DE19816889A1 - New piperazine derivatives useful in treatment of e.g. cardiovascular, renal and central nervous system disorders, obesity and diabetes, in antibody production and as analytical and diagnostics aids - Google Patents

Abstract

Disubstituted piperazine derivatives (I) are new. 1,4-Disubstituted piperazine derivatives of formula (I) and their tautomers, diastereomers, enantiomers, mixtures and salts are new: R<1> = 1-5C alkyl, preferably Me; diphenylmethyl; 5,11-dihydro-6(6H)-oxodibenz(b,e)azepin-11-yl; 5,11-dihydro-6(6H)-oxopyrido(2,3-b)(1,4)benzodiazepin-11-yl; or 5,10-dihydro-11(11H)-oxodibenzo(b,e)(1,4)diazepin-5-yl; Z' = C(O); -C(O)CH2 bonded to piperazinyl N via CH2; or a bond; R<3> and R<4> = H or 1-3C alkyl; or R<3> and R<4> = 2-7C alkylene; B = a bond; divalent glycyl optionally substituted at N<2> by benzyl (optionally ring-substituted with CN); divalent lysyl optionally substituted at N<6> by benzyloxycarbonyl; divalent phenylglycyl; or divalent phenylalanyl optionally ring-substituted in the 2-, 3- or 4-position with CN or -C(NH)NH2 or in the 4-position with NH2 or in the 3- and 5-positions with halo, preferably Cl or Br; Q = NR<5>R<6> or (when B is other than a bond) OH or 1-3C alkoxy; R<5> = H or 1-4C alkyl optionally w-monosubstituted with phenyl; R<6> = 1-4C alkyl (optionally monosubstituted with OH, phenyl (optionally substituted with CN or -C(NH)NH2), 1,2-dihydro-3,5(4H)-dioxo-3H-1,2,4-triazol-4-yl (optionally mono- or disubstituted with phenyl) or 4-(diphenylmethyl)-1-piperazinyl); or phenyl optionally monosubstituted with CN or -C(NH)NH2 An Independent claim is also included for the preparation of compounds (I).

Description

The present invention relates to novel Piperazinderi vate of the general formula

their tautomers, their diastereomers, their enantiomers, their Mixtures and their salts, in particular their physiologically ver suitable salts with inorganic or organic acids or Bases, and process for their preparation.

In the above general formula I mean
R ^{1 represents} a straight-chain or branched alkyl group having one to five carbon atoms, but in particular the methyl group, the diphenylmethyl, 5,11-dihydro-6 (6H) -oxodibenz [b, e] azepine-11-yl, 5,11- Dihydro-6 (6H) -oxopyrido [2,3-b] [1,4] benzodiazepin-11-yl or 5,10-dihydro-11 (11H) -oxodibenzo [b, e] [1,4] diazepine 5-yl group,
Z is the carbonyl group, a group bound to the piperazine via the methylene -COCH ₂ - group or the single bond,
R ³ and R ⁴ , which may be the same or different, are hydrogen atoms, alkyl groups having 1 to 3 carbon atoms or together a straight-chain alkylene group having 2 to 7 carbon atoms,
B is the single bond, the divalent radicals of the amino acids glycine, lysine, phenylglycine or phenylalanine, wherein the amino acid glycine at the N ² atom by a phenyl in the phenyl optionally substituted by a cyano group phenylmethyl group, the amino acid lysine at the N ⁶ atom by a Phenylmethoxycarbonyl group and the amino acid phenylalanine in 2-, 3- or 4-Stel ment of the phenyl moiety by a cyano or aminoiminomethyl group or in the 4-position by an amino group and in the 3- and 5-position each by a halogen atom, preferably a chlorine or Bromine atom, may be substituted,
C is the group -NR ⁵ R ⁶ , in the
R ^{5 is} a hydrogen atom, a straight-chain or branched alkyl group having 1 to 4 carbon atoms, which may be substituted by a phenyl group in ω-position, and
R ⁶ denotes a straight-chain or branched alkyl group having 1 to 4 carbon atoms which is represented by a hydroxyl group, a phenyl group optionally substituted by a cyano or aminoiminomethyl group, a 1,2-dihydro-3,5 (4H) optionally substituted by one or two phenyl groups dioxo-3H-1,2,4-triazol-4-yl group or may be substituted by a 4- (di phenylmethyl) -1-piperazinyl group, or represents an optionally substituted by a cyano or aminoimino methyl group phenyl group,
or, unless B represents the single bond, a hydroxy group or an alkoxy group having 1 to 3 carbon atoms, for example the methoxy, ethoxy, propoxy or 1-methylethoxy group.

The present invention relates to achiral compounds, so far in compounds of the general formula 1, the group B is a single bond or the bivalent radical of the amino acid glycine. Furthermore, the present invention relates Race mate and their individual enantiomers, provided that in compounds of general formula I, the group B is a branched amino acid and their asymmetric carbon atom is the only chirality element or, although B is achiral, the Mo lekül but elsewhere, z. B. in the radical R ¹ , a Chirali tätselement contains. However, the invention also includes the individual NEN diastereomeric antipode pairs and mixtures thereof, which are present when a fall under the general formula I de connection holds two or more than two chirality elements ent. Particular preference is given to the compounds falling within general formula I which are characterized within the partial structure of group B by the remainder of a branched amino acid cha and are L- or (S) -configured.

The compounds of general formula I have valuable NPY antagonistic properties. Another object of the Invention are medicaments containing these compounds, de ren use and their production.

Preferred compounds of the above general formula I are those in which
R ^{1 is} the diphenylmethyl, 5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl, 5,11-dihydro-6 (6H) -oxopyrido [2,3-b] [1,4] benzodi-azepin-11-yl or 5,10-dihydro-11 (11H) -oxodibenzo [b, e] [1,4] diazepin-5-yl group,
Z is the carbonyl group or the single bond,
R ³ and R ⁴ together represent a straight-chain alkylene group having 3 to 7 carbon atoms,
B is the divalent radicals of the amino acids glycine, phenylglycine or phenylalanine, where the amino acid glycine at the N ² atom may be substituted by a phenyl moiety optionally substituted by a cyano group in the phenyl moiety and the amino acid phenylalanine in the 2-, 3- or 4-position of Phenyl may be substituted by a cyano or aminoiminomethyl group or in the 4-position by an amino group and in the 3- and 5-position depending Weil by a bromine atom,
C is the group -NR ⁵ R ⁶ , in the
R ^{5 is} a hydrogen atom and
R ⁶ denotes a straight-chain or branched alkyl group having 1 to 4 carbon atoms which is in the ω-position by a hydroxy group, a phenyl group optionally substituted by a cyano- or amino-iminomethyl group, or a 1,2-dihydroxy radical optionally substituted by one or two phenyl groups. 3,5 (4H) -dioxo-3H-1,2,4-triazol-4-yl group or substituted by a 4- (diphenylmethyl) -1-piperazinyl group,
or a hydroxy or methoxy group,
their tautomers, their diastereomers, their enantiomers, their mixtures and their salts.

Particularly preferred compounds of the above general formula I are those in which
R ^{1 is} the diphenylmethyl, 5,11-dihydro-6 (6H) -oxodibenz [b, e] aze pin-11-yl or 5,10-dihydro-11 (11H) -oxodibenzo [b, e] [1 , 4] diazepine-5-yl group,
Z is the carbonyl group or the single bond,
R ³ and R ⁴ together form the tetramethylene group,
B is the bivalent radical of the amino acid phenylalanine, which may be substituted in the 2-, 3- or 4-position of the phenyl moiety by a cyano or ami nominomethyl group, and
C is the (3-phenylpropyl) amino, [3- [4- (diphenylmethyl) -1-piperazinyl] propyl] amino, [2- [1,2-dihydro-3,5 (4H) dioxo-1 , 2-diphenyl-3H-1,2,4-triazol-4-yl] ethyl] amino or (2-hydroxyethyl) amino group,
their tautomers, their diastereomers, their enantiomers, their mixtures and their salts.

Examples of particularly preferred compounds which may be mentioned are the following:
N- [4-aminoiminomethyl) phenyl] -1- [2 [4- (diphenylmethyl) -1-piperazinyl] -2-oxoethyl] cyclopentanacetamide
(R, S) -3- (4-Cyanophenyl) -N ² - [[1- [2- [4- (diphenylmethyl) -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -N- (3 -phenylpropyl) -aluminamide
(R, S) -3- [4- (aminoiminomethyl) phenyl] -N ² - [[1- [2- [4- (diphenylmethyl) -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -N - (3-phenylpropyl) alanine amide
3- (4-cyanophenyl) -N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl ] -2-oxoethyl] cyclopentyl] acetyl] -N- (3-phenylpropyl) alanine amide
(R, S) -3- (4-cyanophenyl) -N ² - [[1- [2- [4 - [[5,10-dihydro-11 (10H) -oxodibenzo [b, e] [1, 4] diazepin-5-yl] carbonyl] -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -N- (3-phenylpropyl) alaninamide
3- [4- (aminoiminomethyl) phenyl-N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) oxodibenz [b, e] azepin-11-yl] -1-piperazinyl ] -2-oxoethyl] cyclopentyl] acetyl] -N- (3-phenylpropyl) alanine amide
3- [4-aminoiminomethyl) phenyl] -N ² - [[1- [2- [4 - [[5,10-dihydro-11 (10H) -oxodibenzo [b, e] [1,4] diazepine-s -yl] carbonyl] -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -N- (3-phenylpropyl) -alanamide
(R, S) -N ² - [[1- [2- [4- [diphenylmethyl) -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -N- (2-phenylethyl) -lysinamide
N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl ] -N- (3-phenylpropyl) phenylalanine amide
(S) -N ² - [[1- [2- [4 - [[5,10-dihydro-11 (10H) -oxodibenzo [b, e] [1,4] diazepin-5-yl] carbonyl] - 1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -N- (3-phenylpropyl) phenylalanine amide
3- (4-cyanophenyl) -N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] 2-oxoethyl] cyclopentyl] acetyl] alanine methyl ester
N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl ] -N- (3-phenylpropyl) -L-phenylglycine amide
(S) -N ² - [[1- [2- [4- (Diphenylmethyl) -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -N- (3-phenylpropyl) -phenylglycine amide
(S) -N ² - [[1- [2- [4- [5,10-dihydro-11 (10H) -oxodibenzo [b, e] [1,4] diazepine-5-yl] carbonyl] - 1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -N- (3-phenylpropyl) -phenylglycine amide
3- [4- (aminoiminomethyl) phenyl] -N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1 piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] alanine methyl ester
(R, S-3-4-Cyanophenyl) -N ² - [[1- [2- [4- (diphenylmethyl) -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -N- [3- [ 4-diphenylmethyl) -1-piperazinyl] propyl] alaninamide
3- (4-cyanophenyl) -N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] 2-oxoethyl] cyclopentyl] acetyl] -N- [3- [4- (diphenylmethyl) -1-piperazinyl] propyl] alanine amide
(R, S) -3- (4-cyanophenyl) -N- [3- [4- (diphenylmethyl) -1-piperazinyl] propyl] -N ² - [[1- [2- (4-methyl-1-) piperazinyl) -2-oxoethyl] cyclopentyl] acetyl] alaninamide
(R, S) -N- [4- (aminoiminomethyl) phenyl] -1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] - 1-piperazinyl] -2-oxoethyl] cyclopentanacetamide
(R, S) -N - [[4- (aminoiminomethyl) phenyl] methyl] -1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepine-11 -yl] -1-piperazinyl] -2-oxo-ethyl] -N- (3-phenylpropyl) -cyclopentanacetamide
N - [[4- (aminoiminomethyl) phenyl] methyl] -1- [2- [4- (diphenylmethyl) -1-piperazinyl] -2-oxoethyl] -N- (3-phenylpropyl) -cyclopentanacetamide
(R, S) -3- [4- (aminoiminomethyl) phenyl] -N ² - [[1- [2- [4- (diphenylmethyl) -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -N - [3- [4- (diphenylmethyl) -1-piperazinyl] propyl] alaninamide
(R, S) -3- [4- (aminoiminomethyl) phenyl] -N- [3- [4- (diphenylmethyl) -1-piperazinyl] propyl] -N ² - [[1- [2- (4-methyl 1-piperazinyl) -2-oxoethyl] cyclopentyl] acetyl] alaninamide
(R, S) -N ² - [(4-cyanophenyl) methyl] -N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepine -11-yl] -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -glycine methyl ester
(R, S) -N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] -2 -oxoethyl] cyclopentyl] acetyl] glycine
(R, S) -N- (4-cyanophenyl) -1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl ] -2-oxoethyl] -N- (3-phenylpropyl) -cyclopentanacetamide
(R, S) -N ² - [(4-cyanophenyl) methyl] -N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepine -11-yl] -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -glycine
N - [[4- (aminoiminomethyl) phenyl] methyl] -1- [2- [4- (diphenylmethyl) -1-piperazinyl] -2-oxoethyl] -N- (2-phenylethyl) cyclopentane acetamide
3- (4-cyanophenyl) -N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] 2-oxoethyl] cyclopentyl] acetyl] -N- [2- [1,2-dihydro-3,5 (4H) -dioxo-1,2-diphenyl-3H-1,2,4-triazol-4-yl ] ethyl] alaninamide
(R, S) -3- (4-cyanophenyl) -N ² - [[1- [2- [4- (diphenylmethyl) -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl-N- [2- [1,2-dihydro-3,5 (4H) -dioxo-1,2-diphenyl-3H-1,2,4-triazol-4-yl] ethyl] -alanineamide
3- (4-aminoiminomethyl) phenyl] -N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1- piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -N- [2- [1,2-dihydro-3,5 (4H) -dioxo-1,2-diphenyl-3H-1,2,4-triazole] 4-yl] ethyl] alaninamide
(R, S) -3- [4-aminoiminomethyl) phenyl] -N ² - [[1- [2- [4- (diphenylmethyl) -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -N- [2- [1,2-dihydro-3,5 (4H) -dioxo-1,2-diphenyl-3H-1,2,4-triazol-4-yl] ethyl] alaninamide
N ² - [(4-cyanophenyl) methyl] -N ² - [[1- [2- [4- (diphenylmethyl) -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -N- [3- [4 - (diphenylmethyl) -1-piperazinyl) propyl] -glycinamide
(R, S) -N ² - [(4-cyanophenyl) methyl] -N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepine -11-yl] -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] - N - [3- [4- (diphenylmethyl) -1-piperazinyl) propyl] glycinamide
(R, S) -N ² - [(4-cyanophenyl) methyl] -N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepine -11-yl] -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -N- (3-phenylpropyl) glycinamide
N ² - [(4-cyanophenyl) methyl] -N ² - [[1- [2- [4- (diphenylmethyl) -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -N- [2- [1 , 2-dihydro-3,5 (4H) -dioxo-1,2-diphenyl-3H-1,2,4-triazol-4-yl] -ethyl] -glycine amide
3- (4-cyanophenyl) -N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] 2-oxoethyl] cyclopentyl] acetyl] -N- (2-hydroxyethyl) alanine amide
(R, S) -3- (4-Cyanophenyl) -N ² - [[1- [2- [4- (diphenylmethyl) -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -N- (2 -hydroxyethyl) -aluminamide
(R, S) -3- (4-Amino-3,5-dibromophenyl) -N ² - [1- [2- [4- (diphenylmethyl) -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] N- (3-phenylpropyl) alanine amide
(R, S) -N ² - [(4-cyanophenyl) methyl] -N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepine -11-yl] -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] - N - [2- [1,2-dihydro-3,5-4-dioxo-diphenyl-3H-1,2,4 triazol-4-yl] ethyl] glycinamide
(R, S) -N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] -2 -oxoethyl] cyclopentyl] acetyl] -N- (3-phenylpropyl) glycinamide
3- (4-Cyanophenyl-N ² [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] -2 -oxoethyl] cyclopentyl] acetyl] -N- (3-phenylpropyl) alanine amide
(R, S) -N - [[4- (aminoiminomethyl) phenyl] methyl] -1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepine-11- yl] -1-piperazinyl] -2-oxo-ethyl] -N- (2-phenylethyl) -cyclopentanacetamide
(R, S) -N - [(4-cyanophenyl) methyl] -N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepine] 11-yl] -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -N- (3-phenylpropyl) glycinamide
(R, S) -N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] -2 -oxoethyl] cyclopentyl] acetyl] -N- [2- [1,2-dihydro-3,5 (4H) -dioxo-1,2-diphenyl-3H-1,2,4-triazol-4-yl] -ethyl ] glycinamide
1- [2- [4- (diphenylmethyl) -1-piperazinyl] -2-oxoethyl] -N- [2- [1,2-dihydro-3,5 (4H) -dioxo-1,2-diphenyl-3H 1,2,4-triazol-4-yl] ethyl] -cyclopentanacetamide
(R, S) -1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] -2-oxoethyl] -N - [2- [1,2-dihydro-3,5 (4H) -dioxo-1,2-diphenyl-3H-1,2,4-triazol-4-yl] -ethyl] -cyclopentanacetamide
3- (3-cyanophenyl) -N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] 2-oxoethyl] cyclopentyl] acetyl] alanine methyl ester
(R, S) -3- [3- (aminoiminomethyl) phenyl] -N ² - [[1- [2- [4- (diphenylmethyl) -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -N - (3-phenylpropyl) alanine amide
3- (3-cyanophenyl) -N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] 2-oxoethyl] cyclopentyl] acetyl] -N- (3-phenylpropyl) alanine amide
(R, S) -3- (4-cyanophenyl) -N ² - [[1- [2- [4- (diphenylmethyl) -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] alanine methyl ester
3- [3- (aminoiminomethyl) phenyl] -N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1 piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] alanine methyl ester
N ² - [[1- [2- [4- (diphenylmethyl) -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] glycine methyl ester
3- [3- (aminoiminomethyl) phenyl] -N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1 -piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -N- (3-phenylpropyl) alanineamide
(R, S) -3- (4-cyanophenyl) -N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxopyido [2,3-b] [1 , 4] benzodiazepin-11-yl] acetyl] -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -N- (3-phenylpropyl) alanineamide
(R, S) -3- [4- (aminoiminomethyl) phenyl] -N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxopyrido [2,3-b ] [1,4] benzodiazepin-11-yl] acetyl] -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -N- (3-phenylpropyl) -alanineamide
3- (4-cyanophenyl) -N ² - [5- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] -3,3 -dimethyl-1,5-dioxopentyl] -aluminum ethyl ester
3- (4-cyanophenyl) -N ² - [5- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] -1,5 -dioxopentyl] alanine methyl ester
3- (4-cyanophenyl) -N, N-diethyl-N ² - [5- [4- [5,11-dihydro-6 (6H) -oxo-dibenz [b, e] azepin-11-yl] -1 -piperazinyl] -1,5-dioxopentyl] -alanamide
3- (4-cyanophenyl) -N, N-diethyl-N ² - [5- [4- [5,11-dihydro-6 (6H) -oxo-dibenz [b, e] azepin-11-yl] -1 -piperazinyl] -3,3-dimethyl-1,5-dioxo-pentyl] alaninamide
3- (4-cyanophenyl) -N ² - [5- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] -3,3 -dimethyl-1,5-dioxopentyl] -N-propylalaninamide
3- (4-cyanophenyl) -N ² - [5- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] -1,5 dioxopentyl] -N-propylalanine amide
3- [4- (aminoiminomethyl) phenyl] -N ² - [5- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] - 3,3-dimethyl-1,5-di oxopentyl] -N-propyl alanine amide
N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl ] -N ⁶ - (phenylmethoxycarbonyl) -lysine methyl ester
and their salts.

The compounds of the general formula I are prepared by methods known pri ni piell, wherein in particular from the peptide chemistry (see, for example, Houben-Weyl, Methods of Organic Chemistry, Vol. 15/2) derived methods are used. As amino protective groups, those described in Houben-Weyl, Methods of Organic Chemistry, Vol. 15/1, can be used, where in the case of urethane protective groups, such as, for example, As the Fluorenylmethoxycarbo nyl-, phenylmethoxycarbonyl - or tert-Butyloxycarbonylgruppe be preferred. Functional groups which may be present in the side chain of the radical B of the compounds of the general formula I are used to prevent side reactions by suitable protective groups (see, for example: GB Fields et al., Int. J. Peptide Protein Res., 35, 161 (1990). TW Greene, Protective Groups in Organic Synthesis). It is particularly important to ensure that for the protection of the α-amino and the side chain amino group so-called orthogonal Kombinatio NEN be used by protecting groups, for. B .:

Protection of the N (side chain) N ^α protection p-toluenesulfonyl phenylmethoxycarbonyl butyloxycarbonyl @ phenylmethoxycarbonyl (4-methoxyphenyl) methoxycarbonyl Butoxycarbonyl @ adamantyloxycarbonyl @ Biphenylylisopropyloxycarbonyl @ Isonicotinoyloxycarbonyl @ o -nitrophenylsulfenyl @ formyl @ Butoxycarbonyl phenylmethoxycarbonyl p-toluenesulfonyl @ o -nitrophenylsulfenyl @ Biphenylylisopropyloxycarbonyl @ 9-fluorenylmethoxycarbonyl @ Acetyl, trifluoroacetyl, formyl, butyloxycarbonyl (2-chlorophenyl) methoxycarbonyl, @ (4-chloro-phenyl) methoxycarbonyl, @ 4- (nitrophenyl) methoxycarbonyl, phthaloyl

Instead of protecting amino groups in the radical R ² , it is also possible to use precursor functions which are substituted in the side chain, in particular by nitro or cyano, or derivatives thereof, for example 6-nitro-norleucine, 2- (3-cyanopropyl) - Glycine or 3- (3-cyanophenyl) -alanine, and in a later stages late reaction and after principle known from the literature methods in the desired lysine or [(aminoiminomethyl) phenyl] alanine derivatives are converted.

