WO2015022335A1 - Vancomycin analogs - Google Patents

Vancomycin analogs Download PDF

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Publication number
WO2015022335A1
WO2015022335A1 PCT/EP2014/067272 EP2014067272W WO2015022335A1 WO 2015022335 A1 WO2015022335 A1 WO 2015022335A1 EP 2014067272 W EP2014067272 W EP 2014067272W WO 2015022335 A1 WO2015022335 A1 WO 2015022335A1
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Prior art keywords
alkyl
alkynyl
alkenyl
haloci
alkyloxy
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PCT/EP2014/067272
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French (fr)
Inventor
Nigam MISHRA
Yves Briers
Erik Van Der Eycken
Rob Lavigne
Bart Landuyt
Liliane Schoofs
Walter Luyten
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Katholieke Universiteit Leuven
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Priority claimed from GB201314407A external-priority patent/GB201314407D0/en
Priority claimed from GB201318379A external-priority patent/GB201318379D0/en
Priority claimed from GB201410936A external-priority patent/GB201410936D0/en
Application filed by Katholieke Universiteit Leuven filed Critical Katholieke Universiteit Leuven
Publication of WO2015022335A1 publication Critical patent/WO2015022335A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K9/00—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof
    • C07K9/006—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof the peptide sequence being part of a ring structure
    • C07K9/008—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof the peptide sequence being part of a ring structure directly attached to a hetero atom of the saccharide radical, e.g. actaplanin, avoparcin, ristomycin, vancomycin
    • 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 invention can satisfy this need. It relates generally to novel vancomycin analogs and their use as antibacterial agents in infectious diseases of mammals (humans and animals) caused by Gram-positive and Gram-negative infectious bacterial strains and, more particularly to vancomycin analogs against vancomycin resistant Enterococcus and Staphylococcus aureus.
  • Vancomycin is a clinically used glycopeptide antibiotic, which works against Gram-positive bacterial infections caused by S. aureus, Enterococci and Clostridium difficile and other species ⁇ Ashford, P. A. and Bew, S. P. Chem. Soc. Rev. 2012, 41, 957-978).
  • MRSA methicillin-resistant Staphylococcus aureus
  • vancomycin is also highly useful in the treatment of staphylococcal infections in patients who are allergic to penicillins and cephalosporins ⁇ Cooper, M. A.; Betley, J. R.; St. Edmonds, B. US patent, US 7078380B2, 2006; Xie, J.; Pierce, G.; James, R. C; Okano, A.; Boger, D. L. J. Am. Chem. Soc. 2011, 133, 13946-13949).
  • VRE vancomycin-resistant Enterococci
  • VRSA vancomycin-resistant Staphylococcus aureus
  • VISA vancomycin- intermediate resistant Staphylococcus aureus
  • VRSA virus aureus
  • VRE vancomycin-resistant Enterococci
  • Daptomycin and linezolid have emerged as potentially attractive antimicrobial therapies for VRE infections, however, daptomycin- and linezolid-resistant VRE show an increasing incidence too (Kamboy, M.; Cohen, N.; Gilhuley, K.; Babady, N. £.; Seo, S. K.; Sepkowitz, K.A. 2011 , 32, 391 -394; Scheetz, M. H.; Knechtel, S. A.; Malczynski, M.; Postelnick, M. J.; Qi, C. Antimicrob Agents Chemother. 2008, 52, 2256-2259).
  • antibacterial properties of vancomycin are based on its interaction with the terminal D-Ala- D-Ala residues of the pentapeptide moiety of the bacterial peptidoglycan precursor, thereby inhibiting transpeptidation and transglycosylation.
  • Resistant bacteria produce modified peptidoglycan precursors with terminal D-Ala-D-Lactate or D-Ala-D-Ser instead of D-Ala-D-Ala, which reduces the affinity of vancomycin for its target..
  • One aspect of the present invention is a compound of formula (1 ) or a pharmaceutically acceptable salt thereof:
  • R a is a group of formula -NH-R b -NH-R c , wherein
  • R b is a group of formula -R d -, or -R d -CO-, wherein the right side of -R d -CO- is attached to -NH-R c ;
  • R c is -R e , or -CO-R e ;
  • R d is a Ci-i 2 alkylene
  • R e is selected from the group consisting of C 2 - 6 alkynyl, C 6 -i4aryl, C6-i4arylCi- 6 alkyl, C 6- i4arylC 2 - 6 alkenyl, C 6 -i4arylC2- 6 alkynyl, C6-i4arylC2- 6 alkenylC 6 -i4aryl; heteroaryl, -NH-C 3- i 2 cycloalkyl, and wherein said C 2-6 alkynyl; C 6- i4aryl; C 6 -i4arylC2- 6 alkenyl, C 6 -i4arylC2- 6 alkenylC 6 -i4aryl; heteroaryl, -NH-C 3- i2cycloalkyl, can be unsubstituted or substituted with one or more Z 1 ;
  • each Z 1 is independently selected from the group consisting of hydroxyl, halo, nitro, Ci_ i 2 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- i2cycloalkyl, haloCi-i 0 alkyl, Ci -6 alkyloxy, Ci_ 6 alkylamino, haloCi-i 0 alkyloxy, C 6 -i4aryl, C 6 -i4aryloxy, C 6 -i4arylC2- 6 alkenyl, C 6 -i4arylC2- 6 alkynyl, heterocyclyl (e.g.
  • morpholinyl can be unsubstituted or substituted with one or more Z 2 ; or two adjacent Z 2 can be taken together to form a C 3-7 cycloalkyl, or a 5-, 6-, or 7-membered heterocyclyl or heteroaryl ring, which can be unsubstituted or substituted with one or more Z 2 ;
  • each Z 2 is independently selected from the group consisting of hydroxyl, halo, nitro, Ci_ i 2 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- i 2 cycloalkyl, haloCi-i 0 alkyl, Ci -6 alkyloxy, Ci_ 6 alkylamino, haloCi-i 0 alkyloxy, C 6 -i4aryl, C 6 -i4aryloxy, C 6 -i4arylC2- 6 alkenyl, C 6 -i4arylC2- 6 alkynyl, heterocyclyl (e.g.
  • each Z 3 is independently selected from the group consisting of hydrogen, hydroxyl, halo, nitro, Ci-i 2 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- i 2 cycloalkyl, haloCi-i 0 alkyl, Ci -6 alkyloxy, Ci_ 6 alkylamino, haloCi-i 0 alkyloxy, C 6 -i4aryl, C 6 -i4aryloxy, C 6 -i4arylC2- 6 alkenyl, C 6 -i4arylC2- 6 alkynyl, heterocyclyl (e.g.
  • each Z 4 is independently selected from the group consisting of hydrogen, hydroxyl, halo, nitro, Ci-i 2 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- i2cycloalkyl, haloCi-i 0 alkyl, Ci -6 alkyloxy, Ci_ 6alkylamino, haloCi-i 0 alkyloxy, C 6 -i4aryl, C 6 -i4aryloxy, C 6 -i4arylC2- 6 alkenyl, C6-i4arylC 2- 6 alkynyl, heterocyclyl (e.g.
  • Z 4 and Z 3 can be taken together to form a C 3-7 cycloalkyl, or a 5-, 6-, or 7-membered heterocyclyl, which can be unsubstituted or substituted with one or more Z 5 ;
  • each Z 5 is independently selected from the group consisting of hydrogen, K, Na , hydroxyl, halo, nitro, Ci-i 2 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- i 2 cycloalkyl, haloCi-i 0 alkyl, Ci_ 6alkyloxy, Ci -6 alkylamino, haloCi-i 0 alkyloxy, C 6 -i 4 aryl, C 6 -i 4 aryloxy, C 6 -i 4 arylC 2 - 6 alkenyl, C 6 -i 4 arylC 2 - 6 alkynyl, heterocyclyl (e.g.
  • X is a halogen
  • the pharmaceutical composition is for use against a bacterial infection.
  • the bacterial infection may be caused by a bacterial strain with resistance against at least one other antibiotic compound, for example, an antibiotic compound is selected from the group comprising vancomycin, methicillin, ampicillin, erythromycin, tigecycline, teicoplanin, daptomycin, and linezolid.
  • the pharmaceutical composition pharmaceutical composition is suitable for employing an effective concentration of 0.01 to 50 ⁇ g ml.
  • the bacterial infection is caused by a bacterial strain of vancomycin-resistant Enterococci (VRE), vancomycin-intermediate resistant strains (VISA), vancomycin-susceptible Staphylococcus aureus (VSSA) or high-level vancomycin-resistant Staphylococcus aureus (VRSA).
  • VRE vancomycin-resistant Enterococci
  • VSSA vancomycin-susceptible Staphylococcus aureus
  • VRSA high-level vancomycin-resistant Staphylococcus aureus
  • the bacterial infection is caused by vancomycin-resistant Staphylococcus aureus.
  • the bacterial infection is caused by vancomycin-resistant Enterococci (VRE).
  • Figure 1 represents a graph plotting the changes in MIC, expressed as MIC/MICo with MIC, corresponding to the MIC value in cycle i and MIC 0 corresponding to the MIC at the start of the experiment, obtained by monitoring over 20 cycles of exposure to subinhibitory doses of Vanc-N (squares), Vanc-39 (triangles), Vanc-42 (diamonds) and daptomycin (circles).
  • the terms "one or more” or “at least one”, such as one or more or at least one member(s) of a group of members, is clear per se, by means of further exemplification, the term encompasses inter alia a reference to any one of said members, or to any two or more of said members, such as, e.g., any ⁇ 3, ⁇ 4, ⁇ 5, ⁇ 6 or ⁇ 7 etc. of said members, and up to all said members.
  • the term "and/or,” when used in a list of two or more items, means that any one of the listed items can be employed by itself or any combination of two or more of the listed items can be employed. For example, if a list is described as comprising group A, B, and/or C, the list can comprise A alone; B alone; C alone; A and B in combination; A and C in combination, B and C in combination; or A, B, and C in combination.
  • substituted when used herein, it is meant to indicate that one or more hydrogens on the atom indicated in the expression using “substituted” is replaced with a selection from the indicated group, provided that the indicated atom's normal valency is not exceeded, and that the substitution results in a chemically stable compound, i.e. a compound that is sufficiently robust to survive isolation from a reaction mixture.
  • groups can be substituted, such groups may be substituted with one or more, and preferably one, two or three substituents.
  • heteroatoms optionally comprises one or more heteroatoms, said heteroatoms being O
  • halo or "halogen” as a group or part of a group is generic for fluoro, chloro, bromo, iodo.
  • amino refers to the group -NH 2 .
  • hydroxyl or "hydroxy” as used herein refers to the group -OH.
  • nitro refers to the group -N0 2 .
  • Ci-i 4 alkyl groups include all linear, or branched alkyl groups having 1 to 12 carbon atoms, and thus includes for example methyl, ethyl, n-propyl, /-propyl, 2-methyl-ethyl, butyl and its isomers (e.g.
  • Ci-i 0 alkyl includes all linear, or branched alkyl groups having 1 to 10 carbon atoms, and thus includes for example methyl, ethyl, n-propyl, /-propyl, 2-methyl-ethyl, butyl and its isomers (e.g. n-butyl, / ' - butyl and i-butyl); pentyl and its isomers, hexyl and its isomers, heptyl and its isomers, octyl and its isomers, nonyl and its isomers, decyl and its isomers and the like.
  • Ci -6 alkyl includes all linear, or branched alkyl groups having 1 to 6 carbon atoms, and thus includes for example methyl, ethyl, n-propyl, /-propyl, 2-methyl-ethyl, butyl and its isomers (e.g. n-butyl, / ' - butyl and i-butyl); pentyl and its isomers, hexyl and its isomers.
  • a preferred alkyl is Ci -6 alkyl.
  • alkylene groups includes methylene, ethylene, methylmethylene, propylene, ethylethylene, and 1 ,2-dimethylethylene.
  • alkenyl groups as defined herein and alkynyl groups as defined herein, respectively are divalent groups having single bonds for attachment to two other groups, they are termed "alkenylene” and "alkynylene” respectively.
  • C 1-12 alkylene refers to a saturated, branched or straight chain hydrocarbon radical of 1 -12 carbon atoms (more in particular Ci-i 0 or Ci -6 carbon atoms), and having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkane.
  • Typical alkylene radicals include, but are not limited to: methylene (-CH 2 -), 1 ,2-ethyl (-CH 2 CH 2 -), 1 ,3-propyl (- CH 2 CH 2 CH 2 -), 1 ,4-butyl (-CH 2 CH 2 CH 2 CH 2 -), and the like.
  • C 2-6 alkenyl refers to an unsaturated hydrocarbyl group, which may be linear, or branched, comprising one or more carbon-carbon double bonds.
  • C 2-6 alkynyl refers to a class of monovalent unsaturated hydrocarbyl groups, wherein the unsaturation arises from the presence of one or more carbon- carbon triple bonds. Examples include, but are not limited to: ethynyl (-C ⁇ CH), 3-ethyl- cyclohept-1 -ynylene, 4-cyclohept-1 -yn-methylene and 1 -propynyl (propargyl, -CH 2 C ⁇ CH).
  • C 3-12 cycloalkyl refers to a cyclic alkyl group, that is a monovalent, saturated, hydrocarbyl group having 1 or more cyclic structure, and comprising from 3 to 12 carbon atoms, more preferably from 3 to 9 carbon atoms, more preferably from 3 to 6 carbon atoms, still more preferably from 5 to 6 carbon atoms.
  • Cycloalkyi includes all saturated hydrocarbon groups containing 1 or more rings, including monocyclic, bicyclic or multicyclic groups. The further rings of multi-ring cycloalkyls may be either fused, bridged and/or joined through one or more spiro atoms.
  • cycloalkyi group i.e. cycloalkylene
  • this is intended to mean the cycloalkyi group as defined herein having two single bonds as points of attachment to other groups.
  • Examples include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylethylene, methylcyclopropylene, cyclohexyl, cycloheptyl, cyclooctyl, cyclooctylmethylene, norbornyl, fenchyl, trimethyl tricycloheptyl, decalinyl, adamantyl and the like.
  • haloCi- 6 alkyl refers to a Ci -6 alkyl group having the meaning as defined above wherein one or more hydrogens are replaced with one or more halogen as defined above.
  • Non-limiting examples of such haloalkyl groups include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1 ,1 ,1 -trifluoroethyl and the like.
  • Ci -6 alkoxy refers to a group having the Formula -OR x wherein R x is Ci -6 alkyl as defined herein above.
  • suitable Ci -6 alkoxy include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec- butoxy, tert-butoxy, pentyloxy and hexyloxy.
  • C 1-6 alkoxyCi- 6 alkyl or "C 1-6 alkyloxyCi- 6 alky , as a group or part of a group, refers to a group having the Formula -R y -0-R x wherein R x is Ci -6 alkyl as defined herein, and R y is Ci_ 6 alkylene.
  • haloCi -6 alkoxy refers to a group of Formula -0-R z wherein R z is haloCi -6 alkyl as defined herein.
  • suitable haloCi -6 alkoxy include fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, 1 ,1 ,2,2- tetrafluoroethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2,2-difluoroethoxy, 2,2,2-trichloroethoxy, trichloromethoxy, 2-bromoethoxy, pentafluoroethyl, 3,3,3-trichloropropoxy, 4,4,4-trichlorobutoxy.
  • alkylamino refers to a group of formula -N(R')(R S ) wherein R' and R s are each independently selected from hydrogen, or Ci -6 alkyl, wherein at least one of R' or R s is Ci -6 alkyl.
  • alkylamino include mono-alkyl amino group (e.g. mono-Ci. 6 alkylamino group such as methylamino and ethylamino), and di-alkylamino group (e.g. di-C-i. 6 alkylamino group such as dimethylamino and diethylamino).
  • Non-limiting examples of suitable alkylamino groups include n-propylamino, isopropylamino, n-butylamino, / ' -butylamino, sec- butylamino, i-butylamino, pentylamino, n-hexylamino, di-n-propylamino, di-/-propylamino, ethylmethylamino, methyl-n-propylamino, methyl-/ ' -propylamino, n-butylmethylamino, / ' - butylmethylamino, i-butylmethylamino, ethyl-n-propylamino, ethyl-/ ' -propylamino, n- butylethylamino, i-butylethylamino, i-butylethylamino, i-butylethylamino
  • C 6 -i 4 aryl refers to a polyunsaturated, aromatic hydrocarbyl group having a single ring (i.e. phenyl) or multiple aromatic rings fused together (e.g. naphthalene), or linked covalently, typically containing 6 to 14 atoms; wherein at least one ring is aromatic.
  • the aromatic ring may optionally include one to two additional rings (either cycloalkyl, heterocyclyl or heteroaryl) fused thereto.
  • suitable aryl include C 6- ioaryl, more preferably C 6 - 8 aryl.
  • Non-limiting examples of C 6- i 2 aryl comprise phenyl, biphenylyl, biphenylenyl, or 1-or 2-naphthanelyl; 5- or 6-tetralinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-azulenyl, 4-, 5- , 6 or 7-indenyl, 4- or 5-indanyl, 5-, 6-, 7- or 8-tetrahydronaphthyl, 1 ,2,3,4-tetrahydronaphthyl, and 1 ,4-dihydronaphthyl.
  • aryl group when used in conjunction with an aryl group, this is intended to mean the aryl group as defined herein having two single bonds as points of attachment to other groups, such as phenylene, biphenylylene, naphthylene, indenylene, and the like. Where a carbon atom in an aryl group is replaced with a heteroatom, the resultant ring is referred to herein as a heteroaryl ring.
  • C 6 -i 4 arylCi- 6 alkyl as a group or part of a group, means a Ci -6 alkyl as defined herein, wherein at least one hydrogen atom is replaced by at least one C 6- i 4 aryl as defined herein.
  • Non- limiting examples of C 6 -i 4 arylCi- 6 alkyl group include benzyl, phenethyl, dibenzylmethyl, methylphenylmethyl, 3-(2-naphthyl)-butyl, and the like.
  • C 6 -i 4 arylC 2 - 6 alkenyl as a group or part of a group, means a C 2-6 alkenyl as defined herein, wherein at least one hydrogen atom is replaced by at least one C 6- i 4 aryl as defined herein.
  • C 6 -i 4 arylC 2 - 6 alkynyl as a group or part of a group, means a C 2-6 alkynyl as defined herein, wherein at least one hydrogen atom is replaced by at least one C 6- i 4 aryl as defined herein.
  • C 6 -i 4 arylC 2 - 6 alkenylC 6 -i 4 aryl as a group or part of a group, means a C 6 -i 4 aryl, wherein at least one hydrogen atom is replaced by at least one C 6 -i 4 arylC 2 - 6 alkenyl as defined herein.
  • heterocyclyl or “heterocyclo”, as a group or part of a group, refer to non-aromatic, fully saturated or partially unsaturated cyclic groups (for example, 3 to 7 member monocyclic, 7 to 1 1 member bicyclic, or containing a total of 3 to 10 ring atoms) which have at least one heteroatom in at least one carbon atom-containing ring.
  • Each ring of the heterocyclic group containing a heteroatom may have 1 , 2, 3 or 4 heteroatoms selected from N, O and/or S, where the N and S heteroatoms may optionally be oxidized and the N heteroatoms may optionally be quaternized.
  • the heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system, where valence allows.
  • the rings of multi-ring heterocycles may be fused, bridged and/or joined through one or more spiro atoms.
  • Non limiting exemplary heterocyclic groups include aziridinyl, oxiranyl, thiiranyl, piperidinyl, azetidinyl, 2-imidazolinyl, pyrazolidinyl imidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, succinimidyl, 3H-indolyl, indolinyl, isoindolinyl, 2H- pyrrolyl, 1 -pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 4H-quinolizinyl, 2-oxopiperazinyl, piperazinyl, homopiperazinyl, 2-pyrazolinyl, 3-pyrazolinyl, tetrahydro-2H-pyranyl, 2H-pyranyl
  • heteroaryl refers but is not limited to 5 to 12 atom aromatic rings or ring systems containing 1 or more rings which can be fused together or linked covalently, typically containing 5 to 12 atoms; at least one of which is aromatic in which one or more carbon atoms in one or more of these rings can be replaced by N, O and/or S atoms where the N and S heteroatoms may optionally be oxidized and the N heteroatoms may optionally be quaternized.
  • Such rings may be fused to an aryl, cycloalkyl, heteroaryl or heterocyclyl ring.
  • Non-limiting examples of such heteroaryl include: pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, imidazo[2,1 -b][1 ,3]thiazolyl, thieno[3,2-b]furanyl, thieno[3,2- b]thiophenyl, thieno[2,3-d][1 ,3]thiazolyl, thieno[2,3-d]imidazoly
  • pyrrolyl (also called azolyl) as used herein includes pyrrol-1 -yl, pyrrol-2-yl and pyrrol- 3-yl.
  • furanyl (also called “furyl”) as used herein includes furan-2-yl and furan-3-yl (also called furan-2-yl and furan-3-yl).
  • thiophenyl (also called “thienyl”) as used herein includes thiophen-2-yl and thiophen-3-yl (also called thien-2-yl and thien-3-yl).
  • pyrazolyl (also called 1 H-pyrazolyl and 1 ,2-diazolyl) as used herein includes pyrazol-1 -yl, pyrazol-3-yl, pyrazol-4-yl and pyrazol-5-yl.
  • imidazolyl as used herein includes imidazol-1 -yl, imidazol-2-yl, imidazol-4-yl and imidazol-5-yl.
  • oxazolyl (also called 1 ,3- oxazolyl) as used herein includes oxazol-2-yl; oxazol-4-yl and oxazol-5-yl.
  • isoxazolyl (also called 1 ,2-oxazolyl), as used herein includes isoxazol-3-yl, isoxazol-4-yl, and isoxazol-5-yl.
  • thiazolyl (also called 1 ,3-thiazolyl),as used herein includes thiazol-2-yl, thiazol-4-yl and thiazol-5-yl (also called 2-thiazolyl, 4-thiazolyl and 5-thiazolyl).
  • isothiazolyl (also called 1 , 2-thiazolyl) as used herein includes isothiazol-3-yl, isothiazol-4-yl, and isothiazol-5-yl.
  • triazolyl as used herein includes 1 H-triazolyl and 4H-1 ,2,4-triazolyl
  • “1 H-triazolyl” includes 1 H-1 ,2,3-triazol-1 -yl, 1 H-1 ,2,3-triazol-4-yl, 1 H-1 ,2,3-triazol-5-yl, 1 H-1 ,2,4-triazol-1 -yl, 1 H-1 ,2,4-triazol-3-yl and 1 H-1 ,2,4-triazol-5-yl.
  • 4H-1 ,2,4-triazolyl includes 4H-1 ,2,4-triazol-4-yl, and 4H-1 ,2,4-triazol-3-yl.
  • oxadiazolyl as used herein includes 1 ,2,3-oxadiazol-4-yl, 1 ,2,3-oxadiazol-5-yl, 1 ,2,4-oxadiazol -3-yl, 1 ,2,4-oxadiazol-5-yl, 1 ,2,5-oxadiazol-3-yl and 1 ,3,4- oxadiazol-2-yl.
  • thiadiazolyl as used herein includes 1 ,2,3-thiadiazol-4-yl, 1 ,2,3- thiadiazol-5-yl, 1 ,2,4-thiadiazol-3-yl, 1 ,2 ,4-thiad iazol-5-y 1 , 1 ,2,5-thiadiazol-3-yl (also called furazan-3-yl) and 1 ,3,4-thiadiazol-2-yl.
  • tetrazolyl as used herein includes 1 H-tetrazol-
  • oxatriazolyl as used herein includes 1 ,2,3,4-oxatriazol-5-yl and 1 ,2,3,5-oxatriazol-4-yl.
  • thiatriazolyl as used herein includes 1 ,2,3,4-thiatriazol-5-yl and 1 ,2,3,5-thiatriazol-4-yl.
  • pyridinyl (also called “pyridyl”) as used herein includes pyridin-2-yl, pyridin-3-yl and pyridin-4-yl (also called 2- pyridyl, 3-pyridyl and 4-pyridyl).
  • pyrimidyl as used herein includes pyrimid-2-yl, pyrimid-4-yl, pyrimid-5-yl and pyrimid-6-yl.
  • pyrazinyl as used herein includes pyrazin-
  • pyridazinyl as used herein includes pyridazin-3-yl and pyridazin- 4-yl.
  • oxazinyl (also called “1 ,4-oxazinyl”) as used herein includes 1 ,4-oxazin-4-yl and
  • dioxinyl also called “1 ,4-dioxinyl”
  • thiazinyl also called “1 ,4-thiazinyl”
  • thiazinyl as used herein includes 1 ,4-thiazin-2-yl, 1 ,4-thiazin-3-yl, 1 ,4-thiazin-4-yl, 1 ,4-thiazin-5-yl and 1 ,4-thiazin-6-yl.
  • triazinyl as used herein includes 1 ,3,5-triazin-2-yl, 1 ,2,4-triazin-3-yl, 1 ,2,4-triazin-5-yl, 1 ,2,4-triazin-6-yl, 1 ,2,3-triazin-4-yl and 1 ,2,3-triazin-5-yl.
  • imidazo[2,1 -b][1 ,3]thiazolyl includes imidazo[2,1 -b][1 ,3]thiazoi-2-yl, imidazo[2,1 -b][1 ,3]thiazol-3-yl, imidazo[2, 1 -b][1 ,3]thiazol-5-yl and imidazo[2,1 -b][1 ,3]thiazol-6-yl.
  • thieno[3,2- b]furanyl as used herein includes thieno[3,2-b]furan-2-yl, thieno[3,2-b]furan-3-yl, thieno[3,2- b]furan-4-yl, and thieno[3,2-b]furan-5-yl.
  • thieno[3,2-b]thiophenyl as used herein includes thieno[3,2-b]thien-2-yl, thieno[3,2-b]thien-3-yl, thieno[3,2-b]thien-5-yl and thieno[3,2- b]thien-6-yl.
  • thieno[2,3-d][1 ,3]thiazolyl as used herein includes thieno[2,3- d][1 ,3]thiazol-2-yl, thieno[2,3-d][1 ,3]thiazol-5-yl and thieno[2,3-d][1 ,3]thiazol-6-yl.
  • thieno[2,3-d]imidazolyl as used herein includes thieno[2,3-d]imidazol-2-yl, thieno[2,3- d]imidazol-4-yl and thieno[2,3-d]imidazol-5-yl.
  • tetrazolo[1 ,5-a]pyridinyl as used herein includes tetrazolo[1 ,5-a]pyridine-5-yl, tetrazolo[1 ,5-a]pyridine-6-yl, tetrazolo[1 ,5-a]pyridine-7-yl, and tetrazolo[1 ,5-a]pyridine-8-yl.
  • indolyl as used herein includes indol-1 -yl, indol-2-yl, indol-3-yl,-indol-4-yl, indol-5-yl, indol-6-yl and indol-7-yl.
  • indolizinyl as used herein includes indolizin-1 -yl, indolizin-2-yl, indolizin-3-yl, indolizin-5-yl, indolizin-6-yl, indolizin-7-yl, and indolizin-8-yl.
  • isoindolyl as used herein includes isoindol-1 -yl, isoindol-2-yl, isoindol- 3-yl, isoindol-4-yl, isoindol-5-yl, isoindol-6-yl and isoindol-7-yl.
  • benzofuranyl also called benzo[b]furanyl
  • benzofuran-2-yl isobenzofuran-2-yl
  • benzofuran-3-yl isobenzofuran-4-yl
  • benzofuran-5-yl isobenzofuran-6-yl
  • benzofuran-7-yl isobenzofuran-7-yl.
  • benzothiophenyl (also called benzo[b]thienyl) as used herein includes 2-benzo[b]thiophenyl, 3- benzo[b]thiophenyl, 4-benzo[b]thiophenyl, 5-benzo[b]thiophenyl, 6-benzo[b]thiophenyl and -7- benzo[b]thiophenyl (also called benzothien-2-yl, benzothien-3-yl, benzothien-4-yl, benzothien-5- yl, benzothien-6-yl and benzothien-7-yl).
  • isobenzothiophenyl also called benzo[c]thienyl
  • isobenzothien-1 -yl isobenzothien-3-yl
  • isobenzothien- 4-yl isobenzothien-5-yl
  • isobenzothien-6-yl isobenzothien-7-yl.
  • indazolyl (also called 1 H-indazolyl or 2-azaindolyl) as used herein includes 1 H-indazol-1 -yl, 1 H-indazol-3-yl, I H-indazol-4-yl, 1 H-indazol-5-yl, 1 H-indazol-6-yl, 1 H-indazol-7-yl, 2H-indazol-2-yl, 2H-indazol-3- yl, 2H-indazol-4-yl, 2H-indazol-5-yl, 2H-indazol-6-yl, and 2H-indazol-7-yl.
  • benzimidazolyl as used herein includes benzimidazol-1 -yl, benzimidazol-2-yl, benzimidazol-4- yl, benzimidazol-5-yl, benzimidazol-6-yl and benzimidazol-7-yl.
  • 1 ,2-benzisoxazolyl as used herein includes 1 ,2-benzisoxazol-3-yl, 1 ,2-benzisoxazol-4-yl, 1 ,2-benzisoxazol-5-yl, 1 ,2-benzisoxazol-6-yl and 1 ,2-benzisoxazol-7-yl.
  • 2,1 -benzisoxazolyl as used herein includes 2,1 -benzisoxazol-
  • benzotriazolyl as used herein includes benzotriazol-1 -yl, benzotriazol4-yl, benzotriazol-5-yl, benzotriazol-6-yl and benzotriazol-7-yl.
  • 2,1 ,3-benzoxadiazolyl as used herein includes 2,1 ,3- benzoxadiazol-4-yl, 2,1 ,3-benzoxadiazol-5-yl, 2,1 ,3-benzoxadiazol-6-yl and 2,1 ,3- benzoxadiazol-7-yl.
  • 2,1 ,3-benzothiadiazolyl as used herein includes 2,1 ,3- benzothiadiazol-4-yl, 2,1 ,3-benzothiadiazol-5-yl, 2,1 ,3-benzothiadiazol-6-yl and 2,1 ,3- benzothiadiazol-7-yl.
  • thienopyridinyl as used herein includes thieno[2,3-b]pyridinyl, thieno[2,3-c]pyridinyl, thieno[3,2-c]pyridinyl and thieno[3,2-b]pyridinyl.
  • purinyl as used herein includes purin-2-yl, purin-6-yl, purin-7-yl and purin-8-yl.
  • imidazo[1 ,2- a]pyridinyl as used herein includes imidazo[1 ,2-a]pyridin-2-yl, imidazo[1 ,2-a]pyridin-3-yl, imidazo[1 ,2-a]pyridin-4-yl, imidazo[1 ,2-a]pyridin-5-yl, imidazo[1 ,2-a]pyridin-6-yl and imidazo[1 ,2- a]pyridin-7-yl.
  • 1 ,3-benzodioxolyl includes 1 ,3-benzodioxol-4-yl, 1 ,3- benzodioxol-5-yl, 1 ,3-benzodioxol-6-yl, and 1 ,3-benzodioxol-7-yl.
  • quinolinyl as used herein includes quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl and quinolin-8-yl.
  • isoquinolinyl as used herein includes isoquinolin-1 -yl, isoquinolin-3- yl, isoquinolin-4-yl, isoquinolin-5-yl, isoquinolin-6-yl, isoquinolin-7-yl and isoquinolin-8-yl.
  • cinnolinyl as used herein includes cinnolin-3-yl, cinnolin-4-yl, cinnolin-5-yl, cinnolin-6-yl, cinnolin-7-yl and cinnolin-8-yl.
  • quinazolinyl as used herein includes quinazolin-2-yl, quiriazolin-4-yl, quinazolin-5-yl, quinazolin-6-yl, quinazolin-7-yl and quinazolin-8-yl.
  • quixalinyl as used herein includes quinoxalin-2-yl, quinoxalin-5-yl, and quinoxalin-6-yl.
  • heteroalkyl as a group or part of a group, also encompasses groups of Formula -X- R or -R e -X-R , and alkyl substituted with one or more groups of formula -X-R or -R e -X-R , wherein R e is as defined above for Ci -6 alkylene and X is NR C , S or O, and R c is selected from hydrogen, or Ci -6 alkyl, and R is hydrogen, Ci -6 acyl, Ci -6 alkyl, C 3-6 cycloalky; Representative examples include, but are not limited to, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxy-1 - hydroxymethylethyl, 2,3-dihydroxypropyl, 1 -hydroxymethylethyl, 3-hydroxybutyl, 2,3- dihydroxybutyl, 2-hydroxy-1 -methylpropyl, 2-aminoethyl, 3-aminopropyl, and the like.
  • glycosyl refers to a saccharyl moiety such as a mono-, di-, oligo- or an poly-saccharide moiety, a hydroxy-substituted cyclohexyl moiety, the amino derivatives thereof, the thio derivatives thereof or the hydroxyl-protected derivatives thereof such as acetate derivatives thereof.
  • saccharyl refers to a saccharide moiety which comprises monosaccharides, di-, tri-, oligo- and polysaccharides.
  • Exemplary monosaccharide moiety includes but is not limited to a pentosyl, a hexosyl, or a heptosyl moiety.
  • the glycosyl may also be present as a deoxy glycosyl.
  • said glycosyl is a saccharyl moiety, including monosaccharide, L or D isomers thereof, a or ⁇ form thereof, pyranose or furanose form thereof, combination thereof, deoxy derivatives thereof, hydroxyl-protected acetate derivatives thereof, amino derivatives thereof optionally substituted, thio derivatives thereof, di-, tri-, oligo- and polysaccharide thereof.
