DE102004004928A1 - Dibenzoxazepine II - Google Patents

Abstract

The present invention relates to Dibenzoxazepine and process for their preparation, their use for the treatment and / or prophylaxis of diseases and their use for the preparation of medicaments for the treatment and / or prophylaxis of diseases, especially cardiovascular diseases, eg. B. of atherosclerosis, and cancers.

Description

The The present invention relates to dibenzoxazepines and to processes for their preparation, their use for treatment and / or prophylaxis of diseases as well as their use for the production of medicines for the treatment and / or prophylaxis of diseases, in particular of cardiovascular diseases, e.g. of atherosclerosis, and cancers.

Dibenzoxazepines are described in WO 00/48603 as α _V β ₃ , α _V β ₅ and / or α _V β ₆ integrin receptor antagonists inter alia for the treatment of atherosclerosis. WO 99/11626 describes dibenzoxazepines as fibrinogen and / or vitronectin receptor antagonists, inter alia, for the treatment of atherosclerosis.

EP-A 419,861 describes the use of dibenzoxazepine for treatment and / or prophylaxis of AIDS.

US 4,728,735 claims dibenzothiazepines for the treatment of cardiovascular diseases.

dibenzoxazepinones against stomach ulcers are described in CAPLUS 1982, 423831 (JP-A-57002278) and CAPLUS 1984, 191915 (JP-A-58225073).

The inflammatory Component in the pathophysiology of atherosclerosis is today generally accepted. This inflammatory vascular changes are among other things by the immigration of monocytes and the increased distribution characterized by proinflammatory cytokines. Especially the Formation of foam cells from the immigrated monocytes and the changed one Metabolism of these foam cells takes on a central role in terms plaque development and stability. It could be shown, that macrophages greatly alter their gene expression under lipid loading. there is the raised one Expression of aminopeptidase N particularly prominent.

aminopeptidase N is a transmembrane Ectoenzyme (EC 3.4.11.12), which is identical to the CD13 antigen. aminopeptidase N catalyzes the N-terminal cleavage of amino acids, where neutral amino acid residues to be favoured. In synaptic membranes, inactivates aminopeptidase N as neuropeptide hormones as endorphins and enkephalins. Further Substrates include kinins and extracellular matrix components. Furthermore, the influence is on the regulation of chemotactic peptides (MCP-1, IL-8) is discussed. Many publications suggest that aminopeptidase N binds involved in the vascularization and spread of tumors. Membrane proteases can their biological effect not only via the cleavage of proteins, but also about Signal transduction unfold. For aminopeptidase N, a coupling to signal transduction in monocytes is discussed (Santos et al., Cellular Immunology 2000, 201, 22-32). The strenght Expression of aminopeptidase N under conditions similar to foam cell formation, as well as the involvement of aminopeptidase N in inflammatory processes of lymphocytes and monocytes suggest that inhibition of aminopeptidase N is too protective Effects on the vessel wall leads, as well Plaque development and plaque stability positively influenced.

worin
R¹ Halogen, Trifluormethyl, Trifluormethoxy, Cyano, Nitro, Hydroxy, C₁-C₆-Alkyl, Hydroxycarbonyl, C₁-C₆-Alkoxycarbonyl, Aminocarbonyl oder C₁-C₆-Alkylaminocarbonyl bedeutet,
n eine Zahl 0, 1 oder 2 bedeutet,
wobei bei n gleich 2 die Reste R¹ gleich oder verschieden sein können,
R² C₁-C₆-Alkyl bedeutet,
wobei Alkyl substituiert sein kann mit 1 oder 2 Substituenten, wobei die Substituenten unabhängig voneinander ausgewählt werden aus der Gruppe bestehend aus Halogen, Hydroxy, Oxo, C₁-C₆-Alkoxy, Hydroxycarbonyl, C₁-C₆-Alkoxycarbonyl, Aminocarbonyl und C₁-C₆-Alkylaminocarbonyl,
R³ -O-CH₂CO₂H oder -O-(CH₂)₂CO₂H bedeutet,
R⁴ Halogen, Trifluormethyl, Trifluormethoxy, Cyano, Nitro, Amino, C₁-C₆-Alkylamino, Hydroxy, C₁-C₆-Alkyl, C₁-C₆-Alkoxy, Hydroxycarbonyl, C₁-C₆-Alkoxycarbonyl, Aminocarbonyl oder C₁-C₆-Alkylaminocarbonyl bedeutet,
m eine Zahl 0, 1 oder 2 bedeutet,
wobei bei m gleich 2 die Reste R⁴ gleich oder verschieden sein können,
R⁵ 5- bis 10-gliedriges Heteroaryl, -SO₂-R⁶ oder -NR⁷(C=O)R⁸ bedeutet,
wobei Heteroaryl substituiert sein kann mit 1, 2 oder 3 Substituenten, wobei die Substituenten unabhängig voneinander ausgewählt werden aus der Gruppe bestehend aus Halogen, Trifluormethyl, Trifluormethoxy, Cyano, Nitro, Amino, C₁-C₆-Alkylamino, Hydroxy, C₁-C₆-Alkyl, C₁-C₆-Alkoxy, Hydroxycarbonyl, C₁-C₆-Alkoxycarbonyl, Aminocarbonyl, C₁-C₆-Alkylaminocarbonyl, C₆-C₁₀-Aryl und C₃-C₈-Cycloalkyl,
R⁶ C₁-C₆-Alkyl, C₁-C₆-Alkylamino, C₆-C₁₀-Aryl, 5- bis 10-gliedriges Heteroaryl, C₃-C₈-Cycloalkyl oder 4- bis 10-gliedriges Heterocyclyl bedeutet,
wobei Aryl, Heteroaryl, Cycloalkyl und Heterocyclyl substituiert sein können mit 1, 2 oder 3 Substituenten, wobei die Substituenten unabhängig voneinander ausgewählt werden aus der Gruppe bestehend aus Halogen, Trifluormethyl, Trifluormethoxy, Cyano, Nitro, Amino, C₁-C₆-Alkylamino, Hydroxy, C₁-C₆-Alkyl, C₁-C₆-Alkoxy, Hydroxycarbonyl, C₁-C₆-Alkoxycarbonyl, Aminocarbonyl und C₁-C₆-Alkylaminocarbonyl,
R⁷ Wasserstoff oder C₁-C₆-Alkyl bedeutet,
R⁸ C₁-C₆-Alkyl, C₆-C₁₀-Aryl, 5- bis 10-gliedriges Heteroaryl, C₃-C₈-Cycloalkyl oder 4- bis 10-gliedriges Heterocyclyl bedeutet,
wobei Aryl, Heteroaryl, Cycloalkyl und Heterocyclyl substituiert sein können mit 1, 2 oder 3 Substituenten, wobei die Substituenten unabhängig voneinander ausgewählt werden aus der Gruppe bestehend aus Halogen, Trifluormethyl, Trifluormethoxy, Cyano, Nitro, Amino, C₁-C₆-Alkylamino, Hydroxy, C₁-C₆-Alkyl, C₁-C₆-Alkoxy, Hydroxycarbonyl, C₁-C₆-Alkoxycarbonyl, Aminocarbonyl und C₁-C₆-Alkylaminocarbonyl,
und ihre Salze, ihre Solvate und die Solvate ihrer Salze.The invention relates to compounds of the formula

wherein
R ^{1 is} halogen, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, C ₁ -C ₆ -alkyl, hydroxycarbonyl, C ₁ -C ₆ -alkoxycarbonyl, aminocarbonyl or C ₁ -C ₆ -alkylaminocarbonyl,
n is a number 0, 1 or 2,
where, when n is 2, the radicals R ^{1 may be} identical or different,
R ^{2 is} C ₁ -C ₆ -alkyl,
wherein alkyl may be substituted with 1 or 2 substituents, wherein the substituents are independently selected from the group consisting of halogen, hydroxy, oxo, C ₁ -C ₆ alkoxy, hydroxycarbonyl, C ₁ -C ₆ alkoxycarbonyl, aminocarbonyl and C C ₁ -C ₆ -alkylaminocarbonyl,
R ^{3 represents} -O-CH ₂ CO ₂ H or -O- (CH ₂ ) ₂ CO ₂ H,
R ^{4 is} halogen, trifluoromethyl, trifluoromethoxy, cyano, nitro, amino, C ₁ -C ₆ -alkylamino, hydroxy, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, hydroxycarbonyl, C ₁ -C ₆ -alkoxycarbonyl, Aminocarbonyl or C ₁ -C ₆ -alkylaminocarbonyl,
m is a number 0, 1 or 2,
where m is 2, the radicals R ^{4 may be the} same or different,
R ^{5 is} 5- to 10-membered heteroaryl, -SO ₂ -R ⁶ or -NR ⁷ (C = O) R ⁸ ,
where heteroaryl can be substituted by 1, 2 or 3 substituents, where the substituents are selected independently of one another from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, cyano, nitro, amino, C ₁ -C ₆ -alkylamino, hydroxy, C ₁ - C ₆ alkyl, C ₁ -C ₆ alkoxy, hydroxycarbonyl, C ₁ -C ₆ alkoxycarbonyl, aminocarbonyl, C ₁ -C ₆ -alkylaminocarbonyl, C ₆ -C ₁₀ -aryl and C ₃ -C ₈ -cycloalkyl,
R ^{6 is} C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkylamino, C ₆ -C ₁₀ -aryl, 5- to 10-membered heteroaryl, C ₃ -C ₈ -cycloalkyl or 4- to 10-membered heterocyclyl .
wherein aryl, heteroaryl, cycloalkyl and heterocyclyl may be substituted with 1, 2 or 3 substituents, wherein the substituents are independently selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, cyano, nitro, amino, C ₁ -C ₆ alkylamino , Hydroxy, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, hydroxycarbonyl, C ₁ -C ₆ -alkoxycarbonyl, aminocarbonyl and C ₁ -C ₆ -alkylaminocarbonyl,
R ^{7 is} hydrogen or C ₁ -C ₆ -alkyl,
R ^{8 is} C ₁ -C ₆ -alkyl, C ₆ -C ₁₀ -aryl, 5- to 10-membered heteroaryl, C ₃ -C ₈ -cycloalkyl or 4- to 10-membered heterocyclyl,
wherein aryl, heteroaryl, cycloalkyl and heterocyclyl may be substituted with 1, 2 or 3 substituents, wherein the substituents are independently selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, cyano, nitro, amino, C ₁ -C ₆ alkylamino , Hydroxy, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, hydroxycarbonyl, C ₁ -C ₆ -alkoxycarbonyl, aminocarbonyl and C ₁ -C ₆ -alkylaminocarbonyl,
and their salts, their solvates, and the solvates of their salts.

Compounds of the invention are the compounds of formula (I) and their salts, solvates and solvates the salts, below as embodiment (e) mentioned compounds and their salts, solvates and solvates of Salts, as far as those of formula (I), hereinafter not already mentioned salts, solvates and solvates salts.

The Compounds of the invention can dependent on of their structure in stereoisomeric forms (enantiomers, diastereomers) exist. The invention therefore relates to the enantiomers or Diastereomers and their respective mixtures. From such mixtures enantiomers and / or diastereomers can be the stereoisomer isolate uniform components in a known manner.

Provided the compounds of the invention can occur in tautomeric forms, For example, the present invention encompasses all tautomeric forms.

When Salts are physiologically acceptable in the context of the present invention Salts of the compounds of the invention prefers. Also included are salts that are suitable for pharmaceutical applications themselves are not suitable but for example for insulation or cleaning the compounds of the invention can be used.

physiological Safe salts of the compounds of the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, e.g. Salts of hydrochloric acid, hydrobromic, Sulfuric acid, Phosphoric acid, methane, ethanesulfonic, toluene sulfonic acid, benzenesulfonic, naphthalenedisulfonic, Acetic acid, trifluoroacetic, propionic acid, Lactic acid, Tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and Benzoic acid.

physiological acceptable salts of the compounds of the invention also include Salts more usual Bases, such as by way of example and preferably alkali metal salts (e.g. Sodium and potassium salts), alkaline earth salts (e.g., calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines with 1 to 16 carbon atoms, such as by way of example and preferably ethylamine, Diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, Diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, Dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.

When In the context of the invention, solvates are those forms of the compounds according to the invention, which in solid or liquid Condition by coordination with solvent molecules a complex form. Hydrates are a special form of solvates in which the coordination with water takes place.

Unless otherwise specified, in the context of the present invention, the substituents have the following meaning:
Alkyl per se and "Alk" and "alkyl" in alkoxy, alkylamino, alkylaminocarbonyl and alkoxycarbonyl are a linear or branched alkyl radical having 1 to 6 carbon atoms, preferably 1 to 4, particularly preferably 1 to 3 carbon atoms, by way of example and preferably methyl, Ethyl, n-propyl, isopropyl, tert. Butyl, n-pentyl and n-hexyl.
Alkoxy is, by way of example and by way of preference, methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy.
Alkylamino represents an alkylamino radical having one or two (independently selected) alkyl substituents, by way of example and by way of preference methylamino, ethylamino, n-propylamino, isopropylamino, tert-butylamino, n-pentylamino, n-hexylamino, N, N-dimethylamino, N , N-diethylamino, N-ethyl-N-methylamino, N-methyl-Nn-propylamino, N-isopropyl-Nn-propylamino, Nt-butyl-N-methylamino, N-ethyl-Nn-pentylamino and Nn-hexyl-N methylamino. C ₁ -C ₃ -alkylamino is, for example, a monoalkylamino radical having 1 to 3 carbon atoms or a dialkylamino radical having in each case 1 to 3 carbon atoms per alkyl substituent.
Alkylaminocarbonyl represents an alkylaminocarbonyl radical having one or two (independently selected) alkyl substituents, by way of example and preferably methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl, tert-butylaminocarbonyl, n-pentylaminocarbonyl, n-hexylaminocarbonyl, N, N-dimethylaminocarbonyl, N , N-diethylaminocarbonyl, N-ethyl-N-methylaminocarbonyl, N-methyl-Nn-propylaminocarbonyl, N-isopropyl-Nn-propylaminocarbonyl, Nt-butyl-N-methylaminocarbonyl, N-ethyl-Nn-pentylaminocarbonyl and Nn-hexyl-N -methylaminocarbonyl. C ₁ -C ₃ -alkylaminocarbonyl is, for example, a monoalkylaminocarbonyl radical having 1 to 3 carbon atoms or a dialkylaminocarbonyl radical having in each case 1 to 3 carbon atoms per alkyl substituent.
Alkoxycarbonyl is exemplified and preferably methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, n-pentoxycarbonyl and n-hexoxycarbonyl.
Cycloalkyl is a cycloalkyl group having usually 3 to 8, preferably 5 to 7 carbon atoms, by way of example and preferably cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
Aryl is a mono- to tricyclic aromatic radical of usually 6 to 14 carbon atoms; exemplified and preferably for aryl are called phenyl, naphthyl and phenanthrenyl.
Heteroaryl is an aromatic, mono- or bicyclic radical having usually 5 to 10, preferably 5 to 6 ring atoms and up to 5, preferably up to 4 heteroatoms from the series S, O and N, by way of example and preferably for thienyl, furyl , Pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazolyl, imidazolyl, tetrazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, indolyl, indazolyl, benzofuranyl, benzothiophenyl, quinolinyl, isoquinolinyl.
Heterocyclyl is a mono- or polycyclic, preferably mono- or bicyclic, heterocyclic radical having usually 4 to 10, preferably 5 to 8 ring atoms and up to 3, preferably up to 2 heteroatoms and / or hetero groups from the series N, O. , S, SO, SO ₂ . The heterocyclyl radicals may be saturated or partially unsaturated. Preference is given to 5- to 8-membered, monocyclic saturated heterocyclyl radicals having up to two heteroatoms from the series O, N and S, such as, by way of example and by way of preference, tetrahydrofuran-2-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, pyrrolinyl, Piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, perhydroazepinyl.
Halogen is fluorine, chlorine, bromine and iodine, preferably fluorine and chlorine.

