DE19805117A1 - New oxazolidinones with azole-containing tricycles - Google Patents

Abstract

The present invention relates to new oxazolidinones with azol-containing tricycles, to methods for producing the same as well as to the use thereof as drugs, in particular as anti-bacterial drugs.

Description

The present invention relates to new oxazolidinones with azole-containing tricycles, Processes for their production and their use as pharmaceuticals, in particular as an antibacterial drug.

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 from EP-609 905-A1 and oxazolidinones with 4-Azolylphenylreste known from WO 96/23 788 and WO 97/31917.

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 Adhä ion receptor antagonists published.

The present invention relates to new oxazolidinones with azole-containing tricycles of the general formula (I)

in which
A for residues of the formulas

or

stands,
wherein
R ² , R ² 'and R ² ''are the same or different and are hydrogen or halogen,
D, D 'and D''are the same or different and denote a nitrogen atom or a radical of the formula CR ³ ,
wherein
R ^{3 is} hydrogen, trifluoromethyl, halogen, hydroxyl, straight-chain or branched alkoxy having up to 6 carbon atoms or a radical of the formula -NR ⁴ R ⁵ ,
wherein
R ⁴ and R ^{5 are} identical or different and denote hydrogen, aryl having 6 to 10 carbon atoms, benzyl or straight-chain or branched alkyl or acyl each having up to 6 carbon atoms,
E, E 'and E''are the same or different and represent a nitrogen atom or a radical of the formula CR ⁶ ,
wherein
R ^{6 means} hydrogen, trifluoromethyl, nitro, cyano or halogen, or
straight-chain or branched alkyl having up to 6 carbon atoms or benzyl, which are optionally substituted by Hy droxy or by straight-chain or branched alkoxy having up to 4 carbon atoms, or
Aryl with 6 to 10 carbon atoms or an aromatic heterocycle with up to 3 heteroatoms from the series S, N and / or O means, where the ring systems optionally up to 3 times the same or different by halogen, hydroxy, nitro, straight-chain or branched alkyl are substituted with up to 4 carbon atoms or trifluoromethyl, or
R ⁶ denotes radicals of the formulas OR ⁷ , -CO-R ⁸ or -NR ⁹ R ¹⁰ ,
wherein
R ^{7 is} hydrogen, benzoyl, straight-chain or branched alkyl or acyl each having up to 6 carbon atoms, benzyl or aryl having 6 to 10 carbon atoms or an aromatic heterocycle having up to 3 heteroatoms from the series S, N and / or O,
R ^{8 is} hydroxy, straight-chain or branched alkyl or alkoxy each having up to 6 carbon atoms, benzyl or aryl having 6 to 10 carbon atoms or an aromatic heterocycle with up to 3 heteroatoms from the series S, N and / or O,
or
R ^{8 represents} a group of the formula -NR ¹¹ R ¹² ,
wherein
R ¹¹ and R ^{12 are the} same or different and are hydrogen, aryl having 6 to 10 carbon atoms, benzyl or straight-chain or branched alkyl having up to 6 carbon atoms,
R ⁹ and R ^{10 are} identical or different and are hydrogen, benzyl, aryl having 6 to 10 carbon atoms, straight-chain or branched alkyl having up to 6 carbon atoms or a group of the formula -CO ₂ R ¹³ or -CM-NR ¹⁴ R ¹⁵ mean,
wherein
R ¹³ denotes straight-chain or branched alkyl having up to 6 carbon atoms, benzyl or phenyl,
M represents an oxygen or sulfur atom,
R ¹⁴ and R ^{15 are} identical or different and have the meaning of R ⁴ and R ⁵ given above,
or
R ⁹ means hydrogen
and
R ^{10 is} a radical of the formula

means
wherein
R ¹⁶ and R ¹⁶ 'are identical or different and are hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms, aryl having 6 to 10 carbon atoms or benzyl,
R ¹ and R ^{18 are} identical or different and mean straight-chain or branched alkyl having up to 6 carbon atoms, phenyl or benzyl,
L, L 'and L''are the same or different and denote a nitrogen atom or a radical of the formula CR ¹⁹ ,
wherein
R ¹⁹ denotes hydrogen, trifluoromethyl, nitro, cyano, halogen or straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by phenyl or by a radical of the formula -OR ²⁰ ,
wherein
R ²⁰ denotes hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms, aryl having 6 to 10 carbon atoms or benzyl,
or
R ¹⁹ denotes radicals of the formulas -OR ²¹ , -COR ²² or -NR ²³ R ²⁴ ,
wherein
R ²¹ denotes hydrogen, aryl having 6 to 10 carbon atoms, benzyl or straight-chain or branched alkyl or acyl each having up to 6 carbon atoms,
R ^{22 has} the meaning of R ⁸ given above and with which the water is identical or different,
R ²³ and R ^{24 have} the meaning of R ⁴ and R ⁵ given above and are identical or different with these,
or
R ²³ means hydrogen
and
R ^{24 is} cyano or a radical of the formula -CO-NR ²⁵ R ²⁶ or -CS-NR ²⁷ R ²⁸ ,
wherein
R ²⁵ , R ²⁶ , R ²⁷ and R ^{28 are the} same or different and have the meaning of R ⁴ and R ⁵ given above,
or
R ²³ and R ²⁴ together with the nitrogen atom form a 5- to 6-membered, saturated heterocycle which may also contain a further hetero atom from the series S, O or a radical of the formula -NH,
Q represents an oxygen or sulfur atom or radicals of the formulas SO ₂ , SO, C = O or CR ²⁹ R ³⁰ ,
wherein
R ²⁹ and R ^{30 are the} same or different and are hydrogen or halo,
T represents a radical of the formula CR ³¹ R ³² ,
wherein
R ³¹ and R ^{32 are the} same or different and are hydrogen, halogen, hydroxyl, straight-chain or branched alkyl or alkoxy each having up to 6 carbon atoms or benzyloxy,
or
R ³¹ and R ³² together are residues of the formulas = O, = S,

form,
wherein
R ³³ and R ^{34 are} identical or different and denote hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms or benzyl,
or
R ³³ and R ³⁴ together form a 3- to 6-membered, saturated or partially unsaturated carbocycle,
and
R ³⁵ denotes hydrogen, benzyl or straight-chain or branched alkyl or acyl, each having up to 6 carbon atoms,
V represents an oxygen atom, a sulfur atom or a radical of the formula SO or SO ₂ ,
W represents an oxygen or sulfur atom, or radicals of the formulas C = O, C = S, SO, SO ₂ , NR ³⁶ or CR ³⁷ R ³⁸ ,
wherein
R ^{36 has} the meaning of R ³⁵ given above and is the same or different with this,
R ³⁷ and R ^{38 are} identical or different and are hydrogen, halogen, straight-chain or branched alkyl having up to 6 carbon atoms or benzyl,
or
R ³⁷ means hydrogen
and
R ^{38 represents} a radical of the formula -OR ³⁹ ,
wherein
R ³⁹ denotes hydrogen, straight-chain or branched alkyl or acyl each having up to 6 carbon atoms or benzyl,
Y represents a radical of the formula C = O or -CR ⁴⁰ R ⁴¹ ,
wherein
R ⁴⁰ and R ^{41 are} identical or different and denote hydrogen, halogen, benzyl or straight-chain or branched alkyl having up to 6 carbon atoms,
or
R ⁴⁰ means hydrogen
and
R ^{41 is} hydroxy, benzyloxy or straight-chain or branched alkoxy with up to 6 carbon atoms,
R ^{1 represents} azido or a radical of the formula -OR ⁴² , -O-SO ₂ -R ⁴³ or -NR ⁴⁴ R ⁴⁵ ,
wherein
R ⁴² denotes hydrogen or straight-chain or branched acyl having up to 6 carbon atoms,
R ⁴³ denotes straight-chain or branched alkyl having up to 6 carbon atoms or phenyl,
R ⁴⁴ and R ^{45 are} hydrogen,
or
R ⁴⁴ means hydrogen,
and
R ^{45 is} a radical of the formula

or -P (O) (OR ⁴⁷ ) (OR ⁴⁸ ) means
wherein
Z represents an oxygen or sulfur atom,
R ^{46 means} straight-chain or branched alkoxy with up to 8 carbon atoms or trifluoromethyl, or
Cycloalkyl having 3 to 6 carbon atoms means 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-glazed saturated or aromatic heterocycle with up to 3 heteroatoms from the series S, N and / or O means, the ring systems listed under R ⁴⁶ optionally being up to 2 times the same or are differently substituted by halogen, cyano, nitro, hydroxy or phenyl,
or
R ^{46 means} straight-chain or branched alkyl having up to 6 carbon atoms, optionally by phenoxy, benzyl oxy, carboxyl, halogen or straight-chain or branched alkoxycarbonyl or acyl each having up to 6 carbon atoms or by a 5- to 6-membered heterocylcus the series S, N and / or O is substituted,
or
R ^{46 represents} a radical of the formula -NR ⁴⁹ R ⁵⁰ ,
wherein
R ⁴⁹ and R ^{50 are} identical or different and denote hydrogen, phenyl, pyridyl or straight-chain or branched alkyl having up to 5 carbon atoms, which is optionally substituted by morpholine bound via N,
R ⁴⁷ and R ^{48 are} identical or different and are hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,
and their salts and N-oxides.

The compounds according to the invention can exist in stereoisomeric forms 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 racem Like the diastereomers, they can be shaped into stereo in a known manner Separate the isomeric constituents.

The following formula shows the correspondingly marked notation for enantiomerically pure and racemic forms:

In the context of the invention, the oxazolidine skeleton can be attached via the positions numbered 2 to 3 in the following scheme:

for example

The oxazolidinone skeleton is particularly preferably attached in position 3.

Physiologically acceptable salts of the compounds according to the invention can Salts of the substances according to the invention with mineral acids, carboxylic acids or sulfone be acids. Z are particularly preferred. B. salts with hydrochloric acid, bromine hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfone 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 which can be mentioned are salts with conventional bases, for example Alkali metal salts (e.g. sodium or potassium salts), alkaline earth salts (e.g. calcium or magnesium salts) or ammonium salts derived from ammonia or organi amines such as, for example, diethylamine, triethylamine, ethyldiisopropylamine,  Procain, dibenzylamine, N-methylmorpholine, dihydroabietylamine, 1-ephenamine or Methyl piperidine.

Cycloalkyl generally represents a cyclic hydrocarbon radical having 3 to 8 Carbon atoms. Cyclopropyl, cyclopentane and cyclo are preferred hexane ring. Examples include cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl called.

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

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, acyl stands for a straight-chain or branched Acyl radical with 1 to 6 carbon atoms. A straight-chain or ver is preferred branched lower acyl radical with 1 to 4 carbon atoms. Preferred acyl radicals are Acetyl and propionyl.

In the context of the invention, alkyl represents a straight-chain or branched Alkyl radical with 1 to 6 carbon atoms. A straight-chain or ver is preferred branched lower alkyl radical with 1 to 4 carbon atoms. For example, be ge named: methyl, ethyl, propyl, isopropyl, tert-butyl, n-pentyl and n-hexyl.

Heterocycle in the context of the invention represents a 5- to 7-membered aromati ring, which as heteroatoms contains up to 3 oxygen, sulfur and / or stick can contain atoms. Examples include: pyrrolyl, imidazolyl, Furyl, thienyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, pyridyl, pyrimidyl or Pyrazinyl. Pyrrolyl, pyridyl, imidazolyl, furyl, thienyl, isothiazolyl, Thiazolyl, isoxazolyl and oxazolyl.  

A 5- to 6-membered, saturated heterocycle is within the scope of the invention for example for a morpholinyl, piperidinyl and pyrrolidinyl ring. Is preferred a morpholinyl ring.

Compounds of the general formula (I) are preferred
in which
A for residues of the formulas

or

stands,
wherein
R ² , R ² 'and R ² ''are the same or different and are hydrogen or fluorine,
D, D 'and D''are the same or different and denote a nitrogen atom or a radical of the formula CR ³ ,
wherein
R ³ denotes hydrogen, trifluoromethyl, fluorine, chlorine, hydroxy, straight-chain or branched alkoxy with up to 4 carbon atoms,
E, E 'and E''are the same or different and represent a nitrogen atom or a radical of the formula CR ⁶ ,
wherein
R ^{6 is} hydrogen, trifluoromethyl, nitro, cyano, fluorine or chlorine, or
straight-chain or branched alkyl having up to 4 carbon atoms or benzyl, which are optionally substituted by Hy droxy, or
Represents phenyl, naphthyl, pyridyl, pyrimidyl, pyrazinyl, thienyl or furyl,
or
R ⁶ denotes radicals of the formulas OR ⁷ , -CO-R ³ or -NR ⁹ R ¹⁰ ,
wherein
R ⁷ denotes hydrogen, straight-chain or branched alkyl or acyl each having up to 4 carbon atoms, benzyl or phenyl,
R ^{8 is} hydroxy, straight-chain or branched alkyl or alkoxy each having up to 4 carbon atoms, benzyl or phenyl, or
R ^{8 represents} a group of the formula -NR ¹¹ R ¹² ,
wherein
R ¹¹ and R ^{12 are the} same or different and are hydrogen, phenyl, benzyl or straight-chain or branched alkyl having up to 4 carbon atoms,
R ⁹ and R ^{10 are the} same or different and are hydrogen, benzyl, phenyl, straight-chain or branched alkyl having up to 4 carbon atoms or a group of the formula -CO ₂ R ¹³ ,
wherein
R ¹³ denotes straight-chain or branched alkyl having up to 4 carbon atoms, benzyl or phenyl,
L, L 'and L''are the same or different and denote a nitrogen atom or a radical of the formula CR ¹⁹ ,
wherein
R ¹⁹ denotes hydrogen, trifluoromethyl, nitro, cyano, fluorine, chlorine or straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by phenyl or by a radical of the formula -OR ²⁰ ,
wherein
R ^{20 means} hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms, phenyl or benzyl,
or
R ¹⁹ denotes radicals of the formulas -OR ²¹ , -COR ²² or -NR ²³ R ²⁴ ,
wherein
R ²¹ denotes hydrogen, phenyl, benzyl or straight-chain or branched alkyl or acyl each having up to 4 carbon atoms,
R ^{22 has} the meaning of R ⁸ given above and with which the water is identical or different,
R ²³ and R ^{24 have} the meaning of R ⁴ and R ⁵ given above and are identical or different with these,
or
R ²³ and R ²⁴ together with the nitrogen atom form a piperidinyl or morpholinyl ring,
Q represents an oxygen or sulfur atom or radicals of the formulas SO ₂ , C = O or CR ²⁹ R ³⁰ ,
wherein
R ²⁹ and R ^{30 are the} same or different and are hydrogen or fluorine,
T represents a radical of the formula CR ³¹ R ³² ,
wherein
R ³¹ and R ^{32 are the} same or different and are hydrogen, fluorine, hydroxy, straight-chain or branched alkyl or alkoxy each having up to 4 carbon atoms,
or
R ³¹ and R ³² together form radicals of the formulas = O or = S,
V represents an oxygen atom, a sulfur atom or a radical of the formula SO ₂ ,
W represents an oxygen or sulfur atom, or radicals of the formula C = O, C = S, SO, SO ₂ , NR ³⁶ or CR ³⁷ R ³⁸ ,
wherein
R ³⁶ denotes hydrogen, benzyl or straight-chain or branched alkyl or acyl each having up to 4 carbon atoms,
R ³⁷ and R ^{38 are the} same or different and are hydrogen, fluorine, straight-chain or branched alkyl having up to 4 carbon atoms or benzyl,
Y represents a radical of the formula C = O or CR ⁴⁰ R ⁴¹ ,
wherein
R ⁴⁰ and R ^{41 are the} same or different and are hydrogen, fluorine, benzyl or straight-chain or branched alkyl having up to 4 carbon atoms,
R ^{1 represents} azido or a radical of the formula -OR ⁴² , -O-SO ₂ -R ⁴³ or -NR ⁴⁴ R ⁴⁵ ,
wherein
R ⁴² denotes hydrogen or straight-chain or branched acyl having up to 4 carbon atoms,
R ⁴³ denotes straight-chain or branched alkyl having up to 4 carbon atoms or phenyl,
R ⁴⁴ and R ^{45 are} hydrogen,
or
R ⁴⁴ means hydrogen,
and
R ^{45 is} a radical of the formula

or -P (O) (OR ⁴⁷ ) (OR ⁴⁸ ) means
wherein
Z represents an oxygen or sulfur atom,
R ^{46 means} straight-chain or branched alkoxy with up to 6 carbon atoms or trifluoromethyl, or
Cyclopropyl, cyclopentyl, cycloheptyl, cyclobutyl or cyclo hexyl, 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 ⁴⁶ optionally up to 2 times identical or different by fluorine, chlorine, bromine, cyano, nitro, hydroxy or phenyl are substituted,
or
R ⁴⁶ 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 ^{46 represents} a radical of the formula -NR ⁴⁹ R ⁵⁰ ,
wherein
R ⁴⁹ and R ^{50 are} identical or different and denote hydrogen, phenyl, pyridyl or straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by morpholine bonded via N,
R ⁴⁷ and R ^{48 are} identical or different and are hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms,
and their salts and N-oxides.

