EP1613624A2

EP1613624A2 - Novel compounds having an antibacterial activity

Info

Publication number: EP1613624A2
Application number: EP04724014A
Authority: EP
Inventors: Christian Hubschwerlen; Jean Phillippe Surivet; Cornelia Zumbrunn
Original assignee: Morphochem AG; Morphochem AG fuer Kombinatorische Chemie
Current assignee: Morphochem AG; Morphochem AG fuer Kombinatorische Chemie
Priority date: 2003-04-08
Filing date: 2004-03-29
Publication date: 2006-01-11
Also published as: WO2004089947A3; US20060205719A1; RU2005134162A; DE10316081A1; NZ543441A; AU2004228147A1; CA2534891A1; RU2397982C2; EP2298762A2; ZA200508981B; WO2004089947A2

Abstract

The invention relates to novel antibacterial compounds of formula (I). Said compounds are of interest, inter alia, as topoisomerase IV (topo IV) and DNA gyrase inhibitors.

Description

New compounds with antibacterial activity

In many countries around the world, resistance to the antibiotics currently in use has increased considerably in recent years and has become threatening in some cases. The main problem here is that these pathogens usually have multiple resistances. This applies in particular to some Gram-positive pathogen groups, such as staphylococci, pneumococci and enterococci (S. Ewig et al.; Antibiotic resistance in pathogens of community-acquired respiratory infections; Chemother. J. 2002, 11, 12-26; F. Tenover; Development and spread of bacterial resistance to antimicrobial agents: an overview; Clin. Infect. Dis. 2001 Sep 15, 33 Suppl. 3, 108-115)

A long feared development has recently occurred: In the USA, the first strain of Staphylococcus aureus has been described, which is not only methicillin-resistant, but also highly resistant to vancomycin (Centers for Disease Control and Prevention; Staphylococcus aureus resistant to vancomycin - United States, 2002; MMWR 2002, 51, 565-567). In addition to hygienic measures in hospitals, efforts are therefore increasingly required to find new antibiotics that have a new structure and a new mechanism of action, if possible, in order to be effective against these problem germs.

The present application describes novel compounds with antibacterial activity. These compounds are of interest, inter alia, as inhibitors of topoisomerase IV (topo IV) and of DNA gyrase. The present invention relates to compounds of the general formula (I):

in which

A is an oxygen or a sulfur atom, an NH, an alkylene, an alkenylene, an alkynylene or a heteroalkylene group,

X ¹ , X ² , X ³ , X ⁴ and X ^{5 are} independently nitrogen atoms or groups of the formula CH or CR ⁴ ,

Cy is a cycloalkylene, a heterocycloalkylene, an arylene or a heteroarylene group.

R ^{1 represents} a hydrogen atom, a halogen atom, a hydroxy, an amino, a thiol, an alkyl, a heteroalkyl, an alkyloxy, a heteroalkyloxy, a cycloalkyl, a heterocycloalkyl, an alkylcycloalkyl, a heteroalkylcycloalkyl -, is a cycloalkyloxy, an alkylcycloalkyloxy, a heterocycloalkyloxy or a heteroalkylcycloalkyloxy group,

the radicals R ² independently of one another are a halogen atom, a hydroxyl, amino, nitro or thiol group, an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, Heterocycloalkyl, aralkyl or a heteroaralkyl radical, or two of the radicals R ² together form part of an aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aralkyl or heteroaralkyl ring,

R ^{3 is} an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or a heteroaralkyl radical,

R ^{4 is} a halogen atom, a hydroxyl, alkyl, alkenyl, alkynyl or a heteroalkyl group,

n is 0, 1 or 2 and

m is 0, 1 or 2,

or a pharmacologically acceptable salt, solvate, hydrate or a pharmacologically acceptable formulation thereof.

The term alkyl refers to a saturated, straight-chain or branched hydrocarbon group which has 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms, particularly 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.

The terms alkenyl and alkynyl refer to at least partially unsaturated, straight-chain or branched hydrocarbon groups which have 2 to 20 carbon atoms, preferably 2 to 12 carbon atoms, particularly preferably 2 to 6 carbon atoms, e.g. B. the ethenyl, allyl, acetylenyl, propargyl, isoprenyl or hex-2-enyl group. Alkenyl groups preferably have one or two (particularly preferably one) double bonds or alkynyl groups have one or two (particularly preferably one) triple bonds.

Furthermore, the terms alkyl, alkenyl and alkynyl refer to groups in which one or more hydrogen atoms are replaced by a halogen atom (preferably F or Cl), such as, for. B. the 2, 2, 2-trichloroethyl, or the trifluoromethyl group.

The term heteroalkyl refers to an alkyl, an alkenyl or an alkynyl group in which one or more (preferably 1, 2 or 3) carbon atoms are replaced by an oxygen, nitrogen, phosphorus, boron, selenium, Silicon or sulfur atom are replaced (preferably oxygen, sulfur or nitrogen). The term heteroalkyl also refers to a carboxylic acid or a group derived from a carboxylic acid, such as. B. acyl, acylalkyl, alkoxycarbonyl, acyloxy, acyloxyalkyl, carboxyalkylamide or alkoxycarbonyloxy.

Examples of heteroalkyl groups are groups of the formulas R ^a -0-Y ^a -, RSY ^a -, R ^a -N (R ^b ) -Y-, R-CO-Y ^a -, R ^a -0-CO-Y ^a - R ^a -C0-0-Y ^a -, R ^a -C0-N (R) -Y ^a -, R ^a -N (R ^b ) -C0-Y ^a -