If Residues in the compounds of the invention may be substituted the radicals, unless otherwise specified, one or more times be substituted identically or differently. A substitution with up to three identical or different substituents are preferred. Very particular preference is given to the substitution with a substituent.

Preferred within the scope of the present invention are compounds of the formula (I) in which
R ^{1 is} halogen, trifluoromethyl, cyano, hydroxy, C ₁ -C ₄ -alkyl, hydroxycarbonyl, C ₁ -C ₄ -alkoxycarbonyl, aminocarbonyl or C ₁ -C ₆ -alkylaminocarbonyl,
n is a number 0 or 1,
R ^{2 is} C ₁ -C ₄ -alkyl,
wherein alkyl may be substituted with a substituent, wherein the substituent is selected from the group consisting of hydroxy, C ₁ -C ₆ alkoxy, hydroxycarbonyl and C ₁ -C ₆ alkoxycarbonyl,
R ^{3 represents} -O-CH ₂ CO ₂ H or -O- (CH ₂ ) ₂ CO ₂ H,
m is a number 0,
R ^{5 is} thienyl, furyl, pyrrolyl, thiazolyl, isoxazolyl, oxadiazolyl, pyrazolyl, imidazolyl, tetrazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, -SO ₂ -R ⁶ or -NR ⁷ (C =O) R ⁸ ,
wherein thienyl, furyl, pyrrolyl, thiazolyl, isoxazolyl, oxadiazolyl, pyrazolyl, imidazolyl, tetrazolyl, pyridyl, pyrimidyl, pyridazinyl and pyrazinyl may be substituted with 1, 2 or 3 substituents, wherein the substituents are independently selected from the group consisting of halogen , Trifluoromethyl, amino, C ₁ -C ₆ -alkylamino, hydroxy, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, hydroxycarbonyl, C ₁ -C ₆ -alkoxycarbonyl, aminocarbonyl, C ₁ -C ₆ -alkylaminocarbonyl , Phenyl and C ₃ -C ₆ -cycloalkyl,
R ^{6 is} C ₁ -C ₄ -alkyl, C ₁ -C ₆ -alkylamino, phenyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl,
where phenyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl can be substituted by 1, 2 or 3 substituents, where the substituents are selected independently of one another from the group consisting of halogen, trifluoromethyl, amino, C ₁ - C ₆ alkylamino, hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, hydroxycarbonyl, C ₁ -C ₆ alkoxycarbonyl, aminocarbonyl and C ₁ -C ₆ alkylaminocarbonyl,
R ^{7 is} hydrogen, methyl or ethyl,
R ^{8 is} C ₁ -C ₆ -alkyl,
and their salts, their solvates, and the solvates of their salts.

Preferred within the scope of the present invention are also compounds of the formula (I) in which
n is a number 0,
R ^{2 is} C ₁ -C ₄ -alkyl,
wherein alkyl may be substituted with a substituent, wherein the substituent is selected from the group consisting of hydroxy, tert-butoxy, tert-butoxycarbonyl and 2,2-dimethylprop-l-oxycarbonyl,
R ^{3 represents} -O-CH ₂ CO ₂ H,
wherein -O-CH ₂ CO ₂ H is attached ortho to the amide function of the dibenzoxazepin ring,
m is a number 0,
R ^{5 is} thienyl, furyl, isoxazolyl, oxadiazolyl, pyrazolyl, tetrazolyl, -SO ₂ -R ⁶ or -NR ⁷ (C = O) R ⁸ ,
where thienyl, furyl, isoxazolyl, oxadiazolyl, pyrazolyl and tetrazolyl can be substituted by 1 or 2 substituents, where the substituents are selected independently of one another from the group consisting of C ₁ -C ₄ -alkyl and C ₃ -C ₆ -cycloalkyl,
R ^{6 is} C ₁ -C ₄ -alkyl, C ₁ -C ₆ -alkylamino, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl,
wherein piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl may be substituted by 1 or 2 substituents, wherein the substituents are independently selected from the group consisting of C ₁ -C ₄ -alkyl and C ₃ -C ₆ -cycloalkyl,
R ^{7 is} hydrogen, methyl or ethyl,
R ^{8 is} C ₁ -C ₄ -alkyl,
and their salts, their solvates, and the solvates of their salts.

Preferred within the scope of the present invention are also compounds of the formula (I) in which
n is a number 0,
R ^{2 is} tert-butoxycarbonylmethyl,
R ^{3 represents} -O-CH ₂ CO ₂ H,
wherein R ^{3 is} attached in the ortho position to the amide function of the dibenzoxazepine ring,
m is a number 0,
R ^{5 is} thienyl, furyl, isoxazolyl, oxadiazolyl, pyrazolyl or tetrazolyl,
where thienyl, furyl, isoxazolyl, oxadiazolyl, pyrazolyl and tetrazolyl can be substituted by 1 or 2 substituents, where the substituents are selected independently of one another from the group consisting of methyl and cyclopropyl,
and their salts, their solvates, and the solvates of their salts.

Also preferred in the context of the present invention are compounds of the formula (I) in which n is a number 0, ie no substituent R ^{1 is} present.

Also preferred in the context of the present invention are compounds of the formula (I) in which R ^{2 is} C ₁ -C ₄ -alkyl, where alkyl may be substituted by one substituent, the substituent being selected from the group consisting of hydroxycarbonyl and C ₁ -C ₆ alkoxycarbonyl.

Also preferred in the context of the present invention are compounds of the formula (I) in which R ^{2 is} tert-butoxycarbonylmethyl.

Preferred within the scope of the present invention are also compounds of formula (I) wherein R ^{3 is} -O-CH ₂ CO ₂ H, wherein R ^{3 is} attached ortho to the amide function of the dibenzoxazepine ring is.

Also preferred in the context of the present invention are compounds of the formula (I) in which m is a number 0, ie no substituent R ^{4 is} present.

Preferred within the scope of the present invention are also compounds of formula (I) wherein R ^{5 is} 5- to 10-membered heteroaryl, wherein heteroaryl may be substituted with 1 or 2 substituents wherein the substituents are independently selected from the group consisting of Methyl and cyclopropyl.

Preferred within the scope of the present invention are also compounds of the formula (I) in which R ^{5 is} thienyl, furyl, isoxazolyl, oxadiazolyl, pyrazolyl or tetrazolyl, where thienyl, furyl, isoxazolyl, oxadiazolyl, pyrazolyl and tetrazolyl may be substituted by 1 or 2 Substituents, wherein the substituents are independently selected from the group consisting of methyl and cyclopropyl.

Preferred within the scope of the present invention are also compounds of the formula (I) in which R ^{5 is} -SO ₂ -R ⁶ , where R ^{6 is} C ₁ -C ₄ -alkyl, C ₁ -C ₆ -alkylamino, morpholinyl or thiomorpholinyl.

• [A] Verbindungen der Formel
  
  worin R¹, R³, R⁴, R⁵, m und n die oben angegebene Bedeutung aufweisen, mit Verbindungen der Formel R²-X¹ (III),worin R² die oben angegebene Bedeutung aufweist, und X¹ Halogen, bevorzugt Chlor oder Brom, bedeutet, umgesetzt werden oder
• [B] Verbindungen der Formel
  
  worin R¹, R², R⁴, R⁵, m und n die oben angegebene Bedeutung aufweisen, mit Verbindungen der Formel R^3a-X² (V),worin R^3a -CH₂CO₂H oder -(CH₂)₂CO₂H bedeutet, und X² Halogen, bevorzugt Chlor oder Brom, bedeutet, umgesetzt werden.

The invention further provides a process for the preparation of the compounds of the formula (I), wherein

• [A] Compounds of the formula
  
  wherein R ¹ , R ³ , R ⁴ , R ⁵ , m and n have the abovementioned meaning, with compounds of the formula R ² -X ¹ (III), wherein R ^{2 has} the meaning indicated above, and X ^{1 is} halogen, preferably chlorine or bromine, is reacted or
• [B] Compounds of the formula
  
  wherein R ¹ , R ² , R ⁴ , R ⁵ , m and n have the abovementioned meaning, with compounds of the formula R ^3a -X ² (V), wherein R ^{3a is} -CH ₂ CO ₂ H or - (CH ₂ ) ₂ CO ₂ H, and X ^{2 is} halogen, preferably chlorine or bromine, to be reacted.

The radical R ^3a is a part of the radical R ³ , ie R ³ can also be written as -OR ^3a .

The Implementation according to method [A] and method [B] is generally done in inert solvents in Presence of a base, optionally in the presence of potassium iodide, preferably in a temperature range from room temperature to 50 ° C at atmospheric pressure.

bases For example, alkali hydroxides such as sodium, lithium or Potassium hydroxide, or alkali metal carbonates such as cesium carbonate, sodium or Potassium carbonate, optionally in aqueous solution, is preferably potassium carbonate.

inert solvent are, for example, ethers, such as 1,2-dimethoxyethane, dioxane, tetrahydrofuran, Glycol dimethyl ether or diethylene glycol dimethyl ether, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, or dimethylformamide, or mixtures of solvents, preferred is dimethylformamide or dioxane.

The radicals R ¹ , R ² and R ^{3 of} the compounds of the formula (I) may optionally contain protective groups which are split off after the reaction by a deprotection reaction. This is done by standard methods of protecting group chemistry.

The Compounds of formulas (III) and (V) are known or are allowed be synthesized by known methods from the corresponding starting materials.

worin R¹, R³, R⁴, R⁵, m und n die oben angegebene Bedeutung aufweisen, und
R⁹ Alkyl, bevorzugt Methyl oder Ethyl, bedeutet,
mit sauren organischen Katalysatoren umgesetzt werden.The compounds of the formula (II) are known or can be prepared by reacting compounds of the formula

wherein R ¹ , R ³ , R ⁴ , R ⁵ , m and n have the abovementioned meaning, and
R ^{9 is} alkyl, preferably methyl or ethyl,
be reacted with acidic organic catalysts.

The Reaction is generally carried out in inert solvents, preferably in a temperature range of 50 ° C until the reflux the solvent at normal pressure.

Acid Organic catalysts are, for example, para-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid or Champhersulfonsäure, preferred is p-toluenesulfonic acid.

inert solvent are, for example, ethers, such as dioxane, glycol dimethyl ether or diethylene glycol dimethyl ether, Hydrocarbons such as benzene, xylene, toluene or petroleum fractions, preferred is xylene or toluene.

worin R¹, R³, R⁴, R⁵, R⁹, m und n die oben angegebene Bedeutung aufweisen,
mit einem Reduktionsmittel umgesetzt werden.The compounds of the formula (VI) are known or can be prepared by reacting compounds of the formula

in which R ¹ , R ³ , R ⁴ , R ⁵ , R ⁹ , m and n have the abovementioned meaning,
be reacted with a reducing agent.

The reaction is generally carried out in inert solvents, preferably in a temperature range from room temperature to reflux of the solvent at atmospheric pressure to 3 bar. Reducing agents are, for example, palladium on carbon in a hydrogen atmosphere, palladium on carbon in the presence of ammonium formate, iron in concentrated acetic acid, iron / iron (III) chloride, tin (II) chloride or tin in Hydrochloric acid, preferred is stannous chloride. Inert solvents are, for example, ethers, such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert. Butanol, or mixtures of alcohols with water, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as dimethylformamide, dimethylacetamide, acetonitrile, ethyl acetate or pyridine.

Prefers in the case of palladium on carbon, ethanol, methanol, iso-propanol, Tetrahydrofuran or a mixture of ethyl acetate and ethanol, in the case of iron / iron (III) chloride, a mixture of water and Ethanol and in the case of tin (II) chloride dimethylformamide, dioxane or methanol.

The Compounds of formula (VII) are known or can be after synthesize known methods from the corresponding starting materials.

worin R¹, R⁴, R⁵, m und n die oben angegebene Bedeutung aufweisen, mit Verbindungen der Formel R²-X³ (IX),worin R² die oben angegebene Bedeutung aufweist, und
X³ Halogen, bevorzugt Chlor oder Brom, bedeutet,
mit einem Äquivalent der Verbindungen der Formel (IX) umgesetzt werden.The compounds of the formula (IV) are known or can be prepared by reacting compounds of the formula

wherein R ¹ , R ⁴ , R ⁵ , m and n have the abovementioned meaning, with compounds of the formula R ² -X ³ (IX), wherein R ^{2 has} the meaning given above, and
X ^{3 is} halogen, preferably chlorine or bromine,
be reacted with one equivalent of the compounds of formula (IX).

The Implementation is carried out according to the Process [A] and [B] described reaction conditions.

The Compounds of the formula (IX) are known or can be obtained synthesize known methods from the corresponding starting materials.

worin R¹, R⁴, R⁵, m und n die oben angegebene Bedeutung aufweisen, mit schwachen Säuren umgesetzt werden.The compounds of the formula (VIII) are known or can be prepared by reacting compounds of the formula

wherein R ¹ , R ⁴ , R ⁵ , m and n have the abovementioned meaning, are reacted with weak acids.

The Implementation is carried out according to the Compounds of formula (II) described reaction conditions.

worin R¹, R⁴, R⁵, m und n die oben angegebene Bedeutung aufweisen, mit einem Reduktionsmittel umgesetzt werden.The compounds of the formula (X) are known or can be prepared by reacting compounds of the formula

wherein R ¹ , R ⁴ , R ⁵ , m and n have the abovementioned meaning, be reacted with a reducing agent.

The Implementation is carried out according to the Compounds of formula (VI) described reaction conditions.

The Compounds of the formula (XI) are known or can be obtained synthesize known methods from the corresponding starting materials.

worin R¹, R², R⁴, R⁵, m und n die oben angegebene Bedeutung aufweisen, mit Reduktionsmitteln umgesetzt werden, bevorzugt ist die Umsetzung mit Palladium auf Kohle in einer Wasserstoffatmosphäre in Ethanol, Methanol, iso-Propanol oder Tetrahydrofuran in einem Temperaturbereich von Raumtemperatur bis zum Rückfluss der Lösungsmittel bei Normaldruck bis 3 bar.In an alternative method, compounds of formula (IV) can be prepared by reacting compounds of formula

wherein R ¹ , R ² , R ⁴ , R ⁵ , m and n have the abovementioned meaning, are reacted with reducing agents, preferably the reaction with palladium on carbon in a hydrogen atmosphere in ethanol, methanol, iso-propanol or tetrahydrofuran in one Temperature range from room temperature to the reflux of the solvents at normal pressure up to 3 bar.

worin R¹, R⁴, R⁵, m und n die oben angegebene Bedeutung aufweisen, mit Verbindungen der Formel (III) nach den für Verfahren [A] beschriebenen Reaktionsbedingungen umgesetzt werden.The compounds of the formula (XII) are known or can be prepared by reacting compounds of the formula

wherein R ¹ , R ⁴ , R ⁵ , m and n have the abovementioned meaning, are reacted with compounds of the formula (III) according to the reaction conditions described for process [A].

worin R¹, R⁴, R⁵, m und n die oben angegebene Bedeutung aufweisen, und
R¹⁰ Alkyl, bevorzugt Methyl oder Ethyl, bedeutet,
nach den für Verbindungen der Formel (II) beschriebenen Reaktionsbedingungen umgesetzt werden.The compounds of the formula (XIII) are known or can be prepared by reacting compounds of the formula

wherein R ¹ , R ⁴ , R ⁵ , m and n have the abovementioned meaning, and
R ^{10 is} alkyl, preferably methyl or ethyl,
be reacted according to the reaction conditions described for compounds of formula (II).

worin R¹, R⁴, R⁵, R¹⁰, m und n die oben angegebene Bedeutung aufweisen, nach den für Verbindungen der Formel (VI) beschriebenen Reaktionsbedingungen umgesetzt werden.The compounds of formula (XIV) are known or can be prepared by reacting compounds of formula

wherein R ¹ , R ⁴ , R ⁵ , R ¹⁰ , m and n have the abovementioned meaning, are reacted according to the reaction conditions described for compounds of formula (VI).

The Compounds of formula (XV) are known or can be after synthesize known methods from the corresponding starting materials.