The basic functions in the side chain of not purchasli chen α-amino acids, for example, by (aminoiminomes Thyl) groups can be characterized in the same way  protected as that for the side chain protection of Argi nin and its derivatives is known (see also M. Bodanszky, "Peptide Chemistry", Springer-Verlag, 1988, pp. 94-97); when Protecting groups for the (aminoiminomethyl) group particularly ge suitable are the p-toluenesulfonyl, mesitylenesulfonyl (Mts -) -, Methoxytrimethylphenylsulfonyl (Mtr -) -, 2,2,5,7,8-pentamethyl chroman-6-sulfonyl (Pmc -), pentachlorophenoxycarbonyl and Ni tro-protecting group.

The actual coupling will be from the peptide chemistry be knew methods (see eg Houben-Weyl, Methoden der Organi Chemie, Vol. 15/2). Preferably used Carbodiimides, such as. Dicyclohexylcarbodiimide (DCC), diiso propylcarbodiimide (DIC) or ethyl (3-dimethylaminopropyl) - carbodiimide, O- (1H-benzotriazol-1-yl) -N, N, N ', N'-tetramethyl uronium hexafluorophosphate (HBTU) or tetrafluoroborate (TBTU) or 1H-benzotriazol-1-yl-oxy-tris (dimethylamino) -phosphoni umhexafluorophosphate (BOP). By addition of 1-hydroxybenzo triazole (HOBt) or 3-hydroxy-4-oxo-3,4-dihy dro-1,2,3-benzotriazine (HOObt) may be the racemization desired additionally suppressed or the reaction rate be increased. The couplings are usually with Equimolar proportions of the coupling components and the Kupp lungsreagenz in solvents such as dichloromethane, tetrahydrofuran, Acetonitrile, dimethylformamide (DMF), dimethylacetamide (DMA), N-methyl-pyrrolidone (NMP) or mixtures of these and at Temperatures between -30 and + 30 ° C, preferably -20 and + 20 ° C, carried out. If additional auxiliary bases are required, N-ethyldiisoproylamine (DIEA) (Hünig's base) is preferred.

Another coupling method for the synthesis of compounds of the general formula I is the so-called "Anhydridverfah ren" (see also: M. Bodanszky, Peptide Chemistry ", Springer Verlag 1988, pp 58-59, N. Bodanszky," Principles of Peptide Synthesis "Springer-Verlag 1984, pp. 21-27)." The mixed anhydride method "is preferred in the variant according to Vaughan (JR Vaughan Jr., J. Amer. Chem. Soc. 73, 3547 (1951)), in which, using isobutyl chloroformate in the presence of bases such as 4-methylmorpholine or 4-ethylmorpholine, the mixed anhydride is prepared from the optionally N ² -protected or N ² -substituted b-amino acid and the carbonic acid monoisobutyl ester Synthesis of this mixed anhydride and the coupling with amines takes place in a one-pot process, using the above-mentioned solvents and at temperatures between -20 and + 20 ° C, preferably 0 and + 20 ° C.

Any protective groups present in the α-amino acid side chain and no longer required in the end product are finally eliminated after construction of the N- and C-terminally substituted amino acid derivatives with suitable reagents, in principle likewise known from the literature, namely arylsulfonyl and hetarylsulfonyl protective groups, preferably acidolytically, ie by the action of strong acids, preferably trifluoroacetic acid, nitro and Arylmethoxycarbonylschutzgruppen hydroge nolytically, for example with hydrogen in the presence of Palladiummohr and using glacial acetic acid as the solvent. Contains the substrate against hydrogenolysis sensitive Funktio nen, z. As halogen atoms, such as chlorine, bromine or iodine, a Phe nylmethanol- or hetaryl methanol function or another benzyl heteroatom bond, in particular a benzyl-oxygen bond, the cleavage of the nitro group succeeds not hydrogenolytically, z. With zinc / 2N trifluoroacetic acid (see also:
A. Turan, A. Patthy and S. Bajusz, Acta Chim. Acad. Sci. Hung, Tom. 85 (3), 327-332 [1975]; CA 83, 206526y [1975]), with tin (II) chloride in 60% aqueous formic acid (see also: SUNSTAR KK, JA-A-3271-299), with zinc in the presence of acetic acid (s. A. Malabarba, P. Ferrari, G. Cietto, R. Pallanza and M. Berti, J. Antibiot. 42 (12) 1800-1816 (1989)) or excess aqueous 20% titanium (III) chloride in aqueous methanol and in the presence of aqueous ammonium acetate buffer at 24 ° C (see also: RM Freidinger, R. Hirschmann and DF Veber, J. Org. Chem. 43 (25), 4800-4803 [1978]).

Optionally present in the side chain of the b-amino acid Precursor functions can also be terminated by Hy drug metabolism converted into the desired amino functions who the; Nitrobutyl groups give rise to this under the chemist conditions Aminobutylgruppen, the cyanopropyl group goes also into the aminobutyl group.

Nitrile functions can instead also with respect to others gene contained in the molecule critical functions, in particular Amide groups, selective complex hydrides can be reduced (see also: J. Seyden-Penne, "Reductions by the Alumino and Borohydrides in Organic Synthesis ", VCH Publishers Inc., 1991, P. 132ff.), Z. B. with sodium borohydride in methanol and in Ge presently cobalt (II) chloride, with sodium borohydride in tetra hydrofuran in the presence of trifluoroacetic acid or with tetra kis (n-butyl) ammonium borohydride in dichloromethane; also the Re production of aliphatic nitro functions to the primary amino group tion is with sodium borohydride in the presence of stannous chloride or copper (II) acetylacetonate possible without the in Verbin who attacked type I Carboxamidgruppen who attacked (see also: J. Seyden-Penne, ibid., pp. 137ff.).

For the preparation of the compounds of the invention of the general In my Formula I, the following procedures are particularly appropriate net:

a) coupling of compounds of general formula II,

in the
R ¹ , R ³ , R ⁴ and Z are as defined above and
X is the hydroxyl group, a halogen atom, such as the chlorine, bromine or iodine atom, an alkylsulfonyloxy group having 1 to 10 carbon atoms, an optionally substituted by chlorine or bromine atoms, by methyl or nitro groups mono-, di- or trisubstituier te Phenylsulfonyloxy- or Naphthylsulfonyloxy group, where the substituents may be the same or different, or the 1H-imidazol-1-yl radical,
with α-amino acid derivatives of the general formula III,

HBC, (III)

in the
B and C are as defined above and, if necessary, subsequent sequential removal of protective groups or modification of precursor functions by the methods described above.

In the general formula II X is the hydroxy group, then are discussed in detail above, from peptide chemistry used known coupling methods, in particular under Be use of the mentioned coupling reagents DCC, DIC, HBTU, TBTU or BOP, or it is ver mixed by the mixed anhydride drive.

In the general formula II, X represents a halogen atom, the 1H-imidazol-1-yl radical, an alkyl or arylsulfonyloxy group, so the implementation under Schotten-Baumann or unicorn Conditions are carried out, that is, the components are in Presence of at least one equivalent of an auxiliary base Temperatures between -50 ° C and + 120 ° C, preferably -10 ° C and + 30 ° C, and optionally in the presence of solvents to Re action brought. As auxiliary bases are preferred alkali and Alkaline earth hydroxides, for example sodium hydroxide, potassium hy hydroxide or barium hydroxide, alkali carbonates, e.g. B. sodium car carbonate, potassium carbonate or cesium carbonate, alkali metal acetates, eg. B.  Sodium or potassium acetate, and tertiary amines, beispielswei pyridine, 2,4,6-trimethylpyridine, quinoline, triethylamine, N-ethyl-diisopropylamine, N-ethyl-dicyclohexylamine, 1,4-diaza bicyclo [2,2,2] octane or 1,8-diazabicyclo [5,4,0] undec-7-ene, as Solvents, for example, dichloromethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, dimethylformamide, dimethylacetamide, N-methyl-pyrrolidone or mixtures thereof; be considered Auxiliary bases alkali or alkaline earth hydroxides, alkali carbonates or acetates used, the reaction mixture may also be water be added as cosolvent. Transacylation reactions with the imidazolides covered by general formula II the preferred under anhydrous conditions and in the absence performed by auxiliary bases.

b) For the preparation of compounds of the general formula I in which B has the meanings mentioned above, with the exception of a single bond:
Coupling of compounds of general formula IV,

in the
R ¹ , R ³ , ⁴ and Z are as defined above and X are as defined under a) and B has the meanings given at the beginning, with the exception of the egg ner single bond,
with compounds of the general formula V,

HC (V),

in the C as defined above, and, if necessary, on final cleavage of protecting groups or modification of Precursor functions according to the method described above ren.  

The coupling is carried out using peptide chemistry knew and carried out methods described above, in particular using DCC, DIC, HBTU, TBTU or BOP as reagents or by the mixed anhydride method.

If the starting compound IV used is enantiomerically pure, see above even when X is the hydroxy group, it must be the coupling Step with a partial, when using triethylamine as an auxiliary base and of dimethylformamide, dimethylacetamide or N-methyl-pyrrolidone as a solvent with a quantitative Racemization can be expected.

c) For the preparation of compounds of the general formula I, in which C has the meanings given at the beginning, with the exception of one hydroxyl group:
Coupling of compounds of general formula VI,

R ¹ -N NH, (VI)

in the
R ¹ and Z are as defined above,
with carboxylic acid derivatives of the general formula VII,

in the
B, R ³ and R ^{4 are} as defined at the beginning and X is as defined under a) and C has the meanings mentioned at the outset with the exception of the hydroxyl group and, if necessary, subsequent removal of protective groups or modification of precursor functions as described above Method.

The coupling takes place under those described in process a) conditions

d) reaction of halogen compounds of the general formula VIII,

R ¹ -Z-Hal, (VIII)

in the
R ¹ and Z are as defined above and Hal is a halogen atom, preferably the chlorine, bromine or iodine atom, with piperazine derivatives of the general formula IX,

in the
R ³ , R ⁴ , B and C are as defined above, and
if necessary, subsequent cleavage of protecting groups or modification of precursor functions according to the above-described methods.

The reaction is carried out in an inert solvent at Tempe between -10 ° C and the boiling point of the solvent Tels, preferably in the presence of an auxiliary base, if Z is not the single bond means. As a solvent, for example example, chlorinated hydrocarbons such as methylene chloride, Chlo roform or 1,2-dichloroethane, alcohols, such as ethanol, methanol or isopropanol, further tetrahydrofuran, 1,4-dioxane, Acetonitrile, dimethylformamide, dimethylacetamide, N-methylpyrrole lidone or mixtures thereof. As auxiliary bases are For example, tertiary organic bases such as triethylamine, N- Methylpiperidine, diethylaniline, pyridine and 4- (dimethylamino) - pyridine or inorganic bases, such as alkali metal or Erdal alkali metal carbonates or bicarbonates, hydroxides or  called oxides. Optionally, the reaction by addition be accelerated by alkali metal iodides. The reaction time Depending on the amount and type of amine used general formula IX between 15 minutes and 80 hours.

e) For the preparation of compounds of the general formula I in which B is the bivalent radical of the amino acid phenylalanine which is substituted in the 2-, 3- or 4-position of the phenyl moiety by an aminoimino-methyl group,
Reaction of compounds of general formula X,

in the
R ¹ , R ³ ₁ R ⁴ ₁ C and Z are as defined above and B ^{1 is} the bivalent radical of the amino acid phenylalanine, which is substituted by a cyano group in the 2-, 3- or 4-position of the phenyl moiety,
with alcohols of the general formula XI,

R ⁵ -OH, (XI)

in the
R ^{5 is} as defined above, and subsequent treatment with ammonia.

The first stage of the reaction is preferably carried out in an Al kohol of the general formula XI as a solvent, for. In Me ethanol or ethanol, in the presence of dry chlorine water fabric and in the absence of water at temperatures between -30 ° C and + 40 ° C, preferably at 0 ° C to + 20 ° C, performed where in the case of the iminoesters, which are in the form of this acidic variant their hydrochlorides are produced, usually not purified,  but in the second stage directly by treatment with Ammo and at temperatures between -20 ° C and the boiling temperature of the solvent in the sought-after compounds of the general Formula I (see also: A. Pinner and F. Klein, Chem. Ber. 10, 1889 [1877]; A. Pinner, "The imino-ether and their derivatives ", Oppenheim, Berlin, 1892, R. Roger and D.G. Neilson, Chem. Rev. 61, 179 [1961]; G. Wagner and J. Wunder Lich, Pharmacy 31, 766 [1976]; G. Wagner, B. Voigt, D. Danicke and T. Liebermann, Pharmacy 31, 528 [1976]; R. R. Tidwell, L.L. Fox and J.D. Geratz, Biochim. Biophys. Acta 445, 729 [1976]; T. Pantev and R. Georgieva, Farmatsiya (Sofia) 29, 1 [1979]). The Iminoester also arise in the form of their free bases in the base-catalyzed addition of alcohols of general formula mel XI to the nitriles of the formula X. As basic catalysts preferably serve the corresponding alcohols used alkali metal; very particularly preferred is the combination of sodium methoxide and methanol (see also: C. Soula, A. Marsura and C. Luu-Duc, J. Pharm. Belg. 42, 293 [1987]; W. J. Haggerty and W.J. Rost, J. Pharm. Sci. 58, 50 [1969]).

In the acidic version of the synthesis of the general Formula I-covered amidines may take place in the first stage dry hydrogen chloride also other anhydrous acidic agents zien be used, for. For example, hydrogen bromide, p-toluenesulfone acid or sulfuric acid. In the second stage, the implementation the resulting iminoester with ammonia, used in place Of ammonia often its salts with weak organic acid ren, z. For example, ammonium carbonate or acetate.

In the alkaline variant, ammonia is used in the second stage usually used as mineral acid salt, eg. B. as Hy hydrochloride; as solvent can in the second stage with Vor Partly glacial acetic acid are also used.

f) For the preparation of compounds of general formula I in which B is the bivalent radical of the amino acid phenylalanine which is substituted in the 2-, 3- or 4-position of the phenyl moiety by a Aminoimi nomethylgruppe means:
Hydrogenolysis of a compound of general formula XII,

in the
R ¹ , R ³ , R ⁴ ₁ C and Z are as defined above and B ^{2 is} the bivalent radical of the amino acid phenylalanine, which is substituted in the 2-, 3- or 4-position of the phenyl moiety by an amino (hydroxyimino) - methyl group is means.

The hydrogenolysis is carried out using palladium or Nickel catalysts, e.g. B. palladium / animal charcoal, palladium black, Palladium / barium sulfate or Raney nickel, in appropriate solutions such as ethanol, methanol, glacial acetic acid, 1,4-dioxane or it ethyl acetate, at temperatures between 0 and + 100 ° C, be preferably + 15 ° C and + 70 ° C, and a hydrogen pressure of 0.5 to 200 bar, preferably 1 to 5 bar performed.

g) For the preparation of compounds of general formula I in which B is the bivalent radical of the amino acid phenylalanine which is substituted in the 2-, 3- or 4-position of the phenyl moiety by a Aminoimi nomethylgruppe means:
Conversion of nitriles of the general formula X,

in the
R ₁ , R ^3, R ⁴ , C and Z are as defined above and B ^{1 is} the bivalent radical of the amino acid phenylalanine, which is substituted by a cyano group in the 2-, 3- or 4-position of the phenyl moiety,
in thioamides of the general formula XIII

in the
R ¹ , R ³ , R ⁴ , C and Z are as defined above and B ^{3 is} the bivalent radical of the amino acid phenylalanine which is substituted in the 2-, 3- or 4-position of the phenyl moiety by an aminothiocarbonyl group,
subsequent alkylation of a compound of the formula XIII thus obtained with compounds of the general formula XIV

R ⁵ -X ² , (XIV)

in the
R ^{5 is} as defined above and
X ^{2 is} a leaving group such as a halogen atom, an alkylsulfonyloxy, alkoxysulfonyloxy or arylsulfonyloxy group, e.g. B. represents a chlorine, bromine or iodine atom, a methylsulfonyloxy, Me thoxysulfonyloxy- or toluenesulfonyloxy group,
or with a trialkyloxonium tetrafluoroborate of the general formula XV,

(R ⁵ ) ₃ OBF ₄ , (XV)

in the
R ^{5 is} as defined above, and
subsequent aminolysis.

The reactions are carried out by literature methods (see also: P. Chabrier and S.H. Renard, C.R. Acad. Sci. Paris 230, 1673 [1950]; Y. Nii, K. Okano, S. Kobayashi and M. Ohto, Tetrah. Lett. 1979, 2517; Hoffmann-La Roche, EP-A 0 381 033).

For the preparation of thiocarboxamides of the general formula XIII from the nitriles of the general formula X is the Umset with hydrogen sulphide in pyridine and in the presence of gaseous ammonia or triethylamine, optionally also in the pressure autoclave preferred. Suitable reaction temperatures are between 0 ° C and + 100 ° C, preferably at +50 to + 60 ° C. (see also: Houben-Weyl, Methods of Organic Chemistry, 4. Edition, Georg-Thieme Verlag, Stuttgart, from 1952, Volume IX, S. 762). Also suitable is the reaction with thioacetamide in with dry hydrogen chloride saturated dimethylformamide at Temperatures between 80 and 100 ° C (see also: E.C. Taylor and YES. Zoltewicz, J. Amer. Chem. Soc. 82 2656 [1960]).

For the preparation of the thioimidic acid esters or their salts from the Thioamides of the general formula XIII is the reaction with Methyl iodide preferred. The solvents used are ketones, such as acetone or cyclohexanone, and dipolar, aprotic solvents of the type dimethylformamide, dimethylacetamide, N-methyl-pyrrolidone or 1,3-dimethyl-2-imidazolidinone or mixtures thereof in Be costume). Suitable reaction temperatures are between -20 ° C and + 100 ° C, preferably at room temperature.

The aminolysis takes place at temperatures between 0 ° C and + 100 ° C, preferably + 40 ° C and + 80 ° C, and using inert solvents for example, dichloromethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, dimethylformamide, dimethylacetamide, N-methyl-pyrrolidone or mixtures thereof, and under certain circumstances in the presence of auxiliary bases, in particular of alkali metal carbonates such as sodium or potassium carbonate, or tertiary amines, before added N-ethyl-diisopropylamine or triethylamine.  

h) For the preparation of compounds of the general formula I in which B denotes the divalent radical of the amino acid lysine substituted by a phenylmethoxycarbonyl group on the N ⁶ atom:
Reaction of a compound of general formula XVI,

in the
R ¹ , R ³ , R ⁴ , C and Z are as defined above and B ^{4 is} the bivalent radical of the amino acid lysine, with a compound of the general formula of formula XVII,

in the
X ^{3 is} a leaving group such as a halogen atom or an aryloxy group, for. As a chlorine or bromine atom or a p-nitrophen oxy group means.

The reaction is conveniently carried out in a solvent such as Tetrahydrofuran, methylene chloride, chloroform, ethyl acetate or Dimethylformamide conveniently in the presence of a base such as Sodium carbonate, potassium carbonate or sodium hydroxide or in counter a tertiary organic base such as triethylamine, N-ethyl-diisopropylamine, N-methyl-morpholine or pyridine, wel at the same time can serve as a solvent, at tempera temperatures between -30 and 100 ° C, but preferably at tempera temperatures between -10 and 60 ° C.

The piperazine derivatives of the general formula I according to the invention contain at least one center of chirality, provided B is the bivalent radical of an α-position-substituted amino acid. If, in addition, another radical is chiral, for example the radical R ¹ , then the compounds can occur in the form of two diastereomeric antipode pairs. The invention comprises the individual isomers as well as their mixtures.

The separation of the respective diastereomers succeeds on the basis of the different physico-chemical properties, eg. B. by fractional crystallisation from suitable solvents, by high-pressure liquid or column chromatography Use of chiral or preferably achiral stationary Pha sen.

The separation of falling under the general formula I Race Mats succeed, for example, by HPLC on suitable chiral stationary phases (eg Chiral AGP, Chiralpak AD). Racemates, which contain a basic function, can also be over the diastereomeric, optically active salts, which in Umset with an optically active acid, for example (+) - or (-) - tartaric acid, (+) - or (-) - diacetyltartaric acid, (+) - or (-) - Monomethyl tartrate or (+) - camphorsulfonic arise.

After a conventional process for isomer separation is the Racemate of a compound of general formula I with one of the above-mentioned optically active acids in equimolar Amount reacted in a solvent and the kri obtained stallines, diastereomers, optically active salts with use Separation of their different solubility separately. This implementation can be done in any kind of solvent, so long this one sufficient difference in terms of the Having solubility of the salts. Preferably, methanol, Ethanol or mixtures thereof, for example in volume 50: 50, used. Then each of the individual diaste dissolved in water with a base, such as sodium Carbonate or potassium carbonate, neutralized and thereby the corresponding free compound in the (+) - or (-) - form erhal th.  

In each case only the (S) -enantiomer or a mixture of two optical active, falling under the general formula I diastereomeric Compounds are also obtained by using the above written syntheses with one each the corresponding (S) -configured amino acid contained reaction component performs.

For the synthesis of the compounds of general formula I he required starting materials of the general formulas V, XI, XIV, XVII and the amino acids used are commercially available or are prepared by literature methods.

The compounds of the general formula II required as starting compounds, in which X represents the hydroxyl group, are obtained by reacting appropriately substituted glutaric acid anhydrides with compounds of the general formula VI,

in the
R ¹ and Z are as defined above, easily accessible in principle known manner. The compounds of the general For mel II, in which X is the meaning of a halogen atom, an alkyl sulfonyloxy, an optionally substituted Phenylsulfo nyloxy- or Naphthylsulfonyloxygruppe or a 1H-imidazol-1-yl radical occupy per thereof are prepared by known methods per problem ,

The starting compounds of the general formula VI are from commercially available or according to a known model produced halogen compounds of general formula VIII and piperazine under the conditions of an aminolysis reaction produced, for. B. ana log the method described above under d).  

