SK206292A3 - Pharmacologicaly effective hydrazine derivatives and method of their manufacture - Google Patents

Abstract

The invention relates to compounds of the formula <IMAGE> in which R1 and R9 are, independently of one another, hydrogen, acyl, unsubstituted or substituted alkyl, alkenyl or alkynyl; heterocyclyl; sulpho, or sulphonyl which is substituted by unsubstituted or substituted alkyl, aryl, heterocyclyl, alkoxy, which is unsubstituted or substituted, or by aryloxy; sulphamoyl which is unsubstituted or substituted on the nitrogen; or phosphoryl which is substituted by one or two radicals selected independently of one another from unsubstituted or substituted alkyl, from unsubstituted or substituted cycloalkyl, from aryl, from hydroxyl, from unsubstituted or substituted alkoxy, from cycloalkoxy and from aryloxy, with the proviso that not more than one of the radicals R1 and R9 is hydrogen; and R2 and R8 are each, independently of one another, hydrogen or one of the radicals mentioned above for R1 and R9; or the pairs of substituents R1 and R2 or R8 and R9 can each, independently of one another, form together with the nitrogen atom to which they are bonded certain heterocyclic rings; R3 and R4 are, independently of one another, hydrogen, unsubstituted or substituted alkyl or cycloalkyl; aryl; heterocyclyl; or unsubstituted or substituted alkenyl; or R3 and R4 together are unsubstituted or substituted alkylene, alkylidene or benzo-fused alkylene; R5 is hydroxyl; R6 is hydrogen; or R5 and R6 together are oxo; and R7 is unsubstituted or substituted alkyl or cycloalkyl; aryl; heterocyclyl; or unsubstituted or substituted alkenyl; as well as the salts of the said compounds where salt-forming groups are present, furthermore process for the preparation thereof, pharmaceutical products, the use as pharmaceutical composition or for the preparation of pharmaceutical products, as well as intermediates for the preparation of these compounds.

Description

Pharmacologically effective hydrazine production. . I

BACKGROUND OF THE INVENTION

The present invention relates to a novel class of hydrolyzable aspartate protease cleavable peptide analogues, i.e. hydrazine derivatives, a process for their preparation, pharmaceuticals.

compositions which are analogous to peptides containing the same, and their use as medicaments or for the manufacture of pharmaceutical compositions for the control of diseases caused by viruses, as well as novel intermediates for the production of these compounds.

BACKGROUND OF THE INVENTION

Immune deficiency AIDS (acquired immune deficiency syndrome) is a disease with a deadly concern. These diseases are spreading on a global scale to an increasing extent mainly within, but also outside, those at risk groups. This disease affects a million people and its causative suppression is one of the most important goals of modern medicine. Until now, etroviruses have been able to HIV-1. and HIV-2 (HIV is a human immunodeficiency virus) to identify the cause of the disease and be characterized from a molecular biological standpoint. For the treatment, it is beyond the existing possibilities to change the symptoms of AIDS, and thus, certain preventive options are of particular interest, in particular to seek for preparations that limit the reproduction of the virus without damaging the skin of the intact cells and tissue of the patient.

The promise of success shows particular compounds which inhibit the process of protein building units of the biosynthesized virus in human cells, infectious virions, and thus the completion of the precise construction of these building units.

HIV-1 and HIV-2 always have a region in their genome that encodes for a gag protease. This gag protease is responsible for the precise proteolytic cleavage of the precursor protein that arises. gag coding regions (group specific antigens). This releases the structural proteins of the core. gag-Protease itself It is part of the precursor protein encoded by the half-region of the HIV-1 and HIV-2 genome, which also contains the reverse transcriptase and integrase region, and is believed to cleave autoproteolytically.

gag-Protease cleaves the major core protein of p24 HIV-1 and HIV-2, preferably the nitrogen terminus of the proline residue, for example in the bivalent radical Phe-Pro, Leu-Pro or Tyr-Pro. It is a protease with a catalytically active aspartate residue in the active center, the so-called aspartate protease.

If the effect of the gag protease could be avoided, the virus would no longer have the proteins necessary to build the viral core. This would lead to the restriction or complete prevention of the reproduction of the faith. Thus, there is a need for a gag protease inhibitor agent that can be used as an antiviral agent against AIDS and other retroviral diseases.

A number of gag protease suppressants have been synthetically produced and contain middle groups that do not! proteolytically cleavable peptide isomers. However, to date, despite intensive research, it has not been possible to prepare a suitable protease aspartate suppressant formulation for use in humans to control AIDS to a large extent by infection. In particular, pharmacodynamic problems are decisive. In addition, the most commonly known hitherto known gag protease inhibitors have more than two asymmetric carbon atoms in said central building unit, which necessitates a relatively expensive stereospecific synthesis or separation of isomers. It is therefore an object of the present invention to provide a novel family of viral aspartate protease inhibitors with a single central unit. The synthesis of the central unit should be sterically possible. . Furthermore, I have new central building units at both ends of the amino group, so that there are suitable substituents. for example, structures analogous to retro-inverso peptides are obtained.

SUMMARY OF THE INVENTION

The compounds of the present invention are compounds of formula I

(I) in which

R ₁ and R g mean! independently of one another hydrogen, acyl, optionally substituted alkyl, alkenyl or alkynyl, further heterocyclyl, sulfo, sulfonyl optionally substituted by alkyl, aryl, heterocyclyl, alkoxy optionally substituted, or aryloxy, sulfamoyl optionally substituted on the atom or is phosphoryl substituted by one or two independently of one another selected from optionally substituted alkyl, optionally substituted cycloalkyl, aryl, hydroxy, optionally substituted alkoxy, cycloalkoxy and aryloxy, provided that at most one of R a is R a represents a hydrogen atom, and >

£ R ·

·.

R ₂ · ajRg .---------- znamenaji- independently, the hydrogen atom or one of the radicals _RG and above or pairs of substituents and R ₂ or R _q and R _g, can form independently of one another, with the nitrogen atom to which they are attached, a heterocyclyl ring consisting of a nitrogen bonding moiety together with a residue selected from ethylene, trimethylene, tetramethylene and pentamethylene, wherein the carbon atom may be replaced by a nitrogen, oxygen, sulfur or oxygen atom once or twice a substituted sulfur atom which may be unsaturated, or one of the residues with each oxo substituent on both the carbon atoms attached to the carbon atom and, if appropriate, a fused benzene or naphthalene ring,

independently of one another are hydrogen, optionally substituted alkyl or cycloalkyl, aryl, heterocyclyl or optionally substituted alkenyl;

and R ₄ together represent optionally substituted alkylene, alkylidene or benzofused alkylene,

is hydroxy and is hydrogen or

and R 8 together represent oxo and

means optionally substituted alkyl or cycloalkyl, furthermore aryl, heterocyclyl or optionally substituted alkenyl, as well as salts of these compounds, when they contain salt-forming groups.

As used herein, the term "lower" used to define groups or moieties, such as lower alkyl groups, lower alkoxy groups, lower alkanoyl groups, and the like, unless otherwise stated, contains up to 7 carbon atoms including preferably up to 4 carbon atoms inclusive.

Unless otherwise stated, the substituents in the radicals R @ 1 -, R @ ₂ , R @ ₃ , R @ ₄ , R @ ₂ and R @ _{2 are} as follows _. , R g and / or R _g independently of one another, one or more times, in particular one to three times.

The carbon atoms in compounds of formula I, substituted by the substituents R ₃ and R ₄ or R @ ₅ and R _g can, if asymmetric, be in the (R), (S) or (R, S), and may also optionally contain other asymmetric carbon atoms. Thus, the compounds of the invention may be in the form of isomeric mixtures or pure isomers, particularly as diastereomeric mixtures, enantiomeric pairs or pure enantiomers. Preferred compounds of formula I wherein the carbon atom substituted by R _3, or OH R ₅ is (S), and further are optionally available to the asymmetric carbon atom independently of one another in the (R), (S) or (R, S).

The general terms and designations used in the description of the present invention preferably have the following meanings, wherein in the various planes of the definition individual residues or any combination of the above or the following residues may be used in place of the general definition.

The acyl group R, R _2, R g and R _g is, for example up to 25 carbon atoms, preferably up to 19 carbon atoms and, first of all, an acyl group, a carboxylic acid, half-ester of carbonic acid, unsubstituted or N-substituted carbamic

acid, unsubstituted or N-substituted oxalamide, or optionally substituted amino acids, with thiocarbonyl groups always being possible in place of the carbonyl groups in the acyl groups. Preferably, however, the right acylated at most only one of the radical R? And R _2, optionally the radical R _g and R _g.

Preferred carboxy-derived acyl groups R 1, R ₂ , R g and R g are optionally substituted alkanoyl groups of up to 19 carbon atoms, for example n-decanoyl or preferably a lower alkanoyl group such as formyl, acetyl, propionyl, butyryl or pivaloyl, or substituted lower alkanoyl, especially as cycloalkyl-lower alkanoyl), wherein the cycloalkyl moiety contains 3 to 7 carbon atoms and the lower alkanoyl moiety is as defined above, for example, a cycloalkylcarbonyl group, especially having a total of 4 to 8 carbon atoms such as cyclopropyl- , cyclobutyl-, cyclopentyl- or cyclohexylcarbonyl or 2-cyclohexyl- or 2-cyclopentylacetyl, a cycloalkenyl- (lower alkanoyl) group in which the cycloalkenyl moiety contains, for example, 3 to 7 carbon atoms, such as cycloalkenylcarbonyl, preferably 4 to 8 carbon atoms, such as 1-cyclohexenylcarbonyl, 1,4-cyclohexadienylcarbonyl or 1-cyclohexenylacetyl or 1,4-c a cyclohexadienylacetyl, a bicycloalkyl- (lower alkanoyl) group in which the bicycloalkyl moiety contains, for example, 5 to 10 carbon atoms, such as bicycloalkylcarbonyl, preferably having 8 to 11 carbon atoms such as decahydronaphthyl-2-carbonyl, endo- or exo-norbornyl -2-carbonyl, bicyclo [2.2.2] oct-2-ylcarbonyl; . 7-bicyclo [3,3.1] non-9-carbonyl, furthermore bicyclohexyl-, -heptyl-, -octyl-, -nonyl- or -decylacetyl or -3-propionyl, such as bicyclo [3,1,0] hex -1-, -2- or -3-yl, bicyclo [4.1.0] hept-1 or -7-yl, bicyclo [2.2.1] hept-2-yl-, such as endo- or exo- norbornyl, bicyclo [3.2.1] oct-2-yl; bicyclof 3,3,0] oct-3-yl- or bicyclof3,3,1] non-9-yl-, further α- or β-decahydronaphthylacetyl or -3-propionyl;

a bicycloalkenylcarbonyl group, preferably with 8 to 10 carbon atoms. 12 carbon atoms, such as 5-norbornen-2-ylcarbonyl or bicyclof 2,2,2] octen-2-ylcarbonyl, a tricycloalkyl- (lower alkanoyl) group in which the tricycloalkyl moiety contains, for example, 8-10 carbon atoms such as e.g. tricykloalkylkarbonyl, preferably 8 to 11 carbon atoms, such as 1- or 2-adamantylcarbonyl, further tricyclo [5,2,1, O ² · ^6] dec-8-yl- or adamantyl-, such as 1-adamantyl acetyl, aryl a (lower alkanoyl) group in which the aryl moiety contains 6 to 6 carbon atoms. A carbon atom such as phenyl, indenyl, indanyl, naphthyl, anthryl, phenanthryl or fluorenyl, and is unsubstituted or can be substituted one to three times with a particular lower alkyl group, for example methyl, ethyl or propyl, halogen- (lower alkyl), for example trifluoromethyl, phenyl, 1- or 2-naphthyl, hydroxy, lower alkoxy, for example methoxy, carbamoyl- (lower alkoxy), N- (lower alkyl) -carbamoyl- (lower alkoxy) or N, N-di- (lower alkyl) ) -carbamoyl- (lower alkoxy), amino, mono- or di- (lower alkyl) -amino, (lower alkanoyl) -amino, e.g. pivaloylamino, halogen, e.g. fluorine, chlorine or bromine, carboxy, (lower alkoxy) - a carbonyl group such as a tert-butoxycarbonyl, phenyl, naphthyl or fluorenyl (lower alkoxy) carbonyl group such as a benzyloxycarbonyl, lower alkanoyl group, a 1-group, (lower alkyl) -sulfonyl group, for example, methylsulfonyl, a phosphono group, a hydroxy- (lower alkoxy) -phosphoryl or di- (lower alkoxy) -phosphoryl group, a carbamoyl, mono- or di- (lower alkyl) -carbamoyl group, sulfamoyl, mono- or di- (lower alkyl) -aminosulfonyl, nitro and / or cyano, the phenyl being present one to three times, for example in the diphenyl-, dibenzyl- or triphenyl- (lower alkanoyl) group, such as diphenyl- , the dibenzyl- or triphenylacetyl and the lower alkanoyl moiety is optionally substituted by a lower alkyl group, for example methyl, a heterocyclyl group selected from pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, quinolinyl, quinolinyl, quinolinyl, quinolinyl, quinolinyl, quinolinyl, quinol ,. a β-carbolinyl or benzanellated, cyclopentaanellated, cyclohexaanellated or cycloheptaanellated derivative of this series, which may also be partially or fully saturated, by hydroxy, lower alkoxy, (lower alkanoyl) -oxy, for example acetoxy, propionyloxy, pentyloxy, butyryloxy, butyryloxy , amino- or benzyloxycarbonylamino- (lower alkanoyl) oxy, for example 2-amino- or

2-benzyloxycarbonylamino-2-methylpropionyloxy, aryl- (lower alkanoyl) -oxy, wherein the aryl moiety contains 6 to 10 carbon atoms, such as in benzyloxy, phenylacetyloxy, 1- or 2-naphthoyloxy, for example (lower alkoxy) -, ethoxy-, η-propoxy-, isopropo.xy-, η-butoxy-, isobutoxy-, sec-butoxy-, tert-butoxy-, n-pentyloxy-, isopentyloxy-, neopentyloxy-, t-pentyloxy- -, n-hexyloxy-, isohexyloxy- or n-heptyloxycarbonyloxy, mono- or di- (lower alkyl) aminocarbonyloxy, for example ethylaminocarbonyloxy-

A group or diethylaminocarbonyloxy, aryloxycarbonyloxy, wherein. the aryl moiety contains from 6 to 10 carbon atoms, for example, phenoxycarbonyloxy, 1- or 2-naphthyloxycarbonyloxy, aryl- (lower alkoxy) carbonyloxy.

C 6-14 aryl moieties, in particular phenyl (lower alkoxy) carbonyloxy, for example benzyloxycarbonyloxy, 1- or 2-naphthylmethoxycarbonyloxy or 9-fluorenylmethoxycarbonyloxy, sulfonyloxy, lower alkyl) -sulfonyloxy, for example methyl, ethyl, propyl, isopropyl, η-butyl, isobutyl, sec-butyl, tert-butyl, η-pentyl, isopentyl, neopentyl, tert-pentyl-, η-hexyl-, isohexyl- or n-heptylsulfonyloxy, or phenylsulfonyloxy,

2- or 4-toluenesulfonyloxy, 1- or

2-naphthylsulfonyloxy, carboxy, esterified carboxy selected from (lower alkoxy) -carbonyl, for example methoxy-, ethoxy-, η-propoxy-, isopropoxy-, η-butoxy-, isobutoxy-, sec-butoxy-, tert- butoxy-, n-pentyloxy-, isopentyloxy-, neopentyloxy-, tert -pentyloxy-, η-hexyloxy-, isohexyloxy- or n-heptyloxycarbonyl, an aryloxycarbonyl group, wherein the aryl moiety contains 6 to 10 carbon atoms, for example phenyloxycarbonyl, 1- or 2-naphthyloxycarbonyl, aryl- (lower alkoxy) -carbonyl, wherein the aryl moiety contains from 6 to 12 carbon atoms, for example benzyloxycarbonyl, 1- or 2-naphthylmethoxycarbonyl or 9-fluorenylmethoxycarbonyl, lower alkanoyl, (lower alkyl) -sulfonyl , for example methyl or tert-butylsulfonyl, hydroxy- (lower alkoxy) -phosphoryl or di- (lower alkoxy) -phosphoryl, carbamoyl, once or twice from a lower alkyl group, such as methyl, ethyl, propyl u, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl or n-heptyl, for example N-methylcarbamoyl, Nn- butylcarbamoyl or N, N-dimethylcarbamoylcarbamoyl, of a carboxy- (lower alkyl) or (lower alkoxy) -carbonyl- (lower alkyl) group, for example as carboxymethylcarbamoyl (glycinylcarbonyl) or as tert-butoxycarbonylmethylcarbamoyl of di- (lower alkyl) -amino - (lower alkyl) groups, for example 2-dimethylaminoethyl, aminocarboxy- (lower alkyl) groups, for example 5-amino-5-carboxypentyl, from hydroxy- (lower alkyl) groups, for example hydroxymethyl or. hydroxyethyl and from a di- (lower alkoxy) - (lower alkyl) group, for example 2- (2,2-dimethoxyethyl) selected from or selected from ethylene, trimethylene, tetramethylene and pentamethylene, wherein the carbon atom may be replaced by a nitrogen atom, oxygen atom or atom sulfur or an oxygen atom with one or two times a substituted sulfur atom and such groups may be unsaturated with a selected moiety such as piperidin-1-yl-, pyrazih-1-yl, piperazin-1-yl-, pyrimidin-1-yl-, pyridazine 1-yl, morpholino, thiomorpholino or

S, S-dioxothiomorpholinocarbonyl, substituted carbamoyl, sulfamoyl, phosphono, benzofuranyl, oxo and / or cyano, and is unbranched or branched, for example selected from benzoyl, unsubstituted or mono- or poly-substituted, e.g. for example chlorine, hydroxy, lower alkoxy, for example methoxy and / or nitro, such as 4-chloro. 4-methoxy- or 4-nitrobenzoyl, naphthylcarbonyl, such as α- or β-naphthylcarbonyl, or via both carbonyl groups to the amino group bound 1,8-naphthalenedicarbonyl, indenylcarbonyl, such as 1-, 2- or 3-indenylcarbonyl, indanylcarbonyl, such as is 1- or 2-indanylcarbonyl, phenanthrenylcarbonyl, such as 9-phenanthrenylcarbonyl, phenylacetyl, α-naphthyl acetyl, β-naphthyl acyl, (lower alkyl) -phenylacetyl groups such as 4-methylphenylacetyl, (lower alkoxy) -phenylacetyl groups such as 4-methoxyphenylacetyl, 3-phenylpropionyl, 3- (p-hydroxyphenyl) -propionyl, diphenylacetyl, di- (4-methoxyphenyl) acetyl, triphenylacetyl, 2,2-dibenzylation of butyl, in the phenyl residue one or two times from a lower alkyl group, for example methyl or ethyl, hydroxy, lower alkoxy, for example methoxy, amino, mono- or di- (lower alkyl) amino, for example ethylamino or dimethylamino, halogen, for example fluorine or chlorine u, carboxy, sulfo, carbamoyl, sulfamoyl and cyano and / or amino-substituted from lower alkyl and benzyl substituted by anilinophenylacetyl such as 2- (o, o-dichloranilino) phenylacetyl or 2- (o, o-dichloro-N-) benzylanilino) phenylacetyl, 3-or 3-p-naphthylpropionyl, 2-benzyl-3- (1-pyrazolyl) propionyl,

3-phenyl- or 3-α-naphthyl-2-hydroxypropionyl, 3-phenyl- or

3-.alpha.-naphthyl-2- (lower alkoxy) propionyl group such as

3-phenyl- or 3-α-naphthyl-2-neopentyloxypropionyl, 3-phenyl or 3-α-naphthyl-2- (lower alkanoyloxy) -propionyl, such as 3-phenyl-2-pivaloyloxy- or -2-acetoxypropionyl,

2-Berizyl- or 1- or 2-naphthyl-3- (N-methoxy-N-methylamino) propiopropyl, 3-α-naphthyl-2-acetoacetoxypropionyl, 3-α-naphthyl-2-ethylaminocarbonyloxypropionyl or 3-α-naphthyl -2- (2-Amino or 2-benzyloxycarbonylamino-2-methylpropionyloxy) propionyl

3-phenyl- or 3-α-naphthyl-2-carboxymethylpropionyl, 3-phenyl- or 3-α-naphthyl-2- (lower alkoxy) carbonylpropionyl group such as 3-α- (naphthyl-2-ethoxycarbonylpropionyl) , 3-phenyl or 3-α-naphthyl-2-benzyloxycarbonylmethylpropionyl,

2 (S) -benzyl-3-tert-butylsulfonylpropionyl,

3-phenyl-2-phosphono- or -phosphonomethylpropionyl,

3-phenyl-2-dimethoxyphosphoryl- or -dimethoxyphosphorylmethylpropionyl, 3-phenyl-2-diethoxyphosphoryl- or 4-diethoxyphosphorylmethylpropionyl, 3-phenyl-2-ethoxy- or -methoxyhydroxyphosphorylmethylpropionyl, phenyl- (lower alkanoyl), where the lower alkanoyl group is lower) substituted with a carbamoyl group, such as. is 2 (R, S) -carbonyl-3-phenylpropionyl, 3-phenyl- or 3-α-naphthyl-2-carbamoylpropionyl or 3-phenyl or 3-α-naphthyl-2-tert-butylcarbamoylpropionyl, 3-phenyl- or 3-α-naphthyl-2- (dimethylaminoethyl) carbamoylpropionyl,

Vi ''

3-α-naphthyl-2- (carboxy- or tert-butoxycarbonyl) methylcarbamoylpropionyl, 3-phenyl- or 3-α-naphthyl-2- (3-hydroxy-2-propyl) carbamoylpropionyl, 3-phenyl- or 3-α- naphthyl-2- (2,2-dimethoxyethyl) carbamoylpropionyl, 3-phenyl- or 3-α-naphthyl-2- (5-amino-5-carboxypentyl) carbamoylpropionyl, 3-phenyl- or 3-α-naphthyl-2- cyanpropionyl, 3-phenyl- or 3-α-naphthyl-2-cyanomethylpropionyl, 3-phenyl- or

3-α-naphthyl-2-acetonylpropionyl, 4-hydroxyphenylbutyryl,

4-phenyl- or 4-α-naphthyl-3-carboxybutyryl, 4-phenyl- or

4-.alpha.-naphthyl-3-benzyloxycarbonylbutyryl, 2-benzyl- or

2-a-naphthyl-4-cyanobutyryl, 2-benzyl-4- (2-benzofuryl) -4-oxobutyryl, 2-benzyl- or 2-a-naphthylmethyl-5-dimethylaminopentanoyl, 2-benzyl- or 2-a- naphthylmethyl-4-oxopentanoyl, 2

-benzyl- or 2-a-naphthylmethyl-4,4-dimethyl-3-oxopentanoyl,

2-benzyl- or 2-a-naphthylmethyl-5,5-dimethyl-4-oxopentanoyl a

2-benzyl- or 2-α-naphthylmethyl-5,5-dimethyl-4-oxohexanoyl, but especially a phenyl- (lower alkanoyl) group such as phenylacetyl or a phenyl- (lower alkanoyl) group wherein the lower alkanoyl residue is substituted carbamoyl such as 2 (R, S)

-carbamoyl-3-phenylpropionyl, phenyl- (lower alkenoyl) group such as β-phenylacryloyl or β-phenylvinylacetyl, heterocyclyl- (lower alkanoyl) group in which the lower alkanoyl moiety is not substituted or is substituted as defined above under aryl- (lower alkanoyl) R 1, R ₂ , R _g or R _g and wherein the heterocyclyl moiety is preferably a single or two membered ring system of 3 to 10 carbon atoms which is bonded via a carbon atom or a particular nitrogen atom and contains up to 3 additional heteroatoms selected from oxygen, nitrogen, sulfur, selenium and sulfur bonded with 1 or 2 oxygen atoms, wherein said ring system additionally may be fused to 1 or 2 phenyl or naphthylated residues, wherein the naphthyl residue may also be fused over two

The cycloalkyl moiety preferably contains 5 to 7 carbon atoms, and may be unsaturated or partially or completely. saturated, such as thienyl. furyl-, pyranyl-, pyrrolyl-, imidazolyl-, pyrazolyl-, oxazolyl-, isoxazolyl-, thiazolyl-, furazanyl-, tetrazolyl-, pyridyl-, pyrazinyl-, pyrimidinyl-, pyridazinyl-, azepinyl-, indolyl-, benzimidazolyl -, ΙΗ-indazolyl-, quinolyl-, isoquinolyl-, quinoxalinyl-, quinazolinyl-, cinnolyl-, purinyl-, pteridinyl-, naphthyridinyl-, 4H-quinolizinyl-, 3,1-benzofuranyl-, benz [e] indolyl-, 4,1-benzoxazinyl-, 4,1-benzthiazinyl-, carbazolyl-, β-carbolinyl-, phenazinyl-, phenanthridyl-, acrinyl-, phenoxazinyl-, phenothiazinyl-, 1-azaacenaphthenyl-, cyclohexa [b] pyrrolyl-, cycloheptafb] pyrrolyl -, cyclohexa [d] pyrazolyl-, cyclohexafb] pyridyl-, cyclohexafb] pyrazinyl-, cyclohexafbpyrimidinyl-, cyclohexafb] -1,4-oxazinyl-, cyclohexa [b] -1,4-thiazinyl-, pyrrolidinyl-, pyrrolinyl-, imidazolidinyl- , 2-imidazolinyl-

2,3-dihydropyridyl-, piperidyl-, piperazinyl-, 2,3,5,6-tetrahydropyriazinyl-, morpholinyl-, thiomorpholinyl-, S, S-dioxothiomorpholinyl-, indolinyl-, isoindolinyl-, 4,5,6,7 -tetrahydroindolyl-, 1,2,3,4-tetrahydroquinolyl-, 1,2,3,4-tetrahydroisoquinolyl-, chromanyl-, thiochromanyl-, 1,2,3,4-tetrahydro-3,1-perisdiazinyl-, 3,4-dihydro-3H-4,1-benzoxazinyl-, 3,4-dihydro-3H-4,1-benzthiazinyl-, 2,3,4,5-tetrahydro-1H-5,1-benzazepinyl- A 6-dihydrophenanthridinyl- (lower alkanoyl) group wherein said heterocyclyl residues are not. substituted or substituted by lower alkyl, for example methyl, phenyl, 1- or 2-naphthyl, phenyl (lower alkyl), for example benzyl, hydroxy (lower alkyl), for example hydroxymethyl or 2-hydroxyethyl, (lower alkoxy) - (lower alkyl), for example methoxymethyl or 2-methoxyethyl, phenoxy or naphthyloxy (lower alkyl), for example 2-phenoxyethyl, 1- or 2-naphthyloxymethyl, phenyl (lower alkoxy) - or naphthyl - (lower) alkoxy) - (lower alkyl) -

In this case, for example, a benzyloxy- (lower alkyl) group, a (lower alkanoyl) -oxy- (lower alkyl) group, for example, acetoxymethyl, a phenyl or naphthyl- (lower alkanoyl) -oxy- (lower alkyl) group, for example, benzyloxy -, phenylacetoxy- or

1- or 2-naphthoyloxymethyl, -2-ethyl or -2- (2,2-dimime)

thylethyl), a (lower alkoxy) -carbonyloxy- (lower alkyl) group, for example a tert-butoxycarbonyloxy- (lower alkyl) group (phenyl, naphthyl or fluorenyl- (lower) alkoxy) -carbonyloxy- ( lower alkyl), for example

2-benzyloxycarbonyloxyethyl; or

9-fluorenylmethoxycarbonyloxyethyl, amino- (lower alkyl), for example aminomethyl, 2-aminoethyl or 2-aminopropyl, carboxy- (lower alkyl), for example carboxymethyl or 2-carboxyethyl, hydroxy, lower alkoxy, for example methoxy or ethoxy, phenyl- or naphthyl- (lower alkoxy), for example, benzyloxy or 1- or 2-naphthyloxy, amino, (lower alkyl) -amino, for example methyl-, ethyl- or tert-butylamino, di- (lower-alkyl) -amino, for example dimethyl - or diethylamino, carboxy, (lower alkoxy) -carbonyl, for example methoxy, isopropoxy, sec-butoxy or tert-butoxycarbonyl, phenyl or naphthyl- (lower alkoxy) -carbonyl, for example benzyloxycarbonyl, halogen such as fluorine, chlorine, bromine or iodine, especially chlorine or bromine, lower alkanoyl, e.g. d with acetyl or pivaloyl, (lower alkyl) -sulfonyl, for example methyl or ethylsulfonyl, phosphono, hydroxy (lower alkoxy) -phosphoryl or di- (lower alkoxy) -phosphoryl, for example dimethoxy- or diethoxyphosphoryl, carbamoyl, mono - or by a di- (lower alkyl) -carbamoyl group, for example N-methylcarbamoyl, Nn-butylcarbamoyl or N, N-dimethylcarbamoyl, hydroxy- or carboxy- (lower alkyl) -carbamoyl group, for example hydroxy- or carboxymethylcarbamoyl or hydroxy-, or carboxyethylcarbamoyl, sulfamoyl, nitro, oxo, and / or cyano, wherein the heterocyclyl- (lower alkanoyl) group is particularly selected from optionally lower alkyl or phenyl substituted pyrrolylcarbonyl, for example 2- or

3-pyrrolylcarbonyl, 4- or 5-methylpyrrolylcarbonyl; or

4- or 5-phenylpyrrolyl-2-carbonyl, thienylcarbonyl, such as 2-thienylcarbonyl, furylcarbonyl, such as 2-furylcarbonyl, pyridylcarbonyl, such as 2-, 3- or 4-pyridylcarbonyl, pyrimidin-1-ylcarbonyl, optionally as lower alkyl, methyl, phenyl- (lower alkyl), such as benzyl, lower alkoxy, such as methoxy, phenyl- (lower alkoxy), such as benzyloxy, or halogen, such as chloro substituted indolylcarbonyl, such as 2-, 3- or 5-indolylcarbonyl; methyl,

I

5-methyl-, 5-methoxy-, 5-benzyloxy-, 6-chloro- or

4,5-dimethylindol-2-ylcarbonyl, 1-benzylindol-2- or -3-ylcarbonyl, 4,5,6,7-tetrahydroindol-2-ylcarbonyl, optionally hydroxy-substituted quinolyl- (lower alkanyoyl) groups, for example quinolylcarbonyl, such as 2-, 3- or

4-quinolylcarbonyl or 4-hydroxyquinol-2-ylcarbonyl optionally substituted by hydroxy substituted isoquinolylcarbonyl such as 1-, 3- or 4-isoquinolylcarbonyl or 1-oxo-1,2-dihydroisoquinolyl-3-carbonyl, 2-quinoxalinylcarbonyl -benzfuranyl) carbonyl, benz [e] indolyl-2-carbonyl, β-carbolinyl-3-carbonyl, cyclohepta (b] pyrrol-5-ylcarbonyl, 3-chromanylcarbonyl, 3-thiochromanylcarbonyl, pyrrolidinyl-3-carbonyl, hydroxypyrrolidinyl, hydroxypyrrolidinyl 3- or

4-hydroxypyrrolidinyl-2-carbonyl, oxopyrrolidinylcarbonyl, such as 5-oxopyrrolidinyl-2-carbonyl, piperidinylcarbonyl, such as piperidinocarbonyl, or 2-, 3- or 4-piperidylcarbonyl, pyrazinylcarbonyl, such as pyrazin-1-ylcarbonyl, piperazinyl. piperazin-1-ylcarbonyl, morpholinyl- (lower alkanoyl) groups, for example morpholinylcarbonyl, such as morpholinocarbonyl, thiomorpholinyl- (lower alkanoyl) trials, for example thiomorpholinylcarbonyl, such as thiomorpholinocarbonyl, S, S-dioxothiomorphi such as 2- or 3-indolinylcarbonyl, 1,2,3,4-tetrahydroquinolinylcarbonyl, such as 1,2,3,4-tetrahydroquinolin-2-, -3- or -4-ylcarbonyl, 1,2,3,4-tetrahydroisoquinolinylcarbonyl , like

1,2,3,4-tetrahydroisoquinoline-1-, -3- or. 4-ylcarbonyl or 1-oxo-1,2,3,4-tetrahydroisoquinolin-3-ylcarbonyl, tetrazolyl- (lower alkanoyl) groups; like

3- (tetrazol-1-yl) propionyl and pyridyl- (lower alkanoyl) groups, for example pyridylacetyl, such as 2-, 3- or

4-pyridylacetyl, especially selected from morpholinocarbonyl, thiomorpholinocarbonyl, S, S-dioxothiomorpholinocarbonyl, pyridylacetyl, indolylacetyl, benzofuranylacetyl, 4-pyrrolidinylacetyl, 1-imidazolylacetyl, quinolin-2-ylacetylmorpholino-2-ylacetylmorpholino-indolyl-2-ylacetyl, , and 2- (S, S-dioxothiomorpholino) -2-isopropylacetyl, particularly preferred morpholinocarbonyl, thiomorpholinocarbonyl, quinolin-2-ylcarbonyl, 3- (tetrazol-1-yl) propionylcarbonyl, or 2- or 3-pyridylacetyl, heterocyclyl- ) a group in which the heterocyclyl moiety is selected in particular from pyrrole, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl, β-carbolinyl, cyclopentanellate, benzoanelepane, benzene of this series, which may also be partially or fully saturated, for example pyrrolidyl- (lower alkenoyl) a group such as N-pyrrolidylacryloyl, a hydroxy- (lower alkanoyl) group such as 3-hydroxypropionyl or 2-hydroxy-3-methylpentanoyl, a hydroxy- (lower alkoxy) - (lower alkanoyl) group such as 3-hydroxy- n-propoxycarbonyl, (lower alkoxy) - (lower alkanoyl) -, for example, (lower alkoxy) -acetyl, or (lower alkoxy) -propionyl, such as methoxyacetyl, ethoxyacetyl or 3-methoxypropionyl, (lower alkoxy) - ( lower alkoxy) - (lower alkanoyl) group such as 2-methoxymethoxy-3-methylpentanoyl, phenoxy- (lower alkanoyl) or nitrophenoxy- (lower alkanoyl) group such as phenoxyacetyl or 4-nitrophenoxyacetyl, naphthyloxy- (lower alkanoyl) a group such as α- or O-naphthoxyacetyl, a (lower alkanoyl) -oxy- (lower alkanoyl) group in which the (lower alkanoyl) -oxyl moiety is, for example, an acetoxy, propionyloxy, butyloxy, isobutyryloxy or pivaloyloxy group such as ac ethoxyacetyl or 3-acetoxypropionyl, acetoacetoxy- (lower alkanoyl) group such as

A 3-acetoacetoxypropionyl, amino- or benzyloxycarbonylamino- (lower alkanoyl) -oxy- (lower alkanoyl) group, for example a 2-amino- or 2-benzyloxycarbonylamino-2-methylpropionyloxy- (lower alkanoyl) group such as -acetyl or A 3-propionyl, aryl- (lower alkanoyl) -oxy- (lower alkanoyl) group in which the aryl part contains 6 to 10 carbon atoms, such as in benzoyloxy-, phenylacetyloxy- or 1- or 2-naphthoyloxy- (lower alkanoyl) a (lower alkoxy) -carbonyloxy- (lower alkanoyl) group such as methoxy-, ethoxy-, n-propoxy-, isopropoxy-, η-butoxy, isobutoxy-, sec-butoxy-, tert-butoxy- , n-pentyloxy-, isopentyloxy-, neopentyloxy-, tert-pentyloxy-. n-hexyloxy-, isohexyloxy- or n-hepthyloxycarbonyloxy- (lower alkanoyl) group, such as -acetyl or -3-propionyl, mono- or di- (lower alkyl) aminocarbonyloxy- (lower alkanoyl) group, for example ethylaminocarbonyloxy- ( lower alkanoyl) or diethylaminocarbonyloxy- (lower alkanoyl) group, such as -acetyl or -3-propionyl, aryloxycarbonyloxy- (lower alkanoyl) group in which the aryl part contains 6 to 10 carbon atoms, for example phenoxycarbonyloxy- or 1- or 2 -naphthyloxycarbonyloxy- (lower alkanoyl) group such as -acetyl or -3-propionyl, aryl- (lower alkoxy) -carbonyloxy- (lower alkanoyl) group with an aryl moiety of 6 to 12 carbon atoms, for example phenyl- (lower alkoxy) -carbonyloxy- (lower alkanoyl) group such as benzyloxycarbonyloxyacetyl or -3-propionyl, furthermore 1- or 2-naphthylmethoxycarbonyloxy- (lower alkanoyl) or 9-fluorenylmethoxycarbonyloxy- (lower alkanoyl) group such as -a cetyl or -3-propionyl, a sulfonyloxy- (lower alkanoyl) group such as -acetyl or -3-propionyl, (lower alkyl) -sulfonyloxy- (lower alkanoyl) group, for example methyl-, ethyl-, propyl-, isopropyl- , n-butyl-, isobutyl-, sec-butyl-, tert-butyl-, η-pentyl-, isopentyl-, neopentyl-, tert-pentyl-, η-hexyl-, isohexyl- or n-heptylsulfonyloxy- a (lower alkanoyl) group such as -acetyl or -3-propionyl, phenylsulfonyloxy-, 2- or 4-toluenesulfonyloxy- or

1- or 2-naphthylsulfonyloxy- (lower alkanoyl), an arylmercapto- (lower alkanoyl) group in which the aryl moiety contains from 6 to 10 carbon atoms and preferably represents phenyl or naphthyl, for example a phenylmercapto- (lower alkanoyl) group such as - acetyl or -3-propionyl,.

an amino- (lower alkanoyl) group in which the amine moiety is not in the α or β position, such as 5-aminopentanyl, (lower alkanoyl) -amino- (lower alkanoyl) in which the amine moiety is not in the α or β position an alkanoyl radical, such as 5-aminopentanoyl, (lower alkoxy) -carbonylamino- (lower alkanoyl), in which the amine moiety is not in the α or β position of the lower alkanoyl radical, such as 5- (tert-butoxycarbonylamino) pentanoyl, phenyl- a (lower alkoxy) -carbonylamino- (lower alkanoyl) group in which the amine moiety is not in the α or β position of the lower alkanoyl radical, such as 5-benzyloxycarbonylaminopentanoyl or 6-benzyloxycarbonylaminohexanoyl, amino- (lower alkanoyl) substituted amino group - (lower alkanoyl) group, as defined above for a heterocyclyl (lower alkanoyl) group, R, R _2, R g and R _g, particularly N or N-mor.folino- thiomorfolinokarbonylem, the Example N-morpholino or N-thiomorpholinocarbonylaminoacetyl, a halogen- (lower alkanoyl) group preferably containing up to 3 carbon atoms, for example α-haloacetyl such as α-fluoro-, α-chloro-, α-bromo, α-iodo -, α, α, α-trifluoro- or α, α, α-trichloroacetyl, or halopropionyl, such as β-chloro or β-bromopropionyl, a carboxy (lower alkanoyl) group, for example, carboxyacetyl or β-carboxypropionyl, (lower alkoxy a) -carbonyl- (lower alkanoyl) group, for example ice (lower alkoxy) -carbonylacetyl or (lower alkoxy) -carbonylpropionyl, such as methoxycarbonylacetyl or 3-methoxycarbonylpropionyl, ethoxycarbonylacetyl or 3-ethoxycarbonylpropionylpropionyl, a) carbonyl halogeno (lower alkanoyl) group such as 3-ethoxycarbonyl-2-difluoromethylpropionyl,

A 2-halo- (lower alkoxy) -carbonyl- (lower alkanoyl) group such as 2-chloro, 2-bromo-, 2-iodo or 2,2,2-trichloroethoxycarbonylacetyl or -3-propionyl, phenyl or naphthyl - (lower alkoxy) -carbonyl- (lower alkanoyl) group, for example a benzyloxycarbonyl- (lower alkanoyl) group such as 3-benzyloxycarbonyl-2,2-dimethylpropionyl, heterocyclyl- (lower alkoxy) -carbonyl- (lower alkanoyl) group, wherein the heterocyclyl residue is preferably selected from pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl and β-carbolinyl, cyclohexanellate, cyclohexanellate, or cyclohexanellate, or said radicals may also be wholly or partially saturated, such as in 4-pyridylmethoxycarbonylacetyl or -3-propionyl or 2-morpholinocarbonyloxy-4-methylpentanoyl, sulfonyl- (lower alkanoyl) group such as

3-sulfonylpropionyl, (lower alkyl) -sulfonyl- (lower alkanoyl), such as 2-ethylsulfonyl- or 2-tert-butylsulfonylacetyl; an arylsulfonyl- (lower alkanoyl) group in which the aryl moiety preferably contains from 6 to 10 carbon atoms, for example phenyl or naphthyl such as phenylsulfoacetyl, carbamoyl- (lower alkanoyl) group such as carbamoylacetyl or 3-carbamoylpropionyl, (lower an alkyl) -carbamoyl- (lower alkanoyl) group, for example a (lower alkyl) -carbamoylacetyl or methylcarbamoyl- (lower alkanoyl) group such as methylcarbamoylacetyl, a di- (lower alkyl) -carbamoyl- (lower alkanoyl) group, for example a di- ( lower alkyl) -carbamoylacetyl or dimethylcarbamoyl- (lower alkanoyl) group such as dimethylcarbamoylacetyl; a hydroxy- (lower alkyl) -carbamoyl- or di- (hydroxy- (lower alkyl)) -carbamoyl- (lower alkanoyl) group such as a hydroxymethylcarbamoyl- di- (hydroxymethyl) carbamoylacetyl or -propionyl group,

N- (lower alkoxy) - (lower alkoxy) - (lower alkyl) -carbamoyl- (lower alkanoyl) group such as 2-isobutyl-3- / 2- (2-methoxyethoxy) ethylaminocarbonyl / propionyl, carboxy- (lower alkyl) a -carbamoyl- or di- (carboxy- (lower alkyl)) -carbamoyl- (lower alkanoyl) group such as a carboxymethyl- or di- (carboxymethyl) carbamoylacetyl or -propionyl group, - a residue selected from ethylene, trimethylene, tetramethylene and pentamethylene, wherein the carbon atom may be replaced by a nitrogen, oxygen, sulfur or oxygen atom with one or two substituted sulfur atoms, a nitrogen-substituted carbamoyl- (lower alkanoyl) group, the residue thus formed may also be wholly or partially unsaturated, such as piperidino- pyrazin-1-yl-, piperazin-1-yl-, pirimidin-1-yl-, pyridazin-1-yl-, morpholino-, thiomorpholino- or S, S-dioxothiomorpholinocarbonyl- (lower alkanoyl) groups such as morpholinocarbonylacetyl 3- (morpholinocarbonyl) propionyl or 3- (morpholinocarbonyl) -2-isobutylpropionyl,

N-heterocyclyl- (lower alkyl) -carbamoyl- (lower alkanoyl) or N- (lower alkyl) -N-heterocyclyl- (lower alkyl) -carbamoyl- (lower alkanoyl) group in which the heterocyclyl residue is preferably selected from pyrrolyl , furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl and β-carbolinyl, and the benzanlated, cyclopentaanellated, cyclohexa-annulated or cyclohexanellate or partially saturated, or selected from morpholinyl or thiomorpholinyl such as N-methyl-2- (N-2-pyridylmethyl) carbamoylacetyl, 2- (N-morpholino- (lower alkyl) carbamoyl) - (lower alkanoyl) group such as is a 2 (R, S) - [N- (2-morpholinoethyl) carbamoyl] -3-methylbutyryl or 2- [N- [pyridyl- (lower alkyl)] - carbamoyl] - (lower alkanoyl) group such as [2 (R, S) - [N- (2-pyridylmethyl) carbamoyl] -3-methyl] butyryl, sulfamoyl- (lower alkanoyl) group like

2-sulfamoylacetyl;

N- (phenyl- or naphthyl- (lower alkyl)) - sulfamoyl- (lower alkanoyl) group, such as 3-benzylaminosulfonyl-2-isopropylpropionyl, on a nitrogen atom with a residue selected from ethylene, trimethylene, tetramethylene and pentamethylene, where the carbon atom may be replaced by a nitrogen atom, a lower alkyl group, such as a methyl group substituted by a nitrogen atom, an oxygen or sulfur atom or an oxygen atom with one or two times a substituted sulfur atom, a substituted sulfamoyl- (lower alkanoyl) group; partially unsaturated such as piperidino-, pyrazin-1-yl-, piperazin-1-yl-, 4-methylpiperazin-1-yl-, pirimidin-1-yl-, pyridazin-1-yl-, morpholino-, thiomorpholinoneor S A S-dioxothiomorpholinosulfonyl- (lower alkanoyl) group such as 3- (4-methylpiperazinylsulfonyl) -2-isopropylpropionyl or 3- (morpholinosulfonyl) -2-isopropylpropionyl,

X. '- an oxo- (lower alkanoyl) group such as acetoacetyl or propionylacetyl, a cyan- (lower alkanoyl) group,

2- or 3-cyanopropionyl or 2-, 3- or such as cyanacetyl;

4-cyanobutyryl, a hydroxycarboxy- (lower alkanyl) group such as

2-hydroxy-2-carboxyacetyl or 2-hydroxy-3-carboxypropionyl, α-naphthyloxycarboxy- (lower alkanoyl), such as 2-α-naphthoxy-4-carboxybutyryl, hydroxy- (lower alkoxy) -carbonyl- (lower alkanoyl) a group such as a hydroxy- (lower alkoxy) -carbonylacetyl or -propionyl group or a hydroxyethoxy- or hydroxymethoxycarbonyl- (lower alkanoyl) group such as a 2-hydroxy-2-ethoxy- or -methoxycarbonylacetyl or 2-hydroxy-3-

-ethoxy- or -methoxycarbonylpropionyl,. an α-naphthyloxy- (lower alkoxy) -carbonyl- (lower alkanoyl) group, for example an α-naphthyloxy- (lower alkoxy) -carbonylacetyl, -propionyl or'-butyryl group or an α-naphthyloxyethoxycarbonyl- (lower alkanoyl) group such as a -naphthyloxyethoxycarbonylacetyl, 2-α-naphthyloxy-3-ethoxycarbonylpropionyl or 2-α-naphthyloxy-4-tert. -butoxycarbonylbutyryl, α-naphthyloxybenzyloxycarbonyl- (lower alkanoyl) group, such as 2-α-naphthyloxy-3-benzyloxycarbonylpropionyl, esterified hydroxy- (lower alkoxy) -carbonyl- (lower alkanoyl) group, wherein the hydroxy group is esterified by lower alkanoyl, for example acetyl, propionyl or pivaloyl, a cycloalkyl- (lower alkanoyl) group, wherein the cycloalkyl moiety contains from 3 to 7 carbon atoms and the lower alkanoyl moiety is preferably as previously defined, for example, such as cyclohexylcarbonyl or 2-cyclohexyl- or 2-cyclohexyl- -cyclopentylacetyl, a bicycloalkyl- (lower alkanoyl) group, wherein the bicycloalkyl radical contains, for example, 5 to 10 carbon atoms, in particular 6 to 9 carbon atoms, such as in bicycohexyl-, -heptyl-, -octyl-, -nonyl- or -decylacetyl; 3-propionyl such as bicyclo [3.1.0] hex-1-ylacetyl, bicyclo [3.1.0] hex-1-, -2- or -3-yl-, bicyclo [4.1.0] hept- 1- or -7-yl-, bicyclo [2.2. 1] hept-2-yl-, such as endo- or exo-norbornyl-, bicyclo [3,2,1] oct-2-yl-, bicyclof3,3,0] oct-3-yl-, or bicyclof3,3, 1] non-9-yl-, further α- or β-decahydronaphthylacetyl or -3-propionyl, a tricycloalkyl- (lower alkanoyl) group in which the tricycloalkyl moiety contains, for example, 8 to 10 carbon atoms, such as in tricyclof5,2,1,1 O ² · ⁶ ] dec-8-yl- or adamantyl- such as 1-adamantylacetyl, an aryl- (lower alkanoyl) group in which the aryl moiety contains from 6 to 14 carbon atoms such as phenyl, indenyl, indanyl,

Naphthyl, anthryl, phenanthryl, acenaphthyl or fluorenyl which is unsubstituted or can be substituted with one or three times lower alkyl such as isopropyl, halogen- (lower _x alkyl) such as trifluoromethyl, hydroxy, lower alkoxy, carbamoyl- ( lower alkoxy), N- (lower alkyl) -carbamoyl- (lower alkoxy) or N, N-di- (lower alkyl) -carbamoyl- (lower alkoxy), amino, mono- or di- (lower alkyl) amino, halogen, such as fluorine, chlorine or bromine, carboxy, (lower alkoxy) -carbonyl, phenyl, naphthyl or fluorenyl- (lower alkoxy) -carbonyl, lower alkanoyl, (lower alkyl) -sulfonyl, for example methylsulfonyl, phosphono, hydroxy- (lower) alkoxy) -phosphoryl or di- (lower alkoxy) -phosphoryl, carbamoyl, mono- or di- (lower alkyl) -aminocarbamoyl, sulfamoyl, mono- or di- (lower alkyl) -sulfamoyl, nitro and / or cyano, (lower alkoxy) -carbonyl a tert-butoxycarbonyl, 2-halogen- (lower alkoxy) -carbonyl group as defined above, or a phenyl- or fluorenyl- (lower alkoxy) -carbonyl group, for example a benzyloxycarbonyl or 9-fluorenylmethoxycarbonyl group such as a -acetoxy-α-methoxycarbonylacetyl, α-benzyloxy-, α- (1- or 2-naphthoyloxy) -, α- (phenyl-2-acetyloxy) -, α- (1- or 2-naphthyl-2-acetyloxy) - , α- (4-methylphenyl-2-acetyloxy) -, α- (4-methoxyphenyl-2-acetyloxy) - or α- [2- (o, o-dichlorophenyl) -2-acetyloxy] -α-methoxycarbonylacetyl, dihydroxycarboxy a (lower alkanoyl) group such as

2,3-dihydroxy-3-catboxypropionyl, dihydroxy- (lower alkoxy) -carbonyl- (lower alkanoyl) group such as 2,3-dihydroxy-3-ethoxy- or -methoxycarbonylpropionyl, dihydroxy- (lower alkoxy) -carbonyl- (lower alkanoyl). a lower alkanoyl esterified group such as acetyl, propionyl or butyryl, a (lower alkoxy) carbonyl group, for example a tert-butoxycarbonyl, phenyl or fluorenyl- (lower alkoxy) carbonyl group such as benzyloxycarbonyl or 9-fluorenylmethoxycarbonyl, ( lower alkyl) -sulfonyl or toluenesulfonyl, for example a di- (lower alkanoyl) -oxy- (lower alkoxy) -propionyl group such as 2,3-diacetoxy-3-methoxycarbonylpropionyl, α-naphthyloxydi- (lower alkyl) an -amino- (lower alkanoyl) group such as 2-α-naphthyloxy-5-dimethylaminopentanoyl, an α-naphthyloxycarbamoyl- (lower alkanoyl) group such as 2-α-naphthyloxy-4-carbamoylbutyryl, α-naphthyloxyoxo- (lower) alkanoyl), such as 2-α-naphthyloxy-4-oxopentanoyl, i

an α-naphthyloxycyan- (lower alkanoyl) group such as α-naphthyloxycyanacetyl or 2-α-naphthyloxy-4-cyanobutyryl, a lower alkenyl group having 3 to 7 carbon atoms, preferably 3 or 4 carbon atoms, wherein the lower alkenoyl group is not substituted or may be substituted with the same substituents as lower alkanoyl, especially phenyl, hydroxy, lower alkoxy, such as methoxy, phenyl- (lower alkoxy), such as methoxy, phenyl- (lower alkoxy), such as benzyloxy, (lower alkanoyl) -ox such as acetoxy, (lower alkanoyl) -amino, such as acetamino, (lower alkoxy) -carbonyloxy, such as tert-butoxycarbonyloxy, phenyl- or naphthyl- (lower alkoxy) -carbonyloxy, such as benzyloxycarbonyloxy, lower-carboxy , such as a tert-butylcarbonyl, phenyl- or naphthyl- (lower alkoxy) -carbonyl group, a halogen atom such as chlorine or bromine, carbamoyl

- 27 and / or τηοηο- or di- (lower alkyl) -carbamoyl, such as in acryloyl, vinylacetyl, crotonoyl or 3-, or

4-pentenoyl, 3-phenylacryloyl, 3-phenylvinylacetyl or

5-phenyl-4-acetylaminopenten-2-yl.

a cycloalkyl- (lower alkenoyl) group in which the cycloalkyl moiety preferably contains 3 to 7 carbon atoms, for example cyclohexylacryloyl or a lower alkinoyl group having 3 to 7 carbon atoms, preferably 3 or 4 carbon atoms, for example propioloyl or 2- or 3 -butinoyl.

Preferred acyl groups R _{2 l of} R, R g and R _{g of} semi-ester of carbonic acid is (lower alkoxy) carbonyl groups, e.g., methoxy, ethoxy, isopropoxy, isobutoxy or tert .- (lower alkoxy) carbonyl groups such as tert-butoxycarbonyl or isobutoxycarbonyl,

2-halo- (lower alkoxy) -carbonyl, such as 2-chloro, 2-bromo, 2-iodo- or 2,2,2-trichloroethoxycarbonyl, aryloxycarbonyl in which the aryl moiety contains 6 to 14 carbon atoms and is, for example, phenyl, biphenylyl, 1- or 2-naphthyl, fluorenyl or phenyl substituted with one or more lower alkyl groups such as methyl or tert-butyl, hydroxy, lower alkoxy such as methoxy, ethoxy or tert- butoxy, halogen atoms such as chlorine or bromine and / or nitro groups such as phenoxycarbonyl, aryl- (lower alkoxy) -carbonyl, such as arylmethoxycarbonyl, in which the aryl moiety contains from 6 to 14 carbon atoms and is, for example, phenyl, biphenylyl, 1- or 2-naphthyl, fluorenyl or phenyl substituted by one or more lower alkyl groups, for example methyl or tert-butyl, hydroxy, lower alkoxy in, for example, methoxy, ethoxy, or t-butoxy, halogen, such as chlorine or _; bromo and / or nitro groups, for example phenyl- (lower alkoxy) -carbonyl, such as benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-nitrobenzyloxyoxycarbonyl or diphenyl- (lower alkoxy) -carbonyl, such as diphenylmethoxycarbonyl, di- (4-methoxycarbonyl) methoxy or trityloxycarbonyl, or fluorenyl- (lower alkoxy) -carbonyl, such as 9-fluorenylmethoxycarbonyl, with benzyloxycarbonyl, heterocyclyl- (lower alkoxy) -carbonyl being particularly preferred, wherein the heterocyclyl moiety is preferably selected from pyrrolyl, furyl, thienyl. , imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalyl and β-carbolinyl,

And a benzanellated, cyclopentaanellated, cyclohexaanellated or cycloheptaanellated derivative of this moiety, which may also be wholly or partially saturated, or selected from morpholinyl or thiomorpholinyl, and is unsubstituted or may be substituted with a particularly lower alkyl group such as methyl as selected from 1; -methylpyrrolidin-2-ylmethoxycarbonyl or 2-furylmethoxycarbonyl, or 2-tetrahydrofuranyl- (lower alkoxy) carbonyl groups such as 2-tetrahydrofuranylmethoxycarbonyl, 1-methyl-2-piperidylmethoxycarbonyl or 2-morpholinoetho, or 3-morpholinoetho, 4pyridinylmethoxycarbonyl,

A 2-tri- (lower alkyl) -silyl- (lower alkoxy) -carbonyl group such as 2-trimethylsilyloxycarbonyl or

2-triarylsilyl- (lower alkoxy) carbonyl, wherein the aryl moiety is phenyl, 1- or 2-naphthyl such as triphenylsilylethoxycarbonyl.

Preferred acyl groups R _{2 l of} R, R and R _{unsubstituted;} The preferred or substituted carbamic acids are suitable radicals, already mentioned as preferred acyl groups R 1, R ₂ , R 8 and R 8, as follows:

a carbamoyl group or an unsubstituted or substituted N-alkyl- or Ν, Ν-dialkylcarbamoyl group wherein the alkyl moiety contains up to 12 carbon atoms, preferably an optionally substituted (lower alkyl) - or N, N-di- (lower alkyl) -carbamoyl group such as methyl, ethyl, propyl, tert-butyl, dimethyl, diethyl or di-n-propylcarbamoyl, the substituents being selected from phenyl such as benzylcarbamoyl, N-phenyl- (lower alkyl) -N - (lower alkyl) -carbamoyl groups such as N-benzyl-N-methyl-. carbamoyl or dibenzylcarbamoyl, a heterocyclyl group which is defined below a heterocyclyl- (lower alkanoyl) group R ₁ , R ₂ , R g and R g, preferably selected from thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, oxazole, thiazolyl, isoxazolyl, isoxazolyl, isoxazolyl, furazanyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, azepinyl, indolyl, benzimidazolyl, ind-indazolyl, quinylyl, isoquinolyl, quinoxalinyl, quinazolinyl, quinnolyl, purinyl, pteridinyl, naphthydinyl-benzyl, 4-benzimidazolyl, benzimidazolyl, 4 [e] indolyl, 4,1-benzoxazinyl, 4,1-benzthiazinyl, carbazolyl, β-carbolinyl, phenazinyl, phenanthridyl, acryl, phenoxazinyl, phenothiazinyl, 1-azaacenaphthyl, cyclohexa [b] pyrrolyl, cyclohepta, [b] pyrrole, [d] pyrazolyl, cyclohexa [b] pyridyl, cyclohexa [b] pyrazinyl, cyclohexa [b] pyrimidinyl, cyclohexa [b] -1,4-oxazinyl, cyclohexa [b] -1,4-thiazinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, 2-imidazolinyl,

2,3-dihydropyridyl, piperidyl, piperazinyl, 2,3,5,6-tetrahydropyrazinyl, morpholinyl, thiomorpholinyl, S, S-dioxothiomorpholinyl, indolinyl, isoindolinyl, 4,5,6,7-tetrahydroindolyl, 1,2,3, 4-tetrahydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl, chromanyl, thiochromanyl, 1,2,3,4-tetrahydro-3,1-benzdiazinyl, 3,4-dihydro-3H-4,1-benzoxazinyl, 3, 4-dihydro-3H-4,1-benzthiazinyl, 2,3,4,5-tetrahydro-1H-5,1-benzazepinyl and 5,6-dihydrophenanthridinyl, said radicals being optionally substituted by a lower alkyl group such as methyl, phenyl , 1- or 2-naphthyl, phenyl (lower alkyl), for example benzyl, hydroxy- (lower alkyl), for example hydroxymethyl or 2-hydroxyethyl, (lower alkoxy) - (lower alkyl), for example methoxymethyl or 2- methoxyethyl, phenoxy- or naphthyloxy- (lower alkyl) group, for example 2-phenoxyethyl, 1- or 2-naphthyloxymethyl, phenyl- (lower alkoxy) - or naphthyl- (lower alkoxy) - (lower benzyloxy- (lower alkyl), (lower alkanoyl) -oxy- (lower alkyl), for example acetoxymethyl, phenyl- or naphthyl- (lower alkanoyl) -oxy- (lower alkyl), for example benzoyloxy- , phenylacetoxy- or 1- or 2-naphthoyloxymethyl, -2-ethyl or -2- (2,2-dimethylethyl), (lower alkoxy) -carbonyloxy- (lower alkyl), for example tert-butoxycarbonyloxy- (lower alkyl) phenyl, naphthyl or fluorenyl- (lower alkoxy) -carbonyloxy- (lower alkyl) group, for example 2-benzyloxycarbonyloxyethyl or 9-fluorenylmethoxycarbonyloxyethyl, amino- (lower alkyl) group, for example aminomethyl, 2-aminoethyl or 2-aminopropyl , carboxy (lower alkyl), such as carboxymethyl or 2-carboxyethyl, hydroxy, lower alkoxy, such as methoxy or ethoxy, phenyl or naphthyl (lower alkoxy), such as benzyloxy or 1- or. 2-naphthyloxy,. amino, (lower alkyl) -amino, e.g. methyl, ethyl or tert-butylamino, di- (lower alkyl) -amino, e.g. dimethyl- or diethylamino, carboxy, (lower alkoxy) -carbonyl, e.g. methoxy, isopropoxy-, sec-butoxy- or tert-butoxycarbonyl, phenyl- or naphthyl- (lower alkoxy) -carbonyl, for example benzyloxycarbonyl, halogen, for example atora fluorine, chlorine, bromine or iodine, especially chlorine or bromine, alkanoyl, for example acetyl or pivaloyl, (lower alkyl) -sulfonyl, for example methyl- or ethylsulfonyl, phosphono, hydroxy- (lower alkoxy) -phosphoryl or di- (lower alkoxy) -phosphoryl, for example dimethoxy- or diethoxyphosphoryl, carbamoyl , non- or di- (lower alkyl) -carbamoyl, for example N-methylcarbamoyl, Nn-butylcarbamoyl or N, N-dimethylcarbamoyl, hydroxy- or carboxy- (lower alkyl) -carbamoyl, for example hydroxy- or carboxymethylcarbamoyl or sulfamoyl, nitro, oxo and / or cyano, especially pyridyl, such as 2-, 3- or 4-pyridyl, especially in N-heterocyclyl- (lower alkyl) - N- (lower alkyl) carbamoyl groups, for example N-pyridyl- (lower alkyl) -N- (lower alkyl) carbamoyl groups, such as N- (2-, 3- or 4-pyridylmethyl) -N-methylcarbamoyl, or in N-heterocyclyl- (lower alkyl) -carbamoyl, for example 2- or 3-pyridylmethylaminocarbonyl, hydroxy, for example in hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl or 2-hydroxypropyl, N-dihydroxy- (lower alkyl) groups , such as 2,3-dihydroxy-n-propyl or 2-hydroxy-2,2-dimethylethyl, lower alkoxy, preferably in (lower alkoxy) - (lower alkyl), for example methoxymethyl or 2-methoxyethyl, (lower alkanoyl) -oxy groups, preferably in the (lower alkanoyl) -oxy- (lower alkyl) group , for example, (lower alkanoyl) -oxymethyl or (lower alkanoyl) -oxyethyl groups such as acetoxymethyl, 2-acetoxyethyl, 3-propionyloxymethyl, 2-propionyloxyethyl, 4-butyroxymethyl or 2-butyroxyethyl, aryloxy or aryloxy groups

32. and hydroxy groups having an aryl group containing from 6 to 14 carbon atoms, such as phenyl, naphthyl or fluorenyl, preferably in aryloxy- (lower alkyl) or aryloxyhydroxy- (lower alkyl) group such as phenoxymethyl, 2-phenoxyethyl, 1- or 2-naphthyloxymethyl or 1- or 2-naphthyloxyethyl or 2-phenyl-2-hydroxyethyl, wherein the aryl is unsubstituted or substituted once or twice with, for example, a lower alkyl group, for example methyl, ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl, hydroxy, lower alkoxy, for example methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy or tert-butoxy, carboxy, (lower alkoxy) -carbonyl, for example isopropoxycarbonyl, or tert-butoxycarbonyl, or carbamoyl, (lower alkyl) - or di- (lower alkyl) -carbamoyl and / or mono- or di- (hydroxy- or carboxy-) and the substituents may be in various ring positions, for example as 4-methylphenoxy, 2,4,5-trimethylphenoxy, 4-hydroxyphenoxy, 4-methoxyphenoxy, 3,5-dimethoxyphenoxy, 2-carboxyphenoxy, 2-carboxyphenoxy, 2-carboxyphenoxy, 2-carboxyphenoxy, -tert-butoxycarbonylphenoxy, 2- or 4-carbamoylphenoxy, carbamoyl, carboxy- (lower alkyl) -carbamoyl or hydroxy- (lower alkyl) -carbamoyl, such as in 4-carbamoyl-n-butyl, 7-carbamoyl-n- heptyl, 2-hydroxyethylcarbamoyl-n-butyl or 4- (tris (hydroxymethyl) methyl) carbamoyl-n-butyl, furthermore an amino group, for example in 2-aminoethyl or 3-aminopropyl, (lower alkyl) amino, for example methyl or ethylaminomethyl, di- (lower alkyl) -amino, e.g. in dimethylaminomethyl, halogen, especially fluorine, chlorine or bromine, e.g. in 2,2,2-trichloroethyl, sulfo, e.g. in sulfomethyl or 4-sulfobutylamino and sulfamoyl, e.g. 2-sulfa moylethylu.

Preferred acyl groups, _R2, R and _Q R _g nesubstituo33 tub or the substituted N-substituted oxalamide the oxamoyl, or (lower alkyl) -oxamoylová group such as methyl or ethyloxamoyl.

Preferred acyl groups, R ₂ , R _g and R g of the unsubstituted or substituted amino acid are composed of amino acid residues derived from the α- or β-amino acid, a particular natural α-amino acid with an L-configuration, as usually found in proteins or epimer of such amino acid, i.e., non-naturally occurring D-configuration compounds or their D, L-isomeric mixtures, homologues of such amino acids, for example wherein the amino acid side chain is extended or shortened by one or two methylene groups, wherein the amino group is in the β and / or position wherein the methyl group is replaced by a hydrogen atom, a substituted aromatic amino acid in which the aromatic radical contains 6 to 14 carbon atoms, e.g. methoxy, (lower alkanoyl) -oxy a group such as acetoxy, amino, (lower alkyl) -amino, such as methylamino, di- (lower alkyl) -amino, such as dimethylamino, (lower alkanoyl) -amino, such as acetylamino or pivaloylamino, (lower alkoxy) -carbonylamino butoxycarbonylamino, arylmethoxycarbonylamino, wherein the aryl moiety contains 6 to 14 carbon atoms, e.g. benzyloxycarbonylamino or 9-fluorenylmethoxycarbonylamino, halogen, e.g. benzanlated phenylalanine or phenylglycine, such as α-naphthylalanine, or hydrogenated phenylalanine or phenylglycine, such as cyclohexylalanine or cyclohexylglycine.

These amino acids may be substituted on the free functional amino or hydroxy group, preferably on the free functional amino group by one of the abovementioned acyl groups R1, such as the acyl group formed from the remainder of the aforementioned carboxylic acid, carbonic acid semi-ester, unsubstituted or N-substituted carbamic acids. or unsubstituted or N-substituted oxalamide or one of optionally substituted alkyl, aryl (lower alkyl), heterocyclyl, heterocyclyl (lower alkyl) groups, sulfo groups, alkyl, aryl, aryl (lower alkyl), heterocyclyl (lower alkyl) , .alkoxyskupinou, aryloxy, aryl- (lower alkoxy) or a heterocyclyl- (lower alkoxy) substituted sulfonyl group, a phosphoryl R p R _2, R g and R _g, which is substituted with one or two groups selected, independently selected from alkyl, cycloalkyl, cycloalkyl- (lower alkyl), aryl, aryl- (n hydroxy, alkoxy, cycloalkoxy, cycloalkyl- (lower alkoxy), aryloxy and aryl- (lower alkoxy) or sulfamoyl groups ^R 1, ^R 2, ^R 8, ^{or R} 9 'which is optionally substituted with a nitrogen atom or a residue appointed as protecting groups in the paragraph dealing with the method.

