EP1943222A1 - Derives de 5-chinoline a activite antibacterienne - Google Patents

Derives de 5-chinoline a activite antibacterienne

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Publication number
EP1943222A1
EP1943222A1 EP06806274A EP06806274A EP1943222A1 EP 1943222 A1 EP1943222 A1 EP 1943222A1 EP 06806274 A EP06806274 A EP 06806274A EP 06806274 A EP06806274 A EP 06806274A EP 1943222 A1 EP1943222 A1 EP 1943222A1
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EP
European Patent Office
Prior art keywords
group
alkyl
solution
alkenyl
hydroxy
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
EP06806274A
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German (de)
English (en)
Inventor
Glenn E. Dale
Sabine Pierau
Mike Cappi
Christopher Gray
Christian Hubschwerlen
Jean-Philippe Surivet
Cornelia Zumbrunn
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Morphochem AG fuer Kombinatorische Chemie
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Morphochem AG fuer Kombinatorische Chemie
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Priority claimed from DE102006028649A external-priority patent/DE102006028649A1/de
Application filed by Morphochem AG fuer Kombinatorische Chemie filed Critical Morphochem AG fuer Kombinatorische Chemie
Publication of EP1943222A1 publication Critical patent/EP1943222A1/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—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
    • 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
    • C07D215/20—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—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
    • C07D401/02—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
    • C07D401/06—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 linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—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
    • C07D401/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present application describes novel compounds having antibacterial activity. These compounds are, inter alia, as inhibitors of DNA gyrase and Topoisomerases (eg topoisomerase II and IV) of interest.
  • the present invention relates to compounds of the general formula (I):
  • R 1 is a hydrogen atom, a halogen atom, a hydroxy, an amino, a cyano, a nitro, a thiol, a
  • Ci-C 6 alkyl a C 2 ⁇ C 6 alkenyl group, a C 2 -C 6 alkynyl, a heteroalkyl, an alkyloxy, a Heteroalkyloxy-, a cycloalkyloxy, a Alkylcycloalkyloxy-, a hetero - cycloalkyloxy or a heteroalkylcycloalkyloxy group;
  • R 2 is a hydrogen atom, a halogen atom, a hydroxy, an amino, a cyano, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl or a heteroalkyl group;
  • R 3 is a group of the following formula:
  • U and V are independently nitrogen atoms or groups of the formula CH or CR 6 ;
  • R 4 is independently halogen, hydroxy, amino, cyano, nitro or thiol, alkyl, alkenyl, alkynyl or heteroalkyl;
  • n 0, 1 or 2;
  • R 5 is an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl radical;
  • the groups R 6 are independently a halogen atom, a hydroxy, alkyl, alkenyl, alkynyl or heteroalkyl group;
  • R 7 is a hydrogen atom, a trifluoromethyl, Ci-C ⁇ alkyl, C 2 -C 6 alkenyl, Ci-C 6 alkoxycarbonyl, Ci-C ⁇ -alkylcarbonyl or a carbonylamino group wherein the amino group of carbonylamino optionally carbonyl- 6 alkenyloxy by a Ci-C ⁇ - alkoxycarbonyl, Ci-C ⁇ alkylcarbonyl, C2 ⁇ C, C 2 -C 6 -Alkenylcarbonyl-, dC 6 alkyl, C 2 -C 6 - alkenyl, and optionally further substituted by a Ci-C 6 alkyl or a C 2 -C 6 alkenyl group may be substituted;
  • the radicals R 8 , R 9 , R 10 , R 12 and R 13 independently of one another represent a hydrogen atom, a halogen atom, an azide, a trifluoro- methyl, hydroxy, amino, Ci-C ⁇ -alkyloxy, Ci-C ⁇ alkyl thio, Ci-C 6 alkyl, C 2 -C 6 alkenyl, Ci-C ⁇ alkoxycarbonyl, C 2 -C 6 -Alkenyloxycarbonyl-, Ci-C 6 alkylsulfonyl, C 2 -C O - alkenylsulfonyl or a sulfonylamino group are wherein the amino group of the sulfonylamino group may be optionally substituted by a Ci-C ⁇ alkyl or phenyl;
  • R 11 is a hydrogen atom, a trifluoromethyl, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 1 -C 6 -alkoxycarbonyl, C 1 -C 6 -alkylcarbonyl or a carbonylamino group, where the amino group of the carbonylamino group is optionally carbonyl by a C C ⁇ - alkoxycarbonyl, Ci-C ⁇ -alkylcarbonyl, C 2 -C 6 alkenyloxy, C 2 -C 6 -Alkenylcarbonyl-, Ci-C ⁇ alkyl, C 2 -C O - alkenyl - And optionally further substituted by a Ci-C ö alkyl or a C 2 -C 6 alkenyl group may be substituted;
  • alkyl refers to a saturated, straight or branched hydrocarbon group having 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms, e.g. the methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, 2, 2-dimethylbutyl or n-octyl group.
  • alkenyl and alkynyl refer to at least partially unsaturated, straight-chain or branched hydrocarbon groups containing 2 to 20 Carbon atoms, preferably 2 to 12 carbon atoms, more preferably 2 to 6 carbon atoms, eg the ethenyl, allyl, acetylenyl, propargyl, isoprenyl or hex-2-enyl group.