The starting compounds of the general formula IIIa which fall under the general formula III

H-B'-C, (IIIa)

in the
C as defined above and B 'has the meanings mentioned above for B except for a single bond are given by the methods known from peptide chemistry from where appropriate on the N ² atom or in the side chain protected suitable amino acids and the commercially available or analogous Compounds of the general formula HC, (V) which can be prepared by methods known from the literature are readily available. Protecting groups or precursor functions present in the groups B 'or C of the compounds of the formula IIIa are cleaved off or modified, as indicated above, only in a later reaction stage, eg. B. a cyano group to an aminomethyl or aminoiminomethyl group.

Starting compounds of the general formula IV, in which X represents the hydroxyl group, can be prepared, for example, from a compound of the general formula II, in which X is a halogen atom, and an amino acid of the general formula XVIII,

H-B'-OH, (XVIII)

produce in the
B 'can assume the meanings given at the outset for B with the exception of the single bond, wherein the side chains of the initially mentioned for B amino acid residues can also be varied such that the desired residues B are formed by removal of protective groups or modification of Präcursorfunktionen in a later reaction stage ,

The starting compounds of general formula VII in which X the hydroxy group means are by implementation of the corre sponding substituted glutaric anhydrides with α-amino acid derivatives of the general formula III or compounds of the general  my formula V is easily accessible and can be read by literature known processes in such starting compounds of the general to convert my formula VII, in which x is a halogen, an alkyl sulfonyloxy, an optionally substituted phenylsulfonyl oxy or naphthylsulfonyloxy group or a 1H-imidazole group 1-yl radical means.

The starting compounds of general formula IX are at For example, from compounds of general formula VII, in the X represents a halogen atom, by reaction with excess Piperazine available.

The compounds of general formula X are according to the Verfah ren a), b), c) and d) available.

The required as starting compounds amidoximes of all Formula XII can be prepared by addition of Hydroxylamine to nitriles of the general formula X.

The starting compounds of general formula XVI are for example by reducing or hydrogenating modification accordingly the methods described above for the conversion of Präcursorfunktionen from compounds of general formula XX,

in the
B ^{5 is} the bivalent radical of the a-amino acids 2- (4-nitrobutyl) - glycine or 2- (3-cyanopropyl) glycine, easily obtained. The compounds of general formula XX are in turn un ter using the amino acids 2- (4-nitrobutyl) -glycine or 2- (3-cyanopropyl) -glycine, for example, according to the above-described methods a), b), c) or d) synthesizable.

The obtained compounds of general formula I can, especially for pharmaceutical applications, in their physiolo gically compatible salts with inorganic or organic Acids, be transferred. As acids come for this hydrochloric acid, hydrobromic acid, phosphoric acid, Nitric acid, sulfuric acid, methanesulfonic acid, p-toluene sul fonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, Mandelic acid, malic acid, citric acid, tartaric acid or malein acid into consideration.

In addition, the compounds thus obtained the general my formula I, if they contain a carboxy group ge if desired then into their addition salts with anorga nical or organic bases, especially for the pharmazeu table application in their physiologically acceptable addition salt, convict. As bases here are, for example, Na triumhydroxide, potassium hydroxide, ammonia, cyclohexylamine, dicyc lohexylamine, ethanolamine, diethanolamine and triethanolamine in Consideration.

The new compounds of general formula I and their phy biologically compatible salts have NPY agonistic and / or or antagonistic properties and show good affinities in NPY receptor binding studies.

To demonstrate the affinity of compounds of the general Formula I to NPY receptors were binding studies with Kanin chen-bark homogenate:

The kidneys are removed from rabbits and frozen at -80 ° C. For the preparation of the renal cortex, the organs are kept at 0 ° C. The isolated kidney bark tissues are homogenized in 10 ml Tris buffer per 2 g tissue (50 mM Tris, 100 mM NaCl, 5 mM MnCl ₂ , 1 mM EGTA, 0.4 mM PMSF, pH 7.5) and incubated for 5 min. centrifuged at 1075 xg and 0 ° C. The supernatant is 25 min. centrifuged at 20,000 xg and 0 ° C. The resulting sediment is resuspended in buffer and centrifuged again under the above conditions. The resulting pellet is resuspended in 3 ml of buffer per 10 ml of starting homogenate, pottled with 10 strokes, portioned to 0.5 ml and frozen at -80 ° C.

For the assay, the frozen homogenate with buffer (as above, + 0.1% to 1.0% BSA; 0.0025% bacitracin) in the ratio 1: 100 diluted.

100 μl of the homogenate are mixed with about 20,000 cpm [ ¹²⁵ I] NPY (about 20-30 pM) and the corresponding concentrations of the test substance for 2 hours at room temperature (about 22 ° C) in a total volume of 250 ul incubated. The incubation is terminated by centrifugation (7 min at 1500 × g), the supernatant is sucked off and discarded, the pellet is treated with 250 μl buffer, centrifuged again and separated from the supernatant.

This to the receptors of the renal cortex homogenate (pellet) ge bound radioactivity is measured in a gamma counter. The bound radioactivity in the presence of 100 nM NPY in the In The cubation approach is defined as non-specific binding.

The evaluation of the dose-response curves is carried out by means of a computer-controlled non-linear regression according to a 1-Re receptor binding site model, wherein the determined IC ₅₀ values represent that concentration of the individual test substances, in which the specific binding of [ ¹²⁵ I] NPY to the NPY Receptor is inhibited by 50%.
NPY: Neuropeptide Y
EGTA: 1,2-bis (2-aminoethoxyethane) -N, N, N ', N'-tetraacetic acid
PMSF: phenylmethylsulfonyl fluoride
BSA: bovine serum albumin (bovine serum albumin).

The compounds of general formula I show in the test described be IC ₅₀ values ≦ 10,000 nM.

Due to their biological properties, the Ver compounds of the general formula I and their physiologically ver Suitable salts for the treatment of cardiovascular diseases gene, z. For the treatment of hypertension, myocardial, cerebral and renal vasospasm, from pulmonary hypertension, of chronic heart failure, of coronary heart disease such as angina pectoris, myocardial infarction and syndrome X, further for the treatment of subarachnoid hemorrhage, chronic Renal failure, of tumors such as phaeochromocytoma, Hyperthyroidism, Obesity and Diabetes, as well as Diseases of the central nervous system such as depression, anxiety Stands, eventually to improve limited cogniti ver functions, z. B. in Alzheimer's disease.

The necessary to achieve a corresponding effect Dosage is expediently with intravenous administration 0.01 to 3 mg / kg body weight, preferably 0.1 to 1 mg / kg body weight, and when administered orally, 0.1 to 10 mg / kg body weight, preferably 1 to 10 mg / kg of body weight, 1 to 3 times each Every day.

For this purpose, the compounds according to the invention can be prepared gene of general formula I, optionally in combination with other active substances, such as. Antihypertensives, ACE inhibitors, Diuretics and / or calcium antagonists, together with one or more inert customary carriers and / or diluents resources, eg B. with corn starch, lactose, cane sugar, mi microcrystalline cellulose, magnesium stearate, polyvinylpyrroli don, citric acid, tartaric acid, water, water / ethanol, water / Glycerol, water / sorbitol, water / polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or fat containing substances such as hard fat or their suitable Gemi in common pharmaceutical preparations such as tablets, Dra gees, capsules, powders, suspensions or suppositories.  

For the above-mentioned combinations thus come as another Active substances such as bendroflumethiazide, chlorothia zid, hydrochlorothiazide, spironolactone, benzothiazide, cyclothia zid, ethacrynic acid, furosemide, metoprolol, prazosin, atenolol, Propranolol, (di) hydralazine hydrochloride, diltiazem, felodipine, Nicardipine, nifedipine, nisoldipine, nitrendipine, captopril, Enalapril, Lisinopril, Cilazapril, Quinapril, Fosinopril and Ramipri1 into consideration. The dose for these active substances be hereby expediently carries 1/5 of the usual recommended lowest dosage up to 1/1 of the normal recommended lenen dosage, so for example 15 to 200 mg Hydrochloro thiazide, 125 to 2000 mg chlorothiazide, 15 to 200 mg ethacrine acid, 5 to 80 mg furosemide, 20 to 480 mg propranolol, 5 to 60 mg felodipine, 5 to 60 mg nifedipine or 5 to 60 mg nitrene DIPIN.

Another object of the invention is the use of the Compounds of general formula I as valuable tools for the production and purification (affinity chromatography) of An antibodies and, after appropriate radioactive labeling, at For example, by direct labeling with 1251 or 1311 in RIA and ELISA assays and as diagnostic aids medium in neutron transmitter research.

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

Preliminary remarks:

"Mp." means "melting point", "Z." means "decomposition". For all compounds are satisfactory elemental analyzes, IR-, UV-; ¹ H-NMR, usually also mass spectra before. Unless otherwise stated, RF values were determined using DC Finished Plates Kieselgel 60 F254 (E. Merck, Darmstadt, Item No. 5729) and the following solvent systems (each with no chamber saturation):
n-butanol / glacial acetic acid / water = 4/1/1 (v / v / v) (variant A), ethyl acetate (variant B),
Ethyl acetate / methanol = 9/1 (v / v) (variant C),
Ethyl acetate / methanol / glacial acetic acid = 170/2/1 (v / v / v) (variant D),
Ethyl acetate / methanol / cyclohexane / dichloromethane, conc. Ammonia = 195/57/57/720 / 7.5 (v / v / v / v / v) (variant E)

example 1 N- [4- (aminoiminomethyl) phenyl] -1- [2- [4- (diphenylmethyl) -1-pi perazinyl] -2-oxoethyl] cyclopentanacetamid hydrochloride a) 1- [2 - ² -oxoethyl - [(4-cyanophenyl) amino]] acetic acid cyclopenta

The mixture of 20.0 g (118.9 mmol) of 1,1-cyclopentanediacetic acid Anhydride, 15.45 g (130.78 mmol) of 4-aminobenzonitrile and 400 ml Dichloromethane was stirred at room temperature for 30 hours. The solvent was removed in vacuo, the residue through Trituration with diisopropyl ether crystallized, filtered off with suction and washed thoroughly with ice-cold diisopropyl ether rule. After drying, 31.4 g (92% of theory) were obtained. on colorless crystals of mp. 136-138 ° C.  

b) N- (4-Cyanophenyl) -1- [2- [4-diphenylmethyl) -1-piperazinyl] - 2-oxoethyl] cyclopentanacetamid

The mixture of 2.86 g (10 mmol) of 1- [2 - [(4-cyanophenyl) amino] -2- oxoethyl] cyclopentaneacetic acid, 2.52 g (10 mmol) of 1- (diphenyl methyl) piperazine, 1.91 g (14.1 mmol) HOBt, 3.1 g (15.02 mmol) N, N'-dicyclohexylcarbodiimide and 50 ml of anhydrous dimethyl Formamide was stirred overnight at room temperature. The Lö semittel was evaporated in vacuo, the residue in vinegar acid ethyl ester, the resulting solution successively with saturated, aqueous sodium bicarbonate solution, Water, 10% aqueous citric acid solution and water wash, dried over magnesium sulfate and again in vacuo evaporated. The residue was from a mixture of vinegar acid ethyl ester / diisopropyl ether / isopropanol = 48/48/4 (v / v / v) recrystallized and gave after drying in vacuo 3.25 g (62% of theory) of colorless crystals, mp. 193-196 ° C.

c) N - [(4- (aminoiminomethyl) phenyl] -1- [2- [4- (diphenylmethyl) -] 1-piperazinyl] -2-oxoethyl] cyclopentanacetamid hydrochloride

In the coated with petroleum ether solution of 1.2 g (2.3 mmol) of N- [4-cyanophenyl-1- [2- [4- (diphenylmethyl) -1-pipera cinyl] -2-oxoethyl] cyclopentanacetamid in 30 ml anhydrous methanol was hydrogen chloride to external saturation with ice dry hydrogen chloride, then the cooling was removed and stirred overnight at room temperature. The volatiles were removed in vacuo, the residue taken up in as little methanol and brought to pH 9 by careful addition of concentrated aqueous ammonia. Thereafter, the mixture was stirred again overnight at room temperature. The solvent-free product was stirred with 100 ml of a mixture of dichloromethane and methanol (85/15, v / v) and the insolubles were removed by filtration. The filtrate was again brought to dryness and then crystallized with a mixture of diisopropyl ether and ethanol (95/5, v / v). This gave 1.0 g (76% of theory) of colorless crystals of mp. <236 ° C and R _f 0.69 (variant A).
IR (KBr): 1670 cm ^-1 (amide-CO, guanidinium)
MS: (M + H) ⁺ = 538.

Example 2 (R, S) -3- (4-Cyanophenyl) -N ² - [[1- [2- [4- (diphenylmethyl) -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -N- (3 phenylpropyl) -alanamide trifluoroacetate a) 1- [2- [4- (Diphenylmethyl) -1-piperazinyl] -2-oxoethyl] cyclo pentaacetic acid

To the ice-cooled solution of 3.36 g (20 mmol) of 1,1-cyclopentene tandiacetic anhydride in 80 ml of tetrahydrofuran was added dropwise while maintaining a reaction temperature of 5 to 10 ° C and with stirring, the solution of 5.05 g (20 mmol) of 1- (diphenylme ethyl) piperazine in 40 ml trichloromethane. It was still 5 minutes at + 5 ° C and then stirred overnight at room temp temperature. It was filtered from the precipitate and the filtrate in Vacuum removed from the solvent. This gave 7.94 g (94% of Theory) on colorless crystals of mp. 67-72 ° C.

b) (L- (acetylamino) -α - [(4-cyanophenyl) methyl] -malonic acid diethyl ester

A freshly prepared sodium ethylate solution from 8.5 g (0.370 mol) of sodium and 370 ml of anhydrous ethanol was added at room temperature and within about 15 minutes to that of 73.3 g (0.374 mol) of 4- (bromomethyl) benzonitrile, 82 g ( 0.366 moles) of 97% acetamido-maleate, 18.3 g (0.11 mol) of potassium iodide and 1200 ml of dry dioxane obtained added dropwise. The mixture was stirred for 30 minutes at room temperature and then heated for 5 hours under reflux. It was allowed to stand overnight at room temperature, heated again to + 70 ° C, filtered from the insoluble, cooled the filtrate to 15 ° C and stirred it into 3.2 l of ice water. The resulting precipitate was sucked off, washed thoroughly with water and then dried at + 80 ° C. This gave 120 g (99% of theory) of colorless crystals of mp. 168-170 ° C.
IR (CH ₂ Cl ₂ ): 2225 (C~N), 1740 (ester CO), 1683 (amide CO) cm ^-1

c) (R.S) -3- (4-cyanophenyl) alanine hydrochloride

123 g (0.37 mol) of diethyl a- (acetylamino) -α- [(4-cyanophenyl) methyl] malate were dissolved in 330 ml of glacial acetic acid and, after addition of 660 ml of 3N aqueous hydrochloric acid, refluxed for 6 hours. The cooled to + 5 ° C reaction mixture was filtered, the filtrate evaporated in a water-jet vacuum, finally completely by azeotropic distillation with xylene of residual, adhering hydrochloric acid and acetic acid completely freed. The crude preparation obtained was dissolved in the required volume of methanol, filtered hot and the filtrate was stirred thoroughly after cooling with the same volume of diisopropyl ether. The resulting crystals were filtered off with suction and dried at 80 ° C net. This gave 78.1 g (93% of theory) of colorless Kri stallen of mp. 215-218 ° C.
IR (KBr): 2235 (C~N), 1740 (CO ₂ H) cm ^-1

d) (R, S) -N ² - (tert -butoxycarbonyl) -3- (4-cyanophenyl) alanine

To the mixture of 25.5 g (112.5 mmol) of (R, S) -3- (4-cyanophenyl) alanine hydrochloride, 236 ml (236 mmol) of 1N sodium hydroxide solution and 85 ml of tert-butanol was added 25 , 0 g (114.5 mmol) of di-tert-butyl dicarbonate and then stirred overnight at room temperature. It was diluted with 20 ml of water, extracted once with 200 ml of tert.-butyl methyl ether and then freed the WAS serige phase of organic solvents by distillation in vacuo. The aqueous phase was then acidified with 20% aqueous citric acid solution followed by decantation from the precipitate and the residue taken up in diethyl ether. The ether solution was dried over magnesium sulfate and evaporated in vacuo. This gave 21.2 g (65% of theory) of a triturated after trituration with isopropanol / petroleum ether (1/1, v / v) crystallizing substance, mp. 142-144 ° C.
IR (KBr): 2225 (C~N), 1715 (ester-CO), 1695 (amide-CO) cm- ¹

e) (R, S) -N ² - (tert -butoxycarbonyl) -3- (4-cyanophenyl) -N- (3-phenylpropyl) alanineamide

Prepared analogously to Example 1b) but using tetrahydrofuran as the solvent instead of dimethylformamide and adding equimolar amounts of 4-ethylmorpholine, from (R, S) -N ² - (tert-butoxycarbonyl) -3- (4-cyanophenyl) Alanine and Ben zenproanamin in a yield of 71% of theory. Colorless crystals of mp. 150-153 ° C (isopropanol).
IR (CH ₂ Cl ₂ ): 2225 (C~N), 1710 (ester CO), 1680 (amide CO) cm ^-1

f) (R, S) -3- (4-cyanophenyl) -N- (3-phenylpropyl) alanineamide trifluoroacetate

To the externally impacted ice / ethanol cooled solution of 5.7 g (13.99 mmol) of (R, S) -N ² - (tert-butoxycarbonyl) -3- (4-cyanophenyl) -N- (3 -phenylpropyl) -alaninamide in 60 ml of dichloromethane than was added 60 ml of trifluoroacetic acid, then allowed to warm to room temperature and the mixture was stirred for a further 4 hours at this temperature. The resulting clear solution was evaporated in a water-jet vacuum, mixed twice with 10 ml of water and once with 10 ml of toluene and then he brought each time neut to dryness. The crystallized on standing overnight crude product was recrystallized from ethyl acetate-petroleum ether (1/1, v / v) to give 5.7 g (97% of theory) of colorless crystals, mp. 142-145 ° C.
IR (KBr): 2225 (C~N), 1675 (amide CO) cm ^-1
MS: M⁺ = 307

g) (R, S) -3- (4-cyanophenyl) -N ² - [[1- [2- [4- (diphenylmethyl) -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl]] - N- (3-phenylpropyl) alanine amide trifluoroacetate

To the external cooled with ice / ethanol cooled solution of 2.8 g (6.658 mmol) of 1- [2- [4- (diphenylmethyl) -1-piperazinyl] - 2-oxoethyl] -cyclopentanessigsäure in 300 ml of tetrahydrofuran was added successively 1.56 g (13.2 mmol) of N-ethylmorpholine and 0.925 g (6.77 mmol) of isobutyl chloroformate. After stirring for 15 minutes with external cooling, 2.8 g (6.64 mmol) of (R, S) -3- (4-cyanophenyl) -N- (3-phenylpropyl) alaninamide trifluoroacetate was added. The mixture was allowed to warm to room temperature, ver diluted with twice the volume of ethyl acetate and the resulting mixture was washed successively with 200 ml of 0.5 N potassium hydrogen sulfate solution and saturated sodium chloride solution. The Es sigester phase was dried over sodium sulfate and evaporated in vacuo, the residue remaining säulenchromatogra phically on silica gel (MN silica gel 60, 0.063-0.2 mm, 70-230 mesh ASTM) using ethyl acetate as eluents purified. This gave 1.4 g (26% of theory) of a colorless, amorphous substance of R _f 0.43 (variant B).
IR (KBr): 2225 (C~N), 1650 (broad, amide CO) cm ^-1
MS: M⁺ = 709

Example 3 (R, S) -3- [4- (aminoiminomethyl) phenyl] -N ² - [[1- [2- [4- (diphenylmethyl) -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl]] - N- (3-phenylpropyl) alanine amide hydrochloride

Prepared analogously to Example 1c) from (R, S) -3- (4-cyanophenyl) - N ² - [[1- [2- [4- (diphenylmethyl) -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl ]] - N- (3-phenylpropyl) alanine amide in a yield of 85% of theory. Colorless, amorphous substance of R _f 0.69 (variant A).
IR (CH ₂ Cl ₂ ): 1680 (amidinium), 1655, 1618 (amide CO) cm ^-1
MS: (M + H) ⁺ = 727

Example 4 3- (4-cyanophenyl) -N ² - [[i- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] 2-oxoethyl] cyclopentyl] acetyl] -N- (3-phenylpropyl) alanine amide a) (R, S) -1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepine 11-yl] -1-piperazinyl] -2-oxoethyl) -cyclopentanessigsäure

Prepared analogously to Example 2a) from 1- [5,11-dihydro-6 (6H) -oxo dibenz [b, e] azepin-11-yl] piperazine and 1,1-cyclopentanedienes acetic anhydride in a yield of 35% of theory. color Loose crystals of mp. 154-157 ° C (ethyl acetate).

b) 3- (4-Cyanophenyl) -N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodi benz [b, e] azepin-11-yl] 1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -N- (3-phenylpropyl) alanineamide

Prepared analogously to Example 2g) from (R, S) -1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] -2-oxo-ethyl] -cyclopentaneacetic acid, isobutyl chloroformate and (R, S) -3- (4-cyanophenyl) -N- (3-phenylpropyl) alanine amide trifluoroacetate in a yield of 22% of theory. Colorless, amorphous substance of R _f 0.1 (variant B) or R _f 0.29 (variant C).
IR (KBr): 2240 (C~N), 1665 (amide CO) cm ^-1
MS: M⁺ = 750