R ^a -0-CO-N (R ^b ) -Y ^a -, R ^a -N (R ^b ) -C0-0-Y ^a -, R ^a -N (R ^b ) -C0-N (R ^c ) -Y ^a - R ^a -0-CO-0-Y ^a -, R ^a -N (R ^b ) -C (= NR ^d ) -N (R ^c ) -Y ^a -, R ^a -CS-Y- R ^a -0-CS-Y ^a -, R ^a -CS-0-Y ^a -, R ^a -CS-N (R ^b ) -Y ^a -, R ^a -N (R ^b ) -CS-Y ^a - R ^a -0-CS-N (R ^b ) -Y ^a -, R ^a -N (R ^b ) -CS-0-Y ^a -, R ^a -N (R ^b ) -CS-N (R ^c ) -Y ^a -, R ^a -0-CS-0-Y ^a -, R ^a -S-CO-Y ^a -, R ^a -CO-SY ^a -, R ^a -S-CO-N (R ^b ) -Y ^a -, R ^a -N (R ^b ) -CO-SY ^a -, R ^a -S-CO-0-Y ^a -, R ^a -0-CO-SY-, RS-CO-SY ^a - , R ^a -S-CS-Y ^a -, R ^a -CS-SY ^a - R ^a -S-CS-N (R ^b ) -Y ^a -, R ^a -N (R ^b ) -CS-SY ^a -, R ^a -S-CS-0-Y ^a -, R-0-CS-SY ^a -, where R ^{a is} a hydrogen atom, a Cι ~ C ₆ alkyl, a C ₂ -C ₆ ~ alkenyl or a C ₂ -Cs alkynyl group; R ^{b is} a hydrogen atom, a Ci-C _δ alkyl, a C ₂ -C ₆ alkenyl or a C ₂ -C ₆ alkynyl group; R ^{c is} a hydrogen atom, a C ₃ -C ₃ alkyl, a C ₂ -C ₆ alkenyl or a C ₂ -C ₆ alkynyl group; R ^{d is} a hydrogen atom, a Ci-Cg-alkyl, a C ₂ -C ₆ alkenyl or a C ₂ -C ₆ alkynyl group and Y ^{a is} a direct bond, a -C-C ₆ alkylene, a C ₂ -Cg-alkenylene or a C ₂ -C ₆ alkynylene group, where each heteroalkyl group contains at least one carbon atom and one or more hydrogen atoms can be replaced by fluorine or chlorine atoms. Specific examples of heteroalkyl groups are methoxy, trifluoroethoxy, ethoxy, n-propyloxy, iso-propyloxy, tert-butyloxy, methoxymethyl, ethoxymethyl, methoxyethyl, methylamino, ethylamino, dimethylarrtino, diethylamino, iso-propylethylamino, methylaminoethyl, ethylaminomethyl -iso- propylaminoethyl, enol ether, dimethylamino ethyl, dimethylaminoethyl, acetyl, propionyl, butyryloxy, acetyloxy, methoxycarbonyl, ethoxycarbonyl, N-ethyl-N-methylcarbamoyl or N-methylcarbamoyl. Further examples of heteroalkyl groups are nitrile, isonitrile, cyanate, thiocyanate, isocyanate, isothiocyanate and alkyl nitrile groups.

The term cycloalkyl refers to a saturated or partially unsaturated (e.g., cycloalkenyl) cyclic group that has one or more rings (preferred 1 or 2) which form a framework which 3 to

14 carbon atoms, preferably 3 to 10 (in particular

3, 4, 5, 6 or 7) contains carbon atoms. The expression

Cycloalkyl also refers to groups in which one or more hydrogen atoms are replaced by fluorine, chlorine,

Bromine or iodine atoms or OH, = 0, SH, = S, NH ₂ , = NH or

N0 ₂ groups are replaced, for. B. cyclic ketones such. B. cyclohexanone, 2-cyclohexenone or cyclopentanone.

Further specific examples of cycloalkyl groups are the cγcloproρyl, cyclobutyl, cyclopentyl, spiro [4,5] decanyl, norborny, cyclohexyl, cyclopentenyl, cyclohexadienyl, decalinyl, bicyclo [4.3.0] nonyl -, tetralin,

Cyclopentylcyclohexyl, fluorocyclohexyl or the cyclohex-2-enyl group.

The term 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 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. The term heterocycloalkyl also refers to groups in which one or more hydrogen atoms have been replaced by fluorine, chlorine, bromine or iodine atoms or OH, = 0, SH, = S, NH _{2 /} = NH or NO ₂ groups , Examples are the piperidyl, piperazinyl, morpholinyl, urotropinyl, pyrrolidinyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrofuryl or 2-pyrazolinyl group and lactams,

Lactones, cyclic errors and cyclic anhydrides. The term alkylcycloalkyl refers to groups which, in accordance with the above definitions, contain both cycloalkyl and also alkyl, alkenyl or alkynyl groups, e.g. B. alkylcycloalkyl, cycloalkylalkyl, alkylcycloalkenyl, alkenylcycloalkyl and alkynylcycloalkyl groups. An alkylcycloalkyl group preferably contains a cycloalkyl group which has one or two ring systems which form a skeleton which contains 3 to 10 (in particular 3, 4, 5, 6 or 7) carbon atoms and one or two alkyl, Alkenyl or alkynyl groups with 1 or 2 to 6 carbon atoms.

The term 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 heteroakylcycloalkyl group preferably has 1 or 2 ring systems with 3 to 10 (in particular 3, 4, 5, 6 or 7) ring atoms and one or two alkyl, alkenyl, alkynyl or heteroalkyl groups with 1 or 2 to 6 carbon atoms. Examples of such groups are alkyl heterocycloalkyl, alkyl heterocycloalkenyl, alkenyl heterocycloalkyl, alkynyl heterocycloalkyl, heteroalkylcycloalkyl, heteroalkyl heterocycloalkyl and heteroalkyl heterocylcloalkenyl, the cyclic groups being saturated or mono-, di- or trisaturated.

The term aryl or Ar refers to an aromatic group which has one or more rings and is formed by a structure which has 6 to 14 carbon atoms, preferably 6 to 10 (in particular 6) carbon atoms. contains atomic atoms. The term aryl (or Ar) also 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 the phenyl, naphthyl, biphenyl, 2-fluorophenyl, anilinyl, 3-nitrophenyl or 4-hydroxyphenyl group.

The term heteroaryl refers to an aromatic group which has one or more rings and is formed by a structure which 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) contains oxygen, nitrogen, phosphorus or sulfur ring atoms (preferably 0, S or N). The expression heteroaryl also 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.

