DE10243201A1 - New N-acyl-aminoacid N-(succinimidyl-carbonyl-alkyl)-amide compounds, are broad-spectrum antibacterial agents useful in human or veterinary medicine - Google Patents

Abstract

N-(3-((2,5-Dioxo-3-pyrrolidinyl)-carbonyl)-alkyl)-amino)-3-oxo-1-phenyl-propyl)-amide compounds (I) are new. Succinimide derivatives of formula (I) and their salts, solvates and solvated salts are new. R1 = alkyl, alkenyl or alkynyl; R2 = H or Me; R3, R4 = H or 1-3C alkyl; R5 = halo, CF3, OCF3, NO2, NH2, alkylamino, OH, alkyl, alkoxy, COOH, alkoxycarbonyl, CONH2, alkylaminocarbonyl, aryl or heteroaryl; or two R5 groups together complete a 5-8 membered carbocycle or heterocycle (optionally substituted by 1 or 2 groups R51); R51 = halo, NO2, NH2, CF3, OH, alkyl or alkoxy; R6 = 4-8C alkyl or 4-8C cycloalkyl (both optionally substituted by 1 or 2 groups R61); R61 = as R51; n = 0-3. An Independent claim is included for the preparation of (I).

Description

The present invention relates to Compounds, processes for their preparation, pharmaceuticals comprising them Compositions and their use in treatment and / or Prophylaxis of diseases in humans or animals, in particular bacterial infectious diseases.

The natural substances moiramide B (R ^a = hydrogen, R ^b = methyl) and andrimide (R ^a = hydrogen, R ^b = propenyl) are described as having an antibacterial effect, while moiramide C (R ^a = hydroxy, R ^b = propenyl) is ineffective , (A. Fredenhagen, SY Tamura, PTM Kenny, H. Komura, Y. Naya, K. Nakanishi, J. Am. Chem. Soc. 1987, 109, 4409-4411; J. Needham, MT Kelly, M. Ishige, RJ Andersen, J. Org. Chem. 1994, 59, 2058-2063; MP Singh, MJ Mroczenski-Wildey, DA Steinberg, RJ Andersen, WM Maiese, M. Greenstein, J. Antibiot. 1997, 50 (3), 270 -273). The isolation and antibacterial effectiveness of Andrimid is also in EP-A-250 115 described. JP 01301657 describes the use of andrimide and some amidic derivatives as agrochemical antibiotics.

The synthesis of andrimide is described in A.V. Rama Rao, A.K. Singh, Ch. V.N.S. Varaprasad, Tetrahedron Letters 1991, 32, 4393-4396 described that of Moiramid B and Andrimid in S.G. Davies, D. J. Dixon, J. Chem. Soc. Perkin Trans. 1 1998, 2635-2643.

The market is structural different antibacterial agents are available, but it can regularly to one Resistance development come. New means for better and more effective Therapy is therefore desirable.

An object of the present invention It is therefore new and alternative connections with the same or improved antibacterial effect for the treatment of bacterial To provide diseases in humans and animals.

Surprisingly it was found that derivatives of this class of compounds, in which the Isopropyl side chain due to larger alkyl residues is replaced, are antibacterial.

worin
R¹ Alkyl, Alkenyl oder Alkinyl bedeutet,
R² Wasserstoff oder Methyl bedeutet,
R³ Wasserstoff oder C₁-C₃-Alkyl bedeutet,
R⁴ Wasserstoff oder C₁-C₃-Alkyl bedeutet,
R⁵ Halogen, Trifluormethyl, Trifluormethoxy, Nitro, Amino, Alkylamino, Hydroxy, Alkyl, Alkoxy, Carboxyl, Alkoxycarbonyl, Aminocarbonyl, Alkylaminocarbonyl, Aryl oder Heteroaryl bedeutet,
und/oder
zwei Substituenten R⁵ zusammen mit dem Phenylring, an den sie gebunden sind, einen Bicyclus bilden, wobei die beiden Substituenten R⁵ zusammen mit den Kohlenstoffatomen, an die sie gebunden sind, einen 5- bis 8-gliedrigen Carbocyclus oder einen 5- bis 8-gliedrigen Heterocyclus bilden, wobei der gebildete Carbocyclus oder Heterocyclus substituiert sein kann mit 0, 1 oder 2 Substituenten R^5–1, wobei die Substituenten R^5–1 unabhängig voneinander ausgewählt werden aus der Gruppe bestehend aus Halogen, Nitro, Amino, Trifluormethyl, Hydroxy, Alkyl und Alkoxy,
R⁶ C₄-C₈-Alkyl oder C₄-C₈-Cycloalkyl bedeutet,
wobei R⁶ substituiert sein kann mit 0, 1 oder 2 Substituenten R^6–1, wobei die Substituenten R^6–1 unabhängig voneinander ausgewählt werden aus der Gruppe bestehend aus Halogen, Nitro, Amino, Trifluormethyl, Hydroxy, Alkyl und Alkoxy,
n eine Zahl 0, 1, 2 oder 3 bedeutet,
wobei bei n gleich 2 oder 3 die Reste R⁵ gleich oder verschieden sein können.The present invention therefore relates to compounds of the formula

wherein
R ¹ denotes alkyl, alkenyl or alkynyl,
R ^{2 represents} hydrogen or methyl,
R ^{3 represents} hydrogen or C ₁ -C ₃ alkyl,
R ^{4 represents} hydrogen or C ₁ -C ₃ alkyl,
R ⁵ denotes halogen, trifluoromethyl, trifluoromethoxy, nitro, amino, alkylamino, hydroxy, alkyl, alkoxy, carboxyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, aryl or heteroaryl,
and or
two substituents R ⁵ together with the phenyl ring to which they are attached form a bicyclus, the two substituents R ⁵ together with the carbon atoms to which they are attached forming a 5- to 8-membered carbocycle or a 5- to 8th form a membered heterocycle, where the carbocycle or heterocycle formed can be substituted with 0, 1 or 2 substituents R ^5-1 , the substituents R ^{5-1 being} selected independently of one another from the group consisting of halogen, nitro, amino, trifluoromethyl, Hydroxy, alkyl and alkoxy,
R ^{6 is} C ₄ -C ₈ alkyl or C ₄ -C ₈ cycloalkyl,
where R ⁶ can be substituted with 0, 1 or 2 substituents R ^6-1 , where the substituents R ^{6-1 are} independently selected from the group consisting of halogen, nitro, amino, trifluoromethyl, hydro xy, alkyl and alkoxy,
n represents a number 0, 1, 2 or 3,
where n is 2 or 3, the radicals R ^{5 may be the} same or different.

The compounds of the invention can also in the form of their salts, solvates or solvates of the salts.

The compounds of the invention can in dependence their structure in stereoisomeric forms (enantiomers, diastereomers) exist. The invention therefore relates to the enantiomers or diastereomers and their respective mixtures. From such mixtures of enantiomers and / or diastereomers, the stereoisomerically uniform Isolate components in a known manner.

The invention relates in dependence on the structure of the compounds also tautomers of the compounds.

Salts are within the scope of the invention physiologically acceptable salts of the compounds according to the invention prefers.

Physiologically acceptable salts of the compounds (I) include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, e.g. Salts of hydrochloric acid, Hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and Benzoic acid.

Physiologically acceptable salts of the compounds (I) also include salts of conventional bases, for example and preferably alkali metal salts (e.g. sodium and potassium salts), Alkaline earth salts (e.g. calcium and magnesium salts) and ammonium salts, derived from ammonia or organic amines with 1 to 16 carbon atoms, such as, for example and preferably, ethylamine, diethylamine, triethylamine, Ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, Dicyclo-hexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, dihydroabiethylamine, arginine, lysine, ethylenediamine and methylpiperidine.

As solvates within the scope of Invention refers to such forms of connections, which in solid or liquid Condition through coordination with solvent molecules Form complex. Hydrates are a special form of solvate, at which are coordinated with water.

In the context of the present invention, unless otherwise specified, the substituents and the terms used in connection with them have the following meaning:
Alkyl and the alkyl parts in alkoxy, mono- and dialkylamino, alkylsulfonyl stands for straight-chain or branched alkyl and, unless stated otherwise, comprises C ₁ -C ₆ -alkyl, in particular methyl, ethyl, propyl, isopropyl, butyl and isobutyl.

Alkenyl includes linear and branched Alkenyl, e.g. Vinyl, allyl, prop-1-en-1-yl, isopropenyl, but-1-enyls, but-2-enyls, Buta-1,2-dienyls, buta-1,3-dienyls.

Alkynyl includes linear and branched Alkynyl, e.g. Ethynyl, n-prop-2-in-1-yl, n-but-2-in-1-yl.

Carbocycle stands for a saturated or unsaturated, optionally aromatic, cyclic group containing only carbon atoms contains in the ring and is generally 3- to 8-membered. Carbocycles are for example the substituents cycloalkyl and aryl or are of substituents formed together with the carbon atoms to which they are attached are.

Cycloalkyl comprises C ₃ -C ₈ monocyclic alkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl.

Alkoxy is within the scope of the invention preferably for especially with a straight-chain or branched alkoxy radical 1 to 6, 1 to 4 or 1 to 3 carbon atoms. A is preferred straight-chain or branched alkoxy radical with 1 to 3 carbon atoms. The following may be mentioned as examples and preferably: methoxy, ethoxy, n-propoxy, Isopropoxy, t-butoxy, n-pentoxy and n-hexoxy.

Alkoxycarbonyl is part of the Invention preferably for a straight-chain or branched alkoxy radical with 1 to 6 or 1 to 4 carbon atoms, the over linked a carbonyl group is. A straight-chain or branched alkoxycarbonyl radical is preferred with 1 to 4 carbon atoms. Be exemplary and preferred called: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and t-butoxycarbonyl.

