or more O, N or S atoms in Ri, where present, are each independently conjugated to the or each distal carbon atom in Ri by a moiety comprising three or more sequential carbon atoms;
  • Y is selected from -C(0)-; -C(S)-; -C(NH)-; and -S(0) 2 -; m, n and p are each independently 0 or 1 ;
  • R 3 , R4 and R 5 where present and R 2 , Re, R9, Rio and Rj 1 are each independently selected from the side chain of an amino acid selected from ⁇ , ⁇ -diaminobutyric acid, arginine, histidine, lysine, leucine, ornithine,- glutamic acid, aspartic acid, glutamine, asparagine, homoserine, serine, threonine and cysteine;
  • X is a residue of the side chain of an amino acid selected from ⁇ , ⁇ -diaminobutyric acid, arginine, histidine, lysine, ornithine, glutamic acid, aspartic acid, glutamine, asparagine, homoserine, serine, threonine and cysteine;
  • R 7 is a lipophilic group comprising five or more carbon atoms and optionally comprising one or more O, N or S atoms, wherein the or each carbon atom in R 7 that is distal to the peptide backbone is conjugated to the peptide backbone by five or more sequential atoms, and the one or more O, N or S atoms in R 7 , where present, are each independently conjugated to the or each carbon atom in R 7 that is distal to the peptide backbone by a moiety comprising four or more sequential carbon atoms;
  • Re is a lipophilic group comprising two or more carbon atoms and optionally comprising one or more O, N or S atoms, wherein the one or more O, N or S atoms in Re, where present, are each independently conjugated to the or each carbon atom in Kg that is distal to the peptide backbone by a moiety comprising four or more sequential carbon atoms; or a pharmaceutically acceptable salt thereof.
  • the total number of carbon, nitrogen, oxygen and sulfur atoms in Ri is 30 or less.
  • the total number of carbon, nitrogen, oxygen and sulfur atoms in R 7 is 30 or less.
  • the total number of carbon, nitrogen, oxygen and sulfur atoms in Rg is 30 or less.
  • the present invention provides a peptide of formula (I):
  • Ri is a lipophilic group comprising from 5 to 22 carbon atoms selected from Cs-2 2 alkyl, C 5 . 22alkenyl, C ⁇ i l, C 5 .i 2 cycloalkyl, C6-i6arylCi. 6 alkyl, C 6- i6arylC 2 -6alkenyl, cyclopropylC2- 6 alkyl, C 4 .
  • any one or more CH 2 groups in Ri is independently optionally replaced with O, C(O), N(Ri2) or S, wherein the or each carbon atom in Ri that is distal to the peptide backbone is conjugated to the peptide backbone by five or more sequential atoms, and the one or more O, N or S atoms in Rj, where present, are each independently conjugated to the or each distal carbon atom in Ri by a moiety comprising three or more sequential carbon atoms;
  • Y is selected from -C(O)-; -C(S)-; -C(NH)-; and -S(0) 2 -; m, n and p are each independently 0 or 1 ; R3, R4 and R5 where present and R 2 , R ⁇ , R9, Rio and Ru are each independently selected from the side chain of an amino acid selected from ⁇ , ⁇ -diaminobutyric acid, arginine, histidine, lysine, leucine, ornithine, glutamic acid, aspartic acid, glutamine, asparagine, homoserine, serine, threonine and cysteine;
  • X is a residue of the side chain of an amino acid selected from ⁇ , ⁇ -diaminobutyric acid, arginine, histidine, lysine, ornithine, glutamic acid, aspartic acid, glutamine, asparagine, homoserine, serine, threonine and cysteine;
  • R.7 is a lipophilic group comprising from 5 to 22 carbon atoms and is selected from C5. 22 alkyl, C 5-22 alkenyl, C6-i6aryl, C5.12cycloa.kyl, C6-i6arylCi ⁇ alkyl, C6-i6arylC 2 -6alkenyl, cyclopropylC 2- 6alkyl, C4-i 2 cycloalkylCi.6alkyl and C3 -12 cycloalkylC2-6a-kenyl wherein, where present, any one or more CH 2 groups in R 7 is independently optionally replaced with O, C(O), N(Ri 2 ) or S; wherein the or each carbon atom in R7 that is distal to the peptide backbone is conjugated to the peptide backbone by five or more sequential atoms, and the one or more O, N or S atoms in R 7 , where present, are each independently conjugated to the or each distal carbon atom in R 7
  • Rg is a lipophilic group comprising from 2 to 22 carbon atoms and is selected from C 2- 22 alkyl, C 2-2 2alkenyl, C6-i6aryl, C3-i2cycloalkyl, C 6 -i6arylCi ⁇ alkyl, C6-i6arylC 2 ⁇ alkenyl, C 3 .
  • any one or more CH 2 groups in Rg is independently optionally replaced with O, C(O), N(Ri2) or S; wherein the one or more O, N or S atoms in Rg, where present, are each independently conjugated to the or each carbon atom in Rg that is distal to the peptide backbone by a moiety comprising four or more sequential carbon atoms; wherein, where present, Ri 2 is independently selected from hydrogen, Ci ⁇ alkyl, C 2 .
  • the peptides of the present invention are active against Gram- negative bacteria, and surprisingly the peptides are active against not only polymyxin- susceptible but also polymyxin-resistant MDR Gram-negative bacteria. Without wishing to be limited by theory, it is believed that the combination of:
  • the number of sequential atoms that conjugate the peptide backbone to the or each distal carbon atom in R 7 may be greater than 5, greater than 6 or greater than 7.
  • the number of sequential carbon " atoms that conjugate the peptide backbone to the or each distal carbon atom in Rg may be greater than 1 or greater than 2.
  • the number of sequential carbon atoms that conjugate the peptide backbone to the or each distal carbon atom in Rg may be 9 or less atoms, 8 or less atoms, or 7 or less atoms.
