CA2077948A1 - Further novel 5-amino-4-hydroxyhexanoic acid derivatives as therapeutic agents - Google Patents

Abstract

Abstract Further novel 5-amino-4-hydroxyhexanoic acid derivatives as therapeutic agents Described are compounds of the formula

Description

- ~'7~9~8 Further novel 5-amino-4-hvdroxyhexanoic acid derivatives as therapeutic a~ents The invention relates to non-hydrolysable analogues for peptides that can be cleaved by aspartate proteases, namely S-amino-4-hydroxyhexanoic acid derivatives, processes for the preparation thereof, pharmaceutical compositions comprising those peptide analogues, and the use thereof as medicaments or for the preparation of pharmaceutical compositions for combating diseases caused by retroviruses.

According to present-day knowledge, AIDS is a disease of the immune system that is caused by the retrovirus HIV (Human Immunodeficiency Virus). According to W HO
estimates, this disease affects approximately 10 million people and is still spreading. The disease almost always results in the death of the patient.

It has hitherto been possible to identify the retroviruses HIV-l and HIV-2 (HIV stands for Human Immunodeficiency Virus) as the cause of the disease, and to characterise them by molecular biology. As far as treatment of the disease is concerned, beyond the hitherto limited possibilities of alleviating the symptoms of AIDS, and certain preventive possib-ilities, there is a particular interest in searching for compositions that impair the multiplic-ation of the virus itself without damaging the intact cells and tissue of the patients.

An interesting possibility are compounds that block the multiplication of the virus by preventing the assembly of infectious virus particles.

HIV-l and HIV-2 each have in their genome a region that codes for a "gag-protease". This "gag-protease" is responsible for the correct proteolytic cleavage of the precursor proteins that originate from the regions of the genome that code for the "group specific antigens"
(gag). In the course of that cleavage, the structural proteins of the virus core are freed.
"Gag-protease" itself is a constituent of a precursor protein that is coded for by the pol-genome region of HIV-l and HIV-2 and that also comprises the regions for the "reverse transcriptase" and the "integrase" and is presumably cleaved autoproteolytically.

"Gag-protease" cleaves the major core protein p24 of HIV-l and HIV-2 preferentially - 2 - 2~ 8 N-terminally from proline radicals, for example in the bivalent radicals Phe-Pro, Leu-Pro or Tyr-Pro. The protease is one having a catalytically active aspartate radical in the active site, a so-called aspartate protease.

Owing to the central role of "gag-protease" in the processing of the mentioned core proteins, it is assumed that an effective inhibition of that enzyme in vivo would prevent the assembly of mature virions, so that appropriate inhibitors could be used therapeut-ically.

A prerequisite for therapeutic activity in vivo is the attainment of good bioavailability, for example a high level in the blood, in order thus to achieve sufficiently high concentralions at the infected cells.

A number of "gag-protease"-inhibitors have already been synthesised that comprise central groups that are not proteolytically cleavable peptide isosteres. Despite intensive research, however, in the case of the majority of infected patients it has hitherto not been possible to use in the combating of AIDS aspartate protease inhibitors that are suitable for administration to humans. Pharrnacodynarnic problems, especially, are a determining factor in this connection. The aim of the present invention is to make available novel inhibitors of HIV- 1 aspartate protease.

The compounds according to the invention are compounds of the formula 1~ 8~ ~ A1` A ~ N \ (I), wherein Rl is hydrogen; lower alkoxycarbonyl; heterocyclylcarbonyl; benzyloxycarbonyl that is unsubstituted or substituted by up to three radicals which may be the sarne or different and are selected from fluorine, halo-lower alkyl, lower alkanoyl, sulfo, lower alkylsulfonyl and cyano; heterocyclyloxycarbonyl wherein heterocyclyl is bonded by way of a carbon atom; one of the mentioned carbonyl radicals wherein the bonding carbonyl group has been replaced by a thiocarbonyl group; heterocyclylsulfonyl; lower alkyl-sulfonyl; or N-(heterocyclyl-lower alkyl)-N-lower alkylaminocarbonyl, Bl is a bond or a 2~ 9~8 bivalent radical of an o~-amino acid, which radical is bonded N-terminally to Rl and C-terminally to the amino group at the R2-CH2-carrying carbon atom, each of R2 and R3, independently of the other, is phenyl or cyclohexyl, those radicals being unsubstituted or substituted by from one to three radicals which may be the same or different and are selected from hydroxy, lower alkoxy, halogen, halo-lower alkyl, sulfo, lower alkyl-sulfonyl, cyano and nitro, Al is a bond between -C=O and A2 or is a bivalent radical of an oc-amino acid, which radical is bonded N-terminally to the group -C=O and C-terminally to A2, A2 is a bivalent radical of an a-amino acid, which radical is bonded N-terminally to Al and C-terminally to the group NR4Rs, or Al and A2 together form a bivalent radical of a dipeptide, of which the central amide bond is reduced and which is bonded N-terminally to the group -C=O and C-terminally to the group NR4Rs, and R4 and Rs, together with the bonding nitrogen atom, are unsubstituted or substituted thiomorpholino or morpholino, or salts of those compounds if salt-forming groups are present, or hydroxy-protected deriv-atives of those compounds or the salts thereof.

In the description of the present invention, the term "lower" used in the definition of groups or radicals, for example lower alkyl, lower alkoxycarbonyl, etc., denotes that the groups or radicals so defined, unless expressly defined otherwise, contain up to and including 7, and preferably up to and including 4, carbon atoms.

Asymmetric carbon atoms which may be present in the substituents Rl, Bl, R2, R3, A1 and/or A2, and in substituted thiomorpholino or morpholino formed by R4 and Rs together with the bonding nitrogen atom, may be in the (R)-, (S)- or (R,S)-configuration. Accord-ingly, the present compounds may be in the forrn of isome~ic mixtures or in the form of pure isomers, especially in the form of diastereoisomeric mixtures, enantiomeric pairs or pure enantiomers.

The general terms and names used in the description of the present invention preferably have the following meanings, it being possible to use, at the various levels of definition, any combination of the radicals indicated hereinbefore and hereinafter or any individual radicals, instead of the general definitions:

Lower alkoxycarbonyl Rl preferably contains a branched lower alkyl radical, especially a sec- or tert-lower alkyl radical, and is, for example, butoxycarbonyl, such as tert-butoxy-carbonyl or isobutoxycarbonyl. Tert-butoxycarbonyl is especially preferred.

2~ 9~8 Heterocyclylcarbonyl Rl contains, especially, a 5- or 6-membered heterocycle that contains from 1 to 3 hetero atoms which may be the same or different and are selected from S, O and N, is unsaturated or completely or partially saturated and is mono- to tri-benzo-fused or cyclopenta-, cyclohexa- or cyclohepta-fused, it being possible for the mentioned fused rings to contain a further nitrogen atom as hetero atom, for example a heterocyclyl radical that is selected from pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quin-oxalinyl, B-carbolinyl and a benzo-fused or cyclopenta-, cyclohexa- or cyclohepta-fused derivative of those radicals, which may also be completely or partially saturated, prefer-ably partially saturated, or is selected from pyridylcarbonyl, for example pyridyl-3-carbonyl, morpholinylcarbonyl, for example morpholinocarbonyl, and benzofuranoyl, for example 3-benzofuranoyl, or, alternatively or additionally thereto, tetrahydroisoquinolyl-carbonyl, for example tetrahydroisoquinolyl-3-carbonyl, preferably tetrahydroiso-quinolyl-3(S)-carbonyl.

Benzyloxycarbonyl Rl is unsubstituted or substituted by up to three radicals which may be the same or different and are selected from fluorine, halo-lower alkyl, for example tri-fluoromethyl or pentafluoroethyl, lower alkanoyl, such as acetyl, propanoyl, butyryl or pivaloyl, sulfo, lower alkylsulfonyl, for example methylsulfonyl, ethylsulfonyl, n-propyl-sulfonyl or isopropylsulfonyl, and cyano. Preferred is benzyloxycarbonyl that is unsubstit-uted or o-, m- or p-substituted, especially p-substituted, in the phenyl ring by a radical selected from fluorine, trifluoromethyl, sulfo, methylsulfonyl, ethylsulfonyl and cyano, for example benzyloxycarbonyl, fluorophenylmethoxycarbonyl, such as p-fluorophenyl-methoxycarbonyl, trifluoromethylphenylmethoxycarbonyl, such as p-trifluoromethyl-phenylmethoxycarbonyl, methylsulfonylphenylmethoxycarbonyl, such as p-methyl-sulfonylphenylmethoxycarbonyl, or cyanophenylmethoxycarbonyl, such as p-cyano-phenylmethoxycarbonyl .

Heterocyclyloxycarbonyl Rl contains as heterocyclyl especially a 5- or 6-membered heterocycle that contains from 1 to 3 hetero atoms which may be the same or different and are selected from S, O and N, is unsaturated or completely or partially saturated and is mono- to tri-benzo-fused or cyclopenta-, cyclohexa- or cyclohepta-fused, it being possible for the mentioned fused rings to contain a further nitrogen atom as hetero atom, for example a radical selected from pyrrolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thi-azolyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl, B-carbolinyl and a benzo-fused or cyclopenta-, cyclohexa- or cyclohepta-fused derivative of those 2~

radicals, which may- also be completely or partially saturated, the heterocyclyl radicals being bonded by way of a ring carbon atom to the oxygen of the associated oxycarbonyl radical, and preferably being selected from pyrrolyl, thienyl, imidazolyl, pyrazolyl, oxaz-olyl, thiazolyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl, ~-carbolinyl and a completely or partially saturated derivative of those radicals, for example a partially saturated derivative of those radicals or indol-3-yloxycarbonyl, benzothiazol-6-yloxycarbonyl or quinol-8-yloxycarbonyl. In a very especially preferred variant of the definition of Rl, the radicals defmed as substituents of he~,erocyclyloxy-carbonyl are not included at any level of definition.

In the mentioned radicals, the bonding carbonyl group may also have been replaced by a thiocarbonyl group. A carbonyl group is preferred.

Lower alkylsulfonyl Rl is preferably methylsulfonyl, ethylsulfonyl, n-propylsulfonyl or isopropylsulfonyl. The compounds of forrnula I wherein Rl is lower alkylsulfonyl and the other radicals are as defined may be omitted from the definition of the compounds of formula I, or they are especially preferred.

Heterocyclylsulfonyl contains as heterocyclyl preferably one of the heterocycles, mentioned under heterocyclylcarbonyl Rl, that is unsubstituted or substituted by lower alkyl, such as methyl or ethyl, heterocycles having at least one nitrogen atom that is bonded to the sulfur of the sulfonyl group being preferred, and is especially piperidino-sulfonyl, piperazin-1-ylsulfonyl that is unsubstituted or substituted by lower alkyl, such as methyl, at the nitrogen that is not bonded to the sulfonyl-sulfur, pyrrolidin- l-ylsulfonyl, imidazolidin- 1 -ylsulfonyl, pyrimidin- 1-ylsulfonyl, quinolin- 1 -ylsulfonyl, morpholino-sulfonyl or thiomorpholinosulfonyl, especially thiomorpholinosulfonyl or morpholino-sulfonyl. The compounds of formula I wherein R1 is heterocyclylsulfonyl and the other radicals are as defined may be omitted from the definition of the compounds of formula I, or they are especially preferred.

N-(heterocyclyl-lower alkyl)-N-lower alkylaminocarbonyl Rl contains as heterocyclyl preferably one of the heterocycles mentioned under heterocyclylcarbonyl R1, especially pyridyl, such as 2-, 3- or 4-pyridyl, pyrazinyl, pyrimidinyl, morpholinyl, such as morpho-lino, thiomorpholinyl, such as thiomorpholino, or quinolyl, such as 2- or 3-quinolyl, and is, especially, N-(heterocyclylmethyl)-N-methylaminocarbonyl, for example N-(pyridyl-methyl)-N-methylaminocarbonyl, such as N-(2-pyridylmethyl)-N-methylaminocarbonyl.

- 6 2~ 9~ 8 The compounds of formula I wherein Rl is N-(heterocyclyl-lower alkyl)-N-lower aL~cyl-aminocarbonyl and the other radicals are as defined may be omitted from the definition of the compounds of formula I, or they are especially preferred.

A bivalent radical Bl of an a-amino acid, which radical is bonded N-terminally to Rl and C-terminally to the amino group at the R2-CH2-carrying carbon atom, is preferably selected from glycine (H-Gly-OH), alanine ~H-Ala-OH), valine (H-Val-OH), norvaline (a-aminovaleric acid), leucine, (H-Leu-OH), isoleucine (H-Ile-OH), norleucine (a-amino-hexanoic acid, H-Nle-OH), serine (H-Ser-OH), homoserine (a-amino-~-hydroxybutyric acid), threonine (H-Thr-OH), methionine (H-Met-OH), cysteine (H-Cys-OH), proline(H-Pro-OH), trans-3- and trans-4-hydroxyproline, phenylalanine (H-Phe-OH), p-fluoro-phenylalanine (H-(p-F-Phe)-OH), tyrosine (H-Tyr-OH), p-methoxyphenylalanine (H-(p-CH30-Phe)-OH), 4-aminophenylalanine, 4-chlorophenylalanine, 4-carboxyphenyl-alanine, ~-phenylserine (~-hydroxyphenylalanine), phenylglycine, a-naphthylalanine (H-Nal-OH), cyclohexylalanine (H-Cha-OH), cyclohexylglycine, tryptophan (H-Trp-OH), indoline-2-carboxylic acid, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, amino-malonic 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), ~-hydroxylysine, ornithine (a,~-diaminovaleric acid), a,~-diaminobutyric acid and a,~-diaminopropionic acid, or, alternatively or additionally thereto, 4-cyanophenylalanine (H-(p-CN-Phe)-OH), and is especially prefer-ably the radical of a hydrophobic amino acid, for example proline, phenylalanine, p-fluorophenylalanine, p-methoxyphenylalanine, tyrosine, phenylglycine, c~-naphthyl-alanine, cyclohexylalanine, cyclohexylglycine or an aliphatic a-amino acid selected from glycine, valine, norvaline, alanine, leucine, norleucine and isoleucine, especially valine, each of the mentioned a-amino acids being in the D-, L- or (D,L)-form, preferably in the L-forrn, and being linked especially with radicals Rl selected from lower alkoxycarbonyl, for example tert-butoxycarbonyl, or heterocyclylcarbonyl, for example morpholino-carbonyl.

When B1 is a bond, Rl is bonded directly to the amino-nitrogen that is bonded by the carbon atom carrying the radical R2-CH2- in formula I.

Phenyl or cyclohexyl R2 or R3 is unsubstituted or substituted by up to three radicals which may be the same or different and are selected from hydroxy, lower alkoxy, such as methoxy or ethoxy, halogen, for example fluorine, halo-lower alkyl, for example trifluo;o-- 7 - ;~ 8 methyl, sulfo, lower aLkylsulfonyl, for example methyl- or ethyl-sulfonyl, cyano and nitro, preferably by one or two of those radicals, especially preferably selected from hydroxy, methoxy, fluorine, trifluoromethyl, sulfo, lower allcylsulfonyl, for example methyl- or ethylsulfonyl, and cyano; in the case of phenyl, very especially preferably from fluorine and cyano, in the case of cyclohexyl, very especially preferably from fluorine, trifluoro-methyl, sulfo and lower aL~ylsulfonyl, especially fluorine; the mentioned substituents being bonded in the 2-, 3- or 4-position of the phenyl or cyclohexyl ring, especially in the 4-position, as in phenyl, cyclohexyl, 4-fluoro- or 4-cyanophenyl or 4-fluorocyclohexyl, especially in phenyl, cyclohexyl, 4-cyanophenyl or 4-fluorophenyl.

Especially preferred are combinations of R2 and R3 in which at least one of the radicals R2 and R3is substituted by from one to three radicals selected from halogen, especially fluorine, halo-lower alkyl, especially trifluoromethyl, sulfo, lower alkylsulfonyl, especially methyl- or ethyl-sulfonyl, cyano and nitro, a substituent selected from fluorine and cyano being very strongly preferred.

Even more strongly prefer ed is R2 selected from phenyl, 4-hydroxyphenyl, 4methoxy-phenyl, 4-fluorophenyl, cyclohexyl and 4-trifluoromethylphenyl, while R3 is selected from phenyl, 4-hydroxyphenyl, 4-methoxyphenyl, cyclohexyl, 4-fluorophenyl, 4-trifluoro-methylphenyl and 4-cyanophenyl.

R2 is selected especially from phenyl, 4-fluorophenyl and cyclohexyl, while R3is selected from phenyl, cyclohexyl, 4-fluorophenyl and 4-cyanophenyl.
' Most especially preferred are the combinations: R2 phenyl and R3 phenyl; R2 cyclohexyl 1~ and R3 4-cyanophenyl; R2 cyclohexyl and R3 4-fluorophenyl; and R2 and R3 each cyclo-hexyl. Alternatively or additionally thereto, the combinations R2 phenyl and R3 4-fluoro-phenyl; R2 phenyl and R3 4-cyanophenyl; R2 4-fluorophenyl and R3 4-fluorophenyl; R2 4-fluorophenyl and R3 4-trifluoromethylphenyl; R2 4-~rifluoromethylphenyl and R3phenyl; R2 4-trifluoromethylphenyl and R3 4-fluorophenyl; R2 4-trifluoromethylphenyl and R3 4-trifluoromethylphenyl; R2 hydroxyphenyl and R3 phenyl; R2 phenyl and R3hydroxyphenyl; or R2 hydroxyphenyl and R3 hydroxyphenyl are also most especlallypreferred.

- Hydroxy groups, especially the hydroxy group in compounds of formula I at the carbon atom that is vicinal to the carbon atom carrying the radical R2-CH2-, may be free or in . .

- 8- 2~ 8 protected form, suitable hydroxy-protecting groups being the radicals mentioned herein-after in the description of the preparation processes for compounds of formula I, especially free or protected in the form of physiologically cleavable esters, for example in the form of lower aLIcanoyloxy, such as acetoxy.

A bivalent radical of an a-amino acid Al, which radical is bonded N-terminally to the group -C=O and C-terminally to A2, is, for example, one of the a-amino acids mentioned above for Bl, it being possible for those amino acids to be in the (D)-, (L)- or (D,L)-form, preferably the (D) or (L)-form, especially the (L)-form. Preferred are the hydrophobic a-amino acids mentioned under Bl, especially the aliphatic hydrophobic a-amino acids mentioned there, for example glycine, valine or isoleucine. In the mentioned a-amino acids, the carboxy group bonding to A2 is not reduced or is further reduced, especially to a methylene group, for example in the mentioned hydrophobic a-amino acids, such as in the reduced amino acid radicals Gly(red), Val(red) or Ile(red), especially in Val(red), the suffix (red) indicating the reduction of the carbonyl group of the corresponding amino acid radical to the methylene group.

If Al is a bond, then A2 is bonded directly to the carbonyl group at the carbon atom carrying the radical R3-CH2--A bivalent radical of an a-amino acid A2, which radical is bonded N-terminally to A1 and C-terminally to the group NR4Rs, is, for example, one of the a-amino acids mentioned above for Bl, it being possible for those amino acids to be in the (D)-, (L)- or (D,L)-form, preferably the (D) or (L)- form, especially the (L)-form. Preferred are the hydrophobic a-amino acids mentioned under Bl, for example glycine, valine, phenylalanine, p-fluoro-phenylalanine, tyrosine, p-methoxyphenylalanine, phenylglycine, a-naphthylalanine, cyclohexylalanine or cyclohexylglycine, preferably glycine, valine, phenylalanine, p-fluorophenylalanine, p-methoxyphenylalanine or cyclohexylalanine, the mentioned radicals being in the (D)- or (L)-forrn but prefeMbly, with the exception of phenylalanine which is in the (L)- or (D)-form, in the (L)-forrn.

A bivalent radical, forrned from Al and A2, of a dipeptide, of which the central peptide bond is reduced and which is bonded N-terminally to the group -C=O and C-terminally to the group NR4Rs, preferably comprises 2 of the above-mentioned hydrophobic a-amino acids, especially one N-terminal amino acid radical selected from Gly(red), Val(red) and Ile(red) and one C-terminal amino acid selected from glycine, phenylalanine, tyrosine, - 9 - 2~9~8 p-methoxyphenylalanine, cyclohexylalanine and p-fluorophenylalanine.

Especially prefeMbly, Al and A2 together form a bivalent radical of a dipeptide of the formula Val-Phe, lle-Phe, Val-Cha, Ile-Cha, Val-Gly, Val-(p-F-Phe), Val-(p-CH30-Phe) or Gly-(p-F-Phe); and, alternatively or additionally~ of a 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 in which Phe is in the (L)- or (D)-form; or of a derivative thereof having a reduced central amide bond, for example having the formula Val(red)-Phe, which is bonded N-terminally to the group -C-O and C-terminally to the group NR4Rs-A preferred embodiment of the invention relates either to the compounds of formula Iwherein Bl is one of the mentioned bivalent Mdicals of an a-amino acid and one of the radicals Al and A2 is a bond and the other is one of the mentioned a-amino acids, or to those compounds of formula 1 wherein Bl is a bond and each of Al and A2 is one of the mentioned bivalent radicals of an a-amino acid or they are together one of the mentioned bivalent radicals of a dipeptide having a reduced centMl amide bond.

Thiomorpholino or moTholino formed from R4 and Rs together with the bonding nitrogen atom is unsubstituted or substituted at one or more of the carbon atoms, preferably at one carbon atom, by lower alkyl, such as ethyl, propyl, butyl, isobutyl or tert-butyl, by 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, by hydroxy, by lower alkoxy, such as methoxy, ethoxy or tert-butoxy, by amino, by lower alkylamino, such as methyl- or ethyl-amino, or by di-lower alkylamino, such as dimethylamino or diethylamino, by lower alkanoyl, such as acetyl or propionyl, by phenyl- or naphthyl-lower alkanoyl, such as phenylacetyl or 1- or 2-naphthylacetyl, by carboxy, by lower alkoxycarbonyl, such as iso-propoxycarbonyl or tert-butoxycarbonyl, by phenyl-, naphthyl- or fluorenyl-lower alkoxy-carbonyl, such as benzyloxycarbonyl, 1- or 2-naphthylmethoxycarbonyl or 9-fluorenyl-methoxycarbonyl, by carbamoyl, by mono- or di-lower alkylcarbamoyl, such as dimethyl-carbamoyl, by mono- or di-hydroxy-lower alkylcarbamoyl, such as dihydroxymethylcarb-amoyl, by sulfo, by lower alkylsulfonyl, such as methylsulfonyl or ethylsulfonyl, by phenyl- or naphthyl-sulfonyl, wherein phenyl may be substituted by lower alkyl, for example methyl or ethyl, for example phenylsulfonyl or toluenesulfonyl, by sulfamoyl, by halogen, for example fluorine or chlorine, by cyano, by nitro and/or by oxo.

2~ 9'1~8 Very preferably, R4 and Rs form, together with the bonding nitrogen atom, unsubstituted thiomorpholino or morpholino, especially unsubstituted morpholino.

Salts of compounds of formula I are especially acid addition salts, salts with bases or, when several salt-forming groups are present, optionally also mixed salts or internal salts.

Salts are especially the pharrnaceutically acceptable, non-toxic salts of compounds of formula I.

Such salts are formed, for example, from compounds of formula I having an acidic group, for example a carboxy or sulfo group, and are, for example, their salts with suitable bases, such as non-toxic metal salts derived from metals of groups Ia, Ib, IIa and IIb of the Periodic Table of Elements, especially suitable alkali metal salts, for example lithium, sodium or potassium salts, or alkaline earth metals salts, for example magnesium or calcium salts, furthermore zinc salts or ammonium salts, also those salts that are formed with organic amines, such as unsubstituted or hydroxy-substituted mono-, di- or tri-alkylamines, especially mono-, di- or tri-lower alkylamines, or with quaternary ammonium compounds, for example with N-methyl-N-ethylamine, diethylamine, triethyl-amine, 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-hydroxyethyl)-amine or tri-(2-hydroxyethyl)-amine, or N-methyl-D-glucamine, or quaternary ammonium salts, such as tetrabutylammonium salts. The compounds of formula I having a basic group, for example an amino group, can form acid addition salts, for example with inorganic acids, for example a hydrohalic acid, such as hydrochloric acid, sulfuric acid or phosphoric acid, or with organic carboxylic, sulfonic, sulfo or phospho acids or N-substituted sulfamic acids, such as, for example, acetic acid, propionic acid, glycolic acid, succinic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, fumaric acid, malic acid, tartaric acid, gluconic acid, glucaric acid, glucuronic acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, salicylic acid, 4-aminosalicylic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, embonic acid, nicotinic acid or isonico-tinic acid, also with amino acids, such as, for example, the above-mentioned a-amino acids, and also with methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1,2-disulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, naphthalene-2-sulfonic acid, 2- or 3-phosphoglycerate, glucose-6-phosphate, N-cyclo-hexylsulfamic acid (with formation of the cyclamates) or with other acidic organic 2~9~8 compounds, such as ascorbic acid. Compounds of forrnula I having acidic and basic groups can also form internal salts.

For the purpose of isolation or purification, it is also possible to use pharmaceutically unacceptable salts.

The terms "compounds" and "salts" also expressly include individual compounds or indiv-idual salts.

The compounds of the present invention exhibit inhibitory effects on retroviral aspartate proteases, especially gag-protease-inhibiting effects. In the tests described hereinafter, in concentrations of from lo-6 to 10-9M, they especially inhibit the action of the gag-protease of HIV-1 and are accordingly suitable agents against diseases caused by that protease or by related retrovlruses, such as against 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, according to the method described by J. Hansen et aL, The EMBO Journal 7, 1785-1791 (1988). In that method, the inhibition of the action of HIV-l protease on a substrate that is a fusion protein, expressed in E. coli, of the gag-precursor protein and MS-2 is measured. The substrate and its cleavage products are separated by polyacrylamide gel electrophoresis and rendered visible by immunoblotting with monoclonal antibodies against MS-2.

In a test that is even more simple to use and enables accurate quantitative predictions to be made, a synthetic peptide corresponding to one of the cleavage sites of the gag-precursor protein is used as the substrate for the gag-protease. That substrate and its cleavage products can be measured by high pressure liquid chromatography (HPLC).

For example, a synthetic chromophoric peptide (for example HKARVL[NO2lFEANleS
(Bachem, Switzerland) or an eicosapeptide such as RRSNQVSQNYPIVQNIQGRR
(prepared by peptide synthesis according to known processes) corresponding to one of the cleavage sites of the gag-precursor protein is used as the substrate for a recombinant HIV-1 protease (preparation according to Billich, S., et aL, J. Biol. Chem. 263(34), 17905 - 17908 (1990)). That substrate and its cleavage products can be measured by high pressure liquid chromatography (HPLC).

2~9~ !3 For that purpose, an inhibiting compound of formula I to be tested is dissolved in dimethyl sulfoxide; the enzyme test is carried out by adding suitable dilutions of the inhibiting compound in 20 mM ,B-morpholinoethanesulfonic acid (MES)-buffer pH 6.0 to the assay mix which comprises 67.211M of the above-mentioned chromophoric peptide in 0.3M
sodium acetate, O.lM NaCI pH 7.4; or 122 ~M of the above-mentioned eicosapeptide in 20 mM MES-buffer pH 6Ø The size of the batches is 100 IlL The reaction is started by the addition of, in the first case,2 ~11 and, in the second case, 10 111 of HIV- 1 protease and is stopped in the first case after 15 minutes by the addition of 100 111 of 0.3M HCI04, and, in the second case, after one hour's incubation at 37 C by the addition of 101l1 of 0.3M
HCI04. The reaction products, after separating the sample by centrifugation for 5 minutes at 10 000 x g in 100 1ll (batch with chromophoric peptide) and 20111 (eicosapeptide batch) of the resulting supernatant and after application to a 125 x 4.6 mm Nucleosil~g) C18-S~L-HPLC column (Macherey & Nagel, Duren) and elution, are quantified on the basis of the peak height of the cleavage product at 280 nm (batch with chromophoric peptide) or at 215 nm (batch with eicosapeptide), gradient: 100 % el.1 -~ 50 % el.l /50 % el.2 (el.l:
10 % acetonitrile, 90 % H2O, 0.1 % trifluoroacetic acid (TFA); el.2: 75 % acetonitrile, 25 % H2O, 0.08 % TFA) over a period of 15 minutes; rate of flow 1 mVmin (el. = eluant).

Preferablyj ICso values (ICso = the concentration that reduces the activity of the HIV-l protease by 50 % compared with a control without an inhibiting compound) of approx-imately from 10-6 to 10-9M, especially from 10-7 to 10-8M, are determined for compounds of formula I in that test.

In another test, it can be shown that the compounds of the present invention protect cells that are normally infected by HIV from such infection or at least retard such infection. In that test, the human T-cell leukaemia cell-line MT-2 (Science 229, 563 (1985)), which is sensitive to the cytopathogenic effect of HIV, is incubated with HIV- 1 alone or with HIV- 1 in the presence of a compound according to the invention and, after a few days, the viability of the cells so treated is assessed.

For that purpose, the MT-2 cells in RPMI 1640-medium (Gibco, Switzerland; RPMI 1640 contains an amino acid mixture without L-Gln) that has been supplemented with 10 %
heat-inactivated foetal calf's serum, L-glutamine, Hepes (2-[4-(2-hydroxyethyl)-1-piper-azino]-ethanesulfonic acid) and standard antibiotics, are maintained at 37 C in humidified air containing 5 % CO2. 50,ul of the test compound in culture medium and 100,ul of HIV- 1 in culture medium (800 TCID50/ml) (TCID50 = Tissue Culture Infectious Dose 50 2~ 9~8 = dose that infects 50 % of the MT-2 cells) are added to 4x103 exponentially growing MT-2 cells in 50,ul of culture medium per well on 96-well microtitre plates. Parallel batches on another microtitre plate with cells and test compound receive 100111 of culture medium without virus. After 4 days' incubation, reverse transcriptase (RT) activity is determined in 10 ~11 of cell supematant. The RT activity is determined in 50 mM t is (a,a,a-tris(hydroxymethyl)methylamine, Ultra pur, Merck, Federal Republic of Germany) pH 7.8; 75 mM KCI, 2 mM dithiothreitol, S mM MgCI2; 0.05 % Nonidet P-40 (detergent;
Sigma, Switærland); SO Ilg/ml of polyadenylic acid (Pharmacia, Sweden); 1.6 ~,~g/ml of dT(12-18) (Sigma, Switzerland). The mixture is filtered off through a 0.45 ~L Acrodisc(~) filter (Gellman Science Inc, Ann Arbor) and stored at -20 C . There are added to aliquots of that solution 0.1 % (v/v) [alpha-32P]dT~P to obtain a final radioactive activity of 10,lLCVml. 10 ~,11 of the culture supernatant are transferred onto a fresh 96-well microtitre plate and 30 ~,11 of the mentioned RT cocktail are added thereto. After mixing, the plate is incubated for from 1.5 to 3 hours at 37 C.5 1,l1 of the reaction mixture are transferred onto Whatman DE81-paper (Whatman). The dried filters are washed 3 times for 5 minutes each time with 300 mM NaCI/25 mM tri-sodium citrate and once with 95 % ethanol and air-dried again. Evaluation is carried out in a Matrix Packard 96-well counter (Packard).
The ED90 values are calculated and defined as the lowest concentration of the test compound that reduces the RT activity by 90 % in comparison with cell batches that have not been treated with the test compound. The RT activity is a measure of HIV-1 multiplic-ation.

In that test, the compounds according to the invention exhibit an ED90 of approximately from 10-5 to 10-8M, preferably from approximately 10-7 to 10-8M.

The compounds of the present invention exhibit advantageous pharmacokinetic properties which would lead to the assumption that they would exhibit the mentioned inhibiting effects m v~vo. For example, in the case of the mentioned compounds, the blood level is 4,ug/ml blood and higher 10 minutes after the intravenous or intraperitoneal adminis-tration to mice of 20 mg/kg of a compound of formula I. Furthermore, upon the peroral (p.o.) administration of 120 mglkg of a compound of formula I, the concentration after 90 minutes is approximately the same as or higher than the above-mentioned ED90 in the cell test.

The determination of the blood level is carried out, for example, as follows: The compounds to be investigated are dissolved in an organic solvent, such as dimethyl - 14 - 2~

sulfoxide (DMSO). A solution of hydroxypropyl-~-cyclodextrin (20 % w/v) in water is added until the desired concentration of the active ingredient is reached (for example 2 mg/ml in the case of parenteral administration, 12 mg/ml in the case of oral adminis-tration) while at the same time the concentration of DMSO is adjusted to 5 % (v/v).
Compounds that are insoluble under those conditions are, in the case of parenteral use, administered only intraperitoneally, while soluble compounds can also be administered intravenously. After administering the compounds (for example 20 mg/kg intravenously or intraperitoneally, or 120 mg~cg perorally) blood is taken at various times, for example after 10 minutes in the case of parenteral administration, or after 90 minutes in the case of peroral administration. Each time, the blood of three mice is used and, either in the case of each mouse individually or from the combined blood of the three mice, the supernatant is obtained after the addition of a solvent, for example acetonitrile, and subsequent centri-fugation. The concentration of the active ingredient is deterrnined by HPLC, for example on a Nucleosil(~ SCI8 column 120 mm in length and 4.6 mm in diameter, widh either 60 %
acetonitrile/40 % water/0.05 % trifluoroacetic acid (v/v) or 50 % acetonitrile/50 %
water/0.05 % trifluoroacetic acid (v/v) as eluant at a flow rate of 1 ml/min and detection and quantification at 200 nm.

In the case of the groups of compounds of formula I mentioned hereinafter, it is possible, where appropriate, for example in order to replace more general definitions by more specific definitions, to use definitions of radicals from the above-mentioned general definitions or to add or omit definitions from the other groups.

A preferred variant of the invention relates to the compounds of formula I wherein Rl is hydrogen, lower alkoxycarbonyl, heterocyclylcarbonyl, benzyloxycarbonyl that is unsubs-tituted or substituted by up to three Mdicals which may be the same or different and are selected from fluorine, halo-lower alkyl, lower alkanoyl, sulfo, lower alkylsulfonyl and~
cyano, or is heterocyclyloxycarbonyl wherein heterocyclyl is bonded by way of a carbon atom, or is one of the mentioned carbonyl radicals wherein the bonding carbonyl group has been replaced by a thiocarbonyl group, Bl is a bond or a bivalent radical of an a-amino acid, which radical is bonded N-terminally to R1 and C-terminally to the amino group at the R2-CH2-carrying carbon atom, each of R2 and R3, independendy of the other, is phenyl or cyclohexyl, those radicals being unsubstituted or substituted by from one to three radicals which may be the same or different and are selected from hydroxy,methoxy, halogen, halo-lower alkyl, sulfo, lower alkylsulfonyl, cyano and nitro, A1 is a bond between -C=O and A2 or is a bivalent radical of an a-amino acid, which radical is -15- 2,~ B

bonded N-terminally to the group -C=O and C-terminally to A2, A2 is a bivalent radical of an ~-amino acid, which radical is bonded N-terminally to Al and C-terminally to the group NR4Rs, or Al and A2 together form a bivalent radical of a dipeptide, of which the central amide bond is reduced and which is bonded N-terminally to the group -C=O and C-terminally to the group NR4Rs, and R4 and Rs, together with the bonding nitrogen atom, are unsubstituted or substituted thiomorpholino or morpholino; and, alternatively or additionally thereto, the compounds of formula I wherein Rl is heterocyclylsulfonyl, lower aLl~ylsulfonyl or N-(heterocyclyl-lower alkyl)-N-lower aLlcylaminocarbonyl, and the other radicals are as defined; and salts of those compounds, if salt-forming groups are present; the hydroxy group in compounds of formula I, at the carbon atom that is vicinal to the carbon atom carrying the radical R2-CH2-, being free or in protected form, especially protected in the form of a physiologically cleavable ester, for example in the form of lower aLtcanoyloxy, such as acetoxy, both the free compounds of formula I and the protected form in which all the other radicals are as defined, or the salts thereof, being especially preferred. Special mention should be made here of the compounds wherein each of Al and A2 is a bivalent radical of an o~-amino acid and the remaining radicals are as defined, or the salts thereof.

Also preferred are compounds of formula I wherein Rl is hydrogen, lower aLkoxycarbonyl, heterocyclylcarbonyl, benzyloxycarbonyl that is unsubstituted or substituted by up to three radicals which may be the same or different and are selected from fluorine, halo-lower aLIcyl, lower alkanoyl, sulfo, lower alkylsulfonyl and cyano, or is heterocyclyloxycarbonyl wherein heterocyclyl is bonded by way of a carbon atom, or is one of the mentioned carbonyl radicals wherein the bonding carbonyl group has been replaced by a thiocarbonyl group, Bl is a bond or a bivalent radical of an o~-amino acid, which radical is bonded N-terminally to Rl and C-terminally to the amino group at the R2-CH2-carrying carbon atom, each of R2 and R3, independently of the other, is phenyl or cyclohexyl, those radicals being unsubstituted or substituted by from one to three radicals which may be the same or different and are selected from halogen, halo-lower alkyl, sulfo, lower alkyl-sulfonyl, cyano and nitro, Al forms a bond between -C=O and A2 or is a bivalent radical of an cc-amino acid, which radical is bonded N-terminally to the group -C=O and C-term-inally to A2, A2 is a bivalent radical of an c~-amino acid, which radical is bonded N-term-inally to Al and C-terminally to the group NR4Rs, or Al and A2 together form a bivalent radical of a dipeptide, of which the central amide bond is reduced and which is bonded N-terminally to the group -C=O and C-terminally to the group NR4Rs, and R4 and Rs, together with the bonding nitrogen atom, are unsubstituted or substituted morpholino; and, - 16 - 2~ JL8 alternatively or additionally thereto, the compounds of formula I wherein R1 is hetero-cyclylsulfonyl, lower alkylsulfonyl or N-(heterocyclyl-lower aLkyl)-N-lower aL~ylamino-carbonyl, and the other radicals are as defined; and salts of those compounds, if salt-forming groups are present; the hydroxy group in compounds of formula I, at the carbon atom that is vicinal to the carbon atom carrying the radical R2-CH2-, being free or in protected form, especially protected in the form of a physiologically cleavable ester, for example in the form of lower alkanoyloxy, such as acetoxy, both the free compounds of formula I and the protected form in which all the other radicals are as defined, or the salts thereof, being especially preferred.

Also preferred are compounds of formula I wherein at least one of the radicals R2 and R3 is substituted by from one to three radicals selected from hydroxy, methoxy, halogen, halo-lower alkyl, sulfo, lower alkylsulfonyl, cyano and nitro, and the radicals R1, Bl, Al, A2 and NR4Rs are as defined in the last two paragraphs, and salts thereof, if salt-forming groups are present.

