DE10061542A1 - New alkanoylamino-pyrimidine derivatives used as antibacterial agents, especially for prevention and control of Staphylococcal infections - Google Patents

Abstract

Alkanoylamino-pyrimidine derivatives (I) are new. Alkanoylamino-pyrimidine derivatives of formula (I) and their salts are new. A = a group of formula (i) or (ii); X = H, OH or 1-4C alkoxy; Y = 2-5C alkanediyl; Z = NH2, NH(alkyl), N(alkyl)2 or NHCONH2; R<1>-R<3> = H or 1-6C alkyl, and R<4> = 1-6C alkyl. An Independent claim is also included for the preparation of (I).

Description

The present invention relates to alkanoylamino-pyrimidines, processes for their Manufacture, pharmaceutical composition and their use in the treatment of diseases in humans or animals.

WO 00/12484 discloses antibiotics of the general formula:

An object of the present invention is to provide alternative connections to Prophylaxis and chemotherapy of local and systemic infections in the Human and veterinary medicine caused by sensitive pathogens, especially staphylococci, are caused to provide.

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

wherein
A a rest of the structure

is
X is hydrogen, hydroxy or C ₁ -C ₄ alkoxy,
Y is a straight-chain or branched-chain C ₂ -C ₅ alkanediyl group,
Z is amino, alkylamino, dialkylamino or a urea radical,
R ¹ , R ² and R ³ are selected independently of one another from the group hydrogen and C ₁ -C ₆ alkyl,
R ^{4 is} C ₁ -C ₆ alkyl,
and pharmaceutically acceptable salts thereof.

Some of the compounds according to the invention have aromatic properties on the middle ring and can exist in tautomeric or mesomeric forms. This is known to the person skilled in the art, and such compounds are also from Scope of the invention includes.

The compounds of the general formula (I) according to the invention have in contrast No stereo center in the central ring for the compounds of WO 00/12484 on what reduces the number of stereoisomers and combines production and purification kindled. However, depending on the substituents, they can be different Stereoisomeric forms occur that are either like image and mirror image (Enantiomers) or that do not behave like image and mirror image (diastereomers).  

The invention relates to both the enantiomers and the diastereomers as well their respective mixtures. The racemic shapes can be just like that Diastereomers in a known manner into the stereoisomerically uniform constituents separate.

The substances of the general formula (I) according to the invention can also be used as salts available. In the context of the invention, physiologically acceptable salts are in the offing Trains t.

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 chlorinated water are preferred acidic 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, toluene sulfonic acid or naphthalene disulfonic 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), earth alkali salts (e.g. magnesium or calcium salts), as well as ammonium salts, the abge are guided by ammonia or organic amines, such as ethylamine, Di- or triethylamine, ethyldiisopropylamine, monoethanolamine, di- or tri ethanolamine, dicyclohexylamine, dimethylaminoethanol, dibenzylamine, N-methyl morpholine, 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 which are 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.

Halogen in the context of the invention includes fluorine, chlorine, bromine and iodine.
Chlorine or fluorine are preferred.
In the context of the present invention, preference is given to compounds in which R ¹ is methyl.
In the context of the present invention, preference is also given to compounds in which R ² and R ³ are hydrogen.
In the context of the present invention, preference is furthermore given to compounds in which R ⁴ is methyl.
In the context of the present invention, preference is furthermore given to compounds in which Y represents a straight-chain C ₃ alkanediyl group.
In the context of the present invention, preference is furthermore given to compounds in which Z represents amino or a urea radical.

A process for the preparation of the compounds of the general formula (I) according to the invention has also been found, characterized in that compounds of the general formula (II) or (II ')

or their salts,
in which
R ¹ , R ⁴ and X have the meaning given above,
by reaction with compounds of the general formula (III)

in which
R ² , R ³ , Y and Z have the meaning given above,
where any free nitrogen functionalities 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 compounds of the following invention have interesting pharmacological Properties on.

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 Example 1 was 6.3 µg / ml.

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 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 processes for the manufacture provision of these preparations.

