SK280292A3 - New derivatives of 5-amino-4-hydroxyhexane acid effecting as therapeutic agents - Google Patents

Abstract

Disclosed are substituted pyrimidines of the general formula (I) wherein R1, R2, R3 and R4 are independently H, alkyl containing 1 to 6 carbon atoms, or perfluoroalkyl containing 1 to 6 carbon atoms; R5 is H or when n is 1 R5 taken together with R3 comprises a double bond, n is 0 to 1, p is 0 to 2, m is 0 to 3; Ar1 and Ar2 are as disclosed in the Description; and are useful for treating hypertension or congestive heart failure and for preventing or treating restenosis following angioplasty; pharmaceutical compositions; and methods for production thereof.

Description

Technical field

The present invention relates to non-hydrolyzable analogues of aspartate protease cleavable peptides, a 5-amino-4-hydroxyhexanoic acid derivative, to a process for their preparation, to pharmaceutical compositions containing them and to their use as medicaments or for the manufacture of pharmaceutical compositions for controlling diseases caused by retroviruses.

BACKGROUND OF THE INVENTION

To date, AIDS is known to be a disease of the immune system caused by HIV retrovirus (human immunodeficiency virus). This disease is estimated by the World Health Organization (WHO) about 10,000 people and is still expanding. The disease virtually always leads to the death of the patient.

To date, though, the retroviruses HIV-1 and HIV-2 (HIV is a human immunodeficiency virus) indicate the cause of the disease, and characteristics of the polymers with a molecular biological viewpoint _f Kehoe. For treatment, it is interesting to relieve the symptoms of AIDS beyond the limitations so far, and in addition, some preventive options are of particular interest, especially the search for a preparation that limits the reproduction of the virus itself, without damaging the intact cells and tissues of the patient.

Interesting promises are compounds that block the process of virus propagation by preventing the assembly of infectious vortex particles.

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 proteins that arise from the region of the gag coding genome (group specific antigens). This releases the structural proteins of the core. The gag-Protease itself is part of the forerunner of the 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 and toproteolytically.

The 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.

Based on the central role of the gag protease in the core proteins mentioned in the process, it is assumed that effective inhibition of this enzyme is stopped in vivo by co-construction of mature viruses so that the corresponding inhibitors can be used therapeutically.

A prerequisite for in vivo therapeutic efficacy is to achieve good bioavailability, for example high blood levels, to achieve high concentrations that are sufficient for infected cells.

A series of synthetically produced gag-protease suppressants that already contain middle groups that do not represent would already be produced! proteolytically cleavable peptide isosteres. However, to date, despite intensive research, it has not been possible to provide a suitable protease aspartate suppressant formulation for use in humans to suppress AIDS to a large extent by seizure. In particular, pharmacodynamic problems are decisive. It is therefore an object of the present invention to provide a novel class of HIV-1 aspartate protease inhibitor compounds.

SUMMARY OF THE INVENTION

The compounds of the present invention are compounds of formula I

wherein hydrogen is (lower alkoxy) carbonyl, heterocyclylcarbonyl, benzyloxycarbonyl optionally substituted by one to three radicals independently of one another selected from fluorine, halogen (lower alkyl), lower alkanoyl, sulfo, (lower alkyl) sulfonyl and cyano, heterocyclyloxycarbonyl 1, wherein the heterocyclyl moiety is attached via a carbon atom, one of said carbonyl radicals in which the linking carbonyl group is replaced by a thiocarbonyl, heterocyclylsulfonyl, (lower alkyl) sulfonyl or N- (heterocyclyl (lower alkyl)) - N- (lower alkyl) aminocarbonyl means a bond or a bivalent radical derived from an α-amino acid whose terminal nitrogen atom is attached to and the terminal carbon atom is attached to an amino group on a carbon atom containing R ₂ -CH ₂ -,

R ₂ and R 3 are each independently phenyl or cyclohexyl, which radicals are optionally substituted with one to three radicals selected independently of one another from hydroxy, lower alkoxy, halogen, halogen (lower alkyl), sulfo, (lower alkyl) sulfonyl, cyano and nitro groups,

A 1 represents a bond between -C-O and A ₂ or a bivalent radical derived from an α-amino acid which is linked at the terminal nitrogen atom to the group -C = O and the terminal carbon atom is linked to A ₂ and

A ₂ represents a bivalent radical derived from an α-amino acid which is linked at the terminal nitrogen atom with A 1 and the terminal carbon atom is linked to the NR ₄ R 8 group or and A ₂ together form the bivalent radical of the dipeptide whose middle amide bond is reduced and terminal the nitrogen atom is linked to the group -OO and the terminal carbon atom is linked to the group of the formula NR ₄ R ₅ a

R ₄ and _R are taken together with the binding nitrogen atom unsubstituted or substituted thiomorpholino or morpholino, or a salt thereof, if they contain salt-forming groups, or derivatives thereof, or a salt thereof, which contain hydroxy protecting group.

As used herein, the term "lower" used to define groups, moieties or moieties such as lower alkyl, (lower alkoxy) carbonyl groups and the like means that groups, moieties or moieties as defined herein, unless otherwise noted, contain up to 7 including a carbon atom.

preferably up to 4 carbon atoms inclusive.

Optionally present asymmetric carbon atoms in the substituents R ^, B ^, _{R2 »R3,} N and / or A _2, the same as in substituted thiomorpholino or morpholino formed from R ₄ and R _g together with the binding nitrogen atom may be (R), (S) or (R, S) configuration. Thus, the compounds of the invention may be in the form of isomeric mixtures or as pure isomers, particularly as diastereomeric mixtures, enantiomeric pairs or pure enantiomers.

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

(The lower alkoxycarbonyl group R1 preferably contains a lower alkyl moiety, especially a sec- (lower alkyl) or tert- (lower alkyl) residue, and is, for example, butoxycarbonyl such as tert-butoxycarbonyl or isobutoxycarbonyl. butoxycarbonyl.

Heterocyclylcarbonyl R ^ contains a particular five- or six-membered heterocycle which contains 1 to 3 heteroatoms selected independently of one another from a sulfur, oxygen or nitrogen atom, wherein the heterocyclyl moiety is unsaturated or fully or partially saturated and is one to three times benzanlated, cyclopentaanellated, cyclohexa or cycloheptaanellated, wherein said fused rings may contain an additional nitrogen atom as a heteroatom, for example, a heterocyclyl moiety selected from pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinolyl, isoquinolyl, quinolyl, isoquinolyl, quinolyl, carbolinyl and benzanellated, cyclopentaanellated, cyclohexaanellated or cycloheptaanellated derivatives of this series, which may also be partially or fully saturated, preferably partially saturated, or selected from pyridylcarbonyl, for example pyridyl-3-carbonyl, morpholinylcarbones morpholinocarbonyl and benzofuranoyl, e.g.

3-benzofuranoyl, the same as the alternative or complementary tetrahydroisoquinolyl-3-carbonyl selected from them, for example tetrahydroisoquinolyl-3-carbonyl, preferably tetrahydroisoquinolyl-3 (S) -carbonyl.

Benzyloxycarbonyl R 4 is not substituted or is substituted up to three times independently of one another with radicals selected from fluorine, halogen (lower alkyl), for example trifluoromethyl or pentafluoroethyl, lower alkanoyl, such as acetyl, propanoyl, butyryl or pivaloyl, sulfo, (lower alkyl) sulfonyl groups such as methylsulfonyl, ethylsulfonyl, n-propylsulfonyl or isopropylsulfonyl and cyano. Preferred is benzyloxycarbonyl o-, m- or p-substituted, especially p-substituted in the phenyl ring with a radical selected from fluorine, trifluoromethyl, sulfo, methylsulfonyl, ethylsulfonyl and cyano, for example benzyloxycarbonyl, fluorophenylmethoxycarbonylmethyl, such as p-fluorophenyl phenyl, such as p-fluorophenyl trifluoromethylphenylmethoxycarbonyl, methylsulfonylphenylmethoxycarbonyl, such as p-methylsulfonylphenylmethoxycarbonyl or cyanophenylmethoxycarbonyl, such as p-cyanophenylmethoxycarbonyl.

Heterocyclyloxycarbonyl contains as a heterocyclyl moiety a particular 5- or 6-membered heterocycle containing 1 to 3 heteroatoms selected independently of one another from a sulfur, oxygen or nitrogen atom, wherein the heterocyclyl moiety is unsaturated or fully or partially saturated and is one or three times benzanellated, cyclopenta cyclohexaanellated or cycloheptaanellated, wherein said anionic rings may contain an additional nitrogen atom as a heteroatom, for example moieties selected from pyrrolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, benzoquinolinyl, isoxinolinyl, quinolinyl, quinolinyl, quinolinyl, quinolinyl, quinolinyl, quinool , a cyclopenta-fused, cyclohexa-fused or cyclohepta-fused derivative of this series, which may also be partially or fully saturated, wherein the heterocyclyl moiety is attached via a ring carbon atom to the oxygen atom belonging to the oxycarbonyl a residue, preferably selected from pyrrolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl, β-carbolinyl and a fully or partially saturated derivative of this series, for example a partial or saturated derivative thereof -3-yloxycarbonyl, benzthioazol-6-yloxycarbonyl or quinol-8-yloxycarbonyl. In a very particular preferred variant of this definition, R 1 does not include heterocyclyloxycarbonyl radicals in all planes of the definition.

In these residues, the carbonyl-binding group may also be replaced by a thiocarbonyl group. A carbonyl group is preferred.

The (lower alkyl) sulfonyl group R 1 is preferably methylsulfonyl, ethylsulfonyl, n-propylsulfonyl or isopropylsulfonyl. Compounds of formula (I) in which R1 represents a (lower alkyl) sulfonyl group and the remainder of the radicals have the meanings given above may be omitted or are particularly preferred in the definition of compounds of formula (I).

Heterocyclylsulfonyl preferably contains as the heterocyclyl moiety the heterocyclyls mentioned under the heterocyclylcarbonyl R 1 optionally substituted by a lower alkyl group such as methyl or ethyl, with heterocyclyl moieties having at least one nitrogen atom attached to the sulfur atom of the sulfonyl group, and especially piperidinosulfonyl, unsubstituted or on a nitrogen atom, not a sulfur atom bound to a sulfonyl group, lower alkyl such as methyl, substituted piperazin-1-ylsulfonyl, pyrrolidin-1-ylsulfonyl, imidazolidin-1-ylsulfonyl, pyrimidin-1-ylsulfonyl, quinolin -1-ylsulfonyl, morpholinosulfonyl or thiomorpholinosulfonyl, especially thiomorpholinosulfonyl or morpholinosulfonyl. Compounds of formula I wherein R, is heterocyclylsulfonyl and the remainder of the radicals have the meanings indicated may be omitted or are particularly preferred in the definition of compounds of formula I.

N- (Heterocyclyl (lower alkyl)) - N- (lower alkyl) aminocarbonyl R 1 contains preferably as the heterocyclyl moiety the heterocyclyls listed under heterocyclylcarbonyl R _x , especially pyridyl such as 2-, 3- or 4-pyridyl, pyrazinyl, pyrimidinyl , morpholinyl, such as morpholino, thiomorpholinyl, such as thiomorpholino, or quinolyl, such as 2- or

3-quinolyl, and is especially N- (heterocyclylmethyl) -N-methylaminocarbonyl, for example N- (pyridylmethyl) -N-methylaminocarbonyl such as N- (2-pyridylmethyl) -N-methylaminocarbonyl. Compounds of formula I in which R @ 1 is N- (heterocyclyl (lower alkyl)) - N- (lower alkyl) aminocarbonyl and the remainder of the radicals have the meanings indicated may be omitted or are particularly preferred in the definition of compounds of formula (I).

The α-amino acid-derived bivalent radical, which is linked to R 1 at the terminal nitrogen atom and is linked to the amino group at the carbon atom bearing the R ₂ -CH ₂ - group, is preferably 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 acid) -aminohexanoic, H-Nle-OH), serine * (H-Ser-OH), homoserine (α-amino-T-hydroxymethyl 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), p-fluorophenylalanine (H- (pF)) Phe) -OH), tyrosine (H-Tyr-OH), p-methoxyphenylalanine (H- (p-CH ₃ O-Phe) -OH), 4-aminophenylalanine, 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, k 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acids, aminomalonic acid, aminomalonic acid monoamide, aspartic acid (H-Asp-OH), asparagine (H-Asn-OH), 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-diaminovaleric acid) , α, τ-diaminobutyric acid and α, β-diaminopropionic acid, or alternatively and complementary 4-cyanophenylalanine (H- (p-CN-Phe) -OH), a particularly preferred hydrophobic amino acid residue, for example proline, phenylalanine, p -fluorophenylalanine, p-methoxyphenylalanine, tyrosine, phenylglycine, α-naphthylalanine, cyclohexylalanine, cyclohexylglycine or an aliphatic α-amino acid selected from glycine, valine, norvaline, alanine, leucine, norleucine, and isoleucine, each of which is valine, α-amino; in form D, L or (D, L), preferably in form L, and in particular is bound to a residue selected from (lower) alkoxycarbonyl groups, for example tert-butoxycarbonyl, or heterocyclylcarbonyl, for example morpholinocarbonyl.

When B 1 is a bond, it is bound directly to the nitrogen atom of the amino group that binds the carbon atom bearing the radical R ₂ -CH ₂ - in formula (I).

Phenyl or cyclohexyl R ₂ or R ₃ is optionally substituted with up to three radicals independently of one another selected from hydroxy, lower alkoxy, such as methoxy or

10 ethoxy, halogen, for example fluorine, halogen (lower alkyl), for example trifluoromethyl, sulfo, (lower alkyl) sulfonyl, for example methylsulfonyl or ethylsulfonyl, cyano and nitro, preferably substituted by one or two such radicals, particularly preferred selected from hydroxy, methoxy, fluorine, trifluoromethyl, sulfo, (lower alkyl) sulfonyl, for example methylsulfonyl or ethylsulfonyl, and cyano, for phenyl particularly preferably selected from fluorine and cyano, for cyclohexyl, especially preferred fluorine; trifluoromethyl, sulfo or (lower alkyl) sulfonyl, especially a fluorine atom, said substituents being attached at the 2, 3 or 4 position of the phenyl or cyclohexyl ring, especially bonded at the 4-position, such as in the case of phenyl, cyclohexyl, 4-fluoro or 4-cyanophenyl or 4-fl uorocyclohexyl, especially in phenyl, cyclohexyl, 4-cyanophenyl or 4-fluorophenyl.

Particularly preferred are those combinations of R ₂ and R ₃ in which one or more of R ₂ or R ₃ is substituted with one or three residues selected from halogen, especially fluorine, halogen (lower alkyl), especially trifluoromethyl, sulfo, (lower alkyl) sulfonyl, especially methylsulfonyl or ethylsulfonyl, cyano and nitro, wherein in a particularly preferred manner the substituent is selected from a fluorine atom or a cyano group.

More preferably, R _{2 is} selected from phenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-fluorophenyl, cyclohexyl, and 4-trifluoromethylphenyl, while R ₃ is selected from phenyl, 4-hydroxyphenyl, 4-methoxyphenyl, cyclohexyl, 4-fluorophenyl, 4 -trifluoromethylphenyl and 4-cyanophenyl.

R ₂ is primarily selected from phenyl, 4-fluorophenyl and cyclohexyl, while R 1 is selected from phenyl, cyclohexyl, 4-fluorophenyl and 4-cyanophenyl.

Extraordinary preferred are the following combinations: R ₂ is phenyl and R ₃ is phenyl, R ₂ is cyclohexyl and R ₃ is 4-cyanophenyl, R ₂ is cyclohexyl and R ₃ is

4-fluorophenyl, and R ₂ and R ₃ are each cyclohexyl. Alternative or additional to do so also particularly preferably the following combinations: R ₂ is phenyl and R ₃ is 4-fluorophenyl, R ₂ is phenyl and R ₃ is 4-cyanophenyl, R ₂ is 4-fluorophenyl and R ₃ is 4-fluorophenyl, R ₂ is 4-fluorophenyl and R ₃ is 4-trifluoromethylphenyl, R ₂ is 4-trifluoromethylphenyl and R ₃ is phenyl, R ₂ is 4-trifluoromethylphenyl and R ₃ is 4-fluorophenyl, R ₂ is 4-trifluoromethylphenyl and R ₃ is 4-trifluoromethylphenyl, R ₂ is hydroxyphenyl and R ₃ is phenyl, R ₂ is phenyl and R ₃ is hydroxyphenyl or R ₂ is hydroxyphenyl and R ₃ is hydroxyphenyl.

Hydroxy groups, in particular hydroxyl groups in the compounds of formula I on a carbon atom adjacent to a carbon atom containing a radical R ₂ -CH ₂ -, may be in free or protected form, with hydroxyl protecting groups suitable as those described in the description of the process of the formula I, in particular free or protected as physiologically cleavable esters, for example as (lower alkanoyl) oxy, such as acetoxy.

The bivalent radical derived from the α-amino acid A _1f which is linked at the terminal nitrogen atom to the group -C »O and at the terminal carbon atom with A ₂ is, for example, the remainder of the α-amino acids listed above for Β _χ , where the amino acids may be , L or (D, L) form, preferably in the D or L form, especially in the form L. Preferred hydrophobic amino acids and the B _{l of} separate clip in this connection mentioned or

- 12 fatal hydrophobic α-amino acids such as glycine, valine or isoleucine. in said α-amino acids, the A ₂ -binding carboxy group is not reduced or is further reduced, especially to the methylene group, for example in said hydrophobic α-amino acids, such as in the reduced amino acid radicals Gly (red), Val (red) or Ile (red), in Val (red), wherein the addition (red) indicates the reduction of the carbonyl group of the corresponding amino acid radical to a methylene group.

If A _{x is a} bond, then A _{2 is} directly linked to a carbonyl group on a carbon atom containing a radical of formula ^r 3 ^ch 2 "·

The bivalent radical derived from the α-amino acid A ₂ , which is linked at the terminal nitrogen atom with A 1 and at the terminal carbon atom of the group NR ₄ R ₅ , is, for example, one of the α-amino acid residues mentioned above for Β _χ . may be in D, L or (D, L) form, preferably in D or L, particularly in the form L. Preferred hydrophobic α-amino acids mentioned under B _lF as glycine, valine, phenylalanine, p-fluoro-phenylalanine, tyrosine, p-methoxyphenylalanine, phenylglycine, α-naphthylalanine, cyclohexylalanine or cyclohexylglycine, preferably glycine, valine, phenylalanine, p-fluorophenylalanine, p-methoxyphenylalanine or cyclohexylalanine, wherein said residues are in the D or L form, preferably in the L form except c. which is in L or D formé.

The bivalent radical of the dipeptide formed from A 2 and A ₂ , whose central peptide bond is reduced, the terminal nitrogen atom is bonded to a group of formula -C = O, and the terminal carbon atom is bonded to a group of formula NR 1 R 8, preferably consists of the 2 hydrophobic α-amino acids, especially selected from the nitrogen-terminal amino acid radical selected from Gly (red), Val (red) and Ile (red), and the carbon-terminal amino acid selected from glycine, phenylalanine, tyrosine, p-fluorophenylalanine, p-methoxyphenylalanine, cyclohexylalanine and p-fluorophenylalanine.

_"Α χ ₂ and A particularly advantageous together form a bivalent radical of a dipeptide of the formula Val-Phe, Ile-Phe, Val-Cha, Cha-Ile, Val-Gly, Val (pF-Phe), Val- (p-CH ₃ O -Phe), Gly- (pF-Phe) and an alternative or additional dipeptide of the formula Val-Tyr, Ile-Tyr, Gly-Tyr, Ile-Gly or Val-Val, wherein the amino acids are in the D or L form, especially the L form, with the exception of (L) -Val-Phe, wherein Phe is in the form of L or D, or a derivative thereof with a reduced central amide bond, for example of the formula Val (red) -Phe, whose terminal nitrogen atom is linked to -C = oa the terminal carbon atom is linked to the NR ₄ R _{5 group} .

A preferred embodiment of the invention relates either to the compounds of formula I in which B ₁ represents one of said α-amino acid bivalent radicals and one of the residual Α _χ and A ₂ represents a bond and the other represents one of said α-amino acids, or such compounds of the formula I in which the bond and the radicals A @ 1 and A @ ₂ are each one of said bivalent α-amino acid radicals or in common one of said bivalent dipeptide radicals with a reduced central amide bond.

The thiomorpholino or morpholino group formed with Z ₄ and R ₅ together with the nitrogen atom is unsubstituted or substituted on one or more carbon atoms, preferably on one carbon atom, by a lower alkyl group such as ethyl, propyl, butyl, isobutyl or tert- butyl, phenyl or naphthyl (lower alkyl), such as benzyl, 1- or 2-naphthylmethyl or phenyl-1- or phenyl-2-ethyl, especially phenyl-1- or phenyl-2-ethyl, hydroxy, lower alkoxy, such as methoxy , ethoxy or tert-butoxy, amino, (lower alkyl) amino, such as methyl or ethylamino, or di (lower alkyl) amino, such as dimethylamino or diethylamino, lower alkanoyl such as acyl or propionyl, phenyl or naphthyl lower alkanoyl) a group such as phenylacetyl or 1- or 2-naphthylacetyl, a carboxy group (lower alkoxy) carbonyl such as isopropoxycarbonyl or tert-butoxycarbonyl, phenyl, naphthyl or fluorenyl (lower alkoxy) carbonyl, such as benzyloxycarbonyl, 1- or 2-naphthylmethoxycarbonyl or 9-fluorenylmethoxycarbonyl, carbamoyl, mono- or di (lower alkyl) carbamoyl, , mono- or di / hydroxy (lower alkyl) / carbamoyl, such as dihydroxymethylcarbamoyl, sulfo, (lower alkyl) sulfonyl, such as methylsulfonyl or ethylsulfonyl, phenyl or naphthylsulfonyl, the phenyl may be substituted with a lower alkyl group such as methyl or ethyl , for example, phenylsulfonyl, toluenesulfonyl, sulfamoyl, a halogen atom, for example a fluorine or chlorine ton, cyano, nitro and / or oxo.

Highly preferred forms R ₄ and R _s taken together with the binding nitrogen atom unsubstituted thiomorpholino or morpholino, above all unsubstituted morpholino.

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

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

Such salts form, for example, compounds of the general formula

I with an acidic group, for example a carboxy group or a sulfo group, and are, for example, their salts with suitable bases, such as non-toxic metal salts derived from metals from Ia, Ib, IIIa and IIb of the Periodic Table, especially alkali salts such as lithium, sodium or potassium, or alkaline earth salts, for example magnesium or calcium salts, zinc or ammonium salts, and also those formed with organic amines such as optionally substituted by mono-, di- or trialkylamines, in particular 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) methylamine, N, N-di (lower alkyl) -N- (hydroxy (lower alkyl)) amines such as N, N-dimethyl-N- (2-hydroxyeth yl) amine or tri- (2-hydroxyethyl) amine, N-methyl-D-glucamine or quaternary ammonium salts such as tetrabutylammonium salts. The compounds of the formula I with a basic group, for example an amino group, can form acid addition salts with, for example, inorganic acids, for example hydrohalic acids, such as hydrochloric acid, sulfuric acid or phosphoric acid, or with organic carboxylic acids, sulfonic acids, sulfoacids, acids containing phosphorus or N-substituted sulfamic acids such as acetic, propionic, glycolic, succinic, maleic, hydroxymalein, methylmalein, fumaric, malic, tartaric, gluconic, glucuronic, glucuronic, citric, benzoic, cinnamic, mandelic, salicylic, 4 -aminosalicyl, 2-phenoxybenzoic,

2-acetoxybenzoic, embonic, nicotinic or isonicotinic, followed by amino acids such as the aforementioned α-amino acids, the same as methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1,2-disulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, naphtha len-2-sulfonic acid, 2- or 3-phosphoglycerate, glucose-6-phosphaternate, with N-cyclohexylsulfamic acid (to form cyclamate) or with other acidic organic compounds such as asorbic acid. The compounds of formula I with acidic and basic groups may also form inner salts.

The use of a pharmacologically unsuitable salt may also be found for isolation or purification.

The terms compound and salt include expressly also individual compounds or individual salts.

The compounds of the present invention have a suppressing effect on retroviral aspartate protease, especially a gag protease suppressing effect. In particular, these compounds suppress the effects of HIV-1 gag-protease in the tests described below at concentrations ranging from 10 < 10 > to 10 < 0 > mol and are therefore 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 7, 1785-1791 (1988). The inhibition of the effect of HIV-1 protease on the substrate, which is the experimental protein fusion in Escherichia coli from the precursor gag-protein and MS-2, is measured. The substrate and its cleavage products are resolved by polyacrylamide gel electrophoresis and rendered visible by immunoblotting with monoclonal antithesis against MS-2.

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

For example, a synthetic chromophoric peptide (e.g. HKARVL (NO ₂ )) is used as a substrate for recombinant HIV-1 protease (production according to S. Billich et al. In J. Biol. Chem. 264 (34). 17905-17908 (1990)). (FANleS (Bachem, Switzerland)) or a nicoseptide (such as RRSNQVSQNYPIVQNIQGRR (produced by peptide synthesis according to a known method)), which corresponds to the gag-protein precursor cleavage site. This substrate and its cleavage products can be measured by high pressure liquid chromatography (HPLC).

For this purpose, the test compound of the formula I suppressant is dissolved in dimethylsulfoxide and an enzyme test is carried out, while a suitable diluted suppressant compound in 20 mmol of a pH-0-morpholinoethanesulfonic acid buffer (MES buffer) of pH 6.0 is contacted with a test mixture consisting of 67.2 μ mol 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 MES buffer pH 6.0. The handle size is 100 μΐ. The reaction is initiated by the addition of HIV-1 protease of 2 μ 2 in the first case and 10 μ druhém in the second case, and is stopped after 15 minutes of incubation at 37 ° C by addition of 100 μΐ of 0.3 molar perchloric acid and in the second Incubate for one hour at 37 ° C with 10 μΐ of 0,3 molar perchloric acid. The reaction products are quantified after centrifugation for 5 minutes at 10,000 xg in a 100 μΐ (chromophoric peptide feed) or 20 μΐ (icosapeptide feed) supernatant and after loading onto a 125 x 4.6 mm Nucleosil ^R Ο 18-5μ column. -ΗΡΕΟ (Macherey & Nagel, Duren) and elution based on the step height of the step product at 280 nm (chromophore peptide feed) or 215 nm (icosa peptide feed), gradient: 100% El.l -> 50% El .1 / 50% E1.2 (E1: 10% acetonitrile, 90% water, 0.1% trifluoroacetic acid, E1.2: 75% acetonitrile, 25% water, 0.08% trifluoroacetic acid) over 15 minutes , at a flow rate of 1 ml / min (E1 = eluent).

In this case, the set of compounds of formula I, preferably the IC _go (the IC ₅₀ is that concentration at which decreases the activity of HIV-1 protease vs the control mode determination of the absence of substances causing suppression of 50%) of from about 10 ^"6 to 10 ^{- 9} mol, from about 10 ^"7 to about 10 ^-8 mol.

In another assay, the compounds of the invention may be shown to protect cells that are usually infected with HIV from such infection or at least to slow such infection. In this process, human leukemia T cells of the cell line MT-2 (Science 229. 563 (1985)) which are sensitive to the cytopathogenic effect of HIV are incubated with HIV-1 or HIV-1 alone in the presence of the compounds of the invention. determines the lifetime of the cells thus treated.

In addition, MT-2 cells are maintained in RPMI 1640 (Gibco, Switzerland, RPMI 1640 contains a mixture of amionic acids without L-Gln), supplemented with 10% heat-inactivated fetal 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 µl of each test compound in culture medium and 100 µl of HIV-1 in culture medium (800 TCID50 / ml) (TCID50 = dose infecting tissue culture 50, with 50 indicating the dose that infects 50% of MT-2 cells) are added to 4x10 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 four-day incubation, reverse transcriptase (RT) activity is determined in 10 μΐ of the cell supernatant. RT-activity was 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, 0.05% Nonidet P-40 (Sigma, Switzerland, surfactant), 50 μς / ml polyadenylic acid (Pharmacia, Switzerland), 1.6 μς / πιΐ dT (12-18) (Sigma, Switzerland). , 45 μ Acrodisc ^R (Gellman Science Inc., Ann Arbor) and stored at -20 ° C.

To an aliquot of this solution was added 0.1% by volume of [α- ³² P] dTTP to achieve a final activity of 10 ¹⁶ s ^-1 .ml ^-1 , transferring the culture supernatant to a new 96-well microtiter plate and here add 30 μΐ of the RT-cocktail already described. After mixing, the plates are incubated 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 the seed treatment of cells not treated with the test substance. RT-activity is a measure for the multiplication of HIV-1.

The proportion of compounds of the invention have, ED 90 values of from about 10 ^-5 to about 10 ^"8 M, preferably from about 10" ⁷ to 10 ^"8 mol.

The compounds of the present invention possess advantageous pharmacokinetic properties allowing the compounds to be expected to develop said inhibitory effects in vivo. For example, the blood level of said compounds when administered intravenously or intraperitoneally in mice at a dose of 20 mg / kg of a compound of formula I is 10 minutes or more after administration of 4 µg / ml of blood. Further, at an oral (p.o.) dose of 120 mg / kg of a compound of formula I, the concentration after 90 minutes is about the same high as the above ED 90 value in a cell experiment.

For example, blood levels are determined as follows:

Compounds to be tested are dissolved in an organic solvent such as dimethylsulfoxide (DMSO). A 20% (w / v) solution of hydroxypropyl-O-cyclodextrin in water is added to the resulting solution until the desired concentration of the active ingredient (e.g. 2 mg / ml for parenteral use, 12 mg / ml for oral use) is achieved with concomitant concentration adjustment. to 5% by volume of dimethylsulfoxide. Compounds which are insoluble under these conditions are only administered intraperitoneally for parenteral use, and soluble compounds are also administered intravenously. Following administration of the compounds (e.g., 20 mg / kg intravenous or intraperitoneal, or 120 mg / kg oral), blood is collected at various time points, for example after 10 minutes for parenteral administration or after 90 minutes for oral administration. Blood from three mice is used at each time point and either the individual or from the blood of three mice is added to each supernatant after addition of a solvent such as acetonitrile followed by centrifugation. The concentration of the active compound was determined by high pressure liquid chromatography, e.g., column Nucelosil ^ ^{5 C]} _g 120 mm length and 4.6 mm, using a mixture of 60 vol% acetonitrile, 40% water and 0.05% by volume trifluoroacetic acid or a mixture of 50% v / v acetonitrile, 40% v / v water and 0.05% v / v trifluoroacetic acid as eluent at a flow rate of 1 ml / min and detection and quantification at 200 nm.

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

A preferred variant of the invention relates to compounds of formula I in which hydrogen, (lower alkoxy) carbonyl, heterocyclylcarbonyl, benzyloxycarbonyl, optionally substituted with one to three radicals independently of one another selected from fluorine, is halogen (lower alkyl) , lower alkanoyl, sulfo, (lower alkylsulfonyl and cyano, or heterocyclyloxycarbonyl, wherein the heterocyclyl moiety is attached via a carbon atom, or one of said carbonyl moieties in which the connecting carbonyl group is replaced by a thiocarbonyl group represents a bond or a bivalent radical derived from α-amino acid whose terminal nitrogen atom is linked to R _x, and the terminal carbon atom is linked to the amino group on a carbon atom-containing R ₂ ^- CH ₂ -, R ₂ and R ₃ are independently phenyl or cyclohexyl, which radicals are optionally substituted with one up to three residues selected from hydroxy, methoxy, halogen, halogen (lower alkyl), sulfo, (lower alkyl) sulfonyl, cyano and nitro, means a bond between -C = O and A ₂ or a bivalent radical derived from an α-amino acid wherein the terminal nitrogen atom is linked to the group -C = O and the terminal carbon atom is linked to A ₂ , A ₂ is a bivalent radical derived from α-amino acid, the terminal nitrogen atom is linked to A 1 and the terminal carbon atom is linked to NR ₄ R ₅ or A 4 and A ₂ together form a bivalent radical of the dipeptide, whose central amide bond is reduced and the terminal nitrogen atom is linked to the group -C = O and the terminal carbon atom is linked to the group of the formulas NR ₄ R ₅ and R ₄ and R ₅ together with the nitrogen bonding atom optionally have a substituted thiomorpholino or morpholino group, and alternatively or additionally to the compounds of formula I, in which ₁ denotes heterocyclylsulfonyl, (lower alkyl) sulfonyl or N- (heterocyclyl (lower alkyl)) - N- (lower alkyl) aminocarbonyl, and the remainder of the remainder have the meanings indicated, or salts of these compounds, if they contain a salt-forming group with a hydroxy group in the compounds of formula I, the carbon atom adjacent the carbon atom carrying a group of the formula R ₂ CH ₂ -, it is in free or protected form of special protection as a physiologically cleavable esters, such as (lower alkanoyl) oxy group such as acetyloxy, wherein both the free compounds of formula I and their protected form, in which all the other radicals have the meanings indicated, or their salts, are particularly preferred. In particular, it is desirable to highlight compounds wherein A 1 and A ₂ are each a bivalent radical derived from the α-amino acid and the remaining residues having the meanings indicated, or salts thereof.

Also preferred are compounds of formula I wherein R 1 is hydrogen, (lower alkoxy) carbonyl, heterocyclylcarbonyl, benzyloxycarbonyl, optionally substituted with one to three radicals independently of one another selected from fluoro, halogen (lower alkyl), lower alkanoyl, sulfo, (lower alkyl) sulfonyl and cyano, or heterocyclyloxycarbonyl wherein the heterocyclyl moiety is attached via a carbon atom, or one of said carbonyl moieties in which the linking carbonyl group is replaced by a thiocarbonyl group, Bj represents a bond or a bivalent radical derived from an α-amino acid whose terminal nitrogen atom is connected to Rj_ a terminal carbon atom is linked to the amino group on a carbon atom of R ₂ -CH ₂ -, R ₂ and R are independently phenyl or cyclohexyl, which radicals are optionally made is substituted with one to three residues of selected from a halogen atom, a halogen (lower alkyl) group, a sulfo group, a (lower alkyl) sulfonyl group, a cyano group and a nitro group, Aj represents a bond between -C = O and A ₂ or a bivalent radical derived from α-amino acid whose terminal nitrogen atom is linked to -C = O and the terminal carbon atom is linked to A ₂ , A ₂ is a bivalent radical derived from α-amino acid, the terminal nitrogen of which is linked to A 1 and the terminal carbon to the group NR ₄ R 8 or A 2; A ₂ together form the bivalent radical of the dipeptide whose central amide bond is reduced and the terminal nitrogen atom is linked to the group -C = O and the terminal carbon atom is linked to the group NR ₄ R 8 and R ₄ and R 8 together with the nitrogen bonding atom optionally substituted morpholino, and alternatively or additionally to a compound of formula I wherein R 1 is heterocyclylsulfonyl, (lower alkyl) sulfonyl or N- / heteroc yklyl (lower alkyl) / N- (lower alkyl) aminocarbonyl and the remainder of the remainder have the meanings indicated, or salts of these compounds, if they contain salt-forming groups, the hydroxy group in the compounds of formula I on a carbon atom adjacent to the carbon atom bearing the group R ₂ -CH ₂ -, is in free or protected form, in particular it is protected as a physiologically cleavable ester, for example as a (lower alkanoyl) oxy group, such as acetyloxy, wherein both the free compounds of formula I and their protected form in which all of the remaining radicals having the meanings indicated, or salts thereof, are particularly preferred.

Also preferred are compounds of formula I wherein at least one of R ₂ and R ₃ is substituted with one to three residues selected from hydroxy, methoxy, halogen, halogen (lower alkyl), sulfo, (lower alkyl) sulfonyl, cyano and the nitro groups and the radicals R 1, B 1, A ₂ , A ₂ and NR ₄ R g in both last paragraphs have their meanings as defined above, and their salts if they contain salt-forming groups.

Particularly preferred are compounds of formula I in which hydrogen is t. butoxycarbonyl, isobutoxycarbonyl, pyridine-3-carbonyl, morpholinocarbonyl, 3-benzofuranoyl, 1,2,3,4-tetrahydroisoquinoline-3-carbonyl, up to three independently of one another from a fluorine atom, halogen (lower alkyl) groups, lower alkanoyl groups , sulfo, (lower alkyl) sulfonyl, and cyano substituted by benzyloxycarbonyl or heterocyclyloxycarbonyl, wherein the heterocyclyl moiety is attached via a carbon atom and is selected from pyrrolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, indiazolyl, pyrazinyl, pyrazinyl, pyrazinyl, pyrazinyl, pyrazinyl, pyrazinyl, pyrazinyl, isoquinolyl, quinoxalinyl, β-carbolinyl and a fully or partially saturated derivative of this series, or where the meaning of heterocyclyloxycarbonyl for R 1 is absent, means a bond or a divalent radical derived from an α-amino acid whose terminal nitrogen atom is linked to R _x and terminal carbon an amino group on a carbon atom bearing the group R ₂ -CH ₂ -r ^{having a} hydrophobic residue and amino acids, for example proline, phenylalanine, p-fluorophenylalanine, phenylglycine, α-naphthylalanine, cyclohexylalanine, cyclohexylglycine or an aliphatic α-amino acid selected from glycine, valine, norvaline, alanine, leucine, norleucine and isoleucine, each of said valine α; The amino acids are in the form of D, L or (D, L), preferably in the form of L, preferably each of said amino acids being substituted by the radicals listed under R _x which are selected from hydrogen, N-tert-butoxycarbonyl or morpholinocarbonyl. R ₂ and R 3 are each independently phenyl or cyclohexyl, wherein these radicals are optionally substituted with one or two radicals independently of one another selected from hydroxy, methoxy, fluorine, sulfo, (lower alkyl) sulfonyl, trifluoromethyl and cyano, such as referred to above in the general definitions means a bivalent radical derived from a hydrophobic α-amino acid, such as is given above in the general definitions, the terminal nitrogen of which is linked to the group -C vzorceO and the terminal carbon atom is connected to A ₂ , A ₂ is a bivalent radical derived from a hydrophobic α-amino acid as described above in the general definitions wherein the terminal nitrogen atom is linked to A ₁ and the terminal carbon atom is linked to a group of formula NR ₄ R ₅ , wherein the amino acid residues may be in the D or L form, preferably in the L form, except phenylalanine which is in the form L or D, especially Α _χ and A ₂ form the bivalent radical of the dipeptide of formula Val-Phe, Ile-Phe, Val-Cha, Ile-Cha, Ile-Gly, Val-Val, Val-Gyl, Val- (pF-Phe) , Val-Tyr, Val- (p-CH-10-Phe) or Gly- (pF-Phe), and wherein the amino acids are in the D or L form, especially the L form, with the exception of (L) -Val-Phe, in wherein Phe is in the form of L or D, or A 1 and A ₂ together form the bivalent radical of the dipeptide of the two hydrophobic α-amino acids, mentioned preferably above under the general definition whose middle amide bond is reduced and the terminal nitrogen atom is bonded to a group of the formula -C -CO and the terminal carbon atom is bonded to a group of the formula NR ₄ R ₅ as shown in the general definitions, for example Val (red) -Phe and R ₄ and R ₅ together with the nitrogen bonding atom form a thiomorpholino or morpholino group, a particular morpholino group, and alternate or additional thereto compounds of formula I wherein R 1 is morpholinosulfonyl or N- (2-pyridylmethyl) -N-methylaminocarbonyl and the remaining radicals have the meanings indicated, and their pharmaceutically usable salts, if they contain salt-forming groups, wherein the hydroxy group of the compounds of formula I on a carbon atom adjacent to the carbon atom bearing the R ₂ -CH ₂ - group is free or protected. lower alkanoyl, especially in the free form, and heterocyclyloxycarbonyl may also be absent in the definition of R1.

