WO2018065387A1 - Nouveaux analogues du hamamélitannin et leurs utilisations - Google Patents

Nouveaux analogues du hamamélitannin et leurs utilisations Download PDF

Info

Publication number
WO2018065387A1
WO2018065387A1 PCT/EP2017/075036 EP2017075036W WO2018065387A1 WO 2018065387 A1 WO2018065387 A1 WO 2018065387A1 EP 2017075036 W EP2017075036 W EP 2017075036W WO 2018065387 A1 WO2018065387 A1 WO 2018065387A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
het
halo
independently
alkenyl
Prior art date
Application number
PCT/EP2017/075036
Other languages
English (en)
Inventor
Serge Van Calenbergh
Arno VERMOTE
Gilles BRACKMAN
Tom COENYE
Martijn RISSEEUW
Original Assignee
Universiteit Gent
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Universiteit Gent filed Critical Universiteit Gent
Publication of WO2018065387A1 publication Critical patent/WO2018065387A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/20—Oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
    • C07D319/12—1,4-Dioxanes; Hydrogenated 1,4-dioxanes not condensed with other rings

Definitions

  • the present invention relates to hamamelitannin analogues, pharmaceutical compositions comprising the same, and combinations thereof with antimicrobial agents such as antibiotics or disinfectants. It in particular relates to the use of the compounds, compositions and combinations according to this invention in human or veterinary medicine, more in particular for use in the prevention and/or treatment of bacterial infections, such as Staphylococcus aureus infections, in humans or animals.
  • microorganisms such as bacteria, yeasts or fungi were considered non-complex organisms that could easily be eradicated with antimicrobials.
  • AMR antimicrobial resistance
  • Methicillin-resistant Staphylococcus aureus is responsible for nosocomial as well as a communal infections and represents a rapidly growing health threat. Compounding the problem even further is the fact that Staphylococcus aureus (S. aureus) is notorious for its ability to form biofilms, surface-attached encasements of cells in a polymer-based matrix. Biofilm formation provides a multi-level protection to microbes against antibiotics. It alters growth rate and metabolism, raises the fraction of dormant persister cells and hampers the penetration of antimicrobial agents. The global problem of AMR is further aggravated by a lack of novel antibiotic development, which is fraught with scientific risk and business challenges.
  • HAM hamamelitannin
  • 2',5-di-O-galloyl-D-hamamelose a natural compound found in the bark and leaves of Hamamelis virginana (witch hazel)
  • QSI quorum sensing inhibitor
  • HAM interferes with a quorum sensing system in bacteria. It was found that when combining HAM with an antibiotic, a potentiating or synergistic effect is observed, in particular HAM increases the susceptibility of bacterial biofilms to antibiotics in vitro as well as in vivo (2, 3).
  • the natural HAM product is metabolically unstable and only moderately active, and therefore less preferable in the treatment of microbial infections.
  • the invention includes a method of preventing or reducing the growth or proliferation of microorganisms or biofilm-embedded microorganisms, e.g. on a surface of a medical device or in or on subject's body.
  • the present invention provides a compound of Formula I, or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, or solvate thereof
  • R-i is selected from -Ci_ 6 alkyl, -Ar 3 , and -S0 2 -Ri6; wherein said -d- 6 alkyl may be further substituted with -R 25 ;
  • R 2 is selected from -H and -Ci_ 6 alkyl
  • R 3 is selected from -H , -Ci_ 6 alkyl, -C 2 . 6 alkenyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -0-C 3 . 6 alkenyl, -S-C 3 .
  • R 3 taken together with R 5 forms -C 3 . 6 cycloalkyl or Het- ;
  • R 4 is selected from -H, -Ci_ 6 alkyl, -C 2 . 6 alkenyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -0-C 3 . 6 alkenyl, -S-C 3 .
  • R 5 is selected from -H , -Ci_ 6 alkyl, -C 2 . 6 alkenyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -0-C 3 . 6 alkenyl, -S-C 3 .
  • R 6 is selected from -H , -Ci_ 6 alkyl, -C 2 . 6 alkenyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -0-C 3 . 6 alkenyl, -S-C 3 .
  • R 6 taken together with R 9 forms -C 3 . 6 cycloalkyl or Het 12 ;
  • R 7 is selected from -Ci_ 6 alkyl, -Ar 4 , and -S0 2 -Ri 3 ; wherein said -Ci_ 6 alkyl may be further substituted with -R 26 ;
  • R 8 is selected from -H and -Ci_ 6 alkyl
  • R 9 is selected from -H , -Ci_ 6 alkyl, -C 2 . 6 alkenyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -0-C 3 . 6 alkenyl, -S-C 3 .
  • R-io is selected from -H , -Ci_ 6 alkyl, -C 2 . 6 alkenyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -0-C 3 . 6 alkenyl, -S-C 3 .
  • 4 , Ri5, Ri6, R 2 5, and R 26 are each independently selected from -Ci_ 6 alkyl, -C 3 . 6 cycloalkyl, -Ar-i ,
  • Ri 7 , Ris, Rig, R 20 , R 2 i , R 22 , R 23 and R 24 are each independently selected from -H, and -Ci_ 6 alkyl;
  • Ar- ⁇ , Ar 2 , Ar 3 , Ar 4, Ar 5 , Ar 6 , Ar 7 , Ar 8 , Ar 9, and Ar 10 are each independently a 5-10 membered aromatic mono-or bicycle; wherein each of said Ar- ⁇ , Ar 2 , Ar 3 , Ar 4, Ar 5 , Ar 6 , Ar 7 , Ar 8 , Ar 9, and Ar 10 is optionally and independently substituted with from 1 to 5 substituents selected from, -OH , - halo, -Ci- 6 alkyl, -0-Ci_ 6 alkyl, -CN, -CF 3 , -NR21 R22, and -phenyl; wherein said phenyl is optionally substituted with from 1 to 3 substituents selected from, -OH, -halo, -d-
  • R-i is selected from -Ci_ 6 alkyl, -Ar 3 , and -S0 2 -Ri 6 ; wherein said -Ci_ 6 alkyl may be further substituted with -R 25 ;
  • R 2 is selected from -H and -Ci_ 6 alkyl
  • R 3 is -H
  • R 4 is -H
  • R 5 is -H
  • R 6 is selected from -H , -Ci_ 6 alkyl, -C 2 . 6 alkenyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -0-C 3 . 6 alkenyl, -S-C 3 .
  • R 6 taken together with R 9 forms -C 3 . 6 cycloalkyl or Het 12 ;
  • R 7 is selected from -Ci_ 6 alkyl, -Ar 4 , and -S0 2 -Ri 3 ; wherein said -Ci_ 6 alkyl may be further substituted with -R 26 ;
  • R 8 is selected from -H and -Ci_ 6 alkyl
  • R 9 is selected from -H , -Ci_ 6 alkyl, -C 2 . 6 alkenyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -0-C 3 . 6 alkenyl, -S-C 3 .
  • R-io is selected from -H , -Ci_ 6 alkyl, -C 2 . 6 alkenyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -0-C 3 . 6 alkenyl, -S-C 3 .
  • Ri 4 , R-I5, R16, R 2 5, and R 26 are each independently selected from -Ci_ 6 alkyl, -C 3 . 6 cycloalkyl, -Ar-i ,
  • R-I7, Ri8, Ri9, R 2 o, R21 , R22, R 23 and R 24 are each independently selected from -H , and -Ci_ 6 alkyl ;
  • Ar- ⁇ , Ar 2 , Ar 3 , Ar 4 , Ar 5 , Ar 6 , Ar 7 , Ar 8 , Ar 9 , and Ar 10 are each independently a 5-10 membered aromatic mono-or bicycle; wherein each of said Ar- ⁇ , Ar 2 , Ar 3 , Ar 4 , Ar 5 , Ar 6 , Ar 7 , Ar 8 , Ar 9 , and Ar 10 is optionally and independently substituted with from 1 to 5 substituents selected from, -OH , - halo, -Ci- 6 alkyl, -0-Ci_ 6 alkyl, -CN , -CF 3 , -NR 21 R 22 , and -phenyl; wherein said phenyl is optionally substituted with from 1 to 3 substituents selected from -OH
  • R 2 is -H ;
  • R 3 is -H ;
  • R 4 is -H ;
  • R 5 is -H ;
  • R 6 is -H ;
  • R 8 is -H ;
  • R 9 is -H ;
  • Ar- ⁇ , and Ar 2 are each independently a 5-10 membered aromatic mono-or bicycle; wherein each of said Ar- ⁇ , and Ar 2 is optionally and independently substituted with from 1 to 5 substituents selected from, -OH , -halo, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -CN , -CF 3 , -NR 21 R 22 , and -phenyl;
  • R 21 , and R 22 are each independently selected from -H , and -Ci_ 6 alkyl.
  • the present invention provides a compound according to formula
  • R 2 is -H
  • R 3 is -H
  • R 4 is -H
  • R 5 is -H
  • R 6 is -H
  • R 8 is -H
  • R 9 is -H
  • Ar- ⁇ , and Ar 2 are each phenyl; wherein each of said Ar- ⁇ , and Ar 2 is optionally and independently substituted with from 1 to 5 -halo.
  • the present invention provides a compound according to formula I wherein the compound has the stereoisomeric conformation as represented in formula la:
  • the present invention provides a compound of Formula II, or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, or solvate thereof
  • R-i is selected from -d- 6 alkyl, -Ar 3 , and -S0 2 -Ri 6 ; wherein said -Ci_ 6 alkyl may be further substituted with -R 25 ; R 2 is selected from -H and -d- 6 alkyl;
  • R 3 is selected from -H, -OH , and -F;
  • R 4 is selected from -H, -OH , and -F;
  • R 5 is selected from -H, -OH, and -F;
  • R 6 is selected from -H, -OH , -F, -C 1-6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, and -CN;
  • R 7 is selected from -Ci_ 6 alkyl, -Ar 4 , and -SO2-R13; wherein said -Ci_ 6 alkyl may be further substituted with -R 2 6;
  • R 8 is selected from -H and -Ci_ 6 alkyl
  • R16, Ri7, R18, Rig, R20, R21 , R22 and R 23 are each independently selected from -H, and -Ci_ 6 alkyl;
  • Ar- ⁇ , Ar 2 , Ar 3 , and Ar 4 are each independently a 5-10 membered aromatic mono-or bicycle; wherein each of said Ar- ⁇ , Ar 2 , Ar 3 , and Ar 4 is optionally and independently substituted with from 1 to 5 substituents selected from, -OH, -halo, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -CN, -CF 3 , -NR 21 R 22 , and - phenyl; wherein said phenyl is optionally substituted with from 1 to 3 substituents selected from, -OH, -halo, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -CN, -CF 3 , or -NR 21 R 22 ;
  • the present invention provides a compound according to formula II or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, or solvate thereof, wherein
  • R-i is selected from -Ci_ 6 alkyl, -Ar 3 , and -S0 2 -Ri 6 ; wherein said -Ci_ 6 alkyl may be further substituted with -R 25 ;
  • R 2 is selected from -H and -Ci_ 6 alkyl
  • R 3 is -OH;
  • R 4 is -OH;
  • R 5 is -H
  • R 6 is -H
  • R 7 is selected from -d- 6 alkyl, -Ar 4 , and -SO2-R13; wherein said -Ci_ 6 alkyl may be further substituted with -R 2 6;
  • R 8 is selected from -H and -Ci_ 6 alkyl
  • R16, Ri7, R18, Rig, R 20 , R21 , R 22 and R 23 are each independently selected from -H, and -Ci_ 6 alkyl;
  • Ar- ⁇ , Ar 2 , Ar 3 , and Ar 4 are each independently a 5-10 membered aromatic mono-or bicycle; wherein each of said Ar- ⁇ , Ar 2 , Ar 3 , and Ar 4 is optionally and independently substituted with from 1 to 5 substituents selected from, -OH, -halo, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -CN, -CF 3 , -NR 21 R 22 , and - phenyl; wherein said phenyl is optionally substituted with from 1 to 3 substituents selected from -OH, -halo, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -CN, -CF 3 , or -NR 21 R 22 ;
  • Het- ⁇ , Het 2 , Het 3 , and He are each independently a 5-10 membered mono-or bicyclic heterocycle comprising from 1 to 3 heteroatoms selected from N, O and S; wherein each of said Het- ⁇ , Het 2 , Het 3 , and Het 4 is optionally and independently substituted with from 1 to 5 substituents selected from -OH, -halo, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -CN, -CF 3 , -NR 23 R 24 , and -phenyl; wherein said phenyl is optionally substituted with from 1 to 3 substituents selected from -OH, -halo, - Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -CN, -CF 3 , or -NR 23 R 24 .
  • the present invention provides a compound according to formula II or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, or solvate thereof, wherein
  • R 2 is -H
  • R 3 is -OH
  • R 4 is -OH
  • R 5 is -H
  • R 6 is -H
  • R 8 is -H
  • Ar-i , and Ar 2 are each independently a 5-10 membered aromatic mono-or bicycle; wherein each of said Ar- ⁇ , and Ar 2 is optionally and independently substituted with from 1 to 5 substituents selected from, -OH, -halo, -C 1 -6 alkyl, -0-Ci -6 alkyl, -CN, -CF 3 , -NR 2 iR 22 , and -phenyl.
  • the present invention provides a compound according to formula II or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, or solvate thereof,
  • R 2 is -H
  • R 3 is -OH
  • R 4 is -OH
  • R 6 is -H
  • Ar- ⁇ , and Ar 2 are each phenyl; wherein each of said Ar- ⁇ , and Ar 2 is optionally and independently substituted with from 1 to 5 -halo.
  • the present invention provides a compound according to formula II wherein the compound has the stereoisomeric conformation as represented in formula Ila:
  • the present invention encompasses a compound as defined herein, such as any and all compounds represented by formulas I, la, II, Ila or as represented in Table 1 , or stereoisomer, tautomer, racemic, salt, metabolite, pre- or prodrug, hydrate, or solvate thereof, and more specific a stereoisomer, tautomer, racemic, salt, hydrate, or solvate thereof.
  • a compound according to formula I and la and represented as
  • Such compound is for example a compound according to formula II and lla, and represented as follows:
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound according to the present invention and a pharmaceutically acceptable excipient, diluent and/or carrier.
  • Said composition may be administered oral, systemic or topical.
  • the present invention provides a combination of a compound according to the present invention with an antimicrobial agent, in particular an antibiotic or disinfectant.
  • the present invention provides a medical device comprising one or more compounds, a combination or a pharmaceutical composition according to the present invention.
  • medical device is for example selected from the group consisting of grafts, membranes, tubes, connectors, surgical instruments, intra-aortic balloons, stents (including drug-eluting vascular stents), blood bags, catheters, sutures, prostheses, heart valves, tissue adhesives, cardiac pacemaker leads, artificial organs, lenses for the eye, blood handling equipment, apheresis equipment, (bio)sensors, dental devices, skin patches, wound dressings (including drug-eluting wound dressings), implantable devices, tampons, bandages, drug delivery systems, bodily implants, and protein-eluting scaffolds for tissue regeneration.
  • the one or more compounds, the combination or pharmaceutical composition according to the present invention is formulated in or applied on the medical device.
  • the present invention provides a compound, composition, medical device or combination according to the present invention, for use in human or veterinary medicine, more in particular, for use in the preventing, reducing the risk of and/or treating bacterial infections in humans or animals.
  • said bacterial infection is a Staphylococcus aureus infection.
  • the present invention provides a compound, composition, medical device or combination according to the present invention, for use in human or veterinary medicine, more in particular, for use in the preventing, reducing the risk of and/or treating bacterial infections in humans or animals.
  • said bacterial infection is a Staphylococcus aureus infection.
  • the present invention provides a compound, composition, medical device or combination according to the present invention, for usein preventing, reducing the risk of and/or treating wound infections, skin ulcers, diabetic foot ulcers, burn wound infections, catheter- or stent-associated infections, infections resulting from animal bites, mastitis, pneumonia or sepsis.
  • the present invention provides a compound, composition, medical device or combination according to the present invention, for use in preventing or reducing biofilm formation.
  • the present invention provides a method for the prevention and/or treatment of bacterial infections; said method comprising administering to a subject in need thereof a therapeutic effective amount of a compound, a composition or a combination as according to the present invention.
  • VAN vancomycin
  • the present invention provides compounds of Formula I , or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, or solvate thereof
  • R 2 is selected from -H and -d- 6 alkyl
  • R 3 is selected from -H , -Ci_ 6 alkyl , -C 2 . 6 alkenyl, -0-Ci_ 6 alkyl , -S-Ci_ 6 alkyl, -0-C 3 . 6 alkenyl, -S-C 3 .
  • R 3 taken together with R 5 forms -C 3 . 6 cycloalkyl or Het- ;
  • R 4 is selected from -H , -Ci_ 6 alkyl , -C 2 . 6 alkenyl , -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl , -0-C 3 . 6 alkenyl , -S-C 3 .
  • R 5 is selected from -H , -Ci_ 6 alkyl, -C 2 . 6 alkenyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -0-C 3 . 6 alkenyl, -S-C 3 .
  • R 6 is selected from -H , -Ci_ 6 alkyl , -C 2 . 6 alkenyl, -0-Ci_ 6 alkyl , -S-Ci_ 6 alkyl, -0-C 3 . 6 alkenyl, -S-C 3 .
  • R 6 taken together with R 9 forms -C 3 . 6 cycloalkyl or Het 12 ;
  • R 7 is selected from -Ci_ 6 alkyl, -Ar 4 , and -S0 2 -Ri 3 ; wherein said -Ci_ 6 alkyl may be further substituted with -R 2 6;
  • R 8 is selected from -H and -d- 6 alkyl
  • R 9 is selected from -H , -Ci_ 6 alkyl, -C 2 . 6 alkenyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -0-C 3 . 6 alkenyl, -S-C 3 .
  • R-io is selected from -H , -Ci_ 6 alkyl, -C 2 . 6 alkenyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -0-C 3 . 6 alkenyl, -S-C 3 .
  • Ri4, R-I5, Ri6, R25, and R 2 6 are each independently selected from -Ci_ 6 alkyl, -C 3 . 6 cycloalkyl, -Ar-i ,
  • R-i -i , R-12 and R 13 are each independently selected from -Ci_ 6 alkyl, -C 3 . 6 cycloalkyl, -Ar 2 , Het 2 , -NH-
  • R-I7, R18, Rig, R 2 o, R21 , R22, R 23 and R 24 are each independently selected from -H, and -Ci_ 6 alkyl;
  • Ar- ⁇ , Ar 2 , Ar 3 , Ar 4, Ar 5 , Ar 6 , Ar 7 , Ar 8 , Ar 9, and Ar 10 are each independently a 5-10 membered aromatic mono-or bicycle; wherein each of said Ar- ⁇ , Ar 2 , Ar 3 , Ar 4, Ar 5 , Ar 6 , Ar 7 , Ar 8 , Ar 9, and Ar 10 is optionally and independently substituted with from 1 to 5 substituents selected from, -OH , - halo, -Ci- 6 alkyl, -0-Ci_ 6 alkyl, -CN, -CF 3 , -NR 21 R 22 , and -phenyl; wherein said phenyl is optionally substituted with from 1 to 3 substituents selected from, -OH, -halo, -Ci
  • Het- ⁇ , Het 2 , Het 3 , Het 4 , Het 5 , Het 6 , Het 7 , Het 8 , Het 9 , Het 10 , Het-n and Het 12 are each independently a
  • the invention relates to a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, or solvate of the compounds provided herein, and especially any and each of the compounds represented by Formula I, la, II or Ma or compounds as provided in Table 1 . More specific, the invention also encompasses a stereoisomer, tautomer, racemic, salt, hydrate, or solvate of said compounds.
  • alkyl by itself or as part of another substituent refers to a fully saturated hydrocarbon of Formula C x H 2x+ i wherein x is a number greater than or equal to 1 .
  • alkyl groups of this invention comprise from 1 to 20 carbon atoms.
  • Alkyl groups may be linear or branched and may be substituted as indicated herein.
  • a subscript is used herein following a carbon atom, the subscript refers to the number of carbon atoms that the named group may contain.
  • d- 4 alkyl means an alkyl of one to four carbon atoms.
  • alkyl groups are methyl, ethyl, n-propyl, i-propyl, butyl, and its isomers (e.g. n-butyl, i-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.
  • C C6 alkyl includes all linear, branched, or cyclic alkyl groups with between 1 and 6 carbon atoms, and thus includes methyl, ethyl, n-propyl, i-propyl, butyl and its isomers (e.g. n-butyl, i-butyl and t-butyl); pentyl and its isomers, hexyl and its isomers, cyclopentyl, 2-, 3-, or 4-methylcyclopentyl, cyclopentylmethylene, and cyclohexyl.
  • optionally substituted alkyl refers to an alkyl group optionally substituted with one or more substituents (for example 1 to 4 substituents, for example 1 , 2, 3, or 4 substituents or 1 to 2 substituents) at any available point of attachment.
  • substituents for example 1 to 4 substituents, for example 1 , 2, 3, or 4 substituents or 1 to 2 substituents
  • Non-limiting examples of such substituents include halo, hydroxyl, carbonyl, nitro, amino, oxime, imino, azido, hydrazino, cyano, aryl, heteroaryl, cycloalkyl, acyl, alkylamino, alkoxy, thiol, alkylthio, carboxylic acid, acylamino, alkyl esters, carbamate, thioamido, urea, sullfonamido and the like.
  • cycloalkyl by itself or as part of another substituent is a cyclic alkyl group, that is to say, a monovalent, saturated, or unsaturated hydrocarbyl group having 1 , 2, or 3 cyclic structures.
  • Cycloalkyl includes all saturated or partially saturated (containing 1 or 2 double bonds) hydrocarbon groups containing 1 to 3 rings, including monocyclic, bicyclic, or polycyclic alkyl groups.
  • Cycloalkyl groups may comprise 3 or more carbon atoms in the ring and generally, according to this invention comprise from 3 to 15 atoms.
  • the further rings of multi-ring cycloalkyls may be either fused, bridged and/or joined through one or more spiro atoms.
  • Cycloalkyl groups may also be considered to be a subset of homocyclic rings discussed hereinafter.
  • Examples of cycloalkyl groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, adamantanyl and cyclodecyl with cyclopropyl being particularly preferred.
  • An "optionally substituted cycloalkyl” refers to a cycloalkyl having optionally one or more substituents (for example 1 to 3 substituents, for example 1 , 2, 3 or 4 substituents), selected from those defined above for substituted alkyl.
  • Cycloalkylene When the suffix "ene” is used in conjunction with a cyclic group, hereinafter also referred to as "Cycloalkylene", this is intended to mean the cyclic group as defined herein having two single bonds as points of attachment to other groups. Cycloalkylene groups of this invention preferably comprise the same number of carbon atoms as their cycloalkyl radical counterparts. Where alkyl groups as defined are divalent, i.e., with two single bonds for attachment to two other groups, they are termed “alkylene” groups.
  • alkylene groups includes methylene, ethylene, methylmethylene, trimethylene, propylene, tetramethylene, ethylethylene, 1 ,2-dimethylethylene, pentamethylene and hexamethylene.
  • alkenyl groups as defined above and alkynyl groups as defined above, respectively are divalent radicals having single bonds for attachment to two other groups, they are termed "alkenylene” and "alkynylene” respectively.
  • alkylene groups of this invention preferably comprise the same number of carbon atoms as their alkyl counterparts.
  • connectivity to the molecular structure of which it forms part may be through a common carbon atom or different carbon atom, preferably a common carbon atom.
  • a C 3 alkylene group may be for example *-CH 2 CH 2 CH 2 -*, * *, or *-CH 2 CH(-CH 3 )-*.
  • a C 3 cycloalkylene group may be
  • heterocycle refers to non-aromatic, fully saturated or partially unsaturated cyclic groups (for example, 3 to 13 member monocyclic, 7 to 17 member bicyclic, or 10 to 20 member tricyclic ring systems, 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 nitrogen atoms, oxygen atoms and/or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen 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.
  • An optionally substituted heterocyclic refers to a heterocyclic having optionally one or more substituents (for example 1 to 4 substituents, or for example 1 , 2, 3 or 4), selected from those defined above for substituted aryl.
  • heterocyclic groups include piperidinyl, azetidinyl, imidazolinyl, imidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidyl, succinimidyl, 3H- indolyl, isoindolinyl, chromenyl, isochromanyl, xanthenyl, 2H-pyrrolyl, 1 -pyrrolinyl, 2-pyrrolinyl, 3- pyrrolinyl, pyrrolidinyl, 4H-quinolizinyl, 4aH-carbazolyl, 2-oxopiperazinyl, piperazinyl, homopiperazinyl, 2-pyrazolinyl, 3-pyrazolinyl, pyranyl, dihydro-2H-pyranyl, 4H-pyranyl, 3,4- dihydro
  • 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 anthracene) or linked covalently, typically containing 6 to 10 atoms; wherein at least one ring is aromatic.
  • the aromatic ring may optionally include one to three additional rings (either cycloalkyl, heterocyclyl, or heteroaryl) fused thereto.
  • Aryl is also intended to include the partially hydrogenated derivatives of the carbocyclic systems enumerated herein.
  • Non-limiting examples of aryl comprise phenyl, biphenylyl, biphenylenyl, 5- or 6-tetralinyl, 1 -, 2-, 3-, 4-, 5-, 6-, 7-, or 8-azulenyl, 1 - or 2-naphthyl, 1 -, 2-, or 3-indenyl, 1 -, 2-, or 9-anthryl, 1 - 2-, 3-, 4-, or 5-acenaphtylenyl, 3-, 4-, or 5-acenaphtenyl, 1 -, 2-, 3-, 4-, or 10-phenanthryl, 1 - or 2-pentalenyl, 1 , 2-, 3-, or 4-fluorenyl, 4- or 5-indanyl, 5-, 6-, 7-, or 8-tetrahydronaphthyl, 1 ,2,3,4-tetrahydronaphthyl, 1 ,4-dihydronaphthyl, dibenzo[
  • the aryl ring can optionally be substituted by one or more substituents.
  • An "optionally substituted aryl” refers to an aryl having optionally one or more substituents (for example 1 to 5 substituents, for example 1 , 2, 3 or 4) at any available point of attachment.
