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  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen 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
  • C07D213/72—Nitrogen atoms
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  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen 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
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  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
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  • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
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  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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  • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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  • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
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  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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  • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen 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
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  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen 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
  • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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  • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen 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
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  • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen 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
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  • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
  • C07D241/40—Benzopyrazines
  • C07D241/44—Benzopyrazines 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 carbon atoms of the hetero ring
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  • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
  • C07D295/06—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals
  • C07D295/073—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals with the ring nitrogen atoms and the substituents separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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  • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Definitions

• the present invention concerns novel Gram-negative bacteria efflux pump inhibitors. It further relates to the use of Gram-negative bacteria efflux pump inhibitors to prevent and/or treat antibiotic resistance by potentiating the activity of antibiotics.
• MDR multidrug resistant
• R&D Resistance Modulation cell Division
• RND-type efflux pumps comprise three components that assemble into tripartite complexes spanning the entire Gram-negative envelope (Du, D., Wang-Kan, X., Neuberger, A. et al. Multidrug efflux pumps: structure, function and regulation. Nat Rev Microbiol. 2018,16,523-539. doi.org/10.1038/s41579-018-0048-6).
• the canonical RND-type efflux pump is the AcrA-AcrB-TolC tripartite system from Escherichia coli, where AcrB is the inner membrane component, AcrA the periplasmic adapter protein, and TolC the outer- membrane channel.
• EPIs include Phe-Arg b-naphthylamide (RAbN), 1-(1-naphtylmethyl)-piperazine (NMP), pyridopyrimidine (such as D13-9001), and pyranopyridine (the MBX series) that inhibit RND-pump mediated efflux and boost antibiotic activity of all known substrate drugs of the pump in Gram-negative pathogens (Opperman TJ, Nguyen ST. Recent advances toward a molecular mechanism of efflux pump inhibition. Front Microbiol. 2015, 6, 421. doi: 10.3389/fmicb.2015.00421).
• EPIs efflux pump inhibitors
• a phenotypic assay was used to screen a chemical library of 1280 compounds at 300 mM, in combination with a sub-active dose of pyridomycin, an antibiotic identified as a particularly good substrate of the AcrAB-TolC efflux pump.
• the inventors have thus discovered a novel class of RND- EPI. These molecules are used to potentiate the activity of antibiotics.
• the present invention thus relates to a compound of formula (I) :
• - R 1 can be chosen from:
• - R 2 can be chosen from:
• R 2 forms together with the carbon atom in position 6, a fused phenyl or (5-6 membered)heteroaryl in positions 5 and 6; said fused heteroaryl having at least one heteroatom chosen from O, N, or S ; and said fused phenyl or heteroaryl being optionally substituted by one or more of : o one or more halogen atoms, o one or more -(Ci-C 4 )alkyl groups, o one or more -(Ci-C 3 )halogenoalkyl groups, o one or more -(Ci-C 3 )alkoxy groups optionally substituted by one to three fluorine atoms, o a (4-10 membered)heterocycle having at least one N, said heterocycle comprising optionally a bridge of 0 to 2 carbon atoms between 2 members of the heterocycle and being optionally substituted by one or more of a - (C1-C3) alkyl group, a NRR’ group or a
• - Ra is chosen from:
• a -(Ci-C 3 )alkyl-(5-6 membered)heteroaryl optionally substituted by a halogen atom, a methyl group optionally substituted by one to three fluorine atoms, a methoxy group optionally substituted by one to three fluorine atoms;
• - R and R’ identical or different are chosen from -(Ci-C3)alkyl group and H;
• - Rb is chosen from:
• - R 3 is chosen from: a heterocycle comprising 4 to 10 members with at least one N; said heterocycle comprising optionally a bridge of 0 to 2 carbon atoms between 2 members of the heterocycle and being optionally substituted by a -(C1-C3) alkyl group or a -NRR’ group; and
• R 7 and R 8 identical or different are chosen from H, -(Ci-C 6 )alkyl group and -CO-(Ci- C 6 )alkyl group; said -(Ci-C 6 )alkyl group and -CO-(Ci-C 6 )alkyl group being optionally substituted by -NRR’ group; or its pharmaceutically acceptable salts or optical isomers, racemates, diastereoisomers, enantiomers or tautomers ;
• the invention also relates to a pharmaceutical composition
• a pharmaceutical composition comprising a compound of formula (I) as described above and a pharmaceutically acceptable excipient.
• the invention further relates to a compound of formula (I) :
• N; - Y can be chosen from:
• - R 1 can be chosen from:
• R 1 forms together with Y a fused phenyl in positions 3 and 4;
• - R 2 can be chosen from:
• R 2 forms together with the carbon atom in position 6, a fused phenyl or (5-6 membered)heteroaryl in positions 5 and 6; said fused heteroaryl having at least one heteroatom chosen from O, N, or S ; and said fused phenyl or heteroaryl being optionally substituted by one or more: o one or more halogen atoms, o one or more-(Ci-C4)alkyl groups, o one or more -(Ci-C3)halogenoalkyl groups, o one or more -(Ci-C3)alkoxy groups optionally substituted by one to three fluorine atoms, o a (4-10 membered)heterocycle having at least one N, said heterocycle comprising optionally a bridge of 0 to 2 carbon atoms between 2 members of the heterocycle and being optionally substituted by one or more of a - (C1-C3) alkyl group, a NRR’ group or a carbonyl; said -(C
• - Ra is chosen from:
• a -(Ci-C 3 )alkyl-(5-6 membered)heteroaryl optionally substituted by a halogen atom, a methyl group optionally substituted by one to three fluorine atoms, a methoxy group optionally substituted by one to three fluorine atoms;
• - R and R’ identical or different are chosen from -(Ci-C3)alkyl group and H;
• - Rb is chosen from:
• a heterocycle comprising 4 to 10 members with at least one N; said heterocycle comprising optionally a bridge of 0 to 2 carbon atoms between 2 members of the heterocycle and being optionally substituted by a -(C1-C3) alkyl group or a -NRR’ group; and
• a -NH-heterocycle said heterocycle comprising 4 to 10 members with at least one N; said heterocycle comprising optionally a bridge of 0 to 2 carbon atoms between 2 members of the heterocycle;
• R 7 and R 8 identical or different are chosen from H, -(Ci-C 6 )alkyl group and -CO-(Ci- C 6 )alkyl group; said -(Ci-C 6 )alkyl group and -CO-(Ci-C 6 )alkyl group being optionally substituted by -NRR’ group; or its pharmaceutically acceptable salts or optical isomers, racemates, diastereoisomers, enantiomers or tautomers; for use as a medicament, in particular to prevent and/or treat antibiotic resistance.
