EP1054889A1

EP1054889A1 - New oxazolidinones with azol-containing tricycles

Info

Publication number: EP1054889A1
Application number: EP99904817A
Authority: EP
Inventors: Siegfried Raddatz; Stephan Bartel; Walter Guarnieri; Ulrich Rosentreter; Martin Ruppelt; Hanno Wild; Rainer Endermann; Hein-Peter Kroll; Kerstin Henninger
Original assignee: Bayer AG
Current assignee: Bayer AG
Priority date: 1998-02-09
Filing date: 1999-01-27
Publication date: 2000-11-29
Also published as: AU2519599A; WO1999040094A1; DE19805117A1; JP2002502854A

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

New oxazolidinones with azole-containing tricycles

The present invention relates to new oxazolidinones with azole-containing tricycles. Process for their preparation and their use as medicinal products, in particular as antibacterial medicinal products.

From the publications US-5 254 577, US-4 705 799, EP-31 1 090, EP-312 000 and CH. Park et al, J. Med. Chem. 35, 1156 (1992), N-aryloxazolidinones with antibacterial activity are known. In addition, 3- (nitrogen-substituted) phenyl-

5-beta-amidomethyloxazolidin-2-one known from EP-609 905-A1 and oxazolidinones with 4-azolylphenyl radicals from WO 96/23 788 and WO 97/31917.

Furthermore, in EP-609 441 and EP-657 440 oxazolidinone derivatives with a monoamine oxidase-inhibitory effect and in EP-645 376 with effect as

Adhesion receptor antagonists published.

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

O

-N Λ ^' O. (I),

R '

in which

for remnants of the formulas - 2nd

FT

-D.

~ Q

E "= D"

FT

or

W. stands,

wherein

R ² , R ² and R ^{2 are} identical or different and are hydrogen or halogen,

D, D 'and D "are identical 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 with 6 to 10 carbon atoms, benzyl or straight-chain or branched alkyl or acyl each with up to 6 carbon atoms,

E, E 'and E "are identical or different and denote a nitrogen atom or a radical of the formula CR ⁶ , wherein

R ⁶ denotes hydrogen, trifluoromethyl, nitro, cyano or halogen, or denotes straight-chain or branched alkyl having up to 6 carbon atoms or benzyl, which are optionally substituted by hydroxy or by straight-chain or branched alkoxy having up to 4 carbon atoms, or

10 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 being up to 3 times the same or different by halogen, hydroxy, nitro, straight-chain or branched alkyl having up to 4 carbon atoms.

15 lenstoffatomen or trifluoromethyl are substituted, or

R ⁶ denotes radicals of the formulas OR ⁷ , -CO-R ⁸ or -NR ⁹ R ¹⁰ ,

wherein

20th

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 25 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 one

30 means aromatic heterocycle with up to 3 heteroatoms from the series S, N and / or O, or

R is a group of the formula -NR R.

wherein

R "and R ^{12 are the} same or different and are hydrogen, aryl having 6 to 10 carbon atoms, 10 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 ″ or -CM-NR ¹⁴ R ¹⁵ mean

wherein

20th

R ' ³ denotes straight-chain or branched alkyl having up to 6 carbon atoms, benzyl or phenyl,

25 M represents an oxygen or sulfur atom,

R ⁱ⁴ and R ^{15 are the} same or different and have the meaning of R ⁴ and R ⁵ given above,

30 or R ⁹ means hydrogen

and

R ^{1 is} a radical of the formula

NHR ¹⁷ / SR ¹⁸

Means -C or - C,

NR ¹⁶ NR where

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 ' ^{8 are the} same or different and straight-chain or branched alkyl with up to 6

Represent carbon atoms, phenyl or benzyl,

L, L 'and L "are identical 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 ^ιy radicals of the formulas -OR ²¹ , -COR ²² or -NR ²³ R ²⁴ means

10 where

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,

15

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 20 given above and are identical or different with these,

or

R means hydrogen

25 and

R ^{24 is} cyano or a radical of the formula -CO-NR ^{2 :,} R ²⁶ or -CS-NR ²⁷ R ²⁸ ,

30 in which 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 is still

10 a further heteroatom from the series S, O or one

Radical of the formula -NH can contain

Q is an oxygen or sulfur atom or radicals of the formulas S0 ₂ , SO,

C = 0 or CR ²⁹ R ³⁰ , 15 where

R ²⁹ and R ^{30 are} identical or different and are hydrogen or halogen,

20 represents a radical of the formula CR R

wherein

25 R ³¹ and R ^{32 are the} same or different and are hydrogen, halogen,

Is hydroxyl, straight-chain or branched alkyl or alkoxy each having up to 6 carbon atoms or benzyloxy,

30 or R ³ 'and R ³² together are residues of the formulas = 0, = S.

, 33

Form R ° or = NR ³⁵ ,

3

R

wherein

R ³³ and R ^{34 are} identical or different and are 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 S0 ₂ ,

W represents an oxygen or sulfur atom, or radicals of the formulas C = 0, C = S, SO, S0 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

10 R means hydrogen

and

R ^{38 represents} a radical of the formula -OR ³⁹ ,

15 where

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 ⁰ R ⁴¹ ,

wherein

25

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,

30 or R ^4U means hydrogen

and

R ⁴¹ denotes hydroxy, benzyloxy or straight-chain or branched alkoxy with up to 6 carbon atoms,

or

W and Y together represent the group -CH = CH-,

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 or nitro-substituted phenyl,

R ⁴⁴ and R ^{45 are} hydrogen,

or

R ⁴⁴ means hydrogen,

and

R ^{45 is} a radical of the formula WO 99/40094 _ _π _ PCT / EP99 / 00518

Means -C— «or -P (0) (OR ⁷ ) (OR ⁴⁸ ),

wherein

5 Z represents an oxygen or sulfur atom,

R ^{46 is} hydrogen or straight-chain or branched alkoxy having up to 8 carbon atoms, benzyloxy or trifluoromethyl, or

10 means cycloalkyl having 3 to 6 carbon atoms, which is optionally substituted by halogen or aryl having 6 to 10 carbon atoms, or

Aryl with 6 to 10 carbon atoms or a 5- to 6-membered saturated or aromatic heterocycle with up to 3

15 means heteroatoms from the series S, N and / or O, where the ring systems listed under R ⁴⁶ are optionally substituted up to 2 times identically or differently by halogen, cyano, nitro, hydroxy or phenyl,

20 or

R ⁴⁶ denotes straight-chain or branched alkyl having up to 6 carbon atoms, optionally by phenoxy, benzyloxy, carboxyl, halogen or straight-chain or branched 25 alkoxycarbonyl or acyl each having up to 6 carbon atoms or by a 5- to 6-membered heterocycle from the series S, N and / or O is substituted,

or

30th 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 which is bonded via N,

R ⁴⁷ and R ^{48 are} identical or different and denote 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 which either behave like image and mirror image (enantiomers) or do not behave like image and mirror image (diastereomers). The invention relates to both the enantiomers or diastereomers or their respective mixtures. Like the diastereomers, the racemic forms can be separated into the stereoisomerically uniform constituents in a known manner.

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

- -A

(A) (racemate) ( ^B ) (enantiomer) Enantiomer B preferably has the S configuration.

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

1

for example

E- "\ Fr x« or

The oxazolidinone skeleton is particularly preferably attached in position 3.

Physiologically acceptable salts of the compounds according to the invention can be salts of the substances according to the invention with mineral acids, carboxylic acids or sulfonic acids. For example, particular preference is given to Salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.

Salts which can be mentioned are salts with customary bases, such as, for example, alkali metal salts (for example sodium or potassium salts), alkaline earth metal salts (for example calcium or magnesium salts) or ammonium salts derived from ammonia or organic amines such as, for example, diethylamine, triethylamine. Ethyldiisopropylamine, procaine, dibenzylamine, N-methylmorpholine, dihydroabietylamine, 1-ephenamine or methyl-piperidine. Cycloalkyl generally represents a cyclic hydrocarbon radical having 3 to 8 carbon atoms. The cyclopropyl, cyclopentane and cyclohexane ring is preferred. Examples include cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

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

In the context of the invention, alkoxy represents a straight-chain or branched alkoxy radical having 1 to 6 carbon atoms. A straight-chain or branched lower alkoxy radical having 1 to 4 carbon atoms is preferred. Examples include: 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 branched lower acyl radical having 1 to 4 carbon atoms is preferred. 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 branched lower alkyl radical having 1 to 4 carbon atoms is preferred. Examples include: methyl, ethyl, propyl, isopropyl, tert-butyl, n-pentyl and n-hexyl.

Within the scope of the invention, heterocycle stands for a 5- to 7-membered aromatic ring which can contain up to 3 oxygen, sulfur and / or nitrogen atoms as heteroatoms. Examples include: pyrrolyl, imidazolyl, furyl, thienyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, pyridyl, pyrimidyl or pyrazinyl. Pyrrolyl, pyridyl, imidazolyl, furyl, thienyl, isothiazolyl, thiazolyl, isoxazolyl and oxazolyl are preferred. 15

A 5- to 6-membered, saturated heterocycle in the context of the invention represents, for example, a morpholinyl, piperidinyl and pyrrolidinyl ring. A morpholinyl ring is preferred.

Compounds of the general formula (I) are preferred

in which

A for residues of the formulas

FT

-X ^ N- E '= D.

FT

~ Q

E "= D". , / \ R ^ ^L - ^\ , N or stands, w-

Υ wherein

R ² , R ² and R ^{2 are the} same or different and are hydrogen or fluorine,

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 identical or different and denote 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 phenyl, naphthyl, pyridyl, pyrimidyl, pyrazinyl, thienyl or

Furyl means

or

R ⁶ denotes radicals 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 4 carbon atoms, benzyl or phenyl, or R ^{8 represents} a group of the formula -NR "R ¹² ,

wherein

5 R "and R ^{12 are} identical or different and are hydrogen, phenyl, benzyl or straight-chain or branched alkyl having up to 4 carbon atoms,

10 R ⁹ and R ^{10 are} identical or different and denote hydrogen, benzyl, phenyl, straight-chain or branched alkyl having up to 4 carbon atoms or a group of the formula -CO ₂ R ¹³ ,

15 where

R ¹³ denotes straight-chain or branched alkyl having up to 4 carbon atoms, benzyl or phenyl,

20th

wherein

25

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 is} hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms, phenyl or benzyl.

or

R ^{19 is} radicals of the formulas -OR ²¹ , -COR ²² or -NR ^J R ²⁴

10 where

R ² 'denotes hydrogen, phenyl, benzyl or straight-chain or branched alkyl or acyl each having up to 4 carbon atoms,

15

R ²³ and R ^{24 have} the meaning of R ⁴ and R ³ 20 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 ,, C = 0 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 ³ '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 and R together form residues of the formulas = 0 or = S,

V represents an oxygen atom, a sulfur atom or a radical of the formula SO,

W represents an oxygen or sulfur atom, or radicals of the formula C = O, C = S, SO, S0 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 = 0 or CR ⁴⁰ R ⁴¹ , wherein

R ⁴⁰ and R ⁴ 'are the same or different and are hydrogen, fluorine, benzyl or straight-chain or branched alkyl having up to 4 carbon atoms,

or

W and Y together represent the group -CH = CH-,

represents azido or a radical of the formula -OR ⁴² , -0-S0 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 is a radical of the formula -C_ _R ⁴⁶ or -P (0) (OR ⁴⁷⁾ (OR ^48), means

wherein

5 Z represents an oxygen or sulfur atom,

R ^{46 is} hydrogen or straight-chain or branched alkoxy having up to 6 carbon atoms or trifluoromethyl, or cyclopropyl, cyclopentyl, cycloheptyl, cyclobutyl or

10 means 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-

15 times the same or different due to fluorine, chlorine, bromine, cyano,

Nitro, hydroxy or phenyl are substituted,

or

20 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

25 pyrimidyl is substituted,

or

R ^{4ή represents} a radical of the formula -NR ^4y R ⁵⁰ ,

30th 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 which is bonded via N,

R ⁴⁷ and R ^{48 are the} same 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,

wherein

R ³ denotes hydrogen, trifluoromethyl, fluorine, chlorine, hydroxyl, straight-chain or branched alkoxy with up to 3 carbon atoms,

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

Is 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 5

R ^{8 represents} a group of the formula -NR ⁿ R ¹² ,

wherein

10 R "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,

15 R ⁹ and R ^{10 are} identical or different and denote hydrogen, benzyl, phenyl, straight-chain or branched alkyl having up to 3 carbon atoms or a group of the formula -C0 ₂ R ¹³ ,

20 where

R ¹³ denotes straight-chain or branched alkyl having up to 3 carbon atoms, benzyl or phenyl, 25

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 , 5 in which

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 ,

15 where

R ² 'denotes hydrogen, phenyl, benzyl or straight-chain or branched alkyl or acyl each having up to 3 carbon atoms,

25 R ²³ and R ^{24 have} the meaning of R ⁴ and R ³ given above and are the same or different with this,

Q represents an oxygen or sulfur atom or radicals of the formulas SO ,, C = 0 or CR ²⁹ R ³⁰ , 30 in which R ²⁹ and R ^{30 are the} same or different and are hydrogen or fluorine,

T represents a radical of the formula -CR ¹ 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 and R together form residues of the formulas = 0 or = S,

V represents an oxygen atom, a sulfur atom or a radical of the formula SO,

W represents an oxygen or sulfur atom, or

Radicals of the formula C = 0, C = S, SO, S0 ₂ , -NR ³⁶ or -CR ³⁷ R ³⁸ means,

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 = 0 or -CR ⁴⁰ R ⁴¹ ,

wherein

R ⁴⁰ and R ⁴ 'are identical or different and denote hydrogen, fluorine, benzyl or straight-chain or branched alkyl having up to 3 carbon atoms,

or

W and Y together represent the group -CH = CH-,

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 is a radical of the formula

-C - R means in which

represents an oxygen or sulfur atom,

and

R ^{46 is} hydrogen or straight-chain or branched alkoxy having 10 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, 15 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 are substituted,

20 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 with up to 3

Carbon atoms or substituted by pyridyl, thienyl, furyl or pyrimidyl,

or R ^{40 represents} a radical of the formula -NR ^4y R ^bυ ,

wherein

R ⁴⁹ and R ^{50 are} identical or different and represent hydrogen, phenyl, pyridyl or straight-chain or branched alkyl having up to 3 carbon atoms, which is optionally substituted by morpholine which is bonded via N,

and their salts and N-oxides.

Compounds of the general formula (I) are very particularly preferred,

in which

A for residues of the formulas

H

R ' N

R °

N

^{^} O 0 R ° R ^J R °

N, N R X R R

0 ^'

H

N;

N

X N R 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 e.g.

