DE19802235A1 - New oxazolidinone derivatives useful as antibacterial agents for treating local or systemic infections in humans or animals - Google Patents

Abstract

3-Indolyl-2-oxazolidinone derivatives (I) are new. 3-Indolyl-2-oxazolidinone derivatives of formula (I) and their stereoisomers and salts are new: A+D = a group of formula (i) or (ii): L, L' = O or NR13; R13 = H, COOH, 3-6C cyloalkyl or 2-6C alkoxycarbonyl; 1-6C acyl optionally substituted by halogen, OH, 1-5C alkoxy or NR14R15; 1-6C alkyl or 2-6C alkenyl optionally substituted by CN, halogen, COOH, 2-5C alkoxycarbony or NR14'R15' and/or by Ar; R14, R15, R14', R15' = H, phenyl or 1-5C alkyl; Ar = 6-14C aryl optionally substituted by halogen or 1-6C alkyl, alkoxy or acyl; R3-R6 = H, 1-6C alkyl or 1-6C haloalkyl, or R3+R4 and.or R5+R6 = O or S; R7-R12 = H or 1-6C alkyl optionally substituted by OH, halogen, 1-6C alkoxy, 2-6C alkoxycarbonyl, 6-10C aryl or NR16R17, or R7+R8, R9+R10 and/or R11+R12 = O or S, or R10+R11 = a bond; R16, R17 = H, phenyl or 1-5C alkyl; R1 = N3, OR18, OSO2R19 or NR20R21; R18 = H or 1-6C acyl; R19 = 1-6C alkyl or phenyl; R20 = H; R21 = H, C(Q)R22 or P(O)(OR23)(OR24); Q = O or S; R22 = 1-8C alkoxy or CF3; 3-6C cycloalkyl optionally substituted by halogen or 6-10C aryl; 6-10C aryl or 5- or 6-membered saturated or aromatic heterocyclyl containing 1-3 heteroatoms selected from S, N and O, where aryl and heterocyclyl are optionally substituted by 1-2 of halogen, CN, NO2, OH or phenyl; 1-6C alkyl optionally substituted by phenoxy, benzyloxy, COOH, halogen, 2-6C alkoxycarbonyl, 1-6C acyl or 5- or 6-membered heterocyclyl containing S, N and/or O; or NR25R26; R25, R26 = H, phenyl, pyridyl, 1-5C alkyl or morpholino(1-5C)alkyl; R23, R24 = H or 1-4C alkyl; R2 = H, halogen or 1-4C alkyl; E = H or halogen.

Description

The present invention relates to new tricyclic indoles substituted Oxazolidinones, process for their preparation and their use as medicaments, ins special as antibacterial drugs.

From publications US 5 254 577, US 4 705 799, EP 311 090, EP 312 000 and C.H. Park et al., J. Med. Chem. 35 1156 (1992) are N-aryloxazolidinones with antibacterial Effect known. In addition, 3- (nitrogen-substituted) phenyl-5-beta amidomethyloxazolidin-2-one known from EP 609905 A1.

Furthermore, EP 609 441 and EP 657 440 contain oxazolidinone derivatives with a mono amine oxidase inhibitory effect and in EP 645 376 with effect as Adhesion receptor antagorists published.

The present invention relates to new oxazolidinones of the general formula (I) substituted with tricyclic indoles

in which
A and D together with the nitrogen atom form a heterocyclic radical of the formula

form,
wherein
L and L 'are identical or different and represent an oxygen atom or a radical of the formula -NR ¹³ ,
wherein
R ^{13 is} hydrogen carboxyl, cycloalkyl having 3 to 6 carbon atoms, straight-chain or branched alkoxycarbonyl having up to 6 carbon atoms, or
straight-chain or branched acyl having up to 6 carbon atoms, which is optionally substituted by halogen, hydroxy, straight-chain or branched alkoxy having up to 5 carbon atoms or by a group of the formula -NR ¹⁴ R ¹⁵ ,
wherein
R ¹⁴ and R ^{15 are the} same or different and are hydrogen phenyl or straight-chain or branched alkyl having up to 5 carbon atoms,
or
straight-chain or branched alkyl or alkenyl each having up to 6 carbon atoms, which are optionally substituted by cyano, halogen, carboxyl, straight-chain or branched alkoxycarbonyl having up to 5 carbon atoms or by a group of the formula -NR ^{14 '} R ^15' ,
wherein
R ^{14 '} and R ^{15' have} the meaning of R ¹⁴ and R ¹⁵ given above and are the same or different with this,
and / or alkyl or alkenyl are optionally substituted by aryl having 6 to 14 carbon atoms, which in turn can be substituted by halogen or by straight-chain or branched alkyl, alkoxy or acyl each having up to 6 carbon atoms,
R ³ , R ⁴ , R ⁵ and R ^{6 are the} same or different and are hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by halogen,
or
R ³ and R ⁴ and / or R ⁵ and R ⁶ together form radicals of the formula = O or = S,
R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ^{12 are the} same or different and are hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, which may be hydroxyl, halogen, straight-chain or branched alkoxy or alkoxycarbonyl is in each case up to 6 carbon atoms, aryl with 6 to 10 carbon atoms or is substituted by a group of the formula -NR ¹⁶ R ¹⁷ ,
wherein
R ¹⁶ and R ^{17 have} the meaning of R ¹⁴ and R ¹⁵ given above and are the same or different with this,
or
R ⁷ and R ⁸ and / or R ⁹ and R ¹⁰ and / or R ¹¹ and R ¹² together form radicals of the formula = O or = S.
and or
R ¹⁰ and R ¹¹ together form an endocyclic double bond,
R ^{1 represents} azido or a radical of the formula -OR ¹⁸ , -O-SO ₂ -R ¹⁹ or -NR ²⁰ R ²¹ ,
wherein
R ¹⁸ denotes hydrogen or straight-chain or branched acyl having up to 6 carbon atoms,
R ¹⁹ denotes straight-chain or branched alkyl having up to 6 carbon atoms or phenyl,
R ²⁰ and R ^{21 are} hydrogen,
or
R ²⁰ means hydrogen,
and
R ^{21 is} a radical of the formula

means
wherein
Q represents an oxygen or sulfur atom,
R ²² denotes straight-chain or branched alkoxy with up to 8 carbon atoms or trifluoromethyl, or
R ^{22 means} cycloalkyl having 3 to 6 carbon atoms, which is optionally substituted by halogen or aryl having 6 to 10 carbon atoms, or
Aryl with 6 to 10 carbon atoms or a 5- to 6-membered saturated or aromatic heterocycle with up to 3 heteroatoms from the series S, N and / or O means, the ring systems listed under R ²² optionally being up to 2 times the same or are differently substituted by halogen, cyano, nitro, hydroxy or phenyl,
or
R ²² denotes straight-chain or branched alkyl having up to 6 carbon atoms, optionally by phenoxy, benzyloxy, carboxyl, halogen or straight-chain or branched alkoxycarbonyl or acyl, each having up to 6 carbon atoms or by a 5- to 6-membered heterocycle from the series S, N and / or O is substituted,
or
R ^{22 represents} a radical of the formula -NR ²⁵ R ²⁶ ,
wherein
R ²⁵ and R ^{26 are} identical or different and are hydrogen phenyl, pyridyl or straight-chain or branched alkyl having up to 5 carbon atoms, which is optionally substituted by morpholine which is bonded via N,
R ²³ and R ^{24 are} identical or different and are hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,
R ^{2 represents} hydrogen, halogen or straight-chain or branched alkyl having up to 4 carbon atoms,
E represents hydrogen or halogen,
and their salts.

The compounds of the invention can be in stereoisomeric forms, which are either like image and mirror image (enantiomers), or which are not like image and Mirror image (diastereomers) behave, exist. The invention relates to both Enantiomers or diastereomers or their respective mixtures. The racemic forms Like the diastereomers, they can be converted into the stereoisomer in a known manner separate uniform components.

The following schematic diagram illustrates the correspondingly marked notations for enantiomerically pure and racemic forms:

Physiologically acceptable salts of the compounds according to the invention can be salts of the substances according to the invention with mineral acids, carboxylic acids or sulfonic acids. Z are particularly preferred. B. salts with 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, citric acid, fumaric acid, maleic acid or benzoic acid.

Salts with customary bases can also be mentioned, such as, for example Alkaline metal salts (e.g. sodium or potassium salts), alkaline earth salts (e.g. calcium or Magnesium salts) or ammonium salts derived from ammonia or organic Amines such as, for example, diethylamine, triethylamine, ethyldiisopropylamine, procaine, Dibenzylamine, N-methylmorpholine, dihydroabietylamine, 1-ephenamine or methyl piperidine.

For the purposes of this invention, the following numbering should apply to the designation of the point of attachment of the oxazolidine skeleton to the heterocyclic radical:

The oxazolidinone skeleton is preferably attached in positions 5 and 6. The oxazolidinone skeleton is particularly preferably attached in position 5.

Cycloalkyl generally represents a cyclic hydrocarbon radical having 3 to 8 Carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl, Cycloheptyl and Cyclooctyl called. Cyclopropyl, Cyclopentane and the cyclohexane ring.

Aryl generally represents an aromatic radical having 6 to 10 carbon atoms. Preferred aryl radicals are phenyl and naphthyl.

In the context of the invention, acyl stands for a straight-chain or branched acyl radical with 1 to 6 carbon atoms. A straight-chain or branched is preferred  Lower acyl group with 1 to 4 carbon atoms. Preferred acyl radicals are acetyl and Propionyl.

In the context of the invention, alkoxy represents a straight-chain or branched Alkoxy radical with 1 to 6 carbon atoms. A straight-chain or is preferred branched lower alkoxy radical with 1 to 4 carbon atoms. For example called: methoxy, ethoxy, propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy.

