DE19802239A1 - New oxazolidinone derivatives useful as antimicrobial agents against Gram-positive and some Gram-negative bacteria, mycobacteria, etc. - Google Patents

Abstract

3-Heterocyclyl-5-(substituted methyl)-2-oxazolidinone derivatives (I) are new. 3-Heterocyclyl-5-(substituted methyl)-2-oxazolidinone derivatives of formula (I) and their stereosiomers and salts are new: A = a bi- or tricyclic heterocyclic group of formula (i), (ii) or (iii): D, D', D = H, COOH, halogen, CN, CHO, CF3, NO2 or 1-6C alkoxy, alkoxycarbonyl, alkylthio, acyl or alkyl; E, E' = CH2, O, S, SO or SO2; L = O, S or NR13; R<13> = H, phenyl, OH or 1-6C alkoxy; R<2>-R<5>, R<7>-R<10> = H, or 1-6C alkyl or 2-6C alkenyl optionally substituted by Ar<1>; or R<2>+R<3>, R<4>+R<5>, R<7>+R<8> and/or R<9>+R<10> = O, CH2 or CHR<14>; Ar<1> = 6-10C aryl or 5- or 6-membered heteroaryl (containing 1-3 heteroatoms selected from S, N and O) optionally substituted by 1-6C alkoxy, 1-6C alkyl, OH or halogen; R<14> = 6-10C aryl or 5- to 7-membered heteroaryl (containing 1-3 heteroatoms selected from S, N and O) optionally substituted by 1-6C alkoxy, 1-6C alkyl, OH or halogen; R<6>, R<11>, R<12> = H, 1-6C alkyl, 2-6C alkoxycarbonyl or COR<15>; R<15> = 6-10C aryl, 5- to 7-membered heteroaryl (containing 1-3 heteroatoms selected from S, N and O), 1-4C alkyl or (6-10C)aryl(1-4C)alkyl, where (hetero)aryl is optionally substituted by halogen, CF3, NO2, OH, 1-6C alkyl and/or 1-6C alkoxy; R<1> = N3, OR<16>, OSO2R<17> or NHR<19>; R<16> = H or 1-6C acyl; R<17> = 1-6C alkyl or phenyl; R<19> = H, C(Q)R<20> or P(O)(OR<21>)(OR<22>); Q = O or S; R<20> = 1-8C alkoxy or CF3; 3-6C cycloalkyl optionally substituted by halogen or 6-10C aryl; 6-10C aryl or 5- or 6-membered heterocyclyl (containing 1-3 heteroatoms selected from S, N and O) optionally substituted by 1-2 of halogen, CN, NO2, OH and phenyl; 1-6C alkyl optionally substituted by phenoxy, benzyloxy, COOH, halogen 2-6C alkoxycarbonyl, 1-6C acyl or 5- or 6-membered S-, N- and/or O-containing heterocyclyl; or NR<23>R<24>; R<23>, R<24> = H, phenyl, pyridyl, 1-5C alkyl or morpholino(1-5C)alkyl; R<21>, R<22> = H or 1-4C alkyl.

Description

The present invention relates to new bicyclic substituted oxazolidinones, Ver drive to their manufacture and their use as medicines, especially as anti bacterial drugs.

From publications US 5 254 577, US 4 705 799, EP 311 090, EP 312 000 and C.H. Park et al., J. Med. Chem. 35, 1156 (1992) are N-aryloxazolidinones with antibacterial Effect known. In addition, 3- (nitrogen-substituted) phenyl-5-beta-amidomethyl oxazolidin-2-one known from EP 609 905 A1.

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

Other oxazolidinones with antibacterial effects have already been registered EP 694 543, EP 693 491, EP 694 544, EP 697 412, EP 738 726, EP 785 197, EP 785 201, EP 785 200, EP 789 025 and EP 789 026.

The present invention relates to novel bicyclic-substituted oxazolidinones of the general formula (I)

in which
A for residues of the formulas

or

stands,
wherein
D, D 'and D''are the same or different and are hydrogen, carboxy, halogen, cyano, formyl, trifluoromethyl, nitro, straight-chain or branched alkoxy, alkoxycarbonyl, alkylthio or acyl each having up to 6 carbon atoms or straight-chain or branched alkyl having up to to 6 carbon atoms mean
E and E 'are identical or different and denote the -CH ₂ group, an oxygen or sulfur atom or a radical of the formula -SO or -SO ₂ ,
L represents an oxygen or sulfur atom or a group of the formula = NR ¹³ ,
wherein
R ¹³ denotes hydrogen, phenyl, hydroxyl or straight-chain or branched alkoxy having up to 6 carbon atoms,
R ² , R ³ , R ⁴ , R ⁵ , R ⁷ , R ⁸ , R ⁹ and R ^{10 are the} same or different and are hydrogen or straight-chain or branched alkyl or alkenyl each having up to 6 carbon atoms, which may be aryl with 6 to 10 carbon atoms or by a 5- to 6-membered aromatic heterocycle with up to 3 heteroatoms from the series S, N and / or O, which in turn are substituted one or more times by straight-chain or branched alkoxy or alkyl, each with up to 6 carbon atoms, hydroxy or halogen can be substituted,
or
R ² and R ³ , R ⁴ and R ⁵ , R ⁷ and R ⁸ and / or R ⁹ and R ¹⁰ together form groups of the formula = O, = CH ₂ or = CHR ¹⁴ ,
wherein
R ^{14 is} aryl with 6 to 10 carbon atoms or a 5- to 7-membered aromatic heterocycle with up to 3 hetero atoms from the series S, N and / or O, the ring systems optionally one or more times by halogen, hydroxy or by straight-chain or branched alkyl or alkoxy, each having up to 6 carbon atoms, are substituted,
R ⁶ , R ¹ and R ^{12 are} identical or different and denote hydrogen, straight-chain or branched alkyl or alkoxycarbonyl each having up to 6 carbon atoms, or denote a radical of the formula -CO-R ¹⁵ ,
wherein
R ^{15 is} aryl having 6 to 10 carbon atoms, a 5- to 7-membered aromatic heterocycle having up to 3 heteroatoms from the series S, N and / or O or straight-chain or branched alkyl having up to 4 carbon atoms, which may be by aryl is substituted with 6 to 10 carbon atoms, the ring systems listed under R ¹⁵ optionally being substituted one to more times, identically or differently, by halogen, trifluoromethyl, nitro, hydroxyl or by straight-chain or branched alkyl or alkoxy, each having up to 6 carbon atoms,
R ^{1 represents} azido or a radical of the formula -OR ¹⁶ , -O-SO ₂ -R ¹⁷ or -NR ¹⁸ R ¹⁹ ,
wherein
R ¹⁶ denotes hydrogen or straight-chain or branched acyl having up to 6 carbon atoms,
R ¹⁷ denotes straight-chain or branched alkyl having up to 6 carbon atoms or phenyl,
R ¹⁸ and R ^{19 are} hydrogen,
or
R ¹⁸ means hydrogen,
and
R ^{19 is} a radical of the formula

means
wherein
Q represents an oxygen or sulfur atom,
R ²⁰ denotes straight-chain or branched alkoxy having up to 8 carbon atoms or trifluoromethyl, or
R ^{20 means} cycloalkyl having 3 to 6 carbon atoms, which is optionally substituted by halogen or aryl having 6 to 10 carbon atoms, or
Aryl with 6 to 10 carbon atoms or a 5- to 6-membered saturated or aromatic heterocycle with up to 3 heteroatoms from the series S, N and / or O means, the ring systems listed under R ²⁰ optionally being up to 2 times the same or are differently substituted by halogen, cyano, nitro, hydroxy or phenyl,
or
R ²⁰ 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
R ^{20 represents} a radical of the formula -NR ²³ R ²⁴ ,
wherein
R ²³ and R ^{24 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,
R ²¹ and R ^{22 are the} same or different and are hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,
and their salts.

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

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

In the context of the invention, the oxazolidine skeleton can be attached to the heterocyclic radical via the following positions:

The oxazolidinone skeleton is preferably attached in positions 2 and 3. The oxazolidinone skeleton is particularly preferably attached in position 3.

Physiologically acceptable salts of the new oxazolidinones substituted with bicycles can salts of the substances according to the invention with mineral acids, carboxylic acids or Be sulfonic acids. Z are particularly preferred. B. salts with hydrochloric acid, bromine hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, Toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, Lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.

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

Heterocycle in the context of the invention is a 5- to 7-membered aromatic Ring, which as heteroatoms contains up to 3 oxygen, sulfur and / or nitrogen atoms may contain. Examples include: pyrrolyl, imidazolyl, furyl, thienyl, Thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, pyridyl, pyrimidyl or pyrazinyl. Prefers are pyrrolyl, pyridyl, imidazolyl, furyl, thienyl, isothiazolyl, thiazolyl, isoxazolyl and Oxazolyl.

In the further substitution field, heterocycle also stands for a 5- to 6-membered, saturated ring, which as heteroatoms up to 2 oxygen, sulfur and / or May contain nitrogen atoms. The following are preferably mentioned: imidazolyl, pyrrolidinyl, Piperidinyl, piperazinyl and morpholinyl.

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

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

In the context of the invention, acyl stands for a straight-chain or branched acyl radical with 6 to 10 carbon atoms. A straight-chain or branched is preferred Lower acyl group with 1 to 4 carbon atoms. Preferred acyl radicals are acetyl and Propionyl.

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

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

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

or

stands,
wherein
D, D 'and D "are the same or different and are hydrogen, carboxy, fluorine, chlorine, bromine, iodine, cyano, formyl, trifluoromethyl or nitro,
E and E 'are identical or different and denote the -CH ₂ group, an oxygen or sulfur atom or a radical of the formula -SO or -SO ₂ ,
L represents an oxygen or sulfur atom or a group of the formula = NR ¹³ ,
wherein
R ¹³ signifies hydrogen hydroxy or straight-chain or branched alkoxy with up to 4 carbon atoms,
R ² , R ³ , R ⁴ , R ⁵ , R ⁷ , R ⁸ , R ⁹ and R ^{10 are} identical or different and are hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by phenyl or naphthyl, which in turn can be substituted one to more times by straight-chain or branched alkoxy or alkyl each having up to 4 carbon atoms, hydroxyl, fluorine, chlorine or bromine,
or
R ² and R ³ , R ⁴ and R ⁵ , R ⁷ and R ⁸ and / or R ⁹ and R ¹⁰ together form groups of the formula = O, = CH ₂ or = CHR ¹⁴ ,
wherein
R ¹⁴ denotes phenyl, naphthyl, pyridyl, thienyl or furyl, the ring systems optionally being substituted one to more times by fluorine, chlorine, bromine or by straight-chain or branched alkyl or alkoxy each having up to 4 carbon atoms,
R ⁶ , R ¹¹ and R ^{12 are the} same or different and are hydrogen, straight-chain or branched alkyl or alkoxycarbonyl each having up to 4 carbon atoms, or
represent a radical of the formula -CO-R ¹⁵ ,
wherein
R ^{15 is} phenyl, naphthyl, pyridyl, thienyl, furyl, imidazolyl, pyridazolyl, pyrimidyl or straight-chain or branched alkyl having up to 3 carbon atoms, which is optionally substituted by phenyl or naphthyl, the ring systems listed under R ¹⁵ optionally one to are substituted several times, identically or differently, by fluorine, chlorine, bromine, trifluoromethyl, nitro, hydroxy or by straight-chain or branched alkyl or alkoxy, each having up to 4 carbon atoms,
R ^{1 represents} azido or a radical of the formula -OR ¹⁶ , -O-SO ₂ -R ¹⁷ or -NR ¹⁸ R ¹⁹ ,
wherein
R ¹⁶ denotes hydrogen or straight-chain or branched acyl having up to 4 carbon atoms,
R ¹⁷ denotes straight-chain or branched alkyl having up to 4 carbon atoms or phenyl,
R ¹⁸ and R ^{19 are} hydrogen,
or
R ¹⁸ means hydrogen,
and
R ^{19 is} a radical of the formula

means
wherein
Q represents an oxygen or sulfur atom,
R ²⁰ denotes straight-chain or branched alkoxy with up to 6 carbon atoms or trifluoromethyl, or
R ²⁰ denotes cyclopropyl, cyclopentyl, cycloheptyl, cyclobutyl or cyclohexyl, which are optionally substituted by fluorine, chlorine or phenyl, or phenyl, naphthyl, pyridyl, thienyl, oxazolyl, furyl, imidazolyl, pyridazolyl or pyrimidyl, the radicals under R ²⁰ ring systems listed are optionally up to 2 times the same or different substituted by fluorine, chlorine, bromine, cyano, nitro, hydroxy or phenyl,
or
R ²⁰ denotes straight-chain or branched alkyl having up to 4 carbon atoms, optionally by phenoxy, benzyloxy, carboxyl, fluorine, chlorine, bromine or straight-chain or branched alkoxycarbonyl or acyl each having up to 4 carbon atoms or by pyridyl, thienyl, furyl or pyrimidyl is substituted,
or
R ^{20 represents} a radical of the formula -NR ²³ R ²⁴ ,
wherein
R ²³ and R ^{24 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 ²¹ and R ^{22 are the} same or different and are hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms,
and their salts.

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

or

stands,
wherein
D, D 'and D "are the same or different and are hydrogen,
E and E 'are identical or different and denote the -CH ₂ group, an oxygen or sulfur atom or a radical of the formula -SO or -SO ₂ ,
L represents an oxygen or sulfur atom or a group of the formula = NR ¹³ ,
wherein
R ¹³ denotes hydrogen, hydroxy or straight-chain or branched alkoxy with up to 4 carbon atoms,
R ² , R ³ , R ⁴ , R ⁵ , R ⁷ , R ⁸ , R ⁹ and R ^{10 are the} same or different and what is hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms, which is optionally substituted by phenyl or naphthyl which in turn can be substituted one or more times by methoxy, fluorine or chlorine,
R ² and R ³ , R ⁴ and R ⁵ , R ⁷ and R ⁸ and / or R ⁹ and R ¹⁰ together form groups of the formula = O, = CH ₂ or = CHR ¹⁴ ,
wherein
R ¹⁴ denotes phenyl or pyridyl, where the ring systems are optionally substituted one or more times by fluorine, chlorine or by methoxy,
R ⁶ , R ¹¹ and R ^{12 are the} same or different and are hydrogen, straight-chain or branched alkyl or alkoxycarbonyl each having up to 3 carbon atoms, or
represent a radical of the formula -CO-R ¹⁵ ,
wherein
R ^{15 is} phenyl, naphthyl, pyridyl, thienyl, furyl, imidazolyl, pyridazolyl, pyrimidyl or straight-chain or branched alkyl having up to 3 carbon atoms, which is optionally substituted by phenyl or naphthyl, the ring systems listed under R ¹⁵ optionally one to are substituted several times, identically or differently, by fluorine, chlorine, bromine, trifluoromethyl, nitro, hydroxyl or by straight-chain or branched alkyl or alkoxy, each having up to 3 carbon atoms,
R ^{1 represents} azido or a radical of the formula -OR ¹⁶ , -O-SO ₂ -R ¹⁷ or -NR ¹⁸ R ¹⁹ ,
wherein
R ¹⁶ denotes hydrogen or straight-chain or branched acyl having up to 3 carbon atoms,
R ¹⁷ denotes straight-chain or branched alkyl having up to 3 carbon atoms or phenyl,
R ¹⁸ and R ^{19 are} hydrogen,
or
Means hydrogen, and
R ^{19 is} a radical of the formula

means
wherein
Q represents an oxygen or sulfur atom,
R ²⁰ denotes straight-chain or branched alkoxy with up to 4 carbon atoms or trifluoromethyl, or
R ²⁰ denotes cyclopropyl, cyclopentyl, cycloheptyl, cyclobutyl or cyclohexyl, which are optionally substituted by fluorine, chlorine or phenyl, or
Phenyl, naphthyl, pyridyl, thienyl, oxazolyl, furyl, imidazolyl, pyridazolyl or pyrimidyl, the ring systems listed under R ²⁰ optionally up to 2 times identically or differently by fluorine, chlorine, bromine, cyano, nitro, hydroxy or phenyl are substituted,
or
R ²⁰ denotes straight-chain or branched alkyl having up to 3 carbon atoms, which may be by phenoxy, benzyl oxy, carboxyl, fluorine, chlorine, bromine or straight-chain or branched alkoxycarbonyl or acyl each having up to 3 carbon atoms or by pyridyl, thienyl, Furyl or pyrimidyl is substituted,
or
R ^{20 represents} a radical of the formula -NR ²³ R ²⁴ ,
wherein
R ²³ and R ^{24 are the} same or different and are hydrogen, phenyl, pyridyl or straight-chain or branched alkyl having up to 3 carbon atoms, which is optionally substituted by N-bonded morpholine,
R ²¹ and R ^{22 are the} same or different and are hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms,
and their salts.

