WO1996016980A1

WO1996016980A1 - Morpholinoethylamide derivatives

Info

Publication number: WO1996016980A1
Application number: PCT/EP1995/004508
Authority: WO
Inventors: Guido Bold; Shripad Subray Bhagwat; Hans-Georg Capraro; Alexander Fässler; Marc Lang; Satish Chandra Khanna
Original assignee: Novartis Ag
Priority date: 1994-11-29
Filing date: 1995-11-16
Publication date: 1996-06-06
Also published as: AU4117396A

Abstract

According to the invention, compounds of formula (I), wherein R1 is an acyl radical selected from lower alkoxy-lower alkanoyl (including lower alkoxy-carbonyl) wherein the lower alkoxy radical is unsubstituted or substituted by halogen, phenyl or lower alkoxy; or by a heterocyclic radical selected from piperidinyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, thiazolidinyl, thiazolyl, indolyl and 4H-1-benzopyranyl, each of which is unsubstituted or substituted by oxo, hydroxy, amino, lower alkyl, lower alkoxycarbonyl and/or phenyl-lower alkoxycarbonyl; lower alkanoyl which is unsubstituted or substituted by one of the last-mentioned unsubstituted or substituted heterocyclic radicals; and arylcarbonyl or heterocyclylcarbonyl each substituted by heterocyclyl or by heterocyclyl-lower alkyl; or is the residue of an amino acid defined in the description (which is non-acylated or N-acylated by an acyl radical mentioned above); R2 and R3 are each independently of the other cyclohexyl, cyclohexenyl, phenyl, naphthyl or tetrahydronaphthyl, each of which is unsubstituted or substituted by lower alkyl, phenyl-lower alkyl, halogen, halo-lower alkyl, cyano, hydroxy, lower alkoxy, phenyl-lower alkoxy, pyridyl-lower alkoxy, lower alkoxy-lower alkoxy, lower alkoxy-carbonyl-lower alkoxy, carboxy-lower alkoxy, hydroxy-lower alkoxy having at least 2 carbon atoms, wherein hydroxy is not bonded in the 1-position, carbamoyl-lower alkoxy, cyano-lower alkoxy, morpholinyl-lower alkoxy, lower alkylenedioxy, or phenyl-lower alkanesulfonyl which is unsubstituted or substituted in the phenyl radical by halogen; or lower alkyl, R4 is lower alkyl, cyclohexyl or phenyl, and R5, R5', R6, R7, R8, R8', R9 and R10 are each independently of the others hydrogen or lower alkyl, or salts thereof, which have anti-retroviral activity, are described.

Description

Morpholinoethylamide derivatives

Summary and Field of the Invention

The invention relates to morpholinoethylamide derivatives of aspartate protease substrate isosteres and salts thereof, to processes for the preparation of those compounds and salts thereof, to pharmaceutical compositions that comprise those compounds or salts thereof, and to the use of those compounds or salts thereof in the therapeutic or diagnostic treatment of the human or animal body or in the preparation of pharmaceutical composi¬ tions.

Background of the Invention

According to WHO estimates, approximately 17 million people are currently infected with HIV-1 OΓ HIV-2. In the overwhelming majority of persons infected, the symptoms of the AIDS disease develop, followed by death.

For the treatment of retroviral diseases, such as AIDS, up to now inhibitors of reverse transcriptase, an enzyme that is active in the conversion of retroviral RNA into DNA, such as 3'-azido-3'-deoxythymidine (AZT) or dideoxyinosine (DDI), have mainly been used, and, in addition, trisodium phosphonoformate, ammonium-21-tungsto-9-antimonate, l-β-D-ribofuranoxyl-l^. -triazole-S-carboxamides and dideoxycytidine and also adriamycin. In addition, attempts are being made to introduce the T4-cell receptor, which is present on certain cells of the defence system in the human body and is responsible for the anchoring and insertion of infectious virus particles into those cells and hence for their infection, into the body, for example in the form of a recombinant molecule or molecule fragment. This would titrate away binding sites for the virus, with the result that the virions could no longer bind to the cells. Also used are compounds that prevent the virus from penetrating the cell membrane in other ways, such as polymannoacetate.

In addition, initial clinical trials with a hydroxyethylene isostere as an inhibitor of HIV-protease, namely N-tert-butyl-decahydro-2-[2(R)-hydroxy-4-phenyl-3(S)-[[N-2- quinolyl-carbonyl-L-asparaginyl]amino]butyl]-(4aS,8aS)-isoquinoline-3(S)-carboxamide (Ro 31-8959), are being reported. The said compound has exhibited inhibitory action against HIV-protease in vitro and suppression of virus proliferation in cell tests, and, in tests on rodents, useful blood levels have been achieved also with oral administration (see Roberts, N. A., et al, Biochemical Soc. Transactions 20, 513-516 (1992)); useful blood levels have been achieved in humans also (see, for example, G.J. Muirhead et al, Brit. J. Clin. Pharmacol. 34, 170P-171P (1992)). A so-called "surrogate-marker" (titre of the CD4-lymphocytes in the blood, a decrease in which in untreated patients is a measure of the advance of the AIDS disease) has shown initial positive effects in AIDS patients (see "Roche statement on HIV Proteinase Inhibitor (Ro 31-8959) European Trials Results", distributed to participants in the 9th International Congress on AIDS in Berlin, June 7 - 11, 1993).

In the AIDS viruses, HIV-1 and HIV-2, and in other retroviruses, for example the corres¬ ponding viruses in cats (FIV) and monkeys (SIV), proteolytic maturation, for example of the core proteins of the virus, is brought about by an aspartate protease, such as HIV protease. Without that proteolytic maturation, no infectious virus particles can be produced. Because of the central role played by the said aspartate proteases, such as HIV-1 or HTV-2 protease, in the maturation of the virus and on the basis of experimental results, for example in infected cell cultures, it is believed that effective prevention of the maturation step brought about by that protease will prevent the formation of mature virions in vivo. Corresponding inhibitors can therefore be used therapeutically.

The object of the present invention is to provide a new class of compounds that are furthermore equipped, in particular, with advantageous pharmacological properties, such as good pharmacokinetics, such as high bio-availability and/or high achievable blood levels, and/or with good tolerability.

Detailed Description of the Invention

The ethers of aspartate protease substrate isosteres according to the invention are compounds of formula I

wherein Ri is an acyl radical selected from

(a) lower alkoxy-lower alkanoyl, including lower alkoxycarbonyl, wherein the lower alkoxy radical is unsubstituted or substituted by

(i) one or more radicals selected independently of one another from halogen, phenyl and lower alkoxy, or

(ii) a radical selected from piperidinyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, thiazolidinyl, thiazolyl, indolyl and 4H-l-benzopyranyl, each of which is unsubstituted or substituted by one or more radicals selected independently of one another from oxo, hydroxy, amino, lower alkyl, lower alkoxycarbonyl and phenyl-lower alkoxycarbonyl;

(b) lower alkanoyl which is unsubstituted or substituted by piperidinyl, pyrrolidinyl, tetra¬ hydropyranyl, tetrahydrofuranyl, thiazolidinyl, thiazolyl, indolyl, 4H-l-benzopyranyl, piperidinyloxy, pyrrolidinyloxy, tetrahydropyranyloxy, tetrahydrofuranyloxy, thiazol- idinyloxy, thiazolyloxy, indolyloxy or 4H-l-benzopyranyloxy, each of which is unsub¬ stituted or substituted by one or more substituents selected independently of one another from oxo, hydroxy, amino, lower alkyl, lower alkoxycarbonyl and phenyl-lower alkoxy¬ carbonyl; and

(c) arylcarbonyl or heterocyclylcarbonyl each substituted by heterocyclyl or by hetero- cyclyl-lower alkyl;

the residue, bonded via the carbonyl group, of an amino acid selected from glycine, alanine, 3-aminopropanoic acid, 2-aminobutyric acid, 3-aminobutyric acid, 4-aminobutyric acid, 3-aminopentanoic acid, 4-aminopentanoic acid, 5-aminopentanoic acid, 3-aminohexanoic acid, 4-aminohexanoic acid, 5-aminohexanoic acid, valine, norval- ine, leucine, isoleucine, norleucine, serine, homoserine, threonine, methionine, cysteine, phenylalanine, tyrosine, 4-aminophenylalanine, 4-chlorophenylalanine, 4-carboxyphenyl- alanine, β-phenylserine, phenylglycine, α-naphthylalanine, cyclohexylalanine, cyclohexyl- glycine, tryptophan, aspartic acid, aspartic acid β-phenyl-lower alkyl ester, asparagine, aminomalonic acid, aminomalonic acid monoamide, glutamic acid, glutamic acid γ-phenyl-lower alkyl ester, glutamine, histidine, arginine, lysine, δ-hydroxylysine, ornithine, α,γ-diaminobutyric acid and α,β-diaminopropionic acid; or

the residue of one of the last-mentioned amino acids, which residue is bonded via the carbonyl group and is N-acylated at the amino nitrogen by one of the above-mentioned acyl radicals, R₂ and R₃ are each independently of the other cyclohexyl, cyclohexenyl, phenyl, naphthyl or tetrahydronaphthyl, each of which is unsubstituted or substituted by one or more radicals selected independently of one another from lower alkyl, phenyl-lower alkyl, halogen, halo-lower alkyl, cyano, hydroxy, lower alkoxy, phenyl-lower alkoxy, pyridyl- lower alkoxy, lower alkoxy-lower alkoxy, lower alkoxycarbonyl-lower alkoxy, carboxy- lower alkoxy, hydroxy-lower alkoxy having at least 2 carbon atoms, wherein hydroxy is not bonded in the 1 -position, carbamoyl-lower alkoxy, cyano-lower alkoxy, morpholinyl- lower alkoxy, lower alkylenedioxy, and phenyl-lower alkanesulfonyl which is unsubsti¬ tuted or substituted in the phenyl radical by one or more radicals selected independently of one another from halogen, or alternatively or in addition lower alkyl,

R is lower alkyl, cyclohexyl or phenyl, and

R₅, R₅', R , R₇, R_g, R₈', R₉ and R₁₀ are each independently of the others hydrogen or lower alkyl,

or a salt thereof.

Within the scope of this Application, unless stated otherwise the general terms used hereinbefore and hereinafter have preferably the following meanings:

The term "lower", for example in lower alkyl, lower alkoxy, lower alkanoyl or phenyl- lower alkyl, denotes a radical having up to and including not more than 7, especially up to and including not more than 4, carbon atoms, it being possible for the radicals in question to be unbranched or branched one or more times.

Any reference to compounds, salts etc. is always intended to refer also to a compound, a salt etc..

Any asymmetric carbon atoms present, including those in the substituents Rj, R₂, R₃, R₄, R₅, R₅\ R₆, R₇, R₈, R_g', R₉ and R₁₀, may be in the (R)-, the (S)- or the (Reconfigura¬ tion, preferably in the (R)- or the (S)-configuration. Accordingly, the compounds in question may be in the form of mixtures of isomers or in the form of pure isomers, espec¬ ially in the form of diastereoisomeric mixtures, pairs of enantiomers or, preferably, in the form of pure enantiomers. The added phrase "alternatively or in addition" means either that the substituent defini¬ tions so characterised, in combination with the respective groups of substituent definitions not characterised by that added phrase, form a group of substituents, or that the substituent definitions so characterised form a group on their own, or that the substituents not charac¬ terised by that added phrase also form on their own a group of substituent definitions.

Preferably, the compounds of formula I have the formula I'

wherein the radicals are as defined for the compounds of formula I.

In lower alkoxy-lower alkanoyl R_lt the lower alkoxy radical is preferably methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, while lower alkanoyl is preferably foπnyl (the corresponding radical is then a lower alkoxy¬ carbonyl radical, which is preferred, especially methoxycarbonyl, ethoxycarbonyl or tert- butoxycarbonyl), or also acetyl or propionyl.

Piperidinyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, thiazolidinyl, thiazolyl, indolyl and 4H-l-benzopyranyl are unsubstituted or are substituted by one or more radicals selected independently of one another from oxo, hydroxy, amino, lower alkyl, lower alkoxycarbonyl and phenyl-lower alkoxycarbonyl, and are especially unsubstituted or substituted by one or two of the mentioned radicals selected independently of each other.

Halogen is fluorine, chlorine, bromine or iodine, especially fluorine or chlorine.

Piperidinyl is especially piperidin-4-yl that is unsubstituted or substituted, preferably at the nitrogen atom, by lower alkyl, such as methyl, or by lower alkoxycarbonyl, such as ethoxycarbonyl. Pyrrolidinyl is especially pyrrolidin-2-yl or -5-yl that is unsubstituted or, preferably, substituted by oxo or hydroxy at a carbon atom and substituted by phenyl-lower alkoxy¬ carbonyl at the nitrogen or unsubstituted at the nitrogen, and is preferably in the (R)-, the (R,S)- or, especially, the (S)-form at the bonding carbon atom, and is especially 2-oxo- pyrrolidin-5(S)-yl, (L)-trans-4-hydroxyprolyl or (L)-N-benzyloxycarbonyl-trans- 4-hydroxyprolyl.

Tetrahydropyranyl is especially tetrahydropyran-2-yl or -4-yl that is preferably unsubsti¬ tuted and preferably bonded in the (R)-, the (S)- or, especially, the (R,S)-form if it is bonded via the 2-carbon atom.

Tetrahydrofuranyl is especially tetrahydrofuran-3-yl that is preferably unsubstituted and preferably bonded in the (R)-, the (R,S)- or, especially, the (S)-form.

Thiazolidinyl is especially thiazolidin-4-yl that is preferably unsubstituted and preferably in the (S)-, the (R,S)- or, especially, the (R)-form (= (L)-form) at the bonding carbon atom.

Thiazolyl is especially thiazol-4-yl that is preferably substituted by amino, such as 2-amino-4-thiazolyl.

Indolyl is especially indol-2-yl that is preferably unsubstituted.

4H-l-benzopyranyl is especially 4H-l-benzopyran-2-yl that is unsubstituted or preferably substituted by oxo, such as 4-oxo-4H-l-benzopyran-2-yl.

The substituents oxo, hydroxy and amino that may be present in piperidinyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, thiazolidinyl, thiazolyl, indolyl or 4H-l-benzo- pyranyl are preferably bonded to carbon, and the substituents lower alkoxy, lower alkoxy¬ carbonyl and phenyl-lower alkoxycarbonyl to nitrogen or carbon.

The lower alkoxy radical in lower alkoxy-lower alkanoyl Rj is unsubstituted or substituted by one or more, especially by 1 up to and including 3, of the mentioned radicals, espec¬ ially by phenyl, such as in benzyloxycarbonyl, or also (preferably mono- to especially tri- substituted) by halogen, especially fluorine, or (preferably mono-substituted) by one of the other radicals mentioned, especially (preferably mono-substituted) by lower alkoxy, especially methoxy, or (mono-substituted) by pyrrolidinyl, especially pyrrolidin-2-yl or idin-2-yl or -5-yl, that is unsubstituted or, especially, substituted by oxo.

In lower alkanoyl R] that is unsubstituted or substituted by piperidinyl, pyrrolidinyl, tetra¬ hydropyranyl, tetrahydrofuranyl, thiazolidinyl, thiazolyl, indolyl, 4H-l-benzopyranyl, piperidinyloxy, pyrrolidinyloxy, tetrahydropyranyloxy, tetrahydrofuranyloxy, thiazol- idinyloxy, thiazolyloxy, indolyloxy or 4H-l-benzopyranyloxy, each of which is unsubsti¬ tuted or substituted by one or more substituents (preferably one substituent) selected independently of one another from oxo, hydroxy, amino, lower alkyl, lower alkoxy¬ carbonyl and phenyl-lower alkoxycarbonyl, lower alkanoyl is especially formyl (producing with one of the mentioned radicals the correspondingly substituted carbonyl radical), acetyl or 2- or 3-propionyl, preferably the (R)-, the (R,S)- or, especially, the (S)-form being present when the substituent is bonded in the 2-position, while the other radicals are as defined above. Preference is given to N-lower alkoxycarbonyl-piperi- dinyl-lower alkanoyl, for example -carbonyl, such as N-ethoxycarbonyl-piperidin-4-yl- carbonyl, pyrrolidinyl-lower alkanoyl, such as -carbonyl, that is substituted by hydroxy at a carbon atom and/or by phenyl-lower alkoxycarbonyl at the nitrogen atom and that is preferably in the (R)-, the (R,S)- or, especially, the (S)-form at the bonding carbon atom, such as (L)-trans-4-hydroxyprolyl or (L)-N-benzyloxycarbonyl-trans-4-hydroxyprolyl, aminothiazolidinyl-lower alkanoyl, e.g. -acetyl, such as 2-amino-4-thiazolyl-acetyl, thiazolyl-lower alkanoyl, e.g. -carbonyl, such as thiazol-2-ylcarbonyl, indolyl-lower alkanoyl, e.g. -carbonyl, such as indol-2-ylcarbonyl, oxo-substituted 4H-l-benzopyranyl- lower alkanoyl, e.g. -carbonyl, such as 4-oxo-4H-l-benzopyran-2-ylcarbonyl, N-lower alkyl-piperidinyloxy-lower alkanoyl, e.g. -carbonyl, such as N-methylpiperidin-4-yloxy- carbonyl, tetrahydropyranyloxy-lower alkanoyl, e.g. -propionyl or -carbonyl, such as 2(S)-(tetrahydropyran-4-yloxy)propionyl or tetrahydropyran-2(R,S)-yloxycarbonyl, or tetrahydrofuranyloxy-lower alkanoyl, e.g. -carbonyl, such as tetrahydrofuran-3(S)-yloxy- carbonyl.

Heterocyclyl is preferably an unsubstituted or substituted heterocyclic ring having from 5 to 7, preferably 5 or 6, ring atoms, wherein 1 or 2 ring carbon atoms have been replaced by a hetero atom selected from O, N and S, is unsaturated or completely or partially saturated and may be in the form of a single ring or may be benzo-fused, cyclopenta-fused or cyclohexa-fused, the radical preferably being substituted by one or more (preferably one or two) substituents selected independently of one another from oxo, hydroxy, amino, lower alkyl, lower alkoxycarbonyl and phenyl-lower alkoxycarbonyl; and is selected especially from morpholinyl, piperazinyl, e.g. piperazin-1-yl, pyridinyl, e.g. pyridin-3-yl, piperidinyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, thiazolidinyl, thiazolyl, indolyl and 4H-l-benzopyranyl, each of which is unsubstituted or substituted by one or more radicals selected independently of one another from oxo, hydroxy, amino, lower alkyl, lower alkoxycarbonyl and phenyl-lower alkoxycarbonyl, preferably unsubstituted or substituted by one or also two of the mentioned radicals; and is especially morpholinyl, such as morpholin-4-yl, lower alkyl-piperazinyl, especially N-lower alkyl-piperazinyl, e.g. 4-lower alkyl-piperazin-1-yl, such as 4-methyl-piperazin-l-yl, or pyridinyl, such as pyridin-3-yl.

Aryl is preferably C₆-C₁₄aryl, for example phenyl, naphthyl, such as 1- or 2-naphthyl, or also fluorenyl, such as fluoren-9-yl, and is unsubstituted or substituted by one or more (preferably from one to three) radicals selected independently of one another from lower alkyl, phenyl-lower alkyl, halogen, cyano, hydroxy, lower alkoxy, phenyl-lower alkoxy, lower alkoxy-lower alkoxy, lower alkylenedioxy (bonded to two adjacent carbon atoms of the respective aryl ring), pyridyl-lower alkoxy, and phenyl-lower alkanesulfonyl which is unsubstituted or substituted in the phenyl radical by one or more radicals selected indepen¬ dently of one another from halogen, such as chlorine; and is especially phenyl.

In arylcarbonyl substituted by heterocyclyl or by heterocyclyl-lower alkyl, such as espec¬ ially heterocyclylmethyl, or in heterocyclylcarbonyl substituted likewise by one or more of those radicals, aryl and heterocyclyl are as defined immediately above, preferably as stated there as being preferred; preferably, only one substituent heterocyclyl or hetero¬ cyclyl-lower alkyl is present.

Preferred among those radicals are arylcarbonyl mono-substituted by heterocyclyl-lower alkyl and heterocyclylcarbonyl mono-substituted by heterocyclyl.

Arylcarbonyl substituted by heterocyclyl-lower alkyl is especially morpholinyl-lower alkyl-benzoyl, such as 4-(morpholin-4-ylmethyl)-benzoyl.

Heterocyclylcarbonyl substituted by heterocyclyl is especially lower alkyl-piperazinyl- pyridylcarbonyl, such as N-lower alkyl-piperazinyl-pyridylcarbonyl, especially 4-lower alkyl-piperazin-1-yl-pyridylcarbonyl, for example 2- or 3-(4-lower alkyl[such as methyl]- piperazin- l-yl)-pyridin-2-ylcarbonyl or -3-ylcarbonyl.

An amino acid residue bonded to the bonding nitrogen via the carbonyl group (of its carboxy group of the corresponding free amino acid) (i.e. the residue obtainable by removing the OH group in the carboxy group (-COOH)) is selected from the residues of glycine (H-Gly-OH), alanine (H-Ala-OH), 2-aminobutyric acid, 3-aminobutyric acid, 4-aminobutyric acid, 3-aminopentanoic acid, 4-aminopentanoic acid, 5-aminopentanoic acid, 3-aminohexanoic acid, 4-aminohexanoic acid, 5-aminohexanoic acid, valine (H-Val-OH), norvaline (α-aminovaleric acid), leucine, (H-Leu-OH), isoleucine (H-Ile-OH), norleucine (α-aminohexanoic acid, H-Nle-OH), serine (H-Ser-OH), homo- serine (α-amino-γ-hydroxybutyric acid), threonine (H-Thr-OH), methionine (H-Met-OH), cysteine (H-Cys-OH), phenylalanine (H-Phe-OH), tyrosine (H-Tyr-OH), 4-aminophenyl- alanine, 4-chlorophenylalanine, 4-carboxyphenylalanine, β-phenylserine (β-hydroxy- phenylalanine), phenylglycine, α-naphthylalanine (H-Nal-OH), cyclohexylalanine (H-Cha-OH), cyclohexylglycine, tryptophan (H-Tφ-OH), aspartic acid (H-Asp-OH), aspartic acid β-phenyl-lower alkyl ester, such as aspartic acid β-benzyl ester, asparagine (H-Asn-OH), aminomalonic acid, aminomalonic acid monoamide, glutamic acid (H-Glu-OH), glutamine (H-Gln-OH), histidine (H-His-OH), arginine (H-Arg-OH), lysine (H-Lys-OH), δ-hydroxylysine, ornithine (α,δ-diaminovaleric acid), 3-aminopropanoic acid, α,γ-diaminobutyric acid and α,β-diaminopropionic acid; and preferably valine, norvaline, leucine, isoleucine and norleucine and also serine, homoserine, threonine, meth¬ ionine, cysteine, phenylalanine, tyrosine, 4-aminophenylalanine, 4-chlorophenylalanine, 4-carboxyphenylalanine, β-phenylserine, phenylglycine, α-naphthylalanine, cyclohexyl¬ alanine, cyclohexylglycine, tryptophan, aspartic acid, aspartic acid β-phenyl-lower alkyl ester, such as aspartic acid β-benzyl ester, asparagine, aminomalonic acid monoamide, glutamic acid, glutamic acid γ-phenyl-lower alkyl ester, such as glutamic acid γ-benzyl ester, glutamine, histidine, arginine, lysine, δ-hydroxylysine and ornithine; aspartic acid β-benzyl ester, aspartic acid, asparagine or, in particular, valine, being especially preferred; the respective amino group(s) and other functional groups being in free form or (where possible) in salt form; and the amino acid residues mentioned that have asymmet¬ ric carbon atoms being in the (D)-, the (L) or the (D,L)-form, preferably the (L)-form.

In a residue of one of the amino acids last mentioned that is bonded via the (α-)carbonyl group and that is N-acylated at the amino nitrogen by one of the above-mentioned acyl radicals, the acyl radicals are selected from lower alkoxy-lower alkanoyl, wherein the lower alkoxy radical is unsubstituted or substituted by one or more radicals selected independently of one another from halogen, lower alkoxy and, especially, phenyl, or by a radical selected from piperidinyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, thiazolidinyl, thiazolyl, indolyl and 4H-l-benzopyranyl each unsubstituted or substituted by one or more radicals selected independently of one another from oxo, hydroxy, amino, lower alkyl, lower alkoxycarbonyl and phenyl-lower alkoxycarbonyl; lower alkanoyl that is unsubstituted or substituted by piperidinyl, pyrrolidinyl, tetrahydropyranyl, tetrahydro¬ furanyl, thiazolidinyl, thiazolyl, indolyl, 4H-l-benzopyranyl, piperidinyloxy, pyrrolidinyl- oxy, tetrahydropyranyloxy, tetrahydrofuranyloxy, thiazolidinyloxy, thiazolyloxy, indol- yloxy or 4H-l-benzopyranyloxy each unsubstituted or substituted by one or more substi¬ tuents selected independently of one another from oxo, hydroxy, amino, lower alkyl, lower alkoxycarbonyl and phenyl-lower alkoxycarbonyl; and arylcarbonyl and heterocyclyl¬ carbonyl each substituted by heterocyclyl or by heterocyclyl-lower alkyl; the mentioned acyl radicals preferably being as defined above; while the amino acid residue is selected from the residues mentioned above for amino acid residues that are bonded via the carbonyl group, especially the residues mentioned above as being preferred. Special preference is given to lower alkoxy-lower alkanoyl-valyl, such as lower alkoxycarbonyl- valyl, for example methoxycarbonyl-valyl, thiazolidinyl-valyl, especially thiazolidin- 4-yl-valyl, which is preferably in the (S)-, the (R,S)- or, especially, the (R)-form (= (L)-foιτn) at the 4-carbon atom of the thiazolidine ring, phenyl-lower alkoxycarbonyl- valyl, such as benzyloxycarbonyl-valyl, aspartyl, N-phenyl-lower alkoxycarbonyl-β- (O-phenyl-lower alkyl)aspartyl, such as N-benzyl-β-(O-benzyl)aspartyl, asparaginyl or N-phenyl-lower alkoxycarbonyl-asparaginyl, such as N-benzyloxycarbonyl-asparaginyl, the valyl, aspartyl or asparaginyl radical preferably being in the (L)-form; or aspartyl, N-phenyl-lower alkoxycarbonyl-(L)-β-(O-phenyl-lower alkyl)aspartyl, such as N-benzyloxycarbonyl-(L)-β-(O-benzyl)aspartyl, asparaginyl or N-phenyl-lower alkoxy¬ carbonyl-asparaginyl, such as N-benzyloxycarbonyl-asparaginyl.

R_j is especially selected from: tert-butoxycarbonyl, tert-butoxycarbonyl-(L)-valyl, (L)-asparaginyl, N-benzyloxy- carbonyl-(L)-asparaginyl, (L)-aspartyl and N-benzyloxycarbonyl-(L)-β-(O-benzyl)- aspartyl, and also from 2,2,2-trifluoroethoxy-carbonyl, 2-(methoxy)ethoxy-carbonyl, 5(S)-2-oxo-pyrrolidinyl-methoxycarbonyl, l-ethoxycarbonyl-piperidin-4-ylcarbonyl, trans-(L)-4-hydroxyprolyl, N-(benzyloxycarbonyl)-trans-(L)-4-hydroxyprolyl, (L)-thiaz- olidin-4-ylcarbonyl, indol-2-ylcarbonyl, 4H-l-benzopyran-2-ylcarbonyl, N-methyl-piperi- dinyloxycarbonyl, tetrahydropyran-2(R,S)-ylcarbonyl, O-(tetrahydropyran-4-yl)-(L)-lac- toyl (= 2(S)-(tetrahydropyran-4-yloxy)propionyl), 3(S)-tetrahydrofuranyloxycarbonyl, 2-amino-thiazol-4-ylacetyl, 6-(4-methyl-piperazin- l-yl)-ρyridin-3-ylcarbonyl, 4-(mor- pholin-4-ylmethyl)-benzoyl, N-methoxycarbonyl-(L)-valyl and N-[(L)-thiazolidin-4-ylcar- bonyl]-(L)-valyl. Cyclohexyl, cyclohexenyl, phenyl, naphthyl (such as 1- or 2-naphthyl) or tetrahydro- naphthyl R₂ and R₃ are each independently unsubstituted or substituted, as indicated, lower alkylenedioxy being attached to 2, preferably adjacent, carbon atoms of the respec¬ tive ring. Preferably, cyclohexenyl and tetrahydronaphthyl are unsubstituted, while cyclo¬ hexyl and especially phenyl and naphthyl are unsubstituted or substituted by one, two or three radicals selected independently of one another especially from halogen, especially fluorine, and phenyl-lower alkoxy, such as benzyloxy, and from lower alkyl, especially methyl, phenyl-lower alkyl, especially 2-phenylethyl, halo-lower alkyl, preferably having up to three halogen, especially fluorine, atoms, such as trifluoromethyl, cyano, hydroxy, lower alkoxy, especially methoxy or also isobutoxy, lower alkoxy-lower alkoxy, espec¬ ially 2-methoxyethoxy, lower alkylenedioxy, especially ethylene-l,2-dioxy or, especially, methylenedioxy that is attached to 2 adjacent carbon atoms of the respective ring, pyridyl-lower alkoxy, such as pyridin-2-, pyridin-3- or also pyridin-4-ylmethoxy, phenyl- lower alkanesulfonyl (=phenyl-lower alkyl-S(=O)₂-) that is unsubstituted or, especially, substituted in the phenyl radical by one or more, especially 2, radicals selected from halogen, especially chlorine, especially dichlorophenyl-lower alkanesulfonyl, such as 2,6-dichlorobenzylsulfonyl (= 2,6-dichlorophenylmethanesulfonyl), lower alkoxy- carbonyl-lower alkoxy, such as ethoxycarbonylmethoxy, carboxy-lower alkoxy, such as carboxymethoxy, hydroxy-lower alkoxy having at least 2 carbon atoms, wherein hydroxy is not bonded in the 1-position, such as 2-hydroxyethoxy, morpholinyl-lower alkoxy, especially morpholino-lower alkoxy, such as 2-morpholinoethoxy, carbamoyl-lower alkoxy, such as carbamoylmethoxy (H₂N-C(=O)-CH₂-O-), and cyano-lower alkoxy, such as cyanomethoxy.

Lower alkyl R₂ or R₃ is branched or unbranched and is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or sec-butyl, isopropyl being especially preferred.

Preferably, R₂ and R₃ are selected from cyclohexyl, phenyl, phenyl-lower alkoxy-phenyl, especially 4-phenyl-lower alkoxyphenyl, such as 4-(benzyloxy)-phenyl, fluorophenyl, such as 4-, 3- or 2-fluorophenyl, difluorophenyl, especially 2,4-difluorophenyl; also phenyl-lower alkylphenyl, such as 4-phenyl-lower alkylphenyl, e.g. 4-(2-phenylethyl)- phenyl, hydroxy phenyl, especially 4-hydroxyphenyl, cyanophenyl, especially 4-cyano- phenyl, lower alkoxyphenyl, such as 2-, 3- or 4-lower alkoxyphenyl, e.g. 4-isobutyloxy- phenyl and especially 2-, 3- and, more especially, 4-methoxyphenyl, tri-lower alkoxy¬ phenyl, especially trimethoxyphenyl, e.g. having the lower alkoxy substituents in the 3,4,5-positions, such as in 3,4,5-trimethoxyphenyl, in the 2,4,5-positions, such as in 2,4,5- trimethoxyphenyl, in the 2,4,6-positions, such as in 2,4,6-trimethoxyphenyl, the tri-lower alkoxy or methoxy radicals preferably being bonded asymmetrically at the phenyl ring, especially in the 2,3,4-positions, e.g. as in 2,3,4-trimethoxyphenyl, lower alkoxy-lower alkoxyphenyl, such as 4-(lower alkoxy-lower alkoxy )phenyl, especially 4-(2-methoxy- ethoxy)-phenyl, (especially 4-) lower alkoxycarbonyl-lower alkoxyphenyl, such as (espec¬ ially 4-) ethoxycarbonylmethoxyphenyl, (especially 4-) carboxy-lower alkoxyphenyl, such as (especially 4-) carboxymethoxyphenyl, (especially 4-) hydroxy-lower alkoxyphenyl having at least 2 carbon atoms in the lower alkoxy radical, wherein hydroxy is not bonded in the 1-position, such as (especially 4-) 2-hydroxyethylphenyl, (especially 4-) morpholino-lower alkoxyphenyl, such as 4-(2-morpholinoethyl)phenyl, (especially 4-) carbamoyl-lower alkoxyphenyl, such as (especially 4-) carbamoylmethoxyphenyl, (espec¬ ially 4-) cyano-lower alkoxyphenyl, such as (especially 4-) cyanomethoxycarbonyl; and also lower alkylenedioxyphenyl, wherein the lower alkylenedioxy radical is bonded via its two oxygen atoms to two adjacent carbon atoms of the phenyl ring, e.g. methylenedioxy- phenyl, such as 3,4-methylenedioxyphenyl, and pyridyl-lower alkoxyphenyl, such as 4-(pyridin-2- or pyridin-3-yl-lower alkoxy)phenyl, especially pyridin-3-yl-lower alkoxy¬ phenyl, e.g. pyridin-3-yl-methoxyphenyl; and also from 4-lower alkoxy-2-fluorophenyl, such as 4-methoxy-2-fluorophenyl, 4-fluoro-2-lower alkoxyphenyl, such as 4-fluoro- 2-methoxyphenyl, 4-lower alkoxy-2-hydroxyphenyl, such as 4-methoxy-2-hydroxyphenyl, phenyl that is substituted up to three times by lower alkyl, such as methyl, and lower alkoxy, such as methoxy, such as 4-lower alkoxy-2,3-di-lower alkylphenyl, e.g. 4-methoxy-2,3-dimethylphenyl, di-lower alkoxyphenyl, especially dimethoxyphenyl, e.g. 2,4-di-lower alkoxyphenyl, such as 2,4-dimethoxyphenyl, 3,4-di-lower alkoxyphenyl, such as 3,4-dimethoxyphenyl, 2,5-di-lower alkoxyphenyl, such as 2,5-dimethoxyphenyl, or 2,6-di-lower alkoxyphenyl, such as 2,6-dimethoxyphenyl, tetrahydronaphthyl, especially 5,6,7,8-tetrahydro-l -naphthyl, halo-naphthyl, such as fluoronaphthyl, especially 4-fluoro- naphthyl, cyanonaphthyl, especially 4-cyanonaphthyl, lower alkoxynaphthyl, especially 4-lower alkoxynaphthyl, such as 4-methoxy- 1 -naphthyl, and dihalophenyl-lower alkane- sulfonylphenyl, especially dichlorophenyl-lower alkanesulfonylphenyl, such as 4-(2,6-di- chlorobenzylsulfony phenyl; alternatively or in addition R₂ and/or R₃ are/is lower alkyl, such as especially isopropyl.

Preferred are compounds of formula I wherein the following combinations of R₂ and R₃ are present: radical R₂ radical R₃

1) cyclohexyl fluorophenyl, such as 4-fluorophenyl

2) phenyl fluorophenyl, such as 4-fluorophenyl or 2-fluorophenyl, or also 3-fluorophenyl

3) fluorophenyl, such as fluorophenyl, such as 4-fluorophenyl 4-fluorophenyl

4) phenyl 4-phenyl-lower alkoxyphenyl, such as 4-benzyloxyphenyl

5) phenyl trifluoromethylphenyl, such as 4-trifluorophenylmethyl

6) trifluoromethylphenyl, phenyl such as 4-trifluoromethylphenyl

7) trifluoromethylphenyl, trifluoromethylphenyl, such as such as 4-trifluoro- 4-trifluoromethylphenyl methylphenyl

8) phenyl difluorophenyl, such as 2,4-difluorophenyl

9) phenyl hydroxyphenyl, such as 4-hydroxyphenyl

10) phenyl phenyl

11) phenyl lower alkoxycarbonyl-lower alkoxy-phenyl, such as 4-ethoxycarbonylmethoxyphenyl

12) phenyl carboxy-lower alkoxyphenyl, such as 4-carboxymethylphenyl

13) phenyl hydroxy-C₂-C₇alkoxyphenyl, wherein the hydroxy group is not bonded in the

1 -position, such as 4-(2-hydroxyethoxy)phenyl

14) phenyl morpholino-lower alkoxyphenyl, such as

4-(2-morpholinoethoxy)phenyl

15) phenyl carbamoyl-lower alkoxyphenyl, such as

4-carbamoylmethoxyphenyl

16) phenyl cyano-lower alkoxyphenyl, such as

4-cyanomethoxyphenyl

17) phenyl lower alkoxyphenyl, such as

4-methoxyphenyl

18) phenyl lower alkoxy-lower alkoxy-phenyl, such as 4-(2-methoxyethoxy)phenyl

or, alternatively or in addition,

19) phenyl lower alkyl, such as isopropyl.