  • R a is a group of formula -NH-R b -NH-R c , wherein
  • R b is a group of formula -R d -, or -R d -CO-, wherein the right side of -R d -CO- is attached to -NH-R c ;
  • R c is -R e , or -CO-R e ;
  • R d is a Ci-i 2 alkylene
  • R e is selected from the group consisting of C 2-6 alkynyl, C 6 -i4aryl, C 6 -i4arylCi- 6 alkyl, C 6- i4arylC 2 - 6 alkenyl, C 6 -i4arylC2- 6 alkynyl, C6-i4arylC2- 6 alkenylC 6 -i4aryl; heteroaryl, -NH-C 3- i 2 cycloalkyl, and wherein said C 2-6 alkynyl; C 6- i4aryl; C 6 -i4arylC2- 6 alkenyl, C 6 -i4arylC2- 6alkenylC 6 -i4aryl; heteroaryl, -NH-C 3- i2cycloalkyl, can be unsubstituted or substituted with one or more Z 1 ; each Z 1 is independently selected from the group consisting of hydroxyl, halo, nitro, Ci_ i 2 alkyl, C
  • morpholinyl can be unsubstituted or substituted with one or more Z 2 ; or two adjacent Z 2 can be taken together to form a C 3-7 cycloalkyl, or a 5-, 6-, or
  • each Z 2 is independently selected from the group consisting of hydroxyl, halo, nitro, Ci_ i 2 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- i 2 cycloalkyl, haloCi-i 0 alkyl, Ci -6 alkyloxy, Ci_ 6 alkylamino, haloCi-i 0 alkyloxy, C 6 -i4aryl, C 6 -i4aryloxy, C 6 -i4arylC 2 - 6 alkenyl, C 6 -i4arylC 2-
  • each Z 3 is independently selected from the group consisting of hydrogen, hydroxyl, halo, nitro, Ci-i 2 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- i 2 cycloalkyl, haloCi-i 0 alkyl, Ci -6 alkyloxy, Ci_ 6 alkylamino, haloCi-i 0 alkyloxy, C 6 -i4aryl, C 6 -i4aryloxy, C 6 -i4arylC 2 - 6 alkenyl, C 6 -i4arylC 2-
  • each Z 4 is independently selected from the group consisting of hydrogen, hydroxyl, halo, nitro, Ci-i 2 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- i 2 cycloalkyl, haloCi-i 0 alkyl, Ci -6 alkyloxy, Ci_ 6 alkylamino, haloCi-i 0 alkyloxy, C 6 -i 4 aryl, C 6 -i 4 aryloxy, C 6 -i 4 arylC 2 -6alkenyl, C 6 -i 4 arylC 2- 6 alkynyl, heterocyclyl (e.g.
  • Z 4 and Z 3 can be taken together to form a C 3-7 cycloalkyl, or a 5-, 6-, or 7-membered heterocyclyl, which can be unsubstituted or substituted with one or more Z 5 ;
  • each Z 5 is independently selected from the group consisting of hydrogen, K, Na , hydroxyl, halo, nitro, Ci-i 2 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- i 2 cycloalkyl, haloCi-i 0 alkyl, Ci_ 6alkyloxy, Ci -6 alkylamino, haloCi-i 0 alkyloxy, C 6 -i 4 aryl, C 6 -i 4 aryloxy, C6-i 4 arylC 2-6 alkenyl, C6-i 4 arylC 2 - 6 alkynyl, heterocyclyl (e.g.
  • X is a halogen
  • R b is a group of formula -R d -, or -R d -CO-, wherein the right side of -R d -CO- is attached to -NH-R c ;
  • R c is -R e , or -CO-R e ;
  • R d is a Ci -6 alkylene
  • R e is selected from the group consisting of C 2 - 6 alkynyl, C 6 -i4aryl, C6-i4arylCi- 6 alkyl, C 6- i4arylC 2 - 6 alkenyl, C 6 -i4arylC2- 6 alkynyl, C6-i4arylC2- 6 alkenylC 6 -i4aryl; heteroaryl, -NH-C 3- i 2 cycloalkyl, and wherein said C 2-6 alkynyl; C 6- i4aryl; C 6 -i4arylC2- 6 alkenyl, C 6 -i4arylC2- 6 alkenylC 6 -i4aryl; heteroaryl, -NH-C 3- i2cycloalkyl, can be unsubstituted or substituted with one or more Z 1 ;
  • each Z 5 is independently selected from the group consisting of hydrogen, K, Na , hydroxyl, halo, nitro, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- i 2 cycloalkyl, haloCi -6 alkyl, Ci_ 6alkyloxy, Ci -6 alkylamino, haloCi -6 alkyloxy, C 6 -i 4 aryl, C 6 -i 4 aryloxy, C 6 -i 4 arylC 2 - 6 alkenyl, C 6- i 4 arylC 2 - 6 alkynyl, heterocyclyl (e.g.
  • morpholinyl morpholinyl
  • R 13 Ci -8 alkyl, C 6- i4aryl, C 3-8 cycloalkyl, glycosyl or ester
  • a pharmaceutical composition comprising at least one compound of formula (1 ), and at least one pharmaceutically acceptable carrier,
  • R a is a group of formula -NH-R b -NH-R c , or -NH-R ; wherein
  • R b is a group of formula -R d -, or -R d -CO-, wherein the right side of -R d -CO- is attached to -NH-R c ;
  • R c is -R e , or -CO-R e ;
  • R d is a Ci-i 2 alkylene, wherein said Ci-i 2 alkylene; optionally comprises one or more heteroatoms in the alkylene, moiety, said heteroatoms being O;
  • R e is selected from the group consisting of C 2 - 6 alkynyl, C 6 -i4aryl, C6-i4arylCi- 6 alkyl, C 6- i4arylC 2 - 6 alkenyl, C 6 -i4arylC2- 6 alkynyl, C6-i4arylC2- 6 alkenylC 6 -i4aryl; heteroaryl, -NH-C 3- i 2 cycloalkyl, and wherein said C 2-6 alkynyl; C 6- i4aryl; C 6 -i4arylC2- 6 alkenyl, C 6 -i4arylC2- 6 alkenylC 6 -i4aryl; heteroaryl, -NH-C 3- i2cycloalkyl, can be unsubstituted or substituted with one or more Z 1 ;
  • R is a C 2-6 alkynyl
  • each Z 1 is independently selected from the group consisting of hydroxyl, halo, nitro, Ci_ i 2 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- i2cycloalkyl, haloCi-i 0 alkyl, Ci -6 alkyloxy, Ci_ 6 alkylamino, haloCi-i 0 alkyloxy, C 6 -i4aryl, C 6- i4aryloxy, C 6 -i4arylC2- 6 alkenyl, C 6 -i4arylC2- 6 alkynyl, heterocyclyl (e.g.
  • morpholinyl can be unsubstituted or substituted with one or more Z 2 ; or two adjacent Z 2 can be taken together to form a C 3-7 cycloalkyl, or a 5-, 6-, or 7-membered heterocyclyl or heteroaryl ring, which can be unsubstituted or substituted with one or more Z 2 ;
  • each Z 2 is independently selected from the group consisting of hydroxyl, halo, nitro, Ci_ i 2 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- i 2 cycloalkyl, haloCi-i 0 alkyl, Ci -6 alkyloxy, Ci_ 6 alkylamino, haloCi-i 0 alkyloxy, C 6 -i4aryl, C 6 -i4aryloxy, C 6 -i4arylC2- 6 alkenyl, C 6 -i4arylC2- 6 alkynyl, heterocyclyl (e.g.
  • each Z 3 is independently selected from the group consisting of hydrogen, hydroxyl, halo, nitro, Ci-i 2 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- i 2 cycloalkyl, haloCi-i 0 alkyl, Ci -6 alkyloxy, Ci_ 6 alkylamino, haloCi-i 0 alkyloxy, C 6 -i4aryl, C 6 -i4aryloxy, C 6 -i4arylC2- 6 alkenyl, C 6 -i4arylC2- 6 alkynyl, heterocyclyl (e.g.
  • each Z 4 is independently selected from the group consisting of hydrogen, hydroxyl, halo, nitro, Ci-i 2 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- i 2 cycloalkyl, haloCi-i 0 alkyl, Ci -6 alkyloxy, Ci_ 6alkylamino, haloCi-i 0 alkyloxy, C 6 -i 4 aryl, C 6 -i 4 aryloxy, C 6 -i 4 arylC 2 - 6 alkenyl, C 6 -i 4 arylC 2 - 6alkynyl, heterocyclyl (e.g.
  • Z 4 and Z 3 can be taken together to form a C 3-7 cycloalkyl, or a 5-, 6-, or 7-membered heterocyclyl, which can be unsubstituted or substituted with one or more Z 5 ;
  • each Z 5 is independently selected from the group consisting of hydrogen, K, Na , hydroxyl, halo, nitro, Ci-i 2 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- i 2 cycloalkyl, haloCi-i 0 alkyl, Ci_ 6alkyloxy, Ci -6 alkylamino, haloCi-i 0 alkyloxy, C 6 -i 4 aryl, C 6 -i 4 aryloxy, C 6 -i 4 arylC 2 - 6 alkenyl, C 6 -i 4 arylC 2 - 6 alkynyl, heterocyclyl (e.g.
  • X is a halogen
  • a pharmaceutical composition comprising a compound according to any one of statements 1 to 5, 7-12.
  • composition according to statement 12 for use against a bacterial infection.
  • composition according to statement 13 wherein the infection is a bacterial infection, wherein the infecting bacterium has at least one resistance against another antibiotic compound
  • the pharmaceutical composition according to statement 14 wherein the other antibiotic compound is selected from the group comprising vancomycin, methicillin, ampicillin, erythromycin, teicoplanin, linezolid and daptomycin . 16.
  • a pharmaceutical composition comprising a compound for use against a bacterial infection said compound being represented by the following general formula (1 ) or a pharmaceutically acceptable salt thereof: or comprising a compound according to any one of statements 1 -5,
  • R a is selected from a group of formula (A1 ), (A2), or (A3), as defined in the below table 10 wherein
  • a pharmaceutical composition comprising a compound for use against a bacterial infection said represented by the following general formula (1 ) or a pharmaceutically acceptable salt thereof: or comprising a compound according to any one of statements 1 -5,
  • R a is selected from the group comprising the structures as defined in the below table 1 1 :
  • a pharmaceutical composition comprising compound for use against a bacterial infection said represented by the following general formula (1 ) or a pharmaceutically acceptable salt thereof: or comprising a compound according to any one of statements 1 -5,
  • R a is selected from the group comprising structure of formula (A1), (A2), (A3), (A4), (A5), and (A6), as defined in the below table 12
  • composition according to statement 20 wherein the other antibiotic compound is selected from the group comprising vancomycin, methicillin, ampicillin, erythromycin, teicoplanin, linezolid and daptomycin.
  • composition according to any one of the statements 6, 12 to 21 , wherein the pharmaceutical composition is suitable for employing an effective concentration of 0.01 to 50 g/ml.
  • VRE vancomycin-resistant Enterococci
  • VISA vancomycin- intermediate resistant strains
  • VSSA vancomycin susceptible Staphylococcus aureus
  • VRSA high-level vancomycin-resistant Staphylococcus aureus
  • composition according to any one of the statements 6, 12 to 23, characterized in that the infection is caused by vancomycin-resistant Staphylococcus aureus.
  • composition according to any one of the statements 6, 12 to 23, characterized in that the infection is caused by vancomycin-resistant Enterococci (VRE).
  • VRE vancomycin-resistant Enterococci
  • R b is -CH 2 CH 2 CH 2 - and R c is selected from:
  • R b is -CH 2 CH 2 - and R c is selected from:
  • R b is -COCH 2 and R c is selected from:
  • Vanc-N also referred as Vanc-Q
  • a pharmaceutical composition comprising a compound according to any one of statements 1 to 44. 46. The compound according to any one of statements any one of statements 1 -5, 26-44, or the pharmaceutical composition according to statement 45 for use against a bacterial infection.
  • VRE vancomycin-resistant Enterococci
  • VSSA vancomycin-intermediate resistant strains
  • VRSA vancomycin-susceptible Staphylococcus aureus
  • VRSA high- level vancomycin-resistant Staphylococcus aureus
  • VRE vancomycin-resistant Enterococci
  • R a is a group of formula -NH-R b -NH-R c , or -NH-R ; wherein
  • R b is a group of formula -R d -, or -R d -CO-, wherein the right side of -R d -CO- is attached to -NH-R c ;
  • R c is -R e , or -CO-R e ;
  • R d is a Ci-i 2 alkylene, wherein said Ci-i 2 alkylene; optionally comprises one or more heteroatoms in the alkylene, moiety, said heteroatoms being O;
  • R e is selected from the group consisting of C 2-6 alkynyl, C 6 -i4aryl, C 6 -i4arylCi- 6 alkyl, C 6- i4arylC 2 - 6 alkenyl, C 6 -i4arylC 2 - 6 alkynyl, C6-i4arylC 2-6 alkenylC 6 -i4aryl; heteroaryl, -NH-C 3- i 2 cycloalkyl, and wherein said C 2-6 alkynyl; C 6- i4aryl; C 6 -i4arylC 2 - 6 alkenyl, C 6 -i4arylC 2- 6 alkenylC 6 -i4aryl; heteroaryl, -NH-C 3- i 2 cycloalkyl, can be unsubstituted or substituted with one or more Z 1 ;
  • R is a C 2-6 alkynyl
  • Ci-i 2 alkyl C 2-6 alkenyl, C 2-6 alkynyl, C 3- i 2 cycloalkyl, haloCi-i 0 alkyl, Ci -6 alkyloxy, Ci -6 alkylamino, haloCi-i 0 alkyloxy, C 6- i 4 aryl, C 6 -i 4 aryloxy, C 6- i 4 arylC 2 - 6 alkenyl, C 6 -i 4 arylC 2 - 6 alkynyl, heterocyclyl, heteroaryl, glycosyl or ester thereof; can be unsubstituted or substituted with one or more Z 4 ;
  • Z 4 and Z 3 can be taken together to form a C 3-7 cycloalkyl, or a 5-, 6-, or 7-membered heterocyclyl, which can be unsubstituted or substituted with one or more Z 5 ;
  • each Z 5 is independently selected from the group consisting of hydrogen, K, Na , hydroxyl, halo, nitro, Ci-i 2 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- i 2 cycloalkyl, haloCi-i 0 alkyl, Ci_ 6alkyloxy, Ci -6 alkylamino, haloCi-i 0 alkyloxy, C 6 -i 4 aryl, C 6 -i 4 aryloxy, C 6 -i 4 arylC 2 - 6 alkenyl,
  • X is a halogen
  • R a is a group of formula -NH-R b -NH-R c , or -NH-R ; wherein
  • R b is a group of formula -R d -, or -R d -CO-, wherein the right side of -R d -CO- is attached to -NH-R c ;
  • R c is -R e , or -CO-R e ;
  • R d is a Ci-i 2 alkylene, wherein said Ci-i 2 alkylene; optionally comprises one or more heteroatoms in the alkylene, moiety, said heteroatoms being O;
  • R e is selected from the group consisting of C 2-6 alkynyl, C 6 -i4aryl, C 6 -i4arylCi- 6 alkyl, C 6- i4arylC 2 - 6 alkenyl, C 6 -i4arylC 2 - 6 alkynyl, C6-i4arylC 2-6 alkenylC 6 -i4aryl; heteroaryl, -NH-C 3- i 2 cycloalkyl, and wherein said C 2-6 alkynyl; C 6- i4aryl; C 6 -i4arylC 2 - 6 alkenyl, C 6 -i4arylC 2- 6 alkenylC 6 -i4aryl; heteroaryl, -NH-C 3- i 2 cycloalkyl, can be unsubstituted or substituted with one or more Z 1 ;
  • R is a C 2-6 alkynyl
  • Ci-i 2 alkyl C 2-6 alkenyl, C 2-6 alkynyl, C 3- i 2 cycloalkyl, haloCi-i 0 alkyl, Ci -6 alkyloxy, Ci -6 alkylamino, haloCi-i 0 alkyloxy, C 6- i 4 aryl, C 6 -i 4 aryloxy, C 6- i 4 arylC 2 - 6 alkenyl, C 6 -i 4 arylC 2 - 6 alkynyl, heterocyclyl, heteroaryl, glycosyl or ester thereof; can be unsubstituted or substituted with one or more Z 4 ;
  • Ci-i 2 alkyl C 2-6 alkenyl, C 2-6 alkynyl, C 3- i 2 cycloalkyl, haloCi-i 0 alkyl, Ci -6 alkyloxy, Ci -6 alkylamino, haloCi-i 0 alkyloxy, C 6- i 4 aryl, C 6 -i 4 aryloxy, C 6- i 4 arylC 2 - 6 alkenyl, C 6 -i 4 arylC 2 - 6 alkynyl, heterocyclyl, heteroaryl, glycosyl or ester thereof; can be unsubstituted or substituted with one or more Z 5 ;
  • NZ 4 S ( 0 )2Z 3 j .
  • X is a halogen
  • R a is a group of formula -NH-R b -NH-R c , wherein
  • R b is a group of formula -R d -, or -R d -CO-, wherein the right side of -R d -CO- is attached to -NH-R c ;
  • R c is -R e , or -CO-R e ;
  • R d is Ci -4 alkylene, preferably Ci -3 alkylene
  • R e is selected from the group consisting of C 2-6 alkynyl, C 6 -i4aryl, C 6 -i4arylCi- 6 alkyl, C 6- i4arylC 2 - 6 alkenyl, C6-i4arylC 2-6 alkenylC 6 -i4aryl; heteroaryl, and wherein said C 2-6 alkynyl; C 6 -i4aryl; C 6 -i4arylC 2 - 6 alkenyl, C6-i4arylC 2-6 alkenylC 6 -i4aryl; heteroaryl, can be unsubstituted or substituted with one or more Z 1 ;
  • each Z 4 is independently selected from the group consisting of hydrogen, hydroxyl, halo, nitro, Ci -8 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- i 2 cycloalkyl, haloCi -6 alkyl, Ci -6 alkyloxy, Ci_ 6alkylamino, haloCi -6 alkyloxy, C 6 -i 4 aryl, C 6 -i 4 aryloxy, C 6 -i 4 arylC 2 - 6 alkenyl, C 6 -i 4 arylC 2- 6 alkynyl, heterocyclyl, heteroaryl; and wherein each of said Ci -8 alkyl, C 2-6 alkenyl, C 2- 6 alkynyl, C 3- i 2 cycloalkyl, haloCi -6 alkyl, Ci -6 alkyloxy, Ci -6 alkylamino, haloCi -6 alkyloxy, C 6- i
  • each Z 5 is independently selected from the group consisting of hydrogen, K, Na , hydroxyl, halo, nitro, Ci -6 alkyl.
  • R a is a group of formula -NH-R b -NH-R c , wherein
  • R b is a group of formula -R d -, or -R d -CO-, wherein the right side of -R d -CO- is attached to -NH-R c ;
  • R c is -R e , or -CO-R e ;
  • R d is Ci -3 alkylene
  • R e is selected from the group consisting of C 6 -i 4 aryl, C 6 -i 4 arylCi- 6 alkyl, C 6 -i 4 arylC 2- 6 alkenyl, C6-i 4 arylC 2-6 alkenylC 6 -i 4 aryl; heteroaryl, and wherein said C 6- i 4 aryl; C 6 -i 4 arylC 2- 6 alkenyl, C6-i 4 arylC 2-6 alkenylC 6 -i 4 aryl; heteroaryl, can be unsubstituted or substituted with one or more Z 1 ;
  • each Z 3 is independently selected from the group consisting of hydrogen, hydroxyl, halo, nitro, Ci -8 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- i 2 cycloalkyl, haloCi -6 alkyl, Ci -6 alkyloxy, C 6- i 4 aryl, C 6 -i 4 aryloxy, heterocyclyl, heteroaryl, and wherein each of said Ci -8 alkyl, C 2- 6 alkenyl, C 2-6 alkynyl, C 3- i 2 cycloalkyl, haloCi -6 alkyl, Ci -6 alkyloxy, C 6 -i 4 aryl, C 6 -i 4 aryloxy, C 6- i 4 arylC 2 - 6 alkenyl, C 6 -i 4 arylC 2 - 6 alkynyl, heterocyclyl, heteroaryl; can be unsubstituted or substituted with one or more Z
  • each Z 4 is independently selected from the group consisting of hydrogen, hydroxyl, halo, nitro, Ci -8 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- i 2 cycloalkyl, haloCi -6 alkyl, Ci -6 alkyloxy, Ci_ 6alkylamino, haloCi -6 alkyloxy, C 6 -i 4 aryl, C 6 -i 4 aryloxy, C 6 -i 4 arylC 2 - 6 alkenyl, C 6 -i 4 arylC 2- 6 alkynyl, heterocyclyl, heteroaryl; and wherein each of said Ci -8 alkyl, C 2-6 alkenyl, C 2- 6 alkynyl, C 3- i 2 cycloalkyl, haloCi -6 alkyl, Ci -6 alkyloxy, Ci -6 alkylamino, haloCi -6 alkyloxy, C 6- i
  • each Z 5 is independently selected from the group consisting of hydrogen, K, Na , hydroxyl, halo, nitro, Ci -6 alkyl.
  • Z 1 has the same meaning as that defined in any one of statements 1 to 4 and n is an integer selected from 0, 1 , 2, 3, 4, 5, or 6.
  • a pharmaceutical composition comprising a compound according to any one of statements 1 -5, 6-1 1 , 26-44, 53-64, or as defined in any one of statements 5, 12-25, 45-52.
  • the compound or the pharmaceutical composition according to statement 67 or 68 wherein the antibiotic compound is selected from the group comprising vancomycin, methicillin, ampicillin, erythromycin, tigecycline, teicoplanin, daptomycin, and linezolid.
  • composition according to any one of statements 65-69, wherein the pharmaceutical composition is suitable for employing an effective concentration of 0.01 to 50 Mg/ml.
  • VSE vancomycin-susceptible Enterococci
  • VRE vancomycin-resistant Enterococci
  • VSSA vancomycin-susceptible Staphylococcus aureus
  • VRSA vancomycin-intermediate resistant strains
  • VRSA vancomycin-resistant Staphylococcus aureus
  • VSSA vancomycin-susceptible Staphylococcus aureus
  • a method for the prevention or treatment of a bacterial infection in an animal, mammal or human comprising administering to said animal, mammal or human in need for such prevention or treatment an effective dose of the compounds ad defined in any one of statements 1 -77.
  • the antibiotic compound is selected from the group comprising vancomycin, methicillin, ampicillin, erythromycin, tigecycline, teicoplanin, daptomycin, and linezolid.
  • VSE vancomycin-susceptible Enterococci
  • VRE vancomycin-resistant Enterococci
  • VSSA vancomycin-susceptible Staphylococcus aureus
  • VRSA vancomycin-intermediate resistant strains
  • VRSA high-level vancomycin-resistant Staphylococcus aureus
  • VRSA vancomycin-resistant Staphylococcus aureus
  • VRE vancomycin-resistant Enterococci
  • VSE vancomycin-susceptible Enterococci
  • VSSA vancomycin-susceptible Staphylococcus aureus
  • vancomycin analogs (Table 1 and 1 a) were screened against VanA phenotype VRE strains isolated from hospitalized patients and noticed that among all the tested compounds (sixty vancomycin analogs), aromatic substituted ones displayed good results (Table 3, 4 and 4a). These vancomycin analogs were also tested against vancomycin-resistant Staphylococcus aureus (VRSA) and vancomycin-intermediate resistant Staphylococcus aureus (VISA) to investigate their efficacy (Table 4a).
  • VRSA vancomycin-resistant Staphylococcus aureus
  • VISA vancomycin-intermediate resistant Staphylococcus aureus
  • substituent groups also referred to as “substitutions,” “modifying groups,” “modifications”, “extensions,” or “linkers”
  • substituent groups were added to the C-terminus of vancomycin to produce the vancomycin structural analogs (also referred to as “analogs,” “derivatives,” “conjugates,” “linker conjugates,” or “compounds”).
  • All synthesized and commercially available substituent groups were bifunctional possessing a terminal amine and a terminal alkyne group (Table 1 and Table 1 a. Analogs Vane 1 -38 as listed in Table 1 a are also represented in Tables 10-17).
  • DMF ⁇ , ⁇ -dimethylformamide
  • HATU 0-(7-Azabenzotriazole-1 -yl)-1 ,1 ,3,3- tetramethyluroniumhexafluorophosphate
  • DIPEA Diisopropylethylamine
  • HOAt 1 -Hydroxy-7- azabenzotriazole
  • EDC N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride
  • ACN acetonitrile
  • Boc t-Butoxycarbonyl
  • THF tetrahydrofuran
  • TEA Triethylamine
  • TMS-acetylene (trimethylsilyl)acetylene
  • TBAF tetra-n-butylammonium fluoride
  • EA ethylacetate
  • DMSO dimethylsulfoxide.
  • Vancomycin HCI (75 mg, 0.051 mmol), EDC-HCI (12 mg, 0.0.067 mmol) and HOAt (9 mg, 0.067mmol) were dissolved in DMF (5 mL) and the mixture was stirred for 5 min. To this solution were added a solution of amine of formula R c NHR b NH 2 (1 .1 equiv) in DMF (1 mL) and /V-methyl morpholine (till pH 8) and the mixture was stirred for 7-8h at rt. The reaction was monitored by ESI-MS. DMF was removed in vacuo and the residue was purified by preparative RP-HPLC (0-40% ACN/H 2 0 with 0.1 % HCOOH in 40 min).
  • R c NHR b NH 2 was prepared from a) N- Boc Glycine; b) N-Boc-ethylenediamine; or c) N-Boc-1 ,3 propanediamine (as illustrated in Scheme 1 a, 1 b, 1 c))
  • Reagents and conditions i) Ethyl chloroformate, THF, TEA, overnight, 0 °C to room temperature (rt); ii) H 2 0/dioxane (9:1 ), 140 °C, 3h; ii') 4N HCI in 1 ,4-dioxane, DCM, 0 °C to rt, 1 h.
  • Vanc-54-56, 64: R e 4-[(phenylsulfonyl)amino]phenyl ⁇ ethenyl unsubstituted or substituted by one, or two substituents,
  • R e phenyl ⁇ ethenyl unsubstituted or substituted by one, or two substituents, 9H-fluorenyl, alkyl substituted by aryl
  • Reagents and conditions i) HATU, DIPEA, DMF, rt, 4h; ii) 4N HCI in 1 ,4-dioxane, DCM, 0 °C to rt, 1 -2h.
  • R e substituted/unsubstituted heteroaryl ring such as indole, benzothiazole, benzofuran, quinoline, benzimidazole.
  • 1.C.1 arylamines suitable for preparing (11 n, Vane- 1-19, 37-44, 58-59, 67-71, 74, 75)
  • Z 1 internal or terminal alkynyl, alkyl, alkenyl, halide, nitro, aryl, ether, NH-, sulfonamide, sulfone etc.
  • Z 2 is hydrogen, alkyl or cycloalkyl
  • This compound was synthesized from 4-lodo aniline by following the procedure applied for the synthesis of 9n.
  • Z3 H, alkyl, aryl, alkoxy, halide etc
  • Reagents and condition i) Pyridine, rt, 5-6h; ii) 4N HCI in 1 ,4-dioxane, DCM, 0 °C to rt, 2h iii) ethylchloroformate, N-Boc-glycine, THF, TEA, overnight, 0 °C to rt.
  • 9b' was synthesized by following the procedure used for the synthesis of 10n. Yield 90-95%. iii) Synthesis of 9c'.
  • 9c' was synthesized by following the procedure used for the synthesis of 9n. Yield: 65-70%. iv) Synthesis of 9d'.
  • Reagents and condition NaN 3 , Cul, L-Proline, NaOH, DMSO, 60 °C, 7-8h; ii) Cul, DIPEA, THF, 60 °C, 20h; iii) 4N HCI in 1 ,4-dioxane, DCM, 0 °C to rt, 2h.
  • Z3 H, alkyl, aryl, alkoxy, halide etc
  • Reagents and condition i) Pyridine, rt, 5-6h; ii) /V-Boc-1 ,2-ethanediamine, HATU, DIPEA, DMF, rt, 4h; iii) ) 4N HCI in 1 ,4-dioxane, DCM, 0 °C to rt, 2h.
  • Z8 Alkyl, halide, Hydroxy, alkoxy, Sulphone, sulphonamide, triazole, substituted triazole,
  • Z4 H, alkyl, aryl, alkoxy, halide etc Reagents and condition: i) Pyridine, rt, 5-6h; ii) /V-Boc-1 ,3-propanediamine, HATU, DIPEA, DMF, rt, 4h; iii) ) 4N HCI in 1 ,4-dioxane, DCM, 0 oC to rt, 2h.
  • Z8 Alkyl, halide, alkoxy, Sulphone, sulphonamide, triazole, substituted triazole, protected/unprotected
  • Z Alkyl, halo, alkoxy, Sulfonyl, sulfonamidy, triazolyl, substituted triazolyl, protected/unprotected glycosyl etc Reagents and conditions: i) /V-Boc-1 ,3-propanediamine, HATU, DIPEA, DMF, rt, 4h; ii) 4N HCI in 1 ,4-dioxane, DCM, 0 °C to rt, 2h.
  • Z3 H , alkyl, cycloalkyl
  • Z8 Alkyl, halo, alkoxy, sulf nyl, sulfonamidyl, triazolyl, substituted triazolyl,
  • Example 2 General protocol for the screening vancomycin analogs for antibacterial activity.
  • Example 3 General protocol for the cytotoxicity assay.
  • Murine leukemia L1210, human T-lymphocyte CEM and human cervix carcinoma (HeLa) cells were suspended at 300,000-500,000 cells/mL of culture medium, and 100 ⁇ of a cell suspension was added to 100 ⁇ of an appropriate dilution of the test compounds in wells of 96- well microtiter plates. After incubation at 37 °C for two (L1210) or three (CEM, HeLa) days, the cell number was determined using a Coulter counter. The IC 50 was defined as the compound concentration required to inhibit cell proliferation by 50%.
  • Example 4 Antibacterial activity of vancomycin analogs against vancomycin sensitive Gram-positive and Gram-negative model bacterial strains.
  • Enterococcus are Gram-positive bacteria found mainly in the intestines of humans and domestic animals, and in the environment from soil, water, plants, wild animals, birds, insects etc ⁇ Hammerum, A. M. Clin Microbiol Infect 2012, 18, 619-625). Although a number of Enterococcus species have been identified, among them only two i.e., Enterococcus faecalis and Enterococcus. faecium are responsible for the majority of infections in human (Cetinkaya, V.; Falk, P.; Mayhall, C. G. Clin. Microbiol. Rev. 2000, 13, 686-707).
  • Enterococci are currently a dominant nosocomial pathogens, and most common infections caused by them are urinary tract infections (UTIs) endocarditis, surgical wound infection, diarrhea, bacteremia and neonatal sepsis among hospitalized patients (Heintz, B. H.; Halilovic, J.; Christensen, C. L. Pharmacotherapy 2010, 30, 1136-1149 and Moscoso, M.; Domenech, M.; Garcia, E. Env. Microbiol. Rep. 2011, 3, 640-650). Enterococci are intrinsically resistant to a number of first-line antimicrobial agents such as ⁇ -lactams, cephalosporins, clindamycin and aminoglycosides ⁇ Anas, C.
  • UTIs urinary tract infections
  • Vancomycin was in clinical use for more than 30 years without the emergence of marked resistance for the treatment of bacterial infection caused by Enterococci but as mentioned before, due to its widespread clinical use, bacteria have been isolated that show resistance to vancomycin.
  • the first bacterial isolate of vancomycin-resistant Enterococcus was isolated in late 1980's in Europe ⁇ Cetinkaya, Y.; Falk, P.; Mayhall, C. G. Clin. Microbiol. Rev. 2000, 13, 686-707 and Uttley, A. H. C; Collins, C. H.; Naidoo, J.; George. R. C. Lancet 1988, 1, 57-58).
  • VRE vancomycin-resistant S. aureus
  • Example 6 Antibacterial activity of vancomycin analogs against VRE.
  • MICs vancomycin-sensitive Enterococcus faecalis HC-1909-5
  • VSE vancomycin-sensitive Enterococcus faecalis HC-1909-5
  • VRE-6, VRE-29, VRE-37 and VRE-53 patient isolates of vancomycin resistant Enterococcus
  • the MICs of the vancomycin analogs are either given in ⁇ or expressed as fold- improvements in comparison to the MIC of vancomycin (MIC V ancomycin/MIC V ancomycin analog) (Table 3, 4 and 4a). All vancomycin analogs from Table 1 (except 11 d) show improvement in antibacterial activity in comparison to vancomycin on at least one of the tested strains (Table 4). Vancomycin analogs 11f, 11 n, 11t, 11 u, 11v and 11w demonstrated the best improvements, most pronounced against the most resistant VREs. Improvements from 8x up to 512 could be observed. Also VSE is more susceptible for 11 n, 11t, 11 u, 11v and 11w.
  • Vane 1 -38 (Table 1 a) were shown to have a lower MIC value against VSE, VRE-6, VRE-29, VRE-37 and VRE-53 in comparison to vancomycin, showing improvements between 2 and 512-fold.
  • the most active vancomycin analogs include Vanc-14, Vanc-24, Vanc-31 , Vanc-33, Vanc-34, Vanc-35, Vanc-37 and Vanc-38.
  • Example 7 Confirmation of the resistance phenotype of selected pathogenic strains (VRE strains).
  • VRE strains To analyze the underlying resistance mechanism of the different VREs used here, we first tested the susceptibility of all the selected strains for teicoplanin and results indicated that all the strains were resistant to teicoplanin with MIC values of 256, ⁇ 512 and 64 ⁇ g mL for strains VRE-29, VRE-37 and VRE-53, respectively (Table 6). VRE-6 appeared to be more intermediate resistant with a MIC value of 8 ⁇ g ml. According to previously published report (Hubbard, B. K.; Walsh, C. T. Angew. Chem. Int. Ed. 2003, 42, 730-765; 22; Gold H.
  • Example 8 Vancomycin against Staphylococcus aureus.
  • Staphylococcus aureus is a Gram-positive bacterium normally found in the nose and/or on the skin of up to 30% of healthy people. Most of the time, it is not harmful but when S. aureus gets into the bloodstream, it can be fatal and cause a variety of infections from minor skin infections, chronic bone infections to devastating septicemia and endocarditis (Howden, B. P.; Davis, J. K.; Johnson, P. D. R.; Stinear, T. P.; Grayson, M. L. Clin. Microbiol. Rev. 2010, 23, 99-139).
  • VRSA vancomycin-resistant Staphylococcus aureus
  • VISA vancomycin-intermediate resistant Staphylococcus aureus
  • hVISA heterogeneous vancomycin-intermediate resistant Staphylococcus aureus
  • VRSA isolates were found to contain the vanA vancomycin resistance gene. This vanA gene is usually found in Enterococci and confers a high-level of resistance towards vancomycin. Usually, patients who are at the major risk of infections by hVISA, VISA and VRSA are those with previous exposure to vancomycin for the treatment of MRSA and were also infected by vancomycin-resistant Enterococci (VRE) containing vanA. As already mentioned before, it is likely that the vanA operon gets transferred via plasmids or transposons from the VRE to the MRSA strain, resulting in the VRSA ⁇ Howden, B. P.; Davis, J. K.; Johnson, P. D. R.; Stinear, T. P. and Gold H.
  • Example 9 Antibacterial activity of vancomycin analogs against vancomycin susceptible Staphylococcus aureus (VSSA), VRSA and VISA strains.
  • MICs vancomycin-sensitive Staphylococcus aureus Rosenbach ATCC 6538
  • VSSA vancomycin-intermediate resistant Staphylococcus aureus
  • VISA HIP5827 vancomycin-intermediate resistant Staphylococcus aureus
  • the MICs of the vancomycin analogs are either given in ⁇ or expressed as fold-improvements in comparison to the MIC of vancomycin
  • vancomycin analogs 11f, 11 n, 11t-w found during the first previous screening against VRE were selected to test against VSSA, VRSA and VISA. Apart from 11f, all these analogs are 4 to 8 times more active against VSSA, 2-4 times more active against VISA P1 V44 and 2-8 times more active against VISA HIP5827K. The largest improvements (up to 128 times) are obtained against the most resistant strain (VRS1/HIP1 1714), reducing the MIC of 11v against a vancomycin-resistant strain (VRSA) to the same level as vancomycin against a sensitive strain (VSSA).