More strongly preferred are the compounds of formula I wherein Rl is hydrogen, tert-but-oxycarbonyl, isobutoxycarbonyl, pyridine-3-carbonyl, morpholinocarbonyl, 3-benzofuran-oyl, 1,2,3,4-tetrahydroisoquinoline-3-carbonyl, benzyloxycarbonyl substituted by up to three radicals which may be the same or different and are selected from fluorine, halo-lower aLI~yl, lower alkanoyl, sulfo, lower aLkylsulfonyl and cyano, or is heterocyclyloxy-carbonyl wherein heterocyclyl is bonded~ by way of a carbon atom and is selected from pyrrolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl, B-carbolinyl and a completely or partially saturated derivative of those radicals, or wherein the meaning heterocyclyloxycarbonyl R
is omitted, Bl is a bond or a bivalent radical of an a-amino acid, which radical is bonded N-terminally to Rl and C-terminally to the amino group at the R2-CH2-carrying carbon atom, preferably the radical of a hydrophobic amino acid, for example proline, phenyl-alanine, p-fluorophenylalanine, phenylglycine, a-naphthylalanine, cyclohexylalanine or cyclohexylglycine, or of an aliphatic a-amino acid selected from glycine, valine, norvaline, alanine, leucine, norleucine and isoleucine, especially valine, preferably each of the mentioned a-amino acids being in the D-, L- or (D,L)-form, preferably the L-form, preferably each of the mentioned amino acids being substituted by one of the radicals mentioned under Rl selected from hydrogen, N-tert-butoxycarbonyl or morpholino-carbonyl, each of R2 and R3, independently of the other, is phenyl or cyclohexyl, those radicals being unsubstituted or substituted by one or two radicals which may be the same 9~8 or different and are selected from hydroxy, methoxy, fluorine, sulfo, lower alkylsulfonyl, trifluoromethyl and cyano, as indicated above in the general definitions, A1 is a bivalent radical of a hydrophobic a-amino acid, as indicated above under the general definitions, which radical is bonded N-terminally to the group -C=O and C-terminally to A2, A2 is a bivalent radical of a hydrophobic a-amino acid, preferably as defined above under the general definitions, which radical is bonded N-terminally to Al and C-terminally to the radical NR4Rs, the mentioned amino acid radicals being in the (D)- or (L)-form but prefer-ably, with the exception of phenylalanine which is in the (L)- or the (D)-form, in the (L)-form, Al and A2 especially form a bivalent radical of a dipeptide of the formula Val-Phe, Ile-Phe, Val-Cha, Ile-Cha, Ile-Gly, Val-Val, Val-Gly, Val-(p-F-Phe), Val-Tyr, Val-(p-CH30-Phe) or Gly-(p-F-Phe), wherein the amino acids are in the (D)- or ~)-form, especially the (L)-forcn, with the exception of (L)-Val-Phe, in which Phe is in the (L)- or (D)-form; or Al and A2 together form a bivalent radical of a dipeptide comprising two hydrophobic a-amino acids, preferably the hydrophobic a-amino acids mentioned herein-before under the general definitions, of which the central amide bond is reduced and which is bonded N-terminally to the group -C=O and C-terminally to the group NR4Rs, as indicated in the general definitions, for example having the formula Val(red)-Phe, and R4 and Rs, together with the bonding nitrogen atom, are thiomorpholino or morpholino, especially morpholino; and, alternatively or additionally thereto, the compounds of formula I wherein Rl is morpholinosulfonyl or N-(2-pyridylmethyl)-N-methylamino-carbonyl and the other radicals are as defined; and the pharmaceutically acceptable salts of those compounds, if salt-forming groups are present; the hydroxy group in compounds of formula I, at the carbon atom that is vicinal to the carbon atom carrying the radical R2-CH2-, being free or being in a form protected by lower alkanoyl, especially in free form; and it also being possible for heterocyclyloxycarbonyl to be omitted from the defin-ition of Rl.

More strongly preferred are also the compounds of formula I wherein R1 is hydrogen, tert-butoxycarbonyl, isobutoxycarbonyl, pyridine-3-carbonyl, morpholinocarbonyl,3-benzofuranoyl, 1,2,3~4-tetrahydroisoquinoline-3-carbonyl, benzyloxycarbonyl that is substituted by up to three radicals which may be the same or different and are selected from fluorine, halo-lower alkyl, lower alkanoyl, sulfo, lower aIkylsulfonyl and cyano, or is heterocyclyloxycarbonyl wherein heterocyclyl is bonded by way of a carbon atom and is selected from pyrrolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl, B-carbolinyl and a completely or partially saturated derivative of those radicals, or wherein the meaning heterocyclyloxy-2~ 8 carbonyl for Rl is omitted, Bl is a bond or a bivalent radical of an a-amino acid, which radical is bonded N-terminally to Rl and C-terminally to the amino group at the R2-CH2-carrying carbon atom, preferably the radical of a hydrophobic amino acid, for example proline, phenylalanine, p-fluorophenylalanine, phenylglycine, a-naphthylalanine, cyclo-hexylalanine, cyclohexylglycine or an aliphatic a-amino acid selected from glycine, valine, norvaline, alanine, leucine, norleucine and isoleucine, especially valine, preferably each of the mentioned a-amino acids being in the D-, L- or (D,L)-form, preferably in the L-form, and preferably each of the mentioned amino acids being substituted by one of the radicals mentioned under R1 selected from hydrogen, N-tert-butoxycarbonyl and morpho-linocarbonyl, each of R2 and R3, independently of the other, is phenyl or cyclohexyl, those radicals being unsubstituted or substituted by one or two radicals which may be the same or different and are selected from fluorine, sulfo, lower alkylsulfonyl and cyano, as indicated above in the general definitions, Al is a bivalent radical of a hydrophobic a-amino acid, as indicated above under the general definitions, which radical is bonded N-terminally to the group -C=O and C-terminally to A2, A2 is a bivalent radical of a hydrophobic a-amino acid, preferably as defined above under the general definitions, which radical is bonded N-terminally to Al and C-terminally to the radical NR4Rs, the mentioned amino acid radicals being in the (D)- or (L)-form, but preferably, with the exception of phenylalanine which is in the (L)- or the (D)-formj in the (L)-form, Al and A2 especially form a bivalent radical of a dipeptide of the formula Val-Phe, Ile-Phe, Val-Cha, Ile-Cha, Ile-Gly, Val-Val, Val-Gly, Val-(p-F-Phe), Val-(p-CH30-Phe) or Gly-(p-F-Phe), wherein the amino acids are in the (D)- or (L)-form, especially the (L)-form, with the exception of (L)-Val-Phe, in which Phe is in the (L)- or (D)-form; or A
and A2 together form a bivalent radical of a dipeptide, preferably comprising two of the hydrophobic a-amino acids mentioned above under the general definitions, of which the central amide bond is reduced and which is bonded N-terminally to the group -C=O and C-terminally to the group NR4Rs, as indicated in the general definitions, for example having the formula Val(red)-Phe, and R4 and Rs, together with the bonding nitrogen atom, are thiomorpholino or morpholino, especially rnorpholino; and, alternatively or addition-ally thereto, the compounds of formula I wherein R1 is morpholinosulfonyl or N-(2-pyrid-ylmethyl)-N-methylaminocarbonyl; and the pharmaceutically acceptable salts of those compounds, if salt-forming groups are present; the hydroxy group in compounds offormula I, at the carbon aeom that is vicinal to the carbon atom carrying the radical R2-CH2-, being free or being in a form protected by lower alkanoyl, especially in free form; and it also being possible for heterocyclyloxycarbonyl to be omitted from the defin-ition of R1.

2~ 9~8 Very preferred are the compounds of formula I wherein R1 is hydrogen, tert-butoxy-carbonyl, isobutoxycarbonyl, pyridine-3-carbonyl, morpholinocarbonyl, 3-benzofuranoyl or 1,2,3,4-tetrahydroisoquinoline-3-carbonyl; or, alternatively or additionally thereto, morpholinosulfonyl or N-(2-pyridylmethyl)-N-methylaminocarbonyl, B 1 is a bond or a bivalent radical of the a-amino acid valine, which radical is bonded N-terminally to R
and C-terminally to the amino group at the R2-CH2-carrying carbon atom, in the latter case Rl preferably being hydrogen, tert-butoxycarbonyl or morpholinocarbonyl, or, altern-atively or additionally thereto, morpholinosulfonyl or N-(2-pyridylmethyl)-N-methyl-aminocarbonyl, each of R2 and R3, independently of the other, is phenyl or cyclohexyl, those radicals being unsubstituted or substituted by one or two radicals which may be the same or different and are selected from hydroxy, methoxy, fluorine, sulfo, lower alkyl-sulfonyl, cyano and triflùoromethyl, Al is a bivalent radical of one of the a-amino acids glycine, valine and isoleucine, which radical is bonded N-terminally to the group -C=O
and C-terminally to A2, A2 is a bivalent radical of one of the a-amino acids glycine, valine, phenylalanine, tyrosine, cyclohexylalanine, p-methoxyphenylalanine and p-fluoro-phenylalanine, which radical is bonded N-terminally to Al and C-terrninally to the group NR4Rs, or also Al and A2 together form a bivalent radical of a dipeptide having a reduced central peptide bond, which comprises an N-terminal amino acid radical selected from Gly(red), Val(red) and Ile(red) and a C-terminal amino acid radical selected from glycine, phenylalanine, cyclohexylalanine, tyrosine, p-methoxyphenylalanine and p-fluorophenylalanine, and is bonded N-terminally to the group -C-O and C-terminally to the group NR4Rs, as defined above for Al and A2, and R4 and Rs, together with the bonding nitrogen atom, are thiomorpholino or morpholino, especially morpholino, and the pharmaceutically acceptable salts of those compounds, if salt-forming groups are present.

Very preferred are also the compounds of formula I wherein R1 is hydrogen, tert-butoxy-carbonyl, isobutoxycarbonyl, pyridine-3-carbonyl, morpholinocarbonyl, 3-benzofuranoyl or 1,2,3,4-tetrahydroisoquinoline-3-carbonyl; or, alternatively or additionally thereto, is morpholinosulfonyl or N-(2-pyridylmethyl)-N-methylaminocarbonyl, B1 is a bond or a bivalent radical of the a-amino acid valine, which radical is bonded N-terminally to R
and C-terminally to the amino group at the R2-CH2-carrying carbon atom, in the latter case Rl preferably being hydrogen, tert-butoxycarbonyl or morpholinocarbonyl, or, altern-atively or additionally thereto, morpholinosulfonyl or N-(2-pyridylmethyl)-N-methyl-aminocarbonyl, each of R2 and R3, independently of the other, is phenyl or cyclohexyl, those radicals being unsubstituted or substituted by one or two radicals which may be the 2~

same or different and are selected from fluorine, sulfo, lower aL~ylsulfonyl and cyano, and alternatively or additionally thereto, from hydroxy, methoxy and trifluoromethyl, Al is a bivalent radical of one of the o~-amino acids glycine, valine and isoleucine, which radical is bonded N-terminally to the group -C=O and C-terminally to A2, A2 is a bivalent radical of one of the o~-amino acids glycine, valine, phenylalanine, tyrosine, cyclohexylalanine, p-methoxyphenylalanine and p-fluorophenylalanine, which radical is bonded N-terminally to Al and C-terminally to the group NR4Rs, or also Al and A2 together form a bivalent radical of a dipeptide having a reduccd central peptide bond, which comprises an N-term-inal amino acid radical selected from Gly(red), Val(red) and Ile(red), and a C-terminal amino acid radical selected from glycine, phenylalanine, tyrosine, cyclohexylalanine, p-methoxyphenylalanine and p-fluorophenylalanine, and is bonded N-terminally to the group C=O and C-terminally to the group NR4Rs, as defined above for Al and A2, and R4 and R5, together with the bonding nitrogen atom, are thiomorpholino or morpholino, especially morpholino, and the pharmaceutically acceptable salts of those compounds, if salt-forming groups are present.

Even more preferred are the compounds of formula I according to the definitions given hereinbefore wherein Bl is one of the mentioned bivalent radicals of an a-amino acid and one of the radicals Al and A2 is a bond and the other is one of the mentioned a-amino acids, or compounds of formula I wherein Bl is a bond and each of Al and A2 is one of the mentioned bivalent radicals of an ~c-amino acid or they are together one of the mentioned bivalent radicals of a dipeptide having a reduced central amide bond, the other radicals being as deflned.

Also even more preferred are the compounds of formula I according to the definitions given hereinbefore wherein Bl is a bond or one of the mentioned bivalent radicals of an a-amino acid and each of Al and A2 is the bivalent radical of one of the mentioned amino acids, the other radicals being as defined, or the pharmaceutically acceptable salts of those compounds, if at least one salt-forming group is present.

Of especial interest are the compounds of formula I wherein Rl is hydrogen, tert-butoxy-carbonyl, isobutoxycarbonyl, pyridine-3-carbonyl, morpholinocarbonyl, 3-benzofuranoyl or 1,2,3,4-tetrahydroisoquinoline-3-carbonyl, or alternatively or additionally thereto, morpholinosulfonyl or N-(2-pyridylmethyl)-N-methylaminocarbonyl, Bl is a bond or a bivalent radical of the o~-amino acid valine, which radical is bonded N-terminally to Rl and C-terminally to the amino group at the R2-CH2-carrying carbon atom, Rl in the latter - 21 - ;~ 9~-8 case preferably being hydrogen, tert-butoxycarbonyl or morpholinocarbonyl or, altern-atively or additionally thereto, morpholinosulfonyl or N-(2-pyridylmethyl)-N-methyl-aminocarbonyl, each of R2 and R3, independently of the other, is phenyl or cyclohexyl, those radicals being unsubstituted or substituted by one or two radicals which may be the same or different and are selected from hydroxy, methoxy, fluorine and cyano, especially by one of the mendoned radicals, preferably in the 4-posidon, for example in 4-hydroxy-phenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-cyanophenyl or 4-fluorocyclohexyl, as in the combinadons of R2 and R3 that are mentioned under the general definitions above as being especially preferred, or, alternatively or additionally thereto, each of R2 and R3, independ-ently of the other, is phenyl or cyclohexyl that is unsubstituted or substituted by one or two radicals which may be the same or different and are selected from trifluoromethyl, cyano and fluorine, especially by one of those radicals, preferably in the 4-position, for example in 4-trifluoromethylphenyl, 4-cyanophenyl or 4-fluorophenyl, Al and A2 together form a bivalent radical of a dipeptide of the formula Val-Phe, Ile-Phe, Val-Cha, Ile-Cha, Ile-Gly, Val-Val, Val-Gly, Val-(p-F-Phe), Val-Tyr, Val-(p-CH30-Phe) or Gly-(p-F-Phe) or of a derivative thereof having a reduced central amide bond of the formula Yal(red)-Phe, which is bonded N-terminally to the group -C=O and C-terminally to the group NR4Rs,: and R4 and Rs, together with the bonding nitrogen atom, are thiomorpho-lino or morpholino, especially morpholino, and the pharmaceutically acceptable salts of those compounds, if salt-forming groups are present, the hydroxy group in compounds of formula I, at the carbon atom that is vicinal to the carbon atom carrying the radical R2-CH2-, being free or being in a form protected by acetyl, both the free compounds of formula I and the protected form, in which all the other radicals are as defined, or the salts thereo being especially preferred.

Also of especial interest are the compounds of formula I wherein Rl is hydrogen, tert-butoxycarbonyl, isobutoxycarbonyl, pyridine-3-carbonyl, morpholinocarbonyl, 3-benzo-furanoyl or 1,2,3,4-tetrahydroisoquinoline-3-carbonyl, or, alternadvely or addidonally thereto, morpholinosulfonyl or N-(2-pyridylmethyl)-N-methylaminocarbonyl, B 1 is a bond or a bivalent radical of the a-amino acid valine, which radical is bonded N-term-inally to Rl and C-terminally to the amino ,,roup at the R2-CH2-carrying carbon atom, R
in the latter case preferably being hydrogen, tert-butoxycarbonyl or morpholinocarbonyl or, alternadvely or additionally thereto, morpholinosulfonyl or N-(2-pyridylmethyl)-N-methylaminocarbonyl, each of R2 and R3, independently of the other, is phenyl or cyclo-hexyl, those radicals being unsubstituted or substituted by one or two radicals which may be the same or different and are selected from fluorine and cyano, especially by one of the mentioned radicals, preferably in the 4-position, for example in 4-fluorophenyl, 4-cyano-phenyl or 4-fluorocyclohexyl, as in the combinations of R2 and F~3 that are mentioned under the general definitions above as being especially preferred, or alternatively or additionally thereto, each of R2 and R3, independently of the other, is phenyl or cyclo-hexyl that is unsubstituted or substituted by one or two radicals which may be the same or different and are selected from trifluoromethyl, cyano and fluorine, especially by one of those radicals, preferably in the 4-position, for example in 4-trifluoromethylphenyl, 4-cyanophenyl or 4-fluorophenyl, A1 and A2 together form a bivalent radical of a dipep-tide of the formula Val-Phe, Ile-Phe, Val-Cha, Ile-Cha, Ile-Gly, Val-Val, Val-Gly, Val-(p-F-Phe), Val-(p-CH30-Phe) or Gly-(p-F-Phe) or of a derivative thereof having a reduced central amide bond of the formula Val(red)-Phe, which is bonded N-terminally to the group -C=0 and C-terminally to the group NR4Rs, and R~ and Rs, together with the bonding nitrogen atom, are thiomorpl-olino or morpholino, especially morpholino, and the pharmaceutically acceptable salts of those compounds, if salt-forming groups are present, the hydroxy group in compo~nds of formula I, at the carbon atom that is vicinal to the carbon atom carrying the radical R2-CH2-, being free or being in a form protected by acetyl, both the free compounds of formula I and the protected form wherein all the other radicals are as defined, or the salts tllereof, heing especially preferred.

Of most especial interest are the compounds mentioned in the Examples and the salts of those compounds, especially the pharmaceutically acceptable salts, if salt-forming groups are present.

These include the compoLInds of form~ I havi~ the names Boc-Cha[C](p-F)Phe-(L)-Ile-(L)-Phe-morpholin-4-ylamide, Boc-(p-F)Phe[CI(p-F)Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide, Boc-(p-F)Phe[C~(p-F)Phe-(L)-Val-(L)-(p-F-Phe)-morpholin-4-ylamide, Boc-(p-F)Phe[Cl(p-F)Phe-(l,)-Val-(L)-(p-CH30-Phe)-morpholin-4- ylamide, Boc-(p-F)Phel C~(p-F)Phe-(L)-Val-(L)-Cha-morpholin-4-ylamide, Boc-(p-F)Phe[C](p-F)Phe-(L)-lle-(L)-Phe-morpholin-4-ylclmide, Boc-(p-F)Phe[C] (p-CN)Pl-e-(L)-Val-(L)-Phe-morpholin-4-ylamide, Boc-(p-F)Phe[C~ (p-CN)Phe-(L)-Val-(L)-(p-F-Phe)-morpholin-4-ylamide, Boc-(p-F)Phe[Cl(p-CN)Phe-(L)-Val-(L)-(p-CE130-Phe)-morpholin-4-ylamide, Boc-(p-F)Phe[C~(p-CN)Phe-(L)-Val-(L)-Cha--morpholin-4-ylamide, Boc-(p-F)Phe[CI(p-CN)Phe-(L)-lle-(L)-Phe-morpholin-4-ylamide, Boc-Phe[C~(p-F)Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide, 2~ 8 Boc-Phe[C](p-F)Phe-(L)-Val-(L)-(p-F-Phe)-morpholin-4-ylamide, Boc-Phe[C](p-F)Phe-(L)-Val-(L)-(p-CH30-Phe)-morpholin-4-ylamide, Boc-Phe[C](p-F)Phe-(L)-Val-(L)-Cha-morpholin-4-ylamide, Boc-Phe[C] (p-F)Phe-(L)-Ile-(L)-Phe-morpholin-4-ylamide, Boc-Phe[C](p-CN)Phe-(L)-Val-(L)-Phe-morpholin-4-ylarnide, Boc-Phe[C](p-CN)Phe-(L)-Val-(L)-(p-F-Phe)-morpholin-4-ylamide, Boc-Phe[C](p-CN)Phe-(L)-Val-(L)-(p-CH30-Phe)-morpholin-4-ylamide, Boc-Phe[C](p-CN)Phe-(L)-Val-(L)-Cha-morpholin-4-ylamide, Boc-Phe[C](p-CN)Phe-(L)-Ile-(L)-Phe-morpholin-4-ylamide, Boc-Phe[C](p-CH30)Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide, Boc-Phe[C](p-CH30)Phe-(L)-Val-(L)-(p-F-Phe)-morpholin-4-ylamide, Boc-Phe[C](p-CH30)Phe-(L)-Val-(L)-(p-CH30-Phe)-morpholin-4-ylamide, Boc-Phe[C](p-CH30)Phe-(L)-Val-(L)-Cha-morpholin-4-ylamide, Boc-Phe~C](p-CH30)Phe-(L)-Ile-(L)-Phe-morpholin-4-ylamide, Boc-Phe[C](p-CF3)Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide, Boc-Phe[C] (p-CF3)Phe-(L)-Val-(L)-(p-F-Phe)-morpholin-4-ylamide, Boc-Phe[C](p-CF3)Phe-(L)-Val-(L)-(p-CH30-Phe)-morpholin-4-ylamide, Boc-Phe[C] (p-CF3)Phe-(L)-Val-(L)-Cha-morpholin-4-ylamide, Boc-Phe[C](p-CF3)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)-Val-(L)-(p-F-Phe)-morpholin-4-ylamide, Boc-Cha[C](p-CN)Phe-(L)-Val-(L)-(p-CH30-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-CH30)Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide, Boc-Cha[C](p-CH30)Phe-(L)-Val-(L)-(p-F-Phe)-morpholin-4-ylamide, Boc-Cha[C](p-CH30)Phe-(L)-Val-(L)-(p-CH30-Phe)-morpholin-4-ylamide, Boc-Cha[C] (p-CH30)Phe-(L)-Val-(L)-Cha-morpholin-4-ylamide, Boc-Cha[C](p-CH30)Phe-(L)-lle-(L)-Phe-morpholin-4-ylamide, Boc-Cha[C] (p-CF3)Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide, Boc-Cha[C](p-CF3)Phe-(L)-Val-(L)-(p-F-Phe)-morpholin-4-ylamide, Boc-Cha[C](p-CF3)Phe-(L)-Val-(L)-(p-CH30-Phe)-morpholin-4-ylamide, Boc-Cha[C](p-CF3)Phe-(L)-Val-(L)-Cha-morpholin-4-ylamide, or Boc-Cha[C](p-CF3)Phe-(L)-Ile-(L)-Phe-morpholin-4-ylamide, or the corresponding compounds wherein -morpholin-4-ylamide is replaced by the radical -thiomorpholin-4-yl-amide.

- 24 - ;~ 8 These also include the compounds of formula I according to claim 1 having the names Boc-(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-ylar-nide;
Boc-Phe[C]Phe-(L)-Val(red)-(L)-Phe-morpholin-4-ylamide;
or isobutoxycarbonyl-Phe[C]Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide; or the corres-ponding compounds wherein -morpholin-4-ylamide is replaced by the radical-thiomorpho-lin-4-ylamide; or salts thereof, if salt-forming groups are present; or the compounds of formula I according to claim 1 having the names Boc-Cha[C](p-CN)Phe-(L)-Val-(L)-Phe-thiomorpholin-4-ylamide;
or Boc-Cha[C](p-F)Phe-(L)-Val-(L)-Phe-thiomorpholin-4-ylamide; or the compounds of formula I having the names Boc-Cha[C](p-F)Phe-(L)-Ile-(L)-Phe-morpholin-4-ylamide, Boc-Cha[C](p-F)Phe-(L)-Val-(L)-Cha-morpholin-4-ylamide, Boc-(p-CF3)Phe[C]Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide, Boc-(p-CF3)Phe[C]Phe-(L)-Val-(L)-(p-F)Phe-morpholin-4-ylamide, Boc-(p-CF3)Phe[C]Phe-(L)-Val-(L)-(p-CH30)Phe-morpholin-4-ylamide, Boc-(p-CF3)Phe[C]Phe-(L)-Val-(L)-Cha-morpholin-4-ylamide, Boc-(p-CF3)Phe[C]Phe-(L)-Ile-(L)-Phe-morpholin-4-ylamide, Boc-(p-CF3)Phe[C](p-F)Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide, Boc-(p-CF3)Phe[C](p-F)Phe-(L)-Val-(L)-(p-F)Phe-morpholin-4-ylamide, Boc-(p-CF3)Phe[C](p-F)Phe-(L)-Val-(L)-Cha-morpholin-4-ylamide, Boc-(p-CF3)Phe[C](p-F)Phe-(L)-Val-(L)-(p-CH30)Phe-morpholin-4-ylamide, Boc-(p-CF3)Phe[C](p-F)Phe-(L)-Ile-(L)-Phe-morpholin-4-ylamide, Boc-(p-CF3)Phe[C](p-CF3)Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide, Boc-(p-CF3)Phe[C](p-CF3)Phe-(L)-Val-(L)-(p-F)Phe-morpholin-4-ylamide, Boc-(p-CF3)Phe[C](p-CF3)Phe-(L)-Ile-(L)-Phe-morpholin-4-ylamide, Boc-(p-CF3)Phe[C](p-CF3)Phe-(L)-Val-(L)-(p-CH30)Phe-morpholin-4-ylamide, or Boc-(p-CF3)Phe[C](p-CF3)Phe-(L)-Val-(L)-Cha-morpholin-4-ylamide; or the corres-ponding compounds wherein -morpholin-4-ylamide is replaced by the radical -thio-morpholin-4-ylamide, or the compounds of formula I having the names 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;

2~ 9~8 Boc-Phe[ClTyr-(L)-Val-(L)-Tyr-morpholin-4-ylamide;
Boc-Tyr[C]Tyr-(L)-Val-(L)-Phe-morpholin-4-ylamide;
Boc-Tyr[C~Tyr-(L)-Val-(L)-Tyr-morpholin-4-ylamide, or the corresponding compounds wherein -morpholin-4-ylamide is replaced by the radical -thiomorpholin-4-ylamide.

Of very special importance is the compound of formula I wherein R1 is tert-butoxy-carbonyl, B1 is a bond, R2 is cyclohexyl, R3 is p-fluorophenyl, A1 is valine, A2 is phenyl-alanine, and R4 and Rs, together with the bonding nitrogen atom, are morpholino.
Also of very special importance is the compound of formula I wherein R1 is tert-butoxy-carbonyl, Bl is a bond, R2 and R3 are phenyl, A1 is valine, A2 is phenylalanine, and R4 and Rs, together with the bonding nitrogen atom, are morpholino.

Also of very special importance is the compound of formula I wherein R1 is tert-butoxy-carbonyl, Bl is a bond, R2 is cyclohexyl, R3 is p-fluorophenyl, A1 is valine, A2 is p-fluorophenylalanine, and R4 and Rs, together with the bonding nitrogen atom, are morpholino.

Also of very special importance is the compound of formula I wherein Rl is tert-butoxy-carbonyl, Bl is a bond, R2 is cyclohexyl, R3 is p-fluorophenyl, Al is valine, A2 is p-methoxyphenylalanine, and R4 and Rs, together with the bonding nitrogen atom, are morpholino.

Also of very special importance is the compound of formula I wherein Rl is tert-butoxy-carbonyl, Bl is a bond, R2 is cyclohexyl, R3 is p-fluorophenyl, A1 is valine, A2 is cyclo-hexylalanine, and R4 and Rs, together with the bonding nitrogen atom, are morpholino.

Also of very special importance is the compound of formula I wherein R1 is tert-butoxy-carbonyl, B1 is a bond, R2 is cyclohexyl, R3 is p-fluorophenyl, A1 is valine, A2 is phenyl-alanine, and R4 and Rs, together with the bonding nitrogen atom, are thiomorpholino.

Also of very special importance is the compound of formula I wherein R1 is tert-butoxy-carbonyl, B1 is a bond, R2 is cyclohexyl, R3 is p-fluorophenyl, A1 is isoleucine, A2 is phenylalanine, and R4 and Rs, together with the bonding nitrogen atom, are morpholino.

Also of very special importance is the compound of formula I wherein Rl is tert-butoxy-a carbonyl, Bl is a bond, R2 is phenyl, R3 is p-fluorophenyl, A1 is valine, A2 is phenyl-alanine, and R4 and Rs, together with the bonding nitrogen atom, are morpholino.
Also of very special importance is the compound of formula I wherein R1 is tert-butoxy-carbonyl, Bl is a bond, R2 is p-fluorophenyl, R3 is p-fluorophenyl, Al is valine, A2 is phenylalanine, and R4 and Rs, together with the bonding nitrogen atom, are morpholino.

Also of very special importance is the compound of formula I wherein R1 is tert-butoxy-carbonyl, Bl is a bond, R2 is p-fluorophenyl, R3 is p-fluorophenyl, Al is valine, A2 is p-fluorophenylalanine, and R4 and Rs, together with the bonding nitrogen atom, are morpholino.

Also of very special importance is the compound of formula I wherein R1 is tert-butoxy-carbonyl, B1 is a bond, R2 is cyclohexyl, R3 is p-cyanophenyl, A1 is valine, A2 is phenyl-alanine, and R4 and Rs, together with the bonding nitrogen atom, are morpholino.
Also of very special importance is the compound of formula I wherein R1 is tert-butoxy-carbonyl, B 1 is a bond, R2 and R3 are phenyl, Al is valine, A2 is phenylalanine, and R4 and Rs, together with the bonding nitrogen atom, are thiomorpholino.

The compounds of formula I or their hydroxy-protected derivatives, and salts of such compounds having at least one salt-forming group, are obtained according to processes known ~ se, for example as follows:
a) for the preparation of compounds of the formula R~' ~N~' A~ A ~ N ~ (Ib), wherein Rl' is as defined for Rl in compounds of formula I, except that it is not hydrogen, the hydroxy group at the carbon atom that is vicinal to the carbon atom carrying the radical R2-CH2- is free or in protected forçn, and the other radicals are as defined for compounds of formula I, an acid of the formula 2~ B

R 1 '-OH (II) or a reactive acid derivative thereof, wherein Rl ' is as defined for Rl in compounds of formula I, except that it is not hydrogen, is condensed with an amino compound of the formula H B / ~ A N ~ R4 or with a reactive derivative thereof, wherein the radicals are as def1ned for compounds of formula I, free functional groups in the starting materials of formulae II and III, with the exception of the groups participating in the reaction, being, where appropriate, in protected form, and, if desired, protecting groups present are removed, or b) for the preparation of compounds of the formula R1 ~N ~ Al~ A ~ N \ (Ic), wherein B1' represents the same radicals as does Bl in compounds of formula I, except that it is not a bond, the hydroxy group at the carbon atom that is vicinal to the carbon atom carrying the radical R2-CH2- is free or in protected form, and the other radicals are as def1ned for compounds of formula I, a carboxylic acid of the formula R 1 -B 1 '-OH (IV) or a reactive acid derivative thereof, wherein Rl is as defined for compounds of formula I
and B1' is as last defined, is condensed with an amino compound of the formula 2~ a \I`l~A~ ,N~ (V), or with a reactive derivative thereof, wherein the radicals are as defined for compounds of formula I, free functional groups in the starting materials of formulae IV and V, with the exception of the groups participating in the reaction, being, where appropriate, in protected form, and, if desired, protecting groups present are removed, or c) a carboxylic acid of the fonnula H OH ~
` B~ ~OH (VI), R/

or a reactive derivative thereof, wherein the radicals are as defined for compounds of formula I, is condensed with an amino compound of the forrnula A ~R4 HA2 \R (VII), s or with a reactive derivative thereof, wherein the radicals are as defined for compounds of formula 1, free functional groups in the starting materials of formulae VI and VII, with the exception of the groups participating in the reaction, being, where appropriate, in protected form and, if desired, protecting groups present are removed, or d) for the preparation of a compound of the forrnula - 29 - 2~ 8 \B ~ \A~ \R (Id), wherein Al' and A2' are as defined for Al and A2 in compounds of formula I, except that Al' is not a bond and the peptide bond between Al' and A2' is not in reduced form, the hydroxy group at the carbon atom that is vicinal to the carbon atom carrying the radical R2-CH2- is free or in protected form, and the other radicals are as defined for compounds of formula I, a carboxylic acid of the formula H OH I /
\B/ ~ A ' (VIII), O

or a reactive derivative thereof, wherein the radicals are as last defined, is condensed with an amino compound of the formula , R4 H 2 N ~ R (lX), or with a reactive derivative thereof, wherein the radicals are as last defined, free func-tional groups in the staning materials of formulae VIII and IX, with the exception of the groups participating in the reaction, being, where appropriate, in protected form and, if desired, protecting groups present are removed, or - 30 - ;;~ 3 e) a carboxylic acid of the formula H OH ~
B~ ~ A2 (X), or a reactive derivative thereof, wherein the radicals are as defined for compounds of formula I, is condensed with an amino compound of the formula H ~ N \ (XI), or with a reactive derivative thereof, the radicals being as defined for compounds of formula I, free functional groups in the starting materials of formulae X and XI, with the exception of the groups participating in the reaction, being, where appropriate, in protected form and, if desired, protecting groups present are removed, or f) in a compound of formula I wherein the substituents are as defined above, provided that at least one functional group in the compound of formula I concerned is protected by protecting groups, protecting groups present are removed, and/or, if desired, a compound of formula I obtained according to any one of the above processes a) to f) that has at least one salt-forrning group is converted into its salt andJor an obtainable salt is converted into the free compound or into a different salt and/or any obtainable isomeric mixtures of compounds of formula I are separated and/or a compound of formula I according to the invention is converted into a different compound of formula I
according to the invention.
The processes defined above are described in more detail hereinafter:
Process a) (Preparation of an amide bond) - 31 - ;~ 8 In starting materials of formulae II and III1 functional groups, with the exception of the groups that are to participate in the reaction or that do not react under the reaction conditions, are, independently of one another, protected by protecting groups.

Protecting groups for functional groups in starting materials the reaction of which is to be avoided, especially carboxy, amino, hydroxy, mercapto and sulfo groups, include, espec-ially, those protecting groups (conventional protecting groups) that are customarily used in the synthesis of peptide compounds, but also in the synthesis of cephalosporins and peni-cillins and also nucleic acid derivatives and sugars. Those protecting groups may already be present in the precursors and are to protect the functional groups concerned against undes*ed secondary reactions, such as acylations, etherifications, esteri~lcations, oxid-ations, solvolysis etc.. In some cases, the protecting groups can also cause reactions to proceed in a selective, for example stereoselective, manner. A characteristic of protecting groups is that they can be readily removed, that is to say, without undesired secondary reactions, for example by solvolysis, reduction or photolysis or alsb enzymatically, for example also under physiological conditions. Protecting groups may, however, also be present in end products. Compounds of formula I having protected functional groups may have a greater metabolic stability or have otherwise improved pharmacodynamic properties in comparison with the corresponding compounds having free functionalgroups. The corresponding compounds having protected groups, for example having protected hydroxy groups, may also be "prodrugs" which are activated in vivo by enzymatic cleavage, for example by esterases.

The protection of functional groups by such protecting groups, the protecting groups themselves and the reactions for the* removal are described, for example, in standard works, such as J. F. W. McOmie, "Protective Groups in Organic Chemistry", PlenumPress, London and New York 1973, in Th. W. Greene, "Protective Groups in OrganicSynthesis", Wiley, New York 1981, in "The Peptides"; Volume 3 (E. Gross and J.
Meienhofer, Editors), Academic Press, London und New York 1981, in "Methoden derorganischen Chemie", Houben-Weyl, 4th edition, Volume 15/I, Georg Thieme Verlag,Stuttgart 1974, in H.-D. Jakubke and H. Jescheit, "Aminosauren, Peptide, Proteine", Verlag Chemie, Weinheim, Deerfield Beach and Basle 1982, and in Jochen Lehmann, "Chemie der Kohlenhydrate: Monosaccharide und Derivate", Georg Thieme Verlag, Stuttgart 1974.

- 32 - 2~ g 8 A carboxy group is protected, for example, in the form of an ester group that can be cleaved selectively under mild conditions. A carboxy group protected in esterified form is esterified especially by a lower alkyl group that is preferably branched in the 1-position of the lower alkyl group or is substituted by suitable substituents in the 1- or 2-position of the lower alkyl group.

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

A protected carboxy group that is esterified by a lower alkyl group that is branched in the 1-position of the lower alkyl group is, for example, tert-lower alkoxycarbonyl, for example tert-butoxycarbonyl.

A protected carboxy group that is esterified by a lower alkyl group that is substituted by suitable substituents in the 1- or 2-position of the lower alkyl group is, for example, aryl-methoxycarbonyl having one or two aryl radicals wherein aryl is unsubstituted phenyl or phenyl that is mono-, di- or tri-substituted, for example, by lower alkyl, for example tert-lower alkyl, such as tert-butyl, lower alkoxy, for example methoxy, hydroxy, halogen, for example chlorine, and/or by nitro, for example benzyloxycarbonyl, benzyloxycarbonyl substituted by the mentioned substituents, for example 4-nitrobenzyloxycarbonyl or 4-methoxybenzyloxycarbonyl, diphenylmethoxycarbonyl, or diphenylmethoxycarbonyl substituted by the mentioned substituents, for example di-(4-methoxyphenyl)-methoxy-carbonyl; also carboxy esterified by a lower alkyl group, the lower alkyl group being sub-stituted by suitable substituents in the 1- or 2-position, such as l-lower alkoxy-lower alkoxycarbonyl, for example methoxymethoxycarbonyl, 1-methoxyethoxycarbonyl or 1-ethoxyethoxycarbonyl, 1-lower alkylthio-low~r alkoxycarbonyl, for example 1-methyl-thiomethoxycarbonyl or 1-ethylthioethoxycarbonyl, aroylmethoxycarbonyl wherein the aroyl group is benzoyl that is unsubstituted or substituted, for example, by halogen, such as bromine, for example phenacyloxycarbonyl, 2-halo-lower alkoxycarbonyl, for example 2,2,2-trichloroethoxycarbonyl, 2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl, and also 2-(tri-substituted silyl)-lower alkoxycarbonyl, wherein each of the substituents, independ-ently of the others, is an aliphatic, araliphatic, cycloaliphatic or aromatic hydrocarbon radical that is unsubstituted or substituted, for example, by lower alkyl, lower alkoxy, aryl, halogen and/or by nitro, for example lower alkyl, phenyl-lower alkyl, cycloaLkyl or phenyl, each of which is unsubstituted or substituted as indicated above, for example 2-tri-lower alkylsilyl-lower alkoxycarbonyl, such as 2-tri-lower alkylsilylethoxycarbonyl, 33 2~7~hB

for example 2-trimethylsilylethoxycarbonyl or 2-(di-n-butylmethylsilyl)-ethoxycarbonyl, or 2-triarylsilylethoxycarbonyl, such as triphenylsilylethoxycarbonyl.

A carboxy group is also protected in the form of an organic silyloxycarbonyl group. An organic silyloxycarbonyl group is, for example, a tri-lower alkylsilyloxycarbonyl group, for example trimethylsilyloxycarbonyl. The silicon atom of the silyloxycarbonyl group may also be substituted by two lower alkyl groups, for example two methyl groups, and one amino or carboxy group of a second molecule of formula I. Compounds having such protecting groups can be prepared, for example, using dimethylchlorosilane as silylating agent.

A carboxy group is also protected in the form of an internal ester having a hydroxy group that is at a suitable distance, for example in the ~-position, from the carboxy group in the molecule, that is to say, is protected in the form of a lactone, preferably a ~-lactone.

A protected carboxy group is preferably tert-lower alkoxycarbonyl, for example tert-butoxycarbonyl, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyls 9-fluorenylmethoxy-carbonyl or diphenylmethoxycarbonyl, or a carboxy group protected in the forrn of a lactone, especially a ~-lactone.

A protected amino group is protected by an amino-protecting group, for example in the form of an acylamino, arylmethylamino, etherified mercaptoamino, 2-acyl-lower alk-1-enylamino or silylamino group or in the form of an azido group.

In an acylamino group, acyl is, for example, the acyl radical of an organic carboxylic acid having, for example, up to 18 carbon atoms, especially of a lower alkanecarboxylic acid that is unsubstituted or substituted, for example, by halogen or by aryl, or of a benzoic acid that is unsubstituted or substituted, for example, by halogen, lower alkoxy or by nitro, or preferably of a carbonic acid semiester. Such acyl groups are preferably lower alkanoyl, such as formyl, acetyl, propionyl or pivaloyl, halo-lower alkanoyl, for example 2-halo-acetyl, such as 2-chloro-, 2-bromo-, 2-iodo-, 2,2,2-trifluoro- or 2,2,2-trichloro-acetyl, benzoyl that is unsubstituted or substituted, for example, by halogen, lower alkoxy or by nitro, such as benzoyl, 4-chlorobenzoyl, 4-methoxybenzoyl or 4-nitrobenzoyl, lower alkoxycarbonyi, lower alkoxycarbonyl that is preferably branched in the l-position of the lower alkyl radical or suitably substituted in the 1- or 2-position, for example tert-lower alkoxycarbonyl, such as tert-butoxycarbonyl, arylmethoxycarbonyl having one, two or - 34- 2~

three aryl radicals that are phenyl that is unsubstituted or mono- or poly-substituted, for example, by lower alkyl, especially tert-lower alkyl, such as tert-butyl, lower alkoxy, such as methoxy, hydroxy, halogen, such as chlorine, and/or by nitro, for example benzyloxy-carbonyl, 4-nitrobenzyloxycarbonyl, diphenylmethoxycarbonyl, 9-fluorenylmethoxy-carbonyl or di-(4-methoxyphenyl)methoxycarbonyl, aroylmethoxycarbonyl, wherein the aroyl group is preferably benzoyl that is unsubstituted or substituted, for example, by halogen, such as bromine, for example phenacyloxycarbonyl, 2-halo-lower alkoxy-carbonyl, for example 2,2,2-trichloroethoxycarbonyl, 2-bromoethoxycarbonyl or 2-iodo-ethoxycarbonyl, 2-(tri-substituted silyl)-lower alkoxycarbonyl, for example 2-tri-lower alkylsilyl-lower aL~coxycarbonyl, such as 2-trimethylsilylethoxycarbonyl or 2-(di-n-butyl-methylsilyl)-ethoxycarbonyl, or triarylsilyl-lower alkoxycarbonyl, for example 2-tri-phenylsilylethoxycarbonyl.

