WO2012020221A1 - Composés - Google Patents

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Publication number
WO2012020221A1
WO2012020221A1 PCT/GB2011/001193 GB2011001193W WO2012020221A1 WO 2012020221 A1 WO2012020221 A1 WO 2012020221A1 GB 2011001193 W GB2011001193 W GB 2011001193W WO 2012020221 A1 WO2012020221 A1 WO 2012020221A1
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WO
WIPO (PCT)
Prior art keywords
alpha
compound
amino acid
nitrogen
aureus
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PCT/GB2011/001193
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English (en)
Inventor
Sjoerd Nicolaas Wadman
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Novacta Biosystems Limited
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Publication of WO2012020221A1 publication Critical patent/WO2012020221A1/fr

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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
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present disclosure relates to certain novel compounds, pharmaceutical compositions comprising same and use of the compounds and compositions for the treatment of microbial infection, particularly Methicillin-resistant Staphylococcus aureus (MRSA) infection.
  • MRSA Methicillin-resistant Staphylococcus aureus
  • antibiotic compounds have a complicated chemical structure and in particular a complicated stereochemical structure.
  • Actagardine is a natural product prepared from Actinoplanes garbadinensis, and has antibiotic properties, see for example EP0195359, in particular against Streptococcus pyogenes, which causes scarlet fever and strep throat infection.
  • EP0195359 in particular against Streptococcus pyogenes, which causes scarlet fever and strep throat infection.
  • a new family of compounds based on deoxyactagardine B was recently disclosed in
  • Deoxyactagardine B is prepared from A. liguriae and has a number of distinguishing features from actagardine, in particular the compounds have differences in the amino acid sequence of the core structure. Additionally actagardine contains an oxidised lanthionine bridge in contrast to deoxyactagardine B, wherein all the lanthionine bridges are present in a reduced form. Obviously different genes and biological machinery is required to make the different compounds. Furthermore, these compounds show different activity when tested against a range of common pathogens. In some instances actagardine and certain compounds derived therefrom exhibit greater activity against a given pathogen than deoxyactagardine B and derivatives thereof. Interestingly, against certain other pathogens deoxyactagardine B and compounds derived therefrom exhibit greater activity than actagardine and derivatives thereof.
  • Actagardine activity against MRSA when measured by a standard test such as minimum inhibitory concentrations (MICs) may be as high as about 32 pg/mL, depending on the strain tested. Thus actagardine has only low to moderate activitity against MRSA because the higher the MIC value the less antimicrobial activity the compound has.
  • MICs minimum inhibitory concentrations
  • MRSA is a bacterium responsible for d iff i cult-to-treat infections in humans and animals.
  • the particular strain(s) of Staphylococcus aureus, labeled MRSA is/are resistant to a large group of antibiotics called beta-lactams, which include the penicillins and cephalosporins.
  • the strain(s) received a significant amount of attention in the media and was branded a "superbug".
  • Patients with open wounds, those who have procedures involving invasive devices, and those with a weakened immune system are most at risk of infection, especially during hospitalization.
  • the infection is highly contagious and if it is identified on a hospital ward, the ward may be closed until it is decontaminated.
  • antimicrobial compounds with activity against MRSA would be particularly useful.
  • X represents a bond or an amino acid residue
  • R 3 represents H or C1-6 alkyl
  • R 3 together with R 4 and the nitrogen to which they are attached form a 5 or 6 membered heterocyclic group optionally including a further heteroatom selected from N, O or S, wherein said heterocyclic group is substituted by one or two groups independently selected from (Q) m (CH 2 )qNR B C(0)CCI 3 , -YAr 1 , and -C(0)CCI 3 wherein the latter is a substituent on nitrogen;
  • R 5 together with the carbon to which it is attached and the alpha-nitrogen and alpha- carbonyl represents an amino acid residue
  • R A represents a bond, -C 0-9 alkylC 6- ioaryl, -C0-9 alkylC 5 .nheteroaryl,
  • L represents a straight or branched Co-15 alkyl chain wherein optionally one or more carbons is/are replaced by a heteroatom independently selected from N, O or S, wherein said chain is optionally substituted by one or more, halo, oxo or nitro groups with the proviso that there are at least one or two (such as two) carbons between the heteroatom and the N of the group -NR 3 R 4 ;
  • Y represents a straight or branched Co-15 alkyl chain wherein optionally one or more carbons are replaced by a heteroatom independently selected from N, O or S, wherein said chain is optionally substituted by one or more (e.g. 1 or 2), halo, oxo or nitro groups;
  • Ar 1 represents phenyl or naphthyl substituted by:
  • phenyl or naphthyl is optionally substituted by one, two, three or four groups independently selected from halo (such as chloro), nitro, C 1 .3 haloalkyl,
  • R represents H or d -3 alkyl
  • Q represents a heteroatom selected from N, O or S
  • Z represents H, 0 1-6 alkyl, an amino acid residue
  • n 0 or 1 ;
  • n 0, 1 , 2, 3 or 4;
  • p 0 or 1 ;
  • q 0, 1 , 2, 3 or 4;
  • r represents 2, 3 or 4;
  • the compounds according to the present disclosure generally have activity against a broad range of gram positive bacteria, in particular those associated with soft tissue infections, in particular the gram positive bacteria MRSA and thus are likely to be useful in the treatment of infections of the same.
  • an activity of 4 pg/mL or less is considered to be a good indicator of antimicrobial activity, in particular because the compounds of the present disclosure show good activity in vivo.
  • Alkyl in the context of the present disclosure refers to straight chain or branched chain alkyl, for example methyl, ethyl, n-propyl, isopropyl, n-butyl or t-butyl.