  • Vancomycin analogs from the second series generally perform better in terms of antibacterial activity with improvements from 4 to 32 times against VSSA, from 2 to 64 times against VISA HIP5827K and 4 to 128 times against VRSA.
  • the most active vancomycin analogs include Vanc-14, Vanc-24, Vanc-31 , Vanc-33, Vanc-34, Vanc-35, Vanc-37 and Vanc- 38.
  • Example 10 Biological activity of vancomycin analogs against Gram-negative pathogens.
  • Example 11 Cytotoxicity Assay.
  • IC 50 is the concentration of a substance that results in a reduced cell number (50%) after a period of growth. This reduction is due to the cytotoxicity of the tested substance.
  • the most active vancomycin analogs were evaluated for their cytotoxic activity against three different cell lines, specifically murine leukemia cells (L1210), human T-lymphocyte cells (CEM) and human cervix carcinoma (HeLa) cell lines (Tables 9 and 9a) and Table 21 .
  • Example 12 other compounds according to the invention
  • R b is an aliphatic chain which may have a chain length of more than 2 carbons, for example, 2, 3, 4, 5, or 6 carbons, while R c is an aromatic, aliphatic, or heterocyclic ring system.
  • Tables 20 shows the structures of exemplary analogs (named Vane 39-77), and Table 21 summarizes the biological activities.
  • Example 14 Discussion of antibacterial activity.
  • compound 11 d has a PEG derivatized substituent group which is comparatively hydrophilic and longer in length than the other substituent groups. However, it did not show any marked improvement against VRE strains while in contrast, its activity dropped by a 4-fold against sensitive strains as compared to vancomycin. Similarly, compound 11 a and 11 c possessing hydrophilic PEG derivatized substituent group, exhibited no significant improvement in the screening results.
  • the stilbene based analog 11 u proved to be the most active against tested strains. It showed a 4-fold increase in activity against sensitive strain £. faecalis (Table 3). Notably, a 32- to 512-fold increase in activity of 11 u was recorded against various VRE strains (Table 4). However, in the cytotoxicity assay, this compound was found to be toxic on tested murine leukemia cells (L1210), human T-lymphocyte cells (CEM) and human cervix carcinoma cells (HeLa) with IC50 values almost equal to its MIC value against VRE's (Table 9).
  • compound 11v having a biphenyl substituent group maintained its consistency on all tested strains by exhibiting a 32-fold gain in activity against sensitive strain E. faecalis (MIC 25 nM) as compared to vancomycin (MIC 780 nM).
  • This compound exhibited a 32- to 128-fold increase in activity against VRE strains (with MIC ranging between 0.7-25 ⁇ ).
  • it was also found to be toxic (IC 50 value 5-70 ⁇ ). But as its effective concentration on the E. faecalis strain is almost 200 times less than its IC 50 dose, this compound might be selectively or specifically applied for the inhibition of bacterial infections caused by E. faecalis.
  • Analogs 11 n and 11t were not cytotoxic (>250 ⁇ ), but were active against VRE at comparatively higher concentrations (3-50 ⁇ ). These two analogs exhibited an 8-fold increase in activity against sensitive strain as compared to vancomycin with MIC value 0.1 ⁇ . Compound 11 n displayed 32 to 128-fold increase in activity against tested resistant strains and 11t exhibited 16 to 64-fold rise in antibacterial activity as compared to vancomycin.
  • Naphthyl substituted vancomycin analog 11w was also found considerable active against £. faecalis as well as against tested VRE strains. But, against some of the resistant strains, its MIC was closer to its cytotoxic value. Analog 11 f was not cytotoxic; however, the improvement of the antibacterial activity is more limited in comparison to the analogs substituted with aromatic substituent groups. We believe that the further optimization of these analogs in terms of substituent variation and by SAR study, bioactivity of these analogs can be certainly improved. Bioactivity of vancomycin analogs against VSSA, VRSA and VISA. - The most active vancomycin analogs (11f, 11 n, 11t-w) were tested against the VSSA, VRSA and VISA strains (Table 7).
  • analogs 11 n, 11 u 11v and 11w exhibited an 8-fold gain in activity while 11t demonstrated a 4-fold improvement as compared to unmodified vancomycin.
  • Aliphatic analog 11 f did not show any improvement.
  • aromatic analogs proved better in terms of bioactivity.
  • analogs 11f, 11 n and 11t did not demonstrate cytotoxicity at the concentration of their MIC values against VSSA, VISA and VRSA strains (Table 9).
  • 11v the rather limited margin between the MIC and IC 50 requires additional clinical testing before it may be considered as safe enough.
  • cell proliferation was poorly or not at all inhibited at a concentration ranging between 50 to >250 ⁇ , which is notably higher than that required to display antibacterial activity as these analogs display MIC value 0.097 ⁇ in case of susceptible stain and MIC value 1 .56 ⁇ in case of resistant strain.
  • Analog 11 u displays bacterial inhibition at subtoxic concentrations.
  • Vancomycin-naphthyl derivative 11w is not toxic but its inhibitory concentration against VRE is close to the cytotoxic value.
  • Example 15 The compounds according to the invention
  • the invention provides vancomycin analogs which are active antimicrobials against resistant bacterial strains possessing VanA phenotype.
  • Table 10-17 provides a class of hydrophobic vancomycin analogs with different rigid aromatic and heterocyclic ring systems at the position R a in the general structure of formula (1 ).
  • the invention also provides compounds with general formulation vancomycin-NH-R 1 -NH-R 2 represented by the following general formula (2) or a pharmaceutically acceptable salt thereof, wherein R b : is an aliphatic chain composed of 2-4 carbon atoms (example CH2CH2, CH2CH2CH2, COCH2, etc.) and R c : Aromatic substitution/heterocyclic compound or some selected aliphatic chains as demonstrated in the tables 12 to 17, and Table 1 a.
  • Suitable amine for reaction with the carboxyl group of vancomycin A are listed in Table 1.
  • Example 16 Biological activity of tested compounds
  • Table 2 Antibacterial activity of vancomycin analogs (series 11 a-w) against model Gram- positive (B. subtilis ATCC6633) and Gram-negative (£. coli TOP10J bacterial strains.
  • MICvan/MIC ratio of antibacterial activity of vancomycin to the vancomycin analogs, tested against Gram-positive and Gram-negative bacterial strains.
  • Vancomycin 64 to 4 to 1024 2 to 32 128 16
  • Table 6 Antibacterial activity of teicoplanin on tested VRE strains.
  • VanA VanA VanA VanA VanA VanA VanA VanA VanA VanA Second raw of this table indicates the resistance phenotype of selected pathogenic strains which is comparable to prior published results mentioned in Table 5 (the VanA mechanism of VR6 was confirmed by PCR).
  • Table 7 Antibacterial activity of vancomycin analogs 11f, 11 n, 11t-w against VSSA, VRSA and VISA strains expressed as MIC in ⁇ and as fold-improvement in comparison to vancomycin).
  • V vancomycin
  • MICVan/MICi ratio of antibacterial activity of vancomycin to the vancomycin analogs tested against vancomycin susceptible and resistant Staphylococcus aureus
  • VSSA vancomycin-susceptible Staphylococcus aureus Rosenbach ATCC6538
  • VRS1/HIP1 1714 vancomycin-resistant S. aureus (VRSA);
  • VISA/P1V44 & VISA/HIP5827 vancomycin- intermediate resistant Staphylococcus aureus.
  • Table 8 Biological activity of vancomycin analogs 11f, 11 n, 11t-w against different Gram- negative pathogenic bacteria.
  • P. aeruginosa Pseudomonas aeruginosa
  • A. baumannii Acinetobacter baumannii
  • K. pneumoniae Klebsiella pneumoniae
  • S. Typhimurium Salmonella Typhimurium.
  • Table 9 Inhibitory effects of vancomycin analogs 11f, 11n, 11t-won the proliferation of tumour cells (expressed as IC 5 o in ⁇ ).
  • IC 50 50% inhibitory concentration for cell proliferation.
  • Table 9a Inhibitory effects of vancomycin analogs from the Vanc1-38 series on the proliferation of tumour cells. Data is expressed as IC 5 o in ⁇ .
  • Example 17 Examples of compounds according to the invention Suitable compound of formula (1 ) can be selected from the group comprising compound of formula (1 ) wherein R a is selected from a group of formula (A1 ), (A2), or (A3), as defined in the below table 10.
  • Suitable compound of formula (1 ) can be selected from the group comprising compound formula (1 ) wherein R a is selected from a group as defined in the below table 1 1.
  • Table 11 Structure of some heterogeneous substituent groups to synthesize new vancomycin analo s.
  • Suitable compound of formula (1 ) can be selected from the group comprising compound formula (1 ) wherein R a is selected from a group of formula (A1 ), (A2), (A3), (A4), (A5), and (A6), as defined in the below table 12.
  • Suitable amine for reaction with the carboxyl group of vancomycin A are listed in Table 15.
  • Suitable compound of formula (2) can be selected from the group comprising compound formula (2) wherein R b and R c are as defined in the below table 18.
  • Suitable compound of formula (2) can be selected from the group comprising compound formula (2) wherein R b and R c are as defined in the below table 19.
  • Example 17 Biological activity of the tested compounds
  • the MIC was determined according to the guidelines of the Clinical and Laboratory Standards Institute (CLSI), specifically document M07-A9 (edition 2012), using the broth microdilution method. Specifically, two-fold dilution series of the antibiotics in ultrapure water were prepared and mixed with cells in Mueller-Hinton medium, having a final concentration of approximately 5x10e+5 cells/ml (total volume 100 ⁇ ). The multiwell plates were incubated for 24h at 37°C. A negative control (medium only) and a positive control (medium and cells, no antibiotic) were included. The MIC was the lowest concentration that gave complete inhibition of the growth, assessed by the naked eye.
  • CCSI Clinical and Laboratory Standards Institute
  • FIG. 1 shows the results of the resistance development study of vancomycin analogs against VRE-29. Highly selective exposure to subinhibitory doses of the vancomycin-analogs did thus not lead to the recovery of resistant strains after 20 cycles. Exposure to daptomycin selected for cells with a 4-fold increased MIC after 4 cycles and a 8-fold increase after 15 cycles. This example demonstrates that there is a low probability of resistance development against Van-N, Vanc-39 and Vanc-42 by vancomycin-resistant enterococci through randomly occurring genetic mutations, in contrast to daptomycin. Resistance development by vertical transfer can thus be considered very unlikely for vancomycin-analogs.

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Abstract

Efforts have thus been made towards the discovery of the next generation of antibiotics to combat the antibiotic resistance in emerging bacterial strains. In spite of these efforts, there remains a need in the art for novel antibiotics and variations of existing antibiotics. For example, there is a need for low toxicity bearing compounds, which can be used for the treatment of vancomycin resistant as well as sensitive strains, with low molar concentrations as compared to vancomycin. The present invention provides compounds of formula (1), Wherein Ra has the meaning as defined in the claims. The present invention also relates to pharmaceutical composition comprising said compounds. The present invention also relates to said compound and pharmaceutical composition for use as an antibacterial compound.

Description

VANCOMYCIN ANALOGS
FIELD OF THE INVENTION
There is an urgent need for new antibacterial drugs with new mechanisms of actions, especially to overcome drug resistance and to overcome the known dramatic side effects of some available drugs. The present invention can satisfy this need. It relates generally to novel vancomycin analogs and their use as antibacterial agents in infectious diseases of mammals (humans and animals) caused by Gram-positive and Gram-negative infectious bacterial strains and, more particularly to vancomycin analogs against vancomycin resistant Enterococcus and Staphylococcus aureus.
BACKGROUND OF THE INVENTION
Vancomycin is a clinically used glycopeptide antibiotic, which works against Gram-positive bacterial infections caused by S. aureus, Enterococci and Clostridium difficile and other species {Ashford, P. A. and Bew, S. P. Chem. Soc. Rev. 2012, 41, 957-978).
It is reserved as drug of last resort (only used for bacteria that are not killed by other antibiotics), used to cure serious infections caused by methicillin-resistant Staphylococcus aureus (MRSA), including pneumonia, emphysema, endocarditis, osteomyelitis, and soft-tissue abscesses {Cooper, M. A.; Betley, J. R.; St. Edmonds, B. US patent, US 7078380B2, 2006; Xie, J.; Pierce, G.; James, R. C; Okano, A.; Boger, D. L. J. Am. Chem. Soc. 2011, 133, 13946-13949; McComas, C. C; Crowley, B. M.; Boger, D. L. J. Am. Chem. Soc. 2003, 125, 9314-9315).
Moreover, vancomycin is also highly useful in the treatment of staphylococcal infections in patients who are allergic to penicillins and cephalosporins {Cooper, M. A.; Betley, J. R.; St. Edmonds, B. US patent, US 7078380B2, 2006; Xie, J.; Pierce, G.; James, R. C; Okano, A.; Boger, D. L. J. Am. Chem. Soc. 2011, 133, 13946-13949). However, due to frequent use, bacteria have become resistant to it, especially bacterial strains known as vancomycin-resistant Enterococci (VRE), vancomycin-resistant Staphylococcus aureus (VRSA) and vancomycin- intermediate resistant Staphylococcus aureus (VISA) {Murray, B. E. N. Engl. J. Med. 2000, 342, 7† )-72Y,Hubbard, B. K.; Walsh, C. T. Angew. Chem. Int. Ed. 2003, 42, 730-765). E.g., 33 strains of Vancomycin-resistant S. aureus (VRSA) have been reported meanwhile {Morawei, Z., Estaji, F., Askara, E., Solhjou, K., Naderi Nasab, M., Saadat, S. 2013, Int. J. Antimicrob. Agents, doi: 10.1016/j.ijantimicag.2013.06.004).
Notably, vancomycin-resistant Enterococci (VRE) have been distinguished as opportunistic pathogens which are normally isolated from prolonged hospitalized patients who went through several antibiotic treatments {Murray, B. E. N. Engl. J. Med. 2000, 342, 710-721 and Hubbard, B. K.; Walsh, C. T. Angew. Chem. Int. Ed. 2003, 42, 730-765). Such resistance constitutes a threat to human health. By the end of 1990s, 12% of all hospital infections in the clinics of USA occurred due to Enterococci, from which >15% were vancomycin-resistant with a 42- 81 % mortality rate (Olsuf'eva, E. N.; Preobrazhenskaya, M. N. Russ. J. Bioorg. Chem. 2006, 32, 303-322).
Now the situation has become more deteriorate, and virtually not much drugs are left for the treatment of such patients. Daptomycin and linezolid have emerged as potentially attractive antimicrobial therapies for VRE infections, however, daptomycin- and linezolid-resistant VRE show an increasing incidence too (Kamboy, M.; Cohen, N.; Gilhuley, K.; Babady, N. £.; Seo, S. K.; Sepkowitz, K.A. 2011 , 32, 391 -394; Scheetz, M. H.; Knechtel, S. A.; Malczynski, M.; Postelnick, M. J.; Qi, C. Antimicrob Agents Chemother. 2008, 52, 2256-2259). The intensive research for new glycopeptide antibiotics and other antimicrobial agents against multidrug- resistant bacteria is going on throughout the world in the leading pharmaceutical companies and research laboratories (Olsufyeva, E. N. Expert Opinion on Therapeutic Patents 2004, 14, 141- 173; Xie, J.; Okano, A.; Pierce, J. G.; James, R. C, Stamm, S.; Crane, C. M.; Boger D. L. J. Am. Chem. Soc. 2012, 134, 1284-1297; Crane, C. M.; Pierce, J. G.; Leung, S. S. F.; Tirado- Rives, J.; Jorgensen, W. L; Boger, D. L. J. Med. Chem. 2010, 53, 7229-7235; Pinchman, J. R.; Boger, D. L. J. Med. Chem. 2013, 56, 4116-4124)
The antibacterial properties of vancomycin are based on its interaction with the terminal D-Ala- D-Ala residues of the pentapeptide moiety of the bacterial peptidoglycan precursor, thereby inhibiting transpeptidation and transglycosylation. Resistant bacteria produce modified peptidoglycan precursors with terminal D-Ala-D-Lactate or D-Ala-D-Ser instead of D-Ala-D-Ala, which reduces the affinity of vancomycin for its target..
Efforts have thus been made towards the discovery of the next generation of glycopeptide antibiotics to combat the emerging resistance (Crowley, B. M.; Boger, D. L, J. Am. Chem. Soc. 2006, 128, 2885-2892; Leung, S. S. F.; Tirado-Rives, J.; Jorgensen, W. L. Bioorg. Med. Chem. 2009, 17, 5874-5886.; Xie, J.; Pierce, J. G.; James, R. C; Okano, A.; Boger, D. L. J. Am. Chem. Soc. 2011, 133, 13946-13949; James, R. C; Pierce, J. G.; Okano, A.; Xie, J.; Boger, D. L. Chem. Biol. 2012, 7, 797-804).
Regardless this efforts and novel analogs developed, there remains a need in the art for low toxicity bearing compounds, which can be used for the treatment of vancomycin-resistant as well as sensitive strains, with low molar concentrations as compared to vancomycin. Present invention provides such compounds. A study on the synthesis and the effects of hydrophobic substituents at the C-terminus (carboxyl group) of vancomycin on the antibacterial activity surprisingly delivered a class of such compounds. In addition, consistent with the observation that some hydrophobic substituent groups can, under certain conditions, be toxic to human cells, this disclosure also describes a class of compounds comprising combination hydrophilic-hydrophobic extensions/substitutions at the C- terminus. The antibacterial activity of these compounds extends against a broad spectrum of Enterococci, for example, those with the resistant VanA phenotype. Finally, the substituent groups of the compounds are selected to facilitate synthesis from starting material such as vancomycin.
SUMMARY OF THE INVENTION
One aspect of the present invention is a compound of formula (1 ) or a pharmaceutically acceptable salt thereof:
Figure imgf000005_0001
wherein
Ra is a group of formula -NH-Rb-NH-Rc, wherein
Rb is a group of formula -Rd-, or -Rd-CO-, wherein the right side of -Rd-CO- is attached to -NH-Rc;
Rc is -Re, or -CO-Re;
Rd is a Ci-i2alkylene,
or Rd together with one or both of the -NH- form a saturated or 4-, 5-, or 6-membered ring; Re is selected from the group consisting of C2-6alkynyl, C6-i4aryl, C6-i4arylCi-6alkyl, C6- i4arylC2-6alkenyl, C6-i4arylC2-6alkynyl, C6-i4arylC2-6alkenylC6-i4aryl; heteroaryl, -NH-C3- i2cycloalkyl, and wherein said C2-6alkynyl; C6-i4aryl; C6-i4arylC2-6alkenyl, C6-i4arylC2- 6alkenylC6-i4aryl; heteroaryl, -NH-C3-i2cycloalkyl, can be unsubstituted or substituted with one or more Z1;
each Z1 is independently selected from the group consisting of hydroxyl, halo, nitro, Ci_ i2alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, haloCi-i0alkyl, Ci-6alkyloxy, Ci_ 6alkylamino, haloCi-i0alkyloxy, C6-i4aryl, C6-i4aryloxy, C6-i4arylC2-6alkenyl, C6-i4arylC2- 6alkynyl, heterocyclyl (e.g. morpholinyl), heteroaryl, -OZ3, -C(=0)NZ4Z3, -NZ4(C=0)Z3, - NZ4Z3, -N+Z2Z4Z3 X", -NZ4S(=0)2Z3, -S(=0)2Z3, -S(=0)2OZ3, glycosyl or an ester thereof, and phosphateCi-6alkyl; and wherein each of said Ci-i2alkyl, C2-6alkenyl, C2-6alkynyl, C3- i2cycloalkyl, haloCi-i0alkyl, Ci-6alkyloxy, Ci-6alkylamino, haloCi-i0alkyloxy, C6-i4aryl, C6- i4aryloxy, C6-i4arylC2-6alkenyl, C6-i4arylC2-6alkynyl, heterocyclyl (e.g. morpholinyl), heteroaryl, glycosyl or ester thereof; can be unsubstituted or substituted with one or more Z2; or two adjacent Z2 can be taken together to form a C3-7cycloalkyl, or a 5-, 6-, or 7-membered heterocyclyl or heteroaryl ring, which can be unsubstituted or substituted with one or more Z2 ;
each Z2 is independently selected from the group consisting of hydroxyl, halo, nitro, Ci_ i2alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, haloCi-i0alkyl, Ci-6alkyloxy, Ci_ 6alkylamino, haloCi-i0alkyloxy, C6-i4aryl, C6-i4aryloxy, C6-i4arylC2-6alkenyl, C6-i4arylC2- 6alkynyl, heterocyclyl (e.g. morpholinyl), heteroaryl, -OZ3, -C(=0)NZ4Z3, -NZ4(C=0)Z3, - NZ4Z3, -N+Z2Z4Z3 X", -NZ4S(=0)2Z3, -S(=0)2Z3, -S(=0)2OZ3, glycosyl or an ester thereof, and phosphateCi-6alkyl; and wherein each of said Ci-i2alkyl, C2-6alkenyl, C2-6alkynyl, C3- i2cycloalkyl, haloCi-i0alkyl, Ci-6alkyloxy, Ci-6alkylamino, haloCi-i0alkyloxy, C6-i4aryl, C6- i4aryloxy, C6-i4arylC2-6alkenyl, C6-i4arylC2-6alkynyl, heterocyclyl (e.g. morpholinyl), heteroaryl, glycosyl or ester thereof; can be unsubstituted or substituted with one or more Z3;
each Z3 is independently selected from the group consisting of hydrogen, hydroxyl, halo, nitro, Ci-i2alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, haloCi-i0alkyl, Ci-6alkyloxy, Ci_ 6alkylamino, haloCi-i0alkyloxy, C6-i4aryl, C6-i4aryloxy, C6-i4arylC2-6alkenyl, C6-i4arylC2- 6alkynyl, heterocyclyl (e.g. morpholinyl), heteroaryl, -OZ3, -C(=0)NZ4Z3, -NZ4(C=0)Z3, - NZ4Z3, -N+Z2Z4Z3 X", -NZ4S(=0)2Z3, -S(=0)2Z3, -S(=0)2OZ3, glycosyl or an ester thereof, and phosphateCi-6alkyl; and wherein each of said Ci-i2alkyl, C2-6alkenyl, C2-6alkynyl, C3- i2cycloalkyl, haloCi-i0alkyl, Ci-6alkyloxy, Ci-6alkylamino, haloCi-i0alkyloxy, C6-i4aryl, C6- i4aryloxy, C6-i4arylC2-6alkenyl, C6-i4arylC2-6alkynyl, heterocyclyl (e.g. morpholinyl), heteroaryl, glycosyl or ester thereof; can be unsubstituted or substituted with one or more Z4;
each Z4 is independently selected from the group consisting of hydrogen, hydroxyl, halo, nitro, Ci-i2alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, haloCi-i0alkyl, Ci-6alkyloxy, Ci_ 6alkylamino, haloCi-i0alkyloxy, C6-i4aryl, C6-i4aryloxy, C6-i4arylC2-6alkenyl, C6-i4arylC2- 6alkynyl, heterocyclyl (e.g. morpholinyl), heteroaryl, -OZ3, -C(=0)NZ4Z3, -NZ4(C=0)Z3, - NZ4Z3, -N+Z2Z4Z3 X", -NZ4S(=0)2Z3, -S(=0)2Z3, -S(=0)2OZ3, glycosyl or an ester thereof, and phosphateCi-6alkyl; and wherein each of said Ci-i2alkyl, C2-6alkenyl, C2-6alkynyl, C3- i2cycloalkyl, haloCi-i0alkyl, Ci-6alkyloxy, Ci-6alkylamino, haloCi-i0alkyloxy, C6-i4aryl, C6- i4aryloxy, C6-i4arylC2-6alkenyl, C6-i4arylC2-6alkynyl, heterocyclyl (e.g. morpholinyl), heteroaryl, glycosyl or ester thereof; can be unsubstituted or substituted with one or more Z5;
or Z4 and Z3 can be taken together to form a C3-7cycloalkyl, or a 5-, 6-, or 7-membered heterocyclyl, which can be unsubstituted or substituted with one or more Z5;
each Z5 is independently selected from the group consisting of hydrogen, K, Na , hydroxyl, halo, nitro, Ci-i2alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, haloCi-i0alkyl, Ci_ 6alkyloxy, Ci-6alkylamino, haloCi-i0alkyloxy, C6-i4aryl, C6-i4aryloxy, C6-i4arylC2-6alkenyl, C6-i4arylC2-6alkynyl, heterocyclyl (e.g. morpholinyl), heteroaryl, -OZ3, -C(=0)NZ4Z3, - NZ4(C=0)Z3, -NZ4Z3, -N+Z2Z4Z3 X", -NZ4S(=0)2Z3, -S(=0)2Z3, -S(=0)2OZ3, glycosyl or an ester thereof, and phosphateCi-6alkyl; and
X is a halogen,
with the proviso that when Rb is -CH2-C(=0)-, Rc is not -CH2-C≡CH, when the right side of -CH2-C(=0)-, is attached to -NH-RC.
Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound according to the first aspect of the present invention or any one of the aspects listed in any one of the statements listed below. In some embodiments, the pharmaceutical composition is for use against a bacterial infection. The bacterial infection may be caused by a bacterial strain with resistance against at least one other antibiotic compound, for example, an antibiotic compound is selected from the group comprising vancomycin, methicillin, ampicillin, erythromycin, tigecycline, teicoplanin, daptomycin, and linezolid.
In certain embodiments, the pharmaceutical composition pharmaceutical composition is suitable for employing an effective concentration of 0.01 to 50 μg ml. In certain embodiments, the bacterial infection is caused by a bacterial strain of vancomycin-resistant Enterococci (VRE), vancomycin-intermediate resistant strains (VISA), vancomycin-susceptible Staphylococcus aureus (VSSA) or high-level vancomycin-resistant Staphylococcus aureus (VRSA). In some embodiments, the bacterial infection is caused by vancomycin-resistant Staphylococcus aureus. In some embodiments, the bacterial infection is caused by vancomycin-resistant Enterococci (VRE).
Further scope of applicability of the present invention will become apparent from the detailed description given hereinafter. However, it should be understood that the detailed description and specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed.
BRIEF DESCRIPTION OF THE DRAWINGS
The present invention will become more fully understood from the detailed description given herein below and the accompanying drawings which are given by way of illustration only, and thus are not limitative of the present invention, and wherein:
Figure 1 represents a graph plotting the changes in MIC, expressed as MIC/MICo with MIC, corresponding to the MIC value in cycle i and MIC0 corresponding to the MIC at the start of the experiment, obtained by monitoring over 20 cycles of exposure to subinhibitory doses of Vanc-N (squares), Vanc-39 (triangles), Vanc-42 (diamonds) and daptomycin (circles).
DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION
The following detailed description of the invention refers to the accompanying drawings. The same reference numbers in different drawings identify the same or similar elements. Also, the following detailed description does not limit the invention. Instead, the scope of the invention is defined by the appended claims and equivalents thereof.
Several documents are cited throughout the text of this specification. Each of the documents herein (including any manufacturer's specifications, instructions etc.) are hereby incorporated by reference; however, there is no admission that any document cited is indeed prior art of the present invention.
The present invention will be described with respect to particular embodiments and with reference to certain drawings but the invention is not limited thereto but only by the claims. The drawings described are only schematic and are non-limiting. In the drawings, the size of some of the elements may be exaggerated and not drawn to scale for illustrative purposes. The dimensions and the relative dimensions do not correspond to actual reductions to practice of the invention. Furthermore, the terms first, second, third and the like in the description and in the claims, are used for distinguishing between similar elements and not necessarily for describing a sequential or chronological order. It is to be understood that the terms so used are interchangeable under appropriate circumstances and that the embodiments of the invention described herein are capable of operation in other sequences than described or illustrated herein.
As used herein, the singular forms "a", "an", and "the" include both singular and plural referents unless the context clearly dictates otherwise.
It is to be noticed that the term "comprising", used in the claims, should not be interpreted as being restricted to the means listed thereafter; it does not exclude other elements or steps. It is thus to be interpreted as specifying the presence of the stated features, integers, steps or components as referred to, but does not preclude the presence or addition of one or more other features, integers, steps or components, or groups thereof. It will be appreciated that the terms "comprising", "comprises" and "comprised of" as used herein comprise the terms "consisting of", "consists" and "consists of", as well as the terms "consisting essentially of", "consists essentially" and "consists essentially of".
The recitation of numerical ranges by endpoints includes all numbers and fractions subsumed within the respective ranges, as well as the recited endpoints.
Whereas the terms "one or more" or "at least one", such as one or more or at least one member(s) of a group of members, is clear per se, by means of further exemplification, the term encompasses inter alia a reference to any one of said members, or to any two or more of said members, such as, e.g., any≥3, ≥4, ≥5, ≥6 or≥7 etc. of said members, and up to all said members.
As used herein, the term "and/or," when used in a list of two or more items, means that any one of the listed items can be employed by itself or any combination of two or more of the listed items can be employed. For example, if a list is described as comprising group A, B, and/or C, the list can comprise A alone; B alone; C alone; A and B in combination; A and C in combination, B and C in combination; or A, B, and C in combination.
Unless otherwise defined, all terms used in disclosing the invention, including technical and scientific terms, have the meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. By means of further guidance, definitions for the terms used in the description are included to better appreciate the teaching of the present invention.
When describing the present invention, the terms used are to be construed in accordance with the following definitions, unless a context dictates otherwise. Whenever the term "substituted" is used herein, it is meant to indicate that one or more hydrogens on the atom indicated in the expression using "substituted" is replaced with a selection from the indicated group, provided that the indicated atom's normal valency is not exceeded, and that the substitution results in a chemically stable compound, i.e. a compound that is sufficiently robust to survive isolation from a reaction mixture.
Where groups can be substituted, such groups may be substituted with one or more, and preferably one, two or three substituents.
The terminology "optionally comprises one or more heteroatoms, said heteroatoms being O" as used herein, refers to a group where one or more carbon atoms are replaced by at least one oxygen atom. This term therefore comprises, alkoxy, alkoxyalkyl, polyalkoxyalkyl,
The term "halo" or "halogen" as a group or part of a group is generic for fluoro, chloro, bromo, iodo.
The term "amino" refers to the group -NH2.
The term "hydroxyl" or "hydroxy" as used herein refers to the group -OH.
The term "nitro" as used herein refers to the group -N02.
The term "C1-12alkyl", as a group or part of a group, refers to a hydrocarbyl group of Formula CnH2n+i wherein n is a number ranging from 1 to 12. Thus, for example, Ci-i4alkyl groups include all linear, or branched alkyl groups having 1 to 12 carbon atoms, and thus includes for example methyl, ethyl, n-propyl, /-propyl, 2-methyl-ethyl, butyl and its isomers (e.g. n-butyl, /'-butyl and t- butyl); pentyl and its isomers, hexyl and its isomers, heptyl and its isomers, octyl and its isomers, nonyl and its isomers, decyl and its isomers, undecyl and its isomers, dodecyl and its isomers, tridecyl and its isomers, tetradecyl and its isomers, and the like. For example, Ci-i0alkyl includes all linear, or branched alkyl groups having 1 to 10 carbon atoms, and thus includes for example methyl, ethyl, n-propyl, /-propyl, 2-methyl-ethyl, butyl and its isomers (e.g. n-butyl, /'- butyl and i-butyl); pentyl and its isomers, hexyl and its isomers, heptyl and its isomers, octyl and its isomers, nonyl and its isomers, decyl and its isomers and the like. For example, Ci-6alkyl includes all linear, or branched alkyl groups having 1 to 6 carbon atoms, and thus includes for example methyl, ethyl, n-propyl, /-propyl, 2-methyl-ethyl, butyl and its isomers (e.g. n-butyl, /'- butyl and i-butyl); pentyl and its isomers, hexyl and its isomers. A preferred alkyl is Ci-6alkyl. When the suffix "ene" is used in conjunction with an alkyl group, i.e. "alkylene", this is intended to mean the alkyl group as defined herein having two single bonds as points of attachment to other groups. Non-limiting examples of alkylene groups includes methylene, ethylene, methylmethylene, propylene, ethylethylene, and 1 ,2-dimethylethylene. Similarly, where alkenyl groups as defined herein and alkynyl groups as defined herein, respectively, are divalent groups having single bonds for attachment to two other groups, they are termed "alkenylene" and "alkynylene" respectively.
Thus term "C1-12alkylene" as a group or part of a group, refers to a saturated, branched or straight chain hydrocarbon radical of 1 -12 carbon atoms (more in particular Ci-i0 or Ci-6 carbon atoms), and having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkane. Typical alkylene radicals include, but are not limited to: methylene (-CH2-), 1 ,2-ethyl (-CH2CH2-), 1 ,3-propyl (- CH2CH2CH2-), 1 ,4-butyl (-CH2CH2CH2CH2-), and the like.
The term "C2-6alkenyl" as a group or part of a group, refers to an unsaturated hydrocarbyl group, which may be linear, or branched, comprising one or more carbon-carbon double bonds. Alkenyl groups thus preferably comprise between 2 and 6 carbon atoms. Examples include, but are not limited to: ethylene or vinyl (-CH=CH2), allyl (-CH2CH=CH2), cyclopentenyl (-C5H7), cyclohexenyl (-C6H9), cyclopentenylpropylene, methylcyclohexenylene and 5-hexenyl (- CH2CH2CH2CH2CH=CH2).
The term "C2-6alkynyl" as a group or part of a group, refers to a class of monovalent unsaturated hydrocarbyl groups, wherein the unsaturation arises from the presence of one or more carbon- carbon triple bonds. Examples include, but are not limited to: ethynyl (-C≡CH), 3-ethyl- cyclohept-1 -ynylene, 4-cyclohept-1 -yn-methylene and 1 -propynyl (propargyl, -CH2C≡CH).
The term "C3-12cycloalkyl", as a group or part of a group, refers to a cyclic alkyl group, that is a monovalent, saturated, hydrocarbyl group having 1 or more cyclic structure, and comprising from 3 to 12 carbon atoms, more preferably from 3 to 9 carbon atoms, more preferably from 3 to 6 carbon atoms, still more preferably from 5 to 6 carbon atoms. Cycloalkyi includes all saturated hydrocarbon groups containing 1 or more rings, including monocyclic, bicyclic or multicyclic groups. The further rings of multi-ring cycloalkyls may be either fused, bridged and/or joined through one or more spiro atoms. When the suffix "ene" is used in conjunction with a cycloalkyi group, i.e. cycloalkylene, this is intended to mean the cycloalkyi group as defined herein having two single bonds as points of attachment to other groups. Examples include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylethylene, methylcyclopropylene, cyclohexyl, cycloheptyl, cyclooctyl, cyclooctylmethylene, norbornyl, fenchyl, trimethyl tricycloheptyl, decalinyl, adamantyl and the like.