The term aralkyl refers to groups which, according to the above definitions, contain both aryl and also alkyl, alkenyl, alkynyl and / or cycloalkyl groups, such as, for. B. arylalkyl, arylalkenyl, arylalkynyl, arylcycloalkyl, arylcycloalkenyl, alkylarylcycloalkyl and alkylarylcycloalkenyl groups. Specific examples of aralkyls are toluene, xylene, mesitylene, styrene, benzyl chloride, o-fluorotoluene, 1H-indene, tetralin, Dihydronaphthalenes, indanone, phenylcyclopentyl, cumene, cyclohexylphenyl, fluorene and indane. An aralkyl group preferably contains one or two aromatic ring systems (1 or 2 rings) with 6 to 10 carbon atoms and one or two alkyl, alkenyl and / or alkynyl groups with 1 or 2 to 6 carbon atoms and / or a cycloalkyl group with 5 or 6 ring carbon atoms.

The term 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, boron or Sulfur atom (preferably oxygen, sulfur or nitrogen) are replaced, i. H. to groups which, according to the above definitions, contain both aryl or heteroaryl and also alkyl, alkenyl, alkynyl and / or heteroalkyl and / or cycloalkyl and / or heterocycloalkyl groups. A heteroaralkyl group preferably contains one or two aromatic ring systems (1 or 2 rings) with 5 or 6 to 10 carbon atoms and one or two alkyl, alkenyl and / or alkynyl groups with 1 or 2 to 6 carbon atoms and / or a cycloalkyl group with 5 or 6 ring carbon atoms, 1, 2, 3 or 4 of these carbon atoms being replaced by oxygen, sulfur or nitrogen atoms.

Examples are Arylheteroalkyl-, Arylheterocycloalkyl-, Arylheterocycloalkenyl-, Arylalkylheterocycloalkyl-, Arylalkenylheterocycloalkyl-, Arylalkinylheterocyclo- alkyl-, Arylalkylheterocycloalkenyl-, heteroarylalkyl, heteroarylalkenyl-, heteroarylalkynyl-, Heteroarylhetero- alkyl-, Heteroarylcycloalkyl-, Heteroarylcycloalkenyl-, Heteroarylheterocycloalkyl-, Heteroarylheterocycloalken- yl, heteroarylalkylcycloalkyl, heteroarylalkylheterocycloalkenyl, heteroarylheteroalkylcycloalkyl, heteroarylheteroalkylcycloalkenyl and heteroarylheteroalkyl heterocycloalkyl groups, the cyclic groups being saturated or mono-, tri-or tri-unsaturated. Concrete examples are the tetrahydro-isoquinolinyl, benzoyl, 2- or 3-ethylindolyl, 4-methylpyridino, 2-, 3- or 4-methoxyphenyl, 4-ethoxyphenyl, 2-, 3- or 4-carboxyphenylalkyl group ,

The terms cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl and heteroaralkyl also refer to groups in which one or more hydrogen atoms of such groups are represented by fluorine, chlorine, bromine or iodine atoms or OH, = 0, SH, = S, NH ₂ , = NH or N0 ₂ groups are replaced.

The expression "optionally substituted" refers to groups in which one or more hydrogen atoms are replaced by fluorine, chlorine, bromine or iodine atoms or OH, = 0, SH, = S, NH ₂ , = NH or NO ₂ groups are. This expression also refers to groups with unsubstituted Ci-Cε alkyl, C ₂ -C6 alkenyl, C ₂ -C6 alkynyl, Ci-Ce heteroalkyl, C ₃ -Cιo cycloalkyl, C ₂ -C ₉ heterocycloalkyl -, Cε-Cio aryl, -C-C ₉ heteroaryl, C ₇ -Cι ₂ aralkyl or C-Cn heteroaralkyl groups are substituted.

Compounds of formula (I) can contain one or more centers of chirality due to their substitution. The present invention therefore includes both all pure enantiomers and all pure diastereomers, as well as their mixtures in any mixing ratio. Of the present invention also includes all cis / trans isomers of the compounds of the general formula (I) and mixtures thereof. Furthermore, the present invention encompasses all tautomeric forms of the compounds of the formula (I).

Preferred compounds of the formula (I) are those in which A is an oxygen or a sulfur atom or a group of the formula CH ₂ , CH ₂ CH ₂ , CH ₂ N (-CC ₄ -alkyl), N (C ₁ -C -alkyl) ) CH ₂ , CH ₂ 0, OCH ₂ , CH ₂ S, SCH ₂ , CH ₂ CH (OH), CH (OH), CH (0H) CH ₂ , NHCO, CONH, C (= 0) CH ₂ or CH ₂ C (= 0).

Compounds of the formula (I) are further preferred, three, four or five of the groups X ¹ , X ² , X ³ , X ⁴ and X ⁵ being CH groups.

Again, R ¹ is preferably a Cχ-C ₄ alkyloxy or a C ¹ -C ₄ heteroalkyloxy group, it being possible for one or more hydrogen atoms of these groups to be replaced by fluorine atoms.

R ¹ is particularly preferably a methoxy group.

Again, R ² is preferably a hydroxy, a C ₁ -C ₄ alkyl, C ₁ -C ₄ heteroalkyl or a Ce-Ci ₂ heteroaralkyl group.

R ³ is more preferably a heteroalkylcycloalkyl or a heteroaralkyl group.

R ³ is particularly preferably a group of the formula -BY, where B is an alkylene (in particular a C 1 -C ₄ -alkylene group), alkenylene, alkynylene or a hetero- alkylene group (in particular a C 1 -C ₄ heteroalkylene group) and Y is an aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl or a heteroalkylcycloalkyl group (in particular a heterocycloalkyl or an aryl heterocycloalkyl group ) is.

Again, Y preferably has one of the following structures

where X ⁶ , X ⁷ and X ^{8 are} independently nitrogen atoms or groups of the formula CR ⁹ , X ⁹ and X ^{10 are} independently oxygen or sulfur atoms or groups of the formula NR ¹⁰ , o is 0, 1 or 2, R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ^{9 are} independently hydrogen atoms, halogen atoms, hydroxyl, alkyl, alkenyl, alkynyl or heteroalkyl groups and R ¹⁰ and R ^{u are} independently hydrogen atoms, alkyl, alkenyl, alkynyl or heteroalkyl groups.

Y particularly preferably has one of the following structures:

The linker -A- (CH ₂ ) - further preferably has a chain length of 2 or 3 atoms. Furthermore, R ⁴ is preferably a fluorine or a chlorine atom or a C ₁ -C ₄ -alkyloxy or a C ₃ -C _e - dialkylaminomethyl group, it being possible for one or more hydrogen atoms of these groups to be replaced by fluorine atoms.