In the context of the invention, alkoxycarbonyl represents a straight-chain or branched Alkoxycarbonylrest with 1 to 6 carbon atoms. A straight-chain or is preferred branched lower alkoxycarbonyl radical with 1 to 4 carbon atoms. For example may be mentioned: methoxycarbonyl, ethoxycarbonyl, propoxycartonyl, isopropoxycarbonyl, tert-butoxycarbonyl, n-pentoxycarbonyl and n-hexoxycarbonyl.

Compounds of the general formula (I) are preferred
in which
A and D together with the nitrogen atom form a heterocyclic radical of the formula

form,
wherein
L and L 'are identical or different and represent an oxygen atom or a radical of the formula -NR ¹³ ,
wherein
R ¹³ denotes hydrogen, cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl straight-chain or branched alkoxycarbonyl having up to 4 carbon atoms, or
straight-chain or branched acyl having up to 4 carbon atoms, which is optionally substituted by fluorine, chlorine, bromine, hydroxyl, straight-chain or branched alkoxy having up to 4 carbon atoms or by a group of the formula -NR ¹⁴ R ¹⁵ ,
wherein
R ¹⁴ and R ^{15 are the} same or different and are hydrogen phenyl or straight-chain or branched alkyl having up to 4 carbon atoms,
or
straight-chain or branched alkyl or alkenyl each having up to 4 carbon atoms, which are optionally substituted by fluorine, chlorine, bromine, cyano, methoxycarbonyl, ethoxycarbonyl, amino, N, N-dimethylamino or phenyl, which in turn is substituted by fluorine, chlorine, bromine or can be substituted by straight-chain or branched alkyl, alkoxy or acyl each having up to 4 carbon atoms,
R ³ , R ⁴ , R ⁵ and R ^{6 are the} same or different and are hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by fluorine, chlorine or bromine,
or
R ³ and R ⁴ and / or R ⁵ and R ⁶ together form radicals of the formula = O or = S,
R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ^{12 are the} same or different and are hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, optionally by hydroxy, fluorine, chlorine, bromine, straight-chain or branched alkoxy or alkoxycarbonyl each having up to 4 carbon atoms, phenyl or substituted by a group of the formula -NR ¹⁶ R ¹⁷ ,
wherein
R ¹⁶ and R ^{17 have} the meaning of R ¹⁴ and R ¹⁵ given above and are the same or different with this,
or
R ⁷ and R ⁸ and / or R ⁹ and R ¹⁰ and / or R ¹¹ and R ¹² together form radicals of the formula = O or = S.
and or
R ¹⁰ and R ¹¹ together form an endocyclic double bond,
R ^{1 represents} azido or a radical of the formula -OR ¹⁸ , -O-SO ₂ -R ¹⁹ or -NR ²⁰ R ²¹ ,
wherein
R ¹⁸ denotes hydrogen or straight-chain or branched acyl having up to 4 carbon atoms,
R ¹⁹ denotes straight-chain or branched alkyl having up to 4 carbon atoms or phenyl,
R ²⁰ and R ^{21 are} hydrogen,
or
R ²⁰ means hydrogen,
and
R ^{21 is} a radical of the formula

means
wherein
Q represents an oxygen or sulfur atom,
R ²² denotes straight-chain or branched alkoxy with up to 6 carbon atoms or trifluoromethyl, or
R ^{22 means} cyclopropyl, cyclopentyl, cycloheptyl, cyclobutyl or cyclohexyl, which are optionally substituted by fluorine, chlorine or phenyl, or
Phenyl, naphthyl, pyridyl, thienyl, oxazolyl, furyl, imidazolyl, pyridazolyl or pyrimidyl, the ring systems listed under R ²² optionally up to 2 times identical or different by fluorine, chlorine, bromine, cyano, nitro, hydroxy or phenyl are substituted,
or
R ²² denotes straight-chain or branched alkyl having up to 4 carbon atoms, optionally by phenoxy, benzyloxy, carboxyl, fluorine, chlorine, bromine or straight-chain or branched alkoxycarbonyl or acyl each having up to 4 carbon atoms or by pyridyl, thienyl, furyl or Pyrinlidyl is substituted,
or
R ^{22 represents} a radical of the formula -NR ²⁵ R ²⁶ ,
wherein
R ²⁵ and R ^{26 are} identical or different and represent hydrogen, phenyl, pyridyl or straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by morpholine which is bonded via N,
R ²³ and R ^{24 are} identical or different and are hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms,
R ^{2 represents} hydrogen, fluorine, chlorine, bromine or straight-chain or branched alkyl having up to 3 carbon atoms,
E represents hydrogen or fluorine, chlorine or bromine,
and their salts.

Compounds of the general formula (I) are particularly preferred
in which
A and D together with the nitrogen atom form a heterocyclic radical of the formula

form,
wherein
L and L 'are identical or different and represent an oxygen atom or a radical of the formula -NR ¹³ ,
wherein
R ¹³ denotes hydrogen, cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl, straight-chain or branched alkoxycarbonyl having up to 3 carbon atoms, or
straight-chain or branched acyl having up to 3 carbon atoms, which is optionally substituted by fluorine, chlorine, bromine, hydroxyl, amino or N, N-dimethylamino, straight-chain or branched alkoxy having up to 3 carbon atoms
or
straight-chain or branched alkyl having up to 3 carbon atoms, which is optionally substituted by fluorine, chlorine, bromine, cyano, methoxycarbonyl, ethoxycarbonyl, amino, N, N-dimethylamino or phenyl, which in turn is substituted by fluorine, chlorine, bromine or by straight-chain or branched alkyl, alkoxy or acyl, each having up to 3 carbon atoms,
R ³ , R ⁴ , R ⁵ and R ^{6 are} identical or different and are hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms, which is optionally substituted by fluorine, chlorine or bromine,
or
R ³ and R ⁴ and / or R ⁵ and R ⁶ together form radicals of the formula = O or = S,
R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ^{12 are the} same or different and are hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms, which may be substituted by hydroxyl, fluorine, chlorine, straight-chain or branched alkoxy or Alkoxycarbonyl with up to 3 carbon atoms, phenyl is substituted
or
R ⁷ and R ⁸ and / or R ⁹ and R ¹⁰ and / or R ¹¹ and R ¹² together form radicals of the formula = O or = S.
and or
R ¹⁰ and R ¹¹ together form an endocyclic double bond,
R ^{1 represents} azido or a radical of the formula -OR ¹⁸ , -O-SO ₂ -R ¹⁹ or -NR ²⁰ R ²¹ ,
wherein
R ¹⁸ denotes hydrogen or straight-chain or branched acyl having up to 3 carbon atoms,
R ¹⁹ denotes straight-chain or branched alkyl having up to 3 carbon atoms or phenyl,
R ²⁰ and R ^{21 are} hydrogen,
or
R ²⁰ means hydrogen,
and
R ^{21 is} a radical of the formula

means
wherein
Q represents an oxygen or sulfur atom,
R ²² denotes straight-chain or branched alkoxy with up to 4 carbon atoms or trifluoromethyl, or
R ^{22 means} cyclopropyl, cyclopentyl, cycloheptyl, cyclobutyl or cyclohexyl, which are optionally substituted by fluorine, chlorine or phenyl, or
Phenyl, naphthyl, pyridyl, thienyl, oxazolyl, furyl, inlidazolyl, pyridazolyl or pyrimidyl, the ring systems listed under R ²² optionally up to 2 times identical or different by fluorine, chlorine, bromine, cyano, nitro, hydroxy or phenyl are substituted,
or
R ²² denotes straight-chain or branched alkyl having up to 3 carbon atoms, optionally by phenoxy, benzyloxy, carboxyl, fluorine, chlorine, bromine or straight-chain or branched alkoxycarbonyl or acyl each having up to 3 carbon atoms or by pyridyl, thienyl, furyl or Pyrimidyl is substituted,
or
R ^{22 represents} a radical of the formula -NR ²⁵ R ²⁶ ,
wherein
R ²⁵ and R ^{26 are} identical or different and are hydrogen, phenyl, pyridyl or straight-chain or branched alkyl having up to 3 carbon atoms, which is optionally substituted by morpholine which is bonded via N,
R ^{2 represents} hydrogen, fluorine or straight-chain or branched alkyl having up to 3 carbon atoms,
E represents hydrogen or fluorine,
and their salts.

Compounds of the general formula (I) are very particularly preferred,
in which
A and D together for a remainder of the formula

in which
R ^{13 is} hydrogen, straight-chain or branched alkyl having up to 3 carbon atoms, which is optionally substituted by cyano, methoxycarbonyl, ethoxycarbonyl, amino, N, N-dimethylamino or by phenyl, or
straight-chain or branched acyl having up to 3 carbon atoms, which is optionally substituted by hydroxyl, amino or N, N-dimethylamino, or
Methoxycarbonyl means
E represents hydrogen or fluorine,
and
R ¹ for hydroxy or
represents a radical of the formula -OSO ₂ -CH ₃ , -NH-CO-R ²² or -NH-CS-R ²² ,
wherein
R ²² denotes straight-chain or branched alkyl or alkoxy each having up to 3 carbon atoms, amino, N-methylamino or N, N-dimethylamino,
R ^{2 represents} hydrogen fluorine,
and their salts.

R ¹ particularly preferably represents a radical of the formula -NH-CO-R ²² , in which R ²² can have the meanings given above.