Alkylamino is within the scope of the invention for one Amino group with one or two (independently selected) straight-chain or branched alkyl substituents, which are preferably 1 to 6, 1st have up to 4 or 1 to 2 carbon atoms. Straight-chain are preferred or branched alkylamino radicals having 1 to 4 carbon atoms. The following may be mentioned by way of example and preferably: methylamino, ethylamino, n-propylamino, isopropylamino, t-butylamino, n-pentylamino, n-hexylamino, N, N-dimethylamino, N, N-diethylamino, N-ethyl-N-methylamino, N-methyl-N-n-propylamino, N-isopropyl-N-n-propylamino, N-t-butyl-N-methylamino, N-ethyl-N-n-pentylamino and N-n-hexyl-N-methylamino.

In the context of the invention, alkylaminocarbonyl represents an amino group which is linked via a carbonyl group and which has one straight-chain or branched or two identical or different straight-chain or branched alkyl substituents, preferably each having 1 to 4 or 1 to 2 carbon atoms having. The following may be mentioned by way of example and preferably: methylaminocarbonyl, ethylaminocarbonyl, isopropylaminocarbonyl, t-butylaminocarbonyl, N, N-dimethylaminocarbonyl, N, N-diethylaminocarbonyl, N-ethyl-N-methylaminocarbonyl and Nt-butyl-N-methylaminocarbonyl.

Aryl generally represents one aromatic radical with 6 to 10 carbon atoms. Preferred aryl residues are phenyl and naphthyl.

Heteroaryl (heteroaromatic) stands for one 5- to 10-membered aromatic heterocycle with up to 3 heteroatoms from the series S, O and / or N, for example for pyridyl, pyrimidyl, thienyl, Furyl, pyrrolyl, thiazolyl, N-triazolyl, oxazolyl or imidazolyl. Pyridyl, furyl, thienyl and thiazolyl are preferred.

Heterocyclyl (heterocycle) stands for one if necessary via a nitrogen atom bound 3- to 8-membered saturated or unsaturated, non aromatic heterocycle which contains up to 3 heteroatoms from the Row S, O and N may contain. It can consist of two substituent groups together with the nitrogen atom to which they are attached and closes e.g. Morpholinyl, piperidinyl, piperazinyl, methylpiperazinyl, thiomorpholinyl or pyrrolidinyl and 3-, 7- and 8-membered heterocycles, e.g. aziridines (e.g. 1-azacyclopropan-1-yl), azetidines (e.g. 1-azacyclobutan-1-yl) and azepines (e.g. 1-azepan-1-yl). The unsaturated representatives can be 1 to 2 double bonds included in the ring.

Halogen stands for fluorine, chlorine, bromine or iodine, fluorine and chlorine are preferred unless otherwise specified is.

The general or preferred areas listed above The radical definitions given apply to both the end products of the formula (I) as well as for the raw materials required for the production or intermediate products.

The one in the respective combinations or preferred combinations of radicals specified in detail Residual definitions become independent any of the specified combinations of the residues replaced by residual definitions of other combinations.

In a further embodiment, the invention relates to compounds of the formula (I)
wherein
R ^{1 is} C _I -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl or C ₂ -C ₁₀ alkynyl,
R ^{2 represents} hydrogen,
R ^{3 represents} hydrogen or methyl,
R ⁴ means methyl,
R ⁵ denotes fluorine, chlorine, trifluoromethyl, trifluoromethoxy, nitro, amino, alkylamino, hydroxy, alkyl, alkoxy, alkoxycarbonyl, aminocarbonyl, phenyl or 5- to 6-membered heteroaryl,
or
two substituents R ⁵ together with the carbon atoms to which they are attached form a 5- to 6-membered carbocycle or a 5- to 6-membered heterocycle,
R ^{6 is} C ₄ -C ₇ alkyl or C ₄ -C ₇ cycloalkyl,
where R ⁶ can be substituted with 0, 1 or 2 substituents R ^6-1 , where the substituents R ^6-1 are selected independently of one another from the group consisting of halogen, alkoxy, alkyl and trifluoromethyl,
n represents a number 0, 1 or 2,
where n is 2, the radicals R ^{5 may be the} same or different.

In a further embodiment, the invention relates to compounds of the formula (I)
wherein
R ^{1 is} C ₂ -C ₁₀ alkyl or C ₂ -C ₁₀ alkenyl,
R ^{2 represents} hydrogen,
R ^{3 represents} hydrogen or methyl,
R ⁴ means methyl,
R ^{5 is} fluorine, chlorine, trifluoromethyl, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, methoxycarbonyl, phenyl or pyridyl,
or
two substituents R ⁵ together with the phenyl ring to which they are attached form a 1,3-benzodioxole or a 1,4-benzodioxane,
R ^{6 is} C ₄ -C ₆ alkyl or C ₄ -C ₆ cycloalkyl,
n represents a number 0, 1 or 2,
where n is 2, the radicals R ^{5 may be the} same or different.

In a further embodiment, the invention relates to compounds of the formula (I)
wherein
R ^{1 is} C ₅ -C ₈ alkyl or C ₅ -C ₈ alkenyl,
R ^{2 represents} hydrogen,
R ^{3 represents} hydrogen,
R ⁴ means methyl,
R ^{5 is} fluorine, chlorine, trifluoromethyl, C ₁ -C ₄ alkyl, C ₁ -C ₃ alkoxy, phenyl or pyridyl,
R ⁶ denotes isobutyl, isopentyl, cyclopentyl or cyclohexyl,
n represents a number 0, 1 or 2,
where n is 2, the radicals R ^{5 may be the} same or different.

worin
R¹ bis R⁶ und n wie oben definiert sind.In the context of the present invention, preference is given to compounds of the formula (I) which have the formula (Ia):

wherein
R ¹ to R ⁶ and n are as defined above.

In the context of the present invention, preference is also given to compounds of the formula (I) in which
R ^{1 is} C ₅ -C ₈ alkyl or C ₅ -C ₈ alkenyl.

In the context of the present invention, preference is also given to compounds of the formula (I) in which R ^{2 is} hydrogen.

In the context of the present invention, preference is also given to compounds of the formula (I) in which R ^{3 is} hydrogen.

In the context of the present invention, preference is also given to compounds of the formula (I) in which R ^{4 is} methyl.

In the context of the present invention, preference is also given to compounds of the formula (I) in which R ^{5 is} hydrogen.

In the context of the present invention, preference is also given to compounds of the formula (I) in which n is 1 and R ^{5 is} fluorine, chlorine, trifluoromethyl, C ₁ -C ₄ -alkyl, alkoxy, phenyl or pyridyl, where R ^{5 is} meta - Or para position of the ring is present.

Also preferred in the context of the present invention are compounds of the formula (I) in which n is 2 or 3 and two substituents R ⁵ together propane-1,3-diyl, butane-1,4-diyl, 1,3-dioxa- propane-1,3-diyl or 1,4-dioxa-propane-1,4-diyl, the carbocycle or heterocycle formed being substituted by 0, 1 or 2 substituents R ^5-1 , in particular by 0 substituents R ^{5- 1st}

In the context of the present invention, preference is also given to compounds of the formula (I) in which R ^{6 is} C ₄ -C ₆ -alkyl or C ₄ -C ₆ -cycloalkyl.

In the context of the present invention, preference is also given to compounds of the formula (I) in which R ^{6 is} isobutyl, isopentyl, cyclopentyl or cyclohexyl.

The following compounds are also preferred in the context of the present invention:
(2E, 4E) -N - {(1S) -3 - [((1S, 2S) -2-methyl-1 - {[(3R, 4S) -4-methyl-2,5-dioxo-3-pyrrolidinyl ] carbonyl} butyl) amino] -3-oxo-1-phenylpropyl} -2,4-hexadienamid
(2E, 4E) -N - {(1S) -3 - [((1S, 2R) -2-methyl-1 - {[(3R, 4S) -4-methyl-2,5-dioxo-3-pyrrolidinyl ] carbonyl} butyl) amino] -3-oxo-1-phenylpropyl} -2,4-hexadienamid
(2E, 4E) -N - [(1S) -3 - ({1-cyclopentyl-2 - [(3R, 4S) -4-methyl-2,5-dioxo-3-pyrrolidinyl] -2-oxoethyl} amino ) -3-oxo-1-phenylpropyl] -2,4-hexadienamid
(2E, 4F) -N - {(1S) -3 - [(2-ethyl-1 - {[(3R, 4S) -4-methyl-2,5-dioxo-3-pyrrolidinyl] carbonyl} butyl) amino] -3-oxo-1-phenylpropyl} -2,4-hexadienamid
(2E) -N - {(1S) -3 - [(2-ethyl-1 - {[(3R, 4S) -4-methyl-2,5-dioxo-3-pyrrolidinyl] carbonyl} butyl) amino] -3-oxo-1-phenylpropyl} -2-octenamid

• [A] Verbindungen der Formel (II)
  
  worin R² bis R⁶ und n die oben angegebene Bedeutung aufweisen, mit Verbindungen der Formel (III)
  
  worin R¹ die oben angegebene Bedeutung aufweist, wobei diese gegebenenfalls in aktivierter Form vorliegen können, umgesetzt werden, oder
• [B] Verbindungen der Formel (IV)
  
  worin R³, R⁴ und R⁶ die oben angegebene Bedeutung aufweisen, mit Verbindungen der Formel (V)
  
  worin R¹, R², R⁵ und n die oben angegebene Bedeutung aufweisen, wobei diese gegebenenfalls in aktivierter Form vorliegen können, umgesetzt werden.

The invention further relates to processes for the preparation of the compounds of formula (I), characterized in that

• [A] Compounds of Formula (II)
  
  wherein R ² to R ⁶ and n have the meaning given above, with compounds of the formula (III)
  
  wherein R ^{1 has} the meaning given above, which may optionally be present in activated form, or
• [B] Compounds of Formula (IV)
  
  wherein R ³ , R ⁴ and R ^{6 have} the meaning given above, with compounds of the formula (V)
  
  wherein R ¹ , R ² , R ⁵ and n have the meaning given above, where these can optionally be present in activated form.