  • Alkenyl groups preferably have one or two (particularly preferably one) double bonds or alkinyl groups one or two (particularly preferably one) triple bonds.
  • alkyl, alkenyl and alkynyl refer to groups in which one or more
  • Hydrogen atoms are replaced by a halogen atom (preferably F or Cl), e.g. the 2, 2, 2-trichloroethyl or the trifluoromethyl group.
  • a halogen atom preferably F or Cl
  • e.g. the 2, 2, 2-trichloroethyl or the trifluoromethyl group e.g. the 2, 2, 2-trichloroethyl or the trifluoromethyl group.
  • heteroalkyl refers to an alkyl, an alkenyl or an alkynyl group in which one or more (preferably 1, 2 or 3) carbon atoms are represented by an oxygen, nitrogen, phosphorus, boron, selenium, Silicon or sulfur atom are replaced (preferably oxygen, sulfur or nitrogen).
  • heteroalkyl further refers to a carboxylic acid or a carboxylic acid derived group such as e.g. Acyl, acylalkyl, alkoxycarbonyl, acyloxy, acyloxyalkyl, carboxyalkylamide or alkoxycarbonyloxy.
  • heteroalkyl groups are groups of the formulas R a -OY a , R a -SY a , R a -N (R b ) -Y a , R a -CO-Y a , R a -O-CO- Y a -, R a -CO-OY a -, R a -CO-N (R b) -Y a -, R a -N (R b) -CO-Y a -, R a -O-CO- N (R b ) -Y a -, R a -N (R b ) -CO-OY a -, R a -N (R b ) -CO-OY a -, R a -N (R b ) -CO-N (R c ) -Y a -, R a -O -CO-OY a -,
  • R a is -O-CS-Y a -, R a is -CS-OY a -, R a is -CS-N (R b ) -Y a -, R a is -N (R b ) -CS-Y a -, R a -O-CS-N (R b ) -Y a -, R a -N (R b ) -CS-OY a -, R a -N (R b ) -CS-N (R c ) -Y a , R a -O-CS-OY a -, R a -S-CO-Y a -, R a -CO-SY a -, R a -CO-SY a -, R a -CO-SY a -, R a -S-CO-N (R b ) -Y a -, R a
  • Alkynyl group and Y a is a direct bond, a Ci-C 6 - alkylene, a C 2 -C 6 alkenylene or a C 2 -C 6 - alkynylene, wherein each heteroalkyl group at least one carbon atom and one or more hydrogen atoms are replaced by Fluorine or chlorine atoms may be replaced.
  • heteroalkyl groups are methoxy, trifluoromethoxy, ethoxy, n-propyloxy, isopropyloxy, tert-butyloxy, methoxymethyl, ethoxymethyl, -CH 2 CH 2 OH, -CH 2 OH, methoxyethyl, methylamines, ethylamino, dimethylamino, diethylamino, iso- Propylethylamino, methylaminomethyl, ethylaminomethyl, di-iso-propylaminoethyl, enol ether, dimethylaminomethyl, dimethylaminoethyl, acetyl, propionyl, butyryloxy, acetyloxy, methoxycarbonyl, ethoxycarbonyl, N-ethyl-N-methylcarbamoyl or N-methylcarbamoyl.
  • heteroalkyl groups are nitrile, isonitrile, cyanate, thiocyanate, isocyanate, isothiocyanate and alkylnitrile groups.
  • An example of a heteroalkylene group is a group of the formula -CH 2 CH (OH) -.
  • cycloalkyl refers to a saturated or partially unsaturated (eg cycloalkenyl) cyclic Group which has one or more rings (preferably 1 or 2) and contains 3 to 14 ring carbon atoms, preferably 3 to 10 (in particular 3, 4, 5, 6 or 7) ring carbon atoms.
  • the term cycloalkyl furthermore refers to groups in which one or more hydrogen atoms have been replaced by fluorine, chlorine, bromine or iodine atoms or OH, 0O, SH, SS, NH 2 , NHNH or NO 2 groups,
  • cyclic ketones such as cyclohexanone, 2-cyclohexenone or cyclopentanone.
  • Further concrete examples of cycloalkyl groups are the cyclopropyl, cyclobutyl,
  • heterocycloalkyl refers to a cycloalkyl group as defined above in which one or more (preferably 1, 2 or 3) ring carbon atoms are represented by an oxygen, nitrogen, silicon, selenium, phosphorus or sulfur atom (preferably oxygen, sulfur or sulfur) Nitrogen) are replaced.
  • a heterocycloalkyl group preferably has 1 or 2 rings with 3 to 10 (in particular 3, 4, 5, 6 or 7) ring atoms.
  • heterocycloalkyl furthermore refers to groups in which one or more hydrogen atoms are replaced by fluorine,
  • Examples are the piperidyl, piperazinyl, morpholinyl, urotropinyl, pyrrolidinyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrofuryl or 2-pyrazolinyl group as well as lactams, lactones, cyclic imides and cyclic anhydrides.