Compounds of the general formula (I) according to the invention are very particularly preferred,
in which
A for a residue of the formula

stands in what
E represents an oxygen or sulfur atom,
R ^{1 represents} azido or a radical of the formula -OR ¹⁶ , -O-SO ₂ -R ¹⁷ or -NR ¹⁸ R ¹⁹ ,
wherein
R ¹⁶ denotes hydrogen or straight-chain or branched acyl having up to 3 carbon atoms,
R ¹⁷ denotes straight-chain or branched alkyl having up to 3 carbon atoms or phenyl,
R ¹⁸ and R ^{19 are} hydrogen,
or
R ¹⁸ means hydrogen,
and
R ^{19 is} a radical of the formula

means
wherein
Q represents an oxygen or sulfur atom,
R ²⁰ denotes straight-chain or branched alkoxy with up to 4 carbon atoms or trifluoromethyl, or
R ²⁰ denotes straight-chain or branched alkyl having up to 3 carbon atoms,
or
R ^{20 represents} a radical of the formula -NR ²³ R ²⁴ ,
wherein
R ²³ and R ^{24 are} hydrogen,
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 ₂ (II)
  in which
  A has the meaning given above,
  first by a reduction in the compounds of the general formula (III),
  A-NH ₂ (III)
  in which
  A has the meaning given above,
  convicted,
  in a next step with benzyl chloroformate, the compounds of the general formula (IV),
  A-NH-CO ₂ -CH ₂ -C ₆ H ₅ (IV)
  in which
  A has the meaning given above,
  manufactures,
  and finally with bases in inert solvents and subsequent reaction with (R) - (-) - glycidyl butyrate, the compounds of the general formula (Ia),
  in which
  A has the meaning given above,
  manufactures,
  and
• [B] this by reaction with (C ₁ -C ₄ ) alkyl or phenylsulfonic acid chlorides in inert solvents and in the presence of a base in the corresponding compounds of the general formula (Ib),
  in which
  A and R ^{17 have} the meaning given above,
  convicted,
  then the azides of the general formula (Ic) with sodium azide in inert solvents,
  in which
  A has the meaning given above,
  manufactures,
  in a further step by reaction with (C ₁ -C ₄ -O) ₃ -P or Ph ₃ P, preferably (CH ₃ O) ₃ P, in inert solvents and with acids or by catalytic hydrogenation into the amines of the general formula ( Id),
  in which
  A has the meaning given above,
  convicted,
  and by reaction with acetic anhydride, acetyl chloride or other acylating agents of the general formula (V),
  Y-CO-R ²⁰ (V)
  in which
  R ^{20 has} the meaning given above,
  and
  Y represents halogen, preferably chlorine or the radical -OCOR ²⁰ ,
  in the presence of a base in inert solvents, the compounds of the general formula (Ie),
  in which
  A and R ^{20 have} the meaning given above,
  manufactures,
  or
• [C] in case R ¹ = -NH-CO-R ²⁰
  Compounds of the general formula (III) directly with enantiomerically pure compounds of the general formula (VI),
  in which
  R ^{20 has} the meaning given above,
  in inert solvents and in the presence of an auxiliary to form enantiomerically pure compounds of the general formula (Ie)
  and in the case of the S-oxides, an oxidation with m-chloroperbenzoic acid follows and, if appropriate in the case of R ⁶ , R ¹¹ and / or R ¹² ≠ H, an acylation is carried out by customary methods.

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

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

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

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

The reaction with hydrides such as complex borohydrides or aluminum is preferred nium hydrides performed. Sodium borohydride is particularly preferred, Lithium aluminum hydride or sodium cyanoborohydride used.  

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

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

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

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

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

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

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

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

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

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

The usual solvents, which can be found under do not change the reaction conditions. These preferably include alcohols such as Methanol, ethanol, propanol or isopropanol or ether 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 amines 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 hydrocarbon substances such as methylene chloride, chloroform or carbon tetrachloride or pyridine, picoline or N-methylpiperidine. Mixtures of the solvents mentioned can also be used become.

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

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

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

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

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

The oxidation is generally carried out in one of the solvents listed above, preferably as in methylene chloride with oxidizing agents such as metachloroperbenzoic acid, hydrogen peroxide or peracetic acid, preferably with magnesium monoperoxy phthaline salt in a temperature range from 0 ° C to 80 ° C, preferably from 0 ° C to 40 ° C.

Suitable solvents for the alkylation are conventional organic solvents, which can be found under do not change the reaction conditions. These preferably include ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or hydrocarbons such as Benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions or halogen carbons Hydrogen such as dichloromethane, trichloromethane, carbon tetrachloride, dichlorethylene, tri chlorethylene or chlorobenzene or ethyl acetate or triethylamine, pyridine, dimethyl sulfoxide, dimethylformamide, acetonitrile, acetone or nitromethane. It is also possible To use mixtures of the solvents mentioned. Dichloromethane, Di are preferred methyl sulfoxide and dimethylformamide.

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

The compounds of the general formula (H) are dependent on the definition of Substituents A are known per se or can be analogous to processes known from the literature [see. D.R. Shridhar et al. SYNTHESIS 1982, 986-987] in the event that the heterocyclic ring system listed under A has a free N radio tion, this is first alkylated according to the alkylation method described above becomes.  

Some of the compounds of the general formulas (III) and (IV) are known or new and can then be produced, for example, as described above.

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

The compounds of general formula (VI) are known per se or according to übli Chen methods can be produced.

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

The MIC values were determined using the microdilution method in BH medium. Each test substance was dissolved in the sewing medium. In the microtiter plate by se serial dilution a concentration series of the test substances. For inoculation overnight cultures of the pathogens were used, which were previously in the nutrient medium 1: 250 ver were thinned. To 100 µ1 of the diluted nutrient solutions containing active ingredients were each Given 100 µl inoculation solution.

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

MIC values (µg / ml)

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

The compounds of the invention are against a broad spectrum of micro organisms effective, that is, they have a broad antimicrobial effect. With their Gram-positive germs, gram-negative bacteria and bacteria-like micro can help fights organisms such as mycoplasmas as well as those caused by these pathogens Diseases are prevented, corrected and / or cured.

The compounds according to the invention are particularly effective against bacteria and bak series-like microorganisms. They are therefore particularly good for prophylaxis and Chemotherapy of local and systemic infections in human and veterinary medicine suitable, which are caused by such pathogens.

The present invention includes pharmaceutical preparations which, besides not toxic, inert, pharmaceutically suitable carriers one or more fiction contain appropriate compounds, or those of one or more of the invention Active ingredients exist, as well as processes for the preparation of these preparations.

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

The therapeutically active compounds are said to be in the pharmazeu table preparations preferably in a concentration of about 0.1 to 99.5, preferably from about 0.5 to 95% by weight of the total mixture.

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

In general, it has proven to be both in human and in veterinary medicine partially proven, the active ingredient (s) according to the invention in total amounts of about 0.5 to about 500, preferably 5 to 100 mg / kg body weight per 24 hours if necessary in the form of several single doses, to achieve the desired results administer. A single dose contains the active ingredient or ingredients according to the invention preferably in amounts of about 1 to about 80, in particular 3 to 30 mg / kg, body Weight.  

The compounds of the invention can be used for the purpose of expanding the We spectrum and to achieve an increase in effectiveness, also with others Antibiotics can be combined.  

Output connections Example 1A 7-nitro-2H-1,4-benzoxazin-3-one

The substance is known from the literature and was manufactured according to 2 regulations:

• 1. according to DR Shridhar et al. OPPI 14 (3) 1982, 195 - 7 from 2-amino-5-nitro phenol (commercially available from FLUKA), chloroacetic acid chloride and sodium hydrogen carbonate in isobutyl methyl ketone and water
  or
• 2. according to D.R. Shridhar et al. SYNTHESIS 1982, 986 - 7 from commercially available 2- Amino-5-nitrophenol and ethyl bromoacetate in DMF with potassium fluoride yellow crystals, mp <225 ° C (dec.)

Example 2A 4-methyl-7-nitro-2H-1,4-benzoxazin-3-one

0.1 g (0.515 mmol) of compound 1A are dissolved in 2 ml of DMF under an argon atmosphere, 75 mg (0.515 mmol) of anhydrous K ₂ CO _{3 are} added, the mixture is cooled to 0 ° C. and, with stirring, 0.32 ml of methyl iodide are added dropwise (d = 2.28).
The mixture is left to stir at RT for a further 2 h and then poured onto ice. The precipitate is filtered off, washed with a little water and dried in vacuo.
yellowish crystals,
Mp: 198 ° C
R _f (dichloromethane / methanol = 100/3) = 0.89
Yield: 90 mg (84.3% of theory)

Example 3A 4-methyl-7-amino-2H-1,4-benzoxazin-3-one

1 g (4.8 mol) of compound 2A is abs in 30 ml of THF. dissolved, with 100 mg Pd-C, 10%, suspended in a little methanol pa, added and hydrogenated at 5 bar for 6 h. The catalyst is filtered off, the solution is evaporated to dryness iV and dried iV.
fbl. Crystals,
Mp: 155 ° C
R _f (dichloromethane / methanol = 9/1) = 0.55
Yield: 0.82 g (96% of theory)

Example 4A 4-methyl-7-benzyloxycarbonylamino-2H-1,4-benzoxazin-3-one

2 g (11.2 mmol) of compound 3A are dissolved in 25 ml of THF, 25 ml of water and 25 ml of saturated sodium hydrogen carbonate solution, cooled to 0 ° C. and 3.88 g (22.4 mmol) of benzyl chloroformate are added dropwise. Then allowed to stir for four hours at RT. The reaction solution is extracted several times with chloroform, the organic phase is dried, evaporated to dryness in vacuo and the residue is recrystallized from 2-propanol.
fbl. Crystals,
Mp: 163 ° C
R _f (toluene / ethanol = 10/1) = 0.35
Yield: 2.56 g (73% of theory)

Example 5A 4-ethyl-7-nitro-2H-1,4-benzoxazin-3-one

The title compound is prepared in analogy to the procedure of Example 2A from 2 g (10.3 mmol) of the compound of Example 1A, 1.57 g (10.3 mmol) of DBU and 2.4 g (15.45 mmol) of ethyl iodide in 50 ml DMF produced.
yellow crystals (recryst. from 2-propanol),
Mp: 116 ° C
R _f (toluene / ethanol = 10/1) = 0.52
Yield: 1.34 g (59% of theory)

Example 6A 4-ethyl-7-amino-2H-1,4-benzoxazin-3-one

The title compound is prepared in analogy to the procedure of Example 3A from 10.57 g (48 mmol) of the compound from Example 5A in 170 ml of THF (hydrogenated with 3 bar of hydrogen and Pd-C 10% as catalyst) at 60 ° C. .
fbl. Crystals,
Mp: 135 ° C
R _f (toluene / ethanol = 10/1) = 0.28

Example 7A 4-ethyl-7-benzyloxycarbonylamino-2H-1,4-benzoxazin-3-one

The title compound is prepared analogously to the procedure of Example 4A from 0.7 g (3.6 mmol) of the compound from Example 6A in THF and saturated NaHCO ₃ solution with 1.25 g (7.2 mmol) of benzyl chloroformate.
fbl. Crystals
R _f (toluene / ethanol = 10/1) = 0.3
Yield: 0.68 g (58% of theory)

Example 8A 2-methyl-7-nitro-2H-1,4-benzoxazin-3-one

100 g (0.64 mol) of 5-nitro-2-aminophenol were dissolved in 480 ml pa DMF, treated with 96.9 g (1.67 mol) potassium hydroxide and heated to 50-60 ° C. 115.8 g (0.64 mol) of ethyl α-bromopropionate are allowed to drip in with stirring. After the addition, the temperature is left at 50-60 ° C. for 6 h, at RT overnight and the product is precipitated with ice water. The yellow precipitate is filtered off, washed with water and dried.
yellow crystals,
Mp: 215-6 ° C (dec.)
R _f (toluene / ethanol 10/1) = 0.63
Yield, raw: 130 ° (96.2%)

Example 9A 2,4-dimethyl-7-nitro-2H-1,4-benzoxazin-3-one

100 g (0.48 mol) of the compound from Example 8A are dissolved in 2.31 DMF, 72.9 g (0.48 mol) of DBU are added and the mixture is stirred at 50 ° C. for 1 h. 102 g (0.72 mol) of methyl iodide are added dropwise and the mixture is then stirred at 100 ° C. overnight. After cooling, the solvent is largely evaporated off in vacuo, the yellow precipitate is filtered off and washed with benzyl isopropyl ether. The recrystallization takes place from 2-propanol.
yellow crystals,
Mp: 181 ° C
R _f (toluene / ethanol = 10/1) = 0.35
Yield (after recrystallization): 78 g (73.1% of theory)

Example 10A 2,4-dimethyl-7-amino-2H-1,4-benzoxazin-3-one

62.5 g (0.3 mol) of the compound from Example 9A are dissolved in 2.5 l of abs. THF dissolved, mixed with 4.6 g Pd-C, 10% and hydrogenated overnight at 60 ° C at 1-3 bar hydrogen (in a 3 l autoclave). The catalyst is then filtered off and the filtrate is evaporated to dryness.
fbl. Crystals
Mp: 132 ° C
R _f (toluene / ethanol = 10/1) = 0.2
Yield: 51 g (94.4% of theory)

Example 11A 2,4-dimethyl-7-benzyloxycarbonylamino-2H-1,4-benzoxazin-3-one

52 g (0.27 mol) of the amine from Example 10A are dissolved in 546 ml of THF and mixed with 650 ml of water and 650 ml of saturated NaHCO ₃ solution. To do this, 100.8 g (0.58 mol) of benzyl chloroformate are added dropwise at 0 ° C. Then allowed to stir at RT for 4 h. It is extracted 4 × with 500 ml of chloroform, dried over MgSO ₄ and evaporated down in vacuo. Recrystallization from 2-propanol.
fbl. Crystals,
Mp: 120 ° C
R _f (toluene / ethanol = 10/1) = 0.4
Yield: 46 g (52.2% of theory)

Example 12A 4-methoxycarbonyl-7-nitro-2H-1,4-benzoxazin-3-one

1 g (5.15 mmol) of compound 1A and 5.15 ml (5.15 mmol) of bis (trimethylsilyl) lithium amide (LiHMDS) are dissolved in 25 ml of abs. THF dissolved and 0.6 ml (1 molar in hexane) (7.65 mmol) methyl chloroformate (strongly exothermic) was added dropwise at 0 ° C. while stirring. Then it is stirred for 3 hours at RT. The solvent is then distilled off in vacuo and the residue is recrystallized from 2-propanol.
yellow Crystals,
Mp: 190 ° C
R _f (toluene / ethanol = 10/3) = 0.11
Yield: 0.89 g (68.5% of theory)

Example 13A 4-methoxycarbonyl-7-amino-2H-1,4-benzoxazin-3-one

The title compound is prepared in analogy to the procedure of Example 3A from 13 g (51.5 mmol) of the nitro compound from Example 12A and 2 g of Pd-C, 10%, in 400 ml of abs. THF at 60 ° C and 3 bar hydrogen (press hydrogen three times, total duration 18 hours).
fbl. Crystals,
Mp: 180 ° C
R _f (dichloromethane / methanol = 15/1) = 0.69
Yield: 8.9 g (77.8% of theory)

Example 14A 4-methyl-7-amino-3,4-dihydro-2H-1,4-benzoxazine

4.8 g (27 mmol) of the compound of Example 3A are dissolved in 50 ml abs under an argon atmosphere. Dissolved THF, cooled to 5-10 ° C and added dropwise with stirring with 27 ml (94 mmol ≅ 3 5 equivalents) of Red-Al (solution of sodium bis (2-methoxy ethoxy) aluminum hydride in toluene, [(CH ₃ -OCH ₂ CH ₂ O) ₂ AlH ₂ ] Na) in 75 ml THF added dropwise. A strong gas development occurs. The mixture is left to stir at RT overnight, then excess Red-Al is decomposed by carefully adding ice water, the precipitate which has precipitated is filtered off and the filtrate is evaporated to dryness. The residue is separated by column chromatography, silica gel 60, mobile phase: dichloromethane / methanol = 9/1.
fbl. oil
R _f (dichloromethane / methanol = 9/1) = 0.48
Yield: 2.22 g (50.1% of theory)

Example 15A 4-methyl-7-benzyloxycarbonylamino-3,4-dihydro-2H-1,4-benzoxazine

The title compound is prepared in analogy to the procedure of Example 4A from 2.22 g (13.5 mmol) of the amine from Example 14A and 2.53 g (14.8 mmol ≅ equivalents) of benzyl chloroformate in dioxane.
slightly yellowish oil
R _f (dichloromethane / methanol = 100/3) = 0.92
Yield: 4.8 g (raw).