• the present invention also relates to a method for treating a bacterial infection, comprising administering to a subject in need thereof, a compound of formula (I): (I)
• - R 1 can be chosen from:
• R 1 forms together with Y a fused phenyl in positions 3 and 4;
• - R 2 can be chosen from:
• R 2 forms together with the carbon atom in position 6, a fused phenyl or (5-6 membered)heteroaryl in positions 5 and 6; said fused heteroaryl having at least one heteroatom chosen from O, N, or S ; and said fused phenyl or heteroaryl being optionally substituted by one or more: o one or more halogen atoms, o one or more-(Ci-C4)alkyl groups, o one or more -(Ci-C3)halogenoalkyl groups, o one or more -(Ci-C3)alkoxy groups optionally substituted by one to three fluorine atoms, o a (4-10 membered)heterocycle having at least one N, said heterocycle comprising optionally a bridge of 0 to 2 carbon atoms between 2 members of the heterocycle and being optionally substituted by one or more of a - (C1-C3) alkyl group, a NRR’ group or a carbonyl; said -(C
• - Ra is chosen from:
• a -(Ci-C 3 )alkyl-(5-6 membered)heteroaryl optionally substituted by a halogen atom, a methyl group optionally substituted by one to three fluorine atoms, a methoxy group optionally substituted by one to three fluorine atoms;
• - R and R’ identical or different are chosen from -(Ci-C3)alkyl group and H;
• - Rb is chosen from:
• a heterocycle comprising 4 to 10 members with at least one N; said heterocycle comprising optionally a bridge of 0 to 2 carbon atoms between 2 members of the heterocycle and being optionally substituted by a -(C1-C3) alkyl group or a -NRR’ group; and
• heterocycle comprising 4 to 10 members with at least one N; said heterocycle comprising optionally a bridge of 0 to 2 carbon atoms between 2 members of the heterocycle;
• R 7 and R 8 identical or different are chosen from H, -(Ci-C 6 )alkyl group and -CO- (Ci-C 6 )alkyl group; said -(Ci-C 6 )alkyl group and -CO-(Ci-C 6 )alkyl group being optionally substituted by -NRR’ group; or its pharmaceutically acceptable salts or optical isomers, racemates, diastereoisomers, enantiomers or tautomers; in combination with an antibiotic.
• halogen refers to fluorine, chlorine, bromine or iodine atom, in particular bromine, iodine or chlorine atom.
• alkyl represents an aliphatic-hydrocarbon group which may be straight or branched, having 1 to 6 or 1 to 4 or 1 to 3 carbon atoms in the chain (Ci-C 6 )alkyl or (Ci-C4)alkyl or (Ci-C3)alkyl, unless specified otherwise.
• alkyl groups have 1 to 3 carbon atoms in the chain (C1-C3) alkyl.
• Branched means that one or more alkyl groups such as methyl, ethyl or propyl are attached to a linear alkyl chain.
• alkyl groups include methyl, ethyl, n-propyl, i-propyl, n- butyl, t-butyl, 2,2-dimethylbutyl, n-pentyl, n-hexyl, in particular methyl or ethyl.
• said alkyl can be substituted by one heteroatom chosen from O, N or
• halogenoalkyl represents an aliphatic-hydrocarbon group which may be straight or branched, having 1 to 3 carbon atoms in the chain (Ci-C3)halogenoalkyl and in which one or more hydrogen atoms has been replaced by a halogen atom such as fluorine, chlorine, bromine or iodine atom, in particular by one or more fluorine atoms.
• exemplary halogenoalkyl include trifluoromethyl.
• nitrile refers to CoN.
• alkoxy represents an alkyl group as previously defined singular bonded to oxygen.
• Examples of linear or branched (Ci-C3)alkoxy includes methoxy (CH 3 0) and ethoxy (CH 3 CH 2 0-). Said alkoxy can be substituted by one or more fluorine atoms such as trifluoromethoxy.
• alkenyl refers to an aliphatic hydrocarbon group containing a carbon-carbon double bond and which may be straight or branched having 2 to 6 carbon atoms in the chain (C2-C6)alkenyl, unless specified otherwise.
• Preferred alkenyl groups have 2 to 3 carbon atoms in the chain (C2-C3)alkenyl.
• Exemplary alkenyl groups include ethenyl, n-propenyl, i-propenyl, n-butenyl, i-butenyl, 2,2-dimethylbut-1- enyl, n-pentenyl, in particular propenyl.
• said alkenyl can be substituted by one heteroatom chosen from O, N or S (it being understood that it is one of the carbons of the alkyl group which is substituted by O, N or S).
• alkynyl refers to an aliphatic hydrocarbon group containing a carbon-carbon triple bond and which may be straight or branched having 2 to 6 carbon atoms in the chain (C2-Ce)alkynyl, unless specified otherwise.
• Preferred alkynyl groups have 3 to 5 carbon atoms in the chain (C3-C 5 )alkynyl.
• Exemplary alkynyl groups include ethynyl, propynyl, but-1-ynyl, but-2-ynyl, pent-1-ynyl.
• said alkynyl can be substituted by one heteroatom chosen from O, N or S (it being understood that it is one of the carbons of the alkyl group which is substituted by O, N or S).
• aryl refers to an aromatic monocyclic or multicyclic hydrocarbon ring system of
• aryl groups include phenyl, naphthyl, biphenyl, in particular phenyl.
• Said aryl or phenyl can be substituted by one or more halogen atoms such as fluorine, bromine, iodine or chlorine, in particular chlorine; one or more (Ci-C4)alkyl or (Ci-C3)alkyl such as a methyl, said alkyl being optionally substituted by one to 3 fluorine atoms such as trifluoromethyl; one or more (Ci-C3)alkoxy such as methoxy, said alkoxy being optionally substituted by one or more fluorine atoms such as trifluoromethoxy, a NRR’ group, R and R’ being as defined herein, in particular by Nhh; a (4-8- membered)heterocycle having at least one N; a NH-heterocycle; an aryl of 6 to 10
• heteroaryl refers to a 5 to 12, in particular 5 to 6 aromatic mono-, bi- or multicyclic ring wherein at least one member of the ring is a hetero atom. Hetero atoms can be O, S or N, in particular N. In particular, each ring comprises from 1 to 3 hetero atoms. When bi- or multicylcic rings are comtemplated, at least one of the ring is aromatic but the other can be non aromatic, such as 1 ,2,3,4-tetrahydroisoquinoline and isoindoline.