  • alkylcycloalkyl refers to groups containing both cycloalkyl and alkyl, alkenyl or alkynyl groups according to the above definitions, for example alkylcycloalkyl, cycloalkylalkyl, alkylcycloalkenyl, alkenylcycloalkyl and alkynylcycloalkyl groups.
  • an alkylcycloalkyl group contains a cycloalkyl group having one or two rings and containing 3 to 10 (especially 3, 4, 5, 6 or 7) ring carbon atoms and one or two alkyl, alkenyl or alkynyl groups having 1 or 2 to 6 carbon atoms.
  • heteroalkylcycloalkyl refers to alkylcycloalkyl groups as defined above in which one or more (preferably 1, 2 or 3) carbon atoms are represented by an oxygen, nitrogen, silicon, selenium, phosphorus or sulfur atom (preferably oxygen, Sulfur or nitrogen) are replaced.
  • a heteroalkylcycloalkyl group preferably has 1 or 2 rings having 3 to 10 (in particular 3, 4, 5, 6 or 7) ring atoms and one or two alkyl, alkenyl, alkynyl or heteroalkyl groups having 1 or 2 to 6 carbon atoms.
  • Examples of such groups are alkylheterocycloalkyl, alkylheterocycloalkenyl, alkenyl-heterocycloalkyl, alkynylheterocycloalkyl, heteroalkylcycloalkyl, heteroalkylheterocycloalkyl and heteroalkyl-heterocyclic-alkenyl, where the cyclic groups are saturated or mono-, di- or tri-unsaturated.
  • aryl or Ar refers to an aromatic group having one or more rings and containing 6 to 14 ring carbon atoms, preferably 6 to 10 (especially 6) ring carbon atoms.
  • aryl (or Ar) further refers to groups in which one or several hydrogen atoms are replaced by fluorine, chlorine, bromine or iodine atoms or OH, SH, NH 2 , or NO 2 groups. Examples are the phenyl, naphthyl, biphenyl, 2-fluorophenyl, anilinyl, 3-nitrophenyl or 4-hydroxyphenyl group.
  • heteroaryl refers to an aromatic group which has one or more rings and contains 5 to 14 ring atoms, preferably 5 to 10 (in particular 5 or 6) ring atoms and one or more (preferably 1, 2, 3 or 4) oxygen atoms. , Nitrogen, phosphorus or sulfur ring atoms (preferably O, S or N).
  • heteroaryl furthermore refers to groups in which one or more hydrogen atoms have been replaced by fluorine, chlorine, bromine or iodine atoms or OH, SH, NH 2 or NO 2 groups.
  • Examples are 4-pyridyl, 2-imidazolyl, 3-phenylpyrrolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, isoxazolyl, indazolyl, indolyl, benzimidazolyl, pyridazinyl, quinolinyl, purinyl , Carbazolyl, acridinyl, pyrimidyl, 2,3'-bifuryl, 3-pyrazolyl and isoquinolinyl groups.
  • aralkyl refers to groups containing both aryl and alkyl, alkenyl, alkynyl and / or cycloalkyl groups according to the above definitions, such as arylalkyl, arylalkenyl, arylalkynyl, arylcycloalkyl, arylcycloalkenyl, alkylarylcycloalkyl and alkylarylcycloalkenyl groups.
  • aralkyls are toluene, xylene, mesitylene, styrene, benzyl chloride, o-fluorotoluene, 1H-indene, tetralin, dihydronaphthalene, indanone, phenylcyclopentyl, cumene, cyclohexylphenyl, fluorene and indane.
  • an aralkyl group one or two aromatic ring systems (1 or 2 rings) having 6 to 10 carbon atoms and one or two alkyl, alkenyl and / or alkynyl groups having 1 or 2 to 6 carbon atoms and / or a cycloalkyl group having 5 or 6 ring carbon atoms.
  • heteroaralkyl refers to an aralkyl group as defined above in which one or more (preferably 1, 2, 3 or 4) carbon atoms are represented by an oxygen, nitrogen, silicon, selenium, phosphorus,
  • a heteroaralkyl group contains one or two aromatic ring systems (1 or 2 rings) having 5 or 6 to 10 carbon atoms and one or two alkyl, alkenyl and / or alkynyl groups having 1 or 2 to 6 carbon atoms and / or a cycloalkyl group 5 or 6 ring carbon atoms, wherein 1, 2, 3 or 4 of these carbon atoms are replaced by oxygen, sulfur or nitrogen atoms.
  • Examples are arylheteroalkyl, arylheterocycloalkyl,
  • This expression further refers to groups-substituted with unsubsti- Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Ci-C6 - heteroalkyl, C 3 - are heteroaralkyl groups substituted - Ci 0 cycloalkyl, C 2 -C 9 heterocycloalkyl, Ce-Cio-aryl, Ci-C9 heteroaryl, C7-Ci2 aralkyl or C 2 -C n ,
  • A is selected from the following groups: -CH (OH) CH 2 -, -CH 2 CH (OH) -, -OCH 2 CH 2 -, -CH 2 CH 2 O-, -CH 2 SO 2 -, -SO 2 CH 2 -, -CH 2 N (C 1 -C 4 -alkyl) -, -N (C 1 -C 4 -alkyl) CH 2 -, -CH 2 NH-, -NHCH 2 - , -CH 2 O-, -OCH 2 -, -CH 2 S-,
  • R 1 is a cyano, a C 1 -C 4 -alkyloxy or a C 1 -C 4 -Heteroalkyloxy distr, wherein one or more hydrogen atoms of these groups may be replaced by fluorine atoms.