Particularly preferred are also compounds of formula I wherein R R is hydrogen, tert-butoxycarbonyl, isobutoxycarbonyl, pyridine-3-carbonyl, morpholinocarbonyl,

3-benzofuranoyl, 1,2,3,4-tetrahydroisoquinoline-3-carbonyl, up to three independently of one another from a fluorine atom, a halogen (lower alkyl) group, a lower alkanoyl group, a sulfo group, a (lower alkyl) sulfonyl group and a cyano group with selected radicals substituted benzyloxycarbonyl or heterocyclyloxycarbonyl, wherein the heterocyclyl moiety is attached via a carbon atom and is selected from pyrrolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolinyl, quinolinyl or quinoxylol, quinoxolyl, quinolinyl, quinoxyl or quinolinyl the lines, and wherein the meaning of R heterocyclyloxycarbonyl missing, Bj is a bond or a divalent radical derived from an α-amino acid whose terminal nitrogen atom is linked to the terminal carbon atom of the amino group on a carbon atom carrying a group of the formula R ₂ -CH ₂ -, preferably a hydrophobic amino acid residue such as proline, phenylalanine, p-fluorophenylalanine, phenylglycine, and - naphthylalanine, cyclohexylalanine, cyclohexylglycine or an aliphatic α-amino acid selected from glycine, valine, norvaline, alanine, leucine, norleucine and isoleucine, particularly valine, preferably each of said α-amino acids being in the form of D, L or (D, L) , preferably in L form, preferably each of said amino acids being substituted with the radicals listed under R _1f selected from hydrogen, N-tert-butoxycarbonyl or morpholinocarbonyl, R ₂ and R ₃ are each independently phenyl or cyclohexyl, wherein these radicals are optionally substituted by one or two radicals independently of one another selected from a fluorine atom, a sulfo group, a (lower alkyl) sulfonyl group and a cyano group as defined above in the general definitions, Α _χ denotes a bivalent radical derived from a hydrophobic α-amino acid such as is given above in the general definitions whose terminal nitrogen atom is linked to a group of formula -C = O and the terminal at the carbon atom is linked to ₂ , A ₂ is a bivalent radical derived from a hydrophobic α-amino acid, preferably as described above in general terms, the terminal nitrogen of which is linked to A 2 and the terminal carbon of the atom is linked to a group of formula NR ₄ R ₅ , wherein these amino acid residues may be in the D or L form, preferably in the L form, with the exception of phenylalanine, which is in the L or D form, particularly and A ₂ forms the bivalent radical of the dipeptide of formula Val-Phe, Ile-Phe, Val-Cha, Ile-Cha, Ile-Gly, Val-Val, Val-Gyl, Val- (pF-Phe), Val- (p-CH ₃ O-Phe) or Gly- (pF-Phe), with amino acids they are in D or L form, in particular L form, except for (L) -Val-Phe, in which Phe is in L or D form, or A 1 and A ₂ together form a bivalent dipeptide radical preferably of two hydrophobic α- amino acids listed above under the general definitions, wherein the central amide bond is reduced and the terminal nitrogen atom is bonded to the group -C = O and the terminal carbon atom is bound to a group of the formula NR ₄ R _5, as shown in the general definitions, for example of the formula Val (red) -Phe, and R ₄ and R _g, together with the binding nitrogen atom m thiomorpholino or morpholino, morpholino separate and alternative or in addition to a compound of formula I in which morpholinosulfonyl or N- (2-pyridylmethyl) -N-methylaminocarbonyl and pharmaceutically usable salts thereof, when containing salt-forming groups, wherein the hydroxy group in the compounds of formula I on a carbon atom which adjacent to a carbon atom bearing an R ₂ -CH ₂ - group, it is free or in the form protected by a lower alkanoyl group, in particular it is in the free form and in the definition of R 1 | also, heterocyclyloxycarbonyl may be absent.

Highly preferred are compounds of formula I wherein R ₁ is hydrogen, tert-butoxycarbonyl, isobutoxycarbonyl, pyridine-3-carbonyl, morpholinocarbonyl, 3-benzofuranoyl or 1,2,3,4-tetrahydroisoquinoline-3-carbonyl or alternatively and in addition, morpholinosulfonyl or N- (2-pyridylmethyl) -N-methylaminocarbonyl, B _L represents a bond or a divalent radical derived from the α-amino acid valine, the terminal nitrogen of which is linked to the terminal carbon atom with the amino group on the carbon atom bearing the group of the formula R ₂ -CH ₂ -, in which latter case R is preferably a hydrogen atom, a tert-butoxycarbonyl or morpholinocarbonyl, or alternatively or supplementary to morpholinosulfonyl or N- (2-pyridylmethyl) -N-methylaminocarbonyl, R _2, and R ₃ is independently of one another phenyl or cyclohexyl, these radicals being optionally substituted by one or two radicals independently of one another selected from hydroxy, methoxy y, fluoro, sulfo, (lower alkylsulfonyl, cyano, and trifluoromethyl) means a bivalent radical derived from the α-amino acid glycine, valine or isoleucine, the terminal nitrogen of which is linked to the group -C = O and the terminal carbon atom is linked to A ₂ , A ₂ is a bivalent radical derived from the α-amino acid glycine, valine, phenylalanine, tyrosine, cyclohexylalanine, p-methoxyphenylalanine or p-fluorophenylalanine, the terminal nitrogen atom of which is linked to A ₁ and the terminal carbon atom of the formula NR ₄ Rg, or further Aj. and A ₂ together form the bivalent radical of the reduced peptide bond dipeptide, which consists of an amino acid radical at a terminal nitrogen atom selected from Gly (red), Val (red) or Ile (red) and an amino acid radical at a terminal and tonal carbon selected from glycine , phenylalanine, cyclohexylalanine, tyrosine, p-methoxyphenylalanine or p-fluorophenylalanine and whose terminal nitrogen atom is bonded to a group of formula -C = O and the terminal carbon atom is bonded to a group of formula NR ₄ R ₅ as described above for A 4 and A ₂ and R ₄ and R ₅ together with the nitrogen bonding atom form a thiomorpholino group or a morpholino group, in particular a morpholino group, and the pharmaceutically usable salts of these compounds, if they contain salt-forming groups.

Also highly preferred are compounds of formula I wherein R R is hydrogen, tert-butoxycarbonyl, isobutoxycarbonyl, pyridine-3-carbonyl, morpholinocarbonyl, 3-benzofuranoyl or 1,2,3,4-tetrahydroisoquinoline-3-carbonyl, or alternatively and additionally, morpholinosulfonyl or N- (2-pyridylmethyl) -N-methylaminocarbonyl, means a bond or a bivalent radical derived from the α-amino acid valine whose terminal nitrogen atom is linked to the terminal carbon atom with an amino group on the carbon atom bearing the formula R ₂ CH ₂ -, wherein in the latter case, R ₃ is preferably a hydrogen atom, a tert-butoxycarbonyl or morpholinocarbonyl, or alternatively or supplementary to morpholinosulfonyl or N- (2-pyridylmethyl) -N-methylaminocarbonyl, R _2, and R ₃ are, independently of one another, phenyl or cyclohexyl, these radicals being optionally substituted by one or two radicals independently of one another selected from fluorine, sulphose A, is a bivalent radical derived from the α-amino acid glycine, valine or isoleucine, the terminal nitrogen of which is linked to a group of the formula - C 2 O and the terminal carbon atom is linked to A ₂ , A ₂ is a bivalent radical derived from one of the α-amino acids including glycine, valine, phenylalanine, tyrosine, cyclohexylalanine, p-methoxyphenylalanine or p-fluorophenylalanine whose terminal nitrogen atom is linked with A 1 and the terminal carbon atom is linked to a group of the formula NR ₄ R ₅ , or further A 1 and A ₂ together form a bivalent radical of the reduced peptide bond dipeptide selected from the amino acid radical at the terminal nitrogen atom selected from Gly (red) ), Val (red) or Ile (red) and an amino acid radical at a terminal carbon atom selected from glycine, phenylalanine, tyrosine, cyclohexylalanine, p-meth oxyphenylalanine or p-fluorophenylalanine and whose terminal nitrogen atom is bonded to a group of formula -C = O and the terminal carbon atom is bonded to a group of formula NR ₄ R ₅ as above for Α _χ and A ₂ , and R ₄ and R ₅ together with the nitrogen bonding atom form a thiomorpholino or morpholino group, especially a morpholino group, and pharmaceutically usable salts of the compounds, if they contain salt-forming groups.

Even more preferred are compounds of formula I according to hitherto elaborated definitions wherein Βχ is said α-amino acid bivalent radical and one of Αχ and A ₂ is a bond and the other is α-amino acid residue, or compounds of formula I wherein Βχ is the bond and Α _χ and A ₂ are each said α-amino acid bivalent radical or together form said dipeptide bivalent radicals with a reduced central amide bond, the remaining residues having the meanings indicated.

However, even more preferred are compounds of formula I according to hitherto worked up definitions wherein Βχ represents a bond or one of said α-amino acid bivalent radicals and Αχ and _{2 2} are each a bivalent radical of said amino acid, the remaining radicals being as defined or salts of these compounds, provided they contain at least one salt-forming group.

The invention is primarily concerned with compounds of formula I, wherein _R, is hydrogen, t-butoxycarbonyl, isobutoxycarbonyl, pyridine-3-carbonyl, morpholinocarbonyl, 3-benzofuranoyl or 1,2,3,4-tetrahydro-3- carbonyl, or alternatively or additionally morpholinosulfonyl or N- (2-pyridylmethyl) -N-methylaminocarbonyl, Βχ represents a bond or a divalent radical derived from the α-amino acid valine, the terminal nitrogen of which is linked to R _x and the terminal carbon atom of the amino group the carbon atom carrying a group of the formula R ₂ CH ₂ -, wherein in the latter case is preferably a hydrogen atom, a tert-butoxycarbonyl or morpholinocarbonyl, or alternatively or supplemental to the morpholino aminosulfonyl or N- (2-pyridylmethyl) -N- methylaminocarbonyl, R ₂ and R Znamenaj independently are phenyl or cyclohexyl, which radicals are optionally substituted by one or two radicals independently selected from hydroxy upins, methoxy, fluoro and cyano, especially one of the abovementioned radicals, preferably in the 4-position, such as in 4-hydroxyphenyl, 4-methoxyphenyl, 4-fluorophenyl,

4-cyanophenyl or 4-fluorocyclohexyl, such as in the R ₂ and R j combinations mentioned above under the general definitions or as a preferred solution, or alternatively or additionally, R ₂ and R j are each independently phenyl or cyclohexyl, these radicals being optionally substituted with one or two radicals independently of one another selected from trifluoromethyl, cyano and fluorine, in particular one of these radicals, preferably in the 4-position, such as in 4-trifluoromethylphenyl, 4-cyanophenyl or 4-fluorophenyl, A 2 and A ₂ together form the bivalent radical of the dipeptide of formula Val-Phe, Ile-Phe, Val-Cha, Ile-Cha, Ile-Gly, Val-Val, Val-Gyl, Val- (pF-Phe), Val-Tyr, Val- (p -CH3-Phe) or Gly- (pF-Phe), or a derivative thereof with a reduced central amide bond of formula Val (red) -Phe, wherein the terminal nitrogen atom is linked to the group -C = * O and the terminal carbon atom is linked to a group of the formula NR ₄ R ₅ and R ₄ and R ₅ together with the nitrogen atom thiomorpholino or morpholino, especially morpholino, and the pharmaceutically usable salts of these compounds, if they contain salt-forming groups, wherein the hydroxy in the compounds of formula I is on a carbon atom adjacent to a carbon atom bearing an ^R 2 ^-CH 2 ^- ' ^free ® group or an acetyl-protected form, with both the free compounds of formula I and the protected form, wherein all other radicals have the meanings indicated, or salts thereof, are particularly preferred.

In particular, the invention also relates to compounds of formula I wherein R R is hydrogen, tert-butoxycarbonyl, isobutoxycarbonyl, pyridine-3-carbonyl, morpholinocarbonyl, 3-benzofuranoyl or 1,2,3,4-tetrahydroisoquinoline-3- carbonyl, or alternatively or additionally, morpholinocarbonyl or N- (2-pyridylmethyl) -N-methylaminocarbonyl, means a bond or a bivalent radical derived from the α-amino acid valine whose terminal nitrogen atom is linked to Rj and the terminal carbon atom to the amino group on the atom carbon bearing a group of the formula R ₂ -CH ₂ -, wherein in the latter case R 1 is preferably hydrogen, tert-butoxycarbonyl or morpholinocarbonyl, or alternatively or additionally morpholinosulfonyl or N- (2-pyridylmethyl) -N-methylaminocarbonyl R @ ₂ and R @ ₃ are each independently phenyl or cyclohexyl, these radicals being optionally substituted by one or two radicals independently of one another selected from f; and cyano, especially one of the abovementioned radicals, preferably in the 4-position, such as in 4-fluorophenyl, 4-cyanophenyl or

4-fluorocyclohexyl, such as in the R ₂ and R ₃ combinations mentioned above under the general definitions or as a preferred solution, or alternatively or additionally, R ₂ and R ₃ are as defined above. independently of each other phenyl or cyclohexyl, which radicals are optionally substituted by one or two radicals independently of one another selected from trifluoromethyl, cyano and fluorine, especially one of these radicals, preferably in the 4-position, such as in 4-trifluoromethylphenyl, 4- together, cyanophenyl or 4-fluorophenyl, A 1 and A ₂ together form the bivalent radical of the dipeptide of formula Val-Phe, Ile-Phe, Val-Cha, Ile-Cha, Ile-Gly, Val-Val, Val-Gyl, Val- (pF- Phe), Val- (p-CH ₃ O-Phe) or Gly- (pF-Phe), or a derivative thereof with a reduced central amide bond of formula Val (red) -Phe, wherein the terminal nitrogen atom is linked to the group -C = O and the terminal carbon atom is linked to a group of the formula NR ₄ R ₅ and R ₄ and R ₅ together with the nitrogen atom form a thiomorpholino or morpholino group, especially a morpholino group, and pharmaceutically usable salts of these compounds, if they contain salt-forming groups; Compound The compounds of formula I on a carbon atom adjacent to a carbon atom bearing an R ₂ -CH ₂ - group are free or in an acetyl protected form, wherein both the free compounds of formula I and the protected form wherein all the other radicals mentioned above the meanings, or salts thereof, are particularly preferred.

The invention most particularly relates to the compounds mentioned in the examples and salts of these compounds, especially pharmaceutically usable salts, if they contain salt-forming groups.

These include the compounds of formula I with the designation Boc-Cha [C] (pF) Phe- (L) -le- (L) -Phe-morpholin-4-ylamide, Boe- (pF) Phe [C] (pF) Phe- (L) -Val- (L) -Phe-morpholin-4-ylamide, Boe- (pF) Phe (C) (pF) Phe- (L) -Val- (L) - (pF-Phe) - morpholin-4-ylamide,

Boc- (pF) Phe [C] (pF) Phe (L) -Va1- (L) - (p-CH ₃ O-Phe) -morpholin-4-ylamide,

Boe- (pF) Phe [C] (pF) Phe- (L) -Val- (L) -Cha-morpholin-4-ylamide, Boe- (pF) Phe [C] (pF) Phe- (L) - White- (L) -Phe-morpholin-4-ylamide, Boe- (pF) Phe [C] (p-CN) Phe- (L) -Val- (L) -Phe-morpholin-4-ylamide, Boe- (pF) Phe [C] (p-CN) Phe- (L) -Val (L) - (pF-Phe) -morpholin-4-ylamide,

Boe- (pF) Phe [C] (p-CN) Phe- (L) -Val- (L) - (p-CH ₃ O-Phe) -morpholin-4-ylamide,

Boe- (pF) Phe [C] (p-CN) Phe- (L) -Val- (L) -Cha-morpholin-4-ylamide, Boe- (pF) Phe [C] (p-CN) Phe- (L) -I- (L) -Phe-morpholin-4-ylamide, Boc-Phe [CJ (pF) Phe- (L) -Val- (L) -Phe-morpholin-4-ylamide, Boc-Phe [C] (pF) Phe- (L) -Val- (L) - (pF-Phe) -morpholin-4-ylamide, Boc-Phe [C] (pF) Phe- (L) -Val- (L) - (p-CH ₃ O-Phe) -morpholin-4-ylamide,

Boc-Phe [p] (pF) Phe- (L) -Val- (L) -Cha-morpholin-4-ylamide, Boc-Phe [p] (pF) Phe- (L) -le- (L) - Phe-morpholin-4-ylamide, Boc-Phe [C] (p-CN) Phe- (L) -Val- (L) -Phe-morpholin-4-ylamide, Boc-Phe [C] (p-CN) Phe (L) -Val- (L) - (pF-Phe) -morpholin-4-ylamide,

Boe-Phe [C] (p-CN) Phe- (L) - Va 1- (L) - (p-CH ₃ O-Phe) -morpholin-4-yl amide,

Boc-Phe [C] (p-CN) Phe- (L) -Val- (L) -Cha-morpholin-4-ylamide, Boc-Phe [C] (p-CN) Phe- (L) -Ie- (L) -Phe-morpholin-4-ylamide, Boc-Phe [C] (p-CH ₃ O) Phe- (L) -Val- (L) -Phe-morpholin-4-ylamide, Boc-Phe [C] (p-CH ₃ O) Phe- (L) -Val- (L) - (pF-Phe) -morpholin-4-ylamide,

Boc-Phe [C] (p-CH ₃ O) Phe- (L) -Val- (L) - (p-CH ₃ O-Phe) -morpholin-4-ylamide,

Boc-Phe [C] (p-CH ₃ 0) Phe (L) -Val-1- (L) Cha-morpholin-4-yl LAMIDO, Boc-Phe (C] (p-CH ₃ O) Phe- (L) -Ie- (L) -Phe-morpholin-4-ylamide, Boe-Phe [C] (p-CF ₃ ) Phe- (L) -Val- (L) -Phe-morpholin-4 -ylamid, Boc-Phe [CJ _(p-CF3) Phe- (L) -Val (L) - (pF-Phe) -morpholin-4-ylamide, Boc-Phe [C] _(p-CF3 Phe- (L) -Va 1- (L) - (p-CH ₃ O-Phe) -morpholin-4-ylamide,

Boc-Phe [C] (p-CF ₃ ) Phe- (L) -Val- (L) -Cha-morpholin-4-ylamide, Boc-Phe [C] (p-CF ₃ ) Phe- (L) - White- (L) -Phe-morpholin-4-ylamide, Boc-Cha [C] (p-CN) Phe- (L) -Val- (L) -Phe-morpholin-4-ylamide, Boc- Cha CC] (p-CN) Phe- (L) -Val- (L) - (pF-Phe) -morpholin-4-ylamide, Boc-Cha [C] (p-CN) Phe- (L) -Va 1- (L) - (p-CH ₃ O-Phe) -morpholin-4-ylamide,

Boc-Cha [C] (p-CN) Phe- (L) -Val- (L) -Cha-morpholin-4-ylamide, Boc-Cha [C] (p-CN) Phe- (L) -Ile- (L) -Phe-morpholin-4-ylamide, Boc-Cha (C) (p-CH ₃ O) Phe- (L) -Val- (L) -Phe-morpholin-4-ylamide, Boc-Cha [C] (p-CH ₃ O) Phe- (L) -Val- (L) - (pF-Phe) -morpholin-4-ylamide,

Boc-Cha [C] (p-CH ₃ O) Phe- (L) -Val- (L) - (p-CH ₃ O-Phe) -morpholin-4-ylamide,

Boc-Cha (C) (p-CH ₃ O) Phe- (L) -Val- (L) -Cha-morpholin-4-ylamide, Boc-Cha [C] (p-CH ₃ O) Phe- (L) 11-le- (L) -Phe-morpholin-4-ylamide, Boc-Cha CC] (p-CF ₃ ) Phe- (L) -Val- (L) -Phe-morpholin-4- γ-lamide, Boc-Cha [C] (p-CF ₃ ) Phe- (L) -Va 1- (L) - (pF-Phe) -morpholin-4-ylamide, Boc-Cha [C] (p- CF ₃ ) Phe- (L) -Val- (L) - (p-CH ₃ O-Phe) -morpholin-4-ylamide,

Boc-Cha [C] (p-CF ₃ ) Phe- (L) -Val- (L) -Cha-morpholin-4-ylamide or

Boc-Cha [C] (p-CF ₃ ) Phe- (L) -I- (L) -Phe-morpholin-4-ylamide, or the corresponding compounds in which a thiomorpholine- residue is present in place of the morpholin-4-ylamide residue 4-ylamide.

The compounds of formula I as claimed in claim 1 of the appended claims, with the designation

Boe- (L) -Val-Phe [C] Phe- (L) -Val- (L) -Phe-morpholin-4-ylamide, H- (L) -Val-Phe [C] Phe- ( L) -Val- (L) -Phe-morpholin-4-ylamide, Boc-Phe [C] Phe- (L) -Val- (D) -Phe-morpholin-4-ylamide, Boc-Phe [ C] Phe- (L) -Va 1 (red) - (L) -Phe-morpholin-4-ylamide or isobutoxycarbones 1-Phe [C] Phe- (L) -Val- (L) -Phe-morpholin- 4-ylamide or the corresponding compounds in which the thiomorpholin-4-ylamide residue is present in place of the morpholin-4-ylamide moiety, or salts thereof, if they contain a salt-forming group, or compounds of formula I according to claim 1 of the appended claims, with label

Boc-Cha CC] (p-CN) Phe- (L) -Val- (L) -Phe-thiomorpholin-4-ylamide or Boc-Cha [C] (pF) Phe- (L) -Val- (L) -Phe-thiomorpholin-4-yl amide, or a compound of formula I with the designation

Boc-Cha [C] (pF) Phe- (L) -Ile- (L) -Phe-morpholin-4-ylamide, Boc-Cha [C] (pF) Phe- (L) -Val- (L) - Cha-morpholin-4-ylamide,

Boc- (p-CFj) Phe [C] Phe- (L) -Val (L) -Phe-morpholin-4-ylamide, Boc- _(p-CF3) Phe [C] Phe (L) -Val- (L) - (pF) Phe-morpholin-4-ylamide, Boe- (p-CF 3) Phe [C] Phe- (L) -Val- (L) - (p-CH 3 O) Phe- morpholin-4-ylamide,

Boc- _(p-CF3) Phe [C] Phe- (L) -Val (L) Cha-morpholin-4-yl LAMIDO, Boc- _(p-CF3) Phe [C] Phe- (L Ile- (L) -Phe-morpholin-4-ylamide, Boe- (p-CF ₃ ) Phe [C] (pF) Phe- (L) -Val- (L) -Phe-morpholin-4 -ylamide, Boe- (p-CF ₃ ) Phe [C] (pF) Phe- (L) -Val- (L) - (pF) Phe-morpholin-4-yl rf-.

- 36 amides,

Boc- _(p-CF3) Phe [C] (pF) Phe (L) -Val (L) Cha-morpholin-4-ylamide, Boc- _(p-CF3) Phe [C] (pF) Phe- (L) -Va 1- (L) - (p-CH ₃ O) Phe-morpholin-4-ylamide,

Boe- (p-CF ₃ ) Phe [C] (pF) Phe- (L) -Ie- (L) -Phe-morpholin-4-ylamide, Boe- (p-CF ₃ ) Phe CC] (p-CF ₍₃ ) Phe- (L) -Val- (L) -Phe-morpholin-4-yl amide;

Boe- (p-CF ₃ ) Phe [C] (p-CF ₃ ) Phe- (L) -Val- (L) - (pF) Phe-morpholin-4-ylamide,

Boe- (p-CF ₃ ) Phe [C] (p-CF ₃ ) Phe- (L) -le- (L) -Phe-morpholin-4-ylamide,

Boe- (p-CF ₃ ) Phe [C] (p-CF ₃ ) Phe- (L) -Val- (L) - (p-CH ₃ O) Phomorpholin-4-ylamide or

Boe- (p-CF ₃ ) Phe [C] (p-CF ₃ ) Phe- (L) -Val- (L) -Cha-morpholin-4-yl amide, or the corresponding compounds in which morpholine- A 4-ylamide residue of thiomorpholin-4-ylamide or a compound of formula I with the designation Boc-Phe [C] Phe- (L) -Val- (L) -Tyr-Morpholin-4-ylamide, Boc-Tyr [C] Phe - (L) - Val- (L) -Phe-morpholin-4-ylamide, Boc-Tyr [C] Phe- (L) -Val- (L) -Tyr-morpholin-4-ylamide, Boc-Phe [ C] Tyr- (L) -Val- (L) -Phe-morpholin-4-ylamide, Boc-Phe [C] -Tyr- (L) -Val- (L) -Tyr-morpholin-4-ylamide, Boc- Tyr [C] -Tyr- (L) -Val- (L) -Phe-morpholin-4-ylamide or Boc-Tyr [C] -Tyr- (L) -Val- (L) -Tyr-morpholin-4-ylamide, or corresponding compounds in which there is a thiomorpholin-4-ylamide residue in place of the morpholin-4-ylamide residue.

Of particular interest is the compound of formula (I) wherein t is butoxycarbonyl, B 1 is a bond, R ₂ is cyclohexyl, R ₃ is p-fluorophenyl, A 1 is valine, A ₂ is phenylalanine and R and R ₅ together form with a nitrogen-binding morpholino group.

Of particular interest is also a compound of formula I wherein R 1 is tert-butoxycarbonyl, B 1 is a bond, R ₂ and R ₃ are phenyl, A 1 is valine, A ₂ is phenylalanine and R ₄ and R 8 together form a morpholino group together with the nitrogen bonding atom .

Of particular interest is also a compound of formula I wherein R 1 is tert-butoxycarbonyl, R ₁ is a bond, R ₂ is cyclohexyl, R ₃ is p-fluorophenyl, A 1 is valine, A ₂ is p-fluorophenylalanine and R ₄ and R 8 form together with the binding nitrogen atom the morpholino group.

Of particular interest is also a compound of formula I wherein R 1 is tert-butoxycarbonyl, R ₁ is a bond, R ₂ is cyclohexyl, R ₃ is p-fluorophenyl, A 1 is valine, A ₂ is p-methoxyphenylalanine and R ₄ and R 8 form together with the binding nitrogen atom the morpholino group.

Of particular interest is also a compound of formula I wherein R 1 is tert-butoxycarbonyl, R ₁ is a bond, R ₂ is cyclohexyl, R ₃ is p-fluorophenyl, A 1 is valine, A ₂ is cyclohexylalanine and R ₄ and R 8 form together with a morpholino group.

Of particular interest is also a compound of formula I wherein R 1 is tert-butoxycarbonyl, R ₁ is a bond, R ₂ is cyclohexyl, R ₃ is p-fluorophenyl, A 1 is valine, A ₂ is phenylalanine and R ₄ and R 8 form together with a nitrogen-binding thiomorpholino group.

Of particular interest is a compound of formula I wherein R 1 is tert-butoxycarbonyl, R ₁ is a bond, R ₂ is cyclohexyl, R ₃ is p-fluorophenyl, A 1 is isoleucine, A ₂ is phenylalanine and R ₄ and R 8 form together with a morpholino group.

Extremely important is the compound of formula I, wherein R is tert-butoxycarbonyl, Bj is a bond, _R2 is phenyl, _R3 is p-fluorophenyl, also is valine, and phenylalanine is ₂ and _R4 and R, taken together _{with the} with a nitrogen-binding morpholino group.

Of particular interest is also a compound of formula I wherein R 1 is tert-butoxycarbonyl, R ₁ is a bond, R ₂ is p-fluorophenyl, R ₃ is p-fluorophenyl, A 1 is valine, A ₂ is phenylalanine and R ₄ and R 8 form together with the binding nitrogen atom the morpholino group.

Of particular interest is a compound of formula I wherein R 1 is tert-butoxycarbonyl, R ₁ is a bond, R ₂ is p-fluorophenyl, R ₃ is p-fluorophenyl, A is valine, A ₂ is p-fluorophenylalanine and R ₄ and R ₅ together with the nitrogen bonding atom form a morpholino group.

Of particular importance is also a compound of formula I wherein R 1 is tert-butoxycarbonyl, R ₁ is a bond, R ₂ is cyclohexyl, R ₃ is p-cyanophenyl, A 1 is valine, A ₂ is phenylalanine, and R ₄ and R 8 form together with a morpholino group.

Extremely important is the compound of formula I, wherein R is tert-butoxycarbonyl, Bj is a bond, R ₂ and R ₃ are the! phenyl, A 1 is valine, A ₂ is phenylalanine, and R ₄ and R 8 together with the nitrogen bonding atom form a thiomorpholino group.

The compounds of the formula I or their hydroxy-protected derivatives and salts of such compounds with at least one salt-forming group are obtained in a manner known per se, for example by:

a) for the preparation of compounds of the general formula Ib

R3

H OH f ' ³

WW / o

(Ib), in which

RJL R * is as defined for a compound of formula I except hydrogen, a hydroxy group on the carbon atom adjacent to the carbon atom which carries the radical of the formula R ₂ -CH ₂ -, is a free or protected form and the remaining radicals are as defined for compounds of formula I, acid of formula II

Rx'-OH (II) wherein

R 1 has the same meaning as R 1 in the compounds of formula I except hydrogen, or a reactive derivative thereof, is condensed with an amino compound of formula III

wherein the radicals have the meanings given for the compounds of the formula I or a reactive derivative thereof, wherein in the starting compounds of the formulas II and III free functional groups are exempted, optionally in protected form, with the exception of those involved in the reaction; .

b) for the preparation of compounds of formula Ic

in which

B] J has the same meaning as in the compounds of formula I except the bond, the hydroxy group on the carbon atom adjacent to the carbon atom bearing the radical R 2 ' ^CH 2' is free or in protected form and the remaining radicals have the meanings given for the compounds of formula I, a carboxylic acid of formula IV, ^R 1 ^B 1 ^'OH (IV), wherein

R 1 has the meanings given for compounds of formula I and

B * has the meanings indicated immediately above, or a reactive derivative thereof, is condensed with an amino compound of formula V

wherein the radicals have the meanings given for the compounds of formula (I) or a reactive derivative thereof, wherein the free functional groups in the starting compounds of formula (IV) and, except for the groups involved in the reaction, are optionally in protected form; split off »

c) a carboxylic acid of the general formula VI (VI),

in which the radicals have the meanings given for or a reactive derivative thereof, with the general formula (VII) of a compound of the general formula (I) condensed with an amino compound

(VII).

wherein the radicals have the meanings given for the compounds of the formula I or its reactive derivatives, wherein the free functional assays in the starting compounds of the formulas VI and VII, except for the groups involved in the reaction, are optionally in a protected form and the protective sheaths will split off,

d) for the preparation of a compound of the general formula Id (Id),

wherein ^{A l'a and} 2 * ^{m and} it defined the A _x and A ₂ in the compounds of Formula I, the even / bond, however, is not a peptide bond between AJJ and _A2 'is not in reduced form.

hydroxy group on the carbon atom adjacent to the carbon atom bearing the radical R ₂ -CH ₂ -, is a free or protected form and the remaining radicals are as defined for a compound of formula I,

wherein the radicals have the meanings indicated immediately above, or a reactive derivative thereof, are condensed with an amino compound of formula IX (K), ^R 5 wherein the radicals have the meanings indicated immediately above, or a reactive derivative thereof, wherein the free functional groups in the starting compounds of the general formula VIII and IX, with the exception of the groups involved in the reaction, are optionally in a protected form and, if necessary, the protecting groups present are split off,

e) a carboxylic acid of formula X

OH in which the radicals have the meanings given for a compound of the general formula: or a reactive derivative thereof, is condensed with an amino compound of the general formula XI

(XD _Z in which the radicals have the meanings given for the compound of formula I, or a reactive derivative thereof, wherein the free functional groups in the starting compounds of formulas X and XI, with the exception of those involved in the reaction, are optionally protected; Where appropriate, the protecting groups present are cleaved off 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 / or the compound of formula I is removed as appropriate; with at least one salt-forming group obtained by one of methods a) to f) above, is converted to its salt and / or the resulting salt is converted to the free compound or another salt and / or the isomeric mixture of the compounds of formula I obtained is separated and / or a compound of the formula I according to the invention is converted into another compound of the formula I according to the invention.

The above methods are described in more detail below.

Method a) (preparation of an amide bond)

In the starting compounds of the formulas (II) and (III), there are functional groups, with the exception of those having the moiety f

to the reaction or which do not react under the reaction conditions, protected independently of one another by protecting groups.

Functional groups intended to be protected by the starting materials to be reacted, in particular carboxy, amino, hydroxy, mercapto and sulfo groups, include special such protecting groups (conventional protecting groups) which are commonly used in the synthesis of peptide compounds, but also cefarlosporins and penicillin, the same as the nucleic acid and sugar derivatives. These protecting groups may already be present in the materials obtained from the foregoing 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, in addition, the protecting groups may act in a selective, for example stereoselective, manner. Characteristic of protecting groups is that they are easily removed, i.e., without undesired side reactions, for example solvolytically, reductively, photolytically or also enzymatically, for example also under physiological conditions. Protecting groups may also be present in the finished materials. Compounds of formula I with protected functional groups may have higher metabolic stability or other improved pharmacodynamic properties than the corresponding compounds with free functional groups. Corresponding compounds having protecting groups, for example hydroxy-protected groups, may also be prodrugs that are activated in vivo by enzymatic cleavage, for example esterases.

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 J. F. W. McOmie, Protective Groups in Organic Chemistry, Plenum Press, London and New York (1973), 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 der organischen Chemie, Houben-Weyl, 4th Ed., Vol. 15/1, Georg Thieme Verlag, Stuttgart (1974), in H. - D. Jakubke and H. Jescheit, Aminosäuren, Peptide, Protein, Velag Chemie, Weinheim, Deerfield Beach and Basel (1982) and in Jochen Lehmann, Chemie der Kohlenhydrate : Monosaccharide and Derivatives, Georg Thieme Verlag, Stuttgart (1974).

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.

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

A protected carboxy group which is esterified with a lower alkyl group which is branched at the 1-position of the lower alkyl group is, for example, a tert- (lower alkoxy) carbonyl group, for example a tert-butoxycarbonyl.

A protected carboxy group which is esterified with a lower alkyl group which is substituted with a suitable substituent at the 1 or 2 position of the lower alkyl group is, for example, arylmethoxycarbonyl with one or two aryl radicals, aryl being phenyl optionally mono-, di- or trisubstituted with e.g. such as tert- (lower alkyl), such as tert-butyl, lower alkoxy, such as methoxy, hydroxy, halogen, such as chlorine, and / or nitro, such as benzyloxycarbonyl, benzyloxycarbonyl substituted with such substituents such as 4-nitrobenzyloxycarbonyl or 4-methoxybenzyloxycarbonyl, diphenylmethoxycarbonyl optionally substituted by the substituents mentioned, for example di- (4-methoxyphenyl) methoxycarbonyl, further lower-alkyl esterified carboxy, wherein the lower alkyl group is in the 1 or 2 position optionally substituted by a suitable substituent such as 1- (lower alkoxy) - (lower alkoxy) carbonyl, for example methoxymethoxycarbonyl, 1-methoxyethoxycarbonyl or 1-ethoxyethoxycarbonyl, 1- (lower alkyl) thio (lower alkoxy) carbonyl, such as 1-methylcarbonylthiomethoxycarbonylthiomethoxycarbonyl or thiomethoxycarbonylthiomethoxycarbonyl; wherein the aroyl group is benzoyl optionally substituted, for example, by a halogen atom such as bromine, for example phenacyloxycarbonyl, 2-halo (lower alkoxy) carbonyl, for example 2,2,2-trichloroethoxycarbonyl, 2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl, the same as 2- (tris) silyl) - (lower alkoxy) carbonyl wherein the substituents independently of one another represent an aliphatic, araliphatic, cycloaliphatic or aromatic hydrocarbon radical optionally substituted, for example, by a lower alkyl group, a lower alkoxy group, an aryl, a halogen atom and / or a nitro group such as o a substituted lower alkyl, phenyl (lower alkyl) group, cycloalkyl or 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-n) butylmethylsilyl Cyclohexylcarbonyl or 2-triarylsilylethoxycarbonyl such as triphenylsilylethoxycarbonyl.

The carboxy group may also be protected as an organic silyloxycarbonyl group. The organic silyloxycarbonyl group is, for example, a tri (lower alkyl) silyloxycarbonyl group, such as trimethylsilyloxycarbonyl, and the silyloxycarbonyl atom may also be substituted by two lower alkyl groups, for example methyl groups, and the amino or carboxy group may be substituted. may be prepared, for example, by reaction with dimethylchlorosilane as a silylating agent.

The carboxy group is also protected in the form of an internal ester with a hydroxy group present at a suitable distance from the carboxy group in the molecule, for example in the τ-position, i.e. in the form of lactone, preferably t-lactone.

The protected carboxy group is preferably a tert- (lower alkoxy) carbonyl group, for example tert-butoxycarbonyl, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 9-fluorenylmethoxycarbonyl or diphenylmethoxycarbonyl, or carboxy groups protected in the lactone form, especially t-lactone.

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 acylamino moiety, the acyl moiety is, for example, an acyl radical of an organic carboxylic acid with, for example, up to 18 carbon atoms, particularly optionally with halogen or aryl substituted (lower alkane) carboxylic acid or optionally with halogen, lower alkoxy or nitro substituted benzoic acid. of carbonic acid. Such acyl groups are for example lower alkanoyl, such as formyl, acetyl, propionyl or pivaloyl, halo (lower alkanoyl) group, such as 2-haloacetyl, such as 2-chloro-, 2-bromo- _2-iodo-F, 2,2, 2-trifluoro- or 2,2,2-trichloroacetyl, for example halogen, lower alkoxy or nitro substituted benzoyl such as benzoyl, 4-chlorobenzoyl, 4-methoxybenzoyl or 4-nitrobenzoyl, (lower alkoxy) carbonyl, with preferably in the 1-position of the lower alkyl radical branched or in the 1 or 2 position a suitably substituted (lower alkoxy) carbonyl group, for example a tertiary (lower alkoxy) cabonyl group such as tert-butoxycarbonyl, arymethoxycarbonyl with one, two or three aryl radicals which is optionally lower alkyl, in particular tertiary (lower alkyl), such as tert-butyl, lower alkoxy, such as methoxy, hydroxy, halogen n, such as chloro and / or nitro, mono- or polysubstituted phenyl, e.g. such as bromo, substituted benzoyl, for example phenacyloxycarbonyl, 2-halo (lower alkoxy) carbonyl, for example 2,2,2-trichloroethoxycarbonyl, 2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl, 2- (trisubstituted silyl) - (lower alkoxy) carbonyl, for example, a 2-tri (lower alkyl) silyl (lower alkoxy) carbonyl group such as 2-trimethylsilylethoxycarbonyl or 2- (di-n-butylmethylsilyl) ethoxycarbonyl, or a triarylsilyl (lower alkoxy) carbonyl group such as 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;

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, such as chlorine and / or nitro substituted phenyl such as e.g. 4-nitrophenylthio.

