DE19612376A1 - Tricyclic azepine derivatives, medicaments containing these compounds and processes for their preparation - Google Patents

Abstract

Tricyclic azepine derivatives of formula (I) and their tautomers, stereoisomers and salts are new: R1, R3 = H, 1-3C alkyl, aryl, OH, 1-3C alkoxy, CN, COOH etc.; R2, R4, R6, R8 = H or 1-3C alkyl; or R1+R2 or R3+R4 = O; R5, R7 = H, 1-3C alkyl, aryl, COOH, 1-3C alkoxycarbonyl, CONH2 or mono- or di 1-3C alkylaminocarbonyl; R9 = H, 1-8C alkyl, 3-7C cycloalkyl, substituted 1-3C alkyl etc.; X1, X2 = N or CRa; Ra = H, F, Cl, Br, I, 1-3C alkyl, CF3, 1-3C alkoxy or CN; Z1 = CH, Z2 = O, S, CH2, CO or NRb and Z3 = NRc or CRc (sic); or Z1 = CRb, Z2 = O, CH2 or NRb and Z3 = O or CH2; Rb = H, 1-6C alkyl, 3-7C cycloalkyl, or substituted 1-3C alkyl; Rc = H, 1-6C alkyl, 2-7C alkoxycarbonyl, 5-7C cycloalkoxycarbonyl or mono- or di-1-3C alkylaminocarbonyl etc.; A = a bond, 1-6C alkylene, (CH2)kO etc., provided that O or N atoms are not bonded to a heteroatom in D; k = 1-3; D = 4-7C cycloalkylene (optionally substituted), 4-6C azacycloalkylene (optionally substituted and optionally with an oxo alpha to the N), 4-5C diazacycloalkylene (optionally substituted and optionally with an oxo group alpha to the N atoms) or phenylene (optionally substituted); E = a bond or optionally substituted 1-6C alkylene; G = OH, 1-8C alkoxy, aryl(1-3C)alkoxy etc.) etc..

Description

The invention relates to tricyclic azepine derivatives of the general my formula

their tautomers, their stereoisomers including their Gemi and their salts, in particular their physiologically tolerated Liche salts with inorganic or organic acids or Ba sen, which have valuable pharmacological properties, preferably aggregation-inhibiting effects, these compounds containing medicinal products, their use and methods too their production.

In the above general formula I means
R₁ and R₃, which may be the same or different, each represent a hydrogen atom, a C _1-3 alkyl, aryl, hydroxy, C _1-3 alkoxy, cyano, carboxy, C _1-3 Alkoxycarbonyl, aminocarbonyl, C _1-3 -alkylaminocarbonyl or di- (C _1-3 -alkyl) aminocarbonyl group,
R₂, R₄, R₆ and R₈, which may be the same or different, each represent a hydrogen atom or a C _1-3 alkyl group or
R₁ together with R₂ or R₃ together with R₄ also each represent an oxygen atom,
R₅ and R₇, which may be the same or different, each represents a hydrogen atom, a C _1-3 alkyl, aryl, carboxy, C _1-3 alkyloxycarbonyl, aminocarbonyl, C _1-3 alkylaminocarbonyl or Di (C _1-3 alkyl) aminocarbonyl group,
R₉ represents a hydrogen atom, a C _1-8 -alkyl, C _3-7 -cycloalkyl or C _3-7 -cycloalkyl-C _1-3 -alkyl group, an optionally substituted by an aryl group substituted C _3-6 alkenyl or C _3-6 alkynyl group, wherein the alkenyl and alkynyl group may not each be connected via the vinyl or ethynyl moiety to the nitrogen atom, an arylC _1-3 alkyl, heteroarylC _1-3 alkyl, Hy hydroxy-C _1-3 -alkyl, C _1-3 -alkoxy-C _1-3 -alkyl, amino-C _1-3 -alkyl, C _1-3 -alkylamino-C _1-3 -alkyl, Di (C _1-3 alkyl) amino C _1-3 alkyl, C _1-3 alkylcarbonylamino C _1-3 alkyl, N- (C _1-3 alkyl) C _{1- 3-} alkylcarbonylamino-C _1-3 -alkyl, C _1-3 -alkylsulfonylamino-C _1-3 -alkyl, N- (C _1-3 -alkyl) C _1-3 -alkylsulfonylamino-C _1-3 alkyl, cyanoC _1-3 alkyl, carboxyC _1-3 alkyl, C _1-3 alkoxycarbonylC _1-3 alkyl, aminocarbonylC _1-3 alkyl, C _1-3 alkylaminocarbonylC _1-3 alkyl, di (C _1-3 alkyl) aminocarbonylC _1-3 alkyl, C _1-3 alkoxycarbonyl, arylmethyloxycarbonyl, formyl, acetyl, Trifluoroacetyl, 2,2,2-trifluoroethyl, amidino or R₁₀CO-O- (R₁₁CR₁₂) -O-CO- group in which
R₁₀ represents a C _1-8 alkyl, C _5-7 cycloalkyl, aryl or aryl C _1-3 alkyl group,
R₁₁ represents a hydrogen atom, a C _1-3 alkyl, C _5-7 cycloalkyl or aryl group and
R₁₂ represents a hydrogen atom or a C _1-3 alkyl group,
X₁ and X₂, which may be the same or different, each represent a nitrogen atom or a substituted by the radical R _a Me thingruppe, in the
R _{a is in} each case a hydrogen, fluorine, chlorine, bromine or iodine atom, a C _1-3 -alkyl, trifluoromethyl, C _1-3 -alkoxy or cyano group,
Z₁ is a methine group,
Z₂ is an oxygen or sulfur atom, a methylene or Car bonylgruppe or substituted by the radical R _b imino group and
Z₃ is a nitrogen atom or a substituted by the radical R _c methine or
Z₁ is a <CR _b group,
Z₂ represents an oxygen atom, a methyl group or a R _b substituted imino group by the radical, and
Z₃ is an oxygen atom or a methylene group in which
R _b represents a hydrogen atom, a C _1-6 alkyl, C _3-7 cycloalkyl, aryl-C _1-3 -alkyl, carboxy-C _1-3 alkyl, C _1-6 alkoxycarbonyl C _1-3 -alkyl-, C _3-7 -cycloalkoxycarbonyl-C _1-3 -alkyl-, aminocarbonyl-C _1-3 -alkyl-, C _1-3 -alkylaminocarbonyl-C _1-3 -alkyl- or di- (C _1-3 -alkyl) -aminocarbonyl-C _1-3 -alkyl group and
R _{c represents} a hydrogen atom, a C _1-6 -alkyl, C _3-7 -cycloalkyl, carboxy, C _1-6 -alkoxycarbonyl, C _5-7 -cycloalkoxycarbonyl, cyano, aminocarbonyl, C _{1- 3 represents} alkylaminocarbonyl or di (C _1-3 alkyl) aminocarbonyl group,
A is a bond, a straight-chain or branched C _1-6 -alkylene group,
a - (CH₂) ₁-O-, - (CH₂) _m -CO-, -CO- (CH₂) ₁-, - (CH₂) _m -CO-NR _b -, -CO-NR _b - (CH₂) _l - or - (CH₂) _l -NR _b -CO-group in which the oxygen or nitrogen atom can not be linked to a heteroatom of the radical D and
R _b is defined as mentioned above,
l is the number 1, 2 or 3 and
m represent the number 0, 1 or 2,
D is a C _4-7 -cycloalkylene group optionally substituted by one or two C _1-3 -alkyl groups,
an optionally substituted by one or two C _1-3 alkyl groups or by an aryl group substituted C _5-7 cycloalkylene group in which a <CH unit is replaced by a nitrogen atom, where in the above-mentioned 5- to 7-membered rings each Weil a methylene group adjacent to a nitrogen atom may additionally be replaced by a carbonyl group,
a C _6-7 cycloalkylene group optionally substituted by one or two C _1-3 alkyl groups or by an aryl group, in which two 1,4-term <CH units are each replaced by a nitrogen atom, and wherein additionally in the above each of said 6- to 7-membered rings may be replaced by a methylene group adjacent to a nitrogen atom by a carbonyl group, or
a phenylene group represented by fluorine, chlorine or bromine atoms, by C _1-3 -alkyl, trifluoromethyl, hydroxy, C _1-3 -alkoxy, amino, C _1-3 -alkylamino, di- ( C _1-3 alkyl) amino, nitro, cyano, carboxy, C _1-6 alkoxycarbonyl, C _5-7 cycloalkoxycarbonyl, arylC _1-3 alkoxy, carboxyC _1-3 alkoxy, C _1-6 alkoxycarbonyl C _1-3 alkoxy or C _5-7 cycloalkoxycarbonyl C _1-3 alkoxy groups may be mono- or disubstituted, wherein the substituents are the same or different can,
E is a bond, a straight-chain or branched C _1-6 -alkylene group which is represented by a C _1-6 -alkyl, C _2-4 -alkenyl, C _2-4 -alkynyl, hydroxy, C _{1- 3} alkoxy, amino, C _1-3 alkylamino, di (C _1-3 alkyl) amino, aryl, pyridyl, R _b CO-NR _d , R _b O-CO -NR _d -, R _d -SO₂-NR _d -, ArylSO₂-NR _d - or di- (C _1-3 alkyl) -amino-CO-NR _d - may be substituted group in which
R _b is defined as mentioned above and
R _{d represents} a hydrogen atom, a C _1-6 -alkyl or C _5-7 -cycloalkyl group,
and F is a carbonyl group substituted by a hydroxy, C _1-8 alkoxy, aryl C _1-3 alkoxy or R₁₃O group, where
R₁₃ represents a C _4-7 -cycloalkyl, C _3-7 -cycloalkyl-C _1-3 -alkyl, C₉-₁₂-benzocycloalkyl or aryl group,
or a R₁₄CO-O-CHR₁₅-O-CO group, in the
R₁₄ is C _1-3 alkyl, C _1-3 alkoxy, C _5-7 cycloalkyl, C _5-7 cycloalkoxy, aryl, aryloxy, arylC _1-3 alkyl or Aryl-C _1-3 alkoxy group and
R₁₅ represents a hydrogen atom or a C _1-3 alkyl group,
unless stated otherwise
among the aryl moieties mentioned in the definition of the above radicals, a phenyl group represented by fluorine, chlorine or bromine atoms, by C _1-3 alkyl, trifluoromethyl, hydroxy, C _1-3 alkoxy, amino, C _1-3 alkylamino, di (C _1-3 alkyl) amino, nitro, cyano, carboxy, C _1-6 alkoxycarbonyl, C _3-7 cycloalkoxycarbonyl, phenyl-C _1-3 alkoxy, C _1-6 alkoxycarbonyl C _1-3 alkoxy or C _5-7 cycloalkoxycarbonyl C _1-3 alkoxy groups may be mono- or disubstituted, wherein the substituents may be the same or different to understand.

Preferred compounds of the above general formula I are those in which
R₁ and R₃, which may be the same or different, each represent a hydrogen atom, a C _1-3 alkyl, aryl, hydroxy, C _1-3 alkoxy, cyano, carboxy, C _1-3 Alkoxycarbonyl or aminocarbonyl group,
R₂, R₄, R₆ and R₈, which may be the same or different, each represent a hydrogen atom or a C _1-3 alkyl group or
R₁ together with R₂ or R₃ together with R₄ also each represent an oxygen atom,
R₅ and R₇, which may be the same or different, each represents a hydrogen atom, a C _1-3 -alkyl, aryl, carboxy, C _1-3 -alkoxycarbonyl or aminocarbonyl group,
R₉ is hydrogen, C _1-8 alkyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl C _1-3 alkyl, aryl C _1-3 alkyl, heteroaryl C _{1 3-} alkyl, hydroxyC _1-3 alkyl, C _1-3 alkoxyC _1-3 alkyl, aminoC _1-3 alkyl, C _1-3 alkylamino C _{1 3-} alkyl, di (C _1-3 alkyl) amino C _1-3 alkyl, cyano C _1-3 alkyl, carboxy C _1-3 alkyl, C _{1 3-} alkoxycarbonyl-C _1-3 -alkyl, aminocarbonyl-C _1-3 -alkyl, C _1-3 -alkoxycarbonyl, arylmethyloxycarbonyl, formyl, acetyl, trifluoroacetyl, amidino or R₁₀CO-O- (R₁₁CR₁₂) -O-CO group, in the
R₁₀ represents a C _1-8 alkyl, C _5-7 cycloalkyl or aryl C _1-3 alkyl group,
R₁₁ represents a hydrogen atom or a C _1-3 alkyl group and
R₁₂ represents a hydrogen atom or a C _1-3 alkyl group,
X₁ and X₂ are each a substituted by the radical R _a methine group, in the
R _{a is in} each case a hydrogen, fluorine, chlorine or bromine atom, a C _1-3 -alkyl, trifluoromethyl, C _1-3 -alkoxy or cyano group,
Z₁ is a methine group,
Z₂ represents an oxygen or sulfur atom or a by the group R _b substituted imino group and
Z₃ is a nitrogen atom or a substituted by the radical R _c methine or
Z₁ is a <CR _b group,
Z₂ is an oxygen atom or a methylene group and
Z₃ is an oxygen atom or a methylene group in which
R _b represents a hydrogen atom, a C _1-6 alkyl, C _3-7 cycloalkyl, aryl-C _1-3 -alkyl, carboxy-C _1-3 alkyl, C _1-6 alkoxycarbonyl C _1-3 -alkyl-, C _3-7 -cycloalkoxycarbonyl-C _1-3 -alkyl- or aminocarbonyl-C _1-3 -alkyl group and
R _{c represents} a hydrogen atom, a C _1-6 -alkyl, carboxy, C _1-6 -alkoxycarbonyl, C _5-7 -cycloalkoxycarbonyl or cyano group,
A is a bond, a straight-chain or branched C _1-6 -alkylene group,
a - (CH₂) _l -O-, - (CH₂) _m -CO-, - (CH₂) _m -CO-NR _b - or -CO-NR _b - (CH₂) _l - group in which the oxygen or Stick nitrogen atom can not be linked to a heteroatom of the radical D as well
R _b is defined as mentioned above,
l is the number 1 or 2 and
m represent the number 0, 1 or 2,
D is a C _4-7 -cycloalkylene group optionally substituted by one or two C _1-3 -alkyl groups,
a C _5-7 cycloalkylene group optionally substituted by one or two C _1-3 alkyl groups in which a <CH moiety is replaced by a nitrogen atom, one in each of the above-mentioned 5- to 7-membered rings Nitrogen atom adjacent methylene group may additionally be replaced by a carbonyl group,
a C _6-7 cycloalkylene group optionally substituted by one or two C _1-3 alkyl groups, in which two 1,4-position <CH units are each replaced by a nitrogen atom, and additionally in the above-mentioned 6- to In each case a methylene group adjacent to a nitrogen atom may be replaced by a carbonyl group;
a phenylene group represented by fluorine, chlorine or bromine atoms, by C _1-3 alkyl, trifluoromethyl, hydroxy, C _1-3 alkoxy, arylC _1-3 alkoxy, carboxyC _{1 3} -alkoxy, C _1-6 -alkoxycarbonyl, C _1-3 -alkoxy or C _5-7 -cycloalkoxycarbonyl-C _1-3 -alkoxy groups may be mono- or disubstituted, where the substituents may be identical or different,
E is a bond, a straight or branched C _1-6 alkylene group represented by a C _2-4 alkenyl, C _2-4 alkynyl, hydroxy, C _1-3 alkoxy, amino, aryl - or pyridyl group may be substituted, and
F is a carbonyl group which is substituted by a hydroxy, C _1-8 alkoxy, aryl C _1-3 alkoxy or R₁₃O group, wherein
R₁₃ represents a C _4-7 cycloalkyl or C _3-7 cycloalkyl C _1-3 alkyl group,
or a R₁₄CO-O-CHR₁₅-O-CO group, in the
R₁₄ is a C _1-3 alkyl, C _1-3 alkoxy, C _5-7 cycloalkyl, C _5-7 cycloalkoxy, aryl, arylC _1-3 alkyl or aryl C _1-3 alkoxy group and
R₁₅ represents a hydrogen atom or a C _1-3 alkyl group,
their tautomers, their stereoisomers and salts,
unless stated otherwise
among the aryl moieties mentioned in the definition of the above radicals, a phenyl group which is represented by fluorine, chlorine or bromine atoms, by C _1-3 -alkyl, trifluoromethyl, hydroxy, C _1-3 -alkoxy, phenyl-C _{1 3} -alkoxy, C _1-6 -alkoxycarbonyl, C _1-3 -alkoxy or C _5-7 -cycloalkoxycarbonyl-C _1-3 -alkoxy groups may be mono- or disubstituted, where the substituents may be identical or different, to understand.