The implementations of the above Processes [A] and [B] are generally carried out in inert solvents, optionally in the presence of a base, preferably in a temperature range from room temperature to reflux the solvent at normal pressure.

To transfer the connections to the activated forms are e.g. carbodiimides such as e.g. N, N'-diethyl, N, N, '- dipropyl, N, N'-diisopropyl, N, N'-dicyclohexylcarbodiimide, N- (3-dimethylaminoisopropyl) -N'-ethylcarbodiimide hydrochloride (EDC) (optionally in the presence of pentafluorophenol (PFP)), N-cyclohexylcarbodiimide-N'-propyloxymethyl-polystyrene (PS carbodiimide) or carbonyl compounds such as carbonyldiimidazole, or 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1,2-oxazolium-3-sulfate or 2-tert-butyl-5-methyl-isoxazolium perchlorate, or acylamino compounds such as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, or propanephosphonic anhydride, or isobutyl chloroformate, or bis (2-oxo-3-oxazolidinyl) phosphoryl chloride or Benzotriazolyloxy-tri (dimethylamino) phosphonium hexafluorophosphate, or O- (benzotriazol-1-yl) -N, N, N ', N'-tetra-methyluronium hexafluorophosphate (HBTU), 2- (2-oxo-1- (2H) pyridyl) -1,1,3,3-tetramethyluronium tetrafluoroborate (TPTU) or O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyl uronium hexafluorophosphate (HATU), or 1-hydroxybenzetriazole (HOBt), or benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP), or mixtures of these with bases.

Bases are, for example, alkali carbonates, such as. Sodium or potassium carbonate, or hydrogen carbonate, or organic bases such as triallcylamines e.g. Triethylamine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine.

The use of is preferred HATU with diisopropylethylamine and from EDC with HOBt and triethylamine.

Inert solvents are, for example Halogenated hydrocarbons such as dichloromethane or trichloromethane, Hydrocarbon such as benzene, xylene, toluene, hexane, cyclohexane, or petroleum fractions, Nitromethane, dimethylformamide or acetonitrile or ethers such as diethyl ether, Tetrahydrofuran or dioxane. It is also possible to mix the solvents use. Dichloromethane or a mixture of are particularly preferred Dichloromethane and dimethylformamide.

Procedure [A]

worin R² bis R⁶ und n die oben angegebene Bedeutung aufweisen,
mit Säure, insbesondere mit Salzsäure oder Trifluoressigsäure versetzt werden. Die Verbindungen der Formel (II) fallen dabei in Form der entsprechenden Salze an, z.B. in Form ihrer Hydrochloride und können in dieser Form weiter eingesetzt werden oder durch chromatographische Reinigung in ihre salzfreie Form überführt werden.The compounds of the formula (II) are known or can be prepared by compounds of the formula (VI)

wherein R ² to R ⁶ and n have the meaning given above,
with acid, especially with hydrochloric acid or trifluoroacetic acid. The compounds of the formula (II) are obtained in the form of the corresponding salts, for example in the form of their hydrochlorides, and can be used further in this form or converted to their salt-free form by chromatographic purification.

The implementation takes place in general in inert solvents, preferably in a temperature range from room temperature to 40 ° C at normal pressure.

Inert solvents are, for example Halogenated hydrocarbons such as dichloromethane or trichloromethane, Hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane, or petroleum fractions, Nitromethane, dimethylformamide or acetonitrile or ethers such as diethyl ether, Tetrahydrofuran or dioxane. It is also possible to mix the solvents use. The use of hydrochloric acid in dioxane is particularly preferred or trifluoroacetic acid in dichloromethane.

worin
R², R⁵ und n die oben angegebene Bedeutung aufweisen,
wobei diese gegebenenfalls in aktivierter Form vorliegen können, umgesetzt werden.The compounds of the formula (VI) are known or new and can be prepared by compounds of the formula (IV)
with compounds of the formula (VII)

wherein
R ² , R ⁵ and n have the meaning given above,
where appropriate they can be present in activated form.

The implementation takes place in general in inert solvents, optionally in the presence of a base, preferably in a temperature range from room temperature to reflux the solvent at normal pressure.

To transfer the connections to the activated forms are e.g. carbodiimides such as e.g. N, N'-diethyl, N, N, '- dipropyl, N, N'-diisopropyl, N, N'-dicyclohexylcarbodiimide, N- (3-dimethylaminoisopropyl) -N'-ethylcarbodiimide hydrochloride (EDC) (optionally in the presence of pentafluorophenol (PFP)), N-cyclohexylcarbodiimide-N'-propyloxymethyl polystyrene (PS carbodiimide) or carbonyl compounds such as carbonyldiimidazole, or 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1,2-oxazolium-3-sulfate or 2-tert-butyl-5-methyl-isoxazolium perchlorate, or acylamino compounds such as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, or propanephosphonic anhydride, or isobutyl chloroformate, or bis (2-oxo-3-oxazolidinyl) phosphoryl chloride or Benzotriazolyloxy-tri (dimethylamino) phosphonium hexafluorophosphate, or O- (benzotriazol-1-yl) -N, N, N ', N'-tetra-methyluronium hexafluorophosphate (HBTU), 2- (2-oxo-1- (2H) pyridyl) -1,1,3,3-tetramethyluronium tetrafluoroborate (TPTU) or O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyl uronium hexafluorophosphate (HATU), or 1-hydroxybenzetriazole (HOBt), or benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP), or mixtures of these with bases.

Bases are, for example, alkali carbonates, such as. Sodium or potassium carbonate, or hydrogen carbonate, or organic bases such as trialkylamines e.g. Triethylamine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine.

The use of is preferred HATU with diisopropylethylamine and from EDC with HOBt and triethylamine.

Inert solvents are, for example Halogenated hydrocarbons such as dichloromethane or trichloromethane, Hydrocarbon such as benzene, xylene, toluene, hexane, cyclohexane, or petroleum fractions, Nitromethane, dimethylformamide or acetonitrile or ethers such as diethyl ether, Tetrahydrofuran or dioxane. It is also possible to mix the solvents use. Dichloromethane or a mixture of are particularly preferred Dichloromethane and dimethylformamide.

worin
R³, R⁴ und R⁶ die oben angegebene Bedeutung aufweisen,
mit Säure, insbesondere mit Salzsäure oder Trifluoressigsäure versetzt werden. Die Verbindungen der Formel (IV) fallen dabei in Form der entsprechenden Salze an, z.B. in Form ihrer Hydrochloride und können in dieser Form weiter eingesetzt werden oder durch chromatographische Reinigung in ihre salzfreie Form überführt werden.The compounds of formula (IV) are known or new and can be prepared by compounds of formula (VIII)

wherein
R ³ , R ⁴ and R ^{6 have} the meaning given above,
with acid, especially with hydrochloric acid or trifluoroacetic acid. The compounds of the formula (IV) are obtained in the form of the corresponding salts, for example in the form of their hydrochlorides, and can be used further in this form or converted to their salt-free form by chromatographic purification.

The implementation takes place in general in inert solvents, preferably in a temperature range from room temperature to 40 ° C at normal pressure.

Inert solvents are, for example Halogenated hydrocarbons such as dichloromethane or trichloromethane, Hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane, or petroleum fractions, Nitromethane, dimethylformamide or acetonitrile or ethers such as diethyl ether, Tetrahydrofuran or dioxane. It is also possible to mix the solvents use. The use of hydrochloric acid in dioxane is particularly preferred or trifluoroacetic acid in dichloromethane.

The compounds of formula (III) are known or can are produced by processes known from the literature (Houben-Weyl, Methods of organic chemistry, vol. E5, carboxylic acids and carboxylic acid derivatives, Thieme Verlag, Stuttgart, 1985).

The compounds of formula (VII) are known or can be prepared according to instructions known from the literature. (Regarding the representation of aromatic beta amino acids see BS Rault, P. Dallemagne, M. Robba, Bull. Soc. Chim. Fr. 1987, 1079-1083; SG Davies et al., J. Chem. Soc., Chem Commun. 1993, 1153-1155; VA Soloshonok et al., Tetrahedron Asymmetry 1995, 1601-1610; regarding the conversion to the tert-butoxycarbonyl-protected compounds see TW Greene, PGM Wuts, Protective Groups in Organic Synthesis, ^3rd Edt. 1999, J. Wiley & Sons, Inc.).

The compounds of formula (VIII) are known or can be produced by methods known from the literature. (See e.g. S. G. Davies, D. J. Dixon, J. Chem. Soc., Perkin Trans. 1 1998, 2635-2643; A.V. Rama Rao, A.K. Singh, Ch.V.N.S. Varaprasad, Tetrahedron Letters 1991, 32, 4393-4396).

Procedure [B]

worin
R¹, R², R⁵ und n die oben angegebene Bedeutung aufweisen, und R⁷ für einen Alkylrest steht, bevorzugt Methyl oder Ethyl, verseift werden.The compounds of formula (V) are known or. new and can be prepared by using compounds of formula (IX)

wherein
R ¹ , R ² , R ⁵ and n have the meaning given above, and R ^{7 represents} an alkyl radical, preferably methyl or ethyl, are saponified.

The saponification can be carried out using standard methods, for example at room temperature below Normal pressure in a mixture of ethanol and water with 40% sodium hydroxide solution or in a mixture of dioxane and water with 10% methanolic potassium hydroxide solution.

worin
R², R⁵, R⁷ und n die oben angegebene Bedeutung aufweisen,
mit Verbindungen der Formel (III), wobei diese gegebenenfalls in aktivierter Form vorliegen können, umgesetzt werden.The compounds of formula (IX) are known or new and can be prepared by compounds of formula (X)

wherein
R ² , R ⁵ , R ⁷ and n have the meaning given above,
with compounds of formula (III), which may optionally be present in activated form.