  • Heterocyclic group as employed herein is a saturated or partially unsaturated ring (i.e. a non-aromatic mono or bicyclic ring) comprising one or more heteroatoms selected from O, N and S, for example a 5 or 6 membered heterocycle group such as pyrroline (in particular 1-, 2- or 3-pyrroline), pyrrolidine, tetrahydrofuran, tetrahydrothiophene, pyrazoline (in particular 2- or 3-pyrazoline), 2-imidazoline, pyrazolidine, imidazolidine, 3-dioxolane, thiazolidine, isoxazolidine, pyran (in particular 2H or 4H-pyran), 3,4-dihydro-2H-pyran, piperidine, 1 ,4-oxazine, 1 ,4-dioxine, piperazine, morpholine, 1 ,4-dioxane.
  • a 5 or 6 membered heterocycle group
  • heterocycle may replace a carbon atom in the ring and therefore C 5 .n heterocycle and a 5 to 11 membered heterocycle are used interchangeably.
  • Other definitions of heterocycles will be construed similarly.
  • the heterocycle may be linked through carbon or nitrogen.
  • CycloalkyI refers to a saturated or partially unsaturated carbocyclic ring, i.e. a non-aromatic carbocyclic ring, for example a C 3 . 7 cycloalkyl ring, such as cyclopropyl, cyclopentyl or cyclohexyl.
  • Heteroaryl refers to an aromatic carbocycle comprising one or more heteroatoms selected from O, N or S including a bicyclic system wherein one or both rings are aromatic, for example a 5-11 membered heteroaryl, such as pyrrole, furan, thiophene, pyrazole, imidazole, oxazole, isoxazole, thiazole, isothiazole, triazole, oxadiazole, furazan, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine, 1 H-pyrrolizine, indolizine, indole, isoindoie, benzofuran, isobenzofuran, indoiine, isoindoiine, benzothiophene, indazole, benzimidazole, purine, quinoline, isoquinoline, chromane, isochromane, chromene,
  • heteroaryl may replace a carbon atom in the ring and therefore C 5 .n heteroaryl and a 5 to 11 membered heteroaryl are used interchangeably. Other definitions of heteroaryls will be construed similarly.
  • the heteroaryl may be linked through carbon or a nitrogen, as appropriate, in particular carbon.
  • Halogen as employed herein refers to fluoro, chloro or bromo, such as fluoro or chloro.
  • Haloalkyl as employed herein refers to alkyl groups having 1 to 6 halogen atoms, for example 1 to 5 halogens , such as per haloalkyl, in particular perfluoroalkyi, more specifically -CCI2CCI3, CCI3, -CF2CF3 or -CF 3 .
  • Heteroalkyl as employed herein represents a straight or branched C 0 .is alkyl chain wherein optionally one or more carbons (such as 2 or 3) are replaced by a heteroatom independently selected from N, O or S, wherein said chain is optionally substituted by one or more (for example 1 or 2), oxo or nitro groups.
  • heteroatom may replace a primary, secondary or tertiary carbon, that is -CH 3 , -CH 2 -, a -CH- or a branched carbon group, as technically appropriate.
  • An oxo substituent may be located on a carbon or sulphur atom as desired.
  • Amino acid as employed herein is a natural or non-naturally occurring amino acid, for example a natural amino acid such as alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan and tyrosine.
  • a natural amino acid such as alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan and tyrosine.
  • the amino acid of the relevant variable is a proteinogenic amino acid.
  • Proteinogenic amino acid as employed herein, is intended to refer to amino acids found in proteins.
  • R 1 together with the carbon to which it is attached and the alpha- nitrogen and alpha-carbonyl is a natural amino acid, for example cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan and tyrosine.
  • R 2 together with the carbon to which it is attached and the alpha- nitrogen and alpha-carbonyl is a natural amino acid, for example cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan and tyrosine.
  • R 1 together with the carbon to which it is attached and the
  • alpha-nitrogen and alpha-carbonyl is isoleucine or valine.
  • R 2 together with the carbon to which it is attached and the
  • alpha-nitrogen and alpha-carbonyl leucine or valine are alpha-nitrogen and alpha-carbonyl leucine or valine.
  • R 1 together with the carbon to which it is attached and the
  • alpha-nitrogen and alpha-carbonyl is valine and R 2 together with the carbon to which it is attached and the alpha-nitrogen and alpha-carbonyl is leucine.
  • R 1 together with the carbon to which it is attached and the
  • alpha-nitrogen and alpha-carbonyl is isoleucine and R 2 together with the carbon to which it is attached and the alpha-nitrogen and alpha-carbonyl is valine.
  • m is 0.
  • n 0 or 1.
  • p is 0.
  • q is 1.
  • r is 2.
  • R 3 is H.
  • R 4 is:
  • R 4 represents R A -L-
  • R 3 and R 4 together with the nitrogen to which they are attached form a 5 or 6 membered heterocyclic group optionally including a further heteroatom (for example 1 , 2, or 3) selected from N, O, and S, for example pyrrolidine, piperidine, piperazine, such as piperazine or piperidine bearing one -YAr 1 substituent.
  • a further heteroatom for example 1 , 2, or 3 selected from N, O, and S, for example pyrrolidine, piperidine, piperazine, such as piperazine or piperidine bearing one -YAr 1 substituent.
  • R 3 and R 4 together with the nitrogen to which they are attached form a piperazine bearing, for example on the nitrogen at position four, a trichloroacetyl group and optionally in another position in the ring bearing a -YAr 1 substituent.
  • R 3 and R 4 together with the nitrogen to which they are attached form a piperazine bearing, for example on the nitrogen at position four, a -YAr 1 substituent.