In addition, processes for the preparation of the compounds of the general formula (I) according to the invention were found, characterized in that
[A] compounds of the general formula (II)

in which
A, D, E and R ^{2 have} the meaning given above,
first by a reduction in the compounds of the general formula (III)

in which
A, D, E and R ^{2 have} the meaning given above,
convicted,
in a next step with benzyl chloroformate the compounds of general formula (IV)

in which
A, D, E and R ^{2 have} the meaning given above,
manufactures,
and finally with bases in inert solvents and subsequent reaction with (R) - (-) - glycidyl butyrate the compounds of the general formula (Ia)

in which
A, D, E and R ^{2 have} the meaning given above,
manufactures,
or
[B] Compounds of the general formula (Ia) by reaction with (C ₁ -C ₄ ) -alkyl or phenylsulfonic acid chlorides in inert solvents and in the presence of a base in the corresponding compounds of the general formula (Ib)

in which
A, D, E, R ² and R ^{19 have} the meaning given above,
convicted,
then the azides of the general formula (Ic) with sodium azide in inert solvents

in which
A, D, E and R ^{2 have} the meaning given above,
manufactures,
in a further step by reaction with (C ₁ -C ₄ -O) ₃ -P or Ph ₃ P, preferably (CH ₃ O) ₃ P in inert solvents, and with acids, or by catalytic hydrogenation into the amines of the general formula (Id)

in which
A, D, E and R ^{2 have} the meaning given above,
convicted,
and by reaction with acetic anhydride, acetyl chloride or other acylating agents of the general formula (V)

Y-CO-R ²² (V)

in which
R ^{22 has} the meaning given above
and
Y represents halogen, preferably chlorine or the radical -OCOR ²² ,
in the presence of a base in inert solvents, the compounds of the general formula (Ie)

in which
A, D, E, R ² and R ^{22 have} the meaning given above,
manufactures,
or
[C] compounds of the general formula (III) by reaction with racemic and enantiomerically pure compounds of the general formula (VI)

in which
R ^{27 represents} radicals of the formulas NH-CO-R ²² , O-CO-R ²⁸ or NH-R ²⁹ ,
wherein
R ^{22 has} the meaning given above,
R ²⁸ denotes straight-chain or branched alkyl having up to 6 carbon atoms,
and
R ^{29 represents} an amino protecting group, preferably tert-butyloxycarbonyl,
possibly under the action of a catalyst, first in the compounds of the general formula (VII)

in which
A, D, E, R ² and R ^{27 have} the meaning given above,
convicted,
then to the compounds of the general formula (If)

in which
A, D, E, R ² and R ^{27 have} the meaning given above,
cyclized in inert solvents in the presence of carbonyldiimidazole,
and in the case of R ²⁷ = NHR ^29, the amino protective group is then split off in the hydrochloric acid / dioxane system with release of the amine function and then, as described under [A], with compounds of the general formula (V) to give the corresponding compounds with R ¹ = NHCO-R ²² implements
and in the case R ²⁷ = -O-CO-R ²⁸ , first reacted with potassium carbonate in methanol to give the compounds of the general formula (Ia) with R ¹ = OH and then a derivatization as described under [B].

The methods can be illustrated using the following formula schemes:

Amino protecting groups in the context of the invention are the usual ones in peptide chemistry amino protecting groups used. These preferably include: benzyloxycarbonyl, 2,4-dimethoxybenzvloxycarbonyl, 4-methoxybenzyloxycarbonyl, methoxycarbonyl, Ethoxycarbonyl, tert.butoxycarbonyl, allyloxycarbonyl, phthaloyl, 2,2,2-trichloroethoxycarbonyl, fluorenyl-9-methoxycarbonyl, formyl, acetyl, 2-chloroacetyl, Benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, phthalimido, isovaleroyl or  Benzyloxymethylene, 4-nitrobenzyl, 2,4-dinitrobenzyl, 4-nitrophenyl, 4-methoxyphenyl or triphenylmethyl.

The reductions can generally be carried out by hydrogen in water or in inert organic solvents such as alcohols, ethers or halogenated hydrocarbons or their mixtures with catalysts such as Raney nickel, palladium, palladium on animal charcoal or platinum or with hydrides or boranes in inert solvents, optionally in Presence of a catalyst.

The reductions with hydrides such as complex borohydrides or are preferred Aluminum hydrides and boranes performed. Are particularly preferred here Sodium borohydride, lithium borohydride, sodium cyanoborohydride, lithium aluminum hydride, Sodium bis (2-methoxyethoxy) aluminum hydride (Red-Al) or borane tetrahydrofuran used.

The reduction generally takes place in a temperature range from -50 ° C to respective boiling point of the solvent, preferably from -20 ° C to + 90 ° C.

Suitable solvents are all inert organic solvents, which are among the Do not change reaction conditions. These preferably include alcohols such as Methanol, ethanol, propanol or isopropanol or ethers such as diethyl ether, dioxane, Tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether or amides such as Hexamethylphosphoric triamide or dimethylformamide or acetic acid. It is the same possible to use mixtures of the solvents mentioned. Is particularly preferred Methanol.

The reaction with benzyl chloroformate is carried out in one of the above Ether, preferably with tetrahydrofuran.

Suitable bases are generally sodium hydrogen carbonate, sodium methoxide, Hydrazine hydrate, potassium carbonate or cesium carbonate. Sodium hydrogen is preferred carbonate.  

The base is used in an amount of 1 mol to 10 mol, preferably 1 mol to 3 mol based on 1 mol of the compounds of general formula (III) used.

The reaction is generally carried out in a temperature range from -30 ° C to + 30 ° C, preferably at 0 ° C.

The cyclization to compounds of general formula (Ia) is generally carried out in one of the ethers listed above, preferably in tetrahydrofuran.

Lithium alkyl compounds or are generally suitable as bases for this step Lithium-N-silylamides, such as n-butyllithium, lithium diisopropylamide or Lithium bistrimethylsilylamide, preferably lithium bis-trimethylsilylamide or n-butyllithium.

The base is used in an amount of 1 mol to 10 mol, preferably 1 mol to 3 mol based on 1 mol of the compounds of general formula (IV) used.

In general, in a temperature range from -78 ° C to -50 ° C, preferably at -78 ° C worked.

All implementations are generally normal, increased or decreased Pressure carried out (e.g. 0.5 to 5 bar). Generally one works at normal pressure.

The acylation step in process [B] is generally carried out in one of the above listed ethers or halogenated hydrocarbons, preferably tetrahydroturan or Methylene chloride, in a temperature range from -30 ° C to 50 ° C, preferably from -10 ° C to room temperature.

The reductions in process [B] are generally carried out using inert hydrides Solvents or with boranes, diboranes or their complex compounds.  

The reductions can generally be carried out by hydrogen in water or in inert organic solvents such as alcohols, ethers or halogenated hydrocarbons, or their mixtures with catalysts such as Raney nickel, palladium, palladium Animal charcoal or platinum, or with hydrides or boranes in inert solvents, optionally carried out in the presence of a catalyst.

The reductions with hydrides, such as complex borohydrides or Aluminum hydrides and boranes performed. Are particularly preferred here Sodium borohydride, lithium borohydride, sodium cyanoborohydride, lithium aluminum hydride, Sodium bis (2-methoxyethoxy) aluminum hydride or borane tetrahydrofuran used.

The reduction of the azides in process [B] is carried out with (CH ₃ O) ₃ P and hydrochloric acid.

The reduction generally takes place in a temperature range from -50 ° C to respective boiling point of the solvent, preferably from -20 ° C to + 90 ° C.

Suitable solvents are all inert organic solvents, which are among the Do not change reaction conditions. These preferably include alcohols such as Methanol, ethanol, propanol or isopropanol, or ethers such as diethyl ether, dioxane, Tetrahydrofuran, glycol dimethyl ether, or diethylene glycol dimethyl ether or amides such as Hexamethylphosphoric triamide or dimethylformamide, or acetic acid. It is the same possible to use mixtures of the solvents mentioned.

The usual solvents are suitable as solvents for process [C]. Are preferred Dichloromethane and chloroform for the reaction with the epoxy and THF for the Ring closure with carbonyldiimidazole (CD1).

In general, in a temperature range from -78 ° C to + 50 ° C, preferably at Worked at room temperature. The reaction temperature is at the ring closure with CDI between room temperature and the boiling point of tetrahydrofuran.  

All implementations are generally normal, increased or decreased Pressure carried out (e.g. 0.5 to 5 bar). Generally one works at normal pressure.

In the context of the invention, silica gel is suitable as a catalyst for process [C].

Suitable solvents for the alkylation are conventional organic solvents, which can be found under do not change the reaction conditions. These preferably include ethers such as Diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or hydrocarbons such as Benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions or Halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, Dichlorethylene, trichlorethylene or chlorobenzene or ethyl acetate or triethylamine, Pyridine, dimethyl sulfoxide, dimethylformamide, acetoritrile, acetone or nitromethane. It is also possible to use mixtures of the solvents mentioned. Are preferred Dichloromethane, dimethyl sulfoxide and dimethylformamide.

The alkylation is carried out in the solvents listed above at temperatures from 0 ° C to + 150 ° C, preferably at room temperature to + 100 ° C, carried out at normal pressure.

The amino protective group is generally cleaved off, likewise in the usual way Methods, split off and preferably Boc with hydrochloric acid in dioxane, Fmoc with Piperidine and Z with HBr / HOAc or by hydrogenolysis.

Some of the compounds of the general formula (II) are known or can be found in Analogy to methods known from the literature [cf. D.R. Shridhar et al. SYNTHESIS 1982, 986-987; Comprehensive Heterocyclic Chemistry Volume 4, 348-372 (1984); Houben-Weyl, Methods of Organic Chemistry, Volume, E6b2 915-1236, (1994)] getting produced.

The compounds of the general formulas (III), (IV) and (VII) are largely new and can then be produced, for example, as described above.  

The compounds of the general formulas (V) and (VI) are known per se or can be produced according to published procedures.

The compounds of the general formulas (Ia) - (If) are new and can be as above described.

The MIC values were determined using the microdilution method in BH medium. Each test substance was dissolved in the nutrient medium. Was in the microtiter plate serial dilution a concentration series of the test substances. For Inoculation overnight cultures of the pathogens were used that were previously in the nutrient medium Were diluted 1: 250. To 100 µl of the diluted nutrient solutions containing the active ingredient 100 µl of inoculation solution were given.

The microtiter plates were incubated at 37 ° C and after about 20 hours or after 3 to 5 days read. The MIC value (µg / ml) indicates the lowest active substance concentration where there was no growth.

MIC values (µg / ml)

The compounds of the general formulas (I), (Ia), (Ib), (Ic), (Id) according to the invention (Ie) and (If) show a broad antibacterial spectrum, especially with low toxicity against gram-positive germs and some gram-negative bacteria as well as mycobacteria, Corynebacteria, Haemophilus influenzae and anaerobic germs. These properties enable their use as chemotherapeutic agents in human and Veterinary medicine.