Compounds of the general formula (I) are particularly preferred
in which
A for residues of the formulas

or

stands,
wherein
R ² , R ² 'and R ² ''are the same or different and are hydrogen or fluorine,
D, D 'and D''are the same or different and denote a nitrogen atom or a radical of the formula CR ³ ,
wherein
R ³ denotes hydrogen, trifluoromethyl, fluorine, chlorine, hydroxy, straight-chain or branched alkoxy having up to 3 carbon atoms,
E, E 'and E''are the same or different and represent a nitrogen atom or a radical of the formula CR ⁶ ,
wherein
R ^{6 is} hydrogen, trifluoromethyl, nitro, cyano, fluorine, chlorine, straight-chain or branched alkyl having up to 3 carbon atoms or benzyl, which are optionally substituted by hydroxy, or
Represents phenyl, naphthyl, pyridyl, pyrimidyl, pyrazinyl, thienyl or furyl,
R ⁶ denotes radicals of the formulas OR ⁷ , -CO-R ⁸ or -NR ⁹ R ¹⁰ ,
wherein
R ^{7 is} hydrogen, straight-chain or branched alkyl or acyl each having up to 4 carbon atoms, benzyl or phenyl
R ^{8 is} hydroxy, straight-chain or branched alkyl or alkoxy each having up to 3 carbon atoms, benzyl or phenyl, or
R ^{8 represents} a group of the formula -NR ¹¹ R ¹² ,
wherein
R ¹¹ and R ^{12 are the} same or different and are hydrogen, phenyl, benzyl or straight-chain or branched alkyl having up to 3 carbon atoms,
R ⁹ and R ^{10 are} identical or different and are hydrogen, benzyl, phenyl, straight-chain or branched alkyl having up to 3 carbon atoms or a group of the formula -CO ₂ R ¹³ ,
wherein
R ¹³ denotes straight-chain or branched alkyl having up to 3 carbon atoms, benzyl or phenyl,
L, L 'and L''are the same or different and denote a nitrogen atom or a radical of the formula CR ¹⁹ ,
wherein
R ^{19 is} hydrogen, trifluoromethyl, nitro, cyano, fluorine, chlorine or straight-chain or branched alkyl having up to 3 carbon atoms, which is optionally substituted by phenyl or by a radical of the formula -OR ²⁰ ,
wherein
R ^{20 means} hydrogen, straight-chain or branched alkyl having up to 3 carbon atoms, phenyl or benzyl,
or
R ¹⁹ denotes radicals of the formulas -OR ²¹ , -COR ²² or -NR ²³ R ²⁴ ,
wherein
R ²¹ denotes hydrogen, phenyl, benzyl or straight-chain or branched alkyl or acyl each having up to 3 carbon atoms,
R ^{22 has} the meaning of R ³ given above and is the same or different with this,
R ²³ and R ^{24 have} the meaning of R ⁴ and R ⁵ given above and are identical or different with this,
Q represents an oxygen or sulfur atom or radicals of the formulas SO ₂ , C = O or CR ²⁹ R ³⁰ ,
wherein
R ²⁹ and R ^{30 are the} same or different and are hydrogen or fluorine,
T represents a radical of the formula -CR ³¹ R ³² ,
wherein
R ³¹ and R ^{32 are} identical or different and denote hydrogen, fluorine, hydroxyl, straight-chain or branched alkyl or alkoxy each having up to 3 carbon atoms,
or
R ³¹ and R ³² together form radicals of the formulas = O or = S,
V represents an oxygen atom, a sulfur atom or a radical of the formula SO ₂ ,
W represents an oxygen or sulfur atom, or radicals of the formula C = O, C = S, SO, SO ₂ , -NR ³⁶ or -CR ³⁷ R ³⁸ ,
wherein
R ³⁶ denotes hydrogen, benzyl or straight-chain or branched alkyl or acyl each having up to 3 carbon atoms,
R ³⁷ and R ^{38 are} identical or different and denote hydrogen, fluorine, straight-chain or branched alkyl having up to 3 carbon atoms or benzyl,
Y represents a radical of the formula C = O or -CR ⁴⁰ R ⁴¹ ,
wherein
R ⁴⁰ and R ^{41 are} identical or different and are hydrogen, fluorine, benzyl or straight-chain or branched alkyl having up to 3 carbon atoms,
R ^{1 represents} azido or a radical of the formula -OR ⁴² , -O-SO ₂ -R ⁴³ or -NR ⁴⁴ R ⁴⁵ ,
wherein
R ⁴² denotes hydrogen or straight-chain or branched acyl having up to 3 carbon atoms,
R ⁴³ denotes straight-chain or branched alkyl having up to 3 carbon atoms or phenyl,
R ⁴⁴ and R ^{45 are} hydrogen,
or
R ⁴⁴ means hydrogen,
and
R ^{45 is} a radical of the formula

means
wherein
Z represents an oxygen or sulfur atom,
and
R ^{46 means} straight-chain or branched alkoxy with up to 4 carbon atoms or trifluoromethyl, or
Cyclopropyl, cyclopentyl, cycloheptyl, cyclobutyl or cyclo hexyl, 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 ⁴⁶ optionally up to 2 times identical or different by fluorine, chlorine, bromine, cyano, nitro, hydroxy or phenyl are substituted,
or
R ⁴⁶ denotes straight-chain or branched alkyl having up to 3 carbon atoms, which may optionally be phenoxy, benzyl oxy, 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 ^{46 represents} a radical of the formula NR ⁴⁹ R ⁵⁰ ,
wherein
R ⁴⁹ and R ^{50 are} identical or different and denote hydrogen, phenyl, pyridyl or straight-chain or branched alkyl having up to 3 carbon atoms, which is optionally substituted by morpholine bound via N,
and their salts and N-oxides.

Compounds of the general formula (I) are very particularly preferred,
in which
A for residues of the formulas

or

stands,
wherein
n represents a number 0, 1 or 2,
R ² , R ² 'and R ² ''are the same or different and are hydrogen or fluorine,
R ³ and R ^{19 are the} same or different and are hydrogen or methyl,
R ^{6 represents} hydrogen, halogen, cyano, trifluoromethyl, phenyl or straight-chain or branched alkyl, alkoxycarbonyl or alkoxy each having up to 3 carbon atoms,
R ³⁶ denotes hydrogen or methyl,
and
R ^{1 represents} a radical of the formula -NH-R ⁴⁵ ,
wherein
R ^{45 is} a radical of the formula

means
wherein
Z represents an oxygen or sulfur atom,
and
R ^{46 means} straight-chain or branched alkoxy with up to 4 carbon atoms, or
straight-chain or branched alkyl having up to 3 carbon atoms, or
represents a radical of the formula -NR ⁴⁹ R ⁵⁰ ,
wherein
R ⁴⁹ and R ^{50 are} identical or different and denote hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms,
and their salts.

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

A-NO ₂ (II)

in which
A has the meaning given above,
first by a reduction in the compounds of the general formula (III)

A-NH ₂ (III)

in which
A has the meaning given above,
convicted,
in a next step with benzyl chloroformate, the compounds of the general formula (IV)

A-NH-CO ₂ -CH ₂ -C ₆ H ₅ (IV)

in which
A has 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 has the meaning given above,
manufactures,
and or
[B] by reaction with (C ₁ -C ₆ ) 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 and R ^{43 have} the meaning given above,
convicted,
then the azides of the general formula (Ic) with sodium azide in inert solvents

in which
A has 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 has 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 ⁴⁶ (V)

in which
R ^{46 has} the meaning given above
and
Y represents halogen, preferably chlorine or the radical -OCOR ⁴⁸ ,
in the presence of a base in inert solvents, the compounds of the general formula (Ie)

in which
A and R ^{46 have} the meaning given above,
manufactures,
or
[C] in case R ¹ = -NH-CO-R ⁴⁶
Compounds of the general formula (III) directly with enantiomerically pure or race-mixing compounds of the general formula (VI)

in which
R ^{46 has} the meaning given above,
in inert solvents and in the presence of an auxiliary to give enantiomerically pure or racemic, substituted hydroxyamides which are cyclized with carbonyldiimide azole in inert solvents to give enantiomerically pure or racemic compounds of the general formula (Ie),
or
[D] in the case of imidazobenzothiazoles
Compounds of the general formula (VII)

in which
R ^{2 has} the meaning given above,
and
R ⁴⁵ 'has the meaning of R ⁴⁵ given above and is the same or different with it, preferably represents acetyl,
with compounds of the general formula (VIII)

in which
R ³ and R ^{6 have} the meaning given above,
and
R ^{51 represents} halogen, preferably chlorine or bromine,
in alcohols, preferably ethanol, under reflux,
and in the case of the S-oxides, oxidation with m-chlorobenzoic acid follows and, if appropriate, alkylation is carried out by customary methods.

The processes according to the invention can be exemplified by the following formula schemes:

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

Suitable solvents are all inert organic solvents, which are under do not change the 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. Exactly it is possible to use mixtures of the solvents mentioned. Especially be methanol is preferred.

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

Suitable bases are generally sodium hydrogen carbonate, sodium methoxide, Hydrazine hydrate, potassium carbonate or cesium carbonate. Sodium hydro is preferred gene 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 give compounds of the general formula (Ia) is generally carried out in one of the ethers listed above, preferably in tetrahydrofuran.

Lithium alkyl compounds are generally suitable as bases for this step or lithium-N-silylamides, such as, for example, n-butyllithium, lithium diisopropyl amide 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.

Generally, in a temperature range of -78 ° C to -50 ° C, is preferred worked at -78 ° C.  

All reactions are generally normal, elevated or low pressure (e.g. 0.5 to 5 bar). Generally you work at normal pressure.

Suitable solvents for process [B] are the customary solvents, which are do not change under the reaction conditions. These preferably include alcohols such as methanol, ethanol, propanol or isopropanol or ethers such as diethyl ether, Dioxane, 1,2-dimethoxyethane, tetrahydrofuran, glycol dimethyl ether or tert-butyl methyl ether or ketones such as acetone or butanone, or amides such as dimethyl form amide or hexamethyl-phosphoric acid triamide, or hydrocarbons such as hexane, Benzene, dichlorobenzene, xylene or toluene or dimethyl sulfoxide, acetonitrile, vinegar esters or halogenated hydrocarbons such as methylene chloride, chloroform or tetra chlorinated carbon or pyridine, picoline or N-methylpiperidine. Likewise, Ge Mixtures of the solvents mentioned can be used.

Depending on the individual process steps, the bases are suitable for the Method [B] the usual inorganic or organic bases. This includes preferably alkali metal hydroxides such as sodium or potassium hydroxide or Al potash carbonates such as sodium or potassium carbonate or alkali alcoholates such as as sodium or potassium methoxide or sodium or potassium ethanol or organic amines such as ethyldiisopropylamine, triethylamine, picoline, pyridine or N- Methylpiperidine, or amides such as sodium amide or lithium diisopropylamide or Lithium-N-silylalkylamides, such as, for example, lithium-N- (bis) triphenysilylamide or Lithium alkyls such as n-butyllithium.

All reactions are generally normal, elevated or low pressure (e.g. 0.5 to 5 bar). Generally you work at normal pressure.

The usual solvents are suitable as solvents for process [C]. Prefers are dichloromethane and chloroform for reaction with the epoxy and THF for the ring closure.  

Weakly acidic catalysts are suitable as auxiliaries for the reaction with the epoxy ren, e.g. B. silica gel or reaction under pressure.

Carbodiimides such as diiso are suitable as dehydration reagents propylcarbodiimide, dicyclohexylcarbodiimide or N- (3-dimethylaminopropyl) -N'- ethyl carbodiimide hydrochloride or carbonyl compounds such as carbonyldiimidazole or 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1,2-oxazolium-3 sulfonate or propane phosphoric anhydride or isobutyl chloroformate or benzotriazolyl oxy-tris (dimethylamino) phosphonium hexyfluorophosphate or phosphonic acid di phenylesteramide or methanesulfonic acid chloride, optionally in the presence of Bases such as triethylamine or N-ethylmorpholine or N-methylpiperidine or Di cyclohexylcarbodiimide and N-hydroxysuccinimide. Carbonyldiimidazole is preferred (CDI).

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

All reactions are generally normal, elevated or low pressure (e.g. 0.5 to 5 bar). Generally you work at normal pressure.

Alcohols such as metha are suitable as solvents for process [D] nol, ethanol, propanol or isopropanol. Ethanol is preferred.

Process [D] is generally carried out in a temperature range from -50 ° C to to the respective boiling point of the solvent, preferably from -20 ° C to + 90 ° C.

The oxidations generally take place in one of the solvents listed above, preferably in methylene chloride with oxidizing agents such as metachlor perbenzoic acid, hydrogen peroxide or peracetic acid, preferably with magne siummonoperoxyphthaline salt in a temperature range from 0 ° C to 80 ° C before moves from 0 ° C to 40 ° C.  