  • the Y group is -C(O)-. In some embodiments the R 7 group does not comprise O, C(O), N(Ri 2 ) or S.
  • the Re group does not comprise O, C(O), N(R[ 2 ) or S.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a peptide as hereinbefore defined, or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier or diluent.
  • the invention provides a method of preventing or treating a bacterial infection comprising the step of administering a therapeutically effective amount of a peptide as hereinbefore described, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
  • the invention provides a use of a peptide as hereinbefore described, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the prevention or treatment of a bacterial infection.
  • the invention provides a peptide as hereinbefore described, or a pharmaceutically acceptable salt thereof, for the prevention or treatment of a bacterial infection.
  • Figure 1 shows static time-kill of compound 1 and colistin against a polymyxin-resistant MDR clinical P. aeruginosa isolate D.
  • Figure 2 shows static time-kill of compound 1 and colistin against P. aeruginosa ATCC 27853.
  • LPS lipopoly saccharide
  • OM outer membrane
  • Lipid A usually contains six acyl chains. Four ⁇ -hydroxy acyl chains (usually Cio and Q 2 in length) are attached directly to the glucosamine sugars, while a secondary acyl chain is often attached to the ⁇ -hydroxy group on each of two of the chains. Lipid A acts as a hydrophobic anchor with the tight packing of the fatty acyl chains helping to stabilise the overall membrane structure.
  • aeruginosa modification of one or both of the phosphates of lipid A with moieties, such as 4-amino-4-deoxy-L-arabinose (L-Ara4N) and/or phosphoethanolamine (PEtn), reduces the net negative charge of lipid A thereby reducing the initial interaction of a polymyxin with lipid A leading to polymyxin resistance.
  • moieties such as 4-amino-4-deoxy-L-arabinose (L-Ara4N) and/or phosphoethanolamine (PEtn)
  • the peptides of the present invention are not only effective against polymyxin-susceptible but also polymyxin-resistant MDR Gram-negative bacteria. Without wishing to be bound by theory it is believed that sufficient binding between a peptide and lipid A may be achieved by overcoming, or at least ameliorating, the adverse polar interactions between a modified moiety on the phosphate group of lipid A and the positively charged residues on polymyxins through enhancement of the interactions between the lipophilic groups on lipid A and certain residues on the peptide.
  • the lipophilic groups Ri, R 7 and R8 interact with the acyl chains in lipid A
  • the X, R 2 , 3 ⁇ 4, R9, Rio and Ru groups and the R3, R4 and R5, where present, which are generally hydrophilic interact with the polar portions of lipid A.
  • lipid A has undergone glycosylation or modification with phosphoethanolamine as part of the resistance mechanism in the bacteria, it is believed that the lipophilic groups and the generally hydrophilic groups remain able to maintain these same interactions. Without wishing to be bound by theory it is believed that being able to maintain these interactions results in the peptides of the present invention being effective against not only polymyxin-susceptible but also polymyxin-resistant MDR Gram-negative bacteria.
  • peptide backbone takes its standard meaning and typically refers to the regular structure of alternating alpha-carbon units and peptide (amide) bonds.
  • the peptide backbone is the sequence of carbon and nitrogen atoms extending between, and including, the N-terminus nitrogen atom proximal to R] and the C-terminus (in acyclic peptide) carbonyl carbon atom proximal to Ru-
  • conjugated refers to a bonding of two or more elements of the peptide. Typically such conjugation will be by covalent bonding of the two or more elements of the peptide.
  • Ri, R 7 and Rg the interaction between the lipophilic groups Ri, R 7 and Rg and the acyl chains in lipid A can be enhanced by using Ri, R 7 and Rg groups that extend a sufficient distance, or reach, from the peptide backbone.
  • Ri, R 7 and Rg groups that extend a sufficient distance, or reach, from the peptide backbone.
  • the group corresponding to the R 7 position is the benzyl side chain of phenylalanine.
  • the carbon atom in the side chain of phenylalanine that is distal to the peptide backbone is conjugated to the peptide backbone by 4 sequential atoms as shown below:
  • a reference to the or each carbon atom that is "distal" to the peptide backbone refers to the or each carbon atom that is structurally furthest from the peptide backbone, rather than referring to a carbon atom that may conformationally be furthest from the peptide backbone at any particular point in time.
  • the following structure shows the carbon atom in a hexyl group that is distal to the peptide backbone, as distinguished from a different carbon atom that may be more remote conformationally at any particular point in time due to folding of the chain, etc: n atom
  • the hexyl group shown above is one example of an R 7 side chain of the present invention where the carbon atom in the side chain that is distal to the peptide backbone is conjugated to the peptide backbone by five or more sequential atoms.
  • two or more carbon atoms may be equally distal to the peptide backbone.
  • Examples of such groups are cyclopentylbutyl and 2-butyl-2-phenylethyl:
  • each carbon atom that is equally distal to the peptide backbone must be conjugated to the peptide backbone by 5 or more sequential atoms.
  • sequential atoms refers to atoms that are in sequence such that the atoms may be thought of as being part of a linear chain of atoms, although the skilled person will recognise that typically the bonds between atoms are disposed at angles to each other, such as the tetrahedral angle.
  • sequential atoms may form part of a cyclic structure. With reference to the following structure showing a biphenylmethyl side chain, the numbered atoms can be seen to be in sequence:
  • the atoms marked A, B, C and D are not in sequence with all of the other atoms. Such atoms that are not in sequence may be thought of as being in parallel or as part of branches of the side chain. It has also been found that where the R 7 and/or Rg group comprise a O, N or S atom, such atoms must not be located too close to the or each carbon atom in each group that is distal to the peptide backbone. In particular it has been found that such a O, N or S atom must be separated from the or each carbon atom in each group that is distal to the peptide backbone by a moiety comprising four or more sequential carbon atoms. As can be seen in the following example of an R 7 and/or Rg group, the O atom is conjugated to the distal carbon atom by a moiety comprising four or more sequential carbon atoms:
  • any one or more CH 2 groups in the Ri, R 7 and/or Rg groups is independently optionally replaced with O, C(O), N(Ri 2 ) or S.