Particularly preferred compounds of the above general formula I are those in which
R₁ and R₃, which may be the same or different, each represents a hydrogen atom or a methyl group,
R₂, R₄, R₆ and R₈ each represents a hydrogen atom or
R₁ together with R₂ or R₃ together with R₄ also each represent an oxygen atom,
R₅ and R₇ each represent a hydrogen atom,
R₉ represents a hydrogen atom, a C _1-5 -alkyl, C _1-3 -alkanoyl, trifluoroacetyl, C _1-4 -alkoxycarbonyl or benzyloxycarbonyl group,
X₁ and X₂ each have a methine group,
Z₁ is a methine group,
Z₂ represents an oxygen or sulfur atom or a by the group R _b substituted imino group and
Z₃ is a nitrogen atom or
Z₁ is a <CR _b group,
Z₂ is an oxygen atom and
Z₃ is an oxygen atom in which
R _b represents a hydrogen atom, an alkyl- C _1-3 -alkyl, phenyl-C _1-3 -al, carboxy-C _1-3 alkyl, C _1-5 alkoxycarbonyl-C _1-3 alkyl or C _5-7 cyanoalkoxycarbonylC _1-3 alkyl group,
A is a bond, a straight-chain or branched C _1-4 -alkylene group,
a - (CH₂) _m -CO-NR _b - or -CO-NR _b -CH₂ group in which the nitrogen atom can not be linked to a heteroatom of the radical D and
R _b is defined as mentioned above and
m represents the number 0 or 1,
D is a 1,4-cyclohexylene group,
a 1,4-piperidinylene or 1,4-piperazinylene group in each of which an adjacent to a nitrogen atom methylene group may be replaced by a carbonyl group, or
a phenylene group which may be substituted by a carboxy-methoxy or C _1-3 alkoxycarbonylmethoxy group,
E is a bond or a straight-chain or branched C _1-4 -alkylene group and
F represents a carbonyl group which is substituted by a hydroxyl, C _1-5 -alkoxy, benzyloxy, cyclopentyloxy or cyclohexyloxy group,
their tautomers, their stereoisomers and salts.

Very particularly preferred compounds of the above general formula I are those in which
R₁ to R₈ each represent a hydrogen atom,
R₉ represents a hydrogen atom, a C _1-3 -alkyl, acetyl or trifluoroacetyl group,
X₁ and X₂ each have a methine group,
Z₁ is a methine group,
Z₂ is an oxygen atom or an imino group substituted by the radical R _b , where
R _{b represents} a hydrogen atom, a C _1-3 alkyl, carboxymethyl or C _1-5 alkoxycarbonylmethyl group,
A is a bond, a methylene or ethylene group,
D is a 1,4-piperidinylene or 1,4-piperazinylene group,
E is a bond or a straight-chain or branched C _1-3 -alkylene group and
F represents a carbonyl group which is substituted by a hydroxyl or C _1-5 -alkoxy group,
their tautomers, their stereoisomers and salts.

The following are mentioned as particularly preferred compounds:

(1) 2- [2- (1-carboxymethyl-piperidin-4-yl) -ethyl] -1-methyl-6,7,8,9-tetra-hydro-5H-imidazo [4 ', 5': 4, 5] benzo [1,2-d] azepine,
(2) 2- [2- (1-carboxymethyl-piperidin-4-yl) -ethyl] -6,7,8,9-tetra-hydro-5H-imidazo [4 ', 5': 4,5] benzo [ 1,2-d] azepine,
(3) 2- [2- (1-carboxymethyl-piperidin-4-yl) -ethyl] -1,7-dimethyl-6,7,8,9-tetra-hydro-5H-imidazo [4 ', 5 ': 4,5] benzo [1,2-d] azepine,
(4) 2- [2- (1-carboxymethyl-piperidin-4-yl) -ethyl] -6,7,8,9-th-trahydro-5H-oxazolo [4 ', 5': 4,5] benzo [ 1,2-d] azepine
and their salts.

The new connections can be followed, for example to produce the method:

• a) For the preparation of compounds of the general formula I in which R₉ is as defined above and F represents a carboxyl group or F is as defined above and R₉ represents a hydrogen atom: conversion of a compound of the general formula in the
  A, D, E, X₁, X₂, Z₁ to Z₃ and R₁ to R₈ with the proviso as defined above, that F 'has the meanings mentioned for F and R₉' one by hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis starting from cleavable protecting group for an imino group or R₉ 'has the meanings mentioned above for R₉ and F' means a group which can be converted into a carboxyl group by hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis,
  in a compound of the general formula I in which R₉ is defined as a gangue and F represents a carboxyl group or F is as defined above and R₉ represents a hydrogen atom.

For example, functional derivatives of the carboxyl group, such as their unsubstituted or substituted amides, esters, thioesters, trimethylsilyl esters, orthoesters, iminoesters, amidines or anhydrides, or the nitrile group by hydrolysis into a carboxyl group,
Esters with tertiary alcohols, e.g. For example, the tert.Butylester, with means of treatment with an acid or thermolysis in a Carb oxylgruppe and
Esters with aralkanols, e.g. For example, the benzyl ester, by means of Hydroge nolysis in a carboxyl group and
functional derivatives of imino such as their formyl, Ace tyl-, trifluoroacetyl, methoxycarbonyl, ethoxycarbonyl, tert.Butoxycarbonyl- or Benzyloxycarbonylderivate by hydrolysis and
Benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-Dimeth oxybenzylderivate be converted by hydrogenolysis in the corresponding imino compounds.

The hydrolysis is conveniently carried out either in the presence of egg ner acid such as hydrochloric acid, sulfuric acid, phosphoric acid, vinegar acid, trichloroacetic acid, trifluoroacetic acid or their Gemi or in the presence of a base such as lithium hydroxide, sodium hydroxide or potassium hydroxide in a suitable solvent such as water, water / methanol, water / ethanol, water / isopropa nol, methanol, ethanol, water / tetrahydrofuran or water / di oxane at temperatures between -10 and 120 ° C, z. B. at Tempe between room temperature and the boiling point of Re action mixture, carried out.

Under the reaction conditions mentioned above, ge optionally present N-acylamino or N-acylimino groups as an N-trifluoroacetylimino group in the corresponding Amino or imino groups are transferred. In addition, you can optionally present alcoholic hydroxy groups in the Treatment with an organic acid such as trichloroacetic acid or trifluoroacetic acid simultaneously in a corresponding Acyloxygruppe be converted as the trifluoroacetoxy.

If F 'in a compound of formula II is a cyano or Aminocarbonyl group, so these groups can also with a Ni trit, z. As sodium nitrite, in the presence of an acid such as sw felsic acid, which expediently at the same time as Lö is used at temperatures between 0 and 50 ° C are converted into the carboxyl group.  

Means F 'and / or R₉' in a compound of formula II at For example, the tert.Butyloxycarbonylgruppe, so in the case of F 'the tert-butyl group or in the case of R₉' the tert.Bu tyloxycarbonyl group also by treatment with an acid such as Trifluoroacetic acid, formic acid, p-toluenesulfonic acid, m.p. felsic acid, hydrochloric acid, phosphoric acid or polyphosphoric gege if appropriate in an inert solvent such as methylene chloride, Chloroform, benzene, toluene, diethyl ether, tetrahydrofuran or Dioxane preferably at temperatures between - and 120 ° C, z. B. at temperatures between 0 and 60 ° C, or thermally optionally in an inert solvent such as methylene chloride chloride, benzene, toluene, tetrahydrofuran or dioxane and preferably in the presence of a catalytic amount of a Acid such as p-toluenesulfonic acid, sulfuric acid, phosphoric acid or polyphosphoric acid, preferably at the boiling point of used solvent, for. B. at temperatures between 40 and 120 ° C, split off. In the aforementioned Re If necessary, N-tert.Bu tyloxycarbonylamino or N-tert-butyloxycarbonylimino groups converted into the corresponding amino or imino groups become.

Is F 'and / or R₉' in a compound of formula II For example, the benzyloxycarbonyl, so in the case of F 'the benzyl group or in the case of R₉' the benzyloxy carbonyl also hydrogenolytically in the presence of a Hy drierungskatalysators such as palladium / carbon in a suitable Solvents such as methanol, ethanol, isopropanol, ethanol / what glacial acetic acid, ethyl acetate, dioxane or dimethylform amide, preferably at temperatures between 0 and 50 ° C, z. B. at room temperature, and a hydrogen pressure of 1 to 5 bar be split off. In the hydrogenolysis can simultaneously other radicals, eg. B. a nitro group in an amino group, a Benzyloxy group into a hydroxy group and an N-benzylamino, N-benzylimino, N-benzyloxycarbonylamino or N-benzyl oxycarbonylimino group in a corresponding amino or imino be transferred group.

• b) For the preparation of compounds of the general formula I in which R₉ represents one of the above-mentioned in the definition of the radical R₉ optionally substituted alkyl, alkenyl, Alki nyl-, cycloalkyl, Cycloalkylalkyl-, arylalkyl or hetero arylalkylreste: Reaction a compound of the general formula in the A, D to F, X₁, X₂, Z₁ to Z₃ and R₁ to R₈ are as defined defi ned, with a compound of the general formula Y₁ - R₁₆ (IV) in the
  R₁₆ represents a C _1-8 alkyl, C _3-7 cycloalkyl or C _3-7 cycloalkyl C _1-3 alkyl group, an optionally substituted by an aryl C _3-6 alkenyl or C _3-6 Alkynyl group, wherein the alkenyl and alkynyl groups may not each be linked via the vinyl or ethynyl moiety to the nitrogen atom, an arylC _1-3 alkyl, heteroarylC _1-3 alkyl, hydroxyC _{1- 3-} alkyl, C _1-3 alkoxyC _1-3 alkyl, aminoC _1-3 alkyl, C _1-3 alkylamino, C _1-3 alkyl, di (C _{1 3-} alkyl) -amino-C _1-3 -alkyl, C _1-3 -alkylcarbonylamino-C _1-3 -alkyl, N- (C _1-3 -alkyl) C _1-3 -alkylcarbonylamino C _1-3 alkyl, C _1-3 alkylsulfonylaminoC _1-3 alkyl, N- (C _1-3 alkyl) C _1-3 alkylsulfonylaminoC _1-3 alkyl, Cyano C _1-3 alkyl, carboxy C _1-3 alkyl, C _1-3 alkoxycarbonyl C _1-3 alkyl, aminocarbonyl C _1-3 alkyl, C _1-3 -Alkyl-aminocarbonyl-C _1-3 -alkyl or di- (C _1-3 -alkyl) -aminocarbonyl-C _1-3 -alkyl group in which the aryl moiety is as defined above, and
  Y₁ is a nucleofuge leaving group such as a halogen atom, e.g. As a chlorine, bromine or iodine atom, or a Sulfonsäureestergrup pe, z. A methanesulfonyloxy or p-toluenesulfonyloxy group, or
  Y₁ together with an adjacent hydrogen atom of the radical R₁₆ represent an oxygen atom.

The alkylation with a compound of formula IV in which Y₁ represents a nucleofuge leaving group becomes more convenient in a solvent such as methylene chloride, tetrahydrofu ran, dioxane, acetonitrile, dimethyl sulfoxide or dimethylform if appropriate in the presence of a base such as sodium carbonate nat, potassium carbonate or sodium hydroxide or in the presence of a tertiary organic base such as N-ethyl-diisopropylamine or N-methyl-morpholine, which at the same time as solvents the at temperatures between -30 and 150 ° C, preferably However, at temperatures between 20 and 120 ° C, Runaway leads.

The reductive alkylation with a carbonyl compound of all Formula IV is used in the presence of a complex Metallhy such as sodium borohydride, lithium borohydride, sodium triacet oxyborohydride or sodium cyanoborohydride suitably at a pH of 6-7 and at room temperature or in the presence a hydrogenation catalyst, e.g. B. with hydrogen in counter of palladium / carbon, at a hydrogen pressure of 1 to 5 bar performed. However, the methylation is preferably in Presence of formic acid as a reducing agent at increased Temperatures, z. At temperatures between 60 and 120 ° C, carried out.

• c) For the preparation of compounds of the general formula I in which F is a carbonyl group which is substituted by a C _1-8 alkoxy, aryl C _1-3 alkoxy or R₁₃O group represents: reaction of a carboxylic acid of general formula in the
  A, D, E, X₁, X₂, Z₁ to Z₃ and R₁ to R₉ are as defined above, or their optionally producible in the reaction mixture th reactive derivatives with an alcohol of the general formula HO - R₁₇ (VI) in the
  R₁₇ represents a C _1-8 alkoxy, aryl C _1-3 alkoxy or R₁₃O group, wherein R₁₃ is as defined above.

As reactive derivatives of a compound of the general Formula VI, for example, their acid chlorides, acid azides, mixed anhydrides with aliphatic or aromatic Carboxylic acids or carbonic acid monoesters, their imidazolides and their esters such as their alkyl, aryl and aralkyl esters such as Methyl, ethyl, isopropyl, pentyl, phenyl, nitrophenyl or Benzyl ester into consideration.

The reaction of a carboxy compound is optionally in a solvent or solvent mixture such as methylene chloride chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydro furan, benzene / tetrahydrofuran or dioxane or especially partly in a corresponding alcohol of the general formula VI optionally in the presence of an acid such as hydrochloric acid or in the presence of a dehydrating agent, e.g. B. in counter  were of isobutyl chloroformate, thionyl chloride, trime thylchlorosilane, sulfuric acid, methanesulfonic acid, p-toluenesulfide fonic acid, phosphorus trichloride, phosphorus pentoxide, N, N'-dicyclo hexylcarbodiimide, N, N'-dicyclohexylcarbodiimide / N-hydroxysuc cinimide or 1-hydroxy-benzotriazole and optionally additional in the presence of 4-dimethylamino-pyridine, N, N'-carbonyldi Imidazole or triphenyl-phosphine / carbon tetrachloride, purpose moderately at temperatures between 0 and 150 ° C, preferably at temperatures between 0 and 80 ° C, carried out.

The reaction of a corresponding alkoxycarbonyl compound with an alcohol of general formula VI is preferably in an appropriate alcohol as solvent, if appropriate in the presence of another solvent such as methylene chloride or ether, preferably in the presence of an acid such as hydrochloric acid at temperatures between 0 and 150 ° C, preferably at Tempe temperatures between 50 and 100 ° C, carried out.

• d) For the preparation of compounds of general formula I, in which F represents a R₁₄CO-O-HCR₁₅-O-CO group: Reaction of a carboxylic acid of the general formula in the
  A, D, E, X₁, X₂, Z₁ to Z₃ and R₁ to R₉ are as defined above, with a compound of the general formula Y₂ - R₁₈ (VII) in the
  R₁₈ a R₁₄CO-O-HCR₁₅ group, wherein R₁₄ and R₁₅ are defined as mentioned above, and
  Y₂ is a nucleofuge leaving group such as a halogen atom, e.g. As a chlorine or bromine, mean.

The reaction is preferably carried out in a solvent such as Me methylene chloride, tetrahydrofuran, dioxane, dimethylsulfoxide or Dimethylformamide optionally in the presence of a Reaktionsbe accelerator such as sodium or potassium iodide and preferably in Presence of a base such as sodium carbonate, potassium carbonate or Sodium hydroxide solution or in the presence of a tertiary organic base such as N-ethyl-diisopropylamine or N-methyl-morpholine, which can also serve as a solvent at the same time, or give if appropriate in the presence of silver carbonate or silver oxide Temperatures between -30 and 100 ° C, but preferably at Temperatures between -10 and 80 ° C, performed.

• e) For the preparation of compounds of the general formula I in which R₉ represents an alkyl group having 2 carbon atoms which are in the 2-position by a cyano, carboxy, alkoxycarbonyl, aminocarbonyl, N-alkylaminocarbonyl or N, N-dialkylaminocar substituted by the reaction of a compound of the general formula in the
  A, D to F, X₁, X₂, Z₁ to Z₃ and R₁ to R₈ are as defined defi ned,
  with an ethylene substituted by a cyano, C _1-3 alkoxycarbonyl, aminocarbonyl, C _1-3 alkylaminocarbonyl or di (C _1-3 alkyl) amino carbonyl group.

The reaction is preferably carried out in a solvent such as Me ethanol, methylene chloride, tetrahydrofuran, toluene, di oxane, dimethyl sulfoxide or dimethylformamide, optionally in Presence of a tertiary organic base such as N-ethyl-diiso propylamine or N-methyl-morpholine at temperatures between -30 and 150 ° C, but preferably at temperatures between 0 and 100 ° C, performed.