Most especially preferred are the combinations mentioned in numbers 1), 2), 3), 4) and 10), especially the combinations mentioned in 2), 3) and 10).

R₄ is preferably lower alkyl, especially methyl or, more especially, isopropyl or sec-butyl (= 1 -methylpropyl).

R₅, R₅\ R₆, R₇, R₈, R₈', R₉ and R₁₀ are preferably each hydrogen.

Salts of compounds of formula I are especially acid addition salts (if basic groups are present in compounds of formula I), salts with bases (if acid groups are present in compounds of formula I) or, if several salt-forming groups are present, may also be mixed salts or internal salts.

Salts are especially the pharmaceutically acceptable, non-toxic salts of compounds of foimula I.

Such salts are formed, for example, by compounds of formula I having an acid group, for example a carboxy group, a sulfo group, or a phosphoryl group substituted by one or two hydroxy groups, and are, for example, the salts thereof with suitable bases, such as non-toxic metal salts derived from metals of groups la, lb, Ila and lib of the Periodic Table of the Elements, especially suitable alkali metal salts, for example lithium, sodium or potassium salts, or alkaline earth metal salts, for example magnesium or calcium salts, or zinc salts or ammonium salts, also those salts 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, triethylamine, mono-, bis- or tris-(2-hydroxy-lower alkyl)amines, such as mono-, bis- or tris-(2-hydroxyethyl)-amine, 2-hydroxy-tert-butyl- amine 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, 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 hydrohalic acids, such as hydrochloric acid, sulfuric acid or phosphoric acid, or with organic carboxylic, sulfonic, sulfo or phospho acids or N-substituted sulfamic acids, 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 isonicot- inic acid, or with amino acids, for example the α-amino acids mentioned hereinbefore, especially glutamic acid and aspartic acid, or 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-cyclohexylsulfamic acid (with the cyclamates being formed) or with other acidic organic compounds, such as ascorbic acid. Compounds of formula I having acid and basic groups can also form internal salts.

For isolation or purification puφoses, it is also possible to use pharmaceutically unsuitable salts, for example perchlorates or picrates. Only the pharmaceutically acceptable salts, which are non-toxic when used properly, are used therapeutical ly and these are therefore preferred. The compounds of formula I have valuable pharmacological properties. They have anti-retroviral activity, especially against the viruses HTV-1 and HIV-2 considered to be causes of AIDS. The compounds of formula I are inhibitors of retroviral aspartate proteases, especially inhibitors of the aspartate protease of HIV-1 or of HIV-2, and are therefore suitable for the treatment of retroviral diseases, such as AIDS or its preceding stages (for example ARDS). The compounds of formula I can also be shown to have activity against the corresponding animal retroviruses, such as SIV (in monkeys) or FTV (in cats).

Compounds of formula I exhibit, when so used, especially advantageous pharmaco- dynamic properties, for example good pharmacodynamics, such as high bio-availability and/or high blood levels (especially when administered orally), and/or good tolerability.

The inhibitory action of the compounds of formula I on the proteolytic activity of HIV-1 protease can be demonstrated, for example, analogously to the method described by A.D. Richards et al., J. Biol. Chem. 265(14), 7733-7736 (1990). In that method, the inhibition of the action of HIV- 1 protease (prepared in accordance with S. Billich etal., J. Biol. Chem. 263(34), 17905-17908 (1990)) is measured in the presence of the icosapeptide RRSNQVSQNYPrVQNIQGRR (a synthetic substrate of HIV- 1 protease prepared by peptide synthesis according to known methods, see J. Schneider et al., Cell 54, 363-368 (1988)) which, as a substrate analogue, contains one of the cleavage sites of the gag precursor protein (natural substrate of HTV-1 protease). That substrate and its cleavage products are analysed by high-performance liquid chromatography (HPLC).

The active ingredient to be tested is dissolved in dimethyl sulfoxide. The enzymatic test is performed by adding to the test mixture suitable dilutions of the inhibitor in 20mM β-moφholinoethanesulfonic acid (MES) buffer pH 6.0. The test mixture consists of the above-mentioned icosapeptide (122μM) in 20mM MES buffer pH 6.0. 100 μl are used per test batch. The reaction is started by adding 10 μl of HIV- 1 protease solution and is stopped after 1 hour's incubation at 37°C by adding 10 μl of 0.3M HClO₄. After centri- fugation of the sample at 10 000 x g for 5 min, 20 μl of the resulting supernatant are applied to a 125 x 4.6 mm ®Nucleosil C18-5μ-HPLC column ("reverse phase" material produced by Macherey & Nagel, Dϋren, FRG, based on silica gel coated with C,₈alkyl chains). The uncleaved icosapeptide and its cleavage products are eluted from the column by means of the following gradient: 100 % eluant 1 -→ 50 % eluant 1 + 50 % eluant 2 (eluant 1: 10 % acetonitrile, 90 % H₂O, 0.1 % trifluoroacetic acid (TFA); eluant 2: 75 % acetonitrile, 25 % H₂0, 0.08 % TFA) over a period of 15 min, flow rate 1 ml/min. The quantification of the eluted peptide fragments is carried out by measuring the peak height of the cleavage product at 215 nm.

Compounds of formula I exhibit inhibitory actions in the range of from 10"⁵ to 10"⁹M. At those concentrations, IC₅₀ values (IC₅₀ = that concentration which reduces the activity of HIV-1 protease by 50 % in comparison with a control without inhibitor) of approximately from 5 x 10^~5 to 10^~9M are especially obtained.

In another test, it is possible to show that compounds of formula I protect cells that are normally infected by HIN from such an infection or at least slow down such an infection. For that test, the human T-cell leukaemia cell line MT-2 (Science 229, 563 (1985)), which is extremely sensitive to the cytopathogenic effect of HTV since it is a continuous producer of HTLV-1 (a virus causing leukaemia), is used. The MT-2 cells are grown in RPMI 1640 medium (Gibco, Scotland; RPMI comprises an amino acid mixture without glutamine) supplemented by 10 % heat-inactivated foetal calf serum, glutamine and standard anti¬ biotics. In all cases, the cells are free of mycoplasmas. The HTV-1 virus (LAV strain) is cultured in A 3.01 cells (ΝIH, Bethesda, USA), a cell line that is used for culturing HIV-1 and that originates from the CEM cell line. The titre of the virus preparation is 2 x 10⁷ IU/ml according to measurement by the test for reverse transcriptase (see below).

In order to measure the infection-inhibiting action of the test compounds, 50 μl of the respective test substance in culture medium and 100 μl of HIV-1 in culture medium (800 TdD50/ml, TCID50 = Tissue Culture Infective Dose = dose that infects 50 % of the MT-2 cells) are added to 10 x 10⁴ exponentially growing MT-2 cells which have been placed in 50 μl of culture medium in 96-well microtitre plates. After incubation for 4 days, a sample of 10 μl of the supernatant is removed from each well in order to measure the activity of the reverse transcriptase (see Alteri, E., et al., Antimicrob. Agent Chemother. 37(10), 2087-92 (1993)). The titre of the enzyme reverse transcriptase which is specific to retroviruses serves as a measurement of the virus titre. In order to determine the titre, the samples taken are first applied to a further 96-well microtitre plate and kept at -20°C until measurement is carried out.

In the measurement, 30 μl of reverse transcriptase cocktail are added to each well. The reverse transcriptase cocktail consists of 50mM Tris (α,α,α-tris(hydroxymethyl)methyl- amine, Ultra pur, Merck, Germany) pH 7.8; 75mM KCl, 2mM dithiothreitol, 5mM MgCl₂; 0.1% Nonidet P-40 (detergent; Sigma, Switzerland), 0.8mM EDTA, 10 μg ml Poly-A (Pharmacia, Uppsala, Sweden) and 0.16 μg/ml oligo(T) (=pdT(12-18), Pharmacia, Uppsala, Sweden) as a "template primer" - the mixture is filtered through a 0.45 μm Acrodisc filter (Gelman Sciences Inc., Ann Arbor, USA) and kept at -20°C. 0.1 % (v/v) [alpha-³²P]dTTP is added before the test to aliquots of the solution in order to establish a final radioactivity of 10 μCi/ml.

After mixing, the plate is incubated at 37°C for 2 h. 5 μl of the reaction mixture are trans¬ ferred to DE81 paper (Whatman, one filter per well). The dried filters are washed three times for 5 min with 300mM NaCl/25mM trisodium citrate and then once with ethanol and are again air-dried. The radioactivity on the filters is measured in a Matrix Packard 96-well counter (Packard, Zurich, Switzerland). The ED₉₀ values are calculated and are defined as that concentration of the test compound which reduces the RT activity by 90 % in comparison with a control without test compound.

The compounds of formula I wherein R_j is hydrogen especially exhibit in that test an inhibition of the virus proliferation at concentrations of from 5 x 10^"5 to 10'⁸M.

The compounds of formula I are therefore suitable for effectively braking the proliferation of HIV- 1 in cell cultures.

It is also possible to measure the blood levels of compounds of formula I.

The compounds of formula I to be investigated are for that puφose dissolved, for example, in dimethyl sulfoxide (DMSO) at a concentration of 240 mg/ml. The resulting solutions are diluted with 20 % (w/v) hydroxypropyl-β-cyclodextrin (HPβCD) in order to obtain a test substance concentration of 12 mg/ml. That solution is administered orally to mice in a dose of 120 mg/kg by artificial tube feeding. 30, 60, 90 and 120 minutes after the administration, the animals are sacrificed and blood samples are taken. Three or four animals are examined for each point in time. The blood is heparinised and worked up for the analysis as follows: an internal standard is added to the heparinised blood in a final concentration of 4μM. The blood is centrifuged. 0.25 ml of plasma is removed and deproteinised with the same volume of acetonitrile. After centrifugation, the supernatant is concentrated to dryness in vacuo and the residue is suspended in 20 μl of 3M NaCl solu¬ tion and 100 μl of 0.05M phthalate buffer with a pH of 3.0. The suspension is extracted first with 1 ml and then with 0.2 ml of diisopropyl ether. The diisopropyl ether solution is concentrated to dryness by evaporation and the residue is dissolved in 50 % (v/v) aqueous acetonitrile. This solution is examined by reversed phase HPLC.

The analysis by means of reversed phase HPLC is carried out using a 125 x 4.6 mm Nucleosil® Cjg-column (reversed phase material produced by Macherey-Nagel, Dϋren, Federal Republic of Germany, based on silica gel derivatised with hydrocarbon radicals of 18 carbon atoms) that has been equilibrated with a mobile phase of 50 % acetonitrile in water/0.1 % trifluoroacetic acid. The flow rate is 1 ml/min. Detection is carried out at 215 nm. Standards for the compounds in blood are worked up analogously to the blood samples and are used to produce standard curves, on the basis of which the in vivo concen¬ trations are determined.

In these and related experiments and also in experiments with parenteral administration, it is found that it is possible to obtain with the compounds of formula I blood levels above the ED₉₀ in the above-mentioned cell assay. Such compounds are therefore suitable for preventing growth of the virus n vivo also.

The combination of aspartate protease inhibition in vitro, inhibition of virus proliferation in cell culture and measurement of the blood levels in rodents, such as rats or mice, is used in the case of aspartate protease inhibitors to determine their clinical potential (see, for example, Roberts, N. A., et al., Biochemical Soc. Transactions 20, 513-516 (1992)).

Blood levels above the ED₉₀ in the cell assay mentioned above can also be found in dogs upon (for example oral) administration of compounds of formula I. For example, female or male breeding beagles (Ciba Geigy, Sisseln) can be used. The dogs have free access to water during the experiment and are given their last meal approximately 16 hours before the beginning of the experiment. Food is offered again 8 hours after the beginning of the experiment. Each animal is given, for example, 2 capsules of the formulation mentioned in Example 30 which together comprise 1.2 g (active ingredient), corresponding to an average dose of approximately from 80 to 100 mg/kg of body weight. Blood from the saphenous vein is transferred to heparinised test tubes at various points in time after the administration.

In order to analyse the plasma concentration, the heparinised blood is centrifuged (4000 x g, 20 min) and the plasma is removed and mixed with the same volume of aceto- nitrile. The mixture is kept on ice for 30 min. The protein precipitate is removed by centri¬ fugation (10000 x g, 5 min) and the supernatant is centrifuged again. The concentration of the active ingredient in the final supernatant obtained is determined by "reversed phase HPLC": the HPLC analysis is carried out on an analytical 125 x 4.6 mm Nucleosil C18 (5 μm) column (Macherey & Nagel, Dϋren, FRG) that has been equilibrated with a mobile phase of 50 % acetonitrile and 0.1 % trifluoroacetic acid in water. The flow rate is 1 ml/min. Under those conditions, the detection limit is 0.1 μM. The active ingredient is detected by UV absoφtion at 215 nm. The concentrations are determined by the external standard method; the height of the peaks is used to determine the concentrations by comparison with standard curves. The standard curves are obtained by HPLC analysis of canine plasma with known added concentrations of the active ingredient which are worked up by the steps mentioned above analogously to the samples themselves. The plasma concentrations measured at the respective points in time are given in μmol/1.

The combination of the data from the cell test and the blood levels in rodents makes plausible the possibility of treating retroviral diseases, especially the diseases mentioned, in other warm-blooded animals, such as humans.

The compounds of formula I can also be used in the prevention, control and treatment of infections caused by retroviruses, especially HIN, such as HTV-1 or HIV-2, in cell cultures, especially cell cultures of lymphocyte cell lines, from warm-blooded animals, which is advantageous especially in the case of very valuable cell cultures that produce, for example, certain antibodies, vaccines or messenger substances, such as interleukins etc., and are therefore of great commercial value.

Finally, the compounds of formula I can be used as standards in tests, for example as HPLC standards or as standards for comparison of animal models in relation to various aspartate protease inhibitors, for example with regard to the blood levels achievable.

In the groups of preferred compounds of formula I mentioned hereinafter, definitions of substituents from among the general definitions mentioned above can be used where sensible, for example in order to replace more general definitions by more specific defini¬ tions or, especially, by definitions characterised as being preferred. The definitions mentioned above as being preferred or characterised as examples are preferred in each case. Preferred is a compound of formula I (especially of formula I') wherein

R_j is an acyl radical selected from lower alkoxy-lower alkanoyl including lower alkoxy¬ carbonyl, preferably lower alkoxycarbonyl, such as tert-butoxycarbonyl, and phenyl-lower alkoxy-lower alkanoyl, preferably phenyl-lower alkoxycarbonyl, such as benzyloxy- carbonyl;

the residue, bonded via the carboxy group, of an amino acid selected from valine, norva¬ line, leucine, isoleucine and norleucine, and also from serine, homoserine, threonine, methionine, cysteine, phenylalanine, tyrosine, 4-aminophenylalanine, 4-chlorophenyl- alanine, 4-carboxyphenylalanine, β-phenylserine, phenylglycine, α-naphthylalanine, cyclohexylalanine, cyclohexylglycine, tryptophan, aspartic acid, aspartic acid β-(phenyl- lower alkyl) ester, such as aspartic acid β-benzyl ester, asparagine, aminomalonic acid monoamide, glutamic acid, glutamic acid γ-(phenyl-lower alkyl) ester, such as glutamic acid γ-benzyl ester, glutamine, histidine, arginine, lysine, δ-hydroxylysine and ornithine; valine being especially preferred; the respective amino group(s) and other functional groups being free or (where possible) in salt form; and the said amino acid residues that have asymmetric carbon atoms being in the (D)-, the (L)- or the (D,L)-form, preferably in the (L)-form;

or the residue of one of the amino acids last mentioned, which residue is bonded via the carbonyl group and N-acylated at the amino nitrogen by one of the acyl radicals mentioned hereinbefore, especially a β-(O-benzyl)aspartic acid or, more especially, asparagine or valine residue that is bonded via the carbonyl group and N-acylated by one of the acyl radicals mentioned hereinbefore, especially lower alkoxy-lower alkanoyl-valyl, such as lower alkoxycarbonyl-valyl, e.g. lower alkoxycarbonyl-valyl, the respective amino acid residue preferably being in the (L)-form;

R₂ and R₃ are selected independently of each other from cyclohexyl, phenyl, phenyl-lower alkoxy-phenyl, especially 4-phenyl-lower alkoxyphenyl, such as 4-(benzyloxy)-phenyl, fluorophenyl, such as 4-, 3- or 2-fluorophenyl, difluorophenyl, especially 2,4-difluoro- phenyl; also phenyl-lower alkylphenyl, such as 4-phenyl-lower alkylphenyl, e.g. 4-(2- phenylethyl)-phenyl, hydroxyphenyl, especially 4-hydroxyphenyl, lower alkoxyphenyl, such as 2-, 3- or 4-lower alkoxyphenyl, e.g. 4-isobutyloxyphenyl and especially 2-, 3- and, more especially, 4-methoxy phenyl, tri-lower alkoxy-phenyl, especially trimethoxyphenyl, e.g. having the lower alkoxy substituents in the 3,4,5-positions, such as in 3,4,5-tri- methoxyphenyl, in the 2,4,5-positions, such as in 2,4,5-trimethoxyphenyl, in the 2,4,6- positions, such as in 2,4,6-trimethoxyphenyl, the tri-lower alkoxy and methoxy radicals preferably being bonded asymmetrically at the phenyl ring, especially in the 2,3,4- positions, e.g. as in 2,3,4-trimethoxyphenyl, lower alkoxy-lower alkoxy-phenyl, such as 4-(lower alkoxy-lower alkoxy)phenyl, especially 4-(2-methoxy-ethoxy)-phenyl, (espec¬ ially 4-) lower alkoxycarbonyl-lower alkoxyphenyl, such as (especially 4-) ethoxy¬ carbonylmethoxyphenyl, (especially 4-) carboxy-lower alkoxyphenyl, such as (especially 4-) carboxymethoxyphenyl, (especially 4-) hydroxy-lower alkoxyphenyl having at least 2 carbon atoms in the lower alkoxy radical, wherein hydroxy is not bonded in the 1-position, such as (especially 4-) 2-hydroxyethylphenyl, (especially 4-) moφholino-lower alkoxy¬ phenyl, such as 4-(2-moφholinoethyl)ρhenyl, (especially 4-) carbamoyl-lower alkoxy¬ phenyl, such as (especially 4-) carbamoylmethoxyphenyl, (especially 4-) cyano-lower alkoxyphenyl, such as (especially 4-) cyanomethoxycarbonyl; and also lower alkylene¬ dioxyphenyl, wherein the lower alkylenedioxy radical is bonded via its two oxygen atoms to two adjacent carbon atoms of the phenyl ring, e.g. methylenedioxyphenyl, such as 3,4-methylenedioxyphenyl, and pyridyl-lower alkoxyphenyl, such as 4-(pyridin-2- or pyridin-3-yl-lower alkoxy )phenyl, especially pyridin-3-yl-lower alkoxyphenyl, e.g. pyridin-3-yl-methoxyphenyl, and di-lower alkoxyphenyl, especially dimethoxyphenyl, e.g. 2,4-di-lower alkoxyphenyl, such as 2,4-dimethoxyphenyl, 3,4-di-lower alkoxyphenyl, such as 3,4-dimethoxyphenyl, 2,5-di-lower alkoxyphenyl, such as 2,5-dimethoxyphenyl, 2,6-di-lower alkoxyphenyl, such as 2,6-dimethoxyphenyl, and (alternatively or in addition) from lower alkyl, such as isopropyl; preferably, independently of each other from cyclo¬ hexyl, phenyl, fluorophenyl (especially 2- or 4-fluorophenyl), phenyl-lower alkoxyphenyl and (alternatively or in addition) isopropyl; the corresponding radicals preferably being in the combinations specified as being preferred above; especially in one of the following combinations mentioned above in numbers 1), 2), 3), 4) and 10): R₂ = cyclohexyl/R₃ = fluorophenyl, such as 4-fluorophenyl; R₂ = phenyl/R₃ = fluorophenyl, such as 4-fluoro- phenyl or 2-fluorophenyl, or also 3-fluorophenyl; R₂ = fluorophenyl, such as 4-fluoro- phenyl/R₃ = fluorophenyl, such as 4-fluorophenyl; R₂ = phenyl/R₃ = 4-phenyl-lower alkoxyphenyl, such as 4-benzyloxyphenyl; or R₂ = phenyl/R₃ = phenyl; especially in the combinations mentioned in 2), 3) and 10);

R₄ is lower alkyl, preferably isopropyl or sec-butyl;

R₅, R₅', R₆, R₇, R_g and R₈' are each hydrogen; and R and R₁₀ are each independently of the other hydrogen or lower alkyl, such as methyl, preferably each hydrogen;

or a salt thereof.

More preferred is a compound of formula I wherein

R_j is an acyl radical selected from lower alkoxycarbonyl and phenyl-lower alkoxy¬ carbonyl;

the residue, bonded v a the carboxy group, of an amino acid selected from valine, norva¬ line, leucine, isoleucine and norleucine, and also from serine, homoserine, threonine, methionine, cysteine, phenylalanine, tyrosine, 4-aminophenylalanine, 4-chlorophenyl- alanine, 4-carboxyphenylalanine, β-phenylserine, phenylglycine, α-naphthylalanine, cyclohexylalanine, cyclohexylglycine, tryptophan, aspartic acid, aspartic acid β-(phenyl- lower alkyl) ester, asparagine, aminomalonic acid monoamide, glutamic acid, glutamic acid γ-(phenyl-lower alkyl) ester, glutamine, histidine, arginine, lysine, δ-hydroxylysine and ornithine; the mentioned amino acid residues that have asymmetric carbon atoms being in the (L)-form;

or the residue of one of the amino acids last mentioned, which residue is bonded via the carbonyl group and N-acylated at the amino nitrogen by one of the acyl radicals men¬ tioned hereinbefore, the respective amino acid residue preferably being in the (L)-form;

R₂ and R₃ are selected independently of each other from cyclohexyl, phenyl, 4-phenyl- lower alkoxyphenyl, fluorophenyl, 2,4-difluorophenyl, 4-phenyl-lower alkylphenyl, 4-hydroxy phenyl, 4-lower alkoxyphenyl, 4-(lower alkoxy-lower alkoxy )phenyl, 4-lower alkoxycarbonyl-lower alkoxyphenyl, 4-carboxy-lower alkoxyphenyl, 4-hydroxy-lower alkoxyphenyl having at least 2 carbon atoms in the lower alkoxy radical, wherein hydroxy is not bonded in the 1 -position, 4-moφholino-lower alkoxyphenyl, 4-carbamoyl-lower alkoxyphenyl, 4-cyano-lower alkoxyphenyl, di-lower alkoxyphenyl and (alternatively or in addition) lower alkyl, preferably independently of each other from cyclohexyl, phenyl, fluorophenyl (especially 2- or 4-fluorophenyl) and phenyl-lower alkoxyphenyl; the corres¬ ponding radicals preferably being in the combinations specified above as being preferred; especially in one of the following combinations mentioned above in 1), 2), 3), 4) and 10): R₂ = cyclohexyl/R₃ = fluorophenyl, such as 4-fluorophenyl; R = phenyl/R₃ = fluoro- phenyl, such as 4-fluorophenyl or 2-fluorophenyl, or also 3-fluorophenyl; R₂ = fluoro¬ phenyl, such as 4-fluorophenyl/R₃ = fluorophenyl, such as 4-fluorophenyl; R₂ = phenyI/R₃ = 4-phenyl-lower alkoxyphenyl, such as 4-benzyloxyphenyl; or R₂ = phenyl/R₃ = phenyl; more especially in the combinations mentioned in 2), 3) and 10);

R₄ is lower alkyl, preferably isopropyl or sec-butyl;

R₅, R₅', R_β, R₇, R₈ and R₈' are each hydrogen; and

R₉ and R_]0 are each independently of the other hydrogen or lower alkyl, such as methyl, preferably each hydrogen;

or a salt thereof.

Especially preferred is a compound of formula I wherein

R_j is lower alkoxycarbonyl, such as tert-butoxycarbonyl; or also N-phenyl-lower alkoxy¬ carbonyl-valyl or -asparaginyl, especially N-benzyloxycarbonyl-(L)-valyl or also N-benzyloxycarbonyl-(L)-asparaginyl;

R₂ and R₃ are selected independently of each other from cyclohexyl, phenyl, fluorophenyl (especially 2- or 4-fluorophenyl), phenyl-lower alkoxyphenyl and (alternatively or in addition) lower alkyl; the corresponding radicals preferably being in the combinations specified above as being preferred; especially in one of the following combinations mentioned above in numbers 1), 2), 3), 4) and 10): R₂ = cyclohexyl/R₃ = fluorophenyl, such as 4-fluorophenyl; R₂ = phenyl/R₃ = fluorophenyl, such as 4-fluorophenyl or 2-fluorophenyl, or also 3-fluorophenyl; R₂ = fluorophenyl, such as 4-fluorophenyl R₃ = fluorophenyl, such as 4-fluorophenyl; R₂ = phenyl/R₃ = 4-phenyl-lower alkoxyphenyl, such as 4-benzyloxyphenyl; or R₂ = phenyl/R₃ = phenyl; more especially in the combina¬ tions mentioned in 2), 3) and 10);

R₄ is lower alkyl, preferably isopropyl or sec-butyl;

R₅, R₅\ R₆, R₇, R₈ and R₈' are each hydrogen; and

R and R_|0 are each independently of the other hydrogen or methyl, preferably each hydrogen;

or a salt thereof.

Most preferred are the compounds mentioned in the Examples, or pharmaceutically accep¬ table salts thereof.

The compounds of formula I, or salts of such compounds having at least one salt-forming group, are obtained according to processes known per se, for example by

a) condensing an acid of formula

Ri-OH (II),

or a reactive acid derivative thereof, wherein R_j has die same definitions as R_j in compounds of formula I, with an amino compound of formula

(especially of formula

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 (or III'), with the exception of those participating in the reaction, being, if necessary, in protected form, and removing any protecting groups, or b) for the preparation of compounds of formula

(especially of formula

wherein Bj is a bivalent residue of an amino acid bonded via the carbonyl group (to the bonding nitrogen atom shown in formula la') and the amino group (to R_j'), as defined under formula I, and R_| ' is one of the radicals defined for R_j under formula I with the exception of a non-acylated or N-acylated amino acid residue, as defined under formula I, so that B_] and Rj ' form together a residue of an N-acylated amino acid, which residue is bonded via its carbonyl group, as defined for R_j under formula I, and n and the other radicals are as defined for compounds of formula I, condensing a carboxylic acid of formula

R,'-OH (IV),

or a reactive acid derivative thereof, wherein R_j ' may be a radical as defined for R_j in compounds of formula I with the exception of a residue of a non-acylated or N-acylated amino acid, which residue is bonded via its carbonyl group, with an amino compound of formula

(especially of formula

or with a reactive derivative thereof, wherein Bi has the definitions last mentioned and the other radicals are as defined for compounds of formula I, free functional groups in the starting materials of formulae Ilia (or Ilia') and IV, with the exception of those partici¬ pating in the reaction, being, if necessary, in protected form, and removing any protecting groups, or

c) condensing a carboxylic acid of formula

(especially of formula

(V)),

or a reactive derivative thereof, wherein the radicals are as defined for compounds of formula I, with an amino compound of formula

(especially of formula

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 V (or V) and VI (or VI'), with the exception of those participating in the reaction, being, if necessary, in protected form, and removing any protecting groups, or

d) condensing a carboxylic acid of formula

(especially of formula

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 VO (or VH') and Vm, with the exception of those participating in the reaction, being, if necessary, in protected form, and, if desired, removing any protecting groups, or

e) reacting a compound of formula

(especially of formula

wherein Wj is a nucleofugal leaving group and the other radicals are as defined for compounds of formula I, with an imino compound of formula

wherein the radicals are as defined for compounds of formula I, with nucleophilic substi¬ tution taking place, free functional groups in the starting materials of formulae DC (or DC) and X, with the exception of those participating in the reaction, being, if necessary, in protected form, and removing any protecting groups, or

f) in a compound of formula I (especially F) wherein the substituents are as defined above, with the proviso that in the compound of formula I concerned at least one functional group is protected by protecting groups, removing any protecting groups,

and or, if desired, converting a compound of formula I (or F) having at least one salt- forming group that is obtained by one of the above processes a) to f) into its salt and/or converting a salt that may be obtained into the free compound or into a different salt and/or, where applicable, separating isomeric mixtures of compounds of formula I (or F) that may be obtained and/or converting a compound of formula I (or F) according to the invention into a different compound of formula I (or F) according to the invention.

The processes defined above are described in more detail below:

For the puφoses of the description of the respective process steps, unless stated otherwise, hereinbefore and hereinafter the radicals R_j, R₂, R₃, R₄, R₅, R₅', R₅, R₇, R₈, R₈', R and R₁₀ are as defined for compounds of formula I.

In the preparation of compounds of formula I, preference is given in each case to the preparation of compounds of formula

wherein n and the radicals are as defined for compounds of formula I.

For the puφoses of the respective processes, the compounds of the formulae shown with an apostrophe, that is, F, la', m\ πia', V, VF, VH' and DC, having the indicated stereospecificity are especially preferred to the corresponding compounds of formulae I, la, HI, Ilia, V, VI, VII and IX in which the stereospecificity is not indicated; less preferred than the compounds marked with an apostrophe but more preferred than the corresponding compounds in which the stereospecificity is not indicated are in each case the correspond¬ ing compound mixtures in which the carbon atoms carrying the radical R₂-CH -, the radical R₃-CH₂- and the OH group lying between those radicals [in the indicated order C(5), C(2) and C(4)] are in the (2R,4S,5S)- and the (2S,4R,5R)-configuration.

Hereinafter, preferably the corresponding compound mixtures having the (2R,4S,5S)- and (2S,4R,5R)-configuration or, especially, the compounds of the respectively corresponding formulae shown with an apostrophe may be used in each case in place of the compounds of formulae I, la, HI, Ilia, V, VI, VII and DC insofar as that is chemically meaningful; this applies also to the section on Additional Process Steps and Starting Materials.

Process a) (Formation of an amide bond)

In starting materials of formulae II and III, functional groups, with the exception of groups that are intended to participate in the reaction or that do not react under the reaction conditions, are protected independently of one another by protecting groups.

Protecting groups for functional groups in starting materials, the reaction of which is to be avoided, especially carboxy, amino, hydroxy and mercapto groups, include especially those protecting groups (conventional protecting groups) which are customarily used in the synthesis of peptide compounds, and also in the synthesis of cephalosporins and peni¬ cillins as well as nucleic acid derivatives and sugars. Those protecting groups may already be present in the precursors and are intended to protect the functional groups in question against undesired secondary reactions, such as acylation, etherification, esteri- fication, oxidation, solvolysis, etc.. In certain cases the protecting groups may, in addition, cause the reactions to proceed selectively, for example stereoselectively. It is character¬ istic of protecting groups that they can be removed easily, i.e. without undesired secondary reactions taking place, for example by solvolysis, reduction, photolysis or also enzymat- ically, for example also under physiological conditions, and that they are not present in the end products. Compounds of formula I having protected functional groups, the protecting groups of which can be removed under physiological conditions, may have a greater metabolic stability or pharmacodynamic properties that are better in some other way than the corresponding compounds having free functional groups.

The protection of functional groups by such protecting groups, the protecting groups them¬ selves and the reactions for their removal are described, for example, in standard works such as J. F. W. McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973, in Th. W. Greene, "Protective Groups in Organic Synthesis", Wiley, New York 1981, in "The Peptides", Volume 3 (E. Gross and J. Meienhofer, eds.), Academic Press, London and New York 1981, in "Methoden der organischen Chemie", Houben-Weyl, 4th edition, Volume 15/1, Georg Thieme Verlag, Stuttgart 1974, in H.-D. Jakubke and H. Jescheit, "Aminosauren, Peptide, Proteine" ("Amino acids, peptides, proteins"), Verlag Chemie, Weinheim, Deerfield Beach and Basle 1982, and in Jochen Lehmann, "Chemie der Kohlenhydrate: Monosaccharide und Derivate" ("The Chemistry of Carbohydrates: monosaccharides and derivatives"), Georg Thieme Verlag, Stuttgart 1974.

A carboxy group is protected, for example, in the form of an ester group which 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 substituted in the 1- or 2-position of the lower alkyl group by suit¬ able substituents.

A protected carboxy group esterified by a lower alkyl group is, for example, methoxy- carbonyl or ethoxycarbonyl.

A protected carboxy group 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 esterified by a lower alkyl group that is substituted in the 1- or 2-position of the lower alkyl group by suitable substituents is, for example, 1-aryl-lower alkoxycarbonyl, such as arylmethoxycarbonyl, having one or two aryl radicals, wherein aryl is phenyl that is unsubstituted or 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-nitrobenzyl- oxycarbonyl or 4-methoxybenzyloxycarbonyl, diphenylmethoxycarbonyl or diphenyl- methoxycarbonyl substituted by the mentioned substituents, for example di(4-methoxy- phenyl)methoxy carbonyl, and also carboxy esterified by a lower alkyl group, the lower alkyl group being substituted in the 1- or 2-position by suitable substituents, such as 1 -lower alkoxy-lower alkoxycarbonyl, for example methoxymethoxycarbonyl, 1-methoxy- ethoxycarbonyl or 1-ethoxyethoxycarbonyl, 1-lower alkylthio-lower alkoxycarbonyl, for example 1-methylthiomethoxycarbonyl or 1-ethylthioethoxycarbonyl, aroylmethoxy- carbonyl 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, as well as 2-(tri-substituted silyl)-lower alkoxycarbonyl wherein the substituents are each independently of the others an aliphatic, araliphatic, cyclo- aliphatic 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 above, for example 2-tri-lower alkylsilyl-lower alkoxycarbonyl, such as 2-tri-lower alkyl- silylethoxycarbonyl, for example 2-trimethylsilylethoxycarbonyl or 2-(di-n-butyl-methyl- silyl)-ethoxycarbonyl, or 2-triarylsilylethoxycarbonyl, such as triphenylsilylethoxy- carbonyl.

A carboxy group may also be 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 can also be substituted by two lower alkyl groups, for example methyl groups, and by an amino group or a carboxy group of a second molecule of formula I. Compounds having such protecting groups can be prepared, for example, using corresponding tri-lower alkylhalosilanes, such as tert-butyldimethylchlorosilane, as silylating agents.

A carboxy group is also protected in the form of an internal ester with a hydroxy group present in the molecule suitably spaced from the carboxy group, for example in the γ-position with respect to the carboxy group, that is to say in the form of a lactone, prefer¬ ably a γ-lactone.

A protected carboxy group is preferably tert-lower alkoxycarbonyl, for example tert-but¬ oxycarbonyl, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 9-fluorenylmethoxycarbonyl or diphenylmethoxycarbonyl, or a carboxy group protected in the form of a lactone, espe¬ cially a γ-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-l- 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 an unsubstituted or substituted, for example halo- or aryl-substituted, lower alkanecarboxylic acid or an unsubstituted or substituted, for example halo-, lower alkoxy- or nitro-substituted, benzoic acid, or, prefer¬ ably, 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-haloacetyl, such as 2-chloro-, 2-bromo-, 2-iodo-, 2,2,2-trifluoro- or 2,2,2-trichloro-acetyl, unsubsti¬ tuted or substituted, for example halo-, lower alkoxy- or nitro-substituted, benzoyl, such as benzoyl, 4-chlorobenzoyl, 4-methoxybenzoyl or 4-nitrobenzoyl, lower alkoxycarbonyl, preferably lower alkoxycarbonyl that is branched in the 1 -position of the lower alkyl radical or suitably substituted in the 1 - or 2-position, for example tert-lower alkoxy¬ carbonyl, such as tert-butoxycarbonyl, 1-aryl-lower alkoxycarbonyl, such as arylmethoxy- carbonyl, having one, two or three aryl radicals which 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 benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, diphenylmethoxy¬ carbonyl, 9-fluorenylmethoxycarbonyl or di(4-methoxyphenyl)methoxycarbonyl, aroyl- methoxycarbonyl 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 alkoxycarbonyl, for example 2,2,2-trichloroethoxycarbonyl, 2-bromoethoxy- carbonyl or 2-iodoethoxycarbonyl, 2-(tri-substituted silyl)-lower alkoxycarbonyl, for example 2-tri-lower alkylsilyl-lower alkoxycarbonyl, such as 2-trimethylsilylethoxy- carbonyl or 2-(di-n-butyl-rnethyl-silyl)-ethoxycarbonyl, or triarylsilyl-lower alkoxy- carbonyl, for example 2-triphenylsilylethoxycarbonyl.

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-1-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 espe¬ cially of a carbonic acid semiester, such as a carbonic acid lower alkyl semiester. Corres¬ ponding protecting groups are especially 1 -lower alkanoyl-lower alk-l-en-2-yl, for example 1-lower alkanoyl-prop-l-en-2-yl, such as l-acetyl-prop-l-en-2-yl, or lower alkoxycarbonyl-lower alk-l-en-2-yl, for example lower alkoxycarbonyl-prop-l-en-2-yl, such as l-ethoxycarbonyl-prop-l-en-2-yl.