After another column chromatography (silica gel 60, eluent: dichloromethane / methanol = 100/1), this is
Yield: 2.6 g (65.2% of theory)

Example 16A 9-benzyloxycarbonyl-6,7-dihydro-5H-pyrido [1,2,3-de] -2H-1,4-benzoxazin-3-one

The title compound is prepared in analogy to the procedure of Example 4A from 10 g (0.049 mol) of 9-amino-6,7-dihydro-5H-pyrido- [1,2,3, -de] -2H-1,4-benzoxazin- 3-one, 50 ml of dioxane, 100 ml of saturated sodium bicarbonate solution and 9.2 g (0.054 mol) of benzyl chloroformate.
fbl. Crystals,
Mp: 165-7 ° C
R _f (dichlorometane / methanol = 100/2) = 0.39
Yield: 13 g (78.5% of theory)

Example 17A 9-amino-6,7-dihydro-5H-pyrido [1,2,3, -de] -3,4-dihydro-2H-1,4-benzoxazine

The title compound is prepared in analogy to the procedure of Example 14A from 3 g (0.0147 mol) of the compound 9-amino-6,7-dihydro-5H-pyrido- [1,2,3, -de] -2H-1, 4-benzoxazin-3-one and 20.55 ml (5.25 mmol) Red-Al in THF.
fbl. oil
R _f (dichloromethane / methanol = 100/7) = 0.3
Yield: 750 mg (26.9% of theory)

Example 18A 9-benzyloxycarbonylamino-6,7-dihydro-SH-pyrido [1,2,3, -de] -3,4-dihydro-2H-1,4- benzoxazine

The title compound is prepared analogously to Example 4A from 0.4 g (2.11 mmol) of the amine from Example 17A, 0.4 g (2.332 mmol) benzyl chloroformate, 2.5 ml dioxane and 4 ml saturated sodium bicarbonate solution. The chromatographic separation takes place in dichloromethane / methanol = 100/1.
R _f (dichloromethane / methanol = 100/7) = 0.83
Yield: 600 mg (87.8% of theory)

Example 19A 1-methyl-6-nitro-1,2,3,4-tetrahydroquinolin-2-one

50 g (0.266 mol) of 6-nitro-1,2,3,4-tetrahydroquinolin-2-one are dissolved in 500 ml of dimethoxyethane under an argon atmosphere, with stirring first with 36.7 g (0.266 mol) of potassium carbonate and then with 33 , 1 ml (d = 2.28, 0.532 mol) of methyl iodide are added and the mixture is heated to boiling. After cooling, the main amount is precipitated with water (26 g), the aqueous phase is extracted three times with ethyl acetate, the organic phase is dried with sodium sulfate, evaporated to dryness in vacuo and dried in a high vacuum (22 g).
yellowish crystals
Yield: 48 g (97.5% of theory)

Example 20A 1-methyl-6-amino-1,2,3,4-tetrahydroquinolin-2-one

50 g (0.242 mol) of the compound from Example 19A are dissolved in 200 ml of methanol and 200 ml of DMF, 2 g of catalyst (Pd-C, 5%) are added and the mixture is hydrogenated with hydrogen at room temperature at 3 bar overnight. After filtering off the catalyst, the filtrate is concentrated in vacuo to a small volume and the residue is separated by column chromatography (silica gel 60, petroleum ether / ethyl acetate = 10/1)
fbl. Crystals
Yield: 29 g (68.0% of theory)

Example 21A 1-methyl-6-benzyloxycarbonylamino-1,2,3,4-tetrahydroquinolin-2-one

29 g (0.164 mol) of the amine from Example 20A are absorbed in 300 ml. Dissolved dichloromethane, mixed with 26.2 ml (0.189 mol) of triethylamine, cooled to 0 ° C and added dropwise with stirring 29.5 ml (0.173 mol) of benzyl chloroformate. The mixture is stirred overnight at room temperature, the solvent is largely evaporated off and the product is precipitated by adding water. It is filtered off, dried (30 g, crude) and purified by column chromatography (silica gel 60, mobile phase:
Petroleum ether / ethyl acetate = 1/1).
fbl. Crystals
Yield: 6 g (11.7% of theory)

Example 22A 1-ethyl-6-nitro-1,2,3,4-tetrahydroquinolin-2-one

The title compound is prepared in analogy to the procedure of Example 19A from 50 g (0.266 mol) of 6-nitro-1,2,3,4-tetrahydroquinolin-2-one, 36.7 g (0.266 mol) of potassium carbonate and 39.7 ml (0.532 mmol) ethyl bromide.
yellowish crystals
Yield: 49 g (83.6% of theory)

Example 23A 1-ethyl-6-amino-1,2,3,4-tetrahydroquinolin-2-one

The title compound is prepared in analogy to the procedure of Example 20A from 29 g (0.132 mol) of the nitro compound from Example 25A and 2 g of catalyst, Pd-C, 5%.
fbl. product
Yield, raw: 35 g (<100% of theory)

Example 24A 1-ethyl-6-benzyloxycarbonylamino-1,2,3,4-tetrahydroquinolin-2-one

The title compound is prepared in analogy to the procedure of Example 21A from 50 g (0.263 mol) of the amine from Example 26A, 12.6 g (0.526 mol) of sodium hydride and 123 ml (0.867 mol) of benzyl chloroformate in 500 ml of dimethoxyethane and subsequent neutralization with 1N hydrochloric acid produced.
fbl. product
Yield: 66 g (77.4% of theory)

Example 25A 1-isopropyl-6-nitro-1,2,3,4-tetrahydroquinolin-2-one

The title compound is prepared in analogy to the procedure of Example 19A from 50 g (0.266 mol) of 6-nitro-1,2,3,4-tetrahydroquinolin-2-one (21A), 36.7 g (0.266 mol) of potassium carbonate and 52 ml (0.532 mmol, d = 1.743) isopropyl iodide. Column chromatographic separation: silica gel 60, eluent: petroleum ether / ethyl acetate = 20/1 to 10/1
yellowish product
Yield: 24 g (38.5% of theory)

Example 26A 1-isopropyl-6-amino-1,2,3,4-tetrahydroquinolin-2-one

In analogy to the procedure of Example 20A, the title compound is obtained from 24 g (0.102 mol) of the nitro compound from Example 28A and 2 g of Pd-C, 5%, in 300 ml of DMF / methanol = 1/1, at 3 bar hydrogen pressure above 3 Days.
fbl. product
Yield, raw: (<100%)

Example 27A 1-isopropyl-6-benzyloxycarbonylamino-1,2,3,4-tetrahydroquinolin-2-one

The title compound is prepared in analogy to the procedure of Example 21A. 7.52 g (0.313 mol) of sodium hydride are placed in 300 ml of THF and in 15 min. added dropwise while stirring with 32 g (0.1568 mol) of the amine from Example 26A. 73.6 ml (0.518 mol) of benzyl chloroformate are added dropwise at 0.degree. The mixture is then stirred at RT overnight.
fbl. product
Yield: 12 g (22.6% of theory).

Analogous to the reaction of 7-nitro-2H-1,4-benzothiazin-3-one [preparation takes place after: A. Martani et al., Ann. Chim. (Rome) 1968), 58 (11), 1226-1237] were the in Compounds listed in Table 1 receive:

Table I

Example 30A 1,1-dioxo-7-nitro-3,4-dihydro-2H-1,4-benzothiazine

5.7 g (25 mmol) of 1,1-dioxo-7-nitro-3,4-dihydro-2H-1,4-benzothiazine [prepared ana log F. Babudri, J. Chem. Soc. Perkin Trans. 1, 8, 1984, 1949-55 from the corre sponding thiazine and chloroperbenzoic acid] are added to a mixture of 1 g (25 mmol) sodium hydride (60%) in 250 ml THF p.A. added in portions. It will Stirred for 30 minutes, then added 200 mg of sodium hydride and stirred another 30 minutes. Then the solution of 4.97 g (35 mmol) Add methyl iodide in 10 ml THF and stir overnight at room temperature.

The mixture is concentrated, the residue is taken up in dichloromethane, washed with water, dried over sodium sulfate and evaporated. The crude product is chromatographed on silica gel (mobile phase: dichloromethane / methanol = 100 / 0.75).
Yield 5.6 g (92.6% of theory)
Melting point: 201 ° C
R _f (dichloromethane / methanol = 100 / 2.5) = 0.62.

The compounds listed in Table 11 are obtained analogously to Example 30A.

Table II

Example 34A 1,1-dioxo-4-methyl-7-amino-3,4-dihydro-2H-1,4-benzothiazine

5.6 g (23 mmol) of the compound from Example 30A are hydrogenated in 560 ml of THF with 500 mg of Pd / C (10%) at 3 bar for 1 hour. The catalyst is suction filtered through Celite and the solvent is spun in. Yield: 4.9 g (quantitative)
Melting point: 165 ° C
R _f (dichloromethane / methanol = 9/1) = 0.56

Example 35A 4-methyl-7-amino-3,4-dihydro-2H-1,4-benzothiazine

21.6 g (0.096 mol) of the compound from Example 31A are placed in 675 ml of ethanol and 6.72 g of calcium chloride in 163 ml of water. 22 g of zinc dust are then added in portions and the mixture is refluxed for one hour. It is suctioned off hot and the filtrate is concentrated. The residue is taken up in dichloromethane, dried over sodium sulfate and concentrated.
Yield: 7.8 g (42% of theory)
Mp: oil
R _f (dichloromethane / methanol = 100/5) = 0.45

The compounds in Table III are obtained analogously to Example 35A:  

Table III

Example 38A 1,1-dioxo-4-methyl-7-benzyloxycarbonyl-3,4-dihydro-2H-1,4-benzothiazine

4.86 g (22.2 mmol) of 7-amino-1,1-dioxo-4-methyl-3,4-dihydro-2H-benzo-1,4-thiazine (Example 34A) are dissolved in 46.6 ml of water , 38 ml of THF and 46.6 ml of saturated sodium bicarbonate solution at 0 ° C. Then 3.6 ml of benzyl chloroformate are added; it is stirred for 1 hour. The mixture is poured into water and extracted with dichloromethane. The organic phase is concentrated and the crude product obtained is chromatographed on silica gel (mobile phase: dichloromethane / methanol 100/5 to 100/3). The product obtained is taken up in dichloromethane and precipitated with petroleum ether.
Yield: 4.8 g (55% of theory)
Melting point: 157 ° C

The compounds in Table IV were obtained analogously to Example 38A:

Table IV

Example 42A 1,3-dimethyl-3,4-dihydro-2 (1H) -quinazolinone

32.40 g (199.76 mmol) of 3,4-dihydro-3-methyl-2 (1H) -quinazolinone are added in portions to a stirred suspension of 7.99 g (199.76 mmol) of sodium hydride in 200 ml of anhydrous DMF and stir for a further 0.5 hours at room temperature. 12.49 ml (199.76 mmol) of iodomethane are slowly added dropwise and the mixture is stirred at room temperature for 15 hours. The solvent is then evaporated off in vacuo and 500 ml of water are added to the residue. The mixture is extracted with 3 × 100 ml of dichloromethane and the combined organic extracts are dried with MgSO ₄ . After evaporation of the solvent in vacuo and chromatography of the residue on 350 g of silica gel (cyclohexane / ethyl acetate = 4/1), 32.40 g (88% of theory) of the title compound are obtained as a colorless oil.
R _f = 0.35 (dichloromethane / methanol = 95/5)

Example 43A 1,3-dimethyl-3,4-dihydro-6-nitro-2 (1H) -quinazolinone

8.81 g (50 mmol) of the compound from Example 42A are slowly added dropwise to 27.76 ml (0.50 mol) of 96% sulfuric acid with stirring at 0 ° C. and then carefully 2.07 ml at 15-20 ° C. (50 mmol) nitric acid. The mixture is stirred for 3 hours at room temperature and the reaction mixture is stirred into 500 ml of ice water. The precipitate is filtered and dried in a high vacuum. 4.70 g (43% of theory) of the title compound are obtained as bright crystals.
R _f = 0.67 (dichloromethane / methanol = 95/5)

Example 44A 6-amino-1,3-dimethyl-3,4-dihydro-2 (1H) -quinazolinone

A solution of 29.50 g (84 mmol) of the compound from Example 43A in a mixture of 200 ml of methanol and 100 ml of DMF is in the presence of 1 g of palladium on carbon (5%) overnight at a pressure of 3 bar of hydrogen hydrated. The catalyst is separated off by filtration, the filtrate is evaporated in vacuo and the residue is purified by chromatography on 500 g of silica gel (ethyl acetate / cyclohexane = 7/3). 15.9 g (98% of theory) of the title compound are obtained as light yellow crystals.
Mp: 157 ° C
R _f = 0.12 (ethyl acetate / cyclohexane = 7/3)

Example 45A 6-benzyloxycarbonylamino-1,3-dimethyl-3,4-dihydro-2 (1H) -quinazolinone

To a cooled to 0 ° C, stirred solution of 4.20 g (21.96 mmol) of the compound of Example 44A in 100 ml of water and 50 ml of THF within 30 min. 4.12 g (14.16 mmol) benzyl chloroformate were added dropwise, the pH = 10 being maintained by simultaneous addition of a 4N NaOH solution. The mixture is stirred for a further 2 h at 0 ° C., the THF is evaporated off in vacuo and the residue is extracted with 3 × 40 ml of ethyl acetate. The combined organic extracts are dried over MgSO ₄ , the solvent is evaporated in vacuo and the residue is crystallized by rubbing with ether. 6.90 g (95% of theory) of the title compound are obtained as colorless crystals.
Mp: 143 ° C
R _f = 0.32 (ethyl acetate / cyclohexane = 7/3)

Example 46A 7-nitro-3,4-dihydro-2H-1,4-benzoxazine

6 ml of a 1 molar solution of BH ₃ × THF (5.9 mmol) are introduced, cooled to 0 ° C. and mixed with 0.5 g (0.2575 mmol) of the compound from Example 1A under an argon atmosphere. After boiling for 2 hours, the mixture is allowed to cool, 0.75 ml of methanol are carefully added and the mixture is heated under reflux for a further hour. After adding 0.75 ml of concentrated hydrochloric acid and further heating under reflux (about 1 hour), the mixture is allowed to cool and the solvent is evaporated off to dryness. The residue is stirred with diethyl ether, the residue is dissolved in 1N sodium hydroxide solution (if appropriate, a little methanol added) and extracted with ethyl acetate. After drying the organic phase with sodium sulfate and filtering, the solvent is evaporated to dryness in vacuo.
slightly brownish crystals
Mp: 184 ° C
Yield: 280 mg (60.3% of theory)
R _f (dichloromethane / methanol = 100/1) = 0.79

Example 47A 4-methoxycarbonyl-7-nitro-3,4-dihydro-2H-1,4-benzoxazine

200 mg (1.11 mmol) of Example 46A are dissolved in 1 ml of dichloromethane under an argon atmosphere and within 1 minute at 0 ° C. with 0.33 ml (1.33 mmol) of N, O-bis (trimethylsilyl) acetamide (Aldrich) added in 1 ml dichloromethane. The mixture is then left to react for a further 1 hour, the temperature rising to RT. Brief heating and further reaction at RT overnight complete the reaction. After adding 4.5 ml of pH 7 buffer solution, the mixture is extracted with dichloromethane and the organic phase is evaporated to dryness in vacuo. The remaining residue is purified by column chromatography on silica gel 60, mobile phase: dichloromethane / methanol = 100/1.
fbl. Crystals
Mp .: 116 ° C
Yield: 100 mg (37.8% of theory)
R _f (dichloromethane / methanol = 100/1) = 0.48

Example 48A 4-methoxycarbonyl-7-amino-3,4-dihydro-2H-1,4-benzoxazine

0.958 g (4.022 mol) of the compound from Example 47A are dissolved in 10 ml of methanol, 100 mg of Pd-C (5%) are added and the mixture is hydrogenated under 2 bar of hydrogen pressure for 1.5 hours. The catalyst is filtered off over silica gel and evaporated to dryness in vacuo.
fbl. foam
Yield: 0.78 g (93.2% of theory)
R _f (dichloromethane / methanol = 100/1) = 0.78

Manufacturing examples example 1 (5R) -3- (4-Methyl-2H-1,4-benzoxazin-3-one-7-yl) -5-hydroxymethyl-oxazolidin-2-one

