DE10133277A1 - New 2,5-diamino-3,4,5,6-tetrahydro-6-pyrimidinone derivatives useful for treating bacterial infections - Google Patents

Abstract

2,5-Diamino-3,4,5,6-tetrahydro-6-pyrimidinone derivatives (I) are new. Compounds of formula (I) and their salts are new: Y = 1-5C alkanediyl, optionally with a C atoms replaced by O or NH; Z' = NZ1Z2, NZ5-CQ-NZ6Z7 or NZ5-C(NZ9)-Z8; heteroaryl or phenyl optionally substituted with 1-3 of 1-6C alkyl, halo, CF3, 1-4C aminoalkyl or 1-4C dialkylamino; or 1-6C alkyl optionally substituted with heterocyclyl; Z1 = H; 6-10C aryl substituted with 1-3 of CF3, OCF3, OPh, 1-4C alkoxy, halo, CN or SO2NZ11Z12; or 1-4C alkyl optionally substituted with 1-3 of 3-6C cycloalkyl, pyridyl or NZ3Z4; Z3, Z4 = H, 1-4C alkyl, 3-6C cycloalkyl or heteroaryl optionally substituted with 1-4C alkoxy, halo, CF3 or OPh, or NZ3Z4 is a heterocycle optionally substituted with 1-3 of halo or R; R = alkyl optionally substituted with 1-3 of amino, 1-4C alkylamino or 1-4C dialkylamino; Z11 = H or 1-4C alkyl; Z12 = H, 1-4C alkyl or Ph; Z5-Z7 = H, 1-6C alkyl, 1-6C alkanoyl, benzyl or pyridylmethyl; Z8 = H or 1-6C alkyl; Q = O, S or NZ9; Z9 = H, 1-6C alkyl, 1-6C alkanoyl, benzyl or pyridylmethyl; R1 = H or 1-6C alkyl; R2 = H or 1-6C alkyl optionally substituted with 1-3 of OH, 1-4C alkoxy or 1-4C alkoxycarbonyl; R3 = COR31 or heteroaryl; R31 = 1-4C alkyl, 3-6C cycloalkyl, 1-6C alkoxy, NH2, 1-4C alkylamino, 1-4C dialkylamino or heteroaryl; R4 = H; alternatively, NZ1Z2 is a heterocycle optionally substituted with 1-3 of halo or R and/or R2+R4 forms a 5- or 6-membered ring. Independent claims are also included for: (1) a process for preparing compounds (I); (2) a pharmaceutical composition comprising a compound (I) and a carrier or excipient.

Description

The following application relates to new β-alanine derivatives, processes for their Manufacture, pharmaceutical compositions comprising them as well as their Use in the treatment of diseases in humans or animals.

WO 00/12484 discloses antibiotics of the general formula (I)


which among other things
X represents a group of the formula - (CH ₂ ) _m , wherein m is 0, 1 or 2, D is selected from groups of the formulas D ₁ to D ₃

An object of the present invention is to create connections with a new substructure to provide the antibacterial effect in this structural class exhibit.

The problem is solved by the fact that new β-alanine derivatives are available be put.

The present invention therefore relates to compounds of the general formula (I)


wherein
Y represents a straight-chain or branched-chain C ₁ -C ₅ alkanediyl group in which one carbon atom can optionally be replaced by -O- or -NH-,
Z represents a group -NR ^Z1 R ^Z2 , wherein
R ^Z1 denotes C ₆ -C ₁₀ aryl, which has up to 3 substituents selected from the group consisting of trifluoromethyl, trifluoromethoxy, phenoxy, C ₁ -C ₄ alkoxy, halogen, cyano or a group -SO ₂ NR ^Z11 RZ ^{12 is} substituted, wherein
R ^Z11 is hydrogen or C ₁ -C ₄ alkyl, and
R ^Z12 is hydrogen, C ₁ -C ₄ alkyl or phenyl, or
R ^{Z1 is} hydrogen, C ₁ -C ₄ -alkyl, which may optionally be substituted with up to 3 substituents, selected from the group consisting of C ₃ -C ₆ -cycloalkyl, pyridyl or -NR ^Z3 R ^Z4 ,
R ^{Z2 is} hydrogen, C ₁ -C ₄ alkyl, which can optionally be substituted with up to 3 substituents, selected from the group consisting of pyridyl or -NR ^Z3 R ^Z4 -, wherein
R ^Z3 and R ^{Z4 may be the} same or different and denote hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl or a five or six-membered aromatic heterocycle, the latter rings having up to 3 substituents selected from the group Group consisting of C ₁ -C ₄ alkoxy, halogen, trifluoromethyl or phenoxy may be substituted,
or
R ^Z3 and R ^Z4 together with the nitrogen atom to which they are attached form a four- to six-membered ring which optionally has up to two further heteroatoms and which is substituted by up to 3 substituents selected from the group consisting of halogen or (C ₁ -C ₆ ) alkyl, where the alkyl may optionally be substituted with up to 3 substituents selected from the group consisting of amino, C ₁ -C ₄ alkylamino or C ₁ -C ₄ dialkylamino or
R ^Z1 and R ^Z2 together with the nitrogen atom to which they are attached form a four- to six-membered ring which may have up to two further heteroatoms and which is substituted by up to 3 substituents selected from the group consisting of halogen or alkyl, where the alkyl can be optionally substituted with up to 3 substituents selected from the group consisting of amino, C ₁ -C ₄ alkylamino or C ₁ -C ₄ dialkylamino
or
Z stands for a group of the formula


wherein R ^Z5 , R ^Z6 and R ^{Z7 are} each independently selected from the group consisting of hydrogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkanoyl, benzyl and pyridylmethyl,
R ^Z8 denotes hydrogen or (C ₁ -C ₆ ) alkyl,
Q represents double-bonded O or S or a double-bonded group of the formula NR ^Z9 , R ^{Z9 is} hydrogen, (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) -alkanoyl, benzyl or pyridylmethyl,
or
Z stands for a five or six-membered aromatic heterocycle, which can have up to 3 heteroatoms, selected from the group O, S and N or for phenyl, where the heterocycle or phenyl can optionally be substituted with up to 3 substituents, selected from the group consisting of C ₁ -C ₆ alkyl, halogen trifluoromethyl, amino-C ₁ -C ₄ alkylamino or C ₁ -C ₄ dialkylamino,
Z represents C ₁ -C ₆ -alkyl, which can be optionally substituted, with a five or six-membered saturated, unsaturated or aromatic heterocycle which can have up to 3 heteroatoms selected from the group O, S and N,
R ^{1 is} hydrogen or C ₁ -C ₆ alkyl,
R ^{2 is} hydrogen, C ₁ -C ₆ alkyl, which is optionally substituted with up to 3 substituents selected from the group consisting of hydroxy, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkoxycarbonyl or
R ² and R ⁴ together with the nitrogen and the carbon atom to which they are attached form a five to six-membered ring which can have a further heteroatom selected from the group O, S and N,
R ³ stands for a group
-C (O) R ^3-1
wherein
R ^{3-1 is} C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, amino, C ₁ -C ₄ alkylamino, C ₁ -C ₄ dialkylamino or
R ^{3-1 represents} a five to six-membered aromatic heterocycle which can have up to 3 heteroatoms, selected from the group N, S and O,
or
R ³ represents a five to six-membered aromatic heterocycle which can have up to 3 heteroatoms, selected from the group N, S and O,
R ⁴ represents hydrogen or
R ⁴ forms together with R ² a ring, which may have a further heteroatom selected from the group O, S and N, and pharmaceutically acceptable salts thereof.