  • examples of such groups are ethers, ketones, amines and thioethers, such as octyloxymethyl, octanylcarbanylethyl, (4-ethylphenyl)(methyl)amino and (4-phenylethylthio)but-l-yl.
  • the Ri, R 7 and/or Rg groups may contain a plurality of O, C(O), N(Rj 2 ) and/or S groups.
  • the Rj, R 7 and or Rg groups may contain two such groups adjacent to eachother.
  • a CH 2 group in R 7 is replaced with O and an adjacent CH 2 group in R 7 is replaced with C(O) the skilled person will recognise that the combined functionality is an ester.
  • a CH 2 group in Ri is replaced by N(Rj 2 ) and an adjacent CH 2 group in Ri is replaced by C(O) the skilled person will recognise that the combined functionality is an amide.
  • Other functionality combinations are contemplated including carbamate (-0-C(0)-N(R
  • Peroxy (-0-0-) and hydrazine (-N-N-) groups are typically not found in living organisms, in part because of their relative instability. To this end the person skilled in the art would not typically use such peroxy and hydrazine groups in the R ⁇ , R 7 and/or Rg groups of the invention. Surprisingly it has also been found that some compounds of the invention exhibit activity against a number of Gram-positive bacteria such as Staphylococcus aureus and Enterococcus faecium strains, particularly multidrug-resistant strains S. aureus ATCC 43300 (methicillin resistant), S. aureus ATCC 43300 (vancomycin intermediate resistant), S. aureus ATCC 43300 (vancomycin resistant) and E.
  • the side chain residue X is the residue of the side chain of ⁇ , ⁇ - diami
  • the linear peptide portion of the molecule comprises three amino acids, as do the naturally occurring polymyxin structures.
  • m and p may be equal to 1 and n may be equal to 0.
  • , R 7 and Rg are lipophilic groups as hereinbefore defined;
  • R 2 is the side chain of ⁇ , ⁇ -diaminobutyric acid or threonine
  • R5 is the side chain of ⁇ , ⁇ -diaminobutyric acid, serine or threonine.
  • Ri, R 7 and Re are lipophilic groups as hereinbefore defined;
  • R5 is the side chain of ⁇ , ⁇ -diaminobutyric acid or serine. Except for the amino acid residue bearing the R 7 substituent, for which the stereochemistry is as depicted in Formula (I), each amino acid residue within the peptide may have any possible stereochemical configuration such as an L- or D-form. In some embodiments the absolute stereochemistry at each of the stereocentres in the compound of formula (V) shown below is the same as the corresponding stereochemistry in the naturally occurring polymyxin
  • the absolute stereochemistry of the stereocentre adjacent to the Re group has not been defined. It will be understood that where the amino acid(s) providing the Rg group is used as a mixture of enantiomers, such as a racemate, the peptide so formed that includes the Rg group will, in the absence of purification of an intermediate peptide, generally be prepared as a mixture of diastereomers. In some embodiments, the peptide may be used as a mixture of diastereomers, such as in the treatment of a bacterial infection.
  • the peptide may be used as a single diastereomer, which may be isolated from a mixture of diastereomers or may be prepared using an enantiopure, or enantioenriched, amino acid that provides the Rg group. It is believed that preferred peptides are those in which the stereocentre adjacent to the Rg group has the stereochemistry of naturally occurring amino acids such as L-leucine. Where the peptide is used as a single diastereomer, it is typically preferable that the peptide is made using an enantiopure, or enantioenriched, amino acid containing the Rg group rather than being purified following synthesis using a racemic mixture of the amino acid.
  • Rj lipophilic groups are C5.i6a.kyl, C5.gcycl0a.kyl,
  • any one or more CH 2 groups in Ri is independently optionally replaced with O, C(O), N(Rj 2 ) or S, wherein the or each carbon atom in Ri that is distal to the peptide backbone is conjugated to the peptide backbone by five or more sequential atoms, and the one or more O, N or S atoms in Ri, where present, are each independently conjugated to the or each distal carbon atom in Ri by a moiety comprising three or more sequential carbon atoms, wherein any alkyl, cycloalkyl or aryl group within Ri lipophilic group is optionally substituted with one or more groups selected from halo, d.
  • Ri may be 2- chlorophenylamino, phenyl, biphenyl, biphenylmethyl, C4-9alkyl (such as butyl, heptyl or nonyl), (such as trans-4-propylcyclohexanyl).
  • R 7 lipophilic groups are C 6 -i6alkyl (such as Cg- ⁇ alkyl), C3- gcycloalkyl, C3 ⁇ cycloalkylCi-6alkyl, Ce-ioarylCi-ealkyl (such as phenylethyl), C 6- ioarylC6-
  • any one or more CH 2 groups in R 7 is independently optionally replaced with O, C(O), N(Ri 2 ) or S; wherein the or each carbon atom in R 7 that is distal to the peptide backbone is conjugated to the peptide backbone by five or more sequential atoms, and the one or more 0, N or S atoms in R 7 , where present, are each independently conjugated to the or each distal carbon atom in R 7 by a moiety comprising four or more sequential carbon atoms, wherein any alkyl, cycloalkyl or aryl group within R 7 lipophilic group is optionally substituted with one or more groups selected from halo, Ci-2 2 alkyl, C 2 .
  • R 7 may be octyl, biphenylmethyl, (4- phenylmethoxy)phenylmethyl, phenylmethoxymethyl, hexyloxymethyl, hexylthiomethyl, 4-methylphenylmethyl and 4-trifluoromethylphenylmethyl.
  • these amino acids may be derived from naturally occurring and/or commercially available amino acids such as tyrosine, serine and cysteine through 0-, O- and S- alkylation reactions respectively.