Again Cy is preferred a cycloalkylene or a heterocycloalkylene group with one or two rings and 4, 5, 6, 7, 8, 9 or 10 ring atoms.

Cy is particularly preferably a group of the formulas

wherein U is a nitrogen atom or a group of the formula CH or COH and V is a nitrogen atom or a CH group and p is 0 or 1. The substituents can be bound to this group both in an egatory and in an axial manner.

The therapeutic use of the compounds of formula (I), their pharmacologically acceptable salts or solvates and hydrates as well as formulations and pharmaceutical compositions is also within the scope of the present invention.

The pharmaceutical compositions according to the present invention contain at least one compound of the formula (I) as active ingredient and optionally excipients and / or adjuvants. Examples of pharmacologically acceptable salts of the compounds of formula (I) 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, lactic acid, acetic acid, trifluoroacetic acid, citric acid, succinic acid, fumaric acid, maleic acid and salicylic acid. Further examples of pharmacologically acceptable salts of the compounds of formula (I) are alkali or alkaline earth metal salts such as. As sodium, potassium, lithium, calcium or magnesium salts, ammonium salts or salts of organic bases such as. As methylamine, dirnethyla in, triethylamine, piperidine, ethylenediamine, lysine, choline hydroxide, meglumine, morpholine or arginine salts. Compounds of formula (I) can be solvated, in particular hydrated. Hydration can occur, for example, during the manufacturing process or as a result of the hygroscopic nature of the initially anhydrous compounds of formula (I). If the compounds of the formula (I) contain asymmetric carbon atoms, they can be present either as achiral compounds, diastereomeric mixtures, mixtures of enantiomers or as optically pure compounds.

The pro-drugs, which are also the subject of the present invention, consist of a compound of the formula (I) and at least one pharmacologically acceptable protective group which is split off under physiological conditions, for example an alkoxy, aralkyloxy, acyl or acyloxy group such as an ethoxy, benzyloxy, acetyl or acetyloxy group. The present invention also relates to the use of these active ingredients for the production of medicaments. In general, compounds of formula (I) are administered using known and acceptable modes, either individually or in combination with any other therapeutic agent. Such therapeutically useful agents can be administered in one of the following ways: orally, for example as dragées, coated tablets, pills, semi-solid substances, soft or hard capsules, solutions, emulsions or suspensions; parenterally, eg as an injectable solution; rectally as suppositories; by inhalation, for example as a powder formulation or spray, transdermally or intranasally. To produce such tablets, pills, semi-solids, coated tablets, dragees and hard gelatin capsules, the therapeutically usable product can be mixed with pharmacologically inert, inorganic or organic drug carrier substances, for example with lactose, sucrose, glucose, gelatin, malt, silica gel, starch or derivatives the same, talc, stearic acid or its salts, dry skimmed milk and the like. For the production of soft capsules, drug carriers such as vegetable oils, petroleum, animal or synthetic oils, wax, fat, polyols can be used. For the preparation of liquid solutions and syrups, drug carriers such as water, alcohols, aqueous salt solution, aqueous dextrose, polyols, glycerin, vegetable oils, petroleum, animal or synthetic oils can be used. For suppositories, drug carriers such as vegetable oils, petroleum, animal or synthetic oils, wax, fat and polyols can be used. For aerosol formulations one can use compressed gases that are suitable for this purpose are, such as using oxygen, nitrogen and carbon dioxide. The pharmaceutically usable agents can also contain additives for preservation, stabilization, emulsifiers, sweeteners, flavorings, salts for changing the osmotic pressure, buffers, coating additives and antioxidants.

Combinations with other therapeutic agents can include other antimicrobial and antifungal agents.

For the prevention and / or treatment of the diseases described above, the dose of the biologically active compound according to the invention can vary within wide limits and can be adjusted to individual requirements. Generally a dose of 10 mg to 4000 mg per day is suitable, with a preferred dose being 50 to 3000 mg per day. In suitable cases, the dose can also be below or above the values given above. The daily dose can be administered as a single dose or in multiple doses. A typical single dose contains approximately 50 mg, 100 mg, 250 mg, 500 mg, 1 g or 2 g of the active ingredient.

EXAMPLES

Example 1: (R, S) -6- {l-Hydroxy-2- [4- (7-methoxy-naphthalene-1-yloxymethyl) piperidin-1-yl] βthyl} -4H-benzo [1,4 ] oxazin-3-one 17

Synthesis of 4- (7-methoxy-naphthalene-l-yloxymethyl) - piperidine-1-carboxylic acid tert-butyl ester To a solution of triphenylphosphine (1.14 g; 4.3 mmol) in THF (5 ml) was added dropwise diethyazodicarboxylate (755 mg; 4.3 mmol) was added dropwise. 4-Hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (850 mg, 3.95 mmol) was added, followed by 7-methoxy-l-naphthol (synthesized analogously to Aust. J. Chem. 1993, 46, 731) (668 mg ; 3.95 mmol). The yellow solution was stirred overnight at room temperature, concentrated and purified by means of column chromatography on silica gel (hex / EtOAc 4: 1). 1.11 g (76%) of a colorless oil were obtained.

MS (ESI ⁺ ): 372.3 [M + H ⁺ ]

Synthesis of 4- (7-methoxy-naphthalene-l-yloxymethyl) - piperidine A solution of 4- (7-methoxy-naphthalene-l-yloxymethyl) - piperidine-1-carboxylic acid tert-butyl ester (l, .ll g) in dichloroethane (10 ml), trifluoroacetic acid (2 ml) was added at room temperature under argon and the mixture was stirred for two hours. The reaction mixture was concentrated on a rotary evaporator, taken up in dichloromethane and concentrated with conc. Washed ammonia solution. The organic phases were dried over MgS0 ₄ and concentrated. Synthesis of 6- {2- [4- (7-methoxy-naphthalene-1-yloxy ethyl) piperidin-1-yl] acetyl} -4H-benzo [1,4] oxazin-3-one A mixture of 4 - (7-methoxy-naphthalene-l-yloxymethyl) piperidine (271 mg, 1 mmol) and 6- (2-chloro-acetyl) -4H-benzo [1,4] oxazin-3-one (225 mg, 1 mmol) in THF (5 ml) was mixed with triethylamine (1 ml) and heated to 50 ° C. for 2 h. The reaction mixture was poured onto water and extracted with EtOAc. Organic phases washed with NH ₄ C1 solution, dried over MgS0 ₄ and concentrated. The crystalline residue was stirred with MeOH and EtOAc and suction filtered. 250 mg (52%) of pure product were obtained.