In an arylmethylamino group, for example a mono-, di- or, especially, tri-arylmethylamino group, the aryl radicals are, especially, unsubstituted or substituted phenyl radicals. Such groups are, for example, benzyl-, diphenylmethyl- or, especially, trityl-amino.

In an etherified mercaptoamino group, the mercapto group is especially in the form of substituted arylthio or aryl-lower alkylthio, wherein aryl is, for example, phenyl that is unsubstituted or substituted, for example, by lower alkyl, such as methyl or tert-butyl, lower alkoxy, such as methoxy, halogen, such as chlorine, and/or by nitro, for example 4-nitrophenylthio.

In a 2-acyl-lower alk- l-enyl radical that can be used as an amino-protecting group, acyl is, for example, the corresponding radical of a lower alkanecarboxylic acid, of a benzoic acid that is unsubstituted or substituted, for example, by lower alkyl, such as methyl or tert-butyl, lower alkoxy, such as methoxy, halogen, such as chlorine, and/or by nitro, or espec-ially of a carbonic acid semiester, such as a carbonic acid lower alkyl semiester. Corres-ponding protecting groups are especially 1-lower alkanoyl-lower alk-1-en-2-yl, for example 1-lower alkanoyl-prop-1-en-2-yl, such as 1-acetyl-prop-1-en-2-yl, or lower alkoxycarbonyl-lower alk- 1 -en-2-yl, for example lower alkoxycarbonyl-prop- 1-en-2-yl, such as 1-ethoxycarbonyl-prop-1-en-2-yl.

A silylamino group is, for example, a tri-lower alkylsilylamino group, for example trimethylsilylamino or tert-butyldimethylsilylamino. The silicon atom of the silylamino group may also be substituted by only two lower alkyl groups, for example methyl groups, - 35 - ;~ t3 '~

and the amino group or carboxy group of a second molecule of formula I. Cornpounds having such protecting groups can be prepared, for example, using the corresponding chlorosilanes, such as dimethylchlorosilane, as silylating agents.

An amino group can also be protected by conversion into the protonated forrn; suitable corresponding anions are especially those of strong inorganic acids, such as of sulfuric acid, phosphoric acid or hydrohalic acids, for example the chlorine or bromine anion, or of organic sulfonic acids, such as p-toluenesulfonic acid.

Preferred amino-protecting groups are lower alkoxycarbonyl, phenyl-lower alkoxy-carbonyl, fluorenyl-lower alkoxycarbonyl, 2-lower alkanoyl-lower alk- I -en-2-yl or lower alkoxycarbonyl-lower alk- l-en-2-yl, especially preferably tert-butoxycarbonyl or benzyl-oxycarbonyl.

A hydroxy group can be protected, for example, by an acyl group, for example lower alkanoyl that is unsubstituted or substituted by halogen, such as chlorine, such as acetyl or 2,2-dichloroacetyl, or especially by an acyl radical of a carbonic acid semiester mentioned for protected amino groups. A preferred hydroxy-protecting group is, for example, 2,2,2-trichloroethoxycarbonyl, 4-nitrobenzyloxycarbonyl, diphenylmethoxycarbonyl or trityl. A
hydroxy group can also be protected by tri-lower alkylsilyl, for example trimethylsilyl, tri-isopropylsilyl or tert-butyldimethylsilyl, a readily removable etherifying group, for example an alkyl group, such as tert-lower alkyl, for example tert-butyl, an oxa- or a thia-aliphatic or -cycloaliphatic, especially 2-oxa- or 2-thia-aliphatic or -cycloaliphatic, hydro-carbon radical, for example l-lower alkoxy-lower alkyl or l-lower alkylthio-lower alkyl, such as methoxymethyl, I-methoxyethyl, l-ethoxyethyl, rnethylthiomethyl, l-methylthio-ethyl or 1-ethylthioethyl, or 2-oxa- or 2-thia-cycloalkyl having from 5 to 7 ring atoms, such as 2-tetrahydrofuryl or 2-tetrahydropyranyl, or a corresponding thia analogue, and also by l-phenyl-lower alkyl, such as benzyl, diphenylmethyl or trityl, it being possible for the phenyl radicals to be substituted, for example, by halogen, for example chlorine, lower alkoxy, for example methoxy, and/or by nitro.

Two hydroxy groups occurring in a molecule, especially vicinal hydroxy groups or a hydroxy group and an amino group Ihat are vicinal with respect to one another, can be protected, for example, by bivalent protecting groups, such as a methylene group that is preferably substituted, for example by one or two lower alkyl radicals or by oxo, for example by unsubstituted or substituted alkylidene, for example lower alkylidene, such as 2~ 9~L8 isopropylidene, cycloalkylidene, such as cyclohexylidene, a carbonyl group or benzyl-idene.

A hydroxy group that is vicinal to a carboxy group can be protected by the formation of an internal ester (lactone), especially a ~-lactone.

A protected hydroxy group is preferably protected by tri-lower alkylsilyl or in the form of a lactone, especially by tert-butyldimethylsilyl or in the form of a ~-lactone.

A mercapto group, such as, for example, in cysteine, can be protected especially by S-alkylation with unsubstituted or substituted alkyl radicals, by silylation, thioacetal formation, S-acylation or by the formation of asymmetric disulflde groupings. Preferred mercapto-protecting groups are, for example, benzyl that is unsubstituted or substituted in the phenyl radical, for example by methoxy or by nitro, such as 4-methoxybenzyl,diphenylmethyl that is unsubstituted or substituted in the phenyl radical, for example by methoxy, such as di-(4-methoxyphenyl)-methyl, triphenylmethyl, pyridyldiphenylmethyl, trimethylsilyl, benzylthiomethyl, tetrahydropyranyl, acylaminomethyl, such as acetamido-methyl, isobutyrylacetamidometllyl or 2-chloroacetamidomethyl, benzoyl, benzyloxy-carbonyl or alkyl-, especially lower alkyl-aminocarbonyl, such as ethylaminocarbonyl, and also lower alkylthio, such as S-ethylthio or S-tert-butylthio, or S-sulfo.

A sulfo group can be protected, for example, by lower alkyl, for example methyl or ethyl, by phenyl or in the form of sulfonamide, for example in the form of imidazolide.
A protecting group, for example a carboxy-protecting group, in the context of this Application, is expressly also to be understood as being a polymeric carrier that is bonded to the functional group to be protected, for example a carboxy group, in such a manner that it can be readily removed, such as is suitable, for example, for the Merrifield synthesis. Such a suitable polymeric carrier is especially a polystyrene resin that is weakly cross-linked by copolymerisation with divinylbenzene and that carries bridge members suitable for reversible bonding.

The acids of formula Il are carboxylic acids or sulfonic acids.

The carboxylic acids of formula II either have a free carboxy group or are in the form of a reactive derivative, for example in the form of an activated ester derived from the free .

carboxy compound,- in the form of a reactive anhydride, or also in the form of a reactive cyclic amide. The reactive derivatives can also be formed in situ.

Activated esters of compounds of formula Il having a carboxy group are especially esters that are unsaturated at the linking carbon atom of the esterifying radical, for exarnple of the vinyl ester type, such as vinyl esters (obtainable, for example, by transesterification of a corresponding ester with vinyl acetate; activated vinyl ester method), carbamoyl esters (obtainable, for example, by treating the corresponding acid with an isoxazolium reagent;
1,2-oxazolium or Woodward method) or l-lower alkoxyvinyl esters (obtainable, forexample, by treating the corresponding acid with a lower alkoxyacetylene; ethoxyacet-ylene method), or esters of the amidino type, such as N,N'-di-substituted amidino esters (obtainable, for example, by treating the corresponding acid with a suitable N,N'-di-substituted carbodiimide, for example N,N'-dicyclohexylcarbodiimide; carbodiimide method) or N,N-di-substituted amidino esters (obtainable, for example, by treating the corresponding acid with an N,N-di-substituted cyanamide; cyanamide method), suitable aryl esters, especially phenyl esters substituted by electron-attracting substituents (obtain-able, for example, by treating the corresponding acid with a suitably substituted phenol, for example 4-nitrophenol, 4-methylsulfonylphenol, 2,4,5-trichlorophenol, 2,3,4,5,6-penta-chlorophenol or 4-phenyldiazophenol, in the presence of a condensation agent, such as N,N'-dicyclohexylcarbodiimide; activated aryl esters method), cyanomethyl esters(obtainable, for example, by treating the corresponding acid with chloroacetonitrile in the presence of a base; cyanomethyl esters method), thio esters, especially unsubstituted or substituted, for example nitro-substituted, phenylthio esters (obtainable, for example, by treating the corresponding acid with unsubstituted or substituted, for example nitro-substituted, thiophenols, using, inter alia, the anhydride or carbodiimide method; activated thiol esters method) or especially amino or amido esters (obtainable, for example, by treating the corresponding acid with an N-hydroxyamino or N-hydroxyamido compound, respectively, for example N-hydroxysuccinimide, N-hydroxypiperidine, N-hydroxyphthal-imide, N-hydroxy-5-norbornene-2,3-dicarboxylic acid imide, 1-hydroxybenzotriazole or 3-hydroxy-3,4-dihydro-1,2,3-benzotriazin-4-one, for example in accordance with the anhydride or carbodiimide method; activated N-hydroxy esters method). Internal esters, for example ~-lactones, may also be used.

Anhydrides of acids may be symmetric or, preferably, mixed anhydrides of those acids, for example anhydrides with inorganic acids, such as acid halides, especially acid chlorides (obtainable, for example, by treating the corresponding acid with thionyl Z~ 8 chloride, phosphorus pentachloride or oxalyl chloride; acid chloride method), azides (obtainable, for example, from a corresponding acid ester by way of the corresponding hydrazide and treatment thereof with nitrous acid; azide method), anhydrides with carbonic acid semiesters, for example carbonic acid lower aL~yl semiesters (obtainable, for example, by treating the corresponding acid with chloroformic acid lower alkyl esters or with a l-lower alkoxycarbonyl-2-lower alkoxy- 1,2-dihydroquinoline; mixed O-aLkyl-carbonic acid anhydrides method), or anhydrides with dihalogenated, especially dichlor-inated, phosphoric acid (obtainable, for example, by treating the corresponding acid with phosphorus oxychloride; phosphorus oxychloride method), anhydrides with other phos-phoric acid derivatives (for example those which can be obtained with phenyl-N-phenyl-phosphoramidochloridate or by reaction of alkylphosphoric acid amides in the presence of sulfonic acid anhydrides and/or racemisation-reducing additives, such as N-hydroxy-benzotriazole, or in the presence of cyanophosphonic acid diethyl ester) or withphosphorous acid derivatives, or anhydrides with organic acids, such as mixed anhydrides with organic carboxylic acids (obtainable, for example, by treating the corresponding acid with an unsubstituted or substituted lower alkane- or phenyl-lower alkane-carboxylic acid halide, for example phenylacetic acid, pivalic acid or trifluoroacetic acid chloride; mixed carboxylic acid anhydrides method) or with organic sulfonic acids (obtainable, for example, by treating a salt, such as an alkali metal salt, of the corresponding acid with a suitable organic sulfonic acid halide, such as lower alkane- or aryl-, for example methane-or p-toluene-sulfonic acid chloride; mixed sulfonic acid anhydrides method), and also symmetric anhydrides (obtainable, for example, by condensing the corresponding acid in the presence of a carbodiimide or 1-diethylaminopropyne; symmetric anhydrides method).

Suitable cyclic amides are especially amides having five-membered diazacycles ofaromadc nature, such as amides with imidazoles, for example imidazole (obtainable, for example, by treating the corresponding acid with N,N'-carbonyldiimidazole; imidazole method), or pyrazoles, for example 3,5-dimethylpyrazole (obtainable, for example, by way of the acid hydrazide by treatment with acetylacetone; pyrazolide method).

As mentioned, derivatives of carboxylic acids that are used as acylating agents can also be formed in situ. For example, N,N'-di-substituted amidino esters can be formed in situ by reacting a mixture of the starting material of formula III and the acid of formula Il used as acylating agent in the presence of a suitable N,N'-di-substituted carbodiimide, for example N,N'-cyclohexylcarbodiimide, for example in the presence of a suitable base, such as triethylamine. It is also possible to form amino or amido esters of the acids used as 2~ 8 acylating agents in the presence of the starting material of formula III to be acylated, by reacting a mixture of the corresponding acid and amino starting materials in the presence of an N,N'-di-substituted carbodiimide, for example N,N'-dicyclohexylcarbodiirnide, and an N-hydroxyamine or N-hydroxyamide, for example N-hydroxysuccinimide, if approp-riate in the presence of a suitable base, for example 4-dimethylaminopyridine. It is also possible to achieve activation in situ by reacting with N,N,N',N'-tetraaLlcyluronium compounds, such as O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophos-phate. Finally, it is possible to produce phosphoric acid anhydrides of the carboxylic acids of formula II in situ by reacting an alkylphosphoric acid amide, such as hexamethylphos-phoric acid triamide, in the presence of a sulfonic acid anhydride, such as 4-toluene-sulfonic acid anhydride, with a salt, such as a tetrafluoroborate, for example sodium tetra-fluoroborate, or with a different derivative of the hexamethylphosphoric acid triamide, such as benzotriazol-l-yloxy-tris(dimethylamino)phosphonium hexafluoride, preferably in the presence of a racemisation-reducing additive, such as N-hydroxybenzotriazole.

The amino group of compounds of formula III, which participates in the reaction, prefer-ably carries at least one reactive hydrogen atom, especially when the carboxy group reacting therewith is in reactive folm; it may also, however, itself be derivatised, for example by reaction with a phosphite, such as diethyl chlorophosphite, 1,2-phenylene chlorophosphite, ethyl dichlorophosphite, ethylene chlorophosphite or tetraethyl pyro-phosphite. A derivative of such a compound having an amino group is, for example, also a carbamic acid halide, the arnino group participating in the reaction being substituted by a halocarbonyl, for example chlorocarbonyl.

The condensation for the production of an amide bond can be carried out in a manner known ~r se, for example as described in standard works, such as "Houben-Weyl, Methoden der organischen Chemie", 4th edition, Volume 15/lI (1974), Volume IX (1955), Volume E 11 (1985), Georg Thieme Verlag, Stuttgart, "The Peptides" (Editors E. Gross and J. Meienhofer), Volumes 1 and 2, Academic Press, London and New York, 1979/1980, or M. Bodanszlcy, "Principles of Peptide Synthesis", Springer-Verlag, Berlin 1984.

The condensation of a free carboxylic acid with the corresponding amine can preferably be carried out in the presence of one of the customary condensation agents. Customary condensation agents are, for example, carbodiimides, for example diethyl-, dipropyl-, N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide or, especially, dicyclohexylcarbo-2~ B

diimide, also suitable carbonyl compounds, for example carbonylimidazole, 1,2-oxa-zolium compounds, for example 2-ethyl-5-phenyl-1,2-oxazolium 3'-sulfonate and 2-tert-butyl-~-methylisoxazolium perchlorate, or a suitable acylamino compound, for example 2-ethoxy- 1 -ethoxycarbonyl- 1 ,2-dihydroquinoline, N,N,N ',N '-tetraalkyluronium compounds, such as O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophos-phate, also activated phosphoric acid derivatives, for example diphenylphosphorylazide, diethylphosphoryl cyanide, phenyl-N-phenylphosphoramidochloridate, bis(2-oxo-3-oxazolidinyl)phosphinic acid chloride or 1-benzotriazolyloxy-tris(dimethylamino)phos-phonium hexafluorophosphate.

In a manner analogous to the types of reaction mentioned for the condensation ofcarboxylic acids of formula II, it is also possible to react the sulfonic acids of formula II
having a terminal sulfonyl group in the condensation with compounds of formula III to form the corresponding sulfonamides of formula Ib.

For example, activated sulfonic acid esters can be used, for example the corresponding aryl esters, especially the aryl esters substituted by nitro groups, such as phenyl esters, it also being possible to use the amine component of formula Ib in the form of an alkali metal amide, for example an alkali metal arylamide, such as sodium anilinamide, or in the form of an alkali metal salt of a nitrogen-containing heterocycle, for example potassium pyrrolide.

It is also possible to use reactive anhydrides, such as, for example, the corresponding symmetric acid anhydrides (obtainable, for example, by reacting the alkylsulfonic acid silver salts with alkylsulfonyl chlorides) or, preferably, asymmetric acid anhydrides, for example anhydrides with inorganic acids, such as sulfonyl halides, especially sulfonyl chlorides (obtainable, for example, by reacting the corresponding sulfonic acids with inorganic acid chlorides, for example thionyl chloride, sulfuryl chloride or phosphorus pentachloride), with organic carboxylic acids (obtainable, for example, by treating a sulfonic acid halide with the salt of a carboxylic acid, such as an aL~cali metal salt, analogously to the above-mentioned method for the preparation of the mixed acid anhydrides), or azides (obtainable, for example, from a corresponding sulfonic acid chloride and sodium azide or by way of the corresponding hydrazide and treatment thereof with nitrous acid analogously to the above-mentioned azide method).

If desired, an organic base is added, for example a tri-lower alkylamine having 9~3 voluminous radicals, for example ethyldiisopropylamine, and/or a heterocyclic base, for example pyridine, 4-dimethylaminopyridine or, preferably, N-methylmorpholine.

The condensation of activated esters, reactive anhydrides or reactive cyclic amides with the corresponding amines is generally carried out in the presence of an organic base, for example simple tri-lower alkylamines, for example triethylamine or tributylamine, or one of the above-mentioned organic bases. If desired, a condensation agent is also 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 or alicali metal carbonates or hydrogen carbonates, such as sodium or potassium carbonate or hydrogen carbonate(generally together with a sulfate), and the reaction of sulfonic acid halides, such as sulfonic acid chlorides, in the presence of hydroxides, for example alkali metalhydroxides, such as sodium hydroxide or potassium hydroxide.

Carboxylic acid chlorides, for example the chlorocarbonic acid derivatives derived from the acid of formula II, are condensed with the corresponding amines, preferably in the presence of an organic amine, for example the above-mentioned tri-lower alkylamines or heterocyclic bases, where appropriate in the presence of a hydrogen sulfate.

The condensation is preferably carried out in an inert aprotic, preferably non-aqueous solvent or solvent mixture, for example in a carboxylic acid amide, for example formamide or dimethylformamide, a halogenated hydrocarbon, for example methylenechloride, carbon tetrachloride or chlorobenzene, a ketone, for example acetone, a cyclic ether, for example tetrahydrofuran, an ester, for example ethyl acetate, or a nitrile, for example acetonitrile, or in a mixture thereof, where appropriate at reduced or elevated temperature, for example in a temperature range of from approximately -40C to approx-imately +100C, preferably from approximately -10C to approximately +50C, and without an inert gas or under an inert gas atmosphere, for example a nitrogen or argon atmosphere.

Aqueous solvents, for example alcoholic solvents, for example ethanol, or aromatic solvents, for example benzene or toluene, are also possible. When alkali hydroxides are present as bases, acetone may also be added where appropriate.

The condensation can also be carried out in accordance with the technique known as solid-phase synthesis which was developed by R. Merrifield and is described, for example, in Angew. Chem. 97, 801 - 812 (1985), Naturwissenschaften 71, 252 - 258 (1984) or in R.
A. Houghten, Proc. Natl. Acad. Sci. USA 82, 5131 - 5135 (1985).

The freeing of functional groups protected by protecting groups in the resultingcompounds of formula I having protected functions is carried out, where appropriate, in accordance with one or more of the methods mentioned under Process f).

Process b) (Production of an amide bond) In starting materials of formulae IV and V, functional groups, with the exception of the groups that are to participate in the reaction or that do not react under the reaction conditions, are, independently of one another, protected by protecting groups.

The protecting groups, the free carboxylic acids and their reactive derivatives, the free amines and their reactive derivatives and the processes used for the condensation are exactly the same as those described under Process a) for the production of an amide bond starting from compounds of formulae II and III if the carboxylic acids of formula II are replaced by those of formula IV, and the amino compounds of formula III are replaced by those of formula V.

The freeing of funcdonal groups protected by protecdng groups in the resulting compounds of formula I having protected functions is carried out, where appropriate, in accordance with one or more of the methods mentioned under Process f).

Process c) (Production of an amide bond) In starting materials of formulae VI and VII, functional groups, with the exception of the groups that are to participate in the reaction or that do not react under the reacdon conditions, are, independently of one another, protected by protecting groups.

The protecting groups, the free carboxylic acids and their reactive derivatives, the free amines and their reactive derivadves and the processes used for the condensation are exactly the same as those described under Process a) for the production of an amide bond starting from compounds of formulae II and III if the carboxylic acids of formula II are - 43 2~'-f~

replaced by those of formula Vl, and the amino compounds of formula III are replaced by those of formula VII.

The freeing of functional groups protected by protecting groups in the resultingcompounds of formula I having protected functions is carried out, where appropriate, in accordance with one or more of the methods mentioned under Process f).

Process d) (Production of an amide bond) In starting materials of formulae VIII and IX, functional groups, with the exception of the groups that are to participate in the reaction or that do not react under the reaction conditions, are, independently of one another, protected by protecting groups.

The protecting groups, the free carboxylic acids and their reactive derivatives, the free amines and their reactive derivatives and the processes used for the condensation are exactly the same as those described under Process a) for the production of an amide bond starting from compounds of formulae n and III if the carboxylic acids of formula II are replaced by those of formula VIII, and the amino compounds of formula III are replaced by those of formula IX.

The freeing of functional groups protected by protecting groups in the resultingcompounds of formula I having protected functions is carried out, where appropriate, in accordance with one or more of the methods mentioned under Process f).

Process e) (Production of an amide bond) In starting materials of formulae X and XI, functional groups, with the exception of the groups that are to participate in the reaction or that do not react under the reaction conditions, are, independently of one another, protected by protecting groups.

The protecting groups, the free carboxylic acids and their reactive derivatives, the free amines and their reactive derivatives and the processes used for the condensation are exactly the same as those described under Process a) for the production of an amide bond sta~ting from compounds of formulae II and III if the carboxylic acids of formula II are replaced by those of formula X, and the amino compounds of forrnula III are replaced by those of formula XI.

- 44 Z~ 8 A reactive derivative of such a compound of formula XI having an amino group is, for example, also an isocyanate in which the amino group participating in the reaction has been modifled to form an isocyanate group and, in the latter case, only compounds of formula I that carry a hydrogen atom at the nitrogen atom of the amide group formed by the reaction can be obtained.

The freeing of functional groups protected by protecting groups in the resultingcompounds of formula I having protected functions is carried out, where appropriate, in accordance with one or more of the methods mentioned under Process f).

Process f) (Removal of protecting groups) The removal of protecting groups that are not constituents of the desired end product of formula 1, for example carboxy-, amino-, hydroxy-, mercapto- and/or sulfo-protecting groups, is carried out in a manner known Der se, for example by means of solvolysis, especially hydrolysis, alcoholysis or acidolysis, or by means of reduction, especially hydrogenolysis, or by means of other reducing agents, and also photolysis, in stages or simultaneously, as appropriate, it also being possible to use enzymatic methods. The removal of protecting groups is described, for example, in the standard works mentioned hereinbefore in the section relating to "protecting groups".

For oxample, protected carboxy, for example tert-lower alkoxycarbonyl, lower alkoxy-carbonyl substituted in the 2-position by a tri-substituted silyl group or in the l-position by lower alkoxy or by lower alkylthio, or unsubstituted or substituted diphenylmethoxy-carbonyl can be converted into free carboxy by treatment with a suitable acid, such as formic acid, hydrochloric acid or trifluoroacetic acid, where appropriate with the addition of a nucleophilic compound, such as phenol or anisole. Unsubstituted or substituted benzyloxycarbonyl can be freed, for example, by means of hydrogenolysis, that is to say, by treatment with hydrogen in the presence of a metallic hydrogenation catalyst, such as a palladium catalyst. In addition, suitably substituted benzyloxycarbonyl, such as 4-nitro-benzyloxycarbonyl, can also be converted into free carboxy by reduction, for example by treatment with an alkali metal dithionite, such as sodium dithionite, or with a reducing metal, for example zinc, or a reducing metal salt, such as a chromium(II) salt, for example chromium(II) chloride, generally in the presence of a hydrogen-donor that, together with the metal, is capable of producing nascent hydrogen, such as an acid, especially a suitable 2~ 9ax~3 carboxylic acid, such as a lower alkanecarboxylic acid that is unsubstituted or substituted, for example, by hydroxy, for example acetic acid, formic acid, glycolic acid, diphenyl-glycolic acid, lactic acid, mandelic acid, 4-chloromandelic acid or tartaric acid, or an alcohol or thiol, water preferably being added. By treatment with a reducing metal or metal salt, as described above, also 2-halo-lower alkoxycarbonyl (where appropriate after converting a 2-bromo-lower alkoxycarbonyl group into a corresponding 2-iodo-lower alkoxycarbonyl group) or aroylmethoxycarbonyl can be converted into free carboxy.
Aroylmethoxycarbonyl can be cleaved also by treatment with a nucleophilic, preferably salt-forming, reagent, such as sodium thiophenolate or sodium iodide. 2-(Tri-substituted silyl)-lower alkoxycarbonyl, such as 2-tri-lower alkylsilyl-lower alkoxycarbonyl, can be converted into free carboxy also by treatment with a salt of hydrofluoric acid that yields the fluoride anion, such as an alkali metal fluoride, for example sodium or potassium fluoride, where appropriate in the presence of a macrocyclic polyether ("crown ether"), or with a fluoride of an organic quaternary base, such as tetra-lower alkylammonium fluoride or tri-lower alkylaryl-lower alkylammonium fluoride, for example tetraethylammonium fluoride or tetrabutylammonium fluoride, in the presence of an aprotic, polar solvent, such as dimethyl sulfoxide or N,N-dimethylacetamide. Carboxy protected in the form oforganic silyloxycarbonyl, such as tri-lower alkylsilyloxycarbonyl, for example trimethyl-silyloxycarbonyl, can be freed in customary manner by solvolysis, for example by treat-ment with water, an alcohol or an acid, or also a fluoride, as described above. Esterified carboxy can also be freed enzymatically, for example by esterases or suitable peptidases;
for example esterified arginine or Iysine, such as Iysine methyl ester, can be freed by means of trypsin. Carboxy protected in the form of an internal ester, such as in the form of ~-lactone, can be freed by hydrolysis in the presence of a hydroxide-containing base, such as an alkaline earth metal hydroxide or, especially, an alkali metal hydroxide, for example NaOH, KOH or LiOH, especially LiOH, the correspondingly protected hydroxy group being freed at the same time.

A protected amino group is freed in a manner known ~ se and, depending on the type of protecting groups, in various manners, preferably by means of solvolysis or reduction.
Lower alkoxycarbonylamino, such as tert-butoxycarbonylamino, can be cleaved in the presence of acids, for example mineral acids, for example a hydrohalic acid, such as hydrochloric acid or hydrobromic acid, especially hydrobromic acid, or in the presence of sulfuric acid or phosphoric acid, preferably hydrochloric acid, in polar solvents, such as water or a carboxylic acid, such as acetic acid, or ethers, preferably cyclic ethers, such as dioxane, and 2-halo-lower alkoxycarbonylamino (where appropriate after converting a - 46 ~ B

2-bromo-lower alkoxycarbonylamino group into a 2-iodo-lower alkoxycarbonylamino group), aroylmethoxycarbonylamino or 4-nitrobenzyloxycarbonylamino can be cleaved, for example, by treatment with a suitable reducing agent, such as zinc in the presence of a suitable carboxylic acid, such as aqueous acetic acid. Aroylmethoxycarbonylamino can be cleaved also by treatment with a nucleophilic, preferably salt-forming, reagent, such as sodium thiophenolate, and 4-nitrobenzyloxycarbonylamino also by treatment with an alkali metal dithionite, for example sodium dithionite. Unsubstituted or substituted diphenylmethoxycarbonylamino, tert-lower alkoxycarbonylamino or 2-(tri-substituted silyl)-lower alkoxycarbonylamino, such as 2-tri-lower alkylsilyl-lower alkoxycarbonyl-amino, can be freed by treatment with a suitable acid, for example formic acid or trifluoro-acetic acid, unsubstituted or substituted benzyloxycarbonylamino can be freed, for example, by means of hydrogenolysis, that is to say, by 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-lower alkanoylamides, for example dimethyl-formamide, ethers, such as cyclic ethers, for example dioxane, or alcohols, such as methanol, ethanol or propanol, methanol being especially preferred, unsubstituted or sub-stituted triarylmethylamino or formylamino can be freed, for exarnple, by treatment with an acid, such as a mineral acid, for example hydrochloric acid, or an organic acid, for example formic, acetic or trifluoroacetic acid, where appropriate in the presence of water, and an amino group protected in the form of silylamino can be freed, for example, by hydrolysis or alcoholysis. An amino group protected by 2-haloacetyl, for example2-chloroacetyl, can be freed by treatment with thiourea in the presence of a base, or with a thiolate salt, such as an alkali metal thiolate of thiourea, and by subsequent solvolysis, such as alcoholysis or hydrolysis, of the resulting substitution product. An amino group protected by 2-(tri-substituted silyl)-lower alkoxycarbonyl, such as 2-tri-lower alkylsilyl-lower alkoxycarbonyl, can be converted into the free amino group also by treatment with a salt of hydrofluoric acid that yields fluoride anions, as indicated above in connection with the freeing of a correspondingly protected carboxy group. Likewise, silyl, such as trimethylsilyl, bonded directly to a hetero atom, such as nitrogen, can be remo~/ed by fluoride ions.

Amino protected in the form of an azido group is converted into free amino, for example, by reduction, for example by catalytic hydrogenation with hydrogen in the presence of a hydrogenation catalyst, such as platinum oxide, palladium or Raney nickel, by reduction by means of mercapto compounds, such as dithiothreitol or mercaptoethanol, or also by treatment with zinc in the presence of an acid, such as acetic acid. Catalytic hydrogenation 2~ 9~8 is carried out preferably in an inert solvent, such as a halogenated hydrocarbon, for example methylene chloride, or also in water or a mixture of water and an organic solvent, such as an alcohol or dioxane, at approximately from 20 C to 25 C, or also with cooling or heating.

A hydroxy or mercapto group protected by a suitable acyl group, a tri-lower alkylsilyl group or by unsubstituted or substituted 1-phenyl-lower alkyl is freed analogously to a correspondingly protected amino group. A hydroxy or mercapto group protected by 2,2-dichloroacetyl is freed, for example, by basic hydrolysis, and a hydroxy or mercapto group protected by tert-lower alkyl or by a 2-oxa- or 2-thia-aliphatic or -cycloaliphatic hydro-carbon radical is freed by acidolysis, for example by treatment with a mineral acid or a strong carboxylic acid, for example trifluoroacetic acid. Mercapto protected by pyridyl-diphenylmethyl can be freed, for example, by mercury(II) salts at pH 2-6 or by zinc/acetic acid or electrolytic reduction; mercapto protected by acetamidomethyl or by isobutyryl-amidomethyl can be freed, for example, by reaction with mercury(lI) salts at pH 2-6;
mercapto protected by 2-chloroacetamidomethyl can be freed, for example, by 1-piper-idinothiocarboxamide; and mercapto protected by S-ethylthio, S-tert-butylthio and S-sulfo can be freed, for example, by thiolysis with thiophenol, thioglycolic acid, sodium thio-phenolate or 1,4-dithiothreitol. Two hydroxy groups or a vicinal amino and hydroxy group that are together protected by means of a bivalent protecting group, preferably, for example, by means of a methylene group mono- or di-substituted by lower alkyl, such as lower alkylidene, for example isopropylidene, cycloalkylidene, for example cyclohexyl-idene, or benzylidene, can be freed by acidic solvolysis, especially itl the presence of a mineral acid or a strong organic acid. A tri-lower alkylsilyl group is likewise removed by acidolysis, for example by means of a mineral acid, preferably hydrofluoric acid, or a strong carboxylic acid. 2-halo-lower alkoxycarbonyl is removed by the above-mentioned reducing agents, for example a reducing metal, such as zinc, reducing metal salts, such as chromium(lI) salts, or by sulfur compounds, for example sodium dithionite or, preferably, sodium sulfide and carbon disulfide. Esterified hydroxy groups, for example lower alkan-oyloxy, such as acetoxy, can also be freed by esterases, and acylated arnino can be freed, for example, by suitable peptidases.

A sulfo group protected in the form of a sulfonic acid ester or sulfonamide is freed, for example, by acidic hydrolysis, for example in the presence of a mineral acid, or preferably by basic hydrolysis, for example with an alkali metal hydroxide or alkali metal carbonate, for example sodium carbonate.

The temperatures for freeing the protected functional groups are preferably from -80 to 100 C, especially preferably from -20 to 50 C, for example from 10 to 35 C, such as in the region of room temperature.

If several protected functional groups are present, the protecting groups may, if desired, be so chosen that more than one such group can be removed at a time, for example by acid-olysis, such as by treatment with trifluoroacetic acid, or with hydrogen and a hydrogen-ation catalyst, such as a palladium/carbon catalyst. Conversely, the groups may also be so chosen that they are not all removed at the same time but can be removed in the desired se~uence, thè corresponding intermediates being obtained.

Additional process measures In the case of the additional process measures, which are carried out if desired, functional groups of the starting compounds that are not to participate in the reaction may be in unprotected or protected form, for example they may be protected by one or more of the protecting groups mentioned above under Process a). The protecting groups can beretained in the end products or all or some of them can be removed in accordance with one of the methods mentioned under Process f).

Salts of compounds of formula I having at least one salt-forming group can be produced in a manner known ~r s(e. For example, salts of compounds of formula I having acidic groups can be formed, for example, by treatment with metal compounds, such as alkali metal salts of suitable organic carboxylic acids, for example the sodium salt of 2-ethyl-hexanoic acid, with organic alkali metal or alkaline earth metal compounds, such as the corresponding hydroxides, carbonates or hydrogen carbonates, such as sodium and potassium hydroxide, carbonate or hydrogen carbonate, with corresponding calciumcompounds or with ammonia or a suitable organic amine, preferably stoichiometricamounts or only a small excess of the salt-forming agent being used. Acid addition salts of compounds of formula I are obtained in customary manner, for example by treatment with an acid or a suitable anion exchange reagent. Internal salts of compounds of formula I that contain acidic and basic salt-forming groups, for example a free carboxy group and a free amino group, can be formed, for example, by neutralising salts, such as acid addition salts, to the isoelectric point, for example using weak bases, or by treatment with ion exchan-gers.

2~79~3 Salts can be converted in customary manner into the 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 a suitable basic agent or basic ion exchangers.

Stereoisomeric mixtures, that is to say, mixtures of diastereoisomers and/or enantiomers, such as, for example, racemic mixtures, can be separated into the corresponding isomers in a manner known pQ se by suitable separating processes. For example, diastereo-isomeric mixtures can be separated into the individual diastereoisomers by fractional crystallisation, chromatography, solvent partitioning, etc.. Racemates can be separated from one another after converting the optical antipodes into diastereoisomers, for example by reaction with optically active compounds, for example optically active acids or bases, by chromatography on column materials covered with optically active compounds or by enzymatic methods, for example by the selective reaction of only one of the two enantiomers. That separation can be carried out either at the stage of one of the starting materials or when the compounds of forrnula I themselves have been obtained.

In an obtainable compound of formula I wherein the hydroxy group bonded to the carbon atom that is vicinal to the carbon atom carrying the radical R2-CH2- is free, the free hydroxy group can be converted into a protected hydroxy group by introducing a protecting group, as described above under Process a), for example it can be converted into an esterified hydroxy group, for example into lower alkanoyloxy, such as acetoxy.
The esterification is carried out analogously to the condensation to form amidesmentioned under Process a), a hydroxy group reacting instead of the amino component.
The reaction is carried out preferably under conditions analogous to those mentioned under process a), especially using a lower alkanoyl anhydride, for example acetic anhydride, to form the corresponding lower alkanoyloxy group, in an organic solvent, for example a cyclic ether, such as tetrahydrofuran, in the presence of a cyclic tertiary amine, such as dimethylaminopyridine, and/or a tri-lower alkylamine, such as triethylamine, at temperatures of from O C to the boiling point of the reaction mixtures, especially from 10 to 30 C.

In an obtainable compound of formula I, an amino or carboxamide group can be substit-uted, a carboxy group that is in free or reactive form can be esterified or amidated and an esterified or amidated carboxy group can be converted into a free carboxy group.

2~
- so -The substitution of a carboxamide group or another primary or secondary amino group, for example for the preparation of the carbamoyl derivative mono- or di-lower alkyl-carbamoyl, or mono- or di-hydroxy-lower alkylcarbamoyl, mentioned above as substituent of thiomorpholino or morpholino formed by R4 and Rs together with the bonding nitrogen atom, or with the formation of the above-mentioned derivatives of the substituent amino at thiomorpholino or morpholino formed by R4 and Rs together with the bonding nitrogen atom, in compounds of formula I in which the nitrogen of the amino groups to be reacted is bonded to hydrogen, is carried out, for example, by alkylation.

Suitable agents for the alkylation of a carboxamide group in a compound of formula I are, for example, diazo compounds, for example diazomethane. Diazomethane can be decomposed in an inert solvent, the free methylene formed reacting with the carboxamide group in the compound of formula I. The decomposition of diazomethane is carried out preferably catalytically, for example in the presence of a noble metal in finely divided form, for example copper, or in the presence of a noble metal salt, for example copper(I) chloride or copper(II) sulfate.

Alkylating agents are also mentioned in German Offenlegungsschrift 2 331 133, for example alkyl halides, sulfonic acid esters, Meerwein salts or l-substituted 3-aryl-triazenes, which can be reacted under the reaction conditions mentioned in that document with a compound of formula I having a carboxamide group.

Other alkylating agents are selected from corresponding alkyl compounds that carry a substituent X wherein X is a leaving group. A leaving group is especially a nucleofugal leaving group selected from hydroxy esterified by a strong inorganic or organic acid, such as hydroxy esterified by a mineral acid, for example a hydrohalic acid, such as hydro-chloric acid, hydrobromic acid or hydriodic acid, or by a strong organic sulfonic acid, such as a lower alkanesulfonic acid that is unsubstituted or substituted, for example, by halogen, such as fluorine, or an aromatic sulfonic acid, for example a benzenesulfonic acid that is unsubstituted or substituted by lower alkyl, such as methyl, halogen, such as bromine, and/or by nitro, for example a methanesulfonic acid, trimethanesulfonic acid or p-toluenesulfonic acid, or hydroxy esterified by hydrazoic acid.

The reaction can be carried out under the conditions of a first- or second-order nucleo-philic substitution.

- 51 - Z~ 8 For example, one of the compounds having a substituent X wherein X is a leaving group of which the electron shell has a high polarisation property, for example bromine or iodine, can be reacted in a polar aprotic solvent, for example acetone, acetonitrile, nitro-methane, dimethyl sulfoxide or dimethylformamide. The substitution reaction is carried out, where appropriate, at reduced or elevated temperature, for example in a temperature range of from approximately -40 to approximately 100 C, preferably from approx-imately -10 to approxirnately 50 C, and, where appropriate, under an inert gas, for example under a nitrogen or argon atmosphere.