• Examples include pyrrolyl, pyridyl, oxadiazol, thiazol, oxazol, triazol, pyrazolyl, pyrimidinyl, pyrazinyl, indolyl, imidazolyl, in particular pyridyl, triazol or oxadiazol.
• Said heteroaryl can be substituted by one or more halogen atoms such as fluorine, bromine, iodine or chlorine, in particular chlorine; one or more (Ci-C4)alkyl or (C1-C3) alkyl such as a methyl, said alkyl being optionally substituted by one to 3 fluorine atoms such as trifluoromethyl or by a NRR’ group, R and R’ being as defined herein, in particular by methylamine, ethylamine or propylamine; one or more (CrC3)alkoxy such as methoxy, said alkoxy being optionally substituted by one or more fluorine atoms such as trifluoromethoxy; a (4-8-membered)heterocycle having at least one N; a NH-heterocycle; an aryl of 6 to 10 carbon atoms, preferably of 6 carbon atoms, optionally substituted by a NRR’ group, R and R’ being as defined herein (such as
• “-(Ci-C3)alkyl-phenyl” or “-(Ci-C 3 )alkyl-(5-6membered)heteroaryl” means that R a is linked to the oxygen atom of COO- or Rb of -N(H)Rb- is linked to the carbon of the alkyl group; in particular -(Ci-C3)alkyl-phenyl is a benzyl, ethylphenyl or propylphenyl.
• Phenyl can be substituted as above mentioned, in particular by a halogen atom such as fluorine, bromine, iodine or chlorine, in particular chlorine; (Ci-C4)alkyl or (Ci-C3)alkyl such as a methyl, said alkyl being optionally substituted by one to 3 fluorine atoms such as trifluoromethyl; (CrC3)alkoxy such as methoxy, said alkoxy being optionally substituted by one or more fluorine atoms such as trifluoromethoxy.
• a halogen atom such as fluorine, bromine, iodine or chlorine, in particular chlorine
• (Ci-C4)alkyl or (Ci-C3)alkyl such as a methyl, said alkyl being optionally substituted by one to 3 fluorine atoms such as trifluoromethyl
• (CrC3)alkoxy such as methoxy, said alkoxy being optionally substituted by one or more fluorine
• - “-CO-NH-(Ci-C3)alkyl-(C6-Cio)aryl” means that the aryl is linked to the alkyl group by a carbon of the alkyl group; in particular -(Ci-C3)alkyl-(C6-Cio)aryl -is (Ci- C3)alkyl-phenyl, more particularly benzyl, ethylphenyl or propylphenyl. Phenyl can be substituted as above mentioned, in particular by a halogen atom such as fluorine, bromine, iodine or chlorine, in particular chlorine; a methyl or a methoxy.
• CONH-(C 6 -Cio)aryl means that the nitrogen atom of -CO-NH- is linked to a carbon of the aryl; in particular - CONH-(C 6 -Cio)aryl is CONH-phenyl.
• Phenyl can be substituted as above mentioned, in particular by a NRR’ group, R and R’ being as defined herein, in particular ethylamine.
• - “-(Ci-C 3 )alkyl-0-(C 6 -Cio)aryl” means that the alkyl group is linked to the atom of oxygen by a carbon of the alkyl group, the oxygen atom being also linked to a carbon of the aryl group; in particular -(Ci-C 3 )alkyl-0-(C 6 -Cio)aryl -is (Ci-C3)alkyl- O-phenyl, more particularly methyl-O-phenyl.
• Phenyl can be substituted as above mentioned in particular by a NRR’ group, R and R’ being as defined herein, in particular methylamine.
• “-0-(Ci-C 3 )alkyl-(C 6 -Cio)aryl” means that the alkyl group is linked to the atom of oxygen by one of the carbons of the alkyl group, another carbon of the alkyl group being linked to a carbon of the aryl group; in particular -0-(Ci-C 3 )alkyl-(C 6 -Cio)aryl is -0-(Ci-C 3 )alkyl-phenyl, more particularly -O-methyl-phenyl.
• Phenyl can be substituted as above mentioned in particular by a NRR’ group, R and R’ being as defined herein, in particular methylamine.
• Rb in N(H)Rb-Ra is directly linked to the nitrogen atom.
• heterocycle or “heterocycloalkyl” refers to a saturated or partially unsaturated non aromatic stable 4 to 10-membered mono, bi or multicyclic rings which can optionally be bridged and wherein at least one member of the ring is a nitrogen atom.
• the bridge comprises from 0 to 2 carbon atoms between 2 members of the heterocycle. In particular, each ring comprises 1 or 2 nitrogen atoms.
• Suitable heterocycles are also disclosed in the Handbook of Chemistry and Physics, 76th Edition, CRC Press, Inc., 1995-1996, pages 225 to 226, the disclosure of which is hereby incorporated by reference.
• heterocycloalkyl examples include, but are not limited to piperazine, diazepane, piperidine, pyrrolidine, imidazolidine, morpholine, azetidine, diazabicyclo octanyl, diazabicycloheptanyl, azabicyclohexanyl.
• Said heterocycle is optionally substituted by a (C1-C3) alkyl, in particular methyl, or a NRR’ group, R and R’ being as defined herein, in particular NH 2 .
• NH-heterocycle means that the heterocycle is linked by a carbon or nitrogen atom of the heterocycle to the nitrogen atom of NH.
• substituted generally refers to, unless specified otherwise, a substitution with one or more substituents, which may be identical or different, and which are identified herein.
• the compounds of formula (I) as described herein can comprise one or more asymmetric carbon atoms. They can therefore exist in the form of enantiomers or diastereoisomers. These enantiomers and diastereoisomers, as well as their mixtures, including racemic mixtures, form part of the invention.
• the compounds of formula (I) as described herein can be provided in the form of a free base or in the form of addition salts with acids, which also form part of the invention.
• salts are advantageously prepared with pharmaceutically acceptable acids, but salts with other acids, useful for example for the purification or for the isolation of the compounds of formula (I) as described herein, also form part of the invention.
• the expression “pharmaceutically acceptable” refers to those compounds, materials, excipients, compositions or dosage forms which are, within the scope of sound medical judgment, suitable for contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problem complications commensurate with a reasonable benefit/risk ratio.
• pharmaceutically acceptable salts refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.
• the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
• such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like, including mono, di or tri-salts thereof; and the salts prepared from organic acids such as formic, acetic, propionic, succinic, tartaric, citric, methanesulfonic, trifluoromethanesulfonic, benzenesulfonic, trifluoroacetic, glucoronic, glutamic, benzoic, salicylic, toluenesulfonic, oxalic, fumaric, maleic, lactic and the like.