The present compound also relates to compounds of the general formula (I)


wherein
Y is a straight-chain or branched-chain C ₁ -C ₅ alkanediyl group in which one carbon atom can optionally be replaced by -O- or -NH-,
Z represents a group -NR ^Z1 R ^Z2 , wherein
R ^Z1 = hydrogen, C ₁ -C ₄ alkyl, which may optionally be substituted by pyridyl or -NR ^Z3 R ^Z4 -, wherein
R ^Z3 and R ^{Z4 may be the} same or different and denote hydrogen or C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, a five or six-membered aromatic heterocycle, the latter rings having C ₁ -C ₄ alkoxy, Halogen, trifluoromethyl or phenoxy may be substituted, or
R ^Z1 and R ^Z2 together with the nitrogen atom to which they are attached form a four- to six-membered ring which optionally has up to two further heteroatoms and which is optionally up to triply substituted with halogen or alkyl, the alkyl optionally can be substituted with amino, C ₁ -C ₄ alkylamino or C ₁ -C ₄ dialkylamino or
Z stands for a five- or six-membered aromatic heterocycle, which can have up to 3 heteroatoms, selected from the group O, S and N or for phenyl or
Z stands for C ₁ -C ₆ alkyl, which can be optionally substituted, with a five or six-membered saturated, unsaturated or aromatic heterocycle which can have up to 3 heteroatoms selected from the group O, S and N, or for phenyl , where the heterocycle or phenyl may optionally be substituted with C ₁ -C ₆ alkyl, trifluoromethyl, amino- C ₁ -C ₄ alkylamino or C ₁ -C ₄ dialkylamino,
R ^{1 is} hydrogen or C ₁ -C ₆ alkyl,
R ^{2 is} hydrogen, C ₁ -C ₆ alkyl, which is optionally substituted by hydroxy, C ₁ -C ₄ alkoxy, Cl-C ₄ alkoxycarbonyl or
R ² and R ⁴ together with the nitrogen and the carbon atom to which they are attached form a five to six-membered ring which can have a further heteroatom selected from the group O, S and N, R ³ represents a group
-C (O) R ^3-1
wherein
R ^{3-1 is} C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, amino, C ₁ -C ₄ alkylamino, C ₁ -C ₄ dialkylamino or
R ^{3-1 represents} a five to six-membered aromatic heterocycle which can have up to 3 heteroatoms, selected from the group N, S and O,
R ⁴ represents hydrogen or
R ⁴ forms together with R ² a ring which can have a further heteroatom selected from the group O, S and N.

The compounds of general formula (I) according to the invention can in Different stereoisomeric forms occur, which are either like picture and Mirror image (enantiomers), or which do not look like image and mirror image (diastereomers) behavior. The invention relates to both the enantiomers and the diastereomers as well as their respective mixtures. The racemic shapes can be just like that Diastereomers in a known manner into the stereoisomerically uniform constituents separate.

Furthermore, certain compounds can exist in tautomeric forms. This is known to those skilled in the art, and such compounds are also within the scope of Invention includes.

The substances of the general formula (I) according to the invention can also be used as salts available. Physiologically acceptable salts are within the scope of the invention prefers.

Pharmaceutically acceptable (physiologically acceptable) salts can be salts of compounds according to the invention with inorganic or organic acids. Salts with inorganic acids such as, for example, are preferred Hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid, or salts with organic carboxylic or sulfonic acids such as acetic acid, propionic acid, Maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, Benzoic acid, or methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, Toluenesulfonic acid or naphthalenedisulfonic acid.

Physiologically acceptable salts can also be salts of the invention Be compounds with bases, such as metal or ammonium salts. Preferred examples are alkali metal salts (e.g. sodium or potassium salts), Alkaline earth metal salts (e.g. magnesium or calcium salts), as well as ammonium salts, the are derived from ammonia or organic amines, such as ethylamine, Di- or triethylamine, ethyldiisopropylamine, monoethanolamine, di- or Triethanolamine, dicyclohexylamine, dimethylaminoethanol, dibenzylamine, N-methylmorpholine, dihydroabietylamine, 1-ephenamine, methylpiperidine, arginine, lysine, Ethylenediamine or 2-phenylethylamine.

The compounds according to the invention can also be in the form of their solvates, in particular in the form of their hydrates.

In the context of the invention, (C ₁ -C ₆ -) alkyl represents a straight-chain or branched alkyl radical having 1 to 6 carbon atoms. A straight-chain or branched alkyl radical having 1 to 4 carbon atoms is preferred. For example and preferably, the following may be mentioned: methyl, ethyl, n-propyl, isopropyl and t-butyl.

In the context of the invention, (C ₂ -C ₆ ) -alkanediyl represents a straight-chain or branched alkanediyl radical having 2 to 6 carbon atoms. A straight-chain or branched alkanediyl radical having 3 to 5 carbon atoms is preferred, and a 1, ω-alkanediyl radical having 3 to 5 carbon atoms is particularly preferred. Examples include: propane-1,3-diyl, butane-1,4-diyl and pentane-1,5-diyl.

In the context of the invention, (C ₆ -C ₁₀ ) aryl stands for an aromatic radical having 6 to 10 carbon atoms. The preferred aryl radical is phenyl.

In the context of the invention, (C ₁ -C ₆ ) alkoxy represents a straight-chain or branched alkoxy radical having 1 to 6 carbon atoms. A straight-chain or branched alkoxy radical having 1 to 4 carbon atoms is preferred. Examples that may be mentioned are: methoxy, ethoxy, n-propoxy, isopropoxy and t-butoxy.

In the context of the invention, (C ₁ -C ₆ ) alkoxycarbonyl represents a straight-chain or branched alkoxy radical having 1 to 6 carbon atoms, which is linked via a carbonyl group. A straight-chain or branched alkoxycarbonyl radical having 1 to 4 carbon atoms is preferred. Examples that may be mentioned are: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and t-butoxycarbonyl.

Halogen in the context of the invention includes fluorine, chlorine, bromine and iodine. Chlorine or fluorine are preferred.

A 4- to 6-membered, partially unsaturated or aromatic heterocycle with bis to three heteroatoms from the series N, O and / or S is within the scope of the invention generally for a monocyclic heterocycle that has one or more Contain double bonds or may be aromatic, one to three of the same or contains various heteroatoms from the series N, O and / or S and the one Ring carbon atom or optionally linked via a ring nitrogen atom. Examples include: pyridyl, 1,2-dihydropyridinyl, 1,4-dihydropyridinyl, Furyl, thienyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, triazolyl, pyrazolyl, Pyrazinyl, 3,4,5,6-tetrahydropyrimidinyl, pyrimidinyl, pyridazinyl. Are preferred Pyridyl, pyrimidinyl and pyrazinyl.

In a preferred embodiment of the invention, the group Y represents a straight-chain C ₃ alkanediyl group.

In a further preferred embodiment of the invention the group Z stands for a group -NR ^Z1 R ^Z2 -.

In a further preferred embodiment of the invention, the group R ^{1 is} methyl.

In a further preferred embodiment of the invention, the group R ^{4 represents} hydrogen.

In a further preferred embodiment of the invention, the group R ^{2 represents} hydrogen.

The compounds of the present invention have antibacterial activity and can therefore help fight bacterial infections in humans and animals.