- C II - R ₄₆ means

wherein

Z represents an oxygen or sulfur atom,

and

R ^{46 represents} hydrogen or 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} 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 of the general formula (I) according to the invention was found, characterized in that

[A] compounds of the general formula (II)

A-NO, (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 general formula (IV)

A-NH-C0 ₂ -CH, -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)

O

A - N ^ D

(Ia)

in which

A has the meaning given above,

manufactures,

and or

[B] by reaction with (C, -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)

O

A- N Λ O (Ib), OSO "R ⁴³ in which

A and R have the meaning given above,

convicted,

then the azides of the general formula (Ic) with sodium azide in inert solvents

O

N X o (Ic)

• N,

in which

A has the meaning given above,

manufactures,

in a further step by reaction with (C, -C ₄ -0) ₃ -P or Ph ₃ P, preferably (CH ₃ 0) ₃ P in inert solvents, and with acids or by catalytic hydrogenation into the amines of the general formula ( Id)

O

A o

(Id)

NH 2

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 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)

O

N A O (Ie)

NH-CO-R

in which

A and R 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 racemic compounds of the general formula (VI)

NH-CO-R ⁴⁶ (VI)

in which

R ^{46 has} the meaning given above,

in inert solvents and in the presence of an auxiliary to enantiomerically pure or racemic, substituted hydroxyamides, which are cyclized with carbonyl-diimide-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)

9 O

(VII)

• NH-R 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)

QR ³

, 6 /

51 (VIII)

R in which

R and R have the meaning given above,

and

R ⁵ 'represents halogen, preferably chlorine or bromine,

in alcohols, preferably ethanol, under reflux,

and in the case of the S-oxides, oxidation with m-chloroperbenzoic acid follows

and optionally carrying out an alkylation by customary methods.

The processes according to the invention can be illustrated by the following formula schemes: [A]

N. reduction

XX NO- XX ~ NH "

N

Benzyl chloroformate

X ^{^} NH-C0 ₂ -CH ₂ -C ₆ H ₅

1. Butyllithium

N

2. (R) - (-) - glycidyl butyrate v ^N o

"O

OH

[B]

CH_

NL

O

CIS0 ₂ CH ₃ , NEt ₃ , CH ₂ CI ₂

T) ^' 0-5 ° C

OH

CH,

N Nf

0

NaN ₃ , DMF, 70 ° C

Ε>^' N

OSO-.CH ₃

CH_

N .N.

O (MeO) ₃ P, 1,2-DME, 90 ° C 6N HCl, 90 ° C

O ^' N Λ or by catalytic hydrogenation N,

CH_

NL

O X N Λ AcCI, THF

* _^ NH ₂ xHCI Et ₃ N, 0 ° C

CH-

N - ^r O

O ^'NAO

H- .CH,

Y o [C] oo

1-C-CH- NH, silica gel

O

CDI N Λ O

CH,

[D]

O H

-H NH-CO-CH-H

Cl

Ethanol

NH-CO-CH,

The reductions can generally be carried out using 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 animal charcoal or platinum or with hydrides or boranes in inert solvents, if appropriate in Presence of a catalyst.

All inert organic solvents which do not change under the reaction conditions are suitable as solvents. These preferably include alcohols such as methanol, ethanol, propanol or isopropanol or ethers such as diethyl ether, dioxane, Tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether or amides such as hexamethylphosphoric triamide or dimethylformamide or acetic acid. It is also possible to use mixtures of the solvents mentioned. Methanol is particularly preferred.

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

Bases which are generally suitable are sodium hydrogen carbonate, sodium methanolate, hydrazine hydrate, potassium carbonate or cesium carbonate. Is preferred

Sodium bicarbonate.

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 the general formula (III).

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

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

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

In general, a temperature range from -78 ° C to -50 ° C, preferably at -78 ° C. All reactions are generally carried out at normal, elevated or reduced pressure (for example 0.5 to 5 bar). Generally one works at normal pressure.

Suitable solvents for process [B] are the customary solvents which 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

Dimethylformamide or hexamethyl-phosphoric acid triamide, or

Hydrocarbons such as hexane, benzene, dichlorobenzene, xylene or toluene or dimethyl sulfoxide, acetonitrile, ethyl acetate or halogenated hydrocarbons such as methylene chloride, chloroform or carbon tetrachloride or pyridine, picoline or N-methylpiperidine. Mixtures of the solvents mentioned can also be used.

Depending on the individual process steps for process [B], the usual inorganic or organic bases are suitable as bases. These preferably include alkali hydroxides such as sodium or potassium hydroxide

Alkali carbonates such as sodium or potassium carbonate or alkali alcoholates such as sodium or potassium methoxide or sodium or potassium ethoxide 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 carried out under normal, elevated or reduced pressure (for example 0.5 to 5 bar). Generally one works at normal pressure. The usual solvents are suitable as solvents for process [C]. Dichloromethane and chloroform are preferred for the reaction with the epoxy and THF for the ring closure.

Weakly acidic substances are suitable as aids for the reaction with the epoxy

Catalysts, e.g. Silica gel or reaction under pressure.

Suitable dehydration reagents are carbodiimides such as diisopropylcarbodiimide, dicyclohexylcarbodiimide or N- (3-dimethylaminopropyl) -NX ethylcarbodiimide hydrochloride or carbonyl compounds such as carbonyldiimidazole or 1,2-oxazolium compounds such as 2-ethyl-5-phenylol-5-phenyl 3-sulphonate, or propanephosphoric anhydride or isobutyl chloroformate or benzotriazolyl oxy-tris (dimethylamino) phosphonium hexyfluorophosphat or Phosphonsäuredi- phenylesteramid or methanesulphonyl chloride, optionally in the presence of bases such as triethylamine or N-ethylmorpholine or N-methylpiperidine or dicyclohexylcarbodiimide and N-hydroxysuccinimide. Is preferred

Carbonyldiimidazole (CDI).

In general, a temperature range from -78 ° C to + 50 ° C, preferably at room temperature. The ring closure with CDI is the

Reaction temperature between room temperature and the boiling point of tetrahydrofuran.

All reactions are generally carried out at normal, elevated or reduced pressure (e.g. 0.5 to 5 bar). Generally one works at

Normal pressure.

Alcohols such as methanol, ethanol, propanol or isopropanol are suitable as solvents for process [D]. Ethanol is preferred. Process [D] is generally carried out in a temperature range from -50 ° C. 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, for example

Metachloroperbenzoic acid, hydrogen peroxide or peracetic acid, preferably with magnesium monoperoxyphthaline salt in a temperature range from 0 ° C to 80 ° C, preferably from 0 ° C to 40 ° C.

Conventional organic solvents which do not change under the reaction conditions are suitable as solvents for the alkylation. These preferably include ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions or halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, dichlorethylene, trichlorethylene or chlorobenzene dimethyl, or methylene sulfide, dimethyl ether or chlorobenzene dimethyl or chlorobenzene dimethyl or chlorobenzene dimethyl or chlorobenzene amide or dimethylbenzene amide or dimethylbenzene or chlorobenzene amide , Acetonitrile, acetone or nitromethane. It is also possible to use mixtures of the solvents mentioned. Dichloromethane, dimethyl sulfoxide and dimethylformamide are preferred.

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

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 analogy to known publications M. Kato, Chem. Pharm. Bull. Jpn. 43, 1995, 1358-63, in the case of the substituted or unsubstituted 4H-l, 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, lc] [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 ^" | -chinaline, the corresponding nitro-3,4-dihydro-lH-quinolin-2-ones are firstly reacted with sulfuric acid and potassium nitrate at -15 ° C converted into the 2- (2-dimethoxyethylamino) nitro-3,4-dihydroquinoline, 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 analogously to the reactions described in Comprehensive Heterocyclic Chemistry (AR Katritzky) 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 Heterocyclic Compounds (A. Weissberger), Progress in Heterocyclic Chemistry (G.W. Gribble) and Advances in Heterocyclic Chemistry (A.R. Katritzky).

The compound of formula (Ha)

(Ha)

is new and can be made

by first reacting 2-amino-5-nitrobenzyl alcohol and thiourea with HBr under reflux and then in the alkaline position 2-amino-6- nitro-4H-benz-l, 3-thiazine, and finally builds up the imidazole by heating with chloroacetaldehyde solution.

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

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

All reaction steps are carried out at normal pressure.

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

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

Some of the compounds of the general formula (VII) are known or new as species and can be prepared, for example, as described above and in analogy to the regulations of the publication EP 738726.

The compounds of the general formula (V) are known per se or can be prepared by published processes.

The compounds of the general formulas (VI) and (VIII) are known per se or can be prepared by customary methods. The compounds of the general formulas (Ia) - (Ie) are new and can be prepared as described above.

The MIC values were determined using the microdilution method in BH medium. Each test substance was dissolved in the nutrient medium. A series of concentrations of the test substances was created in the microtiter plate by serial dilution. Overnight cultures of the pathogens were used for inoculation, which were previously diluted 1: 250 in the nutrient medium. 100 ml of the inoculation solution were added to 100 ml of the diluted nutrient solutions containing the active substance.

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

MIC values (mg / ml):

E.g. no. S. aureus 133 M. smegmatis DSM 43465

1 4 1

2 32 4

3 1 1

4 8 8

5 0.5 0.5

6 <0.5 <0.5

7 0.5 0.5

8 <0.5 0.5

9 1 1

10 4> 32

11 8 4

12 2 2

13 8 16

14 4 16

15 4 16

16 <0.5 2

17 32 32

18 0.5 0.5

19 <0.5 <0.5

20 8 8

21 0.5 0.5

23 4 8

The compounds of general formulas (I), (Ia), (Ib), (Ic), (Id) and (Ie) according to the invention have a broad antibacterial spectrum with low toxicity, especially against gram-positive germs and some special gram-negative ones Bacteria as well Mycobacteria, Corynebacteria, Haemophilus Influenzae, Mycoplasmas and anaerobic germs. These properties enable their use as chemotherapeutic agents in human and veterinary medicine.

The compounds according to the invention are active against a broad spectrum of microorganisms. With their help, gram-positive germs and gram-negative bacteria and bacteria-like microorganisms such as mycoplasmas can be combated and the diseases caused by these pathogens can be prevented, improved and / or cured.

The compounds according to the invention are particularly effective against bacteria and bacteria-like microorganisms. They are therefore particularly well suited for the prophylaxis and chemotherapy of local and systemic infections in human and veterinary medicine that are caused by such pathogens.

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

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

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

In addition to the compounds according to the invention, the pharmaceutical preparations listed above can also contain further active pharmaceutical ingredients. In general, it has proven to be advantageous in both human and veterinary medicine to use the active ingredient (s) according to the invention in total amounts of about 0.5 to about 500, preferably 5 to 100 mg / kg of body weight per 24 hours, optionally in the form multiple doses to achieve the desired results. A single dose contains the active ingredient (s) according to the invention preferably in amounts of about 1 to about 80, in particular 3 to 30 mg / kg, body weight.

The compounds according to the invention can also be used with others for the purpose of expanding the spectrum of activity and to achieve an increase in activity

Antibiotics can be combined.

Output connections

Example I

2- (pyrrole-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- (pyrrole-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. Dichloromethane dissolved, mixed with 1.33 ml (1.3 g - 16.434 mmol) of pyridine, cooled to 0 ° C., added dropwise with 1.2 ml (1.3 g = 12.734 mmol) of acetic anhydride and stirred overnight, where- at which 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

l-acetoxy-2- (2-formyl-pyrrol-l-yl) -5-nitrobenzene

ON

O CH,

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 minutes in an ice bath and for 15 minutes 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. Add dichloroethane dropwise. 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 the dry state in a vacuum 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-pyrrole-1-yl) -5-nitrophenol

OHC

30 mg (0.1 1 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 at RT for 30 min touched. It is neutralized with glacial acetic acid / water (1: 1), evaporated i. V. everything to dryness and separate the residue by column chromatography (silica gel 60, mobile phase: dichloromethane ethyl acetate =

100/2). yellow crystals, mp: 147 ° CR _f (dichloromethane / ethyl acetate = 100/1) = 0.1 yield 19 mg (74.8% of theory)

Example V

2- (2-hydroxymethyl-pyrrole-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 boranate added. One leaves over Stir overnight at RT, carefully evaporate i. V. to a small volume and stir with a little water. The mixture is carefully acidified with oxalic acid / water, and yellow crystals gradually precipitate out of the initially clear solution; 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 forerun is evaporated in vacuo and purified again 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 (0.1 16 mmol) of the compound from Example VI are dissolved in 15 ml of THF / M ethanol (1: 1), mixed with 30 mg of palladium catalyst on carbon (5%) and 3 h at 2 5 atm hydrogen pressure hydrogenated. 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) (S) -

Acetyl-aminomethyl-oxirane are dissolved in 10 ml of chloroform, 60 mg (1.07 mmol) of keel urchin are added and the mixture is evaporated to dryness in vacuo. The silica gel coated in this way is left 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-l, 4-oxazin-3-one

X>

0 ₂ N O ^'

The production takes place in analogy to the regulation of D.R. 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 a 1: 1 mixture of isobutyl methyl ketone and water at reflux temperature (3 h). The ring is closed by adding 1 equivalent of triethylamine under reflux for 2 h, fbl. Crystals, mp .: 232 ° C (decomp.) 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-l, 4-oxazine

N _^ / S-CH 3

0 ₂ NO

In analogy to the regulation 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, 106 mg (0.75 mmol) of methyl iodide and 138 mg (1 mmol) of potassium carbonate are added, and the mixture is 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 ^ X- N

0 ₂ N ^' Ε>

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 XI in 10 ml of abs. Dissolved ethanol, mixed with 0.28 g (2.68 mmol) of aminoacetaldehyde dimethylacetal and heated to boiling for 8 h (complete reaction, TLC control with dichloromethane / ethyl acetate = 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. NaHC0 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 (decomp.) Yield: 220 mg (56.9% of theory)

Example XIII

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

OCH, CH-

, NH

0 ₂ NO

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 benzoxazinone from Example IX is abs in 160 ml. THF dissolved, with stirring 6.29 g (0.024 mol) of triphenylphosphine and 5.68 g (0.024 mol) of hexachloroethane were added. 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 ethyl acetate / 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 XHIa 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 NaHC0 ₃ solution, filtered and washed 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,) of water hydrogenated fabric. 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, mp: 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-acetamide

N ^' H

H

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) -acetylaminomethyl-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-l, 4-oxazin-3-one

The preparation is carried out analogously to Example IV from 20 g (0.13 mol) of 2-amino-5-nitrophenol, 34.3 g (0.15 mol) of 2-bromo-isobutyric acid bromide and 26.16 (0.31 mol) Sodium bicarbonate in 70 ml water and isobutyl methyl ketone with 13.13 g ≡ 18 ml (0.13 mol) 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

OCH,

The preparation is carried out analogously to Example XIII (instruction a) from 5 g (22.5 mmol) of

Compound from Example XVI, 7.08 g (27 mmol) triphenylphosphine, 6.30 g (27 mmol) hexachloroethane and 2.73 g _ 3.704 ml (27 mmol) triethylamine and subsequent reaction of the resulting imide chloride with 7.1 g (67 , 5 mmol) aminoacetaldehyde 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 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

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 ^

H ₃ C

Ό NH

CH, OH O

H CH,

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-l, 4-oxazine

N NH

0 ₂ N O

a) Analogously to V. Ambrogi, Eur. J. Med. Chem. 30, 1995, 429-37, 0.5 g is added

(2.23 mol) 3-methylsulfanyl-7-nitro-2H-benzo-l, 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. You steam i.V. remove the solvent, stir the residue with a little water and separate it by column chromatography (silica gel 60, mobile phase:

Dichloromethane / ethyl acetate = 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-l, 4-oxazin-3-one (Example IX) are dissolved in 160 ml of abs. Dissolved dichloromethane, mixed with 6.32 g (24.105 mmol) triphenylphosphine and 5.71 g (24.105 mmol) hexachloroethane and heated 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

Analogously to 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 to 120 ° C. under an argon atmosphere Oil bath heated for 6 h. Then distilled i.V. the glacial acetic acid and separates the residue by column chromatography

(Silica gel 60, mobile phase: dichloromethane / ethyl acetate = 9/1), R _r = 0.15. yellow crystals, m.p .: 145 ° C yield: 35 mg (35% of theory) Example XXIII

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

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, 50 mg (0.4 mmol) of (S) -acetylaminomethyl-oxirane are added, treated in an ultrasonic bath with 0.8 g of keel gel, in association with 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, = 0.3. fbl. Foam yield: 37 mg (29.4% of theory)

Example XXV

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

H

I.