• 1) Umsetzung von Verbindungen der Formel (VIII) mit zwei Äquivalenten Bromessigsäuretert.-butylester nach den für Verfahren [A] beschriebenen Reaktionsbedingungen (vergleiche Beispiele 33A bis 35A, 39 A und 44A bis 47A).
• 2) Selektive Abspaltung der tert.-Butylgruppe an R³ durch Umsetzung mit Chlortrimethylsilan und Natriumiodid in Trichlormethan (vergleiche Beispiele 1 bis 8 und 10 bis 13).

In the event that R ^{2 is} tert-butoxycarbonylmethyl, the reaction can be carried out according to the following alternative process:

• 1) Reaction of compounds of formula (VIII) with two equivalents of tert-butyl bromoacetate according to the reaction conditions described for process [A] (see Examples 33A to 35A, 39A and 44A to 47A).
• 2) Selective cleavage of the tert-butyl group on R ³ by reaction with chlorotrimethylsilane and sodium iodide in trichloromethane (compare Examples 1 to 8 and 10 to 13).

The Preparation of the compounds of the invention can be illustrated by the following synthesis scheme:

Synthesis scheme:

The The present invention further relates to compounds of the formula (I) for the treatment of diseases, especially cardiovascular Diseases, e.g. Atherosclerosis, as well as pharmaceuticals containing Compounds of the formula (I) and auxiliaries and also the use of compounds of formula (I) for the manufacture of a medicament for the treatment of cardiovascular Diseases, especially atherosclerosis.

she can be used in the prevention and treatment of cardiovascular Diseases (such as atherosclerosis, reperfusion tissue damage) Stroke, heart attack or peripheral vascular occlusions) or inflammatory Diseases and autoimmune diseases (such as arthritis, rheumatoid arthritis, Osteoporosis, Crohn's disease, chronic inflammatory lung diseases such as Adult Respiratory Distress Syndrome (ARDS), Transplant rejection, chronic inflammatory fibrotic organ changes such as liver fibrosis, or the more generalized autoimmune systemic disease Lupus erythematosus or other forms of lupus erythematosus or dermal inflammatory diseases psoriasis) or cancers (such as lung, breast, Colon cancer and prostate cancer) or chronic pain.

The Compounds of the invention can act systemically and / or locally. For this purpose they can be applied in a suitable manner, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otic or as an implant or stent.

For this Application routes can the compounds of the invention be administered in suitable administration forms.

For the oral Application are functioning according to the prior art rapidly and / or modifies the compounds according to the invention donating Application forms containing the compounds of the invention in crystalline and / or amorphized and / or dissolved form, e.g. Tablets (uncoated or coated Tablets, for example, with enteric or delayed dissolving or insoluble coatings that control the release of the compound of the invention), in the oral cavity rapidly disintegrating tablets or films / wafers, films / lyophilisates, Capsules (for example hard or soft gelatine capsules), dragees, Granules, pellets, powders, emulsions, suspensions, aerosols or Solutions.

The Parenteral administration can bypass a resorption step happen (e.g., intravenously, intraarterial, intracardiac, intraspinal or intralumbar) or involving absorption (e.g., intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal). For parenteral administration are suitable as application forms u.a. Injection and infusion preparations in the form of solutions, Suspensions, emulsions, lyophilisates or sterile powders.

For the others Application routes are suitable, e.g. Inhalation medicines (i.a. Powder inhalers, nebulizers), nasal drops, solutions, sprays; lingual, sublingual or buccally applied tablets, films / wafers or capsules, Suppositories, ear or eye preparations, vaginal capsules, aqueous suspensions (Lotions, shake mixes), lipophilic suspensions, ointments, creams, transdermal therapeutic systems, Milk, pastes, foams, Scattering powders, implants or stents.

The Compounds of the invention can in the cited Application forms are transferred. This can be done in a conventional manner by mixing with inert, Non-toxic, pharmaceutically suitable excipients happen. Among these adjuvants include et al excipients (for example, microcrystalline cellulose, lactose, mannitol), solvent (e.g., liquid Polyethylene glycols), emulsifiers and dispersing or wetting agents (For example, sodium dodecyl sulfate, Polyoxysorbitanoleat), binder (For example, polyvinylpyrrolidone), synthetic and natural polymers (for example, albumin), stabilizers (e.g., antioxidants such as for example ascorbic acid), Dyes (e.g., inorganic pigments such as iron oxides) and flavor and / or scent remedies.

Another The present invention relates to medicaments which are at least a compound of the invention, usually together with one or more inert, non-toxic, pharmaceutical contain suitable excipients, as well as their use to the previously mentioned purposes.

in the In general, it has proven to be beneficial in parenteral Application amounts of about 5 to 250 mg / kg body weight per 24 hours to Achieving effective results. For oral administration is the amount about 5 to 100 mg / kg of body weight every 24 hours.

Nevertheless it may be necessary, if necessary, of the quantities mentioned to deviate, depending on of body weight, Route of administration, individual behavior towards the active substance, type of Preparation and time or interval to which the application he follows. So it can in some cases be sufficient, with less than the aforementioned minimum quantity to get along while in other cases exceeded the mentioned upper limit must become. In case of application of larger quantities it may be recommended be to distribute these in several single doses throughout the day.

The Percentages in the following tests and examples are provided not stated otherwise, weight percentages; Parts are parts by weight. Solvent ratios, dilution ratios and concentration data of liquid / liquid solutions each on the volume.

A) Examples

Abbreviations:

• Boc

  tert-butoxycarbonyl

  BSA

  basal

  CDCl ₃

  deuterochloroform

  CO ₂

  carbon dioxide

  DIEA

  N, N-diisopropylethylamine

  DMAP

  4-N, N-dimethylaminopyridine

  DMF

  dimethylformamide

  DMSO

  dimethyl sulfoxide

  theory

  the theory

  EDCI

  N '- (3-dimethylaminopropyl) -N-ethylcarbodiimide × HCl

  eq.

  equivalent to

  IT I

  Electrospray ionization (in MS)

  ges.

  saturated

  H

  hour

  HATU

  O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate

  HPLC

  High pressure, high performance liquid chromatography

  conc.

  concentrating advantage

  LC-MS

  Liquid chromatography-coupled mass spectroscopy

  min

  Minute (s)

  PUG

  3-morpholino-propane sulfonic acid

  MPLC

  medium pressure

  MS

  mass spectroscopy

  MW

  Molecular weight [g / mol]

  NMR

  Nuclear Magnetic Resonance Spectroscopy

  Pd / C

  Palladium / carbon

  PyBOP

  Benzotriazol-1-yloxy-tris (pyrrolidino) phosphonium hexafluorophosphate

  quant.

  quantitatively

  R _f

  Retention index (at DC)

  RP

  Reverse phase

  RP-HPLC

  Reverse phase HPLC

  RT

  room temperature

  R _t

  Retention time (at HPLC)

  TFA

  trifluoroacetic

  THF

  tetrahydrofuran

  Tris

  Tris (hydroxymethyl) methylamine

  Tris-HCl

  Tris (hydroxymethyl) methylamine hydrochloride

HPLC and LC-MS methods:

Method 1 (HPLC): Instrument: HP 1100 with DAD detection; Column: Kromasil RP-18, 60 mm × 2 mm, 3.5 μm; Eluent A: 5 ml HClO ₄ / l water, eluent B: acetonitrile; Gradient: 0 min 2% B, 0.5 min 2% B, 4.5 min 90% B, 6.5 min 90% B; Flow: 0.75 ml / min; Oven: 30 ° C; UV detection: 210 nm.

method 2 (LC-MS): device type MS: Micromass ZQ; device type HPLC: HP 1100 Series; UV DAD; Pillar: Grom-Sil 120 ODS-4 HE 50 mm × 2.0 mm, 3.0 μm; Eluent A: water + 500 μl 50% formic acid / l, Eluent B: acetonitrile + 500 μl 50% formic acid / L; Gradient: 0.0 min 0% B → 2.9 min 70% B → 3.1 min 90% B → 4.5 min 90% B; Oven: 50 ° C; Flow: 0.8 ml / min; UV detection: 210 nm.

method 3 (LC-MS): Instrument: Micromass Quattro LCZ, with HPLC Agilent series 1100; Column: Grom-SIL120 ODS-4 HE, 50 mm × 2.0 mm, 3.0 μm; Eluent A: 1 l of water + 1 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 1 ml of 50% formic acid; Gradient: 0.0 min 100% A → 0.2 min 100% A → 2.9 min 30% A → 3.1 min 10% A → 4.5 min 10% A; Oven: 55 ° C; Flow: 0.8 ml / min; UV detection: 208-400 nm.

method 4 (LC-MS): Device type MS: Micromass ZQ; device type HPLC: Waters Alliance 2790; Column: Grom-Sil 120 ODS-4 HE 50 mm × 2.0 mm, 3.0 μm; Eluent A: water + 500 μl 50% formic acid / L; Eluent B: acetonitrile + 500 μl 50% formic acid / L; Gradient: 0.0 min 0% B → 0.2 min 0% B → 2.9 min 70% B → 3.1 min 90% B → 4.5 min 90% B; Oven: 45 ° C; Flow: 0.8 ml / min; UV detection: 210 nm.

method 5 (LC-MS): Instrument: Micromass Platform LCZ with HPLC Agilent series 1100; Column: Grom-SIL120 ODS-4 HE, 50 mm × 2.0 mm, 3.0 μm; Eluent A: 1 l of water + 1 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 1 ml of 50% formic acid; Gradient: 0.0 min 100% A → 0.2 min 100% A → 2.9 min 30% A → 3.1 min 10% A → 4.5 min 10% A; Oven: 55 ° C; Flow: 0.8 ml / min; UV detection: 208-400 nm.

Method 6 (HPLC): Instrument: HP 1100 with DAD detection; Column: Kromasil RP-18, 60 mm × 2 mm, 3.5 μm; Eluent A: 5 ml HClO ₄ / l water, eluent B: acetonitrile; Gradient: 0 min 2% B, 0.5 min 2% B, 4.5 min 90% B, 9 min 90% B; Flow: 0.75 ml / min; Oven: 30 ° C; UV detection: 210 nm.

method 7 (LC-MS): Device type MS: Micromass ZQ; device type HPLC: Waters Alliance 2795; Column: Merck Chromolith SpeedROD RP-18e 50mm × 4.6mm; Eluent A: water + 500 μl 50% Formic acid / l; eluent B: acetonitrile + 500 μl 50% formic acid / L; Gradient: 0.0 min 10% B → 3.0 min 95% B → 4.0 min 95% B; Oven: 35 ° C; Flow: 0.0 min 1.0 ml / min → 3.0 min 3.0 ml / min → 4.0 min 3.0 ml / min; UV detection: 210 nm.

method 8 (RP-HPLC): Column material: YMC GEL ODS AQ S 5/15 μm; Eluent: acetonitrile-water gradient 10:90 → 90:10.

Starting Compounds:

Example 1A

4-chloro-N'-hydroxy-3-nitrobenzolcarboximidamid

19 g (104.1 mmol) of 4-chloro-3-nitrobenzonitrile and 10.85 g (156.11 mmol) of hydroxylammonium chloride are mixed with 570 ml of ethanol. 15.8 g (156.11 mmol) of triethylamine are slowly added to the resulting suspension. The mixture is heated to reflux for 5 hours and then the reaction mixture is stirred overnight at RT. The precipitated crystalline solid is filtered off and dried in vacuo. The filtrate is concentrated under reduced pressure, the residue taken up in ethyl acetate and washed three times with water. The organic phase is then dried over magnesium sulfate, filtered and concentrated. The precipitated solid is also filtered off and dried. This gives a total of 22.9 g (quant.) Of product.
HPLC (Method 1): R _t = 2.81 min
MS (ESIpos): m / z = 216 (M + H) ⁺

Example 2A

N '- (acetyloxy) -4-chloro-3-nitrobenzolcarboximidamid

22.87 g (106.1 mmol) of 4-chloro-N'-hydroxy-3-nitrobenzenecarboximidamide are suspended in 540 ml of methylene chloride and treated with 17.62 g (222.8 mmol) of pyridine. The reaction mixture is cooled in an ice bath to 0 ° C and treated dropwise at this temperature with 8.74 g (111.4 mmol) of acetyl chloride. Allow to warm slowly to RT and stir at RT overnight. The organic phase is washed twice with 1N hydrochloric acid, dried over magnesium sulfate and concentrated. By repeated crystallization from the mother liquor, a total of 26.1 g (95% of theory) of product are obtained.
HPLC (Method 1): R _t = 3.74 min
MS (ESIpos): m / z = 258 (M + H) ⁺

Example 3A

4-chloro-N '- [(cyclopropylcarbonyl) oxy] -3-nitrobenzolcarboximidamid

2 g (9.28 mmol) of 4-chloro-N'-hydroxy-3-nitrobenzenecarboximidamide are suspended in 47 ml of methylene chloride and admixed with 1.54 g (19.5 mmol) of pyridine. The reaction mixture is cooled to 0 ° C. in an ice bath and 1.020 g (9.74 mmol) cyclopropanecarboxylic acid chloride are added dropwise at this temperature. Allow to warm slowly to RT and stir at RT overnight. The solvent is removed under reduced pressure to give 2.33 g (77% of theory) of crude product, which is not further purified.
HPLC (Method 1): R _t = 4.12 min
MS (ESIpos): m / z = 284 (M + H) ⁺

Example 4A

3- (4-chloro-3-nitrophenyl) -5-methyl-1,2,4-oxadiazole

29.4 g (114.1 mmol) of N '- (acetyloxy) -4-chloro-3-nitrobenzenecarboximidamide are admixed with 545 ml of anhydrous toluene, and 13.61 g of 3Å molecular sieve are added. The mixture is stirred under reflux overnight, filtered through Celite, washed with methylene chloride, concentrated and purified by flash chromatography (silica gel: methylene chloride). 20.8 g (74% of theory) of product are obtained.
HPLC (Method 1): R _t = 4.59 min
MS (EI): m / z = 239 (M) ⁺

Example 5A

3- (4-chloro-3-nitrophenyl) -5-cyclopropyl-1,2,4-oxadiazol

233 ml of anhydrous toluene are added to 2.33 g (8.21 mmol) of 4-chloro-N '- [(cyclopropylcarbonyl) oxy] -3-nitrobenzenecarboximidamide, and 574 mg of 3Å molecular sieve are added. The mixture is stirred under reflux overnight, filtered through Celite, washed with methylene chloride, concentrated. The organic phase is washed twice with water and once with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. There are obtained 2.5 g (quant.) Of crude product.
HPLC (Method 1): R _t = 4.99 min
MS (EI): m / z = 265 (M) ⁺

Example 6A

4-fluoro-3-nitrobenzoesäurebenzylester

According to a protocol of B. Neises, W. Steglich, Angew. Chem. 1978, 90, 556, 10 g of 4-fluoro-3-nitrobenzoic acid are dissolved in 54 ml of methylene chloride. While stirring, 0.49 g (4.05 mmol) of DMAP and then 6.43 g (59.4 mmol) of benzyl alcohol are added at RT. After cooling to 0 ° C., 12.3 g (59.4 mmol) of 1,3-dicyclohexylcarbodiimide are added. The mixture is stirred for 5 min at 0 ° C, then slowly warm to RT and stir at this temperature for 3 hours. From the precipitated solid is filtered, the filtrate washed twice with 0.5 N hydrochloric acid and once with saturated sodium bicarbonate solution and dried over magnesium sulfate. This is followed by flash-chromatographic coarse purification (silica gel: cyclohexane / ethyl acetate 4: 1 to 3: 1) to give 13.8 g (82% of theory) of product.
HPLC (Method 1): R _t = 4.98 min
MS (DCI): m / z = 293 (M + NH ₄₎ ⁺