In addition, a simple process for preparing the compounds of the general formula (I) according to the invention was found, characterized in that
Compounds of the general formula (II)


or their salts,
in which
R ^{3 has} the meaning given above,
by reaction with compounds of the general formula (III)


in which
R ^{1 has} the meaning given above
and
PG stands for a suitable amino protecting group, preferably for benzyloxycarbonyl,
in the presence of a base in compounds of the general formula (IV)


in which
R ¹ , R ³ and PG have the meaning given above,
convicted
then the amino protective group PG is split off under customary conditions and with compounds of the general formula (V)


in which
R ² , R ⁴ and Y have the meaning given above,
and
Z stands for one of the formulas listed above under Z, where free amino and / or imino groups which may be present are present in a form preferably protected by tert-butoxycarbonyl or benzyloxycarbonyl,
in inert solvents in the presence of an amide coupling reagent and, if appropriate, in the presence of a base and, if appropriate, in a last step the respective amino protecting groups are split off by customary methods.

The process according to the invention can be illustrated by way of example using the following formula: Reaction scheme

As a coupling agent in the reaction of compounds of the general formula (IV) after splitting off the protective group derived amine and the carboxylic acid general formula (V) known reagents such as. B. [O- (7-Azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium] hexafluorophosphate (HATU) or [Bromotrispyrrolidino-phosphonium] hexafluorophosphate (PyßroP) can be used because with them the coupling runs smoothly and with high yields.

The amino protective groups which can be used are those customary in peptide chemistry Amino protecting groups used are used. These preferably include: Benzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxy-carbonyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, allyloxycarbonyl, Phthaloyl, 2,2,2-trichloroethoxycarbonyl, fluorenyl-9-methoxycarbonyl, formyl, Acetyl, isovaleroyl, 2-chloroacetyl, benzoyl, 4-chlorobenzoyl, 4-bromo-benzoyl, 4- Nitrobenzoyl, benzyloxymethylene, benzyl, 4-nitrobenzyl, 2,4-dinitrobenzyl, 4- Nitrophenyl, 4-methoxyphenyl or triphenylmethyl, with tert-butoxycarbonyl and benzyloxycarbonyl are particularly preferred.

The amino protective group is split off according to the conventional method Methods (see T. W. Greene, P. G. M. Wuts, Protective Groups in Organic Synthesis, 2. Edition, John Wiley and Sons, New York, 1991), preferably tert. Butoxycarbonyl with hydrochloric acid in dioxane or with trifluoroacetic acid, fluorenyl-9- methoxycarbonyl with piperidine and benzyloxycarbonyl by hydrogenolysis in Presence of catalysts such. B. Raney nickel, palladium, palladium Charcoal, palladium (II) chloride or platinum, or with hydrogen bromide in glacial acetic acid.

The reactions are in the present invention in inert organic Solvents carried out that do not change under the reaction conditions. These include ethers such as diethyl ether, 1,4-dioxane or tetrahydrofuran, Halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, 1,2-dichloroethane, trichloroethane or tetrachloroethane, hydrocarbons such as benzene, Toluene, xylene, hexane, cyclohexane or petroleum fractions, alcohols such as methanol, Ethanol or iso-propanol, nitromethane, dimethylformamide, acetonitrile or Dimethyl sulfoxide. It is also possible to use mixtures of the solvents. Dichloromethane, tetrahydrofuran, dioxane, methanol, Dimethylformamide or acetonitrile.

The reactions are generally in a temperature range from 0 ° C to 150 ° C, preferably carried out from 0 ° C to 70 ° C. The implementations can be done at nominal, increased or reduced pressure (e.g. 0.5 to 5 bar). Generally one works at normal pressure.

Bases for the processes according to the invention are in general sodium or lithium bistrimethylsilylamide, alkali metal hydroxides such as sodium hydroxide, lithium hydroxide or potassium hydroxide, alkali metal carbonates such as sodium carbonate or hydrogen carbonate, alkali metal acetates such as sodium acetate or potassium acetate, sodium hydride, organic tri (C ₁ -C ₆ ) alkylamines such as triethylamine Diisopropylethylamine, or heterocycles such as 1,4-diazabicyclo [5.4.0] undec-7-ene (DBU), pyridine, N, N-dimethylaminopyridine, N-methylpiperidine or N-methylmorpholine can be used. Lithium hydroxide, sodium hydrogen carbonate, sodium acetate, pyridine, diisopropylethylamine and triethylamine are preferred.

The compounds of general formula (III) are known or can, as in WO-A-00/12484 and A. de Meijere et al., Eur. J. Org. Chem., 1998, 777 described, manufactured.

The compounds of the general formula (V) are known or can be found in Analogy to processes known from the literature [cf. WO-A-00/12484 and H.M.M. Bastiaans et al., Tetrahedron Lett. 35, 7659 (1994)].

The compounds of the general formula (1I) are partly new and can be prepared by amines of the general formula (VI)

R ³ -NH ₂ (VI),

in which
R ^{3 has} the meaning given above,
with a compound of formula (VII)


to compounds of the general formula (VIII)


in which
R ^{3 has} the meaning given above,
in a next step, in the presence of a base, converts the benzoyl group into compounds of the general formula (IX)


in which
R ^{3 has} the meaning given above,
split off and finally with alkylating agents of the general formula (X)

CH ₃ -X (X),

in which
X represents a leaving group such as chlorine, bromine, iodine, tosylate or mesylate, preferably iodine,
implements.

The reactions are carried out in inert organic solvents do not change under the reaction conditions. These include ethers such as Diethyl ether, 1,4-dioxane or tetrahydrofuran, halogenated hydrocarbons such as Dichloromethane, trichloromethane, carbon tetrachloride, 1,2-dichloroethane, trichloroethane or Tetrachloroethane, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, alcohols such as methanol, ethanol or isopropanol, Nitromethane, acetone, acetonitrile, dimethylformamide or dimethyl sulfoxide. Likewise it is possible to use mixtures of solvents or mixtures of individual solvents Use water. Particularly preferred for process steps (VI) + (VII) → (VIII) and (IX) + (X) → (II) acetone or acetonitrile.

The reactions are generally in a temperature range from 0 ° C to 150 ° C, preferably carried out from 0 ° C to 100 ° C. The implementations can be done at nominal, increased or reduced pressure (e.g. 0.5 to 5 bar). Generally one works at normal pressure.

As base for the cleavage of the benzoyl group in process step (VIII) → (IX) In general, alkali metal hydroxides such as sodium hydroxide, Lithium hydroxide or potassium hydroxide, or alkali metal carbonates such as sodium carbonate or Potassium carbonate can be used. Lithium hydroxide and are preferred Sodium hydroxide.

The compounds of the general formulas (VI), (VII) and (X) are known per se or can be produced by conventional methods.

The compounds of the general formulas (VIII) and (IX) are known or new and can be made, for example, as described above.

Because of the process steps described, the process is particularly suitable for Combination chemistry suitable.

The production process is to be exemplified by the following reaction schemes: Examples 1 and 2

Example 3

Example 13

Determination of the minimum inhibitory concentration (MIC)

The MIC was determined in the liquid dilution test. Overnight cultures of the test germs (S. aureus 133) were diluted 1: 1000 in fetal calf serum (FKS) and with Dilutions of the test substances (dilution levels 1: 2) incubated.

The MIC value for some examples is shown in Table 1 below: Table 1

The compounds are good for prophylaxis and chemotherapy from local and systemic infections in human and veterinary medicine, caused by sensitive pathogens, especially staphylococci, are caused.