Example 5 (R, S) -3- (4-cyanophenyl) -N ² - [[1- [2- [4 - [[5,10-dihydro-11 (10H) -oxodibenzo [b, e] [1,4 ] diazepin-5-yl] carbonyl] -1-piperazinyl] - 2-oxoethyl] cyclopentyl] acetyl] - N - (3-phenylpropyl) alanine amide a) 5,10-Dihydro-5 - [(1-piperazinyl) carbonyl] -11H-dibenzo [b, e] [1,4] diazepin-11-one

To the solution of 9.0 g (0.1045 mol) of piperazine in 200 ml of aceto nitrile was added in small portions, the suspension of 3.0 g (0.011 mol) of 5- (chlorocarbonyl) -5,10-dihydro-11H-dibenzo [b, e] [1,4] diazepin-11-one in 100 ml of acetonitrile and stirred the Mixture then 14 hours at room temperature. The release medium was evaporated in vacuo, the residue remaining taken up in 200 ml of dichloromethane and with the solution of 3.1 g (0.0224 mol) of potassium carbonate in 100 ml of water thoroughly stirred. The resulting solid was suction filtered and washed with the remaining on evaporation of the dichloromethane solution Backlog unified. The product was dissolved in the required volume 5N hydrochloric acid, the resulting solution was extracted twice with 100 ml of ethyl acetate and then saturated with fe stem potassium carbonate. It was exhaustively extracted with dichlor methane and received after usual processing of the united Dichloromethane phases 3.0 g (85% of theory) of a colorless Product which will be processed without further purification in the next step was turned.

b) 1 [2- [4 - [[5,10-dihydro-11 (10H) -oxodibenzo [b, e] [1,4] di azepin-5-yl] carbonyl] -1-piperazinyl] -2-oxoethyl] -cyclo pentaacetic acid

Prepared analogously to Example 1a) from 5,10-dihydro-5 - [(1-pi perazinyl) carbonyl] -11H-dibenzo [b, e] [1,4] diazepin-11-one and 1,1-cyclopentanediacetic anhydride in 88% yield the theory. Colorless crystals of mp. 120-130 ° C (methanol).  

c) (R, S) -3- (4-cyanophenyl) -N ² - [[1- [2- [4 - [[5,10-dihydro-11 (10H) -oxodibenzo [b, e] [1 , 4] diazepin-5-yl] carbonyl] -1-piperazinyl] - 2-oxoethyl] cyclopentyl] acetyl] -N- (3-phenylpropyl) alanine amide

Prepared analogously to Example 2g) from 1- [2- [4- [5,10-dihydro-11 (10H) -oxodibenzo [b, e] [1,4] diazepin-5-yl] carbonyl] -1-piperazinyl ] -2-oxoethyl] cyclopentaneacetic acid, isobutyl chloroformate and (R, S) -3- (4-cyanophenyl-N- (3-phenylpropyl) -aluminamide trifluoroacetate in a yield of 45% of theory Colorless crystals of mp 133-136 ° C and R _f 0,11 (variant B) and R _f 0,245 (variant C).
IR (CH ₂ Cl ₂ ): 2230 (C~N), 1668, 1615 (amide CO) cm ^-1
MS: M⁺ = 779.

Example 6 3- [4- (aminoiminomethyl) phenyl] -N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1 -piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -N- (3-phenylpropyl) alanineamide hydrochloride

Prepared analogously to Example 1c) from 3- (4-cyanophenyl) -N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl ] -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -N- (3-phenylpropyl) -aluminamide in a yield of 70% of theory. Colorless crystals of mp. 198-204 ° C and R _f 0.72 (variant A).
IR (KBr): 1645 (amide CO) cm ^-1
MS: (M + H) ⁺ = 768

Example 7 (R, S) -3- [4- (aminoiminomethyl) phenyl] -N ² - [[1- [2- [4 - [[5,10-dihydro-11 (10H) -oxodibenzo [b, e]] [1,4] diazepin-5-yl] carbonyl] -1-pi perazinyl] -2-oxoethyl] cyclopentyl] acetyl] -N- (3-phenylpropyl) -alanineamide hydrochloride

Prepared analogously to Example 1c) from (R, S) -3- [4-cyanophenyl) -N ² - [[1- [2- [4 - [[5,10-dihydro-11 (10H) -oxodibenzo [b, e] [1,4] diazepin-5-yl] carbonyl] -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] - N - (3-phenylpropyl) alanine amide in 98% yield. Colorless crystals of mp. 186 ° C (Z.) (ethanol / diisopropyl ether 1/9, v / v) and R _f 0.65 (variant A).
IR (KBr): 1650 (broad, amide CO) cm ^-1
MS: (M + H) ⁺ 74552 00070 552 001000280000000200012000285917444100040 0002019816889 00004 74433 = 797

Example 8 (S) -N ² - [[1- [2- [4- (Diphenylmethyl) -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] - N - (2-phenylethyl) -lysinamide hydrobromide a) (S) -N ² - (tert -butoxycarbonyl) -N ⁶ - [(phenylmethoxy) carbonyl] - N - (2-phenylethyl) -lysinamide

Prepared analogously to Example 2g) from Boc-Lys (Z) -OH, chlorocarbons isobutyl ester and benzenethanamine in a yield of 67% of theory. Colorless, highly viscous oil.

b) (S) -N ⁶ - [(phenylmethoxy) carbonyl] -N- (2-phenylethyl) -lysinamide trifluoroacetate

Prepared analogously to Example 2f) from (S) -N ² - (tert.butoxycarbonyl) -N ⁶ - [(phenylmethoxy) carbonyl] -N ² - (phenylethyl) -lysine amide and trifluoroacetic acid in quantitative yield. The product was used without complete purification in the next step.

c) (S) -N ² - [[1- [2- [4- (Diphenylmethyl) -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -N ⁶ - [(phenylmethoxy) carbonyl] -N- (2-phenylethyl) -lysinamid

Prepared analogously to Example 2g) from 1- [2- [4- (diphenylmethyl) -1-piperazinyl] -2-oxoethyl] cyclopentaneacetic acid, chlorocarbonic acid isobutyl ester and (S) -N ⁶ - [(phenylmethoxy) carbonyl] -N- (2 -phenylethyl) -lysinamide trifluoroacetate in a yield of 36% of theory. Colorless crystals of mp. 127-130 ° C (isopropanol / diisopropyl ether 1/9, v / v).

d) (S) -N ² - [[1- [2- [4- (Diphenylmethyl) -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -N- (2-phenylethyl) -lysinamide hydrobromide

1.4 g (1.78 mmol) of (S) -N ² - [[1- [2- [4- (diphenylmethyl)] were added with stirring to 20 ml of a 33% strength solution of hydrogen bromide in glacial acetic acid. 1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -N ⁶ - [(phenylmethoxy) carbonyl] -N- (2-phenylethyl) -lysinamide and kept at room temperature for about 20 minutes. After completion of the Koh lendioxid development the reaction mixture was evaporated in vacuo and the residue by column chromatography on silica gel (MN silica gel 60, 0.063-0.2 mm, 78-230 mesh ASTM) using ethyl acetate / methanol 9/1, v / v ) purified as eluent. This gave 0.8 g (61% of theory) of a colorless, slowly crystallizing product.
IR (KBr): 1640 (broad, amide CO) cm ^-1
MS: (M + H) ⁺ = 652

Example 9 N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl ] -N- (3-phenylpropyl) -L-phenylalanine amide a) (S) -N ² - (tert -butoxycarbonyl) -N- (3-phenylpropyl) -phenyl alaninamide

Prepared analogously to Example 2e) from Boc-Phe-OH and Benzenpro panamin in a yield of 98% of theory. Colorless crystals of mp. 109-113 ° C (methanol / water 3/1, v / v).
IR (CH ₂ Cl ₂ ): 1713 (ester CO), 1677 (amide CO) cm ^-1

b) (S) -N- (3-phenylpropyl) phenylalanine amide trifluoroacetate

Prepared analogously to Example 2f) from (S) -N ² - (tert.Butoxycar bonyl) -N- (3-phenylpropyl) -phenylalaninamid in a yield of 76% of theory. Colorless, slowly crystallizing material.
IR (CH ₂ Cl ₂ ): 1675, shoulder at 1690 (amide CO) cm ^-1

c) N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] -2-oxoethyl] cyclopentyl ] acetyl] - N- (3-phenylpropyl) -L-phenylalanine amide

Prepared analogously to Example 2e) from (R, S) -1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] 2-oxo-ethyl] cyclopentanoacetic acid and (S) -N- (3-phenylpropyl) -phenylalanine amide trifluoroacetate in a yield of 60% of theory. Colorless crystals of melting point 118 ° C. (Z.) and of R _f 0.14 (variant B) or 0.29 (variant C).
IR (KBr): 1660, 1655, 1630 (amide CO) cm ^-1
MS: (M + H) ⁺ = 726

Example 10 (S) -N ² 2 - [[1- [2- [4 - [[5,10-dihydro-11 (10H) -oxodibenzo [b, e] [1,4] diazepin-5-yl] carbonyl] 1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -N- (3-phenylpropyl) phenylalanine amide

Prepared analogously to Example 2e) from 1- [2- [4 - [[5,10-dihydro-11 (10H) -oxodibenzo [b, e] [1,4] diazepin-5-yl] carbonyl] -1-pipera inyl] -2-oxoethyl] cyclopentaneacetic acid and (S) -N- (3-phenylpropyl) phenylalanine amide trifluoroacetate in a yield of 57% of theory. Colorless crystals of mp. 111-115 ° C (Z.) and R _f 0.14 (variant B) and 0.28 (variant C).
IR (CH ₂ Cl ₂ ): 165 5 cm ^-1 (amide CO)
MS: (M + H) ⁺ = 755

Example 11 3- (4-cyanophenyl) -N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] 2-oxoethyl] cyclopentyl] acetyl] alanine methyl ester a) (R, S) -3- (4-cyanophenyl) alanine methyl ester p-toluene sulfonate

The mixture of 2.26 g (9.97 mmol) of 3- (4-cyanophenyl) alanine hydrochloride, 3.8 g of p-toluenesulfonic acid monohydrate and 50 ml of methanol was refluxed for 24 hours. The solvent was removed in vacuo and the remaining residue was digested several times with tert-butyl methyl ether. This gave 3.0 g (80% of theory) of colorless crystals, mp. 161- 165 ° C.
IR (KBr): 2235 (C~N), 1750, 1725 (ester CO) cm ^-1
MS: M ₁ = 172 (p-toluenesulfonic acid)
(M ₂ -59) ⁺ = 145

b) 3- (4-Cyanophenyl) -N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodi benz [b, e] azepin-11-yl] -1 -piperazinyl] -2-oxoethyl] cyclopentyl] acetyl-alanine methyl ester

Prepared analogously to Example 2e) from (R, S) -1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] -2-oxo-ethyl] cyclopentaneacetic acid and (R ₁ S) -3- (4-cyanophenyl) alanine methyl ester p-toluenesulfonate in 79% yield. Colorless highly viscous substance of R _f 0.18 (variant B) or 0.31 (variant C).
IR (CH ₂ Cl ₂ ): 2230 (C~N), 1745, 1725 (ester CO), 1665 (amide CO) cm ^-1
MS: (M + H) ⁺ = 648

Example 12 N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] -2-oxoethyl] cyclopentyl] -acetyl ] -N- (3-phenylpropyl) -L-phenylglycine amide a) (S), N ² - (tert-butoxycarbonyl) -N- (3-phenylpropyl) phenylglycinamide

Prepared analogously to Example 1b), but using tetrahydrofuran as solvent instead of dimethylformamide, from Boc-Phg-OH and benzenepropanamine in quantitative yield. Colorless crystals of mp. 100-103 ° C (ethanol / water 1: 1, v / v).
IR (CH ₂ Cl ₂ ): 1715 (ester CO), 1683 (amide CO) cm ^-1

b) (s) -N- (3-phenylpropyl) -phenylglycine amide trifluoroacetate

Prepared analogously to Example 2f) from (S) -N ² - (tert.Butoxycarbo nyl) -N- (3-phenylpropyl) -phenylglycinamid and trifluoroacetic acid in a yield of 90% of theory. Colorless crystals of mp. 119-123 ° C.
IR (KBr): 1670, 1635 (amide CO) cm ^-1

c) N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] -2-oxoethyl] cyclopentyl ] acetyl] -N- (3-phenylpropyl) -L-phenylglycine amide

Prepared analogously to Example 2e) from (R, S) -1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] -2-oxo-ethyl] cyclopentaneacetic acid and (S) -N- (3-phenylpropyl) -phenyl glycinamide trifluoroacetate in a yield of 65% of the theory. Colorless crystals of mp. 135-138 ° C (Z.) and R _f 0.95 (variant A) and 0.32 (variant C).
IR (CH ₂ Cl ₂ ): 1663 (Ester-CO) cm ^-1
MS: (M + H) ⁺ = 712

Example 13 (S) -N ² - [[1- [2- [4- (Diphenylmethyl) -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -N- (3-phenylpropyl) -phenylglycine amide

Prepared analogously to Example 2e) from 1- [2- [4- (diphenylmethyl) -1-piperazinyl] -2-oxoethyl] cyclopentaneacetic acid and (S) -N- (3-phenylpropyl) -phenylglycine amide trifluoroacetate in a yield of 70% the theory. Colorless, amorphous substance of R _f 0.46 (variant B).
IR (CH ₂ Cl ₂ ): 1668 (amide CO) cm ^-1
MS: M⁺ = 670

Example 14 (S) -N ² - [[1- [2- [4 - [[5, 10-dihydro-11 (10H) -oxodibenzo [b, e] [1,4] diazepin-5-yl] carbonyl] - 1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -N- (3-phenylpropyl) -phenylglycine amide

Prepared analogously to Example 2e) from 1- [2- [4 - [[5,10-dihydro-11 (10H) -oxodibenzo [b, e] [1,4] diazepin-5-yl] -1-piperazinyl] - 2-oxoethyl] cyclopentaneacetic acid and (5) -N- (3-phenylpropyl) phenylglycine amide trifluoroacetate in a yield of 35% of theory. Colorless, amorphous substance of R _f 0.14 (variant B) or 0.29 (variant C).
IR (CH ₂ Cl ₂ ): 3430, 3380 (NH), 1665 (amide CO) cm ^-1
MS: (M + H) ⁺ = 741

Example 15 3- [4- (aminoiminomethyl) phenyl] -N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1 -piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] alanine methyl ester hydrochloride

Prepared analogously to Example 1c) from 3- (4-cyanophenyl) -N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl ] -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] alanine methyl ester in a yield of 67% of theory. Colorless crystals of mp. 212-216 ° C and R _f 0.63 (variant A).
IR (KBr): 1650 (broad, amide CO) cm ^-1
MS: (M + H) ⁺ = 665

Example 16 (R, S) -3- (4-cyanophenyl) -N ² - [[1- [2- [4- (diphenylmethyl) -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -N- [3 [4- (di phenylmethyl) -1-piperazinyl] propyl] alaninamide a) 3- [4- (diphenylmethyl) -1-piperazinyl] propanamine

The mixture of 25.2 g (99.86 mmol) of 1- (diphenylmethyl) -pipera zinc, 33.0 g (150.7 mmol) of 3-bromopropanamine hydrobromide, 41.5 g (300.3 mmol) of potassium carbonate and 500 ml of acetone was stirred refluxed for 2 days. The resulting mixture was filtered and freed from the solvent in vacuo. The residue was taken up in 300 ml of ethyl acetate, washed twice with washed 100 ml of water, dried over sodium sulfate and again brought to dryness in vacuo. The crude product obtained silica gel (MN Kiesel 60, 0.063-0.2 mm, 70- 230 mesh ASTM) using column chromatography initially ethyl acetate / methanol / conc. aqueous ammonia 90/10/1 (v / v / v), then ethyl acetate / metha nol / conc. aqueous ammonia 70/30/3 (v / v / v) for elution cleaned. This gave 25.0 g (81% of theory) of a color loose, high-viscosity oil, the waxy after prolonged standing froze.

b) (R, S) -N ² - (tert -butoxycarbonyl) -3- (4-cyanophenyl) -N- [3- [4- (diphenylmethyl) -1-piperazinyl] propyl] alaninamide

Prepared analogously to Example 12a) from (R, S) -N ² - (tert.butoxycarbonyl) -3- (4-cyanophenyl) alanine and 3- [4- (diphenylmethyl) -1-piperazinyl] propanamine in a yield of 23% of theory. Colorless crystals of mp. 135-137 ° C (diisopropyl ether).
IR (CH ₂ Cl ₂ ): 2230 (C~N), 1715 (ester CO), 1675 (amide C = O) cm ^-1
MS: M⁺ = 581

c) (R, S) -3- (4-cyanophenyl) -N- [3- [4- (diphenylmethyl) -1-pipera zinyl] propyl] alaninamide trifluoroacetate

Prepared analogously to Example 2f) from (R, S) -N ² - (tert-butoxycarbonyl) -3- (4-cyclophenyl) -N- [3- [4- (diphenylmethyl) -1-piperazinyl] propyl] - alaninamide and trifluoroacetic acid in a yield of 98% of theory. Colorless, when triturating with diisopropyl ether crystallizing substance.
IR (CH ₂ Cl ₂ ): 2230 (C~N), 1665 (amide C = O) cm ^-1 ; Salt gangs.
MS: M⁺ = 481

d) (R, S) -3- (4-cyanophenyl) -N ² - [[1- [2- [4- (diphenylmethyl) -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -N- [ 3- [4- (diphenylmethyl) -1-piperazinyl] propyl] alaninamide

Prepared analogously to Example 1b), but with addition of triethylamine to the reaction mixture, from 1- [2- [4- (diphenylmethyl) -1-piperazinyl] -2-oxoethyl] cyclopentaneacetic acid and (R, S) -3- (4- Cyanophenyl) -N- [3- [4- (diphenylmethyl) -1-piperazinyl] propyl] alanine amide trifluoroacetate in a yield of 56% of theory. Colorless, on trituration with diisopropyl ether crystallizing substance of R _f 0.67 (variant A).
IR (CH ₂ Cl ₂ : 2230 (C~N), 1662 (amide CO) cm ^-1
MS: M⁺ = 883

Example 17 3- (4-cyanophenyl) -N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] 2-oxoethyl] cyclopentyl] acetyl] -N- [3- [4- (diphenylmethyl) -i-piperazinyl] propyl] alaninamide

Prepared analogously to Example 16d) from (R, S) -1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] - 2-oxoethyl] cyclopentaneacetic acid and (R, S) -3- (4-cyanophenyl) - N - [3- [4- (diphenylmethyl) -1-piperazinyl] propyl] alanine amide trifluoroacetate in a 51% yield of theory. Farblo se, on trituration with diisopropyl ether crystallizing substance of R _f 0.67 (variant A).
IR (CH ₂ Cl ₂ ): 2230 (C~N), 1660 (amide CO) cm ^-1
MS: M ⁺ = 924

Example 18 (R, S) -3- (4-cyanophenyl) -N- [3- [4- (diphenylmethyl) -1-piperazinyl] propyl] -N ² - [[1- [2- (4-methyl-1-) piperazinyl) -2-oxoethyl] cyclopentyl] acetyl] alaninamide a) 1- [2- (4-methyl-1-piperazinyl) -2-oxoethyl] cyclopentane acetic acid acid

Prepared analogously to Example 1a) from 1-methylpiperazine and 1,1-cyclopentanediacetic anhydride in 79% yield the theory. Colorless crystals of mp. 107 ° C (Diisopropyl ether).

b) (R, S) -3- (4-Cyanophenyl) -N- [3- [4- (diphenylmethyl) -1-piperazinyl] propyl] -N ² - [[1- [2- (4-methyl 1-piperazinyl) -2-oxoethyl] cyclopentyl] acetyl] alaninamide

Prepared analogously to Example 16d) from 1- [2- (4-methyl-1-piperazinyl) -2-oxoethyl] cyclopentaneacetic acid and (R, S) -3- (4-cyano phenyl) -N- [3- [4 - (diphenylmethyl) -1-piperazinyl] propyl] -alanine amide trifluoroacetate in a yield of 42% of theory. Colorless, highly viscous oil of R _f 0.16 (variant A).
IR (CH ₂ Cl ₂ ): 2230 (C~N), 1670 (amide CO) cm ^-1
MS: (M⁺H) ⁺ = 732

Example 19 (R, S) -N- [4- (aminoiminomethyl) phenyl] -1- [2- [4- [5,11-dihydro- 6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] -2-oxoethyl] - cyclopentanacetamid hydrochloride a) (R, S) -N- (4-cyanophenyl) -1- [2- [4- [5,11-dihydro-6 (6H) -oxo dibenz [b, e] azepin-11-yl] -1-piperazinyl] -2-oxoethyl] cyclopentanacetamid

Prepared analogously to Example 1b) from (R, S) -1- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] piperazine and 1- [2 - [(4-cyano phenyl) amino] -2-oxoethyl] cyclopentaneacetic acid in a yield of 52% of theory. Colorless crystals of mp. <90 ° C (Z.) (diisopropyl ether).
IR (CH ₂ Cl ₂ ): 2225 (C~N), 1695, 1660 (amide CO) cm ^-1
MS: M⁺ = 561

b) (R, S) -N- [4- (aminoiminomethyl) phenyl] -1- [2- [4- [5,11-dihydro- 6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] -2-oxo ethyl] cyclopentanacetamid hydrochloride