  • Rg lipophilic groups are C2-i6alkyl (such as C 2-7 alkyl), C 3 . gcycloalkyl, C3-gcycloalkylCi.6alkyl, Ce-ioaryl, Ce-ioarylCi ⁇ alkyl Ce-io rylCe-ioarylCi. 6 alkyl, C 6 -ioarylCi -6 alkoxyC6-ioarylCi.6alkyl, C 6- i2alkoxyCi.
  • any one or more CH 2 groups in R 8 is independently optionally replaced with 0, C(O), N(Ri 2 ) or S; wherein the one or more O, N or S atoms in Rg, where present, are each independently conjugated to the or each carbon atom in Rg that is distal to the peptide backbone by a moiety comprising four or more sequential carbon atoms, wherein any alkyl, cycloalkyl or aryl group within Rg lipophilic group is optionally substituted with one or more groups selected from halo, Ci ⁇ alkyl, C 2 .
  • R may be butyl (such as isobutyl), octyl, phenyl, bi-phenyl, cyclohexylbutyl, trans-4-propylcyclohexanyl, cyclododecanyl and cyclopentylphenyl.
  • the Y group may be the residue of functionality that is useful in conjugating an P group to the nitrogen atom of the N-terminus of the peptide.
  • a preferred example of the Y group is -C(O)-.
  • alkyl used either alone or in compound words denotes straight chain or branched alkyl.
  • the alkyl group is a straight chain alkyl group.
  • Prefixes such as “Ci-2 2 " are used to denote the number of carbon atoms within the alkyl group (from 1 to 22 in this case).
  • straight chain and branched alkyl examples include methyl, ethyl, /j-propyl, isopropyl, H-butyl, sec-butyl, /-butyl, n-pentyl, hexyl, heptyl, 5-methylheptyl, 5- methylhexyl, octyl, nonyl, decyl, undecyl, dodecyl and docosyl (C22).
  • cycloalkyl used either alone or in compound words denotes a cyclic alkyl group. Prefixes such as “C3.12" are used to denote the number of carbon atoms within the cyclic portion of the alkyl group (from 3 to 12 in this case).
  • cyclic alkyl include mono- or polycyclic alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and cyclododecyl.
  • alkenyl used either alone or in compound words denotes straight chain or branched hydrocarbon residues containing at least one carbon to carbon double bond including ethylenically mono-, di- or polyunsaturated alkyl groups as previously defined.
  • the alkenyl group is a straight chain alkenyl group.
  • Prefixes such as " €2-22" are used to denote the number of carbon atoms within the alkenyl group (from 2 to 22 in this case).
  • alkenyl examples include vinyl, allyl, 1-methylvinyl, butenyl, iso-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 1-hexenyl, 3-hexenyl, 1-heptenyl, 3- heptenyl, 1-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1 -decenyl, 3-decenyl, 1,3- butadienyl, 1 ,4-pentadienyl, 1 ,3-hexadienyl, 1 ,4-hexadienyl and 5-docosenyl (C22).
  • aryl denotes any single- or polynuclear, conjugated or fused residues of aromatic hydrocarbon ring systems. Prefixes such as “C ⁇ ie” are used to denote the number of carbon atoms within the cyclic portion of the aryl group (from 6 to 16 in this case). Examples of aryl include phenyl (single nuclear), naphthyl (fused polynuclear), biphenyl (conjugated polynuclear) and tetrahydronaphthyl (fused polynuclear).
  • halo refers to halogen atoms such as F, CI, Br, I. In some embodiments halo is CI. In some embodiments halo is F. It will be understood that a fluorine atom may function as an isostere for hydrogen, and accordingly the skilled person may substitute one or more hydrogen atoms in an alkyl, alkenyl, aryl and/or cycloalkyl group, for example, for fluorine atom(s).
  • lipophilic refers to a property of a chemical compound, or part thereof, wherein the chemical compound or part thereof more readily associates with members of a large and diverse group of oils, fats and fat like substances (that occur, for example, in living organisms) than with water.
  • lipophilic groups are groups which, of themselves, display a preference to be solubilised by lipidic solvents rather than aqueous solvents.
  • side chain As used herein, reference to an amino acid "side chain” takes its standard meaning in the art. Examples of side chains of amino acids are shown below:
  • the peptides of the present invention may exist in one or more stereoisomeric forms (eg enantiomers, diastereomers).
  • the present invention includes within its scope all of these stereoisomeric forms either isolated (in for example enantiomeric isolation), or in combination (including racemic mixtures and diastereomic mixtures).
  • the present invention contemplates the use of amino acids in both L and D forms, including the use of amino acids independently selected from L and D forms. For example, where the peptide comprises two Dab residues, each Dab residue may have the same, or opposite, absolute stereochemistry. It is understood that the R7 and Rg groups in the peptide of formula (I):
  • Lipidic amino acids such as:
  • polymyxin peptide analogs of the present invention may be prepared for use as the amino acid bearing the Rg group in the synthesis of the polymyxin peptide analogs of the present invention.
  • Lipidic amino acids such as:
  • fluorine may be used as an isostere of hydrogen.
  • amino acids may be derived from naturally occurring and/or commercially available amino acids such as tyrosine, serine and cysteine through 0-, O- and S- alkylation reactions respectively.
  • the R.7 and Rg appended amino acids (“lipidic" amino acids) may be prepared as racemates or, alternatively, the amino acids or synthetic intermediates may be resolved to provide enantiopure, or at least enantioenriched, products. The resolution may take place chemically or enzymatically for example.
  • the amino acids bearing the R 7 and Rg side chains may be synthesised in enantiopure, or at least enantioenriched, form through stereoselective synthesis and/or purification techniques such as recrystallisation.
  • R 7 and/or Rg A number of amino acids bearing lipophilic groups defined by R 7 and/or Rg in enantiopure, or enantioenriched, form are commercially available. Examples of R 7 appended amino acids that may be used in enantiopure, or at least enantioenriched, form are shown below:
  • Rg appended amino acids that may be used in enantiopure, or at least enantioenriched, form are shown below:
  • Known solid or solution phase techniques may be used in the synthesis of the peptides of the present invention, such as coupling of the N- or C-terminus to a solid support (typically a resin) followed by step-wise synthesis of the linear peptide.