The compounds according to the invention are against a broad spectrum of Microorganisms effective. With their help gram-positive germs, gram-negative Fights bacteria and bacteria-like microorganisms such as mycoplasma as well as the Diseases caused by these pathogens prevented, improved and / or cured become.

The compounds 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 suitable, which are caused by such pathogens.

The present invention includes pharmaceutical preparations which, besides dir toxic, inert, pharmaceutically suitable carriers one or more Contain compounds of the invention, or those of one or more Active substances according to the invention exist, and methods for producing them Preparations.  

The active ingredient (s) may optionally be present in one or more of the above specified carrier substances are also present 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 per 24 hours, if necessary in the form of several single doses to achieve the desired results to administer. A single dose contains the active ingredient or ingredients according to the invention preferably in amounts of about 1 to about 80, in particular 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.  

Appendix to the experimental part List of the solvent mixtures used for chromatography

I dichloromethane: methanol
II toluene: ethyl acetate
III acetonitrile: water
IV ethyl acetate
V petroleum ether: ethyl acetate
VI CH ₂

Cl ₂

: CH ₃

OH: NH _{3 (aq)}

VII CH ₂

Cl ₂

: CH ₃

OH

Abbreviations

Z benzyloxycarbonyl
Boc tert-butoxycarbonyl
DMF dimethylformamide
Ph phenyl
Me methyl
THF tetrahydrofuran
CDI carbonyldiimidazole
DCE dichloroethane

Output connections Example I

5-nitro-indole-1,2-dicarboxylic acid ethyl ester

5.65 g (0.235 mol) of sodium hydride are dissolved in 1000 ml of absolute THF under argon. The mixture is cooled to 5 ° C. and 50 g (0.214 mol) of 5-nitro-indol-2-car ethyl acetate are added in portions. The mixture is stirred at 5 ° C. for 30 min, then the cooling is removed and the batch is stirred for a further 1 h at room temperature. Then 42.9 g (0.257 mmol) of ethyl bromoacetate are added and the mixture is stirred at room temperature. TLC control: ((silica gel) CH ₂ C1 ₂ ).

After stirring overnight, no starting material can be seen. The approach is carefully mixed with 200 ml of water and 500 ml of 10% citric acid. It is evaporated and the residue formed is suspended in water. The mixture is stirred and the product is suctioned off. It is washed well with water and then dried in a forced air cabinet.
Yield 63.7 g (92.9%)
R _f : 0.54 / dichloromethane
MS (DCI) 338 (M + NH ₄ ) ⁺

Example II

5-nitro-indole-1,2-dicarboxylic acid

63 g (0.197 mol) of the compound from Example I are dissolved in 1000 ml of THF. 0.5 l of 2N NaOH are added and the mixture is heated to 60.degree. TLC control: ((CH ₂ Cl ₂ (for starting material) CH ₂ Cl ₂ / CH ₃ OH / HCOOH = 100/10/8). After stirring overnight, the cleavage is complete. The batch is cooled and treated with 6N hydrochloric acid to pH 2. The THF is removed on a rotary evaporator and the residue is mixed with water and stirred in. The product precipitates on cooling. It is filtered off with suction and the residue is washed neutral with a little cold water. The product is in a circulating air cabinet at 75 ° C dried.
Yield: 54.97 g (93.6%)
MS (ESI) 265 (M + NH ₄ ) ⁺

Example III and Example IV

1- (2-hydroxyethyl) -2-hydroxymethyl-5-nitro-indole (Example III) and 1- (2-hydroxyethyl) -5-nitro-indole-2-carboxylic acid (Example IV)

54 g (0.204 mol) of the compound from Example II are dissolved in 1200 ml of THF under argon. It is cooled to 0 ° C. and 820 ml of BH3-THF complex (1 M in THF) are added via a dropping funnel. The mixture is stirred at 0 ° C. for 30 min, then brought to RT and stirred further at room temperature. TLC control: (silica gel CH ₂ Cl ₂ / CH ₃ OH = 100/5). After stirring overnight, no starting material can be detected, but according to HPLC it is still 18% of the monocarboxylic acid. Another 100 ml of BH ₃ -THF complex (1 M in THF) are added; however, no further reduction is discernible. The mixture is carefully mixed with 2N NaOH while cooling with ice until gas evolution is no longer discernible (pH = 8-9). 200 ml of water are added and the THF is removed on a rotary evaporator. Another 800 ml of water are added and the pH is adjusted to 2 with 6N HCL. The product which precipitates is stirred and then suction filtered, washed with water and then dried in a circulating air cabinet at 70.degree. According to HPLC mixture of 1- (2-hydroxyethyl) -2-hydroxymethyl-5 nitro-indole and 1- (2-hydroxyethyl) -5-nitro-indole-2-carboxylic acid in the ratio = 85/15. The extracted product is taken up in 3000 ml of ethyl acetate and extracted with 300 ml of 2N NaOH (10 times). The organic phase is 1 × with water and 1 × with saturated NaCl solution. washed, dried over MgSO ₄ and then spun in and dried in an HV. 21.8 g (44%) of 1- (2-hydroxyethyl) -2-hydroxymethyl-5-nitro-indole are obtained.
MS (DCI) 254 (M + NH ₄ ) ⁺.

The basic extracts are adjusted to pH 2 with ice cooling. The mixture is stirred and then suctioned off from the precipitated product and dried in the circulating air cabinet. 3.15 g (4.9%) of 1- (2-hydroxyethyl) -5-nitro-indole-2-carboxylic acid are thus obtained in a purity of 80%.
MS (ESI negative) 249 (MH) ⁻

Example V

1- (2-methanesulfonyl-ethyl) -2-hydroxymethyl-5-nitro-indole

3 g (12.7 mmol) of the compound from Example III are dissolved in 45 ml of pyrridine under argon. The mixture is cooled to 0 ° C. and 1.454 g (12.7 mmol) of methane sulfonic acid chloride are slowly added. There is a precipitation. The mixture is stirred at 0 ° C. TLC control: (Kieseigel CH ₂ Cl ₂ / CH ₃ OH = 100/5). The approach is implemented very slowly, starting material is still recognizable after 6 hours. A further 0.435 g of methanesulfonic acid chloride are therefore added and stirring is continued at room temperature. The batch is freed of pyridine on the rotary evaporator.
Crude yield: 1.6 g brown oil
The crude yield is purified on a silica gel column; Mobile phase CH ₂ Cl ₂ / CH ₃ OH = 100/2. In addition to the product, 0.83 g of starting material is also obtained.
Yield 0.42 g (10.5%)
R _f : 0.36 / (100/5 CH ₂ Cl ₂ / CH ₃ OH)

Example VI

8-nitro-3,4-dihydro- {1,4} oxazino [4,3-a] indole

60 mg (1.5 mmol) of sodium hydride suspended in 10 ml of THF are cooled to 0 ° C. under argon. A solution of 470 mg (1.5 mmol) of the compound from Example V in 10 ml of THF is added and the mixture is slowly brought to room temperature and stirred. TLC control: (CH ₂ Cl ₂ / CH ₃ OH = 100/5). After 6 hours no starting material can be seen. The approach is saturated with NaCl solution. added and extracted 3 × with 200 ml of ethyl acetate. The combined organic phases are 1 × with sat. NaCl solution. washed and then dried over MgSO ₄ . It is concentrated and dried at the HV.
Yield 505 mg (crude product)

Example VII

8-amino-3,4-dihydro- {1,4} oxazino [4,3-a] indole

350 mg (1.05 mmol) of the crude product of the compound from Example VI are dissolved in 15 ml of THF under argon. Two spatula tips of Raney nickel are added, and 0.31 ml (1.58 mmol) of a 25% aqueous hydrazine hydrate solution (vigorous gas evolution) is slowly added with stirring. The mixture is stirred at room temperature. TLC control: (CH ₂ Cl ₂ / CH ₃ OH = 100/5). After 15 minutes there is no longer any gas development. According to the DC, the approach to the desired product has been implemented. It is separated from the Raney nickel, washed several times and the solution is evaporated to dryness.
Crude yield: 202 mg.

The crude yield is purified on a silica gel column (mobile phase CH ₂ Cl ₂ / CH ₃ OH = 100/4). Suitable fractions are evaporated and dried in a high vacuum.
Yield 129.4 mg (65.4%)
R _f : 0.52 (100/5 CH ₂ Cl ₂ / CH ₃ OH)
MS (DCI) 189 (M + H) ⁺

Example VIII

(2R) -3- (3,4-Dihydro- {1,4} oxazino [4,3-a] indol-8-yl) amino-2-hydroxypropyl acetamide

140 mg (0.744 mmol) of the compound from Example VII are dissolved in 10 ml of CH ₂ Cl ₂ . 73 mg (0.632 mmol) of (2S) -2,3-epoxypropyl acetamide in 5.0 ml of CH ₂ Cl _{2 are added} , and 3.0 g of silica gel are added to the dark solution. It is evaporated to dryness and the resulting residue is left to stand at room temperature for 48 h. TLC control: (silica gel CH ₂ Cl ₂ / CH ₃ OH = 100/5). The mixture is placed on a silica gel column and eluted with CH ₂ Cl ₂ / CH ₃ OH = 100 / 7.5. Suitable fractions are concentrated and dried in a high vacuum. In addition to 66 mg of starting material, the desired product is obtained.
Yield 78.8 mg (41.1%)
R _f : 0.45 (10/1 CH ₂ Cl ₂ / CH ₃ OH)
MS (ES1) 304 (M + H) ⁺