O ^ _N

NO,

11.6 g (0.064 mmol) of 6-nitrobenzothiazole are dissolved in 23.2 ml of ethanol and 23.2 ml

Dissolved 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 h. The mixture is then acidified in an ice bath with concentrated hydrochloric acid and stirred at 50 ° C. for 30 min (DC control)

Dichloromethane methanol = 100/3). The precipitate is filtered off, washed neutral 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

H

NO,

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 everything is evaporated i. V. to dry out. 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-l, 4-thiazine

H ₃ C-, N

NO,

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, it is added again 131.4 mg (0.951 mmol) of potassium carbonate and 101.25 mg (0.713 mmol) of methyl iodide and stirring is continued. The starting material has disappeared after 3 hours. You move with

Water and extracted with dichloromethane. The organic phase becomes saturated

Washed saline, dried with magnesium sulfate and i. V. evaporated to dryness. yellow, crystalline product, R _f (petroleum ether / ethyl acetate = 7/3) = 0.82

Yield: 164.3 mg crude (theoretical yield quantitative: 1 15.2 mg)

Example XXVIII

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

H ₃ CO

164.3 mg of the crude product from Example XXVII and 75 mg (0.714 mmol) of aminoacetaldehyde 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 down i. V. to dry out. 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 i. V. and the residue was 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). You steam i. V. dry and let 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, a further 0.5 equivalent of oxirane is added, i. V. to dryness and repeat the procedure again after 0.5 h with 0.5

Equivalents of oxirane. 2 hours later the silica gel is eluted with 10 ml dichloromethane / methanol = 5/1, the solvent i. V. and the residue was 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-1 H-quinolin-2-one

9.45 g (0.074 mol) of 3,4-dihydro-lH-quinolin-2-one are dissolved in 36 ml of 95% sulfuric acid, cooled to -15 ° C and gradually with 7.04 g (0.08 mol) added potassium nitrate. 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 mixed 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 will be used evaporated to dryness, 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

H ₃ CO

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 for 9 h at room temperature. Then 13.25 g (0.126 mol) are added

Aminoacetaldehyde dimethylacetal (distilled over CaH at 20 mbar and 341 ° C.) and stirred for 3 h at room temperature. After 3 hours, according to the DC control, no further conversion takes place (approx. 50%). The reaction mixture is evaporated down i.V. to about 50 ml, mixed with water and extracted several times with dichloromethane. After washing the organic phase with dichloromethane and drying with magnesium sulfate, the solvent is applied i.V. evaporated. 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

NO,

10.49 g of the compound from Example XXXIII are dissolved in 126 ml of methanol, with

126 ml 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, put it through

Add 1N sodium hydroxide to a pH of 2 and extract several times Dichloromethane. The organic phase is washed with saturated sodium chloride solution, dried with magnesium sulfate and the solvent is evaporated off in vacuo; Residue 8.1 1 g. After separation by column chromatography (silica gel 60, mobile phase: petroleum ether / ethyl acetate = 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

NH,

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 h. The cleaning is carried out by thin layer chromatography (silica gel 60, mobile phase: 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-l, 4-oxazine HIN, _^ N-NH,

0 ₂ N ^' O

Analog D.R. 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 overnight at

RT stirred. 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 (decomp.) Yield: 0.48 g (97% of theory)

Example XXXVII

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

, N

^

0 ₂ O

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. (decomp.) 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 for 2 h hydrated. After filtering the catalyst, evaporate i.V. to dry up. 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} propy-1-acetamide

N;

N -

~ 0

H ₃ C - O

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 for 2 h stand at RT. 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 mixed with 1.67 g of silica gel 60 and

15 ml abs. Toluene added and heated to boiling for 3 h.

R _f (dichloromethane / methanol = 100/3) = 0.44 yellow, amorphous product, mp:> 230 ° C (decomp.) Yield: 0.7 g (75.6% of theory)

Example XLI

1-Methyl 1-7-amino-1, 2,4-triazolo [3, 4-c] [1, 4] benzoxazine 77

In analogy to the preclift of Example XXXVIII, the title compound is obtained 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 (decomp.) Yield: 0.43 g (98.8% of theory)

Example XLH

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

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) -propionylaminomethyloxirane and 4 g of silica gel 60 in 5 ml Chloroform made. 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. Dichloromethane dissolved, mixed with 5 g of silica gel (40 - 63 μm) and i.V. evaporated to dryness. The coated silica gel is left to stand for two days and then eluted with dichloromethane and

Methanol. After evaporation i.V. 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 of 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 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 vacuo, the last traces of DMF also being 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] -benzoxazin-3-carboxylic acid ethyl ester

N:

H ₅ CY ₂ 0 X ⁰ X ^ NH ₂

144 mg (0.5 mmol) of the nitro compound from Example XLIV are dissolved in 2 ml of ethanol, with 129.5 mg (2 mmol) of ammonium formate and a spatula tip Pd / C- Catalyst (10%) was added and the mixture was heated in a bath at 80 ° C. for 5 minutes. After cooling, the catalyst is filtered off over kieselguhr and the filtrate i. V. evaporated. 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 XL VI

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 the IV Evaporated to dryness. The mixture is left to stand overnight, dichloromethane and a further 7 mg (0.06 mmol) of oxirane are added, the mixture is evaporated i. V. dries up and leaves another day. The coated silica gel is eluted with 10 ml dichloromethane methanol = 7/3, evaporated down i. V. on a small volume and separate the residue on a thick-film plate; Mobile phase: 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 XL VII

7-nitro-4H-imidazo [5.1-c] [1.4] -benzoxazin-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 in hydrochloric acid. Colorless crystals gradually fall out. R _f (dichloromethane / methanol = 10/1) = 0.07 Yield: 97 mg (59.9% of theory)

Example XL VIII

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

N

, N

O ^' ^{^} NO,

54 mg (0.21 mmol) of the carboxylic acid from Example XLVII are mixed with 2 ml for 10 min

Diphenyl ether heated in a bath heated to 250 ° C. After cooling, put everything on a silica column, wash the diphenyl ether with dichloromethane and elute the product with dichloromethane / methanol = 100/5. After concentration, colorless crystals are obtained.

Rf (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 XL VIII 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 heated in a preheated bath at 80 ° C for 7 min. After filtering off the catalyst, the solvent is evaporated to dryness. colorless, amorphous product, Rf (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. Lc] [1. 4] -benzoxazin-7-yl) -amino} -propyl-acetamide

20 mg (0.1 1 mmol) of the amine from Example IL are dissolved in 1 ml of dichloromethane, 14.76 mg (0.13 mmol) of (S) -acetylaminomethyloxirane and 64.2 mg (1.07 mmol) of silica gel are added and i. V. evaporated to dryness. After standing for 1 day, the starting materials are again dissolved (hardly any product!) In dichloromethane, mixed with 1.2 further equivalents of oxirane, and steamed i. V. dries up and leaves another day. Then eluted with dichloromethane / methanol (7/3), concentrated i. V. and separates the residue on a thick-film 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

Ethyl l- (2,2-dimethoxyethyl) -5-nitro-indole-2-carboxylate

OCH,

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 dimethyl 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, concentrated i. V. dries up and crystallizes through

Stir 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

OCH,

3.5 mg (10.55 mmol) of the ester from Example LI are dissolved in 50 ml of THF, mixed with 25 ml of sodium hydroxide solution and stirred at 60 ° C. The saponification is complete after 2 hours. The solvent is evaporated off and the remaining dark brown solution is extracted 3 times 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 LIH

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

OCH,

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 you narrow i. V. to about half of the volume, mixed with dilute NaHC0 ₃ solution and extracted several times with dichloromethane. After washing with water and drying with magnesium sulfate, i. V. a. R _f (dichloromethane) = 0.78 yield, crude: 2.9 g (quantitative)

Example LIV

1- (2,2-Dimethoxyethyl) -2-tert-butyl-oxycarbonyl-amino-5-nitroindole

CH,

OCH,

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). One constricts i. V. to dryness and purify the residue 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. It is neutralized with saturated NaHC0 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 87

The residue was 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) -acetylaminomethyl-oxirane and 526 mg (8.75 mmol) of silica gel are slurried in 10 ml of chloroform and i. V. evaporated to dryness. The silica gel coated in this way is left to stand overnight, eluted with 10 ml 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. 88 -

Example LVIII

7-nitro-5H-imidazo [1.2-a] [3, l] -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-l, 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 C1, / MeOH = 100 / 2.5), 5 g of the title compound (40.1% of theory) are obtained. fbl. Solid product, R _f (dichloromethane methanol 10/1) = 0.34

Example LIX

7-amino-5H-imidazo [1.2-a] [3. l] -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% strength) are added and the mixture is hydrogenated with hydrogen for 2 h. The catalyst is filtered through 89

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, lc] [1,4] benzoxazine 90

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-l, 4-oxazin-3-one in 160 ml 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 / l); 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 the mixture is pressure at 2 bar for several hours

Hydrogen hydrogenates. After filtering off the catalyst, i.V. evaporated to dryness.

R _f (dichloromethane / methanol = 100/3) = 0.69 fbl. Crystals, mp:> 250 ° (decomp.) Yield: 0.784 g (90.8% of theory) Example LXIII

2-amino-5-nitro-benzyl alcohol

O OH

25g (0.14 mol) of 2-amino-5-nitro-benzoic acid are dissolved in 800 ml. Dissolved THF and slowly added 38.7 g (0.45 mol) 450 ml BH ₃ x THF complex with ice cooling. During the first hour of dropping (approx. 180 ml of the BH, x THF complex) there is violent gas evolution. Then the remainder is added and the mixture is stirred at RT overnight. 100 ml of water are then added dropwise

(extremely violent gas evolution during the first 20 minutes!) and then 50 ml of 1 N hydrochloric acid. The mixture is stirred for a further 1 h at RT, 25 ml of 1 molar potassium carbonate solution are added and the mixture is evaporated in vacuo. at 30 ° C the THF off. The desired product fails. It is filtered off, washed well with water and dried in a high vacuum. yellow crystals

Yield: 19.7 g (85.4% of theory)

Example LXIV

6-nitro-1,4-dihydro-2H-3,1-benzoxazin-2-one

10 g (0.06 mol) of the benzyl alcohol from Example LXIII are dissolved in 100 ml of dioxane, 1 1 g (0.07 mol) of CDI are added and the mixture is stirred at RT for 3 h. The mixture is heated at 50 ° C. for a further 1 h, the solvent is evaporated off in vacuo, acidified slightly with 1 N hydrochloric acid, neutralized with dilute NaHCO, solution and extracted with ethyl acetate. The evaporated extract is separated by column chromatography. (Silica gel 60,

Mobile solvent: dichloromethane / methanol = 100/5). yellow crystals Yield: 2.7 g (23.4% of theory)

Example LXV

6-nitro-1,4-dihydro-2H-3,1-benzoxazin-2-thione

2.7 g (0.014 mol) of the compound from Example LXIV are dissolved in 200 ml of dioxane, 6.4 g (0.016 mol) of Lawesson ^'s reagent are added and the mixture is heated to boiling for 3 h. After cooling, the solvent is evaporated off in vacuo, methanol is added, the mixture is stirred for 10 minutes, cooled to 0 ° C. and filtered, yellow crystals, mp: 206-208 ° C. (dec.) Yield: 2.3 g (78.7% d.Th.)

Example LXVI

2-methylsulfanyl-6-nitro-4H-3, 1-benzoxazine >r> -

2.3 g (10.9 mmol) of the thione from Example LXV are dissolved in 50 ml of acetone, mixed with 1.82 g (13.1 mmol) of potassium carbonate and 0.75 ml = 1.71 g (12 mmol) of methyl iodide and stirred at RT for 2 h. You steam i.V. dry, stir briefly with a little water and filter, yellow solid product Yield: 2.1 g (85.6% of theory)

Example LXVII

N- (6-Nitro-4H-3, 1-benzoxazin-2-yl) aminoacetaldehyde dimethyl acetal

2.1 g (9.4 mmol) of the compound from Example LXVI are dissolved in 150 ml of ethanol, mixed with 2.1 ml = 1.97 g (18.7 mmol) of aminoacetaldehyde dimethylacetal and heated to 70-80 ° C. overnight . According to the DC control (eluent: dichloromethane / metanol = 100/5), educt is still present. The same amount of acetal is added once more and the mixture is heated to boiling for a further 4 h. Then evaporate everything to dryness in vacuo, stir with a little dilute NaHCO ^ solution and filter the desired product. solid yellow product Yield: 2.37 g (90.0% of theory)

Example LXVIII

7-nitro-4H-imidazo [1, 2-a] [3, 1] benzoxazine

1.98 g (7.04 mmol) of the compound from Example LXVII are dissolved in 40 ml of THF, carefully with 20 ml of conc. Added sulfuric acid so that the temperature does not exceed 50 ° C and then stirred at RT for 15 minutes. To complete the

Ring closure is heated to about 80 ° C for 1 h. After cooling, the reaction mixture is carefully poured onto ice, made alkaline with 180 ml of 4N sodium hydroxide solution and evaporated in vacuo. the THF. The yellowish precipitate is filtered off, washed neutral with water and dried in a high vacuum. Rf: (dichloromethane methanol = 1/1) = 0.42

Yield: 1.28 g (83.7% of theory)

Example LXIX

7- Amino-4H-imidazo- [1,2-a] [3,1] -benzoxazine

1.28 g (5.89 mmol) of the nitro compound from Example LXVIII are suspended in 200 ml of ethanol, 400 mg of Pd / C (10%) are added and the mixture is hydrogenated at RT under normal pressure with hydrogen. The catalyst is filtered off, washed well with ethanol and methanol, the filtrate is evaporated in vacuo to a small volume and the residue is purified by column chromatography (silica gel 40-60 μm, mobile phase: dichloromethane / methanol = 100/1) colorless solid product

Rf: (dichloromethane methanol = 10/1) = 0.88 yield: 200 mg (18.1% of theory)

Example LXX

N- (R) -2-Hydroxy-3 - {(4H-imidazo- [1, 2-a] [3, 1] -benzoxazin-7-yl) -amino} -propy 1-acetamide

H ₃ CO

47.9 mg (0.26 mmol) of the amine from Example LXIX are dissolved in 10 ml of dichloromethane, 35.35 mg (0.31 mmol) of (S) -acetylaminomethyl-oxirane and 154 mg (2.56 mmol) of silica gel 60 are added. Everything is evaporated to dryness and left to stand overnight. It is eluted with 15 ml of dichloromethane / methanol = 7/3, concentrated a little and the residue is purified on a thick-layer plate (mobile phase: dichloromethane / methanol = 10/1, eluent: methanol), colorless solid product Rf: (dichloromethane / methanol = 10/1) = 0.26

Yield: 23.2 mg (30.0% of theory)

In addition, 11.4 mg (23.8% of theory) of starting material were recovered.

