EP0673371A1

EP0673371A1 - Benzazepinone derivatives

Info

Publication number: EP0673371A1
Application number: EP94902689A
Authority: EP
Inventors: Peter Bühlmayer; Pascal Furet
Original assignee: Ciba Geigy AG; Novartis AG
Current assignee: Novartis AG
Priority date: 1992-12-11
Filing date: 1993-12-06
Publication date: 1995-09-27
Also published as: CA2151384A1; FI952803A7; FI952803A0; AU685768B2; KR950704280A; NO952288L; WO1994013651A1; US5610153A; AU5696794A; NZ258889A; JPH08505374A; HU9501693D0; HUT72330A; NO952288D0

Abstract

The invention concerns substituted 3-amino-1-arylalkylbenzazepin-2-ones of general formula (I), in which Ar is aryl; X is -O- or -S(O)n- and n is 0, 1 or 2; X1 is C1-C2 alkylene or a single bond; R1 is hydrogen, lower alkyl, aryl(lower alkyl) or acyl; R2 is lower alkyl, hydroxy(lower alkyl), (lower alkoxy)(lower alkyl), aryl(lower alkoxy)(lower alkyl), aryl(lower alkyl) or (C3-C7 cycloalkyl)(lower alkyl); R3 is a carboxylic group, (lower alkoxy)carbonyl, (lower alkoxy)(lower alkoxy)carbonyl, aryl(lower alkoxy)carbonyl, aryloxycarbonyl, carbamoyl, carbamoyl which is (i) mono-substituted by hydroxy, (lower alkyl)sulphonyl, halo(lower alkyl)sulphonyl or arylsulphonyl, (ii) mono-substituted or independently disubstituted by lower alkyl, lower alkenyl, lower alkinyl or phenyl(lower alkyl) or (iii) disubstituted by lower alkylene or (lower alkylene)-Z1-(lower alkylene), Z1 being O, S or NH; 5-tetrazolyl; PO2H2; PO3H2 or SO3H2; the ring A or aromatic groups, independently of each other, are unsubstituted or singly or multiply substituted by substituents selected from the group comprising lower alkyl, aryl(lower alkyl), (lower alkoxy)(lower alkyl), lower alkoxy, (lower alkoxy)(lower alkoxy), aryl(lower alkoxy), C3-C7 cycloalkyl, (C3-C7 cycloalkyl)(lower alkyl), nitro, halogen, trifluoromethyl, amino or amino which is mono-substituted or independently disubstituted by lower alkyl, aryl(lower alkyl) or aryl or disubstituted by lower alkylene or (lower alkylene)-oxy-(lower alkylene); or a salt thereof. The invention also concerns methods of preparing these compounds, their use, and pharmaceutical preparations containing compounds of formula (I) or pharmaceutically usable salts thereof.

Description

Benzazepinone derivatives

The invention relates to substituted 3-amino-l-arylalkyl-benzazepin-2-ones of the general formula

wherein Ar is aryl;

X represents -O- or -S (O) _n - and n represents 0, 1 or 2;

X _{x is} C ₁ -C ₂ alkylene or represents a direct bond;

R _{x represents} hydrogen, lower alkyl, aryl-lower alkyl or acyl;

R ₂ lower alkyl, hydroxy lower alkyl, lower alkoxy lower alkyl,

Aryl-lower alkoxy-lower alkyl, aryl-lower alkyl or C ₃ -C ₇ -cycloalkyl-lower alkyl;

R ₃ carboxy; Lower alkoxycarbonyl; Lower alkoxy-lower alkoxycarbonyl; Aryl-lower alkoxycarbonyl; Aryloxycarbonyl; Carbamoyl; Carbamoyl, which (i) by hydroxy,

NiederaJkansulfonyl, Halogenmederalkansulfonyl or arylsulfonyl mono-substituted, (ii) mono-substituted by lower alkyl, lower alkenyl, lower alkynyl, phenyl-lower alkyl or di-substituted independently of one another, or (iii) ₁ -lower alkylene is disubstituted by lower alkylene or lower alkylene-Z, wherein Z _j is O, S or NH stands; 5-tetrazolyl;

PO ₂ H ₂ ; PO ₃ H ₂ or SO ₃ H ₂ ; the ring A or aromatic radicals independently of one another are unsubstituted or mono- or polysubstituted by substituents selected from the group consisting of: from

Lower alkyl, aryl-lower alkyl, lower alkoxy-lower alkyl, lower alkoxy,

Lower alkoxy-lower alkoxy, aryl-lower alkoxy, C ₃ -C ₇ cycloalkyl,

C ₃ -C ₇ cycloalkyl-lower alkyl, nitro, halogen, trifluoromethyl, amino, amino which is mono- or independently disubstituted by lower alkyl, aryl-lower alkyl or aryl or is disubstituted by lower alkylene, lower alkyleneoxy-lower alkylene; or a salt thereof; Processes for their manufacture; their use and pharmaceutical preparations containing compounds of formula (I) or pharmaceutically acceptable salts thereof.

In the literature, two receptor subtypes [ATj and AT ₂ ] of angiotensin (II) are described which differ in their different affinities for synthetic angiotensin II analogs.

AT ₂ receptors can be identified in different tissues of the body. The relevant literature describes that such receptors, for example, in neuronal tumor cells, in transformed neural cells, in various areas of the central nervous system, in the heart and arteries, in female reproductive organs, such as the uterus and ovaries, in the adrenals and the pancreas, and are expressed in the healing skin.

Surprisingly, the compounds of the present invention in that described by Whitebread et al, Biochem. Biophys. Res. Comm. 1989; 163, 184-191, described model shown selective binding to the angiotensin-II-AT ₂ receptor. These binding properties of the compounds according to the invention were demonstrated below a concentration of 50 μmol / l. Accordingly, the compounds according to the invention can be used in particular for the prophylactic or therapeutic treatment of symptoms which are brought about by AT ₂ receptors.

An AT ₂ receptor has been shown to stimulate

- modulated the protein tyrosine phosphatase in the rat Pheochromocytoma Zeil line PC12W and in AT ₂ receptor-transfected COS cells [Botari et al., Biochem. Biophys. Res. Cornmun. 1992, 183, 206-211; Botari et al., Front. Neuroendocrinol. 1993, 44, 207-213; Brechler et al., Regul. Pepttde 1993, 44, 207-213; Kambayashi et al, J. Biol. Chem. 1993, 268, 24543-24546]

- inhibits the guanylate cyclase in PC12W and neuron cultures [Botari et al, Biochem. Biophys. Res. Cornmun. 1992, 183, 206-211; Botari et al., Front. Neuroendocrinol. 1993, 44, 207-213; Brechler et al, Regul. Peptides 1993, 44, 207-213; Summers et al, Am, J. Physiol 1991, 260, 679-687; Summers et al, Proc. Natl Acad. Be. USA 1991, 88, 7567-7571] and

- T-type Ca ⁺⁺ currents modulated in Neuroblastoma NG108-15 cells [Buisson et al, FEBS 1992, 309, 161-164]. In addition, the AT receptor is involved in cell growth and proliferation, since it is particularly expressed in high density during fetal life [Grady et al, J. Clin. Invest. 1991, 88 921-933].

As a result of the ability of AT ₂ ligands to inhibit the proliferation of vascular endothelial cells, and since endothelial cell proliferation forms the cause of angiogenesis and this is in turn a prerequisite for tumor growth and metastasis, the compounds according to the invention can be used for the treatment of cancer and such disorders that are generally related to benign and malignant proliferation.

AT ₂ receptors also mediate the modulation of phosphotyrosine phosphatase activity (PTPase activity), which is associated with growth-inhibiting and antiproliferative effects. AT ₂ receptors are expressed in vascular smooth muscle cells during neointimal formation. Therefore, the compounds according to the invention can be used for the treatment of vascular proliferation disorders, including vascular cell wall hypertrophy that follows thrombosis, angioplasty, Bürger's disease, atherosclerosis and arteriosclerosis.

Modulation of PTPase activity also plays a role in the insulin action mediated by a tyrosine kinase receptor and a signaling pathway for the tyrosine phosphorylation / dephosphorylation enzyme system. Accordingly, the compounds according to the invention can also be used for the treatment of diabetic disorders and complications, including diabetic neuropathy, nephropathy and vasculopathy.

AT ₂ receptors also regulate the diameter of cerebral arteries and thus the cerebral blood flow and are therefore suitable for the treatment of cerebral ischemia as well as strokes and related symptoms.

Another important treatment area arises from the fact that AT receptors are located in selective areas of the brain that are linked to the control of motor activity, sensory and visual phenomena, the limbic system and the regulation of appetite. Calcium currents, which are related to the control of neurosecretion and electrical activity, are also modulated by AT ₂ receptors. Accordingly, the inventive compounds for the treatment and diagnosis of numerous neurological, psychiatric, neuroendocrine, neurodegenerative and neuroimmunological disorders, including disorders that are associated with dependency, anxiety, depression, epilepsy, memory, psychosis, pain, sleep, tardive dyskinesis, Hyperactivity and petit mal, with the regulation of autonomous functions, as well as for the treatment of Parkinson's disease, Alzheimer's disease and appetite disorders and associated symptoms such as obesity and anorexia.

Since, as mentioned, the AT ₂ receptors influence the PTPase activity and such receptors have also been identified in healing skin, the compounds according to the invention can also modulate cell growth and differentiation of the skin and play a role in the reorganization of skin tissue and thus promote wound healing and prevent keloid formation.

AT ₂ receptors which have a regulating effect on ovulation have also been found in ovarian follicle cells. In this respect, the compounds according to the invention can be used for a treatment of sterility, which are caused by anovulation, ovulation disorders, dysfunction of the corpus luteum, "missed abortion" and in other such diseases, including premental syndrome, dysmenorrhea associated with ovarian dysfunction Related.

A high AT ₂ receptor density is found in human myometrium. As a result of the stimulation of PTPase activity, uterine contraction can be inhibited and the compounds according to the invention can be used for the treatment of disorders caused by abnormal uterine contraction, including dysmenorrhea, missed abortion, hypertrophy and hyperkinesis.

Likewise, the PTPase activity can modulate the activity of tyrosine kinase and other enzymes which are related to cell proliferation and differentiation, as a result of which the compounds according to the invention can also be used for the treatment and prophylaxis of uterine fribromas.

AT ₂ receptors play a role in regulating heart function. The shown influence on the T-type calcium current by AT ₂ -repores can play an important role in the heart in the arrhythmogenesis and the modulation of the pacemaker function in the sinus node. Accordingly, the compounds of the present invention be used for the therapy of heart failure and arrhymthmia. In addition, they are useful in the treatment of cardiac hypertrophy, since AT ₂ receptors mediate the increase in PTPase activity, which is generally to be regarded as inhibiting growth.

AT ₂ receptors continue to be found in the glomerulosa, fascia and medulla zones of the adrenal glands. Since the T-type cacium currents are modulated via these receptors and, in addition, antiproliferative properties are imparted, the compounds according to the invention can be used in the treatment of hypertrophy and hypersecretion of the adrenal cortex, such as the Cushing syndrome, the adrogenital syndrome and the primary hyperaldosteronimus.

This modulation of the T-type calcium currents allows the compounds according to the invention to be used in the treatment of disorders which are associated with the deregulation of the pancreas and exocrine secretion, such as pancreatitis, hyperinsulinism and the Zollinger-Ellison syndrome.

There is a particular need to have drugs available to treat post myocardial infarction to effectively treat heart failure that occurs after a heart attack. Appropriate therapy should be started after the repair and healing phase of the heart. It is known that an acute myocardial infarction causes both a change in the hemodynamic effects and a change in the structure in the damaged and healthy heart zones. For example, a myocardial infarction reduces the maximum heart output and stroke volume. These hemodynamic effects can be determined in a manner known per se, for example on the rat model [Schoemaker et al. J.MolCellCardiol 23, 187-197 (1991)]. The myocardial infarction is also accompanied by stimulation of the DNA synthesis taking place in the interstitium and an increase in collagen formation in the unaffected heart zones [van Krimpen et al, J. MolCellCardiol 23, 1245-1253 (1991)].

Surprisingly, the compounds according to the invention and their salts reduce DNA synthesis. On the other hand, post-myocardial treatment improves the negative hemodynamic effects. These regulatory effects are due to the binding of these compounds to the AT ₂ receptor. These findings are obtained using the known methodology according to Schoemaker et al. J.MolCellCardiol 23, 187-197 (1991) and van Krimpen et al, J.MolCellCardiol 23, 1245-1253 (1991) and Smits et al, Journal of Cardiovascular Pharmacology, 20: 772-778 (1992). In both approaches, a heart attack is generated in rats in the rat model and the active ingredient is administered for weeks with the help of an osmotic mini pump, for example after the infarction. The active ingredients are advantageously administered three to five weeks after the myocardial infarction generated and the hemodynamic effects and the formation of the DNA in question are determined. The results clearly show that, on the one hand, DNA synthesis is significantly reduced and, on the other hand, the negative hemodynamic effects are normalized. Corresponding animal experimental results with the ACE inhibitor captopril, which is known to be used for the treatment of "post myocardial infarction", could also be confirmed in humans with captopril. [Pfeffer et al. N.EngU.Med. 1992, 327, 669-677]

Overall, the compounds according to the invention and their salts are thus distinguished by a favorable activity profile.

Accordingly, the compounds of the formula I and their pharmaceutically usable salts can be used, for example, as active ingredients which are used, for example, for the treatment of diseases which are caused by the modulation of the AT ₂ receptor, for example for the treatment of diseases of the type shown above An object of the invention is thus the use of the compounds of the formula I and their pharmaceutically usable salts for the production of corresponding medicaments and for the therapeutic treatment of diseases which are caused by the modulation of the AT ₂ receptor. The commercial preparation of the active substances is also included in the manufacture of the medicaments.

The compounds of the formula I can exist as salts, in particular pharmaceutically usable salts. Assign the connections I z. B. at least one basic center, they can form acid addition salts. These are substituted, for example, with strong inorganic acids, such as mineral acids, for example sulfuric acid, a phosphoric acid or a hydrohalic acid, with strong organic carboxylic acids, such as optionally, for example, with halogen eg acetic acid, such as optionally unsaturated dicarboxylic acids, eg oxalic, malonic, succinic, maleic, fumaric, phthalic or terephthalic acid, such as hydroxycarboxylic acids, eg ascorbic, glycolic, lactic, malic, tartaric or citric acid, such as amino acids, for example aspartic or glutamic acid, or such as benzoic acid, or with organic Sulfonic acids, such as optionally substituted, for example by halogen, unsubstituted C _r C ₄ alkane- or aryl-sulfonic acids, for example methane- or p-toluenesulfonic acid. Corresponding acid addition salts can also be formed with an optionally additionally present basic center. Furthermore, the compounds I with at least one acidic group (for example COOH or 5-tetrazolyl) can form salts with bases. Suitable salts with bases are, for example, metal salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium or magnesium salts, or salts with ammonia or an organic amine, such as morpholine, thiomorpholine, piperidine, pyrrolidine, a mono-, di- or tri-lower alkylamine, e.g. B. ethyl, tert-butyl, diethyl, diisopropyl, triethyl, tributyl or dimethyl propyl amine, or a mono-, di- or trihydroxy-lower alkylamine, for example mono-, di- or triethanolamine. Corresponding internal salts can also be formed. Also included are salts which are not suitable for pharmaceutical uses and are used, for example, for the isolation or purification of free compounds I or their pharmaceutically usable salts.

The compounds according to the invention have at least two optically active carbon atoms and can accordingly be present in the form of stereoisomers, stereoisomer mixtures and in the form of the pure enantiomers or diastereomers. Corresponding stereoisomers are also encompassed by the present invention.