• Further addition salts include ammonium salts such as tromethamine, meglumine, epolamine, etc., metal salts such as sodium, potassium, calcium, zinc or magnesium.
• the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
• such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two.
• non-aqueous media like ether, dioxane, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington’s Pharmaceutical Sciences, 20 th ed., Mack PublishingCompany, Easton, PA, 2000, the disclosure of which is hereby incorporated by reference
• the compounds according to the invention are compounds of formula (I):
• - R 1 can be chosen from:
• - R 2 can be chosen from:
• R 2 forms together with the carbon atom in position 6, a fused phenyl or (5-6 membered)heteroaryl in positions 5 and 6; said fused heteroaryl having at least one heteroatom chosen from O, N, or S ; and said fused phenyl or heteroaryl being optionally substituted by one or more of : o one or more halogen atoms, o one or more -(Ci-C 4 )alkyl groups, o one or more -(Ci-C 3 )halogenoalkyl groups, o one or more -(Ci-C3)alkoxy groups optionally substituted by one to three fluorine atoms, o a (4-10 membered)heterocycle having at least one N, said heterocycle comprising optionally a bridge of 0 to 2 carbon atoms between 2 members of the heterocycle and being optionally substituted by one or more of a - (C1-C3) alkyl group, a NRR’ group or a carbony
• - Ra is chosen from:
• a -(Ci-C 3 )alkyl-(5-6 membered)heteroaryl optionally substituted by a halogen atom, a methyl group optionally substituted by one to three fluorine atoms, a methoxy group optionally substituted by one to three fluorine atoms;
• - R and R’ identical or different are chosen from -(Ci-C3)alkyl group and H;
• - Rb is chosen from:
• - R 3 is chosen from: • a heterocycle comprising 4 to 10 members with at least one N; said heterocycle comprising optionally a bridge of 0 to 2 carbon atoms between 2 members of the heterocycle and being optionally substituted by a -(C1-C3) alkyl group or a -NRR’ group; and
• R 7 and R 8 identical or different are chosen from H, -(Ci-C 6 )alkyl group and -CO-(Ci- C 6 )alkyl group; said -(Ci-C 6 )alkyl group and -CO-(Ci-C 6 )alkyl group being optionally substituted by -NRR’ group; or its pharmaceutically acceptable salts or optical isomers, racemates, diastereoisomers, enantiomers or tautomers ;
• - R 1 can be chosen from:
• - R 2 can be chosen from:
• R 2 forms together with the carbon atom in position 6, a fused phenyl or (5-6 membered)heteroaryl in positions 5 and 6; said fused heteroaryl having at least one heteroatom chosen from O, N, or S ; and said fused phenyl or heteroaryl being optionally substituted by one or more of : o one or more halogen atoms, o one or more -(Ci-C4)alkyl groups, o one or more -(Ci-C3)halogenoalkyl groups, o one or more -(Ci-C3)alkoxy groups optionally substituted by one to three fluorine atoms, o a (4-10 membered)heterocycle having at least one N, said heterocycle comprising optionally a bridge of 0 to 2 carbon atoms between 2 members of the heterocycle and being optionally substituted by one or more of a - (C1-C3) alkyl group, a NRR’ group or a carbonyl; said
• R 1 - X and Y are not N at the same time if R 1 is halogen and R 3 a piperazine, and R 2 is not COOCH 3 if R 1 is halogen and R 3 a piperazine.
• R 1 is a halogen atom
• - R 2 can be chosen from:
• R 2 forms together with the carbon atom in position 6, a fused phenyl or (5-6 membered)heteroaryl in positions 5 and 6; said fused heteroaryl having at least one heteroatom chosen from O, N, or S ; and said fused phenyl or heteroaryl being optionally substituted by one or more of : o one or more halogen atoms, o one or more -(Ci-C4)alkyl groups, o one or more -(Ci-C3)halogenoalkyl groups, o one or more -(Ci-C3)alkoxy groups optionally substituted by one to three fluorine atoms, o a (4-10 membered)heterocycle having at least one N, said heterocycle comprising optionally a bridge of 0 to 2 carbon atoms between 2 members of the heterocycle and being optionally substituted by one or more of a - (C1-C3) alkyl group, a NRR’ group or a carbonyl; said
• R 3 is chosen from a heterocycle comprising 4 to 10 members with at least one N; in particular a piperazine; said heterocycle comprising optionally a bridge of 0 to 2 carbon atoms between 2 members of the heterocycle and being optionally substituted by a -(C1-C3) alkyl group or a -NRR’ group.
• R 1 is chosen from chlorine, bromine and iodine;
• - R 2 is chosen from:
• a -COORa group • a (5-6 membered)heteroaryl group having at least one heteroatom chosen from O, N, or S, especially oxadiazol; said group being optionally substituted by a (Ci- C3)alkyl group, especially ethyl, optionally substituted by a -NRR’ group; or
• R 2 forms together with the carbon atom in position 6, a fused phenyl optionally substituted by o a halogen atom, especially chlorine, bromine and iodine; o one or more -(Ci-C4)alkyl groups, especially methyl group; o a (4-10 membered)heterocycle having at least one N, especially a piperazine, a pyrrolidine and a imidazolidine, said heterocycle being optionally substituted by a (Ci-C3)alkyl group, especially methyl, a NRR’ group or a carbonyl; said -(Ci-C3)alkyl group being optionally substituted by a NRR’ group; o a (C 6 -Cio)aryl group, especially phenyl, said group being optionally substituted by one or more of a halogen atom, especially fluorine and chlorine, a methyl group optionally substituted by three fluorine atoms, a methoxy group, a
• - Ra is chosen from:
• - R and R’ identical or different are chosen from -(Ci-C3)alkyl group, especially methyl, and H; and/or
• R 3 is a piperazine optionally substituted by a methyl
• R 7 and R 8 identical or different are chosen from H, -(Ci-C4)alkyl group, especially ethyl, propyl and butyl, and -CO-(Ci-C3)alkyl group, especially -CO-CH 2 -; said -(Ci- C3)alkyl group and -CO-(Ci-C3)alkyl group being optionally substituted by -NH 2 .
• - R 1 is chosen from chlorine, bromine and iodine; and/or - R 2 is chosen from:
• R 2 forms together with the carbon atom in position 6, a fused phenyl optionally substituted by o a halogen atom, especially chlorine, bromine and iodine; o one or more -(Ci-C4)alkyl groups, especially methyl group; o a (4-10 membered)heterocycle having at least one N, especially a piperazine; o a (C 6 -Cio)aryl group, especially phenyl, said group being optionally substituted by a (Ci-C3)alkyl group, especially methyl, optionally substituted by a -NRR’ group; o a NR 7 R 8 group; and/or
• - Ra is chosen from:
• R 3 is a piperazine optionally substituted by a methyl
• R 7 and R 8 identical or different are chosen from H, -(Ci-C3)alkyl group, especially ethyl and propyl, and -CO-(Ci-C3)alkyl group, especially -CO-CH 2 -; said -(Ci- C3)alkyl group and -CO-(Ci-C3)alkyl group being optionally substituted by -NH 2 .