  • Non-limiting examples of such substituents are selected from halogen, hydroxyl, oxo, nitro, amino, hydrazine, aminocarbonyl, azido, cyano, alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkylalkyl, alkylamino, alkoxy, -S0 2 -NH 2 , aryl, heteroaryl, aralkyl, haloalkyl, haloalkoxy, alkoxycarbonyl, alkylaminocarbonyl, heteroarylalkyl, alkylsulfonamide, heterocyclyl, alkylcarbonylaminoalkyl, aryloxy, alkylcarbonyl, acyl, arylcarbonyl, aminocarbonyl, alkylsulfoxide, -S0 2 R a , alkylthio, carboxyl, and the like, wherein R a is alkyl or cycloalky
  • heteroaryl refers but is not limited to 5 to 12 carbon-atom aromatic rings or ring systems containing 1 to 3 rings which are fused together or linked covalently, typically containing 5 to 8 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 oxygen, nitrogen or sulfur atoms where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized.
  • Such rings may be fused to an aryl, cycloalkyl, heteroaryl or heterocyclyl ring.
  • 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[
  • heteroaryls are in particular selected from furanyl, pyrazolyl, imidazolyl, triazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, and isoindolyl.
  • an “optionally substituted heteroaryl” refers to a heteroaryl having optionally one or more substituents (for example 1 to 4 substituents, for example 1 , 2, 3 or 4), selected from those defined above for substituted aryl, such as for example 1 ,3-dioxoindolyl.
  • alkoxy refers to a radical having the Formula -OR b wherein R b is alkyl.
  • alkoxy is C Ci 0 alkoxy, C C 6 alkoxy, or C C 4 alkoxy.
  • suitable alkoxy include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy.
  • the resultant radical is referred to as thioalkoxy.
  • Haloalkoxy is an alkoxy group wherein one or more hydrogen atoms in the alkyl group are substituted with halogen.
  • suitable haloalkoxy 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.
  • aryloxy denotes a group -O-aryl, wherein aryl is as defined above.
  • arylcarbonyl or “aroyl” as used herein denotes a group -C(0)-aryl, wherein aryl is as defined above.
  • carboxyalkyl is an alkyl group as defined above having at least one substituent that is -C0 2 H.
  • alkoxy by itself or as part of another substituent refers to a group consisting of an oxygen atom attached to one optionally substituted straight or branched alkyl group, cycloalkyl group, aralkyl, or cycloalkylalkyl group.
  • Non-limiting examples of suitable alkoxy group include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, hexanoxy, and the like.
  • halo or halogen as a group or part of a group is generic for fluoro, chloro, bromo, or iodo.
  • haloalkyl alone or in combination, refers to an alkyl radical having the meaning as defined above wherein one or more hydrogens are replaced with a halogen as defined above.
  • haloalkyl radicals include chloromethyl, 1 -bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1 ,1 ,1 -trifluoroethyl, and the like.
  • haloaryl alone or in combination, refers to an aryl radical having the meaning as defined above wherein one or more hydrogens are replaced with a halogen as defined above.
  • haloalkoxy alone or in combination refers to a halo-O-alkyl group wherein the alkyl group is substituted by 1 , 2, or 3 halogen atoms.
  • haloalkoxy includes -OCF 3 , - OCHF 2 , -OCH2F, -O-CF2-CF3, -O-CH2-CF3, -O-CH2-CHF2, and -O-CH2-CH2F.
  • substituted 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 to a useful degree of purity from a reaction mixture, and formulation into a therapeutic agent.
  • groups may be optionally substituted, such groups may be substituted once or more, and preferably once, twice or thrice.
  • Substituents may be selected from, for example, the group comprising halogen, hydroxyl, oxo, nitro, amido, carboxy, amino, cyano haloalkoxy, and haloalkyl.
  • alkyl, aryl, or cycloalkyl each being optionally substituted with” or “alkyl, aryl, or cycloalkyl, optionally substituted with” refers to optionally substituted alkyl, optionally substituted aryl and optionally substituted cycloalkyl.
  • some of the compounds of the invention may contain one or more asymmetric carbon atoms that serve as a chiral center, which may lead to different optical forms (e.g. enantiomers or diastereoisomers).
  • the invention comprises all such optical forms in all possible configurations, as well as mixtures thereof.
  • the compounds of the invention may exist in the form of different isomers and/or tautomers, including but not limited to geometrical isomers, conformational isomers, E/Z-isomers, stereochemical isomers (i.e. enantiomers and diastereoisomers) and isomers that correspond to the presence of the same substituents on different positions of the rings present in the compounds of the invention. All such possible isomers, tautomers and mixtures thereof are included within the scope of the invention.
  • the term "compounds of the invention” or a similar term is meant to include the compounds of general Formula I, la, II or II, and any subgroup thereof. This term also refers to the compounds as depicted in Table 1 , their derivatives, /v-oxides, salts, solvates, hydrates, stereoisomeric forms, racemic mixtures, tautomeric forms, optical isomers, analogues, pro-drugs, esters, and metabolites, as well as their quaternized nitrogen analogues.
  • the v-oxide forms of said compounds are meant to comprise compounds wherein one or several nitrogen atoms are oxidized to the so-called /v-oxide.
  • a compound means one compound or more than one compound.
  • the present invention provides a compound according to formula I or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, or solvate thereof, wherein
  • R-i is selected from -d- 6 alkyl, -Ar 3 , and -S0 2 -Ri6; wherein said -Ci_ 6 alkyl may be further substituted with -R 25 ;
  • R 2 is selected from -H and -Ci_ 6 alkyl
  • R 3 is -H
  • R 4 is -H
  • R 5 is -H
  • R 6 is selected from -H , -Ci_ 6 alkyl, -C 2 . 6 alkenyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -0-C 3 . 6 alkenyl, -S-C 3 .
  • R 6 taken together with R 9 forms -C 3 . 6 cycloalkyl or Het 12 ;
  • R 7 is selected from -Ci_ 6 alkyl, -Ar 4 , and -S0 2 -Ri 3 ; wherein said -Ci_ 6 alkyl may be further substituted with -R 26 ;
  • R 8 is selected from -H and -Ci_ 6 alkyl
  • R 9 is selected from -H , -Ci_ 6 alkyl, -C 2 . 6 alkenyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -0-C 3 . 6 alkenyl, -S-C 3 .
  • R- ⁇ is selected from -H , -d- 6 alkyl, -C 2 . 6 alkenyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -0-C 3 . 6 alkenyl, -S-C 3 .
  • Ri4, Ri5, Ri6, R25, and R 2 6 are each independently selected from -Ci_ 6 alkyl, -C 3 . 6 cycloalkyl, -Ar-i ,
  • R-i -i , R-12 and R 13 are each independently selected from -Ci_ 6 alkyl, -C 3 . 6 cycloalkyl, -Ar 2 , Het 2 , -NH-
  • Ri7, R18, Ri9, R 2 o, R21 , R22, R 23 and R 24 are each independently selected from -H, and -Ci_ 6 alkyl;
  • Ar- ⁇ , Ar 2 , Ar 3 , Ar 4, Ar 5 , Ar 6 , Ar 7 , Ar 8 , Ar 9, and Ar 10 are each independently a 5-10 membered aromatic mono-or bicycle; wherein each of said Ar- ⁇ , Ar 2 , Ar 3 , Ar 4, Ar 5 , Ar 6 , Ar 7 , Ar 8 , Ar 9, and Ar 10 is optionally and independently substituted with from 1 to 5 substituents selected from, -OH , - halo, -Ci- 6 alkyl, -0-Ci_ 6 alkyl, -CN, -CF 3 , -NR 21 R 22 , and -phenyl; wherein said phenyl is optionally substituted with from 1 to 3 substituents selected from -OH, -halo, -Ci_ 6 al
  • Het- ⁇ , Het 2 , Het 3 , Het 4 , Het 5 , Het 6 , Het 7 , Het 8 , Het 9 , Het 10 , Het-n and Het 12 are each independently a
  • the present invention provides a compound according to formula I or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, or solvate thereof, wherein
  • R 2 is -H
  • R 3 is -H
  • R 4 is -H
  • R 5 is -H
  • R 6 is -H
  • R 8 is -H
  • R 9 is -H
  • R 14 is -Ar-i R- ⁇ - ⁇ is -Ar 2
  • Ar- ⁇ , and Ar 2 are each independently a 5-10 membered aromatic mono-or bicycle; wherein each of said Ar- ⁇ , and Ar 2 is optionally and independently substituted with from 1 to 5 substituents selected from, -OH, -halo, -d- 6 alkyl, -0-Ci_ 6 alkyl, -CN , -CF 3 , -NR21 R22, and -phenyl;
  • R 2 i , and R 2 2 are each independently selected from -H, and -Ci_ 6 alkyl.
  • the present invention provides a compound according to formula
  • R 2 is -H
  • R 3 is -H
  • R 4 is -H
  • R 6 is -H
  • R 8 is -H
  • R 9 is -H
  • R 10 is -H
  • Ar- ⁇ , and Ar 2 are each phenyl; wherein each of said Ar- ⁇ , and Ar 2 is optionally and independently substituted with from 1 to 5 -halo.
  • the present invention provides a compound according to formula I wherein the compound has the stereoisomeric conformation as represented in formula la:
  • Such compound is for example a compound according to formula I and la, and represented follows:
  • the present invention provides a compound of Formula II, or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, or solvate thereof
  • R-i is selected from -d- 6 alkyl, -Ar -S0 2 -Ri6; wherein said -Ci_ 6 alkyl may be further substituted with -R 25 ;
  • R 2 is selected from -H and -Ci_ 6 alkyl
  • R 3 is selected from -H, -OH , and -F;
  • R 4 is selected from -H, -OH , and -F;
  • R 5 is selected from -H, -OH, and -F;
  • R 6 is selected from -H, -OH , -F, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, and -CN;
  • R 7 is selected from -Ci_ 6 alkyl, -Ar 4 , and -S0 2 -Ri 3 ; wherein said -Ci_ 6 alkyl may be further substituted with -R 26 ;
  • R 8 is selected from -H and -Ci_ 6 alkyl
  • Ri6, Ri7, -I8, Ri9, R20, R21 , R22 and R 2 3 are each independently selected from -H, and -d- 6 alkyl;
  • Ar- ⁇ , Ar 2 , Ar 3 , and Ar 4 are each independently a 5-10 membered aromatic mono-or bicycle; wherein each of said Ar- ⁇ , Ar 2 , Ar 3 , and Ar 4 is optionally and independently substituted with from 1 to 5 substituents selected from, -OH, -halo, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -CN, -CF 3 , -NR 21 R 22 , and - phenyl; wherein said phenyl is optionally substituted with from 1 to 3 substituents selected from, -OH, -halo, -C 1-6 alkyl, -0-Ci_ 6 alkyl, -CN, -CF 3 , or -NR 21 R 22 ;
  • the present invention provides a compound according to formula II or a stereoisomer, tautomer,
  • R-i is selected from -Ci_ 6 alkyl, -Ar 3 , and -S0 2 -Ri 6 ; wherein said -Ci_ 6 alkyl may be further substituted with -R 25 ;
  • R 2 is selected from -H and -Ci_ 6 alkyl
  • R 3 is -OH
  • R 4 is -OH
  • R 5 is -H
  • R 6 is -H
  • R 7 is selected from -Ci_ 6 alkyl, -Ar 4 , and -S0 2 -Ri 3 ; wherein said -Ci_ 6 alkyl may be further substituted with -R 26 ;
  • R 8 is selected from -H and -Ci_ 6 alkyl
  • Ri 4 , R-I5, R16, R 2 5, and R 26 are each independently selected from -Ci_ 6 alkyl, -C 3 . 6 cycloalkyl, -Ar-i ,
  • R16, R-I7, R18, Ri9, R20, R21 , R22 and R 23 are each independently selected from -H, and -Ci_ 6 alkyl;
  • Ar- ⁇ , Ar 2 , Ar 3 , and Ar 4 are each independently a 5-10 membered aromatic mono-or bicycle; wherein each of said Ar- ⁇ , Ar 2 , Ar 3 , and Ar 4 is optionally and independently substituted with from 1 to 5 substituents selected from, -OH , -halo, -d- 6 alkyl, -0-Ci_ 6 alkyl, -CN, -CF 3 , -NR21 R22, and - phenyl; wherein said phenyl is optionally substituted with from 1 to 3 substituents selected from -OH , -halo, -Ci_ 6 alkyl , -0-Ci_ 6 alkyl , -CN, -CF 3 , or -NR 2 iR 22 ;
  • Het- ⁇ , Het 2 , Het 3 , and He are each independently a 5-10 membered mono-or bicyclic heterocycle comprising from 1 to 3 heteroatoms selected from N, O and S; wherein each of said Het- ⁇ , Het 2 , Het 3 , and Het 4 is optionally and independently substituted with from 1 to 5 substituents selected from -OH , -halo, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -CN, -CF 3 , -NR 23 R 24 , and -phenyl; wherein said phenyl is optionally substituted with from 1 to 3 substituents selected from -OH , -halo, - Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -CN, -CF 3 , or -NR 23 R 24 .
  • the present invention provides a compound according to formula I I or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, or solvate thereof,
  • R 2 is -H ;
  • R 3 is -OH ;
  • R 4 is -OH ;
  • R 5 is -H ;
  • R 6 is -H ;
  • R 8 is -H ;
  • Ar- ⁇ , and Ar 2 are each independently a 5-10 membered aromatic mono-or bicycle; wherein each of said Ar- ⁇ , and Ar 2 is optionally and independently substituted with from 1 to 5 substituents selected from, -OH , -halo, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -CN, -CF 3 , -NR 21 R 22 , and -phenyl.