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

The therapeutically active compounds should be in the pharma listed above zeutischen 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 the inventions Compounds according to the invention also contain other active pharmaceutical ingredients.

In general, it has been found in both human and veterinary medicine proven advantageous, 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 ge to deliver the desired results. A single dose contains the inventor Active ingredients according to the invention preferably in amounts of about 1 to about 80, in particular 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

Synthesis of the heterocycle

(3'S) -5- [N-Methyl-N- (3'-amino-6'-guanidinohexanoyl) amino] -4-hydroxy-2-ureidopyrimidine dihydrochloride

Starting material 1a is synthesized according to a literature specification from 5 g (43.0 mmol) of N-formylsarcosine methyl ester, 6.9 g (115.0 mmol) of methyl formate and 2.5 g (46.0 mmol) of sodium methoxide (RG Jones, J. Am. Chem. Soc. 1949, 71, 644-647; JF O'Connel, J. Parquette, WE Yelle, W. Wang, H. Rapoport, Synthesis 1988, 767-771). A solution of the starting material in 10 ml of DMF is mixed with a solution of 5.95 g (43.0 mmol) of N-carbamoylguanidine hydrochloride in 20 ml of DMF at room temperature. The resulting suspension is stirred at 50 ° C. for 20 hours, at 60 ° C. for 4 hours and at 80 ° C. for a further 12 hours. The volatile components are removed in vacuo. Water is added and the pH is adjusted to 1 using 1 M hydrochloric acid, and the suspension is stored at 0 ° C. for 2 h. The precipitate is filtered off, washed with cold water and then dried. 2.1 g (23%) of 5- (N-formyl-N-methyl) amino-4-hydroxy-2-ureidopyrimidine are obtained. ¹ H NMR (DMSO): 2.95 (s, 3H), 6.5-7.2 (s, br, 4H), 7.81 (s, br, 1H), 8.05 (s, 1H). MS (EI, 70 eV): 211 (M ⁺ ).

1.75 g (8.3 mmol) of the intermediate are suspended in 60 ml of 1 M HCl. After heating to reflux for 15 min. a clear solution is obtained which is cooled to room temperature and adjusted to pH 4 using concentrated ammonia solution. The product which precipitates is filtered off and washed with water. 0.76 g (50%) of 5-N-methylamino-4-hydroxy-2-ureidopyrimidine is obtained. ¹ H NMR (DMSO): 2.59 (s, 3H), 6.68 (s, 1H), 6.95-7.63 (s, br, 3H), 7.21 (s, br, 1H). HR-MS: 183.0756.

A mixture of 245 mg (1.34 mmol) of 5-N-methylamino-4-hydroxy-2-ureido pyrimidine, 790 mg (1.34 mmol) of (3S) -3-benzyloxycarbonylamino-6- [bis- (N- benzyl oxycarbonyl) guanidino] hexanoic acid, 257 mg (1.34 mmol) EDCI and 164 mg (1.34 mmol) DMAP in 5 ml DMF is stirred for 10 d at room temperature. Then the solvent is removed in vacuo. The residue is taken up in 30 ml of dichloromethane. It is filtered off from undissolved material and the solution is washed successively with 0.1 M hydrochloric acid, water and 5% sodium hydrogen carbonate solution. It is dried over MgSO ₄ and the solvent is removed in vacuo. The residue is stirred with ether. 532 mg of the intermediate compound are obtained. Hydrogenation of a methanol suspension (462 mg of intermediate compound, 266 mg of palladium (II) chloride, 60 ml of methanol) gives the title compound as a white solid (260 mg) after removal of the catalyst by filtration and the solvent. ¹ H-NMR (400 MHz, CD ₃ OD): 1.63-1.95 (m, 4H), 2.65-2.93 (m, 2H), 3.15 (s, 3H), 3.23 (m, 2H), 3.81 (m, 1H ), 7.52 + 8.03 + 8.18 (s, br, sum 1H). MS (ESI) 354 (M + H) ⁺ .

