EP1622890A2 - Agents bloquants du système quorum sensing des bactéries gram-négatives - Google Patents

Agents bloquants du système quorum sensing des bactéries gram-négatives

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Publication number
EP1622890A2
EP1622890A2 EP04731333A EP04731333A EP1622890A2 EP 1622890 A2 EP1622890 A2 EP 1622890A2 EP 04731333 A EP04731333 A EP 04731333A EP 04731333 A EP04731333 A EP 04731333A EP 1622890 A2 EP1622890 A2 EP 1622890A2
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EP
European Patent Office
Prior art keywords
alkyl
group
aryl
heteroaryl
independently
Prior art date
Legal status (The legal status 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 status listed.)
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Application number
EP04731333A
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German (de)
English (en)
Inventor
Aldo Ammendola
Katharina Aulinger-Fuchs
Astrid Gotschlich
Martin Lang
Wael Saeb
Udo Sinks
Andreas Wuzik
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QuoNova LLC
Original Assignee
4SC AG
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Priority to EP04731333A priority Critical patent/EP1622890A2/fr
Publication of EP1622890A2 publication Critical patent/EP1622890A2/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
    • C07D275/02—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings not condensed with other rings
    • C07D275/03—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings not condensed with other rings 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three 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
    • C07D231/38—Nitrogen atoms
    • C07D231/40—Acylated on said nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more 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
    • C07D261/14—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three 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
    • C07D263/48—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three 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
    • C07D277/38—Nitrogen atoms
    • C07D277/44—Acylated amino or imino radicals
    • C07D277/46—Acylated amino or imino radicals by carboxylic acids, or sulfur or nitrogen analogues thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three 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
    • C07D277/54—Nitrogen and either oxygen or sulfur atoms
    • 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
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three 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
    • C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom 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
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • the present invention relates to the use of compounds such as amide, carbazide and hydrazide derivatives as selective inhibitors of bacterial pathogens.
  • the invention refers to a family of compounds that block the quorum sensing system of Gram- negative bacteria, a process for their manufacture, pharmaceutical compositions containing them and to their use for the treatment and prevention of microbial damages and diseases, in particular for diseases where there is an advantage in inhibiting quorum sensing regulated phenotypes of pathogens.
  • microorganisms including bacteria, fungi, protozoa and algae cause severe damages or diseases in different areas such as industry, agriculture, environment and medicine. Especially bacteria as human pathogens cause tremendous costs in public health systems worldwide.
  • the continuing emergence of multiple-drag-resistant bacterial strains has necessitated finding new compounds that can be used in antibacterial treatment.
  • the discovery that Gram-negative bacteria employ a signal transduction pathway comprising a small molecule to globally regulate the production of virulence determinants offers such a novel target.
  • AHL or HSL, Figure 1 A wide variety of Gram-negative bacteria produce N-acyl-L-homoserine lactone (AHL or HSL, Figure 1) derivatives as signal molecules in intercellular communication. These molecules, also referred to as “pheromones” or “quoromones”, comprise a homo- serine lactone moiety linked to an acyl side chain. Bacteria use this signaling system to monitor their population cell density in a process referred to as "quorum sensing". In each cell of a population an HSL synthase from usually the Luxl family of proteins produce a low basal level of diffusible HSLs.
  • HSL concentration increases with bacterial population density until a threshold concentration is reached which results in expression of various HSL-dependent genes through an HSL-receptor protein belonging generally to tl e LuxR family of transcriptional regulators.
  • This HSL-receptor protein complex serves not only as positive transcription regulator of quorum sensing regulated genes but also as positive regulator for the HSL synthesis itself. Therefore, the entire system is amplified via a process of autoinduction. This system was first discovered in the bioluminescent marine bacteria Vibrio harveyi and V. flscheri where it is used to control biolurninescence expression.
  • Table 1 Summary of HSL-based quorum sensing systems
  • Pseudomonas aeruginosa is perhaps the best understood in terms of the role quorum sensing plays in pathogenicity.