The compounds of the general formula (I) according to the invention have one antibacterial spectrum with a particularly good effect against gram-positive germs on. These properties allow their use as chemotherapeutic Active ingredients in human and veterinary medicine.

With their help, gram-positive germs (with a particularly good effect against Staphylococci, including methillicin-resistant staph. aureus), fought as well as preventing the diseases caused by these pathogens, improved and / or be cured.

They are good for prophylaxis and chemotherapy of local and systemic ones Infections in human and veterinary medicine are suitable due to such pathogens are caused.

The present invention includes pharmaceutical preparations which, in addition to non-toxic, inert, pharmaceutically suitable carriers or excipients contain one or more compounds according to the invention, or which consist of a or more active ingredients according to the invention, and methods for Manufacture of these preparations.

The active ingredient (s) can optionally be in one or more of the above specified carriers are also in microencapsulated form.

The therapeutically active compounds are listed in the above pharmaceutical preparations, preferably in a concentration of about 0.1 to 99.5, preferably from about 0.5 to 95% by weight of the total mixture.

The pharmaceutical preparations listed above can in addition to Compounds according to the invention also contain other active pharmaceutical ingredients.

In general, it has been found in both human and veterinary medicine proven to be advantageous in the active ingredient (s) according to the invention in Total amounts of about 0.5 to about 500, preferably 5 to 100 mg / kg body weight each 24 hours, possibly in the form of several individual doses, to achieve the to deliver the desired results. A single dose contains the Active ingredients according to the invention preferably in amounts of about 1 to about 80, especially 3 to 30 mg / kg, body weight.

The compounds of the invention can be used for the purpose of expanding the Range of effects and to achieve an increase in effectiveness, also with others Antibiotics can be combined.

embodiments example 1

2.75 g (0.01 mol) of tert-butyl-diphenylsilyl chloride were added in portions to a solution of 0.68 g (0.01 mol) of imidazole and 0.75 g (0.01 mol) of 3-amino-1-propanol added. The mixture was stirred at room temperature for 16 h. 20 ml of water were added. The aqueous phase was extracted three times with 20 ml dichloromethane. The combined organic phases were dried over sodium sulfate and the solvent was distilled off on a rotary evaporator. 3.59 g (quant.) 3 - {[tert-butyl (diphenyl) silyl] oxy} propylamine were obtained.
¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1.05 (s, 9H), 1.82 (quint, 2H), 2.98 (t, 2H), 3.74 (t, 2H), 4.60 (s, broad, 2H), 7.40 (m, 6H), 7.65 (m, 4H).

With ice cooling in an argon atmosphere, 44.6 g (275 mmol) of benzyl acrylate were added dropwise to a solution of 90.1 g (250 mmol) of 3 - {[tert-butyl (diphenyl) silyl] oxy} propylamine in 500 ml of acetonitrile within 1 h. The mixture was stirred at room temperature for 16 h. All volatile constituents were distilled off in vacuo and the residue was purified on a flash column (mobile phase: ethyl acetate / cyclohexane 1: 1 becoming more polar to 4: 1). 3.4 g (33%) of the desired N- (3 - {[tert-butyl (diphenyl) silyl] oxy) propyl) -β-alanine benzyl ester were obtained.
MS (DCI, NH ₃ ): [M + H] = 476
¹ H NMR (200 MHz, CDCl ₃ ): δ = 1.0 (s, 9H), 1.64 (m, 2H), 2.41-2.62 (m, 4H), 2.75 (t , 2H), 3.33 (m, broad, 1H), 3.70 (t, 2H), 5.09 (s, 2H), 7.31-7.45 (m, 11H), 7.61 ( m, 4H).

A slurry of 12.0 g (25.2 mmol) of N- (3 - {[tert-butyl (diphenyl) silyl] oxy} propyl) -β-alanine benzyl ester, 6.38 g (63.1 mmol) triethylamine and 12.9 g (12.6 mmol) Rapp chlortrityl polystyrene resin (loading 0.98 mmol / g) in 300 ml dichloromethane was shaken at RT for 16 h.

It was filtered and then three times with 100 ml of DMF, methanol and Washed dichloromethane. The resin was in an oil pump vacuum from Solution center free.

The resin so obtained was slurried in 200 ml of THF, with 15.5 ml (17.0 mmol) of a 1 M tetrabutylammonium fluoride solution in THF and Shaken at RT for 48 h. It was filtered and three times with 100 ml of water, Washed DMF, methanol and dichloromethane. It was in the HV of Removes solvent residues. 13.3 g of polymer-bound N- (3-hydroxypropyl) - were obtained. β-alanine benzyl ester, which was directly implemented further.

There were 6.0 g (loading 0.71 mmol / g) of this resin in 200 ml of 1,2-dichloroethane slurried and with 25.5 ml (146 mmol) of N, N-diisopropylethylamine and 18.6 g (97.6 mmol) toluene-4-sulfonyl chloride was added. Then catalytic Amounts of DMAP were added and it was cautiously 24 h at 40 ° C and 24 h at RT touched. It was filtered and the resin was washed three times with 100 ml dichloromethane, DMSO and washed again with dichloromethane. 7.0 g of the desired were obtained Tosyl resin.

A suspension of 60 mg (42.3 µmol) of this resin was added to 1 ml of DMSO and 0.5 ml of N, N-diisopropylamine with 500 mg of N-methyl-N- (3-pyridinylmethyl) amine and allowed to shake at 80 ° C overnight. It was cooled to RT, filtered and washed three times with 3 ml of DMSO, methanol and dichloromethane.

It was taken up in 2 ml of a 1: 1 mixture of water / dioxane and with 9.5 mg (0.40 mmol) of lithium hydroxide were added. The mixture was left at 80 ° C. overnight shake. It was cooled to RT, filtered and three times with 3 ml each Washed dioxane / water (1: 1), DMF, methanol and dichloromethane.

The polymer thus obtained was abs. In 0.5 ml. Slurried NMP and with a Solution of 51.3 mg (135 µmol) HATU and 17.4 mg (135 µmol) N, N-diisopropylethylamine added. The mixture was shaken at RT for 10 min and then a solution of 29.6 mg (135 µmol) 5- (methylamino) -2- (2-pyridinylamino) -5,6-dihydro-4 (1H) - pyrimidinone in NMP too. It was shaken overnight.

It was washed three times with 1.5 ml of DMSO, DMF, methanol and dichloromethane. 0.5 ml of a solution of dichloromethane / trifluoroacetic acid (5%) / triisopropylsilane (5%) was added, the mixture was shaken at RT for 30 min and filtered. It was washed twice with 1 ml of a solution of dichloromethane / methanol (1: 1) and the combined filtrate was evaporated. 42.7 mg of the title compound were obtained.
MS (ESI): [M + H] = 453; HPLC R _f = 4.03 HPLC conditions column: Kromasil RP-18 125 × 4 mm
Eluent: A: PIC B 7 low UV, 4 bottles / l H20; PIC B7 is heptanesulfonic acid (WAT 084282 from Waters)
B: acetonitrile
gradient program:
0-1 min 90% A
1-9 min 90% A after 90% B
9-13 min 90% B
Flow: 2 ml / min
Temp .: room temperature example 2

Example 2 was synthesized analogously to Example 1
MS (ESI): [M + H] = 433.5; HPLC (conditions see Example 1) R _f = 3.60 Example 3

As the starting material for the synthesis of Example 3, 100 mg (approx. 70.5 µmol) of Tosyl resin used, the synthesis of which is described in Example 1.