The term "haloCi-6alkyl" as a group or part of a group, refers to a Ci-6alkyl group having the meaning as defined above wherein one or more hydrogens are replaced with one or more halogen as defined above. Non-limiting examples of such haloalkyl groups include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1 ,1 ,1 -trifluoroethyl and the like.
The term "C1-6alkoxy" or "C1-6alkyloxy", as a group or part of a group, refers to a group having the Formula -ORx wherein Rx is Ci-6alkyl as defined herein above. Non-limiting examples of suitable Ci-6alkoxy include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec- butoxy, tert-butoxy, pentyloxy and hexyloxy.
The term "C1-6alkoxyCi-6alkyl" or "C1-6alkyloxyCi-6alky , as a group or part of a group, refers to a group having the Formula -Ry-0-Rx wherein Rx is Ci-6alkyl as defined herein, and Ry is Ci_ 6alkylene.
The term "haloCi-6alkoxy", as a group or part of a group, refers to a group of Formula -0-Rz wherein Rz is haloCi-6alkyl as defined herein. Non-limiting examples of suitable haloCi-6alkoxy include fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, 1 ,1 ,2,2- tetrafluoroethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2,2-difluoroethoxy, 2,2,2-trichloroethoxy, trichloromethoxy, 2-bromoethoxy, pentafluoroethyl, 3,3,3-trichloropropoxy, 4,4,4-trichlorobutoxy. The terms "Ci-6alkylamino", as a group or part of a group, refers to a group of formula -N(R')(RS) wherein R' and Rs are each independently selected from hydrogen, or Ci-6alkyl, wherein at least one of R' or Rs is Ci-6alkyl. Thus, alkylamino include mono-alkyl amino group (e.g. mono-Ci. 6alkylamino group such as methylamino and ethylamino), and di-alkylamino group (e.g. di-C-i. 6alkylamino group such as dimethylamino and diethylamino). Non-limiting examples of suitable alkylamino groups include n-propylamino, isopropylamino, n-butylamino, /'-butylamino, sec- butylamino, i-butylamino, pentylamino, n-hexylamino, di-n-propylamino, di-/-propylamino, ethylmethylamino, methyl-n-propylamino, methyl-/'-propylamino, n-butylmethylamino, /'- butylmethylamino, i-butylmethylamino, ethyl-n-propylamino, ethyl-/'-propylamino, n- butylethylamino, i-butylethylamino, i-butylethylamino, di-n-butylamino, di-/-butylamino, methylpentylamino, methylhexylamino, ethylpentylamino, ethylhexylamino, propylpentylamino, propylhexylamino, and the like.
The term "C6-i4aryl", as a group or part of a group, refers to a polyunsaturated, aromatic hydrocarbyl group having a single ring (i.e. phenyl) or multiple aromatic rings fused together (e.g. naphthalene), or linked covalently, typically containing 6 to 14 atoms; wherein at least one ring is aromatic. The aromatic ring may optionally include one to two additional rings (either cycloalkyl, heterocyclyl or heteroaryl) fused thereto. Examples of suitable aryl include C6-ioaryl, more preferably C6-8aryl. Non-limiting examples of C6-i2aryl comprise phenyl, biphenylyl, biphenylenyl, or 1-or 2-naphthanelyl; 5- or 6-tetralinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-azulenyl, 4-, 5- , 6 or 7-indenyl, 4- or 5-indanyl, 5-, 6-, 7- or 8-tetrahydronaphthyl, 1 ,2,3,4-tetrahydronaphthyl, and 1 ,4-dihydronaphthyl. When the suffix "ene" is used in conjunction with an aryl group, this is intended to mean the aryl group as defined herein having two single bonds as points of attachment to other groups, such as phenylene, biphenylylene, naphthylene, indenylene, and the like. Where a carbon atom in an aryl group is replaced with a heteroatom, the resultant ring is referred to herein as a heteroaryl ring.
The term "C6-i4arylCi-6alkyl", as a group or part of a group, means a Ci-6alkyl as defined herein, wherein at least one hydrogen atom is replaced by at least one C6-i4aryl as defined herein. Non- limiting examples of C6-i4arylCi-6alkyl group include benzyl, phenethyl, dibenzylmethyl, methylphenylmethyl, 3-(2-naphthyl)-butyl, and the like.
The term "C6-i4arylC2-6alkenyl", as a group or part of a group, means a C2-6alkenyl as defined herein, wherein at least one hydrogen atom is replaced by at least one C6-i4aryl as defined herein.
The term "C6-i4arylC2-6alkynyl", as a group or part of a group, means a C2-6alkynyl as defined herein, wherein at least one hydrogen atom is replaced by at least one C6-i4aryl as defined herein.
The term "C6-i4arylC2-6alkenylC6-i4aryl", as a group or part of a group, means a C6-i4aryl, wherein at least one hydrogen atom is replaced by at least one C6-i4arylC2-6alkenyl as defined herein.
The terms "heterocyclyl" or "heterocyclo", as a group or part of a group, refer to non-aromatic, fully saturated or partially unsaturated cyclic groups (for example, 3 to 7 member monocyclic, 7 to 1 1 member bicyclic, or containing a total of 3 to 10 ring atoms) which have at least one heteroatom in at least one carbon atom-containing ring. Each ring of the heterocyclic group containing a heteroatom may have 1 , 2, 3 or 4 heteroatoms selected from N, O and/or S, where the N and S heteroatoms may optionally be oxidized and the N heteroatoms may optionally be quaternized. The heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system, where valence allows. The rings of multi-ring heterocycles may be fused, bridged and/or joined through one or more spiro atoms.
Non limiting exemplary heterocyclic groups include aziridinyl, oxiranyl, thiiranyl, piperidinyl, azetidinyl, 2-imidazolinyl, pyrazolidinyl imidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, succinimidyl, 3H-indolyl, indolinyl, isoindolinyl, 2H- pyrrolyl, 1 -pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 4H-quinolizinyl, 2-oxopiperazinyl, piperazinyl, homopiperazinyl, 2-pyrazolinyl, 3-pyrazolinyl, tetrahydro-2H-pyranyl, 2H-pyranyl, 4H-pyranyl, 3,4-dihydro-2H-pyranyl, oxetanyl, thietanyl, 3-dioxolanyl, 1 ,4-dioxanyl, 2,5- dioximidazolidinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, indolinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydroquinolinyl, tetrahydroisoquinolin-1 -yl, tetrahydroisoquinolin-2-yl, tetrahydroisoquinolin-3-yl, tetrahydroisoquinolin-4-yl, thiomorpholin-4- yl, thiomorpholin-4-ylsulfoxide, thiomorpholin-4-ylsulfone, 1 ,3-dioxolanyl, 1 ,4-oxathianyl, 1 ,4- dithianyl, 1 ,3,5-trioxanyl, 1 H-pyrrolizinyl, tetrahydro-1 ,1 -dioxothiophenyl, N- formylpiperazinyl, and morpholin-4-yl.
The term "heteroaryl" as a group or part of a group, refers but is not limited to 5 to 12 atom aromatic rings or ring systems containing 1 or more rings which can be fused together or linked covalently, typically containing 5 to 12 atoms; at least one of which is aromatic in which one or more carbon atoms in one or more of these rings can be replaced by N, O and/or S atoms where the N and S heteroatoms may optionally be oxidized and the N heteroatoms may optionally be quaternized. Such rings may be fused to an aryl, cycloalkyl, heteroaryl or heterocyclyl ring. Non-limiting examples of such heteroaryl, include: pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, imidazo[2,1 -b][1 ,3]thiazolyl, thieno[3,2-b]furanyl, thieno[3,2- b]thiophenyl, thieno[2,3-d][1 ,3]thiazolyl, thieno[2,3-d]imidazolyl, tetrazolo[1 ,5-a]pyridinyl, indolyl, indolizinyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, indazolyl, benzimidazolyl, 1 ,3-benzoxazolyl, 1 ,2-benzisoxazolyl, 2,1 -benzisoxazolyl, 1 ,3- benzothiazolyl, 1 ,2-benzoisothiazolyl, 2,1 -benzoisothiazolyl, benzotriazolyl, 1 ,2,3- benzoxadiazolyl, 2,1 ,3-benzoxadiazolyl, 1 ,2,3-benzothiadiazolyl, 2,1 ,3-benzothiadiazolyl, thienopyridinyl, purinyl, imidazo[1 ,2-a]pyridinyl, 6-oxo-pyridazin-1 (6H)-yl, 2-oxopyridin-1 (2H)-yl, 6-oxo-pyridazin-1 (6H)-yl, 2-oxopyridin-1 (2H)-yl, 1 ,3-benzodioxolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl,
The term "pyrrolyl" (also called azolyl) as used herein includes pyrrol-1 -yl, pyrrol-2-yl and pyrrol- 3-yl. The term "furanyl" (also called "furyl") as used herein includes furan-2-yl and furan-3-yl (also called furan-2-yl and furan-3-yl). The term "thiophenyl" (also called "thienyl") as used herein includes thiophen-2-yl and thiophen-3-yl (also called thien-2-yl and thien-3-yl). The term "pyrazolyl" (also called 1 H-pyrazolyl and 1 ,2-diazolyl) as used herein includes pyrazol-1 -yl, pyrazol-3-yl, pyrazol-4-yl and pyrazol-5-yl. The term "imidazolyl" as used herein includes imidazol-1 -yl, imidazol-2-yl, imidazol-4-yl and imidazol-5-yl. The term "oxazolyl" (also called 1 ,3- oxazolyl) as used herein includes oxazol-2-yl; oxazol-4-yl and oxazol-5-yl. The term "isoxazolyl" (also called 1 ,2-oxazolyl), as used herein includes isoxazol-3-yl, isoxazol-4-yl, and isoxazol-5-yl. The term "thiazolyl" (also called 1 ,3-thiazolyl),as used herein includes thiazol-2-yl, thiazol-4-yl and thiazol-5-yl (also called 2-thiazolyl, 4-thiazolyl and 5-thiazolyl). The term "isothiazolyl" (also called 1 , 2-thiazolyl) as used herein includes isothiazol-3-yl, isothiazol-4-yl, and isothiazol-5-yl. The term "triazolyl" as used herein includes 1 H-triazolyl and 4H-1 ,2,4-triazolyl, "1 H-triazolyl" includes 1 H-1 ,2,3-triazol-1 -yl, 1 H-1 ,2,3-triazol-4-yl, 1 H-1 ,2,3-triazol-5-yl, 1 H-1 ,2,4-triazol-1 -yl, 1 H-1 ,2,4-triazol-3-yl and 1 H-1 ,2,4-triazol-5-yl. "4H-1 ,2,4-triazolyl" includes 4H-1 ,2,4-triazol-4-yl, and 4H-1 ,2,4-triazol-3-yl. The term "oxadiazolyl" as used herein includes 1 ,2,3-oxadiazol-4-yl, 1 ,2,3-oxadiazol-5-yl, 1 ,2,4-oxadiazol -3-yl, 1 ,2,4-oxadiazol-5-yl, 1 ,2,5-oxadiazol-3-yl and 1 ,3,4- oxadiazol-2-yl. The term "thiadiazolyl" as used herein includes 1 ,2,3-thiadiazol-4-yl, 1 ,2,3- thiadiazol-5-yl, 1 ,2,4-thiadiazol-3-yl, 1 ,2 ,4-thiad iazol-5-y 1 , 1 ,2,5-thiadiazol-3-yl (also called furazan-3-yl) and 1 ,3,4-thiadiazol-2-yl. The term "tetrazolyl" as used herein includes 1 H-tetrazol-
1 - yl, 1 H-tetrazol-5-yl, 2H-tetrazol-2-yl, and 2H-tetrazol-5-yl. The term "oxatriazolyl" as used herein includes 1 ,2,3,4-oxatriazol-5-yl and 1 ,2,3,5-oxatriazol-4-yl. The term "thiatriazolyl" as used herein includes 1 ,2,3,4-thiatriazol-5-yl and 1 ,2,3,5-thiatriazol-4-yl. The term "pyridinyl" (also called "pyridyl") as used herein includes pyridin-2-yl, pyridin-3-yl and pyridin-4-yl (also called 2- pyridyl, 3-pyridyl and 4-pyridyl). The term "pyrimidyl" as used herein includes pyrimid-2-yl, pyrimid-4-yl, pyrimid-5-yl and pyrimid-6-yl. The term "pyrazinyl" as used herein includes pyrazin-
2- yl and pyrazin-3-yl. The term "pyridazinyl as used herein includes pyridazin-3-yl and pyridazin- 4-yl. The term "oxazinyl" (also called "1 ,4-oxazinyl") as used herein includes 1 ,4-oxazin-4-yl and
1 ,4-oxazin-5-yl. The term "dioxinyl" (also called "1 ,4-dioxinyl") as used herein includes 1 ,4- dioxin-2-yl and 1 ,4-dioxin-3-yl. The term "thiazinyl" (also called "1 ,4-thiazinyl") as used herein includes 1 ,4-thiazin-2-yl, 1 ,4-thiazin-3-yl, 1 ,4-thiazin-4-yl, 1 ,4-thiazin-5-yl and 1 ,4-thiazin-6-yl. The term "triazinyl" as used herein includes 1 ,3,5-triazin-2-yl, 1 ,2,4-triazin-3-yl, 1 ,2,4-triazin-5-yl, 1 ,2,4-triazin-6-yl, 1 ,2,3-triazin-4-yl and 1 ,2,3-triazin-5-yl. The term "imidazo[2,1 -b][1 ,3]thiazolyl" as used herein includes imidazo[2,1 -b][1 ,3]thiazoi-2-yl, imidazo[2,1 -b][1 ,3]thiazol-3-yl, imidazo[2, 1 -b][1 ,3]thiazol-5-yl and imidazo[2,1 -b][1 ,3]thiazol-6-yl. The term "thieno[3,2- b]furanyl" as used herein includes thieno[3,2-b]furan-2-yl, thieno[3,2-b]furan-3-yl, thieno[3,2- b]furan-4-yl, and thieno[3,2-b]furan-5-yl. The term "thieno[3,2-b]thiophenyl" as used herein includes thieno[3,2-b]thien-2-yl, thieno[3,2-b]thien-3-yl, thieno[3,2-b]thien-5-yl and thieno[3,2- b]thien-6-yl. The term "thieno[2,3-d][1 ,3]thiazolyl" as used herein includes thieno[2,3- d][1 ,3]thiazol-2-yl, thieno[2,3-d][1 ,3]thiazol-5-yl and thieno[2,3-d][1 ,3]thiazol-6-yl. The term "thieno[2,3-d]imidazolyl" as used herein includes thieno[2,3-d]imidazol-2-yl, thieno[2,3- d]imidazol-4-yl and thieno[2,3-d]imidazol-5-yl. The term "tetrazolo[1 ,5-a]pyridinyl" as used herein includes tetrazolo[1 ,5-a]pyridine-5-yl, tetrazolo[1 ,5-a]pyridine-6-yl, tetrazolo[1 ,5-a]pyridine-7-yl, and tetrazolo[1 ,5-a]pyridine-8-yl. The term "indolyl" as used herein includes indol-1 -yl, indol-2-yl, indol-3-yl,-indol-4-yl, indol-5-yl, indol-6-yl and indol-7-yl. The term "indolizinyl" as used herein includes indolizin-1 -yl, indolizin-2-yl, indolizin-3-yl, indolizin-5-yl, indolizin-6-yl, indolizin-7-yl, and indolizin-8-yl. The term "isoindolyl" as used herein includes isoindol-1 -yl, isoindol-2-yl, isoindol- 3-yl, isoindol-4-yl, isoindol-5-yl, isoindol-6-yl and isoindol-7-yl. The term "benzofuranyl" (also called benzo[b]furanyl) as used herein includes benzofuran-2-yl, benzofuran-3-yl, benzofuran-4- yl, benzofuran-5-yl, benzofuran-6-yl and benzofuran-7-yl. The term "isobenzofuranyl" (also called benzo[c]furanyl) as used herein includes isobenzofuran-1 -yl, isobenzofuran-3-yl, isobenzofuran-4-yl, isobenzofuran-5-yl, isobenzofuran-6-yl and isobenzofuran-7-yl. The term "benzothiophenyl" (also called benzo[b]thienyl) as used herein includes 2-benzo[b]thiophenyl, 3- benzo[b]thiophenyl, 4-benzo[b]thiophenyl, 5-benzo[b]thiophenyl, 6-benzo[b]thiophenyl and -7- benzo[b]thiophenyl (also called benzothien-2-yl, benzothien-3-yl, benzothien-4-yl, benzothien-5- yl, benzothien-6-yl and benzothien-7-yl). The term "isobenzothiophenyl" (also called benzo[c]thienyl) as used herein includes isobenzothien-1 -yl, isobenzothien-3-yl, isobenzothien- 4-yl, isobenzothien-5-yl, isobenzothien-6-yl and isobenzothien-7-yl. The term "indazolyl" (also called 1 H-indazolyl or 2-azaindolyl) as used herein includes 1 H-indazol-1 -yl, 1 H-indazol-3-yl, I H-indazol-4-yl, 1 H-indazol-5-yl, 1 H-indazol-6-yl, 1 H-indazol-7-yl, 2H-indazol-2-yl, 2H-indazol-3- yl, 2H-indazol-4-yl, 2H-indazol-5-yl, 2H-indazol-6-yl, and 2H-indazol-7-yl. The term "benzimidazolyl" as used herein includes benzimidazol-1 -yl, benzimidazol-2-yl, benzimidazol-4- yl, benzimidazol-5-yl, benzimidazol-6-yl and benzimidazol-7-yl. The term "1 ,3-benzoxazolyl" as used herein includes 1 ,3-benzoxazol-2-yl, 1 ,3-benzoxazol-4-yl, 1 ,3-benzoxazol-5-yl, 1 ,3- benzoxazol-6-yl and 1 ,3-benzoxazol-7-yl. The term "1 ,2-benzisoxazolyl" as used herein includes 1 ,2-benzisoxazol-3-yl, 1 ,2-benzisoxazol-4-yl, 1 ,2-benzisoxazol-5-yl, 1 ,2-benzisoxazol-6-yl and 1 ,2-benzisoxazol-7-yl. The term "2,1 -benzisoxazolyl" as used herein includes 2,1 -benzisoxazol-
3- yl, 2,1 -benzisoxazol-4-yl, 2,1 -benzisoxazol-5-yl, 2,1 -benzisoxazol-6-yl and 2,1 -benzisoxazol- 7-yl. The term "1 ,3-benzothiazolyl" as used herein includes 1 ,3-benzothiazol-2-yl, 1 ,3- benzothiazol-4-yl, 1 ,3-benzothiazol-5-yl, 1 ,3-benzothiazol-6-yl and 1 ,3-benzothiazol-7-yl. The term "1 ,2-benzoisothiazolyl" as used herein includes 1 ,2-benzisothiazol-3-yl, 1 ,2-benzisothiazol-
4- yl, 1 ,2-benzisothiazol-5-yl, 1 ,2-benzisothiazol-6-yl and 1 ,2-benzisothiazol-7-yl. The term "2,1 - benzoisothiazolyl" as used herein includes 2,1 -benzisothiazol-3-yl, 2,1 -benzisothiazol-4-yl, 2,1 - benzisothiazol-5-yl, 2,1 -benzisothiazol-6-yl and 2,1 -benzisothiazol-7-yl. The term "benzotriazolyl" as used herein includes benzotriazol-1 -yl, benzotriazol4-yl, benzotriazol-5-yl, benzotriazol-6-yl and benzotriazol-7-yl. The term "1 ,2,3-benzoxadiazolyl" as used herein includes 1 ,2,3-benzoxadiazol-4-yl, 1 ,2,3-benzoxadiazol-5-yl, 1 ,2,3-benzoxadiazol-6-yl and 1 ,2,3-benzoxadiazol-7-yl. The term "2,1 ,3-benzoxadiazolyl" as used herein includes 2,1 ,3- benzoxadiazol-4-yl, 2,1 ,3-benzoxadiazol-5-yl, 2,1 ,3-benzoxadiazol-6-yl and 2,1 ,3- benzoxadiazol-7-yl. The term "1 ,2,3-benzothiadiazolyl" as used herein includes 1 ,2,3- benzothiadiazol-4-yl, 1 ,2,3-benzothiadiazol-5-yl, 1 ,2,3-benzothiadiazol-6-yl and 1 ,2,3- benzothiadiazol-7-yl. The term "2,1 ,3-benzothiadiazolyl" as used herein includes 2,1 ,3- benzothiadiazol-4-yl, 2,1 ,3-benzothiadiazol-5-yl, 2,1 ,3-benzothiadiazol-6-yl and 2,1 ,3- benzothiadiazol-7-yl. The term "thienopyridinyl" as used herein includes thieno[2,3-b]pyridinyl, thieno[2,3-c]pyridinyl, thieno[3,2-c]pyridinyl and thieno[3,2-b]pyridinyl. The term "purinyl" as used herein includes purin-2-yl, purin-6-yl, purin-7-yl and purin-8-yl. The term "imidazo[1 ,2- a]pyridinyl", as used herein includes imidazo[1 ,2-a]pyridin-2-yl, imidazo[1 ,2-a]pyridin-3-yl, imidazo[1 ,2-a]pyridin-4-yl, imidazo[1 ,2-a]pyridin-5-yl, imidazo[1 ,2-a]pyridin-6-yl and imidazo[1 ,2- a]pyridin-7-yl. The term "1 ,3-benzodioxolyl", as used herein includes 1 ,3-benzodioxol-4-yl, 1 ,3- benzodioxol-5-yl, 1 ,3-benzodioxol-6-yl, and 1 ,3-benzodioxol-7-yl. The term "quinolinyl" as used herein includes quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl and quinolin-8-yl. The term "isoquinolinyl" as used herein includes isoquinolin-1 -yl, isoquinolin-3- yl, isoquinolin-4-yl, isoquinolin-5-yl, isoquinolin-6-yl, isoquinolin-7-yl and isoquinolin-8-yl. The term "cinnolinyl" as used herein includes cinnolin-3-yl, cinnolin-4-yl, cinnolin-5-yl, cinnolin-6-yl, cinnolin-7-yl and cinnolin-8-yl. The term "quinazolinyl" as used herein includes quinazolin-2-yl, quiriazolin-4-yl, quinazolin-5-yl, quinazolin-6-yl, quinazolin-7-yl and quinazolin-8-yl. The term "quinoxalinyl". as used herein includes quinoxalin-2-yl, quinoxalin-5-yl, and quinoxalin-6-yl.
The term "heteroalkyl", as a group or part of a group, also encompasses groups of Formula -X- R or -Re-X-R , and alkyl substituted with one or more groups of formula -X-R or -Re-X-R , wherein Re is as defined above for Ci-6alkylene and X is NRC, S or O, and Rc is selected from hydrogen, or Ci-6alkyl, and R is hydrogen, Ci-6acyl, Ci-6alkyl, C3-6cycloalky; Representative examples include, but are not limited to, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxy-1 - hydroxymethylethyl, 2,3-dihydroxypropyl, 1 -hydroxymethylethyl, 3-hydroxybutyl, 2,3- dihydroxybutyl, 2-hydroxy-1 -methylpropyl, 2-aminoethyl, 3-aminopropyl, and the like.
The term "phosphateCi-6alkyl" as a group or part of a group, refers to a group of Formula -R'-O- P(=0)(OH)2 wherein R is Ci-6alkyl as defined herein.
The term "glycosyl" as a group or part of a group, refers to a saccharyl moiety such as a mono-, di-, oligo- or an poly-saccharide moiety, a hydroxy-substituted cyclohexyl moiety, the amino derivatives thereof, the thio derivatives thereof or the hydroxyl-protected derivatives thereof such as acetate derivatives thereof. The term "saccharyl" as used herein refers to a saccharide moiety which comprises monosaccharides, di-, tri-, oligo- and polysaccharides. Exemplary monosaccharide moiety includes but is not limited to a pentosyl, a hexosyl, or a heptosyl moiety. Moreover, the glycosyl may also be present as a deoxy glycosyl.
In an embodiment, said glycosyl is a saccharyl moiety, including monosaccharide, L or D isomers thereof, a or β form thereof, pyranose or furanose form thereof, combination thereof, deoxy derivatives thereof, hydroxyl-protected acetate derivatives thereof, amino derivatives thereof optionally substituted, thio derivatives thereof, di-, tri-, oligo- and polysaccharide thereof.
Reference throughout this specification to "one embodiment" or "an embodiment" means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment, but may. Furthermore, the particular features, structures or characteristics may be combined in any suitable manner, as would be apparent to one of ordinary skill in the art from this disclosure, in one or more embodiments.
Similarly it should be appreciated that in the description of exemplary embodiments of the invention, various features of the invention are sometimes grouped together in a single embodiment, figure, or description thereof for the purpose of streamlining the disclosure and aiding the understanding of one or more of the various inventive aspects. This method of disclosure, however, is not to be interpreted as reflecting an intention that the claimed invention requires more features than are expressly recited in each claim. Rather, as the following claims reflect, inventive aspects lie in less than all features of a single foregoing disclosed embodiment. Thus, the claims following the detailed description are hereby expressly incorporated into this detailed description, with each claim standing on its own as a separate embodiment of this invention.
Furthermore, while some embodiments described herein include some but not other features included in other embodiments, combinations of features of different embodiments are meant to be within the scope of the invention, and form different embodiments, as would be understood by those in the art. For example, in the following claims, any of the claimed embodiments can be used in any combination.
In the description provided herein, numerous specific details are set forth. However, it is understood that embodiments of the invention may be practiced without these specific details. In other instances, well-known methods, structures and techniques have not been shown in detail in order not to obscure an understanding of this description.
Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein.
It is intended that the specification and examples be considered as exemplary only.
Each and every claim is incorporated into the specification as an embodiment of the present invention. Thus, the claims are part of the description and are a further description and are in addition to the preferred embodiments of the present invention.
Each of the claims set out a particular embodiment of the invention.
Preferred statements (features) and embodiments of this invention are set herein below. Each statements and embodiments of the invention so defined may be combined with any other statement and/or embodiments unless clearly indicated to the contrary. In particular, any feature indicated as being preferred or advantageous may be combined with any other feature or features or statements indicated as being preferred or advantageous. Hereto, the present invention is in particular captured by any one or any combination of one or more of the below numbered aspects and embodiments 1 to 88, with any other statement and/or embodiments. 1. A compound of formula (1 ), or a pharmaceutically acceptable salt thereof
Figure imgf000019_0001
wherein
Ra is a group of formula -NH-Rb-NH-Rc, wherein
Rb is a group of formula -Rd-, or -Rd-CO-, wherein the right side of -Rd-CO- is attached to -NH-Rc;
Rc is -Re, or -CO-Re;
Rd is a Ci-i2alkylene,
or Rd together with one or both of the -NH- form a saturated or 4-, 5-, or 6-membered ring;
Re is selected from the group consisting of C2-6alkynyl, C6-i4aryl, C6-i4arylCi-6alkyl, C6- i4arylC2-6alkenyl, C6-i4arylC2-6alkynyl, C6-i4arylC2-6alkenylC6-i4aryl; heteroaryl, -NH-C3- i2cycloalkyl, and wherein said C2-6alkynyl; C6-i4aryl; C6-i4arylC2-6alkenyl, C6-i4arylC2- 6alkenylC6-i4aryl; heteroaryl, -NH-C3-i2cycloalkyl, can be unsubstituted or substituted with one or more Z1; each Z1 is independently selected from the group consisting of hydroxyl, halo, nitro, Ci_ i2alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, haloCi-i0alkyl, Ci-6alkyloxy, Ci_ 6alkylamino, haloCi-i0alkyloxy, C6-i4aryl, C6-i4aryloxy, C6-i4arylC2-6alkenyl, C6-i4arylC2- 6alkynyl, heterocyclyl (e.g. morpholinyl), heteroaryl, -OZ3, -C(=0)NZ4Z3, -NZ4(C=0)Z3, - NZ4Z3, -N+Z2Z4Z3 X", -NZ4S(=0)2Z3, -S(=0)2Z3, -S(=0)2OZ3, glycosyl or an ester thereof, and phosphateCi-6alkyl; and wherein each of said Ci-i2alkyl, C2-6alkenyl, C2-6alkynyl, C3- i2cycloalkyl, haloCi-i0alkyl, Ci-6alkyloxy, Ci-6alkylamino, haloCi-i0alkyloxy, C6-i4aryl, C6- i4aryloxy, C6-i4arylC2-6alkenyl, C6-i4arylC2-6alkynyl, heterocyclyl (e.g. morpholinyl), heteroaryl, glycosyl or ester thereof; can be unsubstituted or substituted with one or more Z2; or two adjacent Z2 can be taken together to form a C3-7cycloalkyl, or a 5-, 6-, or
7-membered heterocyclyl or heteroaryl ring, which can be unsubstituted or substituted with one or more Z2 ;
each Z2 is independently selected from the group consisting of hydroxyl, halo, nitro, Ci_ i2alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, haloCi-i0alkyl, Ci-6alkyloxy, Ci_ 6alkylamino, haloCi-i0alkyloxy, C6-i4aryl, C6-i4aryloxy, C6-i4arylC2-6alkenyl, C6-i4arylC2-
6alkynyl, heterocyclyl (e.g. morpholinyl), heteroaryl, -OZ3, -C(=0)NZ4Z3, -NZ4(C=0)Z3, - NZ4Z3, -N+Z2Z4Z3 X", -NZ4S(=0)2Z3, -S(=0)2Z3, -S(=0)2OZ3, glycosyl or an ester thereof, and phosphateCi-6alkyl; and wherein each of said Ci-i2alkyl, C2-6alkenyl, C2-6alkynyl, C3- i2cycloalkyl, haloCi-i0alkyl, Ci-6alkyloxy, Ci-6alkylamino, haloCi-i0alkyloxy, C6-i4aryl, C6- i4aryloxy, C6-i4arylC2-6alkenyl, C6-i4arylC2-6alkynyl, heterocyclyl (e.g. morpholinyl), heteroaryl, glycosyl or ester thereof; can be unsubstituted or substituted with one or more Z3;
each Z3 is independently selected from the group consisting of hydrogen, hydroxyl, halo, nitro, Ci-i2alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, haloCi-i0alkyl, Ci-6alkyloxy, Ci_ 6alkylamino, haloCi-i0alkyloxy, C6-i4aryl, C6-i4aryloxy, C6-i4arylC2-6alkenyl, C6-i4arylC2-
6alkynyl, heterocyclyl (e.g. morpholinyl), heteroaryl, -OZ3, -C(=0)NZ4Z3, -NZ4(C=0)Z3, - NZ4Z3, -N+Z2Z4Z3 X", -NZ4S(=0)2Z3, -S(=0)2Z3, -S(=0)2OZ3, glycosyl or an ester thereof, and phosphateCi-6alkyl; and wherein each of said Ci-i2alkyl, C2-6alkenyl, C2-6alkynyl, C3- i2cycloalkyl, haloCi-i0alkyl, Ci-6alkyloxy, Ci-6alkylamino, haloCi-i0alkyloxy, C6-i4aryl, C6- i4aryloxy, C6-i4arylC2-6alkenyl, C6-i4arylC2-6alkynyl, heterocyclyl (e.g. morpholinyl), heteroaryl, glycosyl or ester thereof; can be unsubstituted or substituted with one or more Z4;
each Z4 is independently selected from the group consisting of hydrogen, hydroxyl, halo, nitro, Ci-i2alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, haloCi-i0alkyl, Ci-6alkyloxy, Ci_ 6alkylamino, haloCi-i0alkyloxy, C6-i4aryl, C6-i4aryloxy, C6-i4arylC2-6alkenyl, C6-i4arylC2- 6alkynyl, heterocyclyl (e.g. morpholinyl), heteroaryl, -OZ3, -C(=0)NZ4Z3, -NZ4(C=0)Z3, - NZ4Z3, -N+Z2Z4Z3 X", -NZ4S(=0)2Z3, -S(=0)2Z3, -S(=0)2OZ3, glycosyl or an ester thereof, and phosphateCi-6alkyl; and wherein each of said Ci-i2alkyl, C2-6alkenyl, C2-6alkynyl, C3- i2cycloalkyl, haloCi-i0alkyl, Ci-6alkyloxy, Ci-6alkylamino, haloCi-i0alkyloxy, C6-i4aryl, C6- i4aryloxy, C6-i4arylC2-6alkenyl, C6-i4arylC2-6alkynyl, heterocyclyl (e.g. morpholinyl), heteroaryl, glycosyl or ester thereof; can be unsubstituted or substituted with one or more Z5;
or Z4 and Z3 can be taken together to form a C3-7cycloalkyl, or a 5-, 6-, or 7-membered heterocyclyl, which can be unsubstituted or substituted with one or more Z5;
each Z5 is independently selected from the group consisting of hydrogen, K, Na , hydroxyl, halo, nitro, Ci-i2alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, haloCi-i0alkyl, Ci_ 6alkyloxy, Ci-6alkylamino, haloCi-i0alkyloxy, C6-i4aryl, C6-i4aryloxy, C6-i4arylC2-6alkenyl, C6-i4arylC2-6alkynyl, heterocyclyl (e.g. morpholinyl), heteroaryl, -OZ3, -C(=0)NZ4Z3, - NZ4(C=0)Z3, -NZ4Z3, -N+Z2Z4Z3 X", -NZ4S(=0)2Z3, -S(=0)2Z3, -S(=0)2OZ3, glycosyl or an ester thereof, and phosphateCi-6alkyl; and
X is a halogen;
with the proviso that when Rb is -CH2-C(=0)-, Rc is not -CH2-C≡CH, when the right side of -CH2-C(=0)-, is attached to -NH-RC.