Aryl or aryl, for example in aryl-lower alkyl, aryl-lower alkoxy-lower alkyl, aryl-lower alkoxycarbonyl or aryloxycarbonyl and in aryl-lower alkanoyl, preferably means carbocyclic aryl, such as phenyl or naphthyl, furthermore heterocyclic aryl, such as monocyclic monoaza-, monooxa-, thothia-, diaza- or diaza -aryl, for example pyrrolyl, pyridyl, furyl, thienyl, imidazolyl, isoxazolyl, or thiazolyl. Such carbocyclic and heterocyclic aryl radicals are, for example, independently of one another unsubstituted or mono- or polysubstituted, for example twice or three times, substituted by substituents selected from the group consisting of: lower alkyl, aryl-lower alkyl, lower alkoxy-lower alkyl, lower alkoxy, lower alkoxy-lower alkoxy, aryl-lower alkoxy, C ₃ -C ₇ -cycloalkyl, C ₃ -C ₇ -cycloalkyl-lower alkyl, nitro, halogen, trifluoromethyl, amino, amino which is mono- or independently disubstituted by lower alkyl, aryl-lower alkyl or aryl or is disubstituted by lower alkylene, lower alkyleneoxy-lower alkylene. Preferred aryl is unsubstituted or one or more, for example two or three, as indicated above substituted phenyl.

Acyl means, for example, lower alkanoyl, aryl-lower alkanoyl, or aroyl, in particular benzoyl, which can be unsubstituted or substituted as indicated above for carbocyclic aryl.

Unless otherwise defined, the general terms used above and below have the following meanings:

The term "lower" means that corresponding groups and compounds each contain in particular up to and with 7, preferably up to and with 4, carbon atoms.

Lower alkyl is in particular C _r C ₇ - alkyl, ie methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, terL-butyl or a corresponding pentyl, hexyl or heptyl radical. Preferred is C ₁ - C ₄ -AlkyL

Lower alkenyl means in particular C3-C7-al enyl and is e.g. 2-propenyl or 1-, 2- or 3-butenyl. C3-C5-alkenyl is preferred.

Lower alkynyl is especially C3-C7-alkynyl and preferably means propargyl.

Hydroxy-lower alkyl means, in particular, hydroxyl-C4-alkyl, such as hydroxymethyl, 2-hydroxyethyl or 3-hydroxypropyl.

C ₁ -C ₂ alkylene is methylene or 1,1-ethylene or 1,2-ethylene.

C ₃ -C ₇ cycloalkyl is in particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Cyclopentyl and cyclohexyl are preferred.

C ₃ -C ₇ -cycloalkyl-lower alkyl is especially C ₃ -C ₇ -cycloalkyl-C ₁ -C ₇ -alkyl, such as cyclopropylmethyl, 2-cyclopropyl-ethyl, 3-cyclopropyl-propyl, cyclopentyl-methyl, 2-cyclopentyl- ethyl, 3-cyclopentyl-propyl, cyclohexylmethyl, 2-cyclohexyl-ethyl or 3-cyclohexyl-propyl. Preferred is C ₅ -C ₆ cycloalkyl-C _r C ₄ alkyl, such as cyclohexylmethyl or 2-cyclohexyl-ethyl.

Lower alkoxy is in particular C _r C ₇ alkoxy, ie methoxy, ethoxy, n-propyloxy, Isopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy or corresponding pentyloxy, hexyloxy or heptyloxy. C _r C ₄ alkoxy is preferred.

Lower alkoxy-lower alkyl is in particular C ₁ -C ₄ -alkoxy-C ₁ -C ₄ -alkyl, such as 2-methoxyethyl, 2-ethoxyethyl, 2- (n-propyloxy) ethyl or ethoxymethyl.

Lower alkoxy-lower alkoxy is in particular C ₁ -C ₄ -alkoxy-C ₁ -C ₄ -alkoxy, such as methoxymethoxy, ethoxymethoxy, 2-methoxy-ethoxy or 2-ethoxy-ethoxy.

Halogen is especially halogen with an atomic number up to and including 35, i.e. H. Fluorine, chlorine or bromine, and also includes iodine.

Lower alkylene is in particular C ₂ -C ₇ alkylene, is straight-chain or branched and in particular means ethylene, 1,3-propylene, 1,4-butylene, 1,2-propylene, 2-methyl-1,3-propylene or 2, 2-dimethyl-1,3-propylene. C ₂ -C ₅ alkylene is preferred.

Lower alkyleneoxy lower alkylene is in particular C ₂ -C ₄ alkyleneoxy-C ₂ -C ₄ alkylene, preferably ethyleneoxyethylene.

Lower alkoxycarbonyl means in particular C2-Cg-alkoxycarbonyl and is e.g. Methoxy, ethoxy, propyloxy or pivaloyloxy carbonyl. C2-C5-alkoxycarbonyl is preferred.

Lower alkoxy lower alkoxycarbonyl means in particular C 1 -C 4 alkoxy C 1 -C 4 alkoxy carbonyl, preferably ethoxy ethoxy carbonyl, methoxy ethoxy carbonyl and isopropyl oxy ethoxy carbonyl.

Naphthyl is especially 1- or 2-naphthyl. Pyrrolyl is especially 2- or 3-pyrrolyl. Pyridyl is especially 2-, 3- or 4-pyridyl. Furyl is especially 2- or 3-furyl. Thienyl is especially 2- or 3-thienyl. Imidazolyl is especially 2-, 4- or 5-imidazolyl. Isoxazolyl is especially 3- or 4-isoxalyl. Thiazolyl is especially 2-, 3- or 5-thiazolyl. Lower alkanoyl is especially C _r C ₇ alkanoyl and is, for example, formyl, acetyl, propionyl, butyryl, isobutyryl or pivaloyl. C ₂ -C ₅ alkanoyl is preferred.

Phenyl-lower alkanoyl is especially phenyl-C ₂ -C ₅ -alkanoyl and is, for example, phenylacetyl, 3-phenylpropionyl or 4-phenylbutyryl.

Lower alkylamino is especially C _r C ₇ alkylamino and is, for example, methyl, ethyl, n-propyl or isopropyl amino. C 1 -C ₄ -Alkylamino is preferred.

Phenyl-lower alkylamino is preferably phenyl-C _r C ₄ -alkylamino, in particular benzyl- or 1- or 2-phenylethylamino.

Diniederalkylamino is especially di-Ci ^ -alkylamino, such as dimethyl, diethyl, di (n-propyl), methyl propyl, methyl ethyl, methyl butyl or dibutyl amino.

N-Lower alkyl-N-phenyl-lower alkyl-amino is especially C ₁ -C ₄ alkylamino, preferably methylbenzylamino or ethylbenzylamino.

Di (phenyl-lower alkyl) amino is especially di (phenyl-C ₁ -C ₄ alkyl) amino, preferably dibenzylamino.

Amino which is disubstituted by lower alkylene is in particular C ₂ -C ₆ alkylene amino, preferably C ₄ -C ₆ alkylene amino, such as 1-pyrrolidino or 1-piperidino.

Amino which is disubstituted by lower alkyleneoxy mineral alkylene is in particular C ₂ -C ₄ -alkyleneoxy-C ₂ -C ₄ -alkyleneamino, preferably 4-morpholino.

Halogenmederalkansulfonyl is in particular halogen -C ₇ alkanesulfonyl, such as chloromethane, fluoro-dichloromethane, trichloromethane or trifluoromethanesulfonyl. Halogen-C _r C ₄ -alkanesulfonyl is preferred.

The invention relates in particular to compounds of the formula I in which Ar denotes aryl;

X represents -O- or -S (O) _n - and n represents 0, 1 or 2;

X, C _r C ₂ alkylene or represents a direct bond;

R _! Represents hydrogen, lower alkyl, aryl-lower alkyl or acyl; R _{2 is} lower alkyl, aryl-lower alkyl or C ₃ -C ₇ cycloalkyl-lower alkyl;

R _{3 represents} carboxy, lower alkoxycarbonyl, lower alkoxy-lower alkoxycarbonyl, aryl-lower alkoxycarbonyl or aryloxycarbonyl; the ring A or aromatic radicals, independently of one another, are unsubstituted or mono- or polysubstituted by substituents selected from the group consisting of: from

Lower alkyl, aryl-lower alkyl, lower alkoxy-lower alkyl, lower alkoxy, lower alkoxy-lower alkoxy, aryl-lower alkoxy, C ₃ -C ₇ cycloalkyl, C ₃ -C ₇ cycloalkyl-lower alkyl, nitro,

Halogen, trifluoromethyl, amino, amino which is mono- or independently disubstituted by lower alkyl, aryl-lower alkyl or aryl or by lower alkylene,

Lower alkylene oxymederalkylene is disubstituted; or a salt of it.

The invention particularly relates to compounds of the formula I in which Ar is phenyl;

X represents -O- or -S (O) _n - and n represents 0, 1 or 2; ^x ι C ₁ -C ₂ alkylene or stands for a direct bond; Rj is hydrogen, lower alkyl, lower alkyl which is substituted by phenyl, naphthyl, pyrrolyl, pyridyl, furyl, thienyl, imidazolyl, isoxazolyl or thiazolyl, lower alkanoyl, lower alkanoyl which is substituted by phenyl, naphthyl, pyrrolyl, pyridyl, furyl, thienyl, imidazolyl or thiazolyl is substituted, or is benzoyl;

R _{2 is} (i) lower alkyl, lower alkyl which is substituted by phenyl, naphthyl, pyrrolyl, pyridyl, furyl, thienyl, imidazolyl, isoxazolyl or thiazolyl, or is C ₃ -C ₇ -cycloalkyl-lower alkyl or (ii) hydroxy-lower alkyl, lower alkoxy-lower alkyl, Nieder¬ alkoxy lower alkyl, the lower alkoxy part being substituted by phenyl, naphthyl, pyrrolyl, pyridyl, furyl, thienyl, imidazolyl, isoxazolyl or thiazolyl; R _{3 is} (i) carboxy, 5-tetrazolyl, PO ₂ H ₂ , PO ₃ H ₂ or SO ₃ H ₂ or (ii) lower alkoxycarbonyl, lower alkoxy-lower alkoxycarbonyl, phenyl-lower alkoxycarbonyl, benzoylcarbonyl, carbamoyl, lower-alkylcarbamoyl, di-lower-alkylcarbamoyl, phenyl-lower-alkylphenylcarbamoyl, carbamoyl, hydroxy-carbamoy 1, lower alkanesulfonyl-carbamoyl, halogenmederalkansulfonyl or phenylsulfonyl; the ring A and carbocyclic and heterocyclic aromatic radicals independently of one another are unsubstituted or mono- or polysubstituted by substituents selected from the group consisting of: lower alkyl, lower alkyl, which is substituted by phenyl, naphthyl, pyrrolyl, pyridyl, furyl, thienyl, Imidazolyl, isoxazolyl or thiazolyl is substituted, lower alkoxy-lower alkyl, lower alkoxy, lower alkoxy-lower alkoxy, phenyl-lower alkoxy, C ₃ -C ₇ -cycloalkyl, C ₃ -C ₇ -cycloalkyl-lower alkyl, nitro, halogen, trifluoromethyl, amino, amino, which is substituted by lower alkyl, phenyl-lower alkyl or phenyl is mono- or independently disubstituted or is disubstituted by lower alkylene, lower alkylene oxymederalkylene; or a salt of it.

X represents -O- or -S (O) _n - and n represents 0, 1 or 2; ^x ι C ₁ -C ₂ alkylene or stands for a direct bond; where R _{x is} hydrogen, lower alkyl, phenyl-lower alkyl, lower alkanoyl,

Phenyl-lower alkanoyl or benzoyl;

R _{2 is} lower alkyl, phenyl-lower alkyl or C ₃ -C ₇ cycloalkyl-lower alkyl;

R _{3 represents} (i) carboxy, 5-tetrazolyl, PO ₂ H ₂ , PO ₃ H ₂ or SO ₃ H ₂ or (ii) represents carbamoyl or hydroxy-carbamoyl; the ring A and carbocyclic and heterocyclic aromatic radicals, independently of one another, are unsubstituted or mono- or polysubstituted by substituents selected from the group consisting of: lower alkyl, phenyl-lower alkyl,

Lower alkoxy-lower alkyl, lower alkoxy, lower alkoxy-lower alkoxy,

Phenyl-lower alkoxy, C ₃ -C ₇ -cycloalkyl, C ₃ -C ₇ -cycloalkyl-lower alkyl, nitro, halogen,

Trifluoromethyl, amino, amino, which by lower alkyl, phenyl lower alkyl or

Phenyl is mono- or independently disubstituted or by lower alkylene,

Lower alkylene oxymederalkylene is disubstituted; or a salt of it.

The invention especially relates to compounds of the formula I wherein Ar is phenyl or means by C _j -C ₄ alkyl substituted phenyl;

X represents -O- or -S (O) _n - and n represents 0, 1 or 2;

Xj is C ₁ -C ₂ alkylene or represents a direct bond; wherein Rj is hydrogen, C ₁ -C ₄ alkyl or C ₂ -C ₅ alkanoyl;

R _{2 is} phenyl-C _r C -alkyl, where phenyl is unsubstituted or by halogen,

Trifluoromethyl, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy is substituted, or R ₂

C ₃ -C ₇ cycloalkyl-C _r C ₄ alkyl;

R _{3 is} carboxy, 5-tetrazolyl, PO ₂ H ₂ , PO ₃ H ₂ or SO ₃ H ₂ ; ring A is unsubstituted or mono- or polysubstituted by substituents selected from the group consisting: of C _r C ₄ - alkyl, halogen, C ₁ -C ₄ alkoxy-C _r C ₄ alkyl, C _r C ₄ - alkoxy, C ₁ -C ₄ -alkoxy-C ₁ -C ₄ -alkoxy, nitro, halogen, trifluoromethyl; or a salt of it.

The invention relates in particular to compounds of the formula I in which Ar is

C _r C ₄ - alkyl, lower alkoxy, halogen, trifluoromethyl, amino, lower alkylamino,

Di-lower alkylamino or nitro substituted phenyl;

X represents -O-;

X _{j represents} methylene;

R _! Represents hydrogen or C ₂ -C ₅ alkanoyl;

R _{2 is} phenyl-C _r C ₄ -alkyl, where phenyl is unsubstituted or by halogen,

C _r C ₄ trifluoromethyl, - alkyl or C ₁ -C ₄ alkoxy; or R ₂

C ₃ -C ₇ cycloalkyl-C _r C ₄ alkyl;

R _{3 represents} carboxy, carbamoyl or hydroxycarbamoyl; the ring A is unsubstituted or mono- or polysubstituted by substituents selected from the group consisting of: C ₁ -C ₄ alkyl, halogen,

C ₁ -C ₄ alkoxy -CC ₄ -alkyl, C _r C ₄ -alkoxy, C ₁ -C ₄ -A__koxy-C ₁ -C ₄ -alkoxy, nitro, halogen,

Trifluoromethyl; or a salt of it.

The invention relates in particular to compounds of the formula I in which Ar is phenyl or phenyl substituted by —C ₄ -alkyl, in particular in the para position, such as p-isopropylphenyl;

X represents -O-;

X _{2 represents} methylene;

R _{t represents} hydrogen or C ₂ -C ₅ alkanoyl;

Trifluoromethyl, C ₁ -C ₄ alkyl or C _r C ₄ alkoxy is substituted; or R ₂

C ₃ -C ₇ cycloalkyl-C _j -C ₄ alkyl;

R _{3 represents} carboxy or 5-tetrazolyl; the ring A is unsubstituted or mono- or polysubstituted by substituents selected from the group consisting of: C ₁ -C ₄ alkyl, halogen,

C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkyl, C _r C ₄ alkoxy, C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkoxy, nitro, halogen,

Trifluoromethyl; or a salt of it. The invention relates in particular to compounds of the formula (Ia)

wherein R _{2 is} hydrogen;

R _{2 is} phenyl-C _r C ₄ -alkyl, such as benzyl, where phenyl is unsubstituted or by

Halogen such as fluorine, trifluoromethyl, C _r C ₄ alkyl, such as methyl, or C ₁ -C ₄ -alkoxy, such as

Is methoxy, or R _{2 is} C ₅ -C ₆ cycloalkyl-C ₁ -C ₄ alkyl, such as cyclohexylmethyl or 2-cyclohexyl-ethyl;

R _{3 represents} carboxy; and

R _{4 is} C ₁ -C ₄ alkyl, in particular isopropyl, which is bonded in particular in the para position; or a salt of it.