A suspension of 100 mg (70.5 µmol) of this resin was added to 0.5 ml DMSO and 0.2 ml N, N-diisopropylethylamine with a solution of 200 mg 4- Ethoxyaniline in 0.5 ml DMSO and allowed to shake at 80 ° C overnight. It was on RT cooled, filtered and three times with 3 ml of DMSO, methanol and dichloromethane washed.

The resin was taken up in 1 ml of a solution of dioxane / isopropanol (3: 1), with 154 mg of BOC anhydride and 20 ul triethylamine. It became overnight shaken at RT. It was then filtered and the residue was washed twice washed with 2 ml of DMF, dioxane / water (1: 1), methanol and dichloromethane.

It was taken up in 2 ml of a 1: 1 mixture of water / dioxane and with 16.8 mg (0.71 mmol) of lithium hydroxide were added. The mixture was left at 80 ° C. overnight shake. It was cooled to RT, filtered and three times with 3 ml of dioxane / - Washed water (1: 1), DMF, methanol and dichloromethane.

From the polymer thus obtained, 50 mg in 0.5 ml of abs. Slurried NMP and with a solution of 51.3 mg (135 µmol) HATU and 17.4 mg (135 µmol) N, N- Diisopropylethylamine added. The mixture was shaken at RT for 10 min and then one was given Solution of 29.6 mg (135 µmol) 5- (methylamino) -2- (2-pyridinylamino) -5,6- dihydro-4 (1H) pyrimidinone in NMP too. It was shaken overnight.

It was washed three times with 1.5 ml of DMSO, DMF, methanol and dichloromethane. 0.5 ml of a solution of dichloromethane / trifluoroacetic acid (5%) / triisopropylsilane (5%) was added, the mixture was shaken at RT for 30 min and filtered. It was washed twice with 1 ml of a solution of dichloromethane / methanol (1: 1) and the combined filtrate was evaporated. 21.2 mg of the title compound were obtained.
MS (ESI): [M + H] = 468.4; HPLC (conditions see Example 1) R _f = 4.67

Examples 4-12

Examples 4-12 were synthesized analogously to example 3.




Example 13

4.50 g (loading: 0.82 mmol / g) of polymer were bound N- (3-hydroxypropyl) -β-alanine benzyl ester (illustration see Example 1) in 20 ml dichloromethane suspended. 5.10 ml (36.6 mmol) of triethylamine were added and the mixture was added at 0.degree dropwise a solution of 2.91 g (18.3 mmol) of sulfur trioxide-pyridine complex in 5 ml of DMSO. The mixture was allowed to come to RT and stirred at RT for 20 h. It was three times washed with 20 ml of methanol and dichloromethane. The polymer was Oil pump vacuum freed from solvent residues.

90 mg (approx. 73.4 μmol) of the resin thus obtained were dissolved in 0.8 ml of a Slurried mixture of trimethyl orthoformate / DMF (8: 1) with 0.2 ml Methanol, 20 µl glacial acetic acid, 70 mg benzotriazole and 100 mg 3-phenoxyaniline were added and shaken at RT for 20 h. 1 ml of a 1 M sodium cyanoborohydride Solution in THF added and shaken at RT for 16 h. It was filtered and washed three times with 2 ml of water, DMF, methanol and dichloromethane.

The resin was taken up in 1 ml THF, with 87 µl triethylamine, 69 mg BOC- Anhydride and 8.6 mg DMAP added. The mixture was shaken at RT for 7 h, filtered and washed twice with 2 ml DMF, methanol and dichloromethane.

It was taken up in 1 ml of a 1: 1 mixture of water / dioxane and with 18 mg of lithium hydroxide added. The mixture was left to shake at 80 ° C. overnight. It was cooled to RT, filtered and twice with 2 ml of dioxane / sat. aq. Ammonium chloride soln. (1: 1), dioxane / water (1: 1), DMF, methanol and dichloromethane washed.

From the polymer thus obtained, 50 mg in 0.5 ml of abs. Slurried NMP and with a solution of 69.5 mg (183 µmol) HATU and 33.1 mg (257 µmol) N, N- Diisopropylethylamine added. The mixture was shaken at RT for 10 min and then one was given Solution of 40.1 mg (183 µmol) 5- (methylamino) -2- (2-pyridinylamino) -5,6- dihydro-4 (1H) pyrimidinone in NMP too. It was shaken overnight.

It was three times with 2 ml of aqueous acetic acid solution (5%), aqueous Sodium bicarbonate solution (S%), DMSO, DMF, methanol and dichloromethane washed.

0.5 ml of a solution of dichloromethane / trifluoroacetic acid (5%) / triisopropylsilane (5%) was added, the mixture was shaken at RT for 30 min and filtered. It was washed twice with 1 ml of a solution of dichloromethane / methanol (1: 1) and the combined filtrate was evaporated. The mixture was taken up in 1 ml of a 2 M trifluoroacetic acid solution in dichloromethane, left to stand at RT for 2 h and evaporated. 26.2 mg of the title compound were obtained.
MS (ESI): [M + H] = 516.4; HPLC (conditions see Example 1) R _f = 5.44

Example 14-19

Examples 14-19 were synthesized analogously to example 13.


Example 20

Example 20 was produced analogously to example 13. Instead of 5- (methylamino) -2- (2-pyridinylamino) -5,6-dihydro-4 (1H) -pyrimidinone, N- [5- (methylamino) -4-oxo-1,4,5 was used here , 6-tetrahydro-2-pyrimidinyl] cyclopropanecarboxamide used. 16.8 mg of the title compound were obtained.
MS (ESI): [M + H] = 507.5; HPLC (conditions see Example 1) R _f = 5.41 Example 21

Example 21 was produced analogously to example 20.
MS (ESI): [M + H] = 483.4; HPLC (conditions see Example 1) R _f = 5.20. Example 22

A solution of 3.00 g (12.3 mmol) of benzyl 3-aminopropyl carbamate in 10 ml of ethanol is cooled to 0 ° C. A solution of 1.35 g (13.5 mmol) of ethyl acrylate in 20 ml of ethanol is added dropwise. After the addition is complete, the mixture is warmed to room temperature and stirred overnight. It is concentrated in vacuo and chromatographed on silica gel. You get two fractions:
Fraction 1: eluent cyclohexane: ethyl acetate = 1: 1, 1.92 g (51%) of ethyl N- (3- {[(benzyloxy) carbonyl] amino} propyl) -β-alaninate. ¹ H NMR (DMSO): 1.21 (t, 3H), 1.73 (quin., 2H), 2.74 (t, 2H), 2.88 (dd, 2H), 3.09 (m , 4H), 4.12 (q, 2H), 5.02 (s, 2H), 7.34 (m, 6H), MS (ESI): 309 [M + H] ⁺ .
Fraction 2: eluent ethyl acetate: methanol = 10: 1, 1.50 g (30%) ethyl-N- (3- {[(benzyloxy) carbonyl] amino} propyl) -N- (3-ethoxy-3-oxopropyl) -β-alaninate. ¹ H NMR (DMSO): 1.18 (t, 6H), 1.49 (quin., 2H), 2.35 (t, 6H), 2.66 (dd, 4H), 2.98 (q , 2H), 4.02 (q, 4H), 5.00 (s, 2H), 7.18 (t, 1H), 7.34 (m, 5H). MS (ESI): 409 [M + H] ⁺ .

