EP0865425A1 - Amino acid derivatives, medicaments containing said compounds and methods of producing them - Google Patents

Abstract

The invention relates to novel amino acid derivatives of general formula (I), in which R, U, V, Y, n, m and R1-R3 have the definitions shown in claim 1, and to their tautomers, diastomers, enantiomers, mixtures and salts, in particular their physiologically tolerable salts with inorganic or organic acids or bases, which have useful pharmacological properties, in particular selective NPY-antagonistic properties. Also disclosed are medicaments containing these compounds, their use and methods of producing them.

Description

 uredeπvate, pharmaceuticals containing these compounds and process for their preparation

μ of the present invention are new amino acid general formula

their tautomers, their diastereomers, their enantiomers, their mixtures and their salts, in particular their physiologically acceptable salts with inorganic or organic acids or bases, medicaments containing these compounds, their use and process for their preparation.

Ammosaur derivatives with NPY-antagonistic properties have already been described in WO 94/17035.

In the above general formula I mean

R is a phenyl, 1-naphthyl or 2-naphthyl group, a 5-membered heteroaromatic ring linked via a carbon atom, which has a nitrogen, oxygen or sulfur atom or a nitrogen and an oxygen, sulfur or contains another nitrogen atom, whereby an embroidery Substance atom of an immune group can be substituted by an alkyl, alkoxycarbonylalkyl, carboxyalkyl, dialkylaminoalkyl, aminocarbonyl, alkylammocarbonyl, dialkylammocarbonyl or alkoxycarbonyl group, or a 6-membered heteroaromatic ring linked via a carbon atom, which Contains 1, 2 or 3 nitrogen atoms, it being possible for a 1,4-butadienenylene group to be added to both the 5-glιedrιgen and the 6-glιedrιgen heteroaromatic rings via two adjacent carbon atoms and the bicyclic heteroaromatic rings formed in this way also via em Carbon atom of the 1,4-butadιenylene group can be bound and

the groups mentioned above for R and the mono- and bicyclic heteroaromatic rings in the carbon structure additionally by fluorine, chlorine or bromine atoms, by alkyl groups, cycloalkyl groups with 3 to 8 carbon atoms, alkoxy, phenyl, phenylalkoxy, trifluoromethyl, Alkoxy- carbonylalkyl-, carboxyalkyl-, dialkylaminoalkyl-, hydroxy-, amino-, acetylamino-, propionylammo-, benzoyl-, benzoylammo-, benzoylmethylamino-, aminocarbonyl-, alkylammocarbonyl-, dialkylammocarbonyl-, alkanoyl-, cyanoxy-, trifluoro Trifluoromethylthio, trifluoromethylsulfmyl or Tπ-fluoromethylsulfonyl groups can be mono-, di- or maximally trisubstituted, whereby the substituents can be the same or different and the above-mentioned benzoyl, benzoylammo- and benzoylmethylamino groups in turn in the phenyl part additionally by em fluorine -, chlorine or bromine atom, an alkyl, trifluoromethyl, amino or acetylamino group can be substituted,

or the diphenylmethyl group, m the

the phenyl groups can be mono- or disubstituted independently of one another by fluorine, chlorine or bromine atoms, methyl, methoxy, hydroxycarbonyl methoxy, alkoxycarbonyl methoxy, hydroxyl or trifluoromethyl groups, where the substituents can each be the same or different,

n the numbers 0, 1 or 2,

U the single bond, the oxygen atom or the -NH group,

R ^{1 is} the hydrogen atom,

a straight-chain or branched alkyl group with 1 to 8 carbon atoms, which may be substituted by a cycloalkyl group with 3 to 8 carbon atoms, or a cycloalkyl group with 3 to 8 carbon atoms, the groups in turn being eme alkoxycarbonyl, phenyl nylalkoxycarbonyl, carboxy, amino, monoalkylammo, dialkylammo or dialkylammomethyl group can be substituted,

a branched or unbranched alkylcarbonyl radical comprising 2 to 5 carbon atoms, which may be substituted in the alkyl part by an alkoxycarbonyl or phenylalkoxycarbonyl group, by a phenyl group or by a 5- or 6-membered heteroaromatic ring linked via a carbon atom, or a benzoyl radical , in which the phenyl part can also be replaced by a 5- or 6-membered heteroaromatic ring linked via a carbon atom, the abovementioned 5-membered heteroaromatic rings having a nitrogen, oxygen or sulfur atom or a nitrogen atom. and contain an additional oxygen, sulfur or further nitrogen atom and can also be substituted on a nitrogen atom by an alkyl group which contain 6-membered heteroaromatic rings 1, 2 or 3 nitrogen atoms and the abovementioned phenyl groups and all of them heteroaromatic rings in carbon skeleton additional I by fluorine, chlorine or bromine atoms, by alkyl groups, cycloalkyl groups with 3 to 8 carbon atoms, alkoxy, trifluoromethyl, alkoxycarbonylalkyl , Carboxyalkyl, hydroxy, amino, acetylammo-, propionylammo-, aminocarbonyl-, alkylammocarbonyl-, dialkyl- ammocarbonyl-, alkanoyl-, cyano-, trifluoromethoxy-, trifluoromethylthio-, trifluoromethylsulfinyl- or trifluoromethylsul- mono- -, di- or maximally trisubstituted sem, where the substituents can be the same or different sem,

the ammocarbonyl group which is formed on the nitrogen atom by alkyl, phenylalkyl, (1-naphthyl) alkyl, (2-naphthyl) alkyl, alkoxycarbonylalkyl, phenylalkoxycarbonylalkyl, phenoxycarbonylyl, carboxyalkyl, diphenylalkyl, phenyl , Cycloalkyl- or Cycloalkylalkylgruppen each with 3 to 8 carbon atoms in the Rmg can be mono- or disubstituted, where the substituents can be the same or different and the above-mentioned phenyl radicals in turn by fluorine, chlorine or bromine atoms, methyl, methoxy -, Hydroxycarbonylmeth- oxy-, Alkoxycarbonylmethoxy-, Hydroxy- or Trifluormethyl- groups can be independently mono- or disubstituted,

an alkoxycarbonyl or phenylalkoxycarbonyl radical, where the phenyl part in turn may be mono- or disubstituted by fluorine, chlorine or bromine atoms, methyl, methoxy, hydroxycarbonylmethoxy, alkoxycarbonyl methoxy, hydroxy or trifluoromethyl groups and the substituents are in each case the same or different could be,

a phenyl or phenylmethyl group, a hetaryl or hetarylmethyl group linked via a carbon atom, where hetaryl has a five-membered heteroaromatic ring which is a nitrogen, oxygen or sulfur atom or a nitrogen and oxygen and sulfur or em further Contains nitrogen atom and in which a nitrogen atom of an immune group can be substituted by an alkyl group or a 6-membered hetero-aromatic ring linked via a carbon atom which contains 1, 2 or 3 nitrogen atoms, means and wherein both the phenyl group and hetaryl in the carbon structure additionally by fluorine, chlorine or bromine atoms, by alkyl groups, cycloalkyl groups having 3 to 8 carbon atoms, phenylalkyl, alkoxy, trifluoromethyl, alkoxycarbonylalkyl, carboxyalkyl -, Hydroxy-, Amo-, Acetyl- ammo, Propionylammo-, Aminocarbonyl-, Alkylammocarbonyl-, Dialkylammocarbonyl-, Alkanoyl-, Cyano-, Trifluoromethoxy-, Trifluoromethylthio-, Trifluoromethylsulfmyl- or Tπfluorme- methyl- sulfonyl groups can be trisubstituted and the substituents can be the same or different,

R2 represents the hydrogen atom, an alkyl or phenylalkyl group, which in the phenyl part can also be mono- or disubstituted by fluorine, chlorine or bromine atoms, alkyl, trifluoromethyl, amino or acetylamino groups, where the substituents can be the same or different,

P ^{3 represents} the hydrogen atom or an alkyl group,

Y is the oxygen atom or the -NR ^ group in which

R ^ represents the hydrogen atom, a branched or unbranched alkyl group having 1 to 6 carbon atoms or the phenylmethyl group,

m the numbers 1 or 2

and

V is the hydrogen atom, the fluorine, chlorine, bromine or iodine atom, a cyano, alkyl, hydroxy, alkoxy, phenylalkoxy, alkylcarbonyl, dialkylamino, hydroxymethyl, hydroxyethyl, hydroxypropyl , Hydroxybutyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio group or the group - (CH2) _Q -Y ^ -WY ² , in which o the numbers 0, 1 or 2,

W is the -Sθ2 ~ group or the group> C = X, in which

X represents the oxygen atom or one of the divalent radicals = N-CONH ₂ or = N-CN,

Y ^{1 is} the single bond, the oxygen atom or the radical -NR - * -, in which

R- ^{> represents} the hydrogen atom or a straight-chain or branched alkyl group having 1 to 6 carbon atoms or

R ^ together with the group Y ² , the enclosed nitrogen atom and the enclosed group> C = X forms a saturated heterocyclic ring with 5 to 7 ring members,

Y ² eme optionally substituted by a hydroxy, alkoxycarbonyl or Ammocarbonylgruppe substituted straight or branched alkyl group having 1 to 10 carbon atoms, a cycloalkyl group having 4 to 10 carbon atoms, eme ge radkettige or branched alkoxy group having 1 to 5 carbons ^¬ atoms, an aminoalkyl , Alkylaminoalkyl, dialkylaminoalkyl, phenylmethoxy or 2-phenylethoxy group, one in the phenyl part optionally by fluorine, chlorine or bromine atoms, by methyl, trifluoromethyl, cyano, amino, hydroxyl, methoxy, acetyl , Acetylammo-, Aminocarbonyl-, Methylaminocarbonyl- or Dimethylaminocarbonylgruppen mono-, di- or tri-substituted phenyl or phenylalkyl group with 1 to 3 carbon atoms in the alkyl part or

the -NR ^ R ⁷ group in which

R ^ is the hydrogen atom, optionally by a hydroxy, carboxy, alkoxycarbonyl or dialkylamino group-substituted straight-chain or branched alkyl group with 1 to 6 carbon atoms with the proviso that the hydroxy group is not bonded in 1-position of the alkyl group, a cycloalkyl group with 4 to 8 carbon atoms or in the phenyl part, optionally by fluorine or chlorine or bromine atoms, mono-, di- or tri-substituted phenyl, phenylmethyl- by methyl-, trifluoromethyl-, hydroxy-, methoxy-, amino-, acetylammo-, aminocarbonyl-, methylaminocarbonyl-, dimethylaminocarbon- or cyano groups. , 2-phenylethyl or 3-phenylpropyl group, where the substituents may be the same or different, represents an alkanoyl, benzoyl, phenylalkanoyl, alkoxycarbonyl or ammocarbonyl group and

R ^{7 has} the meanings given for R with the exception of that of a phenyl, alkanoyl, benzoyl, phenylalkanoyl, alkoxycarbonyl and ammocarbonyl group or

R ⁶ and R ⁷ together represent an n-alkylene group with 4 to 6 carbon atoms or

R ⁷ together with the radical R ^ of the group mentioned above for Y ¹ denotes —NR ^ - an unbranched alkylene group or oxoalkylene group having 2 to 4 carbon atoms,

where all the above-mentioned alkyl, cycloalkylalkyl, alkoxy, phenoxycarbonylalkyl, phenylalkoxy, phenylalkoxycarbonyl, phenylalkoxycarbonylalkyl, phenylalkanoyl, phenylalkyl, diphenylalkyl, naphthylalkyl, alkoxycarbonylalkyl, alkoxycarbonylmethoxy, carboxyalkyl, Aminoalkyl, monoalkylammo, dialkylammo, alkylaminoalkyl, dialkylaminomethyl, dialkylaminoalkyl, alkylammocarbonyl, dialkylammocarbonyl, alkanoyl and alkoxycarbonyl radicals, unless stated otherwise, can each contain 1 to 5 carbon atoms in the alkyl and alkoxy moieties . For the meanings mentioned above when defining the radicals, for example

for R the meaning of phenyl, diphenylmethyl, 2-pyridmyl, 3-pyridnyl, 4-pyridmyl, 2-thenyl, 3-thenyl, 2-furyl, 3-furyl, lH- Pyrrol-2-yl-, 1H-pyrrol-3-yl-, 1-methyl-1H-pyrrol-2-yl-, 1-methyl-1H-pyrrol-3-yl-, 1-naphthyl-, 2 -Naphthyl-, lH-indol-2-yl-, lH-indol-3-yl-, lH-indol-4-yl-, lH-indol-5-yl-, lH-indol-6-yl-, lH -Indol-7-yl-, benzo- [b] furan-2-yl-, benzo [b] furan-3-yl-, benzo [b] thiophen-2-yl-, benzo [b] thiophen-3- yl-, 2-Chιnolmyl-, 3-Chιnolιnyl-, 4-Chmo- Imyl-, Benzo [c] thιophen-1-yl-, 1-Isochmolιnyl-, 3-Iso-quinolinyl-, 4-Isochmolιnyl-, Pyrazmyl- , 2-Pyrιmιdιnyl-, 4-Pyrιmιdιnyl-, 5-Pyrιmιdmnyl-, 3-Pyrιdazmyl-, 4-Pyrιdazm- yl-, 2-Imιdazolyl-, 4-Imιdazolyl-, lH-Benzιmιdazol-5-ylol., 3 -, 4-pyrazolyl-, 1,3-oxazol-2-yl-, 1,3-oxazol-4-yl-, 1,3-oxazol-5-yl-, 3-isoxazolyl-, 4-isoxazolyl -, 5-Isoxazolyl-, 2-Chmazolιnyl-, 4-Chιnazolιnyl- or 2-Chιn-oxalmyl group, these additionally by the above-mentioned rest e can be substituted,

for V the meaning of acetylammomethyl-, ethoxycarbonyl- ammomethyl-, aminosulfonylaminomethyl-, ammocarbonylaminomethyl-, ammocarbonylmethyl-, methylammosulfonylmethyl-, meth- oxycarbonylaminomethyl-, methylammocarbonylammomethyl-, benzoylammomethyl- methylamyl- methylamyl- methylammylammylammyl- methylamyl- methylamyl- methylamyl- methylamyl- methylamyl- methylamyl- methylamyl- methylamyl- methylamyl- methylamyl- methylamyl- methyl-amyl-methyl-amyl-methyl-amyl-methyl-amyl-methyl-amyl-methyl-methyl-phenyl-ammonium-methyl-methyl-phenyl-ammonium-methyl-methyl- , 1-Methylethylamι- nocarbonylammomethyl-, [[Ammo (ammocarbonylimino) methyl] - amino] methyl-, ethoxycarbonylaminocarbonylammomethyl-, prostitute thy 1 aminocarbonyl ammome thyl-, aminocarbonyloxymethyl-, tert. Butoxycarbonylammomethyl-, Aminocarbonylammocarbon- ylammomethyl-, [(Ammo (cyanimmo) methyl] amino] methyl-, Meth-oxycarbonylmethyl-, Methylaminocarbonylmethyl-, [[((Dimethyl¬ amino) carbonyl] methylammo] methyl-, [(Aminocarbonyl) methyl- ammo ] methyl-, [[(methylamino) carbonyl] methylamino] methyl-, [(methoxycarbonyl) methylamιno] methyl-, [[(carboxymethyl) ami- no] carbonyl] methyl-, [[[bis (carboxymethyl)] amino] carbonyl] - methyl-, [[[bis (methoxycarbonylmethyl)] amino] carbonyl] methyl-, [(ethoxycarbonylaminocarbonyl) methylamino] methyl-, ethoxycarbonylmethylaminocarbonylammomethyl-, Carboxymethyl-ammocarbonylammomethyl-, dimethylammocarbonylmethyl-, 2- (aminocarbonyl) ethyl-, (2-0xo-l-ιmιdazolιdmyl) methyl-, 2- (3-methyl-l, 2, 4-oxadιazol-5-yl) ethyl-, 2- (methoxycarbonyl) ethyl, [(4-ammo-l, 4-dioxobutyl) ammo] methyl or 2- (ammocarbonylammo) ethyl group and

for R ^x the meaning of methyl, methoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl, butyloxycarbonyl, methoxycarbonylethylcarbonyl, aminocarbonyl, methylaminocarbonyl, ethylammocarbonyl, dimethylaminocarbonyl, propylaminocarbonyl, butylammocarbonyl, phenylaminocarbonyl , Benzyl- ammocarbonyl-, (2-phenylethyl) aminocarbonyl-, (3-phenylpropyl) aminocarbonyl-, (3, 3-Dιphenylpropyl) aminocarbonyl-, 1-naphthylmethylaminocarbonyl-, 2-naphthylmethylammocarbonyl-, cyclohexylammocarbonyl 4-methoxyphenyl) butyl ammocarbonyl, hydroxycarbonylethylammocarbonyl, ethoxy carbonylethylaminocarbonyl, methoxyphenyl, 4- (dimethyl aminomethyl) cyclohexylmethyl, benzoyl, 4-fluorobenzoyl, nicotmoyl, isomcotmoyl , 3-thιenyl, 2-furyl, 3-furyl, 1H-pyrrol-2-yl, 1H-pyrrol-3-yl, 1-methyl-1H-pyrrol-2-yl, 1-methyl -lH-pyrrol-3-yl-, pyrazmyl-, 2-pyrι- midmyl-, 4-pyrιmιdmyl-, 5-pyrιmιdmyl-, 3-pyrιdazιnyl-, 4-pyrιdazιnyl-, 2-imιdazolyl-, 4-imιd azolyl-, 3-pyrazolyl-, 4-pyrazolyl-, 1,3-oxazol-2-yl-, 1,3-oxazol-4-yl-, 1,3-oxazol-5-yl-, 3- Isoxazolyl-, 4-isoxazolyl-, 5-isoxazolyl-, 2-thιazolyl-, 4-methyl-2-thιazolyl-, 5-methyl-2-thιazolyl-, 4- (2-phenylethyl) -2-thιazolyl-, 4th - (3-Phenylpropyl) -2-thιa- zolyl-, 2-pyrιdmyl-, 3-pyrιdιnyl-, 4-pyπdmyl- or 5-methyl-2-pyπdmylgruppe into consideration.

The present invention relates to the racemates, provided that in compounds of the general formula I the asymmetric carbon atom of the central amino acid is the only chirality element is. However, the application also includes the individual diastereomers or mixtures thereof, which are present when a compound falling under general formula I contains two or more than two chiral elements. Particularly preferred are the compounds falling under general formula I, those with regard to the partial amino acid structure

D or (R) configured.

The compounds of the general formula I have valuable pharmacological properties which are based on their selective NPY-antagonistic properties. The invention further relates to medicaments containing these compounds, their use and their preparation.

The compounds of the general formula are preferred

in the R, n, U, R ¹ , R ² , R ³ , V, Y and m are defined as mentioned at the beginning,

V m 3- or 4-position of the benzene ring is bound and the hydrogen atom, the fluorine, chlorine, bromine or iodine atom, eme cyano, alkyl, hydroxy, alkoxy, alkylcarbonyl, dialkylamino, hydroxymethyl -, Hydroxyethyl, hydroxypropyl, hydroxybutyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio group or the group - (CH ₂ ) o " ^γl ~ < ^c °) -WY ² , in which

o, Y ^ and Y ² are defined as mentioned at the beginning,

where the alkyl, alkoxy, alkylcarbonyl and dialkylamino radicals mentioned above for V, unless otherwise stated, can each contain 1 to 5 carbon atoms in the alkyl and alkoxy parts,

their tautomers, their diastereomers, their enantiomers and their salts.