Prepared analogously to Example 1c) from (R, S) -N- (4-cyanophenyl) -1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepine-11- yl] -1-piperazinyl] -2-oxoethyl] cyclopentanacetamide in a yield of 49% of theory. Colorless crystals of mp. <200 ° C (Z.) and R _f 0.67 (variant A).
IR (KBr): 1650 (broad, amide CO) cm ^-1 ; Salt gangs.
MS: (M + H) ⁺ = 579

Example 20 , S) -N - [[4- (aminoiminomethyl) phenyl] methyl] -1- [2- [4- [5,11 dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] -2- oxoethyl] -N- (3-phenylpropyl) -cyclopentanacetamid hydrochloride a) N - [(4-cyanophenyl) methyl] benzenepropanamine hydrochloride

To the mixture of 45.9 g (0.339 mol) of benzenepropanamine, 30.0 g (0.175 mol) of benzenepropanamine hydrochloride, 6.7 g (0.101 mol) of 95% sodium cyanoborohydride and 500 ml of methanol was added dropwise within 1 hour, the solution of 22.5 g (0.172 mol) of 4-Cybenzaldehyde in 200 ml of methanol. After stirring at room temperature for 4 days, the reaction mixture was quenched by the addition of conc. aqueous hydrochloric acid to pH 1 and then freed from the solvent in vacuo. The residue was triturated with diisopropyl ether, isopropanol (95/5, v / v), filtered with suction, the crystal pulp and dried in vacuo. This gave 34.24 g (69% of theory) of colorless crystals of mp. <200 ° C.
IR (KBr): 2240 (C~N), cm ^-1

b) (R, S) -N - [(4-cyanophenyl) methyl] -1- [2- [4- [5,11-dihydro-6 (6H) - oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] -2-oxoethyl] -N- (3-phenylpropyl) -cyclopentanacetamid

Prepared analogously to Example 12a) from 1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] -2-oxoethyl] cyclopentaneacetic acid and N - [(4-cyanophenyl) methyl] benzene propane in a yield of 54% of theory. Colorless, amor phe substance.
IR (CH ₂ Cl ₂ ): 3383 (N~H), 2230 (C~N), 1650 (amide CO) cm ^-1
MS: M⁺ = 693

c) (R, S) -N - [[4- (aminoiminomethyl) phenyl] methyl] -1- [2- [4- [5,11- dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] - 2-oxoethyl] -N- (3-phenylpropyl) -cyclopentanacetamid hydrochloride chloride

Prepared analogously to Example 1c) from (R, S) -N - [(4-cyanophenyl) phenyl] methyl] -1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] -2-oxoethyl] -N- (3-phenylpropyl) -cyclopentanacetamide in a yield of 59% of theory. Colorless crystals of R _f 0.70 (variant A)
IR (CH ₂ Cl ₂ ): 1645 (amide CO) cm ^-1 ; Salt gangs.
MS: (M + H) ⁺ = 711

Example 21 N - [[4- (aminoiminomethyl) phenyl] methyl] -1- [2- [4- (diphenyl methyl) -1-piperazinyl] -2-oxoethyl] -N- (3-phenylpropyl) -cyclo pentanacetamid a) N - [(4-cyanophenyl) methyl] -1- [2- [4- (diphenylmethyl) -1-pipera zinyl] -2-oxoethyl] -N- (3-phenylpropyl) -cyclopentanacetamid

Prepared analogously to Example 12a) from 1- [2- [4- (diphenylmethyl) -1-piperazinyl] -2-oxoethyl] cyclopentaneacetic acid and N - [(4-cyanophenyl) methyl] benzenepropanamine in a yield of 34% of theory. Colorless, highly viscous oil.
IR (CH ₂ Cl ₂ ): 2230 (amide C~N), 1645 (amide CO) cm ^-1

b) N - [[4- (aminoiminomethyl) phenyl] methyl] -1- [2- [4- (diphenylme thyl) -1-piperazinyl] -2-oxoethyl] -N- (3-phenylpropyl) -cyclo pentanacetamid

Prepared analogously to Example 1c) from N - [(4-cyanophenyl) methyl] -1- [2- [4- (diphenylmethyl) -1-piperazinyl] -2-oxoethyl] -N- (3-phenylpropyl) cyclopentaneacetamide a yield of 23% of theory. Colorless crystals of R _f 0.70 (variant A).
IR (CH ₂ Cl ₂ ): 1683 (amidinium), 1645, 1620 (amide CO) cm ^-1 ; Salt tied.
MS: (M + H) ⁺ = 670

Example 22 (R, S) -3- [4- (aminoiminomethyl) phenyl] -N ² - [[1- [2- [4- (diphenylmethyl) -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -N - [3- [4- (diphenylmethyl) -1-piperazinyl] propyl] alanine amide hydrochloride

Prepared analogously to Example 1c) from (R, S) -3- (4- (cyanophenyl) -N ² - [[1- [2- [4- (diphenylmethyl) -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -N- [3- [4- (diphenylmethyl) -1-piperazinyl] propyl] alaninamide in a yield of 4% of theory Colorless, amorphous substance of R _f 0.42 (variant A).
MS: (M + H) ⁺ = 921

Example 23 (R, S) -3- [4- (aminoiminomethyl) phenyl] - N - [3- [4- (diphenylmethyl) -1-piperazinyl] -propyl] -N ² - [[1- [2- (4- methyl-1-piperazinyl) -2-oxoethyl] cyclopentyl] acetyl] alanine amide hydrochloride

Prepared analogously to Example 1c) from (R, S) -3- (4-cyanophenyl)] - N- [3- [4- (diphenylmethyl) -1-piperazinyl] -propyl] -N ² - [[1- [2 - (4-methyl-1-piperazinyl) -2-oxoethyl] cyclopentyl] acetyl] -alanineamide in a yield of 58% of theory. Colorless, amorphous substance of R _f 0.05 (variant A).
IR (CH ₂ Cl ₂ ): 1675, 1655 (amide CO) cm ^-1 ; Salt gangs.
MS: (M + H) ⁺ = 749

Example 24 (R, S) -N ² - [(4- (cyanophenyl) methyl] -N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -glycine methyl ester

• a) N ² - [(4-cyanophenyl) methyl] glycine methyl ester hydrochloride

Prepared analogously to Example 20a) from 4-cyanobenzaldehyde, glycine methyl ester hydrochloride and sodium cyanoborohydride in a yield of 66% of theory. Colorless crystals of mp. <180 ° C (Z.).
IR (KBr): salt bands 2235 (C~N), 1750 (ester-CO) cm ^-1

b) N ² - [[1- (carboxymethyl) cyclopentyl] acetyl] -N ² - [(4-cyanophenyl) methyl] glycine methyl ester

Prepared analogously to Example 1a) from N ² - [(4-cyanophenyl) methyl] glycine methyl ester and 1,1-cyclopentanediacetic anhydride in a yield of 63% of theory. Colorless crystals that have been processed without complete purification.

c) (R, S) -N ² - [(4-cyanophenyl) methyl] -N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e ] azepin-11-yl] -1-piperazinyl] -2-oxo-ethyl] cyclopentyl] -acetyl] -glycine methyl ester

Prepared analogously to Example 1b) from (R, S) -1- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] piperazine and N ² - [[1- (carboxymethyl ) cyclopentyl] acetyl] -N ² - [(4-cyanophenyl) methyl] -glycine methyl ester in a yield of 57% of theory. Colorless crystals of mp <120 ° C (Z.) and R _f 0.18 (variant B) and 0.35 (variant C).
IR (CH ₂ Cl ₂ ): 3385 (NH), 2230 (C~N), 1753 (ester CO), 1660 (amide CO) cm ^-1
MS: M⁺ = 647

Example 25 (R, S) -N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] -2 -oxoethyl] cyclopentyl] acetyl] glycine a) (R, S) -N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] 2-oxoethyl] cyclopentyl] acetyl] -glycine methyl ester

Prepared analogously to Example 16d) from (R, S) -1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] 2-oxo-ethyl] cyclopentaneacetic acid and glycine methyl ester hydrochloride in 63% yield. Colorless crystals (diisopropyl ether).
IR (CH ₂ Cl ₂ ): 2225 (C~N), 1735 (ester CO), 1685 (amide CO) cm ^-1
MS: M⁺ = 532

b) (R, S) -N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] 2-oxoethyl] cyclopentyl] acetyl] -glycine

The solution of 2.6 g (4.88 mmol) of (R, S) -N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] -azepin-11-yl] -1-piperazinyl] -2-oxoethyl] cyclopentyl] -acetyl] -glycine methyl ester in 20 ml of Me methanol was treated with 5.5 ml (5.5 mmol) of a 1N aqueous sodium hydroxide solution and 2 hours stirred at room temperature. It was acidified with 5.5 ml (5.5 mmol) of 1N hydrochloric acid, the batch was diluted with water to a total volume of 200 ml and then extracted with three times 50 ml of ethyl acetate each time. The combined ethyl acetate extracts were washed once with 50 ml of egg ner saturated saline solution, dried over sodium sulfate and evaporated in vacuo. The remaining residue was chromatographed on silica gel (MN Kieselgel 60, 0.063-0.2 mm, 70-230 mesh ASTM) using initially ethyl acetate, then ethyl acetate / methanol 8/2 (v / v) chromatographically, finally from diisopropyl ether once crystallized around. This gave colorless crystals of melting point 103 ° -105 ° C. and R _f 0.88 (variant A) or 0.26 (variant D) in a yield of 630 mg (25% of theory).
IR (CH ₂ Cl ₂ ): salt bands 3380 (NH), 1730 (CO ₂ H), 1660, 1635 (amide CO) cm ^-1
MS: (M + H) ⁺ = 519

Example 26 (R, S) -N- (4-cyanophenyl) -1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [B, e] azepin-11-yl] -1-piperazinyl] -2-oxoethyl] -N- (3-phenylpro pyl) -cyclopentanacetamid a) N- (4-cyanophenyl) -benzenepropanamine

The mixture of 10.0 g (82.57 mmol) of 4-fluorobenzonitrile, 34.62 g (0.251 mol) of 98% benzenepropanamine and 120 ml of aceto nitrile was refluxed for 24 hours. The ice cold Reaction mixture was filtered and the filtrate in vacuo from Solvent free. The residue was dissolved in 300 ml of acetic acid ethyl ester, twice with 100 ml of 2N hydrochloric acid and shaken out once with 50 ml of water, ge over sodium sulfate dried and evaporated again in vacuo. The residue became triturated with diisopropyl ether / petroleum ether (1/1, v / v), abge Nutscht and dried at room temperature. Yield of colorlo crystals: 4.9 g (25% of theory).

b) 1- (carboxymethyl) -N- (4-cyanophenyl) -N- (3-phenylpropyl) - cyclopentanacetamid

Prepared analogously to Example 1a) from N- (4-cyanophenyl) -benzene propanamine and 1,1-cyclopentanediacetic anhydride in one Yield of 40% of theory. Colorless crystals without Cleaning were processed further.  

c) (R, S) -N- (4-cyanophenyl) -1- [2- [4- [5,11-dihydro-6 (6H) -oxo dibenz [b, e] azepin-11-yl] -1-piperazinyl] -2-oxoethyl] -N- (3-phenylpropyl) -cyclopentanacetamid

Prepared analogously to Example 1b) from 1- (carboxymethyl) -N- (4-cyanophenyl) -N- (3-phenylpropyl) -cyclopentanacetamide and 1- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] piperazine in 44% yield. Colorless crystals of R _f 0.29 (variant B).
IR (CH ₂ Cl ₂ ): 3380 (NH), 2230 (C~N), 1660 (amide CO) cm ^-1
MS: (M + H) ⁺ = 680

Example 27 (R, S) -N ² - [(4-cyanophenyl) methyl] -N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepine -11-yl] -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -glycine

Prepared analogously to Example 25b) from (R, S) -N ² - [(4-cyanophenyl) -methyl] -N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) - oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -glycine methyl ester in a yield of 84% of theory. Colorless crystals of mp. 150-153 ° C and R _f 0.92 (variant A) and 0.37 (variant D).
IR (CH ₂ Cl ₂ ): salt bands, 3380 (NH), 2225 (C~N), 1710 (carboxylic acid-CO), 1655, 1630 (amide-CO) cm ^-1
MS: (M⁺H) ⁺ = 634

Example 28 N - [[- 4- (aminoiminomethyl) phenyl] methyl] -1- [2- [4- (diphenyl methyl) -1-piperazinyl] -2-oxoethyl] -N- (2-phenylethyl) -cyclo pentanacetamid hydrochloride a) N - [(4-cyanophenyl) methyl] benzeneethanamine hydrochloride

Prepared analogously to Example 20a) from 4-cyanobenzaldehyde, benzene ethanamine hydrochloride and sodium cyanoborohydride in a prey of 72% of theory. Colorless crystals.
IR (KBr): 2245 (C~N) cm ^-1

b) N - [(4-cyanophenyl) methyl] -1- [2- [4- (diphenylmethyl) -1 -pipe razinyl] -2-oxoethyl] -N- (2-phenylethyl) -cyclopentanacetamid

Prepared analogously to Example 1b), but using tetrahydrofuran / dimethylformamide 5/2 (v / v) as solvent in place of dimethylformamide, from 1- [4- (diphenylmethyl) -1-piperazinyl] -2-oxoethyl] cyclopentanacetic acid and N - [(4-cyanophenyl) methyl] -benzenethanamine in a yield of 61% of theory. Colorless, amorphous substance.
IR (CH ₂ Cl ₂ ): 2230 (C~N), 1645 (amide CO) cm ^-1

c) N - [[4- (aminoiminomethyl) phenyl] methyl] -1- [2- [4- (diphenyl methyl) -1-piperazinyl] -2-oxoethyl] -N- (2-phenylethyl) -cyclo pentanacetamid hydrochloride

Prepared analogously to Example 1c) from N - [(4-cyanophenyl) methyl] -1- [2- [4- (diphenylmethyl) -1-piperazinyl] -2-oxoethyl] -N- (2-phenylethyl) cyclopentaneacetamide a yield of 59% of theory. Colorless crystals of mp. <140 ° C and R _f 0.73 (variants A).
IR (CH ₂ Cl ₂ ): 1680 (amidinium), 1645, 1615 (amide CO) cm ^-1
MS: (M + H) ⁺ = 656

Example 29 3- (4-cyanophenyl) -N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl ] -2-oxoethyl] cyclopentyl] acetyl] -N- [2- [1,2-dihydro-3,5 (4H) -dioxo-1,2-diphenyl-3H-1,2,4-triazole-4] yl] ethyl] alaninamide a) 1,2-diphenylurazole

The mixture of 50 g (0.38 mol) of ethyl allophanate and 76.6 g (0.42 mol) of 1,2-diphenylhydrazine was heated to 100 ° C. The obtained melt was at this temperature for 30 minutes leave and then after addition of 100 ml of xylene for 6 hours Reflux cooked. The solvent was distilled off, took the Residue again in 150 ml of xylene and allowed to boil briefly. The precipitated after cooling crystals were abge Nutscht, washed with cold xylene and ge in vacuo at 50 ° dries. This gave 60.0 g (62% of theory) of pale yellow ge colored crystals of mp. 216-218 ° C.

b) 4- [2 - [[(tert -butoxycarbonyl) amino] ethyl] -1,2-dihydro-1,2- diphenyl-3H-1,2,4-triazol-3,5 (4H) -dione

The mixture of 61.3 g (242 mmol) of 1,2-diphenylurazole, 17.6 g (267 mmol) of powdered 85% potassium hydroxide and 400 ml of free dimethylformamide was stirred for 1 hour at room temperature. After addition of 59.6 g (266 mmol) of 1-bromo-2 - [(tert-butoxydarbonyl) amino] ethane was stirred for a further 12 hours at room temperature. Then the reaction mixture was diluted with 2 l of water, the precipitate was filtered off with suction and taken up in 300 ml of ethyl acetate. The ethyl acetate solution was washed twice with 100 ml of water, dried over Natriumsul fat and evaporated. This gave 38.0 g (40% of theory) of colorless crystals, mp. 155-157 ° C.
IR (CH ₂ Cl ₂ ): 1785 (five-membered CO), 1730 (ester-CO) cm ^-1
MS: M⁺ = 396

c) 4- (2-aminoethyl) -1,2-dihydro-1,2-diphenyl-3H-1,2,4-tria zol-3,5 (4H) -dione trifluoroacetate

Prepared analogously to Example 2f) from 4- [2 - [[(tert.Butoxycar bonyl) amino] ethyl] -1,2-dihydro-1,2-diphenyl-3H-1,2,4-triazole 3,5 (4H) -dione and trifluoroacetic acid in quantitative yield. After trituration with diisopropyl ether / tert-butanol (95/5, v / v) obtained colorless crystals of mp. <85 ° C (Z.) were used without further purification in the following stage.

d) (R, S) -N ² - (tert -butoxycarbonyl) -3- (4-cyanophenyl) -N- [2- [1,2-dihydro-3,5 (4H) -dioxo-1,2- diphenyl-3H-1,2,4-triazol-4-yl] ethyl] alaninamide

Prepared analogously to Example 16d) from (R, S) -N ² - (tert.butoxycarbonyl) -3- (4-cyanophenyl) alanine and 4- (2-aminoethyl) -1,2-dihy dro-1,2 -diphenyl-3H-1,2,4-triazole-3,5 (4H) -dione trifluoroacetate in a yield of 70% of theory. Colorless crystals of mp. 204-207 ° C (methanol).
IR (KBr): 3350 (NH), 2225 (C~N), 1790, (five-membered CO), 1730 (ester-CO), 1680, 1660 (amide-CO) cm- ¹
MS: M⁺ = 568

e) (R, S) -3- (4-cyanophenyl) -N- [2- [1,2-dihydro-3,5 (4H) -dioxo] 1,2-diphenyl-3H-1,2,4-triazol-4-yl] ethyl] alaninamide trifluoroacetate

Prepared analogously to Example 2f) from (R, S) -N ² - (tert-butoxycarbonyl) -3- (4-cyanophenyl) -N- [2- [1,2-dihydro-3,5 (4H) -dioxo -1,2-diphenyl-3H-1,2,4-triazol-4-yl] ethyl] alaninamide and trifluoroacetic acid in quantitative yield. Colorless crystals of mp. 183-187 ° C (after trituration with diisopropyl ether and tert-butyl methyl ether).
IR (KBr): salt bands, 2230 (C~N), 1780 (five-membered CO), 1730 (CO) cm ^-1

f) 3- (4-cyanophenyl) -N ² - [11- [2- [4- [5,11-dihydro-6 (6H) -oxodi benz [b, e] azepin-11-yl] -1- piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -N- [2- [1,2-dihydro-3,5 (4H) -dioxo-1,2-di-phenyl-3H-1,2,4- triazol-4-yl] ethyl] alaninamide

Prepared analogously to Example 2e), but using triethylamine instead of 4-ethylmorpholine, from 1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepine-11- yl] -1-piperazinyl] -2-oxoethyl] cyclopentaneacetic acid and (R, S) -3- (4-cyanophenyl) -N- [2- [1,2-dihydro-3,5 (4H) -dioxo-1 , 2-diphenyl-3H-1,2,4-triazol-4-yl] ethyl] alanine amide trifluoroacetate in a yield of 77% of theory. Colorless crystals of mp. 163-166 ° C and R _f 0.05 (variant B) and 0.21 (variant C)
IR (CH ₂ Cl ₂ ): 2225 (C~N), 1780, 1730 (five-membered CC), 1665, 1610 (amide-CO) cm ^-1
MS: (M + H) ⁺ = 912

Example 30 (R, S) -3- (4-cyanophenyl) -N ² - [[1- [2- [4- (diphenylmethyl) -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -N- [2 - [1,2-dihydro-3,5 (4H) -dioxo-1,2-diphenyl-3H-1,2,4-triazol-4-yl] -ethyl] -aluminamide

Prepared analogously to Example 29f) from 1- [2- [4- (diphenylmethyl) -1-piperazinyl] -2-oxoethyl] cyclopentaneacetic acid and (R, S) -3- (4-cyanophenyl) -N- [2- [1 , 2-dihydro-3,5 (4H) -dioxo-1,2-diphenyl-3H-1,2,4-triazol-4-yl] -ethyl] -alaninamide trifluoroacetate in 67% of theory yield. Colorless crystals of mp. 112-114 ° C (Z.) and R _f 0.25 (variant B).
IR (CH ₂ Cl ₂ ): 2220 (C~N), 1780, 1725 (five-membered CO), 1675, 1610 (amide-CO) cm ^-1
MS: M⁺ = 870

Example 31 3- [4- (aminoiminomethyl) phenyl] -N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1 -piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] - N - [2- [1,2-dihydro-3,5 (4H) -dioxo-1,2-diphenyl-3H-1,2,4-triazole 4-yl] ethyl] alanine amide hydrochloride

Prepared analogously to Example 1c) from 3- (4-cyanophenyl) -N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl ] -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -N- [2- [1,2-dihydro-3,5 (4H) dioxo-1,2-diphenyl-3H-1,2,4 -triazol-4-yl] ethyl] -aluminamide in a yield of 68% of theory. Colorless amorphous substance of R _f 0.69 (variant A).
IR (KBr): Salzbanden, 1780, 1723 (five-membered CO), 1645 (amide-CO) cm ^-1
MS: (M + H) ⁺ = 929

Example 32 (R, S) -3- [4- (aminoiminomethyl) phenyl] -N ² - [[1- [2- [4- (diphenylmethyl) -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -N - [2- [1,2-dihydro-3,5 (4H) -dioxo-1,2-diphenyl-3H-1,2,4-triazol-4-yl] ethyl] alanine amide hydrochloride