The invention relates in particular to compounds of the formula (Ib)

wherein R _{t is} hydrogen;

R ₂ phenyl-C _r C ₄ -alkyl, such as benzyl, or C ₅ -C ₆ -cycloalkyl-C ₁ -C ₄ -alkyl, such as

Cyclohexylmethyl or 2-Cyclohexyl-ethyl means;

R _{3 represents} carboxy; and

R _{4 is} C ₁ -C ₄ alkyl, especially isopropyl; or a salt of it.

The invention relates to compounds of the formulas I, Ia and Ib, in which the C atom containing the variables R ₂ and R _{3 has} the (S) configuration. Those are preferred Compounds of formula I, la and Ib, wherein both the C atom having the variables R ₂ and R ₃ and the heterocycle C atom to which the amino group is attached have the (S) configuration.

The invention relates in particular to the new compounds of the formula I mentioned in the examples and their stereoisomers or a salt thereof.

Another object of the invention is a process for the preparation of the compounds of formula I and their stereoisomers or a salt thereof; e.g. characterized in that one

a) a compound of the formula

wherein Y _: denotes a radical which can be converted into the variable R ₃ , or a salt thereof, converts Y _λ into the variable R ₃ ; or, b) for the preparation of a compound of formula (I), wherein Rj is hydrogen, or a salt thereof; in a compound of the formula

wherein Y _{2 represents} an amino protecting group, or a salt thereof, which

Splits off amino protecting group; or c) a compound of the formula

with a compound of formula (IVb), wherein Y _{4 is} a nucleophobic Represents leaving group, or with a compound of the formula R ₂ -CO-R ₃ (IVc) or a salt thereof; or d) a compound of the formula

with a compound of the formula Y ₆ -X _r Ar (Vb), in which Y _{6 represents} a nucleofugic leaving group, or a salt thereof; or e) a compound of the formula

wherein Y ₇ for (i) oxo or (ii) reactive esterified hydroxy together with

Is hydrogen, with a compound of formula implements it; and in each case, if desired, a process-related or otherwise obtainable compound of the formula I thereof, in each case isolated in free form or in salt form, converting a process-related or otherwise obtainable compound of the formula I into another compound of the formula I, a process-related separates the available mixture of isomers and isolates the desired isomer and / or a process-related free compound of the formula I thereof into a salt or a process-available salt of a compound of the formula I thereof into the free compound of the formula I or into a transferred other salt.

The reactions described above and below in the variants are carried out in a manner known per se, for example in the absence or usually in the presence of a suitable solvent or diluent or a mixture thereof, with cooling, room temperature or heating being carried out as required , for example in a temperature range from about -80 ° C to the boiling temperature of the reaction medium, preferably from about -10 ° to about + 200 ° C, and, if necessary, in a closed vessel, under pressure, in an inert gas atmosphere and / or under anhydrous Conditions works.

Details of the corresponding procedures and reaction conditions can also be found in the examples.

Option A):

A radical Y _{} which} can be converted into carboxy R ₃ is, for example, functionally modified

Carboxy or a residue which can be converted into carboxy by oxidation.

Suitable functionally modified carboxy is, for example, esterified carboxy, amidated carboxy or cyano which is different from R ₃

Esterified carboxy other than R ₃ is, for example, carboxy esterified with an optionally substituted aliphatic, cycloaliphatic or aromatic alcohol. An aliphatic alcohol is, for example, a lower alkanol, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol or tert-butanol, which is substituted by cyano or a silyl radical, while as a cycloaliphatic alcohol, for example, a 3 to 8-membered cycloalkanol, such as cyclopentanol, hexanol or heptanol, is suitable. An aromatic alcohol is, for example, a phenol or a heterocyclic alcohol, which can each be substituted, in particular hydroxypyridine, for example 2-, 3- or 4-hydroxypyridine .

Amidated carboxy is, for example, carbamoyl, monosubstituted by hydroxy, amino or optionally substituted phenyl, mono- or disubstituted by lower alkyl or by 4- to 7-membered alkylene or 3-aza, 3-lower alkylaza, 3-oxa or 3-thiaalkylene disubstituted carbamoyl. Examples are carbamoyl, N-mono- or N, N-di-lower alkylcarbamoyl, such as N-methyl-, N-ethyl-, N, N-dimethyl-, N, N-diethyl- and N, N-dipropyl-carbamoyl, pyrrolidino - And piperidinocarbonyl, morpholino-, piperazino-, 4-methylpiperazino- and thiomorpholino-carbonyl, anilinocarbonyl and anilinocarbonyl substituted by lower alkyl, lower alkoxy and / or halogen.

Preferred functionally modified carboxy is, for example, cyano-lower alkoxycarbonyl, such as 2-cyanoethoxycarbonyl, silyloxycarbonyl, such as tri-lower alkylsilyloxycarbonyl, for example tri (m) ethylsilyloxycarbonyl, and cyano. Preferred Y _j is, for example, cyano.

Compounds of the formula I in which R _{3 is} carboxy can be prepared, for example, from compounds of the formula II in which Yj is cyano or esterified or amidated carboxy other than R ₃ by hydrolysis, in particular in the presence of a base.

In particular, the following Y _j can be converted into carboxy R ₃ in a manner known per se: 2-cyanoethoxycarbonyl Yj can, for example, in the presence of a base hydrolytically, 2-trimethylsilyloxycarbonyl by treatment with a fluoride, such as alkali metal fluoride, for example sodium fluoride, and silyloxycarbonyl Y _l by treatment be converted into carboxy R ₃ with an acid.

Suitable bases are, for example, alkali metal hydroxides, hydrides, amides, alkanolates, carbonates, triphenylmethylides, lower dinalkylamides, aminoalkylamides or lower alkylsilylamides, naphthalene amines, lower alkylamines, basic heterocycles, ammonium hydroxides and carbocyclic amines. Examples include sodium hydroxide, hydride, amide, potassium tert-butoxide carbonate, lithium triphenylmethylide, diisopropylamide, potassium 3- (aminopropyl) amide, bis (trimethylsilyl) amide, dimethylaminonaphthalene, di - or triethylamine, or ethyl-diisopropylamine, N-methyl-piperidine, pyridine, benzyltrimethyl-ammonium hydroxide, l, 5-diazabicyclo [4.3.0] non-5-ene (DBN) and l, 8-diaza-bicyclo [5.4. 0] undec-7-en (DBU) called

The acid is, for example, a strong inorganic acid, such as mineral acid, for example sulfuric acid, a phosphoric acid or a hydrohalic acid, a strong organic carboxylic acid, such as an organic sulfonic acid, for example C ₁ -C ₄ -alkane carboxylic acid substituted by halogen, for example acetic acid or trifluoroacetic acid , such as optionally, for example by halogen, substituted Cx ^ alkane or aryl sulfonic acid, such as methane or p-toluenesulfonic acid in question.

As an oxidatively convertible carboxy radical, for example hydroxymethyl or formyl optionally formed in question.

Starting from compounds of the formula II in which Y _{1 is} hydroxymethyl or formyl, R ₃ carboxy can be prepared by oxidation. The oxidation takes place, for example, in an inert solvent, such as in a lower alkane carboxylic acid, for example Acetic acid, a ketone, for example acetone, an ether, for example tetrahydrofuran, a heterocyclic aromatic, for example pyridine, or in water, or in a mixture thereof, if necessary with cooling or heating, for example in a temperature range from about 0 ° to about + 150 ° C. Examples of oxidizing agents are oxidizing transition metal compounds, in particular those with elements of L, VI. or VII. subgroup, in question. Examples include: silver compounds, such as silver nitrate, oxide and picolinate, chromium compounds, such as chromium trioxide and potassium dichromate, and manganese compounds, such as potassium, tetrabutylammonium and benzyltriethylammonium permanganate. Other oxidizing agents are, for example, suitable compounds with elements of main group IV , such as lead dioxide, or halogen-oxygen compounds, such as sodium iodate or potassium periodate

A radical Y _{1 which} can be converted into 5-tetrazolyl R ₃ is, for example, cyano and N-protected 5-tetrazolyl.

For the preparation of compounds of the formula I in which R _{3 is} 5-tetrazolyl, one starts, for example, from the starting material of the formula π, in which Y _{λ is} cyano, and sets this with an azide, for. B. with HN ₃ or in particular a salt such as alkali metal salt thereof or with an organotin azide such as tri-lower alkyl or triaryltin azide. Preferred azides are, for example, sodium and potassium azide and tri-C ₁ -C ₄ -alkyl, for example triethyl or tributyltin azide, and triphenyltin azide.

Protecting groups of N-protected 5-tetrazolyl R ₃ are the protective groups usually used in tetrazole chemistry, in particular triphenylmethyl, optionally substituted, for example, by nitro, benzyl, such as 4-nitrobenzyl, lower alkoxymethyl, such as methoxy- or ethoxymethyl, lower alkylthiomethyl , such as methylthio-methyl, and 2-cyanoethyl, further lower alkoxy lower alkoxymethyl, such as 2-methoxyethoxymethyl, benzyloxymethyl and phenacyl. The protecting groups are split off using known methods, for example as described in J. Green, Protective Groups in Organic Synthesis, Wiley-Interscience (1980). For example, triphenylmethyl is usually obtained by hydrolysis, in particular in the presence of an acid, or hydrogenolysis in the presence of a hydrogenation catalyst, 4-nitrobenzyl, for example by hydrogenolysis in the presence of a hydrogenation catalyst, methoxy- or ethoxy-methyl, for example by treatment with a tri-lower alkyl, such as triethyl or Tributyltin bromide, methylthiomethyl, for example by treatment with trifluoroacetic acid, 2-cyanoethyl, for example by hydrolysis, for example with sodium hydroxide solution, Cleave 2-methoxyethoxymethyl, for example by hydrolysis, for example with hydrochloric acid, and benzyloxymethyl and phenacyl, for example by hydrogenolysis in the presence of a hydrogenation catalyst.

A radical Y _{λ which} can be converted into PO ₂ H ₂ or PO ₃ H ₂ R ₃ is, for example, a functional derivative of PO ₂ H ₂ or PO ₃ H ₂ .

A corresponding radical Yj which can be converted into R ₃ is, for example, a group -N ₂ ⁺ A ^" , where A ^{" stands} for an anion of an acid, such as mineral acid. Corresponding diazonium compounds are reacted, for example, in a manner known per se with a P (IEI) halide, such as PC1 ₃ or PBr ₃ , and worked up hydrolytically, it being possible to obtain compounds of the formula I in which R _{3 is} PO ₃ H ₂ .

A residue Y _{j which} can be converted into SO ₃ HR ₃ is, for example, the mercapto group. Starting compounds of the formula π having such a group are oxidized, for example, by oxidation processes known per se to give those compounds of the formula I in which R _{3 is} SO ₃ H The oxidizing agents are, for example, inorganic peracids, such as peracids of mineral acids, for example periodic acid or persulfuric acid, organic peracids, such as percarbonate or persulfonic acids, for example performic, peracetic, trifluoroperacetic or perbenzoic acid or p-toluenesulfonic acid, or mixtures of hydrogen peroxide and acids, for example mixtures of hydrogen peroxide and acetic acid, into consideration. Frequently, the oxidation is carried out in the presence of suitable catalysts, the catalysts being suitable acids, such as optionally substituted carboxylic acids, for example acetic acid or trifluoroacetic acid, or transition metal oxides, such as oxides of elements of VI. Subgroup, for example molybdenum or tungsten oxide, are to be mentioned. The oxidation is carried out under mild conditions, for example at temperatures from about -50 ° to about + 100 ° C.

The starting material of the formula π can be obtained, for example, by using a compound of the formula

or a salt thereof, in which Y _{3 represents} one of the abovementioned amino protecting groups, for example phthaloyl, and with a compound of the formula Ar-X _r Y ₄ (Ilb) in which Y _{4 is} reactive esterified hydroxy and Xj is C _r C ₂ alkylene, in

In the presence of a base. In the next reaction step, is known per se

Cleaved the amino group, the phthaloyl group, for example

Treatment with hydrazine hydrate A compound of the formula so obtainable

is then with a compound of formula

wherein Y _{4 is} a nucleofugic leaving group, such as a diazonium radical or reactive esterified hydroxy, means in the presence of a base converted to a compound of the formula π in which Rj is hydrogen If desired, a corresponding compound can be converted in a manner known per se to a compound of the formula π N - be alkylated or N-acylated.

Reactive esterified hydroxy is, in particular, hydroxy esterified with a strong inorganic acid or organic sulfonic acid, for example halogen, such as chlorine, bromine or iodine, or sulfonyloxy, such as hydroxysulfonyloxy, halosulfonyloxy, for example huorsulfonyloxy, optionally with, for example, halogen-substituted C _j -C- ₇ -Alkane-sulfonyloxy, for example methane or trifluoromethanesulfonyloxy, C ₅ -C ₇ -cycloalkanesulfonyloxy, for example cyclohexanesulfonyloxy, or optionally, for example by or halogen, substituted benzenesulfonyloxy, for example p-bromophenyl- or p-toluenesulfonyloxy, in particular halogen, such as chloride, bromide or iodide, and sulfonyloxy, such as methane or p-toluenesulfonyloxy.

A specific production method for compounds of the formula π can in particular be found in exemplary embodiment 1.

The starting material of the formula Ila, üb and Ild is known or can be prepared by methods known per se.

Variant b): Suitable amino protecting groups Y ₂ are the protective groups usually used in peptide chemistry, in particular triphenylmethyl, optionally substituted, for example, by nitro, benzyl, such as 4-nitrobenzyl, lower alkoxymethyl, such as methoxy- or ethoxymethyl, lower alkylthiomethyl, such as methylthiomethyl, and 2-cyanoethyl, also lower alkoxy lower alkoxymethyl, such as 2-methoxyethoxymethyl, benzyloxymethyl and phenacyl. The protecting groups are split off using known methods, for example as described in J. Green, Protective Groups in Organic Synthesis, Wiley-Interscience (1980). For example, triphenylmethyl is usually obtained by hydrolysis, in particular in the presence of an acid, or hydrogenolysis in the presence of a hydrogenation catalyst, 4-nitrobenzyl, for example by hydrogenolysis in the presence of a hydrogenation catalyst, methoxy- or ethoxy-methyl, for example by treatment with a tri-lower alkyl, such as triethyl or Split off tributyltin bromide, methylthiomethyl, for example by treatment with trifluoroacetic acid, 2-cyanoethyl, for example by hydrolysis, for example using sodium hydroxide solution, 2-methoxyethoxymethyl, for example by hydrolysis, for example using hydrochloric acid, and benzyloxymethyl and phenacyl, for example by hydrogenolysis in the presence of a hydrogenation catalyst.

The starting material of the formula m can be obtained, for example, by using one of the compounds of the formula described above

with a connection of the forms

in which Y is a nucleofugic leaving group, such as a diazonium radical or reactive esterified hydroxy, in the presence of a base to give a compound of the formula II in which R _{j is} hydrogen, and then introduces the amino protective group in a manner known per se.

Variant c):

A nucleophobic leaving group Y is, for example, a diazonium radical or reactive esterified hydroxy as defined above. Y ₄ is advantageously halogen, such as chlorine or bromine, or sulfonyloxy, such as methanesulfonyloxy or 4-nitrophenyl sulfonyloxy.

The reaction is carried out in a manner known per se, advantageously in the presence of one of the bases listed above.

Some of the starting material is known or can be produced by methods known per se.

The starting material of the formula IVa is prepared, for example, as described in connection with the preparation of compounds of the formula HI in variant b).

Variant d):

The nucleofugic leaving group Y ₆ is especially reactive esterified

Hydroxy in question, which has, for example, the meaning described above.

The reaction is advantageously carried out with compounds of the formula Va in which R _{3 is} different from carboxy. The reaction with those compounds of the formula Va in which ^ is also different from hydrogen is particularly advantageous.