The implementation takes place in general in inert solvents, optionally in the presence of a base, preferably in a temperature range from room temperature to reflux the solvent at normal pressure.

To transfer the connections to the activated forms are e.g. carbodiimides such as e.g. N, N'-diethyl, N, N, '- dipropyl, N, N'-diisopropyl, N, N'-dicyclohexylcarbodiimide, N- (3-dimethylaminoisopropyl) -N'-ethylcarbodiimide hydrochloride (EDC) (optionally in the presence of pentafluorophenol (PFP)), N-cyclohexylcarbodiimide-N'-propyloxymethyl-polystyrene (PS carbodiimide) or carbonyl compounds such as carbonyldiimidazole, or 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1,2-oxazolium-3-sulfate or 2-tert-butyl-5-methyl-isoxazolium perchlorate, or acylamino compounds such as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, or propanephosphonic anhydride, or isobutyl chloroformate, or bis (2-oxo-3-oxazolidinyl) phosphoryl chloride or Benzotriazolyloxy-tri (dimethylamino) phosphonium hexafluorophosphate, or O- (benzotriazol-1-yl) -N, N, N ', N'-tetra-methyluronium hexafluorophosphate (HBTU), 2- (2-oxo-1- (2H) pyridyl) -1,1,3,3-tetramethyluronium tetrafluoroborate (TPTU) or O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyl uronium hexafluorophosphate (HATU), or 1-hydroxybenzetriazole (HOBt), or benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP), or mixtures of these with bases.

Bases are, for example, alkali carbonates, such as. Sodium or potassium carbonate, or hydrogen carbonate, or organic bases such as trialkylamines e.g. Triethylamine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine.

The use of is preferred HATU with diisopropylethylamine and from EDC with HOBt and triethylamine.

Inert solvents are, for example Halogenated hydrocarbons such as dichloromethane or trichloromethane, Hydrocarbon such as benzene, xylene, toluene, hexane, cyclohexane, or petroleum fractions, Nitromethane, dimethylformamide or acetonitrile or ethers such as diethyl ether, Tetrahydrofuran or dioxane. It is also possible to mix the solvents use. Dichloromethane or a mixture of are particularly preferred Dichloromethane and dimethylformamide.

The compounds of formula (X) are known or new and can be prepared analogously to processes known from the literature (with respect to Representation of aromatic beta amino acids and their conversion into the corresponding alkyl esters s. z. B. S. Rault, P. Dallemagne, M. Robba, Bull. Soc. Chim. Fr., 1987, 1079-1083; S.G. Davies et al., J. Chem. Soc., Chem. Commun., 1993, 1153-1155; V. A. Soloshonok et l1., Tetrahedron Asymmetry, 1995, 1601-1610; S. J. Faulconbridge et al., Tetrahedron Letters, 2000, 41, 2679-2682).

The preparation of the compounds according to the invention can be illustrated by the following synthesis schemes.

Starting Compounds:

Preparation Examples:

The present invention relates to furthermore compounds of the formula (I) for combating diseases, in particular bacterial diseases, and drugs containing compounds of formula (I) and auxiliaries and also the use of compounds of formula (I) for the manufacture of a medicament for treatment of bacterial diseases.

The preparations according to the invention are particularly effective against bacteria and bacteria-like Microorganisms. They are therefore particularly good for prophylaxis and Chemotherapy of local and systemic infections in human and veterinary medicine caused by these pathogens become.

For example, local and / or systemic diseases that are caused by the following pathogens or by mixtures of the following pathogens can be treated and / or prevented:
Gram-positive cocci, eg staphylococci (Staph. Aureus, Staph. Epidermidis), enterococci (E. faecalis, E. faecius) and streptococci (Strept. Agalactiae, Strept. Pneumoniae); gram-negative cocci (Neisseria gonorrhoeae) as well as gram-negative rods such as enterobacteriaceae, for example Escherichia coli, Haemophilus influenzae, Citrobacter (Citrob. freundii, Citrob. divernis), Salmonella and Shigella; further adhesive sites (Klebs. pneumoniae, Klebs. oxytocy), Enterobacter (Ent. aerogenes, Ent. agglomerans), Hafnia, Serratia (Serr. marcescens), Providencia, Yersinia, and the genus Acinetobacter. In addition, the antibacterial spectrum includes strictly anaerobic bacteria such as Bacteroides fragilis, representatives of the genus Peptococcus, Peptostreptococcus and the genus Clostridium; also mycoplasma (M. pneumoniae, M. hominis, M. urealyticum) as well as mycobacteria, eg Mycobacterium tuberculosis.

The above list of pathogens is only an example and is in no way to be interpreted as limiting. Examples of diseases which can be caused by the pathogens mentioned or mixed infections and which can be prevented, improved or cured by the preparations according to the invention are:
Infectious diseases in humans such as B. septic infections, bone and joint infections, skin infections, postoperative wound infections, abscesses, phlegmon, wound infections, infected burns, burns, infections in the mouth area, infections after dental operations, septic arthritis, mastitis, tonsillitis, genital infections and eye infections.

In addition to humans, bacterial infections can also be treated in other species. Examples include:
Pig: coli diarrhea, enterotoxemia, sepsis, dysentery, salmonellosis, metritis-mastitis-agalaktiae syndrome, mastitis;
Ruminants (cattle, sheep, goats): diarrhea, sepsis, bronchopneumonia, salmonellosis, pasteurellosis, mycoplasmosis, genital infections;
Horse: bronchopneumonia, foal paralysis, puerperal and postpuerperal infections, salmonellosis;
Dog and cat: bronchopneumonia, diarrhea, dermatitis, otitis, urinary tract infections, prostatitis;
Poultry (chicken, turkey, quail, pigeon, ornamental birds and others): mycoplasmosis, E. coli infections, chronic respiratory diseases, salmonellosis, pasteurellosis, psittacosis.

Bacterial diseases can also occur are treated in the rearing and keeping of farm and ornamental fish, whereby the antibacterial spectrum over the previously mentioned pathogens further pathogens such as Pasteurella, Brucella, Campylobacter, Listeria, Erysipelothris, Corynebacteria, Borellia, Treponema, Nocardia, Rikettsie, Yersinia, expanded.

The active ingredient can be systemic and / or act locally. For this purpose, it can be applied in a suitable manner such as oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, transdermal, conjunctival, otic or as an implant.

For the active substance can administer these administration routes in suitable administration forms be administered.

For oral application are known, the active ingredient quickly and / or modified delivery forms of application, such as tablets (Uncoated as well as coated Tablets, e.g. tablets coated with enteric coatings or Film-coated tablets), capsules, dragees, granules, pellets, powders, emulsions, Suspensions and solutions.

Parenteral administration can bypassing a resorption step (intravenous, intraarterial, intracardial, intraspinal or intralumbal) or with activation absorption (intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal). For parenteral application are suitable as application forms Injection and infusion preparations in the form of solutions, Suspensions, emulsions, lyophilisates and sterile powders.

The parenteral is preferred, in particular the intravenous Application.

For the other application routes are e.g. Inhalation dosage forms (e.g. powder inhalers, nebulizers), nose drops / solutions, sprays; Tablets to be applied lingually, sublingually or buccally or capsules, suppositories, ear and eye preparations, vaginal capsules, aqueous Suspensions (lotions, shake mixes), lipophilic suspensions, ointments, creams, milk, pastes, powder or implants.

The active ingredients can be in a manner known per se in the listed Application forms are transferred. This is done using inert non-toxic, pharmaceutical suitable auxiliaries. Which includes et al excipients (e.g. microcrystalline cellulose), solvents (e.g. liquid polyethylene glycols), emulsifiers (e.g. sodium dodecyl sulfate), dispersing agents (e.g. polyvinylpyrrolidone), synthetic and natural Biopolymers (e.g. albumin), stabilizers (e.g. antioxidants such as ascorbic acid), Colorants (e.g. inorganic pigments such as iron oxides) or taste and / or odor correctives.

In general, it has proven to be beneficial proven with parenteral administration amounts of about 5 to 250 mg / kg body weight 24 hours each to achieve effective results. With oral application the amount about 5 to 100 mg / kg body weight 24 hours each.

Nevertheless, it may be necessary to deviate from the amounts mentioned, depending on body weight, route of administration, individual behavior towards the active ingredient, Type of preparation and time or interval at which the application takes place.

The percentages in the following Unless otherwise stated, tests and examples are percentages by weight; Parts are parts by weight. Solvent ratios, dilution ratios and obtain concentration information from liquid / liquid solutions each on the volume.