Example LXXI

2-tert.butyloxycarbonylamino-7-nitro-4H-imidazo- [2, l-c] [l, 4] -benzoxazine

600 mg (3.11 mmol) of 3-amino-7-nitro-2H-l, 4-benzoxazine are abs in 10 ml. DMF dissolved, 2.2 g (9.32 mmol) of tert-butyl bromoacetylcarbamate and 50 granules of 3 Å molecular sieve were added and the mixture was stirred at 60 ° C. for 4 h. After cooling, the mixture is poured onto ice water, filtered and the red-brown residue is separated by column chromatography (silica gel 60, mobile phase: dichloromethane / methanol = 100/2). Yield: 361 mg (35.0% of theory)

Example LXXII

2-tert.butyloxycarbonylamino-7-amino-4H-imidazo- [2, lc] [1,4] benzoxazine - 97 -

50 mg (0.15 mmol) of the compound from Example LXXI are dissolved in 10 ml of dichloromethane / methanol (7/3), mixed with 25 mg of Pd / C catalyst (10%) and hydrogenated at RT within 3 h . The catalyst is filtered off over kieselguhr, the filtrate is evaporated in vacuo. and triturates the residue with diethyl ether. colorless solid product Yield: 30 mg (65.9% of theory)

Example LXXIII

N- (R) -2-Hydroxy-3 - {(2-tert-butyloxycarbonylamino-4H-imidazo- [2, l-c] [1,4, -benz-oxazin-7-yl) -amino} -propyl-acetamide

H ₃ CP ^H ^

H ^H 3 ^C -N

10 mg (30 μmol) of the compound from Example LXXII are dissolved in 1 ml of dichloromethane, and 4.57 mg (40 μmol) of (S) -acetylaminomethyl-oxirane and 19.9 mg (-0.33 mmol) of silica gel are added. After shaking everything well, evaporate to dryness IV and let everything stand overnight. The next day (according to TLC, eluent: dichloromethane methanol = 10/1, educt is still present), the mixture is slurried in a little dichloromethane, mixed with a further 4 mg (35 μmol) oxirane and 10 mg (0.16 mmol) silica gel, evaporated in vacuo and react again overnight. After stirring with a little dichloromethane / methanol (4/1) and filtration, the filtrate is evaporated to a small volume and cleaned on a thick-layer plate (eluent: dichloromethane / methanol = 10/1; Rf = 0.45; eluent: methanol ), colorless foam Yield: 4.7 mg (34.0% of theory)

Example LXXIV

1- (N ² -Nitromethylene hydrazinyl) -2-propynoxy-4-nitrobenzene

Preparation of a 0.2 M nitromethane sodium solution: 100 mg NaOH (2.5 mmol) are dissolved in 490 μl water, cooled to 0 ° C. and added dropwise with a solution of 134 μl (61 g / mol ≡ 1.13 g / ml _ 1 eq.) nitromethane in 930 μl ethanol. The suspension obtained is made up to 12.2 ml with ice water, a clear solution being formed. 30 mg (0.13 mmol) of 2-propinoxy-4-nitroaniline hydrochloride are suspended in 300 μl of 2 N hydrochloric acid, cooled to 0 ° C. and mixed with a solution of 9.6 mg of sodium nitrite in 39 μl of water. This gives a yellow suspension. The pH is adjusted to 5 with cold 2N hydrochloric acid (yellow suspension remains) and 650 μl of the 0.2 M nitromethane-sodium solution prepared above are then added. The suspension turns red-brown. The mixture is stirred for a further 1 h at 0 ° C. and then extracted with a mixture of 0.5 N hydrochloric acid and ethyl acetate (1/1). The organic phase is separated off, dried with magnesium sulfate and concentrated in vacuo to a small volume. The cleaning is carried out by means of thick layer chromatography; Eluent: toluene / acetone = 10/1; Eluens: ethanol. An orange solid product is obtained. Rf (toluene / ethanol = 1/1) = 0.76 Yield: 25 mg (72.1% of theory)

Example LXXV

7-nitro-4H-pyrazolo- [l, 5-d] [l, 4] -benzoxazine

0.57 g (2.16 mmol) of the compound from Example LXXIV are mixed with 15 ml of o-xylene and heated to boiling overnight. After cooling, add

Petroleum ether, filtered, the petroleum ether is distilled off from the filtrate and the residue is purified by column chromatography; Kieselgel 60, mobile phase: petroleum ether / dichloromethane = 2/1 to 1 / 2. A yellow solid product is obtained. Rf (petroleum ether / dichloromethane = 1/1) = 0.67 Yield: 48 mg (10.2% of theory) Example LXXVI

7-Amino-4H-pyrazolo- [l, 5-d] [l, 4] -benzoxazine

50 mg (0.23 mmol) of the compound from Example LXXV are placed in 5 ml of ethanol under an argon atmosphere, mixed with 10 mg of Pd / C catalyst (10%) and hydrogenated at RT and normal pressure. After filtering off the catalyst, i.V. on a small volume and clean the rest using thick-layer chromatography; Mobile phase: dichloromethane / methanol = 100/2; Eluens: methanol. A colorless solid product Rf (dichloromethane / methanol = 100/2) = 0.11 yield: 26 mg (60.3% of theory) is obtained.

Example LXXVII

N- (R) -2-Hydroxy-3- {(4H-pyrazolo- [1,5-d] [1,4] benzoxazin-7-yl) amino} propyl acetamide

26 mg (0.14 mmol) of the compound from Example LXXVI are dissolved in 1 ml of dichloromethane, mixed with 19.2 mg (0.17 mmol) of (S) -acetylaminomethyl-oxirane and 83.45 mg (1.39 mmol) of silica gel, shaken well and IV evaporated to dryness. You react overnight. After stirring with 2 ml of dichloromethane, another 0.6 eq. Add oxirane, evaporate IV and leave for 4 h. It is eluted by stirring with 5 ml of dichloromethane / methanol (4/1), filtered, the filtrate is concentrated in vacuo to a small volume and the residue is separated by means of thick layer chromatography; Mobile phase: dichloromethane / methanol = 10/1; Eluens: methanol. A colorless foam is obtained. Rf (dichloromethane / methanol = 10/1) = 0.51 yield. 20.7 mg (49.3% of theory) and 5.2 mg (20%) of educt

Example LXXVIII

N- (R) -2-Hydroxy-3 - {(4H-imidazo [2, 1-c] [1, 4] -benzoxazin-7-y l) -amino} -propyl-carbamic acid tert-butyl ester

Prepared analogously to Example XV from 1 g (5.34 mmol) of the compound from Example XIV and 1.1 1 g (6.41 mmol) of (S) -tert.Butyloxycarbonylaminomethyl-oxirane. colorless foam

Rf (dichloromethane / methanol = 100/5) = 0.25 Yield: 625 mg (32.5% of theory) 102 -

Example LXXIX

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

100 mg (0.26 mmol) of the compound from Example LXXVIII are suspended in dioxane, a little methanol is added until a clear solution is obtained and the mixture is stirred overnight with 2 ml of a 4N dioxane × HCl solution. It is neutralized with dilute NaHC0 ₃ solution, dried with magnesium sulfate and evaporated to dryness in vacuo. The residue is separated by thin layer chromatography; Kieselgel 60, mobile phase: dichloromethane / methanol = 4/1, Rf = 0.25 colorless solid product yield: 37 mg (49.7% of theory)

Example LXXX

2-bromodifluoroacetylamino-5-nitrophenol O.

N

I I O

7 g (45.4 mmol) of 2-amino-5-nitrophenol are dissolved in 160 ml of DMF, 5.3 g (52.2 mmol; 7.24 ml) of triethylamine are added, the mixture is cooled to 0 ° C. to 5 ° C. in an ice bath and under 10.1 g (52.2 mmol) of bromo difluoroacetyl chloride are added dropwise to the stirring. After the acid chloride has been added, the mixture is stirred for a further 1 h at RT. Then you steam i.V. everything to dryness, take up (stir) in 250 ml dichloromethane / water (1/1), separate the organic phase and wash the organic phase twice with 100 ml dichloromethane each. The combined organic phases are dried with sodium sulfate, i.V. concentrated to a small volume and separated by column chromatography; Kieselgel 60, mobile phase: dichloromethane / ethyl acetate = 100/3, Rf = 0.52. yellow solid product Yield: 6.4 g (45.3% of theory)

Example LXXXI

2,2-difluoro-7-nitro-4H-benz-1,4-oxazin-3-one

O.

N

II O

20 mg (64 μmol) of the compound from Example LXXX are dissolved in 0.5 ml of DMF (or DMSO!), 7.22 mg (64 μmol) of potassium tert-butoxide are added and the mixture is stirred at 50 ° C. for 6 h 104 -

touched. You steam everything i.V. to dryness, stir for 10 minutes with 10 ml of ice water, filter and dry the residue in a high vacuum; yellow solid product, Rf (dichloromethane / ethyl acetate = 100/3) = 0.35 yield: 13.5 mg (91.2% of theory)

Example LXXXII

N- (2,2-difluoro-7-nitro-2H-l, 4-bezoxazin-3-yl) aminoacetaldehyde dimethyl acetal

2 g (8.7 mmol) of the compound from Example LXXXI are dissolved in 80 ml of dichloromethane, 2.74 g (10.4 mmol) of triphenylphosphine and 2.47 g (10.4 mmol) of hexachloroethane are added and the mixture is heated to 40 ° C. for 30 minutes (!) . After cooling, 1.45 ml (1.06 g; 10.4 mmol) of triethylamine are added dropwise with stirring and the mixture is warmed to 40 ° C. for 2 h. After cooling, 2.84 ml (2.74 g; 26.07 mmol) of aminoacetaldehyde dimethyl acetal are added dropwise with stirring at room temperature. After stirring for 1 h, 80 ml of water are added, the organic phase is separated off, the aqueous phase is shaken out twice with 50 ml of dichloromethane each time and the organic phases are combined. After drying with sodium sulfate and concentration in vacuo to a small volume, there is a separation by column chromatography, silica gel 60, mobile phase: dichloromethane / ethyl acetate = 9/1, Rf = 0.77; yellow solid product Yield: 2.1 g (76.2% of theory) Example LXXXIII

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

1.4 g (4.4 mmol) of the compound from Example LXXXII are in an argon atmosphere (preheat the flask beforehand!) In 20 ml abs. Dissolved dioxane, mixed with 2 g molecular sieve (4Ä) and 5.13 g (22.1 mmol) camphor-10-sulfonic acid and heated to 100 ° C. The ring is closed after 10 minutes at the latest (darkening). The mixture is allowed to cool, neutralized with solid sodium hydrogen carbonate and so much water is added that a clear solution is obtained. The desired product is obtained by shaking several times with ethyl acetate and subsequent separation by column chromatography; Kieselgel 60, mobile phase: dichloromethane / ethyl acetate = 100/5, Rf = 0.42. yellow solid product Yield: 0.77 g (68.9% of theory)

Example LXXXIV

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

80 mg (0.32 mmol) of the nitro compound from Example LXXXIII are dissolved in 40 ml of methanol, 50 mg of Pd / C catalyst (10%) are added and the mixture is hydrogenated for 1 h at 2 bar hydrogen pressure. The catalyst is then suctioned off and the filtrate is evaporated to dryness. The residue is stirred with a little diethyl ether, filtered and dried in a high vacuum. Rf (dichloromethane / methanol = 100/1) = 0.19 fbl. Solid product yield: 65 mg (92.2% of theory)

Example LXXXV

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

HN

H, C ^ O

110 mg (0.49 mmol) of the amine from Example LXXXIV, 70 mg (0.59 mmol) of (S) -acetylaminomethyl-oxirane and 0.3 g of silica gel 60 are dissolved in 5 ml of abs. Slurried chloroform, treated in an ultrasonic bath and evaporated to dryness in vacuo. The mixture is left to stand at RT overnight. After elution with 10 ml of warm chloroform, the mixture is filtered, the filtrate is evaporated and the remainder is purified by column chromatography; Kieselgel 60, eluent: dichloromethane / methanol = 9/1, Rf = 0.54. fbl. Solid product Yield: 9 mg (5.4% of theory) In addition, 90 mg (81.8%>) of starting material are recovered.

Example LXXXVI

4,4-difluoro-7-benzyloxycarbonylamino-4H-imidazo [2, l-c] [1,4] benzoxazine

0.5 g (2.24 mmol) of the amine from example LXXXIV are dissolved in 3.1 ml of dioxane, mixed with 4.44 ml of saturated sodium hydrogen carbonate solution and in an ice bath

Cooled to 0 ° C. 0.35 ml (0.42 g; 2.46 mmol) of benzyl chloroformate are added dropwise with stirring. Then allowed to stir at RT for a further 30 minutes. 20 ml of water are added and the mixture is filtered, washed with water and the residue is dried under high vacuum. Rf (dichloromethane / methanol = 100/3) = 0.6 fbl. Crystals yield: 0.73 g (91.2% of theory)

- 108

Example LXXXVII

(5S) -3- (4,4-Difluoro-4H-imidazo- [2, l-c] [1,4, -benzoxazin-7-yl) -5-hydroxymethyl-oxazolidin-2-one

HO-

0.35 g (0.98 mmol) of the compound from Example LXXXVI are dissolved in 1.5 ml of dimethylacetamide under an argon atmosphere, cooled to 0 ° C. and with stirring with a solution of 2.5 molar butyllithium solution cooled to -20 ° C. in n-hexane (2.1 mmol) and 0.35 ml tert. Amyl alcohol (3.16 mmol) was added. One leaves 15

Stir minutes at 0 ° C and 0.17 ml (0.18 g; 1.22 mmol) of (R) - (-) - glycidyl butyrate are added. After stirring overnight at RT, a solution of 3.1 ml of water, 3.1 ml of methanol and 0.19 ml of acetic acid is added. Then evaporate everything to dryness in vacuo and the residue is separated by column chromatography; Kieselgel 60, eluent: dichloromethane / methanol = 100/7, Rf = 0.34. fbl. Solid product Yield: 142 mg (44.8% of theory)

- 109 -

Example LXXXVIII

(5S) -3- (4,4-Difluoro-4H-imidazo- [2, l-c] [1,4, -benzoxazin-7-yl) -5- (3-nitrophenylsulfonyloxymethyl) -oxazolidin-2-one

50 mg (0.155 mmol) of the alcohol from example LXXXVII are dissolved in 1 ml of dichloromethane under an argon atmosphere, 31.3 mg (0.31 mmol) of triethylamine are added, the mixture is cooled to 0 ° C. and, with stirring, 51.4 mg (0.23 mmol) 3-nitrobenzenesulfonic acid chloride added. After stirring at 0 ° C. for 12 h, 5 ml of 1N sodium hydroxide solution are added, the precipitate which has separated out is filtered off, washed with water and dried in a high vacuum.