  • R 1 is a methoxy group.
  • R 2 is a hydrogen or H halo logging ratio.
  • R 2 is a hydrogen, a chlorine or a fluorine atom.
  • R 3 is selected from the following groups
  • R 3 is particularly preferably selected from the following groups:
  • the radicals R 4 are preferably in turn independently of one another a halogen atom, a hydroxy, a cyano, a Ci-C 4 - alkyl or a Ci-C4 heteroalkyl group (for example, a hydroxymethyl group).
  • the radicals R 4 are particularly preferably independently of one another a fluorine or chlorine atom or a C 1 -C 4 -heteroalkyl group (for example a hydroxymethyl group).
  • n is 0 or 1; more preferably 0.
  • R 5 is a heteroalkylcycloalkyl or heteroaralkyl group.
  • Heterocyclicalkylene group and Y is an aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heteroarylheterocycloalkyl or an arylheterocycloalkyl group (in particular a heterocycloalkyl, a heteroaryl,
  • Heteroalkylene group (in particular a C 1 -C 4 -Heteroalkylen- group) and Y 2 is an aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, Heteroalkylcycloalkyl-, Heteroarylhetero- cycloalkyl or a Arylheterocycloalkyl group (in particular a heterocycloalkyl, an aryl, a heteroaryl, aralkyl, heteroaralkyl, a heteroaryl) heterocycloalkyl or an arylheterocycloalkyl group).
  • Y has one of the following structures:
  • X 1 , X 2 and X 3 are independently nitrogen atoms or groups of the formula CR 20 , X 4 and X 5 are independently oxygen or sulfur atoms or groups of the formula NR 21 , o is 0, 1 or 2, R 14 , R 15 , R 16 , R 17 , R 19 and R 20 are independently hydrogen atoms, halogen atoms, hydroxy, Ci-C ⁇ -alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or Ci -C ⁇ -heteroalkyl, and R 18 and R 21 are independently hydrogen, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or C 6 heteroalkyl groups are.
  • Y has one of the following structures:
  • Y has one of the following structures:
  • the radicals R 6 independently of one another are a halogen atom, a hydroxy, a C 1 -C 4 -alkyl or a C 1 -C 4 -heteroalkyl group (for example a hydroxyethyl group).
  • the radicals R 6 are furthermore preferably, independently of one another, a fluorine or a chlorine atom or a hydroxy, a C 1 -C 4 -alkyloxy, a C 1 -C 4 -heteroalkyl (eg a hydroxyethyl group) or a C 3 -C 6 Dialkylamino- methyl group, wherein one or more hydrogen atoms of these groups may be replaced by fluorine atoms.
  • the radicals R 6 are particularly preferably independently of one another a Ci-C 4 -Heteroalkyl distr (eg a hydroxyethyl group).
  • R 2 , R 4a and R 6a are independently a hydrogen or halogen atom or a Ci-C 4 -Heteroalkyl distr (eg a hydroxymethyl or hydroxyethyl group) (in particular R 2 is a hydrogen atom and R 4a and R 6a is a hydrogen or Fluorine atom or a C ⁇ -C 4 heteroalkyl group).
  • B and Y are as defined above.
  • Particular preference is given to compounds of the formula (III):
  • R 2 is a hydrogen or halogen atom (in particular, R 2 is a hydrogen atom).
  • B and Y are as defined above.
  • B is a bond or a group of the formula -CH 2 CH 2 -, -CH 2 CH 2 CH 2 - or -CH 2 CH (OH) -.
  • R 2 is a hydrogen or halogen atom (in particular, R 2 is a hydrogen atom).
  • B and Y are as defined above.
  • Compounds of formulas (I) to (IV) may contain one or more chiral centers due to their substitution.
  • the present invention therefore encompasses both all pure enantiomers and all pure diastereomers, as well as their mixtures in any mixing ratio.
  • all cis / trans isomers of the compounds of the general formulas (I) to (IV) and mixtures thereof are also encompassed by the present invention.
  • all tautomeric forms of the compounds of the formulas (I) to (IV) are encompassed by the present invention.
  • compositions according to the present invention contain at least one compound of formulas (I) to (IV) as active ingredient and optionally excipients and / or adjuvants.
  • Examples of pharmacologically acceptable salts of the compounds of the formulas (I) to (IV) are salts of physiologically acceptable mineral acids such as hydrochloric acid, sulfuric acid and phosphoric acid or salts of organic acids such as methanesulfonic acid, p-toluenesulfonic acid,
  • pharmacologically acceptable salts of the compounds of formulas (I) to (IV) are alkali or alkaline earth salts such as sodium, potassium, lithium, calcium or magnesium salts, ammonium salts or salts of organic see bases such as methylamine, dimethylamine, triethylamine , Piperidine, ethylenediamine, lysine, choline hydroxide, meglumine, morpholine or arginine.
  • Compounds of formula (I) to (IV) may be solvated, in particular hydrated.