  • this human opportunistic pathogen which causes nosocomial infections in immunocompromized patients and has an extremely high potential to develop resistance mechanisms against traditional antibiotic treatment, production of many virulence factors including expression of alkaline protease, endoproteinase, LasA protease, LasB elastase, anthranilate synthase, hemolysins, lectin, cytochrome c oxidase, catalase, Mn- and Fe-dependent superoxide dismutases, exotoxin A, exoenzyme S, chitinase, chitin binding protein, phenazine, hydrogen cyanide, pyocyanin, pyoverdine, phospholipase C, rham
  • Biofilms are defined as an association of microorganisms growing attached to a surface and producing a slime layer of extracellular polymers in which the microbial consortia is embedded in a protective environment (for a review see: Costerton et al., Ann. Rev. Microbiol. 49:711-45, 1995). Biofilms represent a severe problem as bacteria integrated in such a polymer matrix develop resistance to conventional antimicrobial agents. P. aeruginosa cells, for example, growing in an alginate slime matrix have been demonstrated to be resistant to antibiotics (e.g., aminoglycosides, ⁇ -lactam antibiotics, fluoroquinolones) and disinfectants (Govan & Deretic, Microbiol. Rev. 60:539-74, 1996). Several mechanisms for biofilm-mediated resistance development have been proposed (Costerton etal, Science 284:1318-22, 1999).
  • biofilms In most natural, clinical and industrial settings bacteria are predominantly found in biofilms. Drinking water pipes, ship hulls, teeth or medical devices represent typical surfaces colonized by bacteria. On the one hand biofilms decrease the life time of materials through corrosive action in the industrial field, a process also referred to as "biofouling". Furthermore, microbial biofilms growing for example on ship hulls increase fuel consumption through enhanced factional resistance and simultaneously reduce maneuverability. On the other hand two thirds of all bacterial infections in humans are associated with biofilms (Lewis, Antimicrob. Agents Chemother. 45:999-1007, 2001).
  • Pseudomonas aeruginosa forms infectious biofilms on surfaces as diverse as cystic fibrosis lung tissue, contact lenses, and catheter tubes (Stickler et al., Appl Environm. Microbiol. 64:3486-90, 1998). Burkholderia cepacia also forms biofilms in lungs of cystic fibrosis patients and is a major industrial contaminant (Govan et al, J. Med. Microbiol. 45:395-407, 1996). Since biofilm formation of both organisms is demonstrated to require an HSL signaling system, inhibition of their quorum sensing systems would result in an impaired ability to form biofilms and therefore in an increased susceptability to antibacterial treatment.
  • HSL derivatives As signaling molecules of bacterial cell-to-cell communication it has been demonstrated that HSL interfere also with higher organisms. Since HSL derivatives inhibit murine and human leucocyte proliferation and TNF-alpha secretion by lipopolysaccharide (LPS) stimulated human leucocytes (Chliabra et al, J. Med. Chem. 46:97-104, 2003), the suitability of these compounds for iir-munological diseases, particularly autoimmune diseases such as psoriasis, rheumatoid arthritis, multiple sclerosis and type 1 (autoimmune) diabetes is indicated (WO 03/004017, WO 03/022828).
  • LPS lipopolysaccharide
  • HSL molecules are capable of reducing the heart beat without substantially reducing arterial blood pressure. These compounds and analogs of them could, therefore, be suitable for the treatment of cardiac tachyarrhythmias, ischaemic heart disease, congestive heart failure (WO 01/26650). Additionally, HSL compounds have been reported as possible antiallergic drug (WO 95/01175) and for the treatment of a range of diseases including cancer, breast cancer, obesity, lipid metabolism disorders, immune disease, immune deficiency or immune disorders by modulationg STAT activity (WO 03/026641).
  • plants expressing an HSL-lactonase enzyme originally derived from Bacillus sp. have been demonstrated to quench pathogen quorum sensing signaling and to significantly enhance resistance to Erwinia carotovora infections (Dong et al, Nature 411:813-7, 2001).
  • An alternative way to block cell signaling could be to interrupt the HSL synthesis by using analogs of HSL precursors.
  • WO 02/088298 reportedly provides certain nitrogen heterocyclic molecules for controlling biofilms based on the interference with quorum sensing.
  • the compounds of this invention do not show any toxic effect and are therefore suitable for applications in a wide area. Such applications could be the use of the compounds for instance as new antibiotic therapeutics, disinfectants, antifouling coatings or coatings of medical devices.