Those compounds of the above general formula Ia in which

R is a phenyl, 1-naphthyl or 2-naphthyl group, a 5-glutoidal heteroaromatic ring linked via a carbon atom, which contains a nitrogen, oxygen or sulfur atom, with a nitrogen atom of an immune group being substituted by an alkyl group may, or a 6-membered heteroaromatic Rmg linked via a carbon atom, which contains 1 or 2 nitrogen atoms, the groups mentioned above for R and heteroaromatic rings in the carbon skeleton additionally being provided by a fluorine, chlorine or bromine atom, by an alkyl group, by a cycloalkyl group with 3 to 6 carbon atoms, by an alkoxy, phenyl, phenylalkoxy, trifluoromethyl, alkoxycarbonylalkyl, carboxyalkyl, dialkylaminoalkyl, hydroxy, amino, acetyl - 12 -

ammo-, propionylammo-, benzoyl-, benzoylammo-, benzoyl-methylammo-, aminocarbonyl-, alkylammocarbonyl-, dialkylammo- carbonyl-, alkanoyl-, cyano- or trifluoromethoxy-group can be substituted,

or the diphenylmethyl group, m the

the phenyl groups can be substituted independently of one another by a fluorine, chlorine or bromine atom, by a methyl, methoxy, hydroxycarbonylmethoxy, alkoxycarbonylmethoxy, hydroxy or trifluoromethyl group,

n the numbers 0 or 1,

U the education,

R ^{1 is} the hydrogen atom,

a straight-chain or branched alkyl group with 1 to 5 carbon atoms, which may be substituted by a cycloalkyl group with 4 to 7 carbon atoms, or a cycloalkyl group with 4 to 7 carbon atoms, the groups mentioned being themselves a alkoxycarbonyl, phenylalkoxycarbonyl , Carboxy, amino, monoalkylammo, dialkylamino or dialkylammomethyl group can be substituted,

a branched or unbranched aliphatic acyl radical comprising 2 to 4 carbon atoms, which may be substituted by an alkoxycarbonyl, phenylalkoxycarbonyl or optionally by a fluorine, chlorine or bromine atom, by an alkyl group or a cycloalkyl group having 4 to 7 carbon atoms Phenyl group substituted by alkoxy, trifluoromethyl, hydroxy, ammo, acetylammo or cyano group, or a benzoyl radical, the ammocarbonyl group which is formed on the nitrogen atom by an alkyl, phenylalkyl, (1-naphthyl) alkyl, (2-naphthyl) alkyl, alkoxycarbonylalkyl, carboxyalkyl, ω, ω-diphenylalkyl, phenyl, cycloalkyl or cycloalkylalkyl group each having 3 to 6 carbon atoms in the Rmg, where the phenyl radicals in the above-mentioned groups can in turn be substituted by a fluorine, chlorine or bromine atom, by a methyl, methoxy, hydroxyl or trifluoromethyl group,

an alkoxycarbonyl or phenylalkoxycarbonyl radical which can be substituted in the phenyl part by a fluorine, chlorine or bromine atom, by a methyl, methoxy, hydroxyl or trifluoromethyl group

a phenyl group or a five-membered heteroaromatic ring which is bonded via a carbon atom and which contains a nitrogen, oxygen or sulfur atom, where a nitrogen atom of an immune group can be substituted by an alkyl group, or a 6 linked via a carbon atom -glιedrιgen heteroaromatic Rmg, which contains 1 or 2 nitrogen atoms, both the phenyl group and the 5- and 6-glιedrιgen heteroaromatic rings in the carbon structure additionally by a fluorine, chlorine or bromine atom, by an alkyl group, by a Cycloalkyl group with 3 to 6 carbon atoms, can be substituted by a phenylalkyl, alkoxy, trifluoromethyl, hydroxyl or amino group,

R ² is the hydrogen atom, an alkyl group or a phenyl ^¬ in part optionally substituted by em fluorine, chlorine or bromine atom, an alkyl, trifluoromethyl, or ammonium Acetylammogruppe phenylalkyl,

R ^{3 represents} the hydrogen atom or the methyl group,

Y is the oxygen atom or the -NR ⁴ group, m the R ^ represents the hydrogen atom, the methyl or ethyl group,

V, which is bound in the 4-position of the benzene ring, the hydrogen, fluorine, chlorine or bromine atom, a cyano, alkyl, hydroxy, alkoxy, phenylalkoxy, alkylcarbonyl, dialkylamino, Hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl or trifluoromethyl group or the group - (CH ₂ ) o ^{~ γl_} ( ^c °) " ^γ2 means in which

o the numbers 0 or 1,

Y ^x the simple formation, the oxygen atom or the radical -NR5-, m the

R ^ represents the hydrogen atom or a straight-chain or branched alkyl group having 1 to 4 carbon atoms or

R together with the group Y ² , the enclosed nitrogen atom and the enclosed group> C = 0 forms a saturated heterocyclic Rmg with 5 to 7 Rmg limbs, and

Y ² eme, optionally substituted by a hydroxyl, alkoxycarbonyl or ammocarbonyl group, straight-chain or branched alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, an aminoalkyl, alkylaminoalkyl or dialkylammoalkyl group or one in the phenyl part optionally by em fluorine -, Chlor¬ or bromine, by a methyl, trifluoromethyl, cyano, amino, hydroxyl or methoxy group substituted phenyl or phenylalkyl group having 1 to 3 carbon atoms in the alkyl part or the -NR ^ R ⁷ group means m the

R ^{6 is} the hydrogen atom, a straight-chain or branched alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 4 to 6 carbon atoms or one optionally by a fluorine, chlorine or bromine atom, by a methyl, trifluoromethyl, hydroxyl or meth - represents oxy group substituted phenyl group and

R ^{7 has} the meanings given for R ⁶ with the exception of that of a phenyl group,

where all the above-mentioned alkyl, alkoxy, phenylalkyl, ω, ω-diphenylalkyl, naphthylalkyl, cycloalkylalkyl, phenylalkoxy, phenylalkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylmethoxy, carboxyalkyl, alkylamino, dialkylamino , Dialkylaminoalkyl, alkylammocarbonyl, dialkylammocarbonyl, alkanoyl and alkoxycarbonyl radicals, unless stated otherwise, can each contain 1 to 5 carbon atoms in the alkyl and alkoxy parts,

their tautomers, their diastereomers, their enantiomers and their salts.

Those compounds of the general formula Ia, m above are very particularly preferred

R is the diphenylmethyl group, in which the phenyl groups can be substituted independently of one another by a methyl group,

n is the number 0,

U the simplification,

Rl is the hydrogen atom, a straight-chain or branched alkyl group with 1 to 3 carbon atoms, which may be substituted by a cycloalkyl group with 4 to 6 carbon atoms, the cycloalkyl group in turn being substituted by a dialkylammomethyl group with 1 to 3 carbon atoms in the alkyl parts,

the ammocarbonyl group, which can be substituted on the nitrogen atom by an alkyl group having 1 to 3 carbon atoms, or

a phenyl group optionally substituted by an alkyl or alkoxy group having 1 to 3 carbon atoms,

R ^{2 is} the hydrogen atom, an alkyl group with 1 to 3 carbon atoms which is optionally substituted by a phenyl group,

R ^{3 represents} the hydrogen atom or the methyl group,

Y the -NR ^ group, m the

R ^ represents the hydrogen atom, which represents methyl or ethyl group,

m the number 1 and

V, which is bonded in the 4-position of the benzene ring, denotes the hydrogen atom, a hydroxyl or phenylalkoxy group having 1 to 3 carbon atoms in the alkoxy part or the group -CH2-Y ¹ - (CO) -Y ² , in which

Y ^{1 is} the single bond or the residue -NR ^ -, m the R ^ represents the hydrogen atom or a straight-chain or branched alkyl group having 1 to 3 carbon atoms, and

Y ^{2 represents} the -NR ⁶ R ⁷ group, m the

R ⁶ and R ⁷ independently of one another represent the hydrogen atom or a straight-chain or branched alkyl group having 1 to 3 carbon atoms,

their tautomers, their diastereomers, their enantiomers and their salts.

The following may be mentioned as particularly preferred compounds:

(1) (R, S) -3- (Ammolrαmomethylammo) -α- [(diphenylacetyl) - ammo] -N- [(4-hydroxyphenyl) methyl] -benzenacetamide,

(2) (R, S) -N- [[4- (aminocarbonylammomethyl) phenyl] methyl] - 3- (ammoiminomethylammo) -α- [(diphenylacetyl) amino] - benzenacetamide,

(3) (R, S) -N- [[4- (aminocarbonylmethyl) phenyl] methyl] -3- (aminoimmomethylamino) -α- [(diphenylacetyl) ammo] -benzene acetamide,

(4) trans- (R, S) -3- [[4- (dimethylammomethyl) cyclohexylmethyl] aminoimmomethylamino] -α- [(diphenylacetyl) amino] - N-methyl-N- (phenylmethyl) -benzenacetamide,

(5) (R, S) -α- [(diphenylacetyl) amino] -N-methyl-3- (phenylaminoiminomethylammo) -N- (phenylmethyl) -benzenacetamide,

(6) (R, S) -3- (ammolminomethylamino) -α- [(diphenylacetyl) amino] -N-methyl-N- (phenylmethyl) -benzenacetamide, (7) (R, S) -α- [(diphenylacetyl) ammo] -N-methyl-3- (methy1-aminoimmomethylammo) -N- (phenylmethyl) -benzenacetamide,

(8) trans- (R, S) -N- [[4- (ammocarbonylammomethyl) phenyl] methyl] -3- [[4- (dimethylammomethyl) cyclohexylmethyl] ammoimmomethylammo] -α- [(diphenylacetyl) ammo] - benzene acetamide,

(9) (R, S) -N- [[4- (ammocarbonylammomethyl) phenyl] methyl] - α- [(diphenylacetyl) amino] -3- [(methylaminocarbonyl) ammoimmomethylammo] -benzenacetamide,

(10) (R, S) -N- [[4- (ammocarbonylammomethyl) phenyl] methyl] - α- [(diphenylacetyl) ammo] -3- [(4-methoxyphenyl) amino-iminomethylamino] -benzenacetamide,

(11) (R, S) -α- [(diphenylacetyl) ammo] -3- [(4-methoxyphenyl) - ammoimmomethylamino] -N- (phenylmethyl) -benzenacetamide,

(12) (R, S) -N- [[4- (Ammocarbonylammomethyl) phenyl] methyl] - α- [(diphenylacetyl) ammo] -3- [[imino [N-methyl-N- (phenyl¬ methyl) ammo ] methyl] ammo] -benzenacetamide,

(13) (R, S) -N- [[4- (ammocarbonylammomethyl) phenyl] methyl] - α- [(diphenylacetyl) ammo] -3- (methylammoimmomethylamino) -benzenacetamide,

(14) (R, S) -α- [(diphenylacetyl) amino] -3- [(4-methoxyphenyl) - ammoimmomethylamino] -N- [[(4-phenylmethoxy) phenyl] - methyl] -benzenacetamide,

(15) (R, S) -3- (aminolmmomethylammo) -α- [(diphenylacetyl) - ammo] -N- [[(4-phenylmethoxy) phenyl] methyl] -benzenacetamide, (16) (R, S) -3- (aminoiminomethylamino) -α- [(diphenylacetyl) - ammo] -N-methyl-N- [[(4-phenylmethoxy) phenyl] methyl] - benzacetamide,

(17) (R, S) -N- [[4- (aminocarbonylammomethyl) phenyl] methyl] - α- [(diphenylacetyl) ammo] -N-methyl-3- (methylammo-immomethylamino) -benzenacetamide

and their salts.

The compounds of the general formula I are prepared by methods which are known in principle, methods derived in particular from peptide chemistry (see, for example, Houben-Weyl, Methods of Organic Chemistry, Vol. 15/2) being used. The ammo-protecting groups that can be used are those described in Houben-Weyl, Methods of Organic Chemistry, Vol. 15/1, urethane protecting groups, such as. B. the fluorenylmethoxycarbonyl, phenylmethoxycarbonyl or tert-butyloxycarbonyl group, are preferred. Functional groups which may be present in the precursors for the synthesis of the compounds of the general formula I, for example guanidino or ammo functions, can be prevented by suitable protective groups in order to prevent side reactions (see, for example: GB Fields et al., Int. J Peptide Protein Res. _3_5 ' ¹⁶¹ (1990); TW Greene, Protective Groups in Organic Synthesis). It is particularly important to ensure that so-called orthogonal combinations of protective groups are used for the protection of the α-amino and the side chain function, for. B .: Protection of the N (side chain) N ^α protection

p-toluenesulfonyl phenylmethoxycarbonyl tert-butyloxycarbonyl

Phenylmethoxycarbonyl (4-methoxyphenyl) methoxycarbonyl tert. Butoxycarbonyl

Adamantyloxycarbonyl

Biphenylylisopropyloxycarbonyl

Isomcotmoyloxycarbonyl o-nitrophenylsulfenyl

Formyl

tert. Butoxycarbonyl phenylmethoxycarbonyl p-toluenesulfonyl o-nitrophenylsulfenyl biphenylylisopropyloxycarbonyl 9-fluorenylmethoxycarbonyl

Acetyl, trifluoroacetyl, tert-butyloxycarbonyl formyl, (2-chlorophenyl) methoxycarbonyl, (4-chlorophenyl) methoxycarbonyl, 4- (nitrophenyl) methoxycarbonyl, phthaloyl

Instead of protecting side chain amino groups stan-ended, even Pracursor functions may supporting, in the side chain in particular ^¬ sondere substituted by nitro Phenylglycm or its derivatives are used, for example, α-Ammo-3-benz nιtro- acetic acid.

The basic functions m of the side chain of non-commercially available α-amino acids, which are characterized, for example, by (ammoimino-methylammo) groups, can be protected in the same way as is known for the side chain protection of arginine and its derivatives (see also M. Bodanszky, "Peptide Chemistry", Springer-Verlag, 1988, pp. 94-97), Particularly suitable as protective groups for the (ammoimmomethylamino) group are p-toluenesulfonyl-, mesitylenesulfonyl (Mts-), methoxytrimethylphenylsulfonyl (Mtr-) -, 2, 2,5,7, 8-pentamethylchroman-6- sulfonyl (Pmc), pentachlorophenoxycarbonyl and nitro protective group.

The methods known from peptide chemistry are used for the actual coupling (see, for example, Houben-Weyl, Methods of Organic Chemistry, Vol. 15/2). Carbodumides, such as, for example, B. dicyclohexylcarbodiimide (DCC), diisopropylcarbodumide (DIC) or ethyl (3-dimethylammopropyl) carbodumide, 0- (1H-benzotriazol-1-yl) -N, N, N ', N'-tetra-methyluronium hexafluorophosphate ( HBTU) or tetrafluoroborate (TBTU) or lH-Benzotrιazol-1-yl-oxy-tπs- (dimethylamino) - phosphomumhexafluorophosphate (BOP). By adding 1-hydroxybenzotriazole (HOBt) or 3-hydroxy-4-oxo-3, 4-dihydro-1,2,3-benzotrιazm (HOObt), the racemization can, if desired, be additionally suppressed or the Reaction speed can be increased. The couplings are normally made with equimolar proportions of the coupling components and of the coupling reagent in solvents such as dichloromethane, tetrahydrofuran, acetonitrile, dimethylformamide (DMF), dimethyl acetamide (DMA), N-methylpyrrolidone (NMP) or mixtures of these and at temperatures between -30 and + 30 ° C, preferably -20 and + 20 ° C, carried out. If necessary, N-ethyl-diisopropylamm (DIEA; Hunig base) is preferred as the additional auxiliary base.

The so-called "Anhydridverfah¬ ren" (see also: M. Bodanszky, "Peptide Chemistry", Springer-Verlag 1988, pp. 58-59; M. Bodanszky, "Principles of Peptide Synthesis ", Springer-Verlag 1984, pp. 21-27). Preference is given to the "mixed anhydride process" in the variant according to Vaughan (JR Vaughan Jr., J. Amer. Chem. Soc. 7_3 '3547 (1951)), in which using iso-chlorinated carbonate in the presence of bases such as 4-methylmorpholm or 4-Ethylmorpholιn, the mixed anhydride is obtained from the to be coupled, optionally N ² -protected α-amino acid and the carbonic acid monoisobutyl ester. This mixed anhydride is prepared and coupled with amines in a one-pot process, using the abovementioned 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 are finally cleaved off after the N- and C-termally substituted amino acid derivative has been built up using suitable reagents which are also known in principle from the literature, namely arylsulfonyl and hetarylsulfonyl protective groups, preferably acidolytically, ie by Exposure to strong acids, preferably trifluoroacetic acid, nitro and aryl methoxycarbonyl protective groups, hydrogenolytically, for example using hydrogen in the presence of palladium black and using glacial acetic acid as solvent. Does the substrate contain functions sensitive to hydrogenolysis, e.g. B. halogen atoms, such as chlorine, bromine or iodine, a phenylmethanol or hetarylmethanol function or another benzyl heteroatom bond, in particular eme benzyl-oxygen bond, the nitro group can also be split off non-hydrogenolytically, for. B. with Zιnk / 2N trifluoroacetic acid (see also: A. Turan, A. Patthy and S. Bajusz, Acta Chim. Acad. Sei. Hung., Tom. 8_5 (3), 327-332 [1975]; CA 83, 206526y [1975]), with tin (II) chloride in 60% aqueous aqueous formic acid (see also: SUNSTAR KK, JA-A-3271-299), with zinc in the presence of acetic acid (see also: A. Malabarba, P. Ferari, 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 Freidmger, R. Hirschmann and DF Veber, J. Org. Chem. 4_3_ (25), 4800-4803 [1978]). The following processes are particularly suitable for the preparation of the compounds of the general formula I according to the invention:

a) coupling of compounds of the general formula II,

in the

R, R ^x , R ³ , U and n are defined as mentioned at the outset and R ² 'has the meanings mentioned at the outset for R ² or also means one of the protective groups mentioned above for protecting guanidino functions,

with compounds of the general formula III,

in which m, V and Y have the meanings mentioned at the beginning,

and, if necessary, subsequent splitting off of protective groups by the processes described above.

The coupling is carried out using the methods known from peptide chemistry and described above, in particular using DCC, DIC, HBTU, TBTU or BOP as reagents or according to the mixed anhydride method. If the starting compound II used is enantiomeric, then, provided that U is not an oxygen atom and not an NH group, the coupling step must be carried out with a partial solvent using triethylamine as the auxiliary base and dimethylformamide, dimethyl acetamide or N-methylpyrrolidone as the solvent ¬ were also to be expected with extensive or even quantitative racemization.

For the preparation of compounds of the general formula I in which Y represents the oxygen atom, the variant recommended by A. Hassner and V. Alexonian, Tetrahedron Letters 1978, 4475-4478, ie. H. the reaction at room temperature and in the presence of DCC and 4- (1-pyrroleidyl) pyridine as base, particularly preserved.

b) For the preparation of compounds of the general formula I in which U has the meanings mentioned at the outset, with the exception of that of the oxygen atom and the —NH group:

Coupling of compounds of the general formula IV,

R - (CH ₂ ) _n - CO - Nu (IV)

in the

R and n are as defined at the outset and nu eme leaving group, for example the hydroxyl group, em halogen atom, such as the chlorine, bromine or iodine atom, an alkylsulfonyloxy group having 1 to 10 carbon atoms, one optionally by chlorine or bromine atom, by methyl or nitro groups means mono-, di- or tri-substituted phenylsulfonyloxy or naphthylsulfonyloxy group, where the substituents can be the same or different,

with α-ammosa derivatives of the general formula V,

in the

R ¹ , R ³ , V, Y and m are defined as mentioned at the outset and R ² 'has the meanings mentioned at the outset for R ² or also means one of the protective groups mentioned above for the protection of guanidino functions which carry side chains,

and, if necessary, subsequent splitting off of protective groups by the processes described above.

If the general formula IV Nu denotes the hydroxyl group, then the coupling methods known from peptide chemistry, which have been discussed in detail above, are used, in particular using the coupling reagents DCC, DIC, HBTU, TBTU or BOP mentioned, or the mixed method is used Drive anhydride method.

If Nu in the general formula IV denotes a halogen atom, an alkyl or arylsulfonyloxy group, the reaction is carried out under Schotten-Baumann or Einhorn conditions, that is to say the components are in the presence of at least one equivalent of an auxiliary base at temperatures between -50 ° C and + 120 ° C, preferably -10 ° C and + 30 ° C, and optionally reacted in the presence of solvents. Alkali and alkaline earth metal hydroxides, for example sodium hydroxide, potassium hydroxide or barium hydroxide, alkali metal carbonates, eg. B. sodium carbonate, potassium carbonate or casium carbonate, alkali metal acetates, for example sodium or potassium acetate, and tertiary amines, for example Pyridm, 2, 4, 6-methylpyridm, chmoline, triethylamine, N-ethyl-dusopropylamm, N-ethyl-dicyclohexylamine, 1, 4-dιazabιcyclo- [2,2,2] octane or 1, 8-dιazabιcyclo [5, 4 , 0] undec-7-en, as a solvent, for example dichloromethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, dimethylformamide, dimethylacetamide, N-methyl-pyrrolidone or mixtures thereof; If alkali or alkaline earth metal hydroxides, alkali metal carbonates or acetates are used as auxiliary bases, water can also be added to the reaction mixture as cosolvent.

c) For the preparation of compounds of the general formula I in which Y represents an oxygen atom:

Transesterification of amino acid esters of the general formula VI,

m the

R, R ¹ , R ² , R ³ , U and n are defined as mentioned at the beginning and

R ^{8 represents} an alkyl group with 1 to 4 carbon atoms,

with an alcohol of the general formula VII,

in which m and V are as defined at the beginning. The transesterification can be catalyzed acidic or alkaline (see also: J. March, "Advanced Organic Chemistry", John Wiley & Sons, Third Edition, 1985, pp. 351-352). As alkaline catalysts, the corresponding alkali metal alcoholates readily available from the alcohols of the general formulas VII or R ⁸ OH, eg. B. lithium, sodium or potassium alcoholates preferred; as acidic catalysts in addition to anhydrous hydrogen chloride are especially sulfuric acid, p-toluenesulfonic acid, naphthalen-1- or -2-sulfonic acid or acid ions exchangers freshly loaded with hydrogen ions, e.g. B. Wofatit KPS zA. In this process, the equilibrium between the two esters in equilibrium is shifted in the desired direction by distilling off the more volatile alcohol R ⁸ OH.

In alkaline catalysis, even if the starting compound VI has been used enantiomerically, the end product of the general formula I is obtained as a racemate.

d) For the preparation of compounds of the general formula I in which Y represents the oxygen atom:

Reaction of salts, preferably alkali salts, of the carboxylic acids of the general formula II,

m the

R, Rl, R ³ , U and n are defined as mentioned at the beginning and R ^{2 has} the meanings mentioned at the beginning for R ² or else means one of the protecting groups mentioned above for the protection of guanidmo functions,

with compounds of the general formula VIII,

in which m and V are as defined at the beginning and nu ^ eme leaving group, for example a halogen atom, such as the chlorine, bromine or iodine atom, an alkylsulfonyloxy group having 1 to 10 carbon atoms, one optionally by chlorine or bromine atoms Methyl or nitro groups means mono-, di- or tπ-substituted phenylsulfonyloxy or naphthylsulfonyloxy group, where the substituents can be the same or different,

and, if necessary, subsequent splitting off of protective groups by the processes described above.