1 g (3.2 mmol) of Verb. 4A is in an argon atmosphere in abs. Dissolved THF and added dropwise with stirring at -78 ° C with 2.4 g (3.84 mmol) of butyllithium. The mixture is stirred at -78 ° C for 1 hour, then adjusted to -15 ° C and 0.54 g (3.84 mmol) of (R) - (-) - glycidyl butyrate are added dropwise. The temperature is then allowed to rise to RT and the mixture is stirred overnight. A spatula tip of cesium carbonate is added and the mixture is heated to boiling for about 1 h. Saturated NH ₄ Cl solution is then added and the mixture is extracted several times with dichloromethane. The organic phase is dried with sodium sulfate, i. V. evaporated to dryness and dried (high vacuum).
fbl. Crystals;
Mp: 167 ° C
R _f (toluene / ethanol = 10/1) = 0.12
Yield: 0.58 g (65% of theory)

Example 2 (5R) -3- (4-Methyl-2H-1,4-benzoxazin-3-one-7-yl) -5-methanesulfonyloxymethyl oxazolidin-2-one

2.8 g (10.1 mmol) of compound 1 are dissolved in 60 ml of dichloromethane, 1.02 g (10.1 mmol) of triethylamine are added, the mixture is cooled to 0 ° C. and, while stirring, 1.35 g (11 , 8 mmol) of mesyl chloride in 10 ml of dichloromethane. After an hour's reaction at 0 ° C., the mixture is increased to RT and the mixture is left to react overnight.
fbl: crystals
R _f (toluene / ethanol = 10/1) = 0.16
Yield: 3.0 g (84% of theory)

Example 3 (5R) -3- (4-Methyl-2H-1,4-benzoxazin-3-one-7-yl) -5-azidomethyl-oxazolidin-2-one

3.0 g (84 mmol) of compound 2 in 12 ml abs. DMF dissolved, mixed with 0.77 g (11.8 mmol) of sodium azide and warmed to 70 ° C. overnight. The reaction mixture is then mixed with water, the precipitate is suctioned off, washed and dried.
fbl. Crystals
R _f (toluene / ethanol = 10/1) = 0.13
Yield: ≈ quantitative, 2.5 g

Example 4 (5S) -3- (4-Methyl-2H-1,4-benzoxazin-3-one-7-yl) -5-aminomethyl-oxazolidin-2-one

2.5 g (8.2 mmol) of compound 3 are dissolved in 170 ml of ethyl acetate, mixed with 1 g of Pd-C (10%) and hydrogenated at 3 bar hydrogen pressure at 60 ° C (the catalyst addition may have to be repeated) will). After the hydrogenation has ended, the catalyst is filtered off with suction, the filtrate is evaporated to dryness in vacuo and recrystallized from 2-propanol.
fbl. Crystals,
Mp: 154 ° C
R _f (dichloromethane / methanol = 9/1) = 0.31
Yield: 1.42 g (62% of theory)

Example 5 (5S) -3- (4-methyl-2H-1,4-benzoxazin-3-one-7-yl) -5-acetylaminomethyl-oxazolidin-2- on

150 mg (0.6 mmol) of the compound from Example 4 are abs in 10 ml. Dichloromethane dissolved, 122 mg (1.22 mmol) of triethylamine added, the mixture cooled to 0 ° C. and 60 mg (0.75 mmol) of acetyl chloride in 2 ml of dichloromethane were added dropwise with stirring. The mixture is then left to react at RT overnight. It is evaporated to dryness in vacuo and the rest is recrystallized from 2-propanol.
fbl: crystals,
Mp: 167 ° C
R _f (toluene / ethanol = 5/1) = 0.36
Yield: 148 mg (80% of theory)

Example 6 (5S) -3- (4-Methyl-2H-1,4-benzoxazin-3-one-7-yl) -5-methoxycarbonylaminomethyl oxazolidin-2-one

150 mg (0.6 mmol) of the compound from Example 4 and 122 mg (1.2 mmol) of triethyl amine in 10 ml abs. Dissolved dichloromethane, cooled to 0 ° C and with stirring 71 mg (0.75 mmol) of methyl chloroformate were added dropwise.  

The mixture is then left to react overnight at room temperature. It is evaporated to dryness in vacuo and the rest is purified by column chromatography (silica gel 60, mobile phase: toluene / ethanol = 6/1).
fbl. Crystals,
Mp: 169 ° C
R _f (toluene / ethanol = 5/1) = 0.27
Yield: 130 mg (71.7% of theory)

Example 7 (5S) -3- (4-Methyl-2H-1,4-benzoxazin-3-one-7-yl) -5-bromoacetylaminomethyl-oxazo lidin-2-one

0.6 g (2.3 mmol) of the compound from Example 4 and 0.47 g (4.6 mmol) of triethylamine are abs in 30 ml. Dissolved dichloromethane, cooled to 0 ° C and dropwise with stirring with 0.72 g (4.6 mmol) bromoacetyl chloride in 10 ml abs. Dichloromethane displaces. The mixture is then left to react at RT overnight. The reaction solution is evaporated to dryness in vacuo and the rest is recrystallized from 2-propanol.
fbl. Crystals,
Mp <250 ° C (dec.)
R _f (toluene / ethanol = 10/3) = 0.28
Yield: 0.34 g (38.4% of theory)

Example 8 (5S) -3- (4-methyl-2H-1,4-benzoxazin-3-one-7-yl) -5-propionylaminomethyl-oxazolidine 2-one

0.6 g (2.3 mmol) of the compound from Example 4 and 30 ml ≅ 0.44 g (4.3 mmol) of triethylamine are abs in 30 ml. Dissolved dichloromethane, cooled to 0 ° C and 0.43 g (4.3 mmol) of propionic acid chloride was added dropwise with stirring. Then allowed to react at RT overnight. The reaction solution is filtered through silica gel 60, the filtrate is evaporated to dryness and recrystallized from 2-propanol.
fbl. Crystals,
Mp <250 ° C (dec.)
R _f (toluene / ethanol = 10/3) = 0.35
Yield: 190 mg (23.7% of theory)

Example 9 (5S) -3- (4-Methyl-2H-1,4-benzoxazin-3-one-7-yl) -5- (oxazol-5-yl-carbonylamino methyl) oxazolidin-2-one

0.6 g (2.3 mmol) of the compound from Example 4 and 30 ml ≅ 0 44 g (4.3 mmol) of triethylamine are abs in 30 ml. Dissolved dichloromethane, cooled to 0 ° C and dropwise with stirring with 0.62 (4.6 mmol) oxazole-5-carboxylic acid chloride in 10 ml abs. Dichloromethane added. The mixture is left to react at RT overnight. The reaction solution is i. V. evaporated to dryness and the residue recrystallized from 2-propanol.
fbl. Crystals,
Mp: 229 ° C (dec.)
R _f (toluene / ethanol = 10/3) = 0.47
Yield: 320 mg (37% of theory)

Example 10 (5S) -3- (4-Methyl-2H-1,4-benzoxazin-3-one-7-yl) -5 - [(1R, 2R) -2-fluorocyclopropane carbonylamino-methyl] -oxazolidin-2-one

150 mg (0.6 mmol) of the compound from Example 4 and 122 mg (1.2 mmol) of triethylamine in 10 ml of abs. Dissolved dichloromethane, cooled to 0 ° C and dropwise with 0.2 mg (0.75 mmol) (1R, 2R) -2-fluorocyclopropylcarbonyl chloride. The mixture is then left to react at RT overnight. The reaction solution is evaporated in vacuo and separated by column chromatography (silica gel 60, mobile phase:
Toluene / ethanol = 6/1).
fbl. Crystals
R _f (toluene / ethanol = 5/1) = 0.37
Yield: 82 mg (36% of theory)

Example 11 (5R) -3- (4-Ethyl-2H-1,4-benzoxazin-3-one-7-yl) -5-hydroxymethyl-oxazolidin-2-one

In analogy to the procedure of Example 1, the title compound is obtained from 0.68 g (2.1 mmol) of the compound from Example 7A, 1.6 g (25 mmol) of butyllithium and 0.35 g (2.5 mmol) of (R) - (-) - Glycidyl butyrate produced.
fbl. Crystals
R _f (toluene / ethanol = 10/1) = 0.12
Yield (raw): 0.83g (quantitative)

Example 12 (5R) -3- (4-Ethyl-2H-1,4-benzoxazin-3-one-7-yl) -5-methanesulfonyloxymethyl-oxa zolidin-2-one

The title compound is prepared in analogy to the procedure of Example 6A from 2.57 g (approx. 8.8 mmol) of crude material of compound 11, 0.88 g (8.8 mmol) of triethylamine and 1.2 g (10.6 mmol) Mesyl chloride produced.
fbl. Crystals,
R _f (toluene / ethanol = 10/1) = 0.17
Yield: 1 g (31% of theory)

Example 13 (5R) -3- (4-Ethyl-2H-1,4-benzoxazin-3-one-7-yl) -5-azidomethyl-oxazolidin-2-one

The title compound is prepared in analogy to the procedure of Example 3 from 1 g (2.7 mmol) of compound 11 in 10 ml abs DMF and 250 mg (3.78 mmol) sodium azide.
fbl. Crystals,
R _f (toluene / ethanol = 10/1) = 0.37
Yield: 1.0 g (raw)

Example 14 (5S) -3- (4-Ethyl-2H-1,4-benzoxazin-3-one-7-yl) -5-aminomethyl-oxazolidin-2-one

The title compound is prepared in analogy to the procedure of Example 4 from 1 g (2.7 mmol) of the compound from Example 13 and 0.1 g of Pd-C catalyst 10%.
fbl. Crystals,
Mp: 158 ° C
R _f (toluene / ethanol = 5/1) = 0.47
Yield: 0.3 g (32.7% of theory)

Example 15 (5S) -3- (4-ethyl-2H-1,4-benzoxazin-3-one-7-yl) -5-bromoacetylaminomethyl-oxazolidine 2-one

In analogy to the procedure of Example 7, the title compound is obtained from 0.6 g (2.04 mmol) of the amine from Example 14, 0.42 g (4.08 mmol) of triethylamine and 0.64 g (4.10 mmol) of bromoacetyl chloride produced.
fbl. Crystals,
Mp: 138.9 ° C
R _f (toluene / ethanol = 10/3) = 0.14
Yield: 0.66 g (81.2% of theory)

Example 16 (5S) -3- (4-Ethyl-2H-1,4-benzoxazin-3-one-7-yl) -5- (furan-2-yl-carbonylaminomethyl) - oxazolidin-2-one

The title compound is prepared in analogy to the procedure of Example 9 from 0.6 g (2.04 mmol) of the amine from Example 14, 0.42 g (4.08 mmol) of triethylamine and 0.36 g (2.55 mmol) of furan -2-yl-carbonyl chloride produced.
fbl. Crystals
Mp: <250 ° C (dec.) Recrist. from 2-propanol
R _f (toluene / ethanol = 10/3) = 0.48
Yield: 50 mg (6.6% of theory)

Example 17 (5S) -3- (4-Ethyl-2H-1,4-benzoxazin-2-one-7-yl) -5-trifluoroacetylaminomethyl-oxazo lidin-2-one

The title compound is prepared in analogy to the procedure of Example 5 from 0.6 g (2.04 mmol) of the amine from Example 14, 0.42 g (4.08 mmol) of triethylamine and 0.54 g (2.55 mmol) of trifluoroacetic anhydride produced.
fbl. Crystals
Mp: <250 ° C (dec.)
R _f : (toluene / ethanol = 10/3) = 0.46
Yield: 160 mg (20.25% of theory)

Example 18 (5S) -3- (4-Ethyl-2H-1,4-benzoxazin-3-one-7-yl) -5-methoxycarbonylaminomethyl-oxa zolidin-2-one

The title compound is prepared analogously to the procedure of Example 6 from 1 g (3.4 mmol) of the amine from Example 14, 6 g (6.8 mmol) of triethylamine and 0.36 g (3.75 mmol) of methyl chloroformate.
fbl. Crystals, rekrist. from 2-propanol
Mp: 135.6 ° C
R _f : (toluene / ethanol 10/3) = 0.29
Yield: 360 mg (30.3% of theory)

Example 19 (5S) -3- (4-ethyl-2H-1,4-benzoxazin-3-one-7-yl) -5-propionylaminomethyl-oxazolidin-2- on

The title compound is prepared in analogy to the procedure of Example 8 from 1 g (3.4 mmol) of the amine from Example 14, 0.6 g (6.8 mmol) of triethylamine and 0.4 g (3.75 mmol) of propionic acid chloride.
fbl. Crystals recrystallized from n-hexane
Mp: 218 ° C
R _f : (toluene / ethanol = 10/3) = 0.39
Yield: 350 mg (28.8% of theory)

Example 20 (5S) -3- (4-Ethyl-2H-1,4-benzoxazin-3-one-7-yl) -5-acetylaminomethyl-oxazolidin-2-one

The title compound is prepared analogously to the procedure of Example 5 from 0.3 g (1 mmol) of the amine from Example 14, 0.2 g (2 mmol) of triethylamine and 0.1 g (1.25 mmol) of acetyl chloride.
fbl. Crystals recrystallized from 2-propanol
Mp: 132 ° C
R _f : (toluene / ethanol 10/1) = 0.24

Example 21 (5R) -3- (2,4-dimethyl-2H-1,4-benzoxazin-3-one-7-yl) -5-hydroxymethyl-oxazolidin-2- on

46 g (0.14 mol) of the compound from Example 11A are in 11 abs. THF dissolved, cooled to -78 ° C and mixed with 105 g (0.168 mol) of n-butyllithium solution. The mixture is stirred at -78 ° C. for 1 h and 23.6 g (0.168 mol) of (R) - (-) - glycidyl butyrate are added dropwise. Then the temperature is allowed to rise to RT and the mixture is stirred overnight. Then you give 140 ml abs. Add methanol and a spoon spatula K ₂ CO ₃ and warm to 50 ° C for about 3 h. After cooling, saturated NH ₄ Cl solution is added and the mixture is extracted several times with dichloromethane. The organic phases are combined, dried with MgSO ₄ and evaporated in vacuo. The residue is filtered off and washed with a little methanol.
fbl. Crystals
Mp: 183 ° C
R _f (toluene / methanol = 10/3) = 0.17
Yield: 19 g (46.1% of theory)

Example 22 (5R) -3- (2,4-Dimethyl-2H-1,4-benzoxazin-3-one-7-yl) -5-methanesulfonyloxymethyl oxazolidin-2-one

The title compound is prepared analogously to the procedure of Example 2 from 17.9 g (61 mmol) of the alcohol from Example 21, 6.16 g (61 mmol) of triethylamine and 8.37 g (73.2 mmol) of methanesulfonic acid chloride
fbl. Crystals
Mp: 124.5 ° C
R _f (toluene / ethanol = 10/3) = 0.5
Yield: 19.8 g (88% of theory)

Example 23 (5R) -3- (2,4-Dimethyl-2H-1,4-benzoxazin-3-one-7-yl) -5-azidomethyl-oxazolidin-2-one

The title compound is prepared in analogy to the procedure of Example 3 from 19 g (51.3 mmol) of the mesylate from Example 22 in 80 ml abs. DMF and 5.02 g (77 mmol) sodium azide.
fbl. Crystals
Mp: 108 ° C
R _f (toluene / ethanol = 10/3) = 0.4
Yield: 16.3 g (quantitative)

Example 24 (5S) -3- (2,4-Dimethyl-2H-1,4-benzoxazin-3-one-7-yl) -5-aminomethyl-oxazolidin-2-one

The title compound is prepared analogously to the procedure of Example 4 from 15.3 g (48.2 mmol) of the azide from Example 23, 3 g of Pd-C, 10%, in 200 ml of THF at 60 ° C. with 3 bar of hydrogen .
fbl. Crystals
Mp: 131 ° C
R _f (toluene / ethanol = 10/3) = 0.05
Yield: 14 g (quantitative)

Example 25 (5S) -3- (2,4-Dimethyl-2H-1,4-benzoxazin-3-one-7-yl) -5-methoxycarbonyl aminomethyl-oxazolidin-2-one

The title compound is prepared in analogy to the procedure in Example 6 from 1 g (3.4 mmol) of the amine from Example 24, 0.34 g (3.4 mmol) of triethylamine and 0.39 g (4.1 mol) of methyl chloroformate.
fbl. Crystals, rekrist. from 2-propanol
Mp: 168 ° C
R _f (toluene / ethanol = 10/3) = 0.43
Yield: 0.956 g (81% of theory)

Example 26 (5S) -3- (2,4-Dimethyl-2H-1,4-benzoxazin-3-one-7-yl) -5-bromoacetylaminomethyl- oxazolidin-2-one