  • R 5 together with the carbon to which it is attached and the alpha- nitrogen and alpha-carbonyl is a natural amino acid, for example cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan and tyrosine, in particular valine.
  • a natural amino acid for example cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan and tyrosine, in particular valine.
  • R A is a bond.
  • L or Ar 1 is directly linked to the nitrogen of -NR 3 R 4 .
  • R A is C 0 .9 alkylC 6-10 aryl, such as Ci alkyl-, C 2 alkyl-, C 3 alkyl-, C 4 alkyl-, C 5 alkyl-, C 6 alkyl-, C 7 alkyl- or C 8 alkyl-phenyl or naphthyl, in particular phenyl.
  • C 0 is employed then C 6 .ioaryl will be linked directly to the nitrogen of -NR 3 R 4 .
  • R A is C0-9 alkylCs-nheteroaryl, C 0- 9 alkylC 3 . 6 cycloalkyl, or a -Co-9 alkylC 5 -n heterocyclic group.
  • R A is C 0 . 9 alkylC 5 .nheteroaryl, such as alkyl-, C 2 alkyl-, C 3 alkyl-, C 4 alkyl-, C 5 alkyl-, C 6 alkyl-, C 7 alkyl- or C 8 alkyl-heteroaryl, for example selected from pyrrole, furan, thiophene, pyrazole, imidazole, oxazole, isoxazole, thiazole, isothiazole, triazole, oxadiazole, furazan, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine, 1 H-pyrrolizine, indolizine, indole, isoindole, benzofuran, isobenzofuran, indoline, isoindoline, benzothiophene, indazole, benzimi
  • R A is C 0 . 9 alkylC 3-6 cycloalkyl, for example Ci alkyl-, C 2 alkyl-, C 3 alkyl-, C 4 alkyl-, C 5 alkyl-, C 6 alkyl-, C 7 alkyl- or C 8 alkyl-C 3-6 cycloalkyl selected from cyclopropyl, cyclopentyl or cyclohexyl.
  • C 0 is employed then C 3-6 cycloalkyl will be linked directly to the nitrogen of -NR 3 R 4 .
  • R A is -C 0 -g alkylC 5-l1 heterocyclic group for example C alkyl-, C 2 alkyl-, C 3 alkyl-, C 4 alkyl-, C 5 alkyl-, C 6 alkyl-, C 7 alkyl- or C 8 alkyl-heterocyclic group for example selected from pyrroline (such as 1 , 2 or 3-pyrroline), pyrrolidine, tetrahydrofuran, tetrahydrothiophene, pyrazoline (such as 2 or 3-pyrazoline), 2-imidazoline, pyrazolidine, imidazolidine, 3-dioxolane, thiazolidine, isoxazolidine, pyran (such as 2H or 4H-pyran), 3,4-dihydro-2H-pyran, piperidine, 1 ,4-oxazine, 1 ,4-dioxine, piperazine, morpholine and 1 ,4-d
  • R A is a linking group and thus when it comprises a ring such as a cycloalkyl, heterocycle, heteroaryl or any I then -LAr 1 may be attached via the ring.
  • L in one embodiment is C 0 .
  • the Ar 1 may be linked directly to the nitrogen of -NR 3 R 4 .
  • Ar 1 may be linked to R A
  • L is a straight or branched, such as straight, alkyl chain wherein optionally one or more, such as one, carbon(s) is/are replaced by a heteroatom selected from O, N and S, such as N, and optionally substituted by oxo (e.g. 1 or 2).
  • L is a straight C 1-3 alkyl chain (such as ⁇ alkyl), such as wherein none of the carbons are replaced by a heteroatom, e.g. wherein the chain does not bear any optional substituents.
  • L is -(CH 2 )iNH(CH 2 ) j or -(CH 2 ) k NHC(0)- wherein i is an integer 1 to 12, j is 0 or 1 and k is and integer 1 to 14.
  • L is a straight C 6-9 alkyl chain, wherein one carbon is replaced by a heteroatom, such as N, and the chain optionally bears one oxo substituent, in particular -CH 2 CH 2 CH 2 NHCH 2 - or -CH 2 CH 2 CH 2 NHC(0)-.
  • a heteroatom in L is not linked directly to the nitrogen of -NR 3 R 4 .
  • a heteroatom in L is separated from the nitrogen of -NR 3 R 4 by at least two carbon atoms.
  • Y represents C 0 .
  • the Ar 1 will be linked directly to the relevant heterocycle group.
  • Y is a straight or branched, such as straight, C 1-5 alkyl chain (for example C 2 , C 3 or C 4 chain, such as a C 4 alkyl chain) wherein optionally one or more, such as one, carbon(s) is/are replaced by a heteroatom selected from O, N and S, such as N, and optionally substituted by oxo (for example 1 or 2 oxo substituents, in particular on carbon), such as -CH 2 - or -CH 2 CH 2 NHC(0)-.
  • C 1-5 alkyl chain for example C 2 , C 3 or C 4 chain, such as a C 4 alkyl chain
  • oxo for example 1 or 2 oxo substituents, in particular on carbon
  • Y is bonded to a heteroatom, such as a nitrogen, in the heterocyclic moiety formed by NR 3 R 4 .
  • a heteroatom such as a nitrogen
  • Ar 1 bears one group -(Q) m (CH 2 ) q NHC(0)CCI 3 and optionally one or two groups selected from chloro or nitro or a combination thereof.
  • m is 0 and q is 1.
  • Ar 1 does not bear any optional substituents.
  • Ar 1 is phenyl. In one embodiment Ar 1 is naphthyl.