  • traditional antibacterial agents like amide or 1,2-acylhydrazine derivatives in WO 01/51456; for the synthesis of amide or 1,2- acylhydrazine derivatives see also EP 638545 and EP 982292
  • the compounds of the present invention do not kill the microorganisms, but render them aviralent.
  • the present invention provides compounds selectively modulating bacterial cell-cell communication. Through inhibition of this communication system the expression of many HSL-dependent virulence genes and other phenotypes like swarming motility and biofilm formation are significantly reduced or completely abolished rendering a bacterial population more susceptible to the host immune-response or to treatment with traditional antibacterial agents.
  • the invention refers to a method for inhibiting an HSL- regulated process in a microorganism by exposing the microorganism to a new class of compounds with an inhibitory effect on bacterial signaling.
  • the present invention is directed to novel compounds of the general Formula (I) and pharmaceutically acceptable salts thereof:
  • R is H, alkyl, cycloalkyl, aryl or heteroaryl
  • R 1 is alkyl, cycloalkyl, aryl or heteroaryl
  • R 2 is H, alkyl, cycloalkyl, aryl or heteroaryl
  • a 1 is a substituted monocyclic aromatic ring system
  • a 2 is an optionally substituted C 1 -C 2 o-alkyl group which may contain one or more group(s) Z;
  • Z is selected from tlie group consisting of S, O, N, NR 4 , CO, CO 2 , CS, SO or SO;
  • said substituted ring system carries a substituent R 3 on one or more of the carbon atoms of said ring system;
  • said substituted C r C 2 o-alkyl group carries a substituent R 3 on one or more of the carbon atoms of said alkyl group;
  • R 3 is independently H, OR 4 , SR 4 , hydroxyalkyl, hydroxyalkylamine, cycloalkyl, halogen, haloalkyl, haloalkyloxy. NO 2 , CN, SO 2 NR 4 R 5 , CO 2 NR 4 R 5 , COR 4 , CO 2 R 4 , S0 2 R 4 , SO 3 R 4 , NR 4 R 5 , alkyl, aryl or heteroaryl;
  • R 4 is H, alkyl, cycloalkyl, aryl or heteroaryl
  • R 5 is H, O-alkyl, O-aryl, alkyl, heteroaryl or aryl;
  • a cycloalkyl group denotes a non-aromatic ring system containing three to eight carbon atoms, preferably four to eight carbon atoms, wherein one or more of the carbon atoms in the ring can be substituted by a group X, X being as defined above;
  • the C 3 -C 8 -cycloalkyl residue may be selected from the group comprising -cyclo-C 3 H 5 , -cyclo-C 4 H 7 , -cyclo— C 5 H 9 , -cyclo-C 6 Hn, -cyclo-C 7 H 13 , -cyclo-C 8 H 15;
  • an alkoxy group denotes an O-alkyl group, the alkyl group being as defined above; the alkoxy group is preferably a methoxy, ethoxy, isopropoxy, t-butoxy or pentoxy group.
  • an haloalkyl group denotes an alkyl group which is substituted by one to five halogen atoms, the alkyl group being as defined above; the haloalkyl group is preferably a -C(R ) 3 , -CR 10 (R 10' ) 2 , -CR 10 (R 10' )R 10" , -C 2 (R 10 ) 5 , -CH 2 -C(R 10 ) 3 , -CH 2 -CR 10 (R 10' ) 2 , -CH 2 - CR 10 (R 10' )R 10" , -C 3 (R 10 ) 7 or -C 2 H 4 -C(R 10 ) 3; wherein R 10 , R 10' , R 10" represent F, Cl, Br or I, preferably F;
  • a hydroxyalkyl group denotes an HO-alkyl group, the alkyl group being as defined above;
  • an haloalkyloxy group denotes an alkoxy group which is substituted by one to five halogen atoms, the alkyl group being as defined above; tlie haloalkyloxy group is preferably a -OC(R 10 ) 3 , -OCR 10 (R 10' ) 2 , -OCR 10 (R 10' )R 10" , -OC 2 (R 10 ) 5 , -OCH 2 -C(R 10 ) 3 , -OCH 2 - CR 10 (R 10' ) 2 , -OCH 2 -CR 10 (R 10' )R 10" , -OC 3 (R 10 ) 7 or -OC 2 H 4 -C(R 10 ) 3 , wherein R 10 , R 10' , R 10" represent F, Cl, Br or I, preferably F;
  • a hydroxyalkylamino group denotes an (HO-alkyl) 2 -N- group or HO-alkyl-NH- group, the alkyl group being as defined above;
  • a halogen group is chlorine, bromine, fluorine or iodine;
  • a heteroaryl group denotes a 5- or 6-membered heterocyclic group which contains at least one heteroatom like O, N, S.