Rf (dichloromethane / methanol = 100/3) = 0.5 fbl. Crystals yield: 55.3 mg (70.3% of theory)

Example LXXXIX

(5S) -3- (4,4-Difluoro-4H-imidazo- [2, l-c] [1,4, -benzoxazin-7-yl) -5-aminomethyl-oxazolidin-2-one

H ₂ N- 0.27 g (0.53 mmol) of the compound from Example LXXXVIII are dissolved in 2.6 ml of isopropanol and 4.8 ml of DMF, mixed with 4 ml (approx. 53 mmol) of a saturated, aqueous ammonia solution and overnight at Stirred at 40 ° C (suspension). 1.3 ml of isopopanol, 2.4 ml of DMF and 2 ml of the above ammonia solution are added and the mixture is stirred at 40 ° C. for a further 5 h. It is concentrated a little in vacuo, the precipitate is filtered off, washed with a little water and dried in a high vacuum. Rf (dichloromethane / methanol = 9/1) = 0.1 1 fbl. Solid product yield: 130 mg (76.0% of theory)

Example XC

7-Benzyloxycarbonylamino-4H-tetrazolo- [5, 1-c] [1, 4] -benzoxazine

Prepared analogously to Ex. LXXXVI from 0.73 g (3.86 mmol) of the compound from Ex.

LXII, 7.3 ml saturated sodium bicarbonate solution and 0.72 g (4,245 mmol)

Benzyl chloroformate.

Rf (dichloromethane / methanol = 100/1) = 0.54 fbl. Crystals

Yield: 1.2 g (96.2% of theory) 11

Example XCI

(5S) -3- (4H-Tetrazolo- [5, l-c] [1,4, -benzoxazin-7-yl) -5-hydroxymethyl-oxazolidin-2-one

Prepared analogously to Ex. LXXXVII from 0.1 g (0.323 mmol) of the compound from Ex.

XC, 0.1 ml (0.09 g; 1,044 mmol) tert. Amyl alcohol, 0.28 ml (0.04 g; 0.7 mmol) one

2.6 molar butyllithium solution in n-hexane, 0.06 ml (0.06 g; 0.4 mmol) (R) - (-) -

Glycidyl butyrate and 0.06 ml acetic acid in 0.5 ml dimethylacetamide.

Rf (dichloromethane methanol = 100/3) = 0.25 fbl. Solid product

Yield: 30 mg (32.1% of theory)

Example XCII

(5S) -3- (4H-Tetrazolo- [5, lc] [1,4] -benzoxazin-7-yl) -5- (3-nitrophenylsulfonyloxymethyl) oxazolidin-2-one

12th

Prepared analogously to Ex. LXXXVIIl from 100 mg (0.35 mmol) of the alcohol from Ex.

XCI, 0.1 ml (0.07 g; 0.69 mmol) triethylamine and 100 mg (0.43 mmol) 3-nitrobenzenesulfonic acid chloride.

Rf (dichloromethane methanol = 100/3) = 0.48 fbl. Solid product

Yield: 55 mg (33.5% of theory)

Example XCIII

(5S) -3- (4H-Tetrazolo- [5, l-c] [1,4, -benzoxazin-7-yl) -5-aminomethyl-oxazolidin-2-one

Prepared analogously to Example LXXXIX from 50 mg (0.105 mmol) of the alcohol from Example XCII and 0.8 ml (-10.5 mmol) of a saturated (approx. 25%) aqueous ammonia solution. Rf (dichloromethane / methanol = 9/1) = 0.15 fbl. Solid product

Yield: 21.3 mg (70.1% of theory)

Example XCIV

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

2.7 g (10 mmol) of 3-amino-7-nitro-2H-benz-l, 4-oxazine are abs in 10 ml. DMF dissolved, mixed with 3.03 g (1.95 ml; 10 mmol) of ethyl bromobenzenate and heated to 80 ° C. for 1 h under an argon atmosphere. After cooling, the DMF is distilled off (Kugelrohr), the residue is stirred with water / dichloromethane, the organic phase is separated off, dried and purified by column chromatography; Mobile phase: cyclohexane / ethyl acetate = 1/1 to pure ethyl acetate.

Rf (ethyl acetate) = 0.48 orange crystals Yield: 0.9 g (22.7% of theory). In addition, 0.84 g (31.1%) of starting material is recovered and approx. 1 g (37%) from the aqueous phase 7-nitro-4H-benz-l, 4-oxazin-3-one (Ex. IX). Example XCV

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

235 mg (0.58 mmol) of the compound from Example XCIV are abs. In 15 ml. Dissolved THF, cooled to 0 ° C., mixed with 0.58 ml (0.58 mmol) of a 1 molar solution of lithium alanate in THF and stirred at RT for 1 h. 10 ml of methanol are added and the mixture is evaporated in vacuo. everything to dryness and purify the residue by column chromatography; Silica gel 60, mobile phase: dichloromethane methanol = 100/5, Rf = 0.15. yellow crystals, mp: 197 ° C. Yield: 65 mg (45.4% of theory)

Example XCVI

2-tert-butyldimethylsilyloxymethyl-7-nitro-4H-imidazo- [2, 1-c] [1,4] -benzoxazine

H, C CH-

H ₃ C _/ CH ₃ Si

H ₃ C

O

220 mg (0.89 mmol) of the alcohol from Ex. XCV are dissolved in 20 ml abs. Submitted dichloromethane, mixed with 0.16 ml (144.5 mg, 1.33 mmol) of 2,6-lutidine and cooled to - 50 ° C. Then 0.22 ml (252 mg, 0.93 mmol) of trifluoromethanesulfonic acid, tert-butyldimethylsilyl ester are added. The mixture is first reacted at -50 ° C. for 30 minutes, then at RT for 4 h. Then it is mixed with 5 ml of water and extracted with dichloromethane. After drying with magnesium sulfate and filtration, the filtrate is evaporated to dryness in vacuo and the residue is purified by column chromatography; Silica gel 60, mobile phase: dichloromethane / methanol = 100 / 0.5, Rf = 0.65. yellowish foam

Yield: 297 mg (92.3% of theory)

Example XCVH

2-tert-butyldimethylsilyloxymethyl-7-amino-4H-imidazo- [2, 1-c] [1, 4] -benzoxazine

H- 3C \ CH-

H ₃ C CH-

H ₃ C o

293 mg (0.81 mmol) of the nitro compound from Example XCVI are dissolved in 20 ml of methanol under an argon atmosphere, 29.3 mg of Pd / C catalyst (10%) and 511 mg (8.1 mmol) of ammonium formate are added and the mixture is stirred for 2 h Boiling heated. After cooling, the catalyst is filtered off, washed with methanol and the filtrate evaporated to dryness. The residue is separated by column chromatography; Kieselgel 60, mobile phase: dichloromethane / methanol = 100 / 2.Rf (dichloromethane / methanol = 100/5) = 0.32 light brown crystals, mp: 92 -95 ° C yield: 222 mg (82.6% of theory)

Example XCVIII

N- (R) -2-Hydroxy-3 - {(2-tert-butyldimethylsilyloxymethyl-4H-imidazo- [2, 1-c] [1, 4] - benzoxazin-7-yl) -amino} -propy 1- acetamide

H ₃ C CH

222 mg (0.67 mmol) of the amine from Ex. XCVII are dissolved in 10 ml of dichloromethane, 80.8 mg (0.7 mmol) of (S) -acetyl-aminomethyl-oxirane and 2 g of silica gel 60 are added and the mixture is evaporated to dryness in vacuo. After 24 hours, about 30% of the starting material has reacted. There are still 1.05 eq. of oxirane and repeats the above procedure. After a further 3 h, elution is carried out with chloroform, the eluate is concentrated in vacuo to a small volume and separated by column chromatography; Kieselgel 60, mobile phase: dichloromethane / methanol = 100/3 to 100/6. Rf (dichloromethane / methanol = 10/1) - 0.44 yellowish foam Yield: 152.1 mg (51.0% of theory) 1 17

In addition, about 100 mg (45%) of starting material are recovered.

Example IC

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

H ₃ C. CH.

148 mg (0.33 mmol) of the compound from Example XCVIII in 5 ml of abs. Dioxane submitted, mixed with 54 mg (0.33 mmol) CDI and to

Boil heated (clear solution). Another 54 mg of CDI are added and the mixture is left to react overnight at boiling temperature. After cooling, 2 ml of water and 10 ml of dichloromethane are added, the organic phase is separated off, the aqueous phase is shaken twice with 5 ml of dichloromethane, the combined organic phases are dried with magnesium sulfate and evaporated in vacuo. dries up and separates the

Residue by column chromatography; Kieselgel 60, mobile phase: dichloromethane / methanol = 100 / 3. Rf (dichloromethane / methanol = 100/5) = 0.2 fbl. Foam yield: 141 mg (90.0% of theory) 118

Example C

7-nitro-imidazo [1,2-a] quinoline

2.2 g (10.55 mmol) of 2-chloro-6-nitroquinoline are mixed well with 1.09 g (15.82 mmol) of 1H-1,2,3-triazole and heated briefly to 150 ° C under an argon atmosphere (slowly heat up). After cooling, the mixture is stirred for 1 h with 100 ml of dichloromethane, washed twice with water, the organic phase is dried with magnesium sulfate and evaporated down i.V. and separates the residue by column chromatography; Kieselgel 60, running agent dichloromethane / methanol = 100 / 1. Rf (ethyl acetate) = 0.15 yellow crystals yield. 1.39 g (61.8% of theory)

Example CI

7-amino-imidazo [1,2-a] quinoline

200 mg (0.94 mmol) of the nitro compound from Example C are placed in 5 ml of methanol under an argon atmosphere, 20 mg of Pd / C catalyst (10%) and 592 mg (9.4 mmol) of ammonium formate are added and 25 minutes in a 75 ° C heated hot oil bath. After cooling, the catalyst is filtered off, washed well with metha- nol and evaporates to dryness. The residue is purified by column chromatography; Kieselgel 60, mobile phase: dichloromethane / methanol = 100 / 5.Rf (dichloromethane / methanol = 10/1) = 0.33 fbl. Foam, light gray Yield: 128.6 mg (74.8% of theory)

Example CH

N- (R) -2-Hydroxy-3 - {(imidazo- [1,2-a] [1,2-a] -quinolin-7-yl) amino} propyl acetamide

128.6 mg (0.7 mmol) of the amine from example CI and 81.1 mg (0.7 mmol) of (S) -acetylaminomethyl-oxirane are dissolved in 10 ml of dichloromethane. 127 mg (2.1 1 mmol) of silica gel 60 are added, and everything is mixed well after thorough mixing. evaporated to dryness. After 24 h, everything is eluted with 10 ml of dichloromethane and again with 1 eq. Oxirane added. The further reaction on the solid phase (analogous to the procedure above) is stopped after 5 hours. The silica gel is eluted with 20 ml of chloroform and the eluate is separated by column chromatography; Kieselgel 60, running agent PDichloromethane / methanol = 100/5 to 100 / 15. Rf (dichloromethane / methanol = 10/2) = 0.42 fbl. foam

Yield: 74 mg (35.3% of theory). In addition, 83 mg (64.5%) of starting material are recovered. Manufacturing examples

example 1

(5 S) -3 - (1, 2,4-Triazolo [3, 4-c] [1, 4] -benzoxazin-7-yl) -5-acetylaminomethyl-oxazolidin-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 carbonyldiimidazole and warmed for 3 h in a 90 ° C oil bath. You steam i.V. dry to dryness, stir with water and filter, fbl. amorphous product; Mp:> 250 ° C (decomp.) Yield: 34 mg (24.1% of theory)

Example 2

(5S) -3- (l-Methyl-l, 2,4-triazolo [3,4-c] [1,4] benzoxazin-7-yl-5-propionylamino-methyl-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) of carbonyldiimidazole in 5ml 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-one

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 mobile phase dichloromethane / methanol = 10/1). Stirring is continued overnight at room temperature, then dichloromethane and diatomaceous earth are added. After separation by column chromatography on silica gel 60 with dichloromethane / methanol = 100/5 as the eluent, 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, lc] [1,4] -benzoxazin-7-yl) -5-acetaminomethyl-oxazolidin-2-one - 122 -

CH,

N -X _/ N

O

O CH,

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, l-c] [1,4, -benzoxazin-7-yl) -5-acetylaminomethyl-oxazolidin-2-one

H ₃ C

N N .N

O

^{^} O N

O Λ CH,

H

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. - 123 -

fbl. Crystals, mp: 205 ° C (dec.)

R _f (dichloromethane / methanol = 9/1) = 0.5

Example 6

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

20 mg (0.063 mmol) of the compound from Example XV and 15 mg (0.095 mmol) of carbonyldumdazole (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, l-c] [l, 4] benzoxazin-7-yl) -5-propionylaminomethyl-oxazolidin-2-one

O

^{^} O N

O N ^' H, -CH, H 124

Analogously to the procedure of Example XV from 0.2 g (1 mmol) of the compound

Example XIV and 0.37 g (2 mmol) of (S) -propionylaminomethyl-oxirane and subsequent 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, l-c] [l, 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 production 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) and added overnight - 125

Reflux heated. It is then evaporated and the product is purified by preparative thin layer chromatography (dichloromethane methanol = 20/1).