The reaction is carried out in a suitable solvent, preferably in the presence of dipolar aprotic solvents such as dimethyl sulfoxide, hexamethylphosphoric acid triamide, 1,3-dimethyl-2-dimethylazole, dimethylacetamide, dimethylformamide or N-methyl-2-pyrrolidone at temperatures between -10 ° C and + 50 ° C, but preferably at room temperature. The alkali metal salts of the carboxylic acids of the general formula II are preferably in situ by the action of alkali metal carbonates, e.g. As potassium or cesium carbonate, of alkali hydroxides, e.g. B. sodium hydroxide, or of alkali hydrides, e.g. B. sodium hydride, on the compounds of the general formula II, before adding the compounds of the general formula VIII (see also: JE Shaw, DC Kunerth and JJ Sherry, Tetrahedron Letters 1973, 689-692; AM Mac Leod , KJ Merchant, MA Cascieri, S. Sadowski, E. Ber, CJ.Serain and R. Baker, J. Med. Chem. 3_6, 2044-2045 (1993); A. Rosowsky, RA Forsch. Ch.-S. Yu, H. Lazarus and GP Beardsley, J. Med. Chem. 2_7, 605-609 (1984)).

e) reaction of compounds of the general formula IX,

in the

R, U, V, Y, m and n are as defined at the beginning,

with carbonic acid derivatives of the general formula X,

NR ¹

Nu ² - C - NR ² R ³ (X)

in the

R ¹ , R ² and R ^{3 are} as defined at the outset and Nu ^{2 is a} leaving group, for example an alkoxy, alkylthio, alkylsulfinyl or alkylsulfonyl group each having 1 to 10 carbon atoms in the alkyl part, for example the methoxy, ethoxy, Methylthio, ethylthio, methylsulfinyl, ethylsulfmyl, propylsulfmyl, isopropylsulfmyl, methylsulfonyl or ethylsulfonyl group, the chlorine atom, the SO2H, SO3H or OPOCl2 group, or the rest of the general formula XI,

ΛΛΛAΛ

in the R ⁹ and R ¹⁰ , which may be the same or different, represent hydrogen atoms or alkyl radicals having 1 to 3 carbon atoms.

Occasionally with advantage, for example when Nu ^{2 is} an alkoxy group, instead of the compounds of general formula X their mineral acid salts, e.g. B. their neutral sulfates or their hydrochlorides.

The reactions are carried out in analogy to processes known from the literature (see GBL Smith, J. Amer. Chem. Soc. 5_1_, 476 [1929]; B. Rathke, Chem. Ber. 1_7, 297 [1884]; R. Phillips and HT Clarke, J. Amer. Chem. Soc. 4J3, 1755 [1923]; SJ Angyal and WK Warburton, J. Amer. Chem. Soc. ^" 7_3, 2492 [1951]; H. Lecher and F. Graf, Chem. Ber . 5_6_, 1326 [1923]; J. Wityak, SJ Gould, SJ Hein and DA Keszler, J. Org. Chem. B2_, 2179 [1987]; T. Teraji, Y. Nakai, GJ Durant, WO-A-81 / 00109, Chem. Abstr. 94_, 192336z [1981]; CA. Maryanoff, RC Stanzione, JN Plampm and JE Mills, J. Org. Chem. 5_1, 1882-1884 [1986]; AE Miller and JJ Bischoff, Synthesis 1986 , 777; RAB Bannard, AA Casselman, WF Cockburn and GM Brown, Can. J. Chem. 3_6, 1541 [1958]; Aktieselskabet Grea, Kopen¬ hagen, DE 28 26 452-C2; K. Kim, YT. Lin and HS Mosher, Tetrah. Letters, 23_, 3183-3186 [1988]; HB Arzeno et al., Synth. Commun. 2 Q_, 3433-3437 [1990]; H. Bredereck and K. Bredereck, Chem. Ber. _94, 2278 [1961]; H. Eilmgsfeld, G. Neubauer , M. Seefelder and H. Weidmger, Chem. Ber. _9_7, 1232 [1964]; P. Pruszynski, Can. J. Chem. _65, 626 [1987]; DF Gavm, WJ Schnabel, E. Kober and MA Robinson, J. Org. Chem. 32, 2511 [1967]; NK Hart, SR Johns, JA Lamberton and RI Willmg, Aust. J. Chem. 2_3, 1679 [1970]; CIBA Ltd., Belgian patent 655 403; Chem. Abstr. _6_4, 17481 [1966]; JP Greenstem, J. Org. Chem. 2_, 480 [1937]; FL Scott and J. Reilly, J. Amer. Chem. Soc. 74_, 4562 [1952]; WR Roush and AE Walts, J. Amer. Chem. Soc. 1_06, 721 [1984], MS Bernavowicz, Y. Wu and GR Matsueda, J. Org. Chem. 5_7, 2497-2502 [1992]; H. Tsunematsu, T. Imamura and S. Makisumi, J. Biochem. 9_4, 123-128 [1983]) at temperatures between 0 ° C. and + 100 ° C., preferably + 40 ° C. and + 80 ° C., and using inert solvents, for example dichloromethane, tetrahydrofuran, 1,4- Doxane, acetonitrile, dimethylformamide, dimethylacetamide, N-methyl-pyrrolidone or mixtures thereof and - depending on the nature of the Nu ² group - often in the presence of auxiliary bases, in particular alkali metal carbonates such as sodium or potassium carbonate, or tertiary amines, are preferred N-ethyl-disopropylamm or triethylamine.

f) implementation of the uromum salts or thiuromum salts of the general formula XII,

in the

R, Rl, U, V, Y, n and m are as defined at the outset, R ^ ^{1 is} an alkyl radical having 1 to 4 carbon atoms or the phenyl group, Y ^{3 is} the oxygen or sulfur atom and An is a monovalent anion, for example a chloride , Bromide, iodide, methyl sulfate, methanesulfonate or toluenesulfonate anion and 1/2 Sθ4 ^2_ mean, or the corresponding free isoureas or isothioureas

with nurses of the general formula XIII,

R ² R ³ NH (xm:

in which R ² and R ^{3 are} as defined at the beginning. The reaction takes place at temperatures between 0 and 110 ° C, preferably between +15 and + 60 ° C, and optionally in a suitable solvent, for example in water, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, tetrahydrofuran, dioxane , an alcohol such as methanol or ethanol or in a mixture thereof, the compounds of the general formula I being obtained directly as salts with the acid HAN. If the underlying bases, the corresponding free isoureas or isothioureas, are used in the reaction instead of the urum salts or thiurum salts XII, 1 equivalent of a weak acid, preferably acetic acid, must be added to the mixture.

g) For the preparation of compounds of the general formula I in which U denotes the oxygen atom or the —NH group:

Reaction of isocyanates of the general formula XIV,

in the

R ¹ , R ³ , V, Y and m are defined as mentioned at the beginning and R ^{2 has} the meanings mentioned at the beginning for R ² or also means one of the protective groups mentioned above for the protection of guamdmo functions which carry side chains,

with compounds of the general formula XV,

R- (CH ₂ ) _n -U ¹ -H (XV) in the

R and n are as defined at the outset and U ^{1 is} the oxygen atom or the —NH group, and, if necessary, subsequent removal of protective groups by the processes described above.

The reaction is carried out at temperatures between 0 ° C and 150 ° C, preferably between 20 ° C and 100 ° C, and optionally in the presence of anhydrous solvents, e.g. of tetrahydrofuran, 1,4-dioxane, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone or 1, 3-dimethyl-2-imidazolidone or mixtures thereof.

h) For the preparation of compounds of the general formula I in which U represents the —NH group:

Reaction of isocyanates of the general formula XVI,

R- (CH ₂ ) _n -N = C = 0 (XVI:

in the

R and n are as defined at the beginning,

with α-amino acid derivatives of the general formula V,

in the

R ¹ , R ³ , V, Y and m are as defined above and R ² 'has the meanings mentioned above for R ² or also one of the protecting groups mentioned above for the protection of side chains carrying guanidmo functions means

and, if necessary, subsequent splitting off of protective groups according to the processes described above.

The reaction is carried out at temperatures between 0 and 150 ° C, preferably at temperatures between 20 and 100 ° C, and if appropriate in the presence of anhydrous solvents, e.g. Tetrahydrofuran, 1,4-dioxane, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone or 1, 3-dimethyl-2-ιmιdazolιdmon performed

l) For the preparation of compounds of general formula I, in which V is the group - (CH2) ₀ -Y ¹ -WY ² , m the

o and W are as defined at the beginning,

Y ^{x is} the oxygen atom or the residue -NR ^ -, m the

R ^ represents the hydrogen atom or a straight-chain or branched alkyl group having 1 to 6 carbon atoms, and

Y ^{2 is} a straight-chain or branched alkyl group with 1 to 10 carbon atoms optionally substituted by a hydroxy, alkoxycarbonyl or ammocarbonyl group, a cycloalkyl group with 4 to 10 carbon atoms, a straight-chain or branched alkoxy group with 1 to 5 carbon atoms , alkyl- eme aminoalkyl, alkylaminoalkyl, Dialkylaminoal¬, phenylmethoxy or 2-phenylethoxy, in eme Phe ^¬ nylteil optionally substituted by fluorine, chlorine or bromine atoms, by methyl, trifluoromethyl, cyano, ammonium, hydroxy , Methoxy, acetyl, acetylammo, aminocarbonyl, methylamino¬ carbonyl or dimethylammocarbonyl groups mono-, di- or tπ-substituted phenyl or phenylalkyl group with 1 to 3 carbon atoms in the alkyl part or

the -NR ⁶ R ⁷ group means in the R6 is the hydrogen atom, a straight-chain or branched alkyl group having 1 to 6 carbon atoms which is optionally substituted by a hydroxy, carboxy, alkoxycarbonyl or dialkylamino group, with the proviso that the hydroxyl group is not bonded in 1-position of the alkyl group Cycloalkyl group with 4 to 8 carbon atoms or eme in the phenyl part optionally by fluorine, chlorine or bromine atoms, by methyl, trifluoromethyl, hydroxy, meth, oxy, amino, acetylammo, aminocarbonyl, methylamino carbonyl, dimethylaminocarbonyl - or cyano groups mono-, di- or tri-substituted phenyl, phenylmethyl, 2-phenylethyl or 3-phenylpropyl group, where the substituents can be the same or different, such as alkanoyl, benzoyl, phenylalkanoyl, Represents alkoxycarbonyl or ammocarbonyl group and

R ^{7 has} the meanings given for R ⁶ with the exception of that of a phenyl, alkanoyl, benzoyl, phenylalkanoyl, alkoxycarbonyl and ammocarbonyl group:

Modification of compounds of general formula XVII,

^

O in de rm, n, o, R, Rl, R ³ , U and Y are defined as mentioned at the beginning, R ² 'has the meanings mentioned at the beginning for R ² or also one of the side chains mentioned above for the protection of Guamdmo functions Is protective groups and Y ^{x is} the oxygen atom or the radical —NR ⁵ -, in which R ^{5 is} the hydrogen atom or a straight-chain or branched alkyl group having 1 to 6 carbon atoms,

at the (Y ¹ '-H) function and, if necessary, subsequent splitting off of protective groups by the processes described above and / or further modification of the group V obtained in the first place.

The modification to the (Y ¹ '-H) function can, depending on the reagent used, either without solvent or in a suitable solvent, for example in water, alcohols such as methanol, ethanol or propanol, in N-methylpyrrolidone, Di¬ methylformamide or dimethylacetamide or mixtures thereof, optionally ge m the presence of mineral acids, for example hydrochloric acid or sulfuric acid, organic or anorgani ^¬'s bases, for example triethylamine, Hunig's base or Na¬ triumcarbonat, and lung, where appropriate with subsequent Behand¬ with ammonia , with mineral acids such as hydrochloric acid or sulfuric acid or with organic acids such as trifluoroacetic acid, at temperatures between 0 and 150 ° C, preferably between 20 and 100 ° C.

Preferably you get

by reacting compounds of the general formula XVII, where γl 'is the —NR group, where R ^{5 represents} the hydrogen atom or a straight-chain or branched alkyl group having 1 to 6 carbon atoms, with alkali metal cyanates, for example sodium cyanate, in the presence of strong acids , for example hydrochloric acid or aqueous trifluoroacetic acid, such compounds of the general my formula I, where V is the group - (CH2) _o -NR ⁵ -C0-NH2, where o is defined as mentioned at the beginning and R ^{5 represents} the hydrogen atom or a straight-chain or branched alkyl group having 1 to 6 carbon atoms (see also : Org. Synth., Coli. Vol. IV, p. 515),

by reaction with acetic anhydride, m alcohols, eg m ethanol, those compounds of the general formula I in which V denotes the group - (CH2) _o -NR ^ -C0-CH3, where o is defined as mentioned at the beginning and R ^{5 is} the Represents hydrogen atom or a straight-chain or branched alkyl group having 1 to 6 carbon atoms,

by reaction with chlorinated carbonate in the presence of triethylamine, those compounds of the general formula I in which V is the group - (CH2) _O ~ ^{NR5 ~ CO-OC} 2 ^H 5, where o is defined as mentioned above and R ^ is the hydrogen atom or a represents straight-chain or branched alkyl group with 1 to 6 carbon atoms,

by reaction with N- (tert-butyl) chlorosulfonic acid amide, such compounds of the general formula I in which V represents the group - (CH ₂ ) ₀ -NR ⁵ -Sθ2-NH-C (CH ₃ ) 3, and by subsequent treatment with trifluoroacetic acid, compounds of the general formula I in which V denotes the group - (CH2) _o -NR ⁵ -S02 ~ NH2, where o is defined as mentioned at the beginning and R ^ is the hydrogen atom or a straight-chain or branched alkyl group with 1 to 6 carbon atoms, it being noted that if the R ² 'group is the Pmc protecting group, this is also removed,

by reaction with benzoyl chloride, such compounds of the general formula I in which V represents the group - (CH2) _o -NR ⁵ -C0-CgH5, where o is defined as mentioned at the beginning and R ^{5 is} the hydrogen atom or a straight-chain or branched alkyl group with 1 to 6 carbon atoms, by reaction with methyl isocyanate, such compounds of the general formula I, in which V is the group

- (CH2) _o -NR5-CO-NH-CH3, where o is defined as mentioned at the beginning and R ^{5 represents} the hydrogen atom or a straight-chain or branched alkyl group having 1 to 6 carbon atoms,

by reaction with dimethylcarbamoyl chloride, such compounds of the general formula I in which V represents the group - (CH2) ₀ -NR ⁵ -CO-N (CH3) 2, where o is defined as mentioned at the beginning and R ^{5 is} the hydrogen atom or eme represents straight-chain or branched alkyl group having 1 to 6 carbon atoms,

by reaction with nitrobiuret, such compounds of the general formula I in which V represents the group - (CH ₂ ) _o -NR ⁵ -C0-NH-CO-NH ₂ , where o is defined as mentioned at the beginning and R ~ ^> that Represents hydrogen atom or a straight-chain or branched alkyl group having 1 to 6 carbon atoms, (see also: TL Davis et al., J. Am. Chem. Soc. 51, 1801-1806 (1929))

and

by reacting compounds of the general formula XVII, in which Y ^ 'denotes the oxygen atom, with phenyl chlorocarbonate and subsequent ammolysis, such compounds of the general formula I in which V is the group - (CH2) _O "~ ⁰ ~ ^C0-NH 2 means, where o is defined as mentioned at the beginning (see also: GR Allen, Jr., JF Poletto and MJ Weiss, J. Org. Chem. 30, 2897-2904 (1965)).

j) For the preparation of compounds of general formula I in which

Rl is a branched or unbranched aliphatic alkylcarbonyl radical comprising 2 to 5 carbon atoms, which is in the alkyl part by an alkoxycarbonyl or phenylalkoxycarbonyl group, may be substituted by a phenyl group or by a 5- or 6-membered heteroaromatic ring, linked via a carbon atom, or a benzoyl radical in which the phenyl moiety is also substituted by a 5- or 6-membered linker heteroaromatic by a carbon atom The table ring can be replaced, the 5-membered heteroaromatic rings mentioned above containing a nitrogen, em oxygen or sulfur atom or a nitrogen and em additional oxygen, sulfur or further nitrogen atom and on a nitrogen atom also by an alkyl group Substituted sem can contain 6-glιedrιgen hetero¬ aromatic rings 1, 2 or 3 nitrogen atoms and the above-mentioned phenyl groups and all heteroaromatic rings in the carbon structure additionally by fluorine, chlorine or bromine atoms, by alkyl groups, cycloalkyl groups with 3 to 8 Carbon atoms, alkoxy, trifluoromethyl, alkoxycarbonylalky l-, carboxyalkyl-, hydroxy-, amino-, acetyl- amino-, propionylamino-, aminocarbonyl-, alkylammocarbonyl-, dialkylammocarbonyl-, alkanoyl-, cyano-, trifluoromethoxy-, trifluoromethylthio-, trifluoromethylsulfmyl- or tonfluoromethyl- methyl may be di- or maximally trisubstituted, the substituents being the same or different:

Reaction of compounds of the general formula XVIII,

(XVIII;

in which R, R ² , R ³ 'U, V, Y, n and m are as defined at the beginning, with a compound of the general formula XlXa,

R ¹ '-CO-Nu (XlXa)

in which R1 is a branched or unbranched alkyl radical comprising 1 to 4 carbon atoms, which can be substituted by an alkoxycarbonyl or phenylalkoxycarbonyl group, by a phenyl group or by a 5- or 6-membered heteroaromatic ring linked via a carbon atom , a phenyl radical or a 5- or 6-membered heteroaromatic ring linked via a carbon atom, the abovementioned 5-membered heteroaromatic rings having a nitrogen, an oxygen or sulfur atom or a nitrogen and an additional oxygen, sulfur or contain a further nitrogen atom and can also be substituted on an nitrogen atom by an alkyl group which contain 6-membered heteroaromatic rings 1, 2 or 3 nitrogen atoms and the above-mentioned phenyl groups and all heteroaromatic rings in the carbon skeleton additionally by fluorine , Chlorine or bromine atoms, by alkyl groups, Cycloalkyl groups with 3 to 8 carbon atoms, alkoxy-, trifluoromethyl-, alkoxycarbonylalkyl-, carboxyalkyl-, hydroxy-, amino-, acetylammo-, propionylammo-, aminocarbonyl-, alkylammocarbonyl-, dialkylammocarbonyl-, alkanoyl-, cyano-, trifluoromethoxy- , Trifluoromethylthio, trifluoromethylsulfmyl or trifluoromethylsulfonyl groups can be mono-, di- or maximally trisubstituted, where the substituents can be the same or different sem, means and

Nu eme leaving group, for example the hydroxyl group, em halogen atom, such as the chlorine, bromine or iodine atom, an alkyl sulfonyloxy group with 1 to 10 carbon atoms, eme ^¬ possibly by chlorine or bromine atoms, by methyl or nitro groups mono-, di - or tπsubstituted phenylsulfonyloxy or naphthylsulfonyloxy group, where the substituents can be the same or different. The reaction is preferably carried out in aprotic solvents, for example in tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, dimethylacetamide, hexamethylphosphoric acid triamide, sulfolane, 1,3-dimethyl-2-imidazolidone, 1,3-dimethyl-3,4. 5, 6- tetrahydro-2 (IH) pyrimidinone or mixtures thereof, in the presence of tertiary amines, for example pyridine, 2,4,6-trimethylpyridine, quinoline, triethylamine, N-ethyl-diisopropylamm, N- Ethyl-dicyclohexylamine, 1, 4-diazabicyclo [2.2.2] octane or 1, 8-diazabicyclo [5, 4, 0] undec-7-ene, and at temperatures between -20 ° C and + 60 ° C. , very particularly preferably between + 15 ° C and +30 C, carried out. Any acylatable functions present in group V are also implemented in this reaction. Reaction products which may have been formed as by-products in the guanidmo function of the side chain can generally be easily separated off using conventional chromatographic methods.

k) For the preparation of compounds of general formula I in which

R ^{1 is} the aminocarbonyl group which is substituted on the nitrogen atom by alkyl, phenylalkyl, (1-naphthyl) alkyl, (2-naphthyl) alkyl, alkoxycarbonylalkyl, phenylalkoxycarbonylalkyl, phenoxycarbonylalkyl, diphenylalkyl, phenyl, cycloalkyl or cycloalkylalkyl groups each having 3 to 8 carbon atoms in the ring can be mono- or disubstituted, the substituents being the same or different and the phenyl radicals mentioned above being themselves fluorine, chlorine or bromine atoms, methyl, methoxy , Alkoxycarbonylmethoxy, hydroxyl or trifluoromethyl groups can be mono- or disubstituted independently of one another, means:

Reaction of compounds of the general formula XVIII,

m the R, R ² , R ³ 'U, V, Y, n and m are as defined at the beginning,

with a compound of the general formula XlXb,

R 1 '' _ N = C = 0 JXIXb)

in the R ¹ '' eιne alkyl, phenylalkyl, (1-naphthyl) alkyl, (2-naphthyl) alkyl, alkoxycarbonylalkyl, phenylalkoxycarbonylalkyl, phenoxycarbonylalkyl, diphenylalkyl, phenyl, cycloalkyl or cycloalkylalkyl group each having 3 to 8 carbon atoms in the cycloalkane ring, where the phenyl radicals mentioned above can in turn be mono- or disubstituted independently of one another by fluorine, chlorine or bromine atoms, methyl, methoxy, alkoxycarbonyl, methoxy, hydroxyl or trifluoromethyl groups, and

Nu represents a leaving group, for example the hydroxy group, a halogen atom, such as the chlorine, bromine or iodine atom, an alkylsulfonyloxy group with 1 to 10 carbon atoms, one optionally by chlorine or bromine atoms, by methyl or nitro groups, di- or trisubstituted phenylsulfonyloxy or naphthylsulfonyloxy group, where the substituents can be the same or different.