To prepare a compound of the formula (Va), for example, a compound of the formula IIc is used and this is reacted in analogy to variant c) with a compound of the formula IVb or IVc, advantageously in the presence of one of the bases defined above .

Variant e):

The implementation takes place in a manner known per se.

The reductive alkylation (Y ₇ = oxo) takes place in the presence of conventional reducing agents, while the substitutive N-alkylation (Y ₇ = reactive esterified hydroxy together with hydrogen) is preferably carried out in the presence of one of the bases defined above.

The starting material used in the above process variants or the production thereof is described in part in US Pat. No. 4,477,464.

A compound of the formula I obtainable according to the process or in another way can be converted into another compound of the formula I in a manner known per se.

If one of the variables has amino, corresponding compounds I can be N- (ar) alkylated in a manner known per se; carbamoyl or carbamoyl-containing radicals N- (ar) can also be alkylated. The (ar) alkylation is carried out, for example, with an (aryl-JCj-Cγ-alkyl halide, for example bromide or iodide, (aryl) C _r C ₇ alkanesulfonate, for example with methanesulfonate or p-toluenesulfonate or a di -C ₁ -C ₇ alkyl sulfate, for example dimethyl sulfate, preferably under basic conditions, such as in the presence of sodium hydroxide solution or potassium hydroxide solution, and advantageously in the presence of a phase transfer catalyst, such as tetrabutylammonium bromide or benzyltrimethylammomum chloride, but more basic condensation agents, such as Alkali metal amides, hydrides or alcoholates, for example sodium amide, sodium hydride or sodium ethanolate, may be required.

A compound of the formula I in which Ri is hydrogen can be acylated in a manner known per se to give a compound of the formula I in which R] is acyl. The reaction takes place, for example, with a compound of the formula R _r OH or a reactive derivative thereof. Reactive derivatives of compounds of the formula R _r OH are, for example, reactive anhydrides derived therefrom.

Anhydrides of acids of the formula R _r OH can be symmetrical or preferably mixed anhydrides of these acids, for example anhydrides with inorganic acids, such as acid halides, in particular acid chlorides (obtainable, for example, by treating the corresponding acid with thionyl chloride, phosphorus pentachloride or oxalyl chloride; acid chloride method), azides (available eg from a corresponding acid ester via the corresponding hydrazide and its treatment with nitrous acid; azide method), Anhydrides with carbonic acid half-esters, e.g. carbonic acid lower alkyl half-esters (obtainable, for example, by treating the corresponding acid with chloroformic acid lower alkyl esters or with an 1-lower alkoxycarbonyl-2-lower alkoxy-1, 2-dihydroquinoline, e.g. 1-ethoxycarbonyl-2-ethoxy-1, 2-dihydroquinoline; method of mixed O-alkyl carbonic acid anhydrides), anhydrides with dihalogenated, in particular dichlorinated phosphoric acid (obtainable, for example, by treating the corresponding acid with phosphorus oxychloride; phosphorus oxychloride method), anhydrides with other phosphoric acid derivatives (for example those which can be obtained with phenyl-N-phenylphosphoramidochloridate) or with phosphoric acid derivatives, or anhydrides with organic acids, such as mixed anhydrides with organic carboxylic acids (obtainable, for example, by treating the corresponding acid with an optionally substituted lower alkane or phenyl-lower alkane carboxylic acid halide, for example phenylacetic acid, pivalic acid or trif luoroacetic acid chloride; Method of mixed carboxylic acid anhydrides) or with organic sulfonic acids (obtainable, for example, by treating a salt, such as an alkali metal salt, of the corresponding acid with a suitable organic sulfonic acid halide, such as lower alkane or aryl, for example methane or p-toluenesulfonic acid chloride; method of mixed sulfonic anhydrides), as well as symmetrical anhydrides (obtainable, for example, by condensation of the corresponding acid in the presence of a carbodiimide or 1-diethylaminopropine; method of symmetrical anhydrides).

The condensation to produce the amide bond can be carried out in a manner known per se, for example as in standard works, such as "Houben-Weyl, Methods of Organic Chemistry", 4th Edition, Volume 15 / π, Georg Thieme Verlag, Stuttgart 1974, "The Peptides" (Ed. E. Gross and J. Meienhofer), Vol. 1 and 2, Academic Press, London and New York, 1979/1980, or M. Bodanszky, "Principles of Peptide Synthesis", Springer-Verlag, Berlin 1984.

The condensation can be carried out in the presence of one of the customary condensation agents. Common condensing agents are, for example, carbodiimides, for example diethyl, dipropyl, N-ethyl-N '- (3-dimethylaminopropyl) carbodiimide or in particular dicyclohexylcarbodiimide, furthermore suitable carbonyl compounds, for example carbonyldiimidazole, 1,2-oxazolium compounds, for example 2- Ethyl 5-phenyl-l, 2-oxazolium-3'-sulfonate and 2-tert-butyl-5-methylisoxazolium perchlorate, or a suitable acylamino compound, for example 2-ethoxy-l-ethoxycarbonyl-l, 2-dihydroquinoline , also activated phosphoric acid derivatives, for example diphenylphosphoryl azide, diethylphosphoryl cyanide, phenyl-N-phenylphosphoramidochloridate, bis- (2-oxo-3-oxazolidinyl) -phosphinic acid chlorine or l-benzotriazolyloxy-tris (dimethylamino) phosphonium hexafluorophosph.

If desired, an organic base is added, e.g. a tri-lower alkyl amine with bulky residues, e.g. Ethyldiisopropylamine, or a heterocyclic base, e.g. Pyridine, 4-dimethylaminopyridine or preferably N-methylmorpholine.

The condensation of acid anhydrides with amines can e.g. in the presence of inorganic carbonates, e.g. Alkali metal carbonates or bicarbonates, such as sodium or potassium carbonate or bicarbonate (usually together with a sulfate).

The condensation is preferably carried out in an inert, polar, aprotic, preferably anhydrous, solvent or solvent mixture, for example in a carboxamide, e.g. Formamide or dimethylformamide, a halogenated hydrocarbon, e.g. Methylene chloride, carbon tetrachloride or chlorobenzene, a ketone, e.g. Acetone, cyclic ether, e.g. Tetrahydrofuran, an ester, e.g. Ethyl acetate, or a nitrile, e.g. Acetonitrile, or in mixtures thereof, optionally at reduced or elevated temperature, e.g. in a temperature range from about -40 ° C to about + 100 ° C, preferably from about -10 ° C to about + 50 ° C, and optionally under an inert gas, e.g. Nitrogen atmosphere.

Reactive acid derivatives can also be formed in situ.

In compounds of formula I which have an esterified carboxy group as a substituent, such a group, e.g. by means of hydrolysis, e.g. convert to a free carboxy group in the presence of a basic agent or an acidic agent such as a mineral acid. For example, tert-butyloxycarbonyl may further e.g. in a manner known per se, such as by treatment with trihaloacid, such as trifluoroacetic acid, advantageously under anhydrous conditions, and benzyloxycarbonyl e.g. by catalytic hydrogenation in the presence of a hydrogenation catalyst, e.g. be converted to carboxy in the manner described below.

Furthermore, in compounds of the formula I which have a carboxy group as a substituent (in particular if R _{3 is} different from carboxy), this can be done, for example, by treatment with an alcohol, such as a lower alkanol, in the presence of a suitable esterifying agent, such as an acidic reagent , for example an inorganic or organic Acid or a Lewis acid, for example of zinc chloride, or a water-binding condensing agent, for example a carbodiimide, such as of N, N'-dicyclohexylcarbodiimide, or by treatment with a diazo reagent, such as with a diazo-lower alkane, for example diazomethane, into a correspondingly esterified carboxy group. This can also be obtained if compounds of the formula I in which the carboxy group is in free form or in salt, such as ammonium or metal, for example alkali metal, such as sodium or potassium salt form, are present with a C ₁ -C ₇ alkyl halide, for example methyl or ethyl bromide or iodide, or an organic sulfonic acid ester, such as a corresponding CC ₇ alkyl ester, for example methanesulfonic acid or p-toluenesulfonic acid methyl ester or ethyl ester, treated

Compounds of the formula I which have an esterified carboxy group as substituents can be obtained by transesterification, for example by treatment with an alcohol, usually with a higher alcohol than that corresponding to the esterified carboxy group in the starting material, in the presence of a suitable transesterifier, such as a basic one By means of, for example, an alkali metal C ₁ -C ₇ -alkanoate, - -C ^ alkanolate or cyanide, such as sodium acetate, methanolate, ethanolate, tert-butanolate or cyanide, or a suitable acidic agent, if appropriate converting the resulting alcohol, for example by distillation, into other ester compounds of the formula I. It is also possible to start from corresponding, so-called activated esters of the formula I which have an activated esterified carboxy group as substituents (see below) and convert these into another ester by treatment with a C _r C ₇ alkanol.

In compounds of the formula I which contain the carboxy group as substituents, these can also first be converted into a reactive derivative, such as an anhydride (also a mixed anhydride), an acid halide, for example chloride (for example by treatment with a thionyl halide) , for example -chloride), an anhydride with a formic acid ester, for example -C _r C ₇ -alkyl ester (for example by treating a salt such as an ammonium or alkali metal salt with a halogen such as chloro-formic acid ester such as Cj-C _7- alkyl ester), or an activated ester, such as cyanomethyl, nitrophenyl, for example 4-nitro-phenyl, or polyhalophenyl, for example pentachlorophenyl ester (for example by treatment with a corresponding hydroxy compound in the presence of a suitable condensing agent, as from N, N'-dicyclohexylcarbodiimide), and then reacting such a reactive derivative with an appropriate alcohol component and thus obtaining corresponding ester compounds of the formula I. You can do this directly or obtained via interconnections; for example, an activated ester, such as a 4-nitrophenyl ester, of a compound of formula I with a carboxy group can first be reacted with a 1-unsubstituted imidazole and the resulting 1-imidazolylcarbonyl compound can be reacted with a corresponding ester component.

If an aromatic ring has a hydrogen atom as a substituent, this can be replaced by a halogen atom using a halogenating agent in a conventional manner, e.g. with bromine, hypobromic acid, an acyl hypobromite or another organic bromine compound, e.g. N-bromosuccinimide, N-bromoacetamide, N-bromophthalimide, pyridinium perbromide, dioxane dibromide, 1,3-dibromo-5,5-dimethylhydantoin or 2,4,4,6-tetrabromo-2,5-cyclohexandien-l-one, by bromine or with elemental chlorine, e.g. in a halogenated hydrocarbon such as chloroform and under cooling, e.g. down to about -10 ° C by chlorine.

If an aromatic ring contains an amino group, this can be diazotized in the usual way, e.g. by treatment with a nitrite, e.g. Sodium nitrite, in the presence of a suitable protonic acid, e.g. a mineral acid, the reaction temperature advantageously being kept below about 5 ° C. The diazonium group obtained in salt form and obtainable in this way can be substituted by conventional methods, for example as follows: by the hydroxyl group analogous to the phenol boil in the presence of water; by an alkoxy group by treatment with an appropriate alcohol, whereby energy must be supplied; by the fluorine atom analogous to the Schiemann reaction in the thermolysis of corresponding diazonium tetrafluoroborates; or by chlorine, bromine, iodine or the cyano group analogous to the Sandmeyer reaction by reaction with corresponding Cu (I) salts, first with cooling, e.g. to below about 5 ° C, and then heating, e.g. to about 60 ° to about 150 ° C.

The invention particularly relates to the methods described in the examples.

Salts of compounds of the formula I can be prepared in a manner known per se. For example, acid addition salts of compounds of the formula I are obtained by treatment with a suitable acid or a suitable ion exchange reagent. Salts of compounds I can be converted into the free compounds I in a conventional manner, acid addition salts, for example by treatment with a suitable basic agent or a suitable ion exchange reagent. Salts of compounds I can be converted into other salts of compounds I in a manner known per se.

Depending on the procedure or reaction conditions, the compounds I having salt-forming, in particular basic, properties can be obtained in free form or in the form of salts.

As a result of the close relationship between the compound I in free form and in the form of its salts, in the preceding and below, the free compound I or its salts, if appropriate, is also to be understood as meaning the corresponding salts or the free compound I, if appropriate.

The compounds I including their salts of salt-forming compounds can also be obtained in the form of their hydrates and / or others, for. B. used for crystallization, include solvents.

Depending on the choice of starting materials and procedures, the compounds I and their salts can be in the form of one of the possible isomers or as a mixture thereof, e.g. depending on the number, absolute and relative configuration of the asymmetric Kbhlenstoffatom as pure isomers, such as antipodes and / or diastereomers, or as mixtures of isomers, such as mixtures of enantiomers, for. B. racemates, diastereomer mixtures or racemate mixtures are present.

Diastereomer mixtures and racemate mixtures obtained can be separated into the pure diastereomers or racemates in a known manner on account of the physicochemical differences in the constituents, for example by fractional crystallization. Enantiomer mixtures obtained, such as racemates, can be broken down into the optical antipodes by known methods, for example by recrystallization from an optically active solvent, chromatography on chiral adsorbents, with the aid of suitable microorganisms, by cleavage with specific, immobilized enzymes, via the formation of inclusion compounds , for example using chiral crown ether, where only one enantiomer is complexed, or by conversion into diastereomeric salts, for example by reacting a basic end product racemate with an optically active acid, such as carboxylic acid, for example tartaric or malic acid, or sulfonic acid, for example camphorsulfonic acid, and separation of this on this Diastereomer mixture obtained in this way, for example on the basis of their different solubilities, into the diastereomers from which the desired enantiomer can be released by the action of suitable agents.

The invention also relates to those embodiments of the process according to which one starts from a compound obtainable as an intermediate at any stage of the process and carries out the missing steps or uses a starting material in the form of a derivative or salt and / or its racemates or antipodes or in particular forms under the reaction conditions.

In the process of the present invention, preference is given to using starting materials and intermediates which lead to the compounds I described at the outset as being particularly valuable. New starting materials and intermediates for the preparation of the compounds I, their use and a process for their preparation likewise form a subject of the invention, the variables A, X, Xj, R _{according to} R ₂ , R ₃ and R _{4 being} those for the compounds I have the meanings given.

The compounds of formula I and their pharmaceutically usable salts can, preferably in the form of pharmaceutically usable preparations, in a process for the prophylactic and / or therapeutic treatment of the animal or human body, in particular for the treatment of diseases caused by the stimulation or blocking of the AT ₂ receptor are used.

The invention therefore also relates to pharmaceutical preparations which contain a compound I in free form or in the form of a pharmaceutically usable salt as active ingredient, and to a process for their preparation. These pharmaceutical preparations are those for enteral, such as oral, further rectal or parenteral administration to warm-blooded animals, the pharmacological active ingredient being contained alone or together with customary pharmaceutical auxiliaries. The pharmaceutical preparations contain, for example, from about 0.1% to 100%, preferably from about 1% to about 60%, of the active ingredient. Pharmaceutical preparations for enteral or parenteral administration are, for example, those in unit dose forms, such as tablets, tablets, capsules or suppositories, and also ampoules. These are produced in a manner known per se, for example by means of conventional mixing, granulating, coating, solution or lyophilization processes. So you can use pharmaceutical preparations for oral Receive application by combining the active ingredient with solid carriers, optionally granulating a mixture obtained and processing the mixture or granules, if desired or necessary after the addition of suitable auxiliaries, to tablets or Dragέe cores.

Suitable carriers are in particular fillers such as sugar, e.g. Lactose, sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphates, e.g. Tricalcium phosphate or calcium hydrogen phosphate, further binders, such as starch paste, using e.g. of corn, wheat, rice or potato starch, gelatin, gum tragacanth, methyl cellulose and / or polyvinyl pyrrolidone, and, if desired, disintegrants, such as the above-mentioned starches, furthermore carboxymethyl starch, cross-linked polyvinyl pyrrolidone, agar or alginic acid or a salt thereof, such as sodium alginate . Aids are primarily flow regulators and lubricants, e.g. Silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol. Dragée cores are provided with suitable, possibly gastric juice-resistant coatings, whereby one of the things Concentrated sugar solutions, which may contain arabic gum, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, lacquer solutions in suitable organic solvents or solvent mixtures or, for the production of gastric juice-resistant coatings, solutions of suitable cellulose preparations, such as acetyl cellulose phthalate or hydroxypropyl methyl cellulose phthalate. Dyes or pigments, e.g. for identification or for labeling different doses of active ingredient.