Conventional organic solvents which are suitable as solvents for the alkylation are do not change under the reaction conditions. These preferably include ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or hydrocarbon substances such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions or halo hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, Di chlorethylene, trichlorethylene or chlorobenzene or ethyl acetate or triethylamine, Pyridine, dimethyl sulfoxide, dimethylformamide, acetonitrile, acetone or nitromethane. It is also possible to use mixtures of the solvents mentioned. Prefers are dichloromethane, dimethyl sulfoxide and dimethylformamide.

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

Most of the compounds of the general formula (II) are known or known as Species new and can then in the case of 4H-pyrrolo [1,2] [1,4] benzoxazines in analo to known publications M. Kato, Chem. Pharm. Bull. Jpn. 43, 1995, 1358-63, in the case of substituted or unsubstituted 4H-1,2,4-triazolo [3,4-c] [1,4] benzoxazines to the publications L. Garanti, J, Het. Chem. 13, 1976, 1339-41; B.P. Medaer, Tetrahedron 52, 1996, 8813-26; B.P. Medaer, Tetrahedron 35, 1994, 9767-9776 and in the case of 4H-pyrazolo [5,1-c] [1,4] benzoxazines W.-D. Rudorf, J. Prakt. Chem. 329, 1987, 55-61 and 348; in the case of 4H-imidazo- [2,1-c] [1,4] -benzoxazines in Analogy to H. Bartsch, J. Het. Chem. 26, 1989, 205-7.

In the case of 4,5-dihydro-imidazo [1,2-a] quinolines, these will initially correspond the nitro-3,4-dihydro-1H-quinolin-2-one by reaction with sulfuric acid and Potassium nitrate at -15 ° C in the 2- (2-dimethoxyethylamino) nitro-3, 4-dihydroquinolines implemented, in a second step in analogy to the publication T. Jen, J. Med. Chem. 16, 1973, 633-7 with triethyloxonium tetrafluoroborate in dichloromethane and Aminoacetaldehyde dimethyl acetate and finally mixed with hydrochloric acid.  

In addition, the compounds can be prepared in analogy to reactions, which are described in Comprehensive Heterocyclic Chemistry (A.R. Katrizky) Vol. 3, pages 995-1037 and vol. 5, pages 305-345, 631-639, 660-668, 882-890. Please also refer to the following handbook series: The Chemistry of Hetero cyclic compounds (A. Weissberger), Progress in Heterocyclic Chemistry (G.W. Gribble) and Advances in Heterocyclic Chemistry (A.R. Katrizky).

The compound of formula (IIa)

is new and can be made
by first preparing 2-amino-6-nitro-4H-benz-1,3-thiazine by reacting 2-amino-5-nitrobenzyl alcohol and thio urea with HBr under reflux and then in the alkaline position, and finally by heating with chlorine acetaldehyde solution that builds up imidazole.

The first step of the implementation takes place in a temperature range from 80 to 110 ° C, preferably at 100 ° C.

The reaction with chloroacetaldehyde solution takes place in dimethylformamide or ethanol in a temperature range from 30 ° C to 100 ° C, preferably at 70 ° C.

The reaction with the aldehyde solution takes place in a temperature range of 60 ° C up to 90 ° C, preferably at 80 ° C.

All reaction steps are carried out at normal pressure.  

The compounds of general formula (III) are largely new and can be as described under [A] by reduction of the corresponding nitro compounds general formula (II) can be prepared.

The compounds of general formula (IV) are new and can then, for example be prepared as described above under [A].

The compounds of general formula (VII) are known in part or as Species new and can for example as described above and in analogy to the Regulations of the publication EP 738726 are produced.

The compounds of the general formula (V) are known per se or according to publi graceful process.

The compounds of the general formulas (VI) and (VIII) are known per se or can be produced by customary methods.

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

The MIC values were measured using the microdilution method in BH medium Right. Each test substance was dissolved in the nutrient medium. Was in the microtiter plate de a series of concentrations of the test substances was created by serial dilution. Overnight cultures of the pathogens were used for inoculation, which were previously in the nutrient medium were diluted 1: 250. To 100 ml of the diluted, active nutrient Solutions were given 100 ml of inoculation solution.

The microtiter plates were incubated at 37 ° C and after about 20 hours or after 3 read up to 5 days. The MIC value (mg / ml) gives the lowest active ingredient concentration tration where no growth was discernible.  

MIC values (mg / ml)

The compounds of the general formulas (I), (Ia), (Ib), (Ic), (Id) and (Ie) show a broad antibacterial spectrum with low toxicity, spe targeted against gram-positive germs and some special gram-negative bacteria as well Mycobacteria, Corynebacteria, Haemophilus Influenzae, Mycoplasmas and anaero  be germs on. These properties enable their use as chemotherapeu active ingredients in human and veterinary medicine.

The compounds of the invention are against a broad spectrum of micro organisms effective. With their help, gram-positive germs and gram-negative ones Fights bacteria and bacteria-like microorganisms like mycoplasmas as well prevents, improves and / or prevents the diseases caused by these pathogens to be healed.

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 animal suitable medicine that are caused by such pathogens.

The present invention includes pharmaceutical preparations which, besides not toxic, inert, pharmaceutically suitable excipients one or more inventions contain compounds according to the invention, or the invention from one or more Active ingredients exist, as well as processes for the preparation of this preparation gene.

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

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

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

In general, it has been found in both human and veterinary medicine proven advantageous, the active ingredient (s) according to the invention in total amounts from about 0.5 to about 500, preferably 5 to 100 mg / kg body weight per 24 hours  the, if necessary in the form of several individual doses, to achieve the desired Deliver results. A single dose contains the one or more according to the invention Active ingredients 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 We spectrum and to achieve an increase in effectiveness, also with others Antibiotics can be combined.  

Output connections Example I 2- (pyrrol-1-yl) -5-nitrophenol

Analogously to M. Kato, Chem. Pharm. Bull. 43, 1995, 1358-63, 5 g (32.4 mmol) of 2-amino-5-nitrophenol and 5.36 g (40.55 mmol) of 2,5-dimethoxytetrahydrofuran are used dissolved in 50 ml of glacial acetic acid and heated to 60 ° C. for 2 h under an argon atmosphere. The acetic acid is then distilled off in vacuo, the residue is stirred with water and the rest is separated by column chromatography (silica gel 60, mobile phase: toluene / ethyl acetate = 9/1); R _f = 0.55.
fbl. Crystals, m.p .: 105 ° C
Yield: 2.8 g (42.3% of theory)

Example II 1-acetoxy-2- (pyrrol-1-yl) -5-nitrobenzene

1.3 g (6.37 mmol) of the above compound from Example I are analogous to M. Kato, Chem. Pharm. Bull. 43, 1995, 1358-63 in 10 ml abs. Dissolved dichloromethane, mixed with 1.33 ml (1.3 g = 16.434 mmol) pyridine, cooled to 0 ° C, added dropwise with 1.2 ml (1.3 g = 12.734 mmol) acetic anhydride and stirred overnight, where at the temperature rises to RT. The solvent is evaporated off in vacuo, the mixture is stirred with a little water and the residue is separated by column chromatography (silica gel 60, mobile phase: dichloromethane); R _f = 0.7.
fbl. Crystals, m.p .: 104 ° C
Yield: 1 g (63.8% of theory)

Example III 1-acetoxy-2- (2-formyl-pyrrol-1-yl) -5-nitrobenzene

The title compound is prepared in analogy to the instructions from M. Kato, Chem. Pharm. Bull. 43, 1995, 1358-63.

In a flask cooled with an ice bath with 0.18 ml (0.17 g = 2.32 mmol) of DMF, 0.22 ml (0.36 g = 2.32 mmol) of phophoroxy chloride is added dropwise under an argon atmosphere. After stirring for 10 min in an ice bath and 15 min at RT, the mixture is cooled again to 0 ° C. and 0.44 g (1.79 mmol) of the compound from Example II is slowly left in 7 ml of abs. To drop dichloroethane. The mixture is then stirred at RT for 20 min and heated to 70 ° C. for 1 h. After adding 1.32 g (16.1 mmol) of sodium acetate in 10 ml of water, the mixture is heated at 60 ° C. for 20 minutes and, after cooling, extracted with dichloromethane. After drying with sodium sulfate, the mixture is evaporated to dryness in vacuo and the residue is separated by column chromatography (silica gel 60, dichloromethane / ethyl acetate = 100/1); R _f = 0.4. yellow oil; Yield: 64 mg (13.1% of theory).

Example IV 2- (2-formyl-pyrrol-1-yl) -5-nitrophenol

30 mg (0.11 mmol) of the compound from Example III are dissolved in 0.38 ml of ethanol and 0.3 ml of THF, mixed with 0.02 ml of a 28% sodium methylate solution in methanol and stirred at RT for 30 min . It is neutralized with glacial acetic acid / water (1: 1), evaporated to dryness in vacuo and the residue is separated by column chromatography (silica gel 60, mobile phase: dichloromethane / ethyl acetate = 100/2). yellow crystals, mp: 147 ° C
R _f (dichloromethane / ethyl acetate = 100/1) = 0.1
Yield 19 mg (74.8% of theory)

Example V 2- (2-hydroxymethyl-pyrrol-1-yl) -5-nitrophenol

0.7 g (3.015 mmol) of the compound from Example IV are dissolved in 7.5 ml of ethanol and 7.5 ml of THF, cooled in an ice bath and, with stirring, in several portions with 0.21 g (6.03 mmol) sodium carbonate added. The mixture is stirred at RT overnight, carefully evaporated in vacuo to a small volume and stirred with a little water. The mixture is carefully acidified with oxalic acid / water, and yellow crystals gradually precipitate out of the solution which is clear to the next: mp: 114 ° C.
R _f (dichloromethane / methanol = 100/3) = 0.1
Yield: 0.5 g (70.8% of theory)

Example VI 7-nitro-4H-pyrrolo [2.1-c] [1,4] benzoxazine

60 mg (0.256 mmol) of the compound from IV are dissolved in 1 ml of THF under an argon atmosphere, 90 mg (0.36 mmol) of triphenylphosphine are added, the mixture is cooled in an ice bath and 60 mg (0.36 mmol) of diethyl azodicarboxylic acid are added. The mixture is stirred for 14 h, the temperature rising to RT. After adding 2 ml of water, the mixture is extracted with dichloromethane, the organic phase is dried with sodium sulfate, evaporated to dryness in vacuo and the residue is separated by column chromatography (silica gel 60, mobile phase: dichloromethane / methanol = 100/5). The title substance runs in the front, triphenylphosphine oxide with an R _f value of 0.5. The course is evaporated in vacuo and again purified by column chromatography (silica gel 60, mobile phase: dichloromethane / cyclohexane = 3/2); R _f = 0.5.
Yellow crystals are obtained.
Yield: 4 mg (7.2% of theory)

Example VII 7-amino-4H-pyrrolo [2.1-c] [1,4] benzoxazine

30 mg (0.116 mmol) of the compound from Example VI are dissolved in 15 ml of THF / methanol (1: 1), 30 mg of palladium catalyst on carbon (5%) are added and the mixture is hydrogenated at 2.5 atm of hydrogen pressure for 3 h . After filtering off the catalyst and concentrating i. V. you get a dark oil.
Yield: 20 mg (77.4% of theory) crude

Example VIII N- (R) -2-hydroxy-3- {4H-pyrrolo [2.1-c] [1,4] benzoxazin-7-yl) amino} propyl acetamide

20 mg (0.017 mmol) of the compound from Example VII and 10 mg (0.129 mmol) of (S) -acetylaminomethyl-oxirane are dissolved in 10 ml of chloroform, 60 mg (1.07 mmol) of keel gel are added and the mixture is evaporated to dryness in vacuo . The silica gel coated in this way is left to stand under an argon atmosphere for 48 h, eluted with dichloromethane and methanol, evaporated to dryness in vacuo and the residue is separated by column chromatography (silica gel 60, mobile phase: dichloromethane / methanol = 100/7); R _f = 0.4.
fbl. foam
Yield: 12 mg (37.1% of theory)

Example IX 7-nitro-4H-benz-1,4-oxazin-3-one

The preparation takes place in analogy to the instructions of DR Shridhar et al., OPPI, 14 (3), 1982, 195-7 from 1 equivalent of 2-amino-5-nitrophenol, 1.15 equivalents of chloroacetyl chloride and 2.3 equivalents of sodium hydrogen carbonate in one 1: 1 mixture of isobutyl methyl ketone and water at reflux temperature (3 h). The ring closure is carried out by adding 1 equivalent of triethylamine over 2 hours under reflux.
fbl. Crystals, m.p .: 232 ° C (dec.)
Yield: approx. 80% of theory

Example X 7-nitro-4H-benz-1,4-oxazin-3-thione

The preparation takes place in analogy to the regulation of H. Bartsch et al., Monthly Bulletin for Chemistry, 119, 1988, 1439-44. 6.15 g (31.68 mmol) of the compound from Example IX and 6.406 g (15.84 mmol) of Lawesson's reagent in 160 ml of abs. THF stirred. After stirring for 2 h at RT, the initially heterogeneous mixture forms a clear, yellow solution. Allow to stir overnight, add a spatula tip of Lawesson's reagent and stir again overnight. The thion is precipitated by allowing the solution to flow into a large excess of water while stirring. The precipitate is filtered off (stink) and air-dried, the filtrate is treated extensively with an excess of chlorine solution. The purification is carried out by column chromatography on silica gel 60 with the mixture dichloromethane / ethyl acetate = 100/5.
R _f (dichloromethane / ethyl acetate = 100/5) = 0.65 yellow crystals, mp. 221 ° C (dec.)
Yield: 5.5 g (82.7% of theory)

Example XI 3-methylsulfanyl-7-nitro-2H-benzo-1,4-oxazine

In analogy to the instructions by M. Mazharuddin et al., Tetrahedron 25, 1969, 517-525, 125 mg (0.5 mmol) of the compound from Example X are dissolved in 5 ml of acetone, with 106 mg (0.75 mmol) of methyl iodide and 138 mg (1 mmol) of potassium carbonate were added and the mixture was stirred at RT for 2 h. Then it is washed with a little water and the residue is separated by column chromatography (silica gel 60, mobile phase: dichloromethane); R _f (dichloromethane) = 0.9.
yellow crystals, m.p .: 153 ° C
Yield: 77 mg (57.8% of theory)

Example XII 7-nitro-4H-imidazo [2,1-c] [1,4] benzoxazine

In analogy to the regulation by H. Bartsch, J. Heterocycl. Chemistry 26, 1989, 205-7, 0.4 g (1.784 mmol) of the compound from Example M in 10 ml of abs. Dissolved ethanol, mixed with 0.28 g (2.68 mmol) aminoacetaldehyde dimethylacetal and heated to boiling for 8 h (complete reaction, TLC control with dichloromethane / acetic ester = 4/1). Everything is evaporated to dryness, 6 ml of methanol and 6 ml of conc. Hydrochloric acid and heated to boiling for 2 h. One neutralizes with sat. NaHCO ₃ solution, filtered, washed with water and the residue separated by column chromatography (silica gel 60, mobile phase: dichloromethane / methanol = 100/5), R _f = 0.5.
yellowish crystals, m.p .: 209 ° C (dec.)
Yield: 220 mg (56.9% of theory)