The reaction is preferably carried out in aprotic solvents, for example in tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide, Sulfolane, 1, 3-dimethyl-2-imazolide, 1, 3-dimethyl-3, 4, 5, 6-tetrahydro-2 (IH) -pyπmidmon or mixtures thereof, in the presence of tertiary amines, for example Pyπdm, 2,4,6-trimethylpyπdm, quinolm, triethylamine, N-ethyl-dusopropylamm, N-ethyl-dicyclohexylamm, 1, 4-Dιazabιcyclo- [2,2,2] octane or 1, 8-Dιazabιcyclo [5, 4th , 0] undec-7-enes, and at temperatures between -20 ° C and + 60 ° C, very particularly preferably between + 15 ° C and + 30 ° C. Any acylatable functions present in group V are also implemented in this reaction. Reaction products which may have been formed as by-products in the guanidino function of the side chain can generally be easily separated off using customary chromatographic processes.

1) For the preparation of compounds of general formula I, m the

R ^ is an alkoxycarbonyl or phenylalkoxycarbonyl radical, the phenyl part in turn being mono- or disubstituted by fluorine, chlorine or bromine atoms, methyl, methoxy, alkoxycarbonylmethoxy, hydroxyl or trifluoromethyl groups and the substituents in each case being the same or different can means:

Reaction of compounds of the general formula XVIII,

in which R, R ² , R ³ 'U, V, Y, n and m are as defined at the beginning, with a compound of the general formula XIXc,

R ¹ '''-0-C0-C1 (XIXc)

wherein R ^x '' is an alkyl or phenylalkyl radical in which the phenyl part in turn may be mono- or disubstituted by fluorine, chlorine or bromine atoms, methyl, methoxy, alkoxycarbonylmethoxy, hydroxy or trifluoromethyl groups, the substituents in each case being the same or different sem can, means and

Nu eme leaving group, for example the hydroxyl group, em halogen atom, such as the chlorine, bromine or iodine atom, an alkylsulfonyloxy group having 1 to 10 carbon atoms, a phenylsul which is mono-, di- or tri-substituted by chlorine or bromine atoms, by methyl or nitro groups - fonyloxy or naphthylsulfonyloxy group, where the substituents can be the same or different.

The reaction is preferably carried out in aprotic solvents, for example in tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, dimethylacetamide, hexamethylphosphoric acid triamide, sulfolane, 1,3-dimethyl-2-dimethylazolide, 1,3-4-dimethyl 5, 6-tetrahydro-2 (IH) -pyrimidmon or mixtures thereof, in the presence of tertiary amines, for example pyridine, 2, 4, 6-trιmethylpyrιdm, quinolm, triethylamine, N-ethyl-dusopropylamm, N- Ethyl-dicyclohexylamine, 1, 4-Dιazabιcyclo- [2,2,2] octane or 1, 8-Dιazabιcyclo [5, 4, 0] undec-7-en, and at temperatures between -20 ° C and +60 ° C. , very particularly before Trains t ^¬ between +15 ° C and +30 ° C is performed. May be present in the group V acylatable functions are coreacted in ser ^¬ the reaction. Any reaction products diacylated as by-products in the guanidmo function of the side chain can generally be easily separated using conventional chromatographic methods. m) for the preparation of the compounds of the general formula XX falling under the general formula I,

m the R, R ² , R ³ , U, V, Y, n and m are as defined at the beginning:

Partial hydrolysis of cyanguanidines of the general formula XXI,

in which R, R ² , R ³ , U, V, Y, n and m are as defined at the outset, by the action of strong aqueous acids, preferably aqueous trifluoroacetic acid, at temperatures between 0 ° C. and +70 ° C., preferably +15 ° C and +45 ° C (see also: P. Theobald, J. Porter, C Rivier, A. Corrigan, W. Hook, R. Siraganian, M. Perrin, W. Vale and J. Rivier, J. Med. Chem. 34, 2395-2402 (1991); PJ Garratt, SN Thorn and R. Wrigglesworth, Tetrahedron 49, 6885-6898 (1993)). Water-miscible cosolvents can be added to the reaction mixture be, for example tetrahydrofuran or dioxane, but the reaction is also successful in the absence of additional solvents

n) for the preparation of the compounds of the general formula XXII falling under the general formula I,

txxii:

in which R, R ² , R ³ , U, V, Y, m and n are as defined at the beginning and R ^ ² and R - * - ³ independently of one another are the hydrogen atom, an alkyl group having 1 to 5 carbon atoms, a cycloalkyl group with 3 to 8 carbon atoms or a phenylalkyl group with 1 to 5 carbon atoms in the alkyl part, where these radicals can be the same or different:

Conversion of cyanguanidines of the general formula

A in which R, R ² , R ³ , U, V, Y, n and m are as defined above, in aminothiocarbonylguanidines of the general formula XXIII,

in which R, R ² , R ³ , U, V, Y, n and m are as defined in the introduction, and subsequent reaction with α-halocarbonyl compounds of the general formula XXIV,

_R 12_ _C0 _ _{CH (Hal)} _ _R 13 (XXIV)

in which R ^ ² and R ^ ³ independently of one another are the hydrogen atom, an alkyl group having 1 to 5 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms or a phenylalkyl group having 1 to 5 carbon atoms in the alkyl part, these radicals being identical or different can be, and Hal is a chlorine, bromine or iodine atom, under the conditions of a thiazole synthesis according to Hantzsch. If, for example, a chloromethyl ketone of the general formula R ^ ² -CO-CH2-Cl in which R ^{12 is defined} as above is used as the α-halocarbonyl compound, thiazoles of the general formula XXIIa are obtained, AV (XXIIa!

on the other hand, an α-haloaldehyde of the general formula R ¹² -CHHal-CH = 0, m R ^{12 is} as defined above, or more appropriately a mixture of an aldehyde of the general formula R ^ - ² -CH2-CH = 0 and iodine , which forms the required α-iodaldehyde in situ, thiazoles of the general formula XXIIb are obtained.

(XXIIb)

The conversion of the cyanguanidines of the general formula XXI into the ammothiocarbonylguanidme of the general formula XXIII is most easily accomplished by treatment with hydrogen sulfide at temperatures between room temperature and 100 ° C., preferably between 40 ° C. and 80 ° C. (see also: F. Kurzer, J. Chem. Soc. 1955, 1-6; Org. Synth., Coil. Vol. 4, 502-504 (1963)). Pyridine is preferred as the solvent for this reaction. The conversion of the ammothiocarbonyl compounds of the general formula XXII to the thiazoles of the general formula XXII is preferably carried out in boiling acetone and initially gives the hydrohalic salts of Thiazoles of the general formula XXII, which only pass into the free bases in the course of the working up, in particular in the case of column or flash chromatography in the presence of ammonia-containing eluents. However, the reaction can also be carried out in the presence of weak inorganic bases, in particular sodium hydrogen carbonate, and then gives directly the free bases of the general formula XXII.

o) For the preparation of compounds of the general formula I in which U denotes the oxygen atom:

Aminolysis of chlorocarbonic acid esters of the general formula XXV,

R- (CH ₂ ) _n -0-CO-Cl (XXV)

in which R and n are as defined at the beginning,

with α-amino acid derivatives of the general formula XXVI,

in the

R ^x , R ³ , V, Y and m are defined as mentioned at the outset and R ² 'has the meanings mentioned at the outset for R ² or also one of the protective groups mentioned above for the protection of guanidmo functions present in the side chain and orthogonal to carbamates means, and, if necessary, subsequent splitting off of the protective group according to the processes described above. The reaction is carried out at temperatures between 0 and 150 ° C., preferably at temperatures between 20 and 100 ° C., and if appropriate in the presence of anhydrous solvents, for example tetrahydrofuran, 1,4-dioxane, dimethylformamide, dimethylacetamide, N- Methyl 2-pyrrole or 1, 3-dimethyl-2-dimazolidone or mixtures thereof, and in the presence of auxiliary bases. As auxiliary bases come alkali carbonates, e.g. B. sodium carbonate, potassium carbonate or casium carbonate, alkali metal acetates, for example sodium or potassium acetate, but preferably tertiary amines, for example pyridm, 2, 4, 6-trιmethylpyrιdm, quinoline, triethylamine, N-ethyl-dusopropylamine, N-ethyl-dicyclo- hexylamine, 1, 4-dιazabιcyclo [2, 2, 2] octane or 1,8-dιazabι- cyclo [5, 4, 0] undec-7-en into consideration.

p) For the preparation of compounds of the general formula I in which R ^x , R ² and R ^{3 are} hydrogen atoms:

Reaction of compounds of the general formula IX,

^{A v} in the

R, U, V, Y, n and m are as defined at the beginning,

with cyanamide.

The reactions are carried out at temperatures between 20 ° C and 150 ° C, optionally also in an autoclave. Alcohols such as methanol, ethanol or n-propanol, ethers such as dioxane or esters such as ethyl acetate are preferred as solvents. Water can also be used as a further cosolvent. Although the reaction is successful even without the addition of acids, the implementation in the presence of organic acids, e.g. B. Essig¬ acid, and especially strong acids, e.g. B. of methane sulfonic acid, sulfuric acid, hydrogen bromide, hydrogen chloride or hydrochloric acid, preferred. If, for example, the salts of the amines of the general formula IX em are used in the reaction, the compounds of the general formula I are obtained in the form of the corresponding salts (see also: Houben-Weyl, Methods of Organic Chemistry, 4th edition, Georg-Thieme-Verlag, Stuttgart, from 1952, Volume VIII, p. 98, p. 180; Ullmanns Encyclopadie der Technischen Chemie, Verlag Chemie, Weinheim, 1972-1977, Volume VIII, p. 328; EH Sheers, Kirk-Othmer Encycl. Chem. Technol., 2nd ed., 1J], 734 [1966]; A. Kampf, Chem. Ber. 3J7, 1681 [1904]; RA Corral, 0.0. Orazi and MF de Petruccelli, Chem. Commun 1970, 556).

q) For the preparation of compounds of the general formula I in which R ^x denotes the hydrogen atom:

Reaction of cyanamides of the general formula XXVII,

in which R, U, V, Y, m and n are as defined at the beginning,

with mineral acid salts of ammonia or amines of the general formula XIII, in which R ² and R ^{3 are} as defined at the outset.

The reaction is carried out using suitable solvents, for example lower alcohols such as methanol and ethanol or their mixtures, at temperatures between +10 and + 190 ° C, preferably between 90 and 160 ° C. Examples of suitable salt-forming acids are hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, methanesulfonic acid or p-toluenesulfonic acid. The reaction is preferably carried out using equivalent amounts of the ammonium salt and in the presence of additional free ammonia or free amine of the general formula XIII, but is also possible in the absence of these free bases.

The ammosaur derivatives of general formula I according to the invention contain at least one chiral center. In addition, if the radical R is prochiral or chiral, the compounds can occur in the form of two diastereomeric pairs of antipodes. The invention includes the individual isomers as well as their mixtures.

The respective diastereomers can be separated due to the different physico-chemical properties, e.g. by fractional crystallization from suitable solvents, by high pressure liquid or column chromatography using chiral or preferably achiral stationary phases.

The separation of race mats falling under the general formula I is achieved, for example, by HPLC on suitable chiral stationary phases (eg Chiral AGP, Chiralpak AD). Racemates which contain a basic function can also be separated via the diastereomeric, optically active salts which, when reacted with an optically active acid, for example (+) - or (-) -tartaric acid, (+) - or (- ) -Diacetyltartaric acid, (+) - or (-) -monomethyltartrate or (+) -camphorsulfonic acid arise.

According to a conventional method for isomer separation, the racemate of a compound of general formula I is reacted with one of the optically active acids given above in an equimolar amount in a solvent and the crystalline, diastereomeric, optically active salts obtained separated using their different solubility. This reaction can be carried out in any type of solvent as long as it has a sufficient difference in the solubility of the salts. Methanol, ethanol or mixtures thereof are preferably used, for example in a volume ratio of 50:50. Each of the optically active salts is then dissolved in water, neutralized with a base, such as sodium carbonate or potassium carbonate, sodium hydroxide solution or potassium hydroxide solution, and the corresponding free compound is thus obtained in the (+) or (-) form.

In each case only the (R) -enantiomer or a mixture of two optically active diastereomeric compounds falling under general formula I is also obtained by carrying out the syntheses described above with in each case one reaction component containing the corresponding (R) -configured amino acid carries out.

The starting materials of the general formulas III, IV, V, VI, VII, VIII, IX, X, XI, XIII, XV, XVI, XlXa, XlXb, XIXc, XXIV, XXV, XXVI and XXVII are commercially available or are produced using processes known from the literature. Acids II are obtained, for example, under the conditions of a Schotten-Baumann reaction from the corresponding α-amino acids and compounds of the general formula III (see also: M. Bodanszky and A. Bodanszky, "The Practice of Peptide Synthesis", Springer Verlag 1984, pp. 9 to 30). The α-amino-nitrobenzeneacetic acids required as essential starting material for the synthesis of the compounds of the general formula I are also known from the literature (see, for example: P. Frns and A. Kjaer, Acta Chem. Scand. 17, 2391-2396 (1963); J. Plochl and W. Loe, Ber. Dtsch. Chem. Ges. 18, 1179-1182 (1885); Beecham Group, Belgian Patent 662478. Isocyanates of the general formula XIV can easily be obtained from α-amino acid derivatives of the general formula V or from their hydrochlorides by reaction with phosgene, diphosgene or triphosgene in the presence of pyridine (see also: JS Nowick, NA Powell, TM Nguyen and G. Noronha, J. Org. Chem. 57, 7364-7366 [1992]).

The uronium salts falling under the general formula XII are most easily obtained by adding alcohols R ^ -OH to the corresponding cyanamides, for example using potassium cyanide (see also: A. Donetti et al., Tetrah. Lett. 1969, 3327-3328; A Donetti et al., J. Org. Chem. 3_7, 3352-3353 (1972); M. Okahara et al., Tetrah. Lett. 1981, 4105-4106) or sodium methylate (see also: FC Schaefer et al., J. Org. Chem. 2_6, 412-418 (1961); RM Giuliano et al., J. Org. Chem. 51_, 2304-2307 (1986); FHS Hurd et al., J. Chem. Soc. 1949, 1732-1738)) as catalysts, which are described under the general formula XII falling thiuronium salts from corresponding thioureas by reaction with alkylating agents of the type R ^ -X, where X is for example the iodine atom or the groups OSO2CH3 or OSO2C6H4CH3 (p). The starting compounds of the general formula XVII can be produced in a simple manner from precursors which, instead of the terminal group - (CH2) o ^-γ "^ '~ ^{H of} the general formula XVII eme by easily removable protective groups Pg, for example tert. Butoxy¬ carbonyl or phenylmethoxycarbonyl, labeled end group - (CH2) o ~ ^γ "''' ^-p 9 or precursor groups, for example - (CH2) ₀ -χ-C≡N or - (CH2) ₀ ^N0 2' wear.

The starting compounds of the general formula XVIII can be synthesized by at least one of the processes a) to o) described above.

To synthesize cyanogams of general formula XXI, diphenyl cyanocarbimide is reacted in succession with anilines of general formula IX and with amines of general formula XIII (see also: RL Webb and C S. Labaw, J. Het. Chem. 19, 1205 [ 1982]; RL Webb, DS Eggleston, C. S. Labaw, JJ Lewis and K. Wert, J. Het. Chem. 2_4, 275 [1987]; P. Theobald, J. Porter, C Rivier, A. Corrigan, W. Hook, R. Siraganian, M. Perrm, W.Vale and J. Rivier, J. Med. Chem. 3_4, 2395-2402 [1991 ]; J. Hirschfeld, A. Busch-auer, S. Elz, W. Schunack, M. Ruat, E. Traiffort and J.-C Schwartz, J. Med. Chem. 3j ^ 2231-2238 [1992]).

The easiest way to prepare (ammothiocarbonyl) guanides of the general formula XXIII is to treat cyanguanides of the general formula XXI with hydrogen sulfide (see also: F. Kurzer, J. Chem. Soc. 1955, 1-6; Org. Synth., Coil Vol. 4, 502-504 [1963]).

The compounds of general formula I obtained can be converted, especially for pharmaceutical applications, into their physiologically acceptable salts with inorganic or organic acids. The acids for this include, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, almond acid, malic acid, citric acid, tartaric acid or maleic acid.

In addition, the new compounds of formula I obtained in this way, if they contain a carboxy group, can, if desired, subsequently be converted into their addition salts with inorganic or organic bases, in particular for their pharmaceutical use into their physiologically acceptable addition salts. The bases used here are, for example, sodium hydroxide, potassium hydroxide, ammonia, cyclohexylamm, dicyclohexylamm, ethanolamm, diathanolamm and triathanolamm.

The new compounds of general formula I and their physiologically acceptable salts have NPY-antagonistic properties and show good affinities in NPY receptor formation studies. The compounds in the following wrote pharmacological test systems both m vivo and m vitro NPY antagonistic properties.

The following experiments are carried out to demonstrate the affinity of compounds of the general formula I for human NPY receptors and their antagonistic properties:

A. Binding studies with SK-N-MC cells (expressing the human Y N receptor)

The cells are detached by a mixture of 0.02% EDTA in PBS and in 10 ml incubation medium (MEM / 25 mM Hepes + 0.5% BSA, 50 mM PMSF, 0.1% Bacitracm, 3.75 mM CaCl ₂ ) resuspended per approx. 40 million cells. After 5 mm centrifugation (150 xg) the pellet is resuspended in the same volume and after a further washing step in 10 ml of incubation medium, paid out and diluted to 1.25 million cells / ml. Then 200 ml of a suspension of 1.25 million cells / ml for 3 hours at room temperature with 25 ml of a 300 pM solution of [^ - ² ^ I] -Bolton-Hunter-NPY and increasing concentrations (10- ^ ¹ to 10 ^~ 6 M) of the test substances, while maintaining a total volume of 250 ml. The incubation is ended by centrifugation (10 mm at 3000 × g and 4 ° C.). After washing once with PBS, the radioactivity of the pellet is measured in the gamma counter. The radioactivity obtained in this way represents the sum of the specific and non-specific binding of [125χ] -ssolton-Hunter-NPY. The proportion of non-specific binding is defined as that radioactivity which is bound in the presence of 1 mM NPY. The IC5Q values of the unlabelled test substances are determined graphically. They represent the concentration of the respective test substance at which the specific binding of [^ - ²⁵ I] -Bolton-Hunter-NPY to the NPY-Yχ receptor is inhibited by 50%.

In the test described, the compounds of the general formula I show IC5Q values <10000 nM. B. In vitro NPY antagom

Male rats (CHbb: THOM, 300 to 350 g) are given Hepaπn (100 IU, i.v.) and the animals are then killed by a blow to the neck. The abdomen is opened along the middle of the body and the left kidney is removed after the insertion of catheters into the renal artery, the renal vein and the ureter. The isolated kidney is immediately perfused with a modified Krebs-Rmger solution of the following composition (4 ml / minute):

NaCl 118.0 mmol / l

KH ₂ P0 ₄ 1.2 mmol / l

KCI 4.8 mmol / l

HgSθ4 1.2 mmol / l

CaCl2 2.5 mmol / l

NaHC0 ₃ 25.0 mmol / l

Glucose 6.5 mmol / l

A mixture of 95% O2 / 5% CO2 is passed through the solution at a temperature of 37 ° C. The perfusion pressure is continuously measured using a pressure transducer. After a 60 mm stabilization period, the perfusion rate is adjusted so that a perfusion pressure of approximately 100 mm Hg is reached. After a further 30 minutes the experiment is started and NPY (ImM) is administered as a bolus (0.1 ml) at 15 mm intervals until the observed increase in pressure reaches a constant value. The compounds to be examined are administered as a continuous infusion over a period of 5 minutes and then injected with NPY. After a 30 minute washout period, the next higher concentration of the test substance is examined. Each time the experiment is carried out, 3 to 5 different concentrations of the respective compound are tested. Concentration-response curves can be generated by plotting the percentage inhibition of NPY activity against the logarithum of the concentration (mol / l) of the compound. The compounds of general formula I m show the be¬ signed m-vitro test model NPY antagonistic Eigen¬ properties in a dosage range between IO ^-8 to 10 ^-5 M.

C. In vivo NPY antagonism

Male normotensive rats (Chbb: THOM, 300 to 350 g) are anesthetized with hexobarbital sodium (150 mg / kg, l.p.). After intubation of the trachea, the animals are despmalized by inserting a blunt needle through the eye into the spinal canal. The animals are ventilated with oxygen-rich room air with the aid of a respiratory pump (20 pump strokes / mm). A cannula is inserted into the left carotid artery and the arterial blood pressure is measured using a pressure measuring device (Braun Melsungen Combitrans), which is connected to a recording device. For injection purposes, the left jugular vein is placed in a catheter through which hepaπn (200 IU / kg, i.v.) is applied. After the blood pressure has stabilized, the animals receive 2 bolus injections of NPY (10 mg / kg, i.v.) in an interval of 15 minutes. The mean increase in diastolic blood pressure serves as a reference value (= 100%). The test substances are injected in increasing doses (4 to 6 doses) at intervals of 15 minutes. NPY is administered one minute after application of the test substance.