A. Examples

Abbreviations: Boc tert-butoxycarbonyl CDCl ₃ deuterochloroform DIEA N, N-diisopropylethylamine DMSO dimethyl sulfoxide d. Th. of theory EDC N- (3-dimethylaminoisopropyl) -N'-ethylcarbodiimide hydrochloride eq. equivalent to IT Electrospray ionization (for MS) Fmoc fluorenylmethoxycarbonyl ges. saturated HATU O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate H hour HOBt 1-hydroxybenzotriazole HPLC High pressure, high performance liquid chromatography LC-MS Liquid chromatography-coupled mass spectroscopy MS mass spectroscopy MW Molecular weight [g / mol] NMR Nuclear Magnetic Resonance Spectroscopy PS-DIEA N, N-diisopropylethylamine polystyrene (resin) R _f Retention index (for DC) RP-HPLC Reverse phase HPLC RT room temperature R _t Retention time (with HPLC) THF tetrahydrofuran

HPLC and LC-MS methods:

Method 1: Column: Kromasil C18, LR temperature: 30 ° C, flow = 0.75 mlmin ^-1 , eluent: A = 0.01 M HClO ₄ , B = CH ₃ CN, gradient: → 0.5 min 98% A → 4.5 min 10% A → 6.5 min 10% A

Method 2: Column: Kromasil C18 60 * 2, LR temperature: 30 ° C, flow = 0.75 mlmin ^-1 , eluent: A = 0.01 MH ₃ PO ₄ , B = CH ₃ CN, gradient: → 0.5 min 90% A → 4.5 min 10% A → 6.5 min 10% A

Method 3: Column: Kromasil C18 60 * 2, LR temperature: 30 ° C, flow = 0.75 mlmin ^-1 , eluent: A = 0.005 M HClO ₄ , B = CH ₃ CN, gradient: → 0.5 min 98% A → 4.5 min 10% A → 6.5 min 10% A

Method 4: Column: Symmetry C18 2.1x150 mm, column oven: 50 ° C, flow = 0.6 mlmin ^-1 , eluent: A = 0.6 g 30% HCl / l water, B = CH ₃ CN, gradient: 0.0 min 90% A → 4.0 min 10% A → 9 min 10% A

Method 5: Instrument Micromass Quattro LCZ column Symmetry C18, 50 mm x 2.1 mm, 3.5 μm, temperature: 40 ° C, flow = 0.5 mlmin ^–1 , eluent A = CH ₃ CN + 0.1% formic acid, eluent B = water + 0.1 % Formic acid, gradient: 0.0 min 10% A → 4 min 90% A → 6 min 90% A

Method 6: Instrument Micromass Platform LCZ column Symmetry C18, 50 mm x 2.1 mm, 3.5 μm, temperature: 40 ° C, flow = 0.5 mlmin ^–1 , eluent A = CH ₃ CN + 0.1% formic acid, eluent B = water + 0.1 % Formic acid, gradient: 0.0 min 10% A → 4 min 90% A → 6 min 90% A

Method 7: Instrument Micromass Quattro LCZ column Symmetry C18, 50 mm x 2.1 mm, 3.5 μm, temperature: 40 ° C, flow = 0.5 mlmin ^–1 , eluent A = CH ₃ CN + 0.1% formic acid, eluent B = water + 0.1 % Formic acid, gradient: 0.0 min 5% A → 1 min 5% A → 5 min 90% A → 6 min 90% A

Method 8: Column: Symmetry C18 2.1 mm x 150 mm, 5 μm, column oven: 70 ° C, flow = 0.9 mlmin ^-1 , eluent: A = CH ₃ CN, B = 0.3 g 30% HCl / l water, gradient : 0.0 min 2% A → 2.5 min 95% A → 5 min 95% A

Method 9: Column: Symmetry C18 3.9 mm x 150 mm, column oven: 40 ° C, flow = 1.5 mlmin ^-1 , eluent: A = water + 0.05% HP ₃ O ₄ , B = CH ₃ CN, gradient: 0.0 min 10 % B → 0.6 min 10% B → 3.8 min 100% B → 5.0 min 100% B.

Method 10: Instrument: Waters Alliance 2790 LC; Pillar: Symmetry C18, 50 mm x 2.1 mm, 3.5 μm; Eluent A: water + 0.1% formic acid, eluent B: acetonitrile + 0.1% formic acid; Gradient: 0.0 min 5% B → 5.0 min 10% B → 6.0 min 10% B; Temperature: 50 ° C, Flow: 1.0 ml / min, UV detection: 210 nm.

Method 11: MS device type: Micromass ZQ; Device type HPLC: Waters Alliance 2790; Pillar: Symmetry C 18, 50 mm x 2.1 mm, 3.5 μm; Eluent B: acetonitrile + 0.05% formic acid, Eluent A: water + 0.05% formic acid; Gradient: 0.0 min 10% B → 3.5 min 90% B → 5.5 min 90% B; Oven: 50 ° C, Flow: 0.8 ml / min, UV detection: 210 nm.

Method 12: Instrument: Waters Alliance 2790 LC; Pillar: Symmetry C18, 50 mm x 2.1 mm, 3.5 μm; Eluent A: water + 0.05% formic acid, Eluent B: acetonitrile + 0.05% formic acid; Gradient: 0.0 min 5% B → 4.5 min 10% B → 5.5 min 10% B; Temperature: 50 ° C, Flow: 1.0 ml / min, UV detection: 210 nm.

Method 13: Instrument: Micromass Quattro LCZ, HP1100; Pillar: Symmetry C18, 50 mm x 2.1 mm, 3.5 μm; Eluent A: water + 0.05% formic acid, Eluent B: acetonitrile + 0.05% formic acid; Gradient: 0.0 min 90% A → 4.0 min 10% A → 6.0 min 10% A; Oven: 40 ° C, Flow: 0.5 ml / min, UV detection: 208-400 nm.

Method 14: Instrument: Micromass Platform LCZ, HP1100; Pillar: Symmetry C18, 50 mm x 2.1 mm, 3.5 μm; Eluent A: water + 0.05% formic acid, Eluent B: acetonitrile + 0.05% formic acid; Gradient: 0.0 min 90% A → 4.0 min 10% A → 6.0 min 10% A; Oven: 40 ° C, Flow: 0.5 ml / min, UV detection: 208-400 nm.

Method 15: Instrument: Waters Alliance 2790 LC; Pillar: Symmetry C18, 50 mm x 2.1 mm, 3.5 μm; Eluent A: water + 0.05% formic acid, Eluent B: acetonitrile + 0.05% formic acid; Gradient: 0.0 min 10% B → 4.0 min 90% B → 6.0 min 90% B; Temperature: 50 ° C, Flow: 0.0 min 0.5 ml / min → 4.0 min 0.8 ml / min, UV detection: 210 nm.

Method 16: Device type MS: Micromass ZQ; Device type HPLC: Waters Alliance 2790; Pillar: Symmetry C 18, 50 mm x 2.1 mm, 3.5 μm; Eluent B: acetonitrile + 0.05% formic acid, Eluent A: water + 0.05% formic acid; Gradient: 0.0 min 5% B → 4.5 min 90% B → 5.5 min 90% B; Oven: 50 ° C, Flow: 1.0 ml /, UV detection: 210 nm

Method 17: MS device type: Micromass ZQ; Device type HPLC: Waters Alliance 2790; Pillar: Uptisphere C 18, 50 mm x 2.0 mm, 3.0 μm; Eluent B: acetonitrile + 0.05% formic acid, Eluent A: water + 0.05% formic acid; Gradient: 0.0 min 5% B → 2.0 min 40% B → 4.5 min 90% B → 5.5 min 90% B; Oven: 45 ° C, Flow: 0.0 min 0.75ml / min → 4.5 min 0.75 ml / min → 5.5 min 1.25 ml / min, UV detection: 210 nm

Method 18: Instrument: Micromass Platform LCZ, HP1100; Pillar: Grom-SIL120 ODS-4 U, 50 mm x 2.0 mm, 3 μm; Eluent A: water + 0.05% formic acid, Eluent B: acetonitrile + 0.05% formic acid; Gradient: 0.0 min 100% A → 0.2 min 100% A → 2.9 min 30% A → 3.1 min 10% A → 4.5 min 10% A; Oven: 55 ° C; Flow: 0.8 ml / min; UV detection: 208-400 nm.

Starting Compounds:

Example 1A (3S) -1,3-dimethyl-2,5-pyrrolidinedione

600 mg (5.26 mmol) (3S) -3-methyldihydro-2,5-furandione (representation: SG Davies, DJ Dixon, J. Chem. Soc., Perkin Trans. 1 1998, 2635-2643) together with 559 mg (0.77 ml, 5.52 mmol) of triethylamine in 5 ml of dichloromethane at 0 ° C. and 373 mg (5.52 mmol) of methylamine hydrochloride were added. The reaction mixture is stirred at room temperature overnight and 938 mg (5.78 mmol) of N, N-carbonyldiimidazole are then added in portions. The mixture is stirred at room temperature for 1.5 h and at reflux temperature for 30 min. After cooling to room temperature, the reaction mixture is washed with 5% hydrochloric acid and water, the organic phase is dried over magnesium sulfate, filtered and concentrated, and the product is dried under high vacuum. 605 mg of the product are obtained (88% of theory).
MS (ES +): m / z (%) = 128 (M + H) ⁺ (100).
HPLC (method 6): R _t = 0.81 min.
¹ H NMR (300 MHz, CDCl ₃ ): δ = 3.10 (dd, 1H), 2.99 (s, 3H), 2.90-2.82 (m, 1H), 2.32 (dd, 1H), 1.35 (d, 3H) ,

General rule A: Reaction of N-tert-butoxycarbonyl-protected amino acids with 2,5-pyrrolidinedione derivatives

The N-tert-butoxycarbonyl-protected amino acid (1 eq.) and N, N-carbonyldiimidazole (1.1 eq.) are dissolved in tetrahydrofuran (approx. 0.1 - 1 mol / l) stirred for 2 h at room temperature. This mixture becomes then added the 2,5-pyrrolidinedione (1 eq.) and the entire mixture becomes a 1 molar solution of. cooled to -65 ° C within 30 min Lithium hexamethyl disilazide (2 eq.) Dropped in THF. After the addition is complete is stirred for a further 15 min at -65 ° C before saturated aqueous Ammonium chloride solution is added. After warming up the reaction mixture is diluted to room temperature with diethyl ether and the organic phase with saturated aqueous Sodium chloride solution washed, over Magnesium sulfate dried, filtered and then concentrated. The crude product is purified by RP-HPLC (eluent: water acetonitrile, gradient) cleaned.