For the esterification or amidation of a carboxy group in a compound of formula I, for example for the amidation of a free carboxy group of an amino acid, such as Glu or Asp, with ammonia, or of a free carboxy group at thiomorpholino or morpholino formed by R4 and Rs together with the bonding nitrogen atom, it is possible, if desired, to use the free acid or to convert the free acid into one of the above-mentioned reactive derivatives and to react with an alcohol, ammonia, or a primary or a secondary amine, or, for the esterific-ation, it is possible to react the free acid or a reactive salt, for example the caesium salt, with a reactive derivative of an alcohol. For example, the caesium salt of a carboxylic acid can be reacted with a halide or sulfonic acid ester corresponding to the alcohol. The ester-ification of the carboxy group can also be carried out with other customary alkylating agents, for example with diazomethane, alkyl halides, sulfonic acid esters, Meer~,vein salts or 1-substituted 3-aryltriazenes, etc..

One of the methods described above in connection with the removal of the carboxy-protecting groups or, if desired, alkaline hydrolysis under customary reaction conditions, such as those mentioned in Organikum, 17th edition, VEB Deutscher Verlag der Wissen-schaften, Berlin 1988, can be used to convert an esterified or amidated carboxy group into the free carboxy group.

In a compound of formula I, an esterified carboxy group can be converted into an unsub-stituted or substituted carboxamide group by aminolysis with ammonia or a primary or secondary amine. The aminolysis can be carried out in accordance with customary reaction conditions, such as those mentioned for such reactions in Organikum, 15th edition, VEB Deutscher Verlag der Wissenschaften, Berlin (East) 1976.

In a compound of formula I, a free amino group present can be acylated, for example in Z~

order to introduce one of the radicals mentioned for Rl, with the exception of hydrogen.
The acylation is carried out in accordance with the methods mentioned above under Process a) or in accordance with one of the methods mentioned for protecting groups or, for example, in accordance with one of the processes mentioned in Organikum, 17th edition, VEB Deutscher Verlag der Wissenschaften, Berlin (East) 1988.

In an obtainable compound of formula I wherein the substituents are as defined and at least one free hydroxy group is present and the other functional groups are in protected form, the free hydroxy group can be acylated or etherified, for example the hydroxy group at thiomorpholino or morpholino formed from R4 and Rs, together with the bondingnitrogen atom, is formed.

The acylation can be carried out with acylating reagents in accordance with one of the methods mentioned under Processes a) to e) or in accordance with one of the methods mentioned for protecting groups or in accordance with one of the processes mentioned in Organikum, 17th edition, VEB Deutscher Verlag der Wissenschaften, Berlin (East) 1988.

The etherification can be carried out with the above-mentioned alkylating agents and under the same reaction conditions, for example with diazomethane, aLIcyl halides, sulfonic acid esters, Meerwein salts, 1-substituted 3-aryltriazenes, etc..

In a compound of formula I, protecting groups present or suitable radicals R1, with the exception of hydrogen7 can be removed in accordance with one of the processes mentioned under Process f), especially by hydrolysis, for example in the presence of bases, such as alkali hydroxides or alkaline earth hydroxides, for example sodium hydroxide, or acids, such as organic acids or mineral acids, for example a hydrohalic acid, such as hydrochloric acid. The hydrolysis is carried out under customary conditions, for example in aqueous solution or in non-aqueous solvents, especially in ethers, such as dioxane, at temperatures of from -50 C to the reflux temperature of the corresponding reaction mixtures, for example from 0 C to 50 C, preferably in the presence of a protec-tive gas, such as argon or nitrogen.

In a compound of formula I in which at least one of the radicals R2 and R3 is a phenyl group and/or one or more of the radicals B 1. A1 and A2 is phenylalanine, it also being possible for each of the phenyl radicals to be substituted as indicated above, the corres-ponding phenyl radical(s) can be selectively reduced, for example hydrogenated, to form 2~ 3.

corresponding cyclohexyl radical(s). The hydrogenation is carried out preferably in the presence of a catalyst that permits the selective hydrogenation of double bonds in the presence of peptide bonds, especially a catalyst comprising heavy metal oxides, such as a Rh(III)/Pt(VI) oxide catalyst according to Nishimura (S. Nishimura, Bull. Chem. Soc.
Japan 33, 566 (1960), in suitable solvents, especially water, alcohols, such as methanol or ethanol, esters, such as ethyl acetate, or ethers, such as dioxane, for example in methanoi, at temperatures of from 0 to 150 C, preferably from 10 to 50 C, for example at room temperature, and under hydrogen pressures of from 1 to 50 bar, for example under normal pressure.

The invention relates also to those forms of the process in which a compound obtainable as intermediate at any stage is used as starting material and the remaining steps are carried out, or the process is discontinued at any stage, or a starting material is formed under the reaction conditions or is used in the form of a reactive derivative or salt, or a compound obtainable according to the process of the invention is produced under the process conditions and is further processed m sltu. It is preferable to use those starting materials that result in the compounds described above as being preferred, more strongly preferred, very preferred, even more preferred, of especial interest, of most especial interest or of very special importance.

Pharmaceutical compositions:

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

The pharmacologically acceptable compounds of the present invention can be used, for example, for the preparation of pharmaceutical compositions that comprise an effective amount of the active ingredient together or in admixture with a significant amount of inorganic or organic, solid or liquid, pharmaceutically acceptable carriers.

The pharmaceutical compositions according to the invention are compositions for enteral, such as nasal, buccal, rectal or oral, or parenteral, such as intramuscular or intravenous, administration to warm-blooded animals (humans and animals) that comprise an effective dose of the pharmacological active ingredient alone or together with a significant amount of a pharmaceutically acceptable carrier. The dose of the active ingredient depends on the species of warm-blooded animal, body weight, age and individual condition, individual 2~ 8 pharmacokinetic factors, the disease to be treated and the method of administration.

The invention relates also to pharmaceutical compositions and to a method for the treat-ment of diseases caused by retroviruses, for example AIDS, especially when HIV-1 is the cause of the disease, in which method a therapeutically effective arnount of a compound of formula I according to the invention is administered, especially to a warm-blooded animal, for example a human, in need of such treatment owing to one of the mentioned diseases, especially AIDS. The doses to be administered to warm-blooded animals, for example humans weighing approximately 70 kg, are from approximately 3 mg to approximately 10 g, preferably from approximately 40 mg to approximately 4 g, for example approx-imately from 300 mg to 1.5 g per person per day, preferably divided into from 1 to 3 individual doses which may be, for example, of the same size. Children generally receive half the adult dose.

The pharmaceutical compositions comprise from approximately 1 % to approximately95 %, preferably from approximately 20 % to approximately 90 % active ingredient.
Pharmaceutical compositions according to the invention may be, for example, in unit dose form, such as in the form of ampoules, vials, suppositories, dragées, tablets or capsules.

The pharmaceutical compositions of the present invention are prepared in a manner known ~ se, for example by means of conventional dissolving, lyophilising, mixing, granulating or confectioning processes.

It is preferable to use solutions of the active ingredient, also suspensions or dispersions, especially isotonic aqueous solutions, dispersions or suspensions, which, for example in the case of lyophilised compositions that comprise the active ingredient alone or together with a carrier, for example mannitol, may be produced before use. The pharmaceutical compositions may be sterilised and/or may comprise excipients, for example preserv-atives, stabilisers, wetting agents and/or emulsifiers, solubilisers, salts for regulating the osmotic pressure and/or buffers, and are prepared in a manner known ~ se, for example by means of conventional dissolving or lyophilising processes. The mentioned solutions or suspensions may contain viscosity-increasing substances, such as sodium carboxymethyl-cellulose, carboxymethylcellulose, dextran, polyvinylpyrrolidone or gelatin.

Suspensions in oil comprise as oily component the vegetable, synthetic or semi-synthetic oils customarily used for injection purposes. There may be mentioned as such especially 2~ B

liquid fatty acid esters that comprise as acid component a long-chained fatty acid having from 8 to 22, especially from 12 to 22, carbon atoms, such as, for example, lauric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, margaric acid, stearic acid, arachidic acid, behenic acid or corresponding unsaturated acids, such as, for example, oleic acid, elaidic acid, erucic acid, brassidic acid or linoleic acid, where appropriate with the addition of antioxidants, such as, for example, vitamin E, ~-carotene or 3,5-di-tert-butyl-4-hydroxytoluene. The alcohol component of those fatty acid esters has a maximum of 6 carbon atoms and is a mono- or poly-hydric, for example mono-, di- or tri-hydric, alcohol, for example methanol, ethanol, propanol, butanol or pentanol or the isomers thereof, but especially glycol and glycerol. There may accordingly be mentioned as fatty acid esters, for example: ethyl oleate, isopropyl myristate, isopropyl palmitate, "Labrafil M 2375" (polyoxyethylene glycerol trioleate manufactured by Gattefossé, Paris), "Miglyol 812" (triglyceride of saturated fatty acids having a chain length of from C8 to C12 manufactured by Huls AG, Germany), but especially vegetable oils, such as cotton-seed oil, almond oil, olive oil, castor oil, sesame oil, soybean oil, and, especially, ground-nut oil.

The preparation of the injection compositions is carried out in customary manner under sterile conditions, as is also the introduction into ampoules or vials and the sealing of the containers.

Pharmaceutical compositions for oral administration can be obtained by combining the active ingredient with solid carriers, optionally granulating a resulting mixture, and, if desired or necessary after the addition of suitable excipients, processing the mixture or granules to form tablets, dragée cores or capsules, or by preparing dispersions, preferably with phospholipids, which are introduced into small bottles. It is also possible to incorp-orate the active ingredients in plastics carriers that release the active ingredients, or allow them to diffuse, in controlled amounts.

Suitable carriers are, especially, fillers, such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, also binders, such as starch pastes, using, for example, corn, wheat, rice or potato starch, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrol-idone, and/or, if desired, disintegrators, such as the above-mentioned starches, also carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt 2~ 8 thereof, such as sodium alginate. Excipients are especially flow conditioners and lubricants, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol. Dragée cores are provided with suitable coatings that may be resistant to gastric juices, there being used, inter alia, concentrated sugar solutions which may contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, coating solutions in suitable organic solvents, or, for the preparation of enteric coatings, solutions of suitable cellulose preparations, such as ethyl-cellulose phthalate or hydroxypropylmethylcellulose phthalate. Capsules are dry-filled capsules consisting of gelatin, and also soft, sealed capsules consisting of gelatin and a plasticiser, such as glycerol or sorbitol. The dry-filled capsules may contain the active ingredient in the form of granules, for example with fillers, such as lactose, binders, such as starches, and/or glidants, such as talc or magnesium stearate, and, where appropriate, with stabilisers. In soft capsules, the active ingredient is preferably dissolved or suspended in suitable oily excipients, such as fatty oils, paraffin oil or liquid polyethylene glycols, to which stabilisers and/or antibacterial agents may also be added. Colourings or pigments may be added to the tablets or dragée coatings and the capsule shells, for example for identification purposes or to indicate different doses of active ingredient.

Especially preferred as pharmaceutical compositions are dispersions of the active ingred-ient stabilised by phospholipids, preferably for oral administration, comprisinga) one phospholipid or several phospholipids of the formula 3CH2--O--P--O--(CnH2n)--N\ Rb (A), 0~ R

wherein RA is C10 20acyl, RB is hydrogen or C10 20acyl, Ra~ Rb and Rc are each hydrogen or Cl 4alkyl and n is an integer from two to four, if desired b) one other phospholipid or several other phospholipids, c) the active ingredient and d) a pharmaceutically acceptable carrier liquid and, if desired, further excipients and/or preservatives.

The preparation process for those dispersions is as follows: a solution or suspension of components a) and c) or a), b) and c), preferably of a) and b) in a ratio by weight of from 20:1 to 1:5, especially from 5:1 to 1:1, is converted into a dispersion by dilution with water, the organic solvent is then removed, for example by centrifugation, gel filtration, ultrafiltration or, especially, by dialysis, for example tangential dialysis, preferably against water, the resulting dispersion, preferably after the addition of excipients or preservatives, if necessary with adjustment of an acceptable pH value by the addition of pharmaceut-ically acceptable buffers, such as phosphate salts or organic acids, (pure or dissolved in water), such as acetic acid or citric acid, preferably pH 3 to 6, for example pH 4 to 5, is concentrated, if it does not already have the correct concentration of active ingredient, preferably to an active ingredient concentration of from 2 to 30 mg/ml, especially from 10 to 20 mg/ml, the concentration preferably being carried out in accordance with the iast-mentioned methods for the removal of an organic solvent, especially by ultrafiltration, for example using an apparatus for carrying out tangential dialysis and ultrafiltration.

The dispersion, stabilised by phospholipids, that can be prepared in accordance with that process is stable at room temperature for at least several hours, is reproducible with regard to the constituent amounts of the components and is toxicologically harmless, and is accordingly especially suitable for oral administration to humans.

The size of the resulting particles in the dispersion is variable and is preferably from approximately 1.0 x 10-8 to approximately 1.0 x 10-5 m, especially from approximately 10-7 to approximately 2 x lO-6 m.

The nomenclature of the phospholipids of formula I and the numbering of the carbon atoms is in accordance with the recommendations given in Eur. J. of Biochem. 79, 11-21 (1977) "Nomenclature of Lipids" by the IUPAC-IUB Commission on Biochemical Nomenclature (CBN) (sn-nomenclature, stereospecific numbering).

In a phospholipid of formula A, RA and RB each representing C10 20acyl are preferably straight-chained Clo 20alkanoyl having an even number of carbon atoms or straight-chained C10 20alkenoyl having a double bond and an even number of carbon atoms.

Straight-chained C10 20alkanoyl RA and RB having an even number of carbon atoms are, for example, n-dodecanoyl, n-tetradecanoyl, n-hexadecanoyl or n-octadecanoyl.

2~

Straight-chained C10 20alkenoyl RA and RB having a double bond and an even number of carbon atoms are, for example, 6-cis-, 6-trans-, 9-cis- or ~-trans-dodecenoyl, -tetra-decenoyl, -hexadecenoyl, -octadecenoyl or-eicosenoyl, especially 9-cis-octadecenoyl (oleoyl).

In a phospholipid of formula A, n is an integer from two to four, preferably two. The group of the formula -(CnH2n)- is unbranched or branched alkylene, for example l,l-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, naturally-occurring cephalins wherein Ra~
Rb and Rc are each hydrogen, or naturally-occurring lecithins wherein Ra~ Rb and Rc are each methyl, for example cephalin or lecithin from soybeans, bovine brain, bovine liver or hens' eggs having different or identical acyl groups RA and RB or mixtures thereof.

Synthetic, substantially pure phospholipids of formula A having different or identical acyl groups RA and RB are preferred.

The term "synthetic" phospholipid of formula A defines phospholipids, that have a homogeneous composition with regard to RA and RB. Such synthetic phospholipids are preferably the lecithins and cephalins defined below, the acyl groups RA and RB f which have a defined structure and are derived from a defined fatty acid having a degree of purity greater than approximately 95 %. RA and RB may be the same or different and may be unsaturated or saturated. RA is preferably saturated, for example n-hexadecanoyl, and RB is preferably unsaturated, for example 9-cis-octadecenoyl (= oleoyl).

The expression "naturally-occurring" phospholipids of formula A defines phospholipids that do not have a homogeneous composition with regard to RA and RB. Such natural phospholipids are likewise lecithins and cephalins, the acyl groups RA and RB of which cannot be defined structurally and are derived from naturally-occurring fatty acid mixtures.

The expression "substantially pure" phospholipid defines a degree of purity of more than 70 % (by weight) of the phospholipid of formula A which can be determined using suitable methods of analysis, for example paper chromatography.

2~9~3 Especially preferred are synthetic, substantially pure phospholipids of formula A wherein RA is straight-chained C10 20alkanoyl having an even number of carbon atoms and RB is straight-chained C10 20alkenoyl having a double bond and an even number of carbon atoms. Ra~ Rb and RC are each methyl and n is two.

In an especially preferred phospholipid of formula A, RA is n-dodecanoyl, n-tetra-decanoyl, n-hexadecanoyl or n-octadecanoyl and RB is 9-cis-dodecenoyl, 9-cis-tetra-decenoyl, 9-cis-hexadecenoyl, 9-cis-octadecenoyl or 9-cis-eicosenoyl. Ra~ Rb and Rc are each methyl and n is two.

A very especially preferred phospholipid of formula A is synthetic 1-n-hexadecanoyl-2-(9-cis-octadecenoyl)-3-sn-phosphatidylcholine having a purity of more than 95 %.

Preferred natural, substantially pure phospholipids of forrnula A are especially lecithin (L-a-phosphatidylcholine) from soybeans or hens' eggs.

The names given in brackets are also used for the acyl radicals in the phospholipids of forrnula A:
9-cis-dodecenoyl (lauroleoyl), 9-cis-tetradecenoyl (myristoleoyl), 9-cis-hexadecenoyl (palmitoleoyl), 6-cis-octadecenoyl (petroseloyl), 6-trans-octadecenoyl (petroselaidoyl), 9-cis-octadecenoyl (oleoyl), 9-trans-octadecenoyl (elaidoyl), 1 l-cis-octadecenoyl (vaccen-oyl), 9-cis-eicosenoyl (gadoleoyl), n-dodecanoyl (lauroyl), n-tetradecanoyl (myristoyl), n-hexadecanoyl (palmitoyl), n-octadecanoyl (stearoyl), n-eicosanoyl (arachidoyl).

Other phospholipids are preferably esters of phosphatidic acid (3-sn-phosphatidic acid) having the mentioned acyl Mdicals, such as phosphatidylserine and phosphatidylethanol-amine.

Poorly soluble active ingredients may also be in the form of water-soluble pharmaceut-ically acceptable salts, as defined above.

The components a), b) and c) or a) and c) are so contained as liposomes in the carrier liquid d) that for several days to weeks no solids or solid aggregates, such as micelles, are re-formed and the liquid with the mentioned components can be administered, preferably orally, where appropriate after filtration.

- 60- 2~7'~8 The carrier liquid d) may comprise pharmaceutically acceptable non-toxic excipients, for example water-soluble excipients that are suitable for the production of isotonic conditions, for example ionic additives, such as sodium chloride, or non-ionic additives (structure-formers), such as sorbitol, mannitol or glucose, or water-soluble stabilisers for the liposome dispersion, such as lactose, fructose or sucrose.

In addition to the water-soluble excipients, the carrier liquid may comprise emulsifiers, wetting agents or surfactants dhat can be used for liquid pharmaceutical compositions, especially emulsifiers, such as oleic acid, non-ionic surfactants of the fatty acid poly-hydroxyalcohol ester type, such as sorbitan mono-laurate, -oleate, -stearate or -palmitate, sorbitan tristearate or trioleate, polyoxyethylene adducts of fatty acid polyhydroxyalcohol esters, such as polyoxyethylene sorbitan mono-laurate, -oleate, -stearate, -palmitate, tri-stearate or trioleate, polyethylene glycol fatty acid esters, such as polyoxyethyl stearate, polyethylene glycol 400 stearate, polyethylene glycol 2000 stearate, especially ethylene oxide/propylene oxide block polymers of the Pluronic(~) type (Wyandotte Chem. Corp.) or Synperonic(~' type (ICI).

Preferred preservatives are, for example, antioxidants, such as ascorbic acid, or micro-bicides, such as sorbic acid or benzoic acid.

Starting materials:

The present invention relates also to novel starting materials and/or intermediates and also to processes for their preparation. The starting materials used and the reaction conditions chosen are preferably such that the compounds indicated as being preferred are obtained.

In the preparation of all starting materials, free functional groups that are not to participate in the particular reaction concerned, may be unprotected or in protected form, for example they may be protected by the protecting groups mentioned above under Process a). Those protecting groups can be freed at suitable times by the reactions described under Process f). The compounds having salt-forming groups can also be used in the form of salts and salts can be produced at any stage or converted into the free compounds again.

In the formulae, unless the stereochemistry of asymmetric carbon atoms is direcdy defined by the choice of corresponding bonding symbols, the configuration of asymmetric carbon atoms is indicated by the particular configuration symbol given selected from (S), (R) and 2~ 8 (S,R).

The carbo.xylic or sulfonic acids of formula Il, or reactive derivatives thereof, arc known and are commercially available or can be prepared in accordance with processes known ~se.

The compounds of formula III are known or can be prepared in accordance with processes known ~ se. For example, they can be obtained from a compound of the forrnula R COOH
HN (XII) Pa wherein R2 is as defined for compounds of formula I and Pa is an amino-protecting group, especially lower alkoxycarbonyl, such as tert-butoxycarbonyl, or phenyl-lower aLIcoxy-carbonyl, such as benzyloxycarbonyl, by reduction to form a compound of the formula ~r CHO
HN (XIII) Pa wherein the radicals are as last defined.

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

The reduction to the alcohols is carried out, especially by hydrogenation of the corres-ponding acid halides or of other activated carboxylic acid derivatives mentioned under Process a), or by reaction of activated carboxylic acid derivatives of the compounds of formula XII, especially anhydrides with organic carboxylic acids, preferably those of halo-formic acid esters, such as chloroformic acid isobutyl ester (which are preferably obtained 2~ 8 by reacting the compounds of formula XII in the presence of basic amines, for example tri-lower aLkylamines, such as triethylamine, in organic solvents, such as cyclic ethers, for example dioxane, at temperatures of fiom -50 to 80 C, preferably from 0 to 50 C) with complex hydrides, such as allcali metal borohydrides, for example sodium borohydride, in aqueous solution in the presence or absence of the last-used organic solvents at tempera-tures of from -50 to 80 C, preferably from 0 to 50 C. The subsequent oxidation of the resulting alcohols is carried out preferably with oxidising agents that selectively convert the hydroxy group into an aldehyde group, for example chromic acid or its derivatives, such as pyridinium chromate or tert-butyl chromate, dichromate/sulfuric acid, sulfur trioxide in the presence of heterocyclic bases, such as pyridine/SO3, di-lower alkyl sulfoxides, such as dimethyl sulfoxide, also nitric acid, pyrolusite or selenium dioxide, in water, aqueous or organic solvents, such as halogenated solvents, for example 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 of from -70 to 100 C, preferably from -70 to -50 C, or at from - 10 to 50 C, for example as described in European Patent Applic-ation EP-A-0 236 734.

It is also possible to reduce the compounds of formula XII directly to the aldehydes, for example by hydrogenation in the presence of a partially poisoned palladium catalyst or by reduction of the corresponding amino acid esters, for example the lower aL~cyl esters, such as ethyl esters, with complex hydrides, for example borohydrides, such as sodium boro-hydride, or preferably aluminium hydrides, for example lithium aluminium hydride, lithium tri-(tert-butoxy)aluminium hydride or, especially, diisobutylaluminium hydride, in non-polar solvents, for example in hydrocarbons or aromatic solvents, such as toluene, at from -100 to 0 C, preferably from -70 to -30 C, and subsequent reaction to form the corresponding semicarbazones, for example with the corresponding acid salts of semi-carbazones, such as semicarbazide hydrochloride, in aqueous solvent systems, such as alcohol/water, for example ethanol/water, at temperatures of from -20 to 60 C, preferably from 10 to 30 C, and reaction of the resulting semicarbazone 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 of from -30 to 60 C, preferably from 0 to 30 C, and then with an acid, for example a strong mineral acid, such as a hydrohalic acid, in aqueous solution, where appropriate in the presence of the previously used solvent, at temperatures of from -40 to 50 C, preferably from -10 to 30 C. The corresponding esters are obtained by reacting the amino acids with the corres-X~ 8 ponding carboxylic acids, for example ethanol, analogously to the conditions used in the condensation under Process b), for example by reaction with inorganic acid halides, such as thionyl chloride, in organic solvent mixtures, such as mixtures of aromatic and alcoholic solvents, for example toluene and ethanol, at temperatures of from -50 to 50 C, preferably from -10 to 20 C.

The preparation of the compounds of formula XIII is carried out especially preferably under conditions analogous to the reaction conditions mentioned in J. Org. Chem. 47, 3016 (1982), J. Org. Chem. 43, 3624 (1978) orJ. Org. Chem. 51, 3921 (1986).

For the synthesis of the compounds of formula III, the compounds of formula XIII are then reacted with a reactive tetraalkylsilane, preferably a halomethyl tri-lower alkylsilane, such as chloromethyltrimethylsilane, in an inert solvent, for example an ether, such as diethyl ether, a cyclic ether, such as dioxane, or an ester, such as ethyl acetate, at temperatures of from -100 to 50 C, preferably from -65 to 40 C, compounds of the formula OH ~R6 R2~ Sl~-RR87 (XIV) HN
Pa being obtained wherein R6, R7 and R8 are each lower alkyl, for example methyl, and the other radicals are as last defined, the resulting compounds are converted in the presence of a Lewis acid, such as boron trifluoride ethyl etherate, in an inert solvent, especially a halogenated hydrocarbon, such as methylene chloride, with subsequent after-treatment with an aqueous base, for example sodium hydroxide solution, at temperatures of from -30 to 80 C, especially from 0 to 50 C, with elimination and removal of protecting groups, into olefinic compounds of the formula R2~ (XV) 25~ B

wherein R2 is as defined for compounds of formula I, an amino-protecting group Pa is again introduced into the corresponding olefin, as described under Process a) for the introduction of amino-protecting groups, especially with the aid of an acid anhydride in a chlorinated hydrocarbon, such as methylene chloride, at temperatures of from -50 to 80 C, especially from 0 to 35 C, a protected amino-olefin of the formula R ~ (XVI) being obtained in which the radicals are as last defined, the double bond is converted into an oxirane, preferably stereoselectively using peroxides, especially peroxycarboxylic acids, for example haloperbenzoic acid, such as m-chloroperbenzoic acid, in an inert organic solvent, preferably a halogenated hydrocarbon, such as methylene chloride, at temperatures of from -50 to 60 C, especially from -10 to 25 C, and, if necessary, the dia-stereoisomers are separated, epoxides of the formula (R) O
R2~ (XVII), Pa being obtained in which the radicals are as last defined, a suitable malonic acid diester, for example malonic acid dimethyl ester or malonic acid diethyl ester, is added to the olefins concerned, for example by activation of the methylene group of the malonic acid diester by means of an alkali metal, for example sodium, in a non-aqueous polar solvent, such as an alcohol, for example methanol or ethanol, at temperatures of from -50 to 80 C, espec-ially from 0 to 35 C, and the solution is treated with an acid, such as a carboxylic acid, for example citric acid, a lactone of the formula 2~ 9~8 - 6s -(S)/~ Rg R2~0 (XVIII), HN
Pa being obtained wherein Rg is lower alkoxy, for example methoxy or ethoxy, and the other radicals are as last defined, if desired in such compounds in which R2 is phenyl that is unsubstituted or substituted as described for compounds of formula I, that radical is reduced to cyclohexyl, especially by hydrogenation, preferably in the presence of catalysts, such as noble metal oxides, for example mixtures of Rh(III)/Pt(VI) oxides (in accordance with Nishimura), preferably in polar solvents, such as alcohols, for example methanol, under normal pressure or at up to 5 bar, preferably under normal pressure, at temperatures of from -20 to 50 C, preferably from 10 to 35 C, the compounds offormula XVIII obtained directly or after hydrogenation are reacted with a reagent that introduces the radical R3-CH2-, for example of the forrnula R3-CH2-W wherein R3 is as defined for compounds of formula I and W is a nucleofugal leaving group selected from hydroxy esterified by a strong inorganic or organic acid, such as by a mineral acid, for example a hydrohalic acid, such as hydrochloric acid, hydrobromic acid or hydriodic acid, or hydroxy esterified by a strong organic sulfonic acid, such as a lower alkanecarboxylic acid that is unsubstituted or substituted, for example by halogen, such as fluorine, or an aromatic sulfonic acid, for example a benzenesulfonic acid that is unsubstituted or substit-uted by lower aL~cyl, such as methy], halogen, such as bromine, and/or by nitro, for example a methanesulfonic, trimethanesulfonic or p-tohlenesulfonic acid, or hydroxy esterified by hydrazoic acid, especially bromide, in a non-aqueous polar solvent, for example an alcohol, such as ethano], in the presence of an alkali metal, for example sodium, at temperatures of from -50 to 80 C, preferably from 0 to 35 C, to obtain compounds of formula R3 o (S) ~ R9 R2~'0 (XIX), HN
Pa 9~8 wherein the radicals are as last defined, the compounds of formula XIX are hydrolysed and decarboxylated, for example by hydrolysis by means of a base, such as an alkali metal hydroxide, for example lithium hydroxide, at temperatures of from -50 to 80 C, prefer-ably from approximately 0 to 35 C, in an organic solvent, for example an ether, such as dimethoxyethane, and subsequent decarboxylation by heating in an inert solvent, prefer-ably a hydrocarbon, for example an aromatic hydrocarbon, such as toluene, to tempera-tures of from 40 to 120 C, preferably from 70 to 100 C, a compound of the formula (R,S) R
~S)/~, 3 2~0 (XX), HN
Pa being obtained wherein the radicals are as last defined, the resulting (R,S,S)- and (S,S,S)-isomers are separated by column chromatography, the (R,S,S)-isomer is used further and, in order to open the lactone ring, is reacted with a base, such as an alkali metal hydroxide, for example lithium hydroxide, in an inert solvent, such as an ether, for example dimethoxyethane, to obtain a compound of the formula R2~ ~(ROOH (XXI), HN
Pa wherein the radicals are as last defined, there is introduced into the resulting compound a hydroxy-protecting group Py, for example one of the hydroxy-protecting groups mentioned under l'rocess a), under the conditions mentioned there, especially a tri-lower alkylsilyl group, with the aid of the corresponding halo-tri-lower alkylsilane, for exarnple tert-butyldimethylchlorosilane, in a polar solvent, such as a di-lower aL~cyl-lower alkanoyl-amide, such as dimethylformamide, in the presence of a sterically hindered aminocompound, such as a cyclic amine, for example imidazole, at temperatures of from -50 to 80 C, preferably from 0 to 35 C, to obtain a compound of the formula 2~9 Py b ~R3 R2~(R)oH (XXII), HN
Pa wherein the radicals are as last defined, and the compounds of formula III having the radicals indicated under Proeess a) are produced therefrom, for example by condensation with a compound of formula VII wherein the radicals are as defined under Process c), under the conditions indieated for Process a), especially by in situ reaction in the presence of a condensation agent, such as benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate or O-benzotriazol- 1-yl-N,N,N',N'-tetramethyluronium hexafluoro-phosphate, a sterically hindered amine, such as N-methylmorpholine, and a compound preventing racemisation, such as 1-hydroxybenzotriazole, in a polar solvent, preferably an acid amide, for example a di-lower aL~ylamino-lower alkanoylamide, such as dimethyl-formamide, at temperatures of from -50 to 80 C, especially from 0 to 35 C, and by subsequent removal of the protecting groups Pa, as descAbed under Process f), provided Pa is not a radical that corresponds to the above definition of the radical H-B 1- for eompounds of formula I (with the exception from that definition of the case where B1 is a bond), condensation with a eompound of formula H-B 1 '-OH wherein B 1 ' is as defined under Process b), under the eondensation eonditions last mentioned, and finally the removal of Py and/or other protecting groups, as deseribed under Proeess f). For the preparation of the compounds of formula III, it is also possible to react the compounds of formula XXII suecessively with eompounds that introduce the radicals -B 1-, -A1-, -A2-, -Al-A2-, A2-NR4Rs andlor -NR4Rs of the compound of formula VII.

The above-mentioned compounds of formula XV may alternatively be in the (R,S)-config-uration at the carbon atom earrying the radieal -NH2 instead of in the (S)-eonfiguration shown, the compounds of formulae XII, XIII, XIV, and especially those of formulae XVI, XVII, XVIII, XIX, XX, XXI and/or XXII, may alternatively be in the (R,S)-eonfiguration at the earbon atom earrying the radieal Pa-NH- instead of in the (S)-eonfiguration, and eorresponding racemic mixtures or diastereoisomeric mixtures may also be separated at any stage.

2~9~8 Compounds of formula XX wherein the radicals are as defmed are also prepared from compounds of formula XIII wherein the radicals are as defined, by reacting the aldehydes of formula XIII with 2-halopropionic acid esters, especially 2-iodopropionic acid esters, such as 2-iodopropionic acid ethyl ester, to give the compounds of the formula (R,S) (S)~
R2~\0~ 0 (xxm HN
Pa wherein the radicals are as defined and wherein the carbon atom carrying the radical Pa-NH- may alteMatively be in the (R,S)-configuration.

The reaction is carried out first with the formation of the homoenolate of the 2-halo-propionic acid ester in the presence of a mixture of Zn/Cu in a di-lower aLkyl-lower aL~anoylamide, such as dimethylacetamide, at temperatures of from 0 to 100 C, espec-ially from 20 to 80 C. In another batch, a titanium tetrahalide, such as titanium tetra-chloride, is added, preferably under a yrotective gas, such as nitrogen or argon, to a tetra-lower alkyl orthodtanate, such as tetraisopropyl orthotitanate, in an aromatic solvent, such as toluene or xylene, in the presence of a halogenated hydrocarbon, such as methylene chloride, and the whole is stirred at from 0 to 50 C, especially from 20 to 30 C, to form the corresponding dihalotitanium di-lower alkanolate or preferably the trihalotitanium-lower alkanolate, especially trichlorotitanium diisopropanolate. The zinc-homoenolate soludon is added dropwise thereto at temperatures of from -50 to 0 C, especially from -40 to -25 C, and then the aldehyde of formula XIII in a halogenated hydrocarbon, for example methylene chloride, is added dropwise, the reaction taking place at from -50 to 30 C, preferably at approximately from -20 to 5 C, to form the ester, especially the ethyl ester, of the compound of formula XXIII. That ester is then hydrolysed to form the compound of formula xm, as defined above, preferably in an organic solvent, such as an aromatic compound, for example in toluene or xylene, in the presence of an acid, such as a carboxylic acid, for example acetic acid, at temperatures of from 20 C to the boiling point of the reaction mixture, especially at from 70 to 90 C. If necessary, the diastereoisomers are separated, for example by chromatography, for example on silica gel with a mixture of organic solvents, such as a mixture of an alkane and an ester, such as a lower alkane and a X~ 8 lower aL~yl-lower alkanoyl ester, such as hexane/ethyl acetate.

The corresponding compound of formula XX is then obtained from the compound of formula XXIII by deprotonation with a strong base to obtain the carbanion which is formed at the a-carbon adjacent to the oxo group of the lactone, and by subsequent nucleophilic substitution of the radical W of a compound of the formula R3-CH2-W, wherein R3 and W are as defined above in connection with the preparation of compounds of formula XIX, the reaction preferably leading stereoselectively to the (R)-configuration at the carbon atom carrying the radical R3-CH2- in the compound of formula XX. The reaction with a strong base, especially with an alkali meta1 organosilicon amidecompound, for example an allcali metal bis(tri-lower alkylsilyl)amide, such as lithium bis-(trimethylsilyl)amide, or also an alkali metal di-lower alkylamide, such as lithium diiso-propylamide, is carried out preferably in an inert organic solvent, especially an ether, for example a cyclic ether, such as tetrahydrofuran, at temperatures of from -100 tO O C, preferably from -78 to -50 C, and the nucleophilic substitution is preferably carried out in situ by adding the compound of the formula R3-CH2-W, in the same solvent, at tempera-tures of from -100 to 0 C, preferably from -60 to -40 C.

A compound of formula XV wherein the radicals are as defined and wherein the carbon atom carrying the group -NH2 is preferably in the (R,S)-configuration can also be obtained by converting a formic acid ester, for example a formic acid lower aL~cyl ester, such as formic acid ethyl ester, by reaction with allylamine at temperatures of from 20 to 70 C, especially from 50 to 60 C, into formic acid allylamide. That amide is then dehyd-rated under a protective gas, such as nitrogen or argon, preferably with an acid halide, such as phosphorus oxychloride, phosgene or, especially, an organic sulfonic acid halide, for example an arylsulfonic acid chloride, such as toluenesulfonic acid chloride, in the presence of a base, for example a tri-lower alkylamine, such as triethylamine, or, espec-ially, a mono- or bi-cyclic amine, such as pyridine or quinoline, at temperatures of from 50 to 100 C, especially from approximately 80 to approximately 100 C. In so doing, allyl isocyanide is forrned and is converted into the corresponding lithium salt by reaction with an organolithium salt, for example a lower alkyllithium, such as n-butyllithium, the reaction preferably being carried out in an inert organic solvent, especially an ether, such as dioxane or diethyl ether, or an alkane, for example hexane, or a mixture of those solvents, at temperatures of from -120 to -50, especially approximately from -100 to -90 C. The lithium salt formed is then reacted _ situ with a compound of the formula R2-CH2-W, wherein R2 is as defined for compounds of formula I and W is as defined "

2~9~8 above for compounds of the formula R3-CH2-W, and is especially bromine, preferably by the dropwise addition of R2-CH2-W in an organic solvent, for example an ether, such as tetrahydrofuran, at the temperatures last mentioned, and by subsequent heating to from 0 to 50 C, preferably to from 20 to 30 C. An isocyanide of the formula r'2 IC N ~ (XXIV), is formed wherein the radicals are as defined. The compound of formula XXIV is then hydrolysed, preferably in an aqueous solution to which an acid has been added, for example in an aqueous hydrohalic acid, such as hydrochloric acid, especially in concen-trated hydrochloric acid, at temperatures of from -20 to 30 C, especially approximately from 0 to 10 C, and the compound of formula XV is obtained wherein the radicals are as last defined and wherein the carbon atom carrying the group -NH2 is preferably in the (R,S)-configuration .

Compounds of formula IV are known or can be prepared in accordance with processes known Per se, for example by condensation of carboxylic or sulfonic acids of formula II, or reactive derivatives thereof, with amino compounds of the formula H-B 1 '-OH wherein B 1 ' is as defined for compounds of formula IV, the condensation being carried out as last described or, in the case of compounds of formula II wherein Rl ' is N-(heterocyclyl-lower aLkyl)-N-lower alkylaminocarbonyl, such as N-(2-pyridylmethyl)-N-methylamino-carbonyl, analogously to EP 0 402 646 of 19.12.1990, Example 218.

Compounds of formula V are prepared, for example, from compounds of formula XXII by condensation with a compound of formula VII or by successive condensation with compounds (for example H-Al '-OH, H-A2'-OH, H-Al-A2-OH, or the compound of formula XI, in each of which the radicals are as defmed above) that correspond to fragments of the compound of formula VII. The condensation conditions are analogous to those described for the preparation of the compounds of formula nI.

Compounds of formula VI are prepared, for example, from the amino compounds of .

2~

formula XXII by condensation with a carboxylic acid of the formula R1-Bl-OH, wherein the radicals are as defmed for compounds of formula I, for example by introducing a carboxy-protecting group, as described under Process a), and removing the protecting group Pa, as described under Process f).

Compounds of forrnula VII are prepared, for example, from the corresponding amino acids H-A1 '-OH or H-A2'-OH or the peptides H-A1-A2-OH and the amine components of formula XI, in each of which the radicals are as defined above, by condensation analogous to the process described under Process a). For the preparation of compounds having a reduced peptide bond between A1 and A2, the peptide bond between A1 and A2 can be reduced, preferably at the dipeptide stage, for example using hydrogen in the presence of heavy metal or noble metal catalysts, such as platinum or palladium, where appropriate on carriers, such as activated carbon, or using complex hydrides, preferably using complex hydrides, for example lithium aluminium hydride or disiamylborane in polar solvents, such as alcohols, for example ethanol, or ethers, such as cyclic ethers, for example tetra-hydrofuran, at temperatures of from 0 to 150 C, preferably from 20 C to the boiling point of the reaction mixture concerned. The amine of formula XI is known or is prepared in accordance with methods known E~ se-Compounds of formula VIII can be prepared, for example, from compounds of formula VIby condensation with an amino acid that introduces the radical A 1 ' . The reaction is carried out under conditions analogous to those described under Process a).

Compounds of formula IX are prepared by condensation, for example, from an amino acid H-A2'-OH wherein A2' is as defined under Process d), and from an amine of formula XI
wherein the radicals are as defmed for compounds of forrnula I.

Compounds of formula X are prepared, for example, from compounds of formula VI and from the corresponding amino acid H-Al '-OH or H-A2'-OH or the peptides H-Al-A2-OH, in each of which the radicals are as defmed above, by condensation analogous to the process described under Process a). For the preparation of compounds having a reduced peptide bond between A1 and A2, the peptide bond between A1 and A2 is reduced, preferably at the dipeptide stage, for example using hydrogen in the presence of heavy metal or noble metal catalysts, such as platinum or palladium, where appropriate on carriers, such as activated carbon, or using complex hydrides, preferably using complex hydrides, for example lithium aluminium hydride or disiamylborane in polar solvents, 2~

such as alcohols, for example ethanol, or ethers, such as cyclic ethers, for example tetra-hydrofuran, at temperatures of from 0 to 150 C, preferably from 20 C to the boiling point of the reaction mixture.