Example 7A

N- (4-fluoro-3-nitrophenyl) acetamide

2 g (12.8 mmol) of 4-fluoro-3-nitroaniline are dissolved in 17 ml of methylene chloride and treated with 2.43 g (30.8 mmol) of pyridine. After cooling to 0 ° C., 1.21 g (15.4 mmol) of acetyl chloride are slowly added dropwise. It is allowed to slowly warm to 0 ° C and stir at RT for 4 hours. Then it is diluted with methylene chloride and washed once each with 1N hydrochloric acid and saturated sodium bicarbonate solution. The organic phase is dried over magnesium sulfate, filtered and the solvent evaporated. There are obtained 2.68 g (quant.) Of crude product, which is not further purified.
HPLC (Method 1): R _t = 3.59 min
MS (DCI): m / z = 216 (M + NH ₄₎ ⁺

Example 8A

N- (4-fluoro-3-nitrophenyl) -N-methylacetamide

Under an argon atmosphere, 0.59 g (14.8 mmol) of sodium hydride (60%) are suspended in 10 ml of anhydrous THF. The suspension is cooled to 0 ° C and at this temperature with 2.67 g (13.5 mmol) of N- (4-fluoro-3-nitrophenyl) acetamide, dissolved in 20 ml of anhydrous THF, slowly added. Allow to warm to RT and stir for 30 min. Subsequently, 4.78 g (33.7 mmol) of iodomethane are added dropwise. The reaction mixture is stirred at RT overnight. For workup, 2.29 g (33.7 mmol) of ammonia solution (25% strength) are first added and the mixture is stirred for 30 minutes. Then water is added and extracted three times with ethyl acetate. The combined organic extracts are dried over magnesium sulfate, filtered and the solvent evaporated. 2.83 g (97% of theory) of crude product are obtained, which are not further purified.
HPLC (Method 1): R _t = 3.55 min
MS (DCI): m / z = 213 (M + H) ⁺

Example 9A

2,2-dimethyl-5- [4- (5-methyl-1,2,4-oxadiazol-3-yl) -2-nitrophenoxy] -4H-1,3-benzodioxin-4-one

Under argon are added 20.8 g (86.8 mmol) of 3- (4-chloro-3-nitrophenyl) -5-methyl-1,2,4-oxadiazole, 16.86 g (86.8 mmol) of 5-hydroxy-2,2-dimethyl-4H -1,3-benzodioxin-4-one and 13.2 g (95.5 mmol) of anhydrous potassium carbonate mixed with 120 ml of anhydrous DMF. It is stirred for 20 hours at 70 ° C. After cooling, ice is added and the resulting precipitate is filtered off. The filter residue is dissolved in ethyl acetate and washed twice each with water and saturated sodium chloride solution. The organic phase is dried over magnesium sulfate, filtered and concentrated. The purification is carried out by column chromatography (silica gel: cyclohexane / ethyl acetate 10: 1 to pure ethyl acetate). There are obtained 24.2 g (69% of theory) of product.
HPLC (Method 1): R _t = 4.74 min
MS (ESIpos): m / z = 398 (M + H) ⁺

Example 10A

5- [4- (5-cyclopropyl-1,2,4-oxadiazol-3-yl) -2-nitrophenoxy] -2,2-dimethyl-4H-1,3-benzodioxin-4-one

Under argon, 2.5 g (9.41 mmol) of 3- (4-chloro-3-nitrophenyl) -5-cyclopropyl-1,2,4-oxadiazole, 1.83 g (9.41 mmol) of 5-hydroxy-2,2-dimethyl-4H Added -1,3-benzodioxin-4-one and 1.43 g (10.4 mmol) of anhydrous potassium carbonate with 10 ml of anhydrous DMF. It is stirred for 12 hours at 70 ° C. After cooling, 75 ml of ice water are added and the resulting precipitate is filtered off. The filter residue is dissolved in ethyl acetate, washed twice with water and once with saturated sodium chloride solution. The organic phase is dried over magnesium sulfate, filtered and concentrated. The purification is carried out by column chromatography (silica gel: cyclohexane / ethyl acetate 9: 1 to 1: 1). 2.54 g (58% of theory) of product are obtained.
HPLC (Method 1): R _t = 5.01 min
MS (ESIpos): m / z = 424 (M + H) ⁺

Example 11A

4 - [(2,2-dimethyl-4-oxo-4H-1,3-benzodioxin-5-yl) oxy] -3-nitrobenzoesäurebenzylester

Under argon are 13.8 g (50 mmol) of benzyl 4-fluoro-3-nitrobenzoate, 9.7 g (50 mmol) of 5-hydroxy-2,2-dimethyl-4H-1,3-benzodioxin-4-one and 7.6 g (55 mmol ) anhydrous potassium carbonate with 68 ml of anhydrous DMF. It is stirred for 5 hours at 70 ° C. After cooling, ice is added and the resulting precipitate is filtered off. The filter residue is dissolved in ethyl acetate, washed twice with water and twice with saturated sodium chloride solution. The organic phase is dried over magnesium sulfate, filtered and concentrated. There are obtained 20.4 g (82% of theory) of crude product, which is not further purified.
HPLC (Method 1): R _t = 5.19 min
MS (DCI): m / z = 467 (M + NH ₄₎ ⁺

Example 12A

N- {4 - [(2,2-dimethyl-4-oxo-4H-1,3-benzodioxin-5-yl) oxy] -3-nitrophenyl} -N-methylacetamide

Under argon, 742 mg (3.5 mmol) of N- (4-fluoro-3-nitrophenyl) -N-methylacetamide, 679 mg (3.5 mmol) of 5-hydroxy-2,2-dimethyl-4H-1,3-benzodioxin-4 -on and 532 mg (3.85 mmol) of anhydrous potassium carbonate are mixed with 10 ml of anhydrous DMF. It is stirred for 5 hours at 70 ° C. After cooling, ice is added and the resulting precipitate is filtered off. The filter residue is dissolved in ethyl acetate, washed twice with water and once with saturated sodium chloride solution. The organic phase is dried over magnesium sulfate, filtered and concentrated. There are obtained 1.13 g (81% of theory) of crude product, which is not further purified.
HPLC (Method 1): R _t = 4.21 min
MS (ESIpos): m / z = 387 (M + H) ⁺

Example 13A

4 - [(2,2-dimethyl-4-oxo-4H-1,3-benzodioxin-5-yl) oxy] -N, N-dimethyl-3-nitrobenzenesulfonamide

3.0 g (11.33 mmol) of 4-chloro-N, N-dimethyl-3-nitrobenzenesulfonamide and 2.20 g (11.33 mmol) of 5-hydroxy-2,2-dimethyl-4H-1,3-benzodioxin-4-one are dissolved in 20 Dissolved DMF, added with 1.72 g (12.47 mmol) of potassium carbonate and stirred at 70 ° C overnight. For workup, the batch is poured into 250 ml of water and extracted three times with ethyl acetate. The organic phase is dried over sodium sulfate and concentrated. The crude product is purified by Biotage MPLC (eluent: methylene chloride / ethyl acetate 50: 1). This gives 1.79 g (37% of theory) of product.
LC-MS (Method 2): R _t = 3.59 min
MS (ESIpos): m / z = 423 (M + H) ⁺

Example 14A

2,2-dimethyl-5- [4- (methylsulfonyl) -2-nitrophenoxy] -4H-1,3-benzodioxin-4-one

2.37 g (10.06 mmol) of 1-chloro-4- (methylsulfonyl) -2-nitrobenzene and 1.95 g (10.06 mmol) of 5-hydroxy-2,2-dimethyl-4H-1,3-benzodioxin-4-one are dissolved in 25 Dissolved DMF, added with 1.53 g (11.06 mmol) of potassium carbonate and stirred at 70 ° C for 7 hours. For workup, the batch is poured into 150 ml of water and extracted three times with ethyl acetate. The organic phase is dried over sodium sulfate and concentrated. The crude product is purified via a Biotage MPLC (eluent: methylene chloride / ethyl acetate 15: 1). 3.16 g (80% of theory) of product are obtained.
LC-MS (Method 3): R _t = 3.50 min
MS (ESIpos): m / z = 394 (M + H) ⁺

Example 15A

2,2-dimethyl-5- [4- (morpholin-4-ylsulfonyl) -2-nitrophenoxy] -4H-1,3-benzodioxin-4-one

2.0 g (6.52 mmol) of 4 - [(4-chloro-3-nitrophenyl) sulfonyl] morpholine and 1.7 g (6.52 mmol) of 5-hydroxy-2,2-dimethyl-4H-1,3-benzodioxin-4-one dissolved in 25 ml of DMF, treated with 991 mg (7.17 mmol) of potassium carbonate and stirred for 5 hours at 70 ° C. For workup, the batch is poured into 150 ml of water and extracted three times with ethyl acetate. The organic phase is dried over sodium sulfate and concentrated. This gives 2.97 g (98% of theory) of product, which is not further purified.
LC-MS (Method 3): R _t = 3.70 min
MS (ESIpos): m / z = 465 (M + H) ⁺

Example 16A

4 - [(2,2-dimethyl-4-oxo-4H-1,3-benzodioxin-5-yl) oxy] -N-ethyl-3-nitrobenzenesulfonamide

6.82 g (25.75 mmol) of 4-chloro-N-ethyl-3-nitrobenzenesulfonamide and 5.00 g (25.75 mmol) of 5-hydroxy-2,2-dimethyl-4H-1,3-benzodioxin-4-one are dissolved in 100 ml of DMF dissolved, mixed with 4.27 g (30.90 mmol) of potassium carbonate and stirred at 70 ° C for 5 hours. For workup, the mixture is mixed with ethyl acetate and a mixture of water and 1N hydrochloric acid. The aqueous phase is extracted with ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered and concentrated. 7.88 g (67% of theory) of product are obtained, which are not further purified.
LC-MS (Method 7): R _t = 2.21 min
MS (ESIpos): m / z = 423 (M + H) ⁺

Example 17A

5- [2-Amino-4- (5-methyl-1,2,4-oxadiazol-3-yl) phenoxy] -2,2-dimethyl-4H-1,3-benzodioxin-4-one

1 g (2.52 mmol) of 2,2-dimethyl-5- [4- (5-methyl-1,2,4-oxadiazol-3-yl) -2-nitrophenoxy] -4 H -1,3-benzodioxin-4 on the instructions of L. Bertelli, B. Biagi, O. Livi, C. Manera, V. Scartoni, C. Martini, G. Giannaccini, L. Trincavelli, PL Barili, Farmaco 1998, 53 (4), 305 -311 converted to the corresponding amine. For this purpose, the educt is dissolved in 90 ml of 60% ethanol and mixed with 4.4 ml of a 5% aqueous solution of iron trichloride. Subsequently, 0.52 g (9.31 mmol) of iron powder are added and stirred at 80 ° C for 1 hour. The reaction mixture is filtered off with suction through hot Celite, the filtrate diluted with water and made alkaline with a few drops of concentrated ammonia solution. The aqueous phase is extracted three times with methylene chloride, the combined organic extracts dried over magnesium sulfate, filtered and concentrated. 0.94 g (90% of theory) of crude product are obtained.
HPLC (Method 1): R _t = 4.19 min
MS (DCI): m / z = 368 (M + H) ⁺

Example 18A

5- [2-Amino-4- (5-cyclopropyl-1,2,4-oxadiazol-3-yl) phenoxy] -2,2-dimethyl-4H-1,3-benzodioxin-4-one

1 g (2.36 mmol) of 5- [4- (5-cyclopropyl-1,2,4-oxadiazol-3-yl) -2-nitrophenoxy] -2,2-dimethyl-4H-1,3-benzodioxin-4 are suspended in 24 ml of dioxane and treated with 2.66 g (11.81 mmol) of tin dichloride. After adding a few drops of concentrated hydrochloric acid, the mixture is stirred overnight at 70.degree. The reaction mixture is diluted with ethyl acetate and washed twice with 1N sodium hydroxide solution. The organic phase is dried over magnesium sulfate, filtered off with suction through Celite and the solvent is evaporated off under reduced pressure. There are obtained 656 mg (51% of theory) of crude product, which is not further purified.
LC-MS (Method 4): R _t = 3.54 min

MS (ES +): m / z = 394 (M + H) ⁺

Example 19A

3-Amino-4 - [(2,2-dimethyl-4-oxo-4H-1,3-benzodioxin-5-yl) oxy] benzoic acid benzyl ester

19.9 g (44.3 mmol) of 4 - [(2,2-dimethyl-4-oxo-4H-1,3-benzodioxin-5-yl) oxy] -3-nitrobenzoic acid benzyl ester are initially charged in 200 ml of acetic acid and 10 ml of water. 17.3 g (310 mmol) of iron powder are added and the mixture is stirred at 50 ° C. for 2 hours. For working up, it is diluted with acetone and filtered through Celite. It is then concentrated, taken up twice more in toluene and concentrated again. The residue obtained is taken up in ethyl acetate and filtered through silica gel. It is washed with Essigsärueethylester and concentrated the combined organic phases. There are obtained 18.6 g (81% of theory) of crude product, which is not further purified.
HPLC (Method 1): R _t = 4.90 min
MS (ESIpos): m / z = 420 (M + H) ⁺

Example 20A

N- {3-amino-4 - [(2,2-dimethyl-4-oxo-4H-1,3-benzodioxin-5-yl) oxy] phenyl} -N-methylacet-amide

1.11 g (2.87 mmol) of N- {4 - [(2,2-dimethyl-4-oxo-4H-1,3-benzodioxin-5-yl) oxy] -3-nitrophenyl} -N-methylacetamide are dissolved in 10 ml After addition of a few drops of concentrated hydrochloric acid, the mixture is stirred overnight at 70 ° C. The reaction mixture is diluted with ethyl acetate and washed twice with 1N sodium hydroxide solution The organic phase is dried over magnesium sulfate, over Celite is filtered off with suction and the solvent is evaporated off under reduced pressure to give 757 mg (67% of theory) of crude product which is not further purified.
HPLC (method 2): R _t = 3.02 min
MS (ES +): m / z = 357 (M + H) ⁺

Example 21A

3-Amino-4 - [(2,2-dimethyl-4-oxo-4H-1,3-benzodioxin-5-yl) oxy] -N, N-dimethylbenzenesulfonamide

4.27 g (8.96 mmol) of 4 - [(2,2-dimethyl-4-oxo-4H-1,3-benzodioxin-5-yl) oxy] -N, N-dimethyl-3-nitrobenzenesulfonamide are dissolved in a mixture of 50 ml of ethyl acetate and 50 ml of ethanol at room temperature. 0.93 g (0.87 mmol) of 10% palladium on carbon and 3.29 g (52.16 mmol) of ammonium formate are added, and the mixture is stirred at 80 ° C. for 3 hours. After cooling the mixture, the catalyst is filtered through Celite and washed with ethanol. The volatiles are removed in vacuo. 3.55 g (82% of theory) of product are obtained.
LC-MS (Method 4): R _t = 3.04 min
MS (ESIpos): m / z = 393 (M + H) ⁺

Example 22A

5- [2-amino-4- (methylsulfonyl) phenoxy] -2,2-dimethyl-4H-1,3-benzodioxin-4-one

2,2'-Dimethyl-5- [4- (methylsulfonyl) -2-nitrophenoxy] - 2807 mg (7.14 mmol) -4H-1,3-benzodioxin-4-one are added in a mixture of 75 ml of ethyl acetate and 75 ml of ethanol Room temperature dissolved. 1.52 g (1.43 mmol) of 10% palladium on carbon and 2.70 g (42.8 mmol) of ammonium formate are added, and the mixture is stirred at 80 ° C. for 2 hours. After cooling the mixture, the catalyst is filtered through Celite and washed with ethanol. The crude product is purified via a Biotage MPLC (eluent: methylene chloride / ethyl acetate 5: 1). This gives 1882 mg (73% of theory) of product.
LC-MS (Method 2): R _t = 3.17 min
MS (ESIpos): m / z = 364 (M + H) ⁺

Example 23A

5- [2-Amino-4- (morpholin-4-ylsulfonyl) phenoxy] -2,2-dimethyl-4H-1,3-benzodioxin-4-one