Particularly preferred is an amino acid residue selected from glycine (H-Gly-OH), alanine (H-Ala-OH), valine (H-Val-OH), norvaline (α-aminovaleric acid), leucine (H- Leu-OH), isoleucine (H-Ile-OH), norleucine (α-aminohexanoic acid, H-Nle-OH), serine (H-Ser-OH), homoserine (α-amino-T-hydroxybutyric acid), threonine (H-Thr-OH), methionine (H-Met-OH), cysteine (H-Cys-OH), proline (H-Pro-OH), trans-3- and trans-4-hydroxyproline, phenylalanine (H- Phe-OH), tyrosine (H-Tyr-OH), 4-aminophenylalanine, 4-chlorophenylalanine, 4-carboxyphenylalanine, β-phenylserine

- 35 (β-hydroxyphenylalanine), phenylglycine, α-naphthylalanine (H-Nal-OH), cyclohexylalanine (H-Cha-OH), cyclohexylglycine, tryptophan (H-Trp-OH), indoline-2-carboxylic acid, acid 1 , 2,3,4-tetrahydroisoquinoline-3-carboxylic acid, aspartic acid (H-Asp-OH), asparagine (H-Asn-OH), aminomalonic acid, aminomalonic acid monoamide, glutamic acid (H-Glu-OH), glutamine (H-Gln-OH), histidine (H-His-OH), arginine (H-Arg-OH), lysine (H-Lys-OH), δ-hydroxylisin, ornithine (α, δ-diaminovaleric acid), 3-aminopropanoic acid, α, τ-diaminobutyric acid and α, β-diaminopropionic acid, a particularly preferred aliphatic amino acid residue selected from valine, alanine, leucine and isoleucine or an amino acid selected from glycine, glutamic acid and asparagine, wherein (except glycine) each of said amino acids being in the form of D, L or (D, L), preferably (except Val, which may also be in the form of D or (D, L)) may be in the form of L, an α-amino group which. is unsubstituted or is N-alkylated once or twice, for example by a lower alkyl group such as methyl or n-propyl, by an amino- (lower alkyl) group such as 3-aminopropyl, phenyl- or naphthylamino- (lower alkyl) group such as 3- phenylaminopropyl, or a lower alkyl group such as methyl, substituted on the nitrogen atom with a piperazinylcarbonyl- (lower alkyl) group, such as 4-methylpiperazinylcarbonylmethyl, or N-acylated, for example a lower alkanoyl group such as acetyl, aryl- (lower alkanoyl) group, wherein the aryl moiety is selected from phenyl, indenyl, indanyl, naphthyl, anthryl, phenanthryl, acenaphthyl and fluorenyl and may be unsubstituted or in particular may be substituted one to three times, in particular by a lower alkyl group such as methyl, ethyl or propyl, halogen- (lower alkyl) with a group such as tri, f, fluoromethyl, phenyl, 1- or 2-naphthyl, hydroxy, lower alkoxy yskupinou ,. for example, methoxy, carbamoyl- (lower alkoxy), N- (lower alkyl) -carbamoyl- (lower alkoxy) or N, N-di- (lower alkyl) -carbamoyl- (lower alkoxy), amino, mono- or di - (lower alkyl) amino, (lower alkanoyl) amino, for example pivaloylamino, halogen, for example fluorine, chlorine or bromine, carboxy, (lower alkoxy) -carbonyl, such as tert-butoxycarbonyl, phenyl, -, naphthyl or a fluorenyl- (lower alkoxy) -carbonyl group, such as benzyloxycarbonyl, lower alkanoyl, sulfo. (lower alkyl) -sulfonyl, for example methylsulfonyl, phosphono, hydroxy- (lower alkoxy) -phosphoryl or di- (lower alkoxy) -phosphoryl, carbamoyl, mono- or di- (lower alkyl) -carbamoyl, sulfamoyl, mono or di- (lower alkyl) aminosulfonyl, nitro and / or cyano, wherein the phenyl may be present or present one to three times, for example in a diphenyl-, dibenzyl- or triphenyl- (lower alkanoyl) group such as diphenyl-, dibenzyl or triphenylacetyl and the lower alkanoyl moiety is not substituted or is substituted, for example, by a lower alkyl group such as methyl, a heterocyclyl group selected from pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolinyl, indolyl, indolyl, indolyl, indolyl, indolyl, quinolinyl , quinoxalinyl, β-carbolinyl and benzanellated, cyclopentaanellated, cyclohexaanellated or cycloheptanellated derivative of this hints, which may also be partially or fully saturated, by hydroxy, lower alkoxy, (lower alkanoyl) -oxy, e.g. -amino- or 2-benzyloxycarbonylamino-2-methylpropionyloxy, aryl- (lower alkanoyl) -oxy, wherein the aryl moiety contains 6 to 10 carbon atoms, such as in benzoyloxy, phenylacetoxy, 1- or 2-naphthoyloxy, - (lower alkoxy) - (lower alkoxy) - (lower alkoxy) - (lower alkoxy) carbonyloxy, for example methoxy-ethoxy-, ethoxy-, η-propoxy-, isopropoxy-, η-butoxy-, isobutoxy-, sec-butoxy-, tert-butoxy-, n-pentyloxy-, isopentyloxy-, neopentyloxy- , t-pentyloxy-, η-hexyloxy-, isohexyloxy- or n-heptyloxycarbonyloxy, mono- or di- (lower alkyl) aminocarbonyloxy, for example ethylaminocarbonyloxy or diethylam inocarbonyloxy, aryloxycarbonylpxyl, wherein the aryl moiety contains 6 to 10 carbon atoms, for example phenoxycarbonyloxy or 1 or 2-naphthyloxycarbonyloxy, aryl- (lower alkoxy) -carbonyloxy having 6 to 14 -alkyloxy, for example benzyloxycarbonyloxy, 1- or 2-naphthylmethoxycarbonyloxy or 9-fluorenylmethoxycarbonyloxy, sulfonyloxy, (lower alkyl) -sulfonyloxy, for example methyl, ethyl, propyl, isopropyl, sec-butyl, isobutyl -butyl, tert-butyl, n-pentyl-, isopentyl-, neopentyl-, tert-pentyl-, η-hexyl-, isohexyl- or n-heptylsulfonyloxy, or phenylsulfonyloxy, 2- or 4-toluenesulfonyloxy . or 1 or 2-naphthylsulfonyloxy, carboxy, esterified carboxy selected from (lower alkoxy) -carbonyl, for example methoxy-, ethoxy-, η-propoxy-, isopropoxy-, η-butoxy-, isobutoxy-, sec-butoxy-, tert- -butoxy-, η-pentyloxy-, isopentyloxy-, neopentyloxy-, t-pentyloxy-, η-hexyloxy-, isohexyloxy or n-heptyloxycarbonyl, aryloxycarbonyl groups, wherein the aryl moiety contains 6 to 10 carbon atoms, for example phenyloxycarbonyl or 1- or 2-naphthyloxycarbonyl, aryl- (lower alkoxy) -carbonyl groups wherein the aryl moiety contains 6 to 12 carbon atoms, for example benzyloxycarbonyl, 1- or 2-naphthylmethoxycarbonyl or 9-fluorenylmethoxycarbonyl, lower alkanoyl groups, (lower alkyl) -sulfonyl groups , for example, methyl or tert-butylsulfonyl, hydroxy- (lower alkoxy) -phosphoryl or di- (lower alkoxy) -phosphoryl, carbamoyl, once or twice from a lower alkyl group,

such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl or n-heptyl, e.g. N-methylcarbamoyl, Nn-butylcarbamoyl or Ν, Ν-dimethylcarbamoyl, from a carboxy- (lower alkyl) or (lower alkoxy) -carbonyl- (lower alkyl) group, for example as carboxymethylcarbamoyl (glycinylcarbonyl) or as tert-butoxycarbonylmethylcarbamoyl, z - (lower alkyl) -amino- (lower alkyl) groups, for example 2-dimethylaminoethyl, aminocarboxy- (lower alkyl) groups, for example 5-amino-5-carboxypentyl, from a hydroxy- (lower alkyl) group, for example hydroxymethyl or hydroxyethyl and di- (lower alkoxy) - (lower alkyl) groups, for example, a 2- (2,2-dimethoxyethyl) moiety selected from or selected from ethylene, trimethylene, tetramethylene and pentamethylene moieties, wherein the carbon atom may be replaced by nitrogen, oxygen, sulfur and one oxygen atom u or double substituted sulfur and such residues may be unsaturated such as piperidino-, pyrazin-1-yl-, piperazin-1-yl-, pyrimidin-1-yl-, pyridazin-T-yl-, morpholino-, thicomorpholinone or with S, S-dioxothiomorpholinokaibnyl substituted by carbamoyl, sulfamoyl, phosphono, benzofuranyl, oxo and / or cyano and is unbranched or branched, preferably an aryl- (lower alkanoyl) group, wherein the aryl moiety contains from 6 to 14 carbon atoms or substituted, for example, by a lower alkanyl group, such as in 2-benzyl-3-pivaloylpropionyl, or a (lower alkyl) -sulfonyl group, such as in 2-benzyl-3-tert-butylsulfonylpropionyl, wherein the phenyl- (lower alkanoyl) group, for example phenylacetyl is a particularly preferred heterocyclyl- (lower alkanoyl) group

selected from thienyl-, furyl-, pyranyl-, pyrrolyl-, imidazolyl-, pyrazolyl-, oxazolyl-, isoxazolyl-, thiazolyl-, furazanyl-, tetrazolyl-, pyridyl-, pyrazinyl-, pyrimidinyl-, pyridazinyl- ,. azepinyl-1-, indolyl-, benzimidazolyl-, 1H-indazolyl-, quinolyl-, isoquinolyl-, quinoxalinyl-, quinazolinyl-, quinolinyl-, purinyl-, pteridinyl-, naphthydrinyl-, 4H-quinolizinyl-, 3,1- benzofuranyl-, benz [e] indolyl-, 4,1-benzoxazinyl-, 4,1-benzthiazinyl-, carbazolyl-, β-carbolinyl-, phenazinyl-, phenanthridyl-, acridyl-, phenoxazinyl-, phenothiazinyl-, 1 -azaacenaphthenyl-, cyclohexa [b] pyrrolyl-, cyclohepta (b) pyrrolyl-, cyclohexa [d] pyrazolyl-, cyclohexa [b] pyridyl-, cyclohexa (b) pyrazinyl-, cyclohexa (b) pyrimidinyl-, cyclohexa [b] -1,4-oxazinyl-, cyclohexa [b] -1,4-thiazinyl-, pyrrolidinyl-, pyrrolinyl-, imidazolidinyl-, 2-imidazolinyl-, 2,3-dihydropyridyl-, piperidyl-, piperazinyl-, 2,3 5,6-tetrahydropyrazinyl-, morpholinyl-, thiomorpholinyl-, S, S-dioxothiomorpholinyl-, indolinyl-, isoindolinyl-, 4,5,6,7-tetrahydroindolyl-, 1,2,3,4-tetrahydroquinolyl- 2,3,4-tetrahydroisoquinolyl-, chromanyl-, thiochromanyl-, 1,2,3,4-tetrahydro-3,1-benzdiazinyl-,

3,4-dihydro-3H-4,1-benzoxazinyl-, 3,4-dihydro-3H-4,1-benzthiazinyl-, 2,3,4,5-tetrahydro-1H-5,1-benzazepinyl- 6-dihydrophenanthridinyl- (lower alkanoyl) groups wherein said heterocyclyl radicals are not substituted or substituted by a lower alkyl group such as methyl, phenyl, 1- or 2-naphthyl, a phenyl- (lower alkyl) group such as benzyl, hydroxy- lower alkyl), such as hydroxymethyl or 2-hydroxyethyl, (lower alkoxy) (lower alkyl), such as methoxymethyl or 2-methoxyethyl, phenoxy or naphthyloxy (lower alkyl), such as 2-phenoxyethyl, 1- or 2 naphthyloxymethyl, phenyl- (lower alkoxy) - or naphthyl- (lower alkoxy) (lower alkyl), for example benzyloxy- (lower alkyl), (lower alkanoyl) -oxy- (lower alkyl), for example acetoxymethyl, phenyl- or a naphthyl- (lower alkanoyl) -oxy- (lower alkyl) group, e.g. for example benzoyloxy-, phenylacetoxy- or 1- or 2-naphthoyloxymethyl, -2-ethyl or -2- (2,2-dimethylethyl), (lower alkoxy) -carbonyloxy- (lower alkyl), for example tert-butoxycarbonyloxy- ( lower. alkyl, phenyl, naphthyl or fluorenyl (lower alkoxy) -carbonyloxy- (lower alkyl) group such as 2-benzyloxycarbonyloxyethyl or 9-fluorenylmethoxycarbonyloxyethyl, amino- (lower alkyl) group such as aminomethyl, 2-aminoethyl or 2-aminopropyl ,. carboxy (lower alkyl), such as carboxymethyl or 2-carboxyethyl, hydroxy, lower alkoxy, such as methoxy or ethoxy, phenyl or naphthyl (lower alkoxy) / such as benzyloxy or 1- or 2-naphthyloxy, amino, (lower) alkyl) amino, for example methyl, ethyl or tert-butylamino, di- (lower alkyl) amino, for example dimethyl or diethylamino, carboxy, (lower alkoxy) -carbonyl, for example methoxy, isopropoxy, sec -butoxy- or tert-butoxycarbonyl, phenyl- or naphthyl- (lower alkoxy) -carbonyl, for example benzyloxycarbonyl, halogen, for example fluorine, chlorine, bromine or iodine, especially chlorine or bromine, for example lower alkanoyl, for example acetyl or pivaloyl, (lower alkyl) -sulfonyl, for example, methyl- or ethylsulfonyl, phosphono, hydroxy- (lower alkoxy) ) -phosphoryl or di- (lower alkoxy) phosphoryl, for example dimethoxy- or diethoxyphosphoryl, carbamoyl, mono- or di- (lower alkyl) -carbamoyl, for example N-methylcarbamoyl, Nn-butylcarbamoyl or N, N-dimethylcarbamoyl , hydroxy- or carboxy- (lower alkyl) -carbamoyl, for example hydroxy or carboxymethylcarbamoyl or sulfamoyl, nitro, oxo and / or cyano, such as pyridylcarbonyl, such as 2-, 3- or 4-pyridylcarbonyl, 3,4-dihydropyrrolidinylcarbonyl, N-benzyloxycarbonylpiperidin-4-ylcarbonyl, 1-methylpiperazin-4-ylcarbonyl, morpholinocarbonyl;

thiomorpholinocarbonyl, S, S-dioxothiomorpholinocarbonyl, indol-2-ylcarbonyl, quinol-2-ylcarboriyl, pyridylacetyl such as 2- or 3-pyridylacetyl, imidazolylacetyl, such as imidazol-1-ylacetyl, morpholinylacetyl, such as 3-morpholinoacetyl, pyridylpropionyl, pyridylpropionyl (2- or 3-pyridyl) propionyl, pyrrolidinylpropionyl, such as 3- (4-pyrrolidinyl) propionyl, morpholinylpropionyl, such as 3-morpholinylpropionyl, or tetrazolylpropionyl, such as 3- (tetrazol-1-yl) propionyl, heterocyclyl- (lower alkenyol) ) a group wherein the heterocyclyl moiety is particularly selected from pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl, β-carbolinyl, cyclopentanellate, benzoanellate, benzoanellate, or of this series, which may also be partially or fully saturated, for example pyrrolidyl-lower alkenoyl), such as N-pyrrolidyl acryloyl, halogen- (lower) an alkanoyl group containing up to 3 carbon atoms, for example by α-haloacetyl, such as α-fluoro, α-chloro, α-bromo, α-iodo, α, α, α-trifluoro- or α, and , α-trichloroacetyl, or halopropionyl, such as β-chloro- or β-bromopropionyl, (lower alkoxy) -carbonyl, such as tert-butoxycarbonyl, aryl- (lower alkoxy) -carbonyl, wherein the aryl moiety contains 6 to Is selected from phenyl, naphthyl or fluorenyl, for example phenyl- (lower alkoxy) carbonyl, such as benzyloxycarbonyl or 9-fluorenylmethoxycarbonyl, heterocyclyl- (lower alkoxy) carbonyl, wherein the heterocyclyl moiety is particularly selected from pyrrole. , furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl, β-carbolinyl and benzanellated, cyclopentaanellated, cyclohexaanellated, or cyclohexaanellate or cyxocyanellate those radicals which may also be partially or fully saturated and optionally substituted in particular by a lower alkyl group such as methyl, such as 1-methylpyrrolidin-2-ylmethoxycarbonyl, 2-furylmethoxycarbonyl, tetrahydrofuryl- (lower alkoxy) -carbonyl group such as 2 -tetrahydrofuranylmethoxycarbonyl, 1-methyl-2-piperidylmethoxycarbonyl or 2-morpholinoethoxycarbonyl, carboxy- (lower alkanoyl), such as 3-carboxypropionyl, 5-carboxypentanoyl or 6-carboxyhexanoyl, (lower alkoxy) (lower alkoxy) like

5-methoxycarbonylpentanoyl or 6-methoxycarbonylhexanoyl, hydroxy- (lower alkoxy) - (lower alkanoyl), such as 3-hydroxy-n-propoxycarbonyl, amino- (lower alkanoyl), wherein the amine moiety is not in the a position or at the lower alkanoyl position a radical such as 5-aminopentanoyl, phenyl- (lower alkoxy) -carbonylamino- (lower alkanoyl) wherein the amine moiety is not in the α or 0 position of the lower alkanoyl radical, such as 5-benzyloxycarbonylaminopentanoyl or 6-benzyloxycarbonylaminohexanoyl nitrogen, at - (lower alkanoyl) skuq Pina, p, preferably as the above-mentioned heterocyclyl (lower alkanoyl) group as defined for R _{2 l of} R, R and R, in particular N-morpholino or N-substituted amino thiomorfolinokarbonylem (lower alkanoyl) group, for example an N-morpholino- or N-thiomorpholinocarbonylamino- (lower alkanoyl) group such as N-morpholino- or N-thiomorpholinocarbonylaminoacetyl; carbamoyl, phenyl- (lower alkyl) aminocarbonyl, such as benzylaminocarbonyl, N-di- (lower alkyl) amino- (lower alkyl) -N- (lower alkyl) aminocarbonyl, such as N- (2-dimethylamino) ) ethyl-N-methylaminocarbonyl, N-dihydroxy- (lower alkyl) -N- (lower alkyl) aminocarbonyl, such as N- (2,3-dihydroxy-n-propyl) -N-methylaminocarbonyl, N-heterocyclyl- ( lower alkyl) -N- (lower alkyl) carbamoyl, wherein the heterocyclyl moiety is selected from thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, furazanyl, pyridyl ,. pyrazinyl, pyrimidinyl, pyridazinyl, azepinyl, indolyl, benzimidazolyl, ind-indazolyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, cinnolyl, purinyl, pteridinyl, naphthyridinyl, 4H-benzinofuran, 3,1-benzinofuran, 3,1-benzinofuran, 3,1-benzoisofuran, 3,1-benzinofuran; indolyl, 4,1-benzoxazinyl, 4,1-benzthiazinyl, carbazolyl, β-carbolinyl, phenazinyl, phenanthridyl, acridyl, phenoxazinyl, phenothiazinyl, 1-azaacenaphthenyl, cyclohexa [b] pyrrolyl, cyclohepta [b] pyrrolyl, cyclohexyl [b] pyrrolyl, pyrazole [b] pyrrolyl, cyclohexa [b] pyridyl, cyclohexa [b] pyrazinyl, cyclohexa [b] pyrimidinyl, cyclohexa [b] -1,4-oxazinyl, cyclohexa [b] -1,4-thiazinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, 2-imidazolinyl, 2,3-dihydropyridyl, piperidyl, piperazinyl,

2,3,5,6-tetrahydropyrazinyl, morpholinyl, thiomorpholinyl,

S, S-dioxothiomorpholinyl, indolinyl, isoindolinyl, 4,5,6,7-tetrahydroindroyl, 1,2,3,4-tetrahydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl, chromanyl, thiochromanyl, 1,2,3, 4-tetrahydro-3,1-benzdiazinyl, 3,4-dihydro-3H-4,1-benzoxazinyl, 3,4-dihydro-3H-4,1-benzthiazinyl-2,3,4,5-tetrahydro-1H-5, 1-benzazepinyl and 5,6-dihydrophenanthridinyl, said radicals being optionally substituted by a lower alkyl group such as methyl, phenyl, 1- or 2-naphthyl, a phenyl- (lower alkyl) group such as benzyl, hydroxy- (lower alkyl) group , for example, hydroxymethyl or 2-hydroxyethyl, (lower alkoxy) - (lower alkyl), for example methoxymethyl or 2-methoxyethyl, phenoxy or naphthyloxy (lower alkyl), for example 2-phenoxyethyl, 1- or 2-naphthyloxymethyl, phenyl - (lower alkoxy) - or naphthyl- (lower alkoxy) - (lower alkyl), for example benzyloxy- (lower alkyl), (lower alkanoyl) -oxy- ( lower alkyl), for example acetoxymethyl, phenyl or naphthyl- (lower alkanoyl) -oxy- (lower alkyl), for example benzyloxy-, phenylacetoxy- or

1- or 2-naphthoyloxymethyl, -2-ethyl or -2- (2,2-dimethylethyl), (lower alkoxy) -carbonyloxy- (lower alkyl), for example tert-butoxycarbonyloxy- (lower alkyl), phenyl- , naphthyl or fluorenyl- (lower alkoxy) -carbonyloxy- (lower alkyl) group, for example 2-benzyloxycarbonyloxyethyl or 9-fluorenylmethoxycarbonyloxyethyl, amino- (lower alkyl) group, for example aminomethyl,

44. -

2-aminoethyl or 2-aminopropyl, carboxy (lower alkyl) - for example, carboxymethyl or 2-carboxyethyl, hydroxy, lower alkoxy, for example methoxy or ethoxy, phenyl or naphthyl (lower alkoxy), for example benzyloxy or 1- or 2-naphthylmethoxy, amino, (lower alkyl) amino, for example methyl, ethyl or tert-butylamino, di- (lower alkyl) amino, for example dimethyl or diethylamino, carboxy, (lower alkoxy) -carbonyl such as methoxy, isopropoxy, sec-butoxy- or tert-butoxycarbonyl, phenyl or naphthyl- (lower alkoxy) -carbonyl, e.g. benzyloxycarbonyl, halogen, e.g. fluorine, chlorine, bromine or iodine, especially chlorine or bromine, lower alkanoyl, for example acetyl or pivaloyl, (lower alkyl) -sulfonyl, for example methyl or ethylsulfonyl, fo a phenoxy group, a hydroxy- (lower alkoxy) -phosphoryl or di- (lower alkoxy) -phosphoryl group, for example dimethoxy- or diethoxyphosphoryl, carbamoyl, mono- or di- (lower alkyl) -carbamoyl group, for example N-methylcarbamoyl, Nn-butylcarbamoyl or N, N-dimethylcarbamoyl, hydroxy- or carboxy- (lower alkyl) -carbamoyl, for example hydroxy- or carboxymethylcarbamoyl or hydroxy- or carboxyethylcarbamoyl, sulfamoyl, or nitro, oxo and / or cyano, such as a particular pyridyl, such as 2- 3- or 4-pyridyl, for example 2- or 3-pyridyl- (lower alkyl) aminocarbonyl, such as 2 or 3-pyridylmethylaminocarbonyl, N-2-, N-3- or Ν-4-pyridyl- (lower alkyl) -N- (lower alkyl) aminocarbonyl, such as N-2-, N-3- or N-4-pyridylmethyl-N-methylaminocarbonyl,

N-heterocyclyl- (lower alkyl) carbamoyl (lower alkanoyl) group "such as heterocyclyl- (lower alkyl) carbamoyl (lower alkanoyl) group as defined for Rl, _R2, R 45 will not R _g, for example a 2- (N-morpholino- (lower alkyl) -carbamoyl) - (lower alkanoyl) group such as 2 (R, S) - [N- (2-morpholinoethyl) carbamoyl] -3-methylbutyryl, or 2- [N- (pyridyl- (lower alkyl)] - carbamoyl] - (lower alkanoyl) group such as [2 (R, S) - [N- (2-pyridylmethyl) carbamoyl] -3-methyl] butyryl, sulfonyl , (lower alkyl) -sulfonyl, such as methyl or ethylsulfonyl, an arylsulfonyl group, wherein the aryl moiety contains from 6 to 10 carbon atoms and is, for example, selected from phenyl or naphthyl and is optionally substituted with a particularly lower alkyl group such as methyl or lower alkoxy , such as methoxy, such as. is p-toluenesulfonyl, heterocyclylsulfonyl, wherein the heterocyclyl moiety. is preferably selected from pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl, β-carbolinyl, β-carbolinyl, cyclopentaanellate, cyclopentaanellate 'can also be partial'or; is optionally saturated, from morpholinyl and thiomorpholinyl, and is optionally substituted, in particular, by a lower alkyl group such as methyl, such as morpholinosulfonyl, thiomorpholinosulfonyl, piperidinosulfonyl, 4-methylpiperazinylsulfonyl or piperazinosulfonyl (with heterocyclylsulfonyl as the substituent in preferred); a (lower alkyl) group, wherein the heterocyclyl moiety is as defined above, and / or a sulfamoyl substituted lower alkyl group, such as N-2-pyridylmethyl-N-methylaminosulfonyl, a side chain carboxy group in an esterified or amidated form, for example as ( lower alkyl) -ester group such as methoxycarbonyl or tert-butoxycarbonyl, as aryl ester or as aryl- (lower alkyl) -este-

an aryl group. means a phenyl, 4-nitrophenyl, naphthyl or biphenylyl group, for example, such as 4-nitrophenoxycarbonyl, benzyloxycarbonyl or 9-fluorenyloxycarbonyl, or as carbamoyl, such as (lower alkyl) -carbamoyl, such as methylcarbamoyl, di- (lower alkyl) -carbamoyl a group such as dimethylcarbamoyl, such as mono- or di- (hydroxy) (lower alkyl) carbamoyl, such as hydroxymethylcarbamoyl or di- (hydroxymethyl) carbamoyl, or as mono- or di- (carboxy- lower alkyl)] -carbamoyl, such as carboxymethylcarbamoyl or di- (carboxymethyl) carbamoyl, amino. side. in a alkylated form, for example, as a mono- or di- (lower alkyl) amino, such as n-butylamino or dimethylamino, or in an acylated form, for example, as (lower alkanoyl) amino, such as acetylamino or pivaloylamino, such as an amino- (lower alkanoyl) amino group such as 3-amino-3,3-dimethylpropionylamino such as an aryl- (lower alkanoyl) amino group wherein the aryl moiety contains 6 to 14 carbon atoms, such as phenyl, naphthyl or fluorenyl and is optionally substituted by lower alkyl, hydroxy, lower alkoxy, carboxy, carbamoyl or sulfamoyl, such as 4-hydroxyphenylbutyryl, such as (lower alkoxy) -carbonylamino, such as tert-butoxycarbonylamino, such as arylmethoxycarbonylamino, 14 carbon atoms, such as benzyloxycarbonylamino or 9-fluorenylmethoxycarbonylamino, such as piperidyl-1-carbonyl, morpholine ocarbonyl, thiomorpholinocarbonyl or as S, diox-dioxothiomorpholinocarbonyl and / or g

1 - In - '

.. ίί ~ · rú-

'; ύί ^: /' ľν č ' ^-

a hydroxy group of the side chain in an etherized or esterified form, for example, as a lower alkoxy group, such as a methoxy or tert-butoxy group, such as an aryl- (lower alkoxy) group, such as a benzyloxy group, such as

noyl) -oxy, such as acetoxy, or as (lower alkoxy) -carbonyloxy, for example tert-butoxycarbonyl-oxy.

Acyl groups R 1, R ₂ , R 8 and R _{9 of} optionally substituted amino acids are particularly preferred when selected from the group consisting of phenylalanine ^; N- (benzyloxycarbonyl) phenylalanine, N- / 2 (R, S) -benzyl-3-pivaloylpropionyl / phenylalanine, N- (9-fluorenylmethoxycarbonyl) phenylalanine, tyrosine, N-propyltyrosine, O-methyl ether of tyrosine, O-methyl ether of N- (3-amino-3,3-dimethylpropionyl) tyrosine, N- (2 (S) -benzyl-3-tert-butylsulfonylpropionyl) tyrosine O-tert-butyl ether, N- (9-fluorenylmethoxycarbonyl) tyrosine O-methyl ether, N- (9-fluorenylmethoxycarbonyl) tyrosine O-tert-butyl ether, N-morpholinocarbonylglycine, N- / N- (2-, 3- or 4-pyridyl) methyl-N-methylaminocarbonyl / glycine, valine ,. N- (3-phenylaminopropyl) valine, N- (4-methylpiperazinylcarbonylmethyl) valine, N- (trifluoroacetyl) valine, N-phenylacetylvaline, N-acetylvaline, N- (3-phenylpropionyl) valine, N- / 2 (R, S) ) - or -2 (S) -benzyl-3-pivaloylpropionyl / valiri, N- (2-carbamyl-3-phenylpropionyl) valine, N- / 2 (S) -benzyl-3-tert-butylsulfonylpropionyl / valine, N - / 2 (R, S) -carbamoyl-3-phenylpropionyl / valine, N- (2-, 3- or 4-pyridylcarbonyl) valine, N- (1-imidazolylacetyl) valine, N- (2- or 3-pyridylacetyl) ) valine, N- (morpholinoacetyl) valine, N- [3- (2- or 3-pyridyl) propionyl] valine, N- [3- (4-pyrrolidinyl) propionyl] valine, N- [3- (morpholino) propionyl] / valine, N- (N-benzyloxycarbonylpiperidin-4-ylcarbonyl) valine, N-tetrahydrofurylmethoxycarbonylvaline, N-3- (tetrazol-1-yl) propionyl valine, N- (indol-2-ylcarbonyl) valine, N- (quinolin-2) -carbonyl) valine, N- (1-methylpiperazin-4-ylcarbonyl) valine, N- (3,4-dihydroxypyrrolidinylcarbonyl) valine, N-methoxycarbonylvaline, N-isobutoxycarbonylvaline, N-tert-butoxycarbonylvaline, N-benzyloxycarbonylvaline, (2-furylmethoxykarbo nyl) valine, N- (1-methylpyrrolidin-2-ylmethoxycarbonyl) valine, N- (1-methyl-2-piperidylmethoxycarbonyl) valine, N- (1-methyl-3-piperidylmethoxycarbonyl) valine, N

- 2- (morpholino) ethoxycarbonyl / valine, N- (3-carboxypropionyl) valine, N- (5-carboxypentanoyl) valine, N- (6-carboxyhexanoyl) valine ,. N- (5-methoxycarbonylpentanoyl) valine, N- (6-methoxycarbonylhexanoyl) valine, N- (3-aminopropionyl) valine, N- (4-aminobutyryl) valine, N- (5-benzyloxycarbonylamino-pentanoyl) valine, N- (6 - benzyloxycarbonylaminohexanoyl) valine, N- (morpholinocarbonyl) valine, N- (thiomorpholinocarbonyl) valine, N- (S / S-dioxothiomorpholinocarbonyl) valine, N- (N-benzylaminocarbonyl) valine, N- (N-2-pyridylmethyl-N-methylaminocarbonyl) ) valine, N- (N-3-pyridylmethylaminocarbonyl) valine, N- (Ν-2-pyridylmethylaminocarbonyl) valine, N-morpholinocarbonylaminoacetylvaline, N- (2-pyrrolidylacryloyl) valine, N-methylsulfonylvaline, N-morpholinosulfonylvaline, N- (p) -toluenesulfonyl) valine, N- (4-methylpiperazinylsulfonyl) valine, N- / N- (2-pyridylmethyl) -N-methylsulfamoyl / valine, N- (Ν-2-pyridylmethyl-N-methylaminocarbonyl) valine, N- (3 N-acetylleucine, N- (3-aminopropyl) leucine, N- / 2 (R, S) - or -2 (S) -benzyl-3-pivaloylpropionyl / leucine, N- / 2 (S) -benzyl-3-tert-butylsulfonylpropionyl / leucine, N- (2-,

3- or 4-pyridylcarbonyl) leucine, N- (4-thiomorpholinocarbonyl) leucine, N- / 4- (S, S-dioxothiomorpholino) carbonyl / leucine, N- (4-aminobutyryl) leucine, N- (3-hydroxy- n-propoxycarbonyl) leucine, N- (benzyloxycarbonyl) leucine, N- [N- [2- (dimethylamino) ethyl] -N-methylaminocarbonyl] leucine, N- / N- (2,3-dihydroxy-n-propyl) - N-methylaminocarbonyl / leucine, N-acetylisoleucine, N-propionylisoleucine, N- (benzyloxycarbonyl) isoleucine, N- / 2 (R,

S) -benzyl-3-pivaloylpropionyl / norleucine, N- / 2 (S) -benzyl-3- tert -butylsulfonylpropionyl / norleucine, N- (tert-butoxycarbonyl) norleucine, N- (tert-butoxycarbonyl) serine, N- (benzyloxycarbonyl) serine, N-acetylserine O-methyl ether, N- (benzyloxycarbonyl) serine O-methyl ether, N- / 2 (R, S) -benzyl-3-pivaloylpropionyl] serine, N-benzyloxycarbonylglutamic acid, asparagine, N-benzyloxycarbonylasparagine, quinoline-2-carbonylasparagine and N- (morpholinocarbonyl) asparagine, the amino acid residues preferably being in the form of L or (D, L), and in the case of vanillin also in the form of D.

An optionally substituted alkyl group R 1, R ₂ , R g or R g comprises an alkyl radical having 1 to 20 carbon atoms, preferably up to 10 carbon atoms, which is branched or unbranched and may contain a heteroatom selected from an atom in place of the methylene group. sulfur, nitrogen or selenium (such as thia, aza and selenium); and. for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl, n- heptyl, n-octyl, n-nonyl or n-decyl. Preferably, the lower alkyl group is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl or n-heptyl, which are optionally substituted.

Suitable substituents in the substituted alkyl group, preferably substituted lower alkyl groups, are those mentioned for the lower alkanoyl group R @ 1, R @ ₂ , R @ 8.

The substituted lower alkyl group is preferably a cycloalkyl- (lower alkyl) group wherein the cycloalkyl moiety contains 3 to 7 carbon atoms and the lower alkyl moiety is as defined above, for example cycloalkylmethyl or ethyl, preferably having a total of 4 to 13 carbon atoms, such as is a cyclopropyl-, cyclobutyl-, cyclopentyl- or cyclohexyl- (lower alkyl) group, such as - methyl or -ethyl, a cycloalkenyl- (lower alkyl) group, for example a cycloalkenylmethyl group, in which the cycloalkenyl moiety preferably contains 4 to 8 carbon atoms, such as 1-cyclohexenylmethyl, 1,4-cyclohexadienylmethyl, 1-cyclohexenylethyl or 1,4-cyclohexadienylethyl, a bicycloalkyl- (lower alkyl) group in which the bicycloalkyl moiety contains, for example, 5 to 10 carbon atoms, for example bicycloalkylmethyl or -ethyl; preferably having 8 to 11 carbon atoms, such as decahydronaphthyl-2-methyl, endo- or exo-norbornyl-2-methyl, bicyclof2,2,2] oct-2-ylmeth hyl or bicyclo 3.3.1] non-9-ylmethyl, further bicyclohexyl, _•: -heptyl, -oktyl-, -nonyl- or -decylethyl or 3-propyl, and as regards the bicyklof3,1,0 ] hex-1-, -2- or -3-yl-, bicyclo [4.1.0] hept-1- or -7-yl-, bicyclo [2.2.1] hept-2-yl-, e.g. endo- or exo-norbornyl-, bicyclof3,2,1] oct-2-yl-, bicyclof3,3,0] oct-3-yl- or bicyclof3,3,1] non-9-yl-, or else β-decahydronaphthylethyl or -3-propyl, o

a tricycloalkyl- (lower alkyl) group in which the tricycloalkyl moiety contains, for example, 8 to 10 carbon atoms, for example tricycloalkylmethyl or -ethyl, preferably 8 to 11 carbon atoms, such as 1- or 2-adamantylmethyl, further tricyclo [5,2,1,1] , ² ' ⁶ ] dec-8-yl- or adamantyl- such as 1-adamantylethyl, an aryl- (lower alkyl) group, where particular. the aryl moiety contains from 6 to 14 carbon atoms, such as in phenyl, indenyl, indanyl, naphthyl, anthryl, phenanthryl, acenaphthyl or fluorenyl, which is unsubstituted or can be substituted one or three times in particular by lower alkyl, for example methyl, ethyl or isopropyl , halogen- (lower alkyl), such as trifluoromethyl, phenyl, 1- or 2-naphthyl, hydroxy, lower alkoxy, for example methoxy, carbamoyl- (lower alkoxy), N- (lower alkyl) -carbamoyl- (lower alkoxy), or N, N-di- (lower alkyl) -carbamoyl- (lower alkoxy), amino, mono- or di- (lower alkyl) -amino, (lower alkanoyl) -amino, for example pivaloylamino, halogen, for example fluorine or chlo - 51 r, carboxy, (lower alkoxy) -carbonyl, benzyl, naphthyl or fluorenyl- (lower alkoxy) -carbonyl, lower alkanoyl, sulfo u, (lower alkyl) -sulfonyl, phosphono, hydroxy- (lower alkoxy) -phosphoryl or di- (lower alkoxy) -phosphoryl, carbamoyl, mono- or di- (lower alkyl) -carbamoyl, sulfamoyl, mono- or di- (lower alkyl) -sulfamoyl, nitro and / or * cyano, wherein the phenyl may be present up to three times, such as in the diphenyl-, dibenzyl- or triphenyl- (lower alkyl) group, for example in the diphenyl-, dibenzyl- or triphenyl-2-ethyl a

- wherein the lower alkyl moiety is optionally substituted, for example, by a lower alkyl group such as methyl, a heterocyclyl group selected from pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoxinolyl, quinolinyl, isoxinolinyl, quinolinyl, isoxinyl; -carbolinyl and benzanellated, cyclopentaanellated, cyclohexaanellated or cycloheptaanellated derivatives of this series, which may also be partially or fully saturated, by hydroxy, lower alkoxy, (lower alkanoyl) -oxy, for example acetoxy, propionyloxy, pentyloxy, acetyloxy, butyryloxy or a benzyloxycarbonylamino- (lower alkanoyl) oxy group such as

2-amino- or 2-benzyloxycarbonylamino-2-methylpropionyloxy, aryl- (lower alkanoyl) -oxy, wherein the aryl moiety contains 6 to 10 carbon atoms, such as in benzoyloxy, phenylacetoxy, 1- or 2-naphthoyloxy, (lower alkoxy) -carbonyloxy, for example methoxy-, ethoxy-, η-propoxy-, isopropoxy-, n-butoxy-, isobutoxy-, sec-butoxy-, tert-butoxy-, n-pentyloxy-, isopentyloxy-, neopentyloxy-, tert-butoxy- pentyloxy-, n-hexyloxy-, isohexyloxy or n-heptyloxycarbonyloxy, mono- or di- (lower)

.. '. · ·' - 51 -. - alkyl) aminocarbonyloxy, such as ethylaminocarbonyloxy or diethylaminocarbonyloxy, aryloxycarbonyloxy, wherein the aryl moiety contains from 6 to 10 carbon atoms, e.g. phenyl, (lower alkoxy) carbonyloxy, such as benzyloxycarbonyloxy, 1- or 2-naphthylmethoxycarbonyloxy or 9-fluorenylmethoxycarbonyloxy, sulfonyloxy, (lower alkyl) -sulfonyloxy, for example, methyl, n-butyl-, isobutyl-, sec-butyl-, tert-butyl-, η-pentyl-, isopentyl-, neopentyl-, tert-pentyl-, η-hexyl-, isohexyl- or n-heptylsulfonyloxy, or phenylsulfonyloxy, 2- or

4-toluenesulfonyloxy, 1- or 2-naphthylsulfonyloxy, amino, mono- or di- (lower alkyl) -amino, N- (lower alkoxy) -N- (lower alkyl) -amino, such as N-methoxy-N-methylamino, mono- or di (phenyl or naphthyl- (lower alkyl)) - amino, such as benzylamino, (lower alkanoyl) -amino, such as pivaloylamino, carboxy, esterified carboxy selected from (lower alkoxy) -carbonyl, for example methoxy, ethoxy -, η-propoxy-, isopropoxy-, η-butoxy-, isobutoxy-, sec-butoxy-, tert-butoxy-, n-pentyloxy-, isopentyloxy-, neopentyloxy-, t-pentyloxy-, η-hexyloxy- isohexyloxy or n-heptyloxycarbonyl, aryloxycarbonyl, wherein the aryl moiety contains 6 to 10 carbon atoms, for example phenyloxycarbonyl or 1- or 2-naphthyloxycarbonyl, aryl- (lower alkoxy) -carbonyl, wherein the aryl moiety contains 6 to 12 carbon atoms, for example benzyloxycarbonyl, 1- or

2-naphthylmethoxycarbonyl or 9-fluorenylmethoxycarbonyl, lower alkanoyl, such as pivaloyl or acetyl, (lower alkyl) -sulfonyl, for example tert-butylsulfonyl, hydroxy- (lower alkoxy) -phosphoryl and di- (lower alkoxy) -phosphoryl, carbamoyl, one or two times 53 times from a lower alkyl group such as methyl, ethyl, propyl. isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl or n-heptyl, such as in N-methylcarbamoyl, Nn-butylcarbamoyl or N, N-dimethylcarbamoylcarbamoyl, of a carboxy- (lower alkyl) or (lower alkoxy) -carbonyl- (lower alkyl) group, for example as carboxymethylcarbamoyl (glycinylcarbonyl) or as tert-butoxycarbonylmethylcarbamoyl, of di- (lower alkyl) - amino- (lower alkyl) groups, e.g. 2-dimethylaminoethyl, aminocarboxy- (lower alkyl) groups, e.g. 5-amino-5-carboxypentyl, hydroxy- (lower alkyl) groups, e.g. hydroxymethyl or hydroxyethyl, and di- (lower alkoxy) - (lower alkyl) groups, for example 2- (2,2-dimethoxyethyl) - selected radicals or from ethylene, trimethylene, tetramethylene and pentamethylene selected radicals, wherein the carbon atom may be replaced by a nitrogen, oxygen, sulfur or oxygen atom once or double subs by a substituted sulfur atom and such groups may be unsaturated, for example as piperidin-, pyrazin-1-yl-, piperazin-1-yl-, pyrimidin-1-yl-, pyridazin-1-yl-, morpholino-, thiomorpholino- or S , s-dioxothiomorfolinokarbonylem substituted carbamoyl, sulfamoyl, phosphono, benzofuranyl, oxo (which is not on a carbon which is linked to the nitrogen atom of the amino group which is bound to the R · ^, _{R2, Rg} or R), and / or cyano and is unbranched or branched and is especially selected from phenyl (lower alkyl) such as benzyl, wherein the benzyl residue is not substituted or is substituted one or more times by lower alkyl, for example methyl, phenyl, hydroxy, lower alkoxy, for example methoxy, a halogen atom such as chlorine, nitro and / or cyano such as 4-methoxy-, 4-fluoro-, 4-chloro-, 4-nitro- or 4-cyanobenzyl, naphthylmethyl such as α- or β-naphthylmethyl, indenylme ethyl, for example 1-, 2- or 3-indenylmethyl, indanylmethyl, such as 1- or 2-indanylmethyl, and phenanthre54

nylmethyl such as 9-phenanthrenylmethyl, 2-phenylethyl, 2-α-naphthylethyl, 2-O-naphthylethyl, 2- (lower alkyl) phenylethyl, such as 2- (4-methylphenyl) ethyl, 2- (lower alkoxy) - a phenylethyl group such as 2- (4-methoxyphenyl) ethyl, 2,2-diphenylethyl, 2,2-di- (4-methoxyphenyl) ethyl,

2,2,2-triphenylethyl, 2,2-dibenzylethyl, from residues selected from two phenyl- (lower alkoxy) -carbonyl groups such as benzyloxycarbonyl or (lower alkyl) -amino groups such as pivaloylamino in the 2-position and para substituted phenyl- (lower alkyl) groups such as 2, p-dibenzyloxycarbonylaminophenethyl or 2-pivaloylamino-p-benzyloxycarbonylaminophenethyl, 2, p-diaminophenethyl, 3-phenylpropyl, 3- (p-hydroxy.phenyl) propyl, 3- and / or 3-O-naphthylpropyl. 2-benzyl-3- (1-pyrazolyl) propyl, 3-phenyl- or 3-α-naphthyl-2-hydroxypropyl, 3-phenyl- or 3-α-naphthyl-2- (lower alkoxy) propyl, such as 3-phenyl- or 3-α-naphthyl-2-neopentyloxypropyl, 3-phenyl or 3-α-naphthyl-2- (lower alkanoyl) oxypropyl groups such as 3-phenyl-2-pivaloyloxy, -2-acetoxypropyl , 2-benzyl or 1- or 2-naphthyl-3- (N-methoxy-N-methylamino) propyl, ^3: 3-phenyl, or • a-näf.tyl-2-dimethylaminomethylpropyl, 3-a-naphthyl-2 -pivaloyloxy- or -2-acetoxypropyl, 3-α-naphthyl-2-acetoacetoxypropyl, 3-α-naphthyl-2-ethylaminocarbonyloxypropyl or 3-α-naphthyl-2 - [(2-amino- or 2-benzyloxycarbonylamino) -2] -methylpropionyloxy / propyl, 3-phenyl- or 3-α-naphthyl-2-carboxymethylpropyl, 3-phenyl- or 3-α-naphthyl-2- (lower alkoxy) carbonylpropyl groups such as 3-α-naphthyl-2 -ethoxycarbonylpropyl, 3-phenyl- or 3-α-naphthyl-2-benzyloxycarbonylmethylpropyl, 2 (S) -benzyl-3-tert-butylsulfonylpropyl, 3-phenyl-2-phosphono- or -phosphonomethylpropyl, 3-phenyl-2- dimethoxyphosphoryl- or -d imethoxyphosphorylmethylpropyl, 3-phenyl-2-diethoxyphosphoryl- or -diethoxyphosphorylmethylpropyl, 3-phenyl-2-ethoxy- or -methoxyhydroxyphosphorylmethylpropyl, 3-phenyl or 3-α-naphthyl-2-carbamoylpropyl, 3-phenyl- or 3-α-naphthyl- 2-t. 3-phenyl- or 3-.alpha.-naphthyl-2- (2-dimethylaminoethyl) carbamoylpropyl, 3-.alpha.-naphthyl-2- (carboxyphenyl) -butylcarbamoylpropyl;

.M

y ;; r -... I '

Cy

3-α-naphthyl-2- (2,2-dimethoxyethyl) carbamoylpropyl, 3-phenyl or 3-α-naphthyl-2- (5-amino-5-carboxypentyl) carbamoylproo or tert-butoxycarbonyl) methylcarbamoylpropyl, 3-phenyl- or 3-α-naphthyl-2- (3-hydroxy-2-propyl) carbamoylpropyl, 3-phenylbenzyl. pollen, 3-phenyl- or 3-α-naphthyl-2-cyanopropyl, 3-phenyl- or 3-α-naphthyl-2-cyanomethylpropyl, 3-phenyl- or 3-α-naphthyl-2-acetyl. tonylpropyl, 4-hydroxyphenylbutyl, 4-phenyl- or 4-α-naphthyl-3-carboxybutyl, 4-phenyl- or 4-α-naphthyl-3-benzyloxycarbonylbutyl, 2-benzyl-4- (2-benzofuranyl) -4 -oxobutyl, 2-benzyl- or 2-a-naphthylmethyl-4-cyanbutyl, 2-benzyl- or 2-a-naphthylmethyl-5-dimethylaminopentyl, 2-benzyl- or 2-a-naphthylmethyl-4-oxopentyl, 2- benzyl- or 2-α-naphthyl-ethyl-4,4-dimethyl-3-oxopentyl, 2-benzyl- or 2-α-naphthylmethyl-5-dimethylamino-4-oxopentyl, 2-benzyl- or 2-α-naphthylmethyl -5,5-dimethyl-4-oxohexyl, preferred phenyl- (lower alkyl) groups such as benzyl, 2-phenylethyl or 3-phenylpropyl, 4-hydroxybenzyl, 1- or 2-naphthylmethyl or 1- or 2-naphthyl- 2-ethyl, particularly preferred phenyl- (lower alkyl) groups, as defined closest to the above: a heterocyclyl- (lower alkyl) group which in particular contains a heterocyclyl- (lower alkanoyl) group R, _lr R _2., R g and R _g of the optionally substituted by heterocyclyl groups and lower alkanoyl groups optionally substituted lower alkanoyl part is heterocyclyl- (lower alkanoyl) group, R _2, R g and R _g (wherein the oxo group is not on a carbon atom which is linked to a nitrogen atom carrying the radical R @ 1, R @ ₂ , R @ 8 or R @ 8, for example methyl, 2-ethyl or

3-propyl attached to unsubstituted or lower alkyl or phenyl substituted pyrrole such as 2- or

3-pyrrolyl, 4- or 5-methylpyrrolyl or 4- or 5-phenylpyrrolyl, thienyl such as 2-thienyl, furyl such as 2-furyl, pyrazolyl such as 1-pyrazolyl, tetrazolyl such as tetrazol-1- a pyridyl such as 2-, 3- or 4-pyridyl, unsubstituted or lower alkyl, e.g.

·.

methyl, phenyl (lower alkyl), for example benzyl, lower alkoxy, for example methoxy, phenyl (lower alkoxy), for example benzyloxy, or halogen, for example chloro, substituted indolyl, such as 2-, 3- or 5-indolyl, Methyl-methyl-, 2-methyl-,

5-methoxy-, 5-benzyloxy-, 5-chloro- or 4,5-dimethylindol-2-yl, 1-benzindol-2-yl or -3-yl, 4,5,5,7,7-tetrahydroindol-2 -yl, cycloheptaphb] pyrrol-5-yl, unsubstituted or hydroxy substituted quinolyl, such as 2-, 3- or

4-quinolyl or 4-hydroxyquinol-2-yl, unsubstituted or hydroxy substituted isoquinolyl, such as 1-, 3- or

4-isoquinolyl or 1-oxo-1,2-dihydroisoquinol-3-yl, 2-quinoxalinyl, 3,1-benzofuran-2-yl. benz [e] indol-2-yl, β-carbolin-3-yl, 3-chromanyl, 3-thiochromanyl, 3-pyrrolidinyl, hydroxypyrrolidinyl such as 3- or 4-hydroxypyrrolidin-2-yl, oxopyrrolidinyl such as 5 -oxopyrrolidin-2-yl, piperidinyl such as 2-, 3- or 4-piperidinyl, morpholinyl such as 2- or 3-morpholinyl, thiomorpholinyl such as 2- or 3-thiomorpholinyl,

S, S-dioxothiomorpholinyl such as S, S-dioxothiomorpholin-2- or -3-yl, indolinyl such as 2- or -3-indolinyl, 1,2,3,4-tetrahydroquinolyl such as 1,2,3,4 -tetrahydroquinol-2-, -3- or -4-yl, 1,2,3,4-tetrahydroisoquinolyl, such as 1,2,3,4,4-tetrahydroisoquinol-1-, -2- or -3-yl; -oxo-1,2,3,4-tetrahydroiboquinol-3-yl, or also 4-pyrrolidinylmethyl or 1-imidazolylmethyl, a hydroxy- (lower alkyl) group such as 3-hydroxypropyl or 2-hydroxy-3-methylpentyl, (lower alkoxy) - (lower alkyl), for example (lower alkoxy) -ethyl or (lower alkoxy) -propyl, such as 2-methoxyethyl, 2-ethoxyethyl or 3-methoxypropyl, (lower alkoxy) - (lower alkoxy) a (lower alkyl) group such as 2-methoxymethoxy-3-methylpropyl, a phenoxy- (lower alkyl) or nitrophenoxy- (lower alkyl) group such as a phenoxymethyl, phenoxyethyl or 4-nitrophenoxymethyl, naphthyloxy- (lower alkyl) group. a group such as α- or O-naphthyloxymethyl, a (lower alkanoyl) -oxy- (lower alkyl) group such as a (lower alkanoyl) oxyethyl or (lower alkanoyl) -oxyO propyl group such as acetoxyethyl or 3-acetoxypropyl, acetoacetoxy- (lower alkyl), an arylmercapto- (lower alkyl) group wherein the aryl moiety contains from 6 to 10 carbon atoms, for example phenyl or naphthyl, such as phenylmercaptomethyl, an amino- (lower alkyl) group, such as ⁷ 3-aminopropyl, or A 5-aminopentyl, nono- or di- (lower alkyl) -amino- (lower alkyl) group such as dimethylaminoethyl or 2-dimethylamino-2-isopropylethyl, phenyl or naphthylamino- (lower alkyl) group such as 3- phenylaminopropyl, (lower alkanoyl) -amino- (lower alkyl) group such as 4-acetylaminopentyl, lower alkyl group such as methyl, substituted nitrogen-substituted piperazinylcarbonyl- (lower alkyl) group such as 4-methylpiperazinylcarbonylmethyl,

58. (lower alkoxy) -carbonylamino- (lower alkyl) group; such as 5- (tert-butoxycarbonylamino) pentyl or 3-ethoxycarbonylamino-2-isobutylpropyl, phenyl- (lower alkoxy) carbonylamino- (lower alkyl) group such as 5- (benzyloxycarbonylainino) pentyl, aminocarbonylamino- (lower alkyl) a group such as aminocarbonylaminoethyl,

N-phenyl- (lower alkyl) -N- (lower alkyl) aminocarbonylamino- (lower alkyl) group, for example 2-isobutyl-3- (N-benzyl-N-methylaminocarbonylamino) propyl, halogen- (lower alkyl) group, for example

2-haloethyl such as 2-fluoro, 2-chloro, 2-bromo, 2-iodo,

2,2,2-trifluoro- or 2,2,2-trichloroethyl, trifluoro- (lower alkyl) group, such as trifluoromethyl, or halopropyl, such as: 3-chloro- or 3-bromopropyl, carboxy- (lower alkyl) group , for example, carboxyethyl or 3-carboxypropyl, a (lower alkoxy) -carbonyl- (lower alkyl) group, for example a (lower alkoxy) -carbonylethyl or (lower alkoxy) -carbonylpropyl group such as methoxycarbonylethyl, 3-methoxycarbonylpropyl, ethoxycarbonylethyl or

3-ethoxycarbonylpropyl,

2-halo- (lower alkoxy) -carbonyl- (lower alkyl) group such as 2-chloro-, 2-bromo-, 2-iodo-, 2,2,2-trichloroethoxycarbonyl-2-ethyl or -3-propyl a phenyl- or naphthyl- (lower alkoxy) -carbonyl- (lower alkyl) group, for example a benzyloxycarbonyl- (lower alkyl) group such as 3-benzyloxy-2,2-dimethylpropyl, heterocyclyl- (lower alkoxy) -carbonyl- (lower alkyl) group, wherein the heterocyclyl moiety is preferably selected from pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrimidinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, β-quinoxalinyl, β-quinoxalinyl benzanellated, cyclopentaanellated, cyclohexaanellated or cycloheptaanellated derivatives of this series, which may also be partially or fully saturated, such as in 4-pyridylmethoxycarbonyl-2-ethyl or -3-propyl or 2-morpholinocarbonyloxy-4-methylpentyl, (lower alkyl) -sulfonyl- (lower alkyl) group such as 2-ethylsulfonyl- or 2- a tert-butylsulfonylmethyl, arylsulfonyl- (lower alkyl) group, wherein the aryl moiety preferably contains 6 to 10 carbon atoms, for example phenyl or naphthyl, such as a phenylsulfonylmethyl, carbamoyl- (lower alkyl) group such as carbamoylethyl or 3-carbamoylpropyl (lower alkyl) -carbamoyl- (lower alkyl) group, for example (lower alkyl) -carbamoylethyl or methylcarbamoyl- (lower alkyl) group such as 2-methylcarbamoylethyl, di- (lower alkyl) -carbamoyl- (lower alkyl) ) a group such as a 2-di- (lower alkyl) -carbamoylethyl or dimethylcarbamoyl- (lower alkyl) group such as a 2-dimethylcarbamoylethyl, hydroxy- (lower alkyl) -carbamoyl- or di (hydroxy- (lower alkyl)) - carbamoyl a (lower alkyl) group such as 2-hydroxy (60-hydroxymethylcarbamoyl-, dihydroxymethyl) carbamoyl-2-ethyl or -3-propyl;

N- (lower alkoxy) - (lower alkoxy) - (lower alkyl) -carbamoyl- (lower alkyl) group such as 2-isopropyl-3- / 2- (2-methoxyethoxy) ethylaminocarbonyl / propyl, carboxy- (lower) alkyl) -carbamoyl- or di (carboxy- (lower alkyl)) - carbamoyl- (lower alkyl) group such as carboxymethyl- or di (carboxymethyl) carbamoyl-2-ethyl or -3-propyl,

from ethylene, trimethylene, tetramethylene and pentamethylene by a selected residue wherein the carbon atom can be replaced by a nitrogen, oxygen, sulfur or oxygen atom one or two times a substituted sulfur atom, a carbamoyl (lower alkyl) substituted by nitrogen, such residues may be wholly or partially unsaturated, such as piperidino-, pyrazin-1-yl-, piperazin-1-yl-, pyrimidin-1-yl-, pyridazin-1-yl-, morpholino-, thiomorpholinone or S, S- dioxothiomorpholinocarbonyl- (lower alkyl) group, as in. 2-morpholinocarbonylethyl, 3- (morpholinocarbonyl) propyl or 3- (morpholinocarbonyl) -2-isobutylpropyl,

N- (lower alkyl) -N-heterocyclyl- (lower alkyl) -carbamoyl- (lower alkyl) group, wherein the heterocyclyl moiety is preferably selected from pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl, β-carbolinyl and benzanellated, cyclopentaanellated, cyclohexaanellated or cycloheptaanellated derivatives of this series, which may also be partially or fully saturated, such as 2- (Ν-2-pyridylmethyl) -N-methylcarbamlet a sulfamoyl- (lower alkyl) group, such as 2-sulfa;

ύί. Λ moylethyl,

N- (phenyl- or N- (naphthyl- (lower alkyl)) - sulfamoyl- (lower alkyl) group such as 3-benzylaminosulfonyl-2-isopropylpropyl or on a nitrogen atom of ethylene, trimethylene, or the like. pentamethylene is selected from the group in which the carbon atom can be replaced by a nitrogen atom, a lower alkyl group, a methyl, a substituted nitrogen atom, a sulfur oxygen atom or an oxygen atom of one or two substituents of a nitrogen atom; and the residues thus formed may be wholly or partially unsaturated, for example as piperidino-, pyrazin-1-yl-, piperazin-1-yl-, 4-methylpiperazin-1-yl-, pyrimidin-1-yl- a pyridazin-1-yl-, morpholino-, thiomorpholino- or S, S-dioxothiomorpholinosulfonyl- (lower alkyl) group such as propylpropyl or is 3- (4-methylpiperazinylsulfonyl) -2-iso3- (4-morpholinylsulfonyl) -2 isopropylpropyl, alkyl) group (wherein oxozbytek is not at the carbon atom that is linked to the nitrogen atom carrying the radical R ^, R _2, R g and R _g), such as 3-oxo-n-butyl or 3-oxo-n -pentyl, οχο- (lower • · · kýán- (lower al a kanoyl group) such as cyanomethyl,

2-cyanethyl, 2- or 3-cyano-n-propyl or 2-, 3- or 4-cyano-n-butyl, hydroxycarboxy- (lower alkyl) group such as 2-hydroxy-2-carboxyethyl or 2-hydroxy A 3-carboxypropyl, α-naphthyloxycarboxy (lower alkyl) group such as

2-.alpha.-naphthyloxy-4-carboxy-n-butyl;

-. 'J

A hydroxy- (lower alkoxy) -carbonyl- (lower alkyl) group, for example a 2-hydroxy-2- (lower alkoxy) -carbonylethyl or -propyl, hydroxyethoxy- or hydroxymethoxycarbonyl- (lower alkyl) group such as 2 -hydroxy-2-ethoxy- or -methoxycarbonylethyl or 2-hydroxy-3-ethoxy- or -methoxycarbonylpropyl, α-naphthyloxy- (lower alkoxy) -carbonyl- (lower alkyl) group, for example α-naphthyloxy- (lower alkoxy) - carbonyl-2-ethyl, -2-propyl or -2-butyryl or α-naphthyloxyethoxycarbonyl- (lower alkyl) groups such as α-naphthyloxyethoxycarbonyl-2-ethyl, 2-α-naphthyloxy-3-ethoxycarbonylpropyl or 2-α- naphthyloxy-4-tert-butoxycarbonylbutyl, α-naphthyloxybenzyloxycarbonyl- (lower alkyl) group such as 2-α-naphthyloxy-3-benzyloxycarbonylpropyl, esterified hydroxy- (lower alkoxy) -carbonyl- (lower alkyl) group in which the hydroxy group is esterified with a lower alkanoyl group, for example acetyl, propionyl or pivaloyl, a cycloalkyl- (lower alkanoyl) group wherein the cycloalkyl moiety contains 3 to 7 carbon atoms and the lower alkanoyl moiety corresponds to the above definition, for example, cyclohexylcarbonyl or 2-cyclohexyl- or 2-cyclopentylacetyl, bicycloalkyl- (lower alkanoyl) moiety wherein the bicycloalkyl moiety contains 5 to 10 carbon atoms, especially 6 to 9 carbon atoms, such as in bicyclohexyl-, -heptyl-, -octyl-, -nonyl- or -decylacetyl or -3-propionyl, for example such as bicyclof3,1,0] hex-1 -, -2- or -3-yl-, bicyclo [4,1.1] hept-1- or -7-yl-, bicyclo [2.2.1] hept-2-yl-, for example, endo or exo-norbornyl-, bicyclo [3,2,1] oct-2-yl-, bicyclo [3.3.0] oct-3-yl- or _t- bicyclo [3.1.1] trans-9-yl-, followed by α- or β -decahydronaphthylacetyl or -3-propionyl, a tricycloalkyl- (lower alkanoyl) group in which the tricycloalkyl moiety contains, for example, 8 to 10 carbon atoms, such as in a tricyclo-

[5,2,1, O ^{2 '6]} dec-8-yl- or adamantyl-, such as 1-adamantyl-, aryl (jiižší alkanoyl) group, wherein the aryl portion contains 6 to 14 carbon atoms, such as phenyl, indenyl , indanyl, naphthyl, anthryl, phenanthryl, acenaphthyl or fluorenyl, which is unsubstituted or can be 1 to 3 times substituted by lower alkyl, hydroxy, lower alkoxy, carbamoyl (lower alkoxy),. N- (lower alkyl) -carbamoyl- (lower alkoxy) or

N, N-di- (lower-alkyl) -carbamoyl- (lower alkoxy), amino, mono- or di- (lower alkyl) amino, halogen, such as fluorine, chlorine or bromine, carboxy, (lower alkoxy) carbonyl, phenyl, naphthyl or fluorenyl- (lower alkoxy) carbonyl, lower alkanoyl or (lower alkyl) -sulfonyl, for example methylsulfonyl, phosphono. hydroxy- (lower alkoxy) -phosphoryl or di- (lower alkoxy) -phosphoryl, carbamoyl, sulfamoyl, nitro and / or cyano, or further esterified with (lower alkoxy) -carbonyl, for example tert-butoxycarbonyl, 2-halogen- a (lower alkoxy) -carbonyl-group as defined above or a phenyl- or fluorenyl- (lower alkoxy) -carbonyl-group, for example a benzyloxycarbonylene or 9-fluorenylmethoxycarbonyl such as 2-acetoxy-2-methoxycarbonylethyl, 2-benzoyloxy- 2- (1- or 2-naphthoyloxy) -, 2- (phenyl-2-acetoxy) -, 2- (1- or 2-naphthyl-2-acetoxy) -, 2- (4-methylphenyl-2-acetoxy) ) -, 2- (4-methoxyphenyl-2-acetoxy) - or 2- [2- (o, o-dichlorophenyl) -2-acetoxy) -2-methoxycarbonylethyl or -3-propyl,

a dihydroxycarboxy- (lower alkyl) group such as

2,3-dihydroxy-3-carboxypropyl; a dihydroxy (lower alkoxy) -carbonyl- (lower alkyl) group such as 2,3-dihydroxy-3-ethoxy- or methoxycarbonylpropyl; τ t, ·. '• t' · ·> '* í' 2 '“' · _ · '' f- '' · '-. ·. * '

-. · - -r- · i; 7 ~ · ·

lower alkanoyl, such as acetyl, propionyl or butyryl, (lower alkoxy) -carbonyl, for example tert-butylcarbonyl, phenyl or fluorenyl- (lower alkoxy) -carbonyl, such as benzyloxycarbonyl or 9-fluorenylmethoxycarbonyl, (lower alkyl) - a sulfonyl group or a toluenesulfonyl esterified dihydroxy- (lower, alkoxy) j-carbonyl- (lower alkyl) group, for example a di- (lower alkanoyl) -oxy- (lower alkoxy) -propyl group such as 2,3-diacetoxy-3- a methoxycarbonylpropyl, α-naphthyloxy-di- (lower alkyl) -amino- (lower alkyl) group such as 2-α-naphthyloxy-5-dimethylaminopentyl, α-naphthyloxycarbamoyl- (lower alkyl) group such as lys.

2-.alpha.-naphthyloxy-4-carbamoylbutyl;

an α-naphthyloxyoxo (lower alkyl) group (wherein the oxo moiety is not on a carbon atom which is linked to a nitrogen atom bearing a residue R _x , R ₂ , R g or R _g ), such as

2-.alpha.-naphthyloxy-4-oxopentyl or. YF?

α-naphthyloxycyan- (lower alkyl) group such as 2-α-naphthyloxycyanethyl or 2-α-naphthyloxy-4-cyanobutyl. '

Particularly preferred is a lower alkyl group such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl or tert-butyl.

The alkenyl group of R, R _2, R ₈ and _Rg comprises preferably up to 10 carbon atoms, preferably a lower alkenyl group having 2 to 7 carbon atoms, especially 2 to 4 · carbon atoms, for example vinyl, allyl, 2- or 3-butenyl. The lower alkenyl group R 1, R ₂ , R g or R _g may be substituted with the same substituents as the lower alkyl group, for example. one to three times substituted with cycloalkyl, such as defined in the cycloalkyl- (lower alkanoyl) group of R 1, R ₂ , R 8 or R 8, which; not substituted or substituted by one to three times lower alkyl such as isopropyl, halogen- (lower alkyl) such as trifluoromethyl, hydroxy, lower alkoxy, carbamoyl- (lower alkoxy), N- (lower alkyl) -carbamoyl- (lower alkoxy) or ^; N, N-di- (lower alkyl) -carbamoyl- (lower alkoxy), amino, mono- or di- (lower alkyl) amino, halogen, such as fluorine, chlorine or bromine, carboxy, (lower alkoxy) -carbonyl, phenyl-naphthyl- or fluorenyl- (lower alkoxy) -carbonyl, lower alkanoyl, (lower alkyl) -sulfonyl, for example methylsulfonyl, phosphono, hydroxy- (lower alkoxy) -phosphoryl or di- (lower alkoxy) -phosphoryl a carbamoyl, mono- or di- (lower alkyl) -aminocarbamoyl group, sulfamoyl, mono- or di- (lower alkyl) -sulfamoyl, nitro and / or cyano group, and in particular attached to the terminal carbon atom of the lower alkenyl group, such as cyclobutyl- , cyclopentyl-, cyclohexyl- or cycloheptylmethyl-2-vinyl, -2- or -3-allyl or -2-, -3- or -4-but-2-enyl, followed by an aryl group as defined under aryl (lower alkanoyl) R @ 1, R @ ₂ , R @ 8 or R @ 8 which is not s substituted or substituted is preferably attached to a terminal lower alkenyl group such as styryl, 3-phenylallyl (cinnamyl), 2- (α-naphthyl) vinyl or 2- (β-naphthyl) vinyl, optionally substituted with heterocyclyl , as defined below a heterocyclyl- (lower alkanoyl) group R 1, R ₂ , R _g or R _g , preferably selected from pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl , quinolyl, isoquinolinyl, quinoxalinyl, β-carbolinyl and benzanellated, cyclopentaanellated, cyclohexaanellated or cycloheptaanellated derivatives of the same series, which may also be partially or fully saturated and. optionally substituted as indicated above and attached via a nitrogen or carbon atom with lower alkenes

A lower alkenyl group, preferably selected from e.g. vinyl, allyl,

2- or 3-butenyl, for example, as pyrimidin-1-yl-, piperidino-, pyrazin-1-yl-, piperazin-1-yl-, pyridazin-1-yl-, morpholino-, thiomorpholino- or S, S- a dioxothiomorpholino- (lower alkenyl) group such as 2-morpholinovinyl, 3-morpholinoallyl or 4-morpholino-2- or -3-butenyl, a pyrrolyl- (lower alkenyl) group optionally substituted by a lower alkyl group or phenyl such as 2- or 3-pyrrolylvinyl or -allyl, 4- or 5-methylpyrrolylvinyl or -allyl, 5-methylpyrrolylallyl, thienyl- (lower alkenyl) group such as 2-thienylvinyl or -allyl, furyl- (lower alkenyl) group such as 2-furylvinyl or -allyl, pyridyl- (lower alkenyl), such as 2-, 3- or 4-pyridylvinyl or -allyl, unsubstituted or lower alkyl, for example methyl, phenyl- (lower alkyl), for example benzyl, lower alkoxy, such as methoxy, phenyl (lower alkoxy), such as benzyloxy, or halogen, an example of a chloro-substituted indolyl- (lower alkenyl) group, such as 2-, 3- or 5-indolylvinyl or -allyl, 1-methyl-, 2-methyl-, 5-methoxy-, 5-benzyloxy-, 5-chloro or 4,5-dimethylindol-2-yl-, 1-benzindol-2-yl- or -3-ylvinyl or -allyl, 4,5,6,7-tetrahydroindol-2-ylmethyl, -ethyl or -propyl, cyclohepta [b] pyrrol-5-ylvinyl or -allyl, unsubstituted or hydroxy substituted quinolyl- (lower alkenyl), for example 2-, 3- or 4-quinolyl- or 4-hydroxyquinol-2-ylvinyl or -allyl, unsubstituted or hydroxy substituted isoquinolyl- (lower alkenyl), such as 1-, 3- or 4-isoquinolyl- or 1-oxo-1,2-dihydroisoquinol-3-ylvinyl or -allyl, 2-quinoxalinylvinyl or -allyl, 3,1- benzfuran-2-ylvinyl or -allyl, benz [e] indol-2-ylvinyl or -allyl, p-carbolin-3-ylvinyl or -allyl, 3-chromanylvinyl or -allyl, 3-thiochromanylvinyl or -allyl, 3-pyrrolidinylvinyl or an -allyl, hydroxypyrrolidinyl- (lower alkenyl) group, as a 3- or 4-hydroxy-6-oxo-pyrrolidin-2-yl-vinyl or -allyl, oxopyrrolidinyl- (lower alkenyl) group, such as a 5-oxopyrrolidin-2-ylvinyl or -allyl, piperidinyl- (lower alkenyl) group, such as 2-, 3 or 4-piperidinylvinyl or -allyl, morpholinyl- (lower alkenyl) group such as 2- or 3-morpholinylvinyl or -allyl, thiomorpholinyl- (lower alkenyl) group such as 2- or 3-thiomorpholinylvinyl or -allyl, S, S-dioxothiomorpholinyl - (lower alkenyl) group such as S, S-dioxothiomorpholin-2 or -3-ylvinyl or -allyl, indolinyl- (lower alkenyl) group such as 2- or 3-indolinylvinyl or -allyl,

1.2.3.4-tetrahydroquinolyl- (lower alkenyl) group such as

1.2.3.4- tetrahydroquinol-2-, -3- or -4-ylvinyl or -allyl,

1,2.3.4-tetrahydroisoquinolyl- (lower alkenyl), such as 1,2,3,4-tetrahydroisoquinol-1-, -2- or -3-ylvinyl or -allyl, 1-oxo-1,2,3,4 -tetrahydroisoquinol-3-ylvinyl or -allyl. furthermore a hydroxy group, an etherified hydroxy group selected from lower alkoxy such as methoxy or ethoxy, phenoxy, naphthyloxy, phenyl or naphthyl (lower alkoxy) such as benzyloxy and heterocyclyl (lower alkoxy), - wherein heterocyclyl. the moiety is selected from pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, isoquinolyl, quinoxalinyl, β-carbolinyl and benzanlated, cyclopentaanellated, cyclopentaanellated, cyclopentaanellated, be partially or fully saturated, for example 4-pyrrolidinylmethoxy, 1-imidazolylmethoxy, 2-pyridylmethoxy, 3-pyridylmethoxy, quinolin-2-ylmethoxy or indolyl-2-ylmethoxy, the esterified hydroxy group selected from (lower alkyl) is selected from (lower alkyl) , propionyloxy, butyloxy, isobutyloxy or pivaloyloxy, acetoacetoxy, amino- or benzyloxycarbonylamino- (lower alkanoyl) -oxy, such as 2-amino- or 2-benzyloxycarbonylamino-2-methylpropionyloxy

- 68 alkanoyl) oxy, wherein the aryl moiety contains from 6 to 10 carbon atoms, such as in the benzoyloxy, phenylacetyloxy,

1- or 2-naphthoyloxy, (lower alkoxy) -carbonyloxy, for example methoxy, ethoxy, η-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n -pentyloxy-, isopentyloxy-, neopentyloxy-, t-pentyloxy-, n-hexyloxy-, isohexyloxy- or n-heptyloxycarbonyloxy, mono- or di- (lower alkyl) -aminocarbonyloxy, such as ethylaminocarbonyloxy or diethylaminocarbonyloxy; contains up to 10 carbon atoms, for example phenoxycarbonyloxy or 1- or 2-naphthyloxycarbonyloxy, aryl- (lower alkoxy) -carbonyloxy, wherein the aryl moiety contains 6 to 12 carbon atoms, for example phenyl- (lower alkoxy) -carbonyloxy, such as benzyloxycarbonyloxy - or 2-naphthyloxycarbonyloxy or 9-fluorenylmethoxycarbonyloxy, sulfonyloxy, (lower alkyl) -sulfonyloxy, for example methyl-, ethyl-, propyl-, isopropyl-, η-butyl-, isobutyl- , sec-butyl, tert-butyl, n-pentyl-, isopentyl-, neopentyl-, tert-pentyl-, η-hexyl-, isohexyl or n-heptylsulfonyloxy, or phenylsulfonyloxy, 2- or 4-toluenesulfonyloxy, and 1- or

2-naphthylsulfonyloxy, a halogen atom such as chlorine or bromine, a carboxy group, an esterified carboxy group selected from (lower alkoxy) -carbonyl, for example methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, 2-halo- (lower alkoxy) -carbonyl -chloro-, 2-bromo-, 2-iodo- or 2,2,2-trichloroethoxycarbonyl, phenyl- or naphthyl- (lower alkoxy) -carbonyl groups, for example benzyloxycarbonyl and heterocyclyl- (lower alkoxy) -carbonyl groups, wherein heterocyclyl the moiety is selected from pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, isoquinolyl, quinoxalinyl, β-carbolinyl and benzanlated, cyclopentaanellated, cyclopentaanellated, cyclopentaanellate, residues may also be partially or fully saturated, such as in 4-pyridylmethoxycarbonyl, or amidated carb an oxy group selected from carbamolyl, (lower alkyl) -carbamoyl, such as methylcarbamoyl, di- (lower alkyl) -carbamoyl, such as dimethylcarbamoyl, hydroxy- (lower alkyl) -carbamoyl or; dihydroxy- (lower alkyl) -carbamoyl groups such as hydroxymethylcarbamoyl or di (hydroxymethyl) carbamoyl, N- (lower alkoxy) - (lower alkoxy) - (lower alkyl) -carbamoyl groups such as 2- (2-methoxyethoxy) ethylaminocarbamoyl, carboxy - (lower alkyl) -carbamoyl or di / carboxy- (lower alkyl) / -carbamoyl groups, for example, carboxymethyl- or di (carboxymethyl) carbamoyl, and of ethylene, trimethylene, tetramethylene and pentamethylene with a selected radical in which the carbon atom may be replaced by nitrogen, oxygen, sulfur or an oxygen atom substituted once or twice with a substituted sulfur atom on the nitrogen atom of a substituted carbamoyl group, the residues thus formed may be wholly or partially unsaturated, such as piperidino-, pyrazin-1-yl-, piperazine-1- yl-, pyrimidin-1-yl-, pyridazin-1-yl-, morpholino-, thiomorpholino- or S, S-dioxothiomorpholinocarbonyl, N-heterocyclyl- (lower alkyl) carbamoyl, wherein heterocyclyl the moiety is selected from pyrrolyl, furyl, thienyl, imidazolyl; pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl, β-carbolinyl and benzanellated, cyclopentaanellated, cyclohexaanellated or cycloheptaanellated derivative of this series, which may also be partially or partially N -pyridylmethyl-N-methylcarbamoyl.