MS (ESI ⁺ ) 461 [M + H ⁺ ]

Synthesis of (R, S) -6- {l-hydroxy-2- [4- (7-methoxy-naphthalen-1-yloxymethyl) piperidin-1-yl] ethyl} -4H-benzo [1,4] oxazin-3-one

A solution of 6- {2- [4- (7-methoxy-naphthalene-1-yloxymethyl) piperidin-1-yl] acetyl} -4H-benzo [1, 4] oxazin-3-one (150 mg) in EtOH (2 ml), NaBH ₄ (1 eq) was added and the mixture was stirred at rt for 2 h. The reaction mixture was concentrated, taken up in water and the white crystals were filtered off with suction and dried under high vacuum. 140 mg of pure product were obtained.

MS (ESI ⁺ ) 463.5 [M + H ⁺ ]

Example 2: (R, S) -1- (2,3-dihydro-benzo [1,4] dioxin-6-yl) -2- [4- (7-methoxy-naphthalene-1-yloxymethyl) piperidine- 1-yl] - ethanon

Synthesis of 6-oxiranyl-2, 3-dihydro-benzo [1, 4] dioxin

In a 50 ml round bottom flask, 2,3-dihydrobenzofl, 4] dioxine-6-carbaldehyde (lg, 6.09 mmol) was dissolved in acetonitrile (15 ml), trimethylsulfonium iodide (1.28g, 6.28 mmol) and KOH (2.4 g) and some Drop of water added and allowed to stir for 1.5 hours at 60 ° C. The reaction mixture was concentrated on a rotary evaporator. The residue was taken up in water and extracted with EtOAc. The organic phase was dried over Na ₂ S0 ₄ , filtered and concentrated. The residue was chrootographed with Hexl: EEl. 1g (100%) of pure product was obtained.

^ ϊ NMR (CDC1 ₃ ): 6.80-6.77 (m, 3H); 4.27 (s, 4H); 3.78 (dd, J = 2.61, 4.02, 1H); 3.11 (dd, J = 4.02, 5.4, 1H); 2.79 (dd, J = 2.61, 4.5, 1H)

Synthesis of (R, S) -1- (2,3-dihydro-benzo [1,4] dioxin-6-yl) - 2- [4- (7-methoxy-naphthalene-l-yloxymethyl) piperidine-1 - yl] -ethanone To a solution of 4- (7-methoxy-naphthalene-l-yloxymethyl) piperidine (100 mg, 0.36 mmol) and 6-0xiranyl-2, 3-dihydro-benzo [1,4] dioxin (66 mg; 0.36 mmol) in DMF (1 ml) was lithium perchlorate (39.2 mg; 0.36 mmol) and Potassium carbonate (101.9 mg; 0.73 mmol) added. The reaction mixture was stirred at 80 C overnight, concentrated in a high vacuum, taken up in water and extracted with EtOAc. The organic phase was dried over Na ₂ S0 ₄ and concentrated. The product was purified by chromatography on Si0 ₂ (EtOAc). 62.5 mg (38%) were obtained as a beige foam.

MS (ESI ⁺ ) 450.5 [M + H ⁺ ]

Example 3: (R, S) -6- {l-Hydroxy-2- [4- (7-methoxy-phthalazin-1-yloxymethyl) piperidin-1-yl] ethyl} -4H-benzo [1,4 ] oxazin-3-one

Synthesis of l-chloro-7-methoxy-phthalazine

A mixture of 7-methoxy-2H-phthalazin-l-one (2.2 g, 12.5 mmol, prepared as described in J. Am. Chem. Soc 1924, 1889) and POCl ₃ (10 ml) was heated to reflux for 6 h. The excess P0C1 ₃ was distilled off on a rotary evaporator and the residue was taken up in EtOAc. Organic phase washed with water and bicarbonate solution, dried over MgS0 ₄ and concentrated. The product was purified by column chromatography (hex / EtOAc 1: 1). O 20040

21

H NMR (CDCI3): 9.33 (s, 1H); 7.92 (d, J = 8.7 Hz, 1H); 7.58 (dd, J = 8.7, 2.2 Hz, 1H); 7.52 (d, J = 2.2 Hz, 1H); 4.0 (s, 3H)

S (ESI ⁺ ) 195/197 [M + H ⁺ ]

Synthesis of 4- (7-methoxy-phthalazin-l-yloxymethyl) - piperidine-1-carboxylic acid tert-butyl ester

A solution of 4-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (475 mg, 2.2 mmol) in DMF (10 ml) was mixed with NaH dispersion (55%, 96 mg) and allowed to stir for 5 minutes. A solution of l-chloro-7-methoxy-phthalazine (430 mg; 2.2 mmol) in DMF was added dropwise and the reaction mixture was stirred at room temperature for 4 h, diluted with EtOAc and water. The organic

Phase was washed with water and dried over MgSO4 and concentrated. The product became medium

Chromatography on Si0 ₂ (EtOAc) cleaned. There were 709 mg

(86%) received.

MS (ESI ⁺ ) 374.5 [M + H ⁺ ]

Synthesis of 7-methoxy-l- (piperidin-4-ylmethoxy) phthalazine The BOC group was deprotected analogously to Example 1 using TFA in DCM.

MS (ESI ⁺ ) 284.5 [M + H ⁺ ]

Synthesis of 6- {2- [4- (7-methoxy-phthalazin-l-yloxymethyl) piperidin-1-yl] acetyl} -4H-benzo [1, 4] oxazin-3-one A mixture of 7-methoxy-1- (piperidin-4-ylmethoxy) phthalazine (273 mg, 1 mmol) and 6- (2-chloro-acetyl) -4H- Triethylamine (1 ml) was added to benzo [1, 4] oxazin-3-one (225 mg, 1 mmol) in THF (5 ml) and the mixture was heated to 50 ° C. for 2 h. A yellow precipitate formed, which was filtered off with suction and stirred with MeOH / EtOH / THF. In this way, 80 mg of pure product were obtained.