  • the present invention provides a compound according to formula II or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, or solvate thereof,
  • R 2 is -H ;
  • R 3 is -OH ;
  • R 4 is -OH ;
  • R 5 is -H ;
  • R 6 is -H ;
  • R 8 is -H;
  • R is -Ar
  • R is -Ar 2
  • Ar and Ar 2 are each phenyl; wherein each of said Ar and Ar 2 is optionally and independently substituted with from 1 to 5 -halo.
  • the present invention provides a compound according to formula II wherein the compound has the stereoisomeric conformation as represented in formula Ila:
  • the present invention encompasses a compound as defined herein, such as any and all compounds represented by formulas I, la, II, Ila or as represented in Table 1 , or stereoisomer, tautomer, racemic, salt, metabolite, pre- or prodrug, hydrate, or solvate thereof, and more specific a stereoisomer, tautomer, racemic, salt, hydrate, or solvate thereof.
  • Such compound is for example a compound according to formula II and Ila, and represented as follows:
  • the present invention thus further provides a pharmaceutical composition comprising a compound according to the present invention and a pharmaceutically acceptable excipient, diluent and/or carrier.
  • the present invention provides a combination, as part of a composition or in use, of a compound according to the present invention with an antimicrobial agent, in particular an antibiotic or disinfectant.
  • an antimicrobial agent in particular an antibiotic or disinfectant.
  • one or more compounds as described herein and one or more antimicrobial agents can be part of a single composition or can be used in a separate or sequential application.
  • the present invention provides a compound, composition or combination according to the present invention, for use as a human or veterinary medicament, more in particular, for use in the prevention, reduction and/or treatment of bacterial infections in humans or animals.
  • said bacterial infection is a Staphylococcus aureus infection.
  • the compounds of the present invention can be used as an alternative to replace antibiotics for combating (bacterial) infections or can be used as an adjunct therapy in combination with e.g. antibiotics so that lower doses of the conventional antibiotics are required.
  • the present invention provides a method of preventing, reducing the risk of and/or treating a bacterial infection, more in particular a disorder associated with biofilm formation in a subject; said method comprising administering to a subject in need thereof a therapeutic effective amount of a compound, a composition or a combination according to the present invention.
  • the present invention thus also provides a compound, combination or pharmaceutical composition as defined herein for use in preventing or reducing biofilm formation.
  • biofilm refers to biological films that develop and persist at interfaces in aqueous environments, on medical implants, or as foci of chronic infections. Biofilms may also form on biological surfaces such as teeth, or any other natural or artificial surfaces that may be exposed to or are in contact with non-sterile aqueous environments that may include nutrients suitable for the colonization and proliferation of the microorganisms. These biological films are composed of microorganisms embedded in organic gelatinous matrices composed of one or more matrix polymers that are secreted by the resident microorganisms. Biofilms can develop into macroscopic structures several millimeters or centimeters in thickness and can cover large surface areas.
  • Biofilms are also capable of trapping nutrients and particulates that can contribute to their enhanced development and stability. Biofilms can also prevent penetration of antimicrobial agents, which may lead to persistent infections.
  • Disorders associated with biofilm formation include but are not limited to, dental caries, periodontitis, otitis media, muscular skeletal infections, necrotizing fasciitis, biliary tract infection, osteomyelitis, bacterial prostatitis, endocarditis, native valve endocarditis, cystic fibrosis pneumonia, meloidosis, or skin lesions associated with bullous impetigo, atopic dermatitis and pemphigus foliaceus or implanted device-related infections.
  • the disorder is a nosocomial infection, including but not limited to, pneumonia, sepsis (including SIRS (Systemic Inflammatory Response Syndrome), severe sepsis and MODS (multiorgan dysfunction syndrome)), or an infection associated with sutures, exit sites, arteriovenous sites, scleral buckles, contact lenses, urinary catheter cystitis, peritoneal dialysis (CAPD) peritonitis, lUDs, endotracheal tubes, Hickman catheters, central venous catheters, mechanical heart valves, vascular grafts, biliary stent blockage, and orthopedic devices.
  • SIRS Systemic Inflammatory Response Syndrome
  • MODS multiorgan dysfunction syndrome
  • the compounds of the present invention are of particular interest to prevent, limit the risk of and/or treat post-operative wound infections, skin ulcers, diabetic foot ulcers, pressure ulcers such as decubitus ulcers or bedsores, burn wound infections, catheter associated infections, and infections resulting from animal bites.
  • the compounds as described herein are effective in preventing and/or treating mastitis, i.e. inflammation of the breast tissue.
  • S. aureus is the most common etiological organism responsible, but S. epidermidis and streptococci are occasionally isolated as well.
  • Mastitis in dairy cattle is the persistent, inflammatory reaction of the udder tissue.
  • the present invention further provides a method for the prevention, reducing the risk of and/or treatment of microbial infections, in particular bacterial infections, more in particular infections with bacteria of the genus Staphylococcus such as Staphylococcus aureus infections.
  • the method further comprises contacting a surface with the composition in an amount sufficient to prevent or reduce the growth or proliferation of microorganisms or biofilm-embedded microorganisms on said surface.
  • particular preference is given to compounds of Formula I, la, II or II, or any subgroup thereof, that in the inhibition assay as described in the examples, inhibit with an IC 50 value of less than 100 ⁇ , preferably less than 50 ⁇ , and more preferably less than 10 ⁇ .
  • Said inhibition may be effected in vitro and/or in vivo, and when effected in vivo, is preferably effected in a selective manner, as defined above.
  • the bacterium is contacted with the compound as provided herein ex vivo.
  • the contacting comprises administering the compound to a surface in an amount effective to inhibit biofilm formation on said surface, including but not limited to a medical device.
  • the compounds of the invention may be used as a free acid or base, and/or in the form of a pharmaceutically acceptable acid-addition and/or base-addition salt (e.g.
  • solvate includes any combination which may be formed by a compound of this invention with a suitable inorganic solvent (e.g. hydrates) or organic solvent, such as but not limited to alcohols, ketones, esters and the like.
  • suitable inorganic solvent e.g. hydrates
  • organic solvent such as but not limited to alcohols, ketones, esters and the like.
  • the pharmaceutically acceptable salts of the compounds according to the invention include the conventional non-toxic salts or the quaternary ammonium salts which are formed, e.g., from inorganic or organic acids or bases.
  • acid addition salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2- naphthalene-sulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, to
  • Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, and so forth.
  • the basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl-bromides and others.
  • Other pharmaceutically acceptable salts include the sulfate salt ethanolate and sulfate salts.
  • the compounds of the invention may be formulated as a pharmaceutical preparation or pharmaceutical composition comprising at least one compound of the invention and at least one pharmaceutically acceptable carrier, diluent or excipient and/or adjuvant, and optionally one or more further pharmaceutically active compounds.
  • such a formulation may be in a form suitable for oral administration, for parenteral administration (such as by intravenous, intramuscular or subcutaneous injection or intravenous infusion), for topical administration (including ocular), for administration by inhalation, by a skin patch, by an implant, by a suppository, etc.
  • parenteral administration such as by intravenous, intramuscular or subcutaneous injection or intravenous infusion
  • topical administration including ocular
  • inhalation by a skin patch, by an implant, by a suppository, etc.
  • Such suitable administration forms which may be solid, semi-solid or liquid, depending on the manner of administration - as well as methods and carriers, diluents and excipients for use in the preparation thereof, will be clear to the skilled person; reference is again made to for instance US- A-6, 372,778, US-A-6,369,086, US-A-6,369,087 and US-A-6, 372,733, as well as to the standard handbooks, such as the latest edition of Remington's Pharmaceutical Sciences.
  • Such preparations include tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, creams, lotions, soft and hard gelatin capsules, suppositories, eye drops, sterile injectable solutions, and sterile packaged powders (which are usually reconstituted prior to use) which may be administered as a bolus and/or for continuous administration, which may be formulated with carriers, excipients, and diluents that are suitable per se for such formulations, such as lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, polyethylene glycol, cellulose, (sterile) water, methylcellulose, methyl-
  • the compounds, combinations or pharmaceutical compositions may also be formulated in or may be applied on a medical device, such as skin patches, implantable devices, catheters, tampons, wound dressings, gauges and bandages.
  • a medical device such as skin patches, implantable devices, catheters, tampons, wound dressings, gauges and bandages.
  • one or more compounds as described hereinbefore is used to inhibit biofilm formation on a medical device by contacting the device with said compound (or a combination or pharmaceutical composition comprising the same) in an amount effective to inhibit biofilm formation.
  • Percutaneous devices such as catheters
  • implanted medical devices including, but not limited to, pacemakers, vascular grafts, stents, and heart valves
  • the tendency of some microorganisms to adhere to and colonize the surface of the device promotes such infections, which increase the morbidity and mortality associated with use of the devices.
  • one or more compounds of the present invention can be used or applied on substrates used to manufacture medical devices associated with non-invasive and invasive medical procedures.
  • substrates include, without limitation, tubular, sheet, rod and articles of proper shape for use in a number of medical devices such as vascular grafts, aortic grafts, arterial, venous, or vascular tubing, vascular stents, dialysis membranes, tubing or connectors, blood oxygenator tubing or membranes, surgical instruments, ultrafiltration membranes, intra- aortic balloons, stents, blood bags, catheters, sutures, soft or hard tissue prostheses, synthetic prostheses, prosthetic heart valves, tissue adhesives, cardiac pacemaker leads, artificial organs, endotracheal tubes, lenses for the eye such as contact or intraocular lenses, blood handling equipment, apheresis equipment, diagnostic and monitoring catheters and sensors, biosensors, dental devices, drug delivery systems, or bodily implants of any kind.
  • one or more compounds of the present invention can be used or applied on drug-eluting medical implants.
  • These are active implants that induce healing effects in addition to their regular task of support. This effect is achieved by controlled release of the active agent, including the compounds of the present invention, into the surrounding tissue.
  • Examples are drug-eluting vascular stents, drug- eluting wound dressings and protein-eluting scaffolds for tissue regeneration.