Other pharmaceutical preparations that can be used orally are plug-in capsules made of gelatin and soft, closed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The capsules can contain the active ingredient in the form of granules, e.g. in a mixture with fillers such as lactose, binders such as starches and / or lubricants such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active ingredient is preferably dissolved or suspended in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols, stabilizers also being able to be added.

Suitable rectally applicable pharmaceutical preparations are, for example, suppositories which consist of a combination of the active ingredient with a suppository base. Natural or synthetic suppositories are suitable, for example Triglycerides, paraffin hydrocarbons, polyethylene glycols and higher alkanols. Gelatin rectal capsules can also be used, which contain a combination of the active ingredient with a base material. Liquid mass triglycerides, polyethylene glycols and paraffin hydrocarbons are possible as mass masses.

For parenteral administration, primarily aqueous solutions of an active ingredient in water-soluble form, e.g. a water-soluble salt, further suspensions of the active ingredient, such as corresponding oily injection suspensions, using suitable lipophilic solvents or vehicles, such as fatty oils, e.g. Sesame oil, or synthetic fatty acid esters, e.g. Ethyl oleate or triglycerides, or aqueous injection suspensions containing viscosity-increasing substances, e.g. Contain sodium carboxymethyl cellulose, sorbitol and / or dextran, and optionally also stabilizers.

The dosage of the active ingredient can depend on various factors, such as the mode of administration, warm-blooded species, age and / or individual condition. In the normal case, an approximate daily dose of approximately 10 mg to approximately 2250 mg, in particular approximately 10 to approximately 250 mg, is to be estimated for a patient weighing approximately 75 kg when administered orally.

The following examples illustrate the invention described above; however, they are not intended to limit the scope in any way. Temperatures are given in degrees Celsius (° C).

Example 1:

3- (S) -r (1- (S) -carboxy-3-cvclohexylpropyl) amino1-5- (p-isopropylbenzyl) -4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine

1.5 g of 3- (S) - [(S) -l-ethoxycarbonyl-3-cyclohexyl-propyl) amino] -5- (p-isopropylbenzyl) - 4-oxo-2,3,4,5-tetrahydro-l, 5-benzoxazepine are dissolved in 36 ml of methanol, mixed with 5 ml of 2N aqueous sodium hydroxide solution and stirred for 6 hours at room temperature. The reaction mixture is acidified with 1N hydrochloric acid, extracted twice with ethyl acetate and the organic phases are washed twice with water. The combined ethyl acetate phases are dried over sodium sulfate and evaporated. The residue is taken up in a little ether and crystallizes spontaneously. The material is filtered off and dried overnight at 80 ° C. in a high vacuum. Mp 120-122 ° C.

The starting material can be produced, for example, as follows:

a) (S) -3- (tert-Butoxycarbonylamino) -5- (p-isopropylbenzyl) -2,3,4,5-tetrahvdro-1,5-benzoxazepin-4-one

44 g of (S) -3- (tert-butoxycarbonylamino) -2,3-dihydro-1,5 (5H) -benzoxazepin-4-one (Chem. Pharm. Bull. 34, 1128 (1986)) are added in 450 ml absolute dimethylformamide dissolved, mixed with 44 g of potassium carbonate and stirred for 2.5 hours at room temperature. The first third (of a total of 32 g) of p-isopropylbenzyl chloride and 1.4 g of potassium iodide are added and the mixture is stirred at room temperature for 15 hours. The second third of p-isopropylbenzyl chloride is added and after a further 24 hours the last third, after which the mixture is stirred again for 48 hours. The reaction mixture is concentrated in a high vacuum, taken up in ethyl acetate, washed with water, dilute hydrochloric acid and again water and dried over sodium sulfate. Flash chromatography (900 g silica gel, eluent petroleum ether / ethyl acetate 4: 1) provides the product as a resin. R _r value (eluent hexane / ethyl acetate 1: 4): 0.33.

b) (S) -3-Amino-5- (p-isopropylbenzyl) -4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine hydrochloride

55 g of (S) -3- (tert-butoxycarbonylamino) -5- (p-isopropylbenzyl) - 2,3,4,5-tetrahydro-l, 5-benzoxazepin-4-one are in about 5 hydrochloric acid in 180 ml dissolved in ethyl acetate, foam forming. After stirring for two hours, the ocher-colored suspension is concentrated and recrystallized from ether. The hygroscopic product has an mp of 215 ° C (dec.).

c) 3- (S) - [(1- (S) -ethoxycarbonyl-3-cvclohexylpropyl) aminol-5- (p-isopropylbenzyl) - 4-oxo-2,3,4,5-tetrahydro-l, 5- benzoxazepine

1.5 g (S) -3-amino-4-oxo-5- (p-isopropylbenzyl) -2,3,4,5-tetrahydro-l, 5-benzoxazepine hydrochloride, 2.93 g (R) -alpha - [[ (4-nitrophenyl) sulfonyl] oxy] -4-cyclohexylbutyric acid ethyl ester (Helv. Chim. Acta 71 (2), 337, 1988) 1.85 ml of N-methylmorpholine and 2 ml of dimethylformamide are heated to 75 ° C. over 3 days The reaction mixture is concentrated and separated by means of flash chromatography (230 g silica gel, eluent hexane / ethyl acetate 4: 1). The product is obtained as a colorless resin. R _r value (eluent hexane / ethyl acetate 4: 1): 0.36.

Example 2:

3- (R) -r (1- (S) -carboxy-3-cvclohexylpropyl) amino1-5- (p-isopropylbenzyl) -4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine

Analogously to Example 1, starting from 1.3 g of 3- (R) - [(1- (S) -ethoxycarbonyl-3-cyclohexylpropyl) amino] -5- (p-isopropylbenzyl) -4-oxo-2,3,4, 5-tetrahydro-1,5-benzoxazepine. Crystallization from pentane, mp around 80 ° C (amorphous). R _r value (eluent: methylene chloride / methanol / ammonia conc. 60: 10: 1): 0.5. Crystallization from ether.

The starting material can be produced, for example, as follows:

a) (R) -3- (tert-Butoxycarbonylamino) -5- (p-isopropylbenzyl) -2,3.4,5-tetrahydro-5-benzoxazepin-4-one

Obtained analogously to the instructions for Example la) starting from 4.8 g of (R) -3- (tert-butoxycarbonylamino) -2,3-dihydro-1,5-benzoxazepin-4-one (prepared analogously to (S) -3 - (tert-Butoxycarbonylamino) -2,3-dihydro-l, 5-benzoxazepin-4-one, starting from N-Boc- (D) - serine), 4.4 g p-isopropylbenzyl chloride, 2.9 g potassium carbonate and 166 mg potassium iodide. R _r value (eluent: hexane / ethyl acetate 4: 1): 0.33.

b) (R) -3-Amino-5- (p-isopropylbenzyl) -4-oxo-2,3,4,5-tetrahvdro-l, 5) -benzoxazepine hydrochloride Obtained analogously to the procedure for Example 1b) starting from 6.1 g of (R) -3- (tert-butoxycarbonylamino) -2,3,4,5-tetrahydro-5- (p-isopropylbenzyl) -1,5-benzoxazepine 4-on. Mp 214 ° C (dec.).

c) 3- (RH (1- (S) -ethoxycarbonyl-3-cyclohexylpropyl) amino1-5- (p-isopropylbenzyl) -4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine

Obtained analogously to the instructions for example lc) starting from (R) -3-amino-5- (p-isopropylbenzyl) -4-oxo-2,3,4,5-tetrahydro-l, 5-benzoxazepine hydrochloride, 2.93 g of (R) -alpha - [[(4-nitrophenyl) sulfonyl] oxy] -4-cyclohexyl-butyric acid ethyl ester and 1.85 ml of N-methylmorpholine. Colorless resin, R _r value (eluent hexane / ethyl acetate 4: 1): 0.36.

Example 3:

The following can be prepared in an analogous manner, for example as described in Example 1 or 2:

3- (S) - [(1- (S) -carboxyethyl) amino] -5- (p-isopropylbenzyl) -4-oxo-2,3,4,5-tetrahydro-

1,5-benzoxazepine; Mp 200 °;

3- (R) - [(l- (S) -carboxyethyl) amino] -5- (p-isopropylbenzyl) -4-oxo-2,3,4,5-tetrahydro-

1,5-benzoxazepine;

3- (S) - [(1- (S) -carboxypropyl) amino] -5- (p-isopropylbenzyl) -4-oxo-2,3,4,5-tetrahydro-

1,5-benzoxazepine; Mp of hydrochloride: 120 °;

3- (R) - ([l- (S) -carboxypropyl) amino] -5- (p-isopropylbenzyl) -4-oxo-2,3,4,5-tetrahydro-

1,5-benzoxazepine;

3- (S) - [(1- (S) -carboxy-isobutyl) amino] -5- (p-isopropylbenzyl) -4-oxo-2,3,4,5-tetrahydro-

1,5-benzoxazepine; Mp of the hydrochloride: 160 ° (dec.);

3- (R) - [(1- (S) -carboxy-isobutyl) amino] -5- (p-isopropylbenzyl) -4-oxo-2,3,4,5-tetrahydro-

1,5-benzoxazepine;

3- (S) - [(1- (S) -carboxy-butyl) amino] -5- (p-isopropylbenzyl) -4-oxo-2,3,4,5-tetrahydro-

1,5-benzoxazepine; Mp of the hydrochloride: 100 °;

3- (R) - [(1- (S) -carboxy-butyl) amino] -5- (p-isopropylbenzyl) -4-oxo-2,3,4,5-tetrahydro-

1,5-benzoxazepine;

3- (S) - [(1- (S) -carboxypentyl) amino] -5- (p-isopropylbenzyl) -4-oxo-2,3,4,5-tetrahydro-

1,5-benzoxazepine; Mp of the hydrochloride: 145 ° (dec.);

3- (S) - [(1- (R) -carboxypentyl) amino] -5- (p-isopropylbenzyl) -4-oxo-2,3,4,5-tetrahydro-

1,5-benzoxazepine; Mp of hydrochloride: 130 ° (dec.);

3- (S) - [(1- (S) -carboxy-isopentyl) amino] -5- (p-isopropylbenzyl) -4-oxo-2,3,4,5-tetrahydro- 1,5-benzoxazepine; Mp of the hydrochloride: 155 ° (dec.);

3- (R) - [(1- (S) -carboxy-isopentyl) amino] -5- (p-isopropylbenzyl) -4-oxo-2,3,4,5-tetrahydro-

1,5-benzoxazepine;

3- (S) - [(1- (S) -carboxy-2-cyclohexyl-ethyl) amino] -5- (p-isopropylbenzyl) -4-oxo-2,3,4,5-tetrahydro-1,5 -benzoxazepine; Mp of the hydrochloride: 166 ° (dec.);

3- (S) - [(1- (R) -carboxy-2-cyclohexyl-ethyl) amino] -5- (p-isopropylbenzyl) -4-oxo-2,3,4,5-tetrahydro-1,5 -benzoxazepine;

3- (S) - [(1- (S) -carboxy-2-phenyl-ethyl) amino] -5- (p-isopropylbenzyl) -4-oxo-2,3,4,5-tetra-hydro-l , 5-benzoxazepine; Mp of the hydrochloride: 100 °;

3- (R) - [(1- (S) -carboxy-2-phenyl-ethyl) amino] -5- (p-isopropylbenzyl) -4-oxo-2,3,4,5-tetra-hydro-1 , 5-benzoxazepine;

3- (S) - [1- (S) -carboxy-2- (p-methoxyphenyl) -ethyl] amino-5- (p-isopropylbenzyl) -4-oxo-

2,3,4,5-tetrahydro-1,5-benzoxazepine; Mp of hydrochloride: 110 °;

3- (S) - [1- (R) -carboxy-2- (p-methoxyphenyl) ethyl] amino-5- (p-isopropylbenzyl) -4-oxo-

2,3,4,5-tetrahydro-1,5-benzoxazepine; Mp of hydrochloride: 120 °;

3- (S) - [1- (S) -carboxy-2- (p-fluorophenyl) ethyl] amino-5- (p-isopropylbenzyl) -4-oxo-

2,3,4,5-tetrahydro-1,5-benzoxazepine; Mp of hydrochloride: 90 °;

3- (R) - [1- (S) -carboxy-2- (p-fluorophenyl) ethyl] amino-5- (p-isopropylbenzyl) -4-oxo-

2,3,4,5-tetrahydro-1,5-benzoxazepine;

3- (S) - [(1- (S) -carboxy-3-phenyl-propyl) amino] -5- (p-isopropylbenzyl) -4-oxo-2,3,4,5-tetra-hydro-l , 5-benzoxazepine; Mp of hydrochloride: 191-195 °;

3- (R) - [(1- (S) -carboxy-3-phenyl-propyl) amino] -5- (p-isopropylbenzyl) -4-oxo-2,3,4,5-tetra-hydro-1 , 5-benzoxazepine.

Example 4:

In an analogous manner, for example as described in Example 1, the 3- (S) -

Prepare [(1- (S) -carboxy-ethyl) amino] -5- (p-isopropylbenzyl) -4-oxo-2,3,4,5-tetrahydro-l, 5-benzoxazepine starting from 400 mg 3- (S) - [(1- (S) ethoxycarbonyl-ethyl) amino] -

5- (p-isopropylbenzyl) -4-oxo-2,3,4,5-tetrahydro-l, 5-benzoxazepine by hydrolysis with dilute, aqueous NaOH solution. Mp 200 ° C.

The starting material can be produced, for example, as follows:

3- (S) - [(1- (S) -ethoxycarbonyl-ethyl) amino] -5- (p-isopropylbenzyl) -4-oxo-2,3,4,5-tetra-hydro-1,5-benzoxazepine .

Analogous to example lc) starting from 600 mg (R) -3-amino-4-oxo-2,3,4,5-tetrahydro- 5- (p-Isopropylbenzyl) -1, 5 (5H) -benzoxazepine hydrochloride, 1.57 g (R) -alpha - [[(4-nitrophenyl) sulfonyl] oxy] propionic acid ethyl ester and 0.76 ml N-methylmorpholine . Rf value (eluent hexane / ethyl acetate 2: 1) 0.27.

(R) -alpha - [[(4-nitrophenyl) sulfonyl] oxy] propionic acid ethyl ester was obtained analogously to the sulfonic acid ester described in Example lc) starting from 10.3 g of ethyl D-lactic acid, 21.3 g of 4-nitrobenzenesulfonyl chloride and 14.6 ml of triethylamine . Rf value (eluent hexane / ethyl acetate 2: 1) 0.44.

Example 5:

In an analogous manner, for example as described in Example 1, the 3- (S) - [(1- (S) -carboxy-3-methylbutyl) amino] -5- (p-isopropylbenzyl) -4-oxo Prepare 2,3,4,5-tetra-hydro-l, 5-benzoxazepine hydrochloride starting from 650 mg of 3- (S) - [(l- (S) benzyloxycarbonyl-3-methylbutyl) amino] -5- ( p-isopropylbenzyl) -4-oxo-2,3,4,5-tetra-hydro-l, 5-benzoxazepine by normal pressure hydrogenation at room temperature in the presence of 300 mg palladium-carbon in 20 ml dioxane (10%). After filtering off the catalyst, the product is converted into the hydrochloride by treatment with 3.7 N HCl in ethyl acetate, mp. 155 ° C. (dec.).

The starting material can be obtained, for example, as follows:

15 g of D-leucine are placed in 172 ml of 1N aqueous sulfuric acid with ice bath cooling and 11.8 g of sodium nitrate in 45 ml of water are added for 1 hour. The reaction solution is stirred overnight at room temperature, adjusted to pH = 6 with sodium bicarbonate, concentrated to about 60 ml and adjusted to pH = 3 with 40 percent phosphoric acid. It is extracted 3 times with tetrahydrofuran, the organic phase with brine washed, dried and concentrated The crude product is evaporated several times with toluene. The residue is mixed with hexane, whereby the product (R) -alpha- [[(4-nitrophenyl) sulfonyl] oxy] -4-methylvaleric acid as white crystals (mp. 60-62 ° C, after drying) fails.