The alkynyl group of R, R _2, R _Q and R _g include above all 2 to 10 carbon atoms, preferably is a lower alkynyl group containing 2 to 7 carbon atoms, particularly .2 to 4 carbon, atoms and is for example ethynyl, 1- propynyl or 2-propynyl,

- 70 wherein said residues are unsubstituted or can be substituted by radicals which are designated by a lower alkenyl group of R, R _2, R g and R _g.

The heterocyclyl groups of R _{2 l of} R, R, and _Rg is-linked. a carbon atom and contains, in particular, a heterocyclyl moiety optionally substituted as indicated under the heterocyclyl- (lower alkanoyl) group R p of R ₂ , R g and R _g and is preferably unsubstituted or lower alkyl or phenyl substituted pyrrolyl such as 2- or 3-pyrrolyl, 4- or

A

5-methylpyrrolyl or 4- or 5-phenylpyrrolyl, thienyl, such as

2-thienyl, furyl, such as -2-furyl, pyridyl, such as 2-, 3- or 4-pyridyl, optionally lower alkyl such as methyl, phenyl (lower alkyl) such as benzyl, lower alkoxy such as methoxy, phenyl- (lower alkoxy) such as benzyloxy or a halogen atom such as chloro-substituted indolyl such as 2-,

3- or 5-indolyl, 1-methyl-, 2-methyl-, 5-methoxy-, 5-benzyloxy-, 5-chloro- or 4,5-dimethylindol-2-yl, 1-benzylindole-2- or - 3-yl, 4,5,6,7-tetrahydroindol-2-yl, optionally hydroxy substituted quinolyl, such as 2-, 3- or 4-quinolyl, or 4-hydroxyquinol-2-yl, optionally hydroxy substituted isoquinolyl, such as 1 -, 3- or 4-isoquinolyl or 1-oxo-1,2-dihydroisoquinol-3-yl, 2-quinoxalinyl, 3,1-benzfuran-2-yl, benz [e] indol-2-yl, O-carboline -3-yl, cyclohepta [b] pyrrol-5-yl, 3-chromanyl, 3-thiochromanylcarbonyl, 3-pyrrolidinyl, hydroxypyrrolidinyl, such as 3- or 4-hydroxypyrrolidin-2-yl, oxopyrrolidinyl, such as 5-oxopyrrolidin-2- yl, piperidyl, such as 2-, 3- or 4-piperidyl;

3-morpholinyl, thiomorpholinyl, such as 2- or 3-thiomorpholinyl,

S, S-dioxothiomorpholinyl such as S, S-dioxothiomorpholin-2- or -3-yl, indolinyl such as 2- or 3-indolinyl, 1,2,3,4-tetrahydroquinolyl such as 1,2,3,4- tetrahydroquinol-2-, -3- or -4-yl,

1,2,3,4-tetrahydroisoquinolyl such as 1,2,3,4-tetrahydroisoquinol-1-, -2- or -3-yl or 1-oxo-1,2,3,4-tetrahydroisoquinol

nol-3-yl.

Sulfonyl, substituted alkyl, R _x, R _2, ·. R _g and R ₉ includes preferably an optionally substituted alkyl radical designated under R ₁ alkyl, R _2, R g and R a are especially the (lower alkyl) -sulfonyl, such as methylsulfonyl ,: ethylsulfonyl, n-propylsulfonyl or tert. butylsulfonyl,

2 '

Ý ·· ’· fc-

. a sulfonyl group substituted by aryl (lower alkyl) group, which includes, for example, optionally substituted aryl radical designated under the (lower alkyl) groups R, R _2, R _g and R a is in particular selected from benzyl, 4-chloro, 4 -methoxy- or 4-nitrobenzyl-, naphthylmethyl-, for example α- or β-naphthylmethyl-, 2-phenylethyl-, 2-α-naphthylethyl-, 2-p-naphthylethyl-, 2- (4-methylphenyl) ethyl- 2- (4-methoxyphenyl) ethyl, 3-phenylpropyl, 3- (p-hydroxyphenyl) propyl, 2,2-diphenylethyl and

2,2-di- (4-methoxyphenyl) ethylsulfonyl or a sulfonyl group substituted with a heterocyclyl- (lower alkyl) group containing, for example, an optionally substituted radical named under the heterocyclyl- (lower alkyl) group R ₁ , R ₂ , R g and R g and is especially selected from radicals such as 2- or 3-pyrrolyl-, 2-thienyl-, 2-furyl-, 1-pyrazolyl-, 2-, 3- or 4-pyridyl-, 2-, 3- or 5-indolyl -, (1-methyl-, 2-methyl-, 5-methoxy-, 5-benzyloxy-, 5-chloro- or

4,5-dimethylindol-2-yl-), (1-benzylindol-2-yl or -3-yl) -,

4,5,6,7-tetrahydroindol-2-yl-, (2-, 3- or 4-quinolyl);

4-hydroxyquinol-2-yl- (1-, 3- or 4-isoquinolyl or 1-oxo-1,2-dihydroisoquinolyl-3) -, 3-pyrrolidinyl-, (3- or 4-

-hydroxypyrrolidin-2-yl) -, 5-oxopyrrolidin-2-yl-, (2- or 3-morpholinyl) -, (2-: or 3-thiomorpholinyl) -, (S, S-dioxothiomorpholine-2- or - 3-yl) -, (2- or 3-indolinyl) -, (1,2,3,4-

.1.: .- 7

'-i'

rt ·:? - ·.

-tetrahydroquinol-2-, -3- or -4-yl) - and (1,2,3,4-tetrahydroisoquinol-1-, -2- or -3-yl) methylsulfonyl.

A sulfonyl group substituted with an aryl group 7 y

R @ 1, R @ ₂ , R @ 8 and R @ 8 preferably contain optionally substituted?

an aryl radical named under the aryl- (lower alkanoyl) group R ₁ , R ₂ , R ₈ and R 8 and is especially unsubstituted or lower alkyl substituted by one or two phenyl or 1- or 2-naphthylsulfonyl such as phenylsulfonyl,

2- or 4-toluenesulfonyl or 1- or 2-naphthylsulfonyl.

Sulfonyl, substituted heterocyclyl, with R _lr R _2, R and R preferably has heterocyklylovouvý?

a moiety selected from pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazol, zinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl, β-carbolinyl and benzanelolinyl; cyklopentaanelovaného, cyklohexaanelovaného cykloheptaanelovaného or derivative of the lines, which can also be partly or completely saturated, from morpholinyl and thiomorpholinyl, and may optionally _yl ·, · substituted, in particular methyl, as morfolinosulf alkylsulfonyl ,. thiomorpholinosulfonyl, piperidinosulfonyl, 4-methylpiperazinylsulfonyl or piperazinosulfonyl. In a particularly preferred embodiment of the invention, heterocyclylsulfonyl may be absent.

Sulfonyl substituted by C _{l of} R

R ₂ , R g and R g preferably contain optionally substituted α 1 -.

is a lower alkyl group mentioned under the alkyl groups R 1, R ₂ , R g and R g and is especially selected from (lower alkyloxy) -sulfonyl, such as methoxy, ethoxy or tert-butoxy-sulfonyl, heterocyclyl- (lower alkoxy) -sulfonyl groups which

as comprising an optionally substituted heterocyclyl- (lower alkyl) radical designated under a heterocyclyl- (lower alkyl) group R?, R _2, R g and R _g, in particular selected from 2-or 3-pyrrolyl, 2-thienyl, 2-furyl -, 1-pyrazolyl-, 2-, 3- or

4-pyridyl-, 2-, 3- or 5-indolyl-, (Ι-methyl-, 2-methyl-,

5-Methoxy-, 5-benzyloxy-, 5-chloro- or 4,5-dimethylindole-2-

-yl) -, (1-benzylindol-2-yl or -3-yl) -, 4,5,6,7-tetrahydroindol-2-yl-, (2-, 3- or 4-quinolyl or 4-hydroxyquinolol) -2-yl) -, (1-, 3- or 4-isoquinolyl or 1-oxo-1,2-dihydroisoquinol-3-yl) -, 3-pyrrolidinyl-, (3- or 4-hydroxypyrrolidin-2-yl) -, 5-oxopyrrolidin-2-yl-, (2- or 3-morpholinyl) -, (2- or 3-thiomorpholinyl) -, (S, S-dioxothiomorpholin-2- or -3-yl) &quot; (2- or 3-indolinyl) -, (1,2,3,4-tetrahydroquinol-2-, -3- or -4-yl) - and (1,2,3,4-tetrahydroisoquinol-1 -, - 2-or 3-or ylJmethoxysulfonyl -ethoxysulfonyl, aryl- (lower alkoxy) -sulfonyl, e.g., which includes optionally substituted aryl (lower alkyl) radical designated under the aryl (lower alkyl) R _HR R _2, • - · - - ....

Rg. and R 8 is as normal alkoxy sulfonyl, hydroxy- (lower alkoxy) -sulfonyl groups such as 3-hydroxypropoxy- or 2-hydroxy-3-methylpentyloxysulfonyl, (lower alkoxy) - (lower alkoxy) -sulfonyl groups, for example (lower alkoxy) -ethoxy- or (lower alkoxy) -propoxysulfonyl groups such as methoxyethoxy- or 3-methoxypropoxysulfonyl, (lower alkoxy) - (lower alkoxy) - (lower alkoxy) -sulfonyl groups such as 2-methoxymethoxy-3 -methylpentyloxysulfonyl, phenoxy- (lower alkoxy) -sulfonyl or nitrophenoxy- (lower alkoxy) -sulfonyl groups such as phenoxymethoxy-,

74 phenoxyethoxy- or 4-nitrophenoxymethoxysulfonyl, naphthyloxy- (lower alkoxy) -sulfonyl groups such as α- or β-naphthyloxyethoxysulfonyl, (lower alkanoyl) -oxy- (lower alkoxy) -sulfonyl groups, for example (lower alkanoyl). oxyethoxy- or (lower alkanoyl) -oxypropoxysulfonyl groups such as acetoxyethoxy or 3-acetoxypropoxysulfonyl, amino- (lower alkoxy) sulfonyl groups such as

5-aminopentyloxysulfonyl, mono- or di- (lower alkyl) -amino- (lower alkoxy) -sulfonyl groups such as dimethylaminoethoxy- or 2-dimethylamino-2-isopropylethoxysulfonyl, (lower alkanoyl) -amino- (lower alkoxy) -sulfonyl groups groups such as 4-acetylaminopentyloxy-sulfonyl, (lower alkoxy) -carbonylamino- (lower alkoxy) -sulfonyl groups such as 5- (tert-butoxycarbonylamino) pentyloxy or 3'-ethoxycarbonylamino-2-isobutylpropoxysufonyl, phenyl- (lower alkoxy) carbonylamino- (lower alkoxy) -sulfonyl groups such as 5- (benzyloxycarbonylamino) pentyloxysufonyl;

acetoacetoxysulfonyl, aminocarbonylamino- (lower alkoxy) -sulfonyl groups such as aminocarbonylamino-ethoxy-sulfonyl,

N-phenyl- (lower alkyl) -N- (lower alkyl) -aminocarbonylamino- (lower alkoxy) -sulfonyl groups, for example 2-isobutyl-3- (N-benzyl-N-methylaminocarbonylamino) propoxysulfonyl, halogen- (lower alkoxy) -sulfonyl groups, for example 2-halenethoxy-, such as (2-chloro-, 2-bromo-, 2-iodo- or 2,2,2-trichloroethoxy) - or halopropoxy-, such as _: (3-chloro- or 3-bromopropoxy) sulfonyl, carboxy- (lower alkoxy) -sulfonyl groups such as carboxyethoxy- or 3-carboxypropoxysulfonyl, (lower alkoxy) -carbonyl- (lower alkoxy) -sulfonyl groups »

groups, for example, (lower alkoxy) -carbonylethoxy- or (lower alkoxy) -carbonylpropoxysulfonyl groups such as methoxycarbonylethoxy-, 3-methoxycarbonylpropoxy-, ethoxycarbonylethoxy- or 3-ethoxycarbonylpropoxysulfonyl,

2-halogen- (lower alkoxy) -carbonyl- (lower alkoxy) -sulfonyl groups such as (2-chloro, 2-bromo, 2-iodo) or

2,2,2-trichloroethoxycarbonyl-2-ethoxy or -3-propoxy) sulfonyl; : ..- · <·· ....... --5.-: · ·. ·;

(lower alkyl) -sulfonyl- (lower alkoxy) -sulfonyl groups such as (2-ethylsulfonyl- or 2-tert-butylsulfonylmethoxy) sulfonyl, carbamoyl- (lower alkoxy) -sulfonyl groups such as carbamoylethoxy- or 3-carbamoylpropoxysulfonyl and on the nitrogen atom by a residue selected from ethylene, trimethylene, tetramethylene and pentamethylene, wherein the carbon atom may be replaced by a nitrogen, oxygen, sulfur or oxygen atom with one or two substituted sulfur atoms, substituted carbamoyl- (lower alkoxy) -sulfonyl groups, the residue formed can also be wholly or partially unsaturated, for example as piperidino-, pyrazin-1-yl-, piperazin-1-yl-, pirimidin-1-yl-, pyridazin-1-yl-, morpholino-, thiomorpholino- or S, S-dioxothiomorpholinocarbonyl- (lower alkoxy) / -sulfonyl groups such as 2-morpholinocarbonylethoxy-, 3- (morpholinocarbonyl) propoxy- or 3- (morpholinocarbonyl) -2-isobutylpropoxysulfonyl.

Sulfonyl. aryloxy substituted with R _{2 l of} R, R _g and R includes preferably an optionally substituted aryl radical mentioned under aryl (lower alkanoyl) groups Rp _{R2, R8} and _R9 and is selected especially from benzyloxysulfonylu and 1- or 2-naftyloxysulfonylu .

... sulfamoyl groups substituted on the nitrogen, R _x, R _2, R _g and R g may preferably be substituted by the same radicals * such as carbamoyl or carbamoyl (lower alkanoyl) R _{I ',} R _2, R g and R _g and especially selected from a mono- or di- (lower alkyl) -sulfamoyl group such as N, N-dimethylsulfamoyl, N- (phenyl- or naphthyl- (lower alkyl)) -sulfamoyl group such as 3-benzylsulfamoyl, and na a nitrogen atom with a residue selected from ethylene, trimethylene, tetramethylene or pentamethylene, wherein the carbon atom may be replaced by a nitrogen atom optionally substituted by a lower alkyl group such as a methyl, oxygen, sulfur or oxygen atom substituted by one or two times a substituted sulfur atom sulfamoyl, the residue thus formed may also be wholly or partially unsaturated, such as piperidino-, pyrazin-1-yl-, piperazin-1-yl-, methylpiperazin-1-yl-, pirimidin-1-yl-, pyridazine- 1-yl-, mo rfolino-, thiomorpholino- or

S, S-dioxothiomorpholinosulfonyl such as 4-methylpiperazinylsulfonyl or (morpholinosulfonyl) -2-isopropylpropyl.

The phosphoryl group R 1, R ₂ , R g and R _g , substituted with one or two independently selected radicals selected from alkyl, cycloalkyl, cycloalkyl (lower alkyl), aryl, aryl (lower alkyl), hydroxy, alkoxy, cycloalkyloxy, cycloalkyl (lower alkoxy), aryloxy and aryl (lower alkoxy), preferably comprises as an optionally substituted alkyl group one or two substituted or unsubstituted radicals mentioned under alkyl groups, especially lower alkyl, R _{2 l of} R, R and Rg, such as

- a lower alkyl group such as methyl, ethyl, propyl, isopropyl, n-butyl or tert-butyl,

- cycloalkyl (lower alkyl) group is a terminal that particularly the lower alkyl radical substituted cycloalkyl as described below cycloalkyl- (lower alkanoyl) by R ·]., R _2, R g and R _g, such as cyclopropylmethyl, cykobutylmethyl, cyclopentylmethyl, 2 -cyclopentylethyl, 3-cyclopentylpropyl, cyclohexylmethyl, 2-cyclohexylethyl or 3-cyclohexylpropyl,

aryl- (lower alkyl) group as defined under aryl (lower alkyl) R _{2 l of} R, R and »R, Extra benzyl, unsubstituted, mono- or polysubstituted by lower alkyl, for example methyl, phenyl, hydroxy, lower alkoxy such as methoxy. a pin, halogen atom such as chlorine and / or a nitro group such as 4-methoxy-, 4-chloro- or 4-nitrobenzyl, naphthylmethyl such as α- or β-naphthylmethyl, 2-phenylethyl, 2-α-naphthylethyl, 2- β-η 3 Γ ethylethyl, 2- (lower alkyl) -phenylethyl, such as 2- (4-methylphenyl) ethyl, 2- (lower alkoxy) -phenylethyl, such as 2- (4-methoxyphenyl) ethyl,

2,2-diphenylethyl, 2,2-di- (4-methoxyphenyl) ethyl, 2,2,2-triphenylethyl, 2,2-dibenzylethyl, 2, p-diaminophenylethyl phenyl- (lower alkyl) substituted at the 2-position, and para two radicals selected from phenyl- (lower alkoxy)

-carbonyl groups such as benzyloxycarbonyl and (lower alkanoyl) amino groups such as pivaloylamino groups such as 2, p-dibenzyloxycarbonylaminophenethyl or 2-pivaloylamino-p-benzyloxycarbonylaminophenethyl, 3-phenylpropyl, 3- (p-hydroxyphenyl) propyl or 3-p-naphthylpropyl, 2-benzyl-3- (1-pyrazolyl) propyl, 3-phenyl- or 3-α-naphthyl-2-hydroxypropyl, 3-phenyl- or 3-α-naphthyl-2- (lower) alkoxy) -propyl such as 3-phenyl- or 3-α-naphthyl-2-neopentyloxypropyl, 3-phenyl- or 3-α-naphthyl-2- (lower alkanoyl) oxypropyl such as 3-phenyl- or 3-α-naphthyl-2-pivaloyloxy- or -2-acetoxypropyl, 2-benzyl- or 1- or 2-naphthyl-3- (N-methoxy-N-methylamino) propyl, 3-phenyl- or 3-a -naphthyl-2-dimethylaminomethylpropyl, 3-α-naphthyl-2-acetoacetoxypropyl, 3-α-naphthyl-2-ethylaminocarbonyloxypropyl, or 3-α-naphthyl-2- (2-amino- or 2-benzyloxycarbonylamino-2-methylpropionyloxy) propyl , 3-phenyl- or 3-α-naphthyl-2-carboxymethylpropyl, 3-phenyl- or 3-an an aftyl-2- (lower alkoxy) carbonylpropyl group such as 3-α-naphthyl-2-ethoxycarbonylpropyl, 3-phenyl- or 3-α-naphthyl-2-benzyloxycarbonylmethylpropyl, 2 (S) -benzyl-3-tert-butyl . -butylsulphonylpropyl, 3-phenyl-2-phosphono- or -phosphonomethylpropyl, 3-phenyl-2-dimethoxyphosphoryl- or -dimethoxyphosphorylmethylpropyl, 3-phenyl-2-diethoxyphosphoryl- or -diethoxyphosphorylmethylpropyl, 3-phenyl-2-ethoxyphenyl or -methoxymethyl- , 3-phenyl- or 3-α-naphthyl-2-carbamoylpropyl, 3-phenyl- or 3-α-naphthyl-2-tert-butylcarbamoylpropyl, 3-phenyl- or 3-α-naphthyl-2- (2- dimethylaminoethyl) carbamoylpropyl, 3-α-naphthyl-2- (carboxy- or tert-butoxycarbonyl) methylcarbamoylpropyl, 3-phenyl- or 3-α-naphthyl-2- (3-hydroxy-2-propyl) carbamoylpropyl, 3-phenyl - or 3-α-naphthyl-2- (2,2-dimethoxyethyl) carbamoylpropyl, 3-phenyl- or 3-α-naphthyl-2- (5-amino-5-carboxypentyl) carbamoylpropyl, 3-phenyl- or 3- α-naphthyl-2-cyanopropyl, 3-phenyl- or 3-α-naphthyl-2-cyanomethylpropyl, 3-phenyl- or 3-α-naphthyl-2-acetonylpropyl, 4-hydroxyphenylbutyl, 4-phenyl- or 4-.alpha.-naphthyl-3-carboxybutyl, 479

-phenyl- or 4-α-naphthyl-3-benzyloxycarbonylbutyl, 2-benzylor 2-α-naphthylmethyl-4-cyanbutyl, 2-benzyl-4- (benzofuranyl) -4-oxobutyl, 2-benzyl- or 2-a- naphthylmethyl-4-dimethylaminopentyl, 2-benzyl-. or 2-α-naphthylmethyl-4-oxopentyl, 2-benzyl- or 2-α-naphthylmethyl-4,4-dimethyl-3-oxopentyl, 2-benzyl- or 2-α-naphthylmethyl-5-methylamino-4-oxopentyl or 2-benzyl- or 2-α-naphthylmethyl-5, 5-dimethyl-4-oxohexyl,

. cycloalkyl radical as defined for cycloalkyl (lower alkanoyl) with R _{2 l of} R, R g and R _g, in particular cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, an aryl group such as optionally. substituted radicals below the aryl- (lower alkanoyl) group R 1, R ₂ , R g and R g, preferably phenyl, unsubstituted, mono- or polysubstituted lower alkyl, for example methyl, halogen- (lower alkyl), for example trifluoromethyl, phenyl hydroxy, lower alkoxy, e.g. methoxy, halogen, e.g. fluorine or chlorine, and / or nitro, such as 4-methyl-, 3-hydroxy-, 4-methoxy-, 4-chloro- or 4-nitrophenyl, naphthyl, such as α- or β-naphthyl, or in the phenyl radical one or two radicals selected from lower alkyl such as methyl or ethyl, hydroxy, lower alkoxy such as methoxy, amino, mono- or di- (lower alkyl) amino such as ethylamino or dimethylamino, halogen atom such as fluorine or chlorine, carboxy, sulfo, carbamoyl, sulfamoyl and cyano and / or on the amino group a residue selected from an alkyl group and a benzyl substituted anilonophenyl group such as 2- (o, o-dichloroanilino) phenyl or 2- (o, o-dichloro-N-benzylanilino) phenyl,

is alkoxy optionally substituted jme- 80 defined by the sulfonyl group substituted by an alkoxy group R _{2 l of} R, R ₈ and R _g, that is especially lower alkoxy, such as methoxy, ethoxy or tert-butoxy, cycloalkyl (lower alkoxyskupinaj-linked to the rest oxygen atom, which appears in phosphoryl substituted cycloalkyl (lower alkyl) R _{2 l of} R, R and R _8, such as cyclopropylmethoxy, cyklobutylmethoxyskupina, cyclopentylmethoxy, 2-cyklopentylethoxyskupina, 3-cyklopentylprcpoxyskupina, cýklohexýlmethoxyskupina, 2-or 3 cyklohexylethoxyskupina -cyklohexylpropoxyskupina, aryl- (lower alkoxy) radical is linked via an oxygen atom that is listed in the sulfonyl group substituted by aryl (lower alkoxy) R p R _2, R g and R _g, particularly benzyloxy, hydroxy (lower alkoxy) such as 3-hydroxypropoxy or 2-hydroxy-3-methylpentyloxy, (lower alkoxy) - (lower alkoxy), for example, (lower alkoxy) ethoxy group or a (lower alkoxy) propoxy; such as methoxypropoxy or 3-methoxypropoxy, (lower alkoxy) - (lower alkoxy) - (lower alkoxy), such as 2-methoxymethoxy-3-methylpentyloxy, -phenoxy- (lower alkoxy), or nitrophenoxy- (lower alkoxy), such as phenoxymethoxy , phenoxyethoxy, or 4-nitrophenoxymethoxy, naphthyloxy (lower alkoxy), such as α- or β-naphthyloxyethoxy, (lower alkanoyl) -oxy- (lower alkoxy), such as (lower alkanoyl) -oxyethoxypropoxy, or (lower alkanoyloxy), or (lower alkanoyl) , such as acetoxyethoxy, or 3-acetoxypropoxy, amino- (lower alkoxy) -group such as 5-aminopentyloxy, mono- or di- (lower alkyl) -amino- (lower alkoxy) -group such as dimethylaminoethoxy or 2- dimethylamino-2-isopropylethoxy, (lower alkanoyl) -amino- (lower alkoxy) -group such as 4-acetylaminopentyloxy, (lower alkoxy) -carbonylamino- (lower alkoxy), such as 5- (tert-butoxycarbonylamino) p entyloxy or 3-ethoxycarbonylamirio-2-isobutylpropoxy, phenyl- (lower alkoxy) -carbonylamino- (lower alkoxy) such as 5- (benzyloxycarbonylamino) pentyloxy, aminocarbonylamino- (lower alkoxy) amino, such as aminocarbonylamino- lower alkyl) -N- (lower alkyl) aminocarbonylamino- (lower alkoxy) such as 2-isobutyl-3- (N-benzyl-N-methylaminocarbonylamino) propoxy, halogen- (lower alkoxy) such as 2-haloethoxy such as 2-chloro-, 2-bromo-, 2-iodo-, 2,2,2-trichloroethoxy or halopropoxy such as 3-chloro- or 3-bromopropoxy, carboxy- (lower alkoxy) such as carboxyethoxy or 3-carboxypropoxy , (lower alkoxy) -carbonyl- (lower alkoxy), for example (lower alkoxy) -carbonylethoxy or (lower alkoxy) -carbonylpropoxy, such as methoxycarbonylethoxy, 3-methoxycarbonylpropoxy, ethoxycarbonyl-ethoxy or 3 propoxy, 2-halo- (lower alkoxy) -carbonyl- (lower alkoxy) such as 2-chloro, 2-bromo, 2-iodo or 2,4-trichloroethoxycarbonyl-2-ethoxy or -3-propoxy (lower alkyl) -sulfonyl- (lower alkoxy), such as 2-ethylsulfonyl- or 2-tert-butylsulfonylmethoxy, carbamoyl- (lower alkoxy), such as carbamoylethoxy or 3-carbamoylpropoxy, or on the remainder of the nitrogen atom ethylene, trimethylene, tetramethylene and pentamethylene, wherein. the carbon atom may be replaced by a nitrogen, oxygen, sulfur or oxygen atom with a single or double substituted sulfur atom, a substituted carbamoyl- (lower alkoxy) group, and the residue thus formed may also be wholly or partially unsaturated, such as (piperidino-, pyrazine- 1-yl-, piperazin-1-yl-, pirimidin-1-yl-, pyridazin-1-yl-, morpholino-, thiomorpholino- or S, S-dioxothiomorpholinocarbonyl) - (lower alkoxy) as in 2-morpholinocarbonylethoxy, 3- (morpholinocarbonyl) propoxy or 3- (morpholinocarbonyl) -2-isobutylpropoxy, such as cycloalkoxy via a cyclic oxygen atom. 82 .-.

loalkylové radicals mentioned under cycloalkyl (lower alkanoyl) by R _T, R _2, R g and R _g, such as cyclobutoxy, cyclopentyloxy or cyclohexyloxy group or a aryloxy radical designated under sulfonyl substituted aryloxy group R, R _2, R g and R _g, as a particular benzyloxy or 1- or 2-naphthyloxy group, and in a particularly preferred embodiment is (lower alkyl) -phosphoryl, such as tert-butylphosphoryl, hydroxy- (lower alkoxy) -phosphoryl, such as hydroxymethoxyphosphoryl or hydroxyethoxyphosphoryl, or di - (lower alkoxy) -phosphoryl, such as dimethoxyphosphoryl or diethoxyphosphoryl.

The phosphono group and the individually defined radicals R 1, R ₂ , R g or R _g mentioned for the substituted phosphoryl group may also be independent of one another in defining the radicals R ₂ , R 8 or R _g in the compounds of formula I.

Preferably, only a maximum of in each case one of the radicals R ₁ and R _2, or the radicals R and R _g as defined radicals listed under acyl, sulfo, substituted sulfo, phosphono or substituted phosphoryl group, while the other certain radicals are each selected from the remaining designated substituent.

The pairs of substituents R 1 and R ₂ or R _g and R _g , independently of each other, together with the nitrogen atom to which they are attached, form a heterocyclic ring consisting of a bonding nitrogen atom, together with a residue selected from ethylene, trimethylene, tetramethylene and pentamethylene wherein the carbon atom may be replaced by a nitrogen, oxygen, sulfur or oxygen atom with one or two times a substituted sulfur atom, which may also be unsaturated, or with a residue with each oxosubstituent on both carbon atoms bonded to both carbon atoms ä-fused with or without a benzene or naphthalene ring, is preferably piperidino, pyrazin-1-yl, piperazin-1-yl, pirimidin-1-yl, pyridazin-1-yl, morpholino, thiomorpholino, S, S-dioxothiomorpholino, succinimidino, malimido, oxalimido, maleimido, phthalinido or naphthalene-1,8-dicarbonylimido, preferably with only one The line of the substituents R 1 and R ₂ or R 8 and R 8 forms one of said heterocyclic rings.

An optionally substituted alkyl group R, R ₄ and R ₇ preferably is one of substituted or unsubstituted radical mentioned under alkyl groups R _lf R _2, R _g and R a is in particular selected from lower alkyl, such as methyl, ethyl, propy1 , isopropyl, n-butyl, isobutyl or tert-butyl, "cycloalkyl (lower alkyl) group such as a cycloalkyl containing radical defined for cycloalkyl (lower alkanoyl) group of R] _, R _2, R g and R _g, that is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, wherein the cycloalkyl group is unsubstituted or is substituted one or three times by a lower alkyl group such as isopropyl, a halogen- (lower alkyl) group such as trifluoromethyl, hydroxy, lower alkoxy, carbamoyl- alkoxy), N- (lower alkyl) -carbamoyl- (lower alkoxy) or N, N-di- (lower alkyl) -carbamoyl- (lower alkoxy), amino mono- or di- (lower alkyl) amino, halogen, such as fluorine, chlorine or bromine, carboxy, (lower alkoxy) -carbonyl, phenyl, naphthyl or fluorenyl- (lower alkoxy) -carbonyl, lower alkanoyl, (lower alkyl) -sulfonyl, for example methylsulfonyl, phosphono, hydroxy- (lower alkoxy) -phosphoryl or di- (lower alkoxy) -phosphoryl, carbamoyl, mono- or di- (lower alkyl) -aminocarbamoyl sulfamoyl, mono- or di- (lower alkyl) -sulfamoyl, nitro and / or cyano and is bound, preferably at the end position, to the lower; alkyl, especially methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, such as cyclobutyl-, cyclopentyl-, cyclohexyl- or cycloheptyl- (lower alkyl), such as -methyl or -ethyl a particularly preferred cyclohexyl (lower alkyl) group such as cyclohexylmethyl;

. bicycloalkyl- (lower alkyl) groups in which the bicycloalkyl moiety contains, for example, 5 to 10 carbon atoms, especially 6 to 9 carbon atoms, such as, for example, bicycloalkylmethyl or -ethyl, preferably 8 to 11 carbon atoms, such as decahydronaphthyl-2- methyl, endo- or exo-norbornyl-2-methyl, bicyclo [2.2.2] oct-2-ylmethyl or bicyclo [3.3.1] non-9-ylmethyl, followed by bicyclohexyl-, -heptyl-, -octyl; -, -nonyl-, -decylethyl or -3-propyl. for example, bicyclo [3.1.0] hex-1-, -2- or -3-i-yl-, bicyclo [4.1.0] hept-1- or -7-yl-, bicyclo [2.2.1] hept-2-yl-, for example endo- or exo-norbornyl-, bicyclo [3,2,1] oct-2-yl-, bicyclo [3.3.0] oct-3-yl- or bicyclo [3.3. 1] non-9-yl-, further α- or β-decahydronaphthylethyl or -3-propyl; * tricycloalkyl- (lower alkyl) groups in which the tricycloalkyl moiety contains, for example, 8 to 10 carbon atoms, such as tricycloalkylmethyl or -ethyl, preferably from 8 to 11 carbon atoms, such as 1- or 2-adamantylmethyl, further tricyklof5,2,1, O ² '6] dec-8-yl- or adamantyl-, such as 1-adamantylethyl, aryl (lower alkyl ) group, e.g., as defined under aryl (lower alkyl) group, R _2, R g and R _g, which is unsubstituted or substituted as indicated in the body of the text disclosed, for example, phenyl (lower alkyl) groups such as benzyl, 2- phenylethyl, 3-phenylpropyl, 4-fluoro, 4-cyano, 4-methoxy- or 4-hydroxybenzyl, 1- or 2-naphthylmethyl or -2-ethyl, particularly preferred. phenyl- (lower alkyl) groups, as defined above, heterocyclyl- (lower alkyl) groups, defined as below the heterocyclyl- (lower alkyl) group R _x , R ₂ , R g or R _g , which is not substituted or is substituted as is described herein, which is especially selected from pyrimidin-1-yl-, piperidino-, pyrazin-1-yl-, piperazin-1-yl, pyridazin-1-yl-, raorfolino-, thiomorpholino- or S, S -dioxothiomorpholino- (lower alkyl) groups, as in 2-morpholinoethyl. 3-morpholinopropyl or 3-morpholino-2-isobutylpropyl, unsubstituted or lower alkyl or phenyl substituted pyrrolyl- (lower alkyl) groups such as 2-pyrrolyl- or 3-pyrrolylmethyl, ethyl or -n-propyl, 4-or 5-methylpyrrolylmethyl, -ethyl or -n-propyl or 4-or 5-phenylpyrrolylmethyl, -ethyl or -n-propyl, thienyl- (lower alkyl) groups such as 2-thienylmethyl, -ethyl or -n-propyl, 1-imidazolylmethyl , furyl- (lower-alkyl) groups such as 2-furylmethyl, -ethyl or -m-propyl, pyridyl- (lower alkyl) groups such as 2-, 3- or 4-pyridylmethyl, n -ethyl or - n-propyl, unsubstituted or lower alkyl, such as methyl, phenyl (lower alkyl), such as benzyl, lower alkoxy, such as methoxy, phenyl (lower alkoxy), such as benzyloxy, or halogen, such as chloro, substituted indolyl- (lower alkyl) groups such as 2-, 3- or 5-indolylmethyl, -ethyl or -n-propyl, (1-methyl-, 2-methyl-, 5-methoxy-, 5-benzyloxy-, 5-chloro- or

4,5-dimethyl) indol-2-yl-, 1-benzindol-2-yl- or -3-ylmethyl, -ethyl or -n-propyl, 4,5,6,7-tetrahydroindro-2-ylmethyl,

-ethyl or -n-propyl, cyclohepta [b] pyrrol-5-ylmethyl, -ethyl or -n-propyl, unsubstituted or hydroxy substituted quinolyl- (lower alkyl) groups such as 2-, 3- or 4-quinolyl - or 4-hydroxyquinol-2-ylmethyl, -ethyl or -n-propyl, unsubstituted or hydroxy substituted isoquinolyl- (lower alkyl) groups such as 1-, 3- or 4-isoquinolyl- or 1-oxo-1,2 -dihydroisoquinol-3-ylmethyl, -ethyl or -n-propyl, 2-quinoxalinylmethyl; -ethyl or -n-propyl, 3,1-benzfuran-2-ylmethyl, -ethyl or -n-propyl, benz [e] indol-2-ylmethyl, -ethyl or -n-propyl, β-carbolin-3- ylmethyl, -ethyl or -n-propyl, 3-chromanylmethyl, -ethyl or -n-propyl, 3-thiochromanylmethyl-ethyl or -n-propyl, 3- or 4-pyrrolidinylmethyl, -ethyl or -n-propyl, hydroxypyrrolidines 1- (lower alkyl) groups such as 3- or 4-hydroxypyrrolidin-2-ylmethyl, -ethyl or -n-propyl, oxopyrrolidinyl- (lower alkyl ^c ) groups such as 5-oxopyrrolidin-2-ylmethyl; ethyl or -n-propyl, piperidinyl- (lower alkyl) groups such as 2-, 3- or 4-piperidinylmethyl, -ethyl or -n-propyl, morpholinyl- (lower alkyl) groups such as 2- or 3- morpholinylmethyl, -ethyl or -n-propyl, thiomorpholinyl- (lower alkyl) groups such as 2 or 3-thiomorpholinylmethyl, -ethyl or -n-propyl, S, S-dioxothiomorpholinyl- (lower alkyl) groups such as S, S -dioxothiomorpholin-2- or -3-ylmethyl, -ethyl or -n-propyl, indolinyl- (lower alk yl) groups such as 2- or 3-indolinylmethyl, -ethyl or -n-propyl, 1,2,3,4-tetrahydroquinolyl- (lower alkyl) groups such as 1,2,3,4-tetrahydroquinol- 2-, -3- or -4-ylmethyl, -ethyl or -n-propyl, 1,2,3,4-tetrahydroisoquinolyl- (lower alkyl) groups such as

1,2,3,4-tetrahydroisoquinol-1-, -2- or -3-ylmethyl, -ethyl or -n-propyl and 1-oxo-1,2,3,4-tetrahydroisoquinol-3-ylmethyl, -ethyl or -n-propyl, hydroxy- (lower alkyl) groups such as 3-hydroxypropyl or 2-hydroxy-3-methylpentyl,

(lower alkoxy) - (lower alkyl) groups, for example (lower alkoxy) -ethyl or (lower alkoxy) -propyl groups, such as 2-methoxyethyl, 2-ethoxyethyl or 3-methoxypropyl,. . F phenoxy- (lower alkyl) or nitrophenoxy- (lower alkyl) 6 groups such as phenoxymethyl. phenoxyethyl or 4-nitrophenoxymethyl, naphthyloxy- (lower alkyl) groups such as α- or

O-naphthyloxyethyl, (lower alkanoyl) -oxy- (lower alkyl) groups, for example (lower alkanoyl) -oxyethyl or (lower alkanoyl) -oxypropyl groups such as acetoxyethyl or 3-acetoxypropyl, acetoacetoxy- (lower alkanoyl) groups, arylmercapto - (lower alkyl) groups wherein the aryl moiety contains a 6 to 10-carbon atom, for example phenyl or naphthyl such as phenylmercaptomethyl, amino- (lower alkyl) groups such as 5-aminopentyl,

? ·

mono- or di- (lower alkyl) -amino- (lower alkyl). 'PP' groups such as dimethylaminoethyl or 2-dimethylamino-2-isopropylethyl, phenyl or naphthylamino- (lower alkyl) groups such as 3-phenylaminopropyl, (lower alkanoyl) amino- (lower alkyl) groups such as 4-acetylaminopentyl, lower alkyl such as methyl, piperazinylcarbammonium- (lower alkyl) substituted on the atom, such as 4-methylpiperazinylcarbonylmethyl, (lower alkoxy) carbonylamino- (lower alkyl) groups such as 5- (tert. -butoxycarbonylamino) pentyl or 3-ethoxycarbonylamino-2-isobutylpropyl, phenyl- (lower alkoxy) -carbonylamino- (lower alkyl) groups such as 5- (benzyloxycarbonylamino) pentyl, *

aminocarbonylamino- (lower alkyl) groups such as 2-aminocarbonylaminoethyl,

N-phenyl- (lower alkyl) -N- (lower alkyl) -aminocarbonylamino- (lower alkyl) groups such as 2-isobutyl-3- (N-benzyl-N-methylaminocarbonylamino) propyl, halogen- (lower alkyl) groups wherein the halogen atom is selected from fluorine, chlorine, bromine and iodine, for example 2-haloethyl such as 2-fluoro-, 2-chloro, 2-bromo, 2-iodo, 2,2,2-trifluoro - or 2,2,2-trichloroethyl, trifluoro- (lower alkyl) groups such as trifluoromethyl, or halopropyl, such as 3-fluoro-, 3-chloro- or 3-bromopropyl, carboxy- (lower alkyl) groups, such as carboxyethyl or 3-carboxypropyl, (lower alkoxy) -carbonyl- (lower alkyl) groups, for example (lower alkoxy) -carbonylethyl or (lower alkoxy) -carbonylpropyl groups such as methoxycarbonylethyl, 3-methoxycarbonylpropyl, ethoxycarbonylethyl or 3-ethoxycarbonylethyl .

2-halo- (lower alkoxy) -carbonyl- (lower alkyl) groups such as 2-chloro-, 2-bromo-, 2-iodo- or 2,2,2-tri89 chloroethoxycarbonyl-2-ethyl or -3- propyl, phenyl or naphthyl (lower alkoxy) carbonyl (lower alkyl) groups, for example benzyloxycarbonyl (lower alkyl) groups such as 3-benzyloxycarbonyl-2,2-dimethylpropyl; . heterocyclyl- (lower alkoxy) -carbonyl- (lower alkyl) groups, wherein the heterocyclyl moiety is preferably selected from pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolinyl, quinoxolyolyl, isoxinoolino , β-carbolinyl and a benzanellated, cyclopentaanellated, cyclohexaanellated or cycloheptaanellated derivative thereof. and these radicals may also be partially or fully saturated, such as in 4-pyridylmethoxycarbonyl-2-ethyl or -3-propyl or 2-morpholinocarbonyloxy-4-methylpentyl, (lower alkyl) -sulfonyl- (lower alkyl) groups, such as for example, is 2-ethylsulfonyl- or 2-tert-butylsulfonylme. thyl ·, /. ... ·. .. ..

arylsulfonyl- (lower alkyl) groups, wherein the aryl moiety preferably contains 6 to 10 carbon atoms, for example phenyl or naphthyl such as phenylsulfonylmethyl, carbamoyl- (lower alkyl) groups such as carbamoylethyl or 3-carbamoylpropyl, (lower alkyl) -carbamoyl - (lower alkyl) groups, for example (lower alkyl) -carbamoylethyl or methylcarbamoyl- (lower alkyl) groups such as 2-methylcarbamoylethyl, di- (lower alkyl) -carbamoyl- (lower alkyl) groups, for example 2-di- ( lower alkyl) -carbamoylethyl or dimethylcarbamoyl- (lower alkyl) groups such as 2-dimethylcarba

moylethyl, hydroxy- (lower alkyl) -carbamoyl- or di (hydroxy- (lower alkyl)) - carbamoyl- (lower alkyl) groups such as 2-hydroxymethylcarbamoyl- or di (hydroxymethyl) carbamoyl-2-ethyl or -3- propyl,.

N- (lower alkoxy) - (lower alkoxy) - (lower alkyl) -carbamoyl- (lower alkyl) groups such as 2-isopropyl-3- / 2- (2-methoxyethoxy) ethylaminocarbonyl / propyl, carboxy- (lower alkyl) ) -carbamoyl- or di (carboxy- (lower alkyl)) - carbamoyl- (lower alkyl) groups, such as carboxymethyl- or di (carboxymethyl) carbamoyl-2-ethyl or -3-propyl, from ethylene, trimethylene, tet -ramethylene and pentamethylene by a selected radical where the carbon atom can be replaced by a nitrogen, oxygen, sulfur or oxygen atom with one or two substituted sulfur atoms on the nitrogen atom of a substituted carbamoyl- (lower alkyl) group, the residues thus formed may be wholly or partially unsaturated, such as piperidino-, pyrazin-1-yl-, piperazin-1-yl-, pyrimidin-1-yl-, pyridazin-1-yl-, morpholino-, thiomorpholinone or S, S-dioxothiomorpholinocarbonyl- (lower alkyl) ) a group such as in 2-morpholinocarbonylethyl, 3- (morpholinocarbonyl) propyl or 3- (morpholinocarbonyl) -2-isobutylpropylu,

N- (lower alkyl) -N-heterocyclyl- (lower alkyl) -carbamoyl- (lower alkyl) groups wherein the heterocyclyl moiety is s. preferably selected from pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, quinoxalinyl, β-carbolinyl and β-carbolinyl, β-carbolinyl, cyclopentaanellated, cyclohepanellate, partially or fully saturated, such as 2- (N-2-pyridylmethyl) -N-methylcarbamoylethyl, sulfamoyl- (lower alkyl) groups such as 2-sulfamoylethyl,

N- (phenyl- or naphthyl- (lower alkyl)) - sulfamoyl- (lower alkyl) groups such as 3-benzylaminosulfonyl-2-isopropylpropyl. or on a nitrogen atom of ethylene, trimethylene, tetramethylene and pentamethylene by a selected residue in which the carbon atom can be replaced by a nitrogen atom, a lower alkyl group such as methyl, a substituted nitrogen atom, an oxygen atom, a sulfur atom or substituted sulfamoyl- (lower alkyl) groups, the resulting residue may be wholly or partially unsaturated, such as piperidin-, pyrazin-1-yl-, piperazin-1-yl-, 4-methylpiperazin-1-yl-, pyrimidine -1-yl-, pyridazin-1-yl-1'-morpholino-thiomorpholinoor S, S-dioxothiomorpholinosulfonyl- (lower alkyl) group, for example 3- (4-methylpiperazinylsulfonyl) -2-isopropylpropyl or 3- (morpholinylsulfonyl) -2- isopropylpropyl, i

oxo (lower alkyl) groups (wherein the oxo residue is not on a carbon atom that is linked to the nitrogen atom bearing the radical R @ 2), such as 3-oxo-n-butyl or 3-oxo-n-pentyl, cyano- (lower) alkyl) groups such as cyanomethyl, 2-cyanethyl, 2- or 3-cyan-n-propyl or 2-, 3- or 4-cyano-n-butyl, hydroxycarboxy- (lower alkyl) groups such as 2-hydroxy -2-carboxyethyl or 2-hydroxy-3-carboxypropyl,

-92 α-naphthyloxycarboxy- (lower alkyl) groups, such as

2-α-naphthyloxy-4-carboxy-n-butyl, hydroxy- (lower alkoxy) -carbonyl- (lower alkyl) groups, for example 2-hydroxy-2- (lower alkoxy) -carbonylethyl or -propyl or hydroxyethoxy- or hydroxymethoxycarbonyl - (lower alkyl) groups such as 2-hydroxy-2-ethoxy- or -methoxycarbonylethyl or 2-hydroxy-3-ethoxy- or -methoxycarbonylpropyl, α-naphthyloxy- (lower alkoxy) -carbonyl- (lower alkyl) groups such as α-naphthyloxy- (lower alkoxy) carbonyl-2H

-ethyl, -2-propyl or -2-butyryl or α-naphthyloxyethoxycarbonyl- (lower alkyl) groups such as α-naphthyloxyethoxycarbonyl-2-ethyl, 2-α-naphthyloxy-3-ethoxycarbonylpropyl or 2-α-naphthyloxy-4 -tert-butoxycarbonylbutyl, (lower alkyl) -carbonylhalo- (lower alkyl) groups such as 3-ethoxycarbonyl-2-difluoromethyl, α-naphthyloxybenzyloxycarbonyl- (lower alkyl) groups such as 2-α-naphthyloxy-3-benzyloxycarbonylpropyl esterified hydroxy- (lower alkoxy) -carbonyl- (lower alkyl) groups in which the hydroxy group is esterified by a lower alkanoyl group, for example acetyl, propionyl or pivaloyl, a cycloalkyl- (lower alkanoyl) group, wherein the cycloalkyl moiety contains 3 to 7 carbon atoms and the lower alkanoyl moiety is as defined above, for example, cyclohexylcarbonyl, 2-cyclohexyl- or 2-cyclopentylacetyl, bicycloalkyl- (lower alkanoyl), wherein the bicycloalkyl moiety contains from 5 to 10 carbon atoms; especially 6 to 9 carbon atoms, such as in bicyclohexyl-, -heptyl-, -octyl-, -nonyl- or -decylacetyl or -3-propionyl, for example bicyclo [3,1,1] hex-1-, -2- or -3 -yl-, bicyclo [4.1.0] hept-193 or -17-yl-, bicyclo [2.2.1] hept-2-yl-, such as endo- or exo-norbornyl-, bicyclof3,2, 1] oct-2-yl-, bicyclo [3.3.0] oct-3-yl- or bicyclo [3.3.1] inden-9-yl-, further α- or β-decahydronaphthyl-acetyl or -3-propionyl, tricycloalkyl- (lower alkanoyl) group, wherein the tricycloalkyl moiety contains for example 8 to 10 carbon atoms, such as the tricyclo [5,2, l, 0 ^{2 '6th]} dec-8-yl- or adamantyl-, such as 1-adamantyl acetyl, aryl (lower alkanoyl) wherein the aryl moiety contains 6 to 14 carbon atoms, such as phenyl, indenyl, indanyl, naphthyl, anthryl, phenanthryl, acenaphthyl or fluorenyl, and is unsubstituted or can be substituted one to three times by lower alkyl , hydroxy, lower alkoxy, carbamoyl- (lower alkoxy) group), N- (lower alkyl) -carbamoyl- (lower alkoxy) or N, N-di- (lower alkyl) -carbamoyl- (lower alkoxy), amino, mono- or di- (lower alkyl) -amino, atom halogen "such as fluorine, chlorine or bromine, carboxy, (lower alkoxy) -carbonyl, phenyl, naphthyl or fluorenyl- (lower alkoxy) -carbonyl, lower alkanoyl, (loweralkyl) -sulfonyl, for example methylsulfonyl, phosphono, hydroxy- (lower alkoxy) -phosphoryl, di- (lower alkoxy) -phosphoryl, carbamoyl, sulfamoyl, nitro and / or cyano, and (lower alkoxy) -carbonyl, for example tert-butoxycarbonyl, 2-halogen- (lower) an alkoxy) carbonyl group as defined above, or a phenyl- or fluorenyl- (lower alkoxy) carbonyl group, for example, benzyloxycarbonyl or 9-fluorenylmethoxycarbonyl such as 2-acetoxy-2-methoxycarbonylethyl, 2-benzoyloxy-, 2- ( 1- or 2-naphthoyloxy) -, 2 - (phenyl-2-acetoxy) -, 2- (1- or 2-naphthyl-2-acetoxy) -, 2- (4-methylphenyl-2-acetoxy) -, 2- (4-methoxyphenyl-2-acetoxy) - or 2- [2- (o, o-dichlorophenyl) -2-acetoxy] -2-methoxycarbonylethyl or -3-propyl, dihydroxycarboxy- (lower alkyl) groups, such as the

2,3-dihydroxy-3-carboxypropyl, dihydroxy- (lower alkoxy) -carbonyl- (lower alkyl) groups such as 2,3-dihydroxy-3-ethoxy- or -methoxycarbonylpropyl;

a lower alkanoyl group such as acetyl, propionyl or butyryl, a (lower alkoxy) carbonyl group, for example a tert-butylcarbonyl, phenyl- or fluorenyl- (lower alkoxy) -carbonyl group such as benzyloxycarbonyl or 9-fluorenylmethoxycarbonyl, (lower alkyl) -sulfonyl or toluenesulfonyl esterified dihydroxy- (lower alkoxy) -carbonyl- (lower alkyl) groups, for example di- (lower alkanoyl) -oxy- (lower alkoxy) -propyl groups such as 2,3-diacetoxy-3-methoxycarbonylpropyl α-naphthyloxy-di- (lower alkyl) -amino- (lower alkyl) groups such as 2-α-naphthyloxy-5-dimethylaminopentyl, α-naphthyloxycarbamoyl- (lower alkyl) groups such as 2-α- naphthyloxy-4-carbamoylbutyl, .alpha.-naphthyloxyoxo- (lower alkyl) groups (wherein the oxo residue is not on a carbon atom that is linked to the nitrogen atom bearing the radical R @ 2), such as 2-.alpha.-naphthyloxy-4-oxopentyl; naphthyloxycyan- (lower alkyl) groups such as 2-α-naphthyloxy cyanethyl or 2-α-naphthyloxy-4-cyanobutyl.

Preferred is a lower alkyl group which is unsubstituted or is substituted one or more times with hydroxy, lower alkoxy, amino, mono- or di- (lower alkyl) amino, fluorine or chlorine, or keto, with a lower alkyl group such as lower alkyl being particularly preferred. is methyl, ethyl, propyl, isopropyl

pollen, t-butyl, isobutyl or tert-butyl.

The cycloalkyl group R _g, R ₄ and R ₇ is preferably as defined below cycloalkyl- (lower alkanoyl) groups R _lf R _2, R ₈ and _Rg, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, the cycloalkyl group not substituted or substituted by one, or up to three, lower alkyl such as isopropyl, halogen- (lower alkyl) such as trifluoromethyl, hydroxy, lower alkoxy, carbamoyl- (lower alkoxy), N- (lower alkyl) -carbamoyl- (lower alkoxy) or N, N-di- (lower alkyl) -carbamoyl- (lower alkoxy), amino, mono- or di- (lower alkyl) amino, halogen, such as fluorine, chlorine or bromine, carboxy, (lower alkoxy) -carbonyl, phenyl-, naphthyl- or fluorenyl- (lower alkoxy) -carbonyl, lower alkanoyl or (lower alkyl) -sulfonyl, for example methylsulfonyl, phosphonium, hydroxy roxy- (lower alkoxy) -phosphoryl, di- (lower alkoxy) -phosphoryl, carbamoyl, mono- or di- (lower alkyl) -aminocarbamoyl, sulfamoyl, mono- or di- (lower alkyl) -sulfamoyl, nitro and / or or cyano, such as cyclobutyl, cyclopentyl. cyclohexyl or cycloheptyl, particularly preferred cyclohexyl.

/ • ^; ·

E /

Ir

'Ayra

The aryl group of R _g, R ₄ or _R? is preferably one of the unsubstituted or substituted aryl radical mentioned under aryl (lower alkanoyl) with R _{2 l of} R, R _g and R _g, and these are in particular phenyl, naphthyl or fluorenyl, that is unsubstituted or may be mono- or trisubstituted by lower alkyl such as isopropyl, halogen- (lower alkyl) such as trifluoromethyl, hydroxy, lower alkoxy, carbamoyl- (lower alkoxy), N- (lower alkyl) -carbamoyl- (lower alkoxy) or N, N-di- (lower alkyl) -carbamoyl- (lower alkoxy), amino- 96, mono- or di- (lower alkyl) -amino, halogen, such as fluorine of chlorine or bromine, carboxy, (lower alkoxy) -carbonyl, phenyl · -, naphthyl- or fluorenyl- (lower alkoxy) -carbonyl, lower alkanoyl or (lower alkyl) -sulfonyl, for example methylsulfonyl, phosphono, hydroxy- (lower alkoxy) -phosphoryl, di- (lower alkoxy) -phospho rylová,. carbamoyl, mono- or di- (lower alkyl) -aminocarbamoyl, sulfamoyl, mono- or di- (lower alkyl) -sulfamoyl, nitro and / or cyano, such as phenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-nitrophenyl, -cyanphenyl or 1- or 2-naphthyl.

Heterocycles Rg. R ₄ or R? Is preferably defined as mentioned below heterocyclyl R _lf R _2, R g and R _g, and is optionally substituted as in the context described above, and is especially selected from 2-or 3-pyrrolyl, 4- or 5- methylpyrrolyl or 4- or 5-phenylpyrrolyl, 2-thienyl, 2-furyl, 2-, 3- or 4-pyridyl, 2-,

3- or 5-indolyl, 1-methyl-, 2-methyl-, 5-methoxy-, 5-benzyloxy-, 5-chloro- or 4,5-dimethylindol-2-yl, 1-benzindol-2- or -3-yl, 4,5,6,7-tetrahydroindol-2-yl, cyclohepta (b] pyrrol-5-yl, 2-, 3- or 4-quinolyl or 4-hydroxyquinol-2-yl, 1-, 3- or 4-isoquinolyl, 1-oxo-1,2-dihydroisoquinol-3-yl, 2-quinoxalinyl, 3,1-benzfuran-2-yl, benz [e] indol-2-yl, p-carboline- 3-yl, 3-chromanyl, 3-thiochromanyl, 3-pyrrolidinyl, 3- or 4-hydroxypyrrolidin-2-yl, such as 5-oxopyrrolidin-2-yl, 2-, 3- or 4-piperidinyl, 2- or 3-yl; 3-morpholinyl, 2- or 3-thiomorpholinyl, S, S-dioxothiomorpholin-2- or -3-yl, 2- or 3-indolinyl, 1,2,3,4-tetrahydroquinol-2-, -3-, or -4-yl, 1,2,3,4-tetrahydroisoquinol-1-, -2- or -3-yl or 1-oxo-1,2,3,4-tetrahydroisoquinol-3-yl.

An optionally substituted alkenyl group R 8, R ₄ or: R ₇ is preferably defined as indicated under alkenyl. a group R, R _2, R g and R _g, and are especially the unsubstituted

Or a substituted lower alkenyl group, for example a lower alkenyl group, is mentioned in this context. like. vinyl, allyl, 3-butenyl 2nebo, cycloalkyl (lower alkenyl) group wherein the cycloalkyl moiety is as defined for cycloalkyl (lower alkanoyl) groups R, R _2, R g and R _g, and is unsubstituted or substituted by one or up to three times lower alkyl such as isopropyl, halogen- (lower alkyl) such as trifluoromethyl, hydroxy, lower alkoxy, carbamoyl- (lower alkoxy), N- (lower alkyl) -carbamoyl- (lower alkoxy) or N, N-di - (lower alkyl) -carbamoyl- (lower alkoxy), amino, mono- or di- (lower alkyl) -amino, halogen, such as fluorine, chlorine or bromine, carboxy, (lower alkoxy) -carbonyl, phenyl-, naphthyl- or fluorenyl- (lower alkoxy) -carbonyl, lower alkanoyl or (lower alkyl) -sulfonyl group such as methylsulfonyl, phosphono, hydroxy- (lower alkoxy) -phosphoryl, di- (lower alkoxy) -phosphoryl, carbamoyl , mono- or di- (lower, alkyl) -aminocarbamoyl, sulfamoyl, mono- or di- (lower alkyl) -sulfamoyl, nitro and / or cyano. and the substituent is especially attached to the terminal carbon atom of the lower alkenyl group, such as cyclobutyl-, cyclopentyl-, cyclohexyl- or cycloheptylmethyl-2-vinyl, -2- or -3-allyl or -2-, -3 or -4-but- 2-enyl, an aryl- (lower alkenyl) group with an optionally substituted aryl radical as defined under the aryl group R ₃ or R ₄ , which is preferably attached to the terminal lower alkenyl group and comprises a lower alkenyl radical as defined below the lower alkenyl group R 3; RgjRg and R _g, such as styryl, 3-phenyl allyl (cinnamyl), 2- (α-naphthyl) vinyl, or

... - -: ··· -98-.

2- (β-naphthyl) vinyl, or an optionally substituted heterocyclyl- (lower alkenyl) group which, for example, contains an optionally substituted lower alkenyl radical mentioned under the alkenyl group R R, R ₂ , Rg or R _g , for example vinyl, allyl or 2- the sky

3-butenyl, which is preferably substituted on the terminal carbon atom of the heterocyclyl radical optionally substituted heterocyclyl clip that R, R _2, R g and R _g, such as pyrimidin-l-yl, piperidino, pyrazin-1-yl piperazin-1-yl-, pyridazin-1-yl-, morpholino-, thiomorpholino- or S, S-dioxothiomorpholino- (lower alkenyl), such as in 2-morpholinovinyl, 3-morpholinoallyl or 4-morpholino-2- or -3-butenyl, pyrrolyl- (lower alkenyl) optionally substituted by lower alkyl or phenyl such as 2- or 3-pyrrolylvinyl or -allyl, 4- or 5-methylpyrrolylvinyl or -allyl. or 4- or 5-phenylpyrrolylvinyl or -allyl, thienyl- (lower alkenyl) group, such as 2-thienylvinyl or -allyl, furyl- (lower alkenyl) group, such as 2-furylvinyl- or -allyl, pyridyl- (lower alkenyl) group a group such as 2-, 3- or 4-pyridylvinyl or -allyl unsubstituted or lower alkyl such as methyl, phenyl (lower alkyl) such as benzyl, lower alkoxy such as methoxy, phenyl (lower alkoxy) such as benzyloxy, or halogen, such as chloro, substituted indolyl (lower alkenyl),. such as 2-, 3- or 5-indolylvinyl or -allyl, Ι-methyl-, 2-methyl, 5-methoxy-, 5-benzyloxy-, 5-chloro or 4,5-dimethylindol-2-yl-, 1-benzindole -2-yl- or -3-ylvinyl or -allyl, 4,5,6,7-tetrahydroindol-2-ylmethyl, -ethyl or -n-propyl, cyclohepta [b] pyrrol-5-ylvinyl or -allyl, unsubstituted or a hydroxy-substituted quinolyl- (lower alkenyl) group, for example 2-, 3- or 4-quinolyl- or 4-hydroxyquinol-2-ylvinyl or -allyl, unsubstituted or hydroxy-substituted isoquinolyl- (lower alkenyl) group, such as 1-, 3- or 4-isoquinolyl- or 1-oxo-1,2-dihydroisoquinol-3-ylvinyl or -allyl, 2-quinoxalinylvinyl or -allyl, 3,1-benzfuran-2-ylvinyl or -allyl, benz [ e] indol-2-ylvinyl or -allyl, p-carbolin-3-ylvinyl or -allyl, 3-chromanylvinyl or -allyl, 3-thiochromanylvinyl or -allyl, 3-pyrrolidinylvinyl or -allyl, hydroxypyrrolidinyl- (lower alkenyl) group such as 3- or 4-hydroxypyrrolidin-2-ylvinyl or -allyl, oxopyrrolidinyl- (ni lower alkenyl), such as 5-oxopyrrolidin-2-ylvinyl or -allyl, piperidinyl- (lower alkenyl), such as 2-, 3- or 4-piperidinylvinyl or -allyl, morpholinyl- (lower alkenyl), such as 2- or 3-morpholinylvinyl or -allyl, thiomorpholinyl- (lower alkenyl) group such as 2 or 3-thiomorpholinylvinyl or -allyl, S, S-dioxothiomorpholinyl- (lower alkenyl) group such as S, S-dioxothiomorpholine-2 or - 3-ylvinyl or -allyl, indolinyl- (lower alkenyl) group such as 2- or 3-indolinylvinyl or -allyl, 1,2,3,4-tetrahydroquinolyl- (lower alkenyl) group such as 1,2,3,4 -tetrahydroquinol-2-, -3- or -4-ylvinyl or -allyl, 1,2,3,

4-tetrahydroisoquinolyl- (lower alkenyl) group such as 1,2,3,4-tetrahydroisoquinol-1-, -2- or -3-ylvinyl or -allyl *

or oxo-1,2,3,4-tetrahydroisoquinol-3-ylvinyl or -allyl.

The optionally substituted alkylene group, taken together with R 8 and R _4, contains in particular an alkylene radical of up to 20 carbon atoms, said radicals may also contain one or more double bonds, preferably a lower alkylene group, for example ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene or heptamethylene, optionally substituted, separate optionally substituted aryl, as defined under aryl (lower alkanoyl) with R ^ ·, R _2, R g and R _g, preferably phenyl, indenylem, indanylem, naphthyl, anthrylem, fenanthrylem , acenaphthyl or fluorenyl, which is unsubstituted or substituted one to three times the radical

100 alkyl, such as methyl, ethyl or propyl, halogen- (lower alkyl), such as trifluoromethyl, phenyl, 1- or 2-naphthyl, hydroxy, lower alkoxy, such as methoxy, carbamoyl- (lower alkoxy), N- (lower alkyl) -carbamoyl- (lower alkoxy) or N, N-di- (lower alkyl) -carbamoyl- (lower alkoxy), amino, mono- or di- (lower alkyl) amino, (lower alkanoyl) -amino, for example pivaloylamino, halogen, for example fluorine, chlorine or bromine, carboxy, (lower alkoxy) -carbonyl, phenyl, naphthyl or fluorenyl- (lower alkoxy) -carbonyl or lower alkanoyl, sulfo, (lower alkyl) ) -sulfonyl group, for example methylsulfonyl, phosphono, hydroxy- (lower alkoxy) -phosphoryl, di- (lower alkoxy) -phosphoryl, carbamoyl, mono- or di- (lower alkyl) -aminocarbamoyl, sulfamoyl u, mono- or di- (lower alkyl) -sulfamoyl, nitro and / or cyano and / or substituted as a lower alkanoyl group in an aryl- (lower alkanoyl) group RR ₂ , R 8 or R 8, especially lower alkyl, for example methyl , hydroxy, lower alkoxy, for example methoxy or ethoxy, (lower alkanoyl) -oxy, for example acetoxy or propionyloxy, benzoyloxy, phenylacetoxy or 1 or 2'-naphthalkoxy, butoxy, tert-butoxycarbonyloxy, tert-butoxy, - (lower alkoxy) -carbonyloxy, for example benzyloxycarbonyloxy, 9-fluorenylmethoxycarbonyloxy, sulfonyloxy, (lower alkyl) -sulfonyloxy, for example methyl or ethylsulfonyloxy, phenylsulfonyloxy, mono- or 4-, -amino, to an example of mono- or dimethylamino- or -ethylamino (lower alkanoyl) -amino, for example acetylamino or pivaloylamino, carboxy

(Lower alkoxy) -carbonyl, for example isopropoxy- or tert-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, lower alkanoyl, for example acetyl or propionyl, (lower alkyl) -sulfonyl, such as methylsulfonyl or tert-butyl phosphono, carbamoyl, mono- or di- (lower alkyl) aminocarbamoyl, for example N-methylcarbamoyl or N, N-dimethylcarbamoyl, piperidino, pyrazin-1-yl, pyrimidin-1-yl, pyridazin-1-yl, morpholino, thiomorpholino or S, S-dioxothiomorpholino, sulfamoyl, oxo and / or cyano such as ethylene, ethylethylene, trimethylene, propylene or tetramethylene.