The antagonistic effectiveness of the test substances is determined by plotting the percentage inhibition of the NPY-induced blood pressure effects against the logarithm of the active ingredient concentration.

The compounds of general formula I show in the ^¬ be signed m vivo test model after intravenous administration Do ^¬ sisbereich of 0.001 to 10 mg / kg properties NPY antagonistic Eigen¬. On the basis of their pharmacological properties, the compounds of the general formula I and their physiologically tolerable salts are therefore suitable for the treatment of cardiovascular diseases, for example for the treatment of arterial hypertension, the hypertensive crisis, for example that caused by the surrounding environment, by physical disorders Effort or cold stimuli triggered by stress-induced high blood pressure, chronic heart failure, coronary heart diseases such as angina pectoπs, myocardial infarction and syndrome X, furthermore for the treatment of subarachnoid bleeding, vascular-hypertrophic changes, for example restenosis after coronary angioplasty (PC) cerebral and coronary vasospasm, e.g. B. stroke, chronic kidney failure, hyperthyroidism, obesity and diabetes, epileptic diseases and for diagnosis, assessment of the prognosis and treatment of tumor diseases, for example of pheochromocytomas, neur (fibro) blastomas, ganglioneuromas, ganglioneu - roblastomas, rhabdomyosarcomas, malignant ectomesis chymomas, anaplastic astrocytomas or hemangioblastomas.

The dosage required to achieve a corresponding effect is expediently 0.01 to 3 mg / kg body weight when administered intravenously, preferably 0.1 to 1 mg / kg body weight, and 0.1 to 10 mg / kg body weight when administered orally important, preferably 1 to 10 mg / kg body weight, each 1 to 3 times a day.

For this purpose, the compounds of general formula I prepared according to the invention, optionally in combination with other active substances, such as, for example, antihypertensives, ACE inhibitors, diuretics and / or calcium antagonists, can be used together with one or more inert customary carriers and / or diluents , e.g. with corn starch, milk sugar, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycine, water / sorbitol, water / polyethyleneglycol, propylene glycol, cetylstearyl alcohol, carboxyme Incorporate ethyl cellulose or fat-containing substances such as hard fat or their suitable mixtures into conventional galenical preparations such as tablets, dragees, capsules, powders, suspensions or suppositories.

For the combinations mentioned above, there are thus further active substances, for example bendroflumethiazide, chlorothiazide, hydrochlorothiazide, spironolactone, benzothiazide, cyclothiazide, ethacramic acid, furosemide, metoprolol, prazosm, atenolol, propranolol, (di) hydralazmium hydrochloride, Felodipm, Nicardipm, Nifedipin, Nisoldipm, Nitrendipm, Captopril, Enalapril, Lismopril, Cilazapril, Qumapril, Fosinopril and Ramipril. The dose for these active substances is expediently 1/5 of the usually recommended lowest dosage up to 1/1 of the normally recommended dosage, for example 15 to 200 mg hydrochlorothiazide, 125 to 2000 mg chlorothiazide, 15 to 200 mg Ethacramic acid, 5 to 80 mg furosemide, 20 to 480 mg propranolol, 5 to 60 mg felodipm, 5 to 60 mg nifedipine or 5 to 60 mg nitrendipm.

The invention furthermore relates to the use of the compounds of the general formula I as valuable auxiliaries for the production and purification (affinity chromatography) of antibodies and, after suitable radioactive labeling, for example by direct labeling with l ² ~ ^> or ^ ³¹ I or by trituration of suitable precursors, for example by replacing halogen atoms with tritium, in RIA and ELISA assays and as diagnostic or analytical aids in neutrotransmitter research.

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

"Fp." means "melting point", "Z." means "decomposition". For _above all connections are satisfactory elemental analyzes, IR, UV, ^ H-NMR, generally also mass spectra have. Unless otherwise stated, Rf values were determined using ready-made silica gel 60 F254 TLC plates (E. Merck, Darmstadt, item no. 5729) and a plasticizer made from n-butanol / - glacial acetic acid / water = 4/1/1 ( v / v / v), determined without chamber saturation. If further details on the configuration are missing, it remains open whether it is the (R) -enantiomer or whether partial or even complete racemization has occurred.

example 1

(R, S) -3- (Ammoiminomethylamino) -α- [(diphenylacetyl) ammo] -N- [(4-hydroxyphenyl) methyl] -benzenacetamide hydrochloride

a) (R, S) -α- [(Diphenylacetyl) ammo] -3-nιtrobenzenessιgsaure

To the slurry of 43.0 g (0.219 mol) of α-amino-3-nitrobenzenessic acid in a mixture of 400 ml of tetrahydrofuran and 200 ml of water was added the solution of 9.0 g (0.225 mol) of sodium hydroxide in 100 ml of water. The solution of 50.7 g (0.22 mol) of diphenylacetylchloride in 300 ml of tetrahydrofuran and the solution of 9.0 g (0.225 mol) of sodium hydroxide in 100 ml of water without external cooling were then added dropwise to this mixture at the same time, and the mixture was stirred for a further 12 Hours at room temperature and then distilled off the solvent in a water jet vacuum. The remaining oily residue was dissolved in 50 ml of water and acidified with 200 ml of 1 N aqueous hydrochloric acid. The precipitate obtained was boiled up with 300 ml of ethyl acetate, then kept at room temperature for 5 hours. 22.6 g (26% of theory) of pale yellow crystals of mp 238-243 ° C. (Z.) were obtained. IR (KBr): 1645 (broad, amide-CO) cm ^-1

b) (R, S) -α- [(diphenylacetyl) amino] -N- [(4-hydroxyphenyl) - methyl] -3-nιtrobenzenacetamιd

2.5 g (24.7 mmol) were added in succession to the solution of 7.8 g (20 mmol) of (R, S) -α- [(diphenyl acetyl) amino] -3-nitrobenzenessic acid in a mixture of 20 ml of dimethylformamide and 120 ml of tetrahydrofuran. Triethylamine, 2.7 g (20 mmol) HOBT, 6.72 g (20.93 mmol) TBTU and 2.9 g (23.56 mmol) 4-hydroxybenzenemethane and allowed to stir for 1 hour at room temperature. The mixture was largely freed from solvents in a water jet vacuum, stirred in 150 ml of water and then exhaustively extracted with ethyl acetate. The combined ethyl acetate extracts were dried over sodium sulfate and the solvent was again removed in vacuo. 6.0 g (61% of theory) of a yellow crystalline product of mp 238-242 ° C. were obtained, which was used in the following step without further purification. IR (KBr): 1639.4 (amide-CO),

1525.0 (amide-II; aromatic NO2),

1351.2 (N0 ₂ ) cm ^"1

c) (R, S) -3-amino-α- [(diphenylacetyl) ammo] -N- [(4-hydroxyphenyl) methyl] -benzenacetamide

The solution of 6.0 g (0.0121 mol) of (R, S) -α- [(Diphenyl¬ acetyl) ammo] -N- [(4-hydroxyphenyl) methyl] -3-nitrobenzeneacetamide in 500 ml of ethanol was for 16 hours in Ge ^¬ genwart of 2.0 g of Raney nickel as catalyst at a hydrogen pressure of 3.5 bar hydrogenated. The mixture was diluted with a further 250 ml of ethanol and suction filtered while hot from the catalyst. The colorless filtrate was evaporated to a volume of 150 ml and after cooling with added the same volume of diethyl ether. After standing for three hours at room temperature, the resulting crystals were filtered off. 4.75 g (84% of theory) of colorless crystals of mp 215-217 ° C. were obtained

IR (KBr): 1639.4 (amide-CO) cm ^-1 MS: M ⁺ = 465

(R, S) -3- (Ammoiminomethylammo) -α- [(diphenylacetyl) amino] -N- [(4-hydroxyphenyl) methyl] -benzenacetamide hydrochloride

The mixture of 2.3 g (4.94 mmol) (R, S) -3-Ammo-α- [(diphenylacetyl) ammo] -N- [(4-hydroxyphenyl) methyl] -benzene acetamide, 5 ml (5 mmol ) IN aqueous hydrochloric acid and 250 ml of ethanol was boiled under reflux for 5 minutes, the clear solution obtained was then evaporated in vacuo. The residue was taken up in 250 ml of dioxane and, after adding 0.34 g (8.1 mmol) of cyanamide, heated under reflux for 7 hours. The residue remaining after the solvent had been distilled off was partitioned between water and dichloromethane. The dichloromethane phase was discarded, the aqueous was filtered through a glass fiber filter, the residue thus obtained was dried in vacuo and gave 2.58 g (96% of theory) of a colorless, largely amorphous product of Rf 0.79. IR (KBr): 1652.9 (broad, amide-CO) crn ^-1 MS: (M + H) ⁺ = 508

Example 2

(R, S) -N- [[4- (Ammocarbonylammomethyl) phenyl] methyl] -3- (aminoiminomethylamino) -α- [(diphenylacetyl) ammo] -benzenacetamide hydrochloride

(R, S) -N- [[4- (Ammocarbonylammomethyl) phenyl] methyl] - α- [(diphenylacetyl) ammo] -3-nιtrobenzenacetamιd

Prepared analogously to Example 1b) from (R, S) -α- [(Diphenyl¬ acetyl) amino] -3-nιtrobenzenessιgsaure and 4- (Ammocarbonylammomethyl) benzene methane in a yield of 65% of theory. Lemon yellow crystals, mp 226-228 ° C. IR (KBr): 1645.2 (broad, amide-CO),

1529.5 (Amide-II, aromatic NO2) /

1350.1 (N0 ₂ ) cm ^-1

(R, S) -3-amino-N- [[4- (aminocarbonylaminomethyl) phenyl] methyl] -α- [(diphenylacetyl) ammo] -benzenacetamide

Manufactured analogously to Example 1c), but using dimethylformamide as solvent and 10 percent. Palladium on activated carbon as a catalyst, from (R, S) -N- [[4- (aminocarbonylaminomethyl) phenyl] methyl] - α- [(diphenylacetyl) amino] -3-nitrobenzenacetamide in a yield of 64% of theory. Colorless crystals, mp. 208-213 ° C

IR (KBr): 1643.3 (broad, amide-CO) cm ^"1 ESI-MS: (M + H) ⁺ = 522

(M + Na) ⁺ = 544

(M + K) ⁺ = 560

(M + NH4Y = 539 c) (R, S) -N- [[4- (Ammocarbonylammomethyl) phenyl] methyl] - 3- (ammoimmomethylammo) -α- [(diphenylacetyl) ammo] - benzenacetamide hydrochloride

Prepared analogously to Example ld) from (R, S) -3-Ammo-N- [[4- (ammocarbonylammomethyl) phenyl] methyl] -α- [(di¬ phenylacetyl) amino] -benzenacetamide and cyanamide in a yield of 11% of theory. Colorless, amorphous substance of Rf 0.57.

IR (KBr): 1637.5 (broad, amide-CO) cm ^-1 ESI-MS: (M + H) ⁺ = 564 (M + Na) ⁺ = 586

Example 3

(R, S) -N- [[4- (Ammocarbonylmethyl) phenyl] methyl] -3- (ammoimmo¬ methylamino) -α- [(diphenylacetyl) amino] -benzenacetamide hydrochloride

a) (R, S) -N- [[4- (Ammocarbonylmethyl) phenyl] methyl] - α- [(diphenylacetyl) ammo] -3-nιtrobenzenacetamιd

Prepared analogously to Example lb) from (R, S) -α- [(diphenyl ^¬ acetyl) ammo] -3-nιtrobenzenessιgsaure and 4- (Ammocar¬ bonylmethyl) benz methanamine m a yield of 72% of theory. Yellow crystals of mp 193-196 ° C (Z.). IR (KBr): 1656.8 (broad), 1641.3 (amide-CO),

1531.4 (amide-II, aromatic NO2),

1350.1 (N0 ₂ ) cm ^"1

b) (R, S) -3-amino-N- [[4- (ammocarbonylmethyl) phenyl] methyl] - α- [(diphenylacetyl) ammo] -benzenacetamide

Prepared analogously to Example 2b) from (R, S) -N- [[4- (ammo-carbonylmethyl) phenyl] methyl] -α- [(diphenylacetyl) ammo] - 3-nιtrobenzenacetamιd in a yield of 74% of theory. Colorless crystals, mp 235-237 ° C (Z.). IR (KBr): 1645.2 (broad, amide-CO) cm ^-1 MS: M ⁺ = 506

c) R, S) -N- [[4- (ammocarbonylmethyl) phenyl] methyl] -3- (ammo¬ immomethylamino) -α- [(diphenylacetyl) ammo] -benzenacetamide hydrochloride

Prepared analogously to Example ld) from (R, S) -3-Ammo-N- [[4- (ammocarbonylmethyl) phenyl] methyl] -α- [(diphenyl-acetyl) ammo] -benzenacetamide and cyanamide in a yield of 73% of theory. Colorless, amorphous substance of Rf 0.55.

IR (KBr): 1658.7 (broad, amide-CO) cm ^-1 ESI-MS: (M + H) ⁺ = 549

(M + Na) ⁺ = 571

(M + K) ⁺ = 587

Example 4

trans- (R, S) -3- [[4- (dimethylammomethyl) cyclohexylmethyl] ammoimmomethylammo] -α- [(diphenylacetyl) amino] -N-methyl-N- (phenylmethyl) -benzenacetamide hydroiodide

a) (R, S) -α- [(diphenylacetyl) amino] -N-methyl-3-nitro-N- (phenylmethyl) -benzenacetamide

Prepared analogously to Example lb) from (R, S) -α- [(diphenyl acetyl) amino] -3-nitrobenzenessic acid and N-methylbenzene methane in a yield of 43% of theory. Yellow crystals of mp 137-139 ° C IR (KBr): 1641.3 (broad, amide-CO),

1527.5 (amide-II, aromatic NO2),

1346.2 (N0 ₂ ) cm ^'1 (R, S) -3-Ammo-α- [(diphenylacetyl) ammo] -N-methyl-N- (phenylmethyl) -benzenacetamide

Prepared analogously to Example 2b) from (R, S) -α- [(diphenyl-acetyl) ammo] -N-methyl-3-nitro-N- (phenylmethyl) -benzene-acetamide in a yield of 99% of theory. Colorless, highly viscous substance. IR (KBr): 1643.3 (broad, amide-CO) cm ^"1

(R, S) -3- [[(benzoylammo) thiocarbonyl] ammo] -α- [(diphenylacetyl) amino] -N-methyl-N- (phenylmethyl) -benzenacetamide

The solution of 0.82 g (10.77 mmol) of ammonium rhodanide in 140 ml of acetone was mixed with 1.51 g (10.74 mmol) of benzoyl chloride and boiled under reflux for 30 minutes. After the addition of 5.0 g (10.79 mmol) of (R, S) -3-Ammo-α- [(diphenylacetyl) ammo] -N-methyl-N- (phenylmethyl) -benzenacetamide, the mixture was heated to reflux temperature for a further 2 hours Aturature. The cooled reaction mixture was stirred in 900 ml of ice water and the precipitated 01 was taken up in dichloromethane. The dichloromethane solution was dried over sodium sulfate and freed from the solvent. The product obtained in a yield of 95% of theory was used in the following stage without further purification.

IR (KBr): 1643.3 (broad, amide-CO) cm ^"1 ESI-MS: (M + H) ⁺ = 627

(M + Na) ⁺ = 649

(M + K) ⁺ = 665 d) (R, S) -3- [(Ammothiocarbonyl) ammo] -α- [(diphenylacetyl) amino] -N-methyl-N- (phenylmethyl) -benzenacetamide

The mixture of 6.4 g (10.22 mmol) (R, S) -3- [[(benzoyl- ammo) thiocarbonyl] amino] -α- [(diphenylacetyl) ammo] - N-methyl-N- (phenylmethyl) -benzenacetamide, 25.4 ml (25.4 mmol) IN sodium hydroxide solution and 340 ml ethanol was stirred for 7 hours at room temperature. The ethanol was distilled off in vacuo, the residue was taken up in 300 ml of water and stirred vigorously. The resulting crystalline precipitate was filtered off with suction and dried in vacuo. Pale yellow crystals with a melting point of 112-115 ° C. Yield: 4.5 g (84% of theory). IR (KBr): 1643.3 (broad, amide-CO) cm ^"1 ESI-MS: (M + H) ⁺ = 523.1

(M + Na) ⁺ = 545.1

(2M + Na) ⁺ = 1067.4

e) (R, S) -3- [(aminothiocarbonyl) amino] -α- [(diphenylacetyl) amino] -N-methyl-N- (phenylmethyl) -benzenacetamide-metho-did

The mixture of 4.5 g (8,615 mmol) (R, S) -3- [(Ammothio-carbonyl) ammo] -α- [(diphenylacetyl) ammo] -N-methyl-N- (phenylmethyl) -benzenacetamide, 86 ml ethanol and 4.3 ml (69 mmol) of methyl iodide was stirred for 2 hours at room temperature and then ^¬ 2 hours at a reac tion ^¬ temperature of 40 ° C. Solvents and excess reagent were distilled off, finally in vacuo, the residue was stirred vigorously with diisopropyl ether, the precipitated yellowish crystalline product was filtered off with suction and dried in vacuo. Yield: 5.4 g (94% of theory).

IR (KBr): 1633.6 (broad, amide-CO) cm ^"1 ESI-MS: (M + H) ⁺ = 537 (M + Na) ⁺ = 559 f) trans- (R, S) -3- [[4- (dimethylammomethyl) cyclohexyl-methyl] -aminolminomethylamino] -α- [(diphenylacetyl) -ammo] - N-methyl-N- (phenylmethyl) -benzenacetamide -hydroiodide

The mixture of 1.62 g (2.44 mmol) (R, S) -3- [(Ammothio¬ carbonyl) ammo] -α- [(diphenylacetyl) ammo] -N-methyl-N- (phenylmethyl) -benzenacetamide methoiodide, 0.425 g (2.50 mmol) of trans-4- (dimethylammomethyl) cyclohexane-methanamine, 30 ml of ethanol and 0.69 ml of triethylamine were boiled under reflux for 16 hours. The residue that remained after the solvent had been removed was measured on silica gel (32-64 μm) using dichloromethane / methanol / - cyclohexane / conc. aqueous ammonia = 68/15/15/2 purified by column chromatography. 0.6 g of a colorless, amorphous substance of Rf 0.24 was obtained. IR (KBr): 1643.3 (broad, amide-CO) cm ^"1 ESI-MS: (M + H) ⁺ = 659 (M + 2H) ⁺⁺ = 330

Example 5

(R, S) -α- [(diphenylacetyl) amino] -N-methyl-3- (phenylaminolmino¬ methylamino) -N- (phenylmethyl) -benzenacetamide

Prepared analogously to Example 4f), but using n-propanol as solvent, from (R, S) -3- [(ammothiocarbonyl) amino] -α- [(diphenylacetyl) amino] -N-methyl-N- (phenylmethyl) ) - benzenacetamide methoiodide and aniline in a yield of 23% of theory. Colorless, amorphous substance of Rf 0.83. IR (KBr): 1645.2 (broad, amide-CO) cm ^"1 ESI-MS: (M + H) ⁺ = 582

(M + Na) ⁺ = 604

(M + K) ⁺ = 620 Example 6

(R, S) -3- (Ammoimmomethylammo) -α- [(diphenylacetyl) amino] - N-methyl-N- (phenylmethyl) -benzenacetamide hydroiodide

Prepared analogously to Example 4f), but using a bomb tube as reaction kettle, from (R, S) -3- [(ammothiocarbonyl) amino] -α- [(diphenylacetyl) ammo] -N-methyl-N- (phenyl- methyl) -benzenacetamide-methoiodide and ammonia in a yield of 13 <> of theory. Colorless, amorphous substance of Rf 0.75. IR (KBr): 1645.2 (broad, amide-CO) cm ^"1 ESI-MS: (M + H) ⁺ = 506

Example 7

(R, S) -α- [(diphenylacetyl) amino] -N-methyl-3- (methylammoimmo¬ methylamino) -N- (phenylmethyl) -benzenacetamide

Prepared analogously to Example 6 from (R, S) -3- [(Ammothiocarbonyl) ammo] -α- [(diphenylacetyl) ammo] -N-methyl-N- (phenyl-methyl) -benzenacetamide methoiodide and methylamine in a yield of 16% of theory. Colorless, amorphous substance of R _f 0.71.

IR (KBr): 1641.3 (broad, amide-CO) cm ^"1 ESI-MS: (M + H) ⁺ = 520

Example 8

trans- (R, S) -N- [[4- (ammocarbonylaminomethyl) phenyl] methyl] - 3- [[4- (dimethylammomethyl) cyclohexylmethyl] aminoiminomethylamino] -α- [(diphenylacetyl) ammo] -benzenacetamide hydroiodide

a) (R, S) -N- [[4- (Ammocarbonylaminomethyl) phenyl] methyl] - α- [(diphenylacetyl) ammo] -3-nιtrobenzenacetamιd

Prepared analogously to Example lb) from (R, S) -α- [(Diphenyl¬ acetyl) ammo] -3-nιtrobenzenessιgsaure and 4- (Ammocar- bonylammomethyl) -benzenmethanamm in a yield of 94% of theory. Yellow crystals of mp 220-225 ° C. IR (KBr): 1645.2 (broad, amide-CO),

1529.5 (amide-II, aromatic NO2),

1350.1 (N0 ₂ ) cm ^"1

b) (R, S) -3-amino-N- [[4- (ammocarbonylaminomethyl) phenyl] methyl] -α- [(diphenylacetyl) amino] -benzenacetamide

Prepared analogously to Example 2b) from (R, S) -N- [[4- (amomocarbonylammomethyl) phenyl] methyl] -α- [(diphenylacetyl) amino] -3-nitrobenzenacetamid in a yield of 98% of theory. Colorless crystals of mp 207-209 ° C IR (KBr): 1641.3 (broad, amide-CO) cm ^"1

c) (R, S) -N- [[4- (Ammocarbonylaminomethyl) phenyl] methyl] - 3- [[(benzoylamino) thiocarbonyl] ammo] -α- [(diphenyl¬ acetyl) ammo] -benzenacetamide

Prepared analogously to Example 4c) from (R, S) -3-Ammo-N- [[4- (ammocarbonylammomethyl) phenyl] methyl] -α- [(di-phenylacetyl) amino] -benzenacetamide, ammonium rhodanide and benzoylchloride in a yield of 78% of theory. Colorless, amorphous substance.