  • R 1 , R 2 , Ar 1 , Y and Z are defined above for compounds of formula (I).
  • -NR 3 R 4 represents a substituent selected from Table 1
  • Z represents H, C 1-6 alkyl, for example methyl, ethyl, propyl or butyl, or an amino acid residue, for example selected from alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan and tyrosine, such as alanine or serine.
  • amino acid residue for example selected from alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan and tyrosine, such as alanine or
  • Z is H or alanine, such as H. In one embodiment Z is phenylalanine.
  • Deoxyactagardine B (3-(trichloroacetamidomethyl)benzylamine) monocarboxamide; and Deoxyactagardine B (4-(trichloroacetamidomethyl)benzylamine) monocarboxamide.
  • the compounds of the present disclosure may be in the form of and/or may be administered as a pharmaceutically acceptable salt.
  • suitable salts see Berge et a/., J. Pharm. Sci, 1977, 66, 1-19.
  • a pharmaceutically acceptable salt may be readily prepared by using a desired acid or base as appropriate.
  • the salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent, for example, a compound of formula (I) may be dissolved in a suitable solvent, for example an alcohol such as methanol, and the acid may be added in the same solvent or another suitable solvent.
  • a suitable solvent for example an alcohol such as methanol
  • the resulting acid addition salt may then be precipitated directly, or by addition of a less polar solvent such as diisopropyl ether or hexane, and isolated by filtration.
  • Suitable addition salts are formed from inorganic or organic acids which form non-toxic salts and examples are lactobionate, mandelate (including (S)-(+)-mandelate, ( )-(-)- mandelate and (R,S)-mandelate), hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, nitrate, phosphate, hydrogen phosphate, glutamate, acetate, trifluoroacetate, maleate, malate, fumarate, lactate, tartrate, citrate, formate, gluconate, succinate, ethyl succinate (4-ethoxy-4- oxo-butanoate), pyruvate, oxalate, oxaloacetate, saccharate, benzoate, glucolate, glucamate (including N-methyl glucamate and N-ethyl glucamate) glucurinate, alkyl or aryl sulphonates
  • Pharmaceutically acceptable base salts include ammonium salts, alkali metal salts such as those of sodium and potassium, alkaline earth metal salts such as those of calcium and magnesium and salts with organic bases, including salts of primary, secondary and tertiary amines, such as isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexyl amine, /V-ethyl-D-glucamine, /V-methyl-D-glucamine and meglumine.
  • alkali metal salts such as those of sodium and potassium
  • alkaline earth metal salts such as those of calcium and magnesium
  • salts with organic bases including salts of primary, secondary and tertiary amines, such as isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexyl amine, /V-ethyl-D-glucamine, /V-methyl-D-glucamine and meglumine.
  • Salts may be employed to optimize the solubility of the compounds of the present disclosure.
  • solvates For example, a complex with water is known as a "hydrate”.
  • Solvates of the compounds of formula (I) are within the scope of the disclosure.
  • the salts of the compound of the disclosure may form solvates (e.g. hydrates) and the disclosure also includes all such solvates.
  • a process for the preparation of compounds according to the disclosure for example compounds of formula (I) comprising coupling a compound of formula (III :
  • each of the variables are defined above for compounds of formula (I) and X 1 represent -OH or an amino acid with a free C-terminal, with an amine comprising a trichloroacetyl moiety, for example an amine NHR 3 R 4 , wherein R 3 and R 4 are as defined for the compounds of formula (I).
  • prodrug as used herein means a compound which is converted within the body, e.g. by hydrolysis in the blood, into its active form that has medical effects.
  • Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, "Prodrugs as Novel Delivery Systems", Vol. 14 of the A.C.S. Symposium Series; Edward B. Roche, ed., “Bioreversible Carriers in Drug Design", American Pharmaceutical Association and Pergamon Press, 1987; and in D. Fleisher, S. Ramon and H. Barbra "Improved oral drug delivery: solubility limitations overcome by the use of prodrugs", Advanced Drug Delivery Reviews (1996) 19(2) 1 15-130, each of which are incorporated herein by reference.
  • Prodrugs are any covalently bonded carriers that release a compound of formula (I) in vivo when such prodrug is administered to a patient.
  • Prodrugs are generally prepared by modifying functional groups in a way such that the modification is cleaved, either by routine manipulation or in vivo, yielding the parent compound.
  • Prodrugs include, for example, compounds of this disclosure wherein hydroxy, amine or sulfhydryl groups are bonded to any group that, when administered to a patient, cleaves to form the hydroxy, amine or sulfhydryl groups.
  • prodrugs include (but are not limited to) acetate, formate and benzoate derivatives of alcohol, sulfhydryl and amine functional groups of the compounds of formula (I).
  • esters may be employed, such as methyl esters, ethyl esters, and the like. Esters may be active in their own right and/or be hydrolysable under in vivo conditions in the human body. Suitable pharmaceutically acceptable in vivo hydrolysable ester groups include those which break down readily in the human body to leave the parent acid or its salt.
  • references hereinafter to a compound according to the disclosure include both compounds of formula (I) and their pharmaceutically acceptable salts and derivatives. Unless the context specifically indicates otherwise references to compounds of formula (I) includes other compounds within scope of the present invention.
  • the compounds of formula (I) have more than one asymmetric carbon atom.
  • the solid wedge shaped bond indicates that the bond is above the plane of the paper.
  • the broken bond indicates that the bond is below the plane of the paper.
  • substituents in compounds of formula (I) may also have one or more asymmetric carbon atoms.
  • the compounds of structure (I) may occur as individual enantiomers or diastereomers. All such isomeric forms are included within the present disclosure, including mixtures thereof.