Table 1:

R ^J

R ' O

N ' O

NH-CO-CH,

E.g. no. R ⁶ R ³ yield R _f (CH ₂ C1 ₂ / MS MeOH = 10/1)

9 H H 16 0.38 331 (DCI / NH,) M + H

10 H ₅ H 8 0.5 407 (DCI / NH,) M + H

1 1 C0 ₂ C ₂ H ₅ H 18 0.4 403, 425 (ESI) M + H

12 CH ₃ H 7 0.4 345 (ESI) M + H

13 CF ₃ H 8 0.65 399 (DCI / NH ₃ ) M + H

14 CH ₃ CH, 11 0.5 359 (DCI / NH,) M + H

15 CF, CH, 16 0.59 413 (DCI / NH,) M + H Example 16

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

O

O 'N Λ o O

Jl NHH

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. One constricts i. V., takes up with a little ethyl acetate, the product precipitates with water and filters the precipitate. 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

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

H ₃ C. - ^r O

H ', 3C OO

H Λ ^CH 3 The preparation is carried out analogously to Example 1 above from 120 mg (0.363 mmol) of

Compound from Example XX and 90 mg (0.545 mmol) CDI in 5 ml THF overnight at 50 ° C. 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-one

10 mg (0.031 mmol) of the substituted acetamide from Example XXXI are abs. Dissolved THF, added 10.19 mg (0.063 mmol) CDI and heated to boiling (TLC control with dichloromethane / methanol = 10/1 as eluent). After 3 h, only a slight conversion is found. A further 10.19 mg (0.063 mmol) of CDI are added, and the mixture is evaporated i. V. the solvent, dissolve everything in 2 ml of dioxane and heated to boiling overnight. No more educt can be detected. One constricts i. V. to dryness and purify the residue 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-acetylaminomethyl-oxazolidin-2-one

43 mg (0.14 mmol) of the substituted acetamide from Example LX are abs. THF and a few drops of abs. DMF dissolved, treated with 33 mg (0.2 mmol) CDI and heated to boiling for 1 h. There is hardly any implementation. You steam i.V. the THF is removed, taken up with 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 i.V. on. The backlog is by means of

Thin layer plate separated on silica gel; Mobile phase: 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- (3-Ethoxycarbonyl-4H-imidazo [5.1-c] [1.4] -benzoxazin-7-yl) -5-acetylamino-methyl-oxazolidin-2-one

N = O

H ₅ C ₂ 0 O ^'NOO

IN CH,

H ³

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 with 4.03 mg (24.84 μM) CDI in 0.2 ml DMF added and kept at 100 ° C. After 3 hours, more are added

4.03 mg CDI and heated at 100 ° C for a further 2 h. After evaporation i. V. the residue is separated on a thick-film 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-one

N

, N

O

X ^' Λ o O

N "Jl ^{^} CH ₃ H ³

10.8 mg (35.7 μmol) of the substituted acetamide from Example L and 8.7 mg

(53.6 μmol) CDI 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. Everything is narrowed i. V. dry and separate the residue on a thick-film 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 130

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) 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

x HCI

21 mg (67.2 μmol) of the compound from Example 22 are dissolved in a little methanol, mixed with diethyl ether / hydrogen chloride and i. V. evaporated to dryness.

The residue is stirred with diethyl ether and the precipitate is filtered, fbl. Product yield: 8 mg (31.1% of theory) Example 24

(5S) -3- (4H-Imidazo- [l, 2-a] [3, l] -benzoxazin-7-yl) -5-acetylaminomethyl-oxazolidin-2-one

18.5 mg (61.2 μmol) of the compound LXX are dissolved in 200 μl DMF, heated to 80 ° C. and mixed with 14.9 mg (91.8 μmol) CDI in 100 μl DMF. Everything is allowed to react at 80 ° C. After 1.5 h, 7.4 mg (45.6 μmol) of CDI are added and the mixture is heated at 100 ° C. for 4 h. Everything is narrowed on a small volume and purify the rest using thick layer chromatography; Mobile phase: dichloromethane / methanol = 10/1, eluent: methanol, fbl. Foam, Rf (dichloromethane / methanol = 10/1) = 0.44 Yield: 9.1 mg (45.3% of theory)

Example 25

(5S) -3- (2-tert.butyloxycarbonylamino-4H-imidazo- [2, lc] [1,4] benzoxazin-7-yl) -5-acetylaminomethyl-oxazolidin-2-one 132 -

10 mg (24 μmol) of the compound from Example LXXIII are dissolved in 0.5 ml abs. Dissolved THF, mixed with 6 mg (35.9 μmol) CDI and heated to boiling overnight. The

Cleaning takes place using a thick-film plate; Solvent:

Dichloromethane / methanol = 10/2, eluent: methanol fbl. Solid product

Yield: 1.9 mg (17.9% of theory)

Example 26

(5S) -3- (4H-Pyrazolo- [l, 5-d] [l, 4] -benzoxazin-7-yl) -5-acetylaminomethyl-oxazolidin-2-one

- 1 r>r>

20 mg (66.15 μmol) of the compound from Example LXXVII, dissolved in 0.4 ml abs. Dioxane, 16.09 mg (99.2 μmol) CDI are added and the mixture is stirred for 3 hours at 90 ° C. under an argon atmosphere. Another 8 mg (49 μmol) of CDI are added and the mixture is heated at 90 ° C. for a further 1.5 h. After cooling, water is added, i.V. the dioxane largely off and elutes extensively with ethyl acetate. The combined ethyl acetate phases are dried with magnesium sulfate, concentrated and purified by means of thick layer chromatography; Mobile phase: dichloromethane / methanol = 10/1, eluent: methanol. A colorless foam is obtained. Rf (dichloromethane / methanol = 10/1) = 0.49 Yield: 14.8 mg (68.1% of theory)

Example 27

(5S) -3- (5H-Imidazo- [l, 2-a] [3, l] -benzthiazinoxid-7-yl) -5-acetylaminomethyl-oxazolidin-2-one

5 mg (0.015 mmol) of the compound from Example 19 are dissolved in 1 ml of dichloromethane, 3.5 mg (0.01 mmol) of 3-chloroperoxybenzoic acid are added and the mixture is stirred at RT for 2 h. It is shaken out with dilute sodium carbonate solution, dried with magnesium sulfate and purified by means of thick layer chromatography; Mobile phase: dichloromethane / methanol = 10/1, Rf = 0.23, eluent: methanol, col. foam 134

Yield: 1.8 mg (34.4% of theory)

Example 28

(5S) -3- (5H-Imidazo- [l, 2-a] [3, l] -benzthiazindioxid-7-yl) -5-acetylaminomethyl-oxazolidin-2-one

20 mg (58 μmol) of the compound from Example 19 are dissolved in 4 ml of dichloromethane, 33 mg (0.13 mmol) of 3-chloroperoxybenzoic acid are added and the mixture is stirred at RT overnight. It is washed with dilute sodium carbonate solution, dried with magnesium sulfate and purified by means of thick layer chromatography; Mobile phase: dichloromethane / methanol

10/1, Rf = 0.48, eluent: methanol. fbl. Foam yield: 9.6 mg (43.9% of theory)

135 -

Example 29

(5S) -3- (4H-Imidazo- [2, l-c] [l, 4] -benzoxazin-7-yl) -5-tert.butyloxycarbonylaminomethyl-oxazolidin-2-one

Prepared analogously to Example 8 from 0.3 g (0.83 mmol) of the compound from Example LXXVIII and 0.2 g (1.25 mmol) CDI. fbl. foam

Rf (dichloromethane / methanol = 100/5) = 0.4

Yield: 310 mg (80.4% of theory)

Example 30

(5S) -3- (4H-Imidazo- [2, l-c] [1,4, -benzoxazin-7-yl) -5-aminomethyl-oxazolidin-2-one hydrochloride

NH ₂ χ HCI 136

0.31 g (0.8 mmol) of the compound from Example 29 are stirred for 2 h at RT with 2 ml of 4N dioxane x HCl solution. The precipitated, colorless precipitate is filtered, washed with dichloromethane and dried in a desiccator over PO ₁₀ , fbl. Crystals, mp:> 200 ° C (decomp.) Yield: 0.25 g (92.2% of theory)

Example 31

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

50 mg (0.175 mmol) of the compound from Example LXXIX are dissolved in 1 ml of dichloromethane, 21.7 mg (15.3 μl; 0.19 mmol) of chloroacetyl chloride are added and the mixture is cooled to 0 ° C. 38.9 mg (53.3 μl; 0.38 mmol) of triethylamine are added dropwise with stirring. The temperature is then allowed to rise to RT, washed with dilute sodium carbonate solution and extracted with dichloromethane. After drying with magnesium sulfate, evaporated to dryness in vacuo, stirred with diethyl ether, filtered and dried under high vacuum. Rf (dichloromethane / methanol = 10/1) = 0.4 fbl. Solid product Yield: 33 mg (52.1% of theory) 137

Example 32

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

50 mg (0.155 μmol) of the compound from Example 30 are mixed with 1 ml of dichloromethane and 34.5 mg (47.2 μl; 0.34 mmol) of triethylamine. The mixture is cooled to 0 ° C. and 25.1 mg (17.7 μl; 0.15 mmol) of dichloroacetyl chloride are added dropwise. After the temperature has risen to RT, it is washed with dilute sodium carbonate solution and extracted with dichloromethane. It is dried with magnesium sulfate, evaporated to dryness in vacuo, stirred with diethyl ether, filtered and dried under high vacuum. Rf (dichloromethane / methanol = 10/1) = 0.48 fbl. Solid product Yield: 20 mg (32.5% of theory)

Example 33

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

50 mg (0.155 mmol) of the compound from Example 30 are mixed with 2 ml of dichloromethane and 34.5 mg (47.2 μl; 0.34 mmol) of triethylamine. The mixture is cooled to 0 ° C. and 31 mg (17.7 μl; 0.17 mmol) of trichloroacetyl chloride are added dropwise and the mixture is stirred overnight. After the temperature has risen to RT, it is washed with dilute soda solution and extracted with dichloromethane. It is dried with magnesium sulfate, the filtrate is concentrated to a small volume and the rest is separated by means of thick layer chromatography; Eluent: dichloromethane / methanol = 10/1, eluent: dichloromethane / methanol = 7/3 Rf (dichloromethane / methanol = 10/1) = 0.51 fbl. Solid product Yield: 5.8 mg (8.7% of theory)

Example 34

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

2 g (7 mmol) of the compound from Example LXXIX are dissolved in 30 ml of chloroform, cooled to 0 ° C. and mixed with 30 ml of water, 2.1 g (21 mmol) of calcium carbonate and 0.83 ml (1.24 g; 10.48 mmol) of thiophosgene added. The mixture is stirred vigorously at RT overnight. The organic phase is then separated off and the aqueous phase is extracted

Phase three more times with chloroform. The combined organic phases are evaporated down a little and mixed with 10 ml of a 2 N methanolic ammonia solution in 20 ml of methanol. After reaction overnight, everything is evaporated to dryness and separated by column chromatography; Silica gel 60, mobile phase: dichloromethane / methanol = 10/1, Rf = 0.41. fbl. Solid product Yield: 0.7 g (29.0% of theory)

Example 35

(5S) -3- (4H-Imidazo- [2, l-c] [l, 4] -benzoxazin-7-yl) -5-methylthiocarbamoyl-aminomethyl-oxazolidin-2-one

Prepared analogously to Example 34 from 0.3 g (1.05 mmol) of the compound from Example LXXIX, 186.3 mg (123.6 μl; 1.57 mmol) thiophosgene, 314.6 mg (3.14 mmol) calcium carbonate and 15 ml of a methanolic Methylamine solution; Column chromatographic separation with silica gel 60 and the eluent: dichloromethane / methanol = 100/3,

Rf = 0.5. fbl. Solid product yield: 135 mg (35.8% of theory)

141

Example 36

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

20 mg (0.07 mmol) of the compound from Example LXXIX are placed in 0.5 ml of water, 10 mg (0.07 mmol) of potassium cyanate and 0.07 ml of 1N hydrochloric acid are added and the mixture is heated in an oil bath heated to 100 ° C. for 2 h . After cooling, the colorless precipitate is filtered, washed with water and dried in a high vacuum. fbl. Crystals, mp: 246 ° C (dec.) Yield: 18 mg (77.9% of theory)

Example 37

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

- 142

20 mg (0.07 mmol) of the compound from example LXXIX and 0.5 ml (0.46 g; 6.15 mmol) of ethyl formate are reacted overnight in a 40 ° C. oil bath. After cooling, a thin-layer chromatographic separation takes place; Kieselgel 60, mobile phase: dichloromethane / methanol = 4/1, Rf = 0.15. fbl. Foam yield: 10 mg (37.7% of theory)

Example 38

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

20 mg (0.07 mmol) of the compound from Example LXXIX and 50 mg (0.4 mmol) of ethyl dithioacetate in 0.05 ml of dioxane are heated in a 60 ° C oil bath for 2 h. After cooling, everything is cleaned by thin layer chromatography;

Kieselgel 60, mobile phase: dichloromethane / methanol = 9/1. You get an fbl.

Foam.

Rf (dichloromethane / methanol = 4/1) = 0.6 yield: 8 mg (24.8% of theory) 143

Example 39

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

50 mg (0.15 mmol) of the amine hydrochloride from Example 30 are in an argon atmosphere in 1 ml of abs. Slurried THF and mixed with 37.7 mg (1.5 ml; 0.34 mmol) of Hünig base. 18.8 mg (0.17 mmol) of chlorothiocarboxylic acid O-methyl ester are added with stirring and the mixture is left to react overnight. After adding another half

Equivalents of the chlorothiocarboxylic acid O-methyl ester and stirring for 12 h are all in conjunction. evaporated to dryness and purified by column chromatography; Kieselgel 60, mobile phase: dichloromethane / methanol = 100/2. An amorphous, pale yellow solid product is obtained. Rf (dichloromethane / methanol = 100/5) = 0.31

Mp: 161 ° C. Yield: 25.4 mg (45.5% of theory) 144

Example 40

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

-O

- CH,

20 mg (62 μmol) of the amine hydrochloride from Example 30 are slurried in 1 ml of methanol, 0.12 ml (0.124 mmol) of 1N sodium hydroxide solution and 9.78 mg (65.1 μmol) of dimethylthiolothionocarbonate are added and the mixture is stirred at RT overnight . Everything is evaporated to dryness and separated on silica gel plates; Mobile solvent: dichloromethane / methanol = 10/1, Rf = 0.55. A pale yellow, amorphous solid product is obtained. Yield: 4.6 mg (19.8% of theory)

145

Example 41

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

Example 42

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

Br

50 mg (0.152 mmol) of the compound from Example 6 and 20 mg of bromine in 5 ml of dichloromethane are stirred at RT for 3 days. After concentration in vacuo to dryness, there is a separation by column chromatography; Kieselgel 60, mobile phase: dichloro- 146

methane / methanol = 100/7. Two colorless products are obtained, mono- and dibrominated starting material, Example 41 and Example 42. Example 41: Rf (dichloromethane / methanol = 100/7) = 0.5

Yield: 5 mg (7.0% of theory). Example 42: Rf ((dichloromethane / methanol = 100/7) = 0.6

Yield: 10 mg (13.1% of theory)

Example 43

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

a) 35 mg (96 μmol) of the compound from example LXXXV are dissolved in 1 ml of THF under an argon atmosphere, 23.4 mg (0.144 mmol) of CDI are added and the mixture is stirred for 3 hours