The compound according to statement 1 , having general formula (2) wherein Rb and Rc, have the same meaning as that defined in statement 1 ,
Figure imgf000021_0001
The compound according to statement 1 or 2, wherein group of formula -NH-Rb-NH-Rc, wherein
Rb is a group of formula -Rd-, or -Rd-CO-, wherein the right side of -Rd-CO- is attached to -NH-Rc;
Rc is -Re, or -CO-Re;
Rd is a Ci-6alkylene,
or Rd together with one or both of the -NH- form a saturated or 5-, or 6-membered ring;
Re is selected from the group consisting of C2-6alkynyl, C6-i4aryl, C6-i4arylCi-6alkyl, C6- i4arylC2-6alkenyl, C6-i4arylC2-6alkynyl, C6-i4arylC2-6alkenylC6-i4aryl; heteroaryl, -NH-C3- i2cycloalkyl, and wherein said C2-6alkynyl; C6-i4aryl; C6-i4arylC2-6alkenyl, C6-i4arylC2- 6alkenylC6-i4aryl; heteroaryl, -NH-C3-i2cycloalkyl, can be unsubstituted or substituted with one or more Z1;
each Z1 is independently selected from the group consisting of hydroxyl, halo, nitro, Ci_ 8alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, haloCi-6alkyl, Ci-6alkyloxy, Ci-6alkylamino, haloCi-6alkyloxy, C6-i4aryl, C6-i4aryloxy, C6-i4arylC2-6alkenyl, C6-i4arylC2-6alkynyl, heterocyclyl, heteroaryl, -OZ3, -C(=0)NZ4Z3, -NZ4(C=0)Z3, -NZ4Z3, -NZ4S(=0)2Z3, - S(=0)2Z3, -S(=0)2OZ3, glycosyl or an ester thereof, and phosphateCi-6alkyl; and wherein each of said Ci-8alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, haloCi-6alkyl, Ci-6alkyloxy, Ci-6alkylamino, haloCi-6alkyloxy, C6-i4aryl, C6-i4aryloxy, C6-i4arylC2-6alkenyl, C6-i4arylC2- 6alkynyl, heterocyclyl, heteroaryl, glycosyl or ester thereof; can be unsubstituted or substituted with one or more Z2;
each Z2 is independently selected from the group consisting of hydroxyl, halo, nitro, Ci_ 8alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, haloCi-6alkyl, Ci-6alkyloxy, Ci-6alkylamino, haloCi-6alkyloxy, C6-i4aryl, C6-i4aryloxy, C6-i4arylC2-6alkenyl, C6-i4arylC2-6alkynyl, heterocyclyl, heteroaryl, -OZ3, -C(=0)NZ4Z3, -NZ4(C=0)Z3, -NZ4Z3, -NZ4S(=0)2Z3, - S(=0)2Z3, -S(=0)2OZ3, glycosyl or an ester thereof, and phosphateCi-6alkyl; and wherein each of said Ci-8alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, haloCi-6alkyl, Ci-6alkyloxy, Ci-6alkylamino, haloCi-6alkyloxy, C6-i4aryl, C6-i4aryloxy, C6-i4arylC2-6alkenyl, C6-i4arylC2- 6alkynyl, heterocyclyl, heteroaryl, glycosyl or ester thereof; can be unsubstituted or substituted with one or more Z3;
each Z3 is independently selected from the group consisting of hydrogen, hydroxyl, halo, nitro, Ci-8alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, haloCi-6alkyl, Ci-6alkyloxy, Ci_ 6alkylamino, haloCi-6alkyloxy, C6-i4aryl, C6-i4aryloxy, C6-i4arylC2-6alkenyl, C6-i4arylC2- 6alkynyl, heterocyclyl, heteroaryl, -OZ3, -C(=0)NZ4Z3, -NZ4(C=0)Z3, -NZ4Z3, - NZ4S(=0)2Z3, -S(=0)2Z3, -S(=0)2OZ3, glycosyl or an ester thereof, and phosphateCi. 6alkyl; and wherein each of said Ci-8alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, haloCi. 6alkyl, Ci-6alkyloxy, Ci-6alkylamino, haloCi-6alkyloxy, C6-i4aryl, C6-i4aryloxy, C6-i4arylC2- 6alkenyl, C6-i4arylC2-6alkynyl, heterocyclyl, heteroaryl, glycosyl or ester thereof; can be unsubstituted or substituted with one or more Z4;
each Z4 is independently selected from the group consisting of hydrogen, hydroxyl, halo, nitro, Ci-8alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, haloCi-6alkyl, Ci-6alkyloxy, Ci_ 6alkylamino, haloCi-6alkyloxy, C6-i4aryl, C6-i4aryloxy, C6-i4arylC2-6alkenyl, C6-i4arylC2- 6alkynyl, heterocyclyl, heteroaryl, -OZ3, -C(=0)NZ4Z3, -NZ4(C=0)Z3, -NZ4Z3, - NZ4S(=0)2Z3, -S(=0)2Z3, -S(=0)2OZ3, glycosyl or an ester thereof, and phosphateCi. 6alkyl; and wherein each of said Ci-8alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, haloCi. 6alkyl, Ci-6alkyloxy, Ci-6alkylamino, haloCi-6alkyloxy, C6-i4aryl, C6-i4aryloxy, C6-i4arylC2- 6alkenyl, C6-i4arylC2-6alkynyl, heterocyclyl, heteroaryl, glycosyl or ester thereof; can be unsubstituted or substituted with one or more Z5;
each Z5 is independently selected from the group consisting of hydrogen, K, Na , hydroxyl, halo, nitro, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, haloCi-6alkyl, Ci_ 6alkyloxy, Ci-6alkylamino, haloCi-6alkyloxy, C6-i4aryl, C6-i4aryloxy, C6-i4arylC2-6alkenyl, C6- i4arylC2-6alkynyl, heterocyclyl (e.g. morpholinyl), heteroaryl, -OZ3, -C(=0)NZ4Z3, - NZ4(C=0)Z3, -NZ4Z3, -NZ4S(=0)2Z3, -S(=0)2Z3, -S(=0)2OZ3, glycosyl or an ester thereof, and phosphateCi-6alkyl.
The compound according to any one of statements 1-3, wherein Rb and Rc are selected from the groups listed in Table 22,
Table 22
Figure imgf000023_0001
Figure imgf000024_0001
R13 = Ci-8alkyl, C6-i4aryl, C3-8cycloalkyl, glycosyl or ester
thereof, etc., each optionally substituted by one or more Z2
Figure imgf000025_0001
R= H, K, Na etc
5. A pharmaceutical composition comprising at least one compound of formula (1 ), and at least one pharmaceutically acceptable carrier,
Figure imgf000025_0002
wherein
Ra is a group of formula -NH-Rb-NH-Rc, or -NH-R ; wherein
Rb is a group of formula -Rd-, or -Rd-CO-, wherein the right side of -Rd-CO- is attached to -NH-Rc;
Rc is -Re, or -CO-Re;
Rd is a Ci-i2alkylene, wherein said Ci-i2alkylene; optionally comprises one or more heteroatoms in the alkylene, moiety, said heteroatoms being O;
or Rd together with one or both of the -NH- form a saturated or 4-, 5-, or 6-membered ring; Re is selected from the group consisting of C2-6alkynyl, C6-i4aryl, C6-i4arylCi-6alkyl, C6- i4arylC2-6alkenyl, C6-i4arylC2-6alkynyl, C6-i4arylC2-6alkenylC6-i4aryl; heteroaryl, -NH-C3- i2cycloalkyl, and wherein said C2-6alkynyl; C6-i4aryl; C6-i4arylC2-6alkenyl, C6-i4arylC2- 6alkenylC6-i4aryl; heteroaryl, -NH-C3-i2cycloalkyl, can be unsubstituted or substituted with one or more Z1;
R is a C2-6alkynyl,
each Z1 is independently selected from the group consisting of hydroxyl, halo, nitro, Ci_ i2alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, haloCi-i0alkyl, Ci-6alkyloxy, Ci_ 6alkylamino, haloCi-i0alkyloxy, C6-i4aryl, C6-i4aryloxy, C6-i4arylC2-6alkenyl, C6-i4arylC2- 6alkynyl, heterocyclyl (e.g. morpholinyl), heteroaryl, -OZ3, -C(=0)NZ4Z3, -NZ4(C=0)Z3, - NZ4Z3, -N+Z2Z4Z3 X", -NZ4S(=0)2Z3, -S(=0)2Z3, -S(=0)2OZ3, glycosyl or an ester thereof, and phosphateCi-6alkyl; and wherein each of said Ci-i2alkyl, C2-6alkenyl, C2-6alkynyl, C3- i2cycloalkyl, haloCi-i0alkyl, Ci-6alkyloxy, Ci-6alkylamino, haloCi-i0alkyloxy, C6-i4aryl, C6- i4aryloxy, C6-i4arylC2-6alkenyl, C6-i4arylC2-6alkynyl, heterocyclyl (e.g. morpholinyl), heteroaryl, glycosyl or ester thereof; can be unsubstituted or substituted with one or more Z2; or two adjacent Z2 can be taken together to form a C3-7cycloalkyl, or a 5-, 6-, or 7-membered heterocyclyl or heteroaryl ring, which can be unsubstituted or substituted with one or more Z2 ;
each Z2 is independently selected from the group consisting of hydroxyl, halo, nitro, Ci_ i2alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, haloCi-i0alkyl, Ci-6alkyloxy, Ci_ 6alkylamino, haloCi-i0alkyloxy, C6-i4aryl, C6-i4aryloxy, C6-i4arylC2-6alkenyl, C6-i4arylC2- 6alkynyl, heterocyclyl (e.g. morpholinyl), heteroaryl, -OZ3, -C(=0)NZ4Z3, -NZ4(C=0)Z3, - NZ4Z3, -N+Z2Z4Z3 X", -NZ4S(=0)2Z3, -S(=0)2Z3, -S(=0)2OZ3, glycosyl or an ester thereof, and phosphateCi-6alkyl; and wherein each of said Ci-i2alkyl, C2-6alkenyl, C2-6alkynyl, C3- i2cycloalkyl, haloCi-i0alkyl, Ci-6alkyloxy, Ci-6alkylamino, haloCi-i0alkyloxy, C6-i4aryl, C6- i4aryloxy, C6-i4arylC2-6alkenyl, C6-i4arylC2-6alkynyl, heterocyclyl (e.g. morpholinyl), heteroaryl, glycosyl or ester thereof; can be unsubstituted or substituted with one or more Z3;
each Z3 is independently selected from the group consisting of hydrogen, hydroxyl, halo, nitro, Ci-i2alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, haloCi-i0alkyl, Ci-6alkyloxy, Ci_ 6alkylamino, haloCi-i0alkyloxy, C6-i4aryl, C6-i4aryloxy, C6-i4arylC2-6alkenyl, C6-i4arylC2- 6alkynyl, heterocyclyl (e.g. morpholinyl), heteroaryl, -OZ3, -C(=0)NZ4Z3, -NZ4(C=0)Z3, - NZ4Z3, -N+Z2Z4Z3 X", -NZ4S(=0)2Z3, -S(=0)2Z3, -S(=0)2OZ3, glycosyl or an ester thereof, and phosphateCi-6alkyl; and wherein each of said Ci-i2alkyl, C2-6alkenyl, C2-6alkynyl, C3- i2cycloalkyl, haloCi-i0alkyl, Ci-6alkyloxy, Ci-6alkylamino, haloCi-i0alkyloxy, C6-i4aryl, C6- i4aryloxy, C6-i4arylC2-6alkenyl, C6-i4arylC2-6alkynyl, heterocyclyl (e.g. morpholinyl), heteroaryl, glycosyl or ester thereof; can be unsubstituted or substituted with one or more Z4;
each Z4 is independently selected from the group consisting of hydrogen, hydroxyl, halo, nitro, Ci-i2alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, haloCi-i0alkyl, Ci-6alkyloxy, Ci_ 6alkylamino, haloCi-i0alkyloxy, C6-i4aryl, C6-i4aryloxy, C6-i4arylC2-6alkenyl, C6-i4arylC2- 6alkynyl, heterocyclyl (e.g. morpholinyl), heteroaryl, -OZ3, -C(=0)NZ4Z3, -NZ4(C=0)Z3, - NZ4Z3, -N+Z2Z4Z3 X", -NZ4S(=0)2Z3, -S(=0)2Z3, -S(=0)2OZ3, glycosyl or an ester thereof, and phosphateCi-6alkyl; and wherein each of said Ci-i2alkyl, C2-6alkenyl, C2-6alkynyl, C3- i2cycloalkyl, haloCi-i0alkyl, Ci-6alkyloxy, Ci-6alkylamino, haloCi-i0alkyloxy, C6-i4aryl, C6- i4aryloxy, C6-i4arylC2-6alkenyl, C6-i4arylC2-6alkynyl, heterocyclyl (e.g. morpholinyl), heteroaryl, glycosyl or ester thereof; can be unsubstituted or substituted with one or more Z5;
or Z4 and Z3 can be taken together to form a C3-7cycloalkyl, or a 5-, 6-, or 7-membered heterocyclyl, which can be unsubstituted or substituted with one or more Z5;
each Z5 is independently selected from the group consisting of hydrogen, K, Na , hydroxyl, halo, nitro, Ci-i2alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, haloCi-i0alkyl, Ci_ 6alkyloxy, Ci-6alkylamino, haloCi-i0alkyloxy, C6-i4aryl, C6-i4aryloxy, C6-i4arylC2-6alkenyl, C6-i4arylC2-6alkynyl, heterocyclyl (e.g. morpholinyl), heteroaryl, -OZ3, -C(=0)NZ4Z3, - NZ4(C=0)Z3, -NZ4Z3, -N+Z2Z4Z3 X", -NZ4S(=0)2Z3, -S(=0)2Z3, -S(=0)2OZ3, glycosyl or an ester thereof, and phosphateCi-6alkyl; and
X is a halogen.
A compound represented by the following general formula (1 ) or a pharmaceutically acceptable salt thereof: or the compound according to any one of statements 1-5.
Figure imgf000028_0001
7. The compound according to statement 6 having the structure (1 1 n)
Figure imgf000029_0001
Figure imgf000029_0002
9. The compound according to statement 6 having the structure (1 1 u)
Figure imgf000029_0003
The compound according to statement 6 having the structure (1 1v)
Figure imgf000030_0001
The compound according to statement 6 having the structure (1 1w)
Figure imgf000030_0002
A pharmaceutical composition comprising a compound according to any one of statements 1 to 5, 7-12.
The pharmaceutical composition according to statement 12 for use against a bacterial infection.
The pharmaceutical composition according to statement 13, wherein the infection is a bacterial infection, wherein the infecting bacterium has at least one resistance against another antibiotic compound
The pharmaceutical composition according to statement 14 wherein the other antibiotic compound is selected from the group comprising vancomycin, methicillin, ampicillin, erythromycin, teicoplanin, linezolid and daptomycin . 16. The pharmaceutical composition according to any one of the statements 6, 12 to 15, wherein the pharmaceutical composition is suitable for employing an effective concentration of 0.01 to 50 Mg/ml.
17. A pharmaceutical composition comprising a compound for use against a bacterial infection said compound being represented by the following general formula (1 ) or a pharmaceutically acceptable salt thereof: or comprising a compound according to any one of statements 1 -5,
Figure imgf000031_0001
wherein Ra is selected from a group of formula (A1 ), (A2), or (A3), as defined in the below table 10 wherein
Figure imgf000031_0002
Figure imgf000032_0001
18. A pharmaceutical composition comprising a compound for use against a bacterial infection said represented by the following general formula (1 ) or a pharmaceutically acceptable salt thereof: or comprising a compound according to any one of statements 1 -5,
Figure imgf000032_0002
wherein Ra is selected from the group comprising the structures as defined in the below table 1 1 :
Table 1 1
Figure imgf000033_0001
^•"^^ (Vanc-27) A pharmaceutical composition comprising compound for use against a bacterial infection said represented by the following general formula (1 ) or a pharmaceutically acceptable salt thereof: or comprising a compound according to any one of statements 1 -5,
Figure imgf000034_0001
wherein Ra is selected from the group comprising structure of formula (A1), (A2), (A3), (A4), (A5), and (A6), as defined in the below table 12
Figure imgf000034_0002
defined in Table 17 Table 16
Table 17:
O NH o
=J ::-^J H^
NH
(A3)
(A4) (A5)
Figure imgf000035_0001
Table 13:
Figure imgf000035_0002
Figure imgf000036_0001
Table 14:
Figure imgf000036_0002
(A2)
Figure imgf000037_0001
Table 16:
Figure imgf000038_0001
20. The pharmaceutical composition according to any one of the statements 6, 12 to 19, wherein the infection is a bacterial infection, wherein the infecting bacterium has at least one resistance against another antibiotic compound
21 . The pharmaceutical composition according to statement 20, wherein the other antibiotic compound is selected from the group comprising vancomycin, methicillin, ampicillin, erythromycin, teicoplanin, linezolid and daptomycin.
22. The pharmaceutical composition according to any one of the statements 6, 12 to 21 , wherein the pharmaceutical composition is suitable for employing an effective concentration of 0.01 to 50 g/ml.
23. The pharmaceutical composition according to any one of the statements 6, 12 to 22, characterized in that the resistance is vancomycin-resistant Enterococci (VRE), vancomycin- intermediate resistant strains (VISA), vancomycin susceptible Staphylococcus aureus (VSSA) or high-level vancomycin-resistant Staphylococcus aureus (VRSA).
24. The pharmaceutical composition according to any one of the statements 6, 12 to 23, characterized in that the infection is caused by vancomycin-resistant Staphylococcus aureus.
25. The pharmaceutical composition according to any one of the statements 6, 12 to 23, characterized in that the infection is caused by vancomycin-resistant Enterococci (VRE).
26. A compound represented by the following general formula (2) or a compound according to any one of statements 1 -5, or a pharmaceutically acceptable salt thereof:
Figure imgf000039_0001
Figure imgf000040_0001
The compound according to statement 26, wherein Rb is -CH2CH2CH2- and Rc is selected from:
Figure imgf000040_0002
Figure imgf000041_0001
nd accordin to statement 26, wherein Rb is -CH2CH2- and Rc is selected from:
Figure imgf000041_0002
nd accordin to statement 26, wherein Rb is -COCH2 and Rc is selected from:
Figure imgf000041_0003
Figure imgf000042_0001
according to any one of statements 1-5, 26, 27, with the structure:
Figure imgf000042_0002
according to any one of statements 1-5, 26, 27, with the structure:
Figure imgf000043_0001
cording to any one of statements 1-5, 26, 27, with the structure:
Figure imgf000043_0002
cording to any one of statements 1-5, 26, 27, with the structure:
Figure imgf000044_0001
34. The compound according to any one of statements 1 -5, 26, 27, with the structure:
Figure imgf000044_0002
35. The compound according to any one of statements 1 -5, 26, 27, with the structure:
Figure imgf000045_0001
36. The compound according to any one of statements 1-5, 26, 27, with the structure:
Figure imgf000045_0002
37. The compound according to any one of statements 1 -5, 26, 27, with the structure:
Figure imgf000046_0001
38. The compound according to any one of statements 1 -5, 26, 27, with the structure:
Figure imgf000046_0002
39. The compound according to any one of statements 1 -5, 26, 28, with the structure:
Figure imgf000047_0001
The compound according to any one of statements 1 -5, 26, 28 with the structure:
Figure imgf000047_0002
The compound according to any one of statements 1 -5, 26, 28, with the structure:
Figure imgf000048_0001
Figure imgf000048_0002
3. The compound according to any one of statements 1 -5, 26, 28 with the structure:
Figure imgf000049_0001
A compound according to any one of statements 1 -5, represented by any of the following eneral formulas or a pharmaceutically acceptable salt thereof:
1 f] also referred as Vanc-B
Figure imgf000049_0002
n] also referred as Vanc-N
Figure imgf000050_0001
also referred as Vanc-Q
Figure imgf000050_0002
45. A pharmaceutical composition comprising a compound according to any one of statements 1 to 44. 46. The compound according to any one of statements any one of statements 1 -5, 26-44, or the pharmaceutical composition according to statement 45 for use against a bacterial infection.
47. The compound or the pharmaceutical composition according to statement 46, wherein the bacterial infection is caused by a bacterial strain with resistance against at least one other antibiotic compound.
48. The compound or the pharmaceutical composition according to statement 47 wherein the other antibiotic compound is selected from the group comprising vancomycin, methicillin, ampicillin and erythromycin.
49. The pharmaceutical composition according to any one of statements 45-48, wherein the pharmaceutical composition is suitable for employing an effective concentration of 0.01 to
50 μg ml.
50. The compound according to any one of statements 46-48, or the pharmaceutical composition according to any one of statements 45-49, characterized in that the bacterial strain is selected from vancomycin-resistant Enterococci (VRE), vancomycin-intermediate resistant strains (VISA), vancomycin-susceptible Staphylococcus aureus (VSSA) or high- level vancomycin-resistant Staphylococcus aureus (VRSA).
51 . The compound according to any one of statements 46-48, 50, or the pharmaceutical composition according to any one of statements 45-50, characterized in that the bacterial infection is caused by vancomycin-resistant Staphylococcus aureus.
52. The compound according to any one of statements 46-48, 50, or the pharmaceutical composition according to any one of statements 45-50, characterized in that the bacterial infection is caused by vancomycin-resistant Enterococci (VRE).
53. A compound according to any one of statements 1 to 5 represented by one of the following general formulas listed in Table 20 or a pharmaceutically acceptable salt thereof:
Table 20
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
of formula (3) or a pharmaceutically acceptable salt thereof
Figure imgf000064_0002
wherein
Ra is a group of formula -NH-Rb-NH-Rc, or -NH-R ; wherein
Rb is a group of formula -Rd-, or -Rd-CO-, wherein the right side of -Rd-CO- is attached to -NH-Rc;
Rc is -Re, or -CO-Re;
Rd is a Ci-i2alkylene, wherein said Ci-i2alkylene; optionally comprises one or more heteroatoms in the alkylene, moiety, said heteroatoms being O;
or Rd together with one or both of the -NH- form a saturated or 4-, 5-, or 6-membered ring;
Re is selected from the group consisting of C2-6alkynyl, C6-i4aryl, C6-i4arylCi-6alkyl, C6- i4arylC2-6alkenyl, C6-i4arylC2-6alkynyl, C6-i4arylC2-6alkenylC6-i4aryl; heteroaryl, -NH-C3- i2cycloalkyl, and wherein said C2-6alkynyl; C6-i4aryl; C6-i4arylC2-6alkenyl, C6-i4arylC2- 6alkenylC6-i4aryl; heteroaryl, -NH-C3-i2cycloalkyl, can be unsubstituted or substituted with one or more Z1;
R is a C2-6alkynyl,
each Z1 is independently selected from the group consisting of hydroxyl, halo, nitro, Ci_ i2alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, haloCi-i0alkyl, Ci-6alkyloxy, Ci_ 6alkylamino, haloCi-i0alkyloxy, C6-i4aryl, C6-i4aryloxy, C6-i4arylC2-6alkenyl, C6-i4arylC2- 6alkynyl, heterocyclyl, heteroaryl, -OZ3, -C(=0)NZ4Z3, -NZ4(C=0)Z3, -NZ4Z3, -N+Z2Z4Z3 X" , -NZ4S(=0)2Z3, -S(=0)2Z3, -S(=0)2OZ3, glycosyl or an ester thereof, and phosphateCi.
6alkyl; and wherein each of said Ci-i2alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, haloCi-i0alkyl, Ci-6alkyloxy, Ci-6alkylamino, haloCi-i0alkyloxy, C6-i4aryl, C6-i4aryloxy, C6- i4arylC2-6alkenyl, C6-i4arylC2-6alkynyl, heterocyclyl, heteroaryl, glycosyl or ester thereof; can be unsubstituted or substituted with one or more Z2; or two adjacent Z2 can be taken together to form a C3-7cycloalkyl, or a 5-, 6-, or 7-membered heterocyclyl or heteroaryl ring, which can be unsubstituted or substituted with one or more Z2 ;
each Z2 is independently selected from the group consisting of hydroxyl, halo, nitro, Ci_ i2alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, haloCi-i0alkyl, Ci-6alkyloxy, Ci_ 6alkylamino, haloCi-i0alkyloxy, C6-i4aryl, C6-i4aryloxy, C6-i4arylC2-6alkenyl, C6-i4arylC2- 6alkynyl, heterocyclyl, heteroaryl, -OZ3, -C(=0)NZ4Z3, -NZ4(C=0)Z3, -NZ4Z3, -N+Z2Z4Z3 X"
, -NZ4S(=0)2Z3, -S(=0)2Z3, -S(=0)2OZ3, glycosyl or an ester thereof, and phosphateCi. 6alkyl; and wherein each of said Ci-i2alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, haloCi-i0alkyl, Ci-6alkyloxy, Ci-6alkylamino, haloCi-i0alkyloxy, C6-i4aryl, C6-i4aryloxy, C6- i4arylC2-6alkenyl, C6-i4arylC2-6alkynyl, heterocyclyl, heteroaryl, glycosyl or ester thereof; can be unsubstituted or substituted with one or more Z3;
each Z3 is independently selected from the group consisting of hydrogen, hydroxyl, halo, nitro, Ci-i2alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, haloCi-i0alkyl, Ci-6alkyloxy, Ci_ 6alkylamino, haloCi-i0alkyloxy, C6-i4aryl, C6-i4aryloxy, C6-i4arylC2-6alkenyl, C6-i4arylC2- 6alkynyl, heterocyclyl, heteroaryl, -OZ3, -C(=0)NZ4Z3, -NZ4(C=0)Z3, -NZ4Z3, -N+Z2Z4Z3 X" , -NZ4S(=0)2Z3, -S(=0)2Z3, -S(=0)2OZ3, glycosyl or an ester thereof, and phosphateCi. 6alkyl; and wherein each of said Ci-i2alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, haloCi-i0alkyl, Ci-6alkyloxy, Ci-6alkylamino, haloCi-i0alkyloxy, C6-i4aryl, C6-i4aryloxy, C6- i4arylC2-6alkenyl, C6-i4arylC2-6alkynyl, heterocyclyl, heteroaryl, glycosyl or ester thereof; can be unsubstituted or substituted with one or more Z4;
each Z4 is independently selected from the group consisting of hydrogen, hydroxyl, halo, nitro, Ci-i2alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, haloCi-i0alkyl, Ci-6alkyloxy, Ci_ 6alkylamino, haloCi-i0alkyloxy, C6-i4aryl, C6-i4aryloxy, C6-i4arylC2-6alkenyl, C6-i4arylC2- 6alkynyl, heterocyclyl, heteroaryl, -OZ3, -C(=0)NZ4Z3, -NZ4(C=0)Z3, -NZ4Z3, -N+Z2Z4Z3 X"
, -NZ4S(=0)2Z3, -S(=0)2Z3, -S(=0)2OZ3, glycosyl or an ester thereof, and phosphateCi. 6alkyl; and wherein each of said Ci-i2alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, haloCi-i0alkyl, Ci-6alkyloxy, Ci-6alkylamino, haloCi-i0alkyloxy, C6-i4aryl, C6-i4aryloxy, C6- i4arylC2-6alkenyl, C6-i4arylC2-6alkynyl, heterocyclyl, heteroaryl, glycosyl or ester thereof; can be unsubstituted or substituted with one or more Z5;
or Z4 and Z3 can be taken together to form a C3-7cycloalkyl, or a 5-, 6-, or 7-membered heterocyclyl, which can be unsubstituted or substituted with one or more Z5;
each Z5 is independently selected from the group consisting of hydrogen, K, Na , hydroxyl, halo, nitro, Ci-i2alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, haloCi-i0alkyl, Ci_ 6alkyloxy, Ci-6alkylamino, haloCi-i0alkyloxy, C6-i4aryl, C6-i4aryloxy, C6-i4arylC2-6alkenyl,
C6-i4arylC2-6alkynyl, heterocyclyl, heteroaryl, -OZ3, -C(=0)NZ4Z3, -NZ4(C=0)Z3, -NZ4Z3, - N+Z 2 Z 4 Z 3 χ . .N Z4S (= 0 )2Z3j .S(=o)2z3, -S(=0)2OZ3, glycosyl or an ester thereof, and phosphateCi-6alkyl; and
X is a halogen.
55. A compound of formula (4) or a pharmaceutically acceptable salt thereof,
Figure imgf000067_0001
wherein
Ra is a group of formula -NH-Rb-NH-Rc, or -NH-R ; wherein
Rb is a group of formula -Rd-, or -Rd-CO-, wherein the right side of -Rd-CO- is attached to -NH-Rc;
Rc is -Re, or -CO-Re;
Rd is a Ci-i2alkylene, wherein said Ci-i2alkylene; optionally comprises one or more heteroatoms in the alkylene, moiety, said heteroatoms being O;
or Rd together with one or both of the -NH- form a saturated or 4-, 5-, or 6-membered ring;
Re is selected from the group consisting of C2-6alkynyl, C6-i4aryl, C6-i4arylCi-6alkyl, C6- i4arylC2-6alkenyl, C6-i4arylC2-6alkynyl, C6-i4arylC2-6alkenylC6-i4aryl; heteroaryl, -NH-C3- i2cycloalkyl, and wherein said C2-6alkynyl; C6-i4aryl; C6-i4arylC2-6alkenyl, C6-i4arylC2- 6alkenylC6-i4aryl; heteroaryl, -NH-C3-i2cycloalkyl, can be unsubstituted or substituted with one or more Z1;
R is a C2-6alkynyl,
each Z1 is independently selected from the group consisting of hydroxyl, halo, nitro, Ci_ i2alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, haloCi-i0alkyl, Ci-6alkyloxy, Ci_ 6alkylamino, haloCi-i0alkyloxy, C6-i4aryl, C6-i4aryloxy, C6-i4arylC2-6alkenyl, C6-i4arylC2- 6alkynyl, heterocyclyl, heteroaryl, -OZ3, -C(=0)NZ4Z3, -NZ4(C=0)Z3, -NZ4Z3, -N+Z2Z4Z3 X" , -NZ4S(=0)2Z3, -S(=0)2Z3, -S(=0)2OZ3, glycosyl or an ester thereof, and phosphateCi. 6alkyl; and wherein each of said Ci_i2alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, haloCi-i0alkyl, Ci-6alkyloxy, Ci-6alkylamino, haloCi-i0alkyloxy, C6-i4aryl, C6-i4aryloxy, C6- i4arylC2-6alkenyl, C6-i4arylC2-6alkynyl, heterocyclyl, heteroaryl, glycosyl or ester thereof; can be unsubstituted or substituted with one or more Z2; or two adjacent Z2 can be taken together to form a C3-7cycloalkyl, or a 5-, 6-, or 7-membered heterocyclyl or heteroaryl ring, which can be unsubstituted or substituted with one or more Z2 ;
each Z2 is independently selected from the group consisting of hydroxyl, halo, nitro, Ci_ i2alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, haloCi-i0alkyl, Ci-6alkyloxy, Ci_ 6alkylamino, haloCi-i0alkyloxy, C6-i4aryl, C6-i4aryloxy, C6-i4arylC2-6alkenyl, C6-i4arylC2- 6alkynyl, heterocyclyl, heteroaryl, -OZ3, -C(=0)NZ4Z3, -NZ4(C=0)Z3, -NZ4Z3, -N+Z2Z4Z3 X"
, -NZ4S(=0)2Z3, -S(=0)2Z3, -S(=0)2OZ3, glycosyl or an ester thereof, and phosphateCi. 6alkyl; and wherein each of said Ci-i2alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, haloCi-i0alkyl, Ci-6alkyloxy, Ci-6alkylamino, haloCi-i0alkyloxy, C6-i4aryl, C6-i4aryloxy, C6- i4arylC2-6alkenyl, C6-i4arylC2-6alkynyl, heterocyclyl, heteroaryl, glycosyl or ester thereof; can be unsubstituted or substituted with one or more Z3;
each Z3 is independently selected from the group consisting of hydrogen, hydroxyl, halo, nitro, Ci-i2alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, haloCi-i0alkyl, Ci-6alkyloxy, Ci_ 6alkylamino, haloCi-i0alkyloxy, C6-i4aryl, C6-i4aryloxy, C6-i4arylC2-6alkenyl, C6-i4arylC2- 6alkynyl, heterocyclyl, heteroaryl, -OZ3, -C(=0)NZ4Z3, -NZ4(C=0)Z3, -NZ4Z3, -N+Z2Z4Z3 X" , -NZ4S(=0)2Z3, -S(=0)2Z3, -S(=0)2OZ3, glycosyl or an ester thereof, and phosphateCi.
6alkyl; and wherein each of said Ci-i2alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, haloCi-i0alkyl, Ci-6alkyloxy, Ci-6alkylamino, haloCi-i0alkyloxy, C6-i4aryl, C6-i4aryloxy, C6- i4arylC2-6alkenyl, C6-i4arylC2-6alkynyl, heterocyclyl, heteroaryl, glycosyl or ester thereof; can be unsubstituted or substituted with one or more Z4;
each Z4 is independently selected from the group consisting of hydrogen, hydroxyl, halo, nitro, Ci-i2alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, haloCi-i0alkyl, Ci-6alkyloxy, Ci_ 6alkylamino, haloCi-i0alkyloxy, C6-i4aryl, C6-i4aryloxy, C6-i4arylC2-6alkenyl, C6-i4arylC2- 6alkynyl, heterocyclyl, heteroaryl, -OZ3, -C(=0)NZ4Z3, -NZ4(C=0)Z3, -NZ4Z3, -N+Z2Z4Z3 X" , -NZ4S(=0)2Z3, -S(=0)2Z3, -S(=0)2OZ3, glycosyl or an ester thereof, and phosphateCi. 6alkyl; and wherein each of said Ci-i2alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, haloCi-i0alkyl, Ci-6alkyloxy, Ci-6alkylamino, haloCi-i0alkyloxy, C6-i4aryl, C6-i4aryloxy, C6- i4arylC2-6alkenyl, C6-i4arylC2-6alkynyl, heterocyclyl, heteroaryl, glycosyl or ester thereof; can be unsubstituted or substituted with one or more Z5;
or Z4 and Z3 can be taken together to form a C3-7cycloalkyl, or a 5-, 6-, or 7-membered heterocyclyl, which can be unsubstituted or substituted with one or more Z5; each Z5 is independently selected from the group consisting of hydrogen, K, Na , hydroxyl, halo, nitro, Ci-i2alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, haloCi-i0alkyl, Ci_ 6alkyloxy, Ci-6alkylamino, haloCi-i0alkyloxy, C6-i4aryl, C6-i4aryloxy, C6-i4arylC2-6alkenyl, C6-i4arylC2-6alkynyl, heterocyclyl, heteroaryl, -OZ3, -C(=0)NZ4Z3, -NZ4(C=0)Z3, -NZ4Z3, - N +Z2Z4Z3 χ. .NZ4S (=0 )2Z3j .S (=o)2z3, -S(=0)2OZ3, glycosyl or an ester thereof, and phosphateCi-6alkyl; and
X is a halogen.