A solution of 1.9 g (6.2 mmol) of ethyl N- (3 - {[(benzyloxy) carbonyl] amino} - propyl) -β-alaninate and 690 mg (6.8 mmol) of triethylamine in 50 ml of dichloromethane is added at 0 ° C with 1.16 g (6.8 mmol) benzyl chloroformate. After the addition is complete, the mixture is stirred at room temperature for 2 h, concentrated in vacuo and chromatographed on silica gel (eluent cyclohexane: ethyl acetate = 1: 1). 2.64 g (97%) of ethyl N - [(benzyloxy) carbonyl] -N- (3 - {[(benzyloxy) carbonyl] - amino} -propyl) - β-alaninate are obtained. ¹ H NMR (DMSO): 1.17 (t, 3H), 1.63 (quin., 2H), 2.52 (m, 2H), 2.98 (q, 2H), 3.23 (dd, 2H), 3.45 (m, 2H), 4.03 (q, 2H), 5.00 (s, 2H), 5.05 (s, 2H), 7.35 (m, 11H). MS (ESI): 443 [M + H] ⁺ .

A solution of 2.60 g (5.9 mmol) of the intermediate in 20 ml of dichloromethane is mixed with 830 mg (6.5 mmol) of potassium trimethylsilanolate. The mixture is stirred overnight at room temperature, washed with 1 M hydrochloric acid, dried over sodium sulfate and the solvent is removed in vacuo. 2.1 g (86%) of N - [(benzyloxy) carbonyl] -N- (3 - {[(benzyloxy) carbonyl] amino} propyl) -β-alanine are obtained. ¹ H NMR (DMSO): 1.62 (quin., 2H), 2.45 (m, 2H), 2.96 (q, 2H), 3.22 (dd, 2H), 3.39 (m , 2H), 4.98 (s, 2H), 5.05 (s, 2H), 7.33 (m, 11H), 12.30 (s, br, 1H). MS (ESI): 415 [M + H] ⁺ .

A solution of 200 mg (0.48 mmol) of the intermediate compound, 89 mg (0.48 mmol) (5R, S) -3,4,5,6-tetrahydro-2-acetylamino-5-methylaminopyrimidin-4-one, 367 mg (0.97 mmol) of [O- (7-Azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium] hexafluorophosphate (HATU) and 125 mg (0.97 mmol) of diisopropylethylamine in 10 ml of DMF stirred at room temperature for 16 h. The solvent is then removed in vacuo. The residue is stirred with 2 M hydrochloric acid. The aqueous phase is decanted from the residue. The residue is taken up in dichloromethane. The resulting solution is extracted twice with 2 M hydrochloric acid, dried with sodium sulfate and concentrated in vacuo. 155 mg (55%) of the coupling product are obtained as a white solid [MS (ESI): 581 (M + H) ⁺ ]. This is dissolved in 50 ml dichloromethane: methanol = 1: 1. The solution is mixed with 66 mg (0.37 mmol) of palladium (II) chloride and stirred for 4 h under a hydrogen atmosphere (normal pressure). The solution is filtered and concentrated in vacuo. The residue is triturated with acetone. Decanting and drying the residue in vacuo give the title compound as a white solid (96 mg, 99%). ¹ H NMR (CD ₃ OD): 2.12 (m, 2H), 2.31 (s, 3H), 2.99 (m, 2H), 3.08 (dd, 2H), 3.17 ( s, 3H), 3.18 (m, 2H), 3.32 (m, 2H), 3.92 (dd, 1H), 4.07 (dd, 1H), 5.20 (dd, 1H). MS (ESI) 313 [M + H] ⁺ . Example 23

Starting from 89 mg (0.48 mmol) (5R, S) -3,4,5,6-tetrahydro-5-methylamino-2-ureidopyrimidin-4-one, coupling and subsequent removal of the protective groups take place as described in Example 22. 112 mg (60%) of the title compound are obtained as a white solid. ¹ H NMR (CD ₃ OD): 2.11 (m, 2H), 2.98 (m, 2H), 3.07 (dd, 2H), 3.14 (s, 3H), 3.17 ( m, 2H), 3.32 (m, 2H), 3.85 (dd, 1H), 3.99 (dd, 1H), 5.17 (dd, 1H). MS (ESI) 314 [M + H] ⁺ . Example 24

Starting from 101 mg (0.48 mmol) of N- [S- (methylamino) -4-oxo-1,4,5,6-tetrahydro-2-pyrimidinyl] cyclopropanecarboxamide, coupling and subsequent removal of the protective groups take place as described in Example 22. 80 mg (41%) of the title compound are obtained as a white solid. ¹ H NMR (CD ₃ OD): 1.17 (m, 4H), 1.91 (m, 1H), 2.11 (m, 2H), 2.97 (dd, 2H), 3.08 ( dd, 2H), 3.15 (s, 3H), 3.17 (m, 2H), 3.32 (m, 2H), 3.90 (dd, 1H), 4.07 (dd, 1H), 5.21 (dd, 1H). MS (ESI) 339 [M + H] ⁺ . Example 25

A solution of 200 mg (0.53 mmol) of N - [(tert-butoxy) carbonyl) -N- (3 - {[(benzyloxy) carbonyl) amino} -propyl) -β-alanine, 134 mg (0.53 mmol) 5- (methylamino) -2- (2-pyridinylamino) -5,6-dihydro-4 (1H) -pyrimidinone, 400 mg (1.05 mmol) HATU and 136 mg (1.05 mmol) diisopropylethylamine in 10 ml of DMF is stirred at room temperature for 16 h. The volatile constituents are then removed in vacuo. The residue is digested with water and dried in a high vacuum. The coupling product thus obtained is suspended in 5 ml of 33% hydrogen bromide in glacial acetic acid. The mixture is stirred at room temperature for 2 h, filtered and washed with acetone. Drying in vacuo gives 208 mg (77%) of the title compound. ¹ H-NMR (CD ₃ OD): 2.12 (m, 2H), 3.02 (m, 2H), 3.10 (dd, 2H), 3.18 (s, 3H), 3.20 (m, 2H), 3.36 (m, 2H), 4.00 (dd, 1 H), 4.13 (dd, 1 H), 5.28 (dd, 1 H), 7.24 (d, 1H) , 7.34 (dd, 1H), 7.97 (dd, 1H), 8.44 (d, 1H). MS (ESI): 348 [M + H) ⁺ . Example 26

A solution of 1.40 g (3.4 mmol) of ethyl N- (3-f [(benzyloxy) carbonyl) amino} propyl) -N- (3-ethoxy-3-oxopropyl) -β-alaninate (see example 22) in 20 ml of dichloromethane is mixed with 970 mg (7.5 mmol) of potassium trimethylsilanolate. The mixture is stirred overnight at room temperature. It is extracted with 1 M hydrochloric acid. The aqueous extract is divided alkaline by adding concentrated sodium hydroxide solution. The white precipitate obtained is suction filtered and dried in vacuo. 1.25 g (97%) of N- (3 - {[(benzyloxy) carbonyl] amino} propyl) -N- (3-ethoxy-3-oxopropyl) - β-alanine are obtained. ¹ H NMR (DMSO): 1.21 (t, 3H), 1.81 (quin., 2H), 2.82 (m, 4H), 3.10 (m, 4H), 3.30 (m , 4H), 4.12 (q, 4H), 5.03 (s, 2H), 7.35 (m, 6H), 12.7 (s, br, 1H). MS (ESI): 381 [M + H] ⁺ .