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, lower alkoxy, 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) semi-ester of carbonic acid. Corresponding protecting groups are especially 1- (lower alkanoyl) - (lower alk-1-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 (lower alkoxy) carbonylprop-1-en-2-yl such as 1-ethoxycarbonylprop- 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 the formula Z. Compounds with such protecting groups may be prepared, for example, by reaction with corresponding chlorosilanes such as dimethylchlorosilane, agent.

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

Preferred amino protecting groups are (lower alkoxy) carbonyl, phenyl (lower alkoxy) cabonyl, fluorenyl (lower alkoxy) carbonyl, 2- (lower alkanoyl) - (lower alk-1-en-2-yl) or (lower alkoxy) carbonyl (lower alk-1-en-2-yl), preferably tert-butoxycarbonyl or benzyloxycarbonyl.

The hydroxy group may be protected, for example, by an acyl group, for example optionally by a halogen atom, such as chlorine, substituted by a lower alkanoyl group, such as acetyl or 2,2-dichloroacetyl, or in particular by the acyl radical of the semiester carbonic acid 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 further be protected by a tri (lower alkyl) silyl group, for example trimethylsilyl, triisopropylsilyl or tert-butyldimethylsilane, an easily cleavable ether-forming group, for example an alkyl group such as a tert- (lower alkyl) group, for example tert-butyl, oxa- or a thiaaliphatic or -cycloaliphatic, especially a 2-oxa- or 2-thiaaliphatic or -cycloaliphatic hydrocarbon radical, for example a 1- (lower alkoxy) - (lower alkyl) or 1- (lower alkyl) thio (lower alkyl) group such as methoxymethyl 1-methoxyethyl,

1-ethoxyethyl, methylthiomethyl, 1-methylthioethyl or 1-ethylthioethyl, or 2-oxa- or 2-thiacycloalkyl of 5-7 ring atoms, such as 2-tetrahydrofuryl or 2-tetrahydropyranyl, or the corresponding thiaanalog, same as 1-phenyl (lower alkyl) group such as benzyl, diphenylmethyl or triethyl, wherein the phenyl radicals may be substituted, for example, by a halogen atom, for example -chlorine, a lower alkoxy group, for example methoxy and / or nitro.

Two hydroxy groups occurring in a single molecule, especially when adjacent, or adjacent hydroxy and amino, may be protected, for example, by bivalent protecting groups, such as preferably a methylene group optionally substituted by one or two lower alkyl radicals or oxo groups, for example as optionally substituted alkylidene, e.g. lower alkylidene such as isopropylidene, cycloalkylidene such as cyclohexylidene, carbonyl or benzylidene.

The hydroxy group positioned adjacent to the carboxy group can be protected by the formation of an internal ester (lactone), particularly τ-lactone.

Preferred is a protected hydroxy group which is protected with a tri (lower alkyl) silyl group or as a lactone, especially tert-butyldimethylsilyl or as a τ-lactone.

A mercapto group, such as in cysteine, may be particularly protected by S-alkylation with optionally substituted alkyl moieties, silylation, thioacetal formation, 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, such as S- or S-. -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.

For the purposes of the present invention, as a protecting group, for example a carboxy-protecting group, is also expressly meant to include a polymeric carrier which attaches a readily 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 a bridging member suitable for reversible bonding.

The acids of formula (II) are carboxylic acids or sulfonic acids.

The carboxylic acids of the formula II are present with the free carboxy group or as reactive derivatives of these acids, for example as cleavable activated esters, as reactive anhydrides or further as reactive cyclic amides, which are derived from the free carboxylic compound. Reactive derivatives may also be formed in situ.

Activated esters of compounds of formula (II) with a carboxy group are particular esters unsaturated on a bonded carbon atom of an esterifying moiety, for example of the vinyl ester type such as vinyl ester (which can be produced e.g. by reaction of the corresponding ester with vinyl acetate, activated vinyl ester method); by treating the corresponding acid with an isoxazolium reagent, a 1,2-oxazolium or Woodward method) or a 1- (lower alkoxy) vinyl ester (which can be produced, for example, by treating the corresponding acid with a (lower alkoxy) acetylene, ethoxyacetylene method) or an amidine ester such as is an N, N'-disubstituted amidinoester (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 amidinoester (which can be obtained by treating the corresponding acid with N, N-disubstituted cyanamide, the cyanamide method), a suitable aryl ester, a particular phenyl ester substituted with electron-withdrawing substituents (which can be obtained, for example, by treating the corresponding acid with a suitable substituted phenol, e.g. 4-nitrophenol, 4-methylsulfonyl, 4,5-trichlorophenol, 2,3,4,5,6-pentachlorophenol or 4-phenyldiazophenol, in the presence of a condensing agent such as N, N- ^1- dicyclohexylcarbodiimide, activated aryl ester method, cyanomethyl ester (which can be obtained, for example, by treating the corresponding acid with chloroacetonitrile in the presence of a base, cyanomethyl ester 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 by the anhydride or carbodiimide method; or 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 N-hydroxysuccinimide, N-hydroxypiperidine, N-hydroxyphthalimide, N-hydroxy-5-norbornene acid imide *). -2,3-dicarboxylic, 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 τ-lactones, may also be used.

The acid anhydrides may be symmetrical or preferably 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 or oxalyl 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, the azide method), anhydrides with semi-esters of carbonic acid, for example (lower alkyl) semi-esters of carbonic acid (which can be obtained for example lower alkyl) esters of chloroformic acid 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 may be gain 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-phenylphosphoramidochloridate or reaction of alkylphosphoric amides in the presence of sulfonic anhydride and / or racemization-reducing additives such as is N-hydroxybenztriazole, or in the presence of diethyl cyanophosphonic acid ester or orthophosphoric acid derivatives or anhydrides with organic acids, such as mixed anhydrides with organic carboxylic acids (which can be obtained, for example, by treating the corresponding acid with optionally substituted halide (lower alkane) - or phenyl (lower alkane) carboxylic acids, for example the phenylacetic, pivalic or trifluoroacetic acid chloride, mixed carboxylic anhydride method) or with organic sulfonic acids (which can be obtained by treating the salt, e.g. as an alkali metal salt, the corresponding acid with a suitable organic sulfonic acid halide such as chloride (lower alkane) - or aryl-, for example methane- or p-toluenesulfonic acid, mixed sulfonic anhydride method), as well as symmetrical anhydrides (which can be by condensation of the corresponding acid in the presence of carbodiimide or 1-diethylaminopropin, symmetric anhydride method).

Suitable cyclic amides are particular amides with 5-membered aromatic diazacyclic amides, such as amides with imidazoles such as imidazole (which can be obtained, for example, by treating the corresponding acid with N, N'-carbonyldiimidazole, imidazole method) or pyrazole such as 3,5-dimethylpyrazole ( for example, it can be obtained via the 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 a starting compound of formula III and an acid of formula II used as acylating agent is reacted in the presence of a suitable Ν, Ν'-disubstituted carbodiimide such as N, N cyclohexylcarbodiimide, such as in the presence of a suitable base such as triethylamine. Furthermore, an amino or amido ester of an acid used as acylating agent in the presence of a starting compound of formula III to be acylated may be formed by reacting a mixture of the corresponding acid and amino compound as starting materials in the presence of a Ν, Ν'-disubstituted carbodiimide such as 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 a Ν, Ν, Ν ', Ν'-tetraalkyluronium compound such as O-benztriazol-1-yl-N, N, N', N ¹ -tetramethyluronium hexafluorophosphate. Finally, the carboxylic acid anhydrides of the formula II can be prepared in situ with phosphoric acid by reacting an alkylphosphoric amide such as phosphoric acid hexamethylamide in the presence of a sulfonic anhydride such as 4-toluenesulfonic anhydride. a salt, such as tetrafluoroborate, for example sodium tetrafluoroborate, or another compound derived from hexamethylamide of phosphoric acid such as benztriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluoride, preferably in the presence of racemization reducing additives such as N-hydroxybenztriazole.

*

The amino group of the compound of formula (III) involved in the reaction preferably contains at least one hydrogen capable of reacting, especially when a reactive carboxy group is present in the reactive form. This group can also be derivatized by itself, 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, wherein the amino group involved in the reaction is substituted with a halocarbonyl such as chlorocarbonyl.

The coupling to the amide bond can 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. 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-l, 2-oxazolium ^{3-1-sulfonate} and 2-tert-butyl-5-methylisoxazoliumperchlorát, or a suitable acylamino compounds, for example 2-ethoxy-l-ethoxycarbonyl-l, 2-dihydroquinoline, Ν , Ν, Ν ¹ , N ¹ -tetraalkyluronium compounds such as O-benztriazol-1-yl-N, N, N ', N'-tetramethyluronium hexafluorophosphate, further activated phosphoric acid derivatives such as diphenylphosphoryl azide, diethylphosphoryl cyanide, phenyl-N-phenylphosphorophosphoramide , bis- (2-oxo-3-oxazolidinyl) phosphinic acid chloride or 1-benztriazolyloxytris (dimethylamino) phosphonium hexafluorophosphate.

In an analogous manner to the reaction types mentioned for the condensation of the carboxylic acids of the formula II, sulfonic acids of the formula II with a terminal sulfonic group can also be reacted with the compounds of the formula III to form the corresponding sulfonamides of the formula 1b.

Thus, for example, activated sulfonic acid esters, for example aryl esters, such as phenyl esters which are substituted, in particular nitro groups, may be used, and the amine component of formula 1b may also be used as an alkali metal amide, for example an alkali metal arylamide such as sodium aniline amide or nitrogenous alkali metal heterocyclic compounds, for example potassium pyrrolides.

Reactive anhydrides may also be used, such as possibly corresponding symmetrical (obtainable, for example, by reaction of silver salts of alkylsulfonic acids with alkylsulfonyl chlorides) or preferably asymmetric acid anhydrides, for example anhydrides with inorganic acids, such as sulfonyl halides, particular sulfonyl chlorides (which can be reacted). with inorganic acid chlorides such as thionyl chloride, sulfuryl chloride or phosphorus pentachloride), organic carboxylic acids (which can be obtained, for example, by treating a sulfonic acid halide with a carboxylic acid salt, such as an alkali salt analogous to the above method for producing mixed acid anhydride) or azides (which can be prepared, for example, from the corresponding sulfonic acid chloride and sodium azide or via the corresponding hydrazide and its treatment with nitric acid, analogously to the process described above. azide method).

If desired, an organic base such as a tri (lower alkyl) amine with a bulky residue such as ethyldiisopropylamine and / or a heterocyclic base such as pyridine, 4-dimethylaminopyridine or preferably N-methylmorpholine 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 simple tri (lower alkyl) amines, for example triethylamine or tributylamine, or the abovementioned organic bases. If desired, a condensing agent is additionally used, as described for free carboxylic acids.

The condensation of acid anhydrides with amines can be carried out, for example, in the presence of inorganic carbonates, for example ammonium carbonate or bicarbonate or an alkali metal such as sodium or potassium carbonate or bicarbonate (usually together with the sulfate). The reaction of the sulfonic acid halide, such as sulfonic acid chloride, can be carried out in the presence of hydroxides, for example an alkali metal hydroxide, such as sodium hydroxide or potassium hydroxide.

Carboxylic acid chlorides, for example the chlorocarboxylic acid derivatives of the acid of formula II, are condensed with the corresponding amines, preferably in the presence of an organic amine, for example the above three (lower alkyl) amine or heterocyclic bases, 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, for example methylene chloride, carbon tetrachloride or chlorobenzene, a ketone for example acetone, cyclic ether, an ester, for example ethyl acetate or nitrile, for example acetonitrile, or mixtures thereof, optionally at reduced or elevated temperatures, for example in a temperature range of from about -40 to about +100 ° C, preferably from about -10 to about +50 ° C , and optionally under an inert gas atmosphere such as a nitrogen or argon atmosphere.

It is also possible to use an aqueous, for example alcoholic solvent, such as ethanol, or 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).

The liberation of the functional groups protected by the protective groups in the obtained compounds having the functional groups is optionally carried out according to one or more of the methods mentioned under process f).

Method b) (preparation of an amide bond)

In the starting compounds of the formulas (IV) and (V), 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 one another by protecting groups.

The protecting groups, the free carboxylic acids and their reactive derivatives, the free amines and their reactive derivatives, and the condensation method used are quite analogous to those described in (a) for the preparation of an amide bond starting from compounds of formulas II and III if instead of carboxylic acids of formula II, carboxylic acids of formula IV are used, and instead of amino compounds of formula III, amino compounds of formula V are used.

The liberation of the functional groups protected by the protecting groups in the compounds of the formula I obtained with the protected functional groups is optionally carried out according to one or more of the methods mentioned under process f).

Method c) (preparation of an amide bond)

In the starting compounds of the formulas VI and VII, the functional groups, with the exception of those which are to be involved in the reaction or do not react under the reaction conditions, are protected independently of one another by protecting groups.

The protecting groups, the free carboxylic acids and their reactive derivatives, the free amines and their reactive derivatives, and the condensation method used are quite analogous to those described in (a) for the preparation of an amide bond starting from compounds of formulas II and III; when carboxylic acids of formula VI are used in place of the carboxylic acids of formula II and amino compounds of formula VII are used in place of the amino compounds of formula III.

The liberation of the functional groups protected by the protective groups in the obtained functionalized compounds of the formula I is carried out, if appropriate, according to one or more of the methods mentioned under process f).

Method d) (preparation of an amide bond)

In the starting compounds of the formulas VIII and IX, the functional groups, with the exception of those which are to be present in the reaction or which do not react under the reaction conditions, are protected independently of one another by protecting groups.

The protecting groups, the free carboxylic acids and their reactive derivatives, the free amines and their reactive derivatives, and the coupling method used are quite analogous to those described in (a) for the preparation of an amide linkage starting from compounds of formulas II and III if instead of carboxylic acids of formula II, carboxylic acids of formula VIII are used, and instead of amino compounds of formula III, amino compounds of formula IX are used.

The liberation of the functional groups protected by the functional groups in the obtained compounds having the functional groups is optionally carried out according to one or more of the methods mentioned under process f).

Method e) (preparation of an amide bond)

In the starting compounds of formulas (X) and (XI), functional groups, with the exception of those which are intended to participate in the reaction or do not react under the reaction conditions, are protected independently of one another by protecting groups.

The protecting groups, the free carboxylic acids and their reactive derivatives, the free amines and their reactive derivatives, and the coupling method used are quite analogous to those described in (a) for the preparation of an amide linkage starting from compounds of formulas II and III, instead of carboxylic acids of formula II, carboxylic acids of formula X are used, and instead of amino compounds of formula III, amino compounds of formula XI are used.

For example, the reactive derivative of the compound of formula XI with an amino group is also an isocyanate in which the amino group of the reaction is exchanged as an isocyanate group, and only compounds of formula I which carry an amido group on the nitrogen atom forming the reaction hydrogen.

The liberation of the functional groups protected by the protective groups in the obtained compounds having the functional groups protected according to the general formula I is optionally carried out according to one or more of the methods mentioned under process f).

Method f) (cleavage of protecting groups)

The cleavage of 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 in a manner known per se, for example by solvolysis, in particular hydrolysis, alcoholysis or acidolysis, or by hydrogenolysis or by means of other reducing agents, the same as by photolysis, optionally in steps or simultaneously, and enzymatic methods can also be used. For example, the cleavage of the protecting groups is described below in the section dealing with the basic work on the cleavage of the protecting groups.

For example, a protected carboxy group, for example a tertiary- (lower alkoxy) carbonyl group, at the 2-position with a trisubstituted silyl group, or a 1-lower alkoxy group or a (lower alkyl) substituted (lower alkoxy) carbonyl group or an optionally substituted diphenylmethoxycarbonyl group can be converted to the carboxy group with a suitable acid, such as formic, hydrochloric or trifluoroacetic acid, optionally with addition of a nucleophilic compound such as phenol or anisole, optionally substituted benzyloxycarbonyl can be liberated, for example, by hydrogenolysis, i.e. by treatment with hydrogen, in the presence of a metal catalyst hydrogenation catalyst. Further, a suitable substituted benzyloxycarbonyl such as 4-nitrobenzyloxycarbonyl can also be obtained by reduction, such as treatment with an alkali metal dithionite, such as sodium dithionite, or a reducing metal, to for example, zinc, or a reducing metal salt, such as chromium (III) salt, for example chromium (III) chloride, usually in the presence of a hydrogen scavenger, which together with the metal may lead to the production of nascent hydrogen such as acid, particularly suitable carboxylic acids such as (lower alkane) carboxylic acids; substituted with, for example, a hydroxy group, such as acetic acid, formic acid, glycolic acid, diphenylglycolic acid, lactic, almond, 4-chloro-mandelic or tartaric acid, or alcohol or thiol, preferably water is added. Treatment with a reducing metal 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 optionally be cleaved by treatment with a nucleophilic reagent, preferably a salt, such as sodium thiophenolate or sodium iodide. A 2- (trisubstituted silyl) - (lower alkoxy) carbonyl group, such as a 2-tri (lower alkyl) silyl (lower alkoxy) carbonyl group, may also be treated with a salt providing a fluoride anion from hydrofluoric acid such as an alkali metal fluoride such as fluoride sodium or potassium, optionally in the presence of a macrocyclic polyether (crown-ether) or with a fluoride of an organic quaternary base, such as tetra (lower alkyl ammonium fluoride or tri (lower alkyl) aryl (lower alkyl ammonium fluoride, e.g. The carboxy group protected as an organic silyloxycarbonyl such as a tri (lower alkyl) silyloxycarbonyl group, for example trimethylsilyloxycarbonyl, can be liberated in a conventional manner by solvolysis, for example by treatment with water, e.g. The esterified carboxy group can also be released enzymatically, for example by esterases or suitable peptidases, for example by esterified arginine or lysine such as lysine methyl ester, by trypsin. The carboxy group protected as an internal ester, such as τ-lactone, can be liberated by hydrolysis in the presence of a base containing a hydroxide such as an alkaline earth hydroxide or a particular alkali metal hydroxide, for example sodium, potassium or lithium hydroxide, especially lithium hydroxide. protected hydroxy.

The protected amino group is liberated in a manner known per se and, depending on the nature of the protecting group, by various methods, preferably by solvolysis or reduction. (Lower alkoxy) carbonylamino, such as tert. the butoxycarbonylamino group can be cleaved in the presence of acids, for example mineral acids, exemplary hydrohalic acids such as hydrochloric or hydrobromic acid, especially hydrobromic acid, sulfuric acid or phosphoric acid, preferably hydrochloric acid, in polar solvents such as carboxylic, an acid such as acetic acid; or v. ethers, preferably cyclic ethers such as dioxane. 2-Halogen (lower alkoxy) carbonylamino (optionally after conversion of 2-bromo (lower alkoxy) carbonylamino to 2-iodo (lower alkoxy) carbonylamino), aroylmethoxycarbonylamino or 4-nitrobenzyloxycarbonylamino can also be removed as a reducing agent in a suitable reagent, e.g. 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. The 4-nitrobenzyloxycarbonylamino group may also be cleaved by treatment with an alkali metal dithionite, for example sodium dithionite. Optionally substituted diphenylmethoxycarbonylamino, tertiary (lower alkoxy) carbonylamino or 2- (trisubstituted silyl) - (lower alkoxy) carbonylamino, such as 2-tri (lower alkyl) silyl (lower alkoxy) carbonylamino groups may be removed by acid treatment with an acid treatment. for example formic 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 palladium catalyst, preferably in polar solvents such as di (lower alkyl) - alkanoyl) amides, for example dimethylformamide, ethers, such as cyclic ethers, for example dioxane, or alcohols, such as methanol, ethanol or propanol, with methanol being particularly preferred. Optionally substituted triarylmethylamino or formylamino can be removed, for example, by treatment with an acid such as a mineral acid such as hydrochloric acid or an organic acid such as 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, may be liberated by treatment with thiourea in the presence of a base or with a thiolate salt such as an alkali metal thiourea and subsequent solvolysis, such as alcoholysis or hydrolysis, of the resulting substitution product. The amino group protected with 2- (trisubstituted silyl) - (lower alkoxy) carbonyl, such as 2-tri (lower alkyl) silyl (lower alkoxy) carbonyl, can also be converted to the free amino group by treatment with fluoride anion-providing salts from hydrofluoric acid, Likewise, a silyl group bonded to a heteroatom, such as nitrogen, such as trimethylsilyl, using fluoride ions can also be cleaved directly to the heteroatom, such as nitrogen, as described above in connection with the release of the corresponding protected carboxyl group.

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 mercury acids 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 else in a water or a mixture of water and an organic solvent such as alcohol or dioxane, at a temperature of about 20-25 ° C or also 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, the 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 a mineral acid or a strong carboxylic acid, for example trifluoroacetic acid. The pyridyl-protected mercapto group is released, for example, by treatment with a mercury salt at a pH of 2 to 6, by treatment with zinc in acetic acid or by electrolytic reduction. Acetamidomethyl and isobutyrylamidomethyl can be removed, for example, by reaction with mercuric salts at a pH of 2 to 6. 2-Chloroacetamidomethyl is removed, for example, by 1-piperidinothiocarboxamide, S-ethylthio-,

S-tert-butylthio- and S-sulfo-, for example by thiolysis with thiophenol, thioglycolic acid, sodium thiophenolate or

1,4-dithiothreitol. Two hydroxy groups 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, cycloalkylidene group such as cyclohexylidene or benzylidene can be liberated by solvolysis carried out under acidic conditions, 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, and the 2-halo (lower alkoxy) carbonyl group is removed with a reducing agent such as a reducing metal such as zinc, reducing metal. Esterified hydroxy groups, for example (lower alkanoyl) oxy, such as acetyloxy, may also be removed by treatment with esterases, and the acylated amino group may be removed by treatment with appropriate peptides, such as salts of chromium or sulfur compounds, for example sodium dithionite or preferably sodium sulfide and carbon disulfide.

The sulfo group protected as 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, for example sodium carbonate.

The temperatures for the release of the protected functional groups are preferably from -80 to 100 ° C, particularly preferably from -20 to 50 ° C, for example from 10 to 35 ° C, as in the room temperature range.

If there are multiple protected functionalities, 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 treatment with hydrogen in the presence of a hydrogenation catalyst, such as palladium on carbon. . Conversely, the groups may also be selected such that they do not all cleave simultaneously, but may be cleaved in the desired order, yielding the corresponding intermediates.

Additional method characters

For additional features of the process being carried out as necessary, the functional groups of the starting compounds which are not to be involved in the reaction may be in an unprotected or protected form, for example one or more protecting groups named under process a). The protecting groups may be retained in the final compounds or may be totally or partially cleaved 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 compounds of formula I containing acidic groups may be formed, for example, by treatment with metal compounds such as salts and

suitable alkali metal organic carboxylic acids, for example sodium 2-ethylhexanoic acid, with organic alkali metal or alkaline earth metal compounds such as corresponding hydroxides, carbonates or bicarbonates such as sodium or potassium hydroxide, carbonate or bicarbonate, with the corresponding calcium compounds, or with ammonia or a suitable organic amine, preferably stoichiometric amounts of compounds or a small excess of salt-forming agent. The acid addition salts of the compounds of the formula I are obtained in a customary manner, for example by treatment with an acid or a suitable anion exchange agent. The salts of the compounds of formula I which contain acidic and basic salt-forming groups, for example free carboxy and free amino groups, can be formed, for example, by neutralizing the salt, as acid addition salt, to an isoelectric point, for example by weak bases or by ion exchange.

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

Stereomeric mixtures, such as diastereomeric and / or enantiomeric mixtures, such as racemic mixtures, may be elongated to the corresponding isomers in a manner known per se by suitable resolution procedures. Thus, diastomeric mixtures may be resolved into individual diastereomers by fractional crystallization, chromatography, treatment with solvents allowing separation and the like. The racemates can be separated from each other by converting the optical antipodes into diastereomers, for example by reaction with optically active compounds, such as optically active acids or bases, by column chromatography of the material provided with optically active compounds or by enzymatic methods, for example selective reaction of only one of the two enantiomers. This separation can be carried out both in the preparation step of one of the starting compounds and in the compounds of the formula I themselves.

The obtained compound of formula I, wherein the free hydroxy group that is bonded to the carbon atom adjacent to the carbon atom which carries the radical of the formula R ₂ -CH ₂ -, can conveniently the introduction of protecting groups, as described under process a) to convert the free hydroxy to a protected hydroxy group, for example an esterified hydroxy group, such as in a (lower alkanoyl) oxy group, such as acetyloxy. The esterification is carried out analogously to the condensation to the amides mentioned under process a), wherein the hydroxy group is reacted instead of the amine component. The reaction is preferably carried out under similar conditions as described under method a), in particular using (lower alkanoyl) anhydride, e.g. acetic anhydride, to give the corresponding (lower alkanoyl) oxy group in an organic solvent, e.g. cyclic ether, such as tetrahydrofuran in the presence of cyclic tertiary. an amine such as dimethylaminopyridine and / or a tri (lower alkyl) amine such as triethylamine at temperatures from 0 ° C to the boiling point of the reaction mixture, especially from 10 to 30 ° C.

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

Substitution of the carboxamido group or other primary or secondary amino group is carried out, for example, by alkylation, for example to obtain carbamoyl derivatives, mono- or di (lower alkyl) carbamoyl or mono- or dihydroxy (lower alkyl) alkanoyl groups, named above as a thiomorpholino or R morpholino ₄ substituent. R 8 together with the nitrogen bonding atom, or to form the aforementioned amino substituent derivatives on the thiomorpholino or morpholino group formed from R ₄ and R 8 together with the nitrogen bonding atom, in a compound of formula I wherein the nitrogen bonding nitrogen atom is attached to a hydrogen atom.

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 free methylene groups react with the carboxamido group of the compound of formula I. The diazomethane decomposition is preferably carried out catalytically, for example in the presence of a noble metal in a finely divided form, e.g. copper or copper sulfate.

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

Other alkylating agents are selected from the corresponding alkyl compounds which contain the substituent X, wherein X is predetermined by a leaving group. The leaving group is a particular nucleofugic 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, a hydroxy group esterified with a fluorine such as a (lower alkane) sulfonic acid or an aromatic sulfo acid, for example optionally 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, trimethanesulfonic acid or p-toluenesulfonic acid or hydroxy esterified with azide.

The reaction may be carried out under the conditions of first or second order nucleophilic substitution.

For example, one of the compounds with the substituent X, where X represents a leaving group with a high polarisability of the electron shell, for example bromine or iodine, can be used in a polar aprotic solvent, for example acetone, acetonitrile, nitromethane, dimethylsulfoxide or dimethylformamide. The substitution reactions are optionally carried out 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, and optionally under an inert gas atmosphere such as nitrogen or argon. atmosphere.

To esterify or amidate a carboxy group in a compound of formula I, for example, to amidate a free carboxy group of an amino acid, such as Glu or Asp, with ammonia, or a free carboxy group to thiomorpholino or morpholino formed by R ₄ and R ₅ together with the nitrogen bonding need to use free acids or the free acid can be converted into one of the above reactive derivatives and reacted with an alcohol, ammonia, primary or secondary amine, or the free acid or reactive salt, for example cesium salt, can be reacted with reactive to esterify an alcohol derivative. For example, the carboxylic acid cesium salt can be reacted with an alcohol halide or a sulfonic acid ester. The esterification of the carboxy group can also be carried out by other conventional alkylating agents such as diazomethane, alkyl halides, sulfonic acid esters, tartaric acid salts of 1-substituted 3-aryltriazenes and the like.

To convert an esterified or amidated carboxy group to a free carboxy group, the methods described above may be used in conjunction with the cleavage of the carboxy protecting group or, if appropriate, the alkyl saponification using conventional reaction conditions as described in the Organic,

17th ed., VEB Deutscher Verlag der wissenschaften, Berlin GDR (1988).

In the compound of formula (I), an 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), the free amino group present may be acylated, for example to introduce one of the radicals described for R1, except for a hydrogen atom. The acylation is carried out according to method a) above, according to one of the methods described for protecting groups or, for example, one of the methods mentioned in Organikum, 17th ed., VEB Deutscher

Verlag der Wissenschaften, Berlin - East Germany / 1988 /.

In the compound of formula (1) in which the substituents have the meanings indicated, at least one free hydroxy group is present and the remaining functional groups are in a protected form, the free hydroxy group can be acylated or etherified, for example a hydroxy group on thiomorpholino or morpholino formed from R ₄ and R taken together _with the nitrogen atom binding.

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

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

In the compound of formula I can be present in the protecting group or suitable radicals R _x, except hydrogen, cleaving off As described under process f), in particular hydrolysis, e.g. in the presence of a base such as alkali metal or alkaline earth metal, e.g., sodium hydroxide, or acids such as organic or mineral acids, for example 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, especially in ethers such as dioxane, at temperatures from -50 ° C to the reflux temperature of the corresponding reaction mixture, for example from 0 to 50 ° C, preferably in the presence of atmosphere. A shielding gas such as an argon or nitrogen atmosphere.

In the compound of formula I, wherein at least one of the radicals R _2, and R is phenyl, and / or one or more amino Bj, Aj and A ₂ represents a phenylalanine, the phenyl radicals may each also be substituted as described above can be selectively reduce the corresponding phenyl radicals to the corresponding cyclohexyl radicals, for example, hydrogenate. The hydrogenation is preferably carried out in the presence of a catalyst which permits the selective hydrogenation of the double bond in the presence of a peptide bond, especially a heavy metal oxide catalyst, such as a mixed rhodium oxide / platinum oxide Nishimura catalyst (S. Nishimura, Bull. Chem. Soc. Japan £ 3, 566 (1960)), in a suitable solvent, especially aqueous, alcohols such as methanol or ethanol, esters such as ethyl acetate, or ethers such as dioxane, for example methanol, at temperatures from 0 to 150 ° C preferably from 10 to 50 ° C, for example at room temperature, and under a hydrogen pressure of from 100 kPa to 5 MPa, preferably at normal pressure.

The invention also relates to embodiments of the process starting from a compound obtained in any stage as an intermediate and carrying out the missing steps or interrupting the process at any stage or using starting materials which form under the reaction conditions or in the form of a reactive derivative or a salt, or the compound obtained by the process of the invention is formed under the process conditions and further processed in situ. The starting compounds are preferably those which lead to the compounds described above as being preferred, particularly preferred, particularly preferred, even more preferred, preferred, or very particularly important.

Pharmaceutical preparations

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

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

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

usability

The invention relates to pharmaceutical compositions as well as to a method of treating diseases caused by Retroviruses, for example AIDS, especially if the disease is caused by HIV-1, comprising administering a therapeutically significant amount of a compound of formula I according to the invention to a warm-blooded individual, e.g. it needs this treatment against these diseases, especially AIDS. Dosage amounts for treating a warm-blooded individual, such as a human having a body weight of about 70 kg, are from about 3 mg to about 10 g, preferably from about 40 mg to about 4 g, for example from about 300 mg to 1.5 g 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 may be manufactured in a manner known per se, for example by conventional methods of dissolution, lyophilization, mixing, granulation or auctioning.

Preferably, a solution and a suspension or dispersion of the active substance, in particular isotonic aqueous solutions, dispersions or suspensions, are used, and these forms can be prepared, for example, from lyophilized preparations which contain the active substance alone or together with a suitable carrier before use. for example, mannitol. 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 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, 3,5, or vitamin E; di-tert-butyl-4-hydroxytoluene. The alcohol component of these fatty acid esters contains no more than 6 carbon atoms and is a monovalent or polyvalent residue, such as a monovalent, bivalent or trivalent alcohol, such as methanol, ethanol, propanol, butanol or pentanol, or isomers thereof, but especially glycol and glycerin. Fatty acid esters are, for example, ethyl oleate, isopropyl myristate, isopropyl palmitate, Labrafil M 2375 (polyoxyethylene glycerin trioleate from Gattefossé, Paris), Miglyol 812 (chain triglyceride of chain length 8 to 12 carbon atoms, especially Huls carbon), Huls carbon, vegetable oils such as cottonseed oil, almond, olive, castor, sesame or soybean oil, but in particular sunflower oil.

The preparation of the injectables is carried out in the usual manner under sterile conditions, as well as the filling of ampoules or vials, as well as the sale of crayfish containers.

Pharmaceutical compositions for oral use may be obtained if the active ingredient is mixed with a solid carrier, the mixture obtained is optionally granulated and, if appropriate or required, after the addition of suitable excipients is processed into tablets, dragee cores or capsules or by dispersions are produced, preferably with phospholipids which are filled into glasses. The active ingredient can also be introduced into plastic carriers which provide a dose or allow the active ingredient to diffuse.

Suitable carriers are special fillers, such as sugar, for example lactose, sucrose, mannitol or sorbitol, cellulosic and / or calcium phosphates, for example tricalcium phosphate or dibasic phosphate, as well as 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 carboxymethylated starches, cross-linked polyvinylpyrrolidone, agar, or its agar, sodium alginate. 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 optionally include gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, lacquer solutions in suitable organic solvents or solutions. gastric-resistant, 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 poly82 ethylene 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.

Particularly preferred pharmaceutical formulations are phospholipid-stabilized active substance dispersions, preferably for oral use, containing

(a) a phospholipid or a plurality of phospholipids of formula (A)

(A) in which

R _A represents an acyl group having 10 to 20 carbon atoms,

R _b represents a hydrogen atom or an acyl group having 10 to carbon atoms,

R _a , R _b and R _c represent a hydrogen atom or an alkyl group. with 1 to 4 carbon atoms and n is an integer from 2 to 4, as appropriate

b) another phospholipid or more phospholipids,

(c) the active substance; and

d) a pharmaceutically acceptable liquid carrier and optionally other excipients and / or preservatives.

A process for the preparation of these dispersions consists in the solution or suspension of a) and c) or a), b) and c), preferably a) and b), in a weight ratio of from 20: 1 to 1: 5, in particular from 5: 1 to 1: 1, converted by dilution with water into a dispersion, immediately thereafter the organic solvent is removed, for example by centrifugation, gel filtration, ultrafiltration or special dialysis, for example tangential dialysis, preferably against water, the dispersion obtained, preferably after addition of excipients or preservatives. a composition, optionally adjusted to an acceptable pH by the addition of a pharmaceutically acceptable buffer, such as a phosphate salt or an organic acid (pure or dissolved in water), such as acetic acid or citric acid, preferably to a pH of 3 to 6, e.g. , the correct concentration has not yet been reached, preferably to a concentration of active ingredient of from 2 to 30 mg / ml, in particular from 10 to 20 mg / ml wherein the concentration is preferably carried out according to the latter methods for removing the organic solvent, in particular by ultrafiltration, for example using a device for performing tangential dialysis and ultrafiltration.

The dispersions obtainable by this process, which are stabilized by phospholipids, are stable for at least several hours at room temperature, the amount of the components is reproducible and toxicologically harmless and thus the dispersions are suitable for oral administration to humans.

The order of magnitude of the particles contained in the dispersion is variable and is preferably from about 1.0x10 " up to approximately

Ι, ΟχΙΟ ⁵ m, especially from about 10 ^-7 to about 2x10 ^-6 m.

The nomenclature of the phospholipids of the formula I and the numbering of the carbon atom are carried out on the basis of the recommended lipid nomenclature published in Eur. J. of Biochem. 7, 11-21 (1977), Nomenclature of Lipids, which was elaborated by the Commission on Biochemical Nomenclature (CBN) of the IUPAC-IUB (sn nomenclature, stereospecific numbering).

The phospholipids of formula A, the substituents R _R and R defined acyl groups having 10 to 20 carbon atoms, preferably straight-alkanoyl group having 10 to 20 carbon atoms (the same number of carbon atoms) and a straight-alkenoyl group having 10 to 20 carbon atoms with a double bond (and the same number of carbon atoms).

Connecting alkanoyl group having 10 to 20 carbon atoms, R _f and R (the same number of carbon atoms), for example, n-dodecanoyl, n-tetradecanoyl, n-hexadecanoyl or n-octadecanoyl.

Connecting alkenoyl group having 10 to 20 carbon atoms, R _f and R a double bond (and the same number of carbon atoms), for example, 6-cis-, 6-trans-, 9-cis- or 9-trans-dodecenoyloxy, -tetracedenoyl, -hexadecenoyl, -octadecenoyl or -icosenoyl, in particular 9-cis-octadecenoyl (oleoyl).

In the phospholipids of the general formula A n represents an integer from 2 to 4, preferably 2. The group of the formula (C _n H _2n ) - represents an unbranched or branched alkylene, for example 1,1-ethylene, 1,1-, 1,2- or 1,3-propylene or 1,2-, 1,3- or 1,4-butylene. 1,2-ethylene (n-2) is preferred.

Phospholipids of formula (A) are, for example, in naturally occurring cephalins where R _a , R _b and R _c are hydrogen, or in naturally occurring lecithins where R _a , R _b and R _c are methyl, for example cephalin or lecithin from soybean bean, brain or liver of bovine animals or hen eggs with different or the same acyl groups R _A and R g or mixtures thereof.

Synthetic, substantially pure phospholipids of the general formula A with different or the same acyl groups R _a and R g are preferred.

The term synthetic phospholipid of formula A defines phospholipids having a uniform composition with respect to R _A and R 8. Such synthetic phospholipids are preferably substances defined under lecithins and cephalins whose acyl groups R _A and R 8 have a defined structure and are derived from a defined fatty acid having a degree of purity greater than about 95%. R _a and R g may have the same or different meanings and may be unsaturated or saturated. Preferably R _A is a saturated group such as n-hexadecanoyl, and R 8 is an unsaturated group such as 9-cis-octadecenoyl (i.e. oleyl).

The term naturally occurring phospholipids of formula (A) defines phospholipids which have no uniform composition with respect to R _A and R 8. Such naturally occurring phospholipids are also lecithins and cephalins whose acyl groups R _a and R g are structurally indefinable and are derived from a mixture of fatty acids that occur naturally.

The term substantially pure phospholipid defines a degree of purity of greater than 70% by weight of the phospholipid of formula (A) which can be demonstrated by a suitable assay method, for example, by paper chromatography.

Particularly preferred are the synthetic, substantially pure phospholipids of formula (A), wherein R _A is a C 10-20 straight alkanoyl group with the same number of carbon atoms and R 8 is a C 10-20 C straight-chain alkenoyl group having the same number of atoms atoms. R _a , R _b and R _c are methyl and n is 2.

In an especially preferred phospholipid of formula A, _{R, and} n-dodecanoyl, n-tetradecanoyl, n-hexadekanoyl- or n-octadecanoyl and R is 9-cis-dodecenoyloxy, 9-cis-tetradecenoyl, 9-cis-hexadecenoyl, 9-cis -octadecenoyl or 9-cis-icosenoyl. R _a , R _b and R _c are methyl and n is 2.

A particularly preferred phospholipid of formula (A) is synthetic 1-n-hexadecanoyl-2- (9-cis-octacedenoyl) -3-sn-phosphatidylcholine with a purity greater than 95%.

Preferred natural, substantially pure phospholipids of formula A are especially lecithin (L-α-phosphatidylcholine) from soybeans or hen eggs.

For the acyl radicals in the phospholipids of formula (A), the designations indicated in brackets are also applicable:

9-cis-dodecenoyl (lauroleoyl), 9-cis-tetradecenoyl (myristoleoyl), 9-cis-hexadecenoyl (palmitoleoyl), 6-cis-octadecenoyl (petroseloyl), 6-trans-octadecenoyl (petroselaidoyl), 9-cis-octadec (oleoyl), 9-trans-octadecenoyl (elaidoyl), 11-cis-octadecenoyl (vaccenoyl), 9-cis-icosenoyl (gadoleoyl), n-dodecanoyl (lauroyl), n-tetradecanoyl (myristoyl), n-hexadecanoyl (palmitadecanoyl) ), n-octadecanoyl (stearoyl) and n-icosanoyl (arachidoyl).