MS (ESI ⁺ ) 463.5 [M + H ⁺ ]

Synthesis of (R, S) -6- {l-hydroxy-2- [4- (7-methoxy-phthalazin-1-yloxymethyl) piperidin-1-yl] ethyl} -4H-benzo [1,4] oxazin-3-one

A solution of 6- {2- [4- (7-methoxy-phthalazin-l-yloxymethyl) piperidin-1-yl] acetyl] -4H-benzo [1,4] oxazin-3-one (40 mg) in EtOH (2 ml) and THF (2 ml), NaBH ₄ (1 eq) was added and the mixture was stirred at rt for 2 h. The reaction mixture was adsorbed on Si0 ₂ and purified by chromatography (DCM / MeOH 9: 1 + 1% NH40H). 25 mg of pure product were obtained.

MS (ESI ⁺ ) 465.5 [M + H ⁺ ]

Example 4: (R, S) -1- (2,3-dihydro-benzo [1,4] dioxin-β-yl) - 2- [4- (7-methoxy-phthalazin-l-yloxymethyl) piperidine- 1-yl] ethanol

To a solution of 7-methoxy-1- (piperidin-4-ylmethoxy) phthalazine (100 mg, 0.36 mmol) and 6-oxiranyl-2, 3-dihydrobenzofl, 4] dioxin (66 mg; 0.36 mmol) in DMF (1 ml), lithium perchlorate (39.2 mg; 0.36 mmol) and potassium carbonate (101.9 mg; 0.73 mmol) were added. The reaction mixture was stirred at 80 C overnight, concentrated in a high vacuum, taken up in water and extracted with EtOAc. The organic phase was dried over Na ₂ S0 ₄ and concentrated. The product was purified by chromatography on Si0 ₂ (EtOAc). 58.7 mg (35%) were obtained as a white foam.

MS (ESI ⁺ ) 452.5 [M + H ⁺ ]

Example 5: 6- {1-Hydroxy-2- [4- (7-methoxy-isoquinolin-l-yloxymethyl) piperidin-1-yl] ethyl} -4H-benzσ [1,4] oxazin-3-one

Synthesis of l-chloro-7-rrtethoxy-isoquinoline

A mixture of 7-methoxy-2H-isoquinolin-l-one (6.5 g, 37 mmol, prepared analogously to J. Heterocycl. Chem 1985, 22, 328) and P0C1 ₃ (50 ml) was heated to reflux for 6 h. The excess P0C1 ₃ was distilled off on a rotary evaporator and the residue was taken up in EtOAc. Organic phase washed with ice water and bicarbonate solution, dried over MgS0 ₄ and concentrated. The The product was purified by column chromatography (hex / EtOAc 3: 1).

MS (ESI ⁺ ) 194.5 [M + H ⁺ ]

Synthesis of 4- (7-methoxy-isoquinolin-l-yloxymethyl) piperidine-1-carboxylic acid tert-butyl ester

A solution of 4-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (1075 mg, 5 mmol) in THF (20 ml) was mixed with NaH dispersion (55%, 240 mg) and allowed to stir for 5 minutes. A solution of l-chloro-7-methoxy-isoquinoline (965 mg; 5 mmol) in THF was added dropwise and the reaction mixture was stirred for 5 h at 50C and overnight at room temperature, diluted with ether and water. The organic phase was washed with water and dried over MgS0 ₄ and concentrated. The product was purified by chromatography on Si0 ₂ (hex / EtOAc 3: 1). 1.16 g (62%) were obtained.

MS (ESI ⁺ ) 373.5 [M + H ⁺ ]

Synthesis of 7-methoxy-l- (piperidin-4-ylmethoxy) isoquinoline

The BOG group was deprotected as in Example 1 using TFA in DCM.

^X H NMR (CDC1 ₃ ): 7.8 (d, J = 5.97 Hz, 1H); 7.58 (d, J = 8.91, 1H); 7.43 (d, J = 2.52, 1H); 7.24, (dd, J = 8.91, 2.52, 1H); 7.08 (d, J = 5.97, 1H); 4.32 (d, J = 6.51, 2H); 3.88 (s, 3H); 3.26-3.24 (m, 2H); 2.88-2.70 (m, 2H); 2.1-2.05 (m, 1H); 2.0-1.9 (, 2H); 1.60-1.46 (m, 2H) Synthesis of 6- {2- [4- (7-methoxy-isoquinolin-l-yloxyethyl) piperidin-1-yl] acetyl) -4H-benzo [1,4] oxazin-3-one A mixture of 7-methoxy-1- (piperidin-4-ylmethoxy) isoquinoline (272 mg, 1 mmol) and 6- (2-chloro-acetyl) -4H-benzo [1,4] oxazin-3-one (225 mg, 1 mmol) in THF (5 ml) was mixed with K ₂ CO ₃ (1 eq) and heated to 50 C overnight. The reaction mixture was concentrated and the residue was purified by chromatography on Si0 ₂ (EtOAc). In this way, 250 mg (54%) of pure product were obtained.

MS (ESI ⁺ ) 462.5 [M + H ⁺ ]

Synthesis of 6- {l-hydroxy-2- [4- (7-methoxy-isoquinolin-l-yloxymethyl) piperidin-1-yl] ethyl} -4H-benzo [1, 4] oxazin-3-one

A solution of 6- {2- [4- (7-methoxy-isoquinolin-l-yloxymethyl) -ρiρeridin-1-yl] -acetyl} -4H-benzo [1,4] oxazin-3-one (200 mg, 0.5 mmol) in EtOH (20 ml) ^' , NaBH ₄ (40 mg) was added and the mixture was stirred at room temperature for 2 h. The reaction mixture was adsorbed on Si0 ₂ and purified by chromatography (DCM / MeOH 9: 1 + 1% NH40H). The product was crystallized from ether. 55 mg (28%) of pure product were obtained.