  • the present invention encompasses a medical device as mentioned herein comprising one or more compounds of the present invention. The compounds can be incorporated in or applied on the surface of the medical device.
  • the present invention provides dressings or (cotton) gauges loaded with the compounds or compositions as described herein.
  • Said dressing or guzes are typically used to prevent wound infection as well as treat infected wounds.
  • composition or formulation of the present invention can optionally contain other pharmaceutically active substances, especially antimicrobial agents such as antibiotics or disinfectants (which may or may not lead to a synergistic effect with the compounds of the invention) and/or other substances that are commonly used in pharmaceutical formulations, such as lubricating agents, wetting agents, emulsifying and suspending agents, dispersing agents, disintegrants, bulking agents, fillers, preserving agents, sweetening agents, flavoring agents, flow regulators, release agents, etc.
  • antimicrobial agents such as antibiotics or disinfectants (which may or may not lead to a synergistic effect with the compounds of the invention) and/or other substances that are commonly used in pharmaceutical formulations, such as lubricating agents, wetting agents, emulsifying and suspending agents, dispersing agents, disintegrants, bulking agents, fillers, preserving agents, sweetening agents, flavoring agents, flow regulators, release agents, etc.
  • the method and use as described herein further comprises the step of administering a standard of care antimicrobial agent to the subject.
  • Standard of care refers to a treatment that is generally accepted by clinicians for a certain type of patient diagnosed with a type of illness.
  • exemplary standard of care antimicrobial agents include, but are not limited to, (i) ⁇ -lactam antibiotics like penicillins either alone (including but not limited to penicillin G, penicillin V, flucloxacillin, oxacillin, ampicillin, methicillin, amoxicillin, temocillin, and piperacillin), or combined with a ⁇ -lactamase inhibitors (including but not limited to amoxicillin + clavulanic acid, and piperacillin + tazobactam), carbapenems (including but not limited to biapenem, meropenem and imipenem), monobactams (including but not limited to aztreonam) and cephalosporins (including but not limited to cefadroxil, cefalexine, cefazoline, cefuroxime, cefotaxim, ceftazidim, ceftriaxone, cefepim and ceftarolin), (ii)
  • Combination therapy comprising a compound of the present invention and an antimicrobial agent, e.g. an antibiotic or disinfectant, described herein for the treatment of a bacterial infection is specifically contemplated.
  • an antimicrobial agent e.g. an antibiotic or disinfectant
  • the invention provides a method of treating a bacterial infection or a disorder associated with bacterial QS and/or biofilm formation in a subject comprising administering to the subject a therapeutically-effective amount of a combination therapy comprising (a) a compound of formula I, la, II or II or any subgroup thereof such as for example a compound as depicted in table 1 , and (b) an antimicrobial agent.
  • Such combination therapy would be provided in a combined amount effective to prevent or inhibit QS and/or biofilm formation of the bacteria and/or prevent or treat the bacterial infection and/or treat the disorder associated with biofilm formation.
  • This process involves administering to a subject in need thereof the compound and a (standard of care) therapeutic agent at the same time, which may be achieved by administering a single composition or pharmacological formulation that includes both the compound of the invention and a therapeutic agent, or by administering two distinct compositions or formulations, at the same time, wherein one composition includes the compound of the invention and the other includes a (standard of care) therapeutic agent.
  • the combination therapy involves administering to a subject in need thereof the compound of the invention and a (standard of care) therapeutic agent at different times, which may be achieved by administering two distinct compositions or formulations, at different time intervals, wherein one composition includes the compound of the invention and the other includes a (standard of care) therapeutic agent.
  • compositions may also be formulated so as to provide rapid, sustained or delayed release of the active compound(s) contained therein, for example using liposomes or hydrophilic polymeric matrices based on natural gels or synthetic polymers.
  • An interesting way of formulating the compounds in combination with a cyclodextrin or a derivative thereof has been described in EP-A-721 ,331 .
  • the present invention encompasses a pharmaceutical composition comprising an effective amount of a compound according to the invention with a pharmaceutically acceptable cyclodextrin.
  • a specific example is a nontoxic hydroxypropyl- ⁇ - cyclodextrin-functionalized cellulose gauze loaded with one or more of the compounds as described herein, optionally in combination with an antimicrobial agent.
  • co-solvents such as alcohols may improve the solubility and/or the stability of the compounds.
  • addition of salts of the compounds of the invention can be more suitable due to their increased water solubility.
  • compositions, formulations (and carriers, excipients, diluents, etc. for use therein), routes of administration etc. which are known per se for analogous pyridinocarboxamides, such as those described in US-A-4,997,834 and EP-A-0 370 498.
  • compositions may be formulated in a pharmaceutical formulation comprising a therapeutically effective amount of particles consisting of a solid dispersion of the compounds of the invention and one or more pharmaceutically acceptable water-soluble polymers.
  • a solid dispersion defines a system in a solid state (as opposed to a liquid or gaseous state) comprising at least two components, wherein one component is dispersed more or less evenly throughout the other component or components.
  • a solid solution When said dispersion of the components is such that the system is chemically and physically uniform or homogenous throughout or consists of one phase as defined in thermodynamics, such a solid dispersion is referred to as "a solid solution”.
  • Solid solutions are preferred physical systems because the components therein are usually readily bioavailable to the organisms to which they are administered.
  • Suitable surface modifiers can preferably be selected from known organic and inorganic pharmaceutical excipients. Such excipients include various polymers, low molecular weight oligomers, natural products and surfactants. Preferred surface modifiers include nonionic and anionic surfactants.
  • compositions whereby the compounds are incorporated in hydrophilic polymers and applying this mixture as a coat film over many small beads, thus yielding a composition with good bio-availability which can conveniently be manufactured and which is suitable for preparing pharmaceutical dosage forms for oral administration.
  • Materials suitable for use as cores in the beads are manifold, provided that said materials are pharmaceutically acceptable and have appropriate dimensions and firmness. Examples of such materials are polymers, inorganic substances, organic substances, and saccharides and derivatives thereof.
  • the preparations may be prepared in a manner known per se, which usually involves mixing at least one compound according to the invention with the one or more pharmaceutically acceptable carriers, and, if desired, in combination with other pharmaceutical active compounds, when necessary under aseptic conditions.
  • the pharmaceutical preparations of the invention are preferably in a unit dosage form, and may be suitably packaged, for example in a box, blister, vial, bottle, sachet, ampoule or in any other suitable single-dose or multi-dose holder or container (which may be properly labeled); optionally with one or more leaflets containing product information and/or instructions for use.
  • unit dosages will contain between 1 and 1000 mg, and usually between 5 and 500 mg, of the at least one compound of the invention, e.g. about 10, 25, 50, 100, 200, 300 or 400 mg per unit dosage.
  • the compounds can be administered by a variety of routes including the oral, rectal, ocular, transdermal, subcutaneous, intravenous, intramuscular or intranasal routes, depending mainly on the specific preparation used and the condition to be treated or prevented, and with oral and intravenous administration usually being preferred.
  • At least one compound of the invention will generally be administered in an "effective amount", by which is meant any amount of a compound of the Formula I, la, II or II or any subgroup thereof, such as a compound as depicted in table 1 , that, upon suitable administration, is sufficient to achieve the desired therapeutic or prophylactic effect in the individual to which it is administered.
  • the effective amount is determined, at least in part, upon the compound used, the microbial species present, the structure, system, or host, and the desired level of regulation.
  • Modulating the activity or physiological property of the microbial population includes, but is not limited to, slowing, attenuating, inhibiting, or enhancing the colonization of a surface or proliferation of bacteria, inhibiting the formation of a biofilm, and the like. Modulation includes slowing the formation of bacteria or new bacteria if some bacteria are already present, inhibiting the formation of a biofilm.
  • such an effective amount will usually be between 0.01 to 1000 mg per kilogram body weight day of the patient per day, more often between 0.1 and 500 mg, such as between 1 and 250 mg, for example about 5, 10, 20, 50, 100, 150, 200 or 250 mg, per kilogram body weight day of the patient per day, which may be administered as a single daily dose, divided over one or more daily doses, or essentially continuously, e.g. using a drip infusion.
  • the amount(s) to be administered, the route of administration and the further treatment regimen may be determined by the treating clinician, depending on factors such as the age, gender and general condition of the patient and the nature and severity of the disease/symptoms to be treated.
  • compositions of the present invention can be mixed with suitable additives, such as excipients, stabilizers, or inert diluents, and brought by means of the customary methods into the suitable administration forms, such as tablets, coated tablets, hard capsules, aqueous, alcoholic, or oily solutions.
  • suitable inert carriers are gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose, or starch, in particular, corn starch.
  • the preparation can be carried out both as dry and as moist granules.
  • Suitable oily excipients or solvents are vegetable or animal oils, such as sunflower oil or cod liver oil.
  • Suitable solvents for aqueous or alcoholic solutions are water, ethanol, sugar solutions, or mixtures thereof.
  • Polyethylene glycols and polypropylene glycols are also useful as further auxiliaries for other administration forms.
  • these compositions may contain microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and lactose and/or other excipients, binders, extenders, disintegrants, diluents and lubricants known in the art.
  • compositions When administered by nasal aerosol or inhalation, these compositions may be prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.
  • Suitable pharmaceutical formulations for administration in the form of aerosols or sprays are, for example, solutions, suspensions or emulsions of the compounds of the invention or their physiologically tolerable salts in a pharmaceutically acceptable solvent, such as ethanol or water, or a mixture of such solvents.
  • the formulation can also additionally contain other pharmaceutical auxiliaries such as surfactants, emulsifiers and stabilizers as well as a propellant.
  • auxiliaries such as surfactants, emulsifiers and stabilizers as well as a propellant.
  • the compound according to the invention if desired with the substances customary therefore such as solubilizers, emulsifiers or further auxiliaries are brought into solution, suspension, or emulsion.