13.5 g of (R) -alpha - [[(4-nitrophenyl) sulfonyl] oxy] -4-methyl-valeric acid are heated to reflux with 42.1 ml of benzyl alcohol and 2.3 ml of thionyl chloride for 6 hours on a water separator. After cooling, the dark yellow solution is evaporated, taken up in ethyl acetate, washed with brine, dried and concentrated. Distillation at 118-120 ° C / 0.16 mbar gives the pure benzyl ester. (R) -alpha - [[(4-nitrophenyl) sulfonyl] oxy] -2- (4-methylvaleric acid benzyl esters are obtained analogously to the sufonic acid ester described in Example lc) starting from 12.5 g of 2- (R) -hydroxy-5- benzyl valerate, 13.7 g of 4-nitrobenzenesulfochloride and 9.4 ml of triethylamine. Rf value (eluent hexane / ethyl acetate 2: 1) 0.44. Rf value (eluent hexane / ethyl acetate 2: 1) 0.46.

3- (S) - [(1- (S) -benzyloxycarbonyl-l-isobutyl) amino] -5- (p-isopropylbenzyl) -4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine was obtained analogously to Example lc) starting from 600 mg (S) -3-amino-4-oxo-2,3,4,5-tetrahydro-5- (p-isopropylbenzyl) -1,5 (5H) -benzoxazepine hydrochloride , 2.1 g (R) -alpha - [[(4-nitrophenyl) sulfonyl] oxy] -4-methylvaleric acid benzyl ester and 0.76 ml N-methylmorpholine. Rf value (eluent hexane / ethyl acetate 2: 1) 0.56.

Example 6:

In an analogous manner, for example as described in Example 1, the 3- (S) - [(1- (S) -carboxy-2-methylpropyl) amino] -5- (p-isopropylbenzyl) -4-oxo Prepare 2,3,4,5-tetra-hydro-l, 5-benzoxazepine hydrochloride starting from 600 mg of 3- (S) - [(l- (S) benzyloxycarbonyl-

1-isopropyl) amino] -5- (p-isopropylbenzyl) -4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine by normal pressure hydrogenation at room temperature in the presence of 200 mg palladium-carbon in 20 ml dioxane (10%). After filtering off the catalyst, the product is converted into the hydrochloride by treatment with 3.7 N HCl in ethyl acetate. Mp 160 ° C (dec.).

The starting material can be obtained, for example, as follows:

3- (S) - [(1- (S) -benzyloxycarbonyl-l-isobutyl) amino] -5- (p-isopropylbenzyl) -4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine was obtained analogously to Example lc) starting from 600 mg (S) -3-amino-4-oxo-2,3,4,5-tetrahydro-5- (p-isopropylbenzyl) -1,5 (5H) -benzoxazepine hydrochloride , 1.77 g of (R) -alpha- [trifluoromethanesulfonyl3oxy] -3-methylbutyric acid benzyl ester (Tetrahedron 19, 6623, 1990) and 0.76 ml of N-methylmorpholine. Rf value (eluent hexane / ethyl acetate 4: 1) 0.26.

Example 7:

In an analogous manner, for example as described in Example 1, the 3- (S) - [(l- (S) -carboxy-2-cyclohexylethyl) amino] -5- (p-isopropylbenzyl) -4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine hydrochloride, starting from 520 mg of 3- ( S) - [(1- (S) -Benzyloxycarbonyl-2-cyclohexylethyl) amino] -5- (p-isopropylbenzyl) -4-oxo-2,3,4,5-tetrahydro-l, 5-benz- oxazepine by normal pressure hydrogenation at room temperature with palladium-carbon (10%) in 10 ml dioxane. The hydrogenation product is converted into the hydrochloride by treatment with 5N HCl in ethyl acetate and dried. Mp 166 ° C (dec.).

The starting material can be obtained analogously to Example 5 as follows:

1.5 g of D-phenyllactic acid are hydrogenated under normal pressure for 2 hours in the presence of 0.25 g of "Nishimura" catalyst (Rh2θ3 / Ptθ2, Degussa) in 20 ml of methanol until saturated. After filtering off the catalyst and concentrating, the product is obtained as a yellow oil. Rf value (eluent: toluene / methylene chloride / ethyl acetate / formic acid 16: 40: 40: 4) 0.52.

1.9 g of (R) -alpha - [[(4-nitrophenyl) sulfonyl] oxy] -3-cyclohexylpropionic acid are refluxed with 2.27 ml of benzyl alcohol and 0.1 ml of thionyl chloride for 20 hours on a water separator. After cooling, the dark yellow solution is evaporated, taken up in ethyl acetate, washed with brine, dried and concentrated. Flashchromato¬ graphie (mobile phase petroleum ether / ethyl acetate 17: 3) provides the pure product as a colorless resin. Rf value (eluent hexane / ethyl acetate 4: 1) 0.27.

(R) -alpha - [[(4-nitrophenyl) sulfonyl] oxy] -3-cyclohexylpropionic acid benzyl ester was obtained analogously to the sufonic acid ester described in Example lc) starting from 1.9 g of benzyl 2- (R) -3-cyclohexylpropionate, 1.8 g 4 -Nitrobenzenesulfochlorid and 1.21 ml triethylamine. Rf value (eluent hexane / ethyl acetate 4: 1) 0.41.

837 mg (S) -3- amino-4-oxo-2,3,4,5-tetrahydro-5- (p-isopropylbenzyl) - 1, 5 (5H) -benzoxazepin hydrochloride, 3.45 g (R) -alpha - [[(4-nitrophenyl) sulfonyl] oxy] -3-cyclohexylpropionic acid benzyl ester, 1.06 ml of N-methylmorpholine and 4 ml of dimethylformamide are heated to 75 ° C. for 3 days. The reaction mixture is concentrated and by means of flash chromatography separated (360 g silica gel, eluent petroleum ether / ethyl acetate 4: 1). The product is obtained as a yellowish resin. Rf value (eluent hexane / ethyl acetate 4: 1) 0.25.

Example 8: In an analogous manner, for example as described in Example 1, the 3- (S) - [(1- (S) -carboxy-2-phenylethyl) amino] -5- (p-isopropylbenzyl) -4-oxo-2 can be used , 3,4,5-tetrahydro-1,5-benzoxazepine hydrochloride, obtained analogously to Example 5 by hydrogenation of 0.41 g of 3- (S) - [(1- (S) -benzyloxycarbonyl-2-phenylethyl) amino] - 5- (p-isopropylbenzyl) -4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine in the presence of 0.2 g palladium-carbon (10%) in 10 ml dioxane. Mp 100 ° C, Rf value (eluent methylene chloride methanol / ammonia conc. 60: 10: 1) 0.23.

The starting material can be obtained analogously to Example 5 as follows, for example:

Starting from 11 g of benzyl D-phenyllactic acid, 10.5 g of 4-nitrobenzenesulfonyl chloride and 6 ml of triethylamine, (R) -alpha - [[(4-nitrophenyl) sulfonyl] oxy] -3-phenyl-propionic acid benzyl ester is obtained. Rf value (eluent ethyl acetate / hexane 1: 4) 0.3.

Starting from 2.55 g of (R) -alpha - [[(4-nitrophenyl) sulfonyl] oxy] -3-phenylpropionic acid benzyl ester, 800 mg of (R) -3-amino-4-oxo-2,3,4,5- tetrahydro-5- (p-isopropylbenzyl) -1,5 (5H) -benzoxazepine hydrochloride and 0.88 ml N-methylmorpholine are obtained after flash chromatography (1 kg silica gel, eluent petroleum ether / ethyl acetate 3: 1) 3- (S) - [ (1- (S) -Benzyloxycarbonyl-2-phenylethyl) amino] -5- (p-isopropylbenzyl) -4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine as a yellow oil. Rf value (mobile phase petroleum ether / ethyl acetate 3: 1) 0.19.

Example 9:

In an analogous manner, for example as described in Example 1, the 3- (S) - [(1- (S) -carboxy-3-phenylpropyl) amino] -5- (p-methylbenzyl) -4-oxo-2 can be used , 3,4,5-tetrahydro-1,5-benzoxazepine hydrochloride, obtained analogously to Example 1 by hydrolysis of 3- (S) - [(1 - (S) -ethoxycarbonyl-3-phenylpropyl) amino] -5- (p-methylbenzyl) -4-oxo-2,3,4,5-tetrahydro-l, 5-benzoxazepine. The hydrochloride is produced by treatment with 5N HCl in ethyl acetate. Rf value (eluent methylene chloride / methanol - ammonia conc. 60: 10: 1) 0.48.

The preparation of (R) -alpha - [[(4-nitrophenyl) sulfonyl] oxy] -4-phenyl-butyric acid ethyl ester is described in Helv. Chim. Acta 71 (2), 337, 1988.

Example 10:

In an analogous manner, for example as described in Example 1, the 3- (S) - [(! - (S) -carboxy-3-phenylpropyl) amino] -5- (p-isopropylbenzyl) -4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazeρin, obtained analogously to Example 8 by hydrolysis of 0.97 g 3- (S) - [(1- (S) -ethoxycarbonyl-3-phenylpropyl) amino] -5- (p-isopropylbenzyl) -4-oxo-2,3,4,5-tetrahydro-l, 5- benzoxazepine in 22 ml ethanol, 10 ml water and 1.55 g NaOH. Rf value (eluent methylene chloride / methanol / ammonia conc. 60: 10: 1) 0.23. M.p. 191-192 ° C.

The starting material can be obtained, for example, as follows:

17 g (S) -3-amino-4-oxo-2,3,4,5-tetrahydro-5- (p-isopropylbenzyl) -l, 5 (5H) -benzoxazepine hydrochloride, 48.2 g (R) -alpha - [[(4-Nitrophenyl) sulfonyl] oxy] -4-phenyl-butyric acid ethyl ester and 19 ml of N-methylmorpholine are heated to 80 ° C. for 12 hours. After cooling, it is taken up in ethyl acetate, extracted with aqueous sodium hydrogen carbonate solution, dried and evaporated. Rf value (eluent ethyl acetate / hexane 1: 2) 0.34.

Example 11:

In an analogous manner, for example as described in Example 1, the 3- (S) - [(1- (S) -carboxy-3-cyclohexylpropyl) amino] -5- (p-methylbenzyl) -4-oxo-2 can be used , 3,4,5-tetrahydro-1,5-benzoxazepine hydrochloride, analogously to Example 1, by hydrolysis of 29.2 g of 3- (S) - [(1- (S) ethoxycarbonyl-3-phenylpropyl) amino] -5- (p-methylbenzyl) -4-oxo-2,3,4,5-tetrahydro-l, 5-benzoxazepine in 150 ml EtOH, 76 ml 2N NaOH and 25 ml water. Treatment with HCl in methylene chloride gives the hydrochloride of the product. M.p. 124-127 ° C.

The starting product can be obtained, for example, as follows:

Analogously to the procedure for Example la), 20 g of (S) -3-tert-butoxycarbonylamino-2,3-dihydro-1,5, (5H) -benzoxazepin-4-one, 15 g of p-methyllylbenzyl bromide are obtained , 9.67 g of potassium tert-butoxide in 120 ml of DMF (S) -3-tert-butoxycarbonylamino-2,3,4,5-tetrahydro-5- (p-methylbenzyl) -l, 5 (5H) -benzoxazepine 4-on. Rf value (mobile phase ethyl acetate / hexane 1: 4) 0.28.

Analogously to the procedure for Example 1b), starting from 2 g of (R) -3-tert-butoxycarbonylamino-2,3,4,5-tetrahydro-5- (p-methylbenzyl) -1,5 (5H) -benzoxazepin-4-one by treatment with HCl in ethyl acetate (15 ml) (S) -3-amino-4-oxo-2,3,4,5-tetrahydro- 5- (p-methylylbenzyl) -1,5 (5H) -benzoxazepine hydrochloride. After evaporation of the reaction mixture, the residue is triturated with ether, whereby the product is obtained as a beige powder. Rf value (eluent methylene chloride / MeOH 95: 5) 0.3.

3- (S) - [(1- (S) -ethoxycarbonyl-3-cyclohexylpropyl) amino] -5- (p-methylbenzyl) -4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine is obtained analogously to the instructions for example lc) starting from 20 g of (S) -3-amino-4-oxo-2,3,4,5-tetrahydro-5- (p-methylbenzyl) -1,5 (5H) - benzoxazepine hydrochloride, 37.6 g (R) -alpha - [[(4-nitrophenyl) sulfonyl] oxy] -4-cyclo-hexyl-butyric acid, ethyl ester and 8.6 ml of N-methylmorpholine. After rubbing with petroleum ether / methyl tert-butyl ether (7: 1), the product is obtained as a beige powder at -78 ° C. Rf value (eluent petroleum ether / ethyl acetate 4: 1) 0.19.

Example 12:

In an analogous manner, for example as described in Example 1, the 3- (S) - [(l-

(S) -carboxypropyl) amino] -5- (p-isopropylbenzyl) -4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine hydrochloride, mp. 120 ° C., Rf value (eluent methylene chloride V-

Concentrated methanol / ammonia. 60: 10: 1) 0.23, analogously to Example 5, starting from D-2-aminobutyric acid.

Example 13:

(S) -carboxy-butyl) amino] -5- (p-isopropylbenzyl) -4-oxo-2,3,4,5-tetrahydro-l, 5-benzoxazepin hydrochloride, mp 100 ° C., Rf value (eluent methylene chloride / -

Concentrated methanol / ammonia. 60: 10: 1) 0.27; analogously to Example 5 starting from D-norvaline.

Example 14:

(S) -carboxypentyl) amino] -5- (p-isopropylbenzyl) -4-oxo-2,3,4,5-tetrahydro-l, 5-benzoxazepine hydrochloride and 3- (S) - [ Prepare (1- (R) -carboxypentyl) amino] -5- (p-isopropylbenzyl) -4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine hydrochloride.

l- (S) -isomer: mp 145 ° C, Rf value (eluent methylene chloride / methanol / ammonia conc. 60: 10: 1) 0.25. Obtained by hydrolysis of the more polar ethyl ester; 1- (R) _: Isomer: mp 130 ° C (dec.). Obtained by hydrolysis of the less polar ethyl ester; Analogously to Example 5, starting from ethyl D, L-2-hydroxycaproate. The two diastereomers are at stage 3- (S) - [(1- (S) -ethoxycarbonylpentyl) amino] -5- (p-iso- propylbenzyl) -4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine separated by flash chromatography. Rf values (eluent ethyl acetate / petroleum ether 15:85) 0.33 and 0.23.

Example 15:

In an analogous manner, for example as described in Example 1, the 3- (S) - [(1- (S) -carboxy-2- (p-methoxyphenyl) ethyl) amino] -5- (p-isopropylbenzyl) - 4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine hydrochloride and 3- (S) - [(1 - (R) -carboxy-2- (p-methoxyphenyl) ethyl) amino] -5- (p-isopropylbenzyl) -4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine hydrochloride. I- (S) -isomer: mp 120 ° C., Rf value (eluent methylene chloride / methanol / ammonia conc. 60: 10: 1) 0.22. By hydrolysis of the non-polar methyl ester. 2- (R) -isomer: mp 110 ° C, Rf value (eluent methylene chloride / methanol / ammonia conc. 60: 10: 1) 0.18. By hydrolysis of the more polar methyl ester; analogously to Example 5 starting from D, L-p-methoxyphenylalanine. The two diastereomers are at step 3- (S) - [(1- (R / S) -methoxycarbonyl-2- (p-methoxyphenyl) ethyl) amino] -5- (p-isopropylbenzyl) -4-oxo-2 , 3,4,5-tetrahydro-l, 5-benzoxazepine separated by flash chromatography. Rf values (eluent ethyl acetate / petroleum ether 4) 0.3 and 0.28.