• f) For the preparation of compounds of general formula I in which D is an optionally substituted by one or two C _1-3 alkyl or substituted by an aryl C _5-7 cycloalkylene group in which a <CH-unit by a nitrogen atom is replaced, wherein the ring nitrogen atom is linked to a carbon atom of group E, or an optionally substituted by one or two C _1-3 alkyl groups or by an aryl group substituted C _6-7 cycloalkylene, in the two 1,4-permanent <CH units are each replaced by a nitrogen atom, wherein a ring nitrogen atom having a carbon atom of the group A and the other ring nitrogen atom is linked to a carbon atom of group E, means: reaction of a compound of the general formula in the
  A, X₁, X₂, Z₁ to Z₃ and R₁ to R₉ are as defined above and
  D 'is a C _5-7 -cycloalkylene group optionally substituted by one or two C _1-3 -alkyl groups or by an aryl group, in which one <CH-unit is replaced by an imino group, or one optionally substituted by one or two C ₁ groups ₃ alkyl or aryl group substituted by a C _6-7 -cycloalkyl alkylene group in which one of the 1,4-position <CH-units is replaced by a nitrogen atom, this ring Stick atom with a carbon atom of the group a is linked, and the second of the 1,4-position <CH units is replaced by an imino group, means with a compound of the general formula Y₃ - E - F (IX) in the
  E and F are as defined above and
  Y₃ is a nucleofuge leaving group such as a halogen atom, e.g. As a chlorine, bromine or iodine atom, or a Sulfonsäureestergrup pe, z. B. a methanesulfonyloxy or p-toluenesulfonyloxy group.

The reaction is conveniently carried out in a solvent such as Methylene chloride, tetrahydrofuran, dioxane, acetonitrile, dime thylsulfoxide or dimethylformamide, optionally in the presence a base such as sodium carbonate, potassium carbonate or sodium hydroxide solution or in the presence of a tertiary organic base such as N-ethyl diisopropylamine or N-methyl-morpholine, which are simultaneously  can serve as solvents, at temperatures between -30 and 150 ° C, but preferably at temperatures between 20 and 120 ° C, performed.

• g) For the preparation of compounds of the general formula I in which D is an optionally substituted by one or two C _1-3 alkyl or substituted by an aryl C _5-7 cycloalkylene kylengruppe in which a <CH-unit through a nitrogen atom wherein the ring nitrogen atom is linked to a Methinkoh lenstoffatom of the group Z₁, or optionally given by one or two C _1-3 alkyl groups or by an aryl group substituted C _6-7 cycloalkylene, in the two 1,4-permanent <CH units each by a nitrogen atom he sets are, wherein a ring nitrogen atom is linked to a Methinkoh lenstoffatom group Z₁, means: reaction of a compound of the general formula in the
  X₁, X₂, Z₁ to Z₃ and R₁ to R₉ are as defined above and
  Y₄ a nucleofuge leaving group such as a halogen atom, for. A chlorine or iodine atom, or a substituted hydroxy, mer capto, sulfinyl or sulfonyl group, e.g. A methoxy, ethoxy, phenoxy, methylsulfinyl, ethylsulfinyl, methylsulfonyl or ethylsulfonyl group, with a compound of the general formula D "- E - F (XI) in the
  E and F are as defined above and
  D '' an optionally substituted by one or two C _1-3 alkyl groups or by an aryl group substituted C _5-7 -Cycloalkylengrup pe, in which a <CH unit is replaced by an imino group, or optionally by one or two C _{1 3-} alkyl groups or an aryl group-substituted C _6-7 cycloalkylene group in which one of the 1,4-position <CH units is an imino group and the second one is the 1,4-position <CH units represented by a nitrogen atom is replaced, this ring nitrogen atom is linked to a carbon atom of group E means.

The reaction is conveniently carried out in a solvent such as Methylene chloride, tetrahydrofuran, dioxane, acetonitrile, dime thylsulfoxide or dimethylformamide, optionally in the presence a base such as sodium carbonate, potassium carbonate or sodium hydroxide solution or in the presence of a tertiary organic base such as N-ethyl diisopropylamine or N-methyl-morpholine, which are simultaneously can serve as solvents, at temperatures between -30 and 150 ° C, but preferably at temperatures between 20 and 120 ° C, performed.

Is obtained according to the invention a compound of the general For mel I, which contains a carbon-carbon double bond, so this can then by means of hydrogenation in a entspre saturated saturated compound to be transferred.

The subsequent hydrogenation is preferably with hydrogen in the presence of a catalyst such as palladium / carbon in one Solvents such as methanol, ethanol, ethyl acetate or If necessary, glacial acetic acid with the addition of an acid such as hydrochloric acid at temperatures between 0 and 100 ° C, but preferably at Temperatures between 20 and 60 ° C, and with a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar, carried out.  

In the reactions described above can be given if existing reactive groups such as hydroxy, carboxy, amino no, alkylamino or imino groups during the reaction conventional protecting groups are protected, which after Umset be split off again.

For example, the protective radical for a hydroxy group is trimethylsilyl, acetyl, benzoyl, tert-butyl, trityl, benzyl or tetrahydropyranyl,
as protecting groups for a carboxyl group, the trimethylsilyl, methyl, ethyl, tert-butyl, benzyl or tetrahydropyranyl group and
as a protecting group for an amino, alkylamino or imino group, the formyl, acetyl, trifluoroacetyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group, for the imino group additionally the methyl group and, for the amino group, the phthalyl group.

The optional subsequent cleavage of a used Protective residue is, for example, hydrolytically in an aqueous trigen solvent, z. In water, isopropanol / water, vinegar acid / water, tetrahydrofuran / water or dioxane / water, in Ge presence of an acid such as trifluoroacetic acid, hydrochloric acid or Sulfuric acid or in the presence of an alkali metal base such as Natriumhy droxid or potassium hydroxide or by ether cleavage, z. In Presence of iodotrimethylsilane, at temperatures between 0 and 120 ° C, preferably at temperatures between 10 and 100 ° C.

The cleavage of a benzyl, methoxybenzyl or benzyloxy However, carbonyl radical is hydrogenolytically, for example, z. With hydrogen in the presence of a catalyst such as palla dium / carbon in a solvent such as methanol, ethanol, iso propanol, ethyl acetate or glacial acetic acid, if appropriate with the addition of an acid such as hydrochloric acid at temperatures between  0 and 100 ° C, but preferably at temperatures between 20 and 60 ° C, and at a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar.

The cleavage of a tert-butyl or tert-butyloxycarbonyl The rest is preferably carried out by treatment with an acid such as trifluoroacetic acid or hydrochloric acid or by treatment with Iodotrimethylsilane optionally using a Lö such as methylene chloride, dioxane, methanol or ether.

The cleavage of a Trifluoracetylrestes is preferably carried out by treatment with an acid such as hydrochloric acid if necessary in the presence of a solvent such as acetic acid or methanol at temperatures between 50 and 120 ° C or by treatment with sodium hydroxide solution, optionally in the presence of a Lösungsmit Tels such as tetrahydrofuran or methanol at temperatures between 0 and 50 ° C.

The cleavage of a methyl group from a methylimino group is preferably carried out in the presence of chloroformic acid 1-chloroalkyl esters such as 1-chloroethyl chloroformate before preferably in the presence of a base such as 1,8-bis (dimethylamino) naphthalene in the presence of a solvent such as methylene chloride chloride, 1,2-dichloroethane, toluene or dioxane at temperatures between 0 and 150 ° C, preferably at temperatures between 20 ° C and the boiling temperature of the reaction mixture, and after following treatment with an alcohol such as methanol at Tempe between 20 ° C and the boiling point of the used Alcohol.

The cleavage of a phthalyl radical is preferably carried out in Presence of hydrazine or a primary amine such as methyl amine, ethylamine or n-butylamine in a solvent such as Methanol, ethanol, isopropanol, toluene / water or dioxane Temperatures between 20 and 50 ° C.  

Further, the obtained compounds of the general For mel I, as already mentioned, into their enantiomers and / or diastereomers are separated. So can at For example, cis / trans mixtures into their cis and trans isomers and chiral compounds separated into their enantiomers become.

For example, the resulting cis- / trans-Ge mix by chromatography in their cis and trans isomers, the obtained compounds of the general formula I, which in Racemates occur, according to known methods (see Allinger N.L. and Eliel E.L. in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971) into their optical antipodes and compounds of the general formula I with at least 2 stereogenic centers due to their physico-chemical Differences according to known methods, for. B. by Chro Matography and / or fractionated crystallization, in their Diastereomers, which, if they are in racemic form then, as mentioned above, into the enantiomers can be separated.

The enantiomer separation is preferably carried out by columns separation on chiral phases or by recrystallization an optically active solvent or by reacting with ei ner, with the racemic compound salts or derivatives such as z. As esters or amides-forming optically active substance, ins particular acids and their activated derivatives or alcohols, and separating the diastereomeric salt thus obtained mixed or derivative, e.g. B. due to different Lös from the pure diastereomeric salts or Derivatives the free antipodes by the action of appropriate Mit tel can be released. Especially common, optical active acids are z. B. the D and L forms of tartaric acid or Dibenzoyltartaric acid, di-o-toluenoic acid, malic acid, almond acid, camphorsulfonic acid, glutamic acid, aspartic acid or China acid. For example, as an optically active alcohol (+) - or (-) - menthol and as an optically active acyl radical in  Amides, for example, (+) - or (-) - menthyloxycarbonyl in Consideration.

Furthermore, the compounds of the formula I can be obtained in their salts, in particular for pharmaceutical use in their physiologically acceptable salts with inorganic or organic acids are transferred. As acids come here for example, hydrochloric acid, hydrobromic acid, sulfur acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, Citric acid, tartaric acid or maleic acid into consideration.

In addition, the new compounds thus obtained can be Formula I, if they contain a carboxyl group, desired then in their salts with inorganic or or ganic bases, in particular for pharmaceutical use into their physiologically acceptable salts. As Ba Sodium hydroxide, potassium hy, for example, come here droxid, arginine, cyclohexylamine, ethanolamine, diethanolamine and Triethanolamine into consideration.

The compounds used as starting materials are partial known from the literature or obtained according to the literature Process (see Examples I to XXI).

As already mentioned, the new tricyclic Benzazepine derivatives of the general formula I and their salts, in particular their physiologically acceptable salts with organic or organic acids or bases, valuable egg properties, in particular valuable pharmacological properties in addition to an anti-inflammatory and bone resorption inhibitory effect in particular antithrombotic, antiaggre gatoric and tumor or metastasis-inhibiting effects.

For example, the compounds of general formula I examined for their biological effects as follows:  

1. Inhibition of the binding of 3 H-BIBU 52 to human platelets

A suspension of human platelets in plasma is with 3 H-BIBU 52 [= (3S, 5S) -5 - [(4'-amidino-4-biphenylyl) oxymethyl] - 3 - [(carboxy) methyl] -2-pyrrolidinone [3-³H-4-biphenylyl]] containing the The known ligands replaced ¹²⁵J-fibrinogen, (see DE-A-4,214,245) and various concentrations of incubated. The free and bound ligand is separated by centrifugation and by scintillation Counting determined quantitatively. From the measured values, the hem Determination of the ³H-BIBU 52 binding by the test substance.

For this purpose, donor blood is taken from an anticancer vein and anticoagulated with trisodium citrate (final concentration 13 mM). The blood is centrifuged for 10 minutes at 170 x g and the supernatant platelet-rich plasma (PRP) was removed. The rest Blood is again sharply abzentri for the production of plasma fugue. The PRP is diluted 1:10 with autologous plasma. 750 ml are mixed with 50 ml of physiological saline, 100 ml Test substance solution, 50 ml of ¹⁴C-sucrose (3,700 Bq) and 50 ml 3 H-BIBU 52 (final concentration: 5 nM) at room temperature for 20 min incubated. To measure the non-specific binding is on place the test substance 5 ml BIBU 52 (final concentration: 30 mM) used. The samples are centrifuged for 20 seconds at 10,000 × g fugiert and the supernatant subtracted. 100 ml of this will become Determination of the free ligand measured. The pellet is in Dissolve 500 ml of 0.2N NaOH, add 450 ml with 2 ml of scintillator and 25 ml 5N HCl added and measured. The ver still in the pellet residual plasma is determined from the ¹⁴C content, the ge bound ligand from the 3 H-measurement. After deduction of unspezi Fishing binding will increase the pellet activity against the Konzentra tion of the test substance and the concentration for determined a 50% inhibition of binding.  

2. Antithrombotic effect methodology

Platelet aggregation is determined by the method of Born and Cross (J. Physiol 170, 397 (1964)) in platelet-rich plasma measured by healthy subjects. For clotting inhibition is the blood with sodium citrate 3.14% in the volume ratio 1: 10 added.

Collagen-induced aggregation

The course of the decrease in the optical density of the platelets suspension becomes after addition of the aggregation-triggering sub punch measured and registered photometrically. Out of inclination Angle of the density curve is at the aggregation speed closed. The point of the curve where the biggest light permeability, is used to calculate the "optical density ".

The amount of collages is chosen as low as possible, but that results in an irreversible reaction curve. The commercial collagen from Hormonche is used Munich, Munich.

The collagen is added to the plasma for 10 minutes before the collagen is added the substance is incubated at 37 ° C.

From the obtained measurement numbers, an EC₅₀ is determined graphically, referring to a 50% change in the optical density in the sin ne an aggregation inhibition relates.  

The following table contains the results found:

Due to their inhibitory effect on cell-cell or cell-matrix Interactions are the new tricyclic azepine of the general formula I and their physiologically tolerated salts for the control or prevention of diseases smaller or larger cell aggregates or cell Matrix interactions play a role, eg. B. in the fight or prevention of venous and arterial thrombosis, from Cerebrovascular diseases, pulmonary embolism, heart disease farts, arteriosclerosis, osteoporosis and metastasis tion of tumors and therapy genetic or also acquired disorders of cell interactions each other or with solid structures. Furthermore, are suitable these as adjunctive therapy in thrombolysis with fibrinolytica or vascular interventions such as transluminal angioplasty or also in the therapy of shock states, psoriasis, Diabetes and inflammation.

For the control or prevention of the abovementioned Diseases, the dose is between 0.1 mg and 30 mg / kg Kör per weight, preferably at 1 mg to 15 mg / kg body weight, with up to 4 doses per day. For this purpose, the invention can be according to compounds of formula I, optionally  in combination with other active substances such as thromboxane-Re zeptor antagonists and thromboxane synthesis inhibitors or their Combinations, serotonin antagonists, α-receptor antagonists, Alkyl nitrates such as glyceryl trinitrate, phosphodiesterase inhibitors, Prostacyclin and its analogs, fibrinolytics such as tPA, Prouro kinase, urokinase, streptokinase, or anticoagulants like Heparin, dermatan sulfate, activated protein C, vitamin K-An tagonists, hirudin, inhibitors of thrombin or others activated coagulation factors, together with one or more ren inert customary carriers and / or diluents, z. B. with corn starch, lactose, cane sugar, microcrystalline Cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid tartaric acid, water, water / ethanol, water / glycerin, what ser / sorbitol, water / polyethylene glycol, propylene glycol, stearyl alcohol, carboxymethylcellulose or fatty substance such as Hard fat or its suitable mixtures, in usual galenic Preparations such as tablets, dragees, capsules, powders, suspensions instructions, solutions, sprays or suppositories.

The following examples are intended to explain the invention in more detail tern:  

Preparation of the starting materials Example I 7-Nitro-3-trifluoroacetyl-2,3,4,5-tetrahydro-1H-3-benzazepine

To a cooled to -10 ° C solution of 100 g of 3-trifluoroacetyl-2,3,4,5-tetrahydro-1H-3-benzazepin [R _f value: 0.76 (silica gel, cyclohexane / ethyl acetate = 1: 1), prepared by reacting 2,3,4,5-tetrahydro-1H-3-benzazepine with trifluoroacetic acid methyl ester] in 260 ml of concentrated sulfuric acid is within 2 hours, a mixture of 29.9 ml of 65% nitric acid and 10 ml concentrated sulfuric acid at an internal temperature of -12 to -5 ° C added dropwise. Thereafter, the mixture is stirred for 4 hours at -10 ° C. The reaction mixture is added to ice, extracted with ethyl acetate and the combined organic phases are washed with water. The organic phase is separated, dried and evaporated. The residue is heated to boiling with 80 ml of tert.-butyl methyl ether with stirring, then cooled in an ice bath and the precipitate abge sucks. The product obtained is washed with tert-butyl methyl ether and dried.
Yield: 75 g (64% of theory),
Melting point: 121-123 ° C
R _f value: 0.57 (silica gel, cyclohexane / ethyl acetate 2: 1).