The title compound is prepared analogously to the procedure of Example 7 from 1 g (3.4 mmol) of the amine from Example 24, 0.34 g (3.4 mmol) of triethylamine and 0.65 g (4.1 mmol) of bromoacetyl chloride.
fbl. Crystals recrystallized from 2-propanol
Mp: 158 ° C
R _f (toluene / ethanol = 10/3) = 0.41
Yield: 0.983 g (73% of theory)

Example 27 (5S) -3- (2,4-Dimethyl-2H-1,4-benzoxazin-3-one-7-yl) -5-propionylaminomethyl-oxazo lidin-2-one

The title compound is prepared analogously to the procedure of Example 8 from 1 g (3.4 mmol) of the amine from Example 24, 0.34 g (3.4 mmol) of triethylamine and 0.63 g (6.8 mmol) of propionic acid chloride.
fbl. Crystals
Mp: 172 ° C
R _f (toluene / ethanol = 10/3) = 0.5
Yield: 360 mg (29.6% of theory)

Example 28 (5S) -3- (2,4-Dimethyl-2H-1,4-benzoxazin-3-one-7-yl) -5-acetylaminomethyl-oxazolidine 2-one

The title compound is prepared analogously to the procedure in Example 5 from 1 g (3.4 mmol) of the amine from Example 24, 0.34 g (3.4 mmol) of triethylamine and 0.53 g (6.8 mmol) of acetyl chloride.
fbl. Crystals,
Mp: 183 ° C
R _f (toluene / ethanol = 10/3) = 0.39
Yield: 370 mg (38.5% of theory)

Example 29 (5S) -3- (2,4-Dimethyl-2H-1,4-benzoxazin-3-one-7-yl) -5- (turan-2-yl-carbonylamino methyl) oxazolidin-2-one

The title compound is prepared in analogy to the procedure of Example 16 from 1 g (3.4 mmol) of the amine from Example 24, 0.34 g (3.4 mmol) of triethylamine and 0.96 g (6.8 mmol) of furan-2 -carboxylic acid chloride produced.
fbl. Crystals
Mp: 84 ° C
R _f (toluene / ethanol = 10/3) = 0.45
Yield: 270 mg (20.5% of theory)

Example 30 (5S) -3- (2,4-Dimethyl-2H-1,4-benzoxazin-3-one-7-yl) -5- (trifluoroacetylaminomethyl) - oxazolidin-2-one

The title compound is prepared analogously to Example 17 from 1 g (3.4 mmol) of the amine from Example 24, 0.34 g (3.4 mmol) of triethylamine and 1.44 g of 6.8 mmol of trifluoroacetic acid anhydride.
fbl. Crystals,
Mp: 197 ° C
R _f (toluene / ethanol = 10/3) = 0.58
Yield: 380 mg (31.9% of theory)

Example 31 (5S) -3- (2,4-Dimethyl-2H-1,4-benzoxazin-3-one-7-yl) -5 - [(1R, 2S) -2-fluorocyciopropyl carbonylaminomethyl] oxazolidin-2-one

The title compound is prepared in analogy to the procedure of Example 10 from 0.6 g (2.05 mmol) of the amine from Example 24, 0.21 g (2.1 mmol) of triethylamine and 0.5 g (4.08 mmol) ( 1R, 2S) -2-fluorocyclopropanecarboxylic acid chloride.
fbl. Crystals
Mp: 104.3 ° C
R _f (toluene / ethanol = 10/3) = 0.4
Yield: 430 mg (55.4% of theory)

Example 32 (5S) -3- (2,4-Dimethyl-2H-1,4-benzoxazin-3-one-7-yl) -5 - [(1S, 2S) -2-fluorocyclopropane carbonylaminomethyl] oxazolidin-2-one

The title compound is prepared analogously to the instructions in Examples 10 and 31 from 0.6 g (2.05 mmol) of the amine from Example 24, 0.21 g (2.1 mmol) of triethylamine and 0.5 g (4.08 mmol) (1S, 2S) -2-fluorocyclopropanecarboxylic acid chloride.
fbl. Crystals,
Mp: 144 ° C
R _f (toluene / ethanol) = 10/3) = 0.3
Yield: 210 mg (27.1% of theory)

Example 33 (5S) -3- (2,4-Dimethyl-2H-1,4-benzoxazin-3-one-7-yl) -5- (oxazol-5-yl-carbonylamino methyl) oxazolidin-2-one

The title compound is prepared in analogy to the procedure of Example 9 from 0.5 g (1.7 mmol) of the amine from Example 24, 0.17 g (1.7 mmol) of triethylamine and 0.35 g (2.6 mmol) of oxazole -5-carboxylic acid chloride produced.
fbl. Crystals
Mp: 143 ° C
R _f (toluene / ethanol = 10/3) = 0.48
Yield: 200 mg (30.3% of theory)

Example 34 (5R, S) -3- (4-methoxycarbonyl-2H-1,4-benzoxazin-3-one-7-yl) -5-tert-butyloxy carbonyl-aminomethyl-oxazolidin-2-one

4 g (18 mmol) of the compound from Example 13A and 3.12 g of 2-tert-butyloxycarbonylamino-methyl-oxirane [Tetrahedron Lett. (1996), 37 (44), 7934-7940] are treated with 100 ml abs. THF dissolved, mixed with 45 g of silica gel 60, stirred vigorously for half an hour, and then the solvent is evaporated off in vacuo. The silica gel coated in this way is left to stand at RT for two days and then stirred with dichloromethane / methanol 49804 00070 552 001000280000000200012000285914969300040 0002019802239 00004 49685 (1/1). The silica gel is filtered off and the solvent is evaporated off in vacuo. The crude product obtained in this way contains the desired aminoethanol derivative (1: 1 adduct).
Yield: 6.9 g
R _f (dichloromethane / methanol = 15/1) = 0.54.

It is taken up in 80 ml of THF, mixed with the equivalent amount of carbonyldiimidazole (CDI) and stirred overnight. 5 ml of water are added, the mixture is stirred for one hour and extracted with dichloromethane. After drying with magnesium sulfate, the solvent is evaporated to dryness in vacuo and the residue is purified by column chromatography (silica gel 60, mobile phase: dichloromethane / methanol = 50/1)
fbl. Crystals
Mp: 154 ° C
Yield: 1.4 g (19%, based on the amine from Example 13A)
R _f (dichloromethane / methanol = 9/1) = 0.62

Example 35 (5R, S) -3- (4-methoxycarbonyl-2H-1,4-benzoxazin-3-one-7-yl) -5-aminomethyl-oxazo lidin-2-one hydrochloride

1.3 g (3.085 mmol) of the compound from Example 34 are dissolved in dioxane and stirred at RT in 4 N hydrochloric acid until the Boc residue is split off (6 h, TLC control). The solvent is evaporated in vacuo and the residue is dried IV.
fbl. Crystals Mp .: 110-118 ° C (dec.)
Yield: 0.56 g (50.7% of theory)

Example 36 (5R, S) -3- (4-methoxycarbonyl-2H-1,4-benzoxazin-3-one-7-yl) -5-acetylaminomethyl- oxazolidin-2-one

0.56 g (1.565 mmol) of the compound from Example 35 are stirred together with 10 ml of acetic anhydride and 0.48 g (4.7 mmol) of triethylamine at RT. After 1 hour, another equivalent of triethylamine is added and stirring is continued overnight. The mixture is then extracted with dichloromethane, the organic phase is shaken out with water and then re-extracted with dichloromethane. After drying with magnesium sulfate, the mixture is evaporated to dryness.
fbl. Crystals
Mp .: 174 ° C
Yield: 150 mg (26.4% of theory)
R _f (dichloromethane / methanol = 9/1) = 0.44

Example 37 (5R) -3- (4-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl) -5-hydroxymethyl-oxazolidine 2-one

The title compound is prepared in analogy to the procedure of Example 1 from 26 g (87.2 mmol) of the compound from Example 22A, 36.4 ml of butyllithium solution, 2.5N in hexane, and 12.5 ml (12.73 g ≅ 88.3 mmol, d = 1.018) (R) - (-) - glycidyl butyrate prepared in 520 ml THF. The column chromatographic separation is carried out on silica gel 60 using the mobile phase: dichloromethane / methanol = 100/5.
fbl. Crystals
Mp: 150 ° C
R _f (dichloromethane / methanol) = 0.52
Yield: 20 g (86.9% of theory)

Example 38 (5R) -3- (4-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl) -5-methanesulfonyloxy-methyl- oxazoldin-2-one

In analogy to the procedure of Example 2, the title compound is prepared from 4 g (15.2 mmol) of the alcohol from Example 37, 2.8 g of 1.9 ml (24.3 mmol, 1.6 equivalents) of mesyl chloride and 3.6 ml (25.8 mmol) of triethylamine. Column chromatographic separation with dichloromethane / methanol = 100/3 as eluent
fbl. Crystals R _f (dichloromethane / methanol = 100/5) = 0.69
Yield: 3g (57.7% of theory)

Example 39 (5R) -3- (4-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl) -5-azidomethyl-oxazolidin-2- on

The title compound is prepared in analogy to the procedure of Example 3 from 0.65 g (1.9 mmol) of the mesylate from Example 38 and 0.12 g of sodium azide. Column chromatographic separation on silica gel 60 with dichloromethane / methanol = 100/5 as the eluent
yellowish oil
R _f (dichloromethane / methanol = 100/5) = 0.77
Yield: 260 mg (47.3% of theory)

Example 40 (5S) -3- (4-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl) -5-aminomethyl-oxazolidin-2- on

The title compound is analogous to the procedure in Example 4

• a) from 0.7 g (2.42 mmol) of the azide from Example 39 and 70 mg Pd-C, 10%, prepared. Purification by column chromatography with methylene chloride / methanol = 9/1.
  Yield 0.38 g (59.7% of theory)
  or
• b) 0.98 g (3.4 mmol) of the azide from Example 39 are dissolved in 25 ml of methanol under an argon atmosphere and mixed with 0.5 g of Pd-C catalyst (10%) in a little methanol. 1.1 g (17.45 mmol 5 equivalents) of ammonium formate are added and the mixture is stirred at reflux for 10 minutes. After cooling and filtering off the catalyst, the mixture is evaporated to dryness and the rest is separated by column chromatography (silica gel 60, mobile phase dichloromethane / methanol = 85/15 to 8/2)
  Yield: 0.41 g (46% of theory)
  R _f (dichloromethane / methanol = 100/7) = 0.27
  fbl. oil

Example 41 (5S) -3- (4-Methyl-3,4-dihydrn-2H-1,4-benzoxazin-7-yl) -5-acetylaminomethyl-oxazoli din-2-one

The title compound is prepared in analogy to the procedure of Example 5 from 50 mg (0.19 mmol) of the amine from Example 40, 0.016 ml (1.2 equivalents) of acetyl chloride and 0.035 ml (1.35 equivalents) of triethylamine.
fbl. foam
R _f (dichloromethane / methanol = 9/1) = 0.67
Yield: 55 mg (94.9% of theory)

Example 42 (5S) -3- (4-Methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl) -5-acetylaminomethyl-oxazo lidin-2-one hydrochloride

230 mg (0.754 mmol) of the compound from Example 41 are dissolved in 5 ml of 1 molar HCl and 20 ml of water, filtered and the filtrate is lyophilized overnight.
fbl. foam
Yield: quantitative (255 mg)

Example 43 (5S) -3- (4-Methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl) -5-propionylaminomethyl-oxa zolidin-2-one

The title compound is prepared analogously to the procedure of Example 8 from 220 mg (0.836 mmol) of the amine from Example 40, 1.1 mmol = 0.09 ml (1.2 equivalents) of propionyl chloride and 0.16 ml of triethylamine (1.09 mmol ) produced.
fbl. foam
R _f (dichloromethane / methanol = 9/1) = 0.76
Yield: 260 mg (97.4% of theory)

Example 44 (5S) -3- (4-Methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl) -5-propionylaminomethyl-oxa zolidin-2-one hydrochloride

The title compound is prepared analogously to the procedure in Example 42 from 260 mg (0.814 mmol) of the compound from Example 43, 4 ml of 1N hydrochloric acid and 20 ml of water.
fbl. foam
Yield: 240 mg (92.3% of theory)

Example 45 (5S) -3- (4-Methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl) -5-cyclopropylcarbonyl aminomethyl-oxazolidin-2-one

The title compound is prepared in analogy to the procedure of Example 5 from 80 mg (0.304 mmol) of the amine from Example 40, 0.04 ml (0.365 mmol) of cyclopropanecarboxylic acid chloride and 0.06 ml (0.41 mmol) of triethylamine.
fbl. oil
R _f (dichloromethane / methanol = 100/7) = 0.35
Yield: 67 mg (66.6% of theory)

Example 46 (5S) -3- (4-Methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl) -5-methoxycarbonylamino methyl oxazolidin-2-one

In analogy to the procedure of Example 6, the title compound is obtained from 80 mg (0.304 mmol) of the amine from Example 40, 0.03 ml (d = 1.223 ≅ 36.7 mg, 0.39 mmol) of cyclopropanecarboxylic acid chloride and 0.06 ml (0 , 41 mmol) of triethylamine.
fbl. foam
R _f (dichloromethane / methanol = 100/5) = 0.64
Yield: 84 mg (86% of theory)

Example 47 (5S) -3- (4-Methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl) -5-methylthiocarbamoyl aminomethyl-oxazolidin-2-one

50 mg (0.19 mmol) of the amine from Example 40 are dissolved in 2 ml of THF, 14 mg (0.19 mmol) of methyl isothiocyanate are added and the mixture is stirred at RT overnight. Column chromatographic separation with silica gel 60 and dichloromethane / methanol = 100/5 as eluent.
fbl. foam
R _f (dichloromethane / methanol = 100/5) = 0.6
Yield: 58 mg (86.7% of theory)

Example 48 (5S) -3- (4-Methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl) -5-morpholino-propylthio carbamoyl aminomethyl oxazolidin-2-one

Analogously to Example 47, the title compound is prepared from 30 mg (0.114 mmol) of the compound from Example 40 and 21 mg (0.114 mmol) of morpholinopropyl isothiocyanate in 2 ml of THF. Column chromatographic separation with silica gel 60 and dichloromethane / methanol = 9/1 as eluent.
fbl. foam
R _f (dichloromethane / methanol = 9/1) = 0.54
Yield. 41 mg (80% of theory)

Example 49 (5S) -3- (4-Methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl) -5 - (3-pyridylthiocarbamoyl aminomethyl) oxazolidin-2-one

Analogously to Example 47, the title compound is prepared from 30 mg (0.114 mmol) of the amine from Example 40 and 160 mg (0.114 mmol) of 3-pyridyl isothiocyanate in 2 ml of THF. Column chromatographic separation with silica gel 60 and dichloromethane / methanol = 100/7 as eluent.
fbl. foam
R _f (dichloromethane / methanol = 100/7) = 0.49
Yield: 31 mg (67.1% of theory)

Example 50 (5S) -3- (4-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl) -5-carbamoyl aminomethyl- oxazolidin-2-one

0.2 g (0.76 mmol) of the amine from Example 40, 64 mg (0.76 mmol) of potassium cyanate and 0.76 ml (0.76 mmol) of 1 molar HCl solution in 333 ml of water are heated to boiling for 3 hours . After cooling, the mixture is stirred with 10 ml of vinegar, the organic phase is separated off, evaporated to dryness in vacuo and the residue is separated by column chromatography (silica gel 60, mobile phase: dichloromethane / methanol = 9/1)
fbl. foam
R _f (dichloromethane / methanol = 9/1) = 0.55
Yield: 120 mg (51.6% of theory)

Example 51 (5R, S) -3- (4-methoxycarbonyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl) -5-acetylamino methyl oxazolidin-2-one

250 mg (1.2 mmol) of the compound from Example 48A are dissolved in 1 ml of dichloromethane, with 194 mg (1.68 mmol) of 2-acetylaminomethyl-oxirane (lit .: analogously to J. Kitchin et al., J. Med. Chem. 37, 1994, 3707-16) and mixed with 3 g of silica gel and stirred at RT overnight. Since, according to the DC, the conversion is only slight, another 70 mg (≈ 1/2 equivalent) of oxirane are added and the mixture is left to react at RT for 2 days. The silica gel is then eluted with 5 ml of dichloromethane and 3 ml of methanol, the silica gel is filtered off and the organic phase is evaporated to dryness. The column-chromatographic separation on silica gel 60 with dichloromethane / methanol = 100/5 as eluent (R _f = 0.4) gives 70 mg (18% of theory) of the desired amino alcohol. This is taken up in 2 ml of THF, 120 mg (1.4 equivalents) of carbonyl diimidazole are added and the mixture is stirred at 50 ° C. overnight. The mixture is evaporated to dryness in vacuo and column chromatographed (mobile solvent: dichloromethane / methanol = 100/5, R _f = 0.5).
fbl. foam
Yield: 74 mg (17.6% of theory)