Further phospholipids are preferably phosphatidic acid esters (3-sn-phosphatidic acids) with said acyl residues such as phosphatidylserine and phosphatidylethanolamine.

The same soluble active ingredients may also be presented as pharmaceutically acceptable water-soluble salts as defined above.

Thus, in the liquid carrier d), components a), b) and c) or a) and c) are contained as liposomes so that solids or solid aggregates such as micelles and liquid, preferably oral, are not re-formed within a few days to a week. , with said components, optionally after filtration.

Pharmaceutically useful, non-toxic excipients, for example water-soluble excipients which are suitable for production under isotonic conditions, for example isotonic additives such as sodium chloride, non -onic additives (skeletal formers), such as is sorbitol, mannitol or glucose, or water-soluble liposome dispersion stabilizers such as lactose, fructose or sucrose.

In addition to the water-soluble excipients, emulsifying agents, cross-linking agents or surfactants, special emulsifying agents such as oleic acid, nonionic fatty acid ester surfactants with polyhydric alcohols may be present in liquid carriers for liquid pharmaceutical compositions. such as sorbitan monolaurate, -oleate, -stearate or -palmitate, sorbitan tristearate or -trioleate, adducts of still fatty acids with polyhydric alcohols and polyoxyethylene, such as polyoxyethylene sorbitan monolaurate, -oleate, -stearate, -palmitate, -tristoleate or polyethylene glycol fatty acids such as polyoxyethyl stearate, polyethylene glycol 400-stearate, polyethylene glycol 2000 stearate, special block copolymers of ethylene oxide and propylene oxide of the Pluronic ^R type (Wyandotte Chem. Corp.) or Synperonic ^R (ICI).

Preferred preservatives are, for example, antioxidants such as ascorbic acid or microbicides such as sorbic acid or benzoic acid.

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 such that the compounds mentioned are preferred.

In the preparation of the starting materials, the free functional groups which are not to be involved in the respective reactions can be protected or can be presented in a protected form, for example protected with the protecting groups mentioned under process a). These protecting groups may be released at the appropriate time by the reactions described in process f). Compounds with salt-forming groups can also find use as salts in each case, and the salts can be prepared at each stage or converted to the free compounds.

In the general formulas, unless the stereochemistry of the asymmetric carbon atoms is directly defined by the choice of the corresponding bond symbols, the configuration of the asymmetric carbon atoms is always designated by designating the appropriate configuration selected from (S), (R) and (S, R).

The carboxylic or sulfonic acids of the formula II or their reactive derivatives are known compounds and are commercially available or can be prepared according to methods known per se.

The compounds of formula (III) are known or can be prepared according to known methods. Examples are compounds that are accessible from compounds of the general formula

XII

(XII).

in which

R ₂ has the meanings given for compounds of formula I, and

Pa represents an amino protecting group, a particular (lower alkoxy) carbonyl group, such as a tert-butoxycarbonyl, or a phenyl lower alkoxy) carbonyl group, such as a benzyloxycarbonyl group, by reducing to a compound of formula XIII

(ΧΠΙ) in which the radicals have the meanings given above.

The reduction of the amino acid derivatives of the formula XII to the corresponding aldehydes of the formula XIII is carried out, for example, by reduction to the corresponding alcohols and subsequent oxidation to the aldehydes of the formula XIII.

The reduction to the alcohols is carried out by a particular hydrogenation of the corresponding acid halides or other carboxylic acid derivatives activated as described under process a) or by reacting the activated carboxylic acid derivative, a compound of the general formula XII, in particular anhydrides of organic carboxylic acids, preferably

- 90

isobutyl chloroformate (which is preferably obtained by reacting compounds of formula XII in the presence of basic amines such as tri (lower alkyl) amines such as triethylamine in an organic solvent such as cyclic ethers such as dioxane at temperatures from -50 to 80 ° C , preferably from 0 to 50 ° C) with complex hydrides such as alkali metal borohydrides, for example sodium borohydride, in aqueous solution in the presence or absence of the organic solvent used herein at temperatures from -50 to 80 ° C, preferably from 0 to 50 ° C ° C The subsequent oxidation of the alcohols obtained is preferably carried out by oxidizing agents which selectively convert the hydroxy group to an aldehyde group, for example by treatment with chromic acid or its derivatives, such as pyridinium chromate or tert-butylchromate, dichromate and sulfuric acid, sulfur dioxide in the presence of heterocyclic bases. and sulfur trioxide, di (lower alkyl) sulfoxides such as dimethyl sulfoxide, nitric acid, manganese dioxide or selenium dioxide in an aqueous, aqueous or organic solvent such as a halogenated hydrocarbon such as methylene chloride, carboxylic acid amides such as dimethylformamide, and / or cyclic ethers, such as tetrahydrofuran, in the presence or absence of basic amines, for example tri (lower alkyl) amines such as triethylamine, at temperatures from -70 to 100 ° C, preferably from -70 to -50 ° C or from -10 to 50 * C, for example as described in European patent application no. 0 236 734A.

Such a primary reduction of compounds of formula (XII) to aldehydes is possible, for example, by hydrogenation in the presence of a partially poisoned palladium catalyst or reduction of the corresponding amino acid ester such as a (lower alkyl) ester such as ethyl ester by treatment with complex hydrides such as borohydrides such as sodium borohydride or with preferably aluminum hydrides, for example lithium aluminum hydride, lithium tri (tert-butoxy) aluminum hydride or special diisobutyl butylaluminum hydride, in non-polar solvents, for example hydrocarbons or aromatic solvents, such as toluene, at a temperature of from -100 to 0 ° C, preferably -30 ° C, 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 from -20 to 60 ° C, s preferably from 10 to 30 ° C, and react of semicarbazones obtained 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 temperatures from -30 to 60 ° C, preferably from 0 to 30 ° C, and then acid. , for example, a strong mineral acid, such as hydrohalic acid, in an aqueous solution, optionally in the presence of the 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, under conditions used analogously to the condensation described in 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. toluene and ethanol, at temperatures from -50 to 50 ° C, preferably from -10 to 20 ° C.

The preparation of the compounds of the formula XIII is carried out in a particularly preferred manner under conditions analogous to the reaction conditions known from J. Org. Chem. 47, 3016 (1982).

J. Org. Chem. 43, 3624 (1978) or J. Org. Chem. 51, 3921 (1986).

To synthesize compounds of formula III, compounds of formula XIII are then reacted with a reactive tetraalkylsilane, preferably a halomethyltri (lower alkyl) silane, such as chloromethyltrimethylsilane, in an inert solvent such as an ether such as diethyl ether, cyclic ether such as dioxane or ester. , for example ethyl acetate, at temperatures from -100 to 50 ° C, preferably from -65 to 40 ° C, to give compounds of formula XIV

(XIV) in which

R ₆ , R ₇ and R ₈ represent a lower alkyl group, for example methyl, and the remaining radicals have the meanings given above, the obtained compounds are converted in the presence of a Lewis acid, for example boron trifluoride etherate, in an inert solvent, especially a halogenated hydrocarbon such as methylene chloride. by treatment with an aqueous base, for example sodium hydroxide solution, at a temperature of from -30 to 80 ° C, in particular from 0 to 50 ° C, with elution and cleavage of the protecting group, to olefinic compounds of the general formula XV

(XV) in which

R ₂ is as defined in formula I, to the corresponding olefin was again introduced amino protective group Pa, as described under process a) for the introduction of an amino protecting group, in particular through an acid anhydride in a chlorinated hydrocarbon, such as methylene chloride, the tep93 lot of - 50 to 80 ° C, in particular from 0 to 35 ° C, whereby amino-protected olefins of formula XVI are obtained

HN (XVI)

Where the radicals are as defined above, the double bond is converted to an oxirane, preferably stereoselective using peroxides, especially peroxycarboxylic acids, for example haloperoxybenzoic acid, such as m-chloroperbenzoic acid, in an inert organic solvent, such as methylene chloride, at temperatures ranging from - 50 to 60 ° C, in particular from -10 to 25 ° C, and if necessary separating the diomers to give epoxides of formula XVII

Pa (XVII).

wherein the radicals are as defined herein, the appropriate olefins are treated with a suitable malonic acid diester, for example dimethyl or diethyl malonic acid, for example by activating the methylene group of the malonic acid diester with an alkali metal such as sodium in a polar anhydrous solvent such as alcohol; ethanol, at temperatures from -50 to 80 ° C, especially from 0 to 35 ° C, and the solution is treated with an acid, such as carboxylic acid, for example citric acid, to give lactones of formula XVIII.

HN 1 Pa 0 * R = O (Xvrn). in which R8 represents a lower alkoxy group, or ethoxy and such as methoxy

the remaining radicals are as defined above, optionally, in the compounds wherein _R2 is phenyl, optionally substituted as described for compounds of Formula I, such a radical is reduced to the cyclohexyl, separate hydrogenation, preferably in the presence of a catalyst such as a catalyst based on noble metal oxides, as a catalyst based on mixed rhodium oxide and platinum oxide (manufactured by Nishimura), preferably in polar solvents such as alcohols such as methanol, at normal pressure or at elevated pressure up to 500 kPa, at temperatures from -20 to 50 ° C, preferably from 10 to 35 ° C, directly or after hydrogenation of the compound of formula (XVIII) obtained, is reacted with a reagent introducing the radical R ₃ -CH ₂ -, for example with a compound of formula r ₃ -ch ₂ -w in which

R ₃ has the meanings given for the compounds of the general formula I and

W represents a nucleofugable leaving group selected from hydroxy groups esterified with strong inorganic or organic acids, such as mineral acids, such as hydrohalic acid such as hydrochloric, hydrobromic or hydroiodic acid, or a strong organic sulfonic acid such as (lower alkane) sulfonic acid, e.g. such as fluorine or an aromatic sulfonic acid, for example benzenesulfonic acid optionally substituted by a lower alkyl group such as methyl, a halogen atom such as bromine and / or nitro, hydroxy groups esterified for example methanesulfonic acid, trimethanesulfonic acid or p-toluenesulfonic acid ester, or , especially bromide, in an anhydrous polar solvent, for example an alcohol such as ethanol, in the presence of an alkali metal, for example sodium, at temperatures from -50 to 8 0 ° C, preferably from 0 to 35 ° C, to yield a compound of formula XIX

Pa (XIX), wherein the radicals have the above-mentioned values, the compounds of formula XIX are hydrolyzed and decarboxylated, for example by hydrolysis with a base such as an alkali metal hydroxide, for example lithium hydroxide, at temperatures from -50 to 80 ° C, preferably about 0 to 35 ° C, in an organic solvent, for example an ether such as dimethoxyethane, and the subsequent decarboxylation is carried out by heating in an inert solvent such as toluene to temperatures of 40 to 120 ° C, preferably 70 to 100 ° C to obtain a compound of formula XX

(XX).

in which the radicals have the meanings given above, the (R, S, S) - and S, S, S) isomers are separated by column chromatography, the (R, S, S) -isomer being used further to open the lactone ring. reacted with a base such as an alkali metal hydroxide such as lithium hydroxide in an inert solvent such as an ether such as dimethoxyethane to give a compound of formula XXI

(XXI)

in which the radicals have the meanings given above, a hydroxyl-protecting group Py, for example some of the hydroxyl-protecting groups of those mentioned under process a), under the same conditions, in particular a triple alkyl) silyl group, is introduced into the compound obtained by the corresponding halogen-lower tert-butyldimethylchlorosilane, in a polar solvent such as a di (lower alkyl) (lower alkanoyl) amide such as dimethylformamide, in the presence of a sterically hindered amino compound such as a cyclic amine such as imidazole at temperatures from -50 to -50 to 80 ° C, preferably from 0 to 35 ° C, to give a compound of formula XXII

Pa in which the radicals have the meanings given above, and the compounds of the general formula III with the radicals mentioned under process a) are prepared, for example, by condensation with a compound of the general formula VII, wherein the radicals have the meanings given under the method

c), under the conditions described for process a), a special reaction in situ in the presence of a condensing agent such as benztriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate or O-benztriazol-1-yl-N, N, N *, N ^1- tetramethyluronium hexafluorophosphate, a sterically hindered amine such as N-methylmorpholine, and a racemization inhibiting compound such as 1-hydroxybenztriazole, in a polar solvent, preferably an acid amide such as a di (lower alkyl) amino (lower alkanoyl) amide such as dimethylforroamide; temperatures from -50 to 80 ° C, in particular from 0 to 35 ° C, followed by cleavage of the protecting group Pa as described under process f) when Pa is a radical not corresponding to the radical HB? - with the meanings given above for compounds of formula I outside the bonds, condensation with a compound of formula

HB ₁ 'OH, wherein

BJJ has the meanings given under method b), under the condensation conditions mentioned above, and the associated cleavage of the group Py and / or other protecting groups as described under method f). For the preparation of the compounds of the formula III it is also possible to carry out the reaction of the compounds of the formula XXII with compounds which introduce the radicals -Aj-, -A ₂ -,, -A ₂ -NR ₄ R ₅ and / or -NR ₄ R ₅ of formula VII.

The compounds of formula (XV) may also have on the carbon bearing the -NH ₂ (R, S) -configuration instead of the (S) -configuration, compounds of formula (XII), (XIII) and (XIV) and in particular formula (XVI, XVII, XVIII, XIX). , XX, XXI and / or XXII may also have a (S) -configuration on the carbon bearing the remainder of the Pa-NH- (R, S) -configuration, and the corresponding racemic or diastereomeric mixtures may also be separated at all stages.

Compounds of formula XX in which the radicals have the meanings indicated may also be prepared from compounds of the formula XIII in which the radicals have the meanings indicated if the aldehydes of the formula XIII are reacted with esters of 2-halopropionic acid, especially esters of 2-iodopropionic acid as ethyl 2-iodopropionate to give the compound of formula XXIII

Pa (ΧΧΙΠ) in which the radicals have the meanings indicated and the carbon atom bearing the Pa-NH- radical may also be alternatively in the (R, S) -configuration.

The reaction is carried out first to give the 2-halopropionic acid ester homoenolate in the presence of a mixture of zinc and a medium in dibasic alkyl) - (lower alkanoyl amide, such as dimethylacetamide, at temperatures from 0 to 100 ° C, especially from 20 to 80 ° C). , preferably under a protective atmosphere such as nitrogen or argon, contacting a tetra (lower alkyl) orthotitanate, such as tetraisopropyl orthotitanate, in an aromatic solvent such as toluene or xylene, in the presence of a halogenated hydrocarbon such as methylene chloride, with titanium halide, as titanium tetrachloride, and at 0 to 50 ° C, especially 20 to 30 ° C, the reaction mixture is stirred to form the corresponding dihalogen-titanium di (lower alkylate) or preferably trihalogen titanium (lower alkylate), especially trichlorotitanium The solution of zinc homoenolate is added dropwise to the reaction mixture at a temperature of from -50 to 0 ° C, in particular from -40 to -25 ° C, and then the solution is added dropwise. an aldehyde of formula (XIII) in a halogenated hydrocarbon such as methylene chloride, wherein the reaction is carried out at a temperature of from -50 to 30 ° C, preferably from about -20 to 5 ° C, to form an ester, especially ethyl ester, of the compound of formula XXIII. This ester is then hydrolyzed to form a compound of formula XIII as defined above, preferably in an organic solvent such as an aromatic compound such as toluene or xylene in the presence of an acid such as a carboxylic acid such as acetic acid at a temperature of 20 ° C. C to the boiling point of the reaction mixture, especially from 70 to 90 ° C. if necessary, diastereomeric separations are carried out, for example, by chromatography, for example on silica gel, with an organic solvent mixture such as an alkane / ether mixture such as a lower alkane and a (lower alkyl) (lower alkanoyl) ester such as a mixture of hexane and ethyl acetate.

The compound of formula XXIII is then deprotolated by a strong base with the carbanion formed at the α-carbon atom leading to the oxo groups of the lactone and the associated nucleophilic substitution of the residue w of the compound of formula ^r 3 ^-ch 2 ' ^w ' in which

R ₃ and W are as defined above in the preparation of compounds of formula (XIX) to obtain the corresponding compound of formula (XX), wherein the reaction is preferably conducted stereoselectively to the (R) -configuration at the carbon bearing the R ₃ -CH ₂ residue. of formula XX. Reactions with a strong base, especially with a compound formed from an organosilicon amide and an alkali metal, for example with an alkali metal bis / tri (lower alkyl) silyl / amide such as lithium bis (trimethylsilyl) amide, or further an alkali metal di (lower alkyl) amide %, such as lithium diisopropylamide, is preferably carried out in an inert organic solvent, especially an ether, for example a cyclic ether such as tetrahydrofuran, at temperatures from -100 to 0 ° C, preferably from -78 to -50 ° C, with nucleophilic substitution occurring. in situ by the addition of a compound of formula r ₃ -ch ₂ -w wherein

R ₃ and W have the meanings given above, in the solvent alone, at a temperature of from -100 to 0 ° C, preferably from -60 to -40 ° C.

A compound of formula (XV) wherein the residues have

As defined above, and where preferably the carbon atom bearing the NH ₂ group - has the (R, S) -configuration, it can also be obtained when a formic acid ester, for example a (lower alkyl) formic acid ester such as ethyl formate is reacted with allylamine at a temperature of from 20 to 70 ° C, in particular from 50 to 60 ° C, to form allylamide. The amide is then dehydrated under a shielding gas such as nitrogen or argon, preferably by treatment with an acid halide such as phosphorus oxychloride, phosgene or a separate organic sulfonic acid halide such as arylsulfonic acid chloride such as toluenesulfonic acid in the presence of a base such as tri ( lower alkyl) amines, such as triethylamine, or especially mono- or bicyclic amines, such as pyridine or quinoline, at temperatures of from 50 to 100 ° C, especially from about 80 to about 100 ° C. This produces an allyl isocyanide which is converted by reaction with an organolithium salt, for example (lower alkyl) lithium, such as n-butyllithium, to the corresponding lithium salt, the reaction preferably being carried out in an inert organic solvent, especially an ether such as dioxane or diethyl ether; in an alkane, for example hexane, or a mixture of these solvents, at temperatures from -120 to -50 ° C, especially about -100 to -90 ° C. The resulting lithium salt is then reacted with a compound of formula R ₂ -CH ₂ -W, wherein R ₂ has the meanings given for the compound of formula I and w has the meanings given for the compound of formula R ₃ -CH ₂ -W, especially bromine preferably by dropwise addition of a compound of the formula R ₂ -CH ₂ -W in an organic solvent, for example an ether such as tetrahydrofuran, using the above temperatures and ultimately heating to a temperature of from 0 to 50 ° C, preferably to a temperature of from 0 to 50 ° C. 20 to 30 ° C. An isocyanide of formula XXIV is formed

102

(XXIV), in which the radicals have the meanings indicated.

•

The compound of formula (XXIV) is then hydrolyzed, preferably in an aqueous solution to which an acid has been added, for example with aqueous hydrohalic acid such as hydrochloric acid, in particular concentrated hydrochloric acid, at temperatures from -20 to 30 ° C, especially at about 0 to 10 ° C to give a compound of formula XV wherein the radicals have the meanings defined herein and wherein the preferred carbon atom bearing the -NH ₂ group is in the (R, S) -configuration.

The compounds of the formula IV are known or can be prepared in a manner known per se, for example by condensation of a carboxylic or sulphonic acid of the formula II or their reactive derivatives with ammonium compounds of the formula

H-BjJ-OH in which

BJJ has the meanings given for the compounds of the formula IV, wherein the condensation is carried out as described above or in the case of the compounds of the formula II in which R _x 'is N- (heterocyclyl (lower alkyl)) - N- (lower alkyl) aminocarbonyl such as N- (2-pyridylmethyl) -N-methylaminocarbonyl, similar to that described in Example 218 of European Patent No. 0 402 646 of 19 December 1990.

103

Compounds of formula V are prepared, for example, from compounds of formula XXII to condensation with a compound of formula VII or sequential condensation of the compounds (e.g., compounds of Formula H-Aj'-OH HA _2-OH, H-Aj-A ₂ -OH, or a compound of formula XI, wherein the radicals are each as defined above), which correspond to fragments of a compound of formula VII. The condensation conditions are analogous to those described for the preparation of compounds of formula III.

Compounds of formula (VI) are prepared, for example, from amino compounds of formula (XXII), for example by introducing a carboxy-protecting group, as described under

a), and cleavage of the protecting group Pa as described under process f) by condensation with a carboxylic acid of the general formula

Rj-Bj-OH, wherein the radicals have the meanings given in formula I.

Compounds of formula VII are prepared, for example, from the corresponding amino acids of formula

H Aj' -OH or IIA _2-OH or a peptide of the formula

H-A 1 -A ₂ -OH and the amine components of the general formula (XI), where the radicals have the meanings given above, by condensation analogous to the process described under process (a). To produce compounds with reduced peptide bond between A ₂ and A ₂ , the peptide bond between A ₂ and A _{2 can be} reduced, preferably at the dipeptide stage, for example with hydrogen in the presence of a catalyst based on heavy or rare metals such as platinum or palladium. on a carrier such as activated carbon or complex hydrides, preferably complex hydrides such as lithium aluminum hydride, or disiamylborane in a polar solvent such as alcohols such as ethanol or ethers such as cyclic ethers such as tetrahydrofuran at temperatures from 0 to 150 ° C, preferably from 20 ° C to the boiling point of the respective reaction mixture. The amine of formula (XI) is a known compound or can be prepared by processes known per se.

Compounds of formula (VIII) may be prepared, for example, from compounds of formula (VI) by condensation with amino acids introducing the radical A @ 4 *. The reaction is carried out under analogous conditions as described under process a).

Compounds of formula IX are prepared by condensation, for example, from an amino acid of formula

H-Aj'-OH in which

A ₂ 'is as defined for the compounds of formula (I), and an amine of the formula (XI) in which the residues have the meanings as given for compounds of formula (I).

Compounds of formula X are prepared, for example, from compounds of formula VI and the corresponding amino acids of formula

Η-Α _χ --OH or HA ₂ OH -OH

105 or peptides of the general formula ^H " ^A 1" ^A 2 ^OH 'where the residues have the meanings given above, by condensation in an analogous manner to that described under

a). To produce compounds with reduced peptide bond between Aj. and A ₂ , the peptide bond between A 2 and A _{2 can be} reduced, preferably in the dipeptide step, for example with hydrogen in the presence of a catalyst based on heavy or rare metals such as platinum or palladium, optionally on a carrier such as activated carbon or complex hydrides. , preferably complex hydrides such as lithium aluminum hydride, or disiamylborane in polar solvents such as alcohols such as ethanol or ethers such as cyclic ethers such as tetrahydrofuran at temperatures from 0 to 150 ° C, preferably from 20 ° C to temperature boiling the reaction mixture.

The amines of formula (XI) are known, commercially available compounds or can be prepared according to known methods.

The remaining starting compounds are known substances, can be prepared by methods known per se or commercially available.

DETAILED DESCRIPTION OF THE INVENTION

The following examples illustrate the invention in no way limit the scope of the invention.

As usual, temperatures are in degrees Celsius (C). If no temperature data is given, the reaction is run

106 perform at room temperature. The Rf values, which indicate the retardation ratio of each substance to the solvent process, are determined by thin layer chromatography on silica gel thin plates,

using the following solvent systems: DC solvent systems: A hexane and ethyl acetate 1: 1 B ethyl acetate - C hexane and ethyl acetate 4: 1 D hexane and ethyl acetate 2: 1 E hexane and ethyl acetate 3: 1 F methylene chloride and methanol 9: 1 G chloroform, methanol, water and glacial acetic acid 85: 13: 1.5: 0.5 about H ethyl acetate and methanol 9: 1 I hexane and ethyl acetate 1: 2 J chloroform, methanol, acid acetic acid and water 75: 27: 5: 0.5 The ethyl acetate and acid acid 19: 1 L methylene chloride and methanol 7: 3 M methylene chloride and ether 49: 1 N methylene chloride and ether 3: 1 For example, the abbreviation Rf (A) means that the value of Rf is

The ratios of the relative amounts of the solvents are always given in parts by volume. Also, in defining solvent systems for column chromatography, the ratios of the amount of solvent used are in parts by volume.

The abbreviations and abbreviations used hereafter have the following meanings:

107

Boe tert-butoxycarbonyl

TLC by thin layer ethyl acetate ethyl acetate ethyl acetate DMSO dimethylsulfoxide ether diethyl ether

FAB-MS mass spectroscopy, fast atom bombardment technique

IR infrared spectroscopy min minute (s)

Z - benzyloxycarbonyl

Mass spectroscopy values are obtained by a fast atom bombardment (FAB-MS) technique. Mass data refers to the protonated ion of the molecule (M +

H) ⁺ .

Infrared spectroscopy (IR) values are given in cm ^-1 , with solvent in parentheses.

Abbreviations commonly used in peptide chemistry are used to denote the naturally occurring α-amino acid bivalent radicals. The configuration on the α-carbon atom is indicated in front by the symbol (L) or (D). -Cha- represents cyclohexylalanyl, - (pF-Phe) - represents phenylalanyl substituted at the p-position of the phenyl ring by fluorine, (p-CH ₃ O-Phe) - represents phenylalanyl substituted at the p-position of the phenyl ring by methoxy and - (p- CN-Phe) - means phenylalanyl substituted in the β-position of the phenyl ring with cyano.

The abbreviations below are defined by the corresponding representation of the formula and describing:

The residue, abbreviated as -Phe [C] Phe, is the 5 (S) -amino-2 (R) -benzyl-4 (S) -hydro-108 xy-6-phenylhexanoic acid bivalent radical and has the formula

The residue, abbreviated as -Cha [C] (p-CN) Phe, is known to be the 5 (S) -amino-2 (R) - (p-cyanophenylmethyl) -6-cyclohexyl-4 (S) -hydroxyhexanoic acid bivalent radical and has a formula

The residue, abbreviated -Cha [C] Cha-, is known to have the 5 (S) -amino-6-cyclohexyl-2 (R) -cyclohexylmethyl-4 (S) -hydroxyhexaric acid bivalent radical and has the formula

109

The residue with the abbreviated designation -Cha [C] (p-F) Phe- represents the 5 (S) -amino-6-cyclohexyl-2 (R) - (p-fluorophenylmethyl) -4 (S) -hydroxyhexanoic acid bivalent radical and has the formula

The abbreviated - (p-F) Phe [C] Phe- is the 5 (S) -amino-2 (R) -benzyl-6- (p-fluorophenyl) -4 (S) -hydroxyhexanoic acid bivalent radical and has the formula

The below illustrated representation of the formula of the central portion of the response 110 gives the abbreviated designation used in the following examples.

J * ΡΓ about X Y ï ” Y Phe [C] (p-F) Phe H F -Phe (C] (p-CN) Phe H CN -Cha [C] (p-Cl 2 O) Phe-CH 2 O -Phe [C] _(p-CH3 O) Phe- H CH ₃ 0 Cha (C _(p-CF3) Phe-CF Phe (C) (p-CF ₃ ) H cf ₃ - (p-F) Phe [C] (p-F) Phe F F -TP-F) Phe, (C] (p-CN) Phe F CN Tyr [C] Tyr- OH OH -TyrlClPhe- OH H PhcíCJTyr H OH Like that Phe [C] (p • F) Phe corresponds to bivalent

5 (S) -amino-2 (R) - (p-fluorophenylmethyl) -4 (S) -hydroxy-6-phenylhexanoic acid dical, -Phe [C] (p-CN) Phe- corresponds to the bivalent radical 5 (S) ) -amino-2 (R) - (p-cyanophenylmethyl) -4 (S) -hydroxy-6-phenylhexanoic acid, -Phe [C] (p-CH ₃ O) Phe- corresponds to the bivalent 5 (S) -amino acid radical -4- (S) -hydroxy-2 (R) - (p-methoxyphenylmethyl) -6-phenylhexanoic acid, -Phe [C] (p-CF ₃ ) Phe corresponds to bivalent 5 (S) -amino-4 acid radical (Roxy trapping) -6-phenyl-2 (R) - (p-trifluoromethylphenylmethyl) -hexanoic acid, - (pF) Phe (C) (pF) Phe- corresponds to the 5 (S) -amino-6- (p-fluorophenyl) -2 bivalent radical R) - (p-fluorophenylmethyl) -4 (S) -hydroxyhexanoic acid, - (pF-i; c; (p-Cl)) Phe-bivalent 5 (S) -arainc-2 (R) - bivalent radical (p-yanferylmethyl) -6- (p-fluorophenyl) -4 (S) -hydroxynexanoic acid, -Cha [C] (p-CH ₃ O) Phe, corresponds to the bivalent 5 (S) -amino acid radical -2 (R) - (p-methoxyphenylmethyl) -6-cyclopentyl- (S) -hydroxyhexanoic acid, -Cha [C] (p-CF ₃ ) Phe, corresponds to the divalent radical of the acid 5 (S) ) -amino-6-cyclohexyl-4 (S) -hydroxy-2 (R) -p-trifluoromethylphenylmethyl) hexanoic acid, -Tyr [C] Tyr- responsive to the 5 (S) -amino-4 (S) -hydroxy bivalent radical -6- (p-hydroxyphenyl) -2 (R) - (hydroxyphenylmethyl) hexanoic acid, -Phe [CITr] is equivalent to the bivalent 5 (S) -a-ir-4S) -hydroxy-2 (R) acid radical - (p-hydroxyphenylmethyl) -6-phenylhexar-3 and -Tyr [C] Phe - corresponds to the bivalent acid radical: (S) -azino-4 (S) -hydroxy-6- (p-hydroxyphenyl) -2 (R) ) -benzyl.exancvé.

- (pF) Phe [C] _(p-CF3) Phe-

and

(CF ₃ ) Phe (C) Phe-H (CF ₃ ) Phe [C] (pF) Phe-F. (CF ₃ ) Phe [C] (p-CF ₃ ) Phe-CF

The remainder - (pF) Phe (C) (p-CF ₃ ) Phe- therefore corresponds to the bivalent radical 5 (S) -amino-4 (S) -hydroxy-6- (p-fluorophenyl) -2 (R) - (p-Trifluoromethylphenylmethyl; hexarecyl);

The symbol (±) is intended to indicate that the - _(CF3) Phe [C] _Phe-f - _(CF3) Phe [C] (pF) Phe, and

113

- (CF ₃ ) Phe [C] (p-CF) Phe-, which correspond to the bivalent radicals of 5-amino-2-phenyl-4-hydroxy-6- (p-trifluoromethylphenyl) hexanoic acid, 5-amino-2- (p-fluorophenyl) -4-hydroxy-6- (p-trifluoromethylphenyl) hexanoic acid and 5-amino-2- (p-trifluoromethylphenyl) -4-hydroxy-6- (p-trifluoromethylphenyl) hexanoic acid are in the corresponding exemplified as mixtures of the 2 (R), 4 (S), 5 (S) isomers with the 2 (S), 4 (R), 5 (R) isomers.

Example 1

Boc-Cha [C] (p-F) Phe- (L) -Va 1- (L) -Phermorpholin-4-ylamide

A solution of 160 mg of 5 (S) -Boc-amino-4 (S) - (tert-butyldimethylsilyloxy) -6-cyclohexyl-2 (R) - (p-fluorophenylmethyl) hexanoyl- (L) -Val- (L) - Phe-morpholin-4-ylamide in 1.8 ml of absolute dimethylformamide was contacted with 116 mg of tetrabutylammonium fluoride trihydrate and the reaction mixture was stirred at room temperature for 4.5 hours. The colorless solution is poured into 50 ml of water and extracted four times with ethyl acetate. The combined extracts were washed twice with 25 ml each of sodium bicarbonate solution, twice with water and once with saturated sodium chloride solution and finally dried over sodium sulfate overnight. After evaporation of the solvent, the residue was crystallized from diisopropyl ether to give the title compound. DC: _Rf (I) »0.14, FAB-MS (M + H) = ^r 753rd

The starting compound is prepared as follows:

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

24.7 mg of magnesium is placed in 100 ml of absolute ether and contacted with a small amount of iodine over 35 minutes, together with 132.5 ml of chloromethyltrimethylsilane and 300 ml of ether, maintaining the temperature at 38 ° C with ice

114 spa. The reaction mixture was stirred at room temperature for 90 minutes. After cooling to -60 ° C, a suspension of 48.6 g of N-Boc-phenylalaninal (manufactured by DJ Kempf, J. Crg. Chem. 51. 3921 (1986)) in 1.1 liter was added to the reaction mixture over 40 minutes. 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 is then poured onto 2 liters of ice water and 1.5 liters of a 10% aqueous citric acid solution. 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 solution and twice with saturated sodium chloride solution. After drying over sodium sulfate, the reaction mixture was evaporated under reduced pressure and the title compound obtained was used without further purification. DC Rf (C) 0.6, FAB-MS (M + H) < ^{+ >} - 338.

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

A solution of 18.8 g of N-3 (S) - (Boc-amino) -2 (R, S) -hydroxy-4-phenyl-1-trimethylsilylbutane in 420 ml of methylene chloride is contacted with 35.6 ml of approximately 48% solution of boron trifluoride etherate in 5 minutes at 5 ° C. The reaction mixture is then stirred for 16 hours at room temperature, cooled to 10 DEG C. and treated 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 sodium chloride solution and dried over sodium sulfate. The title compound was used without further purification. TLC Rf (C) 0.15, IR (methylene chloride): 3370, 3020, 2920, 1640, 1605 cm @ -1.

1c) N-Boc-1-phenyl-3-buten-2 (S) -amine

21.5 g of 1-phenyl-3-buten-2 (S) -amine are dissolved in 500 ml

115 of absolute methylene chloride was added dropwise to a solution of 38.3 g of Boc-anhydride in 250 ml of methylene chloride. After stirring for 90 minutes at room temperature, the reaction mixture is concentrated to a volume of 100 ml, then diluted with 1.5 liters of ether and successively washed twice with 400 ml of 10% citric acid, once with 400 ml of water, once with 400 µl of saturated aqueous sodium bicarbonate. saturated with brine and dried over sodium sulfate. After evaporation of the solvent, the residue was purified by column chromatography (silica gel, hexane / ethyl acetate 95: 5 to 80:20) and the title compound was crystallized from hexane. Its melting point is 67-68 ° C. DC Rf (C) = 0.4; FAB-MS (M + H) < ^{+ &gt}; = 248.

1d) 2 (R) - / 1 (S) - (Boc-amino) -2-phenylethyl / oxirane

A solution of 1.45 g of N-Boc-1-phenyl-3-buten-2 (S) -amine in 20 ml of methylene chloride was contacted with a solution of 9.74 g of m-chloroperbenzoic acid in 50 ml of methylene chloride at 0-5. 'C within 15 minutes. The reaction mixture is stirred for 18 hours at the same temperature and for another 5 hours while warming to room temperature and then poured onto ice cold 10% sodium carbonate solution. The aqueous phase is extracted three times with ether. The combined organic phases were successively washed three times with 10% sodium sulfite solution, three times with saturated sodium bicarbonate solution, sodium thiosulfate solution and saturated sodium chloride solution and dried over sodium sulfate. After evaporation of the solvent, the title compound was purified by column chromatography (silica gel, hexane / ethyl acetate 4: 1) and crystallized from hexane. Its melting point is 51-52 ° C. R DC _and (C) '0.33, FAB-MS (M + H) ⁺ »264th

1e) 5 (S) - 1 (S) - (Boc-amino) -2-phenylethyl / -3 (R, S) -carbethoxydihydrofuran-2- (3H) -one

- 116 <

To a solution of 26 ml of diethyl ether of malonic acid in

260 ml of absolute ethanol are added portionwise to 3.4 g of sodium. After sodium consumption (approximately 90 minutes), a solution of 13 g of 2 (R) - / 1 (S) - (Boc-amino) -2-phenylethyl / oxirane in 100 ml of ethanol is added dropwise over 10 minutes. The reaction mixture is stirred for 5 hours and then poured onto 1.5 liters of ice water and the pH is adjusted to 4 by addition of 10% citric acid solution. The reaction mixture was extracted four times with ether and then the combined organic extracts were washed successively twice with saturated aqueous sodium bicarbonate solution, once with saturated sodium chloride solution, again with saturated aqueous sodium bicarbonate solution, with water and once more with saturated sodium chloride solution. After evaporation of the solvent, the title compound was obtained by column chromatography (silica gel, hexane / ethyl acetate 4: 1). DC: _Rf (C) - 0.22, FAB-MS (M + H) ⁺ - 378th

1f) 5 (S) - / 1 (5) - (Boc-amino) -2-cyclohexylethyl / -3 (R, S) -carbethoxydihydrofuran-2- (3H) -one g 5 (S) - / 1 (5) 1- (Boc-amino) -2-phenylethyl / -3 (R, S) -carbethoxydihydrofuran-2- (3H) -one in 100 ml of ethanol is hydrogenated under normal hydrogen pressure (about 100 kPa) for 2 hours in the presence of Nishimura catalyst (mixed rhodium oxide and platinum oxide monohydrate, Degussa). The catalyst was filtered through diatomaceous earth (Celite, Sigma, Switzerland), washed with ethanol and the filtrate was evaporated. DC: _Rf (C) = 0.23.

1g) 5 (S) - [1- (S) - (Boc-amino) -2-cyclohexylethyl] -3 (R, S) -carbethoxy-3- (p-fluorophenylmethyl) dihydrofuran-2- (3H) -one

10.2 g of 5 (S) - / 1 (S) - (Boc-amino) -2-cyclohexylethyl / -3 (R, S) -carbethoxydihydrofuran-2- (3H) -one were reacted

117 with 5.39 g of p-fluorobenzyl bromide (Fluka, Buchs, Switzerland) and 0.68 g of sodium in 180 ml of ethanol at room temperature. Since thin-layer chromatography after 90 minutes still did not react all of the lactone, 0.2 g of sodium and 0.7 g of pfluorobenzyl bromide were added. After 16 hours, pour the mixture into 10% citric acid / ice solution and extract three times with ether. The organic phases were washed twice with water and saturated sodium chloride solution, dried over sodium sulfate and evaporated. Upon addition of a mixture of hexane and ethyl acetate, the oily crude product partially crystallized under the influence of ultrasound. The product contains the title compound (diastereomer ratio 4: 1). Column chromatography (silica gel, hexane / ethyl acetate 4: 1) of the mother liquors afforded the next title compound (diastereomer ratio 1: 4). DC: _Rf (C) "0.29, FAB-MS (M + H) ⁺ = 492nd

1h) 5 (S) - [1- (S) - (Boc-amino) -2-cyclohexylethyl] -3 (R) - (p-fluorophenylmethyl) dihydrofuran-2- (3H) -one and 5 (S) -] (S) - (Boc-amino) -2-cyclohexylethyl / -3 (S) - (p-fluorophenyl-methyl) dihydrofuran-2 (3H) -one

10.3 g of 5 (S) - (1 (S) - (Boc-amino) -2-cyclohexylethyl) -

-3 (R, S) -carbethoxy-3- (p-fluorophenylmethyl) dihydrofuran-2- (3H) -one (diastereomer ratio approximately 1: 1) in 174 ml 1,2-dimethoxyethane with room temperature for 5 minutes at room temperature The reaction mixture is treated dropwise with 91 ml of a 1 molar lithium hydroxide solution and stirred for 15 hours at room temperature. After evaporation of the solvent, the residue obtained is poured onto 500 ml of a 10% citric acid solution and extracted three times with ether. The combined ether phases were washed once with saturated sodium chloride solution and dried over sodium sulfate. The solvent was evaporated to give the crude carboxylic acid which was converted to a mixture of the title compounds in 450 mL of toluene followed by decarboxylation by heating at 90 ° C for 9 hours. Column chromatography (silica gel, hexane mixture)

118 and ethyl acetate (from 9: 1 to 4: 1) gave first 3 (R) -epimer (DC R _f (E) = 0.45) and then 3 (S) -epimer (DC R _f (E) = 0.41 /.