According to general regulation A, the reaction of the corresponding N-tert-butoxycarbonyl-protected amino acids (for the representation of unnatural alpha-amino acids, see, for example: AA Cordi et al., J. Med. Chem. 2001, 44 , 787-805; K. Mai, G. Patil, Tetrahedron Lett. 1984, 25, 4583-4586; NA Hassan, E. Bayer, JC Jochims, J. Chem. Soc., Perkin Trans. 1 1998, 3747-3757 ; Regarding tert.-butoxycarbonyl protection see e.g. TW Greene, PGM Wuts, Protective Groups in Organic Synthesis, 3 ^rd Edt. 1999, J. Wiley & Sons, Inc.) with (3S) -1- (Benzyloxy) -3-methyl-2,5-pyrrolidinedione (representation: SG Davies, DJ Dixon, J. Chem. Soc., Perkin Trans. 1 1998, 2635-2643) or (3S) -1,3-dimethyl- 2,5-pyrrolidinedione the following derivatives are obtained:

General rule B: Reductive deprotection of 1-benzyloxy-2,5-pyrrolidinediones

Deprotection is analogous to S. G. Davies, D. J. Dixon, J. Chem. Soc., Perkin Trans. 1 1998, 2635-2643.

The 1-benzyloxy-2,5-pyrrolidinedione (1 eq.) Is dissolved in methanol or ethanol (approx. 0.02 mol / l), with a added catalytic amount of palladium-carbon (10%) and 1 h under Hydrogen atmosphere (Normal pressure) stirred. Then the reaction mixture is filtered and concentrated. The residue is dissolved in acetonitrile (approx. 0.05 mol / l) and to a solution of 2-bromoacetophenone (1 eq) in acetonitrile (approx. 0.03 mol / l) Dropped at room temperature. Then over a period of 2 h 1.5 eq. Triethylamine in acetonitrile (approx. 0.35 mol / l) to the reaction mixture dripped. The reaction mixture is at room temperature overnight touched, concentrated and the crude product is RP-HPLC (eluent: acetonitrile / water + 0.3 ml 37% hydrochloric acid / l, Gradient).

The following compounds can be obtained according to general regulation B:

General rule C: deblocking of Boc-protected derivatives

The tert-butyloxycarbonyl (BOC) protected amine derivative (possibly as a solution in dioxane) is mixed with 4 N hydrochloric acid solution in 1,4-dioxane (approx. 0.1 mol / l) and stirred for 2–24 h at room temperature before is concentrated in vacuo. The residue can be reacted further without further purification or is optionally treated with dichloromethane and diethyl ether. The precipitated crystals are suctioned off and dried in a high vacuum. The product is obtained as the hydrochloride. The following compounds can be obtained according to general rule C.

Example 25A (S) -3-Amino-3-phenylpropionic acid methyl ester

2.3 g (11.65 mmol) of (S) -3-amino-3-phenylpropionic acid are placed in 100 ml of methanol and a catalytic amount of concentrated sulfuric acid (0.02 eq.) Is added. The reaction mixture is heated to reflux for 24 h and then concentrated. The crude product can be used in the next stage without further purification.
Yield: 2.7 g (65% of theory).
¹ H-NMR (300 MHz, d ₆ -DMSO): δ = 8.50 (s, 2H), 7.52-7.37 (m, 5H), 4.61 (t, 1H), 3.58 (s, 3H), 3.13 (dd, 1H), 2.98 (dd, 1H).
MS (ES +): m / z (%) = 180 (M + H) ⁺ (100).

General instruction D: reaction of 3-amino-3-phenyl-propionic acid alkyl esters with carboxylic acids

The carboxylic acid (1.3 - 1.5 eq.) Is in dichloromethane (approx.0.1 mol / l) at 0 ° C submitted and with 1.3 - 1.5 eq. HATU transferred. A solution of the 3-amino-3-phenyl-propionic acid alkyl ester is first added to this mixture (1 eq.) In a 1: 1 mixture of dichloromethane and N, N-dimethylformamide (approx. 0.1 mol / l) and then via a Period of 1h a solution of diisopropylethylamine (3.5 eq.) in a 1: 1 mixture of dichloromethane and N, N-dimethylformamide (about 1 mol / l) were added dropwise. It will take 30 min at 0 ° C and then overnight stirred at room temperature. Then the reaction mixture is concentrated and by means of RP-HPLC (eluent: water-acetonitrile, Gradient).

The following compound can be obtained according to general regulation D:

General instruction E: saponification of the propionic acid alkyl esters

The alkyl propionate is in one 3: 1 mixture of ethanol and water (approx. 0.1 - 0.15 mol / l) and with 5 eq. 40% sodium hydroxide solution added. The reaction mixture is stirred for 24 h at room temperature, with diluted hydrochloric acid acidified (approx. pH 3) and concentrated. The residue is in ethyl acetate added and with saturated aqueous Sodium chloride solution washed. The organic phase is dried over magnesium sulfate, filtered and concentrated. The product obtained can be used without further notice Cleaning in the next Level can be used.

Alternatively, the following method can also be used:
The alkyl propionate is placed in a 1: 1 mixture of dioxane and water (about 0.1-0.15 mol / l) and with 3 eq. a solution of potassium hydroxide in methanol (100 mg / ml). The reaction mixture is stirred at room temperature for 2 h and then concentrated. The residue is taken up in water and acidified with dilute hydrochloric acid. The aqueous phase is extracted three times with a 1: 1 mixture of dichloromethane and ethyl acetate. The combined organic phases are dried over sodium sulfate, filtered and concentrated. The product obtained can be used in the next step without further purification.

According to the general regulation E the following connection can be obtained:

The propionic acid derivatives thus obtained can according to the general rule F (acylation of 3- [2-aminoalkanoyl] -2,5-pyrrolidinedione hydrochloride derivatives implemented with carboxylic acid derivatives) become.

Example 28A (3S) -3 - [(tert-Butoxycarbonyl) amino] -3-phenylpropionic acid

2.82 g (17 mmol) of (S) -3-amino-3-phenylpropionic acid are suspended in 60 ml of dioxane and at 0 ° C with 4.1 g (18.8 mmol) of di-tert-butyl dicarbonate (Boc-anhydride) and 43 ml a 1 N sodium hydroxide solution in water. The reaction mixture is stirred at 0 ° C. for a further 30 min and then at room temperature for 3 h. The reaction mixture is then concentrated and the residue is taken up in methylene chloride. The organic phase is washed with 1N hydrochloric acid and saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The crude product (3.12 g) can be reacted further without further purification.
MS (ES-): m / z (%) = 264 (M-H) ^- (100).
HPLC (method 14): R _t = 3.89 min.

General procedure F: Acylation of 3- [2-aminoalkanoyll-2,5-pyrrolidinedione hydrochloride derivatives with carboxylic acid derivatives

At 0 ° to a solution of the carboxylic acid derivative (1.2 - 1.5 eq.) In absolute dichloromethane or a mixture (5: 1 to 1: 1) of absolute dichloromethane and N, N-dimethylformamide (approx. 0.1 to 0.3 mol / l) C first an equimolar amount of HATU and then the 3- [2-aminoalkanoyl] -2,5-pyrrolidinedione hydrochloride derivative (1 eq., Optionally as a solution in N, N-dimethylformamide or dichloromethane / N, N-dimethyl formamide mixtures) added. Then at 0 ° C a solution of 2.5 - 3.5 eq. Diisopropylethylamine in a 1: 1 mixture of absolute dichloromethane and N, N-dimethylformamide (0.2-1 mol / l) was added dropwise over a period of 1 h. After the addition has ended, the reaction mixture is stirred for a further 30 min at 0 ° C. and then overnight at room temperature before being concentrated in vacuo. The product can be obtained by chromatography on silica gel (eluents: mixtures of cyclohexane / ethyl acetate or mixtures of dichloromethane and ethanol) or by RP-HPLC (eluents: variable gradients of water and acetonitrile), alternatively by a combination of the two methods.

Alternatively, the implementation can also be carried out according to the following procedure:
To a solution of the 3- [2-aminoalkanoyl] -2,5-pyrrolidinedione hydrochloride derivative (1 eq.) In absolute dichloromethane or a mixture (5: 1 to 1: 1) of absolute dichloromethane and N, N-dimethylformamide (approx. 0.1 to 0.3 mol / l) the carboxylic acid derivative (1.1 - 1.5 eq.), triethylamine (3 eq.), HOBt (3 eq.) and finally 1.2 eq. Given EDC. The reaction mixture is stirred at room temperature (2 h to overnight) before being concentrated in vacuo. The residue is taken up in ethyl acetate or dichloromethane and the organic phase is washed with water, saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The product can be purified by chromatography on silica gel (eluents: mixtures of cyclohexane / ethyl acetate or mixtures of dichloromethane and ethanol) or by RP-HPLC (eluents: variable gradients of water and acetonitrile), alternatively by a combination of the two methods.

According to the general regulation F the following connection can be obtained:

General rule G: deblocking of Boc-protected derivatives

The tert-butyloxycarbonyl (BOC) protected Amine derivative (if necessary as a solution in dioxane) is added with 4 N hydrochloric acid solution in 1,4-dioxane added (approx. 0.1 mol / l) and stirred for 2 - 24 h at room temperature before in Vacuum is concentrated. The residue can be implemented without further purification or, if necessary treated with dichloromethane and diethyl ether. The fancy Crystals are suctioned off and dried in a high vacuum. You get the product as hydrochloride.

According to the general regulation G the following connection can be obtained:

Preparation Examples: General Procedure H: Acylation of Acylalkylamino Substituted 3- [2-Aminoalkanoyl] -2,5-pyrrolidinedione Hydrochloride Derivatives with Carboxylic Acid Derivatives

To a mixture of amine hydrochloride (1.0 eq.), Carboxylic acid (1.2 to 1.3 eq.) And HATU (1.2 - 1.4 eq.) Solved in absolute N, N-dimethylformamide or in a 1: 1 mixture of N, N-dimethylformamide and dichloromethane (0.02 - 0.2 mol / l) at 0 ° C a 0.2 - 1.0 molar solution of diisopropylethylamine (2.5 to 3.5 eq.) in N, N-dimethylformamide or a 1: 1 mixture of N, N-dimethylformamide and dichloromethane over the Added dropwise for 1 h. When the addition is complete, the reaction mixture 30 minutes at 0 ° C and over Stirred at room temperature overnight, before the mixture is concentrated in vacuo. The product can by Chromatography on silica gel (eluents: mixtures of cyclohexane / ethyl acetate or mixtures of dichloromethane and ethanol) or by RP-HPLC (Eluents: variable gradients from water and acetonitrile), alternatively by a combination of both methods.