  • This heterocyclic group can be fused to another ring.
  • this group can be selected from an oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, fhiazol-
  • R where R is as defined above.
  • a 8 is independently C(R 1 ) 2 , O, S, or NR 12 ;
  • R 12 is independently H, CH 3 , CH 2 -CH 3 , C 6 H 5 , OCH 3 , OCH 2 -CH 3 , OH, or SH;
  • R is independently H, CH 3 , or CH 2 -CH ;
  • R 14 is independently H, alkyl, alkoxy, OH, or SH;
  • a 5 is an optionally substituted C 3 -C ⁇ 6 -alkyl group by one or more substituents R 3 or an optionally substituted 5 or 6-membered heteroaryl group, wliich contains at least one heteroatom like O, N, S, NR , SO, SO 2 , Se; which can optionally be substituted by one or more substituents R ;
  • A is a substituted aryl group, which contains at least one heteroatom like O, N, S,
  • NR 4 , SO, SO 2 , Se which can optionally be substituted by one or more substituents R 8 , R 8 , or R 9 , or an optionally substituted heteroaryl group, which contains at least one heteroatom like O, N, S, NR 4 , SO, SO 2 , Se; which can optionally be substituted by one or more substituents R 8 , R 8 , or R 9 , or a heterocyclic group, which contains at least one double bond, and which may contain a heteroatom like O, N, S, NR 4 , SO, SO 2 , Se; which can optionally be substituted by one or more substituents R 8 , R 8 , or R 9 , or one of the groups mentioned below:
  • X', X", X'", X"" is independently S, O, N, NR 4 , CO, SO, SO 2 , CR , or CRf 3' ⁇ R>4'
  • R , R ; R is independently H, methyl, ethyl, t-butyl, CN, halogen, haloalkoxy, haloalkyl, OH, alkoxy, NR 4 R 5 , COOR 4 ;
  • R j is independently H, OR 4 , SR 4 , hydroxyalkyl, hydroxyalkylamino, cycloalkyl, halogen, haloalkyl, haloalkyloxy, NO 2 , CN, SO 2 NR 4 R 5 , CONR 4 R s , COR 4 , CO 2 R 4 ,
  • R J is independently H, OR 4 , SR 4 , hydroxyalkyl, hydroxyalkylamino, cycloalkyl, halogen, haloalkyl, haloalkyloxy, NO 2 , CN, SO 2 NR 4 R 5 , CONR 4 R 5 , COR 4 , CO 2 R 4 ,
  • R 4 is H, alkyl, cycloalkyl, aryl or heteroaryl
  • R 5 is H, O-alkyl, O-aryl, alkyl, heteroaryl or aryl;
  • heteroaryl group of A . 5 o _r A A 6 may be selected from the group comprising:
  • said C 3 -C 16 -alkyl residue may be selected from the group comprising -C 3 H 7 , -CH(CH 3 ) 2 , -C 4 H 9 , -CH 2 -CH(CH 3 ) 2 , -CH(CH 3 )-C 2 H 5 , -CH 2 -CH(CH 3 )-CH 3 , -C(CH 3 ) 3 , -C 5 H U , -C 2 H 4 -CH(CH 3 ) 2 , -CH(CH 3 )-C 3 H 7 , -CH 2 -CH(CH 3 )-C 2 H 5 , -CH(CH 3 )-CH(CH 3 ) 2 , -C(CH 3 ) 2 -C 2 H 5 , -CH 2 -C(CH 3 ) 3 , -C 6 H 13 , -C 3 H 6 -CH(CH 3 ) 2 , -C 2 H 4 -CH(CH 3 )
  • an alkyl group denotes a linear or branched C ⁇ -C 6 -alkyl, preferably a linear or branched chain of one to five carbon atoms, a linear or branched Ci-Cg-alkenyl or a linear or branched C ⁇ -C 6 -alkinyl group, wliich can optionally be substituted by one or more substituents R , preferably by halogen;
  • a cycloalkyl group denotes a non-aromatic ring system containing three to eight carbon atoms, preferably four to eight carbon atoms, wherein one or more of the carbon atoms in the ring can be substituted by a group X, X being as defined above;
  • the C 3 -C 8 -cycloalkyl residue may be selected from the group comprising -cyclo-C 3 H 5 , -cyclo-C 4 H , -cyclo- C 5 H 9 , -cyclo-C 6 Hn, -cyclo-C 7 H 13 , -cyclo-C 8 H ⁇ 5;
  • an alkoxy group denotes an O-alkyl group, the alkyl group being as defined above; the alkoxy group is preferably a methoxy, ethoxy, isopropoxy, t-butoxy or pentoxy group.