  • Separation of diastereoisomers or cis and trans isomers may be achieved by conventional techniques, e.g. by fractional crystallisation, chromatography or HPLC.
  • a stereoisomer ⁇ mixture of the agent may also be prepared from a corresponding optically pure intermediate or by resolution, such as by HPLC, of the corresponding mixture using a suitable chiral support or by fractional crystallisation of the diastereoisomeric salts formed by reaction of the corresponding mixture with a suitable optically active acid or base, as appropriate.
  • the compounds of formula (I) may be in crystalline or amorphous form. Furthermore, some of the crystalline forms of the compounds of structure (I) may exist as polymorphs, all forms which are included in the present disclosure.
  • the invention provides a pharmaceutical composition comprising, as active ingredient, a compound of the disclosure or a pharmaceutically acceptable derivative thereof in association with a pharmaceutically acceptable excipient, diluent and/or carrier for use in therapy, and in particular, in the treatment of human or animal subjects suffering from a condition susceptible to amelioration by an antimicrobial compound.
  • the invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present disclosure and a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present disclosure and a pharmaceutical composition
  • compositions comprising a compound of the disclosure adapted for use in human or veterinary medicine.
  • Such compositions may be presented for use in a conventional manner with the aid of one or more suitable excipients, diluents and/or carriers.
  • suitable excipients, diluents and/or carriers are well known in the pharmaceutical art, and are described, for example, in Remington's Pharmaceutical
  • compositions may comprise as - or in addition to - the excipient, diluent and/or carrier any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), solubilising agent(s).
  • Preservatives may be provided in the pharmaceutical composition.
  • preservatives include sodium benzoate, sorbic acid and esters of p-hydroxybenzoic acid.
  • Antioxidants and suspending agents may be also used.
  • the agents of the present disclosure may also be used in combination with a cyclodextrin.
  • Cyclodextrins are known to form inclusion and non- inclusion complexes with drug molecules. Formation of a drug-cyclodextrin complex may modify the solubility, dissolution rate, bioavailability and/or stability property of a drug molecule. Drug-cyclodextrin complexes are generally useful for most dosage forms and administration routes.
  • the cyclodextrin may be used as an auxiliary additive, e. g. as a carrier, diluent or solubiliser.
  • Alpha-, beta- and gamma-cyclodextrins are most commonly used and suitable examples are described in WO 91/11172, WO 94/02518 and WO 98/55148.
  • the compounds of the disclosure may be milled using known milling procedures such as wet milling to obtain a particle size appropriate for tablet formation and for other formulation types.
  • Finely divided (nanoparticulate) preparations of the compounds of the invention may be prepared by processes known in the art, for example see International Patent Application No. WO 02/00196 (SmithKline Beecham).
  • the routes for administration include, but are not limited to, one or more of: oral (e. g. as a dry powder/ free flowing particulate formulation, tablet, capsule, or as an ingestable solution or suspension) rectal, buccal, and sublingual.
  • oral e. g. as a dry powder/ free flowing particulate formulation, tablet, capsule, or as an ingestable solution or suspension
  • compositions of the disclosure include those in a form especially formulated for parenteral, oral, buccal, rectal, topical, implant, ophthalmic, nasal or genito-urinary use.
  • the agents are delivered orally, hence, the agent is in a form that is suitable for oral delivery.
  • a topical or transdermal route including mucosal (e. g. as a nasal spray or aerosol for inhalation), nasal, gastrointestinal, intratracheal or intravaginal,
  • the compounds of the present disclosure are formulated for and/or delivered parenterally, for example intraspinal, intraperitoneal, intramuscular, intravenous, intrauterine, intraocular, intradermal, intracranial, intracerebroventricular, intracerebral, subcutaneous, ophthalmic (including intravitreal or intracameral).
  • parenteral for example intraspinal, intraperitoneal, intramuscular, intravenous, intrauterine, intraocular, intradermal, intracranial, intracerebroventricular, intracerebral, subcutaneous, ophthalmic (including intravitreal or intracameral).
  • compositions may be best used in the form of a sterile aqueous solution which may contain other substances, for example enough salts or monosaccharides to make the solution isotonic with blood.
  • the formulation is provided in a form suitable for slow injection over one or two minutes.
  • the formulation is provided for infusion, for example a liquid formulation in the concentration range 5-10 mg/mL or a concentrate for dilution (eg 50mg/mL).
  • the formulation for infusion is lyophilised for re-constitution with a sterile carrier.
  • the pharmaceutical composition of the present disclosure may be formulated to be delivered using a mini-pump, in particular of the type used to dispense heparin or morphine.
  • the composition is formulated in an injectable form, for delivery by, for example, an intravenous, intramuscular (for example as a bolous formulation) or
  • the pharmaceutical composition of the present disclosure may be formulated to be delivered by a mucosal route, for example, as a nasal spray or aerosol for inhalation or ingestable solution.
  • the formulation may be designed to be delivered by both routes.
  • compositions can be administered by inhalation, in the form of a suppository or pessary, topically in the form of a lotion, solution, cream, ointment or dusting powder, by use of a skin patch, orally in the form of tablets containing excipients such as starch or lactose, or in capsules or ovules either alone or in admixture with excipients, or in the form of elixirs, solutions or suspensions containing flavouring or colouring agents, or they can be injected parenterally, for example intravenously, intramuscularly or subcutaneously.
  • compositions may be administered in the form of tablets or lozenges which can be formulated in a conventional manner.