An optionally substituted alkylidene group formed together substituents R _g, and R ₄ has up to 20 carbon atoms, and none, one or more double bond forming a double bond, and is preferably a lower alkylidene radical, for example methylene, ethylidene, propylidene, butylidene and pentaliden, optionally substituted, cycloalkyl separate, as said clip cycloalkyl- (lower alkanoyl) group RR _2, R g and R _g, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, cycloalkenyl, as said clip cycloalkenyl (lower alkanoyl) groups R, R _2, R g and R _g, such as cyclohexen-y1 or 1,4-cyclohexadienyl, optionally substituted aryl, as said clip aryl- (lower alkanoyl) group R., R ₂ , R g and R _g, preferably phenyl, indenylem, indanylem, naphthyl, anthrylem, fenanthrylem, acenaftylem fluorenylem and which is unsubstituted or is substituted one to three times with a lower alkyl group such as methyl, ethyl or propyl, halogen- (lower alkyl) group such as trifluoromethyl, phenyl, 1- or 2-naphthyl, hydroxy, lower alkoxy such as methoxy, carb

102 moyl- (lower alkoxy), N- (lower alkyl) -carbamoyl- (lower alkoxy) or N, N-di- (lower alkyl) -carbamoyl- (lower alkoxy), amino, mono- or di- (lower alkyl) ) -amino, (lower alkanoyl) -amino, for example pivaloylamino, halogen, such as fluorine, chlorine or bromine, carboxy, (lower alkoxy) -carbonyl, phenyl, naphthyl or fluorenyl- (lower alkoxy) -carbonyl or lower alkanoyl, sulfo, (lower alkyl) -sulfonyl, for example methylsulfonyl, phosphono, hydroxy- (lower alkoxy) -phosphoryl or di- (lower alkoxy) -phosphoryl, carbamoyl, mono- or di- (lower alkyl) -aminocarbamoyl group, sulfamoyl, mono- or di- (lower alky1) sulphamoyl, nitro and / or cyano and / or substituted lower alkanoyl groups such as the aryl (lower an alkanoyl) group of R, R _2, R g and R _{g, more} lower alkyl, such as methyl, hydroxy, lower alkoxy, such as methoxy or ethoxy, (lower alkanoyl) -oxy, such as acetoxy or propionyloxy, benzoyloxy, phenylacethoxy, or 1- or 2-naphthoxycarbonyloxy, or tert-butoxycarbonyloxy, phenyl- (lower alkoxy) -carbonyloxy, for example benzyloxycarbonyloxy, 9-fluorenylmethoxycarbonyloxy, sulfonyloxy, (lower alkyl) -sulfonyloxy, for example methyl- or ethylsulfonyloxy- or di- (lower alkyl) -amino, for example mono- or dimethylamino- or -ethylamino, (lower alkanoyl) -amino, for example acetylamino or pivaloylamino, carboxy, (lower alkoxy) -carbonyl, for example i sopropoxy- or tert-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, a lower alkanoyl group such as acetyl or propionyl, (lower alkyl) -sulfonyl-103 dd · v;

A phenyl group such as methylsulfonyl or tert-butylsulfonyl, phosphono, carbamoyl, mono- or di- (lower alkyl) aminocarbamoyl, for example N-methylcarbamoyl or Ν, Ν-dimethylcarbamoyl, piperidino, pyrazin-1-yl , pyrimidin-1-yl, pyridazin-1-yl, morpholino, thiomorpholino or S, S-dioxothiomorpholino, sulfamoyl, oxo and / or cyano such as ethylidene, propylidene, butylidene, benzylidene or cinnamylidene.

'' R;

£ B

An optionally substituted benzofused alkylene group formed together by R 1 and R ₄ contains up to g.

and is preferably a lower alkylene group, e.g. ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene or heptamethylene to which it is fused. -2: 2 a benzene ring optionally substituted, separate optionally substituted aryl group, as mentioned below aryl (lower alkanoyl) groups R, R _2, R g and R _g, / preferably phenyl, indenylem, indanylem, naphthyl , anthryl, 7 '/> 5:

phenanthryl, acenaphthyl or fluorenyl, which is unsubstituted or substituted one to three times the radical. as lower alkyl, for example methyl, ethyl or propyl, halogen- (lower alkyl), for example trifluoromethyl, phenyl, 1- or 2-naphthyl, hydroxy, lower alkoxy, for example methoxy, carbamoyl- ( lower alkoxy), N- (lower alkyl) carbamoyl-;

- (lower alkoxy) or N, N-di- (lower alkyl) -carbamoyl-7 '

- (lower alkoxy), amino, mono- or di- (lower alkyl) -amino, (lower alkanoyl) -amino, for example pivaloylamino, halogen, for example fluorine, chlorine or bromine, carboxy, (lower alkoxy) -carbonyl, phenyl-, naphthyl- or fluorenyl- (lower alkoxy) -carbonyl or lower alkanoyl, sulfo, (lower alkyl) -sulfonyl, for example methylsulfonyl, phosphonium, hydroxy- (lower alkoxy) -phos

104 foryl, di- (lower alkoxy) -phosphoryl, carbamoyl, mono- or di- (lower alkyl) aminocarbamoyl, sulfamoyl, mono- or di- (lower alkyl) -sulfamoyl, nitro and / or cyano, further lower alkyl for example methyl, hydroxy, lower alkoxy, for example methoxy or ethoxy, (lower alkanoyl) -oxy, for example acetoxy or propionyloxy, benzoyloxy, phenylacetoxy or 1- or 2-naphthoyloxycarbonyloxy, (lower alkoxy) or (lower alkoxy). -butoxycarbonyloxy, phenyl- (lower alkoxy) -carbonyloxy, for example benzyloxycarbonyloxy, 9-fluorenylmethoxycarbonyloxy, sulfonyloxy, (lower alkyl) -sulfonyloxy, for example methyl or ethylsulfonyloxy, monosulfonyloxy, phenylsulfonyl, phenylsulfonyloxy, - or di- (lower alkyl) -am mono or dimethylamino or -ethylamino, (lower alkanoyl) -amino, e.g. acetylamino or pivaloylamino, carboxy. (lower alkoxy) -carbonyl, for example isopropoxy- or tert-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, lower alkanoyl, for example acetyl or propionyl, (lower alkyl) -sulfonyl, such as methylsulfonyl or tert-butylsulfonyl, phosphonosulfonyl , carbamoyl, mono- or di- (lower alkyl) aminocarbamoyl, for example N-methylcarbamoyl or N, N-dimethylcarbamoyl, piperidino, pyrazin-1-yl, pyrimidin-1-yl, pyridazin-1-yl, morpholino , thiomorpholino or S, S-dioxothiomorpholino, sulfamoyl, oxo and / or cyano such as o-phenylene.

In the case of compounds of the formula I substituted by the abovementioned radicals, the nitrogen atoms with free hydrogen and / or hydroxy groups are arranged vicinal to the double or

105 triple bonds (as in the case of optionally substituted alkenyl or alkynyl R ₁ , R ₂ , R _g or R _g ), the corresponding tautomeric imino and optionally oxo compounds are also included in each case.

Salts of the compounds of the formula I are in particular acid addition salts, salts with bases or, in the case of multivalent salt-forming groups present, also mixed or internal salts.

The salts are in particular pharmaceutically usable, non-toxic salts of the compounds of formula I.

Such salts are, for example, compounds of the formula I having an acidic group such as a carboxy, sulfo or phosphoryl group substituted with one or two hydroxy groups and are, for example, their salts with suitable bases, such as non-toxic metal-derived salts of 1a, 1b, IIa and IIb. a periodic group of the element, in particular alkali metal salts, for example lithium, sodium or potassium salts or alkaline earth salts such as magnesium or calcium salts, zinc salts or ammonium salts, and also those formed with organic amines such as monosubstituted hydroxy groups -, di- or trialkylamines, especially mono-, di- or tri- (lower alkyl) -amines, or with quaternary ammonium compounds, for example with N-methyl-N-ethylamine, diethylamine, triethylamine, mono-, bis- or tris - [2- (hydroxy- (lower alkyl)) - amines such as mono-, bis- or tris- (2-hydroxyethyl) amine, 2-hydroxy-tert-butylamine or tris (hydroxymethyl) amine, N, N-di- (lower alkyl) -N- (hydroxy- (lower alkyl)) amines such as N, N-dimethyl-N- (2-hydroxyethyl) amine or tri- (2-hydroxyethyl) amine, N-methyl-D-glucamine or quaternary ammonium salts such as tributylammonium salts. Compounds of formula I with basic groups, for example amino, can form salts with, for example, inorganic acids such as

106 are tralogenic acids, such as hydrochloric, sulfuric or phosphoric acid, or with organic carboxylic, sulfonic acids, sulfoacids or obsa acids. healing phosphorus, such as acetic, propionic, glycolic, succinic, maleic, hydroxymaline, methylmalein, fumaric, malic, tartaric, gluconic, glucaric, gluconic, citric, benzoic, cinnamon, almond, salicylic, 4- aminosalicylic, 2-phenoxybenzoic, 2-acetoxybenzoic, embon, nicotinic or isonicotinic, further with amino acids such as the aforementioned α-amino acids, especially glutamic and aspartic acid, the same as methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, ethanesulfonic acid, ethanesulfonic acid , 2-disulfonic, benzenesulfonic, 4-methylbenzenesulfonic, naphthalene-2-sulfonic, 2- or 3-phosphoglycerate, glucose-6-phosphate, with N-cyclohexylsulfamic acid (to form cyclamate) or other acidic organic compounds such as acid asorbová. The compounds of the formula I with acidic or basic groups can also form internal salts.

The use of a pharmacologically unsuitable salt may also be used for i.elation or purification.

The compounds of the invention have a viral aspartate protease suppressing effect, a particular gag protease suppressing effect. In particular, these compounds suppress the activity of the HIV-1 and HIV-2 gag protease in the tests described below at concentrations ranging from 10 ^-6 to 10 ^-9 mol / l and are thus useful as agents against diseases caused by these or related retroviruses such as AIDS.

- · ·

The ability of the compounds of formula I to inhibit the proteolytic activity of, for example, HIV-1 protease, can be demonstrated, for example, by the method of J. Hansen et al. in The EMBO Journal f, 1785-1791 (1988). The suppression is measured

107 of the effect of gag protease on the substrate, which is the test protein f in the Escherichia coli precursor gag protein and MS-2. The substrate and its cleavage products are resolved by gel electrophoresis on polyamide and rendered visible by immuno-blotting paper (Immunoblotting) with monoclonal anti-titres against MS-2.

In a further simpler assay, which allows a completely quantitative expression of the result, a synthetic peptide is used as the substrate for the gag protease, corresponding to the gag protein precursor step. This substrate and its cleavage products can be measured by high pressure liquid chromatography (HPLC).

As a substrate for recombinant HIV-1 protease (production according to S. Billich et al. In J. Biol. Chem., 264 (34), 17905 - 17908 (1990)), for example, a synthetic c.hromophoric peptide (e.g. HKARVL) is used. (NO2) FEANleS (Bachem, Switzerland)) or icosapeptide (such as RRSNQVSQNYPIVQNIQGRR (produced by peptide synthesis, according to a known method)), which corresponds to the cleavage site of the gag protein precursor. This substrate and its cleavage products can be measured by high pressure liquid chromatography (HPLC).

To this end, the test compound of formula (I) to be tested is dissolved in dimethylsulphoxide and an enzyme test is carried out, whilst a suitable diluted suppressant in 20 mmol of β-morpholinoethanesulfonic acid buffer (MES buffer) is used. a pH of 6.0 is contacted with a test mixture consisting of 67.2 µm of the above chromophore peptide in 0.3 mol of sodium acetate, 0.1 mol of sodium chloride, at a pH of 7.4 or 122 µmol of the above icosapeptide in 20 mmol of MES buffer pH 6.0. The batch size is 100 μΐ. The reaction is initiated by the addition of HIV-1 protease of 2 μΐ in the first case and in the second

108 cases of 10 μΐ and stopped in the first case after 15 minutes of incubation at 37 ° C by the addition of 100 μΐ of 0,3 molar perchloric acid and in the second case after one hour of incubation at 37 ° C by the addition of 10 μΐ 0,3 molar acid perchloric. The reaction product is quantified after centrifugation of the sample for 5 minutes at 10,000 xg overload at 100 μ chrom (chromophoric peptide feed) or at 20 μΐ (icosapeptide feed) of the supernatant obtained and loaded onto a Nucleosil ^R C18-5u-HPLC column ( Macharey & Nagel, Duren) and elution based on the step product peak height at 280 (chromophore peptide feed) or 215 (icosapeptide feed) nm, gradient: 100% El.l -> 50% E1.1 / 50% E1.2 (EI: 75% acetonitrile / 90% water, 0.1% trifluoroacetic acid, E1.2: · 75% acetonitrile, 25% water, 0.08% trifluoroacetic acid) in 15 minutes, at flow rates of 1 ml / min.

IC50 values are preferably determined for the compounds of the formula (IC50 = concentration at which the activity of the HIV-1 protease decreases against the control, in the presence of a 50% suppressant) from about 10 ^-6 to 10 ^-9 mol, in particular from about 10 ^-7 to about 10 ^-8 mol.

‘J: · .- Z '··· - ¾' /.

In another test, the compounds of the invention may be shown to protect cells that are usually infected with HIV from such infection or at least have delayed such infection. In this process, human leukemia T cells of the cell line MT-2 (Science 2 29 563 (1985)) which are particularly sensitive to the cytopathogenic effect of HIV are incubated with HIV alone or with HIV in the presence of the compounds of the invention. treated cells.

To this end, MT-2 cells are maintained in RPMI 1640 medium (Gibco, Switzerland, RPMI 1640 contains a mixture of L-Gln-free amionic acids) supplemented with 10% heat-inactivated fetal. - 109 -. · ...

calf serum, L-glutamine, 2- / 4- (2-hydroxyethyl) -1-piperazino / ethanesulfonic acid (Hepes) and standard antibiotics, at 37 ° C in humid air containing 5% carbon dioxide. 50 μΐ of each test compound in culture and 100 μΐ of HIV-1 in culture (800 TCID50 / ml) (TCID50 = dose infecting cell culture 50, with 50 indicating the dose which infects 50% of MT-2 cells) is added to 4X1O · ³ exponentially washed MT-2 cells in 50 μΐ culture. medium per well on a 96-well microtiter plate. A parallel run on another microtiter plate with cells and test compound contains 100 μΐ virus free culture medium. After a 4-day incubation, reverse transcriptase (RT) activity is determined in 10 μΐ of cell supernatant. RT-activity is determined in 50 mmol of tris- (α, α, α-hydroxymethyl) methylamine (ultrapure, Merck, Germany) having a pH of 7.8, 75 mmol of potassium chloride, 2 mmol of dithiothreitol, 5 mmol of magnesium chloride, 05% Nonidet P-40 (Sigma, Switzerland, surfactant), 50 µg / ml polyadrenylic acid (Pharmacia, Switzerland), 1.6 µg / billion T (12-18) (Sigma, Switzerland). Filter the mixture through a 0.45 μ Acrodisc filter (Gellman Science Inc., Ann Arbor) and store at -20 ° C. To an aliquot of this solution was added 0.1% by volume of [d- ³² P] dTTP to achieve a final activity of 10 ¹⁶ s ^-1 .ml ^-1 . Transfer 10 μΐ of the culture supernatant to a new 96-well microtiter plate, add 30 μΐ of the RT-cocktail described above and incubate the plate for 90 minutes to 3 hours at 37 ° C. Transfer 5 μΐ of this reaction mixture to Whatman DE81 filter paper (Whatman). The dried filter is washed three times for 5 minutes each with 300 mmol of sodium chloride in 25 mmol of tris-sodium citrate and once with 95% ethanol and air-dried again. Evaluation is performed on a Matrix Packard 96well Counter (Packard). ED90 values are obtained and defined as the lowest concentration of test compound that causes a decrease in RT-activity by 90% compared to &quot;

- 110 - about the treatment of cells not treated with the test substance. RT-activity is a measure for increasing HIV-1.

The compounds of the present invention also exhibit ED90 values of from about 10 ^-5 to 10 ^-8 mol, preferably from 5x10 ^-7 to 5x10 ^-8 mol.

T

For the following groups of compounds of formula (I), the definitions of the radicals from the above general definitions or introduce or exclude definitions from other groups may be used, for example, to replace generally defined residues of a particular definition.

Preferred is a compound of formula I wherein:

R y and R g are each independently hydrogen, a lower alkanoyl group such as formyl, acetyl, propionyl, butyryl or pivaloyl, especially acetyl, an aryl- (lower alkanoyl) group in which the aryl moiety is preferably defined as aryl - (lower alkanoyl). is not substituted or substituted as described therein, i.e. containing 6 to 14 carbon atoms such as phenyl, indenyl, indanyl, naphthyl, anthryl, phenanthryl, acenaphthyl or fluorenyl, not substituted or substituted one to three times lower alkyl, such as methyl, ethyl or propyl, halogen- (lower alkyl), such as trifluoromethyl, phenyl, 1- or 2-naphthyl, hydroxy, lower alkoxy, such as methoxy, carbamoyl- (lower alkoxy), N- (lower) alkyl) -carbamoyl- (lower alkoxy) or N, N-di- (lower alkyl) -carbamoyl- (lower alkoxy), amino, mono- or di- (lower alkyl) -amino, (lower alkanoyl) -amino, for example pivaloylamino, halogen, for example fluorine, chlorine or bromine, carboxy, (lower alkoxy) -carbonyl, such as tert-butoxycarbonyl, phenyl, naphthyl tyl- or fluorenyl- (lower alkoxy) -carbonyl, such as benzyloxycarbonyl, lower alkanoyl, sulfo, (lower alkyl) -sulfonyl, e.g. methylsulfonyl, phosphono, hydroxy- (lower alkoxy) -phosphoryl or di- (lower alkoxy) a phosphoryl group, a carbamoyl group, a mono- or di- (lower alkyl) aminocarbamoyl group, a sulfamoyl group _; mono- or di- (lower alkyl) -sulfamoyl, nitro and / or cyano, the phenyl being present up to three times, for example in a diphenyl-, dibenzyl- or triphenyl- (lower alkanoyl) group such as diphenyl-, dibenzyl- or triphenylacetyl, and wherein the lower alkanoyl moiety is not substituted or is substituted by carbamoyl or one or two residues selected from lower alkyl, carboxy- (lower alkyl), (lower alkoxy) -carbonyl- (lower alkyl), di- (lower alkyl) -amino- (lower alkyl), aminocarboxy- (lower alkyl), hydroxy- (lower alkyl) and di- (lower alkoxy) - (lower alkyl) groups, substituted by carbamoyl on the carbon atom, preferably as described above in the general definition . below an aryl- (lower alkanoyl) group, for example 4-chloro-, 4-methoxy- or 4-nitrobenzoyl, naphthylcarbonyl such as α, - or β-naphthylcarbonyl, or over both carbonyl groups on the amino group attached by 1,8-naphthalenedicarbonyl , indenylcarbonyl, such as 1-, 2- or 3-indenylcarbonyl, indanecarbonyl, such as 1- or 2-indanylcarbonyl, phenanthrenylcarbonyl, such as 9-phenanthrenylcarbonyl, phenyl (lower alkanoyl), such as phenylacetyl or 3-phenylpropionyl, α-naphthyl acetyl β-naphthylacetyl, (lower alkyl) -phenylacetyl, such as 4-methylphenylacetyl, (lower alkoxy) -phenylacetyl, such as 4-methoxyphenylacetyl, 3-phenylpropionyl, 3- (p-hydroxyphenyl) propionyl, diphenylacetyl, di- (4-) methoxyphenyl) acetyl, triphenylacetyl, 2,2-dibenzylacetyl, 3-α- or 3'-naphthylpropionyl, phenyl- (lower alkanoyl), wherein the lower alkanoyl residue is substituted with carbamoyl, such as 2 (R, S) -carbamoyl-3 -phenylpropionyl, 3-phenyl- or o 3-α-naphthyl-2-carbamoylprop-112 pionyl or 3-phenyl- or 3-α-naphthyl-2-tert-butylcarbamoylpropionyl, 3-phenyl- or 3-α-naphthyl-2- (dimethylaminoethyl) carbamoylpropionyl, 3-.alpha.-naphthyl-2- (carboxy- or -tert-butoxycarbonyl) methylcarbamoylpropionyl, 3-phenyl- or 3-.alpha.-naphthyl. ethyl 2- (3-hydroxy-2-propyl) carbamoylpropionyl, 3-phenyl- or 3-a-naphthyl-2- (2,2-dimethoxyethyl) carbamoylpropionyl or 3-phenyl- or 3-a-naphthyl-2- (5-amino-5-carboxypentyl) carbamoylpropionyl, in particular a phenyl- (lower alkanoyl) group such as phenylacetyl or a phenyl- (lower alkanoyl) group wherein the lower alkanoyl moiety is substituted by carbamoyl such as 2 (R, S) carbamoyl-3-phenylpropionyl, heterocyclyl- (lower alkanoyl) group, which is preferably as defined above for a heteroaryl (lower alkanoyl) group, R _2, R g and R _{g, more} heterocyclyl- (lower alkanoyl) group ,, the wherein the lower alkanoyl group is unsubstituted and wherein the heterocyclyl moiety is preferably a single or two membered ring system of 3 to 10 carbon atoms, which is bonded via a carbon atom or a particular nitrogen atom and contains up to 3 additional heteroatoms selected from oxygen, nitrogen, sulfur, of the sene and sulfur bound with 1 or 2 at it may be unsaturated or also partially or fully saturated, such as thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, furazanyl, tetrazolyl, pyridyl-, pyrazinyl-, pyrimidinyl-, pyrazinyl-, azepinyl-, indolyl-, benzimidazolyl-, ΙΗ-indazolyl-, quino.lyl-, isoquinolyl-, quinoxalinyl-, quinazolinyl-, quinnolyl-, purinyl-, pteridinyl-, naphthyridinyl -, 4H-quinolizinyl-, 3,1-benzfuranyl-, 4,1-benzoxazinyl-, 4,1-benzthiazinyl-, cyclohexa [b] pyrrolyl-, cyclohepta [b] pyrrolyl-, cyclohexa [d] pyrazolyl-, cyclohexa (b) pyridyl, cyclohexa [b] pyrazinyl, cyclohexa [b] pyrimidinyl, cyclohexa [b] -1,4-oxazinyl, cyclohexa (b) -1,4-thiazinyl, pyrrolidinyl, pyrrolinyl -, imidazolidinyl-, 2-imidazolinyl-, 2,3-dihydropyridyl-, piperidyl-, piperazinyl-, 2,3,5,6-tetrahydropyriazinyl-, morpholinyl-, thiomorpholinyl-, S, S-dioxothiomorpholinyl-, indolinyl-, The isoindole

113 nyl-, 4,5,6,7-tetrahydroindolyl-, 1,2,3,4-tetrahydroquinolyl-, 1,2,3,4-tetrahydroisoquinolyl-, chromanyl-, thiochromanyl-, 1,2,3,4 -tetrahydro-3,1-benzdiazinyl-, 3,4-dihydro-3H-4,1-benzoxazinyl-, 3,4-dihydro-3H-4,1-benzthiazinyl- (lower alkanoyl) group, wherein said heterocyclyl residues are not substituted or substituted by lower alkyl, such as methyl, phenyl, 1- or 2-naphthyl, phenyl (lower alkyl), such as benzyl, hydroxy (lower alkyl), such as hydroxymethyl or 2-hydroxyethyl, (lower alkoxy) - (lower alkyl) group, for example methoxymethyl or 2-methoxyethyl, phenoxy- or naphthyloxy- (lower alkyl) group, for example 2-phenoxyethyl, 1- or 2-naphthyloxymethyl, phenyl- (lower alkoxy) - or naphthyl- (lower alkoxy) - (lower alkyl), for example benzyloxy (lower alkyl), (lower alkanoyl) -4-oxy (lower alkyl), for example acet oxymethyl, phenyl- or naphthyl- (lower alkanoyl) -oxy- (lower alkyl), for example benzyloxy, phenylacetoxy- or 1- or 2-naphthoyloxymethyl, -2-ethyl or -2- (2,2-dimethylethyl), (lower alkoxy) -carbonyloxy- (lower alkyl), for example tert-butoxycarbonyloxy- (lower alkyl), phenyl-, naphthyl- or fluorenyl- (lower alkoxy) -carbonyloxy- (lower alkyl), for example 2 -benzyloxycarbonyloxyethyl or 9-fluorenylmethoxycarbonyloxyethyl, amino- (lower alkyl), for example aminomethyl, 2-aminoethyl or 2-aminopropyl, carboxy- (lower alkyl), for example carboxymethyl or 2-carboxyethyl, hydroxy, lower-alkoxy, for example methoxy or , phenyl- or naphthyl- (lower alkoxy), for example benzyloxy or 1- or 2-naphthyloxy, amino, (lower alkyl) -amino, for example methyl-, ethyl- or tert-butylamino, di- (lower alkyl) -amino, for example dimethyl or diethylamino, carboxy, (lower alkoxy) -carbonyl, for example methoxy-, isopropoxy-, sec- buto-114 xy- or tert-butoxycarbonyl, phenyl- or naphthyl- (lower alkoxy) -carbonyl, for example benzyloxycarbonyl, halogen, for example fluorine, chlorine, bromine or iodine, especially chlorine or bromine, lower alkanoyl, for example acetyl or pivaloyl, (lower alkyl) -sulfonyl, for example methyl or ethylsulfonyl, phosphono hydroxy- (lower alkoxy) -phosphoryl or di- (lower alkoxy) -phosphoryl, for example dimethoxy- or diethoxyphosphoryl, carbamoyl, mono- or di- (lower alkyl) -carbamoyl, for example N-methylcarbamoyl, Nn-butylcarbamoyl or N , N-dimethylcarbamoyl, hydroxy- or carboxy- (lower alkyl) -carbamoyl, for example hydroxy- or carboxymethylcarbamoyl or hydroxy- carboxyethylcarbamoyl, sulfamoyl, nitro, oxo, and / or cyano, wherein the heterocyclyl- (lower alkanoyl) group is particularly selected from optionally lower alkyl or phenyl substituted pyrrolylcarbonyl, for example 2- or 3-pyrrolylcarbonyl, 4- or 5-methylpyrrole or 5-phenylpyrrolyl-2-carbonyl, thienylcarbonyl, such as 2-thienylcarbonyl, furylcarbonyl, such as 2-furylcarbonyl, pyridylcarbonyl, such as 2-, 3- or 4-pyridylcarbonyl, pyrimidin-1-ylcarbonyl, optionally lower alkyl; such as methyl, phenyl (lower alkyl), such as benzyl, lower alkoxy, such as methoxy, phenyl (lower alkoxy), such as benzyloxy, or halogen, such as chlorine, substituted iodolylcarbonyl, such as 2-, 3- or 5- indolylcarbonyl, 1-methyl-,

5-methyl-, 5-methoxy-, 5-benzyloxy-, 5-chloro- or

4,5-dimethylindol-2-carbonyl, 1-benzylindolyl-2- or -3-carbonyl, 4,5,6,7-tetrahydroindolyl-2-carbonyl and optionally substituted hydroxy-substituted quinolyl (lower alkanoyl) groups, for example quinolylcarbonyl, such as 2-, 3- or 4-quinolylcarbonyl or 4-hydroxyquinolyl-2-carbonyl, optionally hydroxy substituted isoquinolylcarbonyl such as 1-, 3- or 4-isoquinolylcarbonyl or 1-oxo-1,2-di

115 hydroisoquinolyl-3-carbonyl, 2-quinoxalinylcarbonyl, 2- (3,1-benzfuranyl) carbonyl, cyclohepta [b] pyrrole-5-carbonyl, 3-chromanylcarbonyl, 3-thiochromanylcarbonyl, pyrrolidinyl-3carbonyl, hydroxypyrrolidinylcarbonyl such as 3- or 4-hydroxypyrrolidinyl-2-carbonyl, oxopyrrolidinylcarbonyl, such as 5-oxopyrrolidinyl-2-carbonyl, piperidinylcarbonyl, such as piperidinocarbonyl, or 2-, 3- or 4-piperidylcarbonyl, pyrazinylcarbonyl, such as pyrazin-1-ylcarbonyl, piperazinylcarbonyl, piperazinylcarbonyl, piperazinylcarbonyl piperazin-1-ylcarbonyl, morpholinyl- (lower alkanoyl) groups, for example morpholinylcarbonyl, such as morpholinylcarbonyl, thiomorpholinyl- (lower alkanoyl) groups, for example thiomorpholinylcarbonyl, such as thiomorpholinylcarbonyl, S, S-dioxothiomorpholinyl

S, S-dioxothiomorpholinylcarbonyl, indolinylcarbonyl, such as 2- or 3-indolinylcarbonyl, i., 2,3,4-tetrahydroquinolinylcarbonyl, such as 1,2,3,4-tetrahydroquinolinyl-2-, -3- or -4- carbonyl, 1,2,3,4-tetrahydroisoquinolinylcarbonyl such as 1,2,3,4-tetrahydroisoquinolinyl-1-, -3- or -4-carbonyl or 1-oxo-1,2,3,4-tetrahydroisoquinolinyl- 3-carbonyl, tetrazolyl- (lower alkanoyl) groups such as 3- (tetrazol-1-yl) -propionyl and pyridyl- (lower alkanoyl) groups, for example pyridylacetyl such as 2-, 3- or 4-pyridylacetyl, especially selected from morpholino- (lower alkanoyl) groups such as morpholinocarbonyl, thiomorpholino- (lower alkanoyl) groups such as thiomorpholinocarbonyl, pyridyl- (lower alkanoyl) groups such as 2-, 3- or 4-pyridylacetyl, quinolinyl- (lower alkanoyl) groups alkanoyl) groups such as quinoline-2-carbonyl and tetrazolyl- (lower alkanoyl) groups such as 3- (tetrazol-1-yl) propionyl, further heterocyclyl- (lower alkanoyl) groups per atom for amino nitrogen substituted amino- (lower alkanoyl) group, wherein heterocyclyl- (lower alkanoyl) group is defined as above for heterocyclyl- (lower alkanoyl) group R _x , R ₂ , R g or R _g , preferably as for heterocyclyl- ( lower alkanoyl), or R _g, in particular N-morpholino or N-atom of the thiomorfolinokarbonylem du

The amino group substituted by an amino (lower alkanoyl) group, in particular an N-morpholino- or N-thiomorpholinocarbonylamino- (lower alkanoyl) group such as N-morpholino or N-thiomorpholinocarbonylaminoacetyl, furthermore a halogen- (lower alkanoyl) group, it preferably contains up to 3 carbon atoms, in the first instance α-haloacetyl, such as α-fluoro, α-chloro, α-bromo, α-iodo, α, α, α-trifluoro- or. α, α, α -tichloroacetyl, or halopropionyl, such as β-chloro- or β-bromopropionyl, especially trifluoroacetyl, further N- (heterocyclyl- (lower alkyl) -carbonyl) - (lower alkanoyl) group in which the heterocyclyl moiety is preferably selected from pyrrolyl, furyl, thienyl, imidazolyl; pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinylyl, isoquinolyl, quinoxalinyl, β-carbolinyl and benzanellated, cyclopentaanellated, cyclohexaanellated or cycloheptanellated derivative of this residue, which may also be completely or partially A 2-N- (morpholino- (lower alkyl) carbamoyl) - (lower alkanoyl) group such as a 2 (R, S) - [N- (2-morpholinoethyl) carbamoyl] -3-methylbutyryl or 2- [N- a (pyridyl- (lower alkyl)) - carbamoyl] - (lower alkanoyl) group such as a 2 (R, S) - [N- (2-pyridylmethyl) carbamoyl] -3-methylbutyryl, (lower alkoxy) -carbonyl group in particular methoxy-, ethoxy-, isopropoxy-, isobutoxy or tert- (lower alkoxy) -carbonyl, for example methoxycarbonyl, tert-butoxycarbonyl or isobutoxycarbonyl, and aryl- (lower alkoxy) -carbonyl, in which the aryl part contains 6 to 14 carbon atoms, such as phenyl, bi phenylyl, 1- or 2-naphthyl or fluorenyl, or a lower alkyl group such as methyl or tert-butyl, hydroxy, lower alkoxy such as methoxy, ethoxy or tert-butoxy, a halogen atom such as chlorine or bromine and / or nitro mono- or poly-substituted phenyl, for example phenyl- (lower alkoxy) -carbonyl, such as benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-nitrobenzyl

117 an oxycarbonyl or fluorenyl- (lower alkoxy) -carbonyl group such as 9-fluorenylmethoxycarbonyl, especially a phenyl- (lower alkoxy) -carbonyl group such as benzyloxycarbonyl, further a heterocyclyl- (lower alkoxy) -carbonyl group wherein the heterocyclyl moiety is s preferably selected from pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, thiazolyl; isoquinolyl, quionoxalinyl, β-carbolinyl and benzanellated, cyclopentaanellated, cyclohexaanellated or cycloheptaanellated derivatives of this series, which may also be partially or fully saturated, and from morpholinyl and thiomorpholinyl α, are optionally substituted, in particular by lower alkyl, such as methyl, such as methyl, -methylpyrrolidin-2-ylmethoxycarbonyl, 2-furylmethoxycarbonyl, 2-tetrahydrofuryl- (lower alkoxy) carbonyl, such as 2-tetrahydrofuranylmethoxycarbonyl, 1-methyl-2-piperidylmethoxycarbonyl or 2-morpholinoethoxycarbonyl or 2-, especially a tetrahydrofuranyl- (lower alkoxy) carbonyl group such as 2 (R, S) -tetrahydrofuranylmethoxycarbonyl, (lower alkyl) -sulfonyl group, for example methyl- or ethylsulfonyl group such as methylsulfonyl, a heterocyclylsulfonyl group, wherein the heterocyclylsulfonyl moiety is preferably from pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl u, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl, β-carbolinyl and benzanellated, cyclopentaanellated, cyclohexaanellated or cycloheptaanellated derivative of this series, which may also be partial or total morpholines, optionally substituted, in particular by a lower alkyl group such as methyl, such as morpholinosulfonyl, thiomorpholinosulfonyl, piperidinosulfonyl, 4-methylpiperazinylsulfonyl or piperazinosulfonyl, N-heterocyclyl- (lower alkyl) -N- (lower alkyl) -carbamoyl group as defined above clip optionally substituted N-alkyl or N, N-dialkylkarba- 118 · moylovou by R ^, R _2, R g and R _g, wherein the heterocyclyl moiety is selected zthienylu, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, furazanyl, pyridyl, pyrazinyl, pyrimidinyl, pyrazinyl, azepinyl, indolvl, benzimi dazolyl, ΙΗ-indazolyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, quinnolyl, purinyl, pteridinyl, naphthyridinyl, 4H-quinolizinyl,

3.1-benzofuranyl, benz [e] indolyl, 4,1-benzoxazinyl,

4.1- benzthiazinyl, carbazolyl, β-carbolinyl, phenazinyl, phenanthridyl, acridyl, phenoxazinyl, phenothiazinyl, 1-azaacenaphthyl, cyclohexa [b] pyrrolyl, cyclohepta [b.] Pyrrolyl, cyclohexa [d] pyrazolyl, [b] pyrazinyl, cyclohexa (b] pyrimidinyl, cyclohexa [b] -1,4-oxazinyl, cyclohexa [b] -1,4-thiazinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, 2-imidazolinyl, 2,3-dihydropyridyl, piperidyl , piperazinyl, 2,3,5,6-tetrahydropyriazinyl, morpholinyl, thiomorpholinyl, S, S-dioxothiomorpholinyl, indolinyl, isoindolinyl, 4,5,6,7-tetrahydroindolyl, 1,2,3,4-tetrahydroquinolyl, 1,2 , 3,4-tetrahydroisoquinolyl, chromanyl, thiochromanyl, 1,2,3,4-tetrahydro-3,1-benzdiazinyl, 3,4-dihydro-3H-4,1-benzoxazinyl, 3,4-dihydro-3H-4 2,3,4,5-tetrahydro-1H-5,1-benzazepinyl and 5,6-dihydrophenanthridinyl, said radicals not being substituted or substituted by a lower alkyl group, for example methyl, phenyl, 1,1-benzothiazinyl, 1,4-benzothiazinyl, 1,3,4,5-tetrahydro-1H-5,1-benzazepinyl and 5,6-dihydrophenanthridinyl. - the sky 2-naphthyl, phenyl- (lower alkyl), for example benzyl, hydroxy- (lower alkyl), for example hydroxymethyl or 2-hydroxyethyl, (lower alkoxy) - (lower alkyl), for example methoxymethyl or 2-methoxyethyl, phenoxy- or a naphthyloxy (lower alkyl) group, for example 2-phenoxyethyl, 1- or 2-naphthyloxymethyl, phenyl (lower alkoxy) - or naphthyl (lower alkoxy) - (lower alkyl) group, for example a benzyloxy (lower alkyl) group (lower alkanoyl) -oxy- (lower alkyl) groups such as acetoxymethyl, phenyl or naphthyl- (lower alkanoyl) -oxy- (lower alkyl) groups, for example

119 examples of benzyloxy-, phenylacetoxy- or 1- or 2-naphthoyloxymethyl, -2-ethyl or -2- (2,2-dimethylethyl), (lower alkoxy) -carbonyloxy- (lower alkyl), for example tert-butoxycarbonyloxy- (lower alkyl), phenyl, naphthyl or fluorenyl- (lower alkoxy) -carbonyloxy- (lower alkyl), for example 2-benzyloxycarbonyloxyethyl or 9-fluorenylmethoxycarbonyloxyethyl, amino- (lower alkyl), for example aminomethyl, 2-aminoethyl the sky

2-aminopropyl, carboxy (lower alkyl), for example carboxymethyl or 2-carboxyethyl, hydroxy, lower alkoxy, for example methoxy or ethoxy, phenyl or naphthyl (lower alkoxy), for example benzyloxy, 1- or 2-naphthylmethoxy , (lower alkyl) amino, for example methyl, ethyl or tert-butylamino, di- (lower alkyl) amino, for example dimethyl or diethylamino, carboxy, (lower alkoxy) -carbonyl, for example methoxy, isopropoxy, sec-butoxy- or tert-butoxycarbonyl, phenyl- or naphthyl- (lower alkoxy) -carbonyl, for example benzyloxycarbonyl, halogen, for example fluorine, chlorine, bromine or iodine, especially chlorine or bromine, lower alkanoyl, for example acetyl or pivaloyl, (lower alkyl) -sulfonyl, for example methyl- or ethylsulfonyl, phosphono, hydroxy- a lower alkoxy) -phosphoryl or di- (lower alkoxy) -phosphoryl group, for example dimethoxy- or diethoxyphosphoryl, carbamoyl, mono- or di- (lower alkyl) -carbamoyl group, for example N-methylcarbamoyl, Nn-butylcarbamoyl or N, N- dimethylcarbamoyl, hydroxy- or carboxy- (lower alkyl) -carbamoyl, for example hydroxy- or carboxymethylcarbamoyl or hydroxy- or carboxyethylcarbamoyl, sulfamoyl, or nitro, oxo and / or cyano, and in particular means pyridyl, such as 2-, 3- or 4 -pyridyl, especially N- (pyridyl- (lower alkyl) -N- (lower alkyl)) carbamoyl, such as N- (2-, 3- or 4-pyridyl)

120 methyl) -N-methylcarbamoyl, or a further amino acid is an acyl radical whose amine function is acylated volnánebo with one of the heretofore mentioned radicals remaining of R ^ and R _g, wherein amino acid residues are preferably independently of one another, as defined for R _{1 (} R ₂ , R _g and R _g as acyls, optionally substituted amino acids, a particular natural α-amino acid residue with an L-configuration, as usually found in the proteins or epimer of such an amino acid, i.e. compounds with a D-configuration not present in the naturally, or a D, L-isomeric mixture thereof, of an amino acid homologue, for example wherein the amino acid side chain is extended or shortened by one or two methylene groups, wherein the amino group is in the β position and / or wherein the methyl group is replaced by hydrogen, substituted aromatic amino acids in which the aromatic residue contains from 6 to 14 carbon atoms, e.g., substituted phenylalanine or bitches glycine, wherein a lower alkyl group such as methyl, hydroxy, lower alkoxy such as methoxy, (lower alkanoyl) -oxy, such as acetoxy, amino, may be used as a phenyl substituent. (lower alkyl) amino, for example methylamino, di- (lower alkyl) amino, for example dimethylamino, (lower alkanoyl) -amino, for example acetylamino or pivaloylamino, (lower alkoxy) -carbonylamino, for example tert-butoxycarbonylamino, the aryl moiety contains 6 to 14 carbon atoms, for example, benzyloxycarbonylamino or 9-fluorenylmethoxycarbonylamino, halogen, for example fluorine, chlorine, bromine or iodine, carboxy and / or nitro, and may be present one or more, benzaneline, phenyl or phenyl-phenyl; is α-naphthylalanine, or hydrated phenylalanine or phenylglycine, such as cyclohexylalanine or cyclohexylglycine, a particularly preferred amino acid residue attached through a carboxy group selected from glycine (H-Gly-OH), alanine (H-Ala-OH), valine (H- Val-OH),

- 121 norvaline (α-aminovaleric acid), leucine (H-Leu-OH), isoleucine (H-Ile-OH), norleucine (α-aminohexanoic acid, H-Nle-OH), serine (H-Ser-OH) , homoserine (α-amino-T-hydroxybutyric acid), threonine (H-Thr-OH), methionine · (H-Met-OH), cysteine (H-Cys-OH), proline (H-Pro-OH), trans-3- and trans-4-hydroxyproline, phenylalanine (H-Phe-OH), tyrosine (H-Tyr-OH), 4-aminophenylalahine, 4-chlorophenylalanine, 4-carboxyphenylalanine, β-phenylserine (β-hydroxyphenylalanine) , phenylglycine, α-naphthylalanine (H-Nal-OH), cyclohexylalanine (H-Cha-OH), cyclohexylglycine, tryptophan (H-Trp-OH), indoline-2-carboxylic acid, 1,2,3,4- tetrahydroisoquinoline-3-carboxylic acid, aspartic acid (H-Asp-OH), asparagine (H-Asn-OH), aminomalonic acid, aminomalonic acid monoamide, glutamic acid (H-Glu-OH), glutamine (H-Gln-OH) , histidine (H-His-OH), arginine (H-Arg-OH), lysine (H-Lys-OH), S-hydroxylysine, ornithine (α, δ-diaminovaleric acid), 3-aminopropylamine opanoic, α, β-diaminobutyric acids and α, β-diaminopropionic acids, a particularly preferred amino acid residue selected from valine, alanine, leucine, isoleucine, glycine, glutamic acid and asparagine, each of said amino acids being in the form of D, L, or (D, L), preferably (except Val, which may also be in the form of D or (D, L)) may be in the form of L, wherein the α-amino groups are unsubstituted or N-acylated by one of the above mentioned radicals R a to R _g, in particular substituted by lower alkanoyl, phenyl (lower an alkanoyl) group such as phenylacetyl, phenyl (lower alkanoyl) group, wherein the lower alkanoyl moiety is substituted by carbamoyl, such as 2 (R, S) -carbamoyl-3-phenylpropionyl, a morpholino- (lower alkanoyl) group such as morpholinocarbonyl, a thiomorpholino- (lower alkanoyl) group, such as a thiomorpholinocarbonyl, a pyridyl- (lower alkanoyl) group, such as a e 2-, 3- or 4-pyridylacetyl, a quinolinyl- (lower alkanoyl) group such as a quinoline-2-carbonyl, a tetrazolyl- (lower alkanoyl) group such as a

122

3-tetrazol-1-ylpropionyl, N-morpholino- or N-thiomorpholinocarbonyl substituted amino- (lower alkanyol) group on the amino nitrogen atom, for example N-morpholino- or N-thiomorpholinocarbonylamino- (lower alkanyol) group such as N-morpholino - or N-thiomorfolinokarbonylaminoacetyl, halo (lower alkanoyl) group, containing up to _3: carbon atoms, e.g., α-halogenacetylem such as α-fluoro, α-chloro-, α-bromo, α-iodo-, α, α, α-trifluoro- or α, α, α-trichloroacetyl, or halopropionyl, such as β-chloro- or β-bromopropionyl, especially trifluoroacetyl, 2-N- (morpholino- (lower alkyl) carbamoyl) - (lower alkanoyl) a group such as 2 (R, S) -N - [(2-morpholinoethyl) carbamoyl] -3-methylbutyryl, 2- (N-pyridyl- (lower alkyl) carbamoyl) - (lower alkanoyl) group such as 2 (R, S) - [N- (2-pyridylmethyl) carbamoyl] - (lower alkanoyl), (lower alkoxy) carbonyl, pyridyl (lower alkoxy) carbonyl, tetrahydrofuranyl- (lower alkoxy) xy) -carbonyl such as 2 (R, S) -tetrahydrofuranylmethoxycarbonyl, (lower alkyl) -sulfonyl such as morpholinosulfonyl, thiomorpholinosulfonyl, piperidinosulfonyl, 4-methylpiperidinosulfonyl or piperazinosulfonyl, or N-pyridyl- (lower alkyl) - (lower alkyl) -carbamoyl, such as N- (2-, 3- or 4-pyridylmethyl) -N-methylcarbamoyl, with N-morpholinocarbonylglycine, N- / N- (2-, 3 or 4-pyridyl) being most preferred methyl-N-methylaminocarbonyl / glycine, valine, N- (trifluoroacetyl) valine, N-phenylacetylvaline, N- (2- or 3-pyridylacetyl) valine, N-acetylvaline, N- (2-carbamoyl-3-phenylpropionyl) valine, N- / 2 (R, S) -carbamoyl-3-phenylpropionyl / valine, N- (2- or 3-pyridylacetyl) valine, Ν-2-tetrahydrofurylmethoxycarbonylvaline, N-3- (1-tetrazolylpropionyl) valine, N- ( quinoline-2-carbonyl) valine, N-methoxycarbonylvaline, N-isobutoxycarbonylvaline, N-tert-butoxycarbonylvaline, N-benzyloxycarbonylvaline, N- (morpholinocarbonyl) valine, N- (thiomorpholinocarbonyl) valine, N- (S, S-dioxothiorphine) linocarbonyl) valine, N- (N-2-pyridylmethyl-N-methylaminocarbonyl) valine, N-morpholinocarbonylaminoacetylvaline, N-methylsulfonylvaline, N-acetylisoleucine,

123

N-propionylisoleucine, N- (benzyloxycarbonyl) isoleucine, N-benzyloxycarbonylglutamic acid, asparagine, N-benzyloxycarbonylasparagine or quinoline-2-carbonylasparagine, said amino acid residues preferably being in the form of L or (D, L '), in form D, with the proviso that at most one of the substituents and R 8 may be hydrogen.

R _2, R _4, R _6, and R is H,

R is lower alkyl, such as isobutyl or n-butyl, cycloalkyl (lower alkyl) group as defined above for a cycloalkyl-alkyl fnižší) with R _3, R _4, and _R? wherein the cycloalkyl group contains 3 to 7 carbon atoms and is unsubstituted or substituted by one to three times lower alkyl such as isopropyl, halogen- (lower alkyl) such as trifluoromethyl, hydroxy, lower alkoxy, carbamoyl- (lower alkoxy) ), N- (lower alkyl) -carbamoyl- (loweralkoxy) or N, N-di- (lower alkyl) -carbamoyl- (loweralkoxy), amino, mono- or di- (lower alkyl) -amino, atom halogen, such as fluorine, chlorine or bromine, carboxy, (lower alkoxy) -carbonyl, phenyl, naphthyl or fluorenyl (lower alkoxy) -carbonyl, lower alkanoyl or (lower alkyl) -sulfonyl, for example methylsulfonyl, phosphono, hydroxy- (lower alkoxy) -phosphoryl or di- (lower alkoxy) -phosphoryl, carbamoyl, mono- or di- (lower alkyl) aminocarbamoyl, sulfamoyl, mono- or di- (lower alkyl) -sulfa moyl, nitro and / or cyano, such as attached to a lower alkyl group, especially methyl, preferably at an end position such as cyclobutyl-, cyclopentyl-, cyclohexyl- or cycloheptyl- (lower alkyl), such as -methyl or -ethyl, especially cyclohexyl- (lower alkyl), especially cyclohexylmethyl, or aryl

124

a (lower alkyl) group, which is preferably defined as below the aryl (lower alkyl) group R 8, R ₄ and R ₇ , wherein the aryl moiety especially contains 6 to 14 carbon atoms, such as in phenyl, indenyl, indanyl. naphthyl, anthryl, phenanthryl, acenaphthyl or fluorenyl, and is not unsubstituted or may be substituted one or three times by a lower alkyl group such as methyl. ethyl or isopropyl, halogen- (lower alkyl), such as trifluoromethyl, phenyl, 1- or 2-naphthyl, hydroxy, lower alkoxy, e.g. methoxy, carbamoyl- (lower alkoxy), N- (lower alkyl) -carbamoyl- (lower) alkoxy) or N, N-di- (lower alkyl) -carbamoyl- (lower alkoxy), amino, mono- or di- (lower alkyl) -amino, (lower alkanoyl) -amino, e.g. pivaloylamino, halogen, e.g. fluorine or chlorine, carboxy, (lower alkoxy) -carbonyl, benzyl, naphthyl or fluorenyl (lower alkoxy) -carbonyl, lower alkanoyl, sulfo, (lower alkyl) -sulfonyl, phosphono, hydroxy- (lower alkoxy) -phosphoryl or di- (lower alkoxy) -phosphoryl, carbamoyl, mono- or di- (lower alkyl) -carbamoyl, sulfamoyl, mono- or di- (lower alkyl) -sulfamoyl, nitro and / or cyano, e.g. wherein phenyl may be present up to three times, such as in a diphenyl, dibenzyl or triphenyl (lower alkyl) group, for example diphenyl, dibenzyl or triphenyl-2-ethyl, in the first order a phenyl (lower alkyl) group which is not substituted or substituted by said substituents, such as, in particular, benzyl, 2-phenylethyl, 3-phenylpropyl, 4-fluoro-, 4-cyano-, 4-methoxy- or 4-hydroxybenzyl,

R 1 is hydroxy and

R ₇ . represents an optionally substituted lower alkyl group, preferably unsubstituted or substituted as described above for an optionally substituted alkyl group R @ ₃ , R @ ₄ or R @ 6, especially isobutyl or n-butyl, a cycloalkyl- (lower alkyl) group such as the above. described for a cycloalkyl- (lower alkyl) group R ₃ , in particular a cyclohexyl- (lower alkyl) group such as cyclohexylmethyl, or an aryl- (lower alkyl) group, as described above for an aryl- (lower alkyl) group R ₃ , especially a phenyl- (lower alkyl) group which is optionally substituted. disubstituted designated substituent, such as benzyl, 2-phenylethyl, 3-phenylpropyl _t, 4-fluoro, 4-cyano, 4-methoxy or 4-hydroxybenzyl, or it salt, if present salt-forming groups.

Of the compounds of formula I above, those particularly preferred are those wherein, and R8 independently of one another is hydrogen, lower alkanoyl, aryl- (lower alkanoyl) wherein the lower alkanoyl moiety is optionally substituted by carbamoyl, which is optionally substituted on a nitrogen atom with one or two radicals selected from lower alkyl, carboxy- (lower alkyl), (lower alkoxy) -carbonyl- (lower alkyl), di- (lower alkyl) -amino- (lower alkyl), aminocarboxy- (lower alkyl) ), hydroxy- (lower alkyl) or di- (lower alkoxy) - (lower alkyl) groups and wherein the aryl moiety contains 6 to 14 carbon atoms, a heterocyclyl- (lower alkanoyl) group in which the heterocyclyl moiety contains 3 to 10 carbon atoms in the ring and up to 4 heteroatoms selected from oxygen, nitrogen, sulfur, selenium and sulfur bound to 1 or 2 oxygen atoms (S = O, O = S = O), halogen- (lower alkanoyl) u) a group having 1 to 3 halogen atoms, N-heterocyclyl- (lower alkyl) -carbamoyl- (lower alkanoyl), (lower alkoxy) -carbonyl or aryl- (lower alkoxy) -carbonyl group, wherein the aryl part contains 6 to 14 carbon atoms, heterocyclyl- (lower alkoxy) -carbonyl, wherein the heterocyclyl moiety is selected from

126.from pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, quinoxalinyl, β-carbolinyl and β-carbolinyl, β-carbolinyl, cyclopentaanellated, cyclohepentanellated, cyclohepentaellated, cycloheplate partially or fully saturated, further (lower alkyl) -sulfonyl, N- (heterocyclyl- (lower alkyl)) - carbamoyl-N- (lower alkyl) -carbamoyl or an amino acid residue selected from glycine, alanine, valine, norvaline via a carboxy group , leucine, isoleucine, norleucine, serine, homoserine, threonine, methoinin, cysteine, proline, trans-3- and trans-4-hydroxyproline, phenylalanine, tyrosine,

4-aminophenylalanine, 4-chlorophenylalanine, 4-carboxyphenylalanine, β-hydroxyphenylalanine, phenylglycine, α-naphthylalanine, cyclohexylalanine, cyclohexylglycine, tryptophan, aspartic acid, asparagine, aminomalonic acid, glutamine amine amine, glutamine amine, histamine amine amine, histamine amine, , δ-hydroxylysine, ornithine, α, β-diaminobutyric acid or α, β-diaminopropionic acid, wherein the amino acid residue is not substituted or is substituted by one of the residues listed for R 6. or R _g , except for an amino acid residue that is itself substituted,

R _2, R _4, R g and R _g are each hydrogen,

R ₃ represents a cycloalkyl (lower alkyl) group having 3 to 7 carbon atoms or an aryl (lower alkyl) group, wherein the aryl moiety especially contains 6 to 14 carbon atoms,

R 8 is hydroxy and

R ₇ represents a lower alkyl group, a cycloalkyl- (lower alkyl) group wherein the cycloalkyl moiety contains from 3 to 7 carbon atoms or an aryl- (lower alkyl) group wherein the aryl moiety contains from 6 to 14 carbon atoms,

127 and salts of compounds having salt-forming groups, the preferred general terms and definitions mentioned hereinbefore preferably having the meanings given in the last recited above.

Also preferred are the compounds described in the preceding section, wherein the substituents have all the meanings indicated except for morpholinosulfonyl, thiomorpholinosulfonyl, piperidinosulfonyl, 4-methylpiperazinylsulfonyl or piperazinosulfonyl for R ^ and / or Rg.

Also preferred are compounds of formula I wherein

R 6 and R 8 are independently of each other

- a hydrogen atom,

- (lower alkoxy) -carbonyl,

- 2-halo- (lower alkoxy) carbonyl,

an aryloxycarbonyl group wherein the aryl moiety contains 6 to 6 carbon atoms; 14 carbon atoms;

- aryl- (lower alkoxy) -carbonyl, wherein the aryl part contains 6 to 14 carbon atoms, and

- heterocyclyl- (lower alkoxy) -carbonyl, wherein the heterocyclyl moiety is selected from pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolinyl, quinoxalinynyl, quinoxaninynyl , a cyclopenta-fused, cyclohexa-fused or cyclohepta-fused derivative of this series, which may also be partially or fully saturated,

128

- 2-tri- (lower alkyl) -silyl- (lower alkoxy) -carbonyl,

- 2-triarylsilyl- (lower alkoxy) -carbonyl, wherein the aryl moiety is phenyl or 1- or 2-naphthyl,

- via a carboxy-linked amino acid residue selected from glycine, alanine, valine, norvaline, leucine, isoleucine, norleucine, serine, homoserine, threonine, methionine, cysteine, proline, trans-3- and trans-4-hydroxyproline, phenylalanine, tyrosine, 4 -aminophenylalanine, 4-chlorophenylalanine, 4-carboxyphenylalanine, β-phenylserine, phenylglycine, α-naphthylalanine, cyclohexylalanine, cyclohexylglycine, tryptophan, indoline-2-carboxylic acid, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid , aspartic acid, asparagine, aminomalonic acid, aminomalonic acid monoamide, glutamic acid, glutamine, histidine, arginine, lysine, δ-hydroxylysine, ornithine, α, τ-diaminobutyric acid in

or α, β-diaminopropionic acid, each of which may be in the form of D, L or (D, L), preferably L, and the α-amino group is unsubstituted or is N-alkylated once or twice, for example lower alkyl , amino- (lower alkyl), phenyl- or naphthylamino- (lower alkyl) or lower alkyl on the nitrogen atom substituted by piperazinylcarbonyl- (lower alkyl), or N-acylated, lower alkanoyl or aryl- (lower alkanoyl), wherein the aryl moiety is selected from phenyl, indenyl, indanyl, naphthyl, anthryl, phenanthryl, acenaphthyl and fluorenyl and may be unsubstituted or especially substituted one to three times with lower alkyl, halogen (lower alkyl), phenyl, 1- or 2- naphthyl, hydroxy, lower alkoxy, carbamoyl- (lower alkoxy);

- 129 xyl), N- (lower alkyl) -carbamoyl- (lower alkoxy) or N, N-di- (lower alkyl) -carbamoyl- (lower alkoxy), amino, mono- or di- (lower alkyl) -amino , (lower alkanoyl) -amino, halogen, carboxy, (lower alkoxy) -carbonyl, phenyl, naphthyl or fluorenyl- (lower alkoxy) -carbonyl, lower alkanoyl: sulfo, (lower alkyl) -sulfonyl, phosphono, hydroxy- (lower alkoxy) -phosphoryl or di- (lower alkoxy) -phosphoryl, carbamoyl, mono- or di- (lower alkyl) -carbamoyl, sulfamoyl, mono- or di- (lower alkyl) -aminosulfonyl , nitro and / or cyano, wherein the phenyl moiety may be present or present, one to three times, and the lower alkanoyl group optionally substituted by a lower alkyl group, a heterocyclyl group selected from pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazo lyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl, β-carbolinyl and benzanellated, cyclopentaanellated, cyclohexaanellated or cycloheptaanellated derivative of this series, which may also be partially or fully saturated, alkoxy, hydroxy, (1) -oxy, acetoacetoxy. amino or benzyloxycarbonylamino- (lower alkanoyl) -oxy, aryl- (lower alkanoyl) -oxy, wherein the aryl moiety contains from 6 to 10 carbon atoms, (lower alkoxy) -carbonyloxy, mono- or di- (lower alkyl) -aminocarbonyloxy, and wherein the aryl moiety contains 6 to 10 carbon atoms, aryl- (lower alkoxy) -carbonyloxy having an aryl moiety containing 6 to 14 carbon atoms, sulfonyloxy, (lower alkyl) -sulfonyloxy, phenylsulfonynyloxy, 2- or 4-toluenesulfonyloxy or 1 - or 2-naphthylsulfonyloxy, carboxy, esterified carboxy selected from (lower alkoxy) -carbonyl, aryloxycarbonyl, wherein the aryl moiety contains 6 to carbon atoms, aryl- (lower alkoxy) -carbonyl, wherein

The aryl moiety contains 6 to 12 carbon atoms, lower alkanoyl groups, (lower alkyl) -sulfonyl groups, hydroxy- (lower alkoxy) -phosphoryl groups and di- (lower alkoxy) -phosphoryl groups, carbamoyl, one or two lower alkyl groups , carboxy- (lower alkyl), (lower alkoxy) -carbonyl- (lower alkyl), di- (lower alkyl) -amino- (lower alkyl), aminocarboxy- (lower alkyl), hydroxy- (lower alkyl) ) a group, and from a di- (lower alkoxy) - (lower alkyl) group selected from or selected from ethylene, trimethylene, tetramethylene and pentamethylene by a selected residue, wherein the carbon atom may be replaced by a nitrogen, oxygen, sulfur or oxygen atom sulfur and such groups may be unsaturated, substituted carbamoyl, hereinafter. sulfamoyl, phosphono, benzfuranyl, oxo and / or cyano and is an unbranched or branched, heterocyclyl- (lower alkanoyl) group selected from thienyl-, furyl-, pyranyl-, pyrrolyl-, imidazolyl-, pyrazolyl-, oxazolyl-, oxazolyl-, oxazolyl-, oxazolyl-, oxazolyl-, oxazolyl-, oxazolyl-, oxazolyl-, oxazolyl-, oxazolyl- thiazolyl-, furazanyl-, pyridyl-, pyrazinyl-, pyrimidinyl-, pyridazinyl-, azepinyl-, indolyl-, benzimidazolyl-, ΙΗ-indazolyl-, quinolyl-, isoquinolyl-, quinoxalinyl-, quinazolinyl-, cinnolyl-, purinyl-, pteridinyl-, naphthyridinyl-, 4H-quinolizinyl-,

3.1-benzofuranyl-, benz [e] indolyl-, 4,1-benzoxazinyl-,

4.1- benzthiazinyl-, carbazolyl-, β-carbolinyl-, phenazinyl-, phenanthridyl-, acridyl-, phenoxazinyl-, phenothiazinyl-, 1-azaacenaphthenyl-, cyclohexa [b] pyrrolyl-, cycloheptafbjpyrrolyl-, cyclohexafdjpyrazolyl-, [b] pyrazinyl-, cyclohexa [b] pyrimidinyl-, cyclohexa [b] -1,4-oxazinyl-, cyclohexa [b] -1,4-thiazinyl-, pyrrolidinyl-, pyrrolinyl-, imidazolidinyl-, 2-imidazolinyl- 2,3-dihydropyridyl-, piperidyl-, piperazinyl-, 2,3,5,6-tetrahydropyrazinyl-, morpholinyl-, thiomorpholinyl-, S, S-dioxothiomorpholinyl-, indolinyl-, isoindolinyl-, 4,5,6, 7-tetrahydroindolyl-,

1,2,3,4-tetrahydroquinolyl-1,2,3,4-tetrahydroisoquinolyl-, chromanyl-, thiochromanyl-, 1,2,3,4-tetrahydro-3,1-benzdia-131-.

zinyl-, 3,4-dihydro-3H-4,1-benzoxazinyl-, 3,4-dihydro-3H-4,1-benzthiazinyl-, 2,3,4,5-tetrahydro-1H-5,1-benzazepinyl - a

5,6-dihydrophenanthridinyl- (lower alkanoyl) groups, said heterocyclyl radicals not substituted or substituted by lower alkyl, phenyl, 1- or 2-naphthyl, phenyl- (lower alkyl), hydroxy- (lower alkyl), - ( lower alkoxy) - (lower alkyl), phenoxy- or naphthyloxy- (lower alkyl), phenyl- (lower alkoxy) - or naphthyl- (lower alkoxy) - (lower alkyl), (lower alkanoyl) -oxy- (lower alkyl) , phenyl- or naphthyl- (lower alkanoyl) -oxy- (lower alkyl), (lower alkoxy) -carbonyloxy- (lower alkyl), phenyl-, naphthyl- or fluorenyl- (lower alkoxy) -carbonyloxy- (lower alkyl), amino- (lower alkyl), carboxy- (lower alkyl), hydroxy, lower alkoxy, phenyl- or naphthyl- (lower alkoxy), amino, (lower alkyl) -amino, di- (lower alkyl) -amino, carboxy , (lower alkoxy) -carbonyl, phenyl or naphthyl- (lower alkoxy) -carbonyl with a halogen atom, a lower alkanoyl, (lower alkyl) -sulfonyl, phosphono, hydroxy- (lower alkoxy) -phosphoryl or di- (lower alkoxy) -phosphoryl group, carbamoyl, mono- or di- (lower alkyl) - carbamoyl, hydroxy or carboxy- (lower alkyl) -carbamoyl, or sulfamoyl, nitro, oxo and / or cyano, heterocyclyl- (lower alkenyol) groups, wherein the heterocyclyl moiety is selected from pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, pyrazolyl, pyrazolyl, pyrazolyl, pyrazolyl, pyrazolyl, pyrazolyl, pyrazolyl, pyrazolyl, , thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl, β-carbolinyl and benzanellated, cyclopentaanellated, cyclohexaanellated or cycloheptaanellated derivatives of this series, which may also be partially or fully saturated, (lower) (lower alkoxy) -carbonyl, wherein the aryl moiety contains from 6 to 14 carbon atoms, heterocyclyl- (lower alkoxy) -carb an onyl group, wherein the heterocyclyl moiety is preferably selected from pyrrolyl, furyl,

132 thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl, β-carbolinyl and benzanellated, cyclopentaanellated, cyclohexaanellated or cycloheptaanelate are optionally substituted with lower alkyl. a carboxy- (lower alkanoyl), (lower alkoxy) -carbonyl- (lower alkanoyl), hydroxy- (lower alkoxy) - (lower alkanoyl), amino- (lower alkanoyl) or benzyloxycarbonylamino- (lower alkanoyl) group wherein the amino group not bound in the α or β position by carbamoyl, phenyl- (lower alkyl) -aminocarbonyl, N- (di- (lower alkyl) amino) - (lower alkyl) -N- (lower alkyl) aminocarbonyl, N- / dihydroxy- (lower alkyl) / - (lower alkyl) -N- (lower alkyl) -aminocarbonyl, 2- or 3-pyridyl- (lower alkyl) -aminocarbonyl, N-2-pyridyl- (lower alkyl) -N- (lower alkyl) ) -aminocarbonyl, sulfonyl, (lower alkyl) -sulfonyl, arylsulfonyl, wherein the aryl moiety contains from 6 to 10 carbon atoms and is optionally substituted by a lower alkyl or lower alkoxy group, a heterocyclylsulfonyl group, wherein the heterocyclyl moiety is selected from ζ pyrrolyl, furyl, furyl, furyl, , thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyr idyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl, β-carbolinyl and benzanellated, cyclopentaanellated, cyclohexaanellated or cycloheptaanellated derivative of this series, which may also be wholly or partially saturated, by sulfamoyl or heterocyclyl, wherein the heterocyclyl moiety is as defined hereinabove, and / or a lower alkyl substituted sulfamoyl, side chain carboxy group in free or esterified. in the form of a (lower alkyl) -ester, aryl ester or an aryl- (lower alkyl) -ester group, wherein aryl is phenyl, 4-nitrophenyl, naphthyl or biphenylyl, or

- 133 amidated form as carbamoyl-, (lower alkyl) -carbamoyl-, di- (lower alkyl) -aminocarbamoyl-, mono- or di (hydroxy- (lower alkyl)) - carbamoyl- or mono- or di- (carboxy-) (lower alkyl) / - carbamoyl, an amino group of the side chain, which is free or in alkylated form as. mono- or di- (lower alkyl) -amino or in acylated form as (lower alkanoyl) -amino, such as amino- (lower alkanoyl) -amino, such as aryl- (lower alkanoyl) -amino, wherein the aryl moiety contains from 6 to 14 and optionally substituted by lower alkyl, hydroxy, lower alkoxy, carboxy, carbamoyl or sulfamoyl, such as (lower alkoxy) -carbonylamino, arylmethoxycarbonylamino, wherein the aryl moiety contains 6 to 14 carbon atoms such as piperidinyl-1-ylcarbonyl, carbonyl , thiomorpholinocarbonyl or as S, S-dioxothiomorpholinocarbonyl and / or a side chain hydroxy group which is free or in an etherified or esterified form such as lower alkoxy, aryl- (lower alkoxy), (lower alkanoyl) -oxy or as (lower alkoxy) .

- (lower alkyl) -sulfonyl,

-2- or 3-pyrrolyl-, 2-thienyl-, 2-furyl-, 1-pyrazolyl-, 2-, 3- or 4-pyridyl-, 2-, 3- or 5-indolyl-, (1- methyl, 2-methyl-, 5-methoxy-, 5-benzyloxy-, 5-chloro- or

4,5-dimethylindol-2-yl) -, (1-benzylindol-2-yl or 3-yl) -,

4,5,6,7-tetrahydroindol-2-yl-, (2-, 3- or 4-quinolyl or 4-hydroxyquinol-2-yl) -, (1-, 3- or 4-isoquinolyl or 1-oxo) -1,2-dihydroisoquinol-3-yl) -, 3-pyrrolidinyl-, (3- or 4-hydroxypyrrolidin-2-yl) -, 5-oxopyrrolidin-2-yl-, (2- or

(2- or 3-thiomorpholinyl) -. (S, S-dioxothiomorpholin-2- or -3-yl) -, (2- or 3-indolinyl) - (1,2,3,4-134-tetrahydroquinol-2-, -3- or -4-yl) ) - or (1,2,3,4-tetrahydroisoquinol-1-, -2- or -3-yl) methylsulfonyl,

- unsubstituted or phenyl- or 1- or 2-naphthylsulphonyl substituted with one or two lower alkyl groups,

- (lower alkoxy) -sulfonyl or benzyloxy-sulfonyl or 1- or 2-naphthyloxy-sulfonyl, wherein at most one of R R or Rg may be hydrogen and R ₂ and Rg are independently of one another hydrogen or the same radicals as and Rg, or pairs of R @ ₁ and R @ ₂ or R @ ₂ and R @ ₂ each independently of one another together with the bonding nitrogen atom and a residue selected from ethylene, trimethylene, tetramethylene and pentamethylene, the carbon atom being replaced by nitrogen, oxygen, sulfur or oxygen a single or double substituted sulfur atom and may be unsaturated to form a heterocyclic ring,

R ₃ represents

- a cycloalkyl- (lower alkyl) group wherein the cycloalkyl moiety contains from 3 to 7 carbon atoms and is optionally substituted one or three times by lower alkyl, halogen- (lower alkyl), hydroxy, lower alkoxy, carbamoyl- (lower alkoxy) groups, N- (lower alkyl) -carbamoyl- (lower alkoxy) or N, N-di- (lower alkyl) -carbamoyl- (lower alkoxy), amino, mono- or di- (lower alkyl) -amino, halogen, carboxy, ( lower alkoxy) -carbonyl, phenyl-, naphthyl- or fluorenyl- (lower alkoxy) -carbonyl, lower alkanoyl,

135 (lower alkyl) -sulfonyl, phosphono, hydroxy- (lower alkoxy) -phosphoryl or di- (lower alkoxy) -phosphoryl, carbamoyl, mono- or di- (lower alkyl) -aminocarbamoyl, sulfamoyl, mono- or di- (lower alkyl) -sulfamoyl, nitro and / or cyano and is bound to a lower alkyl group, or

- an aryl (lower alkyl) group with an aryl moiety selected from phenyl, indenyl, indanyl, naphthyl, anthryl, phenanthryl, acenaphthyl or fluorenyl, unsubstituted or mono- or triple-substituted lower alkyl, halogen- (lower alkyl), phenyl, 1- or 2-naphthyl, hydroxy, lower alkoxy, carbamoyl- (lower alkoxy), N- (lower alkyl) -carbamoyl- (lower alkoxy) or N, N-di- (lower alkyl) -carbamoyl- (lower alkoxy) , amino, mono- or di- (lower alkyl) -amino, (lower alkanoyl) -amino, halogen, carboxy, (lower alkoxy) -carbonyl, phenyl, naphthyl or fluorenyl- (lower alkoxy) -carbonyl or lower alkanoyl, sulfo, (lower alkyl) -sulfonyl, phosphono, hydroxy- (lower alkoxy) -phosphoryl or di- (lower alkoxy) -phosphoryl, carbamoyl, mono- or di- (lower alkyl) aminocarbamoyl, salt famoyl, mono- or di- (lower alkyl) -sulfamoyl, nitro and / or cyano, wherein the phenyl may be present up to three times, and with the lower alkyl moiety optionally substituted by a lower alkyl group, a heterocyclyl group selected from pyrrolyl, furyl, thienyl , imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl, β-carbolinyl or benzanellated, cyclopentaanellated, cyclohexaanellated or cycloheptaanellated derivative of this series, alkoxy, (lower alkanoyl) -oxy, acetoacetoxy, amino

136 or benzyloxycarbonylamino- (lower alkanoyl) -oxy, aryl- (lower alkanoyl) -oxy, wherein the aryl moiety contains 6 to 10 carbon atoms, (lower alkoxy) -carbonyloxy, mono- or di- (lower alkyl) -aminocarbonyloxy, aryloxy wherein the aryl moiety contains 6-10 carbon atoms. (C niž-C 14 části) aryl- (lower alkoxy) -carbonyloxy, (C alkyl-C 14ry) aryl, sulfonyloxy, (lower alkyl) -sulfonyloxy, phenylsulfonyloxy, 2- or 4-toluenesulfonyloxy or 1- or 2-naphthylsulfonyloxy, mono-, or (lower alkyl) -amino, N- (lower alkoxy) -N- (lower alkyl) -amino, mono- or di- (phenyl- or naphthyl- (lower alkyl)) - amino, (lower alkanoyl) -amino, carboxy an esterified carboxy group selected from (lower alkoxy) carbonyl, aryloxycarbonyl, wherein the aryl moiety contains from 6 to 10 carbon atoms, aryl- (lower alkoxy) -carbonyl, wherein the aryl moiety contains from 6 to 12 carbon atoms. lower alkanoyl, (lower alkyl) -sulfonyl, hydroxy- (lower alkoxy) -phosphoryl and di- (lower alkoxy) -phosphoryl, carbamoyl, one or two radicals selected from lower alkyl, carboxy- (lower alkyl) , (lower alkoxy) -carbonyl- (lower alkyl), di- (lower alkyl) -amino- (lower alkyl), aminocarboxy- (lower alkyl), hydroxy- (lower alkyl) and di- (lower alkoxy) - (lower alkyl) or from ethylene, trimethylene, tetramethylene and pentamethylene by a selected radical where the carbon atom can be replaced by a nitrogen, oxygen, sulfur or oxygen atom with one or two substituted sulfur atoms and such groups can be unsaturated, substituted carbamoyl, sulfamoyl, phosphono, benzofuranyl, oxo and / or cyano and is unbranched or branched,

R ₄ is H,

- .. 137 - - .. /.,.