(li) 5 (S) - (Boc-amino) -4 (S) -hydroxy-6-cyclohexyl-2 (R) - (p-fluorophenylmethyl) hexanoic acid

2.05 g of 5 (S) - / 1 (S) - (Boc-amino) -2-cyclohexylethyl / -3 (R) - (fluorophenylmethyl) dihydrofuran-2- (3H) -one in 78 ml of dimethoxyethane and 39 ml of water are added dropwise at 20-25 ° C over 2 minutes with 19.6 ml of 1M sodium hydroxide solution, stirred for 3 hours at room temperature, and then the solvent is evaporated off under reduced pressure. in 100 ml of saturated aqueous ammonium chloride solution and 5 ml of 10% citric acid solution, and extracted four times with methylene chloride. without further purification in the next step.

lj) 5 (S) - (Boc-amino) -4 (S) - (tert-butyldimethylsilyloxy) -6-cyclohexyl-1-2 (R) - (p-fluorophenylmethyl) hexanoic acid

A solution of 2.01 g of 5 (S) - (Boc-amino) -4 (S) -hydroxy-6-cyclohexyl-2 (R) - (p-fluorophenylmethyl) hexanoic acid in 6.4 ml of dimethylformamide is stirred with 2.73 ml. imidazole and 3.39 g of tert-butyldimethylchlorosilane for 18 hours at room temperature, the reaction mixture is then poured onto ice water, extracted with 3 parts of ethyl acetate, and the combined organic phases are washed with 10% citric acid solution, water and saturated sodium chloride solution, dried over sodium sulfate and evaporated to give an oil which was dissolved in 68 ml of methanol and 23 ml of tetrahydrofuran, treated at room temperature with a solution of 4.1 g of sodium carbonate in 23 ml of water, stirred for 1 hour, and The aqueous residue is poured on ice with 10% citric acid solution, extracted three times with ethyl acetate, the organic phase is washed twice with water on a saturated sodium chloride solution, dried over sodium sulphate and evaporated. a mixture of hexane and ethyl acetate (from 5: 1 to 2: 1) affords the title compound. DC Rj (E) = 0.2; FAB-MS (M + H) &lt; ^{+ &gt}; = 552.

1k) 5 (S) - (Boc-amino) -4 (S) - (tert-butyldimethylsilyloxy) -6-cyclohexyl-2 (R) - (fluorophenylmethyl) hexanoyl- (L) -Val- (L) - Phe-morpholin-4-ylamide

A solution of 102 mg of 5 (S) - (Boc-amino) -4 (S) - (tert-butyldimethylsilyloxy) -6-cyclohexyl-2 (R) - (p-fluorophenylmethyl) hexanoic acid, 90 mg of benztriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate and 27 mg of 1-hydroxybenztriazole are stirred for 30 minutes at room temperature with about 2 ml of dimethylformamide and then contacted with 74 mg of H- (L) -Val- (L) -Phemomorpholine-4. The reaction mixture is evaporated after 16 hours at room temperature and the residue is partitioned between 3 parts of ethyl acetate, water, saturated sodium bicarbonate solution, water and saturated sodium chloride solution, and the organic phase is dried over sodium sulfate. TLC R _f (I) 0.57, FAB-MS (M + H) ⁺ = 867.

11) Z- (L) -Phe-morpholin-4-ylaraid

A solution of 4.49 g of Z- (L) -Phe-OH in 190 ml of methylene chloride was cooled to 0 ° C and treated with 3.09 g of dicyclohexylcarbodiimide. After stirring for 20 minutes at 0 DEG C., a solution of 1.31 ml of morpholine in 10 ml of methylene chloride was added dropwise over 15 minutes. The reaction mixture was further stirred for 24 hours at room temperature and after filtration of the precipitated dicycloe

120 xylurea is washed successively with methylene chloride, aqueous sodium bicarbonate solution and saturated sodium chloride solution. After drying over sodium sulfate and evaporation, the crude title compound is obtained which is crystallized from ether. DC R.- (B) &lt; 0.55.

1m) H- (L) -Phemomorpholin-4-ylamide

A solution of 5.5 g of Z- (L) -Phemomorpholin-4-ylamide with 1.5 g of 10% palladium on charcoal in 150 ml of methanol is converted in 1 hour by hydrogenolysis of the calculated amount of hydrogen to give the title compound. After filtering off the catalyst, the reaction mixture is evaporated and, after diluting with ethyl acetate, the solution obtained is washed with a saturated sodium hydrogen carbonate solution, dried over sodium sulphate and evaporated under reduced pressure. Column chromatography (carried out analogously to Example 1o) affords the title compound in pure form. DC Rf (F) = 0.3.

1n) Z- (L) -Val- (L) -Phe-morpholin-4-ylamide

To a solution of 2.14 g of Z- (L) -Val-OH in 80 ml of ice-cold absolute methylene chloride is added 1.75 g of dicyclohexylcarbodiimide, and after 20 minutes of stirring at this temperature, solution 2 is added dropwise over 15 minutes. g of H- (L) -Phemomorpholin-4-ylamide. The reaction mixture was stirred at room temperature for 24 hours and the resulting urea was filtered off. The filtrate was washed successively with aqueous sodium bicarbonate solution and saturated sodium chloride solution and, after drying with sodium sulfate, evaporated. The residue is triturated with ether and the insoluble residue is filtered off and evaporated to give the title compound which is worked up without further purification. DC Rf (F) = 0.7.

lo) H- (L) - Val- (L) -Phemomorpholin-4-ylamide

121

Analogously to Example (Im), 3.9 g of Z- (L) -Val- (L) -Phemomorpholin-4-ylamide is converted by hydrogenolysis in the presence of 0.5 g of 10% palladium on carbon in 150 ml of methanol to the crude compound. The title compound was purified by column chromatography (silica gel, methylene chloride to methylene chloride / methanol 97.5: 2.5, v / v). DC: _Rf (F) = 0.4.

Example 2

Boc-Phe [C1 Phe- (L) -Val- (L) -Phe-morpholin-4-ylamide

Analogous to Example 1, 330.3 mg of 5 (S) -Boc-anino-4 (S) - (tert-butyldimethylsilyloxy) -6-phenyl-2 (R) -phenylmethyl-hexanoyl- (L) -Val- ( Of L-p-morpholin-4-ylamide in 3 ml of absolute dimethylformamide by treating 247.2 mg of tetrabutylammonium fluoride trihydrate to the title compound, which crystallizes from hexane. DC Rf (B) = 0.5; FAB-MS (M + H) &lt; + &gt; = 729.

The starting compound is prepared as follows:

2a) 5 (S) - [1- (S) - (Boc-amino) -2-phenylethyl] -3 (R, S) -carbethoxy-3-phenylmethyldihydrofuran-2- (3H) -one

A solution of 23.8 g of 5 (S) - [1 (S) - (Boc-amino) -2-phenylethyl] -3- (R, S) -carbethoxydihydrofuran-2- (3H) -one in 410 ml of absolute ethanol and 14.4 ml of benzyl bromide are treated with 2.76 g of sodium in 410 ml of absolute ethanol. The reaction mixture was stirred at room temperature under an argon atmosphere for 18 hours and then poured onto a mixture of ice and a 10% citric acid solution. After extraction three times with ether, the combined organic extracts are washed with water and saturated sodium chloride solution and dried over sodium sulfate. Evaporation yields the compound

122 oil, which is used in the next step without additional purification. DC Rf (C) = 0.4; FAB-MS (M + H) &lt; ^{+ &gt}; = 468.

2b) 5 (S) - / 1 (S) - (Boc-amino) -2-phenylethyl / -3 (R) -phenylmethyldihydrofuran-2- (3H) -one and 5 (S) - / 1 (S) - (Boc-amino) -2-phenylethyl / -3 (S) -phenylmethyldihydrofuran-2- (3H) -one

To a solution of 10 g of 5 (S) - [1 (S) - (Boc-amino) -2-phenylethyl] -3 (R, S) -carbethoxy-3-phenylmethyldihydrofuran-2- (3H) -one in 175 ml of dimethoxyethane 81.4 ml of 1 molar lithium hydroxide solution are added dropwise over 5 minutes at room temperature. The reaction mixture is stirred for 15 hours at room temperature and, after evaporation of the solvent, the residue is poured into 500 ml of 10% citric acid solution and extracted three times with ether. The combined ether phases were washed once with saturated sodium chloride solution and dried over sodium sulfate. Evaporation of the solvent afforded 9.8 g of crude carboxylic acid which was decarboxylated to give the title compound by heating in 450 mL of toluene at 90 ° C for 14 hours. This compound was purified by column chromatography (hexane / ethyl acetate 9: 1) to give 5 (S) - / 1 (S) - (Boc-amino) -2-phenylethyl] -3 (R) -phenylmethyldihydrof. furan-2 (3H) -one (TLC R _f (C) = 0.3; FAB-MS (M + H) ⁺ 396) and 5 (S) - / (S) - (Boc-amino) -2-phenylethyl / -3 (S) -fenylmethyldihydrofuran-2 (3H) -one (TLC R _f (C) = 0.25; FAB-MS (M +

H) ^{@ +} = 396).

2c) 5 (S) - (Boc-amino) -4 (S) -hydroxy-6-phenyl-2 (R) -phenylmethylhexanoic acid

To a solution of 17.6 g of 5 (S) - / 1 (S) - (Boc-amino) -2-phenylethyl / -3 (R) -phenylmethyldihydrofuran-2- (3H) -one in 710 ml of ethylene glycol dimethyl ether and 352 ml water was added dropwise over 10 minutes with 176 ml of a 1 molar lithium hydroxide solution at 20 ° C

123 'C. Then the reaction mixture was stirred at room temperature for 90 minutes and the solvent was evaporated. The residue is poured onto 1 liter of cold 10% citric acid solution and the acidic solution is extracted three times with 800 ml of ethyl acetate each time. The combined extracts were washed first with 800 ml of water and then with 800 ml of saturated sodium chloride solution. After drying the organic solution with sodium sulfate, the solvent was distilled off. The crude title compound was used in the next step without further purification. FAB-MS (M + H) &lt; ^{+ &gt}; = 414.

2d) 5 (S) - (Boc-amino) -4 (S) - (tert-butyldimethylsilyloxy) -6-phenyl-2 (R) -phenylmethylhexanoic acid

To a solution of 3.65 g of 5 (S) - (Boc-amino) -4 (S) -hydroxy-6-phenyl-2 (R) -phenylmethylhexanoic acid in 90 ml of dimethylformamide, 8 g of imidazole and 10 g of tert. .-butyldimethylchlorosilane. After stirring at room temperature for 18 hours, the yellow clear solution is poured onto ice water and extracted three times with 250 ml of ethyl acetate each time. The combined extracts were washed successively three times with 10% citric acid solution, once with water, three times with saturated aqueous sodium bicarbonate solution, once with water and finally with saturated sodium chloride solution. After drying over sodium sulfate, the solution is evaporated and the resulting 13.5 g of tert-butyldimethylsilyl ether is dissolved in 53 ml of tetrahydrofuran and treated with 53 ~ 1 of acetic acid and 20 ml of water for 3 hours at room temperature, then It is poured onto water and extracted three times with ether. The combined ether extracts were washed twice with water and once with saturated sodium chloride solution and dried over sodium sulfate. After evaporation, the crude material was purified by column chromatography (silica gel, hexane / ethyl acetate 3.5: 1.5) to give the title compound. DC Rf (D) = 0.37; FAB-MS (M + H) &lt; ^{+ &gt}; = 528.

2e) 5 (S) - (Boc-amino) -4 (S) - (tert-butyldimethylsilyloxy) -6-fe

124 Nyl-2 (R) -phenylmethylhexanoyl- (L) -Val- (L) -Phemomorpholin-4-ylamide

Analogously to Example 1k), 250 mg of 5 (S) - (Boc-amino) -4 (S) - (tert-butyldimethylsilyloxy) -6-phenyl-2 (R) -phenylmethylhexanoic acid in 3 ml of dimethylformamide are converted , reacted with 230.5 mg benztriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, 70.4 mg 1-hydroxybenztriazole, 182.6 ml N-methylmorpholine and 189.5 mg H-Val-Phe-morpholin-4-ylamide , to the title compound. DC: _Rf (A) = 0.24; FAB-MS (M + H) ⁺ = 843rd

Example 3

Boc-Cha [C] (p-CN) Phe- (L) -Val- (L) -Phe-morpholin-4-ylamide

Analogous to Example 1, 185 mg of 5 (S) - (Boc-amino) -4 (S) - (tert-butyldimethylsilyloxy) -6-cyclohexyl-2 (R) - (p-cyanophenylmethyl) hexanoyl- ( L) -Val- (L) -Phemomorpholin-4-ylamide with 13.3 mg of tetrabutylammonium fluoride trihydrate in 2.5 ml of absolute dimethylformamide per title compound. DC: _Rf (B) = 0.33; FAB-MS (M + H) ⁺ - 760th

The starting compound is prepared as follows:

3a) 5 (S) - [1- (S) - (Boc-amino) -2-cyclohexylethyl] -3-carboxynethoxydihydrofuran-2- (3H) -one

2.5 g of 5 (S) - [1 (S) - (Boc-amino) -2-phenylethyl] -3-carbethoxydihydrofuran-2- (3H) -one (Example 1e) was hydrogenated in 50 ml of methanol in the presence of 250 mg of mixed rhodium oxide and platinum oxide monohydrate (Nishimura catalyst, Degussa) for 2 hours at room temperature at normal pressure (approximately 100 kPa). After filtration and subsequent washing of the catalyst with methanol, evaporation is carried out. compound

125 of the title compound is obtained by column chromatography (silica gel, hexane / ethyl acetate 3: 1) in pure form. DC: _Rf (E) = 0.2 FAB-MS (M + H) ⁺ = 370th

3b) 5 (S) - 1 (S) - (Boc-amino) -2-cyclohexylethyl 1 / -3 (R, S) -carbmethoxy-3- (p-cyanophenylmethyl) dihydrofuran-2- (3H) -one

As in Example 1g, 2.25 g of 5 (S) - / 1 (S) - (Boc-amino) -2-cyclohexyl-1 / -3 (R, S) -carbmethoxydihydrofuran-2- (3H) - with 1.32 g of p-cyanobenzyl bromide (Fluka, Buchs, Switzerland) and 156 mg of sodium in methanol per title compound. After work-up, the pure title compound is obtained. DC R _f (E) "0.27.

3c) 5 (S) - [1- (S) - (Boc-amino) -2-cyclohexylethyl] -3 (R) - (p-cyanophenylmethyl) dihydrofuran-2- (3H) -one and 5 (S) -] 1 (S) - (Boc-amino) -2-cyclohexylethyl / -3 (S) - (p-cyanophenylmethyl) dihydrofuran-2- (3H) -one

2.95 g of 5 (S) - / 1 (S) - (Boc-amino) -2-cyclohexylethyl] -3-carbmethoxy- (p-cyanophenylmethyl) dihydrofuran-2- (3H) were converted in analogy to Example 1h). -one in 55 ml of 1,2-dimethoxyethane with 24.4 ml of a 1 molar solution of lithium hydroxide to the corresponding carboxylic acid and then heating in 130 ml of toluene to give the title compound. Separation by column chromatography (silica gel, hexane / ethyl acetate 4: 1 to 3.5: 1.5 by volume) yields first the 3 (R) form of the title compound, which is crystallized from an ether / hexane mixture (temperature). mp 106-108 ° C; TLC R _f (a) = 0.53; FAB-MS (M + H) ⁺ = 427) and 3 (S) form of the title compound (TLC R _f (a) = 0.47, FAB-MS (M + Η) ^τ - 427).

3d) 5 (S) - (Boc-amino) -4 (S) -hydroxy-6-cyclohexyl-2 (R) - (p-cyanophenylmethyl) hexanoic acid

126

To a solution of 550 mg of 5 (S) - / 1 (S) - (Boc-amino) -2-cyclohexylethyl / -3 (R) - (p-cyanophenylmethyl) dihydrofuran-2- (3H) -one in 20 ml of 1, Of 2-dimethoxyethane and 14 ml of water are added dropwise over 2 minutes with 7 ml of a 1 molar lithium hydroxide solution at 20-25 ° C. The mixture is stirred at room temperature for 2 hours, then evaporated under reduced pressure and the residue is taken up in 100 ml of saturated aqueous ammonium chloride solution and 5 ml of 10% citric acid solution and extracted four times with methylene chloride. The combined organic phases were washed with saturated sodium chloride solution and dried over sodium sulfate. After evaporation, the title compound is obtained. DC Rf (F) = 0.4.

3e) 5 (S) - (Boc-amino) -4 (S) - (tert-butyldimethylsilyloxy) -6-cyclohexyl-2 (R) - (p-cyanophenylmethyl) hexanoic acid

A solution of 790 mg of 5 (S) - (Boc-amino) -4 (S) -hydroxy-6-cyclohexyl-2 (R) - (p-cyanophenylmethyl) hexanoic acid in about 10 ml of dimethylformamide is treated with , 18 g of tert-butyldimethylchlorosilane and imidazole. After stirring for 18 hours at room temperature, the yellow clear solution was poured into ice water and extracted three times with 250 ml of ethyl acetate each time. The combined extracts were washed successively three times with 10% citric acid solution, once with water, three times with saturated aqueous sodium bicarbonate solution, once with water and finally with saturated sodium chloride solution. After drying with sodium sulfate, the solvent is evaporated and the thus-obtained tert-butyldimethylsilyl ether (13.5 g) is dissolved in 53 ml of tetrahydrofuran and treated with 53 ml of acetic acid and 20 ml of water. Stir at room temperature for 3 hours, then pour the reaction mixture into water and extract three times with ether. The combined ether extracts were washed twice with water and once with saturated sodium chloride solution and dried over sodium sulfate. After evaporation, the crude material is subjected to final purification by column chromatography (silica gel,

127 hexane / ethyl acetate (3: 1 to 1: 1 by volume). The title compound is obtained. TLC Rf (A) - 0.42, IR (methylene chloride) 2856, 2230, 1711, 1609, 1449 cm ^-1 .

f) 5 (S) - (Boc-amino) -4 (S) - (tert-butyldimethylsilyloxy) -6-cyclohexyl-2 (R) - (p-cyanophenylmethyl) hexanoyl- (L) -Val- (L) -Phe-morpholin-4-ylamide

Analogous to Example 1k), 138 mg of 5 (S) - (Boc-amino) -4 (S) - (tert-butyldimethylsilyloxy) -6-cyclohexyl-2 (R) - (p-cyanophenylmethyl) hexanoic acid were converted with 122 mg benztriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, 37 mg 1-hydroxybenztriazole, 0.069 ml N-methylmorpholine and 100 mg H- (L) -Val- (L) -Phemomorpholin-4-ylamide in 3 ml dimethylformamide per Purification was by column chromatography (silica gel, hexane / ethyl acetate 1: 1) to give the pure title compound DC Rf (A) »0.25, FAB-MS (M + H) + 874.

Example 4

H-Phe [C] Phe- (L) -Val (L) -Phe-morpholin-4-ylamide

A solution of 1.048 g of Boc-Phe [C] Phe- (L) -Val- (L) -Phemomorpholin-4-ylamide (Example 2) in 20 mL of absolute methylene chloride was contacted with 20 mL of trifluoroacetic acid over 3 min. temperature 5 ° C. After stirring for another 90 minutes at room temperature, the reaction mixture was evaporated, the residue was treated with 150 ml of saturated aqueous sodium bicarbonate solution and extracted three times with ethyl acetate. The combined extracts were washed successively with water (100 mL), saturated sodium bicarbonate (100 mL), water (100 mL) and brine. After drying over sodium sulfate, the solvent was evaporated and the crude material was purified by column chromatography (Si

128 g of a mixture of methylene chloride, methanol and ammonia (95: 5: 0.1 to 90: 10: 0.1 by volume) to give the title compound. DC Rf (G) = 0.33; FAB-MS (M + H) &lt; ^{+ &gt}; = 629.

Example 5

3-Benzofuran-1-Phe [C] Phe- (L) -Val- (L) -Phe-morpholin-4-ylamide

A solution of 30.9 mg of benzofuran-3-carboxylic acid (produced according to the data published by Chin-Hsing Chou et al. In J. Org. Chem. 51. 4208-4212 (1986)) in 3 ml dimethylformamide is successively contacted with 93 mg of benztriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, 29 mg of 1-hydroxybenztriazole and 0.044 ml of N-methylmorpholine and then stirred at room temperature for 30 minutes. 100 mg of H-Phe [C] Phe- (L) -Val- (L) -Phemomorpholin-1-ylamide (Example 4) was added to the reaction mixture and stirred at room temperature for 3 hours and the reaction mixture was stirred for 3 hours. Pour the mixture into 100 ml of water. After extraction three times with 50 ml of ethyl acetate each time, the combined organic phases are washed successively with 100 ml of water, 100 ml of saturated aqueous sodium hydrogen carbonate solution, 100 ml of water and 100 ml of saturated sodium chloride solution. After drying over sodium sulfate and evaporation, the residue was digested in ether and the title compound obtained as a solid was dried. DC Rf (G) = 0.73; FAB-MS (M + H) &lt; ^{+ &gt}; = 773.

Example 6

3-nicotinoyl Phe [C] Phe- (L) -Val (L) -Phe-morpholin-4-ylamide

Analogously to Example 5, 23.5 mg of nicotinic acid in 3 ml of dimethylformamide was treated with 93 mg of benztriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, 29 mg of 1-hydroxybenztriazole, 0.044 ml of N-methylmorpholine and 100 mg.

129

H-Phe [C] Phe- (L) -Val- (L) -Phemomorpholin-1-ylamide is converted to the title compound. After crystallization from ether and drying, the pure title compound is obtained. DC: _Rf (G) = 0.57; FAB-MS (M + H) ⁺ - 734th

Example 7

3-morpholinocarbonyl-Val-Phe [C] Phe- (L) -Val (L) -Phe-morpholin-4-ylamide

Analogously to Example 5, 44 mg of N-morpholinocarbonyl- (L) -Val in 3 ml of dimethylformamide was treated with 93 mg of benztriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, 29 mg of 1-hydroxybenztriazole, 0.044 ml of N-methylmorpholine and 100 mg. mg of H-Phe [C] Phe- (L) -Val- (L) -Phemomorpholin-1-ylamide (Example 4) was converted to the title compound. Crystallization from ether and drying gave the pure title compound. DC: _Rf (G) = 0.5; FAB-MS (M + H) ⁺ 841.5.

the starting substance is produced as follows:

7a) N-Chlorocarbonylmorpholine

180 ml of toluene are contacted for 5 minutes at room temperature with 180 ml of a 20% solution of phosgene in toluene and then for 10 minutes under cooling at 5-10 ° C with a solution of 18 ml of morpholine in 180 ml of toluene. The white suspension was stirred for 1 hour at room temperature and for a further 2 hours under a stream of nitrogen. The solid was collected on suction and after washing with toluene, the filtrate was evaporated. The title compound thus obtained is further processed without further purification. IR (CH ₂ C1 _2): 1730, 1400, 1205 cm ^1st

7b) N-Morpholinocarbonyl- (L) -Val-benzyl ester

130 ml of N-chlorocarbonylmorpholine in 210 ml of methylene chloride were contacted with 15 g of the p-toluenesulfonic acid salt of (L) -valinbenzyl ester (Flüka, Buchs, Switzerland) and 15.4 ml of N-ethyldiisopropylamine. After stirring at room temperature for 16 hours, 1.5 ml is added again and after 23 hours again 0.8 ml of N-chlorocarbonylmorpholine. After a total of 39 hours, the reaction mixture was evaporated, diluted with ethyl acetate, and washed successively with 1N hydrochloric acid, once with water, once with saturated aqueous sodium bicarbonate, and twice with saturated brine. After drying over sodium sulfate, the reaction mixture was evaporated under reduced pressure. The crude material was purified by column chromatography (silica gel, ethyl acetate) to give the title compound. DC (B) = 0.5.

7c) N-Morpholinocarbonyl- (L) -Val

A solution of 9.7 g of N-morpholinocarbonyl- (L) -val-benzyl ester in 300 ml of ethyl acetate is hydrogenated for 3 hours at room temperature in the presence of 2 g of 10% palladium on carbon at normal pressure. After filtration and subsequent washing of the catalyst with ethyl acetate, the mother liquors were evaporated. The residue was taken up in ethyl acetate, filtered through Hyflo Super Cel ^R (diatomaceous earth, Fluka, Buchs, Switzerland) and evaporated under reduced pressure. The title compound is worked up without further purification.

Example 8

Boc-Cha [C] Cha- (L) -Va 1- (L) -Cha-morpholin-4-ylamine

Analogous to Example 3a), 100 mg of Boc-Phe [C] Phe- (L) -Val- (L) -Phemomorpholin-4-ylamide (Example 2) is hydrogenated in 30 ml of methanol in the presence of 40 mg of Nishimura catalyst. for 4 hours at room temperature. After from

After filtration of the catalyst and evaporation, the residue was crystallized from hexane and then purified by column chromatography (silica gel, hexane / ethyl acetate 1: 2, v / v) to give the title compound. DC Rf (I) = 0.5; FAB-MS (M + H) &lt; ^{+ &gt}; = 747.

Example 9

Boc-Cha [C] (p-F) Phe- (L) -Val- (L) - (p-F-Phe) -morpholin-4-ylamide

Similar to Example 1, 0.18 g of 5 (S) - (Boc-amino) -4 (s) - (tert-butyldimethylsilyloxy) -6-cyclohexyl-2 (R) - (fluorophenylmethyl) hexanoyl- (L) -Val- (L) - (pF-Phe) -morpholin-4-ylamide was converted to the title compound by treatment with 114 mg of tetrabutylammonium fluoride trihydrate in 1.8 mL of dimethylformamide. DC Rf (B) 0.44; FAB-MS (M + H) &lt; ^{+ &gt}; = 771.

The starting compound is prepared as follows:

9a) Z- (L) -p-Fluorophenylalanine

To a solution of 5.0 g of H- (L) - (pF-Phe) -OH / (L) -p-fluorophenylalanine (Fluka, Buchs, Switzerland) / in 55 ml of tetrahydrofuran and 20 ml of water is added 2-normal sodium hydroxide 4.66 g of benzyl chloroformate were added dropwise and the mixture was further stirred for 4 hours at room temperature while maintaining a pH of approximately 10 by the addition of 2 N sodium hydroxide solution. The reaction mixture was evaporated and the residue was partitioned between ethyl acetate, 10% citric acid solution and saturated sodium chloride solution and then dried over sodium sulfate. Column chromatography (silica gel, dichloromethane / methanol 7: 3) gives the pure title compound. DC: _Rf (C) = 0.50.

132 lit.>

9b) Z- (L) - (β-F-Phe) -morpholin-4-ylamide

Analogously to Example 11), 9.01 g of Z- (L) - (pF-Phe) -OH and 2.38 g of morpholine in 350 ml of dichloromethane are converted by treatment with 5.62 g of dicyclohexylcarbodiimide to give the title compound. in pure form after column chromatography (silica gel, ethyl acetate). DC Rf (B) = 0.6.

9c) H- (L) - (β-F-Phe) -morpholin-4-ylamide

Analogously to Example 1m), 0.90 g of Z- (L) - (pF-Phe) -morpholin-4-ylamide in 50 ml of methanol is converted by hydrogenolysis in the presence of * 0.2 g of 10% palladium on carbon to the title compound. title. DC Rf (L) = 0.4.

9d) Z- (L) -Va 1- (L) - (p-F-Phe) -morpholin-4-ylamide

Analogously to Example 1n), 1.36 g of H- (L) - (pF-Phe) -morpholin-4-ylamide and 1.36 g of Z- (L) -Val in 70 ml of dichloromethane are transferred by treatment with 1.11 g. dicyclohexylcarbodiimide to give the title compound. DC Rf (B) = 0.55.

9e) H- (L) -Val- (L) - (p-F-Phe) -morpholin-4-ylamide

Analogously to Example 1m), 2.80 g of Z- (L) -Val- (L) - (pF-Phe) -morpholin-4-ylamide in 150 ml of methanol is converted by hydrogenolysis performed with 0.6 g of 10% palladium on carbon The title compound is obtained in pure form after column chromatography (silica gel, dichloromethane / methanol 9: 1). DC Rf (F) &lt;0.44; FAB-MS (M + H) &lt; + &gt; = 352.

9f) 5 (S) - (Boc-amino) -4 (S) - (tert-butyldimethylsilyloxy) -6-cyclohexyl-2 (R) - (p-fluorophenylmethyl) hexanoyl- (L) -Val- (L) - (p133

-F-Phe) -morpholin-4-ylamide

A solution of 100 mg of 5 (S) - (Boc-amino) -4 (S) - (tert-butyldimethylsilyloxy) -6-cyclohexyl-2 (R) - (p-fluorophenylmethyl) hexanoic acid (Example 1 j) and 70, 3 mg of H- (L) -Val- (L) - (pF-Phe) -morpholin-4-ylamide in 1.7 ml of 0.25 molar N-methylmorpholine in acetonitrile (0.25 molar solution of N-methylmorpholine) in acetonitrile) was contacted with 76 mg of O-benztriazol-1-yl-Ν, Ν, Ν ¹ , N'-tetramethyluronium hexafluorophosphate. The reaction mixture was evaporated at room temperature after 16 hours. The residue was partitioned between 3 parts ethyl acetate, water, 2 parts 10% citric acid solution, water, 2 parts saturated sodium bicarbonate solution, water and finally saturated sodium chloride solution. Dry the organic phase over sodium sulfate and evaporate to give the title compound. DC Rf (A) = 0.20; FAB-MS (M + H) ⁺ = 885.

Example 10

Boc-Cha [C] (pF) Phe- (L) -Val- (L) - (p-CH ₃ O-Phe) -morpholin-4-yl amide

Analogous to Example 1, 0.18 g of 5 (S) - (Boc-amino) -4 (S) - (tert-butyldimethylsilyloxy) -6-cyclohexyl-2 (R) - (pf) (4-fluorophenylmethyl) hexanoyl- (L) -Val- (L) - (p-CH ₃ O-Phe) -morpholin-4-ylamide was treated with 114 mg of tetrabutylammonium fluoride trihydrate in 1.8 mL of dimethylformamide to give the title compound. DC: _Rf (B) = 0.40; FAB-MS (M + H) ⁺ = 783rd

The starting compound is prepared as follows:

10a) Z- (DL) -p-Methoxyphenylalanine

2.5 g of DL-p-methoxyphenylalanine (Bachem, Bubendorf, Switzerland) was reacted in analogy to Example 9a).

134 in 64 ml of tetrahydrofuran and 17.9 ml of water with 2.3 g of benzyl chloroformate while maintaining a pH of approximately 10 by adding 1N sodium carbonate solution. Evaporation of the reaction mixture and partitioning of the residue between ethyl acetate, dilute hydrochloric acid and saturated sodium chloride solution gives the title compound. DC: _Rf (B) = 0.3. IR (CH ₂ C1 _2): 1720, 1612, 1513 cm ^'1.

10b) Z- (DL) - (p-CH ₃ O-Phe) -raorfolin-4-ylamide

In analogy to Example 11), 2.4 g of Z- (DL) - (p-CH ₃ O-Phe) -OH (Z- (DL) -p-methoxyphenylalanine) were reacted in 36 ml of methylene chloride and 0.63 g. of morpholine in 36 mL of methylene chloride with 1.5 g of dicyclohexylcarbodiimide to give the title compound. DC: Rf (B) "0.5. IR (CH ₂ C1 _2): 1720, 1641, 1612, 1512 cm ^'1.

10c) H- (DL) - (p-CH ₃ O-Phe) -morpholin-4-ylamide

Analogously to Example 1m), 3.8 g of Z- (DL) - (p-CH ₃ O-Phe) -morpholin-4-ylamide in 170 ml of methanol is subjected to hydrogenolysis in the presence of 0.8 g of 10% palladium on carbon, The title compound is obtained in pure form after column chromatography (silica gel, methylene chloride / methanol 9: 1). DC R f (F) "0.3, IR (CH ₂ Cl ₂ ): 1642, 1613, 1514, 1463, 1443 cm ^-1 .

10d) Z- (L) -Val- (DL) - (p-CH ₃ O-Phe) -morpholin-4-ylamide

Analogously to Example 1n), 1.80 g of Z- (L) -Val-OH in 40 ml of methylene chloride and 1.90 g of H- (DL) - (p-CH ₃ O-Phe) -morpholine-4 are reacted. of amylamide in 40 mL of methylene chloride with 1.48 g of dicyclohexylcarbodiimide to give the title compound. DC: _Rf (B) - 0.12, IR (CH ₂ C1 _2): 1722, 1674, 1643, 1612, 1512, 1465, 1443 cm ^'1.

135

10e) H- (L) -Val- (L) - (p-CH ₃ O-Phe) -raorfolin-4-ylamide and H- (L) -Val- (D) - (p-CH ₃ O-Phe) ) -morpholin-4-ylamide

Analogously to Example lm) 3.6 g of Z- (L) -Val§- (DL) - (p-CH ₃ O-Phe) -morpholin-4-yl-amide in 150 ml of methanol and transfered hydrogenolysis in the presence of 0.6 g 10% palladium on charcoal for the mixture of compounds named in the title. Column chromatography (silica gel, dichloromethane to dichloromethane / methanol 19: 1, and then dichloromethane / methanol 9: 1) gave first a fraction which was analyzed by amino acid gas chromatography on a Chirasil-L-Val column (E. Bayer, Z. Naturforschlag, B 38, 1281 (1983), contains H- (L) -Val- (L) - (p-CH ₃ O-Phe) -morpholin-4-ylamide (DC Rf (F) = 0.52, FAB-MS (M + H) ⁺ 364, GC T _{Ret >} / (p-CH ₃ O-Phe) derivative (= 27.65 min) followed by a fraction with the epimer H- (L ) -Val- (D) - (p-CH ₃ O-Phe) -morpholin-4-ylamide (DC R f (F) - 0.37, GC T _Ret .) ((P-CH ₃ O-Phe) derivatives) 27.26 min).

10f) 5 (S) - (Boc-amino) -4 (S) - (tert-butyldimethylsilyloxy) -6-cyclohexyl-2 (R) - (p-fluorophenylmethyl) hexanoyl 1- ( L) -Va 1- (L) - (p-CH ₃ O-Phe) -morpholin-4-ylamide

In analogy to Example 9f), 100 mg of 5 (S) - (Boc-amino) -4 (S) - (tert-butyldimethylsilyloxy) -6-cyclohexyl-1-2 (R) - (p-fluorophenylmethyl) hexanoic acid (50%) was reacted ( Example 1j) and 72.7 mg of H- (L) -Val- (L) - (p-CH ₃ O -Ph) -morpholin-4-ylamide in

1.7 ml of 0.25-molar N-methylmorpholine in acetonitrile and 1 ml of dimethylformamide with 76 mg of O-benztriazol-1-yl-Ν, Ν, Ν ', Ν'-tetramethyluronium hexafluorophosphate to give the title compound. DC Rf (A) - 0.18; FAB-MS (M + H) &lt; ^{+ &gt;} - 897.

Example 11

136

Boc-Cha [C] (p-F) Phe- (L) -Val- (L) -Cha-r: olin-4-ylamide

- Analogous to Example 1, 0.16 g of 5 (S) - (Boc-amino) -4 (S) - (tert-butyldimethylsilyloxy) -6-cyclohexyl-2 (R) - (p-fluorophenylmethyl) hexanoyl- (L) - N- (L) -Cha-morpholin-4-ylamide is converted to 114 mg of tetrabutylaraonium fluoride trihydrate in 1.8 mL of dimethylformamide to give the title compound. DC: _Rf (B) = 0.49; FAB-MS (M + H) ⁺ 759th

The starting compound is prepared as follows:

IIIa) H- (L) -Val- (L) -Cha-morpholin-4-ylamide

Analogously to Example 3a), 1.0 g of H- (L) -Val- (L) -Phemomorpholin-4-ylamide (Example 1o) was hydrogenated in 25 ml of methanol in the presence of 0.15 g of Nishimura catalyst to a compound named of the title product which is obtained by pure column chromatography (silica gel, methylene chloride to methylene chloride / methanol 40: 1) and digested with hexane. DC: _Rf (B) = 0.50; FAB-MS (M + H) + = 340, IR (CH ₂ C1 _2): 1645, 1509, 1463, 1449 cm ^'1.

11b) 5 (S) - (Boc-amino) -4 (S) - (tert-butyldisethylsilyloxy) -6-cyclohexyl-2 (R) - (p-fluorophenylmethyl) hexanoyl- (L) -Val- (L) Cha-morpholin-4-ylamide

Analogously to Example 9f), 100 mg of 5 (S) - (Boc-amino) -4 (S) - (tert-butyldimethylsilyloxy) -6-cyclohexyl-2 (R) - (p-fluorophenylaethyl) hexanoic acid is reacted (Example 1j) and 67.9 mg of H- (L) -Val- (L) -Cha-morpholin-4-ylamide in 1.7 ml of 0.25 molar N-methylmorpholine in acetonitrile with 76 mg of O- benztriazol-1-yl-N, N, N ', N-tetramethylurorium hexafluorophosphate to give the title compound. DC Rf (A) = 0.47; FAB-MS (M + H) &lt; ^{+ &gt}; = 873.

127

Example 12

1,2,3,4-Tetrahydroisoquinolin-3 H -carbonyl-1'-Phe *. C 2 Phe- (L) -Val- (L) -Phe-morpholin-4-ylanide

Step 4 242 mg of N-Boc-1,2,3,4-tetrahydroisoquinoline-3S) -carbonyl-Val-Pr.e [C] Pte- (L) -Val- (L) -Phe step analogously to Example 4. morpholin-4-ylaride in £ ml methylene chloride by treatment with 8 ml trifluoroacetic acid on the title compound. DC R _f (J) =?,?, FAB-XS (M-H) ⁺ ? 887,?,? (KBr): 1639, 1531, 1495, 1453 cm ^-1 .

The starting compound is prepared as follows:

12a) N-Boc-1,2,3,4-tetrahydroisoquinoline-3 (S-carboxylic acid)

In 400 ml, we take dioxane with a 1: 1 ratio of water with a beak of 20 g of 1,2,3,4-tetrahydroiscchirolin-3 (S) -carboxylic acid (production of PL Julian visas, x. J. Karpel, A. Magnani and J. Meyer, J. Am. Chem. Soc. 73, 18C (1348), but starting from (L) -O-phenylalanine), 233.6 g of potassium carbonate and 37 g of Boc-anhydride for a period of time. The reaction mixture was acidified with dilute hydrochloric acid to pH 2 and extracted three times with ethyl acetate, washing the organic phase with 1N potassium bicarbonate solution, water and saturated sodium chloride solution, drying over sodium sulfate, evaporating and crystallizing from methylene chloride mixture. TLC R _f (J) = 0.2, [α] P = 16 (c = 1, methanol).