  • An orthogonal protecting group strategy may be used to facilitate selective deprotection and cyclization to form the cyclic heptapeptide core of the peptide.
  • Protecting group chemistries for the protection of amino acid residues, including side chains, are well known in the art and may be found for example in: Theodora W. Greene and Peter G. M. Wuts, Protecting Groups in Organic Synthesis, (Third Edition, John Wiley & Sons, Inc, 1999) - the entire contents of which is incorporated herein by reference.
  • the synthesis of the peptides of the present invention may be performed in four stages.
  • amino acids may be protected for incorporation into the peptide, such as the protection of -biphenylglycine as Fmoc-biphenylglycine.
  • a partially protected linear peptide which selectively exposes only the functional groups required for cyclization may be synthesised using solid phase techniques.
  • the cyclization reaction may be performed in solution to produce the protected cyclic lipopeptide.
  • Fourth the remaining side chain protecting groups may be deprotected to furnish the peptide.
  • chromatographic techniques such as high-performance liquid chromatography (HPLC) and reversed-phase HPLC may be used.
  • HPLC high-performance liquid chromatography
  • the peptides may be characterised by mass spectrometry and/or other appropriate methods.
  • the peptide comprises one or more functional groups that may be protonated or deprotonated (for example at physiological pH) the peptide may be prepared and/or isolated as a pharmaceutically acceptable salt. It will be appreciated that the peptide may be zwitterionic at a given pH.
  • pharmaceutically acceptable salt refers to the salt of a given compound, wherein the salt is suitable for administration as a pharmaceutical. For example, such salts may be formed by the reaction of an acid or a base with an amine or a carboxylic acid group respectively.
  • Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids.
  • inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like.
  • organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
  • Pharmaceutically acceptable base addition salts may be prepared from inorganic and organic bases.
  • Corresponding counterions derived from inorganic bases include the sodium, potassium, lithium, ammonium, calcium and magnesium salts.
  • Organic bases include primary, secondary and tertiary amines, substituted amines including naturally- occurring substituted amines, and cyclic amines, including isopropylamine, trimethyl amine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2- dimethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N-alkylglucamines, theobromine, purines, piperazine, piperidine, and N-ethylpiperidine.
  • Acid/base addition salts tend to be more soluble in aqueous solvents than the corresponding free acid/base forms.
  • the compounds of the invention may be in crystalline form or as solvates (e.g. hydrates) and it is intended that both forms are within the scope of the present invention.
  • solvate is a complex of variable stoichiometry formed by a solute (in this invention, a peptide of the invention) and a solvent. Such solvents should not interfere with the biological activity of the solute. Solvents may be, by way of example, water, ethanol or acetic acid. Methods of solvation are generally known within the art.
  • the compounds of the invention may be in the form of a "pro-drug".
  • pro-drug is used in its broadest sense and encompasses those derivatives that are converted in vivo to the peptides of the invention. Such derivatives would readily occur to those skilled in the art and include, for example, compounds where a free hydroxy group is converted into an ester derivative or a ring nitrogen atom is converted to an N-oxide. Examples of ester derivatives include alkyl esters (for example acetates, lactates and glutamines), phosphate esters and those formed from amino acids (for example valine). Any compoimd that is a prodrug of a peptide of the invention is within the scope and spirit of the invention. Conventional procedures for the preparation of suitable prodrugs according to the invention are described in text books, such as "Design of Prodrugs” Ed. H. Bundgaard, Elsevier, 1985 - the entire contents of which is incorporated herein by reference.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a peptide as hereinbefore defined, or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier or diluent.
  • composition is intended to include the formulation of an active ingredient with encapsulating material as carrier, to give a capsule in which the active ingredient (with or without other carrier) is surrounded by carriers.
  • the peptide as hereinbefore described, or pharmaceutically acceptable salt thereof may be the sole active ingredient administered to the subject, the administration of other active ingredient(s) with the compound is within the scope of the invention.
  • the compound could be administered with one or more therapeutic agents in combination.
  • the combination may allow for separate, sequential or simultaneous administration of the peptide as hereinbefore described with the other active ingredient(s).
  • the combination may be provided in the form of a pharmaceutical composition.
  • the route of administration and the nature of the pharmaceutically acceptable carrier will depend on the nature of the condition and the mammal to be treated. It is believed that the choice of a particular carrier or delivery system, and route of administration could be readily determined by a person skilled in the art. In the preparation of any formulation containing the peptide actives care should be taken to ensure that the activity of the peptide is not destroyed in the process and that the peptide is able to reach its site of action without being destroyed. In some circumstances it may be necessary to protect the peptide by means known in the art, such as, for example, micro encapsulation. Similarly the route of administration chosen should be such that the peptide reaches its site of action.
  • Those skilled in the art may readily determine appropriate formulations for the peptides of the present invention using conventional approaches. Identification of preferred pH ranges and suitable excipients, for example antioxidants, is routine in the art. Buffer systems are routinely used to provide pH values of a desired range and include carboxylic acid buffers for example acetate, citrate, lactate and succinate. A variety of antioxidants are available for such formulations including phenolic compounds such as BHT or vitamin E, reducing agents such as methionine or sulphite, and metal chelators such as EDTA.
  • phenolic compounds such as BHT or vitamin E
  • reducing agents such as methionine or sulphite
  • metal chelators such as EDTA.
  • the peptide as hereinbefore described, or pharmaceutically acceptable salt thereof may be prepared in parenteral dosage forms, including those suitable for intravenous, intrathecal, and intracerebral or epidural delivery.