The compound according to any one of statements 1 -5, 6-1 1 , 26-44, 54-55, or a pharmaceutical composition according to statement 6, wherein
Ra is a group of formula -NH-Rb-NH-Rc, wherein
Rb is a group of formula -Rd-, or -Rd-CO-, wherein the right side of -Rd-CO- is attached to -NH-Rc;
Rc is -Re, or -CO-Re;
Rd is Ci-4alkylene, preferably Ci-3alkylene;
Re is selected from the group consisting of C2-6alkynyl, C6-i4aryl, C6-i4arylCi-6alkyl, C6- i4arylC2-6alkenyl, C6-i4arylC2-6alkenylC6-i4aryl; heteroaryl, and wherein said C2-6alkynyl; C6-i4aryl; C6-i4arylC2-6alkenyl, C6-i4arylC2-6alkenylC6-i4aryl; heteroaryl, can be unsubstituted or substituted with one or more Z1;
each Z1 is independently selected from the group consisting of hydroxyl, halo, nitro, Ci_ 8alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, haloCi-6alkyl, Ci-6alkyloxy, C6-i4aryl, C6- i4aryloxy, C6-i4arylC2-6alkenyl, C6-i4arylC2-6alkynyl, heteroaryl, -OZ3, -NZ4Z3, - NZ4S(=0)2Z3; and wherein each of said Ci-8alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, haloCi-6alkyl, Ci-6alkyloxy, C6-i4aryl, C6-i4aryloxy, C6-i4arylC2-6alkenyl, C6-i4arylC2-6alkynyl, heterocyclyl, heteroaryl; can be unsubstituted or substituted with one or more Z2;
each Z2 is independently selected from the group consisting of hydroxyl, halo, nitro, Ci_ 8alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, haloCi-6alkyl, Ci-6alkyloxy, Ci-6alkylamino, haloCi-6alkyloxy, C6-i4aryl, C6-i4aryloxy, C6-i4arylC2-6alkenyl, C6-i4arylC2-6alkynyl, heterocyclyl, heteroaryl, -OZ3, -C(=0)NZ4Z3, -NZ4(C=0)Z3, -NZ4Z3, -NZ4S(=0)2Z3, - S(=0)2Z3, -S(=0)2OZ3; and wherein each of said Ci-8alkyl, C2-6alkenyl, C2-6alkynyl, C3- i2cycloalkyl, haloCi-6alkyl, Ci-6alkyloxy, Ci-6alkylamino, haloCi-6alkyloxy, C6-i4aryl, C6- i4aryloxy, C6-i4arylC2-6alkenyl, C6-i4arylC2-6alkynyl, heterocyclyl, heteroaryl; can be unsubstituted or substituted with one or more Z3; each Z3 is independently selected from the group consisting of hydrogen, hydroxyl, halo, nitro, Ci-8alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, haloCi-6alkyl, Ci-6alkyloxy, C6- i4aryl, C6-i4aryloxy, heterocyclyl, heteroaryl, -OZ3, -NZ4Z3, -NZ4S(=0)2Z3; and wherein each of said Ci-8alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, haloCi-6alkyl, Ci-6alkyloxy, C6-i4aryl, C6-i4aryloxy, C6-i4arylC2-6alkenyl, C6-i4arylC2-6alkynyl, heterocyclyl, heteroaryl; can be unsubstituted or substituted with one or more Z4;
each Z4 is independently selected from the group consisting of hydrogen, hydroxyl, halo, nitro, Ci-8alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, haloCi-6alkyl, Ci-6alkyloxy, Ci_ 6alkylamino, haloCi-6alkyloxy, C6-i4aryl, C6-i4aryloxy, C6-i4arylC2-6alkenyl, C6-i4arylC2- 6alkynyl, heterocyclyl, heteroaryl; and wherein each of said Ci-8alkyl, C2-6alkenyl, C2- 6alkynyl, C3-i2cycloalkyl, haloCi-6alkyl, Ci-6alkyloxy, Ci-6alkylamino, haloCi-6alkyloxy, C6- i4aryl, C6-i4aryloxy, C6-i4arylC2-6alkenyl, C6-i4arylC2-6alkynyl, heterocyclyl, heteroaryl; can be unsubstituted or substituted with one or more Z5;
each Z5 is independently selected from the group consisting of hydrogen, K, Na , hydroxyl, halo, nitro, Ci-6alkyl.
The compound according to any one of statements 1-5, 6-1 1 , 26-44, 54-56, or a pharmaceutical composition according to statement 6, wherein
Ra is a group of formula -NH-Rb-NH-Rc, wherein
Rb is a group of formula -Rd-, or -Rd-CO-, wherein the right side of -Rd-CO- is attached to -NH-Rc;
Rc is -Re, or -CO-Re;
Rd is Ci-3alkylene;
Re is selected from the group consisting of C6-i4aryl, C6-i4arylCi-6alkyl, C6-i4arylC2- 6alkenyl, C6-i4arylC2-6alkenylC6-i4aryl; heteroaryl, and wherein said C6-i4aryl; C6-i4arylC2- 6alkenyl, C6-i4arylC2-6alkenylC6-i4aryl; heteroaryl, can be unsubstituted or substituted with one or more Z1;
each Z1 is independently selected from the group consisting of hydroxyl, halo, nitro, Ci_ 8alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, haloCi-6alkyl, Ci-6alkyloxy, C6-i4aryl, C6- i4aryloxy, C6-i4arylC2-6alkenyl, C6-i4arylC2-6alkynyl, heteroaryl, -OZ3, -NZ4Z3, - NZ4S(=0)2Z3; and wherein each of said Ci-8alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, haloCi-6alkyl, Ci-6alkyloxy, C6-i4aryl, C6-i4aryloxy, C6-i4arylC2-6alkenyl, C6-i4arylC2-6alkynyl, heterocyclyl, heteroaryl; can be unsubstituted or substituted with one or more Z2; each Z2 is independently selected from the group consisting of hydroxyl, halo, nitro, Ci_ 8alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, haloCi-6alkyl, Ci-6alkyloxy, Ci-6alkylamino, haloCi-6alkyloxy, C6-i4aryl, C6-i4aryloxy, C6-i4arylC2-6alkenyl, C6-i4arylC2-6alkynyl, heterocyclyl, heteroaryl, and wherein each of said Ci-8alkyl, C2-6alkenyl, C2-6alkynyl, C3- i2cycloalkyl, haloCi-6alkyl, Ci-6alkyloxy, Ci-6alkylamino, haloCi-6alkyloxy, C6-i4aryl, C6- i4aryloxy, C6-i4arylC2-6alkenyl, C6-i4arylC2-6alkynyl, heterocyclyl, heteroaryl; can be unsubstituted or substituted with one or more Z3;
each Z3 is independently selected from the group consisting of hydrogen, hydroxyl, halo, nitro, Ci-8alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, haloCi-6alkyl, Ci-6alkyloxy, C6- i4aryl, C6-i4aryloxy, heterocyclyl, heteroaryl, and wherein each of said Ci-8alkyl, C2- 6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, haloCi-6alkyl, Ci-6alkyloxy, C6-i4aryl, C6-i4aryloxy, C6- i4arylC2-6alkenyl, C6-i4arylC2-6alkynyl, heterocyclyl, heteroaryl; can be unsubstituted or substituted with one or more Z4;
each Z4 is independently selected from the group consisting of hydrogen, hydroxyl, halo, nitro, Ci-8alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, haloCi-6alkyl, Ci-6alkyloxy, Ci_ 6alkylamino, haloCi-6alkyloxy, C6-i4aryl, C6-i4aryloxy, C6-i4arylC2-6alkenyl, C6-i4arylC2- 6alkynyl, heterocyclyl, heteroaryl; and wherein each of said Ci-8alkyl, C2-6alkenyl, C2- 6alkynyl, C3-i2cycloalkyl, haloCi-6alkyl, Ci-6alkyloxy, Ci-6alkylamino, haloCi-6alkyloxy, C6- i4aryl, C6-i4aryloxy, C6-i4arylC2-6alkenyl, C6-i4arylC2-6alkynyl, heterocyclyl, heteroaryl; can be unsubstituted or substituted with one or more Z5;
each Z5 is independently selected from the group consisting of hydrogen, K, Na , hydroxyl, halo, nitro, Ci-6alkyl.
8. The compound according to any one of statements 1-5, 6-1 1 , 26-44, 54-57, or a pharmaceutical composition according to statement 6, wherein Ra is selected from a group of formula A1 ), (A2), or (A3), as defined in the below table, wherein
Figure imgf000071_0001
Figure imgf000072_0001
59. The compound according to any one of statements 1 -5, 6-1 1 , 26-44, 54-57, or a pharmaceutical composition according to statement 6, wherein Ra is selected from a group of formula A1 ), (A2), or (A3), as defined in the below table, wherein
Figure imgf000072_0002
60. The compound according to any one of statements 1 -5, 6-1 1 , 26-44, 54-59, or a pharmaceutical composition according to statement 6, wherein Ra is selected from a group as defined in the below table,
Figure imgf000073_0001
61 . The compound according to any one of statements 1 -5, 6-1 1 , 26-44, 54-59, or a pharmaceutical composition according to statement 6, wherein Ra is selected from the group comprisin structure of formula (A4), (A5), and (A6), as defined in the below table
Figure imgf000073_0002
62. The compound according to any one of statements 1 -5, 6-1 1 , 26-44, 54-59, or a pharmaceutical composition according to statement 6, wherein Ra is selected from the group comprising structure of formula (A1 ), (A2), (A3), (A4), (A5), and (A6), as defined in the below table
Figure imgf000074_0001
defined in Table 17a
Table 17a:
Figure imgf000074_0002
Figure imgf000075_0001
Table 13a:
Figure imgf000075_0002
Figure imgf000076_0001
Table 14a:
Figure imgf000076_0002
Figure imgf000077_0001
Table 16a:
Figure imgf000077_0003
63. The compound according to any one of statements 1 -5, 6-1 1 , 26-44, 54-59, or a pharmaceutical composition according to statement 6, wherein Re is a group of formula :
Figure imgf000077_0002
wherein Z1 has the same meaning as that defined in any one of statements 1 to 4 and X1 CH=CH, CH, N, O, or S and Y1 is CH=CH, CH, N, O, or S. 64. The compound according to any one of statements 1 -5, 54-59, or a pharmaceutical
Figure imgf000078_0001
composition according to statement 6, wherein Re is a group of formula :
wherein Z1 has the same meaning as that defined in any one of statements 1 to 4 and n is an integer selected from 0, 1 , 2, 3, 4, 5, or 6.
65. A pharmaceutical composition comprising a compound according to any one of statements 1 -5, 6-1 1 , 26-44, 53-64, or as defined in any one of statements 5, 12-25, 45-52.
66. A compound according to any one of statements 1 -5, 6-1 1 , 26-44, 53-64 or the pharmaceutical composition according to statement 63 for use against a bacterial infection.
67. The compound or the pharmaceutical composition according to statement 66, wherein the bacterial infection is caused by a bacterial strain with resistance against at least one other antibiotic compound.
68. The compound or the pharmaceutical composition according to statement 66, wherein the bacterial infection is caused by a bacterial strain susceptible to at least one antibiotic compound.
69. The compound or the pharmaceutical composition according to statement 67 or 68 wherein the antibiotic compound is selected from the group comprising vancomycin, methicillin, ampicillin, erythromycin, tigecycline, teicoplanin, daptomycin, and linezolid.
70. The pharmaceutical composition according to any one of statements 65-69, wherein the pharmaceutical composition is suitable for employing an effective concentration of 0.01 to 50 Mg/ml.
71 . The compound according to any one of statements 66-69, or the pharmaceutical composition according to any one of statements 63-68, characterized in that the bacterial strain is vancomycin-susceptible Enterococci (VSE), vancomycin-resistant Enterococci (VRE), vancomycin-susceptible Staphylococcus aureus (VSSA), vancomycin-intermediate resistant strains (VISA), or high-level vancomycin-resistant Staphylococcus aureus (VRSA).
72. The compound according to any one of statements 66-69, 71 , or the pharmaceutical composition according to any one of statements 65-71 , characterized in that the bacterial infection is caused by vancomycin-resistant Staphylococcus aureus (VRSA). 73. The compound according to any one of statements 66-69, 71 , or the pharmaceutical composition according to any one of statements 65-71 , characterized in that the bacterial infection is caused by vancomycin-resistant Enterococci (VRE).
74. The compound according to any one of statements 66-69, 71 , or the pharmaceutical composition according to any one of statements 65-71 , wherein the bacterial infection is caused by vancomycin-intermediate resistant strains (VISA).
75. The compound according to any one of statements 66-69, 71 , or the pharmaceutical composition according to any one of statements 65-71 , wherein the bacterial infection is caused by vancomycin-susceptible Enterococci (VSE).
76. The compound according to any one of statements 66-69, 71 , or the pharmaceutical composition according to any one of statements 65-71 , wherein the bacterial infection is caused by vancomycin-susceptible Staphylococcus aureus (VSSA).
77. The compound according to any one of statements 66-69, or the pharmaceutical composition according to any one of statements 65-70, wherein the bacterial infection is caused by Clostridium difficile.
78. A method for the prevention or treatment of a bacterial infection in an animal, mammal or human comprising administering to said animal, mammal or human in need for such prevention or treatment an effective dose of the compounds ad defined in any one of statements 1 -77.
79. The method according to statement 78, wherein the bacterial infection is caused by a bacterial strain with resistance against at least one antibiotic compound.
80. The method according to statement 78, wherein the bacterial infection is caused by a bacterial strain susceptible to at least one antibiotic compound.
81 . The method according to statement 79 or 80 wherein the antibiotic compound is selected from the group comprising vancomycin, methicillin, ampicillin, erythromycin, tigecycline, teicoplanin, daptomycin, and linezolid.
82. The method according to any one of statements 78-81 , wherein the bacterial strain is vancomycin-susceptible Enterococci (VSE), vancomycin-resistant Enterococci (VRE), vancomycin-susceptible Staphylococcus aureus (VSSA), vancomycin-intermediate resistant strains (VISA), or high-level vancomycin-resistant Staphylococcus aureus (VRSA).
83. The method according to any one of statements 78-82, wherein the bacterial infection is caused by vancomycin-resistant Staphylococcus aureus (VRSA). 84. The method according to any one of statements 78-82,wherein the bacterial infection is caused by vancomycin-resistant Enterococci (VRE).
85. The method according to any one of statements 78-82,wherein the bacterial infection is caused by vancomycin-intermediate resistant strains (VISA).
86. The method according to any one of statements 78-82, wherein the bacterial infection is caused by vancomycin-susceptible Enterococci (VSE).
87. The method according to any one of statements 78-82, wherein the bacterial infection is caused by vancomycin-susceptible Staphylococcus aureus (VSSA).
88. The method according to any one of statements 78-81 , wherein the bacterial infection is caused by Clostridium difficile.
The following terms are provided solely to aid in the understanding of the invention.
Exemplary vancomycin analogs (Table 1 ) as described herein, with modifications at the C- terminus i.e. the carboxyl group (compounds of formula (1 ) and (2)) were tested against model Gram-positive species (Bacillus subtilis) and model Gram-negative species (£. coli). Both species are susceptible for vancomycin and were inhibited significantly by the studied vancomycin analogs (Table 2).
Later, these vancomycin analogs (Table 1 and 1 a) were screened against VanA phenotype VRE strains isolated from hospitalized patients and noticed that among all the tested compounds (sixty vancomycin analogs), aromatic substituted ones displayed good results (Table 3, 4 and 4a). These vancomycin analogs were also tested against vancomycin-resistant Staphylococcus aureus (VRSA) and vancomycin-intermediate resistant Staphylococcus aureus (VISA) to investigate their efficacy (Table 4a).
In general, substituent groups (also referred to as "substitutions," "modifying groups," "modifications", "extensions," or "linkers") were added to the C-terminus of vancomycin to produce the vancomycin structural analogs (also referred to as "analogs," "derivatives," "conjugates," "linker conjugates," or "compounds"). All synthesized and commercially available substituent groups were bifunctional possessing a terminal amine and a terminal alkyne group (Table 1 and Table 1 a. Analogs Vane 1 -38 as listed in Table 1 a are also represented in Tables 10-17). They were conjugated to vancomycin via acid amine coupling at the C-terminus of vancomycin using HOAt/EDC-HCI as coupling agent yielding vancomycin analogs 11 a-w and Vane 1 -38. Substituent groups containing a terminal alkyne group may be conjugated with peptides via click chemistry, as described in patent application GB1222029.9.
EXAMPLES EXAMPLE 1 : Synthesis
Abbreviation list: DMF: Ν,Ν-dimethylformamide; HATU: 0-(7-Azabenzotriazole-1 -yl)-1 ,1 ,3,3- tetramethyluroniumhexafluorophosphate; DIPEA: Diisopropylethylamine; HOAt: 1 -Hydroxy-7- azabenzotriazole; EDC: N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; ACN: acetonitrile; Boc: t-Butoxycarbonyl; THF: tetrahydrofuran; TEA Triethylamine; DCM dichloromethane; TMS-acetylene : (trimethylsilyl)acetylene; TBAF: tetra-n-butylammonium fluoride; EA: ethylacetate; DMSO: dimethylsulfoxide.
1.A General procedure:
Vancomycin. HCI (75 mg, 0.051 mmol), EDC-HCI (12 mg, 0.0.067 mmol) and HOAt (9 mg, 0.067mmol) were dissolved in DMF (5 mL) and the mixture was stirred for 5 min. To this solution were added a solution of amine of formula RcNHRbNH2 (1 .1 equiv) in DMF (1 mL) and /V-methyl morpholine (till pH 8) and the mixture was stirred for 7-8h at rt. The reaction was monitored by ESI-MS. DMF was removed in vacuo and the residue was purified by preparative RP-HPLC (0-40% ACN/H20 with 0.1 % HCOOH in 40 min). The retention time was in the range of 27-35 min. The acetonitrile was removed in vacuo and the remaining water was lyophilized affording compounds 1 1 a-w as a white powder in 30-50% yield. Compounds thus obtained were characterized by mass spectrometric analysis.
1.B- General synthesis of amine of formula FFNHRbNH2
Synthesis was classified into 3 categories based upon the selection of RcNHRbNH2. RcNHRbNH2 was prepared from a) N- Boc Glycine; b) N-Boc-ethylenediamine; or c) N-Boc-1 ,3 propanediamine (as illustrated in Scheme 1 a, 1 b, 1 c))
Scheme 1 a
a) From N-Boc Glycine
Figure imgf000081_0001
Vanc-72, 76,77 Vane- 37, 38, 68-70 11 u, Vanc-58
1 1 n: Re= 4-ethynylphenyl
Vanc-60-62: Re= phenylsulfonyl, 2,4-dichlorophenylsulfonyl, 4-chlorophenylsulfonyl Vanc-1 -19, 39-44, 59, 67, 71 , 74, 75 : Re= phenyl, phenyl substituted by one, two or three substituents, naphthyl, 9H-fluorenyl, 5-chloropyridin-2yl, anthracen-2yl
Reagents and conditions: i) Ethyl chloroformate, THF, TEA, overnight, 0 °C to room temperature (rt); ii) H20/dioxane (9:1 ), 140 °C, 3h; ii') 4N HCI in 1 ,4-dioxane, DCM, 0 °C to rt, 1 h.
Scheme 1 b
b) From N-Boc-ethylenediamine
o
,N H ■A O H ,N H R
N H
BocHN' H2N'
BocHN ' Y Y
I O O
Sonogashira reaction
11t, Vanc-48
Vanc-54-56, 64: Re= 4-[(phenylsulfonyl)amino]phenyl}ethenyl unsubstituted or substituted by one, or two substituents,
Vanc-20-23, 36, 46, 47, 51 , 53: Re= phenyl}ethenyl unsubstituted or substituted by one, or two substituents, 9H-fluorenyl, alkyl substituted by aryl
Reagents and conditions: i) HATU, DIPEA, DMF, rt, 4h; ii) 4N HCI in 1 ,4-dioxane, DCM, 0 °C to rt, 1 -2h.
Scheme 1 c
c) N-Boc-1 ,3-propanediamine
BocHN ' "N H
Figure imgf000082_0001
Sonogashira reaction
11v, 11w
Vanc-24-27, 45. 52: Re= substituted/unsubstituted heteroaryl ring such as indole, benzothiazole, benzofuran, quinoline, benzimidazole.
Vanc-28-35 49-50, 73 : Re= unsubstituted/substituted naphthyl, unsubstituted/substituted phenyl,
Vanc-63, 65-66: Re= naphthyl substituted by unsubstituted or substituted phenylslufonamide Reagents and condition: i) HATU, DIPEA, DMF, rt, 4h; iii) 4N HCI in 1 ,4-dioxane, DCM, 0 °C to rt, 2h.
1.C Detailed synthetic routes for preparing amines of formula R^NHR^NH^
1.C.1: arylamines suitable for preparing (11 n, Vane- 1-19, 37-44, 58-59, 67-71, 74, 75)
Scheme 2
Figure imgf000083_0001
65-85% 9n " oni1 1 Qn
80-95%
Where Z1= internal or terminal alkynyl, alkyl, alkenyl, halide, nitro, aryl, ether, NH-, sulfonamide, sulfone etc.
Reagents and conditions: i) Ethyl chloroformate, /V-Boc-glycine 8b, THF, TEA, overnight, 0 °C to rt; ii) If R= terminal alkyne: H20/dioxane (9:1 ), 140 °C, 3h; ii') 4N HCI in 1 ,4-dioxane, DCM, 0 °C to rt, 1 h.
i) To a solution of N-Boc-Glycine 8b (1 .44 mmol) in THF (2 mL) at 0 °C were added triethylamine (1 .44 mmol) and ethyl chloroformate (1 .44 mmol) over a period of 10 min, and the reaction mixture was stirred for 30 min. After the addition of the 2- aminobenzethyne 7j (1 .44 mmol), the mixture was stirred for an additional 1 h at 0 °C.
Then, the reaction mixture was warmed to room temperature, and kept stirring overnight.
After completion of the reaction, the solvent was evaporated under reduced pressure; the residue was dissolved in ethyl acetate (15ml_ x 2) and washed with brine solution (15 mL).
The organic layer was dried over Na2S04 and the solvent was evaporated under reduced pressure. Crude product was purified by column chromatography using EA / Heptane,
(40/60) as eluents. Yield: 65-85 %. (Cakici, M.; Catir, M.; Karabuga, S.; Ulukanli, S.; Kilic,
H. Tetrahedron Asymm., 201 1 , 22, 300-308)
ii) Compound 9n 100 mg was dissolved in 0.5 mL Dioxane and 4.5 mL H20 in a screw capped vial and heated at 140 °C for 3h. After completion of the reaction, reaction mass was cooled to room temperature hence product failed out as light yellow colored solid. It was filtered through Buchner funnel, washed with diethyl ether and dried under vacuo (Wang, J.; Liang, Y.-L; Qu, J. Chem. Commun. 2009, DOI 10.1039/B910239F, 5144- 5146)
ii') Compounds 9n was dissolved in CH2CI2 (5 mL) and HCI-dioxane (6 M solution, 4 mL) was added and the mixture was stirred at rt for 3-4h. The reaction was monitored by TLC (MeOH/DCM, 1 :9, Rf = 0.1 ). After completion of the reaction, the solvents were removed in vacuo and the product was washed with diethyl ether and dried in vacuo. Yield: 80-95%
1.C.2: arylamines via Sonogashira reaction
Scheme 3 oc
Figure imgf000084_0001
wherein Z2 is hydrogen, alkyl or cycloalkyl
Reagents and conditions: i) Ethyl chloroformate, /V-Boc-glycine, THF, TEA, overnight, 0 °C to rt; ii) alkyne, pyridine, Pd(PPh3)CI2, 85 °C, 30 min; iii) when R=H; water-Dioxane (9:1 ), 140 °C, 4h; when R= cyclic and acyclic alkane; 4N HCI in 1 ,4-dioxane, DCM, 0 °C to rt, 1 h.
i) Synthesis of 9u or a.
This compound was synthesized from 4-lodo aniline by following the procedure applied for the synthesis of 9n.
ii) Synthesis of 9n' or b.
In a 25 mL round bottom flask was placed 9u or a (1 .04 mmol), TMS-acetylene (2.08 mmol), piperidine (1 .10 mL, 10 equiv.), PdCI2(PPh3)2 (0.04 mmol, 4 mol%) and a magnetic stir bar. The reaction mixture was stirred at 85 °C for 30-40 min. After completion of the reaction, the reaction mass was poured in water (25 mL) and extracted with ethyl acetate (3 x 30 mL).The combined organic layer was washed with 1 N HCI solution, brine (25 mL) and dried over Na2S04. After filtration, solvent was evaporated under reduced pressure and crude product was subjected to silica gel column chromatography (2-4% methanol in DCM) to afford the corresponding compounds (Gu, Z.; Li, Z.; Liu, Z.; Wang, Y.; Liu, C; Xiang, J. Catal. Commun. 2008, 9, 2154- 2157)
iii) Synthesis of 10n' or c:
This compound was synthesized by following the procedure used for the synthesis of 10n. 1.C.3: arylamines via Heck reaction
Scheme 4
Figure imgf000085_0001
Z2= NH2 forVanc- 58
Z2= Br fori 1u
Reagents and conditions: i) Ethylchloroformate, /V-Boc-glycine, THF, TEA, overnight, 0 °C to rt; ii) Substituted styrene, Pd(OAc)2, tetrabutylammonium bromide, potassium acetate, 80 °C, 4-5h; iii) 4N HCI in 1 ,4-dioxane, 2-3h; iv) If R= Br; trimethylsilylacetylene, piperidine, Pd(PPh3)CI2, 85 °C, 30 min; v) TBAF, THF, rt, 30 min.
ii) Synthesis of 9u'.
In a round-bottom, 2 necked flask 9u (500 mg, 1.33 mmol) was added to a mixture of tetrabutylammonium bromide (322 mg, 1 .99 mmol), potassium acetate (210 mg, 2.14 mmol), palladium acetate (15 mg, 0.066 mmol) and substituted styrene (1 .46 mmol) stirred in DMF (12 mL) at room temperature under argon. The reaction mixture was heated up to 80 °C for 4-5h and then cooled to room temperature. After completion of the reaction as monitored by TLC (6:4, Heptane/Ethyl acetate) and mass analysis, it was cooled to room temperature, poured in water (50 mL) and extracted with ethylacetae (3x 30 mL). The combined organic layer was washed with brine (50 mL) and dried over Na2S04. After filtration, solvent was evaporated under reduced pressure and crude product was subjected to silica gel column chromatography (30- 40% ethylacetate in heptane) to afford the compound with 55-65% yield (Sun, B.; Hoshino, J.; Jermihov, K.; Marler, L.; Pezzuto, J. M.; Mesecar, A. D.; Cushman, M. Bioorg. Med. Chem. 2010, 18, 5352-5366)
iii) Synthesis of 9u"
This compound 9u" was synthesized by following the procedure used for the synthesis of 10n. iv) Synthesis of 10u. In a 25 mL round bottom flask was placed 9u" (1 .04 mmol), TMS acetylene (2.08 mmol), piperidine (1 .10 mL, 10 equiv.), PdCI2(PPh3)2 (0.04 mmol, 4 mol%) and a magnetic stir bar. The reaction mixture was stirred at 85 °C for 30-40 min. After completion of the reaction, the reaction mass was poured in water (25 mL) and extracted with ethyl acetate (3 x 30 mL). The organic layer was concentrated under reduced pressure yielding brown colored solid.
v) TMS Deprotection:
This product was dissolved in THF (2mL) and cooled in an ice bath at 0 °C. A solution of TBAF (tetrabutylammonium fluoride) in THF (1 .2 equiv, 0.15μΜ solution) was added dropwise to it and allowed to stir at room temperature for 30 min. After completion of reaction, THF was removed in vacuo and the solid residue obtained was dissolved in Water/ACN mixture and purified preparative HPLC using gradient 35% ACN in water/HCOOH. Solvent was removed under reduced pressure and dried to obtain pure product in 50% yield.
1.C.4: Preparation of starting material for preparing Vane- 60-62
Scheme 5
CI
Figure imgf000086_0001
Figure imgf000086_0002
Z3= H, alkyl, aryl, alkoxy, halide etc
Reagents and condition: i) Pyridine, rt, 5-6h; ii) 4N HCI in 1 ,4-dioxane, DCM, 0 °C to rt, 2h iii) ethylchloroformate, N-Boc-glycine, THF, TEA, overnight, 0 °C to rt.
i) Synthesis of 9a'
N-Boc -p-phenylenediamine (1 .0 mmol) and benzenesulfonyl chloride (1 .12 mmol) were dissolved in pyridine (1 mL) and stirred in a screw capped vial for 5-6h at rt. The progress of the reaction was monitored by TLC (EA/Heptane; 1 :1 ). After completion of the reaction 1 N HCI was added till PH 6 and extracted with ethyl acetate (3 x 25 mL), washed with brine. Solvent was removed under reduced pressure. This crude product was subjected to silica gel column chromatography (30-50% ethylacetate in heptane) to afford the compound with 70-84% yield. ii) Synthesis of 9b'.
9b' was synthesized by following the procedure used for the synthesis of 10n. Yield 90-95%. iii) Synthesis of 9c'.
9c' was synthesized by following the procedure used for the synthesis of 9n. Yield: 65-70%. iv) Synthesis of 9d'.
9d' was synthesized by following the procedure used for the synthesis of 10n. Yield 85-90%. 1.C.5: Preparation of starting material for preparing Vane- 72, 76 & 77 (Click chemistry)
Scheme 6
Figure imgf000087_0001
Reagents and condition: NaN3, Cul, L-Proline, NaOH, DMSO, 60 °C, 7-8h; ii) Cul, DIPEA, THF, 60 °C, 20h; iii) 4N HCI in 1 ,4-dioxane, DCM, 0 °C to rt, 2h.
i) Synthesis of substituted/unsubstituted phenyl azide
Substituted or unsubstituted phenyl iodide (4.2 mmol), NaN3 (8.4 mmol), Cul (10 mol%), L- proline (20 mol%) and NaOH (20 mol%) were suspended in DMSO ( 5ml_) in a screw capped vial and stirred at 60 °C for 7-8h. Progress of the reaction was monitored by TLC and mass spectrometer. After completion of the reaction, water was added to the reaction mixture, extracted with ethyl acetate (3 x 30 mL), washed with brine and concentrated under reduced pressure. The crude product was subjected to silica gel column chromatography (5-10% ethylacetate in heptane) to afford the compound with 40-50% yield (Chem. Commun., 2004, 888-889). ii) Synthesis of 9n".
THF 1 .5 mL and DIPEA (1 .0 equiv) were added to the mixture of 9n (0.36 mmol, 1 .0 equiv.), phenyl azide (2.0 equiv.), Cul (10 mol%) and the reaction mixture was stirred at 60 °C for 20h. The progress of the reaction was monitored by TLC (EA Heptane; 6:4). After completion of the reaction, the reaction mixture was concentrated and subjected to silica gel column chromatography (60-70% ethyl acetate in heptane) to afford the compound with 70-75% yield. iii) Synthesis of 10n".
10n" was synthesized by following the procedure used for the synthesis of 10n. Yield: 95%
1.C.6: Preparation of starting material for preparing Vane- 111, Vane- 21-23, 36 (derived from cinnamic acids)
Scheme 7
Figure imgf000088_0001
78= Alkyl, halide, hydroxy, alkoxy, Sulphone, sulphonamide, triazole, substituted triazole, protected/unprotected sugar etc. Z3= Alkyl, halide, hydroxy, alkoxy, Sulphone, sulphonamide, triazole, substituted triazole, protected/unprotected sugar etc.
Reagents and conditions: i) /V-Boc-ethylenediamine, HATU, DIPEA, DMF, rt, 4h; ii) 4N HCI in 1 ,4-dioxane, DCM, 0 °C to rt, 1 h; iii) substituted acetylene, piperidine, Pd(PPh3)CI2, 85 °C, 30 min; iv) If R'= TMS (trimethylsilane): TBAF, THF, rt, 30 min.
i) Synthesis of 9t.
To a solution of compound 9t' (1 .63 mmol) in DMF (5 mL) was added HATU (1 .96 mmol), N- Boc-ethylenediamine 7d (1 .80 mmol) and DIPEA (2.13 mmol) and stirred at rt for 4h. After completion of the reaction, reaction mass was poured into water and extracted with ethyl acetate (2 x 25 mL). The organic layer was washed with brine and concentrated under vacuo pressure and crude product was subjected to silica gel column chromatography (2-4% methanol in DCM) to afford the corresponding compounds. Yield: 82%.
ii) Synthesis of 10f 10f was synthesized by following the procedure used for the synthesis of 10n. Yield 62% iii) Synthesis of 10t.
10t was synthesized by following the procedure used for the synthesis of 10u. Yield 62%.
1.C.7 Preparation of starting material for preparing Vane- 54-56 & 64 (sulfonamide derivative) Scheme 8
Figure imgf000089_0001
Z3= H, alkyl, aryl, alkoxy, halide etc
Reagents and condition: i) Pyridine, rt, 5-6h; ii) /V-Boc-1 ,2-ethanediamine, HATU, DIPEA, DMF, rt, 4h; iii) ) 4N HCI in 1 ,4-dioxane, DCM, 0 °C to rt, 2h.
i) Synthetic procedure is same as the procedure used for the synthesis of 9a'.
ii) 9t' was synthesized by following the procedure used for the synthesis of 9t
iii) 10t" was synthesized by following the procedure used for the synthesis of 10f.
1.C.8: Preparation of starting material for preparing 11 w, Vanc-28-30 (Naphthioc acid derivatives)
Scheme 9
Figure imgf000090_0001
Figure imgf000090_0002
10w"
Z8= Alkyl, halide, Hydroxy, alkoxy, Sulphone, sulphonamide, triazole, substituted triazole,
protected/unprotected sugar etc.
Reagents and conditions: i) /V-Boc-1 ,3 propanediamine, HATU, DIPEA, DMF, rt, 4h; ii) 4N HCI in 1 ,4-dioxane, DCM, 0 °C to rt, 1 h; iii) substituted acetylene, piperidine, Pd(PPh3)CI2, 85 °C, 30 min; iv)lf R'= TMS (trimethylsilane): TBAF, THF, rt, 30 min.
Procedure was the same as for the synthesis of substituents for 1 1t, Vane- 21 -23, 36 (see 1 .C.6)
1.C.9: Preparation of starting material for preparing Vanc-63, 65 & 66 (Naphthioc acid derivatives)
Scheme 10
Figure imgf000090_0003
Z4= H, alkyl, aryl, alkoxy, halide etc Reagents and condition: i) Pyridine, rt, 5-6h; ii) /V-Boc-1 ,3-propanediamine, HATU, DIPEA, DMF, rt, 4h; iii) ) 4N HCI in 1 ,4-dioxane, DCM, 0 oC to rt, 2h.
Synthetic procedure was the same as that described for the synthesis of substituents for Vanc- 54-56 & 64 (sulfonamide derivative 1.C.7).
1.C.10: Preparation of starting material for preparing 11 v, Vanc-33-35 (Biphenyl carboxylic acid derivatives)
Scheme 1 1
Figure imgf000091_0001
73= H, alkyl, cycloalkyl
Z8= Alkyl, halide, alkoxy, Sulphone, sulphonamide, triazole, substituted triazole, protected/unprotected
sugar etc
Reagents and conditions: i) /V-Boc-1 ,3-propanediamine, HATU, DIPEA, DMF, rt, 4h; ii) 4N HCI in 1 ,4-dioxane, DCM, 0 °C to rt, 2h; iii) For R= H; trimethylsilylacetylene, piperidine, Pd(PPh3)CI2, 85 °C, 30 min; iv) TBAF, THF, rt, 30 min.