50 ° C stirred. Then another 23.4 mg of CDI are added and the mixture is stirred at 50 ° C. overnight. Then you steam i.V. to dryness and separate the rest by column chromatography; Silica gel 60, mobile phase: dichloromethane / methanol = 100/7, Rf = 0.4. fbl. Solid product

Yield: 4 mg (1 1.4% of theory)

b) 50 mg (0.155 mmol) of the amine from example LXXXIX are dissolved in 1 ml of DMF, cooled to 0 ° C. and added dropwise with 0.03 ml (25 mg; 0.25 mmol) of triethylamine - 147

and 0.02 ml (22.2 mg; 0.22 mmol) of acetic anhydride were added. The mixture is stirred at RT for 1 h, evaporated i.V. dry and purify the residue by column chromatography (see above). Yield: 18 mg (31.8% of theory)

Example 44

(5S) -3- (4,4-Difluoro-4H-imidazo- [2, l-c] [1,4, -benzoxazin-7-yl) -5-methoxythiocarbonylaminomethyl-oxazolidin-2-one

50 mg (0.155 mmol) of the amine from Example LXXXIX are dissolved in 2 ml of methanol, 0.07 ml of Hünig base and 37.9 mg (0.31 mmol) of dimethylthiolothionocarbonate are added and the mixture is stirred at RT overnight. You steam everything i.V. to dryness and separates the residue by column chromatography; Kieselgel 60, mobile phase: dichloromethane / methanol = 9/1, Rf = 0.57 fbl. Solid product yield: 15 mg (24.4% of theory)

Example 45

7-Benzyloxycarbonylamino-4H-l, 2,4-triazolo- [3,4-c] [1,4, -benzoxazine - 148

The preparation is carried out analogously to Example LXXXVI from 0.28 g (1.49 mmol) of the compound from Example XXXVIII, 0.3 g (1.785 mmol) of benzyl chloroformate and 3 ml of saturated sodium bicarbonate solution in 2.1 ml of dioxane; fbl. Solid product

R _f (dichloromethane / methanol = 9/1) = 0.7 yield: 0.4 g (83.3% of theory)

Example 46

(5S) -3- (4H-l, 2,4-triazolo- [3,4-c] [1,4] benzoxazin-5-yl-5-hydromethyl-oxazolidin-2-one

The preparation is carried out analogously to Example LXXXVII from 0.4 g (1.235 mmol) of the above

Compound (Example 45), 0.35 g (4 mmol) tert. -Amyl alcohol, 0.17 g (2.655 mmol) of a 2.5 molar butyllithium solution in n-hexane, 0.22 g (1.543 mmol (R) - (-) -

Glycidyl butyrate and 0.24 g (4.076 mmol) acetic acid in 1.9 ml dimethylacetamide; fbl. Solid product

R _f (dichloromethane / methanol = 9/1) = 0.6

Yield: 70 mg (19.7% of theory) 149 -

Example 47

(5S) -3- (4H-l, 2,4-triazolo- [3,4-c] [1,4] benzoxazin-7-yl-5- (3-nitrophenylsulfonyl) oxymethyl-oxazolidin-2- on

O-

The preparation is carried out analogously to Example LXXXVIIl from 85 mg (0.295 mmol) of the above compound (Example 46), 59.7 mg, (0.59 mmol) of triethylamine and 98 mg

(0.442 mmol) 3-nitrobenzenesulfonic acid chloride in 2 ml dichloromethane; fbl. Solid product (raw)

R _f . (Dichloromethane / methanol = 10/7) = 0.4

Yield: 75 mg (53.7% of theory)

Example 48

(5S) -3- (4H-l, 2,4-triazolo- [3,4-c] [1,4] benzoxazin-7-yl-5-aminomethyl-oxazolidin-2-one

150

The preparation is carried out analogously to Example LXXXIX from 75 mg (0.158 mmol) of the above compound (Example 47) and 1.2 ml of saturated ammonia solution in a little

Isopropanol; fbl. Solid product (raw)

4- (dichloromethane / methanol = 4/1) = 0.47

Yield: - quantitative

Example 49

(5S) -3- (4H-l, 2,4-triazolo- [3,4-c] [1,4] benzoxazin-7-yl) -5-methoxythiocarbonylaminomethyl-oxazolidin-2-one

N

Prepared analogously to Example 44 from 40 mg (0.14 mmol) of the compound from Example 48, 0.06 ml (0.04 g; 0.35 mmol) of Hunig's base and 30 mg (0.28 mmol) of dimethylthiolothionocarbonate.

Rf (dichloromethane / methanol = 100/7) = 0.55 pale yellow solid product Yield: 10 mg (19.9% of theory) - 151

Example 50

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

Prepared analogously to Example 43 b from 10 mg (35 μmol) of the amine from Example XCIII, 5 mg

(50 µmol) acetic anhydride and 0.01 ml (5.6 mg; 56 µmol) triethylamine.

Rf (dichloromethane / methanol = 9/1) = 0.24 fbl. Solid product

Yield: 2.8 mg (24.4% of theory)

Example 51

(5S) -3- (2-Hydroxymethyl-4H-imidazo- [2, l-c] [1,4, -benzoxazin-7-yl) -5-acetylamino-methyl-oxazolidin-2-one

OH

152 -

56 mg (0.12 mmol) of the compound from Example IC are in an argon atmosphere in 9 ml of abs. THF taken up, cooled to 0 ° C and with 1 13.1 ul of a 1.1 molar tetrabutylammonium fluoride solution in abs. THF (0.12 mmol) added. After 3 hours of stirring at 0 ° C., 3 ml of a 10% citric acid are added and everything is separated by means of column chromatography: silica gel 60, mobile phase: dichloromethane / methanol = 10/1, Rf = 0.48. fbl., amorphous substance, mp:> 300 ° C (decomp.) Yield: 26.2 mg (61.7% of theory)

Example 52

(5S) -3- (Imidazo- [l, 2-a] -quinolin-7-yl) -5-acetylaminomethyl-oxazolidin-2-one

Under an argon atmosphere, 70 mg (0.23 mmol) of the compound from Ex. CII in

2 ml abs. Dichloromethane submitted, mixed with 38.2 mg (0.23 mmol) CDI and heated to boiling. As soon as the reaction solution is clear. 38.2 mg of CDI are added again and the mixture is heated to boiling for a further 5 h. After cooling, take up in 10 ml of dichloromethane, shake twice with water, dry the organic phase with magnesium sulfate, evaporate i.V. to dryness and separates the residue by column chromatography; Kieselgel 60, mobile phase: dichloromethane / methanol = 10/1. Rf (dichloromethane / methanol = 10/2) = 0.29 beige, amorphous product. Mp: 208 ° C. Yield: 55.8 mg (71.4% of theory)

Claims

153

claims

Oxazolidinones with azole-containing tricycles of the general formula (I)

O

-IM X ^' ^{^} O. (I),

R ¹

in which

A for residues of the formulas

R '

E 'N- R'

~ Q

TV.

V

EX-D "

R ^ or stands, wherein

R ² , R ² and R ^{2 are} identical or different and are hydrogen or halogen,

wherein

R ^{3 is} hydrogen, trifluoromethyl, halogen, hydroxy, straight-chain or branched alkoxy with up to 6 carbon atoms. Means atoms or a radical of the formula -NR ⁴ R ⁵ ,

wherein

15 where

R ^{6 is} hydrogen, trifluoromethyl, nitro, cyano or halogen, or straight-chain or branched alkyl having up to 6 carbon atoms.

20 means atomic atoms or benzyl, which are optionally substituted by hydroxy or by straight-chain or branched alkoxy having up to 4 carbon atoms, or aryl having 6 to 10 carbon atoms or an aromatic

25 tables 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, hydroxyl, nitro, straight-chain or branched alkyl having up to 4 carbon atoms or

30 trifluoromethyl are substituted, 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 10 heterocycle having up to 3 heteroatoms from the

Row S, N and / or O means

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 having up to 3 heteroatoms from the series S, N and / or O,

20 or

R is a group of the formula -NR R,

wherein

25

R "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 30 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 -C0 ₂ R ¹³ or -CM-NR ¹⁴ R ¹⁵ mean

wherein

10 R ' ³ denotes straight-chain or branched alkyl having up to 6 carbon atoms, benzyl or phenyl,

M denotes 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,

20 or

R ⁹ means hydrogen

25 and

R is a radical of the formula

NHR ¹⁷ SR ¹⁸

-C or - Q. means

NR ¹⁶ NR where

30th - 157 -

R ' ⁷ and R ^{18 are the} same or different and represent straight-chain or branched alkyl having up to 6 carbon atoms, phenyl or 10 benzyl,

15 where

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 20 phenyl or by a radical of the formula -OR ²⁰ ,

wherein

25 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 WO 99/40094 - _co PCT / EP99 / 00518

- 1 jo -

wherein

10

R ²³ and R ^{24 have} the meaning of R ⁴ and 15 R ⁵ given above and are the same or different with these,

or

20 R ²³ means hydrogen

and

R ^{24 is} cyano or a radical of the formula -CO-NR ²⁵ R ²⁶ 25 or -CS-NR ²⁷ R ²⁸ .

wherein

R ²⁵ , R ²⁶ , R ²⁷ and R ^{28 are the} same or different 30 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 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,

10 Q an oxygen or sulfur atom or residues of the formulas

S0 means ₂ , SO, C = 0 or CR ²⁹ R ³⁰ ,

wherein

15 R ²⁹ and R ^{30 are the} same or different and are hydrogen or

Halogen mean

T represents a radical of the formula CR ³ 'R ³² ,

20 where

R ³¹ and R ^{32 are} identical or different and denote 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 = 0, = S,

R ³³ = or = form NR ^3S ;

3 ₄

R

30th wherein

or

10

15 and

20th

V is an oxygen atom, a sulfur atom or a residue of

Formula SO or S0 ₂ means

W represents an oxygen or sulfur atom, or 25 radicals of the formulas C = 0, C = S, SO, S0 ₂ , NR ³⁶ or CR ³⁷ R ³⁸ ,

wherein

30 R ^{36 has} the meaning of R ³³ given above and is the same or different with this, WO 99/40094, _r , PCT / EP99 / 00518

- 161 -

R ³⁷ and R ^{38 are the} same or different and are hydrogen, halogen, straight-chain or branched alkyl having up to 6 carbon atoms or benzyl, 5 or

R ³⁷ means hydrogen

10 and

R ^{38 represents} a radical of the formula -OR ³⁹ ,

wherein

15

R ³⁹ denotes hydrogen, straight-chain or branched alkyl or acyl each having up to 6 carbon atoms or benzyl,

20 Y is a radical of the formula C = 0 or -CR ^4υ R ⁴ '.

wherein

R ⁴⁰ and R ^{41 are the} same or different and are hydrogen, 25 halogen, benzyl or straight-chain or branched

Is alkyl with up to 6 carbon atoms,

or

R ^υ means hydrogen - l oZ -

and

or

W and Y together represent the group -CH = CH-,

wherein

R ⁴³ denotes straight-chain or branched alkyl having up to 6 carbon atoms, phenyl or nitro-substituted phenyl,

R ⁴⁴ and R ^{45 are} hydrogen,

or

R ⁴⁴ means hydrogen,

and

R ^{45 represents} a radical of the formula z -C_ _R ⁴⁶ _or _p ₍₀ ) (0R ⁷ ) (0R ⁴⁸ ), WO 99/40094. .. PCT / EP99 / 00518

- l oj -

wherein

Z represents an oxygen or sulfur atom,

5

R ^{46 is} hydrogen or straight-chain or branched alkoxy having up to 8 carbon atoms, benzyloxy or trifluoromethyl, or cycloalkyl having 3 to 6 carbon atoms, that is

10 optionally by halogen or aryl with 6 to 10

Carbon atoms is substituted, or aryl with 6 to 10 carbon atoms or a 5- to 6-membered saturated or aromatic heterocylcus with up to 3 heteroatoms from the series S, N

15 and / or O means, where those listed under R ⁴⁶

Ring systems are optionally substituted up to 2 times, identically or differently, by halogen, cyano, nitro, hydroxy or phenyl,

20 or

R ⁴⁶ denotes straight-chain or branched alkyl having up to 6 carbon atoms, optionally by phenoxy, benzyloxy, carboxyl, halogen or straight-chain or branched alkoxycarbonyl or acyl each having up to 6 carbon atoms or by a 5- to 6-membered heterocycle the series S, N and / or O is substituted,

or 164

R ^'is a radical of formula -NR 46 R

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 bonded via N,

and their salts and N-oxides.

Oxazolidinones with azole-containing tricycles of the general formula (I)

O

-IM X ^' . O (I),

R ¹

in which

A for residues of the formulas

R '

^L ^ _/

T. 165

or stands wherein

R ² , R ² and R ^{2 are} identical or different and are hydrogen or halogen,

10 where

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 meaning

15 tet.

wherein

R ⁴ and R ^{5 are the} same or different and

20 is hydrogen, aryl having 6 to 10 carbon atoms, benzyl or straight-chain or branched alkyl or acyl each having up to 6 carbon atoms,

25 E, E 'and E "are identical or different and denote a nitrogen atom or a radical of the formula CR ⁶ ,

wherein WO 99/40094. _rr PCT / EP99 / 00518

- 166 -

R ^{6 represents} hydrogen, trifluoromethyl, nitro, cyano or halogen, or straight-chain or branched alkyl having up to 6 carbon atoms or benzyl, the given

5 if substituted by hydroxy 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

10 series means S, N and / or O, the ring systems optionally being substituted up to 3 times identically or differently by halogen, hydroxy, nitro, straight-chain or branched alkyl having up to 4 carbon atoms or trifluoromethyl, or

15

R ⁶ denotes radicals of the formulas OR ⁷ , -CO-R ⁸ or -NR ⁹ R ¹⁰ ,

where 20

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

Row S, N and / or O means

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 heterocyc - 167 -

lus with up to 3 heteroatoms from the series S, N and / or O means

or

R ^{8 represents} a group of the formula -NR "R ¹² ,

woπn

10 R "and R ' ^{2 are the} same or different and

Is hydrogen, aryl having 6 to 10 carbon atoms, benzyl or straight-chain or branched alkyl having up to 6 carbon atoms, 15

R ⁹ and R '° 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 20 pe of the formula -C0 ₂ R ¹³ or -CM-NR ^I R ¹⁵ mean

wherein

25 R ' ³ denotes straight-chain or branched alkyl having up to 6 carbon atoms, benzyl or phenyl,

M denotes an oxygen or sulfur atom, - 168 -

or

R means hydrogen

and

10

R ^{10 is} a radical of the formula

17 18

NHR S-R

- C or - C means

\ V_ _{1 K} ^X κ., -, 16 '

NR ¹⁶ NR where

15 R ' ⁶ and R ^{16 are the} same or different and

Is hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms, aryl having 6 to 10 carbon atoms or benzyl,

20th

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,

25

wherein - 169 -

R ^{19 is} hydrogen, trifluoromethyl, nitro, cyano, halogen or straight-chain or branched alkyl with up to 6

Carbon atoms means that if necessary

Phenyl or by a radical of the formula -OR ²⁰ sub-

5 is constituted,

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

15 R ¹⁹ radicals of the formulas -OR ²¹ , -COR ²² or -NR ²³ R ²⁴ means.

wherein

20 R ^{21 is} hydrogen, aryl having 6 to 10 carbon atoms, benzyl or straight-chain or branched alkyl or acyl each having up to 6 carbon atoms,

25 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 the same or different with them, - 170 -

or

R means hydrogen

and

R ^{24 is} cyano or a radical of the formula -CO-NR ²⁵ R ²⁶ or -CS-NR ²⁷ R ²⁸ ,

10 where

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,

15 or

R ²³ and R ²⁴ together with the nitrogen atom

5- to 6-membered, saturated heterocycle

Form 20, which may also contain a further heteroatom from the series S, O or a radical of the formula -NH,

Q represents an oxygen or sulfur atom or radicals of the formulas 25 S0 ₂ , SO, C = 0 or CR ²⁹ R ³⁰ ,

wherein

R ²⁹ and R ^{30 are the} same or different and are hydrogen or 30 halogen, - 171 -

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, hydroxy, straight-chain or branched alkyl or alkoxy each having up to 6 carbon atoms or benzyloxy,

10 or

R ³¹ and R ³² together are residues of the formulas = 0, = S,

R 33

Form X or = NR ^Λ .