Example 2

(3'S) -5- [N-Methyl-N- (3 ', 6'-diaminohexanoyl) amino] -4-hydroxy-2-ureido pyrimidine dihydrochloride

A solution of 44 mg (0.24 mmol) of 5-N-methylamino-4-hydroxy-2-ureido pyrimidine, 100 mg (0.24 mmol) of (3S) -3,6-bis (benzyloxycarbonylamino) hexanoic acid, 69 mg (0.26 mmol) EDCI and 29 mg DMAP in 20 ml DMF is stirred for 16 h at RT. The volatile constituents are then removed in vacuo and the residue is stirred with 1 M hydrochloric acid. It is filtered, the residue is washed with ethyl acetate and dried in an HV. Preparative HPLC (column: Kromasil 100 C18, 5 µm, 250 × 20 mm, eluent: water: acetonitrile = 63: 37) provides 28 mg (20%) of the coupling product. MS (ESI): 580 [M + H] ⁺ . The protective group is cleaved off as described in Example 1 and gives 17 mg of the title compound as a white solid. ¹ H NMR (400 MHz, CD ₃ OD): 1.65-1.85 (m, 4H), 2.39-2.66 (m, 2H), 2.98 (m, 2H), 3.14 (s, 3H), 3.58 (m, 1H) ), 8.02 (s, 1H). MS (ESI) 312 (M + H) ⁺ .

Example 3

Synthesis of the heterocycle

20.1 g (210 mmol) of guanidine hydrochloride are added to a solution of 4.8 g (209 mmol) of sodium in 400 ml of anhydrous ethanol cooled to RT. The resulting suspension is 10 min. stirred and suction filtered through Celite. It is washed with a little ethanol and 34.6 g (200 mmol) of the starting material 1a from Example 1 are added to the solution obtained. The resulting mixture is stirred under reflux for 24 h. After cooling to RT, the precipitated solid is filtered off with suction, washed with ice-cold ethanol and diethyl ether and dried. The mother liquor is concentrated in vacuo. It is taken up in 150 ml of water and made up with conc. Hydrochloric acid to pH 6. Product stored again at 0 ° C., which is filtered off, washed and dried as described above. Together, 22.9 g (68%) of 2-amino-5- (N-formyl-N-methylamino) -4-hydroxypyrimidine are obtained as a white solid. ¹ H-NMR (DMSO, 2 rotamers in the ratio 10 *: 1): 2.92 * and 3.06 (s, 3H), 6.81 (s, br, 2H), 7.50 and 7.62 * (s, 1H), 7.93 * and 8.14 (s, 1H), 11.37 (s, br, 1H). MS (EI): 168 [M ⁺ ].

A suspension of 7.11 g (42.3 mmol) of the intermediate described in 90 ml of acetic anhydride is heated to 110 ° C. for 1 h. After cooling to RT, 150 ml of diethyl ether are added, the resulting precipitate is filtered off with suction and dried in vacuo. 8.57 g (96%) of 2-acetylamino-5- (N-formyl-N-methylamino) -4-hydroxypyrimidine are obtained as a white solid. ¹ H-NMR (DMSO, 2 rotamers in the ratio 10 *: 1): 2.14 (s, 3H), 2.99 * and 3.12 (s, 3H), 7.79 and 7.87 * (s, 1H), 8.08 * and 8.19 ( s, 1H), 11.96 (s, br, 1H). MS (EI): 210 [M ⁺ ].

To a suspension of 4.90 g (23.3 mmol) of the intermediate described in 360 ml of methanol and 40 ml of water, 200 ml of ethereal diazomethane solution were added dropwise at 0 ° C. with stirring. Then about two thirds of the solvent is distilled off in vacuo, methanol is added to a total volume of 400 ml and the procedure of adding diazomethane, distilling off and refilling with methanol is repeated five times. The mixture is then evaporated to dryness and the residue is chromatographed on silica gel (eluent methanol: dichloromethane = 1:15). The resulting solid is recrystallized from dichloromethane / diethyl ether. 2.11 g (40%) of 2-acetylamino-5- (N-formyl-N-methylamino) -4-methoxypyrimidine are obtained as a white solid. ¹ H-NMR (DMSO, 2 rotamers in the ratio 5 *: 1): 2.22 (s, 3H), 3.03 * and 3.17 (s, 3H), 3.92 and 3.95 * (s, 3H), 8.10 * and 8.25 (s , 1H), 8.26 and 8.34 * (s, 1H), 10.54 and 10.57 * (s, br, 1H). MS (EI): 224 [M ⁺ ].