Analogously to Example I, the following compounds are obtained:

• (1) 7-Methoxycarbonylamino-8-nitro-3-trifluoroacetyl-2,3,4,5-tetrahydro-1H-3-benzazepine
  The residue is chromatographed over silica gel with ethyl acetate / cyclohexane (4: 1).
  Melting point: 99.5-104.5 ° C
  R _f value: 0.48 (silica gel, cyclohexane / ethyl acetate 1: 1).
• (2) 7 - [(1-Methoxycarbonylpiperidin-4-yl) carbonylamino] -8-nitro-3-trifluoroacetyl-2,3,4,5-tetrahydro-1H-3-benzazepine
  As starting material, the compound 2 of Example VI is used.
  The residue is chromatographed over silica gel with cyclohexane / ethyl acetate (1: 2).
  Melting point: 161-165 ° C
  R _f value: 0.47 (silica gel, cyclohexane / ethyl acetate 2: 3)

Example II 7-amino-3-trifluoroacetyl-2,3,4,5-tetrahydro-1H-3-benzazepine

17.3 g of 7-nitro-3-trifluoroacetyl-2,3,4,5-tetrahydro-1H-3-benz azepine are dissolved in 200 ml of ethyl acetate with hydrogen in the presence of 3 g of 10% palladium on activated carbon at room temperature and a Hydrogen pressure of 50 psi hydrogenated for one hour. The catalyst is filtered off with suction and the filtrate is evaporated. The residue is heated with tert-butyl methyl ether and cooled. The precipitate is filtered off, washed with tert.butyl methyl ether and dried.
Yield: 12.2 g (79% of theory),
Melting point: 102-104 ° C
R _f value: 0.31 (silica gel, cyclohexane / ethyl acetate = 2: 1).

The following compounds are obtained analogously to Example II:

• (1) 8-Amino-7-methylamino-3-trifluoroacetyl-2,3,4,5-tetrahydro-1H-3-benzazepine dihydrochloride
  The hydrogenation of the compound of Example V is carried out in Isopro panol at 40 ° C. To the residue is added isopropanolic hydrochloric acid and evaporated several times with toluene. The crude product is directly further reacted.
  R _f value: 0.51 (silica gel, methylene chloride / methanol = 95: 5).
• (2) 8-Amino-7 - [[2- (1-methoxycarbonyl-piperidin-4-yl) -ethyl] -carbonylamino] -3-trifluoroacetyl-2,3,4,5-tetrahydro-1H-3-benz-azepine
  The hydrogenation is carried out at 40.degree. The residue is crystallized from ether / tert-butyl methyl ether / petroleum ether.
  R _f value: 0.18 (silica gel, methylene chloride / methanol = 95: 5).
• (3) 7,8-diamino-3-trifluoroacetyl-2,3,4,5-tetrahydro-1H-3-benz azepine
  The hydrogenation of compound 2 of Example V is carried out in isopropanol (2 hours room temperature, then 2 hours at 50 ° C). To the residue is added toluene and evaporated.
  R _f value: 0.48 (silica gel, methylene chloride / methanol = 95: 5).
• (4) 8-Amino-7 - [(1-methoxycarbonylpiperidin-4-yl) carbonylamino] -3-trifluoroacetyl-2,3,4,5-tetrahydro-1H-3-benzazepine
  As starting material (starting material), the compound 2 of Example I is used.
  Melting point: 174-176 ° C
  R _f value: 0.38 (silica gel, cyclohexane / ethyl acetate 19: 1).
• (5) 7-Amino-8-hydroxy-3-trifluoroacetyl-2,3,4,5-tetrahydro-1H-3-benzazepine
  The educt used is the compound of Example XVI. The catalyst is filtered off and the solution is evaporated.
  R _f value: 0.36 (silica gel, cyclohexane / ethyl acetate 1: 1).

Example III 7-methoxycarbonylamino-3-trifluoroacetyl-2,3,4,5-tetrahydro-1H- 3-benzazepine

To a cooled to 6 ° C solution of 79.9 g of 7-amino-3-trifluoroacetyl-2,3,4,5-tetrahydro-1H-3-benzazepine and 70 ml of N-ethyl-diisopropylamine in 400 ml of methylene chloride drops slowly adding a solution of 29 ml of methyl chloroformate in 80 ml of methylene chloride, so that the temperature does not exceed 11 ° C. The reaction solution is washed with 2N citric acid solution and saturated brine. The organic phase is dried over magnesium sulfate and evaporated under reduced pressure. The residue is chromatographed over silica gel with methylene chloride.
Yield: 65.5 g (67% of theory),
Melting point: 182-183.5 ° C
R _f value: 0.37 (silica gel, cyclohexane / ethyl acetate 1: 1).

Example IV 7- (N-methoxycarbonyl-N-methyl-amino) -8-nitro-3-trifluoroacetyl- 2,3,4,5-tetrahydro-1H-3-benzazepine

A suspension of 18.0 g of 7-methoxycarbonylamino-8-nitro-3-trifluoroacetyl-2,3,4,5-tetrahydro-1H-3-benzazepine, 18 g of dry potassium carbonate, 11.3 g of methyl iodide and 0.2 ml of tris- (3,6-dioxaheptyl) -amine in 180 ml of acetone is stirred at 45 ° C for 14 hours. An additional 10 g of dry potassium carbonate, 5 ml of methyl iodide and 0.3 ml of N-benzyltriethylammonium hydroxide are added. After stirring for a further 7 hours at 45 ° C., the inorganic salts are filtered off with suction and the filtrate is evaporated. The residue is dissolved in ethyl acetate and washed with water, ver dilute sodium hydrogen sulfate solution, water and saturated brine. The organic phase is evaporated and the residue is chromatographed over silica gel with cyclohexane / ethyl acetate (4: 1). The product will be implemented directly.
Yield: 15.9 g (85% of theory),
R _f value: 0.51 (silica gel, cyclohexane / ethyl acetate 1: 1).

Example V 7-methylamino-8-nitro-3-trifluoroacetyl-2,3,4,5-tetrahydro-1H- 3-benzazepine

22.5 ml of hexamethyldisilane and 16 g of iodine are slowly heated to 120 ° C. under an inert gas atmosphere. After decolorization of the reaction mixture is cooled to 0 ° C and gives a solution of 15.8 g of 7- (N-methoxycarbonyl-N-methyl-amino) -8-nitro-3-trifluoro-acetyl-2,3,4,5 Tetrahydro-1H-3-benzazepine in 80 ml of methylene chloride to. The mixture is stirred for 16 hours at room temperature, then diluted with methylene chloride and slowly added dropwise saturated sodium bicarbonate solution. After completion of the gas evolution, the organic phase is washed twice with sodium hydrogensulfite solution and once with water. The organic phase is dried, evaporated and the crude product with cyclohexane / ethyl acetate (7: 3 to 1: 1) on silica gel.
Yield: 11.6 g (87% of theory),
Melting point 187-190 ° C
R _f value: 0.62 (silica gel, cyclohexane / ethyl acetate 1: 1).

Analogously to Example V, the following compounds are obtained:

• (1) 1-Methyl-2- [2- (piperidin-4-yl) ethyl] -7-trifluoroacetyl-6,7,8,9-tetrahydro-5H-imidazo [4-, 5 ': 4.5 ] benzo [1,2-d] azepine
  The crude product is stirred with tert-butyl methyl ether, filtered off with suction and dried.
  R _f value: 0.57 (reversed phase RP-8, methanol / 5% saline solution 6: 4).
• (2) 7-Amino-8-nitro-3-trifluoroacetyl-2,3,4,5-tetrahydro-1H-3-benzazepine
  The crude product is chromatographed over silica gel with cyclohexane / ethyl acetate (7: 3).
  Melting point: 183.5-186 ° C
  R _f value: 0.37 (silica gel, cyclohexane / ethyl acetate 2: 1).
• (3) 2- [2- (piperidin-4-yl) -ethyl] -7-trifluoroacetyl-6,7,8,9-th-trahydro-5H-imidazo [4 ', 5': 4,5] benzo [ 1,2-d] azepine
  The crude product is stirred with tert-butyl methyl ether, filtered off with suction and dried.
  R _f value: 0.53 (Reversed phase RP-8, methanol / 5% saline solution 6: 4).
• (4) 2- (piperidin-4-yl) -7-trifluoroacetyl-6,7,8,9-tetrahydro-5H-imidazo [4 ', 5': 4,5] benzo [1,2-d] azepine
  R _f value: 0.53 (Reversed phase RP-8, methanol / 5% saline solution 6: 4).
• (5) 1-methyl-2- (piperidin-4-yl) -7-trifluoroacetyl-6,7,8,9-th-trahydro-5H-imidazo [4 ', 5': 4,5] benzo [1, 2-d] azepine
  Melting point: 234-238 ° C
  R _f value: 0.52 (Reversed phase RP-8, methanol / 5% saline solution 6: 4).
• (6) 2- [2- (piperidin-4-yl) -ethyl] -7-trifluoroacetyl-6,7,8,9-th-trahydro-5H-oxazolo [4 ', 5': 4,5] benzo [ 1,2-d] azepine
  After stirring at room temperature for 2.5 hours, 30 ml of methanol are added and the mixture is evaporated. The residue is dissolved in water and adjusted to pH 10 with saturated sodium bicarbonate solution. The precipitate is filtered off with suction, washed with water and dried.
  Melting point: 218-220 ° C
  R _f value: 0.29 (Reversed phase RP-8, methanol / 5% saline solution 6: 4).

Example VI 8 - [[2- (1-methoxycarbonyl-piperidin-4-yl) ethyl] carbonylamino] - 7-methylamino-3-trifluoroacetyl-2,3,4,5-tetrahydro-1H-3-benz-azepine

To the well-stirred solution of 4.8 g of 8-amino-7-methylamino-3-trifluoroacetyl-2,3,4,5-tetrahydro-1H-3-benzazepine in 20 ml of pyridine is added dropwise under inert gas atmosphere, a solution of 3, 66 g of 3- (1-methoxycarbonyl-piperidin-4-yl) -propionic-chloride (prepared by heating 3- (1-methoxycarbonyl-piperidin-4-yl) -propionic acid in thionyl chloride for 5 hours and subsequently distilling off the residue several times excess thionyl chloride with toluene) in 5 ml of methylene chloride. After 15 minutes, the reaction solution is evaporated and the residue is dissolved in ethyl acetate. The solution is washed with aqueous sodium dithionite solution, 2N citric acid, water and saturated brine. The organic phase is dried over sodium sulfate, treated with activated charcoal and filtered. The filtrate is evaporated and the residue chromatographed with methylene chloride / methanol over alum miniumoxid.
Yield: 4.8 g (85% of theory),
R _f value: 0.20 (aluminum oxide, ethyl acetate).

The following compounds are obtained analogously to Example VI:

• (1) 7 - [[2- (1-Methoxycarbonylpiperidin-4-yl) ethyl] carbonylamino] -8-nitro-3-trifluoroacetyl-2,3,4,5-tetrahydro-1H-3- benz azepine
  The starting material used is compound 2 of example V. The residue is chromatographed over silica gel with methylene chloride / ethyl acetate (9: 1 to 8: 2).
  Melting point: 131-135 ° C
  R _f value: 0.38 (silica gel, cyclohexane / ethyl acetate 1: 1).
• (2) 7 - [(1-Methoxycarbonylpiperidin-4-yl) carbonylamino] -3-trifluoroacetyl-2,3,4,5-tetrahydro-1H-3-benzazepine
  The starting materials used are the compound of Example II and the compound of Example XII. The reaction is carried out in methylene chloride in the presence of N-ethyl-diisopropylamine.
  Melting point: 168-171 ° C
  R _f value: 0.34 (silica gel, cyclohexane / ethyl acetate 1: 2).

Example VII 2- [2- (1-methoxycarbonyl-piperidin-4-yl) ethyl] -1-methyl-7-tri fluoroacetyl-6,7,8,9-tetrahydro-5H-imidazo [4 ', 5': 4,5] benzo azepine [1,2-d]

A solution of 4.7 g of 8 - [[2- (1-methoxycarbonyl-piperidin-4-yl) -ethyl] -carboxylamino] -7-methylamino-3-trifluoroacetyl-2,3,4,5-tetrahydro -1H-3-benzazepine in 40 ml of phosphoryl chloride is stirred at 80 ° C for two hours. Excess phosphoryl chloride is distilled off under reduced pressure. The residue is dissolved in ethyl acetate and poured onto ice. After neutralization with potassium carbonate solution, the organic phase is washed with water and saturated brine. The organic phase is dried, evaporated and the residue chromatographed with ethyl acetate over alumina.
Yield: 1.8 g (40% of theory),
Melting point: 164-168 ° C
R _f value: 0.43 (alumina, ethyl acetate).

The following compound is obtained analogously to Example VII:

• (1) 2- [2- (1-Methoxycarbonylpiperidin-4-yl) ethyl] -7-trifluoroacetyl-6,7,8,9-tetrahydro-5H-37032 00070 552 001000280000000200012000285913692100040 0002019612376 00004 36913imidazo [4 ' , 5 ': 4,5] benzo [1,2-d] azepine
  R _f value: 0.25 (alumina, ethyl acetate).

Example VIII 2-keto-7-trifluoroacetyl-2,3,6,7,8,9-hexahydro-1H, 5H-imidazo [4 ', 5': 4,5] benzo [1,2-d] azepine

To a solution of 10.6 g of 7,8-diamino-3-trifluoroacetyl-2,3,4,5-tetrahydro-1H-3-benzazepine in 100 ml of tetrahydrofuran is added at 0 ° C, a solution of 6.3 g N, N'-carbonyldiimidazole in 100 ml of tetrahydrofuran and stirred for 16 hours at room temperature. A further 1.3 g of N, N'-carbonyldiimidazole are added in portions. After 3 hours, the reaction mixture is mixed with 30 ml of water and evaporated off excess tetrahydrofuran. After addition of ethyl acetate, the organic phase is washed three times with 2N citric acid solution, dried and evaporated. The residue is chromatographed over silica gel with methylene chloride / methanol (98: 2).
Yield: 2.6 g (22% of theory),
Melting point: <250 ° C
R _f value: 0.30 (silica gel, methylene chloride / methanol = 95: 5).

Analogously to Example IX, the following compound is obtained:

• (1) 2-Keto-1-methyl-7-trifluoroacetyl-2,3,6,7,8,9-hexahydro-1H, 5H-imidazo [4 ', 5': 4,5] benzo [1,2 -d] azepine
  Melting point 243-246 ° C (decomposition)
  R _f value: 0.40 (silica gel, methylene chloride / methanol = 95: 5).

Example IX 2-chloro-7-trifluoroacetyl-6,7,8,9-tetrahydro-5H-imidazo [4 ', 5': 4,5] benzo [1,2-d] azepine

A suspension of 2.60 g of 2-keto-7-trifluoroacetyl-2,3,6,7,8,9-hexahydro-1H, 5H-imidazo [4 ', 5': 4,5] benzo [1,2 -d] azepine in 40 ml of phosphoryl chloride is heated at 120 ° C for 3 hours. Excess phosphoryl chloride is distilled off and the residue poured onto water, so that the temperature does not exceed 30 ° C. Subsequently, with conc. Neutralized ammonia and the aqueous phase extracted twice with methylene chloride. The combined organic phases are washed with saturated sodium chloride solution, dried and evaporated.
Yield: 2.66 g (96% of theory),
Melting point: 179 ° C (decomposition)
R _f value: 0.33 (silica gel, methylene chloride / methanol = 95: 5).

Analogously to Example IX, the following compound is obtained:

• (1) 2-Chloro-1-methyl-7-trifluoroacetyl-6,7,8,9-tetrahydro-5H-imidazo [4 ', 5': 4,5] benzo [1,2-d] azepine
  Melting point 223-229 ° C (decomposition)
  R _f value: 0.58 (silica gel, methylene chloride / methanol = 95: 5).

Example X 1-t-butyloxycarbonyl-4- (3-ethoxycarbonyl-propyl) -piperazine

A suspension of 10.25 g of 1-tert-butyloxycarbonyl-piperazine, 11.73 g of 4-bromobutyric acid ethyl ester and 10.5 ml of N-ethyl-diisopropylamine in 20 ml of acetonitrile is heated to reflux for 6 hours. The solvent is evaporated and the residue is dissolved in ethyl acetate. The solution is washed twice with saturated Na triumhydrogencarbonat solution and with saturated sodium chloride solution, dried and evaporated. The crude product is chromatographed over silica gel with methylene chloride / methanol.
Yield: 14.85 g (90% of theory) of yellowish oil,
R _f value: 0.47 (silica gel, methylene chloride / methanol = 95: 5).