  • examples of such administration include one or more of: intravenously, intraarterially, intraperitoneally, intrathecally, intraventricularly, intraurethrally, intrasternally, intracranially, intramuscularly or
  • the compounds of the disclosure can be administered (e. g. orally or topically) in the form of tablets, capsules, ovules, elixirs, solutions or suspensions, which may contain flavouring or colouring agents, for immediate-, delayed-, modified-, sustained-, pulsed- or controlled- release applications.
  • the compounds of the disclosure may also be presented for human or veterinary use in a form suitable for oral or buccal administration, for example in the form of solutions, gels, syrups, mouth washes or suspensions, or a dry powder for constitution with water or other suitable vehicle before use, optionally with flavouring and colouring agents.
  • Solid compositions such as tablets, capsules, lozenges, pastilles, pills, boluses, powder, pastes, granules, bullets or premix preparations may also be used.
  • Solid and liquid compositions for oral use may be prepared according to methods well known in the art. Such compositions may also contain one or more pharmaceutically acceptable carriers and excipients which may be in solid or liquid form.
  • the tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, calcium sulphate, dibasic calcium phosphate and glycine, mannitol, pregelatinised starch, corn starch, potato starch, disintegrants such as sodium starch glycollate, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC),
  • excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, calcium sulphate, dibasic calcium phosphate and glycine, mannitol, pregelatinised starch, corn starch, potato starch, disintegrants such as sodium starch glycollate, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC),
  • HPC hydroxypropylcellulose
  • lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included.
  • Solid compositions of a similar type may also be employed as fillers in gelatin or HPMC (hydroxypropyl methylcellulose) capsules.
  • Preferred excipients in this regard include microcrystalline cellulose, lactose, calcium carbonate, calcium sulphate, dibasic calcium phosphate and, mannitol, pregelatinised starch, corn starch, potato starch or high molecular weight polyethylene glycols.
  • the agent may be combined with various sweetening or flavouring agents, colouring matter or dyes, with emulsifying and/or suspending agents and with diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof.
  • Capsules may be filled with a powder (of medicament alone or as blend with selected filler(s)) or alternatively a liquid, each comprising one or more compounds of formula (I) and a carrier. Where the capsule is filled with a powder the compounds of formula (I) and/or the carrier may be milled or micronised to provide material with an appropriate particle size.
  • Compounds of the disclosure may be coated, for example with as an enteric coating when administered orally as a tablet or capsule.
  • the tablet or capsule may, for example be coated by a thin film such as a EUDRAGIT® film available from Rohm Pharma Polymers, which allows controlled dissolution in the gastrointestinal tract.
  • the films are available as cationic polymers such as EUDRAGIT® E 100 (aminoalkyl methacylate copolymers) or as anionic acrylic polymers such as EUDRAGIT® L (methacrylic acid copolymers) and EUDRAGIT S.
  • Permeable acrylic polymers such as EUDRAGIT® RL (amino methacrylate copolymer) and EUDRAGIT® RS are also available.
  • coating formulations may be prepared as an aqueous dispersion including optional ingredients such as talc, silicone antifoam emulsion, polyethylene glycol.
  • the coating formulation may be prepared as an organic polymer solution.
  • tablets may be coated using OPADRY® (Surelease®) coating systems, available from Colorcon.
  • OPADRY® Sudrelease® coating systems
  • Aqueous systems generally comprise up to 15% w/w of
  • OPADRY® Organic solvent systems generally comprise up to 5% w/w of OPADRY®.
  • the coatings may be prepared by known techniques, for example by; 1. weighing the required quantity of OPADRY® film coating system, 2. weighing the required quantity of water or other solvent(s) into a mixing vessel, 3. with a mixing propeller in the centre of the vessel and as close to the bottom of the vessel as possible, stirring the solvents to form a vortex without drawing air into the liquid, 4. steadily and quickly adding the OPADRY® powder to the vortex, avoiding powder flotation on the liquid surface, 5. increasing the stirrer speed in order to maintain the vortex, if required, and 6. after all the powder ingredients have been added, reducing the mixer speed and continuing mixing for approximately 45 minutes. Coatings can be applied by known techniques, using tablet coating machines.
  • the thickness of the coating applied is generally in the range 5 to 35 microns such as 10 to 30 microns, more specifically 10 or 20 microns, depending on the required effect.
  • the tablet or a capsule may be filled into another capsule (preferably a HPMC capsule such as Capsugel®) to provide either a tablet in capsule or capsule in capsule configuration, which when administered to a patient yields controlled dissolution in the gastrointestinal tract thereby providing a similar effect to an enteric coating.
  • a solid dose formulation of a compound of formula (I) for example where the formulation has an enteric coating.
  • the disclosure provides a solid dose formulation comprising a protective capsule as outer layer, for example as a tablet in a capsule or a capsule in a capsule.
  • the enteric coating may provide an improved stability profile over uncoated formulations.
  • the compounds of formula (I) are not particularly susceptible to degradation by stomach acid or intestinal enzymes in vivo.
  • the compounds of the disclosure may also be administered orally, in veterinary medicine, in the form of a liquid drench such as a solution, suspension or dispersion of the active ingredient together with a pharmaceutically acceptable carrier or excipient.
  • the compounds of the invention may also, for example, be formulated as suppositories e.g. containing conventional suppository bases for use in human or veterinary medicine or as pessaries e.g. containing conventional pessary bases.
  • the formulation is provided as a formulation for topical administration including inhalation.
  • suitable inhalable preparations include inhalable powders, metering aerosols containing propellant gases or inhalable solutions free from propellant gases.
  • Inhalable powders according to the disclosure containing the active substance may consist solely of the abovementioned active substances or of a mixture of the abovementioned active substances with physiologically acceptable excipient.