Example 52 (5R) -3- (6,7-Dihydro-5H-pyrido- [1,2,3-de] -2H-1,4-benzoxazin-3-one-9-yl) -5-hydroxy methyl oxazolidin-2-one

The title compound is prepared in analogy to the procedure of Example 1 from 0.5 g (1.48 mmol) of the compound from Example 18A, 0.78 g (1.35 mmol) of n-butyllithium solution in n-pentane (1.7N ) and 0.19 ml (1.35 mmol) (R) - (-) - glycidyl butyrate in THF.
fbl. Crystals
Mp 183-5 ° C
R _f (dichloromethane / methanol = 100/5) = 0.33
Yield: 165 mg (36.7% of theory)

Example 53 (5R) -3- (6,7-Dihydro-5H-pyrido- [1,2,3-de] -2H-1,4-benzoxazin-3-one-9-yl) -5-methane sulfonyloxy-methyl-oxazolidin-2-one

In analogy to the procedure of Example 2, the title compound is prepared from 1 g (3.3 mmol) of the alcohol from Example 52, 0.6 g (5.28 mmol) (1.6 equivalents, 0.41 ml) of mesyl chloride and 0.57 g (5.61 mmol, 1.7 equivalents 0.8 ml) of triethylamine. Column chromatographic separation with silica gel 60 and dichloromethane / methanol = 100/5 as eluent.
fbl. Crystals
Yield 0.94 g (74.6% of theory)

Example 54 (5R) -3- (6,7-Dihydro-5H-pyrido- [1,2,3-de] -2H-1,4-benzoxazin-3-one-9-yl) -5-azido methyl oxazolidin-2-one

The title compound is prepared analogously to the procedure of Example 3 from 0.9 g (2.36 mmol) of the mesylate from Example 53 and 0.15 g (2.34 mmol) of sodium azide in 6 ml of DMF.
fbl. Crystals, mp: 135 ° C
R _f (dichloromethane / methanol = 100/5) = 0.86
Yield: 0.65 g (83% of theory)

Example 55 (5S) -3- (6,7-Dihydro-5H-pyrido- [1,2,3-de] -2H-1,4-benzoxazin-3-one-9-yl) -5-amino methyl oxazolidin-2-one

0.5 g (1.52 mmol) of the azide from Example 54 are placed under an argon atmosphere in 2.5 ml of dimethoxyethane and, while stirring at 50 ° C., dropwise with 0.22 ml (1.82 mmol ethyl 1.2 equivalents) of trimethyl phosphite (P (OCH ₃ ) ₃ ) in 2.5 ml of dimethoxy ethane. Then heated to boiling for 3 hours. 0.3 ml of 6N hydrochloric acid are added and the mixture is heated to boiling for a further 3 hours. After cooling, 3 ml of saturated sodium bicarbonate solution are added and the mixture is extracted with dichloromethane. The organic phase is evaporated to dryness in vacuo and the residue is column chromatographed (silica gel 60, eluent: dichloromethane / methanol = 9/1).
fbl. foam
Yield: 0.28 g (60.8% of theory)

Example 56 (5S) -3- (6,7-Dihydro-5H-pyrido- [1,2,3-de] -2H-1,4-benzoxazin-3-one-9-yl) -5-acetyl aminomethyl-oxazolidin-2-one

The title compound is prepared in analogy to the procedure of Example 5 from 250 mg (0.822 mmol) of the amine from Example 55, 0.08 ml (1.15 mmol 1.4 equivalents, d = 1.104) acetyl chloride and 0.17 ml (1.1 23 mmol 1.5 equivalents) of triethylamine. Chromatographic separation with silica gel 60 and eluent di chloromethane / methanol = 100/4.
fbl. foam
Yield: 170 mg (59.9% of theory)

Example 57 (5S) -3- (6,7-Dihydro-5H-pyrido- [1,2,3-de] -2H-1,4-benzoxazin-3-one-9-yl) -5-propio nyl-aminomethyl-oxazolidin-2-one

The title compound is prepared in analogy to the procedure of Example 8 from 300 mg (0.99 mmol) of the amine from Example 55, 0.1 ml (1.19 mmol d = 1.065) propionyl chloride and 0.19 ml (1.36 mmol ) Triethylamine made. Chromatography: silica gel 60, dichloromethane / methanol = 100/7
fbl. foam
Yield: 210 mg (59.1% of theory)

Example 58 (5S) -3- (6,7-Dihydro-5H-pyrido- [1,2,3-de] -2H-1,4-benzoxazin-3-one-9-yl) -5-cyclo propane-carbonylaminomethyl-oxazolidin-2-one

The title compound is prepared analogously to the procedure of Example 10 from 250 mg (0.825 mmol) of the amine from Example 55, 0.09 ml (0.1 g, 0.99 mmol, 1.2 equivalents d = 1.152) cyclopropanecarboxylic acid chloride and 0, 15 ml (1.1 mmol, 1.35 equivalents) of triethylamine.
fbl. foam
Yield: 198 mg (64.7% of theory)

Example 59 (5S) -3- (6,7-Dihydro-5H-pyrido- [1,2,3-de] -2H-1,4-benzoxazin-3-one-9-yl) -5-methoxy carbonylaminomethyl-oxazolidin-2-one

In analogy to the procedure of Example 6, the title compound is prepared from 300 mg (0.99 mmol) of the amine from Example 55, 0.11 g (1.19 mmol, 1.2 equivalents, 0.9 ml) of methyl chloroformate and 0.18 ml (1.29 mmol) of triethylamine.
fbl. foam
Yield: 90 mg (25.2% of theory)

Example 60 (5R) -3- (6,7-dihydro-5H-pyrido- [1,2,3-de] -3,4-dihydro-2H-1,4-benzoxazin-9-yl) -5- hydroxymethyl-oxazolidin-2-one

The title compound is prepared in analogy to the procedure of Example 1 from 0.54 g (1.7 mmol) of the compound from Example 27A, 0.66 ml (1.7 mmol) of n-butyllithium solution in n-hexane, 2.5 n, and 0.24 ml (1.7 mmol, d = 1.018) (R) - (-) - glycidyl butyrate. Chromatographic separation: silica gel 60, eluent: dichloromethane / methanol = 100/3
fbl. oil
Yield: 356 mg (72.3% of theory)

Example 61 (5R) -3- (6,7-dihydro-5H-pyrido- [1,2,3-de] -3,4-dihydro-2H-1,4-benzoxazin-9-yl) -5- methanesulfonyloxymethyl-oxazolidin-2-one

The title compound is prepared in analogy to the procedure of Example 2 from 0.22 g (0.76 mmol) of the alcohol from Example 60, 0.14 g (1.21 mmol, 1.6 equivalents, 0.09 ml) of mesyl chloride and 0 , 18 ml (1.29 mmol, 1.7 equivalents) of triethylamine.
fbl. oil
Yield: 0.35 g, raw (<100% of theory)
After chromatographic separation on silica gel 60 and dichloromethane / methanol = 100/5 as eluent, 77.5% of theory is obtained

Example 62 (5R) -3- (6,7-dihydro-5H-pyrido- [1,2,3-de] -3,4-dihydro-2H-1,4-benzoxazin-9-yl) -5- azidomethyl-oxazolidin-2-one

The title compound is prepared analogously to the procedure of Example 3 from 3.12 g (8.48 mmol) of the mesylate from Example 61 and 0.55 g (8.48 mmol) of sodium azide in 30 ml of DMF. Chromatographic separation: silica gel 60, eluent: di chloromethane / ethyl acetate = 9/1
col., viscous oil
Yield: 2.15 g (80.5% of theory)

Example 63 (5S) -3- (6,7-dihydro-5H-pyrido- [1,2,3-de] -3,4-dihydro-2H-1,4-benzoxazin-9-yl) -5- aminomethyl-oxazolidin-2-one

The title compound is prepared analogously to the procedure of Example 55 from 0.3 g (0.95 mmol) of the azide from Example 62 and 0.13 ml (1.14 mmol) of triethyl phosphite (1.2 equivalents) in 3 ml of dimethoxyethane. Chromatographic separation:
Kieselgel 60, mobile phase: dichloromethane / methanol = 9/1) = 0.26
Yield: 80 mg (29.1% of theory)
The following by-product was isolated:

Example 64 (5S) -3- (6,7-dihydro-5H-pyrido- [1,2,3-de] -3,4-dihydro-2H-1,4-benzoxazin-9-yl) -5- dimethoxyphosphonylaminomethyl-oxazolidin-2-one

R _f (dichloromethane / methanol = 9/1) = 0.62
Yield: 50 mg (13.3% of theory)

Example 65 (5S) -3- (6,7-dihydro-5H-pyrido- [1,2,3-de] -3,4-dihydro-2H-1,4-benzoxazin-9-yl) -5- acetylamino-methyl-oxazolidin-2-one

The title compound is prepared analogously to the procedure of Example 5 from 80 mg (0.28 mmol) of the amine from Example 63, 0.03 ml (1.4 equivalents) of acetyl chloride and 0.06 ml (1.5 equivalents) of triethylamine. Chromatographic separation: silica gel 60, eluent: dichloromethane / methanol = 9/1) = 0.53
Yield: 70 mg (76.3% of theory)

Example 66 (5S) -3- (6,7-dihydro-5H-pyrido- [1,2,3-de] -3,4-dihydro-2H-1,4-benzoxazin-9-yl) -5- propionyl-aminomethyl-oxazolidin-2-one

The title compound is prepared in analogy to the procedure of Example 8 from 0.1 g (0.346 mmol) of the amine from Example 63, 0.04 ml (0.416 mmol, 1.2 equivalents) of propionyl chloride and 0.065 1 (0.467 mol) of triethylamine. Chromatographic separation, silica gel 60, mobile phase: dichloromethane / methanol = 9/1
fbl. foam
R _f (dichloromethane / methanol = 9/1) = 0.7
Yield 85 mg (71.2% of theory)

Example 67 (5S) -3- (6,7-dihydro-5H-pyrido- [1,2,3-de] -3,4-dihydro-2H-1,4-benzoxazin-9-yl) -5- cylopropane-carbonylaminomethyl-oxazolidin-2-one

In analogy to the procedure of Example 10, the title compound is prepared from 150 mg (0.52 mmol) of the amine from Example 63, 0.056 ml (0.623 mmol, 1.2 equivalents d = 1.152) cyclopropanecarboxylic acid chloride and 0.1 ml (0.702 mmol, 1 , 35 equivalents) of triethylamine. Chromatographic separation: silica gel 60, eluent:
Dichloromethane / methanol = 9/1
fbl. foam
R _f (dichloromethane / methanol = 9/1) = 0.64
Yield: 80 mg (43.1% of theory)

Example 68 (5S) -3- (6.7-dihydro-5H-pyrido- [1,2,3-de] -3,4-dihydro-2H-1,4-benzoxazin-9-yl) -5- methoxycarbonylaminomethyl-oxazolidin-2-one

The title compound is prepared in analogy to the procedure of Example 6 from 190 mg (0.66 mmol) of the amine from Example 63, 0.075 g (0.79 mmol, 1.2 equivalents) of methyl chloroformate and 0.12 ml (0.89 mol) Triethylamine made.
fbl. foam
R _f (dichloromethane / methanol = 9/1) = 0.66
Yield: 100 mg (43.7% of theory)

Example 69 (5R) -3- (1-methyl-1,2,3,4-tetrahydroquinolin-2-one-6-yl-5-hydroxymethyl-oxazolidine 2-one

The title compound is prepared in analogy to the procedure of Example 1 from 6 g (19.2 mmol) of the compound from Example 21A, 7.2 ml (19.2 mmol) of butyllithium solution (2.5 molar) and 3 ml (21 mmol) (R) - (-) - glycidyl butyrate produced.
fbl. Crystals
Yield: 4.5 g (84.8% of theory)

Example 70 (5R) -3- (1-methyl-1,2,3,4-tetrahydroquinolin-2-one-6-yl) 5-methanesulfonyloxymethyl- oxazolidin-2-one

The title compound is prepared in analogy to the procedure of Example 2 from 4.2 g (15.2 mmol) of the alcohol from Example 69, 3.5 ml (25.7 mmol) of triethylamine and 1.75 ml (25.3 mmol) of mesyl chloride made in 50 ml of pyridine.
fbl. product
Yield, raw: 6 g (<100% of theory)

Example 71 (5R) -3- (1-methyl-1,2,3,4-tetrahydroquinolin-2-one-6-yl) -5-azidomethyl-oxazolidin-2- on

The title compound is analogous to the procedure of Example 3 from 0.5 g (1.47 mmol) of the mesylate from Example 70 and 110 mg (169 mmol) of sodium azide in 10 ml DMF produced at 80 ° C.

Example 72 (5S) -3- (1-Methyl-1,2,3,4-terahydroquinone-2-one-6-yl) -5-aminomethyloxazolidin-2-one

The title compound is prepared in analogy to the procedure of Example 4 from 1 g (3.3 mmol) of the azide from Example 71 and 100 mg Pd-C, 5%, at 3 bar hydrogen and RT.
fbl. product
Yield: 0.9 g (quantitative)

Example 73 (5S) -3- (1-Methyl-1,2,3,4-tetrahydroquinolin-2-one-6-yl) -5-acetylaminomethyl-oxazo lidin-2-one

The title compound is prepared analogously to the procedure in Example 5 from 400 mg (1.45 mmol) of the amine from Example 71, 10 ml of pyridine and 0.153 ml (2.17 mmol) of acetyl chloride. Column chromatographic separation: silica gel 60, eluent: dichloromethane / methanol = 100/1
fbl. Crystals,
Mp: 233 ° C (dec.)
Yield: 140 mg (30.4% of theory)

Example 74 (5S) -3- (1-Methyl-1,2,3,4-tetrahydroquinolin-2-one-6-yl) -5-propionylaminomethyl oxazolidin-2-one

The title compound is prepared in analogy to the procedure of Example 8 from 0.39 mg (1.09 mmol) of the amine from Example 72, 10 ml of pyridine and 0.141 g (1.63 mmol) of propionyl chloride. Column chromatographic separation: silica gel 60, eluent: dichloromethane / methanol = 100/1
fbl. Crystals,
Mp: 187 ° C (dec.)
Yield: 208 mg (57.6% of theory)

Example 75 (5S) -3- (1-Methyl-1,2,3,4-tetrahydroquinolin-2-one-6-yl) -5-methoxycarbonylamino methyl oxazolidin-2-one

The title compound is prepared in analogy to the procedure of Example 6 from 300 mg (1.09 mmol) of the amine from Example 72, 10 ml of pyridine and 0.126 ml (1.63 mmol) of methyl chloroformate. Column chromatographic separation: silica gel 60: dichloromethane / methanol = 100/1
fbl. Crystals,
Mp: 181 ° C (dec.)
Yield: 150 mg (41.3% of theory)

Example 76 (5R) -3- (1-ethyl-1,2,3,4-tetrahydroquinolin-2-one-6-yl) -5-hydroxymethyl-oxazolidin-2- on

The title compound is prepared in analogy to the procedure of Example 69 from 1 g (3 mmol) of the compound from Example 23A, 1.1 ml (3 mmol) of butyllithium solution (2.5M) and 0.46 ml (3.3 mmol) (R. ) - (-) - Glycidyl butyrate produced. Column chromatographic separation: silica gel 60, eluent: dichloromethane / methanol = 100/1
fbl. product
Yield: 20.6 mg (23.7% of theory)

Example 77 (5R) -3- (1-ethyl-1,2,3,4-tetrahydroquinolin-2-one-6-yl) -5-methanesulfonyloxymethyl- oxazolidin-2-one

In analogy to the procedure of Example 70, the title compound is obtained from 12 g (41.4 mmol) of the alcohol from Example 76, 100 ml of pyridine, 9.36 ml (69.6 mmol, d = 0.73) of triethylamine and 4.68 ml (68.76 mmol, d = 1.474) mesyl chloride.
fbl. product
Yield: 9 g (59.0% of theory)

Example 78 (5R) -3- (1-Ethyl-1,2,3,4-tetrahydroquinolin-2-one-6-yl) -5-azidomethyl-oxazolidin-2-one

The title compound is prepared analogously to the procedure in Example 71 from 9 g (24.4 mmol) of the mesylate from Example 73 and 1.74 g (26.9 mmol) of sodium azide in 100 ml of DMF.
fbl. product
Yield: 6.4 g (83.2% of theory)