The amine of formula XI is known, is commerciall.y available or is prepared in accordance with methods known ~r se.

The other starting compounds are known, are prepared in accordance with processes known ~ se or can be purchased.

The following Examples serve to illustrate the invention but do not limit the scope thereof in any way.

Temperatures are given in degrees Celsius (C). If no temperature is indicated, the reaction takes place at room temperature. The Rf values, which indicate the relationship between the distance the particular substance concerned has migrated and the migration distance of the solvent front, are determined on silica gel thin-layer plates by thin-layer chromatography (TLC) in the following solvent systems:

TLC solvent systems:

A hexane/ethylacetate 1:1 B ethyl acetate C hexane/ethyl acetate 4:1 D hexane/ethyl acetate 2:1 E hexane/ethyl acetate 3:1 F methylene chloride/methanol 9:1 G chloroforrn/methanoUwater/glacial acetic acid 85:13:1.5:0.5 H ethylacetate/methanol 9:1 hexane/ethyl acetate 1:2 J chlorofor n/methanol/acetic acid/water 75:27:5:0.5 K ethyl acetate/acetic acid 19:1 L methylene chloride/methanol 7:3 M methylene chloride/ether 49:1 N methylene chloride/ether 3:1 The abbreviation "Rf(A)" denotes, for example, that the Rf value was determined in solvent system A. The ratio of solvents to one another is always indicated in parts by volume (v/v). In the definition of the eluant systems for column chromatography, the ratios of the solvents used are also given in parts by volume (v/v).
The other shortened names and abbreviations used have the following meanings:

abs. absolute atm physical atmospheres (pressure unit) - 1 atm corresponds to 1.013 bar Boc tert-butoxycarbonyl BOP benzotriazol-1-yloxy-tris(dimethyl-brine saturated sodium chloride solution amino)phosphonium hexafluorophosphate DCC dicyclohexylcarbodiimide DMF dimethylformamide DMSO dimethyl sulfoxide ether diethyl ether ethyl acetate acetic acid ethyl ester FAB-MS fast-atom-bombardment mass spectroscopy h hour(s) HBTU O-benzotriazol-l-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate HOBt 1-hydroxybenzot~iazole IR infrared spectroscopy min minute(s) m.p. melting point NMM N-methylmorpholine org. organic Pd/C palladium on activated carbon (catalyst) RT room temperature TBAF tetrabutylammonium fluoride (trihydrate) TLC thin-layer chromatography benzyloxycarbonyl 2;~3 Mass spectroscopic measurements are obtained in accordance with the "fast-atom-bombardrnent" (FAB-MS) method. The mass data relate to the protonatedmolecule ion (M+H)+.

The values for IR spectra are indicated in cm~l, and the solvent is given in round bMckets.

The abbreviations customarily used in peptide chemistry are used to denote bivalent radicals of natural a-amino acids. The configuration at the a-carbon atom is indicated by prefixing (L)- or (D)-. -Cha- is cyclohexylalanyl, -(p-F-Phe)- is phenylalanyl that is sub-stituted in the p-position of the phenyl ring by fluorine, -(p-CH30-Phe)- is phenylalanyl that is substituted in the p-position of the phenyl ring by a methoxy group and -(p-CN-Phe)- is phenylalanyl that is substituted in the p-position of the phenyl ring by a cyano group.

The following shortened names for radicals are defined by the corresponding formula drawings and names:

The radical having the shortened name -Phe[C]Phe- is the bivalent radical of 5(S)-amino-2(R)-benzyl-4(S)-hydroxy-6-phenylhexanoic acid and has the formula H OH ~3 ~N~
~ O

The radical having the shortened name -Cha[C](p-CN)Phe- is the bivalent radical of 5(S)-amino-2(R)-(p-cyanophenylmethyl)-6-cyclohexyl-4(S)-hydroxyhexanoic acid and has the formula H OH ~C~N
~N~
oi The radical having the shortened name -Cha[C]Cha- is the bivalent radical of 5(S)-amino-6-cyclohexyl-2(R)-cyclohexylmethyl-4(S)-hydroxyhexanoic acid and has the formula H OH ~O
~N~
oi The radical having the shortened name -Cha[C](p-F)Phe- is the bivalent radical of S(S)-amino-6-cyclohexyl-2(R)-(p-fluorophenylmethyl)-4tS)-hydroxyhexanoic acid and has the formula H OH ~F

~ N ~

O~
The radical having the shortened name -(p-F)Phe[C~Phe- is the bivalent radical of 5(S)-amino-2(R)-benzyl-6-(p-fluorophenyl)-4(S)-hydroxyhexanoic acid and has the formula Z~79~8 H OH ~0 ~N~

~
F

The other formula drawings, shown below, of the central building blocks correspond to the following shortened names which are used in the Examples which follow:

~N ~ H~ ~ ~
~ O o,~ O

X Y Y

-Phe[C](p-F)Phe- H F
-Phe[C](p-CN)Phe- H CN -Cha[C](p-CH30)Phe- CH30 -Phe[C](p-CH30)Phe- H CH30 -Cha[C](p-CF3)Phe- CF3 -Phe[C](p-CF33Phe- H CF3 -~p-F)Phe[C](p-F)Phe- F F
-(p-F)Phe[C](p-CN)Phe- F CN
-Tyr[C]Tyr- OH OH
-Tyr[C]Phe- OH H
-Phe[C]Tyr H OH

Accordingly, -Phe[C](p-F)Phe- corresponds to the bivalent radical of S(S)-amino-2(R)-(p-fluorophenylmethyl)-4(S)-hydroxy-6-phenylhexanoic acid; -Phe[C](p-CN)Phe- to the bivalent radical of 5(S)-amino-2(R)-(p-cyanophenylmethyl)-4(S)-hydroxy-6-phenylhexan-2~ a oic acid; -Phe[C~(p-CH30)Phe- to the bivalent radical of 5(S3-amino-4(S)-hydroxy-2(R)-(p-methoxyphenylmethyl)-6-phenylhexanoic acid; -Phe[C](p-CF3)Phe- to the bivalent radical of 5(S)-amino-4(S)-hydroxy-6-phenyl-2(R)-(p-trifluoromethylphenylmethyl)-hexanoic acid; -(p-F)Phe[C](p-F)Phe- to the bivalent radical of 5(S)-amino-6-(p-fluoro-phenyl)-2(R)-(p-fluorophenylmethyl)-4(S)-hydroxyhexanoic acid;
-(p-F)Phe[C](p-CN)Phe- to the bivalent radical of 5(S)-amino-2(R)-(p-cyanophenyl-methyl)-6-(p-fluorophenylj-4(S)-hydroxyhexanoic acid; -Cha[C](p-CH30)Phe- to thebivalent radical of S(S)-amino-2(R)-(p-methoxyphenylmethyl)-6-cyclohexyl-4(S)-hydroxyhexanoic acid; -Cha[C](p-CF3)Phe- to the bivalent radical of 5(S)-amino-6-cyclo-hexyl-4(S)-hydroxy-2(R)-(p-trifluoromethylphenylmethyl)-hexanoic acid; -Tyr[C]Tyr- to the bivalent radical of 5(S)-amino-4(S)-hydroxy-6-(p-hydr~xyphenyl)-2(R)-(p-hydroxy-phenylmethyl)-hexanoic acid; -Phe[C]Tyr- to the bivalent radical of 5(S)-amino-4(S)-hydroxy-2(R)-(p-hydroxyphenylmethyl)-6-phenylhexanoic acid; and -Tyr[C]Phe- to the bivalent radical of 5(S)-amino-4(S)-hydroxy-6-(p-hydroxyphenyl)-2(R)-benzylhexanoic acid.

CF, -(p-F)Phe[C](p-CF3)Phe- Y

-(CF3)Phe[C]Phe- H
-(CF3)Phe~C](p-F)Phe- F
-(CF3)Phe[C](p-CF3)Phe- CF3 The radical -(p-F)Phe[C](p~CF3)Phe- accordingly corresponds to the bivalent radical of 5(S)-amino-4(S)-hydroxy-6-(p-fluorophenyl)-2(R)-(p-trifluoromethylphenylmethyl)-hexanoic acid.

2~ 8 The symbol ~ ) is intended to signify that the radicals -(CF3)Phe[C]Phe-, -(CF3)Phe[C](p-F)Phe- and -(CF3)Phe[C](p-CF3)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-trifluQromethylphenyl)-hexanoic acid and 5-amino-2-(p-trifluoromethylphenyl)-4-hydroxy-6-(p-trifluoromethylphenyl)-hexanoic acid, are in the form of a mixture of the 2(R),4(S),5(S)-isomer and the 2(S),4(R),5(R)-isomer in the corresponding Examples.

Example 1: Boc-Cha~Cl(p-F)Phe-(L)-Val-~L)-Phe-morpholin-4-Dlamide 116 mg of TBAF are added to a solution of 160 mg of 5(S)-Boc-amino-4(S)-tert-butyl-dimethylsilyloxy)-6-cyclohexyl-2(R)-(p-fluorophenylmethyl)-hexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide in 1.8 ml of abs. DMF and the reaction mixture is then stirred for 4.5 h at RT. The colourless solution is poured onto 50 ml of water and extracted four times with ethyl acetate. The combined extracts are washed twice with 25 ml of sodium hydrogen carbonate solution each time, twice with water and once with brine and then dried over sodium sulfate. After concentrating the solvent by evaporation, the residue is crystallised from diisopropyl ether to yield the title compound. TLC Rf (I)= 0.14;
FAB-MS (M+H)~= 753.

The starting material is prepared as follows:

1 a) N-3(S)-(Boc-amino)-2(R,~ ~ydroxy-4-phenvl-1-trimethylsilylbutane 24.7 g of magnesium are introduced into 100 ml of abs. ether and, over the course of 35 min, a small amount of iodine and, at the same time, 132.5 ml of chloromethyltrimethyl-silane and 300 ml of ether are added, the temperature being maintained at 38 C by means of an ice bath. The resulting reaction mixture is then stirred for 1.5 h at RT. After cooling to -60 C, a suspension of 48.6 g of N-Boc-phenylalaninal (preparation: D. J. Kempf, J.
Org. Chem. 51, 3921 (1986)) in 1.1 litre of ether is added over the course of 40 min. The reaction mixture is heated to RT over the course of 90 min and is stirred for a further 90 min at that temperature. It is then poured onto 2 litres of ice-water and 1.5 litres of 10 % aqueous citric acid. The separated aqueous phase is extracted twice with 500 ml of 2~

ether each lime. All of the ether extracts are washed with 500 ml of a 10 % citric acid solution and twice with brine. After drying over sodium sulfate, concentration is carried out in vacuo and the resulting title compound is used further without additional purif-ication. TLC Rf (C)= 0.6; FAB-MS (M+H)+= 338.

1 b) 1-Phenvl-3-buten-2(S)-amine 35.6 ml of an approximately 48 % solution of boron trifluoride ethyl etherate are added at 5 C over the course of 10 min to 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. The reaction mixture is then stirred for 16 h at RT and cooled to 10 C, and 276 ml of a 4N sodium hydroxide solution are added over the course of 20 min. The aqueous phase is separated off and extracted twice with 400 ml of methylene chloride each time. The combined organic extracts are washed with brine and dried over sodium sulfate. The title product is used further without additional purification. TLC Rf (G)= 0.15; IR (methylene chloride) (cm~l): 3370, 3020, 2920,1640,1605.

1 c) N-Boc-l-phenYl-3-buten-2(s)-amine 21.5 g of 1-phenyl-3-buten-2(S)-amine are dissolved in 500 ml of abs. methylene chloride, and a solution of 38.3 g of Boc-anhydride in 250 ml of methylene chloride is added dropwise thereto. After stirring for 1.5 h at RT, the batch is concentrated to 100 ml, then diluted with 1.5 litres of ether and washed in succession twice with 400 ml of 10 %
citric acid each time, once with 400 ml of water, once with 400 ml of saturated aqueous sodium hydrogen carbonate solution and twice with brine, and dried oYer sodium sulfate.
After concentrating the solvent by evaporation, purification is effected by column chromatography (SiO2, hexane/ethyl acetate: 95/5 to 80/20) and the title compound is recrystallised from hexane. M.p. 67-68 C; TLC Rf (C)= 0.4; FAB-MS (M+H)+= 248.

1 d) 2(R)-[l~S~(Boc-amino)-2-phenylethYll-oxirane A solution of 9.74 g of m-chloroperbenzoic acid in 50 ml of methylene chloride is added over the course of 15 min at from 0 to 5 C to a solution of 1.45 g of N-Boc-1-phenyl-3-buten-2(S)-amine in 20 ml of methylene chloride. The batch is stirred for 18 h at that same temperature and is then stirred for a further 8 h, with heating to RT, to complete the reaction and poured onto ice-cold 10 % sodium carbonate solution. The aqueous phase is extracted three times with ether. The combined organic phases are washed in succession three times with 10 % sodium sulfite solution, three times with saturated sodium hydrogen 2~ 8 carbonate solution, with sodium thiosulfate solution and wilh brine and dried over sodium sulfate. After concentrating the solvents, the title compound is purified by column chromatography (SiO2, hexane/ethyl acetate: 4/1) and recrystallised from hexane. M.p.
51-52 C; TLC Rf (C)= 0.33; FAB-MS (M+H)+= 264.

1 e) 5(S)-rl(S)-(Boc-amino)-2-phenylethyll-3(R~S)-ethoxvcarbonYl-dihydrofuran-2-(3H)-one 3.4 g of sodium are added in portions to a solution of 26 ml of malonic acid diethyl ester in 260 ml of abs. ethanol. When the sodium has been consumed (approximately 1.5 h) a solution of 13 g of 2(R)-[l(S)-(Boc-amino)-2-phenylethyl]-oxirane in 100 ml of ethanol is added dropwise over the course of 10 min. After stirring for S h at RT, the reaction mixture is poured onto 1.5 litres of ice-water and adjusted to pH 4 with 10 % citric acid.
After extracting four times with ether, the combined organic phases are washed in succession twice with saturated aqueous sodium hydrogen carbonate solution, once with brine, again with saturated aqueous sodium hydrogen carbonate solution, with water and again with brine. After concentrating the solvent, the title compound is obtained by column chromatography (SiO2, hexane/ethyl acetate: 4/1). TLC Rf (C)= 0.22; FAB-MS
(M+H)+= 378.

1 f~ S(S)-rl(S)-(Boc-amino)-2-cYclohex-vlethvll-3(R~s)-ethox~ycarbon~vl-dihydr furan-2-(3~-one 10 g of 5(S)-[l(S)-(Boc-amino)-2-phenylethyl]-3(R,S)-ethoxycarbonyl-dihydrofuran-2-(3H)-one in 100 ml of ethanol are hydrogenated with 1 g of Nishimura catalyst (Rh(III) and Pt(VI) oxide (monohydrate, Degussa)) for 2 h under normal pressure (approximately 1 atm). The catalyst is ~lltered off through Celite (diatomaceous earth, Sigma, Switzerland) and washed with ethanol and the filtrate is concentrated by evaporation. TLC
Rf(C)=0.23.

1 g) S(S)-rl(S)-(Boc-amino)-2-cyclohexvlethvll-3(R~S~-ethoxycarbonyl-3-(p-fluoro-phenylmethyl)-dihvdrofuran-2-(3H)-one 10.2 g of 5(S)-[l(S)-(Boc-amino)-2-cyclohexylethyl]-3(R,S)-ethoxycarbonyl-dihydro-furan-2-(3H)-one are reacted at RT with 5.39 g of p-fluorobenzyl bromide (Fluka, Buchs, Switzerland) and 0.68 g of sodium in 180 ml of ethanol. Because, according to TLC, not all of the lactone has reacted after 1.5 h, a further 0.2 g of sodium and 0.7 g of p-fluoro-benzyl bromide are added. After 16 h, the batch is poured onto a mixture of 10 % citric acid and ice and extracted 3 times with ether. The organic phases are washed twice with ~ f ~3 -h ~3 water and twice with brine, dried with Na2SO4 and concentrated by evaporation. After the addition of hexane/ethyl acetate, some of the oily crude product crystallises out under the effect of ultrasound to give the title compound (ratio of diastereoisomers 4:1). Column chromatography (SiO2, hexane/elhyl acetate 4:1) of the mother liquor yields more title compound (ratio of diastereoisomers approximately 1:4). TLC Rf(C)=0.29; FAB-M~
(M+H)+=492.

1 h) 5~S)-~1(S)-(Boc-amino)-2-cyclohexyleth~Yl~(R)-(p-fluoro~en~ethyl)-dihydro-furan-2-(3H)-one and 5(S)-~l(S)-(Boc-amino)-2-cyclollex~letil~Yll-3(S)-(p-fluoro-phenylmethvl)-slihydrofuran-2-(3H)-one 91 ml of lM lithium hydroxide solution are added dropwise at RT over the course of 5 min to 10~3 g of 5(S)-[l(S)-(Boc-amino)-2-cyclohexylethyl]-3(R,S)-ethoxycarbonyl-3-(p-fluorophenylmethyl)-dihydrofuran-2-(3~1)-one (ratio of diastereoisomers approx-imately 1:1) in 174 ml of 1,2-dimethoxyethane and the batch is stirred for 15 h at RT.
After concentrating the solvent by evaporation, the resulting residue is poured onto 500 ml of 10 % citric acid and extracted three times with ether~ The combined ether phases are washed once with brine and dried over sodium sulfate~ After concen~rating the solvent by evaporation, the crude carboxylic acid is obtained which is converted into a mixture of the title compounds by means of subsequent decarboxylation by heating for 9 hours at 90 C
in 450 ml of toluene. Column chromatography (siO2, hexane/ethyl acetate 9:1 ~ 4:1) yields first the 3(R)-epimer [TLC Rf(E)=0.45], followed by the 3(S)-epimer [TLC
Rf(E)=0.41].

1 i) 5(S)-(Boc-amino)-4(S)-t!~ydroxy 6-cycloh~xyl-2(R)-(,p ~luoropllenylmeth~
hexanoic acid 19~6 ml of lM lithium hydroxide solution are added dropwise at from 20 to 25 ''C over the course of 2 min to 2.05 g of 5(S)-[l(S)-(Boc-amino)-2-cyclohexylethyl~-3(R)-(p-fllloro-phenylmethyl)-dihydrofuran-2-(311)-one in 78 ml of dimethoxyethane and 39 ml of water.
After stirring for 3 h at RT, the batch is concentrated under reduced pressure and the residue is taken up in 100 ml of saturated aqueous ammonium chloride solution and 5 ml of 10 % of citric acid and extracted four times with methylene chloride. The combined organic phases are washed with brine and dried over sodium sulfate. Concentration yields the title compound in the form of a foam which is used in the next stage without further purification.

1 j) 5(S)~ oc-amino)-4(S)-(tert-butYldimethylsilvloxy~-6-cyclohexyl-2(R)-(p-fluor 2~7~8 pheny~methYI)-hexanoic acid A solution of 2.01 g of S(S)-(Boc-amino)-4(S)-hydroxy-6-cyclohexyl-2(1~)-(p-fluoro-phenylmethyl)-hexanoic acid in 6.4 ml of DMF is stirred for 18 h at RT with 2.73 g of imidazole and 3.39 g of tert-butyldimethylchlorosilane. The reaction mixture is then poured onto ice-water and extracted with 3 portions of ethyl acetate. The combined organic phases are washed with 10 % citric acid solution, water and brine, dried with sodium sulfate and concentrated by evaporation to yield an oil. The oil is dissolved in 68 ml of methanol and 23 ml of THF, a solution of 4.1 g of potassium carbonate in 23 ml of water is added at RT and the batch is stirred for 1 h and finally partially concentrated by evaporation at RT. The aqueous residue is poured onto 10 % citric acid solution and ice and extracted 3 times with ethyl acetate. The organic phases are washed twice with water and twice with brine, dried with sodium sulfate and concentrated by evaporation. Column chromatography (SiO2, hexane/ethyl acetate 5:1 ~ 2:1) yields the title compound: TLC
Rf(E)=0.2; FAB-MS (M+H)+=552.
1 k) 5(S)-(Boc-amino)-4(S)-(tert-butvldimeth,vlsilvloxv)-6-cvclohexYl-2(R)-(p-fluoro-phen~lmethvl)-hexanovl-(L)-Val-~L)-Phe-morpholin-4-.vlamide A solution of 102 mg of 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-cyclo-hexyl-2(R)-(p-fluorophenylmethyl)-hexanoic acid, 90 mg of BOP and 27 mg of HOBT is stirred for 30 min at RT in approximately 2 ml of DMF, and then 74 mg of H-(L)-Val-(L)-Phe-morpholin-4-ylamide are added [for preparation, see under 1 l) to 1 o)]. After 16 h at RT, the batch is concentrated by evaporation, the residue is partitioned between 3 portions of ethyl acetate, water, sat. sodium hydrogen carbonate solution, water and brine, and the organic phases are dried with sodium sulfate and concentrated by evaporation. The title compound is obtained in the form of a crude product; TLC Rf(I)=0.57; FAB-MS
(M+H)+=867.

1 1) Z-(L)-Phe-mornholin-4-~/lamide A solution of 4.49 g of Z-(L)-Phe-OH in 190 ml of methylene chloride is cooled to 0 C
and 3.09 g of DCC are added. After stirring for 20 min at 0 C, a solution of 1.31 ml of morpholine in 10 ml of methylene chloride is added dropwise over the course of 15 min.
The reaction mixture is stirred for a further 24 h at RT and, after filtering off the precip-itated dicyclohexylurea, washing is carried out in succession with methylene chloride, aqueous sodium hydrogen carbonate solution and brine. After drying over sodium sulfate and concentrating, the crude title compound is obtained and is recrystallised fiom ether.
TLC Rf(B)= 0.55.

2~ 8 1 m) H-(L)-Phe-morPholin-4-,Ylamide A solution of 5.5 g of Z-(L)-Phe-morpholin-4-ylamide with 1.5 g of 10 % Pd/C in 150 ml of methanol is converted into the title compound by hydrogenolysis for 1 h at RT with the calculated amount of hydrogen. After filtering off the catalyst, the filtrate is concentrated and, after dilution with ethyl acetate, the resulting solution is washed with a saturated sodium hydrogen carbonate solution, dried over sodium sulfate and concentrated under reduced pressure. Column chromatography (analogous to Example 1 o)) yields the tide compound in pure form. TLC Rf(F)= 0.3.

1 n) Z-(L)-Val-(L)-Phe-morpholin-4-ylamide 1.75 g of DCC are added to a solution of 2.14 g of Z-(L)-Val-OH in 80 ml of abs. ice-cooled methylene chloride and, after stirring for 20 min at that temperature, a solution of 2 g of H-(L)-Phe-morpholin-4-ylamide is added dropwise over the course of 15 min. The reaction mixture is stirred for a further 24 h at RT and the resulting urea is filtered off. The filtrate is washed in succession with aqueous sodium hydrogen carbonate solution and brine and, after drying over sodium sulfate, is concentrated. Stirring with edher and filtering off the insoluble residue yields, after concentration, the title compound, which is further processed without additional purification. TLC Rf(F)= 0.7.

1 o) H-(L)-Val-(L)-Phe-morpholin-4-Y!amide Analogously to Example 1 m), 3.9 g of Z-(L)-Val-(L)-Phe-morpholin-4-ylamide is converted, by hydrogenolysis over 0.5 g of 10 % Pd/C in 150 ml of methanol, into the crude tide compound which is purified by column chromatography (SiO2, methylene chloride to methylene chloride/methanol: 97.5 to 2.5 (v/v)). TLC l~f(E;)= 0.4.
\
Example 2: Boc-PherClPhe-(L)-Val-(L)-Phe-morpholin-4-Ylamide Analogously to Example 1, 330.3 mg of 5(S)-Boc-amino-4(S)-(tert-butyldimethylsilyl-oxy)-6-phenyl-2(R)-phenylmethylhexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide in 3 ml of abs. DMF are converted with 247.2 mg of TBAF into the title compound, which recrystallises from hexane. TLC Rf (B)= 0.5; FAB-MS (M+H)+=729.

The starting material is prepared as follows:

2 a) 5(S)-[(l(S~-(Boc-amino)-2-PhenvlethYI1-3(~.S)-ethoxYcarbonYl-3-phen~vlmeth-yl-dihvdrofuran-2-(3H)-one 9~8 A solution of 23.8 g of 5(S)-[l(S)-(Boc-amino)-2-phenylethyl]-3(R,S)-ethoxycarbonyl-di-hydrofuran-2-(3H)-one in 410 ml of abs. ethanol and 14.4 ml of benzyl bromide is added to a solution of 2.76 g of sodium in 410 ml of abs. ethanol. The reaction mixture is stirred under argon for 18 h at RT and then poured onto a mixture of ice and 10 % citric acid.
After extracting three times with ether, the combined organic extracts are washed with water and brine and dried over sodium sulfate. Concentration yields the title compound in the form of a colourless oil which is used in the next stage without additional purification.
TLC Rf (C)=0.4; FAB-MS (M+H)+=468.

2 b) 5(S)-Il(S)-(Boc-amino)-2-phenvleth~vll-3(R)-phenYlmeth~l-dihydrofuran-2-(3H)-one and 5(S)-Il(S)-(Boc-amino)-2-Phenyle-thyll-3(S)-Phenylmethvl-dih,vdrofuran-2-(3H)-one 81.4 ml of a lM aqueous lithium hydroxide solution are added dropwise at RT over the course of 5 min to a solution of 10 g of S(S)-[(l(S)-(Boc-amino)-2-phenylethyl]-3(R,S)-ethoxycarbonyl-3-phenylmethyl-dihydrofuran-2-(3H)-one in 175 ml of dimethoxyethane.
The batch is then stirred for 15 h at RT and, after concentrating the solvent by evaporation, the resulting residue is poured onto 500 ml of 10 % citric acid and extracted three times with ether. The combined ether phases are washed once with brine and dried over sodium sulfate. Concentration of the solvent by evaporation yields 9.8 g of the crude carboxylic acid which is decarboxylated to form the title product by heating for 14 hours at 90 C in 450 ml of toluene. The title product is purifled by column chromatography (hexane/ethyl acetate: 9/1) to yield first 5(S)-[l(S)-(Boc-amino)-2-phenylethyl]-3(R)-phenylmethyl-di-hydrofuran-2-(3H)-one [TLC Rf (C)= 0.3; FAB-MS (M+H)+= 396] and then 5(S)-[l(S)-(Boc-amino)-2-phenylethyl]-3(S)-phenylmethyl-dihydrofuran-2-(3H)-one [TLC Rf (C)=0.25; FAB-MS (M+H)~=396].

2 c) 5(S)-(Boc-a nino)-4(S)-hydroxv-6-Phenvl-2(R)-Phen~lmethvlhexanoic acid 176 ml of a lM lithium hydroxide solution are added dropwise at 20 C over the course of 10 min to a solution of 17.6 g of 5(S)-[l(S)-(Boc-amino)-2-phenylethyl]-3(R)-phenyl-methyl-dihydrofuran-2-(3H)-one in 710 ml of ethylene glycol dimethyl ether and 352 ml of water. The reaction mixture is then stirred at RT for 1.5 h and the solvent is concen-trated by evaporation. The residue is poured onto 1 litre of cold 10 % citric acid and the acidic solution is extracted three times with 800 ml of ethyl acetate each time. The combined extracts are washed first with 800 ml of water and then with 800 ml of brine.
After drying the organic solution over sodium sulfate, the solvent is distilled off. The crude title compound is used in the next stage without further purification. FAB-MS

2~ a (M+H)+=414.

2 d) 5(S)-(Boc-amino)-4(S)-(tert-butvldimeth~vlsil~YIoxv)-6- phenvl-2(R)-phenylmethYI-hexanoic acid 8 g of imidazole and 10 g of tert-butyldimethylchlorosilane are added, with stirring, to a solution of 6.35 g of 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-phenylmethyl-hexanoic acid in 90 ml of DMF. After stirring for 18 h at RT, the clear yellow solution is poured onto ice-water and extracted three times with 250 ml of ethyl acetate each time.
The combined extracts are washed in succession three times with 10 % citric acid, once with water, three times with aqueous saturated sodium hydrogen carbonate solution, once with water and finally with brine. After drying over sodium sulfate, the solvent is concen-trated by evaporation and the resulting tert-butyl dimethyl silyl ether (13.5 g) is dissolved in 53 ml of THF and treated with 53 ml of acetic acid and 20 ml of water. After stirring for 3 h at RT, the batch is poured into water and extracted three times with ether. The collected ether extracts are washed twice with water and once with brine and dried over sodium sulfate. After concentration, the crude product is purified by column chromato-graphy (SiO2, hexanelethyl acetate 3.5tl.5) to yield the title compound. TLC Rl~ (D)= 0.37;
FAB-MS (M+H)+= 528.

2 e) 5(S) (Boc-amino)-4(S)-(tert-butvldimethYlsilvloxv)-6-PhenYI-2(R)-phenvlmethvl-hexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide Analogously to Example 1 k), 250 mg of 5(S)-(Boc-amino)-4(S)-tert-butyldimethylsilyl-oxy)-6-phenyl-2(R)-phenylmethylhexanoic acid in 3 ml of DMF are converted into the title compound with 230.5 mg of BOP,70.4 mg of HOBT, 182.6 ml of N-methylmorpho-line and 189.5 mg of H-Val-Phe-morpholin-4-ylamide. TLC Rf (A)= 0.24. FAB-MS
(M+H)~= 843.

Example 3: Boc-CharCI~p-CN)Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide Analogously to Example 1, 185 mg of S(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyl-oxy)-6-cyclohexyl-2(R)-(p-cyanophenylmethyl)-hexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide are converted into the title compound with 133 mg of TBAF in 2.5 ml of abs.
DMF. TLC Rf(B)= 0.33; FAB-MS (M+H)~= 760.

The starting material is prepared as follows:

3 a) 5(S)-Il(S)-(Boc-amino)-2-cvclohexvlethYl1-3-methoxYcarbonvl-dih.vdrofuran-;~? 1 7 2-(3H)-one 2.5 g of 5(S)-[l(S)-(Boc-amino)-2-phenylethyl]-3-ethoxycarbonyl-dihydrofuran-2-(3H)-one (Example 1 e)) are hydrogenated in 50 ml of methanol over 250 mg of Rh(III) and Pt(VI) oxide (monohydrate) (Nishimura catalyst, Degussa) for 2 h at RT and under normal pressure (approximately 1 atm). After filtering off and then washing the catalyst with methanol, concentration is carried out and the title compound is obtained in pure form by column chromatography (SiO2, hexane/ethyl acetate: 3/1 (v/v)). TLC Rf(E)= 0.2;
FAB-MS (M+H)+= 370.

3 b)~.(S)-~1fS)-(Boc-amino)-2-cYclohexyleth,vll-3(R.S)-methoxycarbonvl-3-(p-cyano-phenylmethvl)-dihydrofuran-2-(3H~-one Analogously to Example 1 g), 2.25 g of 5(S)-[l(S)-(Boc-amino)-2-cyclohexylethyl]-3(R,S)-methoxycarbonyl-dihydrofuran-2-(3H)-one are converted into the title compound with 1.32 g of p-cyanobenzyl bromide (Fluka, Buchs, Switzerland) and 156 mg of sodium in methanol. After working up, the title compound is obtained. TLC Rf(E)= 0.27.

3 c) 5(S)-rl(S)-(Boc-amino)-2-cyclohexyleth~Yll-3(R)-(p-cyanophenYlmethyl)-dih~dro-furan-2-~3H)-one and 5(S)-rl(S)-(Boc-amino)-2-c,vclohex.Yleth.vll-3(S)-(p-cvano-pheny methvl)-dihvdrofuran-2-(3H)-one Analogously to Example 1 h), 2.95 g of 5(S)-[1(S)-(Boc-amino)-2-cyclohexylethyl]-3-methoxycarbonyl-(p-cyanophenylmethyl)-dihydrofuran-2-(3H)-one in 55 ml of 1,2-dimethoxyethane are converted into the corresponding carboxylic acid with 24.4 ml of lM lithium hydroxide solution and then converted into the title compound by subsequent decarboxylation by heating in 130 ml of toluene. Separation by column chromatography (SiO2, hexane/ethyl acetate: 4/1 to 3.5/1.5 (v/v)) yields first the 3(R)-form of the title compound, which crystallises from ether/hexane [m.p. 106-108 C, TLC Rf (A)= 0.53;
FAB-MS (M+H)+= 427] and then the 3(S)-form of the title compound [TLC R~(A)= 0.47;
FAB-MS (M+H)+= 427].

3 d) 5(S)-(Boc-amino)-4(S)-h,vdroxv-6-cYclohex.vl-2(R)-(p-cvanoPhenvlmethvl)-hexanoic acid 7 ml of a lM lithium hydroxide solution are added dropwise at from 20 to 25 C over the course of 2 min to a solution of 550 mg of 5(S)-[l(S)-(Boc-amino)-2-cyclohexylethyl]-3(R)-(p-cyanophenylmethyl)-dihydrofuran-2-(3H)-one in 20 ml of 1,2-dimethoxyethane and 14 ml of water. After stirring for 2 h at RT, the batch is concentrated under reduced pressure and the residue is taken up in 100 ml of saturated aqueous ammonium chloride 2~ 9~8 solution and 5 ml of 10 % citric acid and extracted four times with methylene chloride.
The combined organic phases are washed with brine and dried over sodium sulfate.Concentration yields the title compound. TLC R,(~:;)= 0.4.

3 e) 5(S)-(Boc-amino)-4(S)-(tert-butvldimethvlsilyloxv~-6-c~vclohex,yl-2(R)-(p-cxano-phenylmethvl~-hexanoic acid 1.18 g of tert-butyldimethylchlorosilane and imidazole are added, with stirring, to 790 mg of 5(S)-(Boc-amino)-4(S)-hydroxy-6-cyclohexyl-2(R)-(p-cyanophenylmethyl)-hexanoic acid in approximately 10 ml of DMF. After stirring for 18 h at RT, the clear yellow solution is poured onto ice-water and extracted three times with 250 ml of ethyl acetate each time. The combined extracts are washed in succession three times with 10 % citric acid, once with water, three times with aqueous saturated sodium hydrogen carbonate solution, once with water and finally with brine. After drying over sodium sulfate, the solvent is concentrated by evaporation and the resulting tert-butyl dimethyl silyl ether (13.5 g) is dissolved in 53 ml of THF and treated with 53 ml of acetic acid and 20 ml of water. After stirring for 3 h at RT, the batch is poured onto water and extracted three times with ether. The collected ether extracts are washed twice with water and once with brine and dried over sodium sulfate. After concentration, the crude product is subjected to a final purification which is carried out by column chromatography (SiO2, hexane/ethyl acetate: 3/1 to 1/1 (v/v)). The title compound is obtained. TLC Rf (A)= 0.42; IR(methylene chloride) (cm-l) 2856, 2230, 1711, 1609, 1449.

3 f~ 5(S)-(Boc-amino)-4(S)-(tert-butvldimethvlsilvloxv)-6-cYclohexYl-2(R)-(p-cyano-phenvlmethvl)-hexanovl-(L)-Val-(L)-Phe~morpholin-4-,v!amide Analogously to Example 1 k), 138 mg of 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyl-oxy)-6-cyclohexyl-2(R)-(p-cyanophenylmethyl)-hexanoic acid are converted into the title compound with 122 mg of BOP, 37 mg of HOBT, 0.069 ml of N-methylmorpholine and 100 mg of H-(L)-Val-(L)-Phe-morpholin-4-ylamide in 3 ml of DMF. Purification is effected by column chromatography (SiO2, hexane/ethyl acetate: 1/1 (v/v)) to yield the pure title product. TLC Rf(A)= 0.25; FAB-MS (M+H)+= 874.

Example 4: H-PherClPhe-(L)-Val-(L)-Phe-morpholin-4-vlamide 20 ml of trifluoroacetic acid are added at 5 C over the course of 3 min to a solution of 1.048 g of Boc-Phe[C]Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide (Example 2) in 20 ml of abs. methylene chloride. After stirring for a further 90 min at RT, the batch is concentrated by evaporation, 150 ml of saturated aqueous sodium hydrogen carbonate solution are 2~; 7~3 added to the residue and extraction is carried out three times with ethyl acetate. The combined extracts are washed in succession with 100 ml of water, 100 ml of saturated sodium hydrogen carbonate solution, 100 ml of water and with brine. After drying over sodium sulfate, the solvent is concenllated by evaporation and the crude product is purified by column chromatography (SiO2, methylene chloride/methanol/ammonia:
95/5/0.1 to 90/10/0.1 (v/v)) to yield the title compound. TLC Rf(G)= 0.33; FAB-MS
(M+H)+= 629.

Example 5: 3-Benzofuranovl-PherClPhe-(L)-Val-(L)-Phe-morpholin-4-ylamide 93 mg of BOP, 29 mg of HOBT and 0.044 ml of N-methylmorpholine are added in succession to a solution of 30.9 mg of benzofuran-3-carboxylic acid (preparationaccording to Chin-Hsing Chou et aL J. Org. Chem. 51, 4208 - 4212, 1986) in 3 ml of DMF and then the batch is stirred for 30 min at RT. After the addition of 100 mg of H-Phe[C]Phe-(L)-Val-(L)-Phe-morpholin-1-ylamide (Example 4) the batch is stirred for a further 3 hours at RT and then poured onto 100 ml of water. After extracting three times with 50 ml of ethyl acetate each time, the combined organic phases are washed in succes-sion with 100 ml of water, 100 ml of saturated aqueous sodium hydrogen carbonatesolution, 100 ml of water and 100 ml of brine. After drying over sodium sulfate and concentrating by evaporation, the residue is digested with ether, and the title compound, which is obtained in the form of a solid, is dried. TLC Rf(G)= 0.73; FAB-MS (M+H)+=
773.

Example 6: Nicotinovl-PhelClPhe-(L~-Val-(L)-Phe-morpholin-4~vlamide Analogously to Example 5, 23.5 mg of nicotinic acid in 3 ml of DMF are converted into the tide compound with 93 mg of BOP, 29 mg of HOBT, 0.044 ml of N-methylmorpho-line and 100 mg of H-Phe[C]Phe-(L)-Val-(L)-Phe-morpholin-1-ylamide. After crystal-lisation from ether and drying, the pure title compound is obtained. TLC Rf(G)= 0.57;
FAB-MS (M+H)+= 734.

Example 7: Morpholinocarbon~vl-Val-Phe~ClPhe-(L)-Val-(L)-Phe-morPholin-4-vl-amide Analogously to Example 5, 44 mg of N-morpholinocarbonyl-(L)-Val in 3 ml of DMF are converted into the tide compound with 93 mg of BOP, 29 mg of HOBT, 0.044 ml of N-methylmorpholine and 100 mg of H-Phe[C]Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide(Example 4). Crystallisation from ether and drying yields the title compound. TLC Rf(G)=
0.5; FAB-MS (M+H)+= 841.5.

Z~ 8 7 a) N-Chlorocarbonvlmoruholine Over the course of 5 min at RT, 180 ml of a 20 % phosgene solution in toluene, and then, over the course of 10 min with cooling to from 5 to 10 C, a solution of 18 ml of morpholine in 180 ml of toluene are added to 180 ml of toluene. The white suspension is stirred for 1 h at RT and for a further 2 h under a stream of nitrogen. After filtering off the solid with suction and then washing it with toluene, the filtrate is concentrated by evapor-ation. The resulting title compound is processed further without additional purification. IR
(CH2CI2): 1730,1400,1205 cm~l.

7 b) N-Morpholinocarbonvl-(L)-Val-benzvl ester 15 g of the p-toluenesulfonic acid salt of (L)-valine benzyl ester (Fluka, Buchs, Switzer-land) and 15.4 ml of N-ethyldiisopropylamine are added to 3 ml of N-chlorocarbonyl-morpholine in 210 ml of CH2C12. A~ter stirring for 16 h at RT, a further 1.5 ml and, after 23 h, a further 0.8 ml, of N-chlorocarbonylmorpholine are added. After a total of 39 hours, the reaction mixture is concentrated, diluted with ethyl acetate and washed in succession twice with lN hydrochloric acid, once with water, once with saturated aqueous sodium hydrogen carbonate solution and twice with brine. After drying over sodium sulfate, the batch is concentrated under reduced pressure. The crude product is purified by column chromatography (SiO2, ethyl acetate) to obtain the title compound. TLC Rf(B)= 0.5.