4.02 g (17.9 mmol) of the intermediate described are suspended in 120 ml of a mathanolic ammonia solution saturated at 0 ° C. and the mixture is stirred at RT for 36 h. The resulting clear solution is evaporated to dryness in vacuo. The residue is taken up in 60 ml of anhydrous dimethylacetamide. The mixture is cooled to 0 ° C. and the solution is added over 15 min. with 4.1 ml of benzyloxycarbonyl isocyanate. The mixture is stirred for a further 30 min. at RT, diluted with 60 ml dimethylacetamide and added 500 mg Pd / C. A weak stream of hydrogen is then passed through over 4 h. 600 ml of DMF are added and the mixture is filtered through Celite. The filtrate is concentrated in vacuo. It is dissolved in 700 ml of hot methanol, filtered again through Celite, half of the solvent is distilled off and a white precipitate is obtained by cooling to 0.degree. This is suction filtered, washed with diethyl ether and dried. 3.15 g (78%) of 5- (N-formyl-N-methylamino) -4-methoxy-2-ureidopyrimidine are obtained as a grayish solid. ¹ H-NMR (DMSO, 2 rotamers in the ratio 5 *: 1): 3.01 * and 3.16 (s, 3H), 3.92 and 3.93 * (s, 3H), 7.14 (s, br, 1H), 8.07 * and 8.19 (s, 1H), 8.24 and 8.27 * (s, 1H), 8.30 (s, br, 1H), 9.60 and 9.65 * (s, br, 1H). MS (EI): 225 [M ⁺ ].

A suspension of 3.39 g (15.1 mmol) of the intermediate in 45 ml of 1 M methanolic HCl is 45 min. heated under reflux. The resulting clear solution is diluted with 45 ml of water and filtered warm. Concentrated ammonia solution (pH <9) is added to the filtrate while cooling with ice. The resulting product is filtered off, washed with ice water and diethyl ether and dried. 2.83 g (95%) of 5-N-methylamino-4-methoxy-2-ureidopyrimidine are obtained as a white solid. ¹ H-NMR (DMSO, 2 rotamers in the ratio 5 *: 1): 2.65 (d, 3H), 3.90 (s, 3H), 5.00 (q, 1H), 6.82 (s, br, 1H), 7.45 (s , 1H), 8.42 (s, br, 1H), 8.86 (s, 1H). MS (EI): 197 [M ⁺ ].

(3'S) -5- [N-Methyl-N- (3 ', 7'-diamino-heptanoyl) amino] -4-methoxy-2-ureido pyrimidine diacetate

87 mg (0.2 mmol) of (3S) -3,7-bis (benzyloxycarbonylamino) heptanoic acid are slurried in 3 ml of dry DMF, with 154 mg (0.41 mmol) of HATU and 52 mg (0.41 mmol) of diisopropylethylamine offset, 30 min. stirred, mixed with 40 mg (0.2 mmol) of 5-N-methylamino-4-methoxy-2-ureidopyrimidine and stirred overnight at room temperature. It is evaporated to dryness in vacuo, taken up in 10 ml of ethyl acetate and extracted three times with 1 M hydrochloric acid. The organic phase is dried over sodium sulfate, reduced in vacuo to a small volume and chromatographed on silica gel (dichloromethane: methanol = 100: 5). 25 mg (20%) of the coupling product are obtained. MS (ESI): 608 [M + H] ⁺ . R _f (dichloromethane: methanol = 100: 5): 0.3.

15 mg (0.02 mmol) of the coupling product are dissolved in 5 ml of glacial acetic acid, 15 mg of palladium on carbon (5%) are added and the mixture is hydrogenated at room temperature under atmospheric pressure. After filtering off the catalyst, the mixture is evaporated in vacuo and 9 mg of the title compound is obtained as a light foam in 84% purity. MS (ESI): 340 [M + H] ⁺ . HPLC (Kromasil 100 C18, 125 × 2 mm, gradient acetonitrile: 1% aqueous perchloric acid 2: 98 to 10: 90): R _t = 3.27 min.