IR (KBr): 1635.5 (broad, amide-CO) cm ^"1

ESI-MS: (M + H) ⁺ = 685

(M + Na) ⁺ = 707

(MH) ^~ = 683

d) (R, S) -N- [[4- (Ammocarbonylammomethyl) phenyl] methyl] - 3- [(ammothiocarbonyl) ammo] -α- [(diphenylacetyl) ammo] - benzenacetamide

Prepared analogously to Example 4d) from (R, S) -N- [[4- (ammo-carbonylammomethyl) phenyl] methyl] -3- [[(benzoylamino) -thiocarbonyl] ammo] -α- [(diphenylacetyl) amino] benzene ¬ acetamide by saponification with IN sodium hydroxide solution Yield 92% of theory. Colorless crystals, mp 151-153 ° C

IR (KBr): 1637.5 (broad, amide-CO) cm ^-1

ESI-MS: (M + H) ⁺ = 581

(M + Na) ⁺ = 603

(MH) ^" = 579

e) (R, S) -N- [[4- (Ammocarbonylammomethyl) phenyl] methyl] -

3- [(ammothiocarbonyl) ammo] -α- [(diphenylacetyl) ammo] - benzenacetamide methoiodide

Prepared analogously to Example 4e) from (R, S) -N- [[4- (ammo-carbonylammomethyl) phenyl] methyl] -3- [(ammothiocarbonyl) amino] -α- [(diphenylacetyl) amino] -benzenacetamide and Methyl iodide in a yield of 87% of theory. Colorless crystals.

IR (KBr): 1635.5 (broad, amide-CO) cm ^"1

ESI-MS: (M + H) ^{4 "} = 595 (M + Na) ⁺ = 617

f) trans- (R, S) -N- [[4- (ammocarbonylammomethyl) phenyl] methyl] -3- [[4- (dimethylammomethyl) cyclohexylmethyl] -ammo iminomethylammo] -α- [(diphenylacetyl) ammo] -benzenacet amide-hydroiodide

Prepared analogously to Example 4f) from (R, S) -N- [[4- (Ammo ^¬ carbonylaminomethyl) phenyl] methyl] -3- [(ammothiocarbonyl) ammo] -α- [(diphenylacetyl) ammo] benzenacetamide methoiodide and trans-4- (dimethylammomethyl) cyclohexane methane in a yield of 35% of theory. Colorless, amorphous substance of Rf 0.18. IR (KBr): 1652.9 (broad, amide-CO) cm ^"1 ESI-MS: (M + H) ⁺ = 717

(M + Na) ⁺ = 739

(M + 2H) ⁺⁺ = 359

(R, S) -N- [[4- (ammocarbonylaminomethyl) phenyl] methyl] -ot- [(di¬ phenylacetyl) ammo] -3- [(methylaminocarbonyl) aminoimmo-methylammo] benzacetamide

The mixture of 2.5 g (4.80 mmol) (R, S) -3-Ammo-N- [[4- (ammo¬ carbonylaminomethyl) phenyl] methyl] -ct- [(diphenylacetyl) ammo] - benzenacetamide, 18 ml isopropanol, 20 ml of dimethylformamide and 3 ml of acetic acid were heated to 80 ° C. for 72 hours, the mixture at the beginning and after 12, 24, 36, 48 and 60 hours in each case 0.4 g (3.48 mmol) of O-methyl-N- (methylaminocarbonyl) - Isourea was added. The solvent was removed in vacuo, the residue was taken up in 50 ml of dichloromethane, the mixture was stirred at room temperature for 30 minutes and the precipitate formed was filtered off with suction. The filtrate was again evaporated in vacuo, the residue on silica gel (Baker, 30-60 μm) using dichloromethane / ethyl acetate / methanol / - cyclohexane / conc. aqueous ammonia = 59/25 / 7.5 / 7.5 / 1 (v / v / v / v) purified by column chromatography for elution. Working up the suitable eluates gave 60 mg (2% of theory) of a colorless, crystalline substance of Rf 0.66. IR (KBr): 1652.9 (broad, amide-CO) cm ^-1 ESI-MS: (M + H) ⁺ = 621

(M + Na) ⁺ = 643

(M + K) ⁺ = 659

Example 10

(R, S) -N- [[4- (Ammocarbonylaminomethyl) phenyl] methyl] -ot- [(di¬ phenylacetyl) ammo] -3- [(4-methoxyphenyl) aminoimmo-methylamino] -benzenacetamide hydroiodide

Prepared analogously to Example 4f), but using n-propanol as solvent, from (R, S) -N- [[4- (Ammocarbonyl¬ ammomethyl) phenyl] methyl] -3- [(ammothiocarbonyl) ammo] - ot- [(diphenylacetyl) ammo] -benzenacetamide methoiodide and p-aniside in a yield of 8 "of theory. Colorless, amorphous substance of Rf 0.67.

IR (KBr): 1645.2 (broad, amide-CO) cm ^"1

ESI-MS: (M + H) ⁺ = 670

(M + Na) ⁺ = 692

Example 11

(R, S) -ot- [(diphenylacetyl) ammo] -3- [(4-methoxyphenyl) ammolminomethylammo] -N- (phenylmethyl) benzene acetamide

a) (R, S) -ot- [(diphenylacetyl) amino] -3-nitro-N- (phenyl¬ methyl) -benzenacetamide

Prepared analogously to Example lb) from (R, S) -α- [(Diphenyl¬ acetyl) ammo] -3-nιtrobenzenessιgsaure and Benzenmethan¬ amm in a yield of 47% of theory. Yellow crystals. IR (KBr): 1635.5 (broad, amide-CO),

1531.4 (amide-II, aromatic NO2),

1350.1 (N0 ₂ ) cm ^-1

b) (R, S) -3-Ammo-ot- [(diphenylacetyl) ammo] -N- (phenyl-methyl) -benzenacetamide

Prepared analogously to Example 2b) from (R, S) -α- [(Diphenyl¬ acetyl) ammo] -3-nitro-N- (phenylmethyl) -benzenacetamide in a yield of 80% of theory. Colorless crystals. IR (KBr): 1641.3 (broad, amide-CO) cm ^"1 c) (R, S) -3- [[(Benzoylamino) thiocarbonyl] ammo] -ot- [(diphenylacetyl) ammo] -N- (phenylmethyl) -benzenacetamide

Prepared analogously to Example 4c) from (R, S) -3-Ammo-ot- [(diphenylacetyl) amino] -N- (phenylmethyl) -benzenacetamide, ammonium rhodanide and benzoyl chloride in a yield of 97% of theory. Colorless crystals. IR (KBr): 1641.3 (broad, amide-CO) cm ^"1 ESI-MS: (M + H) ⁺ - 613

(M + Na) ⁺ = 635

(MH) ^" = 611

d) (R, S) -3- [(Ammothiocarbonyl) ammo] -α- [(diphenyl-acetyl) - ammo] -N- (phenylmethyl) -benzenacetamide

Prepared analogously to Example 4d) from (R, S) -3- [[(Benzoyl¬ amino) thiocarbonyl] amino] -ot- [(diphenylacetyl) amino] - N- (phenylmethyl) -benzenacetamide by saponification with IN sodium hydroxide solution in one yield of 99% of theory. Colorless, amorphous substance.

IR (KBr): 1637.5 (broad, amide-CO) cm ^"1 ESI-MS: (MH) ^~ = 507 (M + Na) ⁺ = 531

e) (R, S) -3- [(Ammothiocarbonyl) ammo] -α- [(diphenylacetyl) ammo] -N- (phenylmethyl) -benzenacetamide methoiodide

Prepared analogously to Example 4e) from (R, S) -3- [(Ammo¬ thiocarbonyl) ammo] -ot- [(diphenylacetyl) ammo] -N- (phenyl ^¬ methyl) -benzenacetamide and methyl iodide in a yield of 99% of Theory. Colorless, amorphous substance. IR (KBr): 1645.2 (broad, amide-CO) cm ^"1 ESI-MS: (M + H) ⁺ = 523 (M + Na) ⁺ = 545 f) (R, S) -α- [(Diphenylacetyl) ammo] -3- [(4-methoxyphenyl) - aminoiminomethylammo] -N- (phenylmethyl) -benzenacetamide

Prepared analogously to Example 10 from (R, S) -3- [(Ammo¬ thiocarbonyl) ammo] -α- [(diphenylacetyl) ammo] -N- (phenyl¬ methyl) -benzenacetamide methoiodide and p-aniside in a yield of 22% of theory. Colorless, crystalline substance of mp 126-132 ° C and R _f 0.84. IR (KBr): 1649.0 (broad, amide-CO) cm ^"1 ESI-MS: (M + H) ⁺ = 598

(M + Na) ⁺ = 620

(M + K) ⁺ = 636

Example 12

(R, S) -N- [[4- (Ammocarbonylaminomethyl) phenyl] methyl] -α- [(di¬ phenylacetyl) amino] -3- [[imino [N-methyl-N- (phenylmethyl) amino] methyl] ammo] -benzenacetamide

Prepared analogously to Example 10 from (R, S) -N- [[4- (Ammocarbonylammomethyl) phenyl] methyl] -3- [(ammothiocarbonyl) ammo] - α- [(diphenylacetyl) ammo] -benzenacetamide methoiodide and N -Methylbenzenemethane in a yield of 21% of theory. Colorless, amorphous substance of Rf 0.56. IR (KBr): 1649.0 (broad, amide-CO) cm ^"1 ESI-MS: (M + H) ⁺ = 668

(M + Na) ⁺ = 690

Example 13

(R, S) -N- [[4- (Ammocarbonylaminomethyl) phenyl] methyl] -α- [(di¬ phenylacetyl) ammo] -3- (methylaminolminomethylamino) -benzene ^¬ acetamide acetate

Manufactured analogously to Example 10), but using a steel bomb as a reaction vessel, from (R, S) -N- [[4- (Ammocarbonyl¬ aminomethyl) phenyl] methyl] -3- [(ammothiocarbonyl) ammo] - α- [(diphenylacetyl) ammo] -benzenacetamide methoiodide and methylamine in a yield of 63% of theory. Colorless crystals from Rf 0.47.

IR (KBr): 1639.4 (broad, amide-CO) cm ^-1

ESI-MS: (M + H) ⁺ = 578

(M + Na) ⁺ = 600

Example 14

(R, S) -α- [(diphenylacetyl) ammo] -3- [(4-methoxyphenyl) amino-immomethylammo] -N- [[(4-phenylmethoxy) phenyl] methyl] -benzene acetamide

a) (R, S) -α- [(diphenylacetyl) ammo] -3-nitro-N- [[(4-phenyl-methoxy) phenyl] methyl] -benzenacetamide

Prepared analogously to Example lb) from (R, S) -ot- [(Diphenyl¬ acetyl) ammo] -3-nιtrobenzenessιgsaure and 4- (Phenyl-methoxy) -benzenmethanamm in a yield of 57% of theory. Yellow crystals from Fp. 185-190 ° C IR (KBr): 1641.3 (broad, amide-CO),

1531.4 (amide-II, aromatic NO2)

1352.0 (N0 ₂ ) cm ^-1

b) (R, S) -3-amino-ot- [(diphenylacetyl) amino] -N- [[(4-phenyl-methoxy) phenyl] methyl] -benzenacetamide

Prepared analogously to example lc), but using dimethylformamide as solvent, from (R, S) -ot- [(di-phenylacetyl) ammo] -3-nitro-N- [[(4-phenylmethoxy) -phenyl] methyl] -benzenacetamide in a yield of 73% of theory. Colorless crystals. IR (KBr): 1635.5 (broad, amide-CO) cm ^"1 c) (R, S) -3- [[(Benzoylamino) thiocarbonyl] ammo] -ot- [(diphenylacetyl) ammo] -N- [[(4-phenylmethoxy) phenyl] methyl] - benzenacetamide

Prepared analogously to Example 4c) from (R, S) -3-Ammo-α- [(diphenylacetyl) ammo] -N- [[(4-phenylmethoxy) phenyl] methyl] -benzenacetamide, ammonium rhodanide and benzoyl chloride in one yield of 99% of theory. Colorless

Crystals.

IR (KBr): 1637.5 (broad, amide-CO) cm ^"1

d) (R, S) -3- [(ammothiocarbonyl) ammo] -α- [(diphenyl-acetyl) - ammo] -N- [[(4-phenylmethoxy) phenyl] methyl] -benzenacet¬

Prepared analogously to Example 4d) from (R, S) -3- [[(Benzoyl¬ amino) thiocarbonyl] ammo] -ot- [(diphenylacetyl) ammo] - N- [[(4-phenylmethoxy) phenyl] methyl] -benzenacetamide by saponification with IN sodium hydroxide solution in a yield of 81% of theory. Colorless crystals. IR (KBr): 1637.5 (broad, amide-CO) cm ^"1 ESI-MS: (MH) ^" = 613 (M + Na) ⁺ = 637

e) (R, S) -3- [(Ammothiocarbonyl) ammo] -ot- [(diphenylacetyl) - amino] -N- [[(4-phenylmethoxy) phenyl] methyl] -benzenacet ^¬ amide methoiodide

Prepared analogously to Example 4e) from (R, S) -3- [(Ammothio ^¬ carbonyl) ammo] -α- [(diphenylacetyl) ammo] -N- [[(4-phenyl-methoxy) phenyl] methyl] -benzenacetamide and Methyl iodide in a yield of 98% of theory. Colorless, amorphous substance.

IR (KBr): 1633.6 (broad, amide-CO) cm ^"1 ESI-MS: (M + H) ⁺ = 629 (M + Na) ⁺ = 651 f) (R, Ξ) -α- [(Diphenylacetyl) amino] -3- [(4-methoxyρhenyl) - ammoimmomethylammo] -N- [[(4-phenylmethoxy) phenyl] - methyl] -benzenacetamide

Prepared analogously to Example 10 from (R, S) -3- [(Ammothio carbonyl) ammo] -ct- [(diphenylacetyl) ammo] -N- [[(4-phenyl-methoxy) phenyl] methyl] -benzenacetamide methoiodide and p-anisidine in a yield of 27% of theory. Colorless, crystalline substance of mp 196 - 198 ° C and R _f 0.90.

IR (KBr): 1639.4 (broad, amide-CO) cm ^"1 ESI-MS: (M + H) ⁺ = 704 (M + Na) ⁺ = 726

Example 15

(R, S) -3- (aminoimmomethylamino) -α- [(diphenylacetyl) ammo] - N- [[(4-phenylmethoxy) phenyl] methyl] -benzenacetamide

Prepared analogously to Example 4f) from (R, S) -3- [(ammothiocarbonyl) ammo] -α- [(diphenylacetyl) ammo] -N- [[(4-phenylmethoxy) phenyl] methyl] -benzenacetamide- methoiodide and ammonia in a yield of 13% of theory. Colorless crystals of mp 198-200 ° C and R _f 0.79.

IR (KBr): 1645.2 (broad, amide-CO) cm ^-1 ESI-MS: (M + H) ⁺ = 598

(M + Na) ⁺ = 620

Example 16

(R, S) -3- (Ammoimmomethylamino) -α- [(diphenylacetyl) ammo] -N-methyl-N- [[(4-phenylmethoxy) phenyl] methyl] -benzenacetamide

a) (R, S) -ct- [(diphenylacetyl) ammo] -3-nitro-N-methyl-N- [[(4-phenylmethoxy) phenyl] methyl] -benzenacetamide

Prepared analogously to Example lb) from (R, S) -ot- [(Diphenyl¬ acetyl) ammo] -3-nιtrobenzenessιgsaure and N-methyl- 4- (phenylmethoxy) -benzenmethanamm with a yield of 56% of theory. Yellow crystals. IR (KBr): 1643.3 (broad, amide-CO),

1510.2 (amide-II, aromatic NO2),

1350.1 (NO2) cm ^"1

b) (R, S) -3-amino-α- [(diphenylacetyl) ammo] -N-methyl-N- [[(4-phenylmethoxy) phenyl] methyl] -benzenacetamide

Prepared analogously to Example lc), but using methanol as a loose containers, of (R, S) -OT- [(diphenyl ^¬ acetyl) ammo] -3-nιtro-N-methyl-N- [[(4-phenylmethoxy) - phenyl] methyl] -benzenacetamide with a yield of 71 4 of theory. Colorless crystals from Fp. 141-143 ° C IR (KBr): 1643.3 (broad, amide-CO) cm ^-1

(R, S) -3- [[(Benzoylamino) thiocarbonyl] amino] -ot- [(di¬ phenylacetyl) amino] -N-methyl-N- [[(4-phenylmethoxy) - phenyl] methyl] -benzenacetamide

Prepared analogously to Example 4c) from (R, S) -3-amino-α- [(diphenylacetyl) amino] -N-methyl-N- [[(4-phenylmethoxy) phenyl] methyl] -benzenacetamide, ammonium rhodanide and benzoyl chloride in a yield of 98% of theory. Colorless crystals. IR (KBr): 1643.3 (broad, amide-CO) cm ^"1 ESI-MS: (M + H) ⁺ = 733

(M + Na) ⁺ - 755

(M + NH ₄ ) ⁺ = 750

d) (R, S) -3- [(Ammothiocarbonyl) ammo] -α- [(diphenylacetyl) - ammo] -N-methyl-N- [[(4-phenylmethoxy) phenyl] methyl] - benzenacetamide

Prepared analogously to Example 4d) from (R, S) -3- [[(Benzoyl¬ amino) thiocarbonyl] amino] -et- [(diphenylacetyl) amino] - N- [[(4-phenylmethoxy) phenyl] methyl] -benzenacetamide by saponification with IN sodium hydroxide solution in a yield of 99% of theory. Colorless crystals. IR (KBr): 1643.3 (broad, amide-CO) cm ^"1 ESI-MS: (M + H) ⁺ = 629

(M + NH ₄ ) ⁺ = 646

(M + Na) ⁺ = 651

e) (R, S) -3- [(Ammothiocarbonyl) ammo] -ot- [(diphenylacetyl) - amino] -N-methyl-N- [[(4-phenylmethoxy) phenyl] methyl] - benzenacetamide methoiodide

Prepared analogously to Example 4e) from (R, S) -3- [(Ammo thiocarbonyl) ammo] -α- [(diphenylacetyl) ammo] -N-methyl-N- [[(4-phenylmethoxy) phenyl] methyl] - benzenacetamide and methyl iodide in a yield of 89% of theory. Colorless, amorphous substance. IR (KBr): 1631.7 (broad, amide-CO) cm ^"1 ESI-MS: (M + H) ⁺ = 643 (M + Na) ⁺ = 665 f) (R, S) -3- (Ammoimmomethylammo) -α- [(diphenylacetyl) amino] -N-methyl-N- [[(4-phenylmethoxy) phenyl] methyl] benzenacetamide

Prepared analogously to Example 6 from (R, S) -3- [(Ammothio carbonyl) amino] -α- [(diphenylacetyl) ammo] -N-methyl-N- [[(4-phenylmethoxy) phenyl] methyl] -benzenacetamide - methoiodide and ammonia in a yield of 17% of theory. Colorless, crystalline substance of Rf 0.80. IR (KBr): 1645.2 (broad, amide-CO) cm ^"1 ESI-MS: (M + H) ⁺ = 612 (M + Na) ⁺ = 634

Example 17

(R, S) -N- [[4- (Ammocarbonylammomethyl) phenyl] methyl] -ot- [(di¬ phenylacetyl) amino] -N-methyl-3- (methylamino-iminomethylamino) - benzenacetamide hydrochloride

a) (R, S) -N- [[4- (Ammocarbonylaminomethyl) phenyl] methyl] - α- [(diphenylacetyl) ammo] -3-nitro-N-methyl-benzenacet-

Prepared analogously to Example 1b), but using pure dimethylformamide as solvent, from (R, S) -et- [(diphenylacetyl) ammo] -3-nιtrobenzenessιgsaure and 4- (Ammocarbonylaminomethyl) -N-methyl-benzenemethane in one Yield of 71% of theory. Yellow crystals. IR (KBr): 1652.9 (broad, amide-CO),

b) (R, S) -3-Ammo-N- [[4- (ammocarbonylammomethyl) phenyl] methyl] -α- [(diphenylacetyl) ammo] -N-methyl-benzene-acetamide

Prepared analogously to Example lc), but using methanol as solvent, from (R, S) -N- [[4- (Ammo- carbonylaminomethyl) phenyl] methyl] -ot- [(diphenylacetyl) - ammo] -3-nitro-N-methyl-benzenacetamid with a yield of 42% of theory. Colorless, amorphous substance. IR (KBr): 1643.3 (broad, amide-CO) cm ^"1

c) (R, S) -N- [[4- (Ammocarbonylammomethyl) phenyl] methyl] - 3- [[(benzoylamino) thiocarbonyl] ammo] -α- [(diphenylacetyl) ammo] -N-methyl -benzenacetamide

Prepared analogously to Example 4c) from (R, S) -3-amino-N- [[4- (ammocarbonylammomethyl) phenyl] methyl] -ot- [(di-phenylacetyl) ammo] -N-methyl-benzenacetamide, ammonium rhodanide and benzoyl chloride in a yield of 92% of theory. Colorless crystals. IR (KBr): 1647.1 (broad, amide-CO) cm ^"1 ESI-MS: (M + H) ⁺ = 699

(MH) ^" = 697

(M + Na) ⁺ = 721

(M + NH ₄ ) ⁺ = 716

d) (R, S) -N- [[4- (Ammocarbonylaminomethyl) phenyl] methyl] - 3- [(ammothiocarbonyl) ammo] -ot- [(diphenylacetyl) ammo] - N-methyl-benzenacetamide

Prepared analogously to Example 4d) from (R, S) -N- [[4- (Ammo¬ carbonylaminomethyl) phenyl] methyl] -3- [[(benzoylamino) - thiocarbonyl] amino] -ot- [(diphenylacetyl) ammo] - N-methylbenzacetamide by saponification with IN sodium hydroxide solution in a yield of 94% of theory. Colorless crystals. IR (KBr): 1645.2 (broad, amide-CO) cm ^"1 ESI-MS: (M + H) ⁺ = 595

(M + Na) ⁺ = 617

(M + K) ⁺ = 633 e) (R, S) -N- [[4- (Ammocarbonylaminomethyl) phenyl] methyl] -

3- [(ammothiocarbonyl) ammo] -ot- [(diphenylacetyl) ammo] - N-methyl -benzenacetamide methoiodide

Prepared analogously to Example 4e) from (R, S) -N- [[4- (ammo-carbonylammomethyl) phenyl] methyl] -3- [(ammothiocarbonyl) ammo] -α- [(diphenylacetyl) ammo] -N- methyl-benzene-acetamide and methyl iodide in a yield of 95% of theory. Colorless, crystalline substance. IR (KBr): 1639.4 (broad, amide-CO) cm ^"1

ESI-MS: (M + H) ⁺ = 609

(M + Na) ⁺ = 631

(M + K) ⁺ = 647

f) (R, S) -N- [[4- (ammocarbonylammomethyl) phenyl] methyl] - α- [(diphenylacetyl) ammo] -N-methyl-3- (methylamino-imino¬ methylamino) -benzenacetamide hydrochloride

Prepared analogously to Example 13 from (R, S) -N- [[4- (ammo-carbonylaminomethyl) phenyl] methyl] -3- [(ammothiocarbonyl) ammo] -ot- [(diphenylacetyl) ammo] -N-methyl -benzen- acetamide-methoiodide and methylamine in a yield of 68% of theory. Colorless, crystalline substance of R _f 0.45.