A silylamino group is, for example, a tri-lower alkylsilylamino group, for example tri- methylsilylamino or tert-butyl-dimethylsilylamino. The silicon atom of the silylamino group can also be substituted by only two lower alkyl groups, for example methyl groups, and by the amino group or the carboxy group of a second molecule of formula I. Compounds having such protecting groups can be prepared, for example, using the corres¬ ponding chlorosilanes, such as tert-butyldimethylchlorosilane, as silylating agents.

An amino group can also be protected by conversion into the protonated form; suitable corresponding anions are especially those of strong inorganic acids, such as 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 alkoxycar¬ bonyl, fluorenyl-lower alkoxycarbonyl, 2-lower alkanoyl-lower alk- 1 -en-2-yl and lower alkoxycarbonyl-lower alk-l-en-2-yl, especially tert-butoxycarbonyl and benzyloxy¬ carbonyl.

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 hydroxy group can also be protected by tri-lower alkylsilyl, for example trimethylsilyl, triisopropylsilyl or tert-butyl-dimethylsilyl, 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, hydrocarbon radical, for example 1 -lower alkoxy-lower alkyl or 1 -lower alkylthio-lower alkyl, such as methoxymethyl, 1-methoxyethyl, 1-ethoxy- ethyl, methylthiomethyl, 1-methylthioethyl or 1-ethylthioethyl, or 2-oxa- or 2-thia-cyclo- alkyl having from 5 to 7 ring atoms, such as 2-tetrahydrofuryl or 2-tetrahydropyranyl, or a corresponding thia analogue, and also by 1 -phenyl-lower alkyl, such as benzyl, diphenyl- methyl or trityl, wherein the phenyl radicals may be substituted, for example, by halogen, for example chlorine, lower alkoxy, for example methoxy, and/or by nitro. A preferred hydroxy-protecting group is, for example, 2,2,2-trichloroethoxycarbonyl, 4-nitrobenzyl- oxycarbonyl, diphenylmethoxycarbonyl, benzyl or trityl.

Two hydroxy groups, especially adjacent hydroxy groups, occurring in a molecule, or a hydroxy group and an amino group that are adjacent 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 unsub¬ stituted or substituted alkylidene, for example lower alkylidene, such as isopropylidene, cycloalkylidene, such as cyclohexylidene, a carbonyl group or benzylidene.

A hydroxy group adjacent to a carboxy group can be protected by the formation of an internal ester (lactone), especially a γ-lactone.

Preferably, a protected hydroxy group is protected by tri-lower alkylsilyl or in the form of a lactone, especially by tert-butyl-dimethylsilyl or in the form of a γ-lactone.

A mercapto group, for example in cysteine, can be protected especially by S-alkylation with unsubstituted or substituted alkyl radicals, by silylation, by thioacetal formation, by S-acylation or by the formation of asymmetric disulfide 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 acetamidomethyl, iso- butyrylacetamidomethyl or 2-chloroacetamidomethyl, benzoyl, benzyloxycarbonyl or alkylaminocarbonyl, especially lower alkylaminocarbonyl, such as ethylaminocarbonyl, and also lower alkylthio, such as S-ethylthio or S-tert-butylthio, or S-sulfo.

In the context of this Application, a protecting group, for example a carboxy-protecting group, is to be understood as being expressly also a polymeric carrier ttiat is bonded in a readily removable manner to the functional group, for example the carboxy group, to be protected, for example a carrier suitable for the Merrifield synthesis. Such a suitable poly¬ meric carrier is especially a polystyrene resin, weakly cross-linked by copolymerisation with divinylbenzene, that carries bridge members suitable for reversible bonding.

The acids of formula II are carboxylic acids and either contain 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 in the form of a reactive cyclic amide. The reactive derivatives may also be formed in situ.

Activated esters of compounds of formula II having a carboxy group are especially esters that are unsaturated at the linking carbon atom of the esterifying radical, for example 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 treatment of the corresponding acid with an isoxazolium reagent; 1 ,2-oxazolium or Woodward method), or 1 -lower alkoxy vinyl esters (obtainable, for example, by treatment of the corresponding acid with a lower alkoxyacetylene; ethoxy- acetylene method), or esters of the amidino type, such as N,N'-disubstituted amidino esters (obtainable, for example, by treatment of the corresponding acid with a suitable N,N'-disubstituted carbodiimide, for example N,N'-dicyclohexylcarbodiimide; carbo- diimide method), or N,N-disubstituted amidino esters (obtainable, for example, by treatment of the corresponding acid with an N,N-disubstituted cyanamide; cyanamide method), suitable aryl esters, especially phenyl esters substituted by electron-attracting substituents (obtainable, for example, by treatment of the corresponding acid with a suitably substituted phenol, for example 4-nitrophenol, 4-methylsulfonylphenol, 2,4,5-tri- chlorophenol, 2,3,4,5,6-pentachlorophenol 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 treatment of 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 treatment of the corresponding acid with unsubstituted or substituted, for example nitro-substituted, thiophenols, inter alia by the anhydride or carbodiimide method; activated thiol esters method), or especially amino or amido esters (obtainable, for example, by treatment of the corresponding acid with an N-hydroxyamino or N-hydroxyamido compound, for example N-hydroxysuccinimide, N-hydroxypiperidine, N-hydroxyphthalimide, N-hydroxy-5-norbornene-2,3-dicarboxylic acid imide, 1-hydroxy- benzotriazole or 3-hydroxy-3,4-dihydro-l,2,3-benzotriazin-4-one, for example by the anhydride or carbodiimide method; activated N-hydroxy esters method). Internal esters, for example γ-lactones, can 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 treatment of the corresponding acid with thionyl chloride, phosphorus pentachloride or oxalyl chloride; acid chloride method), azides (obtainable, for example, from a corresponding acid ester via the corresponding hydrazide and treatment thereof with nitrous acid; azide method), anhydrides with carbonic acid semiesters, for example carbonic acid lower alkyl semiesters (obtainable, for example, by treatment of the corresponding acid with chloroformic acid lower alkyl esters or with a 1 -lower alkoxy- carbonyl-2-lower alkoxy- 1 ,2-dihydroquinoline; mixed O-alkylcarbonic acid anhydrides method), or anhydrides with dihalogenated, especially dichlorinated, phosphoric acid (obtainable, for example, by treatment of the corresponding acid with phosphorus oxychloride; phosphorus oxychloride method), anhydrides with other phosphoric acid derivatives (for example those obtainable with phenyl-N-phenylphosphoramidochloridate or by reaction of alkylphosphoric acid amides in the presence of sulfonic acid anhydrides and/or racemisation-reducing additives, such as N-hydroxybenzotriazole, or in the presence of cyanophosphonic acid diethyl ester) or with phosphorous acid derivatives, or anhydrides with organic acids, such as mixed anhydrides with organic carboxylic acids (obtainable, for example, by treatment of the corresponding acid with an unsubstituted or substituted lower alkane- or phenyl-lower alkane-carboxylic acid halide, for example phenylacetic acid chloride, pivalic acid chloride or trifluoroacetic acid chloride; mixed carboxylic acid anhydrides method) or with organic sulfonic acids (obtainable, for example, by treatment of a salt, such as an alkali metal salt, of the corresponding acid with a suitable organic sulfonic acid halide, such as a lower alkane- or aryl-, for example methane- or p-toluene-sulfonic acid chloride; mixed sulfonic acid anhydrides method) and symmetric anhydrides (obtainable, for example, by condensation of 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 of aromatic character, such as amides with imidazoles, for example imidazole (obtainable, for example, by treatment of the corresponding acid with N,N'-carbonyldiimidazole; imidazole method), or pyrazole, for example 3,5-dimethylpyrazole (obtainable, for example, via the acid hydrazide by treatment with acetylacetone; pyrazolide method).

As mentioned, derivatives of carboxylic acids that are used as acylating agents may also be formed in situ. For example, N,N'-disubstituted amidino esters may be formed in situ by reacting a mixture of the starting material of formula HI and the acid of formula II used as acylating agent in the presence of a suitable N,N'-disubstituted carbodiimide, for example N,N'-dicyclohexylcarbodiimide, for example in the presence of a suitable base, such as triethylamine, and/or in the presence of a racemisation-reducing additive, such as N-hydroxybenzotriazole. In addition, amino or amido esters of the acids used as acylating agents may be formed in the presence of the starting material of formula HI to be acylated, by reacting a mixture of the corresponding acid and amino starting materials in the presence of an N,N'-disubstituted carbodiimide, for example N,N'-dicyclohexylcarbo- diimide, and of an N-hydroxyamine or N-hydroxyamide, for example N-hydroxysuccin¬ imide, where appropriate in die presence of a suitable base, for example 4-dimethyl- amino-pyridine. Activation in situ can also be achieved by reaction with N,N,N',N'-tetra- alkyluronium compounds, such as O-benzotriazol-l-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (preferably in the presence of a tertiary nitrogen base, especially N-methylmoφholine). Phosphoric acid anhydrides of the carboxylic acids of formula II can also be prepared in situ by reacting an alkylphosphoric acid amide, such as hexa- methylphosphoric acid triamide, in the presence of a sulfonic acid anhydride, such as 4-toluenesulfonic acid anhydride, with a salt, such as a tetrafluoroborate, for example sodium tetrafluoroborate, or with another derivative of hexamethylphosphoric acid tri¬ amide, such as benzotriazol-l-yl-oxy-tris(dimethylamino)phosphonium hexafluoride, preferably in the presence of a racemisation-reducing additive, such as N-hydroxybenzo¬ triazole, and, where appropriate, in the presence of a tertiary nitrogen base, such as N-methylmoφholine. Also possible is the reaction with cyanophosphonic acid di-lower alkyl esters, such as cyanophosphonic acid diethyl ester, in the presence of a tertiary nitrogen base, such as triethylamine. Finally, chlorocarbonic acid derivatives of the carboxylic acids of formula H can be prepared directly in situ by reaction of a corres¬ ponding alcohol with phosgene or an analogue thereof, such as triphosgene (=bis(tri- chloromethyl) carbonate), in the presence or absence of a tertiary nitrogen base, such as triethylamine, and further reacted with a compound of formula HI.

The amino group of compounds of formula πi that participates in the reaction preferably carries at least one reactive hydrogen atom, especially when the carboxy group reacting therewith is in reactive form; it may, however, itself have been derivatised, for example by reaction with a phosphite, such as diethylchlorophosphite, 1,2-phenylenechlorophosphite, ethyldichlorophosphite, ethylenechlorophosphite or tetraethylpyrophosphite. A derivative of such a compound having an amino group is, for example, also a carbamic acid halide, the amino group that participates in the reaction being substituted by halocarbonyl, for example chlorocarbonyl.

The condensation to form an amide bond can be carried out in a manner known per se, for example as described in standard works, such as Houben-Weyl, "Methoden der organ- ischen Chemie", 4th edition, Volume 15/H (1974), Volume DC (1955), Volume E 11 (1985), Georg Thieme Verlag, Stuttgart, "The Peptides" (E. Gross and J. Meienhofer, eds.), Volumes 1 and 2, Academic Press, London and New York, 1979/1980, or M. Bodansky, "Principles of Peptide Synthesis", Springer- Verlag, Berlin 1984.

The condensation of a free carboxylic acid with the corresponding amine can be carried out preferably 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- diimide, also suitable carbonyl compounds, for example carbonyl imidazole, 1,2- oxazolium compounds, for example 2-ethyl-5-phenyl-l,2-oxazolium 3'-sulfonate and 2-tert-butyl-5-methylisoxazolium perchlorate, or a suitable acylamino compound, for example 2-ethoxy- 1 -ethoxycarbonyl- 1 ,2-dihydroquinoline, N,N,N' ,N'-tetraalkyluronium compounds, such as O-benzotriazol-l-yl-N,N,N',N'-tetramethyluronium hexafluoro- phosphate, also activated phosphoric acid derivatives, for example diphenylphosphoryl azide, diethylphosphoryl cyanide (= cyanophosphonic acid diethyl ester), phenyl-N- phenylphosphoroamidochloridate, bis(2-oxo-3-oxazolidinyl)phosphinic acid chloride or l-benzotriazolyloxy-tris(dimethylamino)phosphonium hexafluorophosphate.

If necessary or desired, an organic base is added, preferably a tri-substituted nitrogen base, for example a tri-lower alkylamine, such as one having bulky radicals, for example ethyl- diisopropylamine, or one having unbranched radicals, such as especially triethylamine, and/or a heterocyclic base, for example pyridine, 4-dimethylaminopyridine or, preferably, N-methylmoφholine. The base may also be bonded to a polymeric carrier, for example polystyrene, for example may be in the form of a "poly-HUnig base" (= diisopropylamino- methyl-poly styrene) .

Racemisation-reducing reagents, such as N-hydroxybenzotriazole, may also be added, where appropriate also in combination with organic bases, such as those last defined.

The condensation of activated esters, reactive anhydrides or reactive cyclic amides with the corresponding amines is customarily carried out in the presence of an organic base, for example simple tri-lower alkylamines, for example trieti-ylamine or tributylamine, poly-Hϋnig base or one of the above-mentioned organic bases. Where appropriate, a condensation agent is additionally used, for example as described for free carboxylic acids.

The condensation of acid anhydrides with amines can also be effected, for example, in die presence of inorganic carbonates, for example ammonium or alkali metal carbonates or hydrogen carbonates, such as sodium or potassium carbonate or hydrogen carbonate (usually together with a sulfate).

Carboxylic acid chlorides or carboxylic acid 4-nitrophenyl esters, and also the chloro- carbonic acid derivatives derived from the acid of formula H, 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 anhydrous, solvent or solvent mixture, for example in a carboxylic acid amide, for example formamide or dimethylformamide, a halogenated hydrocarbon, for example methylene chloride, carbon tetrachloride or chlorobenzene, a ketone, for example acetone, a cyclic ether, for example tetrahydrofuran, an ester, for example ethyl acetate, or a nitrile, for example acetonitrile, or in a mixture thereof, as appropriate at reduced or elevated temperature, for example in a temperature range of from approximately -40°C to approx¬ imately +100°C, preferably from approximately -10°C to approximately +50°C, and without an inert gas (= protective gas) or under an inert gas atmosphere, for example a nitrogen or argon atmosphere.

Aqueous, for example alcoholic, solvents, for example ethanol, or aromatic solvents, for example benzene or toluene, may also be used. When alkali metal hydroxides are present as bases, a lower alkanone, such as acetone, can also be added where appropriate.

The condensation can also be carried out in accordance with the technique known as solid-phase synthesis which originates from 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 die resulting compounds of formula I having protected functions is effected in accordance with one or more of the methods mentioned under Process f).

Process b) (Formation of an amide bond)

In starting materials of formulae IHa and IV, functional groups, witii the exception of the groups that are intended to participate in the reaction or that do not react under the reaction conditions, are protected independently of one another by protecting groups.

The protecting groups, the free carboxylic acids and the reactive derivatives thereof, the free amines and the reactive derivatives thereof and the processes used for condensation are entirely analogous to those described under Process a) for the formation of an amide bond starting from compounds of formulae H and HI, except that carboxylic acids of formula IV are used instead of those of formula II and amino compounds of formula Hla are used instead of those of formula πi.

The freeing of functional groups protected by protecting groups in the resulting compounds of formula I having protected functions is effected in accordance with one or more of the methods mentioned under Process f). Process c) (Formation of an amide bond)

In starting materials of formulae V and VI, functional groups, with the exception of the groups that are intended to participate in the reaction or that do not react under the reaction conditions, are protected independently of one anotiier by protecting groups.

The protecting groups, the free carboxylic acids and die reactive derivatives thereof, the free amines and me reactive derivatives thereof and the processes used for condensation are entirely analogous to those described under Process a) for the formation of an amide bond starting from compounds of formulae H and HI, except that carboxylic acids of formula V are used instead of those of formula H and amino compounds of formula VI are used instead of those of formula HI.

The freeing of functional groups protected by protecting groups in the resulting compounds of formula I having protected functions is effected in accordance with one or more of the methods mentioned under Process f).

Process d) (Formation of an amide bond)

In starting materials of formulae Vπ and VHI, functional groups, with the exception of the groups that are intended to participate in the reaction or that do not react under the reaction conditions, are protected independently of one another by protecting groups.

The protecting groups, the free carboxylic acids and the reactive derivatives Uiereof, the free amines and die reactive derivatives Uiereof and the processes used for condensation are entirely analogous to those described under Process a) for the formation of an amide bond starting from compounds of formulae H and HI, except that carboxylic acids of formula VII are used instead of tiiose of formula II and amino compounds of formula VIH are used instead of those of formula HI.

The freeing of functional groups protected by protecting groups in the resulting compounds of formula I having protected functions is effected in accordance with one or more of the methods mentioned under Process f)- Process e) (Formation of a tertiary amine - nucleophilic substitution)

In starting materials of formulae IX and X, functional groups, with the exception of the groups that are intended to participate in die reaction or that do not react under the reaction conditions, are protected independently of one another by protecting groups.

The protecting groups and die methods by which tiiey are introduced correspond to those mentioned under Process a).

A nucleofugal leaving group W_] is selected especially 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 hydrochloric, hydrobromic or hydriodic acid, or hydroxy esteri¬ fied by a strong organic sulfonic acid, such as a lower alkanesulfonic acid mat is unsubsti¬ tuted or substituted, for example by halogen, such as fluorine, or an aromatic sulfonic acid, for example a benzenesulfonic acid mat is unsubstituted or substituted by lower alkyl, such as methyl, halogen, such as bromine, and/or by nitro, for example methanesulfonic acid, p-bromotoluenesulfonic acid or p-toluenesulfonic acid, and hydroxy esterified by hydrazoic acid. It is also possible to prepare the relevant starting material of formula DC in situ by replacement of a different corresponding radical W_j, for example of Cl, by a different radical W_j , for example I (preferably with an alkali metal iodide, such as Nal) and subsequent further reaction in the reaction mixture obtained.

The substitution takes place especially in the absence of bases or in the presence of rela¬ tively weak bases, such as suitable sterically hindered nitrogen bases, that is to say steri- cally hindered nitrogen bases that are not tiiemselves capable of nucleophilic substitution under the reaction conditions, for example a corresponding tertiary nitrogen base, such as 4-dimethylaminopyridine, pyridine, triethylamine or ethyldiisopropylamine, or in the presence of hydroxide-containing bases, especially a metal hydroxide, for example an alkali metal hydroxide, such as sodium or potassium hydroxide; or also in the presence of a strong base, for example an alkali metal alcoholate, which can also be prepared in situ from the corresponding alcohol and an alkali metal, or an alkali metal hydride, such as sodium or potassium hydride; in the absence or, preferably, in the presence of suitable solvents or solvent mixtures, such as an aqueous or non-aqueous alcohol, for example emanol or methanol, esters, such as diethyl acetate, ethers, such as dioxane or tetrahydro- furan, carboxylic acid amides, such as dimethylformamide, or acetonitrile; and, when strong bases are used, especially in the presence of aprotic solvents, for example a urea derivative, such as DMPU (= l,3-dimediyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone), an ether, such as diethyl ether, dioxane or tetrahydrofuran, or a carboxylic acid amide, such as dimemylformamide, or a mixture of two or more of those solvents; at temperatures of from 0°C to the reflux temperature, especially from 20°C to the reflux temperature, if necessary under a protective gas, such as nitrogen or argon.

Depending upon the reaction conditions, die substitution may take the form of a first-order or second-order nucleophilic substitution.

Since, in the reaction according to Process e), when using bases, especially strong bases, a number of secondary reactions are possible (for example racemisation by formation of carbanions, etc.), it is possible in that case that Process e) can be carried out only under very precisely controlled reaction conditions (for example cautious metering-in of the base used or of the particular alcoholate, etc.). Possible interfering reactions and suitable reaction conditions will readily be apparent to one skilled in die art.

Process f) (Removal of protecting groups)

The removal of protecting groups that are not constituents of the desired end product of formula I, for example the carboxy-, amino-, hydroxy- and/or mercapto-protecting groups, is effected in a manner known per 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, as well as photolysis, as appropriate stepwise or simultaneously, it being possible also to use enzymatic methods. The removal of the protecting groups is described, for example, in the standard works mentioned hereinabove in me section relating to protecting groups.

For example, protected carboxy, for example lower alkoxycarbonyl (preferably branched in the 1 -position), such as tert-lower alkoxycarbonyl, lower alkoxycarbonyl substituted in the 2-position by a trisubstituted silyl group or in the 1 -position by lower alkoxy or by lower alkylthio, or unsubstituted or substituted diphenylmethoxycarbonyl can be con¬ verted into free carboxy by treatment with a suitable acid, such as formic acid, acetic acid, hydrogen chloride or trifluoroacetic acid, where appropriate with the addition of a nucleo¬ philic compound, such as phenol or anisole. Unsubstituted or substituted benzyloxy¬ carbonyl can be freed, for example, by means of hydrogenolysis, i.e. by treatment with hydrogen in die presence of a metal hydrogenation catalyst, such as a palladium catalyst. Suitably substituted benzyloxycarbonyl, such as 4-nitrobenzyloxycarbonyl, can further¬ more be converted into free carboxy also 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(H) salt, for example chromium(II) chloride, customarily in the presence of a hydrogen-yielding agent tiiat, together with the metal, is capable of producing nascent hydrogen, such as an acid, especially a suitable carboxylic acid, such as an unsubstituted or substituted, for example hydroxy-substituted, lower alkanecarboxylic acid, for example acetic acid, formic acid, glycolic acid, diphenyl- glycolic acid, lactic acid, mandelic acid, 4-chloromandelic acid or tartaric acid, or in die presence of an alcohol or thiol, water preferably being added. By treatment with a reducing metal or metal salt, as described above, 2-halo-lower alkoxycarbonyl (where appropriate after conversion of a 2-bromo-lower alkoxycarbonyl group into a corres¬ ponding 2-iodo-lower alkoxycarbonyl group) or aroylmethoxycarbonyl can also be con¬ verted into free carboxy. Aroylmethoxycarbonyl can be cleaved also by treatment with a nucleophilic, preferably salt-forming, reagent, such as sodium thiophenolate or sodium iodide. The carboxy group can be freed from 1-aryl-lower alkoxycarbonyl, for example arylmethoxy carbonyl, such as benzyloxycarbonyl, also by hydrolysis in the presence of a base, such as an alkali metal hydroxide, for example sodium or potassium hydroxide. 2-(Tri-substituted silyl)-lower alkoxycarbonyl, such as 2-tri-lower alkylsilyl-lower alkoxy¬ carbonyl, can also be converted into free carboxy by treatment with a salt of hydrofluoric acid tiiat yields die fluoride anion, such as an alkali metal fluoride, for example sodium or potassium fluoride, where appropriate in the presence of a macrocyclic polyetiier ("crown ether"), or with a fluoride of an organic quaternary base, such as a tetra-lower alkyl- ammonium 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, N,N-dimethylformamide or N,N-di- methylacetamide. Carboxy protected in the form of organic silyloxycarbonyl, such as tri- lower alkylsilyloxycarbonyl, for example trimethylsilyloxycarbonyl, can be freed in customary manner by solvolysis, for example by treatment with water, an alcohol or an acid, or, furthermore, a fluoride, as described above. Esterified carboxy can also be freed enzymatically, for example by means of esterases or suitable peptidases, for example esterified arginine or lysine, such as lysine methyl ester, using trypsin. Carboxy protected in the form of an internal ester, such as in the form of γ-lactone, can be freed by hydrolysis in d e 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 die same time.

A protected amino group is freed in a manner known per se and, according to die nature of the protecting groups, in various ways, preferably by solvolysis or reduction. Lower alkoxycarbonylamino, such as tert-butoxycarbonylamino, can be cleaved in die presence of acids, for example mineral acids, for example a hydrogen halide, such as hydrogen chloride or hydrogen bromide, especially hydrogen bromide, or sulfuric or phosphoric acid, preferably hydrogen chloride, or relatively strong organic acids, such as formic acid, trichloroacetic acid or trifluoroacetic acid, in polar solvents, for example water or a carboxylic acid, such as acetic acid or formic acid, halogenated hydrocarbons, such as chlorinated lower alkanes, for example dichloromethane or chloroform, or ethers, prefer¬ ably cyclic ethers, such as dioxane, or without solvent in organic carboxylic acids tiiat are liquid at the reaction temperature, for example in acetic acid. 2-Halo-lower alkoxy¬ carbonylamino (where appropriate after conversion of a 2-bromo-lower alkoxycarbonyl¬ amino group into a 2-iodo-lower alkoxycarbonylamino group), aroylmethoxycarbonyl- amino or 4-nitrobenzyloxycarbonylamino can be cleaved, for example, by treatment with a suitable reducing agent, such as zinc in die 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 tiiiophenolate, and 4-nitrobenzyloxycarbonylamino also by treatment with an alkali metal dithionite, for example sodium ditiiionite. Unsubstituted or substituted diphenylmemoxycarbonylamino, tert-lower alkoxycarbonylamino or 2-(tri-substituted silyl)-lower alkoxycarbonylamino, such as 2-tri-lower alkylsilyl-lower alkoxycarbonylamino, can be cleaved by treatment with a suitable acid, for example formic acid or trifluoroacetic acid, for example in a halo¬ genated hydrocarbon, such as methylene chloride or chloroform (especially when hydroxy protected by benzyl is not to be freed at the same time); 1-aryl-lower alkoxycarbonyl¬ amino, such as unsubstituted or substituted benzyloxycarbonylamino, can be cleaved, for example, by means of hydrogenolysis, i.e. by treatment with hydrogen in the presence of a suitable hydrogenation catalyst, such as a palladium catalyst, for example bonded to a carrier, such as carbon, preferably in polar solvents, such as di-lower alkyl-lower alkanoylamides, for example dimethylformamide, ethers, such as cyclic ethers, for example dioxane, esters, such as lower alkanoic acid lower alkyl esters, for example ethyl acetate, or alcohols, such as methanol, ethanol or propanol, with methanol being espec- ially preferred, preferably at about room temperature; unsubstituted or substituted triaryl- methylamino or formylamino can be cleaved, for example, 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 die presence of water, and triphenyl- amino ethyl can be cleaved especially by hydrogenolysis witii a noble metal or noble metal oxide as catalyst, such as platinum, palladium or, especially, palladium hydroxide, die catalyst preferably being bonded to a carrier, such as carbon, silica gel or aluminium oxide, in inert solvents, such as an ether, preferably a lower alkyl-lower alkanoate, such as ethyl acetate, at temperatures of from 20° to 80°C, especially from 50° to 70°C, if necessary under elevated pressure, for example approximately from 1 to 10 bar; and an amino group protected in die form of silylamino can be freed, for example, by means of hydrolysis or alcoholysis. An amino group protected by 2-haloacetyl, for example 2-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 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 die free amino group also by treatment with a salt of hydrofluoric acid tiiat yields fluoride anions, as indicated above in connection witii die freeing of a correspondingly protected carboxy group. Likewise, silyl, such as trimethylsilyl or tert-butyl-dimethylsilyl, bonded directly to a hetero atom, such as nitrogen, can be removed using fluoride ions, preferably witii a fluoride of an organic quaternary nitrogen base, such as a tetra-lower alkylammonium fluoride or tri-lower alkyl- aryl-lower alkylammonium fluoride, for example tetraethylammonium fluoride or tetra- butylammonium fluoride, in the presence of an aprotic, polar solvent, such as dimethyl sulfoxide or N,N-dimethylacetamide, or especially an ether, such as tetrahydrofuran, at temperatures of from 0 to 50°C, especially at about room temperature.

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 using mercapto compounds, such as dithiothreitol or mercaptoetiianol, or by treatment with zinc in the presence of an acid, such as acetic acid. The catalytic hydrogenation is preferably carried out in an inert solvent, such as a halogenated hydrocarbon, for example methylene chloride, or in water or in a mixture of water and an organic solvent, such as an alcohol or dioxane, at approximately from 20°C to 25°C, or with cooling or heating. A hydroxy or mercapto group protected by a suitable acyl group, by a tri-lower alkylsilyl group or by unsubstituted or substituted l-aryl(such as l-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 hydrocarbon radical is freed by acidolysis, for example by treatment with a mineral acid or a strong carboxylic acid, for example trifluoroacetic acid. A hydroxy group protected by benzyloxy is freed, for example, by hydrogenolysis, mat is to say by treatment with hydrogen in the presence of a suitable hydrogenation catalyst, such as a palladium catalyst, for example bonded to a carrier, such as carbon, preferably in polar solvents, such as di-lower alkyl-lower alkanoylamides, for example dimetiiylformamide, ethers, such as cyclic ethers, for example dioxane, esters, such as lower alkylalkanoates, for example ethyl acetate, or alcohols, such as methanol, ethanol or propanol, with methanol being especially preferred, preferably at about room temperature. Mercapto protected by pyridyldiphenylmetiiyl can be freed, for example, using mercury(H) salts at pH 2-6 or by zinc/acetic acid or by electrolytic reduction; acetamidomethyl and iso- butyrylamidomediyl can be freed, for example, by reaction with mercury(H) salts at pH 2-6; 2-chloroacetamidomedιyl can be freed, for example, using 1-piperidinothio- carboxamide; and S-ethylthio, S-tert-butylthio and S-sulfo can be freed, for example, by thiolysis with thiophenol, tiiioglycolic acid, sodium tiiiophenolate or 1,4-ditiιioti.reitol. Two hydroxy groups or an adjacent amino and hydroxy group that are protected togetiier by means of a bivalent protecting group, preferably, for example, by a methylene group mono- or di-substituted by lower alkyl, such as lower alkylidene, for example isopropyl- idene, cycloalkylidene, for example cyclohexylidene, or benzylidene, can be freed by acid solvolysis, especially in die presence of a mineral acid or a strong organic acid. A tri- lower alkylsilyl group is likewise removed by acidolysis, for example by a mineral acid, preferably hydrofluoric acid, or a strong carboxylic acid. Hydroxy can be freed from tri-lower alkylsilyloxy preferably also by treatment with a salt of hydrofluoric acid mat 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 eti er"), or with a fluoride of an organic quaternary base, such as a tetra-lower alkyl¬ ammonium 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. 2-Halo- lower alkoxycarbonyl is removed using the above-mentioned reducing agents, for example a reducing metal, such as zinc, reducing metal salts, such as chromium(π) salts, or using sulfur compounds, for example sodium ditiiionite or preferably sodium sulfide and carbon disulfide. Esterified hydroxy groups, for example lower alkanoyloxy, such as acetyloxy, can also be freed by esterases, and acylated amino can be freed, for example, by suitable peptidases.

The temperatures for die freeing of the protected functional groups are preferably from -80°C to the boiling temperature of the reaction mixture, especially from -80° to 110°C, most preferably from -20° to 50°C, for example from 10° to 35°C, such as at about room temperature, or at from 80°C to the boiling temperature of the reaction mixture in question, for example at about 100°C.

When several protected functional groups are present, if desired die protecting groups can be so selected tiiat more than one such group can be removed simultaneously, for example by acidolysis, such as by treatment with trifluoroacetic acid, or witii hydrogen and a hydrogenation catalyst, such as a palladium-on-carbon catalyst. Conversely, the groups can also be so selected tiiat they cannot all be removed simultaneously, but rather can be removed in a desired sequence, me corresponding intermediates being obtained.

Additional Process Steps

In me additional process steps, which are optional, functional groups of the starting compounds tiiat are not intended to participate in the reaction may be unprotected or may be in protected form; for example they may be protected by one or more of the protecting groups mentioned above under Process a). Some or all of die protecting groups may 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 prepared in a manner known per se. For example, salts of compounds of formula I having acid groups may 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-ethylhexanoic acid, with inorganic alkali metal or alkaline earth metal compounds, such as the corres¬ ponding hydroxides, carbonates or hydrogen carbonates, such as sodium or potassium hydroxide, carbonate or hydrogen carbonate, witii corresponding calcium compounds or with ammonia or a suitable organic amine, stoichiometric amounts or only a small excess of the salt-forming agent preferably 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 containing acid and basic salt-forming groups, for example a free carboxy group and a free amino group, can be formed, for example, by neutralisation of salts, such as acid addition salts, to the isoelectric point, for example with weak bases, or by treatment with ion-exchangers.

Salts can be converted in customary manner into the free compounds; metal and ammonium salts can be converted, 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 of compounds of formula I, that is to say mixtures of diastereo- isomers and/or enantiomers, such as, for example, racemic mixtures, can be separated into the corresponding isomers in a manner known per se by suitable separating processes. For example, mixtures of diastereoisomers can be separated into the individual diastereo- isomers by fractional crystallisation, chromatography, solvent partition or other customary processes. Racemates can be separated from one anotiier, after conversion of the optical antipodes into diastereoisomers, for example by reaction witii 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 selec¬ tive reaction of only one of the two enantiomers. This separation can be carried out eitiier at the stage of one of the starting materials or with die compounds of formula I them¬ selves.

In a compound of formula I wherein one of the radicals R_j, R₂ and R₃ or more man one of those radicals is substituted by 1 -phenyl-lower alkoxy, such as benzyloxy, die 1-phenyl- lower alkoxy radical can be removed as described under Process f). The corresponding compounds of formula I containing hydroxy in place of 1 -phenyl-lower alkoxy are obtained.

In an obtainable compound of formula I, a carboxy group present in free or reactive form can be esterified or an esterified carboxy group can be converted into a free carboxy - group.

For the esterification of a carboxy group in a compound of formula I, if desired the free acid can be used or the free acid can be converted into one of the reactive derivatives mentioned above under Process a) and reacted with a corresponding alcohol, or the free acid or a reactive salt, for example the caesium salt, can be reacted with a reactive deriv¬ ative of an alcohol for the esterification. For example, the caesium salt of a carboxylic acid can be reacted witii a halide or organic sulfonic acid ester corresponding to the alcohol (with halogen or the radical of an organic sulfonic acid, such as toluenesulfonic acid, in place of the hydroxy group). The esterification of the carboxy group can also be carried out with other customary alkylating agents, for example with diazomethane, lower alkyl halides, sulfonic acid esters, Meerwein salts or 1 -substituted 3-aryltriazenes.

For the conversion of an esterified carboxy group into the free carboxy group (for example in the case of compounds of formula I in which at least one of the radicals R₂ and R₃ is phenyl substituted by lower alkoxycarbonyl-lower alkyl) it is possible to use one of the methods described above for the removal of carboxy-protecting groups or, if desired, alkaline hydrolysis under customary conditions, such as those mentioned in Process f), preferably in the presence of an alkali metal hydroxide, such as sodium or lithium hydroxide, in suitable solvents or solvent mixtures, such as alcohols, for example methanol or ethanol, water or mixtures thereof.

A lower alkoxycarbonyl-lower alkoxy group that is present as a substituent, for example of phenyl or naphti yl R₂ and/or R₃, can be converted by reduction into a hydroxy-lower alkoxy group (wherein the lower alkyl radical has at least 2 carbon atoms), for example by reduction witii complex hydrides that selectively reduce the carbonyl ester group, under suitable reaction conditions, for example with LiBH₄ in 1 ,2-dimetiιoxyetiιane at tempera¬ tures of from 0°C to the reflux temperature, preferably at approximately from 15° to 30°C.

In a compound of formula I, a free amino or imino group can be acylated, for example by introducing a lower alkoxycarbonyl radical at die nitrogen of piperidinylcarbonyl R,. The acylation is carried out analogously to die methods described above under Process a) or to one of the methods mentioned for protecting groups.

In an obtainable compound of formula I wherein the substituents are as defined and at least one free hydroxy group is present and other functional groups are, if necessary, in protected form, it is possible to etherify the free hydroxy group, for example die hydroxy group on phenyl or naphthyl R₂ and/or on phenyl or naphthyl R₃, which can be etherified by the radical of a lower alkanol, a phenyl-lower alkanol, a lower alkoxycarbonyl-lower alkanol, a carbamoyl-lower alkanol, a pyridyl-lower alkanol, a cyano-lower alkanol, a moφholinyl-lower alkanol or a lower alkoxy-lower alkanol, the mentioned alcohols preferably being used in a form in which a nucleofugal leaving group, for example as defined for Wj in compounds of formula X, is present in place of the hydroxy group.

The etherification is preferably effected with diazomethane or witii a lower alkyl, phenyl- lower alkyl, lower alkoxycarbonyl-lower alkyl, carbamoyl-lower alkyl, pyridyl-lower alkyl, cyano-lower alkyl, moφholinyl-lower alkyl or lower alkoxy-lower alkyl halide or sulfonic acid ester. Preference is given to die reaction witii a corresponding lower alkyl, phenyl-lower alkyl, lower alkoxycarbonyl-lower alkyl, carbamoyl-lower alkyl, pyridyl- lower alkyl, cyano-lower alkyl, moφholinyl-lower alkyl or lower alkoxy-lower alkyl halide, such as chloride, iodide or bromide, in the presence of bases, preferably a hydroxy base, especially a basic metal hydroxide, such as sodium or potassium hydroxide, or, especially, a metal carbonate or hydrogen carbonate, such as sodium, potassium or, espec¬ ially, caesium carbonate, in suitable solvents or solvent mixtures, for example in N,N-di- lower alkyl-lower alkanoylamides, such as dimethylformamide or dimed ylacetamide, ketones, such as lower alkanones, for example acetone, or ethers, such as dioxane, or mixtures thereof, at temperatures of from -10°C to the reflux temperature, preferably from 0° to 60°C, for example at approximately from 0° to 50°C.