2.91 g (6.26 mmol) of 2,2-dimethyl-5- [4- (morpholin-4-ylsulfonyl) -2-nitrophenoxy] -4 H -1,3-benzodioxin-4-one are dissolved in a mixture of 40 ml (699 mmol) acetic acid and 2 ml of water and treated with 2.45 g (43.80 mmol) of iron powder. The suspension is stirred at RT for 1 hour and at 50 ° C. for 3 hours. After cooling, it is diluted with 200 ml of acetone, filtered with suction through Celite and washed with plenty of acetone. The filtrate is concentrated and suspended in methylene chloride / ethyl acetate 5: 1, concentrated again and the residue is purified over a Biotage MPLC (eluent: methylene chloride / ethyl acetate 30: 1). This gives 0.745 g (27% of theory) of product.
LC-MS (Method 5): R _t = 3.50 min
MS (ESIpos): m / z = 435 (M + H) ⁺

Example 24A

3-Amino-4 - [(2,2-dimethyl-4-oxo-4H-1,3-benzodioxin-5-yl) oxy] -N-ethylbenzenesulfonamide

500 mg (1.18 mmol) of 4 - [(2,2-dimethyl-4-oxo-4H-1,3-benzodioxin-5-yl) oxy] -N-ethyl-3-nitrobenzenesulfonamide are dissolved in 43 ml of 60% ethanol dissolved and mixed with 2.0 ml of a 5% aqueous iron trichloride solution. Subsequently, 244.6 mg (4.38 mmol) of iron powder are added and heated under reflux for 3 hours. The reaction mixture is filtered off with suction through hot Celite, rinsed with ethanol and the solution concentrated in vacuo. The residue is suspended in a mixture of water and methylene chloride and made alkaline with a few drops of concentrated ammonia solution. It is then again filtered through Celite, and the phases are separated. The organic phase is washed once with water, dried over magnesium sulfate, filtered and concentrated. There are obtained 472 mg (quant.) Product.
LC-MS (Method 3): R _t = 2.66 min
MS (ESIpos): m / z = 393 (M + H) ⁺

Example 25A

1-Hydroxy-8- (5-methyl-1,2,4-oxadiazol-3-yl) dibenzo [b, f] [1,4] oxazepine-11 (10H) -one

0.94 g (2.55 mmol) of 5- [2-amino-4- (5-methyl-1,2,4-oxadiazol-3-yl) -phenoxy] -2,2-dimethyl-4H-1,3-benzodioxin-4 5 ml of xylene and 0.05 g (0.26 mmol) of p-toluenesulfonic acid monohydrate are added and the mixture is stirred overnight at reflux. For workup, the solvent is removed under reduced pressure and the residue is stirred twice with methanol. The solid is filtered off, washed with methanol and then dried in vacuo. 0.57 g (70% of theory) of product are obtained.
HPLC (Method 1): R _t = 4.54 min
MS (ESIpos): m / z = 310 (M + H) ⁺

Example 26A

8- (5-Cyclopropyl-1,2,4-oxadiazol-3-yl) -1-hydroxydibenzo [b, f] [1,4] oxazepine-11 (10H) -one

656 mg (1.67 mmol) of 5- [2-amino-4- (5-cyclopropyl-1,2,4-oxadiazol-3-yl) -phenoxy] -2,2-dimethyl-4H-1,3-benzodioxin-4 -on are mixed with 7 ml of xylene and 32 mg (0.17 mmol) of p-toluene-sulfonic acid monohydrate and overnight. stirred at reflux. For working up, it is diluted with ethyl acetate, washed twice with water and once with saturated sodium chloride solution. The organic phase is dried over magnesium sulfate, filtered and concentrated. This precipitate precipitate, which is stirred with methanol. 273 mg (43% of theory) of product are obtained.
LC-MS (Method 3): R _t = 4.39 min
MS (ES +): m / z = 336 (M + H) ⁺

Example 27A

1-hydroxy-11-oxo-10,11-dihydrodibenzo [b, f] [l, 4] oxazepine-8-carboxylic acid benzyl ester

19 g (45.3 mmol) of benzyl 3-amino-4 - [(2,2-dimethyl-4-oxo-4H-1,3-benzodioxin-5-yl) oxy] benzoate are mixed with 250 ml of xylene and 0.98 (5.16 mmol). p-Toluolsulfonsäuremonohydrat and stirred overnight at reflux. The solvent is removed under reduced pressure and the residue obtained is stirred with methanol. The resulting solid is filtered off, washed with methanol and dried in vacuo. 12.9 g (78% of theory) of product are obtained.
HPLC (Method 1): R _t = 5.10 min
MS (ESIpos): m / z = 362 (M + H) ⁺

Example 28A

N- (1-hydroxy-11-oxo-10,11-dihydrodibenzo [b, f] [1,4] oxazepine-8-yl) -N-methylacetamide

757 mg (1.93 mmol) of N- {3-amino-4 - [(2,2-dimethyl-4-oxo-4H-1,3-benzodioxin-5-yl) oxy] -phenyl} -N-methylacetamide be with 10 ml of xylene and 37.5 mg (0.19 mmol) of p-toluenesulfonic monohydrate and heated to reflux. Since no complete solution is obtained even at boiling heat, 1 ml of DMF is added. It is stirred overnight at reflux. After removal of the solvent, the residue is taken up in ethyl acetate and washed with water. The organic phase is dried over magnesium sulfate, filtered and concentrated. Concentration of the solution precipitates a solid, which is stirred again with methanol. 363 mg (62% of theory) of product are obtained.
HPLC (Method 1): R _t = 3.98 min
MS (ESIpos): m / z = 299 (M + H) ⁺

Example 29A

1-hydroxy-N, N-dimethyl-11-oxo-10,11-dihydrodibenzo [b, f] [1,4] oxazepine-8-sulfonamide

3.53 g (7.11 mmol) of 3-amino-4 - [(2,2-dimethyl-4-oxo-4H-1,3-benzodioxin-5-yl) oxy] -N, N-dimethylbenzenesulfonamide are dissolved in 50.0 ml Xylene dissolved at RT and treated with 270 mg (1.42 mmol) of 4-Toluolsulfonsäuremonohydrat. The suspension is stirred overnight at 140.degree. After cooling the reaction solution, the precipitate is filtered off with suction and washed with cyclohexane. The precipitate is slurried several times with methanol, filtered off with suction and then dried under high vacuum. This gives 2267 mg (95% of theory) of the product, which is not further purified.
LC-MS (Method 2): R _t = 3.36 min
MS (ESIpos): m / z = 335 (M + H) ⁺

Example 30A

1-hydroxy-8- (methylsulfonyl) dibenzo [b, f] [1,4] oxazepine-11 -one (10H)

1875 mg (5.16 mmol) of 5- [2-amino-4- (methylsulfonyl) phenoxy] -2,2-dimethyl-4H-1,3-benzodioxin-4-one dissolved in 25.0 ml of xylene at RT and admixed with 98 mg (0.52 mmol) of 4-toluenesulfonic acid monohydrate. The suspension will over Night at 140 ° C touched. After this

Cool the reaction solution, the precipitate is filtered off with suction and washed with cyclohexane. The precipitate is slurried several times with methanol and filtered with suction and then dried under high vacuum. This gives 1372 mg (87% of theory) of the product, which is not further purified.
LC-MS (Method 5): R _t = 3.20 min
MS (ESIpos): m / z = 306 (M + H) ⁺

Example 31A

1-hydroxy-8- (morpholin-4-ylsulfonyl) dibenzo [b, f] [1,4] oxazepine-11 -one (10H)

741 mg (1.71 mmol) of 5- [2-amino-4- (morpholin-4-ylsulfonyl) phenoxy] -2,2-dimethyl-4H-1,3-benzodioxin-4-one are dissolved in 20.0 ml of xylene at RT and 32 mg (0.17 mmol) of 4-Toluolsulfonsäuremonohydrat added. The suspension is stirred overnight at 140.degree. After cooling the reaction solution, the precipitate is filtered off with suction and washed with cyclohexane. The precipitate is slurried several times with methanol, filtered off with suction and then dried under high vacuum. This gives 517 mg (80% of theory) of the product, which is not further purified.
HPLC (method 5): R _t = 3.40 min
MS (ESIpos): m / z = 377 (M + H) ⁺

Example 32A

N-Ethyl-1-hydroxy-11-oxo-10,11-dihydrodibenzo [b, f] [1,4] oxazepine-8-sulfonamide

3.22 g (8.21 mmol) of 3-amino-4 - [(2,2-dimethyl-4-oxo-4H-1,3-benzodioxin-5-yl) oxy] -N-ethylbenzenesulfonamide are added in 109.3 ml of xylene RT was dissolved and treated with 0.160 g (0.82 mmol) of 4-toluenesulfonic acid monohydrate. The suspension is stirred for 4 hours at 140.degree. After cooling the reaction solution in the refrigerator overnight, the precipitate is filtered off with suction and washed with cyclohexane and diethyl ether. The precipitate is dried under high vacuum. This gives 2.33 g (85% of theory) of the product.
LC-MS (Method 3): R _t = 2.72 min
MS (ESIpos): m / z = 335 (M + H) ⁺

Example 33A

[1- (2-tert-butoxy-2-oxoethoxy) -8- (5-methyl-1,2,4-oxadiazol-3-yl) -11-oxodibenzo [b, f] [1,4] - oxazepine-10 (11H) -yl] acetic acid tert-butyl ester

107 mg (0.35 mmol) of 1-hydroxy-8- (5-methyl-1,2,4-oxadiazol-3-yl) dibenzo [b, f] [1,4] oxazepine-11 (10H) -one are added in Dissolved 1.5 ml of anhydrous DMF and with 143.4 mg (1.04 mmol) of anhydrous potassium added umcarbonat. 169 mg (0.86 mmol) of bromoacetic acid tert-butyl ester are then added at RT and the mixture is stirred at RT overnight. For working up, it is diluted with ethyl acetate, washed twice with water and once with saturated sodium chloride solution. The organic phase is dried over magnesium sulfate, filtered and concentrated. The purification is carried out by means of RP-HPLC. 147 mg (75% of theory) of product are obtained.
HPLC (Method 6): R _t = 5.10 min
MS (ESIpos): m / z = 538 (M + H) ⁺

Example 34A

[1- (2-tert-butoxy-2-oxoethoxy) -8- (5-cyclopropyl-1,2,4-oxadiazol-3-yl) -11-oxodibenzo [b, f] [1,4] oxazepine -10 (11H) -yl] acetic acid tert-butyl ester

124 mg (0.37 mmol) of 8- (5-cyclopropyl-1,2,4-oxadiazol-3-yl) -1-hydroxydibenzo [b, f] [1,4] oxazepine-11 (10H) -one are dissolved in 1.5 Dissolved in anhydrous DMF and treated with 153.3 mg (1.11 mmol) of anhydrous potassium carbonate. 180.3 mg (0.92 mmol) of bromoacetic acid tert-butyl ester are then added at RT and the mixture is stirred at RT overnight. For working up, it is diluted with ethyl acetate, washed twice with water and once with saturated sodium chloride solution. The organic phase is dried over magnesium sulfate, filtered and concentrated. The purification is carried out by means of RP-HPLC. 155 mg (75% of theory) of product are obtained.
HPLC (method 1): R _t = 5.36 min
MS (ESIpos): m / z = 564 (M + H) ⁺

Example 35A

1- oxazepine (2-tert-butoxy-2-oxoethoxy) -10- (2-tert-butoxy-2-oxoethyl) -11-oxo-10,11-dihydrodibenzo [b, f] [1,4] -8-carboxylate

3 g (8.3 mmol) of 1-hydroxy-11-oxo-10,11-dihydrodibenzo [b, f] [1,4] oxazepine-8-carboxylic acid benzyl ester are dissolved in 15 ml of anhydrous DMF and extracted with 3.44 g (24.9 mmol ) anhydrous potassium carbonate. Subsequently, 4.05 g (20.8 mmol) of bromoacetic acid tert-butyl ester are added at RT and the mixture is stirred at RT overnight. For workup, the solvent is evaporated in vacuo, the residue taken up in ethyl acetate, washed once with water and twice with saturated sodium chloride solution. The organic phase is dried over magnesium sulfate, filtered and concentrated. There are obtained 5.2 g (quant.) Of crude product, which is not further purified.
HPLC (Method 6): R _t = 5.49 min
MS (ESIpos): m / z = 590 (M + H) ⁺

Example 36A

1- oxazepine (2-tert-butoxy-2-oxoethoxy) -10- (2-tert-butoxy-2-oxoethyl) -11-oxo-10,11-dihydrodibenzo [b, f] [1,4] -8-carboxylic acid

5.2 g (8.8 mmol) of 1- (2-tert-butoxy-2-oxoethoxy) -10- (2-tert-butoxy-2-oxoethyl) -11-oxo-10,11-dihydrodibenzo [b, f] [1,4] oxazepine-8-carboxylic acid benzyl ester are dissolved in 100 ml of ethyl acetate and, after evacuation and purging with argon, mixed with 0.47 g of palladium on carbon (10%). Stir until it is completely reacted under a hydrogen atmosphere, then filtered through Celite, washed with ethyl acetate and concentrated. There are obtained 4.6 g (quant.) Of crude product, which is not further purified.
HPLC (Method 6): R _t = 4.69 min
MS (ESIpos): m / z = 500 (M + H) ⁺

Becomes the hydrogenation in ethanol as solvent carried out, so takes place in the 1- (2-tert-butoxy-2-oxoethoxy) group partial transesterification to the ethyl ester.

Example 37A

[8 - [({[(1E) -1-Aminoethylidene] amino} oxy) carbonyl] -1- (2-tert-butoxy-2-oxoethoxy) -11-oxodibenzo [b, f] [1,4] oxazepine-10 (11H) -yl] acetic acid tert-butyl ester

2.15 g (about 8.8 mmol) of a mixture of 1- (2-tert-butoxy-2-oxoethoxy) -10- (2-tert-butoxy-2-oxoethyl) -11-oxo-10,11-dihydrodibenzo - [b, f] [1,4] oxazepine-8-carboxylic acid and 1- (2-ethoxy-2-oxoethoxy) -10- (2-tert-butoxy-2-oxo-ethyl) -11-oxo-10, 11-dihydrodibenzo [b, f] - [1,4] oxazepine-8-carboxylic acid are dissolved in 25 ml of anhydrous THF. At RT, a solution of 2.47 g (4.74 mmol) of PyBOP in 10 ml of water-pure methylene chloride is added dropwise. Subsequently, 0.5 g (4.52 mmol) of (1E) -N'-hydroxyethanimidamide hydrochloride and 1.17 g (9.05 mmol) of N, N-diisopropylethylamine are added and the mixture is stirred at RT overnight. The reaction mixture is concentrated, taken up in ethyl acetate and washed once with 1N hydrochloric acid and once with saturated sodium bicarbonate solution. The organic phase is dried over magnesium sulfate, filtered and concentrated. There are obtained 1.52 g (about 63% of theory) of crude product as a mixture of tert-butyl and ethyl ester.
HPLC (Method 6): R _t = 4.51 min
MS (ESIpos): m / z = 556 (M + H) ⁺

Example 38A

[1- (2-tert-butoxy-2-oxoethoxy) -8- (3-methyl-1,2,4-oxadiazol-5-yl) -11-oxodibenzo [b, f] [1,4] oxazepine -10 (11H) -yl] acetic acid tert-butyl ester

1.52 g (2.74 mmol) of a mixture of [8 - [({[(1E) -1-aminoethylidenes] amino} oxy) carbonyl] -1- (2-tert-butoxy-2-oxoethoxy) -11-oxodibenzo [ b, f] [1,4] oxazepine-10 (11H) -yl] -acetic acid tert -butyl ester and [8 - [({[(1E) -1-aminoethylidenedamino} oxy) carbonyl] -1- (2-tert-butoxy-2-oxoethoxy) -11-oxodibenzo [b, f] [1,4] oxazepine-10 (11H) -yl] -acetic acid ethyl ester is added together with 0.7 g of molecular sieve 3Å in 20 ml of xylene overnight Reflux stirred. For workup, the mixture is concentrated and purified by RP-HPLC. 369 mg (25% of theory) of product are obtained.
HPLC (Method 6): R _t = 5.23 min
MS (ESIpos): m / z = 538 (M + H) ⁺