7 c) N-~1orpholinocarbonvl-(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 h at RT in the presence of 2 g of 10 % Pd/C and under normal pressure. After filtering off and then washing the catalyst with ethyl acetate, the mother liquor is concentrated. The residue is taken up in ethyl acetate, filtered over Hyflo Super Cel~9 (kieselguhr, Fluka, Buchs, Switzerland) and concentrated under reduced pressure. The resulting title compound is further processed without additional purification.

Example 8: Boc-Cha~ClCha-(L)-Val-(L)-Cha-morPholin-4-~lamide Analogously to Example 3 a), 100 mg of Boc-Phe[C]Phe-(L)-Val-(L)-Phe-morpho-lin-4-ylamide (Example 2) in 30 ml of methanol are hydrogenated over a period of 4 h at RT in the presence of 40 mg of Nishimura catalyst. After filtering off the catalyst and concentrating, the residue is recrystallised from hexane and purified by column chromato-graphy (SiO2, hexane/ethyl acetate: 1/2 (v/v)) to yield the title compound. TLC Rf(I)= 0.5;
FAB-MS (M+H)+= 747.

Z~
- 9o -Example 9: Boc-Cha~Cl(p-F)Phe-(L)-Val-(L?-~p-F-Phe)-morpholin-4-ylamideAnalogously to Exarnple 1), 0.18 g of 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyl-oxy)-6-cyclohexyl-2(R)-(p-fluorophenylmethyl)-hexanoyl-(L)-Val-(L)-(p-F-Phe)-morpho-lin-4-ylamide is converted into the title compound with 114 mg of TBAF in 1.8 ml of DMF: TLC Rf(B)=0.44; FAB-MS (M+H)+= 771.

The starting material is prepared as follows:

9 a) Z-(L)-p-fluoroPhenvla!anine 2N NaOH is added to a solution of 5.0 g of H-(L)-(p-F-Phe)-OH [(L3-p-fluorophenyl-alanine (Fluka, Etuchs, Switzerland)] in 55 ml of THF and 20 ml of H20 until a pH of approximately 10 is obtained. 4.66 g of chloroformic acid benzyl ester are added dropwise to the resulting suspension and then the batch is stirred for 4 h at RT; the pH is maintained at approximately 10 by the addition of 2N NaOH. The reaction mixture is concentrated by evaporation and the residue is partitioned between ethyl acetate, 10 % citric acid solution and brine and dried with Na2SO4. Column chromatography (SiO2, dichloromethane/-methanol 7:3) yields the pure title compound: TLC Rf(K)=0.50.

9 b) Z-(L)-(P-F-Phe)-morpholin-4-ylamide Analogously to Example 1 1), 9.01 g of Z-(L)-(p-F-Phe)-OH and 2.38 g of morpholine in 350 ml of dichloromethane are converted into the title compound with 5.62 g of DCC, the title compound being obtained in pure form after column chromatography (SiO2, ethyl acetate): TLC Rf(B)= 0.6.

9 c) H-(L)-(p-F-Phe~-morpholin-4-vlamide Analogously to Example 1 m), 0.90 g of Z-(L)-(p-F-Phe)-morpholin-4-ylarnide in 50 ml of MeOH is converted into the title compound by hydrogenolysis with 0.2 g of 10 % Pd/C:
TLC Rf(L)= 0.4.

9 d) Z-(L)-Val-(L)-(p-F-Phe)-morPholin-4-vlamide Analogously to Example 1 n), 1.36 g of H-(L)-(p-F-Phe)-morpholin-4-ylamide and 1.36 g of Z-(L)-Val in 70 ml of dichloromethane are converted into the title compound with 1.11 gofDCC:TLCRf(B)=O.SS.

9 e) H-(L~-Val-a~F-Phe)-morpholin-4-Ylamide 2~

Analogously to Example 1 m), 2.80 g of Z-(L)-Val-(L)-(p-F-Phe)-morpholin-4-ylamide in 150 ml of MeOH are converted into the title compound by hydrogenolysis with 0.6 g of 10 % Pd/C, the title compound being obtained in pure form after column chromatography (SiO2, dichloromethane/methanol 9:1): TLC Rf(F)= 0.44; FAB-MS (M+H)+=352.

9 f~ S(S)-~oc-amino)-4(S)-(tert-butyldimethvlsilyloxv~-6-cvclohex,vl-2(R)-(p-nuoro-phenylmethvl)-hexanovl-(L)-Val-(L)-(p-F-Phe)~morpholin-4 y1amide 76 mg of HBTU are added to a solution of 100 mg of 5(S)-(Boc-amino)-4(S)-(tert-butyl-dimethylsilyloxy)-6-cyclohexyl-2(R)-(p-fluorophenylmethyl)-hexanoic acid (Example 1 j)) and 70.3 mg of H-(L)-Val-(L)-(p-F-Phe)-morpholin-4-ylamide in 1.7 ml of NMM/CH3CN 0.25M (0.25M NMM in CH3CN). After 16 h at RT, the batch is concen-trated by evaporation. The residue is partitioned between 3 portions of ethyl acetate, water, 2 portions of 10 % citric acid solution, water, 2 portions of saturated sodium hydrogen carbonate solution, water and finally brine, and the organic phases are dried with sodium sulfate and concentrated by evaporation to yield the title compound: TLC
Rf(A)=0.20; FAB-MS (M+H)~=885.

Example 10: Boc-CharCl(P-F)Phe-(L)-Val-(L)-(p-CH~O-Phe)-morpholin-4 Ylamide Analogously to Example 1), 0.18 g of 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyl-oxy)-6-cyclohexyl-2(R)-(p-fluorophenylmethyl)-hexanoyl-(L)-Val-(L)-(p-CH30)Phe-morpholin-4-ylamide is converted into the title compound with 114 mg of TBAF in 1.8 ml of DMF: TLC Rf(B)= 0.40; FAB-MS (M+H)+=783.

The starting material is prepared as follows:

10 a) Z-(DL)-p-methoxvphenylalanine Analogously to Example 9 a), 2.5 g of DL-p-methoxyphenylalanine (Bachem, Bubendorf, Switzerland! in 64 ml of THF and 17.9 ml of H2O are reacted with 2.3 g of chloroformic acid benzyl ester, the pH being maintained at approximately 10 by the addition of lN
Na2CO3 solution. The reaction mixture is concentrated by evaporation and the residue is partitioned bet veen ethyl acetate and dilute hydrochloric acid and brine to yield the title compound: TLC Rf(B)= 0.3; IR (CH2CI2): 1720, 1612, 1513 cm~l.

10 b) Z-(DL)-(p-CH30-Phe~-morpholin-4-vlamide Analogously to Example 1 1), 2.4 g of Z-(DL)-(p-CH30-Phe)-OH (Z-(DL)-p-methoxy-phenylalanine) in 36 ml of methylene chloride and 0.63 g of morpholine in 36 ml of methylene chloride are reacted with 1.5 g of DCC to form the title compound: TLCRf(B)= 0.5; IR (CH2Cl2): 1720, 1641, 1612, 1512 cm~l.

lO c) ~
Analogously to Example 1 m), 3.8 g of Z-(DL)-(p-CH30-Phe)-molpholin-4-ylamide in170 ml of methanol are converted into the title compound by hydrogenolysis with 0.8 g of 10 % Pd/C, the title compound being obtained in pure form after column chromatography (SiO2, methylene chloride/methanol 9:1): TLC Rf(F)= 0.3; IR (CH2Cl2): 1642, 1613, 1514, 1463, 1443.

10 d) Z-(L~-Val-(DL)-(p-CH~O-Phe)-morpholin-4-ylamide Analogously to Example 1 n), 1.80 g of Z-(L)-Val-OH in 40 ml of methylene chloride and 1.90 g of H-(DL)-(p-CH30-Phe)-morpholin-4-ylamide in 40 ml of methylene chloride are reacted with 1.48 g of DCC to form the title compound: TLC Rf(B)=0.12; IR (CH2Cl2):
1722, 1674, 1643, 1612,1512, 1465, 1443.
10 e) H-(L~:L~H30-Phe)-morpholin-4-vlamide and H-(L)-Val-(D)-(P~cH~o-phe~morpholin-4--vlamide Analogously to Example 1 m), 3.6 g of Z-(L)-Val-(DL)-(p-CH30-Phe)-morpholin-4-ylamide in 150 ml of MeOH are converted into a mixture of the title compounds by hydrogenolysis with 0.6 g of 10 % Pd/C. Column chromatography (SiO2, dichloro-methane ~ dichloromethane/methanol 19: 1 ~ dichloromethane/methanol 9:1) yields firsta fraction which, according to amino acid analysis by means of GC on a Chirasil-L-Val column (E. Bayer, Z. Natufforschung, B 1983, 38, 1281) contains H-(L)-Val-(L)-(p-CH30-Phe)-morpholin-4-ylamide ~TLC Rf(F)= 0.52; FAB-MS (M~H)+=364; GC TRet [(p-CH30-Phe) derivative] = 27.65 min}, followed by a fraction containing the epimer H-(L)-Val-(D)-(p-CH30-Phe)-morpholin-4-ylamide {TLC Rf(F)= 0.37; GC TRe, (p-CH30)Phe derivadve] = 27.26 min}.

10 f~ S(S)-(Boc-amino)-4(S)-(tert-butvldimethYlsilvlox~)-6-cvclohexvl-2(R)-(P-fluoro-phenvlmethyl)-hexanovl-(L)-Val-(L)-(p-CH~O-Phe~-morPholin-4-,ylamide Analogously to Example 9 f), 100 mg of 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyl-oxy)-6-cyclohexyl-2(R)-(p-fluorophenylmethyl)-hexanoic acid (Example 1 j)) and 72.7 mg of H-(L)-Val-(L)-(p-CH30-Phe)-morpholin-4-ylamide in 1.7 ml of NMM/CH3CN 0.25M and 1 ml of DMF are reacted with 76 mg of HBTU to form the titlecompound: TLC Rf(A)= 0.18; FAB-MS (M+H)+=897.

X~ 78 Example 11: Boc-CharCl(p-F)Phe-(L)-Val-(L)-Cha-morpholin-4-vlamide Analogously to Example 1), 0.16 g of 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyl-oxy)-6-cyclohexyl-2(R)-(p-fluorophenylmethyl)-hexanoyl-(L)-Val-(L)-Cha-morpholin-4-ylamide is converted into the title compound with 114 mg of TBAF in 1.8 ml of DMlF:
TLC Rf(B)= 0.49; FAB-MS (M+H)+= 759.

The starting material is prepared as follows:

11 a) H-(l~-Val-(L)-Cha-morpholin-4-.vlam de Analogously to Example 3 a), 1.0 g of H-(L)-Val-(L)-Phe-morpholin-4-ylamide (Example 1 o)) in 25 ml of methanol is hydrogenated with 0.15 g of Nis~imura catalyst to form the title compound which is obtained in pure form by column chromatography (SiO2, methylene chloride ~ methylene chloride/methanol 40:1) and digestion with hexane:
TLC Rf(F)= 0.50; FAB-MS (M+H)+= 340; IR (CH2Cl2): 1645, 1509, 1463, 1449.

11 b) 5~S~-(Boc-amino)-4(S)-(tert-butvldimethvlsilvloxy~yclohex.Yl-2(R)-(p-fluoro-phen.ylmethvl)-hexano,vl-(L)-Val-(L~-Cha-morpholin-4-vlamide Analogously to Example 9 f), 100 mg of 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyl-oxy)-6-cyclohexyl-2(R)-(p-fluorophenylmethyl)-hexanoic acid (Example 1 j~) and 67.9 mg of H-(L)-Val-(L)-Cha-morpholin-4-ylamide in 1.7 ml of NMM/CH3CN 0.25M
are reacted with 76 mg of HBTU to form the title compound: TLC Rf(A)= 0.47; FAB-MS
(M+H)+=873.

Example 12: 1.2.3.4-tetrahvdroisoquinoline-3(S)-carbonYl-Val-PherClPhe-(L)-Val-(L)-Phe-morpholin-4-,vlamide Analogously to Example 4), 242 mg of N-Boc-1,2,3,4-tetrahydroisoquinoline-3(S)-carbonyl-Val-Phe[C]Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide in 8 ml of methylene chloride are cleaved with 8 ml of trifluoroacetic acid to form the title compound: TLC
Rf(J)= 0.5; FAB-MS (M+H)+= 887.5; IR (KBr): 1639, 1531, 1495, 1453.

The starting material is prepared as follows:

12 a) N-Boc-l 2,3,4-tetrahydroisoquinoline-3(S)-carboxylic acid 20 g of 1,2,3,4-tetrahydroisoquinoline-3(S)-carboxylic acid (for preparation see: P.L.
Julian, W.J. Karpel, A. Magnani and E.W. Meyer, J. Am. Chem. Soc. 1948, 70, 180, except that L)-,B-phenylalanine is used as starting material), 233.6 g of potassium carbonate and 37 g of Boc-anhydride are stirred for 4 h at RT in 400 ml of dioxane/water 1: 1. The reacdon mixture is acidified with dilute HCI to pH 2 and extracted three times with ethyl acetate. After washing the organic phases with lN potassium hydrogen sulfate soludon, water and brine, drying with Na2SO4, concentrating by evaporation and crystal-lising from methylene chloride/hexane, the title compound is obtained: TLC Rf(C)= 0.2;
[~D=16 (c=1, MeOH).

12 b~ N~B c-1,2,3.4-tetrah~vdroisoquinoline-3(S~-carbonvl-L-Val-benzy! ester Under a N2 atmosphere, 6.47 g of N-Boc-1,2,3,4-tetrahydroisoquinoline-3(S)-carboxylic acid in 70 ml of methylene chloride are converted into the corresponding acid chloride at 0C with 4.7 g of 1-chloro-N,N,2-trimethylprop-1-enylamine (Haveaux, B., Dekoker, A., Rens, M., Sidani, A. R., Toye, J. and Ghosez, L., Org. Synth. 59, 26-34) and, after 15 min, 9.0 g of Hunig base and a solution of 6.83 g of L-Val-benzyl ester-HCI in 54 ml of methylene chloride are added thereto. After 15 min at 0C and 16 h at RT, the reaction mixture is washed with 10 % citric acid solution, water, sat. sodium carbonate solution, water and brine. The aqueous phases are extracted with 2 portions of methylene chloride and the combined organic phases are dried with sodium sulfate and concentrated by evaporation. Because, according to lH-NMR, some of the Boc-protecting group has been lost in the course of the }eaction, the crude product is further reacted with 6.8 g of Boc-anhydride in 160 ml of methylene chloride and 2.7 g of Hunig base. Column chromatography (SiO2, hexane/ethyl acetate 3:1) yields the pure title compound: TLC
R~(E)= 0.15.

12 c) N-Boc-1.2.3.4-tetrahvdroisoquinolille-3(S)-carbonYI-L-Val Analogously to Example 7 c), 1.97 g of N-Boc- 1,2,3,4-tetrahydroisoquinoline-3(S)-carbonyl-L-Val-benzyl ester in 50 ml of ethyl acetate are hydrogenated with 0.4 g of 10 %
Pd/C to form the title compound, which is used in the next stage without further purifi-cadon: TLC Rf(J)= 0.53; FAB-MS (M+H)+= 377.

12 d) N-Boc-1,2,3~4-tetrahvdroisoquinoline-3(S)-carbonYI-Val-Phe~ClPhe-(L)-Val-(L)-Phe-morpholin 4-vlamide Analogously to Example 5), 180 mg of N-Boc-1,2,3,4-tetrahydroisoquinoline-3(S)-carbonyl-L-Val in 4 ml of DMF are reacted with 232 mg of BOP, 71 mg of HOBT, 0.11 ml of NMM and a solution of 250 mg of H-Phe[C]Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide (Example 4) in 2 ml of DMF. Column chromatography (SiO2, ethyl acetate) 2~9~8 yields the title compound which, according to amino acid analysis (GC, Chirasil-L-Val:
(E. Bayer, Z. Natur~orschung, B 1983, 38, 1281)) contains an epimer (approximately 14 %
D-Val content) as a secondary product: TLC Rf(B)= 0.4; FAB-MS (M+H)+= 987; IR
(KBr): 1697, 1643, 1523, 1496.

Example 13: Boc-PherClPhe-(L)-Val-(L)-(p-F-Phe)-morpholin-4-vlamide Analogously to Example 1), 375 mg of 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyl-oxy)-6-phenyl-2(R)-phenylmethylhexanoyl-(L)-Val-(L)-(p-F-Phe)-morpholin-4-ylamide in 7 ml of DMF are desilylated with 275 mg of TBAF to form the title compound which, after clystallisation from diethyl ether/hexane, is obtained in pure form: TLC Rf(B)= 0.50;
FAB-MS (M+H)+= 747.

The starting material is prepared as follows:

13 a) 5(S~ oc-amino)-4(S)-(tert-butYldimethylsil,vlox,v)-6-Phenvl-2(R~-Phen.vl-methylhexanoYl-(L)-Val-(L)-(p-F-Phe)-morpholin-4-vlamide Analogously to Example 1 k), 250 mg of 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyl-oxy)-6-phenyl-2(R)-pheoylmethylhexanoic acid (Example 2 d)) in 5 ml of DMF are reacted with 230.6 mg of BOP,70.4 mg of HOBT, 130 ~Ll of NMM and 199.7 mg of H-(L)-Val-(L)-(p-F)Phe-morpholin-4-ylamide (for preparation see Example 9 e)) dissolved in 2 ml of DMF. Column chromatography (SiO2, ethyl acetate/hexane 2: 1) yields the tide compound: TLC Rf(I)= 0.43; FAB-MS (M+H)+=861.

Example 14: Boc-PhelClPhe-(L)-Val-(L)-(p-CH~O-Phe)-morpholin-4-vlamide Analogously to Example 1), 283 mg of 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyl-oxy)-6-phenyl-2(R)-phenylmethylhexanoyl-(L)-Val-(L)-(p-CH30)Phe-morpholin-4-yl-amide in 7 ml of DMF are desilylated with 204.5 mg of TBAF to form the title compound which, after digestion with diethyl ether/hexane and column chromatography (SiO2, ethyl acetate) is obtained in pure form: TLC R~(B)= 0.37; FAB-MS (M+H)+= 759.

The starting material is prepared as follows:

14 a) 5(S)-(Boc-amino~-4(S)-(tert-butvldimethylsilYloxy~-6-phenvl-2(R~-phen.Yl-meth~hexanoYl~(L)-val-(L~-(p~cH~o-phe~-morpholin~4~vlamide Analogously to Example 1 k), 250 mg of 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyl-oxy)-6-phenyl-2(R)-phenylmethylhexanoic acid (Example 2 d)) in 5 ml of DMF are 2~ 8 reacted with 230.6 mg of BOP, 70.4 mg of HOBT, 130 ~ul of NMM and 206.6 mg of H-(L)-Val-(L)-(p-CH30)Phe-morpholin-4-ylamide (for preparation see Example 10 e)) dissolved in 2 ml of DMF. Column chromatography (SiO2, ethyl acetate/hexane 2:1)yields the title compound: TLC Rf(I)= 0.37; FAB-MS (M+H)+= 873.

Example 15: Boc-PherClPhe-(L~-Val-(L~-Cha-morPholin-4-vlamide Analogously to Example 1), 430 mg of 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyl-oxy)-6-phenyl-2(R)-phenylmethylhexanoyl-(L)-Val-(L)-Cha-morpholin-4-ylamide in 5 ml of DMF are desilylated with 320 mg of TBAF to form the title compound which, after column chromatography (SiO2, ethyl acetate) and digestion with hexane, is obtained in pure form: TLC Rf(F)= 0.51; FAB-MS (M+H)+= 735.

The starting material is prepared as follows:

15 a) 5(S~-(Boc-amino)-4(S~-(tert-butvldimethvlsilYIoxv)-6-phenvl-2(R)-phenYI-methx~hexanoyi-(L)-Val-(L)-Cha-morPholin-4-Ylalnide Analogously to Example 1 Ic), 300 mg of S(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyl-oxy)-6-phenyl-2(R)-phenylmethylhexanoic acid (Example 2 d)) in 3 ml of DMF are reacted with 277 mg of BOP, 84.5 mg of HOBT, 0.22 ml of NMM and 231 mg of H-(L)-Val-(L)-Cha-morpholin-4-ylamide (for preparation see Example 11 a)) dissolved in 2 ml of DMF. Column chromatography (SiO2, ethyl acetate/hexane 1:1) yields the title compound: TLC Rf(A)=0.28; FAB-MS (M+H)+=849.

Example 16: Boc-PhelClPhe-(L)-lle-(L)-Phe-morpholin-4-,YIamide Analogously to Example 1), 329.8 mg of 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyl-oxy)-6-phenyl-2(R)-phenylmethylhexanoyl-(L)-Ile-(L)-Phe-morpholin-4-ylamide in 5 ml of DMF are desilylated with 242.7 mg of TBAF to form the title compound which, after digestion with hexane, is obtained in pure form: TLC Rf(B)=0.57; FAB-MS (M+H)+=743.

The starting material is prepared as follows:

16 a) Z-(L)-Ile-(L~-Phe-morpholin-4-vlamide Analogously to Example 1 n), 294 mg of Z-(L)-Ile in 10 ml of dichloromethane areconverted with 229 mg of DCC and 260 mg of H-(L)-Phe-morpholin-4-ylarnide (Example 1 m)) into the title compound which, after column chromatography (SiO2, ethyl acetate/-hexane 1: 1), is obtained in pure form: TLC Rf(A)=0.43, FAB-MS (M+H)+=482.

97 2~ 8 16 b) H-(L)-Ile~(L)-Phe-morPholin-4-,vlamide Analogously to Example 1 m), 0.38 g of Z-(L)-Ile-(L)-Phe-morpholin-4-ylamide in 15 ml of MeOH is converted by hydrogenolysis with 0.12 g of 10 % Pd/C into the title compound which, after column chromatography (SiO2, dichloromethane/methanol 9:1), is obtained in pure form: TLC Rf(F)=0.5; FA~-MS (M+H)+=348.

16 c) 5(S)-(Boc-amino~4~S)-(tert-but,vldim~hylsil.vlox~)-6-phenvl-2(R)-phenyl-meth~lhexanovl-(L)-Ile-(L)-Phe-morpholin-4-vlamide Analogously to Example 1 k), 240.5 mg of 5(S)-(Boc-amino)-4(S)-(tert-butyldimethyl-silyloxy)-6-phenyl-2(R)-phenylmethylhexanoic acid (Example 2 d)) in 5 ml of DMF are reacted with 242 mg of BOP, 73.8 mg of HOBT, 125.5,ul of NMM and 190 mg of H-(L)-Ile-(L)-Phe-morpholin-4-ylamide. Column chromatography (SiO2, ethyl acetate/hexane 1: 1) yields the title compound: TLC Rf(A)=0.21; FAB-MS (M+H)+=857.

Example 17: Boc-PherClPhe-(L)-Val-Glp-morpholin-4-vlamide Analogously to Example 1), 343.7 mg of 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyl-oxy)-6-phenyl-2(R)-phenylmethylhexanoyl-(L)-Val-Gly-morpholin-4-ylamide in 5 ml of DMF are desilylated with 282.7 mg of TBAF to form the title compound which is finally digested with diethyl ether: TLC Rf(B)=0.23; FAB-MS (M+H)+=639.

The starting material is prepared as follows:

17 a) Z-Glv-morpholin-4-vlamide Analogously to Example 1 1), 8.37 g of Z-Gly-OH in 500 ml of dichloromethane areconverted into the title compound with 8.25 g of DCC and 3.49 ml of morpholine: TLC
Rf(B)=0.28.

17 b) H-GIv-morpholin-4-vlamide Analogously to Example 1 m), 10.8 g of Z-Gly-morpholin-4-ylamide in 600 ml of MeOH
are converted by hydrogenolysis with 3 g of 10 % PdlC into the title compound which, after filtering off the catalyst and concentrating the filtrate by evaporation, is used directly in the next stage: TLC Rf(F)=0.2; IR (CH2CI2): 1654, 1461, 1440.

17 c) Z-(L)-Val-Glv-morpholin-4-ylamide Analogously to Example I n), 2.51 g of Z-(L)-Val in 75 ml of dichloromethane are converted into the title compound with 2.06 g of DCC and 1.44 g of H-Gly-morpholin-4-ylamide: TLC R[(B)=0.21.

17 d) H-(L!-Val-Glv-morpholin-4 YIamide Analogously to Example 1 m), 3.7 g of Z-(L)-Val-Gly-morpholin-4-ylamide in 160 ml of MeOH are converted by hydrogenolysis with 0.6 g of 10 % Pd/C into the title compound which, after filtering off the catalyst and column chromatography (SiO2, dichloro-methane/methanol 9: 1 ~ 4: 1) is obtained in pure form: TLC Rf(F)=0.23; FAB-MS
(M+H)+=244; IR (CH2Cl2): 1650, 1508, 1467, 1439.

17 e) 5(S)-(Boc-amino)-4(S)-(tert-butYldimethylsilYIoxv)-6-phenYl-2(R)-Phe-n~
meth,Ylhexanoy~ val-Gly~morpholin4~ylamide Analogously to Example 1 k), 300 mg of S(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyl-oxy)-6-phenyl-2(R)-phenylmethylhexanoic acid (Example 2 d)) in 5 ml of DMF are reacted with 302 mg of BOP, 92.1 mg of HOBT, 156.5,ul of NMM and 175.5 mg of H-(L)-Val-Gly-morpholin-4-y]amide. Column chromatography (SiO2, ethyl acetate/-hexane 1:9 ~ ethyl acetate) yields the title compound: TLC Rf(B)=0.44; FAB-MS
(M+H)+=753.

Example 18: Boc-PhelClPhe-(L)-IIe-Glv-morpholin-4-vlamide Analogously to Example 1), 362.4 mg of 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyl-oxy)-6-phenyl-2(R)-phenylmethylhexanoyl-(L)-Ile-Gly-morpholin-4-ylamide in 5 ml of DMF are desilylated with 292.7 mg of TBAF to form the title compound which is finally digested with diethyl ether: TLC Rf(B)=0.30; FAB-MS (M+H)+=653.

The starting material is prepared as follows:

18 a) Z-(L)-Ile-Gly-morpholin-4-ylamide Analogously to Example 1 n), 2.65 g of Z-(L)-Ile in 75 ml of dichloromethane are reacted with 2.06 g of DCC and 1.44 g of H-Gly-morpholin-4-ylamide (Example 17 b)). After digestion with diethyl ether the title compound is obtained: TLC Rf(F)=0.7.

18 b) H-(L)-Ile-Glv-morpholin-4-Ylamide Analogously to Example 1 m), 3.2 g of Z-(L)-Ile-Gly-morpholin-4-ylamide in 160 ml of MeOH are converted by hydrogenolysis with 0.6 g of 10 % Pd/C into the title compound which, after filtering off the catalyst and column chromatography (SiO2, dichloro--99- 2~ 8 methane/methanol 9:1), is obtained in pure form: TLC Rf(F)=0.3; FAB-MS (M+~I)+=258;
IR (CH2Cl2): 1653, 1510, 1467, 1439.

18 c) 5(S)-(Boc-amino)-4(S)-(tert-butvldimethvlsilYloxv)-6-Phenvl-2(R)-Phenvl-methylhexanoyl-(L)-Ile-Glv-morpholin 4-ylamide Analogously to Example 1 k), 300 mg of 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyl-oxy)-6-phenyl-2(R)-phenylmethylhexanoic acid (Example 2 d)) in 5 ml of DMF are reacted with 301.8 mg of BOP, 92.1 mg of HOBT, 156.5 ,ul of NMM and 185 mg of H-(L)-Ile-Gly-morpholin-4-ylamide. Column chromatography (SiO2, ethyl acetate/~lexane 9:1) yields the title compound: l~C Rf(B)=0.40; FAB-MS (M+H)+=767.

Example 19: Boc-Phe~ClPhe-(L~-Val-(L)-Val-morpholin-4-ylamide Analogously to Example 1), 416 mg of 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyl-oxy)-6-phenyl-2(R)-phenylmethylhexanoyl-(L)-Val-(L)-Val-morpholin-4-ylamide in 10 ml of r '~F are desilylated with 330 mg of TBAF to form the title compound which is ~mally digested with diethyl ether: TLC Rf(B)= 0.39; FAB-MS (M+H)+=681.

The starting material is prepared as follows:

19 a) Z-(L)-Val-(L~-Val-morpholin-4-vla~nide Analogously to Example 1 l), 2.0 g of Z-(L)-Val-(L)-Val-OH (Bachem, Bubendorf, Switærland) in 50 ml of dichloromethane are converted into the title compound with 1.17 g of DCC and 0.96 ml of morpholine dissolved in 50 ml of dichloromethane: TLC
Rf(B)=0.5.

19 b) H-(L~_Val-(L)-Val-morpholin-4-vlamide Analogously to Example 1 m), 2.3 g of Z-(L)-Val-(L)-Val-morpholin-4-yla;nide in 220 ml of MeOH are converted by hydrogenolysis with 0.5 g of 10 % PdJC into the title compound which, after filtering off the catalyst and column chromatography (SiO2, dichloromethane ~ dichloromethane/methanol 19:1 ~ 9:1) and stirring in diethyl ether/-hexane, is obtained in pure form: TLC Rf(F)=0.74; FAB-MS (M+H)+=286; IR (CH2CI2):
1642, 1507, 1461, 1440.

19 c) 5(S)-(Boc-amino)-4(S~-(tert-butvldimethvlsilYloxv)-6-phenyl-2(R)-phen methvlhexanoyl-(L)-Val-(L)-Val-morpholin-4-ylamide Analogously to Example 1 k), 300 mg of 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyl-2~

oxy)-6-phenyl-2(R)-phenylmethylhexanoic acid (Example 2 d)) in 5 ml of DMF are reacted with 277 mg of BOP, 84.5 mg of HOBT, 156.5,~L1 of NMM and 194.6 mg of H-(L)-Val-(L)-Val-morpholin-4-ylamide. Column chromatography (SiO2, ethyl acetate/-hexane 2:1) yields the title compound: TLC Rf(I)=0.27; FAB-MS (M+H)+=79S.

Example 20: Boc-PherClPhe-(L)-Val-(L~-Phe-thiomorPholin-4-vlamide Analogously to Example 1), 484 mg of 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyl-oxy)-6-phenyl-2(R)-phenylmethylhexanoyl-(L)-Val-(L)-Phe-thiomorpholin-4-ylamide in 5 ml of DMF are desilylated with 356 mg of TBAF. Column chromatography (SiO2, ethyl acetate~exane 2:1) and digestion with hexane yields the title compound: TLC R~(I)=0.31;
FAB-MS (M+H)+=745.

The starting material is prepared as follows:

20 a) Z-(L)-Val-~L)-Phe-thiomorpholin-4-,ylamide Analogously to Example 1 l), 1.99 g of Z-(L)-Val-(L)-Phe-OH (Bachem, Bubendorf, Switzerland) in 40 ml of dichloromethane are reacted with 1.03 g of DCC and a solution of 0.52 g of thiomorpholine in 40 ml of dichloromethane to form the title compound which, after extraction, is obtained in the form of an oil: TLC Rf(F)=0.8; IR (CH2C12):
1725, 1675, 1642, 1499, 1465, 1454.

20 b) H-(L~-Val-(L~-Phe-thiomorpholin-4-vlamide 45 ml of HBr/acetic acid 33 % (Fluka, Buchs, Switzerland) are added, while cooling with ice, to 2 g of Z-(L)-Val-(L)-Phe-thiomorpholin-4-ylamide and the reaction mixture is stirred for 1.5 h at RT. It is then concentrated by evaporation, the residue is partitioned between 3 portions of ethyl acetate, sat. sodium hydrogen carbonate sol~ltion, water and brine, and the organic phases are dried with Na2SO4 and concentrated by evaporation.
Column chromatography (SiO2, methylene chloride/methanol 9:1) yields first the title compound, followed by a secondary product, presumably an epimer: TLC Rf(F)=0.56;FAB-MS (M+H)+=350; IR (CH2Cl2): 1641, 1502, 1463, 1454, 1448; amino acid analysis {GC, Chirasil-~Val column (E. Bayer, Z. Na~ufforschung, B 1983,38, 1281)}:
TRet ((L)-Val derivative}= 8.36 min (ee>99 %), TRCt {(L)-Phe derivative}= 22.73 min (ee=94 %).

20 c) S(S)-(Boc-amino)-4(S)-(tert-butvldimethYIsilvloxy)-6-phenYl-2(R)-phenyl-meth,ylhexanoyl-(L)-Val-(L)-Phe-thiomorpholin-4-ylamide 2~ 8 Analogously to Example 1 k), 300 mg of 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyl-oxy)-6-phenyl-2(R)-phenylmethylhexanoic acid (Example 2 d)) in 5 ml of DMF are reacted with 277 mg of BOP, 84.5 mg of HOBT, 219 ~11 of NMM and 238.4 mg of H-(L)-Val-(L)-Phe-thiomorpholin-4-ylamide dissolved in 3 ml of DMF. Column chromato-graphy (SiO2, ethyl acetatelhexane 1:1) yields the title compound: TI,C Rf(A)=0.43;
FAB-MS (M+H)+=859.

Example 21:
In a manner analogous to that described in any one of the above Examples, or in the manner indicated in detail hereinafter, the following compounds are obtained:

A) 1) One of the compounds mentioned hereinafter under B) to J) in which -morpholin-4-ylamide is replaced by the radical -thiomorpholin-4-ylamide;

B) 1) Boc-~p-F)PherC](p-F)Phe-(l,)-Val-(L)-Phe-morpholin-4-vlamide Analogously to Example lj, 83 mg of 5(S)-(Boc-amino)-4(S)-(tert-butyldi-methylsilyloxy)-6-(p-fluorophenyl)-2(R)-(p-fluorophenylmethyl)-hexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide are converted into the title compound with 60 mg of TBAF in 0.95 ml of DMF: FAB-MS (M+H)+=765.

The starting material is prepared as follows:

1) a) N-Boc-(p-fluoroPhenYlalanine~:
In 0.4 litre of dioxane/water 1:1, 20 g (109 mmol) of p-fluorophenylalanine (Fluka; Buchs/Switzerland) are reacted with 35.5 g (163 mmol) of Boc-anhydride and 150 g (1.09 mol) of potassium carbonate. After 4 h, the reaction mixture is acidified with citric acid solution and extracted with 3 portions of ethyl acetate. The organic phases are washed with 10 % citric acid, water and brine, dried with sodium sulfate and concentrated by evapor-ation. The residue is dissolved in a small amount of methylene chloride and crystallisation is carried out by the addition of hexane to yield the title compound.

1) b) N-Boc-(p-fluorophenylalaninol):
At from -5C to -10C, 9.66 ml (69 mmol) of triethylamine are added to a solution of 17.9 g (63 mmol) of N-Boc-(p-fluorophenylalanine) in 73 ml of 2~

abs. THF, and a solution of 9.05 ml (69 mmol) of chloroformic acid isobutyl ester in 44 ml of abs. THF is added dropwise thereto. After stirring for 0.5 h at RT, the precipitate formed is filtered off with suction. The filtrate is added dropwise, with cooling, to 4.77 g (126 mmol) of sodium borohydride in 28 ml of water. After sti~ring for 4 h at RT, the batch is acidified with 10 %
citric acid, some of the THF is evaporated off in a rotary evaporator and the residue is partitioned between 3 portions of ethyl acetate, 2 portions of 2N
sodium hydroxide solution, water, saturated sodium hydrogen carbonate solution and brine. The organic phases are dried with sodium sulfate and concentrated by evaporation and, after dissolving in a small amount of methylene chloride and crystallising by the addition of hexane, the title compound is obtained: TLC Rf(A)=0.36; lH-NMR (200 MHz, CD30D): 7.24 (dd, 8 and SHz, 2 H), 6.98 (t, 8 Hz, 2 H), 3.73 (m, 1 H), 3.47 (d, S Hz, 2 H), 2.88 (dd, 13 and 6 Hz, 1 H), 2.62 (dd, 13 and 8 Hz, 1 H), 1.36 (s,9 H).

1) c) N-Boc-(p-fluorophenYlalaninal):
4.44 ml (62.4 mmol) of DMSO dissolved in 76 ml of methylene chloride are added dropwise under a N2 atmosphere to a solution, cooled to -60C, of 4.0 ml (46.8 mmol) of oxalyl chloride in 44 ml of methylene chloride. After stirring for 15 min, 8.4 g (31.2 mmol) of N-Boc-(p-fluorophenylalaninol) in the form of a solution in 185 ml of methylene chloride/~ 1 are added to the clear reaction solution (~ precipitation) and then the batch is stirred for 25 min. 17.3 ml (124.8 mmol) of triethylamine dissolved in 38 ml of methylene chloride are then added. After stirring for 30 min, 278 ml of a 20 % potassium hydrogen sulfate solution are added dropwise, followed by 220 ml of hexane. The batch is allowed to warm up to RT, and the aqueous phase is separated off and extracted with 2 portions of ether. After washing the organic phases with saturated sodium hydrogen carbonate solution, water and brine, drying with sodium sulfate and concentrating by evaporation, the title compound is obtained and is used in the next stage without further purif-ication: IH-NMR (200 MHz, CDCI3): 9.63 (s, 1 H), 6.9-7.2 (2m,4 H),5.04 (m, 1 H), 4.42 (m, 1 H), 3.10 (m, 2 H), 1.43 (s, 9 H).

1) d) 5(S)-rl(S)-(Boc-amino)-2-(n-fluorophenvl)ethyll-dihYdrofuran-2-(3H)-one Analogously to Example 21 D) 1) b), the Zn homoenolate is formed from 2~ 9~8 16.7 g of 2-iodopropionic acid ethyl ester in 124 ml of toluene, 8.1 g of Zn/Cu and 12.4 ml of dimethylacetamide. The Zn homoenolate is transferred by means of a cannula to the trichlorotitanium isopropanolate, which has been cooled to from -40C to -25C (prepared from 5.11 ml of tetraisopropyl orthotitanate and 5.71 ml of titanium tetrachloride in 16 ml of toluene and 88.5 ml of methylene chloride). The batch is heated for 5 min at -25C and then cooled to -40C again. A solution of 9.28 g of N-Boc-(p-fluorophenyl-alaninal) in 33 ml of methylene chloride is then added dropwise and the batch is subsequently stirred for 15 h at approximately -20C and finally for 1 h at 0C. The reaction mixture is poured onto 0.4 kg of ice-water and 0.55 litre of tert-butyl methyl ether and stirred vigorously for 10 min. The aqueous phase is separated off and extracted with 2 portions of ether, and the organic phases are washed with water, saturated sodium hydrogen carbonate solution, water and brine, dried with sodium sulfate and concentrated by evaporation to yield crystalline 5(S)-(Boc-amino)-4(S)-hydroxy-6-(p-fluoro-phenyl)-hexanoic acid ethyl ester as an intermediate which is heated for 2 h at 100C in 244 ml of toluene and 7.3 ml of acetic acid. 0.5 Iitre of water is added to the cooled reaction mixture and the aqueous phase is separated off and extracted with 2 portions of ether, and the org. phases are washed with saturated sodium hydrogen carbonate solution, water and brine, d~ied with sodium sulfate and concentrated by evaporation. Column chromatography (SiO2, hexane/ethyl acetate 2:1) yields the pure title compound: TLC
Rf(D)=0.22; FAB-MS (M+H)+=324. [a]D=20.7 (c=1; ethanol).