In a compound of formula I, groups that correspond to protecting groups, or also suitable radicals R_j apart from hydrogen, can be removed by one of the methods mentioned under Process f). especially by hydrolysis, for example in the presence of bases, such as alkali metal or alkaline earth metal hydroxides, for example lithium or 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 the customary conditions, for example in aqueous solution or in anhydrous solvents, especially in ethers, such as dioxane, at temperatures of from -50°C to the reflux temperature of the corresponding reaction mixture, for example at from 0°C to 50°C, preferably in the presence of a protective gas, such as argon or nitrogen, or by hydrogenolysis (for example in the case of benzyloxycarbonyl radicals), preferably in polar solvents, such as alcohols, for example methanol or ethanol, or esters, such as lower alkyl-lower alkanoates, for example ethyl acetate, at the temperatures last mentioned and in the presence of suitable hydrogenation catalysts, such as a palladium catalyst, which is preferably bonded to a carrier, such as carbon.

In a compound of formula I in which at least one of the radicals R and R₃ is a phenyl group and/or one or more further phenyl rings are/is present, each of which phenyl radicals can also be substituted, as described above, the phenyl radical(s) in question can be selec¬ tively hydrogenated to form corresponding cyclohexyl radicals. The hydrogenation is preferably carried out in die presence of a catalyst that allows the selective hydrogenation of double bonds in d e presence of amide bonds, especially a catalyst consisting of heavy metal oxides, such as a Rh(IH)/Pt(VI) oxide catalyst according to Nishimura (S. Nishi- mura, Bull. Chem. Soc. Japan 33, 566 (I960)), in suitable solvents, especially water, alcohols, such as methanol or ethanol, esters, such as ethyl acetate, or ethers, such as dioxane, for example in methanol, at temperatures of from 0° to 150°C, preferably from 10° to 50°C, for example at room temperature, at hydrogen pressures of from 0.01 to 50 bar, for example at normal or reduced pressure.

In a compound of formula I wherein at least one of die radicals R₂ and R₃ is cyclohexenyl, the cyclohexenyl radical in question can be selectively hydrogenated to form the corres¬ ponding cyclohexyl radical, in suitable solvents or solvent mixtures, preferably dissolved in an alcohol, such as methanol or ethanol, an ester, for example a lower alkanoic acid lower alkyl ester, such as etiiyl acetate, or in a mixture of those solvents, in the presence of a catalyst, for example palladium, which is preferably bonded to a carrier, such as carbon, preferably activated carbon, at preferred temperatures of from 10° to 50°C, preferably at room temperature, at slightly elevated or reduced pressure or, preferably, at normal pressure.

Pharmaceutical Compositions and Metiiods:

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

The pharmacologically acceptable compounds of die present invention may be used, for example, in the preparation of pharmaceutical compositions that comprise an effective amount of the active ingredient together or in admixture witii 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 (human beings 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 condi¬ tion, individual pharmacokinetic data, the disease to be treated and the mode of admin¬ istration.

The invention relates also to pharmaceutical compositions and to a process or a method for treating diseases caused by retroviruses, for example AIDS or the preceding stages thereof, especially when HIV-2 or more especially HTV-1 is the cause of the disease, or analogous diseases in non-human warm-blooded animals caused, for example, by SIV in monkeys or by FTV in cats, or the preceding stages thereof, preferably wherein a compound of formula I or especially F according to the invention is present in an amount that is dierapeutically effective against retroviral diseases, such as AIDS or the preceding stages thereof or analogous diseases in non-human warm-blooded animals, in a pharma¬ ceutical composition that is suitable for administration to a warm-blooded animal, espec¬ ially a human being, for the treatment of a retroviral disease, such as, especially, AIDS, or analogous diseases in non-human warm-blooded animals, or wherein a compound of formula I or especially F is administered in die treatment method to a warm-blooded animal, for example a human being, tiiat (especially on account of one of the mentioned diseases, especially AIDS or the preceding stages thereof or of corresponding diseases in non-human warm-blooded animals) requires such treatment, in an amount that is thera- peutically effective against retroviral diseases, such as AIDS or the preceding stages thereof or also corresponding diseases in non-human warm-blooded animals. The dose to be administered to warm-blooded animals, for example human beings of approximately 70 kg body weight, is from approximately 3 mg to approximately 10 g, preferably from approximately 20 mg to approximately 4 g, for example approximately from 100 mg to 1.5 g per person per day, divided preferably into 1 to 3 single doses which may, for example, be of equal size. Usually, children receive half the adult dose. "Therapeutically effective" means especially that the onset of the particular disease can be slowed down in comparison with untreated patients, at least one symptom can be delayed or alleviated, at least one cell type (for example human CD4 cells) can be completely or partially protected from the disease or the disease can even be cured competely. Accordingly, the invention relates to a pharmaceutical composition that is suitable for the treatment of diseases caused by retroviruses and that comprises a compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, in an amount that is effective against retroviral diseases, and at least one pharmaceutically acceptable carrier.

The pharmaceutical compositions comprise from approximately 1 % to approximately 95 %, 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, dragees, tablets or capsules.

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

Solutions of the active ingredient, and also suspensions or dispersions, and especially isotonic aqueous solutions, dispersions or suspensions, are preferably used, it being possible, for example in the case of lyophilised compositions at comprise the active ingredient alone or together with a carrier, for example mannitol, for such solutions, dispersions or suspensions to be made up prior to use. The pharmaceutical compositions may be sterilised and/or may comprise excipients, for example preservatives, stabilisers, wetting agents and/or emulsifiers, solubilisers, salts for regulating the osmotic pressure and/or buffers, and are prepared in a manner known per se, for example by means of conventional dissolving or lyophilising processes. The said solutions or suspensions may comprise viscosity-increasing substances, such as sodium carboxymediylcellulose, carboxymethylcellulose, dextran, polyvinylpyrrolidone or gelatin.

Suspensions in oil comprise as the oil component the vegetable, synthetic or semi- synthetic oils customary for injection puφoses. There may be mentioned as such espe¬ cially liquid fatty acid esters that contain as the acid component a long-chained fatty acid having from 8 to 22, especially from 12 to 22, carbon atoms, for example lauric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, margaric acid, stearic acid, arachidic acid, behenic acid or corresponding unsaturated acids, for example oleic acid, elaidic acid, erucic acid, brassidic acid or linoleic acid, if desired with the addition of anti- oxidants, for example vitamin E, β-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 a mono-, di- or tri-hydric, alcohol, for example methanol, ethanol, propanol, butanol or pentanol or the isomers thereof, but especially glycol and glycerol. The following examples of fatty acid esters are therefore to be mentioned: ethyl oleate, isopropyl myristate, isopropyl palmitate, "Labrafil M 2375" (polyoxyethylene glycerol trioleate, Gattefosse, Paris), "Miglyol 812" (triglyceride of saturated fatty acids with a chain length of C₈ to C₁₂, Hϋls AG, Germany), but especially vegetable oils, such as cottonseed oil, almond oil, olive oil, castor oil, sesame oil, soybean oil and more especially groundnut oil.

The injection compositions are prepared in customary manner under sterile conditions; die same applies also to introducing the compositions into ampoules or vials and sealing the containers.

Pharmaceutical compositions for oral administration can be obtained by combining the active ingredient with solid carriers, if desired granulating a resulting mixture, and processing the mixture, if desired or necessary, after the addition of appropriate excipients, into tablets, dragee cores or capsules, or by preparing dispersions, preferably with phospholipids, which are introduced into vials. It is also possible for the active ingredients to be incoφorated into plastics carriers that allow the active ingredients to diffuse or be released in measured amounts.

Suitable carriers are especially fillers, such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose preparations and or calcium phosphates, for example tri- calcium phosphate or calcium hydrogen phosphate, and 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, crosslinked polyvinylpyrrolidone, agar, alginic acid or a salt tiiereof, such as sodium alginate. Excipients are especially flow conditioners and lubri¬ cants, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol. Dragέe cores are provided with suitable, optionally enteric, coatings, there being used, inter alia, concentrated sugar solutions which may comprise gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or coating solutions in suitable organic solvents, or, for the preparation of enteric coatings, solutions of suitable cellulose preparations, such as ethylcellulose phthalate or hydroxypropylmethylcellulose phthalate.

Capsules are dry-filled capsules made of gelatin and also soft, sealed capsules made of gelatin and a plasticiser, such as glycerol or sorbitol. The dry-filled capsules may comprise 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 if desired with stabilisers. In capsules the active ingredient is preferably suspended or dissolved in suitable oily excipients, such as conventional vegetable, synthetic or semi- synthetic oils. As such oils there may be mentioned, especially, liquid fatty acid esters that contain as the acid component a long-chained fatty acid, for example of from 8 to 22, especially from 12 to 22, carbon atoms, for example lauric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, margaric acid, stearic acid, arachidic acid, behenic acid or corresponding unsaturated acids, for example oleic acid, elaidic acid, erucic acid, brassidic acid or linoleic acid, where appropriate with the addition of antioxidants, for example vitamin E, β-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 d ereof, but especially ethylene glycol or propylene glycol and glycerol. There may therefore be mentioned as examples of fatty acid esters: etiiyl oleate, isopropyl myristate, isopropyl palmitate, "Labrafil M 2375" (polyoxyethylene glycerol trioleate, Gattefosse, Paris), "Miglyol 812" (triglyceride of saturated fatty acids of chain length C₈ to Cj₂, Hϋls AG, Germany), but especially vegetable oils, such as cottonseed oil, almond oil, olive oil, castor oil, groundnut oil, soybean oil or, especially, sesame oil. Paraffin oil is also possible. Stabilisers, such as emulsifiers, wetting agents or surfactants, binders, such as starch pastes using, for example, corn, wheat, rice or potato starch, gelatin, tragacanth, methylcellulose, hydroxy¬ propylmethylcellulose (preferred), sodium carboxymetiiylcellulose, cyclodextrin(s) and/or polyvinylpyrrolidone, and/or antibacterial agents can be added. Suitable emulsifiers are especially oleic acid, non-ionic surfactants of the fatty acid polyhydroxy alcohol ester type, such as sorbitan monolaurate, monooleate, monostearate or monopalmitate, sorbitan tristearate or trioleate, polyoxyethylene adducts of fatty acid polyhydroxyalcohol esters, such as polyoxyethylene sorbitan monolaurate, monooleate, monostearate, monopalmitate, tristearate or trioleate, polyethylene glycol fatty acid esters, such as polyoxyethyl stearate, polyoxyethylene glycol (300 or 400) stearate, polyethylene glycol 2000 stearate, espec¬ ially ethylene oxide/propylene oxide block polymers of the ®Pluronic type (Wyandotte Chem. Coφ.; Trade Mark of BASF, FRG) or the ®Synperonic type (ICI). If the active ingredient is not soluble in the mentioned oils, it is preferably in the form of a suspension, for example with a particle size of the active ingredient of approximately from 1 to lOO μm.

Dyes or pigments may be added to the tablets or dragee coatings or to the capsule casings, for example for identification puφoses or to indicate different doses of active ingredient. Starting materials:

The present invention relates also to novel starting materials and/or intermediates and to processes for their preparation. The starting materials used and the reaction conditions selected are preferably those which result in the compounds described as being preferred.

All starting materials can preferably be prepared analogously to the processes mentioned in die Examples or, for example, also as described in EP 0 532466 (published 17th March 1993) or EP 0 618 222 (published 5th October 1994); those Applications are incoφorated herein by reference.

In the preparation of all the starting materials, free functional groups that are not intended to participate in the reaction in question may be in unprotected form or, if necessary, in protected form; for example they may be protected by the protecting groups mentioned above under Process a), which can be introduced at suitable stages analogously to the methods mentioned therein. Protecting groups, or rather the protected groups, can be freed at suitable times analogously to the methods described under Process f). Starting materials and intermediates having salt-forming groups can be used in each case as free compounds or in die form of salts, and at any stage salts can be formed or converted into the free compounds again.

Analogously to the process steps described above for the additional process steps, hydroxy-substituted radicals phenyl R₂ and/or R₃ in intermediates can at suitable stages of die reaction be etherified with the radical of a lower alkanol, a phenyl-lower alkanol, a lower alkoxycarbonyl-lower alkanol, a carbamoyl-lower alkanol, a pyridyl-lower alkanol, a cyano-lower alkanol, a moφholinyl-lower alkanol or a lower alkoxy-lower alkanol. The etherification is preferably effected with diazomethane or witii lower alkyl, phenyl-lower alkyl, lower alkoxycarbonyl-lower alkyl, carbamoyl-lower alkyl, pyridyl-lower alkyl, cyano-lower alkyl, moφholinyl-lower alkyl or lower alkoxy-lower alkyl halides or sulfonic acid esters. Preference is given to the reaction with a corresponding lower alkyl, phenyl-lower alkyl, lower alkoxycarbonyl-lower alkyl, carbamoyl-lower alkyl, pyridyl- lower alkyl, cyano-lower alkyl, moφholinyl-lower alkyl or lower alkoxy-lower alkyl halide, such as iodide, bromide or chloride, in the presence of bases, preferably a hydroxy base, especially a basic metal hydroxide, such as sodium or potassium hydroxide, or, especially, a metal carbonate or hydrogen carbonate, such as sodium, potassium or, espec¬ ially, caesium carbonate, in suitable solvents or solvent mixtures, for example in N,N-di- lower alkyl-lower alkanoylamides, such as dimethylformamide or dimethylacetamide, ketones, such as lower alkanones, for example acetone, or ethers, such as dioxane, or mixtures thereof, at temperatures of from -10°C to the reflux temperature, preferably from 0° to 60°C, for example at approximately from 0° to 50°C.

Analogously to the process steps described above for die additional process steps, in inter¬ mediates in which at least one of the radicals R₂ and R₃ is a phenyl group and/or one or more further phenyl rings are/is present, each of which phenyl radicals can also be substi¬ tuted, as described above, d e phenyl radical in question can at suitable stages of the reaction be selectively reduced, that is to say hydrogenated, to form a corresponding cyclohexyl radical. The hydrogenation is preferably carried out in the presence of a catalyst that allows the selective hydrogenation of double bonds in the presence of peptide bonds, especially a catalyst consisting of heavy metal oxides, such as a Rh(IH)/Pt(VI) oxide catalyst according to Nishimura (see Bull. Chem. Soc. Japan 33, 566 (I960)), in suitable solvents, especially water, alcohols, such as methanol or ethanol, esters, such as ethyl acetate, or ethers, such as dioxane, for example in methanol, at temperatures of from 0° to 150°C, preferably from 10° to 50°C, for example at room temperature, and at hydrogen pressures of from 0.01 to 50 bar, for example at normal or reduced pressure.

Analogously to the process steps described above for the additional process steps, in inter¬ mediates wherein at least one of the radicals R₂ and R₃ is cyclohexenyl, the cyclohexenyl radical in question can at suitable stages of die reaction be selectively hydrogenated to form the corresponding cyclohexyl radical, for example in suitable solvents or solvent mixtures, preferably dissolved in an alcohol, such as metiianol or ethanol, an ester, for example a lower alkanoic acid lower alkyl ester, such as ethyl acetate, or in a mixture of those solvents, in the presence of a catalyst, for example palladium, which is preferably bonded to a carrier, such as carbon, preferably activated carbon, at preferred temperatures of from 10° to 50°C, preferably at room temperature, at slightly elevated or reduced pressure or, especially, at normal pressure.

In the formulae, unless the stereochemistry of asymmetric carbon atoms is defined directly by the corresponding bond symbols chosen, the preferred configuration of asymmetric carbon atoms is indicated by the configuration symbol shown in brackets and selected from (S), (R) and (S,R). It is also possible for other isomers or isomeric mixtures to be present instead.

The carboxylic acids of formulae II and IV, or reactive derivatives thereof, are known, are commercially available or can be prepared in accordance with processes known per se.

The compounds of formulae πi and in' are known or can be prepared in accordance witii processes known per se. They can be obtained, for example, from compounds of formula

_D-^_\-^COOH

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 1 -phenyl-lower alkoxy¬ carbonyl, such as benzyloxycarbonyl, (or analogues thereof containing hydrogen in place of Pa, which can then be protected subsequently) by reduction to a compound of formula

(or to the analogue having hydrogen in place of Pa), wherein the radicals are as last defined.

The reduction of amino acid derivatives of formula XI to the corresponding aldehydes XH is effected, for example, by reduction to the corresponding alcohols and subsequent oxida¬ tion to the aldehydes of formula XH.

The reduction to the alcohols is effected especially by hydrogenation of the corresponding acid halides or other activated carboxylic acid derivatives mentioned under Process a), or by reaction of activated carboxylic acid derivatives of compounds of formula XI, espe¬ cially anhydrides with organic carboxylic acids, preferably those of haloformic acid esters, such as chloroformic acid isobutyl ester, (which are preferably obtained by reaction of compounds of formula XI in the presence of basic amines, for example tri-lower alkyl¬ amines, such as triethylamine, in organic solvents, such as cyclic ethers, for example dioxane, at temperatures of from -50° to 80°C, preferably from 0° to 50°C) with complex hydrides, such as alkali metal borohydrides, for example sodium borohydride, in aqueous solution in the presence or absence of the organic solvents last used, at temperatures of from -50° to 80°C, preferably from 0° to 50°C. The subsequent oxidation of the resulting alcohols is preferably effected with those oxidising agents which selectively convert the hydroxy group into an aldehyde group, for example chromic acid or derivatives thereof, such as pyridinium chromate or tert-butyl chromate, dichromate/sulfuric acid, sulfur trioxide in the presence of heterocyclic bases, such as pyridine/SO₃ (preferably dissolved in di-lower alkyl sulfoxides, such as dimethyl sulfoxide, aromatic solvents, such as toluene, or mixtures of those solvents), 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 die 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 Application EP-A-0 236 734, or by reaction with dicarboxylic acid halides, such as oxalyl chloride, and di-lower alkyl sulfoxides, such as dimethyl sulfoxide, in a halogenated hydrocarbon, such as dichloromediane, in the presence of a tertiary nitrogen base, such as triethylamine, at preferred temperatures of approximately from -70° to 0°C, for example at about -60°C.

Direct reduction of die compounds of formula XI to the aldehydes is also possible, 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 alkyl esters, such as etiiyl esters, with complex hydrides, for example boron hydrides, 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 die 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 hydrogen halide, in aqueous solution, if desired in the presence of the solvent previously used, at temperatures of from -40° to 50°C, preferably from -10° to 30°C. The corresponding esters are obtained by reaction of the amino acids witii the corresponding alcohols, for example ethanol, analogously to the conditions used in die condensation under Process b), for example by reaction with inorganic acid halides, such as tiiionyl 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.

For d e synthesis of a compound of formula HI or HI', a compound of formula XH is then reacted witii a reactive tetraalkylsilane, preferably a halomethyl-tri-lower alkylsilane, such as chloromethyltrimethylsilane, in an inert solvent, for example an ether, such as dietiiyl 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, there being obtained a compound of formula

wherein R_j j, R₁₂ and R₁₃ are lower alkyl, for example methyl, and the remaining radicals are as last defined; die resulting compound is converted in d e presence of a Lewis acid, such as boron trifluoride ethyl etherate, in an inert solvent, especially a halogenated hydro¬ carbon, such as methylene chloride or chloroform, 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 protecting group removal, into an olefinic compound of formula

wherein R₂ is as defined for compounds of formula I; an amino-protecting group Pa, for example tert-butoxycarbonyl, is re-introduced into die 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 mediylene chloride or chloroform, at temperatures of from -50° to 80°C, especially from 0° to 35°C, there being obtained a protected amino-olefin of formula

in which the radicals are as last defined; die 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 or chloroform, at temperatures of from -50° to 60°C, especially from -10° to 25°C, and, if necessary, diastereoisomers are separated, there being obtained an epoxide of formula

in which the radicals are as last defined; a suitable malonic acid diester, for example malonic acid dimetiiyl ester or malonic acid dietiiyl ester, is added to the olefin in question, for example by activation of the methylene group of the malonic acid diester by means of an alkali metal, for example sodium, in a polar anhydrous solvent, such as an alcohol, for example methanol or ethanol, at temperatures of from -50° to 80°C, especially from 0° to 35°C, and the solution is treated with an acid, for example a carboxylic acid, such as citric acid, there being obtained a lactone of formula

wherein Rj₄ is lower alkoxy, for example methoxy or etiioxy, and die remaining radicals are as last defined; if desired, in tiiose compounds in which R₂ is phenyl that is unsubsti¬ tuted or substituted as described for compounds of formula I, that radical is reduced to cyclohexyl, especially by hydrogenation, preferably in die presence of catalysts, such as noble metal oxides, for example mixtures of Rh(IH)/Pt(VI) oxides (in accordance witii Nishimura), preferably in polar solvents, such as alcohols, for example methanol, at normal pressure or at up to 5 bar, preferably at normal pressure, at temperatures of from -20° to 50°C, preferably from 10° to 35°C; a compound of formula XVH obtained directly or after hydrogenation is reacted with a reagent that introduces the radical R₃-CH₂-, for example of formula

R₃-CH₂-W (XVIH),

wherein R₃ is as defined for compounds of formula I and W is a nucleofugal leaving group preferably 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 hydrochloric, hydrobromic or hydriodic acid, or by a strong organic sulfonic acid, such as an unsubsti¬ tuted or substituted, for example halo-substituted, such as fluoro-substituted, lower alkane- sulfonic acid or an aromatic sulfonic acid, for example benzenesulfonic acid tiiat is unsub¬ stituted or substituted by lower alkyl, such as metiiyl, halogen, such as bromine, and/or by nitro, for example a methanesulfonic, trimethanesulfonic or p-toluenesulfonic acid, and hydroxy esterified by hydrazoic acid, especially bromide, in an anhydrous polar solvent, for example an alcohol, such as ethanol, in the presence of an alkali metal, for example sodium, at temperatures of from -50° to 80°C, preferably from 0° to 35°C, yielding a compound of formula

wherein the radicals are as last defined; the compound of formula XDC is hydrolysed and decarboxylated, for example by hydrolysis by means of a base, such as an alkali metal hydroxide, for example lithium hydroxide or sodium hydroxide, at temperatures of from -50° to 80°C, preferably approximately from 0° to 35°C, in an organic solvent, for example an ether, such as 1 ,2-dimethoxyethane, or an alcohol, such as ethanol, and subsequent decarboxylation by heating in an inert solvent, preferably a hydrocarbon, for example an aromatic hydrocarbon, such as toluene, at temperatures of from 40° to 120°C, preferably from 70° to 120°C, there being obtained a compound of formula

wherein die radicals are as last defined; the resulting (R,S,S)- and (S,S,S)-isomers are separated by column chromatography, and the (R,S,S)-isomer is used further and, for die puφose of opening d e lactone ring, is reacted witii a base, such as an alkali metal hydroxide, for example lithium hydroxide or sodium hydroxide, in an inert solvent, such as an etiier, for example dimethoxyethane, or an alcohol, such as ethanol, yielding a compound of formula

(XXI)

wherein the radicals are as last defined; there is introduced into die resulting compound a hydroxy-protecting group Py, for example one of the hydroxy-protecting groups mentioned under Process a) under the conditions mentioned tiierein, especially a tri-lower alkylsilyl group with the aid of the corresponding halo-tri-lower alkylsilane, for example tert-butyldimediylchlorosilane, in a polar solvent, such as a di-lower alkyl-lower alkanoyl- amide, such as dimethylformamide, in die presence of a sterically hindered amino compound, such as a cyclic amine, for example imidazole, at temperatures of from -50° to 80°C, preferably from 0° to 35°C, and die carboxy group, which was silylated at the same time, is freed by reaction with a basic metal salt, especially an alkali metal hydroxide or an alkali metal hydrogen carbonate or, preferably, an alkali metal carbonate, such as potassium carbonate, preferably in an alcohol, such as methanol or ethanol, a cyclic ether, such as tetrahydrofuran, in water or, especially, in a mixture of 2 or 3 of those solvents, at preferred temperatures of from 0° to 50°C, especially from 10° to 35°C, yielding a compound of formula

wherein the radicals are as last defined; and a compound of formula IH or HI' having the radicals indicated under Process a) is prepared from a compound of formula XXH, for example by condensation with a compound of formula VI wherein the radicals are as defined under Process c), under conditions analogous to mose indicated for Process a), especially by in situ reaction in the presence of a condensation agent, such as N,N-di- cyclohexylcarbodiimide, cyanophosphonic acid ethyl ester, benzotriazol-l-yl-oxy-tris(di- methylamino)phosphonium hexafluorophosphate or O-benzotriazol-l-yl-N,N,N',N'-tetra- methyluronium hexafluorophosphate, a sterically hindered amine, such as triethylamine or N-methylmoφholine, and, where appropriate, a compound hindering racemisation, such as 1-hydroxybenzotriazole, in a polar solvent, preferably an acid amide, for example a di-lower alkylamino-lower alkanoylamide, such as dimethylformamide, a cyclic ether, such as tetrahydrofuran, or a nitrile, such as acetonitrile, at preferred temperatures of from -50° to 80°C, especially from 0° to 35°C, where appropriate under protective gas, such as argon or nitrogen, and by subsequent protecting group removal of Pa under conditions analogous to those described under Process f) (provided that Pa is not a radical corres¬ ponding to the radical Rj as defined above for compounds of formula I, which would result directly in compounds of formula I) and finally, if desired, die removal of Py and/or further protecting groups under conditions analogous to those described under Process f). Also possible for the preparation of a compound of formula HI or _0_F is the successive condensation of a compound of formula XXII with compounds at introduce the radicals -HN-(CHR₄)-CO- (starting material: the corresponding amino acid H₂N-(CHR₄)-COOH) and -NH-CH₂CH₂-[(R₅, R₅\ Rβ, R₇, R₈, R₈')moφholino] (starting material: the corres¬ ponding amino compound H₂N-CH₂-C(RgR_j0)-[(R₅, R₅', Rg, R₇, R₈, R₈')moφholino]) of the compound of formula HI or HI', under conditions analogous to those mentioned for Process a), preferably by reaction of a compound analogous to the compound of formula (i) V or V, (ii) VH or VH' or (iii) DC or DC tiiat contains hydrogen in place of R_j, witii a compound of formula (i) VI or VF (corresponds to a compound of formula XXH wherein Pa = hydrogen), (ii) VHI or (iii) X, wherein the remaining radicals are each as defined and the starting materials may also be in the form of reactive derivatives, analogously to the conditions mentioned under (i) Process c), (ii) Process d) or (iii) Process e), it being possible for the protecting group Py to be removed from a compound of formula HI or HI' according to one of the methods described under Process f).

The route from an above-mentioned compound of formula XVH to a compound of formula XX may also be as follows:

Hydrolysis of a racemic compound of formula XVH (which can be prepared from the racemate of a compound of formula XV via the corresponding enantiomeric mixture, for example racemate, of a compound of formula XVI) and decarboxylation under conditions analogous to those employed for the hydrolysis and decarboxylation of compounds of formula XDC result in a compound tiiat is analogous to the compound of formula XDC but in which the radicals R₃-CH₂- and R_j4-(C=O)- are absent and which (if there are no centres of asymmetry other than the three shown in formula XDC, which would also make possible the existence of diastereoisomers/mixtures of diastereoisomers) is in die form of a racemate; this is then reacted with a compound of formula XViπ, as defined above, wherein W is one of the above-mentioned nucleofugal leaving groups, especially halogen, such as bromine or chlorine, by deprotonation in the presence of a strong base, such as an alkali metal bis(tri-lower alkylsilyl)amide, for example lithium bis(trimethylsilyl)amide, followed by alkylation with the compound of the formula R₃-CH₂-W (preferably yielding the [l '(S),3(R)-(R₃-CH₂-),5(S)]- and the [l '(R),3(S)-(R₃-CH₂-),5(R)]-compound of formula XX, that is to say a racemate with regard to the mentioned asymmetric carbon atoms).

The afore-mentioned compounds of formula XTV can also be in the (R,S)-configuration at die carbon atom carrying the radical -NH₂ instead of in die (S)-configuration shown, and the compounds of formulae XI, XH, XIH, and especially those of formulae XV, XVI, XVH, XDC, XX, XXI and/or XXH, can also be in the (R,S)-configuration at the carbon atom carrying the radical Pa-NH- instead of in die (S)-confιguration. The afore-mentioned compounds of formulae XV, XVI and XVH can also be in the form of racemates. Other mixtures of the optical antipodes of die formulae shown are also possible. From those racemates or mixtures it is possible to obtain, for example, corresponding compounds of formula V (for example racemates or mixtures of antipodes if Rj does not contain centres of asymmetry) so that in this manner a compound of formula I or F can be obtained wherein eitiier die carbon atom carrying R₂-CH₂- is in the (S)-confιguration, the carbon atom carrying (HO-) is in the (S)-configuration and die carbon atom carrying R₃-CH₂- is in the (R)-configuration (2R,4S,5S), or the mentioned carbon atoms have the opposite configuration (2S,4R,5R); or mixtures of compounds of formula V or I having those two configurations may also be obtained. Corresponding racemic mixtures or mixtures of diastereoisomers can (preferably) be separated into the individual isomers at suitable stages.

A compound of formula XX wherein the radicals are as defined is also prepared from a compound of formula Xπ wherein the radicals are as defined, by reacting an aldehyde of formula Xπ with a 2-halopropionic acid ester, especially a 2-iodopropionic acid lower alkyl ester, such as 2-iodopropionic acid ethyl ester, there being obtained a compound of formula

wherein the radicals are as defined and wherein the carbon atom carrying the radical Pa-NH- may alternatively also be, for example, in the (R,S)-configuration. The reaction is carried out first with the formation of the homoenolate of the 2-halo- propionic acid lower alkyl (such as ethyl) ester in the presence of a mixture of Zn/Cu in a di-lower alkyl-lower alkanoylamide, such as dimethylacetamide, or an aromatic hydro¬ carbon, such as toluene, or mixtures thereof, at temperatures of from 0° to 100°C, espe¬ cially from 20° to 80°C, where appropriate under protective gas, such as argon or nitrogen. In another batch, preferably under protective gas, such as nitrogen or argon, a titanium tetrahalide, such as titanium tetrachloride, is added at from -50° to 50°C, preferably from -40° to 25°C, to a suitable tetra-lower alkyl orthotitanate, such as tetraisopropyl ortho- titanate, in an aromatic solvent, such as toluene or xylene, in the presence of a halogenated hydrocarbon, such as methylene chloride, and die mixture is stirred, tiiere being formed the corresponding dihalotitanium di-lower alkanolate or preferably the trihalotitanium lower alkanolate, especially trichlorotitanium diisopropanolate. The zinc homoenolate solution is added dropwise thereto at temperatures of from -50° to 0°C, especially from -40° to -25°C, and tiien die aldehyde of formula XH in a halogenated hydrocarbon, for example methylene chloride, is added dropwise, the reaction taking place at from -50° to 30°C, preferably approximately from -40° to 5°C, with the formation of a lower alkyl (especially ethyl) ester precursor, especially the etiiyl ester, of die compound of formula XXH!. That ester is then hydrolysed and cyclised to form the compound of formula XXHI, 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 from 70° to 100°C. If necessary, diastereoisomers are separated, for example by chromatography, for example on silica gel with an organic solvent mixture, such as a mixture of alkane and ester, such as lower alkane and lower alkyl-lower alkanoyl ester, such as hexane/ethyl acetate.

From the compound of formula XXHI, the corresponding compound of formula XX is then obtained by deprotonation with a strong base, to produce the carbanion formed at the α-carbon atom adjacent to the oxo group of the lactone, and by subsequent nucleophilic substitution of the radical W of a compound of formula XVIII wherein R₃ and W are as defined above for the preparation of compounds of formula XDC (W is especially bromo), the reaction preferably resulting stereoselectively in the (R)-configuration at the carbon atom carrying the radical R₃-CH₂- in the compound of formula XX. The reaction with the strong base, especially with an alkali metal organosilicon amide compound, for example an alkali metal bis(tri-lower alkylsilyl)amide, such as lithium bis(trimethylsilyl)amide, or with an alkali metal di-lower alkylamide, such as lithium diisopropylamide, is preferably carried out in an inert organic solvent, especially an ether, for example a cyclic ether, such as tetrahydrofuran, or l,3-dimedιyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone (DMPU), or mixtures of those solvents, at temperatures of from -100° to 0°C, preferably from -78° to -50°C, and the nucleophilic substitution is effected in situ by adding die compound of d e formula R₃-CH₂-W, in the same solvent, at temperatures of from -100° to 0°C, preferably from -60° to -40°C.

A compound of formula XTV 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 alkyl ester, such as formic acid ethyl ester, by reaction witii allylamine at temperatures of from 20° to 70°C, especially from 50° to 60°C, into formic acid allylamide. That amide is tiien dehydrated under 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 die presence of a base, for example a tri-lower alkylamine, such as triethylamine, or especially 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. An allyl isocyanide is formed which is converted by reaction with an organolithium salt, for example lower alkyllithium, such as n-butyllithium, into the corresponding lithium salt, 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°C, especially approximately from -100° to -70°C. The lithium salt formed is men reacted in situ witii a compound of die formula R₂-CH₂-W wherein R₂ is as defined for compounds of formula I and W is as defined above for compounds of formula XVTH, 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 at from 0° to 50°C, preferably from 20° to 30°C, yielding an isocyanide of formula

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 concentrated hydro¬ chloric acid, at temperatures of from -20° to 30°C, especially approximately from 0° to 10°C, yielding the compound of formula XIV wherein the radicals are as last defined and wherein the carbon atom carrying the group -NH₂ is preferably in the (R,S)-configuration.

Amino compounds of formula Hla or Hla', or reactive derivatives tiiereof, are known or can be prepared in accordance with processes that are known per se, for example by condensation of amino acids of the formula H-Bj-OH wherein B_j is as defined for compounds of formula III or IH', or reactive derivatives thereof, with amino compounds of formula HI or in', or with reactive derivatives thereof, the reactive derivatives and die condensation conditions being analogous to tiiose described under Process a).

A compound of formula V or V is prepared, for example, from an amino compound of formula XXII, for example by the introduction of a carboxy-protecting group, as described under Process a), and removal of the protecting group Pa, as described under Process f)» by condensation with a carboxylic acid of die formula Rj-OH, or witii a reactive derivative thereof, wherein the radicals are as defined for compounds of formula I.

Compounds of formula VI (or VI') are prepared, for example, from the corresponding amino acids of formula

(especially of formula O

^H ₂ ^JL OH (XXV)),

R₄

wherein the radicals are as defined, or from reactive acid derivatives ti ereof, and from the amino components of formula VHI wherein the radicals are each as defined above, or from reactive derivatives thereof, by condensation analogously to d e metiiods described under Process a) and, where appropriate, with analogous reactive derivatives.

A compound of formula VH (or VH') can be prepared, for example, from a compound of formula V (or V) by condensation with an amino acid of formula XXV (or XXV') that introduces the radical -NH-CH(R₄)-COOH, as last defined. The reaction is carried out analogously to the conditions described under Process a) witii the corresponding free compounds or reactive derivatives tiiereof.

The amino compound of formula VHI is known or is prepared in accordance witii methods that are known per se. For example, compounds of formula VHI wherein at least one of the two radicals R and R_j0 is lower alkyl, and preferably are each lower alkyl, can be prepared, for example, by reacting a cyanohydrin of the formula R R₁₀C(-OH)-CN, wherein at least one of the radicals R and R_j0 is lower alkyl (this definition also applies to the other formulae in is paragraph), with an imino compound of formula X, as defined above, in the presence of a dehydrating agent, such as diphosphorus pentoxide or MgSO₄, at elevated temperature, for example at approximately 60°C, to form a moφholino compound of the formula R₉R₁₀C[-(R₅, R₅', Rg, R₇, R₈, R₈')moφholino]-CN, then converting the cyano group therein, for example with a strong acid, such as sulfuric acid (preferably in a proportion of from 20 to 90 % by volume in the reaction mixture) at temperatures of from 80 to 110°C, into the amide group and then reacting the latter in a suitable solvent, such as an ether, for example tetrahydrofuran, with a complex hydride, such as lithium aluminium hydride, preferably at elevated temperatures, especially at reflux temperature, to form the corresponding amine of formula VIH.

Compounds of formula IX (or IX') are known or can be prepared in accordance with processes that are known per se and are obtained, for example, by condensation of a compound of formula VII (or VIF) wherein the radicals are as defined, and an (if neces- sary hydroxy-protected) amine of formula

or a reactive derivative tiiereof, wherein the radicals are as defined for compounds of formula I, under reaction conditions analogous to those described under Process a). In compounds of formula XXVI, preferably at least one of the radicals R_$ and R₁₀ is hydrogen, preferably botii. The hydroxy group in die resulting precursor of the compound of formula IX (or DC) can then be converted into the nucleofugal leaving group W_j by customary methods, for example by esterification with a corresponding inorganic or organic acid.