  • the compounds of the invention can also be lyophilized and the lyophilizates obtained used, for example, for the production of injection or infusion preparations.
  • Suitable solvents are, for example, water, physiological saline solution or alcohols, e.g.
  • injectable solutions or suspensions may be formulated according to known art, using suitable non-toxic, parenterally- acceptable diluents or solvents, such as mannitol, 1 ,3-butanediol, water, Ringer's solution or isotonic sodium chloride solution, or suitable dispersing or wetting and suspending agents, such as sterile, bland, fixed oils, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.
  • suitable non-toxic, parenterally- acceptable diluents or solvents such as mannitol, 1 ,3-butanediol, water, Ringer's solution or isotonic sodium chloride solution, or suitable dispersing or wetting and suspending agents, such as sterile, bland, fixed oils, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.
  • these formulations When rectally administered in the form of suppositories, these formulations may be prepared by mixing the compounds according to the invention with a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquefy and/or dissolve in the rectal cavity to release the drug.
  • a suitable non-irritating excipient such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquefy and/or dissolve in the rectal cavity to release the drug.
  • the compounds and compositions of the invention are used locally, for instance topical or in both absorbed and non-adsorbed applications.
  • compositions comprising a compound of the present invention, either alone or in combination as described herein, can be used as a topical agent.
  • the topical agent is a solution, that is, in one aspect, a liquid formulation comprising the compound and a carrier.
  • suitable forms include semi-solid or solid forms comprising a carrier indigenous to topical application and having a dynamic viscosity preferably greater than that of water, provided that the carrier does not deleteriously react with the compound in the composition.
  • Suitable formulations include, but are not limited to, lip balms, suspensions, emulsions, creams, ointments, powders, liniments, salves and the like.
  • compositions may be sterilized or mixed with auxiliary agents, including but not limited to, preservatives, stabilizers, wetting agents, buffers or salts for influencing osmotic pressure and the like well known in the art.
  • auxiliary agents including but not limited to, preservatives, stabilizers, wetting agents, buffers or salts for influencing osmotic pressure and the like well known in the art.
  • Preferred vehicles for semi-solid or solid forms topical preparations include ointment bases, conventional ophthalmic vehicles; creams; and gels.
  • topical preparations optionally contain emollients, perfumes, and/or pigments to enhance their acceptability for various usages, provided that the additives do not deleteriously react with the compound in the composition.
  • sprayable aerosol preparations wherein the compound, preferably in combination with a solid or liquid inert carrier material, is packaged in a squeeze bottle or in admixture with a pressurized volatile, normally gaseous propellant, e.g., a Freon (chlorofluorocarbon) or environmentally acceptable volatile propellant.
  • a pressurized volatile, normally gaseous propellant e.g., a Freon (chlorofluorocarbon) or environmentally acceptable volatile propellant.
  • a pressurized volatile, normally gaseous propellant e.g., a Freon (chlorofluorocarbon) or environmentally acceptable volatile propellant.
  • a pressurized volatile propellant e.g., a Freon (chlorofluorocarbon) or environmentally acceptable volatile propellant.
  • the aerosol or spray preparations optionally contain solvents, buffers, surfactants, perfumes, and/or antioxidants in addition to the compound.
  • compositions of the present invention are further of value in the veterinary field, which for the purposes herein not only includes the prevention and/or treatment of diseases in animals, but also - for economically important animals such as cattle, pigs, sheep, chicken, fish, etc. - enhancing the growth and/or weight of the animal and/or the amount and/or the quality of the meat or other products obtained from the animal.
  • the invention relates to a composition for veterinary use that contains at least one compound of the invention and at least one suitable carrier (i.e. a carrier suitable for veterinary use).
  • the invention also relates to the use of a compound of the invention in the preparation of such a composition.
  • the term "subject” includes humans, mammals (e.g., cats, dogs, horses, chicken, pigs, hogs, cows, fish, crabs, shrimps, cattle, and other), and other living species that are in need of treatment.
  • the term "host” includes humans.
  • a composition comprising a compound of the present invention packaged alone, e.g., in a kit or package or unit dose, or is optionally arranged to permit co-administration with one or more other (therapeutic) agents as described herein, but the compound and the agent are not in admixture.
  • the compound and the agent are in admixture.
  • the two components to the kit/unit dose are packaged with instructions for administering the two agents to a human subject for treatment of one of the above-indicated disorders and diseases.
  • the kit may comprise a composition described herein in combination with a vehicle in a cream or gel base, as a pump-spray, as an aerosol, on an impregnated bandage, or in a dropper.
  • a first scaffold was obtained by transposing the 2-benzamidomethyl moiety to position 1 of the tetrahydrofuran core.
  • a 2,5-substituted 1 ,4-dioxane core was put forward as possible bio-isostere of the tetrahydrofuran ring present in HAM-171 .
  • Antimicrobial potentiator HAM-171 consists of a 5-ortho-chlorobenzamidomethyl and a 2'- benzamidomethyl moiety, linked to a central (3S,4R)-tetrahydrofuran-3,4-diol scaffold. While maintaining both aromatic moieties intact, the impact of transposing the 2-benzamidomethyl fragment to position 1 was investigated.
  • Derivative 15 contains a similar atom connectivity as HAM-1 71 .
  • the synthesis of 15 starts with the reaction of benzyl alcohol with (R)- epichlorohydrin (Scheme 2).
  • the resulting (R)-1 -(benzyloxy)-3-chloropropan-2-ol was treated with (S)-glycidyl tosylate to give intermediate 9.
  • Treatment of the latter with aqueous NaOH solution lead to intramolecular ring closure in a 6-exo-tet process to give monoprotected cis- dioxanedimethanol intermediate 10.
  • Subsequent transformation of 10 into heterobisbenzamide 15 occurred via known procedures (Scheme 2).
  • Reactions were monitored by TLC analysis using TLC aluminium sheets (Macherey-Nagel, Alugram Sil G/UV254) with detection by UV or by spraying with a solution of ( ⁇ 4 )6 ⁇ 7 ⁇ 24-4 ⁇ 2 0 (25 g/L) and (NH 4 ) 4 Ce(S0 4 )4-2H 2 0 (10 g/L) in H 2 S0 4 (10 %) followed by charring or an aqueous solution of KMn0 7 (20 g/L) and K 2 C0 3 (10 g/L) or an ethanolic solution of ninhydrin (2 g/L) and acetic acid (1 % v/v) followed by charring.
  • Silica gel column chromatography was performed manually using Grace Davisil 60A silica gel (40-63 ⁇ ) or automated using a Grace Reveleris X2 system and the corresponding flash cartridges.
  • High resolution spectra were recorded with a Waters LCT Premier XE Mass spectrometer.
  • H- and 3 C-NMR spectra were recorded with a Varian Mercury-300BB (300/75 MHz) spectrometer. Chemical shifts are given in ppm ( ⁇ ) relative to tetramethylsilane as an internal standard ( H NMR) or the NMR solvent ( 3 C NMR).
  • Boc-protected amine 4 (100 mg, 0.305 mmol) was taken up in dry 1 ,2-dichloroethane (2 mL) and molecular sieves (3 A rods) were added. The flask was purged with N 2 gas and cooled on ice to 0 °C. Trifluoroacetic acid (0.179 mL, 2.34 mmol) was added and the reaction mixture was stirred for 3 hours. After filtration, the filtrate was taken to dryness and the residue was adsorbed onto celite. FCC (CH 2 CI 2 /MeOH/NH 4 OH 100:0:0.1 ⁇ 90:10:0.1 ) gave the corresponding primary amine, which was subjected to general procedure 1 .
  • HAM Hamamelitannin
  • VAN vancomycin
  • Methicillin-resistant Staphylococcus aureus Mu50 was cultured in Mueller-Hinton broth (MH , Oxoid, Basingstoke, England) at 37°C under aerobic conditions.
  • MICs of HAM analogues used against S. aureus Mu50 were determined in triplicate using flat- bottom 96-well microtiter plates (TPP, Trasadingen, Switzerland) as previously described (2). Effect of pretreatment and co-treatment on biofilm susceptibilty
  • HAM analogues were evaluated as previously described (3,4,6).
  • overnight cultures in MH were centrifuged, the pellet was resuspended in double-concentrated MH (2 x MH) and diluted to an OD590 nm of 0.2.
  • Fifty microliter of the diluted bacterial suspension was transferred to the wells of a round-bottom 96-well microtiter plate (TPP). Control wells received 50 ⁇ MilliQ.
  • Wells used to evaluate pre-treatment received 50 ⁇ of HAM-analogue solution. Bacteria were allowed to adhere and grow without agitation for 4 h at 37 °C.
  • control wells were filled with 50 ⁇ 2 x MH and 50 ⁇ MilliQ. Other wells were filled with 50 ⁇ 2 ⁇ MH and 50 ⁇ of HAM analogue solution, and the plate was incubated for 20 h at 37 °C.
  • control biofilms were formed in the absence of HAM analogues, as described above. After 24 h of biofilm formation, the medium was removed and the wells were rinsed with PS. Control wells were either filled with 100 ⁇ PS (untreated controls) or with 50 ⁇ PS and 50 ⁇ antibiotic solution.
  • CFU colony forming units
  • the number of CFU/biofilm (for plating) of the control biofilms was set to 100% and the results of the treated biofilms were compared to this.
  • Each condition was tested in at least three wells in each assay, and each assay was carried out at least in triplicate (n > 9).
  • MIC minimum inhibitory concentrations against S. aureus Mu50 were determined to rule out a direct effect on growth. In all cases, MIC values were higher than 500 ⁇ , being the highest concentration tested (data not shown). Subsequently, the HAM derivatives were tested for their in vitro effect on S. aureus biofilm susceptibility to vancomycin (VAN), both under pretreatment and combination treatment regimens. VAN is considered a drug of last resort against MRSA. To evaluate the effect of pretreatment, S. aureus Mu50 was allowed to form a biofilm in the presence of the HAM analogues, after which the biofilm was treated with VAN (20 ⁇ g/ml).
  • the bacteria were allowed to form a mature biofilm after which a HAM analogue and VAN were administered simultaneously.
  • VAN resulted only in a minor reduction of the number of S. aureus sessile cells (30 ⁇ 14% compared to an untreated control, Table 1 ).
  • combined treatment of VAN with 2 resulted in significantly more killing of bacterial biofilm cells, both under pretreatment and under combined treatment regimens (Table 1 ).
  • all of the compounds with alternative scaffolds were tested in a concentration of 100 ⁇ .
  • the effect on biofilm susceptibility towards VAN was tested in lower concentrations, which allowed us to determine an EC 50 value. The latter is defined as the concentration of the analogue needed to double the activity of VAN , as measured by the number of surviving cells.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Oncology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Communicable Diseases (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des analogues du hamamélitannin, des compositions pharmaceutiques comprenant ceux-ci et des combinaisons de ceux-ci avec des agents antimicrobiens tels que des antibiotiques ou des désinfectants. La présente invention concerne en particulier, l'utilisation des composés, des compositions et des combinaisons, en médecine humaine ou vétérinaire, plus particulièrement pour une utilisation dans la prévention et/ou le traitement d'infections bactériennes, telles que des infections au Staphylococcus aureus, chez l'homme ou les animaux.
PCT/EP2017/075036 2016-10-04 2017-10-03 Nouveaux analogues du hamamélitannin et leurs utilisations WO2018065387A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP16192234 2016-10-04
EP16192234.9 2016-10-04