  • the hydration may occur, for example, during the manufacturing process or as a result of the hygroscopic nature of the initially anhydrous compounds of formulas (I) to (IV).
  • the compounds of formulas (I) to (IV) may be present either as achiral compounds, diastereomeric mixtures, mixtures of enantiomers or as optically pure compounds.
  • the prodrugs consist of a compound of formulas (I) to (IV) and at least one pharmacologically acceptable protecting group which is cleaved off under physiological conditions, eg an alkoxy, aralkyloxy, acyl or acyloxy group, e.g. a methoxy, ethoxy, benzyloxy, acetyl or acetyloxy group.
  • compounds of formulas (I) to (IV) will be prepared using the known and acceptable modes, either alone or in combination with any of them administered to other therapeutic agents.
  • Such therapeutically useful agents may be administered by one of the following routes: orally, eg as dragees, coated tablets, pills, semi-solids, soft or hard capsules, solutions, emulsions or suspensions; parenteral, eg as an injectable solution; rectally as suppositories; by inhalation, eg as
  • the therapeutically useful product may be mixed with pharmacologically inert, inorganic or organic excipients, e.g. with lactose, sucrose, glucose, gelatin, malt, silica gel, starch or derivatives thereof, talc, stearic acid or theirs
  • excipients such as vegetable oils, petroleum, animal or synthetic oils, wax, fat, polyols.
  • excipients such as water, alcohols, aqueous saline, aqueous dextrose, polyols, glycerine, vegetable oils, petroleum, animal or synthetic oils may be used.
  • excipients such as vegetable oils, petroleum, animal or synthetic oils, wax, fat and polyols.
  • compressed gases that are suitable for this purpose, such as oxygen, nitrogen and carbon dioxide.
  • the pharmaceutically acceptable agents may also contain additives for preservation, stabilization, emulsifiers, sweeteners, flavorings, salts for Change in osmotic pressure, buffer, coating additives and antioxidants.
  • the compounds of the general formulas (I), (II), (III) and (IV) have improved properties as compared with the antibacterial compounds known in the art. Particularly noteworthy here are improved antibacterial activity, better solubility and improved PK properties.
  • Combinations with other therapeutic agents may include other antimicrobial and antifungal agents.
  • the dose of the biologically active compound of the present invention may vary within wide limits and may be adjusted to individual needs. In general, a dose of 10 mg to 4000 mg per day is suitable, with a preferred dose being 50 to 3000 mg per day. In appropriate cases, the dose may also be below or above the above values.
  • the daily dose may be given as a single dose or in multiple doses. A typical single dose contains about 50 mg, 100 mg, 250 mg, 500 mg, 1 g or 2 g of the active ingredient. Examples
  • tetrakis (triphenylphosphine) -palladium (0) (1155 g) was added to a solution of methoxyquinoline (Ib) (9.52 g) in dry 1, 2-dimethoxyethane (450 ml) at room temperature and stirred for 20 minutes. Then, potassium carbonate (5.57 g), water (120 ml) and 2,4,6-trivinylcycloboroxane-pyridine complex (3.85 g - O'Sheas Reagent - See J. Org. Ex., Vol. 67 (2002), 4968 -4971) was added and heated for 4 hours at 100 0 C.
  • AD mix alpha (90.2 g) and methanesulfonic acid amide (7.6 g) were dissolved in water (280 ml) and tert-butanol (280 ml) at room temperature.
  • the orange solution was cooled to 0 0 C, was added vinylquinoline (Ic) (14.4 g) and stirred for 2 days at 0-4 0 C.
  • vinylquinoline (Ic) (14.4 g) and stirred for 2 days at 0-4 0 C.
  • sodium pyrosulfite (108 g) was added at 0 ° C. and stirred for 30 minutes at this temperature. After warming to room temperature, it was extracted with ethyl acetate (5 x 150 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated.
  • the crude product was purified by flash chromatography (silica gel, dichloromethane / methanol 29: 1, 4: 1) to afford the desired product (14.91 g).
  • Epoxide (If) (689 mg) and 4- (tert-butoxycarbonyl amino) piperidine (686 mg) were dissolved in DMF (11 ml), treated with potassium carbonate (497 mg) and lithium perchlorate (364 mg) at 80 0 C. stirred for 2 days.
  • the solution was concentrated, the residue dissolved in dichloromethane and washed with water and sat. Extracted sodium chloride solution.
  • the organic phase was dried over magnesium sulfate, filtered and concentrated.
  • the residue was purified by flash chromatography (silica gel, dichloromethane / methanol 97: 3) to afford the desired product (1.22 g).
  • Boc-amine (Ig) (1.22 g) was dissolved in dichloromethane (23 ml), treated at 0 C with 0-5 Trifluoressigcicere (2.3 ml) and stirred at room temperature overnight. The solution was basified with 2N sodium hydroxide and the phases separated. The aqueous phase was extracted with dichloromethane. The combined organic phases were washed with sat. Washed sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (silica gel, Dichloromethane / methanol 9: 1 + 1% ammonia) to afford the desired product (557 mg).
  • ester (2e) (2.33 g) in dioxane (354 ml) and water (90 ml) was added dropwise over 2 hours 0.5N sodium hydroxide solution (24 ml) and then stirred at room temperature overnight. The solution was concentrated and the pH adjusted to 4 with 2N hydrochloric acid. The resulting solid was filtered off, washed with a little water and dried under vacuum overnight to yield the desired product (1.72 g).