Compounds of formula X or Xa are known and are commercially available or can be prepared in accordance witii processes that are known per se.

Compounds of formula XVHI and of the formula R₂-CH₂-W are known or can be prepared in accordance witii processes that are known per se or are commercially avail¬ able. There may be mentioned as an example the preparation of a compound of formula XVHI or R₂-CH₂-W wherein W is Br or I, by reaction of the corresponding precursor wherein W is Cl witii an alkali metal iodide or bromide, such as Nal, for example in ketones, such as a lower alkanone, for example acetone, at temperatures of from 0 to 50°C, especially at room temperature, or with a phosphoric acid tri- or penta-iodide or -bromide, such as PBr₃, for example in hydrocarbons, for example an aromatic hydro¬ carbon, such as toluene, at preferred temperatures of from 0 to 40°C, for example at room temperature. The precursor (W = Cl) is commercially available, is known or can be prepared in accordance witii processes that are known per se. For example, a precursor that contains a hydroxy group in place of Cl (=W) can be reacted to form the corres¬ ponding chlorinated compound by reaction with PC1₃, PCl₅ or especially SOCl₂ in the presence of a tertiary nitrogen base, for example poly-Hϋnig base or pyridine, in suitable solvents, for example an ether, such as diethyl ether, or a halogenated hydrocarbon, such as methylene chloride or chloroform, at preferred temperatures of from -10° to 30°C, preferably from 0° to 25°C. The precursors that contain a hydroxy group in place of W are known, can be prepared in accordance with processes that are known per se or are commercially available. The remaining starting compounds are known, are prepared in accordance witii processes that are known per se and/or can be purchased.

The following applies generally to all the processes mentioned hereinabove and herein¬ below:

Owing to die close relationship between d e compounds of formula I and their salts and starting materials (starting compounds and intermediates) in free form and in the form of their salts, hereinabove and hereinbelow any reference to die free compounds or their salts should be understood as including also the corresponding salts or free compounds, respec¬ tively, as appropriate and expedient.

All the above-mentioned process steps can be carried out under reaction conditions that are known per se, preferably the reaction conditions specifically mentioned, in die absence or, usually, in d e presence of solvents or diluents, preferably those solvents or diluents which are inert towards die reagents used and are solvents therefor, in the absence or presence of catalysts, condensation agents or neutralising agents, for example ion- exchangers, such as cation-exchangers, for example in the H⁺ form, and depending upon the nature of the reaction and/or the reactants, at reduced, normal or elevated temperature, for example in a temperature range of from approximately -100°C to approximately 190°C, preferably from approximately -80°C to approximately 150°C, for example at from -80 to -60°C, at room temperature, from -20 to 40°C or at reflux temperature, under atmos¬ pheric pressure, or in a closed vessel, where appropriate under reduced or elevated pres¬ sure, in an inert atmosphere, for example under an argon or nitrogen atmosphere, and/or with the exclusion of light.

At all stages of the reaction it is possible, if desired, for any isomeric mixtures which may occur to be separated into the individual isomers, for example diastereoisomers or enantio¬ mers, or into any desired mixtures of isomers, for example racemates or diastereoisomeric mixtures, for example analogously to the methods described under "Additional Process

Steps".

In certain cases, for example in the case of hydrogenation, it is possible to obtain stereo- selective reactions, so that, for example, individual isomers can be obtained more easily. The solvents from which the solvents suitable for any particular reaction can be selected include, for example, water, esters, such as lower alkyl-lower alkanoates, for example ethyl acetate, ethers, such as aliphatic ethers, for example diethyl etiier or 1 ,2-dimethoxy- ethane, or cyclic ethers, for example tetrahydrofuran, liquid aromatic hydrocarbons, such as benzene, toluene or o-, m- or p-xylene, liquid acyclic hydrocarbons, such as hexane or heptane, alcohols, such as metiianol, ethanol or 1- or 2-propanol, nitriles, such as aceto¬ nitrile, halogenated hydrocarbons, such as methylene chloride or chloroform, acid amides, such as dimethylformamide or dimethylacetamide, ketones, such as lower alkanones, for example acetone, heterocyclic solvents, for example bases, such as heterocyclic nitrogen bases, for example pyridine, or l,3-dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidone (DMPU), carboxylic acids, such as acetic acid or formic acid, carboxylic acid anhydrides, such as lower alkanoic acid anhydrides, for example acetic anhydride, cyclic, linear or branched hydrocarbons, such as cyclohexane, hexane or isopentane, or mixtures of those solvents, for example aqueous solutions, unless indicated to the contrary in the description of die processes. Such solvent mixtures can also be used in working-up, for example by chromatography or partition.

The compounds, including tiieir salts, may also be obtained in die form of hydrates, or their crystals may include, for example, the solvent used for crystallisation.

The working-up which follows reactions is carried out in accordance with processes that are known per se, preferably analogously to the methods described in the Examples.

The invention relates also to those forms of the process in which a compound obtainable as intermediate at any stage of die process is used as starting material and d e remaining process steps are carried out, or in which a starting material is formed under the reaction conditions or is used in the form of a derivative, for example in protected form or in the form of a salt, or a compound obtainable in accordance with the process of die invention is produced under the process conditions and is processed further in situ. In the process of the present invention it is preferable to use those starting materials which result in the compounds described at the beginning as being especially valuable. Reaction conditions analogous to those mentioned in the Examples are especially preferred.

If necessary or desired, protected starting compounds can be used at any stage of the process and the protecting groups can be removed at suitable stages of the reaction. Protecting groups and the manner in which they are introduced and removed are as described under Processes a) and f).

Examples:

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). Where no temperature is specified, die reactions mentioned below take place at approximately room temperature. The R_f values, which indicate die ratio of the seepage propagation of the substance in question to the seepage propagation of the eluant front, are determined on thin-layer silica gel plates (Merck, Darmstadt, FRG) by thin-layer chromatography (TLC) using the following eluant systems:

TLC eluant systems:

A ethyl acetate

B methylene chloride/metiianol 9: 1

C hexane/ethyl acetate 1 : 1

D hexane/ethyl acetate 2: 1

E hexane/ethyl acetate 3:1

F methylene chloride/metiianol 12:1

G hexane/eti yl acetate 6: 1

H methylene chloride/THF 2: 1

I methylene chloride/ether 25:1

J hexane/ethyl acetate 1:2

K chloroform/methanol water/acetic acid 85: 13: 1.5:0.5

L methylene chloride/metiianol 10:1

M methylene chloride/metiianol 15:1

N ethyl acetate/methanol 9: 1

The abbreviation "R_f(A)", for example, indicates that the R_f value was determined in solvent system A. The quantitative ratio of solvents to one another is always given in parts by volume. The above-mentioned letter codes for TLC systems are in some cases also used, for example, to indicate the eluants in column chromatography.

The abbreviation "R^A)", for example, indicates tiiat die R_f value was determined in solvent system A. The quantitative ratio of solvents to one another is always given in parts by volume (v/v). The quantitative ratios of the solvents used in die definition of die eluant systems for column chromatography are also given in parts by volume.

HPLC gradients:

I 20 % → 100 % a) in b) for 35 min.

H 20 % → 100 % a) in b) for 20 min.

IH 5 % → 40 % a) in b) for 15 min.

eluant a): acetonitrile + 0.05 % TFA; eluant b): water + 0.05 % TFA. Column (250 x 4.6 mm) filled with "reversed phase" material C_jg-Nucleosil® (5 μm average particle size, silica gel covalentiy derivatised with octadecylsilanes, Macherey & Nagel, Dϋren, FRG). Detection by UV-absoφtion at 215 nm. The retention times (t_Ret) are given in minutes. Flow rate 1 ml/min.

Mass spectroscopic measurements are obtained as a rule according to die "Fast Atom Bombardment" metiiod. The mass data relate to the protonated molecule ion (M+H)⁺, unless stated otherwise.

The values for IR spectra are given in cm"¹, and the relevant solvent is given in round brackets.

The abbreviations customary in peptide chemistry are used to refer to bivalent radicals of natural α-amino acids. If known, the configuration at the α-carbon atom is indicated by the prefix (L)- or (D)-. (L)-isoleucine ((L)-Ile) has the 2(S),3(S)-configuration.

The other shortened names and abbreviations used have the following meanings:

abs. absolute (indicates that the solvent is anhydrous atm atmospheres ( 1 atm corresponds to 1.013 bar) Boc tert-butoxycarbonyl

BOP benzotriazol- 1 -yloxy-tris(dimethyl- amino)phosphonium hexafluorophosphate

DCC dicyclohexylcarbodiimide

DIPE diisopropyl eti er

DMF dimetiiylformamide

DMPU 1 ,3-dime yl-3 ,4,5 ,6-tetrahydro-2( lH)-pyrimidinone ether diethyl ether sat. saturated h hour(s)

HBTU O-benzotriazol- 1 -yl-N,N,N' ,N' - tetramethyluronium hexafluorophosphate

HOBT 1 -hydroxybenzotriazole

HV high vacuum min minute(s)

MS mass spectroscopy

NMM N-methylmoφholine

RT room temperature

RE rotary evaporator brine saturated sodium chloride solution

THF tetrahydrofuran

TBAF tetrabutylammonium fluoride trihydrate

Z benzyloxycarbonyl

Example 1: 5(S)-(Boc-amino)-4(S)-hγdroxγ-6-cvclohexvl-2(R)-(p-fluoro-phenyl- methγ-)-hexanoyl-(L)-Val-N-(2-(morpholin-4-v-)-ethv-)amide

Under a nitrogen atmosphere, 294 mg (0.931 mmol) of TBAF are added to a solution of 355 mg (0.465 mmol) of 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-cyclo- hexyl-2(R)-(p-fluoro-phenylmethyl)-hexanoyl-(L)-Val-N-(2-(moφholin-4-yl)-ethyl)amide in 4.5 ml of DMF and the reaction mixture is stirred for 16 h at RT. It is poured onto water and extracted with 4 portions of ethyl acetate. The organic phases are washed with sat. NaHCO₃ solution, water and brine, dried with Na₂SO₄ and concentrated by evaporation. Digestion twice from DIPE yields the pure title compound: t_Ret(I)=19.3 min; FAB-MS (M+H)⁺=649.

The starting material is prepared as follows: 1 a) Z-(D- Val-N-(2-(morpholin-4-yl)-ethyl)amide

While cooling with ice, 5.02 g (20 mmol) of Z-(L)-valine are dissolved in 125 ml of methylene chloride and activated with 4.13 g (20 mmol) of DCC. After 20 min, a solution of 2.6 ml (20 mmol) of 4-(2-aminoethyl)-moφholine (Fluka; Buchs/Switzerland) in 125 ml of methylene chloride is added dropwise and the reaction mixture is stirred for 24 h at RT. The reaction mixture is filtered, die filtrate is washed with sat. NaHCO₃ solution, water and brine, dried and concentrated by evaporation. Digestion in ether results in the title compound: TLC R_f(B)=0.5.

1 b) H-(L)- Val-N-(2-(morpholin-4-yl)-ethyl)amide

6.3 g (17.3 mmol) of Z-(L)-Val-N-(2-(moφholin-4-yl)-ethyl)amide are hydrogenated in 300 ml of methanol in the presence of 1.5 g of 10 % Pd/C at RT under reduced pressure. The catalyst is removed by filtration, the filtrate is concentrated by evaporation and the residue is dissolved in metiiylene chloride and filtered until clear. Column chroma¬ tography (SiO₂, methylene chloride -→ methylene chloride/metiianol 19:1 — ♦ 9:1 -→ 4:1) of the evaporation residue and stirring in hexane/ether results in the title compound: TLC R,{B)=0.13; FAB-MS (M+H)⁺=230.

lc) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-cyclohexyl-2(R)-(p-fluoro- phenylmethyl)-hexanoyl-(L)-Val-N-(2-(morpholin-4-yl)-ethyl)amide

Under protective gas, 263 mg (0.477 mmol) of 5(S)-(Boc-am_no)-4(S)-(tert-butyldi- methylsilyloxy)-6-cyclohexyl-2(R)-(p-fluoro-phenylmethyl)-hexanoic acid (see Exam¬ ple lm) for preparation) are dissolved in 4.0 ml (1.19 mmol) of a 0.3M solution of NMM in DMF and activated with 232 mg (0.524 mmol) of BOP and 71 mg (0.524 mmol) of HOBT. After 30 min at RT, 131.1 mg (0.572 mmol) of H-(L)-Val-N-(2-moφholin-4-yl- ethyl)amide are added thereto and die reaction mixture is stirred for 16 h to complete the reaction. The reaction mixture is concentrated by evaporation under HV and the residue is partitioned between 3 x ethyl acetate, water, 2 x sat. NaHCO₃ solution, water and brine. Drying of the organic phases with Na SO₄ and concentration by evaporation yield the title compound: TLC R_f<A)=0.19; t_Ret(I)=31.8 min; FAB-MS (M+H)⁺=763.

ld) N-3(S)-(Boc-amino)-2(R_<S)-hydroxy-4-phenyl-l-trimethylsilyl-butane

24.7 g of magnesium are placed in 100 ml of abs. ether and, over a period of 35 min, a small quantity of iodine and, at the same time, 132.5 ml of chloromethyltrimethylsilane and 300 ml of ether are added thereto, the temperature being maintained at 38°C by means of an ice-bath. The resulting reaction mixture is then stirred at RT for 1.5 h. After cooling to -60°C, a suspension of 48.6 g of N-(S)-Boc-phenylalaninal (preparation: D. J. Kempf, J. Org. Chem. 51_., 3921 (1986)) in 1.1 1 of ether is added within a period of 40 min. Over a period of 90 min, the reaction mixture is heated to RT and is stirred at tiiat temperature for a further 90 min. It is then poured onto 2 1 of ice- water and 1.5 1 of 10 % aqueous citric acid. The separated aqueous phase is extracted twice witii 500 ml of ether. All the ether extracts are washed with 500 ml of a 10 % citric acid solution and twice witii brine. After drying over sodium sulfate, concentration is carried out in vacuo and die resulting title compound is further used without additional purification. TLC R_f (hexane/ethyl acetate 4: 1)= 0.6; FAB-MS (M+H)⁺= 338.

le) l-Phenyl-3-butene-2(S)-amine

35.6 ml of an approximately 48 % solution of boron trifluoride ethyl etherate are added at 5°C, within a period of 10 min, to a solution of 18.8 g of N-3(S)-(Boc-amino)-2-(R,S)- hydroxy-4-phenyl-l-trimethylsilyl-butane in 420 ml of methylene chloride. The reaction mixture is then stirred at RT for 16 h, is cooled to 10°C and 276 ml of a 4N sodium hydroxide solution are added thereto witiiin a period 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 further used without additional purification. TLC R_f (K)= 0.15; IR (methylene chloride) (cm'¹): 3370, 3020, 2920, 1640, 1605.

If) N-Boc-l-phenyl-3-butene-2(S)-amine

21.5 g of l-phenyl-3-butene-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 at RT for 1.5 h, the reaction mixture is concentrated to 100 ml, then diluted with 1.5 1 of ether and washed, in succession, twice witii 400 ml of 10 % citric acid, once with 400 ml of water, once with 400 ml of saturated aqueous sodium hydrogen carbonate solution and twice with brine, and dried over sodium sulfate. After concentration of the solvent by evaporation, the residue is purified by column chromatography (SiO₂, hexane/ethyl acetate: 95/5 to 80/20) and the title compound is crystallised from hexane. M.p. 67-68°C; TLC R_f (hexane/ethyl acetate 4:1)= 0.4; FAB-MS (M+H)⁺= 248.

lg) 2(R)-ri(S)-(Boc-amino)-2-phenylethvn-ox-rane

A solution of 9.74 g of m-chloroperbenzoic acid in 50 ml of methylene chloride is added at 0 to 5°C, within a period of 15 min, to a solution of 1.45 g of N-Boc-1 -phenyl- 3-butene-2(S)-amine in 20 ml of methylene chloride. After stirring at the same tempera¬ ture for 18 h, the reaction mixture is stirred for a further 8 h to complete die reaction, while warming to RT, and is 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 carbonate solution, with sodium thiosulfate solution and brine, and dried over sodium sulfate. After concentration of the solvent, the title compound is purified by column chromatography (SiO₂, hexane/ethyl acetate: 4/1) and crystallised from hexane. M.p. 51-52°C; TLC R_f (hexane/ethyl acetate 4:1)= 0.33; FAB-MS (M+H)⁺= 264.

lh) 5(S)-ri(S)-(Boc-amino)-2-phenylethyll-3(R,S)-carbethoxy-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 (approx. 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 within a period of 10 min. After stirring at RT for 5 h, the reaction mixture is poured onto 1.5 1 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 concentration of the solvent, the title compound is obtained by means of column chromatography (SiO₂, hexane/ethyl acetate: 4/1). TLC R_f (hexane/ethyl acetate 4: 1)= 0.22; FAB-MS (M+H)⁺= 378.

li) 5(S)-ri(S)-(Boc-amino)-2-cyclohexylethyn-3(R_<S)-carbethoxy-dihvdrofuran-2- (3H)-one

10 g of 5(S)-[l(S)-(Boc-amino)-2-phenylethyl]-3(R,S)-carbethoxy-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 (approx. 1 atm). The catalyst is filtered off through Celite (diatomaceous earth, Sigma, Switzerland) and washed with ethanol, and the filtrate is concentrated by evaporation. TLC R^hexane/ethyl acetate 4: 1 ) = 0.23. li) 5(S)-ri(S)-(Boc-aπιino)-2-cyclohexylethvn-3(R,S)-carbethoxy-3-(p-fluoro-phenyl- methyl)-dihydrofuran-2-(3H)-one

Under a nitrogen atmosphere, 0.68 g of Na are dissolved in 100 ml of EtOH. A solution of 10.2 g of 5(S)-[l(S)-(Boc-amino)-2-cyclohexylethyl]-3(R,S)-carbethoxy-dihydrofuran-2- (3H)-one and 5.39 g of p-fluoro-benzyl bromide (Fluka, Buchs, Switzerland) in 80 ml of ethanol is added dropwise thereto at RT. After 1.5 h, according to TLC not all of the lactone has reacted and therefore a further 0.2 g of sodium and 0.7 g of p-fluoro-benzyl bromide are added. After 16 h, the reaction mixture is poured onto a mixture of 10 % citric acid and ice and extracted 3 times with ether. The organic phases are washed twice witii water and with brine, dried with Na₂SO₄ and concentrated by evaporation. After the addi¬ tion of hexane/ethyl acetate, the oily crude product partially crystallises out under the effect of ultrasound to yield the title compound (ratio of die diastereoisomers 4: 1). Column chromatography (SiO₂, hexane/etiiyl acetate 4: 1) of the mother liquor yields further title compound (ratio of the diastereoisomers approx. 1:4). TLC R exane/ethyl acetate 4: 1) = 0.29; FAB-MS (M+H)⁺=492.

1 k) 5(S)-H (S)-(Boc-amino)-2-cyclohexylethyn-3(R)-(p-fluoro-phenylmethyl)-dihydro- furan-2-(3H)-one and 5(S)-ri(S)-(Boc-amino)-2-cvclohexylethyn-3(S)-(p-fluoro- phenyImethyl)-dihydrofuran-2-(3H -one

91 ml of IM lithium hydroxide solution are added dropwise at RT, over a period of 5 min, to 10.3 g of 5(S)-[l(S)-(Boc-amino)-2-cyclohexylethyl]-3(R,S)-carbethoxy-3-(ρ-fluoro- phenylmethyl)-dihydrofuran-2-(3H)-one (ratio of the diastereoisomers approx. 1:1) in 174 ml of 1 ,2-dimethoxyethane, and the reaction mixture is stirred at RT for 15 h. After partial concentration of 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, dried over sodium sulfate and concentrated by evaporation. The residue so obtained is taken up in 350 ml of toluene and boiled under reflux for 9 h. After concentration by evaporation once more, a mixture of the title compounds is obtained. Column chromatography (SiO₂, hexane/ethyl acetate 9: 1 — ^» 4:1) yields first the 3(R)-epimer [TLC R,(E)=0.45], followed by the 3(S)-epimer [TLC R E)=0.41].

ll) 5(S)-(Boc-amino)-4(S)-hydroxy-6-cyclohexyl-2(R)-(p-fluoro-phenylmethyl)-hexan- oic acid

19.6 ml of IM lithium hydroxide solution are added dropwise at from 20 to 25°C to 2.05 g of 5(S)-[ 1 (S)-(Boc-amino)-2-cyclohexylethyl]-3(R)-(p-fluoro-phenylrnethy l)-dihydro- furan-2-(3H)-one in 78 ml of dimethoxyethane and 39 ml of water. After stirring at RT for 3 h, the reaction mixture 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 % citric acid and extracted four times with methylene chloride. The combined organic phases are washed witii brine and dried over Na₂SO₄. After concentration, the title compound is obtained in the form of a foam, which is used in die next step without further purification.

lm) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-cycIohexyl-2(R)-(p-fluoro- phenylmethyD-hexanoic acid

A solution of 2.01 g of 5(S)-(Boc-amino)-4(S)-hydroxy-6-cyclohexyl-2(R)-(p-fluoro- phenylmethyl)-hexanoic acid in 6.4 ml of DMF is stirred with 2.73 g of imidazole and 3.39 g of tert-butyldimethylchlorosilane at RT for 18 h. The reaction mixture is then poured onto ice-water and extracted with 3 portions of ethyl acetate, and the combined organic phases are washed with 10 % citric acid solution, water and brine, dried with sodium sulfate and concentrated by evaporation. An oil is obtained. This oil is dissolved in 68 ml of methanol and 23 ml of THF and, at RT, a solution of 4.1 g of potassium carbonate in 23 ml of water is added thereto and the mixture is stirred for 1 h and finally is partially concentrated by evaporation at RT. The aqueous residue is poured onto 10 % citric acid solution and ice and extracted 3 times witii ethyl acetate, and the organic phases are washed twice with water and brine, dried with sodium sulfate and concentrated by evaporation. Column chromatography (SiO₂, hexane/ethyl acetate 5:1 — * 2:1) yields the title compound: TLC RAΕ)=0.2; FAB-MS (M+H)⁺=552.

Example 2: 5(S)-[Z-(L)-Asn-aminol-4(S)-hydroxy-6-cyclohexyl-2(R)-(p-fluoro- phenylmethyl)-hexanoyl-(L)-Val-N-(2-(morpholin-4-yl)-ethyl)amide

Under a nitrogen atmosphere, 0.49 ml (2.9 mmol) of Hϋnig base is added to a solution of 0.29 mmol of 5(S)-amino-4(S)-hydroxy-6-cyclohexyl-2(R)-(p-fluoro-phenylmethyl)- hexanoyl-(L)-Val-N-(2-(moφholin-4-yl)-ethyl)amide hydrochloride salt in 7.6 ml of DMF and the mixture is reacted with 170 mg (0.44 mmol) of Z-asparagine p-nitrophenyl ester (Bachem, Bubendorf/Switzerland). After 18 h at RT, the precipitate which has formed is filtered off and washed with methylene chloride. Suspension in DMF and dilution with DIPE followed by filtration yields the title compound as residue: t_Ret(I)=16.4 min; FAB-MS (M+H)⁺=797. The starting material is prepared as follows:

2a) 5(S)-Amino-4(S)-hydroxy-6-cycIohexyl-2(R)-(p-fluoro-phenylmethyl)-hexanoyl- (L)-Val-N-(2-(morpholin-4-yl)-ethyI)amide hydrochloride salt

Under protective gas, 10 ml of 4N HC1 in dioxane are added to 160 mg (0.29 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6-cyclohexyl-2(R)-(p-fluoro-phenyl-methyl)-hexanoyl- (L)-Val-N-(2-(moφholin-4-yl)-ethylamide (Example 1) in 10 ml of dioxane and the mixture is stirred at RT for 1 h. Lyophilisation of the reaction mixture results in the title compound, which is used directly in the next step.

Example 3: 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-(p-fluoro-phenylmethyl)- hexanoyl-(I_)-Val-N-(2-(morpholin-4-yl)-ethyl)amide

Analogously to Example 1, 229 mg (0.303 mmol) of 5(S)-(Boc-amino)-4(S)-(tert-butyldi- methylsilyloxy)-6-phenyl-2(R)-(p-fluoro-phenylmethyl)-hexanoyl-(L)-Val-N-(2-(mor- pholin-4-yl)-ethyl)amide are desilylated in 3 ml of DMF with 480 mg (1.51 mmol) of TBAF. Column chromatography (SiO₂, ethyl acetate/THF 9:1) and digestion from DIPE yields the title compound: t_Ret(I)=16.7 min; FAB-MS (M+H)⁺=643.

The starting material is prepared as follows:

3a) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(p-fluoro- phenylmethyl)-hexanoyl-(L)-VaI-N-(2-(morpholin-4-yl)-ethyl)amide

Under a nitrogen atmosphere, 200 mg (0.366 mmol) of 5(S)-(Boc-amino)-4(S)-(tert-butyl- dimethylsilyloxy)-6-phenyl-2(R)-(p-fluoro-phenylmethyl)-hexanoic acid [see Example 3f) for preparation] are dissolved in 4.5 ml (1.35 mmol) of 0.3M NMM/DMF, activated at RT with 268 mg (0.605 mmol) of BOP and 82 mg (0.605 mmol) of HOBT and, after 30 min, reacted with 151 mg (0.66 mmol) of H-(L)-Val-N-(2-(moφholin-4-yl)-ethyl)amide (Example lb). After 34 h, the reaction mixture is worked up analogously to Example lc). Digestion of the crude product from DIPE/hexane yields the title compound: t_Ret(I)=27.3 min.

3b) 2-Iodopropionic acid ethyl ester

A suspension of 170 ml of 2-bromopropionic acid ethyl ester (Fluka; Buchs/Switzerland) and 950 g of sodium iodide in 1.8 1 of acetone is stirred at 60°C for 20 h. The reaction mixture is filtered, and the filtrate is partially concentrated by evaporation, poured onto approximately 2.5 1 of ether, washed with 1.0 1 of 1 % sodium thiosulfate solution and finally with brine, dried with sodium sulfate and concentrated by evaporation. Distillation (83°C; 20 mbar) yields the pure title compound: MS (M)⁺=228; ^lH-NMR (200 MHz, CDC1₃): 4.17 (q, 7 Hz, 2 H), 3.34 and 2.97 (2t, 7 Hz, 2x 2H), 1.28 (t, 7 Hz, 3 H).

3c) 5(S)-ri(S)-(Boc-amino)-2-phenylethyl1-dihvdrofuran-2-(3H)-one

(see also A.E. DeCamp, A.T. Kawaguchi, R.P. Volante, and I. Shinkai, Tetrahedron Lett. 32, 1867 (1991)). Under a nitrogen atmosphere, 8.03 g of Zn/Cu (preparation: see R.D. Smith, H.E. Simmons, W.E. Parham, M.D. Bhavsar, Org. Synth., Coll. Vol 5, 855 (1973)) and 12.96 ml of dimethylacetamide are added to a solution of 17.4 g of 2-iodopropionic acid ethyl ester in 130 ml of toluene and the mixture is then stirred vigorously for 1 h at RT and for 4 h at 80 °C {—*^■ Zn homoenolate solution). In a second apparatus (N₂ atmos¬ phere), 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, stirring is carried out at RT for 15 min (-* yellow solution) and the solution is cooled to -40°C (-→ partial crystallisation of the trichlorotitanium iso- propanolate). Once cooled to RT, the Zn homoenolate solution is decanted from die metallic solid by means of tubules and is added dropwise to the trichlorotitanium isoprop- anolate, the temperature being maintained at from -40°C to -30°C (— » deep-red solution), the solution is heated for 5 min at -25°C and is cooled again to -40°C. A solution of 9.0 g of N-(S)-Boc-phenylalaninal (preparation: see DJ. Kempf, J. Org. Chem. 51_. , 3921 (1986)) in 32.8 ml of methylene chloride is then added dropwise and stirring is tiien carried out for 15 h at approximately -20°C and finally for 1 h at 0°C. The reaction mixture is poured onto 0.5 kg of ice-water and 0.5 1 of ether and stirred 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. Crystalline 5(S)-(Boc- amino)-4(S)-hydroxy-6-phenyl-hexanoic acid ethyl ester is obtained as an intermediate. That intermediate is heated in 295 ml of toluene and 9 ml of acetic acid at 80°C for 2.5 h. 0.5 1 of water is added to the reaction mixture, the aqueous phase is separated off and extracted with 2 portions of ether, and the organic phases are washed with saturated sodium hydrogen carbonate solution, water and brine and dried with sodium sulfate. Partial concentration of the organic phases by evaporation and addition of hexane yield the crystalline title compound which, according to analysis, contains approximately 10 % of the (5R)-epimer (TLC R_j<E)=0.08). Column chromatography (SiO₂, hexane/ethyl acetate 2:1) yields the pure title compound: TLC

[α]^D=17.7° (c=l ; ethanol). 3d) 5(S)-[l(S)-(Boc-amino)-2-phenylethyll-3(R)-(p-fluoro-phenylmethyl)-dihydro- furan-2-(3H)-one

(see also A.K. Ghosh, S.P. McKee, and WJ. Thompson, J. Org. Chem. 56, 6500 (1991)). Under a nitrogen atmosphere, 1.92 ml of lithium bis(trimethylsilyl)amide, IM in THF (Aldrich) are added at -75°C to a solution of 300 mg (0.982 mmol) of 5(S)-[l(S)-(Boc- amino)-2-phenylethyl]-dihydrofuran-2-(3H)-one in 6 ml of THF and the mixture is then stirred at tiiat temperature for 15 min. 132 μl (1.077 mmol) of p-fluorobenzyl bromide (Ruka; Buchs/Switzerland) are then added dropwise and the mixture is stirred at -50°C for 30 min to complete the reaction. After cooling again to -75°C, 0.3 ml of propionic acid and then 0.3 ml of water are added. The mixture is heated to 0°C, 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_f(D)=0.54; FAB-MS (M+H)⁺=414.

3e) S(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-(p-fluoro-phenylmethyl)-hexanoic acid

Analogously to Example 11), 1.46 g of 5(S)-[l(S)-(Boc-amino)-2-phenylethyl]-3(R)- (p-fluoro-phenylmethyl)-dihydrofuran-2-(3H)-one are hydrolysed in 57 ml of dimethoxy¬ ethane and 29 ml of water with 14.1 ml of IM lithium hydroxide solution to yield the title compound, which can be further used without further purification.

3f) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethγlsilyloxy)-6-phenyl-2(R)-(p-fluoro- phenylmethyp-hexanoic acid

Under protective gas and witii stirring at RT for 18 h, 0.9 g of 5(S)-(Boc-amino)-4(S)- hydroxy-6-phenyl-2(R)-(p-fluoro-phenylmethyl)-hexanoic acid is silylated in 4 ml of DMF with 1.49 g of tert-butyldimethylchlorosilane and 1.2 g of imidazole. The reaction mixture is then poured onto ice-water and extracted with 3 portions of ethyl acetate, and 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. Hydrolysis of the silyl ester function with 1.9 g of potassium carbonate in 50 ml of methanol/THF/water 3:1 : 1 analogously to Example 1 m) yields the title compound after acidification with citric acid solution and extraction with ethyl acetate. TLC R_f(D)=0.2. Example 4: 5(S)-(Boc-amino)-4(S)-hydroxy-6-(p-fluoro-phenyl)-2(R)-(p-fluoro- phenylmethyl)-hexanoyl-(L)-Val-N-(2-(morpholin-4-yl)-ethyl)amide

Analogously to Example 1, 250 mg (0.3225 mmol) of 5(S)-(Boc-amino)-4(S)-(tert-butyl- dimetiιylsilyloxy)-6-(p-fluoro-phenyl)-2(R)-(p-fluoro-phenylmethyl)-hexanoyl-(L)-Val- N-(2-(moφholin-4-yl)-ethyl)amide are desilylated in 4.6 ml of DMF with 203.5 mg (0.645 mmol) of TBAF to form the title compound: t_Ret(I)=17.1 min; FAB-MS (M+H)⁺=661.

The starting material is prepared as follows:

4a) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-(p-fluoro-phenyl)-2(R)-

(p-fluoro-phenylmethyl)-hexanoyl-(L)-Val-N-(2-(morpholin-4-yl)-ethyl)amide

Under a nitrogen atmosphere, 200 mg (0.355 mmol) of 5(S)-(Boc-amino)-4(S)-(tert-butyl- dimethylsilyloxy)-6-(p-fluoro-phenyl)-2(R)-(p-fluoro-phenylmethyl)-hexanoic acid [see Example 4h) for preparation] and 89.5 mg (0.390 mmol) of H-(L)-Val-N-(2-moφholin-4- yl-ethyl)amide (Example lb) are dissolved in 3.2 ml of 0.25M NMM in CH₃CN, and 148 mg (0.390 mmol) of HBTU are added thereto. The reaction mixture is stirred at RT for 3 days to complete the reaction and is finally concentrated by evaporation. The residue is taken up in ethyl acetate, the solution is washed with water, 2x 10 % citric acid solution, water, 2x sat. NaHCO₃ solution, water and brine. The aqueous phases are extracted a further 2x with ethyl acetate, and the organic phases are dried with Na₂SO₄ and concen¬ trated by evaporation to yield the title compound: t_Rct(I)=27.3 min; FAB-MS (M+H)⁺=775.

4b) N-(S)-Boc-(p-fluorophenyla_anine) :

In 0.4 1 of dioxane/water 1 : 1, 20 g (109 mmol) of (S)-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 evaporation. Dissolving of the residue in a small amount of methylene chloride and crystallisation by the addition of hexane yields the title compound.

4c) N-(S) -Boc-(p-fluorophenylalaninol):

At from -5°C to -10°C, 9.66 ml (69 mmol) of triethylamine are added to a solution of 17.9 g (63 mmol) of N-(S)-Boc-(p-fluorophenylalanine) in 73 ml of abs. THF, and there is then added dropwise a solution of 9.05 ml (69 mmol) of chloroformic acid isobutyl ester in 44 ml of abs. THF. After stirring at RT for 0.5 h, the precipitate which forms 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 stirring at RT for 4 h, the reaction mixture is acidified with 10 % citric acid, the THF is partially evaporated using a RE, and die 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, dried with sodium sulfate and concentrated by evaporation, are dissolved in a small amount of methylene chloride and crystallised by the addition of hexane to yield the title compound. TLC R_f(C)=0.36; *H-NMR (200 MHz, CD₃OD): 7.24 (dd, 8 and 5 Hz, 2 H), 6.98 (t, 8 Hz, 2 H), 3.73 (m, 1 H), 3.47 (d, 5 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).

4d) N-(S)-Boc-(p -fluorophenylalaninal) :

Under a nitrogen atmosphere, 4.44 ml (62.4 mmol) of DMSO dissolved in 76 ml of methylene chloride are added dropwise to a solution, cooled to -60°C, of 4.0 ml (46.8 mmol) of oxalyl chloride in 44 ml of methylene chloride. To the clear solution obtained after stirring for 15 min, there are added 8.4 g (31.2 mmol) of N-(S)-Boc- (p-fluorophenylalaninol) in the form of a solution in 185 ml of methylene chloride/THF 1:1 (— * precipitation), and the mixture is subsequently 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 reaction mixture is allowed to warm to room temperature, and the aqueous phase is separated off and extracted with 2 portions of ether. The organic phases yield, after washing with saturated sodium hydrogen carbonate solution, water and brine, drying with sodium sulfate and concentration by evaporation, the title compound, which is used in the next step without further purification: ^lH-NMR (200 MHz, CDC1₃): 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).

4e) 5(S.-[l(S)-(Boc-amino)-2-(p-fluoro-phenyl)ethyn-dihvdrofuran-2-(3H)-one

Analogously to Example 3c), the Zn homoenolate is formed from 16.7 g of 2-iodoprop- ionic acid ethyl ester (Example 3b) 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 tubules to trichloro¬ titanium isopropanolate (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) that has been cooled to from -40°C to -25°C. The mixture is heated for 5 min at -25°C and is cooled again to -40°C. A solution of 9.28 g of N-(S)-Boc-(p-fluorophenylalaninal) in 33 ml of methylene chloride is then added dropwise and the reaction mixture is subse¬ quently stirred for 15 h at approximately -20°C and finally for 1 h at 0°C. It is poured onto 0.4 kg of ice-water and 0.55 1 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 die organic phases are washed with water, saturated sodium hydrogen carbonate solution, water and brine, dried with sodium sulfate and concentrated by evaporation. Crystalline 5(S)-(Boc- amino)-4(S)-hydroxy-6-(p-fluorophenyl)-hexanoic acid ethyl ester is obtained as an inter¬ mediate. That intermediate is heated in 244 ml of toluene and 7.3 ml of acetic acid at 100°C for 2 h. When the reaction mixture has cooled, 0.5 1 of water is added thereto, the aqueous phase is separated off and extracted with 2 portions of ether, and the organic phases are washed with saturated sodium hydrogen carbonate solution, water and brine, dried with sodium sulfate and concentrated by evaporation. Column chromatography (SiO₂, hexane/ethyl acetate 2:1) yields the pure title compound: TLC R (D)=0.22; FAB-MS (M+H)⁺=324. [α]^D=20.7° (c=l; ethanol).