  • the alkyl group being as defined above;
  • the haloalkyl group is preferably a -C(R ) 3 , -CR 10 (R 10' ) 2 , -CR 10 (R 10' )R 10" , -C 2 (R 10 ) 5 , -CH 2 -C(R 10 ) 3 , -CH 2 -CR 10 (R 10' ) 2 , -CH 2 - CR 10 (R 10' )R 10" , -C 3 (R 10 ) 7 or - ⁇ Hr-C(R 10 ) 3, wherein R 10 , R 10' , R 10" represent F, Cl, Br or I, preferably F;
  • a hydroxyalkyl group denotes an HO-alkyl group, the alkyl group being as defined above;
  • an haloalkyloxy group denotes an alkoxy group which is substituted by one to five halogen atoms, the alkyl group being as defined above; the haloalkyloxy group is preferably a -OC(R 10 ) 3 , -OCR 10 (R 10, ) 2 , -OCR 10 (R 10' )R 10" , -OC 2 (R 10 ) 5 , -OCH 2 -C(R 10 ) 3 , -OCH 2 - CR 10 (R 10' ) 2 , -OCH 2 -CR 10 (R 10' )R 10" , -OC 3 (R 10 ) 7 or -OC 2 H 4 -C(R 10 ) 3, wherein R 10 , R 1( R 10 represent F, Cl, Br or I, preferably F;
  • a hydroxyall-ylamino group denotes an (HO-alkyl) 2 -N- group or HO-alkyl-NH- group, the alkyl group being as defined above;
  • a halogen group is chlorine, bromine, fluorine or iodine
  • a heteroaryl group denotes a 5- or 6-membered heterocyclic group which contains at least one heteroatom like O, N, S.
  • This heterocyclic group can be fused to another ring.
  • this group can be selected from an oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, thiazol- 2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, 1,2,4- oxadiazol-3-yl, l,2,4-oxadiazol-5-yl, l,2,4-thiadiazol-3-yl, l,2,4-thiadiazol-5-yl, 1,2,5- oxadiazol-3-yl, l,2,5-oxadiazol-4-yl, l,2,5-thiadiazol-3-yl, 1-imidazolyl,
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula (XIII) or of Formula (I) in free form or in the form of pharmaceutically acceptable salts and physiologically functional derivatives, together with a pharmaceutically acceptable diluent or carrier therefore.
  • physiologically functional derivative refers to compounds which are not pharmaceutically active themselves but which are transformed into their pharmaceutical active form in vivo, i.e. in the subject to which the compound is administered.
  • the present invention also provides a method for the treatment or prophylaxis of a condition where there is an advantage in inhibiting quorum sensing which comprises the administration of an effective amount of a compound of Formula (XIII) or of Formula (I) and physiologically acceptable salts or physiologically functional derivatives thereof.
  • quorum sensing is intended to describe cell-density dependent gene regulation through a diffusible signal molecule (Fuqua et al, J. Bacteriol. 176:269-75, 1994).