· R ₅ is hydroxy and

R 8 is hydrogen or

R ₅ and R 8 together represent oxo and.

R ₇ represents

- lower alkyl,

- a cycloalkyl- (lower alkyl) group wherein the cycloalkyl moiety contains from 3 to 7 carbon atoms and is optionally substituted one or three times by lower alkyl, halogen- (lower alkyl), hydroxy, lower alkoxy, carbamoyl- (lower alkoxy) groups, N- (lower alkyl) -carbamoyl- (lower alkoxy) or N, N-di- (lower alkyl) -carbamoyl- (lower alkoxy), amino, mono- or di- (lower alkyl) -amino, halogen, carboxy, ( lower alkoxy) carbonyl, phenyl, naphthyl or fluorenyl- (lower alkoxy) carbonyl, lower alkanoyl, (lower alkyl) -sulfonyl, phosphono, hydroxy- (lower alkoxy) -phosphoryl or di- (lower alkoxy) - phosphoryl, carbamoyl, mono- or di- (lower alkyl) -aminocarbamoyl, sulfamoyl, mono- or di- (lower alkyl) -sulfamoyl, nitro and / or cyano, and is bound to a lower alkyl group,

- a bicycloalkyl- (lower alkyl) group wherein the bicycloalkyl moiety contains 5 to 10 carbon atoms,

- a tricycloalkyl- (lower alkyl) group wherein the tricycloalkyl moiety contains from 8 to 10 carbon atoms,

an aryl (lower alkyl) group wherein the aryl moiety is selected from phenyl. indenyl, _indanyl,: naphthyl, anthryl, phenanthryl, acenaphthyl and fluorenyl and unsubstituted or

138 may be substituted one to three times by lower alkyl, halogen- (lower alkyl), phenyl, 1- or 2-naphthyl, hydroxy, lower alkoxy, carbamoyl- (lower alkoxy), N- (lower alkyl) -carbamoyl- (lower) alkoxy) or N, N-di- (lower alkyl) -carbamoyl- (lower alkoxy), amino, mono- or di- (lower alkyl) -amino, (lower alkanoyl) -amino, halogen, carboxy, (lower alkoxy) -carbonyl, benzyl, naphthyl or fluorenyl- (lower alkoxy) -carbonyl, lower alkanoyl, sulfo, (lower alkyl) -sulfonyl, phosphono, hydroxy- (lower alkoxy) -phosphoryl or di- (lower alkoxy) - phosphoryl, carbamoyl, mono- or di- (lower alkyl) -carbamoyl, sulfamoyl, mono- or di- (lower alkyl) -sulfamoyl, nitro and / or cyano, wherein the phenyl group may be present or present one to three times,and linked to a lower alkyl group unsubstituted or substituted by a lower alkyl group a heterocyclyl group selected from pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolinyl, quinolinyl, isoquinolinyl, quinolinyl, isoquinolinyl, quinolinyl, , cyclohexaanellated or cycloheptaanellated derivatives of this series, which may also be partially or fully illuminated, by hydroxy, lower alkoxy, (lower alkanoyl) -oxy, acetoacetoxy, amino- or benzyloxycarbonylamino- (lower alkanoyl) -oxy-, aryl- (lower alkanoyl) -oxy-, aryl- oxy, wherein the aryl moiety contains 6 to 10 carbon atoms, (lower alkoxy) -carbonyloxy, mono- or di- (lower alkyl) aminocarbonyloxy, aryloxycarbonyloxy, wherein the aryl moiety contains up to 10 carbon atoms, aryl- (lower alkoxy) -carbonyloxy with an aryl moiety containing from 6 to 12 carbon atoms, sulfonyloxy, (lower alkyl) -sulfonyloxy, phenylsulfonyloxy ,. 2- or 4-toluenesulfonyloxy or 1- or 2-naphthylsulfonyloxy, amino, mono- or di-139

- (lower alkyl) -amino, N- (lower alkoxy) -N- (lower alkyl) -amino, mono- or di- / phenyl- or naphthyl- (lower alkyl) -amino, lower alkanoyl, carboxy, esterified carboxy z (lower alkoxy) -carbonyl, aryloxycarbonyl, wherein the aryl moiety contains 6 to 10 carbon atoms, aryl- (lower alkoxy) -carbonyl, wherein the aryl moiety contains 6 to 12 carbon atoms, lower alkanoyl, (lower alkyl) - sulfonyl, hydroxy- (lower alkoxy) -phosphoryl and di- (lower alkoxy) -phosphoryl groups, carbamoyl, once or twice of lower alkyl, carboxy- (lower alkyl), (lower alkoxy) -carbonyl- (lower alkyl), di - (lower alkyl) -amino- (lower alkyl), aminocarboxy- (lower alkyl), hydroxy- (lower alkyl), and di- (lower alkoxy) - (lower alkyl) groups selected from or selected from ethylene, trimethylene, tetramethylene and pentamethylene by a selected residue wherein a the carbon may be replaced by a nitrogen, oxygen, sulfur or oxygen atom with one or two times a substituted sulfur atom, and such groups may be unsaturated, substituted carbamoyl, sulfamoyl, phosphono, benzfuranyl, oxo (not bonded to a carbon atom associated with a nitrogen atom which binds the radical R @ 1 and / or a cyano group and is unbranched or branched,

a heterocyclyl- (lower alkyl) group, wherein the heterocyclyl moiety is preferably selected from pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolinyl, quinoxalinyl carbolinyl and benzanellated, cyclopentaanellated, cyclohexaanellated or cycloheptaanellated derivatives of this series, which may also be partially or fully saturated, such as 4-pyrrolidinylmethyl, 1-imidazolylmethyl, 2-pyridylmethyl, 3-pyridylmethyl, quinolin-2-ylmethyl or indol 2-ylmethyl,

- 140 -

- hydroxy- (lower alkyl) group,

- (lower alkoxy) - (lower alkyl),

- a phenoxy- (lower alkyl) group or a nitrophenoxy- (lower alkyl) group,

- naphthyloxy (lower alkyl) group,

- (lower alkanoyl) -oxy- (lower alkyl) group,

- acetoacetoxy- (lower alkyl) group,

an arylmercapto- (lower alkyl) group in which. the aryl moiety contains 6 to 10 carbon atoms,

- amino- (lower alkyl) group,

- mono- or di- (lower alkyl) -amino- (lower alkyl) group,

- a phenyl or naphthylamino (lower alkyl) group,

- (lower alkanoyl) -amino- (lower alkyl) group,

- a lower alkyl group on the nitrogen atom substituted by a piperazinylcarbonyl- (lower alkyl) group,

- (lower alkoxy) -carbonylamino- (lower alkyl), - phenyl- (lower alkoxy) -carbonylamino- (lower alkyl),

- aminocarbonylamino- (lower alkyl) group,

- N-phenyl- (lower alkyl) -N- (lower alkyl) -aminocarbonylamino- (lower alkyl) group, t

a halogen (lower alkyl) group, a carboxy (lower alkyl) group,.

- (lower alkoxy) -carbonyl- (lower alkyl) group,

- 2-halogen- (lower alkoxy) -carbonyl- (lower alkyl) group,

- a phenyl- or naphthyl- (lower alkoxy) -carbonyl- (lower-alkyl) group,

a heterocyclyl- (lower alkoxy) -carbonyl- (lower alkyl) group, wherein the heterocyclyl moiety is selected from pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolinyl, quinoxolyol, isoquinolinyl β-Carbolinyl and benzanellated, cyclopentaanellated, cyclohexaanellated or. * cycloheptaellated derivatives of this series, which may also be partially or fully saturated,

- (lower alkoxy) -sulfonyl- (lower alkyl) group,

- an arylsulfonyl- (lower alkyl) group, wherein the aryl part contains from 6 to 10 carbon atoms,

- carbamoyl- (lower alkyl), (lower alkyl) -carbamoyl- (lower alkyl),

- di- (lower alkyl) -carbamoyl- (lower alkyl) group,

142

- hydroxy- (lower alkyl) -carbamoyl- or di (hydroxy- (lower alkyl)) - carbamoyl- (lower alkyl) group, N- (lower alkoxy) - (lower alkoxy) - (lower alkyl) -carbamoyl- (lower alkyl),

- ´ - carboxy- (lower alkyl) -carbamoyl- or di / carboxy- (lower alkyl) / -carbamoyl- (lower alkyl) group,

- of ethylene, trimethylene, tetramethylene and pentamethylene by a selected radical where the carbon atom may be replaced by a nitrogen, oxygen, sulfur or oxygen atom with one or two times a substituted sulfur atom, a nitrogen-substituted carbamoyl- (lower alkyl) group; it may also be fully or partially unsaturated,

- N- (lower alkyl) -N-heterocyclyl- (lower alkyl) -carbamoyl- (lower alkyl) group wherein the heterocyclyl moiety is selected from pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl , indolyl, quinolyl, isoquinolyl, quinoxalinyl, β-carbolinyl and benzanellated, cyclopentaanellated, cyclohexaanellated or cycloheptaanelized derivatives of this series, which may also be partially or fully saturated,

- sulfamoyl- (lower alkyl) group,

- N- (phenyl- or naphthyl- (lower alkyl)) - sulfamoyl- (lower alkyl) group,

- a nitrogen atom of ethylene, trimethylene, tetramethylene and pentamethylene with a selected moiety where the carbon atom may be replaced by a nitrogen atom optionally substituted by a lower alkyl, oxygen, sulfur or oxygen atom substituted one or two times by a single atom. Sulfur, a substituted sulfamoyl- (lower alkyl) group, the resulting residue may also be wholly or partially unsaturated,

- an oxo- (lower alkyl) group (wherein the oxo moiety is not bonded to the carbon atom which is bonded to the nitrogen atom v-providing the radical R ₇ ),

- cyano (lower alkyl) group,

- hydroxycarboxy- (lower alkyl) group,

- α-naphthyloxycarboxy (lower alkyl) group,

- hydroxy- (lower alkoxy) -carbonyl- (lower alkyl) group,

- α-naphthyloxy- (lower alkoxy) -carbonyl- (lower alkyl) group,

- (lower alkyl) -carbonylhalogen- (lower alkyl) group,

- α-naphthyl-oxyethoxycarbonyl- (lower alkyl) group, i

- α-naphthyloxybenzyloxycarbonyl- (lower alkyl) group,

- esterified hydroxy- (lower alkoxy) carbonyl-

- (lower alkyl) group wherein the hydroxy group is esterified by a lower alkanoyl group, a cycloalkyl- (lower alkanoyl) group wherein the cycloalkyl moiety contains 3 to carbon atoms, a bicycloalkyl- (lower alkanoyl) group wherein the bicycloalkyl moiety contains 5 to 10 carbon atoms , a tricycloalkyl- (lower alkanoyl) group wherein the tricycloalkyl group contains 8 to 10 carbon atoms, an aryl- (lower alkanoyl) group wherein the aryl moiety contains 6 to 14 carbon atoms, and is unsubstituted or is substituted one to three times by a lower alkyl group , hydroxy, lower alkoxy, carbamoyl- (lower alkoxy), N- (lower alkyl) -carbamoyl- (lower alkoxy) or N, N-di- (lower alkyl) -carbamoyl- (lower alkoxy), amino, mono- or di- (lower alkyl) -amino, halogen, carboxy, (lower alkoxy) -carbonyl, phenyl, naphthyl or fluorenyl- (lower alkoxy) -carbonyl u, lower alkanoyl, (lower alkyl) -sulfonyl, phosphono, hydroxy- (lower alkoxy) -phosphoryl or di- (lower alkoxy) -phosphoryl, carbamoyl, sulfamoyl, nitro and / or cyano, hereinafter (lower alkoxy) -carbonyl, 2-halogen- (lower alkoxy) -carbonyl or phenyl- or fluorenyl- (lower alkoxy) -carbonyl,

- dihydroxycarboxy- (lower alkyl) group,

- dihydroxy- (lower alkoxy) -carbonyl- (lower alkyl) group,

- a dihydroxy- (lower alkoxy) -carbonyl- (lower alkyl) group esterified with a lower alkanoyl, (lower alkoxy) -carbonyl, phenyl- or naphthyl- (lower alkoxy) -carbonyl, (lower alkyl) -sulfonyl or toluenesulfonyl group,

- α-naphthyloxydi- (lower alkyl) -amino- (lower alkyl) group,

- α-naphthyloxycarbamoyl- (lower alkyl) group,

- α-naphthyloxyoxo- (lower alkyl) group (wherein the oxo residue is not attached to the carbon atom which is linked to the atom

145 nitrogen bonding the radical R @ 8) or

an α-naphthyloxycyan- (lower alkyl) group, the same as the salts of said compounds having salt-forming groups.

Particularly preferred are compounds of formula I wherein

R @ 1 and R @ 8 independently of one another are hydrogen, lower alkanoyl, such as formyl, acetyl, propionyl, butyryl or pivaloyl, especially acetyl, aryl- (lower alkanoyl), wherein the aryl moiety is selected from phenyl, indenyl, indanyl, naphthyl, anthryl, phenanthryl, acenaphthyl and fluorenyl, and is unsubstituted or in particular may be substituted one to three times by a lower alkyl group, for example methyl, ethyl or propyl, a halogen- (lower alkyl) group, for example trifluoromethyl, phenyl, 1- or 2 -naphthyl, hydroxy, lower alkoxy, for example methoxy, carbamoyl- (lower alkoxy), N- (lower alkyl) -carbamoyl- (lower alkoxy) or N, N-di- (lower alkyl) -carbamoyl- (lower alkoxy), amino, mono- or di- (lower alkyl) -amino, (lower alkanoyl) -amino, for example pivaloylamino, halogen, for example fluorine, chlorine or bromine, carboxy, (lower alkoxy) -carbonyl, such as tert-butoxycarbonyl, phenyl, naphthyl or fluorenyl- (lower alkoxy) -carbonyl, such as benzyloxycarbonyl, lower alkanoyl, sulfo, (lower alkyl) -sulfonyl, e.g. methylsulfonyl a phosphonium, hydroxy (lower alkoxy) -phosphoryl or di- (lower alkoxy) -phosphoryl group, carbamoyl, mono- or di- (lower alkyl) carbamoyl group, sulfamoyl, mono- or di- (lower alkyl) -aminosulfonyl, nitro and / or cyano, wherein the phenyl may be present or present one to three times, such as

146, for example, in a diphenyl-, dibenzyl- or triphenyl- (lower alkanoyl) group such as diphenyl-, dibenzyl- or triphenylacetyl, and wherein the lower alkanoyl moiety is not substituted or substituted by carbamoyl optionally substituted by one or two radicals selected from lower alkyl, carboxy- (lower alkyl), (lower alkoxy) -carbonyl- (lower alkyl), di- (lower alkyl) -amino- (lower alkyl), aminocarboxy- (lower alkyl), hydroxy- (lower alkyl) and di- (lower alkoxy) - (lower alkyl) groups, for example carbamoyl or carbamoyl substituted with one or two residues selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl and n-heptyl such as in N-methylcarbamoyl, Nn-butylcarbamoyl or N, N-dimethylcarbamoyl, carboxymethylcarbamoyl (glycinylcarbonylcarbonyl, tert-butoxycarbonyl), tert-butoxycarbonyl; 2-di- methylaminoethyl, 5-amino-5-carboxypentyl, hydroxymethyl, hydroxyethyl or 2- (2,2-dimethoxyethyl) carbonyl, for example 4-chloro-, 4-methoxy- or 4-nitrobenzoyl, naphthylcarbonyl, such as α- or β-naphthylcarbonyl, indenylcarbonyl such as 1-, ♦

2- or 3-indenylcarbonyl, indanylcarbonyl, such as Ί- or

2-indanylcarbonyl, phenanthrenylcarbonyl such as 9-phenanthrenylcarbonyl, phenyl- (lower alkanoyl) group such as.

phenylacetyl or 3-phenylpropionyl, a phenyl- (lower alkanoyl) group in which the lower alkanoyl moiety is substituted with carbamoyl such as 2 (R, S) -carbamoyl-3-phenylpropionyl, α-naphthylacetyl, β-naphthylacetyl, (lower alkyl) - a phenylacetyl group such as 4-methylphenylacetyl, a (lower alkoxy) -phenylacetyl group such as 4-methoxyphenylacetyl,

3- (p-hydroxyphenyl) propionyl, diphenylacetyl, di- (4-methoxyphenyl) acetyl, triphenylacetyl, 2,2-benzylacetyl, 3-α- or 3-β-naphthylpropionyl, 3-phenyl- or 3-α-naphthyl- 2-carbamoylpropyl, 3-phenyl- or 3-a-naphthyl-2-tert-butylcarbamoylpropionyl, 3-phenyl- or 3-a-naphthyl-2- (dimethylaminoethyl) carbamoylpropionyl, 3-a-naphthyl-2- (carboxy) - or tert-butoxycarbonyl) me

147 thylcarbamoylpropionyl, 3-phenyl- or 3-α-naphthyl-2- (3-hydroxy-2-propyl) carbamoylpropionyl, 3-phenyl- or 3-α-naphthyl-2- (2,2-dimethoxyethyl) carbamoylpropionyl, 3- phenyl- or 3-α-naphthyl-2- (5-amino-5-carboxypentyl) carbamoylpropionyl, but especially a phenyl- (lower alkanoyl) group such as phenylacetyl, or a phenyl- (lower alkanoyl) group, wherein the lower alkanoyl moiety is substituted with carbamoyl such as 2 (R, S) -carbamoyl-3-phenylpropionyl, heterocyclyl- (lower alkanoyl) group wherein the lower alkanoyl moiety is not substituted and wherein the heterocyclyl moiety is selected from thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl , oxazolyl, isoxazolyl, thiazolyl, furazanyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, azepinyl, indolyl, benzimidazolyl, ind-indazolyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, quinazolinyl, purine, pyridine, purine 1-benzfuranyl, 4,1-benzoxazinyl, 4,1-ben zthiazinyl, cyclohexa [b] pyrrolyl, cyclohepta [b] pyrrolyl, cyclohexa [d] pyrazolyl, cyclohexa [b] pyridyl, cyclohexa [b] pyrazinyl, cyclohexa [b] pyrimidinyl, cyclohexa [b] -1,4-oxazinyl, cyclohexa [b] -1,4-thiazinyl, pyrrolidinyl, pyrrolinyl, imidazolidyl, 2-imidazolinyl, 2,3-dihydropyridyl, piperazinyl, 2,3,3,6,6-tetrahydropyrazinyl, morpholinyl, thiomorpholinyl, S, S-dioxothiomorpholinyl, indolinyl isoindolinyl, 4,5,6,7-tetrahydroindolyl, 1,2,3,4-tetrahydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl, chromanyl, thiochromanyl, 1,2,3,4-tetrahydro-3, 1-benzdiazinylu,

3,4-dihydro-3H-4,1-benzoxazinyl and 3,4-dihydro-3H-4,1-benzthiazinyl wherein said heterocyclyl radicals are not substituted or substituted by lower alkyl, for example methyl, phenyl, 1- or 2 naphthyl, fluorenyl (lower alkyl), for example benzyl, hydroxy (lower alkyl), for example hydroxymethyl or 2-hydroxyethyl, (lower alkoxy) - (lower alkyl), for example methoxymethyl or 2-methoxyethyl, phenoxy- naphthyloxy- (lower alkyl) group, for example 2-phenoxy-1,48 ethyl, 1- or 2-naphthyloxymethyl, phenyl- (lower alkoxy) or naphthyl- (lower alkoxy) - (lower alkyl) group, for example benzyloxy- (lower alkyl) or ( lower alkanoyl) -oxy- (lower alkyl), for example acetoxymethyl, phenyl- or naphthyl- (lower alkanoyl) -oxy- (lower alkyl), for example benzyloxy-, phenylacetoxy- or 1- or 2-naphthoyloxymethyl, -2- ethyl or 2- (2,2-dimethylethyl), (lower alkoxy) -carbonyloxy- (lower alkyl), for example tert-butoxycarbonyloxy- (lower alkyl), phenyl, naphthyl or fluorenyl- (lower alkoxy) -carbonyloxy- (lower alkyl), for example 2-benzyloxycarbonyloxyethyl or 9-fluorenylmethoxycarbonyloxyethyl, amino (lower alkyl), for example aminomethyl, 2-aminoethyl or 2-aminopropyl, carboxy (lower alkyl), for example carboxymethyl or 2-carboxyethyl, hydroxy, lower alkoxy, for example methoxy or ethoxy, phenyl- or naphthyl (lower alkoxy), for example, benzyloxy or 1- or 2-naphthyloxy, amino, (lower alkyl) -amino, for example methyl, ethyl or tert-butylamino, di- (lower alkyl) -amino, for example dimethyl - or diethylamino, carboxy, (lower alkoxy) -carbonyl, for example methoxy-, isopropoxy-, sec-butoxy-, or tert-butoxycarbonyl a phenyl, or naphthyl- (lower alkoxy) carbonyl group, for example benzyloxycarbonyl, a halogen atom, for example fluorine, chlorine, bromine or iodine, especially chlorine or bromine, a lower alkanoyl group, for example acetyl or pivaloyl, (lower alkyl) - a sulfonyl group such as methyl or ethylsulfonyl, a phosphono group, a hydroxy- (lower alkoxy) -phosphoryl or a di- (lower alkoxy) -phosphoryl group such as a dimethoxy- or diethoxyphosphoryl, carbamoyl, mono- or di- (lower alkyl) -carbamoyl group such as N-methylcarbamoyl, Nn-butylcarbamoyl or N, N-dimethylcarbamoyl, hydroxy or carboxy-

149-alkyl) -carbamoyl, for example hydroxy- or carboxymethylcarbamoyl or hydroxy- or carboxyethylcarbamoyl, sulfamoyl, nitro, oxo, and / or cyano, wherein the heterocyclyl- (lower alkanoyl) group is particularly selected from optionally lower alkyl or phenyl; pyrrolylcarbonyl, for example 2- or

3-pyrrolylcarbonyl, 4- or 5-methylpyrrolylcarbonyl; or

4- or 5-phenylpyrrolyl-2-carbonyl, thienylcarbonyl, such as

2-thienylcarbonyl, furylcarbonyl such as 2-furylcarbonyl, pyridylcarbonyl such as 2-, 3- or 4-pyridylcarbonyl, pyrimidin-1-ylcarbonyl, optionally with a lower alkyl group such as methyl, phenyl- (lower alkyl) group such as benzyl, lower alkoxy, such as methoxy, phenyl (lower alkoxy), such as benzyloxy or halogen, such as chloro substituted indolylcarbonyl, such as 2-, 3- or 5-indolylcarbonyl, 1-methyl-,

5-methyl-, 5-methoxy-, 5-benzyloxy-, 5-chloro- or 4,5-dimethylindolyl-2-carbonyl, 1-benzylindolyl-2- or -3-carbonyl, 4,5,6,7- tetrahydroindolyl-2-carbonyl, optionally hydroxy substituted quinolyl- (lower alkanoyl) groups, for example, quinolylcarbonyl such as 2-, 3- or 4-quinolylcarbonyl or 4-hydroxyquinolyl-2-carbonyl, optionally hydroxy substituted isoquinolylcarbonyl; such as 1-, 3- or 4-isoquinolylcarbonyl or 1-oxo-1,2-dihydroisoquinolyl-3-carbonyl, 2-quinoxalinylcarbonyl, 2- (3,1-benzfuranyl) carbonyl, cyclohepta [b] pyrrole-5-carbonyl 3-chromanylcarbonyl, 3-thiochromanylcarbonyl, pyrrolidinyl-3-carbonyl, hydroxypyrrolidinylcarbonyl such as 3- or 4-hydroxypyrrolidinyl-2-carbonyl, oxopyrrolidinylcarbonyl, such as 5-oxopyrrolidinyl-2-carbonyl, piperidinylcarbonyl, piperidinylcarbonyl 3- or 4-piperidylcarbonyl, pyrazinylcarbonyl, such as pyrazin-1-ylcarbonyl, piperazinylcarbonyl, such as piperazin-1-ylcarbonyl, morpholinyl- (lower alkanoyl) groups, for example, morpholinylcarbonyl, such as morpholinocarbonyl, thiomorpholinyl- (lower alkanoyl) - (lower alkanoyl)

150 groups, for example thiomorpholinylcarbonyl such as thiomorpholinocarbonyl, S, S-dioxothiomorpholinylcarbonyl such as

S, S-dioxothiomorpholinocarbonyl, indolinylcarbonyl such as 2- or 3-indolinylcarbonyl, 1,2,3,4-tetrahydroquinolinylcarbonyl such as 1 / 2,3,4-tetrahydroquinolinyl-2-, -3- or -4 -carbonyl, 1,2,3,4-tetrahydroisoquinolinylcarbonyl such as

1,2,3,4-tetrahydroisoquinolinyl-1-, -3- or -4-carbonyl or 1-oxo-1,2,3,4-tetrahydroisoquinolinyl-3-carbonyl, tetrazolyl- (lower alkanoyl) groups such as 3- (tetrazol-1-yl) -propionyl and pyridyl- (lower alkanoyl) groups, for example pyridylacetyl such as 2-, 3- or 4-pyridylacetyl, especially selected from morpholino- (lower alkanoyl) groups such as morpholinocarbonyl, thiomorpholino - (lower alkanoyl) groups such as thiomorpholinocarbonyl, pyridyl- (lower alkanoyl) groups such as 2-, 3- or 4-pyridylacetyl, quinolinyl- (lower alkanoyl) groups such as quinolin-2-ylcarbonyl and tetrazolyl- ( lower alkanoyl) groups such as 3- (tetrazol-1-yl) propionyl, further a heterocyclyl- (lower alkanoyl) group on the amino nitrogen atom substituted with an amino- (lower alkanoyl) group, wherein the heterocyclyl- (lower alkanoyl) group is defined as over, for heterocyclyl- (lower alkanoyl) and R _g, in particular N-morpholino or N-thiourea an amino (lower alkanoyl) substituted amino acid on the amino nitrogen atom, in particular an N-morpholino or N-thiomorpholinocarbonylamino- (lower alkanoyl) group such as N-morpholino- or N-thiomorpholinocarbonylaminoacetyl, and a halogen- (lower) alkanoyl group; preferably, it contains at least 3 halogen atoms, in the first instance α-haloacetyl, such as α-fluoro-, α-chloro-, α-bromo-, α-iodo-, α, α, α-trifluoro- or α, α, and -trichloroacetyl, or halopropionyl, such as β-chloro- or β-bromopropionyl, for example, trifluoroacetyl or N- (heterocyclyl- (lower alkyl) -carbamoyl) - (lower alkanoyl) group in which the heterocyclyl moiety is selected from pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl,

151 pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl, β-carbolinyl and benzanellated, cyclopentaanellated, cyclohexaanellated or cycloheptaanellated derivatives of this residue. wherein said residues may also be wholly or partially saturated, from morpholinyl and thiomorpholinyl, in particular 2- (N-morpholino- (lower alkyl) -carbamoyl) - (lower alkanoyl) groups such as 2 (R, S) - / N- (2-morpholinoethyl) carbamoyl / -3-methylbutyryl, or 2- [N- / pyridyl- (lower alkyl) carbamoyl] - (lower alkanoyl) groups such as 2 (R, S) - / N- (2- pyridylmethyl) carbamoyl-3-methylbutyryl, further a (lower alkoxy) -carbonyl group, in particular a methoxy-, ethoxy-, isopropoxy-, isobutoxy- or tert- (lower alkoxy) -carbonyl group, for example methoxycarbonyl, tert-butoxycarbonyl or isobutoxycarbonyl, aryl- (lower alkoxy) -carbonyl, wherein the aryl moiety is phenyl, biphenylyl, 1- or 2-naphthyl or fluorenyl, or a lower alkyl group such as methyl or tert-butyl, hydroxy, lower alkoxy such as methoxy , ethoxy or tert-butoxy, a halogen atom such as chlorine or bromine and / or nitro groups mono- or poly-substituted phenyl such as phenyl- (lower alkoxy) -carbonyl such as benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl or fluorenyl- (lower alkoxy) -carbonyl group such as 9-fluorenylmethoxycarbonyl; (lower alkoxy) -carbonyl, such as benzyloxycarbonyl, and heterocyclyl- (lower alkoxy) -carbonyl, wherein the heterocyclyl moiety is preferably selected from pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrazinyl, pyrazinyl, pyrazinyl, pyrazinyl , indolyl, quinolyl, isoquinolyl, quinoxalinyl, β-carbolinyl and benzanellated, cyclopentaanellated, cyclohexaanellated or cycloheptaanellated derivatives of this series, which may also be partially or fully saturated, and from the morpholinyl or thiomorpholinyl group are optionally substituted by an alkyl group such as methyl, for example 1-methylpyrrole

152 din-2-ylmethoxycarbonyl, 2-furylmethoxycarbonyl, 2-tetrahydrofuranylmethoxycarbonyl, 1-methyl-2-piperidylmethoxycarbonyl or 2-morpholinoethoxycarbonyl or 2-, 3- or 4-pyridylmethoxycarbonyl, in particular tetrahydrofuranyl, (in particular tetrahydrofuranyl), such as 2 (R, S) -tetrahydrofuranylmethoxycarbonyl, (lower alkyl) -sulfonyl, for example methyl or ethylsulfonyl such as methylsulfonyl, morpholinosulfonyl, thiomorpholinosulfonyl, piperidinosulfonyl, 4-methylpiperazinylsulfonyl or piperazinosulfonyl- (N-heterocyclyl) - N- (lower alkyl) -carbamoyl, wherein the heterocyclyl moiety is selected from thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, furazanyl, pyridyl, pyrazinyl, pyrimidinyl, pyrimidinyl, pyridazinyl, azepinyl, azepinyl, azepinyl, Ind-indazolyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, cinnolyl, purinyl, pteridinyl, naphthyridinyl, 4H-quinolizinyl, 3,1- benzofuranyl, benz [e] indolyl, 4,1-benzoxazinyl, 4,1-benzthiazinyl, carbazolyl, β-carbolinyl, phenazinyl, phenanthridyl, acridyl, phenoxazinyl, phenothiazinyl, 1-azaacenaphthyl, cyclohexa [b] pyrrolyl, cyclohep pyrrolyl, cyclohexa [d] pyrazolyl, cyclohexa [b] pyridyl, cyclohexa [b] pyrazinyl, cyclohexa [b] pyrimidinyl, cyclohexa [b] -1,4-oxazinyl, cyclohexa [b] -1,4-thiazinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, 2-imidazolinyl, 2,3-dihydropyridyl, piperidyl, piperazinyl,

2.3.5.6- tetrahydropyrizinyl, morpholinyl, thiomorpholinyl,

S, S-dioxothiomorpholinyl, indolinyl, isoindolinyl,

4.5.6.7-tetrahydroindolyl, 1,2,3,4-tetrahydroquinolyl,

1.2.3.4- tetrahydroisoquinolyl, chromanyl, thiochromanyl,

1,2.3.4-tetrahydro-3,1-benzdiazinyl, 3,4-dihydro-3H-4,1-benzoxazinyl, 3,4-dihydro-3H-4,1-benzthiazinyl, 2,3,4,5-tetrahydro- 1H-5,1-benzazepinyl and 5,6-dihydrophenanthridinyl, said radicals not being substituted or substituted by lower alkyl, for example methyl, phenyl, 1- or 2-naphthyl, phenyl- (lower alkyl), e.g.

153 is benzyl, hydroxy (lower alkyl), for example hydroxymethyl or 2-hydroxyethyl, (lower alkoxy) - (lower alkyl), for example methoxymethyl or 2-methoxyethyl, phenoxy or naphthyloxy (lower alkyl), for example 2 -phenoxyethyl, 1- or 2-naphthyloxymethyl, phenyl- (lower alkoxy) - or naphthyl- (lower alkoxy) - (lower alkyl), for example benzyloxy- (lower alkyl), (lower alkanoyl) -oxy- (lower alkyl) a group such as acetoxymethyl, phenyl or naphthyl- (lower alkanoyl) -oxy- (lower alkyl) group such as benzyloxy, phenylacetoxy- or 1- or 2-naphthoyloxymethyl, -2-ethyl or - 2- (2,2 dimethylethyl), (lower alkoxy) -carbonyloxy- (lower alkyl), for example tert-butoxycarbonyloxy- (lower alkyl), phenyl-, naphthyl- or fluorenyl- (lower alkoxy) -carbonyloxy- (lower alkyl) a group such as 2-benzyloxycarbonyloxyethyl or 9-fluorenylmetho xycarbonyloxyethyl, amino (lower alkyl), for example aminomethyl, 2-aminoethyl or 2-aminopropyl, carboxy (lower alkyl), for example carboxymethyl or 2-carboxyethyl, hydroxy, lower alkoxy, for example methoxy or ethoxy, phenyl or naphthyl - (lower alkoxy), for example benzyloxy or 1 * or 2-naphthylmethoxy, amino, (lower alkyl) -amino, for example methyl, ethyl or tert-butylamino, di- (lower alkyl) -amino, for example dimethyl- or diethylamino, carboxy, (lower alkoxy) -carbonyl, for example methoxy-, isopropoxy-, sec-butoxy- or tert-butoxycarbonyl, phenyl- or naphthyl- (lower alkoxy) -carbonyl, for example benzyloxycarbonyl, atom halogen, for example by fluorine, chlorine, bromine or iodine, especially chlorine or bromine, by a lower alkanoyl group, for example acetyl or pival oyl, (lower alkyl) -sulfonyl, for example methyl- or ethylsulfonyl, phosphono, hydroxy- (lower alkoxy) -phosphoryl or di- (lower alkoxy) -phosphoryl group

154 pin, for example dimethoxy- or diethoxyphosphoryl, carbamoylene, mono- or di- (lower alkyl) -carbamoyl, for example N-methylcarbamoyl, Nn-butylcarbamoyl or N, N-dimethylcarbamoyl, hydroxy- or carboxy- (lower alkyl) -carbamoyl a hydroxy- or carboxymethylcarbamoyl or hydroxy- or carboxyethylcarbamoy group. , sulfamoyl or nitro, oxo and / or cyano, and in particular means pyridyl, such as 2-, 3- or 4-pyridyl, in particular N- (pyridyl- (lower alkyl)) - N- (lower alkyl) -carbamoyl such as N- (2-, 3- or 4-pyridylmethyl) -N-methylcarbamoyl, and also acyl amino acid residue, the amino functional group is free or acylated with one of the heretofore mentioned for the radical R · N, R _g, where the radicals are derived from amino acids selected from glycine (H.-Gly-OH), alanine (H-Ala-OH), valine (H-Val-OH), norvaline (α-aminovaleric acid), leucine (H-Leu-OH) , isoleucine (H-Ile-OH), norleucine (α-aminohexanoic acid, H-Nle-OH), serine (H-Ser-OH), homoserine (α-amino-T-hydroxybutyric acid), threonine (H-Thr -OH), methionine (H-Met-OH), cysteine (H-Cys-OH), proline, (H-Pro-OH), trans-3- and trans-4-hydroxyproline, phenylalanine (H-Phe- OH), tyrosine (H-Tyr-OH), 4-aminophenylalanine, 4-chlorophenylalanine, 4-carboxyphenylalanine, β-phenylse rhinine (β-hydroxyphenylalanine), phenylglycine, α-naphthylalanine (H-Nal-OH), cyclohexylalanine (H-Cha-OH), cyclohexylglycine, tryptophan (H-Trp-OH), indoline-2-carboxylic acid, 1, 2,3,4-tetrahydroisoquinoline-3-carboxylic acid, aspartic acid (H-Asp-OH), asparagine (H-Asn-OH), aminomalonic acid, aminomalonic acid monoamide, glutamic acid (H-Glu-OH), glutamine ( H-Gln-OH), histidine (H-His-OH), arginine (H-Arg-OH), lysine (H-Lys-OH), δ-hydroxylysine, ornithine (α, δ-diaminok valeric acids), acids 3-aminopropanoic acid, α, τ-diamobutyric acid and α, β-diaminopropionic acid, a particularly preferred amino acid residue selected from valine, alanine, leucine and isoleucine, glycine, glutamic acid and asparagine,

155 (except glycine) each of said amino acids is in the form of D, L, or (D, L), preferably (except Val, which may also be in the form of D or (D, L)) may be in the form of L , the α-amino groups are unsubstituted, or is N-acylated with one · of the above mentioned radicals R a to _g, in particular lower alkanoyl, phenyl (lower alkanoyl) group such as phenylacetyl, phenyl (lower alkanoyl) group, wherein the lower alkanoyl the moiety is substituted with carbamoyl such as 2 (R, S) -carbamoyl-3-phenylpropionyl, morpholino- (lower alkanoyl) group such as morpholinocarbonyl, thiomorpholino- (lower alkanoyl) group such as thiomorpholinocarbonyl, pyridyl- (lower alkanoyl) a group such as 2-, 3 or 4-pyridylacetyl, a quinolinyl- (lower alkanoyl) group such as a quinoline-2-carbonyl, a tetrazolyl- (lower alkanoyl) group such as a 3-tetrazol-1-ylpropionyl, N-morpholino group or an N-thiomorpholinocarbonyl group on a an amino nitrogen atom substituted with an amino- (lower alkanoyl) group, for example an N-morpholino- or N-thiomorpholinocarbonylamino- (lower alkanyol) group, such as N-morpholino or N * -thiomorpholinocarbonylaminoacetyl, a halogen- (lower alkanoyl) group containing up to 3 carbon atoms such as α-haloacetyl, such as α-fluoro-, α-chloro-, α-bromo-, α-iodo-, α, α, α-trifluoro- or α, α, α-trichloroacetyl, or halopropionyl , such as β-chloro- or β-bromopropionyl, especially trifluoroacetyl, 2-N- (morpholino- (lower alkyl) -carbamoyl) - (lower alkanoyl) group such as 2 (R, S) -N - / (2 (morpholinoethyl) carbamoyl] -3-methylbutyryl, 2- (N-pyridyl- (lower alkyl) carbamoyl) - (lower alkanoyl) group such as 2 (R, S) - N - (2-pyridylmethyl) carbamoyl a - (lower alkanoyl), (lower alkoxy) -carbonyl, pyridyl- (lower alkoxy) -carbonyl, tetrahydrofuranyl- (lower alkoxy) -carbonyl group such as 2 (R, S) -tetrahydrofuranylmethoxycarbonyl, ( lower alkyl) -sulfonyl or N-pyridyl- (lower alkyl) -N- (lower alkyl) -carbamoyl group such as N- (2-, 3- or 4-pyridylmethyl) -N-methylcarbamoyl, with most preferred being N-morpholinocarbonylglycine, Ν- / Ν- (2-, 3- or 4-pyridyl) methyl-N-methylaminocarbonyl / glycine, valine, N- (trifluoroacetyl) valine, N-phenylacetylvaline, N- (2- or 3- 3-pyridylacetyl) valine, N-acetylvaline, N- (2-carbamoyl-3-phenylpropionyl) valine, N- / 2 (R, S) -carbamoyl-3-phenylpropionyl] valine, N- (2- or 3-pyridylacetyl) valine, N-tetrahydrofurylmethoxycarbonylvaline, N- [3- (tetrazol-1-yl) propionyl] valine, N- (quinoline-2-carbonyl) valine, N-methoxycarbonylvaline, N-isobutoxycarbonylvaline, N-tert. -butoxycarbonylvaline, N-benzyloxycarbonylvaline, N- (morpholinocarbonyl) valine, N- (thiomorpholinocarbonyl) valine, N- (S, S-dioxothiomorpholinocarbonyl) valine, N- (N-2-pyridylmethyl-N-methylaminocarbonyl) valine, N- morpholinocarbonylaminoacetylvaline, N-methylsulfonylvaline, morpholinosulfonylvaline, N-acetylisoleucine, N-propionylisol eucine, N- (benzyloxycarbonyl) isoleucine, N-benzyloxycarbonylglutamic acid, asparagine, N-benzyloxycarbonylasparagine or quinoline-2-carbonylasparagine, wherein the amino acid residues are preferably in the form of L or (D, L), also in the form of valine D, with the proviso that at most one of the substituents and R _g is hydrogen,

R ₂ , R ₄ , R ₆ and R 8 represent! hydrogen atoms,

R 1 represents a lower alkyl group such as isobutyl or n-butyl, a cycloalkyl- (lower alkyl) group wherein the cycloalkyl moiety contains 3 to 7 carbon atoms and is not substituted or substituted by one or three times lower alkyl group such as isopropyl, halogen- (lower alkyl), such as trifluoromethyl, hydroxy, lower alkoxy, carbamoyl- (lower alkoxy), N- (lower alkyl) -carbamoyl- (lower alkoxy), or N, N-di- (lower alkyl) -carbamoyl- (lower alkyl) alkoxy), amino, mono- or di- (lower alkyl) amino, halogen, such as fluorine, chlorine or bromine, carboxy, (lower alkoxy) -carbonyl, phenyl, naphthyl or fluorenyl- (lower alkoxy) -carbonyl, lower alkanoyl or (lower

(Alkyl) -sulfonyl, for example, methylsulfonyl, phosphono, hydroxy- (lower alkoxy) -phosphoryl or di- (lower alkoxy) -phosphoryl, carbamoyl, mono- or di- (lower alkyl) aminocarbamoyl, sulfamoyl, mono- or di- (lower alkyl) -sulfamoyl, nitro and / or cyano, and is bound to a lower alkyl group, especially methyl, ethyl, n-propyl, isopropyl, N-butyl, isobutyl, tert-butyl, preferably in the terminal a position such as a cyclobutyl-, cyclopentyl-, cyclohexyl- or cycloheptyl- (lower alkyl) group, such as -methyl or -ethyl, especially a cyclohexyl- (lower alkyl) group, especially cyclohexylmethyl, or an aryl- (lower alkyl) group, wherein aryl is phenyl, indenyl, indanyl, naphthyl, anthryl, phenanthryl, acenaphthyl or fluorenyl, and is not unsubstituted or can be substituted one or three times by a lower alkyl group, for example methyl, ethyl or isopropyl, halogen- (lower alkyl), such as trifluoromethyl, phenyl, 1- or 2-naphthyl, hydroxy, lower alkoxy, for example methoxy, carbamoyl- (lower alkoxy), N- (lower alkyl) -carbamoyl- (lower, alkoxy) or N, N-di- (lower alkyl) -carbamoyl- (lower alkoxy), amino, mono- or di- (lower alkyl) -amino, (lower alkanoyl) -amino, e.g. pivaloylamino, halogen, e.g. fluorine or chlorine , carboxy, (lower alkoxy) -carbonyl, benzyl-, naphthyl- or fluorenyl- (lower alkoxy) -carbonyl, lower alkanoyl, sulfo, (lower alkyl) -sulfonyl, phosphono, hydroxy- (lower alkoxy) -phosphoryl, or di- (lower alkoxy) -phosphoryl, carbamoyl, mono- or di- (lower alkyl) -carbamoyl, sulfamoyl, mono- or di- (lower alkyl) -sulfamoyl, nitro and / or cyano, wherein the phenyl may be and present three times, such as in diphenyl, dibenzyl or triphenyl (lower alkyl). groups such as diphenyl-, dibenzyl-. or triphenyl-2-ethyl, especially phenyl (lower alkyl)

- 158 pins which are not substituted or which are substituted by said substituents, in particular benzyl, 4-fluoro or 4-cyanobenzyl,

R 8 is hydroxy and

R? represents optionally substituted lower alkyl, preferably in particular isobutyl or n-butyl, or cycloalkyl (lower alkyl) as described above for cycloalkyl (lower alkyl) R ₃ , in particular cyclohexyl (lower alkyl), such as is cyclohexylmethyl, or an aryl- (lower alkyl) group as described above for an aryl- (lower alkyl) group R ₃ , in particular a phenyl- (lower alkyl) group, which is optionally substituted by said substituents, such as especially benzyl, 4- fluoro- or 4-cyanobenzyl, or salts thereof, if salt-forming groups are present.

Particularly preferred are also compounds of formula I wherein R 1 is (lower alkoxy) -carbonyl, phenyl- (lower alkoxy) -carbonyl, through a carboxyl group attached to a monovalent aliphatic amino acid radical selected from valine, alanine, leucine and isoleucine, or over carboxy the attached radical at the nitrogen atom of the amino group of the aliphatic acid as defined above acylated with a radical selected from phenyl- (lower alkanoyl), morpholinyl- (lower alkanoyl), thiomorpholinyl- (lower alkanoyl),

S, S-dioxo-thiomorpholinyl- (lower alkanoyl), pyridyl- (lower alkanoyl), (lower alkoxy) -carbonyl or phenyl- (lower alkoxy) -carbonyl groups, all of which are in the form of D, (D, L) ) or L, preferably in the form of L, R ₂ is H, R ₃ is phenyl (lower alkyl) group, is hydrogen, R is hydroxy, R ₆ is H, _R? means lower al159

s

É? ·;

keel, cyclohexyl (lower alkyl) or phenyl (lower alkyl) group, R represents a hydrogen atom and R _g is one of the radicals mentioned for R · · ^ and _Rg radicals and having the asymmetric carbon atom is in the S-configuration, the same as pharmaceutically usable salts of these compounds.

Particularly preferred are compounds of formula (I) wherein t-butoxycarbonyl, benzyloxycarbonyl, via a carboxyl group attached to a valine amino acid radical, or through a carboxyl group attached to a nitrogen atom of an amino group of an alanine of an acylated radical selected from phenyloxycarbonyl, .-butoxycarbonyl or benzyloxycarbonyl, R ₂ is H, R ₃ is benzyl, R ₄ is H, R ₅ is hydroxy, R ₆ is H, _R? is isobutyl, cyclohexylmethyl or benzyl, R represents a hydrogen atom and R _g is one of the radicals mentioned for the radicals R ₃ and R ₅ bearing asymmetric carbon atom is in the S-configuration, as well as pharmaceutically acceptable salts of such compounds.

Particularly preferred compounds of formula I wherein R and _G are each independently a hydrogen atom, a lower alkanoyl group such as acetyl, phenyl (lower alkanoyl) group such as phenylacetyl, phenyl (lower alkanoyl) group, the lower alkanoyl radical is substituted with carbamoyl such as 2 (R, S) -carbamoyl-3-phenylpropionyl, morpholino- (lower alkanoyl) group such as morpholinocarbonyl, thiomorpholino- (lower alkanoyl) group such as thiomorpholinocarbonyl, pyridyl- (lower alkanoyl) group such as 2 3-, 4-pyridylacetyl, quinolyl- (lower alkanoyl), such as quinoline-2-carbonyl, tetrazolyl- (lower alkanoyl), such as 3-tetrazol-1-ylpropionyl, N-morpholino- or N-thiomorpholinocarbonyl; an amino nitrogen atom substituted with an amino- (lower alkanoyl) group, for example t;

r.?· «*

· / - ·

160

N-morpholino- or N-thiomorpholinocarbonylamino- (lower alkanoyl) group, such as N-morpholino- or N-thiomorpholinocarbonylaminoacetyl, a halogen- (lower alkanoyl) group containing up to three halogen atoms, such as trifluoroacetyl, 2- / N-morpholino - (lower alkyl) -carbamoyl / - (lower alkanoyl) group such as 2 (R, S) - [N- (2-morpholinoethyl) carbamoyl] -3-methylbutyryl, 2- (N-pyridyl) - (lower alkyl) 1-carbamoyl- (lower alkanoyl) group such as 2 (R, S) - [N- (2-pyridylmethyl) carbamoyl] -3-methylbutyryl, (lower alkoxy) -carbonyl group such as methoxy-, isobutoxy- or tert- (lower alkoxy) -carbonyl, phenyl- (lower alkoxy) -carbonyl, such as benzyloxycarbonyl, tetrahydrofuran- (lower alkoxy) -carbonyl, such as 2 (R, S) -tetrahydrofuranmethoxycarbonyl, (lower alkyl) -sulfonyl a methyl or ethylsulfonyl, morpholinosulfonyl, thiomorpholinosulfonyl, N-pyridyl- (lower alkyl) -N- (lower alkyl) carbamoyl group or an acyl group an amino acid selected from glycine, bacon, valine, leucine, isoluecin, glutamic acid, and .asparagine in the form of D, L or (D, L), wherein the α-amino group is not substituted or acylated by one of the remaining R &apos; or R 2, with N-morpholinocarbonylglycine, N- / N- (2-, 3- or 4-pyridyl) methyl-N-methylaminocarbonyl / glycine, valine, N- (trifluoroacetyl) valine, N-phenylacetylvaline, N- particularly preferred. (2- or 3-pyridylacetyl) valine, N-acetylvaline, N- (2-carbamoyl-3-phenylpropionyl) valine, N- / 2 (R, S) -carbamoyl-3-phenylpropionyl / valine, N- (2- or 3-pyridylacetyl) valine, N-tetrahydrofurylmethoxycarbonylvaline, N-3- (tetrazol-1-ylpropionyl) valine, N- (quinoline-2-carbonyl) valine, N-methoxycarbonylvaline, N-isobutoxycarbonylvaline, N-tert-butoxycarbonylvaline, N-benzyloxycarbonylvaline, N- (morpholinocarbonyl) valine, N- (thiomorpholinocarbonyl) valine, N- (S, S-dioxothiomorpholinocarbonyl) valine, N- (N-2-pyridylmethyl-N-methylaminocarbonyl) valine, N-morpholinocarbonylaminoacetyl aline, N-methylsulfonylvaline, morpholinosulfonylvaline, N-acetylisoleucine, N-propionylisoleucine, N- (benzyloxycarbonyl) isoleucine,

161 N-benzyloxycarbonylglutamic acid, asparagine, N-benzyloxycarbonylasparagine or quinoline-2-carbonylasparagine, the amino acid residues preferably being in the form of L or (D, L), in the case of valine also in the form of D, provided that at most one of the substances R? and R _g is H;

R _2, R _4, R g and R _g are each hydrogen,

R 1 represents a lower alkyl group such as n-butyl or isobutyl, a cyclohexyl- (lower alkyl) group such as cyclohexylmethyl, or a phenyl- (lower alkyl) group optionally substituted by a halogen atom such as fluorine, a lower alkoxy group such as methoxy, or cyano, in particular benzyl, 4-fluorobenzyl or 4-cyanobenzyl,

R ₅ is hydroxy and

R ₇ represents a lower alkyl, cyclohexyl- (lower alkyl) or phenyl- (lower alkyl) group, which is optionally substituted by a halogen atom such as fluorine, a lower alkoxy group such as a methoxy group or a cyano group as defined above for R ₃ , or of these compounds when it contains salt-forming groups, even more preferred are those wherein R ₁ and / or R _g do not represent morpholinosulfonyl or thiomorpholinosulfonyl.

Particularly preferred are the compounds and their salts, which are mentioned in the examples.

The compounds of formula (I) and salts of such compounds with at least one salt-forming group are produced in a manner known per se, for example by:

162

(a) a hydrazine derivative of the general formula III ( ^ΠΙ > · N

^R 8 in which the radicals have the meanings given above add to the epoxide of the formula IV

wherein the radicals have the meanings given above, wherein the free functional groups, except for those involved in the reaction, are optionally in a protected form and, where appropriate, the protecting groups present are cleaved, or

b) For a compound of formula I, wherein R _x and R they mean acyl, sulfo group, an optionally substituted alkyl, aryl, heterocyclyl, alkoxy, optionally substituted, or an aryloxy group substituted sulfonyl, sulfamoyl, optionally substituted at the nitrogen atom, or phosphoryl substituted with one or two radicals selected independently of one another from optionally substituted alkyl, optionally substituted cycloalkyl, aryl, hydroxy, optionally substituted alkoxy, cycloalkoxy and aryloxy, R ₂ and R ₆ are alkyl, alkyl, or alkyl; heterocyclyl and the remainder of the radicals have the meanings indicated, the amino compound of formula (V)

- 163 -

(IN) . . . . ^R 8, in which the radicals have the meanings given hereinbefore, is condensed with an acid of the general formula VI

Rg-OH (VI) wherein

R 8 is as hereinbefore defined, or a reactive derivative thereof, wherein the free functional groups, except for those involved in the reaction, are optionally in a protected form, and where appropriate, the protecting groups present are cleaved, or

(c) for the preparation of compounds of formula I in which Ry and Rg are acyl, sulfo, optionally substituted alkyl, aryl, heterocyclyl, alkoxy optionally substituted, or aryloxy substituted sulfonyl, sulfamoyl optionally substituted on nitrogen, or phosphoryl substituted by one or two groups selected independently from an optionally substituted alkyl, optionally substituted cycloalkyl, aryl, hydroxy, optionally substituted alkoxy, cycloalkoxy and aryloxy groups, R ₂ and R _g are hydrogen, optionally substituted alkyl, alkenyl or alkynyl or heterocyclyl, and the remaining radicals have the meanings indicated, the amino compound of the general formula (VII)

-164. (VII),

in which residues. May, directly as defined herein, is condensed with an acid of formula VIIa

R ₁ -OH (VIII) wherein

R ^ has the above-mentioned meaning,

With or a reactive derivative of the acid, the free functional groups, except for those involved in the reaction, are optionally in protected form and, if appropriate, the protecting groups present are cleaved off or.

d) for the preparation of compounds of formula I in which R a R _g is two. same. radicals selected from acyl, sulfo, optionally substituted alkyl, aryl, heterocyclyl, alkoxy optionally substituted, or aryloxy substituted sulfonyl, sulfamoyl optionally substituted on nitrogen, and independently substituted with one or two radicals selected from one or two; optionally substituted alkyl, optionally substituted cycloalkyl, aryl, hydroxy, optionally substituted alkoxy, cycloalkoxy, and aryloxy, R ₂ and R 8 are hydrogen, optionally substituted alkyl, alkenyl or alkynyl or di-alkynyl or heterocyclyl; .

.-:.

165 '_ ··

-'I ve

(IX),? · Radicals which are directly there above, is condensed with the introduction of the identical residue en R? And R _{g of} the appropriate acid or a reactive derivative thereof, wherein R a R Padé pins have straight pin-mentioned meanings, with the exception of free functional occlusion the groups involved in the reaction are optionally protected form and, if appropriate, protective scavengers present, or

e) For a compound of formula I, wherein R ₇ on the site of the radical R 7 is present, which is optionally substituted alkyl or cycloalkyl, SE Compound of the formula I '

d);

d.

in which

Ry ¹ represents a hydrogen atom and the remaining radicals having the meanings given above, introduces the radical R _{7 by} substitution with a compound of the formula XII, R ₇ -X (XII),

- 166 in which

X represents a leaving group and

R ₇ is optionally substituted alkyl or cycloalkyl, wherein the free functional groups, except those involved in the reaction, are optionally in protected form, and optionally protecting groups present are cleaved, or

f) in a compound of formula I wherein the substituents have the meanings given above with the proviso that in the respective compound of formula I at least one functional group is protected by a protecting group, the protecting groups present are cleaved and, if necessary, a compound of formula I with at least one group the salt-forming salt obtained by one of methods a) to f) above is converted to its salt or the salt obtained is converted to the free compound or to another salt and / or the isomeric mixture obtained is separated and / or the compound of the formula I is of the invention is converted to another compound of formula I according to the invention.

The above methods are described in detail below.

Method a) (Addition of amine to epoxide)

The amino group of the hydrazine derivative of the general formula (III) involved in the reaction always has at least one free hydrogen atom according to R ₇ , but it can also be derivatized itself in order to increase the reactivity of the hydrazine derivative.

In particular, the epoxide of the general formula IV has a structure which allows the quantitative addition of the hydrazine

167 derivative.

The functional groups in the starting materials to be reacted, in particular the carboxy, amino, hydroxy, mercapto and sulfo groups, can be protected by suitable protecting groups, which are usually used in the synthesis of peptide compounds, but also ceparol: spine and penicillin, the same as nucleic acid and sugar derivatives. These protecting groups may already be present in the materials obtained from the preceding steps and may protect the respective functional groups against undesired side reactions such as acylation, etherification, esterification, oxidation, solvolysis and the like. In certain cases, the protecting groups may also act in a selective, for example stereoselective, manner. Characteristic of protecting groups is that they cleave easily, i.e. without undesired side reactions, for example solvolytically, reductively, photolytically or also enzymatically, for example also under physiological conditions. Residues analogous to protecting groups may also be present in the final materials. Compounds of formula I with protected functional groups may have higher metabolic stability or other improved pharmacokinetic properties than the corresponding compounds with free functional groups. In the narrower sense, protecting groups in the foregoing and following description are to be understood as meaning appropriate residues which are no longer present in the final compounds.

Protection of functional groups with such protecting groups, the protecting groups themselves, as well as the reactions leading to their cleavage, are described in basic works such as in JFW McOmie, Protective Groups in Organic Chemistry, Plenum Press, London and New York (1973), in Th. . W. Greene, Protective Groups in Organic Synthesis, Wiley, New York (1981), in The Peptides, Vol. 3 (E. Gross and J. Meienhofer, Ed.), Academic Press, London and New York (1981), in Methoden

168 der organischen Chemie, Houben-Weyl, 4th ed. 15/1, Georg Thieme Verlag, Stuttgart (1974), in H. - D. Jakubke and H. Jescheit, Aminosáuren, Peptide, Protein, Velag Chemie, Weinheim, Deefield Beach and Basel (1982) and in Jochen Lehmann ,.

Chemie der Kohlenhydrate: Monosaccharide and Derivatives, 5

Georg Thieme Verlag, Stuttgart /1974/.c

For example, the carboxy group is protected as an ester group that is selectively cleavable under gentle conditions. The carboxy group protected in the esterified form is esterified primarily by a lower alkyl group, which is preferably branched at the 1-position of the lower alkyl group or substituted at the 1 or 2-position of the lower alkyl group by suitable substituents. 5:

J ·

Ý, -. · O

A protected carboxy group which is esterified with a lower alkyl group is, for example, methoxycarbonyl or ethoxycarbonyl.

Carboxy protected, ^c which is esterified by lower alkyl, that is at the 1-branched lower alkyl, for example tert .- (lower alkoxy) carbonyl groups, e.g., tert-butoxycarbonyl.

Protected carboxy, which is esterified lower?

an alkyl group which is substituted in the 1 or 2 position of the lower alkyl group by a suitable substituent is, for example, arylmethoxycarbonyl with one or two aryl radicals, wherein aryl is phenyl optionally mono-, di- or trisubstituted by, for example, lower alkyl, e.g. alkyl) such as tert-butyl, lower alkoxy, such as methoxy, hydroxy, atom, halogen, such as chlorine, and / or nitro, such as benzyloxycarbonyl, benzyloxycarbonyl substituted with such substituents such as 4-nitrobenzene;

169 zyloxycarbonyl or 4-methoxybenzyloxycarbonyl, diphenylmethoxycarbonyl optionally substituted by said substituents, for example di- (4-methoxyphenyl) methoxycarbonyl, further lower alkyl substituted carboxy, wherein the lower alkyl group in the 1 or 2 position is substituted as a suitable substituent 1- (lower alkoxy) - (lower alkoxy *) carbonyl,. for example methoxymethoxycarbonyl, 1-methoxyethoxycarbonyl or 1-ethoxyethoxycarbonyl, 1- (lower alkyl) -thio- (lower alkoxy) -carbonyl, e.g. such as bromine, for example phenacyloxycarbonyl, 2-halo- (lower alkoxy) carbonyl, for example 2,2,2-trichloroethoxycarbonyl, 2-bromomethoxycarbonyl or 2-iodoethoxycarbonyl, the same as 2- (trisubstituted silyl) - (lower alkoxy) -carbonyl a group wherein the substituents independently of one another are an aliphatic, araliphatic, cycloaliphatic or aromatic hydrocarbon radical optionally substituted, for example, by a lower alkyl, lower alkoxy, aryl, halogen and / or nitro group, for example optionally substituted lower alkyl, phenyl- a cycloalkyl group or a cycloalkyl group; phenyl, for example 2-tri- (lower alkyl) -silyl- (lower alkoxy) -carbonyl, such as 2-tri- (lower alkyl) -silylethoxycarbonyl, for example 2-trimethylsilylethoxycarbonyl or 2- (di-n-butylmethylsilyl) ethoxycarbonyl or 2- triarylsilylethoxycarbonyl such as triphenylsilylethoxycarbonyl.

The carboxy group may also be protected as an organic silyloxycarbonyl group. An organic silyloxycarbonyl group is, for example, a tri- (lower alkyl) -silyloxycarbonyl group such as trimethylsilyloxycarbonyl. The silicon atom of the silyloxycarbonyl group may also be substituted by two lower alkyl groups, for example methyl

Compounds having such protecting groups can be prepared, for example, by reaction with dimethylchlorosilane as a silylating agent.

The protected carboxy group is preferably a tert- (lower alkoxy) carbonyl group, for example tert-butoxycarbonyl, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 9-fluorenylmethoxycarbonyl or diphenylmethoxycarbonyl.

The protected amino group may be protected with an amino-protecting group, for example in the form of acylamino, arylmethylamino, etherified mercapto, 2-acyl- (lower alk-1-enyl) -amino or silylamino or as azido.

In the corresponding acylamino group, the acyl moiety is, for example, an acyl radical of an organic carboxylic acid of, for example, up to 18 carbon atoms, optionally substituted, for example, with halogen or aryl, or substituted (lower alkane) carboxylic acids or optionally with halogen, lower alkoxy or nitro benzoic acid, or preferably a half-carbonic acid ester. Such acyl groups are, for example, a lower alkanoyl group such as formyl, acetyl, propionyl or pivaloyl, a halogen- (lower alkanoyl) group such as 2-haloacetyl such as 2-chloro, 2-bromo, 2-iodo, 2,2 Benzoyl, such as benzoyl, 4-chlorobenzoyl, 4-methoxybenzoyl or 4-nitrobenzoyl, (lower alkoxy) -carbonyl, optionally with halogen, lower alkoxy or nitro substituted benzoyl, 2-trifluoro- or 2,2,2-trichloroacetyl , preferably branched in the 1-position of the lower alkyl radical or in the 1 or 2 position of an optionally substituted (lower alkoxy) -carbonyl group, for example a tert- (lower alkoxy) -carbonyl group such as tert-butoxycarbonyl, arymethoxycarbonyl

171 nyl having one, two or three aryl radicals which, for example, represents a lower alkyl group, in particular a tertiary (lower alkyl) group such as tert-butyl, a lower alkoxy group such as methoxy, hydroxy, a halogen atom such as chlorine and / or a nitro group mono- or polysubstituted phenyl, for example, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, diphenylmethoxycarbonyl, 9-fluorenylmethoxycarbonyl or di- (4-methoxyphenyl) methoxycarbonyl, aroylmethoxycarbonyl, in which the aroyl group is preferably a bromo group such as aroyl radical such as poproyl; for example phenacyloxycarbonyl, 2-halogen- (lower alkoxy) -carbonyl, for example 2,2,2-trichloroethoxycarbonyl, 2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl, 2- (trisubstituted silyl) - (lower alkoxy) -carbonyl, for example 2- a tri- (lower alkyl) -silyl- (lower alkoxy) -carbonyl group such as 2-trimethysilylethoxycarbonyl; or a 2- (di-n-butylmethylsilyl) ethoxycarbonyl, or triarylsilyl- (lower alkoxy) carbonyl group, for example, 2-triphenylsilylethoxycarbonyl.

In arylmethylamino, which for example represents mono-, di- or especially triarylmethylamino, the aryl radicals are especially optionally substituted phenyl radicals. Such groups are, for example, benzyl, diphenylmethyl or especially tritylamino.

In an etherified mercaptoamino group, the mercapto group is primarily as a substituted arylthio group or *

aryl- (lower alkyl) -thio, wherein the aryl moiety is, for example, optionally such as lower alkyl such as methyl or tert-butyl, lower alkoxy such as methoxy, halogen atom such as chlorine and / or nitro substituted phenyl such as e.g. 4-nitrophenylthio.

172

In the 2-acyl- (lower alk-1-enyl) moiety useful as an amino protecting group, the acyl is, for example, the corresponding lower alkanecarboxylic acid, benzoic acid, optionally substituted, for example, by a lower alkyl group such as methyl or tert-butyl. an alkoxy group such as a methoxy group, a halogen atom such as chlorine, and / or a nitro group, or a particular semi-ester of carbonic acid, such as a (lower alkyl) -polo ester of carbonic acid. Corresponding groups are especially 1- (lower alkanoyl) - (lower alk-i-en-2-yl) groups, for example 1- (lower alkanoyl) -prop-1-en-2-yl such as 1-acetylprop-1 -en-2-yl, or (lower alkoxy) -carbonyl- (lower alk-1-en-2-yl) groups, for example a (lower alkoxy) -carbonylprop-1-en-2-yl group such as 1- ethoxykarbonylprop-l-en-2-yl.

A silylamino group is, for example, a tri- (lower alkyl) -silylamino group, for example trimethylsilylamino or tert-butyldimethylsilylamino. The silylamino silicon atom may also be substituted with only two lower alkyl groups, for example methyl, and the amino or carboxy group may be substituted with a second molecule of formula I. Compounds with such protecting groups may be prepared, for example, by reaction with the corresponding chlorosilanes such as dimethylchlorosilane, as a silylating agent.

The amino group may also be protected by conversion to the protonated form and, in particular, anions of strong inorganic acids, such as sulfuric, phosphoric or hydrohalic acids, for example chlorine or bromine, or organic sulfonic acids, such as p-toluenesulfonic acid, may be suitable.

Preferred amino protecting groups are (lower alkoxy) -carbonyl, phenyl- (lower alkoxy) -carbonyl, fluoro

173 Nyl- (lower alkoxy) -carbonyl, 2- (lower alkanoyl) - (lower alk-1-en-2-yl) or (lower alkoxy) -carbonyl- (lower alk-1-en-2-yl) group .

The hydroxy group may be protected, for example, by an acyl group, for example a halogen atom such as chlorine, substituted. a lower alkanoyl group such as _: 2,2-dichloroacetyl, or in particular an acyl radical of the semi-carbonic acid ester mentioned for protected amino groups. A preferred hydroxy protecting group is, for example, 2,2,2-trichloroethoxycarbonyl, 4-nitrobenzyloxycarbonyl, diphenylmethoxycarbonyl or trityl. The hydroxy group may be further protected by a tri- (lower alkyl) -silyl group, for example trimethylsilyl, triisopropylsilyl or tert-butyldimethylsilyl, an easily cleavable ether-forming group, for example an alkyl group such as a tert- (lower alkyl) group, for example tert. -butyl, oxa- or thiaaliphatic or -cycloaliphatic, especially 2-oxa- or 2-thiaaliphatic or -cycloaliphatic hydrocarbon radical, for example 1- (lower alkoxy) - (lower alkyl) or 1- (lower alkyl) -thio- a (lower alkyl) group such as methoxymethyl, 1-methoxyethyl, 1-ethoxyethyl, methylthiomethyl, 1-methylthioethyl or 1-ethylthioethyl, or 2-oxa-or-2-thiacycloalkyl of 5 to 7 ring atoms; such as 2-tetrahydrofuryl or 2-tetrahydropyranyl, or the corresponding thia analog, the same as a 1-phenyl- (lower alkyl) group such as benzyl, diphenylmethyl or trityl, wherein the phenyl radical may be substituted by, for example, a halogen atom, e.g. methoxy and / or nitro.

Two hydroxy groups occurring in a single molecule, especially when adjacent or adjacent hydroxy and amino groups, may be protected, for example, by bivalent protecting groups such as preferably a methylene group substituted by one or two lower alkyl radicals.

174 or oxo groups, such as optionally substituted alkylidene, for example lower alkylidene such as isopropylidene, cycloalkylidene such as cyclohexylidene, carbonyl or benzylidene.