12b) N-Boc-1,2,3,4-tetrahydrcis: quinoline-3 (S-lcartonyl- (1) -Val-benzyl ester)

47 g of the acid are transferred under nitrogen

138

N-Boc-1,2,3,4-tetrahydroisoquinoline-3 (S) -carboxylic acid in 70 ml of methylene chloride at 0 ° C by treatment with 4.7 g of 1-chloro-N, N, 2-trimethylprop-1- of enylamine (B. Haveaux, A. Dekoker, M. Rens, AR Sidani, J. Toye and L. Ghozes, Org. Synth. 59, 26, 34) to the corresponding acid chloride and to it is added 9.0 g of Hunig's after 15 minutes. base and a solution of 6.83 g of L-N-benzyl ester hydrochloride in 54 ml of methylene chloride. The reaction mixture is maintained for 15 minutes at 0 ° C and 16 hours at room temperature and then washed with 10% citric acid solution, water, saturated sodium carbonate solution, water and saturated sodium chloride solution. The aqueous phase is extracted with 2 parts of methylene chloride, the combined organic phases are dried over sodium sulphate and evaporated. As the Boe group is partially cleaved according to @ 1 H-MNR analysis, the crude material is reacted with 6.8 g of Boc-anhydride in 160 ml of methylene chloride and 2.7 g of Hunig's base. Column chromatography (silica gel, hexane / ethyl acetate 3: 1) affords the pure title compound. DC Rf (E) = 0.15.

12c) N-Boc-1,2,3,4-tetrahydroisoquinoline-3 (S) -carbonyl- (L) -Val

Analogous to Example 7c), 1.97 g of N-Boc-1,2,3,4-tetrahydroisoquinoline-3 (S) -carbonyl- (L) -val-benzyl ester is hydrogenated in 50 ml of ethyl acetate in the presence of 0.4 g 10% palladium on charcoal to give the title compound. This material was used in the next step without further purification. DC Rf (J) = 0.53; FAB-MS (M + H) &lt; + &gt; = 377.

12d) N-Boc-1,2,3,4-tetrahydroisoquinoline-3 (S) -carbonyl-Val-Phe [C] Phe- (L) -Val- (L) -Phemomorpholin-4-ylamide

As in Example 5, 180 mg of N-Boc-1,2,3,4-tetrahydroisoquinoline-3 (S) -carbonyl- (L) -Val in 4 ml of dimethylformamide are reacted with 232 mg of benztriazol-1-yloxy-tris. (dimethyl

139 amino) phosphonium hexafluorophosphate, 71 mg of 1-hydroxybenztriazole, 0.11 ml of N-methylmorpholine and a solution of 250 mg of H-Phe [C] Phe- (L) -Val- (L) -Phemomorpholin-4-ylamide (Example 4). ) in 2 ml of dimethylformamide. Column chromatography (silica gel, ethyl acetate) yields the title compound which, as an auxiliary acid analysis (performed by gas chromatography on a Chirasil-L-Val column (E. Bayer, Z. Naturforschung. B 3, 1281 (1983))), contains as a secondary epimer product (about 14% D-Val). DC: _Rf (B) - 0.4, FAB-MS (M + H) ⁺ 987; IR (KBr): 1697, 1643, 1523, 1496 cm ^-1.

Example 13

Boc-Phe [C] Phe- (L) -Va 1- (L) - (p-F-Phe) -morpholin-4-ylamide

Analogous to Example 1, 375 mg of 5 (S) -

- (Boc-amino) -4 (S) - (tert-butyldimethylsilyloxy) -6-phenyl-2 (R) -

- Phenylmethexanoyl 1- (L) -Val- (L) - (pF-Phe) -morpholin-4-ylamide in 7 ml dimethylformamide by treatment with 275 mg of tetrabutylammonium fluoride trihydrate on the title compound, which after crystallization from The mixture of diethyl ether and hexane gets pure. DC: _Rf (B) = 0.50; FAB-MS (M + H) ⁺ »747th

The starting compound is prepared as follows:

13a) 5 (S) - (Boc-amino) -4 (S) - (tert-butyldimethylsilyloxy) -6-phenyl-2 (R) -phenylmethylhexanoyl- (L) -Val- (L) - (pF-Phe) -morpholin-4-ylamide

Analogously to Example 1k), 250 mg of 5 (S) - (Boc-amino) -4 (S) - (tert-butyldimethylsilyloxy) -6-phenyl-2 (R) -phenylmethylhexanoic acid (Example 2d) is reacted in 5 ml dimethylformamide with 230.6 mg benztriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate, 70.4 mg 1-hydroxybenzotriazole, 130 μΐ N-methylmorpholine and 199.7 mg H- (L) -Val- (L) - (p-F140

-Phe) morpholin-4-ylamide (see Example 9e) dissolved in 2 ml of dimethylformamide. Column chromatography (silica gel, 2: 1 ethyl acetate: hexane) affords the title compound. DC: _Rf (L) = 0.43; FAB-MS (M + H) = 861st

Example 14

Boc-Phe [C] Phe- (L) -Val- (L) - (p-CH ₃ o -Phe) -morpholin-4-ylamide

As in Example 1, 283 mg of 5 (S) - (Boc-amino) -4 (S) - (tert-butyldimethylsilyloxy) -6-phenyl-2 (R) -phenyl-ethylhexanoyl- (L) -Val- (L) - (p-CH 2 O-Phe) -morpholin-4-ylamide in 7 ml of dimethylformamide by treatment with 204.5 mg of tetrabutylammonium fluoride trihydrate to give the title compound which was digested from diethyl ether / hexane 1: 1 and column chromatography (silica gel, ethyl acetate) was obtained pure. DC Rf (B) = 0.37; FAB-MS (M + H) &lt; ^{+ &gt}; = 759.

The starting compound is prepared as follows:

14a) 5 (S) - (Boc-amino) -4 (S) - (tert-butyldimethylsilyloxy) -6-phenyl-2 (R) -phenylmethylhexanoyl- (L) -Val- (L) - (p-CH ₃ 0-Phe) -morpholin-4-ylamide

Analogously to Example 1k), 250 mg of 5 (S) - (Boc-amino) -4 (S) - (tert-butyldimethylsilyloxy) -6-phenyl-2 (R) -phenylmethylhexanoic acid (Example 2d) was reacted in Example 2d. 5 ml of dimethylformamide with 230.6 mg of benztriazol-1-yloxy-tris (dimethylamino) phosphoryl hexafluorophosphate, 70.4 mg of 1-hydroxybenzotriazole, 130 µl of N-methylmorpholine and 206.6 mg of H- (L) -Val- ( L) - (p-CH ₃ O-Phe) -morpholin-4-ylamide (see Example 10e for preparation) dissolved in 2 mL of dimethylformamide. Column chromatography (silica gel, ethyl acetate / hexane 2: 1) yields

141 the title compound. DC (L) = 0.37; FAB-MS (M + H) ⁺ = 873rd

Example 15

Boc-Phe [C 1 Phe- (L) -Val- (L) -Cha-morpholin-4-ylamide

Analogous to Example 1, 430 mg of 5 (S) - (Boc-amino) -4 (S) - (tert-butyldimethylsilyloxy) -6-phenyl-2 (R) -phenylmethyl-hexanoyl- (L) -Val- (L) -Cha-morpholin-4-ylamide in 5 ml of dimethylformamide by treating 320 mg of tetrabutylammonium fluoride trihydrate to the title compound, which was purified after column chromatography (silica gel, ethyl acetate) and digested with hexane. DC Rf (F) = 0.51; FAB-MS (M-H) &lt; + &gt; = 735.

The starting compound is prepared as follows:

15a) 5 (S) - (Boc-amino) -4 (S) - (tert-butyldimethylsilyloxy) -6-phenyl-2 (R) -phenylmethylhexanoyl- (L) -Val- (L) -Cha-morpholine- 4-ylamide

Analogously to Example 1k), 300 mg of 5 (S) - (Boc-amino) -4 (S) - (tert-butyldimethylsilyloxy) -6-phenyl-2 (R) -phenylmethylhexanoic acid (Example 2d) is reacted in 3 ml of dimethylforraamide with 277 mg of benztriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, 84.5 mg of 1-hydroxybenztriazole, 22 ml of N-methylmorpholine and 231 mg of H- (L) -Val- (L) -Cha-morpholine- Of 4-ylamide (for preparation see Example 11a) dissolved in 2 ml of dimethylformamide. Column chromatography (silica gel, ethyl acetate / hexane 1: 1) affords the title compound. DC Rf (A) = 0.28; FAB-MS (M + H) &lt; ^{+ &gt}; = 849.

Example 16

142

Boc-PheΓ C] Phe- (L) -Ile- (L) -Phe-morpholin-4-ylamide

Analogous to Example 1, 329.8 mg of 5 (S) - (Boc-amino) -4 (S) - (tert-butyldimethylsilyloxy) -6-phenyl-2 (R) -phenylmethylhexanoyl- (L) - Ile- (L) -Phemomorpholin-4-ylamide in 5 µl of dimethylformamide was treated with 242.7 mg of tetrabutylammonium fluoride trihydrate to give the title compound which was pure after digestion with hexane. DC Rf (B) = 0.57; FAB-MS (M + H) ⁺ = 743.

The starting compound is prepared as follows:

16a) Z- (L) -ILe- (L) -Phemomorpholin-4-ylamide

Analogous to Example 1n), 294 mg of Z- (L) -Ile in 10 ml of dichloromethane are converted with 229 mg of dicyclohexylcarbodiimide and 260 mg of H- (L) -Phemomorpholin-4-ylamide (Example 1m) to the title compound. The residue was purified by column chromatography (silica gel, ethyl acetate / hexane 1: 1) to give purity. DC (A) = 0.43; FAB-MS (M + H) ^τ = 482.

16b) H- (L) -Ile- (L) -Phemomorpholin-4-ylamide

Similar to Example 1m), 0.38 g of Z- (L) -Ile- (L) -Phemomorpholin-4-ylamide in 15 ml of methanol in the presence of 0.12 g of 10% palladium on charcoal was converted to the title compound by hydrogenolysis. The title compound is purified by column chromatography (silica gel, dichloromethane / methanol 9: 1). DC: _Rf (F) = 0.5 FAB-MS (M + H) ⁺ = 348th

16c) 5 (S) - (Boc-amino) -4 (S) - (tert-butyldimethylsilyloxy) -6-phenyl-2 (R) -phenylmethylhexanoyl- (L) -Ile- (L) -Phemomorpholine- 4-ylamide

143

Analogous to Example 1k), 240.5 mg of 5 (S) - (Boc-amino) -4 (S) - (tert-butyldimethylsilyloxy) -6-phenyl-2 (R) -phenylmethylhexanoic acid (Example 2d) is reacted in 5 ml of dimethylformamide with 242 mg of benztriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, 73,8 mg of 1-hydroxybenztriazole,

125.5 μΐ of N-methylmorpholine and 190 mg of H- (L) -Ile- (L) -Phemomorpholin-4-ylamide. Column chromatography (silica gel, ethyl acetate / hexane 1: 1) affords the title compound. DC Rf (A) = 0.21; FAB-MS (M + H) &lt; ^{+ &gt}; = 357.

Example 17

The Boc-Phe; C] Phe- (L) -Val-Gly-morpholin-4-ylamide

Analogous to Example 1, 343.7 mg of 5 (S) - (Boc-amino) -4 (S) - (tert-butyldimethylsilyloxy) -6-phenyl-2 (R) -phenylmethylhexanovl- (L) -Val are desilylated -Gly-morpholin-4-ylamide in 5 ml of dimethylformamide by treatment with 282.7 mg of tetrabutylammonium fluoride trihydrate on the title compound and finally digesting from diethyl ether. DC: Rf (B) = 0.23; FAB-MS (M + H) ⁺ = 639th

The starting compound is prepared as follows:

17a) Z-Gly-morpholin-4-ylamide

Analogous to Example 11), 8.37 g of Z-Gly-OH in 500 ml of dichloromethane are converted by treatment with 8.25 g of dicyclohexylcarbodiimide and 3.49 ml of morpholine to give the title compound. DC Rf (B) = 0.23.

17b) H-Gly-morpholin-4-ylamide

Analogously to Example 1m), 10.8 g of Z-Glymorpholin-4-ylamide in 600 ml of methanol is converted by hydrogenolysis using 3 g of 10% palladium on carbon to the title compound which, after filtering off the catalyst and evaporation, the filtrate is used directly in the next step. DC: Rf (F) = 0.2. IR (CH ₂ C1 _2): 1654, 1461, 1440 cm ^'1.

17c) Z- (L) -Val-Gly-morpholin-4-ylamide

2.51 g of Z- (L) -Val in 75 ml of dichloromethane with 2.06 g of dicyclohexylcarbodiimide and 1.44 g of H-GLγ-morpholin-4-ylamide are converted to the compound named in Example 1n). title. DC R, (B) = 0.21.

17d) H- (L) -Val-Gly-morpholin-4-ylamide

As in Example 1m), hydrogenolysis was carried out

3.7 g of Z- (L) -Va 1-Glymorpholin-4-ylamide in 160 ml of methanol in the presence of 0.6 g of 10% palladium on charcoal to the title compound which, after filtering off the catalyst, pure form by column chromatography (silica gel; dichloromethane / methanol 9: 1 to 4: 1). DC and _Rf (F) = 0.23; FAB-MS (M + H) = 244 ·, IR (CH ₂ C1 _2): 1650, 1508, and 1467, 1439 ^cm-I.

A

17e) 5 (S) - (Boc-amino) -4 (S) - (tert-butyldimethylsilyloxy) -6- * phenyl-2 (R) -phenylmethylhexanoyl- (L) - Val-C-lymorpholine -4-ylamide <

Analogously to Example 1k), 300 mg of 5 (S) - (Boc-amino) -4 (S) - (tert-butyldimethylsilyloxy) - 6-phenyl-2 (R) -phenylmethylhexanoic acid (example) is reacted (example (2d) in 5 ml of dimethylformamide with 302 mg of benztriazol-1-yloxy-tris (dimethylamino-

J no) phosphonium hexafluorophosphate, 92.1 mg 1-hydroxybenztriazole,

156.5 µl of N-methylmorpholine and 175.5 mg of H-1L) - 'al-Gly-morpholine145

4-ylamide. Column chromatography (silica gel, ethyl acetate / hexane 1: 9 to ethyl acetate) yields the title compound. DC Rf (B) = 0.44; FAB-MS (M + H) &lt; ^{+ &gt}; = 753.

Example 18

Boc-Phe [C] Phe (L) -Ile-Gly-morpholin-4-ylamide

362.4 mg of 5 (S) - (Boc-amino) -4 (S) - (tert-butyldimethylsilyloxy) -6-phenyl-2 (R) -phenylmethylhexanoyl- (L) -Ile are desilylated analogously to Example 1. Glymorpholin-4-ylamide in 5 ml of dimethylformamide was treated with 292.7 mg of tetrabutylammonium fluoride trihydrate to give the title compound and finally digested from diethyl ether. DC Rf (B) = 0.30; FAB-MS (M-H) &lt; + &gt; = 653.

The starting compound is prepared as follows:

13a) Z - (L) -Ile-Gly-morpholin-4-ylamide

As in Example 1n), 2.65 g of Z- (L) -Ile in 75 ml of dichloromethane is reacted with 2.06 g of dicyclohexylcarbodiimide and 1.44 g of H-Glymorpholin-4-ylamide (Example 17b). After digestion with diethyl ether, the title compound is obtained. DC Rf (F) = 0.7.

18b) H- (L) -Ile-Gly-morpholin-4-ylamide

Analogously to Example 1m), 3.2 g were converted

Z- (L) -Ile-Gly-morpholin-4-ylamide in 160 mL of methanol by hydrogenolysis using 0.6 q of 10% palladium on carbon to give the title compound, which after filtration of the catalyst and column chromatography (silica gel, a 9: 1 mixture of dichloromethane and methanol is obtained in pure form. DC R _f

146 (F) = 0.3 FAB-MS (M + H) ⁺ = 258, IR (CH ₂ C1 _2): 1653, 1510, 1467, 1439 cm ^'1.

18c) 5 (S) - (Boc-amino) -4 (S) - (tert-butyldimethylsilyloxy) -6-phenyl-2 (R) -phenylmethylhexanoyl- (L) -Ile-Gly-morpholin-4-ylamide

Analogously to Example 1k), 300 mg of 5 (S) - (Boc-amino) -4 (S) - (tert-butyldimethylsilyloxy) -6-phenyl-2 (R) -phenylmethylhexanoic acid (Example 2d) was reacted in Example 2d) in 5 ml dimethylformamide with 301.8 mg benztriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, 92.1 mg 1-hydroxybenztriazole, 156.5 μl N'-methylmorpholine and 185 mg H- (L) -Ile-Gly morpholin-4-ylamide. Column chromatography (silica gel, ethyl acetate / hexane 1: 9) affords the title compound. DC Rf (B) = 0.40; FAB-MS (M + H) &lt; ^{+ &gt}; = 767.

Example 19

Boe-Phef C] Phe- (L) - Va 1- (L) -Val-morpholin-4-ylamide

Analogous to Example 1, 416 mg of 5 (S) - (Boc-amino) -4 (S) - (tert-butyldimethylsilyloxy) -6-phenyl-2 (R) -phenylmethylhexanoyl- (L) -Val- (L) -Val-morpholin-4-ylamide in 10 ml of aimethylformamide by treatment with 330 mg of tetrabutylammonium fluoride trihydrate on the title compound, which was finally digested from diethyl ether. DC R (B) = 0.39; FAB-MS (M - H) = ¹ 681st

The starting compound is prepared as follows:

19a) Z- (L) -Val- (L) -Val-morpholin-4-ylamide

In a similar manner to Example 11), 2.0 g of Z- (L) -Val147 were converted

- (L) -Val-OH (Bachem, Bubendorf, Switzerland) in 50 mL of dichloromethane by treatment with 1.17 g of dicyclohexylcarbodiimide and 0.96 mL of morpholine dissolved in 50 mL of dichloromethane to give the title compound. DC: _Rf (B) = 0.5.

19b) H- (L) -Val- (L) -Val-morpholin-4-ylamide

Analogously to Example 1m), 2.3 g of Z- (L) -Val- (L) -Val-morpholin-4-ylamide in 220 ml of methanol was converted by hydrogenolysis using 0.5 g of 10% palladium on carbon to The title compound is obtained in pure form after filtration of the catalyst, column chromatography (silica gel, dichloromethane to dichloromethane / methanol 19: 1 to 9: 1) and stirring in a mixture of diethyl ether and hexane. DC: Rf (F) = 0.74; FAB-MS (M + H) ⁺ = 286, IR (CH ₂ C1 _2): 1642, 1507, 1461, 1440 cm ^-1.

19c) 5 (S) - (Boc-amino) -4 (S) - (tert-butyldimethylsilyloxy) -6-phenyl-2 (R) -phenylmethylhexanoyl- (L) -Val- (L) -Val-morpholine 4-yiamid

Analogously to Example 1k), 300 mg of 5 (S) - (Boc-amino) -4 (S) - (tert-butyldimethylsilyloxy) -6-Eenyl-2 (R) -phenylmethylhexanoic acid (Example 2d) was reacted in Example 2d) in 5 ml of dimethylformamide with 277 mg of benztriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, 84.5 mg of 1-hydroxybenzotriazole, 156.5 .mu.l of N-methylmorpholine and 194.6 mg of H- (L) -Val- (L). ) -Val-morpholin-4-ylaraidu. Column chromatography (silica gel, ethyl acetate / hexane 2: 1) affords the title compound. DC Rf (I) = 0.27; FAB-MS (M + H) &lt; ^{+ &gt}; = 795.

Example 20

Boc-Phe i C i Phe - (L) - ´. 'And l- (L) -Phe-thiomorpholin-4-y lamid

148

Analogously to Example 1, 484 mg of 5 (S) - (Boc-amino) -4 (S) - (tert-butyldimethylsilyloxy) -6-phenyl-2 (R) -phenylmethylhexanoyl- (L) -Val- ( L) -Phe-thiomorpholin-4-ylamide in 5 ml of dimethylformamide, causing 356 mg of tetrabutylammonium fluoride trihydrate. Column chromatography (silica gel, ethyl acetate / hexane 2: 1) and digestion with hexane gave the title compound. FAB-MS (M + H) &lt; ^{+ &gt}; = 745.

The starting compound is prepared as follows:

20a) Z- (L) -Val- (L) -Phe-thiomorpholin-4-ylamide

Similar to Example 11), 1.99 g of Z- (L) -Val- (L) -Phe-OH (Bachem, Bubendorf, Switzerland) in 40 µl of dichloromethane are reacted with 1.03 g of dicyclohexylcarbodiimide and a solution of 0, 52 g of thiomorpholine in 40 ml of dichloromethane to give the title compound, which precipitated as an oil after extraction. DC Re (F) = 0.8, IR (CH ₂ Cl ₂ ): 1725, 1675, 1642, 1499, 1465, 1454 cm ^-1 .

20b) H- (L) -Val- (L) -Phe-thiomorpholin-4-ylamide

2 g of Z- (L) -Val- (L) -Phe-thiomorpholin-4-ylamide are combined with 45 ml of 33% hydrobromic acid in acetic acid (Fluka, Buchs, Switzerland) under ice-cooling and mixed for a period of time. 90 minutes. Immediately afterwards, the reaction mixture was evaporated, the residue was partitioned between 3 parts of ethyl acetate, saturated sodium bicarbonate solution, water and saturated sodium chloride solution, the organic phase was dried over sodium sulfate and evaporated. Column chromatography (silica gel, methylene chloride / methanol in porosity 9: 1) first affords the title compound and then a byproduct, a putative epilator. DC (F) = 0.56; FAB-MS (M - H) ⁺ = 350, IR (CH ₂ C1 _2): 1641, 1502, 1463,

149

1454, 1448 cm @ -1. Analysis of amino acids (performed by gas chromatography on a Chirasil-L-Val column (E. Bayer, Z. Naturforschung. B 33, 1281 (1983))): T _Ret ((L) -Val derivative) = 3.36 min) epimer purity (ee) > 99% (T _Ret ) (L) -Phe derivative = 22.73 min (ee = 94%).

20c) 5 (S) - (Boc-amino) -4 (S) - (tert-butyldimethylsilyloxy) -6-phenyl-2 (R) -phenylmethylhexanoyl- (L) -Val- (L) -Phe-thiomorpholine- 4-ylamide

S - Analogously to Example 1k), 300 mg of 5 (S) - (Boc-amino) -4 (S) - (tert-butyldimethylsilyloxy) S -6-phenyl-2 (R) -phenylmethylhexanoic acid (example) is reacted (example). 2d) in 5 ml of dimethylformamide with 277 mg of benztriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, 84.5 mg of 1-hydroxybenztriazole,

219 [mu] l of N ' -Rimethylamine and 238.4 mg of H- (L) -Val- (L) -Phe-thiomorpholin-4-ylamide dissolved in 3 ml of dimethylformamide.

Column chromatography (silica gel, 1: 1 ethyl acetate: hexane) gave the title compound. DC: _Rf (A) = 0.43; FAB-MS (M + H) ⁺ = 859th

i.

ä Example 21 no

<·

In an analogous manner to that described in the foregoing

Λ _B \ examples, and as shown below in detajlech, the do.f Stancu I ', the following compounds:

A) 1) One of the compounds listed below under B) to J) wherein in place of the morpholin-4-ylamide moiety there is a thiomorpholin-4-ylamide moiety.

(B) 1) Boe- (p-r) Phe1C; (p-F) Phe- (L) -Val- (L) -Phe-morpholine-4,1-valynide • A and

Analogously to Example 1, 83 mg of 5 (5) 150 are converted

- (Boc-amino) -4 (S) - (tert-butyldimethylsilyloxy) -6- (p-fluorophenyl) -2 (R) - (p-fluorophenylmethyl) hexanoyl- (L) -Val- (L) -Phe -morpholin-4-ylamide is treated with 60 mg of tetrabutylammonium fluoride trihydrate in 0.95 ml of dimethylcormamide to give the title compound. FAB-MS (M + H) + ^r = 76 5th

The starting compound is prepared as follows:

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

20 g (109 mmol) of p-fluorophenylalanine (Fluka, Buchs, Switzerland) were reacted with 35.5 g (163 mmol) of Boc-anhydride and 150 g (1.09) in 400 ml of 1: 1 dioxane / water. mol) of potassium carbonate. After 4 hours, the reaction mixture was acidified with citric acid solution and extracted with 3 parts of ethyl acetate. The organic phases are washed with 10% citric acid solution, water and saturated sodium chloride solution, dried over sodium sulfate and evaporated. Dissolve the residue in a small amount of methylene chloride and crystallize by adding hexane to give the title compound.

1) (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 was contacted at -5 to -10 ° C and the reaction mixture was stirred at room temperature. a solution of 9.05 ml (69 mmol) of isobutyl chloroformate in 44 ml of absolute tetrahydrofuran is added dropwise. The mixture was stirred at room temperature for 30 minutes and the precipitate formed was suction filtered. 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 for 4 hours at room temperature,

151, then acidified with 10% citric acid, the tetrahydrofuran was partially evaporated on a rotary evaporator and the residue was partitioned between 3 parts ethyl acetate, 2 parts 2 N sodium hydroxide, water, saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase, which was dried over sodium sulfate and evaporated, gave, after dissolution in a small amount of methylene chloride and crystallization by addition of hexane, the title compound. DC Rf (A) = 0.36, ¹ 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 methylene chloride cooled to -60 ° C 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) is added as a solution in 185 ml of a 1: 1 mixture of methylene chloride and tetrahydrofuran to precipitate, and everything is silent for 25 minutes. Finally add

17.3 ml (124.8 mmol) of triethylamine dissolved in 38 ml of methylene chloride. The reaction mixture is stirred for 30 minutes and then a solution of 278 ml of 20% potassium hydrogen sulphate and 220 ml of hexane are added dropwise. The reaction mixture was allowed to warm to room temperature, the aqueous phase separated and extracted with 2 parts ether. The organic phases, after washing with saturated sodium bicarbonate solution, water and saturated sodium chloride solution, dried over sodium sulfate and evaporated, afforded the title compound which was used in the next step without further purification.

152 clean another. ¹ H-NMR (200 MHz, CDCl 3): 9.63 (s, 1H), 6.9-7.2 (2m, 4H), 5.04 (n, 1H), 4.42 (m, 1H), 3.10 (m, 2H), 1.43 (s, 9H) ppm.

l) d) 5 (S) - / 1 (S) - (Boc-amino) -2- (p-fluorophenyl) ethyl / dihydrofuran-2- (3H) -one

Analogously to Example 21 (D) (1) (b), zinc homoenolate is prepared from 16.7 g of 2-iodopropionate ethyl ester in 124 ml of toluene, 3.1 g of zinc and medium and 12.4 ml of dimethylacetamide. This was introduced by introducing a tube into trichlorotitanisopropylate (which was made from 5.11 mL of tetraisopropyl orthotitanate and 5.71 mL of titanium tetrachloride in 16 mL of toluene and 38.5 mL of methylene chloride), cooled to -40 to -25 ° C. The reaction mixture is warmed to -25 ° C over 5 minutes and recooled to -40 ° C. Immediately thereafter, a solution of 9.28 g of N-Boc- (p-fluorophenylalaninal) in 33 ml of methylene chloride was added dropwise to the reaction mixture, and the mixture was stirred for 15 hours at about -20 ° C and then for 1 hour at 0 °. C. The reaction mixture is poured onto 400 g of ice water and 550 ml of tert-butyl methyl ether and stirred vigorously for 10 minutes. The aqueous phase is separated, extracted with 2 parts of ether, the organic phase is washed with water, saturated sodium bicarbonate solution, water and saturated sodium chloride solution, dried over sodium sulfate and evaporated. Crystalline 5 (S) - (Boc-amino) -4 (S) -hydroxy-6- (p-fluorophenyl) hexanoic acid ethyl ester is obtained as an intermediate, which is heated in 244 ml of toluene and 7.3 ml of acetic acid during 2 hours. Cooled reaction mixture with 500 ml of water, separated aqueous phase, extracted with 2 parts ether, washed with saturated sodium bicarbonate solution, water and saturated chlorine solution.

The product was dried over sodium sulfate and evaporated. Column chromatography (silica gel, hexane / ethyl acetate 2: 1) affords the pure title compound. DC: _Rf (D) = 0.22; FAB-MS (M + H) ⁺ = 324, [a] _D = 20.7 ° (c = 1, ethanol).

(e) 5 (S) - (1) (S) - (Boc-amino) -2- (p-fluorophenyl) ethyl] -3 (R) - (p-fluorophenylmethyl) dihydrofuran-2- (3H) -one

Analogously to Example 21 (D) (1) (c), 1.0 g of 5 (S) - / 1 (S) - (Boc-amino) -2- (p-fluorophenyl) ethyl / dihydrofuran-2- (3H) is deprotonated -one dissolved in 7.9 ml of tetrahydrofuran 6.05 ml of 1 molar lithium bis (trimethylsilyl) anide in tetrahydrofuran and alkylated for 1 hour 0.673 g of p-fluorobenzyl bromide at -75 ° C. Column chromatography (silica gel, methylene chloride / ether 49: 1) affords the pure title compound. DC (M) = 0.17, ¹ H-NMR (200 MHz, CDCl 3): 7.19-7.05 and 7.04

6.88 (2m, 4H each), 4.50 (d, 10Hz, HN), 4.11 (m, 1H), 3.87 (qm, about 8Hz, IH), 3.1-2 7 (m, 5H), 2.33

2.14 and 2.02-1.85 (2m, 1H each), 1.35 (s, 9H) ppm.

l) f) 5 (S) - (Boc-amino) -4 (S) -hydroxy-6- (p-fluorophenyl) -2 (R) - (p-fluorophenylmethyl) hexanoic acid

Analogously to Example 1i), 790 mg of 5 (S) - / 1 (S) - (Boc-amino) -2- (p-fluorophenyl) ethyl / -3 (R) - (pf fluorophenylmethyl) dihydrofuran-2- ( 3H) -one in 29 ml of dimethoxyethane and 15 ml of water by treating 7.3 ml of a 1 molar lithium hydroxide solution to the title compound, which is used directly below.

(l) (g) 5 (S) - (Boc-amino) -4 (S) - (tert-butyldimethylsilyloxy) -5- (p-fluorophenyl) -2 (R) - (p-fluorophenylmethyl) hexyl) hexanoic acid

Analogously to Example 1j), 956 mg of 5 (S) - (Boc-amino) -4 (S) -hydroxy-6- (p-fluorophenyl) -2 (R) - (p-fluorophenylmethyl) hexanoic acid are silylated in 2 3 ml of dimethylformamide were treated with 1.47 g of tert-butyldimethylchlorosilane and 1.19 g of imidazole. Hydrolysis of the silyl ester function 1.76 g of potassium carbonate in 50 ml of a 3: 1: 1 mixture of methanol, tetrahydrofuran and water gave the title compound after column chromatography (silica gel, hexane / ethyl acetate 2: 1). DC Rf (D) = 0.13; FAB-MS (M + H) &lt; ^{+ &gt}; = 564.

1) h) 5 (S) - (Boc-amino) -4 (S) - (tert-butyldimethylsilyloxy) -6- (p-fluorophenyl) -2 (R) - (p-fluorophenylmethyl) hexanoyl- ( L) -Val (L) -Phe-morpholin-4-ylamide

Analogous to Example 9f), 110 mg of 5 (S) - (Boc-amino) -4 (S) - (tert-butyldimethylsilyloxy) -6- (pfluorophenyl) -2 (R) - (pf) was reacted. luorophenylmethyl) hexane and 71.5 mg of H- (L) -Val- (L) -Phemomorpholin-4-ylamide (Example 1o) in 1.83 ml of 0.25 molar N-methylmorpholine in acetonitrile with 81 5 mg O-benztriazol-1-yl--, Ν, Ν ', N'-tetramethyluronium hexafluorophosphate. The pure title compound is obtained by column chromatography (silica gel, methylene chloride / ether 3: 1). DC: _Rf (N) = 0.14; FAB-MS (M + H) ⁺ = 879th

2) Boc- (p-F) Phe [C] (p-F) Phe- (L) -Val- (L) - (p-F-Phe) -morpholin-4-ylamide

In analogy to Example 1, 150 mg of 5 (S) -f Boc-amino) -4 (S) - (tert-butyldimethylsilyloxy) -6- (p155) was converted.

-fluorophenyl) -2 (R) - (p-fluorophenylmethyl) hexanoyl- (L) -Val- (L) - (pF-Phe) -morpholin-4-ylamide by treating 105 mg of tetrabutylammonium fluoride trihydrate in 2.5 ml of dimethylformamide per compound named in the title. FAB-MS (M + H) &lt; ^{+ &gt}; = 783.

The starting compound is prepared as follows:

2) (a) 5 (S) - (Boc-amino) -4 (S) - (tert-butyldimethylsilyloxy) -6- (pfluorophenyl) -2 (R) - (pfluorophenylmethyl) hexanoyl- (L) -Val- (L) - (pF-Phe) -morpholin-4-ylamide

Analogous to Example 9f), 100 mg of 5 (S) - (Boc-amino) -4 (S) - (tert-butyldimethylsilyloxy) -6- (pfluorophenyl) -2 (R) - (pfluorophenylmethyl) acid is reacted hexane (Example 21B) 1) (g) and 68.5 mg of H- (L) -Val- (L) - (pF-Phe) -morpholin-4-ylamide (Example 9e) in 1.67 ml of 0.25 of molar N-methylmorpholine in acetonitrile with 74 mg of O-benztriazol-1-yl-Ν, Ν, Ν ', N' - tetramethyluronium hexafluorophosphate to the title compound. DC: _Rf (A) = 0.17; FAB-MS (M + H) ⁺ = 897th

(3) Boc- (pF) Phe [C] (pF) Phe- (L) -Val- (L) - (p-CH ₃ O-Phe) -morpholin-4-ylamide

Analogously to Example 1, 126 mg of 5 (S) - (Boc-amino) -4 (S) - (tert-butyldimethylsilyloxy) -6- (p-fluorophenyl) -2 (R) - (p-fluorophenylmethyl) are converted. hexanoyl- (L) -Val- (L) - (p-CH 2 O-Phe) -morpholin-4-ylamide by treating 87 mg of tetrabutylammonium fluoride trihydrate in 2 mL of dimethylformamide to the title compound. FAB-MS (M + H &lt; + &gt; = 795).

The starting compound is prepared as follows:

156

3) (a) 5 (S) - (Boc-amino) -4 (S) - (tert-butyldimethylsilyloxy) -6- (p-fluorophenyl) -2 (R) - (p-fluorophenylmethyl) hexanoyl- (L) -Val- (L) - (p-CH ^ O-Phe) -morpholin-4-ylamide

In analogy to Example 9f), 80 mg of 5 (S) - (Boc-amino) -4 (S) - (tert-butyldimethylsilyloxy) -6- (p-fluorophenyl) -2 (R) - (p) acid is reacted. -fluorophenylmethyl) hexane (Example 21B) (g) and 56.7 mg of H- (L) -Val- (L) - (p-CH ₃ O-Phe) -morpholin-4-ylamide (Example 10e) in 1, 3 mL of 0.25 molar N-methylmorpholine in acetonitrile with 59.2% O-benztriazol-1-yl-Ν, Ν, Ν ', N'-tetramethyluronium hexafluorophosphate to give the title compound FAB-MS (M + H) ) ⁺ = 909.

4) Boc- (p-F) Phe [Cl (p-F) Phe- (L) -Val- (L) -Cha-morpholin-4-ylamide

Analogously to Example 1, 230 mg of 5 (S) - (Boc-amino) -4 (S) - (tert-butyldimethylsilyloxy) -6- (p-fluorophenyl) -2 (R) - (p-fluorophenylmethyl) was converted ) hexanoyl- (L) -Val- (L) -Cha-morpholin-4-ylamide by treating 164 mg of tetrabutylammonium fluoride trihydrate in 3.8 mL of dimethylformamide to the title compound. FAB-MS (M + H) = ¹ · 771st

The starting compound is prepared as follows:

(a) 5 (S) - (Boc-amino) -4 (S) - (tert-butyldimethylsilyloxy) -6- (p-fluorophenyl) -2 (R) - (p-fluorophenylmethyl) hexanoyl- (L) -Val - (L) Cha-morpholin-4-ylamide

150 mg * was reacted as in Example 9f). 5 (S) - (Boc-amino) -4 (S) - (tert-butyldiraethylsilyloxy) -6- (p-fluorophenyl) -2 (R) - (p-fluorophenylmethyl) hexanoic acid (Example 21B) III) and 99.4 mg of H- (L) -Val- (L) -Cha157

-morpholin-4-ylamide (Example 11a) in 2.4 ml of 0.25 molar N-methylmorpholine in acetonitrile with 111 mg of O-benztriazol-1-yl-N, N, N ¹ , N'-tetramethyluronium hexafluorophosphate per compound named in the title. FAB-MS (MH + H) ^T = 885.

(5) Boc- (p-F) Phe [C] (p-F) Phe- (L) -le- (L) -Phe-morpholin-4-ylamide

C) 1) Boc- (pF) Phe [C] (p-CN) Phe- (L) -Val- (L) -Phe-morpholin-4-ylamide) Boc- (pF) Phe [C] (p- CN) Phe- (L) -Val- (L) - (pF-Phe) -morpholin-4-ylamide) Boe- (pF) Phe [C] (p-CN) Phe- (L) -Val- (L) - (p-CH ₃ O-Phe) -morpholin-4-ylamide

4) Boc- (p-F) Phe (C) (p-CN) Phe- (L) -Val- (L) -Cha-morpholin-4-ylamide

5) Boe- (p-F) Phe [C] (p-CN) Phe- (L) -1le- (L) -Phe-morpholin-4-ylamide

D) 1) Boc-PhefC] (p-F) Phe- (L) -Val- (L) -Phe-morpholin-4-ylamide

Similar to Example 1), the protecting group is removed from 0.31 g of 5 (S) - (Boc-amino) -4 (S) - (tert-butyldimethylsilyloxy) -6-phenyl-2 (R) - (p- fluorophenylmethyl) hexanoyl- (L) -Val- (L) -Phemomorpholin-4-ylamide by treating 226 mg of tetrabutylammonium fluoride trihydrate in 3.0 mL of dimethylformamide to give the title compound which was obtained after column chromatography (silica gel, ethyl acetate). net. DC: _Rf (B) = 0.55; FAB-MS (M + H) = ^r 747th

The starting compound is prepared as follows:

158

l) a) Ethyl 2-iodopropionate

A suspension of 170 ml of 2-bromopropionic acid ethyl ester (Fluka, Buchs, Switzerland) and 950 g of sodium iodide in 1.8 liters of acetone is stirred at 60 DEG C. for 20 hours. The reaction mixture is filtered, the filtrate is partially evaporated, poured into approximately 2.5 liters of ether, washed with 1.0 liter of 1% sodium thiosulfate solution and then with saturated sodium chloride solution, dried over sodium sulfate and evaporated. Distillation (temperature 83 ° C, 2660 Pa) gave the pure title compound. MS (M) &lt; ^{+ &gt;} 228, ¹ H-NMR (200 MHz, CDCl 3): 4.17 (q, 7 Hz, 2H), 3.34 and 2.97 (2t, 7 Hz, 2 X 2H), 1 28 (t, 7Hz, 3H) ppm.