  • the invention is also directed to the use of compounds of Formula (XIII) or of Formula (I) and of their pharmacologically tolerable salts or physiologically functional derivatives for the production of a medicament or medical device for the prevention and treatment of diseases, where quorum sensing inhibition is beneficial. Furthermore, the invention is also directed to the use of compounds of Formula (XIII) or of Formula (I) and of their pharmacologically tolerable salts or physiologically functional derivatives for the production of an antibacterial agent for the prevention and treatment of bacterial biofilms in industrial and environmental settings.
  • One method for preparation of compounds of Formula (XIN) comprises the step of reacting a carboxylic acid chloride with Meldrum's acid in presence of a base.
  • this reaction is described in Org. Synth, Coll. Vol. 7, 359-360 (Org. Synth. 1984, Ann. Vol. 63, 198-199), or J Org. Chem. 1978, 43, 2087-2088, and Bull. Chem. Soc. Jpn. 1982, 55, 2186-2189.
  • this method is described in F ⁇ rm ⁇ co Ed. Sci. 1982, 37, 335-342, or in Mon ⁇ tsh. Chemie 1981, 112, 871-874, or in Mon ⁇ tsh. Chemie 1982, 113, 101-110, or in J Am. Chem. Soc. 2000, 122, 8155-8167, or in Synth. Commun. 1989, 19, 3543-3552.
  • R 4 in Formula (XIII) is independently H, alkyl, cycloalkyl, aryl or heteroaryl.
  • R 4 in Formula (XIII) is independently H, alkyl, cycloalkyl, aryl or heteroaryl.
  • R 4 is H.
  • R 5 is H.
  • a preferred compound of Formula (XIII) is a compound wherein R is H or methyl more preferably H.
  • a preferred compound of Formula (XIII) is a compound wherein R is H, phenyl or methyl more preferably H.
  • a preferred compound of Formula (XIII) is a compound wherein A 8 is CH 2 .
  • a preferred compound of Formula (XIII) is a compound wherein A 7 and/ or A 9 are CO.
  • a preferred compound of Formula (XIII) is a compound wherein A 5 is C 6 -C ⁇ -alkyl.
  • a preferred compound of Formula (XIII) is a compound wherein A is selected from the following group:
  • a preferred compound of Formula (XIII) is a compound wherein A 6 is 5-membered heteroaromatic ring system, m is 1, r is 1, q is 0 and R 12 is hydrogen.
  • a preferred compound of Formula (XIII) is a compound wherein A is
  • a preferred compoxmd of Formula (XIII) is a compound wherein A 6 is by R 9 substituted phenyl, m is 1, r is 1, q is 0 and R 12 is methyl or phenyl.
  • a preferred compound of Formula (XIII) is a compound wherein q is 0 and m, r are 1.
  • a preferred compound of Formula (XIII) is a compound wherein r is 1 and m, q are 0.
  • a preferred compound of Formula (XIII) is a compound wherein R is H.
  • a preferred compound of Formula (XIII) is a compound wherein R 8 , R 8 , or R 9 are H, methyl, halogen, hydroxy, or carboxy.
  • the compounds of the present invention can be used to inhibit quorum sensing signaling of bacteria employing HSLs as signal molecules for cell-cell communication.
  • the compounds can be applied to the bacteria listed in Table 1, and more preferably to the bacteria of Table 1 that are pathogens.
  • the compounds of the present invention can be used as antibacterial agents in various applications.
  • the compounds of Formula (XIII) or of Formula (I) are useful for the treatment of a variety of human, animal and plant diseases, where bacterial pathogens regulate the expression of virulence genes and other phenotypes, e.g. biofilm formation, through an HSL-based quorum sensing system.
  • the compounds of the invention can be used also for organisms which will be added to the above listed in fixture.
  • the compounds can be used for the treatment of pulmonary infections caused by Burkholderia cepacia (preferably in immunocompromized and cystic fibrosis patients), gastroenteritis and wound infections caused by Aeromonas hydrophila, sepsis in tropical and subtropical areas caused by Chromobacterium violaceum, diarrhoea with blood and haemolytic uremic syndrome (HUS) caused by Escherichia coli, yersiniosis triggered by Yersinia enterocolitica and Y. pseudotuberculosis, and transfxxsion-related sepsis and fistulous pyoderma caused by Serratia liquefaciens.