Prepared analogously to Example 1c) from (R, S) -3- (4-cyanophenyl) -N ² - [[1- [2- [4- (diphenylmethyl) -1-piperazinyl] -2-oxoethyl] cyclopentyl] - acetyl] - N - [2- [1,2-dihydro-3,5 (4H) -dioxo-1,2-diphenyl-3H-1,2,4-triazol-4-yl] ethyl] alanine amide in one Yield of 71% of theory. Colorless, amorphous substance of R _f 0.69 (variant A).
IR (CH ₂ Cl ₂ ): salt bands, 1785, 1725 (5-ring CO), 1640, 1605 (amide CO) cm ^-1 .
MS: (M + H) ⁺ = 888

Example 33 N ² - [(4-cyanophenyl) methyl] -N ² - [[1- [2- [4- (diphenylmethyl) -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -N-glycinamide a) N ² - [(4-cyanophenyl) methyl] -N ² - [[1- [2- [4- (diphenylmethyl) -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -N-glycine methyl ester

Prepared analogously to Example 1b) from 1- (diphenylmethyl) piperazine and N ² - [[1- (carboxymethyl) cyclopentyl] acetyl] -N ² - [(4-cyanophenyl) methyl] glycine methyl ester in a yield of 75% of Theory. Colorless, highly viscous oil.
IR (CH ₂ Cl ₂ ): 2230 (C~N), 1755, 1740 (ester CO), 1650 (amide CO) cm ^-1
MS: M⁺ = 606

b) N ² - [(4-Cyanophenyl) methyl] -N ² - [[1- [2- [4- (diphenylmethyl) -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] glycine

Prepared analogously to Example 25b) from N ² - [(4-cyanophenyl) methyl] - N ² - [[1- [2- [4- (diphenylmethyl) -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] - Glycinmethylester in a yield of 55% of theory. Colorless crystals of mp <110 ° C (Z.) (diisopropyl ether).
IR (CH ₂ Cl ₂ ): 2230 (C~N), 1650 (amide CO) cm ^-1

c) N ² - [(4-cyanophenyl) methyl] -N ² - [[1- [2- [4- (diphenylmethyl) -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -N- [3 [4- (diphenylmethyl) -1-piperazinyl-propyl] -glycinamide

Prepared analogously to Example 1b) from N ² - [(4-cyanophenyl) methyl] - N ² - [[1- [2- [4- (diphenylmethyl) -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] - glycine and 3- [4- (diphenylmethyl) -1-piperazinyl] propanamine in a yield of 22% of theory. Colorless crystals of mp. <88 ° C (Z.) (diisopropyl ether) and R _f 0.67 (variant A).
IR (CH ₂ Cl ₂ ): 2225 (C~N), 1660, 1615 (amide CO) cm ^-1
MS: M⁺ = 883

Example 34 (R, S) -N ² - [(4-cyanophenyl) methyl] -N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepine -11-yl] -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] - N - [3- [4- (diphenylmethyl) -1-piperazinyl] propyl] -glycinamide

Prepared analogously to Example 1b) from (R, S) -N ² - [(4-cyanophenyl) methyl] -N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -glycine and 3- [4- (diphenylmethyl) -1-piperazinyl] propanamine in a yield of 16% of the Theory. Colorless crystals of mp. <122 ° C (Z.) and R _f 0.67 (variant A)
IR (CH ₂ Cl ₂ ): 3380, 3310 (NH), 2810 (N-alkyl), 2225 (C~N), 1660, 1615 (amide-CO) cm ^-1
MS: (M + H) ⁺ = 925

Example 35 (R, S) -N ² - [(4-cyanophenyl) methyl] -N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepine -11-yl] -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -N- (3-phenylpropyl) -glycinamide

Prepared analogously to Example 1b) from (R, S) -N ² - [(4-cyanophenyl) methyl] -N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -glycine and benzenepropanamine in a yield of 71% of theory. Colorless crystals of mp <107 ° C (Z.) and R _f 0.15 (variant B) or 0.29 (variant C).
IR (CH ₂ Cl ₂ ): 3380, 3320 (NH), 2805 (N-alkyl), 2225 (C~N), 1660, 1615 (amide-CO) cm ^-1
MS: (N + H) ⁺ = 751

Example 36 N ² - [(4-cyanophenyl) -methyl] -N ² - [[1- [2- [4- (diphenylmethyl) -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -N- [2- [ 1,2-dihydro-3,5 (4H) -dioxo-1,2-diphenyl-3H-1,2,4-triazol-4-yl] ethyl] -glycinamide

Prepared analogously to Example 16d) from N ² - [(4-cyanophenyl) methyl] -N ² - [[1- [2- [4- (diphenylmethyl) -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl ] -glycine and 4- (2-aminoethyl) -1,2-dihydro-1,2-diphenyl-3H-1,2,4-triazole-3,5- (4H) -dione trifluoroacetate in a yield of 50% of the theory. Colorless crystals of mp <85 ° C (Z.) (diisopropyl ether) and R _f 0.41 (variant B).
IR (CH ₂ Cl ₂ ): 3300 (NH), 2225 (C~N), 1780, 1727 (five-ring CO) 1660, 1612 (amide CO) cm ^-1
MS: M⁺ = 870

Example 37 3- (4-cyanophenyl) -N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] 2-oxoethyl] cyclopentyl] acetyl] -N- (2-hydroxyethyl) alanine amide a) (R, S) -N ² - (tert -butoxycarbonyl) -3- (4-cyanophenyl) -N- (2-hydroxyethyl) alaninamide

Prepared analogously to Example 1b) from (R, S) -N ² - (tert.butoxycarbonyl) -3- (4-cyanophenyl) alanine and ethanolamine in a yield of 88% of theory. Colorless crystals of mp. 125-128 ° C.
IR (CH ₂ Cl ₂ ): 3615 (OH), 3430 (NH), 2230 (C~N), 1710 (ester CO), 1675 (amide CO) cm ^-1

b) (R, S) -3- (4-cyanophenyl) -N- (2-hydroxyethyl) alanine amide tri trifluoroacetate

Prepared analogously to Example 2f) from (R, S) -N ² - (tert-butoxycarbonyl) -3- (4-cycanphenyl) -N- (2-hydroxyethyl) alanineamide and trifluoroacetic acid in a yield of 60% of theory. Colorless, amorphous substance, which was further processed without purification.
IR (KBr): salt bands, 2230 (C~N), 1670 (broad, amide-CO + trifluoroacetate), 1200, 1135, 1065 (CF ₃ ) cm ^-1
MS: (M + H) ⁺ = 234

c) 3- (4-cyanophenyl) -N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodi benz [b, e] azepin-11-yl] 1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -N- (2-hydroxyethyl) alaninamide

Prepared analogously to Example 29f) from 1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] -2-oxoethyl] cyclopentaneacetic acid and (R, S) -3- (4-cyanophenyl) -N- (2-hydroxyethyl) alanine amide trifluoroacetate in 16% yield of theory. Colorless, amorphous substance of R _f 0.12 (variant B) or 0.26 (variant D).
IR (CH ₂ Cl ₂ ): 2225 (C~N), 1600, 1610 (amide CO) cm ^-1
MS: (M + H) ⁺ = 677

Example 38 (R, S) -3- (4-Cyanophenyl) -N ² - [[1- [2- [4- (diphenylmethyl) -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -N- (2 -hydroxyethyl) -aluminamide

Prepared analogously to Example 16d) from 1- [2- [4- (diphenylmethyl) -1-piperazinyl] -2-oxoethyl] cyclopentaneacetic acid and (R, S) -3- (4-cyanophenyl) -N- (2-hydroxyethyl) alanine amide trifluoroacetate in a yield of 42% of theory. Colorless crystals of mp. 87-91 ° C (Z.) and R _f 0.05 (variant B) and 0.39 (variant D).
IR (CH ₂ Cl ₂ ): 3605 (OH), 3430 (NH), 2810 (N-alkyl), 2230 (C~N) 1670, 1610 (amide-CO) cm ^-1
MS: M⁺ = 635

Example 39 (R, S) -3- (4-Amino-3,5-dibromophenyl) -N ² - [[1- [2- [4- (diphenylmethyl) -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl ] -N- (3-phenylpropyl) alanine amide a) (R, S) -3- (4-amino-3,5-dibromophenyl) -N ² - (tert.butoxycarbonyl) -alanine

To the ice-cold suspension of 20.3 g (60.06 mmol) of (R, S) -3- (4-amino-3,5-dibromophenyl) alanine in 345 ml dioxane / water (2/1, v / v ) were successively added dropwise 6.1 g (60.28 mmol) of triethylamine and the solution of 14.2 g (65.06 mmol) of di-tert-butyl dicarbonate in 10 ml of dioxane, wherein a reaction temperature of 0 to + 5 ° C. einhielt. The mixture was then stirred overnight at room temperature, the dioxane was distilled off in vacuo, the residue was taken up in 200 ml of water and the mixture was brought to a pH between 2 and 3 by addition of solid potassium hydrogen sulfate. The mixture was extracted exhaustively with ethyl acetate and the combined extracts were extracted Extracts over sodium sulfate, the solution was clarified with activated charcoal and evaporated in vacuo. The residue was triturated thoroughly with 50 ml of ether / petroleum ether (1: 9, v / v), filtered off with suction and dried in vacuo. This gave 21.7 g (82% of theory) of colorless crystals of mp. 110-113 ° C.
IR (CH ₂ Cl ₂ ): 3480, 3435, 3385 (NH), 1715 (ester CO) cm ^-1

b) (R, S) -3- (4-Amino-3,5-dibripmphenyl) -N ² - (tert -butoxycarbonyl) -N- (3-phenylpropyl) -alanineamide

Prepared analogously to Example 12a) from (R, S) -3- (4-amino-3,5-di bromophenyl) -N ² - (tert.butoxycarbonyl) alanine and benzenepropan amine in a yield of 84% of theory. Colorless, amorphous substance.
IR (CH ₂ Cl ₂ ): 3480, 3430, 3380 (NH), 1710 (ester CO) 1680 (amide CO) cm ^-1

c) (R, S) -3- (4-Amino-3,5-dibromophenyl) -N- (3-phenylpropyl) -ala ninamid trifluoroacetate

Prepared analogously to Example 2f) from (R, S) -3- (4-amino-3,5-di-bromopheny) -N ² - (tert-butoxycarbonyl) -N - ((3-phenylpropyl) -alanine amide and trifluoroacetic acid in a yield of 85% of theory Colorless crystals (diisopropyl ether) which were processed further without purification.

d) (R, S) -3- (4-Amino-3,5-dibromophenyl) -N ² - [[1- [2- [4- (diphenylmethyl) -1-piperazinyl] -2-oxoethyl] cyclopentyl ] acetyl] -N- (3-phenylpropyl) alanine amide

Prepared analogously to Example 2e) from 1- [2- [4- (diphenylmethyl) -1-piperazinyl] -2-oxoethyl] cyclopentaneacetic acid and (R, S) -3- (4-amino-3,5-dibromophenyl) -N - (3-phenylpropyl) alanine amide trifluoroacetate in a yield of 70% of theory. Colorless, amorphous substance.
IR (CH ₂ Cl ₂ ): 1675, 1605 (amide CO) cm ^-1
MS: (M + H) ⁺ = 855/857/859 (Br ₂ )

Example 40 (R, S) -N ² - [(4-cyanophenyl) methyl] -N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepine -11-yl] -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] - N - [2- [1,2-dihydro-3,5 (4H) -dioxo-1,2-diphenyl-3H- 1,2,4-triazol-4-yl] ethyl] glycinamide

Prepared analogously to Example 16d) from (R, S) -N ² - [(4-cyanophenyl) methyl] -N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] glycine and 4- (2-aminoethyl) -1,2-dihydro-1,2-diphenyl-3H- 1,2,4-triazole-3,5 (4H) -dione trifluoroacetate in a yield of 54% of theory. Colorless crystals of mp <120 ° C (Z.) and R _f 0.11 (variant D) or 0.245 (variant C).
IR (CH ₂ Cl ₂ ): 3380, 3300 (NH), 2225 (C~N), 1780, 1725 (five-membered CO), 1660, 1610 (amide-CO) cm ^-1
MS: (M + H) ⁺ = 912

Example 41 (R, S) -N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] -2 -oxoethyl] cyclopentyl] acetyl] -N- (3-phenylpropyl) -glycinamide

Prepared analogously to Example 12a) from (R, S) -N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] - 1-piperazinyl] -2-oxo-ethyl] cyclopentyl] -acetyl] -glycine and benzenepropanamine in a yield of 9% of theory. Colorless, amorphous substance.
MS: (M + H) ⁺ = 636

Example 42 (R, S) -N - [[4- (aminoiminomethyl) phenyl] methyl] -1- [2- [4- [5,11-di hydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] -2-oxo ethyl] -N- (2-phenylethyl) -cyclopentanacetamid a) (R, S) -N - [(4-cyanophenyl) methyl] -1- [2- [4- [5,11-dihydro-6 (6H) -] oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] -2-oxoethyl] -N- (2- phenylethyl) -cyclopentanacetamid

Prepared analogously to Example 12a) from 1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] -2-oxoethyl] cyclopentaneacetic acid and Benzenethanamine in a yield of 31% of theory.
Colorless crystals of mp. <90 ° C.
IR (CH ₂ Cl ₂ ): 3380 (NH), 2230 (C~N), 1650 (amide Ca) cm ^-1
MS: (M⁺ = 679.

b) (R, S) -N - [[- 4- (aminoiminomethyl) phenyl] methyl] -1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-pipera zinyl] -2-oxoethyl] -N- (2-phenylethyl) -cyclopentanacetamid

Prepared analogously to Example 1c) from (R, S) -N - [(4-cyanophenyl) methyl] -1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] -2-oxoethyl] -N- (2-phenylethyl) -cyclopentanacetamide in a yield of 94% of theory. Colorless crystals of mp. <130 ° C (Z.) And R _f 0.71 (variant A).
IR (KBr): salt bands, 1650 (amide CO) cm ^-1
MS: (M + H) ⁺ = 697;
(M + Na) ⁺ = 719

Example 43 (R, S) -N - [(4-cyanophenyl) methyl] -N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepine] 11-yl] -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -N- (3-phenylpropyl) glycinamide

Prepared analogously to Example 16d) from (R, S) -N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] - 1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] glycine and N - [(4-cyanophenyl) methyl] benzenepropanamine hydrochloride in a yield of 33% of theory. Colorless crystals of mp <120 ° C (Z.) and R _f 0.10 (variant B) or 0.21 (variant C).
IR (CH ₂ Cl ₂ ): 3385 (NH), 2230 (C~N), 1660, 1612 (amide Ca) cm ^-1
MS: (M + H) ⁺ = 751
(M + Na) ⁺ = 773

Example 44 (R, S) -N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] -2 -oxoethyl] cyclopentyl] acetyl] -N- [2- [1,2-dihydro-3,5 (4H) -dioxo-1,2-diphenyl-3H-1,2,4-triazol-4-yl] ethyl] glycinamide

Prepared analogously to Example 29f) from (R, S) -N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] - 1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] glycine and 4- (2-aminoethyl) -1,2-dihydro-1,2-diphenyl-3H-1,2,4-triazole-3, 5 (4H) -dione trifluoroacetate in a yield of 6% of theory. Colorless, amorphous substance of R _f 0.05 (variant B) or 0.38 (variant D).
MS: (M + H) ⁺ = 797

Example 45 1- [2- [4- (diphenylmethyl) -1-piperazinyl] -2-oxoethyl] -N- [2- [1,2- dihydro-3,5 (4H) -dioxo-1,2-diphenyl-3H-1,2,4-triazol-4-yl] ethyl] -cyclopentanacetamid

Prepared analogously to Example 16d) from 1- [2- [4- (diphenylmethyl) -1-piperazinyl] -2-oxoethyl] cyclopentaneacetic acid and 4- (2-aminoethyl) -1,2-dihydro-1,2-diphenyl- 3H-1,2,4-triazole-3,5 (4H) -dione trifluoroacetate in a yield of 70% of theory. Colorless crystals of mp. 82-86 ° C and R _f 0.41 (variant B).
IR (CH ₂ Cl ₂ ): 1785, 1730 (five-membered CO), 1670, 1610 (amide-CO) cm ^-1
MS: M⁺ = 698

Example 46 (R, S) -1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] - 1-piperazinyl] -2-oxoethyl] -N- [2- [1,2-dihydro-3,5 (4H) -dioxo-1,2- diphenyl-3H-1,2,4-triazol-4-yl] ethyl] -cyclopentanacetamid

Prepared analogously to Example 16d) from 1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] -2-oxoethyl] cyclopentaneacetic acid and 4- (2-aminoethyl) -1,2-dihydro-1,2-di-phenyl-3H-1,2,4-triazole-3,5 (4H) -dione trifluoroacetate in a yield of 33% of theory , Colorless crystals of mp. 202-205 ° C and R _f 0.11 (variant B) and 0.22 (variant C).
IR (KBr): 3300 (NH), 1790, 1733 (5-ring CO) 1665, 1630 (amide CO) cm ^-1
MS: M⁺ = 739

Example 47 3- (3-cyanophenyl) -N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] 2-oxoethyl] cyclopentyl] acetyl] alanine methyl ester a) a- (acetylamino) -α - [(3-cyanophenyl) methyl] -malonic acid diethyl ester

Prepared analogously to Example 2b) from 3- (bromomethyl) benzonitrile and α-Acetamido-malonsäurediethylester in a yield of 94% of theory.
Colorless crystals of mp. 139-141 ° C.

b) (R, S) -3- (3-cyanophenyl) alanine hydrochloride

Prepared analogously to Example 2c) from diethyl α- (acetylamino) -α- [(3-cyanophenyl) methyl] malonate by boiling with aqueous hydrochloric acid and glacial acetic acid in a yield of 81% of theory.
Colorless crystals of mp. 206 ° C.
IR (KBr): salt bands, 2240 (C~N), 1735 (carboxylic acid-CO) cm ^-1
MS: (M + H) ⁺ = 191
(M + _NH4) ⁺ = 208
(M + H) ⁻ = 189

c) (R, S) -3- (3-cyanophenyl) alanine methyl ester p-toluenesulfonate

The mixture of 4.0 g (17.65 mmol) of (R, S) -3- (3-cyanophenyl) alanine hydrochloride, 88 mL of methanol and 7.0 g (36.8 mmol) of p-toluenesulfonic acid hydrate Boiled under reflux for 24 hours. The solvent was removed, the residue was taken up in 50 ml of water and the resulting solution was rendered alkaline by the addition of sodium carbonate. It was extracted exhaustively with ether, the combined ether extracts were washed once each with water and saturated sodium chloride solution and dried over sodium sulfate. The residue remaining after removal of the solvent was taken up in 50 ml of ether and converted into the desired salt by addition of 3.36 g (17.66 mmol) of p-toluenesulfonic acid hydrate. The ether was decanted off, the residue was triturated with isopropanol / tert-butyl methyl ether mixture (1/9 v / v) and 6.3 g (95% of theory) of colorless crystals of mp. 144 ° C.
IR (KBr): salt bands, 2230 (C~N), 1745 (ester-CO) cm ^-1
MS: (M + H) ⁺ = 205

d) 3- (3-Cyanophenyl) -N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodi benz [b, e] azepin-11-yl] -1 piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] alanine methyl ester

Prepared analogously to Example 16d) from 1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] -2-oxoethyl] cyclopentaneacetic acid and (R, S) -3- (3-cyanophenyl) -alanine methyl ester p-toluenesulfonate in a yield of 40% of theory. Colorless crystals of mp. 94-98 ° C and R _f 0.21 (variant B) and 0.34 (variant C)
IR (CH ₂ Cl ₂ ): 3380 (NH), 2225 (C~N)
1740 (ester CO),
1660, 1605 (amide CO) cm ^-1
MS: (M + Na) ⁺ = 670;
(M +) ⁺ 648

Example 48 (R, S) -N ² - [3- (aminoiminomethyl) phenyl] -N ² - [[1- [2- [4- (diphenylmethyl) -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] - N- (3-phenylpropyl) alanine amide hydrochloride a) (R, S) -N- ² - (tert-butoxycarbonyl) -3- (3-cyanophenyl) alanine

Prepared analogously to Example 2d) from (R, S) -3- (3-cyanophenyl) -aluminum hydrochloride and di-tert-butyl dicarbonate in a yield of 96% of theory.
Colorless crystals of mp. 142-144 ° C (Z.)
IR (KBr): 3360 (NH); Acid-OH, associated, 2230 (C~N), 1758, 1715 (ester and carboxylic acid CO) cm ^-1
MS: M⁺ = 290

b) (R, S) -N ² - (tert -butoxycarbonyl) -3- (3-cyanophenyl) -N ((3-phenylpropyl) alanineamide

To the mixture of 20.0 g (68.89 mmol) of (R, S) -N ² - (tert-butoxy carbonyl) -3- (3-cyanophenyl) alanine, 14.82 g (109.6 mmol). Benzene propanamine, 8.77 g (57.28 mmol) of HOBt, 7.0 g (69.18 mmol) of triethylamine and 900 ml of anhydrous tetrahydrofuran were added with stirring and external cooling with ice-water to 21.88 g (68.14 mmol). TBTU. The mixture was allowed to warm to room temperature and stirred overnight. It was then evaporated in vacuo, the residue partitioned between dichloromethane and water, and the dichloromethane phase purified by column chromatography on silica gel (MN, 35-70 mesh ASTM; dichloromethane / ethyl acetate / methanol / cyclohexane / concentrated aqueous ammonia = 64 / 25 / 2,5 / 7,5 / 1 (v / v / v / v / v)). This gave 18.9 g (81% of theory) of colorless crystals, mp. 126-128 ° C.

c) (R, S) -3- (3-cyanophenyl) -N- (3-phenylpropyl) alanineamide-tri trifluoroacetate