4f) 5(S)-fl(S)-(Boc-amino)-2-(p-fluoro-phenyl)ethvn-3(R)-(p-fluoro-phenylmethyl)- dihydrofuran-2-(3H)-one

Analogously to Example 3d), 1.0 g of 5(S)-[l(S)-(Boc-amino)-2-(p-fluoro-phenyl)ethyI]- dihydrofuran-2-(3H)-one dissolved in 7.9 ml of THF is deprotonated with 6.05 ml of lithium bis(trimethylsilyl)amide, IM in THF, and alkylated with 0.673 g of p-fluorobenzyl bromide at -75°C (1 h). Column chromatography (SiO₂, methylene chloride/ether 49: 1) yields the pure title compound: TLC R_f(methylene chloride/ether 49:1 )=0.17; 'H-NMR (200 MHz, CDC1₃): 7.19-7.05 and 7.04-6.88 (2m, each 4 H), 4.50 (d, 10 Hz, HN), 4.11 (m, 1 H), 3.87 (qm, approx. 8 Hz, 1 H), 3.1-2.7 (m, 5 H), 2.33-2.14 and 2.02-1.85 (2m, each I H), 1.35 (s, 9 H).

4g) 5(S)-(Boc-amino)-4(S)-hydroxy-6-(p-fluoro-phenyl)-2(R)-(p-fluoro-phenyl- methyQ-hexanoic acid

Analogously to Example 11), 790 mg of 5(S)-[l(S)-(Boc-amino)-2-(p-fluoro-phenyl)- ethyl]-3(R)-(p-fluoro-phenylmethyl)-dihydrofuran-2-(3H)-one are hydrolysed in 29 ml of dimethoxyethane and 15 ml of water with 7.3 ml of IM lithium hydroxide solution to form the title compound, which is further used directly. 4h) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-(p-fluoro-phenyl)-2(R)- (p-fluoro-phenylmethyl)-hexanoic acid

Analogously to Example lm), 956 mg of 5(S)-(Boc-amino)-4(S)-hydroxy-6-(p-fluoro- phenyl)-2(R)-(p-fluoro-phenylmethyl)-hexanoic acid are silylated in 2.3 ml of DMF with 1.47 g of tert-butyldimethylchlorosilane and 1.19 g of imidazole. Hydrolysis of die silyl ester function with 1.76 g of potassium carbonate in 50 ml of methanol/THF/water 3:1:1 yields, after column chromatography (SiO₂, hexane/ethyl acetate 2:1), the title compound: TLC R_f(D)=0.13; FAB-MS (M+H)⁺=564.

Example 5: 5(S)-(Boc-amino)' (S)-hydroxy-6-phenyI-2(R)-[(p-methoxy-phenyl)- methyn-hexanoyl-(L)-Ile-N-(2-(morpholin-4-yl)-ethyl)amide

Analogously to Example 1, 250 mg (0.319 mmol) of 5(S)-(Boc-amino)-4(S)-(tert-butyldi- methylsilyloxy)-6-phenyl-2(R)-[(p-methoxy-phenyl)methyl]-hexanoyl-(L)-Ile-N-(2-(mor- pholin-4-yl)-ethyl)amide are desilylated in 3 ml of DMF with 302 mg (0.958 mmol) of TBAF to form the title compound: TLC R_f(B)=0.5; FAB-MS (M+H)⁺=669.

The starting material is prepared as follows: 5a) Z-(L)-Ile-N-(2-(morpholin-4-y-.-ethyl)amide

At 0°C, 2.65 g (10 mmol) of Z-(L)-isoleucine (2(S),3(S)-form) are dissolved in 120 ml of methylene chloride and activated with 2.06 g (10 mmol) of DCC. After 20 min, a solution of 1.3 ml (10 mmol) of 4-(2-aminoethyl)-moφholine (Fluka; Buchs, Switzerland) in 60 ml of methylene chloride is added dropwise and the reaction mixture is stirred at RT for 24 h. It is then filtered, and the filtrate is washed with sat. NaHCO₃ solution, water and brine. The aqueous phases are extracted 2x with methylene chloride. Drying of the organic phases with Na₂SO₄, concentration by evaporation and digestion from ether results in the title compound: TLC R_f(B)=0.45.

5b, H-(LHle-N-(2-(morpholin-4-yl)-ethyl,amide

Hydrogenation of 3.09 g (8.2 mmol) of Z-(L)-Ile-N-(2-(moφholin-4-yl)-ethyl)amide in 100 ml of methanol in the presence of 0.4 g of 10 % Pd/C yields, after removal of the catalyst by filtration, concentration of the filtrate by evaporation and column chromato¬ graphy (SiO₂, methylene chloride/methanol 9:1), the title compound: TLC R_f(B)=0.2; FAB-MS (M+H)⁺=244. 5c) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-[(p-methoxy- phenyl)methyn-hexanoyl-(L)-Ile-N-(2-(morpholin-4-yl)-ethyl)amide

Under protective gas 200 mg (0.36 mmol) of 5(S)-(Boc-amino)-4(S)-(tert-butyldimethyl- silyloxy)-6-phenyl-2(R)-[(p-methoxy-phenyl)methyl]-hexanoic acid [see Example 5g) for preparation] and 96 mg (0.39 mmol) of H-(L)-Ile-N-(2-moφholin-4-yl-ethyl)amide are dissolved in 3.6 ml of 0.25M NMM/CH₃CN and reacted with 149 mg (0.39 mmol) of HBTU. After 17 h at RT, working-up is carried out analogously to Example 4a) to give the title compound: TLC R_f(C)=0.4.

5d) p-Methoxy-benzyl iodide

A solution of 1.7 ml (12.8 mmol) of 4-methoxy-benzyl chloride (Fluka; Buchs/Switzer¬ land) in 25 ml of acetone is stirred at RT with 9.4 g (62.6 mmol) of sodium iodide. A gas chromatogram of the reaction mixture after 90 min indicates complete conversion and, therefore, the reaction mixture is poured onto ether and washed with 10 % sodium thio¬ sulfate solution and brine. Drying of the organic phases with Na₂SO₄ and concentration by evaporation yields the title compound: 1H-NMR (200 MHz, CD₃OD: 3.78 (s, 3 H), 4.54 (s, 2 H), 6.8-6.95 and 7.2-7.4 (2m, each 2 H).

5e) 5(S)-[l(S)-(Boc-amino)-2-phenyl-ethyl]-3(R)-(p-methoxy-phenylmethyl)-dihydro- furan-2-(3H)-one

Analogously to Ex. 3d), 2.98 g (9.74 mmol) of 5(S)-[l(S)-(Boc-amino)-2-phenylethyl]- dihydrofuran-2-(3H)-one [Example 3c)], dissolved in 40 ml of THF, are deprotonated at -75°C with 19.5 ml of lithium bis(trimethylsilyl)amide, IM in THF, and alkylated with 2.9 g ( 11.7 mmol) of p-methoxy-benzyl iodide in 20 ml of THF (45 min). Column chromatography (SiO₂, hexane/ethyl acetate 2:1) and digestion from DIPE yields the pure title compound: TLC R_f{D)=0.32; t_Ret(H)=16.7 min.

5f) 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-(p-methoxy-phenylmethyl)- hexanoic acid

Analogously to Ex. 11), 1.7 g (3.99 mmol) of 5(S)-[l(S)-(Boc-amino)-2-phenylethyl]- 3(R)-(p-methoxy-phenylmethyl)-dihydrofuran-2-(3H)-one in 43 ml of dimethoxyethane and 11 ml of water are hydrolysed with 16 ml of IM lithium hydroxide solution. Stirring in ether yields the pure title compound: TLC R_f(B)=0.53; t_Ret(II)=14.2 min; FAB-MS (M+Na)⁺=466. 5g) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethyisilyloxy)-6-phenyl-2(R)-(p-methoxy- phenylmethyQ-hexanoic acid

Analogously to Ex. lm), 0.93 g (2.10 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6- phenyl-2(R)-(p-methoxy-phenylmethyl)-hexanoic acid is silylated in 20 ml of DMF with

1.4 g (9.64 mmol) of tert-butyldimettiylchlorosilane and 1.17 g (17.2 mmol) of imidazole. Hydrolysis of the silyl ester function with 1.7 g of potassium carbonate in methanol

(23 ml) THF (7 ml)/water (7 ml) and stirring of the crude product in hexane yields the title compound: t_Ret(H)=20.6 min; FAB-MS (M+ H)⁺=558.

Example 6: 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-f(p-trifluoromethyl- phenyl)methyn-hexanoyl-(L)-Val-N-(2-(morphoIin-4-yl)-ethyl)amide

Analogously to Example 1, 250 mg (0.309 mmol) of 5(S)-(Boc-amino)-4(S)-(tert-butyldi- methylsilyloxy)-6-phenyl-2(R)-[(p-trifluoromethyl-phenyl)methyl]-hexanoyl-(L)-Val- N-(2-(moφholin-4-yl)-ethyl)amide are desilylated in 3 ml of DMF with 293 mg (0.928 mmol) of TBAF. Precipitation with DIPE from a concentrated solution in DMF yields the title compound: t_Ret(I)=18.5 min; FAB-MS (M+H)⁺=693.

The starting material is prepared as follows:

6a) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-[(p-trifluoro- methyl-phenyl)methyl]-hexanoyl-(L)-Val-N-(2-(morpholin-4-yl)-ethyl)amide

Under a nitrogen atmosphere, 200 mg (0.335 mmol) of 5(S)-(Boc-amino)-4(S)-(tert-butyl- dimethylsilyloxy)-6-phenyl-2(R)-[(p-trifluoromethyl-phenyl)methyl]-hexanoic acid [see Example 6d) for preparation] and 85 mg (0.369 mmol) of H-(L)-Val-N-(2-(moφholin- 4-yl)-ethyl)amide (Example lb) are dissolved in 3.2 ml of 0.25M NMM/CH₃CN and reacted with 140 mg (0.369 mmol) of HBTU. After 17 h at RT, working-up is carried out analogously to Example 4a) to give the title compound: t_Rct(I)=28.2 min.

6b) 5(S)-[l(S)-(Boc-amino)-2-phenyl-ethyll-3(R)-(p-trifluoromethyI-phenyl- methyl)-dihydrofuran-2-(3H)-one

Analogously to Ex. 3d), 1.0 g (3.26 mmol) of 5(S)-[ 1 (S)-(Boc-amino)-2-phenylethyl]-di- hydrofuran-2-(3H)-one [Ex. 3c)], dissolved in 20 ml of THF, is deprotonated at -75°C with

6.5 ml of lithium bis(trimethylsilyl)amide, IM in THF, and alkylated with 0.93 g (3.91 mmol) of p-trifluoromethyl-benzyl bromide (Fluka; Buchs/Switzerland) at -75°C initially (warming over a period of 45 min to -60°C). Column chromatography (SiO₂, hexane/ethyl acetate 2:1) yields the pure title compound: TLC R_f<D)=0.4; t_Re,(I)=27.0min; FAB-MS (M+H-butene)⁺=408. 6c) 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-(p-trifluoromethyl-phenylmethyl)- hexanoic acid

Analogously to Ex. 11), 4.3 g (9.3 mmol) of 5(S)-[l(S)-(Boc-amino)-2-phenylethyl]-3(R)- (p-trifluoromethyl-phenylmethyl)-dihydrofuran-2-(3H)-one are hydrolysed in 100 ml of dimethoxyethane and 25 ml of water with 37 ml of IM lithium hydroxide solution to form the title compound: TLC R_f(N)=0.68; t_Ret(I)=22.5 min.

6d) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(p-trifluoro- methyl-phenylmethyQ-hexanoic acid

Analogously to Ex. lm), 3.2 g (6.65 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl- 2(R)-(p-trifluoromethyl-phenylmethyl)-hexanoic acid are silylated in 25 ml of DMF with 4.6 g (30.6 mmol) of tert-butyldimethylchlorosilane and 3.7 g (54.5 mmol) of imidazole. Hydrolysis of the silyl ester function with 5.5 g of potassium carbonate in methanol (75 ml)/THF (22 ml)/water (12 ml) yields the title compound: t_Ret(I)=32.7 min.

Example 7: 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-f(p-trifluoromethyl- phenyl)methyn-hexanoyl-(L)-Ile-N-(2-(morpholin-4-yl)-ethyl)amide

Analogously to Example 1, 250 mg (0.304 mmol) of 5(S)-(Boc-amino)-4(S)-(tert-butyldi- methylsilyloxy)-6-phenyl-2(R)-[(p-trifluoromethyl-phenyl)methyl]-hexanoyl-(L)-Ile-N-

(2-(mθφholin-4-yl)-ethyl)amide are desilylated in 3 ml of DMF with 288 mg

(0.913 mmol) of TBAF. Precipitation with a large quantity of DIPE from a solution in 4 drops of DMF yields the titie compound: t_Ret(I)=19.0 min; FAB-MS (M+H)⁺=707.

The starting material is prepared as follows:

7a) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-[(p-trifluoro- methyl-phenyl)methyl]-hexanoyl-(L)-Ile-N'(2-(morpholin-4-yl)-ethyl)amide

Under a nitrogen atmosphere, 200 mg (0.335 mmol) of 5(S)-(Boc-amino)-4(S)-(tert-butyl- dimethylsilyloxy)-6-phenyl-2(R)-[(p-trifluoromethyl-phenyl)methyl]-hexanoic acid [see Example 6d) for preparation] and 90 mg (0.369 mmol) of H-(L)-Ile-N-(2-moφholin-4-yl- ethyl)amide (Example 5b) are dissolved in 3.2 ml of 0.25M NMM/CH₃CN and reacted with 140 mg (0.369 mmol) of HBTU. After 17 h at RT, working-up is carried out analogously to Example 4a) to give the title compound: t_Ret(I)=29.3 min. Example 8: 5(S)-(Boc-amino)-4(S)-hydroxy-6-(p-trifluoromethyl-phenyl)-2(R)-(p- fluoro-phenylmethyl)-hexanoyl-(L)-Ile-N-(2-(morpholin-4-yl)-ethyl)amide

Analogously to Example 1, 92 mg (0.11 mmol) of 5(S)-(Boc-amino)-4(S)-(tert-butyldi- methylsilyloxy)-6-(p-trifluoromethyl-phenyl)-2(R)-(p-fluoro-phenylmethyl)-hexanoyl- (L)-Ile-N-(2-(moφholin-4-yl)-ethyl)amide are desilylated in 1.1 ml of DMF with 69 mg (0.22 mmol) of TBAF to form the title compound: t_Ret(I)=19.6 min; FAB-MS (M+H)⁺=725.

The starting material is prepared as follows:

8a) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-(p-trifluoromethylphenyl)- 2(R)-(p-fluoro-phenylmethyl)-hexanoyl-(L)-Ile-N-(2-(morpholin-4-yl)-ethyl)amide and 5(R)-(Boc-amino)-4(R)-(tert-butyldimethylsilyloxy)»6-(p-trifluoromethyl- phenyl)-2(S)-(p-fluoro-phenylmethyl)-hexanoyl-(L)-Ile-N-(2-(morpholin-4-yl)-ethyl)- amide

Under a nitrogen atmosphere, 200 mg (0.326 mmol) of a racemic mixture of 5(S)-(Boc- amino)-4(S)-(tert-butyldimethylsilyloxy)-6-(p-trifluoromethyl-phenyl)-2(R)-(p-fluoro- phenylmethyl)-hexanoic acid and 5(R)-(Boc-amino)-4(R)-(tert-butyldimethylsilyloxy)-6- (p-trifluoromethyl-phenyl)-2(S)-(p-fluoro-phenyl-methyl)-hexanoic acid [see Example 8k) for preparation] and 123 mg (0.51 mmol) of H-(L)-Ile-N-(2-(moφholin-4-yl)-ethyl)amide (Example 5b)) are dissolved in 3.1 ml of 0.25M NMM/CH₃CN and reacted with 136 mg (0.358 mmol) of HBTU. After 19 h at RT, the reaction mixture is concentrated by evaporation. The residue is taken up in ethyl acetate and the solution is washed with water, 2x sat. NaHCO₃ solution, water and brine. The aqueous phases are extracted a further 2x with ethyl acetate, and the organic phases are dried with Na₂SO₄ and concentrated by evaporation. Column chromatography (SiO₂, ethyl acetate) yields first, as fraction A, 5(R)-(Boc-amino)-4(R)-(tert-butyldimethylsilyloxy)-6-(p-trifluoromethylphenyl)-2(S)- (p-fluoro-phenylmethyl)-hexanoyl-(L)-Ile-N-(2-(moφholin-4-yl)-ethyl)amide, followed by fraction B - 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-(p-trifluoromethyl- phenyl)-2(R)-(p-fluoro-phenylmethyl)-hexanoyl-(L)-Ile-N-(2-(moφholin-4-yl)-ethyl)- amide: A: TLC

min.

8b) N-allylformamide

A solution of 300 ml of allylamine (Aldrich, Steinheim, FRG) in 1288 ml of formic acid ethyl ester is heated at 60°C for 8 h. The reaction mixture is concentrated using a RE and the residue is distilled over a Vigreux column (77°C; 1 mbar): Η-NMR (200 MHz, CDC1₃): 8.2-7.95 (m, 1 H), 6.5-5.8 (sb, 1 H), 5.9-5.7 ( , 1 H), 5.3-5.05 (m, 2 H), 3.95-3.75 (m, 2 H).

8c) Allyl isocyanide

(see U. Schδllkopf, R. Jentsch, K. Madawinata and R. Harms, Liebigs Ann. Chem., (1976), 2105). Under a nitrogen atmosphere, 517 g of quinoline and 286 g of p-toluene- sulfonic acid chloride are placed in a reaction vessel at 90°C. A vacuum of 2-4 mbar is applied and 85 g of N-allylformamide are added dropwise, the isocyanide produced being continuously distilled off over a Vigreux column into the condensation trap (acetone/dry ice) at an internal temperature of 85-95°C. When the reaction is complete, the distillate is immediately distilled over a Vigreux column once more (nitrogen atmosphere, normal pressure, 100°C): H-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.

8d) rac. l-(p-trifluoromethyl-phenyl)-3-butene -2-amine

Under a nitrogen atmosphere, 4.5 g of allyl isocyanide are dissolved in 100 ml of THF/- ether/pentane abs. 4:1:1 and cooled to -100°C. At from -100° to -90°C, 42 ml of n-butyl- lithium (1.6M in hexane) are added dropwise, a yellow coloration occurring initially and a solid being precipitated shortly before the end. The reaction mixture is allowed to warm slowly to -70°C and is then cooled again to -100°C. At from -100° to -85°C, a solution of 16 g of p-trifluoromethyl-benzyl bromide (Fluka; Buchs/Switzerland) in 10 ml of THF is added dropwise and the reaction mixture is slowly warmed to RT. The reaction mixture is concentrated by evaporation using 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 concentrated by evaporation, 85 ml of methanol and 17 ml of cone, hydrochloric acid are added to the brown residue at 0°C and the mixture is left to stand overnight in a refriger¬ ator. The mixture is concentrated by evaporation using a rotary evaporator and the residue is partitioned between 2 x 150 ml of 2M hydrochloric acid and 2 x 200 ml of ether. The combined aqueous phases are rendered alkaline with solid sodium hydroxide, with cooling, and are extracted with 3 portions of ethyl acetate. Washing of the organic phases with brine, drying with sodium sulfate, concentration by evaporation and distillation in a bulb tube (0.1 mbar; 170°C) yields the pure title compound: Η-NMR (200 MHz, CDC1₃): 7.56 and 7.32 (2d, 8 Hz, each 2 H), 5.96-5.78 (m, 1 H), 5.19-5.02 (m, 2 H), 3.68-3.55 (m, 1 H), 2.87 and 2.71 (AB x d, J_ab= 13 Hz, J,=6 Hz, J₂= 8 Hz, 2 H), 1.4 (sb, 2 H). 8e) rac. N-Boc-l-(p-trifluoromethyl-phenyl)-3-butene-2-amine

Under protective gas, 10.5 g (48.8 mmol) of rac. l-(p-trifluoromethyl-phenyl)-3-butene- 2-amine and 13.8 g (63.4 mmol) of Boc anhydride are reacted at RT in 100 ml of methylene chloride. After 2 h, the reaction mixture is washed with 0.1N HC1 and 2 portions of brine, and the aqueous phases are extracted with 2 portions of methylene chloride. Drying of the organic phases with Na₂SO₄, concentration by evaporation and precipitation with hexane from a concentrated solution in methylene chloride yields the title compound: TLC R_f(hexane/ethyl acetate 8:1)=0.27; t_Ret(I)=25.5 min; Anal: calc. C 60.94 %, H 6.39 %, N 4.44 %, F 18.07 %; found C 61.15 %, H 6.43 %, N 4.27 %, F 18.09 %.

8f) 2(R)-ri(S)-(Boc-amino)-2-(p-trifluoromethyl-phenyl)-ethyll-oxirane and 2(S)- [l(R)-(Boc-amino)-2-(p-trifluoromethyl-phenyl)-ethyl]-oxirane

Analogously to Example lg), 13.5 g (42.8 mmol) of rac. N-Boc-l-(p-trifluoromethyl- phenyl)-3-butene-2-amine and 36.8 g (214 mmol) of m-chloroperbenzoic acid are reacted in 284 ml of chloroform. Partition of the reaction mixture between 3 portions of methylene chloride, 10 % Na₂SO₃ solution, sat, Na₂CO₃ solution, water and brine and column chromatography (SiO₂, hexane/ethyl acetate 4:1) of the crude product yields the racemate of the title compounds: TLC R^hexane/ethyl acetate 4:l)=O.15; t_Ret(I)=22.9 min; Anal: calc. C 58.00 %, H 6.08 %, N 4.23 %, F 17.20 %; found C 58.03 %, H 6.33 %, N 4.45 %, F 17.02 %.

8g) 5(S)-[l(S)-(Boc-amino)-2-(p-trifluoromethylphenyl)-ethyll-3(R,S)-carbethoxy- dihydrofuran-2-(3H)-one and 5(R)-[l(R)-(Boc-amino)-2-(p-trifluoromethylphenyl)- ethy_l-3(S,R)-carbethoxy-dihydrofuran-2-(3H)-one

Analogously to Example lh), 9.6 g (29.0 mmol) of a mixture of 2(R)-[l(S)-(Boc-amino)- 2-(p-trifluoromethyl-phenyl)-ethyl]-oxirane and 2(S)-[l(R)-(Boc-amino)-2-(p-trifluoro- methyl-phenyl)-ethyl]-oxirane are reacted in 48 ml of ethanol and 5 ml of THF with sodium diethylmalonate (prepared from 153 ml of ethanol, 2 g (87 mmol) of sodium and 15.4 ml (101 mmol) of malonic acid diethyl ester). Crystallisation by adding hexane to a concentrated solution in ethyl acetate yields a mixture of the title compounds: TLC R_f<D)=0.40; t_Rct(I)=24.1 min and 24.6 min; FAB-MS (M+Na)⁺=468. 8h) 5(S)-[l(S)-(Boc-amino)-2-(p-trifluoromethylphenyl)-ethyn-dihvdrofuran-2-

(3H)-on and 5(R)-ri(R)-(Boc-amino)-2-(p-trifluoromethylphenyl)-ethyn-dihydro- furan-2-(3H)-one

Analogously to Example Ik), 9.0 g (20.2 mmol) of a mixture of 5(S)-[l(S)-(Boc-amino)- 2-(p-trifluoromethylphenyl)-ethyl]-3(R,S)-carbethoxy-dihydrofuran-2-(3H)-one and 5(R)- [l(R)-(Boc-amino)-2-(p-trifluoromethylphenyl)-ethyl]-3(S,R)-carbethoxy-dihydrofuran- 2-(3H)-one are hydrolysed in 166 ml of dimethoxyethane with 86.9 ml of a IN aqueous LiOH solution. Decarboxylation of the resulting dicarboxylic acids in 350 ml of toluene (9 h 120°C) and crystallisation of the crude product by adding hexane to a concentrated solution in ethyl acetate yields the title compound in the form of a racemate: t_Ret(I)=23.2 min; Anal: calc. C 57.90 %, H 5.94 %, N 3.75 %, F 15.26 %; found C 57.70 %, H 5.78 %, N 3.82 %, F 15.42 %.

8i) 5(S)-[l(S)-(Boc-amino)-2-(p-trifluoromethvIphenyl)-ethyll-3(R)-(p-fluoro-phenyl- methyl)-dihydrofuran-2-(3H)-one and 5(R)-[l(R)-(Boc-amino)-2-(p-trifluoromethyl- phenyl)-ethyl1-3(S)-(p-fluoro-phenylmethyl)-dihydrofuran-2-(3H)-one

Analogously to Example 3d), 700 mg (1.88 mmol) of a mixture of 5(S)-[l(S)-(Boc- amino)-2-(p-trifluoromethylphenyl)-ethyl]-dihydrofuran-2-(3H)-one and 5(R)-[ 1 (R)- (Boc-amino)-2-(p-trifluoromethylphenyl)-ethyl]-dihydrofuran-2-(3H)-one, dissolved in 3.4 ml of THF and 0.38 ml of DMPU, are deprotonated at -75°C with 3.67 ml of lithium bis(trimethylsilyl)amide, IM in THF, and alkylated at -75°C (40 min) with 0.242 ml (1.88 mmol) of 4-fluoro-benzyl bromide (Fluka; Buchs, Switzerland). Column chromato¬ graphy (SiO₂, hexane/ethyl acetate 2:1) yields the titie compound: TLC R {D)=0.59; t_Rct(I)=26.6 min; FAB-MS (M+H)⁺=482.

8i) 5(S)-(Boc-amino)-4(S)-hydroxy-6-(p-trifluoromethyl-phenyl)-2(R)-(p-fluoro- phenylmethyQ-hexanoic acid and 5(R)-(Boc-amino)-4(R)-hydroxy-6-(p-trifluoro- methyl-phenyl)-2(S)-(p-fluoro-phenylmethyl)-hexanoic acid

Analogously to Example 11), 1.1 g (2.28 mmol) of a mixture of 5(S)-[l(S)-(Boc-amino)- 2-(p-trifluoromethylphenyl)-ethyl]-3(R)-(p-fluoro-phenylmethyl)-dihydrofuran-2- (3H)-one and 5(R)-[l(R)-(Boc-amino)-2-(p-trifluoromethylphenyl)-ethyl]-3(S)-(p-fluoro- phenylmethyl)-dihydrofuran-2-(3H)-one are hydrolysed in 37 ml of dimethoxyethane and 19 ml of water with 9.1 ml of IM lithium hydroxide solution. After being partially concentrated by evaporation, the reaction mixture is poured onto a mixture of ice, 1 12 ml of sat. NH C1 solution, 9.4 ml of 10 % citric acid solution and 46 ml of methylene chloride, and methanol is added until the solid which has precipitated dissolves clearly in the 2 phases. The aqueous phase is extracted with 2 portions of methylene chloride/- methanol approx. 9:1, and the organic phases are washed with brine, dried with Na₂SO₄ and concentrated by evaporation: TLC R_f(D)=0.15; t_Ret(H)=22.7 min.

8k) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-(p-trifluoromethyl-phenyl)- 2(R)-(p-fluorophenyl-methyl)-hexanoic acid and 5(R)-(Boc-amino)-4(R)-(tert-butyl- dimethylsiIyloxy)-6-(p-trifluoromethyl-phenyl)-2(S)-(p-fluorophenyi-methyl)- hexanoic acid

Analogously to Example lm), 1.1 g (2.20 mmol) of a mixture of 5(S)-(Boc-amino)-4(S)- hydroxy-6-(p-trifluoromethyl-phenyl)-2(R)-(p-fluoro-phenylmethyl)-hexanoic acid and 5(R)-(Boc-amino)-4(R)-hydroxy-6-(p-trifluoromethyl-phenyl)-2(S)-(p-fluoro-phenyl- methyl)-hexanoic acid are silylated in 2.4 ml of DMF with 1.52 g (10.1 mmol) of tert- butyldimethylchlorosilane and 1.2 g (18.0 mmol) of imidazole. Hydrolysis of the silyl ester function with 1.8 g of potassium carbonate in 50 ml of methanol/THF/water 3:1:1 yields, after extraction and column chromatography (SiO₂, hexane/ethyl acetate 2:1), the title compound: TLC R_f(D)=0.16; t_Ret(I)=32.7 min; FAB-MS (M+H)⁺=614.

Example 9: 5(R)-(Boc-amino)-4(R)-hydroxy-6-(p-trifluoromethylphenyl)-2(S)- (p-fluoro-phenylmethyl)-hexanoyl-(L)-Ile-N-(2-(morpholin-4-yl)-ethyl)amide

Analogously to Example 1, 104 mg (0.124 mmol) of 5(R)-(Boc-amino)-4(R)-(tert-butyldi- methylsilyloxy)-6-(p-trifluoromethyl-phenyl)-2(S)-(p-fluoro-phenylmethyl)-hexanoyl- (L)-Ile-N-(2-(moφholin-4-yl)-ethyl)amide (Example 8a)) are desilylated in 1.25 ml of DMF with 78.2 mg (0.248 mmol) of TBAF to form the titie compound: t_Ret(I)=20.2 min; FAB-MS (M+H)⁺=725.

Example 10: 5(S)-(Boc-amino)-4(S)-hydroxy-6-(p-trifluoromethyl-phenyl)-2(R)- (p-fluoro-phenylmethyl)-hexanoyl-(L)-Val-N-(2-(morpholin-4-yl)-ethyl)amide

Under inert gas, 263 mg (0.301 mmol) of a mixture of 5(S)-(Boc-amino)-4(S)-(tert-butyl- dimethylsilyloxy)-6-(p-trifluoromethyl-phenyl)-2(R)-[(p-trifluoromethyl-phenyl)methyl]- hexanoyl-(L)-Val-N-(2-(moφholin-4-yl)-ethyl)amide and 5(R)-(Boc-amino)-4(R)-(tert- butyldimethylsilyloxy)-6-(p-trifluoromethyl-phenyl)-2(S)-[(p-trifluoromethyl-phenyl)- methyl]-hexanoyl-(L)-Val-N-(2-(moφholin-4-yl)-ethyl)amide are desilylated in 3 ml of DMF with 191 mg (0.602 mmol) of TBAF to form a mixture of the titie compound and 5(R)-(Boc-amino)-4(R)-hydroxy-6-(p-trifluoromethylphenyl)-2(S)-[(p-trifluoromethyl- phenyl)methyl]-hexanoyl-(L)-Val-N-(2-(moφholin-4-yl)-ethyl)amide, which mixture is worked up analogously to Example 1: t_Ret(II)=14.3/14.6 min; FAB-MS (M+H)⁺=761. The starting material is prepared as follows:

10a) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-(p-trifluoromethyl- phenyl)-2(R)-f(p-trifluoromethyl-phenyl)methyll-hexanoyl-(L)-Val-N-(2-(mor- pholin-4-yl)-ethyl)amide and 5(R)-(Boc-amino)-4(R)-(tert-butyldimethylsilyloxy)-6- (p-trifluoromethyl-phenyl)-2(S)-[(p-trifluoromethyl-phenyl)methyπ-hexanoyl-(L)- Val-N-(2-(morpholin-4-yl)-ethyl)amide

Under protective gas, 200 mg (0.301 mmol) of a racemate of 5(S)-(Boc-amino)-4(S)- (tert-butyldimethylsilyloxy)-6-(p-trifluoromethyl-phenyl)-2(R)-[(p-trifluoromethyl- phenyl)methyl]-hexanoic acid and 5(R)-(Boc-amino)-4(R)-(tert-butyldimethylsilyloxy)- 6-(p-trifluoromethyl-phenyl)-2(S)-[(p-trifluoromethyl-phenyl)methyl]-hexanoic acid [see Example lOd) for preparation] and 76 mg (0.331 mmol) of H-(L)-Val-N-(2-moφholin- 4-yl-ethyl)amide (Example lb)) are dissolved in 2.8 ml of 0.25M NMM/CH₃CN and reacted with 126 mg (0.331 mmol) of HBTU. After 18 h, working-up is carried out anal¬ ogously to Example 4a) to give a mixture of the title compounds: t_Ret(H)= 19.4/19.6 min.

10b) 5(S)-[l(S)-(Boc-amino)-2-(p-trifluoromethylphenyl)-ethyll-3(R)-(p-trifluoro- methyl-phenylmethyl)-dihydrofuran-2-(3H)-one and 5(R)-rirR)-(Boc-amino)-2-(p-tri- fluoromethylphenyl)-ethyll-3(S)-(p-trifluoromethyl-phenylmethyl)-dihydrofuran- 2-(3H)-one

Analogously to Example 3d), 1.5 g (4.02 mmol) of a mixture of 5(S)-[l(S)-(Boc-amino)- 2-(p-trifluoromethylphenyl)-ethyl]-dihydrofuran-2-(3H)-one and 5(R)-[ 1 (R)-(Boc- amino)-2-(p-trifluoromethylphenyl)-ethyl]-dihydrofuran-2-(3H)-one, dissolved in 7.3 ml of THF and 0.81 ml of DMPU, are deprotonated at -75°C with 7.86 ml of lithium bis(tri- methylsilyl)amide, IM in THF, and alkylated at -75°C (40 min) with 1.01 g (4.02 mmol) of 4-trifluoromethyl-benzyl bromide (Fluka; Buchs/Switzerland). Column chromato¬ graphy (SiO₂, methylene chloride/hexane/ether 10:10:1) yields the title compound: TLC R_f{methylene chloride/hexane/ether 10:10:1)=0.23; t_Ret(I)=27.7 min; FAB-MS (M+H-Boc)⁺=432.

10c) 5(S)-(Boc-amino)-4(S)-hydroxy-6-(p-trifluoromethyl-phenyl)-2(R)-(p-trifluoro- methyl-phenylmethyP-hexanoic acid and 5(R)-(Boc-amino)-4(R)-hydroxy-6-(p-tri- fluoromethyl-phenyl)-2(S)-(p-trifluoromethyl-phenylmethyl)-hexanoic acid

Analogously to Example 11), 1.43 g (2.69 mmol) of a mixture of 5(S)-[l(S)-(Boc-amino)- 2-(p-trifluoromethylphenyl)-ethyl]-3(R)-(p-trifluoromethyl-phenylmethyl)-dihydrofuran- 2-(3H)-one and 5(R)-[ 1 (R)-(Boc-amino)-2-(p-trifluoromethylρhenyl)-ethyl]-3(S)-(p-tri- fluoromethyl-phenylmethyl)-dihydrofuran-2-(3H)-one are hydrolysed in 43 ml of dimethoxyethane and 22 ml of water with 10.7 ml of IM lithium hydroxide solution. After being partially concentrated by evaporation, the reaction mixture is poured onto a mixture of ice, 132 ml of sat. NH₄C1 solution, 11 ml of 10 % citric acid solution and 54 ml of methylene chloride, and methanol is added until the solid which has precipitated dissolves. The aqueous phase is extracted with 2 portions of methylene chloride/metiianol approx. 4: 1, and the organic phases are washed with brine, dried with Na₂SO₄ and concentrated by evaporation: t_Ret(I)=24.2 min; FAB-MS (M+H)⁺=550.

10d) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilγloxy)-6-(p-trifluoromethyl- phenyl)-2(RHp-trifluoromethylphenyl-methyl)-hexanoic acid and 5(R)-(Boc- amino)-4(R)-(tert-butyldimethylsilyloxy)»6-(p-trifluoromethyl-phenyl)-2(S)-(p-tri- fluoromethylphenyl-methyD-hexanoic acid

Analogously to Example lm), 1.38 g (2.51 mmol) of a mixture of 5(S)-(Boc-amino)-4(S)- hydroxy-6-(p-trifluoromethyl-phenyl)-2(R)-(p-trifluoromethyl-phenylmethyl)-hexanoic acid and 5(R)-(Boc-amino)-4(R)-hydroxy-6-(p-trifluoromethyl-phenyl)-2(S)-(p-trifluoro- methyl-phenylmethyl)-hexanoic acid are silylated in 5.7 ml of DMF with 1.74 g (1 1.6 mmol) of tert-butyldimethylchlorosilane and 1.4 g (20.6 mmol) of imidazole. Hydrolysis of the silyl ester function with 2.1 g of potassium carbonate in 55 ml of methanol THF/water 3:1: 1 yields the title compound: TLC

t_Ret(II)=21.8 min.