• said compound of formula (I) is chosen from: 1-(5-bromo-3-chloro-2-pyridyl)piperazine hydrochloride ; 1-(3-chloro-5-iodo-2-pyridyl)piperazine ;
• said compound of formula (I) is chosen from:
• the present invention thus also relates to a pharmaceutical composition
• a pharmaceutical composition comprising a compound of formula (I) as defined in this section, and a pharmaceutically acceptable excipient.
• compositions may be prepared for use in oral administration, particularly in the form of tablets or capsules, in particular orodispersible (lyoc) tablets; or parenteral administration, particularly in the form of liquid solutions, suspensions or emulsions.
• compositions will generally include an inert diluent carrier or an edible carrier. They can be administered in unit dose forms, wherein the term “unit dose” means a single dose which is capable of being administered to a patient, and which can be readily handled and packaged, remaining as a physically and chemically stable unit dose comprising either the active compound itself, or as a pharmaceutically acceptable composition.
• the tablets, pills, powders, capsules, troches and the like can contain one or more of any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, or gum tragacanth; a diluent such as starch or lactose; a disintegrant such as starch and cellulose derivatives; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, or methyl salicylate.
• a binder such as microcrystalline cellulose, or gum tragacanth
• a diluent such as starch or lactose
• a disintegrant such as starch and cellulose derivatives
• a lubricant such as magnesium stearate
• a glidant such as colloidal silicon dioxide
• a sweetening agent such as sucrose or saccharin
• a flavoring agent
• Capsules can be in the form of a hard capsule or soft capsule, which are generally made from gelatin blends optionally blended with plasticizers, as well as a starch capsule.
• dosage unit forms can contain various other materials that modify the physical form of the dosage unit, for example, coatings of sugar, shellac, or enteric agents.
• Other oral dosage forms syrup or elixir may contain sweetening agents, preservatives, dyes, colorings, and flavorings.
• the active compounds may be incorporated into fast dissolve, modified-release or sustained-release preparations and formulations, and wherein such sustained-release formulations are preferably bi-modal.
• Liquid preparations for administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
• the liquid compositions may also include binders, buffers, preservatives, chelating agents, sweetening, flavoring and coloring agents, and the like.
• Non-aqueous solvents include alcohols, propylene glycol, polyethylene glycol, acrylate copolymers, vegetable oils such as olive oil, and organic esters such as ethyl oleate.
• Aqueous carriers include mixtures of alcohols and water, hydrogels, buffered media, and saline.
• biocompatible, biodegradable lactide polymer, lactide/glycolide copolymer, or polyoxyethylene-polyoxypropylene copolymers may be useful excipients to control the release of the active compounds.
• Intravenous vehicles can include fluid and nutrient replenishers, electrolyte replenishers, such as those based on Ringer's dextrose, and the like.
• Examples of modes of administration include parenteral e.g. subcutaneous, intramuscular, intravenous, intradermal, as well as oral administration.
• the present invention also relates to a compound of formula (I) :
• - R 1 can be chosen from:
• R 1 forms together with Y a fused phenyl in positions 3 and 4;
• R 2 can be chosen from: • a halogen atom, the fluorine atom being excluded;
• R 2 forms together with the carbon atom in position 6, a fused phenyl or (5-6 membered)heteroaryl in positions 5 and 6; said fused heteroaryl having at least one heteroatom chosen from O, N, or S ; and said fused phenyl or heteroaryl being optionally substituted by one or more: o one or more halogen atoms, o one or more-(Ci-C4)alkyl groups, o one or more -(Ci-C3)halogenoalkyl groups, o one or more -(Ci-C3)alkoxy groups optionally substituted by one to three fluorine atoms, o a (4-10 membered)heterocycle having at least one N, said heterocycle comprising optionally a bridge of 0 to 2 carbon atoms between 2 members of the heterocycle and being optionally substituted by one or more of a - (C1-C3) alkyl group, a NRR’ group or a carbonyl; said -(C
• - Ra is chosen from:
• a -(Ci-C 3 )alkyl-(5-6 membered)heteroaryl optionally substituted by a halogen atom, a methyl group optionally substituted by one to three fluorine atoms, a methoxy group optionally substituted by one to three fluorine atoms;
• - R and R’ identical or different are chosen from -(Ci-C3)alkyl group and H;
• - Rb is chosen from:
• a heterocycle comprising 4 to 10 members with at least one N; said heterocycle comprising optionally a bridge of 0 to 2 carbon atoms between 2 members of the heterocycle and being optionally substituted by a -(C1-C3) alkyl group or a -NRR’ group; and
• a -NH-heterocycle said heterocycle comprising 4 to 10 members with at least one N; said heterocycle comprising optionally a bridge of 0 to 2 carbon atoms between 2 members of the heterocycle;
• R 7 and R 8 identical or different are chosen from H, -(Ci-C 6 )alkyl group and -CO-(Ci- C 6 )alkyl group; said -(Ci-C 6 )alkyl group and -CO-(Ci-C 6 )alkyl group being optionally substituted by -NRR’ group; or its pharmaceutically acceptable salts or optical isomers, racemates, diastereoisomers, enantiomers or tautomers; for use as a medicament.