Starting from 145 mg (0.79 mmol) (5R, S) -3,4,5,6-tetrahydro-2-acetlyamino-5-methylaminopyrimidin-4-one, coupling and subsequent removal of the protective groups take place as described in Example 22. 110 mg (29%) of the title compound are obtained as a white solid. ¹ H-NMR (CD30D): 1.29 (t, 3H), 2.23 (m, 2H), 2.32 (s, 3H), 2.97 (m, 2H), 3.12 (m, 4H), 3.19 (s, 3H), 3.38 (m, 2H), 3.56 (m, 4H), 3.95 (dd, 1H), 4.10 (dd, 1H), 4.23 (q, 2H), 5.20 (dd, 1H). MS (ESI) 413 [M + H) ⁺ . Example 27

Starting from 146 mg (0.79 mmol) (5R, S) -3,4,5,6-tetrahydro-5-methylamino-2-ureidopyrimidin-4-one, coupling and subsequent removal of the protective groups take place as described in Example 22. 112 mg (29%) of the title compound are obtained as a white solid. ¹ H NMR (CD ₃ OD): 1.27 (t, 3H), 2.23 (m, 2H), 2.98 (m, 2H), 3.12 (m, 4H), 3.19 (s, 3H) , 3.38 (m, 2H), 3.55 (m, 2H), 3.92 (dd, 1H), 4.04 (dd, 1H), 4.23 (q, 2H), 5.16 ( dd, 1H). MS (ESI) 414 [M + H] ⁺ . Example 28

The required acid N - [(benzyloxy) carbonyl] -N- (3 - {[(benzyloxy) carbonyl] amino} - pentyl) -β-alanine is prepared analogously to the procedure described in Example 22.
1H NMR (DMSO): 1.21 (m, 2H), 1.42 (m, 4H), 2.43 (m, 2H), 2.96 (m, 2H), 3.20 (m, 2H) ), 3.35 (m, 2H), 5.00 (s, 2H), 5.06 (s, 2H), 7.33 (m, 11H), 12.30 (s, br, 1H). MS (ESI): 443 [M + H] ⁺ .

Starting from 42 mg (0.23 mmol) (5R, S) -3,4,5,6-tetrahydro-5-methylamino-2-ureidopyrimidin-4-one, coupling and subsequent removal of the protective groups take place as described in Example 22. 70 mg (73%) of the title compound are obtained as a white solid. ¹ H NMR (CD ₃ OD): 1.53 (m, 2H), 1.75 (m, 4H), 2.96 (m, 4H), 3.07 (dd, 2H), 3.14 ( s, 3H), 3.31 (m, 2H), 3.88 (dd, 1H), 4.02 (dd, 1H), 5.19 (dd, 1H). MS (ESI) 342 [M + H] ⁺ . Example 29

Starting from 42 mg (0.23 mmol) (5R, S) -3,4,5,6-tetrahydro-2-acetylamino-5-methylaminopyrimidin-4-one and using the acid described in Example 29, coupling and subsequent reaction are carried out The protective groups are split off as described in Example 22. 70 mg (32%) of the title compound are obtained as a white solid. ¹ H NMR (CD ₃ OD): 1.52 (m, 2H), 1.76 (m, 4H), 2.31 (s, 3H), 2.95 (m, 4H), 3.05 ( dd, 2H), 3.16 (s, 3H), 3.31 (m, 2H), 3.91 (dd, 1H), 4.07 (dd, 1H), 5.20 (dd, 1H). MS (ESI) 341 [M + H] ⁺

Claims (14)

1. Compound of the general formula (I)


wherein
Y represents a straight-chain or branched-chain C ₁ -C ₅ alkanediyl group in which one carbon atom can optionally be replaced by -O- or -NH-,
Z represents a group -NR ^Z2 R ^Z2 , wherein
R ^Z1 denotes C ₆ -C ₁₀ aryl, which has up to 3 substituents selected from the group consisting of trifluoromethyl, trifluoromethoxy, phenoxy, C ₁ -C ₄ alkoxy, halogen, cyano or a group
-SO ₂ NR ^Z11 RZ ^{12 is} substituted, wherein
R ^Z11 is hydrogen or C ₁ -C ₄ alkyl, and
R ^Z12 is hydrogen, C ₁ -C ₄ alkyl or phenyl, or
R ^{Z1 is} hydrogen, C ₁ -C ₄ -alkyl, which can optionally be substituted with up to 3 substituents, selected from the group consisting of C ₃ -C ₆ -cycloalkyl, pyridyl or -NR ^Z3 R ^Z4 -, R ^{Z2 is} hydrogen , C ₁ -C ₄ alkyl, which may optionally be substituted with up to 3 substituents selected from the group consisting of pyridyl or -NR ^Z3 R ^Z4 -, wherein
R ^Z3 and R ^{Z4 can be the} same or different and are hydrogen,
C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl or a five or six-membered aromatic heterocycle, the latter rings having up to 3 substituents selected from the group consisting of C ₁ -C ₄ alkoxy, halogen, Trifluoromethyl or phenoxy can be substituted,
or
R ^Z3 and R ^Z4 together with the nitrogen atom to which they are attached form a four- to six-membered ring which optionally has up to two further heteroatoms and which is substituted by up to 3 substituents selected from the group consisting of halogen or alkyl, where the alkyl can be optionally substituted with up to 3 substituents selected from the group consisting of amino, C ₁ -C ₄ alkylamino or C ₁ -C ₄ dialkylamino or
R ^Z1 and R ^Z2 together with the nitrogen atom to which they are attached form a four- to six-membered ring which may have up to two further heteroatoms and which is substituted by up to 3 substituents selected from the group consisting of halogen or alkyl, where the alkyl can be optionally substituted with up to 3 substituents selected from the group consisting of amino, C ₁ -C ₄ alkylamino or C ₁ -C ₄ dialkylamino
or Z stands for a group of the formula