1) b) 5 (S) - / 1 (S) - (Boc-amino) -2-phenylethyl / dihydrofuran-2- (3H) -one (Analogous procedure to AE DeCamp, AT Kawaguchi, RP Volante and I. Shinkai, Tetrahedron Lett., 32, 1867 (1991). To a solution of 17.4 g of 2-iodopropionic acid ethyl ester in 130 ml of toluene, 8.03 g of zinc and medium (see RD Smith, HE Simmons, WE Parham and MD Bhavsar in Org. Synth., Coli. Vol.) Are added under nitrogen. 5, 855 (1973)) and 12.96 ml of dimethylacetamide and further stirred vigorously for 1 hour at room temperature and 4 hours at 80 [deg.] C. (formation of zinc homoenolate solution). In a second apparatus (under a nitrogen atmosphere) a solution of 5.58 ml (18.9 mmol) of tetraisopropyl orthotitanate in 16.4 ml of toluene and 91.8 ml of methylene chloride is combined with gentle cooling with 5.90 ml (53.8 ml). mmol) of titanium tetrachloride. Stir for 15 minutes at room temperature to form a yellow solution which is cooled to -40 ’C as a result of which

159

ΐ.

Tr partial crystallization of trichlorotitanisopropylate occurs. Using a feed tube, the zinc homolate solution, cooled to room temperature, is decanted from the metallic solid and added dropwise to trichlorotitanisopropylate while maintaining the temperature between -40 and -30 ° C to form a dark red solution which is warmed to - over 5 minutes. 25 ° C and recooled to -40 ° C. Finally, a solution of 9.0 g is added dropwise

N-Boc-phenylalaninal (manufactured by D. J. Kempf, J. Org.

Chem 51. 3921 (1986)) in 32.8 ml of methylene chloride and stirred for 15 hours at about -20 ° C and finally for 1 hour at 0 ° C. The reaction mixture is poured onto 0.5 kg of ice-water and 500 ml of ether and stirred vigorously for 10 minutes. The aqueous phase was separated and extracted with 2 parts ether. The organic phase was washed with 2 parts of water, saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over sodium sulfate and evaporated. Crystalline 5 (S) - (Boc-amino) -4 (S) -hydroxy-6-phenylhexanoic acid ethyl ester is obtained as an intermediate. This intermediate was heated in 80 ml of toluene and 9 ml of acetic acid at 80 ° C for 2.5 hours. The reaction mixture is added to 500 ml of water, the aqueous phase is separated and extracted with 2 parts of ether. The organic phase was washed with saturated sodium bicarbonate solution, water and saturated sodium chloride solution and dried over sodium sulfate. Partial evaporation of the organic phase and contacting with hexane affords the crystalline title compound which, according to analytical determination, contains approximately 10% (4R) -epimer (DC Rf (E) = 0.08). Column chromatography (silica gel, hexane / ethyl acetate 2: 1) yields the pure title compound. DC Rf (E) = 0.14, [α] _D = 17.7 '(c = 1, ethanol).

160

1) c) 5 (s) - / 1 (S) - (Boc-amino) -2-phenylethyl / -3 (R) - (p-fluorophenylmethyl) dihydrofuran-2- (3H) -one (Analogous procedure to AK Ghosh, SP McKee and WJ Thompson in J. Org. Chem., 56, 6500 (1991). Under a nitrogen atmosphere, 300 mg (0.982 mmol) of 5 (S) - / 1 (S) - (Boc-amino) -2-phenylethyl / dihydrofuran-2- (3H) -one in 6 ml of tetrahydrofuran are contacted at - 75 ° C with 1.92 ml of 1-molar lithium bis (trimethylsilyl) amide in tetrahydrofuran (Aldrich) and further stirred for 15 minutes at this temperature. The reaction mixture was then added dropwise with 13 2 µL (1.077 mmol) of p-fluorobenzyl bromide (Fluka, Buchs, Switzerland) and stirred for 30 minutes at -50 ° C. After re-cooling to -75 ° C, 0.3 ml of propionic acid and then 0.3 ml of water are added. The reaction mixture is warmed to 0 ° C, diluted with ethyl acetate, washed with 10% citric acid solution, saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over sodium sulfate and evaporated. Column chromatography (silakagel, hexane / ethyl acetate 4: 1) gave the pure title compound. DC Rf (D) = 0.54; FAB-MS (M + H) &lt; ^{+ &gt}; = 414.

l) d) 5 (S) - (Boc-amino) -4 (S) -hydroxy-6-phenyl-2 (R) - (p-fluorophenylmethyl) hexanoic acid

1.46 g of (S) - / 1 (S) - (Boc-amino) -2-phenylethyl / -3 (R) - (p-fluorophenylmethyl) dihydrofuran-2- (3H) are hydrolyzed in analogy to Example 1 (a). -one in 57 ml of dimethoxyethane and 29 ml of water by treatment with 14.1 ml of a 1 molar solution of lithium hydroxide to give the title compound which is used without further purification.

l) e) 5 (S) - (Boc-amino) -4 (S) - (tert-butyldime) acid

161 thylsilyloxy) -6-phenyl-1-2 (R) - (p-fluorophenylmethyl) hexane

Analogously to Example Ij), 0.9 g of 5 (S) - (Boc-amino) -4 (S) -hydroxy-6-phenyl-2 (R) - (p-fluorophenylmethyl) hexanoic acid is silylated in 4 ml of dimethylformamide. with 1.49 g of tert-butyldimethylchlorosilane and 1.2 g of imidazole. Hydrolysis of the silyl ester function 1.9 g of potassium carbonate in 50 ml of a 3: 1: 1 mixture of methanol, tetrahydrofuran and water gave the title compound after acidification with citric acid solution and extraction with ethyl acetate. DC R f (D). = 0.2.

1) f) 5 (S) - (Boc-amino) -4 (S) - (tert-butyldimethylsilyl-oxy) -6-phenyl-2 (R) - (fluorophenylmethyl) hexanoyl- (L) - Val (L) -Phe-morpholin-4-ylamide

J

Analogous to Example 9f), 200 mg of 5 (S) - (Boc-amino) -4 (S) - (tert-butyldimethylsilyloxy) -6-phenyl-2 (R) - (pfluorophenylmethyl) acid is reacted. hexane and 134 mg of H- (L) -Val- (L) -Phemomorpholin-4-ylamide (Example 1o) in 3.6 ml of 0.25-molar N-methylmorpholine in aceto. of the nitrile was 153 mg of O-benztriazol-1-yl-N, N, N ', N'-tetramethyluronium hexafluorophosphate. After crystallization from hexane i, the pure title compound was obtained. DC

R _f (A) = 0.25.

2) Boc-Phe [C] (p-F) Phe- (L) -Val- (L) - (p-F-Phe) -morpholin-, 4-ylamide x

3) Boc-Phe [C] (pF) Phe- (L) -Val- (L) - (p-CH ₃ 0-Phe) -morpholinolin-4-ylamide

4) Boc-Phe [C] (p-F) Phe- (L) -Val- (L) -Cha-morpholin-4-yl162 amide

Analogously to Example 1, the protecting group is removed from 120 mg of 5 (S) - (Boc-amino) -4 (S) - (tert-butyldimethylsilyloxy) -6-phenyl-2 (R) - (p-fluorophenylmethyl) hexanoyl - (L) -Val- (L) -Cha-morpholin-4-ylamide by treating 87 mg of tetrabutylammonium fluoride trihydrate in 1.4 mL of dimethylformamide to give the title compound. DC: _Rf (B) = 0.61; FAB-MS (M + H) ⁺ = 753rd

The starting compound is prepared as follows:

(a) 5 (S) - (Boc-amino) -4 (S) - (tert-butyldimethylsilyloxy) -6-phenyl-2 (R) - (p-fluorophenylmethyl) hexanoyl- (L) -Val- (L) ) Cha-morpholin-4-ylamide

As in Example 9f), 100 mg of 5 (S) - (Boc-amino) -4 (S) - (tert-butyldimethylsilyloxy) -6-phenyl-1-2 (R) - (pfluorophenylmethyl) acid is reacted. hexane (Example 21D) (e) and 68 mg of H- (L) -Val- (L) -Cha-morpholin-4-ylamide (Example 11a) in 1.8 mL of 0.25 molar N-methylmorpholine in acetonitrile with 76.4 mg of O-benztriazol-1-yl-Ν, Ν, Ν ', N'-tetramethyluronium hexafluorophosphate. DC Rf (A) = 0.50.

(5) Boc-Phe [C] (p-F) Phe- (L) -Ile- (L) -Phe-morpholin-4-ylamide

E) 1) Boc-Phe [C] (p-CN) Phe- (L) -Val- (L) -Phe-morpholin-4-yl-amide

Analogously to Example 1, the protecting group is removed from 60 mg of 5 (S) - (Boc-amino) -4 (S) - (tert-butyldimethylsilyloxy) -6-phenyl-2 (R) - (p-cyanophenylmethyl) hexanoyl - (L) -Val- (L) -Phe-morpholin-4-ylamide by treatment with

163

64.3 mg tetrabutylammonium fluoride trihydrate in 1.0 mL dimethylformamide to give the title compound. Column chromatography (silica gel, ethyl acetate) affords the pure compound. DC: _Rf (B) = 0.26; FAB-MS (M + H) + = 754th

The starting compound is prepared as follows:

1) (a) 5 (S) - / 1 (S) - (Boc-amino) -2-phenylethyl / -3 (R) - (p-quanophenylmethyl) dihydrofuran-2- (3H) -one

Analogously to Example 21 (D) (1) (c), it is deprotonated

1.5 g of 5 (S) - / 1 (S) - (Boc-amino) -2-phenylethyl / dihydrofuran-2- (3H) -one (Example 21D) (1) (b) dissolved in 32 ml of tetrahydrofuran by treatment with 9, 8 ml of 1-molar lithium bis (trimethylsilyl) amide in tetrahydrofuran and alkylated by treatment with 1.0 g of 4-bromomethylbenzonitrile (Fluka, Buchs, Switzerland) dissolved in 3 ml of tetrahydrofuran. Column chromatography (silica gel, hexane / ethyl acetate 1: 1) affords the pure title compound. DC Rf (D) = 0.33.

l) b) 5 (S) - (Boc-amino) -4 (S) -hydroxy-6-phenyl-2 (R) - (p-cyanophenylmethyl) hexanoic acid

Analogously to Example 1i), 0.50 g of 5 (S) - / 1 (S) - (Boc-amino) -2-phenylethyl] -3 (R) - (p-cyanophenylmethyl) dihydrofuran-2- (3H) is hydrolyzed. 1 -one in 19 ml of dimethoxyethane and 10 ml of water by treating 4.8 ml of a 1 molar lithium hydroxide solution to the title compound. DC: _Rf (F) = 0.3.

l) c) 5 (S) - (Boc-amino) -4 (S) - (tert-butyldimethylsilyloxy) -6-phenyl-1-2 (R) - (p-cyanophenylmethyl) hexanoic acid

164

Analogously to Example 1j), 0.62 g of 5 (S) - (Boc-amino) -4 (S) -hydroxy-6-phenyl-2 (R) - (p-cyanophenylmethyl) hexanoic acid in 6.2 ml of dimethylformamide is silylated. treatment with 0.98 g of tert-butyldimethylchlorosilane and 0.79 g of imidazole Hydrolysis of the silyl ester function 1.2 g of potassium carbonate in 31 ml of a 3: 1: 1 mixture of methanol, tetrahydrofuran and water gave the compound after acidification with citric acid and extraction with ethyl acetate. DC Rf (D) = 0.29; FAB-MS (M + H) &lt; ^{+ &gt}; = 553.

1) d) 5 (S) - (Boc-amino) -4 (S) - (tert-butyldimethylsilyloxy) -6-phenyl-2 (R) - (p-cyanophenylmethyl) hexanoyl- (L) -Val- ( L) -Phe-morpholin-4-ylamide

As in Example 9f), 72 mg of 5 (S) - (Boc-amino) -4 (S) - (tert-butyldimethylsilyloxy) -6-phenyl-2 (R) - (p-cyanophenylmethyl) hexanoic acid is reacted and

43.3 mg of H- (L) -Val- (L) -Phemomorpholin-4-ylamide (Example 1o) in 1.14 ml of 0.25 molar N-methylmorpholine in acetonitrile with 50 mg of O-benztriazole-1 -yl-N, N, N ¹ , N'-tetramethyluronium hexafluorophosphate to give the title compound. DC Rf (A) = 0.19.

2) Boc-Phe [C] (p-CN) Phe- (L) -Val- (L) - (p-F-Phe) -morpholin-4-ylamide

3) Boc-PhelC] (p-CN) Phe- (L) -Val- (L) - (p-CH ₃ 0-Phe) -morpholin-4-ylamide

4) Boc-PhelC1 (p-CN) Phe- (L) -Val- (L) -Cha * -morpholin-4-ylamide

5) Boc-Phe [C] (p-CN) Phe- (L) -Ie- (L) -Phe-morpholin-4-ylamide

165

In analogy to Example 1, 510 mg of 5 (S) - (Boc-amino) -4 (S) - (tert-butyldimethylsilyloxy) -6-phenyl-2 (R) - (p-cyanophenylmethyl) hexanoyl- (L) is desilylated. 1-l- (L) -Phemomorpholin-4-ylamide by treating 362.3 mg of tetrabutylammonium fluoride trihydrate in 10 ml of dimethylformamide. The reaction mixture is poured onto ice water and extracted with 3 parts of methylene chloride, the organic phase is then washed with saturated sodium bicarbonate solution, water and saturated sodium chloride solution, dried over sodium sulfate and evaporated. Column chromatography (silica gel, ethyl acetate) affords the pure title compound. DC: _Rf (B) = 0.51; FAB-MS (M + H) ⁺ = 768th

The starting compound is prepared as follows:

5) (a) 5 (S) - (Boc-amino) -4 (S) - (tert-butyldimethylsilyloxy) -6-phenyl-2 (R) - (p-cyanophenylmethyl) hexanoyl- (L) -Ile- ( L) -Phe-morpholin-4-ylamide

Analogous to Example 9f), 360 mg of 5 (S) - (Boc-amino) -4 (S) - (tert-butyldimethylsilyloxy) -6-phenyl-2 (R) - (p-cyanophenoic acid) is reacted. enylmethylhexane (Example 21E) (d) and 253 mg of H- (L) -Ile- (L) -Phemomorpholin-4-ylamide (Example 16b) in 6.36 ml of 0.25 molar N-methylmorpholine in of acetonitrile with 276 mg of O-benztriazol-1-yl-N, N, N ', N ¹ -tetramethyluronium hexafluorophosphate. After evaporation, the residue was partitioned between methylene chloride, 10% citric acid solution, water, saturated sodium bicarbonate solution, water and saturated sodium chloride solution. The organic phase was dried over sodium sulfate and evaporated to give the title compound. DC: _Rf (D) = 0.07.

1) Boc-Phe [C] (p-CH ₃ 0) Phe (L) -Val (L) -Phe-morpholin-4-ylamide

F)

166

2) Boc-Phe [C] (p-CH ₃ O) Phe- (L) -Val- (L) - (pF-Phe) -morpholin-4-ylamide

3) Boc-Phe [C] (p-CH 2 O) Phe- (L) -Val- (L) - (p-CH 2 O-Phe) -morpholin-4-ylamide

4) Boc-Phe [C] (p-CH ₃ 0) Phe (L) -Val (L) Cha-morpholin-4-ylamide

5) Boc-Phe [C] (p-CH ₃ O) Phe- (L) -Ie- (L) -Phe-morpholin-4-ylamide G) 1) Boc-Phe [C] (p-CF- j) Phe- (L) -Val- (L) -Phe-morpholin-4-yls amide

(2) Boc-Phe [C] (p-CF ₃ ) Phe- (L) -Val- (L) - (p-Phe) -morpholin-4-ylamide; 3) Boc-Phe [C] (p-CF ₃ ) Phe- (L) -Val- (L) - (p-CH ₃ O-Phe) -mor; folin-4-ylamide 4) Boc-Phe [C] (p-CF 3) Phe- (L) -Val- (L) -Cha-morpholin-4-ylamide

5) Boc-Phe [C] (p-CF 3) Phe- (L) -Ile- (L) -Phe-morpholin-4-ylamide

I i

H) 1) Boc-Cha [C] (p-CN) Phe- (L) -Val- (L) - (p-F-Phe) -morpholin-4-ylamide

2) Boc-Cha [C] (p-CN) Phe- (L) -Val- (L) - (p-CH 3 O-Phe) -morpholin-4-ylamide

3) Boc-Cha [C] (p-CN) Phe- (L) -Val- (L) -Cha-morpholin-4-ylamide <4) Boc-Cha [C] (p-CN) Phe- (L) 1-Ile- (L) -Phemomorpholin-4-yl amide

1) Boc-Cha [C] (p-CH ₃ O) Phe- (L) -Val- (L) -Phe-morpholin-4-ylamide

2) Boc-Cha [C] (p-CH ₃ O) Phe- (L) -Val- (L) - (pF-Phe) -morpholin-4-ylamide

3) Boc-Cha [C] (p-CH ₃ 0) Phe (L) -Val- (L) - _(p-CH3 0-Phe) -morpholin-4-ylamide

167

4) of Boc-Cha [C] (p-CH ₃ 0) Phe (L) -Val (L) Cha-morpholin-4-ylamide

5) Boc-Cha [C] (p-CH 2 O) Phe- (L) -Ile- (L) -Phe-morpholin-4-ylamide

J) 1) Boc-Cha1C] (p-CF ₃ ) Phe- (L) -Val- (L) -Phe-morpholin-4-ylamide

2) Boc-Cha [C] (p-CF-j) Phe- (L) -Val- (L) - (p-F-Phe) -morpholin-4-ylamide

3) Boc-Cha [C] (p-CF ₃ ) Phe- (L) -Val- (L) - (p-CH ₃ 0-Phe) -morpholin-4-ylamide

4) Boc-Cha [C] (p-CF ₃ ) Phe- (L) -Val- (L) -Cha-morpholin-4-ylamide) Boc-Cha [C] (p-CF ₃ ) Phe- (L) ) -Ile- (L) -Phe-morpholin-4-y1amid

Example 22

In an analogous manner to that described in any of the foregoing examples, or as always detailed, the following compounds are prepared by selecting the corresponding starting compounds:

A) Boe- (L) -Va1-Phe [C] Phe- (L) -Val- (L) -Phe-morpholin-4-ylamide

B) H- (L) -Val-Phef C] Phe- (L) -Val- (L) -Phe-morpholin-4-ylamide

C) Boc-Cha [C] (p-F) Phe- (L) -Ile- (L) -Phe-morpholin-4-ylamide

Analogously to Example 1, 0.15 g of 5 (S) - (Boc-amino) -4 (S) - (tert-butyldimethylsilyloxy) -6-cyclohexyl-2 (R) - (p-fluorophenylmethyl) hexanoyl- (L) -Ile- (L) -Phemomorpholin-4-ylanide was treated with 117 mg of tetrabutylammonium fluoride trihydrate in 1.7 mL of dimethylformamide to give the title compound. DC: _Rf (L) = 0.18; FAB-MS (M + H) ⁺ = 767th

168

The starting compound is prepared as follows:

C) a) 5 (S) - (Boc-amino) -4 (S) - (tert-butyldimethylsilyloxy) -6-cyclohexyl-2 (R) - (p-fluorophenylmethyl) hexanoyl- (L) -I- ( L) -Phe-morpholin-4-ylamide

In analogy to Example 9f), 102 mg of 5 (S) - (Boc-amino) -4 (S) - (tert-butyldimethylsilyloxy) -6-cyclohexyl-2 (R) - (p-fluorophenylmethyl) hexanoic acid is reacted. (Example 1j) and 70.8 mg of H- (L) -Ile- (L) -Phe-fluoropholin-4-ylamide (Example 16b) in 1.77 mL of 0.25 molar N-methylmorpholine in acetonitrile with 77, 4 mg of O-benztriazol-1-yl-Ν, Ν, Ν ', N'-tetramethyluronium hexafluorophosphate per title compound. DC Rf (A) = 0.17; FAB-MS (M + H) &lt; ^{+ &gt}; = 881.

D) Boc-Cha [C] (pF) Phe- (L) -Val- (L) -Cha-morpholin-4-ylamide E) Boc-Phe [C] Phe- (L) -Val- (D) -Phe-morpholin-4-ylamide

i: F) Boc-Phe [C] Phe- (L) -Val (red) - (L) -Phe-morpholin-4-ylamide

J

J »k

G) Isobutyloxycarbonyl-Phe [C] Phe- (L) -Val- (L) -Phe-morpholin-4'-ylamide

- H) Boc-Cha [C] (p-CN) Phe- (L) -Val- (L) -Phe-thiomorpholin-4-ylamide

(I) Boc-Cha (C) (p-F) Phe- (L) -Val- (L) -Phe-thiomorpholin-4-ylamide

Analogously to Example 1, 0.16 g of 5 (S) - (Boc-amino) -4 (S) - (tert-butyldimethylsilyloxy) -6-cyclohexyl; -2 (R) - (p-fluorophenylmethyl) hexanoyl- (L) -Val- (L) -Phe-thiomorpholin-4-ylamide by treating 114 mg of tetrabutylammonium fluoride trihydrate in 1.8 mL of dimethylformamide to the title compound. DC: _Rf (L) = 0.38; FAB-MS (M + H) ⁺ = 769th

169

The starting compound is prepared as follows:

I) a) 5 (S) - (Boc-amino) -4 (S) - (tert-butyldimethylsilyloxy) -6-cyclohexyl-2 (R) - (p-fluorophenylmethyl) hexanoyl- (L) -Val- ( L) -Phe-thiomorpholin-4-ylamide

As in Example 9f), 100 mg of 5 (S) - (Boc-amino) -4 (S) - (tert-butyldimethylsilyloxy) -6-cyclohexyl-2 (R) - (p-fluorophenylmethyl) hexanoic acid is reacted (Example 1j) and 70 mg of H- (L) -Val- (L) -Phe-thiomorpholin-4-ylamide (Example 20b) in 1.7 ml of 0.25 molar N-methylmorpholine in acetonitrile with 76 mg of O- benzotriazol-l-yl-N ^ N ^ N ' tetramethyluronium hexafluorophosphate. After the reaction mixture was left at room temperature for 18 hours, part of the title compound was obtained directly by filtration from the reaction mixture. Another portion of the title compound was obtained by treating the filtrate residue with 3 parts ethyl acetate, water, 2 parts 10% citric acid, water, 2 parts saturated sodium bicarbonate solution, water and saturated sodium chloride solution, drying the organic phase with sodium sulfate and evaporating. DC Rf (A) = 0.55; FAB-MS (M + H) &lt; ^{+ &gt}; = 883.

J) The compounds of Examples 22A) through 22G) wherein, instead of the morpholin-4-ylamide residue, the thiomorpholin-4-ylamide residue is present.

Example 23

Similar to any of the above, the following compounds were prepared:

a) Boc-Phe [C] Phe- (L) - Va1- (L) -Phe- (4-methylpiperazin-1-yl) amide

b) Boc-Phe [C] Phe- (L) -Val- (L) -Phe-piperidin-1-ylamide

170

c) Boc-Phe [C] Phe- (L) -Val- (L) -Phe-pyrrolidin-1-ylamide

Example 24

Gelatin solution

A sterile filtered aqueous solution of any of the active compounds of the formula (I) in the preceding or following Examples 1 to 23 and 33 to 41, additionally containing 20% cyclodextrin, and a sterile phenol-preserved gelatin solution are mixed while heated under aseptic conditions. so as to obtain 1,0 ml of the solution as follows:

and Active substance 3 mg Ί j gelatin 150.0 mg and phenol 4.7 mg and Distilled water with 20% cyclodextrin 1.0 ml

Example 25

The sterile dry substance for injection of mg of one of the compounds of the formulas I in the preceding or following Examples 1 to 23 and 33 to 41, as active ingredients, is dissolved in 1 ml of an aqueous solution with 20 mg of mannitol and 20% cyclodextrin as a co-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 intramuscularly or intravenously. This composition can also be filled into dual chamber spray ampoules.

171

Example 26

Nasal spray

A mixture of 3.5 ml of Myglyol 812 ^R and 0.08 g of benzyl alcohol is suspended in 500 mg of finely divided powder (particle size less than 5.0 μπι) of one of the compounds of the formula I mentioned in the preceding or following Examples 1 to 23 and 33 to 41 as active ingredients. This suspension is filled into containers fitted with a metering valve. Introduce 5.0 g of Freon 12 ^R into the container under pressure using a 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 27

Lacquered tablets

The following ingredients are processed to produce 10,000 tablets, each containing 100 mg of active ingredient:

Active substance

1000 g

Maize starch

680 g

Colloidal silicic acid

200 g

Magnesium stearate g

Stearic acid g

Sodium carboxymethyl starch

250 g

Water as needed

A mixture containing, as active substance, 50 g of corn starch and colloidal silicic acid, containing one of the compounds of the formula I mentioned in the preceding or following Examples 1 to 23 and 33 to 41, is processed.

172 starch fat prepared from 250 g of corn starch and 2,2 kg of demineralised water per 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, mixed with a previously sieved blend (1 mm mesh) of 330 g of corn starch, magnesium stearate, stearic acid and sodium carboxymethyl starch, and compressed into lightly domed tablets.

Example 28

Oral Dispersion 1 «

625 mg of one of the compounds of the formula I mentioned in the preceding or following Examples 1 to 23 and 33 to 41 as active substances, for example Boc-Phe [C] Phe- (L) -Valj - (L) -Phemomorpholine-4 6-mg of 1-hexadecanoyl-2- (9-cis-octadecenoyl) -3-sn-phosphatidylcholine (POPC, i.e. 1-palmitoyl-2-oleoylphosphatidylcholine) was dissolved in 25 ml of ethanol and the solution was dilute with multiple amounts of water. To this end, the ethanol solution was added dropwise at room temperature at a rate of 10 ml / min to the present amount of water. Ethanol was removed from the mixture by tangential dialysis (Cross Flow Filtration). R * 1750 ml of water (system: Minitan, 700 cm ² polyethersufon membrane with an exclusion limit of 100 kD, manufactured by Millipore (USA)). The mixture was concentrated using the same system to 15 mg of the active ingredient by ultrafiltration. After addition of 1.24 mg / ml citric acid and 1.24 mg / ml disodium phosphate dihydrate to a pH of 4.2 and 1 mg / ml sorbic acid as an antimicrobial preservative, the dispersion is again concentrated to 15 mg / ml and filled. into glasses, for example 20 ml. The dispersed particles have a diameter of 0.1 to 2 µm. The dispersion is at a temperature of +2 to 8 ° C for at least half a year and is suitable for oral administration.

173 i UK- :.

Example 29

Dispersion 2 for oral administration

The preparation is carried out analogously to Example 28 except that 25 mg of the active ingredient and 50 mg of 1-hexadecanoyl-2- (9-cis-octadecenoyl) -3-sn-phosphatodylcholine are used. An ethanol solution was prepared.

Example 30

Dispersion 3 for oral administration

The preparation is carried out analogously to Example 23 except that 25 mg of the active ingredient and 125 mg of 1-hexadecanoyl-2- (9-cis-octadecenoyl) -3-sn-phosphatodylcholine are used. An ethanol solution was prepared.

Example 31

Dispersion 4 for oral administration

The preparation was carried out analogously to Example 28 except that 50 mg of the active ingredient and 50 mg of 1-hexadecanoyl-2- (9-cis-octadecenoyl) -3-sn-phosphatodylcholine were used. An ethanol solution was prepared.

Example 32

Dispersion 5 for oral administration

The preparation is carried out analogously to any one of Examples 23 to 31 except that the active ingredient and soybean phostatidylcholine or egg yolk phosphatidylcholine (purity 70-100%) are used to produce the ethanol solution.

174 instead of 1-hexadecanoyl-2- (9-cis-octadecenoyl) -3-sn-phosphatodylcholine. An antioxidant, such as ascorbic acid, is optionally added at a concentration of 5 mg / ml.

Example 33

Boe- (pF) Phe [C] (p-CF ₃ ) Phe- (L) -Val- (L) -Phe-morpholin-4-ylamide

In analogy to Example 1, 265 mg of 5 (S) - (Boc-amino) -4 (S) - (tert-butyldimethylsilyloxy) -6- (p-fluorophenyl) -2 (R) - (p- trifluoromethylphenylmethyl) hexanoyl- (L) -Val- (L) -Phemomorpholin-4-ylamide by treating 180 mg of tetrabutylammonium fluoride trihydrate in 4.2 mL of dimethylformamide to the title compound. DC Rf (I) 0.3; FAB-MS (M + H) &lt; ^{+ &gt}; = 815.

The starting compound is prepared as follows:

33a) 5 (S) - / 1 (S) - (Boc-amino) -2- (p-fluorophenyl) ethyl / -3 (R) - (p-trifluoromethylphenylmethyl) dihydrofuran-2- (3H) -one

Analogously to Example 21 (D) (1) (c), 1.0 g of 5 (S) - / 1 (S) - (Boc-amino) -2- (p-fluorophenyl) ethyl / dihydrofuran-2- (3H) is deprotonated -one dissolved in 6.3 mL of tetrahydrofuran, treated with 6.05 mL of 1 molar lithium bis (trimethylsilyl) amide in tetrahydrofuran and alkylated with 0.739 g of p-trifluoromethylbenzyl bromide (Fluka, Buchs, Switzerland) at -75 ° C (40 ° C). min). Column chromatography (silica gel, hexane / ethyl acetate 2: 1) affords the pure title compound. DC: _Rf (D) = 0.48; FAB-MS (M + H) ⁺ = 482nd

33b) 5 (S) - (Boc-amino) -4 (S) -hydroxy-6- (p-fluorophenyl) -2 (R) - (p-trimethylphenylmethyl) hexanoic acid

175

1.05 g of 5 (S) - / 1 (S) - (Boc-amino) -2- (p-fluorophenyl) ethyl / -3 (R) - (p-trimethylphenylmethyl) dihydrofuran are hydrolyzed in analogy to Example l1). Of 2- (3H) -one in 35.5 ml of dimethoxyethane and 17.9 ml of water by treating 8.7 ml of a 1 molar lithium hydroxide solution to the title compound, which is used directly below.

33c) 5 (S) - (Boc-amino) -4 (S) - (tert-butyldimethylsilyloxy) -6- (p-fluorophenyl) -2 (R) - (p-trimethylphenylmethyl) hexanoic acid

Analogously to Example 1j), 1.06 g of 5 (S) - (Boc-amino) -4 (S) -hydroxy-6- (p-fluorophenyl) -2 (R) - (p-trimethylphenylmethyl) acid is silylated. hexane in 2.3 ml of dimethylformamide by treating 1.47 g of tert-butyldimethylchlorosilane and 1.18 g of imidazole. Hydrolysis of the silyl ester function 1.76 g of potassium carbonate in 50 ml of a 3: 1: 1 mixture of methanol, tetrahydrofuran and water gave the title compound after column chromatography (silica gel, hexane: ethyl acetate 2: 1). DC (D) = 0.15, ¹ H-NMR (200 MHz, CD 3 OD): 7.59 and 7.39 (2d, 3 Hz, 2H each), 7.19 and 6.98 (2m, 2H each) 6.47 and 5.90 (d, about 9 Hz, common IH), 3.9-3.65 (m, 2H), 3.15-2.8 (m, 4H), 2.53-2 , 37, 2.07-1.9 and 1.6

- 1.4 (3m, each IH), 1.37-1.22 (m, 9H), 0.94 (s, 9H), 0.2

0.1 (m, 6H) ppm.

33d) 5 (S) - (Boc-amino) -4 (S) - (tert-butyldimethylsilyloxy) -6- (p-fluorophenyl) -2 (R) - (p-trifluoromethylphenylmethyl) hexanoyl- (L) -Val - (L) -Phe-morpholin-4-ylamide

Analogous to Example 9f), 180 mg of 5 (S) - (Boc-amino) -4 (S) - (tert-butyldimethylsilyloxy) -6- (p-fluorophenyl) -2 (R) - (p) acid is reacted. (Trifluoromethylphenylmethyl) hexane and 107.5 mg of H- (L) -Val- (L) -Phemomorpholin-4-ylamide (Example 1o) in 2.8 ml of 0.25 molar N-methylmorpholine in acetonitrile are treated with

176

122 mg of O-benztriazol-1-yl-N, N, N ¹ , N'-tetramethyluronium hexafluorophosphate. FAB-MS (M + H) &lt; ^{+ &gt}; = 929.

Example 34

Boe- (pF) Phe [C] (p-CF ₃ ) Phe- (L) -Val- (L) - (pF-Phe) -morpholin-4-ylamide

Analogously to Example 1, 270 mg of 5 (S) - (Boc-amino) -4 (S) - (tert-butyldimethylsilyloxy) -6- (p-fluorophenyl) -2 (R) - (p-trifluoromethylphenylmethyl) are converted. hexanoyl- (L) -Val- (L) - (pF-Phe) -morpholin-4-ylamide was treated with 180 mg of tetrabutylammonium fluoride trihydrate in 4.2 mL of dimethylformamide to give the title compound. DC Rf (I) = 0.2; FAB-MS (M + H) ^τ = 833.

The starting compound is prepared as follows:

34a) 5 (S) - (Boc-amino) -4 (S) - (tert-butyldimethylsilyloxy) -6- (p-fluorophenyl) -2 (R) - (p-trifluoromethylphenylmethyl) hexanoyl- (L) -Val - (L) - (pF-Phe) -morpholin-4-ylamide

Analogous to Example 9f), 180 mg of 5 (S) - (Boc-amino) -4 (S) - (tert-butyldimethylsilyloxy) -6- (p-fluorophenyl) -2 (R) - (p- trifluoromethylphenylmethyl) hexane (Example 33c) and 113.2 mg of H- (L) -Val- (L) - (pF-Phe) -morpholin-4-ylamide (Example 9e) in 2.8 mL of 0.25 molar N methyl morpholine in acetonitrile with 122 mg of O-benztriazol-1-yl-N, N, NN'-tetrarethyluronium hexafluorophosphate. FAB-MS (M + H) &lt; ^{+ &gt}; = 947.

Example 35

Boe- (p-F) Phe [C] (p-CF-j) Phe- (L) -Val- (L) - (p-CH-10-Phe) -morpholin-4-ylamide

177

Analogously to Example 1, 193 mg of 5 (S) - (Boc-amino) -4 (S) - (tert-butyldimethylsilyloxy) -6- (p-fluorophenyl) -2 (R) - (p-trifluoromethylphenylmethyl) are converted. hexanoyl- (L) -Val- (L) - (p-CH ₃ O-Phe) -morpholin-4-ylamide by treating 127 mg of tetrabutylammonium fluoride trihydrate in 3 mL of dimethylformamide to the title compound. DC Rf (I) = 0.47; FAB-MS (M + H) &lt; ^{+ &gt}; = 845.

The starting compound is prepared as follows:

35a) 5 (S) - (Boc-amino) -4 (S) - (tert-butyldimethylsilyloxy) -6- (p-fluorophenyl) -2 (R) - (p-trifluoromethylphenylmethyl) hexanoyl- (L)-Val - (L) - (p-CH-10-Phe) -morpholin-4-ylamide

Analogous to Example 9f), 180 mg of 5 (S) - (Boc-amino) -4 (S) - (tert-butyldimethylsilyloxy) -6- (p-fluorophenyl) -2 (R) -acetic acid are reacted. - (p-trifluoromethylphenylmethyl) hexane (Example 33c) and 117.2 mg of H- (L) -Val- (L) - (p-CH ₃ O-Phe) -morpholin-4-ylamide (Example 10e) in 2.8 ml of 0.25 molar N-methylmorpholine in acetonitrile with 122 mg O-benztriazol-1-yl-N, N, N ¹ , N ¹ -tetramethyluronium hexafluorophosphate FAB-MS (M + H) + = 959.

Example 36

Morpholinosulfonyl- (L) -Val-Phe (C) (p-CF-j) Phe- (L) -Val- (L) -Phe-morpholin-4-ylamide

Analogously to Example 5, 102 mg of N-morpholinosulfonyl- (L) -Val in 4 ml of dimethylformamide was activated with 186 mg of benztriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, 57 mg of 1-hydroxybenztriazole and 0.09 ml of N-methylmorpholine; was reacted with 200 mg of H-Phe [C] Phe- (L) -Val- (L) -Phemomorpholin-4-ylamide (Example 4) in 1 mL of dimethylformamide to give the title compound. Pour the reaction mixture into water, ex

178 is triturated several times with ethyl acetate (a highly soluble substance) and washed with water, saturated sodium bicarbonate solution and saturated sodium chloride solution. Stirring the crude product in ether affords the pure title compound. FAB-MS (M + H) &lt; ^{+ &gt}; = 877.

The starting compound is prepared as follows:

36a) N-Chlorosulfonylmorpholine

With vigorous cooling, 32.7 ml of sulfuryl chloride is added to 23.5 ml of morpholine at a temperature of about 0 ° C. Thereafter, the suspension is carefully heated to 60 ° C, whereupon the development of hydrogen chloride occurs. After 5 hours at 60 ° C the development of hydrogen chloride is complete. The cooled brown reaction mixture is poured onto ice, the separated oil is extracted with ether, washed with water, 5% sodium bicarbonate solution and water and dried over sodium sulfate. Distillation of the evaporated organic phase at elevated temperature (90 ° C) and reduced pressure (100 Pa) affords the title compound. 1 H-NMR (200 MHz, DMSO-d 6): 3.80 and 3.29 (2t, 5 Hz, 4H each) ppm.

36b) N-Morpholinosulfonyl- (L) -Val

To 6.3 g of N'-chlorosulfonylmorpholine in 20 ml of tetrahydrofuran was added dropwise 2 g of (L) -valine dissolved in 50 ml of 1N sodium hydroxide solution and stirred for 17 hours at room temperature. The yellow emulsion was contacted with 15 ml of 1N sodium hydroxide solution and extracted with ether. The aqueous phase was acidified with 2 N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate phase is dried over sodium sulphate and evaporated. Crystallization from ether gave the by-product as determined by 1 H-NMR spectral analysis. The pure title compound is obtained by crystallization of the filtrate residue from hexane. DC R _c (F) = 0.25.

179

Example 37

Morpholinosulphonyl 1-Phe [C] Phe- (L) - Val- (L) -Phe-morpholin-4-ylamide

A solution of 200 mg of H-Phe [C] Phe- (L) -Val- (L) -Phemomorpholin-4-ylamide (Example 4) in 5 ml of dimethylformamide was contacted with 0.13 of 2 ml of triethylamine and 71 mg. Of N-chlorosulfonylmorpholine (Example 36a) in 1 mL of DMF. Since H-Phe mistC] Phe- (L) -Val- (L) -Phe-morpholine is still present after 2 hours at room temperature, thin-layer chromatography is still present; lin-4-ylamide, 71 mg of N-chlorosulfonyl in morpholine was added once more. The reaction mixture is poured into water after 18 hours, extracted with 3 parts of ethyl acetate, washed with saturated sodium bicarbonate solution, water and saturated sodium chloride solution, dried over sodium sulfate and evaporated. Column chromatography (silica gel, methylene chloride / methanol = 1/9: 1) gives the pure title compound. DC Rf (F) = 0.60; FAB-MS (M + H) &lt; ^{+ &gt}; = 778.

J í

and

f.

s! Example 38

Jr.

X.

N- (N- (2-Pyridylmethyl) -N-methylaminocarbonyl) - (L) -Val-Phe [C] Phe- (L) -Val- (L) -Phemomorpholin-4-ylamide

J Analogously to Example 5, 152 mg of N- [N- (2-pyridylmethyl) -N'-methylaminocarbonyl] - (L) -valine (see European Patent No. 402 646 A1 of 19 December 1990) in 5>.