  • the pharmaceutical forms suitable for injectable use include sterile injectable solutions or dispersions, and sterile powders for the extemporaneous preparation of sterile injectable solutions. They should be stable under the conditions of manufacture and storage and may be preserved against reduction or oxidation and the contaminating action of microorganisms such as bacteria or fungi.
  • the solvent or dispersion medium for the injectable solution or dispersion may contain any of the conventional solvent or carrier systems for peptide actives, and may contain, for example, water, ethanol, polyol (for example, glycerol, propylene glycol and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils.
  • the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about where necessary by the inclusion of various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal and the like. In many cases, it will be preferable to include agents to adjust osmolality, for example, sugars or sodium chloride.
  • the formulation for injection will be isotonic with blood.
  • Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminium monostearate and gelatin.
  • Pharmaceutical forms suitable for injectable use may be delivered by any appropriate route including intravenous, intramuscular, intracerebral, intrathecal, epidural injection or infusion.
  • Sterile injectable solutions are prepared by incorporating the active peptide in the required amount in the appropriate solvent with various of the other ingredients such as those enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the various sterilised active ingredient into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
  • preferred methods of preparation are vacuum drying or freeze-drying of a previously sterile-filtered solution of the active ingredient plus any additional desired ingredients.
  • compositions include oral and enteral formulations of the present invention, in which the active peptide may be formulated with an inert diluent or with an assimilable edible carrier, or it may be enclosed in hard or soft shell gelatin capsule, or it may be compressed into tablets, or it may be incorporated directly with the food of the diet.
  • the active peptide may be incorporated with excipients and used in the form of ingestible tablets, buccal or sublingual tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • the amount of active peptide in such therapeutically useful compositions is such that a suitable dosage will be obtained.
  • the tablets, troches, pills, capsules and the like may also contain the components as listed hereafter: a binder such as gum, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such a sucrose, lactose or saccharin may be added or a flavouring agent such as peppermint, oil of wintergreen, or cherry flavouring.
  • a binder such as gum, acacia, corn starch or gelatin
  • excipients such as dicalcium phosphate
  • a disintegrating agent such as corn starch, potato starch, alginic acid and the like
  • a lubricant such as magnesium stearate
  • a sweetening agent such as sucrose, lactose or saccharin may be added or a flavouring agent such as peppermint, oil of winter
  • tablets, pills, or capsules may be coated with shellac, sugar or both.
  • a syrup or elixir may contain the active peptide, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavouring such as cherry or orange flavour.
  • any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed.
  • the active peptide(s) may be incorporated into sustained-release preparations and formulations, including those that allow specific delivery of the active peptide to specific regions of the gut.
  • Liquid formulations may also be administered enterally via a stomach or oesophageal tube.
  • Enteral formulations may be prepared in the form of suppositories by mixing with appropriate bases, such as emulsifying bases or water-soluble bases. It is also possible, but not necessary, for the peptides of the present invention to be administered topically, intranasally, intravaginally, intraocularly and the like.
  • the present invention also extends to any other forms suitable for administration, for example topical application such as creams, lotions and gels, or compositions suitable for inhalation or intranasal delivery, for example solutions, dry powders, suspensions or emulsions.
  • topical application such as creams, lotions and gels
  • compositions suitable for inhalation or intranasal delivery for example solutions, dry powders, suspensions or emulsions.
  • the peptides of the present invention may be administered by inhalation in the form of an aerosol spray from a pressurised dispenser or container, which contains a propellent such as carbon dioxide gas, dichlorodifluoromethane, nitrogen, propane or other suitable gas or combination of gases.
  • a propellent such as carbon dioxide gas, dichlorodifluoromethane, nitrogen, propane or other suitable gas or combination of gases.
  • the peptides may also be administered using a nebuliser.
  • compositions include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like.
  • the use of such media and agents for pharmaceutical active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, use thereof in the therapeutic compositions is contemplated.
  • Supplementary active ingredients can also be incorporated into the compositions. It is especially advantageous to formulate the compositions in dosage unit form for ease of administration and uniformity of dosage.
  • Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with the required pharmaceutically acceptable vehicle.
  • the specification for the novel dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the active material and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding active materials for the treatment of disease in living subjects having a diseased condition in which bodily health is impaired as herein disclosed in detail.
  • the principal active ingredient may be compounded for convenient and effective administration in therapeutically effective amounts with a suitable pharmaceutically acceptable vehicle in dosage unit form.
  • a unit dosage form can, for example, contain the principal active compound in amounts ranging from 0.25 ⁇ g to about 2000 mg. Expressed in proportions, the active compound may be present in from about 0.25 ⁇ g to about 2000 mg/mL of carrier.
  • the dosages are determined by reference to the usual dose and manner of administration of the said ingredients.
  • the term "therapeutically effective amount” refers to that amount which is sufficient to effect treatment, as defined below, when administered to an animal, preferably a mammal, more preferably a human in need of such treatment.
  • treatment and “treating” as used herein cover any treatment of a condition or disease in an animal, preferably a mammal, more preferably a human, and includes: (i) inhibiting the bacterial infection, eg arresting its proliferation; (ii) relieving the infection, eg causing a reduction in the severity of the infection; or (iii) relieving the conditions caused by the infection, eg symptoms of the infection.
  • prevention and preventing cover the prevention or prophylaxis of a condition or disease in an animal, preferably a mammal, more preferably a human and includes preventing the bacterial infection from occurring in a subject which may be predisposed to infection but has not yet been diagnosed as being infected.
  • the bacterial infection is a Gram-negative bacterial infection.
  • the bacterial infection may be caused by one or more species selected from one or more of the genera: Acinetobacter; Actinobacillus; Bartonella; Bordetella; Brucella; Burkholderia; Campylobacter; Cyanobacteria; Enterobacter; Erwinia; Escherichia; Francisella; Helicobacter; Hemophilus; Klebsiella; Legionella; Moraxella; Morganella; Neisseria; Pasteurella; Proteus; Providencia; Pseudomonas; Salmonella; Serratia; Shigella; Stenotrophomonas; Treponema; Vibrio; and Yersinia.