Example XIII

a) N- (7-Nitro-2H-1,4-benzoxazin-3-yl) aminoacetaldehyde dimethyl acetal

3.88 g (0.02 mmol) of the benzoxazinone from Example IX are obtained according to D. Achakzi, Chem. Ber. 114, 1981, 3188-94 converted into the imide chloride, which reacts in situ with aminoacetaldehyde dimethyl acetal to give the above amidine. The benz oxazinone from Example IX is abs in 160 ml. THF dissolved, with stirring with 6.29 g (0.024 mol) triphenylphosphine and 5.68 g (0.024 mol) hexachloroethane. The mixture is heated to 40 ° C. for 30 minutes, 3.32 ml (2.43 g = 0.024 mol) of triethylamine are added dropwise and the mixture is heated to boiling for 1 hour. After cooling, 6.30 g (0.06 mol) of aminoacetaldehyde-dimethylacetal are added while cooling with ice. The mixture is stirred at RT overnight, concentrated in vacuo and the mixture is separated by column chromatography on silica gel 60 using acetic ester / toluene = 7/3 as the eluent; R _f = 0.6.
yellow crystals, mp: 147 ° C
Yield: 3.9 g (69% of theory)

b) In analogy to the regulation by H. Bartsch, J. Heterocycl. Chem. 26, 1989, 205-7, 3.35 g (11.91 mmol) of the above compound from Example XIIIa are concentrated for 4 h with 40.2 ml of methanol and 40.2 ml. Hydrochloric acid heated to boiling. It is then neutralized with saturated NaHCO ₃ solution, filtered and washed until neutral. The residue is recrystallized from ethyl acetate. The compound from Example XII is obtained.
fbl. Crystals, mp: 209 ° C (dec.)
Yield: 2.15 g (83.1% of theory)

Example XIV 7-amino-4H-imidazo [2,1-c] [1,4] benzoxazine

50 mg (0.23 mmol) of the compound from Example XII are dissolved in 20 ml of methanol / THF = 1/1), 50 mg of catalyst (Pd / C, 5%) are added and 1 atm (H ₂ ) of hydrogen hydrated. The column chromatographic separation is carried out on silica gel 60 with dichloromethane / ethyl acetate = 4/1 as the eluent; R _f = 0.2.
fbl. Crystals, m.p .: 187-194 ° C
Yield: 40 mg (92.8% of theory)

Example XV N- (R) -2-Hydroxy-3 - {(4H-imidazo [2,1-c] [1,4] benzoxazin-7-yl) amino} propyl acet amid

65 mg (0.347 mmol) of the compound of Example XIV are dissolved analogously to F. Bennett, Synlett, 1993, 703-4 in 7 ml of chloroform, mixed with 40 mg (0.347 mmol) of (S) -acetyl aminomethyl-oxirane and then by means of ultrasound suspended with 0.6 g of silica gel 60. All is evaporated to dryness in vacuo and left to stand for 48 hours. The silica gel is eluted with dichloromethane and methanol, the solvents are combined, evaporated to a small volume in vacuo and separated by column chromatography (silica gel 60, mobile phase: dichloromethane / methanol = 9/1); R _f = 0.3.
fbl. foam
Yield: 22 mg (20.0% of theory)

Example XVI 2,2-dimethyl-7-nitro-4H-benz-1,4-oxazin-3-one

The preparation is carried out analogously to Example IV from 20 g (0.13 mol) of 2-amino-5-nitro phenol, 34.3 g (0.15 mol) of 2-bromo-isobutyric acid bromide and 26.16 (0.31 mol) of sodium hydrogen carbonate in 70 ml of water and isobutyl methyl ketone with 13.13 g ≅ 18 ml (0.13 mol) of triethylamine.
yellow crystals, mp: 216 ° C
Yield: 16.5 g (57.2% of theory)

Example XVII N- (2,2-Dimethyl-7-nitro-2H-1,4-benzoxazin-3-yl) aminoacetaldehyde dimethyl acetal

The preparation is carried out analogously to Example XIII (instruction a) from 5 g (22.5 mmol) of the compound from Example XVI, 7.08 g (27 mmol) triphenylphosphine, 6.30 g (27 mmol) hexachloroethane and 2.73 g ≅ 3.04 ml (27 mmol) of triethylamine and then reacting the resulting imide chloride with 7.1 g (67.5 mmol) of amino acetaldehyde dimethylacetal.
yellow crystals, R _f (dichloromethane / methanol = 100/3) = 0.8
Yield: 5.56 g (79.5% of theory)

Example XVIII 2,2-dimethyl-7-nitro-4H-imidazo [2.1-c] [1.4] benzoxazine

The synthesis succeeds analogously to Example XII from 5.56 g (approx. 18 mmol) of the compound from Example XVII by heating for 4 hours to boiling with 60 ml of methanol and 60 ml of concentrated hydrochloric acid.
yellow crystals, mp: 155-8 ° C
R _f (dichloromethane / methanol = 100/3) = 0.64
Yield: 4.2 g (95.3% of theory)

Example XIX 2,2-dimethyl-7-amino-4H-imidazo [2.1-c] [1.4] -benzoxazine

The reduction is carried out analogously to Example XIV from 2.6 g (12.08 mmol) of the compound from Example XVIII and 0.85 Pd / C, 5% with 2 bar hydrogen pressure in 200 ml of methanol.
fbl. Product, R _f (dichloromethane / methanol = 100/3) = 0.6
Yield: 2.1 g (90.6%), 83.4% of theory. Th.

Example XX N- (R) -2-hydroxy-3 - {- 2,2-dimethyl-4H-imidazo [2.1-c] [1.4] -benzoxazin-7-yl) -amino} propyl acetamide

The reaction with the oxirane is carried out analogously to Example XV from 0.4 g (1.86 mmol) of the compound from Example XIX, 0.26 g (2.23 mmol) of (S) -acetylaminomethyl-oxirane on 4 g of silica gel.
fbl. Foam, R _f (dichloromethane / methanol = 9/1) = 0.48
Yield: 129 mg (21.0% of theory) and 215 mg (53.8%) of starting material

Example XXI 3-propargylamino-7-nitro-2H-benz-1,4-oxazine

• a) Analogously to V. Ambrogi, Eur. J. Med. Chem. 30, 1995, 429-37, 0.5 g (2.23 mol) of 3-methylsulfanyl-7-nitro-2H-benzo-1,4- oxazine (Example XI), 0.22 g (2.45 mmol) propargylamine hydrochloride and 0.2 g (2.45 mmol) sodium acetate together in 5 ml abs. Ethanol and heated to boiling for 8 h. The solvent is evaporated off in vacuo, the residue is stirred out with a little water and separated by column chromatography (silica gel 60, mobile phase: dichloromethane / vinegar ester = 9/1); R _f = 0.6.
  yellow Crystals, mp: 198 ° C (dec.)
  Yield: 0.46 g (85.3% of theory)
• b) 3.9 g (20.09 mmol) of 7-nitro-4H-benz-1,4-oxazin-3-one (Example IX) are dissolved in 160 ml of abs. Dissolved dichloromethane, mixed with 6.32 g (24.105 mmol) triphenyl phosphine and 5.71 g (24.105 mmol) hexachloroethane and warmed to 40 ° C for 30 min. To this is added 3.34 ml = 2.44 g (24.105 mmol) triethylamine and heated to boiling for 1 h. The mixture is allowed to cool and 5.52 g (60.26 mmol) of propargylamine hydrochloride and 8.35 ml = 6.1 g (60.26 mmol) of triethylamine are added dropwise with ice cooling. The mixture is then left to react at RT overnight. In the DC (ethyl acetate / toluene = 7/3) a new, yellow spot can be seen. All is evaporated to dryness in vacuo, stirred with a little water and the residue is separated by column chromatography (silica gel 60, mobile phase:
  Dichloromethane / ethyl acetate = 9/1); R _f = 0.6.
  yellow Crystals, mp: 198 ° C (dec.)
  Yield: 2.7 g (58.1% of theory)

Example XXII 1-methyl-7-nitro-4H-imidazo [2,1-c] [1,4] benzoxazine

[Analog V. Ambrogi, Eur. J. Med. Chem. 30, 1995, 429-437]

0.1 g (0.43 mmol) of the compound from Example XXI are suspended in 2 ml of glacial acetic acid and heated in an oil bath at 120 ° C. for 6 hours under an argon atmosphere. Finally, the glacial acetic acid is distilled off and the residue is separated by column chromatography (silica gel 60, mobile phase: dichloromethane / ethyl acetate = 9/1), R _f = 0.15.
yellow crystals, m.p .: 145 ° C
Yield: 35 mg (35% of theory)

Example XXIII 1-methyl-7-amino-4H-imidazo [2,1-c] [1,4] benzoxa 42798 00070 552 001000280000000200012000285914268700040 0002019805117 00004 42679zin

0.3 g (1.125 mmol) of the above compound from Example XXII are dissolved in 100 ml of methanol and mixed with 0.2 g of Pd-C catalyst, 5%, and hydrogenated with 2 atm of hydrogen for 4 h. After filtering off the catalyst and concentrating to dryness, the residue is column chromatographed (silica gel 60, mobile phase: dichloromethane / methanol = 100/7); R _f = 0.4.
fbl. Crystals, m.p .: 193 ° C
Yield: 157 ° C (60.15% of theory)

Example XXIV N- (R) -2-Hydroxy-3 - {(1-methyl-4H-imidazo [2,1-c] [1,4] benzoxazin-7-yl) amino} propyl acetamide

80 mg (0.4 mmol) of the compound from Example XXIII are dissolved in 3 ml of chloroform, mixed with 50 mg (0.4 mmol) of (S) -acetylaminomethyl-oxirane, treated in an ultrasonic bath with 0.8 g of keel gel, IV evaporated to dryness and left overnight at RT. It is eluted with dichloromethane and methanol and separated by column chromatography (silica gel 60, eluent: dichloromethane / methanol = 9/1); R _f = 0.3.
fbl. foam
Yield: 37 mg (29.4% of theory)

Example XXV 7-nitro-4H-benzo-1,4-thiazin-3-one

11.6 g (0.064 mmol) of 6-nitrobenzothiazole are dissolved in 23.2 ml of ethanol and 23.2 ml of hydrazine hydrate and heated to 80 ° C. with stirring for 2 h. At room temperature, 6.64 g (0.07 mol) of chloroacetic acid and 6.95 g (0.174 mol) of sodium hydroxide in 70 ml of water are added and the mixture is heated to boiling for 1 hour. The mixture is then acidified in an ice bath with concentrated hydrochloric acid and stirred at 50 ° C. for 30 min (TLC control with dichloromethane / methanol = 100/3). The precipitate is filtered off, washed neutral ge and dried.
solid yellow product
R _f (dichloromethane / methanol = 100/3) = 0.27
Yield: 11.14 g (82.3% of theory)
MS (EI): 210

Example XXVI 7-nitro-4H-benzo-1,4-thiazine-3-thione

100 mg (0.48 mmol) of the compound from Example XXV and 96.2 mg (0.24 mmol) of Lawesson's reagent are dissolved in 3 ml of abs. THF dissolved and stirred at RT for 2 days (TLC control with petroleum ether / ethyl acetate = 7/3). 96.2 mg (0.24 mmol) of Lawesson's reagent are added once more and the mixture is stirred at RT for a further 2 days. Although educt is still present, the reaction is stopped by adding 20 ml of water. It is extracted several times with dichloromethane, washed with saturated sodium chloride solution, dried with magnesium sulfate and evaporated all to dryness.
yellow, crystalline product, R _f (petroleum ether / ethyl acetate = 7/3) = 0.7
Yield: 198.5 mg crude (theoretical yield quantitative: 107.6 mg)

Example XXVII 3-methylsulfanyl-7-nitro-2H-benzo-1,4-thiazine

198.5 mg of the crude product from Example XXVI are dissolved in 5 ml of acetone, 131.4 mg (0.951 mmol) of potassium carbonate and 101.25 mg (0.713 mmol) of methyl iodide are added and the mixture is stirred at RT overnight (TLC control with petroleum ether / Ethyl acetate = 7/3 as eluent). Since educt is still present, 131.4 mg (0.951 mmol) of potassium carbonate and 101.25 mg (0.713 mmol) of methyl iodide are added again and stirring is continued. The starting material has disappeared after 3 hours. Water is added and the mixture is extracted with dichloromethane. The organic phase is washed with saturated sodium chloride solution, dried with magnesium sulfate and evaporated to dryness in vacuo.
yellow, crystalline product, R _f (petroleum ether / ethyl acetate = 7/3) = 0.82
Yield: 164.3 mg crude (theoretical yield quantitative: 115.2 mg)

Example XXVIII N- (7-Nitro-2H-1,4-benzothiazin-3-yl) aminoacetaldehyde dimethyl acetal

164.3 mg of the crude product from Example XXVII and 75 mg (0.714 mmol) of amino acetaldehyde dimethylacetal are dissolved in 3 ml of ethanol and stirred overnight (TLC control with petroleum ether / ethyl acetate = 1/1 as eluent). Then water is added, the mixture is extracted with dichloromethane, the organic phase is washed with saturated sodium chloride solution, dried with magnesium sulfate and evaporated to dryness in vacuo. A yellow, crystalline crude product (235.4 mg) is obtained. The purification is carried out by column chromatography (silica gel 60, mobile phase: petroleum ether / ethyl acetate = 3/2).
R _f (petroleum ether / ethyl acetate = 1/1) = 0.23
yellow crystals
Yield: 107.3 mg (75.2% of theory, based on the compound from Example XXVI)

Example XXIX 7-nitro-4H-imidazo [2.1-c] [1.4] -benzthiazine

97.8 mg (0.33 mmol) of the compound from Example XXVIII are concentrated with 1.2 ml of methanol and 1.2 ml. Hydrochloric acid added and heated to boiling for 2.5 h (TLC control with petroether / ethyl acetate = 1/1 as eluent). After cooling, the pH is adjusted to 2 with dilute sodium hydroxide solution and the mixture is extracted with dichloromethane. It is washed with saturated saline, dried with magnesium sulfate and evaporated i. V. to dry out. The residue (85.4 mg) is separated by column chromatography (silica gel 60, mobile phase: dichloromethane / methanol = 100/3).
yellow crystals, (dichloromethane / methanol = 100/5) = 0.37
Yield: 56.8 mg (74.05% of theory)

Example XXX 7-amino-4H-imidazo [2.1-c] [1.4] -benzthiazine

10 mg (0.043 mmol) of the nitro compound from Example XXIX are dissolved in 1 ml of methanol, 27.03 mg (0.43 mmol) of ammonium formate and 1 mg of palladium-carbon catalyst (10%) are added under an argon atmosphere and heated to boiling. After 8 hours there is no longer any starting material (TLC control with dichloromethane / methanol = 100/5 as eluent). After filtering off the catalyst, the mixture is evaporated down in vacuo and the residue is purified by column chromatography (silica gel 60, mobile phase: dichloromethane / methanol = 100/3).
colorless foam, R _f (dichloromethane / methanol = 10/1) = 0.475
Yield: 5.7 mg (65.4% of theory)

Example XXXI N- (R) -2-Hydroxy-3 - {(4H-imidazo [2.1-c] [1.4] -benzthiazin-7-yl) amino} propyl acetamide

25.5 mg (0.125 mmol) of the amine from Example XXX and 14.44 mg (0.125 mol) (S) - acetylaminomethyl-oxirane are dissolved in 5 ml abs. Dissolved dichloromethane and mixed with 22.61 mg (0.376 mmol) of keel gel (40-60 µM). It is evaporated to dryness in vacuo and left to stand at RT overnight. According to the DC control (eluent: dichloromethane / methanol = 10/1), educt is still present. After dissolving in 5 ml of dichloromethane, another 0.5 equivalents of oxirane are added, the mixture is evaporated to dryness in vacuo and the procedure is repeated after a further 3 h with 0.5 equivalents of oxirane. 2 hours later, the silica gel is eluted with 10 ml dichloromethane / methanol = 5/1, the solvent is evaporated down in vacuo and the residue is purified by column chromatography (silica gel 60, mobile phase: dichloromethane / methanol = 100/3 to 100/8).
fbl. Foam, R _f (dichloromethane / methanol = 10/1) = 0.25
Yield: 10 mg (25.0% of theory)
In addition, 14.9 mg (58.4%) of starting material are recovered.