  • These inhalable powders may include monosaccharides (e.g. glucose or arabinose), disaccharides (e.g. lactose, saccharose, maltose), oligo- and polysaccharides (e.g.
  • dextranes dextranes
  • polyalcohols e.g. sorbitol, mannitol, xylitol
  • salts e.g. sodium chloride, calcium carbonate
  • Mono- or disaccharides are preferably used, the use of lactose or glucose, particularly but not exclusively in the form of their hydrates.
  • Particles for deposition in the lung require a particle size less than 10 microns, such as 1-9 microns suitably from 0.1 to 5 ⁇ , particularly preferably from 1 to 5 pm.
  • the particle size of the active i.e. the compound according to the disclosure).
  • propellent gases which can be used to prepare the inhalable aerosols are known from the prior art.
  • Suitable propellent gases are selected from among hydrocarbons such as n- propane, n-butane or isobutane and halohydrocarbons such as chlorinated and/or fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane.
  • hydrocarbons such as n- propane, n-butane or isobutane
  • halohydrocarbons such as chlorinated and/or fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane.
  • the above-mentioned propellent gases may be used on their own or in mixtures thereof.
  • Particularly suitable propellent gases are halogenated alkane derivatives selected from among TG1 1 , TG 12, TG 134a and TG227.
  • halogenated alkane derivatives selected from among TG1 1 , TG 12, TG 134a and TG227.
  • hydrocarbons TG134a (1 ,1 ,1 ,2-tetrafluoroethane) and TG227 (1 ,1 ,1 ,2,3,3,3- heptafluoro propane) and mixtures thereof are suitable for use in formulations of the present invention.
  • the propellant-gas-containing inhalable aerosols may also contain other ingredients such as co-solvents, stabilisers, surface-active agents (surfactants), antioxidants, lubricants and means for adjusting the pH. All these ingredients are known in the art.
  • the propellant-gas-containing inhalable aerosols according to the invention may contain up to 5 % by weight of active substance. Aerosols according to the disclosure may contain, for example, 0.002 to 5 % by weight, 0.01 to 3 % by weight, 0.015 to 2 % by weight, 0.1 to 2 % by weight, 0.5 to 2 % by weight or 0.5 to 1 % by weight of active.
  • the compounds of the disclosure may also be used in combination with other therapeutic agents.
  • the disclosure thus provides, in a further aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable derivative thereof together with a further therapeutic agent.
  • the combination may, for example be a combination of a compound of formula (I) and an antibiotic, such as vancomycin, a beta-lactam (such as a cephalosporin), an aminoglycoside, a macrolide, a tetracyline, a lipopeptide, an antibiotic, such as vancomycin, a beta-lactam (such as a cephalosporin), an aminoglycoside, a macrolide, a tetracyline, a lipopeptide, an antibiotic, such as vancomycin, a beta-lactam (such as a cephalosporin), an aminoglycoside, a macrolide, a tetracyline, a lipopeptide, an antibiotic, such as van
  • oxazolidinone and/or an anti-inflammatory such as a steriod.
  • the combination may be provided as a co-formulation or simply packaged together as separate formulations, for simultaneous or sequential delivery.
  • the therapy comprises more than one active component, then those components may be administered by different routes.
  • compositions may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations by any convenient route.
  • administration is sequential, either the compound of the disclosure or the second therapeutic agent may be administered first.
  • administration is simultaneous, the combination may be administered either in the same or a different pharmaceutical composition.
  • the combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above together with a pharmaceutically acceptable carrier or excipient comprise a further aspect of the disclosure.
  • the two compounds When combined in the same formulation it will be appreciated that the two compounds must be stable and compatible with each other and the other components of the formulation.
  • When formulated separately may be provided in any convenient formulation, in such manner as are known for such compounds in the art.
  • the compositions may contain from 0.01-99% of the active material.
  • the composition will generally contain from 0.01-10%, more preferably 0.01-1 % of the active material.
  • each compound may be the same or differ from that employed when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art. It will also be appreciated that the amount of a compound of the disclosure required for use in treatment will vary with the nature of the condition being treated and the age and the condition of the patient and will be ultimately at the discretion of the attendant physician or veterinarian. Typically, a physician will determine the actual dosage which will be most suitable for an individual subject.
  • the specific dose level and frequency of dosage for any particular individual may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the individual undergoing therapy.
  • the daily dosage level of the agent may be in single or divided doses.
  • the daily dose as employed for adult human treatment will range from 2-100 mg/Kg body weight, preferably 5-60 mg/Kg body weight, which may be administered in 1 to 4 daily doses, for example, depending on the route of administration and the condition of the patient.
  • each unit will preferably contain 100 mg to 1 g of active ingredient.
  • the duration of treatment will be dictated by the rate of response rather than by arbitrary numbers of days.
  • the treatment regime is continued for 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or more days.
  • the compounds of the present disclosure may be employed in the treatment or prophylaxis of humans and/or animals.
  • a compound of formula (I) is useful in the treatment of skin infections, in particular gram positive infections.
  • a compound of formula (I) is useful in the treatment of skin infections, in particular bacterial skin and soft tissue infection.
  • the disclosure provides use of a compound of formula (I) in therapy, for example, for treatment of microbial infections such as bacteraemia, pneumonia and microbial infection of soft tissue including surgical wounds, in particular staphylococcal infections including MRSA infection.
  • microbial infections such as bacteraemia, pneumonia and microbial infection of soft tissue including surgical wounds, in particular staphylococcal infections including MRSA infection.
  • the compounds of formula (I) are useful for the treatment of enterococcal infections including E. faecalis and E. faecium infection, for example skin and skin structure infections, endocarditis, urinary tract infection and sepsis. In one embodiment the compounds of formula (I) are useful for the treatment of
  • S. pyogenes for example skin infections such as impetigo, erysipelas and cellulitis, throat infections, scarlet fever, and acute glomerulonephritis.