MS (ESI ⁺ ) 464 [M + H ⁺ ]

Example 6: Synthesis of 1- (2,3-dihydro-benzo [1,4] dioxin-6-yl) -2- [4- (7-methoxy-isoquinolin-l-yloxymethyl) piperidin-1-yl] ethanol

To a solution of 7-methoxy-1- (piperidin-4-ylmethoxy) isoquinoline (100 mg, 0.36 mmol) and 6-oxiranyl-2,3-dihydro-benzo [1,] dioxin (66 mg; 0.36 mmol) in DMF (1 ml) was added lithium perchlorate (39.2 mg; 0.36 mmol) and potassium carbonate (101.9 mg; 0.73 mmol). The reaction mixture was stirred at 80 C overnight, concentrated in a high vacuum, taken up in water and extracted with EtOAc. The organic phase was dried over Na ₂ S0 ₄ and concentrated. The product was purified by chromatography on Si0 ₂ (EtOAc). 58.7 mg (35%) were obtained as a white foam.

MS (ESI ⁺ ) 451.5 [M + H ⁺ ]

Example 7: 2- (3- {[(2,3-dihydrobenzo [1,4] dioxin-6-ylmethyl) amino] methyl} piperidin-l-yl) -1- (3- methoxy-quinolin-5-yl) ethanol

Synthesis of 3-azidomethyl-piperidine-1-carboxylic acid tert-butyl ester

To a solution of (3R) -hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (2g, 9.29 mmol prepared analogously to Tetrahedron Lett 2002, 43, 8917 and Gazz. Chim. Ital. 1972, 102, 189.) in DCM (30 inL) were added dropwise at 0C, triethylarrdn (2.6mL, 18.6mmol), and then methanesulfonyl chloride (O.δrnL, 10.3 mmol). The reaction mixture was stirred at this temperature for 30 min. Saturated NaHC0 ₃ solution (20mL) and DCM (30mL) were added. The two phases were separated and the organic phase washed with brine (20mL), dried over MgS0 ₄ and concentrated. The crude product was quickly filtered through silica (AcOEt / Hex 1: 1). The crude product was taken up in DMF (40 ml) and sodium azide (1.2 g, 18.4 mmol) was added. The reaction mixture was stirred at 80 ° C. for 5 hours, concentrated on a rotary evaporator and mixed with ether and water. The organic phase was dried over MgS0 ₄ and concentrated. The crude product was purified by chromatography on Si0 ₂ (hex / EtOAc 4: 1). 2.16 g (9 mmol) could be isolated as an oil.

MS (EI) m / z: 241.4 [M + H ⁺ ]

Synthesis of (R) - (2, 3-dihydro-benzo [1, 4] dioxin-6-yl-ethyl) -piperidin-3-ylmethylamine

A solution of 3-azidomethyl-piperidine-l-carboxylic acid tert-butyl ester (2.16 g, 9 mmol) in THF (60mL) and Polymer-bound triphenylphosphine (6.3 g, 3.6 mmol / g) was added to water (lmL). The mixture was stirred at room temperature for 4 days and filtered. The filtrate was concentrated and taken up in methanol (35 ml). 1, 4-Benzoäioxan-6-carboxaldehyde (1.48 g, 9 mmol) and 3A MS (9.6g) were added. The reaction mixture was stirred at room temperature for 5 h before sodium borohydride (1.2g, 31.7 mmol) was added. The mixture was stirred for a further 16 h at room temperature, concentrated and taken up in water (100 ml). The aqueous phase was extracted with DCM (2 * 200ml). The combined organic phases were dried over MgS0 ₄ and concentrated. The residue was purified by chromatography on SiO ₂ (DCM-MeOH 19-1). 2.2 g of product were obtained as an oil. This oil was taken up in TFA (10 ml) and stirred for 1 h. The mixture was concentrated, taken up in aqueous ammonia solution and extracted with DCM (2 * 30 ml). The combined organic phases were dried over MgS0 ₄ and concentrated. 1.44 g (5.53 mmol) of product could be isolated as an oil.

MS (EI) m / z: 263.0 [M + H ⁺ ]

Synthesis of 2-bromo-1- (3-methoxy-quinolin-5-yl) ethanone

(Synthesis 2002, 83)

A solution of 3-bromoquinoline (10.4 g, 50 mmol) in conc.

H2SO4 (50 ml) was mixed with NBS (10.7 g, 60 mmol) at room temperature and stirred overnight. The reaction mixture was poured onto ice, with aqueous

Ammonia solution made basic and extracted with ether.

The organic phases were dried over MgS0 and concentrated. The product was analyzed by chromatography Si0 ₂ (DCM / hex 6: 4, DCM, EtOAc) cleaned and recrystallized from methanol. 8 g (56%) of 3,5-dibroquinoline were obtained as white crystals.

1H NMR (CDC13): 8.91 (d, J = 2.2 Hz, 1H); 8.80 (d, J = 2.2 Hz, 1H); 8.07 (d, J = 7.8 Hz, 1H); 7.88 (d, J = 7.8 Hz, 1H); 7.60 (t, J = 7.8 Hz, 1H);

MS (ESI +) m / z 285/287/289 [M + H ⁺ ]

This dibromide (2 mmol) was dissolved in HMPT (8 ml) (tetrahedron 2002, 58, 1125) by reaction with sodium methylate (4 mmol) and heated to 90 ° C. in the microwave oven for 2 min. This procedure was repeated 6 times. The combined reaction mixture was poured onto water, extracted with ether, dried over MgS0 ₄ and concentrated. The product was purified by chromatography on Si0 ₂ (hex / EtOAc 4: 1). 2.78 g (67%) of 5-bromo-3-methoxyquinoline were obtained.

This 5-bromo-3-methoxyquinoline was converted to 1- (3-methoxyquinolin-5-yl) ethanone as described in the literature (WO 0208224).

1- (3-methoxy-quinolin-5-yl) -ethanone (500 mg, 2.5 mmol) in AcOH (10 ml) was added Br ₂ (leq) and HBr (33% in AcOH). The mixture was stirred at rt for 2 h. According to MS, a mixture of mono- and dibroated product was formed. The reaction mixture was diluted with water and extracted with DCM. Organic phases washed with water and bicarbonate solution, dried over MgS0 ₄ and concentrated. The products were separated by means of chromatography on Si0 ₂ (hex / EtOAc 2: 1). you received 225 mg of 2-bromo-1- (3-methoxy-quinolin-5-yl) ethanone.