Example XXXII 6-nitro-3,4-dihydro-1H-quinolin-2-one

9.45 g (0.074 mol) of 3,4-dihydro-1H-quinolin-2-one are dissolved in 36 ml of 95% sulfuric acid, cooled to -15 ° C and gradually mixed with 7.04 g (0.05 08 mol) potassium nitrate added. The mixture is stirred at -20 ° C. under constant DC control (every 15 min); Mobile solvent: chloroform / methanol = 100/3 and dichloromethane / methanol = 100/3. After 3 hours there is still some starting product and a trace of the Dinitro product. The reaction mixture is again added in portions with 0.95 g (about 10 mmol) of potassium nitrate and stirring is continued at -15C. After 4 h, everything is stirred into 500 ml of water, the precipitate which has separated out is filtered off and washed neutral. After drying, the crude product is purified by column chromatography (silica gel 60, mobile phase: dichloromethane / methanol = 100/1). The appropriate fraction is evaporated to dryness in vacuo, stirred with diethyl ether, filtered and dried at 60 ° C.
yellow crystals
Yield: 9.1 g (73.7% of theory)
MS (DCI): 193 (M + H)

Example XXXIII N- (6-nitro-3,4-dihydro-quinolin-2-yl) aminoacetaldehyde dimethylacetal

8.07 g (0.042 ml) of the compound from Example XXXII in abs. 240 ml. Dissolved dichloromethane, mixed with 48.3 ml (0.048 mmol) of a 1 molar solution of triethyloxonium tetrafluoroborate in dichloromethane and stirred at room temperature for 9 h. Then 13.25 g (0.126 mol) of aminoacetaldehyde dimethyl acetal (distilled over CaH at 20 mbar and 341 ° C.) are added and the mixture is stirred for 3 hours at room temperature. After 3 hours, according to the DC control, no further conversion takes place (approx. 50%). The reaction mixture is evaporated down in vacuo to about 50 ml, water is added and the mixture is extracted several times with dichloromethane. After washing the organic phase with dichloromethane and drying with magnesium sulfate, the solvent is evaporated off in vacuo. A yellowish solid product remains.
Yield: 10.1 g (86.1% of theory).

Example XXXIV 7-nitro-4,5-dihydro-imidazo [1,2-a] quinoline

10.49 g of the compound from Example XXXIII are dissolved in 126 ml of methanol, with 126 ml of conc. Hydrochloric acid added and heated to boiling for 2.5 h (TLC control with petroleum ether / ethyl acetate = 1/1 as eluent). After cooling, the pH is adjusted to 2 by adding 1N sodium hydroxide solution and the mixture is extracted several times with dichloromethane. The organic phase is washed with saturated sodium chloride solution, dried with magnesium sulfate and the solvent is evaporated off in vacuo; Residue 8.11 g. After the column chromatographic separation (silica gel 60, eluent: petroleum ether / It sigester = 1/1 and dichloromethane / methanol = 100/2), yellow crystals are obtained; R _f = 0.08 (petroleum ether / ethyl acetate = 1/1).
Yield: 1.25 g (13.3% of theory)
MS (DCI): 216 (M + H)

Example XXXV 7-amino-4,5-dihydro-imidazo [1,2-a] quinoline

17 mg (0.079 mmol) of the compound from Example XXXIV are dissolved in 1 ml of methanol under an argon atmosphere and 1.7 mg of 10% palladium-carbon are added. After adding 50 m of ammonium formate, the mixture is heated to boiling. According to the DC control (dichloromethane / methanol = 100/5), the reduction is complete after 2 hours. The cleaning is carried out by thin layer chromatography (silica gel 60, eluent: dichloromethane / methanol = 100/1).
fbl. Solid product; R _f (dichloromethane / methanol = 10/1) = 0.175
Yield: 13 mg (88.9% of theory)
MS (DCI): 186 (M + H)

Example XXXVI 7-nitro-3-hydrazono-3,4-dihydro-2H-benz-1,4-oxazine

Analog DR Shridhar, Indian J. Chem. Sect. B, 23, 1984, 1279-83 and H. Bartsch, monthly. Chem. 120, 1989, 81-84 0.5 g (2.36 mmol) of the compound from Example X and 0.15 g (3.063 mol) of hydrazine hydrate in abs. Ethanol stirred overnight at RT. After the ethanol has been distilled off, the yellow-orange residue is stirred with water, filtered and washed with water. R _f (dichloromethane / methanol = 100/3) = 0.2.
yellow-orange crystals, m.p .: <250 ° C (dec.)
Yield: 0.48 g (97% of theory)

Example XXXVII 7-nitro-1,2,4-triazolo [3,4-c] [1,4] benzoxazine

Analogously to S. Mantegani 29, 1992, 455-459, 0.5 g (2.4 mmol) of the compound from Example XXXVI is heated to boiling with 3.56 g (24 mmol) of triethyl orthoformate (about 150 ° C.) . After evaporation in vacuo, the residue is stirred with a little ethanol and filtered.
yellow crystals, mp. <230 ° C (dec.)
Yield: 0.43 g (82.1% of theory)

Example XXXVIII 7-amino-1,2,4-triazolo [3,4-c] [1,4] benzoxazine

0.41 g (1.88 mmol) of the compound from Example XXXVII are dissolved in 190 ml of methanol / THF (1/1), mixed with 0.1 g of Pd / C, 5% and under 1 bar of hydrogen pressure 2 h hydrogenated. After filtering the catalyst, evaporate to dryness in vacuo.
fbl. foam
Yield: 0.34 g (96.2% of theory)

Example XXXIX N- (R) -2-Hydroxy-3 - {(1,2,4-triazolo [3,4-c] [1,4] benzoxazin-7-yl) amino} propyl acetamide

0.14 g (0.74 mmol) of the compound from Example XXXVIII is dissolved in 5 ml of chloroform and stirred in an ultrasound bath with 2.3 g of silica gel 60 and 0.12 g (1.04 mmol) of (S) -acetylaminomethyl- oxirane. All is evaporated to dryness in vacuo and left at RT for 2 h. The silica gel is eluted with dichloromethane and methanol, evaporated to dryness in vacuo and the rest is separated by column chromatography (silica gel 60, mobile phase: dichloromethane / methanol = 9/1); R _f = 0.22.
fbl. foam
Yield: 75 mg (33.2% of theory)
In addition, 50 mg of the amine (35.7%) are recovered.

Example XL 1-methyl-7-nitro-1,2,4-triazolo [3,4-c] [1,4] benzoxazine

The title compound is obtained in analogy to the procedure of Example XXXVII from 0.83 g (4 mmol) of the compound from Example XXXVI and 6.5 g (40 mmol) of triethyl orthoacetate. The mixture is treated with 1.67 g of silica gel 60 and 15 ml of abs. Toluene added and heated to boiling for 3 h.
R _f (dichloromethane / methanol = 100/3) = 0.44
yellow, amorphous product, m.p .: <230 ° C (dec.)
Yield: 0.7 g (75.6% of theory)

Example XLI 1-methyl-7-amino-1,2,4-triazolo [3,4-c] [1,4] benzoxazine

The title compound is prepared in analogy to the procedure of Example XXXVIII from 0.5 g (2.15 mmol) of the compound from Example XL and 0.3 g of Pd-C catalyst, 5%, in 300 ml of methanol for 3 h at 2 bar Hydrogen pressure produced.
fbl. Crystals, m.p .: 222 ° C (dec.)
Yield: 0.43 g (98.8% of theory)

Example XLII N- (R) -2-hydroxy-3 - {(1-methyl-1,2,4-triazolo [3,4-c] [1,4] benzoxazin-7-yl) amino} - propyl acetamide

The title compound is prepared in analogy to the procedure of Example XXXIX from 0.23 g (1.11 mol) of the compound from Example XLI, 0.17 g (1.335 mmol) of (S) -acetylamino methyloxirane and 4 g of silica gel 60 in 5 ml of chloroform produced.
R _f (dichloromethane / methanol = 9/1) = 0.33
fbl. foam
Yield: 90 mg (23.9% of theory)

Example XLIII N- (R) -2-Hydroxy-3- {4,5-dihydroxyimidazo [1,2-a] quinolin-7-ylamino} propyl acetamide

0.5 g (2.7 mmol) of the compound from Example XXXV and 310.8 mg (2.7 mmol) of (S) - acetylaminomethyl-oxirane in 20 ml abs. Dissolved dichloromethane, mixed with 5 g of silica gel (40-63 µm) and evaporated to dryness in vacuo. The coated silica gel is left to stand for two days and then eluted with dichloromethane and methanol. After evaporation, the residue is separated by column chromatography (silica gel 60, mobile phase: dichloromethane / methanol = 100/5 → fraction 1 = starting amine; mobile phase: dichloromethane / methanol = 10 / 1.5 → fraction 2 = substitute acetamide).
fbl. Solid product
R _f (dichloromethane / methanol = 10/1) = 0.12
Yield: 316.7 mg (39.0% of theory)
+ 303.7 mg amine (60.7% of theory)

Example XLIV 7-nitro-4H-imidazo [5.1-c] [1.4] benzoxazine-3-carboxylic acid ethyl ester

Analogously H. Bartsch, J. Heterocycl. Chemistry 26, 1989, 205-7, a mixture of 207.9 mg (1.82 mmol) and 216.2 mg (1.82 mmol) of ethyl isocyanate is first prepared in 1.5 ml of DMF. When the two components are combined, a significant amount of heat is generated. This solution is cooled to 0 ° C. Then 235 mg (1.21 mmol) of the compound from Example IX are dissolved in 1.5 ml of abs. DMF (light yellow solution) and mixed with 138 mg (1.21 mmol) potassium tert-butoxide (brown solution). The resulting solution is cooled to 0 ° C and mixed with 430.6 mg (2.42 mmol) of phosphoric acid diethyl chloride. This solution is slowly dripped into the first solution at 0.degree. C., the solution turning dark red and the desired end product being formed immediately. The mixture is stirred for a further 2 h at RT and then poured onto 5 ml of glacial acetic acid. After dilution with water, a light precipitate is formed which is difficult to filter. For this reason, the entire heterogeneous mixture is extracted several times with ethyl acetate. The organic phase is dried and then evaporated to dryness in the course of which the last traces of DMF are also removed, if possible. It is taken up in 5 ml of acetone, filtered off from the undissolved and evaporated again to dryness iv. The residue is stirred with 3 ml of ethyl acetate / petroleum ether. The residue is the desired product.
fbl. Crystals, R _f (ethyl acetate) = 0.4
Yield: 125 mg (35.7% of theory)

Example XLV 7-Amino-4H-imidazo (5.1-c] [1.4] benzoxazine-3-carboxylic acid, ethyl ester

144 mg (0.5 mmol) of the nitro compound from Example XLIV are dissolved in 2 ml of ethanol, mixed with 129.5 mg (2 mmol) of ammonium formate and a spatula tip of Pd / C catalyst (10%) and in a 80 ° C hot bath heated for 5 min. After cooling, the catalyst is filtered off over kieselguhr and the filtrate is evaporated in vacuo. The residue is purified by column chromatography (silica gel 60, mobile phase: dichloromethane / methanol = 100/1 to 100/5).
R _f (dichloromethane / methanol = 10/1) = 0.57
fbl. product
Yield: 15.5 mg (12.0% of theory)

Example XLVI N- (R) -2-hydroxy-3 - {(3-ethoxycarbonyl-4H-imidazo [5.1-c] [1.4] -benzoxazin-7-yl) - amino} propyl acetamide

22 mg (0.08 mmol) of the amine from Example XLV are dissolved in 1 ml of dichloromethane, 11.7 mg (0.1 mmol) of (S) -acetylaminomethyloxirane and 51 mg (0.85 mol) of keel gel are added and IV Evaporated to dryness. The mixture is left to stand overnight, mixed with dichloromethane and a further 7 mg (0.06 mmol) of oxirane, evaporated to dryness in vacuo and left to stand for a further day. The coated silica gel is eluted with 10 ml dichloromethane / methanol = 7/3, concentrated in vacuo to a small volume and the residue is separated on a thick-layer plate; Eluent: dichloromethane / methanol = 10/1; Eluens: methanol.
fbl. Foam, R _f (dichloromethane / methanol = 10/1) = 0.435
Yield: 6.2 mg (19.5% of theory)
In addition, 4.9 mg (22.3%) of starting material are recovered.