• - R 1 can be chosen from:
• R 1 forms together with Y a fused phenyl in positions 3 and 4;
• - R 2 can be chosen from:
• R 2 forms together with the carbon atom in position 6, a fused phenyl or (5-6 membered)heteroaryl in positions 5 and 6; said fused heteroaryl having at least one heteroatom chosen from O, N, or S ; and said fused phenyl or heteroaryl being optionally substituted by: o one or more halogen atoms, o one or more -(Ci-C4)alkyl groups, o one or more -(Ci-C3)halogenoalkyl groups, o one or more -(Ci-C3)alkoxy groups optionally substituted by one to three fluorine atoms, o a (4-10 membered)heterocycle having at least one N, said heterocycle comprising optionally a bridge of 0 to 2 carbon atoms between 2 members of the heterocycle and being optionally substituted by a -(C 1 -C 3 ) alkyl group, a NRR’ group or a carbonyl; said -(C 1 -
• - Ra is chosen from:
• a -(Ci-C 3 )alkyl-(5-6 membered)heteroaryl optionally substituted by a halogen atom, a methyl group optionally substituted by one to three fluorine atoms, a methoxy group optionally substituted by one to three fluorine atoms;
• - R and R’ identical or different are chosen from -(Ci-C3)alkyl group and H;
• - Rb is chosen from:
• a heterocycle comprising 4 to 10 members with at least one N; said heterocycle comprising optionally a bridge of 0 to 2 carbon atoms between 2 members of the heterocycle and being optionally substituted by a -(C1-C3) alkyl group or a -NRR’ group; and • a -NH-heterocycle, said heterocycle comprising 4 to 10 members with at least one N; said heterocycle comprising optionally a bridge of 0 to 2 carbon atoms between 2 members of the heterocycle;
• R 7 and R 8 identical or different are chosen from H, -(Ci-C 6 )alkyl group and -CO-(Ci- C 6 )alkyl group; said -(Ci-C 6 )alkyl group and -CO-(Ci-C 6 )alkyl group being optionally substituted by -NRR’ group.
• - R 1 can be chosen from:
• - R 2 can be chosen from:
• R 2 forms together with the carbon atom in position 6, a fused phenyl or (5-6 membered)heteroaryl in positions 5 and 6; said fused heteroaryl having at least one heteroatom chosen from O, N, or S ; and said fused phenyl or heteroaryl being optionally substituted by one or more of : o one or more halogen atoms, o one or more -(Ci-C4)alkyl groups, o one or more -(Ci-C3)halogenoalkyl groups, o one or more -(Ci-C3)alkoxy groups optionally substituted by one to three fluorine atoms, o a (4-10 membered)heterocycle having at least one N, said heterocycle comprising optionally a bridge of 0 to 2 carbon atoms between 2 members of the heterocycle and being optionally substituted by one or more of a - (C1-C3) alkyl group, a NRR’ group or a carbonyl; said
• - Ra is chosen from:
• a -(Ci-C 3 )alkyl-(5-6 membered)heteroaryl optionally substituted by a halogen atom, a methyl group optionally substituted by one to three fluorine atoms, a methoxy group optionally substituted by one to three fluorine atoms;
• - R and R’ identical or different are chosen from -(Ci-C3)alkyl group and H;
• - Rb is chosen from:
• a heterocycle comprising 4 to 10 members with at least one N; said heterocycle comprising optionally a bridge of 0 to 2 carbon atoms between 2 members of the heterocycle and being optionally substituted by a -(C1-C3) alkyl group or a -NRR’ group; and
• a -NH-heterocycle said heterocycle comprising 4 to 10 members with at least one N; said heterocycle comprising optionally a bridge of 0 to 2 carbon atoms between 2 members of the heterocycle;
• R 7 and R 8 identical or different are chosen from H, -(Ci-C 6 )alkyl group and -CO-(Ci- C 6 )alkyl group; said -(Ci-C 6 )alkyl group and -CO-(Ci-C 6 )alkyl group being optionally substituted by -NRR’ group.
• - R 1 is a halogen atom; and/or - R 2 can be chosen from:
• R 2 forms together with the carbon atom in position 6, a fused phenyl or (5-6 membered)heteroaryl in positions 5 and 6; said fused heteroaryl having at least one heteroatom chosen from O, N, or S ; and said fused phenyl or heteroaryl being optionally substituted by one or more of : o one or more halogen atoms, o one or more -(Ci-C4)alkyl groups, o one or more -(Ci-C3)halogenoalkyl groups, o one or more -(Ci-C3)alkoxy groups optionally substituted by one to three fluorine atoms, o a (4-10 membered)heterocycle having at least one N, said heterocycle comprising optionally a bridge of 0 to 2 carbon atoms between 2 members of the heterocycle and being optionally substituted by one or more of a - (C1-C3) alkyl group, a NRR’ group or a carbonyl; said
• - Y can be chosen from: • CH; and . N;
• - R 3 is chosen from a heterocycle comprising 4 to 10 members with at least one N; in particular a piperazine; said heterocycle comprising optionally a bridge of 0 to 2 carbon atoms between 2 members of the heterocycle and being optionally substituted by a -(Ci- C 3 ) alkyl group or a -NRR’ group;
• said compound is characterized in that:
• - X and Y are N or X is N and Y is CH;
• R 1 is a halogen atom
• - R 2 can be chosen from:
• R 2 forms together with the carbon atom in position 6, a fused phenyl optionally substituted by: o one or more a halogen atoms; o one or more -(Ci-C4)alkyl groups; o a (4-10 membered)heterocycle having at least one N, said heterocycle comprising optionally a bridge of 0 to 2 carbon atoms between 2 members of the heterocycle; o a (C 6 -Cio)aryl group, said group being optionally substituted by a (Ci-C3)alkyl group optionally substituted by a -NRR’ group; o a NR 7 R 8 group; and/or
• - Ra is a phenyl group optionally substituted a -(Ci-C3)alkyl group being substituted by a - NRR’ group;
• - R 3 is a heterocycle comprising 4 to 10 members with at least one N; said heterocycle comprising optionally a bridge of 0 to 2 carbon atoms between 2 members of the heterocycle and being optionally substituted by a methyl or -NRR’ group; and/or - R 7 and R 8 , identical or different are chosen from H, -(Ci-C3)alkyl group and -CO-(Ci- C3)alkyl group; said -(Ci-C3)alkyl group and -CO-(Ci-C3)alkyl group being optionally substituted by -NH 2 .
• - X and Y are N or X is N and Y is CH;
• R 1 is chosen from chlorine, bromine and iodine;
• - R 2 is chosen from:
• R 2 forms together with the carbon atom in position 6, a fused phenyl optionally substituted by o a halogen atom, especially chlorine, bromine and iodine; o one or more -(Ci-C4)alkyl groups, especially methyl group; o a (4-10 membered)heterocycle having at least one N, especially a piperazine; o a (C 6 -Cio)aryl group, especially phenyl, said group being optionally substituted by a (Ci-C3)alkyl group, especially methyl, optionally substituted by a -NRR’ group; o a NR 7 R 8 group; and/or
• - Ra is chosen from:
• R 3 is a piperazine optionally substituted by a methyl
• R 7 and R 8 identical or different are chosen from H, -(Ci-C3)alkyl group, especially ethyl and propyl, and -CO-(Ci-C3)alkyl group, especially -CO-CH 2 -; said -(Ci-C3)alkyl group and -CO-(Ci-C3)alkyl group being optionally substituted by -NH 2 .