Publications (1)

Publication Number Publication Date
WO2018065387A1 true WO2018065387A1 (fr) 2018-04-12

Family

ID=57083183

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2017/075036 WO2018065387A1 (fr) 2016-10-04 2017-10-03 Nouveaux analogues du hamamélitannin et leurs utilisations

Country Status (1)

Country Link
WO (1) WO2018065387A1 (fr)

Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0370498A2 (fr) 1988-11-24 1990-05-30 Yoshitomi Pharmaceutical Industries, Ltd. Composés trans-4-amino(alcoyl)-1-pyridylcarbamoylcyclohexane et leur utilisation pharmaceutique
JPH06234784A (ja) 1993-02-12 1994-08-23 Meiji Seika Kaisha Ltd 新規抗生物質ｓｆ２７６８物質及びその製造法
EP0721331A1 (fr) 1993-10-01 1996-07-17 Astra Aktiebolag Procede (i)
US6369086B1 (en) 1997-09-05 2002-04-09 Smithkline Beecham Corporation Substituted oxidole derivatives as protein tyrosine and as protein serine/threonine kinase inhibitors
US6369087B1 (en) 1999-08-26 2002-04-09 Robert R. Whittle Alkoxy substituted benzimidazole compounds, pharmaceutical preparations containing the same, and methods of using the same
US6372778B1 (en) 1992-09-08 2002-04-16 Vertex Pharmaceuticals, Incorporated Sulfonamide inhibitors of aspartyl protease
US6372733B1 (en) 1995-11-01 2002-04-16 Merck & Co., Inc. Hexahydro-5-imino-1,4-1,4-thiazepine derivatives as inhibitors of nitric oxide synthases
WO2007147098A2 (fr) 2006-06-16 2007-12-21 Tufts University Identification et utilisation d'analogues non peptidiques de peptides inhibant l'arniii pour le traitement d'infections par le staphylocoque
WO2015054828A1 (fr) * 2013-10-15 2015-04-23 Rhodia Operations Procédé de formation d'amine primaire, secondaire ou tertiaire par réaction d'amination directe
WO2016005340A1 (fr) 2014-07-08 2016-01-14 Universiteit Gent Analogues du hamamélitanin et leurs utilisations