  • Burkholderia cepacia preferably in immunocompromized and cystic fibrosis patients
  • gastroenteritis and wound infections caused by Aeromonas hydrophila
  • sepsis in tropical and subtropical areas caused by Chromobacterium violaceum
  • the compounds can be used for the prevention and/or treatment of animal diseases, preferably fish diseases such as septicemia caused by Aeromonas hydrophila and Vibrio anguillarum, furunculosis in salmonids caused by Aeromonas salmonicida, prawn infections caused by Vibrio harveyi and enteric redmouth disease caused by Yersinia ruckeri, but also for the prevention and/or treatment of insect diseases caused, for example, by Xenorhabdus nematophilus.
  • animal diseases preferably fish diseases such as septicemia caused by Aeromonas hydrophila and Vibrio anguillarum, furunculosis in salmonids caused by Aeromonas salmonicida, prawn infections caused by Vibrio harveyi and enteric redmouth disease caused by Yersinia ruckeri
  • insect diseases preferably, by Xenorhabdus nematophilus.
  • tlie compounds can be used as antibacterial agent for topical use in cleaning and treatment solutions such as disinfectants, detergents, household cleaner and washing powder formulations in the form of a spray or a dispensable liquid.
  • cleaning and treatment solutions such as disinfectants, detergents, household cleaner and washing powder formulations in the form of a spray or a dispensable liquid.
  • these solutions can be applied to windows, floors, clothes, kitchen and bathroom surfaces and otlier sxxrfaces in the area of food preparation and personal hygiene.
  • the compounds of Formula (XIII) or of Formula (I) can be used as antibacterial ingredients in personal hygiene articles, toiletries and cosmetics such as dentifrices, mouthwashes, soaps, shampoos, shower gels, ointments, creams, lotions, deodorants and disinfectants and storage solutions for contact lenses.
  • the compounds of Formula (XIII) or of Formula (I) can also be applied as coating or additive to the lens material.
  • the compounds can be used to prevent or treat bacterial biofilms in industrial settings such as ship hulls, paper and metal manufacturing, oil recovery, food processing and other applications where process disturbances are referred to biofouling on surfaces.
  • the compounds here can be used in form of a solution, paint or coating, for example as an ingredient in cooling lubricants.
  • the compounds can also be applied to water processing plants or drinking water distribution systems where the colonized surface (preferably by Pseudomonas aeruginosa) is preferably the inside of an aqueous liquid system such as water pipes, water injection jets, heat exchangers and cooling towers.
  • the indwelling catheters are urinary catheters, vascular catheters, peritoneal dialysis catheter, central venous catheters and needleless connectors.
  • the catheter materials can be polyvinylchloride, polyethylene, latex, teflon or similar polymeric materials, but preferably polyurethane and silicone or a mixture thereof.
  • antiseptic or antimicrobial agents such as chlorhexidine/silver- sulfadiazine and minocycline/rifampin, respectively, have been developed.
  • the compounds of the present invention offer the possibility to effectively reduce catheter-related bacterial infections with a low risk of resistance development due to a novel therapeutic strategy targeting highly sensitive signal transduction mechanisms in bacteria.
  • the preferred form of application is the coating and/or impregnating of catheter materials on both the inner and outer catheter sxxrfaces. More preferably, the compoxxnds of Formula (XIII) or of Formula (I) can be included in a mixture of antibacterial agents released continously from a catheter-associated depot into the environment.
  • pharmaceutically inert inorganic or organic excipients can be used.
  • pills tablets, coated tablets and hard gelatin capsules, e.g., lactose, corn starch or derivatives thereof, talc, stearic acid or its salts, etc.
  • Excipients for soft gelatin capsules and suppositories are, e.g., fats, waxes, semi-solid and liquid polyols, natural or hardened oils etc.
  • Suitable excipients for the production of solutions and syrups are, e.g., water, alcohol, sucrose, invert sugar, glucose, polyols etc.
  • Suitable excipients for the production of injection solutions are, e.g., water, alcohol, glycerol, polyols or vegetable oils.
  • a daily dose of approximately 0,1 mg to 5000 mg, preferably 10 to 500 mg, per mammalian in particular human individual is appropriate in the case of the oral administration which is the preferred form of administration according to the invention. In the case of other administration forms too, the daily dose is in similar ranges.