Example 79 (5S) -3- (1-Ethyl-1,2,3,4-tetrahydroquinolin-2-one-6-yl) -5-aminomethyl-oxazolidin-2-one

The title compound is prepared analogously to the procedure of Example 72 from 6 g (19 mmol) of the azide from Example 78 and 500 mg Pd-C, 5%, at 3 bar hydrogen and RT overnight.
fbl. product
Yield: 3g (54.5% of theory)

Example 80 (5S) -3- (1-Ethyl-1,2,3,4-tetrahydroquinolin-2-one-6-yl) -5-acetylaminomethyl-oxazoli din-2-one

The title compound is prepared in analogy to the procedure of Example 73 from 0.4 g (1.38 mmol) of the amine from Example 79, 10 ml of pyridine and 0.15 ml (2.7 mmol) of acetyl chloride. Column chromatographic separation: silica gel 60, eluent: dichloromethane / methanol = 10/1
fbl. Crystals
Mp: 185 ° C (dec.)
Yield: 110 mg (24.1% of theory)

Example 81 (5S) -3- (1-Ethyl-1,2,3,4-tetrahydroquinolin-2-one-6-yl) -5-propionylaminomethyl-oxa zolidin-2-one

The title compound is prepared analogously to the procedure of Example 74 from 0.4 g (1.38 mmol) of the amine from Example 79, 10 ml of pyridine and 0.18 ml (2.07 mmol of propionyl chloride. Separation by column chromatography: silica gel 60, mobile phase : Dichloromethane / methanol = 100/1
fbl. Crystals
Mp: 120 ° C
Yield: 260 mg (54.5% of theory)

Example 82 (5S) -3- (1-ethyl-1,2,3,4-tetrahydroquinolin-2-one-6-yl) -5-methoxycarbonyl aminomethyl-oxazolidin-2-one

The title compound is prepared analogously to the procedure of Example 76 from 0.4 g (1.38 mmol) of the amine from Example 79, 10 ml of pyridine and 0.15 ml (2.07 mmol) of methyl chloroformate. Column chromatographic separation: silica gel 60, eluent: dichloromethane / methanol = 100/1.
fbl. Crystals,
Mp: 188 ° C (dec.)
Yield: 200 mg (41.7% of theory)

Example 83

(5R) -3- (1-isopropyl-1,2,3,4-tetrahydroquinolin-2-one-6-yl) -5-hydroxymethyl oxazo lidin-2-one

The title compound is prepared in analogy to the procedure of Example 69 from 12 g (35.4 mmol) of the compound from Example 27A, 13.27 ml (35.4 mmol) of butyllithium (2.5 molar) and 5.5 ml (38 , 7 mmol) (R) - (-) - glycidyl butyrate.
fbl. product
Yield, raw: 12 g (<100%, 10.8 g)

Example 84 (5R) -3- (1-isopropyl-1,2,3,4-tetrahydroquinolin-2-one-6-yl) -5-methanesulfonyloxy methyl oxazolidin-2-one

The title compound is prepared in analogy to the procedure of Example 70 from 10.8 g (35.5 mmol) of the alcohol from Example 83, 100 ml of pyridine, 8.2 ml (60.3 mmol) of triethylamine and 4.08 ml (59 mmol) mesyl chloride at 0 ° C. Column chromatographic separation: silica gel 60, eluent: dichloromethane / methanol 100/1
fbl. Crystals,
Mp: 156 ° C
Yield: 1.1 g (8.1% of theory); 4 g of educt recovered

Example 85 (5R) -3- (1-isopropyl-1,2,3,4-tetrahydroquinolin-2-one-6-yl) -5-azidomethyl-oxazolidine 2-one

The title compound is prepared analogously to the procedure in Example 71 from 5 g (13.6 mmol) of the mesylate from Example 84 and 1.02 g (15.6 mmol) of sodium azide in 50 ml of DMF.
fbl. product
Yield, crude: 5 g

Example 86 (5S) -3- (1-isopropyl-1,2,3,4-tetrahydroquinolin-2-one-6-yl) -5-aminomethyl-oxazolidine 2-one

The title compound is prepared in analogy to the procedure of Example 72 from 5 g (15.2 mmol) of the azide from Example 85 and 500 mg Pd-C, 5%, in 50 ml of methanol / DMF (1/1).
fbl. product
Yield: 4.2 g (91.1% of theory)

Example 87 (5S) -3- (1-isopropyl-1,2,3,4-tetrahydroquinolin-2-one-6-yl) -5-acetylarninomethyl oxa zolidin-2-one

The title compound is prepared in analogy to the procedure of Example 73 from 0.6 g (2 mmol) of the amine from Example 86, 10 ml of pyridine and 0.21 ml (3 mmol) of acetyl chloride. Column chromatographic separation: silica gel 60, eluent: dichloromethane / methanol 100/1
fbl. product
Yield: 270 mg (39.1% of theory)

Example 88 (5S) -3- (1-isopropyl-1,2,3,4-tetrahydroquinolin-2-one-6-yl) -5-propionylaminomethyl- oxazolidin-2-one

The title compound is prepared in analogy to the procedure of Example 74 from 0.3 g (1 mmol) of the amine from Example 86, 10 ml of pyridine and 0.13 IM (1.5 mmol) of propionyl chloride. Column chromatographic separation: silica gel 60,
Mobile phase: dichloromethane / methanol = 100/1
fbl. product
Yield: 160 mg (44.5% of theory)

Example 89 (5S) -3- (1-isopropyl-1,2,3,4-tetrahydroquinolin-2-one-6-yl) -5-methoxycarbonyl aminomethyl-oxazolidin-2-one

The title compound is prepared analogously to the procedure in Example 75 from 0.3 g (1 mmol) of the amine from Example 86, 10 ml of pyridine and 0.11 ml (1.5 mmol) of methyl chloroformate. Column chromatographic separation: dichloromethane / methanol = 100/1
fbl. product
Yield: 140 mg (38.7% of theory)

Example 90 (5R) -3- (4-methyl-1,1-dioxo-3,4-dihydro-2H-1,4-benzothiazin-7-yl) -5-hydroxymethyl- oxazolidin-2-one

14.3 g (41.3 mmol) of 7-benzyloxycarbonylamino-4-methyl-1,1-dioxo-3,4-dihydro-2H- 1,4-benzothiazine in 85 ml of DMSO with 7 ml (50 mmol) of R - (-) - glycidyl butyrate and 1 ml of tert-butylimino-tris (dimethylamino) -phosphorane at 90 ° C. overnight stirs. Then 0.91 g of potassium carbonate and 13 ml of methanol are added.

The mixture is stirred at 40 ° C for 30 minutes. The mixture is poured into water and extracted with dichloromethane. The organic phase is dried over sodium sulfate and evaporated. The crude product obtained is chromatographed on silica gel (mobile phase: dichloromethane / methanol = 100 / 1.5).
Yield: 1.3 g (10% of theory)

Example 91 (5R) -3- (4-Methyl-2H-1,4-benzothiazin-3-one-7-yl) -5-hydroxymethyl-oxazolidin-2-one

27.6 g (0.084 mol) of 4-methyl-2H-1,4-benzothiazin-3-one are placed in 480 ml of THF pa at -78 ° C under argon. 33.6 ml (0.084 mol) of n-butyllithium (2.5N in hexane) and then 11.76 ml (0.084 mol) of (R) - (-) - glycidyl butyrate are added dropwise and the mixture is stirred overnight with heating to room temperature. The batch is mixed with saturated ammonium chloride solution, extracted with ethyl acetate, the organic phase is dried over sodium sulfate and evaporated. The crude product is triturated with methanol and dried.
Yield: 18 g (73% of theory)
R _f (dichloromethane / methanol = 100/5) = 0.29
Analogously to Example 91, the compounds in Table 1 are obtained:

Table 1

Example 94 (5R) -3- (4-Methyl-1,1-dioxo-2H-1,4-benzothiazin-3-one-7-yl) -5-methanesulfonyloxy methyl oxazolidin-2-one

2.4 g (7.7 mmol) of the compound from Example 91 are initially charged with 1.54 ml of triethylamine in 40 ml of dichloromethane at 0 ° C. The solution of 0.96 ml methane sulfonyl chloride in 3 ml dichloromethane is added dropwise and the mixture is stirred for 30 minutes. All volatile constituents are removed in vacuo, the residue is mixed with ice water and extracted with dichloromethane. It is dried over sodium sulfate and evaporated. The crude product is triturated with ether.
Yield: 1.6 g (53% of theory)
fbl. oil
R _f (dichloromethane / methanol = 9/1) = 0.59

Analogously to Example 94, the compounds contained in Table 2 are synthe tized:  

Table 2

Example 98 (5R) -3- (4-Methyl-1,1-dioxo-1,4-benzothiazin-7-yl) -5-azidomethyl-oxazolidin-2-one

1.6 g (4.1 mmol) of the compound from Example 94 are stirred for 6 hours at 70 ° C. with 346 mg (5.33 mmol) of sodium azide in 5 ml of DMF. The cooled mixture is poured onto ice water, extracted with dichloromethane, dried over sodium sulfate and evaporated.
Crude yield: 1.3 g

The compounds in Table 3 are obtained analogously to Example 98:

Table 3

Example 102 (5S) -3- (4-methyl-1,1-dioxo-2H-1,4-benzothiazin-7-yl) -5-aminomethyl-oxazolidin-2- on hydrochloride

2 g (4.1 mmol) of the compound from Example 98 are hydrogenated in 200 ml of ethyl acetate with 200 mg of Pd / C at 3 bar until the reaction is complete. The mixture is filtered through Celite and evaporated. The crude product is on silica gel (eluent:
Dichloromethane / methanol = 10/1) chromatographed.
Yield: 400 mg (32% of theory)
Fp: amorphous, fbl.
R _f (dichloromethane / methanol = 9: 1): 0.13

Example 103 (5S) -3- (4-Methyl-2H-1,4-benzothiazin-3-one-7-yl) -5 -aminomethyl-oxazolidin-2-one- hydrochloride

9 g (28.13 mmol) of the compound from Example 99 are placed in 40 ml of ethylene glycol dimethyl ether. 4.22 g (33.75 mmol) of trimethyl phosphite are added dropwise at 50 ° C. and the mixture is stirred at 100 ° C. for 1 hour. The cooled batch is mixed with 5 ml of 6N hydrochloric acid and refluxed for 3 hours. The solvent is distilled off in a stream of argon, the residue is taken up in methanol and the product is precipitated with ether.
Yield: 5.9 g (65% of theory)
Melting point: <250 ° C

Analogously to Example 103, the compounds in Table 4 are obtained:  

Table 4

Example 106 (5S) -3- (4-methyl-2H-1,4-benzothiazin-3-one-7-yl) -5-acetylaminomethyl-oxazolidin-2- on

822 mg (2.5 mmol) of the compound from Example 103 are initially charged with 0.76 ml (5.5 mmol) of triethylamine in 30 ml of dichloromethane. The solution of 216 mg of acetyl chloride in 1 ml of dichloromethane is added dropwise at 0 ° C. and the mixture is stirred for 30 minutes. The mixture is spun in and the residue is chromatographed on silica gel (mobile phase: dichloromethane / methanol = 100/5). The product obtained is triturated with ether.
Yield: 700 mg (83% of theory)
Melting point: 216 ° C
R _f (dichloromethane / methanol = 100/5) = 0.21

The compounds listed in Table 5 are analogous to the regulation of Example 106 produced.

Table 5

Example 161 (5S) -3- (2H-1,4-Benzothiazin-3-one-7-yl) -5-acetylaminomethyl-oxazolidin-2-one

4 g (13.6 mmol) (5S) -3- (benzothiazol-6-yl) -5-acetylaminomethyl-oxazolidin-2-one are in 9.6 ml ethanol and 4.8 ml hydrazine hydrate for 2 hours at 80 ° C touched. Then 1.366 g (14.56 mmol) of chloroacetic acid and 1.456 g of sodium hydroxide in 14.6 ml of water are added. The mixture is refluxed for about 30 minutes. The mixture is poured into water, acidified with concentrated hydrochloric acid and stirred at room temperature for 1 hour. The precipitated product is washed with water and dried.
Yield: 2 g (45% of theory)

Example 162 (5S) -3- (4-ethyl-2H-1,4-benzothiazin-3-one-7-yl) -5-acetylaminomethyl-oxazolidin-2- on

612 mg (2 mmol) of the compound from Example 161 are stirred with 456 mg (3 mmol) of DBU in 4 ml of DMF at 60 ° C. for 1 hour. Then 374 mg (2.4 mmol) of iodoethane are added and the mixture is stirred at 100 ° C. for 2 hours. The mixture is poured into water, extracted with dichloromethane, the organic phase is dried over sodium sulfate and evaporated. The crude product is chromatographed on silica gel (mobile phase: dichloromethane / methanol = 100/3).
Yield: 180 mg (25% of theory)
Melting point: 174 ° C
R _f (dichloromethane / methanol = 9/1) = 0.53

Example 163 (5S) -3- (4-isopropyl-2H-1,4-benzothiazin-3-one-7-yl) -5-acetylaminomethyl-oxazolidine 2-one

1 g (3.1 mmol) of the compound from Example 161 is refluxed with 1.95 g (11.5 mmol) of isopropyl iodide and 1.285 g (9.3 mmol) of potassium carbonate in 45 ml of 2-propanol overnight. The same amount of isopropyl iodide is then added again and the mixture is boiled again for 24 hours. The mixture is filtered, concentrated and the residue is chromatographed on silica gel (mobile phase: dichloromethane / methanol = 100/3). The crude product obtained is triturated with ether.
Yield: 200 mg (29% of theory)
Melting point: 150 ° C

Example 164 (5S) -3- (4-methyl-1,1-dioxo-2H-1,4-benzothiazin-3-one-7-yl) -5-acetylaminomethyl- oxazolidin-2-one

402 mg (1.2 mmol) of the compound from Example 106 are refluxed with 1.07 g (2.16 mmol) of magnesium monoperoxyphthalic acid salt (80%) in 80 ml of dichloromethane. The mixture is washed with sodium bisulfite solution and water, dried over sodium sulfate and evaporated. The crude product is chromatographed on silica gel (mobile phase: dichloromethane / methanol = 100/4). The crude product obtained is taken up in ethyl acetate and precipitated by adding petroleum ether.
Yield: 45 mg (10% of theory)
Melting point: 159 ° C
R _f (dichloromethane / methanol = 100/5) = 0.11

Example 165 (5S) -3- (4-Methyl-1-oxo-2H-1,4-benzothiazin-3-one-7-yl) -5-acetylaminomethyl-oxazo lidin-2-one

201 mg (0.6 mmol) of the compound from Example 106 are stirred with 445 mg (0.72 mmol) of magnesium monoperoxyphthalic acid salt in 40 ml of dichloromethane at room temperature for 30 minutes. The approach is worked up analogously to Example 164.
Yield: 28 mg (13% of theory)
Melting point: 166 ° C
R _f (dichloromethane / methanol = 100: 5) = 0.07

Example 166 (5S) -3- (2-benzylidene-4-methyl-2H-1,4-benzothiazin-3-one-7-yl-5-acetylamino-methyl- oxazolidin-2-one

335 mg (0.79 mmol) of the compound from Example 106 are placed in 2 ml of DMF with 176 mg (1.6 mmol) of benzaldehyde. 108 mg (1.9 mmol) of sodium methylate are then added and the mixture is heated to 100 ° C. for 90 minutes. The cooled batch is poured onto water and extracted with ethyl acetate. The organic phase is dried over sodium sulfate and evaporated. The residue is chromatographed on silica gel (mobile solvent: dichloromethane / methanol = 100/4). The intermediate product obtained is stirred with 92 mg (0.057 mmol) of carbonyldiimidazole in 5 ml of tetrahydrofuran at 60 ° C. overnight. The mixture is concentrated and the residue was chromatographed on silica gel (mobile solvent: dichloromethane / methanol = 100/3).
Yield: 110 mg (26% of theory)
Melting point: 226 ° C
R _f (dichloromethane / methanol = 100/5) = 0.47

Analogously to Example 166, the compounds listed in Table 6 are obtained ten:  

Table 6

Example 170 (5S) -3- (2-Benzyl-4-methyl-2H-1,4-benzothiazin-3-one-7-yl) -5-acetylaminomethyl-oxa zolidin-2-one

250 mg (0.55 mmol) of the compound from Example 166 are hydrogenated in 100 ml of THF with 50 mg of Pd / C (10%) at 50 ° C. and 3 bar overnight. The catalyst is filtered off and the solvent is spun in. The crude product is chromatographed on silica gel (mobile phase: dichloromethane / acetone = 2/1).
Yield: 205 mg (82% of theory)
Melting point: 120 ° C