  • species are Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae, Stenotrophomonas maltophilia; Escherichia coli and Salmonella enterica.
  • the bacterial infection is a Gram-positive bacterial infection.
  • the bacterial infection may be caused by one or more species selected from one or more of the genera: Actinobacteria; Bacillus; Clostridium; Corynebacterium; Enterococcus; Listeria; Nocardia; Staphylococcus; and Streptococcus. Specific examples of species are Staphylococcus aureus; and Enterococcus faecium.
  • L-2-aminodecanoic acid is available commercially from a number of sources including: www.chemicalbook.com; www.anaspec.com; www.chemexper.com; and www.icis.com.
  • L-2-aminooctanoic acid is available commercially from a number of sources including: www.chemicalbook.com.
  • Fmoc deprotection was performed using the default instrument protocol: 20% piperidine in DMF (1 x 30 s, 1 x 3 min) at 75 °C (35 W microwave power). Couplings were performed using the default instrument protocol: 5 eq of Fmoc amino acid and HCTU with activation using diisopropylethylamine (10 eq) in dimethylformamide over 2 min at room temperature then at 50 °C (25 W microwave power) over 4 min.
  • Coupling of the N-terminal octanoyl group was performed twice using the default instrument protocol: 5 eq of octanoic acid and HCTU with activation using diisopropylethylamine (10 eq) in dimethylformamide over 2 min at room temperature then at 50 °C (25 W microwave power) over 4 min. Removal of the ivDde group was achieved using 2% hydrazine in DMF.
  • Cyclization of the linear sequence was performed using (DPP A) diphenylphosphorylazide (3 eq) and (DIPEA) diisopropylethylamine (6 eq) in DMF overnight.
  • the crude protected cyclic peptide was isolated by lyophilization from a mixture of acetonitrile and water. The residual protecting groups were removed by treating the peptide with 97.5% TFA: 2.5% triisopropylsilane.
  • Example 2 Measurements of minimum inhibitory concentrations (MICs) MICs of the lipopeptides (trifluoroacetic acid salt, TFA) were determined by broth microdilution in cation-adjusted Mueller-Hinton broth (CAMHB) (Oxoid Australia, Thebarton, SA, Australia) according to Clinical and Laboratory Standards Institute standards (Clinical and Laboratory Standards Institute. Performance standards for antimicrobial susceptibility testing; eighteenth informational supplement M100-S18. Wayne, PA, 2008). Colistin (sulfate) was employed as control.
  • CAMHB cation-adjusted Mueller-Hinton broth
  • Both Gram-negative and Gram-positive bacteria were examined for 1 and 2: (1) for Pseudomonas aeruginosa, ATCC 27853 and 4 polymyxin-resistant multidrug-resistant clinical isolates; (2) for Acinetobacter baumannii, ATCC 19606, one laboratory-derived polymyxin-resistant strain and one polymyxin-resistant multidrug-resistant clinical isolate; (3) for Klebsiella pneumoniae, ATCC 13883 and one polymyxin-resistant clinical isolate; (4) for Stenotrophomonas maltophilia, 3 polymyxin-resistant multidrug-resistant clinical isolates; (5) for Gram-positive bacteria, Staphylococcus aureus ATCC 43300 (methicillin resistant), ATCC 700698 (vancomycin intermediate resistant) and ATCC 700699 (vancomycin resistant), and Enterococcus faecium ATCC 700221 (vancomycin resistant). Compounds 3 to 8 were examined against P. aeruginosa ATCC 27853 and one
  • the peptides of the present invention showed activity against Gram-positive pathogens S. aureus and E. faecium with MICs 4 - 16 mg/L. This implies that the peptides of the present invention may have secondary cellular target(s) because Gram-positive bacteria do not possess lipopolysaccharide, a well-accepted primary target of polymyxins in Gram- negative bacteria.
  • Example 3 Static time-kill studies The time-killing kinetics of compound 1 (TFA) and colistin (sulfate) were examined against a polymyxin-resistant multidrug-resistant clinical P. aeruginosa isolate (strain D) and P. aeruginosa ATCC 27853 (polymyxin susceptible), and compound 1 (TFA) against a vancomycin-resistant S. aureus ATCC 700699 (intrinsically polymyxin resistant).
  • Compound 1 or colistin was added to a logarithmic-phase broth culture of approximately 10 6 CFU/mL to yield concentrations of 0, 0.5, 1 and 4> MIC of the isolate (32 mg/L for colistin against the polymyxin-resistant P.
  • aeruginosa isolate Viable counting was performed on samples collected at 0, 0.5, 1, 2, 3, 4 and 24 h (plus 5 and 6 h for 5. aureus ATCC 700699) after antibiotic addition. After appropriate dilutions with saline, samples of bacterial cell suspension (50 ⁇ ) were spirally plated on nutrient agar plates (Medium Preparation Unit, University of Melbourne) using a Whitley automatic spiral plater (WASP, Don Whitley Scientific, West Yorkshire, UK). Colonies were counted by a ProtoCOL automated colony counter (Synbiosis, Cambridge, UK) after 24 h incubation of subcultures at 35 °C. The lower limit of counting was 20 CFU/mL.
  • Figure 2 shows that compound 1 had comparable antibacterial killing to colistin against polymyxin-susceptible P. aeruginosa ATCC 27853.
  • Compound 1 at 4x MIC achieved >5 log kill at 24 h against vancomycin-resistant S. aureus ATCC 700699, showing its antibacterial activity against Gram-positive S. aureus which is intrinsically resistant to polymyxin B and colistin (Figure 3).
  • the time-kill data are consistent with the MIC results above.

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Abstract

Cette invention concerne des composés antimicrobiens et leurs utilisations, et en particulier, des antibiotiques peptidiques qui peuvent être utilisés pour traiter les infections bactériennes telles que les infections bactériennes à Gram négatif, en particulier, celles provoquées par des pathogènes multirésistants aux médicaments (MDR).