  • the compound was prepared as in Example Ik from aldehyde (2h) in 96% yield.
  • 2,4-Difluorobenzoic acid (5.00 g) was dissolved in ethanol (50 ml) and bubbled through the solution for 20 minutes with HCl gas. The mixture was then refluxed for 5 hours, the solution was concentrated and the residue was dissolved in ether. The organic phase was washed with 1N sodium hydroxide solution and sat. Sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to afford the desired product (3.8 g).
  • Ethyl ester (3a) (3.8 g) was dissolved in fuming nitric acid (3 ml) and conc. Dissolved sulfuric acid (3 ml) at 0 0 C and stirred for 2.5 hours. Then it was washed with water (10 ml) diluted and extracted with dichloromethane (200 ml). The organic phase was washed with sat. Washed sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (silica gel, hexane / ethyl acetate 6: 1) to afford the desired product (3.96 g).
  • Nitrobenzoic acid (3b) (3.96 g) was dissolved in dichloromethane (75 ml), added with triethylamine (2.8 ml) and cooled to 0 ° C. After the addition of methyl thioglycolate (1.5 ml) was stirred at 0-5 0 C 3.5 hours and the solution stored overnight in the refrigerator. The solution was concentrated and the residue was purified by flash chromatography (silica gel, hexane / ethyl acetate 6: 1) to give the desired product (3.86 g).
  • the compound was prepared as in Example Ik from aldehyde (3g) in 93% yield.
  • the compound was prepared as in Example Ik from (2,3-dihydrobenzo [1,4] dioxin-6-carbaldehyde.
  • AD mix beta was used to prepare the diol (Id).
  • the compound was prepared from Boc-amine (7b) in 63% yield as in Example Ih.
  • Example Ik The compound was prepared as in Example Ik from amine (7c) and aldehyde (Ij) in 86% yield.
  • Example 8 7-Fluoro-6- ( ⁇ 1- [2-hydroxy-2- (3-methoxy-quinolin-5-yl) -ethyl] -piperidin-4-ylamino ⁇ -methyl) -4H-benzo [l , 4] thiazine-3-one (enantiomer 1)
  • the compound was prepared from aldehyde (3g) in 78% yield as in Example 7d.
  • the compound was prepared from aldehyde (4b) in 73% yield as in Example 7d.
  • the compound was prepared from aldehyde (2h) in 83% yield as in Example 7d.
  • Example 11 2- ⁇ 4- [(2,3-Dihydro- [l, 4] dioxino [2,3-c] pyridine-7-ylmethyl) -axnino] -piperidin-1-yl ⁇ -1- (3 -methoxy-quinolin-5-yl) -ethanol (enantiomer 1)
  • the compound was prepared from aldehyde (5d) in 78% yield as in Example 7d.
  • the compound was prepared as in Example 7d from 2,3-dihydro-benzo [1,4] dioxin-6-carbaldehyde.
  • Example 14 2- ⁇ 4- [(2,3-Dihydro-benzo [l, 4] dioxin-6-ylmethyl) -amino] -piperidin-1-yl ⁇ -1- (3-methoxy-quinoline-5-) yl) ethanol (racemate)
  • the compound was prepared from Boc-amine (14c) in 78% yield as in Example Ih.
  • Example 16 1- (3-Methoxy-quinolin-5-yl) -2- ⁇ 4- [(2-methyl-benzofuran-5-ylin-ethyl) -amino] -piperidin-1-yl ⁇ -ethanol (racemate)
  • PEG 300 (40 ml) was heated to 220 ° C. A solution of propynyl aldehyde (16a) (5g) in PEG 300 (10ml) was added and stirred at 220 ° C for 90 minutes. After cooling, the reaction mixture was poured onto ice (200 g) and extracted with dichloromethane / ether (1: 1, 2 x 300 ml). The combined organic phases were concentrated. The residue was removed by flash Chromatography (silica gel, hexane / ethyl acetate 9: 1) and gave the desired product (2 g).
  • the compound was prepared from aldehyde (16b) as in Example 14e.
  • Example 17 1- (3-Methoxy-quinolin-5-yl) -2- ⁇ 4- [(quinoxalin-2-ylmethyl) -amino] -piperidin-1-yl ⁇ -ethanol (racemate)
  • Example 18 2- [4- ((E) -3-Furan-2-yl-allylamino) -piperidin-1-yl] -1- (3-methoxy-quinolin-5-yl) -ethanol (racemate)
  • Example 14e The compound was prepared as in Example 14e from (E) -3-furan-2-yl-propenal.
  • the compound was prepared from benzofuran-2-carbaldehyde as in Example 14e.
  • Example 14e The compound was prepared as in Example 14e from phenoxyacetaldehyde (according to Syn. Lett., Vol. 11, 2004, p. 2010).
  • the compound was prepared from aldehyde (2Id) as in Example 14e.