Example 16:

(S) -carboxy-2- (p-fluoro-phenyl) ethyl) amino] -5- (p-isopropylbenzyl) -4-oxo-2,3,4,5-tetra-hydro-l, 5-benzoxazepine Prepare hydrochloride, mp 90 ° C, Rf value (eluent

Methylene chloride / methanol ammonia conc. 60: 10: 1) 0.24; analogous to Example 5 starting from D-p-fluorophenylalanine.

Example 17:

(S) -carboxy-2-benzyloxy-ethyl) amino] -5- (p-isopropylbenzyl) -4-oxo-2,3,4,5-tetrahydro-

Prepare 1,5-benzoxazepine, mp 178-182 ° C; analogous to Example 5 starting from

D-benzylserine.

Example 18:

(S) -carboxy-3-phenylpropyl) amino] -5- (p-isopropylbenzyl) -4-oxo-2,3,4,5-tetrahydro-l, 5-benzoxazepine, m.p. 191-195 ° C. Example 19:

(S) -carboxy-3-phenylpropyl) amino] -5- (m-methylylbenzyl) -4-oxo-2,3,4,5-tetrahydro-

Prepare 1,5-benzoxazepine hydrochloride, Rf value (eluent methylene chloriαV-

Concentrated methanol / ammonia. 60: 10: 1) 0.48, analogous to Example 1, starting from m-methylbenzyl chloride.

Example 20:

The following can be prepared in an analogous manner, for example as described in one of the preceding examples:

3- (S) - [(1- (S) -carboxy-3-phenylpropyl) amino] -5- (p-aminobenzyl) -4-oxo-2,3,4,5-tetrahydro-1,5 -benzoxazepine;

3- (S) - [(1- (S) -carboxy-3-phenylpropyl) amino] -5- (p-dimethylaminobenzyl) -4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine ;

3- (S) - [(1- (S) -carboxy-3-phenylpropyl) amino] -5- (ρ-tertbutylbenzyl) -4-oxo-2,3,4,5-tetrahydro-1,5 -benzoxazepine;

3- (S) - [(1- (S) -carboxy-3-phenylpropyl) amino] -5- (p-methoxybenzyl) -4-oxo-2,3,4,5-tetrahydro-1,5 -benzoxazepine;

3- (S) - [(1- (S) -carboxy-3-phenylpropyl) amino] -5- (p-ethylbenzyl) -4-oxo-2,3,4,5-tetrahydro-1,5 -benzoxazepine;

3- (S) - [(1- (S) -carboxy-3-phenylpropyl) amino] -5- (p-nitrobenzyl) -4-oxo-2,3,4,5-tetrahydro-1,5 -benzoxazepine;

3- (S) - [(1- (S) -carboxy-3-phenylpropyl) amino] -5- (p-fluorobenzyl) -4-oxo-2,3,4,5-tetrahydro-1,5 -benzoxazepine;

3- (S) - [(1- (S) -carboxy-3-phenylpropyl) amino] -5- (p-chlorobenzyl) -4-oxo-2,3,4,5-tetrahydro-1,5 -benzoxazepine;

3- (S) - [(1- (S) -carboxy-3-phenylpropyl) amino] -5- (p-bromobenzyl) -4-oxo-2,3,4,5-tetrahydro-1,5 -benzoxazepine;

3- (S) - [(1- (S) -carboxy-3-phenylpropyl) amino] -5- (p-iodobenzyl) -4-oxo-2,3,4,5-tetrahydro-

1,5-benzoxazepine;

3- (S) - [(1- (S) -carboxy-3-cyclohexylpropyl) amino] -5- (p-aminobenzyl) -4-oxo-2,3,4,5-tetrahydro-1,5 -benzoxazepine;

3- (S) - [(1- (S) -carboxy-3-cyclohexylpropyl) amino] -5- (p-dimethylaminobenzyl) -4-oxo-

2,3,4,5-tetrahydro-1,5-benzoxazepine;

3- (S) - [(1- (S) -carboxy-3-cyclohexylpropyl) amino] -5- (p-tert.butylbenzyl) -4-oxo-2,3,4,5-tetrahydro-1,5 -benzoxazepine; 3- (S) - [(1- (S) -carboxy-3-cyclohexylpropyl) amino] -5- (p-methoxybenzyl) -4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine ;

3- (S) - [(1- (S) -carboxy-3-cyclohexylpropyl) amino] -5- (p-ethylbenzyl) -4-oxo-2,3,4,5-tetrahydro-1,5 -benzoxazepine;

3- (S) - [(1- (S) -carboxy-3-cyclohexylpropyl) amino] -5- (p-nitrobenzyl) -4-oxo-2,3,4,5-tetrahydro-1,5 -benzoxazepine;

3- (S) - [(1- (S) -carboxy-3-cyclohexylpropyl) amino] -5- (p-fluorobenzyl) -4-oxo-2,3,4,5-tetrahydro-1,5 -benzoxazepine;

3- (S) - [(1- (S) -carboxy-3-cyclohexylpropyl) amino] -5- (p-chlorobenzyl) -4-oxo-2,3,4,5-tetrahydro-1,5 -benzoxazepine;

3- (S) - [(1- (S) -carboxy-3-cyclohexylpropyl) amino] -5- (p-bromobenzyl) -4-oxo-2,3,4,5-tetrahydro-1,5 -benzoxazepine;

3- (S) - [(1- (S) -carboxy-3-cyclohexylpropyl) amino] -5- (p-iodobenzyl) -4-oxo-2,3,4,5-tetrahydro-1,5 -benzoxazepine;

3- (S) - [(1- (S) -carboxy-2-cyclohexylethyl) amino] -5- (p-aminobenzyl) -4-oxo-2,3,4,5-tetrahydro-1,5 -benzoxazepine;

3- (S) - [(1- (S) -carboxy-2-cyclohexylethyl) amino] -5- (p-dimethylaminobenzyl) -4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine ;

3- (S) - [(1- (S) -carboxy-2-cyclohexylethyl) amino] -5- (p-tert-butylbenzyl) -4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine ;

3- (S) - [(1- (S) -carboxy-2-cyclohexylethyl) amino] -5- (p-methoxybenzyl) -4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine ;

3- (S) - [(1- (S) -carboxy-2-cyclohexylethyl) amino] -5- (p-ethylbenzyl) -4-oxo-2,3,4,5-tetrahydro-1,5 -benzoxazepine;

3- (S) - [(1- (S) -carboxy-2-cyclohexylethyl) amino] -5- (p-nitrobenzyl) -4-oxo-2,3,4,5-tetrahydro-1, 5-benzoxazepine;

3- (S) - [(1- (S) -carboxy-2-cyclohexylethyl) amino] -5- (p-fluorobenzyl) -4-oxo-2,3,4,5-tetrahydro-1,5 -benzoxazepine;

3- (S) - [(1- (S) -carboxy-2-cyclohexylethyl) amino] -5- (p-chlorobenzyl) -4-oxo-2,3,4,5-tetrahydro-1,5 -benzoxazepine;

3- (S) - [(1- (S) -carboxy-2-cyclohexylethyl) amino] -5- (p-bromobenzyl) -4-oxo-2,3,4,5-tetrahydro-1,5 -benzoxazepine;

3- (S) - [(1- (S) -carboxy-2-cyclohexylethyl) amino] -5- (p-iodobenzyl) -4-oxo-2,3,4,5-tetrahydro-1,5 -benzoxazepine;

3- (S) - [(1- (S) -carboxy-2-phenylethyl) amino] -5- (p-aminobenzyl) -4-oxo-2,3,4,5-tetrahydro-1,5 -benzoxazepine; 3- (S) - [(1- (S) -carboxy-2-phenylethyl) amino] -5- (p-dimethylaminobenzyl) -4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine ;

3- (S) - [(1- (S) -carboxy-2-phenylethyl) amino] -5- (p-tert-butylbenzyl) -4-oxo-2,3,4,5-tetrahydro-1,5 -benzoxazepine;

3- (S) - [(1- (S) -carboxy-2-phenylethyl) amino] -5- (p-methoxybenzyl) -4-oxo-2,3,4,5-tetrahydro-1,5 -benzoxazepine;

3- (S) - [(1- (S) -carboxy-2-phenylethyl) amino] -5- (p-ethylbenzyl) -4-oxo-2,3,4,5-tetrahydro-

1,5-benzoxazepine;

3- (S) - [(1- (S) -carboxy-2-phenylethyl) amino] -5- (p-nitrobenzyl) -4-oxo-2,3,4,5-tetrahydro-

1,5-benzoxazepine;

3- (S) - [(1- (S) -carboxy-2-phenylethyl) amino] -5- (p-fluorobenzyl) -4-oxo-2,3,4,5-tetrahydro-

1,5-benzoxazepine;

3- (S) - [(1- (S) -carboxy-2-phenylethyl) amino] -5- (p-chlorobenzyl) -4-oxo-2,3,4,5-tetrahydro-

1,5-benzoxazepine;

3- (S) - [(1- (S) -carboxy-2-phenylethyl) amino] -5- (p-bromobenzyl) -4-oxo-2,3,4,5-tetrahydro-

1,5-benzoxazepine

3- (S) - [(1- (S) -carboxy-2-phenylethyl) amino] -5- (p-iodobenzyl) -4-oxo-2,3,4,5-tetrahydro-

1,5-benzoxazepine;

3- (S) - [(1- (S) -carbamoyl-3-cyclohexylpropyl) amino] -5- (p-isopropylbenzyl) -4-oxo-

2,3,4,5-tetrahydro-1,5-benzoxazepine;

3- (S) - [(1- (S) -carbamoyl-3-phenylpropyl) amino] -5- (p-isopropylbenzyl) -4-oxo-2,3,4,5-tetrahyro-1, 5- benzoxazepine;

3- (S) - [(1- (S) -carbamoyl-2-phenylethyl) amino] -5- (p-isopropylbenzyl) -4-oxo-2,3,4,5-tetrahydro-1, 5-benzoxazepine;

3- (S) - [(1- (S) -carbamoyl-2-cyclohexylethyl) amino] -5- (p-isopropylbenzyl) -4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine ;

3- (S) - [(1- (S) -carbamoyl-3-cyclohexylpropyl) amino] -5- (p-methylbenzyl) -4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine ;

3- (S) - [(1- (S) -carbamoyl-3-phenyl) propylamino] -5- (p-methylbenzyl) -4-oxo-2,3,4,5-tetrahydro-1,5 -benzoxazepine;

3- (S) - [(1- (S) -carbamoyl-2-phenylethyl) amino] -5- (p-methylbenzyl) -4-oxo-2,3,4,5-tetrahydro-1,5 -benzoxazepine;

3- (S) - [(1- (S) -carbamoyl-2-cyclohexylethyl) amino] -5- (p-methylbenzyl) -4-oxo-2,3,4,5-tetrahydro-1,5 benzoxazepine;

3- (S) - [(1- (S) -N-Hydroxy-carbamoyl-3-cyclohexylpropyl) amino] -5- (p-isopropylbenzyl) -

4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine; 3- (S) - [(1- (S) -N-Hydroxy-carbamoyl-3-phenylpropyl) amino] -5- (p-isopropylbenzyl) -4-oxo-

2,3,4,5-tetrahydro-1,5-benzoxazepine;

3- (S) - [(1- (S) -N-hydroxy-carbamoyl-2-phenylethyl) amino] -5- (p-isopropylbenzyl) -4-oxo

2,3,4,5-tetrahydro-1,5-benzoxazepine;

3- (S) - [(1- (S) -N-Hydroxy-carbamoyl-2-cyclohexylethyl) amino] -5- (p-isopropylbenzyl) -4-oxo-2,3,4,5-tetrahydro-1 , 5-benzoxazepine;

3- (S) - [(1- (S) -N-Hydroxy-carbamoyl-3-cyclohexylpropyl) amino] -5- (p-methylbenzyl) -4-oxo-2,3,4,5-tetrahydro-1 , 5-benzoxazepine;

3- (S) - [(1- (S) -N-hydroxy-carbamoyl-3-phenylpropyl) amino] -5- (p-methylbenzyl) -4-oxo-

2,3,4,5-tetrahydro-1,5-benzoxazepine;

3- (S) - [(1- (S) -N-Hydroxy-carbamoyl-2-phenylethyl) amino] -5- (p-methylbenzyl) -4-oxo-

2,3,4,5-tetrahydro-1,5-benzoxazepine;

3- (S) - [(1- (S) -N-Hydroxy-carbamoyl-2-cyclohexylethyl) amino] -5- (p-methylbenzyl) -4-oxo-2,3,4,5-tetrahydro-1 , 5-benzoxazepine.

Example 21:

Tablets containing 50 mg of active ingredient each, e.g. 3- (S) - [(1- (S) -carboxy-3-cyclohexyl-propyl) amino] -5- (p-isopropylbenzyl) -4-oxo-2,3,4,5-tetrahydro-1 , 5-benzoxazepine can be prepared as follows:

Composition for 10000 tablets:

The active ingredient is mixed with the lactose and 292 g of potato starch, the mixture is moistened with an alcoholic solution of the gelatin and granulated through a sieve. After drying, the rest of the potato starch, the talc, the magnesium stearate and the highly disperse silicon dioxide are mixed in and the mixture is pressed into tablets each having a weight of 145.0 mg and an active substance content of 50.0 mg, which, if desired, with partial notches for fine adjustment of the Dosage can be provided. Example 22: Coated tablets containing 100 mg of active ingredient each, for example 3- (S) - [(1- (S) -carboxy-3-cyclohexyl-propyl) amino] -5- (p-isopropylbenzyl) -4-oxo-2 , 3,4,5-tetrahydro-1,5-benzoxazepine can be prepared as follows:

Composition for 1000 tablets:

The active ingredient, the lactose and 40 g of the corn starch are mixed and moistened and granulated with a paste made from 15 g of corn starch and water (with heating). The granules are dried, the rest of the corn starch, the talc and the calcium stearate are added and with mixed with the granules The mixture is pressed into tablets (weight: 280 mg) and these are coated with a solution of hydroxypropyl methylcellulose and shellac in dichloromethane (final weight of the coating tablet: 283 mg).

Example 23: In an analogous manner, for example as described in Examples 20 and 21, tablets and lacquered tablets containing another compound of the formula I or a pharmaceutically acceptable salt of a compound of the formula I, e.g. according to one of Examples 1 to 20, are prepared.

Claims

1. A 3-amino-l-arylalkyl-benzazepin-2-one of the general formula

wherein Ar is aryl;

X represents -O- or -S (O) _n - and n represents 0, 1 or 2; Xi is C ₁ -C ₂ alkylene or represents a direct bond; R _{2 represents} hydrogen, lower alkyl, aryl-lower alkyl or acyl; R _{2 is} lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, aryl-lower alkoxy-lower alkyl, aryl-lower alkyl or C ₃ -C ₇ -cycloalkyl-lower alkyl; R ₃ carboxy; Lower alkoxycarbonyl; Lower alkoxy-lower alkoxycarbonyl; Aryl-lower alkoxycarbonyl; Aryloxycarbonyl; Carbamoyl; Carbamoyl which (i) mono-substituted by hydroxy, lower alkanesulfonyl, Halogenmederalkansulfonyl or arylsulfonyl, (ii) mono-substituted by lower alkyl, lower alkenyl, lower alkynyl, phenyl-or independently disubstituted each other or (iii) di-substituted lower alkylene by lower alkylene or lower alkylene-Z _r where Zj represents O, S or NH; 5-tetrazolyl; PO ₂ H ₂ ; PO ₃ H ₂ or SO ₃ H ₂ ; the ring A or aromatic radicals, independently of one another, are unsubstituted or mono- or polysubstituted by substituents selected from the group consisting of: lower alkyl, aryl-lower alkyl, lower alkoxy-lower alkyl, lower alkoxy, lower alkoxy-lower alkoxy, aryl-lower alkoxy, C ₃ -C ₇ cycloalkyl, C ₃ -C ₇ cycloalkyl-lower alkyl, nitro, halogen, trifluoromethyl, amino, amino, which is mono- or independently disubstituted by lower alkyl, aryl-lower alkyl or aryl or is disubstituted by lower alkylene, lower alkyleneoxy-methylalkylene; a stereoisomer or a salt thereof.