Example 11: 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-(o-fluoro-phenylmethyl)- hexanoyl-(L)-Val-N-(2-(morpholin-4-yl)-ethyl)amide

Analogously to Example 1, 160 mg (0.21 mmol) of 5(S)-(Boc-amino)-4(S)-(tert-butyldi- methylsilyloxy)-6-phenyl-2(R)-(o-fluoro-phenylmethyl)-hexanoyl-(L)-Val-N-(2-(moφho- lin-4-yl)-ethyl)amide are desilylated in 4 ml of DMF with 200 mg (0.63 mmol) of TBAF. Medium-pressure chromatography (®LiChroprep Si 60 (Merck, Darmstadt, FRG - silica- gel-based phase for medium-pressure chromatography); ethyl acetate/methanol 9:1 -→ 85: 15) yields the title compound: TLC R,<N)=0.45; t_Ret(II)=12.3 min ; FAB-MS (M+H)⁺=643.

The starting material is prepared as follows:

1 1 a) 5(S)-(Boc-amιno)-4(S)-(tert-butyldimethylsilyloxy)-6-phenvI-2(R)-(o-fluoro- pheny-methyl)-hexanoyl-(L)-Val-N-(2-(morpholin-4-yl)-ethyl)amide

Under a nitrogen atmosphere, 150 mg (0.27 mmol) of 5(S)-(Boc-amino)-4(S)-(tert-butyl- dimethylsilyloxy)-6-phenyl-2(R)-(o-fluoiO-phenylmethyl)-hexanoic acid [see Exam- ple 1 Id) for preparation] are dissolved in 3.3 ml (1.0 mmol) of 0.3M NMM/DMF, acti¬ vated at RT with 190 mg (0.43 mmol) of BOP and 58 mg (0.43 mmol) of HOBT and, after 30 min, reacted with 11 1 mg (0.49 mmol) of H-(L)-Val-N-(2-(moφholin-4-yl)-ethyl)- amide (Example lb)). After 17 h, the reaction mixture is worked up analogously to Exam¬ ple lc) to give the title compound: TLC R_f(B)=0.51; t_Ret(H)=18.5 min.

I lb) 5(S)-ri(S)-(Boc-amino)-2-phenyl-ethvn-3(R)-(o-fluorophenylmethyl)-dihvdro- furan-2-(3H)-one

Analogously to Example 3d), 5.0 g (16.37 mmol) of 5(S)-[l(S)-(Boc-amino)-2-phenyl- ethyl]-dihydrofuran-2-(3H)-one [Example 3c)], dissolved in 75 ml of THF, are deproton¬ ated at -75°C with 32.7 ml of lithium bis(trimethylsilyl)amide, IM in THF, and alkylated at -75°C initially (warming over a period of 60 min to a maximum of -60°C) with 2.1 ml (18.0 mmol) of o-fluorobenzyl bromide (Fluka; Buchs/Switzerland). Column chromato¬ graphy (SiO₂, hexane/ethyl acetate 3:1) yields the titie compound: TLC R_f(D)=0.61.

I I c) 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-(o-fluorophenylmethyl)-hexanoic acid

Analogously to Example 11), 4.5 g (10.8 mmol) of 5(S)-[l(S)-(Boc-amino)-2-phenyl- ethyl]-3(R)-(o-fluorophenylmethyl)-dihydrofuran-2-(3H)-one are hydrolysed in 170 ml of dimethoxyethane with 43.5 ml of IM lithium hydroxide solution. The evaporation residue of the reaction mixture is poured onto a mixture of ice, 120 ml of sat. ammonium chloride solution and 240 ml of 10 % citric acid solution and extracted with 3 portions of methylene chloride. The organic phases are washed with water and brine, dried over Na₂SO₄ and concentrated by evaporation: t_Ret(H)=14.5 min.

1 Id) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(o-fluoro- phenyl-methyl)-hexanoic acid

Analogously to Example lm), 1.5 g (3.47 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6- phenyl-2(R)-(o-fluorophenylmethyl)-hexanoic acid are silylated in 15 ml of DMF with 2.4 g (16 mmol) of tert-butyldimethylchlorosilane and 1.95 g (28.5 mmol) of imidazole. Hydrolysis of the silyl ester function with 2.8 g of potassium carbonate in 50 ml of methanol THF/water 4: 1 : 1 yields, after column chromatography (SiO₂, hexane/ethyl acetate 2: 1), the title compound: TLC R,(D)=0.33; t_Ret(II)=20.7 min. Example 12: 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-(m-fluoro-phenyl- methyl)-hexanoyI-(L)-VaI-N-(2-(morpholin-4-yl)-ethyl)amide

Analogously to Example 1, 190 mg (0.251 mmol) of 5(S)-(Boc-amino)-4(S)-(tert-butyldi- methylsilyloxy)-6-phenyl-2(R)-(m-fluoro-phenylmethyl)-hexanoyl-(L)-Val-N-(2-(mor- pholin-4-yl)-ethyl)amide are desilylated in 3 ml of DMF with 158 mg (0.50 mmol) of TBAF. Column chromatography (SiO₂, ethyl acetate/aqueous NH₃ solution 25: 1) yields the title compound: TLC R_f(B)=0.6; t_Ret(II)=12.0 min; FAB-MS (M+H)⁺=643.

The starting material is prepared as follows:

12a) 5(S)-(Eoc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(m-fluoro- phenylmethyl)-hexanoyl-(L)-Val-N-(2-(morpholin-4-yl)-ethyl)amide

Under a nitrogen atmosphere, 150 mg (0.27 mmol) of 5(S)-(Boc-amino)-4(S)-(tert-butyl- dimethylsilyloxy)-6-phenyl-2(R)-(m-fluoro-phenylmethyl)-hexanoic acid [see Exam¬ ple 12d) for preparation] are dissolved in 3.3 ml (1.0 mmol) of 0.3M NMM DMF, acti¬ vated at RT with 190 mg (0.43 mmol) of BOP and 58.4 mg (0.43 mmol) of HOBT and, after 30 min, reacted with 111.4 mg (0.49 mmol) of H-(L)-Val-N-(2-(moφholin-4-yl)- ethyl)amide (Example lb)). After 17 h, the reaction mixture is worked up analogously to Example lc) to give the title compound: t_Ret(II)=19.2 min.

12b) 5(S)-[l(S)-(Boc-amino)-2-phenyl-ethyl1-3(R)-(m-fluorophenylmethyl)-dihydro- furan-2-(3H)-one

Analogously to Example 3d), 5.0 g (16.37 mmol) of 5(S)-[l(S)-(Boc-amino)-2-phenyl- ethyl]-dihydrofuran-2-(3H)-one [Example 3c)], dissolved in 75 ml of THF, are deproton¬ ated at -75°C with 32.7 ml of lithium bis(trimethylsilyl)amide, IM in THF, and alkylated at -75°C initially (warming over a period of 60 min to a maximum of -50°C) with 3.4 g (18.0 mmol) of 3-fluorobenzyl bromide (Fluka; Buchs, Switzerland). Column chromato¬ graphy (SiO₂, hexane/ethyl acetate 3:1) yields the titie compound: TLC R_f(D)=0.6; t_Rct(H)=17.2 min.

12c) 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-(m-fluorophenylmethyl)-hexanoic acid

Analogously to Example 11), 3.7 g (8.95 mmol) of 5(S)-[l(S)-(Boc-amino)-2-phenyl- ethyl]-3(R)-(m-fluorophenylmethyl)-dihydrofuran-2-(3H)-one are hydrolysed in 140 ml of dimethoxyethane with 35.8 ml of IM lithium hydroxide solution. Extraction of the evaporation residue of the reaction mixture from a mixture of ice, 120 ml of sat. ammonium chloride solution and 240 ml of 10 % citric acid solution using a large quantity of methylene chloride (solubility!) yields the title compound: t_Rct(II)=14.6 min.

12d) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(m-fluoro- phenyl-methyl)-hexanoic acid

Analogously to Example lm), 2.7 g (6.25 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy- 6-phenyl-2(R)-(m-fluorophenylmethyl)-hexanoic acid are silylated in 30 ml of DMF with 4.33 g (28.8 mmol) of tert-butyldimethylchlorosilane and 3.51 g (51.3 mmol) of imidazole. Hydrolysis of the silyl ester function with 5.1 g of potassium carbonate in 100 ml of methanol/THF/water 4: 1 : 1 yields, after column chromatography (SiO₂, hexane/- ethyl acetate 2:1), the titie compound: t_Ret(H)=20.8 min.

Example 13: 5(S)-(Boc-amino)-4(S)-hvdroxy-6-phenyl-2(R)-r(2.4-difluoro-phenyl)- methyll-hexanoyI-(L)-VaI-N-(2-(morpholin-4-yl)-ethyl)amide

Analogously to Example 1, 181 mg (0.234 mmol) of 5(S)-(Boc-amino)-4(S)-(tert-butyldi- methylsilyloxy)-6-phenyl-2(R)-[(2,4-difluoro-phenyl)-methyl]-hexanoyl-(L)-Val-N- (2-(moφholin-4-yl)-ethyl)amide are desilylated in 4 ml of DMF with 148 mg (0.47 mmol) of TBAF. Precipitation with DIPE from a concentrated solution in DMF yields the title compound: TLC R_f(C)=0.1 ; t_Ret(H)=12.6 min; FAB-MS (M+H)⁺=661.

The starting material is prepared as follows:

13a) 5(S)-(Boc-amino)-4(S)- ert-butvIdimethylsilyloxy)-6-phenyl-2(R)-[(2,4- difluoro-phenyl)-methyl]-hexanoyl-(L)-Val-N-(2-(morpholin-4-yl)-ethyl)amide

Under a nitrogen atmosphere, 200 mg (0.354 mmol) of 5(S)-(Boc-amino)-4(S)-(tert-butyl- dimethylsilyloxy)-6-phenyl-2(R)-[(2,4-difluoro-phenyl)methyl]-hexanoic acid [see Exam¬ ple 13d) for preparation] are dissolved in 4.4 ml (1.31 mmol) of 0.3M NMM/DMF, acti¬ vated at RT with 251 mg (0.567 mmol) of BOP and 76.7 mg (0.567 mmol) of HOBT and, after 30 min, reacted with 146.4 mg (0.639 mmol) of H-(L)-Val-N-(2-(moφholin-4-yl)- ethyl)amide (Example lb)). After 21 h, the reaction mixture is worked up analogously to Example lc) to give the title compound: t_Re,(II)=18.9 min.

13b) 5(S)-fl(S)-(Boc-amino)-2-phenyl-ethyl]-3(R)-r(2,4-difluorophenyl)methyll-di- hydrofuran-2-(3H)-one

Analogously to Example 3d), 5.0 g (16.37 mmol) of 5(S)-[l(S)-(Boc-amino)-2-phenyl- ethyl]-dihydrofuran-2-(3H)-one [Example 3c)], dissolved in 100 ml of THF, are deproton¬ ated at -75°C with 32.7 ml of lithium bis(trimethylsilyl)amide, IM in THF. and alkylated at -75°C initially (warming over a period of 2 h to a maximum of -60°C) with 2.51 ml (19.6 mmol) of 2,4-difluorobenzyl bromide (Aldrich; Milwaukee/USA). Column chroma¬ tography (SiO₂, hexane/ethyl acetate 2:1) yields the title compound: TLC R_f(D)=0.5; t_Rct(π)=17.2 min.

13c) 5(S)-(Boc-amino)-4(S)-hvdroxy-6-phenvI-2(R)-[(2.4-difluorophenyl)methvI1- hexanoic acid

Analogously to Example 11), 3.1 g (7.18 mmol) of 5(S)-[l(S)-(Boc-amino)-2-phenyl- ethyl]-3(R)-[(2,4-difluorophenyl)methyl]-dihydrofuran-2-(3H)-one are hydrolysed in 77 ml of dimethoxyethane and 19 ml of water with 28.7 ml of IM lithium hydroxide solution (19 h RT): t_Ret(II)=14.7 min.

13d) S(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenvN2(R)-[(2,4-difluoro- phenyDmethyll-hexanoic acid

Analogously to Example lm), 3.2 g (7.12 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy- 6-phenyl-2(R)-[(2,4-difluorophenyl)methyl]-hexanoic acid are silylated in 67 ml of DMF with 4.93 g (32.7 mmol) of tert-butyldimethylchlorosilane and 3.97 g (58.4 mmol) of imidazole. Hydrolysis of the silyl ester function with 5.9 g of potassium carbonate in 77 ml of methanol, 20 ml of THF and 20 ml of water yields, after column chromatography (SiO₂, hexane/ethyl acetate 2: 1), the title compound: TLC R_f(D)=0.22; t_Ret(H)=20.8 min.

Example 14: 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-{fp-(2-phenyl-ethyP- phenyllmethyl)-hexanoyl-(L)-Val-N-(2-(morpholin-4-yl)-ethyPamide

Analogously to Example 1, 130 mg (0.154 mmol) of 5(S)-(Boc-amino)-4(S)-(tert-butyldi- methylsilyloxy)-6-phenyl-2(R)-{ [p-(2-phenyl-ethyl)phenyl]methyl}-hexanoyl-(L)-Val- N-(2-(moφholin-4-yl)-ethyl)amide are desilylated in 2.2 ml of DMF with 97 mg (0.308 mmol) of TBAF to form the title compound: TLC R_j(A)=0.43; t_Ret(II)=15.3 min; FAB-MS (M+H)⁺=729.

The starting material is prepared as follows: 14a) p-(2-Phenyl-ethyI)-benzyl alcohol

Hydrogenation of 10 g (48 mmol) of 4-stilbenemethanol (Aldrich; Milwaukee/USA) in 100 ml of THF in the presence of 0.5 g of 5 % Pd/C under reduced pressure at RT, filter¬ ing through ®Celite (filtration aid based on kieselguhr, Johns-Manville Coφ., obtainable from Fluka, Buchs, Switzerland) and concentration of the filtrate by evaporation yields the title compound which, according to its Η-NMR spectrum, contains approx. 15 % p-(2- phenyl-ethyl)-toluene: TLC R,{A)=0.62; Η-NMR (200 MHz, CDC1₃): 2.92 (s, 4 H). 4.68 (s, 2 H), 7.15-7.35 (m, 9 H).

14b) p-(2 -Phenyl-ethyD-benzyl bromide

Under a nitrogen atmosphere and with cooling, 3.14 ml (33.4 mmol) of phosphorus tribromide in 11 ml of toluene are added dropwise to 8.36 g (85 % purity; 33.4 mmol) of p-(2-phenyl-ethyl)-benzyl alcohol in 100 ml of toluene. After 2 h at RT, the reaction mixture is poured onto ice-water, and the organic phase is separated off and washed with sat. NaHCO₃ solution, water and brine. The aqueous phases are extracted 2x with ether, and die combined organic phases are dried with Na₂SO₄ and concentrated by evaporation: TLC R,(A)=0.77; Η-NMR (200 MHz, CDC1₃): 2.92 (s, 4 H), 4.50 (s, 2 H), 7.15-7.35 (m, 9 H); additional signals of approx. 20 % p-(2-phenyl-ethyl)-toluene.

14c) S(S)-fl(S)-(Boc-amino)-2-phenvI-ethγn-3(R)-{rp-(2-phenylethvP-phenyll- methyl|-dihydrofuran-2-(3H)-one

Under a nitrogen atmosphere, 28 ml of lithium bis(trimethylsilyl)amide, IM in THF (Aldrich, Steinheim, FRG) are added to a solution of 4.4 g (14.53 mmol) of 5(S)-[1(S)- (Boc-amino)-2-phenylethyl]-dihydrofuran-2-(3H)-one [see Example 3d) for preparation] in 21.4 ml of abs. THF and 2.4 ml of DMPU at -75°C and stirring is then carried out at that temperature for 15 min. Then a solution of 6.0 g (approx. 80 % purity, 17.5 mmol) of p-(2-phenyl-ethyl)-benzyl bromide in 5.4 ml of abs. THF is added dropwise and stirring is carried out at -70°C for 30 min to complete the reaction. Subsequently, at -75°C, 5.4 ml of propionic acid and then 5.4 ml of water are added. The reaction mixture is heated to 0°C, diluted with 150 ml of ethyl acetate and washed with 80 ml of 10 % citric acid solution, sat. sodium hydrogen carbonate solution and brine. The aqueous phases are re-extracted 2x with ethyl acetate, and the organic phases are dried over sodium sulfate and concen¬ trated by evaporation. Column chromatography (SiO₂, hexane/ethyl acetate 3: 1) yields the pure title compound: TLC R_j(E)=0.27; t_Ret(II)=20.8 min; FAB-MS (M-butene+H)⁺=444.

14d) 5(S)-(B oc-amino)-4(S)-hγdroxy-6-phenyl-2(R)-{ f p-(2-phenylethyP-phenyl1- methyl }-hexanoic acid

Under protective gas, 5.15 g (10.31 mmol) of 5(S)-[l(S)-(Boc-amino)-2-phenyl-ethyl]- 3(R)-{ [p-(2-phenylethyl)-phenyl]-methyl}-dihydrofuran-2-(3H)-one are hydrolysed in 166 ml of dimethoxyethane and 85 ml of water with 41 ml of IM lithium hydroxide solution. After 3 h, the dimethoxyethane is evaporated off using a RE and an ice-cold mixture of 506 ml of sat. NH C1 solution, 42 ml of 10 % citric acid solution and 207 ml of methylene chloride is added to the residue. In order to dissolve the product completely, methanol is added. The aqueous phase is separated off and extracted 2x with methylene chloride/methanol 10:1. The organic phases are washed with brine, dried with Na₂SO₄ and concentrated by evaporation: t_Ret(H)=17.8 min.

14e) 5(S)-(Boc-amino)-4(S)-(tert>butyldimethylsilyloxγ)-6-phenvI-2(R)-(rp-(2-phenyl- ethyl)-phenyl1-methyl)-hexanoic acid

Under protective gas, 5.08 g (9.81 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6-phe- nyl-2(R)-{[p-(2-phenylethyl)-phenyl]-methyl}-hexanoic acid are silylated in 22 ml of DMF with 6.80 g (45.1 mmol) of tert-butyldimethylchlorosilane and 5.48 g (80.4 mmol) of imidazole at RT for 20 h. The reaction mixture is poured onto 500 ml of ice-water and extracted 3x with ethyl acetate. The organic phases are washed with 10 % citric acid solution, 2x water and brine, dried with Na₂SO₄ and concentrated by evaporation. The residue is dissolved in 119 ml of methanol and 46 ml of THF, 8.1 g of potassium carbonate and 46 ml of water are added thereto and stirring is carried out at RT for 17 h. The reaction mixture is then poured onto ice-cold 10 % citric acid solution and extracted 3x with ethyl acetate. The organic phases are washed with 2 portions of water and brine, dried with Na₂SO₄ and concentrated by evaporation. Column chromatography (SiO₂, hexane/ethyl acetate 2: 1 — »1:1 — ethyl acetate) results in the pure titie compound: TLC R_f<D)=0.22; t_Ret(H)=23.3 min.

14f) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(rp-(2-phenyl- ethyP-phenyl]-methyl)-hexanoyl-(L)-Val-N-(2-(morpholin-4-yl)-ethyPamide

Analogously to Example 4a), 100 mg (0.158 mmol) of 5(S)-(Boc-amino)-4(S)-(tert-butyl- dimethylsilyloxy)-6-phenyl-2(R)-{ [p-(2-phenylethyl)-phenyl]-methyl }-hexanoic acid and 40 mg (0.174 mmol) of H-(L)-Val-N-(2-(moφholin-4-yl)-ethyl)amide (Example lb)) are reacted in 1.52 ml of NMM/CH₃CN 0.25M with 66 mg (0.174 mmol) of HBTU for 20 h to form the title compound: t_Ret(π)=20.2 min.

Example 15: 5(SHBoc-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(p-benzyloxy-phenyD- methyll-hexanoyl-(L)-Val-N-(2-(morpholin-4-yl)-ethyl)amide

Analogously to Example 1, 326 mg (0.387 mmol) of 5(S)-(Boc-amino)-4(S)-(tert-butyldi- methylsilyloxy)-6-phenyl-2(R)-[(p-benzyloxy-phenyl)methyl]-hexanoyl-(L)-Val-N- (2-(moφholin-4-yl)-ethyl)amide are desilylated in 3.9 ml of DMF with 366 mg (1.16 mmol) of TBAF and worked up. Partition of the crude product between 3x methylene chloride, 2x water and finally brine yields the title compound: TLC R_j(F)=0.35; t_Ret(II)=13.9 min; FAB-MS (M+H)⁺=731. The starting material is prepared as follows:

15a) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-[(p-benzyl- oxy-phenyDmethyl1-hexanoyl-(L)-Val-N-(2-morpholin-4-yl)-ethyDaιτtide

Under protective gas, 245 mg (0.386 mmol) of 5(S)-(Boc-amino)-4(S)-(tert-butyldi- methylsilyloxy)-6-phenyl-2(R)-[(p-benzyloxy-phenyl)methyl]-hexanoic acid [see Exam¬ ple 15e) for preparation] and 97.5 mg (0.425 mmol) of H-(L)-Val-N-(2-moφholin-4-yl- ethyl)amide (Example lb)) are dissolved in 3.5 ml of 0.25M NMM/CH₃CN and reacted witii 161 mg (0.425 mmol) of HBTU. After 3 h, the reaction mixture is worked up analog¬ ously to Example 4a) to give the titie compound: t_Ret(H)=19.4 min; FAB-MS (M+H)⁺=846.

15b) p-Benzyloxy-benzyl iodide

A solution of 1.0 g (4.3 mmol) of 4-benzyloxy-benzyl chloride (Fluka; Buchs, Switzer¬ land) in 8 ml of acetone is stirred at RT with 3.13 g (20.9 mmol) of sodium iodide. According to a gas chromatogram, the reaction is complete after 90 min and, therefore, the reaction mixture is poured onto ether and washed with 10 % sodium thiosulfate solution and brine. Drying of the organic phase with Na₂SO₄ and concentration by evaporation yields the title compound: ^lH-NMR (200 MHz, CDC1₃: 4.48 (s, 2 H), 5.06 (s, 2 H), 6.85-6.95 (m, 2 H), 7.25-7.48 (m, 7 H).

15c) 5(S)-[l(S)-(Boc-amino)-2-phenyl-ethγn-3(R)-(p-benzyloxy-phenylmethvP-di- hydrofuran-2-(3H)-one

Analogously to Example 3d), 1.13 g (3.70 mmol) of 5(S)-[l(S)-(Boc-amino)-2-phenyl- ethyl]-dihydrofuran-2-(3H)-one [Example 3c)], dissolved in 4.8 ml of THF and 0.75 ml of DMPU, are deprotonated at -75°C with 7.25 ml of lithium bis(trimethylsilyl)amide, IM in THF, and alkylated (15 min) with 1.2 g (3.7 mmol) of p-benzyloxy-benzyl iodide in 2 ml of THF. Column chromatography (SiO₂, hexane/ethyl acetate 2: 1) yields the pure titie compound: TLC R_f(D)=0.30; t_Ret(I)=28.2 min; FAB-MS (M+H)⁺=502.

15d) 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-(p-benzyloxy-phenylmethyP- hexanoic acid

Analogously to Example 11), 1.4 g (2.79 mmol) of 5(S)-[l(S)-(Boc-amino)-2-phenyl- ethyl]-3(R)-(p-benzyloxy-phenylmethyl)-dihydrofuran-2-(3H)-one are hydrolysed in 45 ml of dimethoxyethane and 23 ml of water with 11 ml of IM lithium hydroxide solution. After being partially concentrated by evaporation, the reaction mixture is poured onto a mixture of ice, 137 ml of sat. NH₄C1 solution, 1 1 ml of 10 % citric acid solution and 56 ml of methylene chloride, and methanol is added until the solid which has precipi¬ tated dissolves. The aqueous phase is extracted with 2 portions of methylene chloride/- methanol approx. 10: 1, and the organic phases are washed with brine, dried with Na₂SO₄ and concentrated by evaporation: t_Ret(I)=24.0 min; FAB-MS (M+H)⁺=520.

15e) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(p-benzyIoxy- phenyl-methyp-hexanoic acid

Analogously to Example lm), 1.4 g (2.69 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6- phenyl-2(R)-(p-benzyloxy-phenylmethyl)-hexanoic acid are silylated in 2.9 ml of DMF with 1.87 g (12.4 mmol) of tert-butyldimethylchlorosilane and 1.5 g (22 mmol) of imidazole. Hydrolysis of the silyl ester function with 2.2 g of potassium carbonate in 63 ml of methanol/THF/water 3:1:1 and column chromatography (SiO₂, hexane/ethyl acetate 2:1) of the crude product yields the titie compound: TLC R_f(D)=0.17; t_Ret(I)=33.7 min; FAB-MS (M+H)⁺=634.

Example 16: 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(p-hydroxy-phenyl)- methyll-hexanoyl-(L)-Val-N-(2-(morpholin-4-yl)-ethyPamide

Low-pressure hydrogenation at RT of a solution of 80 mg (0.109 mmol) of 5(S)-(Boc- amino)-4(S)-hydroxy-6-phenyl-2(R)-[(p-benzyloxy-phenyl)methyl]-hexanoyl-(L)-Val-N- (2-(moφholin-4-yl)-ethyl)amide (Example 15) in 6 ml of methanol in the presence of 20 mg of 10 % Pd/C yields, after removal of the catalyst by filtration and concentration by evaporation, the titie compound: TLC R_f(F)=0.28; t_Ret(II)=10.9 min; FAB-MS (M+H)⁺=641.

Example 17: 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-(phenyl-methyP- hexanoyl-(L)-Val-N-(2-methyl-2-morpholino)propylamide

Analogously to Example 1, 1.03 g (1.34 mmol) of 5(S)-(Boc-amino)-4(S)-(tert-butyldi- methylsilyloxy)-6-phenyl-2(R)-(phenyl-methyl)-hexanoyl-(L)-Val-N-(2-methyl-2-mor- pholino)propylamide are reacted in 14 ml of DMF with 0.854 g (2.68 mmol) of TBAF tri- hydrate to form the title compound. After working-up, stirring with diethyl ether and column chromatography (SiO₂, A), the pure title compound is obtained. TLC R_f (A) = 0.23; t_Ret(II)= 12.35 min; FAB-MS (M+H⁺)= 653 The starting compound is prepared as follows: 17a) 2-Methyl-2-morpholino-propionitrile

A mixture of 42.5 g (45.75 mmol) of acetone cyanohydrin (Aldrich, Steinheim, FRG), 43.55 ml (45.75 mmol) of moφholine and 43 g of magnesium sulfate is stirred at 60°C for 2.5 h. After a further addition of a total of 25 ml of moφholine and stirring for a further 2.5 h, the reaction mixture is stirred overnight at RT to complete the reaction. After extractions with ether, the crude product is obtained which is distilled for purification puφoses, yielding the title compound. B.p. (20 mbar): 108°C. IR (CH₂C1₂) cπr¹: 2970, 2860, 2220, 1455, 1120, 970.

17b) 2-Methyl-2-morpholino-propionamide

A mixture of 11.5 g (75 mmol) of 2-methyl-2-moφholino-propionitrile and 54 ml of concentrated sulfuric acid is heated to 100-110°C and, after the addition of 8.4 ml of water, the mixture is stirred at that temperature for a further 2 h. After cooling to 70°C, the solution obtained is added dropwise to a mixture, stirred at from -20° to 0°C, of 168 ml of 20 % aqueous ammonia solution. The clear yellow solution changes into a suspension. The resulting reaction mixture is extracted 3 times with 70 ml of methylene chloride each time. The combined extracts are washed with brine and dried over sodium sulfate. After concentration under reduced pressure, the title compound is obtained. IR (CH₂C1₂) cm"¹: 3500, 3380, 2980, 2860, 1690, 1555, 1200, 1140.

17c) (2-Methyl-2-morphoIino)propylamine

A solution of 8.33 g (50 mmol) of (2-methyl-2-moφholino)propionamide in 50 ml of THF is added dropwise, over a period of 15 min with vigorous stirring, to a suspension of 3.33 g (90 mmol) of lithium aluminium hydride in 85 ml of THF. After stirring for 2 h under reflux conditions, the reaction mixture is cooled to 0°C and 5 ml of water are added thereto over a period of 25 min. After the further addition of 6.67 ml of 2N sodium hydr¬ oxide solution and 5 ml of water, the resulting suspension is filtered off and rinsed with methylene chloride. The resulting filtrate is washed with brine, dried over sodium sulfate and concentrated to give the title compound. 'H-NMR (CDC1₃) δ (ppm): 0.92 (6H, s), 1.36 (2H, broad), 2.47 (4H, m), 2.51 (2H, s), 3.67 (4H, m).

17d) Z-(L)-Val-N-(2-methyl-2-morpholino)propylamide

A solution of 7.53 g (30 mmol) of Z-(L)-valine in 150 ml of methylene chloride is cooled to 0°C and there are added thereto in succession 6.18 g (30 mmol) of DCC and 4.46 g (33 mmol) of HOBT. After 20 min, the mixture is treated over a period of 15 min with a - I l l -

solution of 4.74 g (30 mmol) of (2-methyl-2-moφholino)propylamine in 100 ml of methylene chloride. After stirring at RT for 19.5 h to complete the reaction, the solid (urea derivative) is removed by filtration. The filtrate is washed in succession with NaHCO₃ solution, water and brine and dried over sodium sulfate. After concentration under reduced pressure, the crude product is further processed without additional purifica¬ tion. TLC R_f (A)= 0.3.

17e) H-(L)- VaI-N-(2-methyl-2-morpholino)propylamide

Analogously to Example 5b), 11.7 g (30 mmol) of Z-(L)-Val-N-(2-methyl-2-moφholino)- propylamide are hydrogenated in 350 ml of methanol in the presence of 2.4 g of 10 % Pd/C. The title compound obtained after working-up is further reacted without additional purification; TLC R_f (B)= 0.33.

17f) 5(S)-ri(S)-(Boc-amino)-2-phenylethyn-3(R)-phenylmethyl-dihydrofuran-2-(3H)- one

(See also A.K. Ghosh, S.P. McKee, and WJ. Thompson, J. Org. Chem. 56, 6500 (1991)). Under a nitrogen atmosphere, a solution of 1943 g (6.32 mol) of 5(S)-[l(S)-(Boc-amino)- 2-phenylethyl]-dihydrofuran-2-(3H)-one (Example 3c)) in 12.01 of THF and 1.9 1 of DMPU is cooled to -75 °C and, at an internal temperature of below -70°C, 14000 ml of lithium bis(trimethylsilyl)amide (IM) in THF (Aldrich) are added thereto and stirring is then carried out at -75°C for 20 min. 835 ml (7.00 mol) of benzyl bromide are added drop¬ wise over a period of 1 h, during which the internal temperature must not exceed -70°C, and stirring is carried out at -75°C for 30 min to complete the reaction. There are then added to the clear solution, at from -75° to -70°C, 2320 ml of propionic acid (90 min) and then 2320 ml of water (1 h), the temperature being allowed to rise to -10°C. The reaction mixture is poured onto 30 1 of ethyl acetate and 35 1 of 10 % citric acid solution and the aqueous phase is separated off and re-extracted with 2x 101 of ethyl acetate. The organic phases are washed with 3x 12 1 of sat. sodium hydrogen carbonate solution, 201 of brine and 2x 201 of water and are concentrated, and the oily residue is taken up in 101 of toluene and concentrated by evaporation to a residual volume of approx. 5 1. Filtration of the evaporation residue through 4 kg of silica gel Merck (0.063-0.200 mm), rinsing with toluene and crystallisation of the crude product from hexane (41 of hexane/kg of crude product) yields the title compound: TLC R_f(D)=0.54; FAB-MS (M+H)⁺=414. 17g) 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-phenylmethyl-hexanoic acid 176 ml of a IM lithium hydroxide solution are added dropwise at 20°C within a period of 10 min to a solution of 17.6 g of 5(S)-[l(S)-(Boc-amino)-2-phenylethyI]-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 concentrated by evaporation. The residue is poured onto 1 1 of cold 10 % citric acid and the acid solution is extracted three times with 800 ml of ethyl acetate each time. The combined extracts are washed first with 800 ml of water, 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 step without further purification. FAB-MS (M+H)⁺= 414.

17h) 5(S)-(Boc-amino)-4(S)-(tert-butγldimethylsiIyloxy)-6- phenyl-2(R. -phenyl - methyl-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 at RT for 18 h, 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 tert-butyldimethylsilyl ether (13.5 g) so obtained is dissolved in 53 ml of THF and treated with 53 ml of acetic acid and 20 ml of water. After stirring at RT for 3 h, the reaction mixture is poured onto water and extracted three times with ether. The ether extracts are collected, washed twice with water and once with brine and dried over sodium sulfate. After concentration, the crude product is purified by column chroma¬ tography (SiO₂, hexane/ethyl acetate: 3.5/1.5) and the title compound is obtained. TLC R_f (D)= 0.37; FAB-MS (M+H)⁺= 528.

17i) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2-(R)-(phenyl- methyD-hexanoy_-(L)-Val-N-(2-methyl-2-morpholino)propylamide

A solution of 1.05 g (2 mmol) of H-(L)-Val-N-(2-methyl-2-moφholino)propylamide in 15 ml DMF is treated in succession with 0.98 g (2.2 mmol) of BOP, 0.3 g (2.2 mmol) of HOBT and 0.55 ml of N-methylmoφholine (NMM). After stirring the reaction mixture at RT for 0.5 h, a solution of 0.62 g (2.42 mmol) of 5(S)-(Boc-amino)-4(S)-(tert-butyl- dimethylsilyloxy)-6-phenyl-2(R)-(phenyl-methyl)-hexanoic acid in 5 ml of DMF is added thereto. After 3 h, the reaction mixture is poured onto 300 ml of water and extracted 3 times with ethyl acetate. The combined organic phases are washed in succession with 50 ml each of water, aqueous sodium hydrogen carbonate solution, water and brine and, after drying over sodium sulfate, are concentrated using a rotary evaporator. The title compound is purified by column chromatography (SiO₂, A); TLC R_f (A) = 0.27.

Example 18: 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl«2(R)-(phenyl-methvP- hexanoyl-(L)-Val-N-(2-morpholino)ethylamide

Analogously to Example 1, 0.38 g (0.514 mmol) of 5(S)-(Boc-amino)-4(S)-(tert-butyl- dimethylsilyloxy)-6-phenyl-2(R)-(phenyl-methyl)-hexanoyl-(L)-Val-N-(2-moφholino)- ethylamide is reacted in 5 ml of DMF with 0.325 g (1.028 mmol) of TBAF trihydrate to form the title compound. After working up, stirring with diethyl ether and filtration, the pure titie compound is obtained. TLC R_f (CHCl₃/MeOH/H₂O/AcOH: 85/13/1.5/0.5) = 0.48; t_Ret(I)= 16.2 min; FAB-MS (M+H⁺)= 625.

The starting compound is prepared as follows:

18a) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(phenyl- methyP-hexanoyl-(L)-Val-N-(2-morpholino)ethylamide

A solution of 0.3 g (0.569 mmol) of 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)- 6-phenyl-2(R)-(phenyl-methyl)-hexanoic acid (Example 17h)), 0.277 g (0.626 mmol) of BOP, 0.085 g (0.626 mmol) of HOBT and 0.157 ml (1.425 mmol) of N-methylmoφholine in 5 ml of DMF is stirred at RT for 30 min and then 0.158 mg (0.686 mmol) of H-(L)- Val-N-(2-moφholino)ethylamide (Example lb)) is added thereto. After stirring at RT for 4 h, the reaction mixture is poured onto 300 ml of water and extracted 3 x with ethyl acetate. The combined organic phases are washed with water, saturated sodium bicar¬ bonate solution (twice) and brine and, after drying over sodium sulfate, are concentrated under reduced pressure. The title compound is purified by column chromatography (SiO₂, ethyl acetate/methanol 9/1); TLC R_f (ethyl acetate/methanol 7/1)= 0.65; t_Ret(I)= 27.16 min. FAB-MS (M+H⁺)= 739.

Example 19: 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-(phenyl-methyl)-hex- anoyl-(L)-Ile-N-(2-morpholino)ethylamide

Analogously to Example 1, 0.317 g (0.421 mmol) of 5(S)-(Boc-amino)-4(S)-(tert-butyl- dimethylsilyloxy)-6-phenyl-2(R)-(phenyl-methyl)-hexanoyl-(L)-Ile-N-(2-moφholino)- ethylamide is reacted in 5 ml of DMF with 0.265 g (0.842 mmol) of TBAF trihydrate to form the title compound. After working up, stirring with diethyl ether and filtration, the pure title compound is obtained. TLC R_f (CHCl₃/MeOH/H₂O/AcOH: 85/13/1.5/0.5) = 0.63; t_Ret(I)= 17.49 min; FAB-MS (M+H⁺)= 639.