Example XI 4-piperazino-butyric acid ethyl ester trifluoroacetate

100 ml of trifluoroacetic acid are slowly added dropwise at room temperature to a solution of 14.83 g of 1-tert-butyloxycarbonyl-4- (3-ethoxycarbonyl-propyl) -piperazine in 100 ml of methylene chloride. It is stirred for 2 hours and evaporated. The residue is dissolved three times in methylene chloride and once in toluene and in each case evaporated. This gives 31.08 g of a dark brown oil, which crystallizes slowly.
Melting point: from 49 ° C sintering
R _f value: 0.09 (silica gel, methylene chloride / methanol = 95: 5).

Example XII (1-methoxycarbonyl-piperidin-4-yl) -carbonsäurechlorid

To a solution of 25.0 g of (1-methoxycarbonyl-piperidin-4-yl) -car Bonsäure [prepared from piperidine-4-carboxylic acid ethyl ester by reaction with methyl chloroformate and N-ethyl diisopropylamine in acetonitrile and subsequent ester cleavage with 2N sodium hydroxide in tetrahydrofuran; (Melting point: 81-84 ° C) in 25 ml of methylene chloride is added dropwise 39.7 g of thionyl chloride and 3 Drop of dimethylformamide. It is stirred for 16 hours Room temperature and evaporated. The crude acid chloride becomes directly implemented.  

Example XIII 2- (1-methoxycarbonyl-piperidin-4-yl) -7-trifluoroacetyl- 6,7,8,9-tetrahydro-5H-imidazo [4 ', 5': 4,5] benzo [1,2-d] azepine

4.95 g of 8-amino-7 - [(1-methoxycarbonylpiperidin-4-yl) carbonylamino] -3-trifluoroacetyl-2,3,4,5-tetrahydro-1H-3-benzazepine are allowed to stand for 40 minutes Heated to 190 ° C. It is allowed to cool and the residue is chromatographed on ethyl acetate / methylene chloride (9: 1) over silica gel.
Yield: 3.6 g (76% of theory),
R _f value: 0.52 (silica gel, ethyl acetate / methylene chloride = 9: 1).

Example XIV 2- (1-methoxycarbonyl-piperidin-4-yl) -1-methyl-7-trifluoroacetyl-6,7,8, 9-tetra hydro-5H-imidazo [4 ', 5': 4,5] benzo [1,2-d] azepine

To a suspension of 1.0 g of 2- (1-methoxycarbonyl-piperidin-4-yl) -7-trifluoroacetyl-6,7,8,9-tetrahydro-5H-imidazo [4 ', 5': 4,5 ] Benzo [1,2-d] azepine in 10 ml of tetrahydrofuran is added 0.27 g of potassium tert-butoxide and stirred for 15 minutes at room temperature. There are added dropwise 0.30 ml of methyl iodide. After 5 hours, add another 54 mg of potassium tert-butylate and stir for 16 hours. Adjusted by addition of aqueous citric acid solution to pH 5 and evaporated excess tetrahydrofuran. The aqueous phase is extracted several times with ethyl acetate and the combined organic phases washed once with water and twice with saturated sodium chloride solution. The organic phase is dried, evaporated and the residue with ethyl acetate / methylene chloride (9: 1) chromatographed on silica gel.
Yield: 0.53 g (52% of theory),
Melting point: 191-194 ° C
R _f value: 0.29 (silica gel, ethyl acetate / methylene chloride = 9: 1).

Example XV 7-hydroxy-3-trifluoroacetyl-2,3,4,5-tetrahydro-1H-3-benzazepine

To a suspension of 10.0 g of 7-amino-3-trifluoroacetyl-2,3,4,5-tetrahydro-1H-3-benzazepine and 9.7 ml of conc. Sulfuric acid in 190 ml of water is added dropwise at 0 ° C, a solution of 2.7 g of sodium nitrite in 10 ml of water. The mixture is stirred for 1 hour at 0 ° C, one hour at room temperature and then heated to 140 ° C for 1.5 hours. The reaction mixture is cooled to 0 ° C and the precipitate filtered off with suction. The precipitate is dissolved in ethyl acetate and the solution washed with water and saturated brine. The organic phase is dried and evaporated.
Yield: 8.9 g (89% of theory),
R _f value: 0.35 (Reversed phase RP-8, methanol / 5% saline solution 6: 4).

Example XVI 8-hydroxy-7-nitro-3-trifluoroacetyl-2,3,4,5-tetrahydro-1H- 3-benzazepine

To a solution of 5.7 g of 7-hydroxy-3-trifluoroacetyl-2,3,4,5-tetra-hydro-1H-3-benzazepine in 150 ml of methylene chloride is added slowly dropwise at a temperature between -5 ° C and 0 ° C 1.53 ml of 65% nitric acid. The reaction solution is diluted with 50 ml of methylene chloride and stirred for 2 hours at room temperature. The solution is dried over sodium sulfate and evaporated. The residue is chromatographed over silica gel with cyclohexane / ethyl acetate (6: 4).
Yield: 3.5 g (52% of theory),
Melting point: 127-129 ° C
R _f value: 0.75 (silica gel, cyclohexane / ethyl acetate = 1: 1).

Example XVII 2- [2- (1-methoxycarbonyl-piperidin-4-yl) ethyl] -7-trifluorace tyl-6,7,8,9-tetrahydro-5H-oxazolo [4 ', 5': 4,5] benzo [1,2-d] azepine

A suspension of 1.1 g of 7-amino-8-hydroxy-3-trifluoroacetyl-2,3,4,5-tetrahydro-1H-3-benzazepine and 1.4 g of 3- (1-methoxycarbonylpiperidine-4 -yl) -propionic acid chloride in 5 ml of xylene is heated to reflux for 5 hours. The solvent is evaporated off and the residue is chromatographed over silica gel with cyclohexane / ethyl acetate (1: 1).
Yield: 1.1 g (61% of theory),
Melting point: 112-120 ° C
R _f value: 0.40 (silica gel, cyclohexane / ethyl acetate = 1: 1)

Example XVIII 2- [2- (pyridin-4-yl) -ethyl] malonate hydrochloride

13.4 g (0.583 mol) of sodium are dissolved in 180 ml of absolute ethanol, and 204 ml of malonic acid diethyl ester are added in portions to the resulting solution, forming a colorless precipitate. The precipitate is dissolved by warming to 30-40 ° C and diluting with absolute ethanol. A solution of 63 ml of 4-vinylpyridine in 120 ml of absolute ethanol is added dropwise within 1.5 hours with stirring. After completion of the addition, the mixture is heated to reflux for 3 hours, evaporated and diluted with 450 ml of 6N hydrochloric acid. It is extracted twice with ether to remove over schüssigen diethyl malonate, the aqueous phase is alkaline with sodium carbonate and the aqueous phase is extracted with methylene chloride. The combined organic phases are dried and evaporated. The residue is chromatographed over silica gel with ethyl acetate / cyclohexane (1: 1). The oily residue (78.6 g = 50.8% of theory) is dissolved in acetone and acidified to pH 3.5 with ethereal hydrochloric acid and evaporated. The slowly crystallizing residue is triturated with acetone / ether and filtered with suction.
Yield: 65 g (37% of theory),
R _f value: 0.80 (silica gel, methylene chloride / methanol = 9: 1)

Example XIX 2- [2- (piperidin-4-yl) ethyl] malonic acid diethyl ester hydrochlo- rid

A solution of 64.5 g of 2- [2- (pyridin-4-yl) ethyl] malonic acid diethyl ester hydrochloride in 400 ml of absolute ethanol is hydrogenated with hydrogen at room temperature and a hydrogen pressure of 50 psi in the presence of platinum dioxide. Subsequently, the catalyst is filtered off and the filtrate is evaporated. The residue is triturated with acetone and filtered with suction.
Yield: 62.8 g (96% of theory) of hygroscopic crystals,
R _f value: 0.22 (silica gel, methylene chloride / methanol = 9: 1)

Example XX 4- (piperidin-4-yl) butyric acid hydrochloride

A solution of 62 g of 2- [2- (piperidin-4-yl) ethyl] malonic acid diethyl ester hydrochloride in 600 ml of concentrated hydrochloric acid is refluxed for 24 hours. It is evaporated, toluene to the residue and evaporated again. This evaporation procedure is repeated three times.
Yield: 44.3 g of colorless crystals containing some toluene,
R _f value: 0.19 (silica gel, methylene chloride / methanol = 9: 1)

Example XXI 4- (piperidin-4-yl) butyric acid methylester hydrochloride

To 800 ml of methanol is added dropwise while stirring at -10 ° C slowly 18 ml of thionyl chloride. Then, at the same temperature, a solution of 44.3 g of 4- (piperidin-4-yl) -butyric acid hydrochloride in 100 ml of methanol is added dropwise and the mixture is stirred for 16 hours at room temperature. It is evaporated and the residue is partitioned between 50% potassium carbonate solution and ether. The aqueous phase is extracted twice with ether. The combined organic phases are dried and evaporated. The residue is dissolved in methanol, acidified to pH 6 with ethereal hydrochloric acid and evaporated. The remaining residue is triturated with acetone and filtered with suction.
Yield: 35.5 g (89% of theory),
Melting point: 99-105 ° C (decomposition)

Preparation of the end compounds example 1 2- [2- (1-tert.Butyloxycarbonylmethyl-piperidin-4-yl) ethyl] - 1-methyl-7-trifluoroacetyl-6,7,8,9-tetrahydro-5H-imidazo [4 ', 5': 4,5] benzo [1,2-d] azepine

A suspension of 1.4 g of 1-methyl-2- [2- (piperidin-4-yl) ethyl] -7-trifluoroacetyl-6,7,8,9-tetrahydro-5H-imidazo [4 ', 5 ': 4,5] benzo [1,2-d] azepine, 716 mg of bromoacetic acid tert-butyl ester and 1.05 g of N-ethyldiisopropylamine in 10 ml of acetonitrile are stirred for 16 hours at room temperature. The solvent is evaporated off under reduced pressure and the residue was dissolved in ethyl acetate. The ethyl acetate phase is washed with water, dilute sodium carbonate solution, sodium thiosulfate solution, water and saturated brine. The or ganic phase is dried, evaporated and the residue chromatographed with ethyl acetate over alumina.
Yield: 0.60 g (33% of theory),
Melting point: 163-167 ° C
R _f value: 0.50 (reversed phase RP-8, methanol / 5% saline solution 6: 4).

Analogously to Example 1, the following compounds are obtained:

• (1) 1-Tert-Butyloxycarbonylmethyl-2- [2- (1-tert-butyl-oxycarbonylmethyl-piperidin-4-yl) -ethyl] -7-trifluoroacetyl-6,7,8,9-th-trahydro-5H-imidazo [4 ', 5': 4,5] benzo [1,2-d] azepine (A) and 2- [2- (1-tert-butyloxycarbonylmethyl-piperidin-4-yl) -ethyl] -7-trifluoroacetyl- 6,7,8,9-tetrahydro-5H-imidazo [4 ', 5': 4,5] benzo [1,2-d] azepine (B)
  As starting material, compound 3 of Example V was used. The crude product was chromatographed with cyclohexane / ethyl acetate (1: 1) over Alumi niumoxid.
  Connection A:
  R _f value: 0.45 (silica gel, methylene chloride / methanol / concentrated ammonia = 95: 5: 1)
  Compound B:
  Mass spectrum: M + = 622
  R _f value: 0.24 (silica gel, methylene chloride / methanol / concentrated ammonia = 95: 5: 1).
• (2) 2- [1- (3-ethoxycarbonyl-propyl) -piperidin-4-yl] -7-trifluoro-acetyl-6,7,8,9-tetrahydro-5H-imidazo [4,5,5]: 5] benzo [1,2-d] azepine
  Compound 4 of Example V is reacted with 3-bromobutyric acid ethyl ester.
  R _f value: 0.51 (alumina, methylene chloride / methanol = 98: 2).
• (3) 2- [1- (3-ethoxycarbonyl-propyl) -piperidin-4-yl] -1-methyl-7-trifluoroacetyl-6,7,8,9-tetrahydro-5H-imidazo [4 ', 5' ,: 4,5] benzo [1,2-d] azepine
  Compound 5 of Example V is reacted with 3-bromobutyric acid ethyl ester.
  Melting point: 154-156 ° C
  R _f value: 0.14 (alumina, methylene chloride / methanol = 99.5: 0.5).
• (4) 2- [2- (1-tert-Butyloxycarbonylmethyl-piperidin-4-yl) -ethyl] -7-trifluoroacetyl-6,7,8,9-tetrahydro-5H-oxazolo [4 ', 5': 4 , 5] benzo [1,2-d] azepine
  The residue is chromatographed over aluminum oxide with cyclohexane / ethyl acetate (3: 2).
  R _f value: 0.54 (silica gel, cyclohexane / ethyl acetate 3: 2).
• (5) 2- [2- (1-ethoxycarbonylmethyl-piperidin-4-yl) -ethyl] -7-me ethyl 6,7,8,9-tetrahydro-2H, 5H-dioxolo [4-, 5-: 4,5] benzo [1,2-d] azepine.
• (6) 2 - [(1-tert-Butyloxycarbonylmethyl-piperidin-4-yl) -aminocar bonyl] -1,7-dimethyl-6,7,8,9-tetrahydro-5H-imidazo [4 ', 5': 4.5] benzo [1,2-d] azepine.  
• (7) 2- [2- (1-ethoxycarbonylmethyl-piperidin-4-yl) -ethyl] -2,7-di Methyl-6,7,8,9-tetrahydro-2H, 5H-dioxolo [4 ', 5': 4,5] benzo [1,2-d] azepine.
• (8) 2- [2- (1-tert-Butyloxycarbonylmethyl-piperidin-4-yl) -ethyl] - 7-trifluoroacetyl-6,7,8,9-tetrahydro-5H-thiazolo [4 ', 5': 4.5] benzo [1,2-d] azepine

Example 2 2- [2- (1-carboxymethyl-piperidin-4-yl) ethyl] -1-methyl- 6,7,8,9-tetrahydro-5H-imidazo [4 ', 5': 4,5] benzo [1,2-d] azepine trihydrochloride

A solution of 580 mg of 2- [2- (1-tert-butyloxycarbonylmethyl-piperidin-4-yl) -ethyl] -1-methyl-7-trifluoroacetyl-6,7,8,9-th-trahydro-5H-imidazo [4 ', 5': 4,5] benzo [1,2-d] azepine in 20 ml of 3N hydrochloric acid is heated at 100 ° C for 4 hours. The solvent is evaporated off. Toluene is added and evaporated again. The remaining, hygroscopic solid is rubbed with acetone, filtered with suction and dried in a desiccator.
Yield: 480 mg (90% of theory),
Melting point: from 200 ° C decomposition
Mass spectrum: M + = 370
R _f value: 0.83 (reversed phase RP-8, methanol / 5% saline solution 6: 4).