A mercapto group, such as in cysteine, may be particularly protected by S-alkylation with optionally substituted alkyl residues, silylation, thioacetal binding, S-acylation or formation of an asymmetric disulfide moiety. Suitable mercapto protecting groups are, for example, in the phenyl moiety, for example methoxy or nitro substituted benzyl, such as 4-methoxybenzyl, or in the phenyl moiety, for example methoxy substituted diphenylmethyl, such as di- (4-methoxyphenyl) methyl, triphenylmethyl, pyridyldiphenylmethyl, pyridyldiphenylmethyl , benzylthiomethyl, tetrahydropyranyl, acylaminomethyl such as acetamidomethyl, isobutyrylacetamidomethyl or 2-chloroacetamidomethyl, benzoyl, benzyloxycarbonyl or alkyl-, especially (lower alkyl) aminocarbonyl, such as ethylaminocarbonyl, the same as (lower alkyl) -thio- ethylthio or S-tert-butylthio, or S-sulfo.

The sulfo group may be protected, for example, by a lower alkyl group, for example, methyl or ethyl, phenyl, or as a sulfonamide, for example, as an imidazolide.

As a protecting group, for example a carboxy-protecting group for the purposes of the present invention, is also meant a polymeric carrier attaching an easily cleavable functional group to be protected, for example a carboxy group, as suitable for example for Merrifield synthesis. Such a suitable polymeric carrier is, for example, a polystyrene resin slightly crosslinked by copolymerization with divinylbenzene, which carries the must member to the backbound.

175

The addition of the compounds of the formula III to the epoxides of the formula IV is preferably carried out under reaction conditions customary for the addition of a nucleophilic agent to the epoxides.

Adice se. in particular in aqueous solution and / or in the presence of polar solvents such as alcohols such as methanol, ethanol or ethyl glycol, ethers such as dioxane, amides such as dimethylformamide, or phenols such as phenol, or also under anhydrous conditions in non-polar a solvent such as benzene or toluene, or in an emulsion of benzene and water, optionally in the presence of an acidic or basic catalyst, for example a hydroxide solution such as sodium hydroxide, or in the presence of a solid-phase hydrazine-doping catalyst such as alumina in ethers such as diethyl ether, generally at temperatures from about 0 ° C to

a boiling point corresponding to the reaction mixture, preferably from 20 to 130 ° C, optionally under reflux (under reflux), at elevated pressure, for example in a pressure tube, whereby the boiling point may also be exceeded, and / or under inert gas, such as argon or nitrogen. In this case, one of the two compounds of the general formulas (III) and (IV) can always be present in excess, for example in a molar ratio of from 1: 1 to 1: 100, preferably in a molar ratio of from 1: 1 to 1:10; : 1 to 1: 3.

Deprotection is carried out, if appropriate, according to the methods described under process f) (cleavage of the protecting groups).

Method b) (preparation of an amide bond)

In the starting compounds of the formulas (V) and (VI), functional groups other than those to be reacted or which do not react under the reaction conditions are protected independently of one another by the protecting groups mentioned under

176 a).

Compounds of formula VI contain a free carboxy, sulfo or phosphoryl group or reactive derivatives of these acids, for example, cleavable activated esters or reactive anhydrides and reactive cyclic amides. Reactive acid derivatives may also form in situ.

Activated esters of compounds of formula (VI) with a carboxy terminus are particular esters unsaturated on a bonded carbon atom of an esterifying residue, for example of the vinyl ester type, such as vinyl ether (which can be produced for example by reaction of the corresponding ester with vinyl acetate, activated vinyl ester method) can be produced, for example, by treating the corresponding acid with an isoxazolium reagent, 1,2-oxazolium or Woodward &apos;

method) or 1- (lower alkoxy) -vinyl ester (which can be prepared, for example, by treating the corresponding acid with (lower alkoxy) -acetylene, ethoxyacetylene method) or an amidine type ester such as N, N'-disubstituted aminoinoester (which can be obtained by treating the corresponding acid with a suitable N, N'-disubstituted carbodiimide, for example N, N'-dicyclohexylcarbodiimide, carbodiimide method) or N, N-.

-disubstituted amino-ester (which can be obtained, for example, by treating the corresponding acid with N, N-disubstituted)

N-cyanamide, cyanamide method), a suitable aryl ester, a particular phenyl ester substituted with electron-withdrawing substituents (obtainable, for example, by treating the corresponding acid with a suitable substituted phenol, for example 4-nitrophenol, 4-methylsulfonylphenol, 2,4,5-trichlorophenol,

2,3,4,5,6-pentachlorophenol or 4-phenyldiazophenol, in the presence of a condensing agent such as N, N'-dicyclohexylcarbodiimide, the active aryl ester method), the cyanomethyl ester (which can be obtained, for example, by treating with the corresponding acid)

177 selins with chloroacetonitrile in the presence of a base, cyanomethyl ether method), thioester, especially phenylthioester optionally substituted with, for example, nitro (which can be obtained, for example, by treating the corresponding acid with thiophenol optionally substituted with, for example, nitro, inter alia using the anhydride or carbodiimide method); a particular amino or amido ester (which can be obtained by treating the corresponding acid with an N-hydroxyamino- or N-hydroxyamido compound, for example an N-hydroxysuccinimide, N-hydroxypiperidine, N-hydroxyphthalimide, N-hydroxy-5-norbornerf-2,3- dicarboxylic acid, 1-hydroxybenztriazole or 3-hydroxy-3,4-dihydro-1,2,3-benztriazin-4-one (for example, the anhydride or carbodiimide method, activated N-hydroxyester method). Internal esters, for example T-lactones, may also be used.

The acid anhydrides may be symmetrical or mixed anhydrides of such acids, for example anhydrides with inorganic acids such as acid halides, special acid chlorides (which may be obtained, for example, by treating the corresponding acid with thionyl chloride, phosphorus pentachloride, phosgene or o; xalyl chloride, acid chloride method) azides (which can be obtained, for example, from the corresponding acid ester via the corresponding hydrazide and its treatment with nitric acid, azide method), anhydrides with semi-carbonic acids, for example (lower alkyl) -carbonic acid esters (which can be obtained, for example, by treating the corresponding acid with (lower alkyl) chloroformic acid esters or 1- (lower alkoxy) -carbonyl-2- (lower alkoxy) -1,2-dihydroquinoline, mixed O-alkylcarbonic anhydride method) or anhydrides with dihalogenated, in particular dichlorophosphoric acid ( which can be obtained n and for example by treating the corresponding acid with phosphorous oxychloride, the phosphorous oxychloride method), anhydrides with other phosphoric acid derivatives (for example, those that may be obtained with phenyl-N-phe)

178 with nylphosphoramidochloridate or by reaction of alkylphosphoric amides in the presence of sulfonic anhydride and / or racemization-reducing additives such as N-hydroxybenztriazole, or in the presence of diethyl cyanophosphonic acid ester or orthophosphoric acid derivatives or anhydrides with organic carboxylic acids acids (which can be obtained, for example, by treating the corresponding acid with an optionally substituted halide (lower alkane) - or phenyl- (lower alkane) -carboxylic acid, for example, phenylacetic, pivalic or trifluoroacetic acid chloride, mixed carboxylic anhydride method) or with organic sulfonic acids (which may be obtained by treating a salt, such as an alkali metal salt, corresponding to an acid with a suitable organic sulfonic acid halide, such as a chloride (lower alkane) - or aryl-, for example methane or p-toluenesulfonic acids. the same as symmetric anhydrides (which can be obtained, for example, by condensation of the corresponding acid in the presence of carbodiimide or 1-diethylaminopropin, symmetric anhydride method).

i i. . . .

Suitable cyclic amides are particular amides with five-membered aromatic diazacyclic amides, such as amides with imidazoles, for example imidazole (which can be obtained, for example, by treating with the corresponding s-N, N'-carbonyldimiidazole, imidazole method) or pyrazole, for example 3,5-dimethylpyazazol. (which can be obtained, for example, via an acid hydrazide by treatment with acetylacetone, the pyrazolide method).

As already mentioned, the carboxylic acid derivatives used as acylating agent can also be formed in situ. For example, N, N'-disubstituted amidinoesters are formed in situ when a mixture of

The compounds of formula V and the acid used as acylating agent in the presence of a suitable N, N'-disubstituted carbodiimide, for example N, N ¹ -cyclohexylcarbodiimide. Furthermore, the amino or amido ester of the acid used as acylating agent in the presence of a starting compound of formula V to be acylated may be formed by reacting a mixture of the corresponding acid and amino compound as starting materials in the presence of N, N'-disubstituted carbodiimide such as N, N n-dicyclohexylcarbodiimide and N-hydroxyamine or N-hydroxyamide, for example N-hydroxysuccinimide, optionally in the presence of a suitable base, for example 4-dimethylaminopyridine. Further, in situ activation can be achieved by reaction with an N, N, N ', N'-tetraalkyluronium compound such as O-benztriazole-1-Ν, Ν, Ν', N'-tetramethyluronium hexafluorophosphate, O- (1,2-dihydro -2-oxo-1-pyridyl) -N, N, N ', N'-tetramethyluronium tetrafluoroborate or O- (3,4-dihydro-4-oxo-1,2,3-benztriazolin-3-yl) -N, N, N ', N'-tetramethyluronium tetrafluoroborate. Finally, carboxylic acid anhydrides of the formula VI or VII can be prepared with phosphoric acid in situ by reacting an alkylphosphoric amide such as hexamethylammonium phosphide in the presence of a sulfonic anhydride such as 4-toluenesulfonic anhydride with a salt such as tetrafluoroborate , for example, sodium tetrafluoroborate, or another phosphoric acid hexamethylamide compound such as benztriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluoride, preferably in the presence of racemization-reducing additives such as N-hydroxybenztriazole.

In a similar manner, a number of the reaction types mentioned above for the carboxylic acids of the formula VI, also with the compounds of the formula III having a terminal sulfonyl or phosphoryl group, can be carried out by condensation with the compound of the formula V to sulfonamides.

For example, activated esters may be used

Sulfone selines, for example the corresponding, especially nitro substituted aryl esters, such as phenyl esters, wherein the amine component of formula (V) may also be used as an alkali metal amide, for example an alkali metal aryl amide such as sodium aniline amide, or an alkaline salt of nitrogen heterocycles, for example potassium pyrrolidine.

In addition, reactive anhydrides such as corresponding symmetric (obtainable, for example, by reaction of a silver alkylsulfonic acid salt with alkylsulfonyl chloride) or preferably asymmetric acid anhydrides, for example anhydrides with inorganic acids such as sulfonyl halides, especially sulfonyl chlorides (obtainable for example by reaction of corresponding sulfonic acids with chlorides) acids, such as thionyl chloride or phosphorus pentachloride), with organic carboxylic acids (which may be obtained, for example, by treating a sulfonic acid halide with a carboxylic acid salt such as an alkali metal salt in a manner similar to the aforementioned mixed sulfonic anhydride method) or azides ( it is possible to obtain from the corresponding sulfonic acid chloride and sodium azide or via the corresponding hydrazide and its treatment with nitric acid, analogous to the above azide method).

Phosphoryl radicals R _{g of} the above-mentioned substituents may be coupled in an analogous manner, as the activated derivatives of phosphorus, such as the corresponding substituted phosphoryl halides with one or more halogen atoms, such as fosforyloxychloridem, in the absence or presence of a base, such as sterically hindered amines, in aqueous or non-aqueous solvent to the compounds of formula (V), whereby eventually the excess halogen atoms are exchanged by hydrolysis or reaction with the corresponding alcohols with suitable substituents.

181

Phosphoryl radicals substituted by hydroxy, alkoxy, cycloalkoxy, cycloalkyl (lower alkoxy), aryloxy or aryl (lower alkoxy) may, for example, be reacted with the corresponding substituted phosphites, for example diaryloxyphosphite or dialkoxyphosphite, or as mono- or mono- or mono- or mono- or mono- or mono- or dichlorophosphates, in the presence of a base such as 2,6-dimethylpyridine, triethylamine or imidazole, may be reacted in an aqueous or anhydrous solvent such as anhydrous alcohols such as ethanol, corresponding esters, dichloromethane or carbon tetrachloride, optionally under protective gas such as argon, from -50 to 100 ° C, preferably from -10 to 50 ° C, with compounds of the general formula V, in particular under the conditions described in European patent application no. No. 0 376 040A, published July 4, 1990.

Corresponding phosphoryl radicals substituted symmetrically or preferably asymmetrically by said radicals attached via the corresponding oxy group can be reacted with phosphorus trichloride *, such as phosphorus trichloride, with the corresponding amines of formula V, in the presence of organic amines such as triethylamine to give the corresponding dichlorophosphoryl compound. of this compound with a first corresponding alcohol or water, which is preferably used in a stoichiometric amount, in the presence of a tertiary amine and optionally thereafter reacting a second halogen atom with another alcohol or water in the presence of a tertiary amine to obtain corresponding disubstituted phosphite compounds which , for example, halogens such as iodine, peroxides such as hydrogen peroxide, peroxyacids such as m-chloroperbenzoic acid, or molecular oxygen.

The amino group of the compound of formula (V) involved in the reaction preferably contains at least one reactive hydrogen atom, especially when a reactive hydrogen is present.

2 - carboxy, sulfonyl or phosphoryl in reactive form. These amino groups can also be derivatized by themselves, for example by reaction with a phosphite such as diethylchlorophosphite, 1,2-phenylene chlorophosphite, ethyldichlorophosphite, ethylene chlorophosphite or tetraethylpyrophosphite. For example, a derivative of such an amino group compound is also a carbamic acid halide or isocyanate, wherein the amino group of the reaction is changed as an isocyanate group with a substituted halocarbonyl, e.g. chlorocarbonyl, in which case only compounds of formula I are available. The reaction is carried by a hydrogen atom.

When the compound of formula (V) in the amino group is simply substituted with a lower alkyl or aryl (lower alkyl) group, the corresponding urea compound is also a reactive derivative. By heating equimolar amounts of the urea compound and a compound of formula VI or VII with a free carboxy group, for example, the corresponding compounds of formula I are obtained.

The coupling to the amide bond may be carried out in a manner known per se, for example as described in basic works such as Houben-Weyl, Methoden der organischen Chemie, 4th ed. 15/11, (1974), vol. IX (1955) and Vol. E 11 (1985), Georg Thieme Verlag, Stuttgart, The Peptides (E. Gross and J. Meienhofer, Ed.), Vol. 1 and 2, Academic Press, London and New York (1979 and 1980) or M. Bodansky, Principles of Peptide Synthesis, Springer-Verlag, Berlin (1984).

The condensation of the free carboxylic acid with the corresponding amine can preferably be carried out in the presence of conventional condensing agents or using carboxylic acid anhydrides or halides, such as chlorides of these acids, or activated carboxylic acid esters, such as p-183.

-nitrofenylestery. Conventional condensing agents are, for example, carbodiimides, for example diethyl, dipropyl-, N-ethyl-N '- (3-dimethylaminopropyl) carbodiimide or particular dicyclohexylcarbodiimide, further suitable carbonyl compounds, for example carbonylimidazole, 1,2-oxazolium compounds, for example 2-ethyl -5-phenyl-1,2-oxazolium-3'-sulfonate and 2-tert-butyl-5-methylisoxazolium perchlorate. or a suitable acylamino compound, for example 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, N, N, N ', N'-tetraalkyluronium compounds such as O-benztriazole-1 N, N, N', N'-tetramethyluronium hexafluorophosphate, further activated phosphoric acid derivatives, for example diphenylphosphoryl azide, diethylphosphoryl cyanide, phenyl-N-phenylphosphoramidochloridate, bis- (2-oxo-3-oxazolidinyl) phosphinic chloride or 1-benztriazolyloxy-tris (dimethylamino) phosphonium hexafluorophosphate.

If desired, an organic base, preferably a tertiary amine, for example tri- (lower alkyl) amine with a bulky residue, for example ethyldiisopropylamine or triethylamine, and / or a heterocyclic base, for example 4-dimethylaminopyridine or preferably 4-methylmorpholine or pyridine, is added.

The condensation of the activated ester, reactive anhydride or reactive cyclic amide with the corresponding amines is usually carried out in the presence of an organic base, for example a simple tri- (lower alkyl) amine, for example triethylamine or tributylamine, or the aforementioned organic bases. If desired, the condensing agent described for free carboxylic acids is also used.

The condensation of the acid anhydride with the amines can be carried out, for example, in the presence of inorganic carbonates, for example ammonium or alkali metal carbonates or bicarbonates, such as sodium or potassium carbonate or bicarbonate (if necessary together with the sulfate).

184

Carboxylic acid chlorides, for example the chlorocarboxylic acid derivatives derived from the acid of formula VI, or sulfonic acid chlorides, are condensed with the corresponding amines, preferably in the presence of an organic amine, for example the above tri- (lower alkyl) amines or hetero, cyclic. based,. optionally in the presence of hydrogen sulphate.

The condensation is preferably carried out in an inert, aprotic, preferably anhydrous solvent or solvent mixture, for example a carboxylic acid amide, for example formamide or dimethylformamide, a halogenated hydrocarbon such as methylene chloride, carbon tetrachloride or chlorobenzene, a ketone such as acetone, cyclic ether such as tetrahydrofuran an ester, for example ethyl acetate, or a nitrile, for example acetonitrile, or mixtures thereof, optionally at a reduced or elevated temperature, for example in a temperature range of about -40 to about +100 C, preferably about -10 to about +50 ° C, in the case of using arylsulfonyl ester also at a temperature in the range of about +100 to +200 ° C and optionally under an atmosphere of an inert gas such as nitrogen or argon.

Aqueous, for example, alcoholic solvents _; an aromatic solvent such as benzene or toluene. Acetone may also be added in the presence of alkali metal hydroxides as a base.

The condensation can also be carried out by a technique known as the solid phase synthesis disclosed by R. Merrifield and described, for example, in Angew. Chem., 97, 801-812 (1985), Naturwissenschaften, 71, 252-258 (1984) or R.A. Houghten, Proc. Natl. Acad. Sci. USA, 82, 5131-5355 (1985).

Always according to the use of the starting compounds may radicals R? And R _{g of} the compound of Formula

- 185 I identical or different from each other.

The deprotection is optionally carried out according to the method described under variant f) (cleavage of the protecting groups).

Method c) (preparation of an amide bond)

In the starting compounds of formulas VII and VIII, the functional groups, with the exception of those which are to be present in the reaction or do not react under the reaction conditions, are protected independently of each other by the protecting groups mentioned under method a).

The method is quite analogous to that described in (b), when a compound of the formula (VII) is used in place of the compound of formula (V) and a compound of the formula (VIII) is used in place of a compound of the formula

are formed on compounds of formula VII instead of Rg in compounds of formula V.

Depending on the starting compounds used, the radicals R1 and R3 in the compounds of the formula I obtained may be identical or different from one another.

The deprotection is optionally carried out according to the method described under variant f) (cleavage of the protecting groups).

Method d) (preparation of an amide bond)

The starting compounds of formula IX and the acid or a reactive derivative suitable for the introduction of the identical radical R and R _G are functional groups that should not participate in the reaction or it do not react under the reaction conditions,

- 186 protected independently of each other by the protecting groups listed under method a).

Acids suitable for introduction, identical residues and R _g preferably have formula VI or formula VIII.

Preferred starting compounds of formula IX as protected by a protecting group are those compounds of the formula II which are described in the section on starting compounds.

The process is quite analogous to the process mentioned in b), wherein instead of the compounds of the formula V, the compounds of the formula IX are used and the compounds of the formula VI or VIII are used instead of the compounds of the formula VI.

Optionally, the deprotection is carried out according to the methods described below for process f) (deprotection).

Method (a) (alkylation of a secondary nitrogen atom) • In the starting compounds of formula (I ') and the compound of formula (XII) or their reactive derivatives suitable for introducing the radical R ₇ , functional groups are intended to be absent or non-reactive. The conditions, independently of each other, are protected by one of the protecting groups mentioned under method a).

The leaving group X is a particular nucleofugile leaving group selected from hydroxy groups esterified with a strong inorganic or organic acid, such as a mineral acid, for example a hydrohalic acid such as hydrochloric, hydrobromic or hydroiodic acid, or from hydroxy groups esterified with a strong organic sulfonic acid such as ) sulfonic acid or aro

187 a sulfonic acid matrix optionally substituted, for example, by a halogen atom, such as fluorine, such as a lower alkyl group such as methyl, a halogen atom such as bromine and / or a nitro group substituted with benzenesulfonic acid such as methanesulfonic acid, p-bromotoluenesulfonic acid or p-toluenesulfonic acid or hydroxy groups esterified with dicarboxylic acid.

T

The substitution may be performed under the condition of first or second order nucleophilic substitution.

Compounds of formula (XII) in which X represents a leaving group with an electron-coat with higher polarisability, for example iodine, may be used, for example, in a polar aprotic solvent such as acetone, acetonitrile, nitromethane, dimethylsulfonate or dimethylformamide. The reaction can also be carried out in water or an organic solvent used as a cosolvent, such as ethanol, tetrahydrofuran or acetone. The substitution reaction is optionally carried out at a reduced or elevated temperature, for example in a temperature range of about -40 ° C to about 100 ° C, preferably about -10 ° C to about 50 ° C, and optionally under an atmosphere of an inert gas such as nitrogen or argon.

The deprotection is carried out, if appropriate, according to the processes described in process f) (deprotection).

Method-f) (cleavage of protecting groups)

The cleavage of the protecting groups which are not part of the desired final compound of formula I, for example carboxy, amino, hydroxy, mercapto and / or sulfo protecting groups, is carried out.

- .. 188

In a manner known per se, for example by solvolysis, in particular by hydrolysis, alcoholysis or acidolysis, or by reduction, in particular by hydrogeholysis or by chemical reduction, the same as by photolysis, optionally in steps or simultaneously, enzymatic processes may also be used. The cleavage of the protecting groups is described, for example, below in the section dealing with the basic work relating to. is cleaved off protecting groups.

Thus, for example, a protected carboxy group, for example a tertiary- (lower alkoxy) -carbonyl group, in the 2-position with a trisubstituted silyl group or in the 1-position with a lower alkoxy or (lower alkyl) -thio group substituted (lower alkoxy) -carbonyl or optionally substituted diphenylmethoxycarbones may be used. can be converted to the free carboxy group by treatment with a suitable acid such as formic, hydrochloric or trifluoroacetic acid, optionally with addition of a nucleophilic compound such as phenol or anisole. The carboxy group can also be liberated from the (lower alkoxy) carbonyl group by treatment with a base such as a hydroxide, for example an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide. The optionally substituted benzyloxycarbonyl group can be liberated, for example, by hydrogenolysis, i.e. by treatment with hydrogen, in the presence of a metal-based hydrogenation catalyst such as a palladium catalyst. Further, a suitable substituted benzyloxycarbonyl, such as 4-nitrobenzyloxycarbonyl, may also be obtained by reduction, for example by treatment with an alkali metal dithionite such as sodium dithionite, a reducing metal such as zinc, or a reducing metal salt such as chromate, e.g. chromium chloride, usually in the presence of chromium chloride. hydrogen releasing, which together with the metal may lead to the production of a nascent hydrogen such as an acid, in particular a suitable carboxylic acid such as a (lower alkane) carboxylic acid optionally substituted by, for example, a hydroxy group such as acetic, formic, glycolic, diphenylglycolic, lactic, mandelic .

189 4-chloromethaned or tartaric, or an alcohol or thiol, with water preferably being added. Treatment with a reducing coke or a metal salt as described above can also be carried out

2-halo- (lower alkoxy) -carbonyl (optionally converting the 2-bromo (lower alkoxy) -carbonyl group to the corresponding 2-iodo- (lower alkoxy) -carbonyl group) or convert the aroylmethoxycarbonyl group to the free carboxy group. The aroylmethoxycarbonyl group may be cleaved, optionally by treatment with a nucleophilic reagent, preferably a salt, such as sodium thiophenolate or sodium iodide. 2- (Trisubstituted silyl) - (lower alkoxy) -carbonyl group, such as 2-tri- (lower alkyl) -silyl- (lower alkoxy) -carbonyl group, may be treated by treatment with a salt giving a fluoride anion from hydrofluoric acid such as alkali fluoride a metal, for example sodium or potassium fluoride, optionally in the presence of a macrocyclic polyether (crown-ether) or a quaternary organic base fluoride such as tetra- (lower alkyl) ammonium fluoride or tri- (lower alkyl) -aryl- (lower alkyl) ammonium fluoride or, for example, tetraethylammonium fluoride or tetrabutylammonium fluoride, in the presence of an aprotic polar solvent such as dimethylsulfoxide or Ν, Ν-dimethylacetamide, can be converted to the free carboxy group. The carboxy group protected as an organic silyloxycarbonyl by a tri- (lower alkyl) -silyloxycarbonyl group, for example trimethylsilyloxycarbonyl, can be released in a conventional manner by solvolytic means, for example by treatment with water, alcohol or acid except for fluoride as described above. The esterified carboxy group can also be released enzymatically, for example by esterases or suitable peptidases, for example esterified with arginine or lysine such as lysine methyl ester, by trypsin.

«

The protected amino group is released in a manner known per se, and in each case, depending on the nature of the protecting groups, in different ways, p. advantage by solvolysis or reduction. (Lower alkoxy) -car- 190 -.

a bonylamino group, such as a tert-butoxycarbonylamino group, can be cleaved in the presence of acids, for example mineral acids, exemplary hydrohalic acids such as hydrochloric or hydrobromic acid, or sic or phosphoric acids, preferably hydrochloric acid, or strong organic acids such as trihalocarboxylic acids for example trifluoroacetic acid or formic acid, in polar solvents, such as water, or ethers, preferably cyclic ethers, such as dioxane. 2-Halogen- (lower alkoxy) -carbonylamino, optionally after conversion of the 2-bromo- (lower alkoxy) -carbonylamino group to 2-iodo- (lower alkoxy) -carbonylamino or directly dissolved in a liquid organic carboxylic acid such as formic acid, aroylmethoxycarbonylamino or the 4-nitrobenzyloxycarbonylamino group can also be cleaved, for example, by treatment with a suitable reducing agent such as zinc in the presence of a suitable carboxylic acid such as aqueous acetic acid. The aroylmethoxycarbonylamino group can also be cleaved by treatment with a nucleophilic reagent, which preferably forms salts such as sodium thiophenolate, and the 4-nitrobenzyloxycarbonylamino group can also be cleaved by treatment with an alkali metal dithionite, for example sodium dithionite. Optionally substituted diphenylmethoxycarbonylamino, tert- (lower alkoxy) -carbonylamino or 2- (trisubstituted silyl) - (lower alkoxy) -carbonylamino, such as 2-tri- (lower alkyl) -silyl- (lower alkoxy) -carbonylamino; treatment with a suitable acid, for example formic acid or trifluoroacetic acid, optionally substituted benzyloxycarbonylamino can be removed, for example, by hydrogenolysis, i.e. treatment with hydrogen in the presence of a suitable hydrogenation catalyst, such as a platinum or palladium catalyst. Optionally, the substituted triarylmethylamino or formylamino group may be removed, for example, by treatment with an acid such as a mineral acid such as hydrochloric acid or an organic acid. . . ......:. .. ... '- 191 -.

, for example in formic, acetic or trifluoroacetic acid, optionally in the presence of water. The amino group protected as a silylamino group can be released, for example, by hydrolysis or alcoholysis. The 2-haloacetyl-protected amino group, for example 2-chloroacetyl, can be liberated by treatment with thiourea in the presence of a base or with a thiolate salt such as an alkali metal thiourea thiolate, followed by solvolysis such as alcoholysis or hydrolysis of the resulting substitution product. The amino group can be liberated from the trifluoroacetamino group by, for example, hydrogenolysis by treatment with a base such as alkali metal hydroxides or carbonates such as sodium or potassium carbonate in polar solvents such as alcohols such as methanol at a temperature of from 0 to T00 ° C, especially from 40 to 30 ° C The amino group protected with 2- (trisubstituted silyl) - (lower alkoxy) -carbonyl, such as 2-tri- (lower alkyl) -silyl- (lower alkoxy) -carbonyl, can be converted to the free amino group by treatment with fluoride anion-providing salts from hydrofluoric acid as described above in connection with the release of the corresponding protected carboxylic acid group. Likewise, a heteroatom such as a nitrogen-protected silyl group such as trimethylsilyl can also be cleaved directly using a fluoride ion.

The azido protected amino group can be converted to the free amino group by, for example, reduction, such as catalytic hydrogenation with hydrogen in the presence of a hydrogenation catalyst such as platinum oxide, palladium or Raney nickel, reduction by mercapto compounds such as dithiothreitol or mercapto presence of an acid such as acetic acid. The catalytic hydrogenation is preferably carried out in an inert solvent such as a halogenated hydrocarbon, for example methylene chloride, or also in water or a mixture of water and an organic solvent. such as an alcohol or dioxane, at a temperature of from about 20 ° C to about 25 ° C, or else with cooling or heating.

A hydroxy- or mercapto group protected with a suitable acyl group, a tri- (lower alkyl) -silyl group or an optionally substituted 1-phenyl-lower alkyl) group is liberated analogously to the corresponding protected amino group. The hydroxy- or mercapto group protected with 2,2-dichloroacetyl is released. for example by basic hydrolysis, a hydroxy- or mercapto group protected with a tertiary (lower alkyl) group or a 2-oxa- or 2-thiaaliphatic or cycloaliphatic hydrocarbon radical is liberated by acidolysis, for example by treatment with a mineral acid or a strong carboxylic acid, for example trifluoroacetic acid . The pyridyldiphenylmethyl protected mercapto group is released, for example, by treating with a mercury salt at a pH of 2 to 6, by treating it. zinc in acetic acid or electrolytic reduction. Acetamidomethyl and isobutyrylamidomethyl can be removed, for example, by reaction with mercury salts at pH 2-6. 2-Chloroacetamidomethyl is removed, for example, by thiolysis with thiophenol, thioglycolic acid, sodium thiophenolate or 1,4-dithiothreitol. Two hydroxy or adjacent amino and hydroxy groups which are protected together by a bivalent protecting group, preferably, for example, a lower alkyl group having one or two substituted methylene groups, such as a lower alkylidene group such as isopropylidene, a cycloalkylidene group such as cyclohexylidene, or benzylideneine released by acid solvolysis, especially in the presence of a mineral acid or a strong organic acid. The tri- (lower alkyl) -silyl group is also cleaved by acidolysis, for example by treatment with a mineral acid, preferably hydrofluoric acid, or a strong carboxylic acid. The 2-halo- (lower alkoxy) -carbonyl group is removed with a reducing agent as described above, for example with a reducing metal such as zinc, reducing metal salts such as chromium salts or sulfur compounds such as sodium dithionite or preferably sodium sulfide and carbon disulfide.

193. A sulfo group protected as a sulfonic acid ester or sulfonamide is released, for example, by hydrolysis under acidic conditions, for example, in the presence of a mineral acid, or preferably by hydrolysis under basic conditions, for example by treatment with an alkali metal hydroxide or carbonate such as sodium carbonate.

When there are multiple protected functional groups, if desired, the protecting groups may be selected by simultaneously cleaving more than one such group, for example, acidolytically, such as treatment with hydrofluoric acid, or hydrogen treatment in the presence of a hydrogenation catalyst, such as palladium. on charcoal. Conversely, groups can also be selected so that they do not all cleave at the same time, but can be cleaved off. in the desired order, yielding the corresponding intermediates.

Additional method characters

For additional features of the process being carried out as needed, the functional groups of the starting compounds that are not to be involved in the reaction may be protected or may be in a protected form, for example, as one or more of the protecting groups mentioned under method a). The protecting groups may remain in the final compounds or be cleaved in whole or in part by the methods described in process f).

Salts of the compounds of the formula I which contain at least one salt-forming group can be prepared in a manner known per se. For example, salts of the compounds of formula I containing acidic groups may be formed, for example, by treatment with metal compounds, such as alkali metal salts of suitable organic carboxylic acids, for example sodium 2-ethylhexanoic acid, with an org. .... ..... -194 ..-. ..

alkali or alkaline earth metal compounds such as corresponding hydroxides, carbonates or bicarbonates such as hydroxide, carbonate or bicarbonate. sodium or potassium, with the corresponding calcium compounds or with ammonia or with a suitable organic amine, preferably with stoichiometric amounts of the compounds or with a small excess of reagent. Acid addition salts of the compounds of formula I are obtained in a conventional manner, for example by treatment with an acid or a suitable anion exchange agent. The salts of the compounds of the formula I which contain acidic or basic salt-forming groups, for example free carboxy and free amino, can be formed, for example, by neutralizing the salt, as acid addition salt, to an isoelectric point, for example by treatment with weak, bases or ion exchangers.

Salts can be converted in the conventional manner into free compounds, metal and ammonium salts, for example by treatment with suitable acids, and acid addition salts, for example, by treatment with suitable basic agents.

Stereoisomeric mixtures, such as diastereomeric and / or enantiomeric mixtures, such as racemic mixtures, may be separated in a manner known per se by appropriate lengthening procedures to the corresponding isomers. Thus, diastomeric mixtures may be extended to individual diastereomers by fractional crystallization, chromatography, treatment with diluents and the like. The racemates can be lengthened by converting optical antipodes into diastereomers, for example by reaction with optically active compounds, such as optically active acids or bases, by chromatography on a column of material consisting of optically active compounds or by enzymatic methods, for example, selective reaction with only one of the two enantiomers. This division. can be carried out both in the preparation step of one of the starting compounds and also in the compounds of the general formula themselves

195 ce I.

The opposite configuration can be achieved at the individual chiral centers in the compound of formula (I). For example, configurations of asymmetric carbon atoms that contain nucleophilic substituents, such as amino or hydroxy, may be reversed. by second order nucleophilic substitution, optionally after conversion of the bound nucleophilic substituent to a suitable nucleofugic group and reaction with the original substituent introducing reagent, or the configuration on the hydroxyl carbon atoms such as Rg bearing a carbon atom of formula I, oxidation and reduction of compounds of general formula can be reversed Formula I.

Hydroxy radicals R and a hydrogen atom R _{g of} the compound of formula I, can be oxidized to an oxo group, whereby. Preferably, an oxidizing agent is used which selectively converts the hydroxy group to a keto group, for example, chromic acid or a derivative thereof, such as pyridinium chromate or tert-butylchromate, dibromide and sulfuric acid, sulfur trioxide in the presence of heterocyclic bases, such as heterocyclic bases. pyridine and sulfur trioxide; nitric acid, burr, selenium dioxide, dimethylsulfoxide in the presence of oxalyl chloride, in aqueous, aqueous or organic solvents, such as halogenated solvents such as methylene chloride, carboxylic acid amides such as dimethylformamide, or di- (lower alkyl) ) sulfoxides, such as dimethyl sulfoxide, in the presence or absence of basic amines, for example tri- (lower alkyl) amines, such as triethylamine, at temperatures from -50 to 100 ° C, preferably from -10 to 50 ° C, e.g. in European patent application 0 236 734A.

On the contrary, the following compound of Formula I, wherein R ₅ and R ₆ form together an oxo group, this oxo group can be reduced to a hydroxy group. To reduce the oxo group in

The compound of formula I is suitable as a reducing agent which, under the reaction conditions, reduces the isolated keto group selectively or more rapidly than the amido group present in the compound of formula I.

In particular, suitable borohydrides, such as alkali metal borohydrides, especially sodium borohydride, lithium borohydride or sodium cyanoborohydride, zinc borohydride or suitable aluminum hydrides such as (lower alkoxy) aluminum alkali metal hydrides with bulky residues such as lithium tris-tert-butoxyalide .

The reduction may also be carried out with hydrogen in the presence of suitable heavy metal catalysts, for example Raney nickel or platinum or palladium catalysts such as platinum or palladium on activated carbon or by means of Meerwein-Ponndorf-Verley using aluminum alkanolate, preferably 2. -propanolate or aluminum ethanolate.

The reduction can be carried out preferably using stoichiometric amounts or a reasonable measured excess of the reducing agent in an inert solvent at a temperature of from -80 ° C to the boiling point of the solvent, for example -20 to +100 ° C, if needed under protective conditions. atmosphere, for example under nitrogen or argon. Excess reagent is particularly needed when the reagent also reacts with a solvent, for example a proton of a protic solvent.

When using sodium borohydride, polar protic solvents, such as methanol, ethanol or isopropanol, are suitable, and polar aprotic solvents such as tetrahydrofuran are suitable for use with other reducing agents.

In a compound of formula I wherein. R, R _2, R _g and R do not contain an aryl radical or one radical is not pri197.

LiS be reactive, may the aryl moiety present in R _7, R _g, and / or R _4, particularly a phenyl group, hydrogen, for example by catalytic hydrogenation, especially in the presence of heavy metal oxides, such as mixed oxide of rhodium and platinum, for example by Nishimura &apos; s catalyst , preferably in a polar solvent such as an alcohol, for example methanol or ethanol, at a temperature of from 0 to 80 ° C, in particular from 10 to 40 ° C and at a hydrogen pressure of from 100 kPa to 1 MPa, preferably at a pressure approaching normal pressure.

The amino or carboxamido group can be substituted in the compound of formula (I) obtained, the carboxy group present in the free or reactive form can be esterified or amidated, or the esterified or amidated carboxy group can be converted to the free carboxy group.

Substitution of the carboxamido group or other primary or secondary group is accomplished, for example, by introducing radicals such as optionally substituted alkyl, acenyl or alkynyl, aryl (lower alkyl) groups through the attached heterocyclyl or heterocyclyl (lower alkyl) groups R 1, R ₂ , R g and R _{g of} the compound of formula I, wherein one or more of these radicals is H, for example by alkylation.

A suitable means for alkylating a carboxamido group in a compound of formula I is, for example, diazo compounds such as diazomethane. The diazomethane may be added in an inert solvent, whereby the resulting methylene free groups are reacted with a carboxamido group in a compound of formula (I). The diazomethane decomposition is preferably carried out catalytically, for example in the presence of a noble metal in finely divided form such as a medium or a noble metal salt. copper or copper sulfate.

-198.-. j \ ....

Alkylating agents are known from German publication no. These may be, for example, alkyl halides, sulfonic acid esters, tartaric acid salts of salts or 1-substituted 3-aryl-triazenes which can be reacted under the reaction conditions with a compound of the formula I containing a carboxamido group.

Other alkylating agents are selected from compounds of Formulas X-XIV

R ₁ -X (X),. ^R 2 - ^x (XI),

...... .Rg-X (XIII) a. R _g -X ··· .- (XIV) kterýchžto.vzorcich

X * denotes a leaving group and the remaining radicals have the meanings indicated except for acyl, unsubstituted or substituted sulfos, phosphono or phosphoryl substituted above.

The leaving group is a particular nucleofugile leaving group selected from a hydroxy group esterified with a strong inorganic or organic acid, such as a mineral acid such as a hydrohalic acid such as hydrochloric, hydrobromic or hydroiodic acid, or a strong organic sulfonic acid such as a hydroxy group esterified with a halogen such as substituted (lower alkane) sulfonic acid or aromatic sulfonic acid, for example optionally lower alkyl, such as methyl, halogen, such as bromine and / or benzenesulfonic acid substituted with nitro

with, for example, methanesulfonic acid, trimethanesulfonic acid or p-toluenesulfonic acid, or hydroxy groups esterified with nitric acid.

The reaction may be carried out under the condition of nucleophilic:

Substitution of the first or second order. *?

For example, one of the compounds of formulas VII-XIII, wherein X represents a leaving group I 'with a high polarity of the electron shell, e.g. iodine, in a polar aprotic solvent such as acetone, acetonitrile, nitromethane, dimethylsulfoxide or dimethylformamide can be used. The reaction can also be carried out in water, optionally mixed with an organic solvent as a co-solvent, for example ethanol, tetrahydrofuran or acetone.

Optionally, the substitution reactions are carried out at a reduced or increased rate. at temperatures ranging from about -40 ° C to about 100 ° C, preferably from about -10 ° C to about 50 ° C, and optionally under an inert gas atmosphere such as nitrogen or argon. ..... 'F

•.

For the esterification or amidation of the carboxy group in the compound of formula (I), the free acid or free acid can be converted, if desired, to one of the above reactive derivatives and reacted with an alcohol, ammonia, primary or secondary amine, or free acid or reactive '1' can be esterified salt, for example cesium salt, to react with a reactive alcohol derivative. For example, cesium carboxylic acid can be reacted with an alcohol halide or sulfonic acid ester. The esterification of the carboxy group can also be carried out with other conventional alkylating agents, such as diazomethane, alkyl halides, sulfonic acid esters of tartaric acid derivatives salts or 1-substituted 3-aryltriazenes and the like.

To convert an esterified or amidated carboxy group to a free carboxy group, the methods described above for the carboxyl group deprotection or optional alkyl saponification may be used using the usual reaction conditions as described in Organic, 17th ed. , Berlin GDR (1988).

and

In the compound of formula (I), the esterified carboxy group can be converted by aminolysis using ammonia or a primary or secondary amine to an optionally substituted carboxamido group. Aminolysis can be carried out under the usual reaction conditions described for such reactions as described in Organikum, 15th ed., VEB Deutscher Verlag der Wissenschaften, Berlin - GDR (1976).

In the compound of formula I can be present in the free amino group acylated, e.g., to introduce one of the groups described for R ^, 'R _2, R g and R _g, acyl, sulfo, substituted sulfonyl, phosphono or substituted phosphoryl. Acylation is performed. as described above under processes b), no) or d) for condensation, or methods mentioned for protecting groups or any of the methods described in Organikum, 17th ed., VEB Deutscher Verlag der Wissenschaften, Berlin - GDR (1988).

In the compound of formula I obtained, wherein the substituents have the meanings indicated, at least one free hydroxy group is present and the remaining functional groups are in protected form, the free hydroxy group may be acylated or etherified.

with··.

7 /.

'\ Y ·

£ '' ť • i ·· 'j

ΐΗ.

; ·. -ú

The acylation may be carried out with acylating agents according to one of the methods mentioned above under b) to d), according to the methods described for protecting groups or by some of the methods known from the Organikum, 17th ed., VEB Deutscher Verlag der Wissenschaften, Berlin. GDR (1988).

Etherification can be carried out by treatment with suitable alkylating agents and under the same reaction conditions as described above, for example with diazomethane, alkyl halides, sulfonic acid esters, tartaric acid salts of salts, 1-substituted 3-aryltriazenes and the like.

In the compound of formula I obtained, oxidation of the sulfinyl or sulfonyl group B, the sulfide corresponding to the sulfoxide or sulfone can also be obtained from the thio group.

Oxidation to the sulfonyl group or sulfone can usually be achieved. may be carried out by the action of a conventional oxidizing agent. Particularly preferred is the use of an oxidizing agent which selectively oxidizes thio or sulfide sulfur in the presence of other functional groups of the corresponding compound of formula I, for example amino or hydroxy groups, for example aromatic or aliphatic percarboxylic acids, for example perbenzoic, monoperoxyphthalic, m-chloroperbenzoic, peracetic , peroxy form or trifluoroperacetate; The oxidation with peroxyacids is usually carried out in solvents suitable for this purpose, for example chlorinated hydrocarbons such as methylene chloride or chloroform, ethers such as diethyl ether, esters such as ethyl acetate or the like at temperatures from -78 ° C to room temperature, e.g. 20 to + 10 ° C, preferably at a temperature of about 0 ° C. Peroxycarboxylic acids can also be formed in situ, for example by treatment with hydrogen peroxide in acetic acid or formic acid containing an anhydride, for example by treatment with 30 to 90% hydrogen peroxide in acetic acid or acetic anhydride. Also suitable are other peroxy compounds, for example peroxomonosulfate in mixtures of lower alkanols and water,

202 for example methanol or ethanol with water, or in aqueous acetic acid at temperatures from -70 to +30 ° C, for example from -20 ° C to room temperature, sodium periodate in methanol or mixtures of methanol with water at temperatures of 0 to 50 ° C, for example at room temperature. By using a stoichiometric amount of a suitable oxidizing agent, the corresponding sulfinic acids or sulfoxides can also be obtained. Suitable for this purpose are, for example, sodium periodate in methanol or mixtures of methanol and water at temperatures from -15 ° C to room temperature, for example about 0 ° C, m m-chloroperbenzoic acid in methylene chloride, chloroform or ethyl acetate at -78 to 10 ' C, preferably from -30 to 0 ° C, further t-butyl hypochlorite in lower alkanols, for example methanol or hydrogen peroxide in acetone or acetic acid at a temperature of about 0 ° C or the aforementioned potassium peroxomonosulphates at low temperatures.

If desired, reduction of the sulfonyl group or sulfone moiety in the compound of formula I obtained may give the corresponding thio compound or the corresponding sulfide. For example, the reduction is carried out with disobutylaluminum hydride in ether or tetrahydrofuran.

In the compound of formula (I) obtained with a sulfinyl group, this group may be reduced to a thio group. Preferably, a selective reducing agent is used which does not have other functional groups in the compound of formula I, for example a functional amide group. Examples of such selective reducing agents are dichloroborane, which is reacted in tetrahydrofuran or dimethoxyethane at temperatures from -30 to +10 ° C, triphenylphosphine in boiling carbon tetrachloride, trichlorosilane or hexachlorodisilane, iron pentacarbonyl, and sodium bisulfite in aqueous aqueous sodium hydroxide, for example. methanol, ethanol, or a mixture of water and tetrahydrofuran, at temperatures from -10 to +50 ° C, and sodium borohydride in the presence of cobalt chloride or sodium chloride. '....

⁷ '..... .. ..- ^ - 203 - will also be hydrogen in the presence of a catalytic amount of palladium, such as palladium on carbon in refluxing ethanol.

Protecting groups or suitable radicals R @ 1, R @ ₂ , R @ 8 or R @ 8, i.e. radicals which are acyl, sulfo, substituted sulf, may be present in the compound of formula (I). phosphonium or substituted phosphoryl, cleaved as described under process f), in particular by hydrolysis, for example in the presence of a base such as an alkali metal or alkaline earth metal hydroxide such as sodium hydroxide, or an acid such as organic or mineral acids such as hydrohalic acids such as Hydrochloric acid. The hydrolysis is carried out under conventional conditions, for example in an aqueous solution or in an anhydrous solvent, in particular in ethers such as dioxane, at a temperature of from -50 ° C to the reflux temperature of the corresponding reaction mixture, for example from 0 to 50 ° C. atmosphere of a protective gas such as argon or nitrogen.

• ·

All of the above process steps may be carried out in known, preferably specifically mentioned reaction conditions, in the absence or usually in the presence of a solvent or diluent, preferably those which are inert to the reagents used and dissolve the reagents, in the absence or presence of a catalyst. condensation or neutralizing agents, for example ion exchangers such as cation exchangers, for example in the H ⁺ form, depending on the nature of the reaction and / or the components involved in the reaction at reduced, normal or elevated temperature, for example in a temperature range of about -100 to about 190 Preferably from about -80 to about 150 ° C, for example from -80 to -60 ° C, at room temperature, or from -20 to 40 ° C or at the boiling point of the solvent used, at atmospheric pressure or in a sealed container optionally under pressure and / or under an inert gas atmosphere, for example under argon or nitrogen ou atmosphere.

204. All of the starting compounds and intermediates, if they contain a salt-forming group, may be presented in the form of a salt. Salts may also be introduced during the reaction of such compounds if this does not interfere with the reaction.

Isomeric mixtures occurring in all reaction steps may be extended to individual isomers, for example diastereomers or enantiomers, or to any mixture of isomers, for example racemates or diastereomeric mixtures, for example by analogous methods as described under the additional features of the process.

In certain cases, such as hydrogenation, stereoselective reactions may be accomplished so that, for example, it is easier to obtain the individual isomers.

Solvents from which solvents suitable for the reaction in question may be chosen are, for example, water, esters such as (lower alkyl) (lower alkanoates), for example diethyl ester of acetic acid, ethers, such as aliphatic ethers, for example diethyl ether, or cyclic ethers, for example tetrahydrofuran, liquid aromatic hydrocarbons such as benzene or toluene, alcohols such as methanol, ethanol or 1- or 2-propanol, nitriles such as acetonitrile, halogenated hydrocarbons such as methylene chloride, acid amides such as dimethylformamide, bases such as heterocyclic nitrogenous bases such as pyridine, carboxylic acid anhydrides such as lower alkanoic anhydrides such as acetic anhydride, cyclic, straight or branched hydrocarbons such as cyclohexane, hexane or isopentane, or mixtures of these solvents, for example aqueous solutions, unless otherwise described in the description. Such solvent mixtures find such use in post-work-up, for example chromatography or separation.

The invention also relates to embodiments of processes starting from compounds obtained at any stage as intermediates and carrying out the remaining steps, or to interrupt the process at any stage or to use starting materials formed under reaction conditions or in in the form of a reactive derivative or salt, or the compounds obtained by the process of the invention are formed under the conditions of the process and further processed in situ. The starting compounds are preferably those which lead to the compounds described above as being preferred, particularly as being particularly preferred and / or preferred.

I

Pharmaceutical preparations

The present invention also relates to pharmaceutical compositions comprising compounds of Formula I.

For example, the pharmacologically useful compounds of the present invention may be used in the manufacture of pharmaceutical compositions comprising an effective amount of the active compound in common or in admixture with a significant amount of inorganic or organic, solid or liquid, pharmaceutically acceptable carriers.

The invention also includes a pharmaceutical composition suitable for administration to warm-blooded individuals, e.g.

for treating or deterring a disease associated with the suppression of retroviral proteases, a particular retroviral aspartate protease such as HIV-1- or HIV-2-gag protease, for example a retroviral disease such as AIDS, comprising an amount of a compound of the general formula or a pharmaceutically acceptable salt thereof, effective for suppressing a retroviral protease, together with at least one pharmaceutically acceptable carrier.

......... 7-206; ......... ·.

f o.

The pharmaceutical compositions of this invention are enteral, such as nasal, rectal or oral, or parenteral, such as intramuscular or intravenous, administration to a warm-blooded individual (human or animal) comprising an effective dose of a pharmacologically active compound, alone or pharmaceutically usable carriers. The dose of the active ingredient depends. , on the species of warm-blooded individual, its body weight, age and individual condition, the individual pharmacokinetic facts relevant to the disease being treated, the same as on application routes.

The invention also relates to a method for the treatment of diseases caused by viruses, in particular Retroviruses, e.g. AIDS, which comprises administering a therapeutically significant amount of a compound of formula I according to the invention to a warm-blooded individual e.g. especially AIDS. Dosage amounts for treating a warm-blooded individual such as a human of about 70 kg body weight are from about 3 mg to about 3 g, preferably from about 10 mg to about 1.5 g, for example from about 300 to 1000 mg per person, and day, preferably divided into 1 to 3 unit doses, which may be, for example, of the same size. Children usually receive half the adult dose.

The pharmaceutical compositions contain from about 1 to about 95%, preferably from about 20 to about 90%, of the active ingredient. For example, the pharmaceutical compositions of the invention may be in unit dosage form, such as ampoules, vials, lace, dragees, tablets or capsules.

The pharmaceutical compositions of the present invention can be prepared in a manner known per se, for example, by conventional methods of dissolution, lyophilization, mixing, granulation or auctioning.

T

Preferably, a solution and a suspension of the active ingredient, in particular isotonic aqueous solutions or suspensions, are used and may be prepared, for example, from lyophilized preparations which contain the active ingredient alone or together with a suitable carrier, for example mannitol, before use. These pharmaceutical compositions may be sterilized and / or contain adjuvants, for example, preservatives, stabilizers, surface active and / or emulsifying agents, solubilizers, salts for regulating the osmotic pressure and / or buffers, and may be prepared in a manner known per se, for example by conventional means. methods of dissolution or lyophilization. These solutions or suspensions may contain viscosity enhancers such as sodium carboxymethylcellulose, carboxymethylcellulose, dextran, polyvinylpyrrolidone or gelatin.

Suspensions in oil contain, as an oil component, the customary injectable oils of vegetable, synthetic or semi-synthetic origin. Particularly mentioned are liquid fatty acid esters which contain, as an acid-derived component, a long chain fatty acid residue of 8 to 22 carbon atoms, in particular of 12 to 22 carbon atoms, such as a residue derived from lauric, tridecylic, myristic, pentadecylic, palmitic, margaric, stearic, arachidic, behenic or correspondingly unsaturated acids such as oleic, elaidic, erucic, brasidic or linoleic acids, optionally with the addition of antioxidants such as vitamin E, β-carotine or β-carotine or .-butyl-4-hydroxytoluene. The alcohol component of these fatty acid esters contains no more than 6 carbon atoms and is a monovalent or polyvalent moiety, such as a monovalent, divalent or trivalent alcohol.

such as methanol, ethanol, propanol, butanol or pentanol or isomers thereof, but especially glycol. 7 and glycerin. Examples of fatty acid esters are ethyl oleate, isopropyl myristate, isopropyl palmitate,

Labrafil M 2375 (polyoxyethylene glycerm trioleate from ´7.

Gattefosse, Paris), Miglyol 812 (unsaturated triglyceride7)

........ ... ...... . .. -. Fatty acids having a chain length of 8 to 12 carbon atoms from the company

Huls AG, SNR), but specific vegetable oils such as cottonseed oil, almond, olive, castor, sesame or soybean oil, but mainly sunflower oil.7

r. ··· .-. '

The manufacture of injectables is carried out in the usual manner under sterile conditions, as well as filling ampoules or vials, and disposing of such containers.

Pharmaceutical compositions for oral use may be formulated with a pharmaceutical composition. The mixture obtained is optionally granulated and the mixture is, if appropriate or required, processed into tablets, dragee cores or capsules, if appropriate. The active substance can also be introduced into plastic carriers which allow the active substances to be metered or allowed to diffuse.7.

Suitable carriers are special fillers, such as sugar, for example sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphates, for example calcium phosphate or dibasic calcium phosphate, binders such as starch seedlings obtained for example using corn, wheat, rice or potato starch, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone and / or, if desired, disintegrants such as the aforementioned starches, further carboxymethyl starches, cross-linked polyvinylpyrrolidone, agar, alginic acid or its

209 sodium. The auxiliaries are, in particular, liquid flow regulators and lubricants, for example silicic acid, talc, stearic acid or salts thereof, for example, magnesium or calcium stearate, and / or polyethylene glycol. The dragee cores are provided with a suitable coating which is optionally resistant to gastric juices, including, but not limited to, concentrated sugar solutions, which may include gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, lacquer solutions in suitable organic solutions. gastric juice resistant coatings, »

solutions of suitable cellulosic agents such as cellulose ethyl phthalate or cellulose hydroxypropyl methyl phthalate. The capsules are push-fit capsules of gelatin as well as soft sealed capsules of gelatin and a plasticizer such as glycerin or sorbitol. The push-fit capsules may contain the active ingredient in the form of a granulate, for example with fillers such as lactose, binders such as starches and / or lubricants such as talc or magnesium stearate, and optionally with stabilizers. In soft capsules, the active ingredient is preferably dissolved or substituted in a suitable oily excipient such as fatty oils, paraffin oil or liquid polyethylene glycols, and stabilizers and / or antibacterial agents may also be added. Dyestuffs or pigments may be added to the tablets or coated tablets and the capsule shells, for example to distinguish or label different doses of the active ingredient.

• i;

·;

Starting compounds

The novel starting materials and / or intermediates, as well as their production process, are also an object of the present invention. Preferably, such starting materials are used, and the reaction conditions are selected so as to obtain the compounds which are said to be preferred.

In the production of starting materials, free functional groups can be formed

- 210 pins not to be involved in the respective reaction, to protect or be presented in a protected form, for example, to protect with the protecting groups mentioned under method a). These protecting groups may be released at the appropriate time by the reactions described. under method f).

The starting materials for process (a) are known compounds or, if new, can be prepared in a manner known per se, for example from hydrazine or its suitable derivatives of the compound of formula III, and from suitable amino acids or analogues thereof, for example with one or two side chains R ₃ and R _4, the compound of formula IV.

. * Compounds of formula (III) are, for example, available from compounds of formula (XV) h ₂ n-nh- _1; (XV) wherein:

R? represents a hydrogen atom or an amino protecting group as described under process b), in particular a tert- (lower alkoxy) carbonyl group such as a tert-butoxycarbonyl, aryl- (lower alkoxy) carbonyl group such as benzyloxycarbonyl or 9- fluorenylmethoxycarbonyl, or one of the abovementioned acyl amino protecting groups such as, jestli'že is for a compound of formula I, wherein R ₇ instead of the radical R · ?, which is optionally substituted alkyl or cycloalkyl, the introduction of the R ·? alkylated with a compound of formula XII as described under Method

e), or the radical R _? by reacting a suitable carbonyl compound with the free amino group of a compound of formula (VIII) or a non-acylated derivative and using it for the following reduction

to obtain the hydrazine derivative of general formula (XVI)

R &lt; ₇ & gt _; -NH-NH-R & apos _; (XVI), wherein any radicals in all of the above compounds have the meanings given above and. functional groups in the reagents, which are not to take part in the reaction, are optionally protected or the protecting group of R _n, where does not match one of the radicals R or R _g in the formula I, and / or other protecting groups are removed and the radicals R and R @ _g with the exception of the hydrogen atom, it is also condensed under the conditions described above under process b) with acids of the formula VI or of the formula XVII

Rg-OH (XVII) wherein

Rg is as defined above,.

or alkylated with a compound of formula XIII or XIV as defined above, or both, under the conditions set forth above for the additional features of the process.

The carbonyl compounds used to produce compounds of formula XVI suitable for the introduction of R ₇ are aldehydes or ketones whose reactive carbonyl group after reaction with a compound of formula XV and subsequent reduction is part of one of said R ₇ residues, preferably aldehydes, which are suitable for introducing lower alkyl, cyclohexyl (lower alkyl) or phenyl (lower alkyl). groups. . .

The reaction of the carbonyl compounds with the compounds of formula XVI to the corresponding hydrazones is carried out under the conditions customary for the reaction of the carbonyl compounds with amines, preferably in polar organic solvents, for example ethers such as ethers. tetrahydrofuran or diethyl ether, alcohol

Iechs, such as methanol or ethanol, carboxylic acid amides. seline, such as dimethylformamide, or esters, such as ethylation. or in aqueous solutions, preferably in methanol, further in the presence or absence of acid catalysts, for example carboxylic acids such as formic or acetic acid, or sulfonic acids, such as p-toluenesulfonic acid, at temperatures from 0 ° C to temperature the reflux temperature of the reaction mixture, preferably at a temperature of from 20 ° C to the reflux temperature of the reaction mixture.

The reduction of the hydrazones obtained is preferably carried out by hydrogenation in the presence of a suitable catalyst. Suitable catalysts for hydrogenation are metals such as nickel, iron, cobalt or ruthenium, or noble metals or oxides thereof, such as palladium or rhodium or its oxides, optionally deposited, for example, on a suitable carrier such as barium sulfate, alumina or active coal, or as skeletal catalysts, such as Raney nickel. Solvents useful for catalytic hydrogenation are, for example, water, alcohols such as methanol or ethanol, esters such as ethyl acetate, ethers such as dioxane, chlorinated hydrocarbons such as dichloromethane, carboxylic acid amides such as dimethylformamide, or carboxylic acids such as acetic acid or mixtures of these solvents. The hydrogenation is carried out at a temperature of from 10 to 250 ° C, preferably from room temperature to 100 ° C, under a hydrogen pressure of from 100 kPa to 20 MPa, preferably from 100 kPa to 1 MPa, in conventional equipment.

Especially. preferred reaction conditions for the preparation of compounds of formula XV are analogous to those described in J. Chem. Soc. Perkin I, 1712 (1975).

Compounds of formula IV are available, for example, by reduction of amino acids of formula XVIII

R, n-NH COOH (xin);

in which

R ₁₀ is H or an amino protecting group in a process referred to a), especially tert .- (lower alkoxy) -carbonyl group such as tert-butoxycarbonyl, aryl (lower alkoxy) -carbonyl group such as benzyloxycarbonyl or 9- fluorenylmethoxycarbonyl, or one of the aforementioned acyl protecting groups

For the amino group a

R1 and R2 have the meanings given for the compounds of the general formula.

preferably amino acids of formula XVIII Å

R _{@ 1} -NH COOH (XVIII / X).

in which the radicals have the meanings indicated, to the aldehydes of the general formula XIX

- 214 -

(XIX).

wherein the radicals have the meanings given above, preferably to the aldehydes of formula XIX A

in which the radicals have the meanings indicated (which can be obtained, for example, from a compound of the formula XVIII A), by reacting these aldehydes with ylide compounds, preferably sulfur ylide compounds, and an epoxide of formula XX

(XX).

wherein the radicals have the meanings indicated, preferably to compounds of formula XX A (XX A).

in which the radicals have the meanings indicated (which can be obtained, for example, from the compounds of the general formula XIX

- 215 A), if appropriate, by cleavage of the protecting group R _n if it does not answer. zbytkura Rθ, or R _g in the formula I, and, acylation of the amino acids, the resulting compound of formula VIII and XXI

R ₂ -OH (XXI), wherein the radicals have the above meanings, under the conditions described for process b) and / or alkylation of the amino group of the resulting compound with a reagent nucleofugic leaving groups of formula X or XI in which the radicals have the above meanings, under the conditions described under the additional characters of the method.

Reduction of the amino acids XVIII or XVIII A to the corresponding aldehydes XIX or XIX A is carried out, for example, by reduction to the corresponding alcohols and the associated oxidation to the aldehydes mentioned.

The reduction to the alcohols is carried out, for example, by hydrogenation of acid halides or other carboxylic acid derivatives activated as described under process b), under the conditions mentioned for the hydrogenation of hydrazone obtained from compounds of the general formula XVI, or by complex hydrides such as sodium borohydride. Followed by oxidation give alcohol as possible under the conditions for the oxidation of compounds of formula I, wherein R ₅ is hydroxy and R ₆ is a hydrogen atom to give compounds wherein R _g and R ₆ taken together represent an oxo group, as described under the supplementary features of the process, the sky "

oxidation of the hydroxy group with a sulfoxide such as dimethylsulfoxide in the presence of a hydroxyl activating reagent such as a carboxylic acid chloride, for example oxalyl chloride in an inert solvent, for example a halogenated hydrocarbon such as dichloromethane, and / or acyclic or cyclic

216 ethers, such as tetrahydrofuran, at a temperature of from -80 to 0 ° C, for example from -78 to -50 ° C.

Such a primary reduction of amino acids to aldehydes is also possible, for example, by hydrogenation in the presence of a partially poisoned palladium catalyst or reduction of the corresponding amino acid ester such as an (lower alkyl) ester such as ethyl ester by treatment with complex hydrides such as borohydrides such as sodium borohydride or preferably aluminum hydride lithium aluminum hydride, lithium (tert-butoxy) aluminum hydride, or especially diisobutylaluminum hydride, in non-polar solvents, for example hydrocarbons or aromatic solvents such as toluene, at a temperature of from -100 to 0 ° C, preferably from -70 to -30 And the attached reaction to the corresponding semicarbazones, for example with the corresponding salts of semicarbazones with acids such as semicarbazide hydrochloride, in an aqueous solvent system such as alcohols with water, e.g. aqueous ethanol, at temperatures ranging from -20 to 60 ° C, 10 to 30 ° C, and the reaction of the obtained semis with a reactive aldehyde, for example formaldehyde, in an inert solvent, for example a polar organic solvent, for example a carboxylic acid amide such as dimethylformamide, at a temperature of from -30 to 60 ° C, preferably from 0 to 30 ° C, and then with an acid, for example, a strong mineral acid, such as hydrohalic acid, in an aqueous solution, optionally in the presence of a solvent used hitherto, at temperatures from -40 to 50 ° C, preferably from -10 to 30 ° C. The corresponding esters are obtained by reacting the amino acids with the corresponding carboxylic acids, for example ethanol, analogously to the condensation used for process b), for example by reaction with inorganic acid halides such as thionyl chloride in organic solvent mixtures such as aromatic and alcoholic solvent mixtures such as toluene and ethanol, at temperatures from -50 to 50 ° C, preferably from -10 to 20 ° C.

- 217 i ':

The preparation of compounds of formula XIX and XIX A is carried out in a particularly preferred manner under conditions analogous to the reaction conditions described in J. Org. Chem. 47, 3016 (1982) or J. Org. Chem. 43, 3624 (1978).

Sulfur-containing ylide suitable for reaction <

The compounds of formula (I) are disclosed. XIX or XIX A for epoxides

- '. M 'of formula XX or XX A, for example, is dialkylsulfonium methylide;

for example dimethylsulfonium methylide, alkyl- or phenyldial-;

cylaminosulfonium methylide, for example methyl or phenyldimethylaminosulfoxonium methylide, or dialkylsulfoxonium methylide, for example dimethyl or diethylsulfoxonium methylide.

I. ï

The corresponding sulfur-containing ylide compound is expedient

f. '' produces in situ from the corresponding sulfonium or sulfoxonium salts and bases, such as sodium hydride, in dipolar aprotic:

a solvent such as dimethylsulfoxide or an ether such as tetrahydrofuran or 1,2-dimethoxyethane with or without reaction. compounds of formula XIX or XIX A.r;

The reaction is usually carried out at room temperature, with cooling down, for example, down to -20 ° C or with slight heating, for example up to .40 ° C. The present sulphide, sulfinamide or sulphoxide is finally removed by treatment in the presence of water.

The reaction with the sulfur-containing ylide compound is carried out in a particularly preferred manner under analogous conditions;

As shown in J. Org. Chem. 50, 4615 (1985).

A compound of formula XX (preferably of formula XX A) can also be prepared from a compound of formula XIX (preferably of formula XIX A) as defined above by reacting it with a tri- (lower alkyl) -silylmethyl Grignard compound, e.g. a corresponding halomethylsilane, such as chloromethyltrimethylsilane, in an inert solvent such as an ether such as dioxane or diethyl-218 at temperatures from 0 to 50 ° C, for example room temperature to about 40 ° C, followed by elimination with removal of the silyl residue to form a double with a Lewis acid such as boron trifluoride, preferably also leaving the amino protecting group R ^ q present in an inert solvent such as an ether such as diethyl ether or a halogenated hydrocarbon such as dichloromethane or a mixture thereof, temperatures from -50 ° C to the reflux temperature, especially from 0 ° C to 30 ° C, if desired e new acylating the introduction of the protecting group of the amino group as a residue "R _Q1 as defined above, and, oxidation of the obtained double bond into an oxirane, preferably by treatment with a peroxycarboxylic acid such as m-chloroperbenzoic acid in an inert solvent such as a chlorinated uhľovodíkujako as dichloromethane, at temperatures of from - 20 ° C to the reflux temperature of the reaction mixture, for example at 10 to 30 ° C.

The starting compounds for processes b), c) and d) are known or, if new, can be prepared by known methods. A compound of formula V can for example be prepared from a suitable hydrazine derivative of formula III, wherein R _g is a hydrogen atom and the other radicals are as defined for a compound of formula V, and suitable epoxides of the formula IV, wherein the radicals are as defined for compound of formula V (method b). The compound of formula (VII) is prepared from a suitable hydrazine derivative of formula (III) wherein the radicals have the meanings indicated for the compounds of formula (VII) and suitable epoxides of formula (IV) in which the hydrogen atom is present. (Method c). The compound of formula (IX) is prepared from suitable hydrazine derivatives of formula (III) in which R _g is hydrogen and the remaining radicals have the meanings given above. the compound of formula (IX) (method d) and the suitable epoxides of formula (IV) in which R @ 1 represents a hydrogen atom and the remaining residues have the meanings indicated for the compound of formula (IX) (process d) analogously to method (a); cleavage of protecting groups.

Compounds of the formula I 'in which the substituents have the meanings given above can be prepared, for example, from compounds of the formula III'

H

I

HN .Rg

(III ') in which the radicals have the meanings given for the compounds of the general formula (I) as described in process b), reacting with

wherein the functional groups present are not to be present in the reaction, as in a protected form, and can be removed after the reaction.

Preferred for process (d) are the starting compounds of formula (II)

(II) in which

R 8 represents optionally substituted alkyl or cycloalkyl, further aryl, heterocyclyl or an optional substituent; bolded acenyl and

220 R ₇ represents optionally substituted alkyl or cycloalkyl, further aryl, heterocyclyl or optionally substituted alkenyl, as well as salts of these compounds, when they contain salt-forming groups which are intermediates according to the invention. .: ....

These compounds may be protected separately on one or both amino groups, and if there are a pair of amino protecting groups, these may be identical or different from each other.

Suitable amino protecting groups are, for example, those mentioned under process a). The radicals R @ ₂ and R @ ₇ given for the compounds of the formula II have the meanings defined above for the compounds of the general formula I in the definition of the radicals R @ 8 and R @ ₇ .

Highly preferred are compounds of Formula II, wherein R is cyclohexyl (lower alkyl), phenyl (lower alkyl) or p-fluorophenyl (lower alkyl) and R ₇ is lower alkyl, cyclohexyl (lower alkyl), phenyl a (lower alkyl), p-cyanophenyl (lower alkyl) or p-fluorophenyl (lower alkyl) group, the same as the salts of said compounds, when they contain such salt-forming groups.

More preferred are a compound of formula II, wherein R is a phenyl (lower alkyl) group and R @ ₇ is lower alkyl, cyclohexyl (lower alkyl) or phenyl- (lower alkyl) group as well as salts of these compounds, if they contain salt-forming groups. ·· '.' · ..... '''

Particularly preferred are compounds of formula II wherein R ₃ is cyclohexylmethyl, benzyl or p-fluorobenzyl and R ₇ is n-butyl, isobutyl, cyclohexylmethyl, benzyl, p-fluorobenzyl. or p-cyanobenzyl, the same as the salts of such compounds, when they contain salt-forming groups.

. Particularly preferred are particular compounds of formula II wherein R ₃ is benzyl and R ₆ is benzyl. represents isobutyl, cyclohexylmethyl or benzyl, as well as salts of such compounds when they contain salt-forming groups.

Particularly preferred are the compounds of formula (II) which are listed in the examples.

Compounds of formula (II) in which the substituents have the meanings indicated, or salts thereof if they contain salt-forming groups, are prepared, for example, by the hydrazino derivative of formula (XVI).

R ₇ -NH-NH-R ₁₁ (XVI) wherein

represents an amino protecting group, adds to the epoxide of formula XX A

(XX A) in which

means an amino acid protecting group,

222 and, if desired, the compound of formula (II) obtained according to process a), with at least one salt-forming group, is converted to its salt or the resulting salt is converted to a free compound or another salt and / or optionally the resulting isomeric mixture is separated and / or the protecting groups present in the compound of formula (II) are cleaved and / or the compound of formula (II) according to the invention is converted to another compound of formula (II) according to the invention.