Example IX

5-Amino-indole-2-carboxylic acid ethyl ester

10 g (42.7 mmol) of 5-nitro-indole-2-carboxylic acid ethyl ester are dissolved in 500 ml of methanol and 300 ml of THF. 1 g of palladium / carbon (10%) is added and hydrogen is consumed: 3200 ml. TLC control: (silica gel CH ₂ Cl ₂ / CH ₃ OH = 100/5). After 2 hours no more hydrogen uptake can be seen, according to DC the approach has been implemented. It is filtered off over kieselguhr and washed with methanol. It is rotated in and the resulting residue is mixed with diethyl ether. It is stirred out and then suctioned off. The solid is dried in an HV.
Yield 7.5 g (86%)
R _f : 0.5 (100/5 CH ₂ Cl ₂ / CH ₃ OH)
MS (ESI) 205 (M + H) ⁺

Example X

(2R, S) -3- (2-ethoxycarbonyl-indol-5-yl) amino-2-hydroxypropyl acetamide

Analogously to the procedure of Example VIII, the target product is obtained as a racemate from 10 g (49 mmol) of the compound from Example IX and 4.8 g (42 mmol) of (2S, R) -2,3-epoxy-propyl-acetamide.
Yield: 4.06 g (24%)
MS (ESI) 320 (M + H) ⁺

Example XI

3,4-dihydro-8-nitro- {1,4} oxazino [4,3-a] indol-1-one

3.1 g of the compound from Example IV are suspended in 100 ml of toluene, mixed with 0.68 g of p-toluenesulfonic acid and boiled on a water separator. TLC control: (silica gel CH ₂ Cl ₂ / CH ₃ OH = 100/5). After stirring overnight, no starting material can be seen. The mixture is brought into solution with methylene chloride, drawn up on silica gel and purified on a silica gel column (mobile phase CH ₂ Cl ₂ / CH ₃ OH = 100/2). Suitable fractions are evaporated and dried at the HV. 2.14 g (91.5%) of the desired product are obtained.
R _f : 0.8 (100: 5 CH ₂ Cl ₂ / CH ₃ OH)
MS (ESI) 233 (M + H) ⁺

Example XII

3,4-dihydro-8-amino- {1,4} oxazino [4,3-a] indol-1-one

Under argon, 1 g (4.3 mmol) of the compound from Example M in 150 ml of THF solved. A spatula tip of Raney nickel is added. While stirring slowly 1.26 ml (6.46 mmol) of a 25% hydrazine hydrate solution in water (strong Gas evolution) and stirred at room temperature. TLC control: pebble gel / pure ethyl acetate). After 1 hour, no gas evolution can be seen. The approach is decanted from the THF. The residue is stirred 5 times with THF and in each case  decanted. The combined THF fractions are filtered through kieselguhr and then evaporated to dryness. The resulting residue is mixed with diethyl ether, briefly stirred and then vacuumed. You dry in the HV. Crude yield: 728.6 mg yellow solid, which is used for the subsequent reactions.

Example XIII

(5R) -3- (3,4-Dihydro-1-oxo - {(1,4} oxazino [4,3-a] indol-8-yl) amino-2-hydroxypropyl acetamide

240 mg of the compound from Example XII and 171 mg (2S) -2,3-epoxypropyl acetamide are dissolved in 10 ml of methylene chloride. 5 g of silica gel (40-63 μm) are added and the mixture is rotated to dryness. The mixture is left to stand at room temperature for 2 days. TLC control: (silica gel CH ₂ Cl ₂ / CH ₃ OH = 100/5). The mixture is poured onto 100 g of silica gel and eluted with CH ₂ Cl ₂ / CH ₃ OH = 100 / 7.5. 76.1 mg of the target product are obtained.
R _f : 0.11 (100/5 CH ₂ Cl ₂ / CH ₃ OH)
MS (DCI) 318 (M + H) ⁺

Example XIV

(5R) -3- (3,4-Dihydro-1-oxo {1,4} oxazino [4,3a] indol-8-yl) amino-2-hydroxypropyl carbamic acid methyl ester

Analogously to the procedure of Example XIII, 359 mg of the target product are obtained from 240 mg of the compound of Example XII and 173 mg of (2S) -2,3-epoxypropylcarbamic acid methyl ester.
R _f : 0.23 (100/5 CH ₂ Cl ₂ / CH ₃ OH)
MS (DCI) 334 (M + H) ⁺

Example XV

(5R) -3- (3,4-Dihydro-1-oxo {1,4} oxazino [4,3-a] indol-8-yl) amino-2-hydroxypropyl propionamide

Analogously to the procedure of Example XIII, 182 mg of the target product are obtained from 240 mg of the compound of Example XII and 204 mg (2S) -2,3-epoxypropylpropionamide.
R _f : 0.18 (100/5 CH ₂ Cl ₂ / CH ₃ OH)
MS (DC1) 332 (M + H) ⁺

Example XVI

2-methylaminomethyl-5-nitro-indole

6.1 g (27.8 mmol) of the compound of Example XXVI in 120 ml of THF are mixed with 7.92 ml (83.5 mmol) of a 1 M solution of borane-dimethyl sulfide in THF and heated under reflux. After 2 h, another 2.6 ml of the 1 M borane-dimethylsulfide solution in THF are added and the mixture is heated under reflux for a further 3 h. After cooling, 230 ml of 6 M HCl are added, the mixture is heated at 80 ° C. for 2 h, cooled, made alkaline with 500 ml of 3N NaOH, extracted 5 times with EA, the combined organic phases are washed with sat. Washed NaHCO ₃ solution, dried (MgSO ₄ ), filtered and evaporated. The crude product is chromatographed on silica gel (dichloromethane / methanol 50: 1). 1.3 g of the title compound are obtained as a light yellow oil.
MS (ESI): 206 (M + H)

Example XVII

1,2-dihydro-2-methyl-7-nitro-imidazo [1,5-a] indol-3-one

210 mg (1.02 mmol) of the compound of Example XVI in 100 ml of DMF are heated to 100-110 ° C., and 249 mg (1.53 mmol of carbonyldiimidazole in 8 ml of DMF are added in portions over 40 min. The mixture is heated for a total of 3 h, provided after cooling with 1M HCl acid and extracted 5 times with EA, the combined organic phases are dried (MgSO ₄ ), evaporated and the residue chromatographed on silica gel (dichloromethane / methanol 100: 1). 132 mg of the title compound are obtained.
MS (ES1): 232 (M + H)

Example XVIII

7-amino-1,2-dihydro-2-methylimidazo [1,5-a] indol-3-one

135 mg (0.58 mmol) of the compound of Example XVII and 152 mg (2.34 mmol) of ammonium formate are mixed with 150 mg of 10% palladium on activated carbon in 30 ml of ethanol and heated under reflux for 15 min. The catalyst is filtered off, the filtrate is spun in and the residue is mixed with 1 M ammonium chloride solution and extracted 3 times with chloroform. The combined organic phases are dried (MgSO ₄ ) and evaporated. 94 mg of the amine of the title compound are obtained.
MS (ESI): 202

Example XIX

(2R, S) -3- (1,2-dihydro-2-methyl-3-oxo-imidazo [1,5-a] indol-7-yl) amino-2-hydroxy propyl acetamide

Analogously to the procedure of Example VIII, the target product is obtained as a racemate from the compound of Example XVIII and (2S, R) -2,3-epoxy-propyl-acetamide.
Yield: 67%
MS (ESI): 317 (M + H)

Example XX

1- (N, N-Benzyl-methyl-2-aminoethyl) -5-nitroindole-2-carboxylic acid ethyl ester

20 g (0.854 mol) of 5-nitroindole-2-carboxylic acid ethyl ester are placed in 800 ml of dimethylformamide and 18.9 g (0.859 mol) of N- (2-chloroethyl) methylbenzylamine hydrochloride are added. Then 7.49 g (1.95 mol) of sodium hydride (60%) are slowly added and the mixture is heated under reflux for one hour. All volatile components are removed in vacuo, the residue is mixed with water, extracted with dichloromethane, dried over sodium sulfate and evaporated. The crude product is chromatographed on silica gel (mobile phase CH ₂ Cl ₂ ).
Yield: 17.6 g (54% of theory)
Mp: 113-115 ° C
R _f (I, 100: 4): 0.71

Example XXI

8-amino-3,4-dihydro-2-methyl-2H-pyrazino [1,2-a] indol-1-one

45.9 g (0.12 mol) of the compound of Example XX are hydrogenated in 850 ml of ethanol and 46 ml of water with 10.53 g of palladium hydroxide at 60 ° C. and 50 bar. The catalyst is suctioned off over Celite and the solvents are spun in. The crude product is chromatographed on silica gel (mobile phase: dichloromethane / methanol 100: 4).
Yield: 16.37 g (63% of theory)
Mp: 240-244 ° C
R _f (I, 100: 4): 0.36

Example XXII

8- (Benzyloxycarbonylamino) -3,4-dihydro-2-methyl-2H-pyrazino [1,2-a] indol-1-one

5.56 g (25.8 mmol) of the compound from Example XXI are in 53 ml of water, 44 ml THF and 53 ml of saturated sodium bicarbonate solution presented. At 0 ° C who added 4.14 ml benzyl chloroformate and stirred for 30 minutes.  