• said compound is chosen from:
• 2-chloro-3-piperazin-1 -yl-quinoxaline hydrochloride 1-[3-bromo-5-(trifluoromethyl)-2-pyridyl]-4-methyl-piperazine; 1-[3-bromo-5-(trifluoromethyl)-2-pyridyl]piperazine hydrochloride; - 3-iodo-2-piperazin-1-yl-quinoline hydrochloride; 3-methyl-2-piperazin-1-yl-quinoline hydrochloride; 2-piperazin-1-ylquinoline-3-carbonitrile hydrochloride;
• said compound is chosen from:
• Said compound can be used to treat a bacterial infection, when administered in combination with an antibiotic.
• the compound of formula (I) as defined in this section allows to treat in combination with antibiotics, both antibiotic sensitive and antibiotic resistant bacteria.
• Antibiotic resistance is well known in the art. Bacteria can acquire resistance, but can also be innately resistant to antibiotic molecules. Antibiotic efflux pumps can be involved in both these processes: Basal efflux pump expression can make bacteria innately resistant to some antibiotics, while mutations leading to the overexpression of these pumps can lead to acquired resistance. Compounds according to the invention act on both these forms of resistance.
• compounds according to the invention can be used to prevent and/or treat infections by bacteria with innate and/or acquired antibiotic resistance.
• Infections such as pneumonia, bronchitis, ear infections, meningitis, urinary tract infections, septicemia and sexually transmitted diseases can be cited as examples.
• said compound is used to prevent and/or treat Gram-negative bacteria with innate or acquired antibiotic resistance.
• said compound is used to prevent and/or treat subjects afflicted by infections caused by Gram-negative bacteria with innate and acquired antibiotic resistance.
• Gram-negative bacteria as used herein has the common meaning known in the art.
• Escherichia coli Escherichia coli
• Salmonella Shigella, and other Enterobacteriaceae, Pseudomonas, Moraxella, Helicobacter, Campylobacter, Stenotrophomonas, Bdellovibrio, acetic acid bacteria, Legionella, cyanobacteria, spirochaetes, green sulfur, and green non sulfur bacteria, Neisseria gonorrhoeae, Neisseria meningitidis, Moraxella catarrhalis, Haemophilus influenza, Klebsiella pneumoniae, Legionella pneumophila, Pseudomonas aeruginosa, Proteus mirabilis, Enterobacter cloacae, Serratia marcescens, Helicobacter pylori, Salmonella enteritidis, Salmonella typhi and Acinetobacter baumannii can be cited as examples.
• said Gram negative bacteria is chosen from E. coli., K. pneumoniae and other Enterobacteriaceae, A. baumannii, P. aeruginosa, Neisseria gonorrhoeae, Shigella species.
• said compound is a Gram-negative bacteria efflux pump inhibitor.
• Bacteria efflux pumps are well known in the art. Efflux pumps are bacterial transport proteins which are involved in extrusion of substrates from the bacteria into the external environment. In the context of the invention, efflux pumps belonging to the Resistance Modulation cell Division (RND) superfamily, in particular in Gram-negative bacteria, are contemplated. RND pumps amongst Gram-negative bacteria are highly conserved, and many efflux pump inhibitors show broad spectrum RND pump inhibition as binding pockets interactions are conserved. Such is the case for the residues interacting with the compounds here presented.
• RND Resistance Modulation cell Division
• compounds of formula (I) are able to bind to the transmembrane domain thereby allosterically impacting the conformational protomer cycling and drug efflux process.
• the present invention also relates to a method for treating a bacterial infection, comprising administering to a subject in need thereof, a compound of formula (I) as defined in this section, in combination with an antibiotic.
• the compound of formula (I) is a Gram negative bacteria efflux pump inhibitor.
• the method according to the present invention allows to prevent and/or treat Gram-negative bacteria when given in combination with antibiotics .
• said Gramnegative bacteria is chosen from E. coli., K. pneumoniae and other Enterobacteriaceae, A. baumannii, P. aeruginosa, Neisseria gonorrhoeae and Shigella species.
• the terms "treat”, “treating”, “treated” or “treatment”, refer to therapeutic treatment wherein the object is to eliminate or lessen antibiotic resistance.
• Beneficial or desired clinical results include, but are not limited to, elimination of resistance, alleviation of resistance, diminishment of extent of condition, stabilized (i.e., not worsening) state of condition, delay or slowing of progression of the condition.
• the treatment of antibiotic resistance refers to the elimination or reduction of the phenomena of resistance.
• prevention refers to the prevention of the onset, recurrence or spread of the antibiotic resistance, or of one or more symptoms thereof.
• the terms refer to the treatment with or administration of a compound provided herein prior to the onset of resistance, particularly to patients at risk of antibiotic resistance.
• the terms encompass the inhibition or reduction of the resistance.
• Subjects with familial history of an infection associated with antibiotic resistance in particular are candidates for preventive regimens in certain embodiments.
• subjects who have a history of recurring symptoms and/or resistances are also potential candidates for the prevention.
• prevention may be interchangeably used with the term “prophylactic treatment”.
• the subject in need of a prevention and/or treatment against antibiotic resistance is a subject afflicted with a disease caused by bacteria, in particular Gram negative bacteria as described herein.
• a therapeutically effective amount can be readily determined by the attending diagnostician, as one skilled in the art, by the use of conventional techniques and by observing results obtained under analogous circumstances. In determining the therapeutically effective amount, a number of factors are considered by the attending diagnostician, including, but not limited to: the species of subject; its size, age, and general health; the specific disease and/or bacteria involved; the degree of involvement or the severity of the disease and/or resistance; the response of the individual subject; the particular compound administered; the mode of administration; the bioavailability characteristic of the preparation administered; the dose regimen selected; the use of concomitant medication; and other relevant circumstances. As used herein, an "effective amount” refers to an amount which is effective in reducing, eliminating, treating or controlling the antibiotic resistance.
• controlling is intended to refer to all processes wherein there may be a slowing, interrupting, arresting, or stopping of the progression of the antibiotic resistance, but does not necessarily indicate a total elimination of all disease and condition symptoms, and is intended to include prophylactic treatment and chronic use.
• patient refers to a warm-blooded animal such as a mammal, in particular a human, male or female, unless otherwise specified, which is afflicted with, or has the potential to be afflicted by antibiotic resistance, as described herein.
• the amount of the compound according to the invention which is required to achieve the desired biological effect, will vary depending upon a number of factors, including the dosage of the drug to be administered, the chemical characteristics (e.g. hydrophobicity) of the compounds employed, the potency of the compounds, the type of resistance, the state of resistance in the patient, and the route of administration.
• Compounds provided herein can be formulated into pharmaceutical compositions, optionally by admixture with one or more pharmaceutically acceptable excipients.