  • Example 22 2- ⁇ 4- [(2,3-Dihydro- [l, 4] dioxino [2,3-c] pyridin-7-ylmethyl) -amino] -piperidin-1-yl ⁇ -1- (3 -methoxy-quinolin-5-yl) -ethanol (racemate)
  • the compound was prepared from aldehyde (5d) as in Example 14e.
  • the compound was prepared from aldehyde (23a) as in Example 14e.
  • the compound was prepared from cinnamic aldehyde as in Example 14e.
  • Example 25 1- (3-Methoxy-quinolin-5-yl) -2- ⁇ 4- [(1-methyl-1H-indol-2-ylmethyl) -amino] -piperidin-1-yl ⁇ -ethanol (racemate )
  • the compound was prepared as in Example 14e from 1-methyl-1H-indole-2-carbaldehyde.
  • the compound was prepared from 3-phenylpropionaldehyde as in Example 14e.
  • Acetic acid 200 ml was added with iron powder (15.4 g) and heated to reflux. It was then filtered through Celite and washed with acetic acid. The filtrate was concentrated, the residue taken up in ethyl acetate and washed with sat. Washed sodium bicarbonate solution. The organic phase was dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography (silica gel, hexane / ethyl acetate 1: 1) to afford the desired product (1.5 g).
  • the compound was prepared from aldehyde (27c) as in Example 14e.
  • Example 28 6- ( ⁇ 1- [2-hydroxy-2- (3-methoxy-quinolin-5-yl) ⁇ ethyl] piperidin-4-ylamino ⁇ -methyl) -4H-benzo [1,4] oxazin -3 ⁇ on (racemate)
  • Example 14e The title compound was prepared as in Example 14e from 3-oxo-3,4-dihydro-2H-pyrido [3, 2-b] [1,4] oxazine-6-carbaldehyde (prepared according to WO2006 / 021448).
  • Example 31 2- ⁇ 4- [(E) -3- (2,5-Difluoro-phenyl) -allylamino] -piperidin-1-yl ⁇ -1- (3-methoxy-quinolin-5-yl) -ethanol ( racemate)
  • Example 14e The title compound was prepared as in Example 14e from (E) -3- (2,5-difluoro-phenyl) -propenal (prepared according to WO2004 / 087647).
  • Example 32 1- (3-Methoxy-quinolin-5-yl) -2- ⁇ 4- [(naphthalen-2-ylmethyl) -amino] -piperidin-1-yl ⁇ -ethanol
  • Example 40 2- ⁇ 4- [(2,3-Dihydro-benzo [l, 4] dioxin-6-ylmethyl) amino] -3-fluoro-piperidin-1-yl ⁇ -1- (3-methoxy) quinolin-5-yl) ethanol (enantiomer 1)
  • the compound was prepared as in Example 7d from amine (40I) and 2, 3-dihydro-benzo [1,4] dioxine-6-carbaldehyde.
  • the compound was prepared from aldehyde (Ij) as in Example 40j.
  • the compound was prepared from cinnamic aldehyde as in Example 40j.
  • the compound was prepared from aldehyde (2h) as in Example 40j.
  • the compound was prepared from aldehyde (5d) as in Example 40j.
  • Example 40j The compound was prepared as in Example 40j from benzo [l, 2,5] thiadiazole-5-carbaldehyde.
  • the compound was prepared from aldehyde (4b) as in Example 40j.
  • Example 48 2- [4- [(2,3-Dihydro-benzo [l, 4] dioxin-6-ylmethyl) -amino] -4- (2-hydroxy-ethyl) -piperidin-1-yl] -l - (3-methoxy-quinolin-5-yl) -ethanol (racemate)
  • Dichloroethane (15 ml) was added with sodium triacetoxyborohydride (0.72 g) and stirred at room temperature for 16 hours. Then sat. Add bicarbonate solution (20 mL) and dichloromethane (50 mL), separate the layers and extract the aqueous layer with dichloromethane (50 mL). The combined organic phases were washed with sat. Washed sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (silica gel, ethyl acetate) to give the desired product (0.75 g).
  • the piperidine (2- ⁇ 4- [(benzo [1,3-dioxol-5-ylmethyl) -amino] -piperidin-4-yl ⁇ -ethanol) was prepared analogously to steps 48c to 48e from benzo [1, 3] dioxole-5-carbaldehyde.
  • the title compound was prepared as in Example 48f from epoxide (14b) and 2- ⁇ 4- [(benzo [1,3-dioxol-5-ylmethyl) -amino] -piperidin-4-yl ⁇ -ethanol.
  • Example 50 6- ( ⁇ 4- (2-Hydroxyethyl) -1- [2-hydroxy-2- (3-methoxy-quinolin-5-yl) -ethyl] -piperidin-4-ylamino ⁇ -methyl) 4H-benzo [1,4] oxazin-3-one (racemate)
  • the piperidine (6- ⁇ [4- (2-hydroxy-ethyl) -piperidin-4-ylamino] -methyl ⁇ -4 H -benzo [1,4] oxazin-3-one) was analogous to steps 48c to 48e Aldehyde (Ij) produced.
  • the title compound was prepared as in Example 48f from epoxide (14b) and 6- ⁇ [4- (2-hydroxy-ethyl) -piperidin-4-ylamino] -methyl ⁇ -4H-benzo [1,4] oxazin-3-one produced .