Analogously to Example 2, the following compounds are obtained:

• (1) 2- [2- (1-Carboxymethyl-piperidin-4-yl) -ethyl] -6,7,8,9-tetrahydro-5H-imidazo [4 ', 5': 4,5] benzo [1 , 2-d] azepine trihydro chloride
  The starting material used is compound 1B of example 1.
  Melting point from 200 ° C decomposition
  Mass spectrum: M + = 356
  R _f value: 0.77 (Reversed phase RP-8, methanol / 5% saline solution 6: 4).
• (2) 1-Carboxymethyl-2- [2- (1-carboxymethyl-piperidin-4-yl) -ethyl] -6,7,8,9-tetrahydro-5H-imidazo [4 ', 5': 4.5] benzo [1,2-d] azepine trihydrochloride
  The starting material used is compound 1A of example 1.
  Melting point: from 195 ° C decomposition
  Mass spectrum: (M + H) ⁺ = 415
  R _f value: 0.74 (Reversed phase RP-8, methanol / 5% saline solution 6: 4).
• (3) 2- [4- (3-carboxy-propyl) -piperazin-1-yl] -6,7,8,9-tetrahydro-5H-imidazo [4 ', 5': 4,5] benzo [1 , 2-d] azepine trihydrochloride
  The starting material used is the compound of Example 5. The hydrolysis is carried out by heating for 3 hours at 110 ° C in a mixture of 6N hydrochloric acid / acetic acid (2: 1).
  Melting point: <250 ° C
  Mass spectrum: (M + H) ⁺ = 358
  R _f value: 0.84 (reversed phase RP-8, methanol / 5% saline solution 6: 4).
• (4) 2- [4- (3-carboxy-propyl) -piperazin-1-yl] -1-methyl-6,7,8,9-tetra-hydro-5H-imidazo [4 ', 5': 4, 5] benzo [1,2-d] azepine trihydro chloride
  The educt used is compound 1 of example 5. The hydrolysis is carried out by heating for 2 hours at 110 ° C in a mixture of 6N hydrochloric acid / acetic acid (2: 1).
  Melting point from 186 ° C decomposition
  Mass spectrum: M⁺ = 371
  R _f value: 0.83 (reversed phase RP-8, methanol / 5% saline solution 6: 4).
• (5) 2- [4- (3-carboxy-propyl) -piperidin-1-yl] -6,7,8,9-tetrahydro-5H-imidazo [4 ', 5': 4,5] benzo [1 , 2-d] azepine dihydrochloride
  As starting material, the compound 2 of Example 5 is used. The hydrolysis is carried out by heating for 4 hours at 110 ° C in a mixture of 6N hydrochloric acid / acetic acid (2: 1).
  Melting point: 213.5 ° C (decomposition)
  Mass spectrum: M⁺ = 356
  R _f value: 0.62 (Reversed phase RP-8, methanol / 5% saline solution 6: 4).
• (6) 2- [4- (3-carboxy-propyl) -piperidin-1-yl] -1-methyl-6,7,8,9-tetra-hydro-5H-imidazo [4 ', 5': 4, 5] benzo [1,2-d] azepine dihydrochloride
  The educt used is compound 3 of example 5. The hydrolysis is carried out by heating for 5 hours at 100 ° C in a mixture of 6N hydrochloric acid / acetic acid (2: 1).
  Melting point: 0 ° C
  Mass spectrum: (M + H) ⁺ = 371
  R _f value: 0.62 (Reversed phase RP-8, methanol / 5% saline solution 6: 4).
• (7) 2- [2- (1-carboxymethyl-piperidin-4-yl) -ethyl] -7-methyl-6,7,8,9-tetra-hydro-5H-imidazo [4 ', 5': 4, 5] benzo [1,2-d] azepine trihydrochloride
  The starting material used is the compound of Example 7. It is heated to 100 ° C for 2 hours.
  Melting point: 213-224 ° C (decomposition)
  Mass spectrum: (M + H) ⁺ = 371
  R _f value: 0.63 (reversed phase RP-8, methanol / 5% saline solution 6: 4).
• (8) 2- [2- (1-carboxymethyl-piperidin-4-yl) -ethyl] -1,7-dimethyl-6,7,8,9-tetrahydro-5H-imidazo [4 ', 5': 4 , 5] benzo [1,2-d] azepine tri hydrochloride
  The educt used is compound 1 of example 7. It is heated to 100 ° C for 6 hours.
  Melting point: from 200 ° C decomposition
  Mass spectrum: (M + H) ⁺ = 385
  R _f value: 0.64 (Reversed phase RP-8, methanol / 5% saline solution 6: 4).
• (9) 2- [1- (3-carboxy-propyl) -piperidin-4-yl] -6,7,8,9-tetrahydro-5H-imidazo [4 ', 5': 4,5] benzo [1 , 2-d] azepine trihydrochloride
  The starting material used is compound 2 of example 1. It is heated to 100 ° C in 2N hydrochloric acid for 5 hours.
  Melting point: 290-294 ° C
  Mass spectrum: (M + H) ⁺ = 357
  R _f value: 0.74 (Reversed phase RP-8, methanol / 5% saline solution 6: 4).
• (10) 2- [1- (3-carboxy-propyl) -piperidin-4-yl] -1-methyl-6,7,8,9-tetra-hydro-5H-imidazo [4 ', 5': 4, 5] benzo [1,2-d] azepine trihydro chloride
  As starting material, the compound 3 of Example 1 is used. It is heated to 100 ° C. in a mixture of 6N hydrochloric acid / acetic acid / water (1: 1: 1) for 3 hours.
  Mass spectrum: M⁺ = 370
  R _f value: 0.72 (reversed phase RP-8; methanol / 5% saline solution 6: 4).
• (11) 2- [2- (1-carboxymethyl-piperidin-4-yl) -ethyl] -6,7,8,9-th-trahydro-5H-oxazolo [4 ', 5': 4,5] benzo [ 1,2-d] azepine dihydrochloride
  The starting material used is the compound of Example 8. It is heated for 45 minutes in 2N hydrochloric acid at 100 ° C. The ver remaining residue is triturated with a little water and abge sucks.
  Mass spectrum: M⁺ = 357
  R _f value: 0.77 (Reversed phase RP-8, methanol / 5% saline solution 6: 4).
• (12) 2- [2- (1-carboxymethyl-piperidin-4-yl) -ethyl] -6,7,8,9-te trahydro-5H-thiazolo [4 ', 5': 4,5] benzo [1,2-d] azepine dihydrochloride.
• (13) 2 - [(1-carboxymethyl-piperidin-4-yl) -aminocarbonyl] -1,7-di methyl 6,7,8,9-tetrahydro-5H-imidazo [4 ', 5': 4,5] benzo [1,2-d] -aze pin trihydrochloride.  
• (14) 2- [2- (4-carboxymethyl-3-oxopiperazin-1-yl) -ethyl] -1,7-di Methyl-6,7,8,9-tetrahydro-5H-imidazo [4 ', 5': 4,5] benzo [1,2-d] azepine trihydrochloride.
• (15) 2 - [[(trans-4-carboxycyclohexyl) methyl] aminocarbonyl] - 1,7-dimethyl-6,7,8,9-tetrahydro-5H-imidazo [4 ', 5': 4,5] benzo [1,2-d] azepine dihydrochloride.
• (16) 2- [2- [4- (carboxymethyloxy) -phenyl] -ethyl] -1,7-dimethyl- 6,7,8,9-tetrahydro-5H-imidazo [4 ', 5': 4,5] benzo [1,2-d] azepine di hydrochloride

Example 3 1-methyl-2- [2- (1-methoxycarbonylmethyl-piperidin-4-yl) ethyl] - 6,7,8,9-tetrahydro-5H-imidazo [4 ', 5': 4,5] benzo [1,2-d] azepine tri hydrochloride

To a well-stirred solution of 200 mg of 2- [2- (1-carboxymethyl-piperidin-4-yl) -ethyl] -1-methyl-6,7,8,9-tetrahydro-5H-imidazo [4 ', 5']. : 4.5] benzo [1,2-d] azepine trihydrochloride in 10 ml of methanol is added dropwise under nitrogen atmosphere at -78 ° C 0.2 ml of thionyl chloride. The mixture is stirred briefly at this temperature, removes the cooling bath and allowed to reach room temperature. The reaction solution is evaporated and the residue is evaporated several times with toluene / methanol. After drying the solid in a desiccator, the product is triturated with acetone, filtered off with suction and dried at 60 ° C under reduced pressure.
Yield: 170 mg (86% of theory),
Melting point: 185-195 ° C (The methyl ester is contaminated with free acid)
Mass spectrum: M⁺ = 384
R _f value: 0.68 (Reversed phase RP-8, methanol / 5% saline solution 6: 4).

Example 4 2- [2- (1-ethoxycarbonylmethyl-piperidin-4-yl) ethyl] -1-methyl-6,7,8,9 - tetra hydro-5H-imidazo [4 ', 5': 4,5] benzo [1,2-d] azepine tri hydrochloride

A solution of 150 mg of 1-methyl-2- [2- (1-methoxycarbonylmethylpiperidin-4-yl) ethyl] -6,7,8,9-tetrahydro-5H-imidazo [4 ', 5 ': 4,5] benzo [1,2-d] azepine trihydrochloride in 20 ml of ethanol is passed 5 minutes hydrogen chloride. The solvent is evaporated. To the residue is added toluene and evaporated again. The residue is redissolved in ethanol and redirected to hydrogen chloride as described above. The crude product is triturated with acetone, filtered off with suction and dried at 60 ° C. under reduced pressure.
Yield: 118 mg (75% of theory),
Melting point: from 210 ° C decomposition
Mass spectrum: M⁺ = 398
R _f value: 0.64 (Reversed phase RP-8, methanol / 5% saline solution 6: 4).

The following compounds are obtained analogously to Example 4:

• (1) 2- [2- (1-Cyclohexyloxycarbonylmethyl-piperidin-4-yl) -ethyl] - 1-methyl-6,7,8,9-tetrahydro-5H-imidazo [4 ', 5': 4,5] benzo [1,2-d] azepine trihydrochloride.
• (2) 2- [2- (1-isopropyloxycarbonylmethyl-piperidin-4-yl) -ethyl] - 1,7-dimethyl-6,7,8,9-tetrahydro-5H-imidazo [4 ', 5': 4,5] benzo [1,2-d] azepine trihydrochloride.
• (3) 2- [2- (1-ethoxycarbonylmethyl-piperidin-4-yl) -ethyl] - 6,7,8,9-tetrahydro-5H-imidazo [4 ', 5': 4,5] benzo [1,2-d] azepine tri hydrochloride.
• (4) 2- [2- (1-isopropyloxycarbonylmethyl-piperidin-4-yl) -ethyl] - 6,7,8,9-tetrahydro-5H-imidazo [4 ', 5': 4,5] benzo [1,2-d] azepine tri hydrochloride.  
• (5) 1-Ethoxycarbonylmethyl-2- [2- (1-ethoxycarbonylmethylpiperi din-4-yl) -ethyl] -6,7,8,9-tetrahydro-5H-imidazo [4 ', 5': 4,5] benzo [1,2-d] azepine trihydrochloride.
• (6) 2- [2- (1-ethoxycarbonylmethyl-piperidin-4-yl) -ethyl] - 6,7,8,9-tetrahydro-5H-oxazolo [4 ', 5': 4,5] benzo [1,2-d] azepine di hydrochloride

Example 5 2- [4- (3-ethoxycarbonyl-propyl) -piperazine-1-yl] -7-trifluoro acetyl-6,7,8,9-tetrahydro-5H-imidazo [4 ', 5': 4,5] benzo [1,2-d] azepin

A suspension of 2.60 g of 2-chloro-7-trifluoroacetyl-6,7,8,9-tetrahydro-5H-imidazo [4 ', 5': 4,5] benzo [1,2-d] azepine, 16 , 7 g of 4-piperazino-butyric acid ethyl ester and 18 ml of N-ethyl-diiso propylamine in 20 ml of dioxane is heated to reflux for 5 hours. The reaction solution is diluted with methylene chloride and washed three times with water. The organic phase is dried, evaporated and the residue with methylene chloride / methanol (95: 5) chromatographed on silica gel.
Yield: 0.92 g (23% of theory),
R _f value: 0.16 (silica gel, methylene chloride / methanol = 95: 5).

The following compounds are obtained analogously to Example 5:

• (1) 2- [4- (3-ethoxycarbonyl-propyl) -piperazin-1-yl] -1-methyl-7-trifluoroacetyl-6,7,8,9-tetrahydro-5H-imidazo [4 ', 5' : 4,5] benzo [1,2-d] azepine
  R _f value: 0.26 (silica gel, methylene chloride / methanol = 95: 5).
• (2) 2- [4- (3-methoxycarbonyl-propyl) -piperidin-1-yl] -7-trifluoroacetyl-6,7,8,9-tetrahydro-5H-imidazo [4 ', 5': 4, 5] benzo [1,2-d] azepine
  The amine component used is 4- (piperidin-4-yl) -butyric acid methyl ester. The reaction mixture is heated to reflux for 27 hours.
  R _f value: 0.25 (silica gel, methylene chloride / methanol = 97: 3).
• (3) 2- [4- (3-Methoxycarbonyl-propyl) -piperidin-1-yl] -1-methyl-7-trifluoroacetyl-6,7,8,9-tetrahydro-5H-imidazo [4 ', 5' : 4,5] benzo [1,2-d] azepine
  The amine component used is 4- (piperidin-4-yl) -butyric acid methyl ester. The reaction mixture is heated to reflux for 37 hours.
  Melting point: 165-167 ° C
  R _f value: 0.58 (silica gel, methylene chloride / methanol = 95: 5).

Example 6 [(3-carboxy-propyl) -piperidin-1-yl 4-] -7-methyl-6,7,8,9-te 2- trahydro-5H-imidazo [4 ', 5': 4,5] benzo [1,2-d] azepine dihydrochloride

1.0 g of 2- [4- (3-carboxy-propyl) -piperidin-1-yl] is added at 0.degree. C. to 0.84 ml of formic acid and 0.66 ml of 37% strength formalin solution in 5 ml of water. 6,7,8,9-tetrahydro-5H-imidazo [4 ', 5': 4,5] benzo [1,2-d] azepine dihydrochloride and portionwise 0.71 g of sodium bicarbonate. The reaction mixture is heated to 80 ° C for 5 hours. It is then evaporated and re-evaporated after adding What What. To the remaining residue is added water and acidified with conc. Hydrochloric acid to pH 1 at. The solvent is evaporated, the residue with little water verrie ben and sucked off. After renewed trituration with acetone and suction the product is dried at 60 ° C under reduced pressure ge.
Yield: 1.0 g (74% of theory),
Melting point from 214 ° C (sintering)
Mass spectrum: M⁺ = 370
R _f value: 0.57 (reversed phase RP-8, methanol / 5% saline solution 6: 4).

Analogously to Example 6, the following compounds are obtained:

• (1) 2- [4- (3-carboxy-propyl) -piperidin-1-yl] -1,7-dimethyl-6,7,8,9-tetrahydro-5H-imidazo [4 ', 5': 4 , 5] benzo [1,2-d] azepine dihydrochloride
  As starting material, the compound 6 of Example 2 is used.
  Melting point: from 206 ° C (sintering)
  Mass spectrum: M⁺ = 384
  R _f value: 0.53 (Reversed phase RP-8, methanol / 5% saline solution 6: 4).
• (2) 2- [4- (3-carboxy-propyl) -piperazin-1-yl] -1,7-dimethyl-6,7,8,9-tetrahydro-5H-imidazo [4 ', 5': 4 , 5] benzo [1,2-d] azepine trihydrochloride
  The educt used is the compound 4 of Example 2.
  Melting point: from 65 ° C sintering, from 138 ° C decomposition Mass spectrum: M⁺ = 385
  R _f value: 0.10 (silica gel, methylene chloride / methanol / concentrated ammonia = 8: 2: 0.2).
• (3) 2- [1- (3-carboxy-propyl) -piperidin-4-yl] -1,7-dimethyl-6,7,8,9-tetrahydro-5H-imidazo [4 ', 5': 4 , 5] benzo [1,2-d] azepine trihydrochloride
  The starting material used is the compound 10 of Example 2. After acidification with hydrochloric acid is evaporated to dryness.
  Mass spectrum: M⁺ = 384
  R _f value: 0.69 (reversed phase RP-8, methanol / 5% saline solution 6: 4).
• (4) 2- [1- (3-carboxy-propyl) -piperidin-4-yl] -7-methyl-6,7,8,9-tetrahydro-5H-imidazo [4 ', 5': 4,5 ] benzo [1,2-d] azepine trihydro chloride
  As starting material, the compound 9 of Example 2 is used. After acidification with hydrochloric acid is evaporated to dryness.
  Mass spectrum: M⁺ = 370
  R _f value: 0.65 (reversed phase RP-8, methanol / 5% saline solution 6: 4).

Example 7 2- [2- (1-ethoxycarbonylmethyl-piperidin-4-yl) ethyl] -7-methyl- 6,7,8,9-tetrahydro-5H-imidazo [4 ', 5': 4,5] benzo [1,2-d] azepine tri hydrochloride

A suspension of 1.0 g of 2- [2- (1-carboxymethyl-piperidin-4-yl) -ethyl] -6,7,8,9-tetrahydro-5H-imidazo [4 ', 5': 4.5 ] Benzo [1,2-d] azepine trihydrochloride, 0, 50 g of sodium bicarbonate, 0.92 g of formic acid and 0.49 g of 37% formalin solution is heated to 100 ° C for 4 hours. The reaction mixture is evaporated. After addition of 3N hydrochloric acid is evaporated again. The residue is suspended in absolute ethanol. About the suspension is passed hydrogen chloride. It is evaporated and re-evaporated after addition of toluene. This esterification procedure is repeated. The remaining residue is suspended in methylene chloride and the product is dissolved in solution with a little absolute ethanol. Inorganic constituents are filtered off and the filtrate is evaporated. The crude product is triturated with acetone, filtered off with suction and dried under reduced pressure.
Yield: 1.0 g (94% of theory),
Melting point: from 205-210 ° C (decomposition)
Mass spectrum: M⁺ = 398
R _f value: 0.65 (alumina, methylene chloride / methanol / concentrated ammonia = 90: 10: 1).