1H NMR (CDC13): 8.75 (d, J = 2.2 Hz, 1H); 8.65 (d, J = 2.2 Hz, 1H); 8.33 (d, J = 7.8 Hz, 1H); 8.13 (d, J = 7.8 Hz, 1H); 7.64 (t, J = 7.8Hz, 1H); 4.65 (s, 2H); 4.01 (ε, 3H).

MS (ESI +) m / z 280/282 [M + H ⁺ ]

Synthesis of (1-RS) -2- (3 (S) - {[(2, 3-dihydro-benzo- [1, 4] - dioxin-6-ylmethyl) -amino] -methyl} -piperidin-l- yl) -1- (3-methoxy-quinolin-5-yl) ethanol

A solution of 2-bromo-l- (3-methoxy-quinolin-5-yl) - ethanone (0.113 g, 0.4 mmol) and (R) - (2, 3-dihydrobenzo [1, 4] dioxin-6 -ylmethyl) -piperidin-3 -ylmethyl-amine (0.106 g, 0.4 mmol) in THF (3mL) was stirred overnight at room temperature. The reaction mixture was concentrated and the residue was taken up in methanol (2 ml). After cooling to 0 ° C, NaBH ₄ (0.031g, 0.8 mmol) was added. The reaction mixture was stirred at 0 ° C for one hour. Water (3 ml) was added and the reaction mixture was concentrated. The residue was purified by chromatography (DCM-MeOH 9-1 1% NH ₄ 0H). This gave (1-RS) -2- (3 (S) - {[(2, 3 -dihydro-benzo [1,4] dioxin-6-ylmethyl) amino] - methyl} -piperidin-l-yl) -1- (3-methoxy-quinolin-5-yl) - ethanol (0.097g, 0.21 mmol).

MS (EI) m / z: 464.5 [M + H ⁺ ]

The following examples were prepared analogously to those described above:

Claims

claims

compounds of formula (I):

in which

R ^{1 is} a hydrogen atom, a halogen atom, a hydroxy, an amino, a thiol, an alkyl, a heteroalkyl, an alkyloxy, a

Heteroalkyloxy, a cycloalkyl, a

Heterocycloalkyl, one alkylcycloalkyl, one

Is heteroalkylcycloalkyl, a cycloalkyloxy, an alkylcycloalkyloxy, a heterocycloalkyloxy or a heteroalkylcycloalkyloxy group, the radicals R ² independently of one another are a halogen atom, a hydroxyl, amino, nitro or thiol group, an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl -, aralkyl or a heteroaralkyl radical, or two of the radicals R ² together form part of an aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aralkyl or heteroaralkyl ring,

R ^{3 is} an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkyl-cycloalkyl, heterocycloalkyl, aralkyl or a heteroaralkyl radical,

n is 0, 1 or 2 and

m is 0, 1 or 2,

2. Compounds according to claim 1, wherein A is a

Oxygen or a sulfur atom or a group of the formula CH ₂ , CH ₂ CH ₂ , CH ₂ N (-CC ₄ alkyl), N (C ₁ -C ₄ -

Alkyl) CH ₂ , CH ₂ 0, 0CH ₂ , CH ₂ S, SCH ₂ , CH ₂ CH (0H), CH (OH),

Is CH (0H) CH ₂ , NHCO, CONH, C (= 0) CH ₂ or CH ₂ C (= 0).

, Compounds according to claim 1 or 2, wherein three, four or five of the groups X ¹ , X ² , X ³ , X ⁴ and X ^{5 are} CH groups.

4. Compounds according to any one of claims 1 to 3, wherein R ^{1 is} a dC ₄ alkyloxy or a C ₄ -C ₄ heteroalkyl oxy group, it being possible for one or more hydrogen atoms of these groups to be replaced by fluorine atoms.

5. Compounds according to any one of claims 1 to 3, wherein R ^{1 is} a methoxy group.

6. Compounds according to any one of claims 1 to 5, wherein R ^{2 is} a hydroxy, a C 1 -C 4 alkyl, C 1 -C 4 heteroalkyl or a C ₆ -Ci ₂ heteroaralkyl group.

7. Compounds according to any one of claims 1 to 6, wherein R ^{3 is} a heteroalkylcycloalkyl or a heteroaralkyl group.

8. Compounds according to any one of claims 1 to 6, wherein R ^{3 is} a group of the formula -BY, where B is an alkylene, alkenylene, alkynylene or a heteroalkylene group and Y is an aryl, heteroaryl, aralkyl , Heteroaralkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl or a heteroalkylcycloalkyl group.

9. Compounds according to claim 8, wherein Y has one of the following structures, where X 'and X ° independently

Nitrogen atoms or groups of the formula CR ° ns-ii ιn_d-I, XV ° and XrlO independently of one another are oxygen or sulfur atoms or groups of the formula NR ¹⁰ , o is 0, 1 or 2, R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ^{9 are} independently hydrogen, halogen, hydroxy, alkyl, alkenyl, alkynyl or heteroalkyl and R ¹⁰ and R ^{11 are} independently hydrogen, alkyl, alkenyl, alkynyl or heteroalkyl.

10. Compounds according to claim 8, wherein Y has one of the following structures:

11. Compounds according to any one of claims 1 to 10, wherein the linker -A- (CH ₂ ) - has a chain length of 2 n or 3 atoms.

12. Compounds according to any one of claims 1 to 11, wherein R ^{4 is} a fluorine or a chlorine atom or a Ci-C ₄ alkyloxy, or a C ₃ -C ₆ dialkylaminomethyl group, one or more hydrogen atoms of these groups can be replaced by fluorine atoms.

3. Compounds according to any one of claims 1 to 12, wherein Cy is a cycloalkylene or a heterocycloalkylene group with one or two rings and 4, 5, 6, 7, 8, 9 or 10 ring atoms.

14. Compounds according to any one of claims 1 to 12, wherein Cy has one of the following structures,

wherein U is a nitrogen atom or a group of the formula CH or COH and V is a nitrogen atom or a CH group and p is 0 or 1.

15. Pharmaceutical compositions containing a compound according to claims 1 to 14 as an active ingredient and optionally carriers and / or adjuvants.

16. Use of a compound or a pharmaceutical composition according to any one of claims 1 to 15 for the treatment of bacterial infections.