Alternatively, the implementation can also be carried out according to the following procedure:
To a mixture of amine hydrochloride (1.0 eq.), Carboxylic acid (1.2 to 1.3 eq.), Triethylamine (2.4 - 3 eq.) And HOBt (2.4 - 3 eq.) In absolute dichloromethane or in a mixture of N, N-dimethylformamide and dichloromethane (0.02 - 0.2 mol / l) are finally 1.2 eq. Given EDC. The reaction mixture is stirred at room temperature (2 h - overnight) before being concentrated in vacuo. The residue is taken up in ethyl acetate or dichloromethane and the organic phase is washed with water, saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The product can be purified by chromatography on silica gel (eluents: mixtures of cyclohexane / ethyl acetate or mixtures of dichloromethane and ethanol) or by RP-HPLC (eluents: variable gradients of water and acetonitrile), alternatively by a combination of the two methods.

According to the regulations described above for the acylation of 3- [2-aminoalkanoyl] -2,5-pyrrolidinedione hydrochloride Derivatives (general rule F) or substituted by acylalkylamino 3- [2-aminoalkanoyl] -2,5-pyrrolidinedione hydrochloride derivatives (general Regulation H) with carboxylic acid derivatives can do the following Connections are obtained.

Example 1 (2E, 4E) -N - {(1S) -3 - [((1S) -3-Methyl-1 - {[(3R, 4S) -4-methyl-2,5-dioxo-3-pyrrolidinyl ] carbonyl} butyl) amino] -3-oxo-1-phenylpropyl} -2,4-hexadienamid

¹ H-NMR (200 MHz, d ₆ -DMSO): δ = 11.32 (s, 1H), 8.48-8.30 (m, 2H), 7.35-7.15 (m, 5H), 6.98 (dd, 1H), 6.30– 5.85 (m, 3H), 5.38-5.21 (m, 1H), 4.52-4.39 (m, 1H), 3.80 (d, 1H), 2.98-2.82 (m, 1H), 2.73-2.60 (m, 2H), 1.80 (d, 3H), 1.60-1.42 (m, 2H), 1.31-1.20 (m, 1H), 1.12-0.98 (m, 3H), 0.86 (d, 3H), 0.78 (d, 3H).
MS (ES +): m / z (%) = 468 (M + H) ⁺ .
HPLC (method 5): R _t = 3.75 min.

Example 2 (2E, 4E) -N - {(1S) -3 - [((1S) -1 - {[(3R, 4S) -4-methyl-2,5-dioxo-3-pyrrolidinyl] carbonyl} - pentyl) amino] -3-oxo-1-phenylpropyl} -2,4-hexadienamid

¹ H-NMR (300 MHz, d ₆ -DMSO): δ = 11.32-11.28 (m, 1H), 8.51-8.22 (m, 2H), 7.35-7.16 (m, 5H), 6.95 (dd, 1H), 6.26-5.87 (m, 3H), 5.35-5.23 (m, 1H), 4.5-4.40 + 4.25-4.15 (m, 1H), 3.85 (dd, 1H), 2.95-2.88 (m, 1H), 2.75-2.59 (m, 2H), 1.81 (d, 3H), 1.80-1.48 (m, 2H), 1.40-1.03 (m, 7H), 0.88-0.78 (m, 3H).
MS (ES-): m / z (%) = 466 (M - H) ^- .
HPLC (method 14): R _t = 4.23 min.

Example 3 (2E, 4E) -N - {(1S) -3 - [((1S, 2S) -2-methyl-1 - {[(3R, 4S) -4-methyl-2,5-dioxo-3 pyrrolidinyl] carbonyl} butyl) amino] -3-oxo-1-phenylpropyl} -2,4-hexadienamid

¹ H NMR (200 MHz, d ₆ -DMSO): δ = 11.37 (s, 1H), 8.40 (d, 1H), 8.12 (d, 1H), 7.40-7.15 (m, 5H), 6.97 (dd, 1H), 6.29-5.86 (m, 3H), 5.38-5.20 (m, 1H), 4.65-4.55 (m, 1H), 3.92 (d, 1H), 2.95-2.80 (m, 1H), 2.78-2.65 ( m, 2H), 2.15-1.98 (m, 1H), 1.80 (d, 3H), 1.30-1.10 (m, 2H), 1.06 (d, 3H), 0.86-0.68 (m, 6H).
MS (ES +): m / z (%) = 468 (M + H) ⁺ .
HPLC (method 12): R _t = 2.90 min.

Example 4 (2E, 4E) -N - [(1S) -3 - ({(1S) -1-Cyclohexyl-2 - [(3R, 4S) -4-methyl-2,5-dioxo-3-pyrrolidinyl] -2-oxoethyl} amino) -3-oxo-1-phenylpropyl] -2,4-hexadienamid

¹ H-NMR (400 MHz, d ₆ -DMSO): δ = 11.34 (s, 1H), 8.48-8.36 (m, 1H), 8.27 + 8.09 (2x d, 1H), 7.33-7.17 (m, 5H) , 6.98 (dd, 1H), 6.25–6.01 (m, 2H), 5.92 (d, 1H), 5.33–5.22 (m, 1H), 4.63 (dd, 1H), 3.95 + 3.90 (2x d, 1H) , 2.95-2.58 (m, 3H), 2.00-1.91 (m, 1H), 1.82 (d, 3H), 1.69-1.28 (m, 5H), 1.25-0.85 (m, 8H).
MS (ES +): m / z (%) = 494 (M + H) ⁺ .
HPLC (method 12): R _t = 2.98 min.

Example 5 (2E, 4E) -N - {(1S) -3 - [((1S, 2R) -2-methyl-1 - {[(3R, 4S) -4-methyl-2,5-dioxo-3 pyrrolidinyl] carbonyl} butyl) amino] -3-oxo-1-phenylpropyl} -2,4-hexadienamid

¹ H NMR (200 MHz, d ₆ -DMSO): δ = 11.37 (s, 1H), 8.49-8.28 (m, 1H), 7.98 (d, 1 H), 7.35-7.16 (m, 5H), 6.96 (dd, 1H), 6.29-5.85 (m, 3H), 5.38-5.20 (m, 1H), 4.99-4.90 (m, 1H), 4.00 (d, 1H), 3.05-2.60 (m, 3H), 2.19 -2.05 (m, 1H), 1.80 (d, 3H), 1.25-1.05 (m, 5H), 0.88-0.65 (m, 6H).
MS (ES +): m / z (%) = 468 (M + H) ⁺ .
HPLC (method 12): R _t = 2.85 min.

Example 6 (2E, 4E) -N - [(1S) -3 - ({1-Cyclopentyl-2 - [(3R, 4S) -4-methyl-2,5-dioxo-3-pyrrolidinyl] -2-oxoethyl } amino) -3-oxo-1-phenylpropyl] -2,4-hexadienamid

¹ H NMR (300 MHz, d ₆ -DMSO): δ = 11.30 (s, 1H), 8.42-8.31 (m, 1H), 8.20 (d, 1 H), 7.33-7.17 (m, 5H), 6.97 (dd, 1H), 6.26-6.01 (m, 2H), 5.90 (d, 1H), 5.35-5.22 (m, 1H), 4.51 (t, 1H), 3.89-3.82 (m, 1H), 2.93-2.55 (m, 3H), 2.38-1.95 (m, 1H), 1.80 (d, 3H), 1.60-1.02 (m, 11H).
MS (ES +): m / z (%) = 480 (M + H) ⁺ .
HPLC (method 16): R _t = 2.85 min.

Example 7 (2E, 4E) -N - {(1S) -3 - [(2-ethyl-1 - {[(3R, 4S) -4-methyl-2,5-dioxo-3-pyrrolidinyl] carbonyl} butyl) amino] -3-oxo-1-phenylpropyl} -2,4-hexadienamid

¹ H-NMR (200 MHz, d ₆ -DMSO): δ = 11.37 (s, 1H), 8.48-8.31 (m, 1H), 8.23-8.16 (m, 1H), 7.34-7.20 (m, 5H), 6.97 (dd, 1H), 6.30–5.87 (m, 3H), 5.36–5.22 (m, 1H), 4.98–4.89 + 4.52–4.43 (m, 1H), 4.01 + 3.92 (2x d, 1H), 3.02– 2.60 (m, 3H), 2.20-2.05 (m, 1H), 1.80 (d, 3H), 1.30-1.00 (m, 7H), 0.89-0.64 (m, 6H).
MS (ES +): m / z (%) = 482 (M + H) ⁺ .
HPLC (method 16): R _t = 2.97 min.

Example 8 (2E, 4E) -N - [(1S) -3 - ({1-Cyclopentyl-2 - [(3R, 4S) -1,4-dimethyl-2,5-dioxo-3-pyrrolidinyl] -2 -oxoethyl} amino) -3-oxo-1-phenylpropyl] -2,4-hexadienamid

¹ H-NMR (200 MHz, d ₆ -DMSO): δ = 8.51-8.22 (m, 2H), 7.38-7.17 (m, 5H), 6.96 (dd, 1H), 6.39-6.00 (m, 2H), 5.92 (d, 1H), 5.36-5.21 (m, 1H), 4.57 + 4.35 (2x t, 1H), 3.83 (d, 1H), 2.98-2.55 (m, 3H), 2.82 (s, 3H), 2.45-2.11 (m, 1H), 1.80 (d, 3H), 1.67-1.34 (m, 6H), 1.28-1.01 (m, 5H).
MS (ES +): m / z (%) = 494 (M + H) +.
HPLC (method 17): R _t = 3.62 min.