R 3

15 where

R ³³ and R ^{34 are the} same or different and mean hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms or benzyl,

or

and R ³⁵ denotes hydrogen, benzyl or straight-chain or branched alkyl or acyl each having up to 6 carbon atoms,

5 V is an oxygen atom, a sulfur atom or a residue of

Formula SO or S0 ₂ means

W represents an oxygen or sulfur atom, or

Radicals of the formulas C = 0, C = S, SO, S0 ₂ , NR ³⁶ or CR ³⁷ R ³⁸ 10,

wherein

R ^{3δ has} the meaning of R ³⁵ given above and is the same or different with 15,

20 or

R means hydrogen

25 and

R represents a radical of the formula -OR,

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 = 0 or -CR ⁴⁰ R ⁴¹ ,

wherein

R ⁴⁰ and R ^{41 are the} same or different and are hydrogen, 10 halogen, benzyl or straight-chain or branched

Is alkyl with up to 6 carbon atoms,

or

15 R ⁴⁰ means hydrogen

and

R ⁴ 'denotes hydroxy, benzyloxy or straight-chain or branched alkoxy having up to 6 carbon atoms,

R 'represents azido or a radical of the formula -OR ⁴² , -0-S0 ₂ -R ⁴³ or -NR ⁴⁴ R ⁴⁵ ,

25 where

30 R ⁴³ denotes straight-chain or branched alkyl having up to 6 carbon atoms, phenyl, R and R are hydrogen,

or

R means hydrogen,

and

R ⁴⁵ denotes a radical of the formula z —C — R ⁴⁶ or —P (O) (OR ⁷ ) (OR ⁴⁸ ),

wherein

Z represents an oxygen or sulfur atom,

15

R ⁴⁶ straight-chain or branched alkoxy with up to 8

Means carbon atoms or trifluoromethyl, or cycloalkyl having 3 to 6 carbon atoms, optionally by halogen or aryl having 6 to 10

20 carbon atoms is substituted, 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, those listed under R ⁴⁶

25 ring systems are optionally substituted up to 2 times, identically or differently, by halogen, cyano, nitro, hydroxy or phenyl,

or

30th R ⁴⁶ denotes straight-chain or branched alkyl having up to 6 carbon atoms, which may be 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 heterocylcus from the S series , N and / or O is substituted,

or

R ^{46 represents} a radical of the formula -NR ⁴⁹ R ⁵⁰ ,

wherein

and their salts and N-oxides.

3. Compounds of the general formula (I) according to claim 1 or 2,

in which

A for residues of the formulas 176 -

R '

-D-

~ N-

Q

or stands wherein

R ² , R ² and R ^{2 "are the} same or different and are hydrogen or fluorine,

10 where

R ^{3 is} hydrogen, trifluoromethyl, fluorine, chlorine, hydroxy, straight-chain or branched alkoxy with up to 4

15 carbon atoms means

E, E 'and E "are the same or different and represent a nitrogen atom or a radical of the formula CR ⁶ .

20 where

R ^{6 is} hydrogen, trifluoromethyl, nitro, cyano, fluorine or chlorine, or WO 99/40094. γ ηη. PCT / EP99 / 00518

denotes straight-chain or branched alkyl having up to 4 carbon atoms or benzyl, which are optionally substituted by hydroxy, or denotes 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 ^{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 ¹ 'R ¹² ,

wherein

25

R "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} identical or different and are hydrogen, benzyl, phenyl, straight-chain or branched alkyl having up to 4 carbon atoms or a group of the formula -C0 ₂ R ¹³ , 5 in which

R ¹³ denotes straight-chain or branched alkyl having up to 4 carbon atoms, benzyl or 10 phenyl,

15 where

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 20 phenyl or by a radical of the formula -OR ²⁰ ,

wherein

25 R ^{20 is} hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms, phenyl or benzyl.

or

30th 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,

10 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 to 15,

or

R ²³ and R ²⁴ together with the nitrogen atom form a 20 piperidinyl or morpholinyl ring,

Q represents an oxygen or sulfur atom or radicals of the formulas SO ₂ , C = 0 or CR ²⁹ R ³⁰ ,

25 where

R ²⁹ and R ^{30 are the} same or different and are hydrogen or fluorine,

30 T is a radical of the formula CR ³¹ R ³² , wherein

or

10 R and R together form residues of the formulas = 0 or = S,

V represents an oxygen atom, a sulfur atom or a radical of the formula S0 ₂ ,

15 W represents an oxygen or sulfur atom, or

Radicals of the formula C = 0, C = S, SO, S0 ₂ , NR ³⁶ or CR ³⁷ R ³⁸ ,

wherein

20th

25 R ³⁷ and R ^{38 are the} same or different and are hydrogen,

Are fluorine, straight-chain or branched alkyl having up to 4 carbon atoms or benzyl,

Y represents a radical of the formula C = 0 or CR ⁴⁰ R ⁴¹ ,

30 in which 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,

or

W and Y together optionally represent the group -CH = CH-,

for azido or for a radical of the formula -OR ⁴² , -0-S0 ₂ -R ⁴³ or

-NR ⁴⁴ R ⁴⁵ stands,

wherein

R ⁴⁴ and R ^{45 are} hydrogen,

or

R ⁴⁴ means hydrogen,

and

R ^{45 is} a radical of the formula e.g.

_C-R ⁴⁶ or - _{P (0} ) (OR ⁴⁷ ) (OR ⁴⁸ ) ^means> wherein

Z represents an oxygen or sulfur atom,

5

R ⁴⁶ denotes straight-chain or branched alkoxy with up to 6 carbon atoms or trifluoromethyl or optionally hydrogen, or cyclopropyl, cyclopentyl, cycloheptyl, cyclobutyl

10 or cyclohexyl, which is optionally by

Fluorine, chlorine or phenyl are substituted, or phenyl, naphthyl, pyridyl, thienyl, oxazolyl, furyl, imidazolyl, pyridazolyl or pyrimidyl, the ring systems listed under R ⁴⁶ optionally

15 up to 2 times the same or different due to fluorine,

Chlorine, bromine, cyano, nitro, hydroxy or phenyl are substituted,

or

20th

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 25 or acyl each having up to 4 carbon atoms or by pyridyl, thienyl, furyl or pyrimidyl is substituted,

or

R ⁴ "denotes a radical of the formula -NR ^4> R ^5U , 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,

and their salts and N-oxides.

4. Compounds of the general formula (I) according to Claim 1 or 2,

in which

A for residues of the formulas

R '

_ 'N-

\ L 'R ^

Q X

wherein

R ^{3 is} hydrogen, trifluoromethyl, fluorine, chlorine, hydroxy, 10 straight-chain or branched alkoxy with up to 3

Carbon atoms means

E, E 'and E "are the same or different and represent a nitrogen atom or a radical of the formula CR ⁶ , 15 in which

R ^{6 is} hydrogen, trifluoromethyl, nitro, cyano, fluorine,

Chlorine, straight chain or branched alkyl with up to

20 denotes 3 carbon atoms or benzyl, which are optionally substituted by hydroxy, or denotes phenyl, naphthyl, pyridyl, pyrimidyl, pyrazinyl, thienyl or furyl,

25 R ⁶ denotes radicals 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 ¹ 'R ¹² ,

10 where

R "and R ^{12 are the} same or different and

Hydrogen, phenyl, benzyl or straight

15 is 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 -C0 ₂ R ¹³ ,

wherein

25 R ¹³ denotes straight-chain or branched alkyl having up to 3 carbon atoms, benzyl or phenyl,

L, L 'and L "are identical or different and represent 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

10

R ²⁰ denotes hydrogen, straight-chain or branched alkyl having up to 3 carbon atoms, phenyl or benzyl,

15 or

20 where

R ²¹ denotes hydrogen, phenyl, benzyl or straight-chain or branched alkyl or acyl each having up to 3 carbon atoms,

25

R ²³ and R ^{24 have} the meaning of R ⁴ and R ⁵ given above and are identical or different with this, Q is an oxygen or sulfur atom or radicals of the formulas

S0 means ₂ , C = 0 or CR ²⁹ R ³⁰ ,

wherein

R ²⁹ and R ^{30 are the} same or different and are hydrogen or fluorine,

10 T is a radical of the formula -CR ³ 'R ³²

wherein

R ³¹ and R ^{32 are} identical or different and denote hydrogen, 15 fluorine, hydroxyl, straight-chain or branched alkyl or alkoxy each having up to 3 carbon atoms,

or

20th

R ³¹ and R ³² together form radicals of the formulas = 0 or = S,

V represents an oxygen atom, a sulfur atom or a radical of the formula S0 ₂ ,

25

W represents an oxygen or sulfur atom, or

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 the} same 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 ⁰ 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,

or

W and Y together optionally represent the group -CH = CH-,

wherein

R ⁴³ denotes straight-chain or branched alkyl having up to 3 carbon atoms or phenyl, WO 99/40094 _ - _gg PCT / EP99 / 00518

R and R are hydrogen,

or

R ⁴⁴ means hydrogen,

and

R ^{45 is} a radical of the formula e.g.

10 - C - R ⁴⁶ means in which

represents an oxygen or sulfur atom,

15 and

R ⁴⁶ denotes straight-chain or branched alkoxy having up to 4 carbon atoms or trifluoromethyl or optionally hydrogen, or

20 means cyclopropyl, cyclopentyl, cycloheptyl, cyclobutyl or cyclohexyl, which are optionally substituted by fluorine, chlorine or phenyl, or phenyl, naphthyl, pyridyl, thienyl, oxazolyl, furyl, imidazolyl, pyridazolyl or pyrimidyl, where

25 the ring systems listed under R ⁴⁶ are optionally substituted up to 2 times, identically or differently, by fluorine, chlorine, bromine, cyano, nitro, hydroxy or phenyl,

or R ⁴⁶ denotes straight-chain or branched alkyl having up to 3 carbon atoms, which is optionally substituted 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

or

R ^{46 represents} a radical of the formula -NR ⁴ R ^5U ,

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 bonded via N,

and their salts and N-oxides.

5. Compounds of the general formula (I) according to claim 1,

in which

A for residues of the formulas - 191

H H

R 'R'

N

R ^J

N \ N / ^ R ^ l ^{^} O

R 'R ^"1 R ^J H

N— <

N ^ N R

> ^ ^R19 ^^ Y ^

^{^} O cA ^ \

H

N = V,

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

Stand 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 represents} a radical of the formula z - CR ⁴⁶ ,

wherein

Z represents an oxygen or sulfur atom,

and

R ⁴⁶ denotes straight-chain or branched alkoxy having up to 4 carbon atoms, or denotes straight-chain or branched alkyl having up to 3 carbon atoms, or denotes 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.

6. A process for the preparation of the compounds of 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 5,

first by a reduction in the compounds of the general formula (III)

A-NH ₂ (III)

in which

has the meaning given in claims 1 to 5; convicted,

in a next step with benzyl chloroformate the compounds of general formula (IV)

A-NH-C0 ₂ -CH ₂ -C ₆ H ₅ (IV)

in which

A has the meaning given in claims 1 to 5,

manufactures,

O

A-N Λ o (Ia)

J ^ OH

in which

A has the meaning given in claims 1 to 5,

manufactures,

and or [B] by reaction with (C, -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)

O

- N X o

(Ib) 3

OSO-.R

in which

A and R ^{43 have} the meaning given in Claims 1 to 5,

convicted,

then the azides of the general formula (Ic) with sodium azide in inert solvents

O

_* N. X ^ O

(Ic). IN THE,

in which

has the meaning given in claims 1 to 5,

manufactures,

in a further step by reaction with (C, -C ₄ -O) ₃ -P or Ph ₃ P, preferably (CH ₃ 0) ₃ P in inert solvents, and with acids or by catalytic hydrogenation into the amines of the general formula ( Id) O

A- X o

(Id)

NH.

in which

A has the meaning given in claims 1 to 5,

convicted,

Y-CO-R ⁴⁶ (V)

in which

R ^{46 has} the meaning given in claims 1 to 5

and

Y represents halogen, preferably chlorine or the radical -OCOR ⁴⁸ ,

O

A N O

I 1 ^(Ie)

NH-CO-R ⁴⁶

in which A and R have the meaning given in Claims 1 to 5,

manufactures,

or

[C] in case R ¹ = -NH-CO-R ⁴⁶

O

\ _ NH- ^ OR ⁴⁶ ( ^VI )

in which

R ^{46 has} the meaning given in Claims 1 to 5,

in inert solvents and in the presence of an auxiliary to form enantiomerically pure or racemic, substituted hydroxyamides which are cyclized with carbonyl-diimidazole 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) R ² O

H ₂ N "^ S ^^ | I (VII) ^ NH-R ^{45 '} in which

R ^{2 has} the meaning given in Claims 1 to 5,

and

R ^{45 has} the meaning of R ⁴⁵ given in Claims 1 to 5 and is identical or different with it, preferably represents acetyl,

with compounds of the general formula (VIII)

OR ³ R ⁶ - ^ \ _R 5i (VIII)

in which

R and R have the meaning given in claims 1 to 5,

and

R ⁵ 'represents halogen, preferably chlorine or bromine,

in alcohols, preferably ethanol, under reflux,

and in the case of the S-oxides, oxidation with m-chloroperbenzoic acid follows

and optionally carrying out an alkylation by customary methods.

7. Use of the compounds according to claims 1 to 5 for the manufacture of medicaments.

8. Medicament containing compounds according to claims 1 to 5.