Synthetic procedure was the same as that described for the synthesis of substituents for vancomycin analog 1 1 t (1 .C.6).
1.C.11: Preparation of starting material for preparing Vanc-24-27, 45, 52 (heteroaryl derivatives) Scheme 12
Figure imgf000091_0002
= CH=CH, CH
Y1= N, O, S
Z = Alkyl, halo, alkoxy, Sulfonyl, sulfonamidy, triazolyl, substituted triazolyl, protected/unprotected glycosyl etc Reagents and conditions: i) /V-Boc-1 ,3-propanediamine, HATU, DIPEA, DMF, rt, 4h; ii) 4N HCI in 1 ,4-dioxane, DCM, 0 °C to rt, 2h.
Synthetic procedure is as same as the synthesis of substituents for vancomycin analog 1 1 t (1 .C.6).
1.C.12: Preparation of starting material for preparing Vane- 31,32, 49, 50 & 73
Scheme 13
Figure imgf000092_0001
Z3= H , alkyl, cycloalkyl
Z8= Alkyl, halo, alkoxy, sulf nyl, sulfonamidyl, triazolyl, substituted triazolyl,
protected/unprotected glycosyl, etc
Reagents and conditions: i) /V-Boc-1 ,3-propanediamine, HATU, DIPEA, DMF, rt, 4h; ii) 4N HCI in 1 ,4-dioxane, DCM, 0 °C to rt, 2h; iii) For R= H; alkyne, piperidine, Pd(PPh3)CI2, 85 °C, 30 min; iv) TBAF, THF, rt, 30 min.
Synthetic procedure is as same as the synthesis of substituents for vancomycin analog 1 1 t (1 .C.6).
Example 2: General protocol for the screening vancomycin analogs for antibacterial activity.
The antibacterial activity of vancomycin and vancomycin analogs were tested on Gram-positive bacterial strains such as Bacillus subtilis ATCC6633, and Gram-negative bacterial strains such as Escherichia coli TOP10 by determination of the minimum inhibitory concentration (MIC). For all MIC assays the guidelines of the Clinical Laboratory Standards Institute (CLSI) were followed (M07-A9; edition 2012).
Example 3: General protocol for the cytotoxicity assay. Murine leukemia L1210, human T-lymphocyte CEM and human cervix carcinoma (HeLa) cells were suspended at 300,000-500,000 cells/mL of culture medium, and 100 μί of a cell suspension was added to 100 μί of an appropriate dilution of the test compounds in wells of 96- well microtiter plates. After incubation at 37 °C for two (L1210) or three (CEM, HeLa) days, the cell number was determined using a Coulter counter. The IC50 was defined as the compound concentration required to inhibit cell proliferation by 50%.
Example 4: Antibacterial activity of vancomycin analogs against vancomycin sensitive Gram-positive and Gram-negative model bacterial strains.
All synthesized vancomycin analogs were tested initially against the Gram-positive bacterial species Bacillus subtilis ATCC6633 and Gram-negative bacterial species Escherichia coli TOP10 because these strains act as model organism in many fundamental cell biology studies. The biological activity is expressed as minimum inhibitory concentration (MIC) and is presented in Table 2.
Generally, 2-fold increases or reductions are not considered as significant with a MIC-assay. Most of the analogs enhance the activity against Escherichia coli as compared to vancomycin. Among these compounds 11 g, 11s and 11t showed an 8-fold increase in the activity against Escherichia coli as compared to vancomycin, while retaining their activity against Bacillus subtilis. Most of the compounds exhibited a 4-fold increase in activity against Escherichia coli as compared to vancomycin. For B. subtilis changes were too small to be considered significant. Example 5: Vancomycin against Enterococcus.
Enterococcus are Gram-positive bacteria found mainly in the intestines of humans and domestic animals, and in the environment from soil, water, plants, wild animals, birds, insects etc {Hammerum, A. M. Clin Microbiol Infect 2012, 18, 619-625). Although a number of Enterococcus species have been identified, among them only two i.e., Enterococcus faecalis and Enterococcus. faecium are responsible for the majority of infections in human (Cetinkaya, V.; Falk, P.; Mayhall, C. G. Clin. Microbiol. Rev. 2000, 13, 686-707). Enterococci are currently a dominant nosocomial pathogens, and most common infections caused by them are urinary tract infections (UTIs) endocarditis, surgical wound infection, diarrhea, bacteremia and neonatal sepsis among hospitalized patients (Heintz, B. H.; Halilovic, J.; Christensen, C. L. Pharmacotherapy 2010, 30, 1136-1149 and Moscoso, M.; Domenech, M.; Garcia, E. Env. Microbiol. Rep. 2011, 3, 640-650). Enterococci are intrinsically resistant to a number of first-line antimicrobial agents such as β-lactams, cephalosporins, clindamycin and aminoglycosides {Anas, C. A.; Murray, B. Nat. Rev. Microbiol. 2012, 10, 266-278). Vancomycin was in clinical use for more than 30 years without the emergence of marked resistance for the treatment of bacterial infection caused by Enterococci but as mentioned before, due to its widespread clinical use, bacteria have been isolated that show resistance to vancomycin. The first bacterial isolate of vancomycin-resistant Enterococcus was isolated in late 1980's in Europe {Cetinkaya, Y.; Falk, P.; Mayhall, C. G. Clin. Microbiol. Rev. 2000, 13, 686-707 and Uttley, A. H. C; Collins, C. H.; Naidoo, J.; George. R. C. Lancet 1988, 1, 57-58). Hence, in last two decades, VRE has been emerged as a notorious pathogen all over the world and have seriously limited the choices for treating infections caused by these agents. Approximately one- third of the reported Enterococcal infections were due to vancomycin-resistant strains. One of the main reasons of resistance of these pathogens towards antibiotics may be the acquired mutation or by receipt of exogenous genetic material through the transfer of plasmids and transposons. This emergence of resistance in Enterococci has also led to the emergence of vancomycin-resistant S. aureus (VRSA) as a result of horizontal gene transfer from resistant Enterococci {Weigel, L. M.; Clewell, D. B.; Gill, S. R.; Clark, N. C; McDougal, L. K.; Flannagan, S. £.; Kolonay, J. F.; Shetty, J.; Killgore, G. £.; Tenover, F. C. Science 2003, 302, 1569-1571).
Example 6: Antibacterial activity of vancomycin analogs against VRE.
The minimum inhibitory concentrations (MICs) of vancomycin and vancomycin analogs were determined against vancomycin-sensitive Enterococcus faecalis HC-1909-5 (VSE, isolate from patient at the KU Leuven hospital, MICvancomycin = 1 -56 μΜ) and four patient isolates of vancomycin resistant Enterococcus (VRE-6, VRE-29, VRE-37 and VRE-53, isolated from patients at the KU Leuven hospital, MICvancomycin = 50-200; 800; >800; 400-800 μΜ, respectively). The MICs of the vancomycin analogs are either given in μΜ or expressed as fold- improvements in comparison to the MIC of vancomycin (MICVancomycin/MICVancomycin analog) (Table 3, 4 and 4a). All vancomycin analogs from Table 1 (except 11 d) show improvement in antibacterial activity in comparison to vancomycin on at least one of the tested strains (Table 4). Vancomycin analogs 11f, 11 n, 11t, 11 u, 11v and 11w demonstrated the best improvements, most pronounced against the most resistant VREs. Improvements from 8x up to 512 could be observed. Also VSE is more susceptible for 11 n, 11t, 11 u, 11v and 11w. Based on these results, a second series of compounds, as described in and selected from Tables 10-17, was tested. These compounds, named Vane 1 -38 (Table 1 a), were shown to have a lower MIC value against VSE, VRE-6, VRE-29, VRE-37 and VRE-53 in comparison to vancomycin, showing improvements between 2 and 512-fold. The most active vancomycin analogs include Vanc-14, Vanc-24, Vanc-31 , Vanc-33, Vanc-34, Vanc-35, Vanc-37 and Vanc-38.
Example 7: Confirmation of the resistance phenotype of selected pathogenic strains (VRE strains). To analyze the underlying resistance mechanism of the different VREs used here, we first tested the susceptibility of all the selected strains for teicoplanin and results indicated that all the strains were resistant to teicoplanin with MIC values of 256, ≥512 and 64 μg mL for strains VRE-29, VRE-37 and VRE-53, respectively (Table 6). VRE-6 appeared to be more intermediate resistant with a MIC value of 8 μg ml. According to previously published report (Hubbard, B. K.; Walsh, C. T. Angew. Chem. Int. Ed. 2003, 42, 730-765; 22; Gold H. S.; Moellering, Jr. R. C. N. Engl. J. Med. 1996, 335, 1445-1453; ; Cetinkaya, Y.; Falk, P.; Mayhall, C. G. Clin. Microbiol. Rev. 2000, 13, 686-707; Dutka-Malen, S.; Evers, S.; Courvalin, P. J. Clin. Microbiol 1995, 33, 24-27; Howden, B. P.; Davis, J. K.; Johnson, P. D. R.; Stinear, T. P.; Grayson, M. L. Clin. Microbiol. Rev. 2010, 23, 99-139) strains with the VanA type are resistant against teicoplanin with MIC values ranging between 16-512 μg mL while strains with the VanB, VanC, VanD and VanE phenotype are susceptible (MIC<0.5; or 4 in case of VanD) (Table 5). These data strongly indicate that the VRE-29, VRE-37 and VRE-53 have the VanA phenotype, whereas the mechanism of VRE-6 was unclear. Therefore, a PCR was performed using specific primers for the vanA gene as described in literature by Dutka-Malen et al. (Dutka-Malen, S.; Evers, S.; Courvalin, P. J. Clin. Microbiol 1995, 33, 24-27). The PCR results confirmed the presence of the vanA gene in all strains. The VanA phenotype can thus be assigned to all VREs.
Example 8: Vancomycin against Staphylococcus aureus.
Staphylococcus aureus is a Gram-positive bacterium normally found in the nose and/or on the skin of up to 30% of healthy people. Most of the time, it is not harmful but when S. aureus gets into the bloodstream, it can be fatal and cause a variety of infections from minor skin infections, chronic bone infections to devastating septicemia and endocarditis (Howden, B. P.; Davis, J. K.; Johnson, P. D. R.; Stinear, T. P.; Grayson, M. L. Clin. Microbiol. Rev. 2010, 23, 99-139).
Most isolates of S. aureus are susceptible to vancomycin, but due to its frequent use, some strains of this bacterium have become resistant to it. There are 3 resistant phenotypes have been described till date. These are: vancomycin-resistant Staphylococcus aureus (VRSA), vancomycin-intermediate resistant Staphylococcus aureus (VISA) and heterogeneous vancomycin-intermediate resistant Staphylococcus aureus (hVISA) (Howden, B. P.; Davis, J. K.; Johnson, P. D. R.; Stinear, T. P.; Grayson, M. L. Clin. Microbiol. Rev. 2010, 23, 99-139).
VRSA isolates were found to contain the vanA vancomycin resistance gene. This vanA gene is usually found in Enterococci and confers a high-level of resistance towards vancomycin. Mostly, patients who are at the major risk of infections by hVISA, VISA and VRSA are those with previous exposure to vancomycin for the treatment of MRSA and were also infected by vancomycin-resistant Enterococci (VRE) containing vanA. As already mentioned before, it is likely that the vanA operon gets transferred via plasmids or transposons from the VRE to the MRSA strain, resulting in the VRSA {Howden, B. P.; Davis, J. K.; Johnson, P. D. R.; Stinear, T. P. and Gold H. S.; Moellering, Jr. R. C. N. Engl. J. Med. 1996, 335, 1445-1453; b) Cetinkaya, V.; Falk, P.; Mayhall, C. G. Clin. Microbiol. Rev. 2000, 13, 686-707 and Dutka-Malen, S.; Evers, S.; Courvalin, P. J. Clin. Microbiol 1995, 33, 24-27).
VRSA strains (vancomycin MIC>16 g/ml) have properties which allow them to transfer resistance to susceptible strains or other organisms while VISA strains (vancomycin MIC = 4- 8μg ml) are characterized by a resistance mechanism that is not transferable to susceptible strains and is usually associated with vancomycin exposure (Howden, B. P.; Davis, J. K.; Johnson, P. D. R.; Stinear, T. P. and Grayson, M. L. Clin. Microbiol. Rev. 2010, 23, 99-139 and Appelbaum, P. C. Int. J. Antimicrob. Agents 2007, 30, 398-408 ; Division of Community and Public Health Section: 4.0 Diseases and Conditions).
Example 9: Antibacterial activity of vancomycin analogs against vancomycin susceptible Staphylococcus aureus (VSSA), VRSA and VISA strains.
The minimum inhibitory concentrations (MICs) of vancomycin analogs were determined against vancomycin-sensitive Staphylococcus aureus Rosenbach ATCC 6538 (VSSA; 0.78 μΜ), vancomycin-intermediate resistant Staphylococcus aureus (VISA HIP5827; Smith et al., New Engl. J. Med. 1999, 340, 517-523; MICvancomycin = 3.13 μΜ and VISA/P1V44; Denis et al., Journal of antimicrobial chemotherapy 2002, I50, 383-391, MICvancomycin = 1 -56 μΜ) and vancomycin- resistant Staphylococcus aureus (VRS1/HIP1 1714, MMWR Morb Mortal Wkly Rep 2002, 51, 565-567; MI Cvancomycin = 100 μΜ). The MICs of the vancomycin analogs are either given in μΜ or expressed as fold-improvements in comparison to the MIC of vancomycin
(MICvancomycin/M ICvancomycin analog) (Table 4a and Table 7).
The most active vancomycin analogs 11f, 11 n, 11t-w, found during the first previous screening against VRE were selected to test against VSSA, VRSA and VISA. Apart from 11f, all these analogs are 4 to 8 times more active against VSSA, 2-4 times more active against VISA P1 V44 and 2-8 times more active against VISA HIP5827K. The largest improvements (up to 128 times) are obtained against the most resistant strain (VRS1/HIP1 1714), reducing the MIC of 11v against a vancomycin-resistant strain (VRSA) to the same level as vancomycin against a sensitive strain (VSSA).
Vancomycin analogs from the second series (Vanc-1 to Vanc-38) generally perform better in terms of antibacterial activity with improvements from 4 to 32 times against VSSA, from 2 to 64 times against VISA HIP5827K and 4 to 128 times against VRSA. The most active vancomycin analogs include Vanc-14, Vanc-24, Vanc-31 , Vanc-33, Vanc-34, Vanc-35, Vanc-37 and Vanc- 38. Example 10: Biological activity of vancomycin analogs against Gram-negative pathogens.
The six most active conjugates from the 11 a-w series were also tested against Gram-negative strains Pseudomonas aeruginosa PA01 , Acinetobacter baumannii RUH875, Klebsiella pneumoniae ATCC13883 and Salmonella typhimurium LT2 (Table 8). In general, the modified vancomycin analogs do not provide an improvement of clinical significance, as the MIC values all remain high. One exception is analog 11t that exhibits an 8-fold gain in activity against S. Typhimurium LT2 as compared to vancomycin without showing any cytotoxicity (mentioned in example 1 1 ). Although the MIC value of this vancomycin analog was high (50 μΜ), it is an indication that further modifications of the vancomycin analogs might improve the bioactivity against Salmonella Typhimurium.
Example 11 : Cytotoxicity Assay.
IC50 is the concentration of a substance that results in a reduced cell number (50%) after a period of growth. This reduction is due to the cytotoxicity of the tested substance. The most active vancomycin analogs were evaluated for their cytotoxic activity against three different cell lines, specifically murine leukemia cells (L1210), human T-lymphocyte cells (CEM) and human cervix carcinoma (HeLa) cell lines (Tables 9 and 9a) and Table 21 .
Example 12: other compounds according to the invention
To expand the selection of vancomycin analogs and identify additional molecules with low toxicity for mammalian cells but high efficacy against both vancomycin-resistant and vancomycin-sensitive strains, a population of hydrophobic vancomycin analogs were synthesized. The synthesized compounds (Table 18 and Table 19) combined a variety of rigid aromatic and heterocyclic ring systems and were based on SAR analysis of vancomycin analogs in Table 1 a. Notably, as particular molecules with the highest hydrophobicity show toxicity towards mammalian cells (see Tables 9 and 9a), the new compounds combined hydrophilic regions, for example, sugar moieties, with the hydrophobic substituent groups on the C-terminus of vancomycin.
The following scheme shows the synthesis route of the vancomycin analogs which have a combination hydrophilic/hydrophobic substituent. Rb is an aliphatic chain which may have a chain length of more than 2 carbons, for example, 2, 3, 4, 5, or 6 carbons, while Rc is an aromatic, aliphatic, or heterocyclic ring system.
Figure imgf000098_0001
Tables 20 shows the structures of exemplary analogs (named Vane 39-77), and Table 21 summarizes the biological activities.
Example 14: Discussion of antibacterial activity.
Bioactivity of vancomycin analogs against VRE.- As per tables 3 and 4, the most promising results were obtained with aliphatic analog 11 f and aromatic analogs 11 n, 11t, 11 u, 11v and 11w. Against VRE strains, aromatic analogs proved more effective as compared to aliphatic analogs.
It was also observed that increase in length and hydrophilicity dropped the potential of these analogs. For example, compound 11 d has a PEG derivatized substituent group which is comparatively hydrophilic and longer in length than the other substituent groups. However, it did not show any marked improvement against VRE strains while in contrast, its activity dropped by a 4-fold against sensitive strains as compared to vancomycin. Similarly, compound 11 a and 11 c possessing hydrophilic PEG derivatized substituent group, exhibited no significant improvement in the screening results.
Among all the selected aromatic analogs, the stilbene based analog 11 u proved to be the most active against tested strains. It showed a 4-fold increase in activity against sensitive strain £. faecalis (Table 3). Notably, a 32- to 512-fold increase in activity of 11 u was recorded against various VRE strains (Table 4). However, in the cytotoxicity assay, this compound was found to be toxic on tested murine leukemia cells (L1210), human T-lymphocyte cells (CEM) and human cervix carcinoma cells (HeLa) with IC50 values almost equal to its MIC value against VRE's (Table 9).
Similarly, compound 11v having a biphenyl substituent group maintained its consistency on all tested strains by exhibiting a 32-fold gain in activity against sensitive strain E. faecalis (MIC 25 nM) as compared to vancomycin (MIC 780 nM). This compound exhibited a 32- to 128-fold increase in activity against VRE strains (with MIC ranging between 0.7-25 μΜ). However, it was also found to be toxic (IC50 value 5-70 μΜ). But as its effective concentration on the E. faecalis strain is almost 200 times less than its IC50 dose, this compound might be selectively or specifically applied for the inhibition of bacterial infections caused by E. faecalis.
Analogs 11 n and 11t were not cytotoxic (>250 μΜ), but were active against VRE at comparatively higher concentrations (3-50 μΜ). These two analogs exhibited an 8-fold increase in activity against sensitive strain as compared to vancomycin with MIC value 0.1 μΜ. Compound 11 n displayed 32 to 128-fold increase in activity against tested resistant strains and 11t exhibited 16 to 64-fold rise in antibacterial activity as compared to vancomycin.
Naphthyl substituted vancomycin analog 11w was also found considerable active against £. faecalis as well as against tested VRE strains. But, against some of the resistant strains, its MIC was closer to its cytotoxic value. Analog 11 f was not cytotoxic; however, the improvement of the antibacterial activity is more limited in comparison to the analogs substituted with aromatic substituent groups. We believe that the further optimization of these analogs in terms of substituent variation and by SAR study, bioactivity of these analogs can be certainly improved. Bioactivity of vancomycin analogs against VSSA, VRSA and VISA. - The most active vancomycin analogs (11f, 11 n, 11t-w) were tested against the VSSA, VRSA and VISA strains (Table 7). Against VSSA, analogs 11 n, 11 u 11v and 11w exhibited an 8-fold gain in activity while 11t demonstrated a 4-fold improvement as compared to unmodified vancomycin. Aliphatic analog 11 f did not show any improvement. Here also the aromatic analogs proved better in terms of bioactivity.
Against VRSA, 64-128 fold increase in activity was observed by compounds 11 n, 11 u, 11v and 11w as compared to vancomycin. Compound 11f and 11t did show a more limited improved inhibition (8-fold improvement) as compared to other vancomycin aromatic analogs.
According to the cytotoxic assay of these analogs, it was found that analogs 11f, 11 n and 11t did not demonstrate cytotoxicity at the concentration of their MIC values against VSSA, VISA and VRSA strains (Table 9). However, in case of 11v, the rather limited margin between the MIC and IC50 requires additional clinical testing before it may be considered as safe enough. Practically, in analogs 11 n and 11w, cell proliferation was poorly or not at all inhibited at a concentration ranging between 50 to >250 μΜ, which is notably higher than that required to display antibacterial activity as these analogs display MIC value 0.097 μΜ in case of susceptible stain and MIC value 1 .56 μΜ in case of resistant strain. Analog 11 u displays bacterial inhibition at subtoxic concentrations. Although analog 11v exhibits better inhibition with MIC 0.78 μΜ (comparable to the MIC value of vancomycin against sensitive strain) this concentration is too close to the toxic dose (5.6 ±1 .1 μΜ on human T-lymphocyte cells (CEM)). In contrast, 11f and 11t exhibited bacterial inhibition against VRSA at a comparatively higher concentration (12.5 μΜ) but were not found toxic.
Against vancomycin intermediate resistant strains (VISA), a 2- to 4-fold improvement in the antibacterial activity of the tested vancomycin analogs (except for 11f) was observed (Table 7). Against these strains, all screened compounds (except 11 u) were not found toxic at bacterial growth inhibition concentrations.
On the basis of the results obtained, it can be concluded that hydrophobicity is necessary for the enhancement of the antibacterial activity of vancomycin conjugates against vancomycin resistant and susceptible strains. It can also be postulated that an additional aromatic ring could be beneficial to improve the bio-activity of vancomycin. Our cytotoxicity results indicate that the analogs 11 u (with stilbene derivatized substituent group) and 11v (with biphenyl derivatized substituent group) show a higher cytotoxicity with IC50-values either close or equal to the minimal inhibition dose against VRE and VRSA. However, it is possible that variations might alter their cytotoxicity.
Vancomycin-naphthyl derivative 11w is not toxic but its inhibitory concentration against VRE is close to the cytotoxic value. We hypothesize that the variation in the substitution pattern of the naphthyl ring might be fruitful to overcome the toxicity. More diversity can be brought on the phenyl as well as the cinnamic acid substituent groups to improve their activity.
Overcoming VanA resistance is challenging because it requires that glycopeptide analogs be able to kill bacterial cells which express D-Ala-D-Lac as terminal residues of the peptide moiety of peptidoglycan precursors {Kerns, R.; Dong, S. D.; Fukuzawa, S.; Carbeck, J.; Kohler, J.;
Silver, L; Kahne, D. J. Am. Chem. Soc. 2000, 122, 12608-12609; Chen, Z; Eggert, U. S.;
Dong, S. D.; Shaw, S. J.; Sun, B.; LaTour, J. V.; Kahne, D. Tetrahedron 2002, 58, 6585-6594; and Leimkuhler, C; Chen, L; Barrett, D.; Panzone, G.; Sun, B.; Falcone, B.; Oberthur, M.; Donadio, S.; Walker, S.; Kahne, D. J. Am. Chem. Soc. 2005, 127, 3250-3251) In our case, vancomycin analogs are working proficiently against resistant bacterial strains possessing VanA phenotype.
Example 15: The compounds according to the invention
The invention provides vancomycin analogs which are active antimicrobials against resistant bacterial strains possessing VanA phenotype. Table 10-17 provides a class of hydrophobic vancomycin analogs with different rigid aromatic and heterocyclic ring systems at the position Ra in the general structure of formula (1 ).
The invention also provides compounds with general formulation vancomycin-NH-R1-NH-R2 represented by the following general formula (2) or a pharmaceutically acceptable salt thereof, wherein Rb: is an aliphatic chain composed of 2-4 carbon atoms (example CH2CH2, CH2CH2CH2, COCH2, etc.) and Rc: Aromatic substitution/heterocyclic compound or some selected aliphatic chains as demonstrated in the tables 12 to 17, and Table 1 a.
Suitable amine for reaction with the carboxyl group of vancomycin A are listed in Table 1.
Table 1 : Structure of various substituent roups
Figure imgf000101_0001
Figure imgf000102_0001
Examples of compounds of formula (2) according to the invention are listed in Table 1 a. Table 1 a
Figure imgf000102_0002
Figure imgf000103_0001
b Rc Name
Figure imgf000104_0001
Figure imgf000105_0001
Example 16: Biological activity of tested compounds
The antibacterial activity and cytotoxicity of the tested compounds is shown in Tables 2 to 9a.
Table 2: Antibacterial activity of vancomycin analogs (series 11 a-w) against model Gram- positive (B. subtilis ATCC6633) and Gram-negative (£. coli TOP10J bacterial strains.
Entry Product MIC (μΜ) MICvan/MICi
B. subtilis E. coli B. subtilis E. coli
Vancomycin 0.375 100 1 1
1 11 a 0.75 50 0.5 2
2 11 b 0.375 25 1 4
3 11e 0.375 50 1 2
4 11f 0.187 25 2 4
5 11 g 0.375 12.5 1 8
6 11 h 0.375 25 1 4
7 11 i 0.187 25 2 4
8 11 k 0.750 50 0.5 2
9 111 0.187 25 2 4
10 11 m 0.375 25 1 4
1 1 11 n 0.187 50 2 2
12 11 o 0.75 12.5 0.5 8
13 11 r 0.375 25 1 4
14 11s 0.375 12.5 1 8
15 11t 0.375 12.5 1 8
16 11 u 0.750 100 0.5 1
17 11v 0.187 50 2 2
18 11 w 0.375 25 1 4
MICvan/MIC,: ratio of antibacterial activity of vancomycin to the vancomycin analogs, tested against Gram-positive and Gram-negative bacterial strains.
Table 3: Antibacterial activity of vancomycin analogs (11 a-w) against vancomycin sensitive
Enterococcus faecalis HC-1909-5 (VSE) and vancomycin resistant Enterococcus (VRE) strains expressed as MIC (expressed in μΜ). MIC (μΜ)
Entry Product £ faecalis VRE-6 VRE-29 VRE-37 VRE-53
1 Vancomycin 0.78 100 800 >800 400
2 11a 1.56 100 >200 >200 50
3 11b 0.39 50 >200 >200 25
4 11c 0.78 200 >200 >200 100
5 11d 3.125 >200 >200 >200 >200
6 11e 0.39 50 >200 >200 100
7 11f 0.78 6.25 100 100 12.5
8 11g 0.78 100 >200 >200 50
9 11h 0.78 25 >200 >200 50
10 11i 0.39 25 >200 >200 100
11 11j 0.78 50 200 100 50
12 11k 0.78 100 >200 >200 50
13 111 0.78 200 >200 >200 100
14 11m 0.78 100 >200 >200 100
15 11n 0.1 3.125 6.25 25 6.25
16 11o 0.39 100 >200 >200 50
17 11r 0.39 100 >200 >200 50
18 11s 0.78 100 >200 >200 50
19 11t 0.10 6.25 25 50 6.25
20 11u 0.19 3.125 1.5 12.5 6.25
21 11v 0.025 0.75 6.25 25 3.125
22 11 w 0.05 3.125 12.5 25 3.125
£ faecalis: Enterococcus faecalis HC-1909-5 (VSE).
Table 4: Ratio of MICs of vancomycin to vancomycin analogs (11a-w) against VRE
(MICvan/MICi).
MICvan/MICi
Entry Product £. faecalis VRE-6 VRE-29 VRE-37 VRE-53
1 11a 0.5 1 - - 8
2 11b 2 2 - - 16
3 11c 1 0.5 - - 4
4 11d 0.25 <0.5 - - -
5 11e 2 2 - - 4
6 11f 1 16 8 ≥8 32
7 Hg 1 1 - - 8
8 11h 1 4 - - 8 9 11 i 2 4 - - 4
10 11j 1 2 4 ≥8 8
1 1 11 k 1 1 - - 8
12 111 1 0,5 - - 4
13 11 m 1 1 - - 4
14 11 n 8 32 128 ≥32 64
15 11 o 2 1 - - 8
16 11 r 2 1 - - 8
17 11s 1 1 - - 8
18 11t 8 16 32 ≥16 64
19 11 u 4 32 512 ≥64 64
20 11v 32 128 128 ≥32 128
21 11 w 16 32 64 ≥32 128
Table 4a: Ratio of the MICs of vancomycin to vancomycin analogs Vane 1 -38 against VRE (MICvan/MICi). nt= not tested.
Code Bacterial strains
VSE VRE-6 VRE-29 VRE-37 VRE-53 VSSA VISA VF
1 11f 1 16 8 ≥8 32 1 1 8
2 11 n 8 32 128 ≥32 64 8 4 64
3 11t 8 16 32 ≥16 64 4 2 8
4 11 u 4 32 512 ≥64 64 8 4 64
5 11v 16 64 256 ≥32 128 32 64 64
6 11 w 16 64 128 ≥32 128 8 16 64
7 Vanc-1 nt 2 <16 nt 16 nt 4 4
8 Vanc-2 nt 4 64 nt 16 nt 4 8
9 Vanc-3 nt 4 32 nt 16 nt 4 4
10 Vanc-4 nt 16 128 nt 64 nt 8 16
1 1 Vanc-5 nt 8 64 nt 32 nt 8 8
12 Vanc-6 nt 16 128 nt 32 nt 8 32
13 Vanc-7 nt 4 64 nt 32 nt 4 8
14 Vanc-8 nt 4 32 nt 32 nt 2 4
15 Vanc-9 nt 8 32 nt 16 nt 2 4
16 Vanc-10 nt 8 64 nt 32 nt 4 8
17 Vanc-11 nt 16 128 nt 32 nt 4 8
18 Vanc-12 nt 8 64 nt 32 nt 8 8
19 Vanc-13 nt 32 256 nt 64 nt 8 32
20 Vanc-14 16 32 256 nt 128 8 32 32
21 Vanc-15 nt 8 64 nt 16 nt 2 8
22 Vanc-16 nt 4 <16 nt 16 nt 4 4
23 Vanc-17 nt 8 32 nt 16 nt 4 8
24 Vanc-18 nt 4 32 nt 16 nt 4 4 25 Vanc-19 nt 16 64 nt 16 nt 1 8
26 Vanc-20 nt 32 128 nt 32 nt 8 32
27 Vanc-21 nt 32 64 nt 32 nt 4 64
28 Vanc-22 nt 32 64 nt 16 nt 2 32
29 Vanc-23 nt 16 64 nt 16 nt 4 16
30 Vanc-24 8 64 64 nt nt 4 16 64
31 Vanc-25 nt 64 128 nt nt nt 8 32
32 Vanc-26 nt 16 128 nt nt nt 8 32
33 Vanc-27 nt 16 64 nt nt nt 8 16
34 Vanc-28 nt 16 128 nt nt nt 8 32
35 Vanc-29 nt 32 128 nt nt nt 8 32
36 Vanc-30 nt 16 64 nt nt nt 8 32
37 Vanc-31 4 128 512 nt nt 16 64 128
38 Vanc-32 nt 16 64 nt nt nt 4 16
39 Vanc-33 16 32 128 nt nt 16 16 128
40 Vanc-34 16 128 256 nt nt 16 32 128
41 Vanc-35 16 128 512 nt nt 32 64 64
42 Vanc-36 nt 32 64 nt nt nt 8 32
43 Vanc-37 8 32 128 nt nt 8 32 64
44 Vanc-38 16 128 512 nt nt 16 64 128
VSE: £ faecalis: Enterococcus faecalis HC-1909-5
Table 5: Characteristics of phenotypes of glycopeptide-resistant Enterococci [Cetinkaya, Y.; Falk, P.; Mayhall, C. G. Clin. Microbiol. Rev. 2000, 13, 686-707).
Characteristic Phenotype
VanA VanB VanC VanD VanE
Vancomycin 64 to 4 to 1024 2 to 32 128 16
MIC^g/mL) >1000
Teicoplanin 16 to 512 <0.5 <0.5 4 0.5
MIC^g/mL)
Most frequent £ faecium £ faecalis £. gallinarum £ faecium £ faecalis
Enterococcal E. faecalis E. faecium E. casseliflavus
species
Genetic Acquired Acquired Intrinsic Acquired Acquired determinant
Transferable Yes Yes No No No
Table 6: Antibacterial activity of teicoplanin on tested VRE strains.
MIC Teicoplanin ^g/mL)
£ faecalis VRE-6 VRE-29 VRE-37 VRE-53
<0,25 8 256 ≥512 64
VanA VanA VanA VanA Second raw of this table indicates the resistance phenotype of selected pathogenic strains which is comparable to prior published results mentioned in Table 5 (the VanA mechanism of VR6 was confirmed by PCR).
Table 7: Antibacterial activity of vancomycin analogs 11f, 11 n, 11t-w against VSSA, VRSA and VISA strains expressed as MIC in μΜ and as fold-improvement in comparison to vancomycin).
Figure imgf000109_0001
V: vancomycin; MICVan/MICi: ratio of antibacterial activity of vancomycin to the vancomycin analogs tested against vancomycin susceptible and resistant Staphylococcus aureus; VSSA: vancomycin-susceptible Staphylococcus aureus Rosenbach ATCC6538; VRS1/HIP1 1714: vancomycin-resistant S. aureus (VRSA); VISA/P1V44 & VISA/HIP5827: vancomycin- intermediate resistant Staphylococcus aureus.
Table 8: Biological activity of vancomycin analogs 11f, 11 n, 11t-w against different Gram- negative pathogenic bacteria.
MIC (μΜ)
P. aeruginosa A. baumannii K. pneumoniae S. Typhimurium
Entry. Product
PA01 RUH875 ATCC13883 LT
1 Vancomycin >800 100 800 400
2 11f >800 400 800 200
3 11 n >800 >800 >800 >800
4 11t 400 200 >800 50
5 11 u >800 >800 >800 >800
6 11v >800 >800 >800 >800
7 11 w >800 >800 >800 >800
P. aeruginosa: Pseudomonas aeruginosa; A. baumannii: Acinetobacter baumannii; K. pneumoniae: Klebsiella pneumoniae; S. Typhimurium: Salmonella Typhimurium. Table 9: Inhibitory effects of vancomycin analogs 11f, 11n, 11t-won the proliferation of tumour cells (expressed as IC5o in μΜ).
IC50 (μΜ)
Entry Product L1210 CEM HeLa
1 11f >250 >250 >250
2 11n >250 >250 >250
3 11t >250 >250 >250
4 11u 5.7 ±0.7 1.4 ± 0.6 15± 1
5 11v 10±4 5.6 ± 1.1 70 ±8
6 11 w 77 ± 17 60 ± 10 75 ±20
7 Vancomycin >250 >250 >250
IC50: 50% inhibitory concentration for cell proliferation.