It is extracted with dichloromethane, the organic phase is dried over sodium sulfate and evaporated. The crude product is chromatographed on silica gel (mobile phase: dichloromethane / methanol 100: 3).
Yield: 7.55 g (83% of theory)
Mp: 213 ° C
R _f (I, 9: 1): 0.68

Example XXIII

(2R) -3- (3,4-Dihydro-2-methyl-1-oxo-2H-pyrazino [1,2-a] indol-8-yl) amino-2-hydroxy propyl acetamide

1.08 g (5 mmol) of the compound from Example XXI and 0.69 g (5.99 mmol) of (R) -2,3-epoxypropyl-1-acetamide are dissolved in 100 ml of chloroform with 12.5 g of silica gel for two days cooked under reflux. The solvent is spun in and the product is purified by chromatography on silica gel (mobile phase: dichloromethane / methanol 100: 4).
Yield: 0.665 g (40% of theory)
R _f (I, 10: 1): 0.21

Example XXIV

2,3-dihydro-2-methyl-8-nitro-pyrazino [1,2-a] indole-1,4-dione

1 g (4.884 mmol) of 5-nitro-indole-2-carboxylic acid are stirred with 12 ml of thionyl chloride in 40 ml of THF for two hours at room temperature. All volatile components are removed in vacuo, the residue is mixed with methyl tert-butyl ether and evaporated again. The suspension of the acid chloride obtained above in 40 ml of dichloromethane is then added to the solution of 0.76 g (4.95 mmol) of Sarco sinethylester hydrochloride and 1 g (10 mmol) of triethylamine in 20 ml of dichloromethane at 0 ° C. The mixture is stirred for one hour while warming to room temperature. The mixture is mixed with water, extracted thoroughly with dichloromethane, the organic phase dried over sodium sulfate and evaporated. The crude product is chromatographed on silica gel (mobile phase: dichloromethane / methanol 10: 1).
Yield: 0.697 g (55% of theory)
Mp: 248-249 ° C
R _f (1.50: 1): 0.24

Example XXV

8-amino-2,3-dihydro-2-methyl-pyrazino [1,2-a] indole-1,4-dione

0.50 g (1.93 mmol) of the compound from Example XX1V are refluxed with 0.48 g (7.7 mmol) of ammonium formate and 80 mg of Pd / C (10%) in 30 ml of ethanol for 90 minutes. The catalyst is suctioned off through Celite and washed well with DMF. The solvents are removed in vacuo.
Yield: 346 mg (78% of theory)
R _f (I, 20: 1): 0.29

Example XXVI

5-nitro-indole-2-carboxylic acid methylamide

8.30 g (40.3 mmol) of 5-nitro-indole-2-carboxylic acid are stirred with 90 ml of thionyl chloride in 350 ml of THF for two hours at room temperature. All volatile components are removed in vacuo, the residue is mixed with methyl tert-butyl ether and evaporated again. The residue is taken up in 250 ml of THF and 44.3 ml of a 2 M methylamine solution in THF are added dropwise at 0.degree. While heating to room temperature, the mixture is stirred under DC control until the reaction is complete. All volatile components are removed in vacuo, the residue is mixed with water and extracted with dichloromethane. The organic phase is dried over sodium sulfate and evaporated. The crude product is chromatographed on silica gel (mobile phase: dichloromethane / methanol 50: 1 → 20: 1 → 10: 1).
Yield: 6.63 g (75% of theory)
Mp: <310 ° C
R _f (I, 10: 1): 0.46

Example XXVII

2-methyl-8-nitro-pyrazino [1,2-a] indole-1,3,4-trione

3.48 g (15.0 mmol) of the compound from Example XXVI are introduced under argon in 80 ml of pyridine and 80 ml of dichloromethane. A solution of 8.69 g (63 mmol) of ethyl chloroformyl formate in 80 ml of dichloromethane is added dropwise at 0 ° C. While warming to room temperature, the mixture is stirred overnight. All volatile components are removed in vacuo, the residue is mixed with water and extracted thoroughly with dichloromethane. The organic phase is dried over sodium sulfate and evaporated.
Yield: 4.2 g (96% of theory)
Mp: 281-286 ° C
R _f (I, 20: 1): 0.31

Example XXVIII

8-amino-2-methyl-pyrazino [1,2-a] indole-1,3,4-trione

200 mg (0.73 mmol) of the compound from Example XXVII are refluxed with 180 mg (2.9 mmol) of ammonium formate and 30 mg of Pd / C (10%) in 15 ml of ethanol for 90 minutes. The catalyst is filtered off with Celite and washed well with DMF. The solvents are spun in, the residue is mixed with water, the pH is adjusted to 8 with concentrated ammonia solution and extracted with dichloromethane. The organic phase is dried over sodium sulfate and rotated.
Yield: 58 mg
Mp: <320 ° C
R _f (I, 20: 1): 0.42

Example XXIX

(5R, S) -3- (2-ethoxycarbonylindol-5-yl) -5-acetaminomethyl-2-oxazolidinone

Analogously to the procedure of Example 1, the desired product is obtained from 4 g (10 mmol) of the compound from Example X and 2.44 g (15 mmol) of CDI.
Yield: 3 g (85%)
R _f : 0.22 (CH ₂ Cl ₂ / CH ₃ OH = 100: 5)
MS (ESI) 346 (M + H)

Example XXX

1,2-dihydro-2-methyl-8-nitro-4H-pyrazino [1,2-a] indol-3-one

460 mg (2.24 mmol) of the compound of Example XVI in 10 ml of dichloromethane are mixed with 1.24 ml (9 mmol) of triethylamine and then with 434 mg (2.47 mmol) of chloroacetic anhydride. The mixture is stirred for 30 min at room temperature, partitioned between water and dichloromethane, filtered off insoluble matter, the aqueous phase is washed with dichloromethane and the combined phases are evaporated. The crude product is chromatographed on silica gel (dichloromethane / methanol 100: 1). 210 mg of the chloroacetamide are obtained. 200 mg (0.71 mmol) of this intermediate compound are stirred in 30 ml of acetone after adding 5 g of potassium carbonate powder overnight at room temperature. It is filtered, the filtrate is concentrated and the residue is chromatographed on silica gel (dichloromethane / methanol 100 / 0.5). 89 mg of the target compound are obtained.
MS (DCI): 263 (M + NH ₄ ) ⁺

Example XXXI

8-amino-1,2-dihydro-2-methyl-4H-pyrazino [1,2-a] indol-3-one

89 mg (0.36 mmol) of the compound of Example XXX and 94 mg (1.45 mmol) of ammonium formate are mixed in 10 ml of ethanol with 200 mg of 10% palladium on activated carbon and heated under reflux for 5 min. The catalyst is filtered off, washed well with ethanol, the filtrate is spun in and dried under high vacuum. 65 mg of the amine are obtained.
MS (DCI): 216 (M + H) ⁺

Example XXXII

(2R) -3- (1,2-Dihydro-2-methyl-3-oxo-4H-pyrazino [1,2-a] indol-8-yl) amino-2-hydroxy propylacetamide

The target product is obtained analogously to the regulation of Example XIII.
Yield: 33%
MS (ES1): 331 (M + H) ⁺

Example XXXIII

1- (N-Benzyl-2-aminoethyl) -5-nitroindole-2-carboxylic acid ethyl ester

Analogously to the procedure of Example XX, the title compound is obtained in the reaction with 2-chloroethylbenzylamine.
Yield: 57% of theory
Mp: 122 ° C
R _f (dichloromethane): 0.57

Example XXXIV

8-amino-3,4-dihydro-2H-pyrazino [1,2-a] indol-1-one

Analogously to the rule of Example XXI, the title compound is obtained in the implementation of the compound XXXIII.
Yield: 55% of theory
Mp: 259 ° C
R _f (I, 10: 1): 0.35

Example XXXV

(2R) -3- (3,4-Dihydro-1-oxo-2H-pyrazino [1,2-a] indol-8-yl) amino-2-hydroxypropyl acetamide

Analogously to Example XXIII, the title compound is obtained in the reaction of the compound from Example XXXIV.
Yield: 67% of theory
R _f (1.5: 1): 0.3

Example XXXVI

(2R) -3- (2,3-Dihydro-1,4-dioxo-2H-pyrazino [1,2-a] indol-8-yl) amino-2-hydroxy-propyl acetamide

Analogously to Example XXIII, the title compound is obtained in the reaction of the compound from Example XXV.
Yield: 31% of theory
R _f (I, 10: 1): 0.23

Example XXXVII

(2R) -3- (1,3,4-Trioxo-2H-pyrazino [1,2-a] indol-8-yl) amino-2-hydroxypropyl acetamide

Analogously to Example XXIII, the title compound is obtained in the reaction of the compound from Example XXVIII.
Yield: 6% of theory
R _f (I, 10: 1): 0.33

Manufacturing examples example 1

(5S) -3- (3,4-Dihydro- {1,4} oxazino [4,3-a] indol-8-yl) -5-acetaminomethyl-2-oxazolidi non

73.7 mg (0.243 mmol) of the compound from Example VIII are dissolved in 3 ml of THF under argon. 79 mg (0.486 mmol) of CDI are added, the mixture is heated to reflux and the mixture is stirred overnight. TLC control: (CH ₂ Cl ₂ / CH ₃ OH = 10/1). Another 39 mg (0.243 mmol) of CDI are added and the mixture is stirred for 6 h. The mixture is cooled, evaporated to dryness and purified on a silica gel column. Mobile solvent CH ₂ Cl ₂ : CH ₃ OH = 100: 7.5. Appropriate fractions are pooled and evaporated. It is dried at the HV.
Yield 60.3 mg (75.4%)
R _f : 0.55 (10/1 CH ₂ Cl ₂ / CH ₃ OH)
MS (ESI) 330 (M + H)

Example 2

(5R, S) -3- (2-Benzylimidazo [1,5-a] indole-1,3-dione-7-yl -) - 5-acetaminomethyl-2-oxazoidininone

20 mg (0.058 mmol) of the compound from Example XXIX, 16 mg (0.116 mmol) of benzyl isocyanate and 5.9 mg (0.058 mmol) of triethylamine are added together under argon and heated to 80.degree. At this temperature, stirring is continued under DC control. TLC control: (silica gel CH ₂ Cl ₂ / CH ₃ OH = 100/5). After 1.5 h no starting material can be seen. The mixture is cooled and dissolved in 1 ml of methylene chloride. The solution is applied to 2 TLC silica gel plates (10 × 20 cm) and eluted with CH ₂ Cl ₂ / CH ₃ OH. 3.9 mg (15.5%) of the desired compound are obtained.
R _f : 0.19 (100/5 CH ₂ Cl ₂ / CH ₃ OH)
MS (ESI) 433 (M + H)

Analogous to the rule of Example 2, the verb in Table 1 are manufactured:  

Table 1

Example 10

(5S) -3- (3,4-Dihydro-1-oxo {1,4} oxazino [4,3-a] indol-8-yl) -5-acetaminomethyl-2-oxazolidinone