Example XLVII 7-nitro-4H-imidazo [5.1-c] [1.4] benzoxazine-3-carboxylic acid

180 mg (0.62 mmol) of the ester from Example XLIV are suspended in 5 ml of ethanol and mixed with 6.3 ml (0.63 mmol) in sodium hydroxide solution (brown color) and stirred at 80 ° C. for 15 min. It is diluted with 5 ml of water and the mixture is acidified with 1N hydrochloric acid. Colorless crystals gradually fall out.
R _f (dichloromethane / methanol = 10/1) = 0.07
Yield: 97 mg (59.9% of theory)

Example XLVIII 7-nitro-4H-imidazo [5.1-c] [1.4] benzoxazine

54 mg (0.21 mmol) of the carboxylic acid from Example XLVII are heated in 10 min with 2 ml of diphenyl ether in a bath heated to 250 ° C. After cooling, everything is placed on a silica column, the diphenyl ether is washed out with dichloromethane and the product is eluted with dichloromethane / methanol = 100/5. After concentration, colorless crystals are obtained.
R _f (dichloromethane / methanol = 20/1) = 0.34
Yield: 36.7 mg (80.5% of theory)

Example IL 7-amino-4H-imidazo [5.1-c] [1.4] benzoxazine

28.5 mg (131 μmol) of the nitro compound from Example XLVIII are dissolved in 0.5 ml of ethanol, mixed with 34.1 mg (0.525 mmol) of ammonium formate and a spatula tip of Pd / C catalyst (10%) and in one heated to 80 ° C preheated bath for 7 min. After filtering off the catalyst, the solvent is evaporated to dryness.
colorless, amorphous product, R _f (dichloromethane / methanol = 10/1) = 0.43
Yield, crude: 20.1 mg (82.0% of theory)

Example L N- (R) -2-Hydroxy-3 - {(4H-imidazo [5.1-c] [1.4] -benzoxazin-7-yl) -amino} -propyl acetamide

20 mg (0.11 mmol) of the amine from Example IL are dissolved in 1 ml of dichloromethane, mixed with 14.76 mg (0.13 mmol) of (S) -acetylaminomethyloxirane and 64.2 mg (1.07 mmol) of silica gel and evaporated to dryness. After standing for 1 day, the starting materials are redissolved (hardly any product!) In dichloromethane, mixed with 1.2 further equivalents of oxirane, evaporated to dryness in vacuo and left to stand for another day. Then eluting with dichloromethane / methanol (7/3), concentrated in vacuo and separating the residue on a thick-layer plate; Mobile phase: dichloromethane / methanol = 10/1; Eluens: methanol.
fbl. Product, R _f (dichloromethane / methanol = 10/1) = 0.185
Yield: 12 mg (36.1% of theory)

Example LI 1- (2,2-Dimethoxyethyl) -5-nitro-indole-2-carboxylic acid ethyl ester

5 g (21.35 mmol) of 5-nitro-indole-2-carboxylic acid ethyl ester (manufactured by A. Guy, SYNTHESIS 3, 1980, 222-3) are dissolved in 50 ml of DMSO and at RT with 3.6 g (32 mmol) potassium tert-butoxide and 3.9 ml (5.58 g = 32 mmol) bromoacetaldehyde di methyl acetal were added. The mixture is heated to 120 ° C. overnight, poured onto ice water after cooling and extracted several times with diethyl ether. It is washed neutral, dried with magnesium sulfate, evaporated to dryness in vacuo and crystallized by stirring with ethanol.
fbl. Crystals, R _f (tert-butyl methyl ether / cyclohexane = 1/1) = 0.51
Yield: 3.5 g (50.9% of theory)

Example LII 1- (2,2-dimethoxyethyl) -5-nitro-indole-2-carboxylic acid

3.5 mg (10.55 mmol) of the ester from Example LI are dissolved in 50 ml of THF, mixed with 25 ml of 1N sodium hydroxide solution and stirred at 60 ° C. The saponification ends after 2 hours. The solvent is evaporated off and the remaining dark brown solution is extracted 3 × with diethyl ether. The aqueous solution is made weakly acidic with 6N hydrochloric acid, the desired carboxylic acid gradually precipitating out.
light brown crystals, R _f (dichloromethane / methanol = 7/3) = 0.54
Yield: 2.9 g (93.5% of theory)

Example LIII 1- (2,2-Dimethoxyethyl) -5-nitro-indole-2-carboxylic acid azide

A suspension of 2.7 g (9, 18 mmol) of the carboxylic acid from Example LII in 30 ml abs. Cooled to -10 ° C. 2.6 ml (1.85 = 18.35 mmol) of triethylamine are added to THF and the mixture is stirred for 10 min. Then 4.1 ml (5.2 g = 18.35 mmol) of diphenylphosphoryl azide are added dropwise and the reaction mixture is left in the refrigerator overnight. Then concentrated in vacuo to about half the volume, mixed with dilute NaHCO ₃ solution and extracted several times with dichloromethane. After washing with water and drying with magnesium sulfate, concentrate in vacuo.
R _f (dichloromethane) = 0.78
Yield, crude: 2.9 g (quantitative)

Example LIV 1- (2,2-dimethoxyethyl) -2-tert-butyl-oxycarbonyl-amino-5-nitroindole

2.9 g of the crude product from Example LIII are taken up in 100 ml of toluene, mixed with 60 ml of tert-butanol and heated to boiling for 2 hours (TLC control with dichloromethane or petroleum ether / ethyl acetate = 1/1). It is evaporated to dryness in vacuo and the residue is purified by column chromatography (silica gel 60, mobile phase: dichloromethane / petroleum ether = 7/3).
R _f (dichloromethane) = 0.45
Yield: 1.4 g (42.2% of theory)

Example LV 7-nitro-9H-imidazo [1.2-a] indole

1.16 g (3.17 mmol) of the substance from Example LIV are mixed with 10 ml of methanol / conc. Hydrochloric acid (1: 1) was added and the mixture was heated to boiling for 1 hour. The mixture is neutralized with saturated NaHCO ₃ solution and extracted with ethyl acetate. After concentration in vacuo, the residue is purified by column chromatography (silica gel 60, mobile phase: dichloromethane / methanol = 100/5).
R _f (dichloromethane / methanol = 10/1) = 0.59
Yield: 0.5 g (78.4% of theory)

Example LVI 7-amino-9H-imidazo [1.2-a] indole

500 mg (2.49 mmol) of the nitro compound from Example LV are dissolved in 100 ml of ethanol, with 626 mg (9.94 mmol) of ammonium formate and 370 mg (3.48 mmol) of Pd / C catalyst (10% - ig) added and heated to boiling for 30 min. After filtering off the catalyst, the solvent is evaporated off in vacuo and the residue is purified by column chromatography (silica gel 60, mobile phase: dichloromethane / methanol = 100/5).
colorless product
R _f (dichloromethane / methanol = 10/1) = 0.44
Yield: 178 mg (41.8% of theory)
By-product: hydrazine compound

Example LVII N- (R) -2-Hydroxy-3 - {(9H-imidazo [1.2-a] indol-7-yl) amino} propyl acetamide

150 mg (0.88 mmol) of the amine from Example LVI, 121 mg (1.05 mmol) of (S) -acetyl aminomethyi-oxirane and 526 mg (8.75 mmol) of silica gel are slurried in 10 ml of chloroform and IV to dryness evaporated. The silica gel coated in this way is left to stand overnight, eluted with 10 ml of dichloromethane / methanol = 10/1, evaporated to dryness in vacuo and the residue is purified by column chromatography (silica gel 60, mobile phase: dichloromethane / methanol = 4/1).
R _f (dichloromethane / methanol = 10/1) = 0.5
fbl. foam
Yield: 95 mg (37.9% of theory)
37 mg (24.7% of theory) of starting material are recovered.

Example LVIII 7-nitro-5H-imidazo [1.2-a] [3.1] -benzthiazine

9 g (53 mmol) of 2-amino-5-nitro-benzyl alcohol and 5.3 g (70 mmol) of thiourea are refluxed in 180 ml of 48% HBr for 18 h. It is then concentrated, made alkaline with Na ₂ CO ₃ solution and the product is filtered. Washing with water and drying gives 9.6 g of 2-amino-6-nitro-4H-benz-1,3-thiazine. In 200 ml of DMF, 9.3 ml (64.5 mmol) of 45% aqueous chloroacetaldehyde solution are added, and the mixture is heated at 70 ° C. for 2 h. Another 3 ml of the aldehyde solution are added and the mixture is heated to 80 ° C. for 4 h. Then it is diluted with ice water, made weakly basic with bicarbonate and the product is filtered off. After purification on silica gel (CH ₂ Cl ₂ / MeOH = 100 / 2.5), 5 g of the title compound are obtained.
fbl. Solid product, R _f (dichloromethane / methanol 10/1) = 0.34

Example LIX 7-Amino-5H-imidazo [1.2-a] [3.1] -benzthiazine

125 mg (0.535 mmol) of the nitro compound from Example LVIII are dissolved in 50 ml of ethanol and 2 ml of dichloromethane, 300 mg of palladium / carbon catalyst (10%) are added and the mixture is hydrogenated with hydrogen for 2 h. The catalyst is filtered off over silica gel, evaporated down in vacuo and the residue is separated by column chromatography (silica gel 60, mobile phase: dichloromethane / methanol = 100/3).
fbl. Foam, R _f (dichloromethane / methanol = 10/1) = 0.65
Yield: 85 mg (78.3% of theory)

Example LX N- (R) -2-Hydroxy-3 - {(5H-imidazo [1.2-a] [3.1] -benzthiazin-7-yl) amino} propyl acetamide

85 mg (0.42 mmol) of the amine from Example LIX are absorbed in 5 ml of abs. Dissolved dichloromethane, mixed with 58 mg (0.5 mmol) of (S) -acetylaminomethyl-oxirane and 250 mg (4.2 mmol) of silica gel and evaporated to dryness in vacuo. The mixture is left to stand at RT overnight. Then it is dissolved in a little dichloromethane, 33 mg (0.29 mmol) of oxirane are added and the mixture is again evaporated to dryness. After standing for 2 hours, the silica gel is eluted with 5 ml of dichloromethane / methanol = 4/1, concentrated in vacuo and the residue is separated by column chromatography (silica gel 60, mobile phase: dichloromethane / methanol = 100/5).
fbl. Foam, R _f (dichloromethane / methanol = 10/1) = 0.3
Yield: 43 mg (32.3% of theory)

Example LXI 7-nitro-4H-tetrazolo [5,1-c] [1,4] benzoxazine

Analog B. Medaer, Tetrahedron Letters 35, 1994, 9767-70 and D. Achakzi, Chem. Ber. 144, 1981, 3188-94, 3.88 g (0.02 mmol) of 7-nitro-4H-benz-1,4-oxazin-3-one in 160 ml of abs. Dissolved dichloromethane, mixed with 6.29 g (0.024 mol) triphenylphosphine and 5.68 g (0.024 mol) hexachloroethane and heated to boiling for 60 min. After cooling, 3.32 ml (2.43 g = 0.024 mol) of triethylamine are added dropwise and the mixture is heated to boiling for a further hour. After cooling, 1.82 g (0.028 mol) of sodium azide in DMF are added and the mixture is stirred overnight at room temperature. The organic solvents are evaporated, the mixture is stirred with a little water and the residue is separated by column chromatography (silica gel 60, mobile phase: dichloromethane / ethyl acetate = 9/1);
R _f = 0.8.
yellowish crystals, mp: 171 ° C
Yield: 3 g (68.5% of theory)

Example LXII 7-amino-4H-tetrazolo [5,1-c] [1,4] benzoxazine

1 g (4.563 mmol) of the compound from Example LXI are dissolved in a little methanol, 0.3 g of Pd / C (5%) is added and hydrogen is hydrogenated for 2 hours at 2 bar. After filtering off the catalyst, the mixture is evaporated to dryness. R _f (dichloromethane / methanol = 100/3) = 0.69
fbl. Crystals, mp: <250 ° (dec.)
Yield: 0.784 g (90.8% of theory)

Manufacturing examples example 1

(5S) -3- (1,2,4-triazolo [3,4-c] [1,4] benzoxazin-7-yl) -5-acetylaminomethyl-oxazolidine 2-one

130 mg (0.43 mmol) of the compound from Example XXXIX are dissolved in 9.5 ml of abs. THF, mixed with 100 mg of carbonyldiimidazole and warmed in a 90 ° C. warm oil bath. It is evaporated to dryness in vacuo, stirred with water and filtered.
fbl. amorphous product; Mp: <250 ° C (dec.)
Yield: 34 mg (24.1% of theory)

Example 2 (5S) -3- (1-methyl-1,2,4-triazolo [3,4-c] [1,4] benzoxazin-7-yl-5-acetylaminomethyl oxazolidin-2-one

In analogy to the procedure of Example 1, the title compound from 90 mg (0.27 mmol) of the compound from Example XLII and 70 mg (0.41 mmol) carbonyldi imidazole in 5 ml abs. THF produced overnight at 60 ° C.
R _f (dichloromethane / methanol = 9/1) = 0.64
fbl. foam
Yield: 9 mg (9.3% of theory)

Example 3 (5S) -3- (4,5-Dihydro-imidazo [1,2-a] quinolin-7-yl) -5-acetylaminomethyl-oxazolidin-2 on

307 mg (0.814 mmol) of the compound from Example XLIII are dissolved in 10 ml of abs. Dissolved tetrahydrofuran, mixed with 298.3 mg (1.84 mmol) of fresh carbonyldiimidazole and heated to boiling (TLC control with the solvent dichloromethane / methanol = 10/1). Stirring is continued overnight at room temperature, then dichloromethane and diatomaceous earth are added. After column chromatographic separation on silica gel 60 with dichloromethane / methanol = 100/5 as running agent, a colorless solid product is obtained.
R _f (dichloromethane / methanol = 10/1) = 0.33
Yield: 206 mg (61.8% of theory)

Example 4 (5S) -3- (1-Methyl-4H-imidazo- [2,1-c] [1,4] -benzoxazin-7-yl) -5-acetaminomethyl oxazolidin-2-one

40 mg (0.111 mmol) of the substituted acetamide from Example XXIV are analogous to the procedure of Example 1 in 1 m abs. Dissolved THF, mixed with 50 mg (0.332 mmol) carbonyldiimidazole and heated to 40 ° C for 8 h. It is evaporated to dryness in vacuo, stirred with a little water and the residue is purified by column chromatography (silica gel 60, mobile phase: dichloromethane / methanol = 100/7); R _f = 0.2.
yellowish oil
Yield: 8 mg (18.5% of theory)

Example 5 (5S) -3- (2-Methyl-4H-imidazo [2,1-c] [1,4] benzoxazin-7-yl) -5-acetylaminomethyl oxazolidin-2-one

In analogy to the procedure of Example 1, the title compound is prepared from 0.3 g (1.388 mol) of the compound from Example XI and 0.24 g of 2-aminopropionaldehyde dimethyl acetal and analogously to the sequence of Examples XII, XIII, XIV and XV.
fbl. Crystals, mp: 205 ° C (dec.)
R _f (dichloromethane / methanol = 9/1) = 0.5

Example 6 (5S) -3- (4H-Imidazo [2,1-c] [1,4] -benzoxazin-7-yl) -5-acetylaminomethyl-oxazolidin-2- on

20 mg (0.063 mmol) of the compound from Example XV and 15 mg (0.095 mmol) of carbonyldiimdazole (CDI) are dissolved in 2 ml of abs. THF dissolved and heated for 3 h (oil bath, 50 ° C). A spatula tip CDI is added and the mixture is heated again. After cooling, the product is precipitated with water and purified by column chromatography (silica gel 60, mobile phase: dichloromethane / methanol = 9/1); R _f = 0.35
fbl. Crystals, mp: 205 ° C (dec.)
Yield: 7 mg (33.6% of theory)

Example 7 (5S) -3- (4H-Imidazo [2,1-c] [1,4] benzoxazin-7-yl) -5-propionylaminomethyl-oxazolidine 2-one

Analogous to the procedure of Example XV from 0.2 g (1 mmol) of the compound from Example XIV and 0.37 g (2 mmol) of (S) -propionylaminomethyl-oxirane and then ring closure with carbonyldiimidazole.
fbl. Crystals, m.p .: 236 ° C (dec.)
R _f (dichloromethane / methanol = 9/1) = 0.5

Example 8 (5S) -3- (4H-Imidazo [2,1-c] [1,4] -benzoxazin-7-yl-5-methoxycarbonylaminomethyl oxazolidin-2-one

Analogous to the procedure of Example XV from 0.29 g (1.53 mmol) of the compound of Example XIV and 0.2 g (1.53 mmol) of (S) -methoxycarbonylaminomethyl-oxirane and subsequent ring closure with carbonyldiimidazole.
fbl. Crystals, m.p .: 223 ° C (dec.)
R _f (dichloromethane / methanol = 9/1) = 0.6

General procedure for the preparation of imidazobenzothiazoles (examples 9-15)

1 mmol (5S) -3- (2-aminobenzthiazol-6-yl) -5-acetylaminomethyl-oxazolidin-2-one (cf. EP 738 726) in 6 ml of ethanol is mixed with 1.5 mmol of the corresponding chlorine or bromine -ketones or aldehydes (R ⁶ -CO-CHR ³ Cl / Br) are added and the mixture is heated under reflux overnight. It is then evaporated and the product is purified by preparative thin layer chromatography (dichloromethane / methanol = 20/1).