IR (KBr): 1645.2 (broad, amide-CO) cm ^-1 ESI-MS: (M + H) ⁺ = 592

Claims

claims

1 . Ammosa derivatives of the general formula

in the

R is a phenyl, 1-naphthyl or 2-naphthyl group, a 5-membered heteroaromatic ring linked via a carbon atom, which has a nitrogen, oxygen or sulfur atom or a nitrogen and an oxygen, sulfur or contains a further nitrogen atom, it being possible for a nitrogen atom of an immune group to be substituted by an alkyl, alkoxycarbonyl-alkyl, carboxyalkyl, dialkylaminoalkyl, aminocarbonyl, alkylammocarbonyl, dialkylammocarbonyl or alkoxycarbonyl group, or one over an carbon atom Substance atom-linked 6-membered heteroaromatic ring which contains 1, 2 or 3 nitrogen atoms, it being possible for both the 5-membered rings and the 6-membered heteroaromatic rings to be attached via two adjacent carbon atoms in each case to 1,4-butadieneenylene groups and so on formed bicyclic heteroaromatic rings can also be bound via a carbon atom of the 1,4-butadienylene group and

the groups mentioned above for R and the mono- and bicyclic heteroaromatic rings in the carbon structure additionally by fluorine, chlorine or bromine atoms, by alkyl groups, cycloalkyl groups having 3 to 8 carbon atoms, Alkoxy, phenyl, phenylalkoxy, trifluoromethyl, alkoxycarbonylalkyl, carboxyalkyl, dialkylaminoalkyl, hydroxy, amino, acetylamino, propionylammo-, benzoyl, benzoylamino, benzoylmethylamino, aminocarbonyl, alkylammocarbonyl, Dialkylammocarbonyl, alkanoyl, cyano, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulfmyl or Tπ-fluoromethylsulfonyl groups can be mono-, di- or maximally trisubstituted, the substituents being the same or different and the above-mentioned benzoyl , Benzoylamino and benzoylmethylamino groups, in turn, in the phenyl part can additionally be substituted by em fluorine, chlorine or bromine atom, an alkyl, trifluoromethyl, amino or acetylamino group,

or the diphenylmethyl group in which

the phenyl groups can be mono- or disubstituted independently of one another by fluorine, chlorine or bromine atoms, methyl, methoxy, hydroxycarbonyl-methoxy, alkoxycarbonylmethoxy, hydroxy or trifluoromethyl groups, where the substituents can in each case be the same or different,

n the numbers 0, 1 or 2,

U the single bond, the oxygen atom or the -NH group,

R ^{1 is} the hydrogen atom,

a straight-chain or branched alkyl group with 1 to 8 carbon atoms, which may be substituted by a cycloalkyl group with 3 to 8 carbon atoms, or a cycloalkyl group with 3 to 8 carbon atoms, the groups in turn being eme alkoxycarbonyl, phenylalkoxycarbonyl, carboxy -, Ammo, monoalkylammo, dialkylammo or dialkylammomethyl group can be substituted sem, a branched or unbranched alkylcarbonyl radical comprising 2 to 5 carbon atoms, which can be substituted in the alkyl part by an alkoxycarbonyl or phenylalkoxycarbonyl group, by a phenyl group or by a 5- or 6-membered heteroaromatic ring linked via a carbon atom, or a benzoyl radical to which the Phenyl part can also be replaced by a 5- or 6-membered heteroaromatic ring linked via a carbon atom, the abovementioned 5-membered heteroaromatic rings having a nitrogen, an oxygen or sulfur atom or a nitrogen and an additional acid ¬ contain a substance, sulfur or other nitrogen atom and can also be substituted on a nitrogen atom by an alkyl group containing 6-membered heteroaromatic rings 1, 2 or 3 nitrogen atoms and the above-mentioned phenyl groups and all heteroaromatic rings in carbon skeleton in addition d By fluorine, chlorine or bromine atoms, by alkyl groups, cycloalkyl groups with 3 to 8 carbon atoms, alkoxy, trifluoromethyl, alkoxycarbonylalkyl, carboxyalkyl, hydroxy, amino, acetylamino, propionylammo-, aminocarbonyl , Alkylammocarbonyl, dialkyl, ammocarbonyl, alkanoyl, cyano, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulfinyl or trifluoromethylsulfonyl groups, mono-, di- or maximally trisubstituted, where the substituents can be the same or different.

the ammocarbonyl group which is formed on the nitrogen atom by alkyl, phenylalkyl, (1-naphthyl) alkyl, (2-naphthyl) alkyl, alkoxycarbonylalkyl, phenylalkoxycarbonylalkyl, phenoxycarbonylyl, carboxyalkyl, diphenylalkyl, phenyl , Cycloalkyl- or Cycloalkylalkylgruppen each with 3 to 8 carbon atoms in the Rmg mono- or disubstituted sem, where the substituents may be the same or different sem and where the above-mentioned phenyl radicals in turn by fluorine, chlorine or bromine atoms, methyl, methoxy -, Hydroxycarbonylmeth- oxy, alkoxycarbonylmethoxy, hydroxy or trifluoromethyl groups can be mono- or disubstituted independently of one another,

an alkoxycarbonyl or phenylalkoxycarbonyl radical, the phenyl part in turn being mono- or disubstituted by fluorine, chlorine or bromine atoms, methyl, methoxy, hydroxycarbonylmethoxy, alkoxycarbonyl methoxy, hydroxyl or trifluoromethyl groups and the substituents in each case being the same or different can,

a phenyl or phenylmethyl group, a hetaryl or hetarylmethyl group linked via a carbon atom, where hetaryl has a five-membered heteroaromatic ring, a nitrogen, oxygen or sulfur atom or a nitrogen atom and an oxygen, sulfur or another Contains nitrogen atom and in which a nitrogen atom of an imino group can be substituted by an alkyl group or means a 6-membered heteroaromatic ring linked via a carbon atom, which contains 1, 2 or 3 nitrogen atoms, and where both the phenyl group and Hetaryl in the carbon skeleton additionally by fluorine, chlorine or bromine atoms, by alkyl groups, cycloalkyl groups with 3 to 8 carbon atoms, phenylalkyl, alkoxy, trifluoromethyl, alkoxycarbonylalkyl, carboxyalkyl, hydroxyl, amino, Acetylamino, propionylamino, aminocarbonyl, alkylammocarbonyl, dialkylammocarbonyl, alkanoyl, cyano, trifluoromethoxy, trifluoromethylthio, Trifluoromethylsulfmyl or trifluoromethylsulfonyl groups can be mono-, di- or maximally tπ-substituted and the substituents can be the same or different,

R ^{2 is} the hydrogen atom, an alkyl or phenylalkyl group which, in the phenyl part, can also be mono- or disubstituted by fluorine, chlorine or bromine atoms, alkyl, trifluoromethyl, amino or acetylamino groups, the substituents being the same or different, R ^{3 represents} the hydrogen atom or an alkyl group,

Y is the oxygen atom or the -NR ^ group, m the

R ^{4 represents} the hydrogen atom, a branched or unbranched alkyl group having 1 to 6 carbon atoms or the phenylmethyl group,

m the numbers 1 or 2 and

V is the hydrogen atom, the fluorine, chlorine, bromine or iodine atom, a cyano, alkyl, hydroxy, alkoxy, phenylalkoxy, alkylcarbonyl, dialkylamino, hydroxymethyl, hydroxyethyl, hydroxypropyl , Hydroxybutyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio group or the group - (CH2) ₀ -Y ¹ -WY ² , in which

o the numbers 0, 1 or 2,

W is the -Sθ2 ~ group or the group> C = X, in which

X represents the oxygen atom or one of the divalent radicals = N-CONH ₂ or = N-CN,

Y ^{1 is} the single bond, the oxygen atom or the radical -NR5-, m the

R ^ represents the hydrogen atom or a straight-chain or branched alkyl group having 1 to 6 carbon atoms or

R- ^ together with the group Y ² , the enclosed nitrogen atom and the enclosed group> C = X forms a saturated heterocyclic Rmg with 5 to 7 ring members, Y ² eme, optionally substituted by a hydroxy, alkoxycarbonyl or ammocarbonyl group, straight-chain or branched alkyl group having 1 to 10 carbon atoms, a cycloalkyl group having 4 to 10 carbon atoms, a straight-chain or branched alkoxy group having 1 to 5 carbon atoms, an aminoalkyl , Alkylaminoalkyl, dialkylaminoalkyl, phenylmethoxy or 2-phenylethoxy group, eme in the phenyl part optionally by fluorine, chlorine or bromine atoms, by methyl, trifluoromethyl, cyano, amino, hydroxy, methoxy, acetyl , Acetylamino, aminocarbonyl, methylaminocarbonyl or dimethylammocarbonyl groups mono-, di- or tπ-substituted phenyl or phenylalkyl group with 1 to 3 carbon atoms in the alkyl part or

the -NR ⁶ R ⁷ group means m the

R ^{6 is} the hydrogen atom, a straight-chain or branched alkyl group with 1 to 6 carbon atoms optionally substituted by a hydroxyl, carboxy, alkoxycarbonyl or dialkylammo group, with the proviso that the hydroxyl group is not bonded in 1-position of the alkyl group is a cycloalkyl group with 4 to 8 carbon atoms or one in the phenyl part optionally by fluorine, chlorine or bromine atoms, by methyl, trifluoromethyl, hydroxy, methoxy, amino, acetylamino, aminocarbonyl, methylaminocarbonyl, Dimethylaminocarbon or cyano groups mono-, di- or tri-substituted phenyl, phenylmethyl, 2-phenylethyl or 3-phenylpropyl group, where the substituents may be the same or different, some alkanoyl, benzoyl, phenylalkanoyl Represents alkoxycarbonyl or ammocarbonyl group and

R ^{7 has} the meanings given for R ^ with the exception of that of a phenyl, alkanoyl, benzoyl, phenylalkanoyl, alkoxycarbonyl and ammocarbonyl group or R ⁶ and R ⁷ together mean a n-alkylene group having 4 to 6 carbon atoms or

R ⁷ together with the radical R ^ of the group mentioned above for Y ¹ denotes —NR ^ - an unbranched alkylene group or oxoalkylene group having 2 to 4 carbon atoms,

where all the above-mentioned alkyl, cycloalkylalkyl, alkoxy, phenoxycarbonylalkyl, phenylalkoxy, phenylalkoxycarbonyl, phenylalkoxycarbonylalkyl, phenylalkanoyl, phenylalkyl, diphenylalkyl, naphthylalkyl, alkoxycarbonylalkyl, alkoxycarbonylmethoxy, carboxyalkyl, Aminoalkyl, monoalkylammo, dialkylammo, alkylaminoalkyl, dialkylammomethyl, dialkylaminoalkyl, alkylammocarbonyl, dialkylammocarbonyl, alkanoyl and alkoxycarbonyl radicals, unless stated otherwise, each have 1 to 5 carbon atoms in the alkyl and alkoxy moieties can contain

their tautomers, their diastereomers, their enantiomers, their mixtures and their salts.

2. Ammosa derivatives of the general formula

according to claim 1, in which

R, n, U, R ¹ , R ² , R ³ , V, Y and m are as defined in claim 1, V is bound in the 3- or 4-position of the benzene ring and the hydrogen atom, the fluorine, chlorine, bromine or iodine atom, eme cyano, alkyl, hydroxy, alkoxy, alkylcarbonyl, dialkyl, amino, hydroxymethyl -, Hydroxyethyl, hydroxypropyl, hydroxybutyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio group or the group - (CH2) _Q -Y ¹ - (CO) -WY ² means m the

o, Y ¹ and Y ^{2 are} as defined in claim 1,

where the alkyl, alkoxy, alkylcarbonyl and dialkylamino radicals mentioned above for V, unless otherwise stated, can each contain 1 to 5 carbon atoms in the alkyl and alkoxy parts,

their tautomers, their diastereomers, their enantiomers and their salts.

3. Amino acid derivatives of the general formula Ia according to claim 2, in which

R is a phenyl, 1-naphthyl or 2-naphthyl group, a 5-membered heteroaromatic ring which is linked via a carbon atom and which contains a nitrogen, oxygen or sulfur atom, with a nitrogen atom of an imino group being substituted by an alkyl group may, or via a carbon atom linked 6-membered heteroaroma¬ tables Rmg containing 1 or 2 nitrogen atoms, wherein the above-mentioned for R groups and heteroaromatic rings in the carbon skeleton additionally by a fluorine, chlorine ^¬ or bromine atom, by eme alkyl group, by a cycloalkyl group with 3 to 6 carbon atoms, by an alkoxy, phenyl, phenylalkoxy, trifluoromethyl, alkoxycarbonylalkyl, carboxyalkyl, dialkylaminoalkyl, hydroxy, amino, acetylamino, propionylamino, benzoyl , Benzoylamino, benzoylmethylamino, aminocarbonyl, alkylammocarbonyl, dialkylamino carbonyl, alkanoyl, cyano or trifluoromethoxy group can be substituted,

or the diphenylmethyl group in which

the phenyl groups can be substituted independently of one another by a fluorine, chlorine or bromine atom, by a methyl, methoxy, hydroxycarbonylmethoxy, alkoxycarbonylmethoxy, hydroxy or trifluoromethyl group,

n the numbers 0 or 1,

U the single bond,

R ^{1 is} the hydrogen atom,

a straight-chain or branched alkyl group with 1 to 5 carbon atoms, which may be terminally substituted by a cycloalkyl group with 4 to 7 carbon atoms, or a cycloalkyl group with 4 to 7 carbon atoms, the groups mentioned in turn being formed by an alkoxycarbonyl, phenylalkoxycarbonyl , Carboxy, amino, monoalkylammo, dialkylamino or dialkylammomethyl group can be substituted,

a branched or unbranched aliphatic acyl radical comprising 2 to 4 carbon atoms, which is characterized by an alkoxy carbonyl, phenylalkoxycarbonyl or optionally by a fluorine, chlorine or bromine atom, by an alkyl group or a cycloalkyl group having 4 to 7 carbon atoms Alkoxy, trifluoromethyl, hydroxyl, amino, acetylamino or cyano group substituted phenyl group, or a benzoyl radical,

the ammocarbonyl group which is formed on the nitrogen atom by an alkyl, phenylalkyl, (1-naphthyl) alkyl, (2-naphthyl) alkyl, alkoxycarbonylalkyl, carboxyalkyl, ω, ω-diphenylalkyl, Phe- nyl, cycloalkyl or cycloalkylalkyl group each having 3 to 6 carbon atoms in the ring can be substituted, the phenyl radicals in the groups mentioned above in turn being em fluorine, chlorine or bromine atom, by a methyl, methoxy, hydroxyl or trifluoromethyl group substituted sem can,

an alkoxycarbonyl or phenylalkoxycarbonyl radical which can be substituted in the phenyl part by a fluorine, chlorine or bromine atom, by a methyl, methoxy, hydroxyl or trifluoromethyl group

a phenyl group or a five-membered heteroaromatic ring which is bonded via a carbon atom and which contains a nitrogen, oxygen or sulfur atom, it being possible for a nitrogen atom of an imino group to be substituted by an alkyl group, or a 6 linked via a carbon atom -glιedrιgen heteroaromatic Rmg, which contains 1 or 2 nitrogen atoms, both the phenyl group and the 5- and 6-glιedrιgen heteroaromatic rings in the carbon structure additionally by a fluorine, chlorine or bromine atom, by an alkyl group, by a cycloalkyl group 3 to 6 carbon atoms, which can be substituted by a phenylalkyl, alkoxy, trifluoromethyl, hydroxyl or amino group,

R ^{2 represents} the hydrogen atom, an alkyl group or a phenylalkyl group in the phenyl part which is optionally substituted by a fluorine, chlorine or bromine atom, an alkyl, trifluoromethyl, amino or acetylamino group,

R ^{3 represents} the hydrogen atom or the methyl group,

Y is the oxygen atom or the -NR ⁴ group in which

R ^{4 represents} the hydrogen atom, the methyl or ethyl group,

V, which is bound in the 4-position of the benzene ring, the hydrogen, fluorine, chlorine or bromine atom, a cyano, alkyl, hydroxy, alkoxy, phenylalkoxy, alkylcarbonyl, dialkylamino, Hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl or trifluoromethyl group or the group - (CH ₂ ) ₀ -Y ¹ - (CO) -Y ² means in which

o the numbers 0 or 1,

Y ^{1 is} the simple bond, the oxygen atom or the radical -NR ^ -, in which

R ^ represents the hydrogen atom or a straight-chain or branched alkyl group having 1 to 4 carbon atoms or

R ^ together with the group Y ² , the enclosed nitrogen atom and the enclosed group> C = 0 forms a saturated heterocyclic ring with 5 to 7 ring members, and

Y ² eme optionally substituted by a hydroxyl, alkoxycarbonyl or ammocarbonyl group, straight-chain or branched alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, an aminoalkyl, alkylaminoalkyl or dialkylaminoalkyl group or eme in the phenyl part optionally by fluorine -, Chlor¬ or bromine, by a methyl, trifluoromethyl, cyano, amino, hydroxyl or methoxy group substituted phenyl or phenylalkyl group with 1 to 3 carbon atoms in the alkyl part or

the -NR ^ R ⁷ group means m the R ^{6 represents} the hydrogen atom, a straight-chain or branched alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 4 to 6 carbon atoms or optionally a fluorine, chlorine or bromine atom, a methyl, trifluoromethyl, hydroxyl or meth - represents oxy group substituted phenyl group and

R ^{7 has} the meanings given for R ⁶ with the exception of that of a phenyl group,

where all the above-mentioned alkyl, alkoxy, phenylalkyl, ω, ω-diphenylalkyl, naphthylalkyl, cycloalkylalkyl, phenylalkoxy, phenylalkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylmethoxy, carboxyalkyl, alkylamino, dialkylammo- Dialkylaminoalkyl, alkylammocarbonyl, dialkylammocarbonyl, alkanoyl and alkoxycarbonyl radicals, unless stated otherwise, can each contain 1 to 5 carbon atoms in the alkyl and alkoxy parts,

their tautomers, their diastereomers, their enantiomers and their salts.