Analogously to the procedure of Example 1, 26 mg (31%) of the target product is obtained from 76 mg of the compound from Example XIII and 58 mg of CDI in 10 ml of THF.
R _f : 0.42 (10/1 CH ₂ Cl ₂ / CH ₃ OH)
MS (ESI) 344 (M + H) ⁺

Example 11

(5S) -3- (3,4-Dihydro-1-oxo {1,4} oxazino [4,3-a] indol-8-yl) -5-carbomethoxymethyl-2-oxazolidinone

Analogously to the instructions in Example 1, from 350 mg of the compound from Example XIV and 255 mg of CDI in 10 ml of THF, 53 mg (14%) of the target product.
R _f : 0.34 (ethyl acetate)
MS (ESI) 360 (M + H) ⁺

Example 12

(5S) -3- (3,4-Dihydro-1-oxo {1,4} oxazino [4,3-a] indol-8-yl) -5-propionaminomethyl-2-oxazolidinone

Analogously to the procedure of Example 1, 11.7 mg (6%) of the target product is obtained from 180 mg of the compound from Example XV and 132 mg of CDI in 10 ml of THF.
R _f : 0.51 (10/1 CH ₂ Cl ₂ / CH ₃ OH)
MS (DCI) 358 (M + H) ⁺

Example 13

(5R, S) -3- (1,2-dihydro-2-methyl-3-oxo-imidazo [1,5-a] indol-7-yl) -5-acetylaminomethyl-oxazolidin-2-one

Analogously to the procedure of Example 1, the title compound is obtained from the combination of Example XIX and CDI.
Yield: 27%
MS (ESI): 343 (M + H)
R _f : 0.46 (dichloromethane / methanol 10: 1)

Example 14

3,4-dihydro-8- [5- (R) - (hydroxymethyl) -2-oxo-3-oxazolidinyl)] - 2-methyl-3,4-dihydro-2H-pyrazino [1,2-a] indole -1-on

6.1 g (17.46 mmol) of the compound from Example XII are placed in 78 ml of THF pa at -78 ° C. 7 ml (17.5 mmol) of 2.5 M n-butyllithium in hexane are added dropwise by first adding 1/3 of the amount, and the remaining 2/3 together with 2.5 ml (17.5 mmol ) (R) glycidyl butyrate can be added. It is stirred overnight while warming to room temperature. The mixture is mixed with 87 ml of saturated ammonium chloride solution. The precipitate is separated off and the organic phase is spun in. The combined crude products are refluxed in methanol with 2 g of cesium carbonate under TLC control. All volatile components are removed in vacuo and the residue is chromatographed on silica gel (mobile phase: dichloromethane: methanol 100: 5).
Yield: 2.85 g (52% of theory)
Mp: 263 ° C
R _f (I, 100: 5): 0.19

Example 15

3,4-dihydro-8- [5- (R) - (methylsulfonyloxymethyl) -2-oxo-3-oxazolidinyl] -2-methyl-2H-pyrazino [1,2-a] indol-1-one

1.3 g (4.3 mmol) of the compound from Example 14 are placed in 70 ml of pyridine. 0.5 ml of methanesulfonic acid chloride are added and the mixture is stirred at room temperature until the reaction is complete. The mixture is poured onto ice water and the product is suctioned off.
Yield: 720 mg (43% of theory)
R _f (1.9: 1) 0.6

Example 16

8- [5 (R) - (Azidomethyl) -2-oxo-3-oxazolidinyl] -3,4-dihydro-2-methyl-2H-pyrazino [1,2-a] indol-1-one

1.6 g (4 mmol) of the compound from Example 15 are heated at 70 ° C. for 8 hours with 780 mg (11.9 mmol) of sodium azide in 5 ml of DMF. The mixture is poured onto ice water and the product is isolated.
Yield: 770 mg (56% of theory)
Mp: 175-180 ° C
R _f (I, 9: 1): 0.57

Example 17

8- [5 (S) - (Aminomethyl) -2-oxo-3-oxazolidinyl] -3,4-dihydro-2-methyl-2H-pyrazino- [1,2-a] indol-1-one hydrochloride

770 mg (2.26 mmol) of the compound from Example 16 are stirred in 1.8 ml of ethylene glycol dimethyl ether and 0.316 ml of trimethyl phosphite at 100 ° C. until the reaction is complete. The cooled batch is mixed with 0.452 ml of 6N hydrochloric acid and boiled again under reflux until the reaction is complete. The solvent is removed and the residue is triturated with methanol.
Yield: 790 mg (quantitative)
Mp: <260 ° C
R _f (1.5: 1): 0.11

Example 18

(5S) -3- (3,4-Dihydro-2-methyl-1-oxo-2H-pyrazino [1,2-a] indol-8-yl) -5-acetaminomethyl-2-oxazolidinone

Regulation A

150 mg (0.428 mmol) of the compound from Example 17 are dissolved in 20 ml of dichloromethane and 0.1 g (0.94 mmol) of triethylamine and then 40 mg (0.449 mmol) of acetyl chloride are added at 0-5 ° C. After one hour, the mixture is placed directly on a silica gel column and chromatographed with dichloromethane / methanol 100: 4. The product is brought to crystallization with ethyl acetate.
Yield: 117 mg (76% of theory)
Mp: 243 ° C
R _f (I, 10: 1): 0.30

Regulation B

665 mg (2 mmol) of the compound from Example XXIII and 392 mg (2.4 mmol) of carbonyldiimidazole are refluxed in 50 ml of THF for three hours. After adding 195 mg (1.2 mmol) of carbonyldiimidazole, the mixture is boiled again for 4 hours. The solvent is removed in vacuo, the residue is mixed with water and extracted with dichloromethane. The organic phase is dried over sodium sulfate and evaporated. The crude product is chromatographed on silica gel (mobile phase: dichloromethane / methanol 100: 4).
Yield: 433 mg (63% of theory)
Mp: 241 ° C
R _f (I, 10: 1): 0.30.

Analogous to the instructions in Example 18A, those listed in Table 2 are listed Connections established:

Table 2

Example 21

(5S) -3- (1,2-Dihydro-2-methyl-3-oxo-4H-pyrazino [1,2-a] indol-8-yl) -5-acetaminomethyl-2-oxazolidinone

The target product is obtained in the same way as in Example 1.
Yield: 31%
MS (DCI): 357 (M + H) ⁺, 374 (M + NH ⁴ ) ⁺
R _f : 0.56 (dichloromethane / methanol 10: 1).

Analogous to the specification of example 18 (specification B), the values in table 3 Connections listed:

Table 3

Claims (7)