Example 9 (2E) -N - {(1S) -3 - [(2-ethyl-1 - {[(3R, 4S) -4-methyl-2,5-dioxo-3-pyrrolidinyl] carbonyl} butyl) amino] -3-oxo-1-phenylpropyl} -2-octenamid

¹ H-NMR (200 MHz, d ₆ -DMSO): δ = 11.37 (s, 1H), 8.39-8.15 (m, 2H), 7.35-7.15 (m, 5H), 6.58 (dt, 1H), 5.90 ( dt, 1H), 5.36–5.19 (m, 1H), 4.99–4.85 + 4.55–4.43 (m, 1H), 4.02 + 3.92 (2x d, 1H), 3.02–2.55 (m, 3H), 2.18–2.03 ( m, 2H), 1.99-1.65 (m, 1H), 1.45-1.00 (m, 12H), 0.95-0.65 (m, 10H).
MS (ES +): m / z (%) = 512 (M + H) ⁺ .
HPLC (method 18): R _t = 3.93 min.

B) Assessment of the physiological effectiveness

The suitability of the compounds according to the invention The following models can be used to treat bacterial diseases to be shown:

Determination of the minimum Inhibitory concentration (MIC):

The MIC is determined in the liquid dilution test. Overnight cultures of the test germs are diluted to a cell count of 10 ⁵ germs per ml in isosensitest medium (Difco, Irvine; USA) and incubated with dilutions of the test substances (dilution levels 1: 2). Exceptions are the tests with S. pneumoniae G9A, in BHI broth (Difco) plus 20% bovine serum, and with H. influenzae, in BHI broth (Difco) plus 20% bovine serum, 10 μg / ml Haemin and 1% Isovitale (Becton Dickinson, New Jersey, USA).

The cultures are incubated at 37 ° C for 18-24 hours; S. pneumoniae and H. influenzae in the presence of 8-10% CO ₂ .

Results

The lowest substance concentration, where there is no visible bacterial growth, is considered MIC defined. The MIC values in μmol / l some compounds of the invention across from A number of test germs are exemplary in the table below listed.

Systemic infection with S. aureus 133

S. aureus 133 cells are grown overnight in BH broth (Oxoid, New York, USA). The overnight culture is diluted 1: 100 in fresh bra broth and turned up for 3 hours. The bacteria in the logarithmic growth phase are centrifuged off and washed twice with buffered, physiological saline. A cell suspension in saline solution with an absorbance of 50 units is then set on the photometer (model LP 2W, Dr. Lange, Berlin, Germany). After a dilution step (1:15), this suspension is mixed 1: 1 with a 10% mucin suspension. 0.25 ml / 20 g mouse ip is applied from this infection solution. This corresponds to a cell count of approximately 1 × 10E ⁶ germs / mouse. The ip or iv therapy is given 30 minutes after the infection. Female CFW1 mice are used for the infection attempt. The survival of the animals is recorded over 6 days.

C) working examples for pharmaceutical compositions

The substances according to the invention can be pharmaceutical as follows Preparations are transferred:

Tablet:

Composition:

100 mg of the compound of the example 1, 50 mg lactose (monohydrate), 50 mg corn starch, 10 mg polyvinylpyrolidone (PVP 25) (from BASF, Germany) and 2 mg of magnesium stearate.

Tablet weight 212 mg. diameter 8 mm, radius of curvature 12 mm.

production:

The mixture of the connection of the Example 1, lactose and starch is with a 5% solution (m / m) of the PVP granulated in water. The granules will dry after with the magnesium stearate for 5 minute mixed. This mixture is compressed using a conventional tablet press (For the format of the tablet, see above).

Oral suspension:

Composition:

1000 mg of the compound of the example 1, 1000 mg ethanol (96%), 400 mg Rhodigel (xanthan gum) (from FMC, USA) and 99 g water.

A single dose of 100 mg compound of the invention correspond to 10 ml oral suspension.

production:

The Rhodigel is suspended in ethanol the compound of Example 1 is added to the suspension. Under stir the water is added. Until the swelling of the Rhodigels is stirred for about 6 hours.

Can be administered intravenously Solution:

Composition:

1 mg of the compound of Example 1, 15 g polyethylene glycol 400 and 250 g water for injections.

production:

The compound of Example 1 is dissolved together with polyethylene glycol 400 in the water with stirring. The solution is sterile filtered (pore diameter 0.22 μm) and under aseptic conditions filled into heat-sterilized infusion bottles. These are with infusion stoppers and crimp caps locked.

Claims (17)

Compounds of the formula

wherein R ^{1 is} alkyl, alkenyl or alkynyl, R ^{2 is} hydrogen or methyl, R ^{3 is} hydrogen or C ₁ -C ₃ alkyl, R ^{4 is} hydrogen or C ₁ -C ₃ alkyl, R ^{5 is} halogen, trifluoromethyl, trifluoromethoxy , Nitro, amino, alkylamino, hydroxy, alkyl, alkoxy, carboxyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, aryl or heteroaryl, and / or two substituents R ⁵ together with the phenyl ring to which they are attached form a bicyclus, the two substituents R ⁵ together with the carbon atoms to which they are attached form a 5- to 8-membered carbocycle or a 5- to 8-membered heterocycle, it being possible for the carbocycle or heterocycle formed to be substituted by 0, 1 or 2 substituents R ^5-1 , where the substituents R ^{5-1 are} independently selected from the group consisting of halogen, nitro, amino, trifluoromethyl, hydroxy, alkyl and alkoxy, R ⁶ C ₄ -C ₈ alkyl or C ₄ -C ₈ -Cycloalkyl means et, where R ⁶ can be substituted with 0, 1 or 2 substituents R ^6-1 , where the substituents R ^6-1 are selected independently of one another from the group consisting of halogen, nitro, amino, trifluoromethyl, hydroxy, alkyl and alkoxy, n is a number 0, 1, 2 or 3, where n is 2 or 3 and the radicals R ^{5 can be the} same or different, and their salts, solvates or solvates of the salts. Compounds of the formula (I) according to Claim 1, in which R ^{1 is} C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl or C ₁ -C ₁₀ alkynyl, R ^{2 is} hydrogen, R ^{3 is} hydrogen or methyl, R ^{4 is} methyl, R ^{5 is} fluorine, chlorine, trifluoromethyl, trifluoromethoxy, nitro, amino, alkylamino, hydroxy, alkyl, alkoxy, alkoxycarbonyl, aminocarbonyl, phenyl or 5- to 6-membered heteroaryl, or two substituents R ⁵ together with the Carbon atoms to which they are attached form a 5- to 6-membered carbocycle or 5- to 6-membered heterocycle, R ^{6 is} C ₄ -C ₇ alkyl or C ₄ -C ₇ cycloalkyl, where R ^{6 may be} substituted With 0, 1 or 2 substituents R ^6-1, where the substituents R ^6-1 are selected independently of one another from the group consisting of halogen, alkoxy, alkyl and trifluoromethyl, n is a number 0, 1 or 2, where n is the same 2 the radicals R ^{5 may be the} same or different. Compounds of formula (I) according to claim 1 or 2, wherein R ^{1 is} C ₅ -C ₈ alkyl or C ₅ -C ₈ alkenyl, R ^{2 is} hydrogen, R ^{3 is} hydrogen, R ^{4 is} methyl, R ^{5 is} fluorine , Chlorine, trifluoromethyl, C ₁ -C ₄ alkyl, C ₁ -C ₃ alkoxy, phenyl or pyridyl, R ^{6 is} isobutyl, isopentyl, cyclopentyl or cyclohexyl, n is a number 0, 1 or 2, where n equals 2 the radicals R ^{5 may be the} same or different. Compounds of formula (I) according to claim 1, 2 or 3, which have the formula (Ia):

wherein R ¹ to R ⁶ and n are as defined in claim 1. Compounds of formula (I) according to any one of the preceding claims, wherein R ^{1 is} C ₅ -C ₈ alkyl or C ₅ -C ₈ alkenyl. Compounds of formula (I) according to any one of the preceding claims, wherein R ^{2 is} hydrogen. Compounds of formula (I) according to any one of the preceding claims, wherein R ^{3 is} hydrogen. Compounds of formula (I) according to any one of the preceding claims, wherein R ^{4 is} methyl. Compounds of formula (I) according to any one of the preceding claims, wherein R ^{5 is} hydrogen. Compounds of formula (I) according to any one of claims 1 to 8, wherein n is 1 and R ^{5 is} fluorine, chlorine, trifluoromethyl, C ₁ -C ₄ alkyl, alkoxy, phenyl or pyridyl, where R ⁵ in the meta- or para position of the ring. Compounds of formula (I) according to any one of the preceding claims, wherein R ^{6 is} C ₄ -C ₆ alkyl or C ₄ -C ₆ cycloalkyl means. A process for the preparation of the compounds of formula (I) according to claim 1, characterized in that [A] compounds of formula (II)

wherein R ² to R ⁶ and n have the meaning given in claim 1, with compounds of the formula (III)

in which R ^{1 has} the meaning given in claim 1, which may optionally be present in activated form, or [B] compounds of the formula (IV)

wherein R ³ , R ⁴ and R ^{6 have} the meaning given in claim 1, with compounds of the formula (V)

wherein R ¹ , R ² , R ⁵ and n have the meaning given in claim 1, which may optionally be present in activated form. Compounds according to one of claims 1 to 11 for the treatment and / or prophylaxis of diseases. Medicament containing at least one compound according to one of the claims 1 to 11 in combination with at least one pharmaceutically acceptable pharmaceutically acceptable carrier or excipients. Use of compounds according to one of claims 1 to 11 for the manufacture of a medicament for treatment and / or prophylaxis of bacterial infections. Medicament according to claim 14 for treatment and / or Prophylaxis of bacterial infections. Procedures to fight bacterial infections in humans and animals by administering an antibacterial effective amount of at least one compound according to any one of claims 1 to 11th