4. Ammosa derivatives of the general formula Ia according to claim 2, in which

R is the diphenylmethyl group, in which the phenyl groups can be substituted independently of one another by a methyl group,

n is the number 0,

U the recommendation,

R ^{1 is} the hydrogen atom,

a linear or branched alkyl group having 1 to 3 Koh ^¬ lenstoffatomen, the terminally with by a cycloalkyl group 4 to 6 carbon atoms can be substituted, the cycloalkyl group in turn being able to be substituted by a dialkylammomethyl group with 1 to 3 carbon atoms in the alkyl parts,

the ammocarbonyl group, which can be substituted on the nitrogen atom by an alkyl group having 1 to 3 carbon atoms, or

a phenyl group optionally substituted by an alkyl or alkoxy group having 1 to 3 carbon atoms,

R ^{2 is} the hydrogen atom, an alkyl group with 1 to 3 carbon atoms optionally substituted by a phenyl group,

R ^{3 represents} the hydrogen atom or the methyl group,

Y the -NR ^ group in which

R ^{4 represents} the hydrogen atom, the methyl or ethyl group,

m the number 1 and

V, which is bonded in the 4-position of the benzene ring, denotes the hydrogen atom, a hydroxyl or phenylalkoxy group having 1 to 3 carbon atoms in the alkoxy part or the group -CH2-Y ¹ - (CO) -Y ² , in which

Y ^{1 is} the single bond or the residue -NR ⁵ -, in which

R ^{5 represents} the hydrogen atom or a straight-chain or branched alkyl group having 1 to 3 carbon atoms, and

Y ^{2 represents} the -NR ⁶ R ⁷ group in which R ⁶ and R ⁷ independently of one another represent the hydrogen atom or a straight-chain or branched alkyl group having 1 to 3 carbon atoms,

their tautomers, their diastereomers, their enantiomers and their salts.

5. The following ammosa derivatives of the general formula Ia according to claim 2:

(1) (R, S) -3- (ammoiminomethylammo) -ot- [(diphenylacetyl) amino] -N- [(4-hydroxyphenyl) methyl] -benzenacetamide,

(2) (R, S) -N- [[4- (aminocarbonylaminomethyl) phenyl] methyl] - 3- (aminoimmomethylamino) -ot- [(diphenylacetyl) ammo] - benzenacetamide,

(3) (R, S) -N- [[4- (ammocarbonylmethyl) phenyl] methyl] -3- (aminoiniminomethylammo) -α- [(diphenylacetyl) ammo] -benzene acetamide,

(4) trans- (R, S) -3 - [[4- (dimethylammomethyl) cyclohexylmethyl] -ammoimmomethylamino] -ot- [(diphenylacetyl) ammo] - N-methyl-N- (phenylmethyl) -benzenacetamide,

(5) (R, S) -α- [(diphenylacetyl) ammo] -N-methyl-3- (phenylaminoiminomethylamino) -N- (phenylmethyl) -benzenacetamide,

(6) (R, S) -3- (aminoimmomethylammo) -ot- [(diphenylacetyl) ammo] -N-methyl-N- (phenylmethyl) -benzenacetamide,

(7) (R, S) -ot- [(diphenylacetyl) ammo] -N-methyl-3- (methy1-ammoimmomethylamino) -N- (phenylmethyl) -benzenacetamide,

(8) trans (R, S) -N- [[4- (Ammocarbonylammomethyl) phenyl] me thyl ^¬] -3- [[4- (dimethylammomethyl) cyclohexylmethyl] - ammoimmomethylammo] -α- [(diphenylacetyl) ammo] - benzenacetamide,

(9) (R, S) -N- [[4- (ammocarbonylaminomethyl) phenyl] methyl] - α- [(diphenylacetyl) amino] -3- [(methylaminocarbonyl) aminoaminomethylammo] -benzenacetamide,

(10) (R, S) -N- [[4- (ammocarbonylaminomethyl) phenyl] methyl] - α- [(diphenylacetyl) ammo] -3- [(4-methoxyphenyl) ammo¬ immomethylamino] -benzenacetamide,

(11) (R, S) -ct- [(diphenylacetyl) ammo] -3- [(4-methoxyphenyl) - ammoimmomethylammo] -N- (phenylmethyl) -benzenacetamide,

(12) (R, S) -N- [[4- (Ammocarbonylaminomethyl) phenyl] methyl] - ot- [(diphenylacetyl) ammo] -3- [[immo [N-methyl-N- (phenyl¬ methyl) amino ] methyl] amino] -benzenacetamide,

(13) (R, S) -N- [[4- (aminocarbonylammomethyl) phenyl] methyl] - α- [(diphenylacetyl) ammo] -3- (methylammoimmomethylammo) -benzenacetamide,

(14) (R, S) -ot- [(diphenylacetyl) ammo] -3- [(4-methoxyphenyl) - ammoimmomethylammo] -N- [[(4-phenylmethoxy) phenyl] - methyl] -benzenacetamide,

(15) (R, S) -3- (ammoimmomethylamino) -et- [(diphenylacetyl) - ammo] -N- [[(4-phenylmethoxy) phenyl] methyl] -benzenacetamide,

(16) (R, S) -3- (ammoimmomethylammo) -ot- [(diphenylacetyl) - ammo] -N-methyl-N- [[(4-phenylmethoxy) phenyl] methyl] - benzacetamide,

(17) (R, S) -N- [[4- (aminocarbonylammomethyl) phenyl] methyl] - ct- [(diphenylacetyl) ammo] -N-methyl-3- (methylamino-iminomethylamino) -benzenacetamide and their salts.

6. Physiologically acceptable salts of the compounds of general formula I according to claims 1 to 5 with inorganic or organic acids or bases.

7. Medicament 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, if appropriate, one or more inert carriers and / or diluents.

8. Use of a compound of general formula I according to claims 1 to 6 for the manufacture of a medicament according to claim 7, which for the treatment of cardiovascular diseases, coronary heart diseases, subarachnoid bleeding, vascular-hypertrophic changes, of cerebral and coronary vasospasm, of chronic kidney failure, of tumor diseases, of hyperthyroidism, of obesity and diabetes.

9. A method for producing a medicament according to claim 7, characterized in that a compound according to at least one of claims 1 to 6 is incorporated in one or more inert carriers and / or diluents in a non-chemical way.

10. Use of a compound of general formula I according to claims 1 to 6 as an aid for the production and cleaning of antibodies.

11. Use of a compound of general formula I according to claims 1 to 6 for radioactive labeling for the purpose of use m RIA or ELISA assays.

12. A process for the preparation of the new ammosa derivative of the general formula I according to claims 1 to 6, characterized in that

A compound of formula II

in the

R, R ¹ , R ³ , U and n are as defined in claims 1 to 5 and R ² 'has the meanings given in claims 1 to 5 for R ² or denotes a protective group for the protection of side chains bearing guanidmo functions ,

with a compound of the general formula III,

m, V and Y have the meanings mentioned in claims 1 to 5, is coupled and, if necessary, then any protective group used is split off or

b) for the preparation of compounds of the general formula I, in which U has the meanings mentioned in claims 1 to 5, with the exception of those of the oxygen atom and the -NH group, a compound of the general formula IV, R - (CH ₂ I n - CO Nu IV)

m the

R and n are as defined in claims 1 to 5 and Nu is a leaving group,

with an α-ammosa derivative of the general formula V,

R ¹ , R ³ , V, Y and m are as defined in claims 1 to 5 and R ² 'has the meanings mentioned in claims 1 to 5 for R ² or denotes a protective group for the protection of side chains bearing guanidino functions , is coupled and, if necessary, then a protective group used is split off or

c) for the preparation of compounds of the general formula I in which Y represents an oxygen atom, an amino acid ester of the general formula VI,

m the

R, R ¹ , R ² , R ³ , U and n are as defined in claims 1 to 5 and R ^ is an alkyl group having 1 to 4 carbon atoms,

with an alcohol of the general formula VII,

in which m and V are as in claims 1 to 5, is transesterified or

d) for the preparation of compounds of the general formula I in which Y represents the oxygen atom, a salt of a carboxylic acid of the general formula II,

O in the

R, R ¹ , R ³ , U and n are as defined in claims 1 to 5 and R ² 'has the meanings given in claims 1 to 5 for R ² or means a protective group for the protection of side chains bearing guamdino functions ,

with a compound of the general formula VIII,

in which m and V are as defined in claims 1 to 5 and Nu ¹ means a leaving group, is reacted and, if necessary, a protective group used is subsequently split off or

e) a compound of the general formula IX,

in the

R, U, V, Y, m and n are as defined in claims 1 to 5,

with a carbonic acid derivative of the general formula X,

NR ^J

Nu 'C - NR ² R ³ (X)

m the R ¹ , R ² and R ^{3 are} as defined in claims 1 to 5 and

NNuu ^{22 is a} leaving group or the rest of the general formula XI,

ΛΛΛΛΛ

R 1 and R ¹ , which can be the same or different, represent hydrogen atoms or alkyl radicals having 1 to 3 carbon atoms, means, is reacted or

f) a uronium or thiuronium salt of the general formula XII,

m the

R, R ¹ , U, V, Y, n and m are as defined in claims 1 to 5, R ^{11 is} an alkyl radical having 1 to 4 carbon atoms or the phenyl group, Y ^{3 is} the oxygen or sulfur atom and an ^" em monovalent anion mean, or em corresponding free isourea or isothiourea

with an amine of the general formula XIII,

R ² R ³ NH (XIII: in which R ² and R ^{3 are} as defined in claims 1 to 5, is implemented or

g) for the preparation of compounds of the general formula I in which U is the oxygen atom or the —NH group, an isocyanate of the general formula XIV,

in the

R ¹ , R ³ , V, Y and m are as defined in claims 1 to 5 and R ² 'has the meanings mentioned in claims 1 to 5 for R ² or denotes a protective group for the protection of side chains bearing guanidmo functions ,

with a compound of the general formula XV,

R- (CH ₂ ) _n -U ¹ -H (XV)

in the

R and n are as defined in claims 1 to 5 and U ¹ represents the oxygen atom or the -NH group, and is reacted, is cleaved if necessary, then eme protection ^¬ used group or

h) for the preparation of compounds of general formula I in which U represents the -NH group, em isocyanate of the general ^¬ my formula XVI

R- (CH ₂ ) _n -N = C = 0 (XVI: R and n are as defined in claims 1 to 5,

with an α-amino acid derivative of the general formula V,

in the

R ¹ , R ³ , V, Y and m are as defined in claims 1 to 5 and R ² 'has the meanings mentioned in claims 1 to 5 for R ² or denotes a protective group for the protection of side chains bearing guanidino functions , is implemented and, if necessary, a protective group used is subsequently split off or

I) for the preparation of compounds of general formula I, in which V is the group - (CH2) _Q -YLWY ² , in which

o and W are as defined in claims 1 to 5,

Y ^{1 is} the oxygen atom or the radical -NR ⁵ -, m the

R ^{5 represents} the hydrogen atom or a straight-chain or branched alkyl group having 1 to 6 carbon atoms, and

Y ² eme a straight-chain or branched alkyl group with 1 to 10 carbon atoms optionally substituted by a hydroxy, alkoxycarbonyl or ammocarbonyl group, a cy- - 10Θ -

cloalkyl group with 4 to 10 carbon atoms, a straight-chain or branched alkoxy group with 1 to 5 carbon atoms, an aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, phenylmethoxy or 2-phenylethoxy group, in the phenyl part optionally by fluorine , Chlorine or bromine atoms, by methyl, trifluoromethyl, cyano, amino, hydroxyl, methoxy, acetyl, acetylamino, aminocarbonyl, methylamino carbonyl or dimethylammocarbonyl groups mono-, di- or tri-substituted phenyl or Phenylalkyl group with 1 to 3 carbon atoms in the alkyl part or

the -NR ⁶ R ⁷ group means in the

R ^ is the hydrogen atom, a straight-chain or branched alkyl group having 1 to 6 carbon atoms which is optionally substituted by a hydroxy, carboxy, alkoxycarbonyl or dialkylamino group, with the proviso that the hydroxy group is not bonded in 1-position of the alkyl group, A cycloalkyl group with 4 to 8 carbon atoms or one in the phenyl part, optionally by fluorine, chlorine or bromine atoms, by methyl, trifluoromethyl, hydroxy, methoxy, amino, acetylamino, aminocarbonyl, methylamino carbonyl, Dimethylaminocarbonyl or cyano groups mono-, di- or tri-substituted phenyl, phenylmethyl, 2-phenylethyl or 3-phenylpropyl group, the substituents being the same or different, such as alkanoyl, benzoyl, phenylalkanoyl Represents alkoxycarbonyl or ammocarbonyl group and

R ^{7 has} the meanings given for R ⁶ with the exception of that of a phenyl, alkanoyl, benzoyl, phenylalkanoyl, alkoxycarbonyl and ammocarbonyl group,

a compound of the general formula XVII,

m of m, n, o, R, R ¹ , R ³ , U and Y are as defined in claims 1 to 5, R ^{2 has} the meanings mentioned in claims 1 to 5 for R ² or a protective group for protection means side chains bearing guanidmo functions and Y ¹ 'represents the oxygen atom or the radical —NR ⁵ -, in which R ^{5 represents} the hydrogen atom or a straight-chain or branched alkyl group having 1 to 6 carbon atoms,

is modified at the (Y ¹ '-H) function and, if necessary, a protective group used is then split off and / or a group V thus obtained is further modified

j) for the preparation of compounds of the general formula I,

R ^{1 is} a branched or unbranched aliphatic alkylcarbonyl radical comprising 2 to 5 carbon atoms, which is substituted in the alkyl part by an alkoxycarbonyl or phenylalkoxycarbonyl group, by a phenyl group or by a 5- or 6-membered heteroaromatic Rmg linked via a carbon atom can, or means a benzoyl radical in which the phenyl part can also be replaced by a 5- or 6-membered heteroaromatic ring linked via a carbon atom, the abovementioned 5-membered heteroaromatic rings emitting nitrogen, em Contain oxygen or sulfur atom or nitrogen and em additional oxygen, sulfur or further nitrogen atom and can also be substituted on a nitrogen atom by an alkyl group which contain 6-membered heteroaromatic rings 1, 2 or 3 nitrogen atoms and the above-mentioned phenyl groups and all heteroaromatic rings in the carbon skeleton additionally by fluorine, chlorine or bromine atoms, by alkyl groups, cycloalkyl groups having 3 to 8 carbon atoms, alkoxy, trifluoromethyl, alkoxycarbonylalkyl, carboxyalkyl, hydroxy, ammo -, Acetyl¬ amino, propionylammo, aminocarbonyl, alkylammocarbonyl, dialkylammocarbonyl, alkanoyl, cyano, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulfmyl or trifluoromethylsulfonyl groups can be mono-, di- or maximally tπsubstituted Substituents may be the same or different,

a compound of the general formula XVIII,

in which R, R ² , R ³ 'U, V, Y, n and m are as defined in claims 1 to 5,

with a compound of the general formula XlXa,

Rl'-r CπO - Nu (XlXa;

in R ¹ 'a branched or unbranched alkyl radical comprising 1 to 4 carbon atoms, which by an alkali oxycarbonyl or phenylalkoxycarbonyl group, can be substituted by a phenyl group or by a 5- or β-membered heteroaromatic Rmg linked via a carbon atom, a phenyl residue or a 5- or 6-membered heteroaromatic Rmg linked by a carbon atom, wherein the abovementioned 5-membered heteroaromatic rings contain a nitrogen, an oxygen or sulfur atom or a nitrogen and an additional oxygen, sulfur or another nitrogen atom and can also be substituted on an nitrogen atom by an alkyl group, the 6th -glιedrιgen heteroaromatic rings contain 1, 2 or 3 nitrogen atoms and the above-mentioned phenyl groups and all heteroaromatic rings in the carbon skeleton additionally by fluorine, chlorine or bromine atoms, by alkyl groups, cycloalkyl groups with 3 to 8 carbon atoms, alkoxy, trifluoromethyl -, alkoxycarbonylalkyl, carboxyalkyl, hydroxy, Amo-, acetylamino, propionylammo, aminocarbonyl, alkylammocarbonyl, dialkylammocarbonyl, alkanoyl, cyano, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulfmyl or trifluoromethylsulfonyl groups can be mono-, di- or semisubstituted tris the substituents can be the same or different, meaning and

Only represents a leaving group, is implemented or

k) for the preparation of compounds of general formula I, m the

R ^{1 is} the ammocarbonyl group which is substituted on the nitrogen atom by alkyl, phenylalkyl, (1-naphthyl) alkyl, (2-naphthyl) alkyl, alkoxycarbonylalkyl, phenylalkoxycarbonylalkyl, phenoxycarbonylalkyl, diphenylalkyl, phenyl, cycloalkyl or cycloalkylalkyl groups each having 3 to 8 carbon atoms in the ring can be mono- or disubstituted, the substituents being the same or different and the phenyl radicals mentioned above in turn being fluorine, chlorine or bromine atoms, methyl or methoxy , Alkoxycarbonylmethoxy, Hydroxy or trifluoromethyl groups can be mono- or disubstituted independently of one another, means

a compound of the general formula XVIII,

(XVIII

in which R, R ² , R ³ 'U, V, Y, n and m are as defined in claims 1 to 5,

with a compound of the general formula XlXb,

R ^I -N = C = 0 (XlXb)

in the R ¹ '' an alkyl, phenylalkyl, (1-naphthyl) alkyl, (2-naphthyl) alkyl, alkoxycarbonylalkyl, phenylalkoxycarbonylalkyl, phenoxycarbonylalkyl, diphenylalkyl, phenyl, cycloalkyl or cycloalkylalkyl group each having 3 to 8 carbon atoms in cycloalkane, the phenyl radicals mentioned above being independently mono- or disubstituted by fluorine, chlorine or bromine atoms, methyl, methoxy, alkoxycarbonylmethoxy, hydroxyl or trifluoromethyl groups , and

Nu eme represents a group, is implemented or

1) for the preparation of compounds of general formula I in which R ^{1 is} an alkoxycarbonyl or phenylalkoxycarbonyl radical, the phenyl part in turn being mono- or disubstituted by fluorine, chlorine or bromine atoms, methyl, methoxy, alkoxycarbonylmethoxy, hydroxyl or trifluoromethyl groups and the substituents in each case being the same or different can means

a compound of the general formula XVIII,

: xvιιι:

in which R, R ² , R ³ 'U, V, Y, n and m are as defined in claims 1 to 5,

with a compound of the general formula XIXc,

-O-CO-Cl (XIXc;

in which R ¹ 'is an alkyl or phenylalkyl radical in which the phenyl part in turn can be mono- or disubstituted by fluorine, chlorine or bromine atoms, methyl, methoxy, alkoxycarbonylmethoxy, hydroxy or trifluoromethyl groups, the substituents each can be the same or different, means and

Only represents a leaving group, is implemented or

m) for the preparation of the compounds of the general formula XX falling under the general formula I,

m the R, R ² , R ³ , U, V, Y, n and m are as defined in claims 1 to 5,

a cyanguamdm of the general formula XXI,

in which R, R ² , R ³ , U, V, Y, n and m are as defined in claims 1 to 5, is partially hydrolyzed or

n) for the preparation of the compounds of the general formula XXII falling under the general formula I,

in which R, R ² , R ³ , U, V, Y, m and n are as defined in claims 1 to 5 and R ¹² and R ¹³ independently of one another are the hydrogen atom, an alkyl group having 1 to 5 carbon atoms, a cycloalkyl group 3 to 8 carbon atoms or a phenylalkyl group with 1 to 5 carbon atoms in the alkyl part, where these radicals can be the same or different,

A cyanguanide of the general formula

m the R, R ² , R ³ , U, V, Y, n and m are as defined in claims 1 to 5, in an aminothiocarbonylguanidm of the general formula XXIII,

in which R, R ² , R ³ , U, V, Y, n and m are as defined in claims 1 to 5, is converted and then with an α-halocarbonyl compound of the general formula XXIV,

R ¹² -CO-CH (Hal) -R ¹³ ; xxιv)

m the R ¹² and R ¹³ independently of one another are the hydrogen atom, an alkyl group with 1 to 5 carbon atoms, a cycloalkyl group with 3 to 8 carbon atoms or a phenylalkyl group with 1 to 5 carbon atoms in the alkyl part, these radicals being able to be identical or different , and Hal em chlorine, bromine or iodine atom, is reacted or

o) for the preparation of compounds of the general formula I in which U is the oxygen atom, em chlorocarbonic acid ester of the general formula XXV,

R- (CH ₂ ) _n -0-CO-Cl (XXV)

in which R and n are as defined in claims 1 to 5,

with an α-ammosa derivative of the general formula XXVI,

m the

R ¹ , R ³ , V, Y and m are as defined in claims 1 to 5 and R ² '' has the meanings mentioned in claims 1 to 5 for R ² or eme for the protection of a guanide moiety present in the side chain Function and protecting group orthogonal to carbamates means is ammolyzed and, if necessary, subsequent protective group used is split off or

p) for the preparation of compounds of the general formula I in which R ¹ , R ² and R ^{3 are} hydrogen atoms, a compound of the general formula IX,

in the

R, U, V, Y, n and m as defined in claims 1 to 5 are reacted with cyanamide or

q) for the preparation of compounds of the general formula I, m in which R ^{1 represents} the hydrogen atom, em cyanamide of the general formula XXVII, ixxvn;

in which R, U, V, Y, m and n are as defined in claims 1 to 5,

is reacted with a mineral acid salt of ammonia or an amine of the general formula XIII in which R ² and R ^{3 are} as defined in claims 1 to 5 and

if desired, a compound of the general formula I thus obtained is then separated into its diastereomers or

The racemate thus obtained of a compound of the general formula I is separated in its enantiomers and / or

a compound of the general formula I thus obtained is converted into its salts with acids or bases, in particular for pharmaceutical use in its physiologically acceptable salts.