1) e) 5(S)-~l(S)-(Boc-amino)-2-(p-fluorophenvl~ethyll-3(R)-(p-fluoro-phen,vlmethvll-dih,Ydrofuran-2-(3H)-one Analogously to Example 21 D) 1~ c), 1.0 g of 5(S)-[l(S)-(Boc-amino)-2-(p-fluorophenyl)ethyl]-dihydrofuran-2-(3H)-one dissolved in 7.9 ml of THF is deprotonated with 6.05 ml of lithium bis(trimethylsilyl)amide lM in l~EIF
and alkylated with 0.673 g of p-fluorobenzyl bromide at -75C (1 h). Column chromatography (SiO2, methylene chloride/ether 49:1) yields the pure title compound: TLC Rf(M)=0.17; IH-NMR (200 MHz, CDCI3): 7.19-7.05 and 7.04-6.88 (2m, per 4 H), 4.50 (d, 10 Hz, HN), 4.11 (m, 1 H), 3.87 (qm, approximately 8 Hz, 1 H), 3.1-2.7 (m,5 H), 2.33-2.14 and 2.02-1.85 (2m, per 1 H), 1.35 (s, 9 H).

2~9~8 1) f~ 5(S)-(Boc-amino~-4(S~-hvdroxv-6-(p-fluoroPhenvl)-2(R)-(p-fluor phenvlmethvl~-hexanoic acid Analogously to Example 1 i), 790 mg of 5(S)-[l(S)-(Boc-arnino)-2-(p-fluoro-phenyl)ethyl]-3(R)-(p-fluorophenylmethyl)-dihydrofuran-2-(3H)-one in 29 ml of dimethoxyethane and 15 ml of water are hydrolysed with 7.3 ml of lM lithium hydroxide solution to form the tide compound which is used further directly.

1) g) 5(S)-(Boc-amino)-4(S)-(tert-butvldimethvlsilY!oxy?-6-(p-fluor phenyl)-2(R~-(p-fluorophenylmeth~vl~-hexanoic acid Analogously to Example 1 j), 956 mg of 5(S)-(Boc-amino)-4(S)-hydroxy-6~-(p-fluorophenyl)-2(R)-(p-fluorophenylmethyl)-hexanoic acid in 2.3 ml of DMF are silylated with 1.47 g of tert-butyldimethylchlorosilane and 1.19 g of imidazole. Hydrolysis of the silyl ester fimction with 1.76 g of potassium carbonate in 50 ml of methanoJtI~F/water 3:1:1 yields, after column chromatography (siO2, hexane/ethyl acetate 2:1)7 the title compound: TLC
Rf(D)=0.13; FAB-MS (M+H)+=564.

1) h) 5(S)-~Boc-amino)-4(S)-(tert-butvldimethvlsilvloxv)-6-(p-iluoro-phen.vl)-2(R)-(p-fluorophen.vlmethvl~-hexano.vl-(L)-Val-(L)-Phe-morpholin-4-vlamide Analogously to Example 9 f), 110 mg of 5(S)-(Boc-amino)-4(S)-(tert-butyl-dimethylsilyloxy)-6-(p-fluorophenyl)-2(R)-(p-fluorophenylmethyl)-hexanoic acid and 71.5 mg of H-(L)-Val-(L)-Phe-morpholin-4-ylamide (Example 1 o)) in 1.83 ml of NMM/CH3CN 0.25M are reacted with 81.5 mg of HBTU. The pure title compound is obtained after column chromatography (SiO2, methylene chloride/ether 3:1): TLC Rf(N)=0.14; FAB-MS (M+H)+=879.

2) Boc-(P-F)PherC~p-F)Phe-(L)-Val-(L)-(p-F~-morpholin-4-~1amide Analogously to Example 1), 150 mg of 5(S)-(Boc-aminoj-4(S)-(tert-butyl-dimethylsilyloxy)-6-(p-fluorophenyl)-2(R)-(p-fluorophenylmethyl)-hexan-oyl-(L)-Val-(L)-(p-F-Phe)-morpholin-4-ylamide are converted into the title compound with 105 mg of TBAF in 2.5 ml of DMF: FAB-MS (M+H)+=783.

The starting material is prepared as follows:

2) a) 5(S)-(Boc-amino)-4($)-(tert-butvldimethvlsilYloxy~-6-(p-iluor phenyl)-2(R)-(p-iluorophenylmethvl~-hexanoyl-(L~-Val-(L)-(P-F-phe) morpholin-4-vlamide Analogously to Example g f), 100 mg of 5(S)-(Boc-amino)-4(S)-(tert-butyl-dimethylsilyloxy)-6-(p-fluorophenyl)-2(R)-(p-fluorophenylmethyl~-hexanoic acid [Example 21 B) 1) g)] and 68.5 mg of H-(L)-Val-(L)-(p-F-Phe)-morpho-lin-4-ylamide (Example 9 e)) in 1.67 ml of NMM/CH3CN 0.25M are reacted with 74 mg of HBTU to form the title compound: TLC R~(A)=0.17;
FAB-MS (M+H)+=897.

3) Boc-(p-F)Phe~Cl(p-F)Phe-(O-Val-(L)-(p-CH~O-Phe)-morpholin-4-vlamide Analogously to Example 1), 126 mg of 5(S)-(Boc-amino)-4(S)-(tert-butyl-dimethylsilyloxy)-6-(p-fluorophenyl)-2(R)-(p-fluorophenylmethyl)-hexan-oyl-(L)-Val-(L)-(p-CH30-Phe)-morpholin-4-ylamide are converted into the title compound with 87 mg of TBAF in 2 ml of DMF: FAB-MS
(M+H)+=795.

The starting material is prepared as follows:

3) a) 5(S)-(Boc-amino)-4(S)-(tert-butvldimethvlsilyloxy)-6-(p-fluoro-phenvl)-2(R)-(p-fluorophenylmethvl)-hexanoyl-(L)-Val-(L)-(p-CH30-Phe)-morpholin-4-vlamide Analogously to Example 9 f), 80 mg of 5(S)-(Boc-amino)-4(S)-(tert-butyl-dimethylsilyloxy)-6-(p-fluorophenyl)-2(R)-(p-fluorophenylmethyl)-hexanoic acid [Example 21 B) 1) g)] and 56.7 mg of H-(L)-Val-(L)-(p-CH3O-Phe)-morpholin-4-ylamide (Example lOe)) in 1.3 ml of NMM/CH3CN 0.25M are reacted with 59.2 mg of HBTU to form 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-butyl-dimethylsilyloxy)-6-(p-fluorophenyl)-2(R)-(p-fluorophenylmethyl)-hexan-oyl-(L)-Val-(L)-Cha-morpholin-4-ylamide are converted into the title compound with 164 mg of TBAF in 3.8 ml of DMF: FAB-MS (M+H)+=771.

2~9~8 The starting material is prepared as follows:

4) a) 5(S~-(Boc-amino)-4(S)-(tert-but,vldimethy!silvlox,~v)-6-(p-tluoro-phen~vl~-2(R)-(p-fluorophen,vlmethvl~-hexanovl-(L)-Val-(L)-Cha-morpholin-4-vlamide Analogously to Example 9 f), 150 mg of 5(S)-(Boc-amino)-4(S)-(tert-butyl-dimethylsilyloxy)-6-(p-fluorophenyl)-2(R)-(p-fluorophenylmethyl)-hexanoic acid [Example 21 B) 1) g)] and 99.4 mg of H-(L)-Val-(L)-Cha-morpholin-4-ylamide (Example 1 la)) in 2.4 ml of NMMICH3CN 0.25M are reacted with 111 mg of HBTU to form the title compound: FAB-MS (M+H)+=885.

5) Boc-(p-F)Phe[C](p-F)Phe-(L)-Ile-(L)-Phe-morpholin-4-ylamide C) 1) Boc-(p-F)Phe[C](p-CNjPhe-(L)-Val-(L~-Phe-morpholin-4-ylamide 2) Boc-(p-F)Phe[C](p-CN)Phe-(L)-Val-(L)-(p-F-Phe)-morpholin-4-ylamide 3) Boc-(p-F)Phe[C](p-CN)Phe-(L)-Val-(L)-(p-CH30-Phe)-morpholin-4-yl-amide 4) Boc-(p-F)Phe[C](p-CN)Phe-(L)-Val-(L)-Cha-morpholin-4-ylamide 5) Boc-(p-F)Phe[C](p-CN)Phe-(L)-Ile-(L)-Phe-morpholin-4-ylamide D) 1) Boc-PhelCl(p-F~he-(L)-Va!-(L)-Phe-morphol_-4-YIamide Analogously to Example 1), 0.31 g of 5(S)-(Boc-amino)-4(S)-(tert-butyl-dimethylsilyloxy)-6-phenyl-2(R)-(p-fluorophenylmethyl)-hexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide is deprotected with 226 mg of TBAF in 3.0 ml of DMF to form the title compound which, after column chromatography (SiO2, ethyl acetate), is obtained in pure form: TLC Rf(B)=0.55; FAB-MS
(M+H)~=747.

The starting material is prepared as follows:

1) a) 2-Iodopropionic acid ethpl ester A suspension of 170 ml of 2-bromopropionic acid ethyl ester (Fluka; Buchs/-Switzerland) and 950 g of sodium iodide in 1.8 litres of acetone is stirred for 20 h at 60 C. The reaction mixture is filtered, the filtrate is partially concen-trated by evaporation, poured onto approximately 2.5 Iitres of ether, washed with 1.0 Iitre of 1 % sodium thiosulfate solution and finally with brine, dried - 107 - 2~9~3 with sodium sulfate and concenlrated by evaporation. Distillation (83C; 20 mbar) yields the pure title compound: MS (M)+=228; IH-NMR (200 MHz, CDCl3): 4.17 (q, 7 Hz, 2 H), 3.34 and 2.97 (2t, 7 Hz, 2x 2H), 1.28 (t, 7 Hz, 3 H).

1) b) 5(S)-[1(S)-(Boc-amino)-2-phenylethYll-dihydrofuran-2-(3H)-on~
(Analogously to A.E. DeCamp, A.T. Kawaguchi, R.P. Volante, and I.
Shinkai, Tetrahedron Lett. 32, 1867 (19gl)). Under a N2 atmosphere, 8.03 g of Zn/Cu (preparation: R.D. Smith, H.E. Simmons, W.E. Parham, M.D.
Bhavsar, Org. Synth., Coll. Vol 5, 855 (1973)) and 12.96 ml of dimethyl-acetamide are added to a solution of 17.4 g of 2-iodopropionic acid ethyl ester in 130 ml of toluene and then the batch is stirred vigorously for 1 h at RT and for 4 h at 80C (~ Zn homoenolate solution). In a second apparatus, (N2 atmosphere), 5.90 ml (53.8 mmol) of titanium tetrachloride are added, with slight cooling, to 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. The batch is stirred for 15 min at RT (~ yellow solution) and cooled to -40C
(~ partial crystallisation of the trichlorotitanium isopropanolate). Using a cannula, the Zn homoenolate solution, which has cooled to RT, is decanted from the metallic solid and is added dropwise to the trichlorotitanium iso-propanolate, the temperature being maintained at from -40C to -30C
(~ dark red solution), and then the batch is heated at -25C for S min and cooled again to -40C. A solution of 9.0 g of N-Boc-phenylalaninal (prepar-ation: D.J. Kempf, J. Org. Chem. 51, 3921 (1986)) in 32.8 ml of methylene chloride is then added dropwise thereto and the batch is subsequently stirred for 15 h at approximately -20C and finally for 1 h at 0C. The reaction mixture is poured onto 0.5 kg of ice-water and 0.5 litre of ether and stiIred vigorously for 10 min. The aqueous phase is separated off and extracted with 2 portions of ether; the organic phases are washed with 2 portions of water, saturated sodium hydrogen carbonate solution and brine, dried with sodium sulfate and concentrated by evaporation to yield crystalline 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenylhexanoic acid ethyl ester as intermediate. This intermediate is heated for 2.5 h at 80C in 295 ml of toluene and 9 ml of acetic acid. 05 litre of water is added to the reaction mixture, the aqueous phase is separated off and extracted with 2 portions of ether, the organic phases are washed with saturated sodium hydrogen carbonate solution, water 2~

and brine and dried with sodium sulfate. Partial concentration of the organic phases by evaporation and the addition of hexane yields the crystalline title compound which, according to analysis, contains approximately 10 % (4R)-epimer (TLC Rf(E)=0.08). Column chromatography (SiO2, hexane/ethyl acetate 2:1) yields the pure title compound: TLC Rf(E)=0.14; [a]D=17.7 (c=l; ethanol).

1) c) 5(S)-~l(S)-(Boc-amino)-2-Phenvlethvll-3(R)-(p-fluorophen methyl)-dihydrofuran-2-(3H)-one (Analogously to A.K. Ghosh, S.P. McKee, and W.J. Thompson, J. Org.
Chem. 56, 6500 (1991)). 1.92 ml of lithium bis(trimethylsilyl)amide lM in THF (Aldrich) are added at -75C under a N2 atmosphere to a solution of 300 mg (0.982 mmol) of S(S)-[l(S)-(Boc-amino)-2-phenylethyl]-dihydro-furan-2-(3H)-one in 6 ml of I~IF and the batch is then s~irred for 15 min at that temperature. 132 ~1(1.077 mmol) of p-fluorobenzyl bromide (Fluka;
Buchs/Switzerland) are then added dropwise and the batch is stirred for 30 min at -50C to complete the reaction. After cooling to -75C again, 0.3 ml of propionic acid and then 0.3 m1 of water are added. The batch is heated to 0C, diluted with ethyl acetate, washed with 10 % citric acid solution, saturated sodium hydrogen carbonate solution and brine, dried over sodium sulfate and concentrated by evaporation. Column chromatography (siO2, hexane/ethyl acetate 4:1 ) yields the pure title compound: TLC
R~(D)=0.54; FAB-MS (M+H)+=414.

1) d) 5(S)-(Boc-amino)-4(S~-hYdroxv-6-PhenYl-2(R)-(p-fluorophen methyll-hexanoic acid Analogously to Example 1 i), 1.46 g of 5(S)-[l(S)-(Boc-amino)-2-phenyl-ethyl]-3(R)-(p-fluorophenylmethylj-dihydrofuran-2-(3H)-one in 57 ml of dimethoxyethane and 29 ml of water are hydro1ysed with 14.1 ml of lM
lithium hydroxide solution to form the title compound which is further used without additional purification.

1) e) 5(S)-(Boc-amino)-4(S)-(tert-butvldimethplsilYloxY)-6-phenpl-2(R~-(P-fluorophenvlmethvl)-hexanoic acid Analogously to Example 1 j), 0.9 g of 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-(p-fluorophenylmethyl)-hexanoic acid in 4 ml of DMF is silyl-2g?~

ated with 1.49 g of tert-butyldimethylchlorosilane and 1.2 g of irnidazole.
Hydrolysis of the silyl ester function with 1.9 g of potassium carbonate in 50 ml of methanoUI~/water 3:1:1 yields, after acidification with citric acid solution and extraction with ethyl acetate, the title compound: TLC
Rf(D)=0.2.

1) f) S(S?-(Bo~-amino)-4(S)-(tert-butvldimcthvlsilvloxv~-6-phenvl-2(R)-(p-nuoroPhen,vlmethvl)-hexanovl-(L~-Val-(L)-Phe-morpholin-4-vlamide Analogously to Example 9 f), 200 mg of 5(S)-(Boc-amino)-4(S)-(tert-butyl-dimethylsilyloxy)-6-phenyl-2(R)-(p-fluorophenylmethyl)-hexanoic acid and 134 mg of H-(L)-Val-(L)-Phe-morpholin-4-ylamide (Example I o)) in 3.6 ml of NMM/CH3CN 0.25M are reacted witll 153 mg of HBTU. Crystallisation from hexane yields the pure title compound: TLC Rf~A)=0.25.

2) Boc-Phe[C](p-F)Phe-(L)-Val-(L)-(p-F-Phe)-morpholin-4-ylamide 3) Boc-Phe[C](p-F)Phe-(L)-Val-(L)-(p-CH30-Phe)-morpholin-4-ylamide 4) Boc-Phe[Cl(p-F~Phe-(L)-Val-(L3-Cha-morpholin-4-vlamide Analogously to Example 1), 120 mg of 5(S)-(Boc-amino)-4(S)-(tert-butyl-dimethylsilyloxy)-6-phenyl-2(R)-(p-fluorophenylmethyl)-hexanoyl-(L)-Val-(L)-Cha-morpholin-4-ylamide are deprotected with 87 mg of TBAF in 1.4 ml of DMF to form the title compound: TLC Rf(B)=0.61; FAB-MS
(M+H)+=753.

The starting material is prepared as follows:

4) a) 5(S)-(Boc-am-no)-4(S)-(tert-butvldimethylsilyloxv)-6-phenvl-2(R)-(p-lluorophen~ylmethvl)-hexanoyl-(L)-Val-(L)-Cha-morpholin-4-v!amide Analogously to Example 9 f), 100 mg of 5(S)-(Boc-amino)~4(S)-(tert-butyl-dimethylsilyloxy)-6-phenyl-2(R)-(p-fluorophenylmethyl)-hexanoic acid [Example 21 D) 1) e)] and 68 mg of H-(L)-Val-(L)-Cha-morpholin-4-yl-amide (Exarnple 1 la)) in 1.8 ml of NMM/CH3CN 0.25M are reacted with 76.4 mg of HBTU: TLC Rf(A)=0.50.

5) Boc-Phe[C](p-F)Phe-(L)-Ile-(L)-Phe-morpholin-4-ylamide 2~'79~8 E) 1) Boc-PherCl(p-CN)Phe-(L)-Val-(L)-Phe-morPholin-4-vlamide Analogously to Example 1), 60 mg of 5(S)-(Boc-amino)-4(S)-(tert-butyl-dimethylsilyloxy)-6-phenyl-2(R)-(p-cyanophenylmethyl)-hexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide are deprotected with 64.3 mg of TBAF in 1.0 ml of DMF to form the title compound. Column chromatography (SiO2, ethyl acetate) yields the pure title compound: TLC Rf(B)=0.26; FAB-MS
(M+H)+=754.

The starting material is prepared as follows:

1) a) 5(S)-~1(Si-(Boc-amino~-2-~envleth,vll-3(R~-(p-cvanoPhenvl-methvl)-dihydrofuran-2-(3H)-one Analogously to Example 21 D) 1) c), 1.5 g of 5(S)-[l(S)-(Boc-amino)-2-phenylethyl]-dihydrofuran-2-(3H)-one [Example 21 D) 1) b)] dissolved in 32 ml of THF are deprotonated with 9.8 ml of lithium bis(trimethylsilyl)-amide lM in THF and alkylated with 1.0 g of 4-bromomethylbenzonitrile (Fluka; Buchs/Switærland~ dissolved in 3 ml of THF. Column chromato-graphy (SiO2, hexane/ethyl acetate 1:1) yields the pure title compound: TLC
Rf(D)=0.33.

I) b) 5(S~-(Boc-amino~-4(S)-hvdroxy-6-phenvl-2(R)-(p-cvan~ophenvl-methvl~-hexanoic acid Analogously to Example 1 i), 0.50 g of 5(S)-[l(S)-(Boc-amino)-2-phenyl-ethyl]-3(R)-(p-cyanophenylmethyl)-dihydrofuran-2-(3H)-one in 19 ml of di-methoxyethane and 10 ml of water is hydrolysed with 4.8 ml of IM lithium hydroxide solution to form the title compound: TLC Rf(F)=0.3.

1) c) 5(S) (Boc-amino)-4(S)-(tert-butvldimethvlsilvloxv)-6-Phenvl-2(R)-(P-cvanoPhenvlmethvl)-hexanoic acid Analogously to Example 1 j), 0.62 g of 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-(p-cyanophenylmethyl)-hexanoic acid in 6.2 ml of DMF is silyl-ated with 0.98 g of tert-butyldimethylchlorosilane and 0.79 g of imidazole.
Hydrolysis of the silyl ester function with 1.2 g of potassium carbonate in 31 ml of methanoUI~F/water 3:1:1 yields, after acidification with citric acid solution and extraction with ethyl acetate, the title compound: TLC
Rf(D)=0.29; FAB-MS (M+H)+=553.

9~3 1) d) 5(S)-(Boc-amino)-4(S)-(tert-butvldimethylsilyloxv)-6-Phenyl-2(R)-(P-cyanophen.ylmethyl~-hexano~yl-(~)-Val-(L)-Phe-morpholin-4-ylamide Analogously to Exarnple 9 f), 72 mg of 5(S)-(Boc-amino)-4(S)-(tert-butyl-dimethylsilyloxy)-6-phenyl-2(R)-(p-cyanophenylmethyl)-hexanoic acid and 43.3 mg of H-(L)-Val-(L)-Phe-morpholin-4-ylamide (Example 1 o)) in 1.14 ml of NMM/CH3CN 0.25M are reacted with 50 mg of HBTU to form the title compound: TLC Rf(A)=0.19.

2) Boc-Phe[C](p-CN)Phe-(L)-Val-(L)-(p-F-Phe)-morpholin-4-ylamide 3) Boc-Phe[C](p-CN)Phe-(L)-Val-(L)-(p-CH30-Phe)-morpholin-4-ylamide 4) Boc-Phe[C](p-CN)Phe-(L)-Val-(L)-Cha-morpholin-4-ylamide 2~9~8 5) Boc-Phe[Cl(p-CN)Phe-(L)-lle-(L)-Phe-morPholin-4-vlamide Analogously to Example 1), 510 mg of 5(S)-(Boc-amino)-4(S)-(tert-butyl-dimethylsilyloxy)-6-phenyl-2(R)-(p-cyanophenylmethyl)-hexanoyl-(L)-Ile-(L)-Phe-morpholin-4-ylamide are desilylated with 362.3 mg of TBAF in 10 ml of DMF. The reaction mixture is poured onto ice-water and extracted with 3 portions of methylene chloride, and the organic phases are washed with saturated sodium hydrogen carbonate solution, water and brine, dried with sodium sulfate and concentrated by evaporation. Column chromato-graphy (SiO2, ethyl acetate) yields the pure title compound: TLC Rf(B)=0.51; FAB-MS (M+H)~=768.

The starting material is prepared as follows:

S) a) 5(S)-(Boc-amino~-4(S~- t~but.vldimethvlsilyloxv)-6-phen,vl-2(R~-(p-cvanophenv!methYl)-hexanoyl-(L)-Ile-(L)-phe-morpholin~4-vlamide Analogously to Example 9 f), 360 mg of 5(S)-(Boc-amino)-4(S)-(tert-butyl-dimethylsilyloxy)-6-phenyl-2(R)-(p-cyanophenylmethyl)-hexanoic acid [Example 21 E) 1) d)] and 253 mg of H-(L)-Ile-(L)-Phe-morpholin-4-yl-amide (Example 16 b)) in 6.36 ml of NMM/CH3CN 0.25M are reacted with 276 mg of HBTU. Partitioning of the residue of concentration by evaporation between methylene chloride, 10 % citric acid solution, water~ saturated sodium hydrogen carbonate solution, water and brine, drying the organic phases with sodium sulfate and concentration by evaporation yields the title compound: TLC Rf(D)=0.07.

F) 1) Boc-Phe[C](p-CH30)Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide 2) Boc-Phe[C](p-CH30)Phe-(L)-Val-(L)-(p-F-Phe)-morpholin-4-ylamide 3) Boc-Phe[C](p-CH30)Phe-(L)-Val-(L)-(p-CH30-Phe)-morpholin-4-yl-amide 4) Boc-Phe[C](p-CH30)Phe-(L)-Val-(L)-Cha-morpholin-4-ylamide 5) Boc-Phe[C](p-CH30)Phe-(L)-Ile-(L)-Phe-morpholin-4-ylamide G) 1) Boc-Phe[C](p-CF3)Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide 2) Boc-Phe[C](p-CF3)Phe-(L)-Val-(L)-(p-F-Phe)-morpholin-4-ylamide 3) Boc-Phe[C](p-CF3)Phe-(L)-Val-(L)-(p-CH30-Phe)-morpholin-4-ylamide 4) Boc-Phe[C](p-CF3)Phe-(L)-Val-(L)-Cha-morpholin-4-ylamide 5~ Boc-Phe[C](p-CF3)Phe-(L)-Ile-(L)-Phe-morpholin-4-ylamide 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-CH30-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)-Ile-(L)-Phe-morpholin-4-ylamide I) 1) Boc-Cha[C](p-CH30)Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide 2) Boc-Cha[C~(p-CH30)Phe-(L)-Val-(L)-(p-F-Phe)-morpholin-4-ylamide 3) Boc-Cha[C](p-CH30)Phe-(L)-Val-(L)-(p-CH30-Phe)-morpholin-4-yl-amide 4) Boc-Cha[C](p-CH30)Phe-(L)-Val-(L)-Cha-morpholin-4-ylamide S) Boc-Cha[C](p-CH30)Phe-(L)-Ile-(L)-Phe-morpholin-4-ylamide 1) 1) Boc-Cha[C](p-CF3)Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide 2) Boc-Cha[C](p-CF3)Phe-(L)-Val-(L)-(p-F-Phe)-morpholin-4-ylamide 3) Boc-Cha[C](p-CF3)Phe-(L)-Val-(L)-(p-CH30-Phe)-morpholin-4-ylamide 4) Boc-Cha[C](p-CF3)Phe-(L)-Val-(L)-Cha-morpholin-4-ylamide 5) Boc-Cha[C](p-CF3)Phe-(L)-Ile-(L)-Phe-morpholin-4-ylamide Example 22: Analogously to any one of the above-mentioned Examples, or in the manner indicated in dctail, there are prepared by selecting appropriate starting materials:

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

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

C) Boc~Cha~Cl(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-butyldimethylsilyl-oxy)-6-cyclohexyl-2(R)-(p-fluorophenylmethyl)-hexanoyl-(L)-Ile-(L)-Phe-morphoiin-4-ylamide is converted into the title compound with 117 mg of TBAF in 1.7 ml of DMF:
TLC Rf(I)=0. 18; FAB-MS (M+H)+=767.

The starting material is prepared as follows:

- 114- 2~ B

C) a) 5(S~-(Boc-amino~-4(S~-(tert-butyldimethvlsilyloxv~-6-cYclohexYI-2(R)-(p-fluoro-phenvlmethyl)-hexanopl-(L~-IIe-(L~-Phe-morpholin-4-vlamide Analogously to Example 9 f), 102 mg of 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyl-oxy)-6-cyclohexyl-2(R)-(p-fluorophenylmethyl)-hexanoic acid (Example 1 j)) and 70.8 mg of H-(L)-Ile-(L)-Phe-morpholin-4-ylamide (Examp1e 16 b)) in 1.77 ml of NMMICH3CN 0.25M are reacted with 77.4 mg of HBTU to form the title compound:
TLC Rf(A)=0.17; FAB-MS (M+H)+=881.

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

E) Boc-Phe~C]Phe-(L)-Val-(D)-Phe-morpholin-4-ylamide;

F) Boc-Phe~C]Phe-(L)-Val(red)-(L)-Phe-morpholin-4-ylamide;

G) Isobutoxycarbonyl-Phe~C]Phe-(L)-Val-(I,)-Phe-morpholin-4-ylamide;

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

I) Boc-Cha~Cl(p-F)Phe-(L)-Val-(L)-Phe-thiomorpholin-4-vlamide Analogously to Example 1), 0.16 g of 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyl-oxy)-6-cyclohexyl-2(R)-(p-fluorophenylmethyl)-hexanoyl-(L)-Val-(L)-Phe-thiomorpho-lin-4-ylamide is converted into the title compound with 114 mg of TBAF in 1.8 ml of DMF: TLC Rf(I)=0.38; FAB-MS (M+H)+=769.

The starting material is prepared as follows:

I) a) 5(S)-(Boc-amino)-4(S)-(tert-butsldimethvlsilvloxy~-6-c,vclohexvl-2(R)-(p-fluoro-phenvlmethvl)-hexanovl-(L)-Val-(L)-Phe-thiomorpholin-4-vlamide Analogously to Example 9 f), 100 mg of 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyl-oxy)-6-cyclohexyl-2(R)-(p-fluorophenylmethyl)-hexanoic acid (Example 1 j)) and 70 mg of H-(L)-Val-(L)-Phe-thiomorpholin-4-ylamide (Example 20 b)) in 1.7 ml of NMM/CH3CN 0.25M are reacted with 76 mg of HBTU. After 18 h at RT, some of the title compound is obtained directly from the reaction mixture by filtration. More title compound is obtained by partitioning the residue, obtained after concentrating the filtrate by evaporation, between 3 portions of ethyl acetate, water, 2 portions of 10 % citric acid solution, water, 2 portions of saturated sodium hydrogen carbonate solution, water and 2~ 8 brine, drying the organic phases with sodium sulfate and concentrating by evaporation:
TLC Rf(A)=0.55; FAB-MS (M+H)+=883.

J) The compounds of Examples 22 A) to 22 G) in which -morpholin-4-ylamide is replaced by the radical -thiomorpholin-4-ylamide.

Example 23 The following are prepared analogously to any one of the preceding processes:
a) Boc-Phe[C]Phe-(L)-Val-(L)-Phe-(4-methylpiperazin-1-yl)-amide b) Boc-Phe[C]Phe-(L)-Val-(L)-Phe-piperidin-1-ylamide c) Boc-Phe[C]Phe-(L)-Val-(L)-Phe-pyrrolidin-1-ylamide Example 24: Gelatin solution A steAle-filtered aqueous solution of any one of the compounds of formula I mentioned in the above or following Examples 1 to 23 and 33 to 41, which solution also additionally compAses 20 % cyclodextrin, and a steAle gelatin solution preserved with phenol, are so mixed under aseptic conditions, with heating, that 1.0 ml of solution having the following composition is obtained:

active ingredient 3 rng gelatin 150.0 mg phenol 4.7 mg dist. water with 20 % cyclodextAn 1.0 ml Example 25: Sterile dr,v substance for injection 5 mg of any one of the compounds of formula I mentioned in the above and following Examples 1 to 23 and 33 to 41 are dissolved as active ingredient in 1 ml of an aqueous solution with 20 mg of mannitol and 20 % cyclo~extAn as solubilisers. The solution is steAle-filtered and introduced under aseptic conditions into a 2 ml-ampoule, deep-frozen and Iyophilised. Before use, the Iyophilisate is dissolved in 1 ml of distilled water or 1 ml of physiological saline solution. The solution is administered intramuscularly or intra-venously. The formulation can also be introduced into double-chamber syringe ampoules.

2~?7 Example 26: Nasal spray 500 mg of finely ground (<5.0 ~lm) powder of any one of the compounds of formula I
mentioned in the above or following Examples 1 to 23 and 33 to 41 are suspended as active ingredient in a mixture of 3.5 ml of Myglyol 812(~) and 0.0~ g of benzyl alcohol.
The suspension is introduced into a container having a metering valve. 5.0 g of Freon 12( are introduced into the container through the valve under pressure. The "Freon" is dissolved in the Myglyol-benzyl alcohol mixture by shaking. The spray container contains approximately 100 individual doses which can be administered individually.

Example 27: Film-coated tablets The following constituents are processed for the preparation of 10 000 tablets each containing 100 mg of active ingredient:

active ingredient 1000 g corn s~arch 680 g colloidal silica 200 g magnesium stearate 20 g stearic acid 50 g sodium carboxymethyl starch 250 g water quantum satis A mixture of any one of the compounds of formula I mentioned in the above or following Examples 1 to 23 and 33 to 41, as active ingredient,50 g of corn starch and colloidal silica are processed with starch paste consisting of 250 g of corn starch and 2.2 kg ofdemineralised water to form a moist mass which is forced through a sieve having a mesh size of 3 mm and dried at 45 for 30 min in a fluidised bed drier. The dried granules are forced through a sieve having a mesh size of 1 mm, mixed with a previously sieved mixture (1 mm sieve) of 330 g of corn starch, the magnesium stearate, the stearic acid and the sodium carboxymethyl starch and compressed to form slightly convex tablets.

Exam~le 28: Orall.y administrable dispersion 1 625 mg of any one of the compounds of forrnula I mentioned in the above or following Examples 1 to 23 and 33 to 41, for example Boc-Phe[C]Phe-(L)-Val-(L)-Phe-morpho-lin-4-ylamide, as active ingredient, and 625 mg of POPC (1-palmitoyl-2-oleoyl-phosphat-idylcholine = 1-hexadecanoyl-2-(9-cis-octadecenoyl)-3-sn-phosphatidylcholine) are dissolved in 25 ml of ethanol. The solution is diluted with 10 times the amount of water.

- 117- 2~9~8 For that purpose, the ethanolic solution is added dropwise at room temperature at a rate of 10 mVmin to the amount of water provided. The ethanol is removed from the mixture by tangential dialysis (cross flow filtration) against 1750 ml of water (system: Minitan(E~), 700 cm2 polyether sulfone membrane having an exclusion limit of 100 kD, manufactured by Millipore (USA)). Using the same system, the mixture is concentrated to 15 mg of active ingredient by ultrafiltration. After the addition of 1.24 mg/ml of citric acid and 1.24 mg/ml of disodium hydrogen phosphate.2 H20 to adjust the pH to 4.2, and of 1 mglml of sorbic acid as antimicrobial preservative, the dispersion is again concentrated to 15 mg/ml and introduced into small bottles, for example having a capacity of 20 ml.
The dispersion particles have a diameter of from 0.1 to 211m. They are stable for at least six months at from +2 to 8 C and are suitable for oral administration.

Example 29: Orallv administrable dispersion 2 The preparation is carried out analogously to Example 28 except that 25 mgof active ingredient and 50 mg of POPC are used to prepare the ethanolic solution.

Example 30: Orallv administrable dispersion 3 The preparation is carried out analogously to Example 28 except that 25 mg of active ingredient and 125 mg of POPC are used to prepare the ethanolic solution.

Example 31: Orall,v administrable dispersion 4 The preparation is carried out analogously to Example 28 except that 50 mg of active ingredient and 50 mg of POPC are used to prepare the ethanolic solution.

ExamPIe 32: Orallv administrable disPersion 5 The preparation is carried out analogously to any one of Examples 28 to 31 except that active ingredient and phosphatidylcholine from soya or phosphatidylcholine from egg yolk (70 - 100 % pure) are used instead of POPC to prepare the ethanolic solution. If desired, an antioxidant, such as ascorbic acid, is added at a concentration of S mg/ml.

Example 33: Boc-(p-F)PherCl(p-CF~)Phe-(L)-Val-(L)-Phe-morpholin-4-vlamide Analogously to Example 1), 265 mg of S(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyl-oxy)-6-(p-fluorophenyl)-2(R)-(p-trifluoromethylphenylmethyl)-hexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide are converted into the title compound with 180 mg of TBAF in 4.2 ml of DMF: TLC Rf(I)= 0.3; FAB-MS (M+H)+=815.

-118- 2~ q8 The starting material is prepared as follows:

33a) 5(S)-[l(S)-(Boc-amino)-2-(p-fluorophenvl)ethvll-3(R)-(p-trifluoromethvlphenyl-methvl2-dihvdrofuran-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)-one dissolved in 6.3 ml of THF is deprotonated with 6.05 ml of lithium bis(trimethylsilyl)amide lM in THF and aLkylated with 0.739 g of p-trifluoro-methylbenzyl bromide (Fluka; Buchs/Switzerland) at -75C (40 min). Column chromato-graphy (SiO2, hexane/ethyl acetate 2:1) yields the pure tide compound: TLC Rf(D)=0.48;
FAB-MS (M+H)+=482.

33b) S(S)-(Boc-amino)-4~S~-h.Ydroxv-6-(p-lluorophenYI)-2(R~-(P-trifluoromethvl-phenylmethvl)-hexanoic acid Analogously to Example 1 i), 1.05 g of 5(S)-[l(S)-(Boc-amino)-2-(p-fluorophenyl)ethyl]-3(R)-(p-trifluoromethylphenylmethyl)-dihydrofuran-2-(3H)-one in 35.5 ml of dimethoxy-ethane and 17.9 ml of water are hydrolysed with 8.7 ml of lM lithium hydroxide solution to form the title compound which is used further directly.

33c) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilvloxy)-6-(p-fluorophenyl)-2(R)-(p-trilluoromethylphenvlmethvl)-hexanoic acid Analogously to Example 1 j), 1.06 g of 5(S)-(Boc-amino)-4(S)-hydroxy-6-(p-fluoro-phenyl)-2(R)-(p-trifluoromethylphenylmethyl)-hexanoic acid in 2.3 ml of DMF are silylated with 1.47 g of tert-butyldimethylchlorosilane and 1.18 g of imidazole. Hydrolysis oi the silyl ester function with 1.76 g of potassium carbonate in 50 ml of methanol/ I~IF/-water 3:1:1 yields, after column chromatography (SiO2, hexane/ethyl acetate 2:1), the title compound: TLC Rf(D)=0.15; IH-NMR (200 MHz, CD30D):-7.59 and 7.39 (2d, 8 Hz, per 2 H),7.19 and 6.98 (2m, per 2 H), 6.47 and 5.90 (d, approximately 9 Hz, together 1 H), 3.9-3.65 (m, 2 H), 3.15-2.8 (m, 4 H), 2.53-2.37, 2.07-1.9 and 1.6-1.4 (3m, per 1 H), 1.37-1.22 (m, 9 H), 0.94 (s, 9 H), 0.2-0.1 (m, 6 H).

33d) 5(S)-(Boc-aminol-4(S)-(tert-butvldimethvlsilvloxv)-6-(p-fluorophenvl)-2(R)-(p-trinuoromethylphenvlmethvl)-hexanovl-(L~-Val-(L)-Phe-morpholin-4-ylamide Analogously to Example 9 f), 180 mg of 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyl-oxy)-6-(p-fluorophenyl)-2(R)-(p-trifluoromethylphenylmethyl)-hexanoic acid and 107.5 mg of H-(L)-Val-(L)-Phe-morpholin-4-ylamide (Example 1 o)) in 2.8 ml of NMM/CH3CN 0.25M are reacted with 122 mg of HBTU: FAB-MS (M+H)+=929.

2~7~8 Example 34: Boc-(p-F)PheLCl(p-CF3)Phe-(Ll-Val-(L)-(p-F-Phe)-morPholin-4-vl-amide Analogously to Example 1), 270 mg of 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyl-oxy)-6-(p-fluorophenyl)-2(R)-(p-trinuoromethylphenylmethyl)-hexanoyl-(L)-Val-(L)-(p-F-Phe)-morpholin-4-ylamide are converted into the title compound with 180 mg of TBAF in 4.2 ml of DMF: TLC Rf(I)=0.2; FAB-MS (M+H)+=833.

The starting material is prepared as follows:

34a) 5(S)-(Boc-amino)-4(S)-(tert-butvldimethvlsily1OxY)-6-(p-tluorophenvl)-2(R)-(p-trinuorometh,ylphen~vlmethYl)-hexanovl-(L)-val-(L)-(p-F-phe)-morpholin-4-amide Analogously to Example 9 f), 180 mg of 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyl-oxy)-6-(p-fluorophenyl)-2(R)-(p-trifluoromethylphenylmethyl)-hexanoic acid (Example 33c) and 113.2 mg of H-(L)-Val-(L)-(p-F-Phe)-morpholin-4-ylamide (Exarnple 9 e)) in 2.8 ml of NMM/CH3CN 0.25M are reacted with 122 mg of HBTU: FAB-MS
(M+H)+=947.

Example 35: Boc-(p-F)PhelCl(p-C~3~Phe-(L)-Val-(I,)-(p-CH30-Phe)-morpholin-4-yl-amide Analogously to Example 1), 193 mg of 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyl-oxy)-6-(p-fluorophenyl)-2(R)-(p-trifluoromethylphenylmethyl)-hexanoyl-(L)-Val-(L)-(p-CH30-Phe)-morpholin-4-ylamide are converted into the title compound with 127 mg of TBAF in 3 ml of DMF: TLC Rf~I)=0.47; FAB-MS (M+H)+=845.

The starting material is prepared as follows:

35a) S(S)-(Boc-amino)-4(S)-(tert-butyldimethvlsilvloxv)-6-(p-fluorophenvl)-2(R)-(p-trifluorometh,vlphenvlmethvl)-hexano,vl-(Ll,-Val-(L)-(P-CH~O-Phe)-morpholin-4-,vl-amide Analogously to Example 9 f), 180 mg of 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyl-oxy)-6-(p-fluorophenyl)-2(R)-(p-trifluoromethylphenylmethyl)-hexanoic acid (Fxample 33c) and 117.2 mg of H-(L)-Val-(L)-(p-CH30-Phe)-morpholin-4-ylamide (Example 10 e)) in 2.8 ml of NMM/CH3CN 0.25M are reacted with 122 mg of HBTU: FAB-MS
(M+H)+=959.