Example 39A

[8- [acetyl (methyl) amino] -1- (2-tert-butoxy-2-oxoethoxy) -11-oxodibenzo [b, f] [1,4] oxazepine-10 (11H) -yl] acetic acid, ethyl tert-butyl

Dissolve 347 mg (1.16 mmol) of N- (1-hydroxy-11-oxo-10,11-dihydrodibenzo [b, f] [1,4] oxazepine-8-yl) -N-methylacetamide in 6 ml of anhydrous DMF and added with 482 mg (3.49 mmol) of anhydrous potassium carbonate. 567 mg (2.91 mmol) of bromoacetic acid tert-butyl ester are then added at RT and the mixture is stirred at RT overnight. For working up, it is diluted with ethyl acetate, washed twice with water and once with saturated sodium chloride solution. The organic phase is dried over magnesium sulfate, filtered and the solvent evaporated. This is followed by a column chromatographic purification (silica gel: cyclohexane / ethyl acetate 2: 1 to 1: 1). This gives 547 mg (89% of theory) of product.
HPLC (Method 1): R _t = 4.71 min
MS (ESIpos): m / z = 527 (M + H) ⁺

General working instructions [A]: Suzuki reaction of (8-bromo-1- (2-tert-butoxy-2-oxoethoxy) -11-oxo-5,11-dihydro-10H-dibenzo [b, e] [1,4 ] diazepin-10-yl] acetic acid tert-butyl ester with heterocyclic boronic acids

According to a specification of JP Wolfe, RA Singer, BH Yang, SL Buchwald, J. Am. Chem. Soc. 1999, 121, 9550-9561 are in a flask under argon 0.01 equivalents of palladium (II) acetate, 0.02 equivalents of 2- (di-cyclohexylphosphino) biphenyl, 1.5 equivalents of the corresponding boronic acid and 2 equivalents submitted lente potassium phosphate and mixed with toluene (0.1-0.2 molar solution). With stirring and in a gentle argon countercurrent, 1 equivalent of [8-bromo-1- (2-tert-butoxy-2-oxoethoxy) -11-oxo-5,11-dihydro-10H-dibenzo [b, e] - [1 , 4] diazepin-10-yl] -acetic acid tert-butyl ester added. Then allowed to stir with stirring for 5 hours at 100 ° C and 24 hours at 80 ° C. Then ethyl acetate is added to the reaction mixture and the organic phase is washed successively with 1N sodium hydroxide solution and saturated sodium chloride solution, then dried over magnesium sulfate, filtered and concentrated. The purification is carried out by means of RP-HPLC.

Example 40A

[1- (2-tert-butoxy-2-oxoethoxy) -11-oxo-8- (3-thienyl) dibenzo [b, f] [1,4] oxazepine-10 (11H) -yl] -acetic acid tert-butyl

According to the general procedure [A] starting from 150 mg (0.28 mmol) of [8-bromo-1- (2-tert-butoxy-2-oxoethoxy) -11-oxo-5,11-dihydro-10H-dibenzo [b, e] [1,4] diazepin-10-yl] -acetic acid tert -butyl ester, 53.9 mg (0.42 mmol) of 3-thiophenylboronic acid, 119.2 mg (0.56 mmol) of potassium phosphate, 0.63 mg (0.003 mmol) of palladium ( II) acetate and 1.97 mg (0.01 mmol) of 2- (di-cyclohexylphosphino) biphenyl in 2 ml of toluene 61.4 mg (41% of theory) of product.
HPLC (Method 1): R _t = 5.45 min
MS (DCI): m / z = 538 (M + H) ⁺

Example 41A

[1- (2-tert-butoxy-2-oxoethoxy) -8- (3-furyl) -11-oxo-dibenzo (b, f] [1,4] oxazepine-10 (11H) -yl] -acetic acid tert .-butyl ester

According to the general procedure [A] starting from 150 mg (0.28 mmol) of [8-bromo-1- (2-tert-butoxy-2-oxoethoxy) -11-oxo-5,11-dihydro-10H-dibenzo [b, e] [1,4] diazepin-10-yl] -acetic acid tert -butyl ester, 47.1 mg (0.42 mmol) 3-furanylboronic acid, 119.2 mg (0.56 mmol) potassium phosphate, 3.15 mg (0.01 mmol) palladium ( II) acetate and 9.84 mg (0.03 mmol) of 2- (di-cyclohexylphosphino) biphenyl in 2 ml of toluene 69 mg (45% of theory) of product.
HPLC (Method 6): R _t = 5.32 min
MS (DCI): m / z = 522 (M + H) ⁺

Example 42A

[1- (2-tert-butoxy-2-oxoethoxy) -8- (2-furyl) -11-oxo-dibenzo [b, f] [1,4] oxazepine-10 (11H) -yl] -acetic acid tert .-butyl ester

According to the general procedure [A] starting from 150 mg (0.28 mmol) of [8-bromo-1- (2-tert-butoxy-2-oxoethoxy) -11-oxo-5,11-dihydro-10H-dibenzo [b, e] [1,4] diazepin-10-yl] -acetic acid tert-butyl ester, 47.1 mg (0.42 mmol) 2-furanylboronic acid, 119.2 mg (0.56 mmol) potassium phosphate, 0.63 mg (0.003 mmol) palladium ( II) acetate and 1.97 mg (0.01 mmol) of 2- (di-cyclohexylphosphino) biphenyl in 2 ml of toluene 33.5 mg (23% of theory) of product.
HPLC (Method 1): R _t = 5.17 min
MS (DCI): m / z = 522 (M + H) ⁺

Example 43A

[1- (2-tert-butoxy-2-oxoethoxy) -8- (3,5-dimethyl-4-isoxazolyl) -11-oxodibenzo [b, f] [1,4] oxazepine-10 (11H) - yl] acetic acid tert-butyl ester

According to the general procedure [A] starting from 150 mg (0.28 mmol) of [8-bromo-1- (2-tert-butoxy-2-oxoethoxy) -11-oxo-5,11-dihydro-10H-dibenzo [b, e] [1,4] diazepin-10-yl] -acetic acid tert -butyl ester, 59.3 mg (0.42 mmol) of 2,5-dimethylisoxazolylboronic acid, 119.2 mg (0.56 mmol) of potassium phosphate, 0.63 mg (0.003 mmol) of palladium ( II) acetate and 1.97 mg (0.01 mmol) of 2- (di-cyclohexylphosphino) biphenyl in 2 ml of toluene 34.8 mg (23% of theory) of product.
HPLC (method 1): R _t = 5.39 min
MS (ESIpos): m / z = 551 (M + H) ⁺

Example 44A

[1- (2-tert-butoxy-2-oxoethoxy) -8 - [(dimethylamino) sulfonyl] -11-oxodibenzo [b, f] [1,4] oxazepine-10 (11H) -yl] acetic acid tert .-butyl ester

500 mg (1.50 mmol) of 1-hydroxy-N, N-dimethyl-11-oxo-10,11-dihydrodibenzo [b, f] [1,4] oxazepine-8-sulfonamide are dissolved in 6 ml of DMF at RT and washed with 1.16 g (5.98 mmol) of tert-butyl bromoacetate and 413 mg (2.99 mmol) of potassium carbonate are added. The mixture is stirred at RT for 10 min and then at 70 ° C. overnight. For workup, the reaction mixture is diluted with plenty of water and extracted three times with ethyl acetate. The organic phase is washed with sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The residue is chromatographed on a Biotage MPLC (eluent: methylene chloride / ethyl acetate 20: 1-10: 1). 430 mg (51% of theory) of the product are obtained.
LC-MS (Method 3): R _t = 4.40 min
MS (ESIpos): m / z = 563 (M + H) ⁺

Example 45A

[1- (2-tert-butoxy-2-oxoethoxy) -8- (methylsulfonyl) -11-oxodibenzo [b, f] [1,4] oxazepine-10 (11H) -yl] acetic acid tert butyl ester

1355 mg (4.44 mmol) of 1-hydroxy-8- (methylsulfonyl) dibenzo [b, f] [1,4] oxazepine-11 (10H) -one are dissolved in 20 ml of DMF at RT and extracted with 1.90 g (9.76 mmol) Bromoacetic acid tert-butyl ester and 1227 mg (8.88 mmol) of potassium carbonate. The mixture is stirred at RT for 10 min and then at 50 ° C. overnight. For workup, the reaction mixture is diluted with plenty of water and extracted three times with ethyl acetate. The organic phase is washed with sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. 2400 mg (99% of theory) of the product are obtained.
LC-MS (Method 2): R _t = 3.70 min
MS (ESIpos): m / z = 534 (M + H) ⁺

Example 46A

[1- (2-tert-butoxy-2-oxoethoxy) -8- (morpholin-4-ylsulfonyl) -11-oxodibenzo [b, f] [1,4] oxazepine-10 (11H) -yl] acetic acid, ethyl tert-butyl

495 mg (1.32 mmol) of 1-hydroxy-8- (morpholin-4-ylsulfonyl) dibenzo [b, f] [1,4] oxazepine-11 (10H) -one are dissolved in 7 ml of DMF at RT and treated with 564 mg (2.89 mmol) tert-butyl bromoacetate and 364 mg (2.63 mmol) of potassium carbonate. The mixture is stirred at RT for 10 min and then at 50 ° C. overnight. For workup, the reaction mixture is diluted with plenty of water and extracted three times with ethyl acetate. The organic phase is washed with sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The residue is slurried in ethyl acetate, filtered off with suction and the filter residue is dried in vacuo. 349 mg (43% of theory) of the product are obtained.
LC-MS (Method 2): R _t = 3.88 min
MS (ESIpos): m / z = 605 (M + H) ⁺

Example 47A

[1- (2-tert-butoxy-2-oxoethoxy) -8 - [(ethylamino) sulfonyl] -11-oxodibenzo [b, f] [1,4] oxazepine-10 (11H) -yl] acetic acid tert .-butyl ester

500 mg (1.50 mmol) of N-ethyl-1-hydroxy-11-oxo-10,11-dihydrodibenzo [b, f] [1,4] oxazepine-8-sulfonamide are dissolved in 10 ml of absolute DMF at RT and washed with 0.55 ml (3.74 mmol) of tert-butyl bromoacetate and 413 mg (2.99 mmol) of potassium carbonate. The mixture is stirred at RT for 10 min and then at 50 ° C. overnight. For workup, the reaction mixture is diluted with plenty of water and extracted with 150 ml of ethyl acetate. The organic phase is dried over magnesium sulfate and concentrated in vacuo. The residue is chromatographed on silica gel (mobile phase: methylene chloride / ethyl acetate 3: 1). 256 mg (25% of theory) of the product are obtained.
LC-MS (Method 3): R _t = 3.27 min
MS (ESIpos): m / z = 563 (M + H) ⁺

Example 48A

4 - [(2,2-dimethyl-4-oxo-4H-1,3-benzodioxin-5-yl) oxy] -3-nitrobenzonitrile

3.0 g (16.43 mmol) of 4-chloro-3-nitrobenzonitrile and 3.2 g (16.43 mmol) of 5-hydroxy-2,2-dimethyl-4H-1,3-benzodioxin-4-one are dissolved in 25 ml of DMF, with 2.498 g (18.08 mmol) of potassium carbonate and stirred overnight at 70 ° C. For workup, the batch is poured into 250 ml of water and extracted three times with ethyl acetate. The organic phase is dried over sodium sulfate and concentrated. This gives 4.89 g (78% of theory) of product which is not further purified.
LC-MS (Method 3): R _t = 3.60 min
MS (ESIpos): m / z = 341 (M + H) ⁺

Example 49A

3-Amino-4 - [(2,2-dimethyl-4-oxo-4H-1,3-benzodioxin-5-yl) oxy] benzonitrile

4.87 g (14.31 mmol) of 4 - [(2,2-dimethyl-4-oxo-4H-1,3-benzodioxin-5-yl) oxy] -3-nitrobenzonitrile are dissolved in a mixture of 60 ml of acetic acid and 3 ml of water dissolved and mixed with 5.595 g (100.18 mmol) of iron powder. The suspension is stirred at RT for 1 hour and at 50 ° C. for 3 hours. After cooling, it is diluted with 300 ml of acetone, filtered off with suction through Celite and washed with plenty of acetone. The filtrate is concentrated and suspended in methylene chloride / ethyl acetate 5: 1. The precipitate is filtered off with suction and after drying gives 1.46 g (32% of theory) of the product, which is not further purified.
LC-MS (Method 5): R _t = 3.50 min
MS (ESIpos): m / z = 311 (M + H) +

Example 50A

1-hydroxy-11-oxo-10,11-dihydrodibenzo [b, f] [1,4] oxazepine-8-carbonitrile

2.9 g (7.29 mmol) of 78% pure 3-amino-4 - [(2,2-dimethyl-4-oxo-4H-1,3-benzodioxin-5-yl) oxy] benzonitrile are dissolved in 50.0 ml of xylene at RT and 0.139 g (0.73 mmol) of 4-toluene sulfonic acid monohydrate. The suspension is stirred overnight at 140.degree. After cooling the reaction solution, the precipitate is filtered off with suction and washed with cyclohexane. The precipitate is slurried several times with methanol and filtered with suction and then dried under high vacuum. This gives 2.33 g (95% of theory) of the product, which is not further purified.
LC-MS (method 5): R _t = 3.40 min
MS (ESIpos): m / z = 253 (M + H) ⁺

Example 51A

tert-butyl [1- (2-tert-butoxy-2-oxoethoxy) -8-cyano-11-oxodibenzo [b, f] [1,4] oxazepine-10 (11H) -yl] acetate

1.70 g (6.74 mmol) of 1-hydroxy-11-oxo-10,11-dihydrodibenzo [b, f] [1,4] oxazepine-8-carbonitrile are dissolved in 20 ml of DMF at RT and extracted with 5.45 ml (26.96 mmol) Bromoacetic acid tert-butyl ester and 2.794 g (20.22 mmol) of potassium carbonate. It will take 10 min. at RT, stirred for 1 hour at 50 ° C and 5 hours at 70 ° C. For workup, the mixture is diluted with plenty of water and extracted three times with ethyl acetate. The organic phase is washed with sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. 3.76 g (quant.) Of the product are obtained.
LC-MS (Method 2): R _t = 3.95 min
MS (ESIpos): m / z = 481 (M + H) ⁺

EXAMPLES

example 1

{[10- (2-tert-butoxy-2-oxoethyl) -8- (5-methy1-1,2,4-oxadiazol-3-yl) -11-oxo-10,11-dihydrodibenzo [b, f ] [1,4] oxazepine-1-yl] oxy} acetic acid

172 mg (0.32 mmol) of [1- (2-tert-butoxy-2-oxoethoxy) -8- (5-methyl-1,2,4-oxadiazol-3-yl) -11-oxodibenzo [b, f] [1,4] -oxazepine-10 (11H) -yl] -acetic acid tert-butyl ester are dissolved in 6.5 ml of anhydrous chloroform and treated with 35 mg (0.32 mmol) of chlorotrimethylsilane and 48 mg (0.32 mmol) of sodium iodide and 10 hours under Reflux stirred. The reaction mixture is diluted with methylene chloride and washed with 1N hydrochloric acid. The organic phase is then dried over magnesium sulfate, filtered and concentrated. The purification is carried out by means of RP-HPLC. 67 mg (43% of theory) of product are obtained.
HPLC (Method 6): R _t = 4.58 min
MS (ESIpos): m / z = 482 (M + H) ^+
1 H-NMR (400MHz, CDCl _3): δ = 1:39 (s, 9 H), 2.66 (s, 3 H), 4.70-4.72 (m 4 H), 6.85 (d, 1 H), 7:03 ( d, 1H), 7.46 (t, 1H), 7.56 (d, 1H), 7.84 (dd, 1H), 8.00 (d, 1H), 13.03 (s _br , 1H).