  • compounds of formula (I) are useful in the treatment of Streptococcus pneumoniae infection, for example pnuemonia, acute sinusitus, otitis media, meningitis, bacteremia, osteomylitis, septic arthritis and endocarditis.
  • the compounds of formula (I) are employed for controlling bacterial overgrowth syndrome.
  • Overgrowth syndrome occurs when the normally low bacterial colonization in the upper Gl tract and/or lower intestines significantly increases.
  • the disclosure provides use of a compound of formula (I) in therapy, for example, for treatment of microbial infections such as C. difficile infection, in particular diarrhoea asssociated therewith, or one or more microbial infections described herein, particularly by oral delivery of a compound of formula (I).
  • microbial infections such as C. difficile infection, in particular diarrhoea asssociated therewith, or one or more microbial infections described herein, particularly by oral delivery of a compound of formula (I).
  • a compound of formula (I) for the prophylaxis, treatment or maintenance of IBS (irritable bowel syndrome). See for example Rifaximin Treatment for Symptoms of Irritable Bowel Syndrome. Andrea L. Fumi and Katherine Trexler, The Annals of Pharmacotherap, 2008, 4, 408.
  • a compound of formula (I) is useful in the treatment of ulcerative colitis including prophylactic treatment to prevent recurrence thereof.
  • the compounds may be particularly suitable for the treatment of steroid refractory ulcerative colitis. See for example steroid-refractory ulcerative colitis treated with corticosteroids, metronidazole and
  • vancomycin a case report J. Miner, M. M Gillan, P. Alex, M Centola, BMC Gastroenterology 2005, 5:3.
  • the compounds of the present disclosure may be useful for long term treatment.
  • a compound of formula (I) or a composition comprising the same for the manufacture of a medicament for one or more of the indications defined above.
  • a method of treatment comprising the step of administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutical composition containing the same to a patient (human or animal) in need thereof, for example for the treatment of an infection/illness or disease as described herein.
  • MSSA S. aureus G15, S. aureus G20, S. aureus G22, S. aureus G23, S. aureus G28, S. aureus G30, S. aureus G31 , S. aureus G32, S. aureus G33, S. aureus G35, S. aureus G12,
  • epidermidis GRL0501 1 S. epidermidis GRL05012, S. epidermidis GRL05016, S.
  • epidermidis GRL05015 S. epidermidis GRL05019, S. epidermidis GRL05020, S.
  • VRE E. faecium 7662769, E. faecium 7634337, E. faecium 7865532, E. faecium 9709024, E. faecium 9710577, E faecalis GRL05031 , E faecalis GRL05032, E. faecalis GRL05033, E. faeca//s GRL05034, E. feeca//s GRL05035, E aeca// ' s 9758512, E. faecium 9704998, E. faecium 7860190
  • N-methyl glucamine salt of compound I (compound of example 1 )
  • Compound I 100 mg
  • f-butanol 50 mL
  • a solution of N-methyl glucamine (1 M aq, 94 ⁇ _) was added and the mixture was stirred for a further 1 hour.
  • the reaction mixture was flash frozen at -80°C and then the material was freeze dried overnight, to afford compound I N-methylglucamine salt as a white solid (112mg).
  • the minimum inhibitory concentration (MIC) was defined as the lowest concentration of drug that prevented visible growth.
  • the N-methylglucamine salt of Example 1 was dissolved in 5% glucose, 1 mM potassium phosphate (pH 5) and each mouse was dosed 25mg/kg iv via the tail vein.
  • Terminal blood samples were collected from groups of 3 mice predose then at 1 min, 5 min, 30 min, 1 h, 2 h, 3 h, 6 h, 8 h and 24 h post dosing.
  • the blood was collected in 1 .5 mL polypropylene microcentrifuge tubes pre-prepared with anti-coagulant and centrifuged at 16.100 x g for 5 mins to separate the plasma.
  • the plasma was subsequently transferred to a fresh microcentrifuge tube and stored at -20"C awaiting analysis by LC-MS/MS.
  • mice Groups of 6 male specific-pathogen-free ICR mice weighing 24 ⁇ 2 g are used. Animals were rendered immunosuppressed by two intraperitoneal injections of cyclophosphamide, with the first at 150 mg/kg 4 days before infection (day -4) and the second at 100 mg/kg 1 day before infection (day -1 ). On day 0, animals were inoculated intramuscularly (0.1 mlJthigh) with 1 x 10 s CFU/mouse of Staphylococcus aureus, methicillin resistant (ATCC 33591 ) into the right thigh. Vehicle (5% glucose) and test substances were then administered intravenously 2 and 14 hours after inoculation.
  • muscle of the right thigh was harvested from each surviving animal.
  • the removed muscle tissues were then homogenized in 3 ml of PBS, pH 7.4 in a ceramic mortar. Homogenates of 0.1 mL were used for serial 10-fold dilutions and plated on Nutrient broth in 1.5% Bacto Agar for CFU determination (see Figure 1).

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Abstract

L'invention décrit un composé de formule (I): R4 représentant un groupe -RA-L-Ar1 de formule (II) : ou R3 ensemble avec R4 et l'azote auquel ils sont liés formant un groupe hétérocyclique à 5 ou 6 chaînons comportant éventuellement un hétéroatome supplémentaire choisi parmi N, O ou S. Ledit groupe hétérocyclique est substitué par un ou deux groupes spécifiés et Z, R1, R2, R5, RA, L et Ar1 sont définis davantage.
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