Example 171 (5R) -3- (1,3-Dimethyl-3,4-dihdyro-2 (1H) -quinazolinon-6-yl) -5-hydroxymethyl-oxazo lidin-2-one

A stirred solution of 1.63 g (5.00 mmol) of the compound from Example 45A and 1 mg of 1,10-phenanthroline hydrate in 25 ml of anhydrous THF, cooled to -78 ° C., is slowly added to 3.13 ml ( 5.00 mmol) of a 1.6 molar solution of n-butyllithium in n-hexane. Then 0.83 g (5.00 mmol) of (R) - (-) - glycidyl butyrate is added dropwise and the temperature of the reaction mixture is allowed to rise to room temperature within 16 hours. Then 20 ml of a saturated aqueous NH ₄ Cl solution are added dropwise within 15 min. The water phase is extracted with 3 × 50 ml of ethyl acetate, the organic phases are combined, washed with 2 × 30 ml of NaCl solution and dried over MgSO ₄ . After evaporation of the solvent in vacuo and chromatography of the residue on 150 g of silica gel (dichloromethane / methanol = 95/5), 0.87 g (58% of theory) of the title compound is obtained as colorless crystals.
Mp: 167 ° C
R _f = 0.21 (dichloromethane / methanol = 95/5)

Example 172 (5R) -3- (1,3-Dimethyl-3,4-dihydro-2 (1H) -quinazolin-6-yl) -5-methanesulfonyloxy methyl oxazolidin-2-one

A stirred solution of 3.20 g (14.42 mmol) of the compound from Example 171 and 3.40 ml (34.51 mmol) of triethylamine in 80 ml of anhydrous dichloromethane, cooled to 0 ° C., is slowly mixed with 1.79 ml (23.07 mmol) methanesulfonic acid chloride added. The mixture is stirred for 10 min at 0-5 ° C and the mixture is stirred in 150 ml of ice water. The organic phase is separated off, washed with 20 ml of saturated NaHCO ₃ solution and 20 ml of ice water and dried over MgSO ₄ . The solvent is evaporated in vacuo and the residue is stirred with 15 ml of methanol, suction filtered and dried at 70 ° C. in a high vacuum. 4.60 g (85% of theory) of the title compound are obtained as colorless crystals.
Mp: 137 ° C
R _f = 0.26 (dichloromethane / methanol = 95/5)

Example 173 (5R) -3- (1,3-dimethyl-3,4-dihydro-2 (1H) -quinazolinon-6-yl) -5-azidomethyl- oxazolidin-2-one

A stirred solution of 4.80 g (13 mmol of the compound from Example 172 in 30 ml of anhydrous DMF is mixed with 0.91 g (14.04 mmol) of sodium azide and stirred for 1 h at 70 ° C. It is allowed to cool to room temperature and The resulting precipitate is separated off by filtration, washed three times with 20 ml of water and dried in air to give 3.70 g (89% of theory) of the title compound as light crystals.
Mp: from 146 ° C (decomp.)
R _f = 0.68 (dichloromethane / methanol = 9/1)

Example 174 (5S) -3- (1,3-Dimethyl-3,4-dihydro-2 (1H) -quinazolinon-6-yl) -5-aminomethyl-oxazo lidin-2-one

A solution of 3.16 g (10 mmol) of the compound from Example 173 in 20 ml of DMF is hydrogenated in the presence of 100 mg of palladium on carbon (5%) at a pressure of 3 bar of hydrogen for 2 hours at room temperature. The catalyst is filtered off over kieselguhr and the filtrate is evaporated in vacuo. After chromatography of the residue on 80 g of silica gel (dichloromethane / methanol = 9/1), 2.31 g (77% of theory) of the title compound are obtained as colorless crystals.
Mp .: 119 ° C (dec.)
R _f = 0.21 (dichloromethane / methanol = 9/1)

Example 175 (5S) -3- (1,3-Dimethyl-3,4-dihydro-2 (1H) -quinazolinon-6-yl) -5-acetylaminomethyl- oxazolidin-2-one

0.19 ml (2.63 mmol) of acetyl chloride is slowly added dropwise to a stirred, cooled to 0 ° C. solution of 0.51 g (1.75 mmol) of the compound from Example 174 in 6 ml of anhydrous pyridine and the mixture is stirred for 1 h at 0 ° C. The reaction mixture is then stirred into ice water. The mixture is evaporated to dryness in vacuo, the residue is purified by chromatography on 50 g of silica gel (dichloromethane / methanol = 9/1) and the product obtained is crystallized by trituration with a little ethyl acetate. 300 mg (49% of theory) of the title compound are obtained as colorless crystals.
Mp .: 201 ° C
R _f = 0.29 (dichloromethane / methanol = 9: 1)

Analogously to the specification of Example 175, those listed in Table 7 are obtained Products.

Table 7

Claims (5)

1. Substituted oxazolidinones of the general formula (I),
in which
A for residues of the formulas
or
stands,
wherein
D, D, and D ', are the same or different and are hydrogen carboxy, halogen, cyano, formyl, trifluoromethyl, nitro, straight-chain or branched alkoxy, alkoxycarbonyl, alkylthio or acyl each having up to 6 carbon atoms or straight-chain or branched alkyl having up to 6 carbon atoms mean
E and E are the same or different and denote the -CH ₂ group, an oxygen or sulfur atom or a radical of the formula -SO or -SO ₂ ,
L represents an oxygen or sulfur atom or a group of the formula = NR ¹³ ,
wherein
R ¹³ denotes hydrogen, phenyl, hydroxyl or straight-chain or branched alkoxy with up to 6 carbon atoms,
R ² , R ³ , R ⁴ , R ⁵ , R ⁷ , R ⁸ , R ⁹ and R ^{10 are the} same or different and are hydrogen or straight-chain or branched alkyl or alkenyl each having up to 6 carbon atoms, which are optionally substituted by aryl with 6 up to 10 carbon atoms or by a 5- to 6-membered aromatic heterocycle with up to 3 heteroatoms from the series S, N and / or O, which in turn are substituted one or more times by straight-chain or branched alkoxy or alkyl, each with up to 6 carbon atoms, hydroxy or halogen can be substituted,
or
R ² and R ³ , R ⁴ and R ⁵ , R ⁷ and R ⁸ and / or R ⁹ and R ¹⁰ together form groups of the formula = O, = CH ₂ or = CHR ¹⁴ , wherein
R ^{14 is} aryl with 6 to 10 carbon atoms or a 5- to 7-membered aromatic heterocycle with up to 3 heteroatoms from the series S, N and / or O, the ring systems optionally one to more times by halogen, hydroxy or by straight-chain or branched alkyl or alkoxy each having up to 6 carbon atoms,
R ⁶ , R ¹¹ and R ^{12 are the} same or different and are hydrogen straight-chain or branched alkyl or alkoxycarbonyl each having up to 6 carbon atoms, or are a radical of the formula -CO-R ¹⁵ ,
wherein
R ¹⁵ aryl having 6 to 10 carbon atoms, a 5- to 7-membered aromatic heterocycle having up to 3 heteroatoms from the series S, N and / or O or straight-chain or branched alkyl having up to 4 carbon atoms, which means, if appropriate is substituted by aryl having 6 to 10 carbon atoms, the ring systems listed under R ¹⁵ optionally being substituted one or more times, identically or differently, by halogen, trifluoromethyl, nitro, hydroxyl or by straight-chain or branched alkyl or alkoxy each having up to 6 carbon atoms are,
R ^{1 represents} azido or a radical of the formula -OR ¹⁶ , -O-SO ₂ -R ¹⁷ or -NR ¹⁸ R ¹⁹ ,
wherein
R ¹⁶ denotes hydrogen or straight-chain or branched acyl having up to 6 carbon atoms,
R ¹⁷ denotes straight-chain or branched alkyl having up to 6 carbon atoms or phenyl,
R ¹⁸ and R ^{19 are} hydrogen,
or
R ¹⁸ means hydrogen,
and
R ^{19 is} a radical of the formula
means
wherein
Q represents an oxygen or sulfur atom,
R ²⁰ denotes straight-chain or branched alkoxy having up to 8 carbon atoms or trifluoromethyl, or
R ²⁰ denotes cycloalkyl having 3 to 6 carbon atoms, which is optionally substituted by halogen or aryl having 6 to 10 carbon atoms, or
Aryl with 6 to 10 carbon atoms or a 5- to 6-membered saturated or aromatic heterocycle with up to 3 heteroatoms from the series S, N and / or O means, the ring systems listed under R ²⁰ optionally up to 2 times the same or are differently substituted by halogen, cyano, nitro, hydroxy or phenyl,
or
R ²⁰ denotes straight-chain or branched alkyl having up to 6 carbon atoms, optionally by phenoxy, benzyloxy, carboxyl, halogen or straight-chain or branched alkoxycarbonyl or acyl each having up to 6 carbon atoms or by a 5- to 6-membered heterocycle from Row S, N and / or O is substituted,
or
R ^{20 represents} a radical of the formula -NR ²³ R ²⁴ ,
wherein
R ²³ and R ^{24 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,
R ²¹ and R ^{22 are} identical or different and are hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,
and their stereoisomers and salts. 2. Compounds of general formula (I) according to claim 1, in which
A for residues of the formulas
or
stands,
wherein
D, D, and D '' are the same or different and are hydrogen, carboxy, fluorine, chlorine, bromine, iodine, cyano, formyl, trifluoromethyl or nitro,
E and E 'are identical or different and denote the -CH ₂ group, an oxygen or sulfur atom or a radical of the formula -SO or -SO ₂ ,
L represents an oxygen or sulfur atom or a group of the formula -NR ¹³ ,
wherein
R ^{13 means} hydrogen, hydroxyl or straight-chain or branched alkoxy with up to 4 carbon atoms,
R ² , R ³ , R ⁴ , R ⁵ , R ⁷ , R ⁸ , R ⁹ and R ^{10 are} identical or different and are hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by phenyl or naphthyl, which in turn can be substituted one to more times by straight-chain or branched alkoxy or alkyl each having up to 4 carbon atoms, hydroxyl, fluorine, chlorine or bromine,
or
R ² and R ³ , R ⁴ and R ⁵ , R ¹ and R ⁸ and / or R ⁹ and R ¹⁰ together form groups of the formula = O, = CH ₂ or = CHR ¹⁴ ,
wherein
R ¹⁴ denotes phenyl, naphthyl, pyridyl, thienyl or furyl, the ring systems optionally being substituted one to more times by fluorine, chlorine, bromine or by straight-chain or branched alkyl or alkoxy each having up to 4 carbon atoms,
R ⁶ , R ¹¹ and R ^{12 are the} same or different and are hydrogen straight-chain or branched alkyl or alkoxycarbonyl each with up to 4 carbon atoms, or
represent a radical of the formula -CO-R ¹⁵ ,
wherein
R ^{15 is} phenyl, naphthyl, pyridyl, thienyl, furyl, imidazolyl, pyridazolyl, pyrimidyl or straight-chain or branched alkyl having up to 3 carbon atoms, which is optionally substituted by phenyl or naphthyl, the ring systems listed under R ¹⁵ optionally being a are substituted up to several times the same or different by fluorine, chlorine, bromine, trifluoromethyl, nitro, hydroxy or by straight-chain or branched alkyl or alkoxy each having up to 4 carbon atoms,
R ^{1 represents} azido or a radical of the formula -OR ¹⁶ , -O-SO ₂ -R ¹⁷ or -NR ¹⁸ R ¹⁹ ,
wherein
R ¹⁶ denotes hydrogen or straight-chain or branched acyl having up to 4 carbon atoms,
R ¹⁷ denotes straight-chain or branched alkyl having up to 4 carbon atoms or phenyl,
R ¹⁸ and R ^{19 are} hydrogen,
or
R ¹⁸ means hydrogen,
and
R ^{19 is} a radical of the formula
means
wherein
Q represents an oxygen or sulfur atom,
R ²⁰ denotes straight-chain or branched alkoxy having up to 6 carbon atoms or trifluoromethyl, or
R ²⁰ denotes cyclopropyl, cyclopentyl, cycloheptyl, cyclobutyl or cyclohexyl, which are optionally substituted by fluorine, chlorine or phenyl, or
Phenyl, naphthyl, pyridyl, thienyl, oxazolyl, furyl, imidazolyl, pyridazolyl or pyrimidyl, the ring systems listed under R ²⁰ optionally being substituted up to 2 times identically or differently by fluorine, chlorine, bromine, cyano, nitro, hydroxy or phenyl are,
or
R ²⁰ denotes straight-chain or branched alkyl having up to 4 carbon atoms, optionally by phenoxy, benzyloxy, carboxyl, fluorine, chlorine, bromine or straight-chain or branched alkoxycarbonyl or acyl each having up to 4 carbon atoms or by pyridyl, thienyl, furyl or pyrimidyl is substituted,
or
R ^{20 represents} a radical of the formula -NR ²³ R ²⁴ ,
wherein
R ²³ and R ^{24 are} identical or different and are hydrogen, phenyl, pyridyl or straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by morpholine bonded via N,
R ²¹ and R ^{22 are} identical or different and are hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms,
and their stereoisomers and salts. 3. Compounds of general formula (I) according to claim 1, in which
A for residues of the formulas
or
stands,
wherein
D, D 'and D''are the same or different and are hydrogen,
E and E 'are identical or different and denote the -CH ₂ group, an oxygen or sulfur atom or a radical of the formula -SO or -SO ₂ ,
L represents an oxygen or sulfur atom or a group of the formula -NR ¹³ ,
wherein
R ¹³ denotes hydrogen, hydroxy or straight-chain or branched alkoxy with up to 4 carbon atoms,
R ² , R ³ , R ⁴ , R ⁵ , R ⁷ , R ⁸ , R ⁹ and R ^{10 are} identical or different and denote hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms, which is optionally substituted by phenyl or naphthyl, which in turn can be substituted one or more times by methoxy, fluorine or chlorine,
R ² and R ³ , R ⁴ and R ⁵ , R ⁷ and R ⁸ and / or R ⁹ and R ¹⁰ together form groups of the formula = O, = CH ₂ or = CHR ¹⁴ ,
wherein
R ¹⁴ denotes phenyl or pyridyl, the ring systems optionally being substituted one to more times by fluorine, chlorine or by methoxy,
R ⁶ , R ¹¹ and R ^{12 are the} same or different and are hydrogen straight-chain or branched alkyl or alkoxycarbonyl each having up to 3 carbon atoms, or
represent a radical of the formula -CO-R ¹⁵ ,
wherein
R ^{15 is} phenyl, naphthyl, pyridyl, thienyl, furyl, imidazolyl, pyridazolyl, pyrimidyl or straight-chain or branched alkyl having up to 3 carbon atoms, which is optionally substituted by phenyl or naphthyl, the ring systems listed under R ¹⁵ optionally one or more times the same or different are substituted by fluorine, chlorine, bromine, trifluoromethyl, nitro, hydroxy or by straight-chain or branched alkyl or alkoxy each having up to 3 carbon atoms,
R ^{1 represents} azido or a radical of the formula -OR ¹⁶ , -O-SO ₂ -R ¹⁷ or -NR ¹⁸ R ¹⁹ ,
wherein
R ¹⁶ denotes hydrogen or straight-chain or branched acyl having up to 3 carbon atoms,
R ¹⁷ denotes straight-chain or branched alkyl having up to 3 carbon atoms or phenyl,
R ¹⁸ and R ^{19 are} hydrogen,
or
R ¹⁸ means hydrogen,
and
R ^{19 is} a radical of the formula
means
wherein
Q represents an oxygen or sulfur atom,
R ²⁰ denotes straight-chain or branched alkoxy having up to 4 carbon atoms or trifluoromethyl, or
R ²⁰ denotes 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 means, the ring systems listed under R ²⁰ optionally up to 2 times the same or different by fluorine, chlorine, bromine, cyano, nitro, hydroxy or phenyl sub are established
or
R ²⁰ denotes straight-chain 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 ,
or
R ^{20 represents} a radical of the formula -NR ²³ R ²⁴ ,
wherein
R ²³ and R ^{24 are} identical or different and are hydrogen, phenyl, pyridyl or straight-chain or branched alkyl having up to 3 carbon atoms, which is optionally substituted by morpholine bonded via N,
R ²¹ and R ^{22 are} identical or different and are hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms,
and their stereoisomers and salts. 4. Use of compounds of general formula (I) according to claim 1 for the manufacture of pharmaceuticals. 5. Medicament containing compounds of the general formula (I) according to Claim 1.