Example 2

{[10- (2-tert-butoxy-2-oxoethyl) -8- (5-cyclopropyl-1,2,4-oxadiazol-3-yl) -11-oxo-10,11-dihydrodibenzo [b, f ] [1,4] oxazepine-1-yl] oxy} acetic acid

140 mg (0.25 mmol) of [1- (2-tert-butoxy-2-oxoethoxy) -8- (5-cyclopropyl-1,2,4-oxadiazol-3-yl) -11-oxodibenzo [b, f ] [1,4] oxazepine-10 (11H) -yl] -acetic acid tert-butyl ester are dissolved in 5 ml of anhydrous chloroform and treated with 27 mg (0.25 mmol) of chlorotrimethylsilane and 37 mg (0.25 mmol) of sodium iodide and overnight Reflux stirred. The reaction mixture is diluted with methylene chloride and washed with 1N hydrochloric acid. The organic phase is then dried over magnesium sulfate, filtered and concentrated. The purification is carried out by means of RP-HPLC. 70 mg (54% of theory) of product are obtained.
HPLC (Method 6): R _t = 4.86 min
MS (ESIpos): m / z = 508 (M + H) ^+
1 H-NMR (200 MHz, CDCl _3): δ = 1.27 (m, 4 H), 1:52 (s, 9 H), 2.23 (m, 1 H), 4:47 (d, 1 H), 4.81 (s, 2 H), 4.85 (d, 1H), 6.86 (dd, 1H), 7.00 (dd, 1H), 7.35 (dd, 1H), 7.46 (t, 1H), 7.87-7.93 (m, 2 H), 12.85 (s _br , 1 H).

Example 3

{[10- (2-tert-butoxy-2-oxoethyl) -8- (3-methyl-1,2,4-oxadiazol-5-yl) -11-oxo-10,11-dihydrodibenzo [b, f ] [1,4] oxazepine-1-yl] oxy} acetic acid

200 mg (0.37 mmol) of [1- (2-tert-butoxy-2-oxoethoxy) -8- (3-methyl-1,2,4-oxadiazol-5-yl) -11-oxodibenzo [b, f] [1,4] -oxazepine-10 (11H) -yl] -acetic acid tert-butyl ester are dissolved in 5 ml of anhydrous chloroform, treated with 40.4 mg (0.37 mmol) of chlorotrimethylsilane and 55.8 mg (0.37 mmol) of sodium iodide and 8 hours at Stirred 60 ° C. It is then diluted with methylene chloride and washed once with 1N hydrochloric acid. The organic phase is dried over magnesium sulfate, filtered and concentrated. Purification by RP-HPLC. There are obtained 102 mg (57% of theory) of product.
HPLC (Method 6): R _t = 4.53 min
MS (ESIpos): m / z = 482 (M + H) ^+
1 H-NMR (200 MHz, CDCl _3): δ = 1:53 (s, 9 H) 2.46 (s, 3 H), 4:47 (d, 1 H), 4.81 (s, 2 H), 4.85 (d, 1H), 6.88 (dd, 1H), 7.02 (dd, 1H), 7.40-7.53 (m, 2H), 7.95-8.00 (m, 2H).

Example 4

{[8- [acetyl (methyl) amino] -10- (2-tert-butoxy-2-oxoethyl) -11-oxo-10,11-dihydrodibenzo [b, f] [1,4] oxazepine-1- yl] oxy} acetic acid

200 mg (0.38 mmol) of [8- [acetyl (methyl) amino] -1- (2-tert-butoxy-2-oxoethoxy) -11-oxodibenzo [b, f] [1,4] oxazepine-10 (11H ) -yl] -acetic acid tert-butyl ester are dissolved in 6.5 ml of anhydrous chloroform, treated with 41.3 mg (0.38 mmol) of chlorotrimethylsilane and 56.9 mg (0.38 mmol) of sodium iodide and stirred at 60 ° C for 3 hours. It is then diluted with methylene chloride and washed once with 1N hydrochloric acid. The organic phase is dried over magnesium sulfate, filtered and concentrated. Purification by RP-HPLC. 109 mg (61% of theory) of product are obtained.
HPLC (Method 1): R _t = 4.08 min
MS (ESIpos): m / z = 471 (M + H) ^+
1 H-NMR) 200 MHz, CDCl _3): δ = 1:51 (s, 9 H), 1.88 (s, 3 H), 3.23 (s, 3 H), 4:34 (d, 1 H), 4.78 (d, 1H), 4.80 (s, 2H), 6.86 (d, 1H), 6.98-7.04 (m, 3H), 7.30 (d, 1H), 7.48 (t, 1H), 12.55 (s _br , 1 H).

Example 5

{[10- (2-tert-butoxy-2-oxoethyl) -11-oxo-8- (3-thienyl) -10,11-dihydrodibenzo [b, f] [1,4] oxazepine-l-yl] oxy} acetic acid

41.1 mg (0.08 mmol) of [1- (2-tert-butoxy-2-oxoethoxy) -11-oxo-8- (3-thienyl) dibenzo [b, f] [1,4] oxazepine-10 (1H) -yl] -acetic acid tert-butyl ester are dissolved in 5 ml of anhydrous chloroform and treated with 0.83 mg (0.01 mmol) of chlorotrimethylsilane and 1.15 mg (0.01 mmol) of sodium iodide and stirred overnight at 60 ° C. The reaction mixture is diluted with methylene chloride and washed with 1N hydrochloric acid. The organic phase is then dried over magnesium sulfate, filtered and concentrated. The purification is carried out by means of RP-HPLC. 9.8 mg (27% of theory) of product are obtained.
HPLC (Method 1): R _t = 4.80 min
MS (ESI): m / z = 480 (MH) ^+
1 H-NMR (200 MHz, DMSO-d ₆ ): δ = 1.36 (s, 9H), 4.63-4.86 (m, 4H), 6.80 (d, 1H), 6.98 (d, 1H), 7.36-7.47 (m, 2H), 7.52-7.55 (m, 2H), 7.64 (dd, 1H), 7.74 (d, 1H), 7.87 (dd, 1H).

Example 6

{[10- (2-tert-butoxy-2-oxoethyl) -8- (3-furyl) -11-oxo-10,11-dihydrodibenzo [b, f] [1,4] oxazepine-1-yl] oxy} acetic acid

40 mg (0.08 mmol) of [1- (2-tert-butoxy-2-oxoethoxy) -8- (3-furyl) -11-oxodibenzo [b, f] [1,4] oxazepine-10 (11H) - yl] tert-butyl acetate are dissolved in 3 ml of anhydrous chloroform and admixed with 2.5 mg (0.02 mmol) of chlorotrimethylsilane and 3.45 mg (0.02 mmol) of sodium iodide and stirred at reflux overnight. The reaction mixture is diluted with methylene chloride and washed with 1N hydrochloric acid. The organic phase is then dried over magnesium sulfate, filtered and concentrated. The purification is carried out by means of RP-HPLC. 16.8 mg (47% of theory) of product are obtained.
HPLC (Method 6): R _t = 4.84 min
MS (ESIpos): m / z = 466 (M + H) ^+
1 H-NMR (200 MHz, DMSO-d ₆ ): δ = 1.36 (s, 9H), 4.60-4.85 (m, 4H), 6.78 (d, 1H), 6.94-6.97 (m, 2H ), 7.33-7.47 (m, 3H), 7.65 (d, 1H), 7.74 (m, 1H), 8.17 (m, 1H).

Example 7

{[10- (2-tert-butoxy-2-oxoethyl) -8- (2-furyl) -11-oxo-10,11-dihydrodibenzo [b, f] [1,4] oxazepine-1-yl] oxy} acetic acid

33.4 mg (0.06 mmol) of [1- (2-tert-butoxy-2-oxoethoxy) -8- (2-furyl) -11-oxodibenzo [b, f) [1,4] oxazepine-10 (11H) - yl) tert-butyl acetate are dissolved in 5 ml of anhydrous chloroform and treated with 0.7 mg (0.01 mmol) of chlorotrimethylsilane and 0.96 mg (0.01 mmol) of sodium iodide and stirred overnight under reflux. Because of incompleteness of the reaction, 0.026 mmol of chlorotrimethylsilane and sodium iodide are then added again and stirred under reflux for a further 3 hours. The reaction mixture is then diluted with methylene chloride and washed with 1N hydrochloric acid. The organic phase is then dried over magnesium sulfate, filtered and concentrated. The purification is carried out by means of RP-HPLC. 22.9 mg (77% of theory) of product are obtained.
HPLC (Method 6): R _t = 4.87 min
MS (ESIpos): m / z = 466 (M + H) ^+
1 H-NMR (200 MHz, DMSO-d ₆ ): δ = 1.38 (s, 9H), 4.62-4.81 (m, 4H), 6.60 (m, 1H), 6.82 (d, 1H), 6.95-7.03 (m, 3H), 7.39-7.56 (m, 3H), 7.72-7.76 (m, 2H).

Example 8

{[10- (2-tert-butoxy-2-oxoethyl) -8- (3,5-dimethyl-4-isoxazolyl) -11-oxo-10,11-dihydrodibenzo [b, f] [1,4] oxazepin-1-yl] oxy} acetic acid

34.8 mg (0.06 mmol) of [1- (2-tert-butoxy-2-oxoethoxy) -8- (3,5-dimethyl-4-isoxazolyl) -11-oxodibenzo [b, f] [1,4] oxazepine Tert-Butyl (10H) -yl] -acetate are dissolved in 5 ml of anhydrous chloroform and treated with 0.7 mg (0.01 mmol) of chlorotrimethylsilane and 0.96 mg (0.01 mmol) of sodium iodide and stirred at reflux overnight. Owing to incompleteness of the reaction, in each case 0.025 mmol of chlorotrimethylsilane and sodium iodide are again added and the mixture is stirred under reflux for a further 3 hours. The reaction mixture is then diluted with methylene chloride and washed with 1N hydrochloric acid. The organic phase is then dried over magnesium sulfate, filtered and concentrated. The purification is carried out by means of RP-HPLC. 22.9 mg (73% of theory) of product are obtained.
HPLC (Method 6): R _t = 4.62 min
MS (DCI): m / z = 495 (M + H) ^+
1 H-NMR (200 MHz, DMSO-d ₆ ): δ = 1.34 (s, 9H), 2.21 (s, 3H), 2.39 (s, 3H), 4.58-4.89 (m, 4H), 6.82 (d, 1H), 7.01 (d, 1H), 7.24 (dd, 1H), 7.41-7.48 (m, 3H), 4.58-4.89 (m, 4H), 13.09 (s _br , 1 H).

Example 9

{[10- (2-tert-butoxy-2-oxoethyl) -11-oxo-8- (1H-tetrazol-5-yl) -10,11-dihydrodibenzo [b, f] [1,4] oxazepin 1-yl] oxy} acetic acid

200 mg (0.42 mmol) of 1- (2-tert-butoxy-2-oxoethoxy) -8-cyano-11-oxodibenzo [b, f] [1,4] oxazepine-10 (11H) -yl] acetic acid tert-butyl ester are dissolved in 3 ml of anhydrous toluene, and 96 mg (0.83 mmol) of trimethylsilyl azide and 10 mg (0.04 mmol) of di-n-butyltin oxide are added and the mixture is stirred overnight at 95 ° C. The reaction mixture is diluted twice with methanol and The residue is diluted with sodium bicarbonate solution and extracted with ethyl acetate, the organic phase is washed with sodium chloride solution, then dried over sodium sulfate, filtered and concentrated, purified by RP-HPLC, 15 mg (8% of theory) are added. Th.) Product.
HPLC (Method 3): R _t = 3.90 min
MS (ESIpos): m / z = 468 (M + H) ^+
1 H-NMR (400 MHz, DMSO-d ₆ ): δ = 1.39 (s, 9H), 4.62-4.78 (m, 4H), 6.84 (dd, 1H), 7.02 (d, 1H), 7:46 (t, 1 H), 7:59 (dd, 2 H), 7.85 (d, 1H), 8:06 (s, 1 H), 12.96 (s _br, 1 H), 16.90 _(br s, 1 H).

Example 10

({10- (2-tert-butoxy-2-oxoethyl) -8 - [(dimethylamino) sulfonyl] -11-oxo-10,11-dihydrodibenzo (b, f] [1,4] oxazepine-1-yl } oxy) acetic acid

400 mg (0.71 mmol) of [1- (2-tert-butoxy-2-oxoethoxy) -8 - [(dimethylamino) sulfonyl] -11-oxodibenzo [b, f] [1,4] oxazepine-10 (11H ) -yl] -acetic acid tert-butyl ester are dissolved in 8 ml of anhydrous chloroform, treated with 77 mg (0.71 mmol) of chlorotrimethylsilane and 107 mg (0.71 mmol) of sodium iodide and stirred overnight at 60 ° C. It is then diluted with methylene chloride and washed once with 1N hydrochloric acid. The organic phase is dried over sodium sulfate, filtered and concentrated. Purification by RP-HPLC. There are obtained 286 mg (72% of theory) of product.
HPLC (Method 2): R _t = 3.40 min
MS (ESIpos): m / z = 507 (M + H) ^+
1 H-NMR (300 MHz, DMSO-d ₆ ): δ = 1.36 (s, 9H), 2.63 (s, 6H), 3.23 (s, 3H), 4.69-4.78 (m, 4H), 6.83 (d, 1H), 7.03 (d, 1H), 7.47 (t, 1H), 7.54-7.63 (m, 2H), 7.77 (d, 1H), 13.00 (s _br , 1H) ,

Example 11

{[10- (2-tert-butoxy-2-oxoethyl) -8- (methylsulfonyl) -11-oxo-10,11-dihydrodibenzo [b, f] [1,4] oxazepine-1-yl] oxy} acetic acid

150 mg (0.28 mmol) of [1- (2-tert-butoxy-2-oxoethoxy) -8- (methylsulfonyl) -11-oxodibenzo [b, f] [1,4] oxazepine-10 (11H) -yl] Acetic acid tert-butyl ester are dissolved in 3 ml of anhydrous chloroform and treated with 31 mg (0.28 mmol) of chlorotrimethylsilane and 42 mg (0.28 mmol) of sodium iodide and stirred overnight at 60 ° C. The reaction mixture is diluted with methylene chloride and washed with 1N hydrochloric acid. The organic phase is then dried over sodium sulfate, filtered and concentrated. The purification is carried out by means of RP-HPLC. There are obtained 35 mg (24% of theory) of product.
HPLC (Method 2): R _t = 3.29 min
MS (ESI): m / z = 478 (MH) +
¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 1.37 (s, 9H), 3.32 (s, 3H), 4.19 (s, 2H), 4.59-4.92 (m, 2H), 6.69 ( d, 1H), 6.89 (d, 1H), 7.37 (t, 1H), 7.62 (d, 1H), 7.75 (dd, 1H), 7.96 (dd, 1H).

Example 12

{[10- (2-tert-butoxy-2-oxoethyl) -8- (morpholin-4-ylsulfonyl) -11-oxo-10,11-dihydrodibenzo [b, f] [1,4] oxazepine-1- yl] oxy} acetic acid

150 mg (0.25 mmol) of [1- (2-tert-butoxy-2-oxoethoxy) -8- (morpholin-4-ylsulfonyl) -11-oxodibenzo [b, f] [1,4] oxazepine-10 (11H ) -yl] -acetic acid tert-butyl ester are dissolved in 3 ml of anhydrous chloroform and treated with 27 mg (0.25 mmol) of chlorotrimethylsilane and 37 mg (0.25 mmol) of sodium iodide and stirred overnight under reflux. The reaction mixture is diluted with methylene chloride and washed with 1N hydrochloric acid. The organic phase is then dried over sodium sulfate, filtered and concentrated. The purification is carried out by means of RP-HPLC. 67 mg (46% of theory) of product are obtained.
HPLC (Method 2): R _t = 3.39 min
MS (ESIpos): m / z = 549 (M + H) ^+
1 H-NMR (300 MHz, DMSO-d ₆ ): δ = 1.36 (s, 9H), 2.90 (bd, 4H), 3.63 (t, 4H), 4.50-4.87 (m, 4H), 6.83 (i.e. , 1H), 7.00 (d, 1H), 7.45 (t, 1H), 7.59 (dd, 1H), 7.65 (d, 1H), 7.77 (m, 1H).