Table 1

Example 16 (5S) -3- (4H-pyrrolo [2.1-c] [1,4] -benzoxazin-7-yl) -5-acetylaminomethyl-oxazolidin-2- on

The preparation is carried out analogously to Production Example 1 from 10 mg (0.04 mmol) of the compound from Example VIII and 10 mg (0.06 mmol) of carbonyldiimidazole in 0.5 ml of abs. THF 6 h at 40 ° C. It is evaporated down in vacuo, taken up with a little ethyl acetate, the product precipitates with water and the precipitate is filtered off. After drying, an amorphous, colorless residue is obtained.
R _f (dichloromethane / methanol = 100/7) = 0.5
Yield: 8 mg (73.7% of theory)

Example 17 (5S) -3- (2,2-Dimethyl-4H-imidazo [2.1-c] [1.4] -benzoxazin-7-yl) -5-acetylaminomethyl oxazolidin-2-one

The preparation is carried out analogously to Example 1 above from 120 mg (0.363 mmol) of the compound from Example XX and 90 mg (0.545 mmol) of carbonyl-diimidazole in 5 ml of THF at 50 ° C. overnight.
fbl. Foam, R _f (dichloromethane / methanol = 100/7) = 0.41
Yield: 86 mg (98.8%) = 65.7% of theory. Th.

Example 18 (5S) -3- (4H-Imidazo [2.1-c] [1.4] -benzthiazin-7-yl) -5-acetylaminomethyl-oxazolidin-2 on

10 mg (0.031 mmol) of the substituted acetamide from Example XXXI in 2 ml of abs. THF dissolved, 10.19 mg (0.063 mmol) carbonyl-diimidazole (CDI) added and heated to boiling (TLC control with dichloromethane / methanol = 10/1 as eluent). After 3 h, only a slight conversion is found. Another 10.19 mg (0.063 mmol) of CDI are added, the solvent is evaporated off in vacuo, everything is dissolved in 2 ml of dioxane and the mixture is heated to boiling overnight. No more educt can be detected. It is evaporated to dryness in vacuo and the residue is purified by column chromatography (silica gel 60, mobile phase: dichloromethane / methanol = 100/5).
fbl. Foam, R _f (dichloromethane / methanol = 10/1) = 0.32
Yield: 7.2 mg (66.5% of theory)

Example 19 (5S) -3- (5H-Imidazo [1,2-a] [3.1] -benzthiazin-7-yl) -5-acetyl-aminomethyl-oxazolidin-2- on

43 mg (0.14 mmol) of the substituted acetamide from Example LX are abs. THF and a few drops of abs. DMF dissolved, 33 mg (0.2 mmol) carbonyl-diimide azole (CDI) added and heated to boiling for 1 h. There is hardly any implementation. The THF is evaporated off in vacuo, taken up in 2 ml of DMF and heated to 100 ° C. for 2.5 h. Water is added, the mixture is extracted with ethyl acetate and evaporated in vacuo. The residue is separated using a thin layer plate on silica gel; Mobile solvent: dichloromethane / methanol = 10/3, R _f = 0.72.
fbl. Foam, R _f (dichloromethane / methanol = 10/1) = 0.52
Yield: 17.3 mg (37.2% of theory)

Example 20 (5S) -3- (3Ethoxycarbonyl-4H-imidazo [5.1-c] [1.4] benzoxazin-7-yl) -5-acetylamino methyl oxazolidin-2-one

6.2 mg (16.56 μM) of the substituted acetamide from Example XLVI are in 0.2 ml abs. DMF dissolved, heated to 100 ° C and mixed with 4.03 mg (24.84 µM) carbonyl diimidazole (CDI) in 0.2 ml DMF and kept at 100 ° C. After 3 h, a further 4.03 mg of CDI are added and the mixture is heated at 100 ° C. for a further 2 h. After evaporation in vacuo, the residue is separated on a thick-layer plate, mobile phase: dichloromethane / methanol = 10/1) = 0.44.
Yield: 18 mg (27.1% of theory)
MS (ESI) = 401 (M + H); 423 (M + Na)
In addition, 3 mg (48.4%) of starting material are recovered.

Example 21 (5S) -3- (4H-imidazo [5.1-c] [1.4] -benzoxazin-7-yl) -5-acetylaminomethyl-oxazolidin-2- on

10.8 mg (35.7 µmol) of the substituted acetamide from Example L and 8.7 mg (53.6 µmol) carbonyl-diimidazole (CDI) are in 0.3 ml abs. DMF dissolved and stirred at 100 ° C for 1 h. Then another 5 mg (30.8 µmol) of CDI are added and the mixture is heated at 100 ° C. for 1 h. All is evaporated to dryness in vacuo and the residue is separated on a thick layer plate; Mobile phase: dichloromethane / methanol = 10/1; Eluens: methanol.
fbl. Foam, R _f (dichloromethane / methanol = 10/1) = 0.32
Yield: 4.2 mg (35.8% of theory) and 4.4 mg (40.7%) of starting material
MS (DCI) = 329 (M + H)

Example 22 (5S) -3- (Imidazo [1.2-a] indol-7-yl) -5-acetylaminomethyl-oxazolidin-2-one

60 mg (0.21 mmol) of the substituted acetamide from Example LVII in 6 ml abs. THF dissolved, mixed with 41 mg (0.25 mmol) carbonyl-diimidazole (CDI) and heated to 70 ° C. After 1 h, 16 mg (0.1 mmol) of CDI are again added and the mixture is left to react at 70 ° C. for a further 2 h. Everything is evaporated to dryness, the residue is taken up in a little dichloromethane / methanol = 4/1 and the mixture is separated on a thick-layer plate (mobile phase: dichloromethane / methanol = 4/1; R _f = 0.65).
fbl. foam
Yield: 21 mg (32.1% of theory)
MS (DCI) = 313 (M + H)

Example 23 (5S) -3- (Imidazo [1.2-a] indol-7-yl) -5-acetylaminomethyl-oxazolidin-2-one hydrochloride

21 mg (67.2 μmol) of the compound from Example 22 are dissolved in a little methanol, diethyl ether / hydrogen chloride is added and the mixture is evaporated to dryness in vacuo. The residue is stirred with diethyl ether and the precipitate is filtered.
fbl. product
Yield: 8 mg (31.1% of theory)

Claims (7)