1 ml dimethylformamide activates 279 mg benztriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, 85 mg 1-hydroxy ·

With droxybenzotriazole and 0.132 ml of 1-methylmorpholine and allowed to react. with 300 mg of H-Phe [C] Phe- (L) -Va 1- (L) -Phe-morpholin-4-ylamide

J (Example 4) to the title compound. Column chromatography (silica gel, ethyl acetate / acetone (180: 9 to acetone)) afforded the title compound after digestion with ether. DC Rf (F) = 0.28; FAB-MS (M + H) &lt; ^{+ &gt}; = 876.

Example 39 5 (S) - (Boc-amino) -4 (S) - (acetoxy) -6-phenyl-2 (R) -phenylmethylhexanoyl- (L) -Val- (L) -Phemomorpholin-4-ylamide

To 400 mg of Boc-Phe [C] Phe- (L) -Val- (L) -Phemomorpholin-4-ylamide (Example 2) in 8 ml of tetrahydrofuran was added 0.114 ml of triethylamine, 1 mg of dimethylaminopyridine and 0.08 ml. acetic anhydride. After stirring for 30 minutes at room temperature, the colorless solution is poured onto water and extracted with 3 portions of ethyl acetate. The organic phases are washed with water, saturated sodium bicarbonate solution, water and saturated sodium chloride solution, dried over sodium sulfate and evaporated to give the title compound which is purified by column chromatography (silica gel, hexane / ethyl acetate 1: 2). state. DC Rf (B) = 0.59; rAB-MS (M + H) &lt; ^{+ &gt}; = 771.

Example 40

In a similar manner, as in any of the foregoing examples, the following compounds are produced:

A) Boc- (p-CF ₃ ) Phef C] Phe- (L) -Val- (L) -Phe-morpholin-4-ylamide

B) Boc- (p-CF) Phel C} Phe- (L) -Val- (L) - (p-F) Phe-morpholin-4-ylamide

C) Boc- (p-CF 3) Phe C; Phe- (L) -Val- (L) - (p-CH ₃ O) Phe-morpholin-4-ylamide

D) Boe- (p-CF ₃ ) Phef C] Phe- (L) -Val- (L) -Cha-morpholin-4-ylamide

E) Boc- (p-Cr ₃ ) Phel C] Phe- (L) -Ile- (L) -Phe-morpholin-4-ylamide

181

F) Boc- (p-CF ₃ ) Phe [C] (pF) Phe- (L) -Val- (L) -Phe-morpholin-4-ylamide

G) Boc- (p-CF ₃ ) Phe [C] (pF) Phe- (L) -Val- (L) - (pF) Phe-morpholin-4-ylamide

H) Boc- (p-CF ₃ ) Phe [C] (pF) Phe- (L) -Val- (L) -Cha-morpholin-4-ylamide

I) Boe- (P-CF ₃ ) Phe [C] (pF) Phe- (L) -Val- (L) - (p-CH ₃ O) Phe-morpholin-4-ylamide

J) Boc- (p-CF 3) Phe [C] (p-F) Phe- (L) -Ile- (L) -Phe-morpholin-4-ylamide

C) Boc- _(p-CF3) Phe [C] _(p-CF3) Phe- (L) -Va1- (L) -Phe-morpholin-4-ylamide

L) Boc- _(p-CF3) Phe [C] _(p-CF3) Phe- (L) -Val (L) - (pF) -Phe-morpholin-4-ylamide

M) Boc- (p-CF ₃ ) Phe 1 C] (p-CF ₃ ) Phe- (L) -Ile- (L) -Phe-morpholin-4-ylamide

N) Boc- (p-CF ₃ ) Phe [C i (p-CF ₃ ) Phe- (L) -Val- (L) - (p-CH ₃ O) Phe-morpholin-4-ylamide

O) Boc- (d-CF ₃ ) Phe [C 1 (p-CF ₃ ) Phe- (L) -Val- (L) -Cha-morpholin-4-ylamide

P) Compounds according to the above Examples A) to O) wherein the morpholin-4-ylamide residue is replaced by a thiomorpholin-4-ylanide residue.

The starting compound is prepared as follows:

40a) N-Allylformamide

A solution of 300 ml of allylanine in 1288 ml of ethyl formate was heated at 60 ° C for 8 hours. The reaction mixture was evaporated on a rotary evaporator and the residue was distilled on a Vigreux distillation column (temperature 77 c, 100 Pa). ¹ H-NMR (200 MHz, CDCl 3): 8.2-7.95 (m, 1H), 6.5

182

5.8 (broad singlet, 1H), 5.9-5.7 (m, 1H), 5.3-5.05 (m, 2H), 3.95-3.75 (m, 2H) ppm .

40b) Allylisocyanide (Proceed as described by U. Schollkopf, R. Jentsch,

K. Madawinata and R. Harms in Liebigs Ann. Chem. 2105 (1976). 517 g of quinoline and 286 g of p-toluenesulfonic acid chloride are introduced under a nitrogen atmosphere. In the system, the vacuum is adjusted to 200 to 400 Pa and 85 g of N-allylformamide are added dropwise, the resulting isocyanide being removed by continuous distillation at an internal temperature of 85-95 ° C on a Vigreux distillation column into a cooled sample (acetone with dry ice). After the reaction was complete, the distillate was distilled once more through a Vigreux distillation column (under a nitrogen atmosphere at normal pressure at 100 ° C). 1 H-NMR (200 MHz, CDCl ₃ ): 5.9-5.7 (m, 1H), 5.45 (d, 16 Hz, 1H), 5.32 (d, 10 Hz, 1H), 4 , 05 (m, 2H) ppm, IR (CH ₂ Cl ₂ ): 2150, 1650 cm ^-1 .

40c) rac.-1- (p-Trifluoromethylphenyl) -3-buten-2-amine

4.5 g of allyl isocyanide are dissolved in 100 ml of a 4: 1: 1 mixture of tetrahydrofuran, ether and pentane under a nitrogen atmosphere and the solution is cooled to -100 ° C. 42 ml of a 1.6 molar solution of n-butyllithium in hexane are added dropwise to the solution at -100 to -90 ° C, at which point a yellow color of the solution first occurs and a solid precipitates shortly before the addition group. The reaction mixture is allowed to warm slowly to -70 ° C and then cooled again to -100 ° C. At a temperature between -100 and -85 ° C, a solution of 16 g of p-trifluoromethylbenzyl bromide (Fluka, Buchs, Switzerland) in 10 ml of tetrahydrofuran is added dropwise to the reaction mixture and allowed to warm slowly to room temperature. The reaction mixture is evaporated on a rotary evaporator (at a pressure of 8 kPa and a temperature of 30 ° C), the residue is poured onto 150 ml of ice-water and extracted three times with ether. The ether phase is evaporated,

The 183-brown residue was treated with 85 ml of methanol and 17 ml of concentrated hydrochloric acid at 0 DEG C. and left in the refrigerator overnight. The mixture was evaporated on a rotary evaporator and the residue was partitioned between 2 x 150 ml 2M hydrochloric acid and 2 x 200 ml ether each time. The combined aqueous phases were made basic with solid sodium hydroxide cooling and extracted with 3 parts of ethyl acetate. Washing the organic phase with saturated sodium chloride solution, drying over sodium sulfate, evaporation, and limestone distillation (10 Pa, 170 ° C) affords the pure title compound. 1 H-NMR (200 MHz, CDCl ₃ ): 7.56 and 7.32 (2d, 8 Hz, 2H each), 5.96-5.78 (m, 1H), 5.19-5.02 ( m, 2H), 3.68-3.55 · (m, 1H), 2.87 and 2.71 (AB xd, J _ab = 13 Hz, J ₁ = 6 Hz, J ₂ = 8 Hz, 2H) 1.4 (broad singlet, 2H) ppm.

Other reactions analogous to Examples 1d) to 1k), and 1), 9f) and 9,10f) and 10, 15a) and 15 or 16c) and 16 result in the compounds mentioned in a) to 1c above. about).

I

J>

Example 41 The following compounds were prepared in an analogous manner to the foregoing examples:

A) Boc-Phe [C] Phe- (L) -Val- (L) -Tyr-morpholin-4-ylamide

b) Boc-Tyr [C] Phe- (L) -Val- (L) -Phe-morpholin-4-ylamide

c) Boc-Tyr [C] Phe- (L) -Va1- (L) -Tyr-morpholin-4-ylamide

d) Boc-Phe [C] Tyr- (L) -Val- (L) -Phe-morpholin-4-ylamide

e) Boc-Phe [C] Tyr- (L) -Val- (L) -Tyr-morpholin-4-ylamide _; f) Boc-Tyr [C] Tyr- (L) -Val- (L) -Phe-morpholin-4-ylamide

'. g) Boc-Tyr [C] Tyr- (L) -Val- (L) -Tyr-morpholin-4-ylamide; h) compounds according to the above examples a) to h), wherein the morpholin-4-ylamide residue is replaced by a thiomorpholin-4-yl amide residue.

Claims (16)

Pharmaceutically active compounds of the general formula I (I), in which R _q is hydrogen, (lower alkoxy) carbonyl, heterocyclylcarbonyl, benzyloxycarbonyl optionally substituted with one to three radicals independently of one another selected from fluorine, halogen (lower alkyl), lower alkanoyl, sulfo, (lower alkyl) sulfonyl and cyano, heterocyclyloxycarbonyl wherein the heterocyclyl moiety is attached via a carbon atom, one of said carbonyl moieties in which the linking carbonyl group is replaced by a thiocarbonyl group, heterocyclylsulfonyl, (lower alkyl) sulfonyl, or N- (heterocyclyl (lower alkyl)) / -N- (lower alkyl) aminocarbonyl means a bond or a bivalent radical derived from an α-amino acid whose terminal nitrogen atom is linked to R ₁ and the terminal carbon atom is linked to an amino group on a carbon atom containing R ₂ -CH ₂ -, R ₂ and R Znamenaj! independently of each other phenyl or cyclohexyl, wherein these radicals are optionally substituted by one to three radicals independently of one another selected from hydroxy, lower alkoxy, halogen, halogen (lower alkyl), sulfo, (lower) 185 alkyl) sulfonyl groups, cyano and nitro groups, means a bond between -C = O and A ₂ or a bivalent radical derived from an α-amino acid which is attached at the terminal nitrogen atom to the -C = O group and the terminal carbon atom is attached to A ₂ a A ₂ represents a bivalent radical derived from an α-amino acid which is linked at the terminal nitrogen atom of A 4 and the terminal carbon atom is linked to the NR ₄ R _{5 group} or and A ₂ together form the bivalent radical of the dipeptide whose central amide bond is reduced; the terminal nitrogen atom is linked to the group -C = O and the terminal carbon atom is linked to the group NR ₄ R 8 and R ₄ and R ₅ together with the nitrogen-binding atom represent optionally substituted thiomorpholino or p-olino, or salts thereof, if they contain groups capable of forming salts, or derivatives of such compounds or salts thereof, which contain a protected hydroxy group. A compound of formula I according to claim 1, wherein R 1 is hydrogen, (lower alkoxy) carbonyl, heterocycliccarbonyl, benzyloxycarbonyl optionally substituted with one to three radicals independently of one another selected from fluoro, halogen (lower alkyl), lower alkanoyl, sulfo, (lower alkyl) sulfonyl and cyano, or heterocyclyloxycarbonyl wherein the heterocyclyl moiety is attached via a carbon atom, or one of said carbonyl moieties in which the linking carboryl group is replaced by a thiocarbonyl group, Bj 186 is a bond or bivalent radical derived from an α-amino acid whose terminal nitrogen atom is linked to and the terminal carbon atom is linked to an amino group on a carbon atom containing R ₂ -CH ₂ -, R ₂ and R ₃ independently of each other phenyl or cyclohexyl; wherein these radicals are optionally substituted by one to three radicals selected from halogen, halogen (lower alkyl), sulfo, (lower alkyl) sulfonyl, cyano and nitro, Αχ represents a bond between -C = O and A ₂ or a bivalent radical derived from an α-amino acid whose terminal nitrogen atom is linked to the group -C = O and the terminal carbon atom is linked to A ₂ , A ₂ is a bivalent radical derived from the α-amino acid whose terminal nitrogen atom is linked to Αχ and the terminal carbon atom is associated with a group of ir, R ₅ and Αχ and _A2 together form a bivalent radical of a dipeptide, of which the central amide bond is reduced and the terminal nitrogen atom is linked with the radical -C = O and the terminal carbon atom being linked to the group of the formulas NR ₄ R ₅ and R ₄ and R ₅ together with the binding nitrogen atom are optionally substituted thiomorpholino or morpholino, or salts thereof if they contain salt-forming groups. A compound of formula I according to claim 1, wherein R 1 is hydrogen, (lower alkoxy) carbonyl, heterocyclylcarbonyl, benzyloxycarbonyl optionally substituted with one to three radicals independently of one another selected from fluorine, halogen (lower alkyl), lower alkanoyl, sulfo, (lower alkyl) sulfonyl and cyano, or heterocyclyloxycarbonyl, wherein the heterocyclyl moiety is attached via a carbon atom, or one of said carbonyl moieties in which the linking carbonyl group is replaced by a thiocarbonyl group, heterocyclylsulfonyl, (lower alkylsulfonyl, or N- (heterocyclyl (lower alkyl)) - N - (lower alkyl) aminocarbonyl, Βχ means a bond or bivalent radical derived from α-amino acid, the terminal nitrogen of which is linked to Rχ 187 and the terminal carbon atom is linked to an amino group on a carbon atom containing R ₂ -CH ₂ -, R ₂ and R ₃ independently of one another being phenyl or cyclohexyl, these radicals being optionally substituted by one to three radicals independently of one another selected from hydroxy, methoxy, halogen, halogen (lower alkyl), sulfo, (lower alkyl) sulfonyl, cyano, and nitro, A 4 represents a bond between -C = O and A ₂ or a bivalent radical derived from an α-amino acid whose terminal atom nitrogen is linked to the group -C = O and the terminal carbon atom is linked to A ₂ , A ₂ is a bivalent radical derived from α-amino acid whose terminal nitrogen atom is linked to A 2 and the terminal carbon atom is linked to the "NR" group R 8, or A 1 and A ₂ together form a bivalent radical of the dipeptide, whose central amide bond is reduced and the terminal nitrogen atom is linked to the group -C = O and the terminal carbon atom is linked to the group with the formulas NR ₄ R ₅ and R ₄ and R ₅ together with the nitrogen bonding atom represent optionally substituted morpholino or salts thereof, provided that i contains salt-forming groups, wherein the hydroxy group in the compounds of formula I on a carbon atom which is gray with the carbon atom bearing the group R ₂ -CH ₂ - is in the Free or protected form. • J A compound of formula I according to claim 3, wherein z R? Is heterocyclylsulfonyl, (lower alkyl) ^sulphonyl: or a group N / heterocyclic (lower alkyl) / - N- (lower alkyl) aminocarbonyl, and the remaining radicals have the meanings indicated, or a salt thereof, if they contain groups capable of forming salt. A compound of formula I according to claim 2, wherein R @ 1 is hydrogen, (lower alkoxy) carbonyl, heterocyclylcarbonyl, benzyloxycarbonyl, optionally substituted with one to three radicals independently of one another selected from fluorine, halogen (lower alkyl), lower alkanoyl, sulfo, (lower alkyl) sulfonyl and cyano, or heterocyclyloxycarbonyl, wherein the heterocyclyl moiety is attached via a carbon atom, or one of said carbonyl radicals in which the linking carbonyl group is replaced by a thiocarbonyl group, Bj represents a bond or a bivalent radical derived from an α-amino acid, wherein the terminal nitrogen atom is linked to R 1 and the terminal carbon atom is linked to an amino group on a carbon atom containing R ₂ -CH ₂ -, R ₂ and R ₃ are each independently phenyl or cyclohexyl, these radicals being optionally substituted by one to three residues selected from halo logene, halogen (lower alkyl); A is a bond between -C = O and A ₂ or a bivalent radical derived from an α-amino acid whose terminal nitrogen atom is linked to the group -C = 0 and the terminal carbon atom is linked to A ₂ , A ₂ is a bivalent radical derived from an α-amino acid whose terminal nitrogen atom is connected to A ₁ and the terminal carbon atom is connected to NR ₄ R ₅ , or A ₂ and A ₂ together form a bivalent radical of the dipeptide whose central amide bond is reduced: and the terminal nitrogen atom is linked to the group -C = O and the terminal carbon atom is linked to the group of the formulas NR ₄ R ₅ and R ₄ and R ₅ together. a nitrogen-binding atom or a substituted morpholino group, or a salt thereof, if they contain salt-forming groups. J? 6. A compound of formula I according to claim 1, wherein the at least one of the radicals R ₂ or R ₃ is the residue of an optionally <substituted by one to three groups selected from a hydrogen haloJ the gene, halo (lower alkyl), sulfo, (lower alkyl i) sulfonyl, cyano and nitro; and the remainder of the residues R 1, B 1, A ₂ , A ₂ and R _{4 of} R 8 have the aforementioned meanings, or salts thereof, if it contains salt-forming groups. 189 A compound of the formula I as claimed in claim 1, wherein hydrogen is t-butoxycarbonyl, isobutoxycarbonyl, pyridine-3-carbonyl, morpholinocarbonyl, 3-benzofuranoyl, 1,2,3,4-tetrahydroisoquinoline-3-carbonyl, up to three. independently of one another of a fluorine atom, a halogen (lower alkyl) group, a lower alkanoyl group, a sulfo group, a (lower alkyl) sulfonyl group and a cyano group substituted by benzyloxycarbonyl or heterocyclyloxycarbonyl radicals, wherein the heterocyclyl moiety is attached via a carbon atom and selected from pyrrolyl; , imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyrazinyl, pyrimidinyl, indolyl, chitolyl, isoquinolyl, quinoxalinyl, β-carbolinyl and wholly or partially saturated derivative of this series, morpholinosulfonyl or H- (2-pyridylmethyl) -N-methylaminomethyl-N- , B _{1 '} represents a bond or a divalent radical derived from an α-amino acid where the terminal nitrogen atom is linked to the terminal carbon atom a group on a carbon atom bearing a group of the formula R ₂ -CH ₂ -, R ₂ and R ₃ are each independently phenyl or cyclohexyl, these radicals being optionally substituted With one or two radicals independently of one another selected from a hydroxy group, a methoxy group, a fluorine atom, a sulfo group, <RTIgt; 5 </RTI> alkylsulfonyl, trifluoromethyl and cyano, means a bivalent radical derived from the hydrophobic .alpha.-amino- 3 of an acid whose terminal nitrogen atom is linked to a group i of the formula -C = O and the terminal carbon atom is linked to A ₂ , A ₂ is? a bivalent radical derived from a hydrophobic α-amino acid, wherein the terminal nitrogen atom is linked to A, and the terminal carbon atom X k is linked to a group of the formula NR ₄ R _g , or A 2 and A ₂ together form the bivalent radical of the dipeptide two hydrophobic α-amino acids, whose central amide bond is reduced and the terminal nitrogen atom is bonded to a group of formula -C = O and equine Driver-4 carbon atom is bound to a group of the formula NR ₄ R _5, and R ₄ and R _g, together with the binding nitrogen atom thiomorfoli- * or a morpholino group, or a pharmaceutically acceptable salt thereof if it contains groups capable of you 190 pressed into shape salt, the hydroxyl group in the compounds of formula I at the carbon atom adjacent to the carbon bearing the group R 2 ^-C 2 ^- "is a free or protected form of a lower alkanoyl group. A compound of formula I according to claim 5, wherein R 6 represents a hydrogen atom, tert-butoxycarbonyl, isobutoxycarbonyl, pyridine-3-carbonyl, morpholinocarbonyl, 3-benzofuranoyl, 1,2,3,4-tetrahydroisoquinoline-3-carbonyl, up to three independently of one another of fluorine atom, halogen (lower alkyl) group, lower alkanoyl group, sulfo group, (lower alkylsulfonyl group and cyano group substituted benzyloxycarbonyl or heterocyclyloxycarbonyl by selected radicals) the heterocyclyl moiety is attached through a carbon atom and is selected from pyrrolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolinyl, quinoxalinyl, β-carbolinyl, or a fully or partially saturated derivative thereof, a divalent radical derived from an α-amino acid whose terminal nitrogen atom is linked to R and the terminal carbon atom of the amino group on a carbon atom carrying a group of the formula R ₂ CH ₂ ", R ₂ ^{and R} 3 ^friend find independently of the other phenyl or cyclohexyl, wherein these radicals are optionally substituted by one or two radicals independently of one another selected from t and t He fluorine, sulfo, (lower alkyl) sulfonyl and cyano, A · ^ is a bivalent radical of a hydrophobic α-amino acid whose terminal nitrogen atom is linked to the group -C = 0, and the terminal carbon atom is linked to A _2, A ₂ is a bivalent radical derived from a hydrophobic α-amino acid whose terminal nitrogen atom is linked to A ₁ and the terminal carbon atom is linked to a group of formula NR ₄ R ₅ , or A 1 and A ₂ together form the bivalent radical of the dipeptide from two hydrophobic α amino acids whose central amide bond is reduced and the terminal nitrogen atom is bonded to a group of formula -C = O and the terminal carbon atom is bonded to a group of formula NR ₄ R 8, and R ₄ and R 8 together form 191 or a pharmaceutically acceptable salt thereof, provided that it contains salt-forming groups. A compound of formula I according to claim 1, wherein R 1 is hydrogen, tert-butoxycarbonyl, isobutoxycarbonyl, pyridine-3-carbonyl, morpholinocarbonyl, 3-benzofuranoyl, 1,2,3,4-tetrahydroisoquinoline-3-carbonyl, morpholinosulfonyl or N- (2-pyridylmethyl) -N-methylaminocarbonyl means a bond or a divalent radical derived from the α-amino acid valine whose terminal nitrogen atom is linked to the terminal carbon atom with an amino group on a carbon atom bearing the group R ₂ , CH ₂ -, R ₂ ^{and R} 3 is independently of one another phenyl or cyclohexyl, wherein these radicals are optionally substituted by one or two radicals independently of one another selected from hydroxy, methoxy, fluorine, sulfo, (lower alkylsulfonyl, trifluoromethyl and cyano), A ^ is a bivalent radical derived from the α-amino acid glycine, valine or isoleucine, the terminal nitrogen of which is linked to the group -C = O and the terminal carbon atom is linked to A ₂ , ₂ is a bivalent radical derived from a-amino acids glycine, valine, phenylalanine, tyrosine, cyclohexylalanine, p-methoxyphenylalanine and p-fluorophenylalanine, the the terminal nitrogen atom is linked to the N terminal carbon atom and is a group of the formula spo.jen NR ₄ R _5, and also N, and A ₂ together are a bivalent radical of a dipeptide having a reduced central peptide bond that consists of an amino acid radical at the terminal carbon a nitrogen selected from Gly (red), Val (red) or Ile (red) and an amino acid radical at the terminal carbon atom selected from glycine, phenylalanine, cyclohexylalanine, tyrosine, p-methoxyphenylalanine or p-fluorophenylalanine and whose terminal nitrogen atom is bonded of formula -C = O and the terminal carbon atom is bonded to a group of formula NR ₄ R ₅ , and R ₅ and R ₅ together with the bonding nitrogen atom form a thiomorpholino or morpholino group, or pharmaceuticals The salts of this compound may be useful as long as they contain salt-forming groups. A compound of formula (I) according to claim 1, wherein R _T is hydrogen, tert-butoxycarbonyl, isobutoxycarbonyl, pyridine-3-carbonyl, morpholinocarbonyl, 3-benzofuranoyl, 1,2,3,4-tetrahydroisoquinoline-3-carbonyl, morpholinosulfonyl or N- (2-pyridylmethyl) -N-methylaminocarbonyl means a bond or a bivalent radical derived from the α-amino acid valine whose terminal nitrogen atom is linked to the terminal carbon atom with an amino group on a carbon atom carrying a pattern- R ₂ -CH ₂ -, R ₂ and R ₃ are each independently phenyl or cyclohexyl, and these radicals are optionally substituted by one or two radicals independently of one another selected from hydroxy, methoxy, fluorine, trifluoromethyl and cyano , and A ₂ together form the bivalent radical j of the dipeptide Val-Phe, Ile-Phe, Val-Cha, Ile-Cha, Val-Gly, 3 Val-Val, Val-Gly, Val (pF-Phe), Val- (p-CH ₃ O-Phe) and Gly (pF-Phe), Val-Tyr, or a derivative thereof having a reduced central .I an amide bond of the formula Val (red) -Phe, whose terminal J is a nitrogen atom bonded to a group of formula -C = O and a terminal atom Carbon is bonded to a group of formula NR ₄ R ₅ , and R ₄ and R ₅ form 4 together with a bonding nitrogen atom, a thiomorpholino or a morpholino group, or a pharmaceutically acceptable salt thereof Γ compounds, if they contain salt-forming groups, wherein the hydroxy group in the compounds of formula I on the carbon atom adjacent to the carbon atom bearing the group R ₂ -CH ₂ -, is free or in a form protected by lower acetyl. Ί OJ A compound of formula I according to claim 10, wherein IN· ;; R 1 represents morpholinosulfonyl or N- (2-pyridylmethyl) -N-methylaminocarbonyl and the remainder of the radicals have the meanings indicated, or a pharmaceutically acceptable salt thereof, when containing J pins able to form salt. 193 A compound of formula I according to claim 1, wherein R ₁ is tert. butoxycarbonyl, B ₁ is a bond, R ₂ and R ₃ are phenyl, A 1 is valine, A ₂ is phenylalanine, and R ₄ and R ₅ together with the nitrogen bonding atom form a morpholino group. A compound of formula (I) according to claim 1, which is selected from compounds with the designation Boc-Cha [C] (p-F) Phe- (L) -Ile- (L) -Phe-morpholin-4-ylamide, Boe- (pF) Phe- (pF) Phe- (L) -Val- (L) -Phe-morpholin-4-ylamide, Boe- (pF) Phe-C1 (pF) Phe- (L) -Val - (L) - (pF-Phe) -morpholin-4-ylamide, Boe- (p-F) Phe-C] (p-F) Phe- (L) -Val- (L) - (p-CH-10-Phe) -morpholin-4-ylamide, Boe- (pF) Phe-C] (pF) Phe- (L) -Val- (L) -Cha-morpholin-4-ylamide, Boe- (pF) Phe-C] (pF) Phe- (L) - White- (L) -Phe-morpholin-4-ylamide, Boe- (pF) Phe [C] (p-CN) Phe- (L) -Val- (L) -Phe-morpholin-4-ylamide, Boe- (pF) Phe [C] (p-CN) Phe- (L) -Val (L) - (pF-Phe) -morpholin-4-y1amid, Boe- (pF) Phe [C] (p-CN) Phe- (L) -Val- (L) - (p-CH ₃ O-Phe) -morpholin-4-ylamide, Boe- (pF) Phe- (p-CN) Phe- (L) -Val- (L) -Cha-morpholin-4-ylamide, Boc- (pF) Phe Ph C] (p-CN) Phe- ( L) -I- (L) -Phe-morpholin-4-ylamide, Boc-Phe [C1 (pF) Phe- (L) -Val- (L) -Phe-morpholin-4-ylamide, Boc-Phe [C] (pF) Phe- (L) -Val- (L) - (pF-Phe) -morpholin-4-ylamide, Boc-Phe [C] (pF) Phe- (L) -Val- (L) - ( p-CH ₃ O-Phe-morpholin-4-ylamide, Boe-PheΓ C] (pF) Phe- (L) -Val- (L) -Cha-morpholin-4-ylamide, Boc-Phe [C] (pF) Phe- (L) -le- (L) -Phe -morpholin-4-ylamide, Boc-Phe [p] (p-CN) Phe- (L) -Val- (L) -Phe-morpholin-4-ylamide, Boc-Phe [p] (p-CN) Phe - (L) -Val- (L) - (pF-Phe) -morpholin-4-ylamide, Boc-Phe [C] (p-CN) Phe- (L) -Val- (L) - (p-CH) _3- O-Phe-morpholin-4-ylamide, Boc-Phe [C] (p-CN) Phe- (L) -Val- (L) -Cha-morpholin-4-ylamide, Boc-PheΓ C] (p-CN) Phe- (L) -Ile- ( L) -Phe-morpholin-4-ylamide, 194 Boc-Phe [C] (p-CH ₃ O) Phe- (L) -Val- (L) -Phe-morpholin-4-ylamide, Boc-Phe [C] (p-CH ₃ O) Phe- (L) ) -Val (L) - (pF-Phe) -morpholin-4-ylamide, Boc-Phe [C] (p-CH ₃ 0) Phe- (L) -Val- (L) - (p-CH ₃ 0-Phe) -morpholin-4-ylamide, Boc-Phe [C] (p-CH ₃ O) Phe- (L) -Val- (L) -Cha-morpholin-4-ylamide, Boc-PhelC] (p-CH ₃ O) Phe- (L) - β- (L) -Phe-morpholin-4-ylamide, Boc-Phe [C] (p-CF ₃ ) Phe- (L) -Val- (L) -Phe-morpholin-4-ylamide, Boc-Phe [ C] (p-CF ₃ ) Phe- (L) -Val- (L) - (pF-Phe) -morpholin-4-ylamide, Boc-Phe [C] (p-CF ₃ ) Phe- (L) - Val- (L) - (p-CH ₃ O-Phe) -morpholin-4-ylamide, Boc-Phe [C] (p-CF ₃ ) Phe- (L) -Val- (L) -Cha-morpholin-4-ylamide, Boc-Phe [C] (p-CF ₃ ) Phe- (L) - Ile- (L) -Phe-morpholin-4-ylamide, Boc-Cha [C] (p-CN) Phe- (L) -Val- (L) -Phe-morpholin-4-ylamide, Boc-Cha [C] (p-CN) Phe- (L) -Va 1- (L) - (pF-Phe) -morpholin-4-ylamide, Boc-Cha [C] (p-CN) Phe- (L) -Val - (L) - (p-CH ₃ O-Phe) -morpholin-4-ylamide, Boc-Cha [C] (p-CN) Phe- (L) -Val - (L) -Cha-morpholin-4-ylamide, Boc-Cha [C] (p-CN) Phe- (L) -Ile - (L) -Phe-morpholin-4-ylamide, Boc-Cha [C] (p-CH ₃ O) Phe- (L) -Val- (L) -Phe-morpholin-4-ylamide, Boc-Chaf C] (p-CH-10) Phe- (L) -Val- (L) - (pF-Phe) -morpholin-4-yl amide, Boc-Cha [C] (p-CH ₃ O) Phe- (L) -Val- (L) - (p-CH ₃ O-Phe) -morpholin-4-ylamide, Boc-ChaΓC] (p-CH ₃ O) Phe- (L) -Val- (L) -Cha-morpholin-4-ylamide, Boc-Cha [C] (p-CH ₃ O) Phe- (L) - Ile (L) -Phe-morpholin-4-ylamide, Boc-Cha [C] (p-CF ₃ ) Phe- (L) -Val- (L) -Phe-morpholin-4-ylamide, Boc-Cha [C] (p-CF ₃ ) Phe- (L) -Val- (L) - (pF-Phe) -morpholin-4-ylamide, Boc-Cha [C] (p-CF ₃ ) Phe- (L) -Val- (L) - (p-CH ₃ O-Phe) -morpholin-4-ylamide, Boc-Cha [C] (p-CF ₃ ) Phe- (L) - Val- (L) -Cha-morpholin-4-ylamide, Boc-Cha [C] (p-CF ₃ ) Phe- (L) -Ile- (L) -Phe-morpholin-4-ylamide, Boe- (L) -Val-Phe [C] Phe- (L) - Val- (L) -Phe-morpholin-4-ylamide, H- (L) -Val-Phe [C] Phe- (L) -Val- (L) -Phe-morpholin-4-ylamide, Boc-Phe 1 ' C] Phe (L) -Val (L) -Phe-morpholin-4-ylamide, 195 Boc-Phe [C] Phe- (L) -Val (red) - (L) -Phe-morpholin-4-ylamide, isobutoxycarbonyl-Phe [C] Phe- (L) -Val- (L) -Phe-morpholine 4-ylamide, Boc-Cha [C] (p-CN) Phe- (L) -Val- (L) -Phe-thiomorpholin-4-ylamide, Boc-Cha [C] (pF) Phe- (L) -Val- (L) ) -Phe-thiomorpholin-4-ylamide, Boc- (p-cFG) Phe [C] Phe (L) -Va1- (L) -Phe-morpholin-4-ylamide, Boc- _(p-CF3) Phe [C] Phe- (L) -Val (L) - (pF) -Phe-morpholin-4-ylamide, Boc- _(p-CF3) PhefC 1Phe- (L) -Va1- (L) - (p CH? O) -Phe-morpholin-4-ylamide, Boc- (p-CF ₃ ) Phe [C] Phe- (L) -Val- (L) -Cha-morpholin-4-ylamide, Boe- (p-CF 3) Phe- C] Phe- (L) -Ile- (L) -Phe-morpholin-4-ylamide, Boe- (p-CF ₃ ) Phe [C] (pF) Phe- (L ) -Val- (L) -Phe-morpholin-4-ylamide, Boc- (p-CF ₃ ) PhelC] (pF) Phe- (L) -Val- (L) - (pF) Phe-morpholin-4- ylamide, Boc- _(p-CF3) Phe [C] (pF) Phe (L) -Val (L) Cha-morpholin-4-ylamide, Boe - _(p-CF3) Phe [C] (pF) Phe- (L) -Val- (L) - (p-CH ₃ O) Phe-morpholin-4-ylamide, Boe- (p-CF ₃ ) Phe [C] (pF) Phe- (L) -Ile- (L) -Phe-morpholin-4-ylamide, Boc- (p-CF ₃ ) PhelC] (p-CF ₃₎ ) Phe- (L) -Val (L) -Phe-morpholin-4-ylamide, Boe- (p-CF 3) Phe [C 1 (p-CF ₃ ) Phe - (L) - Val - (L) - (pF) Phe-morpholin-4-ylamide, Boe- (p-CF ₃ ) PhelC J (d-CF ₃ ) Phe- (L) -Ie- (L) -Phe-morpholin-4-ylamide, Boe- (p-CF ₃ ) Phe-C 1 (p-CF ₃ ) Phe- (L) -Val- (L) - (p-CH ₃ O) Phe-morpholin-4-ylamide, Boe- (p-CF ₃ ) PhelC] (p-CF ₃ ) Phe- (L) -Val- (L) -Cha-morpholin-4-ylamide, Boc-Cha [C] (p-F) Phe (L) -Vai- (L) -Phe-morpholin-4-ylamide, Boc-Chel C] (p-CN) Phe- (L) -Val- (L) -Phe-morpholin-4-ylamide, H-Phel C] Phe- (L) -Vai- (L) -Phe-morpholin-4-ylamide, 3-benzofuranoyl-Phe [C] Phe- (L) -Val- (L) -Phe-morpholin-4-ylamide, nicotinoyl-Phe [C] Phe- (L) -Val- (L) -Phe-morpholine- 4-ylamide, morpholinocarbonyl-Val-Phef C] Phe- (L) -Val- (L) -Phenorpholin-4-ylamide, 196 Boc-Cha [C] Cha- (L) -Val- (L) -Cha-morpholin-4-ylamide, Boc-Cha 1 (pF) Phe- (L) -Val- (L) - (pF-Phe) -morpholin-4-ylamide, Boc-Cha [C] (pF) Phe- (L) -Va 1 - (L) - (p-CH ₃ O-Phe) -morpholin-4-yl 1amid, Boc-Cha [Cj (p-F) Phe- (L) -Val- (L) -Cha-morpholin-4-ylamide, 1,2,3,4-tetrahydroisoquinolin-3 (S) -carbonyl-Val-Phe [C] Phe- (L) -Val- (L) -Phemomorpholin-4-ylamide, Boc-PheΓC] Phe- (L) -Val- (L) - (pF-Phe) -morpholin-4-ylamide, Boc-Phe [C] Phe- (L) -Val- (L) - (p-CH ₃ O-Phe-morpholin-4-ylamide, Boe-Phe [C] Phe- (L) - Val- (L) -Cha-morpholin-4-ylamide, Boe-Phe [C] Phe- ( L) -Ile- (L) -Phe-morpholin-4-ylamide, Boc-Phei C] Phe- (L) -Val-Gly-morpholin-4-ylamide, Boe-Phe [C] Phe- (L) -Ile-Gly-Morpholin-4-ylamide, Boc-Phei C: Phe- (L) -Val- (L) -Val-Morpholin-4-ylamide, Boc-Phe [C: Phe (L) -Val (L) -Phe-thiomorpholin-4-ylamide, Boe- (pF) Phe [C] (p-CF ₃ ) Phe- (L) -Val - (L) -Phe-morpholin-4-ylamide, Boc- (pF) Phe [C] (p-CF ₃₎ ) Phe- (L) -Val (L) - (pF-Phe) -morpholin-4-ylamide, Boe- (pF) Phe [C] (p-CF ₃ ) Phe- (L) -Val- (L) - (p-CH ₃ O-Phe) -morpholin-4-ylamide, morpholinosulfones 1- (L) - Val-Phe [C] Phe- (L) -Val- (L) -Phe-morpholin-4-ylamide, olinosulfonyl-Phe morpholine [C1 Phe - (L) -Val- (L) -Phe-morpholin-4- ylamid, N- (N- (2-pyridylmethyl) -N-methylaminocarbonyl) - (L) -Val-Phe 1 C] Phe- (L) -Val- (L) -Phomorpholin-4-ylamide, 5 ( S) - (Boc-amino) -4 (S) - (acetoxy) -6-phenyl-2 (R) -phenylmethylhexanoyl 1- (L) -Val- (L) -Phermorpholin-4-ylamide, Boe-PheΓ C] Phe- (L) - Val- (L) -Tyr-morpholin-4-ylamide, Boc-Tyr (C) Phe- (L)-Val- (L) -Phe-morpholin-4-ylamide , Boc-Tyr [C] Phe- (L) -Val- (L) -Tyr-morpholin-4-ylamide, Boe-Phe [C] Tyr- (L) -Val- (L) -Phe-morpholin-4 -ylamide, Boc-Pher c-Tyr- (L) -Val- (L) -Tyr-morpholin-4-ylamide, Boc-Tyr [C] Tyr- (L) -Val- (L) -Phe-morpholin-4- ylamide and Boc-Tyr [C] Tyr- (L) - Val- (L) -Tvr-morpholin-4-ylamide, 197 or any of the foregoing compounds with a morpholin-4-ylamide moiety in which the thiomorpholin-4-ylamide moiety is in place of the morpholin-4-ylamide moiety. Compounds of formula I according to any one of claims 1 to 13 for use in a method of therapeutic treatment of the human or animal body. 15. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof comprising at least one salt forming group together with a pharmaceutically acceptable carrier. F Use of a compound of formula I according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, which comprises at least one salt-forming group for the manufacture of a pharmaceutical composition for use in suppressing the action of the gag protease enzyme from HIV-1 or HIV -2. 17. Use of the compounds of the formula I according to some of the following or a pharmaceutically acceptable salt of such a compound which comprises at least one salt-forming group _; for treating diseases caused by retroviruses. 18. A method for treating diseases caused by retroviruses suffering from warm-blooded individuals, characterized in that an effective dose of a compound of formula I according to claim 1 or a pharmaceutically effective salt thereof is administered to treat diseases caused by retroviruses with warm-blooded individuals. A process for the preparation of compounds of the formula I according to claim 1 or a hydroxy-protected derivative thereof and salts of such compounds with at least one group comprising