Prepared analogously to Example 2f) from (R, S) -N ² - (tert-butoxycarbonyl) -3- (3-cyanophenyl-N- (3-phenylpropyl) -alanineamide and trifluoroacetic acid in quantitative yield Colorless amorphous substance, which was further processed without cleaning.
IR (CH ₂ Cl ₂ ): salt bands, 2230 (C~N), 1675 (amide CO) cm ^-1
MS: M⁺ = 307

d) (R, S) -3- (3-cyanophenyl) -N ² - [[1- [2- [4- (diphenylmethyl) -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -N- (3-phenylpropyl) alanine amide

Prepared analogously to Example 29f) from 1- [2- [4- (diphenylmethyl) -1-piperazinyl] -2-oxoethyl] cyclopentaneacetic acid and (R, S) -3- (3-cyanophenyl) -N- (3-phenylpropyl) -alaninamide trifluoroacetate in a yield of 63% of theory.
Colorless, amorphous substance.
IR (CH ₂ Cl ₂ ): 3430 (NH), 2230 (C~N), 1675, 1605 (amide CO) cm ^-1
MS: M⁺ = 709

e) (R, S) -3- [3- (aminoiminomethyl) phenyl] -N ² - [[1- [2- [4- (diphenylmethyl) -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] N- (3-phenylpropyl) alanine amide hydrochloride

2.03 g (2.86 mmol) of (R, S) -3- (3-cyanophenyl) -N ² - [[1- [2- [4- (diphenylmethyl) 1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -N- (3-phenylpropyl) alanineamide were dissolved in 40 ml of dry-hydrogen-saturated methanol anhydrous and stirred at room temperature for 24 hours. The solvent was distilled off in vacuo and at a bath temperature <30 ° C, the residue was taken up in 30 ml of absolute methanol and added to 5 g (52 mmol) of ammonium carbonate. After again stirring at room temperature for 24 hours, the insoluble material was filtered off, the filtr was evaporated in vacuo and the residue was partitioned between water and ethyl acetate. The aqueous phase was evaporated in vacuo, the residue several times with a little water and methanol, finally with ethanol / diisopropyl ether 5/95 (v / v) rubbed ver. This gave 0.6 g (27% of theory) of colorless Kri stallen of mp. 200 ° C and R _f 0.71 (variant A).
IR (KBr): salt bands, 1645 (amide CO) cm ^-1
MS: (M + H) ⁺ = 727;
(M + Na) ⁺ = 749

Example 49 3- (3-cyanophenyl) -N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] 2-oxoethyl] cyclopentyl] acetyl] -N- (3-phenylpropyl) alanine amide

Prepared analogously to Example 29f) from (R, S) -1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] -2-oxo-ethyl] cyclopentaneacetic acid and (R, S) -3- (3-cyanophenyl) -N- (3-phenylpropyl) alanine amide trifluoroacetate in a yield of 42% of theory. Colorless crystals of mp. 150 ° C and R _f 0.16 (variant B) and 0.28 (variant C).
IR (CH ₂ Cl ₂ ): 3380 (NH), 2230 (C~N), 1660, 1605 (amide CO) cm ^-1
MS: (M + Na) ⁺ = 773

Example 50 (R, S) -3- (4-cyanophenyl) -N ² - [[1- [2- [4- (diphenylmethyl) -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] alanine methyl ester

Prepared analogously to Example 1b) from 1- [2- [4-diphenylmethyl) -1-piperazinyl] -2-oxoethyl] cyclopentaneacetic acid and (R, S) -3- (4-cyanophenyl) alanine methyl ester in a yield of 16% of Theory. Colorless crystals of mp. 170-173 ° C and R _f 0.55 (variant B).
IR (CH ₂ Cl ₂ ): 2225 (C~N), 1745 (ester CO), 1670, 1610 (amide CO) cm ^-1

Example 51 3- [3- (aminoiminomethyl) phenyl] -N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1 -piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] alanine methyl ester hydrochloride

Prepared analogously to Example 48e) from 3- (3-cyanophenyl) -N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl ] -1-pi perazinyl] -2-oxoethyl] cyclopentyl] acetyl] alanine methyl ester in a yield of 64% of theory. Colorless crystals (ethanol / diisopropyl ether = 1/1, v / v) which decompose above 165 ° C. R _f 0.62 (variant A) or 0.83 (variant C)
IR (KBr): salt bands, 1745 (ester CO), 1645 (amide CO) cm ^-1
ESI-MS:
(M +) ⁺ 665
(M + Na) ⁺ = 687
(M + K) ⁺ = 703

Example 52 N ² - [[1- [2- [4- (diphenylmethyl) -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] glycine methyl ester

Prepared analogously to Example 29f) from 1- [2- [4- (diphenylmethyl) -1-piperazinyl] -2-oxoethyl] cyclopentaneacetic acid and glycine methyl ester hydrochloride in quantitative yield. Colorless, amorphous substance of R _f 0.44 (variant B).
IR (CH ₂ Cl ₂ ): 1735 (ester CO), 1667 (amide CO) cm ^-1
MS: M⁺ = 491

Example 53 3- [3- (aminoiminomethyl) phenyl] -N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1 -piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -N- (3-phenylpropyl) alanineamide hydrochloride

Prepared analogously to Example 48e) from 3- (3-cyanophenyl) -N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl ] -1-pipe razinyl] -2-oxoethyl] cyclopentyl] acetyl] -N- (3-phenylpropyl) -aluminamide in a yield of 47% of theory. Colorless crystals of melting point 170 ° C (Z.) and R _f 0.72 (variant A).
IR (CH ₂ Cl ₂ ): salt bands, 1655 (amide-CO) cm ^-1 ESI-MS:
(M +) ⁺ = 768
(M + K) ⁺ = 806

Example 54 (R, S) -3- (4-Cyanophenyl) -N ² - [[1- [2- [4 - [[5,11-dihydro-6 (6H) -oxo-pyrido [2,3-b] 1,4] benzodiazepin-11-yl] acetyl] -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -N- (3-phenylpropyl) alanine amide a) 1- [2- [4- [5,11-dihydro-6 (6H) -oxopyrido [2,3-b] [1,4] benzodi Cyclops azepin-11-yl] acetyl] -1-piperazinyl] -2-oxoethyl] tanessigsäure

Prepared analogously to Example Ia) from 5,11-dihydro-11 - [(1-piperazinyl) acetyl] -6H-pyrido [2,3-b] [1,4] benzodiazepine-6-one and 1,1-cyclopentane diacetic anhydride in a yield of 91% of theory. Colorless crystals of mp. 180-184 ° C.
IR (KBr): about 3660 to about 1850 (carboxylic acid OH, broad, associated),
3220 (NH), 1717, 1693 (carboxylic acid-CO) 1665 (amide-CO) cm- ¹

b) (R, S) -3- (4-cyanophenyl) -N ² - [[1- [2- [4 - [[5,11-dihydro-6 (6H) -oxo-pyrido [2,3-b] [1,4] benzodiazepin-11-yl] acetyl] -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -N- (3-phenylpropyl) -alanineamide

Prepared analogously to Example 29f) from 1- [2- [4 - [[5,11-dihydro-6 (6H) -oxopyrido [2,3-b] [1,4] benzodiazepin-11-yl] acetyl] -1 -pi perazinyl] -2-oxoethyl] cyclopentaneacetic acid and (R, S) -3- (4-cyanophenyl) -N- (3-phenylpropyl) alanine amide trifluoroacetate in a yield of 77% of the theories. Colorless crystals of melting point 130-134 ° C and R _f 0.80 (variant B)
IR (CH ₂ Cl ₂ ): 2225 (C~N) 1665 (amide CO) cm ^-1
MS: M⁺ = 794

Example 55 (R, S) -3- [4- (aminoiminomethyl) phenyl] -N ² - [[1- [2- [4 - [[5,11-dihydro-6 (6H) -oxopyrido [2,3- b] [1,4] benzodiazepin-11-yl] acetyl] -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -N- (3-phenylpropyl) alanineamide hydrochloride

Prepared analogously to Example 48e) from (R, S) -3- (4-cyanophenyl) -N ² - [[1- [2- [4 - [[5,11-dihydro-6 (6H) oxopyrido [2,3 -b] [1,4] benzo diazepin-11-yl] acetyl] -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -N- (3-phenylpropyl) alanine amide in 85% yield of theory , Colorless crystals of mp. <185 ° C (Z.) and R _f 0.42 (variant A)
IR (KBr): salt bands, 1655 (amide CO) cm ^-1
ESI-MS:
(M + H) ⁺ = 812

Example 56 3- (4-cyanophenyl) -N ² - [5- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] -3,3 -dimethyl-1,5-dioxopentyl] alanine methyl ester a) (R, S) -5- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] - 1-piperazinyl] -3,3-dimethyl-5-oxopentanoic acid

Prepared analogously to Example 1a) from 5,11-dihydro-11- (1-piperazinyl) dibenz [b, e] azepine-6 (6H) -one and 3,3-dimethylglutaric anhydride in a yield of 86% of theory , Colorless, amorphous product.
IR (CH ₂ Cl ₂ ): 3380 (NH), 1735 (carboxylic acid-CO), 1660, 1580 (amide-CO) cm ^-1
MS: M⁺ = 435

b) 3- (4-cyanophenyl) -N ² - [5- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] -3 , 3-dimethyl-1,5-dioxo-pentyl] alanine methyl ester

Prepared analogously to Example 1b) from (R, S) -5- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] -3,3 -dimethyl-5-oxopentanoic acid and (R, S) -3- (4-cyanophenyl) alanine methyl ester in a yield of 48% of theory. Colorless, amorphous substance of R _f 0.39 (variant E)
IR (CH ₂ Cl ₂ ): 3380 (NH), 2220 (C~N), 1735 (ester CO), 1660, 1605 (amide CO) cm ^-1
MS: M⁺ = 621

Example 57 3- (4-cyanophenyl) -N ² - [5- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] -1,5 dioxopentyl] alanine methyl ester a) (R, S) -5- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] piperazinyl] -5-oxopentanoic acid

Prepared analogously to Example 1a) from 5,11-dihydro-11- (1-piperazinyl) dibenz [b, e] azepine-6 (6H) -one and glutaric anhydride in a yield of 98% of theory. Colorless, amorphous substance.
IR (CH ₂ Cl ₂ ): 3390 (NH) 1700 (carboxylic acid-CO), 1660, 1640, 1605, 1595 (amide-CO) cm ^-1
MS: M⁺ = 407

b) 3- (4-Cyanophenyl) -N ² - [5- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] -1 , 5-dioxopentyl] alanine methyl ester

Prepared analogously to Example Ib) from (R, S) -5- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] -5-oxopentane acid and (R, S) -3- (4-cyanophenyl) alanine methyl ester in a yield of 51% of theory. Colorless, amorphous substance of R _f 0.48 (variant C) or 0.22 (variant E).
IR (CH ₂ Cl ₂ ): 3670 (OH), 3412, 3382 (NH), 2230 (C~N) 1740 (ester CO), 1675 (amide CO) cm ^-1
MS: (M + H) ⁺ = 594
(M + Na) ⁺ = 616

Example 58 3- (4-cyanophenyl) -N, N-diethyl-N ² - [5- [4- [5,11-dihydro-6 (6H) -oxo-dibenz [b, e] azepin-11-yl] -1 -piperazinyl] -1,5-dioxopentyl] alaninamide a) (R, S) -N ² - (tert -butoxycarbonyl) -3- (4-cyanophenyl) -N, N-diethyl alaninamide

Prepared analogously to Example 12a) from (R, S) -N ² - (tert.Butoxycar bonyl) -3- (4-cyanophenyl) alanine and diethylamine in a Ausbeu te of 60% of theory. Colorless crystals of mp 134 ° C.
IR (KBr): 2225 (C~N), 1700 (ester CO), 1620 (amide CO) cm ^-1
MS: M⁺ = 345

b) (R, S) -3- (4-cyanophenyl) -N, N-diethyl-alaninamide

Analogously to Example 2f) was by the action of trifluoroacetic acid on (R, S) -N ² - (tert.butoxycarbonyl) -3- (4-cyanophenyl) - N, N-diethyl-alaninamide in quantitative yield (R, S) - 3- (4-cyanophenyl) -N, N-diethyl-alaninamide trifluoroacetate. Treatment of the aqueous solution of this salt with 20% sodium hydroxide gave the desired base. Colorless oil used in the next stage without further purification.

c) 3- (4-cyanophenyl) -N, N-diethyl-N ² - [5- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] - 1-piperazinyl] -1,5-dioxophenyl] -alaninamide

Prepared analogously to Example 1b) from (R, S) -5- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] -5-oxopentane acid and (R, S) -3- (4-cyanophenyl) -N, N-diethyl-alanineamide in a yield of 41% of theory. Colorless crystals (tert-butyl methyl ether) of R _f 0.26 (variant C) and 0.19 (variant E).
IR (CH ₂ Cl ₂ ): 3380 (NH), 2220 (C~N), 1660, 1635 (amide CO) cm ^-1
ESI-MS: (N + Na) ⁺ = 657

Example 59 3- (4-cyanophenyl) -N, N-diethyl-N ² - [[5- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1 -piperazinyl] -3,3-dimethyl-1,5-dioxopentyl] alaninamide

Prepared analogously to Example 1b) from (R, S) -5- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] -3,3 -dimethyl-5-oxopentanoic acid and (R, S) -3- (4-cyanophenyl) -N, N-diethyl-alamine in a yield of 26% of theory. Colorless amorphous substance of R _f 0.65 (variant C) or 0.33 (variant E).
IR (CH ₂ Cl ₂ ): 3380 (NH), 2220 (C~N), 1660, 1640, 1610 (amide CO) cm ^-1
ESI-MS:
(M + H) ⁺ = 663
(M + Na) ⁺ = 685
(M + K) ⁺ = 701

Example 60 3- (4-cyanophenyl) -N ² - [5- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] -3,3 -dimethyl-1,5-dioxopentyl] -N-propyl-alaninamide a) (R, S) -N ² - (tert-butoxycarbonyl) -3- (4-cyanophenyl) -N-propyl-alaninamide

Prepared analogously to Example 12a) from (R, S) -N ² - (tert.Butoxycar bonyl) -3- (4-cyanophenyl) alanine and propanamine in a yield of 10% of theory. Colorless crystals of mp. 159-160 ° C.
IR (KBr): 3310, 3265 (NH), 2225 (C~N), 1693 (Ester-CO), 1660, 1610 (amide-CO) cm- ¹

b) (R, S) -3- (4-cyanophenyl) -N-propyl-alaninamide

Prepared analogously to Example 58b) from (R, S) -N ² - (tert.butoxycarbonyl) -3- (4-cyanophenyl) -N-propyl-alaninamide in quantitative yield. Colorless, highly viscous oil, which was further processed without purification.

c) 3- (4-Cyanophenyl) -N ² - [5- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] -3 , 3-dimethyl-1,5-dioxopenyl] -N-propyl-alaninamide

Prepared analogously to Example 48b), but using acetonitrile as the solvent in place of tetrahydrofuran, from (R, S) -5- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepine 11-yl] -1-piperazinyl] -3,3-dimethyl-5-oxopentanoic acid, TBTU and (R, S) -3- (4-cyanophenyl) -N-propyl-alanineamide in a yield of 50% of theory. Colorless crystals (tert-butyl methyl ether) of R _f 0.69 (variant C) and 0.30 (variant E).
IR (CH ₂ Cl ₂ ): 3430, 3380 (NH), 2220 (C~N), 1655, 1605 (amide CO) cm ^-1
MS: no M⁺, m / e = 440

Example 61 3- (4-cyanophenyl) -N ² - [5- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] -1, 5 dioxopentyl] -N-propyl-alanine amide

Prepared analogously to Example 60c) from (R, S) -5- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] -5-oxopentane acid, TBTU and (R, S) -3- (4-cyanophenyl) -N-propyl-alanineamide in a yield of 40% of theory. Colorless crystals of R _f 0.30 (variant C) and 0.17 (variant E).
IR (CH ₂ Cl ₂ ): 3430, 3380, 3300 (NH), 2220 (C~N), 1655, 1605 (amide CO) cm ^-1
ESI-MS:
(M + H) ⁺ = 621
(M + Na) ⁺ = 643

Example 62 3- [4- (aminoiminomethyl) phenyl] -N ² - [[5- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] 3,3-dimethyl-1,5-dioxopentyl] -N-propyl-alanineamide hydrochloride

Prepared analogously to Example 48e) from 3- (4-cyanophenyl) -N ² - [5- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1- piperazinyl] - 3,3-dimethyl-1,5-dioxopentyl] -N-propyl-alaninamide in a yield of 63% of theory. Colorless crystals of R _f 0.52 (variant A).
IR (KBr): salt bands, 1675 (amidinium), 1660, 1655, 1645 (amide CO) cm ^-1
ESI-MS: (M + H) ⁺ = 666

Example 63 N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] -2-oxoethyl] cyclopentyl] -acetyl ] -N ⁶ - (phenylmethoxycarbonyl) -lysine methyl ester

Prepared analogously to Example 60c) from (R, S) -1- [2- [4- [5,11-dihydro-6- (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl ] -2-oxo ethyl] cyclopentaneacetic acid and (R, S) -N ⁶ - (phenylmethoxycarbonyl) -lysine methyl ester in a yield of 46% of theory. Colorless, amorphous substance of R _f 0.37 (variant E)
IR (CH ₂ Cl ₂ ): 3440, 3380, 3250 (NH), 1735, 1720 (ester CO) 1660, 1605 (amide CO) cm ^-1

Example 64 Injection solution with 5 mg active substance per 5 ml

Composition:@ active substance 5 mg glucose 250 mg Human serum albumin 10 mg glycofurol 250 mg Water for injections ad 5 ml

production:
Glykofurol and glucose in water for injection dissolve (WfI); Add human serum albumin; Dissolve active ingredient with heating; fill with WfI on batch volume; Fill with nitrogen fumigation in ampoules.

Example 65 Injection solution with 100 mg active substance per 20 ml

Composition:@ active substance 100 mg Monopotassium dihydrogenphosphate = KH ₂ PO ₄ 12 mg Disodium hydrogen phosphate = Na ₂ HPO ₄ .2H ₂ O 2 mg sodium chloride 180 mg Human serum albumin 50 mg Polysorbate 80 20 mg Water for injections ad 20 ml

production:
Dissolve polysorbate 80, sodium chloride, monopotassium dihydrogen phosphate and disodium hydrogen phosphate in water for injections (WfI); Add human serum albumin; Dissolve active ingredient with heating; fill with WfI on batch volume; fill in ampoules.

Example 66 Lyophilisate with 10 mg active substance

Composition:@ active substance 10 mg mannitol 300 mg Human serum albumin 20 mg

production:
Dissolve mannitol in water for injections (WfI); Add human serum albumin; Dissolve active ingredient with heating; fill with WfI on batch volume; to fill in vials; freeze-dry.

Solvent for lyophilisate: @ Polysorbate 80 = Tween 80 20 mg mannitol 200 mg Water for injections ad 10 ml

production:
Dissolve polysorbate 80 and mannitol in water for injections (WfI); fill in ampoules.

Example 67 Tablets containing 20 mg of active substance

Composition:@ active substance 20 mg lactose 120 mg corn starch 40 mg magnesium stearate 2 mg Povidone K 25 18 mg

production:
Mix active substance, lactose and maize starch homogeneously; granulate with an aqueous solution of povidone; mix with magnesium stearate; press on a tablet press; Tablet weight 200 mg.

Example 68 Capsules with 20 mg active substance

Composition:@ active substance 20 mg corn starch 80 mg Silica, highly dispersed 5 mg magnesium stearate 2.5 mg

production:
Mix active substance, corn starch and silica homogeneously; mix with magnesium stearate; Fill the mixture on a capsule filling machine into size 3 hard gelatin capsules.

Example 69 Suppository with 50 mg active substance

Composition:@ active substance 50 mg Hard fat (Adeps solidus) q.s. ad 1700 mg

production:
Melt hard fat at approx. 38 ° C; homogeneously disperse the ground active substance in the molten hard fat; after cooling to approx. 35 ° C pour into pre-cooled molds.