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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9234006B2 (en) 2011-11-18 2016-01-12 Novacta Biosystems Limited Compounds
WO2016083531A1 (fr) * 2014-11-26 2016-06-02 New Pharma Licence Holdings Limited Composés
WO2016100578A2 (fr) 2014-12-16 2016-06-23 Micurx Pharmaceuticals, Inc. Polymyxines antimicrobiennes pour le traitement d'infections bactériennes
WO2017054047A1 (fr) * 2015-09-29 2017-04-06 Monash University Composés antimicrobiens dérivés de polymyxine
WO2019085926A1 (fr) * 2017-10-31 2019-05-09 上海医药工业研究院 Analogue de polymyxine et son procédé de préparation
US10407467B2 (en) 2013-05-22 2019-09-10 New Pharma Licence Holdings Limited Polymyxin derivatives and their use in combination therapy together with different antibiotics
US10526343B2 (en) 2018-03-26 2020-01-07 University Of Sharjah Heterocyclic systems and pharmaceutical applications thereof
CN110669107A (zh) * 2018-07-02 2020-01-10 上海医药工业研究院 抗菌肽及其制备方法
USRE48335E1 (en) 2014-04-01 2020-12-01 Monash University Polymyxin derivatives as antimicrobial compounds
WO2021150792A1 (fr) 2020-01-21 2021-07-29 Micurx Pharmaceuticals, Inc. Nouveaux composés et composition pour la thérapie ciblée de cancers associés au rein
US11459357B2 (en) 2018-06-25 2022-10-04 Spero Therapeutics, Inc. Polymyxin compounds

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006083317A2 (fr) * 2004-07-01 2006-08-10 Biosource Pharm, Inc. Antibiotiques peptidiques et leurs methodes de fabrication
WO2008017734A1 (fr) * 2006-08-11 2008-02-14 Northern Antibiotics Oy Dérivés de polymyxine et leurs utilisations
WO2010130007A1 (fr) * 2009-05-14 2010-11-18 Monash University Composés antimicrobiens

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006083317A2 (fr) * 2004-07-01 2006-08-10 Biosource Pharm, Inc. Antibiotiques peptidiques et leurs methodes de fabrication
WO2008017734A1 (fr) * 2006-08-11 2008-02-14 Northern Antibiotics Oy Dérivés de polymyxine et leurs utilisations
WO2010130007A1 (fr) * 2009-05-14 2010-11-18 Monash University Composés antimicrobiens

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
KANAZAWA ET AL.: "Antimicrobial Activity of Polymyxin B3 Analogs modified at the Hydrophobic Amino Acids", PEPTIDE SCIENCE (2003), 2004, pages 255 - 256 *
KANAZAWA ET AL.: "Contribution of Each Amino Acid Residue in Polymyxin B3 to Antimicrobial and Lipopolysaccharide Binding Activity", CHEMICAL & PHARMACEUTICAL BULLETIN, vol. 57, no. 3, 2009, pages 240 - 244 *

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9234006B2 (en) 2011-11-18 2016-01-12 Novacta Biosystems Limited Compounds
US10407467B2 (en) 2013-05-22 2019-09-10 New Pharma Licence Holdings Limited Polymyxin derivatives and their use in combination therapy together with different antibiotics
USRE48335E1 (en) 2014-04-01 2020-12-01 Monash University Polymyxin derivatives as antimicrobial compounds
CN107108699A (zh) * 2014-11-26 2017-08-29 新药物许可控股有限公司 化合物
AU2015352440B2 (en) * 2014-11-26 2020-02-06 Spero Therapeutics, Inc. Compounds
US12146004B2 (en) 2014-11-26 2024-11-19 Spero Therapeutics, Inc. Polymyxin compounds and uses thereof
WO2016083531A1 (fr) * 2014-11-26 2016-06-02 New Pharma Licence Holdings Limited Composés
WO2016100578A2 (fr) 2014-12-16 2016-06-23 Micurx Pharmaceuticals, Inc. Polymyxines antimicrobiennes pour le traitement d'infections bactériennes
US9771394B2 (en) 2014-12-16 2017-09-26 Micurx Pharmaceuticals, Inc. Antimicrobial polymyxins for treatment of bacterial infections
WO2017054047A1 (fr) * 2015-09-29 2017-04-06 Monash University Composés antimicrobiens dérivés de polymyxine
CN108350034A (zh) * 2015-09-29 2018-07-31 莫纳什大学 抗微生物的多黏菌素衍生的化合物
AU2016331658B2 (en) * 2015-09-29 2021-04-01 Monash University Antimicrobial polymyxin derivative compounds
US11225505B2 (en) 2015-09-29 2022-01-18 Monash University Antimicrobial polymyxin derivative compounds
CN108350034B (zh) * 2015-09-29 2022-03-11 莫纳什大学 抗微生物的多黏菌素衍生的化合物
WO2019085926A1 (fr) * 2017-10-31 2019-05-09 上海医药工业研究院 Analogue de polymyxine et son procédé de préparation
CN111247162A (zh) * 2017-10-31 2020-06-05 正大天晴药业集团股份有限公司 多黏菌素类似物及其制备方法
US10526343B2 (en) 2018-03-26 2020-01-07 University Of Sharjah Heterocyclic systems and pharmaceutical applications thereof
US11459357B2 (en) 2018-06-25 2022-10-04 Spero Therapeutics, Inc. Polymyxin compounds
CN110669107A (zh) * 2018-07-02 2020-01-10 上海医药工业研究院 抗菌肽及其制备方法
CN110669107B (zh) * 2018-07-02 2024-04-02 上海医药工业研究院 抗菌肽及其制备方法
WO2021150792A1 (fr) 2020-01-21 2021-07-29 Micurx Pharmaceuticals, Inc. Nouveaux composés et composition pour la thérapie ciblée de cancers associés au rein

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