1. oxazolidinones with azole-containing tricycles of the general formula (I)
in which
A for residues of the formulas
or
stands,
wherein
R ² , R ² 'and R ² ''are the same or different and are hydrogen or halogen,
D, D 'and D''are the same or different and denote a nitrogen atom or a radical of the formula CR ³ ,
wherein
R ^{3 is} hydrogen, trifluoromethyl, halogen, hydroxyl, straight-chain or branched alkoxy having up to 6 carbon atoms or a radical of the formula -NR ⁴ R ⁵ ,
wherein
R ⁴ and R ^{5 are} identical or different and are hydrogen, aryl having 6 to 10 carbon atoms, benzyl or straight-chain or branched alkyl or acyl each having up to 6 carbon atoms,
E, E 'and E''are the same or different and represent a nitrogen atom or a radical of the formula CR ⁶ ,
wherein
R ^{6 represents} hydrogen, trifluoromethyl, nitro, cyano or halogen, or
straight-chain or branched alkyl having up to 6 carbon atoms or benzyl, which are optionally substituted by hydroxyl or by straight-chain or branched alkoxy having up to 4 carbon atoms, or
Aryl with 6 to 10 carbon atoms or an aromatic heterocycle with up to 3 heteroatoms from the series S, N and / or O means, the ring systems optionally up to 3 times the same or different by halogen, hydroxy, nitro, straight-chain or ver branched alkyl with up to 4 carbon atoms or trifluoromethyl are substituted, or
R ⁶ denotes residues of the formulas OR ⁷ , -CO-R ⁸ or -NR ⁹ R ¹⁰ ,
wherein
R ^{7 represents} hydrogen, benzoyl, straight-chain or branched alkyl or acyl each having up to 6 carbon atoms, benzyl or aryl having 6 to 10 carbon atoms or an aromatic heterocycle having up to 3 heteroatoms from the series S, N and / or O,
R ^{8 is} hydroxyl, straight-chain or branched alkyl or alkoxy each having up to 6 carbon atoms, benzyl or aryl having 6 to 10 carbon atoms or an aromatic heterocycle with up to 3 heteroatoms from the series S, N and / or O,
or
R ^{8 represents} a group of the formula -NR ¹¹ R ¹ ,
wherein
R ¹¹ and R ^{12 are} identical or different and are hydrogen, aryl having 6 to 10 carbon atoms, benzyl or straight-chain or branched alkyl having up to 6 carbon atoms,
R ⁹ and R ^{10 are the} same or different and are hydrogen, benzyl, aryl having 6 to 10 carbon atoms, straight-chain or branched alkyl having up to 6 carbon atoms or a group of the formula -CO ₂ R ¹³ or -CM-NR ¹⁴ R ¹⁵ mean
wherein
R ¹³ denotes straight-chain or branched alkyl having up to 6 carbon atoms, benzyl or phenyl,
M represents an oxygen or sulfur atom,
R ¹⁴ and R ^{15 are} identical or different and have the meaning of R ⁴ and R ⁵ given above,
or
R ⁹ means hydrogen
and
R ^{10 is} a radical of the formula
means
wherein
R ¹⁶ and R ¹⁶ 'are the same or different and are hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms, aryl having 6 to 10 carbon atoms or benzyl,
R ¹⁷ and R ^{18 are} identical or different and denote straight-chain or branched alkyl having up to 6 carbon atoms, phenyl or benzyl,
L, L 'and L''are the same or different and denote a nitrogen atom or a radical of the formula CR ¹⁹ ,
wherein
R ¹⁹ denotes hydrogen, trifluoromethyl, nitro, cyano, halogen or straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by phenyl or by a radical of the formula -OR ²⁰ ,
wherein
R ^{20 is} hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms, aryl having 6 to 10 carbon atoms or benzyl,
or
R ¹⁹ denotes radicals of the formulas -OR ²¹ , -COR ²² or -NR ²³ R ²⁴ ,
wherein
R ²¹ denotes hydrogen, aryl having 6 to 10 carbon atoms, benzyl or straight-chain or branched alkyl or acyl each having up to 6 carbon atoms,
R ^{22 has} the meaning of R ⁸ given above and is the same or different with this,
R ²³ and R ^{24 have} the meaning of R ⁴ and R ⁵ given above and are identical or different with these,
or
Means hydrogen
and
R ^{24 is} cyano or a radical of the formula -CO-NR ²⁵ R ²⁶ or -CS-NR ²⁷ R ²⁸ ,
wherein
R ²⁵ , R ²⁶ , R ²⁷ and R ^{28 are the} same or different and have the meaning of R ⁴ and R ⁵ given above,
or
R ²³ and R ²⁴ together with the nitrogen atom form a 5- to 6-membered, saturated heterocycle which can also contain a further hetero atom from the series S, O or a radical of the formula -NH,
Q represents an oxygen or sulfur atom or radicals of the formulas SO ₂ , SO, C = O or CR ²⁹ R ³⁰ ,
wherein
R ²⁹ and R ^{30 are} identical or different and are hydrogen or halogen,
T represents a radical of the formula CR ³¹ R ³² ,
wherein
R ³¹ and R ^{32 are} identical or different and are hydrogen, halogen, hydroxy, straight-chain or branched alkyl or alkoxy each having up to 6 carbon atoms or benzyloxy,
or
R ³¹ and R ³² together are residues of the formulas = O, = S,
form,
wherein
R ³³ and R ^{34 are the} same or different and are hydrogen, straight-chain or branched alkyl with up to 6 carbon atoms or benzyl,
or
R ³³ and R ³⁴ together form a 3- to 6-membered, saturated or partially unsaturated carbocycle,
and
R ³⁵ denotes hydrogen, benzyl or straight-chain or branched alkyl or acyl each having up to 6 carbon atoms,
V represents an oxygen atom, a sulfur atom or a radical of the formula SO or SO ₂ ,
W represents an oxygen or sulfur atom, or radicals of the formulas C = O, C = S, SO, SO ₂ , NR ³⁶ or CR ³⁷ R ³⁸ ,
wherein
R ^{36 has} the meaning of R ³⁵ given above and is the same or different with this,
R ³⁷ and R ^{38 are} identical or different and denote hydrogen, halogen, straight-chain or branched alkyl having up to 6 carbon atoms or benzyl,
or
R ³⁷ means hydrogen
and
R ^{38 represents} a radical of the formula -OR ³⁹ ,
wherein
R ³⁹ denotes hydrogen, straight-chain or branched alkyl or acyl each having up to 6 carbon atoms or benzyl,
Y represents a radical of the formula C = O or -CR ⁴⁰ R ⁴¹ ,
wherein
R ⁴⁰ and R ^{41 are} identical or different and denote hydrogen, halogen, benzyl or straight-chain or branched alkyl having up to 6 carbon atoms,
or
R ⁴⁰ means hydrogen
and
R ⁴¹ denotes hydroxy, benzyloxy or straight-chain or branched alkoxy with up to 6 carbon atoms,
R ^{1 represents} azido or a radical of the formula -OR ⁴² , -O-SO ₂ -R ⁴³ or -NR ⁴⁴ R ⁴⁵ ,
wherein
R ⁴² denotes hydrogen or straight-chain or branched acyl having up to 6 carbon atoms,
R ⁴³ denotes straight-chain or branched alkyl having up to 6 carbon atoms or phenyl,
R ⁴⁴ and R ^{45 are} hydrogen,
or
R ⁴⁴ means hydrogen,
and
R ^{45 is} a radical of the formula
means
wherein
Z represents an oxygen or sulfur atom,
R ⁴⁶ denotes straight-chain or branched alkoxy with up to 8 carbon atoms or trifluoromethyl, or cycloalkyl with 3 to 6 carbon atoms, which is optionally substituted by halogen or aryl with 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 ⁴⁶ possibly being up to 2 times the same or are differently substituted by halogen, cyano, nitro, hydroxy or phenyl,
or
R ^{46 means} 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 Row S, N and / or O is substituted,
or
R ^{46 represents} a radical of the formula -NR ⁴⁹ R ⁵⁰ ,
wherein
R ⁴⁹ and R ^{50 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 bonded via N,
R ⁴⁷ and R ^{43 are the} same or different and are hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,
and their salts and N-oxides. 2. Compounds of general formula (I) according to claim 1, in which
A for residues of the formulas
or
stands,
wherein
R ² , R ² 'and R ² ''are the same or different and are hydrogen or fluorine,
D, D 'and D''are the same or different and denote a nitrogen atom or a radical of the formula CR ³ ,
wherein
R ³ denotes hydrogen, trifluoromethyl, fluorine, chlorine, hydroxyl, straight-chain or branched alkoxy with up to 4 carbon atoms,
E, E 'and E''are the same or different and represent a nitrogen atom or a radical of the formula CR ⁶ ,
wherein
R ^{6 represents} hydrogen, trifluoromethyl, nitro, cyano, fluorine or chlorine, or
straight-chain or branched alkyl having up to 4 carbon atoms or benzyl, which are optionally substituted by hydroxy, or
Represents phenyl, naphthyl, pyridyl, pyrimidyl, pyrazinyl, thienyl or furyl,
or
R ⁶ denotes residues of the formulas OR ⁷ , -CO-R ⁸ or -NR ⁹ R ¹⁰ ,
wherein
R ⁷ denotes hydrogen, straight-chain or branched alkyl or acyl each having up to 4 carbon atoms, benzyl or phenyl,
R ^{8 is} hydroxy, straight-chain or branched alkyl or alkoxy, each with up to 4 carbon atoms, benzyl or phenyl, or
R ^{8 represents} a group of the formula -NR ¹¹ R ¹² ,
wherein
R ¹¹ and R ^{1 are the} same or different and are hydrogen, phenyl, benzyl or straight-chain or branched alkyl having up to 4 carbon atoms,
R ⁹ and R ^{10 are the} same or different and are hydrogen, benzyl, phenyl, straight-chain or branched alkyl having up to 4 carbon atoms or a group of the formula -CO ₂ R ¹³ ,
wherein
R ¹³ denotes straight-chain or branched alkyl having up to 4 carbon atoms, benzyl or phenyl,
L, L 'and L''are the same or different and denote a nitrogen atom or a radical of the formula CR ¹⁹ ,
wherein
R ¹⁹ denotes hydrogen, trifluoromethyl, nitro, cyano, fluorine, chlorine or straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by phenyl or by a radical of the formula -OR ²⁰ ,
wherein
R ²⁰ denotes hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms, phenyl or benzyl,
or
R ¹⁹ denotes radicals of the formulas -OR ²¹ , -COR ²² or -NR ²³ R ²⁴ ,
wherein
R ²¹ denotes hydrogen, phenyl, benzyl or straight-chain or branched alkyl or acyl each having up to 4 carbon atoms,
R ^{22 has} the meaning of R ⁸ given above and is the same or different with this,
R ²³ and R ^{24 have} the meaning of R ⁴ and R ⁵ given above and are identical or different with these,
or
R ²³ and R ²⁴ together with the nitrogen atom form a piperidinyl or morpholinyl ring,
Q represents an oxygen or sulfur atom or radicals of the formulas SO ₂ , C = O or CR ²⁹ R ³⁰ ,
wherein
R ²⁹ and R ^{30 are the} same or different and are hydrogen or fluorine,
T represents a radical of the formula CR ³¹ R ³² ,
wherein
R ³¹ and R ^{32 are} identical or different and denote hydrogen, fluorine, hydroxyl, straight-chain or branched alkyl or alkoxy each having up to 4 carbon atoms,
or
R ³¹ and R ³² together form radicals of the formulas = O or = S,
V represents an oxygen atom, a sulfur atom or a radical of the formula SO ₂ ,
W represents an oxygen or sulfur atom, or radicals of the formula C = O, C = S, SO, SO ₂ , NR ³⁶ or CR ³⁷ R ³⁸ ,
wherein
R ³⁶ denotes hydrogen, benzyl or straight-chain or branched alkyl or acyl, each having up to 4 carbon atoms,
R ³⁷ and R ^{38 are} identical or different and denote hydrogen, fluorine, straight-chain or branched alkyl having up to 4 carbon atoms or benzyl,
Y represents a radical of the formula C = O or CR ⁴⁰ R ⁴¹ ,
wherein
R ⁴⁰ and R ^{41 are the} same or different and are hydrogen, fluorine, benzyl or straight-chain or branched alkyl having up to 4 carbon atoms,
R ^{1 represents} azido or a radical of the formula -OR ⁴² , -O-SO ₂ -R ⁴³ or -NR ⁴⁴ R ⁴⁵ ,
wherein
R ⁴² denotes hydrogen or straight-chain or branched acyl having up to 4 carbon atoms,
R ⁴³ denotes straight-chain or branched alkyl having up to 4 carbon atoms or phenyl,
R ⁴⁴ and R ^{45 are} hydrogen,
or
R ⁴⁴ means hydrogen,
and
R ^{45 is} a radical of the formula
or -P (O) (OR ⁴⁷ ) (OR ⁴⁸ ) means
wherein
Z represents an oxygen or sulfur atom,
R ⁴⁶ denotes straight-chain or branched alkoxy having up to 6 carbon atoms or trifluoromethyl, or 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 ⁴⁶ optionally up to 2 times the same or different by fluorine, chlorine, bromine, cyano, nitro, hydroxy or phenyl sub are established
or
R ^{46 means} 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 ^{46 represents} a radical of the formula -NR ⁴⁹ R ⁵⁰ ,
wherein
R ⁴⁹ and R ^{50 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 bonded via N,
R ⁴⁷ and R ^{48 are} identical or different and denote hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms,
and their salts and N-oxides. 3. Compounds of general formula (I) according to claim 1, in which
A for residues of the formulas
or
stands,
wherein
R ² , R ² 'and R ² ''are the same or different and are hydrogen or fluorine,
D, D 'and D''are the same or different and denote a nitrogen atom or a radical of the formula CR ³ ,
wherein
R ³ denotes hydrogen, trifluoromethyl, fluorine, chlorine, hydroxyl, straight-chain or branched alkoxy having up to 3 carbon atoms,
E, E 'and E''are the same or different and represent a nitrogen atom or a radical of the formula CR ⁶ ,
wherein
R ^{6 is} hydrogen, trifluoromethyl, nitro, cyano, fluorine, chlorine, straight-chain or branched alkyl having up to 3 carbon atoms or benzyl, which are optionally substituted by hydroxy, or
Represents phenyl, naphthyl, pyridyl, pyrimidyl, pyrazinyl, thienyl or furyl,
R ^{6 means} residues of the formulas OR ⁷ , -CO-R ⁸ or -NR ⁹ R ¹⁰ ,
wherein
R ⁷ denotes hydrogen, straight-chain or branched alkyl or acyl each having up to 4 carbon atoms, benzyl or phenyl,
R ^{8 is} hydroxy, straight-chain or branched alkyl or alkoxy each having up to 3 carbon atoms, benzyl or phenyl, or
R ^{8 represents} a group of the formula -NR ¹¹ R ¹² ,
wherein
R ¹¹ and R ^{12 are the} same or different and are hydrogen, phenyl, benzyl or straight-chain or branched alkyl having up to 3 carbon atoms,
R ⁹ and R ^{10 are the} same or different and are hydrogen, benzyl, phenyl, straight-chain or branched alkyl having up to 3 carbon atoms or a group of the formula -CO ₂ R ¹³ ,
wherein
R ¹³ denotes straight-chain or branched alkyl having up to 3 carbon atoms, benzyl or phenyl,
L, L 'and L''are the same or different and denote a nitrogen atom or a radical of the formula CR ¹⁹ ,
wherein
R ¹⁹ denotes hydrogen, trifluoromethyl, nitro, cyano, fluorine, chlorine or straight-chain or branched alkyl having up to 3 carbon atoms, which is optionally substituted by phenyl or by a radical of the formula -OR ²⁰ ,
wherein
R ²⁰ denotes hydrogen, straight-chain or branched alkyl having up to 3 carbon atoms, phenyl or benzyl,
or
R ¹⁹ denotes radicals of the formulas -OR ²¹ , -COR ²² or -NR ²³ R ²⁴ ,
wherein
R ²¹ denotes hydrogen, phenyl, benzyl or straight-chain or branched alkyl or acyl each having up to 3 carbon atoms,
R ^{22 has} the meaning of R ⁸ given above and is the same or different with this,
R ²³ and R ^{24 have} the meaning of R ⁴ and R ⁵ given above and are identical or different with this,
Q represents an oxygen or sulfur atom or radicals of the formulas SO ₂ , C = O or CR ²⁹ R ³⁰ ,
wherein
R ²⁹ and R ^{30 are the} same or different and are hydrogen or fluorine,
T represents a radical of the formula -CR ³¹ R ³² ,
wherein
R ³¹ and R ^{32 are the} same or different and are hydrogen, fluorine, hydroxyl, straight-chain or branched alkyl or alkoxy each having up to 3 carbon atoms,
or
R ³¹ and R ³² together form radicals of the formulas = O or = S,
V represents an oxygen atom, a sulfur atom or a radical of the formula SO ₂ ,
W represents an oxygen or sulfur atom, or radicals of the formula C = O, C = S, SO, SO ₂ , -NR ³⁶ or -CR ³⁷ R ³⁸ ,
wherein
R ³⁶ denotes hydrogen, benzyl or straight-chain or branched alkyl or acyl, each having up to 3 carbon atoms,
R ³⁷ and R ^{38 are} identical or different and are hydrogen, fluorine, straight-chain or branched alkyl having up to 3 carbon atoms or benzyl,
Y represents a radical of the formula C = O or -CR ⁴⁰ R ⁴¹ ,
wherein
R ⁴⁰ and R ^{41 are the} same or different and are hydrogen, fluorine, benzyl or straight-chain or branched alkyl having up to 3 carbon atoms,
R ^{1 represents} azido or a radical of the formula -OR ⁴² , -O-SO ₂ -R ⁴³ or -NR ⁴⁴ R ⁴⁵ ,
wherein
R ⁴² denotes hydrogen or straight-chain or branched acyl having up to 3 carbon atoms,
R ⁴³ denotes straight-chain or branched alkyl having up to 3 carbon atoms or phenyl,
R ⁴⁴ and R ^{45 are} hydrogen,
or
R ⁴⁴ means hydrogen,
and
R ^{45 is} a radical of the formula
means
wherein
Z represents an oxygen or sulfur atom,
and
R ⁴⁶ denotes straight-chain or branched alkoxy having up to 4 carbon atoms or trifluoromethyl, or 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 ⁴⁶ optionally up to 2 times the same or different by fluorine, chlorine, bromine, cyano, nitro, hydroxy or phenyl sub are established
or
R ⁴⁶ 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 ^{46 represents} a radical of the formula -NR ⁴⁹ R ⁵⁰ ,
wherein
R ⁴⁹ and R ^{50 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 bonded via N,
and their salts and N-oxides. 4. Compounds of general formula (I) according to claim 1, in which
A for residues of the formulas
or
stands,
wherein
n represents a number 0, 1 or 2,
R ² , R ² 'and R ² ''are the same or different and are hydrogen or fluorine,
R ³ and R ^{19 are the} same or different and are hydrogen or methyl,
R ^{6 represents} hydrogen, halogen, cyano, trifluoromethyl, phenyl or straight-chain or branched alkyl, alkoxycarbonyl or alkoxy each having up to 3 carbon atoms,
R ³⁶ denotes hydrogen or methyl,
and
R ^{1 represents} a radical of the formula -NH-R ⁴⁵ ,
wherein
R ^{45 is} a radical of the formula
means
wherein
Z represents an oxygen or sulfur atom,
and
R ⁴⁶ denotes straight-chain or branched alkoxy having up to 4 carbon atoms, or straight-chain or branched alkyl having up to 3 carbon atoms, or a radical of the formula -NR ⁴⁹ R ⁵⁰ ,
wherein
R ⁴⁹ and R ^{50 are the} same or different and are hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms,
and their salts. 5. A process for the preparation of the compounds according to the invention of the general formula (I) according to claim 1, characterized in that
[A] compounds of the general formula (II)
A-NO ₂ (II)
in which
A has the meaning given in claims 1 to 4,
first by a reduction in the compounds of the general formula (III)
A-NH ₂ (III)
in which
A has the meaning given in claims 1 to 4,
convicted,
in a next step with benzyl chloroformate the compounds of general formula (IV)
A-NH-CO ₂ -CH ₂ -C ₆ H ₅ (IV)
in which
A has the meaning given in Claims 1 to 4,
and finally with bases in inert solvents and subsequent reaction with (R) - (-) - glycidyl butyrate the compounds of the general formula (Ia)
in which
A has the meaning given in Claims 1 to 4,
and or
[B] by reaction with (C ₁ -C ₆ ) 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 and R ^{43 have} the meaning given in Claims 1 to 4, then convert the azides of the general formula (Ic) with sodium azide in inert solvents
in which
A has the meaning given in Claims 1 to 4,
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 has the meaning given in Claims 1 to 4,
and by reaction with acetic anhydride, acetyl chloride or other acylation agents of the general formula (V)
Y-CO-R ⁴⁶ (V)
in which
R ^{46 has} the meaning given in Claims 1 to 4
and
Y represents halogen, preferably chlorine or the radical -OCOR ⁴⁸ ,
in the presence of a base in inert solvents, the compounds of the general formula (Ie)
in which
A and R ^{46 have} the meaning given in Claims 1 to 4,
or
[C] in case R ¹ = -NH-CO-R ⁴⁶
Compounds of the general formula (III) directly with enantiomerically pure or racemic compounds of the general formula (VI)
in which
R ^{46 has} the meaning given in Claims 1 to 4,
in inert solvents and in the presence of an auxiliary to give enantiomerically pure or racemic, substituted hydroxyamides which are cyclized with carbonyl-diimidazole in inert solvents to give enantiomerically pure or race-mixed compounds of the general formula (Ie),
or
[D] in the case of imidazobenzothiazoles
Compounds of the general formula (VII)
in which
R ^{2 has} the meaning given in Claims 1 to 4,
and
R ⁴⁵ 'has the meaning of R ⁴⁵ given in Claims 1 to 4 and is the same or different with it, preferably represents acetyl,
with compounds of the general formula (VIII)
in which
R ³ and R ^{6 have} the meaning given in Claims 1 to 4,
and
R ^{51 represents} halogen, preferably chlorine or bromine,
in alcohols, preferably ethanol, under reflux,
and in the case of S-oxides, oxidation with m-chlorobenzoic acid follows
and optionally carrying out an alkylation by customary methods. 6. Use of the compounds according to claims 1 to 4 for Her provision of medicines. 7. Medicament containing compounds according to claims 1 to 4.