2. A compound according to claim 1 of formula I, wherein

Ar represents phenyl;

X represents -O- or -S (O) _n - and n represents 0, 1 or 2;

X _j C _r C ₂ alkylene or represents a direct bond;

Rι hydrogen, lower alkyl, lower alkyl, which by phenyl, naphthyl, pyrrolyl, Pyridyl, furyl, thienyl, imidazolyl, isoxazolyl or thiazolyl is substituted, lower alkanoyl, lower alkanoyl which is substituted by phenyl, naphthyl, pyrrolyl, pyridyl, furyl, thienyl, imidazolyl, isoxazolyl or thiazolyl, or benzoyl;

R _{2 is} (i) lower alkyl, lower alkyl which is substituted by phenyl, naphthyl, pyrrolyl, pyridyl, furyl, thienyl, imidazolyl, isoxazolyl or thiazolyl, or is C ₃ -C ₇ -cycloalkyl-lower alkyl or (ii) hydroxy-lower alkyl, lower alkoxy-lower alkyl, Nieder¬ alkoxy lower alkyl, the lower alkoxy part being substituted by phenyl, naphthyl, pyrrolyl, pyridyl, furyl, thienyl, imidazolyl, isoxazolyl or thiazolyl; R ₃ denotes (i) carboxy, 5-tetrazolyl, PO ₂ H ₂ , PO ₃ H ₂ or SO ₃ H ₂ or (ii) lower alkoxycarbonyl, lower alkoxy lower alkoxycarbonyl, phenyl lower alkoxycarbonyl, benzoylcarbonyl, carbamoyl, lower alkylcarbamoyl, diniederalkylcarbamoyl, phenylnieder- alkycarbamoyl, diphenyl-lower alkyl-carbamoyl, hydroxy-carbamoyl, lower alkanesulfonyl-carbamoyl, halogenmederalkansulfonyl or phenylsulfonyl; the ring A and carbocyclic and heterocyclic aromatic radicals independently of one another are unsubstituted or mono- or polysubstituted by substituents selected from the group consisting of: lower alkyl, lower alkyl, which is substituted by phenyl, naphthyl, pyrrolyl, pyridyl, furyl, thienyl, Imidazolyl, isoxazolyl or thiazolyl is substituted, lower alkoxy-lower alkyl, lower alkoxy, lower alkoxy-lower alkoxy, phenyl-lower alkoxy, C ₃ -C ₇ cycloalkyl, C ₃ -C ₇ cycloalkyl lower alkyl, nitro, halogen, trifluoromethyl, amino, amino, which by Lower alkyl, phenyl-lower alkyl or phenyl is mono- or independently disubstituted or is disubstituted by lower alkylene, lower alkyleneoxy mineral alkylene; a stereoisomer or a salt thereof.

3. Compound according to spoke 1 of formula I, wherein

Ar represents phenyl;

X represents -O- or -S (O) _n - and n represents 0, 1 or 2; ^x ι Ci-0 ₂ alkylene or stands for a direct bond;

R _{j represents} hydrogen, lower alkyl, phenyl-lower alkyl, lower alkanoyl, phenyl-lower alkanoyl or benzoyl;

R _{3 represents} (i) carboxy, 5-tetrazolyl, PO ₂ H ₂ , PO ₃ H ₂ or SO ₃ H ₂ or (ii) represents carbamoyl or hydroxy-carbamoyl; the ring A and carbocyclic and heterocyclic aromatic radicals are independently unsubstituted or mono- or polysubstituted by substituents selected from the group consisting of: lower alkyl from lower alkyl, phenyl-lower alkyl, Niederalkoxy¬, lower alkoxy, lower alkoxy-lower alkoxy, phenyl-lower alkoxy, C ₃ -C ₇ loalkyl -Cyc-, C ₃ -C ₇ -cycloalkyl-lower alkyl, nitro, halogen, trifluoromethyl, amino Amino, which is mono- or independently disubstituted by lower alkyl, phenyl-lower alkyl or phenyl or is disubstituted by lower alkylene, lower alkylene oxymederalkylene; a stereoisomer or a salt thereof.

4. A compound according to claim 1 of formula I, wherein

Ar is phenyl or phenyl substituted by C _r C ₄ alkyl; X represents -O- or -S (O) _n - and n represents 0, 1 or 2; ^x ι C _r C ₂ alkylene or stands for a direct bond; wherein R _{j is} hydrogen, C _r C ₄ alkyl or C ₂ -C ₅ alkanoyl; R _{2 is} phenyl-C ₁ -C ₄ -alkyl, where phenyl is unsubstituted or substituted by halogen, trifluoromethyl, C _r C ₄ -alkyl or C _r C ₄ -alkoxy, or R ₂ C ₃ -C ₇ -cycloalkyl - C _r C ₄ -alkyl;

R _{3 is} carboxy, 5-tetrazolyl, PO ₂ H ₂ , PO ₃ H ₂ or SO ₃ H ₂ ; ring A is unsubstituted or mono- or polysubstituted by substituents selected from the group consisting of: C ₁ -C ₄ alkyl, halogen, C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkyl, C _r C ₄ - alkoxy, C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkoxy, nitro, halogen, trifluoromethyl; a stereoisomer or a salt thereof.

5. A compound according to claim 1 of formula I, wherein

Ar is phenyl substituted by C ₁ -C alkyl, lower alkoxy, halogen, trifluoromethyl, amino, lower alkylamino, di-lower alkylamino or nitro; X represents -O-; X _{j represents} methylene;

R _! Represents hydrogen or C -C ₅ alkanoyl;

R is phenyl-C _r C ₄ -alkyl, where phenyl is unsubstituted or substituted by halogen, trifluoromethyl, C _r C ₄ -alkyl or C _r C ₄ -alkoxy; or R _{2 is} C ₃ -C ₇ cycloalkyl-C ₁ -C ₄ alkyl;

R _{3 represents} carboxy, carbamoyl or hydroxycarbamoyl; the ring A is unsubstituted or mono- or polysubstituted by substituents selected from the group consisting: of C _r C ₄ alkyl, halogen, C ₁ -C ₄ -alkoxy-C ₁ -C ₄ - alkyl, C _r C ₄ - Alkoxy, C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkoxy, nitro, halogen, trifluoromethyl; a stereoisomer or a salt thereof.

6. A compound according to claim 1 of formula I, wherein Ar is phenyl or phenyl substituted by C _r C ₄ alkyl; X represents -O-; X _{j represents} methylene;

R _{j represents} hydrogen or C ₂ -C ₅ alkanoyl;

R _{2 is} phenyl-C _r C ₄ -alkyl, where phenyl is unsubstituted or substituted by halogen, trifluoromethyl, C ₁ -C ₄ -alkyl or CC ₄ -alkoxy; or RC ₃ -C ₇ cycloalkyl- C _r C ₄ alkyl; R _{3 represents} carboxy or 5-tetrazolyl; the ring A is unsubstituted or mono- or polysubstituted by substituents selected from the group consisting: of CC ₄ - alkyl, halogen, C ₁ -C ₄ -alkoxy-C ₁ -C ₄ - alkyl, CJ-alkoxy, _C1 -C ₄ alkoxy-C ₁ -C ₄ alkoxy, nitro, halogen, trifluoromethyl; a stereoisomer or a salt thereof.

7. A compound according to claim 1 of the formula

wherein R _{2 is} hydrogen; R _{2 is} phenyl-C _r C ₄ -alkyl, where phenyl is unsubstituted or substituted by halogen, trifluoromethyl, C _r C ₄ -alkyl or C _r C ₄ -alkoxy, or R ₂ C ₅ -C ₆ -cycloalkyl- C _{r is} C ₄ alkyl; R _{3 represents} carboxy; and RC _{r is} C ₄ alkyl; a stereoisomer or a salt thereof.

8. A compound according to claim 1 of the formula

(Ib),

wherein R _{t is} hydrogen; R _{2 is} phenyl-C _r C ₄ -alkyl or C ₅ -C ₆ cycloalkyl-C _r C ₄ -alkyl; R _{3 represents} carboxy; and R _{4 is} C _r C ₄ alkyl; a stereoisomer or a salt thereof.

9. A compound according to any one of claims 1 to 8, of the formula I, la and Ib, wherein both the C atom containing the variables R ₂ and R ₃ and the heterocycle C atom to which the amino group is bonded, the (S) configuration

10. Connection selected from

3- (S) - [(1- (S) -carboxy-3-cyclohexylpropyl) amino] -5- (p-isopropylbenzyl) -4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine ;

3- (R) - [(1- (S) -carboxy-3-cyclohexylpropyl) amino] -5- (p-isopropylbenzyl) -4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine ; 3- (S) - [(1- (S) -carboxyethyl) amino] -5- (p-isopropylbenzyl) -4-oxo-2,3,4,5-tetrahydro-

1,5-benzoxazepine;

3- (S) - [(1- (S) -carboxy-isopentyl) amino] -5- (p-isopropylbenzyl) -4-oxo-2,3,4,5-tetrahydro-

1,5-benzoxazepine;

3- (R) - [(1- (S) -carboxy-isopentyl) amino] -5- (p-isopropylbenzyl) -4-oxo-2,3,4,5-tetrahydro- 1,5-benzoxazepine;

3- (S) - [(1- (S) -carboxy-2-cyclohexyl-ethyl) amino] -5- (p-isopropylbenzyl) -4-oxo-2,3,4,5-tetrahydro-1,5 -benzoxazepine;

3- (S) - [(1- (S) -carboxy-2-phenyl-ethyl) amino] -5- (p-isopropylbenzyl) -4-oxo-2,3,4,5-tetrahydro-1 , 5-benzoxazepine;

2,3,4,5-tetrahydro-1,5-benzoxazepine;

3- (R) - [1- (S) -carboxy-2- (p-fluoro-henyl) -ethyl] amino-5- (p-isopropylbenzyl) -4-oxo

2,3,4,5-tetrahydro-1,5-benzoxazepine;

3- (S) - [(1- (S) -carboxy-3-phenyl-propyl) amino] -5- (p-isopropylbenzyl) -4-oxo-2,3,4,5-tetra-hydro-1 , 5-benzoxazepine;

3- (R) - [(1- (S) -carboxy-3-phenyl-propyl) amino] -5- (p-isopropylbenzyl) -4-oxo-2,3,4,5-tetra-hydro-1 , 5-benzoxazepine; or a salt of it.

11. Connection selected from

3- (S) - [(1- (S) -carboxyethyl) amino] -5- (p-isopropylbenzyl) -4-oxo-2,3,4,5-tetrahydro-l, 5-benzoxazepine;

3- (S) - [(1- (S) -carboxy-3-methylbutyl) amino] -5- (p-isopropylbenzyl) -4-oxo-2,3,4,5-tetrahydro-1,5 -benzoxazepine;

3- (S) - [(1- (S) -carboxy-2-methylpropyl) amino] -5- (p-isopropylbenzyl) -4-oxo-2,3,4,5-tetrahydro-1,5 -benzoxazepine;

3- (S) - [(1- (S) -carboxy-2-cyclohexylethyl) amino] -5- (p-isopropylbenzyl) -4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine ;

3- (S) - [(1- (S) -carboxy-2-phenylethyl) amino] -5- (p-isopropylbenzyl) -4-oxo-2,3,4,5-tetrahydro-1,5 -benzoxazepine;

3- (S) - [(1- (S) -carboxy-3-phenylpropyl) amino] -5- (p-methylbenzyl) -4-oxo-2,3,4,5-tetrahydro-1,5 -benzoxazepine; 3- (S) - [(1- (S) -carboxy-3-phenylpropyl) amino] -5- (p-isopropylbenzyl) -4-oxo-2,3,4,5-tetrahydro-1,5 -benzoxazepine;

3- (S) - [(1- (S) -carboxy-3-cyclohexylpropyl) amino] -5- (p-methylbenzyl) -4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine ;

1,5-benzoxazepine;

3- (S) - [(1- (S) -carboxy-butyl) amino] -5- (p-isopropylbenzyl) -4-oxo-2,3,4,5-tetrahydro-l, 5-benzoxazepine;

3- (S) - [(1- (S) -carboxypentyl) amino] -5- (p-isopropylbenzyl) -4-oxo-2,3,4,5-tetrahydro-l, 5-benzoxazepine;

1,5-benzoxazepine;

3- (S) - [(1- (S) -carboxy-2- (p-methoxyphenyl) ethyl) amino] -5- (p-isopropylbenzyl) -4-oxo-

2,3,4,5-tetrahydro-1,5-benzoxazepine;

3- (S) - [(1- (R) -carboxy-2- (p-methoxyphenyl) ethyl) amino] -5- (p-isopropylbenzyl) -4-oxo-

2,3,4,5-tetrahydro-1,5-benzoxazepine;

3- (S) - [(1- (S) -carboxy-2- (p-fluoro-phenyl) ethyl) amino] -5- (p-isopropylbenzyl) -4-oxo

2,3,4,5-tetrahydro-1,5-benzoxazepine;

3- (S) - [(1- (S) -carboxy-2-benzyloxy-ethyl) amino] -5- (p-isopropylbenzyl) -4-oxo-2,3,4,5-tetrahydro-1,5 -benzoxazepine;

3- (S) - [(1- (S) -carboxy-3-phenylpropyl) amino] -5- (p-isopropylbenzyl) -4-oxo-2,3,4,5-tetra-hydro-1,5 -benzoxazepine; and

3- (S) - [(1- (S) -carboxy-3-phenylpropyl) amino] -5- (m-methylylbenzyl) -4-oxo-2,3,4,5-tetrahydro-1,5 -benzoxazepine; or a salt of each.

12. A compound according to any one of claims 1 to 11 for use in a method for the therapeutic or prophylactic treatment of the animal or human body.

13. A process for the preparation of a compound of formula I, a stereoisomer or a salt thereof, characterized in that a) a compound of the formula wherein Y _{λ means} a residue which can be converted into the variable R ₃ , or a salt thereof, converts Y _t into the variable R ₃ ; or, b) for the preparation of a compound of formula (I), wherein R _{x is} hydrogen, or a salt thereof; in a compound of the formula

wherein Y _{2 represents} an amino protecting group, or a salt thereof, which cleaves the amino protecting group; or c) a compound of the formula

with a compound a nucleophobic leaving represents group, or with a compound of the formula R ₂ -CO-R ₃ (TVc) or a salt thereof; or d) a compound of the formula

with a compound of the formula Y ₆ -Xι-Aι (Vb), wherein Y _{6 is} a nucleofugic leaving group, or a salt thereof; or e) a compound of the formula wherein Y ₇ for (i) oxo or (ii) reactive esterified hydroxy together with

UM _^^^ _ QU

Is hydrogen, with a compound of formula _\ (VIb) or a salt

implements it; and in each case, if desired, a process-related or otherwise obtainable compound of the formula I thereof, in each case isolated in free form or in salt form, converting a process-related or otherwise obtainable compound of the formula I into another compound of the formula I, a process-related separates the available mixture of isomers and isolates the desired isomer and / or a process-related free compound of the formula I thereof into a salt or a process-available salt of a compound of the formula I thereof into the free compound of the formula I or into a transferred other salt.

14. A pharmaceutical preparation containing as active ingredient a compound according to any one of claims 1-12, a stereoisomer or a pharmaceutically acceptable salt thereof, optionally in addition to customary auxiliaries.

15. Use of a compound according to any one of claims 1-12, a stereoisomer or a pharmaceutically acceptable salt thereof, for the production of a pharmaceutical preparation for the treatment of diseases which are caused by the modulation of the AT ₂ receptor.

16. Method for the treatment of pathological phenomena of the human body, which are caused by the modulation of the AT ₂ receptor, by administration of a therapeutically effective amount of a compound of formula I according to claim 1, a stereoisomer or a pharmaceutically acceptable salt thereof.