*

The preparation and conversion of the salt, the separation of the isomeric mixtures, the cleavage of the protecting groups and the conversion of the compounds of the general formula II are carried out analogously to the process for the preparation of the compounds of the general formula I mentioned above.

Particularly preferred is the preparation of the starting compounds of formula (II) in which the substituents are as defined above by deprotection of the compound of formula (II) in which it is present. one or both of the amino groups protected with amino protecting groups, especially under the conditions described for the hydrolysis of the compounds of the formula I, as mentioned in the additional features of the process.

Methods for the addition of compounds of formula XVI to compounds of formula XX A are described above in process a)

J for the preparation of a compound of formula I.

The preparation of the protected compounds of the formula I is carried out, for example, according to known methods, in particular from the compounds of the formulas III and IV, the functional groups in these compounds being optionally protected by protecting groups as described under method a).

The acids of the formulas VI, VIII, XVII and XXI, as well as the compounds with the nucleofugic groups of the formula X,

- 223

XI, XII, XIII, XIV and XV are known substances or, if new, can be prepared according to a method known per se.

DETAILED DESCRIPTION OF THE INVENTION

The following examples, to illustrate the invention, do not limit the scope of the invention in any way.

As usual, temperatures are given in degrees Celsius (° C). If no temperature data is given, the reaction is carried out at room temperature. _Rf values which indicate the ratio of retardece each substance to that of the solvent, down? thin-layer silica gel plates, thin-layer chromatography,

using the following solvent systems: A Chloroform, methanol, water and acetic acid 75: 27: 5: 0.5 B Chloroform, methanol, water and 90: 10: 1: 0.5 acetic acid C Chloroform, methanol, water and acetic acid 85: 13: 1.5: 0.5 D Chloroform and methanol 8: 1 E Chloroform and methanol 95: 5 F Hexane and ethyl acetate 2: 1 G Methylene chloride, diethyl ether and methanol 20: 20: 1 H * Methylene chloride and diethyl ether 1: 1 I Toluene and ethyl acetate 2: 1 The Chloroform and methanol 5: 1 J Methylene chloride and diethyl ether 5: 1 L Hexane and ethyl acetate 4: 1 M Hexane and ethyl acetate ^{5: 1} N ’ Hexane and ethyl acetate 1: 1 0 ethyl acetate -

i. · - ·· ..... . . ... ...... 224. P Methylene chloride, ethanol and 90: 10: 1 > * · ammonia (3 equivalents) Q Methylene chloride and diethyl ether 10: 1 R Hexane and ethyl acetate 3: 1 WITH Methylene chloride and diethyl ether 20: 1 T Chloroform and methanol 30: 1 U Chloroform and methanol 15: 1. IN Methylene chloride, diethyl ether and 1: 1: 3 hexane W Methylene chloride and diethyl ether 20: 1 X Methylene chloride and methanol 40: 1 Y Toluene and ethyl acetate 4: 1. For example, the abbreviation Rf (A) means that the value of R _f is

The ratios of the relative amounts of the solvents are always given in parts by volume.

Gradient High Performance Liquid Chromatography (HPLC):

I: 20% -> 100% acetonitrile, 0.05% trifluoroacetic acid in water, 0.05% trifluoroacetic acid, over 35 minutes II: 0% -> 40% acetonitrile, 0.05% trifluoroacetic acid in water, 0.05% trifluoroacetic acid, over 30 minutes III: 20% -> 60% acetonitrile, 0.05% trifluoroacetic acid in water, 0.05% trifluoroacetic acid, over 60 minutes IV: 1 10% -> 50% acetonitrile, 0.05% trifluoroacetic acid in water, 0.05% trifluoroacetic acid, over 60 minutes-

225

The column (250 x 4.6 mm) is packed with the reverse phase of _C18- Nucleosil ^R material (mean particle size 5 μιη, with silica gel covalently derivatized octadecylsilane, Macherey).

& Nagel, Duren, Germany). Detection is performed on the basis of absorption in ultraviolet radiation at 215 nm. The retention time (t _Ret ) is given in minutes. The liquid flow rate is 1 ml / min.

The same abbreviations are used to designate the solvent system for flash chromatography and medium pressure chromatography.

The following abbreviations have the following meanings:

Boe tert-butoxycarbonyl ether diethyl ether h hour (s) min minute (s)

MS. mass spectroscopy

Z - benzyloxycarbonyl

Mass spectrometry measurements are obtained either by conventional mass spectroscopy (MS) or by fast atom bombardment (FAB-MS). The mass data in the first case refer to the unprotonated ion of the molecule (M) ⁺ or to the protonated ion of the molecule (M + H) ⁺ .

Proton nuclear resonance spectroscopy ( ¹ H-NMR) values are reported in parts per million (ppm), based on tetramethylsilane as an internal standard. The abbreviations have the following meanings: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = double doublet.

Values for infrared spectroscopy (IR) are given in cm @ ^-1 , with solubilized brackets showing the solvent.

Tedla. When denoting the band intensity, s denotes strong, m medium and w weak intensity.

The residue labeled - [Phe ^N- Phe] - represents the bivalent radical 3 (S) -amino-4-phenyl-1- (N-benzylhydrazino) butan-2 (S) -ole and has the formula

The residue labeled - [Phe ^NN Cha] - represents a bivalent radical u

3 (S) -amino-4-phenyl-1- (N-cyclohexylmethylhydrazino) butan-2 (S) -ol and has the formula

The residue labeled - [Phe ^NN Leu] - represents a divalent radical

3 (S) -amino-4-phenyl-1- (N-isobutylhydrazino) butan-2 (S) -ol and has the formula

-227.-

The residue labeled - [Phe ^NN Nle] - represents the 3 (S) -amino-4-phenyl-1- (Nn-butylhydrazino) butan-2 (S) -ol radical and has the formula

The residue - [Phe ^NN (pF) Phe] - represents the divalent radical 3 (S) -amino-4-phenyl-1- [N- (p-fluorophenylmethyl) hydrazino] butan-2 (S) -ol and has the formula

The residue with the designation - ['. (PF) Phe- ^N (pF) Phe] - represents the bivalent radical 3 (S) -amino-4- (p-fluorophenyl) -1- / N- (p-fluoro-228 phenylmethyl). hydrazino / butane-2 (S) -ole and has the formula

The residue labeled - [Phe ^NN (p-CN) Phe] - represents the divalent radical 3 (S) -amino-4-phenyl-1- [N- (p-cyanophenylmethyl) hydrazino] butan-2 (S) -ol and has formula -

The residue - [Cha ^NN Leu] - represents the divalent radical 3 (S) -amino-4-cyclohexyl-1- (N-isobutylhydrazino) butan-2 (S) -ol and has the formula

229

Abbreviations common in peptide chemistry are used to denote the naturally occurring α-amino acid radicals occurring in nature. However, they have amino acids that are in the names of the compounds to the right of the radical - [Phe ^ ^N Phe] -, - [Phe ^NN Cha] -, -Phe ^HN Leu] -, - (Phe ^NN Nle] -, - [Phe ^NN ( pF) Phe] -,

- (pF) Phe ^NN (pF) Phe] -, - [Phe ^NN (p-CN) Phe] - or - [Cha ^NN Leuj -, deviating from the conventional peptide nomenclature, where the left is a terminal amino group and the right is a terminal carboxy group, a carboxyl group to the left, as indicated by a spike (<-), which in turn symbolizes the direction of binding. The configuration at the carbon atom at position a, as is known, is indicated in front by the symbol (L) - or (D) -. Tyrosine radicals etherified with a phenolic hydroxy group with the radical R are designated Tyr (OR). No is a norleucine radical.

Example 1

Boc- (^^ Phe Phe] -Boe

A solution of 300 mg (1.14 mmol) of (2R) - / 1 '(S) -Boc-amino-2'-phenylethyl / oxirane (J. Org. Chem. 50, 4615 (1985)) and 253 mg 1, 14 mmol) of tert-butyl 3-benzylcarbazate (J. Chem. Soc., Perkin I, 1712 (1975)) in 4 ml of methanol was refluxed for 12 hours. After cooling the reaction mixture to 0 ° C, much of the title compound precipitates. The mother liquors were evaporated and the residue dissolved

230 in a small amount of methylene chloride. After hexane was added dropwise, another portion of the title compound precipitated as a white precipitate. FAB-MS: (M + H) ⁺ = 486, t _Ret (I) = 26.8 min, _Rf (E) = 0.70. .....

Example 2

Z- (L) -Val- [Phe ^NN Phe] <- / (L) -Val-Z /

191 mg (0.76 mmol) of Z- (L) -valine, 336 mg (0.76 mmol) of benztriazol-1-yloxy-tris (dimethylamino) are dissolved in 5 ml of a 0.3 molar solution of N-methylmorpholine in dimethylformamide. oniumhexafluorophosphate and 103 mg (0.76 mmol) of 1'-hydroxybenztriazole are added, after 10 minutes 100 mg (0.25 mmol) of H- [Phe ^NN Phe] -H trihydrochloride are added and stirred for 2 hours at room temperature under a nitrogen atmosphere. The reaction mixture was evaporated, the residue was dissolved in methylene chloride and washed twice with saturated sodium bicarbonate solution. The organic phase is filtered through cotton wool, evaporated and the residue is purified by chromatography on silica gel using a 1: 1 mixture of methylene chloride and ether. After lyophilization of the fractions containing the product from dioxane, the title compound is obtained as a white solid. FAB-MS: (M + H) ⁺ = 752, t _Ret (I) = 27.8 min, _Rf (E) 0.45.

The starting material is produced as follows:

a) H- [Phe ^NN Phe] -H 3 HCl

A solution of 280 mg (0.58 mmol) of Boe- [Phe ^NN Phe] -Boe from Example 1 in 10 ml of 4N hydrogen chloride in dioxane was stirred for 2 hours at room temperature under nitrogen and then lyophilized. Re-lyophilization from a mixture of dioxane and tert-butanol affords the title compound as a flaky solid. FAB-MS: (M + H) &lt; ^{+ &gt}; 231 ... 231.

286, ^fc Ret ^{(I) = 23 (1 min} ' ^R f (°) = °' ¹⁷ ·

Example 3

Boe- (L) -Val- [Phe ^NN Phe] - ((L) -Val-Boc). In an analogous manner to that described in Example 2 _; obtained from 50 mg (0.13 mmol) of H- [Phe-Phe] -H trihydrochloride, 83 mg (0.83 mmol) of Boc- (L) -valine, 168 mg (0.38 mmol) of benzotriazol-1-yloxy -tris (dimethylamino) phosphonium hexafluorophosphate, 51 mg (0.38 mmol) of 1'-hydroxybenztriazole and 2.5. ml of 0.3 molar N-methylmorpholine in dimethylformamide after chromatographic purification on silica gel using a 95: 5 mixture of chloroform and methanol and lyophilization from dioxane of the title compound. FAB-MS: (M + H) &lt; ^{+ &gt}; = 684, t _Ret (I) = 27.4 min, Rf (E) = 0.38.

Example 4

Boc- [Phe ^NN Cha] -Boe

In a similar manner to Example 1, 231 mg (0.88 mmol) of (2R, 3S) -1- (3-Boc-amino-2-phenylethyl) oxirane and 200 mg (0.88 mmol) of tert-butyl are obtained. -3-cyclohexylmethylcarbazate ♦

the title compound which formed as a white precipitate upon treatment with hexane. FAB-MS: (M + H) &lt; ^{+ &gt}; = 492, t _Ret (1H)

30.4 min, _Rf (E) = 0.78.

The starting compound is produced as follows:

a) tert-Butyl 3-cyclohexylmethylcarbazate

10.2 g (45.1 mmol) of cyclohexylcarbaldehyde tert-butoxycarbonylhydrazone, dissolved in 400 ml of methanol, are hydrogenated in the presence of 5.1 g of 5% platinum on carbon at a temperature of

- 232 - room at a hydrogen pressure of 400 kPa. After completion of the reaction, the catalyst was filtered off and the filtrate was evaporated. The residue was dissolved in methylene chloride and washed with water. After evaporation of the organic phase, the title compound is obtained which is a colorless gum. 1 H-NMR (200 MHz, CDCl 3): 6.1 (broad singlet, 1H), 3.9 (broad singlet, 1H), 2.65 (d, 2H), 1.8 - 0.75 (m (11H), 1.45. (s, 9H) ppm, t _Ret (I) = 32.0 min, _Rf (E) = 0.75.

b) cyclohexylcarbaldehyde tert-butoxycarbonylhydrazone

A solution of 10.8 g (81.2 mmol) of tert-butylcarbazate and 10.1 g (90 mmol) of cyclohexylcarbaldehyde in 400 ml of ethanol was refluxed for 2 hours. Finally, half the solvent was distilled off and the title compound was precipitated by the addition of water. The obtained substance is further used directly in step a).

Example 5

H- (L) -Va1- [Phe ^NN Phe] <- / (L) -Val / -H.3HCl

A solution of 40 mg (0.06 mmol) of Boc- (L) -Val- [Phe ^NN Phe] < - &gt; / (L) -Val / -Boc from Example 3 in 4 ml of 4N hydrogen chloride in dioxane was stirred at room temperature. for 1 hour. The reaction mixture was then diluted with dioxane and lyophilized to give the title compound as the hydrochloride salt. FAB-MS: (M + H) ⁺ = 484, t _Ret (II) = 25.8 min, _Rf (A) 0.45.

Example 6

N-Thiomorpholinocarbonyl- (L) -Val- [Phe ^^ Phe] <- (N-thiomorpholinocarbonyl- (L) -Val)

233

A solution of 20 mg (0.03 mmol) of H- (L) -Val- [Phe ^NN Phe] < - &gt; / (L) -Val / -H trihydrochloride from Example 5 in 0.5 ml of dimethylformamide was gradually added to room temperature at room temperature. contact with 3 5 μ1. (Ο, 25 mmol) of triethylamine a.16. mg (0.1 mmol) of (4-thiomorpholinylcarbonyl) chloride and stirred at room temperature for 1 hour. The reaction mixture was diluted with chloroform a. then wash with saturated sodium bicarbonate solution. The organic phase is filtered through cotton wool, evaporated and the residue is chromatographed on silica gel using a mixture of chloroform and methanol with a variable ratio of from 15: 1 to 8: 1. Product containing fractions were evaporated and precipitated with a mixture of methylene chloride and diisopropyl ether. After lyophilization from dioxane, the title compound is obtained as a flocculent solid. FAB-MS: (M + H) ⁺ -742, t _Ret (I) = 21.6 min, _Rf (D) = 0.54.

The starting substance is produced as follows:

a) (4-Thiomorpholinylcarbonyl) chloride

A solution of 10 g (97 mmol) of thiomorpholine in 200 ml of toluene was added dropwise at 0 ° C to a solution of 85 ml (165 mmol) of 20% phosgene in toluene and the white suspension was stirred for 1 hour at room temperature. the excess phosgene is removed by introducing nitrogen, the suspension is filtered and. the filtrate was evaporated. The title compound is obtained as a yellow oil. IR (CH ₂ Cl ₂ ): 1735, 1450, 1440, 1405, 1370, 1290, 1180 cm ^-1 .

Example 7

N-Morpholinocarbonyl- (L) -Val- [Phe ^NN Phe] <- (N-morpholinocarbonyl- (L) -Val)

A solution of 100 mg (0.25 mmol) of H- [Phe ^NN Phe] -H trihydrochloride from Example 2a, was prepared. 16-3 mg (0.76 mmol) of N-morpholinocarbonyl- (L) -valine and 288 mg (0.76 mmol) of O-benztriazol-1-yl. '. · ... 234th

The N, N, N ', N'-tetramethyluronium hexafluorophosphate in 2 ml of dimethylformamide was contacted with 210 μΐ (1.52 mmol) of triethylamine and stirred at room temperature for 16 hours under a nitrogen atmosphere. The reaction mixture was completely evaporated. the residue was dissolved in methylene chloride and washed with saturated sodium bicarbonate solution. The organic phase is filtered through cotton wool. Evaporate and chromatograph on silica gel using methylene chloride / methanol (15: 1). The title compound is precipitated from a mixture of methylene chloride and hexane and lyophilized from a mixture of dioxane and tert-butanol to give a flocculent solid. FAB-MS: (M + H) ⁺ = 710, the third ^ ^{1) = 16 "3 minutes" Rf <E)} = 0.16.

The starting compound is prepared as follows:

a) N-Morpholinocarbonyl- (L) -valine

2.7 g (8.4 mmol) of N-morpholinocarbonyl- (L) -valine benzyl ester are dissolved in 75 ml of ethyl acetate and hydrogenated in the presence of 500 mg of 10% palladium on charcoal under 100 psi of hydrogen at room temperature for 3 hours. . The catalyst was filtered off and the solvent was evaporated to give the title compound as a colorless oil. 1 H-NMR (300 MHz, CD ₃ OD): 4.15 (m, 1H), 3.65 (m, 4H), 3.40 (m, 4H), 2.12 (m, 1H) 0.95 (2d, 6H) ppm.

b) N-Morpholinocarbonyl- (L) -valine benzyl ester

A solution of 4 g (10.5 mmol) of (L) -valine benzyl ester 4-toluenesulfonate in 56 ml of methylene chloride was treated with 0.8 ml (8.1 mmol) of (morpholinocarbonyl) chloride (see J. Med. Chem. 31 for preparation). , 2277 (1988)) and 4.1 ml (24.1 mmol) of N-ethyldiisopropylamine and stirred at room temperature for 24 hours. The reaction mixture was diluted with ethyl acetate and washed sequentially with 1N hydrochloric acid, water, saturated

235 sodium bicarbonate and saturated sodium chloride solution. The organic phase is dried over sodium sulphate and evaporated. Chromatography on silica gel with ethyl acetate as eluent gave N-morpholinocarbonyl- (L) -valine benzyl ester as a colorless oil. The ester was used immediately in step a).

Example 8.

Phenylacetyl- (L) -Val- [Phe ^NN Phe] - (N-phenylacetyl- (L) -Val)

Analogous to Example 7, 100 mg (0.25 mmol) of the H- [Phe ^NN Phe] -H trihydrochloride of Example 2a was obtained, 143 mg (0.61 mmol) of phenylacetyl- (L) -valine (see Mem for preparation). Tokyo Univ. Agric., 20, 51 (1978)), 230 mg (0.61 mmol) of O-benztriazol-1-yl-Ν, Ν, Ν ', N'-tetramethyluronium hexafluorophosphate and 200 μΐ (1.42 mmol) triethylamine after chromatographic purification using a 20: 20: 1 mixture of methylene chloride, ether and methanol and lyophilization from a mixture of dioxane and tert-butanol of the title compound. FAB-MS: (M + H) ⁺ = 720, t _Ret (I) = 23.7 ^{rain "R} f ^(G) = ° '· ²¹

Example 9

N- (3-Pyridylacetyl) - (L) -Val- [Phe ^NN Phe] - (N- (3-pyridylacetyl) - (L) -Val)

Analogously to Example 7, 100 mg (0.25 mmol) of H- [Phe ^N 1 -Phe] -H trihydrochloride from Example 2a was obtained, 567 mg (1.52 mmol) of O-benztriazol-1-yl-N, N , N ¹ , N ¹ -tetramethyluronium hexafluorophosphate, 358 mg (1.52 mmol) of N- (3-pyridylacetyl) - (L) -valine and 316 µl (2.3 mmol) of triethylamine after chromatographic purification using a 5: 1 mixture of chloroform and methanol; and lyophilization from a mixture of dioxane and tert-butanol, the title compound as a white solid. FAB-MS: M + H) ⁺ = 720, t _Ret (II) = 27.9 min, _Rf (A) = 0.71.

236

The starting compound is prepared as follows:

(a) N- (3-Pyridylacetyl) - (L) -valine

3.4 g of N- (3-pyridylacetyl) - (L) -valine tert-butyl ester are dissolved in 20 ml of a mixture; trifluoroacetic acid with methyl chloride in a ratio of 1: 1 and stirred at room temperature for 16 hours. The reaction solution was completely evaporated and the residue was digested with diisopropyl ether. The title compound is obtained as a white amorphous solid. 1 H-NMR (200 MHz, CD 3 OD) δ: 8.9-8.6 (broad multiplet, 1H), 8.5 (m, 1H), 7.95 (m, 1H), 4.33 (m, 1H), 3.93 (s, 2H), 2.2 (m, 1H), 0.98 (2d, 6H) ppm.

b) N- (3-Pyridylacetyl) - (L) -valine tert-butyl ester

To a solution of 3.36 g (16 mmol) of (L) -valine tert-butyl ester hydrochloride, 2 g (14.5 mmol) of 3-pyridylacetic acid and 2.17 ml (14.3 mmol) of cyanophosphonic acid diethyl ester in 20 ml. . 4.2 ml of triethylamine are added dropwise at 0 ° C. The reaction mixture was stirred at room temperature for 48 hours and then diluted with methylene chloride and washed with 10% citric acid as well as saturated sodium bicarbonate solution. The organic phase is filtered through cotton wool and the solvent is evaporated to give N- (3-pyridylacetyl) - (L) -valine tert-butyl ester which is used immediately in step a).

Example 10

Boe- (L) -Val- [Phe ^NN Cha] <- / (L) -Val / -Boc

In a similar manner to Example 7, starting from 500 mg (1.25 mmol) of H- [Phe ^NN Cha] -H trihydrochloride,

237 1.08 (4.98 mmol) of Boe- (L) -valine, 1.89 g (4.98 mmol) of O-benztriazol-1-yl-N, N, N ', N'-tetramethyluronium hexafluorophosphate and 1, 39 ml (9.96 mmol) of triethylamine, after chromatographic purification. on silica gel using a mixture of methylene chloride and ether. in a 1: 1 ratio and lyophilization from dioxane, the title compound consisting of a flaky solid. FAB-MS: (M + H) ⁺ = 690, t _Ret (I) = 29.3 min, _Rf (H) = 0.48. . .

The starting compound is prepared as follows:

a) H- [Phe ^NN Cha] -H 3 HCl

1.10 g (2.2 mmol) of Boe- [Phe ^Ni Cha] -Boe from Example 4 were dissolved in 20 ml of 4N hydrogen chloride in dioxane and stirred at room temperature for 3 hours. After lyophilization of the reaction mixture, the title compound is obtained as the hydrochloride. FAB-MS: (M + H) &lt; ^{+ &gt}; = 292, t _Ret (II) = 27.3 min.

Example 11

Z- (L) -Val- [Phe ^NN Cha] - (L) -Val / -Z

Analogously to Example 2, from 50 mg (0.12 mmol) of H- [Phe ^NN Cha] -H trihydrochloride from Example 10a, 94 mg (0.37 mmol) of Z- (L) -valine, 165 mg (0) were obtained. , 37 mmol) of benztriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, 51 mg (0.37 mmol) of O-benztriazol-1-yl-N, N, N ', N'-tetramethyluronium hexafluorophosphate and 2.5 ml of 0.3 molar N-methylmorpholine in dimethylformamide, after chromatography on silica gel using a 1: 1 mixture of methylene chloride and ether and lyophilization from dioxane, the title compound. FAB-MS: (M + H) ⁺ = 758, t _Ret (I) = 29.1 min, _Rf (H) = 0.55.

Example 12

238

Boe- [Phe ^NN Leu] -Boe

Similar jakov Example 1, when starting from 1.0 i.e. (3.8 mmol) of (2 R) - (1 '(S) -Boc-amino-2 -fenylethoxy ¹⁾ oxirane and 715 mg' (3, 8 mmol) of tert-butyl 3-isobutylcarbazate (production of visas by J. Chem. Soc., Perkin I, 1712 (1975)), the title compound which, after treatment with hexane, is in the form of a precipitate. FAB-MS: (M + H) ⁺ = 452, t _Re ^. (I) = 27.2 min, _Rf (L) = 0.55.

Example 13

Z- (L) -Val- [Phe ^NN Leu] <- / (L) -Val / -Z

- Similar to Example 2, starting from 60 mg (0.17 mmol) of H- [Phe ^NN Leu] -H trihydrochloride, 125 mg (0.50 mmol) of Z- (L) -valine, 221 mg (0.50 mmol) of benztriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, 67 mg (0.50 mmol) of 1'-hydroxybenztriazole and 3.3 ml of 0.3 molar N-methylmorpholine in dimethylformamide, after chromatography on Silica gel, eluting with methylene chloride / ether (1: 1) and freeze-drying from dioxane, title compound. FAB-MS: (M + H) ⁺ = 718, tpetd) ⁼ 26.8 min, _Rf (H) = 0.38.

The starting compound is prepared as follows:

a) H- [Phe ^NN Leu] -H 3 HCl

Analogously to Example 10a, the title compound, as a lyophilisate, was obtained from 1.21 g (2.48 mmol) of Boe- [Phe ^NN Leu] -Boe from Example 12. FAB-MS: (M + H) ⁺ = 252, t _Ret (II) = 20.9 min, _Rf (C) = 0.23.

Example 14

239

Η- (L) -Val- [Phe ^NN Cha] <- / (L) -Val / -H.3HCl

Analogously to Example 10a, the title compound is obtained from 632 mg (0.91 mmol) of Boe- (L) -Val- [Phe-Cha] - [(L) -Val] -Boc from Example 10 after lyophilization, which is in the form of the hydrochloride. FAB-MS: (M + H) ⁴ '= 490, t _Ret (II) = · ...

29.4 min, R _f (K) = 0.23.

Example 15

N- (3-Pyridylacetyl) - (L) -Val- [Phe ^NN Leu] - (N- (3-pyridylacetyl) - (L) -Val)

Analogous to Example 9, starting from 90 mg (0.25 mmol) of H- (Phe ^^ Leu] -H trihydrochloride from Example 13a), 358 mg (1.52 mmol) of N- (3-pyridylacetyl) - (1) -valine, 576 mg (1.52 mmol) of O-benztriazol-1-yl-N, N, N ', N'-tetramethyluronium hexafluorophosphate and 316 μΐ (2.5 mmol) of triethylamine after chromatographic purification using a mixture of methylene chloride and methanol in ratio of 15: 1 and lyophilization from a mixture of dioxane, tert-butanol and water, the title compound FAB-MS: (M + H) ⁺ = 688, ^fc Ret ^{(IV) = 15} ' ^{5 min} ' ^R f (° ) ⁼ 0.37.

Example 16

N-Trifluoroacetyl- [Phe ^RN (pF) Phe] -Boe

A solution of 4.0 g (15.4 mmol) of 2 (R) - 1 '(S) - (trifluoroacetylamino) -2'-phenylethyl / oxirane and 3.89 g (16.2 mmol) of tert-butyl-3- of (p-fluorophenylmethyl) carbazate in 35 ml of methanol was added. It is heated to 80 ° C for approximately 20 hours in a pressure tube. The reaction mixture was evaporated, the residue was dissolved in dichloromethane and the title compound precipitated from solution, working with hexane (in a refrigerator). Next for

240 product gave column chromatography (silica gel, methylene chloride / ether 95: 7). DC: R f (J) = 0.57, t _Ret (I) = 24.3 min, FAB-MS: (M + H) ⁺ = 500.

The starting compound is prepared as follows:

a) N-3 (S) - (Boc-amino) -2 (R, S) -hydroxy-4-phenyl-1-trimethylsilylbutane

Under a nitrogen atmosphere, 24.7 g (1.02 mol) of magnesium are introduced into 100 ml of absolute ether, and a small amount of iodine is added over 35 minutes, while 132.5 ml (0.95 mol) of chloromethyltrimethylsilane and 300 ml of ether are added. is maintained at 38 ° C with an ice bath. The resulting reaction mixture was then stirred at room temperature for 90 minutes. After cooling to -60 ° C, a suspension of 48.6 was added over 40 minutes. g (0.195 mol) of N-Boc-phenylalaninal (for preparation see DJ Kempf, J. Org. Chem. 51, 3921 (1986)) in 1100 ml of ether. The reaction mixture is heated to room temperature for 90 minutes and stirred at this temperature for a further 90 minutes. The reaction mixture was then quenched. is poured into 2 liters of water and 1.5 liters of 10% aqueous citric acid. The separated aqueous phase is extracted twice with 500 ml of ether each time. The two ether extracts were washed with 500 ml of 10% citric acid and twice with saturated sodium chloride solution. After drying over sodium sulfate, evaporation under reduced pressure is carried out and the title compound obtained is used without further purification. DC: R f (L) = 0.6, FAB-MS: (M + 1 H) ⁺ = 338.

b) 1-Phenyl-3-butene-2 (S) -amine

A solution of 18.8 g (0.055 mol) of 3 (S) - (Boc-amino) -2 (R, S) -hydroxy-4-phenyl-1-trimethylsilylbutane in 420 ml of methylene chloride was stirred at 5 ° C for 10 minutes. contact with 35.6 ml (0.28 mol) of an approximately 48% solution of boron trifluoride in ether.

- 241

The reaction mixture was then stirred for 16 hours at room temperature, cooled to 10 ° C and contacted with 276 ml of 4N sodium hydroxide solution over 20 minutes. The aqueous phase was separated and extracted twice with 400 ml of methylene chloride each time. The combined organic extracts were washed with saturated brine and dried over sodium sulfate. The compound named in; The title is used without additional cleaning. TLC: _Rf (C) = 0.15 IR (methylene chloride): 3370, 3020, 2920, 1640, 1605 cm ^1st

c) N-Trifluoroacetyl-1-phenyl-3-butene-2 (S) -amine

11.9 g (81 mmol) of 1-phenyl-3-buten-2 (S) -amine are dissolved in 20 ml of methylene chloride and 70 ml of pyridine and treated dropwise with 17.0 ml (121 ml) at 0 ° C. mmol) of trifluoroacetic anhydride. After stirring for 30 minutes at 0 ° C, the reaction mixture is extracted twice with dilute hydrochloric acid, water and saturated sodium chloride solution. The aqueous phase was washed twice more with methylene chloride, dried over sodium sulfate and evaporated. DC: Rf (M) = 0.4.

d) 2 (R) - / 1 '(S) - (Trifluoroacetylamino) -2 ^1- phenylethyl / oxirane, Solution 14.5 g (60 mmol) of N-trifluoroacetyl-1-phenyl-3-butene-2 (S) of amine in 600 ml of chloroform was added to 54.28 g (314 mmol) of m-chloroperbenzoic acid and stirred at room temperature for 24 hours. The reaction mixture was washed twice with 10% sodium sulfite solution, twice with saturated sodium carbonate solution, water and saturated sodium chloride solution. The aqueous phases are extracted twice more with methylene chloride, the combined organic phases are dried over sodium sulphate and evaporated. This affords the title compound, which is used without further purification in the next step. TLC: R _f (N) = 0.6.

e) tert-Butoxycarbonylhydrazone of p-fluorophenylcarbaldehyde

- 242 -

Analogous to Example 4b, 32 g (242 mmol) of tert-butylcarbazate and 30 g (242 mmol) of p-fluorobenzaldehyde in 300 ml of ethanol at 80 ° C are reacted for 3 hours to give the title compound which, upon cooling and dilution The reaction mixture crystallizes with water. DC: Rf (N) = 0.48. t _Ret (I) = 19.4 min;

f) tert-Butyl-3- (p-fluorophenylmethyl) carbazate

Analogously to Example 4a, 55 g (231 mmol) of t-butoxycarbonylhydrazone of p-fluorophenylcarbaldehyde in 500 ml of tetrahydrofuran are hydrogenated in the presence of 5.5 g of 5% palladium on charcoal to give the title compound. ¹ H-NMR (200 MHz, CD ₃ OD): 7.35 (dd, 8 and 6 Hz, 2H), 7.05 (t, 8 Hz, 2H), 3.9 (s, 2H), 1, 45 (s, 9H) ppm.

Example 17

N-Morpholinocarbonyl- (L) -Val- [Phe ^NN (pF) Phe] -Boe

A mixture of 185 mg (0.80 mmol) of N-morpholinocarbonyl- (L) -valine (for preparation see Example 7a), 270 mg. (0.67 mmol)

H- [Phe-N (pf) phe] -Boe, 311 mg (0.70 mmol) · benztriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate and 95 mg (0.70'mol) of 1'-hydroxybenzotriazole at room temperature, dissolved in 6.8 ml of a 0.3 molar solution of N-methylmorpholine in dimethylformamide and stirred at room temperature for 5 hours. The reaction mixture was evaporated under high vacuum and the residue was partitioned between 4 parts methylene chloride, 2 parts 1 M sodium carbonate solution, water and saturated sodium chloride solution. The combined organic phases dried over sodium sulfate were evaporated and purified by column chromatography (silica gel, ethyl acetate as eluent). DC: R t (O) = 0.38, t R _e (I) = 21.8 min, FAB-MS: (M + H) ⁺ = 616.

243

The starting compound is prepared as follows:

a) H - [Phe ^NN (pF) Phe] -Boc

0.3 g (0.6 mmol) of N-trifluoroacetyl- [Phe ^NN (pF) Phe] -Boc was added to the solution at 70 ° C. (production see Example 16) in 50 ml of methanol dropwise under a nitrogen atmosphere 15 ml of 1M potassium carbonate solution and stirred for 25 hours at this temperature. The reaction mixture was evaporated under high vacuum, the residue was mixed with methylene chloride and washed twice with water and saturated sodium chloride solution. The aqueous phase is extracted twice with methylene chloride, the organic phases are dried over sodium sulphate and evaporated. The crude material was used in the next step without further purification. t _R t (I) = 16.2 min.

Example 18

N-Morpholinocarbonyl- (L) -Val- [Phe ^NN (pF) Phe] <- / (L) -Val / -Z

A solution of 86 mg (0.34 mmol) of Z- (L) -Val and 160 mg (0.31 mmol) of N-morpholinocarbonyl- (L) -Val- [Phe ^ ^R (pF) Phe] -H in 2.7 ml of a 0.25 molar solution of N-methylmorpholine in acetonitrile (0.25 mol of N-methylmorpholine in acetonitrile) was contacted with 129 mg (0.34 mmol) of O-benztriazol-1-yl-N, N, N ' , N'-tetramethyluronium hexafluorophosphate ^. The reaction mixture was allowed to stand at room temperature for 4 hours and the residue was partitioned between 3 parts of methylene chloride, 2 parts of saturated sodium bicarbonate solution and saturated sodium chloride solution. Drying of the organic phase with sodium sulfate and evaporation affords the title compound which is pure after digesting from a 1: 1 mixture of methylene chloride and ether. DC: R _f (P) = 0.4, t _{R e} (I) = 22.4 min, FAB-MS: (M + H) ⁺ = 749.

- 244 The starting compound is prepared as follows:

a) N-Morpholinocarbonyl- (L) -Val- [Phe ^NN (pF) Phe] -H

210 mg (0.34 mmol) of N-morpholithiocarbonylo

(L) -Val- [Phe ^NN (pF) Phe] -Boc (Example 17) is dissolved in 105 ml of mrayenic acid and stirred. at room temperature for 4 hours. The solvent was then evaporated, the residue was taken up in methylene chloride and the solution was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. Extraction of the aqueous phases with 2 parts of methylene chloride, drying of the organic phases with sodium sulfate and evaporation affords the title compound which is used without further purification in the next reaction step. t _Ret (I) = 12.9 mins.

Example 19

N-Morpholinocarbonyl- (L) -Val- [Phe ^NN (pF) Phe] - / (L) -Val / -H

160 mg (0.21 mmol) of N-morpholinocarbonyl- (L) -Val- [Phe ^NN (pF) Phe] - / (L) -Val / -Z (Example 18) at 6 are hydrogenated under normal pressure. ml of ethanol in the presence of 40 mg of 10% palladium on carbon. After filtration through Celite® (Kieselguhr, filter aid from Fluka, Buchs, Switzerland), evaporation and lyophilization from dioxane, the title compound is obtained. t _Ret (hydrochloride, 1) = 13.4 min, FAB-MS: (M + H) ⁺ = 615.

Example 20 »

N-Morpholinocarbonyl- (L) -Val- [Phe ^NN (pF) Phe] <- / (L) -Val / <- / N-Morpholinocarbonyl-Gly /

A solution of 26.9 mg (0.143 mmol) of N-morpholinocarbonylglycine and 80 mg (0.130 mmol) of N-morpholinocarbonyl-245 - (L) -Val- [Phe ^NN (pF) Phe] <- / (L) -Val] - H in 1.1 ml of O, 25-molar N-methylmorpholine in acetonitrile was contacted with 54 mg (0.143 mmol) of O-benztriazol-1-yl-N, N, N ', N'-tetramethyluronium hexafluorophosphate and stirred for 16 hours at room temperature. The reaction mixture was evaporated and the residue partitioned between 3 parts ethyl acetate, water, 2 parts saturated sodium bicarbonate solution, water and saturated sodium chloride solution. Drying of the organic phase with sodium sulfate and evaporation affords the title compound which, when dissolved in a small amount of dimethylformamide, is precipitated with diisopropyl ether as a pure material. Thin layer chromatography: t _Ret (I) = 15.1 min, FAB-MS: (M + H) ⁺ = 785.

The starting compound is prepared as follows:

(a) N-morpholinocarbonylglycine benzyl ester

Analogous to Example 7b, 7.69 g (22.3 mmol) of glycine benzyl ester 4-toluenesulfonate and 2.8 g (19 mmol) of (morpholinocarbonyl) chloride in 118 ml of methylene chloride and 9 ml (53 mmol) of N-ethyldiisopropylamine are reacted. for 18 hours. After extraction with methylene chloride and digestion with hexane, the title compound precipitates pure. t _Ret (.I) = 11.6 min.

b) N-Morpholinocarbonylglycine

Analogously to Example 7a, 4.8 g (18.3 mmol) of N-morpholinocarbonylgyltin benzyl ester in 100 ml of ethyl acetate are hydrogenated in the presence of 1 g of 10% palladium on carbon to give the title compound. ¹ H-NMR (300 MHz, CDCl ₃ ): 3.88 (S, 2H), 3.64 (s, 4H), 3.50 (s, 2H), 3.35 (s,

4H) ppm.

|

Example 21

246 Z- (L) -Val- [Phe ^NN (pF) Phe] -Boe

Solution. 3.35. mg (1.33 mmol) of Z- (L) -Val and 448 mg (1.11 mmol) of H- [Phe ^NN (pF) Phe] -Boe (production see Example 17a) in 9.4 ml of 0.25- molar N-methylmorpholine in acetonitrile (0.25 mol of N-methylmorpholine in acetonitrile). shall be contacted with. 463 mg (1.22 mmol) of O-benzotriazol-1-yl-N, N, N ', N' - tetramethyluronium hexafluorophosphate. After stirring at room temperature for 16 hours, the reaction mixture was evaporated and the residue was partitioned between 3 parts methylene chloride, 2 parts saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase was dried over sodium sulfate and evaporated to give the title compound which was purified by column chromatography (silica gel, hexane / ethyl acetate varying from 4: 1 to 1: 1). t _R t = (I) = 26.6 min, FAB-MS: (M + H) ⁺ = 637.

Example 22

Z- (L) -Val- [Phe ^NN (pF) Phe] <- / (L) -Val / -Boc

Analogous to Example 18, 165 g (0.76 mmol) of Boc- (L) -Val and 371 mg (0.69 mmol) of Z- (L) -Val- [Phe ^NN (pF) Phe] -H were reacted. in 6 ml of 0.25 molar N-methylmorpholine in acetonitrile with 289 mg (0.76 mmol) of O-benzotriazol-1-yl-N, N, N ', N'-tetramethyluronium hexafluorophosphate, to a compound which crystallizes directly from the reaction mixture and can be filtered off. t _Ret (I) = 27.2 min, FAB-MS: (M + H) &lt; ^{+ &gt}; = 736.

The starting compound is prepared as follows:

a) Z- (L) -Val- [Phe ^NN (pF) Phe] -H

Analogous to Example 18a, the protector was removed to 440 mg (0.69 mmol) of Z- (L) -Val- [Phe] (pF) Phe] -Boe by treating with 212 mL of formic acid to give the title compound. . ~ 17.8 min.

Example 23

Z- (L) -Val- [Phe ^NN (pF) Phe] <- / (L) -Val / -H

Similar to Example 18a, the protecting group is removed from 250 mg (0.34 mmol) of Z- (L) -Val- (Phe ^NN (pF) Phe] <7 (L) -Val / -Boc (Example 22) by treatment with 50 mL of formic acid to give the title compound t _Ret (I) = 18.0 min, FAB-MS: (M + H) ⁺ = 636.

Example 24

Z- (L) -Val- (Phe ^Nfi (pF) Phe] <- / (L) -Val / <- / N-morpholinocarbones 1-Gly)

Analogously to Example 20, 32 mg (0.17 mmol) of N-morpholinocarbonylglycine (Example 20b) and 99 mg (0.16 mmol) of Z- (L) -Val- [Phe ^NN (pF) Phe] <- / ( L) -Val / -H in 1.3 ml of 0.25 molar N-methylmorpholine in acetonitrile was treated with 65 mg (0.17 mmol) of O-benztriazol-1-yl-N, N, N ', N ¹ -tetramethyluronium hexafluorophosphate to give the title compound, which crystallizes directly from the reaction solution. t _Ret (I) = 21.1 min, FAB-MS: (M + H) &lt; ^{+ &gt}; = 806.

about

Example 25

Z- (L) -Asn- [Phe ^NN (pF) Phe] -Boe

To a solution of 2.09 g (5.2 mmol) of H- [Phe ^N 1 - (pF) Phe] -Boc (for preparation see Example 17a) in 68 ml of dimethylformamide and 2.7 ml (16 mmol) of N-ethyldiisopropylamine was added 3.times. 0 g (7.8 mmol)

8- (L) -asparagine p-nitrophenyl ester (Bachem, Bubendorf, Switzerland). The reaction mixture is stirred for 16 hours at room temperature, then evaporated under high vacuum, the residue taken up in large quantities with methylene chloride (because it is poorly soluble) and washed with 2 portions of 5% potassium carbonate solution. The aqueous phases are extracted twice more with methylene chloride, the combined organic phases are dried over sodium sulphate and evaporated. Thereafter, the crude product is dissolved in a small amount of methanol and precipitated by the addition of toluene at -20 ° C to give the title compound. t _Ret (I) = 21.2 mins.

Example 26

H- (L) -Asn- [Phe ^NN (pF) Phe] -Boe

Analogously to Example 19, 0.40 g (0.61 mmol) of Z- (L) -Asn- [Phe ^NN (pF) Phe] -Boc in 20 mL of methanol was hydrogenated to give the title compound. t _Ret (I) = 14.9 mins.

Example 27

Quinoline-2-carbonyl- (L) -An- [Phe ^NN (pF) Phe] -Boe

Analogously to Example 17, 134 mg (0.78 mmol) of quinoline-2-carboxylic acid (Fluka, Buchs, Switzerland) were reacted in 4 ml of 0.3 molar N-methylmorpholine in dimethylformamide with 344 mg (0.78 mmol). ) benztriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, 105 mg (0.78 mmol) of 1'-hydroxybenztriazole and 268 mg (0.52 mmol) of H- (L) -Asn- [Phe ^NN (pF) Phe] -Boe. Since H- (L) -Asn- [Phe ^NN (pF) Phe] -Boc is still present after 16 hours of stirring at room temperature, 299 mg of benztriazol-1-yloxy-tris (dimethylamino) is added once more. ) phosphonium hexafluorophosphate, 70 mg 1'-hydroxybenztriazole, 89 mg quinaldic acid and 113 μΐ N-methylmorpholine 249 L. After a further 16 hours, the reaction mixture was evaporated and the residue was partitioned between 3 parts methylene chloride, 2 parts saturated sodium bicarbonate solution and saturated sodium chloride solution. The combined organic phases were dried over sodium sulfate and evaporated. The crude material was dissolved in a small amount of dimethylformamide, precipitated with diisopropyl ether and cooled to 20 ° C. gets compound after named in. title. t _R t (I) = 22.8 min, FAB-MS: (M + H) ⁺ = 673.

Example 28

Z- (L) -Asn- (Phe ^NN (pF) Phe) - / (L) -Val / -Z mg (0.35 mmol) Z- (L) -Val in 3.8 ml 0.3- of normal N-methylmorpholine in dimethylformamide was activated with 153 mg (0.35 mmol) of benztriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate and 47 mg (0.35 mmol) of 1'-hydroxybenztriazole and after 15 minutes reacted with 144 mg (0 Z- (L) -Asn- [Phe (R) (pF) Phe] -H dihydrochloride is stirred for 14 hours at room temperature, then evaporated, the residue is dissolved in 2 ml of methanol and partitioned between 3 parts of methylene chloride and 2 parts of sodium carbonate solution, the organic phase is dried over sodium sulfate and evaporated, repeatedly redissolving the crude material in a small amount of dimethylformamide and precipitating with diisopropyl ether gives the title compound t _Ret (I) = 22.2 min, FAB-MS : (M + H) &lt; ^{+ &gt}; = 785.

The starting compound is prepared as follows:

a) Z- (L) -Asn- [Phe ^NN (pF) Phe] -H.2HCl

A solution of 150 mg (0.23 mmol) of Z- (L) -Asn- [Phe (R) (pF) Phe] -Boe (Example 25) in 1 ml of dioxane was treated with 2 ml of 4-normal hydrogen chloride under a nitrogen atmosphere. in dioxane (Fluka, Buchs, Switzerland). After 90 minutes at room temperature

250 µl of the reaction mixture was lyophilized and the lyophilisate was immediately reacted.

• · ABOUT

Example 29

Trifluoroacetyl- [Phe ^NN (pF) Phe] < - &gt;

In analogy to Example 17, 239 mg (0.95 mmol) of Z- (L) -Val in 10.5 ml of 0.3 molar N-methylmorpholine in dimethylformamide were reacted with 421 mg (0.95 mmol) of benztriazole-1. -yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, 129 mg (0.95 mmol) of 1'-hydroxybenztriazole and 0.3 g (0.3 mmol) of N-trifluoroacetyl- [Phe ^NN (pF) Phe] -H for 15 hours . Column chromatography (silica gel, methylene chloride / ether 10: 1), and precipitation from dimethylformamide solution by treatment with diisopropyl ether gave the title compound;

in the title. R _f (Q) = 0.15, t _Ret (I) = 25.9 min, FAB-MS: (M +

H = ⁺ 633.

The starting compound is prepared as follows:

a) N-Trifluoroacetyl- [Phe ^NN (pF) Phe] -H

0.20 g (0.40 mmol) was contacted at 0 ° C.

N-trifluoroacetyl- [PheNN (pF) Phe] -Boc (production see Example 16) in 5 ml methylene chloride with 5 ml trifluoroacetic acid. The reaction mixture was stirred for 4 hours at 0 ° C and 2 hours at room temperature, then the reaction mixture was evaporated. Lyophilization of the residue from dioxane affords the title compound which is reacted further without further purification. t _Ret (I) = 14.7 min.

Example 30

I

Z- (L) -Ans- [Phe ^NN (pF) Phe] -Boe

251

Analogously to Example 25, 167 mg (0.34 mmol) of H- [Phe ^NN Phe] -Boe in 3.6 ml of dimethylformamide and 0.18 ml (1 mmol) of N-ethyldiisopropylamine were reacted with 0.20 g (0) of the title compound. 52 mmol) of Z- (L) -asparagine p-nitrophenyl ester to give the title compound which was purified after column chromatography (silica gel, ethyl acetate). DC: _Rf (H) = 0.19.

^t Ret ( ^I ) ^{= 20} > ⁹ minThe starting compound is prepared as follows:

a) N-Trifluoroacetyl- [Phe ^NN Phe] -Boc

Analogously to Example 16, 1.82 g (7.0 mmol) of 2 (R) - / 1 '(S) - (trifluoroacetylamino) -2'-phenylethyl / oxirane (Example 16d) and 1.58 g ( 7.1 mmol) of tert-butyl 3-benzylcarbazate (J. Chem. Soc., Perkin I, 1712 (1975)) in 15 ml of methanol in a pressure tube to give the title compound, which is isolated by column chromatography (silica gel, 50: 1 mixture of methylene chloride and ether). DC: R f (J) = 0.38, t _Ret (I) = 24.5 min.

b) H- [Phe ^NN Phe] -Boc

Analogously to Example 17a, 258 mg (0.53 mmol) of N-trifluoroacetyl- [Phe ^NN Phe] -Boe in 60 mL of methanol was reacted with 10.7 mL of 1M potassium carbonate solution to give the title compound.

Example 31

Z- (L) -Val - [(pF) Phe ^{N N} (pF) Phe] -Boc

As in Example 21, 18 mg (0.070 mmol) of Z- (L) -Val and 27 mg (0.064 mmol) were reacted.

252

H - [(pF) Phe ^NN (p-F) Phe] -Boc in 0.6 ml of 0.25 molar N-methylmorpholine in acetonitrile with 26.6 mg (0.070 mmol) of O-benztriazol-1-yl-N N, N ', N'-tetramethyluronium hexafluorophosphate to give the title compound which was purified by dissolving in a small amount of methylene chloride and precipitating with diisopropyl ether. FAB-MS: (M + H) &lt; ^{+ &gt}; = 655.

The starting compound is prepared as follows:

a) N-Boc- (p-fluorophenylalanine) t

20 g (109 mmol) of p-fluorophenylalanine (Fluka, Buchs, Switzerland) were reacted in 400 mL of a 1: 1 dioxane / water mixture with 35.5 g (163 mmol) of Boc-anhydride and 150 g (1.09) mol) of potassium carbonate. After 4 hours the reaction mixture was acidified with citric acid solution and extracted with 3 parts ethyl acetate. The organic phases were washed with 10% citric acid, water and saturated sodium chloride solution and evaporated. Dissolution of the residue in a small amount of methylene chloride and crystallization by addition of hexane affords the title compound. t _Ret (I) = 1 min, 9 min.

b) N-Boc- (p-fluorophenylalaninol)

A solution of 17.9 g (63 mmol) of N-Boc- (p-fluorophenylalanine) in 73 ml of absolute tetrahydrofuran with 9.66 ml (69 mmol) of triethylamine is added at -5 to -10 ° C and the solution is added dropwise. 9.05 ml (69 mmol) of isobutyl chloroformate in 44 ml of absolute tetrahydrofuran. Stir for 30 minutes at room temperature and then separate the precipitate on suction. The filtrate was added dropwise with cooling to 4.77 g (126 mmol) of sodium borohydride in 28 ml of water. The reaction mixture was stirred at room temperature for 4 hours, then acidified with 10% citric acid, the tetrahydrofuran was partially evaporated on a rotary evaporator and the residue was partitioned between 3 parts of ethyl acetate.

253 tu, 2 parts of 2 N sodium hydroxide solution, water, saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase, after drying with sodium sulfate and evaporation, is dissolved in a small amount of methylene chloride and crystallized by the addition of hexane. In this way, a compound is obtained. named in the title. DC: R f (N) = 0.36, t R e = 16.8 min,¹1 H-NMR (200 MHz, CD 3 OD): 7.24 (dd, 8 and 5 Hz, 2H), 6.98 (t, 8 Hz, 2H), 3.73 (m, 1H), 3.47 (d, 5 Hz, 2H), 2.88 (dd, 13 and 6 Hz, 1H), 2.62 (dd, 13 and 8 Hz, 1H), 1.36 (s, 9H) ppm.

c) N-Boc- (p-fluorophenylalaninal)

Under a nitrogen atmosphere, to a solution of 4.0 mL (46.8 mmol) of oxalyl chloride in 44 mL of -60 ° C methylene chloride was added dropwise 4.44 mL (62.4 mmol) of dimethyl sulfoxide dissolved in 76 mL of methylene chloride. After stirring for 15 minutes, a clear reaction solution of 8.4 g (31.2 mmol) of N-Boc- (p-fluorophenylalaninol) as a solution in a mixture of 185 ml of methylene chloride and tetrahydrofuran (1: 1) was added to precipitate a solid. and the mixture is further stirred for 25 minutes. 17.3 ml (124.8 mmol) of triethylamine dissolved in 38 ml of methylene chloride are then added. After stirring for 30 minutes, a solution of 278 ml of 20% potassium hydrogen sulphate solution was added dropwise, followed by 220 ml of hexane. The reaction mixture is allowed to warm to room temperature, the aqueous phase is separated and extracted with 2 parts of ether. The organic phases are washed with saturated sodium bicarbonate solution, water and saturated sodium chloride solution, dried over sodium sulfate and evaporated to give the title compound which is used without further purification in the next step. 1 H-NMR (200 MHz, CDCl ₃ ): 9.63 (s, 1H), 6.9-7.2 (2m, 4H), 5.04 (m, 1H), 4.42 (m, 1H) ), 3.10 (m, 2H), 1.43 (s, 9H) ppm.

d) N-3 (S) - (Bo-amino) -2 (R, S) -hydroxy-4- (p-fluorophenyl) -1-trimethylbutane

254

Analogously to Example 16a, 1.63 &quot;

g (67 mmol) of magnesium in 33 ml of absolute ether with 8.3 ml (60 mmol) of chloromethyltrimethylsilane to the Grignard compound, which can be reacted with 13 mmol of N-Boc- (p-fluorophenylalaninal), is extracted and subjected to column chromatography (silica gel, mixture of hexane and ethyl acetate with variable ratio from 5: 1 to 4: 1). The diastereomeric mixture of the title compound is obtained. DC: R f = 0.32, t _Ret (I) = 24.9 min (22%) / 25.5 min (78%), FAB-MS: (M + H) ⁺ = 356.

e) 1- (p-Fluorophenyl) -3-butene-2 (S) -amine

Analogous to Example 16b, 1.1 g (3.1 mmol) of N-3 (S) - (Boc-amino) -2 (R, S) -hydroxy-4- (p-fluorophenyl) -I- is reacted. trimethylsilylbutane in 22 mL of methylene chloride with 1.9 mL (15.5 mmol) of an approximately 48% solution of boron trifluoride in ether to give the title compound. ¹ H-NMR (300 MHz, CDCl 3): 7.2-7.10 and 7.05-6.9 (2m, 2H each), 5.9-5.8 (m, 1H), 5.2 5.0 (m, 2H), 3.57 (m, 1H), 2.79 (dd, 12 and 6 Hz, 1H), 2.62 (dd, 12 and 8 Hz, 1H), 1.7 (broad singlet, 2H) ppm.

f) N-Trifluoroacetyl-1- (p-fluorophenyl) -3-butene-2 (S) -amine

Analogous to 16c, 364 mg (2.2 mmol) of 1- (p-fluorophenyl) -3-buten-2 (S) -amine in 1.8 ml of methylene chloride and 5.4 ml of pyridine are reacted with 460 μΐ ( 3.3 mmol) of trifluoroacetic anhydride. The title compound is obtained, which precipitates in the pure state by digestion with hexane. TLC: _Rf (F) = 0.58, MS: (M) ⁺ = 261st

g) 2 (R) - 1 '(s) - (Trifluoroacetylamino) -2' - (p-fluorophenyl) ethyl / oxirane

255

Analogously to Example 16d, 359 ml (1.37 mmol) of N-trifluoroacetyl-1- (p-fluorophenyl) -3-buten-2 (S) -amine are oxidized in 9 ml of chloroform by treatment with 1.18 g (6.87 g) mmol) of m-chloroperbezoic acid to the title compound. TLC: R _f (R) = 0.45.

h). N-Trifluoroacetyl - [(pF) Phe ^NN (pF) Phe] -Boe

Analogous to Example 16, 415 mg (1.49 mmol) of 2 (R) - [1 '(S) - (trifluoroacetylamino) -2' - (p-fluorophenyl) ethyl / oxirane and 377 mg (1.57 mmol) were reacted. of tert-butyl 3- (fluorophenylmethyl) carbazate in 9 mL of methanol to give the title compound. DC: R f (S) = 0.53, FAB-MS (M + H) ⁺ = 518, ¹ H-NMR (300 MHz, CD 3 OD): 7.4-7.3 and 7.3-7.2 ( 2m, 2H each, 7.05-6.9 (m, 4H), 4.23 (m, 1H), 3.90-3.65 (m, 3H), 3.03-2.78 and 2 74-2.60 (2m, 2H each), 1.30 (s, 9H) ppm.

i) H - [(pF) Phe] ^NN (pF) Phe] -Boc

Analogous to Example 17a, 285 mg (0.55 mmol) of N-trifluoroacetyl - [(pF) Phe ^NN (pF) Phe] -Boe in 45 ml of methanol are reacted with 14 ml of 1 molar potassium carbonate solution to give. the title compound. t Ret = 16.4 min.

Example 32

Z- (L) -Val - [(pF) Phe ^{N N} (pF) Phe] -H

Analogously to Example 18a, the protecting group was removed from 215 mg (0.33 mmol) of Z- (L) -Val - [(pF) Phe ^N 4 (pF) Phe] -Boc by treatment with 100 ml of formic acid. This gives the title compound. FAB-MS: (M + H) &lt; ^{+ &gt}; = 555.

Example 33

256

Z- (L) -Val - [(pF) Phe ^NN (pF) Phe] - (N- (N- (2-pyridylmethyl) -N-methylaminocarbonyl) - (L) -Val)

Analogously to Example 18, 23.6 g (0.089 mmol) of N- [N- (2-pyridylmethyl) -N-methylaminocarbonyl] - (L) -valine are reacted (for preparation see European Patent No. 402 646 A1, of which of the day

19 December 1990) a. 45 mg (0.081 mmol) of Z- (L) -Val - [(pF) Phe ^NN (pF) Phe] -H with 33.8 mg (0.089 mmol) of O-benztriazol-1-yl-N, N, N 'N'-tetramethyluronium hexafluorophosphate in 0.76 mL of 0.25 molar N-methylmorpholine in acetonitrile to give the title compound which was recrystallized from a mixture of dimethylformamide and diisopropyl ether. TLC: _Rf (H) = 0.39; FAB-MS: (M + H) ⁺ = 802nd

Example 34

Z- (L) -Val - [(pF) Phe ^NN (pF) Phe] - (N- (2 (R, S) -carbamoyl-3-phenylpropionyl)) - (L) -Val]

Analogously to Example 18, 26.0 ml (0.089 mmol) of N- (2 (R, S) -carbamoyl-3-phenylpropionyl) - (L) -valine are reacted (see Synth., Struct., Funct., Proc. Am Pept. Symp., 7'th, 85 (1981)]. 45 mg (0.081 mmol)

Z- (L) -Val - [(pF) Phe ^NN (pF) Phe] -H (Example 32) with 33.8 mg (0.089 mmol) of O-benztriazol-1-yl-N, N, NN'-tetramethyluroniumhexaf luorophosphate in 0.76 mL of 0.25 molar N-methylmorpholine in acetonitrile to give the title compound, which is recrystallized from a mixture of dimethylformamide and diisopropyl ether. _Rf (L) = 0.64, FAB-MS: (M + H) ⁺ = 829th

Example 35

Acetyl-Val - [Phe ^NN Phe] <- (N-acetyl-Val)

Similar to Example 7, 100 mg (0.25%) was obtained

257 mmol) of H- [Phe ^NN Phe] -H trihydrochloride from Example 2a, 121 mg (0.76 mmol) of N-acetyl- (L) -valine, 288 mg (0.76 mmol) of O-benztriazol-1-yl -N, N, N ', N'-tetramethyluronium hexafluorophosphate and

0.211 mL (1.52 mmol) of triethylamine in dimethylformamide is the title compound after lyophilization from dioxane. FAB-MS: (M + H) ⁺ = 568, t _Ret (I) = 15.0 min, _Rf (B) = 0.46.

Example 36

Z- (D) -Val- [Phe ^NN Phe] <- / (D) -Val / -Z • Similar to Example 2, 50 mg (0.123 · 7 mmol) of trihydrochloride H- [Phe [[Phe] is obtained. ] -H from Example 2a, 95 mg (0.38 mmol) of Z- (D) -valine, 168 mg (0.38 mmol) of benztriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, 51 mg

5. "·; (0.38 mmol) of 1'-hydroxybenztriazole and 2.53 ml of 0.3 molar N-

-methylmorpholine in dimethylformamide compound named.

in the title, after freeze drying from dioxane. FAB-MS: (M + H) ⁺ = 752, t _Ret (I) = 26,4.min, _Rf (H) = 0.21.

Example 37

Quinoline-2-carbonyl-Val- [Phe ^NN Phe] - (N-quinoline-2-carboethyl-Val)

145 mg (0.53 mmol) of N- (quinoline-2-carbonyl) - (L) -valine, 235 mg * (0.53 mmol) of benztriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate and 72 mg ( 1'-hydroxybenztriazole is dissolved in 3.5 ml of a 0.3 molar solution of N-methylmorpholine in dimethylformamide and after 10 minutes 70 mg (0.18 mmol) of H- [Phe ^NN Phe] - trihydrochloride are added. H (Example 2a) and stirred for 5 hours at room temperature under a nitrogen atmosphere. The reaction mixture was evaporated, the residue dissolved in methylene chloride and washed twice with saturated sodium bicarbonate solution, once with 10% citric acid and again

258 once with saturated sodium bicarbonate solution. The organic phases are filtered with suction, evaporated and the residue is precipitated twice from a mixture of methylene chloride and methanol with addition of diisopropyl ether. After lyophilization from dioxane, the title compound is obtained as a white solid (a mixture of two diastereomers which can be distinguished by high performance liquid chromatography). FAB-MS: (M + H) ⁺ = 794, t _Ret (I). = 29.1 and 29.3 min, _Rf (B) = 0.81.

The starting compound is prepared as follows:

a) N- (quinoline-2-carbonyl) - (L) -valine

A solution of 2.5 g (14.5 mmol) of (L) -valyl-tert-butyl ester and 2.5 g (14.5 mmol) of quinoline-2-carboxylic acid in 100 ml of a 10: 1 mixture of methylene chloride and tetrahydrofuran This was treated with 3.28 g (15.9 mmol) of N, N-dicyclohexylcarbodiimide and 2.0 ml (14.5 mmol) of triethylamine and stirred at room temperature for 18 hours. The reaction mixture was cooled to -18 ° C and urea was filtered off. The filtrate was evaporated, the residue was dissolved in methylene chloride and washed once with sodium bicarbonate solution and water. The organic phases are filtered through cotton wool, evaporated and chromatographed on silica gel (hexane / ethyl acetate 2: 1) to give N- (quinoline-2-carbonyl) - (L) -valyl-tert-butyl ester. 2.59 g (12.2 mol) of this compound are left in the 1: 1 mixture of methylene chloride and trifluoroacetic acid at room temperature for 4.5 hours. After evaporation, the residue was purified by silica gel chromatography using hexane / ethyl acetate (2: 1). The fractions containing the compound were evaporated, redissolved in methylene chloride and washed with water, 1N sodium hydroxide solution and 1N hydrochloric acid to give the title compound. 1 H-NMR (200 MHz, CD ₃ OD): 1.05 and 1.07 (2d, J = 6Hz, 6H), 2.40 (m, 1H),

259

4.65 (m, 1H); 7.70 (m, 1H); 7.85 (m, 1H); 8.00 (dxd, 1H);

8.20 (m, 1H); 8.48 (d, 1H) ppm.

Example 38

Acetyl- (L) -Val- [Phe ^^ Cha] - (N-acetyl- (L) -Val)

In a similar manner to Example 37, from 160 mg (0.40 mmol) of H- [Phe ^NN Cha] -H trihydrochloride from Example 10a, 190 mg (1.19 mmol) of N-acetyl- (L) -valine, 525 were obtained. mg (1.19 mmol) of benztriazolyl-oxy-tris (dimethylamino) phosphonium hexafluorophosphate, 160 mg (1.19 mmol) of 1'-hydroxybenztriazole and 7.9 ml of a 0.3 molar solution of N-methylmorpholine in dimethylformamide, the title compound after precipitation from a mixture of chloroform and methanol with diisopropyl ether and lyophilization from dioxane. FAB-MS: (M + H) ^+. = 574, t _Ret (I) = 18.1 min, _Rf (B) = 0.30.

Example 39

N- (3-Pyridylacetyl) - (1) -Val- [Phe ^NN Cha] - N- (3-pyridylacetyl) - (L) -Val] .3HCl

Analogously to Example 7, 100- (0.25 mmol) of H- [Phe ^NN Cha] -H trihydrochloride from Example 10a was obtained, 358 mg (1.52 mmol) of N- (3-pyridylacetyl) - (L) - valine of Example 9a, 576 mg (1.52 mmol) of O-benztriazol-1-yl-N, N, Ν ', N'-tetramethyluronium hexafluorophosphate and 0.316 mL (2.28 mmol) of triethylamine in dimethylformamide the title compound, after Purification by silica gel chromatography using a 15: 1 mixture of methylene chloride and methanol and lyophilization of the fractions containing the compound to be prepared from dioxane. FAB-MS: (M + H) ⁺ = 728, t _Ret (I) = 11.3 min, R _f (U) = 0.21.

Example 40

- 260 Acetyl-Ile - [Phe ^NN Cha] <- (N-acetyl-Ile)

Similar to Example 37, was obtained from 160 mg (0.40 mmol) of H- [Phe-4-Cha] -H trihydrochloride from Example 10a, 206 mg (1.19 mmol) of N-acetyl- (L) -isoleucine, 525 mg. (1.19 mmol) benztriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, 160 mg * (1.19 mmol) of 1'-hydroxybenztriazole and 7.9 mL of 0.3 molar N-methylmorpholine in dimethylformamide the title compound After precipitation from a mixture of methylene chloride and methanol by addition of diisopropyl ether and lyophilization from a mixture of dioxane and tert-butanol. (This is a mixture of 2 diastereomers that can be distinguished by high performance liquid chromatography.) FAB-MS: (M + H) ⁺ = 602, t _Ret (I) = 20.4 and 20.7 min, R _f (D) = 0 , 33rd

Example 41

Thiomorpholinocarbonyl- (L) -Val- [Phe ^NN Cha] <- (N-thiomorpholinocarbonyl- (L) -Val)

Starting from 70 mg (0.12 mmol) of H- (L) -Val- [Phe ^NN Cha] - [N- (L) -Val] -H trihydrochloride from Example 14, 58 mg (0.35 mmol). Of (6-thiomorpholinylcarbonyl) chloride from Example 6a and 0.127 ml of triethylamine in 2 ml of dimethylformamide, after chromatography on silica gel using a 95: 5 mixture of methylene chloride and methanol and lyophilization of the dioxane-containing fractions, gave the title compound. . FAB-MS: (M + H) ⁺ = 748, t _Ret (I) = 24.0 min, _Rf (B) = 0.70.

Example 42

Z- (L) -Glu- [Phe ^NN (pF) Phe] - - (L) -Glu / -Z

261 Solution 130 mg (0.14 mmol) of Z- (L) -Glu (O-tert-butyl) - - [Phe ^NN (pF) Phe] - - (L) -Glu (O-tert-) butyl) - Z (where Glu (O-tert-butyl) here means the glutamic acid residue esterified with a tert-butyl group on the carboxy group in the t) position in 8 ml of a 1: 1 mixture of methylene chloride and trifluoroacetic acid for 3 hours at room temperature. The solvent was evaporated under reduced pressure and the residue was precipitated. from methylene chloride with the addition of diisopropyl ether. The title compound was obtained after lyophilization from a mixture of dioxane and tert-butanol. FAB-MS: (M + H) < ^{+ &gt}; = 830, ⁼

19.6 min, _Rf (B) = 0.32.

The starting compounds are prepared as follows:

a) Z- (L) -Glu (O-tert-butyl) - (Phe ^NN (pF) Phe] <- / (L) -Glu (O-tert-butyl) / - Z

Analogously to Example 37, Z- (L) -glutamic acid tert-butyl ester is obtained from 100 mg (0.24 mmol) of H- [Phe ^NN (pF) Phe] -H trihydrochloride. 321 mg (0.73 mmol) of benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, 98 mg (0.73 mmol) of 1'-hydroxybenztriazole and 4.8 ml of 0.3 molar N-methylmorpholine in dimethylformamide title compound, after chromatography on silica gel using a 1: 1 mixture of methylene chloride and ether. t _Ret (I) = 30.2 min, _Rf (H) = 0.17.

b) H- [Phe ^NN (pF) Phe] -H 3 HCl

Starting from 1.77 g (3.51 mmol) of Boc- [Phe ^NN (pF) Phe] -Boc, analogously to Example 2a, the title compound is obtained after lyophilization. FAB-MS: (M + H) ⁺ = 304, _Rf (C) = 0.19.

c) Boe- [Phe ^N 4 (pF) Phe] -Boe

262

Starting from 2.0 g (7.60 mmol) of (2R) - 1 '(S) -Boc-amino-2'-phenylethyl / oxirane and 2.17 g (9.04 mmol) of tert-butyl Example 16f of 3- (4-fluorophenylmethyl) carbazate in analogy to Example 1 gave the title compound after chromatographic purification on silica gel with hexane / ethyl acetate 2: 1. FAB-MS: (M + H) ⁺ = 504, t _Ret (I) = 26.2 min, _Rf (F) = 0.26 ..

Example 43

N- (2-Pyridylmethyl) -N-methylaminocarbonyl- (L) -Val- [Phe ^WN (pF) -Phe] - N- (N- (2-pyridylmethyl) -N-methylaminocarbonyl) - (L) - Va 1 /

Analogous to Example 37, yielding 70 mg (0.17 mmol) of H- [Phe ^NN (pF) -Phe] -H trihydrochloride from Example 42b, 135 mg (0.51 mmol) of N- / N- (2- pyridylmethyl) -N-methylaminocarbonyl / - (L) -valine (described in European Patent No. 0 402 646 A1 of 19 December 1990), 225 mg (0.51 mmol) of ben from trio of 1-1- yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, 69 mg (0.5.1 mmol) of 1'-hydroxybenzotriazole and 3.4 ml of 0.3 molar N-methylmorpholine in dimethylformamide the title compound, after chromatography on silica gel using a 15: 1 mixture of methylene chloride and methanol and lyophilizing the fractions containing the product from dioxane. FAB-MS: (M + H) ⁺ = 798, t _Ret (IV) = 35 min, R _f (U) = 0.21.

Example 44

N- [3- (Tetrazol-1-yl) propionyl] -Val- [Phe ^NN (pF) Phe] - [N- (3- (tetrazol-1-yl) propionyl) -Val]

Analogously to Example 37, 100 mg (0.24 mmol) of the H- [Phe ^NN (pF) -Phe] -H trihydrochloride from Example I are obtained.