Patent Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0370498A2 (fr) 1988-11-24 1990-05-30 Yoshitomi Pharmaceutical Industries, Ltd. Composés trans-4-amino(alcoyl)-1-pyridylcarbamoylcyclohexane et leur utilisation pharmaceutique
US4997834A (en) 1988-11-24 1991-03-05 Yoshitomi Pharmaceutical Industries, Ltd. Trans-4-amino(alkyl)-1-pyridylcarbamoylcyclohexane compounds and pharmaceutical use thereof
US6372778B1 (en) 1992-09-08 2002-04-16 Vertex Pharmaceuticals, Incorporated Sulfonamide inhibitors of aspartyl protease
JPH06234784A (ja) 1993-02-12 1994-08-23 Meiji Seika Kaisha Ltd 新規抗生物質ｓｆ２７６８物質及びその製造法
EP0721331A1 (fr) 1993-10-01 1996-07-17 Astra Aktiebolag Procede (i)
US6372733B1 (en) 1995-11-01 2002-04-16 Merck & Co., Inc. Hexahydro-5-imino-1,4-1,4-thiazepine derivatives as inhibitors of nitric oxide synthases
US6369086B1 (en) 1997-09-05 2002-04-09 Smithkline Beecham Corporation Substituted oxidole derivatives as protein tyrosine and as protein serine/threonine kinase inhibitors
US6369087B1 (en) 1999-08-26 2002-04-09 Robert R. Whittle Alkoxy substituted benzimidazole compounds, pharmaceutical preparations containing the same, and methods of using the same
WO2007147098A2 (fr) 2006-06-16 2007-12-21 Tufts University Identification et utilisation d'analogues non peptidiques de peptides inhibant l'arniii pour le traitement d'infections par le staphylocoque
WO2015054828A1 (fr) * 2013-10-15 2015-04-23 Rhodia Operations Procédé de formation d'amine primaire, secondaire ou tertiaire par réaction d'amination directe
WO2016005340A1 (fr) 2014-07-08 2016-01-14 Universiteit Gent Analogues du hamamélitanin et leurs utilisations

Non-Patent Citations (22)

* Cited by examiner, † Cited by third party
Title
A. VERMOTE; G. BRACKMAN; M. D. P. RISSEEUW; B. VANHOUTTE; P. COS; K. VAN HECKE; K. BREYNE; E. MEYER; T. COENYE; S. VAN CALENBERGH, ANGEWANDTE CHEMIE INTERNATIONAL EDITION, vol. 55, 2016, pages 6551 - 6555
A. VERMOTE; G. BRACKMAN; M. D. P. RISSEEUW; T. COENYE; S. VAN CALENBERGH, ACS MEDICINAL CHEMISTRY LETTERS, 2016
A. VERMOTE; G. BRACKMAN; M. D. P. RISSEEUW; T. COENYE; S. VAN CALENBERGH, BIOORGANIC & MEDICINAL CHEMISTRY, vol. 24, 2016, pages 4563 - 4575
ARTHUR C. COPE ET AL: "Diamines and Bicyclic Amines Derived from cis-2,5-Bis-(hydroxymethyl)-tetrahydrofuran", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 77, no. 4, 1 February 1955 (1955-02-01), US, pages 995 - 998, XP055418756, ISSN: 0002-7863, DOI: 10.1021/ja01609a057 *
BORIS D. ZLATOPOLSKIY; H.-P. KROLL; E. MELOTTO; A. DE MEIJERE, EUROPEAN JOURNAL OF ORGANIC CHEMISTRY, vol. 2004, 2004, pages 4492 - 4502
G. BRACKMAN; K. BREYNE; R. DE RYCKE; A. VERMOTE; F. VAN NIEUWERBURGH; E. MEYER; S. VAN CALENBERGH; T. COENYE, SCIENTIFIC REPORTS, vol. 6, 2016, pages 20321
G. BRACKMAN; P. COS; L. MAES; H. J. NELIS; T. COENYE, ANTIMICROB AGENTS CHEMOTHER, vol. 55, 2011, pages 2655 - 2661
HUMBER L G ET AL: "THE RELATIONSHIP BETWEEN STRUCTURE AND ACTIVITY IN A NOVEL SERIES OF SERUM CHOLESTEROL-LOWERING AGENTS", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, vol. 9, 1 May 1966 (1966-05-01), pages 329 - 337, XP002950247, ISSN: 0022-2623, DOI: 10.1021/JM00321A015 *
JÁNOS KUSZMANN ET AL: "Synthesis of 6-amino-2,5-anhydro-6-deoxy- and -1,6-dideoxy-d-glucitol and some derivatives thereof", CARBOHYDRATE RESEARCH, vol. 123, no. 2, 1 November 1983 (1983-11-01), GB, pages 209 - 229, XP055418768, ISSN: 0008-6215, DOI: 10.1016/0008-6215(83)88478-X *
JIM O'NEILL: "Tackling drug-resistant infections globally: Final report and recommendations", THE REVIEW ON ANTIMICROBIAL RESISTANCE, 2016, Retrieved from the Internet <URL:https://amr-review.org/sites/default/files/160518_Final%20paper_with%20cover.pdf>
K. FUJI; S. NAKANO; E. FUJITA, SYNTHESIS, vol. 1975, 1975, pages 276 - 277
K. HENRICK; M. HIRSHBERG, ACTA CRYSTALLOGRAPHICA SECTION F, vol. 68, 2012, pages 744 - 750
KUSZMANN J ET AL: "1,6-diamino-2,5-anhydro-1,6-dideoxy-l-iditol and some derivatives thereof", CARBOHYDRATE RESEARCH, PERGAMON, GB, vol. 89, no. 1, 16 February 1981 (1981-02-16), pages 103 - 120, XP026759800, ISSN: 0008-6215, [retrieved on 19810216], DOI: 10.1016/S0008-6215(00)85233-7 *
L. BALDASSARRE; E. FORNASARI; C. CORNACCHIA; O. CIRIONI; C. SILVESTRI; P. CASTELLI; A. GIOCOMETTI; I. CACCIATORE, MEDCHEMCOMM, vol. 4, 2013, pages 1114 - 1117
LESLIE G. HUMBER: "Agents Affecting Lipid Metabolism. XVI. The Synthesis of Analogs of trans-1,4-Bis(2-chlorobenzylaminomethyl)cyclohexane 1", JOURNAL OF MEDICINAL CHEMISTRY, vol. 8, no. 3, 1 May 1965 (1965-05-01), pages 401 - 404, XP055419020, ISSN: 0022-2623, DOI: 10.1021/jm00327a033 *
M. I. SIMONE; A. A. EDWARDS; G. E. TRANTER; G. W. J. FLEET, TETRAHEDRON: ASYMMETRY, vol. 19, 2008, pages 2887 - 2894
NOBUO NAKABAYASHI AND AL: "Some reactions of the glycidyl esters of sulfonic acid", BULLETIN OF THE CHEMICALSOCIETY OF JAPAN, vol. 39, 1 January 1966 (1966-01-01), pages 413 - 417, XP002776323 *
O. SIMONETTI; O. CIRIONI; I. CACCIATORE; L. BALDASSARRE; F. ORLANDO; E. PIERPAOLI; G. LUCARINI; E. ORSETTI; M. PROVINCIALI; E. FOR, PLOS ONE, vol. 11, 2016, pages e0151956
P. V. BULATOV ET AL: "Synthesis of mono- and bis(aminomethyl)dioxanes fromN-[3-(2-chloroethoxy)-2-hydroxypropyl]sulfamates", RUSSIAN CHEMICAL BULLETIN, vol. 48, no. 12, 1 December 1999 (1999-12-01), US, pages 2299 - 2301, XP055431009, ISSN: 1066-5285, DOI: 10.1007/BF02498276 *
RENATE M. V. WELL; L. MARINELLI; K. ERKELENS; GIJSBERT A.; VAN D. MAREL; A. LAVECCHIA; HERMAN S. OVERKLEEFT; JACQUES H. V. BOOM; H, EUROPEAN JOURNAL OF ORGANIC CHEMISTRY, vol. 2003, 2003, pages 2303 - 2313
ROBERT K. SUMMERBELL ET AL: "The Stereochemistry of Several 2,5-Disubstituted Dioxanes", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 76, no. 24, 1 December 1954 (1954-12-01), US, pages 6401 - 6407, XP055418791, ISSN: 0002-7863, DOI: 10.1021/ja01653a046 *
Y. GOV; A. BITLER; G. DELL'ACQUA; J. V. TORRES; N. BALABAN, PEPTIDES, vol. 22, 2001, pages 1609 - 1620

Similar Documents

Publication Publication Date Title
KR101203118B1 (ko) 18-원자 거대고리들 및 그 유사체들
US10023602B2 (en) Hamamelitannin analogues and uses thereof
AU2014212485C1 (en) Spiro-lactam NMDA receptor modulators and uses thereof
EP2053920B1 (fr) Inhibition de biofilms bactériens avec dérivés d&#39;imidazole
US20040224981A1 (en) Antibacterial methods and compositions
US20190040084A1 (en) Heterocyclic compounds as rsv inhibitors
NO327312B1 (no) Gyraseinhibitorer og anvendelser derav
CA2881169A1 (fr) Derives de 1,6-diazabicyclo[3,2,1]octan-7-one et leur utilisation dans le traitement d&#39;infections bacteriennes
AU2015281155B9 (en) Novel pyrrolopyrimidine compound or salt thereof, pharmaceutical composition containing same, especially agent for prevention and/or treatment of tumors etc based on NAE inhibitory effect
RU2625305C2 (ru) Твердые формы ингибитора гиразы (r)-1-этил-3-[6-фтор-5[2-(1-гидрокси-1-метил-этил) пиримидин-5-ил]-7-(тетрагидрофуран-2-ил)-1н-бензимидазол-2-ил] мочевины
JP6215827B2 (ja) キサントン化合物の誘導体
CN101365455A (zh) 利福霉素的用法
US20170056405A1 (en) Methods and compositions for treating bacterial infection
US20150132352A1 (en) Methods and compositions for treating bacterial infection
WO2012041934A1 (fr) 2-aminoimidazoles polysubstitués destinés à la lutte contre la formation de biofilms et leur procédé de production
US10441588B2 (en) Methods and compositions for treating bacterial infection
JP6411482B2 (ja) 窒素含有化合物およびその使用
WO2018065387A1 (fr) Nouveaux analogues du hamamélitannin et leurs utilisations
IL263080A (en) Treatment of neurological disorders
AU2018234479A1 (en) 2-aminoimidazole-phenyl derivatives useful for controlling microbial growth
JP2019502667A (ja) 抗菌化合物
US10258640B2 (en) Method of inhibiting quorum sensing in Pseudomonas aeruginosa
US11655225B2 (en) Antimycobacterial heterocyclic amides
KR20190125342A (ko) 항박테리아 화합물로서의 헤테로고리 유도체
US10526278B2 (en) Inhibitors of quorum sensing receptor LasR

Legal Events

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

Ref document number: 17777908

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 17777908

Country of ref document: EP

Kind code of ref document: A1