Table 9a: Inhibitory effects of vancomycin analogs from the Vanc1-38 series on the proliferation of tumour cells. Data is expressed as IC5o in μΜ.
Figure imgf000110_0001
50% inhibitory concentration.
Example 17: Examples of compounds according to the invention Suitable compound of formula (1 ) can be selected from the group comprising compound of formula (1 ) wherein Ra is selected from a group of formula (A1 ), (A2), or (A3), as defined in the below table 10.
Table 10: Substitutions at aniline cinnamic acid and 2-naphtoic acid derivatives.
Figure imgf000111_0001
*substitution is not limited to above structures, more substituents can be included.
Suitable compound of formula (1 ) can be selected from the group comprising compound formula (1 ) wherein Ra is selected from a group as defined in the below table 1 1. Table 11 : Structure of some heterogeneous substituent groups to synthesize new vancomycin analo s.
Figure imgf000112_0002
*substitution is not limited to above structures, more substituents can be included.
Suitable compound of formula (1 ) can be selected from the group comprising compound formula (1 ) wherein Ra is selected from a group of formula (A1 ), (A2), (A3), (A4), (A5), and (A6), as defined in the below table 12.
Table 12:
Figure imgf000112_0001
Figure imgf000113_0001
(A3) wherein R6 is a group (A6) as defined in Table 16
(A5) wherein R is a group as as defined in Table 17
defined in Table 17
Table 13: Variation in moieties.
Figure imgf000113_0002
Table 14: Variation in moieties.
Figure imgf000114_0001
Suitable amine for reaction with the carboxyl group of vancomycin A are listed in Table 15.
.Table 15: Structure of some heterocyclic/miscellaneous substituent groups to synthesize the new vancomycin analogs of present invention.
No. Structure No. Structure
NH2 n= 1 , 2, 3
1 H 5 (n=2, gives Vanc-25)
Figure imgf000115_0001
Table 17: Variation in moieties Ra.
Figure imgf000115_0002
Figure imgf000116_0001
Suitable compound of formula (2) can be selected from the group comprising compound formula (2) wherein Rb and Rc are as defined in the below table 18.
Table 18: New vancomycin analogs of formula (2) (combination hydrophilic/hydrophobic substituent roup)
Figure imgf000116_0002
Figure imgf000117_0001
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
Figure imgf000121_0001
Suitable compound of formula (2) can be selected from the group comprising compound formula (2) wherein Rb and Rc are as defined in the below table 19.
Table 19 New vancomycin analogs
Figure imgf000121_0002
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000125_0001
Table 20 as described in the numbered statements shows exemplary vancomycin analogs
(named Vane 39-77).
Example 17: Biological activity of the tested compounds
Table 21 Summary of biological data
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
(nd: not determined)
Example 18
Exposure of bacteria to novel antibacterials should elicit no or only limited resistance development to avoid rapid and wide accumulation of resistant strains in future. Possible resistance development through spontaneous genetic mutations was tested for three selected vancomycin-analogs (Vanc-N, Vanc-39, Vanc-42) and compared to daptomycin, a novel antibacterial that is used as therapeutic alternative to treat vancomycin-resistant strains. Vancomycin-resistant enterococci (strain VRE-29) were serially exposed to subinhibitory doses of the compounds and changes in the minimum inhibitory concentration (MIC) were monitored over twenty cycles.
The MIC was determined according to the guidelines of the Clinical and Laboratory Standards Institute (CLSI), specifically document M07-A9 (edition 2012), using the broth microdilution method. Specifically, two-fold dilution series of the antibiotics in ultrapure water were prepared and mixed with cells in Mueller-Hinton medium, having a final concentration of approximately 5x10e+5 cells/ml (total volume 100 μΙ). The multiwell plates were incubated for 24h at 37°C. A negative control (medium only) and a positive control (medium and cells, no antibiotic) were included. The MIC was the lowest concentration that gave complete inhibition of the growth, assessed by the naked eye. Cells grown at subinhibitory concentration (MIC/2, or in some occasions at MIC/4, if growth at MIC/2 was too limited) were 1000-fold diluted and used as inoculum in a subsequent MIC assay. This was repeated up to 20 cycles and changes in MIC were recorded for Vanc-N, Vanc-39, Vanc-42 and daptomycin. Negative and positive controls were negative and positive, respectively, throughout the whole experiment.
The MIC did not increase or increased two-fold for the vancomycin-analogs (two-fold changes in a MIC assay are generally considered to be part of the normal intrinsic variation of the assay) (Figure 1 shows the results of the resistance development study of vancomycin analogs against VRE-29). Highly selective exposure to subinhibitory doses of the vancomycin-analogs did thus not lead to the recovery of resistant strains after 20 cycles. Exposure to daptomycin selected for cells with a 4-fold increased MIC after 4 cycles and a 8-fold increase after 15 cycles. This example demonstrates that there is a low probability of resistance development against Van-N, Vanc-39 and Vanc-42 by vancomycin-resistant enterococci through randomly occurring genetic mutations, in contrast to daptomycin. Resistance development by vertical transfer can thus be considered very unlikely for vancomycin-analogs.
Particular and preferred aspects of the invention are set out in the accompanying independent and dependent claims. Features from the dependent claims may be combined with features of the independent claims and with features of other dependent claims as appropriate and not merely as explicitly set out in the claims.
Thus, the claims following the detailed description are hereby expressly incorporated into this detailed description, with each claim standing on its own as a separate embodiment of this invention.

Claims

Claims
1. A compound of formula (1 ), or a pharmaceutically acceptable salt thereof
Figure imgf000132_0001
wherein
Ra is a group of formula -NH-Rb-NH-Rc, wherein
Rb is a group of formula -Rd-, or -Rd-CO-, wherein the right side of -Rd-CO- is attached to -NH-Rc;
Rc is -Re, or -CO-Re;
Rd is a Ci-i2alkylene,
or Rd together with one or both of the -NH- form a saturated or 4-, 5-, or 6-membered ring;
Re is selected from the group consisting of C2-6alkynyl, C6-i4aryl, C6-i4arylCi-6alkyl, C6- i4arylC2-6alkenyl, C6-i4arylC2-6alkynyl, C6-i4arylC2-6alkenylC6-i4aryl; heteroaryl, -NH-C3- i2cycloalkyl, and wherein said C2-6alkynyl; C6-i4aryl; C6-i4arylC2-6alkenyl, C6-i4arylC2- 6alkenylC6-i4aryl; heteroaryl, -NH-C3-i2cycloalkyl, can be unsubstituted or substituted with one or more Z1;
each Z1 is independently selected from the group consisting of hydroxyl, halo, nitro, Ci_ i2alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, haloCi-i0alkyl, Ci-6alkyloxy, Ci_ 6alkylamino, haloCi-i0alkyloxy, C6-i4aryl, C6-i4aryloxy, C6-i4arylC2-6alkenyl, C6-i4arylC2- 6alkynyl, heterocyclyl, heteroaryl, -OZ3, -C(=0)NZ4Z3, -NZ4(C=0)Z3, -NZ4Z3, -N+Z2Z4Z3 X" , -NZ4S(=0)2Z3, -S(=0)2Z3, -S(=0)2OZ3, glycosyl or an ester thereof, and phosphateCi. 6alkyl; and wherein each of said Ci-i2alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, haloCi-i0alkyl, Ci-6alkyloxy, Ci-6alkylamino, haloCi-i0alkyloxy, C6-i4aryl, C6-i4aryloxy, C6- i4arylC2-6alkenyl, C6-i4arylC2-6alkynyl, heterocyclyl, heteroaryl, glycosyl or ester thereof; can be unsubstituted or substituted with one or more Z2; or two adjacent Z2 can be taken together to form a C3-7cycloalkyl, or a 5-, 6-, or 7-membered heterocyclyl or heteroaryl ring, which can be unsubstituted or substituted with one or more Z2 ;
each Z2 is independently selected from the group consisting of hydroxyl, halo, nitro, Ci_ i2alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, haloCi-i0alkyl, Ci-6alkyloxy, Ci_
6alkylamino, haloCi-i0alkyloxy, C6-i4aryl, C6-i4aryloxy, C6-i4arylC2-6alkenyl, C6-i4arylC2-
6alkynyl, heterocyclyl, heteroaryl, -OZ3, -C(=0)NZ4Z3, -NZ4(C=0)Z3, -NZ4Z3, -N+Z2Z4Z3 X"
, -NZ4S(=0)2Z3, -S(=0)2Z3, -S(=0)2OZ3, glycosyl or an ester thereof, and phosphateCi.
6alkyl; and wherein each of said Ci-i2alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, haloCi-i0alkyl, Ci-6alkyloxy, Ci-6alkylamino, haloCi-i0alkyloxy, C6-i4aryl, C6-i4aryloxy, C6- i4arylC2-6alkenyl, C6-i4arylC2-6alkynyl, heterocyclyl, heteroaryl, glycosyl or ester thereof; can be unsubstituted or substituted with one or more Z3;
each Z3 is independently selected from the group consisting of hydrogen, hydroxyl, halo, nitro, Ci-i2alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, haloCi-i0alkyl, Ci-6alkyloxy, Ci_ 6alkylamino, haloCi-i0alkyloxy, C6-i4aryl, C6-i4aryloxy, C6-i4arylC2-6alkenyl, C6-i4arylC2-
6alkynyl, heterocyclyl, heteroaryl, -OZ3, -C(=0)NZ4Z3, -NZ4(C=0)Z3, -NZ4Z3, -N+Z2Z4Z3 X" , -NZ4S(=0)2Z3, -S(=0)2Z3, -S(=0)2OZ3, glycosyl or an ester thereof, and phosphateCi. 6alkyl; and wherein each of said Ci-i2alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, haloCi-i0alkyl, Ci-6alkyloxy, Ci-6alkylamino, haloCi-i0alkyloxy, C6-i4aryl, C6-i4aryloxy, C6- i4arylC2-6alkenyl, C6-i4arylC2-6alkynyl, heterocyclyl, heteroaryl, glycosyl or ester thereof; can be unsubstituted or substituted with one or more Z4;
each Z4 is independently selected from the group consisting of hydrogen, hydroxyl, halo, nitro, Ci-i2alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, haloCi-i0alkyl, Ci-6alkyloxy, Ci_ 6alkylamino, haloCi-i0alkyloxy, C6-i4aryl, C6-i4aryloxy, C6-i4arylC2-6alkenyl, C6-i4arylC2- 6alkynyl, heterocyclyl, heteroaryl, -OZ3, -C(=0)NZ4Z3, -NZ4(C=0)Z3, -NZ4Z3, -N+Z2Z4Z3 X"
, -NZ4S(=0)2Z3, -S(=0)2Z3, -S(=0)2OZ3, glycosyl or an ester thereof, and phosphateCi. 6alkyl; and wherein each of said Ci-i2alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, haloCi-i0alkyl, Ci-6alkyloxy, Ci-6alkylamino, haloCi-i0alkyloxy, C6-i4aryl, C6-i4aryloxy, C6- i4arylC2-6alkenyl, C6-i4arylC2-6alkynyl, heterocyclyl, heteroaryl, glycosyl or ester thereof; can be unsubstituted or substituted with one or more Z5; or Z4 and Z3 can be taken together to form a C3-7cycloalkyl, or a 5-, 6-, or 7-membered heterocyclyl, which can be unsubstituted or substituted with one or more Z5;
each Z5 is independently selected from the group consisting of hydrogen, K, Na , hydroxyl, halo, nitro, Ci-i2alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, haloCi-i0alkyl, Ci_ 6alkyloxy, Ci-6alkylamino, haloCi-i0alkyloxy, C6-i4aryl, C6-i4aryloxy, C6-i4arylC2-6alkenyl, C6-i4arylC2-6alkynyl, heterocyclyl, heteroaryl, -OZ3, -C(=0)NZ4Z3, -NZ4(C=0)Z3, -NZ4Z3, - N +Z2Z4Z3 χ. .NZ4S (=0 )2Z3j .S (=o)2z3, -S(=0)2OZ3, glycosyl or an ester thereof, and phosphateCi-6alkyl; and
X is a halogen;
with the proviso that when Rb is -CH2-C(=0)-, Rc is not -CH2-C≡CH, when the right side of -CH2-C(=0)-, is attached to -NH-RC.
2. The compound according to claim 1 , having general formula (2) wherein Rb and Rc, have the same meaning as that defined in claim 1 ,
Figure imgf000134_0001
3. The compound according to any of claims 1 or 2, wherein
Ra is a group of formula -NH-Rb-NH-Rc, wherein
Rb is a group of formula -Rd-, or -Rd-CO-, wherein the right side of -Rd-CO- is attached to -NH-Rc;
Rc is -Re, or -CO-Re;
Rd is a Ci-6alkylene,
or Rd together with one or both of the -NH- form a saturated or 5-, or 6-membered ring; Re is selected from the group consisting of C2-6alkynyl, C6-i4aryl, C6-i4arylCi-6alkyl, C6- i4arylC2-6alkenyl, C6-i4arylC2-6alkynyl, C6-i4arylC2-6alkenylC6-i4aryl; heteroaryl, -NH-C3- i2cycloalkyl, and wherein said C2-6alkynyl; C6-i4aryl; C6-i4arylC2-6alkenyl, C6-i4arylC2- 6alkenylC6-i4aryl; heteroaryl, -NH-C3-i2cycloalkyl, can be unsubstituted or substituted with one or more Z1;
each Z1 is independently selected from the group consisting of hydroxyl, halo, nitro, Ci_ 8alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, haloCi-6alkyl, Ci-6alkyloxy, Ci-6alkylamino, haloCi-6alkyloxy, C6-i4aryl, C6-i4aryloxy, C6-i4arylC2-6alkenyl, C6-i4arylC2-6alkynyl, heterocyclyl, heteroaryl, -OZ3, -C(=0)NZ4Z3, -NZ4(C=0)Z3, -NZ4Z3, -NZ4S(=0)2Z3, - S(=0)2Z3, -S(=0)2OZ3, glycosyl or an ester thereof, and phosphateCi-6alkyl; and wherein each of said Ci-8alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, haloCi-6alkyl, Ci-6alkyloxy, Ci-6alkylamino, haloCi-6alkyloxy, C6-i4aryl, C6-i4aryloxy, C6-i4arylC2-6alkenyl, C6-i4arylC2- 6alkynyl, heterocyclyl, heteroaryl, glycosyl or ester thereof; can be unsubstituted or substituted with one or more Z2;
each Z2 is independently selected from the group consisting of hydroxyl, halo, nitro, Ci_ 8alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, haloCi-6alkyl, Ci-6alkyloxy, Ci-6alkylamino, haloCi-6alkyloxy, C6-i4aryl, C6-i4aryloxy, C6-i4arylC2-6alkenyl, C6-i4arylC2-6alkynyl, heterocyclyl, heteroaryl, -OZ3, -C(=0)NZ4Z3, -NZ4(C=0)Z3, -NZ4Z3, -NZ4S(=0)2Z3, - S(=0)2Z3, -S(=0)2OZ3, glycosyl or an ester thereof, and phosphateCi-6alkyl; and wherein each of said Ci-8alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, haloCi-6alkyl, Ci-6alkyloxy, Ci-6alkylamino, haloCi-6alkyloxy, C6-i4aryl, C6-i4aryloxy, C6-i4arylC2-6alkenyl, C6-i4arylC2- 6alkynyl, heterocyclyl, heteroaryl, glycosyl or ester thereof; can be unsubstituted or substituted with one or more Z3;
each Z3 is independently selected from the group consisting of hydrogen, hydroxyl, halo, nitro, Ci-8alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, haloCi-6alkyl, Ci-6alkyloxy, Ci_ 6alkylamino, haloCi-6alkyloxy, C6-i4aryl, C6-i4aryloxy, C6-i4arylC2-6alkenyl, C6-i4arylC2- 6alkynyl, heterocyclyl, heteroaryl, -OZ3, -C(=0)NZ4Z3, -NZ4(C=0)Z3, -NZ4Z3, - NZ4S(=0)2Z3, -S(=0)2Z3, -S(=0)2OZ3, glycosyl or an ester thereof, and phosphateCi. 6alkyl; and wherein each of said Ci-8alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, haloCi. 6alkyl, Ci-6alkyloxy, Ci-6alkylamino, haloCi-6alkyloxy, C6-i4aryl, C6-i4aryloxy, C6-i4arylC2- 6alkenyl, C6-i4arylC2-6alkynyl, heterocyclyl, heteroaryl, glycosyl or ester thereof; can be unsubstituted or substituted with one or more Z4;
each Z4 is independently selected from the group consisting of hydrogen, hydroxyl, halo, nitro, Ci-8alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, haloCi-6alkyl, Ci-6alkyloxy, Ci_ 6alkylamino, haloCi-6alkyloxy, C6-i4aryl, C6-i4aryloxy, C6-i4arylC2-6alkenyl, C6-i4arylC2- 6alkynyl, heterocyclyl, heteroaryl, -OZ3, -C(=0)NZ4Z3, -NZ4(C=0)Z3, -NZ4Z3, - NZ4S(=0)2Z3, -S(=0)2Z3, -S(=0)2OZ3, glycosyl or an ester thereof, and phosphateCi. 6alkyl; and wherein each of said Ci-8alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, haloCi. 6alkyl, Ci-6alkyloxy, Ci-6alkylamino, haloCi-6alkyloxy, C6-i4aryl, C6-i4aryloxy, C6-i4arylC2- 6alkenyl, C6-i4arylC2-6alkynyl, heterocyclyl, heteroaryl, glycosyl or ester thereof; can be unsubstituted or substituted with one or more Z5;
each Z5 is independently selected from the group consisting of hydrogen, K, Na , hydroxyl, halo, nitro, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, haloCi-6alkyl, Ci_ 6alkyloxy, Ci-6alkylamino, haloCi-6alkyloxy, C6-i4aryl, C6-i4aryloxy, C6-i4arylC2-6alkenyl, C6- i4arylC2-6alkynyl, heterocyclyl, heteroaryl, -OZ3, -C(=0)NZ4Z3, -NZ4(C=0)Z3, -NZ4Z3, - NZ4S(=0)2Z3, -S(=0)2Z3, -S(=0)2OZ3, glycosyl or an ester thereof, and phosphateCi. 6alkyl.
4. The compound according to any one of claims 1 -3, wherein Ra is selected from a group of formula A1 ), (A2), or (A3), as defined in the below table, wherein
Figure imgf000136_0001
5. The compound according to any one of claims 1 -3, wherein Ra is selected from the group comprisin structure of formula (A4), (A5), and (A6), as defined in the below table
Figure imgf000136_0002
compound according to any one of claims 1 -3, wherein Re is a group of formula
Figure imgf000137_0001
wherein Z1 has the same meaning as that defined in any one of claims 1 to 4 and X1 CH=CH, CH, N, O, or S and Y1 is CH=CH, CH, N, O, or S.
The compound according to any one of claims 1 -3, wherein Re is a group of formula
Figure imgf000137_0002
wherein Z1 has the same meaning as that defined in any one of claims 1 to 4 and integer selected from 0, 1 , 2, 3, 4, 5, or 6.
A compound accordin to any one of claims 1 -7, selected from the group comprising
Figure imgf000137_0003
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000140_0001
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000143_0001
Figure imgf000144_0001
Figure imgf000145_0001
Figure imgf000146_0001
Figure imgf000147_0001
Figure imgf000148_0001
Figure imgf000149_0001
Figure imgf000150_0001
Figure imgf000151_0001
Figure imgf000152_0001
Figure imgf000153_0001
Figure imgf000154_0001
Figure imgf000155_0001
Figure imgf000156_0001
Figure imgf000157_0001
Figure imgf000158_0001
Figure imgf000159_0001
Figure imgf000160_0001
Figure imgf000161_0001
Figure imgf000162_0001
Figure imgf000163_0001
Figure imgf000164_0001
Figure imgf000164_0002
wherein group of formula -NH-Rb-NH-Rc, or -NH-R ; wherein
Rb is a group of formula -Rd-, or -Rd-CO-, wherein the right side of -Rd-CO- is attached to -NH-Rc;
Rc is -Re, or -CO-Re;
Rd is a Ci-i2alkylene, wherein said Ci-i2alkylene; optionally comprises one or more heteroatoms in the alkylene, moiety, said heteroatoms being O;
or Rd together with one or both of the -NH- form a saturated or 4-, 5-, or 6-membered ring;
Re is selected from the group consisting of C2-6alkynyl, C6-i4aryl, C6-i4arylCi-6alkyl, C6- i4arylC2-6alkenyl, C6-i4arylC2-6alkynyl, C6-i4arylC2-6alkenylC6-i4aryl; heteroaryl, -NH-C3- i2cycloalkyl, and wherein said C2-6alkynyl; C6-i4aryl; C6-i4arylC2-6alkenyl, C6-i4arylC2- 6alkenylC6-i4aryl; heteroaryl, -NH-C3-i2cycloalkyl, can be unsubstituted or substituted with one or more Z1;
R is a C2-6alkynyl,
each Z1 is independently selected from the group consisting of hydroxyl, halo, nitro, Ci_ i2alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, haloCi-i0alkyl, Ci-6alkyloxy, Ci_ 6alkylamino, haloCi-i0alkyloxy, C6-i4aryl, C6-i4aryloxy, C6-i4arylC2-6alkenyl, C6-i4arylC2- 6alkynyl, heterocyclyl, heteroaryl, -OZ3, -C(=0)NZ4Z3, -NZ4(C=0)Z3, -NZ4Z3, -N+Z2Z4Z3 X" , -NZ4S(=0)2Z3, -S(=0)2Z3, -S(=0)2OZ3, glycosyl or an ester thereof, and phosphateCi. 6alkyl; and wherein each of said Ci-i2alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, haloCi-i0alkyl, Ci-6alkyloxy, Ci-6alkylamino, haloCi-i0alkyloxy, C6-i4aryl, C6-i4aryloxy, C6- i4arylC2-6alkenyl, C6-i4arylC2-6alkynyl, heterocyclyl, heteroaryl, glycosyl or ester thereof; can be unsubstituted or substituted with one or more Z2; or two adjacent Z2 can be taken together to form a C3-7cycloalkyl, or a 5-, 6-, or 7-membered heterocyclyl or heteroaryl ring, which can be unsubstituted or substituted with one or more Z2 ;
each Z2 is independently selected from the group consisting of hydroxyl, halo, nitro, Ci_ i2alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, haloCi-i0alkyl, Ci-6alkyloxy, Ci_ 6alkylamino, haloCi-i0alkyloxy, C6-i4aryl, C6-i4aryloxy, C6-i4arylC2-6alkenyl, C6-i4arylC2- 6alkynyl, heterocyclyl, heteroaryl, -OZ3, -C(=0)NZ4Z3, -NZ4(C=0)Z3, -NZ4Z3, -N+Z2Z4Z3 X" , -NZ4S(=0)2Z3, -S(=0)2Z3, -S(=0)2OZ3, glycosyl or an ester thereof, and phosphateCi. 6alkyl; and wherein each of said Ci-i2alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, haloCi-i0alkyl, Ci-6alkyloxy, Ci-6alkylamino, haloCi-i0alkyloxy, C6-i4aryl, C6-i4aryloxy, C6- i4arylC2-6alkenyl, C6-i4arylC2-6alkynyl, heterocyclyl, heteroaryl, glycosyl or ester thereof; can be unsubstituted or substituted with one or more Z3; each Z3 is independently selected from the group consisting of hydrogen, hydroxyl, halo, nitro, Ci-i2alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, haloCi-i0alkyl, Ci-6alkyloxy, Ci_ 6alkylamino, haloCi-i0alkyloxy, C6-i4aryl, C6-i4aryloxy, C6-i4arylC2-6alkenyl, C6-i4arylC2- 6alkynyl, heterocyclyl, heteroaryl, -OZ3, -C(=0)NZ4Z3, -NZ4(C=0)Z3, -NZ4Z3, -N+Z2Z4Z3 X" , -NZ4S(=0)2Z3, -S(=0)2Z3, -S(=0)2OZ3, glycosyl or an ester thereof, and phosphateCi.
6alkyl; and wherein each of said Ci-i2alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, haloCi-i0alkyl, Ci-6alkyloxy, Ci-6alkylamino, haloCi-i0alkyloxy, C6-i4aryl, C6-i4aryloxy, C6- i4arylC2-6alkenyl, C6-i4arylC2-6alkynyl, heterocyclyl, heteroaryl, glycosyl or ester thereof; can be unsubstituted or substituted with one or more Z4;
each Z4 is independently selected from the group consisting of hydrogen, hydroxyl, halo, nitro, Ci-i2alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, haloCi-i0alkyl, Ci-6alkyloxy, Ci_ 6alkylamino, haloCi-i0alkyloxy, C6-i4aryl, C6-i4aryloxy, C6-i4arylC2-6alkenyl, C6-i4arylC2- 6alkynyl, heterocyclyl, heteroaryl, -OZ3, -C(=0)NZ4Z3, -NZ4(C=0)Z3, -NZ4Z3, -N+Z2Z4Z3 X" , -NZ4S(=0)2Z3, -S(=0)2Z3, -S(=0)2OZ3, glycosyl or an ester thereof, and phosphateCi. 6alkyl; and wherein each of said Ci-i2alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, haloCi-i0alkyl, Ci-6alkyloxy, Ci-6alkylamino, haloCi-i0alkyloxy, C6-i4aryl, C6-i4aryloxy, C6- i4arylC2-6alkenyl, C6-i4arylC2-6alkynyl, heterocyclyl, heteroaryl, glycosyl or ester thereof; can be unsubstituted or substituted with one or more Z5;
or Z4 and Z3 can be taken together to form a C3-7cycloalkyl, or a 5-, 6-, or 7-membered heterocyclyl, which can be unsubstituted or substituted with one or more Z5;
each Z5 is independently selected from the group consisting of hydrogen, K, Na , hydroxyl, halo, nitro, Ci-i2alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, haloCi-i0alkyl, Ci_ 6alkyloxy, Ci-6alkylamino, haloCi-i0alkyloxy, C6-i4aryl, C6-i4aryloxy, C6-i4arylC2-6alkenyl, C6-i4arylC2-6alkynyl, heterocyclyl, heteroaryl, -OZ3, -C(=0)NZ4Z3, -NZ4(C=0)Z3, -NZ4Z3, - N+Z2Z4Z3 X", -NZ4S(=0)2Z3, -S(=0)2Z3, -S(=0)2OZ3, glycosyl or an ester thereof, and phosphateCi-6alkyl; and
X is a halogen.
10. A pharmaceutical composition comprising a compound according to any one of claims 1 -8.
1 1 . The compound according to any of one of claims 1 -8 or the pharmaceutical composition according to any one of claims 9, 10 for use against a bacterial infection.
12. The compound or the pharmaceutical composition according to claim 1 1 , wherein the bacterial infection is caused by a bacterial strain with resistance against at least one antibiotic compound.
13. The compound or the pharmaceutical composition according to claim 1 1 , wherein the bacterial infection is caused by a bacterial strain susceptible to at least one antibiotic compound.
14. The compound or the pharmaceutical composition according to any one of claims 12, 13 wherein the antibiotic compound is selected from the group comprising vancomycin, methicillin, ampicillin, erythromycin, tigecycline, teicoplanin, daptomycin, and linezolid.
15. The compound or the pharmaceutical composition according to any one of claims 1 1 -14, wherein the bacterial strain is vancomycin-susceptible Enterococci (VSE), vancomycin- resistant Enterococci (VRE), vancomycin-susceptible Staphylococcus aureus (VSSA), vancomycin-intermediate resistant strains (VISA), or high-level vancomycin-resistant
Staphylococcus aureus (VRSA).
16. The compound or the pharmaceutical composition according to any one of claims 1 1 -15, characterized in that the bacterial infection is caused by vancomycin-resistant Staphylococcus aureus (VRSA).
17. The compound or the pharmaceutical composition according to any one of claims 1 1 -15, characterized in that the bacterial infection is caused by vancomycin-resistant Enterococci (VRE).
18. The compound or the pharmaceutical composition according to any one of claims 1 1 -15, wherein the bacterial infection is caused by vancomycin-intermediate resistant strains (VISA).
19. The compound or the pharmaceutical composition according to any one of claims 1 1 -15, wherein the bacterial infection is caused by vancomycin-susceptible Enterococci (VSE).
20. The compound or the pharmaceutical composition according to any one of claims 1 1 -15, wherein the bacterial infection is caused by vancomycin-susceptible Staphylococcus aureus (VSSA).
21 . The compound or the pharmaceutical composition according to any one of claims 1 1 -14, wherein the bacterial infection is caused by Clostridium difficile.
PCT/EP2014/067272 2013-08-12 2014-08-12 Vancomycin analogs WO2015022335A1 (en)

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GB201314407A GB201314407D0 (en) 2013-08-12 2013-08-12 Vancomycin analogs
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106588693A (en) * 2016-11-11 2017-04-26 河南师范大学 Synthesis method for aryl azide compound
WO2020159389A1 (en) * 2019-01-31 2020-08-06 Gdański Uniwersytet Medyczny Compounds of vancomycin and tp10, methods of their preparation, composition and use in antibacterial treatment
WO2022054057A1 (en) 2020-09-11 2022-03-17 Supertrans Medical Ltd Drug conjugates and uses thereof

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995032428A1 (en) * 1994-05-23 1995-11-30 Beckman Instruments, Inc. Reagents and methods for the rapid and quantitative assay of pharmacological agents
US6017511A (en) * 1997-05-30 2000-01-25 Resolution Pharmaceuticals Inc. Glycopeptide-chelator conjugates
WO2004113350A1 (en) * 2003-05-23 2004-12-29 Theravance, Inc. Cross-linked glycopeptide - cephalosporin antibiotics
US20070134729A1 (en) * 1998-06-08 2007-06-14 Christensen Burton G Novel antibacterial agents

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995032428A1 (en) * 1994-05-23 1995-11-30 Beckman Instruments, Inc. Reagents and methods for the rapid and quantitative assay of pharmacological agents
US6017511A (en) * 1997-05-30 2000-01-25 Resolution Pharmaceuticals Inc. Glycopeptide-chelator conjugates
US20070134729A1 (en) * 1998-06-08 2007-06-14 Christensen Burton G Novel antibacterial agents
WO2004113350A1 (en) * 2003-05-23 2004-12-29 Theravance, Inc. Cross-linked glycopeptide - cephalosporin antibiotics

Non-Patent Citations (11)

* Cited by examiner, † Cited by third party
Title
BALZARINI J ET AL: "Inhibition of feline (FIPV) and human (SARS) coronavirus by semisynthetic derivatives of glycopeptide antibiotics", ANTIVIRAL RESEARCH, ELSEVIER BV, NL, vol. 72, no. 1, 1 October 2006 (2006-10-01), pages 20 - 33, XP027893439, ISSN: 0166-3542, [retrieved on 20061001] *
CHRISTOPHER J. ARNUSCH ET AL: "The Vancomycin-Nisin(1-12) Hybrid Restores Activity against Vancomycin Resistant Enterococci +", BIOCHEMISTRY, vol. 47, no. 48, 2 December 2008 (2008-12-02), pages 12661 - 12663, XP055140745, ISSN: 0006-2960, DOI: 10.1021/bi801597b *
JOHN H. GRIFFIN ET AL: "Multivalent Drug Design. Synthesis and In Vitro Analysis of an Array of Vancomycin Dimers", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 125, no. 21, 1 May 2003 (2003-05-01), pages 6517 - 6531, XP055140770, ISSN: 0002-7863, DOI: 10.1021/ja021273s *
MACIEJ ADAMCZYK ET AL: "Structure-Binding Relationships for the Interaction between a Vancomycin Monoclonal Antibody Fab Fragment and a Library of Vancomycin Analogues and Tracers", BIOCONJUGATE CHEMISTRY, vol. 10, no. 2, 1 March 1999 (1999-03-01), pages 176 - 185, XP055140759, ISSN: 1043-1802, DOI: 10.1021/bc980135i *
POLLY-ANNA ASHFORD ET AL: "Recent advances in the synthesis of new glycopeptide antibiotics", CHEMICAL SOCIETY REVIEWS, vol. 41, no. 3, 1 January 2012 (2012-01-01), pages 957, XP055141374, ISSN: 0306-0012, DOI: 10.1039/c1cs15125h *
SHI ZHENG ET AL: "Catalysis of carbamate hydrolysis by vancomycin and semisynthetic derivatives", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, ACS PUBLICATIONS, US, vol. 115, 1 January 1993 (1993-01-01), pages 6482 - 6486, XP002543874, ISSN: 0002-7863, [retrieved on 19930701], DOI: 10.1021/JA00068A002 *
SS PRINTSEVSKAYA ET AL: "Synthesis and study of antibacterial activities of antibacterial glycopeptide antibiotics conjugated with benzoxaboroles", FUTURE MEDICINAL CHEMISTRY, vol. 5, no. 6, 1 April 2013 (2013-04-01), pages 641 - 652, XP055141265, ISSN: 1756-8919, DOI: 10.4155/fmc.13.16 *
SUNDRAM UMA N ET AL: "General and Efficient Method for the Solution- and Solid-Phase Synthesis of Vancomycin Carboxamide Derivatives", THE JOURNAL OF ORGANIC CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, 10 March 1995 (1995-03-10), pages 1102 - 1103, XP002183429, ISSN: 0022-3263, DOI: 10.1021/JO00110A004 *
VENKATESWARLU YARLAGADDA ET AL: "Membrane Active Vancomycin Analogues: A Strategy to Combat Bacterial Resistance", JOURNAL OF MEDICINAL CHEMISTRY, vol. 57, no. 11, 12 June 2014 (2014-06-12), pages 4558 - 4568, XP055140779, ISSN: 0022-2623, DOI: 10.1021/jm500270w *
VENKATESWARLU YARLAGADDA ET AL: "S1 Supporting Information Membrane Active Vancomycin Analogues: A Strategy to Combat Bacterial Resistance", 12 June 2014 (2014-06-12), XP055140780, Retrieved from the Internet <URL:http://pubs.acs.org/doi/suppl/10.1021/jm500270w/suppl_file/jm500270w_si_001.pdf> [retrieved on 20140917] *
XING B ET AL: "MULTIVALENT ANTIBIOTICS VIA METAL COMPLEXES: POTENT DIVALENT VANCOMYCINS AGAINST VANCOMYCIN-RESISTANT ENTEROCOCCI", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 46, no. 23, 6 November 2003 (2003-11-06), pages 4904 - 4909, XP009068764, ISSN: 0022-2623, DOI: 10.1021/JM030417Q *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106588693A (en) * 2016-11-11 2017-04-26 河南师范大学 Synthesis method for aryl azide compound
WO2020159389A1 (en) * 2019-01-31 2020-08-06 Gdański Uniwersytet Medyczny Compounds of vancomycin and tp10, methods of their preparation, composition and use in antibacterial treatment
WO2022054057A1 (en) 2020-09-11 2022-03-17 Supertrans Medical Ltd Drug conjugates and uses thereof

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