  • Example 51 2- ⁇ 4- [(2,3-Dihydro-benzo [l, 4] dioxin-6-ylmethyl) -amino] -3-hydroxymethyl-piperidin-1-yl ⁇ -l- (3-methoxy) quinolin-5-yl) ethanol (racemate)
  • Lithium aluminum hydride (2.55 g) was added and stirred for 1 hour. Then water (2 ml), 3N sodium hydroxide solution (4 ml) and water (9 ml) were added, warmed to room temperature and added ether (150 ml). The solid was filtered off, the filtrate concentrated and afforded the desired product (5.33 g).
  • Example 54 6- (1-Hydroxy-2- ⁇ 4- [2-hydroxy-2- (3-methoxy-quinolin-5-yl) -ethyl] -piperazin-1-yl ⁇ -ethyl) -4H-benzo [1,4] oxazin-3-one (racemate)
  • the piperazine (6- (1-hydroxy-2-piperazin-1-yl-ethyl) -4H-benzo [l, 4] thiazine-3-one) was prepared analogously to steps 54a to 54b from 6- (2-chloro -acetyl) -4H-benzo [1, 4] thiazine-3-one.
  • the piperazine (1- (2,3-dihydro-benzo [1,4] dioxin-6-yl) -2-piperazin-1-yl-ethanol) was prepared analogously to steps 54a to 54b from 2-chloro-1-one (2, 3-dihydro-benzo [1, 4] dioxin-6-yl) -ethanone produced.
  • Example 54c The title compound was prepared as in Example 54c from epoxide (14b) and 1- (2,3-dihydro-benzo [1,4] dioxin-6-yl) -2-piperazin-1-yl-ethanol.
  • Example Ik The compound was prepared as in Example Ik from 3-methoxy-5- (2-piperazin-1-yl-ethoxy) -quinoline (57f) and 2,3-dihydro-benzo [1, 4] dioxin-6-carbaldehyde in 66 % Yield produced.
  • Example 60 6- ⁇ 4- [2- (3-Methoxy-quinolin-5-yloxy) -ethyl] -piperazin-1-ylmethyl ⁇ -4 H -pyrido [3, 2-b] [1,4] thiazine one 3-
  • Example 65 6- ⁇ 4- [2- (3-Methoxy-quinolin-5-yloxy) ethyl] piperazine-1-carbonyl ⁇ -4 H -benzo [1,4] oxazin-3-one
  • the reaction mixture was stirred for 1 hour at room temperature, then treated with 10% sodium sulfite solution (120 ml) and stirred for a further 30 minutes.
  • the phases were separated and the aqueous phase extracted with ethyl acetate (2 x 100 ml).
  • the combined organic phases were washed with sat. Washed sodium chloride solution, dried over sodium sulfate, filtered and concentrated.
  • the residue was purified by flash chromatography (silica gel, ethyl acetate / hexane 2: 1) to afford the desired product (3.75 g).
  • Example 70 2- [4- (2-Benzo [1,3] dioxol-5-yl-ethyl) -piperazin-1-yl] -1- (3-itethoxy-quinolin-5-yl) -ethanol (enantiomer 1)
  • Example 71 1-Cyclopropyl-6-fluoro-7- ⁇ 4- [2-hydroxy-2- (3-methoxy-quinolin-5-yl) -ethyl] -piperazin-1-yl ⁇ -4-oxo-1 4-dihydro-quinoline-3-carboxylic acid
  • Epoxide (14a) (50 mg) and ciprofloxacin (91.4 mg) were suspended in DMF (0.2 ml) and potassium carbonate (34.3 mg) added. The Letsgemsich was stirred overnight at 100 0 C. After cooling to room temperature, the reaction mixture was concentrated. The residue was purified by flash chromatography (silica gel, dichloromethane / methanol 9: 1). The concentrated fractions were recrystallized from ether / dichloromethane.
  • N-tert-Boc-4-piperidinone (5.0 g) and 1-benzyl-piperazine (4.43 g) were dissolved in methanol (60 ml) and washed with
  • Epoxide (14b) (0.39 g), piperazine (72b) (0.29 g), potassium carbonate (0.29 g) and lithium perchlorate (0.12 g) were dissolved in dry DMF (4 ml) and stirred at 100 ° C. under a nitrogen atmosphere for 24 hours , The mixture was on
  • the maximum inhibitory concentration (MIC) ( ⁇ g / ml) of the examples against various organisms was determined: A. baumannii ATCC19606, E. cloacae ATCC23355, E. coli ATCC25922, K. pneumoniae ATCC27736, P. mirabilis ATCC29906, P. aeruginosa ATCC27853, p maltophilia ATCC13637, S. aureus ATCC43300, S. epidermidis ATCC14990, S. haemolyticus ATCC29970, E. faecalis ATCC29212 and E. faecium ATC19434.
  • Examples 1-12, 14-15, 17-20, 22-26, 28-53 and 56-71 have an MIC of less than or equal to 4 ⁇ g / ml against at least two of the above organisms.

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Abstract

L'invention concerne de nouveaux composés antibactériens de formule (I), ces composés étant, entre autres, des inhibiteurs de l'ADN gyrase et de topoisomérases (par ex. topoisomérase II et IV).
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