• compositions may be prepared for use in oral administration, particularly in the form of tablets or capsules, in particular orodispersible (lyoc) tablets; or parenteral administration, particularly in the form of liquid solutions, suspensions or emulsions.
• compositions will generally include an inert diluent carrier or an edible carrier. They can be administered in unit dose forms, wherein the term “unit dose” means a single dose which is capable of being administered to a patient, and which can be readily handled and packaged, remaining as a physically and chemically stable unit dose comprising either the active compound itself, or as a pharmaceutically acceptable composition.
• the tablets, pills, powders, capsules, troches and the like can contain one or more of any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, or gum tragacanth; a diluent such as starch or lactose; a disintegrant such as starch and cellulose derivatives; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, or methyl salicylate.
• a binder such as microcrystalline cellulose, or gum tragacanth
• a diluent such as starch or lactose
• a disintegrant such as starch and cellulose derivatives
• a lubricant such as magnesium stearate
• a glidant such as colloidal silicon dioxide
• a sweetening agent such as sucrose or saccharin
• a flavoring agent
• Capsules can be in the form of a hard capsule or soft capsule, which are generally made from gelatin blends optionally blended with plasticizers, as well as a starch capsule.
• dosage unit forms can contain various other materials that modify the physical form of the dosage unit, for example, coatings of sugar, shellac, or enteric agents.
• Other oral dosage forms syrup or elixir may contain sweetening agents, preservatives, dyes, colorings, and flavorings.
• the active compounds may be incorporated into fast dissolve, modified-release or sustained-release preparations and formulations, and wherein such sustained-release formulations are preferably bi-modal.
• Liquid preparations for administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
• the liquid compositions may also include binders, buffers, preservatives, chelating agents, sweetening, flavoring and coloring agents, and the like.
• Non-aqueous solvents include alcohols, propylene glycol, polyethylene glycol, acrylate copolymers, vegetable oils such as olive oil, and organic esters such as ethyl oleate.
• Aqueous carriers include mixtures of alcohols and water, hydrogels, buffered media, and saline.
• biocompatible, biodegradable lactide polymer, lactide/glycolide copolymer, or polyoxyethylene-polyoxypropylene copolymers may be useful excipients to control the release of the active compounds.
• Intravenous vehicles can include fluid and nutrient replenishers, electrolyte replenishers, such as those based on Ringer's dextrose, and the like.
• Examples of modes of administration include parenteral e.g. subcutaneous, intramuscular, intravenous, intradermal, as well as oral administration.
• the present invention is also concerned with the process of preparation of the compounds of formula (I) as described herein.
• the compounds and process of the present invention may be prepared in a number of ways well-known to those skilled in the art.
• the compounds can be synthesized, for example, by application or adaptation of the methods described below, or variations thereon as appreciated by the skilled artisan.
• the appropriate modifications and substitutions will be readily apparent and well known or readily obtainable from the scientific literature to those skilled in the art.
• the compounds of the present invention may contain one or more asymmetrically substituted carbon atoms, and may be isolated in optically active or racemic forms.
• optically active or racemic forms all chiral, diastereomeric, racemic forms, isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated.
• mixtures of stereoisomers may be separated by standard techniques including, but not limited to, resolution of racemic forms, normal, reverse-phase, and chiral chromatography, preferential salt formation, recrystallization, and the like, or by chiral synthesis either from chiral starting materials or by deliberate synthesis of target chiral centers.
• the compound thus prepared may be recovered from the reaction mixture by conventional means.
• the compounds may be recovered by distilling off the solvent from the reaction mixture or, if necessary, after distilling off the solvent from the reaction mixture, pouring the residue into water followed by extraction with a water- immiscible organic solvent and distilling off the solvent from the extract.
• the product can, if desired, be further purified by various well-known techniques, such as recrystallization, reprecipitation or the various chromatography techniques, notably column chromatography or preparative thin layer chromatography.
• compounds of formula (I) can be prepared according to protocols 1 to 5, as mentioned in Part A of the experimental part below.
• process of the invention may also comprise the additional step of isolating the compound of formula (I). This can be done by the skilled person by any of the known conventional means, such as the recovery methods described above.
• a compound for use for the prevention or treatment of is equivalent to "the use of a compound for the prevention or treatment of” and to "the use of a compound for the manufacture of a medicament for the prevention or treatment of
• Protocol 3 The appropriate Boc-protected compound (0.04-0.7 mmol, 1 eq) was dissolved in 1 ,4- dioxane (0.3-3.0 ml.) and HCI 4N in 1,4-dioxane (8-28 eq) was added. The mixture was stirred at room temperature for 3h to 5 days. The mixture was either filtered under vacuum and rinsed with petroleum ether and MeOH if the compound precipitated, or the mixture was evaporated under vacuum.
• Protocol 5 A 1 M solution of isopropyl chloroformate in toluene (1.5 eq) was added in 3 ml. of anhydrous THF under argon. Intermediate 51 (1.7 mmol, 1 eq) and NEt3 (1.2 eq) were dissolved in 3 ml. of anhydrous THF and added dropwise to the isopropyl chloroformate solution at 0°C. The reaction was allowed to warm to RT and stirred overnight. A solution of saturated NaHCC>3 was added and the product was extracted twice with EtOAc. The organic layer was washed once with a saturated solution of NaHCC>3, once with brine, dried over MgSC>4 and evaporated under reduced pressure.
• intermediate 103 (0.12 mmol, 1 eq), boc-piperazine (1.8 eq), Pd(OAc) 2 (4 mol%), BINAP (4 mol%), and fBuONa (1.7 eq) were purged under argon for 15 min. Then, dry toluene (0.2 ml.) was added and the mixture was heated at 110°C overnight. The reaction mixture was filtered on a plug of celite and rinsed with EtOAc. It was concentrated under reduced pressure and the residue was purified by flash chromatography (cyclohexane/EtOAc 100/0-70/30) to give the title compound.
• Intermediates 112-114 In a tube, were added intermediate 110 (0.23-0.62 mmol), Pd(PPh 3 )2CI 2 (2-3 mol%), Cul (7-10 mol%) and the corresponding iodo derivative (1 .4 eq). Then TEA (14 eq) and 0.9-2.5 ml. anhydrous MeCN were added. The reaction was flushed under argon for 30 min and was heated at 100°C under microwaves for 1h. The reaction was filtered on a celite plug. The filtrate was diluted with EtOAc and was washed three times with water and once with brine. It was then dried over MgS0 4 , filtered and the solvent was removed under reduced pressure. The crude was purified by flash chromatography.

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