263

42b, 146 mg (0.61 mmol) of N- [3- (tetrazol-1-yl) -propionyl] - (L) -valine, 268 mg (0.61 mmol) of benztriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, 82 mg (0.61 mmol) of 1'-hydroxybenzotriazole and 4 ml of 0.3 molar N-methylmorpholine in dimethylformamide the title compound, after precipitation from methylene chloride by addition of diisopropyl ether and lyophilization from dioxane. (High performance liquid chromatography is distinguished by 4 diastereomers.) FAB-MS: (M + H) ⁺ = 750, t _Ret (III) = 30.8, 31.4, 32.4 and 32.8 min, R _f ( K = 0.5.

Example 44a

N- / 3- (tetrazol-l-yl) -propionyl / - (L) -valine

Analogously to Example 9b, starting from 4 g (16.4 mmol) of (L) -valine benzyl ester hydrochloride, 2.1 g (14.9 mmol) of 3- (tetrazol-1-yl) propionic acid (2.1 g, 14.9 mmol) are obtained. for manufacture, see U.S. Patent No. 4,794,109 A, issued December 27

2.4 ml of cyanophosphonic acid diethyl ester and 4.4 ml of triethylamine in dimethylformamide, after chromatographic purification on silica gel using a 30: 1 mixture of methylene chloride and methanol, N- / 3- (tetrazol-1-yl) propio benzyl ester -. ^nyl / (L) -valine. 2.66 g (8.03 mmol) of this compound was hydrogenated in 9: 1 methanol: water in the presence of 530 mg of 10% palladium on carbon at 100 psi of hydrogen and precipitated from methanol and diisopropyl ether to afford the title compound. . 1 H-NMR (200 MHz, CD-iodo): 0.9 (d, J = 7 Hz, 6H), 2.1 (m, 1H), 2.95 (m, 2H), 4.29 ( d, J = 6 Hz, 1H), 4.78 (m, 2H), 9.15 (s, 1H) ppm.

Example 45

Z- (L) -Val- [Phe ^NN (pF) Phe] <- / (L) -Val / -Z

264

Analogous to Example 37, 100 mg (0.24 mmol) of H- [Phe ^NN (pF) Phe] -H trihydrochloride (from Example 42b) were obtained, 182 mg (0.38 mmol) of Z- (L) -valine 321 mg (0.73 mmol) of benztriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, 98 mg (0.73 mmol) of 1'-hydroxybenzotriazole and 4.8 ml of 0.3 molar N-methylmorpholine in dimethylformamide compound named. title compound, after precipitation from methylene chloride with addition of diisopropyl ether and lyophilization from dioxane. FAB-MS: (M + H) ⁺ = 770, t _Ret (I) = 26.3 min, _Rf (H) = 0.25.

Example 46

Acetyl-Val- [Phe ^NN (pF) Phe] - (N-acetyl-Val)

Analogous to Example 37, 80 mg (0.19 mmol) of H- [Phe] (pF) Phe] -H trihydrochloride from Example 42b were obtained, 124 mg (0.78 mmol) of N-acetyl- (L) - valine, 344 mg (0.78 mmol) of benztriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, 105 mg (0.76 mmol) of 1'-hydroxybenztriazole and 4.5 mL of 0.3 molar N-methylmorpholine in dimethylformamide compound The title compound was obtained after reprecipitating twice from a mixture of methylene chloride and methanol by addition of diisopropyl ether and lyophilization from a mixture of dioxane and tert-butanol. FAB-MS: (M + H) ⁺ = 586, t _Ret (I) = 15.8 min, _Rf (E) = 0.32.

Example 47

Acetyl-Val- [Phe ^NN (p-CN) Phe] - (N-acetyl-Val)

In analogy to Example 37, 80 mg (0.19 mmol) of H- [Phe ^NN (p-CN) Phe] -H trihydrochloride are obtained, 124 mg (0.78 mmol) of N-acetyl- (L) -vinyl, 344 mg (0.78 mmol) of benztriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, 105 mg (0.78 mmol) of 1'-hydroxybenztriazole and 4.5 ml of 0.3 molar N-methylmorpholine in dimethylformamide compound named

265, after precipitation from a mixture of methylene chloride and methanol by addition of diisopropyl ether and freeze-drying from dioxane, as a mixture of two diastereomers distinguishable from one another by high performance liquid chromatography. FAB-MS: (M + H) ⁺ = 593, t ^ _Re (I) = 14.4 and 14.6 min, _Rf (D) = 0.39.

. . The starting compounds are prepared as follows:

a) H- (Phe ^NN (p-CN) Phe] -H, 3HCl

Analogously to Example 2a), the title compound is obtained after lyophilization starting from 2.69 g (5.27 mmol) of Boc- (Phe ^NN (p-CN) Phe) -Boc. FAB-MS: ( M + H) ⁺ = 311, _Rf (C) = 0.16.

b) Boe- (Phe ^NN (p-CN) Phe) -Boe

Analogous to Example 1, starting from 2.0 g (7.60 mmol) of (2R) - / 1 '(S) -Boc-amino-2'-phenylethyl / oxirane and 1.87 g of (2R) - 6 mmol) of tert-butyl 3- (4-cyanophenylmethyl) carbazate, the title compound, after crystallization from a mixture of methanol and diisopropyl ether. FAB-MS: (M + H) ⁺ = 511, t _Ret (I) = 25 min, R _f (Y) = 0.19.

c) tert-Butyl 3- (4-cyanophenylmethyl) carbazate

Analogously to Example 4b, 10 g (76.3 mmol) of 4-cyanobenzaldehyde and 10 g (76.3 mmol) of tert-butylcarbazate in ethanol are reacted to 4-cyanophenylcarbaldehyde tert-butoxycarbonylhydrazone. 11.1 g of this compound are hydrogenated in 150 ml of tetrahydrofuran in the presence of 2 g of 10% palladium on carbon at 200 kPa of hydrogen. This gives the title compound. ¹ H-NMR (200 MHz, CDCl 3): 7.65 (d, J = 8 Hz, 2H), 7.45 (d, J = 8 Hz, 2H), 6.08 ^; (broad singlet, 1H), 4.3 (broad singlet, 1H), 4.02 (s, 2H), 1.45 (s, 9H)

266 ppm.

Example 48

Z- (L) -Va1- [Phe ^NN (p-CN) Phe] <- / (L) -Va1 / -Z

Analogously to Example 37, from 70 mg (0.17 mmol) of H- [Phe] - (p-CN) Phe] -H trihydrochloride (from Example 47a), 125 mg (0.5 mmol) of Z- (L) was obtained. -valine, 221 mg (0.5 mmol) of benzothiazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, 68 mg (0.5 mmol) of 1'-hydroxybenzotriazole and 3.33 ml of 0.3 molar N-methylmorpholine in The title compound was precipitated from methylene chloride by addition of hexane and lyophilized from dioxane. FAB-MS: (M + H) &lt; ^{+ &gt}; = 777, t _Ret (I) =

25.3 min, Rf (D) = 0.69.

Example 49

Z- (L) -Ie- [Phe ^NN Leu] - (L) -Ile / -Z

Analogously to Example 37, 70- (0.19 mmol) of H- [Phe ^NN Leu] -H (from Example 13a), 154 mg (0.58 mmol) of Z- (L) -isoleucine, 257 mg, were obtained. (0.58 mmol) of benztriazol-1-yl-oxy-tris (dimethylamino) phosphonium hexafluorophosphate, 79 mg (0.58 mmol) of 1'-hydroxybenztriazole and 3.88 ml of 0.3 molar N-methylmorpholine in dimethylformamide of the title compound, Chromatography on silica gel with methylene chloride / ether (3: 1), precipitation of product-containing fractions from methylene chloride / diisopropyl ether and lyophilization from dioxane. FAB-MS: (M + H) ⁺ = 746, t _Ret (I) = 28.2 min, _Rf (H) = 0.39.

Example 50

Isobutoxycarbonyl- (L) -Va1- [^^ Phe Leu] <- / N-isobutoxykarbonyl267

- (L) -Val /

Analogously to Example 37, 70 mg (0.19 mmol) of H- [Phe ^NN Leu] -H trihydrochloride (from Example 13a), 130 mg (0.58 nunol) of N- (isobutoxycarbonyl) - (L) - are obtained. valine, 256 mg (0.58 mmol) of benztriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, 78 mg (0.58 mmol) of 1'-hydroxybenztriazole and 3.9 ml of 0.3 molar N-methylmorpholine in dimethylformamide The title compound, after chromatography on silica gel, was a 1: 1 mixture of methylene chloride and ether and lyophilized fractions containing the product from dioxane. FAB-MS: (M + H) ⁺ = 650, t _Ret (I) = 26.4 min, _Rf (H) = 0.38.

The starting compound is prepared as follows:

a) N- (Isobutoxycarbonyl) - (L) -valine

A solution of 10 g (85.3 mmol) of (L) -valine in 100 ml of 2 N sodium hydroxide solution was contacted with 11.2 ml (85.3 mmol) of isobutyl chloroformate and stirred at room temperature for 18 hours. The reaction solution was washed with methylene chloride, acidified with 4N hydrochloric acid, and extracted with methylene chloride. The organic extracts were washed with brine, filtered. via cotton wool and evaporation to give the title compound as a colorless resin. ¹ H-NMR (200 MHz, CD-iodo): 0.95 (m, 12H), 1.9 (m, 1H), 2.15 (τη, ΙΗ), 3.85 (d, J = 7 Hz) , 2H), 4.05 (broad doublet, 1H) ppm.

Example 51

N- [3- (Tetrazol-1-yl) -propionyl] - (L) -Val- [Phe] [Leu] - [N-3- (tetrazol-1-yl) propionyl- (L) -Val]. Analogous to Example 37, 150 mg (0.42 mg) were obtained

H- [Phe ^NN Leu] -H trihydrochloride (from Example 13a), 251 mg (1.04 mmol) of N- [3- (tetrazol-1-yl) propionyl] - (L) -valine from Example 44a , 460 mg (1.04 mmol) of benztriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, 140 mg (1.04 mmol) of 1'-hydroxybenzotriazole and 6.9 ml of 0.3 molar N-methylmorpholine in dimethylformamide of the title compound after precipitation of a mixture of methylene chloride and diisopropyl ether and lyophilization from a mixture of dioxane, tert-butanol and water. FAB-MS: (M + H) ⁺ = 689, t _Ret (I) = 14.7 min, _Rf (C) = 0.36.

Example 52

Acetyl-Val- [Phe ^WN Leu] - (N-acetyl-Val)

Analogous to Example 37, 70 mg (0.19 mmol) of H- [Phe ^NN Leu] -H trihydrochloride (from Example 13a) were obtained, 184 mg (1.16 mmol) of N-acetyl- (L) -valine, 512 mg (1.16 mmol) of benztriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, 156 mg (1.16 mmol) of 1'-hydroxybenztriazole and 7.8 ml of 0.3 molar N-methylmorpholine in dimethylformamide of the title compound After precipitation from a mixture of methylene chloride and methanol by addition of diisopropyl ether and lyophilization from a mixture of dioxane tert-butanol and water. (Two diastereomers can be distinguished by HPLC). FAB-MS: (M + H). ⁺ = 534, t _Ret (I) = 14.7 and 15.1 min, R _f (D) = 0.35. »

Example 53

Boe- (L) -Val- [Phe ^NN Leu] <- / (L) -Val / -Boc

Similar to Example 7, 300 mg (0.83 mmol) of H- [Phe ^NN Leu] -H trihydrochloride (from Example 13a), 722 mg (3.33 mmol) of Boe- (L) -valine, 1.262 mg are obtained. (3.33 mmol) O-benztriazo-11-yl-N, N, N ', N'-tetramethyluronium hexafluorophosphate and

269

0.927 ml (6.66 mmol) of triethylamine in dimethylformamide the title compound, after chromatography on silica gel using a 1: 1 mixture of methylene chloride and ether, precipitated product fractions and lyophilized from dioxane. FAB-MS: (M + H) ⁺ = 650, t _Re +. (I) = 26.3 min, _Rf (H) = 0.64.

Example 54

H- (L) -Val- [Phe ^NN Leu] <- / (L) -Val / -H.3HCl

Analogously to Example 5, from 536 mg (0.61 mmol) of Boe- (L) -Val- [Phe ^NN Leu] - [(L) -Val] -Boc from Example 53 and 10 ml of 4-normal hydrogen chloride are obtained. in dioxane, after lyophilization of the reaction solution, the title compound. FAB-MS: (M + H) + = 450, t _Ret (II) = 24.1 min, _Rf (C) = 0.25.

Example 55

N-Thiomorpholinocarbonyl- (L) -Val- (Phe ^NN Leu) <- / (N-thiomorpholinocarbonyl- (L) -Val)

Starting from 100 µg (0.16 mmol) of H- (L) -Val- (Phe ^NN Leu) - (L) -Val-H, trihydrochloride, 78.5 mg (0.47 mmol) (4- of thiomorpholinylcarbonyl chloride of Example 6a and 0.172 ml of triethylamine in dimethylformamide, analogously to Example 6, after chromatographic purification on silica gel using methylene chloride / methanol (95: 5), precipitating the fraction containing the product from a mixture of methylene chloride and hexane to give the title compound as an amorphous solid. FAB-MS: (M + H) ⁺ = 708, t _Ret (I) = 21.4 min, _Rf (E) 0.45.

. ¹

Example 56.

270

2 (R, S) -Tetrahydrofurylmethoxycarbonyl- (L) -Val- [Cha ^NN Leu] <- / N-2 (R, S) -tetrahydrofurylmethoxycarbonyl- (L) -Val]

Analogously to Example 37 was obtained from 80 mg (0.22 mmolJ H trihydrochloride [Cha ^NN Leu] H, 160 mg (0.65 mmol) of N / 2 (R, S)) - tetrahydrofurylmethoxykarbonyl) - (L -valine, 289 mg (0.65. mmol) of benztriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, 88 mg (0.65 mmol) of ^1- hydroxybenztriazole and 4.35 ml of 0.3 molar N-methylmorpholine in dimethylformamide, the title compound, after chromatographic purification on silica gel with ethyl acetate as eluent and lyophilization of the fractions containing the product from dioxane. FAB-MS: (M + H) ⁺ = 712, t _Ret (I) = 22.4 min, _Rf (E) = 0.21.

The starting compound is prepared as follows:

a) H- [Cha ^NN Leu] -H 3 HCl

Similar to Example 5 was obtained from 150 mg (0.33 mmol) Boc- [Cha ^NN Leu] -Boc and 10 ml of 4 N hydrogen chloride in dioxane, 100 mg of the title compound, after lyophilization reaction solution. Yield: 83%. Rf (K) = 0.26. '

b) Boc - [ ^r Cha ^NN Leuj - Boc

A solution of 200 mg (0.24 mmol) of Boe- [Phe ^NN Leu] -Boe (Example

12) hydrogenated in 15 ml of methanol in the presence of 10 mg of Nishimura catalyst (rhodium oxide and platinum oxide monohydrate, Degussa) under a hydrogen pressure of 100 kPa for 4 hours. The catalyst was filtered off, the solvent was evaporated completely, and crystallized from a mixture of methylene chloride and hexane to give the title compound. t _Ret (I) = 26.7 min, _Rf (W) = 0.21.

271

c) N- (2 (R, S) -Tetrahydrofurylmethoxycarbonyl) - (L) -valine

Analogous to Example 50a, 7 g (60 mmol) of (L) -valine and 9.8 g (60 mmol) of 2 (R, S) -tetrahydrofurylmethyl chloroformate (Heterocycles 27, 1155 (1988)) are obtained in 100 g. ml of 2 N sodium hydroxide solution and 30 ml dioxane of the title compound as a mixture of 2 diastereomers. t _Ret (II) = 23.5 and 23.8 min.

Example 57

Z-Val- [Phe ^NN Leu] <- [N- (3- (tetrazol-1-yl) propionyl) -Val]

Analogously to Example 37, N- (3- (tetrazol-1-yl)) - (100 mg, 0.21 mmol), ^N- Val- [Phe ^NN Leu] -H, 75 mg (0.31 mmol) was obtained. L) -valine of Example 44a, 137 mg (0.31 mmol) of benztriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, 42 mg (0.31 mmol) of ^1- hydroxybenzotriazole and 2 mL of 0.3 molar N- methyl morpholine in dimethylformamide, the title compound, after precipitation from a mixture of methylene chloride and hexane and lyophilization from a mixture of dioxane and tert-butanol. (Two diastereomers can be identified by high performance liquid chromatography.) FAB-MS: (M + H) ⁺ = 70, t _Ret (I) = 21.1 and 21.1 min, R _f (D) = 0.45.

The starting compound is prepared as follows:

a) Z- (L) -Val- [Phe ^NN Leu] -H 'A solution of 250 mg (0.43 mmol) of Z- (L) -Val- [Phe ^NN Leu] -Boe in 5 ml of formic acid was stirred room temperature for 7.5 hours. After this time no starting compound can be determined by high performance liquid chromatography (t _R t = (I) = 27.5 min) and the reaction solution is evaporated. The residue was dissolved in chloroform and washed with a saturated hydrogen solution

272 sodium carbonate. The chloroform phase is filtered through cotton wool to give the crude title compound after evaporation of the solvent. t _R t (I) = 16.7 min, R 1 (K) = 0.21.

b) Z- (L) -Val- [Phe ^NN Leu] -Boc

Analogous to Example 37, yielded from 230 mg (0.653 mmol) of H- [Phe ^NN Leu] -Boc, 247 mg (0.98 mmol) of Z- (L) -valine, 434 mg (0.98 mmol) of benztriazole- l-yloxy-tris (dimethylamino) phosphine oniumhexafluorfosfátu, 133 mg (0.98 mmol) of 1-hydroxybenzotriazole and ¹ 6.5 ml of 0.3-molar NMM in DMF the title compound after precipitation from methylene chloride-methanol by addition of diisopropyl ether. FAB-MS; (M + H) ⁺ = 585, t _Ret (I) = 27.5 min, _Rf (C) = 0.71.

c) H- [Phe ^NN Leu] -Boc 'Analogously to Example 17a, starting from 1.27 g (2.84 mmol) of N-trifluoroacetyl- [Phe ^NN Leu] -Boe and 24 ml of 1- of a normal aqueous solution of sodium carbonate in 90 ml of methanol, the title compound which precipitated from methylene chloride by addition of diisopropyl ether. t _Ret (I) = ^{14.9 min R} f ( ^K ) = 0.38. '

d) N-Trifluoroacety 1- [Phe ^NH Leu] -Boe

Similar to Example 16, starting from 3 g (11.57 mmol) of 2 (R) - / 1 '(S) - (trifluoroacetylamino) -2'-phenylethyl / oxirane of Examples 16d and 2.3. g (12.15 mmol) of tert-butyl 3-isobutylcarbazate (see J. Chem. Soc., Perkin I, 1712 (1975)) for the title compound, after chromatography on silica gel using a mixture of methylene chloride and ether in a 20: 1 ratio. t _Ret (I) = 24.7 min, _Rf (W) = o, 36th

273

Example 58

Acetyl-Val- [Phe ^NN Leu] - N - (2 (R, S) -carbamoyl-3-phenylpropionyl) -Val) Analogous to Example 37, 140 mg (0.3 mmol) of dihydrochloride are obtained. acetyl- (L) -Val- [Phe- ^N Leu] -H, 132 mg (0.45 mmol) of N- [2- (R, S) -carbamoyl-3-phenylpropionyl] - (L) -valine (manufacture see Synth., Struct., Funct., Proc. Am. Pept. Symp., 7th, 85 (1981), 199 mg (0.45 mmol) benztriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, 61 mg ( 0.45 mmol) of 1'-hydroxybenztriazole and 3.5 ml of 0.3 molar N-methylmorpholine in dimethylformamide of the title compound after precipitation from the mixture. methylene chloride and diisopropyl ether; and lyophilization from dioxane. (Two diastereomers can be identified by high performance liquid chromatography.) FAB-MS: (M + H) ⁺ = 667, t _Ret (I) = 17.9 and 18.4 min, R _f (D) = 0.33.

The starting compound is prepared as follows:

a) Ace * -yl-Val- [Phe ^NN Leu] -H. 2HC1

Starting from 230 mg (0.46 mmol) of acetyl- (L) -Val- (Phe-4-Leu) -Boe, analogously to Example 2a, the title compound is obtained after lyophilization: t _Ret (I) = 10.5 min, Rf (D) = 0.38.

b) Acetyl-Val- [Phe ^NN Leu] -Boc

Analogously to Example 37, 250 mg (0.71 mmol) of H- [Phe ^NN Leu] -Boe from Example 57c were obtained, 170 mg (1.07 mmol) of N-acetyl- (L) -valine, 471 mg ( 1.07 mmol) of benztriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, 144 mg (1.07 mmol) of 1'-hydroxybenzotriazole and 7.1 ml of 0.3 molar N-methylmorpholine in dimethylformamide, the title compound of above: U; 'U'9 ^! 3 · th · í · j · ·; • UVU-Roe * ····.

After precipitation from methylene chloride by addition of diisopropyl ether and lyophilization from dioxane. FAB-MS: (M + H) ⁺ = 493, t _Ret (I) = 20.5 min, _Rf (D) = 0.59.

Example 59

N-Morpholinocarbonyl- (L) -Val- [Phe- ^N Leu] - N - (3- (tetrazolyl-1-yl) propionyl) -Val]

Analogously to Example 37, N- (3-) tetrazole (67 mg, 0.38 mmol) was obtained from 100 mg (0.19 mmol) of N-morpholinocarbonyl- (L) -Val- [Phe ^NN Leu] -H dihydrochloride. -1-yl) propionyl N- (L) -valine of Example 44a, 124 mg (0.28 mmol) of benztriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, 38 mg (0.28 mmol) of 1'-hydroxybenzotriazole and 2 The title compound was precipitated from methylene chloride by addition of diisopropyl ether and lyophilized from dioxane, 1 mL of 0.3 molar N-methylmorpholine in dimethylformamide. (Two diastereomers are recognizable by high performance liquid chromatography.) FAB-MS: (M + H) ⁺ = 687, t _Ret (I) = 15.2 and 15.4 min, Rj (D) = 0.25. ?

IN:'·.

The starting compound is prepared as follows:

· J.-

a) N-Morpholinocarbonyl- (L) -Val- [Phe- ^N Leu] -H.2HCl

fe.

Analogous to Example 2a, starting from 279 mg (0.49 mmol) of N-morpholinocarbonyl- (L) -Val- [Phe- ^N Leu] -Boc, the title compound was lyophilized to give the title compound. FAB-MS:

(M + H) ⁺ = 464, t _Ret (II) = 30.3 min, _Rf (D) = 0.46.

b) N-Morpholinocarbonyl- (L) -Val- [Phe ^NN Leu] -Boc _: As in Example 37, this is obtained when starting from 250 mg (0.71 mmol) of H- [Phe ^^ Leu] -Boe. (from Example 57c), 265

- 275 mg (1.07 mmol) of N-morpholinocarbonyl- (L) -valine from Example 7a, 471 mg (1.07 mmol) of benztriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, 144 mg (1.07 mmol) of 1'-hydroxybenzotriazole and 7.1 ml of 0.3 molar N-methylmorpholine in dimethylformamide, the title compound, after precipitation from a mixture of methylene chloride and hexane and lyophilization from dioxane. FAB-MS: (M + H) &lt; ^{+ &gt}; = 564; t Ret ( ¹ ) ⁼ 21.5 min, R f (K) = 0.69.

Example 60

N- (2 (R, S) -carbamoyl-3-phenylpropionyl) - (L) -Val N-Trifluoroacetyl- [Phe ^NN Leu] -

Analogous to Example 37, 136 mg (0.32 mmol) of N-trifluoroacetyl- [Phe ^NN Leu] -H dihydrochloride are obtained, 142 mg (0.49 mmol) of N- / 2 (R, S) -carbamoyl-3. -phenylpropionyl / - (L) -valine (Synth., Struct., Funct., Proc. Am. Pept. Symp., 7th, 85 (1981)), 215 mg (0.49 mmol) benztriazole-1- yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, 66 mg (0.49 mmol) of 1'-hydroxybenzotriazole and 3.5 ml of 0.3 molar N-methylmorpholine in dimethylformamide the title compound after chromatography on silica gel using a chloroform mixture and methanol in a ratio of 15: 1, precipitating the fractions containing the product from a mixture of methylene chloride and diisopropyl ether, and lyophilizing it from a mixture of dioxane and tert-butanol. (Two diastereomers can be identified by high performance liquid chromatography.) FAB-MS: (M + H) ⁺ = 622, t _Ret (I) = 21.6 and 22.0 min, R _f (K) = 0.26.

The starting compound is prepared as follows:

a) N-Trifluoroacetyl- [Phe ^MN Leu] -H, 2HCl

Analogous to Example 2a, the title compound is obtained when starting from 300 mg (0.67 mmol).

276

N-trifluoroacetyl- [Phe ^NN Leu] -Boe from Example 57d and finally lyophilized. R _f (V) <0.1.

Example 61.

Z- (L) -Val [Phe ^NN Nle] <- / N- (2 (R, S) - (N- (2-morpholinoethyl) carbamoyl) -3-methyl) butyryl /

Analogously to Example 37, 69 mg (0.27 mmol) of 2 (R, S) - was obtained from 100 mg (0.17 mmol) of Z- (L) -Val- [Phe ^NN Nle] -H dihydrochloride. N- (2-morpholinoethyl) carbamoyl / -3-methylbutyric acid (N- (2-morpholinoethyl) isopropylmalonic acid monoamide), 119 mg (0.27 mmol) benztriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, 36 mg (0 , 27 mmol) of 1'-hydroxybenztriazole and 2.1 ml of 0.3 molar N-methylmorpholine in dimethylformamide the title compound after precipitation from a mixture of methylene chloride and diisopropyl ether and lyophilization from dioxane. (Proportion of high performance liquid chromatography, it is possible to distinguish the two diastereomers.) FAB-MS: (M + H) ⁺ = 725, t _Ret (I) = 17.2 and 17.6 min, _Rf (D) = 0.5 6th

The starting compound is prepared as follows:

a) Z- (L) -Val- [Phe ^NN Nle] -H.2HCl

Starting from 310 mg (0.53 mmol)

From - (L) -Val- [Phe ^NN Mle] -Boe, in a manner analogous to that of Example 2a, the title compound was obtained after lyophilization. t _Ret (I) = 16.4 min, R _f (U) = 0.25.

b) Z- (L) -Val- [Phe ^NN Nle] -Boe

Analogously to Example 37, 250 mg (0.71 mmol) of H- [Phe ^NN Nie] -Boe, 268 mg (1.07 mmol) of Z- (L) -valine, 472 mg (1.07 mmol) are obtained. ) benztriazol-1-yloxy-tris (dimethylamino) phospho

277 niumhexafluorophosphate, 144 mg. (1.07 mmol) of 1'-hydroxybenzotriazole and 7.1 ml of 0.3 molar N-methylmorpholine in dimethylformamide the title compound, after chromatographic purification on silica gel using a 40: 1 mixture of methylene chloride and methanol, and precipitation of a fraction containing product from a mixture of methylene chloride and diisopropyl ether. t _Ret (I) = 25.6 min, _Rf (X) = 0.17.

c) H- [Phe ^NN Nle] -Boe

Starting from 830 mg (1.85 mmol) of N-trifluoroacetyl- [Phe [ ^N ] Nle] -Boe, in a manner analogous to Example 17a, the title compound is obtained after precipitation from a mixture of methylene chloride and diisopropyl ether. t _Ret (I) = 15.4 min, _Rf (C) = 0.54.

d) N-Trifluoroacetyl- (Phe ^NN Nle) -Boc 'Analogous to Example 16, starting from 1 g (3.86 mmol) of 2 (R) - / 1' - (S) - (trifluoroacetylamino) Example 16d and 720 mg (3.86 mmol) of tert-butyl 3-butylcarbazate, the title compound, after chromatographic purification on silica gel using a 20: 1 mixture of methylene chloride and ether. t _Ret (1) =

25.3 min, Rf (Q) = 0.43.

e) tert-Butyl 3-butylcarbazate

Similar to Example 4b, 25 g (99% yield) of 18.0 g (136.2 mmol) of tert-butyl carbazate and 12.3 ml (136.2 mmol) of n-butanal corresponding to tert-butoxycarbonylhydrazone are obtained. ) as a crude material which is hydrogenated as described in Example 4a in the presence of 10 g of 5% platinum on carbon under a hydrogen pressure of 400 kPa. Chromatographic purification of the crude material on silica gel using a mixture of hexane and hexane

278 of ethyl acetate 1: 1 gives the title compound. R _f (N) = 0.44, ¹ H-NMR (200 MHz, CD ₃ OD): 0.92 (t, J = 7 Hz, 3H), 1.43 (s, 9H), 1.30 - 1.50 (m, 4H); 2.75 (t, J = 7Hz, 2H) ppm.

f) 2 (R, S) - [N- (2-Morpholinoethyl) carbamoyl] -3-methylbutyric acid

Analogous to Example 9b, 7 g (43.7 mmol) of racemic isopropylmalonic acid monomethyl ester (Chem.Ber. 119, 1196 (1986)), 6.3 ml (48.1 mmol) of aminoethylmorpholine, 6.6 ml ( 43.7 mmol) of cyanophosphonic acid diethyl ester and 12.8 ml (91.8 mmol) of triethylamine in dimethylformamide methyl ester of 2 (R, S) - [N- (2-morpholinoethyl) carbamoyl] -3-methylbutyric acid (N-morpholinoethylamide methyl ester) isopropylmalonic acid). This material was stirred for 5 hours in a mixture of 28 ml of 2 N sodium hydroxide solution and 28 ml dioxane at room temperature, acidified with 2 N hydrochloric acid and evaporated completely. The residue was digested with ethanol, filtered and evaporated to give the title compound. ¹ H-NMR (200 MHz, CD ₃ OD): 0.95 ° and 1.00. (2d, J = 7Hz, 6H), 2.25 (m, 4H), 2.70 (m, 6H), 2.75 (d, J = 8Hz, 1H), 3.45 (m, 2H) ), 3.75 (m, 4H) ppm.

Example 62

Z- (L) -Val- [Phe ^NN Nle] <- [N- (3- (tetrazol-1-yl) propionyl) -Val]

Similar to Example 37, 100 mg (0.18 mmol) of Z- (L) -Val- [Phe ^NN Nle] -H (from Example 61a), 65 mg (0.27 mmol) of N- / 3 were obtained. - (Tetrazol-1-yl) propionyl / - (L) -valine of Example 44a, 119 mg (0.27 mmol) of benztriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, 36 mg (δ, 27 mmol) 1 1-hydroxybenzotriazole and 2.1 ml of 0.3 molar N-methylmorpholine in dimethylformamide

279, after precipitation from a mixture of methylene chloride and diisopropyl ether and lyophilization from a mixture of dioxane and tert-butanol. (Two diastereomers can be identified by high performance liquid chromatography.) FAB-MS: (M + H) ⁺ · = 708, t _Ret (I) =

20.3 and 20.6 min, R f (D) = 0.43.

Example 63

N- (2 (R, S) - (N- (2-pyridylmethyl) carbamoyl) -3-methyl) -butyl (dibenzenesulfonate) Z- (L) -Val- [Phe ^NN Nle] f

Analogous to Example 37, yielding 95 mg (0.17 mmol) of Z- (L) -Val- [Phe ^NN Nle] -H dihydrochloride from Example 61a, 60 mg (0.26 mmol) of N- (2-picolyl). (R, S) -isopropylmalonic acid monoamide, 113 mg (0.26 mmol) of benztriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, 35 mg (0.26 mmol) of 1'-hydroxybenztriazole and 2.0 mL of 0, Of 3-molar N-methylmorpholine in dimethylformamide the title compound after chromatographic purification on silica gel using a 15: 1 mixture of methylene chloride and methanol. The compound obtained is a free amine which is dissolved from methylene chloride, treated with 2 equivalents of benzenesulfonic acid and precipitated by addition of diisopropyl ether. Lyophilization from tert-butanol affords the dibenzenesulfonate. (Two diastereomers can be identified by high performance liquid chromatography.) FAB-MS: (M + H) ⁺ = 703, t _Ret (I) = 17.7 and 18.0 min, R _f (D) = 0.54 .

The starting compound is prepared as follows:

a) Isopropylmalonic acid N- (2-picolyl) monoamide

A solution of 15 g (93.6 mmol) of isopropylmalonic acid monomethyl ester (see Chem. Ber. 119, 1196 (1986)) in 150 ml of tetrahydrofuran is treated with 10.6 ml (103 mmol) of N-methylmorpholine and then added dropwise. 13.5 ml (103 mmol)

280 isobutyl chloroformate. The reaction mixture is stirred for 30 minutes, then 15.3 ml (150 mmol) of 2-picolylamine are added and the resulting suspension is stirred for 2 hours. The reaction mixture is diluted with methylene chloride, washed with 1N sodium hydroxide solution and water, the organic phase is filtered through cotton wool and evaporated. Crystallization of the residue gave N- (2-picolylamide) methyl isopropylpropyl ester which was hydrolyzed as described in Example 61f by treating a 2-normal solution of sodium hydroxide and dioxane to the title compound. t _Ret (II) = 16.0 mins.

Example 64

Z- (L) - N 1 - [Phe ^{N N} (p F) Phe] - N - (3- (tetrazol-1-yl) propionyl) - (L) -Val] (benzenesulfonate)

Analogously to Example 37, from Example 22a, 59 mg (0.25 mmol) of N- (L) -Val- [Phe- ^N (pF) Phe] -H from 100 mg (0.16 mmol) was obtained. 3- (Tetrazol-1-yl) propionyl / - (L) -valine from Example 44a, 109 mg (0.25 mmol) benztriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, 33 mg (0.25 mmol) 1 hydroxybenzotriazole and 1.19 ml of 0.3 molar N-methylmorpholine in dimethylformamide the title compound after precipitation from a mixture of methylene chloride and diisopropyl ether. This compound is formed from the free amine, which is dissolved in a mixture of methylene chloride and methanol, treated with 1 equivalent of benzenesulfonic acid and precipitated by addition of hexane. Lyophilization from tert-butanol affords the title compound as benzenesulfonate. FAB-MS: (M + H) ⁺ = 760, t _Ret (I) = 21.6 min, _Rf (B) = 0.49.

Example 65

Methylsulfony1- [^ Phe Nphe] <- / N-phenylacetyl (L) -Val /

281

132 mg (0.28 mmol) of methylsulfonyl- [Phe ^NN Phe] -H dihydrochloride were reacted analogously to Example 7 with 197 mg (0.84 mmol) of N-phenylacetyl- (L) -valine (see Mem. Tokyo for manufacture). Univ. Agric., 51, 1978 (), 317 mg (0.84 mmol) of O-benztriazol-1-yl-N, N, N ', N'-tetramethyluronium hexafluorophosphate and 0.23 ml (1.67 mmol) of triethylamine in dimethylformamide and, after precipitation with methanol, addition of ether gives the title compound. FAB-MS: (M + H) &lt; ^{+ &gt}; = 581, t _Ret (I) = 20.2 min, Rf (B) = 0.64.

The starting compound is prepared as follows:

a) Methylsulfonyl- [Phe ^NN PheJ-H, 2HCl]

Analogously to Example 2a, starting from 130 mg (0.28 mmol) of methylsulfonyl- [Phe ^NN Phe] -Boe, the title compound is obtained after lyophilization. FAB-MS: (M + H) ⁺ = 364, t _Ret (II) = 28.5 min, R _f (K) - 0.56.

b) Methylsulfonyl- [Phe ^NN Phe] -Boc

Similar to Example 16a, it is obtained starting from 1.1 g (4.56 mmol) of 2 (R) - / 1 '(S) - (methylsulfonylamino) -2'-phenylethyl / oxirane and 1.11 g (5, Tert-butyl 3-benzylcarbazate (for preparation see J. Chem. Soc., Perkin I, 1712 (1975)), the title compound of which is a 4: 1 diastereomeric mixture. Crystallization from a mixture of methylene chloride and hexane improves the ratio in favor of 2S-diastereomers to 10: 1. FAB-MS: (M + H) ⁺ = 464, t _{R t} (I) = 21.3 min, _Rf (N) = 0.26.

c) 2 (R) - 1 '(S) - (Methylsulfonylamino) -2'-phenylethyl / oxirane

A solution of 1 g (6.8 mmol) of 1-phenyl-3-buten-2 (S) -amine of Example 16b in 10 ml of methylene chloride was stirred at 0 ° C.

282 was contacted with 2.36 g (13.6 mmol) of methanesulfonic anhydride and 1.88 ml (13.6 mmol) of triethylamine and stirred for 1 hour. The reaction mixture was washed with water and saturated sodium bicarbonate solution, the organic phase was filtered through cotton wool and evaporated to give 2 (S) -methylsulfonylamino-1-phenyl-3-butene. 1 g (4.4 mmol) of this crude material was dissolved in 30 ml. methylene chloride, 3.05 g (17.7 mmol) of 4-chloroperbenzoic acid are added at room temperature and stirred for 18 hours. The reaction solution was washed five times with a 10% aqueous solution of sodium sulfite, filtered through cotton wool and evaporated completely. According to 1 H-NMR analysis, the crude product contains both (2R) and (2S) epimers in a 4: 1 ratio. ¹ H-NMR (200 MHz, CD 3 OD): 2.30 and 2.52 (2s, together 3H), 2.6-3.2 (m, 5H), 3.55 (m, 1H), 7.3 2 '(m, 5H) ppm.

Example 66

Methoxycarbonyl- (L) -Val- [Phe ^NN Leu] <- [N-Methoxycarbonyl- (L) -Val] • Analogously to Example 37, 200- (0.55 mmol) of H- [Phe ^NN Leu] trihydrochloride is obtained. ] -H (from Example 13a), 291 mg (1.66 mmol) of N-methoxycarbonyl- (L) -valine (for preparation see Chem. Lett. 705 (1980)), 735 mg (1.66 mmol) of benztriazole-1 -yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, 225 mg (1.66 mmol) of 1'-hydroxybenztriazole and 1.1 ml of 0.3 molar N-methylmorpholine in dimethylformamide the title compound, after precipitation from a mixture of methylene chloride and diisopropyl ether and lyophilization from dioxane. FAB-MS: (M + H) ⁺ = 566, t _Ret (I) = 18.6 min, R _f (U) = 0.33.

Example 67

Methoxycarbonyl- (L) -Val- [Phe ^NN (pF) Phe] <- (N-methoxycarbonyl- (L) -Val)

283

Analogously to Example 37, 200 mg (0.48 mmol) of H- [Phe ^^ Leu] -H trihydrochloride (from Example 42b), 255 mg (1.45 mmol) of N-methoxycarbonyl- (L) -valine are obtained. (see Chem. Lett. 705 (1980)), 643 mg (1.45 mmol) benztriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, 196 mg (1.45 mmol) 1'-hydroxybenzotriazole and 9.7 mL Of 0.3-molar N-methylmorpholine in dimethylformamide the title compound, after precipitation from a mixture of methylene chloride and diisopropyl ether and lyophilization from dioxane. FAB-MS: (M + H) ⁺ = 618 ,, t _Ret (I) = 19.5 min, R _f (U) = 0.22.

Example 68

Methoxycarbonyl- (L) -Val- [Phe ^NN (p-CN) Phe] - (N-methoxycarbonyl- (L) -Val)

Analogous to Example 37, 200 mg (0.48 mmol) of H- [Phe ^NH (p-CN) Phe] -H trihydrochloride (from Example 47a) were obtained, 250 mg (1.43 mmol) of N-methoxycarbonyl- ( L) -valine (see Chem. Lett., 705 (1980)), 631 mg (1.43 mmol) of benztriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, 193 mg (1.43 mmol) of 1'-hydroxybenzotriazole and 9.5 ml of 0.3 molar N-methylmorpholine in dimethylformamide

of the title compound, after chromatography on silica gel using a 15: 1 mixture of methylene chloride and methanol and lyophilization of the fractions containing the product from dioxane. FAB-MS: (M + H) ⁺ = 625, t _Ret (I) = 18 min, R _f (U) = 0.31.

Example 69

Z- (L) -Val - [(pF) Phe ^NN (pF) Phe] - (N- (2 (R, S) - (N- (2-morpholinoethyl) carbamoyl) -3-methyl) butyryl)

Analogously to Example 18, 23.0 was reacted

284 mg (0.089 mmol) of 2 (R, S) - [N- (2-morpholinoethyl) carbamoyl] -3-methylbutyric acid (Example 61f) and 45 mg (0.081 mmol) of Z- (L) -Val - [(pF) Phe ^NN (pF) Phe) -H (Example 32) with 33.8 mg (0.089 mmol) of O-benztriazol-1-yl-Ν, Ν, Ν ', N'-tetramethyluronium hexafluorophosphate in 0.76 mL 0.25 of N-methylmorpholine in acetonitrile to give the title compound, which precipitates from a mixture of dimethylformamide and diisopropyl ether. TLC: _Rf (L) = 0.42, FAB-MS: (M + H) ⁺ = 795th

Example 70

Z- (L) -Val - [(pF) Phe ^NN (pF) Phe] - (N- (2 (R, S) - (N- (2-pyridylmethyl) kerbamoyl) -3-methyl) butyryl)

Analogous to Example 18, 21.0 mg (0.089 mmol) of racemic isopropylmalonic acid N- (2-picolyl) amide (Example 63a) and 45 mg (0.081 mmol) of Z- (L) -Va1 - [(pF) were reacted. Phe- ^N (pF) Phe-H (Example 32) with 33.8 mg (0.089 mmol) of O-benztriazol-1-yl-Ν, Ν, Ν ', N'-tetramethyluronium hexafluorophosphate in 0.76 ml Of 0.25 molar N-methylmorpholine in acetonitrile, to the title compound, and this is precipitated by a mixture of dimethylformamide with diisopropyl ether. DC: Rf (P) = 0.52; FAB-MS: (M + H) &lt; ^{+ &gt}; = 773.

Example 71

Similar to any of the above, the following compounds can also be prepared:

(a) Z- (L) -Val - [(pF) Phe ^NN (pF) Phe] <- / (L) -Val] <- (N-morpholinocarbonyl-Gly),

b) N-morpholinocarbonyl- (L) -Val - [(pF) Phe ^NN (pF) Phe] - [(L) -Val] - (N-morpholinocarbonyl-Gly).

285

c) N- (quinoline-2-carbonyl) .- (L) -Ans- [Phe ^NN (pF) Phe] - / (L) -

I

-Val / -Z a

d) N- (morpholinosulfonyl) - (L) -Val- [Phe ^NN Leu] - (N- (morpholino) sulfonyl) - (L) -Val].

Example 7.2

Gelatin solution

A sterile aqueous solution of 20% cyclodextrin as a co-solvent and one of the compounds of the above formula I as active ingredient is mixed with a sterile gelatin solution containing phenol as a preservative under heating aseptic

conditions to obtain 1.0 ml of solution this composition: Active substance 3 mg gelatin 150.0 mg phenol 4.7 mg Distilled water with 20% cyclodextrin as a co-solvent 1.0 ml

Example 73

The sterile dry substance for injection of mg of one of the compounds of the formula (I) in the preceding examples, as active ingredient, is dissolved in 1 ml of an aqueous solution of 20 mg of mannitol and 20% cyclodextriene as the solvent. The solution is filtered under sterile conditions, filled under aseptic conditions into a 2 ml ampoule, cooled to a deep temperature and lyophilized. Before use, the lyophilisate is dissolved in 1 ml of distilled water or 1 ml of saline. The solution is used in

286 tramuscular or intravenous. This composition can also be filled into dual chamber spray ampoules.

Example 74

Nasal spray

A mixture of 3.5 ml of Myglyol 812 ^R and 0.08 mg of benzyl alcohol is suspended in 500 mg of a finely divided powder (particle size less than 5.0 μπι) of the compound of the formula I mentioned in any of the preceding examples as the active ingredient. This suspension is filled into containers fitted with a metering valve. The tray was introduced 5.0 g of Freon 12 under pressure using ^Λ valve located on the container. By shaking, Freon is dissolved in a mixture of Myglyol and benzyl alcohol. This spray container contains approximately 100 dosage units that can be administered individually.

Example 75

Lacquered tablets

The following are processed to produce 10,000 tablets, mg of active ingredient

Active substance

Maize starch

Colloidal silicic acid Magnesium stearate

Stearic acid Sodium carboxymethyl starch

Water each containing 100 components:

1000 g

680 g

200 g g

g

250 g as needed. A mixture of one of the compounds of the formula I mentioned above

in one of the foregoing examples as active ingredient,

287 mg of corn starch and silicic acid are treated with a starch fat prepared from 250 mg of corn starch and 2.2 kg of demineralized water to a wet mass. This mass is passed through a 3 mm sieve and dried in a fluid bed dryer at 45 ° C for 30 minutes. The dried granulate is passed through a 1 mm sieve and mixed with the previously sieved mixture. (mesh size T mm) 330 mg of corn starch, magnesium stearate, stearic acid and sodium carboxymethylated starch and pressed into weakly domed tablets.

Claims (11)

288 PAT E N T 0 V E N A R 0 K Y 1. Compounds of the general formula I _n * 7 1 y X l Λ Γ - - ω, «3 i: ^R 8 in which R 6 and R 8 are independently hydrogen, acyl, optionally substituted alkyl, alkenyl or alkynyl, heterocyclyl, sulfo, sulfonyl optionally substituted by alkyl, aryl, heterocyclyl, alkoxy optionally substituted, or aryloxy, sulfamoyl, substituted on a nitrogen atom, or a phosphoryl substituted by one or two independently of one another selected from optionally substituted alkyl, optionally substituted cycloalkyl, aryl, hydroxy, optionally substituted alkoxy, cycloalkoxy and R aryloxy; - ^ and R _g is a hydrogen atom, i R @ 1 and R @ 8 are each independently hydrogen or one of the radicals R @ 4 and R @ 8 mentioned above, or pairs of substituents. R 1 and R ₂ or R 8 and R 8 may in each case independently form, with the nitrogen atom to which they are attached, a heterocyclic ring, which consists of a nitrogen binding atom together with a residue selected from ethylene, trimethyl 289 ο XI '<ο · ο ο GB> ο JC <=> nu, tetramethylene and pentamethylene, wherein the carbon atom may be replaced by a nitrogen, oxygen, sulfur or oxygen atom with one or two substituted sulfur atoms and which may be unsaturated, or one of the radicals with each oxosubstituent on both carbon atoms associated with the carbon atom and optionally a fused benzene or naphthalene ring, R ₃ and R ₄ are each independently hydrogen, optionally substituted alkyl or cycloalkyl, aryl, heterocyclyl or optionally substituted alkenyl; R 8 and R ₄ together represent optionally substituted alkylene, alkylidene or benzofused alkylene, R ₅ is hydroxy and R 6 represents a hydrogen atom or a hydrogen atom R ₅ and R ₆ together represent oxo and R y is optionally substituted alkyl or cycloalkyl, further aryl, heterocyclyl or optionally substituted alkenyl, with the exception of a compound of formula I wherein R p R ₂ , R ₃ , R ₄ , R 8 and R 8 are hydrogen, R ₅ is hydroxy, R ₇ is group formula -ch ₂ -c-nh-n-ch ₂ -cooh II I OCH ₃ and R ₉ represent tert-butoxycarbonyl, as well as salts of these compounds, provided they contain groups capable of 289a to form salts. A compound of formula I according to claim 1, wherein R and R _G are! independently of one another a hydrogen atom, a lower alkanoyl group, an aryl- (lower alkanoyl) group in which the lower alkanoyl moiety is optionally substituted by carbamoyl which is optionally substituted on the nitrogen atom by one or two radicals selected from lower alkyl, carboxy- (lower alkyl) ), (lower alkoxy) -carbonyl- (lower alkyl290), di- (lower alkyl) -amino- (lower alkyl), aminocarboxy- (lower alkyl), hydroxy- (lower alkyl) and di- (lower alkoxy) - a (lower alkyl) group, a heterocyclyl- (lower alkanoyl) group, an amino- (lower alkanoyl) group substituted on the amino atom of the amino group, a heterocyclyl- (lower alkanoyl) group, a halogen- (lower alkanoyl) group containing 1 to 3 halogen atoms, (N-heterocyclyl- (lower alkyl) -carbamoyl) - (lower alkanoyl), (lower alkoxy) -carbonyl, aryl- (lower alkoxy) -carbonyl, heterocyclyl- (lower alkoxy) -carbonyl, (lower alkyl) - sulfonyl, heterocyclylsulfonyl, N- (heterocyclyl- (lower alkyl)) - N- (lower alkyl) carbamoyl or an acyl residue of an amino acid whose functional amino group is free or acylated by one of the hitherto mentioned remaining residues for R 1, and R 8, s provided that at most one of the radicals R @ 1 and R @ 8 is hydrogen, R _2, R _to R and R are H, R 1 is lower alkyl, cycloalkyl (lower alkyl) or aryl (lower alkyl), R ₅ is hydroxy and R ₇ represents an optionally substituted lower alkyl group, or salts thereof, if it contains at least one salt-forming group. A compound of formula I according to claim 1, wherein R-L and Rg are each independently hydrogen, lower alkanoyl, aryl (lower alkanoyl) wherein the aryl moiety is selected from phenyl, indenyl, indanyl, naphthyl, 291 anthryl, phenanthryl, acenaphthyl or fluorenyl and is unsubstituted or can be substituted one to three times by lower alkyl, halogen- (lower alkyl), phenyl, 1- or 2-naphthyl, hydroxy, lower alkoxy, carbamoyl- (lower alkoxy), N- (lower alkyl) -carbamoyl- (lower alkoxy), N, N-di- (lower alkyl) -carbamoyl- (lower alkoxy), amino, mono- or di- (lower alkyl) -amino, (lower alkanoyl) ) -amino, halogen, carboxy, (lower alkoxy) -carbonyl, phenyl, naphthyl or fluorenyl- (lower alkoxy) -carbonyl, lower alkanoyl, sulfo, (lower alkyl) -sulfonyl, phosphono, hydroxy- ( lower alkoxy) -phosphoryl, di- (lower alkoxy) -phosphoryl, carbamoyl, mono- or di- (lower alkyl) -carbamoyl, sulfamoyl, mono- or di- (lower alkyl) -aminosulfonyl, nitro and / or cyano, wherein the phenyl may be present or present one to three times, and wherein the lower alkanoyl moiety is not substituted or is substituted with carbamoyl optionally substituted by one or two residues selected from lower alkyl, carboxy (lower alkyl), (lower alkoxy) -carbonyl- (lower alkyl), di- (lower alkyl) -amino- (lower alkyl), aminocarboxy- (lower alkyl), hydroxy- (lower alkyl) and di - (lower alkyl) - (lower alkyl) groups, heterocyclyl- ( lower alkanoyl) wherein the lower alkanoyl moiety is not substituted and wherein the heterocyclyl moiety is selected from thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, furazanyl, tetrazolyl, pyridyl, azidinyl, pyridinyl, pyrazinyl, pyrazinyl, pyridinyl, pyrazinyl, indolyl, benzimidazolyl, ΙΗ-indazolyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, cinnolyl, purinyl, pteridinyl, naphthyridinyl, 4H-quinolizinyl, 3,1-benzfuranyl , 4,1-benzoxazinyl, 4,1-benzthiazinyl, cyclohexa [b] pyrrolyl, cyclohepta [b] pyrrolyl, cyclohexa [d] pyrazolyl, cyclohexafbpyridyl, cyclohexa [b] pyrazinyl, cyclohexa [b] pyrimidinyl, cyc 292 lohexa [b] -1,4-oxazinyl, cyclohexa [b] -1,4-thiazinyl, pyrrolidinyl, pyrrolinyl, imidazolidyl, 2-imidazolinyl, 2,3-dihydropyridyl, piperidyl, piperazinyl, 2,3,5,6 -tetrahydropyrazinyl, morpholinyl, thiomorpholinyl, S, S-dioxothiomorpholinyl, indolinyl, isoindolinyl, 4,5,6,7-tetrahydroindolyl, 1,2,3,4-tetrahydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl; chromanyl ,. thiochromanyl, 1,2,3,4-tetrahydro-3,1-benzdiazinyl, 3,4-dihydro-3H-4,1-benzoxazinyl and 3,4-dihydro-3H-4,1-benzthiazinyl, said heterocyclyl residues * are unsubstituted or substituted by lower alkyl, phenyl, 1- or 2-naphthyl, phenyl- (lower alkyl), hydroxy- (lower alkyl), for example hydroxy- (lower alkyl), (lower alkoxy) - (lower alkyl, phenoxy or naphthyloxy (lower alkyl), phenyl (lower alkoxy) - or naphthyl (lower alkoxy) - (lower alkyl), (lower alkanoyl) -oxy- (lower alkyl), phenyl- or naphthyl- (lower alkanoyl) -oxy- (lower alkyl), (lower alkoxy) -carbonyloxy- (lower alkyl), phenyl-, naphthyl- or fluorenyl- (lower alkoxy) -carbonyloxy- (lower alkyl), amino- (lower alkyl), carboxy- (lower alkyl), hydroxy, lower alkoxy, phenyl- or naphthyl- (lower alkoxy), amino, ( lower alkyl) -amino, di- (lower alkyl) -amino, carboxy, (lower alkoxy) -carbonyl, phenyl- or naphthyl- (lower alkoxy) -carbonyl, halogen, lower alkanoyl, (lower alkyl) -sulfonyl a phosphono group, a hydroxy- (lower alkoxy) -phosphoryl or di- (lower alkoxy) -phosphoryl group, a carbamoyl, a mono- or di- (lower alkyl) -carbamoyl group, a hydroxy- or carboxy- (lower alkyl) -carbamoyl group , a sulfamoyl, nitro, oxo, and / or cyano group, a heterocyclyl- (lower alkanoyl) group on the nitrogen atom of an amino group substituted with an amino- (lower alkanoyl) group, wherein the heterocyclyl- (lower alkanoyl) group is defined as above for heterocyclyl- (lower alkanoy29) and R 8, a halogen- (lower alkanoyl) group containing up to 3 halogen atoms, an N- (heterocyclyl- (lower alkyl) carbamoyl) - (lower alkanoyl) group in which the heterocyclyl moiety t is selected from pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl,. β-carbolinyl and a benzanellated, cyclopentaanellated, cyclohexaanellated or cycloheptaanellated derivative of said residue, wherein said residues may also be wholly or partially saturated, from morpholinyl and thiomorpholinyl, (lower alkoxy) -carbonyl, aryl- (lower alkoxy) -carbonyl, the aryl moiety is phenyl, biphenylyl, 1- or 2-naphthyl or fluorenyl or lower alkyl, hydroxy, lower alkoxy, halogen and / or nitro substituted one or more substituted phenyl, heterocyclyl- (lower alkoxy) -carbonyl, wherein the heterocyclyl moiety is selected from pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, isoquinolyl, quinoxalinyl, β-carbolinyl and benzanlated, cyclohepentaanellated, cyclo-pentanellated, cyclohepentaellate partial or f and are optionally substituted by lower alkyl, (lower alkyl) -sulfonyl, morpholinosulfonyl, thiomorpholinosulfonyl, piperidinosulfonyl, 4-methylpiperazinylsulfonyl or piperazinosulfonyl, N- (heterocyclyl- (lower alkyl)) - an alkyl (1) -carbamoyl group wherein the heterocyclyl moiety is selected from thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, furazanyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyridazinyl, indepinyl, indepinyl, indepinyl, indepinyl, indepinyl, indepinyl, indepinyl, indepinyl, indepinyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, cinnolyl, purinyl, pteridinyl, naphthyrifinyl, 4H-quinolizinyl, 3,1-benzofuranyl, benz [e] in 294 dolyl, 4,1-benzoxazinyl, 4,1-benzthiazinyl, carbazolyl, β-carbolinyl, phenazinyl, phenanthridyl, acridyl, phenoxazinyl, phenothiazinyl, 1-azaacenaphthyl, cyclohexafbpypyrrolyl, cycloheptyl [b] pyrrolylpyridyl [b] pyrrolidyl, , cyclohexafbpyrazinyl, cyclohexafbpyrimidinyl, cyclohexafb] -1,4-oxazinyl, cyclohexa [b] -1,4-thiazinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, 2-imidazolinyl, 2,3-dihydropyridyl, piperidyl, piperazinyl, 2.3.5.6- tetrahydropyrizinyl, morpholinyl, thiomorpholinyl, S, S-dioxothiomorpholinyl, indolinyl, isoindolinyl, 4.5.6.7-tetrahydroindolyl, 1,2,3,4-tetrahydroquinolyl, 1.2.3.4- tetrahydroisoquinolyl, chromanyl, thiochromanyl, 1,2.3.4-tetrahydro-3,1-benzdiazinyl, 3,4-dihydro-3H-4,1-benzoxazinyl, 3,4-dihydro-3H-4,1-benzthiazinyl, 2,3,4,5-tetrahydro- 1H-5, L-benzazepinyl and 5,6-dihydrophenanthridinyl, wherein said residues are unsubstituted or substituted by lower alkyl, phenyl, 1- or 2-naphthyl, phenyl- (lower alkyl), hydroxy- (lower alkyl) (lower alkoxy) - (lower alkyl), phenoxy- or naphthyloxy- (lower alkyl); phenyl- (lower alkoxy) - or naphthyl- (lower alkoxy) - (lower alkyl), (lower alkanoyl) -oxy- (lower alkyl), phenyl- or naphthyl- (lower alkanoyl) -oxy- (lower alkyl), ( lower alkoxy) -carbonyloxy- (lower alkyl), phenyl, naphthyl or fluorenyl- (lower alkoxy) -carbonyloxy- (lower alkyl), amino- (lower alkyl), carboxy- (lower alkyl), hydroxy, lower alkoxy, phenyl- or naphthyl- (lower alkoxy), amino, (lower alkyl) -amino, di- (lower alkyl) -amino, carboxy, (lower alkoxy) -carbonyl, phenyl- or naphthyl- (lower alkoxy) -carbonyl, halogen , lower alkanoyl, (lower alkyl) -sulfonyl, phosphono, hydroxy- (lower alkoxy) -phosphoryl or di- (lower alkoxy) -phosphoryl, carbamoyl, mono- or di- (lower alkyl) -carbamoyl, hydroxy- or a carboxy- (lower alkyl) -carbamoyl, sulfamoyl or nitro group Or amino, the functional amino group of which is free or acylated with one of the remaining R & apos _; and R & lt _; 6 & gt _; residues to date, wherein the amino acids are selected from glycine, alanine, valine, norvaline, leucine, isoleucine, norleucine, serine, homoserine, threonine, methionine, cysteine, proline, trans-3- and trans-4-hydroxyproline, phenylalanine, tyrosine, 4-aminophenylalanine, 4-chlorophenylalanine, 4-carboxyphenylalanine, β-phenylserine α, phenylglycine α, phenylcine -naphthylalanine, cyclohexylalanine, cyclohexylglycine, tryptophan, indoline-2-carboxylic acid, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, aspartic acid, asparagine, aminomalonic acid, aminomalonic acid raonoamide, glutamic acid, glutamine, histidine, arginine, lysine, δ-hydroxylysine, ornithine, 3-aminopropanoic acid, α, τ-diaminobutyric acid and α, β-diaminopropionic acid, with the exception of glycine nu) each of said amino acids are in D, L or (D, L), with the proviso that not more than one of R ^ and R _g is a hydrogen atom, t R _2, R _4, R and R are H, R ₃ represents a lower alkyl group, a cycloalkyl- (lower alkyl) group, wherein the cycloalkyl moiety contains from 3 to 7 carbon atoms and is not substituted or substituted by one to three times lower alkyl, halogen- (lower alkyl), hydroxy, lower alkoxy , carbamoyl- (lower alkoxy), N- (lower alkyl) -carbamoyl- (lower alkoxy), N, N-di- (lower alkyl) -carbamoyl- (lower alkoxy), amino, mono- or di- (lower alkyl) ) -amino, halogen, carboxy, (lower alkoxy) -carbonyl, phenyl, naphthyl, or fluorenyl (lower alkoxy) -carbonyl, lower alkanoyl, (lower alkyl) -sulfonyl, phosphono, hydroxy- (lower alkoxy) ) -phosphoryl or di- (lower alkoxy) -phosphoryl, 296 carbamoyl, mono- or di- (lower alkyl) -aminocarbamoyl, sulfamoyl, mono- or di- (lower alkyl) -sulfamoyl, nitro and / or cyano, or is aryl- (lower alkyl), wherein aryl is phenyl, indenyl, indanyl, naphthyl, anthryl, phenanthryl, acenaphthyl or fluorenyl, and unsubstituted or can be substituted one or three times by lower alkyl, for example isopropyl, halogen- (lower alkyl), phenyl, 1- or 2-naphthyl , hydroxy, lower alkoxy, carbamoyl- (lower alkoxy), N- (lower alkyl) -carbamoyl- (lower alkoxy), N, N-di- (lower alkyl) -carbamoyl- (lower alkoxy), amino, mono- or di- (lower alkyl) -amino, (lower alkanoyl) -amino, halogen, carboxy, (lower alkoxy) -carbonyl, benzyl, riaphthyl or fluorenyl- (lower alkoxy) -carbonyl, lower alkanoyl, sulfo, ( lower a alkyl) -sulfonyl, phosphono, hydroxy- (lower alkoxy) -phosphoryl, di- (lower alkoxy) -phosphoryl, carbamoyl, mono- or di- (lower alkyl) -carbamoyl, sulfamoyl, mono- or di - (lower alkyl) -sulfamoyl, nitro and / or cyano, with phenyl being present up to three times, R ₅ is hydroxy and R ₇ - represents an unsubstituted lower alkyl group or a cycloalkyl- (lower alkyl) group, as described above for a cycloalkyl- (lower alkyl) group, R 8, or an aryl- (lower alkyl) group, as described above for an aryl- (lower alkyl) group R 8, or a salt thereof, if salt groups are present. A compound of formula (I) according to claim 1, wherein 297 wherein and R _g are independently hydrogen, lower alkanoyl, phenyl (lower alkanoyl), phenyl (lower alkanoyl) wherein the lower alkanoyl radical is substituted with carbamoyl, morpholino (lower alkanoyl), thiomorpholino- ( lower alkanoyl), pyridyl- (lower alkanoyl), quinolyl- (lower alkanoyl), tetrazolyl- (lower alkanoyl), N-morpholino- or N-thiomorpholinocarbonyl substituted with amino- (lower alkanoyl) amino, halogen- ( lower alkanoyl) containing up to three halogen atoms, 2- (N-morpholino- (lower alkyl) -carbamoyl) - (lower alkanoyl), 2- (N-pyridyl- (lower alkyl) -carbamoyl) - ( lower alkanoyl), 2 (R, S) - [N- (2-pyridylmethyl) -carbamoyl] -3-methylbutyryl, (lower alkoxy) -carbonyl, (lower alkyl) -sulfonyl, morpholinosulfonyl, thiomorpholinosulfonyl, N-pyridyl - (lower alkyl) -N- (lower alkyl) carbamoy or an acyl residue of an amino acid selected from glycine, alanine, valine, leucine, isoluecin, glutamic acid and asparagine in the form of D, L or (D, L), wherein the α-amino group is not substituted or is acylated with one of the remaining said radicals and R _2, with the proviso that not more than one of the substitueritú R and R _g is H; R _2, R _4, R ₆ and R are hydrogen, R ₃ represents a lower alkyl group, cyclohexyl- (lower al? or a phenyl- (lower alkyl) group optionally substituted by a halogen atom, a lower alkoxy group or a cyano group; R ₅ is hydroxy and R _? is lower alkyl, cyclohexyl (lower alkyl) or phenyl (lower alkyl) group which is optionally substituted by halogen, lower alkoxy or kyanosku298 Pina, as defined above for R _3, '. or a salt thereof, if salt-forming groups are present. A compound of formula I according to claim 1, wherein R 1 and R 8 are the monovalent radical of the amino acid (L) -valine acylated with benzyloxycarbonyl at the amino nitrogen atom. each bonded via a carboxy group, R ₂ and R _g are hydrogen atoms, R 1 is benzyl, R ₄ is hydrogen, R ₅ is hydroxy, R 8 is hydrogen, Ry is benzyl and the radicals R ₃ and R ₅ bearing asymmetric carbon atoms in are S-configuration, as well as pharmaceutically acceptable salts of this compound. • 6. A compound of formula I according to claim 1, wherein Rj_ and R monovaletni they mean a radical of an amino acid (L) -valine acylated 4-thiomorfolinokarbonylem the nitrogen atom of the amino group bonded via the carboxy group each, R ₂ and R are hydrogen, R ₃ is benzyl, R ₄ is hydrogen, R ₅ is hydroxy, R 8 is hydrogen, Ry is isopropyl, and the R ₃ and R ₅ radicals bearing the asymmetric carbon atoms are in the S-configuration, the same as the pharmaceutically acceptable salts of the compound. Compounds of formula (I) according to any one of claims 1 to 6 for use in a method of treatment of the human or animal body. 8. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt of such a compound with at least one salt-forming group, together with at least one pharmaceutically acceptable carrier. 299 Use of a compound of formula I according to any one of claims 1 to 6, or a pharmaceutically acceptable salt of such a compound with at least one salt forming group, for the manufacture of a pharmaceutical composition for use in inhibiting the activity of the HIV-gag protease enzyme. A process for the preparation of a compound of formula I according to claim 1, wherein the substituents have the meanings given in claim 1, and salts thereof, characterized in that a) a hydrazine derivative of the general formula III I ^R E wherein the radicals are as defined above, is coupled with the epoxide of formula IV L '| J / UDÍNISVIA j 0Η3Λ0 iSAWgyd ε 6 .A 6 l 01§00 i c l o ε o f´2 έ ». · - 300 - in which the residues have the meanings given above,. .. wherein the free functional groups, with the exception of those involved in the reaction, are optionally in a protected form, and optionally protecting groups present are cleaved, or b) For a compound of formula I, wherein R · ^ and R _G are acyl, sulfo group, optionally substituted alkyl, aryl, heterocyclyl, alkoxy, which is optionally substituted, or an aryloxy group substituted sulfonyl, sulfamoyl which is optionally substituted on carbon nitrogen, or phosphoryl substituted with one or two radicals selected independently of one another from optionally substituted alkyl, optionally substituted cycloalkyl, aryl, hydroxy, optionally substituted alkoxy, cycloalkoxy and aryloxy, R ₂ and R ₆ are alkyl, or alkyl, or alkyl, or are heterocyclyl and the remainder of the radicals have the meanings indicated, the amino compound of formula V (V) in which the radicals have the meanings indicated hereinbefore are condensed with an acid of the formula VI Rg-OH (VI) 301 in which R 8 is as hereinbefore defined, or a reactive derivative of the acid, wherein the free functional groups, except for those involved in the reaction, are optionally in a protected form, and optionally protecting groups present are cleaved, or (c) for the preparation of compounds of formula (I) in which R @ 1 and R @ 8 are acyl, sulfo, optionally substituted alkyl, aryl, heterocyclyl, optionally substituted, or aryloxy substituted sulfonyl, sulfamoyl, optionally substituted on a nitrogen atom; or phosphoryl substituted by one or two groups selected independently from an optionally substituted alkyl, optionally substituted cykloalŔylu, aryl, hydroxy, optionally substituted alkoxy, cycloalkoxy and aryloxy groups, R ₂ and R _g are hydrogen, optionally substituted alkyl, alkenyl or alkynyl or heterocyclyl and the remainder of the radicals have the above-mentioned meanings, the amino compound of the general formula. VII (VII), in which the radicals have the meanings given hereinbefore, is condensed with an acid of formula VIII R 1 -OH (VIII), 302 in which RL is as hereinbefore defined, or a reactive derivative thereof, wherein the free functional groups, except for those involved in the reaction, are optionally protected _; and, if appropriate, the protecting groups present are cleaved, or d) for the preparation of compounds of formula I in which R1 and Rg are two identical radicals selected from acyl, sulfo, optionally substituted alkyl, aryl, heterocyclyl, optionally substituted, or aryloxy substituted sulfonyl, sulfamoyl optionally substituted on the nitrogen, and phosphorus oxychloride -substituted by one or two groups selected independently from an optionally substituted alkyl, optionally substituted cycloalkyl, aryl, hydroxy, optionally substituted alkoxy, cycloalkoxy and aryloxy groups, R ₂ and R _g are hydrogen, optionally substituted alkyl, alkenyl or alkynyl or heterocyclyl and the remainder of the radicals have the meanings indicated, a diamino compound of formula IX Q (IX), wherein the radicals have direct herein above, is allowed to condense en introduction of the identical residue, and R _g, the appropriate acid or a reactive derivative thereof, wherein R and R are directly mentioned above, where free functional groups with the exception of the groups participating in the The reaction is optionally in a protected form, and optionally a protecting group is present 303 pins, or (e) for the preparation of a compound of formula (I) wherein, in place of R _{7, a} residue of R ₇ , which represents optionally substituted alkyl or cycloalkyl, is present, the compound of formula (I ') is ï) in which: R ^@ ₇ represents a hydrogen atom and the remaining radicals have the meanings given above, f introduces the residue R _{7 by} substitution with a compound of formula XII R ₇ -X (XII) wherein X represents a leaving group and R ₇ is optionally substituted alkyl or cycloalkyl, wherein the free functional groups, except for those involved in the reaction, are optionally in a protected form, and optionally protecting groups present are cleaved, or f) in a compound of formula I wherein the substituents have the meanings given above, with the proviso that at least one functional group is protected in the corresponding compound of formula I 304, the protecting groups present are cleaved and, if necessary, the compound of formula I, with at least one salt-forming group, obtained by one of methods a) to f) above, is converted to its salt or the resulting salt is converted to the free compound or into another salt, and / or optionally the resulting isomeric mixture is separated, and / or a compound of formula I according to the invention into another f i ^1> A compound of formula I according to the invention. 11. A compound of formula II i wherein optionally represents substituted alkyl or aryl, heterocyclyl or optionally substituted alkenyl; and R ₇ represents optionally substituted alkyl or cycloalkyl, aryl, heterocyclyl or optionally substituted alkenyl, as well as salts of this compound when it contains salt-forming groups.