Example 4

(3'S) -5- [N-Methyl-N- (3'-amino-6'-guanidinohexanoyl) amino] -4-methoxy-2-ureidopyrimidine triacetate

The coupling product is prepared analogously to Example 3 starting from 180 mg (0.3 mmol) (3S) -3-benzyloxycarbonylamino-6- [bis- (N-benzyloxycarbonyl) guanidino] hexanoic acid, 2 ml DMF, 231 mg (0 , 61 mmol) HATU, 79 mg (0.61 mmol) diisopropylethylamine and 60 mg (0.3 mmol) 5-N-methylamino-4-methoxy-2-ureidopyrimidine. 20 mg (8%) of a colorless foam are obtained. MS (ESI): 770 [M + H] ⁺ . R _f (glacial acetic acid): 0.5.

The hydrogenolytic removal of the protective groups is carried out as described in Example 3. 9 mg of the Tietel compound are obtained as a colorless foam. MS (ESI): 368 [M + H] ⁺ . HPLC (Kromasil 100 C18, 125 × 2 mm, gradient acetonitrile: 1% aqueous perchloric acid 2: 98 to 10: 90): R _t = 3.60 min.

Example 5

Synthesis of the heterocycle

For the synthesis of the starting material, see Example 3. A mixture of 1.44 g (8.56 mmol) of the heterocycle, 90 mg of ammonium sulfate, 7.2 ml (34.0 mmol) of bis (tri methylsilyl) amine and 25 ml of THF is transferred Heated to reflux overnight. After cooling and concentrating in vacuo, 25 ml of acetonitrile are added, 5 ml of methyl iodide are added and the mixture is stirred at RT for 3 d. The solution is again concentrated in vacuo. The foamy residue is triturated with 35 ml of methanol. The pH is adjusted to 8 by adding concentrated aqueous ammonia solution. The solid is filtered off, washed with diethyl ether and chromatographed (eluent methanol: water = 4: 1). 0.93 g (60%) of 2-amino-5- (N-formyl-N-methyl amino) -1-methyl-4-oxo-1,4-dihydropyrimidine is obtained as a white solid. ¹ H-NMR (DMSO, 2 rotamers in the ratio 10 *: 1): 2.92 * and 3.05 (s, 3H), 3.33 (s, 3H), 7.08 (s, br, 2H), 7.51 and 7.66 * (s, 1H), 7.97 * and 8.13 (s, 1H). MS (EI): 182 [M ⁺ ].

To a suspension of 6.25 g (34.3 mmol) of the intermediate described in 50 ml of anhydrous dimethylacetamide are added with stirring within 15 min. 6.7 ml of benzyloxycarbonyl isocyanate added. The mixture is stirred for a further 30 min. at RT, diluted with 50 ml dimethylacetamide and adds 505 mg Pd / C. A weak stream of hydrogen is then passed through for 3 h. It is filtered through Celite and washed with DMF. The filtrate is concentrated in vacuo. It is dissolved in 150 ml of hot methanol, the solid is filtered off and a first portion of 4.18 g of the product is obtained in this way. Storage of the mother liquor at 0 ° C provides a second portion of product (1.69 g). In addition, a third portion of 0.26 g is obtained from the mother liquor by chromatography (eluent methanol: dichloromethane = 1: 4). The overall yield of 5- (N-formyl-N-methylamino) -1-methyl-4-oxo-2-ureido-1,4-dihydropyrimidine is 6.13 g (79%). ¹ H-NMR (DMSO, 2 rotamers in the ratio 10 *: 1): 2.95 * and 3.09 (s, 3H), 3.33 (s, 3H), 6.67 (s, br, 1H), 6.86 (s, br, 1H ), 8.00 and 8.08 * (s, 1H), 8.02 * and 8.20 (s, 1H), 13.41 (s, br, 1H). MS (EI): 225 [M ⁺ ].