1. oxazolidinones of the general formula (I)
in which
A and D together with the nitrogen atom, a heterocyclic radical of the formula
form,
wherein
L and L 'are identical or different and represent an oxygen atom or a radical of the formula -NR ¹³ ,
wherein
R ^{13 is} hydrogen, carboxyl, cycloalkyl having 3 to 6 carbon atoms, straight-chain or branched alkoxycarbonyl having up to 6 carbon atoms, or
straight-chain or branched acyl with up to 6 carbon atoms, which is optionally substituted by halogen, hydroxy, straight-chain or branched alkoxy with up to 5 carbon atoms or by a group of the formula -NR ¹⁴ R ¹⁵ ,
wherein
R ¹⁴ and R ^{15 are the} same or different and are hydrogen, phenyl or straight-chain or branched alkyl having up to 5 carbon atoms,
or
straight-chain or branched alkyl or alkenyl each having up to 6 carbon atoms, which are optionally substituted by cyano, halogen, carboxyl, straight-chain or branched alkoxycarbonyl having up to 5 carbon atoms or by a group of the formula -NR ^{14 '} R ^15' ,
wherein
R ^{14 '} and R ^{15' have} the meaning of R ¹⁴ and R ¹⁵ given above and are the same or different with this,
and / or alkyl or alkenyl are optionally substituted by aryl having 6 to 14 carbon atoms, which in turn can be substituted by halogen or by straight-chain or branched alkyl, alkoxy or acyl each having up to 6 carbon atoms,
R ³ , R ⁴ , R ⁵ and R ^{6 are} identical or different and are hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by halogen,
or
R ³ and R ⁴ and / or R ⁵ and R ⁶ together form radicals of the formula = O, or = S,
R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ^{12 are the} same or different and are hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, optionally by hydroxy, halogen, straight-chain or branched alkoxy or alkoxycarbonyl with each up to 6 carbon atoms, aryl with 6 to 10 carbon atoms or substituted by a group of the formula -NR ¹⁶ R ¹⁷ ,
wherein
R ¹⁶ and R ^{17 have} the meaning of R ¹⁴ and R ¹⁵ given above and are the same or different with this,
or
R ⁷ and R ⁸ and / or R ⁹ and R ¹⁰ and / or R ¹¹ and R ¹² together form radicals of the formula = O or = S.
and or
R ¹⁰ and R ¹¹ together form an endocyclic double bond,
R ^{1 represents} azido or a radical of the formula -OR ¹⁸ , -O-SO ₂ -R ¹⁹ or -NR ²⁰ R ²¹ ,
wherein
R ¹⁸ denotes hydrogen or straight-chain or branched acyl having up to 6 carbon atoms,
R ¹⁹ denotes straight-chain or branched alkyl having up to 6 carbon atoms or phenyl,
R ²⁰ and R ^{21 are} hydrogen,
or
R ²⁰ means hydrogen,
and
R ^{21 is} a radical of the formula
means
wherein
Q represents an oxygen or sulfur atom,
R ²² denotes straight-chain or branched alkoxy having up to 8 carbon atoms or trifluoromethyl, or
R ²² denotes cycloalkyl having 3 to 6 carbon atoms, which is optionally substituted by halogen or aryl having 6 to 10 carbon atoms, or
Aryl with 6 to 10 carbon atoms or a 5- to 6-membered saturated or aromatic heterocycle with up to 3 heteroatoms from the series S, N and / or O means, the ring systems listed under R ²² optionally up to 2 times the same or are differently substituted by halogen, cyano, nitro, hydroxy or phenyl,
or
R ²² denotes straight-chain or branched alkyl having up to 6 carbon atoms, optionally by phenoxy, benzyloxy, carboxyl, halogen or straight-chain or branched alkoxycarbonyl or acyl each having up to 6 carbon atoms or by a 5- to 6-membered heterocycle from the Row S, N and / or O is substituted,
or
R ^{22 represents} a radical of the formula -NR ²⁵ R ²⁶ ,
wherein
R ²⁵ and R ^{26 are} identical or different and represent hydrogen, phenyl, pyridyl or straight-chain or branched alkyl having up to 5 carbon atoms, which is optionally substituted by morpholine which is bonded via N,
R ²³ and R ^{24 are} identical or different and are hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,
R ^{2 represents} hydrogen, halogen or straight-chain or branched alkyl having up to 4 carbon atoms,
E represents hydrogen or halogen,
and their stereoisomers and salts. 2. oxazolidinones of the general formula (I) according to claim 1, in which
A and D together with the nitrogen atom, a heterocyclic radical of the formula
form
wherein
L and L 'are identical or different and represent an oxygen atom or a radical of the formula -NR ¹³ ,
wherein
R ¹³ denotes hydrogen, cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl straight-chain or branched alkoxycarbonyl having up to 4 carbon atoms, or straight-chain or branched acyl having up to 4 carbon atoms, which may be replaced by fluorine, chlorine, bromine, hydroxyl, straight-chain or ver branched alkoxy with up to 4 carbon atoms or substituted by a group of the formula -NR ¹⁴ R ¹⁵ ,
wherein
R ¹⁴ and R ^{15 are} identical or different and mean hydrogen, phenyl or straight-chain or branched alkyl having up to 4 carbon atoms,
or
straight-chain or branched alkyl or alkenyl each having up to 4 carbon atoms, which are optionally substituted by fluorine, chlorine, bromine, cyano, methoxycarbonyl, ethoxycarbonyl, amino, N, N-dimethylamino or phenyl, which in turn is substituted by fluorine, chlorine, bromine or can be substituted by straight-chain or branched alkyl, alkoxy or acyl each having up to 4 carbon atoms,
R ³ , R ⁴ , R ⁵ and R ^{6 are} identical or different and represent hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by fluorine, chlorine or bromine,
or
R ³ and R ⁴ and / or R ⁵ and R ⁶ together form radicals of the formula = O or = S,
R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ^{12 are the} same or different and are hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, optionally by hydroxyl, fluorine, chlorine, bromine, straight-chain or branched Alkoxy or alkoxycarbonyl each having up to 4 carbon atoms, phenyl or substituted by a group of the formula -NR ¹⁶ R ¹⁷ ,
wherein
R ¹⁶ and R ^{17 have} the meaning of R ¹⁴ and R ¹⁵ given above and are the same or different with this,
or
R ⁷ and R ⁸ and / or R ⁹ and R ¹⁰ and / or R ¹¹ and R ¹² together form radicals of the formula = O or = S.
and or
R ¹⁰ and R ¹¹ together form an endocyclic double bond,
R ^{1 represents} azido or a radical of the formula -OR ¹⁸ , -O-SO ₂ -R ¹⁹ or -NR ²⁰ R ²¹ ,
wherein
R ¹⁸ denotes hydrogen or straight-chain or branched acyl having up to 4 carbon atoms,
R ¹⁹ denotes straight-chain or branched alkyl having up to 4 carbon atoms or phenyl,
R ²⁰ and R ^{21 are} hydrogen,
or
R ²⁰ means hydrogen,
and
R ^{21 is} a radical of the formula
means
wherein
Q represents an oxygen or sulfur atom,
R ²² denotes straight-chain or branched alkoxy having up to 6 carbon atoms or trifluoromethyl, or
R ^{22 means} cyclopropyl, cyclopentyl, cycloheptyl, cyclobutyl or cyclohexyl, which are optionally substituted by fluorine, chlorine or phenyl, or
Phenyl, naphthyl, pyridyl, thienyl, oxazolyl, furyl, imidazolyl, pyridazolyl or pyrimidyl, the ring systems listed under R ²² optionally up to 2 times the same or different by fluorine, chlorine, bromine, cyano, nitro, hydroxyl or phenyl sub are established
or
R ²² denotes straight-chain or branched alkyl having up to 4 carbon atoms, optionally by phenoxy, benzyloxy, carboxyl, fluorine, chlorine, bromine or straight-chain or branched alkoxycarbonyl or acyl each having up to 4 carbon atoms or by pyridyl, thienyl, furyl or pyrimidyl is substituted,
or
R ^{22 represents} a radical of the formula -NR ²⁵ R ²⁶ ,
wherein
R ²⁵ and R ^{26 are} identical or different and represent hydrogen, phenyl, pyridyl or straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by morpholine which is bonded via N,
R ²³ and R ^{24 are} identical or different and are hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms,
R ^{2 represents} hydrogen, fluorine, chlorine, bromine or straight-chain or branched alkyl having up to 3 carbon atoms,
E represents hydrogen or fluorine, chlorine or bromine,
and their stereoisomers and salts. 3. oxazolidinones of the general formula (I) according to claim 1, in which
A and D together with the nitrogen atom, a heterocyclic radical of the formula
form,
wherein
L and L 'are identical or different and represent an oxygen atom or a radical of the formula -NR ¹³ ,
wherein
R ^{13 is} hydrogen, cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl straight-chain or branched alkoxycarbonyl having up to 3 carbon atoms, or straight-chain or branched acyl having up to 3 carbon atoms, which may be fluorine, chlorine, bromine, hydroxyl, amino or N , N-Dimethylamino, straight-chain or branched alkoxy is substituted with up to 3 carbon atoms
or
straight-chain or branched alkyl having up to 3 carbon atoms, which is optionally substituted by fluorine, chlorine, bromine, cyano, methoxycarbonyl, ethoxycarbonyl, amino, N, N-dimethylamino or phenyl, which in turn is substituted by fluorine, chlorine, bromine or by straight-chain or branched alkyl, alkoxy or acyl, each having up to 3 carbon atoms,
R ³ , R ⁴ , R ⁵ and R ^{6 are the} same or different and are hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms, which is optionally substituted by fluorine, chlorine or bromine,
or
R ³ and R ⁴ and / or R ⁵ and R ⁶ together form radicals of the formula = O or = S,
R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ^{12 are the} same or different and are hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms, which may be hydroxyl, fluorine, chlorine, straight-chain or branched alkoxy or Alkoxycarbonyl with up to 3 carbon atoms, phenyl is substituted
or
R ⁷ and R ⁸ and / or R ⁹ and R ¹⁰ and / or R ¹¹ and R ¹² together form radicals of the formula = O or = S.
and or
R ¹⁰ and R ¹¹ together form an endocyclic double bond,
R ^{1 represents} azido or a radical of the formula -OR ¹⁸ , -O-SO ₂ -R ¹⁹ or -NR ²⁰ R ²¹ ,
wherein
R ¹⁸ denotes hydrogen or straight-chain or branched acyl having up to 3 carbon atoms,
R ¹⁹ denotes straight-chain or branched alkyl having up to 3 carbon atoms or phenyl,
R ²⁰ and R ^{21 are} hydrogen,
or
R ²⁰ means hydrogen,
and
R ^{21 is} a radical of the formula
means
wherein
Q represents an oxygen or sulfur atom,
R ²² denotes straight-chain or branched alkoxy having up to 4 carbon atoms or trifluoromethyl, or
R ^{22 means} cyclopropyl, cyclopentyl, cycloheptyl, cyclobutyl or cyclohexyl, which are optionally substituted by fluorine, chlorine or phenyl, or
Phenyl, naphthyl, pyridyl, thienyl, oxazolyl, furyl, imidazolyl, pyridazolyl or pyrimidyl, the ring systems listed under R ²² optionally up to 2 times the same or different by fluorine, chlorine, bromine, cyano, nitro, hydroxyl or phenyl sub are established
or
R ²² denotes straight-chain or branched alkyl having up to 3 carbon atoms, optionally by phenoxy, benzyloxy, carboxyl, fluorine, chlorine, bromine or straight-chain or branched alkoxycarbonyl or acyl each having up to 3 carbon atoms or by pyridyl, thienyl, furyl or pyrimidyl is substituted,
or
R ^{22 represents} a radical of the formula -NR ²⁵ R ²⁶ ,
wherein
R ²⁵ and R ^{26 are} identical or different and represent hydrogen, phenyl, pyridyl or straight-chain or branched alkyl having up to 3 carbon atoms, which is optionally substituted by morpholine which is bonded via N,
R ^{2 represents} hydrogen, fluorine or straight-chain or branched alkyl having up to 3 carbon atoms,
E represents hydrogen or fluorine,
and their stereoisomers and salts. 4. oxazolidinones of the general formula (I) according to claim 1, in which
A and D together for a remainder of the formula
in which
R ¹³ denotes hydrogen, straight-chain or branched alkyl having up to 3 carbon atoms, which is optionally substituted by cyano, methoxycarbonyl, ethoxycarbonyl, amino, N, N-dimethylamino or by phenyl, or
straight-chain or branched acyl with up to 3 carbon atoms, which is optionally substituted by hydroxy, amino or N, N-dimethylamino, or
Methoxycarbonyl means
E represents hydrogen or fluorine,
and
R ¹ for hydroxy or
represents a radical of the formula -OSO ₂ -CH ₃ , -NH-CO-R ²² or -NH-CS-R ²² ,
wherein
R ²² denotes straight-chain or branched alkyl or alkoxy each having up to 3 carbon atoms, amino, N-methylamino or N, N-dimethylamino,
R ^{2 represents} hydrogen, fluorine,
and their stereoisomers and salts. 5. oxazolidinones of general formula (I) according to claim 1 for use in fighting diseases. 6. Use of oxazolidinones of the general formula (I) according to claim 1 for the manufacture of pharmaceuticals. 7. Medicaments containing oxazolidinones of the general formula (I) according to An saying 1.