Claims (12)

1. piperazine derivatives of the general formula
in the
R ^{1 represents} a straight-chain or branched alkyl group having one to five carbon atoms, but in particular the methyl group, the diphenylmethyl, 5,11-dihydro-6 (6H) -oxodibenz [b, e] azepine-11-yl, 5,11- Dihydro-6 (6H) -oxopyrido [2,3-b] [1,4] benzodiazepin-11-yl or 5,10-dihydro-11 (11H) -oxodibenzo [b, e] [1,4] diazepine 5-yl group,
Z is the carbonyl group, a group bound to the piperazine via the methylene -COCH ₂ - group or the single bond,
R ³ and R ⁴ , which may be the same or different, are hydrogen atoms, alkyl groups having 1 to 3 carbon atoms or together a straight-chain alkylene group having 2 to 7 carbon atoms,
B is the single bond, the divalent radicals of the amino acids glycine, lysine, phenylglycine or phenylalanine, wherein the amino acid glycine at the N ² atom by a phenyl in the phenyl optionally substituted by a cyano group phenylmethyl group, the amino acid lysine at the N ⁶ atom by a Phenylmethoxycarbonyl group and the amino acid phenylalanine in 2-, 3- or 4-Stel ment of the phenyl moiety by a cyano or aminoiminomethyl group or in the 4-position by an amino group and in the 3- and 5-position each by a halogen atom, preferably a chlorine or Bromine atom, may be substituted,
C is the group -NR ⁵ R ⁶ , in the
R ^{5 is} a hydrogen atom, a straight-chain or branched alkyl group having 1 to 4 carbon atoms, which may be substituted by a phenyl group in ω-position, and
R ⁶ denotes a straight-chain or branched alkyl group having 1 to 4 carbon atoms which is represented by a hydroxyl group, a phenyl group optionally substituted by a cyano or aminoiminomethyl group, a 1,2-dihydro-3,5 (4H) optionally substituted by one or two phenyl groups - dioxo-3H-1,2,4-triazol-4-yl group or by a 4- (Di phenylmethyl) -1-piperazinyl group may be substituted, or represent an optionally substituted by a cyano or aminoimino methyl group phenyl group .
or, unless B represents the single bond, a hydroxy group or an alkoxy group having 1 to 3 carbon atoms, for example the methoxy, ethoxy, propoxy or 1-methylethoxy group,
their tautomers, their diastereomers, their enantiomers, their mixtures and their salts. 2. Piprazine derivatives of the general formula I according to claim 1, in which
R ^{1 is} the diphenylmethyl, 5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl, 5,11-dihydro-6 (6H) -oxopyrido [2,3-b] [1,4] benzodi-azepin-11-yl or 5,10-dihydro-11 (11H) -oxodibenzo [b, e] [1,4] diazepin-5-yl group,
Z is the carbonyl group or the single bond,
R ³ and R ⁴ together represent a straight-chain alkylene group having 3 to 7 carbon atoms,
B is the divalent radicals of the amino acids glycine, phenylglycine or phenylalanine, where the amino acid glycine at the N ² atom may be substituted by a phenyl moiety optionally substituted by a cyano group in the phenyl moiety and the amino acid phenylalanine in the 2-, 3- or 4-position of Phenyl may be substituted by a cyano or aminoiminomethyl group or in the 4-position by an amino group and in the 3- and 5-position depending Weil by a bromine atom,
C is the group -NR ⁵ R ⁶ , in the
R ^{5 is} a hydrogen atom and
R ⁶ denotes a straight-chain or branched alkyl group having 1 to 4 carbon atoms which is in the ω-position by a hydroxy group, a phenyl group optionally substituted by a cyano- or amino-iminomethyl group, or a 1,2-dihydroxy radical optionally substituted by one or two phenyl groups. 3,5 (4H) -dioxo-3H-1,2,4-triazol-4-yl group or substituted by a 4- (diphenylmethyl) -1-piperazinyl group,
or a hydroxy or methoxy group,
their tautomers, their diastereomers, their enantiomers, their mixtures and their salts. 3. piperazine derivatives of the general formula I according to claim I, in which
R ^{1 is} the diphenylmethyl, 5,11-dihydro-6 (6H) -oxodibenz [b, e] aze pin-11-yl or 5,10-dihydro-11 (11H) -oxodibenzo [b, e] [1 , 4] the azepin-5-yl group,
Z is the carbonyl group or the single bond,
R ³ and R ⁴ together form the tetramethylene group,
B is the bivalent radical of the amino acid phenylalanine, which may be substituted in the 2-, 3- or 4-position of the phenyl moiety by a cyano or ami nominomethyl group, and
C is the (3-phenylpropyl) amino, [3- [4- (diphenylmethyl) -1-piperazinyl] propyl] amino, [2- [1,2-dihydro-3,5 (4H) dioxo-1 , 2-diphenyl-3H-1,2,4-triazol-4-yl] ethyl] amino or (2-hydroxyethyl) -amino group,
their tautomers, their diastereomers, their enantiomers, their mixtures and their salts. 4. piperazine derivatives of the general formula I according to the claims 1 to 3, which are characterized within the partial structure of the group B by the remainder of a branched amino acid and L- or (S) -konfiguriert,
their tautomers, their diastereomers, their enantiomers, their mixtures and their salts. 5. The following compounds of general formula I:
N- [4-aminoiminomethyl) phenyl] -1- [2 [4- (diphenylmethyl) -1-piperazinyl] -2-oxoethyl] cyclopentanacetamide
(R, S) -3- (4-Cyanophenyl) -N ² - [[1- [2- [4- (diphenylmethyl) -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -N- (3 -phenylpropyl) -aluminamide
(R, S) -3- [4- (aminoiminomethyl) phenyl] -N ² - [[1- [2- [4- (diphenylmethyl) -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -N - (3-phenylpropyl) alanine amide
3- (4-cyanophenyl) -N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] 2-oxoethyl] cyclopentyl] acetyl] -N- (3-phenylpropyl) alanine amide
(R, S) -3- (4-cyanophenyl) -N ² - [[1- [2- [4 - [[5,10-dihydro-11 (10H) -oxodibenzo [b, e] [1, 4] diazepin-5-yl] carbonyl] -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -N- (3-phenylpropyl) alaninamide
3- [4- (aminoiminomethyl) phenyl-N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1- piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -N- (3-phenylpropyl) alaninamide
3- [4-aminoiminomethyl) phenyl] -N ² - [[1- [2- [4 - [[5,10-dihydro-11 (10H) -oxodibenzo [b, e] [1,4] diazepine-5 -yl] carbonyl] -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -N- (3-phenylpropyl) -alanamide
(R, S) -N ² - [[1- [2- [4- [Diphenylmethyl) -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -N- (2-phenylethyl) -lysinamide
N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl ] -N- (3-phenylpropyl) phenylalanine amide
(S) -N ² - [[1- [2- [4 - [[s, 10-dihydro-11 (10H) -oxodibenzo [b, e] [1,4] diazepin-5-yl] carbonyl] - 1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -N- (3-phenylpropyl) phenylalanine amide
3- (4-cyanophenyl) -N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl ] -2-oxoethyl] cyclopentyl] acetyl] alanine methyl ester
N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl ] -N- (3-phenylpropyl) -L-phenylglycine amide
(5) -N ² - [[1- [2- [4- (Diphenylmethyl) -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -N- (3-phenylpropyl) -phenylglycine amide
(S) -N ² - [[1- [2- [4- [5,10-dihydro-11 (10H) -oxodibenzo [b, e] [1,4] diazepine-5-yl] carbonyl] - 1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -N- (3-phenylpropyl) -phenylglycine amide
3- [4- (aminoiminomethyl) phenyl] -N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1 piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] alanine methyl ester
(R, S-3-4-Cyanophenyl) -N ² - [[1- [2- [4- (diphenylmethyl) -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -N- [3- [ 4-diphenylmethyl) -1-piperazinyl] propyl] alaninamide
3- (4-cyanophenyl) -N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -N- [3- [4- (diphenylmethyl) -1-piperazinyl] propyl] alanine amide
(R, S) -3- (4-cyanophenyl) -N- [3- [4- (diphenylmethyl) -1-piperazinyl] propyl] -N ² - [[1- [2- (4-methyl-1-) piperazinyl) -2-oxoethyl] cyclopentyl] acetyl] alaninamide
(R, S) -N- [4- (aminoiminomethyl) phenyl] -1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] - 1-piperazinyl] -2-oxoethyl] cyclopentanacetamide
(R, S) -N - [[4- (aminoiminomethyl) phenyl] methyl] -1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepine-11 -yl] -1-piperazinyl] -2-oxo-ethyl] -N- (3-phenylpropyl) -cyclopentanacetamide
N - [[4- (aminoiminomethyl) phenyl] methyl] -1- [2- [4- (diphenylmethyl) -1-piperazinyl] -2-oxoethyl] -N- (3-phenylpropyl) -cyclopentanacetamide
(R, S) -3- [4- (aminoiminomethyl) phenyl] -N ² - [[1- [2- [4- (diphenylmethyl) -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -N - [3- [4- (diphenylmethyl) -1-piperazinyl] propyl] alaninamide
(R, S) -3- [4- (aminoiminomethyl) phenyl] -N- [3- [4- (diphenylmethyl) -1-piperazinyl] propyl] -N ² - [[1- [2- (4-methyl 1-piperazinyl) -2-oxoethyl] cyclopentyl] acetyl] alaninamide
(R, S) -N ² - [(4-cyanophenyl) methyl] -N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepine -11-yl] -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -glycine methyl ester
(R, S) -N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] -2 -oxoethyl] cyclopentyl] acetyl] glycine
(R, S) -N- (4-cyanophenyl) -1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl ] -2-oxoethyl] -N- (3-phenylpropyl) -cyclopentanacetamide
(R, S) -N ² - [(4-cyanophenyl) methyl] -N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepine -11-yl] -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -glycine
N - [[4- (aminoiminomethyl) phenyl] methyl] -1- [2- [4- (diphenylmethyl) -1-piperazinyl] -2-oxoethyl] -N- (2-phenylethyl) cyclopentane acetamide
3- (4-cyanophenyl) -N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] 2-oxoethyl] cyclopentyl] acetyl] -N- [2- [1,2-dihydro-3,5 (4H) -dioxo-1,2-diphenyl-3H-1,2,4-triazol-4-yl ] ethyl] alaninamide
(R, S) -3- (4-cyanophenyl) -N ² - [[1- [2- [4- (diphenylmethyl) -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl-N- [2- [1,2-dihydro-3,5 (4H) dioxo-1,2-diphenyl-3H-1,2,4-triazol-4-yl] ethyl] alaninamide
3- (4-aminoiminomethyl) phenyl] -N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1- piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -N- [2- [1,2-dihydro-3,5 (4H) -dioxo-1,2-diphenyl-3H-1,2,4-triazole] 4-yl] ethyl] alaninamide
(R, S) -3- [4-aminoiminomethyl) phenyl] -N ² - [[1- [2- [4- (diphenylmethyl) -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -N- [2- [1,2-dihydro-3,5 (4H) -dioxo-1,2-diphenyl-3H-1,2,4-triazol-4-yl] ethyl] alaninamide
N ² - [(4-cyanophenyl) methyl] -N ² - [[1- [2- [4- (diphenylmethyl) -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -N- [3- [4 - (diphenylmethyl) -1-piperazinyl) propyl] -glycinamide
(R, S) -N ² - [(4-cyanophenyl) methyl] -N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepine -11-yl] -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] - N - [3- [4- (diphenylmethyl) -1-piperazinyl) propyl] glycinamide
(R, S) -N ² - [(4-cyanophenyl) methyl] -N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepine -11-yl] -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -N- (3-phenylpropyl) glycinamide
N ² - [(4-cyanophenyl) methyl] -N ² - [[1- [2- [4- (diphenylmethyl) -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -N- [2- [1 , 2-dihydro-3,5 (4H) -dioxo-1,2-diphenyl-3H-1,2,4-triazol-4-yl] -ethyl] -glycine amide
3- (4-cyanophenyl) -N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] 2-oxoethyl] cyclopentyl] acetyl] -N- (2-hydroxyethyl) alanine amide
(R, S) -3- (4-cyanophenyl) -N ² - [tl- [2- [4- (diphenylmethyl) -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -N- (2- hydroxyethyl) -aluminamide
(R, S) -3- (4-Amino-3,5-dibromophenyl) -N ² - [1- [2- [4- (diphenylmethyl) -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] N- (3-phenylpropyl) alanine amide
(R, S) -N ² - [(4-cyanophenyl) methyl] -N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepine -11-yl] -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] - N - [2- [1,2-dihydro-3,5 (4H) -dioxo-diphenyl-3H-1,2,4 -triazol-4-yl] ethyl] -glycinamide
(R, S) -N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] -2 -oxoethyl] cyclopentyl] acetyl] -N- (3-phenylpropyl) glycinamide
3- (4-Cyanophenyl-N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] - 2-oxoethyl] cyclopentyl] acetyl] -N- (3-phenylpropyl) alanine amide
(R, S) -N - [[4- (aminoiminomethyl) phenyl] methyl] -1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepine-11- yl] -1-piperazinyl] -2-oxo-ethyl] -N- (2-phenylethyl) -cyclopentanacetamide
(R, S) -N - [(4-cyanophenyl) methyl] -N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepine] 11-yl] -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -N- (3-phenylpropyl) glycinamide
(R, S) -N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] -2 -oxoethyl] cyclopentyl] acetyl] -N- [2- [1,2-dihydro-3,5 (4H) -dioxo-1,2-diphenyl-3H-1,2,4-triazol-4-yl] -ethyl ] glycinamide
1- [2- [4- (diphenylmethyl) -1-piperazinyl] -2-oxoethyl] -N- [2- [1,2-dihydro-3,5 (4H) -dioxo-1,2-diphenyl-3H 1,2,4-triazol-4-yl] ethyl] -cyclopentanacetamide
(R, S) -1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] -2-oxoethyl] -N - [2- [1,2-dihydro-3,5 (4H) -dioxo-1,2-diphenyl-3H-1,2,4-triazol-4-yl] -ethyl] -cyclopentanacetamide
3- (3-cyanophenyl) -N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] 2-oxoethyl] cyclopentyl] acetyl] alanine methyl ester
(R, S) -3- [3- (aminoiminomethyl) phenyl] -N ² - [[1- [2- [4- (diphenylmethyl) -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -N - (3-phenylpropyl) alanine amide
3- (3-cyanophenyl) -N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] 2-oxoethyl] cyclopentyl] acetyl] -N- (3-phenylpropyl) alanine amide
(R, S) -3- (4-cyanophenyl) -N ² - [[1- [2- [4- (diphenylmethyl) -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] alanine methyl ester
3- [3- (aminoiminomethyl) phenyl] -N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1 piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] alanine methyl ester
N ² - [[1- [2- [4- (diphenylmethyl) -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] glycine methyl ester
3- [3- (aminoiminomethyl) phenyl] -N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1 -piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -N- (3-phenylpropyl) alanineamide
(R, S) -3- (4-cyanophenyl) -N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxopyido [2,3-b] [1 , 4] benzodiazepin-11-yl] acetyl] -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -N- (3-phenylpropyl) alanineamide
(R, S) -3- [4- (aminoiminomethyl) phenyl] -N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxopyrido [2,3-b ] [1,4] benzodiazepin-11-yl] acetyl] -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl] -N- (3-phenylpropyl) -alanineamide
3- (4-cyanophenyl) -N ² - [5- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] -3,3 -dimethyl-1,5-dioxopentyl] -aluminum ethyl ester
3- (4-cyanophenyl) -N ² - [5- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] -1,5 -dioxopentyl] alanine methyl ester
3- (4-cyanophenyl) -N, N-diethyl-N ² - [5- [4- [5,11-dihydro-6 (6H) -oxo-dibenz [b, e] azepin-11-yl] -1 -piperazinyl] -1,5-dioxopentyl] -alanamide
3- (4-cyanophenyl) -N, N-diethyl-N ² - [5- [4- [5,11-dihydro-6 (6H) -oxo-dibenz [b, e] azepin-11-yl] -1 -piperazinyl] -3,3-dimethyl-1,5-dioxo-pentyl] alaninamide
3- (4-cyanophenyl) -N ² - [5- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] -3,3 -dimethyl-1,5-dioxopentyl] -N-propylalaninamide
3- (4-cyanophenyl) -N ² - [5- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] -1,5 dioxopentyl] -N-propylalanine amide
3- [4- (aminoiminomethyl) phenyl] -N ² - [5- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] - 3,3-dimethyl-1,5-di oxopentyl] -N-propyl alanine amide
N ² - [[1- [2- [4- [5,11-dihydro-6 (6H) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl] -2-oxoethyl] cyclopentyl] acetyl ] -N ⁶ - (phenylmethoxycarbonyl) -lysine methyl ester
and their salts. 6. Physiologically acceptable salts of the compounds of the general my formula I according to claims 1 to 5 with inorganic or organic acids or bases. 7. Medicaments containing as active ingredient a compound of general formula I according to claims 1 to 5 or its Physiologically acceptable salt according to claim 6 in addition to given  if appropriate, one or more inert carriers and / or Diluents. 8. Use of a compound of general formula I according to to claims 1 to 6 for the preparation of a medicament ge according to claim 7, which is for the treatment of cardiovascular Diseases, chronic heart failure, coronary Heart disease, from subarachnoid hemorrhage, of chroni renal failure, tumors, obesity, Diabetes, diseases of the central nervous system and one limited cognitive functions. 9. A process for the preparation of a medicament according to claim 7, characterized in that non-chemically A compound of general formula I according to claims 1 to 6 in one or more inert customary carriers and / or Diluent is incorporated. 10. Use of a compound of general formula I according to the claims I to 6 as an aid for the production and cleaning supply of antibodies. 11. Use of a compound of general formula I according to Claims 1 to 6 for the radioactive label for Ver in RIA or ELISA assays. 12. A process for the preparation of the novel piperazine derivatives of the general formula I according to claims 1 to 6, characterized in that

• a) a compound of general formula II,
  in the
  R ¹ , R ³ , R ⁴ and Z are as defined in claims 1 to 5 and
  X is the hydroxy group, a halogen atom, an alkylsulfonyloxy group having 1 to 10 carbon atoms, an optionally substituted by chlorine or bromine atoms, by methyl or nitro groups mono-, di- or trisubstituted phenylsulfonyloxy or Naph thylsulfonyloxygruppe, wherein the substituents are the same or different ver may mean, or the 1H-imidazol-1-yl radical,
  with an α-amino acid derivative of the general formula III,
  HBC, (III)
  in the
  B and C are as defined in claims 1 to 5, coupled and, if necessary, subsequently a protecting group used is split off or a precursor function is modified or
• b) for the preparation of a compound of the general formula I in which B has the meanings mentioned in claims 1 to 5 with the exception of a single bond, a compound of the general formula IV,
  in the
  R ¹ , R ³ , R ⁴ and Z are as defined in claims 1 to 5 and X are as defined under a) and B has the meanings indicated in claims 1 to 5 with the exception of a single bond,
  with a compound of general formula V,
  HC (V),
  in which C is as defined in claims 1 to 5, coupled and, if necessary, subsequently a protective group used is split off or a precursor function is modified or
• c) for the preparation of a compound of general formula I in which C has the meanings given in claims 1 to 5 with the exception of a hydroxy group, a compound of general formula VI,
  R ¹ -N NH, (VI)
  in the
  R ¹ and Z are as defined in claims 1 to 5,
  with a carboxylic acid derivative of the general formula VII,
  in the
  B, R ³ and R ^{4 are} as defined in claims 1 to 5 and X are as defined under a) and C has the meanings mentioned in claims 1 to 5 with the exception of the hydroxy group, gekup pelt and, if necessary, then a used Cleaved protection group or a precursor function is modified or
• d) a halogen compound of the general formula VIII,
  R ¹ -Z-Hal, (VIII)
  in the
  R ¹ and Z are as defined in claims 1 to 5 and Hal represents a halogen atom, with a piperazine derivative of general Formula IX,
  in the
  R ³ , R ⁴ , B and C are as defined in claims 1 to 5 defifniert reacted and, if necessary, then cleaved a protecting group used or a precursor function is abgegewan delt or
• e) for the preparation of a compound of the general formula I in which B is the bivalent radical of the amino acid phenylalanine which is substituted in the 2-, 3- or 4-position of the phenyl moiety by an aminoimino group, a compound of the general formula X
  in the
  R ¹ , R ³ , R ⁴ , C and Z are as defined in claims 1 to 5 and B ^{1 is} the bivalent radical of the amino acid phenylalanine which is substituted in the 2-, 3- or 4-position of the phenyl moiety by a cyano group , means
  with an alcohol of general formula XI,
  R ⁵ -OH, (XI)
  in the
  R ^{5 is} as defined in claims 1 to 5, reacted and then a compound thus obtained is treated with ammonia or
• f) for the preparation of a compound of the general formula I in which B is the bivalent radical of the amino acid phenylalanine which is substituted in the 2-, 3- or 4-position of the phenyl moiety by an aminoimino group, a compound of the general formula XII,
  in the
  R ¹ , R ³ , R ⁴ , C and Z are as defined in claims 1 to 5 and B ^{2 is} the bivalent radical of the amino acid phenylalanine which is in the 2-, 3- or 4-position of the phenyl part by an amino (hydroxyimino) methyl group is substituted, is hydrogenolysed or
• g) for the preparation of a compound of general formula I in which B is the bivalent radical of the amino acid phenylalanine, which is substituted in the 2-, 3- or 4-position of the phenyl moiety by a Aminoimi nomethylgruppe, means a nitrile of all general formula X. .
  in the
  R ¹ , R ³ , R ⁴ , C and Z are as defined in claims 1 to 5 and B ^{1 is} the bivalent radical of the amino acid phenylalanine which is substituted in the 2-, 3- or 4-position of the phenyl moiety by a cyano group , means
  in a thioamide of general formula XIII
  in the
  R ¹ , R ³ , R ⁴ , C and Z are as defined in claims 1 to 5 and B ^{3 is} the bivalent radical of the amino acid phenylalanine which is substituted in the 2-, 3- or 4-position of the phenyl moiety by an amino thiocarbonylgruppe , means converted, and then a compound of formula XIII thus obtained with a compound of general formula XIV
  R ⁵ -X ² , (XIV)
  in the
  R ^{5 is} as defined in claims 1 to 5 and X ^{2 represents} a leaving group,
  or with a trialkyloxonium tetrafluoroborate of the general formula XV,
  (R ⁵ ) ₃ OBF ₄ , (XV)
  in the
  R ^{5 is} as defined in claims 1 to 5, alkylated and
  then a resulting compound is aminolysed or
• h) for the preparation of a compound of general formula I in which B is the divalent residue of the amino acid lysine substituted by a phenylmethoxycarbonyl group on the N ⁶ atom, a compound of general formula XVI,
  in the
  R ¹ , R ³ , R ⁴ , C and Z are as defined in claims 1 to 5 and B ⁴ denotes the bivalent radical of the amino acid lysine, with a compound of general formula XVII,
  in the
  X ^{3 is} a leaving group, is reacted and
  if desired, subsequently a diastereomeric mixture of the general formula I obtained in this way is separated into the individual diastereomers and / or
  a resulting racemate of a compound of the general For mel I is separated into their enantiomers and / or
  a compound of the general formula I thus obtained is converted into its salts with inorganic acids or bases, in particular for pharmaceutical use in its physiologically tolerated salts.