Example 13

({10- (2-tert-butoxy-2-oxoethyl) -8 - [(ethylamino) sulfonyl] -11-oxo-10,11-dihydrodibenzo [b, f] [1,4] oxazepine-1- yl} oxy) acetic acid

250 mg (0.44 mmol) of [1- (2-tert-butoxy-2-oxoethoxy) -8 - [(ethylamino) sulfonyl] -11-oxodibenzo [b, f] [1,4] oxazepine-10 (11H) -yl] -acetic acid tert-butyl ester are dissolved in 12 ml of anhydrous chloroform and treated with 72.4 mg (0.67 mmol) of chlorotrimethylsilane and 33.3 mg (0.22 mmol) of sodium iodide and stirred at 60 ° C for 4 hours. After cooling, the reaction mixture is diluted with methylene chloride and washed with 1N hydrochloric acid. The organic phase is dried over magnesium sulfate, filtered and concentrated. The purification is carried out by means of RP-HPLC. 116 mg (52% of theory) of product are obtained.
LC-MS (Method 5): R _t = 2.73 min
MS (ESIpos): m / z = 507 (M + H) ^+
1 H-NMR (400 MHz, DMSO-d ₆ ): δ = 0.96 (t, 3H), 1.37 (s, 9H), 2.77 (q, 2H), 4.65-4.75 (m, 4H), 6.85 (d, 1H), 7.02 (d, 1H), 7.46 (t, 1H), 7.52-7.64 (m, 3H), 7.81 (d, 1H), 13.03 (s _br , 1H).

B) Assessment of physiological effectiveness

The Suitability of the compounds of the invention for the treatment of cardiovascular disease can be in the following Assay systems are shown:

Isolation of the soluble Form of aminopeptidase N from human plasma

human Blood plasma (Sigma, St. Louis, USA) is fractionated by ammonium sulfate precipitation. More than 80% of the total aminopeptidase N activity is in fraction 50-70 % Saturation found. After centrifugation at 10,000g, the pellet becomes buffer T (20 mM Tris-HCl, pH 7.5, 2 mM magnesium sulfate, 0.1 M ethylenediaminetetraacetate and 200 mM Natitumchlorid) resuspended. The resulting protein solution becomes centrifuged again at 10,000 g and assayed on a Sephadex G-25 (Pharmacia Biotech, Uppsala, Sweden). The column is equilibrated with buffer T.

The desalted fraction is loaded onto an affinity chromatography column. This is achieved by coupling monoclonal anti-CD13 mouse antibody (Acris SM1070P, Bad Nauheim, Germany) on an N-hydroxysuccinimide-activated HiTrap column (Pharmacia Biotech, Uppsala, Sweden). The pillar will equilibrated with buffer T.

To the sample application becomes the column with the 5-fold columns Volume buffer T washed. Bound aminopeptidase N is used with Elution buffer (100 mM glycine and 0.5 M sodium chloride, pH 2.5) eluted. The eluate is neutralized with Tris-HCl pH 9.0, aliquoted and in liquid Nitrogen frozen.

In vitro assay the aminopeptidase N

Ala-7-amido-4-methylcoumarin (Bachem, Heidelberg, Germany) is called fluorogenic substrate for the Aminopeptidase N selected.

The enzymatic activity is in a buffer of 20mM MOPS pH 7.0, 100mM sodium chloride, 5mM Calcium chloride, 0.1% BSA, 25μM Substrate and 1-5 ng / ml aminopeptidase N measured. The reaction will 1-3 h at a temperature of 37 ° C in 384 or 1536 microtiter plate format incubated. Fluorescence is fluorescence in the reader Spectra Fluor (Tecan, Crailsheim, Germany).

Table A shows selected compounds with IC ₅₀ values.

Table A:

migration assay

Human coronary arterial vascular smooth muscle cells (hCAVSMC, 1.5 × 10 ⁵ cells / well) (TEBU, Offenbach, Germany) are seeded in a 6-well plate and incubated for 48 h in M 231 medium (growth medium) (TEBU, Offenbach, Germany) at 37 ° C / 5% carbon dioxide. The plates are previously coated with vitronectin (50 ng / cm ² ) (Gibco / Invitrogen, Karlsruhe, Germany). After the incubation period, one half of the confluent cell monolayer is removed. In the cell-free area of the well about 50% of the vitronectin coating is retained.

The Growth medium is determined by the test medium MCDB-131 / 0.2% BSA (molecular cellular developmental biology (MCDB); Basal medium (BSA)) (Gibco / Invitrogen, Karlsruhe, Germany) and the cells are replaced with 0.1 U Aminopeptidase N (pig or human) (Sigma, Taufkirchen, Germany) stimulated.

The Test substances are then added in the concentrations indicated.

To 24- and 48-hour Incubation will microscopy the migration distance of the cells into the free corrugation area certainly.

Everyone Represents measuring point a mean of four different regions, at time 0 h selected were.

PDGF (platelet derived growth factor), a highly potent chemotactic Factor for smooth muscle cells, serves as a positive control (10nM) (R & D systems, Wiesbaden-Nordenstadt, Germany).

In vivo assay the aminopeptidase N

to Determination of the anti-atherosclerotic effect of aminopeptidase N inhibitors will become a widely accepted animal research model used as the ApoE knockout mouse (Reddick, R.L., et al., Arterioscler. Thromb. 1994, 14, 141-147). In the model is either in short-term studies (1-2 months) the anti-atherosclerotic effect of altered gene expression indirectly determined by relevant marker genes in atherosclerosis-susceptible tissue, or in long-term studies (3-6 months) the development of atherosclerotic plaques using histological techniques directly determined.

C) exemplary embodiments for pharmaceutical compositions

The substances according to the invention can as follows be converted into pharmaceutical preparations:

Tablet:

Composition:

100 mg of the compound of Example 1, 50 mg lactose (monohydrate), 50 mg cornstarch, 10 mg polyvinylpyrolidone (PVP 25) (BASF, Germany) and 2 mg of magnesium stearate.

tablet weight 212 mg. Diameter 8 mm, radius of curvature 12 mm.

production:

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

Oral suspension:

Composition:

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

one Single dose of 100 mg of the compound of the invention correspond 10 ml oral suspension.

production:

The Rhodigel is suspended in ethanol, the compound of the example 1 is added to the suspension. While stirring the addition of the water takes place. Until the completion of the swelling of the Rhodigels is stirred for about 6h.

Intravenously administrable Solution:

Composition:

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

production:

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

Claims (11)

Compound of the formula

where R ^{1 is} halogen, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, C ₁ -C ₆ -alkyl, hydroxycarbonyl, C ₁ -C ₆ -alkoxycarbonyl, aminocarbonyl or C ₁ -C ₆ -alkyl-aminocarbonyl, n is a number 0 , 1 or 2, wherein when n is 2, the radicals R ^{1 may be the} same or different, R ^{2 is} C ₁ -C ₆ alkyl, wherein alkyl may be substituted with 1 or 2 substituents, wherein the substituents are independently selected from the group consisting of halogen, hydroxy, oxo, C ₁ -C ₆ -alkoxy, hydroxycarbonyl, C ₁ -C ₆ -alkoxycarbonyl, aminocarbonyl and C ₁ -C ₆ -alkylaminocarbonyl, R ³ -O-CH ₂ CO ₂ H or -O- (CH ₂ ) ₂ CO ₂ H, R ^{4 is} halogen, trifluoromethyl, trifluoromethoxy, cyano, nitro, amino, C ₁ -C ₆ -alkyl-amino, hydroxy, C ₁ -C ₆ -alkyl, C ₁ - C ₆ -alkoxy, hydroxycarbonyl, C ₁ -C ₆ -alkoxycarbonyl, aminocarbonyl or C ₁ -C ₆ -alkylaminocarbonyl, m is a number 0, 1 or 2, where m is 2, the radicals R ^{4 are the} same or different which may be R ^{5 is} 5- to 10-membered heteroaryl, -SO ₂ -R ⁶ or NR ⁷ (C = O) R ⁸ where heteroaryl may be substituted with 1, 2 or 3 substituents wherein the substituents are independently selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, cyano, nitro, amino, C ₁ -C ₆ -alkylamino, hydroxy, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, hydroxycarbonyl, C ₁ -C ₆ -alkoxycarbonyl, aminocarbonyl, C ₁ -C ₆ -alkylaminocarbonyl, C ₆ -C ₁₀ -aryl and C ₃ -C ₈ -cycloalkyl, R ⁶ C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkylamino, C ₆ -C ₁₀ -aryl, 5- to 10-membered heteroaryl, C ₃ -C ₈ -cycloalkyl or 4- to 10-membered heterocyclyl, where aryl, heteroaryl, cycloalkyl and heterocyclyl may be substituted by 1, 2 or 3 Substituents, wherein the substituents are independently selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, cyano, nitro, amino, C ₁ -C ₆ -alkylamino, hydroxy, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, hydroxycarbonyl, C ₁ -C ₆ -alkoxycarbonyl, aminocarbonyl and C ₁ -C ₆ -alkylaminocarbonyl, R ^{7 is} hydrogen or C ₁ -C ₆ -alkyl, R ^{8 is} C ₁ -C ₆ -alkyl , C ₆ -C ₁₀ -aryl, 5- to 10-membered heteroaryl, C ₃ -C ₈ -cycloalkyl or 4- to 10-membered heterocyclyl, where aryl, heteroaryl, cycloalkyl and heterocyclyl may be substituted by 1, 2 or 3 substituents, wherein the substituents are independently selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, cyano, nitro, amino, C ₁ -C ₆ alkylamino, hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ Alkoxy, hydroxycarbonyl, C ₁ -C ₆ -alkoxycarbonyl, aminocarbonyl and C ₁ -C ₆ -alkylaminocarbonyl, or one of their salts, their solvates or the solvates of their salts. Connection according to claim 1, characterized in that R ^{1 is} halogen, trifluoromethyl, cyano, hydroxy, C ₁ -C ₄ -alkyl, hydroxycarbonyl, C ₁ -C ₄ -alkoxycarbonyl, aminocarbonyl or C ₁ -C ₆ -alkylaminocarbonyl, n is a number 0 or 1, R ² C C ₁ -C ₄ -alkyl, where alkyl may be substituted by a substituent, where the substituent is selected from the group consisting of hydroxy, C ₁ -C ₆ -alkoxy, hydroxycarbonyl and C ₁ -C ₆ -alkoxycarbonyl, R ³ - O-CH ₂ CO ₂ H or -O- (CH ₂ ) ₂ CO ₂ H, m is a number 0, R ^{5 is} thienyl, furyl, pyrrolyl, thiazolyl, isoxazolyl, oxadiazolyl, pyrazolyl, imidazolyl, tetrazolyl, pyridyl, pyrimidyl , Pyridazinyl, pyrazinyl, -SO ₂ -R ⁶ or NR ⁷ (C = O) R ⁸ , wherein thienyl, furyl, pyrrolyl, thiazolyl, isoxazolyl, oxadiazolyl, pyrazolyl, imidazolyl, tetrazolyl, pyridyl, pyrimidyl, pyridazinyl and pyrazinyl substituted may be with 1, 2 or 3 substituents, wherein the substituents are independently selected from the group consisting of halogen, T rifluoromethyl, amino, C ₁ -C ₆ -alkylamino, hydroxy, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, hydroxycarbonyl, C ₁ -C ₆ -alkoxycarbonyl, aminocarbonyl, C ₁ -C ₆ -alkylaminocarbonyl, Phenyl and C ₃ -C ₆ -cycloalkyl, R ^{6 is} C ₁ -C ₄ -alkyl, C ₁ -C ₆ -alkylamino, phenyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl, where phenyl, Cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl may be substituted by 1, 2 or 3 substituents, where the substituents are independently selected from the group consisting of halogen, trifluoromethyl, amino, C ₁ -C ₆ - Alkylamino, hydroxy, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, hydroxycarbonyl, C ₁ -C ₆ -alkoxycarbonyl, aminocarbonyl and C ₁ -C ₆ -alkylaminocarbonyl, R ^{7 represents} hydrogen, methyl or ethyl, R ^{8 is} C ₁ -C ₆ -alkyl. A compound according to claim 1 or 2, characterized in that n is a number 0, R ^{2 is} C ₁ -C ₄ -alkyl, wherein alkyl may be substituted with a substituent, wherein the substituent is selected from the group consisting of hydroxy, tert Butoxy, tert-butoxycarbonyl and 2,2-dimethylprop-1-oxycarbonyl, R ^{3 is} -O-CH ₂ CO ₂ H, where -O-CH ₂ CO ₂ H in the ortho position to the amide function of the dibenzoxazepine is attached ring, m is a number 0, R ⁵ represents thienyl, furyl, isoxazolyl, oxadiazolyl, pyrazolyl, tetrazolyl, -SO ₂ -R ⁶ or -NR ⁷ (C = O) R ^8, where thienyl, furyl, isoxazolyl, Oxadiazolyl, pyrazolyl and tetrazolyl may be substituted with 1 or 2 substituents wherein the substituents are independently selected from the group consisting of C ₁ -C ₄ alkyl and C ₃ -C ₆ cycloalkyl, R ^{6 is} C ₁ -C ₄ alkyl , C ₁ -C ₆ alkylamino, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl, where piperidinyl, piperazinyl, morphol inyl and thiomorpholinyl may be substituted with 1 or 2 substituents, wherein the substituents are independently selected from the group consisting of C ₁ -C ₄ alkyl and C ₃ -C ₆ cycloalkyl, R ^{7 is} hydrogen, methyl or ethyl, R is ^{8 is} C ₁ -C ₄ -alkyl. A compound according to claim 1, 2 or 3, characterized in that n is a number 0, R ^{2 is} tert-butoxycarbonylmethyl, R ^{3 is} -O-CH ₂ CO ₂ H, where R ^{3 is} in the ortho-position to the amide function of Dibenzoxazepine rings, m is a number 0, R ^{5 is} thienyl, furyl, isoxazolyl, oxadiazolyl, pyrazolyl or tetrazolyl, wherein thienyl, furyl, isoxazolyl, oxadiazolyl, perazolyl and tetrazolyl may be substituted with 1 or 2 substituents, wherein the Substituents are independently selected from the group consisting of methyl and cyclopropyl. Process for the preparation of a compound of formula (I) according to claim 1, characterized in that [A] is a compound of formula

wherein R ¹ , R ³ , R ⁴ , R ⁵ , m and n have the meaning given in claim 1, with a compound of formula R ² -X ¹ (III), wherein R ^{2 has} the meaning given in claim 1, and X ^{1 is} halogen, preferably chlorine or bromine, is reacted, or [B] a compound of formula

wherein R ¹ , R ² , R ⁴ , R ⁵ , m and n have the meaning given in claim 1, with a compound of formula R ^3a -X ² (V), wherein R ^{3a is} -CH ₂ CO ₂ H or - (CH ₂ ) ₂ CO ₂ H, and X ^{2 is} halogen, preferably chlorine or bromine, is reacted. A compound according to any one of claims 1 to 4 for the treatment and / or prophylaxis of diseases. Use of a compound according to any one of claims 1 to 4 for the manufacture of a medicament for the treatment and / or prophylaxis of diseases. Use of a compound according to any one of claims 1 to 4 for the manufacture of a medicament for the treatment and / or prophylaxis of cardiovascular diseases, inflammatory diseases, autoimmune diseases, Cancer or chronic pain. Medicament containing a compound after one the claims 1 to 4 in combination with an inert, non-toxic, pharmaceutical suitable excipient. Medicament according to claim 9 for the treatment and / or Prophylaxis of cardiovascular diseases, inflammatory Diseases, autoimmune diseases, cancers or chronic Pain. Method of combating atherosclerosis in Humans and animals by administering an effective amount at least A compound according to any one of claims 1 to 4, of a medicament according to claim 9 or a medicament obtained according to one of claims 7 or 8.