The following compounds are obtained analogously to Example 7:

• (1) 1, 7-Dimethyl-2- [2- (1-ethoxycarbonylmethyl-piperidin-4-yl) -ethyl] -6,7,8,9-tetrahydro-5H-imidazo [4 ', 5': 4 , 5] benzo [1,2-d] azepine trihydrochloride
  Melting point: 175 ° C (decomposition)
  Mass spectrum: M⁺ = 412
  R _f value: 0.88 (alumina, methylene chloride / methanol / concentrated ammonia = 90: 10: 1).
• (2) 2- [2- (1-Cyclohexyloxycarbonylmethyl-piperidin-4-yl) -ethyl] - 1,7-dimethyl-6,7,8,9-tetrahydro-5H-imidazo [4 ', 5': 4,5] benzo [1,2-d] azepine trihydrochloride.
• (3) 2- [2- (4-ethoxycarbonylmethyl-3-oxopiperazin-1-yl) -ethyl] - 1,7-dimethyl-6,7,8,9-tetrahydro-5H-imidazo [4 ', 5': 4,5] benzo [1,2-d] azepine trihydrochloride.
• (4) 2 - [[(trans-4-ethoxycarbonyl-cyclohexyl) -methyl] -aminocarbo nyl] -1,7-dimethyl-6,7,8,9-tetrahydro-5H-imidazo [4 ', 5': 4.5] benzo [1,2-d] azepine dihydrochloride.
• (5) 2- [2- [4- (ethoxycarbonylmethyloxy) -phenyl] -ethyl] -1,7-di Methyl-6,7,8,9-tetrahydro-5H-imidazo [4 ', 5': 4,5] benzo [1,2-d] azepine dihydrochloride

Example 8 2- [2- (1-tert.Butyloxycarbonylmethyl-piperidin-4-yl) ethyl] - 6,7,8,9-tetrahydro-5H-oxazolo [4 ', 5': 4,5] benzo [1,2-d] azepine

A mixture of 1.1 g of 2- [2- (1-tert-butyloxycarbonylmethylpiperidin-4-yl) ethyl] -7-trifluoroacetyl-6,7,8,9-tetrahydro-5H-oxazolo [4 ', 5 ': 4.5] benzo [1,2-d] azepine and 2.2 ml of 2N sodium hydroxide solution in 20 ml of methanol and 20 ml of tetrahydrofuran is stirred for 3 hours at room temperature. It is neutralized with 2.2 ml of 2N hydrochloric acid and evaporated. The residue is partitioned between water and ethyl acetate. After addition of a little sodium bicarbonate, the ethyl acetate phase is separated and the aqueous phase extracted with ethyl acetate. The combined or ganic phases are washed with water and saturated brine solution, dried and evaporated.
Yield: 0.88 g (99% of theory),
R _f value: 0.54 (reversed phase RP-8, methanol / 5% saline solution 6: 4).

The following compounds are obtained analogously to Example 8:

• (1) 2- [2- (1-t-Butyloxycarbonylmethyl-piperidin-4-yl) - ethyl] -6,7,8,9-tetrahydro-5H-thiazolo [4 ', 5': 4,5] benzo [1,2-d] azepine.
• (2) 2- [2- (1-carboxymethyl-piperidin-4-yl) -ethyl] -7-methyl-6,7,8,9-tetrahydro-2H, 5H-dioxolo [4 ', 5': 4 , 5] benzo [1,2-d] azepine dihydrochloride
  The residue is chromatographed.
• (3) 2- [2- (1-carboxymethyl-piperidin-4-yl) -ethyl] -2,7-dimethyl-6,7,8,9-tetrahydro-2H, 5H-dioxolo [4 ', 5' : 4,5] benzo [1,2-d] azepine dihydrochloride
  The residue is chromatographed.

Example 9

Dry ampoule containing 2.5 mg of active ingredient per 1 ml

Composition:

Active ingredient | 2.5 mg mannitol 50.0 mg Water for injections, ad 1.0 ml

manufacturing

Active substance and mannitol are dissolved in water. After bottling is freeze-dried. The resolution for ready to use Solution is with water for injections.  

Example 10

Dry ampoule containing 35 mg of active ingredient per 2 ml

Composition:

Active ingredient | 35.0 mg mannitol 100.0 mg Water for injections, ad 2.0 ml

manufacturing

Active substance and mannitol are dissolved in water. After bottling is freeze-dried.

The solution to the ready-to-use solution is water for injections.

Example 11

Tablet with 50 mg active ingredient

Composition:

(1) Active substance | 50.0 mg (2) lactose 98.0 mg (3) corn starch 50.0 mg (4) polyvinylpyrrolidone 15.0 mg (5) magnesium stearate  2.0 mg 215.0 mg

manufacturing

(1), (2) and (3) are mixed and granulated with an aqueous solution of (4). The dried granules are mixed (5). From this mixture tablets are pressed, biplan with double-sided facet and one-sided part score.
Diameter of the tablets: 9 mm.

Example 12

Tablet with 350 mg active ingredient

Composition:

(1) Active ingredient | 350.0 mg (2) lactose 136.0 mg (3) corn starch 80.0 mg (4) polyvinylpyrrolidone 30.0 mg (5) magnesium stearate  4.0 mg 600.0 mg

manufacturing

(1), (2) and (3) are mixed and granulated with an aqueous solution of (4). The dried granules are mixed (5). From this mixture tablets are pressed, biplan with double-sided facet and one-sided part score.
Diameter of the tablets: 12 mm.

Example 13

Capsules with 50 mg active ingredient

Composition:

(1) Active substance | 50.0 mg (2) dried corn starch 58.0 mg (3) powdered milk sugar 50.0 mg (4) magnesium stearate  2.0 mg 160.0 mg

manufacturing

(1) is triturated with (3). This trituration becomes the mix from (2) and (4) with intensive mixing.  

This powder mixture is placed on a capsule filling machine in Hard gelatine capsules size 3 bottled.

Example 14

Capsules with 350 mg active ingredient

Composition:

(1) Active ingredient | 350.0 mg (2) dried corn starch 46.0 mg (3) powdered milk sugar 30.0 mg (4) magnesium stearate  4.0 mg 430.0 mg

manufacturing

(1) is triturated with (3). This trituration becomes the mix from (2) and (4) with intensive mixing.

This powder mixture is placed on a capsule filling machine in Hard gelatine capsules size 0 filled.

Claims (11)

1. tricyclic Azepinderivate the general formula in the
R₁ and R₃, which may be the same or different, each represents a hydrogen atom, a C _1-3 alkyl, aryl, hydroxy, C _1-3 alkoxy, cyano, carboxy, C₁-C₃ alkoxycarbonyl , Aminocarbonyl, C _1-3 -alkylaminocarbonyl or di- (C _1-3 -alkyl) aminocarbonyl group,
R₂, R₄, R₆ and R₈, which may be the same or different, each represent a hydrogen atom or a C _1-3 alkyl group or
R₁ together with R₂ or R₃ together with R₄ also each represent an oxygen atom,
R₅ and R₇, which may be the same or different, each represents a hydrogen atom, a C _1-3 alkyl, aryl, carboxy, C _1-3 alkyloxycarbonyl, aminocarbonyl, C _1-3 alkylaminocarbonyl or Di (C _1-3 alkyl) aminocarbonyl group,
R₉ represents a hydrogen atom, a C _1-8 -alkyl, C _3-7 -cycloalkyl or C _3-7 -cycloalkyl-C _1-3 -alkyl group, an optionally substituted by an aryl group C₃-₆-alkenyl or C _{3 -6-} alkynyl group, wherein the alkenyl and alkynyl group in each case can not be connected via the vinyl or ethynyl moiety with the nitrogen atom, an aryl-C _1-3 -alkyl, heteroaryl-C _1-3 -alkyl, Hy droxy C _1-3 alkyl, C _1-3 alkoxy C _1-3 alkyl, amino C _1-3 alkyl, C _1-3 alkylamino C _1-3 alkyl, di - (C _1-3 alkyl) amino C _1-3 alkyl, C _1-3 alkylcarbonylamino C _1-3 alkyl, N- (C _1-3 alkyl) C _1-3 -alkylcarbonylamino-C _1-3 -alkyl-, C _1-3 -alkylsulphonylamino-C _1-3 -alkyl-, N- (C _1-3 -alkyl) C _1-3 -alkylsulphonylamino-C _1-3 - alkyl, cyanoC _1-3 alkyl, carboxyC _1-3 alkyl, C _1-3 alkoxycarbonylC _1-3 alkyl, aminocarbonylC _1-3 alkyl, C _1-3 alkylaminocarbonylC _1-3 alkyl, di (C _1-3 alkyl) aminocarbonylC _1-3 alkyl, C _1-3 alkoxycarbonyl, arylmethyloxycarbonyl, formyl, acetyl - , Trifluoroacetyl, 2,2,2-trifluoroethyl, amidino or
R₁₀CO-O- (R₁₁CR₁₂) -O-CO- group in which
R₁₀ represents a C _1-8 alkyl, C _5-7 cycloalkyl, aryl or aryl C _1-3 alkyl group,
R₁₁ represents a hydrogen atom, a C _1-3 alkyl, C _5-7 cycloalkyl or aryl group and
R₁₂ represents a hydrogen atom or a C _1-3 alkyl group,
X₁ and X₂, which may be the same or different, each represent a nitrogen atom or a substituted by the radical R _a Me thingruppe, in the
R _{a is in} each case a hydrogen, fluorine, chlorine, bromine or iodine atom, a C _1-3 -alkyl, trifluoromethyl, C _1-3 -alkoxy or cyano group,
Z₁ is a methine group,
Z₂ is an oxygen or sulfur atom, a methylene or Car bonylgruppe or substituted by the radical R _b imino group and
Z₃ is a nitrogen atom or a substituted by the radical R _c methine or
Z₁ is a <CR _b group,
Z₂ represents an oxygen atom, a methyl group or a R _b substituted imino group by the radical, and
Z₃ is an oxygen atom or a methylene group in which
R _b represents a hydrogen atom, a C _1-6 alkyl, C _3-7 cycloalkyl, aryl-C _1-3 -alkyl, carboxy-C _1-3 alkyl, C _1-6 alkoxycarbonyl C _1-3 -alkyl-, C _3-7 -cycloalkoxycarbonyl-C _1-3 -alkyl-, aminocarbonyl-C _1-3 -alkyl-, C _1-3 -alkylaminocarbonyl-C _1-3 -alkyl- or di- (C _1-3 alkyl) -aminocarbonyl-C _1-3 alkyl group and
R _{c represents} a hydrogen atom, a C _1-6 -alkyl, C _3-7 -cycloalkyl, carboxy, C _1-6 -alkoxycarbonyl, C _5-7 -cycloalkoxycarbonyl, cyano, aminocarbonyl, C _{1- 3 represents} alkylaminocarbonyl or di (C _1-3 alkyl) aminocarbonyl group,
A is a bond, a straight-chain or branched C _1-6 -alkylene group,
a - (CH₂) ₁-O-, - (CH₂) _m -CO-, -CO- (CH₂) ₁-, - (CH₂) _m -CO-NR _b -, -CO-NR _b - (CH₂) l - or - (CH₂) ₁-NR _b -CO-group in which the oxygen or nitrogen atom can not be linked to a heteroatom of the radical D and
R _b is defined as mentioned above,
l is the number 1, 2 or 3 and
m represent the number 0, 1 or 2,
D is a C _4-7 -cycloalkylene group optionally substituted by one or two C _1-3 -alkyl groups,
an optionally substituted by one or two C _1-3 alkyl groups or by an aryl group substituted C _5-7 cycloalkylene group in which a <CH unit is replaced by a nitrogen atom, where in the above-mentioned 5- to 7-membered rings each Weil a methylene group adjacent to a nitrogen atom may additionally be replaced by a carbonyl group,
a C _6-7 cycloalkylene group optionally substituted by one or two C _1-3 alkyl groups or by an aryl group, in which two 1,4-term <CH units are each replaced by a nitrogen atom, and wherein additionally in the above each of said 6- to 7-membered rings may be replaced by a methylene group adjacent to a nitrogen atom by a carbonyl group, or
a phenylene group represented by fluorine, chlorine or bromine atoms, by C _1-3 -alkyl, trifluoromethyl, hydroxy, C _1-3 -alkoxy, amino, C _1-3 -alkylamino, di- ( C _1-3 alkyl) amino, nitro, cyano, carboxy, C _1-6 alkoxycarbonyl, C _5-7 cycloalkoxycarbonyl, arylC _1-3 alkoxy, carboxyC _1-3 alkoxy, C _1-6 alkoxycarbonyl C _1-3 alkoxy or C _5-7 cycloalkoxycarbonyl C _1-3 alkoxy groups may be mono- or disubstituted, wherein the substituents are the same or different can,
E is a bond, a straight-chain or branched C _1-6 -alkylene group which is represented by a C _1-6 -alkyl, C _2-4 -alkenyl, C _2-4 -alkynyl, hydroxy, C _{1- 3} alkoxy, amino, C _1-3 alkylamino, di (C _1-3 alkyl) amino, aryl, pyridyl, R _b CO-NR _d , R _b O-CO -NR _d -, R _d -SO₂-NR _d -, ArylSO₂-NR _d - or di- (C _1-3 alkyl) -amino-CO-NR _d - may be substituted group in which
R _b is defined as mentioned above and
R _{d represents} a hydrogen atom, a C _1-6 -alkyl or C _5-7 -cycloalkyl group,
and F is a carbonyl group substituted by a hydroxy, C _1-8 alkoxy, aryl C _1-3 alkoxy or R₁₃O group, where
R₁₃ represents a C _4-7 -cycloalkyl, C _3-7 -cycloalkyl-C _1-3 -alkyl, C₉-₁₂-benzocycloalkyl or aryl group,
or a R₁₄CO-O-CHR₁₅-O-CO group, in the
R₁₄ is C _1-3 alkyl, C _1-3 alkoxy, C _5-7 cycloalkyl, C _5-7 cycloalkoxy, aryl, aryloxy, arylC _1-3 alkyl or Aryl-C _1-3 alkoxy group and
R₁₅ represents a hydrogen atom or a C _1-3 alkyl group,
mean,
their tautomers, their stereoisomers, including their mixtures and their salts,
unless stated otherwise
among the aryl moieties mentioned in the definition of the above radicals, a phenyl group represented by fluorine, chlorine or bromine atoms, by C _1-3 alkyl, trifluoromethyl, hydroxy, C _1-3 alkoxy, amino, C _1-3 alkylamino, di (C _1-3 alkyl) amino, nitro, cyano, carboxy, C _1-6 alkoxycarbonyl, C _3-7 cycloalkoxycarbonyl, phenyl-C _1-3 alkoxy, C _1-6 alkoxycarbonyl C _1-3 alkoxy or C _5-7 cycloalkoxycarbonyl C _1-3 alkoxy groups may be mono- or disubstituted, wherein the substituents may be the same or different to understand. 2. tricyclic Azepinderivate of the general formula I according to claim 1, in which
R₁ and R₃, which may be the same or different, each represent a hydrogen atom, a C _1-3 alkyl, aryl, hydroxy, C _1-3 alkoxy, cyano, carboxy, C _1-3 Alkoxycarbonyl or aminocarbonyl group,
R₂, R₄, R₆ and R₈, which may be the same or different, each represent a hydrogen atom or a C _1-3 alkyl group or
R₁ together with R₂ or R₃ together with R₄ also each represent an oxygen atom,
R₅ and R₇, which may be the same or different, each represents a hydrogen atom, a C _1-3 -alkyl, aryl, carboxy, C _1-3 -alkoxycarbonyl or aminocarbonyl group,
R₉ represents a hydrogen atom, a C _1-8 -alkyl, C _3-7 -cycloalkyl, C _3-7 -cycloalkyl-C _1-3 -alkyl, aryl-C _1-3 -alkyl, heteroaryl-C _{1- 3-} alkyl, hydroxyC _1-3 alkyl, C _1-3 alkoxyC _1-3 alkyl, aminoC _1-3 alkyl, C _1-3 alkylamino C _{1- 3-} alkyl-, di- (C _1-3 -alkyl) -amino-C _1-3 -alkyl-, cyano-C _1-3 -alkyl-, carboxy-C _1-3 -alkyl-, C _{1- 3-} alkoxycarbonyl-C₁-3-alkyl, aminocarbonyl-C _1-3 -alkyl, C _1-3 -alkoxycarbonyl, arylmethyloxycarbonyl, formyl, acetyl, trifluoroacetyl, amidino or R₁₀CO-O- (R₁₁CR₁₂ ) -O-CO-group in which
R₁₀ represents a C _1-8 alkyl, C _5-7 cycloalkyl or aryl C _1-3 alkyl group,
R₁₁ represents a hydrogen atom or a C _1-3 alkyl group and
R₁₂ represents a hydrogen atom or a C _1-3 alkyl group,
X₁ and X₂ are each a substituted by the radical R _a methine group, in the
R _{a is in} each case a hydrogen, fluorine, chlorine or bromine atom, a C _1-3 -alkyl, trifluoromethyl, C _1-3 -alkoxy or cyano group,
Z₁ is a methine group,
Z₂ represents an oxygen or sulfur atom or a by the group R _b substituted imino group and
Z₃ is a nitrogen atom or a substituted by the radical R _c methine or
Z₁ is a <CR _b group,
Z₂ is an oxygen atom or a methylene group and
Z₃ is an oxygen atom or a methylene group in which
R _b represents a hydrogen atom, a C _1-6 alkyl, C _3-7 cycloalkyl, aryl-C _1-3 -alkyl, carboxy-C _1-3 alkyl, C _1-6 alkoxycarbonyl C _1-3 -alkyl-, C _3-7 -cycloalkoxycarbonyl-C _1-3 -alkyl or aminocarbonyl-C _1-3 -alkyl group and
R _{c represents} a hydrogen atom, a C _1-6 -alkyl, carboxy, C _1-6 -alkoxycarbonyl, C _5-7 -cycloalkoxycarbonyl or cyano group,
A is a bond, a straight-chain or branched C _1-6 -alkylene group,
a - (CH₂) ₁-O-, - (CH₂) _m -CO-, - (CH₂) _m -CO-NR _b - or -CO-NR _b - (CH₂) ₁-group in which the oxygen or Stick nitrogen atom can not be linked to a heteroatom of the radical D as well
R _b is defined as mentioned above,
l is the number 1 or 2 and
m represent the number 0, 1 or 2,
D is a C _4-7 -cycloalkylene group optionally substituted by one or two C _1-3 -alkyl groups,
a C _5-7 cycloalkylene group optionally substituted by one or two C _1-3 alkyl groups in which a <CH moiety is replaced by a nitrogen atom, one in each of the above-mentioned 5- to 7-membered rings Nitrogen atom adjacent methylene group may additionally be replaced by a carbonyl group,
a C _6-7 cycloalkylene group optionally substituted by one or two C _1-3 alkyl groups, in which two 1,4-position <CH units are each replaced by a nitrogen atom, and additionally in the above-mentioned 6- to In each case a methylene group adjacent to a nitrogen atom may be replaced by a carbonyl group;
a phenylene group represented by fluorine, chlorine or bromine atoms, by C _1-3 alkyl, trifluoromethyl, hydroxy, C _1-3 alkoxy, arylC _1-3 alkoxy, carboxyC _{1 3} -alkoxy-, C _1-6 -alkoxycarbonyl-C _1-3 -alkoxy- or C₅- ₇-cycloalkoxycarbonyl-C _1-3 -alkoxy groups may be mono- or disubstituted, where the substituents may be identical or different,
E is a bond, a straight or branched C _1-6 alkylene group represented by a C _2-4 alkenyl, C _2-4 alkynyl, hydroxy, C _1-3 alkoxy, amino, aryl - or pyridyl group may be substituted, and
F is a carbonyl group which is substituted by a hydroxy, C _1-8 alkoxy, aryl C _1-3 alkoxy or R₁₃O group, wherein
R₁₃ represents a C _4-7 cycloalkyl or C _3-7 cycloalkyl C _1-3 alkyl group,
or a R₁₄CO-O-CHR₁₅-O-CO group, in the
R₁₄ is a C _1-3 alkyl, C _1-3 alkoxy, C _5-7 cycloalkyl, C _5-7 cycloalkoxy, aryl, arylC _1-3 alkyl or aryl C _1-3 alkoxy group and
R₁₅ represents a hydrogen atom or a C _1-3 alkyl group,
their tautomers, their stereoisomers and salts,
unless stated otherwise
among the aryl moieties mentioned in the definition of the above radicals, a phenyl group which is represented by fluorine, chlorine or bromine atoms, by C _1-3 -alkyl, trifluoromethyl, hydroxy, C _1-3 -alkoxy, phenyl-C _{1 3} -alkoxy-, C _1-6 -alkoxycarbonyl-C _1-3 -alkoxy- or C₅- ₇-cycloalkoxycarbonyl-C _1-3 -alkoxy groups may be mono- or disubstituted, where the substituents may be the same or different understand is. 3. tricyclic Azepinderivate of the general formula I according to claim 1, in which
R₁ and R₃, which may be the same or different, each represents a hydrogen atom or a methyl group,
R₂, R₄, R₆ and R₈ each represents a hydrogen atom or
R₁ together with R₂ or R₃ together with R₄ also each represent an oxygen atom,
R₅ and R₇ each represent a hydrogen atom,
R₉ represents a hydrogen atom, a C _1-5 -alkyl, C _1-3 -alkanoyl, trifluoroacetyl, C _1-4 -alkoxycarbonyl or benzyloxycarbonyl group,
X₁ and X₂ each have a methine group,
Z₁ is a methine group,
Z₂ represents an oxygen or sulfur atom or a by the group R _b substituted imino group and
Z₃ is a nitrogen atom or
Z₁ is a <CR _b group,
Z₂ is an oxygen atom and
Z₃ is an oxygen atom in which
R _b represents a hydrogen atom, an alkyl- C _1-3 -alkyl, phenyl-C _1-3 -al, carboxy-C _1-3 alkyl, C _1-5 alkoxycarbonyl-C _1-3 alkyl or C _5-7 cyanoalkoxycarbonylC _1-3 alkyl group,
A is a bond, a straight-chain or branched C _1-4 -alkylene group,
a - (CH₂) _m -CO-NR _b - or -CO-NR _b -CH₂ group in which the nitrogen atom can not be linked to a heteroatom of the radical D and
R _b is defined as mentioned above and
m represents the number 0 or 1,
D is a 1,4-cyclohexylene group,
a 1, 4-Piperidinylen- or 1, 4-Piperazinylengruppe, in each of which a methylene group adjacent to a nitrogen atom may be replaced by a carbonyl group, or
a phenylene group which may be substituted by a carboxy-methoxy or C _1-3 alkoxycarbonylmethoxy group,
E is a bond or a straight-chain or branched C _1-4 -alkylene group and
F represents a carbonyl group which is substituted by a hydroxyl, C _1-5 -alkoxy, benzyloxy, cyclopentyloxy or cyclohexyloxy group,
their tautomers, their stereoisomers and salts. 4. tricyclic Azepinderivate of the general formula I according to claim 1, in which
R₁ to R₈ each represent a hydrogen atom,
R₉ represents a hydrogen atom, a C _1-3 -alkyl, acetyl or trifluoroacetyl group,
X₁ and X₂ each have a methine group,
Z₁ is a methine group,
Z₂ is an oxygen atom or an imino group substituted by the radical R _b , where
R _{b represents} a hydrogen atom, a C _1-3 alkyl, carboxymethyl or C₁₅ alkoxycarbonylmethyl group,
A is a bond, a methylene or ethylene group,
D is a 1,4-piperidinylene or 1,4-piperazinylene group,
E is a bond or a straight-chain or branched C _1-3 -alkylene group and
F represents a carbonyl group which is substituted by a hydroxyl or C _1-5 -alkoxy group,
their tautomers, their stereoisomers and salts. 5. The following tricyclic azepine derivatives of the general formula I according to claim 1:

• (1) 2- [2- (1-carboxymethyl-piperidin-4-yl) -ethyl] -1-methyl-6,7,8,9-tetrahydro-5H-imidazo [4 ', 5': 4.5 ] benzo [1,2-d] azepine,
• (2) 2- [2- (1-carboxymethyl-piperidin-4-yl) -ethyl] -6,7,8,9-tetrahydro-5H-imidazo [4 ', 5': 4,5] benzo [1 , 2-d] azepine,
• (3) 1-Carboxymethyl-2- [2- (1-carboxymethyl-piperidin-4-yl) -ethyl] -6,7,8,9-tetrahydro-5H-imidazo [4 ', 5': 4.5] benzo [1,2-d] azepine,
• (4) 2- [2- (1-carboxymethyl-piperidin-4-yl) -ethyl] -1,7-dimethyl-6,7,8,9-tetrahydro-5H-imidazo [4 ', 5': 4 , 5] benzo [1,2-d] azepine,
• (5) 2- [2- (1-carboxymethyl-piperidin-4-yl) -ethyl] -6,7,8,9-th-trahydro-5H-oxazolo [4 ', 5': 4,5] benzo [ 1,2-d] azepine

and their salts. 6. Physiologically acceptable salts of the compounds after min at least one of claims 1 to 5 with inorganic or or ganic acids or bases. 7. A pharmaceutical composition containing a compound after at least one of claims 1 to 5 or a physiologically acceptable Lich salt according to claim 6 in addition to optionally one or several inert carriers and / or diluents. 8. Use of a compound according to at least one of Claims 1 to 6 for the manufacture of a medicament intended for Combating or preventing diseases in which smaller or larger cell aggregates occur or cell matrix inter actions play a role.   9. A process for the preparation of a medicament according to claim 7, characterized in that non-chemically A compound according to any one of claims 1 to 6 in one or more inert carriers and / or diluents is incorporated. 10. A process for the preparation of the compounds of general formula I according to claims 1 to 6, characterized in that

• a) for the preparation of compounds of general formula I in which R₉ is as defined in claims 1 to 5 and F represents a carboxyl group or F as defined in claims 1 to 5 and R₉ represents a hydrogen atom, a compound of general formula in the
  A, D, E, X₁, X₂, Z₁ to Z₃ and R₁ to R₈ are defined with the proviso as defined in claims 1 to 5, that F 'has the meanings mentioned for F in claims 1 to 5 and R₉' means Hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis cleavable protecting group for an imino group or
  R₉ 'has the meanings mentioned for R₉ in claims 1 to 5 and F' means a group convertible into a carboxyl group by hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis,
  by hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis in a compound of the general formula I wherein R₉ is as defined in claims 1 to 5 and F represents a carboxyl group or F as in claims 1 to 5 is defined and R₉ is a hydrogen atom, is converted or
• b) for the preparation of compounds of the general formula I in which R₉ is one of the in the definition of the radical R₉ in the on entitlements 1 to 5 mentioned optionally substituted Al kyl-, alkenyl, alkynyl, cycloalkyl, Cycloalkylalkyl-, aryl alkyl - represents or heteroarylalkyl, a compound of the general formula in the
  A, D to F, X₁, X₂, Z₁ to Z₃ and R₁ to R₈ are as defined in claims 1 to 5, with a compound of all the general formula Y₁ - R₁₆ (IV) in the
  R₁₆ represents a C _1-8 alkyl, C _3-7 cycloalkyl or C _3-7 cycloalkyl C _1-3 alkyl group, an optionally substituted by an aryl C _3-6 alkenyl or C _3-6 Alkynyl group, wherein the alkenyl and alkynyl groups may not each be linked via the vinyl or ethynyl moiety to the nitrogen atom, an arylC _1-3 alkyl, heteroarylC _1-3 alkyl, hydroxyC _{1- 3-} alkyl, C _1-3 alkoxyC _1-3 alkyl, aminoC _1-3 alkyl, C _1-3 alkylamino, C _1-3 alkyl, di (C _{1 3-} alkyl) -amino-C _1-3 -alkyl, C _1-3 -alkylcarbonylamino-C _1-3 -alkyl, N- (C _1-3 -alkyl) C _1-3 -alkylcarbonylamino C _1-3 alkyl, C _1-3 alkylsulfonylaminoC _1-3 alkyl, N- (C _1-3 alkyl) C _1-3 alkylsulfonylaminoC _1-3 alkyl, Cyano C _1-3 alkyl, carboxy C _1-3 alkyl, C _1-3 alkoxycarbonyl C _1-3 alkyl, aminocarbonyl C _1-3 alkyl, C _1-3 -Alkyl-aminocarbonyl-C _1-3 -alkyl or di- (C _1-3 -alkyl) -aminocarbonyl-C _1-3 -alkyl group in which the aryl part is as defined in claims 1 to 5 de, U.N d
  Y₁ is a nucleofuge leaving group or
  Y₁ together with an adjacent hydrogen atom of the radical R₁₆ represent an oxygen atom, is reacted or
• c) for the preparation of compounds of general formula I in which F represents a carbonyl group substituted by a C _1-8 alkoxy, aryl C _1-3 alkoxy or R₁₃O group, a carboxylic acid of the general formula in the
  A, D, E, X₁, X₂, Z₁ to Z₃ and R₁ to R₉ are as defined in claims 1 to 5, or optionally prepared in the reaction mixture of reactive derivatives with an alcohol of the general formula HO-R₁₇ (VI) in the
  R₁₇ represents a C _1-8 alkoxy, aryl C _1-3 alkoxy or R₁₃O group, wherein R₁₃ is as defined in claims 1 to 5, is reacted or
• d) for the preparation of compounds of general formula I, in which F represents a R₁₄CO-O-HCR₁₅-O-CO group, a carboxylic acid of the general formula in the
  A, D, E, X₁, X₂, Z₁ to Z₃ and R₁ to R₉ are as defined in claims 1 to 5, with a compound of the general formula Y₂ - R₁₈ (VII) in the
  R₁₈ is a R₁₄CO-O-HCR₁₅ group, wherein R₁₄ and R₁₅ are defined as mentioned in claims 1 to 5, and
  Y₂ is a nucleofuge leaving group, is reacted or
• e) for the preparation of compounds of the general formula I in which R₉ represents an alkyl group having 2 carbon atoms which are in the 2-position by a cyano, carboxy, alkoxycarbonyl, aminocarbonyl, N-alkylaminocarbonyl or N, N-dialkylaminocar substituted bonyyl group, a compound of the general formula in the
  A, D to F, X₁, X₂, Z₁ to Z₃ and R₁ to R₈ are as defined in claims 1 to 5,
  with an ethylene substituted by a cyano, C _1-3 alkoxycarbonyl, aminocarbonyl, C _1-3 alkylaminocarbonyl or di (C _1-3 alkyl) aminocarbonyl group, or
• f) for the preparation of compounds of general formula I in which D is an optionally substituted by one or two C _1-3 alkyl or substituted by an aryl C _5-7 cycloalkylene group in which a <CH-unit by a nitrogen atom is replaced, wherein the ring nitrogen atom is linked to a carbon atom of group E, or an optionally substituted by one or two C _1-3 alkyl groups or by an aryl group substituted C _6-7 cycloalkylene, in the two 1,4-permanent <CH units are each replaced by a nitrogen atom, wherein a ring nitrogen atom having a carbon atom of the group A and the other ring nitrogen atom is linked to a carbon atom of group E, means a compound of the general formula in the
  A, X₁, X₂, Z₁ to Z₃ and R₁ to R₉ are as defined in claims 1 to 5 and
  D 'is a C _5-7 -cycloalkylene group optionally substituted by one or two C _1-3 -alkyl groups or by an aryl group, in which one <CH-unit is replaced by an imino group, or one optionally substituted by one or two C ₁ groups ₃ alkyl or aryl group substituted by a C _6-7 -cycloalkyl alkylene group in which one of the 1,4-position <CH-units is replaced by a nitrogen atom, this ring Stick atom with a carbon atom of the group a is linked, and the second of the 1,4-position <CH units is replaced by an imino group, means with a compound of the general formula Y₃ - E - F (IX) in the
  E and F are as defined in claims 1 to 5 and
  Y₃ is a nucleofuge leaving group, is reacted or
• g) for the preparation of compounds of the general formula I in which D is an optionally substituted by one or two C _1-3 alkyl or substituted by an aryl C _5-7 cycloalkylene kylengruppe in which a <CH-unit by a nitrogen atom wherein the ring nitrogen atom is linked to a Methinkoh lenstoffatom of the group Z₁, or optionally given by one or two C _1-3 alkyl groups or by an aryl group substituted C _6-7 cycloalkylene, in the two 1,4-permanent <CH units in each case by a nitrogen atom he sets are, wherein a ring nitrogen atom is linked to a Methinkoh lenstoffatom group Z₁, means a United bond of the general formula in the
  X₁, X₂, Z₁ to Z₃ and R₁ to R₉ are as defined in claims 1 to 5 and
  Y₄ represents a nucleofuge leaving group, with a compound of the general formula D '' - E - F (XI) in the
  E and F are as defined in claims 1 to 5 and D '' is a C _5-7 -cycloalkylene group optionally substituted by one or two C _1-3 -alkyl groups or by an aryl group, in which a <CH- unit is replaced by a Imino group is replaced, or one optionally substituted by one or two C _1-3 alkyl groups or by an aryl group substituted C _6-7 -Cycloalkylengrup pe, in which one of the 1.4-position <CH-units by an imino group and the second the 1,4-position <CH units is replaced by a nitrogen atom, which ring nitrogen atom is linked to a carbon atom of group E, is reacted, and
  If desired, then a compound of general formula I, which contains a carbon-carbon double bond, is then converted by hydrogenation into a corresponding saturated compound and / or
  if necessary, a protection residue used in the above-described implementation is split off again and / or
  if desired, a compound of general formula I thus obtained is separated into its stereoisomers and / or
  a compound of the general formula I thus obtained is converted into its salts, in particular for the pharmaceutical application, into its physiologically tolerated salts.