A suspension of 7.29 g (32.4 mmol) of the intermediate in 80 ml of 1 M methanolic HCl is heated under reflux for 1 h. It is cooled, the solid which has precipitated is filtered off and washed with ice-cold methanol and then with diethyl ether. Drying in vacuo gives 7.2 g of 1-methyl-5- (N-methylamino) -4-oxo-2-ureido-1,4-dihydropyrimidine hydrochloride. ¹ H NMR (DMSO): 2.61 (s, 3H), 3.70 (s, 3H), 6.91 (s, 1H), 7.80 (s, br, 1H), 8.13 (s, br, 1H). MS (EI): 197 [M ⁺ ].

(3'S) -5- [N-Methyl-N- (3 ', 7'-diamino-heptanoyl) amino] -1-methyl-4-oxo-2-ureido-1,4-dihydropyrimidine diacetate

Under an argon atmosphere, 100 mg (0.23 mmol) of (3S) -3,7-bis (benzyloxy carbonylamino) heptanoic acid are mixed with 0.5 ml of freshly distilled thionyl chloride for 30 min. heated to 80 ° C (oil bath temperature). The excess thionyl chloride is distilled off in a vacuum, 2 ml of DMF are added and 121 mg (0.93 mmol) of diisopropylethylamine and 46 mg (0.23 mmol) of 1-methyl-5- (N-methylamino) -4 are added -oxo-2-ureido-1,4-dihydropyrimidine hydrochloride. It is stirred overnight at room temperature. It is evaporated to the dry state in a vacuum, foamed in 8 ml of ethyl acetate and extracted twice with water. The organic phase is dried over sodium sulfate, reduced in vacuo to a small volume and chromatographed on silica gel (dichloromethane: methanol = 100: 7). 20 mg (15%) of the coupling product are obtained as a colorless foam. MS (ESI): 608 [M + H] ⁺ . R _f (dichloromethane: methanol): 0.5.

The hydrogenolytic removal of the protective groups takes place as described in Example 3. 7 mg (93%) of the title compound are obtained as a colorless foam. MS (ESI): 340 [M + H] ⁺ . R _f (dichloromethane: methanol = 1: 1): 0.1.

Claims (11)

1. Compound of the general formula
wherein
A a rest of the structure
is
X is hydrogen, hydroxy or C ₁ -C ₄ alkoxy,
Y is a straight-chain or branched-chain C ₂ -C ₅ alkanediyl group,
Z is amino, alkylamino, dialkylamino or a urea radical,
R ¹ , R ² and R ³ are selected independently of one another from the group consisting of hydrogen and C ₁ -C ₆ alkyl,
R ^{4 is} C ₁ -C ₆ alkyl,
and pharmaceutically acceptable salts thereof. 2. Compounds according to claim 1, wherein R ¹ is methyl. 3. A compound according to claim 1 or 2, wherein R ² and R ³ are hydrogen. 4. A compound according to any one of claims 1 to 3, wherein R ⁴ is methyl. 5. A compound according to any one of claims 1 to 4, wherein Y is a straight chain C ₃ alkanediyl group. 6. A compound according to any one of claims 1 to 5, wherein Z is amino or a Urea residue remains. 7. A process for the preparation of the compounds of the general formula (I) according to the invention was found, characterized in that compounds of the general formula (II) or (II ')
or their salts,
in which
R ¹ , R ⁴ and X have the meaning given above,
by reaction with compounds of the general formula (III)
in which
R ² , R ³ , Y and Z have the meaning given above,
where free nitrogen functionalities 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. 8. Compounds of general formula (I) according to one of claims 1 to 6 for use as a medicine. 9. Pharmaceutical composition, which is a compound of general Formula (I) according to one of claims 1 to 6 in admixture with a pharma includes compatible carriers or excipients. 10. Use of a compound of general formula (I) according to one of the Claims 1 to 6 for the manufacture of a medicament.   11. Use of a compound of general formula (I) according to one of the Claims 1 to 6 for the manufacture of a medicament for treatment bacterial infections.