The starting compound is prepared as follows:

19a) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(phenyl- methyP-hexanoyl-(L)-Ile-N-(2-morpholino)ethylamide

Analogously to Example 18a), a solution of 0.3 g (0.568 mmol) of 5(S)-(Boc-amino)- 4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(phenyl-methyl)-hexanoic acid (Exam¬ ple 17h)), 0.277 g (0.625 mmol) of BOP, 0.085 g (0.626 mmol) of HOBT and 0.219 ml (1.989 mmol) of N-methylmoφholine in 5 ml of DMF is stirred at RT for 30 min and then 0.166 mg (0.682 mmol) of H-(L)-Ile-N-(2-moφholino)-ethylamide (Example 5b)) is added tiiereto. After stirring at RT for 2 h, the reaction mixture is poured onto 100 ml of water and worked up. The title compound is purified by column chromatography (SiO , A); TLC R_f (ethyl acetate/acetone: 9/1)= 0.3; t_Ret(I)= 28.75 min. FAB-MS (M+H⁺)= 753.

Example 20: 5(S)-(N-(Z-(L)-VaPamino)-4(S)-hydroxy-6-phenyl-2(R)-(phenyl- methyl)-hexanoyl-(L)-Val-N-(2-morpholino)ethylamide

Analogously to Example 18a), a solution of 0.094 g (0.375 mmol) of Z-(L)-valine, 0.182 g (0.412 mmol) of BOP, 0.056 g (0.412 mmol) of HOBT and 0.093 ml (0.84 mmol) of N-methylmoφholine in 3 ml of DMF is stirred at RT for 1.25 h and then 0.164 mg (0.312 mmol) of 5(S)-amino-4(S)-hydroxy-6-phenyl-2(R)-(phenyl-methyl)-hexanoyl- (L)-Val-N-(2-mθφholino)ethylamide is added thereto. After stirring at RT for 2 h, the reaction mixture is worked up and the resulting crude compound is purified by being stirred in ether to yield the title compound. TLC R_f (B)= 0.57; t_Ret(I)= 17.35 min. FAB-MS (M+H⁺)= 758.

The starting compound is prepared as follows:

20a) 5(S)-Amino-4(S)-hvdroxy-6-phenyl-2(R)-(phenyl-methvP-hexanoyl-(L)-Val-

N-(2-morpholino)ethylamide

210 mg (0.336 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-(phenyl- methyl)-hexanoyl-(L)-Val-N-(2-moφholino)ethylamide (Example 18) are suspended in 3 ml of methylene chloride and, at RT, 3 ml of trifluoroacetic acid are added thereto. After stirring at RT for 2 h, the reaction mixture is concentrated and partitioned between ethyl acetate and aqueous sodium hydrogen carbonate solution. The organic phase is washed with water and brine, and then dried over sodium sulfate and concentrated by evaporation. The title compound so obtained is further reacted without additional purification. t_Ret(I)= 8.3 min. Example 21: 5(S)-(Boc-amino)-4(S)-hvdroxy-6-phenyl-2(R)-(isobutyl)-hexanoyl-(L)- Val-N-(2-morpholino)ethylamide

Analogously to Example 1, 1 g (1.418 mmol) of 5(S)-(Boc-amino)-4(S)-(tert-butyl- dimethylsilyloxy)-6-phenyl-2(R)-(isobutyl)-hexanoyl-(L)-Val-N-(2-moφholino)ethyl- amide is reacted in 7 ml of DMF with 0.896 g (2.841 mmol) of TBAF trihydrate to form the titie compound. After working up, stirring with diethyl ether and filtration, the pure title compound is obtained. TLC R_f (CHCl₃/MeOH/H₂O/AcOH: 85/13/1.5/0.5) = 0.3; t_Ret(H)= 11.74 min; FAB-MS (M+H⁺)= 591.

The starting compound is prepared as follows:

21 a) 5(S)-f l(S)-(Boc-amino)-2-phenyl-ethyIl-3(R)-[3-(2-methyl-propenyPl-dihvdro- furan-2-(3H)-one

Analogously to Example 14c), 118 ml of lithium bis(trimethylsilyl)amide, IM in THF, and 7.49 ml (64.9 mmol) of isobutenyl bromide (2-bromomethyl-l-propene; Aldrich, Steinheim, FRG) in 49 ml of THF are added in succession, at -78°C, to 17.99 g (59 mmol) of 5(S)-[l(S)-(Boc-amino)-2-phenyl-ethyl]-dihydro-furan-2-(3H)-one (Example 3c)) in 600 ml of THF. After the addition of 33 ml (436.6 mmol) of propionic acid and subse¬ quent working-up, the crude title compound is obtained, which is purified by column chromatography (SiO₂, ethyl acetate/hexane: 1/8). TLC R_f (E)= 0.5; t_Ret(II)= 16.64 min.; FAB-MS (M+H⁺)= 360.

21 b) 5(S)-[l(S)-(Boc-amino)-2-phenyl-ethyll-3(R)-(isobutyP-dihvdro-furan-2-(3H)- one

12.8 g (35.4 mmol) of 5(S)-[l(S)-(Boc-amino)-2-phenyl-ethyl]-3(R)-[3-(2-methyl-propen- yl)]-dihydro-furan-2-(3H)-one are dissolved in 600 ml of ethyl acetate and hydrogenated in the presence of 1 g of 10 % Pd/C at normal pressure for 14 h. After working-up, column chromatography (SiO₂, ethyl acetate/hexane: 1/9 to 1/1) results in the title compound. TLC R_f (ethyl acetate/hexane: 1/3)= 0.56; t_Ret(II)= 17.22 min.; FAB-MS (M+H⁺)= 362.

21 c) 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-(isobutyp-hexanoic acid

Analogously to Example 14d), 9.2 g (24.45 mmol) of (5(S)-[l(S)-(Boc-amino)-2-phenyl- ethyl]-3(R)-(isobutyl)-dihydro-furan-2-(3H)-one are hydrolysed in 102 ml of dimethoxy¬ ethane by the addition of 102 ml of IM lithium hydroxide solution. After working-up and crystallisation from hexane/ethyl acetate, the pure title compound is obtained. TLC R_f (B)= 0.37; t_RcI(II)= 14.44 min; FAB-MS (M+H⁺)= 380. 21 d) S(S)-(Boc-amino)-4(S)-(tert-butyldimethylsiIyloxy)-6-phenyl-2(R)-(isobutyl)- hexanoic acid

Under an argon atmosphere, 14.9 g (98.95 mmol) of tert-butyldimethylchlorosilane and 12.5 g (189.07 mmol) of imidazole are added to an ice-cooled solution of 8.5 g (22.4 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-(isobutyl)-hexanoic acid in 40 ml of DMF. After 17 h at RT, the reaction mixture is poured onto 400 ml of ice-water and extracted 3 times with 150 ml of ethyl acetate each time. The combined organic phases are washed in succession, twice in each case, with 150 ml of water, saturated NaHCO₃ solution, water and 10 % citric acid solution, water and brine, then dried with Na₂SO₄ and finally concentrated by evaporation. The residue is dissolved in 100 ml of tetrahydrofuran, and 100 ml of acetic acid and 34 ml of water are poured into the solution. After a reaction time of 16 h with stirring, the reaction mixture is poured onto 1 1 of water and extracted 3 times with 200 ml of ethyl acetate each time. The combined organic phases are washed twice with 100 ml of H₂O and brine each time, dried over Na₂SO₄ and concentrated by evaporation. Finally, column chromatography (SiO₂, ethyl acetate/- hexane: 1/3) results in the title compound. TLC R_f (ethyl acetate/hexane: 1/3)= 0.53; t_Ret(H)= 21.75 min.

21 e) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(isobutyP- hexanoyl-(L)-Val-N-(2-morpholino)ethylamide

Analogously to Example 18a), a solution of 0.9 g (1.822 mmol) of 5(S)-(Boc-amino)- 4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(isobutyl)-hexanoic acid, 0.887 g (2 mmol) of BOP, 0.272 g (2 mmol) of HOBT und 0.5 ml (4.54 mmol) of N-methylmor- pholine in 15 ml of DMF is stirred at RT for 30 min and then 0.506 mg (2.21 mmol) of H-(L)-Val-N-(2-moφholino)ethylamide (Example lb)) is added thereto. After stirring at RT for 4 h, the reaction mixture is poured onto 500 ml of water and worked up. The title compound is purified by column chromatography (SiO₂, ethyl acetate/acetone: 2/1); TLC R_f (ethyl acetate/acetone: 2/1)= 0.37; t_Ret(II)= 18.37 min. FAB-MS (M+H⁺)= 705.

Example 22: 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-f(p-(ethoxycarbonyl- methoxy)-phenyl)-methyIl-hexanoyl-(L)-Val-N-(2-morpholin-4-yl-ethyl)amide:

A suspension consisting of 617 mg (0.65 mmol) of 5(S)-(Boc- amino)-4(S)-hydroxy- 6-phenyl-2(R)-[p-hydroxy-phenyl)-methyl]-hexanoyl-(L)-Val-N-(2-moφholin-4-yl-ethyl)- amide from Example 16 and 758 mg of caesium carbonate in 54 ml of dioxane is stirred at RT under a nitrogen atmosphere for 16 h and then 3.57 ml of bromoacetic acid ethyl ester are added thereto. After 6 h, the reaction mixture is diluted with methylene chloride and the precipitate is removed by filtration. The filtrate is concentrated by evaporation and, after digestion of the residue with ethyl acetate/hexane, yields the title compound in die form of a white solid. TLC R_f(M)= 0.4; ^(1)= 12.4 min.; FAB-MS (M+H)⁺= 727.

Example 23: 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyI-2(R)-[(p-(carboxy-methoxy)- phenyP-methyl] ■hexanoyl-(L)-Val-N-(2-morpholin-4-yl-ethyPamide:

34 mg of lithium hydroxide are added to a solution of 109 mg (0.15 mmol) of 5(S)- (Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(p-(ethoxycarbonyl-methoxy)-phenyl)- methyl]-hexanoyl-(L)-Val-N-(2-moφholin-4-yl-ethyl)amide from Example 22 in 6.8 ml of methanol and 0.68 ml of water and the reaction mixture is stirred at RT for 2 h. For working-up, the reaction mixture is concentrated by evaporation, and the residue is dissolved in methylene chloride and washed in succession with sat. ammonium chloride solution, which is adjusted to pH 4 with citric acid, and brine. The organic phases are dried with sodium sulfate and concentrated by evaporation in vacuo. After digestion with hexane, the title compound is obtained in the form of a white solid. TLC R_f(M)= 0.07; ^,(1)= 10.9 min.; FAB-MS (M+H)⁺= 699.

Example 24: 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(p-(carbamoyl- methoxy)-phenyP-methyn-hexanoyl-(L)-Val-N-(2-morpholin-4-yl-ethypamide:

Analogously to Example 22, the titie compound is obtained from 96 mg (0.15 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(p-hydroxy-phenyl)-methyl]-hexanoyl- (L)-Val-N-(2-moφholin-4-yl-ethyl)amide from Example 16, 122 mg of caesium carbonate and 257 mg of chloroacetamide (Fluka, Buchs, Switzerland), after purification by chroma¬ tography on silica gel using system B as eluant (the reaction mixture being heated at 80°C for 3 h, however, before no more starting material is detectable according to TLC monitor¬ ing). TLC R_f(M)= 0.60; ^,(1)= 10.5 min.; FAB-MS (M+H)⁺= 698.

Example 25: 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(p-(cyanomethoxy)- phenyP-methyn-hexanoyl-(L)-Val-N-(2-morpholin-4-yl-ethypamide:

Analogously to Example 24, the title compound is obtained from 128 mg of 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(p-hydroxy-phenyl)-methyl]-hexanoyl- (L)-Val-N-(2-moφholin-4-yl-ethyl)amide from Example 16, 233 mg of caesium carbonate and 1.129 g (9.42 mmol) of bromoacetonitrile, after purification by chromatography on silica gel using methylene chloride/methanol (95:5) as eluant. TLC R_f(L)= 0.50; ^,(1)= 1 1.8 min.; FAB-MS (M+H)⁺= 680. Example 26: 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-f(p-methoxyphenyl)- methyl]-hexanoyl-(L)-Val-N-(2-morpholin-4-yl-ethyl)amide:

Analogously to Example 22, the title compound is obtained from 64 mg (0.1 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(p-hydroxy-phenyl)-methyl]-hexanoyl- (L)-Val-N-(2-moφholin-4-yl-ethyl)amide from Example 16, 117 mg (0.35 mmol) of caesium carbonate and 0.146 ml (2.35 mmol) of methyl iodide, after purification by chromatography on silica gel using methylene chloride/methanol (95:5) as eluant. TLC R_f(L)= 0.35; t_ret(I)= 12.2 min.; FAB-MS (M+H)⁺= 655.

Example 27: 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(p-(morpholinyl-N- ethoxy)-phenyP-methyl]-hexanoyl-(L)-Val-N-(2-morpholin-4-yl-ethyl)amide:

A suspension of 96 mg (0.15 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)- [(p-hydroxy-phenyl)-methyl]-hexanoyl-(L)-Val-N-(2-moφholin-4-yl-ethyl)amide from Example 16 and 122 mg of caesium carbonate in 8 ml of dioxane is stirred at RT under a nitrogen atmosphere for 16 h and then 412 mg of 4-(2-chloroethyl)moφholine (freed from the HC1 salt (Fluka, Buchs, Switzerland) with sodium hydrogen carbonate solution) are added thereto. The reaction mixture is heated at 80°C for 3 h before no more starting material is detectable according to TLC monitoring (eluant M). The reaction mixture is diluted with methylene chloride and the precipitate is removed by filtration. The filtrate is concentrated by evaporation and, after digestion of the residue with ethyl acetate/hexane, yields the title compound. TLC R_f(M)= 0.34; ^,(1)= 9.5 min.; FAB-MS (M+H)⁺= 754.

Example 28: 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(4-{2-hydroxy-ethoxy}- phenyP-methyl]-hexanoyl-(L)-Val-N-(2-morpholin-4-yl-ethyl)amide:

0.44 ml of a 2M solution of lithium borohydride in THF is added to a solution of 109 mg (0.15 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(p-(ethoxycarbonyl- methoxy)-phenyl)-methyl]-hexanoyl-(L)-Val-N-(2-moφholin-4-yl-ethyl)amide (Exam¬ ple 22) in 18 ml of dimethoxyethane and the reaction mixture is stirred at RT under a nitrogen atmosphere for 5 h. For working-up, at 0°C, aqueous 10 % citric acid is added dropwise and the mixture is extracted with methylene chloride. The organic phases are washed with sat. sodium hydrogen carbonate solution, dried with sodium sulfate and concentrated by evaporation. After separation of the resulting mixture by chromatography on silica gel using system L as eluant, the title compound is obtained in the form of an a oφhous solid. TLC R_f<M)= 0.4; t_rc((I,= 10.8 min.; FAB-MS (M+H)⁺= 685. - 119 -

Example 29: 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(p-(2-(methoxy)- ethoxy}-phenyP-methyl1-hexanoyl-(L)-Val-N-(2-morpholin-4-yl-ethyPamide:

Analogously to Example 22, the title compound is obtained from 100 mg (0.15 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(p-hydroxy-phenyl)-methyl]-hexanoyl- (L)-Val-N-(2-moφholin-4-yl-ethyl)amide from Example 16, 183 mg (0.35 mmol) of caesium carbonate and 0.3 g (1.5 mmol) of 2-methoxyethyl iodide (the reaction mixture being heated at 80°C for 3 h, however, before no more starting material is detectable according to TLC monitoring), after purification by chromatography on silica gel using methylene chloride/methanol (95:5) as eluant, followed by crystallisation from hot ethyl acetate. TLC R_f(L)= 0.4; ^(1)= 12.1 min.; FAB-MS (M+H)⁺= 699.

29a) 2-Methoxy-ethyl iodide

80.1 g (534 mmol) of Nal are added in portions to a solution of 10 ml (109 mmol) of 2-chloroethyl methyl ether in 205 ml of acetone and the reaction mixture is boiled under reflux for 20 h. Partitioning of the reaction mixture between 2 portions of ether and brine, drying of the organic phases with Na₂SO₄ and concentration by evaporation (RT, 300 mbar) yields the titie compound: Η-NMR (200 MHz, CDC1₃): 3.25 (t,J=7 Hz,2 H), 3.39 (s,3 H), 3.65 (t,J=7 Hz,2 H).

Example 30: Capsules

A compound of formula I according to any one of the aforementioned Examples (active ingredient) is micronised (particle size approx. from 1 to 100 μm) using a conventional cutter-mixer (e.g. Turmix). ®Pluronic F 68 (block polymer of polyethylene and poly¬ propylene glycols; Wyandotte Chem. Coφ., Michigan, USA; also obtainable from Emkalyx, France; Trade Mark of BASF) is also micronised using a conventional mixer and the fine portion is removed with a sieve (0.5 mm) and further used as described below. 16.00 g of sesame oil are placed in a beaker and, while stirring with a stirring apparatus (IKA-Werk, FRG) that is combined with a toothed stirrer (diameter: 46 mm) (stirring speed: 2000 rev/min), 1.20 g of the micronised active ingredient, 1.20 g of the fine portion of ®Pluronic F 68 and 1.20 g of hydroxypropylmethylcellulose (cellulose HP-M-603 from Shin-Etsu Chemicals Ltd., Tokyo, Japan) are added. By stirring for 20 min at the stirring speed indicated a suspension of pasty consistency is obtained which is introduced into hard gelatin capsules (20 x 40 mm; R. P. Scherer AG, Eberbach, FRG). Example 31: Gelatin solution:

A sterile-filtered aqueous solution, comprising 20 % cyclodextrins as solubilisers, of one of the compounds of formula I mentioned in the preceding Examples as the active ingred¬ ient is so mixed with a sterile gelatin solution comprising phenol as preservative, with heating under aseptic conditions, that 1.0 ml of solution has the following composition:

active ingredient 3 mg gelatin 150.0 mg phenol 4.7 mg dist. water comprising 20 % cyclodextrins as solubilisers 1.0 ml

Example 32: Sterile dry substance for injection

5 mg of one of the compounds of formula I mentioned in the preceding Examples, as active ingredient, are dissolved in 1 ml of an aqueous solution comprising 20 mg of mannitol and 20 % cyclodextrins as solubilisers. The solution is sterile-filtered and intro¬ duced under aseptic conditions into a 2 ml ampoule, deep-frozen and lyophilised. Before use, the lyophilisate is dissolved in 1 ml of distilled water or 1 ml of physiological saline. The solution is administered intramuscularly or intravenously. This formulation can also be introduced into double-chamber disposable syringes.

Example 33: Nasal spray:

500 mg of a finely ground (<5.0 μm) powder of one of the compounds of formula I mentioned in the preceding Examples, as active ingredient, are suspended in a mixture of 3.5 ml of Myglyol 812® and 0.08 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 under pressure through the valve. By shaking, the "Freon" is dissolved in the Myglyol- benzyl alcohol mixture. This spray container contains approximately 100 single doses which can be administered individually.

Example 34: Film-coated tablets

For the preparation of 10000 tablets each comprising 100 mg of active ingredient the following constituents are processed:

active ingredient 1000 g corn starch 680 g - 121 -

colloidal silica 200 g magnesium stearate 20 g stearic acid 50 g sodium carboxymethyl starch 250 g water quantum satis

A mixture of one of the compounds of formula I mentioned in the preceding Examples, as active ingredient, 50 g of corn starch and the colloidal silica is processed with a starch paste prepared from 250 g of corn starch and 2.2 kg of demineralised water to form a moist mass. The mass is forced through a sieve of 3 mm mesh size and dried in a fluidised bed drier at 45° for 30 min. The dried granules are pressed through a sieve of 1 mm mesh size, 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 the resulting mixture is compressed to form slightly convex tablets.

Example 35: Inhibition of HIV-1 protease

In accordance with the method described at the beginning for measuring the inhibition of HTV protease in the presence of the icosapeptide RRSNQVSQNYPIVQNIQGRR, the following IC₅₀ values are obtained:

Example IC₅₀ (μM)

1 0.043

2 0.005

3 0.027

4 0.026

6 0.021

7 0.038

8 0.148

9 0.58

10 0.208

11 0.014

12 0.08

13 0.027

14 0.147

15 0.023 16 0.052 17 0.31 18 0.052 19 0.075 21 0.298 22 0.009 23 0.0056 24 0.03 25 0.018 26 0.023 27 0.062 28 0.03 29 9.026

Example 36: Inhibition of the growth of the virus in MT2 cells

In accordance with the method described at the beginning, the ED₉₀ (effective dose at which only 10 % of the viruses are still found in comparison with a control in the absence of an inhibitor) is determined by measuring the activity of reverse transcriptase. Only the results of measurements resulting in accurate ED₉₀ values are given:

Example EDrø (μM)

1 1

11 0.1

12

13

14

15 0.1

16 10

18

19

21 10

24 10

25 0.3

26 0.1

27 10 28 1

29 1

Example 37: Blood levels in mice

In accordance with the method described at the beginning for determining blood levels, d e following blood levels are obtained in mice for the compound from Example 18:

Example blood level (μM) after

30 min 90 min

18 15.05 2.24

Claims

What is claimed is:

1. A compound of formula I

wherein

Ri is an acyl radical selected from

(c) arylcarbonyl or heterocyclylcarbonyl each substituted by heterocyclyl or by hetero¬ cyclyl-lower alkyl;

the residue, bonded via the carbonyl group, of an amino acid selected from glycine, alanine, 3-aminopropanoic acid, 2-aminobutyric acid, 3-aminobutyric acid, 4-aminobutyric acid. 3-aminopentanoic acid, 4-aminopentanoic acid, 5-aminopentanoic acid, 3-aminohexanoic acid, 4-aminohexanoic acid, 5-aminohexanoic acid, valine, norval¬ ine, leucine, isoleucine, norleucine, serine, homoserine, threonine, methionine, cysteine, phenylalanine, tyrosine, 4-aminophenylalanine, 4-chlorophenylalanine, 4-carboxyphenyl- alanine, β-phenylserine, phenylglycine, α-naphthylalanine, cyclohexylalanine, cyclohexyl¬ glycine, tryptophan, aspartic acid, aspartic acid β-phenyl-lower alkyl ester, asparagine, aminomalonic acid, aminomalonic acid monoamide, glutamic acid, glutamic acid γ-phenyl-lower alkyl ester, glutamine, histidine, arginine, lysine, δ-hydroxylysine, ornithine, α,γ-diaminobutyric acid and α,β-diaminopropionic acid; or

the residue of one of the last-mentioned amino acids, which residue is bonded via the carbonyl group and is N-acylated at the amino nitrogen by one of the above-mentioned acyl radicals,

R₂ and R₃ are each independently of the other cyclohexyl, cyclohexenyl, phenyl, naphthyl or tetrahydronaphthyl, each of which is unsubstituted or substituted by one or more radicals selected independently of one another from lower alkyl, phenyl-lower alkyl, halogen, halo-lower alkyl, cyano, hydroxy, lower alkoxy, phenyl-lower alkoxy, pyridyl- lower alkoxy, lower alkoxy-lower alkoxy, lower alkoxycarbonyl-lower alkoxy, carboxy- lower alkoxy, hydroxy-lower alkoxy having at least 2 carbon atoms, wherein hydroxy is not bonded in the 1 -position, carbamoyl-lower alkoxy, cyano-lower alkoxy, moφholinyl- lower alkoxy, lower alkylenedioxy, and phenyl-lower alkanesulfonyl which is unsubsti¬ tuted or substituted in the phenyl radical by one or more radicals selected independently of one another from halogen, or lower alkyl,

R₄ is lower alkyl, cyclohexyl or phenyl, and

R₅, R₅', R₆, R₇, R₈, R₈', R₉ and R_j0 are each independently of the others hydrogen or lower alkyl,

or a salt thereof.

2. A compound of formula I according to claim 1 , wherein

R_j is an acyl radical selected from lower alkoxy-lower alkanoyl, including lower alkoxy¬ carbonyl, and phenyl-lower alkoxy-lower alkanoyl; the residue, bonded via the carboxy group, of an amino acid selected from valine, norva¬ line, leucine, isoleucine and norleucine, and also from serine, homoserine, threonine, methionine, cysteine, phenylalanine, tyrosine, 4-aminophenylalanine, 4-chlorophenyl- alanine, 4-carboxyphenylalanine, β-phenylserine, phenylglycine, α-naphthylalanine, cyclohexylalanine, cyclohexylglycine, tryptophan, aspartic acid, aspartic acid β-(phenyl- lower alkyl) ester, asparagine, aminomalonic acid monoamide, glutamic acid, glutamic acid γ-(phenyl-lower alkyl) ester, glutamine, histidine, arginine, lysine, δ-hydroxylysine and ornithine;

or the residue of one of the last-mentioned amino acids, which residue is bonded via the carbonyl group and N-acylated at the amino nitrogen by one of the acyl radicals mentioned hereinbefore;

R₂ and R₃ are selected independently of each other from cyclohexyl, phenyl, phenyl-lower alkoxy-phenyl, fluorophenyl, difluorophenyl, phenyl-lower alkylphenyl, hydroxyphenyl, lower alkoxyphenyl, tri-lower alkoxy-phenyl, lower alkoxy-lower alkoxy-phenyl, carboxy-lower alkoxyphenyl, hydroxy-lower alkoxyphenyl having at least 2 carbon atoms in the lower alkoxy radical, wherein hydroxy is not bonded in the 1-position, moφholino- lower alkoxyphenyl, carbamoyl-lower alkoxyphenyl, cyano-lower alkoxyphenyl, lower alkylenedioxyphenyl, wherein the lower alkylenedioxy radical is bonded via its two oxygen atoms to two adjacent carbon atoms of the phenyl ring, pyridyl-lower alkoxy¬ phenyl and di-lower alkoxyphenyl;

R₄ is lower alkyl;

R₅, R₅\ R₆, R₇, R₈ and Rg' are each hydrogen; and

R₉ and RJ_Q are each independently of the other hydrogen or lower alkyl;

or a salt thereof.

3. A compound of formula I according to claim 1, wherein

R_j is an acyl radical selected from lower alkoxycarbonyl and phenyl-lower alkoxycarbonyl; the residue, bonded via the carboxy group, of an amino acid selected from valine, norva¬ line, leucine, isoleucine and norleucine, and also from serine, homoserine, threonine, methionine, cysteine, phenylalanine, tyrosine, 4-aminophenylalanine, 4-chlorophenyl- alanine, 4-carboxyphenylalanine, β-phenylserine, phenylglycine, α-naphthylalanine, cyclohexylalanine, cyclohexylglycine, tryptophan, aspartic acid, aspartic acid β-(phenyl- lower alkyl) ester, asparagine, aminomalonic acid monoamide, glutamic acid, glutamic acid γ-(phenyl-lower alkyl) ester, glutamine, histidine, arginine, lysine, δ-hydroxylysine and ornithine; the mentioned amino acid residues that have asymmetric carbon atoms being in the (L)-form;

or the residue of one of the last-mentioned amino acids, which residue is bonded via the carbonyl group and N-acylated at the amino nitrogen by one of the acyl radicals men¬ tioned hereinbefore, the respective amino acid residue preferably being in the (L)-form;

R₂ and R₃ are selected independently of each other from cyclohexyl, phenyl, 4-phenyl- lower alkoxyphenyl, fluorophenyl, 2,4-difluorophenyl, 4-phenyl-lower alkylphenyl, 4-hydroxyphenyl, 4-lower alkoxyphenyl, 4-(lower alkoxy-lower alkoxy )phenyl, 4-lower alkoxycarbonyl-lower alkoxyphenyl, 4-carboxy-lower alkoxyphenyl, 4-hydroxy-lower alkoxyphenyl having at least 2 carbon atoms in the lower alkoxy radical, wherein hydroxy is not bonded in the 1 -position, 4-moφholino-lower alkoxyphenyl, 4-carbamoyl-lower alkoxyphenyl, 4-cyano-lower alkoxyphenyl and di-lower alkoxyphenyl;

R₄ is lower alkyl;

R₅, R₅', R₆, R₇, R₈ and R₈' are each hydrogen; and

R₉ and R_]0 are each independently of the other hydrogen or lower alkyl;

or a salt thereof.

4. A compound of formula I according to claim 1 , wherein

R_j is lower alkoxycarbonyl or N-phenyl-lower alkoxycarbonyl-valyl or -asparaginyl;

R₂ and R₃ are selected independently of each other from cyclohexyl, phenyl, fluorophenyl and phenyl-lower alkoxyphenyl; R₄ is lower alkyl;

R₅, R₅', R , R₇, R₈ and R₈' are each hydrogen; and

Rg and R₁₀ are each independently of the other hydrogen or methyl;

or a salt thereof.

5. A compound of formula I according to claim 1, wherein

Rj is tert-butoxycarbonyl or N-benzyloxycarbonyI-(L)-valyl or -(L)-asparaginyl;

R₂ and R₃ are in the following combinations: R₂ = cyclohexyl/R₃ = fluorophenyl; R₂ = phenyl/R₃ = fluorophenyl; R₂ = fluorophenyl/R₃ = fluorophenyl; R₂ = phenyl/R₃ = 4- phenyllower alkoxyphenyl; or R₂ = phenyl/R₃ = phenyl;

R₄ is isopropyl or sec-butyl;

R₅, R₅', R₆, R₇, R₈ and R₈' are each hydrogen; and

Rg and R₁₀ are each hydrogen or methyl;

or a salt thereof.

6. 5(S)-(Boc-amino)-4(S)-hydroxy-6-cyclohexyI-2(R)-(p-fluoro-phenylmethyl)-hexanoyl- (L)- Val-N-(2-(moφholin-4-yl)-ethyl)amide of formula I according to claim 1 , or a pharmaceutically acceptable salt thereof.

7. 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-(p-fluoro-phenylmethyl)-hexanoyl- (L)-Val-N-(2-(moφholin-4-yl)-ethyl)amide of formula I according to claim 1, or a pharmaceutically acceptable salt thereof.

8. 5(S)-(Boc-amino)-4(S)-hydroxy-6-(p-fluoro-phenyI)-2(R)-(p-fluoro-phenylmethyl)- hexanoyl-(L)-Val-N-(2-(moφholin-4-yl)-ethyl)amide of formula I according to claim 1 , or a pharmaceutically acceptable salt thereof.

9. 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-(o-fluoro-phenylmethyl)-hexanoyl- (L)-Val-N-(2-(moφholin-4-yl)-ethyl)amide of formula I according to claim 1, or a pharmaceutically acceptable salt thereof.

10. 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(p-benzyloxy-phenyl)methyl]- hexanoyl-(L)-Val-N-(2-(moφholin-4-yl)-ethyl)amide of formula I according to claim 1, or a pharmaceutically acceptable salt thereof.

11. 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-(phenyl-methyl)-hexanoyl-(L)-Val-N- (2-moφholino)ethylamide of formula I according to claim 1, or a pharmaceutically acceptable salt thereof.

12. A compound of formula I according to any one of claims 1 to 11 for use in a method for the diagnostic or therapeutic treatment of the human or animal body.

13. A pharmaceutical composition comprising a compound of formula I, or a pharmaceuti¬ cally acceptable salt thereof, according to any one of claims 1 to 11 , together with a pharmaceutically acceptable carrier.

14. The use of a compound of formula I, or of a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 11, in the preparation of a pharmaceutical composition for the prophylaxis or treatment of a retroviral disease.

15. A pharmaceutical composition suitable for the treatment of diseases caused by retro¬ viruses, which comprises a compound of formula I according to claim 1, or a pharmaceuti¬ cally acceptable salt thereof, in an amount that is effective against retroviral diseases, and at least one pharmaceutically acceptable carrier.

16. A method for the treatment of diseases caused by retroviruses, which comprises administering to a warm-blooded animal in need of such treatment an amount of a compound of formula I according to claim 1 , or a pharmaceutically acceptable salt thereof, that is therapeutically effective against retroviral diseases.

17. The use of a compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, for the treatment of diseases caused by retroviruses.

18. The use according to claim 17, wherein the disease to be treated is AIDS or its preced¬ ing stages.

19. A process for the preparation of a compound of formula I according to claim 1, which comprises

a) condensing an acid of formula

R_.-OH (H),

or a reactive acid derivative thereof, wherein R_j has the same definitions as R_j in compounds of formula I, with an amino compound of formula

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 H and HI, with the exception of those participating in the reaction, being, if necessary, in protected form, and removing any protecting groups, or

b) for the preparation of a compound of formula

wherein B < is a bivalent residue of an amino acid bonded v a the carbonyl group and the amino group, as defined under formula I, and R] ' is one of the radicals defined for Rj under formula I with the exception of a non-acylated or N-acylated amino acid residue, as defined under formula I, so that B, and Rj' form together a residue of an N-acylated amino acid, which residue is bonded via its carbonyl group, as defined for R_j under formula I, and n and the other radicals are as defined for compounds of formula I, condensing a carboxylic acid of formula

R_j'-OH (IV),

or a reactive acid derivative thereof, wherein R_j' may be a radical as defined for R_j in compounds of formula I with the exception of a residue of a non-acylated or N-acylated amino acid, which residue is bonded via its carbonyl group, with an amino compound of formula

or with a reactive derivative thereof, wherein B _j has the definitions last mentioned and the other radicals are as defined for compounds of formula I, free functional groups in the starting materials of formulae Hla and IV, with the exception of those participating in the reaction, being, if necessary, in protected form, and removing any protecting groups, or

c) condensing a carboxylic acid of formula

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 V and VI, with the exception of those participating in the reaction, being, if necessary, in protected form, and removing any protecting groups, or

d) condensing a carboxylic acid of formula

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 VII and VIH, with the exception of those participating in the reaction, being, if necessary, in protected form, and, if desired, removing any protecting groups, or

e) reacting a compound of formula

wherein the radicals are as defined for compounds of formula I, with nucleophilic substi¬ tution taking place, free functional groups in the starting materials of formulae IX and X, with the exception of those participating in the reaction, being, if necessary, in protected form, and removing any protecting groups, or

f) in a compound of formula I wherein the substituents are as defined above, with the proviso that in the compound of formula I concerned at least one functional group is protected by protecting groups, removing any protecting groups,

and/or, if desired, converting a compound of formula I having at least one salt-forming group that is obtained by one of the above processes a) to f) into its salt and/or converting a salt tiiat may be obtained into the free compound or into a different salt and/or, where applicable, separating isomeric mixtures of compounds of formula I that may be obtained and/or converting a compound of formula I according to the invention into a different compound of formula I according to the invention. PCT/EP 95/04508

A. CLASSIFICATION OF SUBJECT MATTER

IPC 6 C07K5/02 C07D265/30 A61K38/55 A61K31/535

According to International Patent Classification (IPQ or to both national classiflcation and IPC

B. FIELDS SEARCHED

Minimum documentation searched (classification system followed by classification symbols)

IPC 6 CΘ7K C07D A61K

Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched

Electronic data base consulted during the mtemaDonal search (name of data base and, where pracocal, search terms used)

C. DOCUMENTS CONSIDERED TO BE RELEVANT

Category ^* Citation of document, with indication, where appropnate, of the relevant passages Relevant to claim No.

EP.A.O 532466 (CIBA GEIGY AG) 17 March 1-19

1993 see the whole document

WO,A,91 10422 (LIP0S0ME CO INC) 25 July

1991 see the whol e document

D Further documents are listed in the continuation of box C. Patent family members are listed in annex.

__

* Speαal categories of αted documents :

T later document published after the international filing date or pπoπty date and not in conflict with the application but

'A' document defining the general state of the art which is not αted to understand the principle or theory underlying the considered to be of particular relevance invention "E^* earlier document but published on or after the international 'X^* document of particular relevance; the claimed invention filing date cannot be considered novel or cannot be considered to

X" document which may throw doubts on priority dairnfs) or involve an inventive step when the document is taken alααe which is αted to establish the publication date of another ^*Y^* document of particular relevance; the claimed invention citation or other speαal reason (as specified) cannot be considered to involve an inventive step when the

'O^* document referring to an oral disclosure, use, exhibition or document is combined with one or more other such docu¬ other means ments, such combination being obvious to a person stalled

'P' document published prior to the international filing date but in the art. later than the priority date claimed '&' document member of the same patent family

Date of the actual completion of the internauonal search Date of mailing of the internauonal search report

21 February 1996 15. 03. 96

Name and mailing address of the ISA Authorized officer

European Patent Office, P.B. Stl 8 PatenUaan 2 NL - 2280 HV Rijswijk Tel. ( ^■+ 31-70) 340-2040, Tx. Jl 651 epo nl, Fax: ( + 31-70) 340-3016 Cha ravarty, A

Form PCτiSΛ.210 (Mcond »!_•-) (July IM) Information on patent family members

PCT/EP 95/04508

Patent document Publication Patent family Publication cited in search report date member(s) date

EP-A-0532466 17-03-93 AU-B- 661018 13-07-95 AU-B- 2288992 18-03-93 CA-A- 2077948 13-03-93 CZ-A- 9202802 19-01-94 JP-A- 5230095 07-09-93 NZ-A- 244288 28-03-95 SK-A- 280292 08-02-95 ZA-A- 9206938 11-03-94

WO-A-9110422 25-07-91 AU-B- 652552 01-09-94 AU-B- 7181791 05-08-91 CA-A- 2073431 13-07-91 EP-A- 0510086 28-10-92 JP-T- 5503521 10-06-93

Form PCT/1SAΛ10 (paunt family annex) (July IM2)