  • the compounds of Formula (XIII) or of Formula (I) can also be used in the form of a precursor (prodrug) or a suitably modified form, that releases the active compound in vivo.
  • the acyl Meldrxxm's acid (1.2 eq) was dissolved in anhydrous benzene (concentration approximately 0.4 mol/1), and the amine (1.0 eq) was added.
  • amine hydrochlorides one equivalent of triethylamine or N,N-diisopropylethylamine was added.
  • the mixture was refluxed until tic showed complete conversion (typically, 4 to 6 h).
  • the benzene solutions were directly chromatographed on silica gel in an appropriate solvent mixture (isohexane - ethyl acetate, dichloromethane - methanol, or dichloromethane - acetonitrile mixtures). Yields of the purified products typically were in the range from 30 to 75 %.
  • the bacterial biofilm formation assay was performed in polystyrene microtitre dishes (Greiner Bio-One) according to the method described by O oole & Kolter (Mol. Microbiol. 28:449-61, 1998) and Pratt & Kolter (Mol. Microbiol. 30:285-93, 1998) with few modifications (Huber et al, Microbiology, 147:2517-28, 2001). Cells of Burkholderia cepacia Hill (Romling et al, J. Infect. Dis. 170:1616-21, 1994; Gotschlich et al, Syst. Appl Microbiol.
  • the crystal violet was solubilized in a 80:20 (v/v) mixture of ethanol and acetone and the absorbance was determined at 570 nm (Sunrise, Tecan). Inhibitor-mediated reduction of biofilm formation was correlated with the value obtained without addition of the test compounds. The determined inhibition range (in %) of each compound is listed in Table 2.

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  • General Chemical & Material Sciences (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne l'utilisation de composés de formule générale (XIII), dans laquelle A7 désigne C=O, C=S, S02, CH-OR13, C=NR12 ou CH2-CHOR13 ; A8 désigne C(R14)2, 0, S ou NR12 ; A9 désigne C=O, C=S, SO2, CH-OR13, C=NR12 ou CH2-CHOR13 ; m représente 0 ou 1 ; q représente 0 ou 1 ; r représente 0 ou 1 ; R12 désigne H, CH3, CH2-CH3, C6H5, OCH3, OCH2-CH3, OH ou SH ; R13 désigne H, CH3 ou CH2-CH3 et R14 désigne H, alkyle, alcoxy, OH ou SH.
EP04731333A 2003-05-06 2004-05-06 Agents bloquants du système quorum sensing des bactéries gram-négatives Withdrawn EP1622890A2 (fr)

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EP03010185A EP1475092A1 (fr) 2003-05-06 2003-05-06 Bloqueurs du system de detection de quorum des bacteries Gram-negatives
EP04731333A EP1622890A2 (fr) 2003-05-06 2004-05-06 Agents bloquants du système quorum sensing des bactéries gram-négatives
PCT/EP2004/004850 WO2004099175A2 (fr) 2003-05-06 2004-05-06 Modulation de pouvoir pathogene

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US20070129690A1 (en) 2005-12-02 2007-06-07 Joel Rosenblatt Catheter with polymeric coating
TW200825050A (en) * 2006-10-27 2008-06-16 Univ Tokyo Amide compound or salt thereof, and biofilm formation inhibitor, biofilm remover and bactericide each using the amide compound or salt thereof
US8258307B2 (en) 2006-11-07 2012-09-04 University Of Tokyo Amide compound or salt thereof, and biofilm inhibitor, biofilm remover and disinfectant containing the same
EP2078713A1 (fr) * 2007-12-28 2009-07-15 QuoNova GmbH Inhibiteurs de formation de biofilm de bactérie gram-positive et gram-négative
EP2100602A1 (fr) * 2008-03-12 2009-09-16 QuoNova Europe GmbH Procédé et compositions convenant au traitement des plaies
KR101349752B1 (ko) 2012-04-26 2014-01-13 세종대학교산학협력단 정족수 감지 억제 활성 및 항균 활성을 갖는 항균용 조성물

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EP1475092A1 (fr) 2004-11-10

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