wherein
R ^Z5 , R ^Z6 and R ^{Z7 are} each independently selected from the group consisting of hydrogen, (C ₁ -C ₆ ) alkyl, (C ₁ - C ₆ ) alkanoyl, benzyl and pyridylmethyl,
R ^Z8 denotes hydrogen or (C ₁ -C ₆ ) alkyl,
Q represents double-bonded O or S or a double-bonded group of the formula NR ^Z9 ,
R ^{Z9 is} hydrogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkanoyl, benzyl or pyridylmethyl,
or
Z stands for a five or six-membered aromatic heterocycle which can have up to 3 heteroatoms selected from the group O, S and N or for phenyl, where the heterocycle or phenyl can optionally be substituted with up to 3 substituents selected from the group consisting of C ₁ -C ₆ alkyl, halogen trifluoromethyl, amino-C ₁ -C ₄ alkylamino or C ₁ -C ₄ dialkylamino,
Z stands for C ₁ -C ₆ -alkyl, which can be optionally substituted, with a five or six-membered saturated, unsaturated or aromatic heterocycle which can have up to 3 heteroatoms selected from the group O, S and N,
R ^{1 is} hydrogen or C ₁ -C ₆ alkyl,
R ^{2 is} hydrogen, C ₁ -C ₆ alkyl, which is optionally substituted with up to 3 substituents selected from the group consisting of hydroxy, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkoxycarbonyl or
R ² and R ⁴ together with the nitrogen and the carbon atom to which they are attached form a five to six-membered ring which can have a further hetero atom selected from the group O, S and N,
R ³ stands for a group
-C (O) R ^3-1
wherein
R ^{3-1 is} C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, amino, C ₁ -C ₄ alkylamino, C ₁ -C ₄ dialkylamino or
R ^{3-1 represents} a five to six-membered aromatic heterocycle which can have up to 3 heteroatoms, selected from the group N, S and O,
or
R ³ represents a five to six-membered aromatic heterocycle which can have up to 3 heteroatoms, selected from the group N, S and O,
R ⁴ represents hydrogen or
R ⁴ forms together with R ² a ring which can have a further heteroatom selected from the group O, S and N,
as well as pharmaceutically acceptable salts thereof. 2. Compounds of general formula (I) according to claim 1, wherein
Y is a straight-chain or branched-chain C ₁ -C ₅ alkanediyl group in which one carbon atom can optionally be replaced by -O- or -NH-,
Z represents a group -NR ^Z1 R ^Z2 -, in which
R ^Z1 = hydrogen, C ₁ -C ₄ alkyl, which may optionally be substituted by pyridyl or -NR ^Z3 R ^Z4 -, wherein
R ^Z3 and R ^{Z4 can be the} same or different and denote hydrogen or C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, a five or six-membered aromatic heterocycle, the latter rings having C ₁ -C ₄ alkoxy, Halogen, trifluoromethyl or phenoxy may be substituted, or
R ^Z1 and R ^Z2 together with the nitrogen atom to which they are attached form a four- to six-membered ring which optionally has up to two further heteroatoms and which is optionally up to triply substituted with halogen or alkyl, the alkyl optionally can be substituted with amino, C ₁ -C ₄ alkylamino or C ₁ -C ₄ dialkylamino or
Z stands for a five or six-membered aromatic heterocycle which can have up to 3 heteroatoms, selected from the group O, S and N or for phenyl or
Z stands for C ₁ -C ₆ alkyl, which can be optionally substituted, with a five or six-membered saturated, unsaturated or aromatic heterocycle which can have up to 3 heteroatoms selected from the group O, S and N, or for phenyl , where the heterocycle or phenyl may optionally be substituted by C ₁ -C ₆ alkyl, trifluoromethyl, amino-C ₁ -C ₄ alkylamino or C ₁ -C ₄ dialkylamino,
R ^{1 is} hydrogen or C ₁ -C ₆ alkyl,
R ^{2 is} hydrogen, C ₁ -C ₆ alkyl, which is optionally substituted by hydroxy, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkoxycarbonyl or
R ² and R ⁴ together with the nitrogen and the carbon atom to which they are attached form a five to six-membered ring which can have a further heteroatom selected from the group O, S and N,
R ³ stands for a group

-C (O) R ^3-1

wherein
R ^{3-1 is} C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, amino, C ₁ -C ₄ alkylamino, C ₁ -C ₄ dialkylamino or
R ^{3-1 represents} a five to six-membered aromatic heterocycle which can have up to 3 heteroatoms, selected from the group N, S and O,
R ⁴ represents hydrogen or
R ⁴ forms together with R ² a ring, which may have a further heteroatom selected from the group O, 5 and N, and pharmaceutically acceptable salts thereof. 3. Compound of general formula (I) according to claim 1,
wherein
Y is a straight-chain or branched-chain C ₁ -C ₅ alkanediyl group in which one carbon atom can optionally be replaced by -O- or -NH-,
Z represents a group -NR ^Z1 R ^Z2 , wherein
R ^Z1 = hydrogen, C ₁ -C ₄ alkyl, which may optionally be substituted by pyridyl or -NR ^Z3 R ^Z4 -, wherein
R ^Z3 and R ^{Z4 can be the} same or different and denote hydrogen or C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, a five or six-membered aromatic heterocycle, the latter rings having C ₁ -C ₄ alkoxy, Halogen, trifluoromethyl or phenoxy may be substituted, or
R ^Z1 and R ^Z2 together with the nitrogen atom to which they are attached form a four- to six-membered ring which optionally has up to two further heteroatoms and which is optionally up to triply substituted with halogen or alkyl, the alkyl optionally can be substituted with amino, C ₁ -C ₄ alkylamino or C ₁ -C ₄ dialkylamino or
Z stands for a five or six-membered aromatic heterocycle which can have up to 3 heteroatoms, selected from the group O, S and N or for phenyl or
Z stands for C ₁ -C ₆ alkyl, which can be optionally substituted, with a five or six-membered saturated, unsaturated or aromatic heterocycle which can have up to 3 heteroatoms selected from the group O, S and N, or for phenyl wherein the heterocycle or phenyl may be optionally substituted with C ₁ - C ₆ alkyl, trifluoromethyl, amino-C ₁ -C ₄ alkylamino or C ₁ -C ₄ - dialkylamino,
R ^{1 is} hydrogen or C ₁ -C ₆ alkyl,
R ^{2 is} hydrogen, C ₁ -C ₆ alkyl, which is optionally substituted by hydroxy, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkoxycarbonyl or
R ² and R ⁴ together with the nitrogen and the carbon atom to which they are attached form a five to six-membered ring which can have a further heteroatom selected from the group O, S and N,
R ³ stands for a group

-C (O) R ^3-1

wherein
R ^3-1 C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, amino,
C ₁ -C ₄ alkylamino, C ₁ -C ₄ dialkylamino or
R ^{3-1 represents} a five to six-membered aromatic heterocycle which can have up to 3 heteroatoms, selected from the group N, S and O,
R ⁴ represents hydrogen or
R ⁴ forms together with R ² a ring which can have a further heteroatom selected from the group O, S and N. 4. A compound according to claim 1, wherein
Y represents a straight-chain C ₃ alkanediyl group. 5. A compound according to claim 1, wherein
Z stands for a group -NR ^Z1 R ^Z2 -. 6. A compound according to claim 1, wherein
R ^{1 represents} methyl. 7. A compound according to claim 1, wherein
R ^{4 represents} hydrogen. 8. A compound according to claim 1, wherein
R ^{2 represents} hydrogen. 9. A process for the preparation of the compounds of general formula (I) according to claim 1, characterized in that first
Compounds of the general formula (II)


or their salts,
in which
R ^{3 has} the meaning given above,
by reaction with compounds of the general formula (III)


in which
R ^{1 has} the meaning given above and
PG stands for a suitable amino protecting group,
in the presence of a base in compounds of the general formula (IV)


in which
R ¹ , R ³ and PG have the meaning given above,
convicted
then splits off the amino protective group PG and with compounds of the general formula (V)


in which
R ² , R ⁴ and Y have the meaning given above,
and
Z stands for one of the formulas listed above, in which free amino and / or imino groups which may be present are present in protected form, in inert solvents in the presence of an amide coupling reagent and optionally in the presence of a base and, if appropriate, in a last step the respective amino protecting groups are split off by customary methods. 10. Compounds of general formula (I) according to claim 1 for use as a medicine. 11. Pharmaceutical composition, which is a compound of general Formula (I) according to claim 1 in admixture with a pharmaceutical compatible carriers or excipients. 12. Use of a compound of general formula (I) according to claim 1 to 7 for the manufacture of a drug. 13. Use of a compound of general formula (I) according to claim 1 for the manufacture of a medicament for the treatment of bacterial infections. 14. Medicament containing a compound of general formula (I) according to Claim 1.