2~

Example 36: Morpholinosulfonvl-(L)-Val-PherClPhe-(L)-Val-(L)-Phe-morpholin-4-vlamide Analogously to Example 5), 102 mg of N-morpholinosulfonyl-(L)-Val in 4 ml of DMF are activated with 186 mg of BOP,57 mg of HOBT and 0.09 ml of NMM and reacted with 200 mg of H-Phe[C]Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide (Example 4) in 1 ml ofDMF to form the title compound. The reaction mixture is poured into water, extracted with a large amount of ethyl acetate (poorly soluble) and washed with water, saturated sodium hydrogen carbonate solution, water and brine. The crude product is stilred in ether to yield the pure title compound: FAB-MS (M+H)+=877.

The starting material is prepared as follows:

36a) N-Chlorosulfonvlmorpholine With intensive cooling, 32.7 ml of sulfuryl chloride are added at approximately 0 C to 23.5 ml of morpholine. The suspension is then careful!y heated to 60C, causing the onset of hydrogen chloride evolution. After 5 h at 60 C, the evolution of hydrogen chloride is complete. The cooled br~wn reaction mixture is poured onto ice, and the precipitating oil is extracted with ether, washed with water,5 % sodium hydrogen carbonate solution and water and dried with sodium sulfate. The organic phases are concentrated by evaporation and distilled at elevated temperature and reduced pressure (90C; 1 mbar) to yield the tide compound: lH-NMR (200 MHz, DMSO-d6): 3.80 and 3.29 (2t, 5 Hz, per 4 H).

36b) N-MorDholinosulfonvl-(L)-Val 2 g of (L)-valine dissolved in 50 ml of lN NaOH are added dropwise to 6.3 g of N-chloro-sulfonylmorpholine in 20 ml of THF and the batch is stirred for 17 h at RT to complete the reaction. 15 ml of IN NaOH are added to the yellow emulsion and the batch is extracted with ether. The aqueous phase is acidified with 2N HCI and extracted with ethyl acetate.
The ethyl acetate phase is dried with sodium sulfate and concentrated by evaporation.
According to the IH-NMR spectrum, crystallisation from ether yields a secondary product.
The pure tide compound is obtained from dhe residue, resulting from concentration of the filtrate by evaporation, by crystallisation from hexane: TLC Rf~F)=0.25.

Example 37: Morpholinosulfon,vl-PherClPhe-(L~-Val-(L)-Phe-morpholin-4-vlamide 0.132 ml of triethylamine and 71 mg of N-chlorosulfonylmorpholine (Exasnple 36a) in 1 ml of DMF are added to a solution of 200 mg of H-Phe[C]Phe-(L)-Val-(L)-Phe-morpho-2~

lin-4-ylamide ~Example 4) in 5 ml of DMF. Because, after 2 h at RT, there is still a large amount of H-Phe[C]Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide present according to TLC, another 71 mg of N-chlorosulfonylmorpholine are added. After 18 h, the batch is poured into water, extracted with 3 portions of ethyl acetate, washed with saturated sodium hydrogen carbonate solution, water and brine, dried with sodium sulfate and concentrated by evaporation. Column chromatography (SiO2, methylene chloride/methanol 9:1) yields the pure title compound: TLC Rf(F)=0.60; FAB-MS (M+H)+=778.

Example 38: N-(N-(2-pvridylmeth.vl)-N-methvlarninocarbonvl)-(L)-Val-PherClPhe-(L)-Val-(L)-Phe-morpholin-4-vlamide Analogously to Example 5), 152 mg of N-(N-(2-pyridylmethyl)-N-methylamino-carbonyl)-(L)-valine (for preparation see EP 402 646 A 1, l9th Dec. 1990) in 5 ml of DMF
are activated with 279 mg of BOP, 85 mg of HOBT and 0.132 ml of NMM and reacted with 300 mg of H-Phe[C]Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide (Example 4) to form the title compound. Column chromatography (SiO2, ethyl acetate/acetone 9: 1 ~ acetone) yields the pure title compound after digestion with ether: TLC Rf(F)=0.28; FAB-MS
(M+H)+=876.

Example 39: 5(S)-(l~oc-amino)-4(S)-(acetoxv)-6-Phen,vl-2(R~-PhenYlmethYlhexan (L)-Val-(L)-Phe-morpholin-4~1amide 0.114 ml of triethylamine, 1 mg of dimethylaminopyridine and 0.08 ml of acetic anhydride are added to 400 mg of Boc-Phe[C]Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide (Example 2) in 8 ml of THF. After 30 min at RT, the colourless solution is poured onto water and extracted with 3 portions of ethyl acetate. The organic phases are washed with water, saturated sodium hydrogen carbonate solution, water and brine, dried with sodium sulfate and concentrated by evaporation to yield the title compound which, after column chromatography (SiO2, hexane/ethyl acetate 1:2), is obtained in pure form: TLC
Rf(B)=0.59; FAB-MS (M+H)+=771.

Example 40:
In a manner analogous to that described in any one of the preceding Examples, the following compounds are obtained:

A) Boc-(p-CF3)Phe[C]Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide B) Boc-(p-CF3)Phe[C]Phe-(L)-Val-(L)-(p-F)Phe-morpholin-4-ylamide C) Boc-(p-CF3)Phe[C]Phe-(L)-Val-(L)-(p-CH30)Phe-morpholin-4-ylamide 2~

D) Boc-(p-CF3)Phe[C]Phe-(L)-Val-(L)-Cha-morpholin-4-ylamide E) Boc-(p-CF3)Phe[CIPhe-(L)-Ile-(L)-Phe-morpholin-4-ylamide F) Boc-(p-CF3)Phe[C](p-F)Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide G) Boc-(p-CF3)Phe[C](p-F)Phe-(L)-Val-(L)-(p-F)Phe-morpholin-4-ylamide H) Boc-(p-CF3)Phe[C](p-F)Phe-(L)-Val-(L)-Cha-morpholin-4-ylamide I) Boc-(p-CF3)Phe[C](p-F)Phe-(L)-Val-(L)-(p-CH30)Phe-morpholin-4-ylamide J) Boc-(p-CF3)Phe[C](p-F)Phe-(L)-Ile-(L)-Phe-morpholin-4-ylamide K) Boc-(p-CF3)Phe[C](p-CF3)Phe-(L)-Val-(L)-Phe-moIpholin-4-ylamide L) Boc-(p-CF3)Phe[C](p-CF3)Phe-(L)-Val-(L)-(p-F)Phe-morpholin-4-ylamide M) Boc-(p-CF3)Phe[C~(p-CF3)Phe-(L)-Ile-(L)-Phe-morpholin-4-ylamide N) Boc-(p-CF3)Phe[C](p-CF3)Phe-(L)-Val-(L)-(p-CH30)Phe-morpholin-4-ylamide O) Boc-(p-CF3)Phe[C](p-CF3)Phe-(L)-Val-(L)-Cha-morpholin-4-ylamide P) The compounds according to the preceding Examples A) to O) in which the radical -morpholin-4-ylamide is replaced by the radical -thiomorpholin-4-ylamide.
The starting material is prepared as follows:

40a) N-AII /lformamide A solution of 300 ml of allylamine in 1288 ml of formic acid ethyl ester is heated at 60C
for 8 h. The reaction mixture is concentrated in a rotary evaporator and the residue is distilled via a Vigreux column (77C; 1 mbar): IH-NMR (200 MHz, CDCI3): 8.2-7.95 (m, 1 H), 6.5-5.8 (sb, 1 H), 5.9-5.7 (m, 1 H), 5.3-5.05 (m, 2 H), 3.95-3.75 (m, 2 H).

40b) Allvl isocYanide (U. Schollkopf, R. Jentsch, K. Madawinata and R. Harms, Liebigs Ann. Chem., (1976) 2105). 517 g of quinoline and 286 g of p-toluenesulfonic acid chloride are placed under a N2 atmosphere at 90C. A vacuum of from 2 to 4 mbar is applied and 85 g of N-allyl-formamide are added dropwise, the resulting isocyanide being distilled off continuously into the condensation trap (acetone/dry ice) via a Vigreux column at an internal temper-ature of 85-95C. When the reaction is complete, the distillate is immediately distilled off again via a Vigreux column (N2 atmosphere, normal pressure; 100C): IH-NMR
(200 MHz, CDC13): 5.9-5.7 (m, 1 H), 5.45 (d, 16 Hz, 1 H), 5.32 (d, 10 Hz, 1 H), 4.05 (m, 2 H); IR (CH2C12): 2150, 1650.

2~

40c) rac. 1~ trilluoromethy~phenvl)-3-buten-2-amine Under a N2 atmosphere, 4.5 g of allyl isocyanide are dissolved in 100 ml of THF/ether/-pentane abs. 4:1:1 and cooled to -100C. 42 ml of n-butyllithium (1.6M in hexane) are added dropwise at from -100 to -90C, a yellow colouring first appearing and a solid being precipitated shortly before the end of the addition. The reaction mixture is allowed to warm up to -70C slowly and is then cooled to -100C again. At from -100 to -85C, a solution of 16 g of p-trifluoromethylbenzyl bromide (Fluka; Buchs/Switzerland) in 10 ml of THF is added dropwise and the reaction mixture is slowly heated to RT. It is concen-trated by evaporation in a rotary evaporator (80 mbar; 30 C), and the residue is poured onto 150 ml of ice-water and extracted 3 times with ether. The ether phases are concen-trated by evaporation; 85 ml of methanol and 17 ml of conc. hydrochloric acid are added to the brown residue at 0C and the mixture is left overnight in a refrigerator. The mixture is concentrated by evaporation in a rotary evaporator and the residue is partitioned between 2 x 150 ml of 2M hydrochloric acid and 2 Px 200 ml of ether. The combined aqueous phases are rendered alkaline with solid sodium hydroxide, with cooling, and extracted with 3 portions of ethyl acetate. The organic phases are washed with brine, dried with sodium sulfate, concentrated by evaporation and distilled in a bulb tube (0.1 mbar;
170 C) to yield the pure title compound: 1H-NMR (200 MHz, CDC13): 7.56 and 7.32 (2d, 8 Hz, per 2 H), 5.96-5.78 (m, 1 H), 5.19-S.C2 (m, 2 H), 3.68-3.55 (m, 1 H), 2.87 and 2.71 (AB x d, Jab= 13 Hz, Jl= 6 Hz, J2= 8 Hz, 2 H), 1.4 (sb, 2 H).

Further reaction analogously to Examples 1 d) to 1 k) and 1), 9 f) and 9, 10 f) and 10, 15 a) and 15 or 16 c) and 16 leads to the compounds mentioned above under a) to o).

Example 41:
The following are prepared analogously to any one of the preceding 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~ClPhe-(L)-Val-(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) the compounds according to the above-mentioned Examples a) to h) in which theradical -morpholin-4-ylamide is replaced by the radical -thiomorpholin-4-ylamide.

Claims (18)

1. A compound of the formula (I), wherein R1 is hydrogen; lower alkoxycarbonyl; heterocyclylcarbonyl; benzyloxycarbonyl that is unsubstituted or substituted by up to three radicals which may be the same or different and are selected from fluorine, halo-lower alkyl, lower alkanoyl, sulfo, lower alkylsulfonyl and cyano; heterocyclyloxycarbonyl wherein heterocyclyl is bonded by way of a carbon atom; one of the mentioned carbonyl radicals wherein the bonding carbonyl group has been replaced by a thiocarbonyl group; heterocyclylsulfonyl; lower alkyl-sulfonyl; or N-(heterocyclyl-lower alkyl)-N-lower alkylaminocarbonyl, B1 is a bond or a bivalent radical of an a-amino acid, which radical is bonded N-terminally to Rl and C-terminally to the amino group at the R2-CH2-carrying carbon atom, each of R2 and R3, independently of the other, is phenyl or cyclohexyl, those radicals being unsubstituted or substituted by from one to three radicals which may be the same or different and are selected from hydroxy, lower alkoxy, halogen, halo-lower alkyl, sulfo, lower alkyl-sulfonyl, cyano and nitro, A1 is a bond between -C=O and A2 or is a bivalent radical of an .alpha.-amino acid, which radical is bonded N-terminally to the group -C=O and C-terminally to A2, A2 is a bivalent radical of an .alpha.-amino acid, which radical is bonded N-terminally to A1 and C-terminally to the group NR4R5, or A1 and A2 together form a bivalent radical of a dipeptide, of which the central amide bond is reduced and which is bonded N-terminally to the group -C=O and C-terminally to the group NR4R5, and R4 and R5, together with the bonding nitrogen atom, are unsubstituted or substituted thiomorpholino or morpholino, or a salt of that compound if salt-forming groups are present, or a hydroxy-protected deriv-ative of that compound or a salt thereof.

2. A compound of formula I according to claim 1, wherein R1 is hydrogen, lower alkoxy-carbonyl, heterocyclylcarbonyl, benzyloxycarbonyl that is unsubstituted or substituted by up to three radicals which may be the same or different and are selected from fluorine, halo-lower alkyl, lower alkanoyl, sulfo, lower alkylsulfonyl and cyano, or is heterocyclyl-oxycarbonyl wherein heterocyclyl is bonded by way of a carbon atom, or is one of the mentioned carbonyl radicals wherein the bonding carbonyl group has been replaced by a thiocarbonyl group, B1 is a bond or a bivalent radical of an .alpha.-amino acid, which radical is bonded N-terminally to R1 and C-terminally to the amino group at the R2-CH2-carrying carbon atom, each of R2 and R3, independently of the other, is phenyl or cyclohexyl, those radicals being unsubstituted or substituted by from one to three radicals which may be the same or different and are selected from halogen, halo-lower alkyl, sulfo, lower alkyl-sulfonyl, cyano and nitro, Al is a bond between -C=O and A2 or is a bivalent radical of an .alpha.-amino acid, which radical is bonded N-terminally to the group -C=O and C-terminally to A2, A2 is a bivalent radical of an .alpha.-amino acid, which radical is bonded N-terminally to Al and C-terminally to the group NR4R5, or Al and A2 together form a bivalent radical of a dipeptide, of which the central amide bond is reduced and which is bonded N-terminally to the group -C=O and C-terminally to the group NR4R5, and R4 and R5, together with the bonding nitrogen atom, are unsubstituted or substituted thiomorpholino or morpholino, or a salt of that compound, if salt-forming groups are present.

3. A compound of formula I according to claim 1, wherein R1 is hydrogen, lower alkoxy-carbonyl, heterocyclylcarbonyl, benzyloxycarbonyl that is unsubstituted or substituted by up to three radicals which may be the same or different and are selected from fluorine, halo-lower alkyl, lower alkanoyl, sulfo, lower alkylsulfonyl and cyano, or is heterocyclyl-oxycarbonyl wherein heterocyclyl is bonded by way of a carbon atom; one of the mentioned carbonyl radicals wherein the bonding carbonyl group has been replaced by a thiocarbonyl group; heterocyclylsulfonyl, lower alkylsulfonyl or N-(heterocyclyl-lower alkyl)-N-lower alkylaminocarbonyl, B1 is a bond or a bivalent radical of an .alpha.-amino acid, which radical is bonded N-terminally to R1 and C-terminally to the amino group at the R2-CH2-carrying carbon atom, each of R2 and R3, independently of the other, is phenyl or cyclohexyl, those radicals being unsubstituted or substituted by from one to three radicals which may be the same or different and are selected from hydroxy, methoxy, halogen, halo-lower alkyl, sulfo, lower alkylsulfonyl, cyano and nitro, Al forms a bond between -C=O and A2 or is a bivalent radical of an .alpha.-amino acid, which radical is bonded N-term-inally to the group -C=O and C-terminally to A2, A2 is a bivalent radical of an .alpha.-amino acid, which radical is bonded N-terminally to Al and C-terminally to the group NR4R5, or Al and A2 together form a bivalent radical of a dipeptide, of which the central amide bond is reduced and which is bonded N-terminally to the group -C=O and C-terminally to the group NR4R5, and R4 and R5, together with the bonding nitrogen atom, are unsubstituted or substituted morpholino; or a salt of that compound, if salt-forming groups are present;
the hydroxy group in a compound of formula I, at the carbon atom that is vicinal to the carbon atom carrying the radical R2-CH2-, being free or in protected form.

4. A compound of formula I according to claim 3, wherein R1 is heterocyclylsulfonyl, lower alkylsulfonyl or N-(heterocyclyl-lower alkyl)-N-lower alkylaminocarbonyl and the other radicals are as defined, or a salt thereof, if salt-forming groups are present.

5. A compound of formula I according to claim 2, wherein R1 is hydrogen, lower alkoxy-carbonyl, heterocyclylcarbonyl, benzyloxycarbonyl that is unsubstituted or substituted by up to three radicals which may be the same or different and are selected from fluorine, halo-lower alkyl, lower alkanoyl, sulfo, lower alkylsulfonyl and cyano, or is heterocyclyl-oxycarbonyl wherein heterocyclyl is bonded by way of a carbon atom, or is one of the mentioned carbonyl radicals wherein the bonding carbonyl group has been replaced by a thiocarbonyl group, B1 is a bond or a bivalent radical of an a-amino acid, which radical is bonded N-terminally to R1 and C-terminally to the amino group at the R2-CH2-carrying carbon atom, each of R2 and R3, independently of the other, is phenyl or cyclohexyl, those radicals being unsubstituted or substituted by from one to three radicals which may be the same or different and are selected from halogen, halo-lower alkyl, sulfo, lower alkyl-sulfonyl, cyano and nitro, Al forms a bond between -C=O and A2 or is a bivalent radical of an a-amino acid, which radical is bonded N-terminally to the group -C=O and C-term-inally to A2, A2 is a bivalent radical of an a-amino acid, which radical is bonded N-term-inally to Al and C-terminally to the group NR4R5, or Al and A2 together form a bivalent radical of a dipeptide, of which the central amide bond is reduced and which is bonded N-terminally to the group -C=O and C-terminally to the group NR4R5, and R4 and R5, together with the bonding nitrogen atom, are unsubstituted or substituted morpholino, or a salt of that compound, if salt-forming groups are present.

6. A compound of formula I according to claim 1, wherein at least one of the radicals R2 and R3 is substituted by from one to three radicals selected from halogen, halo-lower alkyl, sulfo, lower alkylsulfonyl, cyano and nitro, and the other radicals R1, B1, Al, A2 and NR4R5 are as defined, or a salt thereof, if salt-forming groups are present.

7. A compound of formula I according to claim 1, wherein R1 is hydrogen, tert-butoxy-carbonyl, isobutoxycarbonyl, pyridine-3-carbonyl, morpholinocarbonyl, 3-benzofuranoyl, 1,2,3,4-tetrahydroisoquinoline-3-carbonyl, benzyloxycarbonyl substituted by up to three radicals which may be the same or different and are selected from fluorine, halo-lower alkyl, lower alkanoyl, sulfo, lower alkylsulfonyl and cyano, or is heterocyclyloxycarbonyl wherein heterocyclyl is bonded by way of a carbon atom and is selected from pyrrolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl, B-carbolinyl and a completely or partially saturated derivative of those radicals, or is morpholinosulfonyl or N-(2-pyridylmethyl)-N-methyl-aminocarbonyl, B1 is a bond or a bivalent radical of an .alpha.-amino acid, which radical is bonded N-terminally to Rl and C-terminally to the amino group at the R2-CH2-carrying carbon atom, each of R2 and R3, independently of the other, is phenyl or cyclohexyl, those radicals being unsubstituled or substituted by one or two radicals which may be the same or different and are selected from hydroxy, methoxy, fluorine, sulfo, lower alkylsulfonyl, trifluoromethyl and cyano, Al is a bivalent radical of a hydrophobic .alpha.-amino acid, which radical is bonded N-terminally to the group -C=O and C-terminally to A2, A2 is a bivalent radical of a hydrophobic .alpha.-amino acid, which radical is bonded N-terminally to Al and C-terminally to the radical NR4Rs, or A1 and A2 together form a bivalent radical of a dipeptide comprising two hydrophobic .alpha.-amino acids, of which the central amide bond is reduced and which is bonded N-terrninally to the group -C=O and C-terminally to the group NR4Rs, and R4 and Rs, together with the bonding nitrogen atom, are thiomorpho-lino or morpholino, or a pharmaceutically acceptable salt of that compound, if salt-forming groups are present; the hydroxy group in a compound of forrnula I, at the carbon atom that is vicinal to the carbon atom carrying the radical R2-CH2-, being free or being in a form protected by lower alkanoyl.

8. A compound of formula I according to claim 1, wherein R1 is hydrogen, tert-butoxy-carbonyl, isobutoxycarbonyl, pyridine-3-carbonyl, morpholinocarbonyl, 3-benzofuranoyl, 1,2,3,4-tetrahydroisoquinoline-3-carbonyl, benzyloxycarbonyl that is substituted by up to three radicals which may be the same or different and are selected from fluorine, halo-lower alkyl, lower alkanoyl, sulfo, lower alkylsulfonyl and cyano, or is heterocyclyloxy-carbonyl wherein heterocyclyl is bonded by way of a carbon atom and is selected from pyrrolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyrazinyl, pyrimidinyl, indol-yl, quinolyl, isoquinolyl, quinoxalinyl, .beta.-carbolinyl and a completely or partially saturated derivative of those radicals, B1 is a bond or a bivalent radical of an .alpha.-amino acid, which radical is bonded N-terminally to R1 and C-terminally to the amino group at the R2-CH2-carrying carbon atom, each of R2 and R3, independently of the other, is phenyl or cyclo-hexyl, those radicals being unsubstituted or substituted by one or two radicals which may be the same or different and are selected from fluorine, sulfo, lower alkylsulfonyl and cyano, Al is a bivalent radical of a hydrophobic .alpha.-amino acid, which radical is bonded N-terminally to the group -C=O and C-terminally to A2, A2 is a bivalent radical of a hydrophobic .alpha.-amino acid, which radical is bonded N-terminally to Al and C-terminally to the radical NR4R5, or A1 and A2 together form a bivalent radical of a dipeptide comprising two hydrophobic .alpha.-amino acids, of which the central amide bond is reduced and which is bonded N-terminally to the group -C=O and C-terminally to the groupNR4R5, and R4 and R5, together with the bonding nitrogen atom, are morpholino, or a pharmaceutically acceptable salt of that compound, if salt-forming groups are present.

9. A compound of formula I according to claim 1, wherein R1 is hydrogen, tert-butoxy-carbonyl, isobutoxycarbonyl, pyridine-3-carbonyl, morpholinocarbonyl, 3-benzofuranoyl, 1,2,3,4-tetrahydroisoquinoline-3-carbonyl, morpholinosulfonyl or N-(2-pyridylmethyl)-N-methylaminocarbonyl, B1 is a bond or a bivalent radical of the .alpha.-amino acid valine, which radical is bonded N-terminally to R1 and C-terminally to the amino group at the R2-CH2-carrying carbon atom, each of R2 and R3, independently of the other, is phenyl or cyclohexyl, those radicals being unsubstituted or substituted by one or two radicals which may be the same or different and are selected from hydroxy, methoxy, fluorine, sulfo, lower alkylsulfonyl, trifluoromethyl and cyano, A1 is a bivalent radical of one of the .alpha.-amino acids glycine, valine and isoleucine, which radical is bonded N-terminally to the group -C=O and C-terminally to A2, A2 is a bivalent radical of one of the .alpha.-amino acids glycine, valine, phenylalanine, tyrosine, cyclohexylalanine, p-methoxyphenylalanine and p-fluorophenylalanine, which radical is bonded N-terminally to A1 and C-terminally to the group NR4R5, or A1 and A2 together form a bivalent radical of a dipeptide having a reduced central peptide bond, which comprises an N-terminal amino acid radical selected from Gly(red), Val(red) and Ile(red) and a C-terminal amino acid radical selected from glycine, phenylalanine, tyrosine, cyclohexylalanine, p-methoxyphenylalanine and p-fluorophenylalanine, and is bonded N-terminally to the group -C=O and C-terminally to the group NR4R5, as defined above for A1 and A2, and R4 and R5, together with the bonding nitrogen atom, are thiomorpholino or morpholino, or a pharmaceutically accept-able salt of that compound, if salt-forming groups are present.

10. A compound of formula I according to claim 1, wherein R1 is hydrogen, tert-butoxy-carbonyl, isobutoxycarbonyl, pyridine-3-carbonyl, morpholinocarbonyl, 3-benzofuranoyl, 1,2,3,4-tetrahydroisoquinoline-3-carbonyl, morpholinosulfonyl or N-(2-pyridylmethyl)-N-methylaminocarbonyl, B1 is a bond or a bivalent radical of the .alpha.-amino acid valine, which radical is bonded N-terminally to R1 and C-terminally to the amino group at the R2-CH2-carrying carbon atom, each of R2 and R3, independendy of dhe other, is phenyl or cyclohexyl, those radicals being unsubstituted or substituted by one or two radicals which may be the same or different and are selected from hydroxy, medhoxy, fluorine, trifluoro-methyl and cyano, A1 and A2 together form a bivalent radical of a dipeptide of the formula Val-Phe, Ile-Phe, Val-Cha, Ile-Cha, Ile-Gly, Val-Val, Val-Gly, Val-(p-F-Phe), Val-(p-CH3O-Phe), Gly-(p-F-Phe) or Val-Tyr or of a derivative thereof having a reduced central amide bond of the formula Val(red)-Phe, which is bonded N-terminally to the group -C=O and C-terminally to the group NR4R5, and R4 and R5, together with thebonding nitrogen atom, are thiomorpholino or molpholino, or a pharmaceutically accept-able salt of that compound, if salt-forming groups are present; the hydroxy group in a compound of formula I, at the carbon atom that is vicinal to the carbon atom carrying the radical R2-CH2- being free or being in a form protected by acetyl.

11. A compound of formula I according to claim 10, wherein R1 is morpholinosulfonyl or N-(2-pyridylmethyl)-N-methylaminocarbonyl and the other radicals are as defined, or a pharmaceutically acceptable salt thereof, if salt-forming groups are present.

12. The compound of formula I according to claim 1, wherein R1 is tert-butoxycarbonyl, B1 is a bond, R2 and R3 are each phenyl, Al is valine, A2 is phenylalanine, and R4 and R5 together with the bonding nitrogen atom are morpholino.

13. Any one compound of formula I according to claim 1 being selected from the compounds of formula I with the name Boc-Cha[C](p-F)Phe-(L)-Ile-(L)-Phe-morpholin-4-ylamide Boc-(p-F)Phe[Cl(p-F)Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide, Boc-(p-F)Phe[C](p-F)Phe-(L)-Val-(L)-(p-F-Phe)-morpholin-4-ylamide, Boc-(p-F)Phe[C](p-F)Phe-(L)-Val-(L)-(p-CH3O-Phe)-morpholin-4-ylamide, Boc-(p-F)Phe[C](p-F)Phe-(L)-Val-(L)-Cha-morpholin-4-ylamide, Boc-(p-F)Phe[C](p-F)Phe-(L)-lle-(L)-Phe-morpholin-4-ylamide, Boc-(p-F)Phe[C](p-CN)Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide, Boc-(p-F)Phe[C](p-CN)Phe-(L)-Val-(L)-(p-F-Phe)-morpholin-4-ylamide, Boc-(p-F)Phe[C](p-CN)Phe-(L)-Val-(Lj-(p-CH3O-Phe)-morpholin-4-ylamide, Boc-(p-F)Phe[C](p-CN)Phe-(L)-Val-(L)-Cha-morpholin-4-ylamide, Boc-(p-F)Phe[C](p-CN)Phe-(L)-Ile-(L)-Phe-morpholin-4-ylamide, Boc-Phe[C](p-F)Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide, Boc-Phe[C](p-F)Phe-(L)-Val-(L)-(p-F-Phe)-morpholin-4-ylamide, Boc-Phe[C](p-F)Phe-(L)-Val-(L)-(p-CH3O-Phe)-morpholin-4-ylamide, Boc-Phe[C](p-F)Phe-(L)-Val-(L)-Cha-morpholin-4-ylamide, Boc-Phe[C](p-F)Phe-(L)-Ile-(L)-Phe-morpholin4-ylamide, Boc-Phe[C](p-CN)Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide, Boc-Phe[C](p-CN)Phe-(L)-Val-(L)-(p-F-Phe)-morpholin-4-ylamide, Boc-Phe[C](p-CN)Phe-(L)-Val-(L)-(p-CH3O-Phe)-morpholin-4-ylamide, Boc-Phe[C](p-CN)Phe-(L)-Val-(L)-Cha-morpholin-4-ylamide, Boc-Phe[C](p-CN)Phe-(L)-Ile-(L)-Phe-morpholin-4-ylamide, Boc-Phe[C](p-CH3O)Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide, Boc-Phe[C](p-CH3O)Phe-(L)-Val-(L)-(p-F-Phe)-morpholin-4-ylamide, Boc-Phe[C](p-CH3O)Phe-(L)-Val-(L)-(p-CH3O-Phe)-morpholin-4-yl amide, Boc-Phe[C](p-CH3O)Phe-(L)-Val-(L)-Cha-morpholin-4-ylamide, Boc-Phe[C](p-CH3O)Phe-(L)-Ile-(L)-Phe-morpholin-4-ylamide, Boc-Phe[C](p-CF3)Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide, Boc-Phe[C](p-CF3)Phe-(Ll-Val-(L)-(p-F-Phe)-morpholin-4-ylamide, Boc-Phe[C](p-CF3)Phe-(L)-Val-(L)-(p-CH3O-Phe)-morpholin-4-yl-amide, Boc-Phe[C](p-CF3)Phe-(L)-Val-(L)-Cha-morpholin-4-ylamide, Boc-Phe[C](p-CF3)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)-Val-(L)-(p-F-Phe)-morpholin-4-ylamide, Boc-Cha[C](p-CN)Phe-(L)-Val-(L)-(p-CH3O-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-CH3O)Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide, Boc-Cha[C](p-CH3O)Phe-(L)-Val-(L)-(p-F-Phe)-morpholin4-ylamide, Boc-Cha[C](p-CH3O)Phe-(L)-Val-(L)-(p-CH3O-Phe)-morpholin-4-ylamide, Boc-Cha[C](p-CH3O)Phe-(L)-Val-(L)-Cha-morpholin-4-ylamide, Boc-Cha[C](p-CH3O)Phe-(L)-Ile-(L)-Phe-morpholin-4-ylamide, Boc-Cha[C](p-CF3)Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide, Boc-Cha[C](p-CF3)Phe-(L)-Val-(L)-(p-F-Phe)-morpholin-4-ylamide, Boc-Cha[C](p-CF3)Phe-(L)-Val-(L)-(p-CH3O-Phe)-morpholin- 4-ylamide, Boc-Cha[C](p-CF3)Phe-(L)-Val-(L)-Cha-morpholin-4-ylamide, Boc-Cha[C](p-CF3)Phe-(L)-ne-(L)-Phe-morpholin-4-ylamide, Boc-(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)-Val(red)-(L)-Phe-morpholin4-ylamide, Isobutyloxycarbonyl-Phe[C]Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide, Boc-Cha[C](p-CN)Phe-(L)-Val-(L)-Phe-thiomorpholin-4-ylamide, Boc-Cha[C](p-F)Phe-(L)-Val-(L)-Phe-thiomorpholin-4-ylamide, Boc-(p-CF3)Phe[C]Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide, Boc-(p-CF3)Phe[C]Phe-(L)-Val-(L)-(p-F)Phe-morpholin-4-ylamide, Boc-(p-CF3)Phe[C]Phe-(L)-Val-(L)-(p-CH3O)Phe-morpholin-4-ylamide, Boc-(p-CF3)Phe[ClPhe-(L)-Val-(L)-Cha-morpholin-4-ylamide, Boc-(p-CF3)Phe[C]Phe-(L)-Ile-(L)-Phe-morpholin-4-ylamide, Boc-(p-CF3)Phe[Cl(p-F)Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide, Boc-(p-CF3)Phe[C](p-F)Phe-(L)-Val-(L)-(p-F)Phe-morpholin-4-ylamide, Boc-(p-CF3)Phe[C](p-F)Phe-(L)-Val-(L)-Cha-morpholin-4-ylamide, Boc-(p-CF3)Phe[C](p-F)Phe-(L)-Val-(L)-(p-CH3O)Phe-morpholin-4 -ylamide, Boc-(p-CF3)Phe[C](p-F)Phe-(L)-Ile-(L)-Phe-morpholin-4-ylamide, Boc-(p-CF3)PhelC](p-CF3)Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide, Boc-(p-CF3)Phe[C](p-CF3)Phe-(L)-Val-(L)-(p-F)Phe-morpholin-4-ylamide, Boc-(p-CF3)Phe[C](p-CF3)Phe-(L)-Ile-(L)-Phe-morpholin-4-ylamide, Boc-(p-CF3)Phe[C](p-CF3)Phe-(L)-Val-(L)-(p-CH3O)Phe-morpholin-4-ylamide, Boc-(p-CF3)Phe[C](p-CF3)Phe-(L)-Val-(L)-Cha-morpholin-4-ylamide, Boc-Cha[C](p-F)Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide, Boc-Cha[C](p-CN)Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide, H-Phe[C]Phe-(L)-Val-(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-morpholin-4-ylamide, Morpholinocarbonyl-Val-Phe[C]Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide, Boc-Cha[ClCha-(L)-Val-(L)-Cha-morpholin-4-ylamide, Boc-Cha[C](p-P)Phe-(L)-Val-(L)-(p-F-Phe)-morpholin-4-ylamide, Boc-Cha[C](p-F)Phe-(L)-Val-(L)-(p-CH3O-Phe)-morpholin-4-ylamide, Boc-Cha[C](p-F)Phe-(L)-Val-(L)-Cha-morpholin-4-ylamide, 1,2,3,4-Tetrahydroisochinolin-3(S)-carbonyl-Val-Phe[C]Phe-(L) -Val-(L)-Phe-morpholin-4-ylamide, Boc-Phe[C]Phe-(L)-Val-(L)-(p-F-Phe)-morpholin-4-ylamide, Boc-Phe[ClPhe-(L)-Val-(L)-(p-CH3O-Phe)-morpholin-4-ylamide, Boc-Phe[C]Phe-(L)-Val-(L)-Cha-morpholin-4-ylamide, Boc-Phe[C]Phe-(L)-Ile-(L)-Phe-morpholin-4-ylamide, Boc-Phe[C]Phe-(L)-Val-Gly-morpholin-4-ylamide, Boc-Phe[C]Phe-(L)-Ile-Gly-morpholin-4-ylamide, Boc-Phe[C]Phe-(L)-Val-(L)-Val-morpholin-4-ylamide, Boc-Phe[C]Phe-(L)-Val-(L)-Phe-thiomorpholin-4-ylamide, Boc-(p-F)Phe[C](p-CF3)Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide, Boc-(p-F)Phe[C](p-CF3)Phe-(L)-Val-(L)-(p-F-Phe)-morpholin-4-ylamide, Boc-(p-F)Phe[C](p-CF3)Phe-(L)-Val-(L)-(p-CH3O-Phe)-morpholin-4-ylamide, Morpholinosulfonyl-(L)-Val-Phe[C]Phe-(L)-Val-(L )-Phe-morpholin-4-ylamide, Morpholinosulfonyl-Phe[C]Phe-(L)-Val-(L)- Phe-morpholin-4-ylamide, N-(N-(2-Pyridylmethyl)-N-methyl-aminocarbonyl)-(L)-Val-Phe[C]Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide, 5(S)-(Boc-amino)-4(S)-(acetoxy)-6-phenyl-2(R)-phenylmethyl-hexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide, 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 and Boc-Tyr[C]Tyr-(L) -Val-(L)-Tyr-morpholin-4-ylamide, or any one of these compounds having the radical -morpholin-4-ylamide, wherein the radical -morpholin-4-ylamide is replaced by the radical -thiomorpholin-4-ylamide, or a salt thereof provided that at least one salt-forming group is present.

14. A pharmaceutical composition comprising a compound of formula I according to any one of claims 1 to 3, 6 to 9 and 12, or a pharmaceutically acceptable salt of such a compound having at least one salt-forming group, together with a pharmaceutically acceptable carrier.

15. The use of any one of the compounds of formula I mentioned in any one of claims 1 to 3, 6 to 9 and 12, or of a pharmaceutically acceptable salt of such a compound having at least one salt-forming group, in the preparation of a phalmaceudcal composition for use in inhibiting the action of the enzyme HIV gag-protease.

16. The use of any one of the compounds mentioned in any one of claims 1 to 3, 6 to 9 and 12, or of a pharmaceutically acceptable salt of such a compound having at least one salt-forming group, in the inhibition of HIV-1 gag-protease.

17. A compound of formula I mentioned in any one of claims 1 to 3, 6 to 9 and 12 or a pharmaceutically acceptable salt of such a compound having at least one salt-forming group for use for the treament of AIDS.

18. A process for the preparation of a compound of formula I according to claim 1 or a hydroxy-protected derivative thereof, or a salt of such a compound having at least one salt-forming group, wherein a) for the preparation of a compound of the formula (Ib), wherein R1' is as defined for R1 in compounds of formula I, except that it is not hydrogen, the hydroxy group at the carbon atom that is vicinal to the carbon atom carrying the radical R2-CH2- is free or in protected form, and the other radicals are as defined for compounds of formula I, an acid of the formula R1'-OH (II), or a reactive acid derivative thereof, wherein R1' is as defined for R1 in compounds of formula I, except that it is not hydrogen, is condensed with an amino compound of the formula (III), or with a reactive derivative thereof, wherein the radicals are as defined for compounds of formula I, free functional groups in the starting materials of formulae II and III, with the exception of the groups participating in the reaction, being, where appropriate, in protected form, and, if desired, protecting groups present are removed or b) for the preparation of a compound of the formula (Ic), wherein B1' represents the same radicals as does B1 in compounds of formula I, except that it is not a bond, the hydroxy group at the carbon atom that is vicinal to the carbon atom carrying the radical R2-CH2- is free or in protected form, and the other radicals are as defined for compounds of formula I, a carboxylic acid of the formula R1-B1'-OH (IV), or a reactive acid derivative thereof, wherein R1 is as defined for compounds of formula I
and B1' is as last defined, is condensed with an amino compound of the formula (V), or with a reactive derivative thereof, wherein the radicals are as defined for compounds of formula I, free functional groups in the starting materials of formulae IV and V, with the exception of the groups participating in the reaction, being, where appropriate, in protected form. and, if desired, protecting groups present are removed, or c) a carboxylic acid of the formula (VI), or a reactive derivative thereof, wherein the radicals are as defined for compounds of formula I, is condensed with an amino compound of the formula (VII), or with a reactive derivative thereof, wherein the radicals are as defined for compounds of formula I, free functional groups in the starting materials of formulae VI and VII, with the exception of the groups participating in the reaction, being, where appropriate, in protected form and, if desired, protecting groups present are removed, or d) for the preparation of a compound of the formula (Id), wherein A1' and A2' are as defined for Al and A2 in compounds of formula I, except that Al' is not a bond and the peptide bond between Al' and A2' is not in reduced form, the hydroxy group at the carbon atom that is vicinal to the carbon atom carrying the radical R2-CH2- is free or in protected form, and the other radicals are as defined for compounds of formula I, a carboxylic acid of the formula (VIII), or a reactive derivative thereof, wherein the radicals are as last defined, is condensed with an amino compound of the formula (IX).

or with a reactive derivative thereof, wherein the radicals are as last defined, free func-tional groups in the starting materials of formulae VIII and IX, with the exception of the groups participating in the reaction, being, where appropriate, in protected form and, if desired, protecting groups present are removed, or e) a carboxylic acid of the formula (X), or a reactive derivative thereof, wherein the radicals are as defined for compounds of formula I, is condensed with an amino compound of the formula (XI), or with a reactive derivative thereof, the radicals being as defined for compounds of formula I, free functional groups in the starting materials of formulae X and XI, with the exception of the groups participating in the reaction, being, where appropriate, in protected form and, if desired, protecting groups present are removed, or f) in a compound of formula I wherein the substituents are as defined above, provided that at least one functional group in the compound of formula I concerned is protected by protecting groups, protecting groups present are removed, and/or, if desired, a compound of formula I obtained according to any one of the above processes a) to f) that has at least one salt-forming group is converted into its salt and/or an obtainable salt is converted into the free compound or into a different salt and/or any obtainable isomeric mixtures of compounds of formula I are separated and/or a compound of formula I according to the invention is converted into a different compound of formula I
according to the invention.